PMID- 24752419 TI - Automatic string generation for estimating in vivo length changes of the medial patellofemoral ligament during knee flexion. AB - Modeling ligaments as three-dimensional strings is a popular method for in vivo estimation of ligament length. The purpose of this study was to develop an algorithm for automated generation of non-penetrating strings between insertion points and to evaluate its feasibility for estimating length changes of the medial patellofemoral ligament during normal knee flexion. Three-dimensional knee models were generated from computed tomography (CT) scans of 10 healthy subjects. The knee joint under weight-bearing was acquired in four flexion positions (0 degrees -120 degrees ). The path between insertion points was computed in each position to quantify string length and isometry. The average string length was maximal in 0 degrees of flexion (64.5 +/- 3.9 mm between femoral and proximal patellar point; 62.8 +/- 4.0 mm between femoral and distal patellar point). It was minimal in 30 degrees (60.0 +/- 2.6 mm) for the proximal patellar string and in 120 degrees (58.7 +/- 4.3 mm) for the distal patellar string. The insertion points were considered to be isometric in 4 of the 10 subjects. The proposed algorithm appears to be feasible for estimating string lengths between insertion points in an automatic fashion. The length measurements based on CT images acquired under physiological loading conditions may give further insights into knee kinematics. PMID- 24752420 TI - Negative Reinforcement and Premonitory Urges in Youth With Tourette Syndrome: An Experimental Evaluation. AB - Tourette syndrome (TS) is marked by the chronic presence of motor and vocal tics that are usually accompanied by aversive sensory experiences called "premonitory urges." Phenomenological accounts suggest that these urges occur before tics and diminish following their occurrence. This has led some to suggest that tics are negatively reinforced by removal of premonitory urges. This hypothesis has proven difficult to test experimentally, however, due in part to challenges in measuring premonitory urge strength. We tested predictions of the negative reinforcement conceptualization of premonitory urges using novel experimental tactics within the context of the "tic detector" paradigm. We compared tic rates and ratings of premonitory urge strength exhibited by youth with TS or chronic tic disorder under free-to-tic baseline (BL), reinforced tic suppression (RTS), and reinforced tic suppression with escape (RTS + E) conditions. Results were consistent with previous research and hypotheses of the present study. Participants rated the strength of their premonitory urges as higher during RTS conditions than during BL conditions. Within RTS + E conditions, tic rates were higher during escape portions when the contingency supporting tic suppression was inactive than during components where the contingency was active, and ratings of urge strength were higher at the onset of break periods than at the offset. All participants engaged in some level of escape from reinforced suppression during the course of the experiment. Results of this study support the notion that tics may be negatively reinforced by removal of aversive premonitory urges. Future directions for basic and clinical research are discussed. PMID- 24752421 TI - Hepatic microsomal UDP-glucuronosyltransferase (UGT) activities in the microminipig. AB - The microminipig, a small minipig, was bred as a novel experimental animal for nonclinical pharmacology/toxicology studies by Fuji Micra Inc. (Shizuoka, Japan). Species differences in drug metabolism between humans and the microminipig need to be elucidated in more detail in order to discuss the results of nonclinical studies. Glucuronidation catalysed by UDP-glucuronosyltransferase (UGT) is an important pathway in the metabolism of a wide variety of compounds. The aim of the present study was to identify the characteristics of hepatic UGT activity in the microminipig and compare them with those in humans and other experimental animals. This study examined in vitro UGT activities using liver microsomes from microminipigs (8 months old and 1 day old), humans, mice, rats, dogs, monkeys and minipigs. The glucuronides of estradiol, imipramine, serotonin, propofol, 3' azido-3'-deoxythymidine (AZT) and morphine, selective substrates of human UGT1A1, 1A4, 1A6, 1A9 and 2B7 (AZT and morphine), respectively, were measured using LC MS/MS. Estradiol-3-glucuronidation activity was higher in the microminipig than in humans and the other animals. High levels of estradiol-3-glucuronidation were observed in the microsomes of 1-day-old microminipigs. Imipramine-N glucuronidation, a distinctive conjugation by human UGT1A4, was catalysed by microminipig liver microsomes, but not by dog liver microsomes. Although AZT glucuronidation activity was low in the microminipig compared with humans, morphine-3-glucuronidation activity in the microminipig was higher than that in humans. The UGT activities in the microminipig were similar to those in the minipig. The results of the present study have provided useful information for selecting an appropriate animal model for nonclinical studies. PMID- 24752423 TI - Hearing preservation surgery for vestibular schwannomas via the retrosigmoid transmeatal approach: surgical tips. AB - Maximum tumor extirpation with preservation of the facial and cochlear nerve function is the goal of surgery for vestibular schwannoma. To preserve cochlear nerve function, the surgeon must employ a detailed knowledge of microanatomy, precise microsurgical techniques, and persistence. This paper describes the "pearls" of surgical techniques based on the anatomical study inside the mastoid from the view of the retrosigmoid transmeatal approach. A total of 592 consecutive patients underwent surgical removal of unilateral vestibular schwannoma (VS) between January 1994 and December 2009. The hearing preservation rate was 53.7 % for large vestibular schwannomas (>20 mm in diameter) and 74.1 % for tumors of all sizes. The key procedures for hearing preservation surgery are as follows: bloodless microdissection, sufficient coring-debulking, capsular elevation to locate the facial and cochlear nerves both electrophysiologically and by visual observation, sharp dissection of the facial and cochlear nerves, and avoidance of heat and mechanical injury to the nerves, the internal auditory artery, and the brain stem. Besides these techniques, appropriate instruments are essential to preserve hearing. The function of the facial and cochlear nerves should be the foremost concern. Meticulous techniques and the knowledge of microsurgical anatomy lead to hearing preservation with maximum tumor removal. PMID- 24752422 TI - Hybridization capture reveals evolution and conservation across the entire Koala retrovirus genome. AB - The koala retrovirus (KoRV) is the only retrovirus known to be in the midst of invading the germ line of its host species. Hybridization capture and next generation sequencing were used on modern and museum DNA samples of koala (Phascolarctos cinereus) to examine ca. 130 years of evolution across the full KoRV genome. Overall, the entire proviral genome appeared to be conserved across time in sequence, protein structure and transcriptional binding sites. A total of 138 polymorphisms were detected, of which 72 were found in more than one individual. At every polymorphic site in the museum koalas, one of the character states matched that of modern KoRV. Among non-synonymous polymorphisms, radical substitutions involving large physiochemical differences between amino acids were elevated in env, potentially reflecting anti-viral immune pressure or avoidance of receptor interference. Polymorphisms were not detected within two functional regions believed to affect infectivity. Host sequences flanking proviral integration sites were also captured; with few proviral loci shared among koalas. Recently described variants of KoRV, designated KoRV-B and KoRV-J, were not detected in museum samples, suggesting that these variants may be of recent origin. PMID- 24752424 TI - Early evidence kits in sexual assault: an observational study of spermatozoa detection in urine and other forensic specimens. AB - PURPOSE: To determine the detection frequency of spermatozoa in early evidence kit specimens and in subsequent full forensic specimens in alleged sexual assault. METHODS: Observational cohort study of 100 consecutive alleged sexual assault cases, presenting in Western Australia between 19th July 2008 and 6th February 2012, with both early evidence kit and full forensic evidence specimen collections. Eighty-eight cases were included in the study. Smears from all forensic specimens were analyzed by light microscopy to determine the detection frequency and structural characteristics of spermatozoa. Patient demographic features, characteristics of the alleged assault and details and timing of forensic collections were also recorded. RESULTS: Spermatozoa were detected in early evidence kit specimens in 35 % (31/88) and in full forensic specimens in 42 % (37/88) of all cases (irrespective of type of alleged penetration). In alleged penile-vaginal penetration, spermatozoa were detected in early evidence kit specimens in 40 % (21/53) of cases when both first void urine and vulval gauze wipe were collected. Spermatozoa were detected in full forensic specimens in 45 % (31/69) of cases. Spermatozoa were detected in early evidence kit oral rinse specimens in 6 % (1/18) of cases of alleged penile-oral penetration and in early evidence perianal gauze wipe specimens in 33 % (2/6) cases of alleged penile-anal penetration. Spermatozoa were detected in the early evidence kit first void urine specimen in a single case, 11 % (1/9), in which the nature of the alleged assault was unknown. Spermatozoa were detected in early evidence kit specimens and not in full forensic specimens in 3 % (3/88) of cases. CONCLUSIONS: Early evidence kit specimens are effective in recovery of spermatozoa, and in particular urine and vulval gauze wipe are worthwhile early forensic specimens for the detection of spermatozoa. Collection of early evidence specimens led to detection of spermatozoa-positive cases, which were not detected by subsequent full forensic specimen collection. PMID- 24752425 TI - Aortic intimal staining in drowning. PMID- 24752426 TI - Immersion deaths and drowning: issues arising in the investigation of bodies recovered from water. PMID- 24752427 TI - Efficient 3D kinetic Monte Carlo method for modeling of molecular structure and dynamics. AB - Self-assembly of molecular systems is an important and general problem that intertwines physics, chemistry, biology, and material sciences. Through understanding of the physical principles of self-organization, it often becomes feasible to control the process and to obtain complex structures with tailored properties, for example, bacteria colonies of cells or nanodevices with desired properties. Theoretical studies and simulations provide an important tool for unraveling the principles of self-organization and, therefore, have recently gained an increasing interest. The present article features an extension of a popular code MBN EXPLORER (MesoBioNano Explorer) aiming to provide a universal approach to study self-assembly phenomena in biology and nanoscience. In particular, this extension involves a highly parallelized module of MBN EXPLORER that allows simulating stochastic processes using the kinetic Monte Carlo approach in a three-dimensional space. We describe the computational side of the developed code, discuss its efficiency, and apply it for studying an exemplary system. PMID- 24752428 TI - Specific duplication and dorsoventrally asymmetric expression patterns of Cycloidea-like genes in zygomorphic species of Ranunculaceae. AB - Floral bilateral symmetry (zygomorphy) has evolved several times independently in angiosperms from radially symmetrical (actinomorphic) ancestral states. Homologs of the Antirrhinum majus Cycloidea gene (Cyc) have been shown to control floral symmetry in diverse groups in core eudicots. In the basal eudicot family Ranunculaceae, there is a single evolutionary transition from actinomorphy to zygomorphy in the stem lineage of the tribe Delphinieae. We characterized Cyc homologs in 18 genera of Ranunculaceae, including the four genera of Delphinieae, in a sampling that represents the floral morphological diversity of this tribe, and reconstructed the evolutionary history of this gene family in Ranunculaceae. Within each of the two RanaCyL (Ranunculaceae Cycloidea-like) lineages previously identified, an additional duplication possibly predating the emergence of the Delphinieae was found, resulting in up to four gene copies in zygomorphic species. Expression analyses indicate that the RanaCyL paralogs are expressed early in floral buds and that the duration of their expression varies between species and paralog class. At most one RanaCyL paralog was expressed during the late stages of floral development in the actinomorphic species studied whereas all paralogs from the zygomorphic species were expressed, composing a species specific identity code for perianth organs. The contrasted asymmetric patterns of expression observed in the two zygomorphic species is discussed in relation to their distinct perianth architecture. PMID- 24752429 TI - Calculating disability-adjusted life years to quantify burden of disease. PMID- 24752430 TI - Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension. AB - Renovascular hypertension alters cardiac structure and function. Autophagy is activated during left ventricular hypertrophy and linked to adverse cardiac function. The angiotensin II receptor blocker, valsartan, lowers blood pressure and is cardioprotective, but whether it modulates autophagy in the myocardium is unclear. We hypothesized that valsartan would alleviate autophagy and improve left ventricular myocardial mitochondrial turnover in swine renovascular hypertension. Domestic pigs were randomized to control, unilateral renovascular hypertension, and renovascular hypertension treated with valsartan (320 mg/d) or conventional triple therapy (reserpine+hydralazine+hydrochlorothiazide) for 4 weeks after 6 weeks of renovascular hypertension (n=7 each group). Left ventricular remodeling, function, and myocardial oxygenation and microcirculation were assessed by multidetector computer tomography, blood oxygen level-dependent MRI, and microcomputer tomography. Myocardial autophagy, markers for mitochondrial degradation and biogenesis, and mitochondrial respiratory-chain proteins were examined ex vivo. Renovascular hypertension induced left ventricular hypertrophy and myocardial hypoxia, enhanced cellular autophagy and mitochondrial degradation, and suppressed mitochondrial biogenesis. Valsartan and triple therapy similarly decreased blood pressure, but valsartan solely alleviated left ventricular hypertrophy, ameliorated myocardial autophagy and mitophagy, and increased mitochondrial biogenesis. In contrast, triple therapy only slightly attenuated autophagy and preserved mitochondrial proteins, but elicited no improvement in mitophagy. These data suggest a novel potential role of valsartan in modulating myocardial autophagy and mitochondrial turnover in renovascular hypertension-induced hypertensive heart disease, which may possibly bolster cardiac repair via a blood pressure-independent manner. PMID- 24752431 TI - Serum aldosterone and death, end-stage renal disease, and cardiovascular events in blacks and whites: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study. AB - Prior studies have demonstrated that elevated aldosterone concentrations are an independent risk factor for death in patients with cardiovascular disease. Limited studies, however, have evaluated systematically the association between serum aldosterone and adverse events in the setting of chronic kidney disease. We investigated the association between serum aldosterone and death and end-stage renal disease in 3866 participants from the Chronic Renal Insufficiency Cohort. We also evaluated the association between aldosterone and incident congestive heart failure and atherosclerotic events in participants without baseline cardiovascular disease. Cox proportional hazards models were used to evaluate independent associations between elevated aldosterone concentrations and each outcome. Interactions were hypothesized and explored between aldosterone and sex, race, and the use of loop diuretics and renin-angiotensin-aldosterone system inhibitors. During a median follow-up period of 5.4 years, 587 participants died, 743 developed end-stage renal disease, 187 developed congestive heart failure, and 177 experienced an atherosclerotic event. Aldosterone concentrations (per SD of the log-transformed aldosterone) were not an independent risk factor for death (adjusted hazard ratio, 1.00; 95% confidence interval, 0.93-1.12), end-stage renal disease (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.17), or atherosclerotic events (adjusted hazard ratio, 1.04; 95% confidence interval, 0.85-1.18). Aldosterone was associated with congestive heart failure (adjusted hazard ratio, 1.21; 95% confidence interval, 1.02-1.35). Among participants with chronic kidney disease, higher aldosterone concentrations were independently associated with the development of congestive heart failure but not for death, end-stage renal disease, or atherosclerotic events. Further studies should evaluate whether mineralocorticoid receptor antagonists may reduce adverse events in individuals with chronic kidney disease because elevated cortisol levels may activate the mineralocorticoid receptor. PMID- 24752432 TI - Arterial stiffness and hypertension. PMID- 24752433 TI - Decreased endothelial progenitor cells in preeclampsia and consequences for developmental programming. PMID- 24752434 TI - Decreased level of cord blood circulating endothelial colony-forming cells in preeclampsia. AB - Preeclampsia is a pregnancy-related disorder associated with increased cardiovascular risk for the offspring. Endothelial colony-forming cells (ECFCs) are a subset of circulating endothelial progenitor cells that participate in the formation of vasculature during development. However, the effect of preeclampsia on fetal levels of ECFCs is largely unknown. In this study, we sought to determine whether cord blood ECFC abundance and function are altered in preeclampsia. We conducted a prospective cohort study that included women with normal (n=35) and preeclamptic (n=15) pregnancies. We measured ECFC levels in the umbilical cord blood of neonates and characterized ECFC phenotype, cloning forming ability, proliferation, and migration toward vascular endothelial growth factor-A and fibroblast growth factor-2, in vitro formation of capillary-like structures, and in vivo vasculogenic ability in immunodeficient mice. We found that the level of cord blood ECFCs was statistically lower in preeclampsia than in control pregnancies (P=0.04), a reduction that was independent of other obstetric factors. In addition, cord blood ECFCs from preeclamptic pregnancies required more time to emerge in culture than control ECFCs. However, once derived in culture, ECFC function was deemed normal and highly similar between preeclampsia and control, including the ability to form vascular networks in vivo. This study demonstrates that preeclampsia affects ECFC abundance in neonates. A reduced level of ECFCs during preeclamptic pregnancies may contribute to an increased risk of developing future cardiovascular events. PMID- 24752435 TI - Applanation tonometry in mice: a novel noninvasive technique to assess pulse wave velocity and arterial stiffness. AB - Arterial stiffening is the root cause of a range of cardiovascular complications, including myocardial infarction, left ventricular hypertrophy, stroke, renal failure, dementia, and death, and a hallmark of the aging process. The most important in vivo parameter of arterial stiffness is pulse wave velocity (PWV). Clinically, PWV is determined noninvasively using applanation tonometry. Unlike the clinical value of arterial stiffness and PWV, techniques to determine PWV in mice are scarce. The only way to determine aortic PWV noninvasively in the mouse is by using ultrasound echo Doppler velocimetry. It is a fast, efficient, and accurate technique, but the required tools are expensive and technically complex. Here, we describe the development and validation of a novel technique to assess carotid-femoral PWV noninvasively in mice. This technique is based on applanation tonometry as used clinically. We were able to establish a reproducible reference value in wild-type mice (3.96+/-0.05 m/s) and to detect altered carotid-femoral PWV values in endothelial nitric oxide synthase knockout mice (4.66+/-0.05 m/s; P<0.001 compared with control), and in mice sedated with sodium pentobarbital (2.89+/-0.17 m/s; P<0.001 compared with control). Also, carotid-femoral PWV was pharmacologically modulated and measured in a longitudinal experiment with endothelial nitric oxide synthase knockout mice to demonstrate the applicability of this technique. In general, applanation tonometry can be used to measure carotid-femoral PWV noninvasively in mice. The experimental setup is simple, and the technical requirements are basic, making this technique readily implementable in any mouse model-based research facility interested in arterial stiffness. PMID- 24752438 TI - Tuning the oxygen reduction activity of the Pt-Ni nanoparticles upon specific anion adsorption by varying heat treatment atmospheres. AB - Heat treatment of Pt based nanoparticles under various conditions is one of the conventional ways to modify the electrocatalytic properties for enhancement of the oxygen reduction reaction (ORR). However, the effect of the heat treatment atmosphere on the ORR activity especially upon specific anion adsorption still remains unclear. This paper investigates the Pt-Ni bimetallic nanoparticles (Pt2Ni1), under various heat treatment atmospheres, as enhanced cathodic electrocatalysts for the high temperature-proton exchange membrane fuel cell (HT PEMFC) using a phosphoric acid doped polybenzimidazole (p-PBI) membrane. The X ray spectroscopic measurement showed the variations of the electronic structures of Pt-Ni nanoparticles under the heat treatment condition. In the half-cell measurement, the argon treated electrocatalyst demonstrated the highest catalytic activity owing to the appropriate electronic interaction between Pt and Ni. The single cell test with a p-PBI membrane, at 160 degrees C, also confirmed the excellent oxygen reduction reactivity and durability of the argon-treated Pt-Ni nanoparticles. This result suggested that the alteration of the electronic structure by a proper heat treatment atmosphere upon specific anion adsorption decisively influenced the ORR activity both at half-cell and single-cell scales. PMID- 24752437 TI - Longitudinal clinical course of three Japanese patients with Leber congenital amaurosis/early-onset retinal dystrophy with RDH12 mutation. AB - PURPOSE: To report the longitudinal clinical course of three Japanese patients from two families with Leber congenital amaurosis/early-onset retinal dystrophy (LCA/EORD), and the results of next-generation DNA sequences on them. PATIENTS AND METHODS: The patients were three Japanese children: a 4-year-old girl, a 6 year-old boy, and a 3-year-old girl. Patients 1 and 2 were siblings, and patient 3 was from an unrelated family. Standard ophthalmic examinations including perimetry, electroretinography, optical coherence tomography, and ultrasonography were performed on each patient. The patients were observed for 28, 16, and 10 years. Whole exomes of the patients and their non-symptomatic parents were analyzed using a next-generation sequence technique. RESULTS: The decimal visual acuity varied between 0.07 and 0.6 at the initial visit and decreased to counting finger to hand motion in their teens. Funduscopy showed diffuse retinal and macular degeneration. During the follow-up period, a posterior staphyloma developed and the macular area became atrophic. Patient 1 developed cataracts in her early twenties. Genetic analysis revealed a homozygous A126V substitution in the RDH12 gene in all patients. CONCLUSIONS: The three patients with LCA/EORD had a progressive decrease of their vision with the formation of a posterior staphyloma. This is the first report of Japanese patients with LCA/EORD with a RDH12 mutation. PMID- 24752439 TI - Identification of Mott insulators and Anderson insulators in self-assembled gold nanoparticles thin films. AB - How the interparticle tunnelling affects the charge conduction of self-assembled gold nanoparticles is studied by three means: tuning the tunnel barrier width by different molecule modification and by substrate bending, and tuning the barrier height by high-dose electron beam exposure. All approaches indicate that the metal-Mott insulator transition is governed predominantly by the interparticle coupling strength, which can be quantified by the room temperature sheet resistance. The Hubbard gap, following the prediction of quantum fluctuation theory, reduces to zero rapidly as the sheet resistance decreases to the quantum resistance. At very low temperature, the fate of devices near the Mott transition depends on the strength of disorder. The charge conduction is from nearest neighbour hopping to co-tunnelling between nanoparticles in Mott insulators whereas it is from variable-range hopping through charge puddles in Anderson insulators. When the two-dimensional nanoparticle network is under a unidirectional strain, the interparticle coupling becomes anisotropic so the average sheet resistance is required to describe the charge conduction. PMID- 24752440 TI - Physical activity programs for promoting bone mineralization and growth in preterm infants. AB - BACKGROUND: Lack of physical stimulation may contribute to metabolic bone disease of preterm infants, resulting in poor bone mineralization and growth. Physical activity programs combined with adequate nutrition might help to promote bone mineralization and growth. OBJECTIVES: The primary objective was to assess whether physical activity programs in preterm infants improve bone mineralization and growth and reduce the risk of fracture.The secondary objectives included other potential benefits in terms of length of hospital stay, skeletal deformities and neurodevelopmental outcomes, and adverse events.Subgroup analysis:* Given that the smallest infants are most vulnerable for developing osteopenia (Bishop 1999), a subgroup analysis was planned for infants with birth weight < 1000 g.* Calcium and phosphorus intake may affect an infant's ability to increase bone mineral content (Kuschel 2004). Therefore, an additional subgroup analysis was planned for infants receiving different amounts of calcium and phosphorus, along with full enteral feeds as follows. ? Below 100 mg/60 mg calcium/phosphorus or equal to/above 100 mg/60 mg calcium/phosphorus per 100 mL milk. ? Supplementation of calcium without phosphorus. ? Supplementation of phosphorus without calcium. SEARCH METHODS: The standard search strategy of the Cochrane Neonatal Review Group (CNRG) was used. The search included the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 9), MEDLINE, EMBASE, CINAHL (1966 to March 2013), and cross-references, as well as handsearching of abstracts of the Society for Pediatric Research and the International Journal of Sports Medicine. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing physical activity programs (extension and flexion, range-of motion exercises) versus no organized physical activity programs in preterm infants. DATA COLLECTION AND ANALYSIS: Data collection, study selection, and data analysis were performed according to the methods of the CNRG. MAIN RESULTS: Eleven trials enrolling 324 preterm infants (gestational age 26 to 34 weeks) were included in this review. All were small (N = 16 to 50) single-center studies that evaluated daily physical activity for three and one-half to eight weeks during initial hospitalization. Methodological quality and reporting of included trials were variable.Four trials demonstrated moderate short-term benefits of physical activity for bone mineralization at completion of the physical activity program. The only trial assessing long-term effects on bone mineralization showed no effect of physical activity administered during initial hospitalization on bone mineralization at 12 months corrected age. Meta-analysis from four trials demonstrated a positive effect of physical activity on daily weight gain (weighted mean difference (WMD) 2.21 g/kg/d, 95% confidence interval (CI) 1.23 to 3.19). Data from four trials showed a positive effect on linear growth (WMD 0.12 cm/wk, 95% CI 0.01 to 0.24) but not on head growth (WMD -0.03 cm/wk, 95% CI -0.14 to 0.08) during the study period. Only one trial reported on fractures (this outcome did not occur in intervention and control groups) and complications of preterm birth (no significant differences between intervention and control groups). None of the trials assessed other outcomes relevant to this review. AUTHORS' CONCLUSIONS: Some evidence suggests that physical activity programs might promote short-term weight gain and bone mineralization in preterm infants. Data are inadequate to allow assessment of harm or long-term effects. Current evidence does not support the routine use of physical activity programs in preterm infants. Further trials incorporating infants with a high baseline risk of osteopenia are required. These trials should address adverse events, long-term outcomes, and the effects of nutritional intake (calories, protein, calcium, phosphorus). PMID- 24752441 TI - An engineered palette of metal ion quenchable fluorescent proteins. AB - Many fluorescent proteins have been created to act as genetically encoded biosensors. With these sensors, changes in fluorescence report on chemical states in living cells. Transition metal ions such as copper, nickel, and zinc are crucial in many physiological and pathophysiological pathways. Here, we engineered a spectral series of optimized transition metal ion-binding fluorescent proteins that respond to metals with large changes in fluorescence intensity. These proteins can act as metal biosensors or imaging probes whose fluorescence can be tuned by metals. Each protein is uniquely modulated by four different metals (Cu2+, Ni2+, Co2+, and Zn2+). Crystallography revealed the geometry and location of metal binding to the engineered sites. When attached to the extracellular terminal of a membrane protein VAMP2, dimeric pairs of the sensors could be used in cells as ratiometric probes for transition metal ions. Thus, these engineered fluorescent proteins act as sensitive transition metal ion responsive genetically encoded probes that span the visible spectrum. PMID- 24752442 TI - Aneurysmal lesions of patients with abdominal aortic aneurysm contain clonally expanded T cells. AB - Abdominal aortic aneurysm (AAA) is a common disease with often life-threatening consequences. This vascular disorder is responsible for 1-2% of all deaths in men aged 65 years or older. Autoimmunity may be responsible for the pathogenesis of AAA. Although it is well documented that infiltrating T cells are essentially always present in AAA lesions, little is known about their role in the initiation and/or progression of the disease. To determine whether T cells infiltrating AAA lesions contain clonally expanded populations of T cells, we amplified beta-chain TCR transcripts by the nonpalindromic adaptor-PCR/Vbeta-specific PCR and/or Vbeta specific PCR, followed by cloning and sequencing. We report in this article that aortic abdominal aneurysmal lesions from 8 of 10 patients with AAA contained oligoclonal populations of T cells. Multiple identical copies of beta-chain TCR transcripts were identified in these patients. These clonal expansions are statistically significant. These results demonstrate that alphabeta TCR(+) T lymphocytes infiltrating aneurysmal lesions of patients with AAA have undergone proliferation and clonal expansion in vivo at the site of the aneurysmal lesion, in response to unidentified self- or nonself Ags. This evidence supports the hypothesis that AAA is a specific Ag-driven T cell disease. PMID- 24752443 TI - Murine B-1 B cell progenitors initiate B-acute lymphoblastic leukemia with features of high-risk disease. AB - B-1 and B-2 B cells derive from distinct progenitors that emerge in overlapping waves of development. The number of murine B-1 progenitors peaks during fetal development whereas B-2 B cell production predominates in adult bone marrow. Many genetic mutations that underlie B-acute lymphoblastic leukemia (B-ALL) occur in the fetus, at which time B-1 progenitor numbers are high. However, whether B-ALL can initiate in B-1 progenitors is unknown. In the present study, we report that BCR-ABL-transformed murine B-1 progenitors can be B-ALL cells of origin and demonstrate that they initiate disease more rapidly than do oncogene-expressing B 2 progenitors. We further demonstrate that B-1 progenitors exhibit relative resistance to apoptosis and undergo significant growth following oncogene expression, and we propose that these properties underlie the accelerated kinetics with which they initiate leukemia. These results provide a developmental perspective on the origin of B-ALL and indicate B cell lineage as a factor influencing disease progression. PMID- 24752445 TI - Leukocyte HMGB1 is required for vessel remodeling in regenerating muscles. AB - Signals of tissue necrosis, damage-associated molecular patterns (DAMPs), cause inflammation. Leukocytes migrating into injured tissues tonically release DAMPs, including the high mobility group box 1 protein (HMGB1). In the absence of suitable models, the relative role of DAMPs released because of necrosis or leukocyte activation has not, so far, been dissected. We have generated a mouse model lacking Hmgb1 in the hematopoietic system and studied the response to acute sterile injury of the skeletal muscle. Regenerating fibers are significantly less numerous at earlier time points and smaller at the end of the process. Leukocyte Hmgb1 licenses the skeletal muscle to react to hypoxia, to express angiopoietin 2, and to initiate angiogenesis in response to injury. Vascularization of the regenerating tissue is selectively jeopardized in the absence of leukocyte Hmgb1, revealing that it controls the nutrient and oxygen supply to the regenerating tissue. Altogether, our results reveal a novel nonredundant role for leukocyte Hmgb1 in the repair of injured skeletal muscle. PMID- 24752444 TI - Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection. AB - The detrimental impact of tobacco on human health is clearly recognized, and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease are susceptible to recurrent respiratory infections with pathogens, including nontypeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. Because mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study, to our knowledge, to investigate chronic infection and the generation of adaptive immune responses to NTHI after chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-gamma and IL-4, and B cells produced reduced levels of Abs against outer membrane lipoprotein P6, with impaired IgG1, IgG2a, and IgA class switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke-exposed mice exhibited a similar defect in the generation of adaptive immunity after immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes chronic obstructive pulmonary disease patients to recurrent infections, leading to exacerbations and contributing to mortality. PMID- 24752446 TI - The number of responding CD4 T cells and the dose of antigen conjointly determine the TH1/TH2 phenotype by modulating B7/CD28 interactions. AB - Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC. PMID- 24752447 TI - Soluble HLA-I/peptide monomers mediate antigen-specific CD8 T cell activation through passive peptide exchange with cell-bound HLA-I molecules. AB - Accumulating evidence that serum levels of soluble class I HLA molecules (sHLA-I) can, under various pathological conditions, correlate with disease stage and/or patient survival, has stimulated interest in defining whether sHLA-I can exert immunological functions. However, despite a mounting number of publications suggesting the ability of sHLA-I to affect immune effectors in vitro, the precise underlying mechanism still remains controversial. In this article, we address potential functions of both classical and nonclassical sHLA-I, using soluble recombinant HLA-I/peptide monomers, and clearly demonstrate their ability to trigger Ag-specific activation of CD8 T cells in vitro. Furthermore, we provide strong evidence that this behavior results from the passive transfer of peptides from monomers to T cell-bound HLA-I molecules, allowing for fratricide representation and activation. Hence, we proposed a unifying model of T cell activation by HLA-I/peptide monomers, reappraising the potential involvement of sHLA-I molecules in the immune response. PMID- 24752448 TI - Contemporary cost-effectiveness analysis comparing sequential bacillus Calmette Guerin and electromotive mitomycin versus bacillus Calmette-Guerin alone for patients with high-risk non-muscle-invasive bladder cancer. AB - BACKGROUND: Sequential bacillus Calmette-Guerin (BCG) and electromotive mitomycin (sequential therapy) have been shown in a randomized prospective trial to be superior to therapy with BCG alone in patients with high-risk non-muscle-invasive bladder cancer. The objective of the current study was to compare the costs and benefits of these 2 treatment strategies by performing a 5-year and 10-year cost effectiveness study. METHODS: A Markov model was developed to estimate the incremental cost-effectiveness ratio over a 5-year and 10-year period. Estimates of disease progression, death, and treatment efficacy were obtained from what to the authors' knowledge is the only randomized trial comparing the 2 therapies. Costs included: 1) medical costs (physician fees); 2) drug costs (preparation and instillation); and 3) hospital costs (procedure fees, admission fees, and tests and procedures done during surveillance). Patients were allowed a second course of induction therapy. RESULTS: Sequential therapy was found to be associated with a higher initial material cost for induction and maintenance. The average effectiveness for the patients treated with therapy with BCG alone was 4.39 years with a mean cost of $9236 (95% confidence interval, $9118-$9345) per patient. The sequential group resulted in an average effectiveness of 4.65 years, with a mean cost of $16,468 (95% confidence interval, $16,371-$16,527). The 5-year incremental cost-effectiveness ratio of sequential versus BCG-alone therapy was $27,815 per life-year gained. The corresponding figure over a 10-year period was $8618 per life-year gained. CONCLUSIONS: The results of the current study suggest that sequential therapy is a cost-effective treatment for patients with high-risk non-muscle-invasive bladder cancer. PMID- 24752449 TI - A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors. AB - PURPOSE: Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors. METHODS: LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m2/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia. RESULTS: Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/MUl within 7 days. All patients at 4 and 5 mg/m2/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m2/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed. CONCLUSIONS: The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day in Japanese patients with advanced solid tumors. PMID- 24752450 TI - Synthesis and electrocatalytic performance of atomically ordered nickel carbide (Ni3C) nanoparticles. AB - Atomically ordered nickel carbide, Ni3C, was synthesized by reduction of nickel cyclopentadienyl (NiCp2) with sodium naphthalide to form Ni clusters coordinated by Cp (Ni-Cp clusters). Ni-Cp clusters were thermally decomposed to Ni3C nanoparticles smaller than 10 nm. The Ni3C nanoparticles showed better performance than Ni nanoparticles and Au nanoparticles in the electrooxidation of sodium borohydride. PMID- 24752452 TI - Comprehensive multiplex one-step real-time TaqMan qRT-PCR assays for detection and quantification of hemorrhagic fever viruses. AB - BACKGROUND: Viral hemorrhagic fevers (VHFs) are a group of animal and human illnesses that are mostly caused by several distinct families of viruses including bunyaviruses, flaviviruses, filoviruses and arenaviruses. Although specific signs and symptoms vary by the type of VHF, initial signs and symptoms are very similar. Therefore rapid immunologic and molecular tools for differential diagnosis of hemorrhagic fever viruses (HFVs) are important for effective case management and control of the spread of VHFs. Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay is one of the reliable and desirable methods for specific detection and quantification of virus load. Multiplex PCR assay has the potential to produce considerable savings in time and resources in the laboratory detection. RESULTS: Primers/probe sets were designed based on appropriate specific genes for each of 28 HFVs which nearly covered all the HFVs, and identified with good specificity and sensitivity using monoplex assays. Seven groups of multiplex one-step real time qRT-PCR assays in a universal experimental system were then developed by combining all primers/probe sets into 4-plex reactions and evaluated with serial dilutions of synthesized viral RNAs. For all the multiplex assays, no cross reactivity with other HFVs was observed, and the limits of detection were mainly between 45 and 150 copies/PCR. The reproducibility was satisfactory, since the coefficient of variation of Ct values were all less than 5% in each dilution of synthesized viral RNAs for both intra-assays and inter-assays. Evaluation of the method with available clinical serum samples collected from HFRS patients, SFTS patients and Dengue fever patients showed high sensitivity and specificity of the related multiplex assays on the clinical specimens. CONCLUSIONS: Overall, the comprehensive multiplex one-step real-time qRT-PCR assays were established in this study, and proved to be specific, sensitive, stable and easy to serve as a useful tool for rapid detection of HFVs. PMID- 24752454 TI - Axonal dysfunction, dysmyelination, and conduction failure in hereditary neuropathy with liability to pressure palsies. AB - INTRODUCTION: Patients with hereditary neuropathy with liability to pressure palsies (HNPP) manifest with episodes of focal paresis when exposed to mechanical stress, although the basis for vulnerability to conduction block remains relatively unexplained. METHODS: Axonal excitability techniques were utilized to provide insights into pathophysiological mechanisms in 13 HNPP patients, stimulating median motor and sensory axons at the wrist. RESULTS: In HNPP, distal latencies were prolonged, and motor and sensory amplitudes were reduced. Threshold was increased. Depolarizing and hyperpolarizing electrotonus was greater, and resting current-threshold slope was reduced. There were greater threshold changes in superexcitability, and refractoriness was decreased. CONCLUSIONS: Taken together, excitability testing in patients with HNPP established axonal hyperpolarization in both motor and sensory axons that may be attributable to changes in nerve architecture. In turn, the hyperpolarized resting membrane potential in HNPP may be a major predisposing factor for development of conduction block with mechanical stresses. PMID- 24752453 TI - Recurrent arthritis by Candida glabrata, a diagnostic and therapeutic challenge. AB - Infectious arthritis due to Candida glabrata is very rare. A 40-year-old Iranian man had developed a painful swelling on the left knee since a year ago. A surgery (meniscectomy) was performed on his knee. However, in follow-up visit after 2 months, the patient's condition was deteriorated. Direct examination of synovial fluid with Gram and hematoxylin-eosin stains were negative for any bacterial or fungal infection or crystal elements; however, inoculation into BACTECTM Mycosis IC/F and Plus Aerobic/F culture bottles led to the isolation of a yeast strain. The macroscopic examination on CHROMagarTM Candida medium combined with microscopical examination on CMT80 agar made a presumptive identification of the isolate to be considered as C. glabrata, and it was later on confirmed by ITS sequencing. Initial empirical treatment was started with intravenous amphotericin B for 4 weeks followed by oral itraconazole which was unsuccessful. Prescription of an oral 150-mg tablet of fluconazole was considered for a 2-month course. All symptoms completely declined, and no recurrence of infection was detected. Antifungal susceptibility testing (AFST) was performed for this isolate, and the result showed sensitivity to both amphotericin B and itraconazole and less susceptibility to fluconazole while clinical recovery was achieved by fluconazole. In any suspected clinical case caused by infectious agents, application of an effective fungal diagnostic test should be considered to avoid complications due to misdiagnosis. The correlation of AFST result with real in vivo therapeutic responses can be strain or patient dependent, and this should be considered for a successive treatment. PMID- 24752455 TI - Nutritive value of maize silage in relation to dairy cow performance and milk quality. AB - Maize silage has become the major forage component in the ration of dairy cows over the last few decades. This review provides information on the mean content and variability in chemical composition, fatty acid (FA) profile and ensiling quality of maize silages, and discusses the major factors which cause these variations. In addition, the effect of the broad range in chemical composition of maize silages on the total tract digestibility of dietary nutrients, milk production and milk composition of dairy cows is quantified and discussed. Finally, the optimum inclusion level of maize silage in the ration of dairy cows for milk production and composition is reviewed. The data showed that the nutritive value of maize silages is highly variable and that most of this variation is caused by large differences in maturity at harvest. Maize silages ensiled at a very early stage (dry matter (DM) < 250 g kg(-1)) were particularly low in starch content and starch/neutral detergent fibre (NDF) ratio, and resulted in a lower DM intake (DMI), milk yield and milk protein content. The DMI, milk yield and milk protein content increased with advancing maturity, reaching an optimum level for maize silages ensiled at DM contents of 300-350 g kg(-1), and then declined slightly at further maturity beyond 350 g kg(-1). The increases in milk (R(2) = 0.599) and protein (R(2) = 0.605) yields with maturity of maize silages were positively related to the increase in starch/NDF ratio of the maize silages. On average, the inclusion of maize silage in grass silage based diets improved the forage DMI by 2 kg d(-1), milk yield by 1.9 kg d(-1) and milk protein content by 1.2 g kg(-1). Further comparisons showed that, in terms of milk and milk constituent yields, the optimum grass/maize silage ratio depends on the quality of both the grass and maize silages. Replacement of grass silage with maize silage in the ration, as well as an increasing maturity of the maize silages, altered the milk FA profile of the dairy cows, notably, the concentration of the cis-unsaturated FAs, C18:3n-3 and n-3/n-6 ratio decreased in milk fat. Despite variation in nutritive value, maize silage is rich in metabolizable energy and supports higher DMI and milk yield. Harvesting maize silages at a DM content between 300 and 350 g kg(-1) and feeding in combination with grass silage results in a higher milk yield of dairy cows. PMID- 24752456 TI - Effects of the chemical structure of polyfluorene on selective extraction of semiconducting single-walled carbon nanotubes. AB - The selective recognition/extraction of semiconducting (sem)- and metallic (met) single-walled carbon nanotubes (SWNTs) is still a great challenge in the science and technology of carbon nanotubes because their selective synthesis is still difficult. Poly(9,9-dioctyl-fluorene-2,7-diyl) (2C8-PF) and its derivatives are widely used polymers in carbon nanotube science and technology since they only extract sem-SWNTs from the mixture of sem-/met-SWNTs, while the separation mechanism is still unclear. In this study, we focus on the alkyl chain number on the polyfluorenes (PFs) to understand the mechanism for selective recognition. Here we describe the synthesis of mono-octyl moiety-carrying polyfluorene (poly(9 octyl-9H-fluorene-2,7-diyl), C8H-PF), and characterized its selective SWNT recognition/extraction ability, and found that the C8H-PF solubilized sem-SWNTs with a diameter of 0.9-1.1 nm, whose behavior is similar to that of 2C8-PF. In addition, C8H-PF selectively extracted sem-SWNTs with larger diameters (average diameter = 1.4 nm), whose behavior is different from that of 2C8-PF. Molecular mechanics simulations were carried out to understand such specific solubilization behavior. This study provides an insight into the design and synthesis of PF based polymers and copolymers that exhibit efficient selective sem-SWNT recognition/extraction ability and their applications. PMID- 24752457 TI - Comparison of Baseline Tremor Under Various Microsurgical Conditions. AB - This paper presents the characterization and comparison of physiological tremor for pointing tasks in multiple environments, as a baseline for performance evaluation of microsurgical robotics. Previous studies have examined the characteristics of physiological tremor under laboratory settings as well as different operating conditions. However, different test methods make the comparison of results across trials and conditions difficult. Two vitroretinal microsurgeons were evaluated while performing a pointing task with no entry-point constraint, constrained by an artificial eye model, and constrained by a rabbit eye in vivo. For the three respective conditions the 3D RMS positioning error was 144 MUm, 258 MUm, and 285 MUm, and maximum 3D error was 349 MUm, 647 MUm, and 696 MUm. A spectral analysis was also performed, confirming a distinct peak near in the 6-12 Hz frequency range, characteristic of hand tremor during tasks in all three environments. PMID- 24752458 TI - Vitamin D ameliorates hepatic ischemic/reperfusion injury in rats. AB - Vitamin D, most commonly associated with the growth and remodeling of bone, has been shown to ameliorate ischemia/reperfusion injury (IRI) in some tissues, yet its underlying mechanism remains elusive. This study was designed to examine the protective effect of vitamin D, if any, against hepatic IRI in rats and the underlying mechanism involved. Adult female Wistar rats were randomly divided into control, sham-operated (sham), ischemia/reperfusion (I/R), and ischemic reperfused vitamin D-treated (vit D) groups. Rats in the I/R and vit D groups were subjected to partial (70%) hepatic ischemia for 45 min, followed by 1 h of reperfusion. Vitamin D was given to rats orally in a dose of 500 IU/kg daily for 2 weeks before being subjected to I/R. Markers of liver damage, oxidative stress, inflammation and apoptosis were evaluated. Hepatic morphology was also examined. Vit D-treated rats had significantly lower serum levels of alanine aminotransferase, aspartate aminotransferase, and gamma glutamyl transferase compared to rats in the I/R group. Also, vit D-treated rats showed a significant decrease in malondialdehyde, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, nuclear factor kappaB, B cell leukemia/lymphoma 2-associated X protein, cytochrome c, and caspase-3 levels, with higher levels of glutathione peroxidase and B cell lymphoma 2 protein levels in liver tissues compared to I/R rats. Histological examination showed less damaged liver tissues with amelioration of apoptotic signs in the vit D group compared to the I/R group. In conclusion, vitamin D supplementation ameliorates hepatic IRI mostly by alleviating the inflammatory-apoptotic response mediated by the oxidative reperfusion injury insult. PMID- 24752459 TI - Severe leukoaraiosis portends a poor outcome after traumatic brain injury. AB - BACKGROUND AND PURPOSE: It is now well accepted that traumatic white matter injury constitutes a critical determinant of post-traumatic functional impairment. However, the contribution of preexisting white matter rarefaction on outcome following traumatic brain injury (TBI) is unknown. Hence, we sought to determine whether the burden of preexisting leukoaraiosis of presumed ischemic origin is independently associated with outcome after TBI. METHODS: We retrospectively analyzed consecutive, prospectively enrolled patients of >=50 years (n = 136) who were admitted to a single neurological/trauma intensive care unit. Supratentorial white matter hypoattenuation on head CT was graded on a 5 point scale (range 0-4) reflecting increasing severity of leukoaraiosis. Outcome was ascertained according to the modified Rankin Scale (mRS) and Glasgow outcome scale (GOS) at 3 and 12 months, respectively. RESULTS: After adjustment for other factors, leukoaraiosis severity was significantly associated with a poor outcome at 3 and 12 months defined as mRS 3-6 and GOS 1-3, respectively. The independent association between leukoaraiosis and poor outcome remained when the analysis was restricted to patients who survived up to 3 months, had moderate-to-severe TBI [enrollment Glasgow Coma Scale (GCS) <=12; p = 0.001], or had mild TBI (GCS 13 15; p = 0.002), respectively. CONCLUSION: We provide first evidence that preexisting cerebral small vessel disease independently predicts a poor functional outcome after closed head TBI. This association is independent of other established outcome predictors such as age, comorbid state as well as intensive care unit complications and interventions. This knowledge may help improve prognostic accuracy, clinical management, and resource utilization. PMID- 24752460 TI - Sema3A chemorepellant regulates the timing and patterning of dental nerves during development of incisor tooth germ. AB - Semaphorin 3A (Sema3A) axon repellant serves multiple developmental functions. Sema3A mRNAs are expressed in epithelial and mesenchymal components of the developing incisor in a dynamic manner. Here, we investigate the functions of Sema3A during development of incisors using Sema3A-deficient mice. We analyze histomorphogenesis and innervation of mandibular incisors using immunohistochemistry as well as computed tomography and thick tissue confocal imaging. Whereas no apparent disturbances in histomorphogenesis or hard tissue formation of Sema3A (-/-) incisors were observed, nerve fibers were prematurely seen in the presumptive dental mesenchyme of the bud stage Sema3A (-/-) tooth germ. Later, nerves were ectopically present in the Sema3A (-/-) dental papilla mesenchyme during the cap and bell stages, whereas in the Sema3A (+/+) mice the first nerve fibers were seen in the pulp after the onset of dental hard tissue formation. However, no apparent topographic differences in innervation pattern or nerve fasciculation were seen inside the pulp between postnatal and adult Sema3A (+/+) or Sema3A (-/-) incisors. In contrast, an abnormally large number of nerves and arborizations were observed in the Sema3A (-/-) developing dental follicle target field and periodontium and, unlike in the wild-type mice, nerve fibers were abundant in the labial periodontium. Of note, the observed defects appeared to be mostly corrected in the adult incisors. The expressions of Ngf and Gdnf neurotrophins and their receptors were not altered in the Sema3A (-/-) postnatal incisor or trigeminal ganglion, respectively. Thus, Sema3A is an essential, locally produced chemorepellant, which by creating mesenchymal exclusion areas, regulates the timing and patterning of the dental nerves during the development of incisor tooth germ. PMID- 24752461 TI - On the induced-fit mechanism of substrate-enzyme binding structures of nylon oligomer hydrolase. AB - We present a detailed computational investigation of the induced-fit motion in a nylon-oligomer hydrolase (NylB) upon substrate binding. To this aim, we resort on the recently introduced parallel cascade selection molecular dynamics approach, allowing for an accelerated access to the set of conformational changes from an open- to a closed-state structure to form the enzyme-substrate complex in a specific induce-fit mechanism. The structural investigation is quantitatively complemented by free energy analyses within the umbrella sampling algorithm accompanied by weighted histogram analysis. We find that the stabilization free energy is about 1.4 kcal/mol, whereas the highest free energy barrier to be overcome is about 2.3 kcal/mol. Conversely, the energetic contribution for the substrate binding is about 20 kcal/mol, as estimated from Generalized Born/Surface Area. This means that the open-close induced-fit motion could occur frequently once the substrate binds to the open state of NylB. PMID- 24752462 TI - Developmental changes of ENaC expression and function in the inner ear of pendrin knock-out mice as a perspective on the development of endolymphatic hydrops. AB - Pendrin mutations cause enlarged vestibular aqueducts and various degrees of sensorineural hearing loss. The selective abolition of pendrin causes dilation of the membranous labyrinth known as endolymphatic hydrops, loss of the endocochlear potential, and consequently loss of hearing function. Because Na+ transport is one of the most important driving forces for fluid transport, the epithelial Na+ channel (ENaC) is believed to play an important role in fluid volume regulation in the inner ear. Therefore, the dysfunction of Na+ transport through ENaC by the acidification of endolymph in Pendred syndrome is one of the potential causes of endolymphatic hydrops. We investigated the changes of ENaC expression and function during the development of the pendrin knock-out mouse. In the cochlea, the expression of beta and gammaENaC was significantly increased at P56 in Pds-/- mice compared with Pds+/+ mice. In the vestibule, the expression of betaENaC was significantly increased at P56, and gammaENaC expression significantly increased from P6 to P56 in Pds-/- mice. The ENaC-dependent trans-epithelial current was not significantly different between Pds+/+ and Pds-/- mice in Reissner's membrane or the saccular extramacular roof epithelium at P0, but the current was significantly increased in Pds-/- mice at P56 compared with Pds+/+ mice. These findings indicate that the expression and function of ENaC were enhanced in Pds-/ mice after the development of endolymphatic hydrops as a compensatory mechanism. This result provides insight into the role of Na+ transport in the development and regulation of endolymphatic hydrops due to pendrin mutations. PMID- 24752463 TI - Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. AB - The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients. Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection. Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix metalloprotease (MMP) 2, MMP9 and membrane type 1 MMP. In this work we demonstrate that, MMP9 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells. Supernatant from glioma cells induced the expression of MMP9 in cultured microglial cells. Using mice deficient for different Toll-like receptors we identified Toll-like receptor 2/6 as the signaling pathway for the glioma induced upregulation of microglial MMP9. Also in an experimental mouse glioma model, Toll-like receptor 2 deficiency attenuated the upregulation of microglial MMP9. Moreover, glioma supernatant triggered an upregulation of Toll like receptor 2 expression in microglia. Both, the upregulation of MMP9 and Toll like receptor 2 were attenuated by the antibiotic minocycline and a p38 mitogen activated protein kinase antagonist in vitro. Minocycline also extended the survival rate of glioma bearing mice when given to the drinking water. Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using Toll-like receptor 2 as an important signaling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy. PMID- 24752464 TI - Cataract may be a non-memory feature of Alzheimer's disease in older people. AB - The aim of this study was to explore whether there is a relationship between cataract and Alzheimer's disease in older people in Taiwan. We conducted a retrospective cohort study by using the database of the Taiwan National Health Insurance Program from 1999 to 2004. There were 19,954 subjects aged 65-84 with newly diagnosed cataract as the cataract group and 19,954 randomly selected subjects without cataract as the non-cataract group. Both groups were matched with sex, age and index year of diagnosing cataract. The risk of Alzheimer's disease associated with cataract was assessed. The overall incidence of Alzheimer's disease was 1.21 per 1,000 person-years in the cataract group and 0.73 per 1,000 person-years in the non-cataract group (crude hazard ratio 1.62, 95 % CI 1.28, 2.04). After adjustment for potential confounders, the adjusted HR of Alzheimer's disease was 1.43 (95 % CI 1.13, 1.82) for the cataract group, compared to the non-cataract group. Male (HR 1.36, 95 % CI 1.09, 1.70), age (every 1 year, HR 1.08, 95 % CI 1.06, 1.10) and head injury (HR 1.79, 95 % CI 1.08, 2.96) were other factors significantly associated with Alzheimer's disease. Older people with cataract are at 1.43-fold increased risk of developing Alzheimer's disease. More research is necessary to determine whether cataract is one of non-memory features of Alzheimer's disease. PMID- 24752465 TI - Diet and risk of kidney stones in the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - The lifetime prevalence of kidney stones is around 10 % and incidence rates are increasing. Diet may be an important determinant of kidney stone development. Our objective was to investigate the association between diet and kidney stone risk in a population with a wide range of diets. This association was examined among 51,336 participants in the Oxford arm of the European Prospective Investigation into Cancer and Nutrition using data from Hospital Episode Statistics in England and Scottish Morbidity Records. In the cohort, 303 participants attended hospital with a new kidney stone episode. Cox proportional hazards regression was performed to calculate hazard ratios (HR) and their 95 % confidence intervals (95 % CI). Compared to those with high intake of meat (>100 g/day), the HR estimates for moderate meat-eaters (50-99 g/day), low meat-eaters (<50 g/day), fish-eaters and vegetarians were 0.80 (95 % CI 0.57-1.11), 0.52 (95 % CI 0.35-0.8), 0.73 (95 % CI 0.48-1.11) and 0.69 (95 % CI 0.48-0.98), respectively. High intakes of fresh fruit, fibre from wholegrain cereals and magnesium were also associated with a lower risk of kidney stone formation. A high intake of zinc was associated with a higher risk. In conclusion, vegetarians have a lower risk of developing kidney stones compared with those who eat a high meat diet. This information may be important to advise the public about prevention of kidney stone formation. PMID- 24752466 TI - Excited states of protonated DNA/RNA bases. AB - The very fast relaxation of the excited states to the ground state in DNA/RNA bases is a necessary process to ensure the photostability of DNA and its rate is highly sensitive to the tautomeric form of the bases. Protonation of the bases plays a crucial role in many biochemical and mutagenic processes and it can result in alternative tautomeric structures, thus making important the knowledge of the properties of protonated DNA/RNA bases. We report here the photofragmentation spectra of the five protonated DNA/RNA bases. In most of the cases, the spectra exhibit well resolved vibrational structures, with broad bands associated with very short excited state lifetimes. The similarity between the electronic properties, e.g. excitation energy and very short excited state lifetimes for the canonical tautomers of protonated and neutral DNA bases, suggests that the former could also play an important role in the photostability mechanism of DNA. PMID- 24752467 TI - Nanomanipulation, nanotribology and nanomechanics of Au nanorods in dry and liquid environments using an AFM and depth sensing nanoindenter. AB - Nano-objects in dry and liquid conditions have shown reductions in friction and wear on the macroscale. In this research, for the first time, Au nanorods were studied on the nanoscale under dry conditions and submerged in water for their effect on friction and wear reduction. The data were compared with spherical Au nanoparticles. Atomic force microscopy (AFM) experiments on the nanoscale were performed in single-nano-object contact with an AFM tip, where nano-objects were laterally manipulated, and multiple-nano-object contact with a tip attached to a glass sphere sliding over several nano-objects. Nanoscale and macroscale wear tests with an AFM and ball-on-flat tribometer were performed to relate friction and wear reduction on both scales. Results indicate that Au nano-objects contribute to friction and wear reduction due to the reduced contact area and possible rolling and sliding on the nanoscale. Compression tests (global deformation) using a nanoindenter with a flat punch were used to investigate the mechanical behavior under load and its relation to friction and wear reduction. Repeat compression tests of nano-objects were performed which showed a strain hardening effect and increased pop-ins during subsequent loads. PMID- 24752468 TI - Formula versus donor breast milk for feeding preterm or low birth weight infants. AB - BACKGROUND: When sufficient maternal breast milk is not available, alternative sources of enteral nutrition for preterm or low birth weight infants are donor breast milk or artificial formula. Donor breast milk may retain some of the non nutritive benefits of maternal breast milk for preterm or low birth weight infants. However, feeding with artificial formula may ensure more consistent delivery of optimal levels of nutrients. Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or low birth weight infants. OBJECTIVES: To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or low birth weight infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 3), MEDLINE (1966 to March 2014), EMBASE (1980 to March 2014), CINAHL (1982 to March 2014), conference proceedings and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing feeding with formula versus donor breast milk in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Group, with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: Nine trials, in which 1070 infants participated, fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and five compared nutrient-enriched preterm formula versus donor breast milk. Only the two most recent trials used nutrient-fortified donor breast milk. The trials contain various methodological quality weaknesses, specifically uncertainty about adequate allocation concealment methods in three trials and lack of blinding in most of the trials.Formula-fed infants had higher in hospital rates of increase in weight [mean difference (MD): 2.58 (95% confidence interval (CI) 1.98 to 3.71) g/kg/day], length [MD 1.93 (95% CI 1.23 to 2.62) mm/week] and head circumference [MD 1.59 (95% CI 0.95 to 2.24) mm/week]. We did not find evidence of an effect on post-discharge growth rates or neurodevelopmental outcomes. Formula feeding increased the risk of necrotising enterocolitis: typical risk ratio 2.77 (95% CI 1.40 to 5.46); risk difference 0.04 (95% CI 0.02 to 0.07). AUTHORS' CONCLUSIONS: In preterm and low birth weight infants, feeding with formula compared with donor breast milk results in a higher rate of short-term growth but also a higher risk of developing necrotising enterocolitis. Limited data on the comparison of feeding with formula versus nutrient-fortified donor breast milk are available. This limits the applicability of the findings of this review as nutrient fortification of breast milk is now a common practice in neonatal care. Future trials may compare growth, development and adverse outcomes in infants who receive formula milk versus nutrient-fortified donor breast milk given as a supplement to maternal expressed breast milk or as a sole diet. PMID- 24752469 TI - Electrical impedance myography for the in vivo and ex vivo assessment of muscular dystrophy (mdx) mouse muscle. AB - INTRODUCTION: Sensitive, non-invasive techniques are needed that can provide biomarkers of disease status and the effects of therapy in muscular dystrophy. METHODS: We evaluated electrical impedance myography (EIM) to serve in this role by studying 2-month-old and 18-month-old mdx and wild-type (WT) animals (10 animals in each of 4 groups). RESULTS: Marked differences were observed in EIM values between mdx and WT animals; the differences were more pronounced between the older age groups (e.g., reactance of 92.6 +/- 4.3 Omega for mdx animals vs. 130 +/- 4.1 Omega for WT animals, P<0.001). In addition, in vivo EIM parameters correlated significantly with the extent of connective tissue deposition in the mdx animals. CONCLUSIONS: EIM has the potential to serve as a valuable non invasive method for evaluating muscular dystrophy. It can be a useful biomarker to assist with therapeutic testing in both pre-clinical and clinical studies. PMID- 24752471 TI - Long-term cause-specific mortality in survivors of adolescent and young adult bone and soft tissue sarcoma: a population-based study of 28,844 patients. AB - BACKGROUND: Despite improved cure rates for bone and soft tissue sarcomas, to the authors' knowledge, no large population-based study to date has evaluated long term cause-specific mortality in patients diagnosed in the adolescent and young adult (AYA) age range (15 years-39 years). METHODS: A total of 28,844 survivors of AYA bone and soft tissue sarcoma, who accrued 113,206 person-years of follow up, were identified in the population-based Surveillance, Epidemiology, and End Results program. Standardized mortality ratios (SMR) and absolute excess risks (AER) (per 10,000 person-years) were calculated to evaluate associations with histology (chemotherapy-sensitive subtypes: Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma vs all other subtypes), age, and initial therapy. RESULTS: All cause mortality in survivors of AYA sarcoma was found to be significantly increased compared with that of the general population (SMR, 1.76; 95% confidence interval [95% CI], 1.60-1.92 [AER of 19]), and persisted for > 20 years (SMR, 1.39; 95% CI, 1.04-1.82 [AER of 20]). Significant excess mortality was observed for both second malignant neoplasms (SMR, 2.05; 95% CI, 1.71-2.43 [AER of 7]) and noncancer causes (SMR, 1.66; 95% CI, 1.49-1.85 [AER of 19]). Significant excess deaths occurred among patients with chemotherapy-sensitive (SMR, 2.76; 95% CI, 2.20-3.41 [AER of 32]) and nonchemosensitive (SMR, 1.63; 95% CI, 1.47-1.80 [AER of 17]) subtypes. Significantly elevated noncancer mortality in the former group included cardiovascular disease (SMR, 2.33) and infections (SMR, 15.6), whereas significant excess deaths in the latter group included diabetes (SMR, 2.40) and infections (SMR, 2.77). CONCLUSIONS: Survivors of AYA bone and soft tissue sarcoma experience significant long-term mortality due to second malignant neoplasms and noncancer causes. Further research is needed to develop preventive and surveillance guidelines in this understudied population to prevent and reduce long-term excess mortality. PMID- 24752472 TI - An update for the controversies and hypotheses of regulating nonthyroidal illness syndrome in chronic kidney diseases. AB - Nonthyroidal illness syndrome (NTIS) is widely found in the patients with chronic kidney disease (CKD) or critical illness. However, the exact pathogenesis and reasonable treatment remain unclear. To identify suitable studies for inclusion in present review, a search for articles using PubMed search engine with combined terms: (thyroid OR hypothyroidism OR hyperthyroidism OR triiodothyronine) AND (glomerulonephritis OR chronic kidney disease OR chronic renal failure OR end stage renal disease OR hemodialysis OR peritoneal dialysis OR kidney transplantation OR renal transplantation) was performed. The bibliographies of relevant articles were also hand searched. The search was updated on November 8, 2013. Mechanisms for the alternations of thyroid hormone concentrations in NTIS are complicated. Inflammatory cytokines and oxidative stress may play pivotal roles in the pathogenesis of NTIS in patients with CKD. It was controversial whether CKD patients with NTIS should be treated with thyroid hormone replacement. N-Acetyl cysteine or sodium bicarbonate may negatively regulate the progress of micro-inflammation in CKD. Large-scale, multi-centered randomized controlled trials should be conducted to verify the NTIS hypothesis in CKD patients. PMID- 24752473 TI - Herbal medicine in the treatment of Alzheimer's disease. AB - Associated with the aging of our world population is a sharp increase in the incidence of Alzheimer's disease, which not only poses a significant health issue but also presents a serious social problem. Although pharmacological treatments were developed based on existing hypotheses, the disease pathogenesis remains to be fully elucidated. Given the complexity of Alzheimer's disease, Chinese herbal medicine appears to have therapeutic potential for Alzheimer's disease through multi-target and multi-pathway approach at cellular and molecular levels and holistic adjustment of the body at organ system levels. Recently, a significant breakthrough has been made in the research of Chinese medicine for Alzheimer's disease. In this article, we review the experimental research progress in understanding how Chinese medicine could be used for the treatment of Alzheimer's disease. PMID- 24752474 TI - Efficacy of classic Chinese medicine formula Ditan Decoction () for Alzheimer's disease. AB - OBJECTIVE: Determine the efficacy and safety of classic Chinese medicine formula Ditan Decoction (, DTD) for the treatment of Alzheimer's disease (AD) by reviewing the methods and results reported in laboratory and clinical studies in order to suggest strategies for developing more effective drugs for AD. METHODS: Embase (OVID) and China Journal Net (CJN) were searched for articles published between 1947 to November 2011 and 1915 to November 2011 respectively. Articles that fulfilled the inclusion criteria and did not meet the exclusion criteria were collected and compared in terms of research method, interventions and outcomes. RESULTS: No articles were found in Embase (OVID); 8 were found in CJN (4 laboratory studies; 4 clinical studies). The laboratory studies showed that memory impairment of AD mice models were significantly improved by DTD. The clinical studies showed that Chinese medicine which include DTD, can also relieve the memory impairment of AD patients, however, the data about the exactly effectiveness of DTD was inconclusive. CONCLUSIONS: All the clinical trials have not been fully designed yet. The evidences for recommending DTD in clinical practice were methodologically flawed. Rigid randomization in controlled clinical trials of DTD with adequate blinding and rating methods are highly recommended. PMID- 24752476 TI - Sensory evaluation and acceptability of gluten-free Andean corn spaghetti. AB - BACKGROUND: Although pasta is one of the most widely demanded products among gluten-intolerant people, few studies have focused on the sensory analysis and acceptability of these products. Spaghetti was made from Andean corn (Zea mays var. amylacea), capia and cully varieties from northern Argentina, and the flash profile technique was applied by semi-trained assessors to compare the sensory profile of this type of spaghetti with those made with rice and wheat flours. Acceptability of capia corn spaghetti was studied in celiac and non-celiac consumer groups using a 9-point hedonic scale and check-all-that-apply (CATA) questions. RESULTS: Two Andean corn spaghetti samples were described by assessors as rough, odd-smelling and odd-tasting. These terms were also used by non-celiac consumers to describe the capia corn spaghetti sample, which explained its low acceptability scores. However, celiac consumers assigned high acceptability scores to the same sample and described it as tasty, smooth, tender, novel, having a pleasant flavor and good quality, and as a product that can be consumed every day and by the whole family. CONCLUSIONS: The results of this study suggest that Andean corn flours are a suitable and acceptable product for celiac consumers and can be used in the production of spaghetti for celiac consumers but should be reformulated for non-celiac consumers. PMID- 24752475 TI - Scutellaria baicalensis in stroke management: nature's blessing in traditional Eastern medicine. AB - Scutellaria baicalensis Georgi is the most widely used medicinal plant in traditional Eastern medicine, especially in Chinese medicine. The major phytochemicals isolated from S. baicalensis are flavonoids, glycosides and their glucoronides such as baicalin, baicalein, wogonin etc. More than 30 different kinds of flavonoids are isolated from this plant. S. baicalensis and its flavonoids are reported to have several pharmacological activities, which includes anti-allergic, antioxidant, anti apoptic, anti-inflammatory effects and many more. Recently, S. baicalensis and its isolated flavonoids have been studied for their neuroprotective effects, through a variety of in vitro and in vivo models of neurodegenerative diseases, plausibly suggesting that S. baicalensis has salutary effect as a nature's blessing for neuroprotection. In this review, we are focousing on the neuroprotective effects of S. baicalensis and its flavonoids in ischemia or stroke-induced neuronal cell death. We aimed at compiling all the information regarding the neuroprotective effect of S. baicalensis in various experimental models of cerebral ischemia or stroke. PMID- 24752477 TI - Characterization and evaluation of multi-component crystals of hydrochlorothiazide. AB - PURPOSE: The present work aims at improving the physicochemical properties of hydrochlorothiazide, a poorly water soluble antihypertensive drug by preparing its multi-component crystals with nicotinic acid (HCT-NA) and 2-picolinic acid (HCT-PIC). METHODS: The crystals prepared by solution crystallization were investigated by thermoanalytical techniques. The crystal structures of HCT-NA (1) and HCT-PIC (2) were determined by the single crystal X-ray diffraction and were assessed for their aqueous solubility, antihypertensive activity and acute toxicity in rats. RESULTS: Both 1 and 2 crystallized in the orthorhombic space group P212121 and formation of salts were confirmed. The solubility profiles of 1 and 2 in basic media showed a maximum release of 2.5 mg/ml and 1.9 mg/ml, respectively, in comparison to the drug (0.82 mg/ml). The in-vivo antihypertensive activity of 1 in deoxycorticosterone acetate salt induced hypertensive rats showed 1.5 fold improvement. No increase in the signs of toxicity were revealed in rats during the acute toxicity studies even at doses of 2,000 mg/kg by body weight in comparison to the free drug. Histopathological findings supported the safety of these multi-component crystals. CONCLUSIONS: The new solid phases exhibit potential to be explored for the oral drug delivery of HCT with improved solubility and therapeutic outcome. PMID- 24752479 TI - Biodistribution, tumor uptake and efficacy of 5-FU-loaded liposomes: why size matters. AB - PURPOSE: We have investigated the impact of particle size on the biodistribution, tumor uptake and antiproliferative efficacy of 5-FU-loaded liposomes. METHODS: Three different batches of pegylated liposomes varying in size (i.e., 70, 120 and 250 nm respectively) were tested. The active compounds encapsulated were an equimolar mix of 5-FU, 2'-deoxyinosine and folinic acid. Liposomes were subsequently tested on the human breast cancer model MDA231 cells, a model previously found to be resistant to 5-FU. In vitro, antiproliferative efficacy and microscopy studies of liposomes uptake were carried out. In vivo, comparative biodistribution and efficacy studies were performed in tumor-bearing mice. RESULTS: Difference in size did not change in vitro antiproliferative activity. Fluorescence-Microscopy studies showed that liposomes were mainly uptaken by tumor cells through a direct internalization process, regardless of their size. Biodistribution profiles in tumor-bearing mice revealed higher accumulation of small liposomes in tumors throughout time as compared with normal and large liposomes (p < 0.05). Additionally, we observed that the bigger were the tumors, the more vascularised they were and the greater was the difference in accumulation between small and large liposomes. Consequently, in vivo efficacy studies showed at study conclusion that a 68% reduction in tumor size was achieved with small liposomes (p < 0.05), whereas larger liposomes failed to reduce significantly tumor growth. Similarly, at study conclusion a trend towards higher survival-rate in animals treated with smaller liposomes was observed. CONCLUSION: This study suggests that particle size is critical to achieve higher selectivity and efficacy in experimental oncology, including in resistant tumors. PMID- 24752478 TI - A floating hydrogel system capable of generating CO2 bubbles to diminish urinary obstruction after intravesical instillation. AB - AIM: Intravesical instillation is commonly used to decrease the tumor recurrence after transurethral resection. However, most drug solutions would be eliminated from bladder after the first voiding of urine, so its clinical efficacy is limited. To overcome this obstacle, we developed a floating hydrogel system for controlled delivery of antitumor drugs. METHODS: The floating hydrogel was made of Adriamycin, thermo-sensitive polymer (Poloxamer 407) and NH4HCO3, which was liquid at low temperature while forming hydrogel at high temperature. Meanwhile, at high temperature, NH4HCO3 decomposed to produce CO2 bubbles, which helped hydrogel float in bladder without urinary obstruction. RESULTS: The mixture containing 45% P407 and 6% NH4HCO3 was selected as the optimal formulation. At 37 degrees C, the mixture formed hydrogel and produced many bubbles which could be observed by B ultrasound. The vitro study showed that the antitumor drug Doxorubicin was released in a controlled manner. After the mixture was instilled into rabbit bladder, it formed hydrogel and floated in the bladder. The bladder stimuli was reduced and antitumor drugs could be released continuously in the bladder. CONCLUSION: Our results suggested that the floating hydrogel was a feasible intravesical drug delivery system and may have application prospects in intravesical therapy for bladder cancer. PMID- 24752480 TI - Dissolution testing of hardly soluble materials by surface sensitive techniques: clotrimazole from an insoluble matrix. AB - PURPOSE: The low aqueous solubility of many drugs impedes detailed investigation as the detection limit of standard testing routines is limited. This is further complicated within application relevant thin films typical used in patches or stripes for buccal or topical routes. METHODS: In this work a model system is developed based on spin - casting technique allowing defined clotrimazole and clotrimazole - polystyrene composite films preparation at a solid surface. Various highly sensitive techniques including quarz crystal microbalance (QCM), X ray reflevtivity (XRR) and X-ray photon spectroscopy (XPS) are used to investigate the drug release over time into an aqueous media. RESULTS: The results reveal a steady drug release for both samples over the course of the experiments but with the release from the composite being significantly slower. In addition the dissolution rate of the clotrimazole sample initially increases up to 30 min after which a decrease is noted. XRR shows that this is a result of surface roughening together with film thickness reduction. The results for the composite show that the release in the composite film is a result of drug diffusion within the matrix and collapsing PS film thickness whereby XPS shows that the amount of clotrimazole at the surface after 800 min immersion is still high. CONCLUSION: It can be stated that the applied techniques allow following low mass drug release in detail which may also be applied to other systems like pellets or surface loaded nano-carriers providing information for processing and application relevant parameters. PMID- 24752481 TI - Nano composite emulsion for sustained drug release and improved bioavailability. AB - PURPOSE: To propose a novel composite nanoemulsion formulation that contains no surfactant, but offers great stability and improved oral absorption capabilities. METHODS: The nanoemulsions were prepared by dispersing the oil phase into aqueous solutions containing different amounts of the PMMA/silica composite nanoparticles. The stability was tested under extreme conditions. The structure features of the nanoemulsion droplets were investigated using Electron microscope. The in vitro drug release and in vivo drug absorption profiles after oral administration were investigated using Cyclosporin A as a model drug. RESULTS: The composite nanoemulsion demonstrated great stability under various disruptive conditions. Electron microscopy studies indicated the existence of internal and surface domains in the nano-droplet structure. In vitro drug release and in vivo uptake characterizations also confirmed the unique interfacial properties of such nanoemulsion structures. CONCLUSIONS: The novel nanoemulsion formulation may have modulated drug release profiles and alternative oral absorption mechanisms, which could offer significant advantages compared to traditional emulsion formulations. PMID- 24752482 TI - The regulatory effect of citric acid on the co-production of poly(epsilon-lysine) and poly(L-diaminopropionic acid) in Streptomyces albulus PD-1. AB - Streptomyces albulus PD-1 can co-produce antimicrobial homo-polymers poly(epsilon lysine) (epsilon-PL) and poly(L-diaminopropionic acid) (PDAP). In this study, a novel feeding strategy of citric acid coupled with glucose-(NH4)2SO4 feeding was employed to S. albulus PD-1. When the pH of the culture broth dropped to 4.0, the feeding solution was added continuously to maintain the concentrations of glucose and citric acid at 10 and 4 g L(-1), respectively. As a result, the final concentration of epsilon-PL increased from 21.7 to 29.7 g L(-1) and the final concentration of PDAP decreased from 4.8 to 3.2 g L(-1). Assays on intracellular nucleotide levels and key enzyme activities were performed to elucidate the underlying regulation mechanism. The addition of citric acid increased NADH/NAD(+) ratio and decreased intracellular ATP level; meanwhile, the activities of pyruvate kinase, citrate synthase and isocitrate dehydrogenase decreased while aspartate aminotransferase activity increased. Therefore, we deduced that citric acid feeding resulted in metabolic flux redistribution at the node of phosphoenolpyruvate; the metabolic pathway from phosphoenolpyruvate directed into tricarboxylic acid cycle was weakened and thus PDAP production was inhibited. On the other hand, the metabolic pathway from phosphoenolpyruvate directed into oxaloacetate and L-aspartate was enhanced, thereby improving epsilon-PL production. This fermentation strategy may be potentially useful in epsilon-PL production because it can effectively inhibit the formation of by products, such as PDAP. PMID- 24752483 TI - Inhibition of murine fibrocyte differentiation by cross-linked IgG is dependent on FcgammaRI. AB - Monocyte-derived, fibroblast-like cells, called fibrocytes, participate in wound healing and the formation of fibrotic lesions. Aggregated or cross-linked IgG are key effectors in infections, autoimmune diseases, anaphylaxis, and immunotherapy. Cells, including monocytes and fibrocytes, bind IgG using FcgammaRs, and aggregated or cross-linked IgG inhibits fibrocyte differentiation. Mice have four different FcgammaRs, and which of these, if any, mediate the cross-linked IgG effect on fibrocyte differentiation is unknown. We find that in mice, deletion of FcgammaRI or the common signaling protein FcRgamma significantly reduces the ability of cross-linked IgG or IgG2a to inhibit fibrocyte differentiation. Cells from FcgammaRIIb/III/IV KO mice are still sensitive to cross-linked IgG, whereas cells from FcgammaRI/IIb/III/IV KO mice are insensitive to cross-linked IgG. These observations suggest that IgG-mediated inhibition of fibrocyte differentiation is mediated by FcgammaRs, with FcgammaRI mediating most of the signaling. PMID- 24752484 TI - A triple-channel lab-on-a-molecule for triple-anion quantification using an iridium(III)-imidazolium conjugate. AB - A lab-on-a-molecule, based on the iridium(iii)-imidazolium conjugate 1, allows competitive quantification of three distinct anions in a mixture using three interrogation channels: F(-) is detected and quantified via UV-Vis, H2PO4(-) using photoluminescence and AcO(-) using electrochemiluminescence. PMID- 24752485 TI - Automatic Steering of Manually Inserted Needles. AB - Bevel-tipped flexible needles can be robotically steered to reach clinical targets along curvilinear paths in 3D. Manual needle insertion allows the clinician to control the insertion speed, ensuring patient safety. This paper presents a control law for automatic 3D steering of manually inserted flexible needles, enabling path-following control. A look-ahead proportional controller for position and orientation is presented. The look-ahead distance is a linear function of insertion speed. Simulations in a 3D brain-like environment demonstrate the performance of the proposed controller. Experimental results also show the feasibility of this technique in 2D and 3D environments. PMID- 24752486 TI - Surface electronic structure calculations using the MBJLDA potential: application to Si(111)2 * 1. AB - The Si(111)2 * 1 surface has been widely studied via a range of different experimental and theoretical techniques, and found to adopt a pi-bonded chain configuration. To determine an accurate electronic structure for this system, however, it has been found necessary to use sophisticated and very computationally expensive methods such as GW or hybrid functionals. In this article, we show that the MBJLDA approach, originally proposed by Tran and Blaha for bulk materials (Tran and Blaha, Phys. Rev. Lett. 2009, 102, 226401), yields results which are comparable to GW, and generally superior to those obtained from hybrid functional density functional theory calculations. The MBJLDA method is also substantially more computationally efficient. A procedure and justification for the application of the MBJLDA approach to surfaces in general is also provided. PMID- 24752487 TI - Electronic and magnetic properties of armchair graphene nanoribbons with 558 grain boundary. AB - Grain boundaries (GBs) that inevitably appear in CVD-grown graphene affect the electronic properties of graphene-based nanomaterials. In this paper, we introduce 558 GB (composed of a pair of pentagons and one octagon alternately) into armchair graphene nanoribbons (AGNRs) and divide them into three groups in light of the end configurations of 558 GB at the ribbon edges. By using first principles calculations, the variations of electronic and magnetic properties with two adjustable parameters W (ribbon widths) and NZ (the distances between 558 GBs) are systematically investigated for each group. The results show that different electronic and magnetic behaviors versus W and NZ are presented for varying end configurations of 558 GB, including nonmagnetic metals, ferromagnetic metals and nonmagnetic semiconductors. By introducing 558 GB into AGNRs, the impurity states that are completely contributed by 558 GB appear around the Fermi level. Furthermore, a ferromagnetic ordering on the two zigzag chains of 558 GB occurs for the ferromagnetic metals due to the spin splitting energy bands near the Fermi level. These unique electronic and magnetic properties of AGNRs with 558 GB would find their potential applications in electronic and spintronic devices. PMID- 24752488 TI - Simvastatin pretreatment protects cerebrum from neuronal injury by decreasing the expressions of phosphor-CaMK II and AQP4 in ischemic stroke rats. AB - Excitotoxicity and cytotoxic edema are the two major factors resulting in neuronal injury during brain ischemia and reperfusion. Ca2+/calmodulin-dependent protein kinase II (CaMK II), the downstream signal molecular of N-methyl-D aspartate receptors (NMDARs), is a mediator in the excitotoxicity. Aquaporin 4 (AQP4), expressed mainly in the brain, is an important aquaporin to control the flux of water. In a previous study, we had reported that pretreatment of simvastatin protected the cerebrum from ischemia and reperfusion injury by decreasing neurological deficit score and infarct area (Zhu et al. PLoS One 7:e51552, 2012). The present study used a middle cerebral artery occlusion (MCAO) model to further explore the pleiotropic effect of simvastatin via CaMK II and AQP4. The results showed that simvastatin reduced degenerated cells and brain edema while decreasing the protein expressions of phosphor-CaMK II and AQP4, and increasing the ratios of Bcl-2/Bax, which was independent of cholesterol-lowering effect. Immunocomplexes formed between the subunit of NMDARs-NR3A and AQP4 were detected for the first time. It was concluded that simvastatin could protect the cerebrum from neuronal excitotoxicity and cytotoxic edema by downregulating the expressions of phosphor-CaMK II and AQP4, and that the interaction between NR3A and AQP4 might provide the base for AQP4 involving in the signaling pathways mediated by NMDARs. PMID- 24752489 TI - Catalytic nanomotors for environmental monitoring and water remediation. AB - Self-propelled nanomotors hold considerable promise for developing innovative environmental applications. This review highlights the recent progress in the use of self-propelled nanomotors for water remediation and environmental monitoring applications, as well as the effect of the environmental conditions on the dynamics of nanomotors. Artificial nanomotors can sense different analytes-and therefore pollutants, or "chemical threats"-can be used for testing the quality of water, selective removal of oil, and alteration of their speeds, depending on the presence of some substances in the solution in which they swim. Newly introduced micromotors with double functionality to mix liquids at the microscale and enhance chemical reactions for the degradation of organic pollutants greatly broadens the range of applications to that of environmental. These "self-powered remediation systems" could be seen as a new generation of "smart devices" for cleaning water in small pipes or cavities difficult to reach with traditional methods. With constant improvement and considering the key challenges, we expect that artificial nanomachines could play an important role in environmental applications in the near future. PMID- 24752490 TI - Formic acid and acetic acid induce a programmed cell death in pathogenic Candida species. AB - Cutaneous fungal infections are common and widespread. Antifungal agents used for the treatment of these infections often have undesirable side effects. Furthermore, increased resistance of the microorganisms to the antifungal drugs becomes the growing problem. Accordingly, the search for natural antifungal compounds continues to receive attention. Apoptosis is highly regulated programmed cell death. During yeast cell apoptosis, amino acids and peptides are released and can stimulate regeneration of human epithelium cells. Thus, detection of chemical compounds inducing apoptosis in yeast and nontoxic for humans is of great medical relevance. The aim of this study was to detect chemical compound inducing apoptosis in pathogenic Candida species with the lowest toxicity to the mammalian cells. Five chemical compounds--acetic acid, sodium bicarbonate, potassium carbonate, lithium acetate, and formic acid--were tested for evaluation of antifungal activity on C. albicans, C. guilliermondii, and C. lusitaniae. The results showed that acetic acid and formic acid at the lowest concentrations induced yeast cells death. Apoptosis analysis revealed that cells death was accompanied by activation of caspase. Minimal inhibitory concentrations of potassium carbonate and sodium bicarbonate induced Candida cells necrosis. Toxicity test with mammalian cell cultures showed that formic acid has the lowest effect on the growth of Jurkat and NIH 3T3 cells. In conclusion, our results show that a low concentration of formic acid induces apoptosis-like programmed cell death in the Candida yeast and has a minimal effect on the survivability of mammalian cells, suggesting potential applications in the treatment of these infections. PMID- 24752493 TI - Wartime toxicology: evaluation of a military medical toxicology telemedicine consults service to assist physicians serving overseas and in combat (2005-2012). AB - Those medical providers deployed to remote countries and tasked with caring for military personnel must diagnose and treat diseases and nonbattle injuries that result from exposures rarely seen in developed countries. Military providers must also function with limited resources and a lack of access to physician specialists, to include medical toxicologists. There have been limited published approaches to addressing this clinical gap for medical toxicology. To address this void, the US Army Medical Department deployed an electronic mail telemedicine system to provide teleconsultations for remote health-care providers worldwide, including Iraq and Afghanistan. This study aimed to describe the types and the frequency of toxicology teleconsultation and consultant responses using electronic mail to assist physicians serving in resource-limited locations. This was a retrospective observational study in which an unblinded data extractor independently reviewed all medical toxicology email consultations. Using a previously developed data collection worksheet, the extractor recorded the type of question asked by the consultant (overdose case, envenomation, occupational exposure, etc.) and the duration of time from when the teleconsultation was placed until the consultant replied. The extractor also recorded if the patient was adult or pediatric and if the patient was US military, US contractor, or local national. The extractor also recorded how often the toxicologist provided the consulting physician with information, resources, or protocols to aid in the management of future cases. In addition, for clinical teleconsultations, the extractor documented the frequency that the consulted toxicologist (i) provided a differential diagnosis or specific diagnosis, (ii) provided specific management guidelines for a patient, and (iii) recommended to evacuate or not evacuate a patient. The results were analyzed using descriptive statistics. Of the 99 consultations evaluated, the most common consultation was for snake envenomation and antivenom recommendations (n = 23, 23 %) followed by accidental chemical exposures (n = 14, 14 %), drug testing (n = 13, 13 %), and substance abuse (n = 10, 10 %). In 41 % of consults, the toxicologist provided a differential diagnosis or specific diagnosis, and in 60 % of cases, the toxicologist provided specific management or evaluation guidelines. In 11 % of cases, the toxicologist recommended for or against evacuation of the patient. In 25 % of consults, the toxicologist provided the consulting physician with information, resources, or protocols to aid in the management of future cases. The most frequent consultations for the military telemedicine consultation service were for direct patient cases, specifically snake envenomation management and accidental chemical exposures. Our results may be used to educate physicians prior to military deployment or international humanitarian efforts and to create toxicology clinical guidelines for remote locations. Expansion of the current military teleconsultation program capabilities to include video teleconsultation may improve the effectiveness of military medical toxicology teleconsultation. PMID- 24752496 TI - Small molecule BHJ solar cells based on DPP(TBFu)2 and diphenylmethanofullerenes (DPM): linking morphology, transport, recombination and crystallinity. AB - The effect of alkyl chains in substituted diphenylmethano[70]fullerenes (C70-DPM) on the device characteristics of DPP(TBFu)2 small molecule-based bulk heterojunction (BHJ) organic solar cell devices is investigated. By measuring charge carrier mobilities as well as the morphology and crystallinity of each device we have been able to understand and explain the differences found between solar cells made with the different C70-DPM fullerenes despite the general lack of simple relationships between the molecular structure, orbital level positioning and power conversion efficiency. Our study then concludes with some general rules for the future design of acceptors for DPP(TBFu)2 containing photoactive layers in the search for efficient organic solar cells. PMID- 24752497 TI - Personality in chimpanzees (Pan troglodytes): exploring the hierarchical structure and associations with the vasopressin V1A receptor gene. AB - One of the major contributions of recent personality psychology is the finding that traits are related to each other in an organized hierarchy. To date, however, researchers have yet to investigate this hierarchy in nonhuman primates. Such investigations are critical in confirming the cross-species nature of trait personality helping to illuminate personality as neurobiologically-based and evolutionarily-derived dimensions of primate disposition. Investigations of potential genetic polymorphisms associated with hierarchical models of personality among nonhuman primates represent a critical first step. The current study examined the hierarchical structure of chimpanzee personality as well as sex-specific associations with a polymorphism in the promoter region of the vasopressin V1a receptor gene (AVPR1A), a gene associated with dispositional traits, among 174 chimpanzees. Results confirmed a hierarchical structure of personality across species and, despite differences in early rearing experiences, suggest a sexually dimorphic role of AVPR1A polymorphisms on hierarchical personality profiles at a higher-order level. PMID- 24752498 TI - Evaluating and Quantifying the Specific Deterrent Effects of DNA Databases. AB - BACKGROUND: Today, the ability of deoxyribonucleic acid (DNA) evidence to place persons at crime scenes with near certainty is broadly accepted by criminal investigators, courts, policy makers, and the public. However, the public safety benefits of investments in DNA databases are largely unknown and research attempting to quantify these benefits is only gradually emerging. Given the inherent difficulty in randomly assigning offenders to treatment and comparison groups for the purpose of inferring specific deterrence and probative effects (PREs) of DNA databases, this study developed an alternate strategy for extracting these effects from transactional data. RESEARCH DESIGN: Reoffending patterns of a large cohort of offenders released from the Florida Department of Corrections custody between 1996 and 2004 were analyzed across a range of criminal offense categories. First, an identification strategy using multiple clock models was developed that linked the two simultaneous effects of DNA databases to different clocks measuring the same events. Then, a semiparametric approach was developed for estimating the models. RESULTS: The estimation models yielded mixed results. Small deterrent effects-2-3% reductions in recidivism risk attributable to deterrence-were found only for robbery and burglary. However, strong PREs-20-30% increase in recidivism risk attributable to PREs-were uncovered for most offense categories. CONCLUSION: The probative and deterrent effects of DNA databases can be elucidated through innovative semiparametric models. PMID- 24752499 TI - Season of birth and risk of Hodgkin and non-Hodgkin lymphoma. AB - Infectious etiologies have been hypothesized for Hodgkin and non-Hodgkin lymphoma (HL and NHL) in early life, but findings to date for specific lymphomas and periods of susceptibility are conflicting. We conducted the first national cohort study to examine whether season of birth, a proxy for infectious exposures in the first few months of life, is associated with HL or NHL in childhood through young adulthood. A total of 3,571,574 persons born in Sweden in 1973-2008 were followed up through 2009 to examine the association between season of birth and incidence of HL (943 cases) or NHL (936 cases). We found a sinusoidal pattern in NHL risk by season of birth (p = 0.04), with peak risk occurring among birthdates in April. Relative to persons born in fall (September-November), odds ratios for NHL by season of birth were 1.25 [95% confidence interval (CI), 1.04-1.50; p = 0.02] for spring (March-May), 1.22 (95% CI, 1.01-1.48; p = 0.04) for summer (June August) and 1.11 (95% CI, 0.91-1.35; p = 0.29) for winter (December-February). These findings did not vary by sex, age at diagnosis or major subtypes. In contrast, there was no seasonal association between birthdate and risk of HL (p = 0.78). In this large cohort study, birth in spring or summer was associated with increased risk of NHL (but not HL) in childhood through young adulthood, possibly related to immunologic effects of delayed infectious exposures compared with fall or winter birth. These findings suggest that immunologic responses in early infancy may play an important role in the development of NHL. PMID- 24752500 TI - Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNFalpha-mediated hepatotoxicity. AB - Drug-induced liver injury (DILI) is an important clinical problem. Here, we used a genomics approach to in detail investigate the hypothesis that critical drug induced toxicity pathways act in synergy with the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and nuclear factor-erythroid 2 (NF E2)-related factor 2 (Nrf2) antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. Compounds displaying weak or no TNFalpha synergism, namely ketoconazole, nefazodone, and methotrexate, failed to synchronously induce both pathways. The ER stress induced was primarily related to protein kinase R like ER kinase (PERK) and activating transcription factor 4 (ATF4) activation and subsequent expression of C/EBP homologous protein (CHOP), which was all independent of TNFalpha signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that whereas ER stress signaling through inositol-requiring enzyme 1alpha (IRE1alpha) and activating transcription factor 6 (ATF6) acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNFalpha-induced apoptosis. Whereas inhibition of the Nrf2 dependent adaptive oxidative stress response enhanced the drug/TNFalpha cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNFalpha-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing toward caspase-8-dependent TNFalpha-induced apoptosis. PMID- 24752501 TI - Air pollution upregulates endothelial cell procoagulant activity via ultrafine particle-induced oxidant signaling and tissue factor expression. AB - Air pollution exposure is associated with cardiovascular events triggered by clot formation. Endothelial activation and initiation of coagulation are pathophysiological mechanisms that could link inhaled air pollutants to vascular events. Here we investigated the underlying mechanisms of increased endothelial cell procoagulant activity following exposure to soluble components of ultrafine particles (soluble UF). Human coronary artery endothelial cells (HCAEC) were exposed to soluble UF and assessed for their ability to trigger procoagulant activity in platelet-free plasma. Exposed HCAEC triggered earlier thrombin generation and faster fibrin clot formation, which was abolished by an anti tissue factor (TF) antibody, indicating TF-dependent effects. Soluble UF exposure increased TF mRNA expression without compensatory increases in key anticoagulant proteins. To identify early events that regulate TF expression, we measured endothelial H2O2 production following soluble UF exposure and identified the enzymatic source. Soluble UF exposure increased endothelial H2O2 production, and antioxidants attenuated UF-induced upregulation of TF, linking the procoagulant responses to reactive oxygen species (ROS) formation. Chemical inhibitors and RNA silencing showed that NOX-4, an important endothelial source of H2O2, was involved in UF-induced upregulation of TF mRNA. These data indicate that soluble UF exposure induces endothelial cell procoagulant activity, which involves de novo TF synthesis, ROS production, and the NOX-4 enzyme. These findings provide mechanistic insight into the adverse cardiovascular effects associated with air pollution exposure. PMID- 24752502 TI - Aryl hydrocarbon receptor (AhR) attenuation of subchronic cigarette smoke-induced pulmonary neutrophilia is associated with retention of nuclear RelB and suppression of intercellular adhesion molecule-1 (ICAM-1). AB - Cigarette smoke is associated with chronic and enhanced pulmonary inflammation characterized by increased cytokine production and leukocyte recruitment to the lung. Although the aryl hydrocarbon receptor (AhR) is well-known to mediate toxic effects of manmade environmental contaminants, the AhR has emerged as a suppressor of acute cigarette smoke-induced neutrophilia by a mechanism involving the NF-kappaB protein RelB. Yet individuals who smoke often smoke for many years and vary in their cigarette consumption. As there is currently no information on the AhR prevention of lung inflammation, including neutrophilia, due to varied and prolonged exposure regimes, we exposed control and AhR(-/-) mice to cigarette smoke for 2 weeks (subchronic exposure) utilizing low and high exposure protocols and evaluated pulmonary inflammation. Subchronic cigarette smoke exposure significantly increased pulmonary neutrophilia dose-dependently in AhR(-/-) mice. Surprisingly, there was no difference between smoke-exposed AhR(+/-) and AhR(-/-) mice in the expression of cytokines associated with neutrophil recruitment. Expression of pulmonary intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule involved in neutrophil migration and retention, was higher in pulmonary endothelial cells from AhR(-/-) mice. Although total lung RelB expression was increased by cigarette smoke, nuclear RelB was significantly lower in subchronically exposed AhR(-/-) mice. Inhibition of AhR activity by CH-223191 in endothelial cells potentiated ICAM-1 expression and prevented RelB nuclear translocation but had no effect on neutrophil adhesion. These data support that genetic absence of the AhR contributes to heightened pulmonary neutrophilia in response to ongoing cigarette smoke exposure. Interindividual variations in AhR expression may enhance the susceptibility to cigarette smoke-induced diseases. PMID- 24752503 TI - Aggregate culture of human embryonic stem cell-derived hepatocytes in suspension are an improved in vitro model for drug metabolism and toxicity testing. AB - Early phase drug development relies on primary human hepatocytes for studies of drug metabolism, cytotoxicity, and drug-drug interactions. However, primary human hepatocytes rapidly lose metabolic functions ex vivo and are refractory to expansion in culture and thus are limited in quantity. Hepatocytes derived from human pluripotent stem cells (either embryonic stem (ES) or induced pluripotent stem (iPS) cells), have the potential to overcome many of the limitations of primary human hepatocytes, but to date the use of human pluripotent stem cell derived hepatocytes has been limited by poor enzyme inducibility and immature metabolic function. Here, we present a simple suspension culture of aggregates of ES cell-derived hepatocytes that compared to conventional monolayer adherent culture significantly increases induction of CYP 1A2 by omeprazole and 3A4 by rifampicin. Using liquid chromatography-tandem mass spectrometry, we further show that ES cell-derived hepatocytes in aggregate culture convert omeprazole and rifampicin to their human-specific metabolites. We also show that these cells convert acetaminophen (APAP) to its cytotoxic metabolite (N-acetyl-p-benzoquinone imine (NAPQI)), although they fail to perform APAP glucuronidation. In summary, we show that human pluripotent stem cell-derived hepatocytes in aggregate culture display improved enzymatic inducibility and metabolic function and is a promising step toward a simple, scalable system, but nonetheless will require further improvements to completely replace primary human hepatocytes in drug development. PMID- 24752504 TI - PARP-1 hyperactivation and reciprocal elevations in intracellular Ca2+ during ROS induced nonapoptotic cell death. AB - The generation of reactive oxygen species (ROS) has been implicated in the pathogenesis of renal ischemia/reperfusion injury, and many other pathological conditions. DNA strand breaks caused by ROS lead to the activation of poly(ADP ribose)polymerase-1 (PARP-1), the excessive activation of which can result in cell death. We have utilized a model in which 2,3,5-tris(glutathion-S yl)hydroquinone (TGHQ), a nephrotoxic and nephrocarcinogenic metabolite of hydroquinone, causes ROS-dependent cell death in human renal proximal tubule epithelial cells (HK-2), to further elucidate the role of PARP-1 in ROS-dependent cell death. TGHQ-induced ROS generation, DNA strand breaks, hyperactivation of PARP-1, rapid depletion of nicotinamide adenine dinucleotide (NAD), elevations in intracellular Ca(2+) concentrations, and subsequent nonapoptotic cell death in both a PARP- and Ca(2+)-dependent manner. Thus, inhibition of PARP-1 with PJ34 completely blocked TGHQ-mediated accumulation of poly(ADP-ribose) polymers and NAD consumption, and delayed HK-2 cell death. In contrast, chelation of intracellular Ca(2+) with BAPTA completely abrogated TGHQ-induced cell death. Ca(2+) chelation also attenuated PARP-1 hyperactivation. Conversely, inhibition of PARP-1 modulated TGHQ-mediated changes in Ca(2+) homeostasis. Interestingly, PARP-1 hyperactivation was not accompanied by the translocation of apoptosis inducing factor (AIF) from mitochondria to the nucleus, a process usually associated with PARP-dependent cell death. Thus, pathways coupling PARP-1 hyperactivation to cell death are likely to be context-dependent, and therapeutic strategies designed to target PARP-1 need to recognize such variability. Our studies provide new insights into PARP-1-mediated nonapoptotic cell death, during which PARP-1 hyperactivation and elevations in intracellular Ca(2+) are reciprocally coupled to amplify ROS-induced nonapoptotic cell death. PMID- 24752505 TI - Contribution of carboxylesterase and cytochrome P450 to the bioactivation and detoxification of isocarbophos and its enantiomers in human liver microsomes. AB - Organophosphorus pesticides are the most widely used pesticides in modern agricultural systems to ensure good harvests. Isocarbophos (ICP), with a potent acetylcholinesterase inhibitory effect is widely utilized to control a variety of leaf-eating and soil insects. However, the characteristics of the bioactivation and detoxification of ICP in humans remain unclear. In this study, the oxidative metabolism, esterase hydrolysis, and chiral inversion of ICP in human liver microsomes (HLMs) were investigated with the aid of a stereoselective LC/MS/MS method. The depletion of ICP in HLMs was faster in the absence of carboxylesterase inhibitor (BNPP) than in the presence of NADPH and BNPP, with t1/2 of 5.2 and 90 min, respectively. Carboxylesterase was found to be responsible for the hydrolysis of ICP, the major metabolic pathway. CYP3A4, CYP1A2, CYP2D6, CYP2C9, and CYP2C19 were all involved in the secondary metabolism pathway of desulfuration of ICP. Flavin-containing monooxygenase (FMO) did not contribute to the clearance of ICP. The hydrolysis and desulfuration of (+/-)ICP, (+)ICP, and (-)ICP in HLMs follow Michaelis-Menten kinetics. Individual enantiomers of ICP and its oxidative desulfuration metabolite isocarbophos oxon (ICPO) were found to be inhibitors of acetylcholinesterases at different extents. For example, (+/-)ICPO is more potent than ICP (IC50 0.031MUM vs. 192MUM), whereas (+)ICPO is more potent than (-)ICPO (IC50 0.017MUM vs. 1.55MUM). Given the finding of rapid hydrolysis of ICP and low abundance of oxidative metabolites presence in human liver, the current study highlights that human liver has a greater capacity for detoxification of ICP. PMID- 24752506 TI - Localization of cytochrome P450 and related enzymes in adult rat testis and downregulation by estradiol and bisphenol A. AB - There is a growing body of evidence that exposure to endocrine disrupting chemicals and to estrogenic compounds in particular can affect the testis and male fertility. In the present study, the constitutive expression of steroidogenic and non-steroidogenic cytochrome P450 (CYP) and related enzymes in adult rat testis, and their regulation by estradiol and bisphenol A, were investigated. CYP1B1, CYP2A1, NADPH-cytochrome P450 oxidoreductase (POR) and microsomal epoxide hydrolase (mEH) proteins, together with CYP17A1 and 3beta hydroxysteroid dehydrogenase (HSD3B), were detected by immunoblot analysis in testicular microsomes prepared from untreated adult Sprague Dawley rats. In contrast, CYP1A, CYP2B, CYP2E, CYP2D, CYP2C, CYP3A, and CYP4A enzymes were not detected. Immunofluorescence staining of cryosections of perfusion-fixed testes showed that CYP1B1, CYP2A1, CYP17A1, and HSD3B were expressed exclusively or mainly in interstitial cells, whereas mEH and POR protein staining was detected both in interstitial cells and in seminiferous tubules. Testicular CYP1B1 and CYP2A1 protein levels were decreased following treatment of adult rats with estradiol benzoate at 0.004, 0.04, 0.4, or 4 MUmol/kg/day or bisphenol A at 400 or 800 MUmol/kg/day, for 14 days, whereas expression of HSD3B was unaffected. Testicular CYP17A1, POR, and mEH protein expression was also downregulated at the three highest dosages of estradiol benzoate and at both dosages of bisphenol A. The present study is the first to establish the cellular localization of CYP1B1, mEH, and POR in rat testis and to demonstrate the suppressive effect of bisphenol A on testicular CYP1B1, CYP2A1, mEH, and POR protein levels. PMID- 24752508 TI - A new look at ichthyosaur long bone microanatomy and histology: implications for their adaptation to an aquatic life. AB - BACKGROUND: Ichthyosaurs are Mesozoic reptiles considered as active swimmers highly adapted to a fully open-marine life. They display a wide range of morphologies illustrating diverse ecological grades. Data concerning their bone microanatomical and histological features are rather limited and suggest that ichthyosaurs display a spongious, "osteoporotic-like" bone inner structure, like extant cetaceans. However, some taxa exhibit peculiar features, suggesting that the analysis of the microanatomical and histological characteristics of various ichthyosaur long bones should match the anatomical diversity and provide information about their diverse locomotor abilities and physiology. METHODOLOGY/PRINCIPAL FINDINGS: The material analyzed for this study essentially consists of mid-diaphyseal transverse sections from stylopod bones of various ichthyosaurs and of a few microtomographic (both conventional and synchrotron) data. The present contribution discusses the histological and microanatomical variation observed within ichthyosaurs and the peculiarities of some taxa (Mixosaurus, Pessopteryx). Four microanatomical types are described. If Mixosaurus sections differ from those of the other taxa analyzed, the other microanatomical types, characterized by the relative proportion of compact and loose spongiosa of periosteal and endochondral origin respectively, seem to rather especially illustrate variation along the diaphysis in taxa with similar microanatomical features. Our analysis also reveals that primary bone in all the ichthyosaur taxa sampled (to the possible exception of Mixosaurus) is spongy in origin, that cyclical growth is a common pattern among ichthyosaurs, and confirms the previous assumptions of high growth rates in ichthyosaurs. CONCLUSIONS/SIGNIFICANCE: The occurrence of two types of remodelling patterns along the diaphysis, characterized by bone mass decrease and increase respectively is described for the first time. It raises questions about the definition of the osseous microanatomical specializations bone mass increase and osteoporosis, notably based on the processes involved, and reveals the difficulty in determining the true occurrence of these osseous specializations in ichthyosaurs. PMID- 24752509 TI - Cloning of TTG1 gene and PCR identification of genomes A, B and C in Brassica species. AB - Arabidopsis Transparent Testa Glabra 1 (TTG1) genes were cloned from three diploid Brassica species (B. rapa, B. nigra and B. oleracea) and two amphidiploids species (B. juncea and B. carinata) by homology cloning. TTG1 homologues identified in all the accessions of the investigated species had a coding sequence of 1,014 bp. One copy was obtained from each diploid species and two copies from each amphidiploid species. Combined analysis of the TTG1 sequences cloned in this study with those obtained from public databases demonstrated that three, forty-five and seven nucleotides were specific variations in TTG1 genes from genomes A, B and C, respectively. Primers designed with genome-specific nucleotide variations were able to distinguish among TTG1 genes originating from genomes A, B and C in Brassica. Therefore, the TTG1 gene could serve as a candidate marker gene to detect the pollen flow of Brassica and provide an alternative method for the detection of pollen drift and risk assessment of gene flow in Brassica species. PMID- 24752507 TI - Investigation of the effects of subchronic low dose oral exposure to bisphenol A (BPA) and ethinyl estradiol (EE) on estrogen receptor expression in the juvenile and adult female rat hypothalamus. AB - Concerns have been raised regarding the long-term impacts of early life exposure to the ubiquitous environmental contaminant bisphenol A (BPA) on brain organization. Because BPA has been reported to affect estrogen signaling, and steroid hormones play a critical role in brain sexual differentiation, there is also concern that BPA exposure could alter neural sex differences. Here, we examine the impact of subchronic exposure from gestation to adulthood to oral doses of BPA below the current no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day on estrogen receptor (ESR) expression in sexually dimorphic brain regions of prepubertal and adult female rats. The dams were gavaged daily with vehicle (0.3% carboxymethylcellulose), 2.5, 25, 260, or 2700 MUg BPA/kg bw/day, or 0.5 or 5.0 MUg ethinyl estradiol (EE)/kg bw/day from gestational day 6 until labor began. Offspring were then gavaged directly from the day after birth until the day before scheduled sacrifice on postnatal days 21 or 90. Using in situ hybridization, one or more BPA doses produced significant decreases in Esr1 expression in the juvenile female rat anteroventral periventricular nucleus (AVPV) of the hypothalamus and significant decreases in Esr2 expression in the adult female rat AVPV and medial preoptic area (MPOA), relative to vehicle controls. BPA did not simply reproduce EE effects, indicating that BPA is not acting solely as an estrogen mimic. The possible consequences of long-term changes in hypothalamic ESR expression resulting from subchronic low dose BPA exposure on neuroendocrine effects are discussed and being addressed in ongoing, related work. PMID- 24752510 TI - Characterization of polycyclic aromatic hydrocarbons in emissions of different mosquito coils. AB - Emission rates and emission factors of particulate matter and polycyclic aromatic hydrocarbons (PAHs) were determined in the emissions of three prevalent mosquito coil brands available in the market in India, under controlled conditions in an environmental chamber. The emission rates varied between the brands and ranged between 2.0 +/- 1.9 to 27.1 +/- 1.5 MUg h(-1) for brand A, 3.4 +/- 1.1 to 32.3 +/ 1.2 MUg h(-1) for brand B and 3.1 +/- 1.0 to 72.2 +/- 1.1 MUg h(-1) for brand C for different compounds. Five and six ring PAHs were not detected, however four and three ring PAHs dominated. Three ring PAHs contributed 24 %, 42 % and 29 %, while four ring compounds contributed 53 %, 35 % and 61 % to total PAHs in the three brands. Carcinogenic PAH compounds were also present in the emissions, indicating the potential risks associated with the inhalation of coil smoke. PMID- 24752511 TI - Dissipation rate and residue distribution of dufulin in tomato and soil under field conditions. AB - Dissipation rate and residue distribution of dufulin in tomato and soil under field conditions were investigated in Guiyang, Tianjin, and Haikou during 2011 2012, using ultra-performance liquid chromatography. Average recoveries of dufulin in tomato and soil ranged from 91.03 % to 95.16 % and 94.35 % to 98.34 %, respectively, with relative standard deviations of 1.16 %-3.97 %. Dufulin dissipation followed first-order kinetics. Dufulin had half-lives of 2.8, 4.7, and 9.0 days in tomato and 6.1, 8.2, and 17.2 days in soil in Guiyang, Tianjin, and Haikou, respectively. At harvest, dufulin residues in tomato samples collected 5 days after the last application at 3 times recommended dosage applied every 5 days were below 1.0 mg kg(-1). PMID- 24752512 TI - Cytoplasmic 5'-nucleotidase autoantibodies in inclusion body myositis: Isotypes and diagnostic utility. AB - INTRODUCTION: Recent studies have identified circulating immunoglobulin (Ig) G autoantibodies against cytoplasmic 5'-nucleotidase 1A (cN1A; NT5C1A) in patients with inclusion body myositis (IBM), whose detection provides for an IBM blood diagnostic test. Whether or not anti-cN1A autoantibody isotypes other than IgG are present in IBM has not previously been reported. METHODS: Plasma and serum samples from 205 patients (50 with and155 without IBM) were studied for the presence of IgM and IgA, in addition to IgG, anti-cN1A autoantibodies using immunoblots and enzyme-linked immunoassays (ELISAs). RESULTS: IgM, IgA, and IgG anti-cN1A autoantibodies were detected by ELISA with similar sensitivities (49 53%) and specificities (94-96%), but with differing patterns of autoantibody isotype presence. Combination assays of all 3 autoantibody levels improved diagnostic sensitivity to 76%. CONCLUSIONS: In addition to previously recognized IgG anti-cN1A autoantibodies, IBM patients have circulating IgM and IgA anti-cN1A autoantibodies. Differing patterns of these isotypes may be present and useful for diagnosis. PMID- 24752513 TI - Cysteine protease activity of feline Tritrichomonas foetus promotes adhesion dependent cytotoxicity to intestinal epithelial cells. AB - Trichomonads are obligate protozoan parasites most renowned as venereal pathogens of the reproductive tract of humans and cattle. Recently, a trichomonad highly similar to bovine venereal Tritrichomonas foetus but having a unique tropism for the intestinal tract was recognized as a significant cause of colitis in domestic cats. Despite a high prevalence, worldwide distribution, and lack of consistently effective drugs for treatment of the infection, the cellular mechanisms of T. foetus pathogenicity in the intestinal tract have not been examined. The aims of this study were to determine the pathogenic effect of feline T. foetus on porcine intestinal epithelial cells, the dependence of T. foetus pathogenicity on adhesion of T. foetus to the intestinal epithelium, and the identity of mediators responsible for these effects. Using an in vitro coculture approach to model feline T. foetus infection of the intestinal epithelium, these studies demonstrate that T. foetus promotes a direct contact-dependent activation of intestinal epithelial cell apoptosis signaling and progressive monolayer destruction. Moreover, these pathological effects were demonstrated to be largely dependent on T. foetus cell-associated cysteine protease activity. Finally, T. foetus cysteine proteases were identified as enabling cytopathic effects by promoting adhesion of T. foetus to the intestinal epithelium. The present studies are the first to examine the cellular mechanisms of pathogenicity of T. foetus toward the intestinal epithelium and support further investigation of the cysteine proteases as virulence factors in vivo and as potential therapeutic targets for ameliorating the pathological effects of intestinal trichomonosis. PMID- 24752514 TI - Chronicity of dermal leishmaniasis caused by Leishmania panamensis is associated with parasite-mediated induction of chemokine gene expression. AB - Chronic tegumentary leishmaniasis is characterized by a scarcity of parasites in lesions and a heightened inflammatory response. Deregulated and hyperactive inflammation contributes to tissue damage and parasite persistence. The mechanisms by which immune cells are recruited to the lesion and their relationship to clinical outcomes remain elusive. We examined the expression levels of chemokines and their receptors in relation to clinical outcome in dermal leishmaniasis caused by Leishmania (Viannia) panamensis. Primary macrophages from healthy donors were infected with L. panamensis strains isolated from self-healing patients (n = 4) and those presenting chronic disease (n = 5). A consistent pattern of upregulation of neutrophil (cxcl1, cxcl2, cxcl5, and cxcl8/il-8) and monocyte (ccl2, ccl7, ccl8, cxcl3, and cxcl10) chemotactic chemokines and ccr1 and ccr5 receptor genes, evaluated by reverse transcription quantitative PCR (qRT-PCR), was observed upon infection with strains from patients with chronic dermal leishmaniasis; induction of CXCL5 and CCL8 was corroborated at the protein level. No apparent upregulation was elicited in macrophages infected with strains from self-healing patients. Expression levels of ccl8, cxcl2, cxcl3, and cxcl5 in lesion biopsy specimens from patients with chronic cutaneous leishmaniasis (CL) were compared to those in biopsy specimens from Montenegro skin tests of individuals with asymptomatic infection. Increased expression levels of cxcl5 (P < 0.05), ccl8, and cxcl3 were corroborated in chronic CL lesions. Our study revealed a dichotomy in macrophage chemokine gene expression elicited by L. panamensis strains from patients with self-healing disease and those presenting chronic disease, consistent with parasite-mediated hyperactivation of the inflammatory response driving chronicity. The predominant upregulation of neutrophil and monocyte chemoattractants indicates novel mechanisms of sustained inflammatory activation and may provide new therapeutic targets against chronic dermal leishmaniasis. PMID- 24752515 TI - VCAM-1/alpha4beta1 integrin interaction is crucial for prompt recruitment of immune T cells into the brain during the early stage of reactivation of chronic infection with Toxoplasma gondii to prevent toxoplasmic encephalitis. AB - Reactivation of chronic infection with Toxoplasma gondii can cause life threatening toxoplasmic encephalitis in immunocompromised individuals. We examined the role of VCAM-1/alpha4beta1 integrin interaction in T cell recruitment to prevent reactivation of the infection in the brain. SCID mice were infected and treated with sulfadiazine to establish a chronic infection. VCAM-1 and ICAM-1 were the endothelial adhesion molecules detected on cerebral vessels of the infected SCID and wild-type animals. Immune T cells from infected wild type mice were treated with anti-alpha4 integrin or control antibodies and transferred into infected SCID or nude mice, and the animals received the same antibody every other day. Three days later, sulfadiazine was discontinued to initiate reactivation of infection. Expression of mRNAs for CD3delta, CD4, CD8beta, gamma interferon (IFN-gamma), and inducible nitric oxide synthase (NOS2) (an effector molecule to inhibit T. gondii growth) and the numbers of CD4(+) and CD8(+) T cells in the brain were significantly less in mice treated with anti alpha4 integrin antibody than in those treated with control antibody at 3 days after sulfadiazine discontinuation. At 6 days after sulfadiazine discontinuation, cerebral tachyzoite-specific SAG1 mRNA levels and numbers of inflammatory foci associated with tachyzoites were markedly greater in anti-alpha4 integrin antibody-treated than in control antibody-treated animals, even though IFN-gamma and NOS2 mRNA levels were higher in the former than in the latter. These results indicate that VCAM-1/alpha4beta1 integrin interaction is crucial for prompt recruitment of immune T cells and induction of IFN-gamma-mediated protective immune responses during the early stage of reactivation of chronic T. gondii infection to control tachyzoite growth. PMID- 24752516 TI - Mechanism of Asp24 upregulation in Brucella abortus rough mutant with a disrupted O-antigen export system and effect of Asp24 in bacterial intracellular survival. AB - We previously showed that Brucella abortus rough mutant strain 2308 DeltaATP (called the DeltarfbE mutant in this study) exhibits reduced intracellular survival in RAW264.7 cells and attenuated persistence in BALB/c mice. In this study, we performed microarray analysis to detect genes with differential expression between the DeltarfbE mutant and wild-type strain S2308. Interestingly, acid shock protein 24 gene (asp24) expression was significantly upregulated in the DeltarfbE mutant compared to S2308, as confirmed by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Further studies using additional strains indicated that the upregulation of asp24 occurred only in rough mutants with disrupted O-antigen export system components, including the ATP-binding protein gene rfbE (bab1_0542) and the permease gene rfbD (bab1_0543), while the DeltawboA rough mutant (which lacks an O-antigen synthesis-related glycosyltransferase) and the RB51 strain (a vaccine strain with the rough phenotype) showed no significant changes in asp24 expression compared to S2308. In addition, abolishing the intracellular O-antigen synthesis of the DeltarfbE mutant by deleting the wboA gene (thereby creating the DeltarfbE DeltawboA double-knockout strain) recovered asp24 expression. These results indicated that asp24 upregulation is associated with intracellular O-antigen synthesis and accumulation but not with the bacterial rough phenotype. Further studies indicated that asp24 upregulation in the DeltarfbE mutant was associated neither with bacterial adherence and invasion nor with cellular necrosis on RAW264.7 macrophages. However, proper expression of the asp24 gene favors intracellular survival of Brucella in RAW264.7 cells and HeLa cells during an infection. This study reveals a novel mechanism for asp24 upregulation in B. abortus mutants. PMID- 24752517 TI - Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma. AB - Recently, bendamustine has become an important agent in the treatment for patients with lymphoid malignancies. Although the drug has received approval for second-line therapy in indolent lymphoma, a growing body of evidence suggests its efficacy and safety in first-line use. The results of randomised and observational studies with bendamustine as front-line therapy in non-Hodgkin lymphoma (NHL) with emphasis on efficacy and toxicity are presented. Furthermore, completed and ongoing clinical trials evaluating upfront bendamustine effectiveness in combination with other agents are discussed. The review refers mainly to indolent lymphoma, mantle cell lymphoma and aggressive lymphoma, as the most commonly diagnosed NHL types. Finally, we elaborated on the safety profile of bendamustine and the perspectives of using the drug as a first-line therapy. PMID- 24752518 TI - A simple structural hydrazide-based gelator as a fluoride ion colorimetric sensor. AB - A 4-nitrobenzohydrazide derivative, N-(3,4,5-octyloxybenzoyl)-N'-(4' nitrobenzoyl)hydrazine (C8), was synthesized. It could form stable gels in some of the tested organic solvents. The wide-angle X-ray diffraction analysis showed that the xerogels exhibited a layered structure. SEM images revealed that the molecules self-assembled into fibrous aggregates in the xerogels. FT-IR studies confirmed that the intermolecular hydrogen bonding between C=O and N-H groups was the major driving force for the formation of self-assembling gel processes. The gel is utilized for a 'naked eye' detection of fluoride ions, through a reversible gel-sol transition, which is associated with a color change from colorless to red. An extended conjugated system formed through the phenyl group and a five-membered ring based on intramolecular hydrogen bonding between the oxygen atom near the deprotonation nitrogen atom and the other NH, which is responsible for the dramatic color change upon addition of fluoride ions. PMID- 24752520 TI - Novel syntheses of aryl quinoxaline C-nucleoside analogs by mild and efficient three-component sequential reactions. AB - Novel syntheses of C-nucleoside analogs with aryl quinoxalines as nucleobase surrogates have been accomplished by mild and efficient three-component sequential reactions in high yields with a wide scope of substrates. The mechanism was clarified by isolation of novel sugar 1,2-diketone derived from oxidation of the corresponding alkyne. PMID- 24752521 TI - On the faradaic selectivity and the role of surface inhomogeneity during the chlorine evolution reaction on ternary Ti-Ru-Ir mixed metal oxide electrocatalysts. AB - The faradaic selectivity of the chlorine evolution reaction (CER) and oxygen evolution reaction (OER) on the industrially important Ti-Ru-Ir mixed metal oxide is discussed. Absolute evolution rates as well as volume fractions of Cl2 and O2 were quantified using differential electrochemical mass spectrometry (DEMS), while the catalyst surface redox behavior was analyzed using cyclic voltammetry. The spatial inhomogeneity of the surface catalytic reaction rate was probed using Scanning Electrochemical Microscopy (SECM). Although the nature of the competition between electrochemical discharging of chloride ions and water molecules remains elusive on a molecular scale, new insights into the spatial reactivity distribution of the CER and OER were obtained. Oxidation of water is the initial step in corrosion and concomitant deactivation of the oxide electrodes; however, at the same time the nature of interaction between the oxide surface and water is used as a rational indicator of selectivity and catalytic activity. An experimental procedure was established that would allow the study of selectivity of a variety of different catalyst materials using polycrystalline electrode surfaces. PMID- 24752522 TI - Re-moralizing the suicide debate. AB - Contemporary approaches to the study of suicide tend to examine suicide as a medical or public health problem rather than a moral problem, avoiding the kinds of judgements that have historically characterised discussions of the phenomenon. But morality entails more than judgement about action or behaviour, and our understanding of suicide can be enhanced by attending to its cultural, social, and linguistic connotations. In this work, I offer a theoretical reconstruction of suicide as a form of moral experience that delineates five distinct, yet interrelated domains of understanding: the temporal, the relational, the existential, the ontological, and the linguistic. Attention to each of these domains, I argue, not only enriches our understanding of the moral realm but also provides a heuristic for examining the moral traditions and practices that constitute contemporary understandings of suicide. PMID- 24752523 TI - Human dignity as a component of a long-lasting and widespread conceptual construct. AB - For some decades, the concept of human dignity has been widely discussed in bioethical literature. Some authors think that this concept is central to questions of respect for human beings, whereas others are very critical of it. It should be noted that, in these debates, dignity is one component of a long lasting and widespread conceptual construct used to support a stance on the ethical question of the moral status of an action or being. This construct has been used from Modernity onward to condemn slavery and torture as violations of human dignity. In spelling it out, we can come to a better understanding of what "dignity" means and become aware that there exists a quite useful place for this notion in our ethical thought, albeit a modest one. PMID- 24752524 TI - WATsite: hydration site prediction program with PyMOL interface. AB - Water molecules that mediate protein-ligand interactions or are released from the binding site on ligand binding can contribute both enthalpically and entropically to the free energy of ligand binding. To elucidate the thermodynamic profile of individual water molecules and their potential contribution to ligand binding, a hydration site analysis program WATsite was developed together with an easy-to use graphical user interface based on PyMOL. WATsite identifies hydration sites from a molecular dynamics simulation trajectory with explicit water molecules. The free energy profile of each hydration site is estimated by computing the enthalpy and entropy of the water molecule occupying a hydration site throughout the simulation. The results of the hydration site analysis can be displayed in PyMOL. A key feature of WATsite is that it is able to estimate the protein desolvation free energy for any user specified ligand. The WATsite program and its PyMOL plugin are available free of charge from http://people.pnhs.purdue.edu/~mlill/software. PMID- 24752526 TI - Synthesis and near-infrared fluorescence of K5NdLi2F10 nanocrystals and their dispersion with high doping concentration and long lifetime. AB - K5NdLi2F10 nanocrystals were synthesized by a novel synthetic route in the liquid phase, which could improve the morphology and reduce the size effectively, for the first time. The luminescence intensities of the K5NdLi2F10 nanocrystals and their dispersion in polyethylene glycol 400 (PEG-400) approximate to that of neodymium doped phosphate glass (3 mol%), while the lifetimes of the nanocrystals alone and when dispersed with Nd(3+) ions (1 * 10(20) cm(-3)) are 303.4 MUs and 174.6 MUs respectively. Based on the Judd-Ofelt analysis, the emission quantum yield of the dispersion reaches 39.57%. In all, the K5NdLi2F10 nanocrystals and their dispersion have promising applications as liquid laser materials and biological fluorescent markers. PMID- 24752525 TI - Heterogeneous calretinin expression in the avian cochlear nucleus angularis. AB - Multiple calcium-binding proteins (CaBPs) are expressed at high levels and in complementary patterns in the auditory pathways of birds, mammals, and other vertebrates, but whether specific members of the CaBP family can be used to identify neuronal subpopulations is unclear. We used double immunofluorescence labeling of calretinin (CR) in combination with neuronal markers to investigate the distribution of CR-expressing neurons in brainstem sections of the cochlear nucleus in the chicken (Gallus gallus domesticus). While CR was homogeneously expressed in cochlear nucleus magnocellularis, CR expression was highly heterogeneous in cochlear nucleus angularis (NA), a nucleus with diverse cell types analogous in function to neurons in the mammalian ventral cochlear nucleus. To quantify the distribution of CR in the total NA cell population, we used antibodies against neuronal nuclear protein (NeuN), a postmitotic neuron-specific nuclear marker. In NA neurons, NeuN label was variably localized to the cell nucleus and the cytoplasm, and the intensity of NeuN immunoreactivity was inversely correlated with the intensity of CR immunoreactivity. The percentage of CR + neurons in NA increased from 31 % in embryonic (E)17/18 chicks, to 44 % around hatching (E21), to 51 % in postnatal day (P) 8 chicks. By P8, the distribution of CR + neurons was uniform, both rostrocaudal and in the tonotopic (dorsoventral) axis. Immunoreactivity for the voltage-gated potassium ion channel Kv1.1, used as a marker for physiological type, showed broad and heterogeneous postsynaptic expression in NA, but did not correlate with CR expression. These results suggest that CR may define a subpopulation of neurons within nucleus angularis. PMID- 24752527 TI - The carbon concentrating mechanism in Chlamydomonas reinhardtii: finding the missing pieces. AB - The photosynthetic, unicellular green alga, Chlamydomonas reinhardtii, lives in environments that often contain low concentrations of CO2 and HCO3 (-), the utilizable forms of inorganic carbon (Ci). C. reinhardtii possesses a carbon concentrating mechanism (CCM) which can provide suitable amounts of Ci for growth and development. This CCM is induced when the CO2 concentration is at air levels or lower and is comprised of a set of proteins that allow the efficient uptake of Ci into the cell as well as its directed transport to the site where Rubisco fixes CO2 into biomolecules. While several components of the CCM have been identified in recent years, the picture is still far from complete. To further improve our knowledge of the CCM, we undertook a mutagenesis project where an antibiotic resistance cassette was randomly inserted into the C. reinhardtii genome resulting in the generation of 22,000 mutants. The mutant collection was screened using both a published PCR-based approach (Gonzalez-Ballester et al. 2011) and a phenotypic growth screen. The PCR-based screen did not rely on a colony having an altered growth phenotype and was used to identify colonies with disruptions in genes previously identified as being associated with the CCM related gene. Eleven independent insertional mutations were identified in eight different genes showing the usefulness of this approach in generating mutations in CCM-related genes of interest as well as identifying new CCM components. Further improvements of this method are also discussed. PMID- 24752528 TI - Carbon allocation and element composition in four Chlamydomonas mutants defective in genes related to the CO2 concentrating mechanism. AB - Four mutants of Chlamydomonas reinhardtii with defects in different components of the CO2 concentrating mechanism (CCM) or in Rubisco activase were grown autotrophically at high pCO2 and then transferred to low pCO2, in order to study the role of different components of the CCM on carbon allocation and elemental composition. To study carbon allocation, we measured the relative size of the main organic pools by Fourier Transform Infrared spectroscopy. Total reflection X ray fluorescence was used to analyze the elemental composition of algal cells. Our data show that although the organic pools increased their size at high CO2 in all strains, their stoichiometry was highly homeostatic, i.e., the ratios between carbohydrates and proteins, lipid and proteins, and carbohydrates and lipids, did not change significantly. The only exception was the wild-type 137c, in which proteins decreased relative to carbohydrates and lipids, when the cells were transferred to low CO2. It is noticeable that the two wild types used in this study responded differently to the transition from high to low CO2. Malfunctions of the CCM influenced the concentration of several elements, somewhat altering cell elemental stoichiometry: especially the C/P and N/P ratios changed appreciably in almost all strains as a function of the growth CO2 concentration, except in 137c and the Rubisco activase mutant rca1. In strain cia3, defective in the lumenal carbonic anhydrase (CA), the cell quotas of P, S, Ca, Mn, Fe, and Zn were about 5-fold higher at low CO2 than at high CO2. A Principle Components Analysis showed that, mostly because of its elemental composition, cia3 behaved in a substantially different way from all other strains, at low CO2. The lumenal CA thus plays a crucial role, not only for the correct functioning of the CCM, but also for element utilization. Not surprisingly, growth at high CO2 attenuated differences among strains. PMID- 24752529 TI - The action of JAK, SMAD and ERK signal pathways on hepcidin suppression by polysaccharides from Angelica sinensis in rats with iron deficiency anemia. AB - A crude polysaccharide was obtained by water extraction and ethanol precipitation from the root of Angelica sinensis (AS) to investigate its suppressive effect on hepcidin expression in rats with iron deficiency anemia (IDA). In this study, we showed that the Angelica sinensis polysaccharide (ASP) was mainly composed of arabinose, glucose and galactose in a molar ratio of 1 : 2.5 : 7.5, with the molecular weight of 72 900 Da and the sugar content of 95.1%. ASP markedly decreased hepcidin expression by suppressing the expression of JAK1/2, phospho JAK1/2, phospho-SMAD1/5/8, phospho-ERK1/2, and promoting the expression of SMAD7 in the liver. These findings suggest that ASP can prevent the janus-kinase (JAK), son of mother against decapentaplegic (SMAD) and extracellular signal-regulated kinase (ERK) pathways to down-regulate hepcidin expression in IDA rats, and may be useful for the treatments of diseases induced by hepcidin over-expression. PMID- 24752530 TI - Why do female Callosobruchus maculatus kick their mates? AB - Sexual conflict is now recognised as an important driver of sexual trait evolution. However, due to their variable outcomes and effects on other fitness components, the detection of sexual conflicts on individual traits can be complicated. This difficulty is exemplified in the beetle Callosobruchus maculatus, where longer matings increase the size of nutritious ejaculates but simultaneously reduce female future receptivity. While previous studies show that females gain direct benefits from extended mating duration, females show conspicuous copulatory kicking behaviour, apparently to dislodge mating males prematurely. We explore the potential for sexual conflict by comparing several fitness components and remating propensity in pairs of full sibling females where each female mated with a male from an unrelated pair of full sibling males. For one female, matings were terminated at the onset of kicking, whereas the other's matings remained uninterrupted. While fecundity (number of eggs) was similar between treatments, uninterrupted matings enhanced adult offspring numbers and fractionally also longevity. However, females whose matings were interrupted at the onset of kicking exhibited an increased propensity to remate. Since polyandry can benefit female fitness in this species, we argue that kicking, rather than being maladaptive, may indicate that females prefer remating over increased ejaculate size. It may thus be difficult to assess the presence of sexual conflict over contested traits such as mating duration when females face a trade off between direct benefits gained from one mating and indirect benefits from additional matings. PMID- 24752531 TI - Influence of PEG length on conformational and binding properties of CCK peptides exposed by supramolecular aggregates. AB - Five novel peptide amphiphiles (PAs), with common formula (C18)2-PEGx-CCK8 in which the CCK8 peptide and the (C18)2-hydrophobic moiety are spaced by polyethylene linkers of different length (PEG moieties with molecular weights of 700, 1000, 1500, 2000, and 3000 Daltons) are described. They act as potential target-selective nanocarriers towards tumor cells overexpressing cholecistokynin receptors. PAs self-assemble in supramolecular aggregates, with hydrodynamic radius ranging between 63 and 104 nm, as indicated by DLS measurements. Fluorescence studies suggested that, irrespective from the PEG length, the tryptophan residue located at the center of the CCK8 sequence is completely surrounded by water molecules at high mobility. This result indicates a potential capability of all formulated nanovectors to recognize the overexpressed CCK-2 receptors. CD data suggest that CCK8 peptide, in most of PAs in their aggregate form, adopts a conformation allowing the interaction with the receptor. Anyway, biological data obtained by flow cytometry analysis indicate that the five PAs have a different binding ability towards the CCK-2 receptors, with higher binding properties shown by PA containing PEG with MW of 2000 Dalton. Therefore, PEG2000 can be considered as the best spacer in the formulation of nanovectors based on CCK8 peptide amphiphiles. PMID- 24752533 TI - A multimarker panel for circulating tumor cells detection predicts patient outcome and therapy response in metastatic colorectal cancer. AB - Circulating tumor cells (CTCs), proposed as major players in cancer dissemination, have demonstrated clinical prognostic significance in several cancer types. However, their predictive value remains unclear. Here we evaluated the clinical utility of six CTC markers (tissue specific and epithelial to mesenchymal transition transcripts) both as prognostic and predictive tools in metastatic colorectal cancer (mCRC) patients. CTCs were immunoisolated from blood in 50 mCRC patients at baseline and at 4 and 16 weeks after treatment onset. Expression levels of GAPDH, VIL1, CLU, TIMP1, LOXL3 and ZEB2 were determined by qualitative polymerase chain reaction and normalized to the unspecific cell isolation marker CD45. At baseline, median progression-free survival (PFS) and overall survival (OS) for patients with high CTC markers were 6.3 and 12.7 months, respectively, versus 12.7 and 24.2 for patients with low CTC markers (PFS; p = 0.0003; OS; p = 0.044). Concerning response to therapy, PFS and OS for patients with increased CTC markers along treatment were, respectively, 6.6 and 13.1 months, compared with 12.7 and 24.3 for patients presenting CTC markers reduction (PFS; p = 0.004; OS; p = 0.007). Of note, CTC markers identified therapy-refractory patients not detected by standard image techniques. Patients with increased CTC markers along treatment, but classified as responders by computed tomography, showed significantly shorter survival times (PFS: 7.8 vs. 13.2; OS: 14.4 vs. 24.4; months). In conclusion, we have generated a CTC marker panel for prognosis evaluation and the identification of patients benefiting or not from therapy in mCRC. Our methodology efficiently classified patients earlier than routine computed tomography and from a minimally invasive liquid biopsy. PMID- 24752534 TI - Arthroscopic partial shoulder resurfacing. AB - PURPOSE: The purpose of this study was to report patients' clinical and subjective outcomes 2 years after arthroscopic-assisted partial resurfacing of the humeral head. METHODS: In this prospective case series, 11 patients (4 females, 7 males; median age, 59 years; range 47-72) underwent arthroscopic assisted partial shoulder resurfacing between April 2010 and March 2011. Clinical conditions and subjective assessments were evaluated before surgery and at 6 weeks, 3 and 6 months, and then annually after surgery using the Constant score (CS), active range of motion (ROM), the visual analogue scale (VAS) for pain, the American Shoulder and Elbow Surgeons scale (ASES), and the subjective shoulder value (SSV). Radiological outcomes and major complications were monitored. RESULTS: The mean CS improved significantly from 54.6 +/- 13.6 preoperatively to 72.9 +/- 17.2 points 6 weeks postoperatively (P = 0.009). At the 2-year follow up, the mean CS had further increased to 86.5 +/- 14.3 points (P < 0.001). Trends towards increasing ROMs were detected. VAS, ASES, and SSV significantly improved from baseline to the first follow-up and maintained improvement after 2 years. One patient required revision surgery owing to a technical failure and two patients because of rapidly progressive osteoarthritis. Ten of 11 patients (91 %) claimed that they would undergo arthroscopic partial shoulder resurfacing again. CONCLUSION: Arthroscopic-assisted partial humeral head resurfacing, which has the advantages of bone stock preservation and the maintenance of an intact subscapularis tendon, allowed immediate postoperative mobilization and provided significant improvements in subjective outcomes, especially for pain relief in active patients without severe glenoid cartilage wear. LEVEL OF EVIDENCE: Therapeutic case series, Level IV. PMID- 24752535 TI - Arthroscopic Bankart shoulder stabilization in athletes: return to sports and functional outcomes. AB - PURPOSE: The aim of this study was to evaluate return to sports after arthroscopic Bankart stabilization. METHODS: This is a retrospective study including all athletes aged <50 years who underwent arthroscopic stabilization in 2010 and 2011 (m, 36; f, 10; mean age 28.9 +/- 8.1 years; follow-up 24.4 +/- 7.7 months). Sixteen patients were practicing competitive sports and 30 recreational sports. Level and delay of return to sports, sports classification according to Allain, Western Ontario Shoulder Instability Index (WOSI) score, patient satisfaction, apprehension level and avoidance behaviour were noted. RESULTS: 95.7 % returned to the same level after an average of 9.8 +/- 5.4 months. Sports level was unchanged or better in 82.6 %, lower in 8.7, and 4.5 % changed sport because of their shoulder. Patients with more than 10 dislocations returned to sports and to their preoperative level later than patients with <10. Male athletes returned to preoperative sports levels faster than female athletes (p < 0.001). The WOSI score and also its item "sports" were worse in those who had not returned (p = 0.0002 and 0.006, respectively). Satisfaction correlated with the WOSI score (p = 0.0004) while 93.3 % were satisfied/very satisfied. The decrease in the apprehension level was significant (p < 0.00001). 36.9 % still experienced avoidance behaviour. CONCLUSIONS: Most athletes resumed their main sport often at the same level, but the threshold of 10 dislocations should be considered a risk factor for longer return to sports at any level. The WOSI score is a valuable outcome score after Bankart stabilization. Postoperative avoidance should be distinguished from apprehension. LEVEL OF EVIDENCE: IV. PMID- 24752536 TI - Lipoma arborescens of the knee. AB - PURPOSE: Lipoma arborescens (LA) is a benign lesion described as replacement of mature fat cells with sub-synovial tissue, which causes the formation of villous projections. Underlying inflammatory conditions might predispose LA. This study demonstrates the treatment, post-operative survey and MRI demonstrations of this rare entity. METHODS: Five patients (6 knees) diagnosed and treated with arthroscopic (5/6) and open (1/6) synovectomy were reviewed retrospectively. An additional mini-transquadricipital incision is used for excision of the extensive suprapatellar lesions. The patients had post-operative follow-ups at first and sixth months and then yearly. Radiographs and MRI of the affected knees were taken at the final follow-up. RESULTS: The median follow-up was 59 (4-105) months. Major symptom was painless swelling of the joint. The presenting age was under 18 years in four patients. Recurrent lesions were detected in MRI scan of three patients with JRA, ARF and Tbc. Two out of three were located adjacent to the posterior capsule. The median of the Kujala questionnaire scores was 88 (74 95), and the median of the Knee Society Clinical Rating System scores was 95 (80 100) at the final follow-up. CONCLUSIONS: Lipoma arborescens should be considered in the differential diagnosis of paediatric patients who have painless swelling of the knee joint. The lesion is totally curable. However, underlying persistent disease might aggravate the inflammatory process and might cause recurrent lesions. Although resecting the lesion adjacent to the posterior capsule of the knee joint is technically demanding, arthroscopic treatment is an effective procedure and transquadricipital approach may help resection of the extensive lesions in suprapatellar pouch. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24752537 TI - The use of a prosthetic inlay resurfacing as a salvage procedure for a failed cartilage repair. AB - PURPOSE: This study was designed to describe the clinical and radiographical outcome of the HemiCAP((r)) resurfacing system as a salvage treatment for a failed index cartilage procedure. METHODS: Fourteen patients were treated consecutively and clinically prospectively followed for a mean period of 26.1 +/- 12.8 months. All patients were previously treated for their cartilage lesion. Radiographical data were analysed based on the Kellgren and Lawrence system. RESULTS: The patients involved in this study demonstrated a gradual clinical improvement in time. However, radiographically significant osteoarthritic changes were observed during the follow-up period. The position of the HemiCAP((r)) resurfacing system was adequate in all cases, and no signs of loosening were observed during the follow-up period. CONCLUSIONS: The HemiCAP((r)) resurfacing system is feasible as a salvage treatment for a failed index cartilage procedure and resulted in a gradual clinical improvement. However, the favourable clinical outcome was not confirmed by the radiographical findings. LEVEL OF EVIDENCE: IV. PMID- 24752538 TI - Arthroscopic reconstruction of the popliteus complex: accuracy and reproducibility of a new surgical technique. AB - PURPOSE: With combined PCL reconstruction and a minimal invasive (extra anatomical) Larson's procedure, dorsal instability can be reduced by about 50-70 %. Better results are described by open and more anatomical procedures. In this study, a new, standardized, arthroscopic technique for anatomical popliteus tendon (PLT) reconstruction is evaluated. METHODS: In 13 cadaver knees, an arthroscopic reconstruction of the PLT and the lateral collateral ligament was performed. Twelve defined landmarks were used for arthroscopic tunnel placement, and the distance of the tunnel locations to these specific landmarks was evaluated. RESULTS: The femoral drill channel was located with a high degree of accuracy and reproducibility in the centre of the femoral footprint of the PLT (on average 1.1 (+/-1.6) mm distal from the centre). On the tibial side, the drill channel was in the distal third of the sulcus popliteus in all cases. On average, the channel was placed exactly at the level of the tip of the fibula (+/ 1.5 mm) and 0.6 (+/-1.7) mm medially from the medial edge of the fibula. The centre of the channel was 13.4 (+/-2.3) mm distal from the joint line. CONCLUSIONS: The presented arthroscopic technique for PLT reconstruction is standardized, reproducible and has a high accuracy for the placement of the tibial and femoral tunnel. The technique could be clinically relevant for future arthroscopic posterolateral corner reconstructions. LEVEL OF EVIDENCE: III. PMID- 24752539 TI - Current concepts on trochleoplasty procedures for the surgical treatment of trochlear dysplasia. AB - Trochleoplasty is a surgical procedure, whose goal is to change the abnormal shape of the femoral trochlea in patients with recurrent patellar dislocation. Such surgeries that aim to reshape the articular surface of a bone without damaging it are quite unique in orthopaedic surgery. Although in the beginning, trochleoplasty was reserved for the refractory cases where previous surgery has failed, the last years it became more and more popular because of a better knowledge of anatomy and biomechanics and a greater availability of instruments. The roots of the deepening trochleoplasty could be found in the previous century when the first surgeons tried to directly remove the dysplastic bone with pioneer interventions but with devastating consequences. Since then, multiple procedures have been described and are analysed in this review; each one with its unique features, advantages and pitfalls. Regardless of the technique used, the very recent bibliography presents very encouraging results from the application of trochleoplasty with other procedures in a selected population with severe trochlear dysplasia and recurrent patellar dislocation, in whom the benign neglect of dysplasia would lead to unfavourable results. LEVEL OF EVIDENCE: IV. PMID- 24752540 TI - Genetic analysis of genes related to tight junction function in the Korean population with non-syndromic hearing loss. AB - Tight junctions (TJs) are essential components of eukaryotic cells, and serve as paracellular barriers and zippers between adjacent tissues. TJs are critical for normal functioning of the organ of Corti, a part of the inner ear that causes loss of sensorineural hearing when damaged. To investigate the relation between genes involved in TJ function and hereditary loss of sensorineural hearing in the Korean population, we selected the TJP2 and CLDN14 genes as candidates for gene screening of 135 Korean individuals. The TJP2 gene, mutation of which causes autosomal dominant non-syndromic hearing loss (ADNSHL), lies at the DFNA51 locus on chromosome 9. The CLDN14 gene, mutation of which causes autosomal recessive non-syndromic hearing loss (ARNSHL), lies at the DFNB29 locus on chromosome 21. In the present study, we conducted genetic analyses of the TJP2 and CLDN14 genes in 87 unrelated patients with ADNSHL and 48 unrelated patients with either ARNSHL or potentially sporadic hearing loss. We identified two pathogenic variations, c.334G>A (p.A112T) and c.3562A>G (p.T1188A), and ten single nucleotide polymorphisms (SNPs) in the TJP2 gene. We found eight non-pathogenic variations in the CLDN14 gene. These findings indicate that, whereas mutation of the TJP2 gene might cause ADNSHL, CLDN14 is not a major causative gene for ARNSHL in the Korean population studied. Our findings may improve the understanding of the genetic cause of non-syndromic hearing loss in the Korean population. PMID- 24752541 TI - Mechanism of the Rpn13-induced activation of Uch37. AB - Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-inhibited. Structural comparisons revealed that within a homo-dimer of Uch37, each of the catalytic domains was blocking the other's ubiquitin (Ub)-binding site. This blockage likely prevented Ub from entering the active site of Uch37 and might form the basis of auto-inhibition. To understand the mode of auto-inhibition clearly and shed light on the activation mechanism of Uch37 by Rpn13, we investigated the Uch37-Rpn13 complex using a combination of mutagenesis, biochemical, NMR, and small-angle X-ray scattering (SAXS) techniques. Our results also proved that Uch37 oligomerized in solution and had very low activity against the fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC) of de ubiquitinating enzymes. Uch37Delta(Hb,Hc,KEKE), a truncation removal of the C terminal extension region (residues 256-329) converted oligomeric Uch37 into a monomeric form that exhibited iso-peptidase activity comparable to that of a truncation-containing the Uch37 catalytic domain only. We also demonstrated that Rpn13C (Rpn13 residues 270-407) could disrupt the oligomerization of Uch37 by sequestering Uch37 and forming a Uch37-Rpn13 complex. Uch37 was activated in such a complex, exhibiting 12-fold-higher activity than Uch37 alone. Time-resolved SAXS (TR-SAXS) and FRET experiments supported the proposed mode of auto inhibition and the activation mechanism of Uch37 by Rpn13. Rpn13 activated Uch37 by forming a 1:1 stoichiometric complex in which the active site of Uch37 was accessible to Ub. PMID- 24752542 TI - ROR1, an embryonic protein with an emerging role in cancer biology. AB - Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR family consisting of ROR1 and ROR2. RORs contain two distinct extracellular cysteine-rich domains and one transmembrane domain. Within the intracellular portion, ROR1 possesses a tyrosine kinase domain, two serine/threonine-rich domains and a proline-rich domain. RORs have been studied in the context of embryonic patterning and neurogenesis through a variety of homologs. These physiologic functions are dichotomous based on the requirement of the kinase domain. A growing literature has established ROR1 as a marker for cancer, such as in CLL and other blood malignancies. In addition, ROR1 is critically involved in progression of a number of blood and solid malignancies. ROR1 has been shown to inhibit apoptosis, potentiate EGFR signaling, and induce epithelial-mesenchymal transition (EMT). Importantly, ROR1 is only detectable in embryonic tissue and generally absent in adult tissue, making the protein an ideal drug target for cancer therapy. PMID- 24752543 TI - Comparing axonal excitability in past polio to amyotrophic lateral sclerosis. AB - INTRODUCTION: Poliomyelitis causes selective destruction of anterior horn cells and usually has a stable disease course post-infection. We assessed the excitability characteristics in patients with a stable course after past poliomyelitis and compared them with changes described in amyotrophic lateral sclerosis (ALS). METHODS: The excitability characteristics of motor and sensory nerves were studied in 10 subjects with stable past poliomyelitis. RESULTS: Motor rheobase was increased, but there were no significant changes in strength duration properties or depolarizing threshold electrotonus, as have been seen in previous studies of ALS. CONCLUSIONS: There is minimal change in axonal excitability properties in patients with stable past poliomyelitis. The results may signify sufficient compensation in the stable state of the disease. Increased subexcitability in 1 subject with demonstrable hyperexcitability may represent compensation for increased ectopic activity rather than a different process in surviving motor neurons. Muscle Nerve 50: 602-604, 2014. PMID- 24752544 TI - Clinical trials in systemic lupus erythematosus: a status report on ongoing trials. AB - To describe the characteristics of trials in systemic lupus erythematous (SLE) listed in ClinicalTrials.gov such as study design, funding sources and aspects of the disease and drugs under investigation. We conducted a survey of ongoing clinical trials that were registered in the ClinicalTrials.gov website. We used the advanced search option and applied the following inclusion criteria, "SLE," "open studies," "interventional," and "adults 18 years or older." Of 97 eligible studies, 34.0 % were phase 3 or 4, 49.5 % were phase 1, 2 or 2/3 and in 16.5 %, we could not determine the study phase. Most trials were randomized (69.0 %) and 48.4 % were double blinded; 34 % of the trials were placebo controlled, 19.6 % had an active agent comparator and 46.4 % had no comparator. Universities and pharmaceutical industries were the primary sponsors for 45.3 and 39.1 % of the trials, respectively, and government agencies for 10.3 %. Multi-center trials based in the USA (US) accounted for 40.2 % of the trials, 46.4 % were outside of the US and 13.4 % were in the US as well as other countries. The most frequently used endpoint was drug efficacy (30.9 %) followed by disease severity indices (25.7 %), drug safety (14.4 %), remission rates and times to remission (7.2 %), and inflammatory markers and antibody titers (7.2 %). The majority of ongoing clinical trials in SLE are university or industry-funded, randomized phase 1, 2, or 2/3 trials, focused on drug efficacy. Federal funding for trials in SLE within and outside the US remains low. PMID- 24752545 TI - Using the landmark method for creating prediction models in large datasets derived from electronic health records. AB - With the integration of electronic health records (EHRs), health data has become easily accessible and abounded. The EHR has the potential to provide important healthcare information to researchers by creating study cohorts. However, accessing this information comes with three major issues: 1) Predictor variables often change over time, 2) Patients have various lengths of follow up within the EHR, and 3) the size of the EHR data can be computationally challenging. Landmark analyses provide a perfect complement to EHR data and help to alleviate these three issues. We present two examples that utilize patient birthdays as landmark times for creating dynamic datasets for predicting clinical outcomes. The use of landmark times help to solve these three issues by incorporating information that changes over time, by creating unbiased reference points that are not related to a patient's exposure within the EHR, and reducing the size of a dataset compared to true time-varying analysis. These techniques are shown using two example cohort studies from the Cleveland Clinic that utilized 4.5 million and 17,787 unique patients, respectively. PMID- 24752546 TI - IVF cycle cost estimation using Activity Based Costing and Monte Carlo simulation. AB - The Authors present a new methodological approach in stochastic regime to determine the actual costs of an healthcare process. The paper specifically shows the application of the methodology for the determination of the cost of an Assisted reproductive technology (ART) treatment in Italy. The reason of this research comes from the fact that deterministic regime is inadequate to implement an accurate estimate of the cost of this particular treatment. In fact the durations of the different activities involved are unfixed and described by means of frequency distributions. Hence the need to determine in addition to the mean value of the cost, the interval within which it is intended to vary with a known confidence level. Consequently the cost obtained for each type of cycle investigated (in vitro fertilization and embryo transfer with or without intracytoplasmic sperm injection), shows tolerance intervals around the mean value sufficiently restricted as to make the data obtained statistically robust and therefore usable also as reference for any benchmark with other Countries. It should be noted that under a methodological point of view the approach was rigorous. In fact it was used both the technique of Activity Based Costing for determining the cost of individual activities of the process both the Monte Carlo simulation, with control of experimental error, for the construction of the tolerance intervals on the final result. PMID- 24752547 TI - Selective fluorescence sensing of polynitroaromatic explosives using triaminophenylbenzene scaffolds. AB - A supramolecular fluorophore, 1,3,5-tris(4'-aminophenyl)benzene (TAPB), selectively senses polynitroaromatic compounds (PNAC), viz. 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), picric acid (PA), m-dinitrobenzene (m-DNB) and p dinitrobenzene (p-DNB) through donor-acceptor complexation. Steady-state and time resolved fluorescence measurements indicate predominantly static quenching of the TAPB fluorophore with TNT, DNT, m-DNB and p-DNB. In the case of PA, a new emissive band with a marginally longer lifetime emerges due to complex formation with TAPB. The selectivity of sensing action is rationalized through computation of HOMO and LUMO energies for both the fluorophore and the analytes using the M06 2X/6-311+G(d,p) level of theory. Practical utility of the fluorophore has also been demonstrated with TNT and DNT vapour. PMID- 24752548 TI - Hormones and phenotypic plasticity in an ecological context: linking physiological mechanisms to evolutionary processes. AB - Hormones are chemical signaling molecules that regulate patterns of cellular physiology and gene expression underlying phenotypic traits. Hormone-signaling pathways respond to an organism's external environment to mediate developmental stage-specific malleability in phenotypes, so that environmental variation experienced at different stages of development has distinct effects on an organism's phenotype. Studies of hormone-signaling are therefore playing a central role in efforts to understand how plastic phenotypic responses to environmental variation are generated during development. But, how do adaptive, hormonally mediated phenotypes evolve if the individual signaling components (hormones, conversion enzymes, membrane transporters, and receptors) that comprise any hormone-signaling pathway show expressional flexibility in response to environmental variation? What relevance do these components hold as molecular targets for selection to couple or decouple correlated hormonally mediated traits? This article explores how studying the endocrine underpinnings of phenotypic plasticity in an ecologically relevant context can provide insights into these, and other, crucial questions into the role of phenotypic plasticity in evolution, including how plasticity itself evolves. These issues are discussed in the light of investigations into how thyroid hormones mediate morphological plasticity in Death Valley's clade of pupfishes (Cyprinodon spp.). Findings from this work with pupfish illustrate that the study of hormone-signaling from an ecological perspective can reveal how phenotypic plasticity contributes to the generation of phenotypic novelty, as well as how physiological mechanisms developmentally link an organism's phenotype to its environmental experiences. PMID- 24752549 TI - Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. AB - We investigated the hypotriglyceridemic mechanism of action of linalool, an aromatic monoterpene present in teas and fragrant herbs. Reporter gene and time resolved fluorescence resonance energy transfer assays demonstrated that linalool is a direct ligand of PPARalpha. Linalool stimulation reduced cellular lipid accumulation regulating PPARalpha-responsive genes and significantly induced FA oxidation, and its effects were markedly attenuated by silencing PPARalpha expression. In mice, the oral administration of linalool for 3 weeks reduced plasma TG concentrations in Western-diet-fed C57BL/6J mice (31%, P < 0.05) and human apo E2 mice (50%, P < 0.05) and regulated hepatic PPARalpha target genes. However, no such effects were seen in PPARalpha-deficient mice. Transcriptome profiling revealed that linalool stimulation rewired global gene expression in lipid-loaded hepatocytes and that the effects of 1 mM linalool were comparable to those of 0.1 mM fenofibrate. Metabolomic analysis of the mouse plasma revealed that the global metabolite profiles were significantly distinguishable between linalool-fed mice and controls. Notably, the concentrations of saturated FAs were significantly reduced in linalool-fed mice. These findings suggest that the appropriate intake of a natural aromatic compound could exert beneficial metabolic effects by regulating a cellular nutrient sensor. PMID- 24752550 TI - Cyanidin-3-O-beta-glucoside inhibits lipopolysaccharide-induced inflammatory response in mouse mastitis model. AB - Cyanidin-3-O-beta-glucoside (C3G) (CAS number 7084-24-4), a typical anthocyanin pigment that exists in the human diet, has been reported to have anti inflammatory properties. However, the effect of C3G on lipopolysaccharide (LPS) induced mastitis and the molecular mechanisms have not been investigated. In this study, we detected the protective effects of C3G on a LPS-induced mouse mastitis model and investigated the molecular mechanisms in LPS-stimulated mouse mammary epithelial cells (MMECs). Our results showed that C3G could attenuate mammary histopathologic changes and myeloperoxidase activity, and inhibit TNF-alpha, interleukin (IL)-1beta, and IL-6 production caused by LPS. Meanwhile, C3G dose dependently inhibited TNF-alpha and IL-6 in LPS-stimulated MMECs. C3G suppressed LPS-induced nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF3) activation. Furthermore, C3G disrupted the formation of lipid rafts by depleting cholesterol. Moreover, C3G activated liver X receptor (LXR)-ABCG1 dependent cholesterol efflux. Knockdown of LXRalpha abrogated the anti inflammatory effects of C3G. In conclusion, C3G has a protective effect on LPS induced mastitis. The promising anti-inflammatory mechanisms of C3G are associated with upregulation of the LXRalpha-ABCG1 pathway which result in disrupting lipid rafts by depleting cholesterol, thereby suppressing toll-like receptor 4-mediated NF-kappaB and IRF3 signaling pathways induced by LPS. PMID- 24752551 TI - Regioselective synthesis of novel 4,5-diaryl functionalized 3,4-dihydropyrimidine 2(1H)-thiones via a non-Biginelli-type approach and evaluation of their in vitro anticancer activity. AB - An easy and novel approach to synthesize 4,5-diaryl functionalized 3,4 dihydropyrimidine-2(1H)-thiones via addition of aryllithiums to 5-aryl substituted pyrimidine-2(1H)-thiones, which could be regarded as a method complementary to the most widely used Biginelli-type synthesis, is described. In the reaction of aryllithiums with N-(Me)Bn substituted pyrimidine-2(1H)-thiones a high degree of regioselectivity of addition, leading to 4-aryl adducts, was achieved. Selected compounds tested for their in vitro anticancer activity against four human cancer cell lines showed the greatest activity against breast cancer (MCF7). 1-Benzyl-4-(3-hydroxyphenyl)-5-phenyl substituted 3,4 dihydropyrimidine-2(1H)-thione (10g) exhibiting 10-fold more potent activity than the best known monastrol (MON) stands as a promising candidate for further scaffold and asymmetric synthesis. PMID- 24752553 TI - Room-temperature Cu(II)-catalyzed aromatic C-H azidation for the synthesis of ortho-azido anilines with excellent regioselectivity. AB - Cu(ii)-catalyzed aromatic C-H azidation with azido-benziodoxolone under mild conditions has been described. The primary amine exhibits an excellent ortho directing effect, providing ortho-azidated anilines as the sole products. PMID- 24752552 TI - Heritable changes in regional cortical thickness with age. AB - It is now well established that regional indices of brain structure such as cortical thickness, surface area or grey matter volume exhibit spatially variable patterns of heritability. However, a recent study found these patterns to change with age during development, a result supported by gene expression studies. Changes in heritability have not been investigated in adulthood so far and could have important implications in the study of heritability and genetic correlations in the brain as well as in the discovery of specific genes explaining them. Herein, we tested for genotype by age (G *A) interactions, an extension of genotype by environment interactions, through adulthood and healthy aging in 902 subjects from the Genetics of Brain Structure (GOBS) study. A "jackknife" based method for the analysis of stable cortical thickness clusters (JASC) and scale selection is also introduced. Although additive genetic variance remained constant throughout adulthood, we found evidence for incomplete pleiotropy across age in the cortical thickness of paralimbic and parieto-temporal areas. This suggests that different genetic factors account for cortical thickness heritability at different ages in these regions. PMID- 24752554 TI - Antibody directed against human YKL-40 increases tumor volume in a human melanoma xenograft model in scid mice. AB - Induced overexpression of the secretory protein YKL-40 promotes tumor growth in xenograft experiments. We investigated if targeting YKL-40 with a monoclonal antibody could inhibit tumor growth. YKL-40 expressing human melanoma cells (LOX) were injected subcutenously in Balb/c scid mice. Animals were treated with intraperitoneal injections of anti-YKL-40, isoptype control or PBS. Non-YKL-40 expressing human pancreatic carcinoma cell line PaCa 5061 served as additional control. MR imaging was used for evaluation of tumor growth. Two days after the first injections of anti-YKL-40, tumor volume had increased significantly compared with controls, whereas no effects were observed for control tumors from PaCa 5061 cells lacking YKL-40 expression. After 18 days, mean tumor size of the mice receiving repeated anti-YKL-40 injections was 1.82 g, >4 times higher than mean tumor size of the controls (0.42 g). The effect of anti-YKL-40 on the increase of tumor volume started within hours after injection and was dose dependent. Intratumoral hemorrhage was observed in the treated animals. The strong effect on tumor size indicates important roles for YKL-40 in melanoma growth and argues for a careful evaluation of antibody therapy directed against YKL-40. PMID- 24752557 TI - The evaluation of body image in children with type 1 diabetes: A case-control study. AB - This study evaluated the body image perception in children with type 1 diabetes in order to identify symptoms of disordered eating behaviours early. Children with type 1 diabetes and controls showed underestimation and dissatisfaction with body size. The patients, especially girls, were more accurate in their perception of body size than the control group. The study sheds light on some of the underlying factors that may contribute to the development of disordered eating behaviours in adolescence. The causes of the differences of perception of body size are discussed. PMID- 24752558 TI - Mood changes following social dance sessions in people with Parkinson's disease. AB - Dance interventions have physical benefits for the elderly, especially those with Parkinson's disease. This study assessed the psychological benefits of dance. A total of 37 participants, with either Parkinson's disease (n= 22) or age-matched controls (n= 15) completed mood questionnaires before and after a 10-week dance intervention. An overall reduction in total mood disturbance and a specific reduction in anger were observed. In addition, less fatigue was found for those initially scoring higher in depression. This suggests that dance can provide psychological benefits for both people with Parkinson's disease and the elderly, with findings suggesting that this is an avenue to be explored further. PMID- 24752559 TI - Clustering effects on postprandial insulin secretion and sensitivity in response to meals with different fatty acid compositions. AB - Dietary fatty acids play a role in glucose homeostasis. The aim of this study was to assess the individual relationship between dietary saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids with postprandial beta-cell function and insulin sensitivity in subjects with normal and high fasting triglycerides. We assessed postprandial beta-cell function (by the insulinogenic index and the ratio of the insulin to glucose areas under the time concentration curve) and insulin sensitivity (by the oral glucose and the minimal model insulin sensitivity indices) over four nonconsecutive, randomly assigned, high-fat meals containing a panel of SFA (palmitic and stearic acids), MUFA (palmitoleic and oleic acids) and PUFA (linoleic and alpha-linolenic acids) in 14 subjects with normal and in 14 subjects with high fasting triglycerides. The proportions of each fatty acid in the meals and the values for surrogate measures of postprandial beta-cell function and insulin sensitivity were subjected to a Pearson correlation and hierarchical cluster analysis, which revealed two classes of dietary fatty acids for regulating postprandial glucose homeostasis. We successfully discriminated the adverse effects of SFA palmitic acid from the beneficial effects of MUFA oleic acid on postprandial beta-cell function (r >= 0.84 for SFA palmitic acid and r >= -0.71 for MUFA oleic acid; P < 0.05) and insulin sensitivity (r >= -0.92 for SFA palmitic acid and r >= 0.89 for MUFA oleic acid; P < 0.001) both in subjects with normal and high fasting triglycerides. In conclusion, dietary MUFA oleic acid, in contrast to SFA palmitic acid, favours the tuning towards better postprandial glycaemic control in subjects with normal and high fasting triglycerides. PMID- 24752560 TI - The effect of albumin fusion structure on the production and bioactivity of the somatostatin-28 fusion protein in Pichia pastoris. AB - Somatostatin, a natural inhibitor of growth hormone (GH), and its analogs have been used in clinical settings for the treatment of acromegaly, gigantism, thyrotropinoma, and other carcinoid syndromes. However, natural somatostatin is limited for clinical usage because of its short half-life in vivo. Albumin fusion technology was used to construct long-acting fusion proteins and Pichia pastoris was used as an expression system. Three fusion proteins (SS28)(2)-HSA, (SS28)(3) HSA, and HSA-(SS28)(2), were constructed with different fusion copies of somatostatin-28 and fusion orientations. The expression level of (SS28)(3)-HSA was much lower than (SS28)(2)-HSA and HSA-(SS28)(2) due to the additional fusion of the somatostatin-28 molecule. MALDI-TOF mass spectrometry revealed that severe degradation occurred in the fermentation process. Similar to the standard, somatostatin-14, all three fusion proteins were able to inhibit GH secretion in blood, with (SS28)(2)-HSA being the most effective one. A pharmacokinetics study showed that (SS28)(2)-HSA had a prolonged half-life of 2 h. These results showed that increasing the number of small protein copies fused to HSA may not be a suitable method for improving protein bioactivity. PMID- 24752561 TI - Molecular approach for the rapid detection of Bacillus and Pseudomonas genera- dominant antagonistic groups--from diverse ecological niches using colony multiplex PCR. AB - Bacillus and Pseudomonas are the dominant groups of bacteria known for their antagonistic potential against many plant and animal pathogens. Presently, exploration of these genera with antagonistic property for disease management of aquaculture system is gaining more importance to overcome the use of antibiotics and related resistance issues. Rapid screening and identification of these genera from diverse bacterial populations by conventional methods is laborious, cost intensive, and time-consuming. To overcome these limiting factors, in the present study, a colony multiplex PCR (cmPCR) method was developed and evaluated for the rapid detection of Bacillus and Pseudomonas. The technique amplifies the partial 16S rRNA gene of Bacillus and Pseudomonas with a product size of ~1,100 and ~375 bp, respectively, using single forward (BSF2) and two reverse primers (PAGSR and BK1R). Reliability of the cmPCR method was confirmed by screening 472 isolates obtained from ten different eco-stations, of which 133 isolates belonged to Bacillus and 32 to Pseudomonas. The cmPCR method also helped to identify six different Pseudomonas spp. and 14 different Bacillus spp. from environmental samples. Of the total 472 isolates studied, 46 showed antagonistic activity, among which 63 % were Bacillus and 17.4 % were Pseudomonas. Thus, the newly developed molecular approach provides a quick, sensitive, and potential screening tool to detect novel, antagonistically important Bacillus and Pseudomonas genera for their use in aquaculture. Further, it can also act as a taxonomic tool to understand the distribution of these genera from wide ecological niches and their exploitation for diverse biotechnological applications. PMID- 24752562 TI - Operation performance and microbial community dynamics of phosphorus removal sludge with different electron acceptors. AB - Operation performances of phosphorus removal sludge with different electron acceptors in three parallel SBRs were firstly compared in the present study, and the effect of post-aeration on denitrifying phosphorus removal was also studied. Moreover, community dynamics of different phosphorus removal sludge was systematically investigated with high-throughput sequencing for the first time. TP removal rates for nitrate-, nitrite-, and oxygen-based phosphorus removal sludge were 84.8, 78.5, and 87.4 %, with an average effluent TP concentration of 0.758, 0.931, and 0.632 mg/l. The average specific phosphorus release and uptake rates were 20.3, 10.8, and 21.5, and 9.43, 8.68, and 10.8 mgP/(gVSS h), respectively. Moreover, electron utilization efficiency of denitrifying phosphorus removal sludge with nitrate as electron acceptor was higher than nitrite, with P/e(-) were 2.21 and 1.51 mol-P/mol-e(-), respectively. With the assistance of post-aeration for nitrate-based denitrifying phosphorus removal sludge, settling ability could be improved, with SVI decreased from 120 to 80 and 72 ml/g when post-aeration time was 0, 10, and 30 min, respectively. Moreover, further phosphorus removal could be achieved during post-aeration with increased aeration time. However, the anoxic phosphorus uptake was deteriorated, which was likely a result of shifted microbial community structure. Post-aeration of approximately 10 min was proposed for denitrifying phosphorus removal. Nitrate- and nitrite-based denitrifying phosphorus removal sludge exhibited similar community structure. More phosphorus accumulating organisms were enriched under anaerobic-aerobic conditions, while anaerobic-anoxic conditions were favorable for suppressing glycogen-accumulating organisms. Significant differences in pathogenic bacterial community profiles revealed in the current study indicated the potential public health hazards of non-aeration activated sludge system. PMID- 24752563 TI - Characteristics of taste and smell alterations reported by patients after starting treatment for lung cancer. AB - PURPOSE: Taste and smell alterations (TSAs) in patients with lung cancer are poorly understood. This study investigates characteristics of TSAs when most severe, reported by patients after starting treatment for lung cancer. METHODS: Data was collected regarding TSAs, symptoms, food intake and nutritional status through structured interviews using the Taste and Smell Survey, the Patient Generated Subjective Global Assessment and 3-day food diaries. This data derives from a longitudinal project and the interview with each patient when TSAs were most severe was purposefully selected for analysis. RESULTS: Sixty-one of the 89 patients reported TSAs, and the TSAs group were on average younger and more frequently smokers. Thirty-one patients reported symptoms impacting negatively on food intake, with 87 % in the TSAs group and 13 % in the no-TSAs group. Most commonly reported were loss of appetite, nausea and early satiety. Gender differences were seen with more women reporting stronger sensation(s) and more men reporting weaker sensation(s) and other changes. TSAs were described as affecting enjoyment of food and eating. A trend was seen where energy intakes declined with increasing TSAs. Energy intakes in the total study population were below recommended. CONCLUSION: TSAs varied in characteristics and interacted with other symptoms. Gender differences may highlight a need to investigate approaches for identification and management of TSAs in men and women. Patients reported TSAs impacting on food enjoyment, and the hypothesis that patients with higher TSS scores have lower nutritional intakes should be followed up with a larger study in the lung cancer population. PMID- 24752564 TI - Oral evaluation and procedures performed by dentists in patients admitted to the intensive care unit of a cancer center. AB - BACKGROUND: Most of the oral problems affecting patients in the ICU (intensive care unit) are conditions resulting from their general health status/immunosuppression, medications, and trauma due to tracheal intubation. Furthermore, microorganisms present in the oral cavity and oropharynx may be transported into the lungs resulting in pneumonia. PURPOSE: The objectives of this study were to evaluate the oral problems in patients in the ICU of a cancer center and describe the procedures performed by the dentists in such patients. METHODS: The sample consisted of 116 patients and 329 procedures performed in the period between May 2007 and July 2011 at A.C. Camargo Cancer Center. RESULTS: Oral mucositis was the main problem (20.3 %), especially in immunosuppressed patients (p < 0.001). Other most prevalent problems were candidiasis (16.6 %), bacterial biofilm (14.9 %), and xerostomia (7.18 %). The main procedures performed were clinical evaluation and medication prescription corresponding to 35.10 and 27.81 %, respectively. CONCLUSIONS: In conclusion, most of the patients presented oral problems related to side effects of oncological treatment. The dentist's participation in the ICU is important for the prevention, diagnosis, and treatment of oral problems. PMID- 24752565 TI - Perceived information needs and social support of Chinese-Australian breast cancer survivors. AB - BACKGROUND: Both informational and social support are vital components in achieving a high quality of life as a cancer survivor. The study aims to explore the perceptions of information needs and social support among Chinese-Australian breast cancer survivors and how these resources impacted their cancer experience. METHODS: Three focus groups were conducted with 23 Chinese-Australian women diagnosed with breast cancer in their native language (Mandarin and Cantonese). Each interview was translated and transcribed. Content analysis was used to uncover the major themes. RESULT: Themes for information needs were identified as (1) using linguistically appropriate information, (2) the need for culturally sensitive information for the management of expected side effect and promotion of recovery and (3) the need for information on signs and symptoms of recurrence. Families were described as a primary source of multifaceted social support, although it was challenging to obtain. Support groups were also an important support source, but health care professionals were not identified as a source of support. CONCLUSION: Our study has provided practical insight into the information needs and social support of Chinese women with breast cancer. These findings can be used to inform the development of linguistically and culturally tailored support and survivorship interventions for this vulnerable population. PMID- 24752566 TI - A cross-sectional survey of the diagnosis and management of bone metastasis in breast cancer patients in Turkey. AB - PURPOSE: This study aimed to report the practice of managing breast cancer with bone metastasis in Turkey and to determine the adherence to the British Association of Surgical Oncology (BASO) guidelines. METHODS: This multicenter, cross-sectional epidemiological survey was conducted in 38 centers across Turkey. Data from 1,026 breast cancer patients with bone metastases (mean age 54.0 +/- 11.9 years) were analyzed. RESULTS: Over 30 % of patients had a diagnosis of metastatic breast cancer (stage IV) at the time of primary diagnosis. The imaging modalities used for diagnosing bone metastases were bone scintigraphy (57.8 %), radiography (22.8 %), and bone survey (4.4 %). Tumor markers were detected in 94.9 %, and markers of bone metabolism were measured in 90.4 % of patients. A total of 3.5 % of patients underwent surgery for bone metastasis, 26.4 % underwent palliative chemotherapy (most commonly docetaxel + capecitabine), and 56.5 % endured radiotherapy. Most patients (96 %) also received bisphosphonate. Radiography, bone scintigraphy, and CT were the main imaging tools used for postoperative follow-up of bone metastasis. Our results were >95 % in line with the BASO guidelines for the management of bone metastasis, except that interventional procedures, such as biopsy, were applied less frequently in our survey. CONCLUSIONS: The diagnosis and management practices of breast cancer with bone metastasis in Turkey were generally compatible with international guidelines. However, the awareness and knowledge of physicians on the current guidelines should be increased, and equipment for the appropriate interventional procedures should be provided in every clinic to obtain optimal and standard management of bone metastases. PMID- 24752567 TI - An investigation of the role of the adiponectin variable domain on the stability of the collagen-like domain. AB - The chemical synthesis is described of a polypeptide construct possessing both the variable and the collagen-like domain of adiponectin, which can be used as a model system for probing the influence of the variable domain on multimerization of this important circulating hormone. Using a collagen domain repeat peptide unit derived from native adiponectin or a glutamic acid analogue was ineffective due to noncollagenous conformational properties in both cases. However, employing a collagen model peptide and linking this to the variable domain thioester peptide using native chemical ligation proved effective. The 63 residue peptide was characterized by circular dichroism and mass spectrometry which demonstrated that a collagen-like triple-helical structure was preserved. PMID- 24752568 TI - Effectiveness of a teacher-based indicated prevention program for preschool children with externalizing problem behavior. AB - Externalizing behavior is common in preschool children and shows stability over the lifespan implying that strategies for early intervention and prevention are needed. Improving parenting reduces child behavior problems but it is unproven whether the effects transfer to kindergarten. Strategies implemented directly by teachers in the kindergarten may be a promising approach. The effectiveness of the teacher's module of the Prevention Program for Externalizing Problem Behavior (PEP-TE) was investigated in a study using a within-subject control group design. Each of the 144 teachers enrolled identified one child with externalizing problem behavior (aged 3-6 years) and rated that child's behavior problems [broadband externalizing, attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder] as well as their own behavior (attending skills) and burden by the child. Changes in child symptoms and teacher behavior or burden during the 3 month waiting period (control) and 3-month treatment period were compared. Stability of treatment effects at both 3- and 12-months follow-up after treatment was examined. Multilevel modeling analyses showed that, despite a reduction in externalizing behavior and ADHD scores during the waiting period, all child problem behavior scores decreased during the treatment period compared with the waiting period. The teacher's behavior also improved and their burden decreased. These treatment effects were stable during follow-up for the subsample remaining in the kindergarten for up to 1 year. This study shows that a teacher-based intervention alone is associated with improvements in both the externalizing behavior of preschoolers and teacher behavior and burden. Indications of long term stability of effects were found. PMID- 24752569 TI - Sample Size Considerations in Prevention Research Applications of Multilevel Modeling and Structural Equation Modeling. AB - When the goal of prevention research is to capture in statistical models some measure of the dynamic complexity in structures and processes implicated in problem behavior and its prevention, approaches such as multilevel modeling (MLM) and structural equation modeling (SEM) are indicated. Yet the assumptions that must be satisfied if these approaches are to be used responsibly raise concerns regarding their use in prevention research involving smaller samples. In this article, we discuss in nontechnical terms the role of sample size in MLM and SEM and present findings from the latest simulation work on the performance of each approach at sample sizes typical of prevention research. For each statistical approach, we draw from extant simulation studies to establish lower bounds for sample size (e.g., MLM can be applied with as few as ten groups comprising ten members with normally distributed data, restricted maximum likelihood estimation, and a focus on fixed effects; sample sizes as small as N = 50 can produce reliable SEM results with normally distributed data and at least three reliable indicators per factor) and suggest strategies for making the best use of the modeling approach when N is near the lower bound. PMID- 24752570 TI - Neuroanatomical basis for cholinergic modulation of locomotor networks by sacral relay neurons with ascending lumbar projections. AB - Synaptic excitation by sacrocaudal afferent (SCA) input of sacral relay neurons projecting rostrally through the ventral white matter funiculi (VF neurons) is a potent activator of the hindlimb central pattern generators (CPGs) in rodent spinal cords lacking descending supraspinal control. Using electrophysiological recordings from the sacral and lumbar spinal segments, we show that the motor output of the lumbar segments produced by SCA stimulation is enhanced by exposing the sacral segments of the neonatal rat spinal cord to the acetylcholinesterase inhibitor edrophonium (EDR). Histochemical and immunostaining of the sacral cord reveals expression of acetylcholinesterase activity, ability to synthesize acetylcholine, and/or innervation by cholinergic synaptic inputs in significant proportions of fluorescently back-labeled sacral VF neurons. Moreover, the majority of the VF neurons express M2 muscarinic receptors, raising the possibility that the elevated acetylcholine levels resulting from inhibition of acetylcholinesterase act on such receptors. Indeed, sacral application of atropine or the M2 -type receptor antagonist methoctramine was found to reverse the effects of EDR. We suggest that variations in the sacral level of acetylcholine modulate the SCA-induced locomotor rhythm via muscarinic receptor dependent mechanisms and that the modified activity of sacral VF neurons in the presence of an acetylcholinesterase inhibitor can be partially ascribed to the cholinergic components associated with them. Thus, pharmacological manipulations of the sacral cholinergic system may be used to modulate the locomotor-related motor output in the absence of descending supraspinal control. PMID- 24752571 TI - Effects of arm crossing on spatial perspective-taking. AB - Human social interactions often require people to take a different perspective than their own. Although much research has been done on egocentric spatial representation in a solo context, little is known about how space is mapped in relation to other bodies. Here we used a spatial perspective-taking paradigm to investigate whether observing a person holding his arms crossed over the body midline has an impact on the encoding of left/right and front/back spatial relations from that person's perspective. In three experiments, we compared performance in a task in which spatial judgments were made from the perspective of the participant or from that of a co-experimenter. Depending on the experimental condition, the participant's and the co-experimenter's arms were either crossed or not crossed over the midline. Our results showed that crossing the arms had a specific effect on spatial judgments based on a first-person perspective. More specifically, the responses corresponding to the dominant hand side were slower in the crossed than in the uncrossed arms condition. Crucially, a similar effect was also found when the participants adopted the perspective of a person holding his arms crossed, but not when the other person's arms were held in an unusual but uncrossed posture. Taken together these findings indicate that egocentric space and altercentric space are similarly coded in neurocognitive maps structured with respect to specific body segments. PMID- 24752572 TI - Different degree of heart failure. PMID- 24752573 TI - Graphene-based hybrid structures combined with functional materials of ferroelectrics and semiconductors. AB - Fundamental studies and applications of 2-dimensional (2D) graphene may be deepened and broadened via combining graphene sheets with various functional materials, which have been extended from the traditional insulator of SiO2 to a versatile range of dielectrics, semiconductors and metals, as well as organic compounds. Among them, ferroelectric materials have received much attention due to their unique ferroelectric polarization. As a result, many attractive characteristics can be shown in graphene/ferroelectric hybrid systems. On the other hand, graphene can be integrated with conventional semiconductors and some newly-discovered 2D layered materials to form distinct Schottky junctions, yielding fascinating behaviours and exhibiting the potential for various applications in future functional devices. This review article is an attempt to illustrate the most recent progress in the fabrication, operation principle, characterization, and promising applications of graphene-based hybrid structures combined with various functional materials, ranging from ferroelectrics to semiconductors. We focus on mechanically exfoliated and chemical-vapor-deposited graphene sheets integrated in numerous advanced devices. Some typical hybrid structures have been highlighted, aiming at potential applications in non volatile memories, transparent flexible electrodes, solar cells, photodetectors, and so on. PMID- 24752574 TI - Connexins in colorectal cancer pathogenesis. AB - The connexins constitute a family of integral membrane proteins that form channels between adjacent cells. These channels are assembled in plasma membrane domains known as gap junctions and enable cells to directly exchange ions and small molecules. Intercellular communication via gap junctions plays important roles in regulating cell growth and differentiation and in maintaining tissue homeostasis. This type of cell communication is often impaired during cancer development, and several members of the connexin protein family have been shown to act as tumor suppressors. Emerging evidence suggests that the connexin protein family has important roles in colorectal cancer development. In the normal colonic epithelial tissue, three connexin isoforms, connexin 26 (Cx26), Cx32 and Cx43, have been shown to be expressed at the protein level. Colorectal cancer development is associated with loss of connexin expression or relocalization of connexins from the plasma membrane to intracellular compartments. Downregulation of connexins in colorectal carcinomas at the transcriptional level involves cancer-specific promoter hypermethylation. Recent studies suggest that Cx43 may constrain growth of colon cancer cells by interfering with the Wnt/beta-catenin pathway. There is also increasing evidence that the connexins may have potential as prognostic markers in colorectal cancer. This review discusses the role of connexins in colorectal cancer pathogenesis, as well as their potential as prognostic markers and targets in the prevention and treatment of the disease. PMID- 24752575 TI - Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children. AB - Wheezing is one of the most common respiratory symptoms in preschool children under six years old. Currently, no tests are available that predict at early stage who will develop asthma and who will be a transient wheezer. Diagnostic tests of asthma are reliable in adults but the same tests are difficult to use in children, because they are invasive and require active cooperation of the patient. A non-invasive alternative is needed for children. Volatile Organic Compounds (VOCs) excreted in breath could yield such non-invasive and patient friendly diagnostic. The aim of this study was to identify VOCs in the breath of preschool children (inclusion at age 2-4 years) that indicate preclinical asthma. For that purpose we analyzed the total array of exhaled VOCs with Gas Chromatography time of flight Mass Spectrometry of 252 children between 2 and 6 years of age. Breath samples were collected at multiple time points of each child. Each breath-o-gram contained between 300 and 500 VOCs; in total 3256 different compounds were identified across all samples. Using two multivariate methods, Random Forests and dissimilarity Partial Least Squares Discriminant Analysis, we were able to select a set of 17 VOCs which discriminated preschool asthmatic children from transient wheezing children. The correct prediction rate was equal to 80% in an independent test set. These VOCs are related to oxidative stress caused by inflammation in the lungs and consequently lipid peroxidation. In conclusion, we showed that VOCs in the exhaled breath predict the subsequent development of asthma which might guide early treatment. PMID- 24752576 TI - AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells. AB - It is known that aquaporin 5 (AQP5) may represent a novel therapeutic target for treating colon cancer (CC), but whether AQP5 plays a role in the regulation of multidrug resistance (MDR) of colon cancer still remains unclear. In the present study, AQP5 and P-glycoprotein (P-gp), glutathione S-transferase-pi (GST-pi), topoisomerase II (TOPO II), and thymidylate synthase (TS) were checked in CC and adjacent cancer tissues; AQP5-siRNA was applied to silencing AQP5 in CC cell line HT-29, 5-fluorouracil (5-FU), and cisplatin (DDP) added on cells, and sulforhodamine B (SRB) was used; fluorescence real-time quantitative RT-PCR and Western blot were employed to detect changes in multidrug resistance factor and expression mitogen-activated protein kinase (MAPK) signaling pathway in HT-29. The results showed that AQP5 is significantly induced in cancer tissues than that in adjacent cancer tissues. The expression of AQP5 is positively correlated with drug resistance factors, as demonstrated by the increased expressions of P-gp, GST-pi, and TOPO II in CC tissues compared to that in adjacent cancer tissues. Conversely, knockdown of AQP5 in HT-29 human colon cancer cells increased inhibition rates of cancer chemotherapeutic drugs such as 5-FU and DDP. The improved efficacies of chemotherapeutic drugs are associated with the decreased expression of P-gp, GST-pi, and TOPO II. In addition, phosphorylation of p38 MAPK was increased by knockdown of AQP5 in HT-29 cells while phosphorylation and expression of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and Protein kinase B (AKT) were not affected. P38 MAPK inhibitor increased the drug sensitivity of HT-29 cells in a similar way as AQP5-siRNAs do. So these results indicate that AQP5 is associated with drug resistance of colon cancer, and that the AQP5-P38 MAPK pathway may represent a potential drug target to improve drug resistance of colon cancer cells. PMID- 24752577 TI - Expression of BAMBI and its combination with Smad7 correlates with tumor invasion and poor prognosis in gastric cancer. AB - Bone morphogenetic proteins and activin membrane-bound inhibitor (BAMBI) and drosophila mothers against decapentaplegic protein 7 (Smad7) are known to negatively regulate the transforming growth factor-beta (TGF-beta) signaling and play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of BAMBI alone or in combination with Smad7 is associated with the progression of gastric cancer. In the present study, we investigated the expression of BAMBI and Smad7 in 276 cancer tissues and 263 tumor-adjacent tissues from gastric cancer patients, using tissue-microarray based immunohistochemistry. The expression of BAMBI and Smad7 was significantly higher in cancer tissues than in tumor-adjacent tissues. The expression of BAMBI was significantly correlated with increased depth of invasion (P = 0.010), lymphatic invasion (P < 0.001), lymph node metastasis (P = 0.001), TNM stage (P = 0.008), and decreased differentiation (P = 0.046). The expression of BAMBI was associated with a significantly shorter overall survival (OS) (P = 0.006) and disease-free survival (DFS) (P = 0.011). The combined expression of BAMBI and Smad7 was associated with more invasion and metastasis as well as less survival time in gastric cancer patients. The univariate analysis showed that the expression of BAMBI alone or in combination with Smad7 was significantly associated with the OS and DFS. These findings suggest that BAMBI and Smad7 may cooperatively inhibit the TGF-beta signaling, and thus promote the progression of gastric cancer. PMID- 24752578 TI - miR-22 inhibits osteosarcoma cell proliferation and migration by targeting HMGB1 and inhibiting HMGB1-mediated autophagy. AB - Acquisition of drug-resistant phenotypes is often associated with chemotherapy in osteosarcoma. Studies show that high-mobility group box 1 (HMGB1) plays an important role in facilitating autophagy and promotes drug resistance in osteosarcoma cells. In this study, we determined the targeting role of miR-22 to HMGB1 and the regulation of miR-22 on the HMGB1-mediated cell autophagy and on the cell proliferation, migration, and invasion of osteosarcoma cells. Results demonstrated that miR-22 well paired with the 3'-UTR of HMGB1 downregulated the HMGB1 expression and blocked the HMGB1-mediated autophagy during chemotherapy in osteosarcoma cells in vitro. Further study showed that the blockage of autophagy by miR-22 inhibited the osteosarcoma cell proliferation, migration, and invasion. In summary, this study implied the negative regulation of miR-22 on the HMGB1 mediated autophagy in osteosarcoma cells. PMID- 24752579 TI - Acceptance of wife beating and its association with physical violence towards women in Nepal: a cross-sectional study using couple's data. AB - BACKGROUND: Intimate partner violence (IPV) is a serious global public health issue. Acceptance of wife beating is known to be associated with IPV, but few studies have analysed the acceptance of wife beating from both women and men's points of view. The objective of this study was to examine whether acceptance of wife beating among couples is associated with lifetime and past one-year physical IPV perpetration towards wives in Nepal. METHODS: A cross-sectional study was conducted from August to September 2011, with 717 randomly selected couples with wives aged 18 to 49 years old from the Kirtipur municipality and Bhaktapur district of Nepal. Wives' and husbands' acceptance of wife beating was measured by six scale items, while physical IPV experience among wives was measured by seven physical assault scale items. To assess the association between acceptance of wife beating and physical IPV, multiple logistic regression analysis was used. RESULTS: Nearly 30% of wives and husbands indicated that beating of wives is acceptable under certain circumstances. Statistically, no significant difference was detected between wives' and husbands' level of acceptance of wife beating. However, husbands' acceptance of wife beating was positively associated with lifetime and past one-year perpetration of physical IPV, whereas wives' acceptance of wife beating was neither associated with lifetime nor past one-year victimization of physical IPV. The positive association for husbands remained even after controlling for their partner's factors. CONCLUSIONS: Acceptance of wife beating is an important risk factor, which must be considered to prevent perpetration of physical IPV towards wives in Nepal. Future studies should include men to better understand the structure and dynamics of IPV in Nepal, and prevention programs should also target men to change their attitudes or to identify which couples are at more risk of physical IPV occurring toward wives. PMID- 24752580 TI - 14-Year risk of all-cause mortality according to hypoglycaemic drug exposure in a general population. AB - PURPOSE: Guidelines for management of patients with type 2 diabetes mellitus recommend the use of hypoglycaemic drugs when lifestyle interventions remain insufficient for glycaemic control. Recent trials have provided worrying safety data on certain hypoglycaemic drugs. The aim of this study was to assess 14-year risk of all-cause mortality according to hypoglycaemic drug exposure at baseline, in a general population. METHODS: Our analysis was based on the observational Third French MONICA survey on cardiovascular risk factors (1995-1997). Vital status was obtained 14 years after inclusion, and assessment of determinants of mortality was based on multivariable Cox modelling. RESULTS: There were 3336 participants and 248 deaths over the 14-year period. At baseline, there were 3162 (95%) non-diabetic, 46 (1%) untreated type 2 diabetic and 128 (4%) type 2 diabetic subjects with hypoglycaemic drug treatment (metformin alone (31%), sulfonylureas alone or in combination (49%), insulin alone or in combination (10%), or other treatments (9%)). After adjustment for duration of diabetes, history of diabetes complications, area of residence (centre), age, gender, educational level, alcohol consumption, smoking, blood pressure, LDL and HDL cholesterol, which all were significant and independent determinants of mortality, the hazard ratio for all-cause mortality was 3.22 [95% confidence interval: 0.87-11.9] for untreated diabetic subjects, 2.28 [0.98-5.26] for diabetics treated with metformin alone, 1.70 [0.92-3.16] for diabetics with sulfonylureas and 4.92 [1.70-14.3] for diabetic with insulin versus non-diabetic subjects. CONCLUSIONS: Our results support the conclusion that until more evidence is provided from randomized trials, a prudent approach should be to restrain use of insulin to situations in which combinations of non-insulin agents have failed to appropriately achieve glycemic control, as it is recommended in the current guidelines for the management of type 2 diabetes. PMID- 24752582 TI - 27th International Mammalian Genome Conference meeting report. PMID- 24752581 TI - Toward the positional cloning of qBlsr5a, a QTL underlying resistance to bacterial leaf streak, using overlapping sub-CSSLs in rice. AB - Bacterial leaf steak (BLS) is one of the most destructive diseases in rice. Studies have shown that BLS resistance in rice is quantitatively inherited, controlled by multiple quantitative trait loci (QTLs). A QTL with relatively large effect, qBlsr5a, was previously mapped in a region of ~ 380 kb on chromosome 5. To fine map qBlsr5a further, a set of overlapping sub-chromosome segment substitution lines (sub-CSSLs) were developed from a large secondary F2 population (containing more than 7000 plants), in which only the chromosomal region harboring qBlsr5a was segregated. By genotyping the sub-CSSLs with molecular markers covering the target region and phenotyping the sub-CSSLs with artificial inoculation, qBlsr5a was delimited to a 30.0-kb interval, in which only three genes were predicted. qRT-PCR analysis indicated that the three putative genes did not show significant response to the infection of BLS pathogen in both resistant and susceptible parental lines. However, two nucleotide substitutions were found in the coding sequence of gene LOC_Os05g01710, which encodes the gamma chain of transcription initiation factor IIA (TFIIAgamma). The nucleotide substitutions resulted in a change of the 39th amino acid from valine (in the susceptible parent) to glutamic acid (in the resistant parent). Interestingly, the resistant parent allele of LOC_Os05g01710 is identical to xa5, a major gene resistant to bacterial leaf blight (another bacterial disease of rice). These results suggest that LOC_Os05g01710 is very possibly the candidate gene of qBlsr5a. PMID- 24752583 TI - The genetic basis of obesity-associated type 2 diabetes (diabesity) in polygenic mouse models. AB - Obesity-associated diabetes ("diabesity") in mouse strains is characterized by severe insulin resistance, hyperglycaemia and progressive failure, and loss of beta cells. This condition is observed in inbred obese mouse strains such as the New Zealand Obese (NZO/HlLt and NZO/HlBomDife) or the TALLYHO/JngJ mouse. In lean strains such as C57BLKS/J, BTBR T+tf/J or DBA/2 J carrying diabetes susceptibility genes ("diabetes susceptible" background), it can be induced by introgression of the obesity-causing mutations Lep (ob) or Lepr (db). Outcross populations of these models have been employed in the genome-wide search for mouse diabetes genes, and have led to positional cloning of the strong candidates Pctp, Tbc1d1, Zfp69, and Ifi202b (NZO-derived obesity) and Sorcs1, Lisch-like, Tomosyn-2, App, Tsc2, and Ube2l6 (obesity caused by the ob or db mutation). Some of these genes have been shown to play a role in the regulation of the human glucose or lipid metabolism. Thus, dissection of the genetic basis of obesity and diabetes in mouse models can identify regulatory mechanisms that are relevant for the human disease. PMID- 24752584 TI - Electrochemical and thermodynamic properties of Ln(III) (Ln = Eu, Sm, Dy, Nd) in 1-butyl-3-methylimidazolium bromide ionic liquid. AB - The electrochemical behavior and thermodynamic properties of Ln(III) (Ln = Eu, Sm, Dy, Nd) were studied in 1-butyl-3-methylimidazolium bromide ionic liquid (BmimBr) at a glassy carbon (GC) electrode in the range of 293-338 K. The electrode reaction of Eu(III) was found to be quasi-reversible by the cyclic voltammetry, the reactions of the other three lanthanide ions were regarded as irreversible systems. An increase of the current intensity was obtained with the temperature increase. At 293 K, the cathodic peak potentials of -0.893 V (Eu(III)), -0.596 V (Sm(III)), -0.637 V (Dy(III)) and -0.641 V (Nd(III)) were found, respectively, to be assigned to the reduction of Ln(III) to Ln(II). The diffusion coefficients (Do), the transfer coefficients (alpha) of Ln(III) (Ln = Eu, Sm, Dy, Nd) and the charge transfer rate constants (ks) of Eu(III) were estimated. The apparent standard potential (E0*) and the thermodynamic properties of the reduction of Eu(III) to Eu(II) were also investigated. PMID- 24752585 TI - Shock, stress or signal? Implications of freshwater flows for a top-level estuarine predator. AB - Physicochemical variability in estuarine systems plays an important role in estuarine processes and in the lifecycles of estuarine organisms. In particular, seasonality of freshwater inflow to estuaries may be important in various aspects of fish lifecycles. This study aimed to further understand these relationships by studying the movements of a top-level estuarine predator in response to physicochemical variability in a large, temperate south-east Australian estuary (Shoalhaven River). Mulloway (Argyrosomus japonicus, 47-89 cm total length) were surgically implanted with acoustic transmitters, and their movements and migrations monitored over two years via fixed-position VR2W acoustic receivers configured in a linear array along the length of the estuary. The study period included a high degree of abiotic variability, with multiple pulses (exponentially high flows over a short period of time) in fresh water to the estuary, as well as broader seasonal variation in flow, temperature and conductivity. The relative deviation of fish from their modal location in the estuary was affected primarily by changes in conductivity, and smaller fish (n = 4) tended to deviate much further downstream from their modal position in the estuary than larger fish (n = 8). High-flow events which coincided with warmer temperatures tended to drive mature fish down the estuary and potentially provided a spawning signal to stimulate aggregation of adults near the estuary mouth; however, this relationship requires further investigation. These findings indicate that pulse and press effects of freshwater inflow and associated physicochemical variability play a role in the movements of mulloway, and that seasonality of large freshwater flows may be important in spawning. The possible implications of river regulation and the extraction of freshwater for consumptive uses on estuarine fishes are discussed. PMID- 24752586 TI - Late miocene-pliocene paleoclimatic evolution documented by terrestrial mollusk populations in the western Chinese Loess Plateau. AB - The Neogene eolian deposits in the Chinese Loess Plateau (CLP) are one of the most useful continental deposits for understanding climatic changes. To decipher Late Neogene paleoclimatic changes in the CLP, we present a terrestrial mollusk record spanning the time interval between 7.1 and 3.5 Ma from the western CLP. The results indicate four stages of paleoclimatic evolution: From 7.1 to 6.2 Ma, cold and dry climatic conditions prevailed as evidenced by high values of the total number of cold-aridiphilous (CA) mollusk species and by low values of all of the thermo-humidiphilous (TH) mollusk indices. From 6.2 to 5.4 Ma, the climate remained cold and dry but was not quite as dry as during the preceding phase, as indicated by the dominance of CA mollusks and more TH species and individuals. From 5.4 to 4.4 Ma, a warm and moist climate prevailed, as indicated by high values of the TH species and individuals and by the sparsity of CA species and individuals. From 4.4 to 3.5 Ma, all of the CA indices increased significantly and maintained high values; all of the TH indices exhibit high values from 4.4 to 4.0 Ma, an abrupt decrease from 4.0 Ma and a further increase from 3.7 Ma. The CA species of Cathaica pulveraticula, Cathaica schensiensis, and Pupopsis retrodens are only identified in this stage, indicating that the CA species were diversified and that the climate was becoming drier. Moreover, the CA mollusk group exhibits considerable diversity from 7.1 to 5.4 Ma when a cold, dry climate prevailed; whereas the diversity of the TH group was high during the relatively warm, wet interval from 5.4 to 4.4 Ma. This indicates that variations in the diversity of the CA and TH mollusk groups were closely related to climatic changes during the Late Miocene to Pliocene. PMID- 24752587 TI - Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. AB - Histamine is a potent mediator of inflammation and a regulator of innate and adaptive immune responses. However, the influence of histamine on microglia, the resident immune cells in the brain, remains uninvestigated. In the present study, we found that microglia can constitutively express all four histamine receptors (H1R, H2R, H3R, and H4R), and the expression of H1R and H4R can be selectively upregulated in primary cultured microglia in a dose-dependent manner by histamine. Histamine can also dose-dependently stimulate microglia activation and subsequently production of proinflammatory factors tumor necrosis factor (TNF) alpha and interleukin-6 (IL-6). The antagonists of H1R and H4R but not H2R and H3R reduced histamine-induced TNF-alpha and IL-6 production, MAPK and PI3K/AKT pathway activation, and mitochondrial membrane potential loss in microglia, suggesting that the actions of histamine are via H1R and H4R. On the other hand, inhibitors of JNK, p38, or PI3K suppressed histamine-induced TNF-alpha and IL-6 release from microglia. Histamine also activated NF-kappa B and ammonium pyrrolidinedithiocarbamate, an inhibitor of NF-kappa B, and reduced histamine induced TNF-alpha and IL-6 release. In summary, the present study identifies the expression of histamine receptors on microglia. We also demonstrate that histamine induced TNF-alpha and IL-6 release from activated microglia via H1R and H4R-MAPK and PI3K/AKT-NF-kappa B signaling pathway, which will deepen the understanding of microglia-mediated neuroinflammatory symptoms of chronic neurodegenerative disease. PMID- 24752588 TI - Proteasome inhibition-induced downregulation of Akt/GSK-3beta pathway contributes to abnormality of tau in hippocampal slice. AB - Proteasome inhibition can induce abnormal accumulation and phosphorylation of microtubule-associated protein tau. The major function of tau protein is to promote microtubules assembly and stabilization, and abnormal tau protein would disturb its microtubule-binding function. In this study, proteasome inhibitor MG132 was used to treat hippocampal slices to explore the role and mechanism of Akt/glycogen synthase kinase-3beta (GSK-3beta) in proteasome inhibition-induced tau abnormality. During the culture period, we measure the lactate dehydrogenase (LDH) content to assay the viability of hippocampal slices. Following 2.5 and 5 MUM MG132 treatment for 6 h, we detected the expression, phosphorylation modification, and microtubule-binding function of tau protein of slices. We also analyzed the changed activities of glycogen synthase kinase-3beta (GSK-3beta) and protein kinase B (PKB/Akt) and the level of heat shock protein 90 (Hsp90) in the process. In addition, co-immunoprecipitation was used to investigate the interaction between Akt and Hsp90, Akt and protein phosphatase-2A (PP2A) in the MG132-treated organotypic hippocampal slices. Our results indicated that proteasome inhibition led to degradation obstacles and abnormal phosphorylation of tau protein. The downregulated Akt/GSK-3beta signaling pathway might be responsible for the abnormal phosphorylation of tau protein at multiple sites which further reduced the microtubule-binding function of tau protein. Furthermore, proteasome inhibition decreased the binding capacity of Akt-Hsp90 while increased the Akt-PP2A binding ability which mediated Akt inactivity. This current study establishes a hippocampal slice model targeting Akt/GSK-3beta signaling pathway to explore the pivotal role of proteasome inhibition in tau pathology. PMID- 24752589 TI - Beyond the glutamine expansion: influence of posttranslational modifications of ataxin-1 in the pathogenesis of spinocerebellar ataxia type 1. AB - Posttranslational modifications are crucial mechanisms that modulate various cellular signaling pathways, and their dysregulation is associated with many human diseases. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease characterized by progressive ataxia, mild cognitive impairments, difficulty with speaking and swallowing, and respiratory failure. It is caused by the expansion of an unstable CAG trinucleotide repeat encoding a glutamine tract in Ataxin-1 (ATXN1). Although the expansion of the polyglutamine tract is the key determinant of the disease, protein domains outside of the polyglutamine tract and posttranslational modifications of ATXN1 significantly alter the neurotoxicity of SCA1. ATXN1 undergoes several posttranslational modifications, including phosphorylation, ubiquitination, sumoylation, and transglutamination. Such modifications can alter the stability of ATXN1 or its activity in the regulation of target gene expression and therefore contribute to SCA1 toxicity. This review outlines different types of posttranslational modifications in ATXN1 and discusses their potential regulatory mechanisms and effects on SCA1 pathogenesis. Finally, the manipulation of posttranslational modifications as a potential therapeutic approach will be discussed. PMID- 24752590 TI - Aberrant expression of RCAN1 in Alzheimer's pathogenesis: a new molecular mechanism and a novel drug target. AB - AD, a devastating neurodegenerative disorder, is the most common cause of dementia in the elderly. Patients with AD are characterized by three hallmarks of neuropathology including neuritic plaque deposition, neurofibrillary tangle formation, and neuronal loss. Growing evidences indicate that dysregulation of regulator of calcineurin 1 (RCAN1) plays an important role in the pathogenesis of AD. Aberrant RCAN1 expression facilitates neuronal apoptosis and Tau hyperphosphorylation, leading to neuronal loss and neurofibrillary tangle formation. This review aims to describe the recent advances of the regulation of RCAN1 expression and its physiological functions. Moreover, the AD risk factors induced RCAN1 dysregulation and its role in promoting neuronal loss, synaptic impairments and neurofibrillary tangle formation are summarized. Furthermore, we provide an outlook into the effects of RCAN1 dysregulation on APP processing, Abeta generation and neuritic plaque formation, and the possible underlying mechanisms, as well as the potential of targeting RCAN1 as a new therapeutic approach. PMID- 24752593 TI - Adolescent MDMA exposure diminishes the physiological and neurotoxic consequences of an MDMA binge in female rats. AB - Intermittent MDMA pretreatment blocked the reductions in serotonin transporter (SERT) binding induced by an MDMA binge in a prior study in adolescent male rats. The objective of this investigation was to determine if the physiological, behavioral, and neurochemical responses to MDMA are sexually dimorphic. Female Sprague-Dawley rats received MDMA (10 mg/kg * 2) or Saline on every fifth day from postnatal day (PD) 35-60 and an MDMA binge (5 mg/kg * 4) on PD 67. The MDMA binge induced a pronounced temperature dysregulation in MDMA-naive, but not MDMA pretreated, groups. Similarly, MDMA-pretreated animals were resistant to the binge-induced SERT reductions, especially in the hippocampus. Motor activity at PD 68 was not reduced by the binge, unlike the responses found in males. These results show that female rats differ from males in their responses to an MDMA binge but are similar with respect to preconditioning from prior MDMA exposure. PMID- 24752594 TI - Assessment of quadriceps muscle inactivation with a new electrical stimulation paradigm. AB - INTRODUCTION: In this study we evaluated the validity of garment-based quadriceps stimulation (GQS) for assessment of muscle inactivation in comparison with femoral nerve stimulation (FNS). METHODS: Inactivation estimates (superimposed doublet torque), self-reported discomfort, and twitch and doublet contractile properties were compared between GQS and FNS in 15 healthy subjects. RESULTS: Superimposed doublet torque was significantly lower for GQS than for FNS at 20% and 40% maximum voluntary contraction (MVC) (P < 0.01), but not at 60%, 80%, and 100% MVC. Discomfort scores were systematically lower for GQS than for FNS (P < 0.05). Resting twitch and doublet peak torque were lower for GQS, and time to peak torque was shorter for GQS than for FNS (P < 0.01). CONCLUSIONS: GQS can be used with confidence for straightforward evaluation of quadriceps muscle inactivation, whereas its validity for assessment of contractile properties remains to be determined. PMID- 24752592 TI - Peripheral nerve injury modulates neurotrophin signaling in the peripheral and central nervous system. AB - Peripheral nerve injury disrupts the normal functions of sensory and motor neurons by damaging the integrity of axons and Schwann cells. In contrast to the central nervous system, the peripheral nervous system possesses a considerable capacity for regrowth, but regeneration is far from complete and functional recovery rarely returns to pre-injury levels. During development, the peripheral nervous system strongly depends upon trophic stimulation for neuronal differentiation, growth and maturation. The perhaps most important group of trophic substances in this context is the neurotrophins (NGF, BDNF, NT-3 and NT 4/5), which signal in a complex spatial and timely manner via the two structurally unrelated p75(NTR) and tropomyosin receptor kinase (TrkA, Trk-B and Trk-C) receptors. Damage to the adult peripheral nerves induces cellular mechanisms resembling those active during development, resulting in a rapid and robust increase in the synthesis of neurotrophins in neurons and Schwann cells, guiding and supporting regeneration. Furthermore, the injury induces neurotrophin mediated changes in the dorsal root ganglia and in the spinal cord, which affect the modulation of afferent sensory signaling and eventually may contribute to the development of neuropathic pain. The focus of this review is on the expression patterns of neurotrophins and their receptors in neurons and glial cells of the peripheral nervous system and the spinal cord. Furthermore, injury-induced changes of expression patterns and the functional consequences in relation to axonal growth and remyelination as well as to neuropathic pain development will be reviewed. PMID- 24752597 TI - Direct olefination of benzaldehydes into 1,3-diarylpropenes via a copper catalyzed heterodomino Knoevenagel-decarboxylation-Csp(3)-H activation sequence. AB - Copper-catalyzed direct olefination of benzaldehydes into 1,3-diarylpropenes by a novel domino Knoevenagel-decarboxylation-Csp(3)-H activation sequence is reported. This method provides a concise and effective route toward the synthesis of unsymmetrical 1,3-diarylpropene derivatives. PMID- 24752595 TI - Role of membrane microdomains in compartmentation of cAMP signaling. AB - Spatially restricting cAMP production to discrete subcellular locations permits selective regulation of specific functional responses. But exactly where and how cAMP signaling is confined is not fully understood. Different receptors and adenylyl cyclase isoforms responsible for cAMP production are not uniformly distributed between lipid raft and non-lipid raft domains of the plasma membrane. We sought to determine the role that these membrane domains play in organizing cAMP responses in HEK293 cells. The freely diffusible FRET-based biosensor Epac2 camps was used to measure global cAMP responses, while versions of the probe targeted to lipid raft (Epac2-MyrPalm) and non-raft (Epac2-CAAX) domains were used to monitor local cAMP production near the plasma membrane. Disruption of lipid rafts by cholesterol depletion selectively altered cAMP responses produced by raft-associated receptors. The results indicate that receptors associated with lipid raft as well as non-lipid raft domains can contribute to global cAMP responses. In addition, basal cAMP activity was found to be significantly higher in non-raft domains. This was supported by the fact that pharmacologic inhibition of adenylyl cyclase activity reduced basal cAMP activity detected by Epac2-CAAX but not Epac2-MyrPalm or Epac2-camps. Responses detected by Epac2-CAAX were also more sensitive to direct stimulation of adenylyl cyclase activity, but less sensitive to inhibition of phosphodiesterase activity. Quantitative modeling was used to demonstrate that differences in adenylyl cyclase and phosphodiesterase activities are necessary but not sufficient to explain compartmentation of cAMP associated with different microdomains of the plasma membrane. PMID- 24752596 TI - Effect of propofol on prostaglandin E2 production and prostaglandin synthase-2 and cyclooxygenase-2 expressions in amniotic membrane cells. AB - PURPOSE: Surgery during pregnancy can be a cause of preterm labor or birth, possibly resulting from anesthetic agents or direct effects of surgery. This study was aimed to investigate the effect of propofol on uterine contractility by examining prostaglandin E2 (PGE2) production and the expression of PGE synthase 2 (PGES2) and cyclooxygenase-2 (COX-2) in amniotic membrane cells. METHODS: Amniotic membranes were collected from healthy full-term women who underwent cesarean section at 37-40 weeks of gestation. The amniotic cells were cultured in alpha-modified-Eagle's medium with 10% fetal bovine serum for 24 h at 5% CO2 in a 37 degrees C incubator. Then, various doses of propofol (0.01-10 MUg/ml) were used for treatment for 3 h. PGE2 concentrations in conditioned media were evaluated using ELISA. PGES2 and COX-2 expression were examined using RT-PCR and Western blot. Cell viability and apoptosis were examined by MTT, ATP assays, and the TUNEL method. RESULTS: PGE2 production significantly decreased at 0.1 and 1.0 MUg/ml propofol concentrations compared to controls. COX-2 and PGES2 mRNA expression was decreased in a dose-dependent manner with a significant difference at 0.1 MUg/ml propofol compared to controls. The protein expression of COX-2 showed a similar result to mRNA expression, but protein expression of PGES2 was not significantly decreased. No effect of propofol was found in cell viability. CONCLUSIONS: This study showed that propofol reduced the production of PGE2 and the expression of COX-2 and PGES2 without affecting cell viability. PMID- 24752591 TI - The glutathione system: a new drug target in neuroimmune disorders. AB - Glutathione (GSH) has a crucial role in cellular signaling and antioxidant defenses either by reacting directly with reactive oxygen or nitrogen species or by acting as an essential cofactor for GSH S-transferases and glutathione peroxidases. GSH acting in concert with its dependent enzymes, known as the glutathione system, is responsible for the detoxification of reactive oxygen and nitrogen species (ROS/RNS) and electrophiles produced by xenobiotics. Adequate levels of GSH are essential for the optimal functioning of the immune system in general and T cell activation and differentiation in particular. GSH is a ubiquitous regulator of the cell cycle per se. GSH also has crucial functions in the brain as an antioxidant, neuromodulator, neurotransmitter, and enabler of neuron survival. Depletion of GSH leads to exacerbation of damage by oxidative and nitrosative stress; hypernitrosylation; increased levels of proinflammatory mediators and inflammatory potential; dysfunctions of intracellular signaling networks, e.g., p53, nuclear factor-kappaB, and Janus kinases; decreased cell proliferation and DNA synthesis; inactivation of complex I of the electron transport chain; activation of cytochrome c and the apoptotic machinery; blockade of the methionine cycle; and compromised epigenetic regulation of gene expression. As such, GSH depletion has marked consequences for the homeostatic control of the immune system, oxidative and nitrosative stress (O&NS) pathways, regulation of energy production, and mitochondrial survival as well. GSH depletion and concomitant increase in O&NS and mitochondrial dysfunctions play a role in the pathophysiology of diverse neuroimmune disorders, including depression, myalgic encephalomyelitis/chronic fatigue syndrome and Parkinson's disease, suggesting that depleted GSH is an integral part of these diseases. Therapeutical interventions that aim to increase GSH concentrations in vivo include N-acetyl cysteine; Nrf-2 activation via hyperbaric oxygen therapy; dimethyl fumarate; phytochemicals, including curcumin, resveratrol, and cinnamon; and folate supplementation. PMID- 24752598 TI - Engineering of chromosomal wax ester synthase integrated Saccharomyces cerevisiae mutants for improved biosynthesis of fatty acid ethyl esters. AB - In recent years, significant advances have been made to engineer robust microbes for overproducing biochemical products from renewable resources. These accomplishments have to a large extend been based on plasmid based methods. However, plasmid maintenance may cause a metabolic burden on the host cell and plasmid-based overexpression of genes can result in genetically unstable strains, which contributes to loss in productivity. Here, a chromosome engineering method based on delta integration was applied in Saccharomyces cerevisiae for the production of fatty acid ethyl esters (FAEEs), which can be directly used as biodiesel and would be a possible substitute for conventional petroleum-based diesel. An integration construct was designed and integrated into chromosomal delta sequences by repetitive transformation, which resulted in 1-6 copies of the integration construct per genome. The corresponding FAEE production increased up to 34 mg/L, which is an about sixfold increase compared to the equivalent plasmid based producer. The integrated cassette in the yeast genome was stably maintained in nonselective medium after deletion of RAD52 which is essential for efficient homologous recombination. To obtain a further increase of FAEE production, genes encoding endogenous acyl-CoA binding protein (ACB1) and a bacterial NADP(+) dependent glyceraldehyde-3-phosphate dehydrogenase (gapN) were overexpressed in the final integration strain, which resulted in another 40% percent increase in FAEE production. Our integration strategy enables easy engineering of strains with adjustable gene copy numbers integrated into the genome and this allows for an easy evaluation of the effect of the gene copy number on pathway flux. It therefore represents a valuable tool for introducing and expressing a heterologous pathway in yeast. PMID- 24752599 TI - Vitamin D supplementation enhances the fixation of titanium implants in chronic kidney disease mice. AB - Vitamin D (Vit D) deficiency is a common condition in chronic kidney disease (CKD) patients that negatively affects bone regeneration and fracture healing. Previous study has shown that timely healing of titanium implants is impaired in CKD. This study aimed to investigate the effect of Vit D supplementation on implant osseointegration in CKD mice. Uremia was induced by 5/6 nephrectomy in C57BL mice. Eight weeks after the second renal surgery, animals were given 1,25(OH)2D3 three times a week intraperitoneally for four weeks. Experimental titanium implants were inserted into the distal end of femurs two weeks later. Serum measurements confirmed decreased 1,25(OH)2D levels in CKD mice, which could be successfully corrected by Vit D injections. Moreover, the hyperparathyroidism observed in CKD mice was also corrected. X-ray examination and histological sections showed successful osseointegration in these mice. Histomorphometrical analysis revealed that the bone-implant contact (BIC) ratio and bone volume (BV/TV) around the implant were significantly increased in the Vit D supplementation group. In addition, resistance of the implant, as measured by a push-in method, was significantly improved compared to that in the vehicle group. These results demonstrate that Vit D supplementation is an effective approach to improve the fixation of titanium implants in CKD. PMID- 24752600 TI - Cognitive decline in patients with Alzheimer's disease and its related factors in a memory clinic setting, Shanghai, China. AB - OBJECTIVES: Progressive cognitive decline is a characteristic hallmark of AD. It is important to identify prognostic markers to improve patient care and long-term planning. We aimed to identify the characteristics of disease progression in AD patients, focusing on cognitive decline and its related factors. METHODS: Clinically diagnosed AD patients in a memory clinic were followed. The mini mental state examination (MMSE) and a battery of other neuropsychological tests were performed to assess the rate of cognitive decline and to analyze the related factors. RESULTS: A total of 165 AD patients were analyzed for cognitive changes. The MMSE scores declined at a rate of 1.52 points per year. Most neuropsychological test scores deteriorated significantly over time. Younger and early-onset AD patients deteriorated more rapidly than older and late-onset patients in global cognition and executive function. Men declined faster in memory but slower in attention than women. Higher education was associated with more rapid deterioration in visuo-spatial ability. Family history, hypertension and cerebral vascular disease were also associated with disease progression. CONCLUSION: Attention, executive and visuo-spatial functions deteriorate at faster rates than other cognitive functions in AD patients. Age and age at onset were the main factors that associated with deterioration. PMID- 24752602 TI - Pinacyanol chloride forms mesoscopic H- and J-aggregates in aqueous solution--a spectroscopic and cryo-transmission electron microscopy study. AB - The aggregation behaviour of the cationic pinacyanol chloride in aqueous solution is investigated using absorption and linear dichroism spectroscopies, optical microscopy and cryogenic transmission electron microscopy (cryo-TEM). The investigations are focused on solutions in a concentration range from 50 MUM up to 1 mM. At a concentration of 0.7 mM H-aggregates are detected that are characterized by a broad absorption band centred at ~511 nm. The aggregates possess a tubular architecture with a single-layer wall thickness of ~2.5 nm and an outer diameter of ~6.5 nm. Linear dichroism spectroscopy indicates that the molecules are packed with their long axis parallel to the tube axis. These H aggregates are not stable, but transform into J-aggregates on the time scale of weeks. The kinetics of J-aggregation depends on the dye concentration and the route of sample preparation, but can also be enhanced by shear stress. J aggregates possess a split absorption spectrum composed of two longitudinally polarized J-bands and one H-band that is polarized perpendicular to the aggregate axis. The J-aggregates are ~9 nm wide and several micrometer long fibrils consisting of stacked pairs of ribbons with a dumbbell-shaped density cross section. Upon aging these ribbons laterally stack face-to-face to form tape-like aggregates. PMID- 24752601 TI - Reactive oxygen species generation is essential for cisplatin-induced accelerated senescence in hepatocellular carcinoma. AB - Accelerated senescence is important because this process is involved in tumor suppression and has been induced by many chemotherapeutic agents. The platinum based chemotherapeutic agent cisplatin displays a wide range of antitumor activities. However, the molecular mechanism of cisplatin-induced accelerated senescence in hepatocellular carcinoma (HCC) remains unclear. In the present study, the growth inhibitory effect of cisplatin on HepG2 and SMMC-7721 cells was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cellular senescence was then assessed by beta-galactosidase assay. Senescence related factors, including p53, p21, and p16, were evaluated by quantitative reverse transcription-polymerase chain reaction. Reactive oxygen species (ROS) was analyzed by flow cytometry. Our results revealed that cisplatin reduced the proliferation of HepG2 and SMMC-7721 cells in a dose- and time-dependent manner. Senescent phenotype observed in cisplatintreated hepatoma cells was dependent on p53 and p21 activation but not on p16 activation. Furthermore, cisplatininduced accelerated senescence depended on intracellular ROS generation. The ROS scavenger N-acetyl-L-cysteine also significantly suppressed the cisplatin-induced senescence of HepG2 and SMMC-7721 cells. In conclusion, our results revealed a functional link between intracellular ROS generation and cisplatin-induced accelerated senescence, and this link may be used as a potential target of HCC. PMID- 24752603 TI - Anthropometric factors and risk of molecular breast cancer subtypes among postmenopausal Norwegian women. AB - Adult height and body weight are positively associated with breast cancer risk after menopause, but few studies have investigated these factors according to molecular breast cancer subtype. A total of 18,562 postmenopausal Norwegian women who were born between 1886 and 1928 were followed up for breast cancer incidence from the time (between 1963 and 1975) height and weight were measured until 2008. Immunohistochemical and in situ hybridization techniques were used to subtype 734 incident breast cancer cases into Luminal A, Luminal B [human epidermal growth factor receptor 2 (HER2-)], Luminal B (HER2+), HER2 subtype, basal-like phenotype (BP) and five-negative phenotype (5NP). We used Cox regression analysis to assess adult height and body mass index (BMI) in relation to risk of these subtypes. We found a positive association of height with risk of Luminal A breast cancer (ptrend , 0.004), but there was no clear association of height with any other subtype. BMI was positively associated with risk of all luminal breast cancer subtypes, including Luminal A (ptrend , 0.002), Luminal B (HER2-) (ptrend , 0.02), Luminal B (HER2+) (ptrend , 0.06), and also for the HER2 subtype (ptrend , 0.04), but BMI was not associated with risk of the BP or 5NP subtypes. Nonetheless, statistical tests for heterogeneity did not provide evidence that associations of height and BMI differed across breast cancer subtypes. This study of breast cancer risk among postmenopausal women suggests that height is positively associated with risk of Luminal A breast cancer. BMI is positively associated with risk of all luminal subtypes and for the HER2 subtype. PMID- 24752604 TI - Phylogenetic patterns in the microbial response to resource availability: amino acid incorporation in San Francisco Bay. AB - Aquatic microorganisms are typically identified as either oligotrophic or copiotrophic, representing trophic strategies adapted to low or high nutrient concentrations, respectively. Here, we sought to take steps towards identifying these and additional adaptations to nutrient availability with a quantitative analysis of microbial resource use in mixed communities. We incubated an estuarine microbial community with stable isotope labeled amino acids (AAs) at concentrations spanning three orders of magnitude, followed by taxon-specific quantitation of isotopic incorporation using NanoSIMS analysis of high-density microarrays. The resulting data revealed that trophic response to AA availability falls along a continuum between copiotrophy and oligotrophy, and high and low activity. To illustrate strategies along this continuum more simply, we statistically categorized microbial taxa among three trophic types, based on their incorporation responses to increasing resource concentration. The data indicated that taxa with copiotrophic-like resource use were not necessarily the most active, and taxa with oligotrophic-like resource use were not always the least active. Two of the trophic strategies were not randomly distributed throughout a 16S rDNA phylogeny, suggesting they are under selective pressure in this ecosystem and that a link exists between evolutionary relatedness and substrate affinity. The diversity of strategies to adapt to differences in resource availability highlights the need to expand our understanding of microbial interactions with organic matter in order to better predict microbial responses to a changing environment. PMID- 24752605 TI - E50K-OPTN-induced retinal cell death involves the Rab GTPase-activating protein, TBC1D17 mediated block in autophagy. AB - The protein optineurin coded by OPTN gene is involved in several functions including regulation of endocytic trafficking, autophagy and signal transduction. Certain missense mutations in the gene OPTN cause normal tension glaucoma. A glaucoma-causing mutant of optineurin, E50K, induces death selectively in retinal cells. This mutant induces defective endocytic recycling of transferrin receptor by causing inactivation of Rab8 mediated by the GTPase-activating protein, TBC1D17. Here, we have explored the mechanism of E50K-induced cell death. E50K OPTN-induced cell death was inhibited by co-expression of a catalytically inactive mutant of TBC1D17 and also by shRNA mediated knockdown of TBC1D17. Endogenous TBC1D17 colocalized with E50K-OPTN in vesicular structures. Co expression of transferrin receptor partially protected against E50K-induced cell death. Overexpression of the E50K-OPTN but not WT-OPTN inhibited autophagy flux. Treatment of cells with rapamycin, an inducer of autophagy, reduced E50K-OPTN induced cell death. An LC3-binding-defective mutant of E50K-OPTN showed reduced cell death, further suggesting the involvement of autophagy. TBC1D17 localized to autophagosomes and inhibited autophagy flux dependent on its catalytic activity. Knockdown of TBC1D17 rescued cells from E50K-mediated inhibition of autophagy flux. Overall, our results suggest that E50K mutant induced death of retinal cells involves impaired autophagy as well as impaired transferrin receptor function. TBC1D17, a GTPase-activating protein for Rab GTPases, plays a crucial role in E50K-induced impaired autophagy and cell death. PMID- 24752606 TI - Clinical management of renal cell carcinoma with venous tumor thrombus. AB - OBJECTIVES: Venous invasion is common in advanced renal cell carcinoma (RCC) due to the unique biology of this cancer. The presence of a tumor thrombus often makes clinical management challenging. In this review, we detail specific preoperative, perioperative, and surgical strategies involving the care of the complex kidney cancer patient with venous tumor involvement. METHODS: We performed a comprehensive review of selected peer-reviewed publications regarding RCC tumor thrombus biology, medical and surgical management techniques, and immediate and long-term outcomes. RESULTS: The perioperative management may require special imaging techniques, preoperative testing, very recent imaging, and consultation with other surgical services. There are various approaches to these patients as the clinical presentation, stage of disease, primary tumor size, level of thrombus, degree of venous occlusion, presence of bland thrombus, and primary tumor laterality influence management. Select patients with metastatic disease can do well with cytoreductive nephrectomy and thrombectomy. Those with localized disease have a high risk of recurrence; however, some patients can exhibit durable survival with surgery alone. The evolving surgical and medical treatments are discussed. CONCLUSIONS: Even when these surgeries are performed in high volume centers, significant perioperative complications are common and greater complications are seen with higher thrombus extent. If surgery is attempted, it is important for urologic oncologists to follow strict attention to specific surgical principles. These general principles include complete vascular control, avoidance of thrombus embolization, close hemodynamic monitoring, and institutional resources for caval resection/replacement and venous bypass if necessary. PMID- 24752607 TI - Do we need the nerve sparing radical prostatectomy techniques (intrafascial vs. interfascial) in men with erectile dysfunction? Results of a single-centre study. AB - OBJECTIVES: To report effect of different nerve sparing techniques (NS) during radical prostatectomy (RP) (intrafascial-RP vs. interfascial-RP) on post-RP incontinence outcomes (UI) in impotent/erectile dysfunction (ED) men. PATIENTS AND METHODS: A total of 420 impotent/ED patients (International Index of Erectile Function-score <15) with organ-confined prostate cancer were treated with bilateral-NS [intrafascial-RP (239) or interfascial-RP (181)] in our institution. Intrafascial-RP was indicated for biopsy Gleason score <=6 and PSA <=10 ng/ml while interfascial-RP for Gleason score <=7 and higher serum PSA. Seventy-seven patients with bilateral non-NS-RP were taken for comparison. No patient received pre-/postoperative radiation/hormonal therapy or had prostatic enlargement surgery. UI was assessed 3, 12 and 36 months postoperatively by third party. Continence was defined as no pads/day, safety 1 pad/day as separate group, 1-2 pads/day as "mild-incontinence" and >2 pads/day as "incontinence". RESULTS: All groups had comparable perioperative criteria without significant preoperative morbidities. International Prostate Symptom Score showed severe symptoms in 5 % of patients without correlation to UI. UI-recovery increased until 36 months. Full continence was reported from 56 versus 62 and 53 % patients after intrafascial-RP versus interfascial-RP and wide excision at 3 months, respectively (p = 0.521). Corresponding figures at 12 months were 70 versus 61 versus 51 % (p = 0.114) and at 36 months 85 versus 75 versus 65 % (p = 0.135), respectively. After 12 and 36 months, there was tendency to better UI-results in advantage of NS-technique; best results were achieved in intrafascial-RP group. UI-recovery was age-dependant. Advantage was found in NS-group compared with non NS-group in older patients (>70 years, p = 0.052). CONCLUSIONS: Impotent/ED patients have higher chances of recovering full continence after NS-RP. NS should be planned independently of preoperative potencystatus whenever technically and oncologically feasible. Age and lower urinary symptoms are not restrictions. Current data should be considered in preoperative patient counselling. PMID- 24752608 TI - A comparison of two 810 diode lasers for hair removal: low fluence, multiple pass versus a high fluence, single pass technique. AB - BACKGROUND & OBJECTIVE: Laser hair removal has become an increasingly popular method to remove unwanted or excessive hair. We have assessed the relative efficacy and discomfort associated with competing hair removal techniques, namely a high average power 810 nm diode laser using an "in-motion" technique with a market-leading 810 nm device with a single-pass vacuum-assisted technique. This study has determined the long-term (6-12 months) hair reduction efficacy and the relative pain induction intensities of these devices. STUDY DESIGN/MATERIALS AND METHODS: Prospective, randomized, side-by-side comparison of either the legs or axillae was performed comparing the Soprano XL 810 nm diode in super hair removal (SHR) mode (Alma Lasers, Buffalo Grove, IL) hereafter known as the "in-motion" device vs. the LightSheer Duet 810 nm diode laser (Lumenis) hereafter known as the "single pass" device. Five laser treatments were performed 6 to 8 weeks apart with 1, 6, and 12 months follow-ups for hair counts. Pain was assessed in a subjective manner by the patients on a 10-point grading scale. Hair count analysis was performed in a blinded fashion. RESULTS: There was a 33.5% (SD 46.8%) and 40.7% (SD 41.8%) reduction in hair counts at 6 months for the single pass and in-motion devices respectively (P = 0.2879). The average pain rating for the single pass treatment (mean 3.6, 95% CI: 2.8 to 4.5) was significantly (P = 0.0007) greater than the in-motion treatment (mean 2.7, 95% CI 1.8 to 3.5). CONCLUSIONS: This data supports the hypothesis that using diode lasers at low fluences and high average power with a multiple pass in-motion technique is an effective method for hair removal, with less pain and discomfort, while maintaining good efficacy. The 6 month results were maintained at 12 month for both devices. PMID- 24752609 TI - Fate of a novel strobilurin fungicide pyraoxystrobin in flooded soil. AB - Pyraoxystrobin, ((E)-2-(2-((3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yloxy) methyl) phenyl)-3-methoxyacrylate) is a novel strobilurin fungicide with excellent and broad spectrum antifungal efficiency. Environmental behaviors of the new fungicide must be assessed to understand its potential risks to the environment. In this study, the extractable residues, bound residues and mineralization, as well as the dissipation rates of pyraoxystrobin were investigated in three flooded soils using a (14)C tracing technique. Results showed that pyraoxystrobin didn't undergo appreciable dissipation during the 100 day incubation period in some tested soils, with 70.01%, 28.58% and 83.85% of the parent compound remaining in the solonchak, cambisol and acrisol soils at the end of the experiment, respectively. Almost no (14)C-pyraoxystrobin was mineralized to (14)CO2 (<0.5%) over the experimental period. Organic matter had a dominating influence on the bound residues formation and the fractions of bound residues increased as the soil organic matter content increased. Less than 9% of the radioactivity was found in the aqueous phase, while the majority of extractable residues (>65.39%) were recovered in the organic extracts. This study aims to give a deep insight into the environmental behaviors of pyraoxystrobin and may be beneficial for the risk assessment of other analogous fungicides. PMID- 24752610 TI - Design, synthesis, and biological evaluation of novel trifluoromethyl indoles as potent HIV-1 NNRTIs with an improved drug resistance profile. AB - A novel series of trifluoromethyl indole derivatives have been designed, synthesized and evaluated for anti-HIV-1 activities in MT-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were predicted. Trifluoromethyl indoles 10i and 10k showed extremely promising activities against WT HIV-1 with IC50 values at the low nanomolar level, similar to efavirenz, better than nevirapine, and also possessed higher potency towards the drug-resistant mutant strain Y181C than nevirapine. Preliminary SAR and docking studies of detailed binding mode provided some insights for discovery of more potent NNRTIs. PMID- 24752612 TI - Breast cancer biology: implications for local-regional therapy. PMID- 24752611 TI - Pancreastatin predicts survival in neuroendocrine tumors. AB - BACKGROUND: Serum neurokinin A, chromogranin A, serotonin, and pancreastatin reflect tumor burden in neuroendocrine tumors. We sought to determine whether their levels correlate with survival in surgically managed small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs). METHODS: Clinical data were collected with Institutional Review Board approval for patients undergoing surgery at one center. Progression-free (PFS) and overall (OS) survival were from the time of surgery. Event times were estimated by the Kaplan-Meier method. Preoperative and postoperative laboratory values were tested for correlation with outcomes. A multivariate Cox model adjusted for confounders. RESULTS: Included were 98 SBNETs and 78 PNETs. Median follow-up was 3.8 years; 62 % had metastatic disease. SBNETs had lower median PFS than PNETs (2.0 vs. 5.6 years; p < 0.01). Median OS was 10.5 years for PNETs and was not reached for SBNETs. Preoperative neurokinin A did not correlate with PFS or OS. Preoperative serotonin correlated with PFS but not OS. Higher levels of preoperative chromogranin A and pancreastatin showed significant correlation with worse PFS and OS (p < 0.05). After multivariate adjustment for confounders, preoperative and postoperative pancreastatin remained independently predictive of worse PFS and OS (p < 0.05). Whether pancreastatin normalized postoperatively further discriminated outcomes. Median PFS was 1.7 years in patients with elevated preoperative pancreastatin versus 6.5 years in patients with normal levels (p < 0.001). CONCLUSIONS: Higher pancreastatin levels are significantly associated with worse PFS and OS in SBNETs and PNETs. This effect is independent of age, primary tumor site, and presence of nodal or metastatic disease. Pancreastatin provides valuable prognostic information and identifies surgical patients at high risk of recurrence who could benefit most from novel therapies. PMID- 24752614 TI - The relationship of the natural sphenoid ostium to the skull base. AB - OBJECTIVES/HYPOTHESIS: Various intranasal landmarks have been described to aid in the localization of the natural sphenoid sinus ostium. The objectives of this study are to identify the ostium location relative to the skull base and assess the relationships between the location of the ostium and sphenoid disease or pneumatization pattern. DESIGN: Descriptive study. METHODS: Consecutive Xoran Mini-CAT (Ann Arbor, MI) scans of patients with no history of sinus surgery (n = 202) were evaluated. The natural sphenoid ostium was identified in axial, coronal, and sagittal planes. Distances from the planum to the ostium and from the planum to the sinus floor were calculated. Lund-Mackay score and pneumatization pattern were recorded for each sphenoid sinus. RESULTS: The mean distance from planum to ostium was 11.2 +/- 2.6 mm (range 4.4-19.2). On average, this encompassed 45.5% +/- 10% of the total sphenoid height. ANOVA with posthoc Tukey analysis revealed that the ostium was closer to the planum in sinuses with sellar (P = 0.05) or presellar (P = 0.02) pneumatization, compared to those with postsellar pneumatization. There was no significant relationship between the ostium location and degree of sinus disease. There was a significant difference in the pneumatization pattern between males and females (P = .04). More males had postsellar pneumatization than expected, and more females had sellar pneumatization than expected. CONCLUSIONS: The natural ostium of the sphenoid sinus is located at approximately the midpoint of the sphenoid face. Nevertheless, significant variability can be observed based on the pneumatization pattern. Surgeons should recognize that the ostium may be closer to the skull base when the sinus is less pneumatized. PMID- 24752613 TI - Synthesis and mechanistic studies of a novel homoisoflavanone inhibitor of endothelial cell growth. AB - Preventing pathological ocular angiogenesis is key to treating retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. At present there is no small molecule drug on the market to target this process and hence there is a pressing need for developing novel small molecules that can replace or complement the present surgical and biologic therapies for these neovascular eye diseases. Previously, an antiangiogenic homoisoflavanone was isolated from the bulb of a medicinal orchid, Cremastra appendiculata. In this study, we present the synthesis of a novel homoisoflavanone isomer of this compound. Our compound, SH-11052, has antiproliferative activity against human umbilical vein endothelial cells, and also against more ocular disease-relevant human retinal microvascular endothelial cells (HRECs). Tube formation and cell cycle progression of HRECs were inhibited by SH-11052, but the compound did not induce apoptosis at effective concentrations. SH-11052 also decreased TNF-alpha induced p38 MAPK phosphorylation in these cells. Intriguingly, SH-11052 blocked TNF-alpha induced IkappaB-alpha degradation, and therefore decreased NF-kappaB nuclear translocation. It decreased the expression of NF-kappaB target genes and the pro-angiogenic or pro-inflammatory markers VCAM-1, CCL2, IL8, and PTGS2. In addition SH-11052 inhibited VEGF induced activation of Akt but not VEGF receptor autophosphorylation. Based on these results we propose that SH-11052 inhibits inflammation induced angiogenesis by blocking both TNF-alpha and VEGF mediated pathways, two major pathways involved in pathological angiogenesis. Synthesis of this novel homoisoflavanone opens the door to structure-activity relationship studies of this class of compound and further evaluation of its mechanism and potential to complement existing antiangiogenic drugs. PMID- 24752615 TI - Bufalin exerts inhibitory effects on IL-1beta-mediated proliferation and induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes. AB - Rheumatoid arthritis fibroblast-like synoviocytes (RAFLSs) proliferate abnormally and resist apoptosis. Bufalin inhibits cell proliferation and induces apoptosis in human cancer cells. In this study, we explored the effects of bufalin on interleukin-1beta (IL-1beta)-induced proliferation and apoptosis of RAFLSs. The cell proliferation and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazoliumbromide assay and annexin V/propidium iodide staining, respectively. Bufalin dose-dependently inhibited IL-1beta-induced RAFLS proliferation. Mechanistically, bufalin decreased the activation of mitogen activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB), both of which are involved in IL-1beta-mediated RAFLS proliferation. Moreover, bufalin induced apoptosis and mitochondrial damage of RAFLSs, which was associated with Bcl-2 downregulation, Bax upregulation, mitochondrial cytochrome c release, and enhanced cleavages of caspase-3 and poly-(ADP-ribose) polymerase. Collectively, our results reveal that bufalin suppresses IL-1beta-induced proliferation of RAFLSs through MAPK and NF-kappaB signaling pathways and induces RAFLS apoptosis via the mitochondria-dependent pathway. PMID- 24752616 TI - The development of anticipation in the fetus: a longitudinal account of human fetal mouth movements in reaction to and anticipation of touch. AB - Research suggests that fetuses open or close their mouth in relation to directed movements but it is unclear whether mouth opening anticipates the touch or is a reaction to touch, as there has been no analysis so far of (1) the facial area of touch and (2) the sequential ordering of touch and mouth movements. If there is prenatal development of the anticipation of touch we would expect the frequency of fetal mouth opening immediately preceding the arriving hand at the mouth area to increase with fetal age. Fifteen healthy fetuses, eight girls and seven boys, underwent four additional 4-D scans at 24, 28, 32, and 36 weeks gestation. Changes in the frequency of touch for different facial regions indicated a significant decline in touch of the upper and side parts of the face and a significant increase in touching lower and perioral regions of the face with increasing gestational age. Results supporting the hypothesis showed a significant increase in the proportion of anticipatory mouth movements before touch increasing by around 8% with each week of gestational age. Additionally there was a decrease in the proportion of reactive mouth movements decreasing by around 3% for each week of gestational age. PMID- 24752617 TI - Specific binding and characteristics of 18beta-glycyrrhetinic acid in rat brain. AB - 18beta-Glycyrrhetinic acid (GA) is the aglycone of glycyrrhizin that is a component of Glycyrrhiza, and has several pharmacological actions in the central nervous system. Recently, GA has been demonstrated to reach the brain by crossing the blood-brain barrier in rats after oral administration of a Glycyrrhiza containing traditional Japanese medicine, yokukansan. These findings suggest that there are specific binding sites for GA in the brain. Here we show evidence that [3H]GA binds specifically to several brain areas by quantitative autoradiography; the density was higher in the hippocampus, moderate in the caudate putamen, nucleus accumbens, amygdala, olfactory bulb, cerebral cortex, thalamus, and mid brain, and lower in the brain stem and cerebellum. Several kinds of steroids, gap junction-blocking reagents, glutamate transporter-recognized compounds, and glutamate receptor agonists did not inhibit the [3H]GA binding. Microautoradiography showed that the [3H]GA signals in the hippocampus were distributed in small non-neuronal cells similar to astrocytes. Immunohistochemical analysis revealed that immunoreactivity of 11beta hydroxysteroid dehydrogenase type-1 (11beta-HSD1), a defined molecule recognized by GA, was detected mainly in neurons, moderately in astrocytes, and very slightly in microglial cells, of the hippocampus. These results demonstrate that specific binding sites for GA exist in rat brain tissue, and suggest that the pharmacological actions of GA may be related to 11beta-HSD1 in astrocytes. This finding provides important information to understand the pharmacology of GA in the brain. PMID- 24752618 TI - Gastric bypass for obesity in the elderly: is it as appropriate as for young and middle-aged populations? AB - BACKGROUND: Obesity prevalence increases in elderly population. Bariatric surgery has been underused in patients over 60 because of fears of complications and lower weight loss. We postulated worse outcomes in the elderly in comparison to young and middle-aged population 1 year after gastric bypass. METHODS: We retrospectively analyzed gastric bypass outcomes in young (<40 years), middle aged (40 to 55 years), and elderly (>60 years) patients between 2007 and 2013. Each subject over 60 (n = 24) was matched with one subject of both the other groups according to gender, preoperative body mass index (BMI), surgical procedure, and history of previous bariatric surgery (n = 72). RESULTS: Older subjects demonstrated higher prevalence of preoperative metabolic comorbidities (70 vs 30 % in the <40-year-old group, p < 0.0001). Mean duration of the surgical procedure, mean length of stay, and early and late complication rates were similar between age groups. A trend towards fewer early complications and less severe complications in the younger groups was noted. One-year weight loss results were similar between young, middle-aged, and elderly patients (percentage of excess BMI loss (EBL%), 74.4 +/- 3.5; 78.9 +/- 4.5, and 73.7 +/- 4.5 respectively, p = 0.69). Age was not predictive of weight loss failure 1 year after surgery. Remission and improvement rates of comorbidities were similar between age groups 6 months after surgery. CONCLUSIONS: Our study confirms weight loss efficacy of gastric bypass in the elderly with acceptable risks. Further studies evaluating the benefit-risk balance of bariatric surgery in the elderly population will be required so as to confirm the relevance of increasing age limit. PMID- 24752619 TI - Effects of obesity on posture and walking: study prior to and following surgically induced weight loss. AB - BACKGROUND: We investigate whether in severely obese people a marked weight loss may influence individual postural control and motor activities and then reverse the alterations caused by the extra load of body mass. Recent studies have shown that most severely obese patients have various degrees of impairment of postural control, but only a few studies considered those subjects before and after a marked weight loss. METHODS: Ten obese and ten subjects of average weight took part in our experiment. The subjects were requested to perform four different tasks. All obese patients repeated the tasks 1 year after undergoing bariatric surgery. RESULTS: We have found differences between obese and normal-weight people in the execution of all four work tasks. However, a year after surgery, obese patients showed a change in the execution of only two tasks, keeping the same performance in the other two. CONCLUSIONS: The excess of fat mass alters the execution of some tasks, as confirmed by the improvement obtained after weight loss. For other work tasks, we can hypothesize that the neurophysiological plasticity of the neuro-muscular system would require more time to adapt. PMID- 24752620 TI - Bipolar disorder symptoms in patients seeking bariatric surgery. AB - BACKGROUND: Mood disorders are common among patients seeking bariatric surgery although little data exist regarding the prevalence of bipolar symptoms in this population and how they influence surgical outcomes. Our aim was to describe baseline rates of bipolar symptoms and their relationship to psychological factors and completing surgery in a sample of adults seeking bariatric surgery at an academic medical center. METHODS: We retrospectively reviewed the relationship of bipolar symptoms to demographic characteristics, baseline weight, psychological factors, and bariatric surgery completion. RESULTS: Nine hundred thirty-five patients completed the preoperative psychological evaluation. Six percent of the preoperative sample screened positive for symptoms of bipolar disorder. Patients with bipolar symptoms endorsed more robust psychopathology, trauma history, and problematic eating behaviors than patients without bipolar symptoms. Twenty-two percent of the patients with bipolar symptoms underwent bariatric surgery (n = 12), yet only 13 % were denied bariatric surgery for psychiatric reasons, suggesting that other variables may influence the completion of bariatric surgery for these patients. CONCLUSION: Prevalence rates of bipolar symptoms may be greater in patients seeking bariatric surgery compared with the general population, and few patients with bipolar symptoms actually undergo bariatric surgery. Psychological factors differentiate patients with bipolar symptoms who undergo bariatric surgery vs those who do not. PMID- 24752621 TI - A preferable molecular crystal membrane for H2 gas separation. AB - A novel molecular crystal membrane [Cu(II)2(9-AC)4(pyz)]n (9-AC: 9 anthracenecarboxylate, pyz: pyrazine) shows high permselectivity for H2/CO (79.0), H2/CH4 (137), and H2/CO2 (12.1) due to the high rate of H2 permeation (3820 Barrer) while inhibiting the permeation of such a large gaseous particle even in its wider channel than the Lennard-Jones diameter of each gas. PMID- 24752622 TI - SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. AB - Cyclophosphamide-dacarbazine-vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP. This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation-wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression free survival (PFS) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point. Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m(2) /d for 5 days every 28 days. Median PFS was 13.3 months after a median follow-up of 35 months. There were five partial responses (33%), seven stable (47%) and three progressive diseases (20%). Grade 3 toxicities were lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation-wide independent cohort. This study demonstrates that TMZ is an effective antitumour agent in patients with SDHB-related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumours may explain this finding. PMID- 24752623 TI - Motor nerve conduction study and muscle strength in newly diagnosed POEMS syndrome. AB - INTRODUCTION: Mixed demyelination and axonal loss are electrophysiological features of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome. It is unclear whether the demyelination and axonal loss occur concurrently. METHODS: Electromyography was performed in 37 patients with newly diagnosed POEMS syndrome. Compound muscle action potential (CMAP) amplitude, distal motor latency, motor conduction velocity (MCV), and spontaneous activity were collected. Muscle strength was measured according to the Medical Research Council (MRC) scale. RESULTS: MCV decreased in all nerves with decreased CMAP amplitude and in 93% of nerves with normal amplitude. CMAP amplitude decreased in 54% of nerves with decreased MCV and was normal in all nerves with normal MCV. MCV deceased in 95% of nerves with normal MRC. Abnormal spontaneous activity was detected in 32% of upper limb muscles. CONCLUSIONS: Demyelination may be the main manifestation in POEMS neuropathy at an early stage, and axonal loss may be secondary to demyelination as the disease progresses. PMID- 24752624 TI - Sacrum pubic incidence and sacrum pubic posterior angle: two morphologic radiological parameters in assessing pelvic sagittal alignment in human adults. AB - PURPOSE: The morphology and position of pelvis are critical in regulating the biomechanical organization of spine-pelvis-leg in the sagittal plane. Several radiological parameters have been developed to present the sagittal morphology of the pelvis such as pelvic incidence (PI) and Jackson's angle (PRS1). In addition, the femoral sacral posterior angle (FSPA) was developed for patients with a dome shaped deformity in the upper plate of the sacrum. The identification of hip axis, which was represented by the line connecting the centers of femoral heads in normal subjects, was important for these parameters measurement. However, in subjects with fused hip joint or deformed femoral heads, the accurate localization of hip axis become imprecise. Herein, the upper edge of the pubic symphysis, which is easy to identify on the lateral X-ray film, was selected as an alternative landmark of the hip axis, and two morphologic parameters, the sacrum pubic incidence (SPI) and sacrum pubic posterior angle (SPPA), were proposed accordingly. The present study aimed to understand the reliability of these two parameters and their value in predicting PI, PRS1 and FSPA. METHODS: Upright standing spine and pelvis radiographs of 60 normal adults (30 male and 30 female) with an average age of 38.5 years were obtained. Two independent observers then measured the following radiological parameters on the films: PI, PRS1, FSPA, SPI, SPPA, sacral slope, pelvic tilt and lumbar lordosis. The SPI is the angle between the line perpendicular to the superior plate of the first sacral vertebra at its midpoint and the line connecting this point to the upper edge of the pubic symphysis, while the SPPA is the angle between the line extending from the posterior upper edge of the sacrum to the upper edge of the pubic symphysis and the posterior side of the first sacral vertebral body. The intra-observer and inter-observer reliabilities of the parameters were analyzed using intraclass correlations. The correlations between parameters were analyzed by Pearson's correlation coefficients. Regression analysis was carried out to establish formulas to predict the values of PI, PRS1 and FSPA using the SPI and SPPA. A p < 0.05 was considered statistically significant. RESULTS: The SPI was 64.4 degrees +/- 9.5 degrees and 68.3 degrees +/- 9.4 degrees , and the SPPA was 77.7 degrees +/- 7.5 degrees and 78.7 degrees +/- 9.4 degrees in males and females, respectively. These radiological parameters showed excellent intra- and inter-observer reliabilities, with an intraclass correlation >0.8. No gender differences were identified in these morphologic and positional radiological parameters. The SPI demonstrated strong correlation with PI and PRS1 (R (2) > 0.9, p < 0.001). In addition, strong correlation was also found between SPPA and FSPA (R (2) > 0.9, p < 0.001). Furthermore, both SPPA and FSPA showed close correlations with the other morphologic and positional parameters. Linear regression analysis established equations to predict PI and PRS1 using SPI and to predict FSPA by SPPA with significantly high reliability. CONCLUSIONS: Both SPI and SPPA are reliable parameters for determining the morphology of the pelvis. The SPI is precise in predicting PI and PRS1, while SPPA is reliable in predicting FSPA. The SPI and SPPA will allow further study on lateral spinal pelvic alignment in patients with hip joint abnormalities. PMID- 24752625 TI - Design and synthesis of paracaseolide A analogues as selective protein tyrosine phosphatase 1B inhibitors. AB - A series of structurally related analogues of the natural product paracaseolide A were synthesized and identified as potent PTP1B inhibitors. Among these analogues, compound 10 in particular showed improved PTP1B enzyme inhibitory activity, high selectivity for PTP1B over TC-PTP, and improved cellular effects. PMID- 24752626 TI - Benzo[a]acridinylmethyl esters as pH sensitive fluorescent photoactive precursors: synthesis, photophysical, photochemical and biological applications. AB - A newsworthy class of carboxylate esters based on the (benzo[a]acridin-12 yl)methyl (BAM) chromophore has been shown to perform dual functions as a "pH sensitive fluorescent probe" and a "phototrigger" for acids. The photophysical properties of all the BAM ester conjugates were investigated and found to be highly sensitive to solvent polarity, H-bonding capability and pH of the environment. On irradiation using UV light (>=410 nm), BAM ester conjugates underwent heterolytic cleavage of C-O bonds resulting in efficient release of carboxylic and amino acids. Interestingly, the newly synthesized BAM chromophore was also explored for the construction of a drug delivery system (DDS). In the current DDS, the BAM chromophore plays two important roles: (i) a "fluorophore" for cell imaging and (ii) a "phototrigger" for the drug release. In vitro biological studies revealed that the newly developed BAM based DDS has a good biocompatibility, cellular uptake properties and efficient photoregulated anticancer drug release ability. PMID- 24752627 TI - Biotechnological production of plant-specific hydroxylated phenylpropanoids. AB - Hydroxylated phenylpropanoid compounds (e.g., esculetin, piceatannol, and eriodictyol) have been proved to possess important biological activities and pharmacological properties. These compounds exist at low abundance in nature, which hampers their cost-effective isolation, and broad application. Meanwhile, regiospecific hydroxylation of complex aromatic compounds is still quite challenging for chemical synthesis. In past decades, biocatalytic hydroxylation of plant phenylpropanoids was achieved due to the identification and engineering of some cytochrome P450 hydroxylases; however, the conversion efficiency was still too low for scale-up production use. In this work, we identify a non-P450 monooxygenase (HpaBC) from Escherichia coli, which is able to catalyze the efficient ortho-hydroxylation towards plant phenylpropanoids umbelliferone and resveratrol; meanwhile it also exhibits activity towards naringenin. On this basis, whole-cell biocatalysis enables the production of esculetin and piceatannol at high titers (2.7 and 1.2 g/L, respectively, in shake flasks) and high yields (close to 100%). To our knowledge, this work reports the highest titers and yields for biotechnological production of esculetin and piceatannol, representing a promising hydroxylation platform. PMID- 24752628 TI - Approach to chronic cough. AB - Chronic cough does affect quality of life in children. Most of the times it is treated with over-the-counter cough syrups and antibiotics. The etiology of chronic cough is so diverse, that treatment needs to be directed to the specific etiology, rather than treating symptomatically. Grossly, chronic cough is classified as specific and non-specific cough. Allergic conditions, followed by tuberculosis are more commonly encountered etiologies in India. Baseline investigations to be performed are chest radiograph and peak flow metry. If specific cause of cough is not obvious, then therapeutic trial with beta2 agonist, followed by peak flowmetry to evaluate reversibility of airway hypersensitivity, is useful to label the child asthmatic or non-asthmatic. Rampant uses of antibiotics need to be avoided for conditions like asthma. If tuberculosis is diagnosed or suspected, it is better to treat the child, rather than giving therapeutic trial. Over-the-counter cough syrups are as good as placebo, and should be avoided. Trial of anti asthma, anti allergic rhinitis and anti reflux therapies are avoided, unless the diagnosis is one of these conditions. If the child is distressed or the case seems to be complicated, it is best to refer the child to a tertiary care centre and keep a close follow up. PMID- 24752629 TI - Decline in immunization coverage across well-performing districts in India: an urban conundrum? PMID- 24752630 TI - Shared decision-making in pediatric intensive care units: a qualitative study with physicians, nurses and parents. AB - OBJECTIVES: To understand how decisions are made in Intensive Care Unit (ICU) settings where critically-ill children require life-support decisions and what are the perceptions of health professionals and parents. METHODS: In this qualitative study, in-depth, semi-structured, face to face interviews with 8 doctors, 9 nurses and 6 parents of critically ill children were conducted. Interviews were digitally recorded and transcribed. The transcriptions were further analyzed following open coding and formation of themes. RESULTS: The themes were discussed in two major titles: perceived roles and emotions during the decision-making process. All nurses and patients agreed that the decision maker should be the physician. Nurses understood patients' emotions better and had a closer relation with the parents. Both doctors and nurses thought that parents could not have all responsibilities about treatment choices, because they do not have the required knowledge. Similarly parents were afraid to make a wrong decision, thus they wanted to leave this to the doctors. CONCLUSIONS: The present study revealed that shared-decision making is not well understood by health care professionals in Turkey. Doctor is the major decision-making authority and this is also accepted and preferred by the patients and nurses. PMID- 24752631 TI - Bilateral central retinal artery occlusion: an unusual presentation of Polyarteritis Nodosa. PMID- 24752632 TI - Nanoparticle emissions from traditional pottery manufacturing. AB - Traditional pottery manufacturing involves firing of the ceramics in kilns, a process that leads to high concentrations of airborne particles that are harmful to human health. In order to assess the associated exposure levels and the involved risks, here, for the first time, we investigate the size, the concentration and the elemental composition of the particles emitted during the different stages of the ceramic firing process. Number size distributions of the emitted particles, having diameters in the range from 10 nm to 20 MUm, were measured in a traditional small-sized pottery studio using a Scanning Mobility Particle Sizer (SMPS) and an Optical Particle Counter (OPC). The measurements showed dominance of the nanoparticle mode (i.e., particles smaller than 100 nm) when the kiln reached temperatures above 600 degrees C. The mean size of the particles ranged from 30 to 70 nm and their peak number concentration was 6.5 * 10(5) cm(-3) during the first stage of the firing process where the ceramics were unpainted and unglazed. During the second stage of the firing process, where the ceramics were painted and glazed, the mean particle size ranged from 15 to 40 nm and their number concentration peaked at 1.2 * 10(6) cm(-3). Elemental analysis of individual particles collected during the two firing stages and studied by Energy-Dispersive X-ray (EDX) spectroscopy showed that the emitted nanoparticles contain significant amounts of lead. These findings provide new information for understanding the health impacts of traditional pottery manufacturing, and underline the need for adopting adequate measures to control nanoparticle emissions at the source. PMID- 24752633 TI - Pancreatico-duodenectomy and postoperative pancreatic fistula: risk factors and technical considerations in a specialized HPB center. AB - Postoperative pancreatic fistula (POPF) is a common complication of pancreatic resection. Aim of this study is to identify variables related to the development of POPF, analyze their clinical significance and discuss our current approach to the pancreatico-jejunal anastomosis. A series of 129 patients undergoing pancreatico-duodenectomy (PD) have been analyzed. Patients were divided in two groups: group F, 26 patients who have developed POPF; group NF, 103 patients who have not developed POPF. Demographic, clinical and intraoperative data were compared. Seventy-six patients had an end-to-side (ES) pancreatico-jejuno anastomosis, 53 an end-to-end (EE) anastomosis. Fifteen patients developed grade A fistulas, seven grade B, and four grade C; two patients with grade C fistula died from septic shock. Preoperative bile duct lithiasis, diameter of the pancreatic duct and consistency of the pancreatic stump were significantly different between F and NF groups at multivariate analysis. POPF has been related to clinical and biological parameters: preoperative bile duct lithiasis and challenging pancreatico-jejunal anastomosis (with small pancreatic duct and friable pancreatic stump) are the most prominent according to our experience. As the incidence of POPF seems to be related to technically demanding surgery, we presently reserve the EE anastomosis to the cases in which a friable gland or a very small duct will make a direct anastomosis on the pancreatic duct unreliable. In case of grade C fistulas a total spleen-preserving pancreatectomy should be considered an adequate treatment to prevent the onset of a multi-organ failure or a septic shock if no other treatment seems suitable. PMID- 24752634 TI - Effect of silica-based nanomaterials and their derivate with PEGylation on cementoblasts. AB - The applications of silica-based nanomaterials in dental fields as multifunctional scaffolds and carriers have been widely documented in recent years. However, toxicity of this type of nanoparticles in dental cells has not been elucidated in detail. The aim of present study was to investigate the effects of naked and PEGylated silica nanoparticles on cementoblasts. Methods including MTT assay, apoptosis, LDH, as well as ROS analysis were introduced in our study. Moreover, ALP analysis and alizarin red staining were additionally performed to indicate the influence of SiO2 and PEG-SiO2 on cementoblast differentiation. Results obtained from our designs and experiments demonstrated that naked silica nanoparticles could induce more cell toxicity than PEG-SiO2 nanoparticles, indicating PEGylation could efficiently reduce in vitro toxicity from several sections including ROS, LDH, and other important routes. Based on above results, we concluded that it was so necessary to process PEGylation while silica-based materials were applied in biomedicine and related fields including dental area. PMID- 24752635 TI - Ultrasound effect on neural differentiation of gingival stem/progenitor cells. AB - Dental pulp loss due to caries or pulpitis can affect the longevity of teeth. Dental pulp tissue engineering necessitates the use of progenitor cells that has the potential to differentiate into neural, vascular and odontoblasts like cells. Previous reports have shown that human gingival progenitor cells (HGPCs) can be differentiated into different cell types; however neural differentiation of these cells, to the best of our knowledge, has not been reported. Low intensity pulsed ultrasound (LIPUS) has been reported to enhance cell differentiation. The aims of this study were (1) to explore the potential neural differentiation of HGPCs and (2) to investigate the effect of LIPUS on the differentiation of HGPCs when incubated under neuroinductive conditions. The HGPCs were isolated from human interdental papilla proximal to the premolar teeth that were extracted for orthodontic purpose. The HGPCs were induced to differentiate into neural lineage using a neuroinductive culture medium. HGPCs were divided into four groups; control group, neuro-induction (NI) group, ultrasound group (LIPUS), and a combined NI+LIPUS group. HGPCs were harvested for immunostaining and q-PCR after 1 day. Immunostaining for neuron specific antigens and q-PCR suggested that HGPCs can be differentiated into neural lineage and that selected neurodifferentiation markers can be enhanced by LIPUS. PMID- 24752636 TI - Outcomes of ethnic minority groups with node-positive, non-metastatic breast cancer in two tertiary referral centers in Sydney, Australia. AB - PURPOSE: There is a lack of information in ethnic minority groups with regard to presentation and treatment of early node-positive breast cancer. We carried out a retrospective study of patients referred to two tertiary cancer centers in South Western Sydney, both of which serve a high proportion of this ethnic minority population. PATIENTS AND METHODS: Women who had pathologically node-positive non metastatic breast cancer (T1-3, N1-3, M0) diagnosed between 2003 and 2006 were studied, with variables of interest being tumor size, number of positive nodes, histological grade, hormone receptor status, age at diagnosis, country of birth and treatment. We compared the Asian and Western subgroups with regard to tumor characteristics, treatment and clinical outcomes. RESULTS: A total of 652 eligible patients were identified, with a median follow-up of 6.1 years. Women with Asian backgrounds (n = 125, 20%) were significantly younger at presentation (48 years versus 55 years, p-value <0.0001) and more likely to undergo mastectomy (53% versus 39%, p-value 0.0009) and chemotherapy (86% versus 72%, p-value 0.0063) than their non-Asian counterparts. Tumor stage, grade and receptor status were not statistically different between these two groups. There were also no differences in disease-free survival and overall survival, with medians of 12.7 and 14.8 years respectively. CONCLUSION: Women of Asian background are younger at diagnosis, which may reflect population epidemiology and likely results in higher uptake of chemotherapy. Higher mastectomy rates may be influenced by cultural factors. Future research is warranted to investigate potential differences in tumor biology, psychosocial, economic and cultural factors. PMID- 24752637 TI - Fetal gender adjustment decreases the expected variance in non-invasive prenatal testing analysis. PMID- 24752638 TI - Illicit Drug Use Among South Korean Offenders: Assessing the Generality of Social Learning Theory. AB - Since the mid-1990s, illicit drug use has become a problem in Korean society. This trend is likely due to the rapid globalization and expansion that occurred with the Internet revolution, which led to greater numbers of people socially learning about drug culture. The current study attempts to uncover criminogenic causality of such social learning about drug use by studying adult felony drug offenders in South Korea. The data used for the study were obtained from self reported surveys, originally collected by the Korean Institution of Criminology (KIC). The final sample comprised 1,452 felony offenders convicted of illicit drug use, and their responses were analyzed with a set of multiple logistic regression tests. The current study found supportive evidence for the generalizability of social learning theory from the sample of the South Korean adult drug offenders. We argue that the current study provides additional empirical evidence that supports the generalizability of social learning theory. PMID- 24752639 TI - Risky or Needy? Dynamic Risk Factors and Delinquent Behavior of Adolescents in Secure Residential Youth Care. AB - Although it is known that adolescents in secure residential care often show multiple behavior problems, it is largely unknown which dynamic risk factors are associated with their problems. The aim of the present study is to examine dynamic risk factors for 164 Dutch adolescents in secure residential care. Results show that a majority reports multiple risk factors in both an individual and contextual domain but that about a fifth shows relatively few risk factors. Substance abuse and delinquent friends were among the five most prevalent risk factors and predicted the seriousness of the adolescents' delinquent behavior prior to admission. The four groups that were found by cluster analysis could be distinguished by problem type and seriousness. The findings indicate that treatment for some adolescents should be mainly focused on their individual needs, while other adolescents need intensive, multimodal treatment focusing on both risks in the individual, family, and peer domains. PMID- 24752640 TI - A facile sol-gel synthesis of impurity-free nanocrystalline titania. AB - This paper reports an original technique that provides a highly pure crystalline sol of titania with controllable particle size by ultrasonic activation of the hydrolysis products of titanium isopropoxide in an aqueous medium at a near neutral pH, which is potentially promising in impurity-sensitive electronics and biochemical engineering. Optimal conditions (H2O/TIP ratio, sonication time, etc.) for preparation of stable nanocrystalline titania sol were adopted. A new mechanism of regulation of aggregation and polycondensation under ultrasonic irradiation is proposed. Entrapment of human serum albumin (HSA) in the formed porous titania matrix results in high thermal stability of the protein dopants: the denaturation temperature of HSA is shifted by 31 degrees C. PMID- 24752641 TI - In response to preapproval of sinus computed tomography for otolaryngologic evaluation of chronic rhinosinusitis does not save health care costs. PMID- 24752642 TI - Working memory and inhibitory control in visually guided manual search in toddlers. AB - Toddlers undergo a transition at about 2.5-3 years-of-age that dramatically improves their ability to search for hidden objects. The development of these skills seems to depend on the development of executive functions. We used a correlational design to investigate which components of executive function might be involved in this improved search. Three tests of working memory did not correlate with search performance, but a test of inhibitory/cognitive control was associated with performance increases. Improvement seemed to be the result of control of visual attention and responding in the face of misleading visual events and not the result of improvements in working memory. PMID- 24752644 TI - The detection of thrombin using a mixture of a fluorescent conjugated polyelectrolyte and fibrinogen and implementation of a logic gate. AB - A highly sensitive and selective detection of thrombin is accomplished using an emission color-tunable conjugated polyelectrolyte. The implementation of a combined logic gate is realized upon emission modulation of the system including the polymer, fibrinogen, thrombin, and heparin. PMID- 24752643 TI - Cortical innervation of the hypoglossal nucleus in the non-human primate (Macaca mulatta). AB - The corticobulbar projection to the hypoglossal nucleus was studied from the frontal, parietal, cingulate, and insular cortices in the rhesus monkey by using high-resolution anterograde tracers and stereology. The hypoglossal nucleus received bilateral input from the face/head region of the primary (M1), ventrolateral pre- (LPMCv), supplementary (M2), rostral cingulate (M3), and caudal cingulate (M4) motor cortices. Additional bilateral corticohypoglossal projections were found from the dorsolateral premotor cortex (LPMCd), ventrolateral proisocortical motor area (ProM), ventrolateral primary somatosensory cortex (S1), rostral insula, and pregenual region of the anterior cingulate gyrus (areas 24/32). Dense terminal projections arose from the ventral region of M1, and moderate projections from LPMCv and rostral part of M2, with considerably fewer hypoglossal projections arising from the other cortical regions. These findings demonstrate that extensive regions of the non-human primate cerebral cortex innervate the hypoglossal nucleus. The widespread and bilateral nature of this corticobulbar connection suggests recovery of tongue movement after cortical injury that compromises a subset of these areas, may occur from spared corticohypoglossal projection areas located on the lateral, as well as medial surfaces of both hemispheres. Since functional imaging studies have shown that homologous cortical areas are activated in humans during tongue movement tasks, these corticobulbar projections may exist in the human brain. PMID- 24752645 TI - Direct angiotensin AT2 receptor stimulation using a novel AT2 receptor agonist, compound 21, evokes neuroprotection in conscious hypertensive rats. AB - BACKGROUND: In this study, the neuroprotective effect of a novel nonpeptide AT2R agonist, C21, was examined in a conscious model of stroke to verify a class effect of AT2R agonists as neuroprotective agents. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) were pre-treated for 5 days prior to stroke with C21 alone or in combination with the AT2R antagonist PD123319. In a separate series of experiments C21 was administered in a series of 4 doses commencing 6 hours after stroke. A focal reperfusion model of ischemia was induced in conscious SHR by administering endothelin-1 to the middle cerebral artery (MCA). Motor coordination was assessed at 1 and 3 days after stroke and post mortem analyses of infarct volumes, microglia activation and neuronal survival were performed at 72 hours post MCA occlusion. When given prior to stroke, C21 dose dependently decreased infarct volume, which is consistent with the behavioural findings illustrating an improvement in motor deficit. During the pre-treatment protocol C21 was shown to enhance microglia activation, which are likely to be evoking protection by releasing brain derived neurotrophic factor. When drug administration was delayed until 6 hours after stroke, C21 still reduced brain injury. CONCLUSION: These results indicate that centrally administered C21 confers neuroprotection against stroke damage. This benefit is likely to involve various mechanisms, including microglial activation of endogenous repair and enhanced cerebroperfusion. Thus, we have confirmed the neuroprotective effect of AT2R stimulation using a nonpeptide compound which highlights the clinical potential of the AT2R agonists for future development. PMID- 24752646 TI - Evaluation of a novel eyelid-warming device in meibomian gland dysfunction unresponsive to traditional warm compress treatment: an in vivo confocal study. AB - The purpose of the study was to evaluate the efficacy and safety of wet chamber warming goggles (Blephasteam((r))) in patients with meibomian gland dysfunction (MGD) unresponsive to warm compress treatment. We consecutively enrolled 50 adult patients with low-delivery, non-cicatricial, MGD, and we instructed them to apply warm compresses twice a day for 10 min for 3 weeks and to use Blephasteam((r)) (Laboratoires Thea, Clermont-Ferrand, France) twice a day for 10 min for the following 3 weeks. We considered "not-responders" to warm compress treatment the patients who showed no clinically significant Ocular Surface Disease Index (OSDI) improvement after the first 3 weeks. Clinical and in vivo confocal outcome measures were assessed in the worst eye (lower BUT) at baseline, after 3 weeks, and after 6 weeks. Eighteen/50 patients were not-responders to warm compress treatment. These patients, after 3 weeks of treatment with Blephasteam((r)), showed significant improvement of OSDI score (36.4 +/- 15.8 vs 20.2 +/- 12.4; P < 0.05, paired samples t test), increased BUT (3.4 +/- 1.6 vs 7.6 +/- 2.7; P < 0.05), and decreased acinar diameter and area (98.4 +/- 18.6 vs 64.5 +/- 14.4 and 8,037 +/- 1,411 vs 5,532 +/- 1,172, respectively; P < 0.05). Neither warm compresses nor Blephasteam((r)) determined adverse responses. In conclusion, eyelid warming is the mainstay of the clinical treatment of MGD and its poor results may be often due to lack of compliance and standardization. Blephasteam((r)) wet chamber warming goggles are a promising alternative to classical warm compress treatment, potentially able to improve the effectiveness of the "warming approach." PMID- 24752647 TI - OLEDs as prospective light sources for microstructured photoreactors. AB - In this work, the use of OLEDs as light sources to initiate photochemical reactions is presented for the first time. A newly developed modular photoreactor system utilising microstructured reactors was equipped with commercially available OLED panels. The technical feature of being a surface emitter, the low thickness and the potentially high luminescent efficiency give reason to expect this kind of light source to be well suited for photochemical reactions. The reactor system was investigated by using photooxygenations as benchmark reactions. In detail, photosensitised [4 + 2]-cycloadditions and [2 + 2] cycloadditions of (1)O2 were examined as well as Schenck-ene-reactions. It was demonstrated that OLEDs can be successfully used for conducting photochemical reactions. Moreover the equilibrium concentration of (1)O2 can be increased by varying the process conditions. Based on the experimental investigations, a reactor comparison showed that, with respect to productivity and efficiency, the investigated microstructured photoreactor is currently not outperforming conventional batch reactors. PMID- 24752648 TI - Balance and coordination training and endurance training after nerve injury. AB - INTRODUCTION: Different rehabilitation treatments have proven useful in accelerating regeneration. METHODS: After sciatic nerve crush in rats, we tested balance and coordination training (BCT) and endurance training (ET) through sensorimotor tests and analyzed nerve and muscle morphology. RESULTS: After BCT and ET, rats performed better in sensorimotor tests than did non-trained animals. However, only BCT maintained sensorimotor function during training. Furthermore, BCT and ET produced significantly larger muscle area than in non-trained animals. CONCLUSIONS: These findings indicate that BCT and ET, when initiated in the early phase after sciatic nerve injury, improve morphological properties of the soleus muscle and sciatic nerve, but only the task-oriented BCT maintained sensorimotor function. The success of rehabilitative strategies appears to be highly task specific, and strategies that stimulate sensory pathways are the most effective in improving balance and/or coordination parameters. PMID- 24752650 TI - Carbohydrate-based first stereoselective total synthesis of bioactive cytospolide P. AB - A facile carbohydrate-based highly stereoselective synthetic route has been developed for the cytospolide P (1) from D-ribose for the first time. Key steps of the synthesis include Wittig homologation, regioselective epoxide ring opening, Sharpless asymmetric epoxidation, Evans aldol reaction, and Yamaguchi macrolactonization. PMID- 24752649 TI - Bdnf DNA methylation modifications in the hippocampus and amygdala of male and female rats exposed to different caregiving environments outside the homecage. AB - We have previously shown in infant rats that brief and repeated experiences with a stressed dam outside the homecage (maltreatment) alters methylation of DNA associated with the brain-derived neurotrophic factor (bdnf) gene within the developing and adult prefrontal cortex. BDNF is a key mediator of activity dependent processes that have a profound influence on neural development and plasticity. Here we examined whether maltreatment also alters bdnf DNA methylation in two additional regions known to be prominently affected by diverse forms of early life adversity in humans- the hippocampus and amygdala. We found significant bdnf DNA methylation modifications present within the adult hippocampus (dorsal and ventral) and amygdala (central/basolateral complex). We observed that the nature of change differed between sexes, gene locus (bdnf I vs. IV), and brain region. Furthermore, a manipulation that did not produce any obvious behavior difference in infants (brief and repeated experiences with a nurturing foster dam) also had long-term effects on methylation. These data provide further empirical support of DNA methylation modifications as biological consequences of caregiving environments. PMID- 24752651 TI - ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: study in African-American and Caucasian prostate cancer models. AB - High-risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non-availability of reliable phenotype-discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis-associated gene) in human CaP. Employing CaP-progression models and prostatic tissues of Caucasian and African-American patients, we show that ROBO1 expression is localized to cell-membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African-Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African-American metastatic CaP cells. Using African-American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1-expressing/ROBO1-C2C3-mutant constructs, immunoprecipitation, confocal-microscopy and luciferase-reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3-SH2-domain) controls the Rac activation. However, loss of ROBO1 results in Rac1-activation which in turn causes E-Cadherin/beta-catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high-risk populations such as African-Americans. PMID- 24752652 TI - Rare case of survival after traumatic disruption of the cervical spine with combined complete spinal cord injury and bilateral vertebral arterial breakdown in an 18-month-old patient. AB - Complete cervical disruption is a rare and lethal injury secondary to high-energy trauma. Bilateral vertebral arterial breakdown is also a rare and lethal injury. This is the first reported clinical case of an 18-month-old girl who survived after combined cervical spinal cord disruption and bilateral vertebral arterial breakdown. Although she developed cardiopulmonary arrest at the accident site, resuscitation by a bystander, early fluid resuscitation, appropriate respiratory management, and subsequent surgical stabilization resulted in survival and preservation of higher cortical functions. She underwent surgery 1 week after hospitalization; her cervical spine was stabilized by posterior fixation using pedicle screws and transarticular screws. After the operation, the burst vertebra was gradually remodeled. Approximately 4 months later, she was transferred to a rehabilitation facility. Ten years later, she is attending to an elementary school, and she is able to speak and operate a wheelchair using a portable respiratory organ. We herein report an exceedingly rare case of cervical cord injury involving a combination of disruption of the cervical spine and bilateral vertebral arterial breakdown in a young child. PMID- 24752653 TI - Communication skills training in medical students: do motivational orientations predict changes over time in psychosocial attributes? AB - Perceived psychosocial abilities (i.e., competence in addressing the psychosocial aspects of patient care) and low frustration tolerance (LFT) (i.e., intolerance of physical or emotional discomfort) have been established as significant attributes of experienced medical professionals. We aimed to expand our understanding of the role motivation plays within communication skills training by investigating whether motivation precedes or, conversely, follows psychosocial attributes. According to goal orientations theory, motivation denotes the goals students pursue when engaging in learning tasks. We hypothesized that goal orientations would predict development of psychosocial attributes. More specifically, an adaptive goal orientation (i.e., mastery goal orientation) was expected to predict perceived psychosocial abilities, whereas the maladaptive goal orientations (i.e., performance-approach and avoidance goal orientations) were hypothesized to predict LFT (frustration intolerance). The study spanned two sequential years, in which two cohorts of first-year medical students (N = 151) completed questionnaires at the beginning and end of an annual physician-patient communication course. The questionnaires assessed goal orientations, perceived psychosocial abilities, and LFT. Cross-lagged analyses using Structural Equation Modeling indicated that goal orientations significantly predicted perceived psychosocial abilities, as hypothesized; however, LFT predicted maladaptive goal orientation, rather than the other way around. These findings provided further support for the contribution of goal orientations theory within medical education contexts. Medical schools are advised to consider motivational aspects when planning and implementing training programs. PMID- 24752654 TI - Inferring alterations in cell-to-cell communication in HER2+ breast cancer using secretome profiling of three cell models. AB - Challenges in demonstrating durable clinical responses to molecular-targeted therapies have sparked a re-emergence in viewing cancer as an evolutionary process. In somatic evolution, cellular variants are introduced through a random process of somatic mutation and are selected for improved fitness through a competition for survival. In contrast to Darwinian evolution, cellular variants that are retained may directly alter the fitness competition. If cell-to-cell communication is important for selection, the biochemical cues secreted by malignant cells that emerge should be altered to bias this fitness competition. To test this hypothesis, we compared the proteins secreted in vitro by two human HER2+ breast cancer cell lines (BT474 and SKBR3) relative to a normal human mammary epithelial cell line (184A1) using a proteomics workflow that leveraged two-dimensional gel electrophoresis (2DE) and MALDI-TOF mass spectrometry. Supported by the 2DE secretome maps and identified proteins, the two breast cancer cell lines exhibited secretome profiles that were similar to each other and, yet, were distinct from the 184A1 secretome. Using protein-protein interaction and pathway inference tools for functional annotation, the results suggest that all three cell lines secrete exosomes, as confirmed by scanning electron microscopy. Interestingly, the HER2+ breast cancer cell line exosomes are enriched in proteins involved in antigen-processing and presentation and glycolytic metabolism. These pathways are associated with two of the emerging hallmarks of cancer: evasion of tumor immunosurveillance and deregulating cellular energetics. PMID- 24752655 TI - Progesterone in transient ischemic stroke: a dose-response study. AB - RATIONALE: Previous studies demonstrate the neuroprotective effects of progesterone in numerous animal injury models, but a systematic dose-response study in a transient ischemic stroke model is lacking. OBJECTIVES: We investigated the effects of progesterone at different doses on post-stroke brain infarction and functional deficits in middle-aged rats. METHODS: Cerebral ischemia was induced in 13-month-old male Sprague-Dawley rats by right middle cerebral artery occlusion for 2 h followed by reperfusion. Rats received intraperitoneal injections of 8, 16, or 32 mg/kg of progesterone (P8, P16, P32) or vehicle at 2 h post-occlusion followed by subcutaneous injections at 6 h and every 24 h post-injury for 7 days. Functional recovery was evaluated at intervals over 22 days using motor, sensory, and cognitive tests. Infarct size was evaluated at 22 days post-stroke. RESULTS: Repeated-measures ANOVA showed significant group effects on grip strength, rotarod, and sensory neglect. All progesterone-treated groups had improved (p < 0.05) spatial memory performance. The P8 and P16 groups showed maximum improvement in long-term memory compared to vehicle. Significant (p < 0.05) gait impairments were observed in the vehicle group compared to shams. Animals receiving the P8 dose showed maximum gait improvement compared to vehicle. Post hoc analysis revealed that the P8 and P16 groups showed significant attenuation in infarct volume compared to vehicle. Animals receiving the P32 dose did not show any effect on infarct volume. CONCLUSIONS: Although all doses were somewhat effective, progesterone given at 8 mg/kg led to the most consistent improvements across a panel of behavioral/functional tests and reduced the severity of ischemic infarct injury. PMID- 24752656 TI - The self-administration of rapidly delivered cocaine promotes increased motivation to take the drug: contributions of prior levels of operant responding and cocaine intake. AB - RATIONALE: Rapid drug delivery to the brain might increase the risk for developing addiction. In rats, increasing the speed of intravenous cocaine delivery (5 vs. 90 s) increases drug intake and the subsequent motivation to self administer cocaine. Increased motivation for cocaine could result not only from more extensive prior drug intake and operant responding for drug, but also from neuroplasticity evoked by rapid drug uptake. OBJECTIVE: We determined the contributions of prior drug intake and operant responding to the increased motivation for cocaine evoked by rapid delivery. We also investigated the effects of cocaine delivery speed on corticostriatal expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) mRNA. METHODS: Rats self-administered cocaine (0.25 mg/kg/infusion) delivered over 5 or 90 s during short-access (1 h/session; ShA) or long-access (6 h; LgA) sessions. Motivation for cocaine was then assessed by measuring responding under a progressive ratio schedule of reinforcement. Next, BDNF and TrkB mRNA levels were measured in 5- and 90-s rats. RESULTS: Five-second ShA and 5-s-LgA rats were more motivated for cocaine than their 90-s counterparts. This effect was dissociable from previous levels of drug intake or of operant responding for cocaine. In parallel, only rats self-administering rapid cocaine injections had altered BDNF and TrkB mRNA levels in corticostriatal regions. CONCLUSIONS: Rapid drug delivery augments the motivation for cocaine independently of effects on the levels of drug intake or operant responding for drug. We suggest that rapid delivery might increase the motivation for drug by promoting neuroplasticity within reward pathways. This neuroplasticity could involve increased regulation of BDNF/TrkB. PMID- 24752657 TI - Effects of acute alcohol tolerance on perceptions of danger and willingness to drive after drinking. AB - RATIONALE: Drinking and driving is associated with elevated rates of motor vehicle accidents and fatalities. Previous research suggests that alcohol impairs judgments about the dangers of risky behaviors; however, how alcohol affects driving-related judgments is less clear. Impairments have also been shown to differ across limbs of the blood alcohol concentration (BAC) curve, which is known as acute tolerance. OBJECTIVES: The objectives of this study were to examine whether perceptions about the dangerousness of driving after drinking and willingness to drive differed across the ascending and descending limbs of the BAC curve and to test whether reductions in perceived danger were associated with willingness to drive on the descending limb. METHODS: Fifty-six participants were randomly assigned to receive either a moderate dose of alcohol (peak BAC = 0.10 g%) or placebo. We assessed perceived dangerousness and willingness to drive at matched BACs (~0.067-0.068 g%) on the ascending and descending limbs. RESULTS: Both perceived danger and willingness to drive showed acute tolerance in the alcohol group. Participants judged driving to be significantly less dangerous and were more willing to drive on the descending limb compared to the ascending limb. The magnitude of change in perceived danger significantly predicted willingness to drive on the descending limb. CONCLUSIONS: Decreased impairment associated with acute tolerance may lead individuals to underestimate the dangerousness of driving after drinking and in turn make poor decisions regarding driving. This study further emphasizes the descending limb as a period of increased risk and offers support for enhancing prevention efforts by targeting drivers at declining BAC levels. PMID- 24752658 TI - Differential regulation of observational fear and neural oscillations by serotonin and dopamine in the mouse anterior cingulate cortex. AB - RATIONALE: The aberrant regulation of serotonin (5-HT) and dopamine (DA) in the brain has been implicated in neuropsychiatric disorders associated with marked impairments in empathy, such as schizophrenia and autism. Many psychiatric drugs bind to both types of receptors, and the anterior cingulate cortex (ACC) is known to be centrally involved with empathy. However, the relationship between the 5 HT/DA system in the ACC and empathic behavior is not yet well known. OBJECTIVES: We investigated the role of 5-HT/DA in empathy-like behavior and in the regulation of ACC neural activity. METHODS: An observational fear learning task was conducted following microinjections of 5-HT, DA, 5-HT and DA, methysergide (5 HT receptor antagonist), SCH-23390 (DA D1 receptor antagonist), or haloperidol (DA D2 receptor antagonist) into the mouse ACC. The ACC neural activity influenced by 5-HT and DA was electrophysiologically characterized in vitro and in vivo. RESULTS: The microinjection of haloperidol, but not methysergide or SCH 23390, decreased the fear response of observing mice. The administration of 5-HT and 5-HT and DA together, but not DA alone, reduced the freezing response of observing mice. 5-HT enhanced delta-band activity and reduced alpha- and gamma band activities in the ACC, whereas DA reduced only alpha-band activity. Based on entropy, reduced complexity of ACC neural activity was observed with 5-HT treatment. CONCLUSIONS: The current results demonstrated that DA D2 receptors in the ACC are required for observational fear learning, whereas increased 5-HT levels disrupt observational fear and alter the regularity of ACC neural oscillations. PMID- 24752660 TI - Special issue in memory of Robert H. Purdy. PMID- 24752659 TI - Oxidative stress and the antipsychotic-induced vacuous chewing movement model of tardive dyskinesia: evidence for antioxidant-based prevention strategies. AB - RATIONALE: Despite decades of research, tardive dyskinesia (TD) remains a poorly understood iatrogenic movement disorder with few effective treatments and no known cure. Accordingly, the development of an innocuous strategy to prevent or mitigate antipsychotic (AP)-associated TD would represent an important clinical advance. Supporting evidence for antioxidant (AX)-based treatment regimens can be found in the preclinical literature, where AP-induced vacuous chewing movements (VCMs) in rats are attenuated by the concurrent administration of direct and indirect AXs. OBJECTIVES: Our aim was to review the preclinical literature examining the role of AX-promoting treatments in the prevention of AP-induced VCMs in rats. METHODS: A literature search using Google Scholar and PubMed was performed. Relevant results were qualitatively reviewed. RESULTS: Studies featuring a variety of naturally occurring and synthetic AX treatments were identified and included in the review. The majority of studies used haloperidol (HAL), a typical AP, to induce VCMs. Studies revealed reduced VCMs in co-treated rats, with favorable changes seen in markers of oxidative stress (OS) and AX status, but were limited by their short durations. CONCLUSIONS: Some preclinical evidence suggests that the inclusion of a naturally occurring and benign AX compound as an adjunct to AP treatment may help guard patients against TD, but additional long-duration studies are needed. This AX-based strategy is further substantiated by accumulating evidence of preexisting OS abnormalities in schizophrenia (SZ). PMID- 24752661 TI - Lentiviral-induced high-grade gliomas in rats: the effects of PDGFB, HRAS-G12V, AKT, and IDH1-R132H. AB - In human gliomas, the RTK/RAS/PI(3)K signaling pathway is nearly always altered. We present a model of experimental gliomagenesis that elucidates the contributions of genes involved in this pathway (PDGF-B ligand, HRAS-G12V, and AKT). We also examine the effect on gliomagenesis by the potential modifier gene, IDH1-R132H. Injections of lentiviral-encoded oncogenes induce de novo gliomas of varying penetrance, tumor progression, and histological grade depending on the specific oncogenes used. Our model mimics hallmark histological structures of high-grade glioma, such as pseudopalisades, glomeruloid microvascular proliferation, and diffuse tumor invasion. We use our model of gliomagenesis to test the efficacy of an experimental brain tumor gene therapy. Our model allowed us to test the contributions of oncogenes in the RTK/RAS/PI(3)K pathway, and their potential modification by over-expression of mutated IDH1, in glioma development and progression in rats. Our model constitutes a clinically relevant system to study gliomagenesis, the effects of modifier genes, and the efficacy of experimental therapeutics. PMID- 24752662 TI - Complex refractive indices in the near-ultraviolet spectral region of biogenic secondary organic aerosol aged with ammonia. AB - Atmospheric absorption by brown carbon aerosol may play an important role in global radiative forcing. Brown carbon arises from both primary and secondary sources, but the mechanisms and reactions of the latter are highly uncertain. One proposed mechanism is the reaction of ammonia or amino acids with carbonyl products in secondary organic aerosol (SOA). We generated SOA in situ by reacting biogenic alkenes (alpha-pinene, limonene, and alpha-humulene) with excess ozone, humidifying the resulting aerosol, and reacting the humidified aerosol with gaseous ammonia. We determined the complex refractive indices (RI) in the 360-420 nm range for these aerosols using broadband cavity enhanced spectroscopy (BBCES). The average real part (n) of the measured spectral range of the NH3-aged alpha pinene SOA increased from n = 1.50 (+/-0.01) for the unreacted SOA to n = 1.57 (+/-0.01) after 1.5 h of exposure to 1.9 ppm NH3, whereas the imaginary component (k) remained below k < 0.001((+0.002)(-0.001)). For the limonene and alpha humulene SOA the real part did not change significantly, and we observed a small change in the imaginary component of the RI. The imaginary component increased from k = 0.000 to an average k = 0.029 (+/-0.021) for alpha-humulene SOA, and from k < 0.001((+0.002)(-0.001)) to an average k = 0.032 (+/-0.019) for limonene SOA after 1.5 h of exposure to 1.3 and 1.9 ppm of NH3, respectively. Collected filter samples of the aged and unreacted alpha-pinene SOA and limonene SOA were analyzed off-line by nanospray desorption electrospray ionization high resolution mass spectrometry (nano-DESI/HR-MS), and in situ using a Time-of-Flight Aerosol Mass Spectrometer (ToF-AMS), confirming that the SOA reacted and that various nitrogen-containing reaction products formed. If we assume that NH3 aging reactions scale linearly with time and concentration, which will not necessarily be the case in the atmosphere, then a 1.5 h reaction with 1 ppm NH3 in the laboratory is equivalent to 24 h reaction with 63 ppbv NH3, indicating that the observed aerosol absorption will be limited to atmospheric regions with high NH3 concentrations. PMID- 24752663 TI - Single-trocar thoracoscopy under local anesthesia for pleural space infection. AB - OBJECTIVE: The role of single-trocar thoracoscopy for complicated parapneumonic effusion (CPE) and pleural empyema is not established as yet. The aim of this study was to report our experience and analyze the efficacy and safety of debridement by single-trocar thoracoscopy for the patients with CPE and multiloculated empyema. METHODS: We performed a retrospective study reviewing the medical records of the patients treated parapneumonic effusion and multiloculated empyema by single-trocar thoracoscopy under local anesthesia at our department from January 2000 to December 2012. RESULTS: A total 29 patients with CPE and multiloculated empyema were treated by single-trocar thoracoscopy. As the staging of pleural infection, class 5 and class 7 by Light classification were 21 and 8 patients, respectively. The onset of the symptom was on average 13.9 +/- 11.7 days before the procedure. This procedure was successful in 23 of 29 patients (79.3%) without further operation under general anesthesia. Complication occurred in 1 case of 29 patients (3.4%). Six patients required subsequently the operation under general anesthesia, and one of the 6 patients died to multiple organ failure caused by sepsis. A microbiological diagnosis could be made in fifteen patients (51.7%). CONCLUSIONS: Debridement by single-trocar thoracoscopy can be an acceptable approach as the first-line procedure in patients with CPE and empyema. This procedure can provide not only appropriate and expeditious treatment but also information of pleural cavity to decide indication for thoracotomy under general anesthesia. PMID- 24752664 TI - Skull base osteomyelitis: incidence of resistance, morbidity, and treatment strategy. AB - OBJECTIVES/HYPOTHESIS: The pathogeny of osteomyelitis of the skull base has evolved over time with the emergence of ciprofloxacin-resistant Pseudomonas strains and significant fungal infections, both of which seem to bring a higher morbidity. The aims of this study were 1) to document the incidence of ciprofloxacin-resistant Pseudomonas aeruginosa over the past 7 years; 2) to assess morbidity by a radiologic score, the occurrence of cranial nerve palsies, and the duration of the hospital stay, according to the pathogenesis; and 3) to propose a treatment strategy. STUDY DESIGN: Retrospective chart review of necrotizing external otitis cases from 2004 to 2011. The setting was the Department of ENT Surgery, Lariboisiere Hospital, Paris. METHODS: Thirty-one patients were included. Radiological scores were assessed based on the initial computed tomography scans or magnetic resonance imaging, which specified the anatomical territory involved. Nerve palsies, the duration of hospitalization, and the radiological scores were analyzed with regard to the pathogen. RESULTS: Twenty-eight patients had a bacterial disease. Of the 20 strains of P. aeruginosa identified, five (25%) were ciprofloxacin-resistant P. aeruginosa. Three patients (10%) had a fungal infection due to Aspergillus flavus. Nerve palsies, radiological scores, and hospitalization durations were significantly higher for patients with resistant strains and A. flavus. CONCLUSIONS: In our series, the prevalence of ciprofloxacin-resistant Pseudomonas strains increased over time. Along with fungal infections, they formed a group with a higher morbidity than that of ciprofloxacin-sensitive Pseudomonas infections that furthermore did not respond to oral outpatient treatment. This is why pathogen identification using biopsies is sometimes required to start a prolonged treatment. PMID- 24752665 TI - The Sex Ratio of Full and Half Siblings of People Diagnosed With ADHD in Childhood and Adolescence: A Danish Nationwide Register-Based Cohort Study. AB - OBJECTIVE: It has been suggested that high levels of prenatal testosterone exposure are implied in the etiology of male preponderance disorders such as autism spectrum disorder and ADHD. Within this scope, we studied the sex ratio (proportion of males) in siblings of individuals diagnosed with ADHD in childhood and adolescence. METHOD: We did a nationwide, register-based cohort study of the sex ratio in siblings of the 16,381 patients in Denmark diagnosed with ADHD at age 17 years and younger and registered in the nationwide Danish Psychiatric Central Register between January 1, 1994 and May 28, 2013. RESULTS: Among the 33,151 siblings, 17,041 were males and 16,110 females. This yields a sex ratio of 0.514, which is not statistically significant different from the Danish live birth sex ratio of 0.513 during the relevant years (p = .70). CONCLUSION: These findings provide no support for the hypothesis that the sex ratio is elevated among the siblings of people with ADHD. PMID- 24752667 TI - Molecularly imprinted nanoparticles as tailor-made sensors for small fluorescent molecules. AB - Water-soluble nanoparticles molecularly imprinted against naphthyl derivatives could bind the templates with high affinity and excellent selectivity among structural analogues in aqueous solution. Fluorescent dansyl groups installed during template polymerization allowed these nanoparticles to detect the presence of the target analytes by Forster resonance energy transfer. PMID- 24752666 TI - Ablation of ErbB4 from excitatory neurons leads to reduced dendritic spine density in mouse prefrontal cortex. AB - Dendritic spine loss is observed in many psychiatric disorders, including schizophrenia, and likely contributes to the altered sense of reality, disruption of working memory, and attention deficits that characterize these disorders. ErbB4, a member of the EGF family of receptor tyrosine kinases, is genetically associated with schizophrenia, suggesting that alterations in ErbB4 function contribute to the disease pathology. Additionally, ErbB4 functions in synaptic plasticity, leading us to hypothesize that disruption of ErbB4 signaling may affect dendritic spine development. We show that dendritic spine density is reduced in the dorsomedial prefrontal cortex of ErbB4 conditional whole-brain knockout mice. We find that ErbB4 localizes to dendritic spines of excitatory neurons in cortical neuronal cultures and is present in synaptic plasma membrane preparations. Finally, we demonstrate that selective ablation of ErbB4 from excitatory neurons leads to a decrease in the proportion of mature spines and an overall reduction in dendritic spine density in the prefrontal cortex of weanling (P21) mice that persists at 2 months of age. These results suggest that ErbB4 signaling in excitatory pyramidal cells is critical for the proper formation and maintenance of dendritic spines in excitatory pyramidal cells. PMID- 24752668 TI - Thermogenesis, vocalization, and temperature preference of 1-day-old chicken hatchlings after cold-exposure in late embryogenesis. AB - In a thermal gradient the preferred ambient temperature (T(a) pref) of chicken hatchlings is a few degrees lower than thermoneutrality. To investigate whether a correlation may exist between T(a) pref and the autonomic thermogenic capacity or not we studied a group of hatchlings (N = 15) exposed to cold at end-incubation, a procedure known to increase their postnatal thermogenesis. Chicken embryos were exposed to cold (34.5 degrees C instead of 38 degrees C) at days 18-20 of incubation. By comparison to Controls (N = 15), they hatched a few hours later, with similar body weight, body temperature, vocalization (number of sounds produced per unit time), and oxygen consumption (VO2, measured in a respirometer by an open-flow methodology). When exposed to slow cooling these hatchlings had a higher lower critical temperature (LCT) of thermoneutrality and higher VO2, and slightly higher vocalization than Controls. In a thermal gradient, T(a) pref averaged 34.3 +/- 0.3 degrees C, or 1 degrees C higher than in Controls (33.4 +/- 0.3 degrees C; P < 0.05), in proportion with their higher LCT (38 +/- 0.1 degrees C instead of 36.7 +/- 0.3 degrees C; P < 0.001), so that the T(a) pref - LCT difference (-3.6 +/- 0.3 degrees C) was similar to Controls (-3.3 +/- 0.3 degrees C). In conclusion, in chicken hatchlings T(a) pref was lower than LCT irrespective of the magnitude of their thermogenic response. It was estimated that, at T(a) pref, VO2 was ~20 % higher than at thermoneutrality. Such metabolic increase could carry some physiological advantage and the choice of T a pref may reflect the hatchling's needs to maintain VO2 slightly elevated. PMID- 24752669 TI - Evidence for role of acid-sensing ion channels in nucleus ambiguus neurons: essential differences in anesthetized versus awake rats. AB - Acid-sensing ion channels (ASIC) are widely expressed in several brain regions including medulla; their role in physiology and pathophysiology is incompletely understood. We examined the effect of acidic pH of 6.2 on the medullary neurons involved in parasympathetic cardiac control. Our results indicate that retrogradely labeled cardiac vagal neurons of nucleus ambiguus are depolarized by acidic pH. In addition, acidic saline of pH 6.2 increases cytosolic Ca(2+) concentration by promoting Ca(2+) influx in nucleus ambiguus neurons. In vivo studies indicate that microinjection of acidic artificial cerebrospinal fluid (pH 6.2) into the nucleus ambiguus decreases the heart rate in conscious rats, whereas it has no effect in anesthetized animals. Pretreatment with either amiloride or benzamil, two widely used ASIC blockers, abolishes both the in vitro and in vivo effects elicited by pH 6.2. Our findings support a critical role for ASIC in modulation of cardiac vagal tone and provide a potential mechanism for acidosis-induced bradycardia, while identifying important differences in the response to acidic pH between anesthetized and conscious rats. PMID- 24752671 TI - Prognostic value of metabolic tumor volume and total lesion glycolysis in head and neck cancer: a systematic review and meta-analysis. AB - We conducted a comprehensive systematic review of the literature on volumetric parameters and a meta-analysis of the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with head and neck cancer (HNC). METHODS: A systematic search of MEDLINE and EMBASE was performed using the key words PET, head and neck, and volume. Inclusion criteria were (18)F-FDG PET used as an initial imaging tool; studies limited to HNC; patients who had not undergone surgery, chemotherapy, or radiotherapy before PET scans; and studies reporting survival data. Event-free survival and overall survival were considered markers of outcome. The impact of MTV or TLG on survival was measured by the effect size hazard ratio (HR). Data from each study were analyzed using Review Manager. RESULTS: Thirteen studies comprising 1,180 patients were included in this study. The combined HR for adverse events was 3.06 (2.33-4.01, P < 0.00001) with MTV and 3.10 (2.27-4.24, P < 0.00001) with TLG, meaning that tumors with high volumetric parameters were associated with progression or recurrence. Regarding overall survival, the pooled HR was 3.51 (2.62-4.72, P < 0.00001) with MTV and 3.14 (2.24-4.40, P < 0.00001) with TLG. There was no evidence of significant statistical heterogeneity at an I(2) of 0%. CONCLUSION: MTV and TLG are prognostic predictors of outcome in patients with HNC. Despite clinically heterogeneous HNC and the various methods adopted between studies, we can confirm that patients with a high MTV or TLG have a higher risk of adverse events or death. PMID- 24752672 TI - Textural Parameters of Tumor Heterogeneity in 18F-FDG PET/CT for Therapy Response Assessment and Prognosis in Patients with Locally Advanced Rectal Cancer. AB - (18)F-FDG PET/CT is effective in the assessment of therapy response. Changes in glucose uptake or tumor size are used as a measure. Tumor heterogeneity was found to be a promising predictive and prognostic factor. We investigated textural parameters for their predictive and prognostic capability in patients with rectal cancer using histopathology as the gold standard. In addition, a comparison to clinical outcome was performed. METHODS: Twenty-seven patients with rectal cancer underwent (18)F-FDG PET/CT before, 2 wk after the start, and 4 wk after the completion of neoadjuvant chemoradiotherapy. In all PET/CT scans, conventional parameters (tumor volume, diameter, maximum and mean standardized uptake values, and total lesion glycolysis [TLG]) and textural parameters (coefficient of variation [COV], skewness, and kurtosis) were determined to assess tumor heterogeneity. Values on pretherapeutic PET/CT as well as changes early in the course of therapy and after therapy were compared with histopathologic response. In addition, the prognostic value was assessed by correlation with time to progression and survival time. RESULTS: The COV showed a statistically significant capability to assess histopathologic response early in therapy (sensitivity, 68%; specificity, 88%) and after therapy (79% and 88%, respectively). Thereby, the COV had a higher area under the curve in receiver operating-characteristic analysis than did any analyzed conventional parameter for early and late response assessment. The COV showed a statistically significant capability to evaluate disease progression and to predict survival, although the latter was not statistically significant. CONCLUSION: Tumor heterogeneity assessed by the COV, being superior to the investigated conventional parameters, is an important predictive factor in patients with rectal cancer. Furthermore, it can provide prognostic information. Therefore, its application is an important step for personalized treatment of rectal cancer. PMID- 24752673 TI - Optical Imaging of Renal Cell Carcinoma with Anti-Carbonic Anhydrase IX Monoclonal Antibody Girentuximab. AB - Near-infrared dye-tagged antibodies can be used for the sensitive detection of tumor tissue in vivo. Surgery for clear-cell renal cell carcinoma (ccRCC) might benefit from the use of optical imaging to facilitate the intraoperative detection of carbonic anhydrase IX (CAIX)-expressing tumor lesions with chimeric monoclonal antibody (mAb) girentuximab, which has been shown to have excellent imaging capabilities for ccRCC. Here we studied the potential of fluorescence imaging to detect ccRCC tumors in nude mice with RCC xenografts by using mAb girentuximab conjugated with IRDye800CW; SPECT imaging was used as a reference. METHODS: Groups of athymic BALB/c mice with subcutaneous CAIX-positive SK-RC-52 ccRCC tumors were injected intravenously with (125)I-labeled girentuximab IRDye800CW or (125)I-labeled girentuximab. For determination of the specificity of the accumulation of the anti-CAIX antibody conjugate in ccRCC, separate groups of mice bearing a CAIX-positive tumor (SK-RC-52) and a CAIX-negative tumor (SK-RC 59) received (125)I-girentuximab-IRDye800CW or (125)I-labeled MOPC21-IRDye800CW (control mAb). Optical images and micro-SPECT images were acquired until 3 d after injection. Mice were euthanized after the last imaging session, and the biodistribution of the radiolabeled antibody preparations was determined. RESULTS: Optical imaging and micro-SPECT imaging at 1 d after the injection of (125)I-girentuximab-IRDye800CW showed clear delineation of the CAIX-expressing ccRCC xenografts, and image contrast improved with time. Fluorescence imaging and biodistribution studies showed high and specific uptake of (125)I-girentuximab IRDye800CW in CAIX-positive ccRCC xenografts (SK-RC-52, 31.5 +/- 9.6 percentage injected dose per gram [%ID/g] at 72 h after injection). Tumor uptake was specific, as very low uptake of (125)I-girentuximab-IRDye800CW was noted in the CAIX-negative SK-RC-59 tumor (4.1 +/- 1.5 %ID/g), and no uptake of (125)I-MOPC21 IRDye800CW (control mAb) was noted in the CAIX-positive SK-RC-52 tumor (1.2 +/- 0.1 %ID/g). CONCLUSION: Subcutaneous CAIX-expressing ccRCC xenografts were visualized by optical imaging with (125)I-girentuximab-IRDye800CW. Optical images showed good concordance with micro-SPECT images. The accumulation of (125)I girentuximab-IRDye800CW in ccRCC tumors was high and specific. Girentuximab IRDye800CW potentially could be used for the intraoperative detection of CAIX expressing tumors and the assessment of residual tumor in resection margins or metastatic lesions in patients with ccRCC. PMID- 24752674 TI - Ethanol-Based Post-processing of Generator-Derived 68Ga Toward Kit-Type Preparation of 68Ga-Radiopharmaceuticals. AB - Post-processing by means of a cation-exchanger-based protocol is an efficient strategy for purification and concentration of generator-derived (68)Ga. It ensures the removal of (68)Ge before (68)Ga-radiopharmaceutical preparation and high labeling yields of (68)Ga-labeled radiopharmaceuticals for routine medical application. METHODS: In an effort to overcome the problem associated with acetone in the currently applied method, we have investigated the feasibility of replacing it with ethanol. The purification of (68)Ga from coeluted metallic impurities ((68)Ge(4+), Fe(3+), Zn(2+), and Ti(4+)) on various cation-exchange columns has been investigated with a variety of post-processing solutions. As a proof of principle, the post-processed (68)Ga was used to radiolabel DOTATOC in combination with high-purity water and various buffer solutions. RESULTS: An effective protocol for the processing of generator-produced (68)Ga on the basis of cation-exchange chromatography using EtOH/HCl medium has been developed. Up to 95% of the initially eluted (68)Ga activity can be collected in a 1-mL fraction of 90% EtOH/0.9N HCl after removal of (68)Ge-breakthrough in a washing step. The post-processed eluate has been used to radiolabel DOTATOC in yields of approximately 97% +/- 0.25% at 80 degrees C in 5 min. CONCLUSION: The described novel protocol improves the radiolabeling efficiency and efficacy of DOTATOC, providing yields of greater than 99% (decay-corrected). As a result, further purification to separate the desired product from uncomplexed (68)Ga is not necessary. The developed post-processing and labeling protocols permit reliable and high-yield preparation of injectable (68)Ga-DOTATOC (or other (68)Ga-labeled radiopharmaceuticals) that are suitable for routine application. It is possible to incorporate this protocol into existing automated modules. PMID- 24752675 TI - LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells. AB - LAMTOR2 (p14), a part of the larger LAMTOR/Ragulator complex, plays a crucial role in EGF-dependent activation of p42/44 mitogen-activated protein kinases (MAPK, ERK1/2). In this study, we investigated the role of LAMTOR2 in nerve growth factor (NGF)-mediated neuronal differentiation. Stimulation of PC12 (rat adrenal pheochromocytoma) cells with NGF is known to activate the MAPK. Pharmacological inhibition of MEK1 as well as siRNA-mediated knockdown of both p42 and p44 MAPK resulted in inhibition of neurite outgrowth. Contrary to expectations, siRNA-mediated knockdown of LAMTOR2 effectively augmented neurite formation and neurite length of PC12 cells. Ectopic expression of a siRNA resistant LAMTOR2 ortholog reversed this phenotype back to wildtype levels, ruling out nonspecific off-target effects of this LAMTOR2 siRNA approach. Mechanistically, LAMTOR2 siRNA treatment significantly enhanced NGF-dependent MAPK activity, and this effect again was reversed upon expression of the siRNA resistant LAMTOR2 ortholog. Studies of intracellular trafficking of the NGF receptor TrkA revealed a rapid colocalization with early endosomes, which was modulated by LAMTOR2 siRNA. Inhibition of LAMTOR2 and concomitant destabilization of the remaining members of the LAMTOR complex apparently leads to a faster release of the TrkA/MAPK signaling module and nuclear increase of activated MAPK. These results suggest a modulatory role of the MEK1 adapter protein LAMTOR2 in NGF-mediated MAPK activation required for induction of neurite outgrowth in PC12 cells. PMID- 24752676 TI - Synthesis and characterization of novel zinc phthalocyanines as potential photosensitizers for photodynamic therapy of cancers. AB - Two novel zinc phthalocyanines (Pcs): tetramethyl tetrakis-2,(3)-[(4-methyl-2 pyridyloxy)phthalocyaninato] zinc(II) (4) and (the negatively charged form) tetrakis-2,(3)-[(3-carboxylicacid-6-sulfanylpyridine)phthalocyaninato] zinc(II) (5), water soluble by virtue of their ionic substituent groups were synthesized. The spectroscopic properties of both compounds were determined and their photodynamic activities were investigated in a human tumor cell model. In aqueous media the two peripherally substituted water soluble Pcs are highly aggregated. The phototoxic activity of the two novel Pcs (Pc 4 and Pc 5; 0-20 MUM) was shown to be time- and dose-dependent in human pancreatic carcinoid BON cells, leading to a reduction of tumor cells of >80% compared to the controls. The effectiveness of the treatment appeared to be attenuated by the aggregation of Pcs under aqueous conditions. Interestingly, even those cells that were not immediately killed by the photoactivated photosensitizer seemed to be affected by the Pc photodynamic activity, as a single PDT induced long-lasting effects on cell survival. Even 4 days after PDT, the number of surviving cells did not re increase or still dropped, as compared to control cells. The underlying mechanism of this observation has to be deciphered in future investigations. PMID- 24752677 TI - The neural substrates of self-evaluation of mental fatigue: a magnetoencephalography study. AB - There have been several studies of the neural mechanisms underlying sensation of fatigue. However, little is known about the neural mechanisms underlying self evaluation of the level of fatigue. The aim of this study was to identify the neural substrates involved in self-evaluation of the level of mental fatigue. We used magnetoencephalography (MEG) with high temporal resolution on 14 healthy participants. During MEG recordings, participants were asked to evaluate their level of mental fatigue in time with execution cues (evaluation trials) or to do nothing in time with execution cues (control trials). The MEG data were analyzed with equivalent current dipole (ECD) and spatial filtering methods to localize the neural activity related to the evaluation of mental fatigue. The daily level of fatigue sensation was assessed using the Checklist Individual Strength questionnaire. In evaluation trials, ECDs were observed in the posterior cingulate cortex (PCC) in seven of 14 participants, with a mean latency of 366.0 ms. The proportion of the participants with ECDs in the PCC was higher in evaluation trials than in control trials (P<0.05, McNemar test). The extent of the decreased delta band power in the PCC (Brodmann's area 31) 600-700 ms after the onset of the execution cue and that in the dorsolateral prefrontal cortex (DLPFC; Brodmann's area 9) 800-900 ms after the onset of the execution cue were greater in the evaluation trials than in the control trials. The decrease in delta band power in the DLPFC was positively related to that in the PCC and to the daily level of fatigue sensation. These data suggest that the PCC and DLPFC are involved in the self-evaluation of mental fatigue. PMID- 24752678 TI - Distinguishing neuromuscular disorders based on the passive electrical material properties of muscle. AB - INTRODUCTION: The passive electrical properties of muscle, including conductivity and permittivity and their directional dependence, may be altered in neuromuscular disease; however, the character of these alterations is unknown. METHODS: Fifteen wild-type mice, 13 amyotrophic lateral sclerosis mice, 9 muscular dystrophy (mdx) mice, and 15 mice with induced disuse atrophy were euthanized, and the gastrocnemius was excised. A 50-kHz current was applied immediately to the ex vivo muscle, and its material properties were calculated. RESULTS: The disease groups showed distinct material property values [F(12, 119) = 14.6, P < 0.001] according to MANOVA. Post-hoc tests confirmed that differences existed between all 4 groups. They were most pronounced in the mdx mice, which had markedly increased conductivity. Direction-dependent properties of current flow also were significantly different among the groups (P < 0.001). CONCLUSIONS: These data confirm that the inherent passive electrical properties of muscle differ by disease type. We anticipate that similar data could eventually be obtained via surface measurements, providing an innovative approach to muscle disease diagnosis. PMID- 24752679 TI - Symbolizing as interpersonally grounded shifts in meaning: social play in children with and without autism. AB - The aim of this study was to examine the relation between symbolic play and communicative engagement among children with and without autism. Our predictions were firstly, that in moment-by-moment interactions during semi-structured interactive play with an adult, children with and without autism would tend to show shifts in meanings in symbolic play when engaged in coordinated states of joint engagement (events involving 'sharing-of-meaning'); secondly, that across atypically developing participants, sharing-of-meaning would (a) correlate with scores on a standardized test of pretend play, and (b) be inversely correlated with scores on the Autism Diagnostic Observation Schedule; and finally, that participants with autism would contrast with matched developmentally delayed participants in manifesting lower levels of joint engagement, lower levels of symbolic play, and fewer shifts in symbolic meaning. Each of these predictions was borne out. The intimate developmental relation between social engagement and symbolic play appears to be important for explaining the developmental psychopathology of autism. PMID- 24752680 TI - Melatonin in children with autism spectrum disorders: endogenous and pharmacokinetic profiles in relation to sleep. AB - Supplemental melatonin has been used to treat sleep onset insomnia in children with autism spectrum disorders (ASD), although the mechanism of action is uncertain. We assessed endogenous and supplemental melatonin profiles in relation to sleep in nine children with ASD. In endogenous samples, maximal melatonin concentration (C(max)) and time to peak concentration (T(max)) were comparable to those previously published in the literature for typically developing children, and dim light melatonin onsets were captured in the majority of children. In treatment samples (supplemental melatonin), melatonin parameters were also comparable to those previously published for typically developing children. Our findings support that children with ASD and insomnia responsive to low dose melatonin treatment have relatively normal profiles of endogenous and supplemental melatonin. PMID- 24752681 TI - Brief report: emotion regulation and respiratory sinus arrhythmia in autism spectrum disorder. AB - Emotion regulation (ER) may be an important transdiagnostic factor for understanding mental and behavioral health given its association with several psychiatric disorders, including autism spectrum disorder (ASD). However, there is limited research on ER in ASD, particularly using biomarkers such as respiratory sinus arrhythmia (RSA). The aim of the current study was to examine RSA among school-aged children with ASD in relation to symptoms of anxiety, executive functioning, and adaptive socialization skills. Results showed decreased RSA in children with ASD (relative to typically developing controls), reflecting decreased parasympathetic nervous system activity. In addition, decreased RSA was associated with increased symptoms of anxiety and lower socialization skills. These findings emphasize the need for interventions targeting emotional and arousal regulation in ASD. PMID- 24752682 TI - Efficacy of three different regimens of primaquine for the prevention of relapses of Plasmodium vivax malaria in the Amazon Basin of Peru. AB - We evaluated the efficacy of three primaquine (PQ) regimes to prevent relapses with Plasmodium vivax through an open-label randomized trial in Loreto, Peru. Vivax monoinfections were treated with chloroquine for 3 days and PQ in three different regimes: 0.5 mg/kg per day for 5 days (150 mg total), 0.5 mg/kg per day for 7 days (210 mg total), or 0.25 mg/kg per day for 14 days (210 mg total). Biweekly fever assessments and bimonthly thick smears were taken for 210 days. Recurrences after 35 days were considered relapses. One hundred eighty cases were enrolled in each group; 90% of cases completed follow-up. There were no group related differences in age, sex, or parasitemia. Relapse rates were similar in the 7- and 14-day regimes (16/156 = 10.3% and 22/162 = 13.6%, P = 0.361) and higher in the 5-day group (48/169 = 28.4%, P < 0.001 and P = 0.001, respectively). The 7-day PQ regimen used in Peru is as efficacious as the recommended 14-day regimen and superior to 5 treatment days. PMID- 24752684 TI - Pernicious and threatening Plasmodium vivax as reality. PMID- 24752683 TI - Plasmodium vivax hospitalizations in a monoendemic malaria region: severe vivax malaria? AB - Severe malaria caused by Plasmodium vivax is no longer considered rare. To describe its clinical features, we performed a retrospective case control study in the subregion of Luciano Castillo Colonna, Piura, Peru, an area with nearly exclusive vivax malaria transmission. Severe cases and the subset of critically ill cases were compared with a random set of uncomplicated malaria cases (1:4). Between 2008 and 2009, 6,502 malaria cases were reported, including 106 hospitalized cases, 81 of which fit the World Health Organization definition for severe malaria. Of these 81 individuals, 28 individuals were critically ill (0.4%, 95% confidence interval = 0.2-0.6%) with severe anemia (57%), shock (25%), lung injury (21%), acute renal failure (14%), or cerebral malaria (11%). Two potentially malaria-related deaths occurred. Compared with uncomplicated cases, individuals critically ill were older (38 versus 26 years old, P < 0.001), but similar in other regards. Severe vivax malaria monoinfection with critical illness is more common than previously thought. PMID- 24752685 TI - Improving the radical cure of Plasmodium vivax malaria. PMID- 24752686 TI - Absence of close-range excitorepellent effects in malaria mosquitoes exposed to deltamethrin-treated bed nets. AB - Flight behavior of insecticide-resistant and susceptible malaria mosquitoes approaching deltamethrin-treated nets was examined using a wind tunnel. Behavior was linked to resulting health status (dead or alive) using comparisons between outcomes from free-flight assays and standard World Health Organization (WHO) bioassays. There was no difference in response time, latency time to reach the net, or spatial distribution in the wind tunnel between treatments. Unaffected resistant mosquitoes spent less time close to (< 30 cm) treated nets. Nettings that caused high knockdown or mortality in standard WHO assays evoked significantly less mortality in the wind tunnel; there was no excitorepellent effect in mosquitoes making contact with the nettings in free flight. This study shows a new approach to understanding mosquito behavior near insecticidal nets. The methodology links free-flight behavior to mosquito health status on exposure to nets. The results suggest that behavioral assays can provide important insights for evaluation of insecticidal effects on disease vectors. PMID- 24752687 TI - A new molecular surveillance system for leishmaniasis. AB - Presently, global efforts are being made to control and eradicate the deadliest tropical diseases through the improvement of adequate interventions. A critical point for programs to succeed is the prompt and accurate diagnosis in endemic regions. Rapid diagnostic tests (RDTs) are being massively deployed and used to improve diagnosis in tropical countries. In the present report, we evaluated the hypothesis of, after use for diagnosis, the reuse of the Leishmania RDT kit as a DNA source, which can be used downstream as a molecular surveillance and/or quality control tool. As a proof of principle, a polymerase chain reaction-based method was used to detect Leishmania spp. minicircle kinetoplast DNA from leishmaniasis RDT kits. Our results show that Leishmania spp. DNA can be extracted from used RDTs and may constitute an important, reliable, and affordable tool to assist in future leishmaniasis molecular surveillance methods. PMID- 24752688 TI - Dengue virus in bats from southeastern Mexico. AB - To identify the relationship between landscape use and dengue virus (DENV) occurrence in bats, we investigated the presence of DENV from anthropogenically changed and unaltered landscapes in two Biosphere Reserves: Calakmul (Campeche) and Montes Azules (Chiapas) in southern Mexico. Spleen samples of 146 bats, belonging to 16 species, were tested for four DENV serotypes with standard reverse transcriptase polymerase chain reaction (RT-PCR) protocols. Six bats (4.1%) tested positive for DENV-2: four bats in Calakmul (two Glossophaga soricina, one Artibeus jamaicensis, and one A. lituratus) and two bats in Montes Azules (both A. lituratus). No effect of anthropogenic disturbance on the occurrence of DENV was detected; however, all three RT-PCR-positive bat species are considered abundant species in the Neotropics and well-adapted to disturbed habitats. To our knowledge, this study is the first study conducted in southeastern Mexico to identify DENV-2 in bats by a widely accepted RT-PCR protocol. The role that bats play on DENV's ecology remains undetermined. PMID- 24752690 TI - Overproduction of fatty acids in engineered Saccharomyces cerevisiae. AB - The long hydrocarbon fatty acyl chain is energy rich, making it an ideal precursor for liquid transportation fuels and high-value oleo chemicals. As Saccharomyces cerevisiae has many advantages for industrial production compared to Escherichia coli. Here, we attempted to engineer Saccharomyces cerevisiae for overproduction of fatty acids. First, disruption of the beta-oxidation pathway, elimination of the acyl-CoA synthetases, overexpression of different thioesterases and acetyl-CoA carboxylase ACC1, and engineering the supply of precursor acetyl-CoA. The engineered strain XL122 produced more than 120 mg/L of fatty acids. In parallel, we inactivated ADH1, the dominant gene for ethanol production, to redirect the metabolic flux to fatty acids synthesis. The engineered strain DG005 produced about 140 mg/L fatty acids. Additionally, Acetyl CoA carboxylase was identified as a critical bottleneck of fatty acids synthesis in S. cerevisiae with a cell-free system. However, overexpression of ACC1 has little effect on fatty acids biosynthesis. As it has been reported that phosphorylation of ACC1 may influent its activity, so phosphorylation sites of ACC1 were further identified. Although the regulatory mechanisms remain unclear, our results provide rationale for future studies to target this critical step. All these efforts, particularly the discovery of the limiting step are critical for developing a "cell factory" for the overproduction of fatty acids by using type I fatty acids synthase in yeast or other fungi. PMID- 24752689 TI - Maripa hantavirus in French Guiana: phylogenetic position and predicted spatial distribution of rodent hosts. AB - A molecular screening of wild-caught rodents was conducted in French Guiana, South America to identify hosts of the hantavirus Maripa described in 2008 in a hantavirus pulmonary syndrome (HPS) case. Over a 9-year period, 418 echimyids and murids were captured. Viral RNA was detected in two sigmodontine rodents, Oligoryzomys fulvescens and Zygodontomys brevicauda, trapped close to the house of a second HPS case that occurred in 2009 and an O. fulvescens close to the fourth HPS case identified in 2013. Sequences from the rodents had 96% and 97% nucleotide identity (fragment of S and M segments, respectively) with the sequence of the first human HPS case. Phylogenetic reconstructions based on the complete sequence of the S segment show that Maripa virus is closely related to Rio Mamore hantavirus. Using environmental descriptors of trapping sites, including vegetation, landscape units, rain, and human disturbance, a maximal entropy-based species distribution model allowed for identification of areas of higher predicted occurrence of the two rodents, where emergence risks of Maripa virus are expected to be higher. PMID- 24752691 TI - Distal migration of a transanastomotic pancreatic stent resulting in bowel perforation 19 years after pancreatoduodenectomy: report of a case. AB - A 75-year-old woman who had undergone pancreatoduodenectomy 19 years earlier was referred to us for investigation of progressive abdominal pain without conclusive preliminary complementary tests. Computed tomography enabled us to identify that the transanastomotic pancreatic stent had migrated distally, resulting in bowel perforation. She underwent surgery and the foreign body was removed. PMID- 24752693 TI - History of Polish analytical chemistry since 1945. PMID- 24752692 TI - Evaluation of the toxicity of ZnO nanoparticles to Chlorella vulgaris by use of the chiral perturbation approach. AB - The toxicity of ZnO nanoparticles (NPs) has been widely investigated because of their extensive use in consumer products. The mechanism of the toxicity of ZnO NPs to algae is unclear, however, and it is difficult to differentiate between particle-induced toxicity and the effect of dissolved Zn(2+). In the work discussed in this paper we investigated particle-induced toxicity and the effects of dissolved Zn(2+) by using the chiral perturbation approach with dichlorprop (DCPP) as chiral perturbation factor. The results indicated that intracellular zinc is important in the toxicity of ZnO NPs, and that ZnO NPs cause oxidative damage. According to dose-response curves for DCPP and the combination of ZnO NPs with (R)-DCPP or (S)-DCPP, the toxicity of DCPP was too low to perturb the toxicity of ZnO NPs, so DCPP was suitable for use as chiral perturbation factor. The different glutathione (GSH) content of algal cells exposed to (R)-DCPP or (S) DCPP correlated well with different production of reactive oxygen species (ROS) after exposure to the two enantiomers. Treatment of algae with ZnO NPs and (R) DCPP resulted in reduced levels of GSH and the glutathione/oxidized glutathione (GSH/GSSG) ratio in the cells compared with the control. Treatment of algae with ZnO NPs and (S)-DCPP, however, resulted in no significant changes in GSH and GSH/GSSG. Moreover, trends of variation of GSH and GSH/GSSG were different when algae were treated with ZnSO4.7H2O and the two enantiomers. Overall, the chiral perturbation approach revealed that NPs aggravated generation of ROS and that released Zn(2+) and NPs both contribute to the toxicity of ZnO NPs. PMID- 24752694 TI - Spectroscopic detection of exogenous materials in latent fingerprints treated with powders and lifted off with adhesive tapes. AB - Fingerprint evidence offers great value to criminal investigations since it is an internationally recognized and established means of human identification. With recent advances in modern technology, scientists have started analyzing not only the ridge patterns of fingerprints but also substances which can be found within them. The aim of this work was to determine whether Fourier transform infrared (FTIR) spectromicroscopy could be used to detect contamination in a fingerprint which was dusted with powder (a technique already recognized as an effective and reliable method for developing latent fingerprints) and subsequently lifted off with adhesive tape. Explosive materials (pentaerythritol tetranitrate, C-4, TNT) and noncontrolled substances (sugar, aspirin) were used to prepare contaminated fingerprints on various substrates. Freshly deposited fingermarks with powders which were lifted off with adhesive tapes (provided by Singapore Police Force) were analyzed using a Bruker Hyperion 2000 microscope at the ISMI beamline (Singapore Synchrotron Light Source) with an attenuated total reflection objective. FTIR spectroscopy is a nondestructive technique which requires almost no sample preparation. Further, the fingerprint under analysis remains in pristine condition, allowing subsequent analysis if necessary. All analyzed substances were successfully distinguished using their FTIR spectra in powdered and lifted fingerprints. This method has the potential to significantly impact forensic science by greatly enhancing the information that can be obtained from the study of fingerprints. PMID- 24752695 TI - Retention mechanism assessment and method development for the analysis of iohexol and its related compounds in hydrophilic interaction liquid chromatography. AB - Hydrophilic interaction liquid chromatography (HILIC) has emerged in recent years as a valuable alternative to reversed-phase liquid chromatography in the analysis of polar compounds. Research in HILIC is divided into two directions: the assessment of the retention mechanism and retention behavior, and the development of HILIC methods. In this work, four polar neutral analytes (iohexol and its related compounds A, B, and C) were analyzed on two silica and two diol columns in HILIC mode with the aim to investigate thoroughly the retention mechanisms and retention behavior of polar neutral compounds on these four columns. The adsorption and partition contribution to the overall HILIC retention mechanism was investigated by fitting the retention data to linear (adsorption and partition) and nonlinear (mixed-retention and quadratic) theoretical models. On the other hand, the establishment of empirical second-order polynomial retention models on the basis of D-optimal design made possible the estimation of the simultaneous influence of several mobile-phase-related factors. Furthermore, these models were also used as the basis for the application of indirect modeling of the selectivity factor and a grid point search approach in order to achieve the optimal separation of analytes. After the optimization goals had been set, the grids were searched and the optimal conditions were identified. Finally, the optimized method was subjected to validation. PMID- 24752696 TI - Improvements in analytical methodology for the determination of frequently consumed illicit drugs in urban wastewater. AB - Rapid and sensitive analytical methodology based on ultra high-performance liquid chromatography-tandem mass spectrometry has been developed for the determination of widely consumed drugs of abuse (amphetamines, MDMA, cocaine, opioids, cannabis and ketamine) and their major metabolites in urban wastewaters. Sample clean-up and pre-concentration was performed by a generic off-line SPE procedure using Oasis HLB. Special effort was made to incorporate amphetamine, which was found highly problematic in the wastewater samples tested, including an additional clean-up with Oasis MCX SPE and dispersive primary secondary amine. Correction for possible SPE losses or degradation during storage was made by the use of isotope-labelled internal standards (ILIS), available for all compounds, which were added to the samples as surrogates. Although ILIS were also efficient for matrix effects correction, the strong ionization suppression observed was not eliminated; therefore, a four-fold dilution prior to SPE was applied to influent wastewaters and a low injection volume was selected (3 MUL), in order to reach a compromise between matrix effects, chromatographic performance and sensitivity. The method was validated at 25 and 200 ng L(-1) (effluent), and 100 and 800 ng L( 1) (influent), obtaining limits of quantification (i.e. the lowest level that the compound can be quantified and also confirmed with at least two MS/MS transitions) between 0.4-25 ng L(-1) (effluent) and 2-100 ng L(-1) (influent). The applicability of the method was demonstrated by analysis of 14 influent and 14 effluent wastewater samples collected over 2 weeks in Castellon (Spain) within a European collaborative study. PMID- 24752697 TI - The rising cost of medical education and its significance for (not only) psychiatry. PMID- 24752698 TI - Human antigen-specific CD4+ CD25+ CD134+ CD39+ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses. AB - Human Ag-specific CD4(+) T cells can be detected by their dual expression of CD134 (OX40) and CD25 after a 44 hours stimulation with cognate Ag. We show that surface expression of CD39 on Ag-specific cells consistently identifies a substantial population of CD4(+) CD25(+) CD134(+) CD39(+) T cells that have a Treg-cell-like phenotype and mostly originate from bulk memory CD4(+) CD45RO(+) CD127(low) CD25(high) CD39(+) Treg cells. Viable, Ag-specific CD25(+) CD134(+) CD39(+) T cells could be expanded in vitro as cell lines and clones, and retained high Forkhead Box Protein 3, CTLA-4 and CD39 expression, suppressive activity and Ag specificity. We also utilised this combination of cell surface markers to measure HIV-Gag responses in HIV(+) patients before and after anti-retroviral therapy (ART). Interestingly, we found that the percentage of CD39(-) cells within baseline CD4(+) T-cell responses to HIV-Gag was negatively correlated with HIV viral load pre-ART and positively correlated with CD4(+) T-cell recovery over 96 weeks of ART. Collectively, our data show that Ag-specific CD4(+) CD25(+) CD134(+) CD39(+) T cells are highly enriched for Treg cells, form a large component of recall responses and maintain a Treg-cell-like phenotype upon in vitro expansion. Identification and isolation of these cells enables the role of Treg cells in memory responses to be further defined and provides a development pathway for novel therapeutics. PMID- 24752699 TI - Peripheral blood hematopoietic stem and progenitor cell frequency is unchanged in patients with alpha-1-antitrypsin deficiency. AB - Granulocyte-colony-stimulating factor (G-CSF)-induced hematopoietic stem and progenitor cell (HSPC) mobilization is associated with the release of neutrophil derived proteases. Previously, we have shown that alpha-1-antitrypsin (AAT) inhibits these proteases in mice, resulting in inhibition of HSPC mobilization. Here, we studied the relationship between AAT and HSPC in steady state and cytokine-induced mobilization in humans. Patients with alpha-1-antitrypsin deficiency (AATD) have an 85-90 % decrease of AAT in the peripheral blood (PB). We hypothesized that this leads to increased proteolytic activity in the bone marrow and increased steady-state PB HSPC numbers. Using flow cytometry and semi solid cell culture, we found no significant difference in PB HSPC in AATD patients (n = 18) as compared to controls (n = 22). Healthy stem cell donors (n = 43) were mobilized with G-CSF for 5 days and the number of CD45(+)/CD34(+) HSPC were determined in PB. We found that, during mobilization, PB AAT levels increased significantly, positively correlating with PB CD45(+)/CD34(+) cells (r = 0.31, p = 0.005). In conclusion, although serum AAT levels and HSPC mobilization in healthy stem cell donors are positively correlated, AAT is not an indispensable protease-inhibitor in the constitutive circulation of HSPC. These findings suggest a model in which both protease-dependent and -independent pathways contribute to HSPC mobilization. PMID- 24752700 TI - Peptide catalysis in aqueous emulsions. AB - Amphiphilic tripeptides catalyze conjugate addition reactions of aldehydes to nitroolefins in water with high yields and stereoselectivities. The amphiphilic nature shields the peptidic catalyst from the water and stabilizes the emulsion formed by the reactants in the aqueous environment. The findings have intriguing implications for the chemical evolution of enzymes. PMID- 24752701 TI - Psychosocial interventions to support partners of men with prostate cancer: a systematic and critical review of the literature. AB - PURPOSE: Prostate cancer poses many challenges for both the man and his partner. Partners have reported a range of issues that impact their own mental health following their partner's diagnosis of prostate cancer. The aim of this review is to summarise and critically evaluate the current literature reporting psychosocial intervention studies for partners of prostate cancer patients. METHODS: An extensive literature search of electronic databases was conducted (OvidMEDLINE 1946, 26th September 2013, and psychINFO 1967, 26th September 2013) using the keywords prostate cancer AND intervention* OR therapy* OR psychosocial intervention* OR support* AND couple* or Spouse* or Partner* or Intimate partner* matched to the title as well as secondary scanning of reference lists. Studies were included if they described interventions for partners of prostate cancer patients, either solely for the partners or as a couple, intended to alleviate distress and enhance the partner's or couple's quality of life, and reported a measurable outcome for partners. RESULTS: A total of 11 prostate cancer-specific intervention studies that included partners and reported separate results for the partners were found. Only one of these interventions was partner specific, the other eight involved the patient-partner dyad. The studies identified primarily focussed on two areas: emotional distress and sexual intimacy, and mixed findings were reported for efficacy of interventions. CONCLUSIONS: Despite strong evidence that partners of men with prostate cancer experience difficulties associated with the impact of prostate cancer, there is limited research that has investigated the efficacy of psychosocial interventions for partners. Of the reviewed studies, it is evident that interventions targeting the reduction of emotional distress, improved communication and sexual intimacy between the couple and utilisation of strategies that enable partners to express their distress, learn new strategies and implement behavioural change show the most promising results in enhancing partner well-being. IMPLICATIONS FOR CANCER SURVIVORS: Significant progress is required in developing and evaluating appropriate and effective psychosocial support interventions for partners of prostate cancer survivors as partners appear to have significant unmet needs in this area. PMID- 24752702 TI - Characterization of the octopaminergic and tyraminergic neurons in the central brain of Drosophila larvae. AB - Drosophila larvae are able to evaluate sensory information based on prior experience, similarly to adult flies, other insect species, and vertebrates. Larvae and adult flies can be taught to associate odor stimuli with sugar reward, and prior work has implicated both the octopaminergic and the dopaminergic modulatory systems in reinforcement signaling. Here we use genetics to analyze the anatomy, up to the single-cell level, of the octopaminergic/tyraminergic system in the larval brain and subesophageal ganglion. Genetic ablation of subsets of these neurons allowed us to determine their necessity for appetitive olfactory learning. These experiments reveal that a small subset of about 39 largely morphologically distinguishable octopaminergic/tyraminergic neurons is involved in signaling reward in the Drosophila larval brain. In addition to prior work on larval locomotion, these data functionally separate the octopaminergic/tyraminergic system into two sets of about 40 neurons. Those situated in the thoracic/abdominal ganglion are involved in larval locomotion, whereas the others in the subesophageal ganglion and brain hemispheres mediate reward signaling. PMID- 24752703 TI - Willingness to use HIV pre-exposure prophylaxis among opiate users. AB - Few studies of pre-exposure prophylaxis (PrEP) to prevent HIV infection have focused on drug users. Between February to September 2013, we asked 351 opiate injectors entering detoxification treatment about HIV risk, knowledge about PrEP, and willingness to use a once daily PrEP pill under one of two randomly assigned effectiveness scenarios-40 % (low) or 90 % (high) effective in reducing HIV risk. Participants were 70 % male and 87 % non-Hispanic White. Only 7 % had heard of a drug to reduce HIV risk, yet once informed, 47 % would be willing to take such a pill [35 % of those in the low effectiveness scenario and 58 % in the high group (p < 0.001)]. Higher perceived HIV risk was associated with greater willingness to take medication. Increasing knowledge of PrEP and the rate of HIV reduction effectiveness promised will influence its use among targeted high-risk drug users. PMID- 24752704 TI - Synthesis and gene transfection activity of cyclen-based cationic lipids with asymmetric acyl-cholesteryl hydrophobic tails. AB - A series of novel 1,4,7,10-tetraazacyclododecane (cyclen)-based cationic lipids with asymmetric double hydrophobic tails (cholesteryl and long aliphatic chains) were designed and synthesized. Lysine was chosen as a linking moiety in the molecular backbone. The liposomes formed from 8 and dioleoylphosphatidylethanolamine (DOPE) could bind and condense plasmid DNA into nanoparticles under a low N/P ratio. These nano-scaled lipoplexes have low cytotoxicity, and might efficiently transfect A549 cells. In vitro transfection results revealed that all cationic lipids showed a comparable or better transfection efficiency (TE) than commercially available Lipofectamine 2000. The length and saturation degree of the aliphatic chain would affect their gene transfection performance, and the linoleic acid-containing 8e could give the best TE. PMID- 24752705 TI - A ferroelectric photocatalyst for enhancing hydrogen evolution: polarized particulate suspension. AB - A particle-based photocatalyst with a permanent internal field prepared by a corona poling method is presented as a novel approach to enhance the hydrogen evolution reaction in a particulate-suspension system. Photocatalytic activity of K0.5Na0.5NbO3 was significantly improved by 7.4 times after the polarization. PMID- 24752706 TI - Intracranial hemorrhage in infants as a serious, and preventable consequence of late form of vitamin K deficiency: a selfie picture of Turkey, strategies for tomorrow. AB - PURPOSE: Vitamin K deficiency bleeding is one of the most common causes of acquired hemostatic disorder in early infancy. Although vitamin K is practiced routinely after every birth in Turkey, children with type of vitamin K deficiency bleedings (L-VKDB) can be encountered. We aimed to evaluate the clinical features of the children with L-VKDB reported from Turkey. METHODS: Between 1995 and 2013, 48 studies reporting 534 children with L-VKDB were evaluated in this study. RESULTS: Of the 534 reported children (178 girls, 356 boys), 486 (91 %) were extremely breastfed. The most common bleeding sites were intracranial hemorrhage, gastrointestinal, and umbilical in 414 (77.4 %), 33 (6.2 %), and 33 (6.2 %) children, respectively, and 35 (6.6 %) children had been diagnosed incidentally without any bleeding. The etiology of 399 (74.7 %) children were classified as idiopathic, whereas 135 (25.3 %) were secondary. Intramuscular vitamin K was administered in 248 (46.4 %), not administered in 228 (42.7 %), and the administration of vitamin K were not determined in 58 (10.9 %) children. The outcomes of Turkish cohort showed that 111 (20.8) children died, 257 (48.1 %) cases developed neurologic deficit (mainly epilepsy and psychomotor retardation), and only 166 (31.1 %) patients recovered without squeal. CONCLUSIONS: The compliance of prophylactic measures in Turkey does not seem to be satisfactory. As a further measure of tomorrow, we vigorously emphasize that a national surveillance program may be initiated. An additional intramuscular dose or oral supplementation of vitamin K especially for exclusively breast-fed infants may reduce this catastrophic problem in our country. PMID- 24752707 TI - Thalamic tumors in children. AB - INTRODUCTION: Thalamic tumors are rare tumors which are usually diagnosed in the pediatric age group. Although recent developments in neurosurgical practice allow more radical treatments, information about outcome is scarce for these deep seated challenging tumors. METHODS: Medical records of 45 pediatric patients who presented with thalamic tumors between 1999 and 2012 were reviewed. DISCUSSION: Prognostic implication of tumor characteristics and patient variables are discussed. Although challenging, recent innovations in the field of neurosurgery and refinements in technique may prolong survival in some cases. PMID- 24752708 TI - Primary intracranial leiomyosarcoma of the torcular Herophili associated with Fanconi anemia and allogenic stem cell transplantation. AB - PURPOSE: Fanconi anemia is associated with a high risk for developing malignant tumors. The occurrence of primary intracranial leiomyosarcoma, however, which in general has a poor prognosis, has not been described thus far. The purpose of this study is to report on management and outcome of leiomyosarcoma of the torcular Herophili associated with Fanconi anemia in a pediatric patient. CASE REPORT: A 12-year-old girl with Fanconi anemia presented with a primary intracranial leiomyosarcoma arising from the torcular Herophili and infiltrating the adjacent venous sinuses after previous allogenic hematopoietic stem cell transplantation. Radical tumor resection followed by radiotherapy resulted in tumor-free survival and good outcome at a 2-year follow-up. CONCLUSION: Despite occurrence of leiomyosarcoma in a site thought unfavorable for surgery, combined tumor resection and radiosurgery may yield excellent outcome. PMID- 24752709 TI - Patterns of treatment and associated short-term outcomes of unruptured intracranial aneurysms in children. AB - BACKGROUND: The rates and outcomes of treatments for intracranial aneurysms have not been exclusively determined within the pediatric population. We determined the rates of endovascular and microsurgical treatments for unruptured intracranial aneurysms (UIA) and associated rates of favorable outcome in patients aged <18 years. METHODS: We analyzed data obtained as part of the Kids' Inpatient Database between 2003 and 2009 with primary diagnosis of UIA. Patients undergoing endovascular treatment were compared to those undergoing microsurgical treatment. We determined rates of intracerebral hemorrhage, subarachnoid hemorrhage, neurological complications, and favorable outcome. RESULTS: There were 818 cases of UIA during the study period. A total of 111 patients (mean age 14 +/- 6 years, 37.6 % female) underwent microsurgical treatment, and another 200 patients (mean age 13 +/- 7 years, 42.5 % female) underwent endovascular treatment. A high rate of favorable outcome was observed in patients who received either treatment (microsurgical treatment 87.7 % versus endovascular treatment 91.6 %, p = 0.4). There was a trend towards a significantly shorter mean hospitalization stay among those who received endovascular treatment compared with microsurgical treatment (6 +/- 12 versus 9 +/- 11 days, p = 0.06). There was a significant trend towards higher utilization of endovascular treatment as opposed to microsurgical treatment from 2003 to 2009 (p = 0.02). CONCLUSIONS: Although outcomes except for length of stay were comparable between endovascular treatment and microsurgical treatment patients, there was a trend towards higher utilization of endovascular treatment among children with UIAs from 2003 to 2009. PMID- 24752710 TI - MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions. AB - The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p = 0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR 31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum. PMID- 24752711 TI - Hearing outcomes in children with cleft palate and referred newborn hearing screen. AB - OBJECTIVES/HYPOTHESIS: To determine the prevalence of long-term hearing loss in patients with cleft palate who fail their universal newborn hearing screen. STUDY DESIGN: The study is a retrospective chart review from a tertiary pediatric center and tertiary children's hospital. METHODS: Newborns with cleft palate born between January 2002 and July 2012 were identified from a pediatric otolaryngology practice database. This cohort was then reduced to include only those patients who referred their universal newborn hearing screen. Postpressure equalization tube audiology results, follow-up audiology results, type of cleft, and comorbid conditions were collected for each patient who was both born with a cleft palate and referred their universal newborn hearing screen. RESULTS: A total of 317 newborns presented to the pediatric otolaryngology practice for cleft palate, with 89 (28%) having documented referred universal newborn hearing screen. At the time of data collection, 67 (75%) of 89 had normal hearing results, whereas 22 (25%) of 89 did not yet have normal hearing results. Fourteen patients had permanent hearing loss, and all 14 had a comorbid condition. Type of cleft and presence of a comorbid condition were correlated to hearing outcomes. CONCLUSIONS: Newborns with cleft palate who refer their universal newborn hearing screen could postpone diagnostic hearing testing until after placement of pressure equalization tubes, unless there is a clue to permanent hearing loss such as a comorbid condition. PMID- 24752714 TI - Phase transition behaviours of a single dendritic polymer. AB - Dendritic polymers with highly branching structures exhibit many unique properties. In this paper, a computational study using the Wang-Landau sampling technique is carried out to reveal the phase transition behaviours of dendritic homopolymers with various branching structures. Two types of dendritic homopolymers, dendrimers/dendrigrafts (D/D) and hyperbranched (HB) polymers are studied. It is found that with increasing degree of branching in the dendritic polymer, the liquid-solid (LS) transition temperature increases and the coil globule (CG) transition becomes weak. Additionally, under similar degrees of branching and polymerization, D/D polymers have a higher LS transition temperature than HB polymers. The reason is that the D/D polymers have greater regularity in the radial distribution of the branching units, which facilitates monomer packing during the LS transition. The distinctive internal unit distribution at various temperatures is quantitatively analysed. Our results show the importance of dendritic polymer structure regularity in phase transition behaviours and are valuable in guiding the structural design of dendritic macromolecules for functionalization applications. PMID- 24752713 TI - Human embryo cryopreservation: one-step slow freezing does it all? AB - PURPOSE: Previous studies have shown that a modified one-step slow freezing method with higher sucrose concentration (0.2 M) can achieve higher embryo and blastomere survival rates that are comparable to vitrification. However, no study has evaluated the efficacy of a one-step method using commercial slow freezing kit without altering its composition. This retrospective study examines the effects of using 1.5 M PROH with 0.1 M sucrose (F2 medium) alone in a one-step slow freezing method compared to the conventional two-step method. METHODS: Cleavage stage embryos from 526 thaw cycles previously cryopreserved by either the conventional two-step slow freezing method or the modified one-step method were studied. The embryo and blastomere survival rates, cleavage rate, clinical pregnancy rate and live birth rate were compared between the two groups. RESULTS: The results showed that the embryo survival rate was significantly higher in the modified one-step method compared to the conventional two-step method (86.9 % and 83.1 %, respectively; p = 0.04). Total blastomere survival rate was also significantly increased as a result of the modification (81.0 % versus 76.5 %; p < 0.001). However, there was no statistical difference in the cleavage rates, clinical pregnancy rates (CPR/ET) and live birth rates between the two methods. CONCLUSIONS: Slow freezing using the one-step method is superior to the conventional two-step method in terms of embryo and blastomere survival rates without affecting cleavage rate and clinical outcomes. It can be routinely applied to cleavage stage embryo cryopreservation in IVF centres for greater workflow efficiency. PMID- 24752716 TI - Glycerol production by Oenococcus oeni during sequential and simultaneous cultures with wine yeast strains. AB - Growth and fermentation patterns of Saccharomyces cerevisiae, Kloeckera apiculata, and Oenococcus oeni strains cultured in grape juice medium were studied. In pure, sequential and simultaneous cultures, the strains reached the stationary growth phase between 2 and 3 days. Pure and mixed K. apiculata and S. cerevisiae cultures used mainly glucose, producing ethanol, organic acids, and 4.0 and 0.1 mM glycerol, respectively. In sequential cultures, O. oeni achieved about 1 log unit at 3 days using mainly fructose and L-malic acid. Highest sugars consumption was detected in K. apiculata supernatants, lactic acid being the major end-product. 8.0 mM glycerol was found in 6-day culture supernatants. In simultaneous cultures, total sugars and L-malic acid were used at 3 days and 98% of ethanol and glycerol were detected. This study represents the first report of the population dynamics and metabolic behavior of yeasts and O. oeni in sequential and simultaneous cultures and contributes to the selection of indigenous strains to design starter cultures for winemaking, also considering the inclusion of K. apiculata. The sequential inoculation of yeasts and O. oeni would enhance glycerol production, which confers desirable organoleptic characteristics to wines, while organic acids levels would not affect their sensory profile. PMID- 24752717 TI - Outcomes of routine ilioinguinal lymph node dissection for palpable inguinal melanoma nodal metastasis. AB - BACKGROUND: Patients who present with palpable inguinal melanoma nodal metastasis have two surgical options: inguinal or ilioinguinal lymph node dissection. Indications for either operation remain controversial. This study examined survival and recurrence outcomes following ilioinguinal dissection for patients with palpable inguinal nodal metastasis, and assessed the incidence and preoperative predictors of pelvic nodal metastasis. METHODS: This was a retrospective clinicopathological analysis of consecutive surgical patients with stage III malignant melanoma. All patients underwent a standardized ilioinguinal dissection at a specialist tertiary oncology hospital over a 12-year period (1998 2010). RESULTS: Some 38.9 per cent of 113 patients had metastatic pelvic nodes. Over a median follow-up of 31 months, the 5-year overall survival rate was 28 per cent for patients with metastatic inguinal and pelvic nodes, and 51 per cent for those with inguinal nodal metastasis only (P = 0.002). The nodal basin control rate was 88.5 per cent. Despite no evidence of pelvic node involvement on preoperative computed tomography (CT), six patients (5.3 per cent) with a single metastatic inguinal lymph node had metastatic pelvic lymph nodes. Logistic regression analysis showed that the number of metastatic inguinal nodes (odds ratio 1.56; P = 0.021) and suspicious CT findings (odds ratio 9.89; P = 0.001) were both significantly associated with metastatic pelvic nodes. The specificity of CT was good (89.2 per cent) in detecting metastatic pelvic nodes, but the sensitivity was limited (57.9 per cent). CONCLUSION: Metastatic pelvic nodes are common when palpable metastatic inguinal nodes are present. Long-term survival can be achieved following their resection by ilioinguinal dissection. As metastatic pelvic nodes cannot be diagnosed reliably by preoperative CT, patients presenting with palpable inguinal nodal metastasis should be considered for ilioinguinal dissection. PMID- 24752718 TI - Extraspinal ossifications after implantation of vertical expandable prosthetic titanium ribs (VEPTRs). AB - INTRODUCTION: Though developed for thoracic insufficiency syndrome, the spinal growth-stimulating potential and the ease of placement of vertical expandable titanium ribs (VEPTRs) has resulted in their widespread use for early-onset spine deformity. Observation of implant-related ossifications warrants further assessment, since they may be detrimental to the function-preserving non-fusion strategy. PATIENTS AND METHODS: Radiographs (obtained pre and post index procedure, and at 4-year follow-up) and the records of 65 VEPTR patients from four paediatric spine centres were analysed. Ossifications were classified as type I (at anchor points), type II (along the central part) or type III (re ossification after thoracostomy). RESULTS: The average age at the index procedure was 6.5 years (min 1, max 13.7). The most prevalent spine problem was congenital scoliosis (37) with rib fusions (34), followed by neuromuscular and syndromic deformities (13 and 8, respectively). Idiopathic and secondary scoliosis (e.g. after thoracotomy) were less frequent (3 and 4, respectively). Forty-two of the 65 (65 %) patients showed ossifications, half of which were around the anchors. Forty-five percent (15/33) without pre-existing rib fusions developed a type II ossification along the implant. Re-ossifications of thoracostomies were less frequent (5/34, 15 %). The occurrence of ossifications was not associated with patient-specific factors. CONCLUSIONS: Implant-related ossifications around VEPTR are common. In contrast to harmless bone formation around anchors, ossifications around the telescopic part and the rod section are troublesome in view of their possible negative impact on chest cage compliance and spinal mobility. This potential side effect needs to be considered during implant selection, particularly in patients with originally normal thoracic and spinal anatomy. PMID- 24752719 TI - When assay format matters: a case study on the evaluation of three assay formats to support a clinical pharmacokinetic study. AB - Data generated using various immunoassay methods are an integral part of the development of protein therapeutics. These assays are used in clinical and preclinical studies to establish the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics as well as to assess the immunogenicity properties of a therapeutic. PK assays measure therapeutic levels post-administration which is essential for understanding the effective dose and dose regimen for a therapeutic. Anti-OX40L is a fully humanized monoclonal antibody designed for the potential treatment of an autoimmune disease. The anti-OX40L human PK assay is required to be sensitive, robust, and precise. To address challenges due to assay sensitivity and reproducibility, as well as assay technology limitations, during development of the anti-OX40L human PK assay, three different assays, including an MSD-based electrochemiluminescence assay (ECLA), a fluorometric enzyme-linked immunosorbent assay (ELISA), and a colorimetric ELISA, were evaluated. The MSD based assay was the most sensitive but posed risk of inter-well signal crosstalk. The fluorescence ELISA fell short on reproducibility. The colorimetric ELISA was ultimately chosen for supporting sample analysis. This paper presents characterization data obtained from each of these assay formats, challenges that were encountered in the development of the assay, and the rationale for selecting the ultimate assay format. PMID- 24752721 TI - Histopathology of subcutaneously preserved autologous bone flap after decompressive craniectomy: a prospective study. AB - BACKGROUND: Limited reports are available regarding the viability of subcutaneously preserved autologous bone flaps after decompressive craniectomy. The present study was undertaken to evaluate the histopathological changes in these autologous bone flaps. METHODS: Between January 2011 and July 2012, 50 patients were prospectively studied at the time of cranioplasty. Bone flap retrieved from the abdominal wall was subjected to histopathological examination to look for mononuclear cell infiltration into the Haversian system, presence of osteocytes, osteoblastic activity, angiogenesis and new bone formation. Microbiological culture of bone specimens was also done. RESULTS: Of the 50 patients, there were 40 cases of trauma, 6 of aneurysmal bleed, 2 of tumor, and a single case of intracerebral hemorrhage and middle cerebral artery infarct, respectively. Mean age of the patients was 35.8 years (range, 10-64 years). Histopathological examination revealed the presence of osteocytes in 86 %, which indicates the viability of bone flaps. Osteoblastic activity was noted in 38 % and angiogenesis in 14 % of bone flaps, respectively. New bone formation was found in 6 %, and all had underlying osteoblastic activity. No significant correlation was found between the presence of osteocytes, osteoblasts, angiogenesis and duration of preservation of bone flaps. Acinetobacter species were cultured in a single patient. However, there was no evidence of clinical infection. CONCLUSIONS: Subcutaneously preserved bone flap in the anterior abdominal wall remains viable and retains its osteogenic potential, and it is a simple, cost-effective option for storage of bone flaps during decompressive craniotomy. It has a negligible infection rate. PMID- 24752720 TI - Optimized approaches for quantification of drug transporters in tissues and cells by MRM proteomics. AB - Drug transporter expression in tissues (in vivo) usually differs from that in cell lines used to measure transporter activity (in vitro). Therefore, quantification of transporter expression in tissues and cell lines is important to develop scaling factor for in vitro to in vivo extrapolation (IVIVE) of transporter-mediated drug disposition. Since traditional immunoquantification methods are semiquantitative, targeted proteomics is now emerging as a superior method to quantify proteins, including membrane transporters. This superiority is derived from the selectivity, precision, accuracy, and speed of analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode. Moreover, LC-MS/MS proteomics has broader applicability because it does not require selective antibodies for individual proteins. There are a number of recent research and review papers that discuss the use of LC MS/MS for transporter quantification. Here, we have compiled from the literature various elements of MRM proteomics to provide a comprehensive systematic strategy to quantify drug transporters. This review emphasizes practical aspects and challenges in surrogate peptide selection, peptide qualification, peptide synthesis and characterization, membrane protein isolation, protein digestion, sample preparation, LC-MS/MS parameter optimization, method validation, and sample analysis. In particular, bioinformatic tools used in method development and sample analysis are discussed in detail. Various pre-analytical and analytical sources of variability that should be considered during transporter quantification are highlighted. All these steps are illustrated using P glycoprotein (P-gp) as a case example. Greater use of quantitative transporter proteomics will lead to a better understanding of the role of drug transporters in drug disposition. PMID- 24752722 TI - Effect of amantadine in minimally conscious state of non-traumatic etiology. PMID- 24752723 TI - Routine but risky: a multi-centre analysis of the outcomes of cranioplasty in the Northeast of England. AB - BACKGROUND: Cranioplasty is undertaken as a routine secondary operation following craniectomy. At a time when decompressive craniectomy is being evaluated by several large trials, we aimed to evaluate the morbidity associated with cranioplasty and investigate its potential effect on outcome. METHODS: The outcomes of 166 patients undergoing cranioplasty at two centres in the United Kingdom between June 2006 and September 2011 were retrospectively analysed. Outcome measures included mortality, morbidity and functional outcome determined by the modified Rankin score (mRS) at last follow-up. A logistic regression analysis was performed to model and predict determinants related to neurological outcome following cranioplasty. RESULTS: Sixty-seven out of 166 patients (40.4 %) experienced at least one complication during a median follow-up time of 15 months (inter-quartile range 5-38 months). Thirty six patients (21.7 %) developed infection requiring antibiotics, with 27 (16.3 %) requiring removal of the cranioplasty. Nine of 25 patients (36 %) with bi-frontal defects developed an infection whereas 21 of the 153 patients (16.4 %) with a defect other than bi frontal developed an infection (Chi square p = 0.009). Further surgery in the two groups was required in 16.4 % and 11.7, % respectively. Pseudomeningocoele (9 %), seizures (8.4 %) and poor cosmesis (7.2 %) were also commonly observed. Logistic regression analysis identified initial operation (p < 0.03), mRS at the time of cranioplasty (p < 0.0001) and complications (p < 0.04) as being predictive of neurological outcome at last follow-up. Age at the time of cranioplasty and the timing of cranioplasty were not predictive of last mRS score at follow-up. CONCLUSIONS: Cranioplasty harbours significant morbidity, a risk that appears to be higher with a bifrontal defect. The complications experienced influence subsequent functional outcome. The timing of cranioplasty, early or late, after the initial operation does not impact on the ultimate outcome. These findings should be considered when making decisions relating to craniectomy and cranioplasty. PMID- 24752724 TI - Surgical adverse events of deep brain stimulation in the subthalamic nucleus of patients with Parkinson's disease. The learning curve and the pitfalls. AB - BACKGROUND: Several surgical adverse events (SAEs) have been associated with Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson's Disease (PD) patients, leading to certain confusion about the risk/benefit ratio of this technique, and giving rise to the need of more and more extensive control studies over longer periods. The aim of this article is to identify and quantify the factors associated with the most frequent AEs from STN DBS in PD-diagnosed patients. METHODS: The following variables were studied: aborted procedure, misplaced leads, intracranial haemorrhage, and seizures. This study was carried out in 233 patients diagnosed with PD, with 455 STN electrodes implanted and follow-up after 7 (8-14) years follow up. RESULTS: A total amount of 56 SAEs occurred in 49 patients (11.76 % of total procedures, 12.31 % of implanted leads, 21.03 % of patients). SAEs were: five aborted procedures, 26 misplaced leads, ten intracranial haemorrhages, and 15 seizures. Of all the SAEs, long-term effects only happened in two cases of hemiparesis caused by intracranial haemorrhage; the other SAEs were reversible and didn't leave any long-term clinical consequences (0.42 % of procedures, 0.44 % of leads, and 0.86 % of patients). CONCLUSIONS: STN DBS in PD patients is a safe surgical procedure, with good risk/benefit ratios: procedure reliability/correct lead implantation in 95.59 %, 0 mortality/implanted lead, 0.12 morbidity/implanted lead, and 0.0043 neurological sequelae/implanted lead. PMID- 24752725 TI - Selection of surgical approaches based on semi-quantifying the skull-base invasion by petroclival meningiomas: a review of 66 cases. AB - BACKGROUND: Petroclival meningiomas are still challenging for neurosurgeons. In the present study, we reviewed 66 petroclival meningiomas that underwent craniotomy to assess the surgical approaches for petroclival meningiomas based on semi-quantifying tumor extension to skull base and to evaluate the outcomes. METHODS: According to invasion characteristics, skull base related to petroclival meningiomas was semi-quantitatively divided into five regions: upper, middle, and lower petroclival regions (region A, B, and C, respectively), cerebellopontine angle region (region D), and parasellar and cavernous sinus region (region E). Appropriate surgical approaches were adopted for petroclival meningiomas with varying degrees of invasion, including the subtemporal (11/66), retrosigmoid (15/66), presigmoid (32/66), combined retrosigmoid and far-lateral (2/66), supra infratentorial (4/66), and extended middle cranial fossa (2/66) approaches. RESULTS: The results showed that involvement of region A, B, and C was in 64, 50, and eight patients, respectively. Invasion to region D and E occurred in 13 and 39 cases, respectively. The ratio of single region involvement was only 7.6 %, whereas most petroclival meningiomas tended to invade more regions (39.4 % for two, 37.9 % for three, 12.1 % for four, and 3.0 % for five regions, respectively). Gross total resection was achieved in 29 cases (43.9 %), near total resection in 27 cases (40.9 %), and subtotal resection in ten cases (15.2 %). After a mean follow-up period of 32.21 months, obvious cranial nerve deficits existed in seven patients, and recurrence occurred in eight patients. CONCLUSIONS: We introduced a simple and practicable method for classification of petroclival meningiomas, which could semi-quantify tumor invasion and help to select surgical approaches. With careful preoperative evaluation, a cautiously selected approach would improve the prognosis. PMID- 24752726 TI - Changes in number of water-filled vesicles of choroid plexus in early and late phase of experimental rabbit subarachnoid hemorrhage model: the role of petrous ganglion of glossopharyngeal nerve. AB - BACKGROUND: Cerebrospinal fluid (CSF) secretion may be increased in the early phases of subarachnoid hemorrhage (SAH), possibly via ischemic glossopharyngeal nerve discharges, and decreased due to glossopharyngeal nerve degeneration in the late phase of SAH; but this reflex pathway has not been definitively investigated. We studied the relationship between petrous ganglion of the glossopharyngeal nerve (GPN) and water vesicles of the choroid plexus (CP) in the early and late phases of SAH. METHODS: This study was conducted on 30 rabbits, divided into four groups, with five rabbits in the control group (group I), five rabbits in the sham group (Group II), and 20 rabbits in the SAH group. In the SAH group, five of the animals were decapitated after 4 days of cisternal blood injections (Group III), and the other 15 animals were decapitated after 20 days of injections (Group IV). The Petrous Ganglia and CPs of lateral ventricles were removed and stained for stereological analysis. RESULTS: The mean number of follicles per cubic millimeter was 5.3 +/- 1.2 the in control group (Group I), 4.5 +/- 0.9 in the sham group (Group II), 16.60 +/- 3.77 the in early decapitated group (Group III), and 4.30 +/- 0.84 in the late decapitated group (Group IV). The mean number of degenerated neuron density of petrous ganglions was 6 +/- 2, 50 +/- 6, 742 +/- 96, and 2.420 +/- 350 in the control (Group I), sham (Group II), early decapitated (Group III), and late decapitated group (Group IV), respectively. The mean number of water vesicles was statistically different after SAH between the early decapitated group (group III) and the late decapitated group (group IV) (P < 0.05). CONCLUSIONS: We studied the relationship between petrous ganglion cells of the GPN and water vesicles of CP in the early and late phases of SAH, and found that CP vesicles are increased in the early phase of SAH due to irritation of GPN, and decreased in the late phase due to ischemic insult of the petrous ganglion and parasympathetic innervation of the CP. PMID- 24752727 TI - DBS for Parkinson's disease in a HIV-positive patient: long-term follow-up. PMID- 24752728 TI - Novel tartrate-derived guanidine-catalyzed highly enantio- and diastereoselective Michael addition of 3-substituted oxindoles to nitroolefins. AB - The Michael addition of 3-substituted oxindoles to nitroolefins was catalyzed by a novel tartrate-derived guanidine in high yield with excellent diastereo- and enantioselectivity. This method showed an extraordinarily broad substrate scope in terms of both reaction partners. PMID- 24752730 TI - Predicting paramagnetic 1H NMR chemical shifts and state-energy separations in spin-crossover host-guest systems. AB - The behaviour of metal-organic cages upon guest encapsulation can be difficult to elucidate in solution. Paramagnetic metal centres introduce additional dispersion of signals that is useful for characterisation of host-guest complexes in solution using nuclear magnetic resonance (NMR). However, paramagnetic centres also complicate spectral assignment due to line broadening, signal integration error, and large changes in chemical shifts, which can be difficult to assign even for known compounds. Quantum chemical predictions can provide information that greatly facilitates the assignment of NMR signals and identification of species present. Here we explore how the prediction of paramagnetic NMR spectra may be used to gain insight into the spin crossover (SCO) properties of iron(II) based metal organic coordination cages, specifically examining how the structure of the local metal coordination environment affects SCO. To represent the tetrahedral metal-organic cage, a model system is generated by considering an isolated metal-ion vertex: fac-ML3(2+) (M = Fe(II), Co(II); L = N-phenyl-2 pyridinaldimine). The sensitivity of the (1)H paramagnetic chemical shifts to local coordination environments is assessed and utilised to shed light on spin crossover behaviour in iron complexes. Our data indicate that expansion of the metal coordination sphere must precede any thermal SCO. An attempt to correlate experimental enthalpies of SCO with static properties of bound guests shows that no simple relationship exists, and that effects are likely due to nuanced dynamic response to encapsulation. PMID- 24752729 TI - The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B-cell lymphopoiesis and implicates microRNA-34a in diabetes protection. AB - NOD.B10 Idd9.3 mice are congenic for the insulin-dependent diabetes (Idd) Idd9.3 locus, which confers significant type 1 diabetes (T1D) protection and encodes 19 genes, including microRNA (miR)-34a, from T1D-resistant C57BL/10 mice. B cells have been shown to play a critical role in the priming of autoantigen-specific CD4(+) T cells in T1D pathogenesis in non-obese diabetic (NOD) mice. We show that early B-cell development is impaired in NOD.B10 Idd9.3 mice, resulting in the profound reduction of transitional and mature splenic B cells as compared with NOD mice. Molecular analysis revealed that miR-34a expression was significantly higher in B-cell progenitors and marginal zone B cells from NOD.B10 Idd9.3 mice than in NOD mice. Furthermore, miR-34a expression in these cell populations inversely correlated with levels of Foxp1, an essential regulator of B-cell lymphopoiesis, which is directly repressed by miR-34a. In addition, we show that islet-specific CD4(+) T cells proliferated inefficiently when primed by NOD.B10 Idd9.3 B cells in vitro or in response to endogenous autoantigen in NOD.B10 Idd9.3 mice. Thus, Idd9.3-encoded miR-34a is a likely candidate in negatively regulating B-cell lymphopoiesis, which may contribute to inefficient expansion of islet-specific CD4(+) T cells and to T1D protection in NOD.B10 Idd9.3 mice. PMID- 24752731 TI - Linking the levels: network and relational perspectives for community psychology. AB - In this article, we assert that relationships and networks are of paramount importance for understanding and improving settings, neighborhoods, communities, and larger social systems. Despite previous acknowledgements of their relevance, relational and social network perspectives and analyses remain underrepresented in community psychological research and action. Here, we claim that network and relational perspectives can provide conceptual and empirical 'links' between levels of analysis, more fully reflecting a transactional view. We also describe some of the sophisticated methodologies that can be employed in empirical studies drawing on these perspectives. Additionally, we contend that core concepts in community psychology such as health promotion, empowerment, coalition building, and dissemination and implementation can be better understood when employing relational and network perspectives. As an introduction to this special issue of American Journal of Community Psychology, we draw out themes and key points from the articles in the issue, and offer recommendations for future advancement of these perspectives in the field. PMID- 24752732 TI - Commentary: demonstrating cost-effectiveness in pediatric psychology. AB - OBJECTIVE: Changes in the health care system and payment plans will likely require pediatric psychologists to illustrate the impact of their services. Cost effectiveness analyses are one method of demonstrating the potential economic benefits of our services but are rarely used by pediatric psychologists. METHOD: A hypothetical cost-effectiveness analysis was conducted, comparing the costs and outcomes between a behavioral adherence intervention and no intervention for youth with acute lymphoblastic leukemia. RESULTS: Results illustrate how pediatric psychologists can use cost-effectiveness analyses to demonstrate the economic impact of their work. CONCLUSIONS: Efforts to conduct economic analyses could allow pediatric psychologists to advocate for their services. Implications and future directions are discussed. PMID- 24752733 TI - Diastereoselective formation of aziridines from diazocarbonyl compounds and N-(O pivaloylated D-galactosyl)benzylideneamines and ring-opening reactions with p toluenethiol. AB - N-Galactosyl aziridines were synthesized via BF3.OEt2 promoted addition of carbenes generated from diazocarbonyl compounds with O-pivaloylated beta-D galactosylimines in good yields and high diastereoselectivity. The ring-opening reactions with p-toluenethiol of the aziridines provided enantiometrically pure beta-S-substituted phenylalanine derivatives in a highly regioselective manner. PMID- 24752735 TI - Rectal cancer only metastasis to the thyroid which has a primary papillary thyroid cancer. PMID- 24752734 TI - Virus transcript levels and cell growth rates after naturally occurring HPV16 integration events in basal cervical keratinocytes. AB - Cervical carcinogenesis is characterized by a clonal selection process in which the high-risk human papillomavirus (HRHPV) genome usually changes from the extra chromosomal (episomal) state seen in productive infections to DNA that is integrated into host chromosomes. However, it is not clear whether all HRHPV integration events provide cells with a selective growth advantage compared with the episome-containing cells from which they originate. It is also unclear whether selection of cells containing a particular integrant from a mixed population simply reflects the highest levels of virus oncogene expression or has additional determinants. These early events in cervical carcinogenesis cannot readily be addressed by cross-sectional studies of clinical samples. We used the W12 model system to generate a panel of cervical squamous cell clones that were derived from an identical background under non-competitive conditions and differed only by the genomic site of HPV16 integration. Compared with the 'baseline' episome-containing cells from which they were isolated, only 9/17 clones (53%) showed significantly greater growth rates and only 7/17 (41%) showed significantly greater expression of the major virus oncogenes E7/E6. There were significant variations in levels of HPV16 transcription per DNA template, changes that were associated with histone modifications in the integrated virus chromatin. Cell growth rates showed only weak and non-significant associations with protein and mRNA levels for E7, E6, and the mean E7/E6 values. We conclude that HPV16 integration in basal cervical cells does not necessarily lead to increased levels of virus oncogenes, or to a competitive growth advantage, when compared with the initiating episome-containing cells. PMID- 24752736 TI - Sigmoid volvulus: is it related to Marfan syndrome? PMID- 24752737 TI - Intestinal permeability, systemic endotoxemia, and bacterial translocation after open or laparoscopic resection: the critical role of bowel preparation. PMID- 24752739 TI - Normalisation of colon transit time in a spina bifida adolescent after neurosurgery for retethering. PMID- 24752738 TI - A hundred patients with vertical rectus abdominis myocutaneous (VRAM) flap for pelvic reconstruction after total pelvic exenteration. AB - PURPOSE: We analysed the outcomes of a series of 100 consecutive patients with anorectal cancer with neoadjuvant radiochemotherapy and abdominoperineal exstirpation or total pelvic exenteration, who received a transpelvic vertical rectus abdominis myocutaneous (VRAM) flap for pelvic, vaginal and/or perineal reconstruction and compare a cohort to patients without VRAM flaps. METHODS: Within a 10-year period (2003-2013) in our institution 924 patients with rectal cancer stage y0 to y IV were surgically treated. Data of those 100 consecutive patients who received a transpelvic VRAM flap were collected and compared to patients without flaps. RESULTS: In 100 consecutive patients with transpelvic VRAM flaps, major donor site complications occurred in 6 %, VRAM-specific perineal wound complications were observed in 11 % of the patients and overall 30 day mortality was 2 %. CONCLUSIONS: The VRAM flap is a reliable and safe method for pelvic reconstruction in patients with advanced disease requiring pelvic exenteration and irradiation, with a relatively low rate of donor and recipient site complications. In this first study, to compare a large number of patients with VRAM flap reconstruction to patients without pelvic VRAM flap reconstruction, a clear advantage of simultaneous pelvic reconstruction is demonstrated. PMID- 24752741 TI - Response to: standardized templates for shaping the fibula free flap in mandible reconstruction. J Reconstr Microsurg 2013;29:619-622. PMID- 24752740 TI - HS3ST2 modulates breast cancer cell invasiveness via MAP kinase- and Tcf4 (Tcf7l2)-dependent regulation of protease and cadherin expression. AB - Heparan sulfate 3-O-sulfotransferase 2 (HS3ST2), an enzyme mediating 3-O sulfation of heparan sulfate (HS), is silenced by hypermethylation in breast cancer. As HS has an important co-receptor function for numerous signal transduction pathways, the phenotypical changes due to HS3ST2 reexpression were investigated in vitro using high and low invasive breast cancer cell lines. Compared to controls, highly invasive HS3ST2-expressing MDA-MB-231 cells showed enhanced Matrigel invasiveness, transendothelial migration and motility. Affymetrix screening and confirmatory real-time PCR and Western blotting analysis revealed increased expression of several matrix metalloproteinases, cadherin-11, E-cadherin and CEACAM-1, while protease inhibitor and annexin A10 expression were decreased. Low invasive HS3ST2 -expressing MCF-7 cells became even less invasive, with no change in gelatinolytic MMP activity. HS3ST2 expression increased HS dependent basal and FGF2-specific signaling through the constitutively active p44/42 MAPK pathway in MDA-MB-231 cells. Increased MAPK activation was accompanied by upregulation of beta-catenin in MDA-MB-231, and of the transcription factor Tcf4 in both cell lines. Dysregulation of Tcf4-regulated ion transporters and increased cytosolic acidification were observed in HS3ST2 expressing MDA-MB-231 cells, which is a possible underlying cause of increased chemosensitivity towards doxorubicine and paclitaxel in these cells. This study provides the first in vitro evidence of the involvement of HS3ST2 in breast cancer cell invasion and chemosensitivity. PMID- 24752742 TI - The bone-in-fillet flap: a spare-parts approach to achieving simultaneous bony pelvic stabilization and soft tissue reconstruction following external hemipelvectomy. PMID- 24752743 TI - Predicting skin flap viability using a new intraoperative tissue oximetry sensor: a feasibility study in pigs. AB - BACKGROUND: Operations for soft-tissue reconstruction, orthopedic, vascular, and other types of surgery can be complicated by unexpected skin flap necrosis. At present, surgeons utilize subjective clinical judgment and physical findings to estimate the potential for tissue compromise. As the validity of these subjective methods is questionable, there is a need for objective, quantitative tools to determine the risk of flap necrosis during surgery. METHODS: Three 9-month-old Yorkshire pigs were used for the study. Four laterally based random pattern fasciocutaneous flaps were dissected on each animal. After the flaps were elevated, a prototype oximeter (ViOptix Inc., Fremont, CA), was used to measure tissue oxygenation (StO2) at 2 cm intervals along the flaps. Measurements were performed immediately after the flaps were dissected, and again at the same points after they were sutured. The animals were reevaluated 4 days later, and assessed for areas of tissue necrosis. RESULTS: For each flap, StO2 at the base was compared with StO2 at the more distal points. The median delta StO2, as measured immediately after dissection, was -3.9% points for tissue that remained viable and -34.0% points for tissue that became necrotic (p = 0.039). After the flaps were sutured back to the chest wall, the median delta StO2 for tissue that remained viable was -1.7% points versus -24.7% points for tissue that became necrotic (p = 0.006). CONCLUSIONS: This new handheld surface sensor can be used to measure StO2 of skin flaps and may potentially reduce complications associated with unexpected tissue necrosis. PMID- 24752744 TI - Traumatic lower limb injury and microsurgical free flap reconstruction with the use of negative pressure wound therapy: is timing crucial? AB - BACKGROUND: The timing of microsurgical free flap reconstruction for traumatic lower limb injury has been described as being optimal if conducted within the early period following injury, as higher rates of infection and flap loss were reported in the subsequent time period. However, for various reasons, reconstruction of these defects may be delayed. The aim of this article is to show that adequate debridement, negative pressure wound dressing, and sound reconstructive principles has led to increased free flap success rates regardless of the period between injury and reconstruction. PATIENTS AND METHODS: A 10-year retrospective single-center analysis of 50 traumatic lower limb cases from 2002 to 2012 was conducted. All patients had microsurgical free flap reconstruction after a period of negative pressure wound therapy (NPWT). Patient factors and reconstructive methods were analyzed and outcomes were compared. RESULTS: Mean interval between admission and free flap coverage was 17.5 days, and patients underwent NPWT for an average of 12 days (range, 1-35). Approximately 8% of patients had postoperative infections. Overall free flap success rate was 96%. Approximately 90% of patients were able to return to their premorbid footwear, with 96% able to mobilize independently approaching the end of their follow-up period. CONCLUSION: Our study shows that traumatic lower limb reconstruction in the delayed period is no longer associated with high rates of flap failure. Improvements in microsurgery and the advent of NPWT have made timing no longer crucial in free flap coverage of traumatic lower limb injuries. PMID- 24752745 TI - Overview of low molecular weight heparin for preventative treatment of adverse obstetric outcomes related to abnormal placentation. AB - Different proportions of cases of preterm and severe preeclampsia, placental abruption, fetal growth restriction, and fetal death share a common causal pathway of abnormal placental implantation. Documentation of an association between the risk of such adverse pregnancy outcomes (APOs) and inherited thrombophilias prompted initial studies to evaluate the benefit of anticoagulants for the prevention of recurrences both in patients with and without inherited thrombophilias. Prenatal administration of low molecular weight heparin (LMWH) has been evaluated in case control, cohort and randomized clinical trials. The evidence suggests a benefit of LMWH in the reduction of recurrences of APOs, with a number needed to treat of 6 (95% confidence interval: 4-10) to prevent one case of recurrent APOs. Such benefit is independent of the presence of inherited thrombophilias or the administration of low dose aspirin. Further studies are needed to establish the optimal duration for the prophylaxis, to better delineate the mechanism of action of LMWH and to explore the role, if any, of maternal serum markers and uterine artery Doppler findings in the modulation of the LMWH prophylaxis. PMID- 24752746 TI - Differential pulse adsorptive stripping voltammetric determination of nanomolar levels of atorvastatin calcium in pharmaceutical and biological samples using a vertically aligned carbon nanotube/graphene oxide electrode. AB - A novel vertically aligned carbon nanotube/graphene oxide (VACNT-GO) electrode is proposed, and its ability to determine atorvastatin calcium (ATOR) in pharmaceutical and biological samples by differential pulse adsorptive stripping voltammetry (DPAdSV) is evaluated. VACNT films were prepared on a Ti substrate by a microwave plasma chemical vapour deposition method and then treated with oxygen plasma to produce the VACNT-GO electrode. The oxygen plasma treatment exfoliates the carbon nanotube tips exposing graphene foils and inserting oxygen functional groups, these effects improved the VACNT wettability (super-hydrophobic) which is crucial for its electrochemical application. The electrochemical behaviour of ATOR on the VACNT-GO electrode was studied by cyclic voltammetry, which showed that it underwent an irreversible oxidation process at a potential of +1.08 V in pHcond 2.0 (0.2 mol L(-1) buffer phosphate solution). By applying DPAdSV under optimized experimental conditions the analytical curve was found to be linear in the ATOR concentration range of 90 to 3.81 * 10(3) nmol L(-1) with a limit of detection of 9.4 nmol L(-1). The proposed DPAdSV method was successfully applied in the determination of ATOR in pharmaceutical and biological samples, and the results were in close agreement with those obtained by a comparative spectrophotometric method at a confidence level of 95%. PMID- 24752748 TI - Bisphenol A, 4-tert-octylphenol, and 4-nonylphenol in the Gulf of Gdansk (Southern Baltic). AB - The organic derivatives of phenol are classed as dangerous compounds, and their presence has been detected in surface water, bottom water, phytoplankton, zooplankton, and mussel as well as liver and muscle of fish from the Gulf of Gdansk and in liver, muscle, and guano of gulls residing in the coastal zone of this basin. The greatest sources of bisphenol A (BPA), 4-tert-octylphenol (OP), and 4-nonylphenol (NP) were found to be the Vistula River and the water purification plant in Debogorze. In living organisms, concentrations of BPA, OP, and NP ranged between the limit of quantification and several hundred ng g(-1) dry weight (dw), and the highest concentrations were found for BPA. Prolonged alimentary exposure to BPA, OP, and NP in fish and birds was indicated by liver/muscle concentration ratios generally >1. The most influential factors on BPA and alkylphenol concentrations in the tissues of fishes and gulls were mainly diet and habitat. The study confirmed possible bioaccumulation in the food web. High BPA and NP concentrations in guano (<=2,700 and <=300 ng g(-1) dw, respectively) indicated the ability of birds to detoxify and signalled the reintroduction of these compounds to seawater. Herring, flounder, and cod from the Southern Baltic are a safe food source for human consumption because their BPA and alkylphenol contents are low. PMID- 24752749 TI - Potential bioavailability enhancement of bioactive compounds using food-grade engineered nanomaterials: a review of the existing evidence. AB - The development of engineered nanometre sized materials (ENM) produced with food grade ingredients and designed as delivery systems for organic and inorganic materials has gained increasing interest. The major reason for this trend is the aim to overcome problems associated with the low bioavailability of many bioactive compounds (BC) which are usually claimed to benefit human health. In this review, outcomes of studies investigating the potential bioavailability enhancement of BC using ENM as delivery systems are summarised and discussed. It focuses on in vitro and in vivo studies carried out with ENM produced with food grade materials and designed for the delivery of vitamins, other secondary plant metabolites and minerals. Furthermore, the physical and physicochemical aspects governing the preparation of the systems, the loading of the BC, the stability of the delivery systems in food applications and finally the release of the BC in the gastrointestinal tract are also considered. The mechanisms leading to an enhanced bioavailability are based on (i) improved solubility of the BC under gastrointestinal conditions, (ii) the protection of the BC from the chemical conditions in the gastrointestinal tract (GIT), (iii) the controlled release within the GIT or (iv) an improved transfer through the intestinal wall. The main outcome of the review is that particle size, surface properties and physical state of the ENM are key parameters to be controlled aiming at an enhanced nutritional value of food materials. Furthermore, the bioavailability classification scheme (BCS) can help to understand the efficacy of different ENM for the delivery of specific BC. PMID- 24752750 TI - From promotion to management: the wide impact of bacteria on cancer and its treatment. AB - In humans, the intestine is the major reservoir of microbes. Although the intestinal microbial community exists in a state of homeostasis called eubiosis, environmental and genetics factors can lead to microbial perturbation or dysbiosis, a state associated with various pathologies including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Dysbiotic microbiota is thought to contribute to the initiation and progression of CRC. At the opposite end of the spectrum, two recently published studies in Science reveal that the microbiota is essential for chemotherapeutic drug efficacy, suggesting a beneficial microbial function in cancer management. The dichotomy between the beneficial and detrimental roles of the microbiota during cancer initiation, progression, and treatment emphasize the interwoven relationship between bacteria and cancer. Moreover, these findings suggest that the microbiota could be considered as a therapeutic target, not only at the level of cancer prevention, but also during management, i.e. by enhancing the efficacy of chemotherapeutics. PMID- 24752752 TI - A facile exfoliation-crystal growth route to multicomponent Ag2CO3/Ag-Ti5NbO14 nanohybrids with improved visible light photocatalytic activity. AB - Multicomponent Ag2CO3/Ag-layered Ti5NbO14 nanohybrids are synthesized by the crystal growth of silver carbonate on the surface of exfoliated layered titanoniobate 2D nanosheets. In the obtained nanohybrids, the spherical Ag2CO3 nanoparticles with a size of 5-10 nm are immobilized on the surface of the titanoniobate nanosheets with partial formation of neutral Ag metal caused by electron transfer from anionic titanoniobate nanosheets to silver cations. An electronic coupling between Ag2CO3/Ag and Ti5NbO14 nanosheets leads to a remarkable enhancement of visible light absorption and a significant depression of electron-hole recombination. The present Ag2CO3/Ag-layered Ti5NbO14 nanohybrids show much higher visible light photocatalytic activity than the unhybridized Ag2CO3, underscoring the beneficial effect of hybridization with metal oxide nanosheets on the photocatalytic activity of silver oxosalts. Before and after the photoreaction, the crystal structure and crystal morphology of the Ag2CO3/Ag-layered Ti5NbO14 nanohybrids remain unchanged, highlighting the excellent photostability of these materials. All the present experimental findings clearly demonstrate the usefulness of the exfoliation-crystal growth method in exploring novel efficient visible light active photocatalysts. PMID- 24752751 TI - Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease. AB - Acute graft-versus-host disease (aGvHD) is a major limitation to the use of allogeneic stem cell transplantation for the treatment of patients with relapsed malignant disease. Previous work using animals lacking secondary lymphoid tissue (SLT) suggested that activation of donor T cells in SLT is critically important for the pathogenesis of aGvHD. However, these studies did not determine if impaired migration into, and more importantly, out of SLT, would ameliorate aGvHD. Here, we show that T cells from mice lacking Coronin 1A (Coro 1A(-/-)), an actin-associated protein shown to be important for thymocyte egress, do not mediate acute GvHD. The attenuation of aGvHD was associated with decreased expression of the critical trafficking proteins C-C chemokines receptor type 7 (CCR7) and sphingosine 1 phosphate receptor on donor T cells. This was mediated in part by impaired activation of the canonical NF-kappaB pathway in the absence of Coro 1A. As a result of these alterations, donor T cells from Coro 1A(-/-) mice were not able to initially traffic to SLT or exit SLT after BM transplantation. However, this alteration did not abrogate the graft-versus leukemia response. Our data suggest that blocking T-cell migration into and out of SLT is a valid approach to prevent aGvHD. PMID- 24752753 TI - The effect of age, diagnosis, and their interaction on vertex-based measures of cortical thickness and surface area in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is accompanied by an atypical development of brain maturation. So far, brain development has mainly been studied during early childhood in ASD, and using measures of total or lobular brain volume. However, cortical volumetric measures are a product of two distinct biological neuroanatomical features, cortical thickness, and surface area, which most likely also have different neurodevelopmental trajectories in ASD. Here, we therefore examined age-related differences in cortical thickness and surface area in a cross-sectional sample of 77 male individuals with ASD ranging from 7 to 25 years of age, and 77 male neurotypical controls matched for age and FSIQ. Surface-based measures were analyzed using a general linear model (GLM) including linear, quadratic, and cubic age terms, as well as their interactions with the main effect of group. When controlling for the effects of age, individuals with ASD had spatially distributed reductions in cortical thickness relative to controls, particularly in fronto-temporal regions, and also showed significantly reduced surface area in the prefrontal cortex and the anterior temporal lobe. We also observed significant group * age interactions for both measures. However, while cortical thickness was best predicted by a quadratic age term, the neurodevelopmental trajectory for measures of surface area was mostly linear. Our findings suggest that ASD is accompanied by age-related and region-specific reductions in cortical thickness and surface area during childhood and early adulthood. Thus, differences in the neurodevelopmental trajectory of maturation for both measures need to be taken into account when interpreting between-group differences overall. PMID- 24752755 TI - Triggering receptor expressed on myeloid cells-1 (TREM-1) improves host defence in pneumococcal pneumonia. AB - Streptococcus (S.) pneumoniae is a common Gram-positive pathogen in community acquired pneumonia and sepsis. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a receptor on phagocytes known to amplify inflammatory responses. Previous studies showed that TREM-1 inhibition protects against lethality during experimental Gram-negative sepsis. We here aimed to investigate the role of TREM 1 in an experimental model of pneumococcal pneumonia, using TREM-1/3-deficient (Trem-1/3(-/-) ) and wild-type (Wt) mice. Additionally ex vivo responsiveness of Trem-1/3(-/-) neutrophils and macrophages was examined. S. pneumoniae infection resulted in a rapid recruitment of TREM-1-positive neutrophils into the bronchoalveolar space, while high constitutive TREM-1 expression on alveolar macrophages remained unchanged. TREM-1/3 deficiency led to increased lethality, accompanied by enhanced growth of S. pneumoniae at the primary site of infection and increased dissemination to distant organs. Within the first 3-6 h of infection, Trem-1/3(-/-) mice demonstrated a strongly impaired innate immune response in the airways, as reflected by reduced local release of cytokines and chemokines and a delayed influx of neutrophils. Trem-1/3(-/-) alveolar macrophages produced fewer cytokines upon exposure to S. pneumoniae in vitro and were less capable of phagocytosing this pathogen. TREM-1/3 deficiency did not influence neutrophil responsiveness to S. pneumoniae. These results identify TREM 1 as a key player in protective innate immunity during pneumococcal pneumonia, most likely by enhancing the early immune response of alveolar macrophages. PMID- 24752756 TI - Knowledge and attitudes about Parkinson's disease among a diverse group of older adults. AB - Underserved minorities are vulnerable to diagnostic delays and under-treatment of Parkinson's disease (PD). The purpose of this mixed-methods study was to understand knowledge and attitudes about PD among a racially/ethnically diverse group of community members. In the qualitative arm, ten homogeneous focus groups of 6 to 8 White, African-American and Chinese American older adults at senior centers in Philadelphia were conducted. Next, for the quantitative arm, a questionnaire of knowledge and attitudes about PD was administered among a larger group of senior center members. Themes were identified from the focus group discussions. ANOVA and chi-square tests were used to assess differences in PD knowledge and attitudes among the different racial/ethnic groups. Logistic regression analyzed for independent factors associated with barriers to treatment. Seventy-five adults participated in the focus groups (23 Whites, 36 African-Americans and 16 Chinese-Americans) and 154 completed the questionnaire (62 Whites, 47 African-Americans and 45 Chinese-Americans). One common theme about developing PD was fear of losing independence. Racial/ethnic groups identified unique barriers to care: mistrust in the healthcare system by African Americans and language difficulties by Chinese-Americans. Eighty percent of all participants had no to some knowledge of PD. African-Americans and Chinese Americans were more likely to perceive PD as a part of normal aging than whites. Chinese-Americans were more likely to perceive barriers to treatment than whites. A diverse sample of older adults demonstrated low levels of PD knowledge through both qualitative and quantitative methods. Many barriers to PD care were identified. Targeted community outreach and education efforts should incorporate information about PD and how to receive care. PMID- 24752757 TI - "If I Don't Like the Way I Feel With a Certain Drug, I'll Tell Them.": Older Adults' Experiences With Self-Determination and Health Self-Advocacy. AB - Health self-advocacy is associated with positive health outcomes, though existing research indicates that older adults may be at a disadvantage when self advocating within the health care and disability support systems. This study examined perceptions of older adults' health self-advocacy behaviors and the context under which they self-advocate for their chronic conditions. The study involved in-depth interviews with 37 older adults with chronic illnesses and disabilities and 9 geriatric case managers in South and Central Florida. Data were systematically analyzed for themes. Thematic findings revealed that concerns over quality of life is the most common motivator for older adults to engage in health self-advocacy and that self-advocacy involves gathering information to prepare for decision-making and confronting providers about the information gathered. The findings suggest that providers may help facilitate self determination by framing health communication within the context of quality of life. PMID- 24752754 TI - The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. AB - Glutamate is the major excitatory neurotransmitter in the brain and may be a key neurotransmitter involved in autism. Literature pertaining to glutamate and autism or related disorders (e.g., Fragile X syndrome) is reviewed in this article. Interest in glutamatergic dysfunction in autism is high due to increasing convergent evidence implicating the system in the disorder from peripheral biomarkers, neuroimaging, protein expression, genetics and animal models. Currently, there are no pharmaceutical interventions approved for autism that address glutamate deficits in the disorder. New treatments related to glutamatergic neurotransmission, however, are emerging. In addition, older glutamate-modulating medications with approved indications for use in other disorders are being investigated for re-tasking as treatments for autism. This review presents evidence in support of glutamate abnormalities in autism and the potential for translation into new treatments for the disorder. PMID- 24752758 TI - Organ Donation in the 50+ Age Demographic: Survey Results on Decision Rationale and Information Preferences. AB - The rate of organ donation by older potential donors is significantly declining even though recent studies show positive clinical outcomes with organs transplanted from older donors. This study examined the 50+ age demographic to identify the rationale for donation decisions, preferred media methods of donation information delivery, and responsiveness to an age-tailored donation message. Results from 579 surveys, 87% from the 50+ age demographic, found respondents prone to self-select themselves as medically ineligible based on current medication and health status, even though they might be medically suitable donors. Their incentive to pursue additional information on donation is limited except when motivated by personal accounts within their families and communities. In addition, even when computer literate, they continue to favor the printed or spoken word for donation information delivery. The results suggest an opportunity for those working with older adults to develop more personalized, localized donation education programs targeting this age demographic. PMID- 24752759 TI - What Factors Influence the Relationship Between Feedback on Cognitive Performance and Subsequent Driving Self-Regulation? AB - Recent research indicates that providing feedback about cognitive abilities (i.e., UFOV(r) test performance) may change driving self-regulation; however, 42% of participants who received negative feedback failed to increase driving self regulation (Ackerman, Ball, Crowe, Owsley, Vance, & Wadley, 2011). The current study extends those findings, using the same sample (N = 129) to investigate factors that may influence the relationship between feedback regarding cognitive abilities and driving self-regulation. Feedback by age and feedback by number of eye conditions showed significant interactions, and feedback by baseline driving exposure interaction approached significance. Older participants (80-94; n = 38) who received negative feedback significantly increased subsequent avoidance of challenging driving conditions relative to baseline. Participants with no reported eye conditions (n = 36) who received negative feedback significantly increased subsequent driving avoidance, and participants below median baseline driving exposure (n = 66) tended to increase subsequent driving avoidance. These results identify individual level factors that may influence the relationship between feedback regarding cognitive abilities and self-regulation and have implications for encouraging older adults to make informed decisions about appropriate driving behavior. PMID- 24752760 TI - Unusual redox stability of neptunium in the ionic liquid [Hbet][Tf(2)N]. AB - The behavior of neptunium in the ionic liquid betaine bistriflimide, [Hbet][Tf2N], has been studied spectroscopically at room temperature and 60 degrees C for the first time. An unprecedented complex redox chemistry is observed, with up to three oxidation states (iv, v and vi) and up to six Np species existing simultaneously. Both redox reactions and coordination of betaine are observed for Np(iv), (v) and (vi). Elevating the temperature accelerates the coordination of Np(v) with betaine and reduction reactions slow down. PMID- 24752761 TI - Microtiter plate-sized standalone chip holder for microenvironmental physiological control in gas-impermeable microfluidic devices. AB - We present a microtiter plate-sized standalone chip holder for precise control of physiological conditions inside closed microfluidic cell culture systems, made from gas-impermeable materials. Specifically, we demonstrate the suitability of the holder to support cell growth in a glass chip, to allow time-lapse imaging of live cells and the creation of a hypoxic environment, all relevant for applications in regenerative medicine research. PMID- 24752762 TI - Pithovirus: a new giant DNA virus found from more than 30,000-year-old sample. PMID- 24752763 TI - Single amino acid substitution of VP1 N17D or VP2 H145Y confers acid-resistant phenotype of type Asia1 foot-and-mouth disease virus. AB - Infection by foot-and-mouth disease virus (FMDV) is triggered by the acidic pH in endosomes after virus uptake by receptor-mediated endocytosis. However, dissociation of the FMDV 146S particle in mildly acidic conditions renders inactivated foot-and-mouth disease (FMD) vaccines much less effective. Type Asia1 FMDV mutants with increased resistance to acid inactivation were selected to study the molecular basis of viral resistance to acid-induced disassembly and improve the acid stability of FMDV. Sequencing of capsid-coding regions revealed four amino acid replacements (VP1 N17D, VP2 H145Y, VP2 G192D, and VP3 K153E) in the viral population of the acid-selected 10th passage. We performed single or combined mutagenesis using a reverse genetic system, and our results provide direct experimental evidence that VP2 H145Y or VP1 N17D substitution confers an acid-resistant phenotype to type Asia1 FMDV. PMID- 24752764 TI - High-throughput sequencing exclusively identified a novel Torque teno virus genotype in serum of a patient with fatal fever. AB - Torque teno virus (TTV) has been found to be prevalent world-wide in healthy populations and in patients with various diseases, but its etiological role has not yet been determined. Using high-throughput unbiased sequencing to screen for viruses in the serum of a patient with persistent high fever who died of suspected viral infection and prolonged weakness, we identified the complete genome sequence of a TTV (isolate Hebei-1). The genome of TTV-Hebei-1 is 3649 bp in length, encoding four putative open reading frames, and it has a G+C content of 49%. Genomic comparison and a BLASTN search revealed that the assembled genome of TTV-Hebei-1 represented a novel isolate, with a genome sequence that was highly heterologous to the sequences of other reported TTV strains. A phylogenetic tree constructed using the complete genome sequence showed that TTV Hebei-1 and an uncharacterized Taiwanese strain, TW53A37, constitute a new TTV genotype. The patient was strongly suspected of carrying a viral infection and died eventually without any other possible causes being apparent. No virus other than the novel TTV was identified in his serum sample. Although a direct causal link between the novel TTV genotype infection and the patient's disease could not be confirmed, the findings suggest that surveillance of this novel TTV genotype is necessary and that its role in disease deserves to be explored. PMID- 24752765 TI - Ultrastructural characterization of avian influenza A (H7N9) virus infecting humans in China. PMID- 24752766 TI - 3'-UTR sequence of Macrobrachium rosenbergii extra small virus (XSV) is important for viral RNA packaging. PMID- 24752767 TI - An electrochemical immunosensor for detection of a breast cancer biomarker based on antiHER2-iron oxide nanoparticle bioconjugates. AB - A label free immunosensor was designed for ultra-detection of human epidermal growth factor receptor 2 (HER2) in real samples using a differential pulse voltammetry (DPV) method. In a separate process, antiHER2 antibodies were attached to iron oxide nanoparticles (Fe3O4 NPs) to form stable bioconjugates which were later laid over the gold electrode surface. In this way, by the advantage of their long terminals, the bioconjugates provided the most possible space for the immuno-reaction between biomolecules. Under optimal conditions, the immunosensor was responsive to HER2 concentrations over the ranges of 0.01-10 ng mL(-1) and 10-100 ng mL(-1) linearly and benefited from a satisfactory detection limit as low as 0.995 pg mL(-1) and a favorable sensitivity as sharp as 5.921 MUA mL ng(-1). The reliability of the method in clinical analysis was proved by successful quantization of HER2 levels in serum samples obtained from patients. Furthermore, the precision and the stability of the method were evaluated and verified to be acceptable in immunoassay studies. PMID- 24752768 TI - The role of allogeneic stem cell transplantation in Hodgkin's lymphoma. AB - OPINION STATEMENT: The treatment of patients with classical Hodgkin's lymphoma relapsing after autologous stem cell transplantation represents a clear unmet need. Overall long-term outcome is not the same in these patients and therapeutic options in this setting are very heterogeneous and include salvage CT and/or RT followed or not by a second stem cell transplantation, palliative care, new drugs, or biological agents. Despite the absence of prospective, randomized, clinical trials, allogeneic stem cell transplantation either from a HLA identical sibling or a matched, unrelated donor represents an attractive option for those young patients with chemosensitive disease after being treated with a salvage protocol. The use of reduced intensity conditioning regimens has been able to drastically decrease nonrelapse mortality, although relapse rate remains a significant issue in this setting. More intense conditioning protocols could eventually decrease the relapse rate after the allogeneic procedure and, as indicated by a recent retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation, nonrelapse mortality does not represent a major problem nowadays for patients with multiply relapsed Hodgkin's lymphoma. Brentuximab vedotin is an antibody-drug conjugate that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30 expressing cells. Its use has been approved recently for patients with Hodgkin's lymphoma relapsing after autologous stem cell transplantation. As a single dose, brentuximab vedotin is able to achieve an objective response rate of 75 % with 34 % of the patients achieving a complete remission. Its widespread use will most certainly change the treatment paradigm of this subgroup of patients, either avoiding the allogeneic procedure in some patients or by increasing the group of potential candidates to an allogeneic transplant being used as a "bridge to allo." Additional information on long-term outcome of patients being treated with this drug or the development of prospective clinical trials in this setting will most probably give some light to this question we have nowadays. PMID- 24752769 TI - Potential beneficial effects of granulocyte colony-stimulating factor therapy for spastic paraparesis in a patient with kyphoscoliosis: a case report. AB - Congenital kyphosis and kyphoscoliosis are much less common than congenital scoliosis and more serious because these curves can progress rapidly and can lead to spinal cord compression and paraplegia. A 15-year-old boy presented with congenital kyphoscoliosis along with spastic paraparesis (American Spinal Injury Association Impairment Scale grade C). We examined the safety and effectiveness of a low dose of analog granulocyte colony-stimulating factor (G-CSF) in this patient. G-CSF 5 ug/kg was given subcutaneously, daily for 5 days per month for 3 months. Laboratory tests, including blood, biochemical tests, and CD34+ cells (marker hematopoietic progenitor cells) were performed, in addition to clinical examination. Clinical examination revealed an increase of muscle strength in the upper limbs and decrease spasticity in the lower limbs between baseline and day 90 and day 180. We found no serious adverse event, drug-related platelet reduction, or splenomegaly. Leukocyte levels remained below 21,000/uL. CD34+ increased significantly at day 5 of G-CSF administration. Low-dose G-CSF was safe and well tolerated by the patient. A significant increase in muscle strength in this patient with spastic paraparesis after 3 months of treatment may indicate beneficial effects of G-CSF factor in this disorder. These results are inspiring and warrant further studies. PMID- 24752770 TI - Cyclodextrin ion channels. AB - Seventeen derivatives of alpha- and beta-cyclodextrins were prepared from the cyclodextrin per-6-azide by "click" cyclization with terminal alkynes. Sixteen of these "half-channel" compounds showed significant activity as ion channels in planar bilayer members as assessed by the voltage-clamp technique. Activity ranged from persistent square-top openings to highly erratic conductance; mixed behaviours were evident in virtually all data recorded. Some of the erratic behaviours were shown to follow an apparent power-law distribution of open duration times. The activities observed for the suite were summarized using a model-free activity grid method which displays conductance, duration, and opening behaviour. The overall activity shows the clustering of conductance-duration indicating that activity arises from system properties rather that solely as a property of the compound. The activity grids also support an analysis of structure-activity relationships as they apply to the global behaviour of the compounds and reveal the complexity of a single structure change in controlling the distribution of concurrent conductance behaviours. Transient blockage of channel activity by the hydrophobic guest of the cyclodextrin (1-adamantyl carboxylate) is consistent with the formation of an end-to-end dimer channel among several other competing and interconverting structures. PMID- 24752771 TI - No association of pri-miR-143 rs41291957 polymorphism with the risk of congenital heart disease in a Chinese population. AB - MiR-143 plays an important role in the heart development of zebra fish. The rs41291957 variant located in the pri-miR-143 sequence is associated with colorectal carcinogenesis. Therefore, the authors hypothesized that rs41291957 in pri-miR-143 might be involved in the risk of sporadic congenital heart disease (CHD). The authors conducted a case-control study of CHD in a Chinese population to test their hypothesis by genotyping pri-miR-143 rs41291957 in 1,109 CHD cases and 915 non-CHD control subjects. Logistic regression analyses showed no significant association of genotype or allele frequencies of pri-miR-143 rs41291957 A/G polymorphism with the CHD cases in overall or various subtypes compared with the control group. To the authors' knowledge, this is the first study to investigate the relationship between miR-143 and CHD cases. The results demonstrated that rs41291957 in pri-miR-143 has no major role in genetic susceptibility to sporadic CHD, at least in the current study population. PMID- 24752772 TI - Early sac shrinkage predicts a low risk of late complications after endovascular aortic aneurysm repair. AB - BACKGROUND: Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). Patients with early postoperative shrinkage may experience fewer subsequent complications, and consequently require less intensive surveillance. METHODS: Patients undergoing EVAR from 2000 to 2011 at three vascular centres (in 2 countries), who had two imaging examinations (postoperative and after 6-18 months), were included. Maximum diameter, complications and secondary interventions during follow-up were registered. Patients were categorized according to early sac dynamics. The primary endpoint was freedom from late complications. Secondary endpoints were freedom from secondary intervention, postimplant rupture and direct (type I/III) endoleaks. RESULTS: Some 597 EVARs (71.1 per cent of all EVARs) were included. No shrinkage was observed in 284 patients (47.6 per cent), moderate shrinkage (5-9 mm) in 142 (23.8 per cent) and major shrinkage (at least 10 mm) in 171 patients (28.6 per cent). Four years after the index imaging, the rate of freedom from complications was 84.3 (95 per cent confidence interval 78.7 to 89.8), 88.1 (80.6 to 95.5) and 94.4 (90.1 to 98.7) per cent respectively. No shrinkage was an independent risk factor for late complications compared with major shrinkage (hazard ratio (HR) 3.11; P < 0.001). Moderate compared with major shrinkage (HR 2.10; P = 0.022), early postoperative complications (HR 3.34; P < 0.001) and increasing abdominal aortic aneurysm baseline diameter (HR 1.02; P = 0.001) were also risk factors for late complications. Freedom from secondary interventions and direct endoleaks was greater for patients with major sac shrinkage. CONCLUSION: Early change in aneurysm sac diameter is a strong predictor of late complications after EVAR. Patients with major sac shrinkage have a very low risk of complications for up to 5 years. This parameter may be used to tailor postoperative surveillance. PMID- 24752773 TI - An intragenic long noncoding RNA interacts epigenetically with the RUNX1 promoter and enhancer chromatin DNA in hematopoietic malignancies. AB - RUNX1, a master regulator of hematopoiesis, is the most commonly perturbed target of chromosomal abnormalities in hematopoietic malignancies. The t(8;21) translocation is found in 30-40% of cases of acute myeloid leukemia (AML). Recent whole-exome sequencing also reveals mutations and deletions of RUNX1 in some solid tumors. We describe a RUNX1-intragenic long noncoding RNA RUNXOR that is transcribed as unspliced transcript from an upstream overlapping promoter. RUNXOR was upregulated in AML samples and in response to Ara-C treatment in vitro. RUNXOR utilizes its 3'-terminal fragment to directly interact with the RUNX1 promoter and enhancers and participates in the orchestration of an intrachromosomal loop. The 3' region of RUNXOR also participates in long-range interchromosomal interactions with chromatin regions that are involved in multiple RUNX1 translocations. These data suggest that RUNXOR noncoding RNA may function as a previously unidentified candidate component that is involved in chromosomal translocation in hematopoietic malignancies. PMID- 24752774 TI - Activation of extrinsic apoptosis pathway in HCV monoinfected and HIV-HCV coinfected patients, irrespective of liver disease severity. AB - Chronic hepatitis C virus (HCV) infection is associated with increased levels of peripheral T cell apoptosis. We aimed to study whether T cell apoptosis markers indicate pathways that may contribute to clinical progression in HCV monoinfected and HIV-HCV coinfected patients. Activation of the extrinsic apoptosis pathways was measured by levels of death receptor Fas, initiator caspase 8 and effector caspases 3 and 7 activity and Annexin V binding on peripheral CD4 and CD8 T cells of HCV monoinfected and HIV/HCV coinfected patients, as well as healthy controls and HIV-infected, hepatitis B virus-infected and primary biliary cirrhosis disease controls. Association with liver fibrosis was assessed by biopsy or by transient elastography. HCV monoinfected and HIV-HCV coinfected patients displayed enhanced peripheral CD4 and CD8 T cell apoptosis. Caspase 8 activity was highest in HIV-HCV coinfection, without enhanced downstream activity of caspases 3 and 7. Level of peripheral T cell apoptosis was independent of liver fibrosis or other disease parameters in all disease groups. The extrinsic apoptosis pathway is upregulated in HCV monoinfection and HIV-HCV coinfection, but this is independent of liver disease severity. PMID- 24752776 TI - Evaluation of the impact of density gradient centrifugation on fetal cell loss during enrichment from maternal peripheral blood. AB - OBJECTIVE: Physical separation by density gradient centrifugation (DGC) is usually used as an initial step of multistep enrichment protocols for purification of fetal cells (FCs) from maternal blood. Many protocols were designed but no single approach was efficient enough to provide noninvasive prenatal diagnosis. Procedures and methods were difficult to compare because of the nonuniformity of protocols among different groups. Recovery of FCs is jeopardized by their loss during the process of enrichment. Any loss of FCs must be minimized because of the multiplicative effect of each step of the enrichment process. The main objective of this study was to evaluate FC loss caused by DGC. METHODS: Fetal cells were quantified in peripheral blood samples obtained from both euploid and aneuploid pregnancies before and after enrichment by buoyant DGC using Histopaque 1.119 g/mL. RESULTS: Density gradient centrifugation results in major loss of 60% to 80% of rare FCs, which may further complicate subsequent enrichment procedures. Eliminating aggressive manipulations can significantly minimize FC loss. CONCLUSION: Data obtained raise questions about the appropriateness of the DGC step for the enrichment of rare FCs and argues for the use of the alternative nonaggressive version of the procedure presented here or prioritizing other methods of enrichments. PMID- 24752775 TI - Habitual consumption of coffee and green tea in relation to serum adipokines: a cross-sectional study. AB - PURPOSE: Coffee and green tea consumption may be associated with circulating adipokines, but data are inconsistent, scarce or lacking. We examined the association of coffee and green tea consumption with serum adiponectin, leptin, visfatin, resistin and plasminogen activator inhibitor-1 (PAI-1) among a Japanese working population. METHODS: The authors analyzed data (n = 509) from a cross sectional survey among Japanese workers aged 20-68 years. Serum adipokines were measured using a Luminex suspension bead-based multiplexed array. Coffee and green tea consumption was assessed using a validated diet history questionnaire, and caffeine consumption from these beverages was estimated. Multiple regression analysis was performed with adjustment for potential confounding variables. RESULTS: Coffee consumption was significantly, inversely associated with leptin and PAI-1 (P for trend = 0.007 and 0.02, respectively); compared with subjects consuming <1 cup per day, those consuming >=4 cups per day had 13 and 10 % lower means of leptin and PAI-1, respectively. Similar associations were observed for caffeine consumption (P for trend = 0.02 for both leptin and PAI-1). Additionally, we noted a significant positive association between coffee consumption and adiponectin in men (P for trend = 0.046), but not in women (P for trend = 0.43, P for interaction = 0.11). Moreover, there was a positive association between coffee consumption and resistin in current male smokers (P for trend = 0.01), but not in male non-smokers (P for trend = 0.35, P for interaction = 0.11). Green tea consumption was not associated with any adipokine. CONCLUSIONS: Higher consumption of coffee and caffeine but not green tea was associated with lower serum levels of leptin and PAI-1 in Japanese adults. PMID- 24752777 TI - A novel PPARgamma agonist monascin's potential application in diabetes prevention. AB - Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways. PMID- 24752778 TI - Transferrin' activation: bonding with transferrin receptors tunes KLRG1 function. AB - The inhibitory C-type lectin-like immunoreceptor KLRG1 enables mature NK cells and differentiated T cells to sense cadherin-expressing cells by ligating "classical" cadherins. Upon engagement of the KLRG1 ectodomain, an inhibitory signal emanates from the cytoplasmic immunoreceptor-tyrosine-based inhibition motif (ITIM), dampening functional responses of these lymphocytes. Malignancy associated loss of cadherins has been proposed to relieve KLRG1-mediated inhibition of cytotoxic lymphocytes and thereby to contribute to tumor surveillance by an alternate mode of "missing self-recognition". In this issue of the European Journal of Immunology, Schweier et al. [Eur. J. Immunol. 2014. 44: 1851-1856] propose another intriguing mechanism that may relieve KLRG1-mediated inhibition in the course of lymphocyte activation. Subsequent to identification of the transferrin receptor (TfR) as a component of a high molecular mass KLRG1 complex, they demonstrate that a fraction of mouse KLRG1 molecules undergoes disulfide-bonding with TfRs and colocalises with the latter at the cell surface. In functional terms, high levels of TfRs such as those found on activated lymphocytes were found to be associated with decreased KLRG1 inhibitory function, indicating that TfRs may sequester KLRG1 from interacting with cadherins. Hence, this unexpected liaison between KLRG1 and TfR may represent a regulatory link between metabolic activation and responses of lymphocytes. PMID- 24752779 TI - A study on the synthesis of Ni50Co50 alloy nanostructures with tuned morphology through metal-organic chemical routes. AB - NiCo bimetallic nanostructures with various morphologies have been synthesized using a broad range of solvents, surfactants and precursors that are available in the metal-organic chemical toolbox. Polygonal particles, nanowires and isotropic nanospheres have been obtained, among others. We describe the chemical pathways to achieve anisotropic growth either by an 'in situ' seed-mediated approach or by simply selecting suitable reaction media and growth modifiers. We describe the role of a variety of synthetic factors that influence the final shape of such an alloy material at the nanoscale. The alloying between cobalt and nickel is evidenced by XRD and HRTEM techniques. Room-temperature ferromagnetic behavior is observed for NiCo nanoparticles and high values for saturation magnetization and coercivity are recorded by SQuID magnetometry. The saturation magnetization value for the NiCo nanostructures is typically set between the corresponding "bulk" ones of cobalt and nickel metals. It is always comparable to the suggested value of the Ni50Co50 bulk alloy. The synthetic protocols derived from our extensive study are quantitative and versatile, allowing high reaction yields. Although macroscopic characterization techniques evidence the presence of a stoichiometric NiCo alloy, we show that in certain cases nanoscale characterization analyses are also needed for a more accurate evaluation of the alloy composition at the atomic level. PMID- 24752780 TI - Plasticity in the GABAergic regulation of the HPA axis (comment on DOI 10.1002/bies.201300178). PMID- 24752781 TI - No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. AB - Whole-exome sequencing (WES) is revolutionizing medical diagnostics and taxonomy. In less than 5 years since its first use, WES has revealed unexpected molecular drivers of numerous cancers. Here, we describe our use of WES to uncover the true nature of an enigmatic pathological entity, small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), which has resisted definitive characterisation since it was first described in 1979. We conducted WES using three families with SCCOHT and identified deleterious mutations in the chromatin-remodelling gene SMARCA4 (encoding BRG1) in all cases. Follow-up of these findings, using both Sanger sequencing and WES of formalin-fixed paraffin-embedded tumours, showed that virtually all SCCOHTs we studied lacked functional SMARCA4/BRG1. Notably, this gene, and the related SMARCB1 gene, is mutated in most, if not all, atypical teratoid/rhabdoid tumours and malignant rhabdoid tumours. Other groups have similar findings. We review the relationship between these three neoplasms, discuss how they were distinguished from morphologically similar neoplasms, consider their similarities and show how WES has revealed that SCCOHTs are in fact rhabdoid tumours. We propose that SCCOHT be renamed 'malignant rhabdoid tumour of the ovary' (MRTO) to reflect these observations. PMID- 24752782 TI - Do sex chromosomes affect speciation rate? (Retrospective on DOI 10.1002/bies.201100164). PMID- 24752783 TI - Transposons, environmental changes, and heritable induced phenotypic variability. AB - The mechanisms of biological evolution have always been, and still are, the subject of intense debate and modeling. One of the main problems is how the genetic variability is produced and maintained in order to make the organisms adaptable to environmental changes and therefore capable of evolving. In recent years, it has been reported that, in flies and plants, mutations in Hsp90 gene are capable to induce, with a low frequency, many different developmental abnormalities depending on the genetic backgrounds. This has suggested that the reduction of Hsp90 amount makes different development pathways more sensitive to hidden genetic variability. This suggestion revitalized a classical debate around the original Waddington hypothesis of canalization and genetic assimilation making Hsp90 the prototype of morphological capacitor. Other data have also suggested a different mechanism that revitalizes another classic debate about the response of genome to physiological and environmental stress put forward by Barbara McClintock. That data demonstrated that Hsp90 is involved in repression of transposon activity by playing a significant role in piwi-interacting RNA (piRNAs)-dependent RNA interference (RNAi) silencing. The important implication is that the fixed phenotypic abnormalities observed in Hsp90 mutants are probably related to de novo induced mutations by transposon activation. In this case, Hsp90 could be considered as a mutator. In the present theoretical paper, we discuss several possible implications about environmental stress, transposon, and evolution offering also a support to the concept of evolvability. PMID- 24752785 TI - Single vs. two-photon microscopy for label free intrinsic tissue studies in the UV light region. AB - Fibrillar distribution in the rat tail tendon and mice liver can be measured using optical methods. Two-photon excitation provides easy assessment of fibrotic collagen types I and II. Single photon deep ultraviolet (DUV) excitation imaging highlights all collagen types without discrimination. Their combination on the same tissue area provides a better overview of collagens in fibrillar diseases. PMID- 24752784 TI - Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC associated fibroblasts. AB - We previously established a role for cancer-associated fibroblasts (CAF) in enhancing the self-renewal and differentiation potentials of putative prostate cancer stem cells (CSC). Our published work focused on androgen-dependent prostate cancer (ADPC) using the conditional Pten deletion mouse model. Employing the same model, we now describe the interaction of CAF and CSC in castration resistant prostate cancer (CRPC). CAF isolated from ADPC (ADPCAF) and from CRPC (CRPCAF) were compared in terms of their ability to support organoid formation and tumor initiation by CSC from CRPC (CRPCSC) in vitro and in vivo. CRPCSC formed spheroids in vitro and well-differentiated glandular structures under the renal capsules of recipient mice in vivo more effectively in the presence of CRPCAF compared to ADPCAF. Furthermore, whereas CSC with CAF from ADPC formed mostly well-differentiated tumors in our previous study, we now show that CRPCSC, when combined with CRPCAF (but not ADPCAF), can form aggressive, poorly differentiated tumors. The potential of CRPCAF to support organoid/tumor formation by CRPCSC remained greater even when compared to 10-fold more ADPCAF, suggesting that paracrine factors produced specifically by CRPCAF preferentially potentiate the stemness and tumorigenic properties of the corresponding CSC. This apparently unique property of CRPCAF was notable when the CAF and CSC were grafted in either intact or castrated recipient mice. In both environments, CRPCAF induced in the epithelial compartment higher proliferative activity compared to ADPCAF, indicated by a higher Ki67 index. Factors released by CRPCAF to regulate CRPCSC may be targeted to develop novel therapeutic approaches to manage advanced prostate cancer. PMID- 24752786 TI - Dynamics of tRNA translocation, mRNA translocation and tRNA dissociation during ribosome translation through mRNA secondary structures. AB - The ribosome can translate through the duplex region or secondary structure of mRNA. Recent single-molecule experimental data showed that downstream mRNA secondary structures have more sensitive effects on deacylated tRNA dissociation from the E site than on tRNA translocation in the 50S subunit. However, it is unclear how the downstream mRNA secondary structure can affect the tRNA dissociation from the E site, which is distant from the secondary structure. Here, based on our proposed ribosomal translocation model, we theoretically study the dynamics of tRNA translocation in the 50S subunit, mRNA translocation and tRNA dissociation, giving quantitative explanations of the single-molecule experimental data. It is shown that the effect of the downstream mRNA secondary structure on tRNA dissociation is via the effect on mRNA translocation, while the mRNA secondary structure has no effect on the rate of deacylated tRNA dissociation from the posttranslocation state. The slow mRNA translocation, which results in slow tRNA dissociation, derives from the occurrence of the futile transition, which is induced by the energy barrier from base pair unwinding to resist the forward translocation. The reduced translation rate through the mRNA secondary structure is induced by the slow mRNA translocation rather than the slow tRNA dissociation. PMID- 24752787 TI - Scanning and transmission electron microscopic observation of the parasitic form of Trichophyton violaceum in the infected hair from tinea capitis. AB - Trichophyton violaceum is a pathogen of tinea capitis and usually cause infection of scalp and hair in children. To investigate the parasitic form of T. violaceum in the human hair tissue, the infected hair strands were collected from a 9-year old boy with tinea capitis due to T. violaceum and observed under both the scanning electron microscope (SEM) and transmission electron microscope (TEM). The SEM and TEM findings revealed that T. violaceum parasitically lives in the hair shaft in various forms and the morphological transformation of the fungus from hyphae into arthrospores was noted. The involved hair shaft was damaged to the great extent and its ultrastructural changes were evident. Those morphological characteristics of T. violaceum and the three-dimensional ultastructure changes of infected hairs give a better knowledge about the host fungus relationship in tinea capitis. PMID- 24752788 TI - Same-sex practicing men in Tanzania from 1860 to 2010. AB - This article offers a review of published texts describing sexual relations between men in Tanzania in the period 1860-2010. It explores ways in which men who have sex with men have been named and understood; describes the sexual and social roles associated with differing same-sex identities and subjectivities; tracks politics, policies, and sociocultural expressions relating to sex between men; and explores the ways in which men's same-sex sexual practices have been responded to in the context of health and HIV. Among the impressions emerging from the historical record is that sex between men is not (and has not been) uncommon in Tanzania; that a significant conceptual distinction exists between men who are anally receptive and men who penetrate anally; and that there has been a range of views on, and opinions about, same-sex relations within the wider society. There is evidence that same-sex practicing men in Tanzania have been affected by HIV at least since 1982, with one seroprevalence study indicating that the burden of HIV among men who have sex with men was quite disproportionate as far back as 2007. However, while men who have sex with men have been defined as a "vulnerable population" with respect to HIV in national frameworks since 2003, this had not led to any significant amount of targeted HIV prevention work being reported by either local or international actors by 2010. PMID- 24752789 TI - Evidence to suggest that women's sexual behavior is influenced by hip width rather than waist-to-hip ratio. AB - Waist-to-hip ratio (WHR) is an important ornament display that signals women's health and fertility. Its significance derives from human development as a bipedal species. This required fundamental changes to hip morphology/musculature to accommodate the demands of both reproduction and locomotion. The result has been an obstetric dilemma whereby women's hips are only just wide enough to allow the passage of an infant. Childbirth therefore poses a significant hip width related threat to maternal mortality/risk of gynecological injury. It was predicted that this would have a significant influence on women's sexual behavior. To investigate this, hip width and WHR were measured in 148 women (M age = 20.93 + 0.17 years) and sexual histories were recorded via questionnaire. Data revealed that hip width per se was correlated with total number of sexual partners, total number of one night stands, percentage of sexual partners that were one night stands, number of sexual partners within the context of a relationship per year sexually active, and number of one night stands per year sexually active. By contrast, WHR was not correlated with any of these measures. Further analysis indicated that women who predominantly engaged in one night stand behavior had wider hips than those who did not. WHR was again without effect in this context. Women's hip morphology has a direct impact on their risk of potentially fatal childbirth related injury. It is concluded that when they have control over this, women's sexual behavior reflects this risk and is therefore at least in part influenced by hip width. PMID- 24752790 TI - Sexually coercive behavior following childhood maltreatment. AB - Child maltreatment is associated with adult sexually coercive behavior. The association may be causal or confounders that increase the risk of both childhood victimization and sexually coercive behavior might explain the observed links. We examined if childhood maltreatment was related to sexual coercion independently of familial (genetic or common family environment) risk factors, thereby addressing potential causality. Participants were 6,255 18 to 33-year-old twins from the Finnish population-based study "Genetics of Sex and Aggression" who responded to self-report questionnaires of child maltreatment and sexually coercive behavior. We used generalized estimating equations to elucidate risk of sexual coercion in maltreated compared to unrelated, non-maltreated individuals. To adjust for unmeasured familial factors, we used the co-twin control method and compared sexual coercion risk within maltreatment-discordant twin pairs. Further, we examined possible differential effects of maltreatment subtypes and compared mean differences in maltreatment summary scores between sexually coercive individuals and controls. Sexual coercion was moderately more common among individuals maltreated as children versus unrelated controls (38.3 vs. 22.8 %; age- and gender-adjusted odds ratio, aOR = 2.31, 95 % CI 1.75-3.05) and the risk increase remained similar within maltreatment-discordant twins (OR = 2.82, 95 % CI 1.42-5.61). Moreover, different maltreatment subtypes predicted sexual coercion equally well and effect sizes remained similar within discordant twin pairs. We conclude that associations between child maltreatment and sexual coercion are largely independent of shared familial confounds, consistent with a causal inference. Importantly, detection and targeted interventions for maltreated children should remain a priority to reduce societal sexually coercive behavior. PMID- 24752791 TI - HIV prevalence and demographic determinants of unprotected anal sex and HIV testing among men who have sex with men in Beirut, Lebanon. AB - The limited epidemiological data in Lebanon suggest that HIV incident cases are predominantly among men who have sex with men (MSM). We assessed the prevalence of HIV and demographic correlates of condom use and HIV testing among MSM in Beirut. Respondent-driven sampling was used to recruit 213 participants for completion of a behavioral survey and an optional free rapid HIV test. Multivariate regression analysis was used to examine demographic correlates of unprotected anal sex and any history of HIV testing. Nearly half (47 %) were under age 25 years and 67 % self-identified as gay. Nearly two-thirds (64 %) reported any unprotected anal intercourse (UAI) with men in the prior 3 months, including 23 % who had unprotected anal intercourse with men whose HIV status was positive or unknown (UAIPU) to the participant. Three men (1.5 % of 198 participants tested) were HIV-positive; 62 % had any history of HIV testing prior to the study and testing was less common among those engaging in UAIPU compared to others (33 % vs. 71 %). In regression analysis, men in a relationship had higher odds of having UAI but lower odds of UAIPU and any university education was associated with having UAI; those with any prior history of HIV testing were more likely to be in a relationship and have any university education. HIV prevention efforts for MSM need to account for the influence of relationship dynamics and promotion of testing needs to target high-risk MSM. PMID- 24752792 TI - Atrial fibrillation ablation in patients with known sludge in the left atrial appendage. AB - PURPOSE: Transesophageal echocardiography (TEE) is routinely used to assess for thrombus in the left atrium (LA) and left atrial appendage (LAA) in patients undergoing atrial fibrillation (AF) ablation. However, little is known about the outcome of AF ablation in patients with documented LAA sludge. We hypothesize that AF ablation can be performed safely in a proportion of patients with sludge in the LAA and may have a significant benefit for these patients. METHODS: We performed a retrospective analysis of all patients undergoing AF ablation at New York University Langone Medical Center (NYULMC) from January 1st 2011 to June 30, 2013. Patients with sludge found on their TEE immediately prior to AF ablation were identified and followed for stroke, AF recurrence, procedural complications, major bleeding, or death. RESULTS: Among 1,076 patients who underwent AF ablation, 8 patients (mean age 69 +/- 13 years; 75 % men) with sludge were identified. Patients with sludge in their LAA had no incidence of early or late occurrence of stroke during mean follow-up of 10 months. One patient had a left groin hematoma, and two patients had atrial tachycardias that needed a repeat ablation. TEE at the time of repeat ablation demonstrated the presence of spontaneous echo contrast (smoke) and resolution of sludge. There were no deaths. CONCLUSION: In a cohort of eight patients with LAA sludge who underwent AF ablation, no significant thromboembolic events occurred during or after the procedure. AF ablation can be performed safely and may be beneficial in these patients. Larger studies are warranted to better determine the most appropriate management route. PMID- 24752793 TI - Large right ventricular laceration during insertion of lariat device. PMID- 24752794 TI - Snapshot of adult invasive cardiac electrophysiology in Canada: results of the web-based registry. AB - PURPOSE: Interventional cardiac electrophysiology (EP) has experienced a significant growth in Canada. Our aim is to establish a periodic registry as a nationwide initiative. METHODS: The registry is designed to collect information regarding EP laboratory infrastructure, human resources, and the spectrum and volumes of EP procedures. Respective administrative staff were contacted electronically. RESULTS: Out of 25 identified Canadian EP centers, 19 centers (76%) have participated in the registry. Responding centers have access on average to 5.3 lab days per week to perform EP studies/ablations; average lab time per full- and part-time (prorated to 0.5) EP physician is 0.8 day per week. Diagnostic EP studies and radio-frequency ablations are performed in all (19) centers; cryoablation is available in 83% of centers. Two centers have remote magnetic navigation systems. EnSite NavX is the most widely available 3D mapping system utilized in 15 (83%) centers, followed by CARTO and intracardiac echo which are each available in 14 (78%) centers; LocaLisa is actively used in one center. The number of full-time physicians ranges between 0 and 7, with a mean of 3.5 full-time physicians per center. The ratio of staff to trainees is 1.6:1. A total of 8,041 EP procedures are performed in the 19 centers per annum. On an annual average, 104 procedures per one operator and 159 procedures per trainee are performed. CONCLUSIONS: This registry provides contemporary information on invasive EP lab resources and procedures in Canada. It also demonstrates that Canadian EP procedural intensities of practice and training are comparable to international standards. PMID- 24752796 TI - Extracellular compounds produced by fungi associated with Botryosphaeria dieback induce differential defence gene expression patterns and necrosis in Vitis vinifera cv. Chardonnay cells. AB - Three major grapevine trunk diseases, esca, botryosphaeria dieback and eutypa dieback, pose important economic problems for vineyards worldwide, and currently, no efficient treatment is available to control these diseases. The different fungi associated with grapevine trunk diseases can be isolated in the necrotic wood, but not in the symptomatic leaves. Other factors seem to be responsible for the foliar symptoms and may represent the link between wood and foliar symptoms. One hypothesis is that the extracellular compounds produced by the fungi associated with grapevine trunk diseases are responsible for pathogenicity.In the present work, we used Vitis vinifera cv. Chardonnay cells to test the aggressiveness of total extracellular compounds produced by Diplodia seriata and Neofusicoccum parvum, two causal agents associated with botryosphaeria dieback. Additionally, the toxicity of purified mellein, a characteristic toxin present in the extracellular compounds of Botryosphaeriaceae, was assessed.Our results show that the total extracellular compounds produced by N. parvum induce more necrosis on Chardonnay calli and induce a different defence gene expression pattern than those of D. seriata. Mellein was produced by both fungi in amounts proportional to its aggressiveness. However, when purified mellein was added to the culture medium of calli, only a delayed necrosis and a lower-level expression of defence genes were observed. Extracellular compounds seem to be involved in the pathogenicity of the fungi associated with botryosphaeria dieback. However, the doses of mellein used in this study are 100 times higher than those found in the liquid fungal cultures: therefore, the possible function of this toxin is discussed. PMID- 24752795 TI - Exogenous sodium nitroprusside and glutathione alleviate copper toxicity by reducing copper uptake and oxidative damage in rice (Oryza sativa L.) seedlings. AB - Nitric oxide (NO) and glutathione (GSH) regulate a variety of physiological processes and stress responses; however, their involvement in mitigating Cu toxicity in plants has not been extensively studied. This study investigated the interactive effect of exogenous sodium nitroprusside (SNP) and GSH on Cu homeostasis and Cu-induced oxidative damage in rice seedlings. Hydroponically grown 12-day-old seedlings were subjected to 100 MUM CuSO4 alone and in combination with 200 MUM SNP (an NO donor) and 200 MUM GSH. Cu exposure for 48 h resulted in toxicity symptoms such as stunted growth, chlorosis, and rolling in leaves. Cu toxicity was also manifested by a sharp increase in lipoxygenase (LOX) activity, lipid peroxidation (MDA), hydrogen peroxide (H2O2), proline (Pro) content, and rapid reductions in biomass, chlorophyll (Chl), and relative water content (RWC). Cu-caused oxidative stress was evident by overaccumulation of reactive oxygen species (ROS; superoxide (O2 (*-)) and H2O2). Ascorbate (AsA) content decreased while GSH and phytochelatin (PC) content increased significantly in Cu-stressed seedlings. Exogenous SNP, GSH, or SNP + GSH decreased toxicity symptoms and diminished a Cu-induced increase in LOX activity, O2 (*-), H2O2, MDA, and Pro content. They also counteracted a Cu-induced increase in superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR), monodehydroascorbate reductase (MDHAR), and glyoxalase I and glyoxalase II activities, which paralleled changes in ROS and MDA levels. These seedlings also showed a significant increase in catalase (CAT), glutathione peroxidase (GPX), dehydroascorbate reductase (DHAR), glutathione S-transferase (GST) activities, and AsA and PC content compared with the seedlings stressed with Cu alone. Cu analysis revealed that SNP and GSH restricted the accumulation of Cu in the roots and leaves of Cu-stressed seedlings. Our results suggest that Cu exposure provoked an oxidative burden while reduced Cu uptake and modulating the antioxidant defense and glyoxalase systems by adding SNP and GSH play an important role in alleviating Cu toxicity. Furthermore, the protective action of GSH and SNP + GSH was more efficient than SNP alone. PMID- 24752798 TI - Train the trainer. PMID- 24752797 TI - Development of serous ovarian cancer is associated with the expression of homologous recombination pathway proteins. AB - To investigate the expressions of key markers in the homologous recombination (HR) pathway and the correlation with clinicopathological parameters in serous ovarian cancer (SOC). We analyzed the protein expression of MRE11, MDC1, ATM, ATR and BRCA1 by immunohistochemistry (IHC) in 97 SOC samples, and correlated with clinical parameters including age, tumor grades, clinical stage, status of menstruation and chemotherapy. Low expression of MRE11 and MDC1 was detected in 14.4 % and 3.1 % of the patient samples, and negative expression of ATM, ATR and BRCA1 was found in 11.3 %, 6.3 % and 29.9 % of the patient samples, respectively. ATR deficiency was significantly associated with menopause (P = 0.025), strong expression of ATM (P = 0.017) and MRE11 (P = 0.040) with pre-menopausal SOC, strong expression of MRE11 (P = 0.016) with low tumor grade, and strong expression of BRCA1 (P = 0.015) with early clinical stage. In addition, low expression of MRE11 was strongly associated with negativity of ATR (P < 0.001) and BRCA1 (P = 0.004) Furthermore, ATR deficiency was associated with low expression of ATM (P = 0.028) and loss expression of BRCA1 (P = 0.009). Our results suggest that reduced expression or loss of proteins in HR pathway is associated with SOC development. Abnormality of MRE11 and BRCA1 are strongly associated with late clinical stage in SOC patients. PMID- 24752799 TI - Design, synthesis and evaluation of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease. AB - In this paper we report the design, synthesis and evaluation of a series of seleno-dihydropyrimidinones as potential multi-targeted therapeutics for Alzheimer's disease. The compounds show excellent results as acetylcholinesterase inhibitors, being as active as the standard drug. All these compounds also show very good antioxidant activity through different mechanisms of action. PMID- 24752800 TI - NK cells gain higher IFN-gamma competence during terminal differentiation. AB - NK cells are the main cells of the innate immune system that produce IFN-gamma, and they express this cytokine at early stages of maturation in response to cytokine stimulation. Conversely, acquisition of IFN-gamma-competence in CD4(+) T helper cells requires a differentiation process from naive toward type 1 (Th1) cells, which is associated with epigenetic remodeling at the IFNG locus. In the present study, we show that the ability of NK cells to produce IFN-gamma in response to activating receptor (actR) engagement is gradually acquired during terminal differentiation and is accompanied by progressively higher NF-kappaB activation in response to actR triggering. Moreover, during the differentiation process NK cells gradually display increasing expression of IFNG and TBX21 (encoding T-bet) transcripts and demethylation at the IFNG promoter. This study provides new insights in the molecular mechanisms underlying NK-cell ability to express IFN-gamma upon actR engagement. Thus, we propose that in order to efficiently produce IFN-gamma in response to infected or transformed cells, NK cells gain Th1-like features, such as higher IFN-gamma competence and epigenetic remodeling of the IFNG promoter, during their terminal differentiation. PMID- 24752801 TI - The intrinsic disorder status of the human hepatitis C virus proteome. AB - Many viral proteins or their biologically important regions are disordered as a whole, or contain long disordered regions. These intrinsically disordered proteins/regions do not possess unique structures and possess functions that complement the functional repertoire of "normal" ordered proteins and domains, with many protein functional classes being heavily dependent on the intrinsic disorder. Viruses commonly use these highly flexible regions to invade the host organisms and to hijack various host systems. These disordered regions also help viruses in adapting to their hostile habitats and to manage their economic usage of genetic material. In this article, we focus on the structural peculiarities of proteins from human hepatitis C virus (HCV) and use a wide spectrum of bioinformatics techniques to evaluate the abundance of intrinsic disorder in the completed proteomes of several human HCV genotypes, to analyze the peculiarities of disorder distribution within the individual HCV proteins, and to establish potential roles of the structural disorder in functions of ten HCV proteins. We show that the intrinsic disorder or increased flexibility is not only abundant in these proteins, but is also absolutely necessary for their functions, playing a crucial role in the proteolytic processing of the HCV polyprotein, the maturation of the individual HCV proteins, and being related to the posttranslational modifications of these proteins and their interactions with DNA, RNA, and various host proteins. PMID- 24752802 TI - Effect of regional cooperation on outcomes from ruptured abdominal aortic aneurysm. AB - BACKGROUND: Care for patients with a ruptured abdominal aortic aneurysm (rAAA) in the Amsterdam ambulance region (The Netherlands) was concentrated into vascular centres with a 24-h full emergency vascular service in cooperation with seven referring regional hospitals. Previous population-based survival after rAAA in the Netherlands was 46 (95 per cent confidence interval (c.i.) 43 to 49) per cent. It was hypothesized that regional cooperation would improve survival. METHODS: This was a prospective observational cohort study carried out simultaneously with the Amsterdam Acute Aneurysm Trial. Consecutive patients with an rAAA between 2004 and 2011 in all ten hospitals in the Amsterdam region were included. The primary outcome was 30-day survival after admission. Multivariable logistic regression, including age, sex, co-morbidity, intervention (endovascular or open repair), preoperative systolic blood pressure, cardiopulmonary resuscitation and year of intervention, was used to assess the influence of hospital setting on survival. RESULTS: Of 453 patients with rAAA from the Amsterdam ambulance region, 61 did not undergo intervention; 352 patients were treated surgically at a vascular centre and 40 at a referring hospital. The regional survival rate was 58.5 (95 per cent c.i. 53.9 to 62.9) per cent (265 of 453). After multivariable adjustment, patients treated at a vascular centre had a higher survival rate than patients treated surgically at a referring hospital (adjusted odds ratio 3.18, 95 per cent c.i. 1.43 to 7.04). CONCLUSION: After regional cooperation, overall survival of patients with an rAAA improved. Most patients were treated in a vascular centre and in these patients survival rates were optimal. PMID- 24752804 TI - The first indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing carborane. AB - Indoleamine-2,3-dioxygenase-1 (IDO1) is a critical immunoregulatory enzyme responsible for the metabolism of tryptophan during inflammation and disease. Based upon a pyranonaphthoquinone framework, the first examples of indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors containing a carborane cage are reported. The novel closo-1,2-carboranyl-N-pyranonaphthoquinone derivatives display low MUM binding affinity for the human recombinant enzyme, with IC50 values ranging from 0.78 to 1.77 MUM. PMID- 24752803 TI - MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer. AB - Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERalpha) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer. PMID- 24752806 TI - Label-free detection of C-reactive protein using highly dispersible gold nanoparticles synthesized by reducible biomimetic block copolymers. AB - Biomimetic block copolymer-protected gold nanoparticles (AuNPs) were prepared by autoreduction. Excellent colloidal stability of the AuNPs was observed at a high salt concentration and over a wide pH range. Functional AuNPs are useful for label-free detection of an inflammation biomarker, C-reactive protein (CRP). PMID- 24752805 TI - Awareness and motives for use and non-use of preimplantation genetic diagnosis in familial amyloid polyneuropathy mutation carriers. AB - OBJECTIVE: To assess awareness of preimplantation genetic diagnosis (PGD) and to identify the reasons surrounding its use and non-use by familial amyloidotic polyneuropathy (FAP) carriers. METHOD: Between January and May 2013, a self administered questionnaire was applied to a representative sample of Portuguese FAP carriers, aged between 18 and 55 years and followed at the Northern surveillance unit. Odds ratios (OR) and respective 95% confidence intervals (95% CI) were estimated using multivariate logistic regression. RESULTS: Those who reported being aware of PGD (75.4%) were younger (age >= 35 years: OR = 0.51; 95% CI 0.26-1.01), had higher household income (>?1000/month: OR = 2.18; 95% CI 1.14 4.14), and were less likely to have children (OR = 0.35; 95% CI 0.16-0.76) and to have an individual diagnosis after 2001 (OR = 0.40; 95% CI 0.20-0.80). The main reasons for use of PGD were to avoid offspring suffering (48.9%), more frequently reported by men, more educated and wealthier, and the ability to raise a healthy child (39.4%). The main reasons for non-use of PGD were financial costs (29.6%), technical distrust (29.1%), and the time to get pregnant (17.3%). CONCLUSION: The results reveal the importance of cognitive dimensions and mutation carriers' socioeconomic position in the assessment of PGD, highlighting the need to disseminate accurate information and improve accessibility to this technique. PMID- 24752807 TI - Cervical dystonia and pain: characteristics and treatment patterns from CD PROBE (Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy). AB - To compare profiles of subjects with and without cervical dystonia (CD) associated pain, to evaluate the contribution of pain and the motor component of CD on quality of life, and to compare the initial botulinum toxin treatment paradigm between pain groups, baseline data were used from the CD Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE), a multicenter, prospective, observational registry designed to capture real-world practices and outcomes for onabotulinumtoxinA CD treatment. Subjects were divided into no/mild pain [Pain Numeric Rating Scale (PNRS) score 0-3] and moderate/severe pain groups (PNRS score 4-10). Descriptive and differential statistics were utilized to compare groups. 1,037 subjects completed the first treatment session, reported baseline botulinum toxin status, and completed baseline PNRS. Those with no/mild pain were significantly older at baseline. Those subjects with moderate/severe pain had higher Toronto Western Spasmodic Torticollis Rating Scale Severity (17.7 +/- 5.1 vs. 16.2 +/- 5.6, p < 0.0001) and Disability (12.7 +/- 6.1 vs. 7.5 +/- 5.6, p < 0.0001). CD subjects with moderate/severe pain received a higher mean dose (177.3 +/- 82.9 vs. 158.0 +/- 67.1 U, p = 0.0001) of onabotulinumtoxinA and were injected in more muscles (4.1 +/- 1.4 vs. 3.7 +/- 1.2, p < 0.0001) at initial treatment. CD PROBE clearly demonstrates the frequency of pain in CD and substantiates its importance when determining an optimal treatment paradigm. Future analyses of CD PROBE will further our understanding of the treatment patterns and outcomes related to onabotulinumtoxinA therapy for this disabling condition. PMID- 24752809 TI - Non-cell autonomous or secretory tumor suppression. AB - Many malignancies result from deletions or loss-of-function mutations in one or more tumor suppressor genes, the products of which curb unrestrained growth or induce cell death in those with dysregulated proliferative capacities. Most tumor suppressors act in a cell autonomous manner, and only very few proteins are shown to exert a non-cell autonomous tumor suppressor function on other cells. Examples of these include members of the secreted frizzled-related protein (SFRP) family and the secreted protein acidic and rich in cysteine (SPARC)-related proteins. Very recent findings have, however, considerably expanded our appreciation of non cell autonomous tumor suppressor functions. Broadly, this may occur in two ways. Intracellular tumor suppressor proteins within cells could in principle inhibit aberrant growth of neighboring cells by conditioning an antitumor microenvironment through secreted factors. This is demonstrated by an apparent non-cell autonomous tumor suppressing property of p53. On the other hand, a tumor suppressor produced by a cell may be secreted extracellularly, and taken up by another cell with its activity intact. Intriguingly, this has been recently shown to occur for the phosphatase and tensin homolog (PTEN) by both conventional and unconventional modes of secretion. These recent findings would aid the development of therapeutic strategies that seek to reinstate tumor suppression activity in therapeutically recalcitrant tumor cells, which have lost it in the first place. PMID- 24752808 TI - Rate of intravenous thrombolysis for acute ischaemic stroke in the North-of France region and evolution over time. AB - The proportion of patients with ischaemic stroke treated by intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) is an indicator of quality of stroke care. The objective of the study is to evaluate the rate of i.v. thrombolysis in the North-of-France region and its evolution over time. We determined the proportion of inhabitants treated by i.v. rt-PA in 2009-2010 (period A; 8 stroke units, no telemedicine) and 2012 (period B; population campaigns, 12 stroke units with telemedicine in 5). We used hospital registries from the 12 stroke units, and population-based data were collected in a subpopulation of 226,827 inhabitants (5.6% of the whole population). 1,563 inhabitants received i.v. rt-PA for stroke (period A: 835 in 24 months; period B: 728 in 12 months). Hospital and population data were similar. Annual rates of thrombolysis increased from 103 per million inhabitants [95% confidence interval (CI) 85-125] to 181 (95% CI 157-209; relative increase 76%, 95% CI 67-83%). This rate increased in 12 districts (significantly in 6), but the increase was greater in districts where new stroke units, telemedicine, or both were implemented. In conclusion, although the proportion of patients treated was already high in period A, there was still place for improvement. Implementation of new stroke units, extension of the telemedicine network and new population campaigns are necessary to improve the rate of thrombolysis in several areas, to ensure an equal access to treatment over the whole territory. The next step is now to determine whether this high rate of i.v. rt-PA delivery at the population level translates into clinical results. PMID- 24752810 TI - Are genomic translocations predictable? (Retrospective on DOI 10.1002/bies.201100122). PMID- 24752811 TI - Investigation of hidden periodic structures on SEM images of opal-like materials using FFT and IFFT. AB - We have developed a method to use fast Fourier transformation (FFT) and inverse fast Fourier transformation (IFFT) to investigate hidden periodic structures on SEM images. We focused on samples of natural, play-of-color opals that diffract visible light and hence are periodically structured. Conventional sample preparation by hydrofluoric acid etch was not used; untreated, freshly broken surfaces were examined at low magnification relative to the expected period of the structural features, and, the SEM was adjusted to get a very high number of pixels in the images. These SEM images were treated by software to calculate autocorrelation, FFT, and IFFT. We present how we adjusted SEM acquisition parameters for best results. We first applied our procedure on an SEM image on which the structure was obvious. Then, we applied the same procedure on a sample that must contain a periodic structure because it diffracts visible light, but on which no structure was visible on the SEM image. In both cases, we obtained clearly periodic patterns that allowed measurements of structural parameters. We also investigated how the irregularly broken surface interfered with the periodic structure to produce additional periodicity. We tested the limits of our methodology with the help of simulated images. PMID- 24752812 TI - The role of malic enzyme as the provider of NADPH in oleaginous microorganisms: a reappraisal and unsolved problems. AB - Malic enzyme (ME; NADP(+)-dependent; EC 1.1.40) provides NADPH for lipid biosynthesis in oleaginous microorganisms. Its role in vivo depends on there being an adequate supply of NADH to drive malate dehydrogenase to convert oxaloacetate to malate as a component of a cycle of three reactions: pyruvate -> oxaloacetate -> malate and, by the action of ME, back to pyruvate. However, the availability of cytosolic NADH is limited and, consequently, ancillary means of producing NADPH are necessary. Stoichiometries are given for the conversion of glucose to triacylglycerols involving ME with and without the reactions of the pentose phosphate pathway (PPP) as an additional source of NADPH. Some oleaginous microorganisms (such as Yarrowia lipolytica), however, lack a cytosolic ME and, if the PPP is the sole provider of NADPH, the theoretical yield of triacylglycerol from glucose falls to 27.6 % (w/w) from 31.6 % when ME is present. An alternative route for NADPH generation via a cytosolic isocitrate dehydrogenase (NADP(+)-dependent) is then discussed. PMID- 24752813 TI - Tomato terpene synthases TPS5 and TPS39 account for a monoterpene linalool production in tomato fruits. AB - Recombinant tomato terpene synthases, TPS5/37/39, catalyze the formation of linalool or nerolidol in vitro. However, little is known about their actual biological activities in tomato plants, especially in their fruits. Here, when all three TPSs were induced in tomato fruits by a chemical elicitor, geraniol, a significant linalool peak was detected in fruit tissues but not in control fruits. Considering the compartments of these TPS proteins and available substrates, the linalool peak induced by geraniol might be attributed to TPS5 and TPS37, both of them putatively localized in the plastids where high levels of monoterpene substrate geranyl diphosphate exist. In addition, application of geraniol also triggered jasmonic acid (JA)-related defense genes suggesting that the inducible TPSs might be correlated with JA-signaled defense responses. PMID- 24752814 TI - Optimisation of the mRNA secondary structure to improve the expression of interleukin-24 (IL-24) in Escherichia coli. AB - Interleukin-24 (IL-24) is a novel cytokine selectively inhibiting proliferation of cancer cells but with little effect on normal cells. However, IL-24 is difficult to express in Escherichia coli. In this study, we optimised the secondary structure of the translation initiation region using computational approach to obtain non-fusion recombinant IL-24 (nrIL-24). The Gibbs free energy of the region was decreased from -22 to -9.07 kcal mol(-1), potentially promoting a loose secondary structure formation and improving the translation initiation efficiency. As a result, the expression of nrIL-24 was increased to 26 % of the total cellular protein from being barely initially detectable. nrIL-24 showed a concentration-dependent inhibition of A375 cells but had little effect on normal human cells. These results demonstrate that this method in increasing nrIL-24 expression is effective and efficient. PMID- 24752815 TI - The endoplasmic reticulum and unfolded protein response in the control of mammalian recombinant protein production. AB - The endoplasmic reticulum (ER) of eukaryotic cells is involved in the synthesis and processing of proteins and lipids in the secretory pathway. These processing events that proteins undergo in the ER may present major limiting steps for recombinant protein production. Increased protein synthesis, accumulation of improperly processed or mis-folded protein can induce ER stress. To cope with ER stress, the ER has quality control mechanisms, such as the unfolded protein response (UPR) and ER-associated degradation to restore homeostasis. ER stress and UPR activation trigger multiple physiological cellular changes. Here we review cellular mechanisms that cope with ER stress and illustrate how this knowledge can be applied to increase the efficiency of recombinant protein expression. PMID- 24752817 TI - Magnetic resonance imaging in patients with newly diagnosed breast cancer: a review of the literature. AB - The use of magnetic resonance imaging (MRI) in patients with newly diagnosed breast cancer remains controversial. Here we review the current use of breast MRI and the impact of MRI on short-term surgical outcomes and rates of local recurrence. In addition, we address the use of MRI in specific patient populations, such as those with ductal carcinoma in situ, invasive lobular carcinoma, and occult primary breast cancer, and discuss the potential role of MRI for assessing response to neoadjuvant chemotherapy. Although MRI has improved sensitivity compared with conventional imaging, this has not translated into improved short-term surgical outcomes or long-term patient benefit, such as improved local control or survival, in any patient population. MRI is an important diagnostic test in the evaluation of patients presenting with occult primary breast cancer and has shown promise in monitoring response to neoadjuvant chemotherapy; however, the data do not support the routine use of perioperative MRI in patients with newly diagnosed breast cancer. Cancer 2014;120:120:2080 2089. (c) 2014 American Cancer Society. PMID- 24752816 TI - Eco-immunology of fish invasions: the role of MHC variation. AB - The relationship between invaders and the pathogens encountered in their new environment can have a large effect on invasion success. Invaders can become free from their natural pathogens and reallocate costly immune resources to growth and reproduction, thereby increasing invasion success. Release from enemies and relaxation of selective pressures could render newly founded populations more variable at immune-related genes, such as the major histocompatibility complex (MHC), particularly when they have different origins. Using rainbow and brown trout, two of the world's most successful fish invaders, we tested the general hypothesis that invaders should display high intrapopulation immunogenetic diversity and interpopulation divergence, due to the interplay between genetic drift and successive waves of genetically divergent introductions. We analysed genetic diversity and signatures of selection at the MHC class II beta immune related locus. In both species, MHC diversity (allelic richness and heterozygosity) for southern hemisphere populations was similar to values reported for populations at their native range. However, MHC functional diversity was limited, and population immunogenetic structuring weaker than that observed using neutral markers. Depleted MHC functional diversity could reflect a decrease in immune response, immune-related assortative mating or selection for resistance to newly encountered parasites. Given that the role of MHC diversity in the survival of these populations remains unclear, depleted functional diversity of invasive salmonids could compromise their long-term persistence. A better understanding of the eco-immunology of invaders may help in managing and preventing the impact of biological invasions, a major cause of loss of biodiversity worldwide. PMID- 24752818 TI - Indications for liver transplant and AASLD guidelines. PMID- 24752820 TI - Triphenylphosphine-catalysed amide bond formation between carboxylic acids and amines. AB - Unactivated carboxylic acids and amines undergo organocatalytic Ph3P/CCl4 mediated amide bond formation by employing in situ reduction of triphenylphosphine oxide to triphenylphosphine in the presence of diethoxymethylsilane and bis(4-nitrophenyl)phosphate. PMID- 24752821 TI - Two-stage melting induced by dislocations and grain boundaries in monolayers of hard spheres. AB - Melting in two-dimensional systems has remained controversial as theory, simulations, and experiments show contrasting results. One issue that obscures this discussion is whether or not theoretical predictions on strictly 2D systems describe those on quasi-2D experimental systems, where out-of-plane fluctuations may alter the melting mechanism. Using event-driven molecular dynamics simulations, we find that the peculiar two-stage melting scenario of a continuous solid-hexatic and a first-order hexatic-liquid transition as observed for a truly 2D system of hard disks [Bernard and Krauth, Phys. Rev. Lett., 2011, 107, 155704] persists for a quasi-2D system of hard spheres with out-of-plane particle motions as high as half the particle diameter. By calculating the renormalized Young's modulus, we show that the solid-hexatic transition is of the Kosterlitz-Thouless type and occurs via dissociation of bound dislocation pairs. In addition, we find a first-order hexatic-liquid transition that seems to be driven by spontaneous proliferation of grain boundaries. PMID- 24752819 TI - Sensitivity gains, linearity, and spectral reproducibility in nonuniformly sampled multidimensional MAS NMR spectra of high dynamic range. AB - Recently, we have demonstrated that considerable inherent sensitivity gains are attained in MAS NMR spectra acquired by nonuniform sampling (NUS) and introduced maximum entropy interpolation (MINT) processing that assures the linearity of transformation between the time and frequency domains. In this report, we examine the utility of the NUS/MINT approach in multidimensional datasets possessing high dynamic range, such as homonuclear (13)C-(13)C correlation spectra. We demonstrate on model compounds and on 1-73-(U-(13)C,(15)N)/74-108-(U-(15)N) E. coli thioredoxin reassembly, that with appropriately constructed 50% NUS schedules inherent sensitivity gains of 1.7-2.1-fold are readily reached in such datasets. We show that both linearity and line width are retained under these experimental conditions throughout the entire dynamic range of the signals. Furthermore, we demonstrate that the reproducibility of the peak intensities is excellent in the NUS/MINT approach when experiments are repeated multiple times and identical experimental and processing conditions are employed. Finally, we discuss the principles for design and implementation of random exponentially biased NUS sampling schedules for homonuclear (13)C-(13)C MAS correlation experiments that yield high-quality artifact-free datasets. PMID- 24752822 TI - Supraphysiological 25-hydroxy vitamin D3 level at admission is associated with illness severity and mortality in critically ill patients. AB - We studied the association between admission serum 25-hydroxy vitamin D3 level and in-hospital mortality in a prospective cohort of critically ill patients admitted to the medical intensive care unit of a tertiary care referral center. Of the 180 patients enrolled, 129 were included. Vitamin D3 deficiency was observed in 37% (n = 48) and supra-physiological levels (>=250 nmol/L) in 15.5% (n = 20). Patients with supraphysiological vitamin D3 levels were grouped as outliers. There was no difference in mortality (p = 0.41) between vitamin D3 deficient (21/48) and non-deficient (36/81) patients in analysis with and without outliers. Patients with vitamin D3 >=250 nmol/L had a significantly higher (p = 0.02) Simplified Acute Physiology Score (SAPS) II and mortality (p = 0.003) [mean (SD) 60.1 +/- 17.1 and 75% (15/20), respectively] when compared with the rest [45.6 +/- 18 and 38.5% (42/109), respectively]. The sensitivity, specificity and SAPS II independent odds ratio to predict mortality in patients with supraphysiological vitamin D3 levels were 26.3, 93.1 and 3.7% (95% confidence interval 1.2-11.4; p = 0.03), respectively. In conclusion, vitamin D3 deficiency in our cohort was not associated with mortality. A patient subset with supra physiological vitamin D levels had higher illness severity scores and mortality. Extrinsic factors interfering with test results were ruled out. A biological hypothesis to explain this observation is proposed. Further clarification of mechanisms leading to this observation is warranted. PMID- 24752823 TI - 7 Tesla MRI of bone microarchitecture discriminates between women without and with fragility fractures who do not differ by bone mineral density. AB - Osteoporosis is a disease of poor bone quality. Bone mineral density (BMD) has limited ability to discriminate between subjects without and with poor bone quality, and assessment of bone microarchitecture may have added value in this regard. Our goals were to use 7 T MRI to: (1) quantify and compare distal femur bone microarchitecture in women without and with poor bone quality (defined clinically by presence of fragility fractures); and (2) determine whether microarchitectural parameters could be used to discriminate between these two groups. This study had institutional review board approval, and we obtained written informed consent from all subjects. We used a 28-channel knee coil to image the distal femur of 31 subjects with fragility fractures and 25 controls without fracture on a 7 T MRI scanner using a 3-D fast low angle shot sequence (0.234 mm * 0.234 mm * 1 mm, parallel imaging factor = 2, acquisition time = 7 min 9 s). We applied digital topological analysis to quantify parameters of bone microarchitecture. All subjects also underwent standard clinical BMD assessment in the hip and spine. Compared to controls, fracture cases demonstrated lower bone volume fraction and markers of trabecular number, plate-like structure, and plate-to-rod ratio, and higher markers of trabecular isolation, rod disruption, and network resorption (p < 0.05 for all). There were no differences in hip or spine BMD T-scores between groups (p > 0.05). In receiver-operating characteristics analyses, microarchitectural parameters could discriminate cases and controls (AUC = 0.66-0.73, p < 0.05). Hip and spine BMD T-scores could not discriminate cases and controls (AUC = 0.58-0.64, p >= 0.08). We conclude that 7 T MRI can detect bone microarchitectural deterioration in women with fragility fractures who do not differ by BMD. Microarchitectural parameters might some day be used as an additional tool to detect patients with poor bone quality who cannot be detected by dual-energy X-ray absorptiometry (DXA). PMID- 24752824 TI - The need for PGY2-trained clinical pharmacy specialists. AB - The American College of Clinical Pharmacy and other stakeholder organizations seek to advance clinical pharmacist practitioners, educators, and researchers. Unfortunately, there remains an inadequate supply of residency-trained clinical specialists to meet the needs of our health care system, and nonspecialists often are called on to fill open specialist positions. The impact of clinical pharmacy specialists on pharmacotherapy outcomes in both acute care and primary care settings demonstrates the value of these specialists. This commentary articulates the need for postgraduate year two (PGY2)-trained clinical specialists within the health care system by discussing various clinical and policy rationales, interprofessional support, economic justifications, and their impact on quality of care and drug safety. The integrated practice model that has grown out of the American Society of Health-System Pharmacists Pharmacy Practice Model Initiative (PPMI) could threaten the growth and development of future clinical specialists. Therefore, the ways in which PGY2-trained clinical pharmacist specialists are deployed in the PPMI require further consideration. PGY2 residencies provide education and training opportunities that cannot be achieved in traditional professional degree programs or postgraduate year one residencies. These specialists are needed to provide direct patient care to complex patient populations and to educate and train pharmacy students and postgraduate residents. Limitations to training and hiring PGY2-trained clinical pharmacy specialists include site capacity limitations and lack of funding. A gap analysis is needed to define the extent of the mismatch between the demand for specialists by health care systems and educational institutions versus the capacity to train clinical pharmacists at the specialty level. PMID- 24752826 TI - Imbalance of iron influx and efflux causes brain iron accumulation over time in the healthy adult rat. AB - Brain iron accumulation is supposed to play a central role in neurodegeneration by inducing oxidative stress. Currently it is unknown to which extent iron entering brain over lifetime exchanges with body iron or if uptake of iron is unidirectional without significant efflux from brain. To study brain iron dynamics in vivo, up to three stable isotope tracers were fed continuously with a standard rodent diet up to 5 months to healthy adult male Wistar rats (n = 8) in a staggered design. Brain iron uptake was found to be bi-directional but iron influx and efflux were unbalanced leading inevitably to brain iron accumulation over time. Brain iron turnover was found to be very low at a half-life of ca. 9 months for tracer iron entering brain. Observed tracer accumulation in brain iron can be extrapolated to an increase of brain iron by ca. 30% in the healthy rats from early adulthood to the end of their lives. In contrast to current beliefs that brain uptake of dietary iron is negligible during adulthood following short term radiotracer studies, our long-term feeding experiments point to a possible role of the diet in brain iron accumulation and, subsequently, neurodegeneration. PMID- 24752825 TI - Studies on solvatomorphism of betulinic acid. AB - Five solvates of betulinic acid with dimethyl sulfoxide (I), methanol (II), ethanol (III), isopropyl alcohol (IV), and 2-butanol (V) have been described in this work. Methods of X-ray crystallography, thermal analysis, and Fourier transform infrared spectroscopy were introduced for solvatomorphic identifications and characterizations. The orientation of isopropenyl and carboxylic groups might differ because of single-bonding rotations. The incorporation of solvents resulted in changes of the crystal symmetry, intermolecular arrangements, stoichiometry, hydrogen bonding interactions, and so on. Adducted solvents contributed most to the stability of crystal lattices and led to the formation of crystalline forms. Solvates II-V with their single crystal structures determined have been reported for the first time. PMID- 24752827 TI - Noggin Expression in the Adult Retina Suggests a Conserved Role during Vertebrate Evolution. AB - Vertebrates share common mechanisms in the control of development and in the maintenance of neural and retinal function. The secreted factor Noggin, a BMP inhibitor, plays a crucial role in neural induction during embryonic development. Moreover, we have shown its involvement in retinal differentiation of pluripotent cells. Here we show Noggin expression in the adult retina in three vertebrate species. Four Noggin genes are present in zebrafish (Danio rerio; ZbNog1, 2, 3, 5), three in frog (Xenopus laevis; XenNog1, 2 and 4), and one in mouse (Mus musculus; mNog). Quantitative RT-PCR experiments show the presence of ZbNog3 and ZbNog5 mRNAs, but not ZbNog1 and ZbNog2, in the adult zebrafish retina. All three genes are expressed in the frog retina, and mNog in the mouse. Immunohistochemistry data show that Noggin proteins are predominantly localized in the Golgi apparatus of photoreceptors and in the fibers of the outer plexiform layer. Lower expression levels are also found in inner plexiform layer fibers, in ganglion cells, in the ciliary marginal zone, and in retinal pigmented epithelium. Our results show that Noggin has a specific cellular and sub-cellular expression in the adult vertebrate retina, which is conserved during evolution. In addition to its established role during embryonic development, we postulate that Noggin also exerts a functional role in the adult retina. PMID- 24752828 TI - Approach to metastasis-suspected nodule accompanying operable non-small cell lung cancer. AB - BACKGROUND: Operability is difficult to determine in patients with additional pulmonary nodules in nonprimary lobes accompanying resectable lung cancer. Because these nodules could either be malignant or benign, the differential diagnosis is fundamental but still remains a diagnostic challenge. The aim of this study was to evaluate metastasis-suspected solid nodules in nonprimary lobes accompanying resectable non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: From 2003 to 2009, 2,997 patients underwent pulmonary resection for NSCLC. Among them, 62 patients who underwent pulmonary resection for additional nodules in nonprimary lobes to exclude metastasis were identified. Their medical records were analyzed retrospectively. RESULTS: There were 48 males and 14 females, with a mean age of 61 years (range, 35-76 years). Tumors were located in ipsilateral nonprimary lobes in 16 patients, contralateral lobes in 21 patients, and bilateral lobes in 25 patients. Sixty-six resections were performed in the 62 patients including four cases of multiple resections. Forty-six nodules (70%) were pathologically confirmed as benign and 20 nodules (30%) were diagnosed with malignancy. The accuracy of radiologic malignancy diagnosis was 32% (20 out of 62). Two patients died of acute respiratory distress syndrome during the postoperative period. Both of these patients underwent lobectomy following additional resection for satellite nodules, which were located on the contralateral side. CONCLUSION: If patients have satellite nodules accompanying resectable NSCLC, aggressive pathological assessment should be considered. However, bilateral procedures can increase postoperative morbidity and mortality; therefore, staged operation or close follow-up might be the alternative strategy. PMID- 24752829 TI - Characteristics and outcome of primary congenital left ventricular aneurysm and diverticulum: analysis of cases from the literature. AB - OBJECTIVE: Congenital left ventricular aneurysm (LVA) and diverticulum (LVD) are rare cardiac anomalies. We aimed to analyse the characteristics and long-term outcome of prenatal diagnosed patients with LVA/LVD. METHODS: We performed a systematic review of the literature to identify and analyse patients diagnosed prenatally with LVA/LVD. RESULTS: Twenty-six fetuses with prenatal diagnosis of LVA (50% male subjects) and 16 with LVD (38% male subjects) were identified. Fetal age at diagnosis was 23.8 +/- 6.1 weeks. Mean maternal age was 30.6 +/- 6.1 years old. LVA was larger (375 +/- 237 vs 60 +/- 71 mm(2); p = 0.002), and LVA/LVD was frequently observed in an apical location (62%). Associated cardiac/extracardiac defects were reported in 13/42 (31%). Symptomatic patients presented with arrhythmias (LVA 16% vs LVD 0%), hydrops fetalis (LVA 27% vs LVD 18.8%), or rupture (LVA 4% vs LVD 38%; p = 0.02). Size changes of the LVA/LVD during pregnancy were reported in 17%. Fetal death occurred in nine cases (21.4%); termination of pregnancy was performed in six cases (14.3%). All other babies were delivered at term. During follow-up (mean 29.1 +/- 38.2 months), the rate of adverse events was significantly increased in patients with LVA (40 vs 0%; p = 0.04) CONCLUSION: The rate of fetal complications including fetal death is high. Long-term outcome among the survivors is significantly worse in patients with LVA. PMID- 24752830 TI - A transgenic approach to controlling wheat seed dormancy level by using Triticeae DOG1-like genes. AB - Seed dormancy is an important agronomic trait: low levels can cause premature germination, while too much can inhibit uniform germination. As an approach to controlling the seed dormancy level in crops, we used Triticeae DOG1-like genes as transgenes. DOG1 is an Arabidopsis gene that underlies natural variation in seed dormancy. We previously showed that although their sequence similarities to DOG1 were low, some cereal DOG1-like genes enhanced seed dormancy in Arabidopsis. Here, we introduced two DOG1-like genes, TaDOG1L4 from wheat and HvDOG1L1 from barley, individually into the wheat cultivar Fielder. Their overexpression under the control of a maize ubiquitin promoter enhanced the seed dormancy level while leaving other traits unchanged. TaDOG1L4 was more effective than HvDOG1L1, which accords with the previously revealed difference in the effectiveness of these two genes in Arabidopsis seed dormancy. Knockdown of endogenous TaDOG1L4 in Fielder using double-strand RNA interference decreased the seed dormancy level by several tens of percent. This result indicates that some degree of seed dormancy inherent in wheat is imparted by DOG1-like genes. PMID- 24752831 TI - Pharmacokinetics, pharmacodynamics, safety, and tolerability of hyzetimibe (HS 25) in healthy Chinese subjects. AB - Hyzetimibe (HS-25) is a new cholesterol absorption inhibitor. We performed the first-in-human study to assess the safety, tolerability, and pharmacokinetics (including the effect of food) and pharmacodynamics (effect on blood lipid level) following single (1, 3, 5, 10, 20, and 30 mg) and multiple (5, 10, and 20 mg) ascending-dose of hyzetimibe in healthy subjects. An increase of exposure (area under the plasma concentration-time curve and maximum plasma concentration) to hyzetimibe and hyzetimibe-glucuronide (HS-25M1) was observed in an approximately dose-proportional manner. A terminal half-life of approximately 21 hours was observed with doses ranging between 5 and 30 mg. Steady state was achieved by day 8 of once-daily dosing with 1.6- and 1.2-fold accumulation for hyzetimibe and hyzetimibe-glucuronide, respectively. Food did not have any effect on hyzetimibe and hyzetimibe-glucuronide exposure. Administration of hyzetimibe once daily for 10 days reduced the levels of low-density lipoprotein cholesterol levels in healthy subjects and these recovered after discontinuation of this drug. All of the adverse events were mild or moderate in severity, and the majority of them were unrelated to hyzetimibe, with no dose-dependent trends. These findings suggest that hyzetimibe could be a potential treatment for hypercholesterolemia. PMID- 24752833 TI - Optical quality of aspheric toric intraocular lenses at different degrees of decentering. AB - PURPOSE: To analyze the optical quality of aspheric toric intraocular lenses (IOLs) at different degrees of decentering. METHODS: Wavefront aberrations of Acrysof IQ Toric IOLs (SN6AT3, SN6AT4, and SN6AT5; Alcon Laboratories Inc, Fort Worth, TX, USA) for different powers (15.00, 20.00 and 23.50 diopters [D]) and for different degrees of decentering (diagonal, horizontal, and vertical decentering of 0.3 and 0.6mm) were measured in vitro at 3- and 5-mm pupils. The Zernike coefficients of trefoil, coma, tetrafoil, secondary astigmatism, and spherical aberration were evaluated. The point spread functions (PSFs) and modulation transfer function (MTF) of each IOL evaluated were calculated from the wavefront aberrations. RESULTS: Coma aberration increased significantly with IOL decentration. Statistically significant differences were found between centered and all decentered positions in coma aberration (p < 0.05). Although, we only found visible differences between centered and decentered positions in PSF images and MTF curves for horizontal and vertical 0.6 mm of decentering at 3- and 5-mm pupil. CONCLUSIONS: Despite the coma increment, these values were clinically negligible and have no effect on visual performance, except for vertical and horizontal 0.6 mm of decentering, which could have a negative effect on visual quality. PMID- 24752832 TI - Macular pigment optical density measurements by one-wavelength reflection photometry--influence of cataract surgery on the measurement results. AB - PURPOSE: The main objective of the present study was the investigation of possible influence of lens opacification on macular pigment optical density (MPOD) measurements. METHODS: Eighty-six eyes of 64 patients (mean age 73.4 +/- 8.3 years) were included in the study. MPOD was prospectively measured using the one-wavelength reflection method (Visucam500, Carl Zeiss Meditec AG) before and after cataract extraction, with implantation of a blue-light filtering intraocular lens (AlconSN60WF). The median of the maximum optical density (MaxOD) and the median of the mean optical density (MeanOD) measurements of macular pigment across the subject group were evaluated. RESULTS: Statistically significant differences were noticed between pre-operative and post-operative measurements, the absolute values were generally lower after cataract extraction. The following median (lower/upper quartile) differences across the group were determined: MaxOD -33.8 % (-46.2 to -19.1 %), MeanOD -44.0 % (-54.6 to -26.6 %). Larger changes were observed in elderly patients [<70 years of age (n = 25 eyes): MaxOD -13.4 % (-20.5 to 3.6 %), MeanOD -23.6 % (-30.5 to -15.3 %) versus patients >=70 years (n = 61 eyes) MaxOD -40.5 % (-53.2 to -30.1 %), MeanOD -47.2 % (-57.8 to -40.1 %)] and in patients with progressed stage of cataract. MaxOD for lens opacification grade 1 (n = 9 eyes): -27.4 % (-42.1 to -19.6 %), grade 2 (n = 26 eyes): -35.0 % (-44.2 to -25.3 %), grade 3 (n = 21 eyes): -34.4 % (-45.4 to -11.4 %), grade 4 (n = 25 eyes): -32.6 % (-53.2 to -6.4 %), and grade 5 (n = 5 eyes): 53.5 % (-61.7 to -38.7 %) and MeanOD for cataract stage 1 (n = 9 eyes): -42.6 % ( 46.0 to -26.0 %), stage 2 (n = 26 eyes): -44.1 % (-51.8 to -26.2 %), stage 3 (n = 21 eyes): -45.7 % (-54.7 to -24.7 %), stage 4 (n = 25 eyes): -39.5 % (-59.4 to 26.1 %), and stage 5 (n = 5 eyes): -57.0 % (-66.1 to -51.4 %). CONCLUSIONS: As established by comparison of pre- to post-operative measurements, cataract presented a strong effect on MPOD measured by one-wavelength reflection method. Particular care should therefore be taken when evaluating MPOD using this method in elderly patients with progressed stage of cataract. Future optimization of correcting parameters of scattered light and consideration of cataract influence may allow more precise evaluation of MPOD. PMID- 24752837 TI - Predictors of anger treatment outcomes. AB - OBJECTIVE: This study investigated predictors of therapeutic outcomes for veterans who received treatment for dysregulated anger. METHOD: Data are from a randomized controlled trial investigating the effectiveness of video teleconferencing compared to in-person delivery of anger management therapy (AMT) among 125 military veterans. Multilevel modeling was used to assess 2 types of predictors (demographic characteristics and mental health factors) of changes in anger symptoms after treatment. RESULTS: Results showed that while veterans benefited similarly from treatment across modalities, veterans who received two or more additional mental health services and who had longer commutes to care showed the greatest improvement on a composite measure of self-reported anger symptoms. CONCLUSION: Results highlight that veterans with a range of psychosocial and mental health characteristics benefited from AMT, while those receiving the most additional concurrent mental health services had better outcomes. PMID- 24752835 TI - Use of metformin in diseases of aging. AB - Metformin is the most commonly prescribed medication for type 2 diabetes (T2DM) in the world. It has primacy in the treatment of this disease because of its safety record and also because of evidence for reduction in the risk of cardiovascular events. Evidence has accumulated indicating that metformin is safe in people with stage 3 chronic kidney disease (CKD-3). It is estimated that roughly one-quarter of people with CKD-3 and T2DM in the United States (well over 1 million) are ineligible for metformin treatment because of elevated serum creatinine levels. This could be overcome if a scheme, perhaps based on pharmacokinetic studies, could be developed to prescribe reduced doses of metformin in these individuals. There is also substantial evidence from epidemiologic studies to indicate that metformin may not only be safe, but may actually benefit people with heart failure (HF). Prospective, randomized trials of the use of metformin in HF are needed to investigate this possibility. PMID- 24752836 TI - The negative effects of obesity and poor glycemic control on cognitive function: a proposed model for possible mechanisms. AB - Obesity has reached epidemic proportions and is a contributor to many adverse health outcomes, including increased risk for dementia and adverse structural and functional brain changes. Milder forms of cognitive impairment in multiple domains can also be found in obese individuals of all ages that are believed to stem from brain abnormalities long prior to onset of neurologic conditions such as dementia. However, the mechanisms for adverse brain changes and subsequent cognitive dysfunction in obesity are complex and poorly understood. This paper proposes a possible etiologic model for obesity associated cognitive impairment with emphasis on the role of poor glycemic control and conditions like type 2 diabetes mellitus. Clinical implications associated with treatment of obesity in persons with cognitive deficits in addition to the cognitive promoting effects of weight loss surgery are also discussed. PMID- 24752838 TI - Engineering class I cytochrome P450 by gene fusion with NADPH-dependent reductase and S. avermitilis host development for daidzein biotransformation. AB - Daidzein C6 hydroxylase (6-DH, nfa12130), which is a class I type of cytochrome P450 enzyme, catalyzes a hydroxylation reaction at the C6-position of the daidzein A-ring and requires auxiliary electron transfer proteins. Current utilization of cytochrome P450 (CYP) enzymes is limited by low coupling efficiency, which necessitates extramolecular electron transfers, and low driving forces, which derive electron flows from tightly regulated NADPH redox balances into the heterogeneous CYP catalytic cycle. To overcome such limitations, the heme domain of the 6-DH enzyme was genetically fused with the NADPH-reductase domain of self-sufficient CYP102D1 to enhance electron transfer efficiencies through intramolecular electron transfer and switching cofactor preference from NADH into NADPH. 6-DH-reductase fusion enzyme displayed distinct spectral properties of both flavoprotein and heme proteins and catalyzed daidzein hydroxylation more efficiently with a k cat/K m value of 120.3 +/- 11.5 [10(3) M( 1) s(-1)], which was about three times higher than that of the 6-DH-FdxC-FdrA reconstituted system. Moreover, to obtain a higher redox driving force, a Streptomyces avermitilis host system was developed for heterologous expression of fusion 6-DH enzyme and whole cell biotransformation of daidzein. The whole cell reaction using the final recombinant strain, S. avermitilisDeltacyp105D7::fusion 6-DH (nfa12130), resulted in 8.3 +/- 1.4 % of 6-OHD yield from 25.4 mg/L of daidzein. PMID- 24752839 TI - Illumina-based analysis of endophytic bacterial diversity and space-time dynamics in sugar beet on the north slope of Tianshan mountain. AB - Plants harbors complex and variable microbial communities. Endophytic bacteria play an important function and potential role more effectively in developing sustainable systems of crop production. To examine how endophytic bacteria in sugar beet (Beta vulgaris L.) vary across both host growth period and location, PCR-based Illumina was applied to revealed the diversity and stability of endophytic bacteria in sugar beet on the north slope of Tianshan mountain, China. A total of 60.84 M effective sequences of 16S rRNA gene V3 region were obtained from sugar beet samples. These sequences revealed huge amount of operational taxonomic units (OTUs) in sugar beet, that is, 19-121 OTUs in a beet sample, at 3 % cutoff level and sequencing depth of 30,000 sequences. We identified 13 classes from the resulting 449,585 sequences. Alphaproteobacteria were the dominant class in all sugar beets, followed by Acidobacteria, Gemmatimonadetes and Actinobacteria. A marked difference in the diversity of endophytic bacteria in sugar beet for different growth periods was evident. The greatest number of OTUs was detected during rossette formation (109 OTUs) and tuber growth (146 OTUs). Endophytic bacteria diversity was reduced during seedling growth (66 OTUs) and sucrose accumulation (95 OTUs). Forty-three OTUs were common to all four periods. There were more tags of Alphaproteobacteria and Gammaproteobacteria in Shihezi than in Changji. The dynamics of endophytic bacteria communities were influenced by plant genotype and plant growth stage. To the best of our knowledge, this study is the first application of PCR-based Illumina pyrosequencing to characterize and compare multiple sugar beet samples. PMID- 24752840 TI - Bacterial synthesis of D-amino acids. AB - Recent work has shed light on the abundance and diversity of D-amino acids in bacterial extracellular/periplasmic molecules, bacterial cell culture, and bacteria-rich environments. Within the extracellular/periplasmic space, D-amino acids are necessary components of peptidoglycan, and disruption of their synthesis leads to cell death. As such, enzymes responsible for D-amino acid synthesis are promising targets for antibacterial compounds. Further, bacteria are shown to incorporate a diverse collection of D-amino acids into their peptidoglycan, and differences in D-amino acid incorporation may occur in response to differences in growth conditions. Certain D-amino acids can accumulate to millimolar levels in cell culture, and their synthesis is proposed to foretell movement from exponential growth phase into stationary phase. While enzymes responsible for synthesis of D-amino acids necessary for peptidoglycan (D alanine and D-glutamate) have been characterized from a number of different bacteria, the D-amino acid synthesis enzymes characterized to date cannot account for the diversity of D-amino acids identified in bacteria or bacteria-rich environments. Free D-amino acids are synthesized by racemization or epimerization at the alpha-carbon of the corresponding L-amino acid by amino acid racemase or amino acid epimerase enzymes. Additionally, D-amino acids can be synthesized by stereospecific amination of alpha-ketoacids. Below, we review the roles of D amino acids in bacterial physiology and biotechnology, and we describe the known mechanisms by which they are synthesized by bacteria. PMID- 24752842 TI - Enhancing recombinant protein production with an Escherichia coli host strain lacking insertion sequences. AB - The genomic stability and integrity of host strains are critical for the production of recombinant proteins in biotechnology. Bacterial genomes contain numerous jumping genetic elements, the insertion sequences (ISs) that cause a variety of genetic rearrangements, resulting in adverse effects such as genome and recombinant plasmid instability. To minimize the harmful effects of ISs on the expression of recombinant proteins in Escherichia coli, we developed an IS free, minimized E. coli strain (MS56) in which about 23 % of the genome, including all ISs and many unnecessary genes, was removed. Here, we compared the expression profiles of recombinant proteins such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and bone morphogenetic protein-2 (BMP2) in MG1655 and MS56. Hopping of ISs (IS1, IS3, or IS5) into the TRAIL and BMP2 genes occurred at the rate of ~10(-8)/gene/h in MG1655 whereas such events were not observed in MS56. Even though IS hopping occurred very rarely (10(-8)/gene/h), cells containing the IS-inserted TRAIL and BMP2 plasmids became dominant (~52 % of the total population) 28 h after fermentation began due to their growth advantage over cells containing intact plasmids, significantly reducing recombinant protein production in batch fermentation. Our findings clearly indicate that IS hopping is detrimental to the industrial production of recombinant proteins, emphasizing the importance of the development of IS-free host strains. PMID- 24752841 TI - Generation of food-grade recombinant Lactobacillus casei delivering Myxococcus xanthus prolyl endopeptidase. AB - Prolyl endopeptidases (PEP) (EC 3.4.21.26), a family of serine proteases with the ability to hydrolyze the peptide bond on the carboxyl side of an internal proline residue, are able to degrade immunotoxic peptides responsible for celiac disease (CD), such as a 33-residue gluten peptide (33-mer). Oral administration of PEP has been suggested as a potential therapeutic approach for CD, although delivery of the enzyme to the small intestine requires intrinsic gastric stability or advanced formulation technologies. We have engineered two food-grade Lactobacillus casei strains to deliver PEP in an in vitro model of small intestine environment. One strain secretes PEP into the extracellular medium, whereas the other retains PEP in the intracellular environment. The strain that secretes PEP into the extracellular medium is the most effective to degrade the 33-mer and is resistant to simulated gastrointestinal stress. Our results suggest that in the future, after more studies and clinical trials, an engineered food grade Lactobacillus strain may be useful as a vector for in situ production of PEP in the upper small intestine of CD patients. PMID- 24752843 TI - Schizosaccharomyces pombe and its Ni(II)-insensitive mutant GA1 in Ni(II) uptake from aqueous solutions: a biodynamic model. AB - In the present study, Ni(II) uptake from aqueous solution by living cells of the Schizosaccharomyces pombe haploid 972 with h (-) mating type and a Ni(II) insensitive mutant GA1 derived from 972 was investigated at various initial glucose and Ni(II) concentrations. A biodynamic model was developed to predict the unsteady and steady-state phases of the uptake process. Gompertz growth and uptake process parameters were optimized to predict the maximum growth rate MU m and the process metric C r, the remaining Ni(II) content in the aqueous solution. The simulated overall metal uptake values were found to be in acceptable agreement with experimental results. The model validation was done through regression statistics and uncertainty and sensitivity analyses. To gain insight into the phenomenon of Ni(II) uptake by wild-type and mutant S. pombe, probable active and passive metal transport mechanisms in yeast cells were discussed in view of the simulation results. The present work revealed the potential of mutant GA1 to remove Ni(II) cations from aqueous media. The results obtained provided new insights for understanding the combined effect of biosorption and bioaccumulation processes for metal removal and offered a possibility for the use of growing mutant S. pombe cell in bioremediation. PMID- 24752844 TI - Influence of ferric iron on gene expression and rhamnolipid synthesis during batch cultivation of Pseudomonas aeruginosa PAO1. AB - Bioprocesses based on sustainable resources and rhamnolipids in particular have become increasingly attractive in recent years. These surface-active glycolipids with various chemical and biological properties have diverse biotechnological applications and are naturally produced by Pseudomonas aeruginosa. Their production, however, is tightly governed by a complex growth-dependent regulatory network, one of the major obstacles in the way to upscale production. P. aeruginosa PAO1 was grown in shake flask cultures using varying concentrations of ferric iron. Gene expression was assessed using quantitative PCR. A strong increase in relative expression of the genes for rhamnolipid synthesis, rhlA and rhlC, as well as the genes of the pqs quorum sensing regulon was observed under iron-limiting conditions. Iron repletion on the other hand caused a down regulation of those genes. Furthermore, gene expression of different iron regulation-related factors, i.e. pvdS, fur and bqsS, was increased in response to iron limitation. Ensuing from these results, a batch cultivation using production medium without any addition of iron was conducted. Both biomass formation and specific growth rates were not impaired compared to normal cultivation conditions. Expression of rhlA, rhlC and pvdS, as well as the gene for the 3-oxo C12-HSL synthetase, lasI, increased until late stationary growth phase. After this time point, their expression steadily decreased. Expression of the C4-HSL synthetase gene, rhlI, on the other hand, was found to be highly increased during the entire process. PMID- 24752845 TI - Recycling cellulases by pH-triggered adsorption-desorption during the enzymatic hydrolysis of lignocellulosic biomass. AB - Recycling of cellulases is an effective way to reduce the cost of enzymatic hydrolysis for the production of cellulosic ethanol. In this study, we examined the adsorption and desorption behaviors of cellulase at different pH values and temperatures. Furthermore, we developed a promising way to recover both free and bound cellulases by pH-triggered adsorption-desorption. The results show that acidic pH (e.g., pH 4.8) was found to favor adsorption, whereas alkaline pH (e.g., pH 10) and low temperature (4-37 degrees C) favored desorption. The adsorption of cellulases reached an equilibrium within 60 min at pH 4.8 and 25 degrees C, leading to approximately 50 % of the added cellulases bound to the substrate. By controlling the pH of eluent (citrate buffer, 25 degrees C), we were able to increase the desorption efficiency of bound cellulases from 15 % at pH 4.8 to 85 % at pH 10. To recover cellulases after enzymatic hydrolysis, we employed adsorption by fresh substrate and desorption at pH 10 to recover the free cellulases in supernatant and the bound cellulases in residue, respectively. The recycling performance (based on the glucose yield) of this simple strategy could reach near 80 %. Our results provided a simple, low-cost, and effective approach for cellulase recycling during the enzymatic hydrolysis of lignocellulosic biomass. PMID- 24752846 TI - Nitrilase superfamily aryl acylamidase from the halotolerant mangrove Streptomyces sp. 211726. AB - A novel nitrilase superfamily amidase gene, designated azl13, was cloned from Streptomyces sp. 211726. Bioinformatic and biochemical analysis indicated that Azl13 belongs to a new subfamily in branch 13 of the nitrilase superfamily. His6 Azl13 was expressed in Escherichia coli BL21(DE3) and had the expected molecular mass of 31 kDa, and the enzymatic activity was best at 40 degrees C, pH 8.0. His6-Azl13 had amidase, aryl acylamidase, and acyl transferase activities, and it displayed an unusually wide substrate spectrum. His6-Azl13 was most active on 4 guanidinobutyramide, which is probably its natural substrate, moderately active on short-chain aliphatic amides and weakly active hydrolyzing aromatic and heterocyclic amides. His6-Azl13 also catalyzed acyl transfer to hydroxylamine from acetamide or the herbicide propanil. The substrate spectrum differs from that of the Pseudomonas amidase RamA, probably reflecting high salinity adaptation. The broad substrate spectrum of Azl13 is potentially useful for chemical synthesis and biodegradation. PMID- 24752853 TI - Association of gestational maternal hypothyroxinemia and increased autism risk: the role of brain-derived neurotrophic factor. PMID- 24752854 TI - Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons. AB - Serotonin (5-HT) production and expression of 5-HT receptors (5-HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5-HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5-HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G-protein-coupled 5-HT1A R and 5-HT7 R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5-HT promotes neurite outgrowth through 5-HT1A R and 5-HT7 R. The involvement of 5-HT1A R and 5-HT7 R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5-HT and specific antagonists for 5-HT1A R and 5-HT7 R (WAY-100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5-HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT7 R was blocked, the addition of 5-HT increased the number of primary neurites, suggesting that 5HT7 R could inhibit neuritogenesis. In contrast, 5-HT induced secondary neurite outgrowth, an effect inhibited by 1 MUM WAY-100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5-HT1A R and 5-HT7 R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth. PMID- 24752855 TI - Separation of Scaptotrigona postica workers into defined task groups by the chemical profile on their epicuticle wax layer. AB - During evolution, the cuticle surface of insects acquired functions in communication, such as inter- and intra-specific recognition, identification of gender, physiological state, and fertility. In eusocial bees, the information in the cuticular surface is important not only to discriminate nestmates from non nestmates but also to identify an individual's class, life phase or task. A comparative study of the cuticular surface chemical profile of workers of Scaptotrigona postica in different phases of life, i.e., newly emerged workers (NE), brood comb area workers (CA), and forager workers (FO) was undertaken by gas chromatography linked to mass spectrometry. Multivariate statistical analysis was performed to verify how workers are grouped according to their chemical profile and to determine which compounds are responsible for separating them into groups. The cuticle surface of workers contains mainly hydrocarbons and a small amount of oxygenated compounds. Multivariate statistical analysis showed qualitative and quantitative variation in relation to the life phases/tasks performed, and all groups were distinct. The most abundant compound found in NE and CA was n-heptacosane, while in FO, it was (Z)-9-heptacosene. The compounds that differentiate NE from other groups are n-tricosane and n-hexacosane. A (Z)-X octacosene and n-nonacosane are the chemicals that distinguish CA from NE and FO, while 11- and 13-methylpentacosane, (Z)-X-hexacosene, and (Z)-9-heptacosene characterize FO as distinct from NE and CA. The probable function of alkenes is nestmate recognition, mainly in FO. The results show that the cuticle surfaces of workers are characteristic of the phase of life/task performed by workers, allowing intra-colonial recognition. PMID- 24752856 TI - Chemical defenses (glucosinolates) of native and invasive populations of the range expanding invasive plant Rorippa austriaca. AB - Due to global warming, species are expanding their range to higher latitudes. Some range expanding plants have become invasive in their new range. The Evolution of Increased Competitive Ability (EICA) hypothesis and the Shifting Defense Hypothesis (SDH) predict altered selection on plant defenses in the introduced range of invasive plants due to changes in herbivore pressures and communities. Here, we investigated chemical defenses (glucosinolates) of five native and seven invasive populations of the Eurasian invasive range expanding plant, Rorippa austriaca. Further, we studied feeding preferences of a generalist and a specialist herbivore among the populations. We detected eight glucosinolates in the leaves of R. austriaca. 8-Methylsulfinyloctyl glucosinolate was the most abundant glucosinolate in all plants. There were no overall differences between native and invasive plants in concentrations of glucosinolates. However, concentrations among populations within each range differed significantly. Feeding preference between the populations by a generalist herbivore was negatively correlated with glucosinolate concentrations. Feeding by a specialist did not differ between the populations and was not correlated with glucosinolates. Possibly, local differences in herbivore communities within each range may explain the differences in concentrations of glucosinolates among populations. Little support for the predictions of the EICA hypothesis or the SDH was found for the glucosinolate defenses of the studied native and invasive R. austriaca populations. PMID- 24752857 TI - Eucalyptol is an attractant of the Redbay ambrosia beetle, Xyleborus glabratus. AB - The redbay ambrosia beetle, Xyleborus glabratus, is an invasive wood-boring beetle that has become established in the southeastern United States. The beetle transmits the causal pathogen of lethal laurel wilt to susceptible host trees, which include redbay, an important forest community species, and avocado, a valuable food crop. By examining odors of redbay wood, we developed an artificial lure that captured X. glabratus in redbay forests. Eucalyptol was a critical component of the blend for beetle attraction, and eucalyptol alone in large quantities attracted X. glabratus. Furthermore, eucalyptol stimulated boring by X. glabratus into paper arenas. The results suggest that eucalyptol contributes to host selection behavior of X. glabratus and may be useful for management of this pathogen vector. PMID- 24752858 TI - Catechol--an oviposition stimulant for cigarette beetle in roasted coffee beans. AB - The cigarette beetle, Lasioderma serricorne, is a serious global pest that preys on stored food products. Larvae of the beetle cannot grow on roasted coffee beans or dried black or green tea leaves, although they oviposit on such products. We investigated oviposition by the beetles on MeOH extracts of the above products. The number of eggs laid increased with an increase in dose of each extract, indicating that chemical factors stimulate oviposition by the beetles. This was especially true for ? coffee bean extracts, which elicited high numbers of eggs even at a low dose (0.1 g bean equivalent/ml) compared to other extracts. Coffee beans were extracted in hexane, chloroform, 1-butanol, MeOH, and 20% MeOH in water. The number of eggs laid was higher on filter papers treated with chloroform, 1-butanol, MeOH, and 20% MeOH in water extracts than on control (solvent alone) papers. The chloroform extract was fractionated by silica-gel column chromatography. Nine compounds were identified by gas chromatography/mass spectrometry from an active fraction. Of these compounds, only a significant ovipositional response to catechol was observed. PMID- 24752859 TI - Behavioral effects of bovine lactoferrin administration during postnatal development of rats. AB - We tested the hypothesis that rats consuming bovine lactoferrin (bLf) during postnatal development would show better performance of stressful tasks during adolescence. In the first study, we orally administered bLf (750 mg/kg) once daily between postnatal days 16-34. Rats then underwent a battery of behavioral tests: open field (forced exploration of risky environment), light-dark emergence (voluntary exploration of risky environment), baited holeboard (working and reference memory), food neophobia (preference for familiar versus novel food), forced swim (test for antidepressant efficacy), and shuttle-box escape (learning to escape footshock). bLf-supplemented rats showed less exploration of the risky environment, greater preference for the familiar food odor, and faster escape responses. The effect of bLf on forced-swim behavior depended on sex: immobility increased for males and decreased for females. In the next study, we replaced the forced-swim test with an escape-swim test in which rats learned to use a visual cue to locate an escape platform, and we tested the dose response of bLf on this and the shuttle-box escape test, with subjects receiving vehicle or bLf at 500, 1,000, or 2,000 mg/kg. Under this modified testing battery, improvement of escape from footshock was not observed at any dose. However, males, but not females, showed a significant dose-dependent effect of bLf on acquisition of the water escape task. On average, males receiving a higher dose mastered the task 20-25 % sooner than rats receiving a lower dose or vehicle. These results offer preliminary evidence that bLf supplementation during development can improve subsequent cognitive performance during stress. PMID- 24752860 TI - Antiviral effects of Phyllanthus urinaria containing corilagin against human enterovirus 71 and Coxsackievirus A16 in vitro. AB - Human enterovirus 71 (EV71) and Coxsackievirus A16 (CA16) are major causative agents of hand, foot, and mouth disease (HFMD) especially in infants and children under 5 years of age. Despite recent outbreaks of HFMD, there are no approved therapeutics against EV71 and CA16 infection. Moreover, in a small percentage of cases, the disease progression can lead to serious complications of the central nervous system. In this study, we investigated the antiviral effect of corilagin and Phyllanthus urinaria extract, which contains corilagin as a major component, on EV71 and CA16 infection in vitro. Our results indicate that corilagin reduces the cytotoxicity induced by EV71 or CA16 on Vero cells with and IC50 value of 5.6 and 32.33 MUg/mL, respectively. We confirmed the presence of corilagin in EtOAc and BuOH fractions from P. urinaria extract and this correlated with antiviral activity of the fractions against EV71 or CA16. Future studies will be required to confirm the antiviral activity of corilagin and P. urinaria extract in vivo. Challenging a model with a lethal dose of viral infection will be required to test this. Collectively, our work provides potential candidates for the development of novel drugs to treat HFMD. PMID- 24752861 TI - Synthesis and biological evaluation of pyrazole chalcones and derived bipyrazoles as anti-inflammatory and antioxidant agents. AB - A series of bipyrazoles functionalized with sulfonamide, N(1),N(3)-disubstituted sulfonylurea, sulfonylthiourea pharmacophores, and some derived thiazolidinone and thiazoline ring systems were synthesized. The structures of the newly synthesized compounds were substantiated by analytical and diverse spectroscopic data. The anti-inflammatory and antioxidant activity of some of the newly synthesized compounds were tested and the results reveled that compounds 14, 16, 20, 24 and 25 proved to be the most active anti-inflammatory agents according to the Carrageenan-induced rat paw edema bioassay. Whereas, the analogs 14, 16 and 24 were able to exhibit good to moderate antioxidant activity in the DPPH radical scavenging assay. Hence, compounds 14, 16 and 24 can be considered as lead structures for dual anti-inflammatory and antioxidant activities. PMID- 24752862 TI - Semi solid matrix formulations of meloxicam and tenoxicam: an in vitro and in vivo evaluation. AB - The objective of this study was to improve the dissolution and subsequently the therapeutic efficacy of poorly water soluble BCS class-II drugs meloxicam and tenoxicam, by lipid semi solid matrix (SSM) systems filled in hard gelatin capsules by liquid fill technology. The present research involved preparation of SSM formulations using Gelucire 44/14 as a carrier due to its self emulsifying, wetting and hydrophilic properties. The SSM capsules were characterized by assay, in vitro dissolution studies, moisture uptake, FTIR and DSC. The optimized formulations were also evaluated for their in vivo anti inflammatory activity in rat model. Six to ten fold enhancement in vitro drug release, in both acidic and basic media, was obtained with formulations containing drug to carrier in 1:6 ratio. The absence of drug peak in DSC scans indicated complete dissolution of the drug in carrier, while IR revealed no chemical interaction of pure drug and Gelucire 44/14. The optimized SSM formulations of meloxicam and tenoxicam showed a rapid decrease in paw edema with a significant increase in anti-inflammatory activity. The SSM formulations were successful in providing rapid release of drugs with improved dissolution and in vivo anti-inflammatory activity by liquid fill technology in hard gelatin capsules. PMID- 24752863 TI - Evolutionarily conserved stress responses as potential anticancer therapeutic targets? (Comment on DOI 10.1002/bies.201300170). PMID- 24752865 TI - FISH analysis of washing urine from the upper urinary tract for the detection of urothelial cancers. AB - INTRODUCTION: To evaluate FISH analysis of washing urine from the upper urinary tract (UUT) in comparison with cytology (Cyt) for the detection of urothelial cancers. PATIENTS AND METHODS: In 82 patients with symptoms or abnormalities of the UUT sampling of washing urine for FISH and Cyt and a stepwise diagnostic work up (e.g. retrograde ureteropyelography, ureterorenoscopy and endoscopic biopsy) were performed. In case of endoscopically and/or histologically proven malignancy patients either underwent nephroureterectomy, partial ureterectomy or local treatment. Sensitivity and specificity for FISH and Cyt as well as its combination were determined. RESULTS: Urothelial cancer of the UUT was detected in 20 patients. Eleven patients underwent nephroureterectomy, six partial ureterectomy and three endoscopic tumour treatment. This revealed nine pTa, three pT1 and seven muscle-invasive tumours. Twelve tumours were classified as low and seven as high-grade tumours. In one patient with a macroscopic unequivocal finding of tumour, endoscopic laser ablation without histologic confirmation was performed. FISH was evaluable in 76 patients and detected 16 tumours with a sensitivity and specificity of 84.2 and 91.1 %, respectively. Cyt was performed in 79 and was evaluable in 78 patients. It detected ten tumours with a sensitivity and specificity of 52.6 and 91.4 %, respectively. Cyt and FISH together detected 19 tumours with (sensitivity 100 % and specificity 83.6 %). CONCLUSION: FISH was more sensitive than and equally specific to Cyt in the detection of urothelial cancers of the UUT. Both markers in combination revealed the best sensitivity, making it a possible approach in future settings. PMID- 24752864 TI - A journey into the active center of nitrogenase. AB - Nitrogenase catalyzes the reduction of N2 to NH3, a key step in the global nitrogen cycle. This article describes our journey toward the definition of a complete molecular structure of the active site of nitrogenase, with an emphasis on the discovery of the interstitial carbide and the radical SAM-dependent insertion of this atom into the active FeMo cofactor site of nitrogenase. PMID- 24752866 TI - Mortality among capacitor workers exposed to polychlorinated biphenyls (PCBs), a long-term update. AB - PURPOSE: Polychlorinated biphenyls (PCBs) are ubiquitous in the environment. Concerns have been raised about cancer and other disease risks. This follow-up mortality study of PCB workers addresses some of these concerns. METHODS: Mortality among 7,061 PCB capacitor workers was updated through 2008 (287,712 person-years; mean follow-up 41 years). Adjusted standardized mortality ratios (SMRs) and 95 % confidence intervals (CIs) were calculated for USA and New York State referent rates. Standardized rate ratios (SRRs) were calculated based on employment duration and latency. RESULTS: Standardized mortality ratios for all causes of death were statistically significantly lower in the total cohort (SMR 92; 95 % CI 89-96) and in males (SMR 88; 95 % CI 83-92), but not in females (SMR 100; 95 % CI 94-106). For all cancers combined, SMRs for the total cohort (SMR 103; 95 % CI 96-111) and for males (SMR 96; 95 % CI 87-105) did not differ from the expected rates, in contrast to females (SMR 114; 95 % CI 103-126). Buccal cavity and pharyngeal cancers were statistically increased in the combined cohort (SMR 169; 95 % CI 108-251) and in females (SMR 273; 95 % CI 131-502). Respiratory system malignancies were statistically lower in males (SMR 83; 95 % CI 70-97), while they were increased in females (SMR 143; 95 % CI 118-172). Melanomas were statistically significantly increased in male salaried workers only. No positive trends (SRRs) with increasing length of employment and increasing latency were found. CONCLUSIONS: The positive results lacking exposure-response relationships are subject to confounding and probably do not represent causal associations. PMID- 24752867 TI - Dual inhibition of the vascular endothelial growth factor pathway: a phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors. AB - BACKGROUND: The current study was conducted to evaluate the safety and biological activity of dual inhibition of the vascular endothelial growth factor (VEGF) pathway with combined bevacizumab and cediranib (a VEGF receptor tyrosine kinase inhibitor). METHODS: This was a 3 + 3 dose escalation study in patients with advanced solid tumors. Cediranib was given orally daily for 21 days and bevacizumab intravenously every 2 weeks. Pharmacokinetics and correlates (nitric oxide synthase, nitrate oxide, and circulating tumor cells) were assessed. RESULTS: Fifty-one patients were treated. Dose-limiting toxicities (DLTs) (grade 3-4; graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events [version 3.0]) observed included 1 patient with chest pain, 1 patient with fatigue, 2 patients with thrombocytopenia, 3 patients with hypertension (1 with intracranial hemorrhage), and 1 patient with grade 5 hemoptysis. Moreover, 2 patients presented with grade 3 intracranial bleeding beyond the DLT window. Dose level 2 (cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks) was selected as the recommended phase 2 dose (RP2D); 17 patients were treated at dose level 2 with 1 DLT and no intracranial bleeding or severe hypertension reported. Pharmacokinetics of cediranib at dose level 3 demonstrated a 46% to 77% increase in area under the curve (0-24 hours) on cycle 1 day 1 compared with historical controls. Four patients attained partial remissions: inflammatory breast cancer (-54%), basal cell carcinoma (-33%), alveolar soft part sarcoma (-33%), and synovial sarcoma ( 32%). Patients with a lower circulating tumor cell count (< 30) at the predose period had a longer time to tumor progression (P = .024, log-rank test). CONCLUSIONS: Cediranib at a dose of 20 mg/day and bevacizumab at a dose of 5 mg/kg every 2 weeks was found to be the RP2D. Activity in several tumor types was noted. Central nervous system bleeding and severe hypertension were observed at doses above the RP2D. PMID- 24752868 TI - Hepatocyte nuclear factor 4alpha-nuclear factor-kappaB feedback circuit modulates liver cancer progression. AB - Hepatocyte nuclear factor 4alpha (HNF4alpha) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4alpha in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4alpha expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4alpha levels were even lower in metastatic HCCs, and ectopic HNF4alpha expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4alpha expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-kappaB activation through an IKK independent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4alpha on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4alpha, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-kappaB) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4alpha levels through down-regulating HNF4alpha-3'UTR activity. CONCLUSIONS: Collectively, an HNF4alpha-NF-kappaB feedback circuit including miR-124, miR-7, and miR-21 was identified in HCC, and the combination of HNF4alpha and NF-kappaB exhibited more powerful predictive efficiency of patient prognosis. These findings broaden the knowledge of hepatic inflammation and cancer initiation/progression, and also provide novel prognostic biomarkers and therapeutic targets for HCC. PMID- 24752869 TI - The influence of the metabolic syndrome on atrial fibrillation occurrence and outcome after coronary bypass surgery: a 3-year follow-up study. AB - BACKGROUND: We sought to investigate the influence of the metabolic syndrome (MS) on new-onset postoperative atrial fibrillation (POAF), and occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in a period of 3 years after isolated coronary artery bypass grafting (CABG) surgery. METHODOLOGY: The study included 460 patients who underwent the first CABG operation without baseline atrial fibrillation. The MS was defined by the presence of three or more Adult Treatment Panel (ATP)-American Heart Association (AHA)- National Heart, Lung, and Blood (NHLB) Institute criteria. POAF was diagnosed by continuous electrocardiographic monitoring during the first 48 to 72 hours after CABG. All the patients were followed up for at least 3 years after surgery. RESULTS: The MS and its criteria were significantly associated with POAF and MACCE occurrence in the 3-year period after isolated CABG surgery. Among the MS risk factors, hypertension, abdominal obesity, and the increased fasting glucose level were independently associated with both POAF and MACCE onset in the observed patients. Individuals with four or five MS criteria have similar risk of POAF or MACCE as individuals with three MS criteria. In the 3-year period of follow-up, the MS was proven to be associated with MACCE occurrence, independently of hypertension, diabetes, and obesity defined by body mass index. CONCLUSIONS: The MS and its criteria significantly increased risk of POAF and MACCE in a 3-year period. The MS, irrespective of hypertension, diabetes, and obesity, was associated with POAF and MACCE in the patients who underwent CABG. PMID- 24752870 TI - Clinical performance of the EuroSCORE II compared with the previous EuroSCORE iterations. AB - BACKGROUND: The European System for Cardiac Operative Risk Evaluation (EuroSCORE) II has been recently introduced as an update to the previous versions. We sought to evaluate the predictive performance of the EuroSCORE II model against the original additive and logistic EuroSCORE models. PATIENTS AND METHODS: The study included 1,247 consecutive patients who underwent cardiac surgery procedures during a 14-month period starting from the beginning of 2012. The original additive and logistic EuroSCORE models were compared with the EuroSCORE II focusing on the accuracy of predicting hospital mortality. RESULTS: The overall hospital mortality rate was 3.45%. The discriminative power of the EuroSCORE II was modest and similar to other algorithms (C-statistics 0.754 for additive EuroSCORE; 0.759 for logistic EuroSCORE; and 0.743 for EuroSCORE II). The EuroSCORE II significantly underestimated the all-patient hospital mortality (3.45% observed vs. 2.12% predicted), as well as in the valvular (3.74% observed vs. 2% predicted), and combined surgery cohorts (6.87% observed vs. 3.64% predicted). The predicted EuroSCORE mortality significantly differed from the observed mortality in the third and the fourth quartile of patients stratified according to the EuroSCORE II mortality risk (p < 0.05). The calibration of the EuroSCORE II was generally good for the entire patient population (Hosmer Lemeshow [HL] p = 0.139), for the valvular surgery subset (HL p = 0.485), and for the combined surgery subset (HL p = 0.639). CONCLUSION: The EuroSCORE II might be considered a solid predictive tool for hospital mortality. Although, the EuroSCORE II employs more sophisticated calculation methods regarding the number and definition of risk factors included, it does not seem to significantly improve the performance of previous iterations. PMID- 24752871 TI - Elastic Stable Chest Repair as a Means of Stabilizing the Anterior Chest Wall in Recurrent Pectus Excavatum with Sternocostal Pseudarthrosis: An Innovative Fixation Device. AB - INTRODUCTION: Open surgical procedures in the treatment of pectus excavatum (PE) involve predetermined incisions in the parasternal cartilage and the bony ribs. For some procedures, the ribs are even dissected from the sternum for better sternal mobilization and thus better elevation of the funnel. Secure restoration of the sternocostal junction is then required, with the consequence that healing may be quite impaired. Patients may also subsequently suffer from sternocostal nonunion, for example, pseudarthrosis, and dislocated ribs, as well as pain and a recurrence of PE. MATERIALS AND METHODS: Patients underwent another open surgery with revision of the pseudarthrotic sternocostal junctions and sufficient mobilization of the anterior chest wall, followed by an open reduction and internal fixation using Matrix Rib titanium plates (Synthes, Oberdorf, Switzerland). This procedure consisted of elevating the anterior chest wall and fixing the ribs to the sternum. In 2011 and 2012, we studied this procedure, known as elastic stable chest repair (ESCR), in a series of 20 patients. The patients underwent clinical and ultrasound examinations and X-ray radiographs after the operation, after 6 weeks, and at 3- and 12-month intervals. RESULTS: Follow-up showed high patient tolerance, although a loose plate was observed in one patient and a broken plate in three patients. A stable union was achieved for all sternocostal pseudarthroses. PE improved highly significantly (p < 0.001), as the Haller index decreased from 3.6 (range: 2.7-6.6, standard deviation [SD]: 0.92) to 2.7 (range: 2.0-3.7, SD: 0.42). Pain in the anterior chest wall was significantly reduced after the operation in the majority of cases. All but one patient was mobilized already the day after the operation. CONCLUSIONS: ESCR in recurrent PE achieved functional stabilization of the anterior chest wall combined with satisfactory results. PMID- 24752872 TI - TEVAR for symptomatic Stanford B dissection: a systematic review of 30-day mortality and morbidity. AB - BACKGROUND: The aim of this study was to determine morbidity and 30-day mortality rates of thoracic endovascular aortic repair (TEVAR) for Stanford B dissection over a 16-year period and determine if these rates have improved with better stent-graft technology and surgical technique. METHODS: Electronic databases were searched in all languages and a systematic review conducted. A comparison of the early (1998-2007 = 787 patients) and later (2007-2013 = 787 patients) halves of the patient population was done. Studies were chosen based on availability of details regarding morbidity and mortality. Ambiguous studies were excluded. RESULTS: A total of 69 suitable studies published between 1998 and 2013 (1,574 patients) were examined including 1 randomized control trial, 55 retrospective studies, 3 prospective, 1 mixed, and 9 case reports. Overall mortality and morbidity rates for TEVAR was 8.07% (n = 127) and 30.8% (n = 485), respectively. The stent-graft-related death rate was 6.20% (97 cases excluding medically related deaths). The endoleak rate was 5.9% of which most were type I. Major complications include stroke (2.7%), paraplegia (1.9%), partial thrombosis of false lumen (2.5%), retrograde type A dissection (3.1%), visceral malperfusion (2.0%), conversion to open intervention (1.9%), and secondary intervention (4.1%). The stent-graft-related mortality rate increased in the 2007 to 2013 group compared with the 1998 to 2007 group (56.2 vs. 24% of patients who died; p < 0.05). There was also an increase in the overall morbidity rates from 25% (1998 2007) to 36.6% (2007-2013) but did not reach statistical significance p > 0.05. CONCLUSION: Mortality and morbidity rates for TEVAR seemed to have increased over the past 16 years despite improved technology and surgical technique. This may be explained by the increasing liberal use of TEVAR intervention and quite possibly better reporting. The current data are highly heterogenous making it difficult for solid conclusions to be drawn. The only way forward is through better data registries and well-designed clinical trials. PMID- 24752873 TI - Iron mapping using the temperature dependency of the magnetic susceptibility. AB - PURPOSE: The assessment of iron content in brain white matter (WM) is of high importance for studying neurodegenerative diseases. While R2 * mapping and quantitative susceptibility mapping is suitable for iron mapping in gray matter, iron mapping in WM still remains an unsolved problem. We propose a new approach for iron mapping, independent of diamagnetic contributions of myelin by assessing the temperature dependency of the paramagnetic susceptibility. THEORY AND METHODS: We used unfixed human brain slices for relaxometry and calculated R2 ' as a measure for microscopic susceptibility variations at several temperatures (4 degrees C-37 degrees C) at 3 Tesla. The temperature coefficient of R2 ' (TcR2p) was calculated by linear regression and related to the iron concentration found by subsequent superconducting quantum interference device (SQUID) magnetometry and by inductively coupled plasma mass spectrometry. RESULTS: In line with SQUID measurements, R2 ' mapping showed a linear temperature dependency of the bulk susceptibility with the highest slope in gray matter. Even in WM, TcR2p yielded a high linear correlation with the absolute iron concentration. CONCLUSION: According to Curie's law, only paramagnetic matter exhibits a temperature dependency while the diamagnetism shows no effect. We have demonstrated that the temperature coefficient (TcR2p) can be used as a measure of the paramagnetic susceptibility despite of an unknown diamagnetic background. PMID- 24752874 TI - Internet gaming disorder treatment: a review of definitions of diagnosis and treatment outcome. AB - OBJECTIVE: Internet gaming disorder (IGD) is a new disorder currently positioned in the appendix of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Few clinical studies report that psychological and pharmacological interventions can significantly reduce the severity of IGD symptomatology. The aim of this review was to assess current knowledge of the short- and long-term benefits of IGD interventions. This review presents a systematic evaluation of definitions of diagnosis and treatment outcomes employed in IGD treatment studies, including an assessment of goodness of fit with the DSM-5 classification. METHOD: A computer database search of Academic Search Premier, PubMed, PsychINFO, ScienceDirect, Web of Science, and Google Scholar was conducted to identify all available research evidence on Internet gaming disorder treatment (N = 8 studies). Diagnostic and treatment outcome parameters were systematically evaluated. RESULTS: Several weaknesses of IGD treatment literature were identified. Only 2 treatment studies have employed an equivalent method of diagnosis for IGD. Studies have not assessed formative change in diagnostic status at posttreatment or follow-up. Duration of follow-up has been inadequate to assess relapse and remission. Posttreatment assessment has been predominantly limited to IGD symptomatology, comorbidity, and frequency of gaming behavior. CONCLUSION: Currently, there is insufficient evidence to warrant suggestion that trialled IGD interventions confer a long-term therapeutic benefit. Several improvements to study design and reporting are proposed to guide future studies of IGD. PMID- 24752875 TI - Magnetic resonance arthrography assessment of the superior labrum using the BLC system: age-related changes mimicking SLAP-2 lesions. AB - OBJECTIVE: The purpose of the study was to describe the variation of the superior labrum with increasing age by assessing magnetic resonance (MR) arthrograms. METHODS: Inclusion criteria were used to include only the MR arthrograms of patients devoid of clinical labral pathology. Two hundred thiry-six MR arthrograms were blindly assessed for biceps-labral complex (BLC) type 1-3 and sublabral recess size by a musculoskeletal radiologist. We have chosen the BLC system, which defines normal superior labral variants, since it is established in the literature and is used by reporting musculoskeletal (MSK) radiologists. RESULTS: The MR arthrograms demonstrated that the majority of patients <40 years old were BLC type 1 and showed a steady increase in BLC types 2 and 3 with increasing age. Assessments demonstrated significantly greater (p < 0.01) mean BLC types (1.62 vs 1.29) and recess size (1.35 vs 0.66 mm) in those over 40 compared with those less than 40 years of age. Furthermore, significant differences (p < 0.05) were noted between mean BLC assessments between different decades of age. CONCLUSIONS: There appears to be a physiologic deepening of the superior labrum sulcus with age, which becomes significant after the age of 40. These findings can contribute to whether the superior labrum is considered abnormal when assessed radiographically. The differentiation of normal age related changes in the shoulder, from those of a type 2 SLAP tear can reduce the rates of unnecessary SLAP-2 repairs. This is the first reported series to use the BLC system; we believe it provides a common nomenclature to allow clear communication between specialists. PMID- 24752876 TI - Accuracy of 3-Tesla MR and MR arthrography in diagnosis of meniscal retear in the post-operative knee. AB - PURPOSE: This study assesses the accuracy of 3-Tesla (3-T) conventional MR imaging, 3-T MR arthrography, and the combined use of conventional MR and MR arthrography in the diagnosis of meniscal retears as compared with arthroscopy. The study also assess whether there are false-negative cases in which injected contrast does not extend into the meniscus despite a meniscal retear being seen on arthroscopy. MATERIALS AND METHODS: One hundred consecutive knee MR arthrograms performed on patients with previous knee surgery were reviewed retrospectively. 3-T conventional MR imaging, 3-T MR arthrography, and the combined use of conventional MR and MR arthrography were assessed for meniscal retears as compared with arthroscopy. The criterion used to diagnose a meniscal retear on MR arthrogram was injected contrast tracking into the meniscus. All patients underwent second-look arthroscopy. RESULTS: Seventy-four patients had conventional MR findings consistent with a meniscal retear. In 83 of the 100 patients, intraarticular contrast helped in demonstrating a retear. In ten patients, there were MR findings consistent with a meniscal retear despite intra articular contrast not tracking into the meniscus. Ninety-four of the 100 patients had meniscal retears on second-look arthroscopy. Three-Tesla conventional MR examination was 78 % sensitive and 75 % specific, MR arthrogram examination was 88 % sensitive and 100 % specific, and the combined use of MR and MR arthrogram imaging was 98 % sensitive and 75 % specific in the diagnosis of a meniscal retear. CONCLUSIONS: The combined use of 3-T MR and MR arthrography allows for high sensitivity and specificity in meniscal retear detection. In some patients, intraarticular contrast will not track into a meniscal retear. When MR findings are consistent with a meniscal retear but contrast does not extend into the meniscus, a meniscal retear is likely. PMID- 24752878 TI - Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas. AB - BACKGROUND: Negative surgical margins are uncommon for spine sarcomas; hence, adjuvant radiotherapy (RT) may be recommended but tumor dose may be constrained by spinal cord, nerve, and viscera tolerance. METHODS: Prospective Phase II clinical trial incorporating high dose RT. Eligible patients had primary or locally recurrent thoracic, lumbar, and/or sacral spine/paraspinal chordomas or sarcomas. Treatment included pre- and/or post-operative photon/proton RT +/- radical resection. RESULTS: Fifty patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). RT dose was <=72.0 GyRBE in 25 patients and 76.6-77.4 GyRBE in 25 patients. With 7.3-year median follow-up, the 5 and 8-year actuarial local control (LC) rates were 94% and 85% for primary tumors and 81% and 74% for the entire group. Local recurrence was less common for primary tumors, 4/36 (11%) versus 7/14 (50%) for recurrent tumors, P = 0.002. The 8-year actuarial risk of grade 3-4 late RT morbidity was 13%. No myelopathies were seen. No late neurologic toxicities noted with radiation doses <=72.0 GyRBE while three sacral neuropathies appeared after doses of 76.6-77.4 GyRBE. CONCLUSIONS: LC with this treatment is high in patients with primary tumors. Late morbidity appears to be acceptable. PMID- 24752879 TI - Role of maternal plasma levels of placental growth factor for the prediction of maternal complications in preeclampsia according to the gestational age at onset. AB - OBJECTIVE: This study aimed to describe the distribution of placental growth factor (PlGF) plasma levels in pregnancies complicated by preeclampsia (PE) according to the gestational age at clinical onset and to assess PlGF's predictive role for maternal complications. METHODS: A total of 84 women whose pregnancies were complicated by PE before 37 weeks' gestation were enrolled. According to gestational age at onset, three groups were defined: group I, <28 weeks; group II, 28 to 31(+6) weeks; and group III, 32 to 36(+6) weeks. PlGF plasma levels were measured at diagnosis, and their association with maternal complications was investigated. Plasma PlGF levels below 12 pg/mL were designated as very low. RESULTS: PlGF levels were very low in seven (87.5%) of eight women diagnosed before 28 weeks' gestation, 29 (78.4%) of 37 patients diagnosed between 28 and 32 weeks' gestation, and 16 (41%) of 39 cases diagnosed after 32 weeks' gestation. The sensitivity of very low PlGF values for predicting maternal complications was 76.9%, but the false positive rate was 65.5%. Positive and negative predictive values were 34.5% and 76.9%, respectively. CONCLUSION: The predictive role of a low PlGF level in predicting maternal complications in very early PE is limited because of both its low specificity and low positive predictive value. PMID- 24752880 TI - Population exposure-response model to support dosing evaluation of ixekizumab in patients with chronic plaque psoriasis. AB - Ixekizumab (LY2439821), a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that selectively binds and neutralizes interleukin (IL) 17A has demonstrated efficacy in the treatment of psoriasis. A population pharmacokinetics-pharmacodynamics model was developed using NONMEM 7.2 to describe the temporal relationship between ixekizumab concentrations and absolute Psoriasis Area and Severity Index (PASI) scores from a phase 2 dose-finding study in chronic plaque psoriasis. The objective was to inform dose-selection for further development. The primary endpoint, PASI 75 (75% or greater improvement from baseline PASI score) was then derived from each individual's absolute PASI score. The population pharmacokinetics of ixekizumab was characterized by a two compartment model, while the exposure-response relationship was characterized using an indirect response model that described the pharmacological effects of ixekizumab and placebo in the form of inhibition of the formation of psoriatic skin lesions. PASI 75 responder status at the Week 12 primary endpoint was found to be a significant covariate on the concentration producing half maximal effect (EC50 ). While the results suggested patient may have different levels of sensitivity to ixekizumab, it is possible that nonresponder patients assigned to lower doses of ixekizumab may potentially become responders to ixekizumab if given doses that yield adequate exposures. PMID- 24752881 TI - Activation of the prelimbic medial prefrontal cortex induces anxiety-like behaviors via N-Methyl-D-aspartate receptor-mediated glutamatergic neurotransmission in mice. AB - We investigated the possible roles of the prelimbic medial prefrontal cortex (PL) in the regulation of anxiety-like behaviors by pharmacologically activating the terminals of neuronal inputs or postsynaptic efferent neurons with a sodium channel activator veratrine. The extracellular glutamate levels were measured by in vivo microdialysis, and the behaviors were assessed with the open field (OF) test in mice simultaneously. The samples were collected every 10 min for 60 min, as basal levels of glutamate. The medium containing drugs were perfused for 30 min. The OF test was performed in the last 10 min of drug perfusion. After the drug treatments, the perfusion medium containing drugs was switched back to perfusion medium without drugs, and then samples were collected for another 90 min. The extracellular glutamate levels were significantly elevated after local perfusion of veratrine in the PL. At the same time, perfusion of veratrine in the PL produced anxiety-like behaviors in mice. Local coperfusion of a sodium channel blocker, lamotrigine, completely diminished the veratrine-induced elevated extracellular glutamate levels and the behavioral changes. Local coperfusion of an NMDA receptor antagonist, MK-801, but not a non-NMDA (AMPA/kainate) receptor antagonist, CNQX, completely diminished the behavioral changes without any effects on the veratrine-induced elevated extracellular glutamate levels. This study demonstrates that the activation of the PL with veratrine induces anxiety like behaviors via NMDA receptor-mediated glutamatergic neurotransmission in mice. PMID- 24752884 TI - Personalized medicine in systemic sclerosis: facts and promises. AB - The concept of personalized medicine has led to a paradigm shift in recent years. It integrates multiple clinical and biological levels of investigation aimed at offering the best possible and patient-tailored healthcare. This holds great potential in a rare and heterogeneous disease such as systemic sclerosis (SSc). The development of validated clinical screening algorithms and the identification of predictors for disease outcomes can help in stratifying patients according to their individual risk of progression. The ongoing search for biomarkers and key pathogenic molecules has brought valuable insights into molecular networks operative in SSc. In parallel, genetic and genomic studies have revealed new SSc susceptibility loci and validated gene expression profiles that might identify patients benefiting from specific therapies. In this review, we focus on recent findings relevant for the concept of personalized medicine in patients with SSc. PMID- 24752885 TI - Hyperintense cortical signal on magnetic resonance imaging reflects focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy. AB - OBJECTIVE: To determine the frequency of hyperintense cortical signal (HCS) on T1 weighted precontrast magnetic resonance (MR) images in progressive multifocal leukoencephalopathy (PML) patients, its association with seizure risk and immune reconstitution inflammatory syndrome (IRIS), and its pathologic correlate. METHODS: We reviewed clinical data including seizure history, presence of IRIS, and MR imaging scans from PML patients evaluated at our institution between 2003 and 2012. Cases that were diagnosed either using cerebrospinal fluid JC virus (JCV) polymerase chain reaction, brain biopsy, or autopsy, and who had MR images available were included in the analysis (n=49). We characterized pathologic findings in areas of the brain that displayed HCS in 2 patients and compared them with isointense cortex in the same individuals. RESULTS: Of 49 patients, 17 (34.7%) had seizures and 30 (61.2%) had HCS adjacent to subcortical PML lesions on MR images. Of the 17 PML patients with seizures, 15 (88.2%) had HCS compared with 15 of 32 (46.9%) patients without seizures (p=0.006). HCS was associated with seizure development with a relative risk of 4.75 (95% confidence interval=1.2-18.5, p=0.006). Of the 20 patients with IRIS, 16 (80.0%) had HCS compared with 14 of 29 (49.3%) patients without IRIS (p=0.04). On histological examination, HCS areas were associated with striking JCV-associated demyelination of cortical and subcortical U fibers, significant macrophage infiltration, and a pronounced reactive gliosis in the deep cortical layers. INTERPRETATION: Seizures are a frequent complication in PML. HCS is associated with seizures and IRIS, and correlates histologically with JCV focal leukocortical encephalitis. PMID- 24752886 TI - The prevalence and determinants of short stature in HIV-infected children. AB - BACKGROUND: Children with HIV infection are often reported to be short. The aim of this study was to assess the prevalence of HIV-associated short stature in HIV endemic setting. METHODS: Data were obtained by retrospective review of the electronic medical records. Patients were grouped into various clinical categories. For each category, the proportion of patients with height-for-age Z score of less than -2 standard deviation [SD] and of less than -3 SD was determined. RESULTS: The prevalence of short stature (less than -2 SD) was 28.4%. Severe short stature (less than -3 SD) is more likely with percentage of CD4 <15% (odds ratio [OR]: 3.30, confidence interval [CI]: 1.51-7.09, P = .002) and with males (OR: 1.49, CI: 1.19-1.87, P = .001). Severe short stature is more likely with viral load >400 copies/mL (OR 2.64, CI 1.27-5.38, P = .008) and poor adherence (<95%; OR 1.72, CI 1.03-2.05, P = .037). CONCLUSION: In Botswana, short stature affects a quarter of HIV-infected children and severe short stature is associated with poor adherence to antiretroviral treatment, severe immunosuppression, and virologic failure. PMID- 24752887 TI - Dihaploidy yields diploid apomicts and parthenogens in Erigeron (Asteraceae). AB - * PREMISE OF THE STUDY: Dihaploids result when tetraploids produce reduced eggs that develop without fertilization into diploid progeny. This process is useful for reducing genome complexity and studying trait expression at different ploidal levels. In this study we evaluated genetic inheritance and expression of diplospory (D) and parthenogenesis (P) in a population of dihaploids produced by tetraploid apomictic Erigeron* METHODS: From 400 mostly maternal (tetraploid) progeny, we identified 64 (16%) dihaploids with 2n = 18 (53 plants) or 2n = 19 (11 plants). Differential interference contrast (DIC) imaging of ovules was used to evaluate megasporogenesis (meiosis vs. diplospory) and capacity for parthenogenetic embryo development. Seed production was estimated as the proportion of filled seeds.* KEY RESULTS: For 60 analyzed dihaploids, diplospory vs. meiosis segregated approximately 1: 1 (P = 0.44) while all exhibited parthenogenetic embryo development. Parthenogenesis for meiotic progeny (n = 27) was observed in approximately 50% of ovules. Apomictic dihaploids (combining D and P; n = 33) produced seeds with mean 24.8% (range 1.3-74.4%) of total flowers.* CONCLUSIONS: The dihaploid population consisted of half apomicts (D + P) and half parthenogens (P only). We infer that formation of dihaploid seeds requires the parthenogenesis locus. The highest seed values obtained for diploid apomicts are comparable to those recorded for wild type polyploid apomicts. This is one of the first reports of diploid apomixis in the Asteraceae and it demonstrates that both diplospory and parthenogenesis can be transmitted and expressed at a high level in the diploid condition. PMID- 24752888 TI - Branching morphology of decapitated arborescent monocotyledons with secondary growth. AB - * PREMISE OF THE STUDY: Dragon trees (Dracaenaceae) are arborescent monocotyledons with anomalous secondary growth and are able to branch, exhibiting a treelike habit. Studies of the morphology and anatomy of ramifications allow for a better understanding of the complex course and arrangement of the vascular bundles in the stem-branch attachment region for Dracaena and other arborescent monocots with anomalous secondary growth.* METHODS: Morphological and anatomical analyses of ramifications induced in decapitated specimens of D. marginata and D. reflexa included serial sectioning, maceration, staining, and bleaching techniques as well as high and low resolution optical microscopy and three dimensional (3D)-visualization techniques.* KEY RESULTS: The use of innovative 3D reconstruction and high-resolution imaging revealed the extent of connections between branch and stem on various hierarchical levels in Dracaena A stem clasping attachment of the side shoot was observed, which in more detail shows a strong regional dependence of course and connectivity of individual vascular bundles to the main stem. Consequently, the attachment of branch tissue is strongly limited to the outer periphery of the main stem.* CONCLUSIONS: Our results indicate that the observed course of vascular bundles with fiber caps cannot only be a result of physiological need for water and nutrient supply but are interpreted in terms of mechanical constraints acting on the branching region. In addition, the used 3D cine technique and coupled 3D reconstruction provide a valuable tool for botanists working in the field of anatomy. PMID- 24752889 TI - Characterization of selenium and sulfur accumulation across the genus Stanleya (Brassicaceae): A field survey and common-garden experiment. AB - * PREMISE OF STUDY: Selenium (Se) hyperaccumulation, the capacity to concentrate the toxic element Se above 1000 mg.kg(-1).dry mass, is found in relatively few taxa native to seleniferous soils. While Se hyperaccumulation has been shown to likely be an adaptation that protects plants from herbivory, its evolutionary history remains unstudied. Stanleya (Brassicaceae) is a small genus comprising seven species endemic to the western United States. Stanleya pinnata is a hyperaccumulator of selenium (Se). In this study we investigated to what extent other Stanleya taxa accumulate Se both in the field and a greenhouse setting on seleniferous soil.* METHODS: We collected multiple populations of six of the seven species and all four varieties of S. pinnata We tested leaves, fruit, and soil for in situ Se and sulfur (S) concentrations. The seeds collected in the field were used for a common garden study in a greenhouse.* KEY RESULTS: We found that S. pinnata var. pinnata is the only hyperaccumulator of Se. Within S. pinnata var. pinnata, we found a geographic pattern related to Se hyperaccumulation where the highest accumulating populations are found on the eastern side of the continental divide. We also found differences in genome size within the S. pinnata species complex.* CONCLUSIONS: The S. pinnata species complex has a range of physiological properties making it an attractive system to study the evolution of Se hyperaccumulation. Beyond the basic scientific value of understanding the evolution of this fascinating trait, we can potentially use S. pinnata or its genes for environmental cleanup and/or nutrient-enhanced dietary material. PMID- 24752890 TI - Is gene flow the most important evolutionary force in plants? AB - Although theory has demonstrated rather low levels of gene flow are sufficient to counteract opposing mutation, drift, and selection, widespread recognition of the evolutionary importance of gene flow has come slowly. The perceived role of gene flow as an evolutionary force has vacillated over the last century. In the last few decades, new methods and analyses have demonstrated that plant gene flow rates vary tremendously-from nil to very high-depending on the species and specific populations involved, and sometimes over time for individual populations. In many cases, the measured gene flow rates are evolutionarily significant at distances of hundreds and sometimes thousands of meters, occurring at levels sufficient to counteract drift, spread advantageous alleles, or thwart moderate levels of opposing local selection. Gene flow in plants is likely to often act as a cohesive force, uniting individual plant species into real evolutionary units. Also, gene flow can evolve under natural selection, decreasing or increasing. The fact of frequent, but variable, plant gene flow has important consequences for applied issues in which the presence or absence of gene flow might influence the outcome of a policy, regulatory, or management decision. Examples include the unintended spread of engineered genes, the evolution of invasiveness, and conservation. New data-rich genomic techniques allow closer scrutiny of the role of gene flow in plant evolution. Most plant evolutionists now recognize the importance of gene flow, and it is receiving increased recognition from other areas of plant biology as well. PMID- 24752891 TI - An improved LC-MS/MS method for quantitation of indapamide in whole blood: application for a bioequivalence study. AB - An improved LC-MS/MS method for the quantitation of indapamide in human whole blood was developed and validated. Indapamide-d3 was used as internal standard (IS) and liquid-liquid extraction was employed for sample preparation. LC separation was performed on Synergi Polar RP-column (50 * 4.6 mm i.d.; 4 um) and mobile phase composed of methanol and 5 mm aqueous ammonium acetate containing 1 mm formic acid (60:40), at flow rate of 1 mL/min. The run time was 3.0 min and the injection volume was 20 MUL. Mass spectrometric detection was performed using electrospray ion source in negative ionization mode, using the transitions m/z 364.0 -> m/z 188.9 and m/z 367.0 -> m/z 188.9 for indapamide and IS, respectively. Calibration curve was constructed over the range 0.25-50 ng/mL. The method was precise and accurate, and provided recovery rates >80% for indapamide and IS. The method was applied to determine blood concentrations of indapamide in a bioequivalence study with two sustained release tablet formulations. The 90% confidence interval for the geometric mean ratios for maximum concentration was 95.78% and for the area under the concentration-time curve it was 97.91%. The tested indapamide tablets (Eurofarma Laboratorios S.A.) were bioequivalent to Natrilix(r), according to the rate and extent of absorption. PMID- 24752892 TI - Visual detection of norovirus genogroup II by reverse transcription loop-mediated isothermal amplification with hydroxynaphthol blue dye. AB - A simple, rapid, specific, and sensitive colorimetric reverse transcription loop mediated isothermal amplification (RT-LAMP) assay with hydroxynaphthol blue dye (HNB) was established, targeting RNA-dependent RNA polymerase and capsid protein gene for the detection of the dominant norovirus genogroup in China-NoV GII. The assay was carried out at 65 degrees C for 60 min with no cross-reactivity with other common gastroenteritis viruses. The sensitivity of this assay was 10(3) copies per reaction which is equivalent to the conventional RT-PCR test. The clinical test showed 94.83% coincidence rate for NoV genogroup II detection compared with the results, confirmed by the Department of Viral Diarrhea of Chinese Center for Disease Control and Prevention via conventional RT-PCR. The HNB dye-based RT-LAMP could be a novel rapid screening method for prevalent norovirus genogroup II in China, especially in those resource-limited hospitals and rural local clinics. PMID- 24752893 TI - TRF1 ensures the centromeric function of Aurora-B and proper chromosome segregation. AB - A cancer is a robustly evolving cell population originating from a normal diploid cell. Improper chromosome segregation causes aneuploidy, a driving force of cancer development and malignant progression. Telomeric repeat binding factor 1 (TRF1) has been established as a telomeric protein that negatively regulates telomere elongation by telomerase and promotes efficient DNA replication at telomeres. Intriguingly, overexpression of a mitotic kinase, Aurora-A, compromises efficient microtubule-kinetochore attachment in a TRF1-dependent manner. However, the precise role of TRF1 in mitosis remains elusive. Here we demonstrate that TRF1 is required for the centromeric function of Aurora-B, which ensures proper chromosome segregation. TRF1 depletion abolishes centromeric recruitment of Aurora-B and loosens sister centromere cohesion, resulting in the induction of merotelic kinetochore attachments, lagging chromosomes, and micronuclei. Accordingly, an absence of TRF1 in human and mouse diploid cells induces aneuploidy. These phenomena seem to be telomere independent, because a telomere-unbound TRF1 mutant can suppress the TRF1 knockdown phenotype. These observations indicate that TRF1 regulates the rigidity of the microtubule kinetochore attachment, contributing to proper chromosome segregation and the maintenance of genomic integrity. PMID- 24752894 TI - The canonical wnt signal restricts the glycogen synthase kinase 3/fbw7-dependent ubiquitination and degradation of eya1 phosphatase. AB - Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is posttranslationally modified by ubiquitin and that its ubiquitination level is self-limited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decrease Eya1 ubiquitination. Conversely, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1(+/-); Wnt9b(+/-) mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and they further suggest that dysregulation of this novel axis contributes to tumorigenesis. PMID- 24752895 TI - Dynamic estrogen receptor interactomes control estrogen-responsive trefoil Factor (TFF) locus cell-specific activities. AB - Estradiol signaling is ideally suited for analyzing the molecular and functional linkages between the different layers of information directing transcriptional regulations: the DNA sequence, chromatin modifications, and the spatial organization of the genome. Hence, the estrogen receptor (ER) can bind at a distance from its target genes and engages timely and spatially coordinated processes to regulate their expression. In the context of the coordinated regulation of colinear genes, identifying which ER binding sites (ERBSs) regulate a given gene still remains a challenge. Here, we investigated the coordination of such regulatory events at a 2-Mb genomic locus containing the estrogen-sensitive trefoil factor (TFF) cluster of genes in breast cancer cells. We demonstrate that this locus exhibits a hormone- and cohesin-dependent reduction in the plasticity of its three-dimensional organization that allows multiple ERBSs to be dynamically brought to the vicinity of estrogen-sensitive genes. Additionally, by using triplex-forming oligonucleotides, we could precisely document the functional links between ER engagement at given ERBSs and the regulation of particular genes. Hence, our data provide evidence of a formerly suggested cooperation of enhancers toward gene regulation and also show that redundancy between ERBSs can occur. PMID- 24752896 TI - The leukocyte activation receptor CD69 controls T cell differentiation through its interaction with galectin-1. AB - CD69 is involved in immune cell homeostasis, regulating the T cell-mediated immune response through the control of Th17 cell differentiation. However, natural ligands for CD69 have not yet been described. Using recombinant fusion proteins containing the extracellular domain of CD69, we have detected the presence of a ligand(s) for CD69 on human dendritic cells (DCs). Pulldown followed by mass spectrometry analyses of CD69-binding moieties on DCs identified galectin-1 as a CD69 counterreceptor. Surface plasmon resonance and anti-CD69 blocking analyses demonstrated a direct and specific interaction between CD69 and galectin-1 that was carbohydrate dependent. Functional assays with both human and mouse T cells demonstrated the role of CD69 in the negative effect of galectin-1 on Th17 differentiation. Our findings identify CD69 and galectin-1 to be a novel regulatory receptor-ligand pair that modulates Th17 effector cell differentiation and function. PMID- 24752897 TI - The histone variant MacroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1. AB - MacroH2A1 is a histone variant harboring an ~25-kDa carboxyl-terminal macrodomain. Due to its enrichment on the inactive X chromosome, macroH2A1 was thought to play a role in transcriptional repression. However, recent studies have shown that macroH2A1 occupies autosomal chromatin and regulates genes in a context-specific manner. The macrodomain may play a role in the modulation of gene expression outcomes via physical interactions with effector proteins, which may depend on the ability of the macrodomain to bind NAD(+) metabolite ligands. Here, we identify proline, glutamic acid, and leucine-rich protein 1 (PELP1), a chromatin-associated factor and transcriptional coregulator, as a ligand independent macrodomain-interacting factor. We used chromatin immunoprecipitation coupled with tiling microarrays (ChIP-chip) to determine the genomic localization of PELP1 in MCF-7 human breast cancer cells. We find that PELP1 genomic localization is highly correlated with that of macroH2A1. Additionally, PELP1 positively correlates with heterochromatic chromatin marks and negatively correlates with active transcription marks, much like macroH2A1. MacroH2A1 specifically recruits PELP1 to the promoters of macroH2A1 target genes, but macroH2A1 occupancy occurs independent of PELP1. This recruitment allows macroH2A1 and PELP1 to cooperatively regulate gene expression outcomes. PMID- 24752898 TI - Angiogenin-cleaved tRNA halves interact with cytochrome c, protecting cells from apoptosis during osmotic stress. AB - Adaptation to changes in extracellular tonicity is essential for cell survival. However, severe or chronic hyperosmotic stress induces apoptosis, which involves cytochrome c (Cyt c) release from mitochondria and subsequent apoptosome formation. Here, we show that angiogenin-induced accumulation of tRNA halves (or tiRNAs) is accompanied by increased survival in hyperosmotically stressed mouse embryonic fibroblasts. Treatment of cells with angiogenin inhibits stress-induced formation of the apoptosome and increases the interaction of small RNAs with released Cyt c in a ribonucleoprotein (Cyt c-RNP) complex. Next-generation sequencing of RNA isolated from the Cyt c-RNP complex reveals that 20 tiRNAs are highly enriched in the Cyt c-RNP complex. Preferred components of this complex are 5' and 3' tiRNAs of specific isodecoders within a family of isoacceptors. We also demonstrate that Cyt c binds tiRNAs in vitro, and the pool of Cyt c interacting RNAs binds tighter than individual tiRNAs. Finally, we show that angiogenin treatment of primary cortical neurons exposed to hyperosmotic stress also decreases apoptosis. Our findings reveal a connection between angiogenin generated tiRNAs and cell survival in response to hyperosmotic stress and suggest a novel cellular complex involving Cyt c and tiRNAs that inhibits apoptosome formation and activity. PMID- 24752901 TI - Vitamin D deficiency and liver cancer: more than just an epidemiological association? PMID- 24752899 TI - LIN-35/Rb causes starvation-induced germ cell apoptosis via CED-9/Bcl2 downregulation in Caenorhabditis elegans. AB - Apoptosis is an important mechanism for maintaining germ line health. In Caenorhabditis elegans, germ cell apoptosis occurs under normal conditions to sustain gonad homeostasis and oocyte quality. Under stress, germ cell apoptosis can be triggered via different pathways, including the following: (i) the CEP 1/p53 pathway, which induces germ cell apoptosis when animals are exposed to DNA damage; (ii) the mitogen-activated protein kinase kinase (MAPKK) pathway, which triggers germ cell apoptosis when animals are exposed to heat shock, oxidative stress, or osmotic stress; and (iii) an unknown mechanism that triggers germ cell apoptosis during starvation. Here, we address how starvation induces germ cell apoptosis. Using polysomal profiling, we found that starvation for 6 h reduces the translationally active ribosomes, which differentially affect the mRNAs of the core apoptotic machinery and some of its regulators. During starvation, lin 35/Rb mRNA increases its expression, resulting in the accumulation of this protein. As a consequence, LIN-35 downregulates the expression of the antiapoptotic gene ced-9/Bcl-2. We observed that the reduced translation of ced 9/Bcl-2 mRNA during food deprivation together with its downregulation drastically affects its protein accumulation. We propose that CED-9/Bcl-2 downregulation via LIN-35/Rb triggers germ cell apoptosis in C. elegans in response to starvation. PMID- 24752900 TI - Function and control of RNA polymerase II C-terminal domain phosphorylation in vertebrate transcription and RNA processing. AB - The C-terminal domain of the RNA polymerase II largest subunit (the Rpb1 CTD) is composed of tandem heptad repeats of the consensus sequence Y(1)S(2)P(3)T(4)S(5)P(6)S(7). We reported previously that Thr 4 is phosphorylated and functions in histone mRNA 3'-end formation in chicken DT40 cells. Here, we have extended our studies on Thr 4 and to other CTD mutations by using these cells. We found that an Rpb1 derivative containing only the N-terminal half of the CTD, as well as a similar derivative containing all-consensus repeats (26r), conferred full viability, while the C-terminal half, with more-divergent repeats, did not, reflecting a strong and specific defect in snRNA 3'-end formation. Mutation in 26r of all Ser 2 (S2A) or Ser 5 (S5A) residues resulted in lethality, while Ser 7 (S7A) mutants were fully viable. While S2A and S5A cells displayed defects in transcription and RNA processing, S7A cells behaved identically to 26r cells in all respects. Finally, we found that Thr 4 was phosphorylated by cyclin dependent kinase 9 in cells and dephosphorylated both in vitro and in vivo by the phosphatase Fcp1. PMID- 24752902 TI - Arthroscopic management of calcific tendonitis of the subscapularis tendon with subcoracoid stenosis. PMID- 24752904 TI - Molecular keypad locks based on gated photochromism and enhanced fluorescence by protonation effects. AB - Being a "lock-unlock" system, gated photochromism is generally applied in nondestructive readout for optical memory materials. In the presented paper, we successfully constructed molecular keypad locks by introduction of the gated photochromism. A series of diarylethenes compounds (DAEs) based on fluorescent 5 methoxy-2-pyridyl thiazoles, were prepared and then characterized as photochromic fluorescent switches. Protoantion of the reported DAEs resulted in both protonation-locked photo-reactivities, i.e., gated photochromism, and enhancement of fluorescence. Molecular keypad locks were then successfully constructed, which are also featured by "one-key" lock operation. PMID- 24752903 TI - Enhanced cell immune responses to hepatitis C virus core by novel heterologous DNA prime/lambda nanoparticles boost in mice. AB - Hepatitis C virus (HCV) is a worldwide problem which does not have an effective vaccine and more than 170 million people worldwide are chronically infected by HCV. T cell responses are associated with spontaneous clearance of HCV infection. We report here the development of recombinant Lambda bacteriophage nanoparticles encoding HCV Core antigen. The aim of this study was to investigate the antigen specific immune responses triggered in mice by different prime-boost combinations of DNA and Lambda phage nanoparticles encoding the HCV Core. The homologous prime/boost with recombinant Lambda nanoparticles induced higher levels of cellular and humoral immune response than the DNA vaccines. However, a heterologous prime/boost of HCV Core protein, using DNA vaccine priming followed by Lambda boost, induced highest level of lymphocyte proliferation, CD8 lymphocytes with cytotoxic function, and shifting the immune response toward a T helper (Th1) pattern and in overall improved immunity. Our study provides a new, safe, and effective vaccine for the prime-boost regimen which augments robust immunity and highlights novel promising strategies in HCV vaccine development. PMID- 24752906 TI - A perspective on the mechanism of the light-rise of the electrooculogram. AB - The light-rise of the electrooculogram is believed to originate from a substance released from the rods after dark adaptation. The identity of this "elusive" light-rise substance has not been demonstrated, and therefore a new perspective on the light-rise is presented. The light-rise is caused by the depolarization of the basolateral membrane of the retinal pigment epithelium (RPE) has become clearer in the last decade with the identification of calcium as the intracellular secondary messenger and the role of bestrophin as a regulator of intracellular stores of calcium and controlling the cytosolic calcium levels through L-type calcium channels. The light-rise depends upon a change from darkness to light, which triggers the intracellular cascade resulting in the depolarization of the basolateral membrane. The same intracellular signaling molecules, notably calcium and inositol triphosphate (IP3), are strongly implicated in this cascade. Recent studies have now led to a clearer understanding of the roles and functions of the ion channels and their contribution to the light-rise with IP3 regulating the release of calcium for intracellular stores. Given that calcium and IP3 are also regulators of phagocytosis, and that the initiation of rod outer segment phagocytosis is initiated with light-onset, it may be that the light-rise is generated in response to this physiological event. Therefore, the putative light-rise substance may not be released by the rods, but follow directly from IP3 release from the RPE's phospholipid membrane following the onset of light and the initiation of phagocytosis. The light rise substance, could be considered to be light itself. PMID- 24752907 TI - Investigating the neural correlates of the Stroop effect with magnetoencephalography. AB - Reporting the ink color of a written word when it is itself a color name incongruent with the ink color (e.g. "red" printed in blue) induces a robust interference known as the Stroop effect. Although this effect has been the subject of numerous functional neuroimaging studies, its neuronal substrate is still a matter of debate. Here, we investigated the spatiotemporal dynamics of interference-related neural events using magnetoencephalography (MEG) and voxel based analyses (SPM8). Evoked magnetic fields (EMFs) were acquired in 12 right handed healthy subjects performing a color-word Stroop task. Behavioral results disclosed a classic interference effect with longer mean reaction times for incongruent than congruent stimuli. At the group level, EMFs' differences between incongruent and congruent trials spanned from 380 to 700 ms post-stimulus onset. Underlying neural sources were identified in the left pre-supplementary motor area (pre-SMA) and in the left posterior parietal cortex (PPC) confirming the role of these regions in conflict processing. PMID- 24752908 TI - A pharmacokinetic/pharmacodynamic model for AMG 416, a novel calcimimetic peptide, following a single intravenous dose in healthy subjects. AB - AMG 416 is a novel peptide agonist of the calcium-sensing receptor. In support of the clinical development program, a pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to describe the relationship between plasma AMG 416 levels and serum intact parathyroid hormone (iPTH) concentrations in healthy male subjects. AMG 416 plasma concentrations were characterized by a three-compartment linear PK model, while serum iPTH levels were described by an indirect response model with drug effect on the production of iPTH characterized with an inhibitory Emax model. The production of iPTH was modeled by a circadian rhythm function. The systemic clearance of plasma AMG 416 was estimated to be 6.94 L/h. Two sine functions best described iPTH circadian rhythm with an amplitude estimated to be 0.15 and 0.08, respectively. The maximum response Emax and the potency parameter EC50 were estimated to be 0.69 and 21.0 ng/mL, respectively. This work improved our understanding of the interaction between AMG 416 PK and iPTH concentrations in healthy adult male subjects. Data suggest additional PK/PD studies with AMG 416 are warranted in the hemodialysis population. PMID- 24752909 TI - Material proximities and hotspots: toward an anthropology of viral hemorrhagic fevers. AB - This article outlines a research program for an anthropology of viral hemorrhagic fevers (collectively known as VHFs). It begins by reviewing the social science literature on Ebola, Marburg, and Lassa fevers and charting areas for future ethnographic attention. We theoretically elaborate the hotspot as a way of integrating analysis of the two routes of VHF infection: from animal reservoirs to humans and between humans. Drawing together recent anthropological investigations of human-animal entanglements with an ethnographic interest in the social production of space, we seek to enrich conceptualizations of viral movement by elaborating the circumstances through which viruses, humans, objects, and animals come into contact. We suggest that attention to the material proximities-between animals, humans, and objects-that constitute the hotspot opens a frontier site for critical and methodological development in medical anthropology and for future collaborations in VHF management and control. PMID- 24752911 TI - Obituary: A remembrance: Gael R. Frank (1930-2012). PMID- 24752910 TI - Shoulder instability in the setting of bipolar (glenoid and humeral head) bone loss: the glenoid track concept. AB - BACKGROUND: An assortment of variables has been used in predicting anterior shoulder instability resulting from pathologic engagement of Hill-Sachs lesions on the glenoid. The glenoid track is a unique biomechanical model that relates both Hill-Sachs and bony Bankart lesions to predict shoulder engagement. We examined the glenoid track concept to determine if it provides a model that unifies glenoid rim and humeral head bone loss in predicting engagement. QUESTIONS/PURPOSES: In this review we addressed two questions: (1) How are humeral head and glenoid rim bony defects and their interactions quantified? (2) Why is the concept of the glenoid track important? METHODS: We performed a systematic review of the literature using PubMed (MEDLINE) and OVID for biomechanical studies and peer-reviewed articles published until March 2013. Twenty-four studies fit the inclusion criteria. These were subdivided into four anatomic studies, four studies quantifying glenohumeral bone loss, nine studies biomechanically defining shoulder engagement, six studies analyzing current treatment models, and one clinical study to be included in the final review. RESULTS: Data demonstrate pathologic engagement is dependent on the medial margin of the Hill-Sachs lesion traveling outside the glenoid track. The width of the glenoid track decreases accordingly if there is a glenoid defect, making engagement more likely. Most treatment models focus on widening the glenoid track before addressing Hill-Sachs lesions. CONCLUSIONS: The glenoid track uses both glenoid and humeral head bone loss to predict subsequent risk of humeral head engagement and possible dislocation. The glenoid track shows us that restoring the track to its natural width should be among the surgeon's first priority in restoring shoulder stability. Humeral head lesions, also known as Hill-Sachs lesions, are surgically addressed when they cause clinical symptoms. Symptoms arise when the medial margin of the defect engages the glenoid track. PMID- 24752912 TI - Transfemoral amputations: is there an effect of residual limb length and orientation on energy expenditure? AB - BACKGROUND: Energy cost of ambulation has been evaluated using a variety of measures. With aberrant motions resulting from compensatory strategies, persons with transfemoral amputations generally exhibit a larger center of mass excursion and an increased energy cost. However, few studies have analyzed the effect of residual femur length and orientation or energy cost of ambulation. QUESTIONS/PURPOSES: The purpose of this study was to compare residual limb length and orientation with energy efficiency in patients with transfemoral amputation. We hypothesized that patients with shorter residual limbs and/or more abnormal residual femur alignment would have higher energy expenditure cost and greater center of mass movement than those with longer residual limbs resulting from lacking musculature, shorter and/or misoriented lever arms, and greater effort required to ambulate through use of compensatory movements. METHODS: Twenty-six adults with acute, trauma-related unilateral transfemoral amputations underwent gait and metabolic analysis testing. Patients were separated into groups for analysis based on residual limb length and residual femoral angle. RESULTS: Cohorts with longer residual limbs walked faster than those with shorter residual limbs (self-selected walking velocity 1.28 m/s versus 1.11 m/s, measured effect size = 1.08; 95% confidence interval = short 1.10-1.12, long 1.26-1.30; p = 0.04). However, there were no differences found with the numbers available between the compared cohorts regardless of limb length or orientation in regard to O2 cost or other metabolic variables, including the center of mass motion. CONCLUSIONS: Those with longer residual limbs after transfemoral amputation chose a faster self-selected walking velocity, mirroring previous studies; however, metabolic energy and center of mass metrics did not demonstrate a difference in determining whether energy expenditure is affected by length or orientation of the residual limb after transfemoral amputation. These factors may therefore have less effect on transfemoral amputee gait efficiency and energy requirements than previously thought. PMID- 24752914 TI - Isatis canescens is a rich source of glucobrassicin and other health-promoting compounds. AB - BACKGROUND: Glucobrassicin (GBS), a glucosinolate contained in many brassica vegetables, is the precursor of chemopreventive compounds such as indole-3 carbinol. Large amounts of GBS would be needed to perform studies aimed at elucidating its role in the diet. This study was mainly undertaken to evaluate the flower buds of Isatis canescens as a source for GBS purification. In order to investigate the health-promoting potential of this species, glucosinolate, phenol and flavonoid content as well as the whole antioxidant capacity were also determined. Flower bud samples were collected in four localities around Mount Etna in Sicily, Italy, where I. canescens is widespread, as they are locally traditionally eaten. RESULTS: I. canescens flower buds displayed high GBS concentrations, up to 60 umol g(-1) dry weight. The purification method consisted of two chromatographic steps, which made it possible to obtain GBS with a purity of 92-95%, with a yield of 21 g kg(-1) . The total glucosinolates, phenols, flavonoids and antioxidant activity were considerable, with the southern locality showing the highest concentrations for all the phytochemicals. CONCLUSION: I. canescens flower buds represent a naturally rich source of GBS, at a level suitable for its purification. Furthermore, flower bud consumption could provide an intake of health-promoting compounds, with possible antioxidant and chemopreventive properties. PMID- 24752913 TI - A history of lumbar disc herniation from Hippocrates to the 1990s. AB - In ancient times, a supernatural understanding of the syndrome of lumbar radiculopathy often involved demonic forces vexing the individual with often crippling pain. The ancient Greeks and Egyptians began to take a more naturalistic view and, critically, suspected a relationship between lumbar spinal pathology and leg symptoms. Relatively little then changed for those with sciatica until the classic works by Cotugno and Kocher arrived in the late 18th century. Early lumbar canal explorations were performed in the late 1800s and early 1900s by MacEwen, Horsley, Krause, Taylor, Dandy, and Cushing, among others. In these cases, when compressive pathologies were found and removed, the lesions typically were (mis-)identified as enchondromas or osteochondritis dissecans. To better understand the history, learn more about the first treatments of lumbar disc herniation, and evaluate the impact of the early influences on modern spine practice, searches of PubMed and Embase were performed using the search terms discectomy, medical history, lumbar spine surgery, herniated disc, herniated nucleus pulposus, sciatica, and lumbar radiculopathy. Additional sources were identified from the reference lists of the reviewed papers. Many older and ancient sources including De Ischiade Nervosa are available in English translations and were used. When full texts were not available, English abstracts were used. The first true, intentional discectomy surgery was performed by Mixter and Barr in 1932. Early on, a transdural approach was favored. In 1938, Love described the intralaminar, extradural approach. His technique, although modified with improved lighting, magnification, and retractors, remains a staple approach to disc herniations today. Other modalities such as chymopapain have been investigated. Some remain a part of the therapeutic armamentarium, whereas others have disappeared. By the 1970s, CT scanning after myelography markedly improved the clinical evaluation of patients with lumbar disc herniation. In this era, use of discectomy surgery increased rapidly. Even patients with very early symptoms were offered surgery. Later work, especially by Weber and Hakelius, showed that many patients with lumbar disc herniation would improve without surgical intervention. In the ensuing decades, the debate over operative indications and timing continued, reaching another pivotal moment with the 2006 publication of the initial results of Spine Patient Outcomes Research Trial. PMID- 24752915 TI - Misophonia: incidence, phenomenology, and clinical correlates in an undergraduate student sample. AB - OBJECTIVE: Individuals with misophonia display extreme sensitivities to selective sounds, often resulting in negative emotions and subsequent maladaptive behaviors, such as avoidance and anger outbursts. While there has been increasing interest in misophonia, few data have been published to date. METHOD: This study investigated the incidence, phenomenology, correlates, and impairment associated with misophonia symptoms in 483 undergraduate students through self-report measures. RESULTS: Misophonia was a relatively common phenomenon, with nearly 20% of the sample reporting clinically significant misophonia symptoms. Furthermore, misophonia symptoms demonstrated strong associations with measures of impairment and general sensory sensitivities, and moderate associations with obsessive compulsive, anxiety, and depressive symptoms. Anxiety mediated the relationship between misophonia and anger outbursts. CONCLUSION: This investigation contributes to a better understanding of misophonia and indicates potential factors that may co-occur and influence the clinical presentation of a person with misophonia symptoms. PMID- 24752916 TI - Protective effects of geraniol (a monoterpene) in a diabetic neuropathy rat model: attenuation of behavioral impairments and biochemical perturbations. AB - Involvement of oxidative stress, inflammatory response, and mitochondrial dysfunction in the development of diabetic neuropathy (DN) is well appreciated. The present study examines the potential of geraniol (GE), a well-known phytoconstituent commonly found in lemon, spices, rose oil, etc., to attenuate DN associated oxidative/nitrosative stress by employing a streptozotocin (STZ) diabetic rat model. STZ-induced diabetic rats provided with oral supplements of GE (100 mg/kg bw/day, 8 weeks) exhibited significant improvement in tail-flick latency (sensory function) and the narrow beam test (motor function). Terminally, elevated levels of oxidative markers (reactive oxygen species, malondialdehyde, hydroperoxides) in cytosol of the sciatic nerve (SN) and in selected regions of the brain of diabetic rats were markedly reduced by GE supplements. Furthermore, GE significantly diminished the levels of protein carbonyls (a measure of protein oxidation) and nitrites in diabetic rats. In addition, in mitochondria, GE supplements restored the activities of enzymes, such as complexes I-III, succinate dehydrogenase, and citrate synthase, in brain regions of diabetic rats, with a concomitant reduction in the levels of oxidative markers. GE significantly lowered the enhanced cytosolic calcium levels and acetylcholinesterase activity in the SN and the brain regions of diabetic rats. Depleted dopamine levels evident in the SN and the cortex/striatum among diabetic rats were restored by GE. From our data, we hypothesize that GE may be a promising therapeutic candidate in the management of DN in humans. Further understanding of the molecular mechanisms of its neuromodulatory effects is essential in order to exploit its therapeutic efficacy. PMID- 24752917 TI - Cancer rehabilitation and prehabilitation may reduce disability and early retirement. PMID- 24752918 TI - Advice for clinician educators. PMID- 24752919 TI - Toward product control in ring-opening oligomerization of 9H-9-borafluorenes. AB - To get deep insights into the structure-reactivity relationship for ring-opening oligomerization reactions toward targeted design of novel main-chain boron containing materials, detailed DFT B97D/TZVP calculations are carried out to compare the ring-opening oligomerization of both unsubstituted and tert-butyl (tBu)-substituted 9H-9-borafluorenes. In contrast to substituent exchange between normal boranes, such reactions are initiated by substituent exchanges involving double B-C-B bridged intermediates. On tBu-substitution, the B-C-B, and B-H-B bridged dimer intermediate is stabilized mainly due to enhanced barrier of 18.1 kcal/mol toward further trimerization channel and higher isomerization barrier of 22.5 kcal/mol toward the double B-H-B bridged dimer. In good agreement with available experiments, it is clearly shown that various product channels can be efficiently controlled by bulky substitution and by reaction temperatures, pointing out the way toward desired higher oligomers with improved thermal stability. PMID- 24752920 TI - Management of intraoperative complications in arthroscopic primary anterior cruciate ligament reconstruction. AB - Arthroscopic anterior cruciate ligament reconstruction is a commonly performed procedure which is technically demanding and involves multiple surgical steps with the potential for a wide range of intraoperative complications. In this article, we review these potential complications and give algorithms for dealing with them based on our experience and published evidence. We discuss the use of both bone-patellar tendon-bone and hamstring grafts and examine complications associated with suspensory button and interference screw fixation. PMID- 24752921 TI - Joint salvage using sandwich technique for giant cell tumors around knee. AB - The most common site for giant cell tumors (GCT) is knee, where the tumor characteristically extends right up to the subarticular bone plate. Extensive curettage with preservation of the joint should be done wherever possible. The alternatives for filling the void left after curettage are either bone graft or bone cement. Sandwich technique uses the advantages of both, taking care to prevent damage to articular cartilage. This study was done to evaluate the results of sandwich technique in tumors around the knee joint. It was a prospective study of 26 consecutive patients (15 females and 11 males) with Campanacci grade II and grade III GCT around the knee, which qualified the inclusion criterion and underwent knee reconstruction with sandwich technique, after extended curettage of the tumor. The mean age of the patients at the time of surgery was 32.73 +/- 11.30 years (range, 18-62 years), and the mean follow-up was 3.87 +/- 1.26 years (range, 6.5-2 years). At final follow-up, the functional evaluation was done using Musculoskeletal Tumor Society (MSTS) score and measuring range of motion around the knee. Three patients had recurrence of tumor; in one case, we were able to salvage the joint and repeat sandwich surgery was performed, and in the other two cases, the joint was breached; therefore, we resorted to resection arthrodesis. At final follow-up, the mean functional arc of motion around the knee and the mean MSTS score in patients without arthrodesis was 123.52 +/- 10.21 degrees (range, 100-130 degrees) and 27.04/30, respectively; all patients were able to do their activities of daily living with ease. Sandwich technique is a good reconstruction procedure in GCT around knee joint with good survival rate, minimal complications, and good functional outcome. PMID- 24752922 TI - Can cementing technique reduce the cost of a primary total knee arthroplasty? AB - Studies on cost containment of total knee arthroplasty (TKA) have generated substantial interest over the past decade. Although multiple studies have evaluated the various intraoperative methods to control cost, no prior study has evaluated the economic impact and the clinical outcome based on amount of bone cement needed for a primary TKA. At a minimum of 3 years follow-up, we observed no difference in implant survivorship or Knee Society scores, but did observe substantial cost savings when one versus two packets of bone cement were used in combination with a hand mixing technique. By eliminating several extra cement mixing products, we achieved an approximately $1,000 cost saving per case with no difference in clinical outcomes at midterm follow-up. PMID- 24752923 TI - Role for irrigation and debridement in periprosthetic infections. AB - Irrigation and debridement (I&D) has been described as a possible option to eradicate early postoperative periprosthetic hip and knee infections, as well as late, acute, and hematogenous ones. Still, the literature fails to uniquely assess the effectiveness of this procedure and often provides conflicting evidence. To reconcile this difference, a systematic review of the available literature from 1970 to 2013 was undertaken. Fifteen articles, for a total of 796 patients, met the inclusion criteria; the average success rate was 44.9 and 52% after a single or repeated I&D procedures, respectively, at an average of 4 years follow-up. Despite the methodological differences and the heterogeneity of the material reviewed, this study demonstrates that this procedure only attains a relatively low success rate of infection eradication, depending on when patients are selected for surgical intervention according to the timeframe of their symptoms. PMID- 24752924 TI - Analysis of Parkinson's disease brain-derived DNA for alpha-synuclein coding somatic mutations. AB - BACKGROUND: Although alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD. METHODS: Expanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible. RESULTS: We did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA. CONCLUSION: Using DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n = 20 each), we have not detected any somatic coding SNCA point mutations. PMID- 24752925 TI - Urinary incontinence and disability in community-dwelling women: a cross sectional study. AB - AIMS: Disability, an individual's reduced capacity to perform physical tasks encountered in daily routine, is associated with urinary incontinence in the elderly. Our objective was to determine if urinary incontinence is associated with disability in community-dwelling women 40 years and older. METHODS: Cross sectional study among US women >=40 years (n = 4,458) from National Health and Nutrition Examination Surveys 2005-2010. We estimated the age-stratified weighted prevalence and factors independently associated with disability (Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), mobility, and functional limitations) in women with and without urinary incontinence while controlling for confounders of the association between disability and urinary incontinence. RESULTS: The weighted prevalence of all disabilities was higher in women with urinary incontinence than women without urinary incontinence across most decades of life with the greatest difference in the prevalence of mobility disabilities: 40-49 years (12.1% vs. 7.0%), 50-59 years (17.0% vs. 9.2%), 60-69 years (28.3% vs. 19.8%), and 70+ years (43.8% vs. 33.0%, all P < 0.05). On multivariable analysis, after controlling for the confounding effect of age, co morbidities, and income-poverty ratio, urinary incontinence was weakly associated with disabilities. The adjusted odds ratio (95% confidence interval) of disabilities for urinary incontinence was ADL 1.96 (1.07, 3.58), IADL 1.18 (0.78, 1.78), mobility 1.26 (1.01, 1.56), and functional limitations 1.36 (1.07, 1.73). CONCLUSIONS: Urinary incontinence is weakly associated with disabilities and cannot be implicated as a cause of disability in community dwelling women. PMID- 24752926 TI - In vivo lung morphometry with hyperpolarized (3) He diffusion MRI: reproducibility and the role of diffusion-sensitizing gradient direction. AB - PURPOSE: Lung morphometry with hyperpolarized gas diffusion MRI is a highly sensitive technique for the noninvasive measurement of acinar microstructural parameters traditionally only accessible by histology. The goal of this work is to establish the reproducibility of these measurements in healthy volunteers and their dependence on the direction of the applied diffusion-sensitizing gradient. METHODS: Hyperpolarized helium-3 ((3) He) lung morphometry MRI was performed on a total of five healthy subjects. Two subjects received duplicate imaging on the same day and three subjects received duplicate imaging after a 4-month or 27 month delay to assess reproducibility. Four subjects repeated the measurement during the same session with different diffusion-sensitizing gradient directions to determine the effect on the parameter estimates. RESULTS: The (3) He lung morphometry measurements were reproducible over the short term and long term (e.g., % coefficient of variation [CV] of mean chord length, Lm = 2.1% and 2.9%, respectively) and across different diffusion gradient directions (Lm % CV = 2.6%). Results also show independence of field inhomogeneity effects at 1.5T. CONCLUSION: (3) He lung morphometry is a reproducible technique for measuring acinar microstructure and is effectively independent of the choice of diffusion gradient direction. This provides confidence for the use of this technique to compare populations and treatment efficacy. PMID- 24752927 TI - Changes in plant cell-wall structure of corn stover due to hot compressed water pretreatment and enhanced enzymatic hydrolysis. AB - Corn stover is a potential feedstock for biofuel production. This work investigated physical and chemical changes in plant cell-wall structure of corn stover due to hot compressed water (HCW) pretreatment at 170-190 degrees C in a tube reactor. Chemical composition analysis showed the soluble hemicellulose content increased with pretreatment temperature, whereas the hemicellulose content decreased from 29 to 7 % in pretreated solids. Scanning electron microscopy revealed the parenchyma-type second cell-wall structure of the plant was almost completely removed at 185 degrees C, and the sclerenchyma-type second cell wall was greatly damaged upon addition of 5 mmol/L ammonium sulfate during HCW pretreatment. These changes favored accessibility for enzymatic action. Enzyme saccharification of solids by optimized pretreatment with HCW at 185 degrees C resulted in an enzymatic hydrolysis yield of 87 %, an enhancement of 77 % compared to the yield from untreated corn stover. PMID- 24752929 TI - Objectivity and reliability of panoramic radiographic signs of intimate relationship between impacted mandibular third molar and inferior alveolar nerve. AB - INTRODUCTION: The results of prior studies assessing the accuracy of panoramic radiographic signs of intimate relationship between inferior alveolar nerve (IAN) and impacted molars are controversial. This may be partly due to inadequate objectivity and reliability of these radiographic signs, which is evaluated in the present study. MATERIALS AND METHODS: Three hundred radiographs in which impacted third molar reached the superior border of the inferior alveolar canal or was superimposed by the canal were evaluated by three examiners independently, twice 3 months apart. Inter- and intra-examiner agreements were analyzed using kappa statistics. RESULTS: The inter-examiner agreement for all radiographic signs was poor (k < 0.2). The intra-examiner agreement for radiographic signs 2, 3, and 6 was poor with mean kappa values of 0.08, 0.00, and 0.09, respectively. Concerning the radiographic signs 4, 5, 7, and 8, the intra-examiner agreement was moderate with mean kappa values of 0.54, 0.49, 0.44, and 0.57, respectively. The mean kappa coefficient for the radiographic sign 1 yielded a good agreement (k = 0.65). CONCLUSIONS: In the present study, the examiners were unable to reliably assess radiographic signs of intimate relationship between IAN and third molar, indicating that panoramic images should not be relied upon for preoperative prediction of IAN injury. PMID- 24752928 TI - Improvement of mitochondrial function by paliperidone attenuates quinolinic acid induced behavioural and neurochemical alterations in rats: implications in Huntington's disease. AB - Quinolinic acid (QA)-induced neurotoxicity involves a cascade of events such as increased calcium concentration in cytoplasm, exhaustive ATP depletion, oxidative stress, as well as selective GABAergic, dopaminergic, and cholinergic neuronal death. Clinical data hint towards the connection between signalling of dopaminergic system and efficient amelioration of chorea following a tetrabenazine administration in Huntington's disease patients. Therefore, the present study has been designed to explore the neuroprotective potential of paliperidone, an active metabolite of risperidone (a dopaminergic antagonist) against QA-induced neurotoxicity and related complications in rats. QA (200 nmol) was administered bilaterally to the striatum over a period of 2 min by means of a 28-gauge stainless steel needle attached to a Hamilton syringe. The study protocol involves seven treatment groups (n = 12): naive, sham, control (QA), paliperidone (0.5, 1 and 2 mg/kg) and paliperidone (2) per se. Single bilateral intrastriatal injection of QA (200 nmol/2 MUl saline) significantly caused motor incordination, memory impairment, oxidative damage, decrease in biogenic amines levels, cellular alterations (TNF-alpha, IL-6, PGE2, PGF2alpha, caspase-3, BDNF, mitochondrial function) and damage of striatal neurons compared to the sham treatment. Treatment with paliperidone (0.5, 1 and 2 mg/kg) for 21 days significantly attenuated the QA-induced behavioural (motor and memory function), neurochemical (antioxidant enzymes and biogenic amines) and cellular alterations, as well as striatal neurodegeneration. The study indicated that modulation of dopaminergic pathway by paliperidone treatment could be a useful approach in the management of motor and memory abnormality in HD patients. PMID- 24752930 TI - Osteonecrosis of the maxilla related to long-standing methamphetamine abuse: a possible new aspect in the etiology of osteonecrosis of the jaw. AB - BACKGROUND: Osteonecrosis of the jaw (ONJ) related to toxic effects of illicit drugs such as cocaine is not very common and might be overshadowed today by the incidence of bisphosphonate-related osteonecrosis of the jaw. However, we present a case which suggests a close relationship between abuse of the illicit drug methamphetamine (MA) and ONJ. CASE REPORT: A 44-year-old male with extended osteonecrosis of the maxilla admitted chronic abuse and synthesis of MA for at least the previous two decades. Furthermore, he confessed self-extracting teeth since he became addicted to MA. However at presentation, he had been successfully cured of his addiction to MA. A step-by-step surgical treatment was planned using computer-aided design/computer-aided manufacturing techniques. After resection of necrotic bone, a vascularized osteomyocutaneous fibular flap was applied secondarily. DISCUSSION: Two possible mechanisms, alone or in combination, could possibly lead to MA-related ONJ. Self-extraction of teeth as a psychopathologic behavior of self-destruction among MA abusers results in wounds that allow unhindered invasion of microorganisms causing osteomyelitis and ONJ, while on the other hand, the heating of white phosphor releases toxic phosphorous vapor, which could be inhaled and consequently cause ONJ of the maxilla. However, since the worldwide prevalence of MA abuse is remarkably high, a relationship between MA abuse and ONJ will offer a new aspect in the etiology of ONJ and might present a further therapeutic challenge. PMID- 24752931 TI - Anatomical study of the canalis sinuosus in 100 cone beam computed tomography examinations. AB - OBJECTIVE: To identify and describe the morphology and location of the canalis sinuosus (CS) and make correlations with gender, age, and distance of this canal to important adjacent structures on the region, thus mapping the anatomy of this structure. METHODOLOGY: A total of 100 cone beam computed tomography (CBCT) examinations were collected from the files of a dental clinic in the Municipality of Belem, Para, Brazil, and analyzed to identify the site of bifurcation, the diameter of CS right after such bifurcation and in its terminal portion as well as the direction of its course and the distance to the alveolar bone crest region. The anatomical views were evaluated using InVivoDental software on sagittal, axial, and coronal sections, and the results were submitted to Fisher's exact test, Kendall correlation coefficients, Mann-Whitney tests, and T tests. RESULTS: CS was present in 88 % of the sample. There were no statistically significant changes in the presence of CS regarding gender, age and direction of course. A strong positive correlation between CS's diameter on its initial and terminal portions was observed (p < 0.0001). There was a statistically significant change in the distance to alveolar bone crest related to gender, which is higher in men (p = 0.0303). CONCLUSION: In the sample, CS was frequent and similar in both genders, with course distance to the alveolar bone crest and termination in different locations that ought to be analyzed on CBCT prior to surgical procedures. PMID- 24752932 TI - Reply: To PMID 24691943. PMID- 24752933 TI - 5,10-Methylene-tetrahydrofolate dissociates into tetrahydrofolate and formaldehyde at physiological pH and acidic pH, typical conditions used during sample extraction and LC-MS/MS analysis of biological samples. PMID- 24752934 TI - Predicting who benefits most from cognitive-behavioral therapy for anxiety and depression. AB - OBJECTIVES: We examined core features of patient suitability for cognitive behavioral therapy (CBT) and their ability to predict CBT outcomes. METHOD: A sample of 256 outpatients diagnosed with depression and anxiety disorders were assessed using the Suitability for Short-Term Cognitive Therapy (SSCT) scale. Therapists rated patients' symptom severity using the Clinical Global Impression scale before and after therapy. RESULTS: A factor analysis of the SSCT scale yielded 2 factors: (a) Capacity for Participation in CBT Process and (b) Attitudes Relevant to the CBT Process. A multiple regression analysis revealed that only Capacity for Participation in CBT Process uniquely predicted improvement at termination. CONCLUSIONS: These findings highlight the importance of assessing the suitability of CBT for individual patients. Specifically, patients with greater capacity to identify and articulate thoughts and feelings and to share them in a nondefensive, focused way benefit most from CBT. PMID- 24752936 TI - Computational identification of microRNAs and their targets in perennial Ryegrass (Lolium perenne). AB - MicroRNAs (miRNAs) are small non-coding RNA molecules of 22 nucleotides in length that have been characterized as regulators of messenger RNA (mRNA) regulating a number of developmental processes in plants and animals by silencing genes using multiple mechanisms. miRNAs have been extensively studied in various plant species; however, few information are available about miRNAs in perennial ryegrass, animal feed, and industrial raw materials. In this study, the 12 potential perennial ryegrass miRNAs were identified for the first time by computational approach. Using the newly identified miRNA sequences, the perennial ryegrass mRNA database was further used for BLAST search and detected 33 potential targets of miRNAs. Prediction of potential miRNA target genes revealed their functions involved in various important plant biological processes. Our result should be useful for further investigation into the biological functions of miRNAs in perennial ryegrass. The selected miRNAs representing four families were verified by RT-PCR experiment, indicating that the prediction method that we used to identify the miRNAs was effective. PMID- 24752937 TI - Copper response of Proteus hauseri based on proteomic and genetic expression and cell morphology analyses. AB - The copper response of Proteus hauseri ZMd44 was determined using one-dimensional (1D) gel electrophoresis coupled with MALDI-TOF-TOF mass spectrometry for a similarity analysis of proteins isolated from P. hauseri ZMd44 cultured in CuSO4 bearing LB medium. Candidate proteins identified as a copper-transporting P-type ATPase (CTPP), phosphoenolpyruvate carboxykinase (PEPCK), flagellin (Fla), and outer membrane proteins (Omps) were the major copper-associated proteins in P. hauseri. In a comparative analysis of subcellular (i.e., periplasmic, intracellular, and inner membranes) and cellular debris, proteomics analysis revealed a distinct differential expression of proteins in P. hauseri with and without copper ion exposure. These findings were consistent with the transcription level dynamics determined using quantitative real-time PCR. Based on a genetic cluster analysis of copper-associated proteins from P. hauseri, Fla and one of the Omps showed greater diversity in their protein sequences compared to those of other Proteus species. Transmission electron microscopy (TEM) and the observed growth on LB agar plates showed that the swarming motility of cells was significantly suppressed and inhibited upon Cu(II) exposure. Thus, copper stress could have important therapeutic significance due to the loss of swarming motility capacity in P. hauseri, which causes urinary tract infections. PMID- 24752938 TI - Mixtures of thermostable enzymes show high performance in biomass saccharification. AB - Optimal enzyme mixtures of six Trichoderma reesei enzymes and five thermostable enzyme components were developed for the hydrolysis of hydrothermally pretreated wheat straw, alkaline oxidised sugar cane bagasse and steam-exploded bagasse by statistically designed experiments. Preliminary studies to narrow down the optimization parameters showed that a cellobiohydrolase/endoglucanase (CBH/EG) ratio of 4:1 or higher of thermostable enzymes gave the maximal CBH-EG synergy in the hydrolysis of hydrothermally pretreated wheat straw. The composition of optimal enzyme mixtures depended clearly on the substrate and on the enzyme system studied. The optimal enzyme mixture of thermostable enzymes was dominated by Cel7A and required a relatively high amount of xylanase, whereas with T. reesei enzymes, the high proportion of Cel7B appeared to provide the required xylanase activity. The main effect of the pretreatment method was that the required proportion of xylanase was higher and the proportion of Cel7A lower in the optimized mixture for hydrolysis of alkaline oxidised bagasse than steam exploded bagasse. In prolonged hydrolyses, less Cel7A was generally required in the optimal mixture. Five-component mixtures of thermostable enzymes showed comparable hydrolysis yields to those of commercial enzyme mixtures. PMID- 24752939 TI - The application of the starfish hatching enzyme for the improvement of scar and keloid based on the fibroblast-populated collagen lattice. AB - Various bioactivities of the starfish hatching enzyme (HE) including collagen gel contraction, MMPs activity, hydroxyproline release, and gene regulation based on the fibroblast-populated collagen lattice (FPCL) in three-dimensional medium were investigated for the improvement of scar and keloid. The starfish HE significantly inhibited the collagen gel contraction over 2 days of culture. MMP 2 and MMP-9 activities were also identified by gelatin zymography and RT-PCR products with both HE and collagenase treatments, which resulted in the high amount of hydroxyproline release. The HE treatment on the FPCL significantly inhibited the fibroblast proliferation at 3 days of culture. The LPS-induced NO level and iNOS mRNA expression at low concentrations of HE presented a certain ability to inflammatory response. The COX-2 mRNA from the FPCL indicated no significant inflammation-mediated activity at 5 MUg/mL of HE, whereas the cytokines of TNF-alpha and IL-1beta were significantly higher than those of the control. Hence, the starfish hatching enzyme can regulate the fibroblast populated collagen gel conditions by the contraction, MMP production, inflammatory gene expression, etc. Therefore, the starfish HE could be a potential cosmeceutical to heal the scar and keloid tissue. PMID- 24752935 TI - Luminol-based chemiluminescent signals: clinical and non-clinical application and future uses. AB - Chemiluminescence (CL) is an important method for quantification and analysis of various macromolecules. A wide range of CL agents such as luminol, hydrogen peroxide, fluorescein, dioxetanes and derivatives of oxalate, and acridinium dyes are used according to their biological specificity and utility. This review describes the application of luminol chemiluminescence (LCL) in forensic, biomedical, and clinical sciences. LCL is a very useful detection method due to its selectivity, simplicity, low cost, and high sensitivity. LCL has a dynamic range of applications, including quantification and detection of macro and micromolecules such as proteins, carbohydrates, DNA, and RNA. Luminol-based methods are used in environmental monitoring as biosensors, in the pharmaceutical industry for cellular localization and as biological tracers, and in reporter gene-based assays and several other immunoassays. Here, we also provide information about different compounds that may enhance or inhibit the LCL along with the effect of pH and concentration on LCL. This review covers most of the significant information related to the applications of luminol in different fields. PMID- 24752940 TI - Effect of cortisol on caspases in the co-cultured C2C12 and 3 T3-L1 cells. AB - The present study was carried out to understand the effect of cortisol on caspase expression in the C2C12 and 3 T3-L1 cells under co-culture system. Cells were co cultured by using transwell inserts with a 0.4-MUm porous membrane to separate C2C12 and 3 T3-L1 preadipocyte cells. Each cell type was grown independently on the transwell plates. Following cell differentiation, inserts containing 3 T3-L1 cells were transferred to C2C12 plates and inserts containing C2C12 cells were transferred to 3 T3-L1 plates. A total of 10 MUg/MUl of cortisol was added to the medium. Following treatment of cortisol for 3 days, the cells in the lower well were harvested for analysis. Caspases such as caspase 3, caspase 7, and caspase 9 were selected for the analysis. qRT-PCR results indicated the significant increase in the mRNA expression of caspase 3, caspase 7, and caspase 9. Caspase 3, 7, and 9 activities were also increased in the mono- and co-cultured C2C12 and 3 T3-L1 cells. In addition, confocal microscopical investigation indicated that cortisol increases caspase expressions in the mono- and co-cultured C2C12 and 3 T3-L1 cells. Taking all these together, we concluded that the co-culture system reflects the exact effect of cortisol on caspase expression, which is quite distinct from one dimensional mono-cultured experiments. PMID- 24752941 TI - Synthesis of nano-hydroxyapatite via microbial method and its characterization. AB - Nanoparticles of hydroxyapatite were successfully synthesized by microbial method at ambient temperature and pressure, using calcium chloride and specific substrate as reactants. The compositional and morphological properties of products of the syntheses were studied by means of X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and thermogravimetric analysis (TGA). The characterization data obtained showed that the phase composition, functional groups, and surface morphology of samples obtained by microbial method were mainly similar to that by chemical precipitation method. The hydroxyapatite powder was shown to be nanometer-grade in size and sphere-like in shape. PMID- 24752942 TI - Ethnography, fidelity, and the evidence that anthropology adds: supplementing the fidelity process in a clinical trial of supported employment. AB - This discussion considers the role and findings of ethnographic research within a clinical trial of supported employment for veterans with spinal cord injury. Contributing to qualitative evaluation research and to debates over anthropological evidence vis-a-vis clinical trials, we demonstrate how enactors of a randomized controlled trial can simultaneously attend to both the trial's evidentiary and procedural requirements and to the lived experiences and needs of patients and clinicians. Three major findings are described: (1) contextual information essential to fidelity efforts within the trial; (2) the role of human interrelationships and idiosyncratic networks in the trial's success; and (3) a mapping of the power and authority structures relevant to the staff's ability to perform the protocol. We emphasize strengths of anthropological ethnography in clinical trials that include the provision of complementary, qualitative data, the capture of otherwise unmeasured parts of the trial, and the realization of important information for the translation of the clinical findings into new settings. PMID- 24752943 TI - Thyroid metastasis from breast cancer presenting with diffuse microcalcifications on sonography: a case report. AB - Microcalcifications are frequently associated with papillary thyroid cancers. Metastatic nodules from extrathyroid malignancies may mimic primary thyroid neoplasm on sonography, but do not present with microcalcifications. We report the case of a 45-year-old woman with a history of invasive ductal carcinomas of bilateral breasts, status post surgery and neoadjuvant chemotherapy. Four years after surgery, thyroid sonography revealed diffuse microcalcifications without nodular component. Core needle biopsy confirmed thyroid metastasis from primary breast cancer. PMID- 24752944 TI - Investigation of antihyperglycaemic activity of banana (Musa sp. var. Nanjangud rasa bale) pseudostem in normal and diabetic rats. AB - BACKGROUND: Postprandial hyperglycaemia in diabetes could be ameliorated by inhibiting intestinal alpha-glucosidases, responsible for starch hydrolysis and its absorption. Different parts of banana have been in use in conventional medicinal formulations since ancient times. Its role as an antihyperglycaemic agent has also been studied. This study was aimed at explaining the mechanism of hypoglycaemic effect by ethanol extract of banana pseudostem (EE). Additionally, studies on the active components involved in the effect have also been attempted. RESULTS: EE significantly inhibited mammalian intestinal alpha-glucosidases and yeast alpha-glucosidase (IC50 , 8.11 +/- 0.10 ug mL(-1) ). The kinetic studies showed that EE inhibited sucrase, maltase and and p-nitrophenyl-alpha-d glucopyranoside hydrolysis by mixed-type inhibition. Further, in vivo studies identified that the oral administration (100-200 mg kg(-1) body weight) of EE significantly suppressed the maltose/glucose-induced postprandial plasma glucose elevation and wielded an antihyperglycaemic effect in normal and alloxan-induced diabetic rats. GC-MS analysis of EE revealed high levels of beta-sitosterol (29.62%), stigmasterol (21.91%), campesterol (10.85%) and other compounds. CONCLUSION: These findings suggest that EE might exert an anti-diabetic effect by inhibition of alpha-glucosidases from the intestine, in turn suppressing the carbohydrate absorption into the bloodstream. Hence the results extend a foundation to the future prospects of the food-derived enzyme inhibitors in treatment of diabetes. PMID- 24752946 TI - Reply: To PMID 24375753. PMID- 24752945 TI - A phase 2 cooperative group adjuvant trial using a biomarker-based decision algorithm in patients with stage I non-small cell lung cancer (SWOG-0720, NCT00792701). AB - BACKGROUND: This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non-small cell lung cancer with tumor diameters measuring >= 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm. METHODS: At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin-fixed and paraffin-embedded tumor specimen were required. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence-based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2-year survival. RESULTS: Treatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2-year disease-free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected. CONCLUSIONS: Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development. PMID- 24752948 TI - Shlomo Stern Z.L.(February 10th, 1928 - October 27th, 2013). PMID- 24752947 TI - Toward the understanding of the environmental effects on core ionizations. AB - Experimental X-ray absorption spectra are extensively used to determine electronic structure of small molecules but remain difficult to exploit for proteins due to the large number of peaks within their spectra. For such complex systems, theoretical tools like quantum mechanics/molecular mechanics methodology can greatly ease the assignment of the spectra. This study presents a systematic methodology to evaluate core-ionization energies (E(ion)) in proteins with the help of the asymptotic projection approach (Glushkov and Tsaune, Z. Vichislit. Matem. Mat. Fiz. 1985, 25, 298; Glushkov, Chem. Phys. Lett. 1997, 273, 122; Glushkov, Chem. Phys. Lett. 1998, 287, 189; Glushkov, J. Math. Chem. 2002, 31, 91; Glushkov, Opt. Spectrosc. 2002, 93, 15). An in-depth inspection of E(ion) of systems of increasing complexity is considered, going from amino acids to polyglycine and to glycine in human serum albumin (HSA). Computational analysis can help to better understand experimental data and to discriminate environmental effects by tracing them back to individual and collective electrostatic contributions. In the present work, it was found that E(ion) of alpha carbon of glycine residues in HSA ranges from 285 to 295 eV depending on their surroundings. PMID- 24752949 TI - The Vioxx(r) legacy: Enduring lessons from the not so distant past. PMID- 24752950 TI - The association between vitamin D level and extent of coronary stenotic lesions. PMID- 24752951 TI - Authors' response. PMID- 24752952 TI - Metabolic syndrome in clinical practice. PMID- 24752953 TI - Authors' response. PMID- 24752954 TI - Assessment of left-atrial strain parameters in patients with frequent ventricular ectopic beats without structural heart disease. AB - Ventricular ectopic beats (VEBs) are often encountered in daily clinical practice. Clinical significance of VEBs seen in patients without structural cardiovascular diseases is controversial. We aimed to investigate the effects of VEBs on left atrium (LA) function using speckle tracking echocardiography with LA strain parameters. Patients with frequent VEBs (more than 30 times in 1 h, according to the Lown classification) were identified. Identified patients were evaluated by speckle tracking methods. There were 40 patients with frequent VEBs and 40 controls in our study. The general characteristics were similar of the study population. The LA global longitudinal strain parameters were significantly different. Global Peak atrial longitudinal strain (PALS) (38.39 +/- 7.93 vs. 44.15 +/- 6.71, p = 0.001) and peak atrial contraction strain (PACS) (16.37 +/- 4.58 vs. 20.49 +/- 3.65, p = 0.000) were revealed significantly lower in the VEBs group. Time to peak longitudinal strain (TPLS) was found significantly longer in the VEBs group [485.5 (352-641) vs. 435 (339-516.5) p = 0.000]. Number of VEBS was correlated with TPLS (r = 0.499, p = 0.000). PALS and PACS were negatively correlated with number of VEBs (r = -0.348, p = 0.002 and r = -0.444, p = 0.000, respectively). We described that in this study, The LA functions are affected by VEBs adversely. This deterioration is increasing as the number of VEBs. PMID- 24752955 TI - MR assessment of abdominal circulation in Fontan physiology. AB - The Fontan operation allows for longer survival of those born with functionally single ventricle physiology. Although it effectively eliminates cyanosis, increased systemic venous pressure is an unavoidable consequence and low cardiac output is frequent. The abdomen is particularly vulnerable to these alterations in hemodynamics because the hepatic blood flow consists predominantly of portal venous flow, which relies on a low pressure gradient between the portal and hepatic veins. Therefore, any subtle increase in systemic venous pressure will adversely affect the hemodynamic balance of the liver as well as the intestine. As the clinical manifestations and routine laboratory findings of abdominal complications can lag behind the hemodynamic and pathologic changes in the abdominal organs, regular imaging surveillance is critical. Magnetic resonance (MR) provides excellent visualization of both cardiovascular and abdominal systems. It provides robust anatomic and hemodynamic data which can be used for timely implementation of treatment options. In this review paper, we discuss the pathogenesis and MR findings of abdominal complications following the Fontan operation. Specifically we explore the utility of phase-contrast MR for assessment of the abdominal circulation in children following the Fontan palliation. PMID- 24752956 TI - Comment on: characterization of the embB gene in Mycobacterium tuberculosis isolates from Barcelona and rapid detection of main mutations related to ethambutol resistance using a low-density DNA array. PMID- 24752958 TI - Utilization of a free fitness center-based exercise referral program among women with chronic disease risk factors. AB - Physical activity (PA) reduces the risk for a number of chronic diseases including heart disease, hypertension, hyperlipidemia, and diabetes mellitus type 2. However, most Americans do not meet expert recommendations for exercise, and minorities and low-income persons are the most inactive. Community-based approaches to promoting PA include primary care exercise referral programs. This study examines patient characteristics associated with utilization of a community health center-based exercise referral program. Adult female patients of a community health center with an affiliated fitness center, in Boston, MA, were included in the study if they received a referral to the fitness center from their primary care provider. Demographic and medical information was abstracted from the medical chart, and fitness records were abstracted to measure activation of a fitness center membership (creation of an account denoting at least an initial visit) and utilization over time. Overall, 503 (40%) of the 1,254 referred women in the study sample activated their membership. Black women were almost 60% more likely to activate their membership (adjusted OR 1.6, 95% CI 1.2 2.2), and women with higher co-morbidity counts were almost 45% more likely to activate (adjusted OR 1.4, 95% CI 1.0-2.0). Once activated, a minority of women participated at levels likely to improve cardiometabolic fitness. Of the 503 activations, 96 (19%) had no participation, 359 (71%) had low participation, and only 48 (10%) had high participation. No independent predictors of participation were identified. These findings suggest that program design may benefit from developing activation, initial participation, and retention strategies that address population-specific barriers. PMID- 24752957 TI - Safety and efficacy of levofloxacin versus rifampicin in tuberculous meningitis: an open-label randomized controlled trial. AB - OBJECTIVES: We report the efficacy and safety of levofloxacin versus rifampicin in tuberculous meningitis (TBM). PATIENTS AND METHODS: In this open-label, randomized controlled trial from India, patients with TBM diagnosed on the basis of clinical, MRI and CSF findings were included. Patients with hepatic or renal dysfunction, organ transplantation, malignancy, pregnancy, lactation, allergy, seizure, age <15 years and antitubercular treatment >=1 month were excluded. Sixty patients each were randomized to levofloxacin (10 mg/kg, maximum 500 mg) or rifampicin (10 mg/kg, maximum 450 mg). They also received isoniazid, pyrazinamide, ethambutol, prednisolone and aspirin. The primary outcome was death and secondary outcome measures were 6 month disability, repeat MRI changes and serious adverse events (SAEs). RESULTS: The median age of the patients was 34.5 (16-75) years. The baseline clinical and MRI findings were similar between the two groups. At 6 months, 13 out of 60 (21.7%) patients in the levofloxacin arm and 23 out of 60 (38.3%) patients in the rifampicin arm had died (P = 0.07). On Cox regression analysis, survival in the levofloxacin group was significantly better than in the rifampicin group (hazard ratio 2.13, 95% CI 1.04-4.34, P = 0.04). The functional outcome (P = 0.47) was, however, not significantly different between the two groups. On intention-to-treat analysis, 10 out of 47 (21.3%) in the levofloxacin arm and 5 out of 37 (13.5%) in the rifampicin arm had poor recovery. Repeat MRI findings did not differ between the groups. Levofloxacin was discontinued more frequently than rifampicin due to SAEs (16 versus 4, P = 0.01). CONCLUSIONS: Levofloxacin is superior to rifampicin in reducing 6 month death in TBM but not disability. Levofloxacin may be used in TBM especially in those patients with hepatotoxicity and without seizure. PMID- 24752959 TI - Dynamic ASL and T2-weighted MRI in exercising calf muscle at 7 T: a feasibility study. AB - PURPOSE: The aim of this study was to develop a measurement protocol for noninvasive simultaneous perfusion quantification and T2 *-weighted MRI acquisition in the exercising calf muscle at 7 Tesla. METHODS: Using a nonmagnetic ergometer and a dedicated in-house built calf coil array, dynamic pulsed arterial spin labeling (PASL) measurements with a temporal resolution of 12 s were performed before, during, and after plantar flexion exercise in 16 healthy volunteers. RESULTS: Postexercise peak perfusion in gastrocnemius muscle (GAS) was 27 +/- 16 ml/100g/min, whereas in soleus (SOL) and tibialis anterior (TA) muscles it remained at baseline levels. T2 *-weighted and ASL time courses in GAS showed comparable times to peak of 161 +/- 72 s and 167 +/- 115 s, respectively. The T2 *-weighted signal in the GAS showed a minimum during exercise (88 +/- 6 % of the baseline signal) and a peak during the recovery (122 +/- 9%), whereas in all other muscles only a signal decrease was observed (minimum 91 +/- 6% in SOL; 87 +/- 8% in TA). CONCLUSION: We demonstrate the feasibility of dynamic perfusion quantification in skeletal muscle at 7 Tesla using PASL. This may help to better investigate the physiological processes in the skeletal muscle and also in diseases such as diabetes mellitus and peripheral arterial disease. PMID- 24752960 TI - Insights into a highly conserved network of hydrogen bonds in the agonist binding site of nicotinic acetylcholine receptors: a structural and theoretical study. AB - Structural and theoretical studies on the geometrical features of a hydrogen-bond network occurring in the binding site of nicotinic acetylcholine receptors (nAChRs) and composed of interconnected WxPD (Trp-x-Pro-Asp) and SWyz (Ser-Trp yz) sequences from loops A and B, respectively, have been carried out. Multiple sequence alignments using as template the sequence of the apoform of Aplysia californica acetylcholine binding protein (Ac-AChBP) show the strict conservation of serine and tryptophan residues of the loop B SWyz sequence. Considering a sample of 19 high resolution AChBP structures, the strong conformational preferences of the key tryptophan residue has been pointing out, whatever the form, free or bounded, of AChBP. The geometry of the motif hydrogen-bond network has been characterized through the analyses of seven distances. The robustness of the various hydrogen-bond interactions is pointed out, the one involving the aspartate carboxylate group and the serine residue being the shortest of the network. The role of a cooperative effect involving a NH(His145)...OH (Ser142) hydrogen bond is highlighted. Density functional theory calculations on several simplified models based on the motif hydrogen-bond network allow probing the importance of the various hydrogen-bond interactions. The removal of the Ser142 hydroxyl group induces strong structural rearrangements, in agreement with the structural observations. Molecular electrostatic potential calculations on model systems highlight the importance of a cooperative effect in the whole hydrogen bond network. More precisely, the key role of the Ser142 hydroxyl group, involved in several hydrogen bonds, is underlined. PMID- 24752961 TI - Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal is bad, then administration is good (right?). PMID- 24752962 TI - Evaluation of retrobulbar blood flow with color doppler ultrasonography in patients with central serous chorioretinopathy. AB - BACKGROUND: To compare retrobulbar blood flow in patients with central serous chorioretinopathy (CSC) and healthy subjects using color Doppler ultrasonography. METHODS: Thirty patients (age 23-54 years) with a first episode of acute CSC and 30 healthy controls (age 30-44 years) were evaluated. The peak systolic blood flow velocity, end-diastolic velocity (EDV), resistance index (RI), and pulsatility index (PI) were measured in the ophthalmic, posterior ciliary, and central retinal arteries. RESULTS: The posterior ciliary and central retinal artery EDV were lower in the patient group than in the control group, whereas RI and PI values were significantly higher (p < .05). The ophthalmic artery peak systolic blood flow velocity and EDV were lower in the CSC than in the control group (p < .05) without significant difference in RI and PI. CONCLUSIONS: Color Doppler ultrasonography provides additional insights into the pathophysiology of CSC and may support the vasospasm hypothesis. PMID- 24752963 TI - Anatomical observations of the human acromioclavicular joint. AB - The condition of the acromioclavicular joint (ACJ) is considered to be one factor in the etiology of shoulder impingement syndrome, but there are few supporting morphological data. Fifty-two sides of 35 cadavers were investigated macroscopically and histologically using Safranin O, Fast green, and Weigert's iron hematoxylin staining. The ACJs were classified into three major types depending on the presence or absence of the articular disk. In type 1, the articular disk divided the articular cavity completely (n = 2; 3.8%). In type 2, the articular disk was incomplete and divided the joint cavity incompletely (n = 13; 25%). Type 2 was further divided into subtypes 2a and 2b depending on the configurations of the articular facets. In type 3, no articular disk was found in the joint cavity (n = 37; 71.2%). Type 3 was further divided into subtypes 3a, 3b, and 3c depending on the configurations of the articular surfaces. Fewer than half of the ACJ specimens (22/52 or 42.3%) demonstrated an ellipsoid character in which axial rotation was limited. Histological observation revealed that the upper part of the articular disk of the ACJ comprised fibrocartilage while the lower part comprised dense connective tissue. In cases where the ACJ appears to be an ellipsoid joint, its limited axial rotation restricts posterior tilting of the scapula during arm elevation, which could contribute to shoulder impingement syndrome. PMID- 24752964 TI - Epithelial-to-mesenchymal transition and estrogen receptor alpha mediated epithelial dedifferentiation mark the development of benign prostatic hyperplasia. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) has been reported involved in the pathogenesis of fibrotic disorders and associated with stemness characteristics. Recent studies demonstrated that human benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium. However, the inductive factors of EMT in the adult prostate and the cause-and-effect relationship between EMT and stemness characteristics are not yet resolved. METHODS: EMT expression patterns were immunohistochemically identified in the human epithelia of normal/BPH prostate tissue and in a rat BPH model induced by estrogen/androgen (E2/T, ratio 1:100) alone or in the presence of the ER antagonist raloxifene. Gene expression profiles were analyzed in micro-dissected prostatic epithelia of rat stimulated by E2/T for 3 days. RESULTS: Two main morphological features both accompanied with EMT were observed in the epithelia of human BPH. Luminal cells undergoing EMT dedifferentiated from a cytokeratin (CK) CK18(+) /CK8(+) /CK19(+) to a CK18( ) /CK8(+) /CK19(-) phenotype and CK14 expression increased in basal epithelial cells. ERalpha expression was closely related to these dedifferentiated cells and the expression of EMT markers. A similar pattern of EMT events was observed in the E2/T induced rat model of BPH in comparison to the prostates of untreated rats, which could be prevented by raloxifene. CONCLUSIONS: Epithelial and mesenchymal phenotype switching is an important mechanism in the etiology of BPH. ERalpha mediated enhanced estrogenic effect is a crucial inductive factor of epithelial dedifferentiation giving rise to activation of an EMT program in prostate epithelium. PMID- 24752965 TI - Elucidating posttraumatic stress symptom profiles and their correlates among women experiencing bidirectional intimate partner violence. AB - OBJECTIVE: This study employed latent class analysis to identify profiles of women experiencing intimate partner violence (IPV) based on the severity of posttraumatic stress disorder (PTSD) symptoms. METHOD: Self-report data from a sample of 369 women experiencing bidirectional IPV was used. RESULTS: A 3-class solution comprising low, moderate, and high PTSD severity profiles best fit the data. Profiles were differentially related to whether IPV victimization was considered traumatic (PTSD criterion A); whether functioning was impaired as a result of PTSD symptoms (PTSD criterion F); whether the woman met full diagnostic criteria for PTSD; depression symptom severity; and severity of psychological, physical, and sexual IPV victimization and use of IPV. An extremely high percentage of women in the high (96%) and moderate (88%) severity classes experienced functional impairment, although many did not meet full diagnostic criteria for PTSD. CONCLUSIONS: Findings support the need for interventions individually tailored to one's treatment needs based on the nature of one's traumatic stressor and the impact of PTSD on daily functioning. PMID- 24752966 TI - Electric field manipulation of magnetization rotation and tunneling magnetoresistance of magnetic tunnel junctions at room temperature. PMID- 24752968 TI - Deep brain stimulation in the ventrolateral thalamus/subthalamic area in dystonia with head tremor. AB - BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) effectively ameliorates idiopathic dystonia, although approximately 15% of patients respond insufficiently. Although various thalamic and subthalamic targets have been suggested for dystonic tremor, no systematic studies have been published on thalamic DBS in dystonic tremor. We assessed the effect of thalamic/subthalamic area DBS (Th-DBS) on dystonic head tremor and dystonia in a single-blind design. METHODS: Dystonic head tremor and dystonia before and 3 months after surgery were quantified via blinded video-ratings using the Fahn-Tolosa-Marin-Tremor-Scale and the Burke-Fahn-Marsden-Dystonia-Rating-Scale in seven patients with idiopathic cervical or segmental dystonia, dystonic head tremor, and bilateral Th-DBS. Pain, side effects, adverse events, and stimulation parameters were assessed. RESULTS: Th-DBS improved dystonic tremor and dystonia (P < 0.05; 57.1% and 70.4%, respectively). Head tremor amplitude and pain were also improved (P < 0.05; 77.5% and 90.0%, respectively). Side effects included dysarthria, gait disturbance, slowness of movement, and weight gain. CONCLUSION: Dystonic head tremor and dystonia can be improved with Th-DBS. PMID- 24752969 TI - ZIP1 and zinc inhibits fluoride-induced apoptosis in MC3T3-E1 cells. AB - Excess fluoride intake could induce apoptosis in the cells. As an essential micronutrient and cytoprotectant, zinc is involved in many types of apoptosis. Here, we studied the effects of zinc and ZIP1 on fluoride-induced apoptosis in mouse MC3T3-E1 cells and examined the underlying molecular mechanisms. Our study found that fluoride not only inhibited cell proliferation and increased the intracellular reactive oxygen species (ROS) but also induced cell apoptosis. Whereas pretreatment with zinc significantly attenuated fluoride-induced ROS production and partly protected cells against fluoride-induced apoptosis through MAPK/ERK signaling pathway. Our study also found that fluoride upregulated the expression of ZIP1 in a time-dependent manner. Moreover, overexpression of ZIP1 also inhibited fluoride-induced apoptosis by activation of PI3K/Akt pathway. This cytoprotective effect of zinc and ZIP1 may be new factors that affect the physiological activity of fluoride and need study further. PMID- 24752967 TI - Functional and anatomical differences between continent and incontinent men post radical prostatectomy on urodynamics and 3T MRI: a pilot study. AB - AIMS: There are competing hypotheses about the etiology of post prostatectomy incontinence (PPI). The purpose of this study was to determine the anatomical and functional differences between men with and without PPI. METHODS: Case-control study of continent and incontinent men after radical prostatectomy who underwent functional and anatomic studies with urodynamics and 3.0 Tesla MRI. All men were at least 12 months post prostatectomy and none had a history of pelvic radiation or any prior surgery for incontinence. RESULTS: Baseline demographics, surgical approach, and pathology were similar between incontinent (cases) (n = 14) and continent (controls) (n = 12) men. Among the cases, the average 24 hr pad weight was 400.0 +/- 176.9 g with a mean of 2.4 +/- 0.7 pads per day. Urethral pressure profiles at rest did not significantly differ between groups; however, with a Kegel maneuver the rise in urethral pressure was 2.6 fold higher in controls. On MRI, the urethral length was 31-35% shorter and the bladder neck was 28.9 degrees more funneled in cases. There were no differences in levator ani muscle size between groups. There was distortion of the sphincter area in 85.7% of cases and in 16.7% of controls (P = 0.001). CONCLUSIONS: Men with PPI were not able to increase urethral pressure with a Kegel maneuver despite similar resting urethral pressure profiles. Additionally, incontinent men had shorter urethras and were more likely to have distortion of the sphincter area. All suggesting that the sphincter in men with PPI is both diminutive and poorly functional. PMID- 24752970 TI - Protective role of cactus cladodes extract on sodium dichromate-induced testicular injury and oxidative stress in rats. AB - Cactus (Opuntia ficus-indica) is a xerophyte plant that belongs to the Cactaceae family. The present study was designed to investigate the possible protective effects of cactus cladodes extract (CCE) on sodium dichromate-induced testis damage in adult male Wistar rats. For this purpose, CCE at a dose of 100 mg/kg was orally administrated, followed by 10 mg/kg sodium dichromate (intraperitoneal injection). After 40 days of treatment, the rats were sacrificed, and the testes were excised for histological, lipid peroxidation (LPO), and antioxidant enzyme analyses. Sodium dichromate treatment significantly (P<0.01) decreased the body, testis, and accessory sex organ weights, sperm count and motility, and serum testosterone level. In addition, histological analysis revealed pronounced morphological alterations with tubular necrosis and reduction in the number of gametes in the lumen of the seminiferous tubules of sodium dichromate-intoxicated rats. Furthermore, exposure to sodium dichromate significantly (P<0.01) increased LPO level and decreased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in testis. Interestingly, pretreatment with CCE significantly (P<0.01) restored the serum testosterone level, sperm count, and motility to the levels of the control group. Moreover, CCE administration was capable of reducing the elevated level of LPO and significantly (P<0.01) increased SOD, CAT, and GPx activities in testis. Cactus cladodes supplementation minimized oxidative damage and reversed the impairment of spermatogenesis and testosterone production induced by sodium dichromate in the rat testis. PMID- 24752972 TI - Blood serum and seminal plasma selenium, total antioxidant capacity and coenzyme q10 levels in relation to semen parameters in men with idiopathic infertility. AB - In this case-control study, we aimed to evaluate the serum and seminal plasma levels of Selenium (Se), total antioxidant capacity (TAC), and Coenzyme Q10 (CoQ 10) and determine their relationship with sperm concentration, motility, and morphology in men with idiopathic infertility. A total of 59 subjects were enrolled in the study. Forty four patients were diagnosed with idiopathic male infertility and had abnormal sperm parameters, and 15 subjects had normal sperm parameters with proven fertility. Serum Se, semen Se, and semen TAC levels were significantly different in the fertile and infertile groups (p<0.01, p<0.001, and p<0.001, respectively). However, serum TAC, serum, and seminal plasma CoQ-10 levels did not differ between fertile and infertile groups. When the levels of the measured parameters were compared in serum and seminal plasma, serum levels of Se were found to be correlated positively with the semen levels in all subjects included into the study (N=59) (r=0.46, p<0.01). A relationship was found between neither serum and semen levels of TAC nor between serum and semen levels of CoQ-10. Correlations among measured serum and semen parameters with sperm parameters demonstrated that both the serum and semen levels of Se were correlated positively with spermatozoa concentration, motility, and morphology. Additionally, seminal plasma levels of TAC correlated positively with all these sperm parameters. On the other hand, seminal plasma levels of CoQ-10 correlated only with sperm morphology but not with concentration or motility. No relationship was observed between serum levels of TAC or serum levels of CoQ-10 and sperm parameters. In conclusion, serum and seminal plasma Se deficiency may be a prominent determinant of abnormal sperm parameters and idiopathic male infertility. Measurement of serum Se levels may help determine nutritional status and antioxidant capacity in infertile patients, which may help distinguish those patients who will benefit from supplementation therapy. PMID- 24752971 TI - Effects of exposure to dietary chromium on tissue mineral contents in rats fed diets with fiber. AB - This study evaluated the effects of diets with fiber (cellulose and/or pectin) supplemented with chromium(III) on homeostasis of selected minerals in femurs, thigh muscles, livers, and kidneys of rats. For 6 weeks, male rats were fed experimental diets: a fiber-free diet (FF), a diet containing 5% cellulose (CEL), 5% pectin (PEC), or 2.5% cellulose and 2.5% pectin (CEL+PEC). These diets had 2.53 or 0.164 mg Cr/kg diet. The tissue levels of Ca, Mg, Zn, Fe, and Cr were determined by using atomic absorption spectrometry. Supplementing diets with Cr resulted in significantly higher Cr levels in the femurs of rats fed the CEL diet and significantly higher Cr and Fe levels in the rats fed the CEL+PEC diet compared to the rats fed FF diet. Muscle Ca content was significantly lower in the rats fed the CEL+PEC+Cr diet compared to the rats fed FF+Cr diet. The rats consuming the PEC+Cr diet had the highest liver Cr content. The highest kidney Zn content was observed in the rats fed diets containing Cr and one type of fiber. These results indicate that diets containing chromium at elevated dose and fiber have a significant effect on the mineral balance in rat tissues. PMID- 24752973 TI - Zinc chloride inhibits human lens epithelial cell migration and proliferation involved in TGF-beta1 and TNF-alpha signaling pathways in HLE B-3 cells. AB - Zinc is one of the most abundant essential elements in the human body, which is an essential, coenzyme-like component of many enzymes, and is indispensable to their functions. However, high levels of zinc ions can lead to cell damage. In the present study, we explored the effects of high concentrations of zinc chloride (ZnCl2) on lens epithelial cell proliferation and migration and further investigated the effects of different concentrations of ZnCl2 on caspase-9 and caspase-12, transforming growth factor-beta 1 (TGF-beta1), and tumor necrosis factor-alpha (TNF-alpha). We found that ZnCl2 could inhibit human lens epithelial (HLE) B-3 cell migration and induce apoptosis/necrosis. In addition, ZnCl2 can efficiently decrease the expressions of caspase-9 and caspase-12, increase the expression of TNF-alpha at both gene and protein levels, and thus induces cell death. Taken together, our results indicate that ZnCl2 can inhibit HLE B-3 cell migration and proliferation by decreasing the expression of TGF-beta1 and increasing the expression of TNF-alpha and finally lead to HLE B-3 cell death. PMID- 24752975 TI - How women in Bangladesh confront the stigma of childlessness: agency, resilience, and resistance. AB - In a context where motherhood is an integral part of a woman's stereotype, being childless is a devastating experience. We explore how these so-called deviant women manage this situation. The objective of this article is to contribute to the debate regarding infertile women's agency, resilience, and resistance. This article is based on anthropological fieldwork among urban middle-class and rural poor women. Their life histories reveal that childless women in Bangladesh, a pro natalist, patriarchal society, are not passive victims, but rather actively fight their stigmatization and manage to survive. The childless women follow overt and covert strategies to overcome their stigmatized identity and create space for themselves in various innovative ways. The women do not resist in a coordinated way as a group, but do so individually. Given the collective nature of a society like rural Bangladesh, we believe that the women's individual acts will eventually have collective effects. PMID- 24752974 TI - Multipurpose assessment for the quantification of Vibrio spp. and total bacteria in fish and seawater using multiplex real-time polymerase chain reaction. AB - BACKGROUND: This study describes the first multiplex real-time polymerase chain reaction assay developed, as a multipurpose assessment, for the simultaneous quantification of total bacteria and three Vibrio spp. (V. parahaemolyticus, V. vulnificus and V. anguillarum) in fish and seawater. The consumption of raw finfish as sushi or sashimi has been increasing the chance of Vibrio outbreaks in consumers. Freshness and quality of fishery products also depend on the total bacterial populations present. RESULTS: The detection sensitivity of the specific targets for the multiplex assay was 1 CFU mL-1 in pure culture and seawater, and 10 CFU g-1 in fish. While total bacterial counts by the multiplex assay were similar to those obtained by cultural methods, the levels of Vibrio detected by the multiplex assay were generally higher than by cultural methods of the same populations. Among the natural samples without Vibrio spp. inoculation, eight out of 10 seawater and three out of 20 fish samples were determined to contain Vibrio spp. CONCLUSION: Our data demonstrate that this multiplex assay could be useful for the rapid detection and quantification of Vibrio spp. and total bacteria as a multipurpose tool for surveillance of fish and water quality as well as diagnostic method. PMID- 24752976 TI - Toll-like receptor 2/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage. AB - OBJECTIVE: Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH remain elusive. Our previous studies suggested that Toll-like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH-induced brain injury. However, it is unclear how TLR2 functions in ICH-induced inflammatory injury and how TLR2 interacts with TLR4. METHODS: The role of TLR2 and TLR2/TLR4 heterodimerization in ICH-induced inflammatory injury was investigated in both in vivo and in vitro models of ICH. RESULTS: TLR2 mediated ICH-induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin (Hb), but not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimers. MyD88 (myeloid differentiation primary response gene 88), but not TRIF (Toll/IR-1 domain containing adaptor protein inducing interferon-beta), was required for ICH induced TLR2/TLR4 heterodimerization. Mutation of MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization. INTERPRETATION: Our results suggest that a novel TLR2/TLR4 heterodimer induced by Hb initiates inflammatory injury in ICH. Interfering with the assembly of the TLR2/TLR4 heterodimer may be a novel target for developing effective treatment of ICH. PMID- 24752977 TI - Surgical management of localized soft tissue tumors. AB - Soft tissue tumors are rare and can arise from a variety of soft tissues and viscera in a variety of body sites. Their management requires a thorough understanding of the biology of the different histologies and molecular subtypes as well as the constraints of specific anatomic sites. The surgical approach has undergone significant changes thanks to a better understanding of the natural history of the different histologic subtypes, the importance of site, and the different sensitivity to available drugs. The soft tissue tumor family includes 3 major, distinct categories: desmoid-type fibromatosis, soft tissue sarcoma, and gastrointestinal stromal tumor. In general, limb-sparing and function-sparing approaches should be used when feasible for tumors located in the extremities and girdles. Resections of adherent structures/viscera, which may be close but not invaded, may be needed in tumors arising in the retroperitoneum/abdomen to minimize microscopic intralesional margins, maximize local tumor control, and possibly improve survival. Margins of resection and the use of adjuvant/neadjuvant radiation therapy and/or chemotherapy are contingent on an accurate histologic diagnosis. Treatment planning should include multidisciplinary consultation to determine optimal therapy, taking into consideration tumor histology, site and extent of the disease, its natural history and sensitivity to available treatments, surgical challenges, and-of course-quality of life. PMID- 24752978 TI - All-atom polarizable force field for DNA based on the classical Drude oscillator model. AB - Presented is a first generation atomistic force field (FF) for DNA in which electronic polarization is modeled based on the classical Drude oscillator formalism. The DNA model is based on parameters for small molecules representative of nucleic acids, including alkanes, ethers, dimethylphosphate, and the nucleic acid bases and empirical adjustment of key dihedral parameters associated with the phosphodiester backbone, glycosidic linkages, and sugar moiety of DNA. Our optimization strategy is based on achieving a compromise between satisfying the properties of the underlying model compounds in the gas phase targeting quantum mechanical (QM) data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude FF yields stable DNA duplexes on the 100-ns time scale and satisfactorily reproduce (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII substates of B form DNA. Consistency with the gas phase QM data for the model compounds is significantly better for the Drude model as compared to the CHARMM36 additive FF, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA. PMID- 24752979 TI - Comparison of simulated parallel transmit body arrays at 3 T using excitation uniformity, global SAR, local SAR, and power efficiency metrics. AB - PURPOSE: We compare the performance of eight parallel transmit (pTx) body arrays with up to 32 channels and a standard birdcage design. Excitation uniformity, local specific absorption rate (SAR), global SAR, and power metrics are analyzed in the torso at 3 T for radiofrequency (RF)-shimming and 2-spoke excitations. METHODS: We used a fast cosimulation strategy for field calculation in the presence of coupling between transmit channels. We designed spoke pulses using magnitude least squares optimization with explicit constraint of SAR and power and compared the performance of the different pTx coils using the L-curve method. RESULTS: PTx arrays outperformed the conventional birdcage coil in all metrics except peak and average power efficiency. The presence of coupling exacerbated this power efficiency problem. At constant excitation fidelity, the pTx array with 24 channels arranged in three z-rows could decrease local SAR more than 4 fold (2-fold) for RF-shimming (2-spoke) compared to the birdcage coil for pulses of equal duration. Multi-row pTx coils had a marked performance advantage compared to single row designs, especially for coronal imaging. CONCLUSION: PTx coils can simultaneously improve the excitation uniformity and reduce SAR compared to a birdcage coil when SAR metrics are explicitly constrained in the pulse design. PMID- 24752980 TI - Endocannabinoids and energy homeostasis: an update. AB - The endocannabinoid system (ECS) is a widespread intercellular signaling system that plays a critical role in energy homeostasis, meant as the precise matching of caloric intake with energy expenditure which normally keeps body weight stable over time. Complex interactions between environmental and neurohormonal systems directly contribute to the balance of energy homeostasis. This review highlights established and more recent data on the brain circuits in which the ECS plays an important regulatory role, with focus on the hypothalamus, a region where numerous interacting systems regulating feeding, satiety, stress, and other motivational states coexist. Although not meant as an exhaustive review of the field, this article will discuss how endocannabinoid tone, in addition to reinforcing reward circuitries and modulating food intake and the salience of food, controls lipid and glucose metabolism in several peripheral organs, particularly the liver and adipose tissue. Direct actions in the skeletal muscle and pancreas are also emerging and are briefly discussed. This review provides new perspectives into endocannabinoid control of the neurochemical causes and consequences of energy homeostasis imbalance, a knowledge that might lead to new potential treatments for obesity and related morbidities. PMID- 24752981 TI - Erratum to: Breast Cancer Clinical Characteristics and Outcomes in Trinidad and Tobago. PMID- 24752982 TI - Exposure to Traumatic Experiences Among Asylum Seekers from Eritrea and Sudan During Migration to Israel. AB - Little is known about the experiences of displaced individuals en route to destination countries. We investigated the reported prevalence of exposure to traumatic experiences during migration among a consecutive sample of adult asylum seekers (n = 895 Eritrean, n = 149 Sudanese) who sought health services in the Physicians for Human Rights Open-Clinic in Israel. Percentage of Eritrean and Sudanese men and women who reported witnessing violence (Eritrea: men: 41.3 %, women: 29.3 %; Sudan: men: 16.8 %, women: 22.2 %) and/or being a victim of violence (Eritrea: men: 56.0 %, Women: 34.9 %; Sudan: men: 51.9 % women: 44.4 %) during migration varied by gender and country of origin. Findings highlight the need for a well-coordinated international cooperation to document and prevent these transgressions. PMID- 24752983 TI - Burial of nonpolar surface area and thermodynamic stabilization of globins as a function of chain elongation. AB - Proteins are biosynthesized from N to C terminus before they depart from the ribosome and reach their bioactive state in the cell. At present, very little is known about the evolution of conformation and the free energy of the nascent protein with chain elongation. These parameters critically affect the extent of folding during ribosome-assisted biosynthesis. Here, we address the impact of vectorial amino acid addition on the burial of nonpolar surface area and on the free energy of native-like structure formation in the absence of the ribosomal machinery. We focus on computational predictions on proteins bearing the globin fold, which is known to encompass the 3/3, 2/2, and archaeal subclasses. We find that the burial of nonpolar surface increases progressively with chain elongation, leading to native-like conformations upon addition of the last C terminal residues, corresponding to incorporation of the last two helices. Additionally, the predicted folding entropy for generating native-like structures becomes less unfavorable at nearly complete chain lengths, suggesting a link between the late burial of nonpolar surface and water release. Finally, the predicted folding free energy takes a progressive favorable dip toward more negative values, as the chain gets longer. These results suggest that thermodynamic stabilization of the native structure of newly synthesized globins during translation in the cell is significantly enhanced as the chain elongates. This is especially true upon departure of the last C-terminal residues from the ribosomal tunnel, which hosts ca., 30-40 amino acids. Hence, we propose that release from the ribosome is a crucial step in the life of single-domain proteins in the cell. PMID- 24752984 TI - Measuring membrane protein bond orientations in nanodiscs via residual dipolar couplings. AB - Membrane proteins are involved in numerous vital biological processes. To understand membrane protein functionality, accurate structural information is required. Usually, structure determination and dynamics of membrane proteins are studied in micelles using either solution state NMR or X-ray crystallography. Even though invaluable information has been obtained by this approach, micelles are known to be far from ideal mimics of biological membranes often causing the loss or decrease of membrane protein activity. Recently, nanodiscs, which are composed of a lipid bilayer surrounded by apolipoproteins, have been introduced as a more physiological alternative than micelles for NMR investigations on membrane proteins. Here, we show that membrane protein bond orientations in nanodiscs can be obtained by measuring residual dipolar couplings (RDCs) with the outer membrane protein OmpX embedded in nanodiscs using Pf1 phage as an alignment medium. The presented collection of membrane protein RDCs in nanodiscs represents an important step toward more comprehensive structural and dynamical NMR-based investigations of membrane proteins in a natural bilayer environment. PMID- 24752985 TI - Fetal intracardiac rhabdomyoma in beckwith-wiedemann syndrome. AB - Fetal cardiac tumors are a rare finding in prenatal ultrasonography. Most of them are rhabdomyoma, which are thought to be pathognomonic for tuberous sclerosis complex. We present an infant with prenatally diagnosed cardiac rhabdomyoma (CR), who was found to suffer from Beckwith-Wiedemann syndrome (BWS). This congenital overgrowth syndrome is characterized by macrosomia, macroglossia, omphalocele, hypoglycemia, and hemihypertrophy. BWS patients have an increased risk for formation of benign and malignant tumors, typically intra-abdominally located, but, to the best of our knowledge, fetal CRs have not been reported before. BWS must be added to the list of differential diagnoses and to the prenatal counseling of the parents in cases of prenatal detection of CR. PMID- 24752986 TI - Association between response to pegylated interferon/ribavirin therapy and ribavirin levels. PMID- 24752987 TI - Higher versus lower protein intake in formula-fed low birth weight infants. AB - BACKGROUND: The ideal quantity of dietary protein for formula-fed low birth weight infants is still a matter of debate. Protein intake must be sufficient to achieve normal growth without negative effects such as acidosis, uremia, and elevated levels of circulating amino acids. OBJECTIVES: To determine whether higher (>= 3.0 g/kg/d) versus lower (< 3.0 g/kg/d) protein intake during the initial hospital stay of formula-fed preterm infants or low birth weight infants (< 2.5 kilograms) results in improved growth and neurodevelopmental outcomes without evidence of short- and long-term morbidity.To examine the following distinctions in protein intake. 1. Low protein intake if the amount was less than 3.0 g/kg/d. 2. High protein intake if the amount was equal to or greater than 3.0 g/kg/d but less than 4.0 g/kg/d. 3. Very high protein intake if the amount was equal to or greater than 4.0 g/kg/d.If the reviewed studies combined alterations of protein and energy, subgroup analyses were to be carried out for the planned categories of protein intake according to the following predefined energy intake categories. 1. Low energy intake: less than 105 kcal/kg/d. 2. Medium energy intake: greater than or equal to 105 kcal/kg/d and less than or equal to 135 kcal/kg/d. 3. High energy intake: greater than 135 kcal/kg/d.As the Ziegler-Fomon reference fetus estimates different protein requirements for infants based on birth weight, subgroup analyses were to be undertaken for the following birth weight categories. 1. < 800 grams. 2. 800 to 1199 grams. 3. 1200 to 1799 grams. 4. 1800 to 2499 grams. SEARCH METHODS: The standard search methods of the Cochrane Neonatal Review Group were used. MEDLINE, CINAHL, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library) were searched. SELECTION CRITERIA: Randomized controlled trials contrasting levels of formula protein intake as low (< 3.0 g/kg/d), high (>= 3.0 g/kg/d but < 4.0 g/kg/d), or very high (>= 4.0 g/kg/d) in formula-fed hospitalized neonates weighing less than 2.5 kilograms were included. Studies were excluded if infants received partial parenteral nutrition during the study period or were fed formula as a supplement to human milk. Studies in which nutrients other than protein also varied were added in a post-facto analysis. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used. MAIN RESULTS: Five studies compared low versus high protein intake. Improved weight gain and higher nitrogen accretion were demonstrated in infants receiving formula with higher protein content while other nutrients were kept constant. No significant differences were seen in rates of necrotizing enterocolitis, sepsis, or diarrhea.One study compared high versus very high protein intake during and after an initial hospital stay. Very high protein intake promoted improved gain in length at term, but differences did not remain significant at 12 weeks corrected age. Three of the 24 infants receiving very high protein intake developed uremia.A post-facto analysis revealed further improvement in all growth parameters in infants receiving formula with higher protein content. No significant difference in the concentration of plasma phenylalanine was noted between high and low protein intake groups. However, one study (Goldman 1969) documented a significantly increased incidence of low intelligence quotient (IQ) scores among infants of birth weight less than 1300 grams who received a very high protein intake (6 to 7.2 g/kg). AUTHORS' CONCLUSIONS: Higher protein intake (>= 3.0 g/kg/d but < 4.0 g/kg/d) from formula accelerates weight gain. However, limited information is available regarding the impact of higher formula protein intake on long-term outcomes such as neurodevelopmental abnormalities. Available evidence is not adequate to permit specific recommendations regarding the provision of very high protein intake (> 4.0 g/kg/d) from formula during the initial hospital stay or after discharge. PMID- 24752988 TI - MRI in transverse myelitis. AB - Transverse myelitis is an acute inflammatory disease of the spinal cord, characterized by rapid onset of bilateral neurological symptoms. Weakness, sensory disturbance, and autonomic dysfunction evolve over hours or days, most progressing to maximal clinical severity within 10 days of onset. At maximal clinical severity, half will have a paraparesis, and almost all patients have sensory disturbance and bladder dysfunction. Residual disability is divided equally between severe, moderate and minimal or none. The causes of transverse myelitis are diverse; etiologies implicated include demyelinating conditions, collagen vascular disease, and parainfectious causes, however, despite extensive diagnostic work-up many cases are considered idiopathic. Due to heterogeneity in pathogenesis, and the similarity of its clinical presentation with those of various noninflammatory myelopathies, transverse myelitis has frequently been viewed as a diagnostic dilemma. However, as targeted therapies to optimize patient outcome develop, timely identification of the underlying etiology is becoming increasingly important. In this review, we describe the imaging and clinical features of idiopathic and disease-associated transverse myelitis and its major differentials, with discussion of how MR imaging features assist in the identification of various sub-types of transverse myelitis. We will also discuss the potential for advanced MR techniques to contribute to diagnosis and prognostication. PMID- 24752989 TI - Impairments in experience-dependent scaling and stability of hippocampal place fields limit spatial learning in a mouse model of Alzheimer's disease. AB - Impaired spatial memory characterizes many mouse models for Alzheimer's disease, but we understand little about how this trait arises. Here, we use a transgenic model of amyloidosis to examine the relationship between behavioral performance in tests of spatial navigation and the function of hippocampal place cells. We find that amyloid precursor protein (APP) mice require considerably more training than controls to reach the same level of performance in a water maze task, and recall the trained location less well 24 h later. At a single cell level, place fields from control mice become more stable and spatially restricted with repeated exposure to a new environment, while those in APP mice improve less over time, ultimately producing a spatial code of lower resolution, accuracy, and reliability than controls. The limited refinement of place fields in APP mice likely contributes to their delayed water maze acquisition, and provides evidence for circuit dysfunction underlying cognitive impairment. PMID- 24752990 TI - Evaluating TBK1 as a therapeutic target in cancers with activated IRF3. AB - TBK1 (TANK-binding kinase 1) is a noncanonical IkappaB protein kinase that phosphorylates and activates downstream targets such as IRF3 and c-Rel and, mediates NF-kappaB activation in cancer. Previous reports demonstrated synthetic lethality of TBK1 with mutant KRAS in non-small cell lung cancer (NSCLC); thus, TBK1 could be a novel target for treatment of KRAS-mutant NSCLC. Here, the effect of TBK1 on proliferation in a panel of cancer cells by both genetic and pharmacologic approaches was evaluated. In KRAS-mutant cancer cells, reduction of TBK1 activity by knockdown or treatment with TBK1 inhibitors did not correlate with reduced proliferation in a two-dimensional viability assay. Verification of target engagement via reduced phosphorylation of S386 of IRF3 (pIRF3(S386)) was difficult to assess in NSCLC cells due to low protein expression. However, several cell lines were identified with high pIRF3(S386) levels after screening a large panel of cell lines, many of which also harbor KRAS mutations. Specifically, a large subset of KRAS-mutant pancreatic cancer cell lines was uncovered with high constitutive pIRF3(S386) levels, which correlated with high levels of phosphorylated S172 of TBK1 (pTBK1(S172)). Finally, TBK1 inhibitors dose-dependently inhibited pIRF3(S386) in these cell lines, but this did not correlate with inhibition of cell growth. Taken together, these data demonstrate that the regulation of pathways important for cell proliferation in some NSCLC, pancreatic, and colorectal cell lines is not solely dependent on TBK1 activity. IMPLICATIONS: TBK1 has therapeutic potential under certain contexts and phosphorylation of its downstream target IRF3 is a biomarker of TBK1 activity. PMID- 24752991 TI - The use of semen evaluation and assisted reproduction in Spix's macaws in terms of species conservation. AB - The Spix's macaw (Cyanopsitta spixii) is the rarest parrot on earth. The remaining captive population consists of 79 individuals. Captive propagation is ongoing to increase the number of individuals for future reintroduction back into the wild. Unfortunately, from 2004 to 2012, only 33 chicks hatched from 331 eggs. Semen evaluation and assisted reproduction might help to overcome this problem. Therefore, a recently developed electro-stimulated semen collection technique was used in Spix's macaws. Semen collection was successful in 39 of 78 attempts in 10 out of 17 males. Examination of the semen included evaluation of volume, color, consistency, contaminations and pH, as well as determination of motility, viability, morphology, concentration, and total count of spermatozoa. The median volume of semen samples was 5.6 ul. On average, 34.7 +/- 21.9% (median 30%) of the sperm were motile and 23.1 +/- 22.1% (median 16.5%) were progressively motile. In addition to spermatozoa, round cells were detected in the samples. Median sperm concentration was 15,500/ul (range 500-97,500/ul) and median viability was 50% (range 5-87%). Morphological examination revealed in 26.5% normal spermatozoa, high numbers of malformations of the head (50.2%) and tail region (20.5%), with 29% of all sperm showing multiple abnormalities. Artificial insemination was performed in three females; two eggs laid after artificial insemination had spermatozoa present on the perivitelline layer, suggesting the possible success of the insemination technique. Although no fertilization could be demonstrated, these preliminary results are promising, as they indicate that assisted reproduction might be a tool for species conservation in the Spix's macaw. PMID- 24752992 TI - GC separation of enantiomers of alkyl esters of 2-bromo substituted carboxylic acids enantiomers on 6-TBDMS-2,3-di-alkyl- beta- and gamma-cyclodextrin stationary phases. AB - The gas chromatographic separation of enantiomers of 2-Br carboxylic acid derivatives was studied on four different 6-TBDMS-2,3-di-O-alkyl- beta- and gamma-CD stationary phases. The differences in thermodynamic data {DeltaH and DeltaS} for the 15 structurally related racemates were evaluated. The influence of structure differences in the alkyl substituents covalently attached to the stereogenic carbon atom, as well as in the ester group of the homologous analytes, and the selectivity of modified beta- and gamma- cyclodextrin derivatives was studied in detail. The cyclodextrin cavity size, as well as elongation of alkyl substituents in positions 2 and 3 of 6-TBDMS-beta-CD, also affected their selectivity. The quality of enantiomeric separations is influenced mainly by alkyl chains of the ester group of the molecule and this appears to be independent of the CD stationary phase used. In some cases the separations occur as the result of external adsorption rather than inclusion complexations with the chiral selector. It was found that the temperature dependencies of the selectivity factor were nonlinear. PMID- 24752993 TI - Meta-analysis and aggregation of multiple published prediction models. AB - Published clinical prediction models are often ignored during the development of novel prediction models despite similarities in populations and intended usage. The plethora of prediction models that arise from this practice may still perform poorly when applied in other populations. Incorporating prior evidence might improve the accuracy of prediction models and make them potentially better generalizable. Unfortunately, aggregation of prediction models is not straightforward, and methods to combine differently specified models are currently lacking. We propose two approaches for aggregating previously published prediction models when a validation dataset is available: model averaging and stacked regressions. These approaches yield user-friendly stand-alone models that are adjusted for the new validation data. Both approaches rely on weighting to account for model performance and between-study heterogeneity but adopt a different rationale (averaging versus combination) to combine the models. We illustrate their implementation in a clinical example and compare them with established methods for prediction modeling in a series of simulation studies. Results from the clinical datasets and simulation studies demonstrate that aggregation yields prediction models with better discrimination and calibration in a vast majority of scenarios, and results in equivalent performance (compared to developing a novel model from scratch) when validation datasets are relatively large. In conclusion, model aggregation is a promising strategy when several prediction models are available from the literature and a validation dataset is at hand. The aggregation methods do not require existing models to have similar predictors and can be applied when relatively few data are at hand. PMID- 24752994 TI - Neuropathological features of multiple system atrophy with cognitive impairment. AB - Cognitive impairment (CI) is an exclusion criterion for the diagnosis of multiple system atrophy (MSA), according to the second consensus statement. This view was recently challenged by patients with pathologically confirmed MSA who were reported to have dementia. With an aim to investigate the pathological substrate of CI in MSA, quantitative assessment of the glial and neuronal cytoplasmic inclusions and semiquantitative assessment of neuronal loss in the cortical and limbic regions was performed. No differences in the severity of these MSA-related pathological findings were identified between nine MSA cases with CI and nine MSA cases with normal cognition. Alzheimer's-related pathological changes, cerebral amyloid angiopathy, and cerebrovascular disease did not differ between the two MSA groups. MSA-specific alpha-synuclein and secondary pathological conditions were not more severe in MSA cases with CI, suggesting that although CI may be intrinsic to the MSA disease process, further investigation into the pathological basis of cognitive impairment in MSA is warranted. PMID- 24752995 TI - Computational models reveal genotype-phenotype associations in Saccharomyces cerevisiae. AB - Genome sequencing is essential to understand individual variation and to study the mechanisms that explain relations between genotype and phenotype. The accumulated knowledge from large-scale genome sequencing projects of Saccharomyces cerevisiae isolates is being used to study the mechanisms that explain such relations. Our objective was to undertake genetic characterization of 172 S. cerevisiae strains from different geographical origins and technological groups, using 11 polymorphic microsatellites, and computationally relate these data with the results of 30 phenotypic tests. Genetic characterization revealed 280 alleles, with the microsatellite ScAAT1 contributing most to intrastrain variability, together with alleles 20, 9 and 16 from the microsatellites ScAAT4, ScAAT5 and ScAAT6. These microsatellite allelic profiles are characteristic for both the phenotype and origin of yeast strains. We confirm the strength of these associations by construction and cross validation of computational models that can predict the technological application and origin of a strain from the microsatellite allelic profile. Associations between microsatellites and specific phenotypes were scored using information gain ratios, and significant findings were confirmed by permutation tests and estimation of false discovery rates. The phenotypes associated with higher number of alleles were the capacity to resist to sulphur dioxide (tested by the capacity to grow in the presence of potassium bisulphite) and the presence of galactosidase activity. Our study demonstrates the utility of computational modelling to estimate a strain technological group and phenotype from microsatellite allelic combinations as tools for preliminary yeast strain selection. PMID- 24752996 TI - Persistent viremia in human immunodeficiency virus/hepatitis B coinfected patients undergoing long-term tenofovir: virological and clinical implications. AB - Tenofovir (TDF) is considered the ideal treatment for patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus (HBV). However, certain coinfected patients exhibit incomplete viral suppression, with persistent, and sometimes transient, bouts of HBV replication. The reasons for this, including clinical effect, are unclear. A total of 111 HIV-HBV-infected patients undergoing TDF-containing antiretroviral therapy were prospectively followed. Serum HBV-DNA viral load, hepatitis surface (HBsAg) and e antigen (HBeAg) status were obtained at baseline and every 6-12 months. Amino acid (aa) changes on the polymerase gene were assessed using direct sequencing after nested polymerase chain reaction in patients with persistent viremia (PV). After a median of 74.7 months (interquartile range: 33.4-94.7), virological response (VR; <60 IU/mL) occurred in 96 of 111 (86.5%) patients. Of these, 86 of 96 (89.6%) remained completely undetectable during follow-up (stabilized VR). The remaining 10 of 96 (10.4%) patients had a transient blip of detectable HBV-DNA (transient PV), during which time 9 of 9 (100%) with available samples had detectable plasma TDF. Low-level PV (LL-PV; 61-2,000 IU/mL) was observed in 11 of 111 (9.9%) patients, the majority of which had detectable plasma TDF (8 of 9; 88.9%). High-level PV (>2,000 IU/mL) was rare (4 of 111; 3.6%) and was associated with nonadherence. At TDF initiation, patients with stabilized VR had significantly higher nadir CD4(+) count, compared to those with transient PV (P = 0.006) or LL-PV (P = 0.04). No consistent aa changes, other than those associated with lamivudine resistance, were observed in patients with persistent viremia. Importantly, HBeAg loss, HBeAg seroconversion, and HBsAg loss only occurred in patients with stabilized VR. Two patients with stabilized VR developed hepatocellular carcinoma and 2 with LL PV died, 1 of a liver-related cause. CONCLUSION: Suboptimal HBV control during TDF treatment has a negative effect on serological outcomes, but not necessarily clinical events. Immunoregulation may provide more insight into this phenomenon. PMID- 24752997 TI - Inactivation of Geobacillus stearothermophilus spores in low-acid foods by pressure-assisted thermal processing. AB - BACKGROUND: The effect of pressure-assisted thermal processing (PATP) on the inactivation of Geobacillus stearothermophilus spores was determined in deionized water, cooked ground beef, egg patty mince, whole milk and mashed potatoes at 105 degrees C under 500 and 700 MPa. RESULTS: The numbers of G. stearothermophilus spores in deionized water and milk were reduced by more than 6 log CFU mL(-1) at 700 MPa and 105 degrees C, whereas those in cooked beef were reduced by 4.27 log CFU g(-1). The inactivation patterns of G. stearothermophilus spores in all food matrices followed nonlinear behavior, showing that Weibull model fitted well to the inactivation curves of G. stearothermophilus spores in low-acid foods. CONCLUSION: The complex food matrices caused a protective effect on the inactivation of G. stearothermophilus spores during PATP. The results provide useful information in inactivation kinetics of bacterial spores for validating PATP-processed low-acid foods. PMID- 24752998 TI - Combined intravoxel incoherent motion and diffusion tensor imaging of renal diffusion and flow anisotropy. AB - PURPOSE: We used a combined intravoxel incoherent motion-diffusion tensor imaging (IVIM-DTI) methodology to distinguish structural from flow effects on renal diffusion anisotropy. METHODS: Eight volunteers were examined with IVIM-DTI at 3T with 20 diffusion directions and 10 b-values. Mean diffusivity (MD) and fractional anisotropy (FA) from DTI analysis were calculated for low (b <= 200 s/mm(2) ), high (b > 200 s/mm(2) ), and full b-value ranges. IVIM-parameters perfusion-fraction fP , pseudo-diffusivity Dp , and tissue-diffusivity Dt were first calculated independently on a voxelwise basis for all directions. After estimating a fixed isotropic fp from these data, global anisotropies of Dt and Dp in the cortex and medulla were determined in a constrained cylindrical description and visualized using polar plots and cosine scatterplots. RESULTS: For all b-value ranges, medullary FA was significantly higher than that of the cortex. The corticomedullary difference was smaller for the high b-value range. Significantly higher fp and Dt were determined for the cortex and showed a significantly higher directional variance in the medulla. Polar plot analysis displayed nearly isotropic Dp and Dt in the cortex and anisotropy in the medulla. CONCLUSION: Both flow and microstructure apparently contribute to the medullary diffusion anisotropy. The described novel method may be useful in separating decreased tubular flow from irreversible structural tubular damage, for example, in diabetic nephropathy or during allograft rejection. PMID- 24752999 TI - Early retirement in cancer patients with or without comorbid mental health conditions: a prospective cohort study. AB - BACKGROUND: The authors investigated whether cancer patients who have comorbid mental health disorders (MD) are at greater risk of early retirement compared with those who do not have MD. METHODS: Individuals ages 18 to 55 years from a consecutive sample of patients who were admitted for inpatient oncologic treatment were interviewed using structured clinical interviews to ascertain MD. The patients were followed for 15 months, and the date of early retirement was documented. Rates of early retirement per 100 person-years (py) in patients with and without MD were compared using multivariate Poisson regression models. RESULTS: At baseline, 491 patients were interviewed, and 150 of those patients (30.6%) were diagnosed with MD. Forty-one patients began full early retirement during follow-up. In patients with MD, the incidence of early retirement was 9.3 per 100 py compared with 6.1 per 100 py in mentally healthy patients. The crude rate ratio (RR) was 1.5 (95% confidence interval [CI], 0.8-2.8). The effect of MD on early retirement was modified in part by income: in patients with low income, the adjusted RR was 11.7, whereas no effect was observed in higher income groups. Patients with depression were at greater risk of retirement when they had higher income (RR, 3.4; P = .05). The effects of anxiety (RR, 2.4; P = .05), adjustment disorders (RR, 1.7; P = .21), and alcohol dependence (RR, 1.8; P = .40) on early retirement were equal across income groups. CONCLUSIONS: Mental health conditions are risk factors for early retirement in cancer patients, although this effect differs according to the type of disorder and the patient's income level. PMID- 24753000 TI - DEPDC5 does it all: shared genetics for diverse epilepsy syndromes. PMID- 24753001 TI - Hand-rearing, growth, and development of common loon (Gavia immer) chicks. AB - Common loon chicks were reared in captivity in association with studies to evaluate the effects of radiotransmitter implants and to assess the ecological risk of dietary methylmercury. Here we report on hatching and rearing methods used to successfully raise chicks to 105 days of age. We experienced a 91.5% hatch rate, and 89.6% of loon chicks survived to the end of the study at 105 days. Baseline information on observed rates of fish consumption, behavioral development, and growth patterns are provided. Husbandry techniques are provided that should prove valuable to wildlife rehabilitators caring for abandoned or injured loons, and biologists contemplating methods for restoring loons to areas within their former breeding range. PMID- 24753002 TI - Redox-switchable supramolecular graft polymer formation via ferrocene cyclodextrin assembly. AB - The redox switchable formation of very well-defined supramolecular graft polymers in aqueous solution driven by host-guest interactions between ferrocene (Fc) and cyclodextrin (CD) is presented. The Fc-containing acrylic backbone copolymer (PDMA-stat-Fc) is prepared via reversible addition-fragmentation chain transfer (RAFT) copolymerization of N,N-dimethyl-acrylamide (DMA) and the novel monomer N (ferrocenoylmethyl)acrylamide (NFMA). Via the RAFT process, copolymers containing variable Fc ratios (5-10 mol%) are prepared, affording polymers of molecular masses of close to 11,000 g mol(-1) and molar mass dispersities (D) of 1.2. The beta-cyclodextrin (beta-CD) containing building block is synthesized via RAFT polymerization, too, in order to afford a polymer with well-defined molecular mass and low dispersity (Mn = 10 300 g mol(-1) , D = 1.1), employing a propargyl functionalized chain transfer agent for the polymerization of N,N diethylacrylamide (DEA). The polymerization product is subsequently terminated with beta-CD via the regiospecific copper (I)-catalyzed 1,3-cycloaddition (PDEA betaCD). Host-guest interactions between Fc and CD lead to the formation of supramolecular graft-polymers, verified via nuclear Overhauser enhancement spectroscopy (NOESY). Importantly, their redox-responsive character is clearly confirmed via cyclic voltammetry (CV). The self-assembly of the statistical Fc containing lateral polymer chain in aqueous solution leads to mono- and multi core micelle-aggregates evidenced via TEM. Only diffused cloud-like, non spherical nanostructures are observed after addition of PDEA-betaCD (TEM). PMID- 24753003 TI - Effective automated prediction of vertebral column pathologies based on logistic model tree with SMOTE preprocessing. AB - This study develops a logistic model tree based automation system based on for accurate recognition of types of vertebral column pathologies. Six biomechanical measures are used for this purpose: pelvic incidence, pelvic tilt, lumbar lordosis angle, sacral slope, pelvic radius and grade of spondylolisthesis. A two phase classification model is employed in which the first step is preprocessing the data by use of Synthetic Minority Over-sampling Technique (SMOTE), and the second one is feeding the classifier Logistic Model Tree (LMT) with the preprocessed data. We have achieved an accuracy of 89.73 %, and 0.964 Area Under Curve (AUC) in computer based automatic detection of the pathology. This was validated via a 10-fold-cross-validation experiment conducted on clinical records of 310 patients. The study also presents a comparative analysis of the vertebral column data with the use of several machine learning algorithms. PMID- 24753004 TI - A maximum likelihood method for secondary analysis of nested case-control data. AB - Many epidemiological studies use a nested case-control (NCC) design to reduce cost while maintaining study power. Because NCC sampling is conditional on the primary outcome, routine application of logistic regression to analyze a secondary outcome will generally be biased. Recently, many studies have proposed several methods to obtain unbiased estimates of risk for a secondary outcome from NCC data. Two common features of all current methods requires that the times of onset of the secondary outcome are known for cohort members not selected into the NCC study and the hazards of the two outcomes are conditionally independent given the available covariates. This last assumption will not be plausible when the individual frailty of study subjects is not captured by the measured covariates. We provide a maximum-likelihood method that explicitly models the individual frailties and also avoids the need to have access to the full cohort data. We derive the likelihood contribution by respecting the original sampling procedure with respect to the primary outcome. We use proportional hazard models for the individual hazards, and Clayton's copula is used to model additional dependence between primary and secondary outcomes beyond that explained by the measured risk factors. We show that the proposed method is more efficient than weighted likelihood and is unbiased in the presence of shared frailty for the primary and secondary outcome. We illustrate the method with an application to a study of risk factors for diabetes in a Swedish cohort. PMID- 24753006 TI - Shape analysis, a field in need of careful validation. AB - In the last two decades, the statistical analysis of shape has become an actively studied field and finds applications in a wide range of areas. In addition to algorithmic development, many researchers have distributed end-user orientated toolboxes, which further enable the utilization of the algorithms in an "off the shelf" fashion. However, there is little work on the evaluation and validation of these techniques, which poses a rather serious challenge when interpreting their results. To address this lack of validation, we design a validation framework and then use it to test some of the most widely used toolboxes. Our initial results show inconsistencies and disagreement among four different methods. We believe this type of analysis to be critical not only for the community of algorithm designers but also perhaps more importantly to researchers who use these tools without knowing the algorithm details and seek objective criteria for tool selection. PMID- 24753005 TI - Coffee, alcohol and other beverages in relation to cirrhosis mortality: the Singapore Chinese Health Study. AB - Limited experimental and epidemiologic data suggest that coffee may reduce hepatic damage in chronic liver disease. The association between consumption of coffee and other beverages and risk of cirrhosis mortality was evaluated in the Singapore Chinese Health Study. This is a prospective population-based cohort of 63,275 middle-aged and older Chinese subjects who provided data on diet, lifestyle, and medical histories through in-person interviews using a structured questionnaire at enrollment between 1993 and 1998. Mortality from cirrhosis in the cohort was ascertained through linkage analysis with nationwide death registry. After a mean follow-up of 14.7 years, 114 subjects died from cirrhosis; 33 of them from viral hepatitis B (29%), two from hepatitis C (2%), and 14 from alcohol-related cirrhosis (12%). Compared to nondrinkers, daily alcohol drinkers had a strong dose-dependent positive association between amount of alcohol and risk of cirrhosis mortality. Conversely, there was a strong dose-dependent inverse association between coffee intake and risk of nonviral hepatitis-related cirrhosis mortality (P for trend = 0.014). Compared to non-daily coffee drinkers, those who drank two or more cups per day had a 66% reduction in mortality risk (hazard ratio [HR] = 0.34, 95% confidence interval [CI] = 0.14-0.81). However, coffee intake was not associated with hepatitis B-related cirrhosis mortality. The inverse relationship between caffeine intake and nonviral hepatitis-related cirrhosis mortality became null after adjustment for coffee drinking. The consumption of black tea, green tea, fruit juices, or soft drinks was not associated with risk of cirrhosis death. CONCLUSION: This study demonstrates the protective effect of coffee on nonviral hepatitis-related cirrhosis mortality, and provides further impetus to evaluate coffee as a potential therapeutic agent in patients with cirrhosis. PMID- 24753007 TI - Effective solution- and vacuum-processed n-doping by dimers of benzimidazoline radicals. PMID- 24753008 TI - Effectiveness of different treatment modalities for the management of adult-onset granulosa cell tumours of the ovary (primary and recurrent). AB - BACKGROUND: Granulosa cell tumour is a rare gynaecological tumour of the ovary with recurrences many years after initial diagnosis and treatment. Evidence-based management of granulosa cell tumour of the ovary is limited, and treatment has not been standardised. Surgery, including fertility-sparing procedures for young women, has traditionally been the standard treatment. Adjuvant treatments following surgery have been based on non-randomised trials. A combination of bleomycin, etoposide and cisplatin (BEP) has traditionally been used for treatment of advanced and/or recurrent disease that cannot be optimally managed surgically. OBJECTIVES: To evaluate the effectiveness and safety of different treatment modalities offered in current practice for the management of primary, residual and recurrent adult-onset granulosa cell tumours (GCTs) of the ovary. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE up to December 2013. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs), quasi RCTs and observational studies that examined women with adult-onset granulosa cell tumours of the ovary (primary and recurrent). For non-randomised studies, we included studies that used multivariate analysis to adjust for baseline characteristics. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. Studies were heterogeneous with respect to treatment comparisons, so data were not synthesised in meta-analyses, and methods for assessing heterogeneity were not needed. Risk of bias in included studies was assessed by using the six core items used to assess RCTs and by evaluating four additional criteria specifically addressing risk of bias in non randomised studies. MAIN RESULTS: Five retrospective cohort studies (535 women with a diagnosis of GCT) that used appropriate statistical methods for adjustment were included in the review.Two studies, which carried out multivariate analyses that attempted to identify factors associated with better outcomes (in terms of overall survival), reported no apparent evidence of a difference in overall survival between surgical approaches, whether a participant underwent lymphadenectomy or received adjuvant chemotherapy or radiotherapy. Only percentage of survival for all participants combined was reported in two trials and was not reported at all in one study.One study showed that women who received postoperative radiotherapy had lower risk of disease recurrence compared with those who underwent surgery alone (adjusted hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.1 to 0.6, P value 0.04). Three studies reportedthat there was no evidence of differences in disease recurrence based on execution and type of adjuvant chemotherapy or on type of surgery or surgical approach, other than that surgical staging may be important. One study described no apparent evidence of a difference in disease recurrence between fertility-sparing surgery and conventional surgery. Recurrence-free survival was not reported in one study.Toxicity and adverse event data were incompletely reported in the five studies. None of the five studies reported on quality of life (QoL). All studies were at very high risk of bias. AUTHORS' CONCLUSIONS: One study showed a lower recurrence rate with the use of adjuvant radiotherapy, although this study was at high risk of bias and the results should be interpreted with caution. After evaluating the five small retrospective studies, we are unable to reach any firm conclusions as to the effectiveness and safety of different types and approaches of surgery, including conservative surgery, as well as adjuvant chemotherapy or radiotherapy, for management of GCTs of the ovary. The available evidence is very limited, and the review provides only low-quality evidence. Further research is very likely to have an important impact on our confidence in the estimate of effect and may alter our findings.Ideally, multinational RCTs are needed to answer these questions. The disease is relatively rare and generally has a good prognosis. RCTs are challenging to conduct, but three ongoing trials have been identified, demonstrating that they are feasible, although two of these studies are single-arm trials. The study that may be able to provide answers to the question of which chemotherapeutic regimen should be selected for management of sex cord stromal tumours is an ongoing, randomised, phase 2 study, led by the Gynaecological Oncology Group to compare the efficacy of carboplatin and paclitaxel versus standard BEP. These investigators are also looking into the value of inhibin A and inhibin B as predictive biomarkers. Additional trials are required to assess toxicity and QoL associated with different treatment regimens as well as the safety of conservative surgical options. PMID- 24753009 TI - Dynamic expression of the polysialyltransferase in adult rat hippocampus performing an olfactory associative task. AB - Neural cell adhesion molecule (NCAM) is associated with polysialic acid (PSA), and its function is highly dependent on the extent of polysialylation through the activity of two polysialyltransferases, sialyltransferase-X (STX) and polysialyltransferase (PST). PSA-NCAM plays an important role in synaptic plasticity in the hippocampus. The involvement of STX and PST during mnesic processes was assessed in the adult rat hippocampus. We investigated whether different levels in learning and memory using an olfactory associative task influenced STX and PST gene expression in the hippocampus using semiquantitative transcription-polymerase chain reaction. Then, NCAM polysialylation and cell proliferation were quantified in the dentate gyrus of a "Learning and Memory" group using immunohistochemistry. We found that only the expression level of PST mRNA increased with learning performance and returned to an initial level when learned associations were consolidated in long-term memory, while STX mRNA levels remained unchanged. This phenomenon was accompanied by an increase in PSA on NCAM but not by cell proliferation in the dentate gyrus. Our results suggest a different involvement for STX and PST in neural plasticity: while STX is probably involved in the proliferation of neural progenitor cells, PST could play a key role in synaptic plasticity of mature neural networks. The expression of the STX and PST genes could, therefore, be useful markers of neurobiological plasticity in the brain, allowing to follow chronological events in limbic and cortical structures related first to learning and memory processes (for PST) and, second, to adult neurogenesis processes (for STX). PMID- 24753011 TI - Sonographic diagnosis of lateral asynclitism: a new subtype of fetal head malposition as a main determinant of early labor arrest. AB - We report on the sonographic appearance of a new type of fetal head malposition in labor that has not been previously described systematically. In some circumstances, the fetal lie is characterized by a lateral orientation of the head with respect to the trunk and, on suprapubic ultrasound, a transverse section of the fetal chest together with the facial profile can be seen on the same image. These sonographic findings were documented in five cases of first stage labor arrest. This report illustrates how, in these circumstances, ultrasound might be helpful in clarifying the precise cause of obstructed labor. PMID- 24753010 TI - Postoperative MRI of the shoulder. AB - Magnetic resonance imaging (MRI) evaluation of the postoperative shoulder presents technical and diagnostic challenges related to imaging artifacts from hardware and micrometallic shavings, postsurgical scarring, and morphological alterations. Improved visualization of postoperative shoulder anatomy and pathology can be obtained with the use of metal artifact reduction techniques as well as MR arthrography. In this article we review the MR techniques that are designed to address these technical and diagnostic challenges, and we discuss the definitions and indications, normal MRI appearance, and complications of routine surgical procedures for treatment of injuries to the rotator cuff, labral ligamentous complex, and biceps tendon. PMID- 24753012 TI - SAR reduction in 7T C-spine imaging using a "dark modes" transmit array strategy. AB - PURPOSE: Local specific absorption rate (SAR) limits many applications of parallel transmit (pTx) in ultra high-field imaging. In this Note, we introduce the use of an array element, which is intentionally inefficient at generating spin excitation (a "dark mode") to attempt a partial cancellation of the electric field from those elements that do generate excitation. We show that adding dipole elements oriented orthogonal to their conventional orientation to a linear array of conventional loop elements can lower the local SAR hotspot in a C-spine array at 7 T. METHODS: We model electromagnetic fields in a head/torso model to calculate SAR and excitation B1 (+) patterns generated by conventional loop arrays and loop arrays with added electric dipole elements. We utilize the dark modes that are generated by the intentional and inefficient orientation of dipole elements in order to reduce peak 10g local SAR while maintaining excitation fidelity. RESULTS: For B1 (+) shimming in the spine, the addition of dipole elements did not significantly alter the B1 (+) spatial pattern but reduced local SAR by 36%. CONCLUSION: The dipole elements provide a sufficiently complimentary B1 (+) and electric field pattern to the loop array that can be exploited by the radiofrequency shimming algorithm to reduce local SAR. PMID- 24753013 TI - Sensory tricks and brain excitability in cervical dystonia: a transcranial magnetic stimulation study. AB - BACKGROUND: Sensory tricks such as touching the face with fingertips often improve cervical dystonia [CD]. This study is to determine whether sensory tricks modulate motor cortex excitability, assessed by paired-pulse transcranial magnetic stimulation [p-pTMS]. METHODS: Eight patients with rotational CD underwent p-pTMS, at rest and when the sensory trick was applied. To test intracortical inhibition [ICI] and facilitation [ICF], the amplitude ratio between conditioned and unconditioned cortical motor evoked potentials was measured at several interstimulus intervals (ISI 1, 3, 15, and 20 ms) and compared with controls mimicking patients' sensory tricks. RESULTS: At rest, a significant ICF enhancement was found at ISIs 15 through 20 in patients compared with controls, whereas no significant ICI changes were observed. Sensory tricks significantly reduced the abnormal ICF in patients and did not induce any change in controls. CONCLUSIONS: In our CD patients, sensory tricks seem to improve dystonia through an inhibitory effect on motor cortex excitability. PMID- 24753014 TI - Increased calcium absorption from synthetic stable amorphous calcium carbonate: double-blind randomized crossover clinical trial in postmenopausal women. AB - Calcium supplementation is a widely recognized strategy for achieving adequate calcium intake. We designed this blinded, randomized, crossover interventional trial to compare the bioavailability of a new stable synthetic amorphous calcium carbonate (ACC) with that of crystalline calcium carbonate (CCC) using the dual stable isotope technique. The study was conducted in the Unit of Clinical Nutrition, Tel Aviv Sourasky Medical Center, Israel. The study population included 15 early postmenopausal women aged 54.9 +/- 2.8 (mean +/- SD) years with no history of major medical illness or metabolic bone disorder, excess calcium intake, or vitamin D deficiency. Standardized breakfast was followed by randomly provided CCC or ACC capsules containing 192 mg elemental calcium labeled with 44Ca at intervals of at least 3 weeks. After swallowing the capsules, intravenous CaCl2 labeled with 42Ca on was administered on each occasion. Fractional calcium absorption (FCA) of ACC and CCC was calculated from the 24-hour urine collection following calcium administration. The results indicated that FCA of ACC was doubled (+/- 0.96 SD) on average compared to that of CCC (p < 0.02). The higher absorption of the synthetic stable ACC may serve as a more efficacious way of calcium supplementation. PMID- 24753015 TI - Microwave-synthesized magnetic chitosan microparticles for the immobilization of yeast cells. AB - An extremely simple procedure has been developed for the immobilization of Saccharomyces cerevisiae cells on magnetic chitosan microparticles. The magnetic carrier was prepared using an inexpensive, simple, rapid, one-pot process, based on the microwave irradiation of chitosan and ferrous sulphate at high pH. Immobilized yeast cells have been used for sucrose hydrolysis, hydrogen peroxide decomposition and the adsorption of selected dyes. PMID- 24753016 TI - Asymmetrical expression of BDNF and NTRK3 genes in frontoparietal cortex of stress-resilient rats in an animal model of depression. AB - The current study is based on the "approach-withdrawal" theory of emotional regulation and lateralization of brain function in rodents, which has little been studied. The aim was to indentify asymmetry in hemispheric genes expression during depression. Depressive-like symptoms were induced in rats using chronic mild stress protocol. The sucrose consumption test was performed to identify the anhedonic and stress-resilient rats. After decapitation, RNA was extracted from frontotemporal cortex of both hemispheres of anhedonic and stress-resilient rats. The pattern of gene expression in these samples was compared with controls by real-time polymerase chain reaction. A linear mixed model analysis of variance was fitted to the data to estimate the effect of rat line. From the total of 30 rats in the experimental group, five rats were identified to be anhedonic and five were stress-resilient, according to the result of sucrose-consumption test. BDNF and NTRK-3 were expressed at significantly lower levels in the right hemisphere of anhedonic rats compared with stress-resilient rats. No significant difference was found between left hemispheres. Hemispheric asymmetry in the level of gene expression was only observed for the BDNF gene in stress-resilient rats, upregulated in right hemisphere compared with the left. Expression of NTRK3, HTR2A, COMT, and SERT was not lateralized. There was no significant asymmetry between hemispheres of anhedonic rats. This study supports the evidence for the role of genes responsible for neural plasticity in pathophysiology of depression, emphasizing probable hemispheric asymmetry at level of gene expression. PMID- 24753017 TI - Is Project Towards No Drug Abuse (Project TND) an evidence-based drug and violence prevention program? A review and reappraisal of the evaluation studies. AB - This paper critically reviews the published evidence pertaining to Project Towards No Drug Abuse (Project TND). Publications from seven evaluation studies of Project TND are reviewed, and the results from these are discussed as related to the following outcomes: main effects on the use of cigarettes, alcohol and marijuana; main effects on the use of "hard drugs," defined in the evaluations as cocaine, hallucinogens, stimulants, inhalants, ecstasy and other drugs (e.g., depressants, PCP, steroids and heroin); subgroup and interaction analyses of drug use; and violence-related behaviors. Very few main effects have been found for cigarette, alcohol and marijuana use in the Project TND evaluations. While studies do report main effects for hard drug use, these findings are subject to numerous threats to validity and may be attributable to the data analyses employed. Similarly, while isolated subgroup and interaction effects were found for alcohol use among baseline nonusers and some violence-related behaviors in the early Project TND evaluations, these findings have not been replicated in more recent studies and may result from multiple comparisons between study conditions. In conclusion, there is little evidence to support the assertion that Project TND is an effective drug or violence prevention program. The broader implications of these findings for prevention science are discussed and suggestions are made as to how the quality of research in the field might be improved. PMID- 24753018 TI - Combined usage of stem cells in end-stage heart failure therapies. AB - Remarkable achievements have been made in the clinical application of mechanical circulatory support and cardiac transplantation for patients with end-stage heart failure. Despite the successes, complications associated with these therapies continue to drive cardiac regenerative research utilizing stem cell based therapies. Multiple stem cell lineages hold clinical promise for cardiac regeneration-mostly through cellular differentiation, cellular fusion, and paracrine signaling mechanisms. Bone marrow-derived endothelial progenitor cells are among the most intriguing and controversial cell types currently being investigated. Formidable barriers exist, however, in finding the ideal cardiac regenerative stem cell, such as identifying specific lineage markers, optimizing in vitro cellular expansion and improving methods of stem cell delivery. Hybrid approaches of cardiac regeneration using stem cell therapies in conjunction with immunomodulation after cardiac transplantation or with mechanical circulatory support produce cutting edge stem cell technologies. This review summarizes the current knowledge and therapeutic applications of stem cells in patients with end stage heart failure, including stem cell therapy after implantation of mechanical circulatory support and cardiac transplantation. PMID- 24753019 TI - Electrostatic interactions enable rapid penetration, enhanced uptake and retention of intra-articular injected avidin in rat knee joints. AB - Intra-articular (i.a.) drug delivery for local treatment of osteoarthritis remains inadequate due to rapid clearance by the vasculature or lymphatics. Local therapy targeting articular cartilage is further complicated by its dense meshwork of collagen and negatively charged proteoglycans, which can prevent even nano-sized solutes from entering. In a previous in vitro study, we showed that Avidin, due to its size (7 nm diameter) and high positive charge (pI 10.5), penetrated the full thickness of bovine cartilage and was retained for 15 days. With the goal of using Avidin as a nano-carrier for cartilage drug delivery, we investigated its transport properties within rat knee joints. Avidin penetrated the full thickness of articular cartilage within 6 h, with a half-life of 29 h, and stayed inside the joint for 7 days after i.a. injection. The highest concentration of Avidin was found in cartilage, the least in patellar tendon and none in the femoral bone; in contrast, negligible Neutravidin (neutral counterpart of Avidin) was present in cartilage after 24 h. A positive correlation between tissue sGAG content and Avidin uptake (R(2) = 0.83) confirmed the effects of electrostatic interactions. Avidin doses up to at least 1 uM did not affect bovine cartilage explant cell viability, matrix catabolism or biosynthesis. PMID- 24753020 TI - SCAI expert consensus statement for femoral-popliteal arterial intervention appropriate use. AB - Successful endovascular intervention for femoral-popliteal (FP) arterial disease provides relief of claudication and offers limb-salvage in cases of critical limb ischemia. Technologies and operator technique have evolved to the point where we may now provide effective endovascular therapy for a spectrum of lesions, patients, and clinical scenarios. Endovascular treatment of this segment offers a significant alternative to surgical revascularization, and may confer improved safety for a wide range of patients, not solely those deemed high surgical risk. Although endovascular therapy of the FP segment has historically been hampered by high rates of restenosis, emerging technologies including drug-eluting stents, drug-coated balloons, and perhaps bio-absorbable stent platforms, provide future hope for more durable patency in complex disease. By combining lessons learned from clinical trials, international trends in clinical practice, and insights regarding emerging technologies, we may appropriately tailor our application of endovascular therapy to provide optimal care to our patients. This document was developed to guide physicians in the clinical decision-making related to the contemporary application of endovascular intervention among patients with FP arterial disease. PMID- 24753021 TI - Joint longitudinal and survival-cure models in tumour xenograft experiments. AB - In tumour xenograft experiments, treatment regimens are administered, and the tumour volume of each individual is measured repeatedly over time. Survival data are recorded because of the death of some individuals during the observation period. Also, cure data are observed because of a portion of individuals who are completely cured in the experiments. When modelling these data, certain constraints have to be imposed on the parameters in the models to account for the intrinsic growth of the tumour in the absence of treatment. Also, the likely inherent association of longitudinal and survival-cure data has to be taken into account in order to obtain unbiased estimators of parameters. In this paper, we propose such models for the joint modelling of longitudinal and survival-cure data arising in xenograft experiments. Estimators of parameters in the joint models are obtained using a Markov chain Monte Carlo approach. Real data analysis of a xenograft experiment is carried out, and simulation studies are also conducted, showing that the proposed joint modelling approach outperforms the separate modelling methods in the sense of mean squared errors. PMID- 24753022 TI - HBV reactivation in immunosuppressed patients: prevention or containment? PMID- 24753023 TI - Cup-stacked carbon nanotube Schottky diodes for photovoltaics and photodetectors. PMID- 24753024 TI - Reversible chemical reactions for single-color multiplexing microscopy. AB - Recent developments in biology demand an increasing number of simultaneously imaged structures with standard fluorescence microscopy. However, the number of multiplexed channels is limited for most multiplexing modalities, such as spectral multiplexing or fluorescence-lifetime imaging. We propose extending the number of imaging channels by using chemical reactions, controlling the emissive state of fluorescent dyes. As proof of concept, we reversibly switch a fluorescent copper sensor to enable successive imaging of two different structures in the same spectral channel. We also show that this chemical multiplexing is orthogonal to existing methods. By using two different dyes, we combine chemical with spectral multiplexing for the simultaneous imaging of four different structures with only two spectrally different channels. We characterize and discuss the approach and provide perspectives for extending imaging modalities in stimulated emission depletion microscopy, for which spectral multiplexing is technically demanding. PMID- 24753025 TI - Reply: To PMID 23907815. PMID- 24753026 TI - The influence of group membership and individual differences in psychopathy and perspective taking on neural responses when punishing and rewarding others. AB - Understanding how neural processes involved in punishing and rewarding others are altered by group membership and personality traits is critical in order to gain a better understanding of how socially important phenomena such as racial and group biases develop. Participants in an fMRI study (n = 48) gave rewards (money) or punishments (electroshocks) to in-group or out-group members. The results show that when participants rewarded others, greater activation was found in regions typically associated with receiving rewards such as the striatum and medial orbitofrontal cortex, bilaterally. Activation in those regions increased when participants rewarded in-group compared to out-group members. Punishment led to increased activation in regions typically associated with Theory of Mind including the medial prefrontal cortex and posterior superior temporal sulcus, as well as regions typically associated with perceiving others in pain such as the dorsal anterior cingulate cortex, anterior insula and lateral orbitofrontal cortex. Interestingly, in contrast to the findings regarding reward, activity in these regions was not moderated by whether the target of the punishment was an in or out-group member. Additional regression analysis revealed that participants who have low perspective taking skills and higher levels of psychopathy showed less activation in the brain regions identified when punishing others, especially when they were out-group members. In sum, when an individual is personally responsible for delivering rewards and punishments to others, in-group bias is stronger for reward allocation than punishments, marking the first neuroscientific evidence of this dissociation. PMID- 24753027 TI - Neurodevelopmental outcome in twin anemia-polycythemia sequence after laser surgery for twin-twin transfusion syndrome. AB - OBJECTIVE: To evaluate the long-term neurodevelopmental outcome in children who developed twin anemia-polycythemia sequence (TAPS) after fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS). METHODS: Neurological, motor and cognitive development was assessed in a consecutive cohort of TTTS survivors treated with laser surgery between 2004 and 2011 and complicated by post-laser TAPS. Primary outcome was neurodevelopmental impairment, a composite outcome including any of the following: cerebral palsy, bilateral deafness, blindness, severe motor and/or cognitive developmental delay (>2 SD below the mean). A risk analysis on cognitive outcome was performed. RESULTS: During the study period, 33/306 (11%) monochorionic twin pairs developed TAPS after laser surgery for TTTS. Survival was 53/66 (80%). Long-term outcome was assessed in 47/53 (89%) children. The incidence of neurodevelopmental impairment was 4/47 (9%), occurring in one donor (1/20; 5%) and three recipients (3/27; 11%) (P=0.63). Mild-to moderate cognitive delay, i.e. scores below 85, was detected in 8/47 (17%) children. Risk factors for low cognitive scores were low gestational age at birth (P=0.02) and low birth weight (P<0.01). The lowest cognitive scores were detected in the subgroup of TAPS survivors treated with intrauterine transfusion (median score, 82.5). CONCLUSIONS: Neurodevelopmental impairment and cognitive delay were found in almost one in five children surviving post-laser TAPS. Better treatment and, ideally, prevention of this complication after laser treatment for TTTS is urgently needed. PMID- 24753028 TI - Three-dimensional regional strain computation method with displacement encoding with stimulated echoes (DENSE) in non-ischemic, non-valvular dilated cardiomyopathy patients and healthy subjects validated by tagged MRI. AB - PURPOSE: Fast cine displacement encoding with stimulated echoes (DENSE) MR has higher spatial resolution and enables rapid postprocessing. Thus we compared the accuracy of regional strains computation by DENSE with tagged MR in healthy and non-ischemic, non-valvular dilated cardiomyopathy (DCM) subjects. MATERIALS AND METHODS: Validation of three-dimensional regional strains computed with DENSE was conducted in reference to standard tagged MRI (TMRI) in healthy subjects and patients with DCM. Additional repeatability studies in healthy subjects were conducted to increase confidence in DENSE. A meshfree multiquadrics radial point interpolation method (RPIM) was used for computing Lagrange strains in sixteen left ventricular segments. Bland-Altman analysis and Student's t-tests were conducted to observe similarities in regional strains between sequences and in DENSE repeatability studies. RESULTS: Regional circumferential strains ranged from -0.21 +/- 0.07 (Lateral-Apex) to -0.11 +/- 0.05 (Posterorseptal-Base) in healthy subjects and -0.15 +/- 0.04 (Anterior-Apex) to -0.02 +/- 0.08 (Posterorseptal-Base) in DCM patients. Computed mean differences in regional circumferential strain from the DENSE-TMRI comparison study was 0.01 +/- 0.03 (95% limits of agreement) in normal subjects, -0.01 +/- 0.06 in DCM patients and 0.0 +/- 0.02 in repeatability studies, with similar agreements in longitudinal and radial strains. CONCLUSION: We found agreement between DENSE and tagged MR in patients and volunteers in terms of evaluation of regional strains. PMID- 24753029 TI - Determination of tropical deforestation rates and related carbon losses from 1990 to 2010. AB - We estimate changes in forest cover (deforestation and forest regrowth) in the tropics for the two last decades (1990-2000 and 2000-2010) based on a sample of 4000 units of 10 *10 km size. Forest cover is interpreted from satellite imagery at 30 * 30 m resolution. Forest cover changes are then combined with pan-tropical biomass maps to estimate carbon losses. We show that there was a gross loss of tropical forests of 8.0 million ha yr(-1) in the 1990s and 7.6 million ha yr(-1) in the 2000s (0.49% annual rate), with no statistically significant difference. Humid forests account for 64% of the total forest cover in 2010 and 54% of the net forest loss during second study decade. Losses of forest cover and Other Wooded Land (OWL) cover result in estimates of carbon losses which are similar for 1990s and 2000s at 887 MtC yr(-1) (range: 646-1238) and 880 MtC yr(-1) (range: 602-1237) respectively, with humid regions contributing two-thirds. The estimates of forest area changes have small statistical standard errors due to large sample size. We also reduce uncertainties of previous estimates of carbon losses and removals. Our estimates of forest area change are significantly lower as compared to national survey data. We reconcile recent low estimates of carbon emissions from tropical deforestation for early 2000s and show that carbon loss rates did not change between the two last decades. Carbon losses from deforestation represent circa 10% of Carbon emissions from fossil fuel combustion and cement production during the last decade (2000-2010). Our estimates of annual removals of carbon from forest regrowth at 115 MtC yr(-1) (range: 61-168) and 97 MtC yr(-1) (53-141) for the 1990s and 2000s respectively are five to fifteen times lower than earlier published estimates. PMID- 24753032 TI - Inter-echo variance as a weighting factor for multi-channel combination in multi echo acquisition for local frequency shift mapping. AB - PURPOSE: To develop and evaluate a local frequency shift (LFS) mapping method specifically designed for multi-echo acquisitions and multi-channel receive coils. METHODS: The proposed method uses the pixel-by-pixel inter-echo variance (IEV) as a weighting factor during channel-combination. Five healthy volunteers were scanned at 7 T. The IEV-weighted method was quantitatively compared to established (adaptive and Hermitian product) channel-combination methods with respect to IEV of LFS over the entire brain. RESULTS: In all experiments, the IEV weighted method generated LFS maps free of artifacts caused by unwrapping errors. Based on measurements of the inter-echo frequency variance throughout the whole brain, the IEV-weighted method produced the lowest variation and the best contrast at the edge of the brain. CONCLUSION: The primary finding of the present study is that accurate LFS maps are achievable if the data from each channel is processed independently prior to combination followed by a weighted combination using IEV as the weighting term. The software is freely available to the scientific community. PMID- 24753030 TI - NG2 cells (polydendrocytes): listeners to the neural network with diverse properties. AB - NG2 cells (polydendrocytes) are the fourth major non-neuronal cell type in the central nervous system parenchyma. They exhibit diverse properties, ranging from their well-established role as oligodendrocyte precursors to their ability to respond to neurotransmitters released by synaptic and non-synaptic mechanisms. The functional diversity of NG2 cells has prompted the question of whether they represent a single cellular entity or multiple distinct cell populations. This review first summarizes recent findings on the nature and mechanism underlying the diversity of NG2 cells with regard to their proliferative and differentiation behavior. This will be followed by a synopsis of observations on how their microenvironment, particularly neuronal activity, influences their dynamic behavior, and how these changes in NG2 cells could in turn influence neural function and animal behavior. PMID- 24753033 TI - Globus pallidus involvement as initial presentation of methylmalonic acidemia. PMID- 24753031 TI - Epiphyseal chondrocyte secondary ossification centers require thyroid hormone activation of Indian hedgehog and osterix signaling. AB - Thyroid hormones (THs) are known to regulate endochondral ossification during skeletal development via acting directly in chondrocytes and osteoblasts. In this study, we focused on TH effects on the secondary ossification center (SOC) because the time of appearance of SOCs in several species coincides with the time when peak levels of TH are attained. Accordingly, micro-computed tomography (uCT) evaluation of femurs and tibias at day 21 in TH-deficient and control mice revealed that endochondral ossification of SOCs is severely compromised owing to TH deficiency and that TH treatment for 10 days completely rescued this phenotype. Staining of cartilage and bone in the epiphysis revealed that whereas all of the cartilage is converted into bone in the prepubertal control mice, this conversion failed to occur in the TH-deficient mice. Immunohistochemistry studies revealed that TH treatment of thyroid stimulating hormone receptor mutant (Tshr( /-) ) mice induced expression of Indian hedgehog (Ihh) and Osx in type 2 collagen (Col2)-expressing chondrocytes in the SOC at day 7, which subsequently differentiate into type 10 collagen (Col10)/osteocalcin-expressing chondro/osteoblasts at day 10. Consistent with these data, treatment of tibia cultures from 3-day-old mice with 10 ng/mL TH increased expression of Osx, Col10, alkaline phosphatase (ALP), and osteocalcin in the epiphysis by sixfold to 60 fold. Furthermore, knockdown of the TH-induced increase in Osx expression using lentiviral small hairpin RNA (shRNA) significantly blocked TH-induced ALP and osteocalcin expression in chondrocytes. Treatment of chondrogenic cells with an Ihh inhibitor abolished chondro/osteoblast differentiation and SOC formation. Our findings indicate that TH regulates the SOC initiation and progression via differentiating chondrocytes into bone matrix-producing osteoblasts by stimulating Ihh and Osx expression in chondrocytes. PMID- 24753034 TI - Determination of an appropriate cut-off value for ferritin in the diagnosis of hemophagocytic lymphohistiocytosis. AB - Hyperferritinemia is a hallmark of hemophagocytic lymphohistiocytosis (HLH). In the HLH-2004 criteria, a ferritin value >500 ug/L is considered positive. However, this level was not determined based on evidence. We compared 123 patients with HLH and 320 patients with other hyperferritinemic conditions, calculated a receiver-operating characteristic, and determined sensitivity and specificity for different values. At 2,000 ug/L a trade-off is reached with sensitivity at 70% and specificity at 68%. If familial HLH and virus-associated acquired HLH are analyzed separately, sensitivity and specificity are similar for this level. The results may guide a potential modification of the current HLH criteria. PMID- 24753035 TI - Double dissociation between the contributions of the septal and temporal hippocampus to spatial learning: the role of prior experience. AB - The mammalian hippocampus is anatomically heterogeneous along its longitudinal axis, and there is evidence that distinct functions are executed by different septotemporal subregions. The best documented example is the dependency of spatial learning on the septal, but not the temporal, hippocampus. Here, we carried out a watermaze memory task in rats with partial lesions of the septal or temporal hippocampus made either before or after training. We then studied memory retention, reversal, and new spatial learning in a novel environment. This resulted in the surprising finding that spatial learning in a new environment is dependent on the temporal hippocampus in rats with preoperative experience of a different pool. Rats with septal hippocampal lesions made after learning not only retained the focused search strategy that was acquired during preoperative training, but were also capable of rapid spatial learning in a second pool. This demonstrates that once spatial information has been acquired in one context, related new learning in a different context can be mediated by the temporal hippocampus, a result that challenges the widely held view that spatial memory is an exclusive function of the septal hippocampus. PMID- 24753036 TI - Clinical outcome of patients with implantation of second-generation drug-eluting stents in the right coronary ostium: insights from 2-year follow-up of the TWENTE trial. AB - OBJECTIVES: The aim of the present study was to assess the impact on clinical outcome of right coronary artery (RCA) ostial coverage with second-generation drug-eluting stents (DES). BACKGROUND: Treatment of the aorta-ostial (AO) region of the RCA with bare metal stents and first-generation DES has been associated with a higher risk of target-lesion revascularization (TLR). METHODS: Of the 1,391 patients of the prospective TWENTE trial, we identified 321 (23%) with single-vessel RCA treatment, who were categorized into stenting with AO stent coverage (AOC) versus stenting without AOC. The AO region was defined as 3 mm from the aortic orifice. RESULTS: The 67 (20.9%) patients with AOC showed more severe lesion calcifications than the 254 patients without AOC (31.3% vs. 12.6%; P < 0.01). In the AOC group, there was a higher prevalence of hypercholesterolemia and family history of coronary disease (75.4% vs. 61.6%, and 68.7% vs. 53.5%, respectively; P = 0.03). During 2-year follow-up, patients in the AOC group had a higher incidence of TLR (7.5% vs. 1.6%; P = 0.02). Following adjustment for confounders, AOC independently predicted TLR with an adjusted hazard ratio of 4.1 (95% CI: 1.17-14.39; P = 0.03). CONCLUSION: AO treatment of the RCA with second-generation DES is feasible, but our data suggest that stent coverage of the right AO segment remains a predictor of TLR. PMID- 24753037 TI - Mitigating pesticide pollution in China requires law enforcement, farmer training, and technological innovation. AB - To feed an ever-growing population, it is necessary to take all measures to increase crop yields, including the use of pesticides. It has long been a difficult task to boost agricultural production and simultaneously minimize the impact of pesticide application on the environment, particularly in China, a developing country with more than 1.3 billion people. China has recently become the world's leading producer and consumer of pesticides, with production and consumption reaching 265 tons and 179 tons, respectively, in 2011, and a national average pesticide application dosage of more than 14 kg/ha. The large quantities of pesticides applied in agricultural fields have resulted in serious environmental deterioration. Organochlorine pesticides, such as dichloro-diphenyl trichloroethane and hexachlorohexane, have become ubiquitous in the environment of China, with spatial distributions in soils and aquatic systems similar to their historic application patterns in different geographic regions: southeast > central > northwest. Pollution by current-use pesticides, for example, organophosphates and pyrethroids, has also been of great concern. To mitigate pesticide pollution in China, a significant reduction in pesticide inputs into the environment is mandatory. This can be accomplished only with joint efforts by the government, professionals, and citizens in combination with rigorous enforcement of laws and regulations, training of farmers in pesticide knowledge and environmental awareness, and technological innovation for producing low-risk pesticides and developing efficient application approaches. Restoring contaminated sites is also an urgent task. Finally, food security and environmental pollution are not problems for a sole country, and international cooperation and communication are necessary. PMID- 24753038 TI - Assessing the goodness of fit of personal risk models. AB - We describe a flexible family of tests for evaluating the goodness of fit (calibration) of a pre-specified personal risk model to the outcomes observed in a longitudinal cohort. Such evaluation involves using the risk model to assign each subject an absolute risk of developing the outcome within a given time from cohort entry and comparing subjects' assigned risks with their observed outcomes. This comparison involves several issues. For example, subjects followed only for part of the risk period have unknown outcomes. Moreover, existing tests do not reveal the reasons for poor model fit when it occurs, which can reflect misspecification of the model's hazards for the competing risks of outcome development and death. To address these issues, we extend the model-specified hazards for outcome and death, and use score statistics to test the null hypothesis that the extensions are unnecessary. Simulated cohort data applied to risk models whose outcome and mortality hazards agreed and disagreed with those generating the data show that the tests are sensitive to poor model fit, provide insight into the reasons for poor fit, and accommodate a wide range of model misspecification. We illustrate the methods by examining the calibration of two breast cancer risk models as applied to a cohort of participants in the Breast Cancer Family Registry. The methods can be implemented using the Risk Model Assessment Program, an R package freely available at http://stanford.edu/~ggong/rmap/. PMID- 24753039 TI - The distribution of lymph nodes and their nutrient vessels in the groin region: an anatomic study for design of the lymph node flap. AB - BACKGROUND: The groin lymph node flap transfer has been used for treatment of extremity lymphedema. The design of this flap is based on the superficial circumflex iliac artery/vein (SCIA/V), or superficial inferior epigastric artery/vein (SIEA/V). The purpose of this study is to delineate the distribution of lymph nodes in the groin area and their relationship to inguinal vessels by the use of multidirector-row CT angiography (MDCTA). METHODS: MDCTA was performed in 52 patients who underwent the deep inferior epigastric perforator (DIEP) flap or transverse rectus abdominis musculocutaneous (TRAM) flap for breast reconstruction. The MDCTA data were used to analyze the locations of lymph nodes and their adjacent vascular vessels. The groin region was divided into the superior lateral (I), superior medial (II), inferior lateral (III), and inferior medial (IV) quadrants based on the point where SCIV joined into great saphenous vein. The number of lymph nodes in each of the four quadrants was counted and the dominant vessels were observed. RESULTS: The mean number of lymph nodes in quadrants I-IV were 3.3 +/- 1.6, 2.0 +/- 1.2, 1.5 +/- 1.3, and 1.9 +/- 1.4, respectively. The difference between the four quadrants was statistically significant (P < 0.001). In quadrant I, the appearance rate of SCIA was 100% while SIEA was 6.6%. In quadrant II, no SCIA was observed but the appearance rate of SIEA was 78.0%. There were neither SCIA nor SIEA observed in quadrants III and IV. CONCLUSIONS: The superior lateral quadrant of the groin region was found to have the most lymph nodes. The superficial circumflex iliac vessels are the major sources for blood supply to this region. The findings from this study provide evidence for the clinical design of the lymph node flap from the groin area. PMID- 24753041 TI - Non-invasive prenatal testing for trisomy 13: more harm than good? AB - A 35-year-old primigravida, pregnant after in-vitro fertilization, was seen because of a trisomy 13/trisomy 18 (T13/T18) risk of 1:55, based on the result of her first-trimester combined test. She elected for non-invasive prenatal testing (NIPT) at 14 + 5 weeks' gestation, which was positive for T13. After counseling, the patient elected to undergo amniocentesis. Quantitative fluorescence polymerase chain reaction (QF-PCR) showed no signs of trisomy, and full karyotyping confirmed a normal 46,XY result. Analysis of the published literature on NIPT for T13 gives an overall detection rate of 91.6%, with a false-positive rate of 0.097%. Based on this detection rate, hypothetical calculations show that the positive predictive value is highly dependent on the prevalence of the disease, resulting in an unfavorable balance between benefit and harm in a general population. PMID- 24753040 TI - Feeling safe in the plane: neural mechanisms underlying superior action control in airplane pilot trainees--a combined EEG/MRS study. AB - In day-to-day life, we need to apply strategies to cascade different actions for efficient unfolding of behavior. While deficits in action cascading are examined extensively, almost nothing is known about the neuronal mechanisms mediating superior performance above the normal level. To examine this question, we investigate action control in airplane pilot trainees. We use a stop-change paradigm that is able to estimate the efficiency of action cascading on the basis of mathematical constraints. Behavioral and EEG data is analyzed along these constraints and integrated with neurochemical data obtained using Magnetic Resonance Spectroscopy (MRS) from the striatal gamma-aminobutyric acid (GABA) ergic system. We show that high performance in action cascading, as exemplified in airplane pilot trainees, can be driven by intensified attentional processes, circumventing response selection processes. The results indicate that the efficiency of action cascading and hence the speed of responding as well as attentional gating functions are modulated by striatal GABA and Glutamate + Glutamine concentrations. In superior performance in action cascading similar increases in the concentrations of GABA and Glutamate + Glutamine lead to stronger neurophysiological and behavioral effects as compared to subjects with normal performance in action cascading. PMID- 24753042 TI - Rationally designed single-crystalline nanowire networks. AB - Rational bottom-up assembly of nanowire networks may be a way to successfully continue the miniaturization in the semiconductor industry. A generic method is developed that ensures InSb nanowires meet under the optimal angle for the formation of single-crystalline structures, which represents a promising platform for the future random access memories based on Majorana fermions. PMID- 24753043 TI - Genomic DNA recombination with cell-penetrating peptide-tagged cre protein in mouse skeletal and cardiac muscle. AB - The Cre-loxP recombination system has been used to promote DNA recombination both in vitro and in vivo. For in vivo delivery, Cre expression is commonly achieved through the use of tissue/cell type-specific promoters, viral infection, or drug inducible transcription and protein translocation to promote targeted DNA excision. The development of cell permeable (or penetrating) peptide tagged proteins has facilitated the delivery of Cre recombinase protein into cells in culture, organotypic slide culture, or in living animals. In this report, we generated bacterially expressed, his-tagged Cre protein with either a cardiac targeting peptide or an antennapedia peptide at the C-terminus and demonstrated efficient uptake and recombination in both cell culture and mice. To facilitate delivery to cardiac and skeletal muscle, we mixed proteins with pluronic F-127 hydrogel and delivered Cre protein into reporter Rosa26mTmG mouse skeletal muscle or Rosa26LacZ cardiac muscle via ultrasound guided injection. Activation of reporter gene expression indicated that these Cre proteins were enzymatically active. Recombination events were detected only in the vicinity of injection areas. In conclusion, we have developed a method to deliver enzymatically active Cre protein locally to skeletal muscle and cardiac muscle that may be adapted for use with other proteins. PMID- 24753044 TI - Prognostic impact of telomere maintenance gene polymorphisms in hepatocellular carcinoma patients: some issues need to be clarified. PMID- 24753045 TI - Regio- and stereospecificity in the oxygenation of arachidonic acid catalyzed by Leu597 mutants of rabbit 15-lipoxygenase: a QM/MM study. AB - We combined quantum mechanics/molecular mechanics calculations with molecular dynamics simulations to study the addition of O2 to the pentadienyl radical of arachidonic acid (AA) catalyzed by the Leu597Val and Leu597Ala mutants of rabbit 15-lipoxygenase (15-rLO). In the Leu597Val mutant, the addition of O2 to C15 of AA is the predominant path, although it reduces the C15/C11 product ratio by almost ten times with respect to the wildtype enzyme. The S stereochemistry is kept. Mutation to Ala causes just the opposite effect: regiospecificity favoring addition to C15 is somewhat sharper than that in the wildtype, but the stereochemistry is R. This is because the extra space created by the mutation to Ala is big enough for AA to move so that it can adopt an alternative binding mode, and this opens new feasible paths for the attack of O2 . So, we showed that the Leu597Ala mutant of 15r-LO works as an aspirin-acetylated cyclooxygenase-2, which makes 15-(R)- hydroperoxyeicosatetraenoic acid. PMID- 24753046 TI - Permafrost conditions in peatlands regulate magnitude, timing, and chemical composition of catchment dissolved organic carbon export. AB - Permafrost thaw in peatlands has the potential to alter catchment export of dissolved organic carbon (DOC) and thus influence downstream aquatic C cycling. Subarctic peatlands are often mosaics of different peatland types, where permafrost conditions regulate the hydrological setting of each type. We show that hydrological setting is key to observed differences in magnitude, timing, and chemical composition of DOC export between permafrost and nonpermafrost peatland types, and that these differences influence the export of DOC of larger catchments even when peatlands are minor catchment components. In many aspects, DOC export from a studied peatland permafrost plateau was similar to that of a forested upland catchment. Similarities included low annual export (2-3 g C m(-2) ) dominated by the snow melt period (~70%), and how substantial DOC export following storms required wet antecedent conditions. Conversely, nonpermafrost fens had higher DOC export (7 g C m(-2) ), resulting from sustained hydrological connectivity during summer. Chemical composition of catchment DOC export arose from the mixing of highly aromatic DOC from organic soils from permafrost plateau soil water and upland forest surface horizons with nonaromatic DOC from mineral soil groundwater, but was further modulated by fens. Increasing aromaticity from fen inflow to outlet was substantial and depended on both water residence time and water temperature. The role of fens as catchment biogeochemical hotspots was further emphasized by their capacity for sulfate retention. As a result of fen characteristics, a 4% fen cover in a mixed catchment was responsible for 34% higher DOC export, 50% higher DOC concentrations and ~10% higher DOC aromaticity at the catchment outlet during summer compared to a nonpeatland upland catchment. Expansion of fens due to thaw thus has potential to influence landscape C cycling by increasing fen capacity to act as biogeochemical hotspots, amplifying aquatic C cycling, and increasing catchment DOC export. PMID- 24753047 TI - Diminished bone strength is observed in adult women and men who sustained a mild trauma distal forearm fracture during childhood. AB - Children and adolescents who sustain a distal forearm fracture (DFF) owing to mild, but not moderate, trauma have reduced bone strength and cortical thinning at the distal radius and tibia. Whether these skeletal deficits track into adulthood is unknown. Therefore, we studied 75 women and 75 men (age range, 20 to 40 years) with a childhood (age < 18 years) DFF and 150 sex-matched controls with no history of fracture using high-resolution peripheral quantitative computed tomography (HRpQCT) to examine bone strength (ie, failure load) by micro-finite element (uFE) analysis, as well as cortical and trabecular bone parameters at the distal radius and tibia. Level of trauma (mild versus moderate) was assigned using a validated classification scheme, blind to imaging results. When compared to sex-matched, nonfracture controls, women and men with a mild trauma childhood DFF (eg, fall from standing height) had significant reductions in failure load (p < 0.05) of the distal radius, whereas women and men with a moderate trauma childhood DFF (eg, fall while riding a bicycle) had values similar to controls. Consistent findings were observed at the distal tibia. Furthermore, women and men with a mild trauma childhood DFF had significant deficits in distal radius cortical area (p < 0.05), and significantly lower dual-energy X-ray absorptiometry (DXA)-derived bone density at the radius, hip, and total body regions compared to controls (all p < 0.05). By contrast, women and men with a moderate trauma childhood DFF had bone density, structure, and strength that did not differ significantly from controls. These findings in young adults are consistent with our observations in children/adolescents with DFF, and they suggest that a mild trauma childhood DFF may presage suboptimal peak bone density, structure, and strength in young adulthood. Children and adolescents who suffer mild trauma DFFs may need to be targeted for lifestyle interventions to help achieve improved skeletal health. PMID- 24753049 TI - Neurotransmitter signaling in white matter. AB - White matter (WM) tracts are bundles of myelinated axons that provide for rapid communication throughout the CNS and integration in grey matter (GM). The main cells in myelinated tracts are oligodendrocytes and astrocytes, with small populations of microglia and oligodendrocyte precursor cells. The prominence of neurotransmitter signaling in WM, which largely exclude neuronal cell bodies, indicates it must have physiological functions other than neuron-to-neuron communication. A surprising aspect is the diversity of neurotransmitter signaling in WM, with evidence for glutamatergic, purinergic (ATP and adenosine), GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic and serotonergic signaling, acting via a wide range of ionotropic and metabotropic receptors. Both axons and glia are potential sources of neurotransmitters and may express the respective receptors. The physiological functions of neurotransmitter signaling in WM are subject to debate, but glutamate and ATP-mediated signaling have been shown to evoke Ca(2+) signals in glia and modulate axonal conduction. Experimental findings support a model of neurotransmitters being released from axons during action potential propagation acting on glial receptors to regulate the homeostatic functions of astrocytes and myelination by oligodendrocytes. Astrocytes also release neurotransmitters, which act on axonal receptors to strengthen action potential propagation, maintaining signaling along potentially long axon tracts. The co-existence of multiple neurotransmitters in WM tracts suggests they may have diverse functions that are important for information processing. Furthermore, the neurotransmitter signaling phenomena described in WM most likely apply to myelinated axons of the cerebral cortex and GM areas, where they are doubtless important for higher cognitive function. PMID- 24753048 TI - An N-terminal threonine mutation produces an efflux-favorable, sodium-primed conformation of the human dopamine transporter. AB - The dopamine transporter (DAT) reversibly transports dopamine (DA) through a series of conformational transitions. Alanine (T62A) or aspartate (T62D) mutagenesis of Thr62 revealed T62D-human (h)DAT partitions in a predominately efflux-preferring conformation. Compared with wild-type (WT), T62D-hDAT exhibits reduced [(3)H]DA uptake and enhanced baseline DA efflux, whereas T62A-hDAT and WT hDAT function in an influx-preferring conformation. We now interrogate the basis of the mutants' altered function with respect to membrane conductance and Na(+) sensitivity. The hDAT constructs were expressed in Xenopus oocytes to investigate if heightened membrane potential would explain the efflux characteristics of T62D hDAT. In the absence of substrate, all constructs displayed identical resting membrane potentials. Substrate-induced inward currents were present in oocytes expressing WT- and T62A-hDAT but not T62D-hDAT, suggesting equal bidirectional ion flow through T62D-hDAT. Utilization of the fluorescent DAT substrate ASP(+) [4-(4-(dimethylamino)styryl)-N-methylpyridinium] revealed that T62D-hDAT accumulates substrate in human embryonic kidney (HEK)-293 cells when the substrate is not subject to efflux. Extracellular sodium (Na(+) e) replacement was used to evaluate sodium gradient requirements for DAT transport functions. The EC50 for Na(+) e stimulation of [(3)H]DA uptake was identical in all constructs expressed in HEK-293 cells. As expected, decreasing [Na(+)]e stimulated [(3)H]DA efflux in WT- and T62A-hDAT cells. Conversely, the elevated [(3)H]DA efflux in T62D-hDAT cells was independent of Na(+) e and commensurate with [(3)H]DA efflux attained in WT-hDAT cells, either by removal of Na(+) e or by application of amphetamine. We conclude that T62D-hDAT represents an efflux willing, Na(+)-primed orientation-possibly representing an experimental model of the conformational impact of amphetamine exposure to hDAT. PMID- 24753050 TI - Testing for publication bias in diagnostic meta-analysis: a simulation study. AB - The present study investigates the performance of several statistical tests to detect publication bias in diagnostic meta-analysis by means of simulation. While bivariate models should be used to pool data from primary studies in diagnostic meta-analysis, univariate measures of diagnostic accuracy are preferable for the purpose of detecting publication bias. In contrast to earlier research, which focused solely on the diagnostic odds ratio or its logarithm ( ln omega), the tests are combined with four different univariate measures of diagnostic accuracy. For each combination of test and univariate measure, both type I error rate and statistical power are examined under diverse conditions. The results indicate that tests based on linear regression or rank correlation cannot be recommended in diagnostic meta-analysis, because type I error rates are either inflated or power is too low, irrespective of the applied univariate measure. In contrast, the combination of trim and fill and ln omega has non-inflated or only slightly inflated type I error rates and medium to high power, even under extreme circumstances (at least when the number of studies per meta-analysis is large enough). Therefore, we recommend the application of trim and fill combined with ln omega to detect funnel plot asymmetry in diagnostic meta-analysis. PMID- 24753051 TI - Lanthanum ions intervened in enzymatic production and elimination of reactive oxygen species in leaves of rice seedlings under cadmium stress. AB - Rare earth elements at proper concentrations were observed to alleviate heavy metal stress. However, the potential mechanisms of alleviation are not clear. Thus, the present study focused on the mechanisms of lanthanum (La) ions on the generation and elimination of reactive oxygen species (ROS) production in leaves of rice seedlings hydroponically cultivated in 30 uM cadmium chloride (CdCl2) for 2 d. Results showed that the decline of superoxide (O2 . (-)) or hydrogen peroxide (H2O2) was attributed not only to the decreased expressions of nicotinamide adenine dinucleotide phosphate oxidases-related gene, protein synthesis, and isozymes, but also to the decrease of xanthine oxidase, diamine oxidase, and guaiacol peroxidases isozymes and activities. Genes and isozymes related to superoxide dismutase, catalase, and ascorbate peroxidase were also differentially upregulated to control ROS accumulation when proper concentrations of La were combined with 30 uM Cd. Based on the results, one may conclude that La at proper concentrations not only limited the generation of O2 . (-) and H2O2 from the enzymatic sources but also promoted the elimination of O2 . (-) and H2O2 via the upregulating expressions of antioxidant enzyme-related genes and activities in the rice seedling's leaves under Cd stress. PMID- 24753052 TI - Mechanistic target of rapamycin (MTOR) signaling during ovulation in mice. AB - A complex network of endocrine/paracrine signals regulates granulosa-cell function in ovarian follicles. Mechanistic target of rapamycin (MTOR) has recently emerged as a master intracellular integrator of extracellular signals and nutrient availability. The objectives of the present study were to characterize the expression pattern and kinase activity of MTOR during follicular and corpus luteum development, and to examine how inhibition of MTOR kinase activity affects preovulatory maturation of ovarian follicles. MTOR expression was constitutive throughout follicular and corpus luteum development. Gonadotropins induced MTOR kinase activity in the ovary, which was inhibited by rapamycin treatment (10 ug/g body weight, intraperitoneal injection). Inhibition of human chorionic gonadotropin (hCG)-induced MTOR activity during preovulatory follicle maturation did not change key events of ovulation. Granulosa cells of rapamycin-treated mice showed reduced MTOR kinase activity at 1 and 4 hr post-hCG and overexpression of hCG-induced ovulation genes at 4 hr post-hCG. Overexpression of these ovulatory genes was associated with hyper-activation of extracellular signal-regulated kinase 1/2 (ERK1/2), which occurred in response to inhibition of MTOR with rapamycin and suggested that MTOR may function as a negative regulator of the mitogen-activated protein kinase (MAPK) pathway. Indeed, simultaneous inhibition of MTOR and ERK1/2 activities during preovulatory follicle maturation caused anovulation. Inhibition of hCG-induced ERK1/2 activity alone suppressed MTOR kinase activity, indicating that MAPK pathway is upstream of MTOR. Thus, normal ovulation appears to be a result of complex interactions between MTOR and MAPK signaling pathways in granulosa cells of ovulating follicles in mice. PMID- 24753053 TI - Angiographic characteristics of definite stent thrombosis: role of thrombus grade, collaterals, epicardial coronary flow, and myocardial perfusion. AB - OBJECTIVES: To characterize the prevalence of thrombus burden, collateral vessels to the infarct-related artery, epicardial coronary artery flow, and myocardial perfusion in patients with angiographically confirmed definite stent thrombosis (ST), and to define their relationship with associated treatments and outcomes. BACKGROUND: Angiographic characteristics of ST are not well defined. METHODS: All cases of angiographically determined ST at five academic hospitals from 2005 to 2012 were reviewed. Demographic, procedural, and angiographic characteristics were recorded. In-hospital and 1-year follow-up data were obtained. RESULTS: Among 205 cases of angiographic definite ST (60 +/- 8 years; 87% male), the majority presented with late/very late ST (69%) and STEMI (66%). High-risk angiographic findings at presentation included thrombus grade 4-5 (87%), absence of collateral vessels (76%), and reduced initial TIMI 3 flow (90%). Final TIMI 3 flow was achieved in 90% of patients and was associated with greater use of aspiration thrombectomy (60% vs. 25%; P = 0.003), glycoprotein IIb/IIIa inhibitors (80% vs. 30%, P < 0.001), and repeat stenting (67% vs. 10%, P < 0.001). A final myocardial perfusion grade of 2-3 was achieved in 79% of patients and was associated with greater use of aspiration thrombectomy (61% vs. 36%, P = 0.003). After multivariable logistic regression, aspiration thrombectomy (AOR 2.6, 95% CI 1.3-5.2) and implantation of a new stent (AOR 2.1, 95% CI 1.1-4.3) were associated with optimal combined epicardial flow and myocardial perfusion. At 1-year follow-up, significantly lower risk of repeat ST (HR 0.1; 95% CI 0.1,0.2; P < 0.001) among patients with initial TIMI 3 flow at index ST was observed. CONCLUSIONS: The majority of ST patients present with late/very late ST with high thrombus burden and STEMI. Presence of collateral vessels and low thrombus burden is cardioprotective, while reduced initial TIMI flow is associated with larger infarct size and recurrent ST. Aspiration thrombectomy and repeat stenting are associated with improved epicardial coronary artery flow and myocardial perfusion among patients treated for ST. (c) 2014 Wiley Periodicals, Inc. PMID- 24753054 TI - Measurement of socio-economic status in families of children with cancer in Guatemala. AB - The prospects for survival of children in low and middle income countries are linked to their families socio-economic status (SES), of which income is only one component. Developing a comprehensive measure of SES is required. Informed by clinical experience, a 15-item instrument was designed in Guatemala to categorize SES by five levels in each item. Almost 75% of families attending the Unidad Nacional de Oncologia Pediatrica were in the lowest three of six categories, providing a framework for stratified financial and nutritional support. The measure of SES offers an opportunity for examining associations with health outcomes throughout Latin America. PMID- 24753055 TI - Multi-directional anisotropy from diffusion orientation distribution functions. AB - PURPOSE: To evaluate a model-independent, multi-directional anisotropy (MDA) metric that is analytically and experimentally equivalent to fractional anisotropy (FA) in single-direction diffusivity, but potentially superior to FA in its sensitivity to the underlying anisotropy of multi-directional diffusivity. MATERIALS AND METHODS: An expression for MDA was defined from the orientation distribution function (ODF) and its analytical relation to FA was derived. Simulations of single and crossed double-fibers were performed using a compressed sensing-accelerated diffusion-spectrum-imaging (CS-DSI) scheme. In vivo brain imaging using CS-DSI was performed on eight healthy subjects. MDA was compared with FA and with another ODF-based metric known as generalized FA (GFA). RESULTS: In simulated single-direction fibers, MDA was shown to be equivalent to FA (from FA = 0.2 to 0.8). In crossed fibers, MDA provided superior differentiation of the underlying anisotropy as compared to FA and GFA. In vivo analysis shows that the MDA was superior to both FA (P = 0.015) and GFA (P = 0.021) in terms of its relative accuracy in crossed fiber regions. CONCLUSION: MDA provides a potentially superior measure of fiber anisotropy relative to conventional FA or GFA, and may be used to improve the assessment of disease in regions with multi directional brain fibers. PMID- 24753058 TI - Excursions out-of-lane versus standard deviation of lateral position as outcome measure of the on-the-road driving test. AB - BACKGROUND: The traditional outcome measure of the Dutch on-the-road driving test is the standard deviation of lateral position (SDLP), the weaving of the car. This paper explores whether excursions out-of-lane are a suitable additional outcome measure to index driving impairment. METHODS: A literature search was conducted to search for driving tests that used both SDLP and excursions out-of lane as outcome measures. The analyses were limited to studies examining hypnotic drugs because several of these drugs have been shown to produce next-morning sedation. RESULTS: Standard deviation of lateral position was more sensitive in demonstrating driving impairment. In fact, solely relying on excursions out-of lane as outcome measure incorrectly classifies approximately half of impaired drives as unimpaired. The frequency of excursions out-of-lane is determined by the mean lateral position within the right traffic lane. Defining driving impairment as having a DeltaSDLP > 2.4 cm, half of the impaired driving tests (51.2%, 43/84) failed to produce excursions out-of-lane. Alternatively, 20.9% of driving tests with DeltaSDLP < 2.4 cm (27/129) had at least one excursion out-of lane. CONCLUSIONS: Excursions out-of-lane are neither a suitable measure to demonstrate driving impairment nor is this measure sufficiently sensitive to differentiate adequately between differences in magnitude of driving impairment. PMID- 24753059 TI - Extracellular vesicle noncoding RNA: new players in the diagnosis and pathogenesis of cholangiocarcinoma. PMID- 24753060 TI - Multi-atlas based representations for Alzheimer's disease diagnosis. AB - Brain morphometry based classification from magnetic resonance (MR) acquisitions has been widely investigated in the diagnosis of Alzheimer's disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). In the literature, a morphometric representation of brain structures is obtained by spatial normalization of each image into a common space (i.e., a pre-defined atlas) via non-linear registration, thus the corresponding regions in different brains can be compared. However, representations generated from one single atlas may not be sufficient to reveal the underlying anatomical differences between the groups of disease-affected patients and normal controls (NC). In this article, we propose a different methodology, namely the multi-atlas based morphometry, which measures morphometric representations of the same image in different spaces of multiple atlases. Representations generated from different atlases can thus provide the complementary information to discriminate different groups, and also reduce the negative impacts from registration errors. Specifically, each studied subject is registered to multiple atlases, where adaptive regional features are extracted. Then, all features from different atlases are jointly selected by a correlation and relevance based scheme, followed by final classification with the support vector machine (SVM). We have evaluated the proposed method on 459 subjects (97 AD, 117 progressive-MCI (p-MCI), 117 stable-MCI (s-MCI), and 128 NC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, and achieved 91.64% for AD/NC classification and 72.41% for p-MCI/s-MCI classification. Our results clearly demonstrate that the proposed multi-atlas based method can significantly outperform the previous single-atlas based methods. PMID- 24753061 TI - Correcting partial volume effects in biexponential T2 estimation of small lesions. AB - PURPOSE: T2 mapping provides a quantitative approach for focal liver lesion characterization. For small lesions, a biexponential model should be used to account for partial volume effects (PVE). However, conventional biexponential fitting suffers from large uncertainty of the fitted parameters when noise is present. The purpose of this work is to develop a more robust method to correct for PVE affecting small lesions. METHODS: We developed a region of interest-based joint biexponential fitting (JBF) algorithm to estimate the T2 of lesions affected by PVE. JBF takes advantage of the lesion fraction variation among voxels within a region of interest. JBF is compared to conventional approaches using Cramer-Rao lower bound analysis, numerical simulations, phantom, and in vivo data. RESULTS: JBF provides more accurate and precise T2 estimates in the presence of PVE. Furthermore, JBF is less sensitive to region of interest drawing. Phantom and in vivo results show that JBF can be combined with a reconstruction method for highly undersampled data, enabling the characterization of small abdominal lesions from data acquired in a single breath hold. CONCLUSION: The JBF algorithm provides more accurate and stable T2 estimates for small structures than conventional techniques when PVE is present. It should be particularly useful for the characterization of small abdominal lesions. PMID- 24753062 TI - Percutaneous minimal-access fetoscopic surgery for spina bifida aperta. Part II: maternal management and outcome. AB - OBJECTIVE: To assess maternal morbidity and outcome in women undergoing minimal access fetoscopic surgery for spina bifida aperta. METHODS: This was a retrospective study of 51 women undergoing minimal-access fetoscopic surgery to improve postnatal neurological outcome of spina bifida aperta, at a mean gestational age of 24 weeks, at our center between July 2010 and June 2013. We analyzed various perioperative complications of surgery, namely: maternal and fetal death, need for maternal blood transfusion, placental abruption, pulmonary edema, spontaneous labor, oligohydramnios, chorioamnionitis, chorioamniotic membrane separation, duration of hospitalization, amniotic fluid leakage, gestational age at delivery and status of hysterotomy site. RESULTS: In none of the 51 women was there maternal demise, spontaneous labor, placental abruption or a need for maternal blood transfusion in the perioperative period. Chorioamniotic membrane separation occurred in one patient, mild pulmonary edema occurred in one and oligohydramnios occurred in seven. All fetuses survived surgery, but there was one very early preterm delivery 1 week after the procedure and this neonate died immediately, from early postoperative chorioamnionitis. Amniotic fluid leakage occurred in 43 patients, at a mean gestational age of 29.7 (range, 22.6 37.3) weeks; two of these patients developed chorioamnionitis. Duration of maternal hospitalization after surgery was 7.2 (range, 4-12) days. Mean gestational age at delivery was 33 (range, 24.6-38.1) weeks. All abdominal and uterine trocar insertion sites healed well. CONCLUSION: Minimal-access fetoscopic surgery for spina bifida aperta is apparently safe for most maternal patients. Despite the common occurrence of amniotic leakage, the majority of women deliver beyond 32 weeks of gestation. PMID- 24753064 TI - Median nerve fascicle transfer versus ulnar nerve fascicle transfer to the biceps motor branch in C5-C6 and C5-C7 brachial plexus injuries: nonrandomized prospective study of 23 consecutive patients. AB - The purpose of this study was to observe whether the results of the median nerve fascicle transfer to the biceps are equivalent to the classical ulnar nerve fascicle transfer, in terms of elbow flexion strength and donor nerve morbidity. Twenty-five consecutive patients were operated between March 2007 and July 2013. The patients were divided into two groups. In Group 1 (n = 8), the patients received an ulnar nerve fascicle transfer to the biceps motor branch. In Group 2 (n = 15), the patients received a median nerve fascicle transfer to the biceps motor branch. Two patients with follow-up less than six months were excluded. Both groups were similar regarding age (P = 0.070), interval of injury (P = 0.185), and follow-up period (P = 0.477). Elbow flexion against gravity was achieved in 7 of 8 (87.5%) patients in Group 1, versus 14 of 15 (93.3%) patients in Group 2 (P = 1.000). The level of injury (C5-C6 or C5-C7) did not affect anti gravity elbow flexion recovery in both the groups (P = 1.000). It was concluded that the median nerve fascicle transfer to the biceps is as good as the ulnar nerve fascicle transfer, even in C5-C7 injuries. PMID- 24753063 TI - Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging. AB - Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously, we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here, we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 h at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-h retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation. PMID- 24753069 TI - Complete spontaneous liver graft disappearance after auxiliary liver transplantation. PMID- 24753065 TI - Follow your gut: relaying information from the site of left-right symmetry breaking in the mouse. AB - A central unresolved question in the molecular cascade that drives establishment of left-right (LR) asymmetry in vertebrates are the mechanisms deployed to relay information between the midline site of symmetry-breaking and the tissues which will execute a program of asymmetric morphogenesis. The cells located between these two distant locations must provide the medium for signal relay. Of these, the gut endoderm is an attractive candidate tissue for signal transmission since it comprises the epithelium that lies between the node, where asymmetry originates, and the lateral plate, where asymmetry can first be detected. Here, focusing on the mouse as a model, we review our current understanding and entertain open questions concerning the relay of LR information from its origin. PMID- 24753070 TI - Risk of diffuse large B-cell lymphoma after solid organ transplantation in the United States. AB - Non-Hodgkin lymphoma arising in the context of immunosuppression is an important adverse outcome after solid organ transplantation. Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed subtype of post-transplantation non Hodgkin lymphoma, but few studies of transplant recipients have examined subtype specific risks. Therefore, we examined DLBCL risk in the Transplant Cancer Match Study, including registry-based cancer ascertainment among 96,615 solid organ transplants performed from 2000 to 2008. We determined standardized incidence ratios (SIRs) and 95% confidence intervals comparing DLBCL risk in transplant recipients with that in the general population, and used multivariable Poisson regression models to assess the impact of potential risk factors. We identified 321 incident cases of DLBCL, over 12 times more than expected based on general population rates (SIR = 12.6, 95% confidence interval = 11.2-14.0). SIRs were highest in young recipients and those receiving a lung or pancreas/kidney pancreas transplant, and were greatly elevated for extranodal DLBCLs at the site of the transplantation compared with other sites. DLBCL risk was highest in the first year following transplantation, and SIRs for early-onset DLBCL risk were elevated in association with Epstein-Barr virus-negative serostatus and use of polyclonal antibody induction therapy. In conclusion, associations between recipient and transplant factors and post-transplantation DLBCL risk suggest a complicated interrelationship among multiple risk factors and timing of disease. PMID- 24753071 TI - A survey of psychological support provision for people with inflammatory arthritis in secondary care in England. AB - OBJECTIVES: The consequences of inflammatory arthritis can include depression, anxiety and low mood, reducing patients' quality of life and increasing pressure on the healthcare system. Treatment guidelines recommend psychological support, but data are lacking on the provision available. METHODS: A postal survey concerning psychological support provision was sent to rheumatology units in 143 acute trusts across England. Nurses from 73 rheumatology units (51%) responded. RESULTS: Overall, 73% rated their unit's psychological support provision as 'inadequate' and only 4% rated it as 'good'. Few units believed that psychological support did not fall within their remit (12%), yet only 8% had a psychologist in the team. Most units (68%) did not routinely screen patients to identify psychological difficulties. Referral to other service providers was reported in 42% of units, with 3% very satisfied with this provision. Within units, services containing elements of psychological support ranged from occupational therapy (81%) to psychology/counselling (14%). Psychological approaches used by team members ranged from shared decision making (77%) to cognitive-behavioural approaches (26%). The current barriers to providing psychological support were lack of clinical time and available training (86% and 74%, respectively), and delivery costs (74%). Future facilitators included management support (74%) and availability of skills training (74%). CONCLUSIONS: Rheumatology units viewed psychological support provision as part of their remit but rated their overall provision as inadequate, despite some team members using psychological skills. To improve provision, clinicians' training needs must be addressed and organizational support generated, and further research needs to define adequate psychological support provision from the patient perspective. PMID- 24753072 TI - Conditional disruption of the prolyl hydroxylase domain-containing protein 2 (Phd2) gene defines its key role in skeletal development. AB - We have previously shown that the increase in osterix (Osx) expression during osteoblast maturation is dependent on the activity of the prolyl hydroxylase domain-containing protein 2 (Phd2), a key regulator of protein levels of the hypoxia-inducible factor family proteins in many tissues. In this study, we generated conditional Phd2 knockout mice (cKO) in osteoblast lineage cells by crossing floxed Phd2 mice with a Col1alpha2-iCre line to investigate the function of Phd2 in vivo. The cKO mice developed short stature and premature death at 12 to 14 weeks of age. Bone mineral content, bone area, and bone mineral density were decreased in femurs and tibias, but not vertebrae of the cKO mice compared to WT mice. The total volume (TV), bone volume (BV), and bone volume fraction (BV/TV) in the femoral trabecular bones of cKO mice were significantly decreased. Cross-sectional area of the femoral mid-diaphysis was also reduced in the cKO mice. The reduced bone size and trabecular bone volume in the cKO mice were a result of impaired bone formation but not bone resorption as revealed by dynamic histomorphometric analyses. Bone marrow stromal cells derived from cKO mice formed fewer and smaller nodules when cultured with mineralization medium. Quantitative RT-PCR and immunohistochemistry detected reduced expression of Osx, osteocalcin, and bone sialoprotein in cKO bone cells. These data indicate that Phd2 plays an important role in regulating bone formation in part by modulating expression of Osx and bone formation marker genes. PMID- 24753073 TI - Afforestation effects on SOC in former cropland: oak and spruce chronosequences resampled after 13 years. AB - Chronosequences are commonly used to assess soil organic carbon (SOC) sequestration after land-use change, but SOC dynamics predicted by this space-for time substitution approach have rarely been validated by resampling. We conducted a combined chronosequence/resampling study in a former cropland area (Vestskoven) afforested with oak (Quercus robur) and Norway spruce (Picea abies) over the past 40 years. The aims of this study were (i) to compare present and previous chronosequence trends in forest floor and top mineral soil (0-25 cm) C stocks; (ii) to compare chronosequence estimates with current rates of C stock change based on resampling at the stand level; (iii) to estimate SOC changes in the subsoil (25-50 cm); and (iv) to assess the influence of two tree species on SOC dynamics. The two chronosequence trajectories for forest floor C stocks revealed consistently higher rates of C sequestration in spruce than oak. The chronosequence trajectory was validated by resampling and current rates of forest floor C sequestration decreased with stand age. Chronosequence trends in topsoil SOC in 2011 did not differ significantly from those reported in 1998, however, there was a shift from a negative rate (1998: -0.3 Mg C ha(-1) yr(-1) ) to no change in 2011. In contrast SOC stocks in the subsoil increased with stand age, however, not significantly (P = 0.1), suggesting different C dynamics in and below the former plough layer. Current rates of C change estimated by repeated sampling decreased with stand age in forest floors but increased in the topsoil. The contrasting temporal change in forest floor and mineral soil C sequestration rates indicate a shift in C source-sink strength after approximately 40 years. We conclude that afforestation of former cropland within the temperate region may induce soil C loss during the first decades followed by a recovery phase of yet unknown duration. PMID- 24753074 TI - Gap junction blockade induces apoptosis in human endometrial stromal cells. AB - One of the most dynamic adult human tissues is the endometrium. Through coordinated, cyclical proliferation, differentiation, leukocyte recruitment, apoptosis, and desquamation, the uterine lining is expanded and shed monthly, unless pregnancy is established. Errors in these steps potentially cause endometrial dysfunction, abnormal uterine bleeding, failed embryonic implantation, infertility, or endometrial carcinoma. Our prior studies showed that gap junctions comprised of Gap junction alpha-1 (GJA1) protein, also known as connexin 43 (CX43), subunits are critical to endometrial stromal cell differentiation. The current studies were undertaken to explore the mechanism of endometrial dysfunction when gap junction intercellular communication (GJIC) is disrupted. Gap junction blockade by two distinct GJIC inhibitors, 18alpha glycyrrhetinic acid (AGA) and octanol (OcOH), suppressed proliferation and induced apoptosis in endometrial stromal cells, as manifested by reduced biomarkers of cell viability, increased TUNEL staining, caspase-3 activation, sub G1 chromosomal DNA complement, as well as shortened telomere length. Unexpectedly, we also observed that the chemical inhibitors blocked CX43 gene expression. Moreover, when endometrial stromal cells were induced to undergo hormonal decidualization, following a 7-day exposure to 10 nM 17beta-estradiol + 100 nM progesterone + 0.5 mM dibutyryl cAMP, characteristic epithelioid changes in cell shape and secretion of prolactin were blunted in the presence of AGA or OcOH, recapitulating effects of RNA interference of CX43. Our findings indicate that endometrial stromal cell proliferation and maintenance of decidualized endometrial function are GJIC-dependent, and that disruption of gap junctions induces endometrial stromal cell apoptosis. These observations may have important implications for several common clinical endometrial pathologies. PMID- 24753075 TI - Functionalization of a ruthenium-diacetylide organometallic complex as a next generation push-pull chromophore. AB - The design and preparation of an asymmetric ruthenium-diacetylide organometallic complex was successfully achieved to provide an original donor-pi-[M]-pi-acceptor architecture, in which [M] corresponds to the [Ru(dppe)2] (dppe: bisdiphenylphosphinoethane) metal fragment. The charge-transfer processes occurring upon photoexcitation of the push-pull metal-dialkynyl sigma complex were investigated by combining experimental and theoretical data. The novel push pull complex, appropriately end capped with an anchoring carboxylic acid function, was further adsorbed onto a semiconducting metal oxide porous thin film to serve as a photosensitizer in hybrid solar cells. The resulting photoactive material, when embedded in dye-sensitized solar cell devices, showed a good spectral response with a broad incident photon-to-current conversion efficiency profile and a power conversion efficiency that reached 7.3 %. Thus, this material paves the way to a new generation of organometallic chromophores for photovoltaic applications. PMID- 24753076 TI - Predictors of perceived functional ability in early-stage dementia: self-ratings, informant ratings and discrepancy scores. AB - OBJECTIVE: Assessing functional ability is an important element in diagnosing and monitoring the progression of dementia, with research suggesting a link between functional ability and cognition. We investigated the predictors of total score and individual item functional ratings made by people with dementia (PwD), carers of PwD and the resulting discrepancy score. METHODS: People with early-stage Alzheimer's disease, vascular or mixed dementia (n = 100) and their carers completed the Functional Activities Questionnaire. PwD also completed tests of memory, verbal executive function, language and cognitive screening, and provided ratings of mood. Carers provided a rating of stress. RESULTS: Immediate memory predicted self-rated functioning, whereas carer stress predicted informant-rated functioning. Letter fluency predicted the discrepancy between self-rated and informant-rated functioning. For self-rated functioning, the direction and pattern of the individual item predictors suggested a degree of functional awareness. Informant ratings were dominated by carer stress and, to a lesser extent, everyday memory. The discrepancy scores were also predicted by carer stress and everyday memory, but also letter fluency. CONCLUSIONS: Self-rated functioning showed evidence of awareness based on the direction and pattern of significant individual item predictors. Informant ratings, however, were found to be significantly influenced by carer stress. The findings have implications for the use of perceived functional ratings in clinical and research settings. PMID- 24753077 TI - Preclinical evaluation of nanoparticle albumin-bound paclitaxel for treatment of pediatric bone sarcoma. AB - The combination of docetaxel and gemcitabine is frequently used to treat recurrent bone sarcoma. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is less toxic and more active than docetaxel or paclitaxel for breast cancer patients. The combination of nab-paclitaxel and gemcitabine has preclinical synergy and is approved to treat pancreatic cancer. We observed growth inhibition and improved survival with nab-paclitaxel in a Ewing sarcoma xenograft, and activity was additive with gemcitabine in an osteosarcoma model. Primary Ewing sarcoma tumors expressed the transport protein SPARC, previously associated with nab-paclitaxel activity. These findings provide rationale for further evaluation of nab-paclitaxel with gemcitabine for bone sarcoma. PMID- 24753078 TI - Evaluation of alpha and gamma aluminum oxide nanoparticle accumulation, toxicity, and depuration in Artemia salina larvae. AB - In this study, Artemia salina (crustacean filter feeders) larvae were used as a test model to investigate the toxicity of aluminum oxide nanoparticles (Al2O3 NPs) on marine microorganisms. The uptake, toxicity, and elimination of alpha Al2O3 (50 nm and 3.5 MUm) and gamma-Al2O3 (5 nm and 0.4 MUm) NPs were studied. Twenty-four and ninety-six hour exposures of different concentrations of Al2O3 NPs to Artemia larvae were conducted in a seawater medium. When suspended in water, Al2O3 NPs aggregated substantially with the sizes ranging from 6.3 nm to >0.3 um for spherical NPs and from 250 to 756 nm for rod-shaped NPs. The phase contrast microscope images showed that NPs deposited inside the guts as aggregates. Inductively coupled plasma mass spectrometry analysis showed that large particles (3.5 MUm alpha-Al2O3) were not taken up by Artemia, whereas fine NPs (0.4 MUm gamma-Al2O3) and ultra-fine NPs (5 nm gamma-Al2O3 and 50 nm alpha Al2O3) accumulated substantially. Differences in toxicity were detected as changing with NP size and morphology. The malondialdehyde levels indicated that smaller gamma-Al2O3 (5 nm) NPs were more toxic than larger gamma-Al2O3 (0.4 um) particulates in 96 h. The highest mortality was measured as 34% in 96 h for gamma Al2O3 NPs (5 nm) at 100 mg/L (LC50 > 100 mg/L). gamma-Al2O3 NPs were more toxic than alpha-Al2O3 NPs at all conditions. PMID- 24753079 TI - Nuchal Translucency Quality Review (NTQR) program: first one and half million results. AB - OBJECTIVE: To evaluate the performance of first-trimester nuchal translucency (NT) measurement by providers (physician-sonologists and sonographers) within the Nuchal Translucency Quality Review (NTQR) program. METHODS: After training and credentialing providers, the NTQR monitored performance of NT measurement by the extent to which an individual's median multiple of the normal median (MoM) for crown-rump length (CRL) was within the range 0.9-1.1 MoM of a published normal median curve. The SD of log10 MoM and regression slope of NT on CRL were also evaluated. We report the distribution between providers of these performance indicators and evaluate potential sources of variation. RESULTS: Among the first 1.5 million scans in the NTQR program, performed between 2005 and 2011, there were 1 485 944 with CRL in the range 41-84 mm, from 4710 providers at 2150 ultrasound units. Among the 3463 providers with at least 30 scans in total, the median of the providers' median NT-MoMs was 0.913. Only 1901 (55%) had a median NT-MoM within the expected range; there were 89 above 1.1 MoM, 1046 at 0.8-0.9 MoM, 344 at 0.7-0.8 MoM and 83 below 0.7 MoM. There was a small increase in the median NT-MoM according to providers' length of time in the NTQR program and number of scans entered annually. On average, physician-sonologists had a higher median NT-MoM than did sonographers, as did those already credentialed before joining the program. The median provider SD was 0.093 and the median slope was 13.5%. SD correlated negatively with the median NT-MoM (r = -0.34) and positively with the slope (r = 0.22). CONCLUSION: Even with extensive training, credentialing and monitoring, there remains considerable variability between NT providers. There was a general tendency towards under-measurement of NT compared with expected values, although more experienced providers had performance closer to that expected. PMID- 24753080 TI - Rapid settling of nanoparticles due to heteroaggregation with suspended sediment. AB - Sedimentation of engineered nanoparticles (ENPs) has been studied mainly in artificial media and stagnant systems mimicking natural waters. This neglects the role of turbulence and heteroaggregation with sediment. The authors studied the apparent sedimentation rates of selected ENPs (cerium dioxide [CeO2 ], polyvinylpyrrolidone-capped silver [PVP-Ag], and silica-coated silver [SiO2 -Ag]) in agitated sediment-water systems resembling fresh, estuarine, and marine waters. Experiments were designed to mimic low energy and periodically resuspended sediment water systems (14 d), followed by a long-term aging, resuspension, and settling phase (6 months), as would occur in receiving shallow lakes. The ENPs in systems with periodical resuspension of sediment were removed with sedimentation rates between 0.14 m/d and 0.50 m/d. The sedimentation rates did not vary much among ENP type, salinity, and aging time, which is attributed to the capture of ENPs in sediment flocks. The sedimentation rates were 1 to 2 orders of magnitude higher than those reported for aggregation-sedimentation in stagnant systems without suspended sediment. Heteroaggregation rates were estimated and ranged between 0.151 L/mg/d and 0.547 L/mg/d, which is up to 29 times higher than those reported for natural colloids under quiescent settling conditions. The authors conclude that rapid scavenging and sedimentation drives removal of ENPs from the water column. PMID- 24753082 TI - The multifaceted functions of ribavirin: antiviral, immunomodulator, or both? PMID- 24753081 TI - Sumoylation of the astroglial glutamate transporter EAAT2 governs its intracellular compartmentalization. AB - EAAT2 is a predominantly astroglial glutamate transporter responsible for the majority of synaptic glutamate clearance in the mammalian central nervous system (CNS). Its dysfunction has been linked with many neurological disorders, including amyotrophic lateral sclerosis (ALS). Decreases in EAAT2 expression and function have been implicated in causing motor neuron excitotoxic death in ALS. Nevertheless, increasing EAAT2 expression does not significantly improve ALS phenotype in mouse models or in clinical trials. In the SOD1-G93A mouse model of inherited ALS, the cytosolic carboxy-terminal domain is cleaved from EAAT2, conjugated to SUMO1, and accumulated in astrocytes where it triggers astrocyte mediated neurotoxic effects as disease progresses. However, it is not known whether this fragment is sumoylated after cleavage or if full-length EAAT2 is already sumoylated prior to cleavage as part of physiological regulation. In this study, we show that a fraction of full-length EAAT2 is constitutively sumoylated in primary cultures of astrocytes in vitro and in the CNS in vivo. Furthermore, the extent of sumoylation of EAAT2 does not change during the course of ALS in the SOD1-G93A mouse and is not affected by the expression of ALS-causative mutant SOD1 proteins in astrocytes in vitro, indicating that EAAT2 sumoylation is not driven by pathogenic mechanisms. Most interestingly, sumoylated EAAT2 localizes to intracellular compartments, whereas non-sumoylated EAAT2 resides on the plasma membrane. In agreement, promoting desumoylation in primary astrocytes causes increased EAAT2-mediated glutamate uptake. These findings could have implications for optimizing therapeutic approaches aimed at increasing EAAT2 activity in the dysfunctional or diseased CNS. PMID- 24753083 TI - Analyzing task-dependent brain network changes by whole-brain psychophysiological interactions: a comparison to conventional analysis. AB - While fMRI activation studies contrasting task conditions regularly assess the whole brain, this is usually not true for studies analyzing task-dependent brain connectivity changes by psychophysiological interactions (PPI). Here we combine standard PPI (sPPI) and generalized PPI (gPPI) with a priori brain parcellation by spatially constrained normalized cut spectral clustering (NCUT) to analyze task-dependent connectivity changes in a whole brain manner, and compare the results to multiseed conventional PPI analyses over all activation peaks in an episodic memory recall task. We show that, depending on the chosen parcellation frame, the whole-brain PPI approach is able to detect a large amount of the information that is detected by the conventional approach. Over and above, whole brain PPI allows identification of several additional task-modulated connections, particularly from seed regions without significant activation differences between conditions. PMID- 24753084 TI - Shorter (<=6 months) versus longer (>=12 months) duration dual antiplatelet therapy after drug eluting stents: a meta-analysis of randomized clinical trials. AB - OBJECTIVE: Optimal duration of dual antiplatelet therapy (DAPT), defined as use of both aspirin and a P2Y12 receptor inhibitor, after implantation of drug eluting stents (DES) is still subject of ongoing debate. We systematically review efficacy and safety of <=6 months versus >=12 months DAPT after implantation of DES. METHODS: PubMed, Scopus, Cochrane, and clinicaltrials.gov databases were searched for studies published until 30th November 2013. The studies were limited to randomized clinical trials. Independent observers abstracted the data on outcomes, characteristics, and qualities of studies included. Random effect model was employed for meta-analysis. Heterogeneity of studies included was analyzed using I(2) statistics. RESULTS: In four randomized clinical trials published involving 8,163 patients with DES, 4,081 patients were randomized to shorter and 4,082 patients to longer duration DAPT. The P2Y12 receptor inhibitor used in all four studies was clopidogrel. Longer duration of DAPT did not reduce risk of all cause mortality (pooled OR 0.89, 95% CI 0.67-1.17, P = 0.4, I(2) = 0%), myocardial infarction (pooled OR 1.16, 95% CI 0.85-1.57, P = 0.35, I(2) = 0%) cardiac death (pooled OR 0.88, 95% CI 0.61-1.25, P = 0.47, I(2) = 0%), stent thrombosis (pooled OR 1.29, 95% CI 0.76-2.21, P = 0.35, I(2) = 0%) or cerebrovascular accidents (pooled OR 0.73, 95% CI 0.41-1.27, P = 0.26, I(2) = 0%). Longer duration of DAPT was associated with increased risk of TIMI major bleeding (pooled OR 0.51, 95% CI 0.29-0.89, P = 0.02, I(2) = 0%). CONCLUSION: There was no difference in efficacy outcomes between <=6 months of DAPT and >=12 months of DAPT in patients with coronary artery disease and DES implantation. Moreover, longer duration of DAPT is associated with increased risk of bleeding complications. (c) 2014 Wiley Periodicals, Inc. PMID- 24753085 TI - Robust myocardial T2 and T2 * mapping at 3T using image-based shimming. AB - PURPOSE: Intramyocardial hemorrhage and area at risk are both prognostic markers in acute myocardial infarction (AMI). Myocardial T2 and T2 * mapping have been used to detect such tissue changes at 1.5T but these techniques are challenging at 3.0T due to additional susceptibility variation. We studied T2 and T2 * myocardial mapping techniques at 3.0T on a system employing B1 shimming and compared two different methods of B0 shimming. MATERIALS AND METHODS: Fifteen volunteers and six AMI patients were scanned on a 3T system. Volume and image based (IB) B0 shimming techniques were implemented. Single breath-hold, multiecho gradient, and spin echo sequences were employed from which T2 * and T2 maps were calculated. RESULTS: In volunteers, there was no significant difference in mean values obtained with volume or IB shimming for T2 mapping (39.1 +/- 6.0 msec vs. 39.4 +/- 6.1 msec; P > 0.05) or for T2 * mapping (24.2 +/- 6.7 msec vs. 24.1 +/- 5.2 msec; P > 0.05). There were no significant regional differences in mean T2 values between septal, anterior, and posterior segments with either shimming technique (all P > 0.05); but there were significant regional differences in mean T2 * values using volume shimming (27.8 +/- 5.2 msec vs. 28.4 +/- 5.8 msec vs. 15.9 +/- 8.3 msec; P < 0.05)-but not with IB shimming (25.7 +/- 5.4 msec vs. 25.3 +/- 5.9 msec vs. 18.7 +/- 4.6 msec; P > 0.05). CONCLUSION: At 3.0T, cardiac T2 mapping is robust. Although T2 * mapping is prone to more regional heterogeneity this can be reduced by using IB instead of conventional volume B0 shimming. PMID- 24753086 TI - Age-related differences in oligodendrogenesis across the dorsal-ventral axis of the mouse hippocampus. AB - Oligodendrocyte precursor cells (OPCs) continue to divide and generate new oligodendrocytes (OLs) in the healthy adult brain. Although recent studies have indicated that adult oligodendrogenesis may be vital for the maintenance of normal brain function, the significance of adult oligodendrogenesis in brain aging remains unclear. In this study, we report a stereological estimation of age related oligodendrogenesis changes in the mouse hippocampus: the dorsal subdivision is related to learning and memory, while the ventral subdivision is involved in emotional behaviors. To identify OPCs and OLs, we used a set of molecular markers, OL lineage transcription factor (Olig2) and platelet-derived growth factor receptor-alpha (PDGFalphaR). Intracellular dye injection shows that PDGFalphaR+/Olig2+ cells and PDGFalphaR-/Olig2+ cells can be defined as OPCs and OLs, respectively. In the dorsal Ammon's horn, the numbers of OPCs decreased with age, while those of OLs remained unchanged during aging. In the ventral Ammon's horn, the numbers of OPCs and OLs generally decreased with age. Bromodeoxyuridine (BrdU) fate-tracing analysis revealed that the numbers of BrdU+ mitotic OPCs in the Ammon's horn remained unchanged during aging in both the dorsal and ventral subdivisions. Unexpectedly, the numbers of BrdU+ newly generated OLs increased with age in the dorsal Ammon's horn, but remained unchanged in the ventral Ammon's horn. Together, the numbers of OLs in the dorsal Ammon's horn may be maintained during aging by increased survival of adult born OLs, while the numbers of OLs in the ventral Ammon's horn may be reduced with age due to the lack of such compensatory mechanisms. These observations provide new insight into the involvement of adult oligodendrogenesis in age-related changes in the structure and function of the hippocampus. PMID- 24753087 TI - Parallel imaging with phase scrambling. AB - PURPOSE: Most existing methods for accelerated parallel imaging in MRI require additional data, which are used to derive information about the sensitivity profile of each radiofrequency (RF) channel. In this work, a method is presented to avoid the acquisition of separate coil calibration data for accelerated Cartesian trajectories. METHODS: Quadratic phase is imparted to the image to spread the signals in k-space (aka phase scrambling). By rewriting the Fourier transform as a convolution operation, a window can be introduced to the convolved chirp function, allowing a low-resolution image to be reconstructed from phase scrambled data without prominent aliasing. This image (for each RF channel) can be used to derive coil sensitivities to drive existing parallel imaging techniques. As a proof of concept, the quadratic phase was applied by introducing an offset to the x(2) - y(2) shim and the data were reconstructed using adapted versions of the image space-based sensitivity encoding and GeneRalized Autocalibrating Partially Parallel Acquisitions algorithms. RESULTS: The method is demonstrated in a phantom (1 * 2, 1 * 3, and 2 * 2 acceleration) and in vivo (2 * 2 acceleration) using a 3D gradient echo acquisition. CONCLUSION: Phase scrambling can be used to perform parallel imaging acceleration without acquisition of separate coil calibration data, demonstrated here for a 3D Cartesian trajectory. Further research is required to prove the applicability to other 2D and 3D sampling schemes. PMID- 24753088 TI - Triterpene acids from apple peel inhibit lepidopteran larval midgut lipases and larval growth. AB - Fruit extracts from apple, kiwifruit, feijoa, boysenberry, and blueberry were screened for the presence of lipase inhibitory compounds against lepidopteran larval midgut crude extracts. From 120 extracts, six showed significant inhibition with an extract from the peel of Malus * domestica cv. "Big Red" showing highest levels of inhibition. Because this sample was the only apple peel sample in the initial screen, a survey of peels from seven apple cultivars was undertaken and showed that, despite considerable variation, all had inhibitory activity. Successive solvent fractionation and LC-MS of cv. "Big Red" apple peel extract identified triterpene acids as the most important inhibitory compounds, of which ursolic acid and oleanolic acid were the major components and oxo- and hydroxyl-triterpene acids were minor components. When ursolic acid was incorporated into artificial diet and fed to Epiphyas postvittana Walker (Tortricidae: Lepidoptera) larvae at 0.16% w/v, a significant decrease in larval weight was observed after 21 days. This concentration of ursolic acid is less than half the concentration reported in the skin of some apple cultivars. PMID- 24753089 TI - Elevated atmospheric CO2 stimulates soil fungal diversity through increased fine root production in a semiarid shrubland ecosystem. AB - Soil fungal communities are likely to be central in mediating microbial feedbacks to climate change through their effects on soil carbon (C) storage, nutrient cycling, and plant health. Plants often produce increased fine root biomass in response to elevated atmospheric carbon dioxide (CO2 ), but the responses of soil microbial communities are variable and uncertain, particularly in terms of species diversity. In this study, we describe the responses of the soil fungal community to free air CO2 enrichment (FACE) in a semiarid chaparral shrubland in Southern California (dominated by Adenomstoma fasciculatum) using large subunit rRNA gene sequencing. Community composition varied greatly over the landscape and responses to FACE were subtle, involving a few specific groups. Increased frequency of Sordariomycetes and Leotiomycetes, the latter including the Helotiales, a group that includes many dark septate endophytes known to associate positively with roots, was observed in the FACE plots. Fungal diversity, both in terms of richness and evenness, increased consistently in the FACE treatment, and was relatively high compared to other studies that used similar methods. Increases in diversity were observed across multiple phylogenetic levels, from genus to class, and were distributed broadly across fungal lineages. Diversity was also higher in samples collected close to (5 cm) plants compared to samples in canopy gaps (30 cm away from plants). Fungal biomass correlated well with soil organic matter (SOM) content, but patterns of diversity were correlated with fine root production rather than SOM. We conclude that the fungal community in this ecosystem is tightly linked to plant fine root production, and that future changes in the fungal community in response to elevated CO2 and other climatic changes will be primarily driven by changes in plant belowground allocation. Potential feedbacks mediated by soil fungi, such as soil C sequestration, nutrient cycling, and pathogenesis, are discussed. PMID- 24753090 TI - A new Adamts9 conditional mouse allele identifies its non-redundant role in interdigital web regression. AB - ADAMTS9 is the most conserved member of a large family of secreted metalloproteases having diverse functions. Adamts9 null mice die before gastrulation, precluding investigations of its roles later in embryogenesis, in adult mice or disease models. We therefore generated a floxed Adamts9 allele to bypass embryonic lethality. In this mutant, unidirectional loxP sites flank exons 5-8, which encode the catalytic domain, including the protease active site. Mice homozygous for the floxed allele were viable, lacked an overt phenotype, and were fertile. Conversely, mice homozygous for a germ-line deletion produced from the floxed allele by Cre-lox recombination did not survive past gastrulation. Hemizygosity of the deleted Adamts9 in combination with mutant Adamts20 led to cleft palate and severe white spotting as previously described. Previously, Adamts9 haploinsufficiency combined with either Adamts20 or Adamts5 nullizygosity suggested a cooperative role in interdigital web regression, but the outcome of deletion of Adamts9 alone remained unknown. Here, Adamts9 was conditionally deleted in limb mesoderm using Prx1-Cre mice. Unlike other ADAMTS single knockouts, limb-specific Adamts9 deletion resulted in soft-tissue syndactyly (STS) with 100% penetrance and concurrent deletion of Adamts5 increased the severity of STS. Thus, Adamts9 has both non-redundant and cooperative roles in ensuring interdigital web regression. This new allele will be useful for investigating other biological functions of ADAMTS9. PMID- 24753091 TI - Genomic ancestry and somatic alterations correlate with age at diagnosis in Hispanic children with B-cell acute lymphoblastic leukemia. AB - Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) than non-Hispanic whites but tend to be diagnosed at older ages. In genome-wide association studies, Native American ancestry and polymorphisms in six genes have been associated with ALL risk. In multivariable regression models, we investigated whether genomic ancestry, inherited risk SNPs, or acquired somatic alterations were associated with differences in age at diagnosis in Hispanic children with B-cell ALL. Genome-wide array data were used to estimate each participant's percent membership in the three Hispanic ancestral populations: Native American, African, and European. Each 20% increase in European ancestry was associated with a six month younger age at diagnosis (95% CI = 0.36-11.6 months, P = 0.037). Correspondingly, each 20% increase in Native American ancestry was associated with a six-month older age at diagnosis (P = 0.037). Both the TEL-AML1 translocation and high-hyperdiploidy were associated with younger age at diagnosis (24.4 months, P = 2.0 x 10(-4) and 12.4 months, P = 0.011, respectively), while CDKN2A and IKZF1 deletions were associated with older age at diagnosis (19.7 months, P = 7.0 x 10(-4) and 18.1 months, P = 0.012, respectively). No associations with age at diagnosis were observed for RAS mutation, PAX5 deletion or for known heritable risk alleles in IKZF1, CDKN2A, PIP4K2A, GATA3, ARID5B, or CEBPE. Because younger age at diagnosis is associated with improved treatment outcomes for children with ALL, the effect of European ancestry on ALL survival may be mediated by its effect on age at diagnosis, or by proxy, its association with more treatable molecular subtypes of ALL. PMID- 24753092 TI - Sclerostin deficiency is linked to altered bone composition. AB - High bone mass in animals and humans with sclerostin deficiency is associated with increased bone strength, which is not the case for all disorders with high bone mineral density, some of which are even associated with fragility fractures owing to unfavorable bone composition. In the current study we investigated whether alterations in bone composition may contribute to the bone strength characteristics associated with lack of sclerostin. We examined cortical bone of Sost-knockout (KO) mice (n = 9, 16 weeks old) and sclerosteosis patients (young [4 to 14 years], n = 4 and adults [24 and 43 years], n = 2) by quantitative backscattered electron imaging and Raman microspectroscopy and compared it to bone from wild-type mice and healthy subjects, respectively. In Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged. When comparing endocortical bone tissue of identical tissue age as defined by sequential dual fluorochrome labeling the average bone matrix mineralization was reduced -1.9% (p < 0.0001, younger tissue age) and -1.5% (p < 0.05, older tissue age), and the relative proteoglycan content was significantly increased. Similarly, bone matrix mineralization density distribution was also shifted toward lower matrix mineralization in surgical samples of compact bone of sclerosteosis patients. This was associated with an increase in mineralization heterogeneity in the young population. In addition, and consistently, the relative proteoglycan content was increased. In conclusion, we observed decreased matrix mineralization and increased relative proteoglycan content in bone subcompartments of Sost-KO mice-a finding that translated into sclerosteosis patients. We hypothesize that the altered bone composition contributes to the increased bone strength of patients with sclerostin deficiency. PMID- 24753093 TI - Nasal bone length, prenasal thickness, prenasal thickness-to-nasal bone length ratio and prefrontal space ratio in second- and third-trimester fetuses with Down syndrome. AB - OBJECTIVES: To evaluate nasal bone length (NBL), prenasal thickness (PT), prenasal thickness-to-nasal bone length (PT-NBL) ratio and prefrontal space ratio (PFSR) as markers for Down syndrome in the second and third trimesters. METHODS: NBL, PT, PT-NBL ratio and PFSR were measured retrospectively in stored two dimensional images or three-dimensional volumes (corrected to the mid-sagittal plane) of fetuses with Down syndrome, which were retrieved from the digital databases of participating units. Measurements were performed on the stored images and volumes by two experienced operators, and the values obtained were compared to our previously reported normal ranges for euploid fetuses in order to assess the detection rates for Down syndrome. RESULTS: A total of 159 fetuses with Down syndrome were included in the analysis, six of which were excluded because of inadequate available images. Median maternal age was 36.0 years and median gestational age was 23 + 1 weeks. NBL and PT were correlated with gestational age (P < 0.001), but the PT-NBL ratio and PFSR were not. Mean NBL, PT, PT-NBL ratio and PFSR were 4.42 mm, 5.56 mm, 1.26 and 0.34, respectively. The nasal bone was absent in 23 (15.4%) cases. As a marker for Down syndrome, the PT NBL ratio yielded the highest detection rate (86.2%), followed by PFSR (79.7%), PT (63.4%) and NBL (61.9%). All markers were abnormal in 33.6% of cases, whilst all were normal in 4.7%. At least one of the four markers was abnormal in 95.3%, and either the PT-NBL ratio or PFSR was abnormal in 93.8%. Detection rates were not related to gestational age. CONCLUSIONS: The PT-NBL ratio and PFSR are robust second- and third-trimester markers for Down syndrome. Both provide high detection rates and are easy to use, as the cut-off for normality is constant throughout gestation. Ltd. PMID- 24753094 TI - Determination of nanosilver dissolution kinetics and toxicity in an environmentally relevant aqueous medium. AB - Assessing the dissolution of silver nanoparticles (AgNPs) in laboratory test media and in the aquatic environment is critical for determining toxicity. In the present study, the ion-release kinetics for 20-nm, 50-nm, and 80-nm AgNPs in environmentally relevant freshwaters with different electrical conductivity values (30 uS/cm, 150 uS/cm) were examined and related to the associated impact on Daphnia magna. The acute toxicity of the AgNP suspensions to D. magna was assessed after 0 d and 7 d of interaction time between the particles and test media. When 48-h lethal median concentrations were expressed as total silver, D. magna was more sensitive to AgNPs suspended in low ionic strength media relative to higher ionic strength media, with the exception of 50-nm AgNPs suspended in the 150-uS/cm medium. A 3.3-fold increase in hydrodynamic diameter measured by dynamic light scattering and field flow fractionation was observed over time for 20-nm particles in the 150-uS/cm medium, but only a small increase in aggregation size for 50-nm and 80-nm particles (1.4-fold and 1.2-fold increase, respectively) was observed. At a lower conductivity of 30 uS/cm, a 1.7-fold, 1.0-fold, and 1.2 fold increase in aggregation size was observed in the 20-nm, 50-nm, and 80-nm particles, respectively. Thus, the impact of higher conductivity test media on increased aggregation and decreased toxicity (after 7 d) was relatively greater for the smaller (20-nm) AgNP higher compared to the 50-80 nm AgNPs. PMID- 24753095 TI - Guideline for the prevention and treatment of anticipatory nausea and vomiting due to chemotherapy in pediatric cancer patients. AB - This guideline provides an approach to the prevention and treatment of anticipatory chemotherapy-induced nausea and vomiting (CINV) in children. It was developed by an international, inter-professional panel using AGREE II methods and is based on systematic literature reviews. Evidence-based recommendations for pharmacological and non-pharmacological interventions to prevent and treat anticipatory CINV in children receiving antineoplastic agents are provided. Gaps in the evidence used to support the recommendations are identified. The contribution of this guideline to anticipatory CINV control in children requires prospective evaluation. PMID- 24753096 TI - From the Lindlar catalyst to supported ligand-modified palladium nanoparticles: selectivity patterns and accessibility constraints in the continuous-flow three phase hydrogenation of acetylenic compounds. AB - Site modification and isolation through selective poisoning comprise an effective strategy to enhance the selectivity of palladium catalysts in the partial hydrogenation of triple bonds in acetylenic compounds. The recent emergence of supported hybrid materials matching the stereo- and chemoselectivity of the classical Lindlar catalyst holds promise to revolutionize palladium-catalyzed hydrogenations, and will benefit from an in-depth understanding of these new materials. In this work, we compare the performance of bare, lead-poisoned, and ligand-modified palladium catalysts in the hydrogenation of diverse alkynes. Catalytic tests, conducted in a continuous-flow three-phase reactor, coupled with theoretical calculations and characterization methods, enable elucidation of the structural origins of the observed selectivity patterns. Distinctions in the catalytic performance are correlated with the relative accessibility of the active site to the organic substrate, and with the adsorption configuration and strength, depending on the ensemble size and surface potentials. This explains the role of the ligand in the colloidally prepared catalysts in promoting superior performance in the hydrogenation of terminal and internal alkynes, and short-chain alkynols. In contrast, the greater accessibility of the active surface of the Pd-Pb alloy and the absence of polar groups are shown to be favorable in the conversion of alkynes containing long aliphatic chains and/or ketone groups. These findings provide detailed insights for the advanced design of supported nanostructured catalysts. PMID- 24753097 TI - Cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS), innate immune responses, and viral hepatitis. PMID- 24753098 TI - Repeated dose and reproductive/developmental toxicity of perfluorododecanoic acid in rats. AB - Perfluoroalkyl carboxylic acids (PFCAs) are a series of environmental contaminants that have received attention because of their possible adverse effects on wildlife and human health. Although many toxicological studies have been performed on perfluorooctanoic acid with carbon chain length C8, available toxicity data on PFCAs with longer chains are still insufficient to evaluate their hazard. A combined repeated dose and reproductive/developmental toxicity screening study for perfluorododecanoic acid (PFDoA; C12) was conducted in accordance with OECD guideline 422 to fill these toxicity data gaps. PFDoA was administered by gavage to male and female rats at 0.1, 0.5, or 2.5 mg/kg/day. The administration of PFDoA at 0.5 and 2.5 mg/kg/day for 42-47 days mainly affected the liver, in which hypertrophy, necrosis, and inflammatory cholestasis were noted. Body weight gain was markedly inhibited in the 2.5 mg/kg/day group, and a decrease in hematopoiesis in the bone marrow and atrophic changes in the spleen, thymus, and adrenal gland were also observed. Regarding reproductive/developmental toxicity, various histopathological changes, including decreased spermatid and spermatozoa counts, were observed in the male reproductive organs, while continuous diestrous was observed in the females of the 2.5 mg/kg/day group. Seven of twelve females receiving 2.5 mg/kg/day died during late pregnancy while four other females in this group did not deliver live pups. No reproductive or developmental parameters changed at 0.1 or 0.5 mg/kg/day. Based on these results, the NOAELs of PFDoA were concluded to be 0.1 mg/kg/day for repeated dose toxicity and 0.5 mg/kg/day for reproductive/developmental toxicity. PMID- 24753099 TI - Complex difference constrained compressed sensing reconstruction for accelerated PRF thermometry with application to MRI-induced RF heating. AB - PURPOSE: Introduce a novel compressed sensing reconstruction method to accelerate proton resonance frequency shift temperature imaging for MRI-induced radiofrequency heating evaluation. METHODS: A compressed sensing approach that exploits sparsity of the complex difference between postheating and baseline images is proposed to accelerate proton resonance frequency temperature mapping. The method exploits the intra-image and inter-image correlations to promote sparsity and remove shared aliasing artifacts. Validations were performed on simulations and retrospectively undersampled data acquired in ex vivo and in vivo studies by comparing performance with previously published techniques. RESULTS: The proposed complex difference constrained compressed sensing reconstruction method improved the reconstruction of smooth and local proton resonance frequency temperature change images compared to various available reconstruction methods in a simulation study, a retrospective study with heating of a human forearm in vivo, and a retrospective study with heating of a sample of beef ex vivo. CONCLUSION: Complex difference based compressed sensing with utilization of a fully sampled baseline image improves the reconstruction accuracy for accelerated proton resonance frequency thermometry. It can be used to improve the volumetric coverage and temporal resolution in evaluation of radiofrequency heating due to MRI, and may help facilitate and validate temperature-based methods for safety assurance. PMID- 24753100 TI - The anticoagulant activated protein C (aPC) promotes metaplasticity in the hippocampus through an EPCR-PAR1-S1P1 receptors dependent mechanism. AB - Thrombin and other clotting factors regulate long-term potentiation (LTP) in the hippocampus through the activation of the protease activated receptor 1 (PAR1) and consequent potentiation of N-methyl-d-aspartate receptor (NMDAR) functions. We have recently shown that the activation of PAR1 either by thrombin or the anticoagulant factor activated protein C (aPC) has differential effects on LTP. While thrombin activation of PAR1 induces an NMDAR-mediated slow onset LTP, which saturates the ability to induce further LTP in the exposed network, aPC stimulation of PAR1 enhances tetanus induced LTP through a voltage-gated calcium channels mediated mechanism. In this study, we addressed the mechanisms by which aPC enhances LTP in hippocampal slices. Using extracellular recordings, we show that a short tetanic stimulation, which does not induce LTP, is able to enhance plasticity in the presence of aPC through a mechanism that requires the activation of sphingosine-1 phosphate receptor 1 and intracellular Ca(2+) stores. These data identify aPC as a "metaplastic molecule", capable of shifting the threshold of LTP towards further potentiation. Our findings propose novel strategies to enhance plasticity in neurological diseases associated with the breakdown of the blood brain barrier and alterations in synaptic plasticity. PMID- 24753101 TI - The content of amino acids in artificial diet influences the development and reproduction of brown planthopper, Nilaparvata lugens (STAL). AB - Nitrogen availability from dietary protein has profound effects on the physiology and ecology of insect herbivores. The amount of amino acids consumed by Nilaparvata lugens impacts its phenotypic characteristics and reproduction. In this work, we hypothesized that amino acids deficiency leads to physiological trade-offs between survival and reproduction. We investigated the effect of larval nutrition on larval period, wing dimorphism, egg production, ovarian development, lifespan, and stored nutrients. Larvae were reared on the standard medium and an amino acid deficient medium (AADM), adults were reared on the standard medium. Nymphs reared on AADM had shorter larval period (20.78 d/23.09 d), higher brachypterous forms (34.06%/16.52%), the adults females were fed back on standard medium after emergency, they featured extended preoviposition period (11.41/13.45 d), declining number of laid eggs (2.27/37.44), ovarian dysplasia, and shorter lifespan compared with control group. Adults from both dietary treatment groups had approximately the same proportion of total lipids and protein nutrients carried over from larvae feeding into adulthood. We infer that N. lugens makes a physiological trade-off between survival and reproduction by suppressing ovarian development. This is probably a common strategy during times of nutritional deficiency in nature. PMID- 24753103 TI - Adaptability in stone tool use by wild capuchin monkeys (Sapajus libidinosus). AB - Capuchin monkeys are well known for population variation in the use of stone tools and the types of food items consumed. In order to determine adaptability in stone tool use, we investigated a never before studied population of wild capuchin monkey (Sapajus libidinosus) displaying terrestrial habits in a Caatinga environment. To carry out this study we recorded physical evidence of the use of stone tools as well as made direct observations through trap cameras. During a 15 month period, we studied a group of Sapajus libidinosus in Serra Talhada, Pernambuco, Brazil. In total, 257 anvils and 395 hammers were identified, characterized, and monitored. We identified five types of food items exploited at these "tool use sites": Syagrus oleracea (catole palm), Manihot epruinosa (manioc), Pilosocereus pachycladus (facheiro), Tacinga inamoena (quipa), and Commiphora leptophloeos (imburana de cambao). Five hundred three video clips of capuchin monkeys were recorded, 43 of which involved the use of stone tools. The results indicated evidence of adaptability in tool use by the capuchins. We verified that the rigidity and size of the food item, along with the presence or absence of spines seem to influence the choice of stone tools made by the animals for processing the food. The recurring use of tools for the processing of cacti was especially noteworthy and it appears that the presence of spines predisposes the capuchins to use stones to process them. A significant difference was observed between the characteristics of the anvils and the weight of the hammers according to the food item consumed. The use of tools enabled the animals to access otherwise unavailable or difficult to acquire food items within a Caatinga habitat. Adaptability in the use of stone tools by the capuchin monkey population of Serra Talhada provides an example of the complexity that these primates demonstrate in food processing. PMID- 24753102 TI - Automated detection of the arterial input function using normalized cut clustering to determine cerebral perfusion by dynamic susceptibility contrast magnetic resonance imaging. AB - PURPOSE: To propose a new clustering method for the automatic detection of arterial input function (AIF) with high accuracy in dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI). MATERIALS AND METHODS: A novel method for automatically determining the AIF was proposed to facilitate the analysis of MR perfusion, which relied on normalized cut (Ncut) clustering. Its performance was compared with those of two other previously reported clustering methods: k-means and fuzzy c-means (FCM) techniques, in terms of the detection accuracy and computational time. Both simulated perfusion data and data collected from 42 healthy human subjects were applied to investigate the feasibility of the proposed approach. RESULTS: In the simulation study, the partial volume effect (PVE) level, peak value (PV), time to peak (TTP), full width at half maximum (FWHM), area under AIF curve (AUC), root mean square error (RMSE) between the estimated AIF and true AIF, and M value given by [PV/(FWHM*TTP)] were 45.45, 4.2737, 29.92, 6.4563, 76.4836, 0.0519, and 0.0221 for Ncut-based AIF, 96.45, 3.8385, 31.74, 7.5133, 75.7364, 0.3295, and 0.0161 for FCM-based AIF, 91.18, 3.8990, 31.73, 7.4544, 76.0476, 0.3128, and 0.0165 for k-means-based AIF, 0, 4.4592, 29.51, 6.2016, 76.8669, 0, and 0.0244 for true AIF. In the clinical study, the mean PV, TTP, FWHM, AUC, M, error between estimated AIF and manual AIF were 1.7395, 30.95, 5.5923, 19.1081, 0.0397, and 0.4406 for Ncut-based AIF, 1.3629, 31.31, 6.8616, 17.9992, 0.0123, and 0.0846 for k-means-based AIF, 1.2101, 31.61, 7.1729, 16.6238, 0.0102, and 0.1016 for FCM-based AIF. The differences in PV, M, FWHM, and error reached a significant level (P = 0.032, 0.010, 0.003, and 0.002, respectively) between Ncut and k-means methods as well as between Ncut and FCM methods (P = 0.013, 0.008, 0.007, and 0.009, respectively). There was no significant difference in TTP between Ncut and each of the other two methods (P = 0.173 and 0.097, respectively). For AUC, a significant difference was found between Ncut and FCM algorithms (P = 0.025), but not between Ncut and k-means methods (P = 0.138). The mean execution time was 0.4406 for the Ncut method, 0.2649 for the k-means method, and 0.1371 for the FCM method, and the differences were significant both between Ncut and k-means methods (P = 0.002) and between Ncut and FCM methods (P = 0.004). CONCLUSION: Ncut clustering yield AIFs more in line with the expected AIF, and might be preferred to FCM and k-means clustering methods sensitive to randomly selected initial centers. PMID- 24753104 TI - Inhibitor development: The last enemy to be defeated in hemophilia A and B. PMID- 24753106 TI - Nrf2 regulates neurogenesis and protects neural progenitor cells against Abeta toxicity. AB - Neural stem/progenitor cells (NPCs) proliferate and produce new neurons in neurogenic areas throughout the lifetime. While these cells represent potential therapeutic treatment of neurodegenerative diseases, regulation of neurogenesis is not completely understood. We show that deficiency of nuclear factor erythroid 2-related factor (Nrf2), a transcription factor induced in response to oxidative stress, prevents the ischemia-induced increase in newborn neurons in the subgranular zone of the dentate gyrus. Consistent with this finding, the growth of NPC neurospheres was increased by lentivirus-mediated overexpression of Nrf2 gene or by treatment with pyrrolidine dithiocarbamate (PDTC), an Nrf2 activating compound. Also, neuronal differentiation of NPCs was increased by Nrf2 overexpression or PDTC treatment but reduced by Nrf2 deficiency. To investigate the impact of Nrf2 on NPCs in Alzheimer's disease (AD), we treated NPCs with amyloid beta (Abeta), a toxic peptide associated with neurodegeneration and cognitive abnormalities in AD. We found that Abeta1-42-induced toxicity and reduction in neurosphere proliferation were prevented by Nrf2 overexpression, while Nrf2 deficiency enhanced the Abeta1-42-induced reduction of neuronal differentiation. On the other hand, Abeta1-40 had no effect on neurosphere proliferation in wt NPCs but increased the proliferation of Nrf2 overexpressing neurospheres and reduced it in Nrf2-deficient neurospheres. These results suggest that Nrf2 is essential for neuronal differentiation of NPCs, regulates injury induced neurogenesis and provides protection against Abeta-induced NPC toxicity. PMID- 24753107 TI - Obesity and hepatocellular carcinoma: hype and reality. PMID- 24753105 TI - Novel domains of expression for orphan receptor tyrosine kinase Ror2 in the human and mouse reproductive system. AB - BACKGROUND: The noncanonical Wnt receptor and tyrosine kinase Ror2 has been associated with recessive Robinow syndrome (RRS) and dominant brachydactyly type B1. The phenotypes of mouse mutants implicate Ror2 in the development of the heart, lungs, bone, and craniofacial structures, which are affected in RRS. Following a recently identified role of Ror2 in the migration of mouse primordial germ cells, we extensively characterized its expression throughout the fetal internal reproductive system and the postnatal ductal system. RESULTS: We show that Ror2 gene products are present in the germ cells and somatic cells of the testis and the ovary of both the mouse and human fetus. In reproductive tract structures, we find that Ror2 is expressed in the mesonephros, developing Wolffian and Mullerian ducts, and later in their derivatives, the epididymal epithelium and uterine epithelium. CONCLUSIONS: This study sets the stage to explore function for this tyrosine kinase receptor in novel regions of expression in the developing reproductive system in both mouse and human. PMID- 24753108 TI - Essential function of the N-termini tails of the proteasome for the gating mechanism revealed by molecular dynamics simulations. AB - Proteasome is involved in the degradation of proteins. Proteasome activators bind to the proteasome core particle (CP) and facilitate opening a gate of the CP, where Tyr8 and Asp9 in the N-termini tails of the CP form the ordered open gate. In a double mutant (Tyr8Gly/Asp9Gly), the N-termini tails are disordered and the stabilized open-gate conformation cannot be formed. To understand the gating mechanism of the CP for the translocation of the substrate, four different molecular dynamics simulations were carried out: ordered- and Tyr8Gly/Asp9Gly disordered-gate models of the CP complexed with an ATP-independent PA26 and ordered- and disordered-gate models of the CP complexed with an ATP-dependent PAN like activator. The free-energies of the translocation of a polypeptide substrate moving through the gate were estimated. In the ordered-gate models, the substrate in the activator was more stable than that in the CP. The conformational entropy of the N-termini tails of the CP was larger when the substrate was in the activator than in the CP. In the disordered-gate models, the substrate in the activator was more destabilized than in the ordered-gate models. The mutated N termini tails became randomized and their increased conformational entropy could no longer increase further even when the substrate was in the activator, meaning the randomized N-termini tails had lost the ability to stabilize the substrate in the activator. Thus, it was concluded that the dynamics of the N-termini tails entropically play a key role in the translocation of the substrate. PMID- 24753109 TI - Pyrene-based bisazolium salts: from luminescence properties to janus-type bis-N heterocyclic carbenes. AB - A series of pyrene-based bisazolium salts have been obtained starting from 4,5,9,10-tetrabromo-2,7-di-tert-butylpyrene. The synthetic procedure to the pyrene-bisazoliums (PBIs) reveals an unexpected behavior, as a consequence of the presence of the alkyl groups (alkyl=Me, Et, n-Pr, and n-Bu) coming from the trisalkoxyformate in the final products, instead of the expected tBu of tAmyl groups from the starting tetra-aminated pyrenes. All bisazoliums show fluorescence properties, with emissions in the range of 370-420 nm, and quantum yields ranging from 0.29 to 0.41. The PBIs were used as bis-NHC precursors in the preparation of a series of dirhodium and diiridium complexes, which have been fully characterized. The electrochemical studies on selected dimetallic complexes reveal that the electronic communication between the metals through the polyaromatic linker is negligible. PMID- 24753110 TI - Hypothyroxinemia induced by maternal mild iodine deficiency impairs hippocampal myelinated growth in lactational rats. AB - Hypothyroxinemia induced by maternal mild iodine deficiency causes neurological deficits and impairments of brain function in offspring. Hypothyroxinemia is prevalent in developing and developed countries alike. However, the mechanism underlying these deficits remains less well known. Given that the myelin plays an important role in learning and memory function, we hypothesize that hippocampal myelinated growth may be impaired in rat offspring exposed to hypothyroxinemia induced by maternal mild iodine deficiency. To test this hypothesis, the female Wistar rats were used and four experimental groups were prepared: (1) control; (2) maternal mild iodine deficiency diet inducing hypothyroxinemia; (3) hypothyroidism induced by maternal severe iodine deficiency diet; (4) hypothyroidism induced by maternal methimazole water. The rats were fed the diet from 3 months before pregnancy to the end of lactation. Our results showed that the physiological changes occuring in the hippocampal myelin were altered in the mild iodine deficiency group as indicated by the results of immunofluorescence of myelin basic proteins on postnatal day 14 and postnatal day 21. Moreover, hypothyroxinemia reduced the expressions of oligodendrocyte lineage transcription factor 2 and myelin-related proteins in the treatments on postnatal day 14 and postnatal day 21. Our data suggested that hypothyroxinemia induced by maternal mild iodine deficiency may impair myelinated growth of the offspring. PMID- 24753111 TI - Pulsed electromagnetic fields partially preserve bone mass, microarchitecture, and strength by promoting bone formation in hindlimb-suspended rats. AB - A large body of evidence indicates that pulsed electromagnetic fields (PEMF), as a safe and noninvasive method, could promote in vivo and in vitro osteogenesis. Thus far, the effects and underlying mechanisms of PEMF on disuse osteopenia and/or osteoporosis remain poorly understood. Herein, the efficiency of PEMF on osteoporotic bone microarchitecture, bone strength, and bone metabolism, together with its associated signaling pathway mechanism, was systematically investigated in hindlimb-unloaded (HU) rats. Thirty young mature (3-month-old), male Sprague Dawley rats were equally assigned to control, HU, and HU + PEMF groups. The HU + PEMF group was subjected to daily 2-hour PEMF exposure at 15 Hz, 2.4 mT. After 4 weeks, micro-computed tomography (uCT) results showed that PEMF ameliorated the deterioration of trabecular and cortical bone microarchitecture. Three-point bending test showed that PEMF mitigated HU-induced reduction in femoral mechanical properties, including maximum load, stiffness, and elastic modulus. Moreover, PEMF increased serum bone formation markers, including osteocalcin (OC) and N-terminal propeptide of type 1 procollagen (P1NP); nevertheless, PEMF exerted minor inhibitory effects on bone resorption markers, including C-terminal crosslinked telopeptides of type I collagen (CTX-I) and tartrate-resistant acid phosphatase 5b (TRAcP5b). Bone histomorphometric analysis demonstrated that PEMF increased mineral apposition rate, bone formation rate, and osteoblast numbers in cancellous bone, but PEMF caused no obvious changes on osteoclast numbers. Real time PCR showed that PEMF promoted tibial gene expressions of Wnt1, LRP5, beta catenin, OPG, and OC, but did not alter RANKL, RANK, or Sost mRNA levels. Moreover, the inhibitory effects of PEMF on disuse-induced osteopenia were further confirmed in 8-month-old mature adult HU rats. Together, these results demonstrate that PEMF alleviated disuse-induced bone loss by promoting skeletal anabolic activities, and imply that PEMF might become a potential biophysical treatment modality for disuse osteoporosis. PMID- 24753113 TI - Cocaine-induced microangiopathic hemolytic anemia mimicking idiopathic thrombotic thrombocytopenic purpura: a case report and review of the literature. AB - Our understanding of the pathogenesis of idiopathic thrombotic thrombocytopenic purpura (TTP) has increased, but remains incomplete, particularly with respect to cases of suspected TTP that are either unresponsive to therapeutic plasma exchange (TPE) or have normal ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13) activity. A 53-year-old woman presented with severe anemia (hemoglobin 1.8 g/dL) and clinical and laboratory findings consistent with TTP in conjunction with acute cocaine use. The patient was treated with TPE until the pre-treatment ADAMTS13 activity was reported as normal without evidence of an inhibitor. TPE was stopped and the patient continued to improve without treatment. This patient's microangiopathic hemolytic anemia (MAHA) appeared to be secondary to cocaine use. The proposed pathogenesis is likely a combination of cocaine-induced vasoconstriction, vascular damage, platelet activation, and procoagulation. This is the fifth published report of cocaine-induced MAHA and to our knowledge the first with ADAMTS13 testing. PMID- 24753114 TI - Unexpected role of winter precipitation in determining heat requirement for spring vegetation green-up at northern middle and high latitudes. AB - Heat requirement, expressed in growing degree days (GDD), is a widely used method to assess and predict the effect of temperature on plant development. Until recently, the analysis of spatial patterns of GDD requirement for spring vegetation green-up onset was limited to local and regional scales, mainly because of the sparse and aggregated spatial availability of ground phenology data. Taking advantage of the large temporal and spatial scales of remote sensing based green-up onset data, we studied the spatial patterns of GDD requirement for vegetation green-up at northern middle and high latitudes. We further explored the correlations between GDD requirement for vegetation green-up and previous winter season chilling temperatures and precipitation, using spatial partial correlations. We showed that GDD requirement for vegetation green-up onset declines towards the north at a mean rate of 18.8 degrees C-days per degree latitude between 35 degrees N and 70 degrees N, and vary significantly among different vegetation types. Our results confirmed that the GDD requirement for vegetation green-up is negatively correlated with previous winter chilling, which was defined as the number of chilling days from the day when the land surface froze in the previous autumn to the day of green-up onset. This negative correlation is a well-known phenomenon from local studies. Interestingly, irrespective of the vegetation type, we also found a positive correlation between the GDD requirement and previous winter season precipitation, which was defined as the sum of the precipitation of the month when green-up onset occur and the precipitation that occurred during the previous 2 months. Our study suggests that GDD requirement, chilling and precipitation may have complex interactions in their effects on spring vegetation green-up phenology. These findings have important implications for improving phenology models and could therefore advance our understanding of the interplay between spring phenology and carbon fluxes. PMID- 24753112 TI - Neurotransmitter map of the asymmetric dorsal habenular nuclei of zebrafish. AB - The role of the habenular nuclei in modulating fear and reward pathways has sparked a renewed interest in this conserved forebrain region. The bilaterally paired habenular nuclei, each consisting of a medial/dorsal and lateral/ventral nucleus, can be further divided into discrete subdomains whose neuronal populations, precise connectivity, and specific functions are not well understood. An added complexity is that the left and right habenulae show pronounced morphological differences in many non-mammalian species. Notably, the dorsal habenulae of larval zebrafish provide a vertebrate genetic model to probe the development and functional significance of brain asymmetry. Previous reports have described a number of genes that are expressed in the zebrafish habenulae, either in bilaterally symmetric patterns or more extensively on one side of the brain than the other. The goal of our study was to generate a comprehensive map of the zebrafish dorsal habenular nuclei, by delineating the relationship between gene expression domains, comparing the extent of left-right asymmetry at larval and adult stages, and identifying potentially functional subnuclear regions as defined by neurotransmitter phenotype. Although many aspects of habenular organization appear conserved with rodents, the zebrafish habenulae also possess unique properties that may underlie lateralization of their functions. PMID- 24753115 TI - Novel inductive decoupling technique for flexible transceiver arrays of monolithic transmission line resonators. AB - PURPOSE: This article presents a novel inductive decoupling technique for form fitting coil arrays of monolithic transmission line resonators, which target biomedical applications requiring high signal-to-noise ratio over a large field of view to image anatomical structures varying in size and shape from patient to patient. METHODS: Individual transmission line resonator elements are mutually decoupled using magnetic flux sharing by overlapping annexes. This decoupling technique was evaluated by electromagnetic simulations and bench measurements for two- and four-element arrays, comparing single- and double-gap transmission line resonator designs, combined either with a basic capacitive matching scheme or inductive pickup loop matching. The best performing array was used in 7T MRI experiments demonstrating its form-fitting ability and parallel imaging potential. RESULTS: The inductively matched double-gap transmission line resonator array provided the best decoupling efficiency in simulations and bench measurements (<-15 dB). The decoupling and parallel imaging performance proved robust against mechanical deformation of the array. CONCLUSION: The presented decoupling technique combines the robustness of conventional overlap decoupling regarding coil loading and operating frequency with the extended field of view of nonoverlapped coils. While demonstrated on four-element arrays, it can be easily expanded to fabricate readily decoupled form-fitting 2D arrays with an arbitrary number of elements in a single etching process. PMID- 24753116 TI - Experience of barriers and motivations for physical activities and exercise during treatment of pediatric patients with cancer. AB - BACKGROUND: Due to growing evidence about the value of exercise in pediatric cancer patients, the purpose of this study was to determine factors that influence participation in physical activities and exercise in children and adolescents during treatment. PROCEDURE: This cross-sectional qualitative study included 40 pediatric cancer patients during intensive treatment. Patients were recruited at the Department for Pediatric Hematology and Oncology, University Hospital of Muenster where a supervised exercise program has been implemented for hospital stays. The qualitative approach included semi-structured guideline interviews, transcription and coding based on grounded theory. Four major topics were discussed in the interviews: (1) values and beliefs, (2) barriers to exercise, (3) motivations to exercise, and (4) encouragement from parents and physicians. RESULTS: Patients reported mainly positive attitudes toward physical activities during treatment and the local exercise program was desired and valued as essential for engaging in exercise during in-patient stays. Identified barriers included physical, psychological, and organizational aspects. Motivational aspects were based on improvements in physical fitness and mental well-being. Parents' behavior related to physical activities of their children differed between being supportive, inhibiting, and inert. Few patients received information about exercise during treatment by their physicians. CONCLUSIONS: Interventions that aim at maintaining physical activities during treatment and eliminating exercise barriers are required due to the patients' positive attitudes and multiple motivations toward exercise. These interventions need to be supervised and should include health-counseling programs for patients, parents, and physicians to underline the importance of physical activities in childhood cancer patients. PMID- 24753119 TI - Role of self-generated odor cues in contextual representation. AB - As first demonstrated in the patient H.M., the hippocampus is critically involved in forming episodic memories, the recall of "what" happened "where" and "when." In rodents, the clearest functional correlate of hippocampal primary neurons is the place field: a cell fires predominantly when the animal is in a specific part of the environment, typically defined relative to the available visuospatial cues. However, rodents have relatively poor visual acuity. Furthermore, they are highly adept at navigating in total darkness. This raises the question of how other sensory modalities might contribute to a hippocampal representation of an environment. Rodents have a highly developed olfactory system, suggesting that cues such as odor trails may be important. To test this, we familiarized mice to a visually cued environment over a number of days while maintaining odor cues. During familiarization, self-generated odor cues unique to each animal were collected by re-using absorbent paperboard flooring from one session to the next. Visual and odor cues were then put in conflict by counter-rotating the recording arena and the flooring. Perhaps surprisingly, place fields seemed to follow the visual cue rotation exclusively, raising the question of whether olfactory cues have any influence at all on a hippocampal spatial representation. However, subsequent removal of the familiar, self-generated odor cues severely disrupted both long-term stability and rotation to visual cues in a novel environment. Our data suggest that odor cues, in the absence of additional rule learning, do not provide a discriminative spatial signal that anchors place fields. Such cues do, however, become integral to the context over time and exert a powerful influence on the stability of its hippocampal representation. PMID- 24753120 TI - A Randomized controlled trial of motivational interviewing + self-help versus psychoeducation + self-help for binge eating. AB - OBJECTIVE: Motivational Interviewing (MI) is a collaborative therapy that focuses on strengthening a person's internal motivation to change. Research suggests that MI may be helpful for treating binge eating; however, findings are limited and little is known about how MI for binge eating compares to active therapy controls. The present study aimed to build on current research by comparing MI as a prelude to self-help treatment for binge eating with psychoeducation as a prelude to self-help treatment for binge eating. METHOD: Participants with full or subthreshold DSM-IV Binge Eating Disorder or nonpurging Bulimia Nervosa were randomly assigned to receive either 60 minutes of MI followed by a self-help manual (n = 24) or 60 minutes of psychoeducation followed by a self-help manual (n = 21). Questionnaires were completed pre- and postsession, and at 1 and 4 months postsession. RESULTS: MI significantly increased readiness to change and confidence in ability to control binge eating, whereas psychoeducation did not. No group differences were found when changes in eating disorder attitudes and behaviors were examined. DISCUSSION: MI offers benefits for increasing motivation and self-efficacy. However, it may not be a uniquely effective treatment approach for reducing binge eating. PMID- 24753121 TI - An NAD(+) biosynthetic pathway enzyme functions cell non-autonomously in C. elegans development. AB - BACKGROUND: Disruption of cellular metabolite levels can adversely impact development. Specifically, loss-of-function of the C. elegans NAD(+) salvage biosynthesis gene PNC-1 results in an array of developmental phenotypes. Intriguingly, PNC-1 and its functional equivalent in vertebrates are secreted, but the contributions of the extracellular enzymes are poorly understood. We sought to study the tissue-specific requirements for PNC-1 expression and to examine the role of the secreted isoform. RESULTS: A thorough analysis of PNC-1 expression did not detect expression in tissues that require PNC-1 function. Limited expression of both the secreted and intracellular PNC-1 isoforms provided function at a distance from the tissues with phenotypes. We also find that the secreted isoform contributes to in vivo PNC-1 activity. Furthermore, uv1 cell survival has the most stringent requirements in terms of PNC-1 expression pattern or level. CONCLUSIONS: Using careful promoter analysis and a restricted expression approach, we have shown that both the secreted and the intracellular PNC-1 isoforms function cell non-autonomously, and that the PNC-1a isoform is functionally relevant in vivo. Our work suggests a model where PNC-1 function is provided cell non-autonomously by a mix of intra and extracellular activity, most likely requiring NAD(+) salvage metabolite transport between tissues. PMID- 24753122 TI - Ex vivo gene editing of the dystrophin gene in muscle stem cells mediated by peptide nucleic acid single stranded oligodeoxynucleotides induces stable expression of dystrophin in a mouse model for Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutations in the dystrophin gene, which result in the complete absence of dystrophin protein throughout the body. Gene correction strategies hold promise to treating DMD. Our laboratory has previously demonstrated the ability of peptide nucleic acid single stranded oligodeoxynucleotides (PNA-ssODNs) to permanently correct single-point mutations at the genomic level. In this study, we show that PNA-ssODNs can target and correct muscle satellite cells (SCs), a population of stem cells capable of self-renewing and differentiating into muscle fibers. When transplanted into skeletal muscles, SCs transfected with correcting PNA-ssODNs were able to engraft and to restore dystrophin expression. The number of dystrophin-positive fibers was shown to significantly increase over time. Expression was confirmed to be the result of the activation of a subpopulation of SCs that had undergone repair as demonstrated by immunofluorescence analyses of engrafted muscles using antibodies specific to full-length dystrophin transcripts and by genomic DNA analysis of dystrophin-positive fibers. Furthermore, the increase in dystrophin expression detected over time resulted in a significant improvement in muscle morphology. The ability of transplanted cells to return into quiescence and to activate upon demand was confirmed in all engrafted muscles following injury. These results demonstrate the feasibility of using gene editing strategies to target and correct SCs and further establish the therapeutic potential of this approach to permanently restore dystrophin expression into muscle of DMD patients. PMID- 24753123 TI - Functional characterization of an antennal esterase from the noctuid moth, Spodoptera exigua. AB - Odorant-degrading esterases (ODEs) act in the fast deactivation of ester pheromone components and plant volatiles in insects. However, only few ODEs have been characterised to date. In this study, six full-length putative ODE genes (designated SexiCXE4, 5, 17, 18, 20, and 31) were cloned from the male antennae of Spodoptera exigua. The deduced amino acid sequences possessed typical characteristics of a carboxylesterase (CXE) and shared high identities with reported insect CXEs. The tissue and temporal expression patterns were investigated by quantitative real time PCR. Although all six SexiCXEs are expressed in antennae of both sexes, SexiCXE4, 17 and 20 are antennae-enriched; while SexiCXE5 and SexiCXE18 are dominantly expressed in wings, and SexiCXE31 is mainly expressed in proboscises, heads and legs. With the highly biased expression in antennae and proboscises, SexiCXE4 was selected for further functional assay. The recombinant SexiCXE4 were expressed in High-five cells and purified by a Ni(2+) affinity column. SexiCXE4 has much higher enzyme activity against plant volatiles (Z)-3-hexenyl acetate and hexyl acetate than to the sex pheromone components, suggesting that it may function mostly in the degradation of the plant volatiles. PMID- 24753125 TI - Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. AB - CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n = 402) and validation (n = 625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type 1 (P = 0.005) and younger age with type-2 (P = 0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P = 0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P = 0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. PMID- 24753126 TI - Object Oriented Data Analysis: A few methodological challenges. AB - This is a discussion of the paper "Overview of object oriented data analysis" by J. Steve Marron and Andres M. Alonso. PMID- 24753127 TI - Rapid plant species loss at high rates and at low frequency of N addition in temperate steppe. AB - Humans are both intentionally (fertilization) and unintentionally (atmospheric nutrient deposition) adding nutrients worldwide. Increasing availability of biologically reactive nitrogen (N) is one of the major drivers of plant species loss. It remains unclear, however, whether plant diversity will be equally reduced by inputs of reactive N coming from either small and frequent N deposition events or large and infrequent N fertilization events. By independently manipulating the rate and frequency of reactive N inputs, our study teases apart these potentially contrasting effects. Plant species richness decreased more quickly at high rates and at low frequency of N addition, which suggests that previous fertilization studies have likely over-estimated the effects of N deposition on plant species loss. N-induced species loss resulted from both acidification and ammonium toxicity. Further study of small and frequent N additions will be necessary to project future rates of plant species loss under increasing aerial N deposition. PMID- 24753124 TI - Endogenous bone regeneration is dependent upon a dynamic oxygen event. AB - Amputation of the digit tip within the terminal phalangeal bone of rodents, monkeys, and humans results in near-perfect regeneration of bone and surrounding tissues; however, amputations at a more proximal level fail to produce the same regenerative result. Digit regeneration is a coordinated, multifaceted process that incorporates signaling from bioactive growth factors both in the tissue matrix and from several different cell populations. To elucidate the mechanisms involved in bone regeneration we developed a novel multi-tissue slice-culture model that regenerates bone ex vivo via direct ossification. Our study provides an integrated multi-tissue system for bone and digit regeneration and allows us to circumvent experimental limitations that exist in vivo. We used this slice culture model to evaluate the influence of oxygen on regenerating bone. Micro computed tomography (uCT) and histological analysis revealed that the regenerative response of the digit is facilitated in part by a dynamic oxygen event, in which mutually exclusive high and low oxygen microenvironments exist and vacillate in a coordinated fashion during regeneration. Areas of increased oxygen are initially seen in the marrow and then surrounding areas of vasculature in the regenerating digit. Major hypoxic events are seen at 7 days postamputation (DPA 7) in the marrow and again at DPA 12 in the blastema, and manipulation of oxygen tensions during these hypoxic phases can shift the dynamics of digit regeneration. Oxygen increased to 21% oxygen tension can either accelerate or attenuate bone mineralization in a stage-specific manner in the regenerative timeline. These studies not only reveal a circumscribed frame of oxygen influence during bone regeneration, but also suggest that oxygen may be one of the primary signaling influences during regeneration. PMID- 24753128 TI - Randomization is not associated with socio-economic and demographic factors in a multi-center clinical trial of children with sickle cell anemia. AB - BACKGROUND: Few studies have investigated factors influencing participation rates for minority children with a chronic disease in clinical trials. The Silent Cerebral Infarct Multi-Center Clinical (SIT) Trial provides an opportunity to study the impact of demographic and socio-economic factors on randomization in a clinical trial among Black children. Our primary objective was to characterize the factors associated with successful randomization of children with sickle cell disease (SCD) and silent cerebral infarct (SCI) in the SIT Trial after initial consent. PROCEDURE: Differences in socio-economic and demographic variables, family history and disease-related variables were determined between eligible participants who were successfully randomized and those who were not randomized following initial consent. Head of household educational level and family income were examined separately for US versus non-US sites. RESULTS: Of 1,176 children enrolled in the SIT Trial, 1,016 (86%) completed screening. Of 208 (20%) children with qualifying SCI on pre-randomization MRI, 196 (94%) were successfully randomized. There were no differences in socio-economic, demographic, or disease related variables between children who were or were not randomized. Participants from non-US sites were more likely to be randomized (22% vs. 12%, P = 0.011); although, randomization by country was associated with neither head of household education nor family income. CONCLUSION: In the SIT Trial, acceptance of random allocation was not associated with socio-economic or demographic factors. Although these factors may represent barriers for some participants, they should not bias investigators caring for children with SCD in their approach to recruitment for clinical trial participation. PMID- 24753129 TI - Amazonian societies on the brink of extinction. AB - OBJECTIVES: Greater Amazonia harbors as many as 100 locations of isolated indigenous peoples. Few options are available to assess the demographic health of these populations given their limited contact with the outside world. Remote sensing offers one option. METHODS: An isolated village in Brazil near the Peruvian border is visible with Google Earth imagery from 2006. The area of the fields and village, as well as the living area of the four longhouses, are measured and compared to population-by-area measurements for 71 other Brazilian indigenous communities. RESULTS: The estimated population of the village is no more than 40 people. A village as small as this one, if it has become disconnected from a metapopulation, risks imminent extinction if it has fallen below a minimum viable population size. CONCLUSIONS: An active remote surveillance program is urgently needed to track the movements and demographic health of isolated peoples in hopes of improving their dire chances for long-term survival. They need protected areas that are large enough to mitigate against external threats. PMID- 24753130 TI - Optimized saturation pulse train for human first-pass myocardial perfusion imaging at 7T. AB - PURPOSE: To investigate whether saturation using existing methods developed for 3T imaging is feasible for clinical perfusion imaging at 7T, and to propose a new design of saturation pulse train for first-pass myocardial perfusion imaging at 7T. METHODS: The new design of saturation pulse train consists of four hyperbolic secant (HS8) radiofrequency pulses, whose peak amplitudes are optimized for a target range of static and transmit field variations and radiofrequency power deposition restrictions measured in the myocardium at 7T. The proposed method and existing methods were compared in simulation, phantom, and in vivo experiments. RESULTS: In healthy volunteer experiments without contrast agent, average saturation efficiency with the proposed method was 97.8%. This is superior to results from the three previously published methods at 86/95/90.8%. The first series of human first-pass myocardial perfusion images at 7T have been successfully acquired with the proposed method. CONCLUSION: Existing saturation methods developed for 3T imaging are not optimal for perfusion imaging at 7T. The proposed new design of saturation pulse train can saturate effectively, and with this method first-pass myocardial perfusion imaging is feasible in humans at 7T. PMID- 24753131 TI - Binuclear trans-bis(beta-iminoaryloxy)palladium(II) complexes doubly linked with pentamethylene spacers: structure-dependent flapping motion and heterochiral association behavior of the clothespin-shaped molecules. AB - The synthesis, structure, and solution-state behavior of clothespin-shaped binuclear trans-bis(beta-iminoaryloxy)palladium(II) complexes doubly linked with pentamethylene spacers are described. Achiral syn and racemic anti isomers of complexes 1-3 were prepared by treating Pd(OAc)2 with the corresponding N,N' bis(beta-hydroxyarylmethylene)-1,5-pentanediamine and then subjecting the mixture to chromatographic separation. Optically pure (100 % ee) complexes, (+)-anti-1, (+)-anti-2, and (+)-anti-3, were obtained from the racemic mixture by employing a preparative HPLC system with a chiral column. The trans coordination and clothespin-shaped structures with syn and anti conformations of these complexes have been unequivocally established by X-ray diffraction studies. (1)H NMR analysis showed that (+/-)-anti-1, (+/-)-anti-2, syn-2, and (+/-)-anti-3 display a flapping motion by consecutive stacking association/dissociation between cofacial coordination planes in [D8]toluene, whereas syn-1 and syn-3 are static under the same conditions. The activation parameters for the flapping motion (DeltaH(?) and DeltaS(?)) were determined from variable-temperature NMR analyses as 50.4 kJ mol(-1) and 60.1 J mol(-1) K(-1) for (+/-)-anti-1, 31.0 kJ mol(-1) and -22.7 J mol(-1) K(-1) for (+/-)-anti-2, 29.6 kJ mol(-1) and -57.7 J mol(-1) K(-1) for syn-2, and 35.0 kJ mol(-1) and 0.5 J mol(-1) K(-1) for (+/-)-anti-3, respectively. The molecular structure and kinetic parameters demonstrate that all of the anti complexes flap with a twisting motion in [D8]toluene, although (+/-) anti-1 bearing dilated Z-shaped blades moves more dynamically than I-shaped (+/-) anti-2 or the smaller (+/-)-anti-3. Highly symmetrical syn-2 displays a much more static flapping motion, that is, in a see-saw-like manner. In CDCl3, (+/-)-anti-1 exhibits an extraordinary upfield shift of the (1)H NMR signals with increasing concentration, whereas solutions of (+)-anti-1 and the other syn/anti analogues 2 and 3 exhibit negligible or slight changes in the chemical shifts under the same conditions, which indicates that anti-1 undergoes a specific heterochiral association in the solution state. Equilibrium constants for the dimerizations of (+/-)- and (+)-anti-1 in CDCl3 at 293 K were estimated by curve-fitting analysis of the (1)H NMR chemical shift dependences on concentration as 26 M(-1) [KD(racemic)] and 3.2 M(-1) [KD(homo)], respectively. The heterochiral association constant [KD(hetero)] was estimated as 98 M(-1), based on the relationship KD(racemic) = 1/2 KD(homo) +1/4 KD(hetero). An inward stacking motif of interpenetrative dimer association is postulated as the mechanistic rationale for this rare case of heterochiral association. PMID- 24753132 TI - Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease. AB - Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, a drawback especially in evaluation of biopsies for clinical trials. We previously developed a scoring system (steatosis, activity, fibrosis [SAF]) allowing the use of an algorithm (fatty liver inhibition of progression [FLIP]) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance in classification increased in Group 1 from moderate (kappa = 0.54) to substantial (kappa = 0.66) and from fair (kappa = 0.35) to substantial (kappa = 0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (kappa = 0.61), activity (kappa = 0.75), and almost perfect for fibrosis (kappa = 0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (kappa = 0.54 for S, kappa = 0.68 for A, and kappa = 0.72 for F). CONCLUSION: The FLIP algorithm based on the SAF score should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. PMID- 24753133 TI - Left-right asymmetry of the gnathostome skull: its evolutionary, developmental, and functional aspects. AB - Much of the gnathostome (jawed vertebrate) evolutionary radiation was dependent on the ability to sense and interpret the environment and subsequently act upon this information through utilization of a specialized mode of feeding involving the jaws. While the gnathostome skull, reflective of the vertebrate bauplan, typically is bilaterally symmetric with right (dextral) and left (sinistral) halves essentially representing mirror images along the midline, both adaptive and abnormal asymmetries have appeared. Herein we provide a basic primer on studies of the asymmetric development of the gnathostome skull, touching briefly on asymmetry as a field of study, then describing the nature of cranial development and finally underscoring evolutionary and functional aspects of left right asymmetric cephalic development. PMID- 24753134 TI - Impaired hippocampus-dependent spatial flexibility and sociability represent autism-like phenotypes in GluK2 mice. AB - Autism is a complex neurodevelopmental disorder with high heritability. grik2 (which encodes the GluK2 subunit of kainate receptors) has been identified as a susceptibility gene in Autism Spectrum Disorders (ASD), but its role in the core and associated symptoms of ASD still remains elusive. We used mice lacking GluK2 (GluK2 KO) to examine their endophenotype with a view to modeling aspects of autism, including social deficits, stereotyped and repetitive behavior and decreased cognitive abilities. Anxiety was recorded in the elevated plus maze, social behavior in a three-chamber apparatus, and cognition in different water maze protocols. Deletion of the GluK2 gene reduced locomotor activity and sociability as indicated by the social interaction task. In addition, GluK2 KO mice learnt to locate a hidden platform in a water maze surrounded by a curtain with hanging cues faster than wild-type mice. They maintained a bias toward the target quadrant when some of these cues were removed, at which point wild-types orthogonalized the behavior and showed no memory. However, GluK2 KO mice were impaired in spatial reversal learning. These behavioral data together with previously published electrophysiology showing severe anomalies in CA3 network activity, suggest a computational shift in this network for enhanced propensity of pattern completion that would explain the loss of behavioral flexibility in GluK2 KO mice. Although a single mutation cannot recapitulate the entire core symptoms of ASD, our data provide evidence for glutamatergic dysfunction underlying a number of social- and cognition-related phenotypes relevant to ASD. PMID- 24753136 TI - Barrett's esophagus in anorexia nervosa: a case report. AB - Barrett's esophagus (BE) is a metaplastic lesion that may result from long lasting gastroesophageal reflux and it is an established precursor of esophageal adenocarcinoma. There are reports of an increased prevalence of BE, and eventually esophageal adenocarcinoma, in patients with eating disorders characterized by purging behaviors like those with bulimia nervosa (BN). Among patients with eating disorders, those affected by anorexia nervosa binging purging subtype (ANBP), are behaviorally very similar to those with BN, but to our knowledge there are no data in literature about BE in patients with ANBP. We present the case of a 37-year-old female with a 20-year history of ANBP in comorbidity with bipolar disorder, who developed a BE requiring multi specialistic intervention. PMID- 24753135 TI - PRL2/PTP4A2 phosphatase is important for hematopoietic stem cell self-renewal. AB - Hematopoietic stem cell (HSC) self-renewal is tightly controlled by cytokines and other signals in the microenvironment. While stem cell factor (SCF) is an early acting cytokine that activates the receptor tyrosine kinase KIT and promotes HSC maintenance, how SCF/KIT signaling is regulated in HSCs is poorly understood. The protein tyrosine phosphatase 4A (PTP4A) family (aka PRL [phosphatase of regenerating liver] phosphatases), consisting of PTP4A1/PRL1, PTP4A2/PRL2, and PTP4A3/PRL3, represents an intriguing group of phosphatases implicated in cell proliferation and tumorigenesis. However, the role of PTP4A in hematopoiesis remains elusive. To define the role of PTP4A in hematopoiesis, we analyzed HSC behavior in Ptp4a2 (Prl2) deficient mice. We found that Ptp4a2 deficiency impairs HSC self-renewal as revealed by serial bone marrow transplantation assays. Moreover, we observed that Ptp4a2 null hematopoietic stem and progenitor cells (HSPCs) are more quiescent and show reduced activation of the AKT and ERK signaling. Importantly, we discovered that the ability of PTP4A2 to enhance HSPC proliferation and activation of AKT and ERK signaling depends on its phosphatase activity. Furthermore, we found that PTP4A2 is important for SCF-mediated HSPC proliferation and loss of Ptp4a2 decreased the ability of oncogenic KIT/D814V mutant in promoting hematopoietic progenitor cell proliferation. Thus, PTP4A2 plays critical roles in regulating HSC self-renewal and mediating SCF/KIT signaling. PMID- 24753138 TI - The Drosophila Chmp1 protein determines wing cell fate through regulation of epidermal growth factor receptor signaling. AB - BACKGROUND: Receptor down-regulation by the multivesicular body (MVB) pathway is critical for many cellular signaling events. MVB generation is mediated by the highly conserved ESCRT (0, I, II, and III) protein complexes. Chmp1 is an ESCRT III component and a putative tumor suppressor in humans. However, published data on Chmp1 activity are conflicting and its role during tissue development is not well defined. RESULTS: We investigated the function of Drosophila Chmp1 and found that it is an essential gene. In the wing, loss of Chmp1 activity causes a cell fate change from intervein to vein, and interactions between Chmp1 and Drosophila Epidermal Growth Factor Receptor (DER) regulators suggest that Chmp1 negatively regulates DER signaling. Chmp1 knockdown also decreases Blistered expression, which is repressed by DER signaling. We find that Chmp1 protein localizes to the late endosome in Drosophila embryos, which is consistent with its effects on DER signaling resulting from its function in the ESCRT-III complex. CONCLUSIONS: Drosophila Chmp1 negatively regulates DER signaling, likely through its role in MVB formation. Loss of Chmp1 activity in the Drosophila wing induces a cell fate change from intervein to vein that should provide a useful tool for future studies of ESCRT protein activity. PMID- 24753137 TI - Dietary lufenuron reduces egg hatch and influences protein expression in the fruit fly Bactrocera latifrons (Hendel). AB - Lufenuron (LFN), a chitin synthase inhibitor, impacts the fertility of Ceratitis capitata, Bactrocera dorsalis, B. cucurbitae, and B. latifrons. We posed the hypothesis that LFN curtails egg hatch in the solanaceous fruit fly, B. latifrons. In this study, newly emerged virgin adults were sexed and fed for 12 days with varying concentrations of LFN-laced agar diets until sexual maturation. Eggs were collected from 12-d-old adults and the egg hatch was assessed. Egg hatch decreased in adults reared on LFN-treated diets. LFN-treated media did not influence fertility after one gender was reared on experimental and the other on control media before mating. Exposure to LFN-treated medium after mating led to reduced egg hatch. We infer that LFN is not a permanent sterilant, and reduced egg hatch depends on continuous exposure to dietary LFN after mating. Proteomic analysis identified two differentially expressed proteins, a pheromone binding protein and a chitin binding protein, between adults maintained on LFN-treated and control diets. Expression of two genes encoding chitin synthase 2, and chitin binding protein, was altered in adults exposed to dietary LFN. LFN treatments also led to increased expression of two odorant binding proteins one in females and one in males. We surmise these data support our hypothesis and provide insight into LFN actions. PMID- 24753139 TI - Mammalian nerve globins in search of functions. AB - Nerve globins are present in nonvertebrates and vertebrates, the first nerve globin having been recognized in the nerve cord of the polychaete annelid Aphrodite aculeata in 1872. Later, in 2000, the first vertebrate nerve globin, named neuroglobin (Ngb), has been identified in neuronal tissues of humans and mice. Recently, cytoglobin, hemoglobin, and myoglobin have also been reported to be expressed in the mammalian nervous system. The concentration of mammalian nerve globins is ~1 MUM, with the exception of Ngb that reaches approximately 100 200 MUM only in the retina rod cells. Mammalian nerve globins have been hypothesized to be involved in the excitability of the nervous system, in the metabolism of reactive nitrogen and oxygen species, and in intracellular signaling pathways leading to the neuronal cell survival. Only in retina cells, mammalian Ngb may help to sustain O2 supply to mitochondria, thereby supporting the visual process in the eye. Here, the putative roles of mammalian nerve globins are reviewed. PMID- 24753140 TI - Swift heavy ion induced structural and luminescence characterization of Y2O3:Eu3+ phosphor: a comparative study. AB - We report a comparative study on structural and thermoluminescence modifications of Y2O3:Eu(3+) phosphor induced by 150 MeV Ni(7+), 120 MeV Ag(9+) and 110 MeV Au(8+) swift heavy ions (SHI) in the fluence range 1 * 10(11) to 1 * 10(13) ions/cm(2). X-Ray diffraction and transition electron microscopy studies confirm the loss of crystallinity of the phosphors after ion irradiation, which is greater in the case of Au ion irradiation. Structural refinement using the Rietveld method yields the various structural parameters of ion-irradiated phosphors. Thermoluminescence glow curves of ion-irradiated phosphors show a small shift in the position of the peaks, along with an increase in intensity with ion fluence. Stopping range of ions in Matter (SRIM) calculations were performed to correlate the change in thermoluminescence properties of various ion irradiated phosphors. It shows that the defects created by 110 MeV Au(8+) ions are greater in number. Trapping parameters of ion-irradiated phosphors were calculated from thermoluminescence data using various glow curve analysis methods. PMID- 24753141 TI - Asymptotics for Object Descriptors. AB - This is a discussion of the following paper: "Overview of object oriented data analysis" by J. Steve Marron and Andres M. Alonso. PMID- 24753142 TI - Is segmental transarterial yttrium 90 radiation a curative option for solitary hepatocellular carcinoma <=5 cm? PMID- 24753143 TI - DFT simulations of water adsorption and activation on low-index alpha-Ga2O3 surfaces. AB - Density functional theory (DFT) calculations are used to explore water adsorption and activation on different alpha-Ga2O3 surfaces, namely (001), (100), (110), and (012). The geometries and binding energies of molecular and dissociative adsorption are studied as a function of coverage. The simulations reveal that dissociative water adsorption on all the studied low-index surfaces are thermodynamically favorable. Analysis of surface energies suggests that the most preferentially exposed surface is (012). The contribution of surface relaxation to the respective surface energies is significant. Calculations of electron local density of states indicate that the electron-energy band gaps for the four investigated surfaces appears to be less related to the difference in coordinative unsaturation of the surface atoms, but rather to changes in the ionicity of the surface chemical bonds. The electrochemical computation is used to investigate the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) on alpha-Ga2O3 surfaces. Our results indicate that the (100) and (110) surfaces, which have low stability, are the most favorable ones for HER and OER, respectively. PMID- 24753145 TI - The relation between cigarette smoking and risk of acute myeloid leukemia: an updated meta-analysis of epidemiological studies. AB - Smoking has been postulated as an environmental risk factor for acute myeloid leukemia (AML). The primary objective of this meta-analysis of observational studies was to evaluate the epidemiologic relationship between smoking and the risk of development of AML. Twenty-three studies published between January 1993 and December 2013 were included in our analysis, and accounted for 7,746 cases of AML. The outcome of interest was the relative risk (RR) with 95% confidence interval (CI) of developing AML in adult cigarette smokers in comparison with non smokers, and was estimated using the random-effects model. Our results showed that current and ever smokers have 40% (RR 1.40, 95% CI 1.22-1.60; P < 0.001) and 25% (RR 1.25, 95% CI 1.15-1.36; P < 0.001) increased risk of developing AML when compared with non-smokers. The increased RR of AML was increased regardless of sex, study design, geographical region, and quality of the studies. Intensity of smoking of <10, 10-20, 20-30, and >30 cigarettes per day was associated with RRs of AML of 1.27, 1.36, 1.55, and 1.77, respectively (P < 0.001 for trend). Duration of smoking of <20 and >20 years was associated with RRs of 1.07 and 1.44, respectively (P < 0.001 for trend). Cumulative smoking of <10, 10-20, 20 30, and >30 pack-years was associated with RRs of 1.13, 1.23, 1.39, and 1.71, respectively (P < 0.001 for trend). Overall, cigarette smoking proves to be a significant risk factor for the development of AML in adults. PMID- 24753146 TI - The hippocampus, medial prefrontal cortex, and selective memory retrieval: evidence from a rodent model of the retrieval-induced forgetting effect. AB - Inhibition is an important component of many cognitive functions, including memory. For example, the retrieval-induced forgetting (RIF) effect occurs when extra practice with some items from a study list inhibits the retrieval of the nonpracticed items relative to a baseline condition that does not involve extra practice. Although counterintuitive, the RIF phenomenon may be important for resolving interference by inhibiting potentially competing retrieval targets. Neuroimaging studies suggest that the hippocampus and prefrontal cortex are involved in the RIF effect, but controlled lesion studies have not yet been performed. We developed a rodent model of the RIF training procedure and trained control rats and rats with temporary inactivation of the hippocampus or medial prefrontal cortex (mPFC). Rats were trained on a list of odor cues, presented in cups of digging medium with a buried reward, followed by additional practice trials with a subset of the cues. We then tested the rats' memories for the cues and their association with reward by presenting them with unbaited cups containing the test odorants and measuring how long they persisted in digging. Control rats exhibited a robust RIF effect in which memory for the nonpracticed odors was significantly inhibited. Thus, extra practice with some odor cues inhibited memory for the others, relative to a baseline condition that involved an identical amount of training. Inactivation of either the hippocampus or the mPFC blocked the RIF effect. We also constructed a computational model of a representational learning circuit to simulate the RIF effect. We show in this model that "sideband suppression" of similar memory representations can reproduce the RIF effect and that alteration of the suppression parameters and learning rate can reproduce the lesion effects seen in our rats. Our results suggest that the RIF effect is widespread and that inhibitory processes are an important feature of memory function. PMID- 24753149 TI - Do difficulties in swallowing medication impede the use of hydroxyurea in children? AB - BACKGROUND: Use of hydroxyurea (HU) in children with sickle cell disease (SCD) may be hampered by its formulation as a capsule and the limited availability of liquid HU. PROCEDURE: At four Pediatric SCD clinics, parents of children with SCD ages 5-17 years were surveyed about their children's medication use and ability to swallow medication. Data were stratified by HU therapy and analyzed using descriptive statistics, Chi square tests, Fisher exact tests and univariate analysis. RESULTS: Of the 116 parents surveyed, 97% were the primary caregiver. One fourth (26%) of parents reported that their child's difficulty swallowing medication interfered with daily medication use. Age-related differences were found in ability to swallow medication, but not by HU use. Children taking HU were more likely to take multiple daily medications, with more frequent dosing schedules. Among 65 HU users, children using the liquid formulation (28%, n = 18) were younger than capsule users (P < 0.0001). Nonetheless, half of liquid HU users were aged 8-13. Children using liquid HU were more likely to have difficulties swallowing medication than those who use HU capsules (OR 4.29, 95% CI 1.14-16.18, P = 0.032). Few had received training for swallowing medication. CONCLUSIONS: One fourth of surveyed parents viewed swallowing as challenging to daily medication use. These findings suggest that difficulty swallowing capsules is a fairly frequent barrier to for children prescribed HU, especially for younger children. HU use appears more likely in families with daily and more complex medication schedules. Coaching for swallowing capsules may improve HU utilization and adherence. PMID- 24753144 TI - Optimal therapy of type 2 diabetes: a controversial challenge. AB - Type 2 diabetes mellitus (T2DM) is one of the most common chronic disorders in older adults and the number of elderly diabetic subjects is growing worldwide. Nonetheless, the diagnosis of T2DM in elderly population is often missed or delayed until an acute metabolic emergency occurs. Accumulating evidence suggests that both aging and environmental factors contribute to the high prevalence of diabetes in the elderly. Clinical management of T2DM in elderly subjects presents unique challenges because of the multifaceted geriatric scenario. Diabetes significantly lowers the chances of "successful" aging, notably it increases functional limitations and impairs quality of life. In this regard, older diabetic patients have a high burden of comorbidities, diabetes-related complications, physical disability, cognitive impairment and malnutrition, and they are more susceptible to the complications of dysglycemia and polypharmacy. Several national and international organizations have delivered guidelines to implement optimal therapy in older diabetic patients based on individualized treatment goals. This means appreciation of the heterogeneity of the disease as generated by life expectancy, functional reserve, social support, as well as personal preference. This paper will review current treatments for achieving glycemic targets in elderly diabetic patients, and discuss the potential role of emerging treatments in this patient population. PMID- 24753150 TI - Biodegradable, polymer encapsulated, metal oxide particles for MRI-based cell tracking. AB - Metallic particles have shaped the use of magnetic resonance imaging (MRI) for molecular and cellular imaging. Although these particles have generally been developed for extracellular residence, either as blood pool contrast agents or targeted contrast agents, the coopted use of these particles for intracellular labeling has grown over the last 20 years. Coincident with this growth has been the development of metal oxide particles specifically intended for intracellular residence, and innovations in the nature of the metallic core. One promising nanoparticle construct for MRI-based cell tracking is polymer encapsulated metal oxide nanoparticles. Rather than a polymer coated metal oxide nanocrystal of the core: shell type, polymer encapsulated metal oxide nanoparticles cluster many nanocrystals within a polymer matrix. This nanoparticle composite more efficiently packages inorganic nanocrystals, affording the ability to label cells with more inorganic material. Further, for magnetic nanocrystals, the clustering of multiple magnetic nanocrystals within a single nanoparticle enhances r2 and r2* relaxivity. Methods for fabricating polymer encapsulated metal oxide nanoparticles are facile, yielding both varied compositions and synthetic approaches. This review presents a brief history into the use of metal oxide particles for MRI-based cell tracking and details the development and use of biodegradable, polymer encapsulated, metal oxide nanoparticles and microparticles for MRI-based cell tracking. PMID- 24753151 TI - AP-2alpha is required after lens vesicle formation to maintain lens integrity. AB - BACKGROUND: Transcription factors are critical in regulating lens development. The AP-2 family of transcription factors functions in differentiation, cell growth and apoptosis, and in lens and eye development. AP-2alpha, in particular, is important in early lens development, and when conditionally deleted at the placode stage defective separation of the lens vesicle from the surface ectoderm results. AP-2alpha's role during later stages of lens development is unknown. To address this, the MLR10-Cre transgene was used to delete AP-2alpha from the lens epithelium beginning at embryonic day (E) 10.5. RESULTS: The loss of AP-2alpha after lens vesicle separation resulted in morphological defects beginning at E18.5. By P4, a small highly vacuolated lens with a multilayered epithelium was evident in the MLR10-AP-2alpha mutants. Epithelial cells appeared elongated and expressed fiber cell specific betaB1 and gamma-crystallins. Epithelial cell polarity and lens cell adhesion was disrupted and accompanied by the misexpression of ZO-1, N-Cadherin, and beta-catenin. Cell death was observed in the mutant lens epithelium between postnatal day (P) 14 and P30, and correlated with altered arrangements of cells within the epithelium. CONCLUSIONS: Our findings demonstrate that AP-2alpha continues to be required after lens vesicle separation to maintain a normal lens epithelial cell phenotype and overall lens integrity and to ensure correct fiber cell differentiation. PMID- 24753153 TI - Calcium and vitamin D in sarcoidosis: is supplementation safe? AB - Granulomas in sarcoidosis express high levels of 1alpha-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH)2 vitamin D. Overproduction of 1alpha-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25 (OH)D), 1,25-dihydroxy vitamin D (1,25(OH)2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented. PMID- 24753154 TI - Ocean warming, a rapid distributional shift, and the hybridization of a coastal fish species. AB - Despite increasing awareness of large-scale climate-driven distribution shifts in the marine environment, no study has linked rapid ocean warming to a shift in distribution and consequent hybridization of a marine fish species. This study describes rapid warming (0.8 degrees C per decade) in the coastal waters of the Angola-Benguela Frontal Zone over the last three decades and a concomitant shift by a temperature sensitive coastal fish species (Argyrosomus coronus) southward from Angola into Namibia. In this context, rapid shifts in distribution across Economic Exclusive Zones will complicate the management of fishes, particularly when there is a lack of congruence in the fisheries policy between nations. Evidence for recent hybridization between A. coronus and a congener, A. inodorus, indicate that the rapid shift in distribution of A. coronus has placed adults of the two species in contact during their spawning events. Ocean warming may therefore revert established species isolation mechanisms and alter the evolutionary history of fishes. While the consequences of the hybridization on the production of the resource remain unclear, this will most likely introduce additional layers of complexity to their management. PMID- 24753152 TI - Barx2 and Pax7 have antagonistic functions in regulation of wnt signaling and satellite cell differentiation. AB - The canonical Wnt signaling pathway is critical for myogenesis and can induce muscle progenitors to switch from proliferation to differentiation; how Wnt signals integrate with muscle-specific regulatory factors in this process is poorly understood. We previously demonstrated that the Barx2 homeobox protein promotes differentiation in cooperation with the muscle regulatory factor (MRF) MyoD. Pax7, another important muscle homeobox factor, represses differentiation. We now identify Barx2, MyoD, and Pax7 as novel components of the Wnt effector complex, providing a new molecular pathway for regulation of muscle progenitor differentiation. Canonical Wnt signaling induces Barx2 expression in muscle progenitors and perturbation of Barx2 leads to misregulation of Wnt target genes. Barx2 activates two endogenous Wnt target promoters as well as the Wnt reporter gene TOPflash, the latter synergistically with MyoD. Moreover, Barx2 interacts with the core Wnt effectors beta-catenin and T cell-factor 4 (TCF4), is recruited to TCF/lymphoid enhancer factor sites, and promotes recruitment of beta-catenin. In contrast, Pax7 represses the Wnt reporter gene and antagonizes the activating effect of Barx2. Pax7 also binds beta-catenin suggesting that Barx2 and Pax7 may compete for interaction with the core Wnt effector complex. Overall, the data show for the first time that Barx2, Pax7, and MRFs can act as direct transcriptional effectors of Wnt signals in myoblasts and that Barx2 and Wnt signaling participate in a regulatory loop. We propose that antagonism between Barx2 and Pax7 in regulation of Wnt signaling may help mediate the switch from myoblast proliferation to differentiation. PMID- 24753155 TI - Educational outcomes necessary to enter pharmacy residency training. AB - It is the position of the American College of Clinical Pharmacy (ACCP) that formal postgraduate residency training, or equivalent experience, is required to enter direct patient care practice. Therefore, it is important to align professional degree educational outcomes with the knowledge, skills, and attitudes needed to enter residency training. This position statement addresses the outcomes necessary in the professional degree program curriculum to ensure the ability of pharmacy graduates to transition effectively into postgraduate year one residency training. Five key outcome areas are identified: communication, direct patient care, professionalism, research, and practice management. The position statement examines how performance in each of the five outcome areas should be addressed by professional degree programs. The ACCP believes that for the student to achieve the clinical proficiency necessary to enter residency training, the professional degree program should emphasize, assess, and provide adequate opportunities for students to practice: communication with patients, caregivers, and members of the health care team in direct patient care environments; provision of direct patient care in a wide variety of practice settings, especially those involving patient-centered, team based care; professionalism under the supervision and guidance of faculty and preceptors who model and teach the traits of a health care professional; application of principles of research that engender an appreciation for the role of research and scholarship in one's professional development; and application of practice management, including documentation of direct patient care activities that affect drug-related outcomes. PMID- 24753156 TI - Warfarin dosing changes after bariatric surgery: implications on the mechanism for altered dose requirements and safety concerns--an alternative viewpoint. PMID- 24753157 TI - Survey of the literature on mechanoluminescence from 1605 to 2013. AB - Mechanoluminescence (ML) is a type of luminescence induced by any mechanical action on solids. The light emissions induced by elastic deformation, plastic deformation and fracture of solids are called elastico ML (EML), plastico ML (PML) and fracto ML (FML), respectively. Whereas nearly 50% of all organic molecular solids and inorganic salts exhibit FML, only a few solids exhibit EML and PML. The EML and FML of certain solids are so intense that they can be seen during daylight with the naked eye. Mechanolumnescence has a great potential for use in different types of mechano-optical devices such as stress sensors, damage sensors, impact sensors, fracture sensors and safety management monitoring systems. This article reports a survey of the literature from 1605 to 2013. Mechanoluminescence is studied by physicists, chemists, material scientists, geologists, medical scientists, engineers and technologists, among others and researchers will certainly benefit from the literature survey on ML given here. In addition, the field of mechanoluminescence may attract the interest of many new researchers. PMID- 24753158 TI - Saturated free fatty acids induce cholangiocyte lipoapoptosis. AB - Recent studies have identified a cholestatic variant of nonalcoholic fatty liver disease (NAFLD) with portal inflammation and ductular reaction. Based on reports of biliary damage, as well as increased circulating free fatty acids (FFAs) in NAFLD, we hypothesized the involvement of cholangiocyte lipoapoptosis as a mechanism of cellular injury. Here, we demonstrate that the saturated FFAs palmitate and stearate induced robust and rapid cell death in cholangiocytes. Palmitate and stearate induced cholangiocyte lipoapoptosis in a concentration dependent manner in multiple cholangiocyte-derived cell lines. The mechanism of lipoapoptosis relied on the activation of caspase 3/7 activity. There was also a significant up-regulation of the proapoptotic BH3-containing protein, PUMA. In addition, palmitate-induced cholangiocyte lipoapoptosis involved a time-dependent increase in the nuclear localization of forkhead family of transcription factor 3 (FoxO3). We show evidence for posttranslational modification of FoxO3, including early (6 hours) deacetylation and dephosphorylation that coincide with localization of FoxO3 in the nuclear compartment. By 16 hours, nuclear FoxO3 is both phosphorylated and acetylated. Knockdown studies confirmed that FoxO3 and its downstream target, PUMA, were critical for palmitate- and stearate-induced cholangiocyte lipoapoptosis. Interestingly, cultured cholangiocyte-derived cells did not accumulate appreciable amounts of neutral lipid upon FFA treatment. CONCLUSION: Our data show that the saturated FFAs palmitate and stearate induced cholangiocyte lipoapoptosis by way of caspase activation, nuclear translocation of FoxO3, and increased proapoptotic PUMA expression. These results suggest that cholangiocyte injury may occur through lipoapoptosis in NAFLD and nonalcoholic steatohepatitis patients. PMID- 24753159 TI - Human chorionic gonadotropin decreases human breast cancer cell proliferation and promotes differentiation. AB - Human chorionic gonadotropin (hCG) is a glycoprotein produced by placental trophoblasts. Previous studies indicated that hCG could be responsible for the pregnancy-induced protection against breast cancer in women. It is reported that hCG decreases proliferation and invasion of breast cancer MCF-7 cells. Our research also demonstrates that hCG can reduce the proliferation of MCF-7 cells by downregulating the expression of proliferation markers, proliferating cell nuclear antigen (PCNA), and proliferation-related Ki-67 antigen (Ki-67). Interestingly, we find here that hCG elevates the state of cellular differentiation, as characterized by the upregulation of differentiation markers, beta-casein, cytokeratin-18 (CK-18), and E-cadherin. Inhibition of hCG secretion or luteinizing hormone/hCG receptors (LH/hCGRs) synthesis can weaken the effect of hCG on the induction of cell differentiation. Furthermore, hCG can suppress the expression of estrogen receptor alpha. hCG activated receptor-mediated cyclic adenosine monophosphate/protein kinase A signaling pathway. These findings indicated that a protective effect of hCG against breast cancer may be associated with its growth inhibitory and differentiation induction function in breast cancer cells. PMID- 24753160 TI - Maximum type 1 error rate inflation in multiarmed clinical trials with adaptive interim sample size modifications. AB - Sample size modifications in the interim analyses of an adaptive design can inflate the type 1 error rate, if test statistics and critical boundaries are used in the final analysis as if no modification had been made. While this is already true for designs with an overall change of the sample size in a balanced treatment-control comparison, the inflation can be much larger if in addition a modification of allocation ratios is allowed as well. In this paper, we investigate adaptive designs with several treatment arms compared to a single common control group. Regarding modifications, we consider treatment arm selection as well as modifications of overall sample size and allocation ratios. The inflation is quantified for two approaches: a naive procedure that ignores not only all modifications, but also the multiplicity issue arising from the many to-one comparison, and a Dunnett procedure that ignores modifications, but adjusts for the initially started multiple treatments. The maximum inflation of the type 1 error rate for such types of design can be calculated by searching for the "worst case" scenarios, that are sample size adaptation rules in the interim analysis that lead to the largest conditional type 1 error rate in any point of the sample space. To show the most extreme inflation, we initially assume unconstrained second stage sample size modifications leading to a large inflation of the type 1 error rate. Furthermore, we investigate the inflation when putting constraints on the second stage sample sizes. It turns out that, for example fixing the sample size of the control group, leads to designs controlling the type 1 error rate. PMID- 24753161 TI - A systematic study of peripherally multiple aromatic ester-functionalized poly(benzyl ether) dendrons for the fabrication of organogels: structure-property relationships and thixotropic property. AB - A new class of peripherally multiple aromatic ester-functionalized poly(benzyl ether) dendrons and/or dendrimers with different focal point substituents, surface groups, interior structures, as well as different generations have been synthesized and their structure-property relationships with respect to their gelation ability have been investigated systematically. Most of these dendrons are able to gel organic solvents over a wide polarity range. Evident dendritic effects were observed not only in gelation capability but also in thermotropic, morphological, and rheological characterizations. It was disclosed that subtle changes in peripheral ester functionalities and interior dendritic structures affected the gelation behavior of the dendrons significantly. Among all the dendrons studied, the second- and third-generation dendrons G0G2-Me and G0G3-Me with dimethyl isophthalates (DMIP) as peripheral groups exhibited the best capability in gelation, and stable gels were formed in more than 22 aromatic and polar organic solvents. The lowest critical gelation concentration (CGC) reached 2.0 mg mL(-1), indicating that approximately 1.35*10(4) solvent molecules could be entrapped by one dendritic molecule. Further study on driving forces in gel formation was carried out by using a combination of single-crystal/powder X-ray diffraction (XRD) analysis and concentration-dependent (CD)/temperature-dependent (TD) (1)H NMR spectroscopy. The results obtained from these experiments revealed that the multiple pi-pi stacking of extended pi-systems due to the peripheral DMIP rings, cooperatively assisted by non-conventional hydrogen-bonding, is the key contributor in the formation of the highly ordered supramolecular and fibrillar network. In addition, these dendritic organogels exhibited unexpected thixotropic-responsive properties, which make them promising candidates with potential applications in the field of intelligent soft materials. PMID- 24753162 TI - Stress exposure across the life span cumulatively increases depression risk and is moderated by neuroticism. AB - BACKGROUND: Even though traumatic stress is a major risk factor for depression, most people do not develop a depression. The effects of stress may particularly emerge after repeated exposure in vulnerable individuals. Therefore, we hypothesized that (1) increased exposure to stress across the life span is associated with an increased depression risk and (2) this effect is the most pronounced in individuals with high levels of neuroticism. METHODS: We investigated the effect of childhood maltreatment, major life events, daily hassles, and a composite index thereof (cumulative stress index) on depressive symptoms and major depressive disorder (MDD) including the possible moderating role of neuroticism in a discovery sample from the general population (N = 563) and an independent replication sample from the Netherlands Study of Depression and Anxiety (N = 2,274). RESULTS: All stress domains were independently associated with depressive symptoms in the discovery sample. In the replication sample, we confirmed these findings for childhood maltreatment and daily hassles but not for major life events with depressive symptoms as outcome. Nevertheless, all stress domains significantly contributed to the presence of MDD in the replication sample. The cumulative stress index was significantly associated with depression in the discovery (beta = 1.42, P < .001) and replication sample (beta = 3.79, P < .001), especially in those individuals with high levels of trait neuroticism (discovery: beta = 0.013, P < .001; replication: beta = 0.367, P < .001). CONCLUSIONS: This is the first study to show that cumulative stress exposure across different stress domains contributes to depressive symptoms and MDD in adulthood. Moreover, we show that increased exposure to stress across the life span has more impact on vulnerable individuals with high levels of trait neuroticism. PMID- 24753163 TI - Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis. AB - BACKGROUND: Heparan sulfate proteoglycans (HSPG) are important for embryonic development by means of the regulation of gradient formation and signaling of multiple growth factors and morphogens. Previous studies have shown that Bmp/Shh/Fgf signaling are required for the regionalization of the optic vesicle (OV) and for the closure of the optic fissure (OF), the disturbance of which underlie ocular anomalies such as microphthalmia, coloboma, and optic nerve hypoplasia. RESULTS: To study HSPG-dependent coordination of these signaling pathways during mammalian visual system development, we have generated a series of OV-specific mutations in the heparan sulfate (HS) N-sulfotransferase genes (Ndst1 and Ndst2) and HS O-sulfotransferase genes (Hs2st, Hs6st1, and Hs6st2) in mice. Of interest, the resulting HS undersulfation still allowed for normal retinal neurogenesis and optic fissure closure, but led to defective optic disc and stalk development. The adult mutant animals further developed optic nerve aplasia/hypoplasia and displayed retinal degeneration. We observed that MAPK/ERK signaling was down-regulated in Ndst mutants, and consistent with this, HS related optic nerve morphogenesis defects in mutant mice could partially be rescued by constitutive Kras activation. CONCLUSIONS: These results suggest that HSPGs, depending on their HS sulfation pattern, regulate multiple signaling pathways in optic disc and stalk morphogenesis. PMID- 24753164 TI - Noncontrast peripheral MRA with spiral echo train imaging. AB - PURPOSE: To develop a spin echo train sequence with spiral readout gradients with improved artery-vein contrast for noncontrast angiography. THEORY: Venous T2 becomes shorter as the echo spacing is increased in echo train sequences, improving contrast. Spiral acquisitions, due to their data collection efficiency, facilitate long echo spacings without increasing scan times. METHODS: Bloch equation simulations were performed to determine optimal sequence parameters, and the sequence was applied in five volunteers. In two volunteers, the sequence was performed with a range of echo times and echo spacings to compare with the theoretical contrast behavior. A Cartesian version of the sequence was used to compare contrast appearance with the spiral sequence. Additionally, spiral parallel imaging was optionally used to improve image resolution. RESULTS: In vivo, artery-vein contrast properties followed the general shape predicted by simulations, and good results were obtained in all stations. Compared with a Cartesian implementation, the spiral sequence had superior artery-vein contrast, better spatial resolution (1.2 mm(2) versus 1.5 mm(2) ), and was acquired in less time (1.4 min versus 7.5 min). CONCLUSION: The spiral spin echo train sequence can be used for flow-independent angiography to generate three-dimensional angiograms of the periphery quickly and without the use of contrast agents. PMID- 24753165 TI - Intact CA3 in the hippocampus is only sufficient for contextual behavior based on well-learned and unaltered visual background. AB - Computational models suggest that the dentate gyrus and CA3 subfields of the hippocampus are responsible for discrete memory representations using pattern separation and pattern completion when a modified external stimulus is recognized as an old memory or encoded as a new memory. Experimental evidence of such computational processes in the hippocampus has been obtained mostly from spatial navigational tasks, and little is known about the proposed computational functions of the hippocampal subfields in "nonspatial" memory tasks. We tested whether rats with major damage in the dentate gyrus induced by colchicine lesions could remember patterned visual scene stimuli presented on LCD screens in the background. Rats responded using a touchscreen to indicate the identity of the visual scene. Performance of the lesion group was normal when tested with familiar visual scenes that had been learned prior to surgery. Lesioned rats exhibited severe deficits in learning novel visual scenes, but eventually reached the same level of performance as controls. However, unlike in controls, novel scene-associated memories formed in the lesion group were unstable and easily disrupted when ambiguous versions of the novel scenes were presented intermixed with the original stimuli. Our findings confirm that the prior computational models can also be applied to the nonspatial memory domain and suggest that the dentate gyrus is not necessary for the retrieval of learned visual scene associated behavioral responses but plays a crucial role in forming novel visual scene-dependent memory and recognizing altered or ambiguous visual scenes in the background. PMID- 24753166 TI - Surgical site infections after liver retransplantation: incidence and risk factors. AB - Surgical site infections (SSIs) after liver transplantation (LT) are associated with an increased risk of graft loss and death. The incidence of SSIs after LT and their risk factors have been determined for first LT but not for second LT. The importance of reporting the incidence of SSIs risk-stratified by first LT versus second LT is not known. All patients undergoing second LT at a single institution between 2003 and 2011 (n = 152) were reviewed. The Kaplan-Meier method was used to estimate the cumulative SSI incidence. Relative risks (RRs) and 95% confidence intervals (CIs) from Cox proportional hazards regression models were used to evaluate associations of potential risk factors with SSIs after second LT. Thirty-one patients developed SSIs (6 superficial SSIs, 1 deep SSI, and 24 organ/space SSIs). The cumulative incidence of SSIs 30 days after LT was 20.8% (95% CI = 14%-27%), which was slightly but not significantly higher than the previously reported incidence of SSIs after first LT at our institution between 2003 and 2008 (16%, RR = 1.32, 95% CI = 0.90-1.93, P = .16). Units of transfused red blood cells [RR (doubling) = 1.38, 95% CI = 1.02-1.86, P = .04] and hepaticojejunostomy (RR = 2.22, 95% CI = 1.05-4.72, P = .04) were the only factors associated with SSIs after second LT in single-variable analysis. The associations weakened in a multivariate analysis (P = .07 and P = .07, respectively), potentially because of the correlation of red blood cell transfusions and hepaticojejunostomy (P = .08). In conclusion, the incidence of SSIs after second LT was slightly higher but not significantly different than the published incidence of SSIs (16%) after first LT at the same institution. Significant independent risk factors for SSIs after second LT were not identified. Risk stratification for retransplantation may not be necessary when the incidence of SSIs after LT is being reported. PMID- 24753167 TI - Is "the bigger the better" still valid for drug-eluting stents? PMID- 24753168 TI - Fixer upper methods. PMID- 24753169 TI - Treatment of coronary bifurcations with third generation drug-eluting stent: making major headway or just baby steps? PMID- 24753170 TI - Routine postdilation of drug-eluting stents: worth the gain. PMID- 24753171 TI - A proposal to reduce contrast nephropathy: eliminate the NPO order. PMID- 24753172 TI - Robotic-assist PCI: precision guided PCI or a rube goldberg solution? PMID- 24753173 TI - Faster, easier, safer: "guideliner reverse CART" for retrograde chronic total occlusion interventions. PMID- 24753174 TI - Tibio-pedal arterial minimally invasive retrograde revascularization: pushing the limits of endovascular therapy in critical limb ischemia. PMID- 24753175 TI - Moving south to work north-transpedal access for critical limb ischemia. PMID- 24753176 TI - Patterns of antibacterial use and impact of age, race/ethnicity, and geographic region on antibacterial use in an outpatient medicaid cohort. AB - STUDY OBJECTIVES: To describe patterns of outpatient antibacterial use among California Medicaid (Medi-Cal) fee-for-service system beneficiaries, and to investigate the influence of demographic factors-age, race/ethnicity, state county, and population density-on those patterns. DESIGN: Retrospective analysis of administrative claims data. DATA SOURCE: Medi-Cal fee-for-service system claims database. PATIENTS: All outpatient Medi-Cal fee-for-service system beneficiaries enrolled between 2006 and 2011 who had at least one systemic antibacterial claim. MEASUREMENTS AND MAIN RESULTS: Rates of antibacterial prescribing and the proportion of broad-spectrum antibacterial use were measured over the study period and among age, racial/ethnic, and geographic (county) groups. Of the 10,018,066 systemic antibacterial claims selected for analysis, antibacterial prescribing rates decreased from 542 claims/1000 beneficiaries in 2006 to 461 claims/1000 beneficiaries in 2011 (r = -0.971, p=0.0012; tau-b = 1.00, p=0.009). Among age groups, children had the highest rate of use (605 claims/1000 beneficiaries, chi(2) (2) = 320,000, p<0.001); among racial/ethnic groups, Alaskan Natives and Native Americans had the highest rate of use (1086/1000 beneficiaries, chi(2) (5) = 197,000, p<0.001). Broad-spectrum antibacterial prescribing increased from 28.1% (95% confidence interval [CI] 28.1 28.2%) to 32.7% (95% CI 32.6-32.8%) over the study period. Senior age groups and whites received the highest proportions of broad-spectrum agents (53.4% [95% CI 52.5-54.3%] and 36.6% [95% CI 36.6-36.7%], respectively). Population density was inversely related to both overall antibacterial use (rho = -0.432, p=0.0018) and broad-spectrum antibacterial prescribing (rho = -0.359, p<0.001). The rate of prescribing decreased over the study period for all antibacterial classes with the exception of macrolides and sulfonamides. Amoxicillin was the most frequently prescribed agent. CONCLUSION: Overall and broad-spectrum antibacterial use in the Medi-Cal fee-for-service program are less than that observed nationally. Significant variations in prescribing exist between age and racial/ethnic groups, and heavily populated areas are associated with both less antibacterial use and less broad-spectrum antibacterial prescribing. Studies are needed to determine the reasons for the observed differences in antibacterial use among demographic groups. PMID- 24753178 TI - Potassium permanganate-acridine yellow chemiluminescence system for the determination of fluvoxamine, isoniazid and ceftriaxone. AB - Based on the oxidation of acridine yellow by permanganate in basic medium, a new chemiluminescence system was developed for the sensitive determination of some important drugs. The remarkable inhibiting effect of fluvoxamine, ceftriaxone and isoniazid on this reaction was applied to their detection. A possible mechanism was proposed for this system based on chemiluminescence emission wavelengths and experimental observations. Under optimum conditions, calibration graphs were obtained for 1 * 10(-9) to 1 * 10(-6) mol/L of fluvoxamine; 2 * 10(-8) to 8 * 10( 6) mol/L of ceftriaxone and 5 * 10(-8) to 4 * 10(-5) mol/L of isoniazid. This proposed method was satisfactorily used in the determination of these drugs in pharmaceutical samples and human urine and serum. PMID- 24753177 TI - Using dynamic contrast-enhanced MRI to quantitatively characterize maternal vascular organization in the primate placenta. AB - PURPOSE: The maternal microvasculature of the primate placenta is organized into 10-20 perfusion domains that are functionally optimized to facilitate nutrient exchange to support fetal growth. This study describes a dynamic contrast enhanced magnetic resonance imaging method for identifying vascular domains and quantifying maternal blood flow in them. METHODS: A rhesus macaque on the 133rd day of pregnancy (G133, term = 165 days) underwent Doppler ultrasound procedures, dynamic contrast-enhanced magnetic resonance imaging and Cesarean-section delivery. Serial T1 -weighted images acquired throughout intravenous injection of a contrast reagent bolus were analyzed to obtain contrast reagent arrival time maps of the placenta. RESULTS: Watershed segmentation of the arrival time map identified 16 perfusion domains. The number and location of these domains corresponded to anatomical cotyledonary units observed following delivery. Analysis of the contrast reagent wave front through each perfusion domain enabled determination of volumetric flow, which ranged from 9.03 to 44.9 mL/s (25.2 +/- 10.3 mL/s). These estimates are supported by Doppler ultrasound results. CONCLUSIONS: The dynamic contrast-enhanced magnetic resonance imaging analysis described here provides quantitative estimates of the number of maternal perfusion domains in a primate placenta and estimates flow within each domain. Anticipated extensions of this technique are to the study placental function in non-human primate models of obstetric complications. PMID- 24753179 TI - Electrically induced brain-derived neurotrophic factor release from Schwann cells. AB - Regulating the production of brain-derived neurotrophic factor (BDNF) in Schwann cells (SCs) is critical for their application in traumatic nerve injury, neurodegenerative disorders, and demyelination disease in both central and peripheral nervous systems. The present study investigated the possibility of using electrical stimulation (ES) to activate SCs to release BDNF. We found that short-term ES was capable of promoting BDNF production from SCs, and the maximal BDNF release was achieved by ES at 6 V (3 Hz, 30 min). We further examined the involvement of intracellular calcium ions ([Ca2+]i) in the ES-induced BDNF production in SCs by pharmacological studies. We found that the ES-induced BDNF release required calcium influx through T-type voltage-gated calcium channel (VGCC) and calcium mobilization from internal calcium stores, including inositol triphosphate-sensitive stores and caffeine/ryanodine-sensitive stores. In addition, calcium-calmodulin dependent protein kinase IV (CaMK IV), mitogen activated protein kinase (MAPK), and cAMP response element-binding protein (CREB) were found to play important roles in the ES-induced BDNF release from SCs. In conclusion, ES is capable of activating SCs to secrete BDNF, which requires the involvement of calcium influx through T-type VGCC and calcium mobilization from internal calcium stores. In addition, activation of CaMK IV, MAPK, and CREB were also involved in the ES-induced BDNF release. The findings indicate that ES can improve the neurotrophic ability in SCs and raise the possibility of developing electrically stimulated SCs as a source of cell therapy for nerve injury in both peripheral and central nervous systems. PMID- 24753180 TI - Regulation of intestinal calcium absorption by luminal calcium content: role of intestinal alkaline phosphatase. AB - SCOPE: Intestinal alkaline phosphatase is a brush border enzyme that is stimulated by calcium. Inhibition of intestinal alkaline phosphatase increases intestinal calcium absorption. We hypothesized that intestinal alkaline phosphatase acts as a minute-to-minute regulatory mechanism of calcium entry. The aim of this study was to evaluate the mechanism by which intestinal luminal calcium controls intestinal calcium absorption. METHODS AND RESULTS: We performed kinetic studies with purified intestinal alkaline phosphatase and everted duodenal sacs and showed that intestinal alkaline phosphatase modifies the luminal pH as a function of enzyme concentration and calcium luminal content. A decrease in pH occurred simultaneously with a decrease in calcium absorption. The inhibition of intestinal alkaline phosphatase by l-phenylalanine caused an increase in calcium absorption. This effect was also confirmed in calcium uptake experiments with isolated duodenal cells. CONCLUSION: Changes in luminal pH arising from intestinal alkaline phosphatase activity induced by luminal calcium concentration modulate intestinal calcium absorption. PMID- 24753181 TI - Widespread differential maternal and paternal genome effects on fetal bone phenotype at mid-gestation. AB - Parent-of-origin-dependent (epi)genetic factors are important determinants of prenatal development that program adult phenotype. However, data on magnitude and specificity of maternal and paternal genome effects on fetal bone are lacking. We used an outbred bovine model to dissect and quantify effects of parental genomes, fetal sex, and nongenetic maternal effects on the fetal skeleton and analyzed phenotypic and molecular relationships between fetal muscle and bone. Analysis of 51 bone morphometric and weight parameters from 72 fetuses recovered at day 153 gestation (54% term) identified six principal components (PC1-6) that explained 80% of the variation in skeletal parameters. Parental genomes accounted for most of the variation in bone wet weight (PC1, 72.1%), limb ossification (PC2, 99.8%), flat bone size (PC4, 99.7%), and axial skeletal growth (PC5, 96.9%). Limb length showed lesser effects of parental genomes (PC3, 40.8%) and a significant nongenetic maternal effect (gestational weight gain, 29%). Fetal sex affected bone wet weight (PC1, p < 0.0001) and limb length (PC3, p < 0.05). Partitioning of variation explained by parental genomes revealed strong maternal genome effects on bone wet weight (74.1%, p < 0.0001) and axial skeletal growth (93.5%, p < 0.001), whereas paternal genome controlled limb ossification (95.1%, p < 0.0001). Histomorphometric data revealed strong maternal genome effects on growth plate height (98.6%, p < 0.0001) and trabecular thickness (85.5%, p < 0.0001) in distal femur. Parental genome effects on fetal bone were mirrored by maternal genome effects on fetal serum 25-hydroxyvitamin D (96.9%, p < 0.001) and paternal genome effects on alkaline phosphatase (90.0%, p < 0.001) and their correlations with maternally controlled bone wet weight and paternally controlled limb ossification, respectively. Bone wet weight and flat bone size correlated positively with muscle weight (r = 0.84 and 0.77, p < 0.0001) and negatively with muscle H19 expression (r = -0.34 and -0.31, p < 0.01). Because imprinted maternally expressed H19 regulates growth factors by miRNA interference, this suggests muscle-bone interaction via epigenetic factors. PMID- 24753182 TI - HER-2 expression is not prognostic in osteosarcoma; a Children's Oncology Group prospective biology study. AB - BACKGROUND: Since the initial reports of human epidermal growth factor receptor 2 (HER-2) expression as being prognostic in osteosarcoma, numerous small studies varying in the interpretation of the immunohistochemical (IHC) staining patterns have produced conflicting results. The Children's Oncology Group therefore embarked on a prospective biology study in a larger sample of patients to define in osteosarcoma the prognostic value of HER-2 expression using the methodology employed in the initial North American study describing an association between HER-2 expression and outcome. PROCEDURE: The analytic patient population was comprised of 149 patients with newly diagnosed osteosarcoma, 135 with localized disease and 14 with metastatic disease, all of whom had follow up clinical data. Paraffin embedded material from the diagnostic biopsy was stained with CB11 antibody and scored by two independent observers. Correlation of HER-2 IHC score and demographic variables was analyzed using a Fisher's exact test and correlation with survival using a Kaplan-Meier analysis. RESULTS: No association was found with HER-2 status and any of the demographic variables tested including the presence or absence of metastatic disease at diagnosis. No association was found between HER-2 status and either event free survival or overall survival in the patients with localized disease. CONCLUSION: HER-2 expression is not prognostic in osteosarcoma in the context of this large prospective study. HER-2 expression cannot be used as a basis for stratification of therapy. Identification of potential prognostic factors should occur in the context of large multi-institutional biology studies. PMID- 24753183 TI - Neuropsychological function before and after subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression. AB - BACKGROUND: Treatment-resistant depression (TRD) is a pervasive and difficult to treat condition for which deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) is an emerging therapeutic option. However, neuropsychological safety data for this novel treatment have only been published for a small number of subjects. Moreover, little is known regarding the neuropsychological profile present in TRD patients at baseline, prior to initiation of DBS therapy. This report describes the neuropsychological effects of TRD and acute and chronic DBS of the SCCwm in patients with unipolar and bipolar TRD. METHODS: Patients with TRD (N = 17) were compared to a healthy control group (N = 15) on subtests from the Cambridge Neuropsychological Test Automated Battery and the Stroop Task. Patients were then tested again at subsequent time points of 1 and 6 months following the initiation of chronic DBS of the SCCwm. RESULTS: Patients with TRD showed similar levels of performance to healthy controls on most neuropsychological measures, with the exception that the TRD group had slower processing speed. Patients with bipolar TRD, relative to those with unipolar TRD, obtained lower scores on measures of executive function and memory only at baseline. With acute and chronic SCCwm DBS, neuropsychological function improved in multiple domains including processing speed and executive function (planning, set shifting, response inhibition), and memory remained stable. CONCLUSIONS: Patients with TRD show slowed processing speed but otherwise largely preserved neuropsychological functioning. DBS of the SCCwm does not result in worsening of any aspect of neuropsychological function and may improve certain domains. Future research is warranted to better understand the effects of TRD and DBS on neuropsychological function. PMID- 24753184 TI - The TP53 gene network in a postgenomic era. AB - Inactivation of TP53 pathways are the most common defects observed in human cancer. Although missense mutations remain the most frequent genetic event, it is now evident that dysfunction of several members of this network such as MDM2, MDM4 (mdmX), or miR-125b can substitute for TP53 mutations. This special issue on TP53 brings the TP53 gene into the post-genomic era. Several fundamental features of wild type and mutant proteins and their modifications are reviewed, as well as animal models and clinical aspects such as recommendations for patient care. The complex structure of this gene warrants innovative strategies to infer a more accurate status of human tumors. Recommendations and guidelines for reporting and annotating TP53 variants are also provided, to help researchers generate standardized data that are easy to understand, analyze, and exchange across various cancer variant databases. PMID- 24753185 TI - Major pitfalls in BAT performance may be caused by gating protocols and CD63% cut off evaluation. PMID- 24753190 TI - Chemical and toxicological investigations of a previously unknown poisonous European mushroom Tricholoma terreum. AB - The established tradition of consuming and marketing wild mushrooms has focused attention on mycotoxicity, which has become a global issue. In the present study, we describe the toxins found in a previously unknown poisonous European mushroom Tricholoma terreum. Fifteen new triterpenoids terreolides A-F (1-6) and saponaceolides H-P (8-16) were isolated from the fruiting bodies of the toxic mushroom T. terreum. Terreolides A-C (1-3) possessed a unique 5/6/7 trioxaspiroketal system, whereas terreolides D-F (4-6) possessed an unprecedented carbon skeleton. Two abundant compounds in the mushroom, saponaceolide B (7) and saponaceolide M (13), displayed acute toxicity, with LD50 values of 88.3 and 63.7 mg kg(-1) when administered orally in mice. Both compounds were found to increase serum creatine kinase levels in mice, indicating that T. terreum may be the cause of mushroom poisoning ultimately leading to rhabdomyolysis. PMID- 24753196 TI - Long-term effect of childhood liver transplantation on body cell mass. AB - Malnutrition is common in end-stage liver disease, but a correction after transplantation is expected. Body cell mass (BCM) assessment using total body potassium (TBK) measurements is considered the gold standard for assessing nutritional status. The aim of this study was to examine the BCM and, therefore, nutritional status of long-term survivors after childhood liver transplantation. This was a longitudinal nested cohort study of patients undergoing transplantation at <18 years of age and surviving >3 years with ongoing review at our center. TBK measurements were obtained before transplantation and during long term follow-up. BCM was calculated from TBK and was adjusted for the height raised to power p, which depended on sex (BCM/height(p)). The effects of the age at transplant, linear growth impairment, a diagnosis of biliary atresia, and steroid use were assessed. Thirty-two patients (20 males) participated; 59% had biliary atresia. The median age at transplant was 2.11 years (range = 0.38-10.92 years). Posttransplant testing was performed at a median of 7.23 years (range = 3.28-14.99 years) when they were 10.12 years old (range = 4.56-20.77 years). This cohort attained mean z scores for height, weight, and body mass index of -0.41 +/ 1.36, -0.26 +/- 1.14, and 0.04 +/- 0.99, respectively. BCM/height(p) was reduced before transplantation but was further reduced after transplantation (P < 0.001) despite the normalization of height and weight. Weight recovery, therefore, likely came from increased fat mass and not BCM. Linear growth impairment was associated with a greater reduction in posttransplant BCM/height(p) (P = 0.02). In multivariate analyses, only an older age at transplant predicted reduced posttransplant BCM/height(p) (P = 0.02). The age at transplant, sex, steroid use, and underlying diagnosis did not predict changes in BCM/height(p) after transplantation. In conclusion, weight recovery in long-term survivors of childhood liver transplantation is likely due to increased fat mass because BCM remains reduced. Nutritional compromise persists in long-term survivors of childhood liver transplantation. PMID- 24753197 TI - Differential effects of early life stress on hippocampus and amygdala volume as a function of emotional abilities. AB - Early life stress (ELS) is known to have considerable influence on brain development and affective functioning. Previous studies in clinical populations have shown that hippocampus and amygdala, two central structures of limbic emotion processing circuits, are predominantly affected by early stress exposure. Given the inconsistent findings on ELS-related effects in healthy populations and the associations of ELS and affective functioning, the question arises which additional emotion-relevant variables need to be considered to better understand the effects of ELS. We, therefore, investigated the volume of hippocampus and amygdala in 25 high alexithymic (h-ALEX) and 25 low alexithymic (l-ALEX) individuals, which were matched with regard to ELS, but significantly differed in their degree of emotional functioning. Volumetric analyses were performed using FSL-FIRST, a method to automatically segment subcortical structures on T1 weighted magnetic resonance images. Alexithymia was assessed using the Toronto Alexithymia Scale and Bermond-Vorst Alexithymia Questionnaire. ELS was assessed by Childhood Trauma Questionnaire (CTQ) and Early Trauma Inventory. Our data showed that ELS was negatively associated with right hippocampus volume in h-ALEX individuals, while there was no such association in the l-ALEX group. Furthermore, ELS was positively associated with left amygdala volume in l-ALEX individuals, but not in individuals with high levels of alexithymia. The present study emphasizes a substantial relationship between intrapersonal factors, such as alexithymia and neural alterations related to the experience of ELS. Longitudinal study designs are necessary to pursue the question of how emotional abilities interact with individual adaptations to early stress exposure on the neural level. PMID- 24753199 TI - Thermomechanical properties of the stimulus transducing cuticle in the infrared organ of Merimna atrata (Coleoptera, Buprestidae). AB - The pyrophilous Australian "fire-beetle" Merimna atrata strongly depends on the occurrence and localization of forest fires for its reproduction. As a special adaptation to its unusual biology, elaborate infrared (IR) organs have evolved in this species. The IR-organs consist of a specialized cuticular portion, the absorbing area, innervated by a sensory complex. The sensory complex contains a thermosensitive multipolar neuron with a specialized dendritic region, the terminal dendritic mass, and a mechanosensitive unit represented by a chordotonal organ (CO). Evidence for the IR-receptive function so far has only been provided for the multipolar neuron. Based on morphological data, it has been hypothesized that the CO could also be involved in IR-reception by measuring minute thermal deformations of the absorbing area. To test this hypothesis, we investigated structural features like cuticle thickness, reduced Young's modulus and hardness of the absorbing area. The results were used in finite element simulations to analyze the thermomechanical behavior and performance of the IR-organ. Our findings indicate that considerable thermal deformation of the absorbing area occurs, supporting the hypothesis that the CO could function as photomechanical IR-receptor. Interestingly, at the innervation site of the CO the lowest relative displacements of the absorbing area were found. This may indicate that the CO as putative photomechanic IR-receptor has not been adapted according to the requirements of highest sensitivity. Probable benefits of the bimodal innervation by a thermosensory and a mechanosensory unit and their possible interaction for an improved performance of the IR-organ are discussed. PMID- 24753198 TI - Arterial cerebral blood volume-weighted functional MRI using pseudocontinuous arterial spin tagging (AVAST). AB - PURPOSE: Neurovascular regulation, including responses to neural activation that give rise to the blood oxygenation level-dependent (BOLD) effect, occurs mainly at the arterial and arteriolar level. The purpose of this study is to develop a framework for fast imaging of arterial cerebral blood volume (aCBV) signal suitable for functional imaging studies. METHODS: A variant of the pseudocontinuous arterial spin tagging technique was developed in order to achieve a contrast that depends on aCBV with little contamination from perfusion signal by taking advantage of the kinetics of the tag through the vasculature. This technique tailors the tagging duration and repetition time for each subject. The proposed technique, called AVAST, is compared empirically with BOLD imaging and standard (perfusion-weighted) arterial spin labeling (ASL) technique, in a motor-visual activation paradigm. RESULTS: The average Z-scores in the activated area obtained over all the subjects were 4.25, 5.52, and 7.87 for standard ASL, AVAST, and BOLD techniques, respectively. The aCBV contrast obtained from AVAST provided 80% higher average signal-to-noise ratio and 95% higher average contrast to-noise ratio compared with that of the standard ASL measurements. CONCLUSION: AVAST exhibits improved activation detection sensitivity and temporal resolution over the standard ASL technique, in functional MRI experiments, while preserving its quantitative nature and statistical advantages. AVAST particularly could be useful in clinical studies of pathological conditions, longitudinal studies of cognitive function, and studies requiring sustained periods of the condition. PMID- 24753200 TI - Binding characteristics and interactive region of 2-phenylpyrazolo[1,5 c]quinazoline with DNA. AB - The interaction between 2-phenylpyrazolo[1,5-c]quinazoline (PQ) and DNA under physiological conditions was investigated using multi-spectroscopic techniques, atomic force microscopy and gel electrophoresis. The thermodynamic parameters were estimated and were discussed in detail. The results of fluorescence quenching experiments indicated that the main interactive force between PQ and DNA was a hydrophobic interaction and that it was a static quenching process. Potassium iodide and single-strand (ss)DNA quenching studies, together with circular dichroism spectra implied groove binding of PQ with DNA. Atomic force microscopy and gel electrophoresis experiments suggested that there were no major conformational changes in DNA upon interaction with PQ. In addition, UV/vis absorption titration of DNA bases confirmed that PQ bound with DNA mainly through a minor groove interaction and preferentially interacted with adenine and thymine. We anticipate that this work will provide useful information for the application of quinazoline derivatives in the fields of medicinal and pharmaceutical chemistry. PMID- 24753204 TI - Stress and glucocorticoid regulation of NR4A genes in mice. AB - The NR4A nuclear receptors subgroup, comprising Nur77 (NR4A1), Nurr1 (NR4A2), and Nor1 (NR4A3), are orphan receptors induced by a variety of signals, including stress. These receptors are described as early response genes and in vitro studies have shown that they take part in regulation of the hypothalamic pituitary-adrenal (HPA) axis, the major stress-responsive neuroendocrine system. This study analyzes further the interweaving of NR4A receptors with the HPA axis at rest and after a restraint stress in vivo in mice. We show that each NR4A member has a similar mRNA expression pattern and low levels of expression at rest except, in particular in hippocampus for Nurr1 and in adrenals for Nur77. After restraint stress, mRNA expression of each NR4A is markedly induced in adrenals and pituitary and significantly in hypothalamus. In higher cerebral regions, such as cortex, hippocampus, and amygdala, induction of NR4A mRNA elicited by stress was very moderate or undetected. The influence of glucocorticoids on NR4A mRNA expression was analyzed by comparing wild-type and Cbg k.o. mice used as a model of glucocorticoid hyposignaling. Nur77 mRNA and protein expression and a downstream Nur77 target gene were found to be affected in the hypothalamus and pituitary of the Cbg k.o. mice but not in hippocampus and cortex. These results further support a physiological role of NR4A orphan receptors in the glucocorticoid response to stress. PMID- 24753205 TI - TCIRG1-associated congenital neutropenia. AB - Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1. PMID- 24753206 TI - Pilot study of high-intensity focused ultrasound ablation as a bridging therapy for hepatocellular carcinoma patients wait-listed for liver transplantation. AB - The objective of this study was to investigate the outcomes of high-intensity focused ultrasound (HIFU) ablation as a bridging therapy for patients with hepatocellular carcinoma (HCC) who had been wait-listed for deceased donor liver transplantation (DDLT). Adult patients with unresectable and unablatable HCCs within the University of California San Francisco criteria who had been wait listed for DDLT were screened for their suitability for HIFU ablation as a bridging therapy if they were not suitable for transarterial chemoembolization (TACE). Treatment outcomes for patients receiving HIFU ablation, TACE, and best medical treatment (BMT) were compared. Fifty-one patients were included in the analysis. Before the introduction of HIFU ablation, only 39.2% of the patients had received bridging therapy (TACE only, n = 20). With HIFU ablation in use, the rate increased dramatically to 80.4% (TACE + HIFU, n = 41). The overall dropout rate was 51% (n = 26). Patients in the BMT group had a significantly higher dropout rate (P = 0.03) and significantly poorer liver function as reflected by higher Model for End-Stage Liver Disease scores and higher Child-Pugh grading. Clinically relevant ascites was found in 5 patients in the HIFU group and 2 patients in the BMT group, but none was found in the TACE group (P = 0.01 and P = 0.03, respectively). The TACE and HIFU groups had comparable percentages of tumor necrosis in excised livers (P = 0.35), and both were significantly higher than that in the BMT group (P = 0.01 and P = 0.02, respectively). In conclusion, HIFU ablation was safe even for HCC patients with Child-Pugh C disease. Its adoption increased the percentage of patients receiving bridging therapy from 39.2% to 80.4%. A randomized controlled trial for further validation of its efficacy is warranted. PMID- 24753207 TI - Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. AB - Antibody-mediated rejection (AMR), also known as B-cell-mediated or humoral rejection, is a significant complication after kidney transplantation that carries a poor prognosis. Although fewer than 10% of kidney transplant patients experience AMR, as many as 30% of these patients experience graft loss as a consequence. Although AMR is mediated by antibodies against an allograft and results in histologic changes in allograft vasculature that differ from cellular rejection, it has not been recognized as a separate disease process until recently. With an improved understanding about the importance of the development of antibodies against allografts as well as complement activation, significant advances have occurred in the treatment of AMR. The standard of care for AMR includes plasmapheresis and intravenous immunoglobulin that remove and neutralize antibodies, respectively. Agents targeting B cells (rituximab and alemtuzumab), plasma cells (bortezomib), and the complement system (eculizumab) have also been used successfully to treat AMR in kidney transplant recipients. However, the high cost of these medications, their use for unlabeled indications, and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of AMR in kidney transplant recipients. PMID- 24753208 TI - First proposed panels on acute leukemia for four-color immunophenotyping by flow cytometry from the Brazilian group of flow cytometry-GBCFLUX. AB - Multiparameter flow cytometry is a highly sensitive, fast, and specific diagnostic technology with a wide range of applicability in hematology. Although well-established eight-color immunophenotyping panels are already available, most Brazilian clinical laboratories are equipped with four-color flow cytometer facilities. Based on this fact, the Brazilian Group of Flow Cytometry (Grupo Brasileiro de Citometria de Fluxo, GBCFLUX) for standardization of clinical flow cytometry has proposed an antibody panel designed to allow precise diagnosis and characterization of acute leukemia (AL) within resource-restricted areas. Morphological analysis of bone marrow smears, together with the screening panel, is mandatory for the primary identification of AL. The disease-oriented panels proposed here are divided into three levels of recommendations (mandatory, recommendable, and optional) in order to provide an accurate final diagnosis, as well as allow some degree of flexibility based on available local resources and patient-specific needs. The proposed panels will be subsequently validated in an interlaboratory study to evaluate its effectiveness on the diagnosis and classification of AL. (Assoc editor comm. 2). PMID- 24753209 TI - A nondigestible saccharide, fructooligosaccharide, increases the promotive effect of a flavonoid, alpha-glucosyl-isoquercitrin, on glucagon-like peptide 1 (GLP-1) secretion in rat intestine and enteroendocrine cells. AB - This study conducted in vivo and in situ experiments with rats to investigate the glucagon-like peptide-1 (GLP-1) secretion in response to oral or ileal administration of alpha-glucosyl-isoquercitrin (20-40 mmol in 2 mL; Q3G), fructooligosaccharides (200 mmol in 2 mL; FOS) and Q3G + FOS. Direct effects on GLP-1-producing l-cells were also examined by an in vitro study using a murine enteroendocrine cell line, GLUTag. To evaluate the plasma GLP-1 level, blood samples from jugular cannula for in vivo and portal cannula for in situ experiments were obtained before and after administration of Q3G, FOS, or Q3G + FOS. We found tendencies for increases but transient stimulation of GLP-1 secretion by Q3G in in vivo and in situ experiments. Although FOS alone did not have any effects, Q3G + FOS enhanced and prolonged high plasma GLP-1 level in both experiments. In addition, application of Q3G on GLUTag cells stimulated GLP 1 secretion while FOS enhanced the effect of Q3G. Our results suggest that Q3G + FOS possess the potential for the management or prevention of Type 2 diabetes mellitus (T2DM) by enhancing and prolonging the GLP-1 secretion via direct stimulation of GLP-1 producing l-cell. PMID- 24753210 TI - Asymmetric dimethylarginine levels in children with beta-thalassemia and their correlations to tricuspid regurgitant jet velocity. AB - BACKGROUND: Pulmonary hypertension (PHT) may be the leading cause of death in beta-thalassemia patients; however, its pathophysiologic mechanisms are still unclear. Recent studies indicate that asymmetric dimethylarginine (ADMA) plays a role in the initiation and progression of a variety of diseases, especially the cardiovascular system. The aim of this study is to assess the levels of ADMA in children with beta-thalassemia and their correlations with tricuspid regurgitant jet velocity. PROCEDURES: This study was carried out on 30 children with beta thalassemia major and 30 healthy children served as a control group. Both groups underwent the following investigations: Blood sampling for CBC, LDH, serum ferritin, reticulocytic count, serum bilirubin, AST, ALT, in addition to plasma levels of ADMA. Doppler echocardiography was done for thalassemic group. Patients with tricuspid regurgitant jet velocity (TRV >= 2.5 m/sec) were considered risky for PHT. RESULTS: Plasma ADMA levels were significantly higher in patients with beta-thalassemia than control group with a mean value 0.91 +/- 0.14 and 0.62 +/- 0.10 umol/L respectively (P = 0.001). There was a significant positive correlation between plasma ADMA levels and tricuspid regurgitant jet velocity. The prevalence of elevated tricuspid regurgitant jet velocity (TRV >= 2.5 m/sec) in patients with thalassemia was 33.3%, with a significant increase of elevated TVR (>= 2.5 m/sec) in patients with thalassemia with splenectomy than in patients without splenectomy. CONCLUSION: High plasma ADMA levels may be implicated in the pathogenesis of PHT in children with beta-thalassemia. PMID- 24753212 TI - Solvothermal transformation of a calcium oleate precursor into large-sized highly ordered arrays of ultralong hydroxyapatite microtubes. AB - Hydroxyapatite (HAP), a well-known member of the calcium phosphate family, is the major inorganic component of bones and teeth in vertebrates. The highly ordered arrays of HAP structures are of great significance for hard tissue repair and for understanding the formation mechanisms of bones and teeth. However, the synthesis of highly ordered HAP structure arrays remains a great challenge. In this work, inspired by the ordered structure of tooth enamel, we have successfully synthesized three-dimensional bulk materials with large sizes (millimeter scale) that are made of highly ordered arrays of ultralong HAP microtubes (HOAUHMs) by solvothermal transformation of calcium oleate precursor. The core-shell structured oblate sphere consists of a core that is composed of HAP nanorods and a shell that consists of highly ordered HAP microtube arrays. The prepared HOAUHMs are large: 6.0 mm in diameter and up to 1.4 mm in thickness. With increasing solvothermal reaction time, the HOAUHMs grow larger; the microtubes become more uniform and more ordered. This work provides a new synthetic method for synthesizing highly ordered arrays of uniform HAP ultralong microtubes that are promising for biomedical applications. PMID- 24753211 TI - Neurocircuitry underlying risk and resilience to social anxiety disorder. AB - BACKGROUND: Almost half of children with an inhibited temperament will develop social anxiety disorder by late adolescence. Importantly, this means that half of children with an inhibited temperament will not develop social anxiety disorder. Studying adults with an inhibited temperament provides a unique opportunity to identify neural signatures of both risk and resilience to social anxiety disorder. METHODS: Functional magnetic resonance imaging (fMRI) was used to measure brain activation during the anticipation of viewing fear faces in 34 young adults (17 inhibited, 17 uninhibited). To identify neural signatures of risk, we tested for group differences in functional activation and connectivity in regions implicated in social anxiety disorder, including the prefrontal cortex, amygdala, and insula. To identify neural signatures of resilience, we tested for correlations between brain activation and both emotion regulation and social anxiety scores. RESULTS: Inhibited subjects had greater activation of a prefrontal network when anticipating viewing fear faces, relative to uninhibited subjects. No group differences were identified in the amygdala. Inhibited subjects had more negative connectivity between the rostral anterior cingulate cortex (ACC) and the bilateral amygdala. Within the inhibited group, those with fewer social anxiety symptoms and better emotion regulation skills had greater ACC activation and greater functional connectivity between the ACC and amygdala. CONCLUSIONS: These findings suggest that engaging regulatory prefrontal regions during anticipation may be a protective factor, or putative neural marker of resilience, in high-risk individuals. Cognitive training targeting prefrontal cortex function may provide protection against anxiety, especially in high-risk individuals, such as those with inhibited temperament. PMID- 24753213 TI - Algebraic reconstruction technique for parallel imaging reconstruction of undersampled radial data: application to cardiac cine. AB - PURPOSE: To investigate algebraic reconstruction technique (ART) for parallel imaging reconstruction of radial data, applied to accelerated cardiac cine. METHODS: A graphics processing unit (GPU)-accelerated ART reconstruction was implemented and applied to simulations, point spread functions and in 12 subjects imaged with radial cardiac cine acquisitions. Cine images were reconstructed with radial ART at multiple undersampling levels (192 Nr * Np = 96 to 16). Images were qualitatively and quantitatively analyzed for sharpness and artifacts, and compared to filtered back-projection, and conjugate gradient SENSE. RESULTS: Radial ART provided reduced artifacts and mainly preserved spatial resolution, for both simulations and in vivo data. Artifacts were qualitatively and quantitatively less with ART than filtered back-projection using 48, 32, and 24 Np , although filtered back-projection provided quantitatively sharper images at undersampling levels of 48-24 Np (all P < 0.05). Use of undersampled radial data for generating auto-calibrated coil-sensitivity profiles resulted in slightly reduced quality. ART was comparable to conjugate gradient SENSE. GPU-acceleration increased ART reconstruction speed 15-fold, with little impact on the images. CONCLUSION: GPU-accelerated ART is an alternative approach to image reconstruction for parallel radial MR imaging, providing reduced artifacts while mainly maintaining sharpness compared to filtered back-projection, as shown by its first application in cardiac studies. PMID- 24753214 TI - Contributions of the hippocampus and entorhinal cortex to rapid visuomotor learning in rhesus monkeys. AB - The hippocampus and adjacent structures in the medial temporal lobe are essential for establishing new associative memories. Despite this knowledge, it is not known whether the hippocampus proper is essential for establishing such memories, nor is it known whether adjacent regions like the entorhinal cortex might contribute. To test the contributions of these regions to the formation of new associative memories, we trained rhesus monkeys to rapidly acquire arbitrary visuomotor associations, i.e., associations between visual stimuli and spatially directed actions. We then assessed the effects of reversible inactivations of either the hippocampus (Experiment 1) or entorhinal cortex (Experiment 2) on the within-session rate of learning. For comparison, we also evaluated the effects of the inactivations on performance of problems of the same type that had been well learned prior to any inactivations. We found that inactivation of the entorhinal cortex but not hippocampus produced impairments in acquiring novel arbitrary associations. The impairment did not extend to the familiar, previously established associations. These data indicate that the entorhinal cortex is causally involved in establishing new associations, as opposed to retrieving previously learned associations. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID- 24753215 TI - Protein marker profiling in different T classification in laryngeal squamous cell carcinoma. AB - BACKGROUND: The identification of specific biomarkers related to laryngeal squamous cell carcinoma (SCC) will be helpful in early detection and determination of reasonable treatment options, which are crucial for the prognosis of patients with laryngeal SCC. The purpose of this study was to profile the protein markers that can be used for diagnosis and prognosis of laryngeal SCC and to observe laryngeal SCC progression with distinct stages of malignant transformation. METHODS: Two hundred twenty-five proteins were tested in 84 pairs of tumors and adjacent nontumor mucosa samples using protein pathway arrays (PPAs). Ingenuity pathway analysis (IPA) enrichment analysis was performed and protein expression profiles in different T classification were mapped by grid analysis of time-series expression (GATE). RESULTS: Among 16 proteins differently expressed between tumors and normal tissues, we selected 9 proteins (TTF-1, CDK2, Eg5, proliferating cell nuclear antigen [PCNA], Bcl-xL, 14-3-3beta, p27, SRC-1, cytokeratin 18) as markers for classification. From the IPA analysis, we observed a more malignant transformation from T3 to T4 at the protein level and described the changing patterns of the proteins' expression in this progression. JAK2, keratin 10, and IL-3Ralpha were identified as markers for prognosis. The risk model based on histological grade, T classification, N classification, JAK2, and IL-3Ralpha can predict the prognosis with 85.5% accuracy. CONCLUSION: This study indicated that dysregulated signaling proteins can be selected as useful biomarkers for tumor classification and predicting the outcome in patients with laryngeal SCC. The changing patterns of the proteins' expression in different stages were related to the more malignant transformation and further studies will focus on the role of these proteins in laryngeal SCC progression. PMID- 24753216 TI - Fast T2 mapping with multiple echo, Caesar cipher acquisition and model-based reconstruction. AB - PURPOSE: Fast, quantitative T2 mapping is of value to both clinical and research environments. However, many protocols utilizing fast spin echo (FSE) pulse sequences contain acceleration-induced artifacts that are compounded when fitting parameter maps, especially in the presence of imperfect refocusing. This work presents a B1 -corrected, model-based reconstruction and associated Cartesian FSE phase-encode ordering that provides enhanced accuracy in T2 estimates compared with other common accelerated protocols. THEORY AND METHODS: The method, known as multiple echo, Caesar cipher acquisition and model-based reconstruction (ME CAMBREC), directly fitted T2 , flip angle, and proton density maps on a row-by row basis to k-space data using the extended phase graph model. Regularization was enforced in order to minimize noise amplification effects. ME-CAMBREC was evaluated in computational and physical phantoms, as well as human brain, and compared with other FSE-based T2 mapping protocols, DESPOT2, and parallel imaging acceleration. RESULTS: In computational, phantom, and human experiments, ME CAMBREC provided T2 maps with fewer artifacts and less or similar error compared with other methods tested at moderate-to-high acceleration factors. In vivo, ME CAMBREC provided error rates approximately one-half those of other methods. CONCLUSION: Directly fitting multi-echo data to k-space using the extended phase graph can increase fidelity of T2 maps significantly, especially when using an appropriate phase-encode ordering. PMID- 24753217 TI - Why is the biological hydrophobicity scale more accurate than earlier experimental hydrophobicity scales? AB - The recognition of transmembrane helices by the translocon is primarily guided by the average hydrophobicity of the potential transmembrane helix. However, the exact hydrophobicity of each amino acid can be identified in several different ways. The free energy of transfer for amino acid analogues between a hydrophobic media, for example, octanol and water can be measured or obtained from simulations, the hydrophobicity can also be estimated by statistical properties from known transmembrane segments and finally the contribution of each amino acid type for the probability of translocon recognition has recently been measured directly. Although these scales correlate quite well, there are clear differences between them and it is not well understood which scale represents neither the biology best nor what the differences are. Here, we try to provide some answers to this by studying the ability of different scales to recognize transmembrane helices and predict the topology of transmembrane proteins. From this analysis it is clear that the biological hydrophobicity scale as well scales created from statistical analysis of membrane helices perform better than earlier experimental scales that are mainly based on measurements of amino acid analogs and not directly on transmembrane helix recognition. Using these results we identified the properties of the scales that perform better than other scales. We find, for instance, that the better performing scales consider proline more hydrophilic. This shows that transmembrane recognition is not only governed by pure hydrophobicity but also by the helix preferences for amino acids, as proline is a strong helix breaker. PMID- 24753218 TI - Withdrawal from chronic amphetamine reduces dopamine transmission in the rat lateral septum. AB - The lateral septum (LS) is a brain nucleus implicated in the addictive process. This study investigated whether withdrawal from chronic amphetamine (AMPH) induces alterations in dopamine (DA) transmission within the LS. Male Sprague Dawley rats were injected with AMPH (2.5 mg/kg i.p.) or saline during 14 days and thereafter subjected to 24 hr or 14 days of withdrawal. After these withdrawal periods, we measured DA extracellular levels by in vivo microdialysis, DA tissue levels, and tyrosine hydroxylase (TH) and vesicular monoamine transporter-2 (VMAT2) expression in the LS. Our results showed a significant decrease in K(+) induced release of DA in the LS of AMPH-treated rats, 14 days after withdrawal compared with saline-treated rats. There were no significant differences in DA tissue content and TH expression. Interestingly, there was a decrease of LS VMAT2 expression in AMPH-treated rats, 14 days after withdrawal compared with saline treated rats. This is the first neurochemical evidence showing that withdrawal from repeated AMPH administration decreases K(+) -induced DA release in the rat LS. Our results suggest that this decrease in DA releasability could be due to a decrease in DA vesicular uptake. The possibility that these neurochemical changes are associated with AMPH abstinence syndrome should be further explored. PMID- 24753219 TI - European Union policy on pesticides: implications for agriculture in Ireland. AB - European Community (EC) legislation has limited the availability of pesticide active substances used in effective plant protection products. The Pesticide Authorisation Directive 91/414/EEC introduced the principle of risk assessment for approval of pesticide active substances. This principle was modified by the introduction of Regulation (EC) 1107/2009, which applies hazard, the intrinsic toxicity of the active substance, rather than risk, the potential for hazard to occur, as the approval criterion. Potential impacts of EC pesticide legislation on agriculture in Ireland are summarised. While these will significantly impact on pesticide availability in the medium to long term, regulations associated with water quality (Water Framework Directive 2000/60/EC and Drinking Water Directive 1998/83/EC) have the potential to restrict pesticide use more immediately, as concerns regarding public health and economic costs associated with removing pesticides from water increase. This rationale will further reduce the availability of effective pesticide active substances, directly affecting crop protection and increasing pesticide resistance within pest and disease populations. In addition, water quality requirements may also impact on important active substances used in plant protection in Ireland. The future challenge for agriculture in Ireland is to sustain production and profitability using reduced pesticide inputs within a framework of integrated pest management. PMID- 24753220 TI - Iron-induced oxidative rat liver injury after non-heart-beating warm ischemia is mediated by tumor necrosis factor alpha and prevented by deferoxamine. AB - This study investigated iron-induced injury after warm ischemia in a non-heart beating (NHB) rat liver model and the effects of deferoxamine (DFO). Livers from heart-beating (HB) rats or rats that were NHB for 60 minutes were stored in University of Wisconsin solution for 5 hours at 4 degrees C [cold storage (CS)] and then were subjected to 2 hours of machine reperfusion (MRP) at 37 degrees C. Three NHB groups were compared: (1) no DFO, (2) DFO 30 minutes before cardiac arrest and during CS and MRP, and (3) DFO during CS and MRP. Aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels in the NHB perfusate were significantly elevated (P < 0.01) in comparison with levels in HB controls after CS and MRP. After CS, the levels of iron and tumor necrosis factor alpha (TNF-alpha) were 0.077 +/- 0.007 MUmol/g and 151 +/- 26 pg/g, respectively, in the NHB group and 0.022 +/- 0.004 MUmol/g and 17 +/- 7 pg/g, respectively, in the HB group (P < 0.01). After MRP, LDH significantly correlated with iron (R(2) = 0.81, P < 0.01). The DFO pretreatment of NHB donors decreased AST (7.3 +/- 0.8 versus 4.0 +/- 0.5 U/g of liver, P < 0.05) and LDH (42.5 +/- 4.1 versus 20.4 +/- 2.5 U/g of liver, P < 0.05) with 2 hours of MRP and increased bile flow during MRP (142 +/- 34 versus 240 +/- 18 MUL/g, P < 0.05). It also reduced the levels of iron (0.077 +/- 0.007 versus 0.050 +/- 0.008 MUmol/g, P < 0.05) and TNF-alpha (151 +/- 26 versus 51 +/- 13 pg/g, P < 0.05) after CS and the levels of lipid peroxidation products F2-isoprostane (149 +/- 11 versus 99 +/- 10 ng/g, P < 0.05) and malondialdehyde (1.58 +/- 0.1 versus 1.14 +/- 0.08 MUmol/g, P < 0.05) after MRP. In conclusion, iron-initiated oxidative stress is likely involved in NHB donor liver injury, and importantly, DFO pretreatment reduces liver damage. PMID- 24753221 TI - Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. AB - STUDY OBJECTIVE: To evaluate the observed incidence of acute kidney injury (AKI) in adult patients receiving either piperacillin-tazobactam and vancomycin or cefepime-vancomycin for more than 48 hours. DESIGN: Retrospective matched cohort. SETTING: Large academic medical center. PATIENTS: Adult patients without preexisting renal dysfunction admitted over an 8-month time period who received either the combination of piperacillin-tazobactam and vancomycin or cefepime vancomycin for more than 48 hours were evaluated for AKI, defined by the Acute Kidney Injury Network criteria. MEASUREMENTS AND MAIN RESULTS: A total of 224 patients receiving either antimicrobial combination were evaluated for AKI. The incidence of AKI was significantly higher in the piperacillin-tazobactam and vancomycin group (34.8%) compared with the cefepime-vancomycin group (12.5%) in the unmatched analysis (p<0.0001). After adjusting for potential sources of bias through propensity score matched pairs and conditional logistic regression, piperacillin-tazobactam and vancomycin combination therapy (p=0.003) was an independent predictor of AKI. There were no significant differences in time to AKI or hospital length of stay between groups. CONCLUSIONS: The results of this study suggest that there may be an association between piperacillin-tazobactam and vancomycin combination therapy and increased incidence of AKI. PMID- 24753222 TI - On-line reaction monitoring and mechanistic studies by mass spectrometry: Negishi cross-coupling, hydrogenolysis, and reductive amination. AB - Reaction monitoring using inductive ESI mass spectrometry allows chemical reactions to be tracked in real time, including air- and moisture-sensitive as well as heterogeneous reactions. Highly concentrated solutions can also be monitored for long periods without emitter clogging. Sheath gas assists in nebulization and a sample splitter reduces the delay time and minimizes contamination of the instrument. Short-lived intermediates (ca. 5 s) were observed in Pd/C-catalyzed hydrogenolysis, and several intermediates were seen in Negishi cross-coupling reactions. PMID- 24753223 TI - Diverse pereopodal secretory systems implicated in thread production in an apseudomorph tanaidacean crustacean. AB - Among arthropods, various insects, spiders, and crustaceans produce thread. The crustacean Tanaidacea include species that use thread mainly to construct dwelling tubes. While thread production was previously known only in Tanaoidea and Paratanaoidea, it was recently discovered in two species in Kalliapseudidae (Apseudoidea), although information on the morphology of the thread-producing system was lacking. Using histology, light and scanning electron microscopy, we found that the kalliapseudid Phoxokalliapseudes tomiokaensis comb. nov. lacks the sort of glandular structures associated with thread production in the pereonites, but has these structures in pereopods 1-6. We observed four types of glandular systems defined by the types and distribution of glands they contain: Type A (pereopod 1), Type B (pereopods 2 and 3), Type C (pereopods 4 and 5), and Type D (pereopod 6). All types have small rosette glands and lobed glands; Type A additionally has large rosette glands. The inferred thread-producing apparatus in P. tomiokaensis is very different from that in Tanaoidea and Paratanaoidea, suggesting that kalliapseudids evolved thread production independently from the latter two groups. PMID- 24753224 TI - The maintenance of long-term memory in the hippocampus depends on the interaction between N-ethylmaleimide-sensitive factor and GluA2. AB - The maintenance of established memories has recently been shown to involve the stabilization of GluA2-containing AMPA receptors (GluA2/AMPARs) at postsynaptic membranes. Previous studies have suggested that N-ethylmaleimide-sensitive factor (NSF) regulates the stabilization of AMPARs at the synaptic membrane. We therefore disrupted the interaction between GluA2 and NSF in the dorsal hippocampus and examined its effect on the maintenance of object location and contextual fear memory. We used two interference peptides, pep2m and pepR845A, that have been shown to block the binding of NSF to GluA2 and reduce GluA2 synaptic content. Either peptide disrupted consolidated memory, and these effects persisted for at least 5 or 28 days after peptide administration. Following peptide administration and long-term memory disruption, rats were able to acquire new memories. Memory acquisition or consolidation was not impaired when pepR845A was given immediately before the training sessions. Blocking GluA2 endocytosis with the peptide GluA23Y prevented the memory impairment effect of pepR845A. Taken together, our results indicate that the persistence of long-term memory depends on the maintenance of a steady-state level of synaptic GluA2/AMPARs, which requires the interaction of NSF with GluA2. PMID- 24753225 TI - Cognitive-emotional training as an intervention for major depressive disorder. AB - BACKGROUND: There is an urgent need for more effective treatments for major depressive disorder (MDD). As understanding of the cognitive and affective neuroscience underlying psychiatric disorders expands, so do opportunities to develop interventions that capitalize on the capacity for brain plasticity. Cognitive training is one such strategy. In this article, we report a proof-of concept study of a novel cognitive-emotional training exercise designed to enhance cognitive control for emotional information processing and targeting components of the neural networks that have been implicated in MDD. METHODS: Twenty-one participants with MDD in a current episode were randomly assigned to one of the two treatment conditions: 11 participating in a cognitive-emotional training paradigm (emotional faces memory task (EFMT)) involving eight sessions over 4 weeks, and 10 participating in an active control condition (control training, CT). Assessments of MDD symptoms, negative affective bias in cognitive processing, and neurocognition (attention and working memory) were administered at baseline and after 4 weeks. RESULTS: Participants in the EFMT group exhibited a greater reduction in MDD symptoms compared to the CT group, and 6 of the 11 EFMT participants achieved clinical response (>= 50% reduction in symptoms). EFMT participants also exhibited changes in negative affective bias in the hypothesized direction whereas the CT participants did not. Both groups exhibited similar, small improvements in attention and working memory. CONCLUSIONS: Cognitive-emotional training may represent a feasible and effective intervention strategy for MDD. This proof-of-concept study highlights the need for future studies to fully understand the effectiveness, and mechanisms of effect, of these training strategies. PMID- 24753226 TI - Prelamin A accumulation and stress conditions induce impaired Oct-1 activity and autophagy in prematurely aged human mesenchymal stem cell. AB - Aging, a time-dependent functional decline of biological processes, is the primary risk factor in developing diseases such as cancer, cardiovascular or degenerative diseases. There is a real need to understand the human aging process in order to increase the length of disease-free life, also known as "health span". Accumulation of progerin and prelamin A are the hallmark of a group of premature aging diseases but have also been found during normal cellular aging strongly suggesting similar mechanisms between healthy aging and LMNA-linked progeroid syndromes. How this toxic accumulation contributes to aging (physiological or pathological) remains unclear. Since affected tissues in age associated disorders and in pathological aging are mainly of mesenchymal origin we propose a model of human aging based on mesenchymal stem cells (hMSCs) which accumulate prelamin A. We demonstrate that prelamin A-accumulating hMSCs have a premature aging phenotype which affects their functional competence in vivo. The combination of prelamin A accumulation and stress conditions enhance the aging phenotype by dysregulating the activity of the octamer binding protein Oct-1This experimental model has been fundamental to identify a new role for Oct-1 in hMSCs aging. PMID- 24753227 TI - Resveratrol stimulates AP-1-regulated gene transcription. AB - SCOPE: Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants, including the regulation of transcription. Here, we have analyzed the impact of resveratrol on the activity of the transcription factor activator protein-1 (AP-1). METHODS AND RESULTS: Using a chromosomally embedded AP-1-responsive reporter gene, we show that the AP-1 activity was significantly elevated in resveratrol-treated 293 human embryonic kidney and HepG2 hepatoma cells. The 12-O-tetradecanoylphorbol-13 acetate-responsive element, a binding site for c-Jun and c-Fos, was identified as resveratrol-responsive element. Expression of c-Jun and c-Fos, two proteins that constitute AP-1, is upregulated in resveratrol-stimulated HEK293 cells. On the transcriptional level, c-Jun and the ternary complex factor Elk-1 are essential for the activation of AP-1 in resveratrol-treated cells. In addition, mitogen activated protein kinases and protein kinase C are required to connect resveratrol stimulation with enhanced AP-1 controlled transcription. Finally, we show that resveratrol increased the activities of the AP-1 responsive cyclin D1 and tumor necrosis factor alpha promoters. CONCLUSION: Resveratrol regulates gene transcription via activation of stimulus-regulated protein kinases and the stimulus-responsive AP-1 transcription factors. The fact that resveratrol regulates AP-1 activity may explain many of the pleiotropic intracellular alterations induced by resveratrol. PMID- 24753228 TI - Performance of protein disorder prediction programs on amino acid substitutions. AB - Many proteins contain intrinsically disordered regions, which may be crucial for function, but on the other hand be related to the pathogenicity of variants. Prediction programs have been developed to detect disordered regions from sequences and used to predict the consequences of variants, although their performance for this task has not been assessed. We tested the performance of protein disorder prediction programs in detecting changes to disorder caused by amino acid substitutions. We assessed the performance of 29 protein disorder predictors and versions with 101 amino acid substitutions, whose effects have been experimentally validated. Disorder predictors detected the true positives at most with 6% success rate and true negatives with 34% rate for variants. The corresponding rates for the wild-type forms are 7% and 90%, respectively. The analysis revealed that disorder programs cannot reliably predict the effects of substitutions; consequently, the tested methods, and possibly similar programs, cannot be recommended for variant analysis without other information indicating to the relevance of disorder. These results inspired us to develop a new method, PON-Diso (http://structure.bmc.lu.se/PON-Diso), for disorder-related amino acid substitutions. With 50% success rate for independent test set and 70.5% rate in cross-validation, it outperforms the evaluated methods. PMID- 24753229 TI - Molecular characterisation of a sodium channel gene and identification of a Phe1538 to Ile mutation in citrus red mite, Panonychus citri. AB - BACKGROUND: The citrus red mite, Panonychus citri (McGregor), is regarded as one of the most serious citrus pests in many countries and has developed high resistance to pyrethroids as a result of the intensive use of these acaricides. RESULTS: The para sodium channel gene of P. citri (named PcNav ), containing an entire coding region of 6729 bp, was cloned in this study. Three alternative splicing sites and 12 potential RNA editing sites were identified in PcNav . Thus, exons alt 1 and alt 3-v3 were found to be unique to PcNav . Comparison of field fenpropathrin-resistant (WZ) and susceptible (LS) strains identified the point mutation F1538I in IIIS6 of the sodium channel, which is known to confer strong resistance to pyrethroids in mites. Moreover, it was also found that the PcNav mRNA was present during all life stages, and the transcript seems to be more abundant in larvae than in other developmental stages. CONCLUSION: These results suggest that the F1538I mutation plays an important role in fenpropathrin resistance in citrus red mites. This is the first study of the sodium channel in P. citri and provides abundant information for further research on the mechanism of pyrethroid resistance. PMID- 24753230 TI - Structural studies of bovine, equine, and leporine serum albumin complexes with naproxen. AB - Serum albumin, a protein naturally abundant in blood plasma, shows remarkable ligand binding properties of numerous endogenous and exogenous compounds. Most of serum albumin binding sites are able to interact with more than one class of ligands. Determining the protein-ligand interactions among mammalian serum albumins is essential for understanding the complexity of this transporter. We present three crystal structures of serum albumins in complexes with naproxen (NPS): bovine (BSA-NPS), equine (ESA-NPS), and leporine (LSA-NPS) determined to 2.58 A (C2), 2.42 A (P61), and 2.73 A (P212121) resolutions, respectively. A comparison of the structurally investigated complexes with the analogous complex of human serum albumin (HSA-NPS) revealed surprising differences in the number and distribution of naproxen binding sites. Bovine and leporine serum albumins possess three NPS binding sites, but ESA has only two. All three complexes of albumins studied here have two common naproxen locations, but BSA and LSA differ in the third NPS binding site. None of these binding sites coincides with the naproxen location in the HSA-NPS complex, which was obtained in the presence of other ligands besides naproxen. Even small differences in sequences of serum albumins from various species, especially in the area of the binding pockets, influence the affinity and the binding mode of naproxen to this transport protein. PMID- 24753231 TI - Nanostructured graphene/TiO2 hybrids as high-performance anodes for microbial fuel cells. AB - A new nanostructured graphene/TiO2 (G/TiO2) hybrid was synthesized by a facile microwave-assisted solvothermal process in which amorphous TiO2 was assembled on graphene in situ. The resulting G/TiO2 hybrids were characterized by XRD, SEM, TEM, Raman spectroscopy, and N2 adsorption/desorption analysis. The electrochemical properties of the hybrids as anode materials for Shewanella inoculated microbial fuel cells (MFCs) were studied for the first time, and they proved to be effective in improving MFC performance. The significantly improved bacterial attachment and extracellular electron-transfer efficiency could be attributed to the high specific surface area, active groups, large pore volume, and excellent conductivity of the nanostructured G/TiO2 hybrid, and this suggests that it could be a promising candidate for high-performance MFCs. PMID- 24753232 TI - Long-term fate of grafted hippocampal neural progenitor cells following ischemic injury. AB - The adult CNS has a very limited capacity to regenerate neurons after insult. To overcome this limitation, the transplantation of neural progenitor cells (NPCs) has developed into a key strategy for neuronal replacement. This study assesses the long-term survival, migration, differentiation, and functional outcome of NPCs transplanted into the ischemic murine brain. Hippocampal neural progenitors were isolated from FVB-Cg-Tg(GFPU)5Nagy/J transgenic mice expressing green fluorescent protein (GFP). Syngeneic GFP-positive NPCs were stereotactically transplanted into the hippocampus of FVB mice following a transient global cerebral ischemia model. Behavioral tests revealed that ischemia/reperfusion induced spatial learning disturbances in the experimental animals. The NPC transplantation promoted cognitive function recovery after ischemic injury. To study the long-term fate of grafted GFP-positive NPCs in a host brain, immunohistochemical approaches were applied. Confocal microscopy revealed that grafted cells survived in the recipient tissue for 90 days following transplantation and differentiated into mature neurons with extensive dendritic trees and apparent spines. Immunoelectron microscopy confirmed the formation of synapses between the transplanted GFP-positive cells and host neurons that may be one of the factors underlying cognitive function recovery. Repair and functional recovery following brain damage represent a major challenge for current clinical and basic research. Our results provide insight into the therapeutic potential of transplanted hippocampal progenitor cells following ischemic brain injury. PMID- 24753233 TI - Liver transplantation outcomes for Australian Aboriginal and Torres Strait Islanders. AB - An increased liver disease burden has been reported for Aboriginal and Torres Strait Islanders (ATSIs) in Australia; however, few proceed to liver transplantation (LT). We aimed to compare overall survival and graft survival after LT between ATSI and non-ATSI populations, assess the factors influencing survival within ATSIs, and finally examine the proportion of ATSIs undergoing LT. This study was a retrospective review of the Australia and New Zealand Liver Transplant Registry from 1985 to 2012 and examined consecutive primary LT performed in Australia. Overall and graft survival were compared between ATSI and non-ATSI groups. The Accessibility/Remoteness Index of Australia (ARIA) was used to calculate the remoteness of individuals. There were 3493 primary LT performed, and 45 patients (1.3%; 14 children and 31 adults) were ATSIs. The median (range) ages of the ATSI children and adults at the time of LT were 9.6 (0.2-15.3) years and 44.5 (19.5-65.5) years, respectively. There were 10 deaths in the ATSI cohort. The median (range) overall survival was similar for ATSI and non-ATSI children [6.5 (0.1-23.5) years versus 9.0 (0-28.2) years, P = 0.9] and adults [7.1 (0.1-15.7) years versus 6.3 0-26.7) years, P = 0.8]. The cumulative graft survival was similar for ATSI and non-ATSI children (P = 0.8) and adults (P = 0.8). High ARIA scores [hazard ratio (HR) = 1.2, 95% confidence interval (CI) = 1.01-1.53, P = 0.03] in children and blood group O (HR = 3.8, 95% CI = 1.1-12.7, P = 0.03) in adults predicted worse outcomes for ATSIs. Although ATSIs accounted for 4.7% and 1.8% of the Australian pediatric and adult populations, respectively, they represented only 2.2% of pediatric LT recipients (chi(2) = 8.2, P = 0.004) and 1.1% of adult LT recipients (chi(2) = 7.9, P = 0.005). In conclusion, overall survival and graft survival after LT are comparable in ATSIs and non-ATSIs. There is a trend toward increased death/retransplantation in ATSIs from remote areas. ATSI children and adults appear to be underrepresented in the Australian LT population. PMID- 24753234 TI - Visualization of oxidative stress in ex vivo biopsies using electron paramagnetic resonance imaging. AB - PURPOSE: The purpose of this study was to develop an X-Band electron paramagnetic resonance imaging protocol for visualization of oxidative stress in biopsies. METHODS: The developed electron paramagnetic resonance imaging protocol was based on spin trapping with the cyclic hydroxylamine spin probe 1-hydroxy-3 methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine and X-Band EPR imaging. Computer software was developed for deconvolution and back-projection of the EPR image. A phantom containing radicals of known spatial characteristic was used for evaluation of the developed protocol. As a demonstration of the technique electron paramagnetic resonance imaging of oxidative stress was performed in six sections of atherosclerotic plaques. Histopathological analyses were performed on adjoining sections. RESULTS: The developed computer software for deconvolution and back-projection of the EPR images could accurately reproduce the shape of a phantom of known spatial distribution of radicals. The developed protocol could successfully be used to image oxidative stress in six sections of the three ex vivo atherosclerotic plaques. CONCLUSIONS: We have shown that oxidative stress can be imaged using a combination of spin trapping with the cyclic hydroxylamine spin probe cyclic hydroxylamine spin probe 1-hydroxy-3-methoxycarbonyl-2,2,5,5 tetramethylpyrrolidine and X-Band EPR imaging. A thorough and systematic evaluation on different types of biopsies must be performed in the future to validate the proposed technique. PMID- 24753235 TI - Prospective study of obesity, hypertension, high cholesterol, and risk of restless legs syndrome. AB - Because previous cross-sectional studies suggest an association between metabolic disorders and restless legs syndrome (RLS), we prospectively evaluated whether obesity, hypercholesterolemia, and hypertension were associated with increased risk of RLS. Our study consisted of 42,728 female participants from the Nurses' Health Study II and 12,812 male participants from the Health Professionals Follow up Study, free of RLS at baseline (2002 for men and 2005 for women), and free of diabetes and arthritis through follow-up (2002-2008 for men and 2005-2009 for women). RLS symptoms were assessed using the International RLS Study Group's standardized questionnaire. We considered RLS symptoms a "case" if the symptoms occurred >=5 times/month and met International RLS Study Group criteria. We found that obesity was associated with an increased risk RLS among both men and women (P difference for sex >0.5). The pooled multivariate-adjusted odds ratio (OR) for RLS was 1.57 (95% confidence interval [CI]: 1.33-1.85; P trend <0.0001) for body mass index >30 versus <=23 kg/m(2) and 1.56 (95% CI: 1.29-1.89; P trend = 0.0001) comparing two extreme waist circumference quintiles, adjusting for age, ethnicity, smoking, physical activity, use of antidepressant, and other covariates. A similar significant association was found for high cholesterol; the pooled adjusted OR for total serum cholesterol >240 versus <159 mg/dL was 1.33 (95% CI: 1.11-1.60; P trend = 0.002). There was no significant association between hypertension and RLS risk (adjusted OR: 0.90; 95% CI: 0.79-1.02). In this large, prospective study, we found that obesity and high cholesterol, but not high blood pressure, were significantly associated with an increased risk of developing RLS. (c) 2014 International Parkinson and Movement Disorder Society. PMID- 24753236 TI - Occult Intra-articular Knee Injuries in Children With Hemarthrosis. AB - BACKGROUND: Hemarthrosis after acute knee trauma is a sign of a potentially serious knee injury. Few studies have described the epidemiology and detailed injury spectrum of acute knee injuries in a general pediatric population. PURPOSE: To document the current injury spectrum of acute knee injuries with hemarthrosis in children aged 9 to 14 years and to describe the distribution of sex, age at injury, type of activity, and activity frequency in this population. STUDY DESIGN: Descriptive epidemiology study. METHODS: All patients in the Stockholm County area aged 9 to 14 years who suffered acute knee trauma with hemarthrosis were referred to Astrid Lindgren Children's Hospital, Karolinska University Hospital, from September 2011 to April 2012. The patients underwent clinical examination, radiography, and magnetic resonance imaging (MRI). The type of activity when injured, regular sports activity/frequency, and patient sex and age were registered. The diagnoses were classified into minor and serious injuries. RESULTS: The study included 117 patients (47 girls and 70 boys; mean age, 13.2 years). Seventy percent had a serious knee injury. Lateral patellar dislocations, anterior cruciate ligament ruptures, and anterior tibial spine fractures were the most common injuries, with an incidence of 0.6, 0.2, and 0.1 per 1000 children, respectively. The sex distribution was equal up to age 13 years; twice as many boys were seen at the age of 14 years. The majority of injuries occurred during sports. Forty-six patients (39%) had radiographs without a bony injury but with a serious injury confirmed on MRI. CONCLUSION: Seventy percent of the patients aged 9 to 14 years with traumatic knee hemarthrosis had a serious intra-articular injury that needed specific medical attention. Fifty-six percent of these patients had no visible injury on plain radiographs. Physicians who treat this group of patients should consider MRI to establish the diagnosis when there is no or minimal radiographic findings. The most common serious knee injury was a lateral patellar dislocation. This should be taken into consideration to improve prevention strategies and treatment algorithms in pediatric knee injuries. PMID- 24753237 TI - The Cost-Effectiveness of Measures to Prevent Recurrent Ankle Sprains: Results of a 3-Arm Randomized Controlled Trial. AB - BACKGROUND: Ankle sprains are the most common sports-related injury, associated with a high rate of recurrence and societal costs. Recent studies have emphasized the effectiveness of both neuromuscular training and bracing for the secondary prevention of ankle sprains. PURPOSE: To evaluate the cost-effectiveness of the separate and combined use of bracing and neuromuscular training for the prevention of the recurrence of ankle sprains. STUDY DESIGN: Economic and decision analysis; Level of evidence, 2. METHODS: A total of 340 athletes (157 male and 183 female; aged 12-70 years) who had sustained a lateral ankle sprain up to 2 months before inclusion were randomized to a neuromuscular training group (n = 107), brace group (n = 113), and combined intervention group (n = 120). Randomization was stratified by medical treatment of the inclusion sprain. Participants in the neuromuscular training group underwent an 8-week home-based exercise program. Participants in the brace group received a semirigid ankle brace to be worn during all sports activities for a period of 12 months. Participants allocated to the combined group underwent both interventions, with the ankle brace to be worn during all sports activities for a period of 8 weeks. The recurrence of ankle sprains and associated costs were registered during the 1 year follow-up. RESULTS: There were no differences between groups at baseline with regard to age, sex, sports participation, previous injury, or knowledge of preventive measures. The incremental cost-effectiveness ratio (ICER) of the brace group in comparison with the combined group was -?2828.30 (approximately- US$3865.00), based on a difference in the mean cost of -?76.16 (approximately- US$104.00) and a difference in the mean effects of 2.68%. The ICER of the neuromuscular training group in comparison with the combined group was ?310.08 (approximately US$424.00), based on a difference in the mean cost of -?28.37 (approximately--US$39.00) and a difference in the mean effects of 9.15%. CONCLUSION: Bracing was found to be the dominant secondary preventive intervention over both neuromuscular training and the combination of both measures. PMID- 24753238 TI - Incidence of Second ACL Injuries 2 Years After Primary ACL Reconstruction and Return to Sport. AB - BACKGROUND: The incidence of second anterior cruciate ligament (ACL) injuries in the first 12 months after ACL reconstruction (ACLR) and return to sport (RTS) in a young, active population has been reported to be 15 times greater than that in a previously uninjured cohort. There are no reported estimates of whether this high relative rate of injury continues beyond the first year after RTS and ACLR. HYPOTHESIS: The incidence rate of a subsequent ACL injury in the 2 years after ACLR and RTS would be less than the incidence rate reported within the first 12 months after RTS but greater than the ACL injury incidence rate in an uninjured cohort of young athletes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Seventy-eight patients (mean age, 17.1 +/- 3.1 years) who underwent ACLR and were ready to return to a pivoting/cutting sport and 47 controls (mean age, 17.2 +/- 2.6 years) who also participated in pivoting/cutting sports were prospectively enrolled. Each participant was followed for injury and athlete exposure (AE) data for a 24-month period after RTS. Twenty-three ACLR and 4 control participants suffered an ACL injury during this time. Incidence rate ratios (IRRs) were calculated to compare the rates (per 1000 AEs) of ACL injury in athletes in the ACLR and control groups. For the ACLR group, similar comparisons were conducted for side of injury by sex. RESULTS: The overall incidence rate of a second ACL injury within 24 months after ACLR and RTS (1.39/1000 AEs) was nearly 6 times greater (IRR, 5.71; 95% CI, 2.0-22.7; P = .0003) than that in healthy control participants (0.24/1000 AEs). The rate of injury within 24 months of RTS for female athletes in the ACLR group was almost 5 times greater (IRR, 4.51; 95% CI, 1.5-18.2; P = .0004) than that for female controls. Although only a trend was observed, female patients within the ACLR group were twice as likely (IRR, 2.43; 95% CI, 0.8-8.6) to suffer a contralateral injury (1.13/1000 AEs) than an ipsilateral injury (0.47/1000 AEs). Overall, 29.5% of athletes suffered a second ACL injury within 24 months of RTS, with 20.5% sustaining a contralateral injury and 9.0% incurring a retear injury of the ipsilateral graft. There was a trend toward a higher proportion of female participants (23.7%) who suffered a contralateral injury compared with male participants (10.5%) (P = .18). Conversely, for ipsilateral injuries, the incidence proportion between female (8.5%) and male (10.5%) participants was similar. CONCLUSION: These data support the hypothesis that in the 24 months after ACLR and RTS, patients are at a greater risk to suffer a subsequent ACL injury compared with young athletes without a history of ACL injuries. In addition, the contralateral limb of female patients appears at greatest risk. PMID- 24753239 TI - Ligamentous Injuries and the Risk of Associated Tissue Damage in Acute Ankle Sprains in Athletes: A Cross-sectional MRI Study. AB - BACKGROUND: Ankle joint injuries are extremely common sports injuries, with the anterior talofibular ligament involved in the majority of ankle sprains. There have been only a few large magnetic resonance imaging (MRI) studies on associated structural injuries after ankle sprains. PURPOSE: To describe the injury pattern in athletes who were referred to MRI for the assessment of an acute ankle sprain and to assess the risk of associated traumatic tissue damage including lateral and syndesmotic ligament involvement. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 261 ankle MRI scans of athletes with acute ankle sprains were evaluated for: lateral and syndesmotic ligament injury; concomitant injuries to the deltoid and spring ligaments and sinus tarsi; peroneal, flexor, and extensor retinacula and tendons; traumatic and nontraumatic osteochondral and osseous changes; and joint effusion. Patients were on average 22.5 years old, and the average time from injury to MRI was 5.7 days. Six exclusive injury patterns were defined based on lateral and syndesmotic ligament involvement. The risk for associated injuries was assessed by logistic regression using ankles with no or only low-grade lateral ligament injuries and no syndesmotic ligament damage as the reference. RESULTS: With regard to the injury pattern, there were 103 ankles (39.5%) with complete anterior talofibular ligament disruption and no syndesmotic injury, and 53 ankles (20.3%) had a syndesmotic injury with or without lateral ligament damage. Acute osteochondral lesions of the lateral talar dome were seen in 20 ankles (7.7%). The percentage of chronic lateral osteochondral lesions was 1.1%. The risk for talar bone contusions increased more than 3-fold for ankles with complete lateral ligament ruptures (adjusted odds ratio [aOR], 3.43; 95% CI, 1.72-6.85) but not for ankles with syndesmotic involvement. The risk for associated deltoid ligament injuries increased for ankles with complete lateral ligament injuries (aOR, 4.04; 95% CI, 1.99-8.22) compared with patients with no or only low-grade lateral ligament injuries. CONCLUSION: About 20% of athletes referred for MRI after suffering an acute ankle sprain had evidence of a syndesmotic injury regardless of lateral ligament involvement, while more than half had evidence of any lateral ligament injury without syndesmotic involvement. Concomitant talar osseous and deltoid ligament injuries are common. PMID- 24753240 TI - Rotator cuff repair: published evidence on factors associated with repair integrity and clinical outcome. AB - BACKGROUND: Rotator cuff tears are common, and rotator cuff repair represents a major health care expense. While patients often benefit from rotator cuff repair, anatomic failure of the repair is not unusual. PURPOSE: To identify the published evidence on the factors associated with retears and with suboptimal clinical outcomes of rotator cuff repairs. STUDY DESIGN: Systematic review and meta analysis of articles with evidence levels 1-4. METHODS: A total of 2383 articles on rotator cuff repairs published between 1980 and 2012 were identified. Only 108 of these articles, reporting on over 8011 shoulders, met the inclusion criteria of reporting quantitative data on both imaging and clinical outcomes after rotator cuff repair. Factors related to the patients, their shoulders, the procedures, and the results were systematically categorized and submitted for meta-analysis. RESULTS: While the number of relevant articles published per year increased dramatically over the period of the study, the clinical and anatomic results did not show improvement over this period. The weighted mean retear rate was 26.6% at a mean of 23.7 months after surgery. Retears were associated with more fatty infiltration, larger tear size, advanced age, and double-row repairs. Clinical improvement averaged 72% of the maximum possible improvement. Patient reported outcomes were generally improved whether or not the repair restored the integrity of the rotator cuff. The inconsistent and incomplete data in the published articles limited the meta-analysis of factors affecting the outcome of rotator cuff repair. CONCLUSION: In spite of a dramatic increase in the number of publications per year, there is little evidence that the results of rotator cuff repair are improving. The information needed to guide the management of this commonly treated and costly condition is seriously deficient. To accumulate the evidence necessary to inform practice, future clinical studies on the outcome of rotator cuff repair must report important data relating to each patient's condition, the surgical technique, the outcome in terms of integrity, and the change in patient self-assessed comfort and function. PMID- 24753241 TI - A methodology to detect abnormal relative wall shear stress on the full surface of the thoracic aorta using four-dimensional flow MRI. AB - PURPOSE: To compute cohort-averaged wall shear stress (WSS) maps in the thoracic aorta of patients with aortic dilatation or valvular stenosis and to detect abnormal regional WSS. METHODS: Systolic WSS vectors, estimated from four dimensional flow MRI data, were calculated along the thoracic aorta lumen in 10 controls, 10 patients with dilated aortas, and 10 patients with aortic valve stenosis. Three-dimensional segmentations of each aorta were coregistered by group and used to create a cohort-specific aortic geometry. The WSS vectors of each subject were interpolated onto the corresponding cohort-specific geometry to create cohort-averaged WSS maps. A Wilcoxon rank sum test was used to generate aortic P-value maps (P<0.05) representing regional relative WSS differences between groups. RESULTS: Cohort-averaged systolic WSS maps and P-value maps were successfully created for all cohorts and comparisons. The dilation cohort showed significantly lower WSS on 7% of the ascending aorta surface, whereas the stenosis cohort showed significantly higher WSS on 34% of the ascending aorta surface. CONCLUSIONS: The findings of this study demonstrated the feasibility of generating cohort-averaged WSS maps for the visualization and identification of regionally altered WSS in the presence of disease, compared with healthy controls. PMID- 24753242 TI - Transdiagnostic dimensions of anxiety and depression moderate motivation-related brain networks during goal maintenance. AB - BACKGROUND: Advancing research on the etiology, prevention, and treatment of psychopathology requires the field to move beyond modular conceptualizations of neural dysfunction toward understanding disturbance in key brain networks. Although some studies of anxiety and depression have begun doing so, they typically suffer from several drawbacks, including: (1) a categorical approach ignoring transdiagnostic processes, (2) failure to account for substantial anxiety and depression comorbidity, (3) examination of networks at rest, which overlooks disruption manifesting only when networks are challenged. Accordingly, the present study examined relationships between transdiagnostic dimensions of anxiety/depression and patterns of functional connectivity while goal maintenance was challenged. METHODS: Participants (n = 179, unselected community members and undergraduates selected to be high/low on anxiety/depression) performed a task in which goal maintenance was challenged (color-word Stroop) while fMRI data were collected. Analyses examined moderation by anxiety/depression of condition dependent coupling between regions of dorsolateral prefrontal cortex (dlPFC) previously associated with approach and avoidance motivation and amygdala/orbitofrontal cortex (OFC). RESULTS: Anxious arousal was positively associated with amygdala<->right dlPFC coupling. Depression was positively associated with OFC<->right dlPFC coupling and negatively associated with OFC< >left dlPFC coupling. CONCLUSIONS: Findings advance the field toward an integrative model of the neural instantiation of anxiety/depression by identifying specific, distinct dysfunctions associated with anxiety and depression in networks important for maintaining approach and avoidance goals. Specifically, findings shed light on potential neural mechanisms involved in attentional biases in anxiety and valuation biases in depression and underscore the importance of examining transdiagnostic dimensions of anxiety/depression while networks are challenged. PMID- 24753243 TI - Functional studies of tyrosine hydroxylase missense variants reveal distinct patterns of molecular defects in Dopa-responsive dystonia. AB - Congenital tyrosine hydroxylase deficiency (THD) is found in autosomal-recessive Dopa-responsive dystonia and related neurological syndromes. The clinical manifestations of THD are variable, ranging from early-onset lethal disease to mild Parkinson disease-like symptoms appearing in adolescence. Until 2014, approximately 70 THD patients with a total of 40 different disease-related missense mutations, five nonsense mutations, and three mutations in the promoter region of the tyrosine hydroxylase (TH) gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of TH variants previously not studied (N = 23). We compared the in vitro solubility, thermal stability, and kinetic properties of the TH variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some TH variants had specific kinetic anomalies and phenylalanine hydroxylase, and Dopa oxidase activities were measured for variants that showed signs of altered substrate binding. p.Arg233His, p.Gly247Ser, and p.Phe375Leu had shifted substrate specificity from tyrosine to phenylalanine and Dopa, whereas p.Cys359Phe had an impaired activity toward these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for THD patients. PMID- 24753244 TI - Functional identification of conserved residues involved in Lactobacillus rhamnosus strain GG sortase specificity and pilus biogenesis. AB - In Gram-positive bacteria, sortase-dependent pili mediate the adhesion of bacteria to host epithelial cells and play a pivotal role in colonization, host signaling, and biofilm formation. Lactobacillus rhamnosus strain GG, a well known probiotic bacterium, also displays on its cell surface mucus-binding pilus structures, along with other LPXTG surface proteins, which are processed by sortases upon specific recognition of a highly conserved LPXTG motif. Bioinformatic analysis of all predicted LPXTG proteins encoded by the L. rhamnosus GG genome revealed a remarkable conservation of glycine residues juxtaposed to the canonical LPXTG motif. Here, we investigated and defined the role of this so-called triple glycine (TG) motif in determining sortase specificity during the pilus assembly and anchoring. Mutagenesis of the TG motif resulted in a lack or an alteration of the L. rhamnosus GG pilus structures, indicating that the TG motif is critical in pilus assembly and that they govern the pilin-specific and housekeeping sortase specificity. This allowed us to propose a regulatory model of the L. rhamnosus GG pilus biogenesis. Remarkably, the TG motif was identified in multiple pilus gene clusters of other Gram positive bacteria, suggesting that similar signaling mechanisms occur in other, mainly pathogenic, species. PMID- 24753245 TI - Carbohydrate sequence of the prostate cancer-associated antigen F77 assigned by a mucin O-glycome designer array. AB - Monoclonal antibody F77 was previously raised against human prostate cancer cells and has been shown to recognize a carbohydrate antigen, but the carbohydrate sequence of the antigen was elusive. Here, we make multifaceted approaches to characterize F77 antigen, including binding analyses with the glycolipid extract of the prostate cancer cell line PC3, microarrays with sequence-defined glycan probes, and designer arrays from the O-glycome of an antigen-positive mucin, in conjunction with mass spectrometry. Our results reveal F77 antigen to be expressed on blood group H on a 6-linked branch of a poly-N-acetyllactosamine backbone. We show that mAb F77 can also bind to blood group A and B analogs but with lower intensities. We propose that the close association of F77 antigen with prostate cancers is a consequence of increased blood group H expression together with up-regulated branching enzymes. This is in contrast to other epithelial cancers that have up-regulated branching enzymes but diminished expression of H antigen. With knowledge of the structure and prevalence of F77 antigen in prostate cancer, the way is open to explore rationally its application as a biomarker to detect F77-positive circulating prostate cancer-derived glycoproteins and tumor cells. PMID- 24753246 TI - Rabies virus envelope glycoprotein targets lentiviral vectors to the axonal retrograde pathway in motor neurons. AB - Rabies pseudotyped lentiviral vectors have great potential in gene therapy, not least because of their ability to transduce neurons following their distal axonal application. However, very little is known about the molecular processes that underlie their retrograde transport and cell transduction. Using multiple labeling techniques and confocal microscopy, we demonstrated that pseudotyping with rabies virus envelope glycoprotein (RV-G) enabled the axonal retrograde transport of two distinct subtypes of lentiviral vector in motor neuron cultures. Analysis of this process revealed that these vectors trafficked through Rab5 positive endosomes and accumulated within a non-acidic Rab7 compartment. RV-G pseudotyped vectors were co-transported with both the tetanus neurotoxin-binding fragment and the membrane proteins thought to mediate rabies virus endocytosis (neural cell adhesion molecule, nicotinic acetylcholine receptor, and p75 neurotrophin receptor), thus demonstrating that pseudotyping with RV-G targets lentiviral vectors for transport along the same pathway exploited by several toxins and viruses. Using motor neurons cultured in compartmentalized chambers, we demonstrated that axonal retrograde transport of these vectors was rapid and efficient; however, it was not able to transduce the targeted neurons efficiently, suggesting that impairment in processes occurring after arrival of the viral vector in the soma is responsible for the low transduction efficiency seen in vivo, which suggests a novel area for improvement of gene therapy vectors. PMID- 24753247 TI - Allosteric modulation of M1 muscarinic acetylcholine receptor internalization and subcellular trafficking. AB - Allosteric modulators are an attractive approach to achieve receptor subtype selective targeting of G protein-coupled receptors. Benzyl quinolone carboxylic acid (BQCA) is an unprecedented example of a highly selective positive allosteric modulator of the M1 muscarinic acetylcholine receptor (mAChR). However, despite favorable pharmacological characteristics of BQCA in vitro and in vivo, there is limited evidence of the impact of allosteric modulation on receptor regulatory mechanisms such as beta-arrestin recruitment or receptor internalization and endocytic trafficking. In the present study we investigated the impact of BQCA on M1 mAChR regulation. We show that BQCA potentiates agonist-induced beta-arrestin recruitment to M1 mAChRs. Using a bioluminescence resonance energy transfer approach to monitor intracellular trafficking of M1 mAChRs, we show that once internalized, M1 mAChRs traffic to early endosomes, recycling endosomes and late endosomes. We also show that BQCA potentiates agonist-induced subcellular trafficking. M1 mAChR internalization is both beta-arrestin and G protein dependent, with the third intracellular loop playing an important role in the dynamics of beta-arrestin recruitment. As the global effect of receptor activation ultimately depends on the levels of receptor expression at the cell surface, these results illustrate the need to extend the characterization of novel allosteric modulators of G protein-coupled receptors to encapsulate the consequences of chronic exposure to this family of ligands. PMID- 24753248 TI - Determination of carbohydrate structure recognized by prostate-specific F77 monoclonal antibody through expression analysis of glycosyltransferase genes. AB - This study reports the determination of the carbohydrate epitope of monoclonal antibody F77 previously raised against human prostate cancer PC-3 cells (Zhang, G., Zhang, H., Wang, Q., Lal, P., Carroll, A. M., de la Llera-Moya, M., Xu, X., and Greene, M. I. (2010) Proc. Natl. Acad. Sci. U. S. A. 107, 732-737). We performed a series of co-transfections using mammalian expression vectors encoding specific glycosyltransferases. We thereby identified branching enzymes and FUT1 (required for Fucalpha1->2Gal linkage) as being essential for F77 antigen formation. When immortalized normal prostate 267B1 cells were transfected with FUT1 alone, cells showed weak expression of F77 antigen. By contrast, cells co-transfected with FUT1 plus either GCNT1, GCNT2, or GCNT3 (an enzyme required to form GlcNAcbeta1->6Gal/GalNAc) showed robust F77 antigen expression, suggesting that F77 specifically binds to Fucalpha1->2Galbeta1->4GlcNAcbeta1 >6Gal/GalNAc. RT-PCR for FUT1, GCNT1, GCNT2, and GCNT3 showed that F77-positive cell lines indeed express transcripts encoding FUT1 plus one GCNT. F77-positive prostate cancer cells transfected with siRNAs targeting FUT1, GCNT2, and GCNT3 showed significantly reduced F77 antigen, confirming the requirement of these enzymes for epitope synthesis. We also found that hypoxia induces F77 epitope expression in immortalized prostate RWPE1 cells, which express F77 antigen moderately under normoxia but at an elevated level under hypoxia. Quantitative RT PCR demonstrated up-regulation of FUT1, GCNT2, and GCNT3 transcripts in RWPE1 cells under hypoxia, suggesting that hypoxia up-regulates glycosyltransferase expression required for F77 antigen synthesis. These results define the F77 epitope and provide a potential mechanism for F77 antigen synthesis in malignant prostate cancer. PMID- 24753249 TI - E2-mediated small ubiquitin-like modifier (SUMO) modification of thymine DNA glycosylase is efficient but not selective for the enzyme-product complex. AB - Thymine DNA glycosylase (TDG) initiates the repair of G.T mismatches that arise by deamination of 5-methylcytosine (mC), and it excises 5-formylcytosine and 5 carboxylcytosine, oxidized forms of mC. TDG functions in active DNA demethylation and is essential for embryonic development. TDG forms a tight enzyme-product complex with abasic DNA, which severely impedes enzymatic turnover. Modification of TDG by small ubiquitin-like modifier (SUMO) proteins weakens its binding to abasic DNA. It was proposed that sumoylation of product-bound TDG regulates product release, with SUMO conjugation and deconjugation needed for each catalytic cycle, but this model remains unsubstantiated. We examined the efficiency and specificity of TDG sumoylation using in vitro assays with purified E1 and E2 enzymes, finding that TDG is modified efficiently by SUMO-1 and SUMO-2. Remarkably, we observed similar modification rates for free TDG and TDG bound to abasic or undamaged DNA. To examine the conjugation step directly, we determined modification rates (kobs) using preformed E2~SUMO-1 thioester. The hyperbolic dependence of kobs on TDG concentration gives kmax = 1.6 min(-1) and K1/2 = 0.55 MUM, suggesting that E2~SUMO-1 has higher affinity for TDG than for the SUMO targets RanGAP1 and p53 (peptide). Whereas sumoylation substantially weakens TDG binding to DNA, TDG~SUMO-1 still binds relatively tightly to AP-DNA (Kd ~50 nM). Although E2~SUMO-1 exhibits no specificity for product-bound TDG, the relatively high conjugation efficiency raises the possibility that E2-mediated sumoylation could stimulate product release in vivo. This and other implications for the biological role and mechanism of TDG sumoylation are discussed. PMID- 24753250 TI - Age-related marrow adipogenesis is linked to increased expression of RANKL. AB - With advancing age bone marrow is progressively replaced with adipose tissue, accompanied by a concomitant decline in bone mass and strength. The mechanism underlying the increase in marrow fat and bone destruction remains elusive. We found that on the way of adipogenic differentiation of marrow stromal cells, receptor activator for NF-kappaB ligand (Rankl) expression was induced, concomitantly with a down-regulation of osteoprotegerin, which prompted us to hypothesize that cells at a preadipocyte stage express RANKL. This concept was supported by the findings that the early adipogenic transcription factors C/EBPbeta and C/EBPdelta, but not the late factor peroxisome proliferator activated receptor gamma, bind to the Rankl promoter and stimulate Rankl gene transcription. In fact, when cells isolated from the bone marrow of aging mice were analyzed by flow cytometry, we found that cells expressing the pre-adipocyte marker Pref-1 were RANKL-positive, and the number of these cells was increased with aging, with concomitant down-regulation of osteoprotegerin, and most importantly, that these RANKL(+)/Pref-1(+) marrow cells were capable of generating osteoclasts from bone marrow macrophages. Thus, the capacity of cells at a pre-adipocyte stage to express RANKL via C/EBPbeta and C/EBPdelta and to support osteoclastogenesis may account partly for the co-progression of fatty marrow and bone destruction with aging. PMID- 24753251 TI - Regulation of the interferon regulatory factor-8 (IRF-8) tumor suppressor gene by the signal transducer and activator of transcription 5 (STAT5) transcription factor in chronic myeloid leukemia. AB - Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). Unfortunately, some patients are resistant primarily to imatinib and others develop drug resistance, prompting interest in the discovery of new drug targets. Although much of this resistance can be explained by the presence of mutations within the tyrosine kinase domain of BCR-ABL, such mutations are not universally identified. Interferon regulatory factor-8 (IRF-8) is a transcription factor that is essential for myelopoiesis. Depressed IRF-8 levels are observed in a majority of CML patients and Irf-8(-/-) mice exhibit a CML-like disease. The underlying mechanisms of IRF-8 loss in CML are unknown. We hypothesized that BCR-ABL suppresses transcription of IRF-8 through STAT5, a proximal BCR-ABL target. Treatment of primary cells from newly diagnosed CML patients in chronic phase as well as BCR-ABL(+) cell lines with imatinib increased IRF-8 transcription. Furthermore, IRF-8 expression in cell line models was necessary for imatinib induced antitumor responses. We have demonstrated that IRF-8 is a direct target of STAT5 and that silencing of STAT5 induced IRF-8 expression. Conversely, activating STAT5 suppressed IRF-8 transcription. Finally, we showed that STAT5 blockade using a recently discovered antagonist increased IRF-8 expression in patient samples. These data reveal a previously unrecognized BCR-ABL-STAT5-IRF-8 network, which widens the repertoire of potentially new anti-CML targets. PMID- 24753252 TI - Heparan sulfate containing unsubstituted glucosamine residues: biosynthesis and heparanase-inhibitory activity. AB - Degradation of heparan sulfate (HS) in the extracellular matrix by heparanase is linked to the processes of tumor invasion and metastasis. Thus, a heparanase inhibitor can be a potential anticancer drug. Because HS with unsubstituted glucosamine residues accumulates in heparanase-expressing breast cancer cells, we assumed that these HS structures are resistant to heparanase and can therefore be utilized as a heparanase inhibitor. As expected, chemically synthetic HS tetrasaccharides containing unsubstituted glucosamine residues, GlcAbeta1-4GlcNH3 (+)(6-O-sulfate)alpha1-4GlcAbeta1-4GlcNH3 (+)(6-O-sulfate), inhibited heparanase activity and suppressed invasion of breast cancer cells in vitro. Bifunctional NDST-1 (N-deacetylase/N-sulfotransferase-1) catalyzes the modification of N acetylglucosamine residues within HS chains, and the balance of N-deacetylase and N-sulfotransferase activities of NDST-1 is thought to be a determinant of the generation of unsubstituted glucosamine. We also report here that EXTL3 (exostosin-like 3) controls N-sulfotransferase activity of NDST-1 by forming a complex with NDST-1 and contributes to generation of unsubstituted glucosamine residues. PMID- 24753253 TI - alpha-N-methylation of damaged DNA-binding protein 2 (DDB2) and its function in nucleotide excision repair. AB - DDB2 exhibits a high affinity toward UV-damaged DNA, and it is involved in the initial steps of global genome nucleotide excision repair. Mutations in the DDB2 gene cause the genetic complementation group E of xeroderma pigmentosum, an autosomal recessive disease manifested clinically by hypersensitivity to sunlight exposure and an increased predisposition to skin cancer. Here we found that, in human cells, the initiating methionine residue in DDB2 was removed and that the N terminal alanine could be methylated on its alpha-amino group in human cells, with trimethylation being the major form. We also demonstrated that the alpha-N methylation of DDB2 is catalyzed by the N-terminal RCC1 methyltransferase. In addition, a methylation-defective mutant of DDB2 displayed diminished nuclear localization and was recruited at a reduced efficiency to UV-induced cyclobutane pyrimidine dimer foci. Moreover, loss of this methylation conferred compromised ATM (ataxia telangiectasia mutated) activation, decreased efficiency in cyclobutane pyrimidine dimer repair, and elevated sensitivity of cells toward UV light exposure. Our study provides new knowledge about the posttranslational regulation of DDB2 and expands the biological functions of protein alpha-N methylation to DNA repair. PMID- 24753254 TI - Functional rescue of Kallmann syndrome-associated prokineticin receptor 2 (PKR2) mutants deficient in trafficking. AB - Mutations in the G protein-coupled prokineticin receptor 2 (PKR2) are known to cause Kallmann syndrome and idiopathic hypogonadotropic hypogonadism manifesting with delayed puberty and infertility. Some of the mutant receptors are not routed to the cell surface; instead, they are trapped in the cellular secretory pathway. The cell-permeant agonists/antagonists have been used to rescue some membrane receptors that are not targeted onto the cell membrane. Here, we chose three disease-associated mutations (W178S, G234D, and P290S), which all resulted in retention of PKR2 intracellularly. We show that a small molecule PKR2 antagonist (A457) dramatically increased cell surface expression and rescued the function of P290S PKR2, but had no effect on W178S and G234D PKR2. Furthermore, we also tested chemical chaperone glycerol on the cell surface expression and function of PKR2 mutants. Treatment with 10% glycerol significantly increased the cell surface expression and signaling of P290S and W178S PKR2. These data demonstrate that some Kallmann syndrome-associated, intracellularly retained mutant PKR2 receptors can be functionally rescued, suggesting a potential treatment strategy for patients bearing such mutations. PMID- 24753255 TI - Tumor necrosis factor (TNF)-alpha induction of CXCL10 in endothelial cells requires protein arginine methyltransferase 5 (PRMT5)-mediated nuclear factor (NF)-kappaB p65 methylation. AB - The chemokine CXCL10/IP-10 facilitates recruitment of Th1-type leukocytes to inflammatory sites. In this study, we show that the arginine methyltransferase PRMT5 is critical for CXCL10 transcription in TNF-alpha-activated human endothelial cells (EC). We found that depletion of PRMT5 results in significantly reduced levels of CXCL10 mRNA, demonstrating a positive role for PRMT5 in CXCL10 induction. Chromatin immunoprecipitation experiments revealed the presence of the symmetrical dimethylarginine modification catalyzed by PRMT5 associated with the CXCL10 promoter in response to TNF-alpha. However, symmetrical dimethylarginine modified proteins were not detected at the promoter in the absence of PRMT5, indicating that PRMT5 is essential for methylation to occur. Furthermore, NF kappaB p65, a critical driver of TNF-alpha-mediated CXCL10 induction, was determined to be methylated at arginine residues. Crucially, RNAi-mediated PRMT5 depletion abrogated p65 methylation and CXCL10 promoter binding. Mass spectrometric analysis in EC identified five dimethylated arginine residues in p65, four of which are uncharacterized in the literature. Expression of Arg-to Lys point mutants of p65 demonstrated that both Arg-30 and Arg-35 must be dimethylated to achieve full CXCL10 expression. In conclusion, we have identified previously uncharacterized p65 post-translational modifications critical for CXCL10 induction. PMID- 24753256 TI - The capsular polysaccharide of Staphylococcus aureus is attached to peptidoglycan by the LytR-CpsA-Psr (LCP) family of enzymes. AB - Envelope biogenesis in bacteria involves synthesis of intermediates that are tethered to the lipid carrier undecaprenol-phosphate. LytR-CpsA-Psr (LCP) enzymes have been proposed to catalyze the transfer of undecaprenol-linked intermediates onto the C6-hydroxyl of MurNAc in peptidoglycan, thereby promoting attachment of wall teichoic acid (WTA) in bacilli and staphylococci and capsular polysaccharides (CPS) in streptococci. S. aureus encodes three lcp enzymes, and a variant lacking all three genes (Deltalcp) releases WTA from the bacterial envelope and displays a growth defect. Here, we report that the type 5 capsular polysaccharide (CP5) of Staphylococcus aureus Newman is covalently attached to the glycan strands of peptidoglycan. Cell wall attachment of CP5 is abrogated in the Deltalcp variant, a defect that is best complemented via expression of lcpC in trans. CP5 synthesis and peptidoglycan attachment are not impaired in the tagO mutant, suggesting that CP5 synthesis does not involve the GlcNAc-ManNAc linkage unit of WTA and may instead utilize another Wzy-type ligase to assemble undecaprenyl-phosphate intermediates. Thus, LCP enzymes of S. aureus are promiscuous enzymes that attach secondary cell wall polymers with discrete linkage units to peptidoglycan. PMID- 24753257 TI - Structural and functional profiling of the lateral gate of the Sec61 translocon. AB - The evolutionarily conserved Sec61 translocon mediates the translocation and membrane insertion of proteins. For the integration of proteins into the membrane, the Sec61 translocon opens laterally to the lipid bilayer. Previous studies suggest that the lateral opening of the channel is mediated by the helices TM2b and TM7 of a pore-forming subunit of the Sec61 translocon. To map key residues in TM2b and TM7 in yeast Sec61 that modulate lateral gating activity, we performed alanine scanning and in vivo site-directed photocross linking experiments. Alanine scanning identified two groups of critical residues in the lateral gate, one group that leads to defects in the translocation and membrane insertion of proteins and the other group that causes faster translocation and facilitates membrane insertion. Photocross-linking data show that the former group of residues is located at the interface of the lateral gate. Furthermore, different degrees of defects for the membrane insertion of single- and double-spanning membrane proteins were observed depending on whether the mutations were located in TM2b or TM7. These results demonstrate subtle differences in the molecular mechanism of the signal sequence binding/opening of the lateral gate and membrane insertion of a succeeding transmembrane segment in a polytopic membrane protein. PMID- 24753258 TI - Glucose starvation inhibits autophagy via vacuolar hydrolysis and induces plasma membrane internalization by down-regulating recycling. AB - Cellular energy influences all aspects of cellular function. Although cells can adapt to a gradual reduction in energy, acute energy depletion poses a unique challenge. Because acute depletion hampers the transport of new energy sources into the cell, the cell must use endogenous substrates to replenish energy after acute depletion. In the yeast Saccharomyces cerevisiae, glucose starvation causes an acute depletion of intracellular energy that recovers during continued glucose starvation. However, how the cell replenishes energy during the early phase of glucose starvation is unknown. In this study, we investigated the role of pathways that deliver proteins and lipids to the vacuole during glucose starvation. We report that in response to glucose starvation, plasma membrane proteins are directed to the vacuole through reduced recycling at the endosomes. Furthermore, we found that vacuolar hydrolysis inhibits macroautophagy in a target of rapamycin complex 1-dependent manner. Accordingly, we found that endocytosis and hydrolysis are required for survival in glucose starvation, whereas macroautophagy is dispensable. Together, these results suggest that hydrolysis of components delivered to the vacuole independent of autophagy is the cell survival mechanism used by S. cerevisiae in response to glucose starvation. PMID- 24753259 TI - Binding of CD157 protein to fibronectin regulates cell adhesion and spreading. AB - CD157/BST-1 behaves both as an ectoenzyme and signaling receptor and is an important regulator of leukocyte trafficking and ovarian cancer progression. However, the molecular interactions underpinning the role of CD157 in these processes remain obscure. The biological functions of CD157 and its partnership with members of the integrin family prompted us to assume the existence of a direct interaction between CD157 and an unknown component of the extracellular matrix. Using solid-phase binding assays and surface plasmon resonance analysis, we demonstrated that CD157 binds fibronectin with high affinity within its heparin-binding domains 1 and 2. Furthermore, we found that CD157 binds to other extracellular matrix proteins containing heparin-binding domains. Finally, we proved that the CD157-fibronectin interaction occurs with living cells, where it elicits CD157-mediated cell responses. Indeed, knockdown of CD157 in Met-5A mesothelial cells changed their morphology and cytoskeleton organization and attenuated the activation of intracellular signaling pathways triggered by fibronectin. This led to impaired cell spreading and adhesion to selected extracellular matrix proteins. Collectively, these findings indicate a central role of CD157 in cell-extracellular matrix interactions and make CD157 an attractive therapeutic target in inflammation and cancer. PMID- 24753261 TI - A biomimetic catalytic aerobic functionalization of phenols. AB - The importance of aromatic C-O, C-N, and C-S bonds necessitates increasingly efficient strategies for their formation. Herein, we report a biomimetic approach that converts phenolic C-H bonds into C-O, C-N, and C-S bonds at the sole expense of reducing dioxygen (O2) to water (H2O). Our method hinges on a regio- and chemoselective copper-catalyzed aerobic oxygenation to provide ortho-quinones. ortho-Quinones are versatile intermediates, whose direct catalytic aerobic synthesis from phenols enables a mild and efficient means of synthesizing polyfunctional aromatic rings. PMID- 24753260 TI - The cochaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) demonstrates regulatory specificity for the androgen, glucocorticoid, and progesterone receptors. AB - Steroid hormone receptors are ligand-dependent transcription factors that require the ordered assembly of multichaperone complexes for transcriptional activity. Although heat shock protein (Hsp) 90 and Hsp70 are key players in this process, multiple Hsp70- and Hsp90-associated cochaperones associate with receptor chaperone complexes to regulate receptor folding and activation. Small glutamine rich tetratricopeptide repeat-containing protein alpha (SGTA) was recently characterized as an Hsp70 and Hsp90-associated cochaperone that specifically regulates androgen receptor activity. However, the specificity of SGTA for additional members of the steroid hormone receptor superfamily and the mechanism by which SGTA regulates receptor activity remain unclear. Here we report that SGTA associates with and specifically regulates the androgen, glucocorticoid, and progesterone receptors and has no effect on the mineralocorticoid and estrogen receptors in both yeast and mammalian cell-based reporter assays. In both systems, SGTA knockdown/deletion enhances receptor activity, whereas SGTA overexpression suppresses receptor activity. We demonstrate that SGTA binds directly to Hsp70 and Hsp90 in vitro with similar affinities yet predominately precipitates with Hsp70 from cell lysates, suggesting a role for SGTA in early, Hsp70-mediated folding. Furthermore, SGTA expression completely abrogates the regulation of receptor function by FKBP52 (52-kDa FK506-binding protein), which acts at a later stage of the chaperone cycle. Taken together, our data suggest a role for SGTA at distinct steps in the chaperone-dependent modulation of androgen, glucocorticoid, and progesterone receptor activity. PMID- 24753262 TI - Efficacy and safety of analgosedation with fentanyl compared with traditional sedation with propofol. AB - OBJECTIVES: To compare the efficacy and safety of analgosedation with fentanyl versus traditional sedation with propofol in critically ill patients receiving mechanical ventilation. METHODS: Retrospective, observational study evaluating adult critically ill patients on mechanical ventilation at a community teaching hospital who received continuous infusion fentanyl (n=50) or propofol (n=50) from September 2011-March 2013. RESULTS: Median duration of mechanical ventilation was similar between patients receiving propofol and fentanyl infusions (46.7 hr vs 46.0 hr, p=0.19). No difference was noted in median intensive care unit length of stay between groups (p=0.42). A larger percentage of patients receiving propofol required rescue opioids compared with patients receiving fentanyl (56% vs 34%, p=0.04). Furthermore, patients receiving propofol required significantly more rescue opioid therapy during the course of mechanical ventilation as calculated by fentanyl equivalents (150 MUg vs 100 MUg, p=0.03). No difference in the rate of intensive care unit delirium was noted between groups (fentanyl 23% vs propofol 27%, p=0.80). CONCLUSION: Analgosedation with fentanyl appears to be a safe and effective strategy to facilitate mechanical ventilation. This regimen does not appear to affect duration of mechanical ventilation when compared with propofol, but may allow for more optimal pain management in critically ill patients. PMID- 24753263 TI - The anatomy of the bifurcated neural spine and its occurrence within Tetrapoda. AB - Vertebral neural spine bifurcation has been historically treated as largely restrictive to sauropodomorph dinosaurs; wherein it is inferred to be an adaptation in response to the increasing weight from the horizontally extended cervical column. Because no extant terrestrial vertebrates have massive, horizontally extended necks, extant forms with large cranial masses were examined for the presence of neural spine bifurcation. Here, I report for the first time on the soft tissue surrounding neural spine bifurcation in a terrestrial quadruped through the dissection of three Ankole-Watusi cattle. With horns weighing up to a combined 90 kg, the Ankole-Watusi is unlike any other breed of cattle in terms of cranial weight and presence of neural spine bifurcation. Using the Ankole-Watusi as a model, it appears that neural spine bifurcation plays a critical role in supporting a large mobile weight adjacent to the girdles. In addition to neural spine bifurcation being recognized within nonavian dinosaurs, this vertebral feature is also documented within many members of temnospondyls, captorhinids, seymouriamorphs, diadectomorphs, Aves, marsupials, artiodactyls, perissodactyls, and Primates, amongst others. This phylogenetic distribution indicates that spine bifurcation is more common than previously thought, and that this vertebral adaptation has contributed throughout the evolutionary history of tetrapods. Neural spine bifurcation should now be recognized as an anatomical component adapted by some vertebrates to deal with massive, horizontal, mobile weights adjacent the girdles. PMID- 24753265 TI - Polymeric nanocarriers for siRNA delivery to murine macrophages. AB - This work investigates the interactions of a polycationic nanocarrier with siRNA and with cells in order to better understand the capabilities and limitations of the carrier. The polycationic nanocarriers are cross-linked copolymer nanoparticles synthesized in a single-step reaction using ARGET ATRP (activators regenerated by electron transfer atom transfer radical polymerization). The polycationic nanocarriers efficiently bind siRNA for polymer/siRNA mass ratios less than 1. A method to prepare fluorescently labeled polycationic nanocarriers is presented. The fluorescently labeled polycationic nanocarriers are used to investigate cellular internalization with RAW264.7 murine macrophage cells. Flow cytometry demonstrates that the uptake increased with nanoparticle concentration and incubation time. Confocal microscopy confirmed internalization of fluorescently labeled nanoparticles. The investigation of siRNA-induced knockdown demonstrates that higher concentrations of nanoparticles and siRNA are associated with increased knockdown. For the conditions tested in the knockdown experiments, the ARGET ATRP polycationic nanocarriers outperformed a commercially available Lipofectamine control. PMID- 24753264 TI - Multifunctional yolk-in-shell nanoparticles for pH-triggered drug release and imaging. AB - Multifunctional nanoparticles are synthesized for both pH-triggered drug release and imaging with radioluminescence, upconversion luminescent, and magnetic resonance imaging (MRI). The particles have a yolk-in-shell morphology, with a radioluminescent core, an upconverting shell, and a hollow region between the core and shell for loading drugs. They are synthesized by controlled encapsulation of a radioluminescent nanophosphor yolk in a silica shell, partial etching of the yolk in acid, and encapsulation of the silica with an upconverting luminescent shell. Metroxantrone, a chemotherapy drug, was loaded into the hollow space between X-ray phosphor yolk and up-conversion phosphor shell through pores in the shell. To encapsulate the drug and control the release rate, the nanoparticles are coated with pH-responsive biocompatible polyelectrolyte layers of charged hyaluronic acid sodium salt and chitosan. The nanophosphors display bright luminescence under X-ray, blue light (480 nm), and near infrared light (980 nm). They also served as T1 and T2 MRI contrast agents with relaxivities of 3.5 mM(-1) s(-1) (r1 ) and 64 mM(-1) s(-1) (r2 ). These multifunctional nanocapsules have applications in controlled drug delivery and multimodal imaging. PMID- 24753266 TI - Multicomponent, flow diazotization/Mizoroki-Heck coupling protocol: dispelling myths about working with diazonium salts. AB - A single pass flow diazotization/Mizoroki-Heck protocol has been developed for the production of cinnimoyl and styryl products. The factors that govern aryl diazonium salt stability have been examined in detail leading to the development of a MeOH/DMF co-solvent system in which the diazonium salts can be generated in the presence of all other reaction components and then coupled selectively to give the desired products. Finally the key role of the reaction quench for flow reactions has been demonstrated. PMID- 24753267 TI - Effect of rainfall regimes and mulch decomposition on the dissipation and leaching of S-metolachlor and glyphosate: a soil column experiment. AB - BACKGROUND: Interception by plant residues is a major process affecting pesticide persistence and leaching in conservation agriculture. Dissipation and leaching of S-metolachlor and glyphosate was studied in repacked soil columns covered with a mulch of maize and lablab residues. The columns were submitted to two contrasting simulated rainfall regimes: one with light but frequent rain (LF) and one with less frequent but more intense rain (HI). In both treatments, columns received the same amount of rainwater by the end of the experiment. RESULTS: Decomposing crop residues on the soil surface retained more than 50% of the applied amount of pesticide. S-metolachlor dissipation in mulch residues was faster under the LF rainfall regime. This was attributed to more humid surface conditions, under which mulch decomposition was also faster. The formation of metabolites of both molecules was higher under the LF rainfall regime. However, leaching of S metolachlor and its metabolites to deeper soil layers was greater under the HI rainfall regime, whereas they accumulated in the surface layer under the LF rainfall regime. Glyphosate remained in the surface soil layer because of its strong adsorption capacity, whereas aminomethylphosphonic acid leached down in small amounts without any difference between the two rainfall regimes. CONCLUSION: The impact of mulch residues on herbicide dissipation was strongly dependent on molecule type and rainfall regime. (c) 2014 Society of Chemical Industry. PMID- 24753268 TI - Characterization of brown adipose tissue in the human perirenal depot. AB - OBJECTIVE: To characterize brown adipose tissue (BAT) in the human perirenal adipose tissue depot. METHOD: Perirenal adipose tissue biopsies were obtained from 55 healthy kidney donors. Expression analysis was performed using microarray, real-time PCR, immunoblotting and immunohistochemistry. Additional studies using human stem cells were performed. RESULTS: UCP1 gene expression analysis revealed a large intra-individual variation in the perirenal adipose tissue biopsies. Both multi- and unilocular UCP1-positive adipocytes were detected in several of the adipose tissue samples analyzed by immunohistochemical staining. Microarray analysis identified 54 genes that were overexpressed in UCP1 positive perirenal adipose tissue. Real-time PCR analysis of BAT candidate genes revealed a set of genes that were highly correlated to UCP1 and a set of three transcription factor genes (PRDM16, PGC1alpha, and RXRgamma) that were highly correlated to each other. RXRgamma displayed nuclear immunoreactivity in brown adipocytes and an increased gene expression during brown adipogenesis in human stem cells. CONCLUSION: Our data provides the first molecular characterization of BAT in the perirenal adipose tissue depot. Furthermore, it highlights the transcription factor RXRgamma as a new player in BAT development. PMID- 24753269 TI - Physician-anatomists of Italy in Sanizade Mehmed Ataullah Efendi's work Mir'at al abdan (Mirror of bodies). AB - Sanizade Mehmed Ataullah Efendi was a pioneer in the history of Turkish medical education with his work Hamse-i Sanizade (Five Works of Sanizade). The first of these works, Mir'at al-abdan fi tasrih-i a'dai'l-insan (Mirror of the bodies in the dissection of the members of the human body), concerns anatomy and was written in 1816. Sanizade's Mir'at al-abdan is an important milestone in the teaching of anatomy in the Ottoman Empire and was also the first book on anatomy both written in a modern manner and printed in the Ottoman Empire. This paper is based on investigation of a printed copy of Mir'at al-Abdan in the library of the History of Medicine and Ethics Department, Ankara University Faculty of Medicine. The main text and explanations were transliterated into the contemporary Turkish alphabet. The names of European physicians and their eponyms in the main text and in the explanations of illustrations were identified and evaluated. The names of European masters of anatomy in Sanizade are mentioned either in the text or in plate explanations. These names and plates indicate well-known physicians and masters of anatomy whose works were examined and quoted by Sanizade. The references in Sanizade's book and presented in this study relate to Italian physician-anatomists such as Bartolomeo Eustachi, Gabriele Fallopio, Costanzo Varolio and to others, such as Andreas Vesalius and Adriaan van den Spiegel, who were also Padua-educated but not Italian. PMID- 24753270 TI - Importance of polarization effect in the study of metalloproteins: application of polarized protein specific charge scheme in predicting the reduction potential of azurin. AB - Molecular dynamics (MD) simulation is commonly used in the study of protein dynamics, and in recent years, the extension of MD simulation to the study of metalloproteins is gaining much interest. Choice of force field is crucial in MD studies, and the inclusion of metal centers complicates the process of accurately describing the electrostatic environment that surrounds the redox centre. Herein, we would like to explore the importance of including electrostatic contribution from both protein and solvent in the study of metalloproteins. MD simulations with the implementation of thermodynamic integration will be conducted to model the reduction process of azurin from Pseudomonas aeruginosa. Three charge schemes will be used to derive the partial charges of azurin. These charge schemes differ in terms of the amount of immediate environment, respective to copper, considered during charge fitting, which ranges from the inclusion of copper and residues in the first coordination sphere during density functional theory charge fitting to the comprehensive inclusion of protein and solvent effect surrounding the metal centre using polarized protein-specific charge scheme. From the simulations conducted, the relative reduction potential of the mutated azurins respective to that of wild-type azurin (DeltaEcal) were calculated and compared with experimental values. The DeltaEcal approached experimental value with increasing consideration of environmental effect hence substantiating the importance of polarization effect in the study of metalloproteins. This study also attests the practicality of polarized protein-specific charge as a computational tool capable of incorporating both protein environment and solvent effect into MD simulations. PMID- 24753271 TI - A longitudinal study of stress-induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat. AB - Hippocampal shrinkage is a commonly found neuroanatomical change in stress related mood disorders such as depression and post-traumatic stress disorders (PTSD). Since the onset and severity of these disorders have been found to be closely related to stressful life events, and as stress alone has been shown to reduce hippocampal volume in animal studies, vulnerability to mood disorders may be related to a susceptibility to stress-induced hippocampal shrinkage. However, a smaller hippocampal volume before stress exposure has also been suggested to confer vulnerability of stressed individuals to PTSD or depression. In this study, we examined the contribution of either innate hippocampal volume differences or hippocampal susceptibility to stress-induced shrinkage to the formation of stress-related psychopathology using longitudinal MRI measurements of hippocampal volume in inbred C57 mice before and after chronic social defeat stress. We found that only half of the stressed C57 mice were susceptible to stress and developed psychopathological behaviors such as social avoidance. The other half was resilient to stress and exhibited no social avoidance. Before exposure to stress, we observed a positive correlation between hippocampal volume and social avoidance. After chronic social defeat stress, we found significant increases in left hippocampal volume in resilient and nonstressed control mice. Intriguingly, this increase in hippocampal volume was not found in susceptible mice, suggesting an arrestment of hippocampal growth in these mice. Our findings suggest that both a susceptibility to stress-induced hippocampal volume changes and a larger hippocampus before stress exposure confer vulnerability to psychopathology after chronic stress. PMID- 24753273 TI - Issue editors' notes. PMID- 24753272 TI - Staging and treatment of oropharyngeal cancer in the human papillomavirus era. AB - BACKGROUND: Oropharyngeal squamous cell carcinoma (SCC) is staged using the TNM system. Human papillomavirus (HPV)-positive tumors have improved prognosis, despite presenting at advanced stage. Optimal treatment and stratification of HPV positive patients are not clearly defined. METHODS: We retrospectively analyzed 266 patients with oropharyngeal SCC for mortality and feeding tube dependency related to TNM stage, HPV status, and treatment. RESULTS: TNM staging was prognostic in HPV-negative patients (stage III/IV hazard ratio [HR], 2.00; p = .05; N(+) HR, 2.19; p = .02). Only T classification was prognostic in HPV positive tumors (T3/T4 HR 3.31; p = .006). HPV-positive tumors showed improved survival regardless of treatment. Patients receiving chemotherapy had a significantly increased risk of feeding tube dependency (odds ratio [OR], 1.72; p = .03). CONCLUSION: These data suggest that the current TNM system has little prognostic value in HPV-positive oropharyngeal SCC. Patients with HPV-positive tumors show improved survival independent of treatment. The addition of chemotherapy increases the risk of feeding tube dependency and could potentially be avoided in T1/T2 HPV-positive tumors without compromising survival. PMID- 24753275 TI - Substance use: determinants and opportunities for prevention in the family and school context. AB - During adolescence, teenagers try a range of risk behaviors including smoking, drinking, and the use of soft drugs. Because substance use contributes to an unhealthy lifestyle of teenagers on the short term and can lead to serious health problems on the longer term, prevention in this target group is important. This chapter provides an overview of the determinants of substance use on the one hand, and primary and secondary prevention opportunities on the other hand, especially in the school context. At the end, future directions and recommendations for school, youth, and family are discussed. PMID- 24753276 TI - Applying neurodevelopmental theory to school-based drug misuse prevention during adolescence. AB - Adolescence is characterized by incredible development in the prefrontal cortex of the brain, which is responsible for behavioral and emotional self-regulation, and higher order cognitive decision-making skills (that is, executive function). Typically late prefrontal cortical development and its integration with limbic areas of the brain associated with reward, pleasure, novelty seeking, and emotion can contribute to substance misuse vulnerability during adolescence. In this chapter, literature on the developmental integration of the prefrontal cortex with emotion and motivation centers of the brain is reviewed. Then this research is applied to school-based adolescent substance misuse prevention, highlighting two examples of preventive interventions incorporating neurocognitive models into comprehensive prevention approaches. Finally, innovative strategies (for example, mindfulness training) for promoting neurocognition as a mediator to substance misuse vulnerability are discussed. PMID- 24753277 TI - Substance misuse prevention: addressing anhedonia. AB - Anhedonia refers to the inability of experiencing pleasure in positive life events. It has been conceptualized as a stable yet malleable characteristic and is associated with hypoactivity in the mesolimbic and mesocortical dopaminergic systems. Very recently, it has been posited as an etiologic factor associated with drug addiction onset, escalation, and relapse. Prevention programming could be developed to counteract the harmful impact of anhedonia, so as to minimize its impact on drug misuse. Remedial efforts are those that either (1) permit the individual to tolerate low levels of pleasure without resorting to drug misuse or other maladaptive behaviors that may unhealthily besot pleasure (for example, through normalization, structuring time, or meditation) or (2) counteract anhedonia by enhancing ones capability to experience pleasure (for example, behavioral activation, positive psychology, pharmacotherapy, or pursuit of positive addictions). School-based activities could be developed that can be completed by individuals, small workgroups, or the whole classroom. The concept of anhedonia is described in this chapter, and possible prevention strategies that might be utilized in schools as well as other contexts are discussed. PMID- 24753278 TI - Life skills training: preventing substance misuse by enhancing individual and social competence. AB - Research concerning the etiology and prevention of substance misuse has led to the development of preventive interventions that are theory-based and effective. One such approach, Life Skills Training (LST), targets key etiologic factors using a conceptual framework derived from social learning theory and problem behavior theory. LST has been extensively tested in a series of randomized trials and found effective in preventing the use/misuse of alcohol, tobacco, marijuana, and other psychoactive drugs. Research demonstrates that it is effective when implemented under different delivery conditions, by different program providers, with different age groups, and with different populations. Follow-up studies provide evidence of the long-term effectiveness of LST. Independent economic analysis indicates that LST produces cost savings of as much as $38 for every dollar invested. Finally, LST offers the potential of reducing other health risk behaviors and fostering academic success. PMID- 24753279 TI - "Unplugged," a European school-based program for substance use prevention among adolescents: overview of results from the EU-Dap trial. AB - The EU-Dap study aimed to develop and evaluate a school-based curriculum for the prevention of substance use among young people. The school curriculum, "Unplugged," is based on social influence approach and addresses social and personal skills, knowledge, and normative beliefs. It consists of 12 one-hour interactive sessions delivered by teachers. Its effectiveness was evaluated through a randomized trial involving 7,079 pupils of seven European countries. Unplugged was effective in reducing cigarette smoking, episodes of drunkenness, and the use of cannabis at short term. This association, however, was confined to boys, with age and self-esteem as possible explanations of this difference. Beneficial effects associated with the program persisted at fifteen-month follow up for drunkenness, alcohol-related problems, and cannabis use, and were stronger among adolescents in schools of average low socioeconomic level. These results are of scientific importance and may inform the adoption of effective public health interventions at population level. PMID- 24753280 TI - Translation of etiology into evidence-based prevention: the life skills program IPSY. AB - IPSY (Information + Psychosocial Competence = Protection) is a universal life skills program aiming at the promotion of generic intra- and interpersonal life skills, substance specific skills (for example, resistance skills), school bonding, knowledge, and the prevention of substance misuse with a focus on alcohol and tobacco in youth. This program is based on the WHO's life skills approach as well as on theories and empirical findings concerning the development of substance misuse during early adolescence. IPSY is implemented by teachers over three years of schooling (grades 5-7 in Germany). Guided by models of translational research dealing with conditions of a successful translation of etiological findings into evidence-based prevention programs, the chapter highlights the results of a more than ten-year research program focusing on the development and evaluation of the IPSY program. Findings on long-term general effects, mediators and moderators of program effectiveness, and cross-cultural transferability of the program to other European countries are summarized and discussed in light of dissemination issues. PMID- 24753281 TI - You've shown the program model is effective. Now what? AB - Rigorous tests of theory-based programs require faithful implementation. Otherwise, lack of results might be attributable to faulty program delivery, faulty theory, or both. However, once the evidence indicates the model works and merits broader dissemination, implementation issues do not fade away. How can developers enhance the likelihood that the program will be delivered as designed and thus get results close to what was possible under controlled conditions? How can they address program weaknesses without undermining conceptual integrity? What role can they play in making the program visible and attractive to institutional adopters? This chapter uses field experience from a theory-based program, Project ALERT, to suggest possible strategies for enhancing program attractiveness to potential adopters and users, facilitating program fidelity while maintaining room for adaptation and taking a program to scale. PMID- 24753282 TI - Improving dissemination of evidence-based programs through researcher practitioner collaboration. AB - Prevention field has achieved major advances in developing, implementing, and testing the efficacy of preventive interventions in controlled settings. Nevertheless, there is still a gap in translating the success of programs in efficacy trials into real-life settings. Dissemination of evidence-based programs is a major challenge. The authors argue that promoting adoption of evidence-based programs requires further improvements in three areas, and collaboration between researchers and practitioners. First, there is a need to develop a holistic assessment system encompassing both risk/need and readiness assessments. Second, there is need for new methods for improving implementation quality. Third, prevention research needs to focus more on identifying the mechanisms that explain how programs work and the core elements of the program. Both researchers and practitioners have roles and opportunities to collaborate to achieve developments in these areas. PMID- 24753283 TI - Advancing school-based interventions through economic analysis. AB - Commentators interested in school-based prevention programs point to the importance of economic issues for the future of prevention efforts. Many of the processes and aims of prevention science are dependent upon prevention resources. Although economic analysis is an essential tool for assessing resource use, the attention given economic analysis within school-based prevention remains cursory. Largely, economic analyses of school-based prevention efforts are undertaken as secondary research. This limits these efforts to data that have been collected previously as part of epidemiological and outcomes research. Therefore, economic analyses suffer from gaps in the knowledge generated by these studies. This chapter addresses the importance of economic analysis for the future of school based substance abuse prevention programs and highlights the role of prevention research in the development of knowledge that can be used for economic analysis. PMID- 24753284 TI - Verification bias in diagnostic accuracy studies for fine-needle aspiration cytology. PMID- 24753285 TI - T1 rho mapping for the evaluation of high intensity focused ultrasound tumor treatment. AB - PURPOSE: This study was aimed to assess the effects of High Intensity Focused Ultrasound (HIFU) thermal ablation on tumor T1rho . METHODS: In vivo T1rho measurements of murine tumors at various spin-lock amplitudes (B1 = 0-2000 Hz) were performed before (n = 13), directly after (n = 13) and 3 days (n = 7) after HIFU treatment. T2 maps were obtained from the measurements at B1 = 0 Hz. RESULTS: Average tumor T1rho distributions at the different experimental time points showed a shift toward lower T1rho values after HIFU for all spin-lock amplitudes, which became larger with increasing spin-lock amplitude at 3 days after treatment. Statistical analysis confirmed a significant effect of spin-lock amplitude on the average change in T1rho (DeltaT1rho ) as compared to baseline at 3 days after HIFU. At 3 days after treatment, DeltaT1rho values at B1 above 100 Hz were significantly lower (more negative) than at B1 = 0 Hz (T2 ). CONCLUSION: Significant changes in tumor T1rho were observed after HIFU treatment. These T1rho changes were distinctly more pronounced than HIFU-induced changes in T2 . The results indicate that T1rho imaging is sensitive to HIFU-induced tissue changes and may thus be a suitable MR method for the evaluation of HIFU treatment. Magn Reson Med 73:1593-1601, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 24753286 TI - Comparison of R2' measurement methods in the normal brain at 3 Tesla. AB - PURPOSE: R2', the reversible component of transverse relaxation, is an important susceptibility measurement for studies of brain physiology and pathologies. In existing literature, different R2' measurement methods are used with assumption of equivalency. This study explores the choice of measurement method in healthy, young subjects at 3T. METHODS: In this study, a modified gradient-echo sampling of free induction decay and echo (GESFIDE) sequence was used to compare four standard R2' measurement methods: asymmetric spin echo (ASE), standard GESFIDE, gradient echo sampling of the spin echo (GESSE), and separate R2 and R2* mapping. RESULTS: GESSE returned lower R2' measurements than other methods (P < 0.05). Intersubject mean R2' in gray matter was found to be 2.7 s(-1) using standard GESFIDE and GESSE, versus 3.4-3.8 s(-1) using other methods. In white matter, mean R2' from GESSE was 2.3 s(-1) while other methods produced 3.7-4.3 s(-1) . R2 correction was applied to partially reduce the discrepancies between the methods, but significant differences remained, likely due to violation of the fundamental assumption of a single-compartmental tissue model, and hence monoexponential decay. CONCLUSION: R2' measurements are influenced significantly by the choice of method. Awareness of this issue is important when designing and interpreting studies that involve R2' measurements. PMID- 24753288 TI - The clinical spectrum of laryngeal dystonia includes dystonic cough: observations of a large series. AB - Laryngeal dystonia is a movement disorder of the muscles within the larynx, which most commonly manifests as spasmodic dysphonia (SD). Rarer reported manifestations include dystonic respiratory stridor and dyscoordinate breathing. Laryngeal dystonia has been treated successfully with botulinum neurotoxin (BTX) injections since 1984. We reviewed prospectively collected data in a consecutive series of 193 patients with laryngeal dystonia who were seen at St. Vincent's Hospital between 1991 and 2011. Patient data were analyzed in Excel, R, and Prism. Laryngeal dystonia manifested as SD (92.7%), stridor (11.9%), dystonic cough (6.2%), dyscoordinate breathing (4.1%), paroxysmal hiccups (1.6%), and paroxysmal sneezing (1.6%). There were more women (68.4%) than men (31.6%), and the average age at onset was 47 years. A positive family history of dystonia was present in 16.1% of patients. A higher incidence of extra-laryngeal dystonia (ie, torticollis and blepharospasm) and concurrent manifestations of laryngeal dystonia were present in patients with dystonic cough, dyscoordinate breathing, paroxysmal sneezing, and hiccups than in other patients (P = 0.003 and P < 0.0001, respectively). The average starting dose of BTX decreased from 2.3 to 0.5 units between 1991 and 2011. The median treatment rating was excellent across all subgroups. Patients with adductor SD, stridor, extra-laryngeal dystonia and male patients had relatively better treatment outcomes. Technical failures were rare (1.1%). Dysphonia secondary to vocal cord paresis followed 38.7% of treatments. Laryngeal dystonia manifests predominantly as SD, but other manifestations include stridor, dyscoordinate breathing, paroxysmal cough, hiccups, and sneezing. BTX injections are very effective across all subgroups. Severe adverse events are rare. PMID- 24753290 TI - Nucleophilic reactivity of a copper(II)-superoxide complex. AB - Metal-bound superoxide intermediates are often implicated as electrophilic oxidants in dioxygen-activating metalloenzymes. In the nonheme iron alpha ketoglutarate dependent oxygenases and pterin-dependent hydroxylases, however, Fe(III)-superoxide intermediates are postulated to react by nucleophilic attack on electrophilic carbon atoms. By reacting a Cu(II)-superoxide complex (1) with acyl chloride substrates, we have found that a metal-superoxide complex can be a very reactive nucleophile. Furthermore, 1 was found to be an efficient nucleophilic deformylating reagent, capable of Baeyer-Villiger oxidation of a number of aldehyde substrates. The observed nucleophilic chemistry represents a new domain for metal-superoxide reactivity. Our observations provide support for the postulated role of metal-superoxide intermediates in nonheme iron alpha ketoglutarate dependent and pterin-dependent enzymes. PMID- 24753289 TI - Collagen gel contraction as a measure of fibroblast function in carpal tunnel syndrome. AB - Noninflammatory subsynovial connective tissue (SSCT) fibrosis with nerve compression is a prominent feature of carpal tunnel syndrome (CTS). Studies have shown that SSCT matrix synthesis and material property changes in CTS are associated with increased activity of transforming growth factor (TGF)-beta1. The aim of this study were to (1) investigate the ability of SSCT fibroblasts from CTS patients and unaffected individuals to contract a collagen gel ring and (2) determine how the addition of TGF-beta1 affects this ability. SSCT fibroblasts from three normal cadavers and three age-matched female patients who had undergone surgery for CTS were used. Results showed patient cell-seeded gels had a significantly higher contraction rate (p < 0.001) than control cells, and fully contracted gel rings possessed a significantly higher tensile strength (p = 0.003) and stiffness (p < 0.001). Furthermore, TGF-beta1 significantly intensified contraction rate (p < 0.001), tensile strength (p < 0.001), and stiffness (p < 0.001). In conclusion, SSCT cells from normal donors and CTS patients contract collagen gel rings differently, and this ability is affected by TGF-beta1 treatment. This cell-seeded collagen gel model may be useful for developing new methods of stopping or eliminating the effect of TGF-beta1 on the SSCT fibroblasts and surrounding matrix, which might aid in the identification of medical treatment for CTS. PMID- 24753287 TI - Optimizing cationic and neutral lipids for efficient gene delivery at high serum content. AB - BACKGROUND: Cationic liposome (CL)-DNA complexes are promising gene delivery vectors with potential application in gene therapy. A key challenge in creating CL-DNA complexes for application is that their transfection efficiency (TE) is adversely affected by serum. In particular, little is known about the effects of a high serum content on TE, even though this may provide design guidelines for application in vivo. METHODS: We prepared CL-DNA complexes in which we varied the neutral lipid [1,2-dioleoyl-sn-glycerophosphatidylcholine, glycerol-monooleate (GMO), cholesterol], the headgroup charge and chemical structure of the cationic lipid, and the ratio of neutral to cationic lipid; we then measured the TE of these complexes as a function of serum content and assessed their cytotoxicity. We tested selected formulations in two human cancer cell lines (M21/melanoma and PC-3/prostate cancer). RESULTS: In the absence of serum, all CL-DNA complexes of custom-synthesized multivalent lipids show high TE. Certain combinations of multivalent lipids and neutral lipids, such as MVL5(5+)/GMO-DNA complexes or complexes based on the dendritic-headgroup lipid TMVLG3(8+) exhibited high TE both in the absence and presence of serum. Although their TE still dropped to a small extent in the presence of serum, it reached or surpassed that of benchmark commercial transfection reagents, particularly at a high serum content. CONCLUSIONS: Two-component vectors (one multivalent cationic lipid and one neutral lipid) can rival or surpass benchmark reagents at low and high serum contents (up to 50%, v/v). We propose guidelines for optimizing the serum resistance of CL-DNA complexes based on a given cationic lipid. PMID- 24753292 TI - Silicon decorated cone shaped carbon nanotube clusters for lithium ion battery anodes. AB - In this work, we report the synthesis of an three-dimensional (3D) cone-shape CNT clusters (CCC) via chemical vapor deposition (CVD) with subsequent inductively coupled plasma (ICP) treatment. An innovative silicon decorated cone-shape CNT clusters (SCCC) is prepared by simply depositing amorphous silicon onto CCC via magnetron sputtering. The seamless connection between silicon decorated CNT cones and graphene facilitates the charge transfer in the system and suggests a binder free technique of preparing lithium ion battery (LIB) anodes. Lithium ion batteries based on this novel 3D SCCC architecture demonstrates high reversible capacity of 1954 mAh g(-1) and excellent cycling stability (>1200 mAh g(-1) capacity with ~ 100% coulombic efficiency after 230 cycles). PMID- 24753291 TI - Crystal structure of the Campylobacter jejuni CmeC outer membrane channel. AB - As one of the world's most prevalent enteric pathogens, Campylobacter jejuni is a major causative agent of human enterocolitis and is responsible for more than 400 million cases of diarrhea each year. The impact of this pathogen on children is of particular significance. Campylobacter has developed resistance to many antimicrobial agents via multidrug efflux machinery. The CmeABC tripartite multidrug efflux pump, belonging to the resistance-nodulation-cell division (RND) superfamily, plays a major role in drug resistant phenotypes of C. jejuni. This efflux complex spans the entire cell envelop of C. jejuni and mediates resistance to various antibiotics and toxic compounds. We here report the crystal structure of C. jejuni CmeC, the outer membrane component of the CmeABC tripartite multidrug efflux system. The structure reveals a possible mechanism for substrate export. PMID- 24753293 TI - Crystal structures of beta-primeverosidase in complex with disaccharide amidine inhibitors. AB - beta-Primeverosidase (PD) is a disaccharide-specific beta-glycosidase in tea leaves. This enzyme is involved in aroma formation during the manufacturing process of oolong tea and black tea. PD hydrolyzes beta-primeveroside (6-O-beta-d xylopyranosyl-beta-d-glucopyranoside) at the beta-glycosidic bond of primeverose to aglycone, and releases aromatic alcoholic volatiles of aglycones. PD only accepts primeverose as the glycone substrate, but broadly accepts various aglycones, including 2-phenylethanol, benzyl alcohol, linalool, and geraniol. We determined the crystal structure of PD complexes using highly specific disaccharide amidine inhibitors, N-beta-primeverosylamidines, and revealed the architecture of the active site responsible for substrate specificity. We identified three subsites in the active site: subsite -2 specific for 6-O-beta-d xylopyranosyl, subsite -1 well conserved among beta-glucosidases and specific for beta-d-glucopyranosyl, and wide subsite +1 for hydrophobic aglycone. Glu-470, Ser 473, and Gln-477 act as the specific hydrogen bond donors for 6-O-beta-d xylopyranosyl in subsite -2. On the other hand, subsite +1 was a large hydrophobic cavity that accommodates various aromatic aglycones. Compared with aglycone-specific beta-glucosidases of the glycoside hydrolase family 1, PD lacks the Trp crucial for aglycone recognition, and the resultant large cavity accepts aglycone and 6-O-beta-d-xylopyranosyl together. PD recognizes the beta primeverosides in subsites -1 and -2 by hydrogen bonds, whereas the large subsite +1 loosely accommodates various aglycones. The glycone-specific activity of PD for broad aglycone substrates results in selective and multiple release of temporally stored alcoholic volatile aglycones of beta-primeveroside. PMID- 24753294 TI - Synthesis, crystal structure, herbicidal activities and 3D-QSAR study of some novel 1,2,4-triazolo[4,3-a]pyridine derivatives. AB - BACKGROUND: 1,2,4-Triazolo[4,3-a]pyridine derivatives represent a new series of compounds that possess good herbicidal activity against Echinochloa crusgalli (L.) Beauv., Setaria faberii, Digitaria sanguinalis (L.) Scop., Brassica juncea Coss., Amaranthus retroflexus L. and Eclipta prostrata L. RESULTS: A total of 23 novel 1,2,4-triazolo[4,3-a]pyridine derivatives were synthesised and identified by (1) H NMR, IR, single-crystal X-ray diffraction, mass-spectroscopic and elemental analysis, and their herbicidal activities were tested against E. crusgalli (L.) Beauv., S. faberii, D. sanguinalis (L.) Scop., B. juncea Coss., A. retroflexus L. and E. prostrata L. at 150 g a.i. ha(-1) . It was found that the title compound 8-chloro-3-(4-propylphenyl)-[1,2,4]-triazolo[4,3-a]pyridine possesses high herbicidal activity and a broad spectrum against the 22 test weeds, with an inhibition effect of about 50% at a dosage of 37.5 g a.i. ha(-1) , and is safe for corn, cotton and rice at a dosage of 150 g a.i. ha(-1) . Furthermore, comparative molecular field analysis contour models were established to study the structure-activity relationship of the title compounds. CONCLUSION: It is possible that, with further structure modification, 1,2,4-triazolo[4,3 a]pyridine derivatives, which possess good herbicidal activities, may become novel lead compounds for the development of herbicides against dicotyledonous weeds. PMID- 24753295 TI - All-nitrogen analogue of ozone: Li3N3 species. AB - A theoretical study of ozone isoelectronic Li3N3 species has been performed. Ab initio electronic structure calculations prove the viability of the ozone-like Li3N3 molecule that might become synthesized. The predicted Li3N3 species with a novel N3(3-) molecular motif possess structural and chemical bonding features similar to that of O3 molecules and can thus be considered as an "all-nitrogen ozone". PMID- 24753296 TI - Obesity independently influences gonadal function in very long-term adult male survivors of childhood cancer. AB - OBJECTIVE: Although obesity is associated with gonadal dysfunction in the general population, gonadotoxic treatment might diminish the impact of obesity in childhood cancer survivors (CCS). The aim was to evaluate whether altered body composition is associated with gonadal dysfunction in male CCS, independent of gonadotoxic cancer treatment. METHODS: Three hundred fifty-one male CCS were included. Median age at diagnosis was 5.9 years (0-17.8) and median age at follow up 25.6 years (18.0-45.8). Total and non-SHBG-bound testosterone, sex hormone binding globulin, inhibin B, and follicle-stimulating hormone (FSH) were studied. Potential determinants were BMI, waist circumference, waist-hip ratio, and body composition measures (dual energy X-ray absorptiometry). RESULTS: Non-SHBG-bound testosterone was significantly decreased in survivors with BMI >= 30 kg/m(2) (adjusted mean 9.1 nmol/L vs. 10.2 nmol/L, P = 0.015), high fat percentage (10.0 vs. 11.2, P = 0.004), and high waist circumference (>102 cm) (9.0 vs. 11.0, P = 0.020). Survivors with high fat percentage (>=25%) had significantly lower inhibin B/FSH ratios (inhibin B/FSH ratio: beta -34%, P = 0.041). CONCLUSION: Obesity is associated with gonadal dysfunction in male CCS, independent of the irreversible effect of previous cancer treatment. Randomized controlled trials are required to evaluate whether weight normalization could improve gonadal function, especially in obese survivors with potential other mechanisms than lifestyle causing their obesity. PMID- 24753297 TI - Heinrich Obersteiner and his contributions. AB - Heinrich Obersteiner (1847-1921) was amongst the most influential neuroscientists in the 19th century. Born into a family of physicians, he gained early exposure to medicine, and as a medical student, he focused much of his research in neuroanatomy, eventually becoming a professor of neuroanatomy at the University of Vienna. Throughout his academic career, he focused greatly on neuropathology, and incorporated much of his research into his textbook, "Introduction to the Study of the Structure of the Central Nervous Organs in Health and Disease," which was considered the foremost reference text of neurology for many generations of scholars. The culmination of his contributions to the neurological world can be seen as the Neurological Institute of Vienna, which he founded in 1882. Scholars from all over the world sought out his expertize and tutelage. While he was the director of the Institute, over 500 articles were published within the Obersteiner-Arbeiten. Much of this work helped set the foundation for the eventual development of neurology as a medical discipline. A review of his life will help us better understand the legacy Heinrich Obersteiner left in the field of neurology. PMID- 24753298 TI - Complexity of ruminant masticatory evolution. AB - The evolution of robust jaws, hypsodont teeth, and large chewing muscles among grazing ruminants is a quintessential example of putative morphological adaptation. However, the degree of correlated evolution (i.e., to what extent the grazer feeding apparatus represents an evolutionary module), especially of soft and hard tissues, remains poorly understood. Recent generation of large datasets and phylogenetic information has made testing hypotheses of correlated evolution possible. We, therefore, test for correlated evolution among various traits of the ruminant masticatory apparatus including tooth crown height, jaw robustness, chewing muscle size, and characters of the molar occlusal surfaces, using phylogenetic and nonphylogenetic comparative methods as well as phylogenetic evolutionary model selection. We find that the large masseter muscles of grazing ruminants evolved with the inclusion of grass in the diet, an increase in the proportion of occlusal enamel bands oriented parallel to the chewing stroke, and possibly hypsodonty. We suggest that the masseter evolved under two evolutionary regimes: i) selection for higher masticatory forces during chewing and ii) flattening of the tooth profile, which resulted in reduced tooth guidance and, thus, a requirement for more chewing muscle activity during each chewing stroke, in agreement with previous research. The linear jaw metrics (depth of the mandibular angle, mandibular angle width, and length of the superficial masseteric scar) all show correlated evolution with hypsodonty and the proportion of enamel bands oriented parallel to the chewing stroke. We suggest that changes in the shape of the mandible represent the combined effects of selection for a reorientation of the chewing stroke, so as to emphasize horizontal translation of the teeth, and accommodation of high-crowned teeth. Our analyses show that the ruminant feeding apparatus is an evolutionary mosaic with its various components showing both correlated and independent evolution. PMID- 24753299 TI - Honoring our donors: a survey of memorial ceremonies in United States anatomy programs. AB - Many anatomy programs that incorporate dissection of donated human bodies hold memorial ceremonies of gratitude towards body donors. The content of these ceremonies may include learners' reflections on mortality, respect, altruism, and personal growth told through various humanities modalities. The task of planning is usually student- and faculty-led with participation from other health care students. Objective information on current memorial ceremonies for body donors in anatomy programs in the United States appears to be lacking. The number of programs in the United States that currently plan these memorial ceremonies and information on trends in programs undertaking such ceremonies remain unknown. Gross anatomy program directors throughout the United States were contacted and asked to respond to a voluntary questionnaire on memorial ceremonies held at their institution. The results (response rate 68.2%) indicated that a majority of human anatomy programs (95.5%) hold memorial ceremonies. These ceremonies are, for the most part, student-driven and nondenominational or secular in nature. Participants heavily rely upon speech, music, poetry, and written essays, with a small inclusion of other humanities modalities, such as dance or visual art, to explore a variety of themes during these ceremonies. PMID- 24753301 TI - Sigmoid sinus occlusion infiltrated by inflammatory myofibroblastic tumor from mastoid. AB - BACKGROUND: Inflammatory myofibroblastic tumor (IMT) and some types of immunoglobulin (Ig) G4-related disease are often involved in the spectrum of inflammatory pseudotumor (IPT) and the concept of IgG4-related IPT/IMT has recently been proposed. METHODS: A 38-year-old man complained of initial symptoms of blurred vision and headache. RESULTS: A tumor was found in the right mastoid, which caused occlusion of the right sigmoid sinus and intracranial hypertension. A diagnosis of IMT with IgG4+ plasma cell infiltration was established by surgical, pathological, and immunohistochemistry findings. His symptoms were completely relieved after corticosteroid therapy and no recurrence was detected during 22 months of follow-up. CONCLUSION: A case with cerebral venous sinus infiltrated by IMTs in the head and neck has never been reported; corticosteroid therapy proved satisfactory in IMT with IgG4+ plasma cell infiltration. PMID- 24753302 TI - Budding process during the organogenesis of the ventral prostatic lobe in Mongolian gerbil. AB - The prostate is a mammalian gland that shows a complex process of organogenesis. Here, a morphological study to characterize the organogenesis of the ventral prostate lobe in male gerbils was conducted. The urogenital sinus (UGS) was dissected out and processed for paraffin embedding. Histological sections were subjected to cytochemical, immunofluorescence, immunohistochemical, and three dimensional reconstruction techniques. We found that the first ventral buds emerged from the ventral urethral epithelium between the days 20 and 21 of prenatal life, reaching the ventral mesenchymal pad and initiating the branching process on the first day of postnatal life. The buds presented a V-shaped elongation, suggesting that the smooth muscle layer (SML) plays an important role during budding events. Indeed, whereas the androgen receptor (AR) was preferentially found in the UGS mesenchyme (UGM), estrogen receptor alpha (ERalpha) was localized in both the UGM and in the emerging buds. This study characterized the morphological aspects of the budding process in a different rodent from rat and mice, serving as a new model for future studies on developmental biology of the prostate. PMID- 24753303 TI - DNA nanoflowers for multiplexed cellular imaging and traceable targeted drug delivery. AB - We present a facile approach to make aptamer-conjugated FRET (fluorescent resonance energy transfer) nanoflowers (NFs) through rolling circle replication for multiplexed cellular imaging and traceable targeted drug delivery. The NFs can exhibit multi-fluorescence emissions by a single-wavelength excitation as a result of the DNA matrix covalently incorporated with three dye molecules able to perform FRET. Compared with the conventional DNA nanostructure assembly, NF assembly is independent of template sequences, avoiding the otherwise complicated design of DNA building blocks assembled into nanostructures by base-pairing. The NFs were uniform and exhibited high fluorescence intensity and excellent photostability. Combined with the ability of traceable targeted drug delivery, these colorful DNA NFs provide a novel system for applications in multiplex fluorescent cellular imaging, effective screening of drugs, and therapeutic protocol development. PMID- 24753304 TI - MAPK signaling: a key element in plant defense response to insects. AB - Insects have long been the most abundant herbivores, and plants have evolved sophisticated mechanisms to defend against their attack. In particular, plants can perceive specific patterns of tissue damage associated with insect herbivory. Some plant species can perceive certain elicitors in insect oral secretions (OS) that enter wounds during feeding, and rapidly activate a series of intertwined signaling pathways to orchestrate the biosynthesis of various defensive metabolites. Mitogen-activated protein kinases (MAPKs), common to all eukaryotes, are involved in the orchestration of many cellular processes, including development and stress responses. In plants, at least two MAPKs, salicylic acid induced protein kinase (SIPK) and wound-induced protein kinase (WIPK), are rapidly activated by wounding or insect OS; importantly, genetic studies using transgenic or mutant plants impaired in MAPK signaling indicated that MAPKs play critical roles in regulating the herbivory-induced dynamics of phytohormones, such as jasmonic acid, ethylene and salicylic acid, and MAPKs are also required for transcriptional activation of herbivore defense-related genes and accumulation of defensive metabolites. In this review, we summarize recent developments in understanding the functions of MAPKs in plant resistance to insect herbivores. PMID- 24753306 TI - Rapid field-cycling MRI using fast spin-echo. AB - PURPOSE: Fast field-cycling MRI (FFC-MRI) is a technique that promises to expand upon the diagnostic capabilities of conventional MRI by allowing the main field, B0 , to be varied during a pulse sequence, thus allowing access to new types of endogenous contrast. However, this necessitates longer scan times, which can limit the technique's application to clinical research. In this paper, an adaptation of the fast spin-echo (FSE) pulse sequence for use with FFC-MRI is presented, known as field-cycling fast spin-echo (FC-FSE). This technique allows much faster image acquisition, thus shortening scan times significantly. METHODS: Image quality and relaxometric accuracy were assessed by comparison of phantom images with data obtained using conventional techniques. As proof of principle, relaxometric images were obtained from the thighs of a human volunteer. RESULTS: Image quality remains good for speedup factors of up to 4-fold. The accuracy of relaxometry data is in good agreement with conventional techniques. Results from a volunteer study were encouraging, demonstrating that the technique is sensitive enough to detect quadrupole peaks in vivo. CONCLUSION: The technique has been demonstrated in phantom experiments with little loss of image quality or relaxometric accuracy. Initial in-vivo results pave the way for future clinical studies. PMID- 24753305 TI - Structural evolution and membrane interactions of Alzheimer's amyloid-beta peptide oligomers: new knowledge from single-molecule fluorescence studies. AB - Amyloid-beta peptide (Abeta) oligomers may represent the proximal neurotoxin in Alzheimer's disease. Single-molecule microscopy (SMM) techniques have recently emerged as a method for overcoming the innate difficulties of working with amyloid-beta, including the peptide's low endogenous concentrations, the dynamic nature of its oligomeric states, and its heterogeneous and complex membrane interactions. SMM techniques have revealed that small oligomers of the peptide bind to model membranes and cells at low nanomolar-to-picomolar concentrations and diffuse at rates dependent on the membrane characteristics. These methods have also shown that oligomers grow or dissociate based on the presence of specific inhibitors or promoters and on the ratio of Abeta40 to Abeta42. Here, we discuss several types of single-molecule imaging that have been applied to the study of Abeta oligomers and their membrane interactions. We also summarize some of the recent insights SMM has provided into oligomer behavior in solution, on planar lipid membranes, and on living cell membranes. A brief overview of the current limitations of the technique, including the lack of sensitive assays for Abeta-induced toxicity, is included in hopes of inspiring future development in this area of research. PMID- 24753308 TI - Phosphine resistance in Australian Cryptolestes species (Coleoptera: Laemophloeidae): perspectives from mitochondrial DNA cytochrome oxidase I analysis. AB - BACKGROUND: The flat grain beetle (FGB) species Cryptolestes ferrugineus, C. pusillus, C. pusilloides and C. turcicus are major stored-product pests worldwide, of which the first three are present in Australia. C. ferrugineus is also a species with high phosphine resistance status in various countries. Morphological identification of Cryptolestes species is difficult and represents an additional barrier to effective management of phosphine resistance in FGBs. RESULT: Mitochondrial DNA cytochrome oxidase I (mtDNA COI) gene characterisation enabled differentiation of the four major FGB pest species through direct sequence comparison, and enabled the development of a PCR-RFLP method for rapid species differentiation. We detected two mtDNA haplotypes (Cunk-01, 02) present at low frequencies with an average nucleotide divergence rate of 0.079 +/- 0.011 (SE) from C. pusillus. This nucleotide divergence rate is similar to that between C. ferrugineus and C. pusilloides (0.088 +/- 0.012). Male and female genitalia morphologies of the Cunk-02 individuals indicated they were consistent with C. pusillus, yet DNA sequence analyses suggested species-level divergence. The mtDNA COI gene of phosphine-bioassayed, lab-reared F1 generation survivors supported the presence of strong phosphine resistance in C. ferrugineus, but unexpectedly also in C. pusilloides and C. pusillus F1 survivors. CONCLUSION: We demonstrated the utility of molecular DNA techniques for differentiating closely related insect species, and its usefulness in assisting the management of pest insect species. The likely presence of a cryptic C. pusillus species in Australia and the possible development of strong phosphine resistance in Australian FGB pest species require further investigation. (c) 2014 Society of Chemical Industry. PMID- 24753307 TI - Influence of a heptad repeat stutter on the pH-dependent conformational behavior of the central coiled-coil from influenza hemagglutinin HA2. AB - The coiled-coil is one of the most common protein structural motifs. Amino acid sequences of regions that participate in coiled-coils contain a heptad repeat in which every third then forth residue is occupied by a hydrophobic residue. Here we examine the consequences of a "stutter," a deviation of the idealized heptad repeat that is found in the central coiled-coil of influenza hemagluttinin HA2. Characterization of a peptide containing the native stutter-containing HA2 sequence, as well as several variants in which the stutter was engineered out to restore an idealized heptad repeat pattern, revealed that the stutter is important for allowing coiled-coil formation in the WT HA2 at both neutral and low pH (7.1 and 4.5). By contrast, all variants that contained idealized heptad repeats exhibited marked pH-dependent coiled-coil formation with structures forming much more stably at low pH. A crystal structure of one variant containing an idealized heptad repeat, and comparison to the WT HA2 structure, suggest that the stutter distorts the optimal interhelical core packing arrangement, resulting in unwinding of the coiled-coil superhelix. Interactions between acidic side chains, in particular E69 and E74 (present in all peptides studied), are suggested to play a role in mediating these pH-dependent conformational effects. This conclusion is partially supported by studies on HA2 variant peptides in which these positions were altered to aspartic acid. These results provide new insight into the structural role of the heptad repeat stutter in HA2. PMID- 24753309 TI - Anti-inflammatory and protective effects of 2-methacryloyloxyethyl phosphorylcholine polymer on oral epithelial cells. AB - Periodontitis is a chronic inflammatory disease initiated by a microbial biofilm formed in the periodontal pocket. Gingival epithelium plays important roles as the first physical barrier to bacterial invasion and in orchestrating the innate immune reaction via toll-like receptors (TLRs), which recognize various bacterial products, and maintaining its function. Newly developed oral care products to inhibit bacterial adherence, subsequent inflammatory reaction and protect the gingival epithelium are expected. We previously reported that 2 methacryloyloxyethyl phosphorylcholine (MPC)-polymer coating decreased bacterial adhesion to human oral keratinocytes, RT-7, and mouth-rinsing with MPC-polymer inhibited the increase of oral bacteria. In this study, regarding the possibility of MPC-polymer application for preventing the adherence of periodontal pathogen, subsequent inflammatory reaction and protection of gingival epithelium, we examined the effects of MPC-polymer on the adherence of Porphyromonas gingivalis, major periodontitis-related pathogen, and TLR2 ligand to RT-7 and subsequent interleukin (IL)-8 production. MPC-polymer treatment significantly reduced P. gingivalis adherence by 44% and TLR2-mediated IL-8 production by blocking the binding of its specific-ligand in a concentration-dependent manner. Furthermore, MPC-polymer pretreatment protected RT-7 from injury by chemical irritants, cetylpyridinium chloride. These findings suggest that MPC-polymer is potentially useful for oral care to prevent oral infection and to maintain oral epithelial function. PMID- 24753310 TI - Fly-eye inspired superhydrophobic anti-fogging inorganic nanostructures. AB - Fly-eye bio-inspired inorganic nanostructures are synthesized via a two-step self assembly approach, which have low contact angle hysteresis and excellent anti fogging properties, and are promising candidates for anti-freezing/fogging materials to be applied in extreme and hazardous environments. PMID- 24753311 TI - Synthesis and characterization of [N-methyl-3H]loperamide. AB - Loperamide is a piperidine butyramide mu-opiate receptor agonist and currently employed to treat diarrhea. Because a single past report of tritiating loperamide was limited to only a very low specific activity product without technical details or extensive analysis, the synthesis of [N-methyl-(3)H]loperamide at high specific activity is now described in detail. An imine precursor was alkylated with [(3)H]methyl iodide to obtain a quaternary intermediate, which was then reacted with 4-(4-chlorophenyl)-4-hydroxypiperidine to afford the desired product [N-methyl-(3)H]loperamide, characterized by thin layer chromatography (TLC), HPLC, MS, UV, and proton-decoupled tritium NMR. PMID- 24753312 TI - Growth, motility and resistance to oxidative stress of the melioidosis pathogen Burkholderia pseudomallei are enhanced by epinephrine. AB - Burkholderia pseudomallei causes melioidosis, a severe invasive disease endemic in South-East Asia and Northern Australia. Bacterial pathogens of several genera have been reported to be able to sense and respond to the stress-related catecholamine hormone epinephrine. Here, we report that epinephrine induces growth of B. pseudomallei in minimal serum-rich medium and heat-inactivated whole human serum and enhances bacterial motility, transcription of flagellar genes and flagellin synthesis. The effect of epinephrine on motility, but not bacterial growth, could be partially reversed by the alpha-adrenergic receptor antagonist phentolamine. Epinephrine also altered the transcription of iron-regulated genes encoding superoxide dismutase (sodB) and the malleobactin receptor (fmtA). Consistent with induction of sodB expression, epinephrine-treated B. pseudomallei exhibited increased resistance to superoxide. Epinephrine treatment did not stimulate Type III secretion via the virulence-associated Bsa apparatus or the ability of B. pseudomallei to invade epithelial cells in culture. This study provides the first evidence that epinephrine, a hormone released from the host under stress and upon therapy, can affect B. pseudomallei virulence-associated properties. PMID- 24753313 TI - Ectopia cordis: a rare congenital anomaly. AB - Ectopia cordis (EC) is a rare congenital anomaly associated with the heart positioned outside of the thoracic cavity either partially or completely. The ectopic heart can be found along a spectrum of anatomical locations, including the cervical, thoracic and abdominal regions and in most cases, it protrudes outside the chest through a split sternum. Although the first case of EC was identified during the early 1600s only 91 cases have been reported since then in the literature. This review will discuss the history and prevalence of EC, its etiology, morphology, presentation and symptoms, complications, diagnosis, treatment and management and prognosis. PMID- 24753314 TI - First-class health: amenity wards, health insurance, and normalizing health care inequalities in Tanzania. AB - In 2008, a government hospital in southwest Tanzania added a "first-class ward," which, unlike existing inpatient wards defined by sex, age, and ailment, would treat patients according to their wealth. A generation ago, Tanzanians viewed health care as a right of citizenship. In the 1980s and 1990s, structural adjustment programs and user fees reduced people's access to biomedical attention. Tanzania currently promotes "amenity" wards and health insurance to increase health care availability, generate revenue from patients and potential patients, and better integrate for-profit care. In this article, I examine people's discussions of these changes, drawing on ethnographic fieldwork in the 2000s and 1990s. I argue that Tanzanians criticize unequal access to care and health insurance, although the systemic structuring of inequalities is becoming normalized. People transform the language of socialism to frame individualized market-based care as mutual interdependence and moral necessity, articulating a new biomedical citizenship. PMID- 24753315 TI - De novo 2q36.1q36.3 interstitial deletion involving the PAX3 and EPHA4 genes in a fetus with spina bifida and cleft palate. AB - BACKGROUND: Interstitial 2q36 deletion is a rare event. Only two previously published cases of 2q36 deletions were characterized using array-CGH. This is the first case diagnosed prenatally. METHODS: We report on the prenatal diagnosis of a 2q36.1q36.3 interstitial deletion in a fetus with facial dysmorphism, spina bifida, and cleft palate. RESULTS: Array-CGH analysis revealed a 5.6 Mb interstitial deletion of the long arm of chromosome 2q36.1q36.3, including the PAX3 and EPHA4 genes. CONCLUSION: The present study reinforces the hypothesis that PAX3 haploinsufficiency may be associated with neural tube defects in humans and suggests that the EPHA4 gene might be implicated during palate development. This report also illustrates the added value of array-CGH to detect cryptic chromosomal imbalances in malformed fetuses and to improve genetic counseling prenatally. PMID- 24753316 TI - Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder. AB - The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor "A" allele of rs6311 to offspring with ASD (permuted P = 0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5' untranslated region (UTR) in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5'UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk. PMID- 24753317 TI - Penetrability of AH plus and MTA fillapex after endodontic treatment and retreatment: a confocal laser scanning microscopy study. AB - The aim of the study was to assess the penetrability of two endodontic sealers (AH Plus and MTA Fillapex) into dentinal tubules, submitted to endodontic treatment and subsequently to endodontic retreatment. Thirty ex vivo incisors were prepared using ProTaper rotary system up to F3 instrument and divided in three groups according to the endodontic sealer used for root canal filling: AH Plus (AHP), MTA Fillapex (MTAF), and control group (CG) without using EDTA previously to the root canal filling. Rhodamine B dye (red) was incorporated to the sealers in order to provide the fluorescence which will enable confocal laser scanning microscopy (CLSM) assessment. All specimens were filled with gutta percha cones using the lateral compaction technique. The specimens were submitted to endodontic retreatment using ProTaper Retreatment system, re-prepared up to F5 instruments and filled with gutta-percha cones and the same sealer used during endodontic retreatment. Fluorescein dye (green) was incorporated to the sealer in order to distinguish from the first filling. The roots were sectioned 2 mm from the apex and assessed by CLSM. No difference was found between the two experimental groups (P > 0.05). On the other hand, in the control group the sealers were not capable to penetrate into dentinal tubules after endodontic treatment (P > 0.05). In retreatment cases, none of the sealers were able to penetrate into dentin tubules. It can be concluded that sealer penetrability is high during endodontic treatment. However, MTA Fillapex and AH Plus do not penetrate into dentinal tubules after endodontic retreatment. PMID- 24753318 TI - The mechanism of binding of the KIX domain to the mixed lineage leukemia protein and its allosteric role in the recognition of c-Myb. AB - The KIX domain is a mediator of the interaction between different transcription factors. This complex function is carried out via two distinct binding sites located on opposite sides of the protein; namely, the 'c-Myb site' and the 'MLL site', named after their characteristic ligands-the transactivation domain of c Myb and the mixed lineage leukemia protein (MLL). Both these ligands are unstructured in isolation and fold only upon binding, posing the KIX domain as an ideal candidate to explore the binding induced folding reaction of intrinsically unstructured proteins. Here, we complement the recent kinetic description on the interaction between KIX and c-Myb, by characterizing the binding kinetics between KIX and MLL, at different pH and ionic strength conditions. Furthermore, we analyze quantitatively the mechanism of allosteric communication between the topologically distinct c-Myb and MLL sites. The implications of our results are discussed in the light of previous work on other intrinsically unstructured systems. PMID- 24753319 TI - Kinetics of protein fibrillation controlled by fibril elongation. AB - Numerous proteins have the ability to assemble into fibrillar aggregates which are of great interest, because they feature in scores of human diseases and many technological products. In the present work, we analyze the kinetics of protein fibrillation when the process is governed solely by elongation of initially appeared fibrils in the protein solution. We derive exact expressions for the time dependences of the fibrillation degree, the concentration of monomeric protein in the solution, and the average fibril size. Furthermore, we present formulas for the initial fibrillation rate and the half-fibrillation time in terms of experimentally controllable quantities. The results obtained provide a mechanistic insight into the kinetics of protein fibrillation mediated by fibril elongation. We confront theory with experiment and find that it allows a good description of available experimental data for fibrillation of the Alzheimer's disease-associated protein Abeta(1-40) and the yeast prion protein Sup35. PMID- 24753320 TI - Real time visualization and characterization of platelet deposition under flow onto clinically relevant opaque surfaces. AB - Although the thrombogenic nature of the surfaces of cardiovascular devices is an important aspect of blood biocompatibility, few studies have examined platelet deposition onto opaque materials used for these devices in real time. This is particularly true for the metallic surfaces used in current ventricular assist devices (VADs). Using hemoglobin depleted red blood cells (RBC ghosts) and long working distance optics to visualize platelet deposition, we sought to perform such an evaluation. Fluorescently labeled platelets mixed with human RBC ghosts were perfused across six opaque materials (a titanium alloy (Ti6Al4V), silicon carbide (SiC), alumina (Al2O3, 2-methacryloyloxyethyl phosphorylcholine polymer coated Ti6Al4V (MPC-Ti6Al4V), yttria partially stabilized zirconia (YZTP), and zirconia toughened alumina (ZTA)) for 5 min at wall shear rates of 400 and 1000 s(-1). Ti6Al4V had significantly increased platelet deposition relative to MPC Ti6Al4V, Al2 O3 , YZTP, and ZTA at both wall shear rates (p < 0.01). For all test surfaces, increasing the wall shear rate produced a trend of decreased platelet adhesion. The described system can be a utilized as a tool for comparative analysis of candidate blood-contacting materials with acute blood contact. PMID- 24753322 TI - Genetic structure of the whitefly Bemisia tabaci populations in Colombia following a recent invasion. AB - The whitefly Bemisia tabaci (Gennadius) is one of the most important pests causing economic losses in a variety of cropping systems around the world. This species was recently found in a coastal region of Colombia and has now spread inland. To investigate this invasive process, the genetic structure of B. tabaci was examined in 8 sampling locations from 2 infested regions (coastal, inland) using 9 microsatellite markers and the mitochondrial COI gene. The mitochondrial analysis indicated that only the invasive species of the B. tabaci complex Middle East-Asia Minor 1 (MEAM 1 known previously as biotype B) was present. The microsatellite data pointed to genetic differences among the regions and no isolation by distance within regions. The coastal region in the Caribbean appears to have been the initial point of invasion, while the inland region in the Southwest showed genetic variation among populations most likely reflecting founder events and ongoing changes associated with climatic and topographical heterogeneity. These findings have implications for tracking and managing B. tabaci. PMID- 24753321 TI - Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. AB - Consensus diagnostic criteria for multiple system atrophy consider dementia as a nonsupporting feature, despite emerging evidence demonstrating that cognitive impairments are an integral part of the disease. Cognitive disturbances in multiple system atrophy occur across a wide spectrum from mild single domain deficits to impairments in multiple domains and even to frank dementia in some cases. Frontal-executive dysfunction is the most common presentation, while memory and visuospatial functions also may be impaired. Imaging and neuropathological findings support the concept that cognitive impairments in MSA originate from striatofrontal deafferentation, with additional contributions from intrinsic cortical degeneration and cerebellar pathology. Based on a comprehensive evidence-based review, the authors propose future avenues of research that ultimately may lead to diagnostic criteria for cognitive impairment and dementia associated with multiple system atrophy. PMID- 24753323 TI - Characterization of droplet impact and deposit formation on leaf surfaces. AB - BACKGROUND: Elucidation of droplet dynamic impact and deposit formation on leaf surfaces would assist in modifying application strategies potentially to improve biological control efficiency and minimize pesticide waste. RESULTS: The mechanics of the three-dimensional droplet impact and formation process on hydrophilic and hydrophobic leaf surfaces was investigated with a system that independently controlled droplet diameter, impact speed and impact angle. Spray solutions were made with a nonionic surfactant in distilled water. Water-only droplets rebounded or splashed on hydrophobic leaves of Euphorbia pulcherrima and Zea mays, but not on hydrophilic Dracaena deremensis leaves. Droplet spread areas on D. deremensis at 5.0 m s(-1) impact speed increased 1.9-fold when the droplet diameter was increased from 175 to 481 um. Similarly, spread areas of 306 um water-only droplets increased 2.0-fold when the impact speed was increased from 3.5 to 7.0 m s(-1) . At surfactant concentrations of 0, 0.25, 0.50 and 0.75% (v/v), percentages of droplets that either splashed or bounced off Z. mays were 56, 37, 2 and 0% respectively. CONCLUSION: Microscopic measurements of droplet impact clarified the effectiveness of surfactants in enhancing droplet retention on hydrophobic leaves and also revealed that water droplets did not rebound or splash on hydrophilic leaves. (c) 2014 Society of Chemical Industry. PMID- 24753324 TI - Ploidy and clinical characteristics of childhood acute myeloid leukemia: A NOPHO AML study. AB - We report the first large series (n = 596) of pediatric acute myeloid leukemia (AML) focusing on modal numbers (MN) from the population-based NOPHO-AML trials. Abnormal karyotypes were present in 452 cases (76%) and numerical aberrations were present in 40% (n = 237) of all pediatric AML. Among patients with an abnormal karyotype, the MN 46 was most common (n = 251; 56%) of which 36 (8%) were pseudodiploid with numerical aberrations, followed by MN 47 (n = 80; 18%) and MN 43-45 (n = 48; 8%). No cases had MN less than 43. Hyperdiploid AML with MN 48-65 comprised 11% of all cases and was associated with early onset (median age 2 years), female sex (57%), and a dominance of acute megakaryoblastic leukemia (AMKL) (29%). Hypodiploidy constituted 8% of all AML and was associated with older age (median age 9 years), male predominance (60%), FAB M2 (56%), and t(8;21)(q22;q22) (56%) with loss of sex chromosomes. Inferior outcome was observed for hypodiploid cases (5-year event-free survival 40% and 5-year overall survival 40%) but did not reach statistical significance. Chromosomes were gained in a nonrandom pattern, where chromosomes 8, 21, 19, and 6 were the most commonly gained. In conclusion, based on MNs, two cytogenetic subgroups with characteristic clinical features are described; hypodiploidy found in 8% and associated with high median age, male sex, t(8;21)(q22;q22), and FAB M2 and possibly associated with inferior outcome (P = 0.13), and hyperdiploidy with MN 48-65 in 11% associated with early onset, female sex, and AMKL. PMID- 24753325 TI - Why do some intervertebral discs degenerate, when others (in the same spine) do not? AB - This review suggests why some discs degenerate rather than age normally. Intervertebral discs are avascular pads of fibrocartilage that allow movement between vertebral bodies. Human discs have a low cell density and a limited ability to adapt to mechanical demands. With increasing age, the matrix becomes yellowed, fibrous, and brittle, but if disc structure remains intact, there is little impairment in function, and minimal ingrowth of blood vessels or nerves. Approximately half of old lumbar discs degenerate in the sense of becoming physically disrupted. The posterior annulus and lower lumbar discs are most affected, presumably because they are most heavily loaded. Age and genetic inheritance can weaken discs to such an extent that they are physically disrupted during everyday activities. Damage to the endplate or annulus typically decompresses the nucleus, concentrates stress within the annulus, and allows ingrowth of nerves and blood vessels. Matrix disruption progresses by mechanical and biological means. The site of initial damage leads to two disc degeneration "phenotypes": endplate-driven degeneration is common in the upper lumbar and thoracic spine, and annulus-driven degeneration is common at L4-S1. Discogenic back pain can be initiated by tissue disruption, and amplified by inflammation and infection. Healing is possible in the outer annulus only, where cell density is highest. We conclude that some discs degenerate because they are disrupted by excessive mechanical loading. This can occur without trauma if tissues are weakened by age and genetic inheritance. Moderate mechanical loading, in contrast, strengthens all spinal tissues, including discs. PMID- 24753326 TI - Molecular cloning of VIP and distribution of VIP/VPACR system in the testis of Podarcis sicula. AB - Using molecular, biochemical, and cytological tools, we studied the nucleotide and the deduced amino acid sequence of PHI/VIP and the distribution of VIP/VPAC receptor system in the testis of the Italian wall lizard Podarcis sicula to evaluate the involvement of such a neuropeptide in the spermatogenesis control. We demonstrated that (1) Podarcis sicula VIP had a high identity with other vertebrate VIP sequences, (2) differently from mammals, VIP was synthesized directly in the testis, and (3) VIP and its receptor VPAC2 were widely distributed in germ and somatic cells, while the VPAC1 R had a distribution limited to Leydig cells. Our results demonstrated that in Podarcis sicula the VIP sequence is highly preserved and that this neuropeptide is involved in lizard spermatogenesis and steroidogenesis. PMID- 24753327 TI - ARVs and ARTs: medicoscapes and the unequal place-making for biomedical treatments in sub-Saharan Africa. AB - Asking why some diseases gain global attention whereas others are neglected, we present two case studies that demonstrate the unequal treatment and financing options available for HIV/AIDS versus infertility treatments. We track three key phenomena central to understanding the unequal public attention given to certain ailments: peace and security, subordination of the social to the biological, and a "global" quality. Existing concepts such as global assemblages or therapeutic citizenship are quite limited when it comes to bodily conditions that result in social suffering and do not satisfy the conditions of advocacy. Since it is not enough to observe "flowing" and "moving," we propose the concept of medicoscapes, to acknowledge that such activities simultaneously entail channeling and carving out. Medicoscapes enhance the analysis of linkages between different health conditions regardless of whether they are biological or social and how they interconnect places, sites, and people. PMID- 24753328 TI - Prior to Foxp3+ regulatory T-cell induction, interleukin-10-producing B cells expand after Helicobacter pylori infection. AB - Regulatory T (Treg) cells play a critical role in Helicobacter pylori immune evasion and persistent infection. In addition to Treg cells, it is still unknown whether a newly defined B-cell subset, interleukin (IL)-10-producing B cells, is involved. Using a mouse model of H. pylori infection, we investigated the dynamic changes of IL-10-producing B cells and Foxp3(+) Treg cells in gastrointestinal mucosa, spleen and mesenteric lymph nodes following H. pylori infection. We observed that in addition to Foxp3(+) Treg cells, IL-10-producing B cells could also be induced after H. pylori infection and they expanded earlier than Foxp3(+) Treg cells did. Moreover, the regulatory immune responses induced by H. pylori were not limited to gastric mucosa. Our findings may provide new clues for further research on H. pylori immune evasion and diseases associated with H. pylori infection. PMID- 24753329 TI - Live-cell stimulated Raman scattering imaging of alkyne-tagged biomolecules. AB - Alkynes can be metabolically incorporated into biomolecules including nucleic acids, proteins, lipids, and glycans. In addition to the clickable chemical reactivity, alkynes possess a unique Raman scattering within the Raman-silent region of a cell. Coupling this spectroscopic signature with Raman microscopy yields a new imaging modality beyond fluorescence and label-free microscopies. The bioorthogonal Raman imaging of various biomolecules tagged with an alkyne by a state-of-the-art Raman imaging technique, stimulated Raman scattering (SRS) microscopy, is reported. This imaging method affords non-invasiveness, high sensitivity, and molecular specificity and therefore should find broad applications in live-cell imaging. PMID- 24753330 TI - Identification of the roles of individual amino acid residues of the helix E of the major antenna of photosystem II (LHCII) by alanine scanning mutagenesis. AB - The functions of the helix E (W97-F105), an amphiphilic lumenal 310 helix of the major antenna of photosystem II (LHCII), are still unidentified. To elucidate the roles of individual amino acid residue of the helix E, alanine scanning mutagenesis has been performed to mutate every residue of this domain to alanine. The influence of every alanine substitution on the structure and function of LHCII has been investigated biochemically and spectroscopically. The results show that all mutations have little impact on the pigment binding and configuration. However, many mutants presented decreased thermo- or photo-stability compared with the wild type, highlighting the significance of this helix to the stability of LHCII. The most critical residue for stability is W97. The mutant W97A yielded very fragile trimeric pigment protein complexes. The structural analysis revealed that the hydrogen bonding and aromatic interactions between W97, F195, F194 and a water molecule contributed greatly to the stability of LHCII. Moreover, Q103A and F105A have been identified to be able to reinforce the tendency of aggregation in vitro. The structural analysis suggested that the enhancement in aggregation formation for Q103A and F105A might be attributed to the changing hydrophobicity of the region. PMID- 24753331 TI - Dermal developmental toxicity of N-phenylimide herbicides in rats. AB - BACKGROUND: S-53482 and S-23121 are N-phenylimide herbicides and produced embryolethality, teratogenicity (mainly ventricular septal defects and wavy ribs), and growth retardation in rats in conventional oral developmental toxicity studies. Our objective in this study was to investigate whether the compounds induce developmental toxicity via the dermal route, which is more relevant to occupational exposure, hence better addressing human health risks. METHODS: S 53482 was administered dermally to rats at 30, 100, and 300 mg/kg during organogenesis, and S-23121 was administered at 200, 400, and 800 mg/kg (the maximum applicable dose level). Fetuses were obtained by a Cesarean section and examined for external, visceral, and skeletal alterations. RESULTS: Dermal exposure of rats to S-53482 at 300 mg/kg produced patterns of developmental toxicity similar to those resulting from oral exposure. Toxicity included embryolethality, teratogenicity, and growth retardation. Dermal administration of S-23121 at 800 mg/kg resulted in an increased incidence of embryonic death and ventricular septal defect, but retarded fetal growth was not observed as it was following oral exposure to S-23121. CONCLUSIONS: Based on the results, S-53482 and S-23121 were teratogenic when administered dermally to pregnant rats as were the compounds administered orally. Thus, investigation of the mechanism and its human relevancy become more important. PMID- 24753332 TI - Dose-dependent effects and reversibility of the injuries caused by nandrolone decanoate in uterine tissue and fertility of rats. AB - This study is the first to investigate the effects of different doses of nandrolone decanoate (ND) upon uterine tissue and fertility, and if the reproductive alterations can be restored after cessation of the treatment. Wistar female rats were treated with ND at doses of 1.87, 3.75, 7.5, and 15 mg/kg body weight, diluted in vehicle (n = 30/group), or received only mineral oil (control group, n = 45). The animals were divided into three periods of study: ND-treated receiving a daily subcutaneous injection for 15 consecutive days (1), and treatment with ND followed by 30-day recovery (2), and 60-day recovery (3). At the end of each period, five females per group were induced to death to histopathological analysis and the others were allowed to fertility evaluation (at 19th gestational day). Animals that received ND followed by 30-day recovery exhibited persistent diestrous and marked suppression of reproductive capacity. Conversely, after 60-day recovery, only lowest doses females (1.87 and 3.75 mg/kg) exhibited restoration of normal estrous cyclicity. Uterine weights were increased after ND treatment similarly to that of the controls after 60-day recovery. The ND-treated groups showed histopathological changes in the endometrium, myometrium, and perimetrium, and an increase in the thickness of both muscular and serous layers. Notably, the recovery of uterine tissue after ND treatment was dose- and period-dependent. We reported that administration of ND promoted damage in uterine tissue and fertility of rats, and the recovery periods were insufficient to restore all of the side effects caused by ND under a dose dependent response. PMID- 24753333 TI - Placental transfer of a fully human IgG2 monoclonal antibody in the cynomolgus monkey, rat, and rabbit: a comparative assessment from during organogenesis to late gestation. AB - Understanding species differences in the placental transfer of monoclonal antibodies is important to inform species selection for nonclinical safety assessment, interpret embryo-fetal changes observed in these studies, and extrapolate their human relevance. Data presented here for a fully human immunoglobulin G2 monoclonal antibody (IgG2X) revealed that, during organogenesis, in both the cynomolgus monkey (gestation day 35 [gd35]) and the rat (gd10) the extent of IgG2X placental transfer (approximately 0.5% maternal plasma concentration, MPC) was similar to the limited published human data for endogenous IgG. At this early gestational stage, IgG2X placental transfer was approximately 6-fold higher in the rabbit (gd10). By the end of organogenesis, rat embryonic plasma concentrations (gd16) exceeded those in the cynomolgus monkey (gd50) by approximately 3-fold. These data suggest that relative to the cynomolgus monkey, the rabbit (and to a lesser extent the rat) may overestimate potential harmful effects to the human embryo during this critical period of development. Beyond organogenesis, fetal IgG2X plasma concentrations increased approximately 10-fold early in the second trimester (gd50-70) in the cynomolgus monkey and remained relatively unchanged thereafter (at approximately 5% MPC). Late gestational assessment was precluded in rabbits due to immunogenicity, but in rats, fetal IgG2X plasma concentrations increased more than 6-fold from gd16 to gd21 (reaching approximately 15% MPC). In rats, maternal exposure consistent with that achieved by ICH S6(R1) high-dose selection criteria resulted in embryonic plasma concentrations, reaching pharmacologically relevant levels during organogenesis. Furthermore, dose proportional exposure in both mothers and embryos indicated that this was unlikely to occur at the lower therapeutic dose levels used in humans. PMID- 24753334 TI - Effects of macrolide antibiotics on rat embryonic heart function in vitro. AB - The Swedish Medical Product Agency (MPA) has listed erythromycin as a suggested human teratogen, causing cardiovascular malformations. It is further suggested that this may be a class effect of macrolide antibiotics. The proposed teratogenic mechanism is blockade of the human ether-a-go-go-related (hERG)/IKr current in the embryonic heart causing bradycardia and arrhythmia resulting in altered cardiac blood flow and/or embryonic hypoxia. To test this hypothesis, we examined the effect of three macrolide antibiotics on the function of the rat embryonic heart. Gestational day 13 rat embryos in vitro were exposed to erythromycin (25-500 MUM), clarithromycin (25-500 MUM), or azithromycin (100 MUM to 1 mM) for 3 hr. The effect on the embryonic heart was monitored every hour. The results showed that erythromycin and clarithromycin caused a concentration dependent bradycardia. Twenty-five micromolar was a no-effect concentration for erythromycin and was close to a no-effect concentration for clarithromycin. Azithromycin only caused significant bradycardia at 1 mM. Additional studies were performed with the embryos cultured at 40 degrees C instead of 38 degrees C, to mimic fever. The increased temperature increased the number of arrhythmias but did not worsen the drug-induced bradycardia. The results support the concept that erythromycin and clarithromycin can adversely affect the embryonic heart but only at concentrations well outside expected embryonic exposure in the human. PMID- 24753336 TI - Gastrointestinal dysfunction in children with autism spectrum disorders. AB - Gastrointestinal (GI) dysfunctions are frequently reported by parents of children with autism spectrum disorders (ASD) and have been recently recognized as a comorbid condition. However, the clinical significance of these GI dysfunctions remains to be delineated. This study describes the clinical characteristics, associated comorbid disorders, and endoscopic and colonoscopic evaluation of GI dysfunction in a cohort of 164 children with ASD evaluated at a pediatric neurology practice. Symptoms of GI dysfunction were prevalent: 49% of the children reported one or more chronic GI complaints, 22% exhibited diarrhea, 26% suffered from constipation. Furthermore 13% of the parents reported their children to suffer from bloating and/or being gassy and while 10% of the parents reported vomiting or gastroesophageal reflux problems. Similar rates of GI symptoms were reported among pre-school and school-aged children. Inflammation of the gut was found in 6 of the 12 subjects who underwent endoscopic and colonoscopic evaluations, however clinical symptoms did not predict the results of the evaluation. GI dysfunction was significantly associated with sleep disorders and food intolerance, but not with irritability or aggressiveness. In summary, GI dysfunction was prevalent in this cohort of children with ASD, observations consistent with the reports of parents and other clinicians. We conclude that the GI dysfunction in ASD requires proper evaluation and treatment. PMID- 24753338 TI - Intrinsic alpha-helical and beta-sheet conformational preferences: a computational case study of alanine. AB - A fundamental question in protein science is what is the intrinsic propensity for an amino acid to be in an alpha-helix, beta-sheet, or other backbone dihedral angle ( phi-psi) conformation. This question has been hotly debated for many years because including all protein crystal structures from the protein database, increases the probabilities for alpha-helical structures, while experiments on small peptides observe that beta-sheet-like conformations predominate. We perform molecular dynamics (MD) simulations of a hard-sphere model for Ala dipeptide mimetics that includes steric interactions between nonbonded atoms and bond length and angle constraints with the goal of evaluating the role of steric interactions in determining protein backbone conformational preferences. We find four key results. For the hard-sphere MD simulations, we show that (1) beta-sheet structures are roughly three and half times more probable than alpha-helical structures, (2) transitions between alpha-helix and beta-sheet structures only occur when the backbone bond angle tau (N?Calpha ?C) is greater than 110 degrees , and (3) the probability distribution of tau for Ala conformations in the "bridge" region of phi-psi space is shifted to larger angles compared to other regions. In contrast, (4) the distributions obtained from Amber and CHARMM MD simulations in the bridge regions are broader and have increased tau compared to those for hard sphere simulations and from high-resolution protein crystal structures. Our results emphasize the importance of hard-sphere interactions and local stereochemical constraints that yield strong correlations between phi-psi conformations and tau. PMID- 24753339 TI - Upholding the legacy: East African Association for Paleoanthropology and Paleontology held Its 4(th) biennial meeting in Kenya. PMID- 24753340 TI - International Prosimian Congress at Centre Valbio. PMID- 24753341 TI - Third annual meeting of the European Society for the study of Human Evolution. PMID- 24753342 TI - An update on new world colonization research: The Paleoamerican Odyssey conference. PMID- 24753343 TI - Anthropology in comparative biology. PMID- 24753344 TI - What works works. But what works?: Genomes as works in progress. PMID- 24753345 TI - The role of "the aquatic" in human evolution: constraining the aquatic ape hypothesis. AB - Few things show the distinctiveness of human evolution research better than the Aquatic Ape Hypothesis (AAH). On one hand, we have "orthodox" research into human evolution, firmly based on land; on the other, we have the aquatic ape community, convinced not only that our ancestors went through an aquatic phase, but that the professional scientific community ignores their work and keeps it out of the mainstream. How many fields of science have two entirely parallel communities that essentially are hermetically sealed from each other? PMID- 24753346 TI - Sinuses and flotation: does the aquatic ape theory hold water? AB - The idea that people went through an aquatic phase at some time in their evolutionary past is currently undergoing a popular resurgence (see Foley & Lahr). This idea has even started to gain some traction in more learned circles; the late paleoanthropologist Phillip Tobias wrote in support of aspects of it in an edited e-book and a conference on the topic held recently in London was endorsed by celebrities such as the television presenter Sir David Attenborough. Despite (or perhaps because of) the lack of interest within the academic community, advocates of the concept continue to fill the media (and blogosphere) with challenges to the "savannah hypothesis" of the origins of people and to bemoan the fact that their views are not taken seriously by mainstream academia. PMID- 24753347 TI - How humans evolved large brains: comparative evidence. AB - The human brain is about three times as large as that of our closest living relatives, the great apes. Overall brain size is a good predictor of cognitive performance in a variety of tests in primates. Therefore, hypotheses explaining the evolution of this remarkable difference have attracted much interest. In this review, we give an overview of the current evidence from comparative studies testing these hypotheses. If cognitive benefits are diverse and ubiquitous, it is possible that most of the variation in relative brain size among extant primates is explained by variation in the ability to avoid the fitness costs of increased brain size (allocation trade-offs and increased minimum energy needs). This is indeed what we find, suggesting that an energetic perspective helps to complement approaches to explain variation in brain size that postulate cognitive benefits. The expensive brain framework also provides a coherent scenario for how these factors may have shaped early hominin brain expansion. PMID- 24753350 TI - Feasibility and reproducibility of free fatty acid profiling in abdominal adipose tissue with 1H-magnetic resonance spectroscopy at 3 T: differences between lean and obese individuals. AB - PURPOSE: To evaluate the feasibility and reproducibility of free fatty acid (FFA) measurement for diagnosing adipose tissue dysfunction by (1)H-magnetic resonance spectroscopy ((1)H-MRS) in different abdominal adipose tissue depots in healthy obese and lean subjects. MATERIALS AND METHODS: Polyunsaturated fatty acids (PUFA), total unsaturated fatty acids (TUFA), triglycerides (TG), and their ratios were determined in three adipose tissue depots of 12 obese and 13 lean subjects. Subjects underwent two separate examinations to assess reproducibility. RESULTS: In lean subjects, 44% of measurements failed due to inclusion of nonadipose tissue in the spectroscopy voxel, as opposed to 23% in obese subjects. Reproducibility of PUFA, TUFA, and TG was moderate to good in obese subjects (intraclass correlation coefficients [ICCs] 0.18-0.75), and poor to moderate in lean subjects (ICCs -1.04-0.55) in subcutaneous and omental adipose tissue. In the perirenal adipose tissue, ICCs were poor in both lean and obese subjects ( 0.794-0.013). PUFA/TUFA and PUFA/TG were higher in omental adipose tissue in obese vs. lean subjects (35*10(-3) vs. 0.16*10(-3), P = 0.01 and 2.05*10(-3) vs. 0.01*10(-3), P = 0.02, respectively). CONCLUSION: (1)H-MRS is a feasible and reproducible method for FFA profiling in abdominal adipose tissue in abdominally obese individuals. (1)H-MRS has potential as diagnostic tool for noninvasive identification of adipose tissue dysfunction. PMID- 24753351 TI - Improving fragment quality for de novo structure prediction. AB - De novo structure prediction can be defined as a search in conformational space under the guidance of an energy function. The most successful de novo structure prediction methods, such as Rosetta, assemble the fragments from known structures to reduce the search space. Therefore, the fragment quality is an important factor in structure prediction. In our study, a method is proposed to generate a new set of fragments from the lowest energy de novo models. These fragments were subsequently used to predict the next-round of models. In a benchmark of 30 proteins, the new set of fragments showed better performance when used to predict de novo structures. The lowest energy model predicted using our method was closer to native structure than Rosetta for 22 proteins. Following a similar trend, the best model among top five lowest energy models predicted using our method was closer to native structure than Rosetta for 20 proteins. In addition, our experiment showed that the C-alpha root mean square deviation was improved from 5.99 to 5.03 A on average compared to Rosetta when the lowest energy models were picked as the best predicted models. PMID- 24753349 TI - Scaffold structure and fabrication method affect proinflammatory milieu in three dimensional-cultured chondrocytes. AB - Cartilage tissue engineering has emerged as an attractive therapeutic option for repairing damaged cartilage tissue in the arthritic joint. High levels of proinflammatory cytokines present at arthritic joints can cause cartilage destruction and instability of the engineered cartilage tissue, and thus it is critical to engineer strong and stable cartilage that is resistant to the inflammatory environment. In this study, we demonstrate that scaffolding materials with different pore sizes and fabrication methods influence the microenvironment of chondrocytes and the response of these cells to proinflammatory cytokines, interleukin-1beta, and tumor necrosis factor alpha. Silk scaffolds prepared using the organic solvent hexafluoroisopropanol as compared to an aqueous-based method, as well as those with larger pore sizes, supported the deposition of higher cartilage matrix levels and lower expression of cartilage matrix degradation-related genes, as well as lower expression of endogenous proinflammatory cytokines IL-1beta in articular chondrocytes. These biochemical properties could be related to the physical properties of the scaffolds such as the water uptake and the tendency to leach or adsorb proinflammatory cytokines. Thus, scaffold structure may influence the behavior of chondrocytes by influencing the microenvironment under inflammatory conditions, and should be considered as an important component for bioengineering stable cartilage tissues. PMID- 24753352 TI - Valve-in-valve implantation of a novel and small self-expandable transcatheter heart valve in degenerated small surgical bioprostheses: the Hamburg experience. AB - BACKGROUND: Transcatheter valve-in-valve (VIV) implantation has emerged as a novel treatment option in patients with degenerated aortic bioprostheses and high surgical risk. However, VIV implantation in small aortic bioprostheses using first generation TAVI devices has frequently resulted in high postprocedural gradients and small effective orifice areas. Recently, an updated version of the self-expandable Medtronic CoreValve prosthesis, which is particularly suitable for small aortic annuli, has become available. We report on the feasibility and early results of VIV implantation using this novel device in a series of patients with degenerated small aortic bioprostheses. METHODS AND RESULTS: 16 patients from two Hamburg hospitals (age range 72-92 years) underwent implantation of a 23 mm CoreValve Evolut (Medtronic, Minneapolis, MN, USA) transcatheter heart valve into failing aortic bioprostheses with internal diameters below 21 mm. All patients were considered high risk for surgical aortic valve replacement after evaluation by an interdisciplinary heart team mean (logistic EuroSCORE range 9.0 88%). Implantation was successful without relevant remaining aortic regurgitation or signs of stenosis and a marked reduction in postprocedural gradientswas observed in 14 out of 16 patients. The mean gradient was reduced from from 34 mm Hg (SEM 10 mm Hg) to 14 mm Hg (SEM 6 mm Hg). No major device- or procedure related adverse events occurred during 30-day follow up and clinical improvement was observed. CONCLUSIONS: Failing aortic bioprostheses with small internal diameters continue to be a challenging pathology for TAVI due to the risk of high residual gradients and small aortic orifice areas. This report provides first evidence that the 23-mm CoreValve Evolut, a novel self-expanding prosthesis, provides an improved treatment option in these specific patients due to its low profile which resulted in promising early results. (c) 2013 Wiley Periodicals, Inc. PMID- 24753353 TI - Gut feelings about smoking and coffee in Parkinson's disease. AB - Strong epidemiologic evidence suggests that smokers and coffee drinkers have a lower risk of Parkinson's disease (PD). The explanation for this finding is still unknown, and the discussion has focused on two main hypotheses. The first suggests that PD patients have premorbid personality traits associated with dislike for coffee-drinking and smoking. The second posits that caffeine and nicotine are neuroprotective. We propose an alternative third hypothesis, in which both cigarette and coffee consumption change the composition of the microbiota in the gut in a way that mitigates intestinal inflammation. This, in turn, would lead to less misfolding of the protein alpha-synuclein in enteric nerves, reducing the risk of PD by minimizing propagation of the protein aggregates to the central nervous system, where they otherwise can induce neurodegeneration. PMID- 24753355 TI - Aza[6]helicene platinum complexes: chirality control of cis-trans isomerism. AB - It was serendipitously observed that cis-[PtCl2(NCEt)PPh3] reacted differently with either racemic or enantiopure 4-aza[6]helicene, giving respectively cis (racemic) and trans (enantiopure) [Pt(II)Cl2(4-aza[6]helicene)PPh3] complexes. This unexpected reactivity is explained through a dynamic process (crystallization-induced diastereoselective transformation) and enables a new aspect of reactivity in chiral transition-metal complexes to be addressed. PMID- 24753354 TI - Tissue engineering red blood cells: a therapeutic. AB - The use of red blood cells (RBCs) in transfusion is widespread in modern medicine. Limitations in blood transfusion have made an urgent argument for the focus on alternatives, as particular medical treatments heavily rely on the supply of donated blood. Stem cells have been successfully used in vitro to produce RBCs and researchers are currently challenged with developing larger scale culture methods to meet the requirements for clinically relevant cell numbers. The ultimate conditions that will be beneficial for this type of research are trivial. A successful human clinical trial has shown that tremendous progress has already been made in this field. Other alternatives are based on the oxygen carrier protein that RBCs contain, i.e. haemoglobin (Hb). Chemically defined molecules and crosslinked proteins, which are able to bind and transport oxygen, have been found to be functional in vivo. Major progress has been achieved, but developing highly suitable products for the transfusion market still remains an enormous challenge for these acellular blood substitutes. We provide a review about developing alternatives for blood transfusion, with the emphasis on tissue-engineering approaches. PMID- 24753356 TI - Monitoring cotton bollworm resistance to Cry1Ac in two counties of northern China during 2009-2013. AB - BACKGROUND: Transgenic cotton that expresses a gene derived from the bacterium Bacillus thuringiensis (Bt) has been deployed for combating cotton bollworm in China since 1997. As a follow-up on research started in 2002, the quantitative shifts in larval Cry1Ac resistance of field Helicoverpa armigera populations were monitored from 2009-2013 using bioassays of isofemale lines. RESULTS: A total of 2837 lines from Xiajin and 2055 lines from Anci were screened for growth rate on normal artificial diet and on a diet containing 1.0 ug mL(-1) of Cry1A(c) toxin. In 2009-2013, the mean relative average development rates (RADRs) of H. armigera larvae in the Xiajin population were 0.62, 0.59, 0.59, 0.58 and 0.62 respectively, and in the Anci population 0.54, 0.58, 0.60, 0.53 and 0.62 respectively. CONCLUSIONS: Compared with previous results in 2002, there was an increase in the RADR of H. armigera during 2009-2013, with ratios of 1.53-1.63 and 1.77-2.07 in the respective Xiajin and Anci populations, suggesting that resistance to Cry1Ac has increased in H. armigera populations in northern China. PMID- 24753357 TI - Undermining optimistic denial reactions to domestic and campus emergency warning messages. AB - BACKGROUND: Individuals who prepare for public emergencies can mitigate the effects of an incident, but denial of personal susceptibility may reduce the likelihood of preparation. Some denial may be due to a positive self-image that is at odds with being "at risk". The potential for an enhanced warning message that included a positive image of a protector to circumvent this denial was tested in two studies. METHODS: Optimistic denial threat orientation was measured. Then participants received either a traditional or a positive protector warning message about terrorism (Study 1; nationally representative sample of US adults; N = 587) or campus emergency preparation (Study 2; US college students; N = 179). RESULTS: As predicted, in the enhanced image condition optimistic denial was no longer related to stronger denial reactions and lower intentions to protect oneself. In addition, Study 2 tested explanatory mediators and found that negative perceptions of and low similarity to a protector partially explained the denial of those higher in optimistic denial and why their denial was dampened in the positive image condition. CONCLUSIONS: An enhanced message including a positive image of protector may be an effective way to encourage protection for those prone to optimistic denial. PMID- 24753358 TI - Hippocampal control of repetition effects for associative stimuli. AB - Recent findings suggest that repetition effects interact with episodic memory processes that are putatively supported by the hippocampus. Thus, the formation or refinement of episodic memories may be related to a modulating signal from the hippocampus to the neocortex which leads to sparser or more extended stimulus representations (repetition suppression or enhancement), depending on the type of stimulus and the brain site. This framework suggests that hippocampal activity during the initial presentation of a stimulus correlates with the magnitude of repetition effects. Here, we tested this hypothesis in an fMRI study in which associations between faces and buildings were presented twice. BOLD responses showed repetition suppression in fusiform face area (FFA) and parahippocampal place area (PPA), most likely due to a refinement of existing category representations. Hippocampal activity during the first presentations was correlated with the amount of repetition suppression, in particular in the FFA. Repetition enhancement effects were observed on BOLD responses in posterior parietal cortex, possibly related to the formation of new representations of associative stimuli. The magnitude of parietal BOLD repetition effects depended on successful memory formation. These findings suggest that both repetition enhancement and repetition suppression effects are influenced by a modulating signal from the hippocampus. PMID- 24753359 TI - Increase in IkappaB kinase alpha expression suppresses the tumor progression and improves the prognosis for nasopharyngeal carcinoma. AB - Recent studies have suggested that the action of IkappaB kinase alpha (IKKalpha) as a tumor suppressor is crucial in the development of skin carcinoma, but its role in nasopharyngeal carcinoma (NPC) remains unknown. We examined the IKKalpha expression in specimens from 157 NPC patients by immunohistochemistry and analyzed the effect of IKKalpha on prognosis. The functional significance of IKKalpha expression in NPC cell lines was investigated by IKKalpha overexpression or downregulation in in vitro studies. The in vitro assays revealed that the IKKalpha expression was negatively correlated with the invasiveness, migration, and angiogenesis of NPC cells. Overexpression or downregulation of IKKalpha could significantly repress or enhance the above characteristics, respectively, and these effects were independent of IKKalpha kinase or EBNA1. In 157 NPC cases, IKKalpha was differentially expressed in NPC tissues. High expression of IKKalpha was associated significantly with a high disease-free survival (DFS; P = 0.002) or overall survival (OS; P = 0.014). Multivariate analyses showed that the IKKalpha expression was an independent risk factor for DFS (HR, 2.302; P = 0.011) and OS (HR, 3.578; P = 0.006). Our findings indicated that IKKalpha plays a crucial role as a tumor suppressor that suppresses the invasion, metastasis, and angiogenesis of NPC cells in vitro and correlates with the survival in NPC patients. Therefore, IKKalpha is not only a novel independent prognostic indicator in NPC, but also targeting IKKalpha expression may provide a potential therapeutic strategy for NPC. PMID- 24753360 TI - Bioreducible carboxymethyl dextran nanoparticles for tumor-targeted drug delivery. AB - Bioreducible carboxymethyl dextran (CMD) derivatives are synthesized by the chemical modification of CMD with lithocholic acid (LCA) through a disulfide linkage. The hydrophobic nature of LCA allows the conjugates (CMD-SS-LCAs) to form self-assembled nanoparticles in aqueous conditions. Depending on the degree of LCA substitution, the particle diameters range from 163 to 242 nm. Doxorubicin (DOX), chosen as a model anticancer drug, is effectively encapsulated into the nanoparticles with high loading efficiency (>70%). In vitro optical imaging tests reveal that the fluorescence signal of DOX quenched in the bioreducible nanoparticles is highly recovered in the presence of glutathione (GSH), a tripeptide capable of reducing disulfide bonds in the intracellular compartments. Bioreducible nanoparticles rapidly release DOX when they are incubated with 10 mm GSH, whereas the drug release is greatly retarded in physiological buffer (pH 7.4). DOX-loaded bioreducible nanoparticles exhibit higher toxicity to SCC7 cancer cells than DOX-loaded nanoparticles without the disulfide bond. Confocal laser scanning microscopy observation demonstrate that bioreducible nanoparticles can effectively deliver DOX into the nuclei of SCC7 cells. In vivo biodistribution study indicates that Cy5.5-labeled CMD-SS-LCAs selectively accumulate at tumor sites after systemic administration into tumor-bearing mice. Notably, DOX-loaded bioreducible nanoparticles exhibit higher antitumor efficacy than reduction-insensitive control nanoparticles. Overall, it is evident that bioreducible CMD-SS-LCA nanoparticles are useful as a drug carrier for cancer therapy. PMID- 24753361 TI - Distribution of anticoagulant rodenticide resistance in Rattus norvegicus in the Netherlands according to Vkorc1 mutations. AB - BACKGROUND: Rodenticide resistance to anticoagulants in Rattus norvegicus will lead to increased difficulties in combating these pest animals. Here, the authors present the results of a survey in the Netherlands where tissue samples and droppings were tested using a newly developed TaqMan PCR test for genotypic variation at codon 139 in the Vkorc1 gene associated with anticoagulant rodenticide resistance. Test results are linked to results of a questionnaire that was conducted among pest controllers. RESULTS: Genetic mutations at codon 139 of the Vkorc1 gene in R. norvegicus can be encountered in many parts of the Netherlands. In 34/61 rat tails, a genotype was found that is linked to anticoagulant rodenticide resistance (56%). In droppings, 42/169 samples (25%) showed a resistance-mediating genotype. In addition, indications of a clear genetic substructure in the Netherlands were found. In some regions, only resistance-mediating genotypes were found, corroborating results from the questionnaire in which pest controllers indicated they suspected resistance to anticoagulant rodenticides. CONCLUSION: This is the first study to demonstrate the presence of multiple genetic mutations at codon 139 of the Vkorc1 gene in R. norvegicus in the Netherlands. As rodenticides should keep their efficacy because they are a last resort in rodent management, more studies are urgently needed that link specific genetic mutations to the efficacy of active substances. PMID- 24753362 TI - Viscoelastic properties of collagen-adhesive composites under water-saturated and dry conditions. AB - To investigate the time- and rate-dependent mechanical properties of collagen adhesive composites, creep and monotonic experiments are performed under dry and wet conditions. The composites are prepared by infiltration of dentin adhesive into a demineralized bovine dentin. Experimental results show that for small stress level under dry conditions, both the composite and the neat adhesive have similar behavior. On the other hand, in wet conditions, the composites are significantly soft and weak compared to the neat adhesives. The behavior in the wet condition is found to be affected by the hydrophilicity of both the adhesive and the collagen. As the adhesive-collagen composites are a part of the complex construct that forms the adhesive-dentin interface, their presence will affect the overall performance of the restoration. We find that Kelvin-Voigt model with at least four elements is required to fit the creep compliance data, indicating that the adhesive-collagen composites are complex polymers with several characteristic time scales whose mechanical behavior will be significantly affected by loading rates and frequencies. Such mechanical properties have not been investigated widely for these types of materials. The derived model provides an additional advantage that it can be exploited to extract other viscoelastic properties which are, generally, time consuming to obtain experimentally. The calibrated model is utilized to obtain stress relaxation function, frequency dependent storage and loss modulus, and rate-dependent elastic modulus. PMID- 24753363 TI - Using and respecting the dead human body: an anatomist's perspective. AB - In his stimulating article enquiring into what the living owe the dead, Wilkinson (2013, Clin. Anat. DOI: 10.1002/ca.22263) sought to unpack a range of ethical questions of considerable interest to anatomists. In this, he looked closely at the extent to which we are or are not to respect all the prior wishes of the deceased, and the implications of this for the role of the family in providing consent, the use of unclaimed bodies, and the public display of bodies. Some of his conclusions challenge widely encountered views by anatomists. In this response I have re-visited these topics in an attempt to ground his arguments in the experience of anatomists, by emphasizing the many intimate connections that exist between each of these areas. The following emerge as issues for further debate. I accept that the wishes of the deceased are preeminent, so that authorities should make every effort to abide by these. This reiterates the importance of body bequests over against unclaimed bodies, and provides a context for assessing the role of family consent. This has repercussions for all activities employing dead bodies, from the dissecting room to public plastination exhibitions. In determining the extent to which the wishes of the deceased are followed the input of other interested parties is a relevant consideration. An ethical assessment of the public display of bodies needs to take into account the nature of the plastination process. PMID- 24753364 TI - Low-spin pseudotetrahedral iron(I) sites in Fe2(MU-S) complexes. AB - Fe(I) centers in iron-sulfide complexes have little precedent in synthetic chemistry despite a growing interest in the possible role of unusually low valent iron in metalloenzymes that feature iron-sulfur clusters. A series of three diiron [(L3Fe)2(MU-S)] complexes that were isolated and characterized in the low valent oxidation states Fe(II)-S-Fe(II), Fe(II)-S-Fe(I), and Fe(I)-S-Fe(I) is described. This family of iron sulfides constitutes a unique redox series comprising three nearly isostructural but electronically distinct Fe2(MU-S) species. Combined structural, magnetic, and spectroscopic studies provided strong evidence that the pseudotetrahedral iron centers undergo a transition to low-spin S=1/2 states upon reduction from Fe(II) to Fe(I). The possibility of accessing low-spin, pseudotetrahedral Fe(I) sites compatible with S(2-) as a ligand was previously unknown. PMID- 24753365 TI - Effects of recent and past climatic shifts on the genetic structure of the high mountain yellow-spotted ringlet butterfly Erebia manto (Lepidoptera, Satyrinae): a conservation problem. AB - Mountain species have evolved important genetic differentiation due to past climatic fluctuations. The genetic uniqueness of many of these lineages is now at risk due to global warming. Here, we analyse allozyme polymorphisms of 1306 individuals (36 populations) of the mountain butterfly Erebia manto and perform Species Distribution Models (SDMs). As a consensus of analyses, we obtained six most likely genetic clusters: (i) Pyrenees with Massif Central; (ii) Vosges; (iii v) Alps including the Slovakian Carpathians; (vi) southern Carpathians. The Vosges population showed the strongest genetic split from all other populations, being almost as strong as the split between E. manto and its sister species Erebia eriphyle. The distinctiveness of the Pyrenees-Massif Central group and of the southern Carpathians group from all other groups is also quite high. All three groups are assumed to have survived more than one full glacial-interglacial cycle close to their current distributions with up-hill and down-slope shifts conforming climatic conditions. In contrast with these well-differentiated groups, the three groups present in the Alps and the Slovakian Carpathians show a much shallower genetic structure and thus also should be of a more recent origin. As predicted by our SDM projections, rising temperatures will strongly impact the distribution of E. manto. While the populations in the Alps are predicted to shrink, the survival of the three lineages present here should not be at risk. The situation of the three other lineages is quite different. All models predict the extinction of the Vosges lineage in the wake of global warming, and also the southern Carpathians and Pyrenees-Massif Central lineages might be at high risk to disappear. Thus, albeit global warming will therefore be unlikely to threaten E. manto as a species, an important proportion of the species' intraspecific differentiation and thus uniqueness might be lost. PMID- 24753366 TI - Murine neural crest stem cells and embryonic stem cell-derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion. AB - Spinal root avulsion results in paralysis and sensory loss, and is commonly associated with chronic pain. In addition to the failure of avulsed dorsal root axons to regenerate into the spinal cord, avulsion injury leads to extensive neuroinflammation and degeneration of second-order neurons in the dorsal horn. The ultimate objective in the treatment of this condition is to counteract degeneration of spinal cord neurons and to achieve functionally useful regeneration/reconnection of sensory neurons with spinal cord neurons. Here we compare survival and migration of murine boundary cap neural crest stem cells (bNCSCs) and embryonic stem cells (ESCs)-derived, predifferentiated neuron precursors after their implantation acutely at the junction between avulsed dorsal roots L3-L6 and the spinal cord. Both types of cells survived transplantation, but showed distinctly different modes of migration. Thus, bNCSCs migrated into the spinal cord, expressed glial markers and formed elongated tubes in the peripheral nervous system (PNS) compartment of the avulsed dorsal root transitional zone (DRTZ) area. In contrast, the ESC transplants remained at the site of implantation and differentiated to motor neurons and interneurons. These data show that both stem cell types successfully survived implantation to the acutely injured spinal cord and maintained their differentiation and migration potential. These data suggest that, depending on the source of neural stem cells, they can play different beneficial roles for recovery after dorsal root avulsion. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24753367 TI - Dementia behavior management advisory service northern territory pilot program: reaching out to rural communities using technology. PMID- 24753368 TI - Olfactory groove meningioma presenting as pure depression without neurological symptoms. PMID- 24753370 TI - The novel use of a heterozygous knockout mouse for embryofetal development assessment of a glucokinase activator. AB - Glucokinase activators (GKAs), such as AZD1656, are designed as antihyperglycemic agents for diabetics and can cause dose-limiting hypoglycemia in normal animals used in embryofetal development studies. Genetically modified heterozygous GK knockout (gkdel/wt) mice are less susceptible to severe GKA-induced hypoglycemia than wild-type mice due to their elevated baseline glucose levels. In this study, the gkdel/wt mouse was used as an alternative rodent strain for embryofetal development studies with AZD1656. Heterozygous global knockout gkdel/wt females were dosed with 20, 50, or 130 mg/kg/day of AZD1656 or vehicle for a minimum of 14 consecutive days before mating with wild-type males and throughout organogenesis. Maternal effects were confined to slightly reduced food consumption, reduced body weight gain, and the pharmacologic effect of decreased plasma glucose. Fetuses were genotyped. Fetal weights at the high dose were slightly reduced but there was no effect on fetal survival. There were two specificmajormalformations, omphalocele and right-sided aortic arch, with increased fetal incidence in mid- and high-dose fetuses (e.g., omphalocele fetal incidence of 0.6, 0.7, 4.6, and 2% across the dose groups) plus increased incidences of minor abnormalities and variants indicative of either delayed or disturbed development. Fetal weight and abnormalities were unaffected by fetal genotype. The fetal effects are considered hypoglycemia related. There was no effect on embryofetal survival in the gkdel/wt mouse at AZD1656 exposures, which were 70* higher than those causing 75% fetal death in rabbits. This illustrates the value of genetically modified animals in unraveling target versus chemistry related effects. PMID- 24753369 TI - Structural dynamics of the monoamine transporter homolog LeuT from accelerated conformational sampling and channel analysis. AB - The bacterial leucine transporter LeuT retains significant secondary structure similarities to the human monoamine transporters (MAT) such as the dopamine and serotonin reuptake proteins. The primary method of computational study of the MATs has been through the use of the crystallized LeuT structure. Different conformations of LeuT can give insight into mechanistic details of the MAT family. A conformational sampling performed through accelerated molecular dynamics simulations testing different combinations of the leucine substrate and bound sodium ions revealed seven distinct conformational clusters. Further analysis has been performed to target salt-bridge residues R30-D404, Y108-F253, and R5-D369 and transmembrane domains on both the seven isolated structures and the total trajectories. In addition, solvent accessibility of LeuT and its substrate binding pockets has been analyzed using a program for calculating channel radii. Occupation of the Na2 site stabilizes the outward conformation and should bind to the open outward conformation before the leucine and Na1 sodium while two possible pathways were found to be available for intracellular transport. PMID- 24753371 TI - Machine learning in preoperative glioma MRI: survival associations by perfusion based support vector machine outperforms traditional MRI. AB - PURPOSE: To retrospectively evaluate the performance of an automatic support vector machine (SVM) routine in combination with perfusion-based dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for preoperative survival associations in patients with gliomas and compare our results to traditional MRI. MATERIALS AND METHODS: The study was approved by the Ethics Committee and informed consent was signed. Structural, diffusion- and perfusion weighted MRI was performed at 1.5-T preoperatively in 94 adult patients (49 males, 45 females, 23-82 years; mean 51 years) later diagnosed with a primary glioma. Patients were randomly assigned in training and test datasets and the resulting DSC-based survival associations by SVM were compared to traditional MRI features including contrast-agent enhancement, perfusion- and diffusion-weighted imaging, tumor size, and location. The results were adjusted for age, neurological status, and postoperative factors associated with survival, including surgery and adjuvant therapy. RESULTS: For 1- (26/33 alive, 11/14 deceased), 2- (15/21, 21/26), 3- (12/16, 27/31) and 4- (12/15, 28/32) year survival associations in the test dataset (47 patients), the SVM routine was the only biomarker to consistently associate with survival (Cox; P < 0.001). CONCLUSION: The automatic machine learning routine presented in our study may provide the operator with a reliable instrument for assessing survival in patients with glioma. PMID- 24753372 TI - Saphenous vein graft intervention. PMID- 24753373 TI - Integrating omics into the cardiac differentiation of human pluripotent stem cells. AB - Time-dependent extracellular manipulations of human pluripotent stem cells can yield as much as 90% pure populations of cardiomyocytes. While the extracellular control of differentiation generally entails dynamic regulation of well-known pathways such as Wnt, BMP, and Nodal signaling, the underlying genetic networks are far more complex and are poorly understood. Notably, the identification of these networks holds promise for understanding heart disease and regeneration. The availability of genome-wide experimentation, such as RNA and DNA sequencing, as well as high throughput surveying with small molecule and small interfering RNA libraries, now enables us to map the genetic interactions underlying cardiac differentiation on a global scale. Initial studies demonstrate the complexity of the genetic regulation of cardiac differentiation, exposing unanticipated novel mechanisms. However, the large datasets generated tend to be overwhelming and systematic approaches are needed to process the vast amount of data to improve our mechanistic understanding of the complex biology. Systems biology methods spur high hopes for parsing vast amounts of data into genetic interaction models that can be verified experimentally and ultimately yield functional networks that expose the genetic connections underlying biological processes. PMID- 24753374 TI - N-Acyl amino acids and their impact on biological processes. AB - Over the last two decades a large number of N-long-chain acyl amino acids have been identified in the mammalian body. The pharmacological activities of only a few of them have been investigated and some have been found to be of considerable interest. Thus arachidonoyl serine is vasodilatory and neuroprotective, arachidonoyl glycine is antinociceptive, and oleoyl serine rescues bone loss. However, the pathophysiological/biochemical roles of these amides are mostly unknown. PMID- 24753375 TI - Measuring patient flow in a children's hospital using a scorecard with composite measurement. AB - BACKGROUND: Although patient flow is a focus for improvement in hospitals, commonly used single or unaggregated measures fail to capture its complexity. Composite measures can account for multiple dimensions of performance but have not been reported for the assessment of patient flow. OBJECTIVES: To present and discuss the implementation of a composite measure system as a way to measure and monitor patient flow and improvement activities at an urban children's hospital. METHODS: A 5-domain patient flow scorecard with composite measurement was designed by an interdisciplinary workgroup using measures involved in multiple aspects of patient flow. RESULTS: The composite score measurement system provided improvement teams and administrators with a comprehensive overview of patient flow. It captured overall performance trends and identified operational domains and specific components of patient flow that required improvement. DISCUSSION: A patient flow scorecard with composite measurement holds advantages over a single or unaggregated measurement system, because it provides a holistic assessment of performance while also identifying specific areas in need of improvement. PMID- 24753376 TI - Molecular-scale heteroassembly of redoxable hydroxide nanosheets and conductive graphene into superlattice composites for high-performance supercapacitors. AB - Artificial superlattice nanocomposites are successfully prepared by electrostatic heteroassembly of redoxable Co-Al or Co-Ni layered double hydroxide (LDH) nanosheets with graphene. The superlattice electrodes exhibit a high capacity up to ca. 650 F/g, which is approximately 6 times that of pure graphene. The composites are found to be capable of superfast charging and discharging, up to ca. 100 Hz, comparable with the high-power performance of graphene electrodes. PMID- 24753377 TI - Prevalence, severity, and relationships of lung lesions, liver abnormalities, and rumen health scores measured at slaughter in beef cattle. AB - An array of management tools exists within the beef industry to improve animal welfare and productivity; however, the ability to assess the outcomes of these tools is needed. Deficiencies in management commonly manifest as bovine respiratory disease complex or nutritional disorders such as acidosis; therefore, lung, liver, and rumen gross pathology lesions present at slaughter were measured as part of the Harvest Audit Program (HAP) and associations with performance determined. Individual gross pathology data from 19,229 cattle at commercial packing plants in Kansas and Texas were collected. Corresponding individual preharvest and carcass data were obtained on a subset of 13,226 cattle. Associations between lesions and performance were modeled using multivariable mixed effect models. Regression coefficients were used for estimation of lesion associative effects on continuous outcomes and odds ratios for dichotomous outcomes. Across the entire population, 67.3% of the cattle had no pulmonary lesions; 22.5 and 9.8% of cattle displayed mild and severe lesions, respectively. Severe pulmonary lesions were associated with a decreased ADG of 0.07 kg and a HCW 7.1 kg less than cohorts with no pulmonary lesions (P < 0.01). Overall, 68.6% of cattle observed had normal livers. Of cattle severely affected by liver abscesses (A+; 4.6%), 14.9% also displayed severe pulmonary lesions and 28.3% displayed mild pulmonary lesions. Rumenitis lesions were observed in 24.1% of the overall study population. Of cattle with mildly abscessed livers (A-), moderately abscessed livers (A), and severely abscessed livers, 20.6, 21.6, and 9.24% displayed mild or severe rumenitis lesions at slaughter. Severe rumenitis lesions were associated with a significant decrease in ADG and HCW (0.025 and 2.20 kg, respectively; P < 0.001). Although the majority of the cattle in this population would be considered low risk, after adjustments for cattle with multiple lesions, 22.9% of cattle in the overall population were observed with a severe lesion (lung, liver, or rumen). In conclusion, a gross pathology monitoring system is feasible and the 22.9% prevalence of severe lesions (lung, liver, or rumen) indicates that significant opportunity exists to improve beef cattle health, well being, and productivity. Data generated using HAP may be used to support decisions concerning the implementation or removal of managerial practices and health interventions in beef cattle production systems. PMID- 24753378 TI - Milk yield and composition from Angus and Angus-cross beef cows raised in southern Brazil. AB - This study assessed milk yield and composition of Angus and Angus-cross beef cows raised in southern Brazil. A total of 128 records were collected in 2 consecutive calving seasons from cows between 3 and 5 yr of age of 4 breed compositions: Angus (ANAN), Caracu * Angus (CRAN), Hereford * Angus (HHAN), and Nelore * Angus (NEAN). These cows were mated to Brangus (BN) or Braford (BO) bulls and managed under extensive grazing conditions in southern Brazil. Milk production of these cows was assessed by 2 procedures: indirectly by the calf weigh-suckle-weigh procedure (WD) and directly by machine milking (MM). Lactation curves were estimated using nonlinear regression and the following related traits were derived: peak yield (PY), peak week (PW), total yield at 210 d (TY210), and lactation persistence (PERS). Milk composition and calf weaning weight adjusted to 210 d (WW210) were also determined. The MM technique was considered more accurate because of lower standard errors of estimated means, greater statistical power, and greater correlation between TY210 and WW210 (0.50) compared to WD (0.36). Considering the more precise evaluation by MM, the CRAN and NEAN cows had greater TY210 (1070 and 1116 kg, respectively) and PY (8.1 and 7.8 kg, respectively) compared to ANAN and HHAN cows, which had 858 and 842 kg for TY210 and 6.6 and 6.3 kg for PY, respectively. The NEAN cows had the latest PW at 10.8 wk. Late-calving cows had 21% lower TY210 compared to cows that calved earlier. Milk composition was influenced by cow genotype, with CRAN and NEAN cows producing milk with greater fat (3.8 and 3.9%, respectively) and protein (3.2 and 3.1%, respectively) content compared to ANAN and HHAN cows. Regardless of the genotype, fat, protein, and total solids increased in concentration from beginning to end of lactation, while lactose content decreased. Crossbreeding of Angus with adapted breeds of taurine or indicine origin can be effective in increasing milk yield and nutrient content and, consequently, producing heavier calves at weaning under extensive grazing in southern Brazil and other similar subtropical climate regions. PMID- 24753379 TI - Evaluation of Columbia, USMARC Composite, Suffolk, and Texel rams as terminal sires in an extensive rangeland production system: VII. Accuracy of ultrasound predictors and their association with carcass weight, yield, and value. AB - Use of lamb BW or chilled carcass weights (CCW), live-animal ultrasound or direct carcass measurements of backfat thickness (BF; mm) and LM area (LMA; cm(2)), and carcass body wall thickness (BWall; mm) to predict carcass yield and value was evaluated using 512 crossbred lambs produced over 3 yr by mating Columbia, U.S. Meat Animal Research Center Composite, Suffolk, and Texel rams to adult Rambouillet ewes. Lambs were harvested at 3 BW endpoints within each year. The predictive value of 3 to 5 additional linear measurements of live-animal or carcass size and shape was also evaluated. Residual correlations (adjusted for effects of year, breed, and harvest group) between ultrasound and direct measurements were 0.69 for BF and 0.65 for LMA. Increasing ultrasound or carcass LMA had positive effects (P < 0.001) on yield of chilled carcass (i.e., on dressing percentage) and, at comparable CCW, on weight of high-value cuts (rack, loin, leg, and sirloin) before trimming (HVW), weight of trimmed high-value cuts (trimmed rack and loin and trimmed boneless leg and sirloin; TrHVW), and carcass value before (CVal) and after (TrCVal) trimming of high-value cuts. By contrast, ultrasound and direct measures of BF had positive effects on yields of CCW and on HVW and CVal but large negative effects on TrHVW and TrCVal. After adjusting for BW at scanning, increases of 1 mm in ultrasound BF or 1 cm(2) in ultrasound LMA were associated with changes of US$-0.32 (P < 0.10) and $1.62 (P < 0.001), respectively, in TrCVal. Carcass BWall was generally superior to carcass BF as a predictor of TrHVW and TrCVal. Carcass LMA was superior to ultrasound LMA but carcass BF was inferior to ultrasound BF for prediction of carcass yield and value. Increasing LMA thus would be expected to improve carcass yield and value. Addition of linear measurements of live-animal or carcass size and shape to the prediction model reduced residual SD (RSD) for TrHVW and TrCVal by 0.4 to 2.2%, but subsequent removal of ultrasound or direct measures of BF and LMA from the prediction model increased RSD by 7.4 to 12.2%. Measurements of CCW, LMA, BF, and BWall would thus be appropriate to support programs for value-based marketing of lamb carcasses and are superior to systems based only on measurements of size and shape in unribbed carcasses. PMID- 24753380 TI - Electronic bolus design impacts on administration. AB - Electronic identification of animals has become increasingly important worldwide to improve and ensure traceability. In warm and hot climates, such as Brazil, boluses can have advantages over ear tags as the internal devices reduce the risks of ear tag losses, tissue damage, and lesions on the ear. Electronic boluses, however, are often perceived as having negative characteristics, including reported difficulties of administration in small ruminants. This paper describes the factors associated with bolus design that affect the swallowing of a bolus in sheep. Other factors that might influence bolus swallowing time have also been considered. In addition, the effect of bolus design on its performance was evaluated. A total of 56 Suffolk ewes were used to assess the ease of administration and retention of 3 types of electronic ruminal boluses (mini, 11.5 * 58.0 mm and 21.7 g; small, 14.8 * 48.5 mm and 29.5 g; standard, 19.3 * 69.8 mm and 74.4 g) during a whole productive year, including pregnancy and lamb suckling. Ewe age (5.6 +/- 2.3 yr) and weight (85.07 +/- 8.2 kg BW) were recorded, as well as time for bolus swallowing. The deglutition of the bolus and any resulting blockages in the esophagus were monitored by visual observations. Retention and readability of the boluses were regularly monitored for d 1, wk 1, mo 1, and every mo until 1 yr. Time for bolus swallowing differed substantially with bolus type and was greater (P < 0.05) for the standard bolus (32.8 +/- 6.9 s) when compared to small and mini boluses, which did not differ (8.5 +/- 2.0 vs. 9.2 +/- 2.7 s; P > 0.05). The bolus o.d. and length were positively correlated with swallowing time (P < 0.01). The ewe weight was negatively correlated with swallowing time (P < 0.05). At 6 mo all electronic boluses showed 100% retention rate, and at 12 mo, bolus retention was 100%, 94.5%, and 100% for mini, small, and standard boluses, respectively (P > 0.05). At 12 mo, all boluses showed 100% readability, except for small boluses, which had a readability of 94.5%. In conclusion, bolus design affected swallowing time and bolus readability. A reduction in boluses length and o.d. needs to be carried out to provide ease of administration and for boluses to be used as an effective means of electronic identification. Therefore, this study shows that adequately designed boluses are safe and suitable for identifying adult sheep and can therefore be used in hot climates. PMID- 24753381 TI - Impact of a leptin single nucleotide polymorphism and ractopamine hydrochloride on growth and carcass characteristics in finishing steers. AB - A total of 2,958 steers (mean initial BW = 549.6 +/- 3.88 kg) were used to test for the interactive effects, of leptin R25C genotypes (CC, CT, or TT) and feeding of ractopamine hydrochloride (RH) on growth performance and carcass traits. Before application of the drug, steers were blocked by arrival at the feed yard, genotyped for the leptin SNP, allotted to genotype-specific pens, and assigned randomly within genotype and block to 0 or 28 d of dietary RH. All pens within a block were slaughtered on the same day. Final BW of steers fed RH was 9.1 kg heavier (P < 0.001), and RH-fed steers had greater (P < 0.001) ADG and greater (P = 0.001) HCW than steers not fed RH. Feeding RH did not (P = 0.723) affect DMI but it did increase (P = 0.001) with increased frequency of the T allele (8.62, 8.70, and 8.82 kg/d for CC, CT, and TT, respectively). Consistent with the effect of leptin on DMI, increased frequency of the T allele also positively affected 12th rib fat (P = 0.001) and empty body fat (P = 0.001). Regardless of RH-feeding duration, TT steers produced a greater (P = 0.001) percentage of USDA yield grade (YG) 4 or higher carcasses (6.46 vs. 2.98%) and a lesser (P = 0.023) percentage of YG 1 carcasses (16.0 vs. 21.9%) than CC steers. In addition, RH-fed steers produced a lesser (P = 0.034) percentage of USDA YG 4 or higher carcasses (3.70 vs. 5.31%) and a lesser percentage (P = 0.019) of USDA Choice or higher carcasses (57.5 vs. 62.5%) than steers fed the control diet. Results indicated that leptin R25C genotype impacted most traits associated with fatness, whereas feeding RH for 28 d affected HCW and ADG positively but impacted marbling and USDA quality grades negatively. PMID- 24753382 TI - Effects of alternate-day feeding of dried distiller's grain plus solubles to forage-fed beef cows in mid- to late gestation. AB - Forty-six nonlactating beef cows were used to examine effects of dried distiller's grains plus solubles (DG) supplementation strategies to cows fed grass hay during mid- to late gestation on BW, ultrasound body composition characteristics, concentrations of serum NEFA and urea, feeding behavior, and calf birth weight. Cows were assigned to dietary treatments in a completely randomized design: 1) control, where hay was fed each day of the week (CON), 2) both hay and DG fed daily during the week (DG7), 3) hay fed daily but DG fed 3 d of the week (DG3), and 4) hay fed 4 d of the week alternating with DG fed on the remaining 3 d (DGA). Hay was offered ad libitum on days it was fed. The DG were fed at 0.40% of BW when offered daily and 0.93% of BW when offered 3 d per week (Monday, Wednesday, and Friday). Feed intake was monitored continuously over the 84-d feeding period. Hay intake and total DMI were reduced (P < 0.05) in DGA compared with DG7 and DG3. Gain and G:F were decreased (P < 0.05) for CON compared with other treatments. No differences (P > 0.05) were observed among treatments for change in BCS, intramuscular fat, rib fat, or rump fat from d 1 to 84. On a day when DG7, DG3, and DGA all received DG (Friday), DGA had reduced (P < 0.05) concentrations of urea compared with DG3 and DG7. On a day when only DG7 received DG (Saturday), urea was greater (P < 0.01) for DG3 and DGA compared with DG7, and concentrations of NEFA were greater (P < 0.01) in CON and DGA compared with DG7. On the second consecutive day when only DG7 received DG (Sunday), concentrations of NEFA were less (P < 0.001) for DG7 compared with other treatments. On days when all cows received hay, DGA spent more time eating (P < 0.05) compared with DG7 and DG3. Cows fed DGA had greater (P < 0.05) hay intake per meal and time per meal compared with other treatments. On days when DG7, DG3, and DGA all received DG, cows in the DG3 and DGA treatments had greater (P < 0.05) number of DG meals, time spent eating, intake per meal, and time per meal but a slower (P < 0.05) rate of DG intake compared with DG7. No differences (P > 0.05) were observed in calf birth weights among treatments. The alternate-day feeding strategy reduced hay and total intake, altered concentrations of serum urea and NEFA, and altered feeding behavior compared with other supplementation methods. PMID- 24753383 TI - Relative availability of zinc in ground beef and soybean protein for young swine compared with zinc carbonate as the standard. AB - The experimental objective was to determine the relative availability of endogenous Zn in soybean protein (SP) and cooked ground beef (GB) compared with the availability of Zn from ZnCO(3) for young swine. Crossbred pigs (4 trials with total n = 104) were weaned at an average age of 11 d, placed in metabolism cages, and allotted to 13 treatments. The basal semipurified negative control (NC) diet contained 2 mg of Zn/kg and wet-autoclaved spray-dried egg albumen (AEA) as the protein source. Reference diets were made by adding 3, 6, or 9 mg of Zn/kg from ZnCO(3) to the NC diet. The AEA in the NC diet was replaced with SP or GB to make diets with 3, 6, and 9 mg of Zn/kg from SP and GB. Positive control (PC) diets were made by adding 101 mg of Zn/kg from ZnCO(3) to the diets with 9 mg of Zn/kg from ZnCO(3), SP, or GB. Diets were mixed with deionized water and fed to appetite in gruel form every 3 h from 0800 to 2300 h. Pigs were weighed and blood samples were taken on d 7, 14, 21, and 28. Plasma concentrations of Cu, Fe, Zn, glucose, and urea N were determined. Total urine and fecal grab samples (Cr(2)O(3) in diets) were collected from d 7 to 14 and d 21 to 28 to determine Cu, Fe, Zn, and N apparent balance and energy utilization. On d 29, pigs were scored visually for parakeratosis and dosed orally with (65)Zn from ZnCl(2). Pigs were counted for whole body gamma radioactivity on d 29 and d 34 to 36, with Zn retention estimated by extrapolation to zero time. Pigs were killed on d 36 (NC on d 29). Samples of skin, tongue, and esophagus were taken for histological evaluation, and a tibia bone was excised for measurements and breaking strength. Pigs fed the diets with 9 mg Zn/kg from GB or ZnCO(3) were not different in Zn availability and retained about 70% Zn (apparent balance and (65)Zn) compared with 30% (P <= 0.05) for pigs fed the diet with 9 mg Zn/kg from SP. Also, pigs fed the diets with 9 mg Zn/kg from GB or ZnCO(3) had greater (P <= 0.05) growth performance, bone weight and breaking strength, % N retention, and % ME utilization, and smaller plasma urea N concentrations and parakeratosis scores (visual and histological) than pigs fed the diet with 9 mg Zn/kg from SP. Pigs fed the PC diets were not different in any response criteria. In conclusion, apparent Zn availability was not different from cooked GB and ZnCO(3), and Zn availability from cooked GB and ZnCO(3) was markedly greater than Zn availability from SP for young swine. PMID- 24753384 TI - Evaluation of bull prolificacy on commercial beef cattle ranches using DNA paternity analysis. AB - SNP-based DNA testing was used to assign paternity to 5,052 calves conceived in natural service multisire breeding pastures from 3 commercial ranches in northern California representing 15 calf crops over 3 yr. Bulls present for 60 to 120 d at a 25:1 cow to bull ratio in both fall and spring breeding seasons in ~40 ha or smaller fenced breeding pastures sired a highly variable (P < 0.001) number of calves (Ncalf), ranging from 0 (4.4% of bulls present in any given breeding season) to 64 calves per bull per breeding season, with an average of 18.9 +/- 13.1. There was little variation in Ncalf among ranches (P = 0.90), years (P = 0.96), and seasons (P = 0.94). Bulls varied widely (P < 0.01) in the average individual 205-d adjusted weaning weight (I205) of progeny, and I205 varied between years (P < 0.01) and seasons (P < 0.01) but not ranches (P = 0.29). The pattern for cumulative total 205-d adjusted weaning weight of all progeny sired by a bull (T205) was highly correlated to Ncalf, with small differences between ranches (P = 0.35), years (P = 0.66), and seasons (P = 0.20) but large differences (P < 0.01) between bulls, ranging from an average of 676 to 8,838 kg per bull per calf crop. The peak Ncalf occurred at about 5 yr of age for bulls ranging from 2 to 11 yr of age. Weekly conception rates as assessed by date of calving varied significantly and peaked at wk 3 of the calving season. The distribution of calves born early in the calving season was disproportionately skewed toward the highly prolific bulls. The DNA paternity testing of the subset of those calves born in wk 3 of the calving season was highly predictive of overall bull prolificacy and may offer a reduced-cost DNA-based option for assessing prolificacy. Prolificacy of young bulls in their first breeding season was positively linearly related (P < 0.05) to subsequent breeding seasons, explaining about 20% of the subsequent variation. Prolificacy was also positively linearly related (P < 0.05) to scrotal circumference (SC) EPD for Angus bulls that had SC EPD Beef Improvement Federation accuracies greater than 0.05. Varying prolificacy of herd bulls has implications for the genetic composition of replacement heifers, with the genetics of those bulls siring an increased number of calves being disproportionately represented in the early-born replacement heifer pool. PMID- 24753386 TI - Informal care and caregiver's health. AB - This study aims to measure the causal effect of informal caregiving on the health and health care use of women who are caregivers, using instrumental variables. We use data from South Korea, where daughters and daughters-in-law are the prevalent source of caregivers for frail elderly parents and parents-in-law. A key insight of our instrumental variable approach is that having a parent-in-law with functional limitations increases the probability of providing informal care to that parent-in-law, but a parent-in-law's functional limitation does not directly affect the daughter-in-law's health. We compare results for the daughter-in-law and daughter samples to check the assumption of the excludability of the instruments for the daughter sample. Our results show that providing informal care has significant adverse effects along multiple dimensions of health for daughter-in-law and daughter caregivers in South Korea. PMID- 24753387 TI - Response to O'Reilly et al. (2014). PMID- 24753388 TI - Minimizing fucosylation in insect cell-derived glycoproteins reduces binding to IgE antibodies from the sera of patients with allergy. AB - The baculovirus/insect cell system has proven to be a very powerful tool for the expression of several therapeutics. Nevertheless, these products sometimes suffer from reduced biological activity and unwanted side effects. Several studies have demonstrated that glycosylation can greatly influence the structure, function, half-life, antigenicity and immunogenicity of various glycoproteins. Yet, the glycosylation pattern of insect cell-derived products is not favorable for many applications. Especially, the presence of core alpha1,3-linked fucose bears the risk of causing immediate hypersensitivity reactions in patients with allergy. In this study, we evaluated the impact of fucose residues on the allergenic potential of an insect cell-expressed vaccine candidate. In order to block the GDP-L-fucose de novo synthesis pathway, we integrated the Pseudomonas aeruginosa GDP-6-deoxy-D-lyxo-4-hexulose reductase (RMD) gene into a baculovirus backbone. This virus was then used for the expression of soluble influenza A virus hemagglutinin (HA). Expression studies showed that the co-expression of RMD did not influence the overall level of recombinant protein secretion. We confirmed the result of our strategy by analyzing PNGase A-released N-glycans using MALDI TOF-MS. In order to evaluate the biological impact of defucosylation of influenza HA we tested the binding activity of IgE derived from the sera of patients with allergy to the purified antigen. The non-fucosylated HA showed a 10-fold decrease in IgE binding levels as compared to wildtype variants. PMID- 24753389 TI - Survey on whiteflies and their parasitoids in cassava mosaic pandemic areas of Tanzania using morphological and molecular techniques. AB - BACKGROUND: Bemisia tabaci (Gennadius) is the vector of cassava mosaic geminiviruses (CMGs) and cassava brown streak viruses (CBSVs) in Africa, which cause devastating yield losses. As a prerequisite to developing biological control methods and enhancing knowledge of the fauna of whitefly parasitoids in sub-Saharan Africa, endemic parasitoids were surveyed in the cassava-growing regions of Tanzania and analysed using both morphological and molecular methods. An attempt was made to corroborate the identification of the parasitoid species on the basis of consideration of their morphology and sequence analyses of three DNA fragments, namely partial cytochrome oxidase I (COI), the D2 expansion segment of the 28S rRNA and the internal transcribed spacer I (ITS1). RESULTS: Eight whitefly species colonising cassava and twelve species of parasitoids were detected. A species in the Encarsia strenua group and a species in the Eretmocerus mundus group were the most common parasitoids. Molecular systematics indicated the occurrence of two new species of Eretmocerus Haldeman parasitising B. tabaci. CONCLUSION: The accurate identification of natural enemies is an essential first step in developing effective biological control solutions for B. tabaci in Tanzania and the wider cassava-growing environments of Africa. The new data provided here represent an important contribution to this goal. PMID- 24753390 TI - Delivering stem cells to the healthy heart on biological sutures: effects on regional mechanical function. AB - Current cardiac cell therapies cannot effectively target and retain cells in a specific area of the heart. Cell-seeded biological sutures were previously developed to overcome this limitation, demonstrating targeted delivery with > 60% cell retention. In this study, both cell-seeded and non-seeded fibrin-based biological sutures were implanted into normal functioning rat hearts to determine the effects on mechanical function and fibrotic response. Human mesenchymal stem cells (hMSCs) were used based on previous work and established cardioprotective effects. Non-seeded or hMSC-seeded sutures were implanted into healthy athymic rat hearts. Before cell seeding, hMSCs were passively loaded with quantum dot nanoparticles. One week after implantation, regional stroke work index and systolic area of contraction (SAC) were evaluated on the epicardial surface above the suture. Cell delivery and retention were confirmed by quantum dot tracking, and the fibrotic tissue area was evaluated. Non-seeded biological sutures decreased SAC near the suture from 0.20 +/- 0.01 measured in sham hearts to 0.08 +/- 0.02, whereas hMSC-seeded biological sutures dampened the decrease in SAC (0.15 +/- 0.02). Non-seeded sutures also displayed a small amount of fibrosis around the sutures (1.0 +/- 0.1 mm2 ). Sutures seeded with hMSCs displayed a significant reduction in fibrosis (0.5 +/- 0.1 mm2 , p < 0.001), with quantum dot labelled hMSCs found along the suture track. These results show that the addition of hMSCs attenuates the fibrotic response observed with non-seeded sutures, leading to improved regional mechanics of the implantation region. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24753391 TI - Carbon nanotube composites as multifunctional substrates for in situ actuation of differentiation of human neural stem cells. PMID- 24753392 TI - Trophic-level dependent effects on CO2 emissions from experimental stream ecosystems. AB - Concern over accelerating rates of species invasions and losses have initiated investigations into how local and global changes to predator abundance mediate trophic cascades that influence CO2 fluxes of aquatic ecosystems. However, to date, no studies have investigated how species additions or losses at other consumer trophic levels influence the CO2 flux of aquatic ecosystems. In this study, we added a large predatory stonefly, detritivorous stonefly, or grazer tadpole to experimental stream food webs and over a 70-day period quantified their effects on community composition, leaf litter decomposition, chlorophyll-a concentrations, and stream CO2 emissions. In general, streams where the large grazer or large detritivore were added showed no change in total invertebrate biomass, leaf litter loss, chlorophyll-a concentrations, or stream CO2 emissions compared with controls; although we did observe a spike in CO2 emissions in the large grazer treatment following a substantial reduction in chlorophyll-a concentrations on day 28. However, the large grazer and large detritivore altered the community composition of streams by reducing the densities of other grazer and detritivore taxa, respectively, compared with controls. Conversely, the addition of the large predator created trophic cascades that reduced total invertebrate biomass and increased primary producer biomass. The cascading effects of the predator additions on the food web ultimately led to decreased CO2 emissions from stream channels by up to 95%. Our results suggest that stream ecosystem processes were more influenced by changes in large predator abundance than large grazer or detritivore abundance, because of a lack of functionally similar large predators. Our study demonstrates that the presence/absence of species with unique functional roles may have consequences for the exchange of CO2 between the ecosystem and the atmosphere. PMID- 24753393 TI - Transcatheter closure of sinus venosus atrial septal defect with anomalous drainage of right upper pulmonary vein into superior vena cava--an innovative technique. AB - Sinus venosus atrial septal defect (SVASD) is located high in the atrial septum where the right superior vena cava (RSVC) enters the right atrium, and is commonly associated with partial anomalous pulmonary venous return of right upper pulmonary vein (RUPV) into RSVC. Transcatheter closure of such defects has not been described in the literature. We have developed an innovative technique to close this defect by transcatheter means. We present here a 35-year old patient with SVASD and anomalous drainage of RUPV in RSVC in whom we closed the defect along with rerouting of RUPV to left atrium (LA) using a 12 mm * 61 mm adventa V12 covered stent in the RSVC with good outcome. PMID- 24753394 TI - Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas. AB - BACKGROUND: Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. PROCEDURE: Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as >= 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. RESULTS: Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. CONCLUSIONS: Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN. PMID- 24753395 TI - Endocannabinoid signaling and its regulation by nutrients. AB - Diet plays a central role in maintaining health throughout life and a controlled food intake is associated to a reduced risk of certain diseases. A proper diet should include vitamins, minerals, carbohydrates, proteins, and fats that have to be optimally balanced in order to exert their physiological functions. The endogenous ligands of type-1 and type-2 cannabinoid receptors, N-arachidonoyl ethanolamine and 2-arachidonoylglycerol, are arachidonic acid (AA) derivatives whose levels are regulated by the activity of metabolic enzymes, as well as by AA availability. Since the only sources of AA in mammals are diet and the enzymatic production in the liver from shorter-chain essential fatty acids like linoleic acid, it is realistic to hypothesize that endocannabinoid levels might be modulated by fatty acid composition of food. Therefore, in this review we summarize literature data indicating that endocannabinoid levels, and hence their activity at cannabinoid receptors, might be modulated by food composition. We focused our attention on dietary fatty acid content, and on type and esterified form of fatty acids in the different diets. PMID- 24753396 TI - Functional lateralization of the anterior insula during feedback processing. AB - Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self- and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence * attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self-attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self-attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello-thalamic-cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations. PMID- 24753397 TI - Urinary detection of conjugated and unconjugated anabolic steroids by dilute-and shoot liquid chromatography-high resolution mass spectrometry. AB - Anabolic androgenic steroids (AAS) are an important class of doping agents. The metabolism of these substances is generally very extensive and includes phase-I and phase-II pathways. In this work, a comprehensive detection of these metabolites is described using a 2-fold dilution of urine and subsequent analysis by liquid chromatography-high resolution mass spectrometry (LC-HRMS). The method was applied to study 32 different metabolites, excreted free or conjugated (glucuronide or sulfate), which permit the detection of misuse of at least 21 anabolic steroids. The method has been fully validated for 21 target compounds (8 glucuronide, 1 sulfate and 12 free steroids) and 18 out of 21 compounds had detection limits in the range of 1-10 ng mL(-1) in urine. For the conjugated compounds, for which no reference standards are available, metabolites were synthesized in vitro or excretion studies were investigated. The detection limits for these compounds ranged between 0.5 and 18 ng mL(-1) in urine. The simple and straightforward methodology complements the traditional methods based on hydrolysis, liquid-liquid extraction, derivatization and analysis by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). PMID- 24753398 TI - Metal/Semiconductor hybrid nanostructures for plasmon-enhanced applications. AB - Hybrid nanostructures composed of semiconductor and plasmonic metal components are receiving extensive attention. They display extraordinary optical characteristics that are derived from the simultaneous existence and close conjunction of localized surface plasmon resonance and semiconduction, as well as the synergistic interactions between the two components. They have been widely studied for photocatalysis, plasmon-enhanced spectroscopy, biotechnology, and solar cells. In this review, the developments in the field of (plasmonic metal)/semiconductor hybrid nanostructures are comprehensively described. The preparation of the hybrid nanostructures is first presented according to the semiconductor type, as well as the nanostructure morphology. The plasmonic properties and the enabled applications of the hybrid nanostructures are then elucidated. Lastly, possible future research in this burgeoning field is discussed. PMID- 24753399 TI - Blood culture use in the emergency department in patients hospitalized with respiratory symptoms due to a nonpneumonia illness. AB - BACKGROUND: Guidelines and performance measures recommend obtaining blood cultures in selected patients hospitalized with community-acquired pneumonia (CAP). Due to inherent diagnostic uncertainty, there may be spillover effects of these recommendations on other conditions that resemble pneumonia. METHODS: Using data from the 2002 to 2010 National Hospital Ambulatory Medical Care Survey, a nationally representative sample of emergency department (ED) visits in the United States, we analyzed trends in obtaining cultures in patients hospitalized with respiratory symptoms due to a nonpneumonia illness using linear regression. RESULTS: The most common primary admission diagnoses for these visits included heart failure (16%), chronic obstructive pulmonary disease (13%), and chest pain (12%). The proportion of cultures collected in the ED during these visits increased from 10% (95% confidence interval [CI]: 7%-14%) in 2002 to 20% (95% CI: 16%-26%) in 2010 (P<0.001 for the trend). This represented a parallel increase compared to patients hospitalized with CAP (P=0.12 for the difference in trends). CONCLUSIONS: The increase in collecting cultures in the ED in patients hospitalized with respiratory symptoms due to a nonpneumonia illness suggests an important potential unintended consequence of blood culture recommendations for CAP. More attention to the judicious use of blood cultures to reduce harm and costs is needed. PMID- 24753400 TI - Synthesis of a glycopeptide vaccine conjugate for induction of antibodies recognizing O-mannosyl glycopeptides. AB - In spite of the clear importance of protein O-mannosylation in brain glycobiology, tools are lacking for specific detection, enrichment, and identification of proteins containing these modifycations. We envisioned inducing antibodies that specifically recognize O-mannose glycans on proteins and peptides. With this in mind, we prepared a glycopeptide vaccine construct containing the N-acetyllactosamine-extended mannose motif Galbeta1-4GlcNAcbeta1 2ManalphaThr, found as a common core structure on almost all mammalian O-mannosyl glycoproteins identified. O-mannose glycosylated amino acid building blocks and the corresponding glycopeptides were prepared by chemical synthesis and then conjugated to an immune carrier protein. After administration of the synthetic vaccine into rabbits, strong immune responses were obtained. Further evaluation by ELISA neutralization experiments and glycopeptide microarrays showed that the induced antibodies were highly specific to the glycopeptide antigen. PMID- 24753402 TI - The role of persistence in chemical evaluations. AB - The initial stage in the assessment and priority setting of chemicals for their potential to cause harm to humans and the environment is usually a hazard assessment employing metrics for persistence, bioaccumulation, and inherent toxicity. This hazard assessment is followed, when necessary, by the more demanding task of risk assessment. Hazard assessment of data and processes influencing persistence are discussed, leading to a number of suggestions for more effective evaluation. These include 1) an initial focus on accurate data for intensive chemical partitioning and reaction half-life properties that are universally applicable as distinct from extensive properties that can be included later on a location-specific basis; 2) separate treatments of near-field and far field exposures; 3) a focus on persistence and its effect on levels of exposure, especially for substances for which "time to exposure" is less than "time to degradation" and have been termed "pseudo-persistent." We show that "continuously present" is a better descriptor of this concern. Case studies illustrate and support these suggestions. Data on the intensive properties and on exposure pathways are best combined in evaluative multimedia mass balance models that can provide a clear depiction of the likely chemical fate, exposure routes, and levels. The information generated by the mass balance models can serve to justify and direct a full risk assessment that includes region-specific information on chemical quantities, estimates of exposure, and potential for adverse effects. PMID- 24753403 TI - Cas6 specificity and CRISPR RNA loading in a complex CRISPR-Cas system. AB - CRISPR-Cas is an adaptive prokaryotic immune system, providing protection against viruses and other mobile genetic elements. In type I and type III CRISPR-Cas systems, CRISPR RNA (crRNA) is generated by cleavage of a primary transcript by the Cas6 endonuclease and loaded into multisubunit surveillance/effector complexes, allowing homology-directed detection and cleavage of invading elements. Highly studied CRISPR-Cas systems such as those in Escherichia coli and Pseudomonas aeruginosa have a single Cas6 enzyme that is an integral subunit of the surveillance complex. By contrast, Sulfolobus solfataricus has a complex CRISPR-Cas system with three types of surveillance complexes (Cascade/type I-A, CSM/type III-A and CMR/type III-B), five Cas6 paralogues and two different CRISPR repeat families (AB and CD). Here, we investigate the kinetic properties of two different Cas6 paralogues from S. solfataricus. The Cas6-1 subtype is specific for CD-family CRISPR repeats, generating crRNA by multiple turnover catalysis whilst Cas6-3 has a broader specificity and also processes a non-coding RNA with a CRISPR repeat-related sequence. Deep sequencing of crRNA in surveillance complexes reveals a biased distribution of spacers derived from AB and CD loci, suggesting functional coupling between Cas6 paralogues and their downstream effector complexes. PMID- 24753404 TI - RAG2 mutants alter DSB repair pathway choice in vivo and illuminate the nature of 'alternative NHEJ'. AB - DNA double-stranded breaks (DSBs) can be repaired by several mechanisms, including classical NHEJ (c-NHEJ) and a poorly defined, error-prone process termed alternative NHEJ (a-NHEJ). How cells choose between these alternatives to join physiologic DSBs remains unknown. Here, we show that deletion of RAG2's C terminus allows a-NHEJ to repair RAG-mediated DSBs in developing lymphocytes from both c-NHEJ-proficient and c-NHEJ-deficient mice, demonstrating that the V(D)J recombinase influences repair pathway choice in vivo. Analysis of V(D)J junctions revealed that, contrary to expectation, junctional characteristics alone do not reliably distinguish between a-NHEJ and c-NHEJ. These data suggest that a-NHEJ is not necessarily mutagenic, and may be more prevalent than previously appreciated. Whole genome sequencing of a lymphoma arising in a p53(-/-) mouse bearing a C terminal RAG2 truncation reveals evidence of a-NHEJ and also of aberrant recognition of DNA sequences resembling RAG recognition sites. PMID- 24753405 TI - Targeting vertebrate intron-encoded box C/D 2'-O-methylation guide RNAs into the Cajal body. AB - Post-transcriptional pseudouridylation and 2'-O-methylation of splicesomal small nuclear ribonucleic acids (snRNAs) is mediated by box H/ACA and box C/D small Cajal body (CB)-specific ribonucleoproteins (scaRNPs), respectively. The WD repeat protein 79 (WDR79) has been proposed to interact with both classes of modification scaRNPs and target them into the CB. The box H/ACA scaRNAs carry the common CAB box motif (consensus, ugAG) that is required for both WDR79 binding and CB-specific accumulation. Thus far, no cis-acting CB-localization element has been reported for vertebrate box C/D scaRNAs. In this study, systematic mutational analysis of the human U90 and another newly identified box C/D scaRNA, mgU2-47, demonstrated that the CB-specific accumulation of vertebrate intron encoded box C/D scaRNAs relies on GU- or UG-dominated dinucleotide repeat sequences which are predicted to form the terminal stem-loop of the RNA apical hairpin. While the loop nucleotides are unimportant, the adjacent terminal helix that is composed mostly of consecutive G.U and U.G wobble base-pairs is essential for CB-specific localization of box C/D scaRNAs. Co-immunoprecipitation experiments confirmed that the newly identified CB localization element, called the G.U/U.G wobble stem, is crucial for in vivo association of box C/D scaRNPs with WDR79. PMID- 24753406 TI - NuMA promotes homologous recombination repair by regulating the accumulation of the ISWI ATPase SNF2h at DNA breaks. AB - Chromatin remodeling factors play an active role in the DNA damage response by shaping chromatin to facilitate the repair process. The spatiotemporal regulation of these factors is key to their function, yet poorly understood. We report that the structural nuclear protein NuMA accumulates at sites of DNA damage in a poly[ADP-ribose]ylation-dependent manner and functionally interacts with the ISWI ATPase SNF2h/SMARCA5, a chromatin remodeler that facilitates DNA repair. NuMA coimmunoprecipitates with SNF2h, regulates its diffusion in the nucleoplasm and controls its accumulation at DNA breaks. Consistent with NuMA enabling SNF2h function, cells with silenced NuMA exhibit reduced chromatin decompaction after DNA cleavage, lesser focal recruitment of homologous recombination repair factors, impaired DNA double-strand break repair in chromosomal (but not in episomal) contexts and increased sensitivity to DNA cross-linking agents. These findings reveal a structural basis for the orchestration of chromatin remodeling whereby a scaffold protein promotes genome maintenance by directing a remodeler to DNA breaks. PMID- 24753407 TI - Live-cell imaging of Pol II promoter activity to monitor gene expression with RNA IMAGEtag reporters. AB - We describe a ribonucleic acid (RNA) reporter system for live-cell imaging of gene expression to detect changes in polymerase II activity on individual promoters in individual cells. The reporters use strings of RNA aptamers that constitute IMAGEtags (Intracellular MultiAptamer GEnetic tags) that can be expressed from a promoter of choice. For imaging, the cells are incubated with their ligands that are separately conjugated with one of the FRET pair, Cy3 and Cy5. The IMAGEtags were expressed in yeast from the GAL1, ADH1 or ACT1 promoters. Transcription from all three promoters was imaged in live cells and transcriptional increases from the GAL1 promoter were observed with time after adding galactose. Expression of the IMAGEtags did not affect cell proliferation or endogenous gene expression. Advantages of this method are that no foreign proteins are produced in the cells that could be toxic or otherwise influence the cellular response as they accumulate, the IMAGEtags are short lived and oxygen is not required to generate their signals. The IMAGEtag RNA reporter system provides a means of tracking changes in transcriptional activity in live cells and in real time. PMID- 24753408 TI - Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks. AB - Aberrant DNA replication is a primary cause of mutations that are associated with pathological disorders including cancer. During DNA metabolism, the primary causes of replication fork stalling include secondary DNA structures, highly transcribed regions and damaged DNA. The restart of stalled replication forks is critical for the timely progression of the cell cycle and ultimately for the maintenance of genomic stability. Our previous work has implicated the single stranded DNA binding protein, hSSB1/NABP2, in the repair of DNA double-strand breaks via homologous recombination. Here, we demonstrate that hSSB1 relocates to hydroxyurea (HU)-damaged replication forks where it is required for ATR and Chk1 activation and recruitment of Mre11 and Rad51. Consequently, hSSB1-depleted cells fail to repair and restart stalled replication forks. hSSB1 deficiency causes accumulation of DNA strand breaks and results in chromosome aberrations observed in mitosis, ultimately resulting in hSSB1 being required for survival to HU and camptothecin. Overall, our findings demonstrate the importance of hSSB1 in maintaining and repairing DNA replication forks and for overall genomic stability. PMID- 24753409 TI - Sumoylation of the Rad1 nuclease promotes DNA repair and regulates its DNA association. AB - The Saccharomyces cerevisiae Rad1-Rad10 complex is a conserved, structure specific endonuclease important for repairing multiple types of DNA lesions. Upon recruitment to lesion sites, Rad1-Rad10 removes damaged sequences, enabling subsequent gap filling and ligation. Acting at mid-steps of repair, the association and dissociation of Rad1-Rad10 with DNA can influence repair efficiency. We show that genotoxin-enhanced Rad1 sumoylation occurs after the nuclease is recruited to lesion sites. A single lysine outside Rad1's nuclease and Rad10-binding domains is sumoylated in vivo and in vitro. Mutation of this site to arginine abolishes Rad1 sumoylation and impairs Rad1-mediated repair at high doses of DNA damage, but sustains the repair of a single double-stranded break. The timing of Rad1 sumoylation and the phenotype bias toward high lesion loads point to a post-incision role for sumoylation, possibly affecting Rad1 dissociation from DNA. Indeed, biochemical examination shows that sumoylation of Rad1 decreases the complex's affinity for DNA without affecting other protein properties. These findings suggest a model whereby sumoylation of Rad1 promotes its disengagement from DNA after nuclease cleavage, allowing it to efficiently attend to large numbers of DNA lesions. PMID- 24753410 TI - The histone variant H2A.Bbd is enriched at sites of DNA synthesis. AB - Histone variants play an important role in shaping the mammalian epigenome and their aberrant expression is frequently observed in several types of cancer. However, the mechanisms that mediate their function and the composition of the variant-containing chromatin are still largely unknown. A proteomic interrogation of chromatin containing the different H2A variants macroH2A.1.2, H2A.Bbd and H2A revealed a strikingly different protein composition. Gene ontology analysis reveals a strong enrichment of splicing factors as well as components of the mammalian replisome in H2A.Bbd-containing chromatin. We find H2A.Bbd localizing transiently to sites of DNA synthesis during S-phase and during DNA repair. Cells that express H2A.Bbd have a shortened S-phase and are more susceptible to DNA damage, two phenotypes that are also observed in human Hodgkin's lymphoma cells that aberrantly express this variant. Based on our experiments we conclude that H2A.Bbd is targeted to newly synthesized DNA during replication and DNA repair. The transient incorporation of H2A.Bbd may be due to the intrinsic instability of nucleosomes carrying this variant or a faster chromatin loading. This potentially leads to a disturbance of the existing chromatin structure, which may have effects on cell cycle regulation and DNA damage sensitivity. PMID- 24753411 TI - A piggyBac-based reporter system for scalable in vitro and in vivo analysis of 3' untranslated region-mediated gene regulation. AB - Regulation of messenger ribonucleic acid (mRNA) subcellular localization, stability and translation is a central aspect of gene expression. Much of this control is mediated via recognition of mRNA 3' untranslated regions (UTRs) by microRNAs (miRNAs) and RNA-binding proteins. The gold standard approach to assess the regulation imparted by a transcript's 3' UTR is to fuse the UTR to a reporter coding sequence and assess the relative expression of this reporter as compared to a control. Yet, transient transfection approaches or the use of highly active viral promoter elements may overwhelm a cell's post-transcriptional regulatory machinery in this context. To circumvent this issue, we have developed and validated a novel, scalable piggyBac-based vector for analysis of 3' UTR-mediated regulation in vitro and in vivo. The vector delivers three independent transcription units to the target genome--a selection cassette, a turboGFP control reporter and an experimental reporter expressed under the control of a 3' UTR of interest. The pBUTR (piggyBac-based 3' UnTranslated Region reporter) vector performs robustly as a siRNA/miRNA sensor, in established in vitro models of post-transcriptional regulation, and in both arrayed and pooled screening approaches. The vector is robustly expressed as a transgene during murine embryogenesis, highlighting its potential usefulness for revealing post transcriptional regulation in an in vivo setting. PMID- 24753412 TI - Robustly detecting differential expression in RNA sequencing data using observation weights. AB - A popular approach for comparing gene expression levels between (replicated) conditions of RNA sequencing data relies on counting reads that map to features of interest. Within such count-based methods, many flexible and advanced statistical approaches now exist and offer the ability to adjust for covariates (e.g. batch effects). Often, these methods include some sort of 'sharing of information' across features to improve inferences in small samples. It is important to achieve an appropriate tradeoff between statistical power and protection against outliers. Here, we study the robustness of existing approaches for count-based differential expression analysis and propose a new strategy based on observation weights that can be used within existing frameworks. The results suggest that outliers can have a global effect on differential analyses. We demonstrate the effectiveness of our new approach with real data and simulated data that reflects properties of real datasets (e.g. dispersion-mean trend) and develop an extensible framework for comprehensive testing of current and future methods. In addition, we explore the origin of such outliers, in some cases highlighting additional biological or technical factors within the experiment. Further details can be downloaded from the project website: http://imlspenticton.uzh.ch/robinson_lab/edgeR_robust/. PMID- 24753413 TI - High-efficiency genome editing via 2A-coupled co-expression of fluorescent proteins and zinc finger nucleases or CRISPR/Cas9 nickase pairs. AB - Targeted endonucleases including zinc finger nucleases (ZFNs) and clustered regularly interspaced short palindromic repeats (CRISPRs)/Cas9 are increasingly being used for genome editing in higher species. We therefore devised a broadly applicable and versatile method for increasing editing efficiencies by these tools. Briefly, 2A peptide-coupled co-expression of fluorescent protein and nuclease was combined with fluorescence-activated cell sorting (FACS) to allow for efficient isolation of cell populations with increasingly higher nuclease expression levels, which translated into increasingly higher genome editing rates. For ZFNs, this approach, combined with delivery of donors as single stranded oligodeoxynucleotides and nucleases as messenger ribonucleic acid, enabled high knockin efficiencies in demanding applications, including biallelic codon conversion frequencies reaching 30-70% at high transfection efficiencies and ~ 2% at low transfection efficiencies, simultaneous homozygous knockin mutation of two genes with ~ 1.5% efficiency as well as generation of cell pools with almost complete codon conversion via three consecutive targeting and FACS events. Observed off-target effects were minimal, and when occurring, our data suggest that they may be counteracted by selecting intermediate nuclease levels where off-target mutagenesis is low, but on-target mutagenesis remains relatively high. The method was also applicable to the CRISPR/Cas9 system, including CRISPR/Cas9 mutant nickase pairs, which exhibit low off-target mutagenesis compared to wild-type Cas9. PMID- 24753414 TI - VAP: a versatile aggregate profiler for efficient genome-wide data representation and discovery. AB - The analysis of genomic data such as ChIP-Seq usually involves representing the signal intensity level over genes or other genetic features. This is often illustrated as a curve (representing the aggregate profile of a group of genes) or as a heatmap (representing individual genes). However, no specific resource dedicated to easily generating such profiles is currently available. We therefore built the versatile aggregate profiler (VAP), designed to be used by experimental and computational biologists to generate profiles of genomic datasets over groups of regions of interest, using either an absolute or a relative method. Graphical representation of the results is automatically generated, and subgrouping can be performed easily, based on the orientation of the flanking annotations. The outputs include statistical measures to facilitate comparisons between groups or datasets. We show that, through its intuitive design and flexibility, VAP can help avoid misinterpretations of genomics data. VAP is highly efficient and designed to run on laptop computers by using a memory footprint control, but can also be easily compiled and run on servers. VAP is accessible at http://lab jacques.recherche.usherbrooke.ca/vap/. PMID- 24753415 TI - A novel approach to represent and compare RNA secondary structures. AB - Structural information is crucial in ribonucleic acid (RNA) analysis and functional annotation; nevertheless, how to include such structural data is still a debated problem. Dot-bracket notation is the most common and simple representation for RNA secondary structures but its simplicity leads also to ambiguity requiring further processing steps to dissolve. Here we present BEAR (Brand nEw Alphabet for RNA), a new context-aware structural encoding represented by a string of characters. Each character in BEAR encodes for a specific secondary structure element (loop, stem, bulge and internal loop) with specific length. Furthermore, exploiting this informative and yet simple encoding in multiple alignments of related RNAs, we captured how much structural variation is tolerated in RNA families and convert it into transition rates among secondary structure elements. This allowed us to compute a substitution matrix for secondary structure elements called MBR (Matrix of BEAR-encoded RNA secondary structures), of which we tested the ability in aligning RNA secondary structures. We propose BEAR and the MBR as powerful resources for the RNA secondary structure analysis, comparison and classification, motif finding and phylogeny. PMID- 24753416 TI - HIV-1 Rev protein specifies the viral RNA export pathway by suppressing TAP/NXF1 recruitment. AB - Nuclear RNA export pathways in eukaryotes are often linked to the fate of a given RNA. Therefore, the choice of export pathway should be well-controlled to avoid an unfavorable effect on gene expression. Although some RNAs could be exported by more than one pathway, little is known about how the choice is regulated. This issue is highlighted when the human immunodeficiency virus type 1 (HIV-1) Rev protein induces the export of singly spliced and unspliced HIV-1 transcripts. How these RNAs are exported is not well understood because such transcripts should have the possibility of utilizing CRM1-dependent export via Rev or cellular TAP/NXF1-dependent export via the transcription/export (TREX) complex, or both. Here we found that Rev suppressed TAP/NXF1-dependent export of model RNA substrates that recapitulated viral transcripts. In this effect, Rev interacted with the cap-binding complex and inhibited the recruitment of the TREX complex. Thus, Rev controls the identity of the factor occupying the cap-proximal region that determines the RNA export pathway. This ribonucleoprotein remodeling activity of Rev may favor viral gene expression. PMID- 24753418 TI - The ETS family member GABPalpha modulates androgen receptor signalling and mediates an aggressive phenotype in prostate cancer. AB - In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPalpha, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPalpha enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPalpha has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPalpha bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPalpha in CRPC and reveals potential targets for therapeutic intervention. PMID- 24753417 TI - A novel tRNA variable number tandem repeat at human chromosome 1q23.3 is implicated as a boundary element based on conservation of a CTCF motif in mouse. AB - The human genome contains numerous large tandem repeats, many of which remain poorly characterized. Here we report a novel transfer RNA (tRNA) tandem repeat on human chromosome 1q23.3 that shows extensive copy number variation with 9-43 repeat units per allele and displays evidence of meiotic and mitotic instability. Each repeat unit consists of a 7.3 kb GC-rich sequence that binds the insulator protein CTCF and bears the chromatin hallmarks of a bivalent domain in human embryonic stem cells. A tRNA containing tandem repeat composed of at least three 7.6-kb GC-rich repeat units reside within a syntenic region of mouse chromosome 1. However, DNA sequence analysis reveals that, with the exception of the tRNA genes that account for less than 6% of a repeat unit, the remaining 7.2 kb is not conserved with the notable exception of a 24 base pair sequence corresponding to the CTCF binding site, suggesting an important role for this protein at the locus. PMID- 24753419 TI - DMINDA: an integrated web server for DNA motif identification and analyses. AB - DMINDA (DNA motif identification and analyses) is an integrated web server for DNA motif identification and analyses, which is accessible at http://csbl.bmb.uga.edu/DMINDA/. This web site is freely available to all users and there is no login requirement. This server provides a suite of cis-regulatory motif analysis functions on DNA sequences, which are important to elucidation of the mechanisms of transcriptional regulation: (i) de novo motif finding for a given set of promoter sequences along with statistical scores for the predicted motifs derived based on information extracted from a control set, (ii) scanning motif instances of a query motif in provided genomic sequences, (iii) motif comparison and clustering of identified motifs, and (iv) co-occurrence analyses of query motifs in given promoter sequences. The server is powered by a backend computer cluster with over 150 computing nodes, and is particularly useful for motif prediction and analyses in prokaryotic genomes. We believe that DMINDA, as a new and comprehensive web server for cis-regulatory motif finding and analyses, will benefit the genomic research community in general and prokaryotic genome researchers in particular. PMID- 24753421 TI - Deciphering key features in protein structures with the new ENDscript server. AB - ENDscript 2 is a friendly Web server for extracting and rendering a comprehensive analysis of primary to quaternary protein structure information in an automated way. This major upgrade has been fully re-engineered to enhance speed, accuracy and usability with interactive 3D visualization. It takes advantage of the new version 3 of ESPript, our well-known sequence alignment renderer, improved to handle a large number of data with reduced computation time. From a single PDB entry or file, ENDscript produces high quality figures displaying multiple sequence alignment of proteins homologous to the query, colored according to residue conservation. Furthermore, the experimental secondary structure elements and a detailed set of relevant biophysical and structural data are depicted. All this information and more are now mapped on interactive 3D PyMOL representations. Thanks to its adaptive and rigorous algorithm, beginner to expert users can modify settings to fine-tune ENDscript to their needs. ENDscript has also been upgraded as an open platform for the visualization of multiple biochemical and structural data coming from external biotool Web servers, with both 2D and 3D representations. ENDscript 2 and ESPript 3 are freely available at http://endscript.ibcp.fr and http://espript.ibcp.fr, respectively. PMID- 24753420 TI - Mechanistic insight into ligand binding to G-quadruplex DNA. AB - Specific guanine-rich regions in human genome can form higher-order DNA structures called G-quadruplexes, which regulate many relevant biological processes. For instance, the formation of G-quadruplex at telomeres can alter cellular functions, inducing apoptosis. Thus, developing small molecules that are able to bind and stabilize the telomeric G-quadruplexes represents an attractive strategy for antitumor therapy. An example is 3-(benzo[d]thiazol-2-yl)-7-hydroxy 8-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-2H-chromen-2-one (compound 1: ), recently identified as potent ligand of the G-quadruplex [d(TGGGGT)]4 with promising in vitro antitumor activity. The experimental observations are suggestive of a complex binding mechanism that, despite efforts, has defied full characterization. Here, we provide through metadynamics simulations a comprehensive understanding of the binding mechanism of 1: to the G-quadruplex [d(TGGGGT)]4. In our calculations, the ligand explores all the available binding sites on the DNA structure and the free-energy landscape of the whole binding process is computed. We have thus disclosed a peculiar hopping binding mechanism whereas 1: is able to bind both to the groove and to the 3' end of the G quadruplex. Our results fully explain the available experimental data, rendering our approach of great value for further ligand/DNA studies. PMID- 24753422 TI - Direct optical mapping of transcription factor binding sites on field-stretched lambda-DNA in nanofluidic devices. AB - Mapping transcription factor (TF) binding sites along a DNA backbone is crucial in understanding the regulatory circuits that control cellular processes. Here, we deployed a method adopting bioconjugation, nanofluidic confinement and fluorescence single molecule imaging for direct mapping of TF (RNA polymerase) binding sites on field-stretched single DNA molecules. Using this method, we have mapped out five of the TF binding sites of E. coli RNA polymerase to bacteriophage lambda-DNA, where two promoter sites and three pseudo-promoter sites are identified with the corresponding binding frequency of 45% and 30%, respectively. Our method is quick, robust and capable of resolving protein binding locations with high accuracy (~ 300 bp), making our system a complementary platform to the methods currently practiced. It is advantageous in parallel analysis and less prone to false positive results over other single molecule mapping techniques such as optical tweezers, atomic force microscopy and molecular combing, and could potentially be extended to general mapping of protein-DNA interaction sites. PMID- 24753423 TI - TEMP: a computational method for analyzing transposable element polymorphism in populations. AB - Insertions and excisions of transposable elements (TEs) affect both the stability and variability of the genome. Studying the dynamics of transposition at the population level can provide crucial insights into the processes and mechanisms of genome evolution. Pooling genomic materials from multiple individuals followed by high-throughput sequencing is an efficient way of characterizing genomic polymorphisms in a population. Here we describe a novel method named TEMP, specifically designed to detect TE movements present with a wide range of frequencies in a population. By combining the information provided by pair-end reads and split reads, TEMP is able to identify both the presence and absence of TE insertions in genomic DNA sequences derived from heterogeneous samples; accurately estimate the frequencies of transposition events in the population and pinpoint junctions of high frequency transposition events at nucleotide resolution. Simulation data indicate that TEMP outperforms other algorithms such as PoPoolationTE, RetroSeq, VariationHunter and GASVPro. TEMP also performs well on whole-genome human data derived from the 1000 Genomes Project. We applied TEMP to characterize the TE frequencies in a wild Drosophila melanogaster population and study the inheritance patterns of TEs during hybrid dysgenesis. We also identified sequence signatures of TE insertion and possible molecular effects of TE movements, such as altered gene expression and piRNA production. TEMP is freely available at github: https://github.com/JialiUMassWengLab/TEMP.git. PMID- 24753424 TI - TargetRNA2: identifying targets of small regulatory RNAs in bacteria. AB - Many small, noncoding RNAs (sRNAs) in bacteria act as posttranscriptional regulators of messenger RNAs. TargetRNA2 is a web server that identifies mRNA targets of sRNA regulatory action in bacteria. As input, TargetRNA2 takes the sequence of an sRNA and the name of a sequenced bacterial replicon. When searching for targets of RNA regulation, TargetRNA2 uses a variety of features, including conservation of the sRNA in other bacteria, the secondary structure of the sRNA, the secondary structure of each candidate mRNA target and the hybridization energy between the sRNA and each candidate mRNA target. TargetRNA2 outputs a ranked list of likely regulatory targets for the input sRNA. When evaluated on a comprehensive set of sRNA-target interactions, TargetRNA2 was found to be both accurate and efficient in identifying targets of sRNA regulatory action. Furthermore, TargetRNA2 has the ability to integrate RNA-seq data, if available. If an sRNA is differentially expressed in two or more RNA-seq experiments, TargetRNA2 considers co-differential gene expression when searching for regulatory targets, significantly improving the accuracy of target identifications. The TargetRNA2 web server is freely available for use at http://cs.wellesley.edu/~btjaden/TargetRNA2. PMID- 24753425 TI - AlignMe--a membrane protein sequence alignment web server. AB - We present a web server for pair-wise alignment of membrane protein sequences, using the program AlignMe. The server makes available two operational modes of AlignMe: (i) sequence to sequence alignment, taking two sequences in fasta format as input, combining information about each sequence from multiple sources and producing a pair-wise alignment (PW mode); and (ii) alignment of two multiple sequence alignments to create family-averaged hydropathy profile alignments (HP mode). For the PW sequence alignment mode, four different optimized parameter sets are provided, each suited to pairs of sequences with a specific similarity level. These settings utilize different types of inputs: (position-specific) substitution matrices, secondary structure predictions and transmembrane propensities from transmembrane predictions or hydrophobicity scales. In the second (HP) mode, each input multiple sequence alignment is converted into a hydrophobicity profile averaged over the provided set of sequence homologs; the two profiles are then aligned. The HP mode enables qualitative comparison of transmembrane topologies (and therefore potentially of 3D folds) of two membrane proteins, which can be useful if the proteins have low sequence similarity. In summary, the AlignMe web server provides user-friendly access to a set of tools for analysis and comparison of membrane protein sequences. Access is available at http://www.bioinfo.mpg.de/AlignMe. PMID- 24753426 TI - The CDK regulators Cdh1 and Sic1 promote efficient usage of DNA replication origins to prevent chromosomal instability at a chromosome arm. AB - Robustness and completion of DNA replication rely on redundant DNA replication origins. Reduced efficiency of origin licensing is proposed to contribute to chromosome instability in CDK-deregulated cell cycles, a frequent alteration in oncogenesis. However, the mechanism by which this instability occurs is largely unknown. Current models suggest that limited origin numbers would reduce fork density favouring chromosome rearrangements, but experimental support in CDK deregulated cells is lacking. We have investigated the pattern of origin firing efficiency in budding yeast cells lacking the CDK regulators Cdh1 and Sic1. We show that each regulator is required for efficient origin activity, and that both cooperate non-redundantly. Notably, origins are differentially sensitive to CDK deregulation. Origin sensitivity is independent on normal origin efficiency, firing timing or chromosomal location. Interestingly, at a chromosome arm, there is a shortage of origin firing involving active and dormant origins, and the extent of shortage correlates with the severity of CDK deregulation and chromosome instability. We therefore propose that CDK deregulation in G1 phase compromises origin redundancy by decreasing the number of active and dormant origins, leading to origin shortage and increased chromosome instability. PMID- 24753427 TI - GalaxySite: ligand-binding-site prediction by using molecular docking. AB - Knowledge of ligand-binding sites of proteins provides invaluable information for functional studies, drug design and protein design. Recent progress in ligand binding-site prediction methods has demonstrated that using information from similar proteins of known structures can improve predictions. The GalaxySite web server, freely accessible at http://galaxy.seoklab.org/site, combines such information with molecular docking for more precise binding-site prediction for non-metal ligands. According to the recent critical assessments of structure prediction methods held in 2010 and 2012, this server was found to be superior or comparable to other state-of-the-art programs in the category of ligand-binding site prediction. A strong merit of the GalaxySite program is that it provides additional predictions on binding ligands and their binding poses in terms of the optimized 3D coordinates of the protein-ligand complexes, whereas other methods predict only identities of binding-site residues or copy binding geometry from similar proteins. The additional information on the specific binding geometry would be very useful for applications in functional studies and computer-aided drug discovery. PMID- 24753428 TI - A role for [Fe4S4] clusters in tRNA recognition--a theoretical study. AB - Over the past several years, structural studies have led to the unexpected discovery of iron-sulfur clusters in enzymes that are involved in DNA replication/repair and protein biosynthesis. Although these clusters are generally well-studied cofactors, their significance in the new contexts often remains elusive. One fascinating example is a tryptophanyl-tRNA synthetase from the thermophilic bacterium Thermotoga maritima, TmTrpRS, that has recently been structurally characterized. It represents an unprecedented connection among a primordial iron-sulfur cofactor, RNA and protein biosynthesis. Here, a possible role of the [Fe4S4] cluster in tRNA anticodon-loop recognition is investigated by means of density functional theory and comparison with the structure of a human tryptophanyl-tRNA synthetase/tRNA complex. It turns out that a cluster coordinating cysteine residue, R224, and polar main chain atoms form a characteristic structural motif for recognizing a putative 5' cytosine or 5' 2 thiocytosine moiety in the anticodon loop of the tRNA molecule. This motif provides not only affinity but also specificity by creating a structural and energetical penalty for the binding of other bases, such as uracil. PMID- 24753429 TI - InterMine: extensive web services for modern biology. AB - InterMine (www.intermine.org) is a biological data warehousing system providing extensive automatically generated and configurable RESTful web services that underpin the web interface and can be re-used in many other applications: to find and filter data; export it in a flexible and structured way; to upload, use, manipulate and analyze lists; to provide services for flexible retrieval of sequence segments, and for other statistical and analysis tools. Here we describe these features and discuss how they can be used separately or in combinations to support integrative and comparative analysis. PMID- 24753430 TI - Avoiding antibody aggregation during processing: establishing hold times. AB - Aggregation of biotech products used therapeutically, such as antibodies, can contribute to potential immunogenicity of the product. Charge-based heterogeneities may also impact the safety and/or efficacy of a therapeutic. In this study, an approach based on empirical modeling and least squares regression is suggested for establishing hold times for process intermediates during production of monoclonal antibody (Mab) therapeutics. Two immunoglobulins were analyzed with respect to aggregation and charge heterogeneity in buffer conditions that are typically used during downstream processing of Mab products. Size exclusion chromatography, ion exchange chromatography (IEC), and circular dichroism were used. We found that aggregation primarily occurs at pH 3 (buffers used in affinity chromatography) and is higher in citrate buffer compared to acetate and glycine buffers. Aggregation is minimal in buffers used in anion exchange chromatography (Tris-HCl buffer at pH 7.2 and 8) and in cation exchange chromatography (citrate buffer at pH 6, acetate buffer at pH 6, and phosphate buffer at pH 6.5 and 7.5). The behavior is opposite in the case of charged heterogeneities (basic and acidic variants) as measured by IEC. The product is more susceptible to degradation at high pH than at low pH. The data presented here demonstrate that product stability can be a significant issue within the routinely used manufacturing conditions. We suggest that the approach presented needs to be adopted by all manufacturers to ensure product stability during processing. PMID- 24753431 TI - Regulatory and logistical issues influencing access to antineoplastic and supportive care medications for children with cancer in developing countries. AB - Globally there are numerous impediments, both logistical, regulatory and more recently global drug shortages, hindering pediatric access to therapeutic drugs of all types. Efforts to reduce barriers are ongoing and are especially important in low and middle income countries and for children requiring treatment of conditions such as those encountered in pediatric oncology characterized by the risk of life threatening treatment failures. Progress has been made through the efforts of the World Health Organization and regulators in the US and Europe to encourage the development of therapeutic agents for use in pediatrics and measures taken have fostered the availability of stronger pediatric data to guide therapeutic decisions. Nonetheless, pharmaceuticals remain a global commodity, subject to regulation by the World Trade Organization and this has often had detrimental effects in low and middle income countries. This article emphasizes the need for closer international collaboration to address the barriers currently impeding access to antineoplastic and supportive care medicines for children. PMID- 24753432 TI - Dopamine D2 receptor controls hilar mossy cells excitability. AB - Hippocampal control of memory formation is regulated by dopaminergic signaling. Whereas the role of dopamine D1 receptors is well documented in such regulations, functions of dopamine D2 receptors (DRD2) are not fully understood. Using fluorescence in situ hybridization we demonstrate that Drd2 expression in the hippocampus of wild-type mice is limited to glutamatergic hilar mossy cells. Using whole cell electrophysiological recordings in hippocampal slice preparations, we provide evidence that unlike in basal ganglia, activation of DRD2 by the selective agonist, quinpirole, induces a long-lasting increase in excitability of hilar mossy cells, which can be blocked by the DRD2 antagonist raclopride. Such activity is mediated by the Akt/GSK pathway, as application of specific inhibitors such as A1070722 or SB216763 prevented quinpirole activity. Long-term effects of acute DRD2 activation in vitro suggest that volume transmission of dopamine may modulate mossy cell activities in vivo. This is supported by the presence of dense tyrosine hydroxylase positive varicosities in the hilus, which are rarely seen in the vicinity of mossy cell dendrites. From these data we discuss how dopamine could control mossy cell activity and thus dentate gyrus functions. PMID- 24753433 TI - Mixed-effects modeling of clinical DCE-MRI data: application to colorectal liver metastases treated with bevacizumab. AB - PURPOSE: Most dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data are evaluated for individual patients with cohorts analyzed to detect significant changes from baseline values, repeating the process at each posttreatment timepoint. Our study aimed to develop a statistically valid model for the complete time course of DCE-MRI data in a patient cohort. MATERIALS AND METHODS: Data from 10 patients with colorectal cancer liver metastases were analyzed, including two baseline scans and four post-bevacizumab scans. Apparent changes in tumor median K(trans) were adjusted for changes in observed enhancing tumor fraction (EnF) by multiplying K(trans) by EnF (KEnF). A mixed-effects model (MEM) was defined to describe the KEnF time course for all patients simultaneously by assuming a three-parameter indirect response model with model parameters lognormally distributed across patients. RESULTS: The typical cohort time course showed a KEnF reduction to 59% of baseline at 24 hours, returning to 65% of baseline values by day 12. Interpatient variability of model parameters ranged from 11% to 307%. CONCLUSION: The MEM approach has potential for comparing responses at a group level in clinical trials with different doses, schedules, or combination regimens. Furthermore, the KEnF biomarker successfully resolved confounds in interpreting K(trans) arising from therapy induced changes in the volume of enhancing tumor. PMID- 24753434 TI - Selection of functional human sperm with higher DNA integrity and fewer reactive oxygen species. AB - Fertilization and reproduction are central to the survival and propagation of a species. Couples who cannot reproduce naturally have to undergo in vitro clinical procedures. An integral part of these clinical procedures includes isolation of healthy sperm from raw semen. Existing sperm sorting methods are not efficient and isolate sperm having high DNA fragmentation and reactive oxygen species (ROS), and suffer from multiple manual steps and variations between operators. Inspired by in vivo natural sperm sorting mechanisms where vaginal mucus becomes less viscous to form microchannels to guide sperm towards egg, a chip is presented that efficiently sorts healthy, motile and morphologically normal sperm without centrifugation. Higher percentage of sorted sperm show significantly lesser ROS and DNA fragmentation than the conventional swim-up method. The presented chip is an easy-to-use high-throughput sperm sorter that provides standardized sperm sorting assay with less reliance on operators's skills, facilitating reliable operational steps. PMID- 24753435 TI - Transcatheter closure of an iatrogenic ventricular septal defect after SAPIEN valve implantation. AB - A 57-year-old woman developed progressive calcific mitral and aortic valve disease with a porcelain aorta secondary to a history of radiation therapy. She was considered a very poor operative candidate and referred for transcatheter aortic valve replacement (TAVR). Four weeks after extensive coronary artery stenting, a TAVR was performed with a 23 mm Edwards SAPIEN valve (Edwards Life Sciences, Irvine, CA) through a transapical approach. Post-operatively, her symptoms of dyspnea persisted and worsened. She was found to have an acquired ventricular septal defect (VSD) measuring 8 mm by 5 mm by transesophageal echocardiogram and by a CT angiogram. Percutaneous VSD closure was accomplished with an 8 mm Muscular VSD Occluder (St. Jude Medical, St. Paul, MN) with elimination of her shunt, improvement of her dyspnea, and marked improvement in exercise tolerance. PMID- 24753436 TI - A simple extraction and LC-MS/MS approach for the screening and identification of over 100 analytes in eight different matrices. AB - In the present study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) multi-analyte approach using one single work-up approach in whole blood, plasma, serum, post-mortem blood, liver tissue, gastric content, hair, and urine was developed for fast target screening and reliable identification of 130 analytes often requested in clinical and forensic toxicology. Samples (500 MUL each) of whole blood, plasma, serum, post-mortem blood, tissue (homogenized 1 + 4 with water), as well as 3 g of distilled gastric contents, 1 mL of urine, or 20 mg of pulverized hair were extracted at different pH values with an diethyl ether-ethyl acetate mixture (1:1). Separation and identification were performed using LC QTRAP with electrospray ionization in positive mode. For identification 1 scheduled multi-reaction-mode (sMRM) method with 390 transitions was developed covering benzodiazepines, Z-drugs, antidepressants, neuroleptics, opioids, new synthetic drugs, and phosphodiesterase type 5 inhibitors. For positive sMRM transitions with intensities exceeding 5000 cps, dependent scans (EPI scan collision energy, 35 eV, collision energy spread, 15 eV) were performed for library search using our in-house library. The method was developed with respect to selectivity, matrix effects, recovery, process efficiency, limit of detection, and applicability. The simple work-up procedure was suitable for all biosamples with exception of urine in respect to low concentrated analytes, which showed median recovery values of 59%. The method was selective for 130 analytes in all 8 biosamples. For 106 analytes, the limit of detection in whole blood, plasma, and serum was lower than the lowest therapeutic concentration listed in blood level lists. PMID- 24753437 TI - Does excited-state proton-transfer reaction contribute to the emission behaviour of 4-aminophthalimide in aqueous media? AB - 4-Aminophthalimide (AP) is an extensively used molecule both for fundamental studies and applications primarily due to its highly solvent-sensitive fluorescence properties. The fluorescence spectrum of AP in aqueous media was recently shown to be dependent on the excitation wavelength. A time-dependent blue shift of its emission spectrum is also reported. On the basis of these findings, the excited-state solvent-mediated proton-transfer reaction of the molecule, which was proposed once but discarded at a later stage, is reintroduced. We report on the fluorescence behaviour of AP and its imide-H protected derivative, N-BuAP, to prove that a solvent-assisted excited-state keto enol transformation does not contribute to the steady-state and time-resolved emission behaviour of AP in aqueous media. Our results also reveal that the fluorescence of AP in aqueous media arises from two distinct hydrogen-bonded species. The deuterium isotope effect on the fluorescence quantum yield and lifetime of AP, which was thought to be a reflection of the excited-state proton transfer reaction in the system, is explained by considering the difference in the influence of H(2)O and D(2)O on the nonradiative rates and ground-state exchange of the proton with the solvent. PMID- 24753438 TI - Sub-second proton imaging of 13C hyperpolarized contrast agents in water. AB - Indirect proton detection of (13)C hyperpolarized contrast agents potentially enables greater sensitivity. Presented here is a study of sub-second projection imaging of hyperpolarized (13)C contrast agent addressing the obstacle posed by water suppression for indirect detection in vivo. Sodium acetate phantoms were used to develop and test water suppression and sub-second imaging with frequency selective RF pulses using spectroscopic and imaging indirect proton detection. A 9.8 mm aqueous solution of (13)C PHIP hyperpolarized 2-hydroxyethyl-(13)C propionate-d2,3,3 (HEP),

~25% was used for demonstration of indirect proton sub-second imaging detection. Balanced 2D FSSFP (fast steady-state free precession) allowed the recording of proton images with a field of view of 64 * 64 mm(2) and spatial resolution 2 * 2 mm(2) with total acquisition time of less than 0.2 s. In thermally polarized sodium 1-(13)C-acetate, (13) C to (1)H polarization transfer efficiency of 45.1% of the theoretically predicted values was observed in imaging detection corresponding to an 11-fold overall sensitivity improvement compared with direct (13)C FSSFP imaging. (13)C to (1)H polarization transfer efficiency of 27% was observed in imaging detection, corresponding to a 3.25-fold sensitivity improvement compared with direct (13)C FSSFP imaging with hyperpolarized HEP. The range of potential applications and limitations of this sub-second and ultra-sensitive imaging approach are discussed. PMID- 24753439 TI - Somatic mosaicism in ACVRL1 with transmission to several offspring affected with severe pulmonary arterial hypertension. PMID- 24753440 TI - Calcium influx and postsynaptic proteins coordinate the dendritic filopodium spine transition. AB - Dendritic spines are the major locations of excitatory synapses in the mammalian central nervous system. The transformation from dendritic filopodia to dendritic spines has been recognized as one type of spinogenesis. For instance, syndecan-2 (SDC2), a synaptic heparan sulfate proteoglycan, is highly concentrated at dendritic spines and required for spinogenesis. It induces dendritic filopodia formation, followed by spine formation. However, the molecular regulation of the filopodium-spine transition induced by SDC2 is still unclear. In this report, we show that calcium is an important signal downstream of SDC2 in regulation of filopodium-spine transition but not filopodia formation. SDC2 interacted with the postsynaptic proteins calmodulin-dependent serine kinase (CASK) and LIN7 and further recruited NMDAR to the tips of filopodia induced by SDC2. Calcium influx via NMDAR promoted spine maturation because addition of EGTA or AP5 to the culture medium effectively prevented morphological change from dendritic filopodia to dendritic spines. Our data also indicated that F-actin rearrangement regulated by calcium influx is involved in the morphological change, because the knockdown of gelsolin, a calcium-activated F-actin severing molecule, impaired the filopodium-spine transition induced by SDC2. In conclusion, our study demonstrates that postsynaptic proteins coordinate to trigger calcium signalling and cytoskeleton rearrangement and consequently control filopodium-spine transition. PMID- 24753443 TI - Small-dose-sensitive X-ray image pixel with HgI2 photoconductor and amorphous oxide thin-film transistor. AB - A new X-ray image sensor is demonstrated with an oxide thin-film transistor backplane and HgI2 sensing material. It displays outstanding image quality under a low X-ray exposure and a low electric field. It is promising as a state-of-the art device to realize highly resolved images at a low X-ray dose for a variety of medical X-ray imaging applications. PMID- 24753444 TI - Copper thiocyanato complexes and cocaine - a case of 'black cocaine'. AB - The chemical composition of a black powder confiscated by German customs was elucidated. Black powders are occasionally used as a 'transporter' for cocaine and are obviously especially designed to cloak the presence of the drug. The material consisting of cocaine, copper, iron, thiocyanate, and graphite was approached by analytical tools and chemical modelling. Graphite is added to the material probably with the intention of masking the typical infrared (IR) fingerprints of cocaine and can be clearly detected by powder X-ray diffraction (XRD) and Raman spectroscopy. Cu(2+) and NCS(-) ions, when carefully reacted with cocaine hydrochloride, form the novel compound (CocH)2 [Cu(NCS)4 ] (CocH(+) = protonated cocaine), which has been characterised by single crystal XRD, IR, NMR, UV/Vis absorption and EPR spectroscopy. Based on some further experiments the assumed composition of the original black powder is discussed. PMID- 24753442 TI - N-cadherin regulates molecular organization of excitatory and inhibitory synaptic circuits in adult hippocampus in vivo. AB - N-Cadherin and beta-catenin form a transsynaptic adhesion complex required for spine and synapse development. In adulthood, N-cadherin mediates persistent synaptic plasticity, but whether the role of N-cadherin at mature synapses is similar to that at developing synapses is unclear. To address this, we conditionally ablated N-cadherin from excitatory forebrain synapses in mice starting in late postnatal life and examined hippocampal structure and function in adulthood. In the absence of N-cadherin, beta-catenin levels were reduced, but numbers of excitatory synapses were unchanged, and there was no impact on number or shape of dendrites or spines. However, the composition of synaptic molecules was altered. Levels of GluA1 and its scaffolding protein PSD95 were diminished and the density of immunolabeled puncta was decreased, without effects on other glutamate receptors and their scaffolding proteins. Additionally, loss of N cadherin at excitatory synapses triggered increases in the density of markers for inhibitory synapses and decreased severity of hippocampal seizures. Finally, adult mutant mice were profoundly impaired in hippocampal-dependent memory for spatial episodes. These results demonstrate a novel function for the N cadherin/beta-catenin complex in regulating ionotropic receptor composition of excitatory synapses, an appropriate balance of excitatory and inhibitory synaptic proteins and the maintenance of neural circuitry necessary to generate flexible yet persistent cognitive and synaptic function. PMID- 24753445 TI - Burkitt lymphoma and Ewing sarcoma in a child with Williams syndrome. AB - Williams syndrome (WS) is a relatively rare multisystem neurodevelopmental disorder caused by a hemizygous deletion of contiguous genes on chromosome 7q11.23. Although WS does not predispose carriers to cancers, alterations of chromosome 7 are common in several human neoplasms. We report here a patient with WS and two different cancers, Burkitt lymphoma and Ewing sarcoma. Array-CGH analysis of the patient blood revealed a constitutive 1.4 million base pair deletion at 7q11.23, compatible with WS diagnosis. PMID- 24753446 TI - Multimodal imaging of micron-sized iron oxide particles following in vitro and in vivo uptake by stem cells: down to the nanometer scale. AB - In this study, the interaction between cells and micron-sized paramagnetic iron oxide (MPIO) particles was investigated by characterizing MPIO in their original state, and after cellular uptake in vitro as well as in vivo. Moreover, MPIO in the olfactory bulb were studied 9 months after injection. Using various imaging techniques, cell-MPIO interactions were investigated with increasing spatial resolution. Live cell confocal microscopy demonstrated that MPIO co-localize with lysosomes after in vitro cellular uptake. In more detail, a membrane surrounding the MPIO was observed by high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). Following MPIO uptake in vivo, the same cell MPIO interaction was observed by HAADF-STEM in the subventricular zone at 1 week and in the olfactory bulb at 9 months after MPIO injection. These findings provide proof for the current hypothesis that MPIO are internalized by the cell through endocytosis. The results also show MPIO are not biodegradable, even after 9 months in the brain. Moreover, they show the possibility of HAADF-STEM generating information on the labeled cell as well as on the MPIO. In summary, the methodology presented here provides a systematic route to investigate the interaction between cells and nanoparticles from the micrometer level down to the nanometer level and beyond. PMID- 24753447 TI - Chiral resolution and pharmacological characterization of the enantiomers of the Hsp90 inhibitor 2-amino-7-[4-fluoro-2-(3-pyridyl)phenyl]-4-methyl-7,8-dihydro-6H quinazolin-5-one oxime. AB - Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in the stabilization of key oncogenic signaling proteins, and therefore, inhibition of Hsp90 represents a new strategy in cancer therapy. 2-Amino-7-[4-fluoro-2-(3 pyridyl)phenyl]-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime is a racemic Hsp90 inhibitor that targets the N-terminal adenosine triphosphatase site. We developed a method to resolve the enantiomers and evaluated their inhibitory activity on Hsp90 and the consequent antitumor effects. The (S) stereoisomer emerged as a potent Hsp90 inhibitor in biochemical and cellular assays. In addition, this enantiomer exhibited high oral bioavailability in mice and excellent antitumor activity in two different human cancer xenograft models. PMID- 24753448 TI - Opposing effects of hypoxia on catecholaminergic locus coeruleus and hypocretin/orexin neurons in chick embryos. AB - Terrestrial vertebrate embryos face a risk of low oxygen availability (hypoxia) that is especially great during their transition to air-breathing. To better understand how fetal brains respond to hypoxia, we examined the effects of low oxygen availability on brain activity in late-stage chick embryos (day 18 out of a 21-day incubation period). Using cFos protein expression as a marker for neuronal activity, we focused on two specific, immunohistochemically identified cell groups known to play an important role in regulating adult brain states (sleep and waking): the noradrenergic neurons of the Locus Coeruleus (NA-LC), and the Hypocretin/Orexin (H/O) neurons of the hypothalamus. cFos expression was also examined in the Pallium (the avian analog of the cerebral cortex). In adult mammalian brains, cFos expression changes in a coordinated way in these areas. In chick embryos, oxygen deprivation simultaneously activated NA-LC while deactivating H/O-producing neurons; it also increased cFos expression in the Pallium. Activity in one pallial primary sensory area was significantly related to NA-LC activity. These data reveal that at least some of the same neural systems involved in brain-state control in adults may play a central role in orchestrating prenatal hypoxic responses, and that these circuits may show different patterns of coordination than seen in adults. PMID- 24753449 TI - Evaluation of Delta(9) -tetrahydrocannabinol detection using DrugWipe5S((r)) screening and oral fluid quantification after QuantisalTM collection for roadside drug detection via a controlled study with chronic cannabis users. AB - Oral fluid (OF) is potentially useful to detect driving under the influence of drugs because of its ease of sampling. While cannabis is the most prevalent drug in Europe, sensitivity issues for Delta(9) -tetrahydrocannabinol (THC) screening and problems during OF collection are observed. The ability of a recently improved OF screening device - the DrugWipe5S((r)) , to detect recent THC use in chronic cannabis smokers, was studied. Ten subjects participated in a double blind placebo-controlled study. The subjects smoked two subsequent doses of THC; 300 ug/kg and 150 ug/kg with a pause of 75 min using a Volcano vapourizer. DrugWipe5S((r)) screening and OF collection using the QuantisalTM device were performed at baseline, 5 min after each administration and 80 min after the last inhalation. Blood samples were drawn simultaneously. The screening devices (n = 80) were evaluated visually after 8 min, while the corresponding OF and serum samples were analyzed respectively with ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) or gas chromatography-mass spectrometry (GC MS). Neat OF THC concentrations ranged from 12 361 ng/g 5 min after smoking down to 34 ng/g 80 min later. Under placebo conditions, a median THC concentration of 8 ng/g OF (0-746 ng/g) and < 1 ng/ mL serum (0-7.8 ng/mL) was observed. The DrugWipe5S((r)) was positive just after smoking (90%); however, sensitivity rapidly decreased within 1.5 h (50%). Sensitivity of DrugWipe5S((r)) should be improved. As chronic cannabis users have high residual THC concentrations in their serum and OF, confirmation cut-offs should be set according to the aim of detecting recent drug use or establishing zero tolerance. PMID- 24753450 TI - A platform for controlled dual-drug delivery to the retina: protective effects against light-induced retinal damage in rats. AB - Controlled transscleral co-delivery of two drugs, edaravone (EDV) and unoprostone (UNO), using a platform that comprises a microfabricated reservoir, controlled release cover, and drug formulations, which are made of photopolymerized poly(ethyleneglycol) dimethacrylates, shows synergistic retinal neuroprotection against light injury in rats when compared with single-drug-loaded devices. The device would offer a safer therapeutic method than intravitreal injections for retinal disease treatments. PMID- 24753451 TI - Nucleophilic cross-linked, dextran coated iron oxide nanoparticles as basis for molecular imaging: synthesis, characterization, visualization and comparison with previous product. AB - We present a new synthesis protocol for a multivalent, multimodality, nucleophilic nanoparticle ideal for in vivo imaging. Stability requirements necessitated covalent cross-linking of the carbohydrate cage, easy functionalization the introduction of sterically accessible amine groups. The new protocol aimed at more uniform particle size, less clustering and superior magnetic properties compared with commercial nanoparticles. Particles were precipitated from Fe(2+) and Fe(3+) in the presence of 10 kDa dextran monodispersed from the aerosol phase. Cross-linking was achieved with epichlorhydrin, nuclophilication with NH3, purification with ultrafiltration and dialysis. Particles and a commercial product (Rienso(r), Takeda Pharma) underwent physicochemical characterizations. Biocompatibility was assessed by Resazurin on LLC-PK1 cells; the internalization rate was measured for three cell lines (HAEC, HASMC, HT29). Core size was 5.61 +/- 1.25 nm; hydrodynamic size was 49.56 +/- 11.73 nm. The number of sterically accessible amine groups averaged 9.9. The cores showed cubic magnetite structure. Values of r1 and r2 were 10.9 and 148.17 mM(-1) s(-1). Cellular viability was unchanged after incubation. Introduction of aerosol phase dextran resulted in a reduction of the overall hydrodynamic diameter and a narrower size distribution of the synthesized particles. Electron tomography visualized for the first time the postulated 'hairy layer' of the dextran coating and enabled the measurement of the overall diameter of 100.2 +/- 7.92 nm. The resulting nanoparticle is biocompatible, functionalizable and detectable at nanomolar concentrations with MRI and optical imaging. It can potentially serve as a platform for multimodal molecular imaging and targeted therapy approaches. PMID- 24753452 TI - Preparative separation of five flavones from flowers of Polygonum cuspidatum by high-speed countercurrent chromatography. AB - A preparative high-speed countercurrent chromatography method was successfully used for the isolation of five minor flavones from Polygonum cuspidatum flowers. Among them, three compounds were obtained from P. cuspidatum for the first time. A twin two-phase solvent system composed of n-hexane/ethyl acetate/ethanol/water (1:6:3:6, v/v/v/v) and petroleum ether/ethyl acetate/methanol/water (2:4:3:3, v/v/v/v) was developed. Compounds were obtained from the fraction B and fraction C prepurified by silica gel column chromatography. Five minor compositions, 6.8 mg of hesperidin, 11.2 mg of phloridzin, 4.9 mg of luteolin, 5.3 mg of hyperin, and 3.7 mg of luteoloside were obtained from 140 mg of the fraction B and 110 mg of fraction C with a purity of 95.3, 96.4, 98.0, 96.8, and 95.3%, respectively, as determined by high-performance liquid chromatography. The structures of these compounds were identified by (1) H and (13) C NMR spectroscopy. PMID- 24753453 TI - Investigation of a vitamin B12 conjugate as a PET imaging probe. AB - Nutrient demand is a fundamental characteristic of rapidly proliferating cells. Vitamin B12 is vital for cell proliferation; thus neoplastic cells have an increased demand for this essential nutrient. In this study we exploited the vitamin B12 uptake pathway to probe the nutritional demand of proliferating cells with a radiolabeled B12 derivative in various preclinical tumor models. We describe the synthesis and biological evaluations of copper-64-labeled B12 ethylenediamine-benzyl-1,4,7-triazacyclononane-N,N',N''-triacetic acid (B12 -en Bn-NOTA-(64) Cu), the first example of a B12 derivative for positron emission tomography (PET) imaging. Small-animal imaging and pharmacological evaluation show high tumor uptake ranging from 2.20 to 4.84% ID g(-1) at 6 h post administration. Competition studies with excess native B12 resulted in a 95% decrease in tumor accumulation, indicating the specificity of this radiopharmaceutical for B12 endocytotic transport proteins. These results show that a vitamin B12 PET radiopharmaceutical has potential utility for non-invasive imaging of enhanced nutrient demand in proliferating cells. PMID- 24753454 TI - Changes in the social environment induce neurogenic plasticity predominantly in niches residing in sensory structures of the zebrafish brain independently of cortisol levels. AB - The social environment is known to modulate adult neurogenesis. Studies in mammals and birds have shown a strong correlation between social isolation and decreases in neurogenesis, whereas time spent in an enriched environment has been shown to restore these deficits and enhance neurogenesis. These data suggest that there exists a common adaptive response among neurogenic niches to each extreme of the social environment. We sought to further test this hypothesis in zebrafish, a social species with distinct neurogenic niches within primary sensory structures and telencephalic nuclei of the brain. By examining stages of adult neurogenesis, including the proliferating stem/progenitor population, their surviving cohort, and the resulting newly differentiated neuronal population, we show that niches residing in sensory structures are most sensitive to changes in the social context, and that social isolation or novelty are both capable of decreasing the number of proliferating cells while increasing the number of newborn neurons within a single niche. Contrary to observations in rodents, we demonstrate that social novelty, a form of enrichment, does not consistently rescue deficits in cell proliferation following social isolation, and that cortisol levels do not negatively regulate changes in adult neurogenesis, but are correlated with the social context. We propose that enhancement or suppression of adult neurogenesis in the zebrafish brain under different social contexts depends largely on the type of niche (sensory or telencephalic), experience from the preceding social environment, and occurs independently of changes in cortisol levels. PMID- 24753455 TI - Gel scaffolds of BMP-2-binding peptide amphiphile nanofibers for spinal arthrodesis. AB - Peptide amphiphile (PA) nanofibers formed by self-assembly can be customized for specific applications in regenerative medicine through the use of molecules that display bioactive signals on their surfaces. Here, the use of PA nanofibers with binding affinity for the bone promoting growth factor BMP-2 to create a gel scaffold for osteogenesis is reported. With the objective of reducing the amount of BMP-2 used clinically for successful arthrodesis in the spine, amounts of growth factor incorporated in the scaffolds that are 10 to 100 times lower than that those used clinically in collagen scaffolds are used. The efficacy of the bioactive PA system to promote BMP-2-induced osteogenesis in vivo is investigated in a rat posterolateral lumbar intertransverse spinal fusion model. PA nanofiber gels displaying BMP-2-binding segments exhibit superior spinal fusion rates relative to controls, effectively decreasing the required therapeutic dose of BMP 2 by 10-fold. Interestingly, a 42% fusion rate is observed for gels containing the bioactive nanofibers without the use of exogenous BMP-2, suggesting the ability of the nanofiber to recruit endogenous growth factor. Results obtained here demonstrate that bioactive biomaterials with capacity to bind specific growth factors by design are great targets for regenerative medicine. PMID- 24753456 TI - Signal enhancement of glucuronide conjugates in LC-MS/MS by derivatization with the phosphonium propylamine cation tris(trimethoxyphenyl) phosphonium propylamine, for forensic purposes. AB - Although chemical derivatization for signal enhancement in drug testing is most often associated with gas chromatography, it also has the potential to improve the detection of analytes poorly ionized by atmospheric pressure ionization techniques, such as electrospray ionization used in liquid chromatography-mass spectrometry. A number of acidic compounds, namely drug glucuronides (e.g. conjugates of temazepam, oxazepam, lorazepam, morphine, testosterone, epitestosterone, 5-alpha-dihydrotestosterone, androsterone, p-nitrophenol, and paracetamol) were successfully derivatized with tris(trimethoxyphenyl) phosphoniumpropylamine to introduce a quaternary cation functionality to the analytes. Benzodiazepine glucuronides were more specifically investigated, and following positive mode electrospray ionization mass spectrometry, average improvements to peak areas as a result of derivatization were 67-, 6-, and 7- fold for temazepam, oxazepam, and lorazepam glucuronides. Average improvements to the signal-to-noise ratios for temazepam, oxazepam, and lorazepam glucuronides were 1336-, 371- and 217-fold, respectively. The values obtained for the derivatized conjugate were also typically higher than those for the underivatized parent drug. Urine containing benzodiazepine glucuronides was also successfully derivatized. The data indicates potential for the use of charge derivatization to improve the detection of molecules with acidic functionalities by liquid chromatography-mass spectrometry (LC-MS) techniques in certain scenarios. PMID- 24753457 TI - Glycolaldehyde and maleyl conjugated human serum albumin as potential macrophage targeting carriers for molecular imaging purposes. AB - Maleylated bovine serum albumin is a known ligand for targeting macrophages and has potential as a carrier for molecular imaging purposes. We present a novel synthesis of glycolaldehyde-conjugated human serum albumin (GA-HSA) and maleylated human serum albumin (Mal-HSA). Seventeen modifications of fluorescently tagged GA-HSA and Mal-HSA molecules with different degrees of conjugation were prepared. The comparative uptake studies, using 12 of these modifications, were done in vitro on mouse monocytes/macrophages (RAW264.7), and evaluated qualitatively by confocal microscopy and quantitatively by flow cytometry. The GA modifications are taken up by the macrophages approximately 40% better than the maleyl modifications at low concentrations (<= 3 MUM), while at higher concentrations it appears that the maleyl modifications are taken up around 25-44% better than the GA-modified HSA. However, high uptake at low concentrations will be beneficial for in vivo localizing inflammation in areas with low penetration of the probe as in an atherosclerotic plaque. Further, another advantage of GA-HSA is that GA competes less than the maleyl group for the free reactive amine sites that are to be used for conjugation of metal chelating ligands (e.g. tetraazacyclododecanetetraacetic acid and triazacyclononanetriacetic acid). Metal ions such as Gd(3+) and Mn(2+) can be chelated for positive Magnetic Resonance (MR) contrast and positron emitting ions such as (64) Cu(2+) and (68) Ga(3+) for Positron Emission Tomography (PET) imaging. These are important properties, especially, when considering the MR contrast possibilities owing to the low sensitivity of the technique, and would motivate the use of GA-HSA before Mal-HSA. PMID- 24753458 TI - Poly(glycidyl methacrylate-co-N-methylolacrylamide-co-ethylene dimethacrylate) monolith coupled to high-performance liquid chromatography for the determination of adenosine phosphates in royal jelly. AB - A polymer monolith microextraction method coupled with high-performance liquid chromatography was developed for the determination of adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate. The monolithic column was synthesized inside fused-silica capillaries using thermal initiation free-radical polymerization with glycidyl methacrylate as the monomer, ethylene dimethacrylate as the cross-linker, cyclohexanol, and 1-dodecanol as the porogen. N Methylolacrylamide, an important hydrophilic monomer, was incorporated into the polymerization mixture to enhance the hydrophilicity of the poly(glycidyl methacrylate-co-ethylene dimethacrylate) column. The obtained poly(glycidyl methacrylate-co-N-methylolacrylamide-co-ethylene dimethacrylate) monolith was characterized by scanning electron microscopy, Fourier-transform infrared spectra, and X-ray photoelectron spectroscopy. Optimum conditions for the preconcentration and separation of the target adenosines were also investigated. Under the optimum conditions, we obtained acceptable linearities, low limits of detection, and good relative standard deviations. The developed polymer monolith microextraction with high-performance liquid chromatography method exhibited a good performance with recovery values in the range of 76.9-104.7% when applied to the determination of the adenosines in five royal jelly samples. PMID- 24753459 TI - The economic impact of acute kidney injury in England. AB - BACKGROUND: Acute kidney injury (AKI) is one of the most common complications affecting hospital inpatients around the world. It is associated with high mortality and adverse long-term outcomes, but there is uncertainty regarding its prevalence and cost. We estimate the prevalence of AKI in hospital inpatients in a universal health-care system, and the immediate and long-term impacts on survival, quality of life and health-care costs. METHODS: We examined prevalence of AKI in inpatients using both routine national data for the National Health Service (NHS) in England, and laboratory data from East Kent Hospitals. We used regression analyses to estimate the impact of AKI on mortality and length of hospital stay, and a Markov model to estimate the impact on quality-adjusted life years and NHS costs. RESULTS: AKI was recorded in 2.43% of hospital admissions in Hospital Episode Statistics (HES), but age- and gender-standardized estimates derived from laboratory data suggest the true prevalence may be more than five times as high (14.15%). We estimate that the annual number of excess inpatient deaths associated with AKI in England may be above 40,000. The annual cost of AKI related inpatient care in England is estimated at L1.02 billion, just over 1% of the NHS budget. The lifetime cost of post-discharge care for people who had AKI during hospital admission in 2010-11 is estimated at L179 million. CONCLUSIONS: AKI prevalence in inpatients may be considerably higher than previously thought, and up to four fifths of cases may not be captured in routine hospital data. AKI is associated with large numbers of in-hospital deaths and with high NHS costs. Comparison of HES and East Kent data suggests that most of the cases recorded in HES may be relatively severe AKI (AKIN 2-3). PMID- 24753460 TI - Obesity and renal disease: not all fat is created equal and not all obesity is harmful to the kidneys. AB - The prevalence of obesity is increasing worldwide and contributes to many health problems, including kidney disease. Unexpectedly, 10-30% of obese individuals are apparently not at increased risk of metabolic diseases, e.g. type 2 diabetes, cardiovascular disease and risk of renal disease. Their phenotype is labeled 'metabolically healthy obesity'. In the search for mechanisms explaining this unexpected condition, a favourable type of body fat distribution with low insulin resistance and with low subclinical inflammation has been identified. Furthermore, signalling pathways have been found that distinguish between metabolically benign and malignant obesity. In addition, the important roles of fatty acids, adipokines and hepatokines were identified. These factors regulate insulin resistance and subclinical inflammation. Onset and evolution of chronic kidney disease (CKD) are affected by obesity. CKD also increases the risk of insulin resistance and subclinical inflammation, two pathways that play an important role in the pathogenesis of renal malfunction. This brief review summarizes novel insights, specifically how distinct body fat compartments (including perivascular and even renal sinus fat) may have an impact on progression of CKD. PMID- 24753461 TI - Fluid intake and mortality: drinking in the data. PMID- 24753462 TI - The K-factor in chronic kidney disease: biomarkers of calcification inhibition and beyond. PMID- 24753463 TI - Photoinduced intercalation and coordination of a dirhodium complex to DNA: dual DNA binding. AB - Two new complexes, cis-H,H-[Rh2 (OCCH3 NH)2 (LL)(CH3 CN)2 ](2+) , where LL=bpy (2, bpy=2,2'-bipyridine) and dppz (3, dppz=dipyrido[3,2-a:2',3'-c]phenazine), were prepared from the reaction of cis-H,H-[Rh2 (OCCH3 NH)2 (CH3 CN)6 ](2+) (1) with the corresponding bidentate ligand. The bpy and dppz ligands chelate to the same rhodium atom and are positioned trans to the amidato N atoms, as determined by the single crystal X-ray structure of 2. Irradiation of 2 and 3 with visible light in water results in the exchange of one CH3 CNeq ligand for an H2 O molecule with quantum yields, Phi400 , of 0.040 and 0.044, respectively (lambdairr =400 nm). The identities of the photoproducts of 2 and 3 were determined to be cis-H,H-[Rh2 (OCCH3 NH)2 (L)(H2 O)(CH3 CN)](2+) , where L is bpy (4) and dppz (5), respectively. Mobility shift assays show that 4 crosslinks double-stranded DNA, and ESI-MS experiments indicate that both 4 and 5 form covalent adducts with single-stranded DNA. In addition, relative viscosity and 2D NMR experiments show that the dppz ligand of 5 also intercalates into DNA upon irradiation, making 3 a dual-binding agent that both intercalates and covalently binds to DNA upon the absorption of visible light. PMID- 24753464 TI - A look into the cockpit of the developing locust: looming detectors and predator avoidance. AB - For many animals, the visual detection of looming stimuli is crucial at any stage of their lives. For example, human babies of only 6 days old display evasive responses to looming stimuli (Bower et al. [1971]: Percept Psychophys 9: 193 196). This means the neuronal pathways involved in looming detection should mature early in life. Locusts have been used extensively to examine the neural circuits and mechanisms involved in sensing looming stimuli and triggering visually evoked evasive actions, making them ideal subjects in which to investigate the development of looming sensitivity. Two lobula giant movement detectors (LGMD) neurons have been identified in the lobula region of the locust visual system: the LGMD1 neuron responds selectively to looming stimuli and provides information that contributes to evasive responses such as jumping and emergency glides. The LGMD2 responds to looming stimuli and shares many response properties with the LGMD1. Both neurons have only been described in the adult. In this study, we describe a practical method combining classical staining techniques and 3D neuronal reconstructions that can be used, even in small insects, to reveal detailed anatomy of individual neurons. We have used it to analyze the anatomy of the fan-shaped dendritic tree of the LGMD1 and the LGMD2 neurons in all stages of the post-embryonic development of Locusta migratoria. We also analyze changes seen during the ontogeny of escape behaviors triggered by looming stimuli, specially the hiding response. PMID- 24753465 TI - In vivo MR imaging of intercellular adhesion molecule-1 expression in an animal model of multiple sclerosis. AB - Upregulation of intercellular adhesion molecule 1 (ICAM-1) is an early event in lesion formation in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Monitoring its expression may provide a biomarker for early disease activity and allow validation of anti inflammatory interventions. Our objective was therefore to explore whether ICAM-1 expression can be visualized in vivo during EAE with magnetic resonance imaging (MRI) using micron-sized particles of iron oxide (MPIO), and to compare accumulation profiles of targeted and untargeted MPIO, and a gadolinium containing agent. Targeted alphaICAM-1-MPIO/untargeted IgG-MPIO were injected at two model-characteristic phases of EAE (in myelin oligodendrocyte glycoprotein35 55 -immunized C57BL/6 J mice), that is, at the peak of the acute phase (14 +/- 1 days post-immunization) and during the chronic phase (26 +/- 1 days post immunization), followed by T2 *-weighted MRI. Blood-brain barrier (BBB) permeability was measured using gadobutrol-enhanced MRI. Cerebellar microvessels were analyzed for ICAM-1 mRNA expression using quantitative PCR (qPCR). ICAM-1 and iron oxide presence was examined with immunohistochemistry (IHC). During EAE, ICAM-1 was expressed by brain endothelial cells, macrophages and T-cells as shown with qPCR and (fluorescent) IHC. EAE animals injected with alphaICAM-1-MPIO showed MRI hypointensities, particularly in the subarachnoid space. alphaICAM-1 MPIO presence did not differ between the phases of EAE and was not associated with BBB dysfunction. alphaICAM-1-MPIO were associated with endothelial cells or cells located at the luminal side of blood vessels. In conclusion, ICAM-1 expression can be visualized with in vivo molecular MRI during EAE, and provides an early tracer of disease activity. PMID- 24753469 TI - AR WOW - video articles. PMID- 24753468 TI - Developing new methods to answer old and new questions in neurodegenerative diseases: 21(st) Workshop of the HUPO Brain Proteome Project (HBPP) 23-24 January 2014, Honolulu, Hawaii. AB - The HUPO Brain Proteome Project (HUPO BPP) held its 21(st) workshop in Honolulu, Hawaii. During the 23-24 January 2014 the island became the center of the open workshop of the scientific community. PMID- 24753470 TI - Human embryos are turning on the e-pages of AR. PMID- 24753475 TI - Enigmatic cranial superstructures among Chamorro ancestors from the Mariana Islands: gross anatomy and microanatomy. AB - This study focuses on the gross anatomy, anatomic relations, microanatomy, and the meaning of three enigmatic, geographically patterned, and quasi-continuous superstructures of the posterior cranium. Collectively known as occipital superstructures (OSSs), these traits are the occipital torus tubercle (TOT), retromastoid process (PR), and posterior supramastoid tubercle (TSP). When present, TOT, PR, and TSP develop at posterior cranial attachment sites of the upper trapezius, superior oblique, and sternocleidomastoid muscles, respectively. Marked expression and co-occurrence of these OSSs are virtually circumscribed within Oceania and reach highest recorded frequencies in protohistoric Chamorros (CHamoru) of the Mariana Islands. Prior to undertaking scanning electron microscopy (SEM) work, our working multifactorial model for OSS development was that early-onset, long-term, and chronic activity-related microtrauma at enthesis sites led to exuberant reactive or reparative responses in a substantial minority of genetically predisposed (and mostly male) individuals. SEM imaging, however, reveals topographic patterning that questions, but does not negate, activity induction of these superstructures. Although OSSs appear macroscopically as relatively large and discrete phenomena, SEM findings reveal a unique, widespread, and seemingly systemic distribution of structures over the occipital surface that have the appearance of OSS microforms. Nevertheless, apparent genetic underpinnings, anatomic relationships with muscle entheses, and positive correlation of OSS development with humeral robusticity continue to suggest that these superstructures have potential to at once bear witness to Chamorro population history and inform osteobiographical constructions of chronic activity patterns in individuals bearing them. Further work is outlined that would illuminate the proximate and ultimate meanings of OSS. PMID- 24753476 TI - Gasoline from biomass through refinery-friendly carbohydrate-based bio-oil produced by ketalization. AB - The introduction of biomass-derived compounds as an alternative feed into the refinery structure that already exists can potentially converge energy uses with ecological sustainability. Herein, we present an approach to produce a bio-oil based on carbohydrate-derived isopropylidene ketals obtained by reaction with acetone under acidic conditions directly from second-generation biomass. The obtained bio-oil showed a greater chemical inertness and miscibility with gasoil than typical bio-oil from fast pyrolysis. Catalytic upgrading of the bio-oil over zeolites (USY and Beta) yielded gasoline with a high octane number. Moreover, the co-processing of gasoil and bio-oil improved the gasoline yield and quality compared to pure gasoil and also reduced the amount of oxygenated compounds and coke compared with pure bio-oil, which demonstrates a synergistic effect. PMID- 24753477 TI - A comparative study of orthotropic and isotropic bone adaptation in the femur. AB - Functional adaptation of the femur has been studied extensively by embedding remodelling algorithms in finite element models, with bone commonly assumed to have isotropic material properties for computational efficiency. However, isotropy is insufficient in predicting the directionality of bone's observed microstructure. A novel iterative orthotropic 3D adaptation algorithm is proposed and applied to a finite element model of the whole femur. Bone was modelled as an optimised strain-driven adaptive continuum with local orthotropic symmetry. Each element's material orientations were aligned with the local principal stress directions and their corresponding directional Young's moduli updated proportionally to the associated strain stimuli. The converged predicted density distributions for a coronal section of the whole femur were qualitatively and quantitatively compared with the results obtained by the commonly used isotropic approach to bone adaptation and with ex vivo imaging data. The orthotropic assumption was shown to improve the prediction of bone density distribution when compared with the more commonly used isotropic approach, whilst producing lower comparative mass, structurally optimised models. It was also shown that the orthotropic approach can provide additional directional information on the material properties distributions for the whole femur, an advantage over isotropic bone adaptation. Orthotropic bone models can help in improving research areas in biomechanics where local structure and mechanical properties are of key importance, such as fracture prediction and implant assessment. PMID- 24753478 TI - The capsaicin analog nonivamide decreases total energy intake from a standardized breakfast and enhances plasma serotonin levels in moderately overweight men after administered in an oral glucose tolerance test: a randomized, crossover trial. AB - SCOPE: Since bolus administration of capsaicin has been shown to reduce appetite and ad libitum energy intake, this study elucidated the satiating effect of the less pungent capsaicin analog, nonivamide, on subjective feelings of hunger, ad libitum food intake, and satiating hormones in moderately overweight male subjects. METHODS AND RESULTS: Following a randomized, crossover design, 24 male subjects (BMI 27.5 +/- 1.53 kg/m(2) ) received either 75 g glucose in 300 mL water (control treatment, CT) or the same glucose solution supplemented with 0.15 mg nonivamide (nonivamide treatment, NT). Ratings of hunger were assessed before and 2 h after each intervention by means of visual analog scales. Ad libitum energy and macronutrient intakes from a standardized breakfast 2 h postintervention were calculated. Plasma glucose, insulin, peptide YY (3-36), glucagon-like peptide 1, and serotonin were quantified in blood samples drawn before and 15, 30, 60, 90, and 120 min after each intervention. NT reduced subjective feelings of hunger and ad libitum energy and carbohydrate intakes from a standardized breakfast compared to CT. Plasma analysis revealed higher mean plasma glucagon-like peptide 1 and serotonin concentrations after NT versus CT. CONCLUSION: Addition of 0.15 mg nonivamide to a glucose solution reduced ad libitum energy intake from a standardized breakfast in moderately overweight men. PMID- 24753479 TI - Proteomic analysis of mouse astrocytes and their secretome by a combination of FASP and StageTip-based, high pH, reversed-phase fractionation. AB - Astrocytes are the most abundant cells in the CNS, but their function remains largely unknown. Characterization of the whole-cell proteome and secretome in astrocytes would facilitate the study of their functions in various neurodegenerative diseases and astrocyte-neuron communication. To build a reference proteome, we established a C8-D1A astrocyte proteome to a depth of 7265 unique protein groups using a novel strategy that combined two-step digestion, filter-aided sample preparation, StageTip-based high pH fractionation, and high resolution MS. Nearly, 6000 unique protein groups were identified from conditioned media of astrocyte cultures, constituting the largest astrocyte secretome that has been reported. High-confidence whole-cell proteomes and secretomes are valuable resources in studying astrocyte function by label-free quantitation and bioinformatics analysis. All MS data have been deposited in the ProteomeXchange with identifier PXD000501 (http://proteomecentral.proteomexchange.org/dataset/PXD000501). PMID- 24753480 TI - Fractionation of hemp hurds by organosolv pretreatment and its effect on production of lignin and sugars. AB - Fractionation of hemp hurds into its three main components, cellulose, hemicellulose, and lignin, was carried out using organosolv pretreatment. The effect of processing parameters, such as temperature, catalyst concentration, reaction time, and methanol (MeOH) concentration, on the dissolution and recovery of hemicellulose and lignin was determined. More than 75% of total hemicellulose and 75% of total lignin was removed in a single step with low amounts of degradation products under the following conditions: 165 degrees C, 3% H2 SO4 , 20 min reaction time, and 45% MeOH. Enzymatic hydrolysis of the residual pretreated biomass yielded up to 60% of cellulose-to-glucose conversion. The maximum recovery of the main components was obtained at a combined severity factor value of around one. Characterization of pretreated biomass and isolated lignin was carried out with FTIR and 2D (13) C-(1) H correlation HSQC NMR spectroscopy, the latter technique providing detailed structural information about the obtained methanol organosolv lignin (MOSL). Results suggested that xylopyranoside is the major carbohydrate associated with hemp lignin. The chemical properties of MOSL samples in terms of their phenolic group content and antioxidant capacity were also investigated. The results showed that MOSL samples have a high phenolic group content and antioxidant capacity relative to Klason lignin. PMID- 24753482 TI - 3D geometry and quantitative variation of the cervico-thoracic region in Crocodylia. AB - This study aims to interpret the axial patterning of the crocodylian neck, and to find a potential taxonomic signal that corresponds to vertebral position. Morphological variation in the cervico-thoracic vertebrae is compared in fifteen different crocodylian species using 3D geometric morphometric methods. Multivariate analysis indicated that the pattern of intracolumnar variation was a gradual change in shape of the vertebral series (at the parapophyses, diapophyses, prezygapohyses, and postzygapohyses), in the cervical (C3 to C9) and dorsal (D1-D2) regions which was quite conservative among the crocodylians studied. In spite of this, we also found that intracolumnar shape variation allowed differentiation between two sub regions of the crocodylian neck. Growth is subtly correlated with vertebral shape variation, predicting changes in both the vertebral centrum and the neural spine. Interestingly, the allometric scaling for the pooled sample is equivalently shared by each vertebra studied. However, there were significant taxonomic differences, both in the average shape of the entire neck configuration (regional variation) and by shape variation at each vertebral position (positional variation) among the necks. The average neck vertebra of crocodylids is characterized by a relatively cranio-caudally short neural arch, whereby the spine is relatively longer and pointed orthogonal to the frontal plane. Conversely, the average vertebra in alligatorids has cranio caudally longer neural spine and arch, with a relatively (dorso-ventrally) shorter spine. At each vertebral position there are significant differences between alligatorids and crocodylids. We discuss that the delayed timing of neurocentral fusion in Alligatoridae possibly explains the observed taxonomic differences. PMID- 24753481 TI - Mannose-binding lectin 2 gene polymorphism and lung damage in primary ciliary dyskinesia. AB - BACKGROUND: Mannose-binding lectin (MBL) plays an important role in innate immunity and has been reported to be associated with the age-related decline in lung function in cystic fibrosis. HYPOTHESIS: MBL polymorphisms are associated with lung function decline in Primary Ciliary Dyskinesia (PCD). METHODS: We performed sputum microbiology, spirometry pre- and post-administration of salbutamol, ciliary motion analysis, ultrastructural assessment of cilia, ciliogenesis in culture, and chest high resolution computed tomography in children with a clinical history of respiratory tract infections and/or presence of bronchiectasis suggestive of PCD or secondary ciliary dyskinesia (SCD). All subjects were evaluated for single nucleotide polymorphisms in the gene encoding MBL-2. RESULTS: The diagnosis of PCD was established in 45 subjects, while in the remaining 53 the diagnosis was SCD. A significant bronchodilator response was observed only in PCD associated with the MBL2-3 genotype, which is known to be associated with low/undetectable MBL serum levels. Also, bronchiectasis severity was significantly greater in subjects with MBL2-3 in both PCD and SCD. No other association was found between MBL genotypes and clinical findings. CONCLUSIONS: MBL plays a relatively minor role as a disease modifier in PCD. A similar finding in SCD supports the likely significance of this result. PMID- 24753483 TI - Modeling and simulation of the effects of cyclic loading on articular cartilage lesion formation. AB - We present a model of articular cartilage lesion formation to simulate the effects of cyclic loading. This model extends and modifies the reaction-diffusion delay model by Graham et al., 2012 for the spread of a lesion formed though a single traumatic event. Our model represents 'implicitly' the effects of loading, meaning through a cyclic sink term in the equations for live cells. Our model forms the basis for in silico studies of cartilage damage relevant to questions in osteoarthritis, for example, that may not be easily answered through in vivo or in vitro studies. Computational results are presented that indicate the impact of differing levels of erythropoietin on articular cartilage lesion abatement. PMID- 24753484 TI - Efficient Bayesian inference under the structured coalescent. AB - MOTIVATION: Population structure significantly affects evolutionary dynamics. Such structure may be due to spatial segregation, but may also reflect any other gene-flow-limiting aspect of a model. In combination with the structured coalescent, this fact can be used to inform phylogenetic tree reconstruction, as well as to infer parameters such as migration rates and subpopulation sizes from annotated sequence data. However, conducting Bayesian inference under the structured coalescent is impeded by the difficulty of constructing Markov Chain Monte Carlo (MCMC) sampling algorithms (samplers) capable of efficiently exploring the state space. RESULTS: In this article, we present a new MCMC sampler capable of sampling from posterior distributions over structured trees: timed phylogenetic trees in which lineages are associated with the distinct subpopulation in which they lie. The sampler includes a set of MCMC proposal functions that offer significant mixing improvements over a previously published method. Furthermore, its implementation as a BEAST 2 package ensures maximum flexibility with respect to model and prior specification. We demonstrate the usefulness of this new sampler by using it to infer migration rates and effective population sizes of H3N2 influenza between New Zealand, New York and Hong Kong from publicly available hemagglutinin (HA) gene sequences under the structured coalescent. AVAILABILITY AND IMPLEMENTATION: The sampler has been implemented as a publicly available BEAST 2 package that is distributed under version 3 of the GNU General Public License at http://compevol.github.io/MultiTypeTree. PMID- 24753485 TI - MRMPROBS suite for metabolomics using large-scale MRM assays. AB - We developed new software environment for the metabolome analysis of large-scale multiple reaction monitoring (MRM) assays. It supports the data format of four major mass spectrometer vendors and mzML common data format. This program provides a process pipeline from the raw-format import to high-dimensional statistical analyses. The novel aspect is graphical user interface-based visualization to perform peak quantification, to interpolate missing values and to normalize peaks interactively based on quality control samples. Together with the software platform, the MRM standard library of 301 metabolites with 775 transitions is also available, which contributes to the reliable peak identification by using retention time and ion abundances. AVAILABILITY AND IMPLEMENTATION: MRMPROBS is available for Windows OS under the creative-commons by-attribution license at http://prime.psc.riken.jp. PMID- 24753486 TI - aLFQ: an R-package for estimating absolute protein quantities from label-free LC MS/MS proteomics data. AB - MOTIVATION: The determination of absolute quantities of proteins in biological samples is necessary for multiple types of scientific inquiry. While relative quantification has been commonly used in proteomics, few proteomic datasets measuring absolute protein quantities have been reported to date. Various technologies have been applied using different types of input data, e.g. ion intensities or spectral counts, as well as different absolute normalization strategies. To date, a user-friendly and transparent software supporting large scale absolute protein quantification has been lacking. RESULTS: We present a bioinformatics tool, termed aLFQ, which supports the commonly used absolute label free protein abundance estimation methods (TopN, iBAQ, APEX, NSAF and SCAMPI) for LC-MS/MS proteomics data, together with validation algorithms enabling automated data analysis and error estimation. AVAILABILITY AND IMPLEMENTATION: aLFQ is written in R and freely available under the GPLv3 from CRAN (http://www.cran.r project.org). Instructions and example data are provided in the R-package. The raw data can be obtained from the PeptideAtlas raw data repository (PASS00321). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24753487 TI - Multiscale DNA partitioning: statistical evidence for segments. AB - MOTIVATION: DNA segmentation, i.e. the partitioning of DNA in compositionally homogeneous segments, is a basic task in bioinformatics. Different algorithms have been proposed for various partitioning criteria such as Guanine/Cytosine (GC) content, local ancestry in population genetics or copy number variation. A critical component of any such method is the choice of an appropriate number of segments. Some methods use model selection criteria and do not provide a suitable error control. Other methods that are based on simulating a statistic under a null model provide suitable error control only if the correct null model is chosen. RESULTS: Here, we focus on partitioning with respect to GC content and propose a new approach that provides statistical error control: as in statistical hypothesis testing, it guarantees with a user-specified probability [Formula: see text] that the number of identified segments does not exceed the number of actually present segments. The method is based on a statistical multiscale criterion, rendering this as a segmentation method that searches segments of any length (on all scales) simultaneously. It is also accurate in localizing segments: under benchmark scenarios, our approach leads to a segmentation that is more accurate than the approaches discussed in the comparative review of Elhaik et al. In our real data examples, we find segments that often correspond well to features taken from standard University of California at Santa Cruz (UCSC) genome annotation tracks. AVAILABILITY AND IMPLEMENTATION: Our method is implemented in function smuceR of the R-package stepR available at http://www.stochastik.math.uni-goettingen.de/smuce. PMID- 24753488 TI - Improving B-cell epitope prediction and its application to global antibody antigen docking. AB - MOTIVATION: Antibodies are currently the most important class of biopharmaceuticals. Development of such antibody-based drugs depends on costly and time-consuming screening campaigns. Computational techniques such as antibody antigen docking hold the potential to facilitate the screening process by rapidly providing a list of initial poses that approximate the native complex. RESULTS: We have developed a new method to identify the epitope region on the antigen, given the structures of the antibody and the antigen-EpiPred. The method combines conformational matching of the antibody-antigen structures and a specific antibody-antigen score. We have tested the method on both a large non-redundant set of antibody-antigen complexes and on homology models of the antibodies and/or the unbound antigen structure. On a non-redundant test set, our epitope prediction method achieves 44% recall at 14% precision against 23% recall at 14% precision for a background random distribution. We use our epitope predictions to rescore the global docking results of two rigid-body docking algorithms: ZDOCK and ClusPro. In both cases including our epitope, prediction increases the number of near-native poses found among the top decoys. AVAILABILITY AND IMPLEMENTATION: Our software is available from http://www.stats.ox.ac.uk/research/proteins/resources. PMID- 24753489 TI - A new era in bioimage informatics. PMID- 24753490 TI - Rgb: a scriptable genome browser for R. AB - SUMMARY: Thanks to its free licensing and the development of initiatives like Bioconductor, R has become an essential part of the bioinformatics toolbox in the past years and is more and more confronted with genomically located data. While separate solutions are available to manipulate and visualize such data, no R package currently offers the efficiency required for computationally intensive tasks such as interactive genome browsing. The package proposed here fulfills this specific need, providing a multilevel interface suitable for most needs, from a completely interfaced genome browser to low-level classes and methods. Its time and memory efficiency have been challenged in a human dataset, where it outperformed existing solutions by several orders of magnitude. AVAILABILITY AND IMPLEMENTATION: R sources and packages are freely available at the CRAN repository and dedicated Web site: http://bioinformatics.ovsa.fr/Rgb. Distributed under the GPL 3 license, compatible with most operating systems (Windows, Linux, Mac OS) and architectures. CONTACT: maressyl@gmail.com or fabrice.jardin@chb.unicancer.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24753491 TI - Polymorphism at the TNF-alpha gene interacts with Mediterranean diet to influence triglyceride metabolism and inflammation status in metabolic syndrome patients: From the CORDIOPREV clinical trial. AB - SCOPE: To examine whether the consumption of a Mediterranean diet (MedDiet), compared with a low-fat diet, interacts with two single nucleotide polymorphisms at the tumor necrosis factor alpha gene (rs1800629, rs1799964) in order to improve triglycerides (TG), glycemic control, and inflammation markers. METHODS AND RESULTS: Genotyping, biochemical measurements, dietary intervention, and oral fat load test meal were determined in 507 metabolic syndrome (MetS) patients selected from all the subjects included in CORDIOPREV clinical trial (n = 1002). At baseline, G/G subjects (n = 408) at the rs1800629 polymorphism, showed higher fasting and postprandial TG (p = 0.003 and p = 0.025, respectively), and high sensitivity C-reactive protein (hsCRP) (p = 0.003) plasma concentrations than carriers of the minor A-allele (G/A + A/A) (n = 99). After 12 months of MedDiet, baseline differences between genotypes disappeared. The decrease in TG and hsCRP was statistically significant in G/G subjects (n = 203) compared with carriers of the minor A-allele (p = 0.005 and p = 0.034, respectively) (n = 48). No other gene-diet interactions were observed in either diet. CONCLUSION: These results suggest that the rs1800629 at the tumor necrosis factor alpha gene interacts with MedDiet to influence TG metabolism and inflammation status in MetS subjects. Understanding the role of gene-diet interactions may be the best strategy for personalized treatment of MetS. PMID- 24753492 TI - Efficacy of occlusion of hepatic artery and risk of carbon dioxide gas embolism during laparoscopic hepatectomy in a pig model. AB - BACKGROUND: The important point in safely performing laparoscopic hepatectomy (LH) is to control bleeding. The aims of this study were: (i) to assess the bleeding reduction effect by occlusion of the hepatic artery in LH; and (ii) to evaluate the risk of carbon dioxide (CO2 ) gas embolism (GE) in the case of high pneumoperitoneum (PP). METHODS: Nine piglets underwent laparoscopic left medial lobe and left lateral lobe resection, receiving either occlusion of the hepatic artery (hepatic artery clamping group: HACG, n = 9) or no occlusion (hepatic artery declamping group: HADCG, n = 9) using a PP of 15 mmHg. In addition, we observed changes in hemodynamics induced by PP. The state of GE was observed using transesophageal echocardiography (TEE) during LH (n = 8). GE was graded as grade 0 (none), grade 1 (minor), and grade 2 (major). RESULTS: The HACG had significantly less bleeding compared to the HADCG (P < 0.01). During LH, four animals showed grade 1 (37.5%) and one animal showed grade 2 (12.5%) GE at 15 mmHg. At 20 mmHg, all animals showed grade 2 (100%) GE. CONCLUSION: The occlusion of the hepatic artery in LH reduces blood loss. The control of bleeding from the hepatic vein is feasible with a high PP, but there is a possibility of GE. PMID- 24753493 TI - A new method for estimating subject-specific muscle-tendon parameters of the knee joint actuators: a simulation study. AB - A new method for the estimation of subject-specific muscle-tendon parameters of the knee actuators based on dynamometry experiments is presented. The algorithm aims at estimating the tendon slack length and the optimal muscle fiber length by minimizing the difference between experimentally reproduced and model-based joint moments. The key innovative features are as follows: (i) the inclusion of a priori physiological knowledge to define a physiologically feasible set, the hot start for the optimization, and constraints for the optimization and (ii) the introduction of a new (affine) transformation of the muscle-tendon parameters, which greatly improves the numerical condition of the optimization. The influence of the initial guess and of measurement noise was studied in a simulation environment, and the performance was compared with that of the method presented earlier by Garner and Pandy for the upper limb. The tendon slack length was estimated for 97.5/63% (extensors/flexors) of all initial guesses within 2% of the ground truth. The optimal fiber length was estimated for 89/90% (extensors/flexors) of all initial guesses within 2% of the ground truth. When 10 Nm measurement noise was added, the mean value of the estimated tendon slack length deviated at most 1.9/1.6% (extensors/flexors) from the ground truth whereas the standard deviations were at most 5.1/3.9%. The mean value of the estimated optimal fiber length deviated at most 4.3/3.0% (extensors/flexors) from the ground truth whereas the standard deviations were at most 10.2/15.5%. In comparison, mean values resulting from the method of Garner and Pandy deviated up to 181% ( +/- 123%) and 119% ( +/- 30%) from the ground truth for, respectively, optimal fiber length and tendon slack length of rectus femoris. We concluded that the presented method had a low dependency on the initial guess and outperformed the method of Garner and Pandy in terms of accuracy by at least one order of magnitude when parameters were estimated from noisy data. The improvements open new perspectives for subject-specific modelling of muscles and tendons, which is beneficial for the accuracy of human motion simulations. PMID- 24753494 TI - Binding of insecticidal lectin Colocasia esculenta tuber agglutinin (CEA) to midgut receptors of Bemisia tabaci and Lipaphis erysimi provides clues to its insecticidal potential. AB - The insecticidal potential of Galanthus nivalis agglutinin-related lectins against hemipterans has been experimentally proven. However, the basis behind the toxicity of these lectins against hemipterans remains elusive. The present study elucidates the molecular basis behind insecticidal efficacy of Colocasia esculenta tuber agglutinin (CEA) against Bemisia tabaci and Lipaphis erysimi. Confocal microscopic analyses highlighted the binding of 25 kDa stable homodimeric lectin to insect midgut. Ligand blots followed by LC MS/MS analyses identified binding partners of CEA as vacuolar ATP synthase and sarcoplasmic endoplasmic reticulum type Ca(2+) ATPase from B. tabaci, and ATP synthase, heat shock protein 70 and clathrin heavy chain assembly protein from L. erysimi. Internalization of CEA into hemolymph was confirmed by Western blotting. Glycoprotein nature of the receptors was identified through glycospecific staining. Deglycosylation assay indicated the interaction of CEA with its receptors to be probably glycan mediated. Surface plasmon resonance analysis revealed the interaction kinetics between ATP synthase of B. tabaci with CEA. Pathway prediction study based on Drosophila homologs suggested the interaction of CEA with insect receptors that probably led to disruption of cellular processes causing growth retardation and loss of fecundity of target insects. Thus, the present findings strengthen our current understanding of the entomotoxic potentiality of CEA, which will facilitate its future biotechnological applications. PMID- 24753495 TI - Technical review, types of imaging, part 4--magnetic resonance imaging. PMID- 24753496 TI - Insulin-like growth factor 1 receptor signaling induced by supraphysiological doses of IGF-1 in human peripheral blood lymphocytes. AB - Insulin-like growth factor-1 (IGF-1) mediates some of growth hormone anabolic functions through its receptor, IGF-1R. Following ligand binding, intracellular signaling pathways are activated favouring proliferation, cell survival, tissue growth, development, and differentiation. IGF-1 is included in the World Anti Doping Agency Prohibited List. While the evidence for IGF-1 as performance enhancing substrate in healthy humans is still weak, clinical studies demonstrated that the endogenous growth hormone/IGF-1 excess is associated with cardiovascular implications. Previously, we demonstrated that human peripheral blood lymphocytes represent a suitable system to identify a gene signature, related to dihydrotestosterone or IGF-1 abuse, independent from the type of sport. In addition, in a proteomic study, we demonstrated that dihydrotestosterone hyperdosage affects cell motility and apoptosis. Here, we investigate the doping action of IGF-1 by means of a differential proteomic approach and specific protein arrays, revealing an active cytoskeletal reorganization mediated by Stat-1; moreover, IGF-1 stimulation produces a sustained activation of different signaling pathways as well as an overproduction of cytokines positively related to immune response and inflammation. In conclusion, these data indicate that, following IGF-1 hyperdosage, circulating peripheral blood lymphocytes could be more prone to transendothelial migration. PMID- 24753498 TI - Effect of criminal defendant's history of childhood sexual abuse and personality disorder diagnosis on juror decision making. AB - This study investigated whether a defendant's history of childhood sexual abuse (CSA) and/or personality disorder (PD) diagnosis affected juror decision making in a child sexual abuse trial. The PDs in the study were borderline PD and antisocial PD. Participants were 385 college students, 121 men and 264 women, who read a summary of a mock criminal trial and then made various juror decisions. Trial summaries were prepared by the principal investigator and were all uniform in content, length and detail. For the trial, both the defendant's gender and victim's gender were specified. The defendant was male, and the alleged victim was female. When the verdict was assessed, the results yielded that when the defendant's CSA history was presented, juror guilt ratings were higher than when there was no history of CSA. Similarly, when the defendant had a PD diagnosis, there were higher guilt ratings than when there was no PD diagnosis. CSA history and PD diagnosis were significant predictors of guilt ratings, suggesting that jurors perceive defendants more negatively if they have either been sexually abused as a child or have borderline or antisocial PD. PMID- 24753497 TI - Anti-gastroesophageal reflux surgery in infants with severe bronchopulmonary dysplasia. AB - Gastroesophageal reflux may exacerbate lung disease in infants with bronchopulmonary dysplasia (BPD). Anti-reflux surgery may therefore reduce the severity of this disease in some infants. We report a retrospective series of 22 infants with severe BPD who underwent anti-reflux surgery. Our experience indicates that these procedures can be safely performed in this population and that early post-operative initiation of gastric feeds is well tolerated. Modest post-operative reductions in required oxygen and median respiratory rate were observed. PMID- 24753499 TI - Patient-specific assessment of cardiovascular function by combination of clinical data and computational model with applications to patients undergoing Fontan operation. AB - The assessment of cardiovascular function is becoming increasingly important for the care of patients with single-ventricle defects. However, most measurement methods available in the clinical setting cannot provide a separate measure of cardiac function and loading conditions. In the present study, a numerical method has been proposed to compensate for the limitations of clinical measurements. The main idea was to estimate the parameters of a cardiovascular model by fitting model simulations to patient-specific clinical data via parameter optimization. Several strategies have been taken to establish a well-posed parameter optimization problem, including clinical data-matched model development, parameter selection based on an extensive sensitivity analysis, and proper choice of parameter optimization algorithm. The numerical experiments confirmed the ability of the proposed parameter optimization method to uniquely determine the model parameters given an arbitrary set of clinical data. The method was further tested in four patients undergoing the Fontan operation. Obtained results revealed a prevalence of ventricular abnormalities in the patient cohort and at the same time demonstrated the presence of marked inter-patient differences and preoperative to postoperative changes in cardiovascular function. Because the method allows a quick assessment and makes use of clinical data available in clinical practice, its clinical application is promising. PMID- 24753500 TI - Risk stratification in follicular neoplasm: a cytological assessment using the modified Bethesda classification. AB - BACKGROUND: The 2007 Bethesda classification for thyroid cytology defines follicular neoplasm as a category of cases with cellular specimens demonstrating abundant follicular cells arranged in a microfollicular pattern with little or no colloid. The current recommendation for the management of these cases is diagnostic lobectomy. There has been great difficulty and variability in triaging and reporting follicular neoplasm. To increase diagnostic accuracy, at the study institution, this category is subclassified further into 3 categories: 1) microfollicular-patterned neoplasm (MN); 2) Hurthle cell neoplasm (HN); and 3) follicular lesion with some features suggestive of but not diagnostic of the follicular variant of papillary thyroid carcinoma (FL). The authors reviewed the cases of follicular neoplasm observed over a period of 5 years to document the follow-up trend using this modified classification. METHODS: A search of the cytology records was performed for the period between January 2008 and December 2012. All thyroid fine-needle aspiration cases were reviewed and those with a diagnosis of follicular neoplasm (including Hurthle cell neoplasm) were identified. Correlating follow-up surgical pathology reports were reviewed. RESULTS: A total of 399 cases of follicular neoplasm with surgical follow-up were identified. Malignancy was identified in 32% of all cases of follicular neoplasm and was found to be disproportionately higher in the FL category (73%). A cytological diagnosis of FL is more likely to be called malignant (73%) than benign neoplastic (9%) or benign nonneoplastic (18%). A cytological diagnosis of MN or HN is more likely to be benign neoplastic (46% and 46%, respectively) than malignant (29% and 26%, respectively) or benign nonneoplastic (25% and 28%, respectively). Of the cytological features examined, 2 (nuclear enlargement and nuclear grooves) were significantly associated with the follicular variant of papillary thyroid carcinoma. CONCLUSIONS: The results of the current study clearly indicate that follicular lesions with even subtle nuclear atypia have a high positive predictive value for malignancy and therefore should be distinguished from other follicular lesions because these cases require more aggressive surgical management. The current study also raises an important issue concerning the current thyroid classification based on the 2007 Bethesda classification for thyroid cytology. Future thyroid fine-needle aspiration classification schemes should consider subclassifying follicular neoplasms for the purpose of risk stratification. PMID- 24753501 TI - Three-dimensional CFD/MRI modeling reveals that ventricular surgical restoration improves ventricular function by modifying intraventricular blood flow. AB - Surgical ventricular restoration (SVR) is designed to normalize distorted ventricular shape and size in patients with left ventricular (LV) dysfunction and akinetic and dyskinetic segments. This study is aimed to quantify the characteristics of LV as a pump for a case before and after SVR, which is followed by coronary artery bypass grafting (CABG). We hypothesize that SVR+CABG improves heart flow. A patient with heart failure had magnetic resonance (MR) scans before and 4 months after SVR. LV endocardial geometries were semi automated segmented and reconstructed using our customized algorithm. The arbitrary Lagrangian-Eulerian formulation of Navier-Stokes equations was solved to derive the flow patterns and calculate pressure differences in LV. After SVR, LV ejection fraction increased from 34% to 48% in patient but was still lower than normal (70%). Second, LV vortices were stronger than pre-surgery but still weaker than normal. The maximum pressure differences between ventricular base and apex increased from 180 to 400 Pa during diastole, from 252 to 560 Pa during systole, respectively. As anticipated, SVR reduced LV volumes and augmented LV ejection fraction. Three-dimensional CFD/MRI modeling suggests that improved diastolic and systolic ventricular function after SVR is associated with changes in intraventricular blood flow. PMID- 24753502 TI - Excess weight in preschool children with a history of severe bronchiolitis is associated with asthma. AB - BACKGROUND: The relationship between excess weight gain and asthma in childhood remains inadequately defined. The aim of this study was to evaluate, as part of a prospective post-bronchiolitis follow-up, whether there is a link between earlier or current overweight or obesity and asthma or asthma symptoms at 5-7 years of age. METHODS: In all, 151 former bronchiolitis patients were followed-up until the mean age of 6.45 years. At the control visit, the weights and heights were measured, and the asthma symptoms and medications for asthma were recorded. The weight status was expressed as body mass index (BMI) z-scores (zBMI). RESULTS: There were 10 obese and 31 overweight (zBMI over national references) children. In adjusted analyses, presence of current asthma at 6-7 years of age (aOR 3.05, 95% CI 1.02-9.93) differed between overweight and normal weight children. Further, asthma ever, asthma at age 4-5 years, asthma at age 5-6 years, use of bronchodilators ever and use of ICSs during the last 12 months were more common in currently overweight than in normal weight children. Obesity was associated only with current asthma and asthma ever. Instead, there were no significant associations between birth weight, excess weight gain in infancy, or overweight at age 1.5 years, and later asthma, asthma symptoms or use of asthma medication. CONCLUSION: Asthma was more common in currently overweight than in normal weight former bronchiolitis patients at preschool age and early school age. PMID- 24753503 TI - Clustering effects in group-based behavioral weight loss trials. PMID- 24753504 TI - From medical images to flow computations without user-generated meshes. AB - Biomedical flow computations in patient-specific geometries require integrating image acquisition and processing with fluid flow solvers. Typically, image-based modeling processes involve several steps, such as image segmentation, surface mesh generation, volumetric flow mesh generation, and finally, computational simulation. These steps are performed separately, often using separate pieces of software, and each step requires considerable expertise and investment of time on the part of the user. In this paper, an alternative framework is presented in which the entire image-based modeling process is performed on a Cartesian domain where the image is embedded within the domain as an implicit surface. Thus, the framework circumvents the need for generating surface meshes to fit complex geometries and subsequent creation of body-fitted flow meshes. Cartesian mesh pruning, local mesh refinement, and massive parallelization provide computational efficiency; the image-to-computation techniques adopted are chosen to be suitable for distributed memory architectures. The complete framework is demonstrated with flow calculations computed in two 3D image reconstructions of geometrically dissimilar intracranial aneurysms. The flow calculations are performed on multiprocessor computer architectures and are compared against calculations performed with a standard multistep route. PMID- 24753505 TI - Evaluation of intraoperative cytological assessment of bone resection margins in patients with oral squamous cell carcinoma. AB - BACKGROUND: Frozen sections are routinely applied to control for adequate resection margins. In cases in which carcinoma infiltrates bone, the intraoperative microscopic assessment of bone margins remains challenging due to technical difficulties to section native bone. The objective of the current study was to evaluate an intraoperative cytological approach to control bone resection margins in patients with bone-infiltrating oral squamous cell carcinomas. METHODS: A total of 174 cytological preparations obtained from bone margins of bone-infiltrating oral squamous cell carcinomas (28 patients) were assessed intraoperatively and compared with the corresponding histological findings. In a validation cohort (45 patients) the intraoperative cytological assessment of bone resection margins (ICAB) (104 margins) was evaluated as a diagnostic tool for routine clinical application. RESULTS: In the first patient cohort, the ICAB revealed 95.3% sensitivity and 96% specificity. The results provided an accuracy of 95.7% with a significant correlation noted between cytological and histological results (kappa, 0.91; P < .001), and a positive predictive value and negative predictive value of 93.8% and 96.9%, respectively. In the validation cohort, ICAB revealed 80% sensitivity and 98.9% specificity with 98% accuracy. There was a significant correlation found between cytological and histological results (kappa, 0.91; P < .001), providing a positive predictive value and negative predictive value of 80% and 98%, respectively. ICAB could predict final resection status at bone margins with 80% sensitivity and 97.5% specificity. A significant correlation was found between the cytological and histological resection status at bone margins (kappa, 0,75; P < .001). CONCLUSIONS: ICAB could supplement intraoperative frozen sections of soft tissue margins as a standard procedure to control for adequate resection at bone margins. PMID- 24753506 TI - Subcutaneous adipose tissue zinc-alpha2-glycoprotein is associated with adipose tissue and whole-body insulin sensitivity. AB - OBJECTIVE: To examine the regulatory aspects of zinc-alpha2-glycoprotein (ZAG) association with obesity-related insulin resistance. METHODS: ZAG mRNA and protein were analyzed in subcutaneous adipose tissue (AT) and circulation of lean, obese, prediabetic, and type 2 diabetic men; both subcutaneous and visceral AT were explored in lean and extremely obese. Clinical and ex vivo findings were corroborated by results of in vitro ZAG silencing experiment. RESULTS: Subcutaneous AT ZAG was reduced in obesity, with a trend to further decrease with prediabetes and type 2 diabetes. ZAG was 3.3-fold higher in subcutaneous than in visceral AT of lean individuals. All differences were lost in extreme obesity. Obesity-associated changes in AT were not paralleled by alterations of circulating ZAG. Subcutaneous AT ZAG correlated with adiposity, adipocyte hypertrophy, whole-body and AT insulin sensitivity, mitochondrial content, expression of GLUT4, PGC1alpha, and adiponectin. Subcutaneous AT ZAG and adipocyte size were the only predictors of insulin sensitivity, independent on age and BMI. Silencing ZAG resulted in reduced adiponectin, IRS1, GLUT4, and PGC1alpha gene expression in primary human adipocytes. CONCLUSIONS: ZAG in subcutaneous, but not in visceral AT, was markedly reduced in obesity. Clinical, cellular, and molecular evidence indicate that ZAG plays an important role in modulating whole-body and AT insulin sensitivity. PMID- 24753508 TI - Targeted multiprobe fluorescence in situ hybridization analysis for elucidation of inconclusive pancreatobiliary cytology. AB - BACKGROUND: Endoscopic fine-needle aspiration (FNA) and brush cytology are standard methods for the diagnosis of pancreatobiliary malignancies. Although the majority of cytological diagnoses are straightforward, there remains a difficult category of inconclusive cytology. This study explored the utility of fluorescence in situ hybridization (FISH) to improve the diagnostic stratification between reactive and malignant cells in cases of inconclusive cytology. METHODS: The multiprobe FISH assay UroVysion was used for copy number assessment of chromosomes 3, 7, 17, and the 9p21 locus on Papanicolaou-stained specimens with a diagnosis of inconclusive cytology (n = 50), adenocarcinoma (n = 31) and no evidence of malignancy (n = 9). The target cells were photographed and their coordinates saved on an automated stage prior to hybridization. A positive test was defined as increased copy number (> 2) of at least 2 chromosomes (3, 7, or 17) in at least 4 atypical cells, or loss of 9p21 in at least 12 cells. RESULTS: FISH confirmed all 31 cytological diagnoses of pancreatobiliary adenocarcinomas, and was negative in the 9 patients with negative cytology. Among the 50 cases with inconclusive cytology, FISH detected 19 of 31 cases with a final diagnosis of adenocarcinoma, and was negative in all 19 cases with no final evidence of malignancy (sensitivity of 61.3%, specificity of 100%, positive predictive value of 100%, negative predictive value of 61.3%). Loss of 9p21 was found in 43 (86%) of all 50 FISH-positive cases. CONCLUSIONS: Multiprobe FISH combined with automated relocation of atypical cells is a powerful technique to clarify inconclusive cytology of the pancreatobiliary tract, allowing for a better distinction between reactive atypia and malignancy. PMID- 24753507 TI - Effect of prednisone on nasal symptoms and peripheral blood T-cell function in chronic rhinosinusitis. AB - BACKGROUND: Systemic corticosteroids are the most effective anti-inflammatory drugs used for controlling chronic rhinosinusitis (CRS) symptoms. The potential mechanisms for their beneficial effects include increasing the number and function of T regulatory cells (Tregs), as reported in the local tissue post intranasal steroid treatment. We investigated the effect of systemic corticosteroids on peripheral blood (PB) Tregs in subjects with CRS. METHODS: Twenty CRS subjects and 19 controls were recruited. PB mononuclear cells (PBMCs) were isolated from CRS subjects before and after systemic corticosteroid administration in the course of clinical treatment. Control subjects received no treatment and were studied at one visit. Nasal symptoms were recorded. CD4(+) CD25(+) Foxp3(+) cells (Tregs) were analyzed by flow cytometry. Messenger RNA (mRNA) levels for interferon gamma (IFN-gamma), interleukin 4 (IL-4), IL-10, IL 13, IL-17A, transforming growth factor beta1 (TGF-beta1), forkhead box P3 (FoxP3), and GATA-binding factor 3 (GATA-3) were measured in PBMCs using real time polymerase chain reaction (PCR). RESULTS: CRS subjects reported improved nasal symptoms (p = 0.005) and significantly reduced PB Tregs after treatment with corticosteroids (p = 0.042). The transcript levels of IL-4 and GATA-3 were significantly higher in the CRS subjects at their first visit when compared to controls (p = 0.019 and p = 0.05, respectively). Corticosteroid treatment lowered the transcript levels of immunoregulatory transcription factors [FoxP3 (p = 0.048) and GATA-3 (p = 0.012)] and IFN-gamma (p = 0.036) in PB. CONCLUSION: In contrast to prior work in local nasal tissue, our study reports reduced PB Tregs and decreased T helper 1 (T(H)1) and T(H)2 function after treatment with systemic corticosteroids. These data indicate that corticosteroid effects on Tregs in CRS are complex involving local signals in the tissue that are distinct from those in circulating cells. PMID- 24753510 TI - Reply to verification bias in diagnostic accuracy studies for fine-needle aspiration cytology. PMID- 24753511 TI - Neurology education in resource-limited settings. PMID- 24753509 TI - A mariner transposon vector adapted for mutagenesis in oral streptococci. AB - This article describes the construction and characterization of a mariner-based transposon vector designed for use in oral streptococci, but with a potential use in other Gram-positive bacteria. The new transposon vector, termed pMN100, contains the temperature-sensitive origin of replication repATs-pWV01, a selectable kanamycin resistance gene, a Himar1 transposase gene regulated by a xylose-inducible promoter, and an erythromycin resistance gene flanked by himar inverted repeats. The pMN100 plasmid was transformed into Streptococcus mutans UA159 and transposon mutagenesis was performed via a protocol established to perform high numbers of separate transpositions despite a low frequency of transposition. The distribution of transposon inserts in 30 randomly picked mutants suggested that mariner transposon mutagenesis is unbiased in S. mutans. A generated transposon mutant library containing 5000 mutants was used in a screen to identify genes involved in the production of sucrose-dependent extracellular matrix components. Mutants with transposon inserts in genes encoding glycosyltransferases and the competence-related secretory locus were predominantly found in this screen. PMID- 24753512 TI - Clinical reasoning: a case of slowly progressive painful paraparesis. PMID- 24753513 TI - Postictal generalized EEG suppression: an inconsistent finding in people with multiple seizures. PMID- 24753514 TI - Limited short-term prognostic utility of cerebral NIRS during neonatal therapeutic hypothermia. PMID- 24753516 TI - Education research: case logs in the assessment of medical students in the neurology outpatient clinic. AB - OBJECTIVE: Using outpatient neurology clinic case logs completed by medical students on neurology clerkships, we examined the impact of outpatient clinical encounter volume per student on outcomes of knowledge assessed by the National Board of Medical Examiners (NBME) Clinical Neurology Subject Examination and clinical skills assessed by the Objective Structured Clinical Examination (OSCE). METHODS: Data from 394 medical students from July 2008 to June 2012, representing 9,791 patient encounters, were analyzed retrospectively. Pearson correlations were calculated examining the relationship between numbers of cases logged per student and performance on the NBME examination. Similarly, correlations between cases logged and performance on the OSCE, as well as on components of the OSCE (history, physical examination, clinical formulation), were evaluated. RESULTS: There was a correlation between the total number of cases logged per student and NBME examination scores (r = 0.142; p = 0.005) and OSCE scores (r = 0.136; p = 0.007). Total number of cases correlated with the clinical formulation component of the OSCE (r = 0.172; p = 0.001) but not the performance on history or physical examination components. CONCLUSION: The volume of cases logged by individual students in the outpatient clinic correlates with performance on measures of knowledge and clinical skill. In measurement of clinical skill, seeing a greater volume of patients in the outpatient clinic is related to improved clinical formulation on the OSCE. These findings may affect methods employed in assessment of medical students, residents, and fellows. PMID- 24753517 TI - Comment: Making a case for seeing more cases but not a case for more case logs. PMID- 24753518 TI - Clinical reasoning: a 14-year-boy with spells of somnolence and cognitive changes. PMID- 24753521 TI - Outpatient course and complications associated with home oxygen therapy for mild bronchiolitis. AB - BACKGROUND: Home oxygen has been incorporated into the emergency department management of bronchiolitis in high-altitude settings. However, the outpatient course on oxygen therapy and factors associated with subsequent admission have not been fully defined. METHODS: We conducted a retrospective cohort study in consecutive patients discharged on home oxygen from the pediatric emergency department at Denver Health Medical Center from 2003 to 2009. The integration of inpatient and outpatient care at our study institution allowed comprehensive assessment of follow-up rates, outpatient visits, time on oxygen, and subsequent admission. Admitted and nonadmitted patients were compared by using a chi(2) test and multivariable logistic regression. RESULTS: We identified 234 unique visits with adequate follow-up for inclusion. The median age was 10 months (interquartile range [IQR]: 7-14 months). Eighty-three percent of patients were followed up within 24 hours and 94% within 48 hours. The median length of oxygen use was 6 days (IQR: 4-9 days), and the median number of associated encounters was 3 (range: 0-9; IQR: 2-3). Ninety-three percent of patients were on room air at 14 days. Twenty-two patients (9.4%) required subsequent admission. Fever at the initial visit (>38.0 degrees C) was associated with admission (P < .02) but had a positive predictive value of 15.4%. Age, prematurity, respiratory rate, oxygen saturation, and history of previous bronchiolitis or wheeze were not associated with admission. CONCLUSIONS: There is a significant outpatient burden associated with home oxygen use. Although fever was associated with admission, we were unable to identify predictors that could modify current protocols. PMID- 24753522 TI - Influence of caregivers and children's entry into the dental care system. AB - OBJECTIVES: Early preventive dental visits are essential in improving children's oral health, especially young children at high risk for dental caries. However, there is scant information on how these children enter the dental care system. Our objectives were as follows: (1) to describe how a population-based cohort of young Medicaid-enrolled children entered dental care; and (2) to investigate the influence of caregiver characteristics on their children's dental care-seeking patterns. METHODS: We relied on Medicaid claims and interview data of caregiver child dyads who were enrolled in the Carolina Oral Health Literacy study during 2007-2008. The analytical cohort comprised 1000 children who had no dental visits before enrollment. Additional information was collected on sociodemographic characteristics, oral health status, health literacy, dental neglect, and access to care barriers. Our analyses relied on descriptive, bivariate, and multivariate methods. RESULTS: During the 25-month median follow-up period, 39% of the children (mean baseline age: 16 months) entered the dental care system, and 13% of their first encounters were for emergency care. Caregivers' dental neglect emerged as a significant predictor of nonentrance. Children with reported oral health problems at baseline were more likely to enter the dental care system compared with children with better oral health, but they were also more likely to require emergency care. CONCLUSIONS: Caregivers have a pivotal role in children's oral health and care. Interventions aimed at improving children's oral health should involve community outreach to engage caregivers in a culturally appropriate manner when their children are infants or toddlers. PMID- 24753523 TI - Academic achievement of children and adolescents with oral clefts. AB - BACKGROUND AND OBJECTIVE: Previous studies of academic achievement of children with oral clefts have mostly relied on small, clinic-based samples prone to ascertainment bias. In the first study in the United States to use a population based sample with direct assessment, we evaluated the academic achievement of children with oral clefts relative to their classmates. METHODS: Children born with isolated oral clefts in Iowa from 1983 to 2003 were identified from the Iowa Registry for Congenital and Inherited Disorders and matched to unaffected classmates by gender, school/school district, and month and year of birth. Academic achievement was assessed by using standardized tests of academic progress developed by the Iowa Testing Programs. Iowa Testing Programs data were linked to birth certificates for all children. Regression models controlled for household demographic and socioeconomic factors. The analytical sample included 588 children with clefts contributing 3735 child-grade observations and 1874 classmates contributing 13 159 child-grade observations. RESULTS: Children with oral clefts had lower scores than their classmates across all domains and school levels, with a 5-percentile difference in the overall composite score. Children with clefts were approximately one-half grade level behind their classmates and had higher rates of academic underachievement and use of special education services by 8 percentage points. Group differences were slightly lower but remained large and significant after adjusting for many background characteristics. CONCLUSIONS: Children with oral clefts underperformed across all academic areas and grade levels compared with their classmates. The results support a model of early testing and intervention among affected children to identify and reduce academic deficits. PMID- 24753524 TI - Progress toward a new tool for the toolbox: supplemental home oxygen for viral bronchiolitis. PMID- 24753525 TI - Effectiveness of trivalent flu vaccine in healthy young children. AB - BACKGROUND: There are few studies evaluating the effectiveness of trivalent influenza vaccination (TIV) in young children, particularly in children <2 years. The Western Australian Influenza Vaccine Effectiveness Study commenced in 2008 to evaluate a program providing TIV to children aged 6 to 59 months. METHODS: An observational study enrolling children with influenza-like illness presenting to a tertiary pediatric hospital was conducted (2008-2012). Vaccination status was determined by parental questionnaire and confirmed via the national immunization register and/or vaccine providers. Respiratory virus polymerase chain reaction and culture were performed on nasopharyngeal samples. The test-negative design was used to estimate vaccine effectiveness (VE) by using 2 control groups: all influenza test-negative subjects and other-virus-detected (OVD) subjects. Adjusted odds ratios were estimated from models with season, month of disease onset, age, gender, indigenous status, prematurity, and comorbidities as covariates. Subjects enrolled in 2009 were excluded from VE calculations. RESULTS: Of 2001 children enrolled, influenza was identified in 389 (20.4%) children. Another respiratory virus was identified in 1134 (59.6%) children. Overall, 295 of 1903 (15.5%) children were fully vaccinated and 161 of 1903 (8.4%) children were partially vaccinated. Vaccine uptake was significantly lower in 2010-2012 after increased febrile adverse events observed in 2010. Using test negative controls, VE was 64.7% (95% confidence interval [CI]: 33.7%-81.2%). No difference in VE was observed with OVD controls (65.8%; 95% CI: 32.1%-82.8%). The VE for children <2 years was 85.8% (95% CI: 37.9%-96.7%). CONCLUSIONS: This study reveals the effectiveness of TIV in young children over 4 seasons by using test negative and OVD controls. TIV was effective in children aged <2 years. Despite demonstrated vaccine effectiveness, uptake of TIV remains suboptimal. PMID- 24753526 TI - Hemostatic abnormalities in Noonan syndrome. AB - BACKGROUND: A bleeding diathesis is a common feature of Noonan syndrome, and various coagulation abnormalities have been reported. Platelet function has never been carefully investigated. METHODS: The degree of bleeding diathesis in a cohort of patients with Noonan syndrome was evaluated by a validated bleeding score and investigated with coagulation and platelet function tests. If ratios of prothrombin time and/or activated partial thromboplastin time were prolonged, the activity of clotting factors was measured. Individuals with no history of bleeding formed the control group. RESULTS: The study population included 39 patients and 28 controls. Bleeding score was >=2 (ie, suggestive of a moderate bleeding diathesis) in 15 patients (38.5%) and >=4 (ie, suggestive of a severe bleeding diathesis) in 7 (17.9%). Abnormal coagulation and/or platelet function tests were found in 14 patients with bleeding score >=2 (93.3%) but also in 21 (87.5%) of those with bleeding score <2. The prothrombin time and activated partial thromboplastin time were prolonged in 18 patients (46%) and partial deficiency of factor VII, alone or in combination with the deficiency of other vitamin K-dependent factors, was the most frequent coagulation abnormality. Moreover, platelet aggregation and secretion were reduced in 29 of 35 patients (82.9%, P < .01 for all aggregating agents). CONCLUSIONS: Nearly 40% of patients with the Noonan syndrome had a bleeding diathesis and >90% of them had platelet function and/or coagulation abnormalities. Results of these tests should be taken into account in the management of bleeding or invasive procedures in these patients. PMID- 24753528 TI - Validity of brief screening instrument for adolescent tobacco, alcohol, and drug use. AB - BACKGROUND AND OBJECTIVE: The National Institute on Alcohol Abuse and Alcoholism developed an alcohol screening instrument for youth based on epidemiologic data. This study examines the concurrent validity of this instrument, expanded to include tobacco and drugs, among pediatric patients, as well as the acceptability of its self-administration on an iPad. METHODS: Five hundred and twenty-five patients (54.5% female; 92.8% African American) aged 12 to 17 completed the Brief Screener for Tobacco, Alcohol, and other Drugs (BSTAD) via interviewer administration or self-administration using an iPad. Diagnostic and Statistical Manual, Fifth Edition substance use disorders (SUDs) were identified using a modified Composite International Diagnostic Interview-2 Substance Abuse Module. Receiver operating characteristic curves, sensitivities, and specificities were obtained to determine optimal cut points on the BSTAD in relation to SUDs. RESULTS: One hundred fifty-nine (30.3%) adolescents reported past-year use of >=1 substances on the BSTAD: 113 (21.5%) used alcohol, 84 (16.0%) used marijuana, and 50 (9.5%) used tobacco. Optimal cut points for past-year frequency of use items on the BSTAD to identify SUDs were >=6 days of tobacco use (sensitivity = 0.95; specificity = 0.97); >=2 days of alcohol use (sensitivity = 0.96; specificity = 0.85); and >=2 days of marijuana use (sensitivity = 0.80; specificity = 0.93). iPad self-administration was preferred over interviewer administration (z = 5.8; P < .001). CONCLUSIONS: The BSTAD is a promising screening tool for identifying problematic tobacco, alcohol, and marijuana use in pediatric settings. Even low frequency of substance use among adolescents may indicate need for intervention. PMID- 24753529 TI - Why can't we retire codeine? PMID- 24753527 TI - Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. AB - Despite the emerging role of mitochondria in immunity, a link between bioenergetics and the immune response in autism has not been explored. Mitochondrial outcomes and phorbol 12-myristate 13-acetate (PMA)-induced oxidative burst were evaluated in granulocytes from age-, race-, and gender matched children with autism with severity scores of >=7 (n = 10) and in typically developing (TD) children (n = 10). The oxidative phosphorylation capacity of granulocytes was 3-fold lower in children with autism than in TD children, with multiple deficits encompassing >=1 Complexes. Higher oxidative stress in cells of children with autism was evidenced by higher rates of mitochondrial reactive oxygen species production (1.6-fold), higher mitochondrial DNA copy number per cell (1.5-fold), and increased deletions. Mitochondrial dysfunction in children with autism was accompanied by a lower (26% of TD children) oxidative burst by PMA-stimulated reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase and by a lower gene expression (45% of TD children's mean values) of the nuclear factor erythroid 2-related factor 2 transcription factor involved in the antioxidant response. Given that the majority of granulocytes of children with autism exhibited defects in oxidative phosphorylation, immune response, and antioxidant defense, our results support the concept that immunity and response to oxidative stress may be regulated by basic mitochondrial functions as part of an integrated metabolic network. PMID- 24753530 TI - Language problems in children with ADHD: a community-based study. AB - OBJECTIVES: To examine the prevalence of language problems in children with attention-deficit/hyperactivity disorder (ADHD) versus non-ADHD controls, and the impact of language problems on the social and academic functioning of children with ADHD. METHODS: Children (6 to 8 years) with ADHD (n = 179) and controls (n = 212) were recruited through 43 Melbourne schools. ADHD was assessed by using the Conners 3 ADHD Index and the Diagnostic Interview Schedule for Children IV. Oral language was assessed by using the Clinical Evaluation of Language Fundamentals, fourth edition, screener. Academic functioning was measured via direct assessment (Wide Range Achievement Test 4) and teacher report (Social Skills Improvement System). Social functioning was measured via parent and teacher report (Strengths and Difficulties Questionnaire; Social Skills Improvement System). Logistic and linear regression models were adjusted for sociodemographic factors and child comorbidities. RESULTS: Children with ADHD had a higher prevalence of language problems than controls after adjustment for sociodemographic factors and comorbidities (odds ratio, 2.8; 95% confidence interval [CI], 1.5 to 5.1). Compared with children with ADHD alone, those with language problems had poorer word reading (mean difference [MD], -11.6; 95% CI, -16.4 to -6.9; effect size, 0.7), math computation (MD, -11.4; 95% CI, -15.0 to -7.7; effect size, -0.8), and academic competence (MD, -10.1; 95% CI, -14.0 to -6.1; effect size, -0.7). Language problems were not associated with poorer social functioning. CONCLUSIONS: Children with ADHD had a higher prevalence of language problems than controls, and language problems in children with ADHD contributed to markedly poorer academic functioning. PMID- 24753531 TI - A 14-year-old boy with sore throat and tea-colored urine. AB - Granulomatosis with polyangiitis (GPA; previously Wegener granulomatosis) is a rare, multisystem, necrotizing granulomatous vasculitis that classically affects the upper and lower respiratory tracts and kidneys but can have diverse clinical features. The clinical course is often rapidly progressive, and without appropriate treatment is almost universally fatal. Early symptoms are often nonspecific and a high index of suspicion is needed to recognize this serious disease, particularly in the absence of overt pulmonary or renal manifestations. Because initial symptoms can mimic those of infection, patients often present first to the general pediatrician. We present a case of pediatric GPA in a 14 year-old boy who initially presented with constitutional symptoms, sore throat, and hematuria, and then developed grossly necrotic-appearing tonsils before rapid deterioration requiring intensive life-saving measures. We review the common manifestations of GPA, including those that may be unique to the pediatric population, and emphasize the importance of early diagnosis and intervention in preventing devastating outcomes from this disease. PMID- 24753532 TI - Sleep in healthy black and white adolescents. AB - BACKGROUND AND OBJECTIVES: Inadequate sleep among adolescents has negative consequences for self-regulation, emotional well-being, and risk behaviors. Using multiple assessment methods, we evaluated the adequacy of sleep among healthy adolescents from a lower socioeconomic community and expected differences by race. METHODS: A total of 250 healthy high school students enrolled in public school (mean age: 15.7 years; 57% black, 54% female) from families of low to middle class according to the Hollingshead scale participated in weeklong assessments of sleep duration and fragmentation, assessed by using actigraphy; sleep duration and perceived quality, assessed by using daily diaries; and daytime sleepiness and sleep delay, assessed by using a questionnaire. RESULTS: Students slept during the school week a mean +/- SD of 6.0 +/- 0.9 hours per night according to actigraphy and 6.8 +/- 1.1 hours according to daily diary, and during the weekend, a mean of 7.4 +/- 1.2 and 8.7 +/- 1.4 hours, respectively. Black participants and male participants slept less and had more fragmented sleep; female participants reported poorer quality of sleep in their daily diaries and more daytime sleepiness. The results remained significant after adjustments for age, physical activity, smoking status, and percentile BMI. CONCLUSIONS: Most students slept less than the 8 to 9 hours suggested by the guidelines of the Centers for Disease Control and Prevention. Black male participants had the least amount of sleep, which may play a role in the substantial risks experienced by this demographic group. Our findings are consistent with recommendations that pediatricians should routinely screen their adolescent patients about their sleep, especially those from at-risk subgroups. PMID- 24753533 TI - National patterns of codeine prescriptions for children in the emergency department. AB - BACKGROUND AND OBJECTIVES: National guidelines have recommended against codeine use in children, but little is known about prescribing patterns in the United States. Our objectives were to assess changes over time in pediatric codeine prescription rates in emergency departments nationally and to determine factors associated with codeine prescription. METHODS: We performed a serial cross sectional analysis (2001-2010) of emergency department visits for patients ages 3 to 17 years in the nationally representative National Hospital Ambulatory Medical Care Survey. We determined survey-weighted annual rates of codeine prescriptions and tested for linear trends over time. We used multivariate logistic regression to identify characteristics associated with codeine prescription and interrupted time-series analysis to assess changes in prescriptions for upper respiratory infection (URI) or cough associated with two 2006 national guidelines recommending against its use for these indications. RESULTS: The proportion of visits (N = 189 million) with codeine prescription decreased from 3.7% to 2.9% during the study period (P = .008). Odds of codeine prescription were higher for children ages 8 to 12 years (odds ratio [OR], 1.42; 95% confidence interval [1.21 1.67]) and among providers outside the northeast. Odds were lower for children who were non-Hispanic black (OR, 0.67 [0.56-0.8]) or with Medicaid (OR, 0.84 [0.71-0.98]). The 2006 guidelines were not associated with a decline in codeine prescriptions for cough or URI visits. CONCLUSIONS: Although there was a small decline in codeine prescription over 10 years, use for cough or URI did not decline after national guidelines recommending against its use. More effective interventions are needed to prevent codeine prescription to children. PMID- 24753534 TI - Anxiety in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVES: Although anxiety is common in children with attention deficit/hyperactivity disorder (ADHD), it is unclear how anxiety influences the lives of these children. This study examined the association between anxiety comorbidities and functioning by comparing children with ADHD and no, 1, or >=2 anxiety comorbidities. Differential associations were examined by current ADHD presentation (subtype). METHODS: Children with diagnostically confirmed ADHD (N = 392; 5-13 years) were recruited via 21 pediatrician practices across Victoria, Australia. Anxiety was assessed by using the Anxiety Disorders Interview Schedule for Children-IV. Functional measures included parent-reported: quality of life (QoL; Pediatric Quality of Life Inventory 4.0), behavior and peer problems (Strengths and Difficulties Questionnaire), daily functioning (Daily Parent Rating of Evening and Morning Behavior), and school attendance. Teacher-reported behavior and peer problems (Strengths and Difficulties Questionnaire) were also examined. Linear and logistic regression controlled for ADHD severity, medication use, comorbidities, and demographic factors. RESULTS: Children with >=2 anxiety comorbidities (n = 143; 39%) had poorer QoL (effect size: -0.8) and more difficulties with behavior (effect size: 0.4) and daily functioning (effect size: 0.3) than children without anxiety (n = 132; 36%). Poorer functioning was not observed for children with 1 anxiety comorbidity (n = 95; 26%). Two or more anxiety comorbidities were associated with poorer functioning for children with both ADHD-Inattentive and ADHD-Combined presentation. CONCLUSIONS: Children with ADHD demonstrate poorer QoL, daily functioning and behavior when >=2 anxiety comorbidities are present. Future research should examine whether treating anxiety in children with ADHD improves functional outcomes. PMID- 24753535 TI - Prenatal vitamin D and dental caries in infants. AB - OBJECTIVES: Inadequate maternal vitamin D (assessed by using 25-hydroxyvitamin D [25OHD]) levels during pregnancy may affect tooth calcification, predisposing enamel hypoplasia and early childhood caries (ECC). The purpose of this study was to determine the relationship between prenatal 25OHD concentrations and dental caries among offspring during the first year of life. METHODS: This prospective cohort study recruited expectant mothers from an economically disadvantaged urban area. A prenatal questionnaire was completed and serum sample drawn for 25OHD. Dental examinations were completed at 1 year of age while the parent/caregiver completed a questionnaire. The examiner was blinded to mothers' 25OHD levels. A P value <= .05 was considered significant. RESULTS: Overall, 207 women were enrolled (mean age: 19 +/- 5 years). The mean 25OHD level was 48 +/- 24 nmol/L, and 33% had deficient levels. Enamel hypoplasia was identified in 22% of infants; 23% had cavitated ECC, and 36% had ECC when white spot lesions were included in the assessment. Mothers of children with ECC had significantly lower 25OHD levels than those whose children were caries-free (41 +/- 20 vs 52 +/- 27 nmol/L; P = .05). Univariate Poisson regression analysis for the amount of untreated decay revealed an inverse relationship with maternal 25OHD. Logistic regression revealed that enamel hypoplasia (P < .001), infant age (P = .002), and lower prenatal 25OHD levels (P = .02) were significantly associated with ECC. CONCLUSIONS: This study found that maternal prenatal 25OHD levels may have an influence on the primary dentition and the development of ECC. PMID- 24753536 TI - Next-generation sequencing of peripheral B-lineage cells pinpoints the circulating clonotypic cell pool in multiple myeloma. AB - The identity of the proliferative compartment of myeloma progenitor cells remains a matter of debate. Polymerase chain reaction-based studies suggested pre-switch "clonotypic" B cells sharing the immunoglobulin (Ig) rearrangement of the malignant plasma cell (M-PC), to circulate in the blood and possess stem cell like properties. Here, we disprove this hypothesis. We screened peripheral blood IgM, IgG, and IgA repertoires of myeloma patients for the clonotypic rearrangement by next-generation sequencing. None of 12 cases showed pre-switch clonotypic transcripts. In the post-switch IgG/IgA repertoires, however, the clonotypic rearrangement was detected at high frequency in 6 of 8 patients with active disease, whereas it was undetectable after treatment, correlating with flow cytometric presence or absence of circulating M-PCs. Minor subclones with alternative post-switch isotypes suggested ongoing switch events and clonal evolution at the M-PC level. Our findings consistently show an absence of pre switch clonotypic B cells, while M-PCs circulate in the peripheral blood and may contribute to spreading of the disease. PMID- 24753537 TI - Inherited biallelic CSF3R mutations in severe congenital neutropenia. AB - Severe congenital neutropenia (SCN) is characterized by low numbers of peripheral neutrophil granulocytes and a predisposition to life-threatening bacterial infections. We describe a novel genetic SCN type in 2 unrelated families associated with recessively inherited loss-of-function mutations in CSF3R, encoding the granulocyte colony-stimulating factor (G-CSF) receptor. Family A, with 3 affected children, carried a homozygous missense mutation (NM_000760.3:c.922C>T, NP_000751.1:p.Arg308Cys), which resulted in perturbed N glycosylation and aberrant localization to the cell surface. Family B, with 1 affected infant, carried compound heterozygous deletions provoking frameshifts and premature stop codons (NM_000760.3:c.948_963del, NP_000751.1:p.Gly316fsTer322 and NM_000760.3:c.1245del, NP_000751.1:p.Gly415fsTer432). Despite peripheral SCN, all patients had morphologic evidence of full myeloid cell maturation in bone marrow. None of the patients responded to treatment with recombinant human G-CSF. Our study highlights the genetic and morphologic SCN variability and provides evidence both for functional importance and redundancy of G-CSF receptor-mediated signaling in human granulopoiesis. PMID- 24753538 TI - Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. AB - Adoptive transfer of donor-derived T lymphocytes expressing a safety switch may promote immune reconstitution in patients undergoing haploidentical hematopoietic stem cell transplant (haplo-HSCT) without the risk for uncontrolled graft versus host disease (GvHD). Thus, patients who develop GvHD after infusion of allodepleted donor-derived T cells expressing an inducible human caspase 9 (iC9) had their disease effectively controlled by a single administration of a small molecule drug (AP1903) that dimerizes and activates the iC9 transgene. We now report the long-term follow-up of 10 patients infused with such safety switch modified T cells. We find long-term persistence of iC9-modified (iC9-T) T cells in vivo in the absence of emerging oligoclonality and a robust immunologic benefit, mediated initially by the infused cells themselves and subsequently by an apparently accelerated reconstitution of endogenous naive T lymphocytes. As a consequence, these patients have immediate and sustained protection from major pathogens, including cytomegalovirus, adenovirus, BK virus, and Epstein-Barr virus in the absence of acute or chronic GvHD, supporting the beneficial effects of this approach to immune reconstitution after haplo-HSCT. This study was registered at www.clinicaltrials.gov as #NCT00710892. PMID- 24753540 TI - Reply: Shared environmental effects on multiple sclerosis susceptibility: conflicting evidence from twin studies. PMID- 24753539 TI - A Shoot-Specific Hypoxic Response of Arabidopsis Sheds Light on the Role of the Phosphate-Responsive Transcription Factor PHOSPHATE STARVATION RESPONSE1. AB - Plant responses to biotic and abiotic stresses are often very specific, but signal transduction pathways can partially or completely overlap. Here, we demonstrate that in Arabidopsis (Arabidopsis thaliana), the transcriptional responses to phosphate starvation and oxygen deficiency stress comprise a set of commonly induced genes. While the phosphate deficiency response is systemic, under oxygen deficiency, most of the commonly induced genes are found only in illuminated shoots. This jointly induced response to the two stresses is under control of the transcription factor PHOSPHATE STARVATION RESPONSE1 (PHR1), but not of the oxygen-sensing N-end rule pathway, and includes genes encoding proteins for the synthesis of galactolipids, which replace phospholipids in plant membranes under phosphate starvation. Despite the induction of galactolipid synthesis genes, total galactolipid content and plant survival are not severely affected by the up-regulation of galactolipid gene expression in illuminated leaves during hypoxia. However, changes in galactolipid molecular species composition point to an adaptation of lipid fluxes through the endoplasmic reticulum and chloroplast pathways during hypoxia. PHR1-mediated signaling of phosphate deprivation was also light dependent. Because a photoreceptor-mediated PHR1 activation was not detectable under hypoxia, our data suggest that a chloroplast-derived retrograde signal, potentially arising from metabolic changes, regulates PHR1 activity under both oxygen and phosphate deficiency. PMID- 24753541 TI - Oncolytic viruses targeting tumor stem cells. AB - A workshop "Targeting Oncolytic Viruses to Tumor Stem Cells," organized by the Division of Cancer Biology, NCI, NIH, was held on September 6, 2013 in Rockville, MD. Seventeen invited experts presented an overview of their current research in this area and discussed the state of current research on the use of oncolytic viruses targeted to stem cells as a potential cancer therapy. The goal was to evaluate the evidence that this approach might increase the efficacy of oncolytic virus therapy and to identify gaps in knowledge that have retarded progress in this area. PMID- 24753542 TI - The RAD51-stimulatory compound RS-1 can exploit the RAD51 overexpression that exists in cancer cells and tumors. AB - RAD51 is the central protein that catalyzes DNA repair via homologous recombination, a process that ensures genomic stability. RAD51 protein is commonly expressed at high levels in cancer cells relative to their noncancerous precursors. High levels of RAD51 expression can lead to the formation of genotoxic RAD51 protein complexes on undamaged chromatin. We developed a therapeutic approach that exploits this potentially toxic feature of malignancy, using compounds that stimulate the DNA-binding activity of RAD51 to promote cancer cell death. A panel of immortalized cell lines was challenged with the RAD51-stimulatory compound RS-1. Resistance to RS-1 tended to occur in cells with higher levels of RAD54L and RAD54B, which are Swi2/Snf2-related translocases known to dissociate RAD51 filaments from dsDNA. In PC3 prostate cancer cells, RS 1-induced lethality was accompanied by the formation of microscopically visible RAD51 nuclear protein foci occurring in the absence of any DNA-damaging treatment. Treatment with RS-1 promoted significant antitumor responses in a mouse model, providing proof-of-principle for this novel therapeutic strategy. PMID- 24753543 TI - Shared and independent colorectal cancer risk alleles in TGFbeta-related genes in African and European Americans. AB - Genome-wide association studies (GWAS) in colorectal cancer (CRC) identified five regions near transforming growth factor beta-related genes BMP4, GREM1, CDH1, SMAD7 and RPHN2. The true risk alleles remain to be identified in these regions, and their role in CRC risk in non-European populations has been understudied. Our previous work noted significant genetic heterogeneity between African Americans (AAs) and European Americans (EAs) for single nucleotide polymorphisms (SNPs) identified in GWAS. We hypothesized that associations may not have been replicated in AAs due to differential or independent genetic structures. In order to test this hypothesis, we genotyped 195 tagging SNPs across these five gene regions in 1194 CRC cases (795 AAs and 399 EAs) and 1352 controls (985 AAs and 367 EAs). Imputation was performed, and association testing of genotyped and imputed SNPs included ancestry, age and sex as covariates. In two of the five genes originally associated with CRC, we found evidence for association in AAs including rs1862748 in CDH1 (OR(Add) = 0.82, P = 0.02) and in GREM1 the SNPs rs10318 (OR(Rec) = 60.1, P = 0.01), rs11632715 (OR(Rec) = 2.36; P = 0.004) and rs12902616 (OR(Rec) = 1.28, P = 0.005), the latter which is in linkage disequilibrium with the previously identified SNP rs4779584. Testing more broadly for associations in these gene regions in AAs, we noted three statistically significant association peaks in GREM1 and RHPN2 that were not identified in EAs. We conclude that some CRC risk alleles are shared between EAs and AAs and others are population specific. PMID- 24753544 TI - Genetic variation in prostate-specific antigen-detected prostate cancer and the effect of control selection on genetic association studies. AB - BACKGROUND: Only a minority of the genetic components of prostate cancer risk have been explained. Some observed associations of SNPs with prostate cancer might arise from associations of these SNPs with circulating prostate-specific antigen (PSA) because PSA values are used to select controls. METHODS: We undertook a genome-wide association study (GWAS) of screen-detected prostate cancer (ProtecT: 1,146 cases and 1,804 controls); meta-analyzed the results with those from the previously published UK Genetic Prostate Cancer Study (1,854 cases and 1,437 controls); investigated associations of SNPs with prostate cancer using either "low" (PSA < 0.5 ng/mL) or "high" (PSA >= 3 ng/mL, biopsy negative) PSA controls; and investigated associations of SNPs with PSA. RESULTS: The ProtecT GWAS confirmed previously reported associations of prostate cancer at three loci: 10q11.23, 17q24.3, and 19q13.33. The meta-analysis confirmed associations of prostate cancer with SNPs near four previously identified loci (8q24.21,10q11.23, 17q24.3, and 19q13.33). When comparing prostate cancer cases with low PSA controls, alleles at genetic markers rs1512268, rs445114, rs10788160, rs11199874, rs17632542, rs266849, and rs2735839 were associated with an increased risk of prostate cancer, but the effect-estimates were attenuated to the null when using high PSA controls (Pheterogeneity in effect-estimates < 0.04). We found a novel inverse association of rs9311171-T with circulating PSA. CONCLUSIONS: Differences in effect-estimates for prostate cancer observed when comparing low versus high PSA controls may be explained by associations of these SNPs with PSA. IMPACT: These findings highlight the need for inferences from genetic studies of prostate cancer risk to carefully consider the influence of control selection criteria. PMID- 24753545 TI - Cell phone use and parotid salivary gland alterations: no molecular evidence. AB - BACKGROUND: The association between cell phone use and the development of parotid tumors is controversial. Because there is unequivocal evidence that the microenvironment is important for tumor formation, we investigated in the parotid glands whether cell phone use alters the expression of gene products related to cellular stress. METHODS: We used the saliva produced by the parotid glands of 62 individuals to assess molecular alterations compatible with cellular stress, comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to the saliva from the opposite, unexposed parotid gland (contralateral) of each individual. We compared salivary flow, total protein concentration, p53, p21, reactive oxygen species (ROS), and salivary levels of glutathione (GSH), heat shock proteins 27 and 70, and IgA between the ipsilateral and contralateral parotids. RESULTS: No difference was found for any of these parameters, even when grouping individuals by period of cell phone use in years or by monthly average calls in minutes. CONCLUSION AND IMPACT: We provide molecular evidence that the exposure of parotid glands to cell phone use does not alter parotid salivary flow, protein concentration, or levels of proteins of genes that are directly or indirectly affected by heat-induced cellular stress. PMID- 24753546 TI - Prospective examination of objectively assessed physical activity and sedentary time after breast cancer treatment: sitting on the crest of the teachable moment. AB - BACKGROUND: This study prospectively examined patterns of objectively assessed sedentary time and moderate-to-vigorous physical activity (MVPA) during a 1-year period following completion of primary treatment among breast cancer survivors. The potential moderating effect of weight status on sedentary and MVPA time was also examined. METHODS: Breast cancer survivors [n = 177; M(SD)age = 54.9 (11.1) years, 85% White/Caucasian; 82% stage I or II cancer; M(SD)time since treatment = 3.5 (2.4) months] who were recruited into a convenience sample had weight, height, and waist circumference measured and wore Actigraph GT3X accelerometers for 1 week every 3 months for 1 year. Data were analyzed using repeated measures ANOVA. RESULTS: Survivors spent nearly 78% of their day sedentary across all time points compared with less than 2% of their day engaged in MVPA. Sedentary time remained fairly stable over 12 months, whereas MVPA levels significantly decreased. Survivors with an overweight body mass index and unhealthy waist-to height ratio engaged in significantly less MVPA than healthy weight survivors, with significant waist-to-height ratio moderator effects for both sedentary and MVPA. CONCLUSIONS: Sedentary time remains high in the first year following treatment for breast cancer, and MVPA decreases. These trends are more pronounced for survivors who are overweight, with stronger effects noted when waist-to height ratio was examined compared with body mass index. IMPACT: These findings suggest that breast cancer survivors may be doing very little to improve their lifestyle behaviors following a cancer diagnosis and treatments. PMID- 24753548 TI - Periprocedural management of new oral anticoagulants in patients undergoing atrial fibrillation ablation. PMID- 24753547 TI - Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33. AB - RATIONALE: Several reports suggest that antisense oligonucleotides against miR-33 might reduce cardiovascular risk in patients by accelerating the reverse cholesterol transport pathway. However, conflicting reports exist about the impact of anti-miR-33 therapy on the levels of very low-density lipoprotein triglycerides (VLDL-TAG). OBJECTIVE: We test the hypothesis that miR-33 controls hepatic VLDL-TAG secretion. METHODS AND RESULTS: Using therapeutic silencing of miR-33 and adenoviral overexpression of miR-33, we show that miR-33 limits hepatic secretion of VLDL-TAG by targeting N-ethylmaleimide-sensitive factor (NSF), both in vivo and in primary hepatocytes. We identify conserved sequences in the 3'UTR of NSF as miR-33 responsive elements and show that Nsf is specifically recruited to the RNA-induced silencing complex following induction of miR-33. In pulse-chase experiments, either miR-33 overexpression or knock-down of Nsf lead to decreased secretion of apolipoproteins and TAG in primary hepatocytes, compared with control cells. Importantly, Nsf rescues miR-33 dependent reduced secretion. Finally, we show that overexpression of Nsf in vivo increases global hepatic secretion and raises plasma VLDL-TAG. CONCLUSIONS: Together, our data reveal key roles for the miR-33-NSF axis during hepatic secretion and suggest that caution should be taken with anti-miR-33-based therapies because they might raise proatherogenic VLDL-TAG levels. PMID- 24753549 TI - Pregnancy-associated acute myocardial infarction: a review of contemporary experience in 150 cases between 2006 and 2011. PMID- 24753550 TI - Having a heavy heart: approaches to infiltrative cardiomyopathy. PMID- 24753551 TI - ECG response: April 22, 2014. PMID- 24753552 TI - An uncommon cause of typical cardiac chest pain. PMID- 24753553 TI - A surgical case of expanding bilateral coronary aneurysms regarded as immunoglobulin G4-related disease. PMID- 24753554 TI - Letter by Eberlein and Reed regarding article, "transplantation for idiopathic pulmonary arterial hypertension: improvement in the lung allocation score era". PMID- 24753556 TI - Letter by Liu et al regarding article, "rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial". PMID- 24753555 TI - Response to letter regarding article, "transplantation for idiopathic pulmonary arterial hypertension: improvement in the lung allocation score era". PMID- 24753557 TI - Response to letter regarding article, "rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial". PMID- 24753562 TI - Nrf2 target genes can be controlled by neuronal activity in the absence of Nrf2 and astrocytes. PMID- 24753563 TI - Theory for plasticity of face-centered cubic metals. AB - The activation of plastic deformation mechanisms determines the mechanical behavior of crystalline materials. However, the complexity of plastic deformation and the lack of a unified theory of plasticity have seriously limited the exploration of the full capacity of metals. Current efforts to design high strength structural materials in terms of stacking fault energy have not significantly reduced the laborious trial and error works on basic deformation properties. To remedy this situation, here we put forward a comprehensive and transparent theory for plastic deformation of face-centered cubic metals. This is based on a microscopic analysis that, without ambiguity, reveals the various deformation phenomena and elucidates the physical fundaments of the currently used phenomenological correlations. We identify an easily accessible single parameter derived from the intrinsic energy barriers, which fully specifies the potential diversity of metals. Based entirely on this parameter, a simple deformation mode diagram is shown to delineate a series of convenient design criteria, which clarifies a wide area of material functionality by texture control. PMID- 24753564 TI - The dynamic role of genetics on cortical patterning during childhood and adolescence. AB - Longitudinal imaging and quantitative genetic studies have both provided important insights into the nature of human brain development. In the present study we combine these modalities to obtain dynamic anatomical maps of the genetic contributions to cortical thickness through childhood and adolescence. A total of 1,748 anatomic MRI scans from 792 healthy twins and siblings were studied with up to eight time points per subject. Using genetically informative latent growth curve modeling of 81,924 measures of cortical thickness, changes in the genetic contributions to cortical development could be visualized across the age range at high resolution. There was highly statistically significant (P < 0.0001) genetic variance throughout the majority of the cerebral cortex, with the regions of highest heritability including the most evolutionarily novel regions of the brain. Dynamic modeling of changes in heritability over time demonstrated that the heritability of cortical thickness increases gradually throughout late childhood and adolescence, with sequential emergence of three large regions of high heritability in the temporal poles, the inferior parietal lobes, and the superior and dorsolateral frontal cortices. PMID- 24753566 TI - Visuospatial selective attention in chickens. AB - Voluntary control of attention promotes intelligent, adaptive behaviors by enabling the selective processing of information that is most relevant for making decisions. Despite extensive research on attention in primates, the capacity for selective attention in nonprimate species has never been quantified. Here we demonstrate selective attention in chickens by applying protocols that have been used to characterize visual spatial attention in primates. Chickens were trained to localize and report the vertical position of a target in the presence of task relevant distracters. A spatial cue, the location of which varied across individual trials, indicated the horizontal, but not vertical, position of the upcoming target. Spatial cueing improved localization performance: accuracy (d') increased and reaction times decreased in a space-specific manner. Distracters severely impaired perceptual performance, and this impairment was greatly reduced by spatial cueing. Signal detection analysis with an "indecision" model demonstrated that spatial cueing significantly increased choice certainty in localizing targets. By contrast, error-aversion certainty (certainty of not making an error) remained essentially constant across cueing protocols, target contrasts, and individuals. The results show that chickens shift spatial attention rapidly and dynamically, following principles of stimulus selection that closely parallel those documented in primates. The findings suggest that the mechanisms that control attention have been conserved through evolution, and establish chickens--a highly visual species that is easily trained and amenable to cutting-edge experimental technologies--as an attractive model for linking behavior to neural mechanisms of selective attention. PMID- 24753567 TI - Emergence of the A20/ABIN-mediated inhibition of NF-kappaB signaling via modifying the ubiquitinated proteins in a basal chordate. AB - In the past decade, ubiquitination has been well documented to have multifaceted roles in regulating NF-kappaB activation in mammals. However, its function, especially how deubiquitinating enzymes balance the NF-kappaB activation, remains largely elusive in invertebrates. Investigating bbtA20 and its binding proteins, bbt A20-binding inhibitor of NF-kappaB (bbtABIN1) and bbtABIN2, in Chinese amphioxus Branchiostoma belcheri tsingtauense, we found that bbtABIN2 can colocalize and compete with bbt TNF receptor-associated factor 6 to connect the K63-linked polyubiquitin chains, whereas bbtABIN1 physically links bbtA20 to bbt NF-kappaB essential modulator (bbtNEMO) to facilitate the K48-linked ubiquitination of bbtNEMO. Similar to human A20, bbtA20 is a dual enzyme that removes the K63-linked polyubiquitin chains and builds the K48-linked polyubiquitin chains on bbt receptor-interacting serine/threonine protein kinase 1b, leading to the inhibition of NF-kappaB signaling. Our study not only suggests that ubiquitination is an ancient strategy in regulating NF-kappaB activation but also provides the first evidence, to our knowledge, for ABINs/A20-mediated inhibition of NF-kappaB via modifying the ubiquitinated proteins in a basal chordate, adding information on the stepwise development of vertebrate innate immune signaling. PMID- 24753565 TI - The evolution of self-control. AB - Cognition presents evolutionary research with one of its greatest challenges. Cognitive evolution has been explained at the proximate level by shifts in absolute and relative brain volume and at the ultimate level by differences in social and dietary complexity. However, no study has integrated the experimental and phylogenetic approach at the scale required to rigorously test these explanations. Instead, previous research has largely relied on various measures of brain size as proxies for cognitive abilities. We experimentally evaluated these major evolutionary explanations by quantitatively comparing the cognitive performance of 567 individuals representing 36 species on two problem-solving tasks measuring self-control. Phylogenetic analysis revealed that absolute brain volume best predicted performance across species and accounted for considerably more variance than brain volume controlling for body mass. This result corroborates recent advances in evolutionary neurobiology and illustrates the cognitive consequences of cortical reorganization through increases in brain volume. Within primates, dietary breadth but not social group size was a strong predictor of species differences in self-control. Our results implicate robust evolutionary relationships between dietary breadth, absolute brain volume, and self-control. These findings provide a significant first step toward quantifying the primate cognitive phenome and explaining the process of cognitive evolution. PMID- 24753568 TI - Parallel independent evolution of pathogenicity within the genus Yersinia. AB - The genus Yersinia has been used as a model system to study pathogen evolution. Using whole-genome sequencing of all Yersinia species, we delineate the gene complement of the whole genus and define patterns of virulence evolution. Multiple distinct ecological specializations appear to have split pathogenic strains from environmental, nonpathogenic lineages. This split demonstrates that contrary to hypotheses that all pathogenic Yersinia species share a recent common pathogenic ancestor, they have evolved independently but followed parallel evolutionary paths in acquiring the same virulence determinants as well as becoming progressively more limited metabolically. Shared virulence determinants are limited to the virulence plasmid pYV and the attachment invasion locus ail. These acquisitions, together with genomic variations in metabolic pathways, have resulted in the parallel emergence of related pathogens displaying an increasingly specialized lifestyle with a spectrum of virulence potential, an emerging theme in the evolution of other important human pathogens. PMID- 24753569 TI - Molecular tracing of the emergence, diversification, and transmission of S. aureus sequence type 8 in a New York community. AB - During the last 2 decades, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains have dramatically increased the global burden of S. aureus infections. The pandemic sequence type (ST)8/pulsed-field gel type USA300 is the dominant CA-MRSA clone in the United States, but its evolutionary history and basis for biological success are incompletely understood. Here, we use whole-genome sequencing of 387 ST8 isolates drawn from an epidemiological network of CA-MRSA infections and colonizations in northern Manhattan to explore short-term evolution and transmission patterns. Phylogenetic analysis predicted that USA300 diverged from a most common recent ancestor around 1993. We found evidence for multiple introductions of USA300 and reconstructed the phylogeographic spread of isolates across neighborhoods. Using pair-wise single-nucleotide polymorphism distances as a measure of genetic relatedness between isolates, we observed that most USA300 isolates had become endemic in households, indicating their critical role as reservoirs for transmission and diversification. Using the maximum single-nucleotide polymorphism variability of isolates from within households as a threshold, we identified several possible transmission networks beyond households. Our study also revealed the evolution of a fluoroquinolone-resistant subpopulation in the mid-1990s and its subsequent expansion at a time of high-frequency outpatient antibiotic use. This high resolution phylogenetic analysis of ST8 has documented the genomic changes associated with USA300 evolution and how some of its recent evolution has been shaped by antibiotic use. By integrating whole-genome sequencing with detailed epidemiological analyses, our study provides an important framework for delineating the full diversity and spread of USA300 and other emerging pathogens in large urban community populations. PMID- 24753570 TI - Pronounced zonal heterogeneity in Eocene southern high-latitude sea surface temperatures. AB - Paleoclimate studies suggest that increased global warmth during the Eocene epoch was greatly amplified at high latitudes, a state that climate models cannot fully reproduce. However, proxy estimates of Eocene near-Antarctic sea surface temperatures (SSTs) have produced widely divergent results at similar latitudes, with SSTs above 20 degrees C in the southwest Pacific contrasting with SSTs between 5 and 15 degrees C in the South Atlantic. Validation of this zonal temperature difference has been impeded by uncertainties inherent to the individual paleotemperature proxies applied at these sites. Here, we present multiproxy data from Seymour Island, near the Antarctic Peninsula, that provides well-constrained evidence for annual SSTs of 10-17 degrees C (1sigma SD) during the middle and late Eocene. Comparison of the same paleotemperature proxy at Seymour Island and at the East Tasman Plateau indicate the presence of a large and consistent middle-to-late Eocene SST gradient of ~7 degrees C between these two sites located at similar paleolatitudes. Intermediate-complexity climate model simulations suggest that enhanced oceanic heat transport in the South Pacific, driven by deep-water formation in the Ross Sea, was largely responsible for the observed SST gradient. These results indicate that very warm SSTs, in excess of 18 degrees C, did not extend uniformly across the Eocene southern high latitudes, and suggest that thermohaline circulation may partially control the distribution of high-latitude ocean temperatures in greenhouse climates. The pronounced zonal SST heterogeneity evident in the Eocene cautions against inferring past meridional temperature gradients using spatially limited data within given latitudinal bands. PMID- 24753571 TI - A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1. AB - The human RNA-editing enzyme adenosine deaminase acting on RNA (ADAR1) carries a unique nuclear localization signal (NLS) that overlaps one of its double-stranded RNA-binding domains (dsRBDs). This dsRBD-NLS is recognized by the nuclear import receptor transportin 1 (Trn1; also called karyopherin-beta2) in an RNA-sensitive manner. Most Trn1 cargos bear a well-characterized proline-tyrosine-NLS, which is missing from the dsRBD-NLS. Here, we report the structure of the dsRBD-NLS, which reveals an unusual dsRBD fold extended by an additional N-terminal alpha-helix that brings the N- and C-terminal flanking regions in close proximity. We demonstrate experimentally that the atypical ADAR1-NLS is bimodular and is formed by the combination of the two flexible fragments flanking the folded domain. The intervening dsRBD acts only as an RNA-sensing scaffold, allowing the two NLS modules to be properly positioned for interacting with Trn1. We also provide a structural model showing how Trn1 can recognize the dsRBD-NLS and how dsRNA binding can interfere with Trn1 binding. PMID- 24753572 TI - Storytelling and story testing in domestication. AB - The domestication of plants and animals marks one of the most significant transitions in human, and indeed global, history. Traditionally, study of the domestication process was the exclusive domain of archaeologists and agricultural scientists; today it is an increasingly multidisciplinary enterprise that has come to involve the skills of evolutionary biologists and geneticists. Although the application of new information sources and methodologies has dramatically transformed our ability to study and understand domestication, it has also generated increasingly large and complex datasets, the interpretation of which is not straightforward. In particular, challenges of equifinality, evolutionary variance, and emergence of unexpected or counter-intuitive patterns all face researchers attempting to infer past processes directly from patterns in data. We argue that explicit modeling approaches, drawing upon emerging methodologies in statistics and population genetics, provide a powerful means of addressing these limitations. Modeling also offers an approach to analyzing datasets that avoids conclusions steered by implicit biases, and makes possible the formal integration of different data types. Here we outline some of the modeling approaches most relevant to current problems in domestication research, and demonstrate the ways in which simulation modeling is beginning to reshape our understanding of the domestication process. PMID- 24753573 TI - Archaeological and genetic insights into the origins of domesticated rice. AB - Rice (Oryza sativa) is one of the most important cereal grains in the world today and serves as a staple food source for more than half of the world's population. Research into when, where, and how rice was brought into cultivation and eventually domesticated, along with its development into a staple food source, is thus essential. These questions have been a point of nearly continuous research in both archaeology and genetics, and new information has continually come to light as theory, data acquisition, and analytical techniques have advanced over time. Here, we review the broad history of our scientific understanding of the rice domestication process from both an archaeological and genetic perspective and examine in detail the information that has come to light in both of these fields in the last 10 y. Current findings from genetics and archaeology are consistent with the domestication of O. sativa japonica in the Yangtze River valley of southern China. Interestingly, although it appears rice was cultivated in the area by as early 8000 BP, the key domestication trait of nonshattering was not fixed for another 1,000 y or perhaps longer. Rice was also cultivated in India as early as 5000 BP, but the domesticated indica subspecies currently appears to be a product of the introgression of favorable alleles from japonica. These findings are reshaping our understanding of rice domestication and also have implications for understanding the complex evolutionary process of plant domestication. PMID- 24753574 TI - Neural sensitivity to eudaimonic and hedonic rewards differentially predict adolescent depressive symptoms over time. AB - The pursuit of happiness and reward is an impetus for everyday human behavior and the basis of well-being. Although optimal well-being may be achieved through eudaimonic activities (e.g., meaning and purpose), individuals tend to orient toward hedonic activities (e.g., pleasure seeking), potentially placing them at risk for ill-being. We implemented a longitudinal study and followed adolescents over 1 y to examine whether neural sensitivity to eudaimonic (e.g., prosocial decisions) and hedonic (e.g., selfish rewards and risky decisions) rewards differentially predicts longitudinal changes in depressive symptoms. Ventral striatum activation during eudaimonic decisions predicted longitudinal declines in depressive symptoms, whereas ventral striatum activation to hedonic decisions related to longitudinal increases in depressive symptoms. These findings underscore how the motivational context underlying neural sensitivity to rewards can differentially predict changes in well-being over time. Importantly, to our knowledge, this is the first study to show that striatal activation within an individual can be both a source of risk and protection. PMID- 24753575 TI - Network analysis reveals multiscale controls on streamwater chemistry. AB - By coupling synoptic data from a basin-wide assessment of streamwater chemistry with network-based geostatistical analysis, we show that spatial processes differentially affect biogeochemical condition and pattern across a headwater stream network. We analyzed a high-resolution dataset consisting of 664 water samples collected every 100 m throughout 32 tributaries in an entire fifth-order stream network. These samples were analyzed for an exhaustive suite of chemical constituents. The fine grain and broad extent of this study design allowed us to quantify spatial patterns over a range of scales by using empirical semivariograms that explicitly incorporated network topology. Here, we show that spatial structure, as determined by the characteristic shape of the semivariograms, differed both among chemical constituents and by spatial relationship (flow-connected, flow-unconnected, or Euclidean). Spatial structure was apparent at either a single scale or at multiple nested scales, suggesting separate processes operating simultaneously within the stream network and surrounding terrestrial landscape. Expected patterns of spatial dependence for flow-connected relationships (e.g., increasing homogeneity with downstream distance) occurred for some chemical constituents (e.g., dissolved organic carbon, sulfate, and aluminum) but not for others (e.g., nitrate, sodium). By comparing semivariograms for the different chemical constituents and spatial relationships, we were able to separate effects on streamwater chemistry of (i) fine-scale versus broad-scale processes and (ii) in-stream processes versus landscape controls. These findings provide insight on the hierarchical scaling of local, longitudinal, and landscape processes that drive biogeochemical patterns in stream networks. PMID- 24753576 TI - Genomic and cranial phenotype data support multiple modern human dispersals from Africa and a southern route into Asia. AB - Despite broad consensus on Africa as the main place of origin for anatomically modern humans, their dispersal pattern out of the continent continues to be intensely debated. In extant human populations, the observation of decreasing genetic and phenotypic diversity at increasing distances from sub-Saharan Africa has been interpreted as evidence for a single dispersal, accompanied by a series of founder effects. In such a scenario, modern human genetic and phenotypic variation was primarily generated through successive population bottlenecks and drift during a rapid worldwide expansion out of Africa in the Late Pleistocene. However, recent genetic studies, as well as accumulating archaeological and paleoanthropological evidence, challenge this parsimonious model. They suggest instead a "southern route" dispersal into Asia as early as the late Middle Pleistocene, followed by a separate dispersal into northern Eurasia. Here we test these competing out-of-Africa scenarios by modeling hypothetical geographical migration routes and assessing their correlation with neutral population differentiation, as measured by genetic polymorphisms and cranial shape variables of modern human populations from Africa and Asia. We show that both lines of evidence support a multiple-dispersals model in which Australo-Melanesian populations are relatively isolated descendants of an early dispersal, whereas other Asian populations are descended from, or highly admixed with, members of a subsequent migration event. PMID- 24753577 TI - Convergent evolution and parallelism in plant domestication revealed by an expanding archaeological record. AB - Recent increases in archaeobotanical evidence offer insights into the processes of plant domestication and agricultural origins, which evolved in parallel in several world regions. Many different crop species underwent convergent evolution and acquired domestication syndrome traits. For a growing number of seed crop species, these traits can be quantified by proxy from archaeological evidence, providing measures of the rates of change during domestication. Among domestication traits, nonshattering cereal ears evolved more quickly in general than seed size. Nevertheless, most domestication traits show similarly slow rates of phenotypic change over several centuries to millennia, and these rates were similar across different regions of origin. Crops reproduced vegetatively, including tubers and many fruit trees, are less easily documented in terms of morphological domestication, but multiple lines of evidence outline some patterns in the development of vegecultural systems across the New World and Old World tropics. Pathways to plant domestication can also be compared in terms of the cultural and economic factors occurring at the start of the process. Whereas agricultural societies have tended to converge on higher population densities and sedentism, in some instances cultivation began among sedentary hunter-gatherers whereas more often it was initiated by mobile societies of hunter-gatherers or herder-gatherers. PMID- 24753578 TI - GTP activator and dNTP substrates of HIV-1 restriction factor SAMHD1 generate a long-lived activated state. AB - The HIV-1 restriction factor sterile alpha-motif/histidine-aspartate domain containing protein 1 (SAMHD1) is a tetrameric protein that catalyzes the hydrolysis of all dNTPs to the deoxynucleoside and tripolyphosphate, which effectively depletes the dNTP substrates of HIV reverse transcriptase. Here, we establish that SAMHD1 is activated by GTP binding to guanine-specific activator sites (A1) as well as coactivation by substrate dNTP binding to a distinct set of nonspecific activator sites (A2). Combined activation by GTP and dNTPs results in a long-lived tetrameric form of SAMHD1 that persists for hours, even after activating nucleotides are withdrawn from the solution. These results reveal an ordered model for assembly of SAMHD1 tetramer from its inactive monomer and dimer forms, where GTP binding to the A1 sites generates dimer and dNTP binding to the A2 and catalytic sites generates active tetramer. Thus, cellular regulation of active SAMHD1 is not determined by GTP alone but instead, the levels of all dNTPs and the generation of a persistent tetramer that is not in equilibrium with free activators. The significance of the long-lived activated state is that SAMHD1 can remain active long after dNTP pools have been reduced to a level that would lead to inactivation. This property would be important in resting CD4(+) T cells, where dNTP pools are reduced to nanomolar levels to restrict infection by HIV-1. PMID- 24753579 TI - Heat of supersaturation-limited amyloid burst directly monitored by isothermal titration calorimetry. AB - Amyloid fibrils form in supersaturated solutions via a nucleation and growth mechanism. Although the structural features of amyloid fibrils have become increasingly clearer, knowledge on the thermodynamics of fibrillation is limited. Furthermore, protein aggregation is not a target of calorimetry, one of the most powerful approaches used to study proteins. Here, with beta2-microglobulin, a protein responsible for dialysis-related amyloidosis, we show direct heat measurements of the formation of amyloid fibrils using isothermal titration calorimetry (ITC). The spontaneous fibrillation after a lag phase was accompanied by exothermic heat. The thermodynamic parameters of fibrillation obtained under various protein concentrations and temperatures were consistent with the main chain dominated structural model of fibrils, in which overall packing was less than that of the native structures. We also characterized the thermodynamics of amorphous aggregation, enabling the comparison of protein folding, amyloid fibrillation, and amorphous aggregation. These results indicate that ITC will become a promising approach for clarifying comprehensively the thermodynamics of protein folding and misfolding. PMID- 24753581 TI - Multiple lines of evidence for the origin of domesticated chili pepper, Capsicum annuum, in Mexico. AB - The study of crop origins has traditionally involved identifying geographic areas of high morphological diversity, sampling populations of wild progenitor species, and the archaeological retrieval of macroremains. Recent investigations have added identification of plant microremains (phytoliths, pollen, and starch grains), biochemical and molecular genetic approaches, and dating through (14)C accelerator mass spectrometry. We investigate the origin of domesticated chili pepper, Capsicum annuum, by combining two approaches, species distribution modeling and paleobiolinguistics, with microsatellite genetic data and archaeobotanical data. The combination of these four lines of evidence yields consensus models indicating that domestication of C. annuum could have occurred in one or both of two areas of Mexico: northeastern Mexico and central-east Mexico. Genetic evidence shows more support for the more northern location, but jointly all four lines of evidence support central-east Mexico, where preceramic macroremains of chili pepper have been recovered in the Valley of Tehuacan. Located just to the east of this valley is the center of phylogenetic diversity of Proto-Otomanguean, a language spoken in mid-Holocene times and the oldest protolanguage for which a word for chili pepper reconstructs based on historical linguistics. For many crops, especially those that do not have a strong archaeobotanical record or phylogeographic pattern, it is difficult to precisely identify the time and place of their origin. Our results for chili pepper show that expressing all data in similar distance terms allows for combining contrasting lines of evidence and locating the region(s) where cultivation and domestication of a crop began. PMID- 24753580 TI - Millisecond dynamics of RNA polymerase II translocation at atomic resolution. AB - Transcription is a central step in gene expression, in which the DNA template is processively read by RNA polymerase II (Pol II), synthesizing a complementary messenger RNA transcript. At each cycle, Pol II moves exactly one register along the DNA, a process known as translocation. Although X-ray crystal structures have greatly enhanced our understanding of the transcription process, the underlying molecular mechanisms of translocation remain unclear. Here we use sophisticated simulation techniques to observe Pol II translocation on a millisecond timescale and at atomistic resolution. We observe multiple cycles of forward and backward translocation and identify two previously unidentified intermediate states. We show that the bridge helix (BH) plays a key role accelerating the translocation of both the RNA:DNA hybrid and transition nucleotide by directly interacting with them. The conserved BH residues, Thr831 and Tyr836, mediate these interactions. To date, this study delivers the most detailed picture of the mechanism of Pol II translocation at atomic level. PMID- 24753582 TI - Control of MT1-MMP transport by atypical PKC during breast-cancer progression. AB - Dissemination of carcinoma cells requires the pericellular degradation of the extracellular matrix, which is mediated by membrane type 1-matrix metalloproteinase (MT1-MMP). In this article, we report a co-up-regulation and colocalization of MT1-MMP and atypical protein kinase C iota (aPKCiota) in hormone receptor-negative breast tumors in association with a higher risk of metastasis. Silencing of aPKC in invasive breast-tumor cell lines impaired the delivery of MT1-MMP from late endocytic storage compartments to the surface and inhibited matrix degradation and invasion. We provide evidence that aPKCiota, in association with MT1-MMP-containing endosomes, phosphorylates cortactin, which is present in F-actin-rich puncta on MT1-MMP-positive endosomes and regulates cortactin association with the membrane scission protein dynamin-2. Thus, cell line-based observations and clinical data reveal the concerted activity of aPKC, cortactin, and dynamin-2, which control the trafficking of MT1-MMP from late endosome to the plasma membrane and play an important role in the invasive potential of breast-cancer cells. PMID- 24753583 TI - Modulation of a voltage-gated Na+ channel by sevoflurane involves multiple sites and distinct mechanisms. AB - Halogenated inhaled general anesthetic agents modulate voltage-gated ion channels, but the underlying molecular mechanisms are not understood. Many general anesthetic agents regulate voltage-gated Na(+) (NaV) channels, including the commonly used drug sevoflurane. Here, we investigated the putative binding sites and molecular mechanisms of sevoflurane action on the bacterial NaV channel NaChBac by using a combination of molecular dynamics simulation, electrophysiology, and kinetic analysis. Structural modeling revealed multiple sevoflurane interaction sites possibly associated with NaChBac modulation. Electrophysiologically, sevoflurane favors activation and inactivation at low concentrations (0.2 mM), and additionally accelerates current decay at high concentrations (2 mM). Explaining these observations, kinetic modeling suggests concurrent destabilization of closed states and low-affinity open channel block. We propose that the multiple effects of sevoflurane on NaChBac result from simultaneous interactions at multiple sites with distinct affinities. This multiple-site, multiple-mode hypothesis offers a framework to study the structural basis of general anesthetic action. PMID- 24753584 TI - Interepithelial signaling with nephric duct is required for the formation of overlying coelomic epithelial cell sheet. AB - In most organs of the body, epithelial tissues are supported by their own basement membrane and underlying stroma, the latter being regarded as a complex of amorphous cells, extracellular matrices, and soluble factors. We demonstrate here that an epithelial tube can serve as a component of stroma that supports the formation of epithelial cell sheet derived from a different origin. During development of the mesonephros in chicken embryos, the intermediate mesoderm (IMM), which contains the Wolffian duct (WD) and its associated tubules, is overlain by a sheet of epithelial cells derived from lateral plate (coelomic) mesoderm. We describe that in normal embryos, epitheliogenesis of IMM tubes and the adjacent coelomic cell sheet proceed in a coordinated manner. When the WD was surgically ablated, the overlying coelomic epithelium exhibited aberrant morphology accompanied by a punctated basement membrane. Furthermore, the WD ablated coelomic epithelium became susceptible to latent external stress; electroporation of Rac1 resulted in epithelial-to-mesenchymal transitions (EMTs) within the coelomic epithelium. The distorted coelomic epithelium was rescued by implanting fibronectin-producing cells in place of the WD, suggesting that fibronectin provided by WD has an important role acting interepithelially. This notion was corroborated further by directly visualizing a translocation of EGFP tagged fibronectin from fibronectin-producing to -receiving epithelia in vivo. Our findings provide a novel insight into interepithelial signaling that also might occur in adult tissues to protect against EMT and suggest a possible new target for anticancer therapeutic strategy. PMID- 24753585 TI - Mechanisms of noise robust representation of speech in primary auditory cortex. AB - Humans and animals can reliably perceive behaviorally relevant sounds in noisy and reverberant environments, yet the neural mechanisms behind this phenomenon are largely unknown. To understand how neural circuits represent degraded auditory stimuli with additive and reverberant distortions, we compared single neuron responses in ferret primary auditory cortex to speech and vocalizations in four conditions: clean, additive white and pink (1/f) noise, and reverberation. Despite substantial distortion, responses of neurons to the vocalization signal remained stable, maintaining the same statistical distribution in all conditions. Stimulus spectrograms reconstructed from population responses to the distorted stimuli resembled more the original clean than the distorted signals. To explore mechanisms contributing to this robustness, we simulated neural responses using several spectrotemporal receptive field models that incorporated either a static nonlinearity or subtractive synaptic depression and multiplicative gain normalization. The static model failed to suppress the distortions. A dynamic model incorporating feed-forward synaptic depression could account for the reduction of additive noise, but only the combined model with feedback gain normalization was able to predict the effects across both additive and reverberant conditions. Thus, both mechanisms can contribute to the abilities of humans and animals to extract relevant sounds in diverse noisy environments. PMID- 24753586 TI - Structural basis for diversity in the SAM clan of riboswitches. AB - In bacteria, sulfur metabolism is regulated in part by seven known families of riboswitches that bind S-adenosyl-l-methionine (SAM). Direct binding of SAM to these mRNA regulatory elements governs a downstream secondary structural switch that communicates with the transcriptional and/or translational expression machinery. The most widely distributed SAM-binding riboswitches belong to the SAM clan, comprising three families that share a common SAM-binding core but differ radically in their peripheral architecture. Although the structure of the SAM-I member of this clan has been extensively studied, how the alternative peripheral architecture of the other families supports the common SAM-binding core remains unknown. We have therefore solved the X-ray structure of a member of the SAM-I/IV family containing the alternative "PK-2" subdomain shared with the SAM-IV family. This structure reveals that this subdomain forms extensive interactions with the helix housing the SAM-binding pocket, including a highly unusual mode of helix packing in which two helices pack in a perpendicular fashion. Biochemical and genetic analysis of this RNA reveals that SAM binding induces many of these interactions, including stabilization of a pseudoknot that is part of the regulatory switch. Despite strong structural similarity between the cores of SAM I and SAM-I/IV members, a phylogenetic analysis of sequences does not indicate that they derive from a common ancestor. PMID- 24753588 TI - Lead in ancient Rome's city waters. AB - It is now universally accepted that utilization of lead for domestic purposes and water distribution presents a major health hazard. The ancient Roman world was unaware of these risks. How far the gigantic network of lead pipes used in ancient Rome compromised public health in the city is unknown. Lead isotopes in sediments from the harbor of Imperial Rome register the presence of a strong anthropogenic component during the beginning of the Common Era and the Early Middle Ages. They demonstrate that the lead pipes of the water distribution system increased Pb contents in drinking water of the capital city by up to two orders of magnitude over the natural background. The Pb isotope record shows that the discontinuities in the pollution of the Tiber by lead are intimately entwined with the major issues affecting Late Antique Rome and its water distribution system. PMID- 24753587 TI - Dystroglycan mediates homeostatic synaptic plasticity at GABAergic synapses. AB - Dystroglycan (DG), a cell adhesion molecule well known to be essential for skeletal muscle integrity and formation of neuromuscular synapses, is also present at inhibitory synapses in the central nervous system. Mutations that affect DG function not only result in muscular dystrophies, but also in severe cognitive deficits and epilepsy. Here we demonstrate a role of DG during activity dependent homeostatic regulation of hippocampal inhibitory synapses. Prolonged elevation of neuronal activity up-regulates DG expression and glycosylation, and its localization to inhibitory synapses. Inhibition of protein synthesis prevents the activity-dependent increase in synaptic DG and GABAA receptors (GABAARs), as well as the homeostatic scaling up of GABAergic synaptic transmission. RNAi mediated knockdown of DG blocks homeostatic scaling up of inhibitory synaptic strength, as does knockdown of like-acetylglucosaminyltransferase (LARGE)--a glycosyltransferase critical for DG function. In contrast, DG is not required for the bicuculline-induced scaling down of excitatory synaptic strength or the tetrodotoxin-induced scaling down of inhibitory synaptic strength. The DG ligand agrin increases GABAergic synaptic strength in a DG-dependent manner that mimics homeostatic scaling up induced by increased activity, indicating that activation of this pathway alone is sufficient to regulate GABAAR trafficking. These data demonstrate that DG is regulated in a physiologically relevant manner in neurons and that DG and its glycosylation are essential for homeostatic plasticity at inhibitory synapses. PMID- 24753589 TI - Endoscopic photoconversion reveals unexpectedly broad leukocyte trafficking to and from the gut. AB - Given mounting evidence of the importance of gut-microbiota/immune-cell interactions in immune homeostasis and responsiveness, surprisingly little is known about leukocyte movements to, and especially from, the gut. We address this topic in a minimally perturbant manner using Kaede transgenic mice, which universally express a photoconvertible fluorescent reporter. Transcutaneous exposure of the cervical lymph nodes to violet light permitted punctual tagging of immune cells specifically therein, and subsequent monitoring of their immigration to the intestine; endoscopic flashing of the descending colon allowed specific labeling of intestinal leukocytes and tracking of their emigration. Our data reveal an unexpectedly broad movement of leukocyte subsets to and from the gut at steady state, encompassing all lymphoid and myeloid populations examined. Nonetheless, different subsets showed different trafficking proclivities (e.g., regulatory T cells were more restrained than conventional T cells in their exodus from the cervical lymph nodes). The novel endoscopic approach enabled us to evidence gut-derived Th17 cells in the spleens of K/BxN mice at the onset of their genetically determined arthritis, thereby furnishing a critical mechanistic link between the intestinal microbiota, namely segmented filamentous bacteria, and an extraintestinal autoinflammatory disease. PMID- 24753590 TI - Crystal structure of Streptococcus pyogenes EndoS, an immunomodulatory endoglycosidase specific for human IgG antibodies. AB - To evade host immune mechanisms, many bacteria secrete immunomodulatory enzymes. Streptococcus pyogenes, one of the most common human pathogens, secretes a large endoglycosidase, EndoS, which removes carbohydrates in a highly specific manner from IgG antibodies. This modification renders antibodies incapable of eliciting host effector functions through either complement or Fc gamma receptors, providing the bacteria with a survival advantage. On account of this antibody specific modifying activity, EndoS is being developed as a promising injectable therapeutic for autoimmune diseases that rely on autoantibodies. Additionally, EndoS is a key enzyme used in the chemoenzymatic synthesis of homogenously glycosylated antibodies with tailored Fc gamma receptor-mediated effector functions. Despite the tremendous utility of this enzyme, the molecular basis of EndoS specificity for, and processing of, IgG antibodies has remained poorly understood. Here, we report the X-ray crystal structure of EndoS and provide a model of its encounter complex with its substrate, the IgG1 Fc domain. We show that EndoS is composed of five distinct protein domains, including glycosidase, leucine-rich repeat, hybrid Ig, carbohydrate binding module, and three-helix bundle domains, arranged in a distinctive V-shaped conformation. Our data suggest that the substrate enters the concave interior of the enzyme structure, is held in place by the carbohydrate binding module, and that concerted conformational changes in both enzyme and substrate are required for subsequent antibody deglycosylation. The EndoS structure presented here provides a framework from which novel endoglycosidases could be engineered for additional clinical and biotechnological applications. PMID- 24753591 TI - Investigations of heme distortion, low-frequency vibrational excitations, and electron transfer in cytochrome c. AB - Cytochrome (cyt) c is an important electron transfer protein. The ruffling deformation of its heme cofactor has been suggested to relate to its electron transfer rate. However, there is no direct experimental evidence demonstrating this correlation. In this work, we studied Pseudomonas aeruginosa cytochrome c551 and its F7A mutant. These two proteins, although similar in their X-ray crystal structure, display a significant difference in their heme out-of-plane deformations, mainly along the ruffling coordinate. Resonance Raman and vibrational coherence measurements also indicate significant differences in ruffling-sensitive modes, particularly the low-frequency gammaa mode found between ~50-60 cm(-1). This supports previous assignments of gammaa as having a large ruffling content. Measurement of the photoreduction kinetics finds an order of magnitude decrease of the photoreduction cross-section in the F7A mutant, which has nearly twice the ruffling deformation as the WT. Additional measurements on cytochrome c demonstrate that heme ruffling is correlated exponentially with the electron transfer rates and suggest that ruffling could play an important role in redox control. A major relaxation of heme ruffling in cytochrome c, upon binding to the mitochondrial membrane, is discussed in this context. PMID- 24753592 TI - Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice. AB - Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and vascular cells differentially regulates the response to vascular injury, reflecting distinct effects of mPGES-1-derived PGE2 in these cell types on discrete cellular components of the vasculature. The cell selective roles of mPGES-1 in atherogenesis are unknown. Mice lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1-KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endothelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic low-density lipoprotein receptor-deficient animals. En face aortic lesion analysis revealed markedly reduced atherogenesis in Mac-mPGES-1-KOs, which was concomitant with a reduction in oxidative stress, reflective of reduced macrophage infiltration, less lesional expression of inducible nitric oxide synthase (iNOS), and lower aortic expression of NADPH oxidases and proinflammatory cytokines. Reduced oxidative stress was reflected systemically by a decline in urinary 8,12-iso iPF2alpha-VI. In contrast to exaggeration of the response to vascular injury, deletion of mPGES-1 in VSMCs, ECs, or both had no detectable phenotypic impact on atherogenesis. Macrophage foam cell formation and cholesterol efflux, together with plasma cholesterol and triglycerides, were unchanged as a function of genotype. In conclusion, myeloid cell mPGES-1 promotes atherogenesis in hyperlipidemic mice, coincident with iNOS-mediated oxidative stress. By contrast, mPGES-1 in vascular cells does not detectably influence atherogenesis in mice. This strengthens the therapeutic rationale for targeting macrophage mPGES-1 in inflammatory cardiovascular diseases. PMID- 24753593 TI - Accumulation and enhanced cycling of polyphosphate by Sargasso Sea plankton in response to low phosphorus. AB - Phytoplankton alter their biochemical composition according to nutrient availability, such that their bulk elemental composition varies across oceanic provinces. However, the links between plankton biochemical composition and variation in biogeochemical cycling of nutrients remain largely unknown. In a survey of phytoplankton phosphorus stress in the western North Atlantic, we found that phytoplankton in the phosphorus-depleted subtropical Sargasso Sea were enriched in the biochemical polyphosphate (polyP) compared with nutrient-rich temperate waters, contradicting the canonical oceanographic view of polyP as a luxury phosphorus storage molecule. The enrichment in polyP coincided with enhanced alkaline phosphatase activity and substitution of sulfolipids for phospholipids, which are both indicators of phosphorus stress. Further, polyP appeared to be liberated preferentially over bulk phosphorus from sinking particles in the Sargasso Sea, thereby retaining phosphorus in shallow waters. Thus, polyP cycling may form a feedback loop that attenuates the export of phosphorus when it becomes scarce, contributes bioavailable P for primary production, and supports the export of carbon and nitrogen via sinking particles. PMID- 24753595 TI - Cytokinin pathway mediates APETALA1 function in the establishment of determinate floral meristems in Arabidopsis. AB - In angiosperms, after the floral transition, the inflorescence meristem produces floral meristems (FMs). Determinate growth of FMs produces flowers of a particular size and form. This determinate growth requires specification of floral organs and termination of stem-cell divisions. Establishment of the FM and specification of outer whorl organs (sepals and petals) requires the floral homeotic gene APETALA1 (AP1). To determine FM identity, AP1 also prevents the formation of flowers in the axils of sepals. The mechanisms underlying AP1 function in the floral transition and in floral organ patterning have been studied extensively, but how AP1 terminates sepal axil stem-cell activities to suppress axillary secondary flower formation remains unclear. Here we show that AP1 regulates cytokinin levels by directly suppressing the cytokinin biosynthetic gene LONELY GUY1 and activating the cytokinin degradation gene CYTOKININ OXIDASE/DEHYDROGENASE3. Restoring the expression of these genes to wild-type levels in AP1-expressing cells or suppressing cytokinin signaling inhibits indeterminate inflorescence meristem activity caused by ap1 mutation. We conclude that suppression of cytokinin biosynthesis and activation of cytokinin degradation mediates AP1 function in establishing determinate FM. A deeper understanding of axil-lateral meristem activity provides crucial information for enhancing yield by engineering crops that produce more elaborated racemes. PMID- 24753594 TI - Defining functional DNA elements in the human genome. AB - With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease. PMID- 24753596 TI - Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices. AB - The brainstem nucleus locus coeruleus (LC) is the primary source of norepinephrine (NE) to the mammalian neocortex. It is believed to operate as a homogeneous syncytium of transmitter-specific cells that regulate brain function and behavior via an extensive network of axonal projections and global transmitter-mediated modulatory influences on a diverse assembly of neural targets within the CNS. The data presented here challenge this longstanding notion and argue instead for segregated operation of the LC-NE system with respect to the functions of the circuits within its efferent domain. Anatomical, molecular, and electrophysiological approaches were used in conjunction with a rat model to show that LC cells innervating discrete cortical regions are biochemically and electrophysiologically distinct from one another so as to elicit greater release of norepinephrine in prefrontal versus motor cortex. These findings challenge the consensus view of LC as a relatively homogeneous modulator of forebrain activity and have important implications for understanding the impact of the system on the generation and maintenance of adaptive and maladaptive behaviors. PMID- 24753597 TI - Effects of side chains in helix nucleation differ from helix propagation. AB - Helix-coil transition theory connects observable properties of the alpha-helix to an ensemble of microstates and provides a foundation for analyzing secondary structure formation in proteins. Classical models account for cooperative helix formation in terms of an energetically demanding nucleation event (described by the sigma constant) followed by a more facile propagation reaction, with corresponding s constants that are sequence dependent. Extensive studies of folding and unfolding in model peptides have led to the determination of the propagation constants for amino acids. However, the role of individual side chains in helix nucleation has not been separately accessible, so the sigma constant is treated as independent of sequence. We describe here a synthetic model that allows the assessment of the role of individual amino acids in helix nucleation. Studies with this model lead to the surprising conclusion that widely accepted scales of helical propensity are not predictive of helix nucleation. Residues known to be helix stabilizers or breakers in propagation have only a tenuous relationship to residues that favor or disfavor helix nucleation. PMID- 24753598 TI - Beyond the single gene: How epistasis and gene-by-environment effects influence crop domestication. AB - Domestication is a multifaceted evolutionary process, involving changes in individual genes, genetic interactions, and emergent phenotypes. There has been extensive discussion of the phenotypic characteristics of plant domestication, and recent research has started to identify the specific genes and mutational mechanisms that control domestication traits. However, there is an apparent disconnect between the simple genetic architecture described for many crop domestication traits, which should facilitate rapid phenotypic change under selection, and the slow rate of change reported from the archeobotanical record. A possible explanation involves the middle ground between individual genetic changes and their expression during development, where gene-by-gene (epistatic) and gene-by-environment interactions can modify the expression of phenotypes and opportunities for selection. These aspects of genetic architecture have the potential to significantly slow the speed of phenotypic evolution during crop domestication and improvement. Here we examine whether epistatic and gene-by environment interactions have shaped how domestication traits have evolved. We review available evidence from the literature, and we analyze two domestication related traits, shattering and flowering time, in a mapping population derived from a cross between domesticated foxtail millet and its wild progenitor. We find that compared with wild progenitor alleles, those favored during domestication often have large phenotypic effects and are relatively insensitive to genetic background and environmental effects. Consistent selection should thus be able to rapidly change traits during domestication. We conclude that if phenotypic evolution was slow during crop domestication, this is more likely due to cultural or historical factors than epistatic or environmental constraints. PMID- 24753599 TI - Evaluating the roles of directed breeding and gene flow in animal domestication. AB - For the last 150 y scholars have focused upon the roles of intentional breeding and genetic isolation as fundamental to understanding the process of animal domestication. This analysis of ethnoarchaeological, archaeological, and genetic data suggests that long-term gene flow between wild and domestic stocks was much more common than previously assumed, and that selective breeding of females was largely absent during the early phases of animal domestication. These findings challenge assumptions about severe genetic bottlenecks during domestication, expectations regarding monophyletic origins, and interpretations of multiple domestications. The findings also raise new questions regarding ways in which behavioral and phenotypic domestication traits were developed and maintained. PMID- 24753600 TI - Symbol addition by monkeys provides evidence for normalized quantity coding. AB - Weber's law can be explained either by a compressive scaling of sensory response with stimulus magnitude or by a proportional scaling of response variability. These two mechanisms can be distinguished by asking how quantities are added or subtracted. We trained Rhesus monkeys to associate 26 distinct symbols with 0-25 drops of reward, and then tested how they combine, or add, symbolically represented reward magnitude. We found that they could combine symbolically represented magnitudes, and they transferred this ability to a novel symbol set, indicating that they were performing a calculation, not just memorizing the value of each combination. The way they combined pairs of symbols indicated neither a linear nor a compressed scale, but rather a dynamically shifting, relative scaling. PMID- 24753601 TI - Particularism and the retreat from theory in the archaeology of agricultural origins. AB - The introduction of new analytic methods and expansion of research into previously untapped regions have greatly increased the scale and resolution of data relevant to the origins of agriculture (OA). As a result, the recognition of varied historical pathways to agriculture and the continuum of management strategies have complicated the search for general explanations for the transition to food production. In this environment, higher-level theoretical frameworks are sometimes rejected on the grounds that they force conclusions that are incompatible with real-world variability. Some of those who take this position argue instead that OA should be explained in terms of local and historically contingent factors. This retreat from theory in favor of particularism is based on the faulty beliefs that complex phenomena such as agricultural origins demand equally complex explanations and that explanation is possible in the absence of theoretically based assumptions. The same scholars who are suspicious of generalization are reluctant to embrace evolutionary approaches to human behavior on the grounds that they are ahistorical, overly simplistic, and dismissive of agency and intent. We argue that these criticisms are misplaced and explain why a coherent theory of human behavior that acknowledges its evolutionary history is essential to advancing understanding of OA. Continued progress depends on the integration of human behavior and culture into the emerging synthesis of evolutionary developmental biology that informs contemporary research into plant and animal domestication. PMID- 24753602 TI - Myosin-10 produces its power-stroke in two phases and moves processively along a single actin filament under low load. AB - Myosin-10 is an actin-based molecular motor that participates in essential intracellular processes such as filopodia formation/extension, phagocytosis, cell migration, and mitotic spindle maintenance. To study this motor protein's mechano chemical properties, we used a recombinant, truncated form of myosin-10 consisting of the first 936 amino acids, followed by a GCN4 leucine zipper motif, to force dimerization. Negative-stain electron microscopy reveals that the majority of molecules are dimeric with a head-to-head contour distance of ~50 nm. In vitro motility assays show that myosin-10 moves actin filaments smoothly with a velocity of ~310 nm/s. Steady-state and transient kinetic analysis of the ATPase cycle shows that the ADP release rate (~13 s(-1)) is similar to the maximum ATPase activity (~12-14 s(-1)) and therefore contributes to rate limitation of the enzymatic cycle. Single molecule optical tweezers experiments show that under intermediate load (~0.5 pN), myosin-10 interacts intermittently with actin and produces a power stroke of ~17 nm, composed of an initial 15-nm and subsequent 2-nm movement. At low optical trap loads, we observed staircase like processive movements of myosin-10 interacting with the actin filament, consisting of up to six ~35-nm steps per binding interaction. We discuss the implications of this load-dependent processivity of myosin-10 as a filopodial transport motor. PMID- 24753603 TI - Solid MRI contrast agents for long-term, quantitative in vivo oxygen sensing. AB - Targeted MRI contrast agents have proven useful in research and clinical studies for highlighting specific metabolites and biomarkers [Davies GL, et al. (2013) Chem Commun (Camb) 49(84):9704-9721] but their applicability in serial imaging is limited owing to a changing concentration postinjection. Solid enclosures have previously been used to keep the local concentration of contrast agent constant, but the need to surgically implant these devices limits their use [Daniel K, et al. (2009) Biosens Bioelectron 24(11):3252-3257]. This paper describes a novel class of contrast agent that comprises a responsive material for contrast generation and an injectable polymeric matrix for structural support. Using this principle, we have designed a contrast agent sensitive to oxygen, which is composed of dodecamethylpentasiloxane as the responsive material and polydimethylsiloxane as the matrix material. A rodent inspired-gas model demonstrated that these materials are functionally stable in vivo for at least 1 mo, which represents an order of magnitude improvement over an injection of liquid siloxane [Kodibagkar VD, et al. (2006) Magn Reson Med 55(4):743-748]. We also observed minimal adverse tissue reactions or migration of contrast agents from the initial injection site. This class of contrast agents, thus, represented a new and complementary method to monitor chronic diseases by MRI. PMID- 24753604 TI - Decreased abundance of type III secretion system-inducing signals in Arabidopsis mkp1 enhances resistance against Pseudomonas syringae. AB - Genes encoding the virulence-promoting type III secretion system (T3SS) in phytopathogenic bacteria are induced at the start of infection, indicating that recognition of signals from the host plant initiates this response. However, the precise nature of these signals and whether their concentrations can be altered to affect the biological outcome of host-pathogen interactions remain speculative. Here we use a metabolomic comparison of resistant and susceptible genotypes to identify plant-derived metabolites that induce T3SS genes in Pseudomonas syringae pv tomato DC3000 and report that mapk phosphatase 1 (mkp1), an Arabidopsis mutant that is more resistant to bacterial infection, produces decreased levels of these bioactive compounds. Consistent with these observations, T3SS effector expression and delivery by DC3000 was impaired when infecting the mkp1 mutant. The addition of bioactive metabolites fully restored T3SS effector delivery and suppressed the enhanced resistance in the mkp1 mutant. Pretreatment of plants with pathogen-associated molecular patterns (PAMPs) to induce PAMP-triggered immunity (PTI) also restricts T3SS effector delivery and enhances resistance by unknown mechanisms, and the addition of the bioactive metabolites similarly suppressed both aspects of PTI. Together, these results demonstrate that DC3000 perceives multiple signals derived from plants to initiate its T3SS and that the level of these host-derived signals impacts bacterial pathogenesis. PMID- 24753605 TI - Conceptual dynamical models for turbulence. AB - Understanding the complexity of anisotropic turbulent processes in engineering and environmental fluid flows is a formidable challenge with practical significance because energy often flows intermittently from the smaller scales to impact the largest scales in these flows. Conceptual dynamical models for anisotropic turbulence are introduced and developed here which, despite their simplicity, capture key features of vastly more complicated turbulent systems. These conceptual models involve a large-scale mean flow and turbulent fluctuations on a variety of spatial scales with energy-conserving wave-mean-flow interactions as well as stochastic forcing of the fluctuations. Numerical experiments with a six-dimensional conceptual dynamical model confirm that these models capture key statistical features of vastly more complex anisotropic turbulent systems in a qualitative fashion. These features include chaotic statistical behavior of the mean flow with a sub-Gaussian probability distribution function (pdf) for its fluctuations whereas the turbulent fluctuations have decreasing energy and correlation times at smaller scales, with nearly Gaussian pdfs for the large-scale fluctuations and fat-tailed non-Gaussian pdfs for the smaller-scale fluctuations. This last feature is a manifestation of intermittency of the small-scale fluctuations where turbulent modes with small variance have relatively frequent extreme events which directly impact the mean flow. The dynamical models introduced here potentially provide a useful test bed for algorithms for prediction, uncertainty quantification, and data assimilation for anisotropic turbulent systems. PMID- 24753606 TI - Radiometric 81Kr dating identifies 120,000-year-old ice at Taylor Glacier, Antarctica. AB - We present successful (81)Kr-Kr radiometric dating of ancient polar ice. Krypton was extracted from the air bubbles in four ~350-kg polar ice samples from Taylor Glacier in the McMurdo Dry Valleys, Antarctica, and dated using Atom Trap Trace Analysis (ATTA). The (81)Kr radiometric ages agree with independent age estimates obtained from stratigraphic dating techniques with a mean absolute age offset of 6 +/- 2.5 ka. Our experimental methods and sampling strategy are validated by (i) (85)Kr and (39)Ar analyses that show the samples to be free of modern air contamination and (ii) air content measurements that show the ice did not experience gas loss. We estimate the error in the (81)Kr ages due to past geomagnetic variability to be below 3 ka. We show that ice from the previous interglacial period (Marine Isotope Stage 5e, 130-115 ka before present) can be found in abundance near the surface of Taylor Glacier. Our study paves the way for reliable radiometric dating of ancient ice in blue ice areas and margin sites where large samples are available, greatly enhancing their scientific value as archives of old ice and meteorites. At present, ATTA (81)Kr analysis requires a 40-80-kg ice sample; as sample requirements continue to decrease, (81)Kr dating of ice cores is a future possibility. PMID- 24753607 TI - Patterns of coding variation in the complete exomes of three Neandertals. AB - We present the DNA sequence of 17,367 protein-coding genes in two Neandertals from Spain and Croatia and analyze them together with the genome sequence recently determined from a Neandertal from southern Siberia. Comparisons with present-day humans from Africa, Europe, and Asia reveal that genetic diversity among Neandertals was remarkably low, and that they carried a higher proportion of amino acid-changing (nonsynonymous) alleles inferred to alter protein structure or function than present-day humans. Thus, Neandertals across Eurasia had a smaller long-term effective population than present-day humans. We also identify amino acid substitutions in Neandertals and present-day humans that may underlie phenotypic differences between the two groups. We find that genes involved in skeletal morphology have changed more in the lineage leading to Neandertals than in the ancestral lineage common to archaic and modern humans, whereas genes involved in behavior and pigmentation have changed more on the modern human lineage. PMID- 24753608 TI - Establishing the validity of domestication genes using DNA from ancient chickens. AB - Modern domestic plants and animals are subject to human-driven selection for desired phenotypic traits and behavior. Large-scale genetic studies of modern domestic populations and their wild relatives have revealed not only the genetic mechanisms underlying specific phenotypic traits, but also allowed for the identification of candidate domestication genes. Our understanding of the importance of these genes during the initial stages of the domestication process traditionally rests on the assumption that robust inferences about the past can be made on the basis of modern genetic datasets. A growing body of evidence from ancient DNA studies, however, has revealed that ancient and even historic populations often bear little resemblance to their modern counterparts. Here, we test the temporal context of selection on specific genetic loci known to differentiate modern domestic chickens from their extant wild ancestors. We extracted DNA from 80 ancient chickens excavated from 12 European archaeological sites, dated from ~ 280 B.C. to the 18th century A.D. We targeted three unlinked genetic loci: the mitochondrial control region, a gene associated with yellow skin color (beta-carotene dioxygenase 2), and a putative domestication gene thought to be linked to photoperiod and reproduction (thyroid-stimulating hormone receptor, TSHR). Our results reveal significant variability in both nuclear genes, suggesting that the commonality of yellow skin in Western breeds and the near fixation of TSHR in all modern chickens took place only in the past 500 y. In addition, mitochondrial variation has increased as a result of recent admixture with exotic breeds. We conclude by emphasizing the perils of inferring the past from modern genetic data alone. PMID- 24753609 TI - An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity. AB - The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Many bacteria use toxins to kill host cells and evade immune responses. Such toxins are unknown in Mycobacterium tuberculosis. Virulent M. tuberculosis strains induce necrotic cell death in macrophages by an obscure molecular mechanism. Here we show that the M. tuberculosis protein Rv3903c (channel protein with necrosis-inducing toxin, CpnT) consists of an N terminal channel domain that is used for uptake of nutrients across the outer membrane and a secreted toxic C-terminal domain. Infection experiments revealed that CpnT is required for survival and cytotoxicity of M. tuberculosis in macrophages. Furthermore, we demonstrate that the C-terminal domain of CpnT causes necrotic cell death in eukaryotic cells. Thus, CpnT has a dual function in uptake of nutrients and induction of host cell death by M. tuberculosis. PMID- 24753610 TI - Interferon induction of IFITM proteins promotes infection by human coronavirus OC43. AB - IFNs are a family of cytokines that are essential for the antiviral response in vertebrates. Not surprisingly, viruses have adapted to encode virulence factors to cope with the IFN response. Intriguingly, we show here that all three types of interferons, IFN-alpha, IFN-gamma, and IFN-lambda, efficiently promote infection by a human coronavirus, HCoV-OC43, one of the major etiological agents of common cold, through the induction of IFN-inducible transmembrane (IFITM) proteins. IFITMs typically exert their antiviral function by inhibiting the entry of a broad spectrum of viruses into their host cells, presumably by trapping and degrading invading virions within the endocytic compartments. In contrast, HCoV OC43 uses IFN-induced human IFITM2 or IFITM3 as an entry factor to facilitate its infection of host cells. Reverse genetics analyses suggest that the structural motifs critical for the IFITM proteins' enhancement of HCoV-OC43 infection are distinct from those required for inhibiting infection by other viruses. We also present evidence showing that IFITM family members work as homo- and hetero oligomers to modulate virus entry. The observed enhancement of HCoV-OC43 infection by IFNs may underlie the propensity of the virus to invade the lower respiratory tract under inflammatory conditions. PMID- 24753611 TI - A tick-borne segmented RNA virus contains genome segments derived from unsegmented viral ancestors. AB - Although segmented and unsegmented RNA viruses are commonplace, the evolutionary links between these two very different forms of genome organization are unclear. We report the discovery and characterization of a tick-borne virus--Jingmen tick virus (JMTV)--that reveals an unexpected connection between segmented and unsegmented RNA viruses. The JMTV genome comprises four segments, two of which are related to the nonstructural protein genes of the genus Flavivirus (family Flaviviridae), whereas the remaining segments are unique to this virus, have no known homologs, and contain a number of features indicative of structural protein genes. Remarkably, homology searching revealed that sequences related to JMTV were present in the cDNA library from Toxocara canis (dog roundworm; Nematoda), and that shared strong sequence and structural resemblances. Epidemiological studies showed that JMTV is distributed in tick populations across China, especially Rhipicephalus and Haemaphysalis spp., and experiences frequent host switching and genomic reassortment. To our knowledge, JMTV is the first example of a segmented RNA virus with a genome derived in part from unsegmented viral ancestors. PMID- 24753612 TI - Transcriptional regulators ChlR and CnfR are essential for diazotrophic growth in nonheterocystous cyanobacteria. AB - Leptolyngbya boryana (Plectonema boryanum) is a diazotrophic cyanobacterium lacking heterocysts. How nitrogen fixation is regulated in filamentous nonheterocystous cyanobacteria remains unclear. Here we describe a large 50-kb nitrogen fixation (nif) gene cluster in L. boryana containing 50 genes. This gene cluster contains 14 nif genes (nifBSUHDKVZT and nifPENXW), two genes encoding transcriptional regulators showing high similarity to ChlR (chlorophyll regulator) and PatB, three genes encoding ferredoxin, three genes encoding cytochrome oxidase subunits, and 28 genes encoding nif-related proteins and proteins with putative or unknown functions. Eleven mutants lacking one gene or a subset of genes were isolated. Five of them did not grow under diazotrophic conditions, including two mutants lacking the transcriptional regulators. Although the chlR homolog-lacking mutant showed a normal level of nitrogenase activity, various intermediates of chlorophyll biosynthesis were accumulated under micro-oxic conditions. The phenotype suggested that ChlR activates the expression of the genes responsible for anaerobic chlorophyll biosynthesis to support energy supply for nitrogen fixation. In another mutant lacking the patB homolog, no transcripts of any nif genes were detected under nitrogen fixation conditions, which was consistent with no activity. Constitutive expression of patB in a shuttle vector resulted in low but significant nitrogenase activity even under nitrate-replete conditions, suggesting that the PatB homolog is the master regulator of nitrogen fixation. We propose to rename the patB homolog as cnfR, after cyanobacterial nitrogen fixation regulator. PMID- 24753613 TI - Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells. AB - Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ~40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk. PMID- 24753614 TI - Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1. AB - Parkinson disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Although growing evidence indicates that endoplasmic reticulum (ER) stress is a hallmark of PD, its exact contribution to the disease process is not well understood. Here we report that developmental ablation of X-Box binding protein 1 (XBP1) in the nervous system, a key regulator of the unfolded protein response (UPR), protects dopaminergic neurons against a PD-inducing neurotoxin. This survival effect was associated with a preconditioning condition that resulted from induction of an adaptive ER stress response in dopaminergic neurons of the SNpc, but not in other brain regions. In contrast, silencing XBP1 in adult animals triggered chronic ER stress and dopaminergic neuron degeneration. Supporting this finding, gene therapy to deliver an active form of XBP1 provided neuroprotection and reduced striatal denervation in animals injected with 6-hydroxydopamine. Our results reveal a physiological role of the UPR in the maintenance of protein homeostasis in dopaminergic neurons that may help explain the differential neuronal vulnerability observed in PD. PMID- 24753615 TI - Crystal structure of Arabidopsis glutamyl-tRNA reductase in complex with its stimulator protein. AB - Tetrapyrrole biosynthesis in plants, algae, and most bacteria starts from the NADPH-dependent reduction of glutamyl-tRNA by glutamyl-tRNA reductase (GluTR). The GluTR-catalyzed reaction is the rate-limiting step, and GluTR is the target of multiple posttranslational regulations, such as heme feedback inhibition, for the tetrapyrrole biosynthetic pathway. A recently identified GluTR regulator, GluTR binding protein (GluBP), has been shown to spatially organize tetrapyrrole synthesis by distributing GluTR into different suborganellar locations. Here we report the complex structure of GluTR-GluBP from Arabidopsis thaliana. The dimeric GluBP binds symmetrically to the catalytic domains of the V-shaped GluTR dimer via its C-terminal domain. A substantial conformational change of the GluTR NADPH-binding domain is observed, confirming the postulated rotation of the NADPH binding domain for hydride transfer from NADPH to the substrate. Arg146, "guarding the door" for metabolic channeling, adopts alternative conformations, which may represent steps involved in substrate recognition and product release. A coupled enzyme assay shows that GluBP stimulates GluTR catalytic efficiency with an approximate threefold increase of the 5-aminolevulinic acid formation rate. In addition, the GluTR activity can be inhibited by heme in a concentration dependent way regardless of the presence of GluBP. A structural alignment indicates that GluBP belongs to a heme-binding family involved in heme metabolism. We propose a catalytic mechanism model for GluTR, through which photosynthetic organisms can achieve precise regulation of tetrapyrrole biosynthesis. PMID- 24753618 TI - Nonlinear simulations to optimize magnetic nanoparticle hyperthermia. AB - Magnetic nanoparticle hyperthermia is an attractive emerging cancer treatment, but the acting microscopic energy deposition mechanisms are not well understood and optimization suffers. We describe several approximate forms for the characteristic time of Neel rotations with varying properties and external influences. We then present stochastic simulations that show agreement between the approximate expressions and the micromagnetic model. The simulations show nonlinear imaginary responses and associated relaxational hysteresis due to the field and frequency dependencies of the magnetization. This suggests that efficient heating is possible by matching fields to particles instead of resorting to maximizing the power of the applied magnetic fields. PMID- 24753617 TI - Automatic ultrarapid activation and inhibition of cortical motor systems in spoken word comprehension. AB - To address the hotly debated question of motor system involvement in language comprehension, we recorded neuromagnetic responses elicited in the human brain by unattended action-related spoken verbs and nouns and scrutinized their timecourse and neuroanatomical substrates. We found that already very early on, from ~80 ms after disambiguation point when the words could be identified from the available acoustic information, both verbs and nouns produced characteristic somatotopic activations in the motor strip, with words related to different body parts activating the corresponding body representations. Strikingly, along with this category-specific activation, we observed suppression of motor-cortex activation by competitor words with incompatible semantics, documenting operation of the neurophysiological principles of lateral/surround inhibition in neural word processing. The extremely early onset of these activations and deactivations, their emergence in the absence of attention, and their similar presence for words of different lexical classes strongly suggest automatic involvement of motor specific circuits in the perception of action-related language. PMID- 24753616 TI - Hypermutable DNA chronicles the evolution of human colon cancer. AB - Intratumor genetic heterogeneity reflects the evolutionary history of a cancer and is thought to influence treatment outcomes. Here we report that a simple PCR based assay interrogating somatic variation in hypermutable polyguanine (poly-G) repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer. We use poly-G repeat genotyping to study the evolution of colon carcinoma. In a cohort of 22 patients, we detect poly-G variants in 91% of tumors. Patient age is positively correlated with somatic mutation frequency, suggesting that some poly-G variants accumulate before the onset of carcinogenesis during normal division in colonic stem cells. Poorly differentiated tumors have fewer mutations than well-differentiated tumors, possibly indicating a shorter mitotic history of the founder cell in these cancers. We generate poly-G mutation profiles of spatially separated samples from primary carcinomas and matched metastases to build well-supported phylogenetic trees that illuminate individual patients' path of metastatic progression. Our results show varying degrees of intratumor heterogeneity among patients. Finally, we show that poly-G mutations can be found in other cancers than colon carcinoma. Our approach can generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure. PMID- 24753619 TI - Hydrostatic piezoelectric properties of [011] poled Pb(Mg1/3Nb2/3)O3-PbTiO3 single crystals and 2-2 lamellar composites. AB - The hydrostatic piezoelectric properties of [011] poled Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) crystals and corresponding 2-2 crystal/epoxy composites were investigated. The crystal volume ratio and compositional dependencies of the hydrostatic charge and voltage coefficients (dh and gh ) and hydrostatic figure of merit (FOM) dh * gh were determined, where large FOM value of 3.2 pm2/N with high stability as a function of hydrostatic pressure was achieved for rhombohedral crystal composites. In addition, the stress amplification effects of the face-plate and different epoxy matrixes were investigated, with maximum FOM value being on the order of 92 pm2/N, indicating that 2-2 crystal/epoxy composites are promising materials for hydrostatic applications. PMID- 24753620 TI - Nonlinear contrast enhancement in photoacoustic molecular imaging with gold nanosphere encapsulated nanoemulsions. AB - A composite contrast agent, a nanoemulsion bead with assembled gold nanospheres at the interface, is proposed to improve the specific contrast of photoacoustic molecular imaging. A phase transition in the bead's core is induced by absorption of a nanosecond laser pulse with a fairly low laser fluence (~3.5 mJ/cm2), creating a transient microbubble through dramatically enhanced thermal expansion. This generates nonlinear photoacoustic signals with more than 10 times larger amplitude compared to that of a linear agent with the same optical absorption. By applying a differential scheme similar to ultrasound pulse inversion, more than 40 dB contrast enhancement is demonstrated with suppression of background signals. PMID- 24753621 TI - Ordering recombinant silk-elastin-like nanofibers on the microscale. AB - Self-assembled peptide/polypeptide nanofibers are appealing building blocks for creating complex three-dimensional structures. However, ordering assembled peptide/polypeptide nanofibers into three-dimensional structures on the microscale remains challenging and often requires the employment of top-down approaches. We report that silk-elastin-like protein polymers self-assemble into nanofibers in physiologically relevant conditions, the assembled nanofibers further form fiber clusters on the microscale, and the nanofiber clusters eventually coalesce into three-dimensional structures with distinct nanoscale and microscale features. It is believed that the interplay between fiber growth and molecular diffusion leads to the ordering of the assembled silk-elastin-like nanofibers at the microscale. PMID- 24753622 TI - Five-dimensional visualization of phase transition in BiNiO3 under high pressure. AB - Colossal negative thermal expansion was recently discovered in BiNiO3 associated with a low density to high density phase transition under high pressure. The varying proportion of co-existing phases plays a key role in the macroscopic behavior of this material. Here, we utilize a recently developed X-ray Absorption Near Edge Spectroscopy Tomography method and resolve the mixture of high/low pressure phases as a function of pressure at tens of nanometer resolution taking advantage of the charge transfer during the transition. This five-dimensional (X, Y, Z, energy, and pressure) visualization of the phase boundary provides a high resolution method to study the interface dynamics of high/low pressure phase. PMID- 24753623 TI - Capacitive micromachined ultrasonic transducer arrays as tunable acoustic metamaterials. AB - Capacitive Micromachined Ultrasonic Transducers (CMUTs) operating in immersion support dispersive evanescent waves due to the subwavelength periodic structure of electrostatically actuated membranes in the array. Evanescent wave characteristics also depend on the membrane resonance which is modified by the externally applied bias voltage, offering a mechanism to tune the CMUT array as an acoustic metamaterial. The dispersion and tunability characteristics are examined using a computationally efficient, mutual radiation impedance based approach to model a finite-size array and realistic parameters of variation. The simulations are verified, and tunability is demonstrated by experiments on a linear CMUT array operating in 2-12 MHz range. PMID- 24753624 TI - Polymer-loaded propagating modes on a one-dimensional photonic crystal. AB - We numerically and experimentally demonstrate that a polymer film-coated one dimensional photonic crystal (1DPC) can sustain transverse electric (TE) polarized modes without the limit of guided layer's thickness. Our results indicate that two propagating modes are existing inside the polymer film, the first one is the TE polarized Bloch surface wave, and the second one is the TE polarized guided mode. Here in, the evolution of these two modes with change in the polymer film thickness is presented. Our numerical simulation results are in well-agreement with the experimental data obtained using back focal plane imaging. PMID- 24753626 TI - X-ray phase contrast imaging: Transmission functions separable in cylindrical coordinates. AB - A Fresnel-Kirchhoff integral can be used to calculate x-ray phase contrast images when the transmission function is known. Here expressions for image intensity are derived for objects with axial symmetry for an x-ray source with non-vanishing dimensions. An expression for the image intensity is given for an x-ray source whose intensity distribution is described by a Gaussian function, from which an expression for the limiting case of a point source of radiation is found. The expressions for image intensity are evaluated for cases where the magnification is substantially greater than one, as would be employed in biological imaging. Experiments using a microfocus x-ray tube and charge coupled device camera are reported to determine the capability of the method for imaging small spherical objects, such as gold particles, which might find application as contrast agents in biomedical imaging. PMID- 24753625 TI - Position- and orientation-controlled polarized light interaction of individual indium tin oxide nanorods. AB - We have systematically investigated the position, orientation, and polarization angle dependence of scattered light from well-characterized, indium tin oxide nanorods (ITO NRs) upon illumination with monochromatic light. Scattering signals from individual ITO NRs of horizontal and vertical configurations are probed quantitatively by examining signal response with respect to the analyzer angle and position along the length of the NR. Our efforts can be highly beneficial in providing fundamental understanding for the light interaction behavior of ITO NRs. Our results can provide valuable bases for comprehending optical emission from individual NRs, with their ever-growing applications in optoelectronics, photonics, and biosensing. PMID- 24753627 TI - Device considerations for development of conductance-based biosensors. AB - Design and fabrication of electronic biosensors based on field-effect-transistor (FET) devices require understanding of interactions between semiconductor surfaces and organic biomolecules. From this perspective, we review practical considerations for electronic biosensors with emphasis on molecular passivation effects on FET device characteristics upon immobilization of organic molecules and an electrostatic model for FET-based biosensors. PMID- 24753628 TI - Electromechanical characterization of [Formula: see text] crystals as a function of crystallographic orientation and temperature. AB - Relaxor based [Formula: see text] ternary single crystals (PIN-PMN-PT) were reported to have broader temperature usage range [Formula: see text] and comparable piezoelectric properties to [Formula: see text] (PMNT) crystals. In this work, the orientation dependent dielectric, piezoelectric and electromechanical properties for PIN-PMN-PT crystals were investigated along [Formula: see text] and [Formula: see text] directions. The electromechanical couplings [Formula: see text] and [Formula: see text] for [Formula: see text] poled crystals were found to be 0.91 and 0.91, respectively, with piezoelectric coefficients [Formula: see text] and [Formula: see text] on the order of 925 and 1420 pC/N. Of particular significance was the mechanical quality factor [Formula: see text] for [Formula: see text] oriented crystals, which was found to be [Formula: see text], much higher than the [Formula: see text] values of [Formula: see text] oriented relaxor-PT crystals [Formula: see text]. The temperature dependence of the piezoelectric properties exhibited good temperature stability up to their ferroelectric phase transition [Formula: see text], indicating [Formula: see text] and [Formula: see text] oriented PIN-PMN-PT are promising materials for transducer applications, with the latter for high power resonant devices where low loss (high [Formula: see text]) was required. PMID- 24753629 TI - Conductive shield for ultra-low-field magnetic resonance imaging: Theory and measurements of eddy currents. AB - Eddy currents induced by applied magnetic-field pulses have been a common issue in ultra-low-field magnetic resonance imaging. In particular, a relatively large prepolarizing field-applied before each signal acquisition sequence to increase the signal-induces currents in the walls of the surrounding conductive shielded room. The magnetic-field transient generated by the eddy currents may cause severe image distortions and signal loss, especially with the large prepolarizing coils designed for in vivo imaging. We derive a theory of eddy currents in thin conducting structures and enclosures to provide intuitive understanding and efficient computations. We present detailed measurements of the eddy-current patterns and their time evolution in a previous-generation shielded room. The analysis led to the design and construction of a new shielded room with symmetrically placed 1.6-mm-thick aluminum sheets that were weakly coupled electrically. The currents flowing around the entire room were heavily damped, resulting in a decay time constant of about 6 ms for both the measured and computed field transients. The measured eddy-current vector maps were in excellent agreement with predictions based on the theory, suggesting that both the experimental methods and the theory were successful and could be applied to a wide variety of thin conducting structures. PMID- 24753630 TI - Electrodeposition of FeCoCd films with in-plane uniaxial magnetic anisotropy for microwave applications. AB - FeCoCd thin films with 500 nm thickness are directly prepared through electrodeposition in the sulphate bath in which glycine and citric acid were added as complex agents. The composition, structure, and magnetic of FeCoCd films were investigated as a function of Cd2+ concentration, cathode current density, and deposition temperature. A wonderful soft magnetic FeCoCd film was prepared and its coercivity of easy axis and hard axis are 5 Oe and 4 Oe, respectively. The natural resonance frequency is about 3.0 GHz, which imply that the FeCoCd film is potential candidate for high frequency applications. PMID- 24753631 TI - Effect of Zr, V, Nb, Mo, and Ta substitutions on magnetic properties and microstructure of melt-spun SmCo5 magnets. AB - We have investigated effects of metal substitutions on the magnetic properties and microstructure of melt-spun Sm-Co-Cu-Fe-M (M = Zr, V, Nb, Mo, Ta) magnets. We prepared melt-spun ribbons with compositions of Sm(Co1-x Cu x )5Fe0.54-y M y (x = 0.1-0.5, y = 0-0.43, M = Zr, V, Nb, Mo, Ta). For compositions of Sm(Co1-x Cu x )5Fe0.54 (x = 0.1-0.5), coercivity increased with increasing of annealing temperature, and a high coercivity of 17.6 kOe was obtained at a Cu content of x = 0.3. The coercivity was found to increase with increasing melting point of the substitution element. A high coercivity of 24.5 kOe was obtained for a composition of Sm(Co0.7Cu0.3)5Fe0.34Ta0.2. PMID- 24753632 TI - Intracellular performance of tailored nanoparticle tracers in magnetic particle imaging. AB - Magnetic Particle Imaging (MPI) is a quantitative mass-sensitive, tracer-based imaging technique, with potential applications in various cellular imaging applications. The spatial resolution of MPI, in the first approximation, improves by decreasing the full width at half maximum (FWHM) of the field-derivative of the magnetization, dm/dH of the nanoparticle (NP) tracers. The FWHM of dm/dH depends critically on NPs' size, size distribution, and their environment. However, there is limited information on the MPI performance of the NPs after their internalization into cells. In this work, 30 to 150 MUg of the iron oxide NPs were incubated in a lysosome-like acidic buffer (0.2 ml, 20 mM citric acid, pH 4.7) and investigated by vibrating sample magnetometry, magnetic particle spectroscopy, transmission electron microscopy, and dynamic light scattering (DLS). The FWHM of the dm/dH curves of the NPs increased with incubation time and buffer to NPs ratio, consistent with a decrease in the median core size of the NPs from ~20.1 +/- 0.98 to ~18.5 +/- 3.15 nm. Further, these smaller degraded NPs formed aggregates that responded to the applied field by hysteretic reversal at higher field values and increased the FWHM. The rate of core size decrease and aggregation were inversely proportional to the concentration of the incubated NPs, due to their slower biodegradation kinetics. The results of this model experiment show that the MPI performance of the NPs in the acidic environments of the intracellular organelles (i.e., lysosomes and endosomes) can be highly dependent on their rate of internalization, residence time, and degradation. PMID- 24753633 TI - Methods for characterizing magnetic footprints of perpendicular magnetic recording writer heads. AB - In this work, the magnetic footprints, along with some of its dynamic features in recording process, of perpendicular magnetic recording writer heads have been characterized by using three different techniques. Those techniques are the spin stand stationary footprint technique, the spin-stand dynamic footprint technique, and the coherent writing technique combined with magnetic force microscope imaging method. The characteristics of those techniques have been compared to one another. It was found experimentally that the spin-stand stationary method could not precisely catch some peculiar recording dynamics of the write heads in certain conditions. The advantages and disadvantages among all those techniques are also examined and discussed in detail. PMID- 24753634 TI - Design and fabrication of a perpendicular magnetic tunnel junction based nonvolatile programmable switch achieving 40% less area using shared-control transistor structure. AB - A compact nonvolatile programmable switch (NVPS) using 90 nm CMOS technology together with perpendicular magnetic tunnel junction (p-MTJ) devices is fabricated for zero-standby-power field-programmable gate array. Because routing information does not change once it is programmed into an NVPS, high-speed read and write accesses are not required and a write-control transistor can be shared among all the NVPSs, which greatly simplifies structure of the NVPS. In fact, the effective area of the proposed NVPS is reduced by 40% compared to that of a conventional MTJ-based NVPS. The instant on/off behavior without external nonvolatile memory access is also demonstrated using the fabricated test chip. PMID- 24753635 TI - Influence of damping constant on inverse spin hall voltage of La0.7Sr0.3MnO3(x)/platinum bilayers. AB - Pure spin transport via spin pumping in the condition of ferromagnetic resonance can be transformed to charge current in the ferromagnetic/paramagnetic bilayer systems, based on inverse spin Hall effect (ISHE). Here, we explore La0.7Sr0.3MnO(x)/Pt(5.5 nm) [x = 10 to 65 nm] bilayers to investigate the influence of damping constant on spin pumping efficiency. The results show that the ISHE voltage depend on the damping constant of magnetic moment, suggesting that the precession energy tansferred to lattice/electron of normal metal is a key parameter to control the magnitude of spin current. PMID- 24753636 TI - An exclusive fluoride receptor: Fluoride-induced proton transfer to a quinoline based thiourea. AB - A new quinoline-based tripodal thiourea has been synthesized, which exclusively binds fluoride anion in DMSO, showing no affinity for other anions including, chloride, bromide, iodide, perchlorate, nitrate and hydrogen sulfate. As investigated by 1H NMR, the receptor forms both 1:1 and 1:2 complex yielding the binding constants of 2.32(3) (in log beta1 ) and 4.39(4) (in log beta2 ), respectively; where quinoline groups are protonated by the fluoride-induced proton transfer from the solution to the host molecule. The 1:2 binding is due to the interactions of one fluoride with NH binding sites of urea sites and another fluoride with secondary +NH binding sites within the tripodal pocket. The formation of both 1:1 and 1:2 complexes has been confirmed by the theoretical calculations based on density functional theory (DFT). PMID- 24753637 TI - Parent Stress and Perceptions of Language Development: Comparing Down Syndrome and Other Developmental Disabilities. AB - This study extended research on the Down syndrome advantage by examining differences in parent stress and parent perceptions of language development between 29 parents of young children with Down syndrome and 82 parents of children with other developmental disabilities. Parents of children with Down syndrome reported lower levels of total stress, child-related stress, and stress surrounding the parent-child interaction. Parents of children in both groups reported that they felt successful in their ability to impact their children's communication development but did differ on perceptions of difficulty such that parents of children with Down syndrome perceived their children's communication difficulties as less severe despite the children exhibiting similar language skills. Finally, after accounting for potential explanatory confounding variables, child diagnosis remained a significant predictor of parent stress and perceptions of language development. Results highlight the importance of considering etiology when assisting families raising a child with a disability. PMID- 24753640 TI - Comparison between Topical and Oral Tranexamic Acid in Management of Traumatic Hyphema. AB - BACKGROUND: We sought to determine the efficacy of topical tranexamic acid (5%) in the management of traumatic hyphema. METHODS: Thirty eyes with gross traumatic hyphema were enrolled in this study. The patients were treated with tranexamic acid (5%) eye drop every 6 hours for 5 days. The main outcome measures were best corrected visual acuity (BCVA), Intra-ocular pressure (IOP), day of clot absorption, and rate of rebleeding. These parameters were evaluated daily for 4 days and thereafter at the 8(th) and 14(th) days after treatment. The patients were also compared with two historical control groups of patients (80 eyes) with traumatic hyphema; the first control group was treated with oral placebo and the other group was treated with oral tranexamic acid at our department. RESULT: Prior to treatment, the mean logarithm of the minimum angle of resolution (logMAR) BCVA was 0.59+/-0.62. BCVA was increased to 0.08+/-0.14 at day 14 (P<0.001) and the mean IOP before treatment was 13.7+/-3.9 mm Hg, which was reduced to 11.4+/-1.8 mm Hg at day 14 (P=0.004). Rebleeding occurred in one (3.3%) patient on the 4(th) day post treatment. Comparison between the case group and the other two historical control groups with respect to the rebleeding rate demonstrated statistically significant differences between the case group and the first control group (P=0.008) but no statistically significant differences between the case group and the second control group (P=0.25). CONCLUSION: Topical tranexamic acid seems promising in the management of traumatic hyphema. However, the small sample size of the present study precludes the conclusion that topical tranexamic acid can replace the oral tranexamic acid. PMID- 24753639 TI - Comparison between Intravenous Sodium Valproate and Subcutaneous Sumatriptan for Treatment of Acute Migraine Attacks; Double-Blind Randomized Clinical Trial. AB - BACKGROUND: Sodium valproate (SV) has been approved for migraine prophylaxis and its intravenous form is used to treat acute migraine attacks. We compared the efficacy and safety of intravenous SV and subcutaneous Sumatriptan in managing acute migraine attacks. METHODS: This double-blind randomized clinical trial divided 90 patients into two groups: one group received 400 mg of intravenous SV and the second group received 6 mg of subcutaneous Sumatriptan. Headache severity before treatment and half an hour, one hour, and two hours after treatment was measured based on the VNRS in the groups. Associated symptoms, i.e., photophobia, phonophobia, nausea, and vomiting, were assayed on admission and 2 hours after treatment. Side effects of the drugs were checked 2 hours after injection. Obtained data from the groups were compared. RESULTS: In both groups, pain decrement at the mentioned time points was significant (P<0.001), but had no significant difference (P>0.05), indicating the similar effect of both drugs on pain improvement. In the SV group, photophobia, phonophobia, nausea, and vomiting were improved significantly, while in the Sumatriptan group, only photophobia and vomiting were decreased significantly, indicating the advantage of SV in improving the associated symptoms. Nausea, vomiting, facial paresthesia, and hypotension were more significantly frequent in the Sumatriptan group than in the SV group (P<0.05). CONCLUSION: Intravenous SV (400 mg) was as effective as subcutaneous Sumatriptan in the treatment of acute migraine attacks, but with more improvement in associated symptoms and with fewer side effects. TRIAL REGISTRATION NUMBER: IRCT201108025943N4. PMID- 24753638 TI - Peripheral lymphadenopathy: approach and diagnostic tools. AB - Peripheral lymph nodes, located deep in the subcutaneous tissue, clean antigens from the extracellular fluid. Generally, a normal sized lymph node is less than one cm in diameter. Peripheral lymphadenopathy (LAP) is frequently due to a local or systemic, benign, self-limited, infectious disease. However, it could be a manifestation of underlying malignancy. Seventy-five percent of all LAPs are localized, with more than 50% being seen in the head and neck area. LAP may be localized or generalized. Cervical lymph nodes are involved more often than the other lymphatic regions. Generally, it is due to infections, but most of the supraclavicular lymphadenopathies are associated with malignancy. Based on different geographical areas, the etiology is various. For example, in tropical areas, tuberculosis (TB) is a main benign cause of LAP in adults and children. Complete history taking and physical examination are mandatory for diagnosis; however, laboratory tests, imaging diagnostic methods, and tissue samplings are the next steps. Tissue diagnosis by fine needle aspiration biopsy or excisional biopsy is the gold standard evaluation for LAP. We concluded that in patients with peripheral LAP, the patient's age and environmental exposures along with a careful history taking and physical examination can help the physician to request step by step further work-up when required, including laboratory tests, imaging modalities, and tissue diagnosis, to reach an appropriate diagnosis. PMID- 24753641 TI - Slums' access to and coverage of primary health care services: a cross-sectional study in shiraz, a metropolis in southern iran. AB - BACKGROUND: The United Nations has predicted that the population of slum dwellers will have grown from one billion people worldwide to 2 billion by 2030. This trend is also predictable in Iran. In the Iranian metropolis of Shiraz, more than 10% of the residents live in slum areas. There are several problems regarding the delivery of social services in these areas. The aim of this study was to evaluate slums dwellers' access to and coverage of health care. METHODS: This cross sectional face-to-face study included 380 household of slum dwellers via stratified random sampling. Demographics, accessibility of health services, coverage of health care, and route of receiving health services were recorded through interviews. RESULTS: Approximately, 21.6% of the households had no physical access to health centers. The coverage rate of family planning programs for safe methods was 51.4% (95% CI: 48.86-53.9%). Vaccination coverage among children under 5 years old was 98% (95% CI: 97-99%). Furthermore, 34% of pregnant women had not received standard health care due to a lack of access to health centers. CONCLUSION: Limited access to health services along with inadequate knowledge of slum residents about health care facilities was the main barrier to the utilization of the health care in the slums. PMID- 24753642 TI - Association between HLA-Class I and HLA-Class II Alleles and Mycobacterium Tuberculosis Infection in Iraqi Patients from Baghdad City. AB - BACKGROUND: Pulmonary tuberculosis (PT) is one of the endemic diseases in Iraq, and among the suggested predisposing factors are alleles of the human leukocyte antigen (HLA) system. We sought to investigate the association between HLA-class I (A and B) and -class II (DR and DQ) alleles in a sample of PT Iraqi patients. METHODS: lymphocytes of 105 PT patients and 40 controls were phenotyped for HLA A, -B, -DR, and -DQ alleles by means of the microlymphocytotoxicity test using a panel of monoclonal antisera. RESULTS: HLA frequencies of B18 (16.2 vs. 2.5%; OD=7.53) and DR1 (51.4 vs. 10.0%; OD=9.53) alleles were significantly increased in the patients as compared with the controls, while B5 (6.7 vs. 25.0%), DR8 (1.9 vs. 17.5%), and DQ3 (11.4 vs. 45.0%) alleles were significantly decreased. However, a significant corrected level was maintained for only DR1, DR8, and DQ3 alleles (Pc=1.9*10(-5), 0.02 and 1.0*10(-4), respectively). CONCLUSION: The results confirm the predisposing and protecting roles of HLA alleles in PT. PMID- 24753643 TI - Expression Status of UBE2Q2 in Colorectal Primary Tumors and Cell Lines. AB - BACKGROUND: Activation of the ubiquitin-proteasome pathway in various malignancies, including colorectal cancer, is established. This pathway mediates the degradation of damaged proteins and regulates growth and stress response. The novel human gene, UBE2Q2, with a putative ubiquitin-conjugating enzyme activity, is reported to be overexpressed in some malignancies. We sought to investigate the expression levels of the UBE2Q2 gene in colorectal cell lines as well as in cancerous and normal tissues from patients with colorectal cancer. METHODS: Levels of UBE2Q2 mRNA in cell lines were assessed by Real-Time PCR. Western blotting was employed to investigate the levels of the UBE2Q2 protein in 8 colorectal cell lines and 43 colorectal tumor samples. RESULTS: Expression of UBE2Q2 was observed at the level of both mRNA and protein in colorectal cell lines, HT29/219, LS180, SW742, Caco2, HTC116, SW48, SW480, and SW1116. Increased levels of UBE2Q2 immunoreactivity was observed in the 65.11% (28 out of 43) of the colorectal carcinoma tissues when compared with their corresponding normal tissues. Difference between the mean intensities of UBE2Q2 bands from cancerous and normal tissues was statistically significant at P<0.001 (paired t test). CONCLUSION: We showed the expression pattern of the novel human gene, UBE2Q2, in 8 colorectal cell lines. Overexpression of UBE2Q2 in the majority of the colorectal carcinoma samples denotes that it may have implications for the pathogenesis of colorectal cancer. PMID- 24753644 TI - Cardiomyocyte marker expression in mouse embryonic fibroblasts by cell-free cardiomyocyte extract and epigenetic manipulation. AB - BACKGROUND: The regenerative capacity of the mammalian heart is quite limited. Recent reports have focused on reprogramming mesenchymal stem cells into cardiomyocytes. We investigated whether fibroblasts could transdifferentiate into myocardium. METHODS: Mouse embryonic fibroblasts were treated with Trichostatin A (TSA) and 5-Aza-2-Deoxycytidine (5-aza-dC). The treated cells were permeabilized with streptolysin O and exposed to the mouse cardiomyocyte extract and cultured for 1, 10, and 21 days. Cardiomyocyte markers were detected by immunohistochemistry. Alkaline phosphatase activity and OCT4 were also detected in cells treated by chromatin-modifying agents. RESULTS: The cells exposed to a combination of 5-aza-dC and TSA and permeabilized in the presence of the cardiomyocyte extract showed morphological changes. The cells were unable to express cardiomyocyte markers after 24 h. Immunocytochemical assays showed a notable degree of myosin heavy chain and alpha-actinin expressions after 10 days. The expression of the natriuretic factor and troponin T occurred after 21 days in these cells. The cells exposed to chromatin-modifying agents also expressed cardiomyocyte markers; however, the proportion of reprogrammed cells was clearly smaller than that in the cultures exposed to 5-aza-dC , TSA, and extract. CONCLUSION: It seems that the fibroblasts were able to eliminate the previous epigenetic markers and form new ones according to the factors existing in the extract. Since no beating was observed, at least up to 21 days, the cells may need an appropriate extracellular matrix for their function. PMID- 24753645 TI - Indicators developed to evaluate the international framework convention on tobacco control in iran; a grounded theory study. AB - This study aimed to develop indicators for evaluating the implementation of The Framework Convention on Tobacco Control (FCTC) in Iran. We used the "grounded theory" framework. Totally, 265 policy-makers, stakeholders, and community members were recruited by purposeful sampling in 2008. After analyzing the gathered data, 251 indicators, including 82 indicators as "applied indicators", were derived from second-level codes for three groups. A suitable evaluation questionnaire can be designed based on the extracted indicators for policy makers, stakeholders, and the community to follow the implementation of the FCTC in Iran. PMID- 24753646 TI - Safety of a Trivalent Inactivated Influenza Vaccine in Health Care Workers in Kurdistan Province, Western Iran; A Longitudinal Follow-up Study. AB - We studied the safety of a trivalent inactivated surface antigen (split virion, inactivated) influenza vaccine, Begrivac(r) (Novartis Company), widely used in health care workers in Kurdistan. A longitudinal follow-up study was performed in Sanandaj city, west of Iran, recruiting 936 people. A questionnaire was completed for each participant, and all symptoms or abnormal physical findings were recorded. In part 1 of the study, the post-vaccination complaints were headache (5.3%), fever (7.9%), weakness (9.6%), chills (10.1%), sweating (10.5%), arthralgia (20.2%), and malaise (21.5%). Swelling of the injection site was seen in 267 (30.3%) participants, and pruritus of the injection site was seen in 290 (32.9%) participants. Redness and induration were also reported in 42.5% of the participants. Local reactions were mainly mild and lasted for 1-2 days. No systemic reactions were reported in the second part of the study. None of the participants experienced any inconvenience. We concluded that local adverse reactions after the trivalent inactivated split influenza vaccine, Begrivac(r), in health care workers were far more common than expected. Continuous surveillance is needed to assess the potential risks and benefits of newly produced influenza vaccines. PMID- 24753647 TI - Prolonged hemoptysis caused by primary pulmonary epithelioid hemangioendothelioma; a case report and review of the literature. AB - Epithelioid hemangioendothelioma is a vascular tumor with an intermediate malignant potential. This tumor is very rare in the lung parenchyma, and most of the previously reported cases have been asymptomatic. There is no standard therapy for this tumor and prognosis in the previous reports has been variable. Herein we report our experience with a 60-year-old woman presenting with hemoptysis and multiple lung consolidation, leading to a diagnosis of epithelioid hemangioendothelioma after surgical resection and pathological examination. After surgery and chemotherapy, the patient had an acceptable course. PMID- 24753648 TI - Gastric Duplication Cyst in a man Presenting with Elevated Liver Enzymes and Icterus. AB - Gastric duplication cysts comprise 2-7% of gastrointestinal duplications, rare congenital malformations that can be present at almost any part of the alimentary tract. They mostly present with gastrointestinal obstruction symptoms, ulceration, and painless hemorrhage. Symptoms include nausea, vomiting, and fullness sensation. Gastric duplications are mostly cystic in shape. Herein, we present a 58-year-old man with a gastric duplication cyst, 70*30*35 mm in size, with the initial presentation of abdominal pain, icterus, and elevated liver enzymes. The patient provided informed consent for this report. PMID- 24753649 TI - Month of birth and the incidence of multiple sclerosis in southern iran. PMID- 24753651 TI - Babinski the great: Failure did not deter him. AB - Joseph Babinski (1857-1932) was born on November 17, 1857. He worked in a clinical arena dominated by Charcot and a focus on hysteria. His primary aim was in trying to find the reliable clinical signs to distinguish organic from non organic disease of the nervous system. He was considered as masterly diagnostician, relying considerably less on neuropathological reports. Babinski's first attention to the reflex of the toes occurred during a chance observation of the contrasting responses between two female patients, one a hysteric and the other a hemiplegic. He first published description of his famous "sign" in 1896. Babinski's love for research works could be gauzed from his desire to publish and by the age of 27 years, he had to this credit, 12 important articles, mainly concerned with histological and neurological themes and one of his articles on the basic description of muscle spindles was considered to be a significant one. He was awarded the doctorate degree in 1885. Babinski introduced the concept of pithiatism, meaning "curable by suggestion." He anticipated the emergence of neurosurgery in France and only 6 days prior to his death he is on record to have said that his most vital contribution to the cause of neurosciences was not the sign he described, but that he could goad Clovis Vincent and Martel to take up neurosurgery as a specialty. PMID- 24753650 TI - Role of vascular endothelial growth factor and other growth factors in post stroke recovery. AB - Stroke is a major health problem world-wide and its burden has been rising in last few decades. Until now tissue plasminogen activator is only approved treatment for stroke. Angiogenesis plays a vital role for striatal neurogenesis after stroke. Administration of various growth factors in an early post ischemic phase, stimulate both angiogenesis and neurogenesis and lead to improved functional recovery after stroke. However vascular endothelial growth factors (VEGF) is the most potent angiogenic factor for neurovascularization and neurogenesis in ischemic injury can be modulated in different ways and thus can be used as therapy in stroke. In response to the ischemic injury VEGF is released by endothelial cells through natural mechanism and leads to angiogenesis and vascularization. This release can also be up regulated by exogenous administration of Mesenchymal stem cells, by various physical therapy regimes and electroacupuncture, which further potentiate the efficacy of VEGF as therapy in post stroke recovery. Recent published literature was searched using PubMed and Google for the article reporting on methods of up regulation of VEGF and therapeutic potential of growth factors in stroke. PMID- 24753652 TI - Balint syndrome. AB - We report a patient who presented with complaints of blindness following stroke and was subsequently diagnosed to have Balint syndrome. PMID- 24753653 TI - Visuo-cognitive skill deficits in Alzheimer's disease and Lewy body disease: A comparative analysis. AB - Dementia is a chronic neurodegenerative disorder characterized by progressive cognitive loss. Alzheimer's disease (AD) and the Lewy body disease are the two most common causes of age-related degenerative dementia. Visuo-cognitive skills are a combination of very different cognitive functions being performed by the visual system. These skills are impaired in both AD and dementia with Lewy bodies (DLB). The aim of this review is to evaluate various studies for these visuo cognitive skills. An exhaustive internet search of all relevant medical databases was carried out using a series of key-word applications, including The Cochrane Library, MEDLINE, PSYCHINFO, EMBASE, CINAHL, AMED, SportDiscus, Science Citation Index, Index to Theses, ZETOC, PEDro and occupational therapy (OT) seeker and OT search. We reviewed all the articles until March 2013 with key words of: Visual skills visual cognition dementia AD, but the direct neurobiological etiology is difficult to establish., Dementia of Lewy body disease. Although most studies have used different tests for studying these abilities, in general, these tests evaluated the individual's ability of (1) visual recognition, (2) visual discrimination, (3) visual attention and (4) visuo-perceptive integration. Performance on various tests has been evaluated for assessing these skills. Most studies assessing such skills show that these skills are impaired in DLB as compared with AD. Visuo-cognitive skills are impaired more in DLB as compared with AD. These impairments have evident neuropathological correlations, but the direct neurobiological etiology is difficult to establish. PMID- 24753654 TI - Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. AB - BACKGROUND AND OBJECTIVE: To assess whether methylcobalamin and alpha lipoic acid (ALA) added to pregabalin provide additional benefit compared to pregabalin alone in type 2 diabetes mellitus associated peripheral neuropathy. SETTING AND DESIGN: An open label, randomized, controlled parallel-group pilot study. MATERIALS AND METHODS: Thirty adult patients with type 2 diabetes mellitus with symptoms of peripheral neuropathy for >=6 months were randomized to receive pregabalin 75 mg, methylcobalamin 750 MUg, and ALA 100 mg (PMA, n = 15); or pregabalin 75 mg (PG, n = 15) for 12 weeks. Assessment variables were numeric rating scale (NRS), sleep interference scores (SIS), response rate to pain, and global assessment for the usefulness of therapy. The nerve conduction velocity was assessed for sensory and motor nerves. Safety assessment included adverse events reported by the patients, clinical laboratory, and general medical, neurological examinations. STATISTICAL ANALYSIS: Efficacy analyses were done on per-protocol (PP) population, whereas safety analyses were done on intent-to-treat (ITT) population. RESULTS: Significant improvement was seen in pain and sleep interference in both groups. Mean nerve conduction velocity of left common peroneal nerve (CPN) showed significant improvement in PMA group at week 12 compared to baseline (P = 0.018). For right CPN both groups showed significant improvement. (PMA, P = 0.002, PG, P = 0.007). For sensory testing, at week 12, right superficial peroneal nerve showed reduction in nerve conduction velocity in PG group compared to baseline (P = 0.043). CONCLUSION: Methylcobalamine, ALA and pregabalin combination provides pain relief and improves sleep interference. Addition of methylcobalamin and ALA to pregabalin improves the nerve function. Due to small sample size, most of the efficacy parameters could not reach significant difference between groups; hence benefit of the 3-drug-combimation should be interpreted with reservation. PMID- 24753655 TI - A retrospective study of toddlers with autism spectrum disorder: Clinical and developmental profile. AB - OBJECTIVE: To retrospectively examine the developmental and clinical characteristics of children with autism spectrum disorders (ASD) in the first 2 years of life in order to narrow the interval between parental concern and getting a reliable diagnosis of autism. MATERIALS AND METHODS: The case records of 21 children in whom a diagnosis of ASD was made in the first 2 years of life and confirmed 6 months to 1 year later were examined. The inclusion criterion was absence of neurological, metabolic, or genetic disorders and sensory or motor impairments. These case records were maintained in the Pediatric Psychology Clinic at the Department of Pediatrics of a tertiary care teaching hospital in North India. RESULTS: The average age at presentation to the clinic was 21.23 months (SD = 2.18). The clinical characteristics that were found in two-thirds or more children included lack of speech, inability to follow verbal commands, lack of pretend play, no index finger pointing, difficulty in playing with toys in a constructive manner, lack of joint attention, and motor stereotypies. The mean IQ was 66.62 (SD = 15.11) and the mean SQ as measured by the Vineland Social Maturity Scale was 80.43 (SD = 17.45). CONCLUSIONS: Given the validity of early diagnosis over time, clinicians should be encouraged not only to make an early diagnosis but also to initiate early interventions in children with ASD. PMID- 24753656 TI - Acute confusional state/delirium: An etiological and prognostic evaluation. AB - INTRODUCTION: Acute confusional state/delirium is a frequent cause of hospital admission, in the elderly. It is characterized by an acute fluctuating impairment of cognitive functions and inattention. Recognition and prompt treatment is crucial to decrease the morbidity and mortality associated with it. MATERIALS AND METHODS: In this retrospective study, we determined the etiology and prognostic factors of an acute confusional state. A total of 52 patients of acute confusional state were clinically evaluated. All patients were also subjected to a battery blood biochemical examination, cerebrospinal fluid analysis and neuroimaging. Disability was assessed by using modified Barthel index (MBI). Patients were followed-up for 3 months. RESULTS: The mean age of our cohort was 65.04 +/- 10.6 years. 32 (61.5%) patients were male. In 33 patients, we were able to identify possible precipitating cause of an acute confusional state. In the rest of the patients results of all the tests were normal. Leukocytosis and hyponatremia were frequent factors associated with delirium. The mean duration of the hospital stay was 10.73 +/- 3.6 days (range 5-21 days). Patients with an abnormal work-up (possible precipitating cause) had significantly lower mortality, less duration of hospital stay and less severe disability after 3 months. Age, underlying illness, serum creatinine, abnormal neuroimaging and MBI were identified as a significant prognostic indicator. 18 (34.6%) of our patients died, of these in 10 patients we could not find a precipitating cause. CONCLUSION: Patients, in whom a cause was found out, had better prognosis in terms of lesser mortality and the duration of hospital stay. PMID- 24753657 TI - Seizure frequency and severity: How really important are they for the quality of life of patients with refractory epilepsy. AB - INTRODUCTION: The data in the scientific literature about the significance of seizure severity and frequency for the quality of life (QOL) of patients with refractory epilepsy (RE) are contradictory. OBJECTIVE: Our objective was to assess the impact of the seizure severity and frequency on the QOL of Bulgarian patients with RE. MATERIALS AND METHODS: A total of 70 patients with RE were studied by examining the medical documentation and seizure diaries. All study participants completed quality of life epilepsy inventory (QOLIE-89). Seizure severity of only 59 patients who had a seizure in the last month was assessed by the Liverpool seizure severity scale. RESULTS: A limited negative impact of the seizure severity and frequency on some aspects of the physical health, epilepsy, all aspects of the social health and epilepsy and the overall QOL has been demonstrated. A weak to moderate reverse correlation between the specified factors and the respective QOLIE-89 subscales has been found. CONCLUSION: The clinical factors seizure severity and seizure frequency have a limited negative impact mostly on the social aspects of QOL. The study results support the multidisciplinary approach to persons with epilepsy. PMID- 24753659 TI - Alzheimer disease: An interactome of many diseases. AB - Alzheimer Disease (AD) is an outcome as well as source of many diseases. Alzheimer is linked with many other diseases like Diabetes type 2, cholesterolemia, hypertension and many more. But how each of these diseases affecting other is still unknown to scientific community. Signaling Pathways of one disease is interlinked with other disease. But to what extent healthy brain is affected when any signaling in human body is disturbed is the question that matters. There is a need of Pathway analysis, Protein-Protein interaction (PPI) and the conserved interactome study in AD and linked diseases. It will be helpful in finding the potent drug or vaccine target in conscious manner. In the present research the Protein-Protein interaction of all the proteins involved in Alzheimer Disease is analyzed using ViSANT and osprey tools and pathway analysis further reveals the significant genes/proteins linking AD with other diseases. PMID- 24753658 TI - Clinical characteristics and long-term outcome of surgery for hypothalamic hamartoma in children with refractory epilepsy. AB - CONTEXT: Hypothalamic hamartomas (HH) are ectopic masses of neuronal and glial tissue most commonly presenting with medically refractory gelastic seizures with evolution to other seizure types. They are also associated with cognitive and behavioral problems to varying extent. Surgery has been found to improve quality of life in more than 50% of patients. AIM: To evaluate the clinical characteristics and long-term outcome of surgery in children with HH and refractory epilepsy. MATERIALS AND METHODS: A retrospective analysis of presurgical, surgical, and postsurgical data of six children who underwent surgery for HH and had at least 3 years follow-up was performed. RESULTS: SIX CHILDREN (MALE: female = 5:1) aged 3-16 years (at the time of surgery) underwent surgical resection of HH for refractory epilepsy. At last follow-up (range 3-9 years), three children were in Engel's class I, two in Class II, and one in class III outcome. Significant improvement in behavior, quality of life was noted in four children; while the change in intelligence quotient (IQ) was marginal. CONCLUSIONS: Medically refractory epilepsy associated with behavioral and cognitive dysfunction is the most common presentation of HH. Open surgical resection is safe with favorable outcome of epilepsy in 50% with significant improvement in behavior and marginal change in cognitive functions. PMID- 24753660 TI - Hyponatremia in stroke. AB - INTRODUCTION: Hyponatremia is a common electrolyte disorder encountered in patients of neurological disorders which is usually either due to inappropriate secretion of Antidiuretic hormone (SIADH) or cerebral salt wasting syndrome (CSWS). We conducted this study in a tertiary care hospital to determine the incidence and etiology of hyponatremia in patients of stroke admitted in the hospital. MATERIALS AND METHODS: It was a prospective study done over a period of two years that included established cases of stroke diagnosed on the basis of clinical history, examination and neuroimaging. 1000 stoke patients were evaluated for hyponatremia (serum sodium <130 meq/l). The data was analysed using Chi-square test using SPSS (Statistical package for social science) software. RESULTS: Out of 1000 patients, 353 patients had hyponatremia. Out of this 353 patients, 238 (67%) had SIADH and 115 (33%) had CSWS. SIADH was seen in 83 patients who had ischemic stroke and 155 patients of hemorrhagic stroke. CSWS was found in 38 patients with ischemic stroke and 77 patients with hemorrhagic stroke. Statistical analysis revealed that hyponatremia significantly affects the outcome of stroke especially when it is due to CSWS rather than SIADH. CONCLUSION: Incidence of hyponatremia in our study population was 35%. In patients of hyponatremia 67% were having SIADH and 33% were having CSWS. Overall hyponatremia affected the outcome of stroke especially when caused by CSWS. Therefore close monitoring of serum sodium must be done in all patients who are admitted with stroke and efforts must be made to determine the cause of hyponatremia, in order to properly manage such patients thereby decreasing the mortality rate. PMID- 24753661 TI - Susceptibility weighted magnetic resonance imaging of brain: A multifaceted powerful sequence that adds to understanding of acute stroke. AB - CONTEXT: To evaluate the additional information that susceptibility weighted sequences and datasets would provide in acute stroke. AIMS: The aim of this study were to assess the value addition of susceptibility weighted magnetic resonance imaging (SWI) of brain in patients with acute arterial infarct. MATERIALS AND METHODS: All patients referred for a complete brain magnetic resonance imaging (MRI) between March 2010 and March 2011 at our institution had SWI as part of routine MRI (T1, T2, and diffusion imaging). Retrospective study of 62 consecutive patients with acute arterial infarct was evaluated for the presence of macroscopic hemorrhage, petechial micro-bleeds, dark middle cerebral artery (MCA) sign and prominent vessels in the vicinity of infarct. RESULTS: SWI was found to detect hemorrhage not seen on other routine MRI sequences in 22 patients. Out of 62 patients, 17 (10 petechial) had hemorrhage less than 50% and 5 patients had greater than 50% area of hemorrhage. A "dark artery sign" due to thrombus within the artery was seen in 8 out of 62 patients. Prominent cortical and intraparenchymal veins were seen in 14 out of 62 patients. CONCLUSIONS: SWI has been previously shown to be sensitive in detecting hemorrhage; however is not routinely used in stroke evaluation. Our study shows that SWI, by virtue of identifying unsuspected hemorrhage, central occluded vessel, and venous congestion is additive in value to the routine MR exam and should be part of a routine MR brain in patients suspected of having an acute infarct. PMID- 24753662 TI - A simple bedside test to assess the swallowing dysfunction in Parkinson's disease. AB - BACKGROUND: Swallowing changes are common in Parkinson's disease (PD). Early identification is essential to avoid complications of aspiration. OBJECTIVES: To evaluate the swallowing ability of the PD patients and to correlate it with the indicators of disease progression. MATERIALS AND METHODS: A total of 100 PD patients (70 males and 30 females) aged between 50 years and 70 years with varying stage, duration, and severity were enrolled in a cross-sectional study carried out between January and May 2012. A simple bedside water swallowing test was performed using standard 150 ml of water. Swallowing process was assessed under three categories-swallowing speeds (ml/s), swallowing volume (ml/swallow) and swallowing duration (s/swallow). Equal number of age and sex matched controls were also evaluated. RESULTS: All of them completed the task of swallowing. A mean swallowing speed (27.48 ml/s), swallowing volume (28.5 ml/s), and swallowing duration (1.05 s/swallow) was established by the control group. The PD patients showed decreased swallowing speed (7.15 ml/s in males and 6.61 ml/s in females), decreased swallowing volume (14.59 ml/swallow and 14 ml/swallow in females), and increased swallowing duration (2.37 s/swallow and 2.42 s/swallow) which are statistically significant. There was a significant positive correlation between the severity, duration, and staging of the disease with the swallowing performance and a poor correlation between the subjective reports of dysphagia and the objective performance on water swallow test. CONCLUSION: The water swallowing test is a simple bedside test to identify the swallowing changes early in PD. It is recommended to do the test in all PD Patients to detect dysphagia early and to intervene appropriately. PMID- 24753663 TI - Gender influence on selection and outcome of deep brain stimulation for Parkinson's disease. AB - BACKGROUND: Gender differences exist in Parkinson's disease (PD), both in clinical manifestations and response to medical treatment. We investigated whether gender differences occur in the clinical characteristics of patients selected for bilateral subthalamic nucleus deep brain stimulation (STN DBS) or in the outcome when resource limits influence treatment choices made by patients. MATERIALS AND METHODS: Fifty-one consecutive patients were evaluated 1 month before, and 12 months after bilateral STN DBS. All patients were rated using Unified Parkinson's Disease Rating Scale, Parkinson's Disease Quality of Life (PDQL) Scale, Addenbrooke's Cognitive Examination and Beck Depression Inventory. RESULTS: Pre-operative characteristics did not differ between the genders except for lower doses of drugs (P = 0.03), worse emotional scores in PDQL (P = 0.01) and worse depression (P = 0.03) in women. There was no gender difference in the surgical outcome, except a lesser reduction of dopaminergic drugs in women. Depression and quality of life (QOL) improved equally well in women and men. CONCLUSION: Bilateral STN DBS is equally efficacious in both genders as a treatment for motor complications of PD and for improving QOL. Women are likely to be undertreated because of more severe dyskinesia and may experience less emotional well-being, and could therefore potentially benefit from earlier surgical treatment. PMID- 24753664 TI - Relationship between activities of daily living and cognitive ability in a sample of older adults with heterogeneous educational level. AB - INTRODUCTION: A number of studies have shown the impact of cognitive abilities on instrumental activities of daily living, in particular executive functions. Nevertheless, it is not clear to what extent these results can be generalized, given that most samples studied have not included people with a low educational level. OBJECTIVES: The current study aims to investigate the association between cognitive abilities and activities of daily living in older adults - with and without dementia - from a middle-income country. SAMPLE: The sample consisted of 48 healthy older adults and 29 people with dementia, who were evaluated in an Outpatient Care Unit in a University Reference Center in Rio de Janeiro. RESULTS: Regression analyses indicated that the best predictors for activities of daily living were performance in immediate verbal memory in the case of controls and in a categorical fluency task in the patient group. The educational level itself was not a significant predictor of functional ability in either sample, but showed moderate correlation with the predictors. CONCLUSIONS: These results suggest that educational level may be a mediating factor in the association of cognitive variables and activities of daily living, and indicate a potential dissociation in terms of predictors according to the diagnostic status, pointing to relevant treatment directions. PMID- 24753665 TI - A clinical and radiological profile of neuromyelitis optica and spectrum disorders in an Indian cohort. AB - BACKGROUND: There is insufficient data on the clinical and radiological features of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) from India. OBJECTIVE: The objective of the following study is to examine the clinico-radiological features of NMO and NMOSD in an Indian cohort. MATERIALS AND METHODS: This retrospective study included 44 consecutive patients who (1) satisfied the 2006 Wingerchuk criteria for NMO (16 seropositive and 7 seronegative); or (2) had isolated or recurrent optic neuritis (ON) with seropositivity (n = 4); or (3) had isolated or recurrent myelitis with seropositivity (n = 17). RESULTS: The female:male ratio was 7.8:1 with median age of onset 26.5 (range 8-72). Annualized relapse rate (ARR) was comparable across all groups (F [3, 40] = 0.938 and P = 0.431). Various presentations other than ON and myelitis were noted. All 40 patients with myelitis had spinal cord lesions involving >=3 vertebral segments during the course of the disease. Cervicomedullary involvement was seen in 32.5% (13/40) patients. Brain magnetic resonance imaging was available for 40 patients; eight of these (20%) had brain lesions in locations described in multiple sclerosis (MS), 27.5% (11/40) had lesions at sites unusual for MS and 52.5% (21/40) had normal brain imaging. CONCLUSION: NMO and NMOSD patients in this cohort have comparable ARR regardless of clinical presentation, supporting the emerging trend of treating all patients with immunotherapeutic agents at an early stage. Varied presentations seen in NMO and NMOSD highlight the need for a high index of suspicion for NMO in demyelinating episodes not classical for MS. PMID- 24753666 TI - Mycotic aneurysms of the intracranial and peripheral circulation: A rare complication of bacterial endocarditis. PMID- 24753667 TI - Acute flaccid paralysis due to West nile virus infection in adults: A paradigm shift entity. AB - Three cases of acute flaccid paralysis (AFP) with preceding fever are described. One patient had a quadriparesis with a florid meningoencephalitic picture and the other two had asymmetric flaccid paralysis with fasciculations at the onset of illness. Magnetic resonance imaging in two cases showed prominent hyperintensitities in the spinal cord and brainstem with prominent involvement of the grey horn (polio-myelitis). Cerebrospinal fluid (CSF) polymerase chain reaction was positive for West Nile virus (WNV) in the index patient. All three cases had a positive WNV immunoglobulin M antibody in serum/CSF and significantly high titer of WNV neutralizing antibody in serum, clearly distinguishing the infection from other Flaviviridae such as Japanese encephalitis. WNV has been recognized in India for many decades; however, AFP has not been adequately described. WNV is a flavivirus that is spread by Culex mosquitoes while they take blood meals from humans and lineage 1 is capable of causing a devastating neuro invasive disease with fatal consequences or severe morbidity. We describe the first three laboratory confirmed cases of WNV induced AFP from Kerala and briefly enumerate the salient features of this emerging threat. PMID- 24753668 TI - An unusual cause of ischemic stroke - Cerebral air embolism. AB - Air embolism is a preventable, often undiagnosed but potentially treatable cause of ischemic stroke with a high morbidity and mortality. It is usually iatrogenic ocurring especially in patients in ICU setting. We describe the case and neuroimaging of a patient with ischaemic stroke due to air embolism during manipulation of central venous line. We also review the literature with respect to aetiology, incidence pathophysiology, diagnosis, and treatment options for venous and air embolism. Cerebral air embolism should be considered in patients with sudden neurological deterioration after central venous or arterial manipulations or certain neurological procedures. Prevention, as well as early diagnosis and management, may reduce morbidity and mortality. PMID- 24753669 TI - Isolated primary craniosynostosis in an adult: Imaging findings of a case. AB - Craniosynostosis means premature closure of calvarial sutures. It may be primary or secondary. The patient presents with unexplained neuropsychological impairment and radiological imaging clinches the diagnosis. We present a case of 31-year-old female having primary isolated craniosynostosis who survived into adulthood without any surgical intervention. The imaging findings of such a case are rarely described in the literature. PMID- 24753670 TI - Rare ocular manifestation in a case of West Nile virus meningoencephalitis. AB - West Nile Virus (WNV) is an arthropod-borne flavivirus, which causes flu-like illness and is sporadically associated with encephalitis. Transmission to humans occurs following a bite from an infected mosquito, which acquires the virus after feeding on dead birds. WNV meningoencephalitis is a rare infection with a neuroinvasive disease occurring in less than 1% of the cases, with varied presentations including aseptic meningitis, meningoencephalitis, and acute flaccid paralysis. Chorioretinitis is the most common eye finding in this infection, while other ocular manifestations have been rarely reported in the literature. We present the first case report of WNV meningoencephalitis, with rare ocular manifestations of acute hemorrhagic conjunctivitis, bilateral subconjunctival hemorrhages, and nystagmus. The rare ocular findings of acute hemorrhagic conjunctivitis, bilateral subconjunctival hemorrhages, and nystagmus diagnosed in our case can guide clinicians toward early diagnosis of WNV meningoencephalitis, while serologic testing is still pending. PMID- 24753672 TI - Reversible electrophysiological abnormalities in hypokalemic paralysis: Case report of two cases. AB - Compound muscle action potential (CMAP) amplitude declines during a paralytic attack in patients with hypokalemic periodic paralysis (HPP). However, serial motor nerve conduction studies in hypokalemic paralysis have not been commonly reported. We report two cases with hypokalemic paralysis, who had severely reduced CMAPs in all motor nerves at presentation during the episode of quadriparesis. However, the amplitude of CMAPs increased and reached normal levels, as the serum potassium concentration and motor power returned to normal state. PMID- 24753671 TI - An interesting case of metabolic dystonia: L-2 hydroxyglutaric aciduria. AB - L-2-hydroxyglutaric aciduria (L-2-HGA), a neurometabolic disorder caused by mutations in the L-2 hydroxyglutarate dehydrogenase (L-2-HGDH) gene, presents with psychomotor retardation, cerebellar ataxia, extrapyramidal symptoms, macrocephaly and seizures. Characteristic magnetic resonance imaging findings include subcortical cerebral white matter abnormalities with T2 hyperintensities of the dentate nucleus, globus pallidus, putamen and caudate nucleus. The diagnosis can be confirmed by elevated urinary L-2 hydroxyglutaric acid and mutational analysis of the L-2-HGDH gene. We report two siblings with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid. Riboflavin therapy has shown promising results in a subset of cases, thus highlighting the importance of making the diagnosis in these patients. PMID- 24753673 TI - Atypical Wernicke's syndrome sans encephalopathy with acute bilateral vision loss due to post-chiasmatic optic tract edema. AB - A middle aged male presented with acute bilateral vision loss, 4 weeks after undergoing gastric bypass surgery for gastric carcinoma. He had normal sensorium, fundoscopy, normal pupillary reaction to light, but had mild opthalmoparesis and nystagmus with ataxia. Magnetic resonance imaging of the brain revealed post chiasmatic optic tract edema along with other classical features of Wernicke's syndrome. Thiamine supplementation leads to complete resolution of clinical as well as imaging findings. In appropriate clinical settings, a high index of suspicion and early treatment are essential for managing Wernicke's syndrome even in patients with atypical clinical and imaging presentation. PMID- 24753674 TI - Essential thrombocythemia: Rare cause of chorea. AB - Essential thrombocythemia (ET) is a clonal myeloproliferative disorder (MPD), characterized predominantly by a markedly elevated platelet count without known cause. It is rare hematological disorder. In ET clinical picture is dominated by a predisposition to vascular occlusive events and hemorrhages. Headache, transient ischemic attack, stroke, visual disturbances and light headedness are some of the neurological manifestations of ET. Here, we describe a 55 year-old female who presented to us with generalized chorea. On evaluation, she was found to have thrombocytosis. After ruling out the secondary causes of thrombocytosis and other MPD we confirmed diagnosis of ET in her by bone marrow studies. Polycythemia vera (PV) another MPD closely related to ET may be present with generalized chorea. There are few case reports of PV presenting as chorea in the literature, but none with ET. We report the first case of ET presenting as generalized chorea. PMID- 24753675 TI - Acanthamoeba meningoencephalitis. AB - Report of a case of young immunocompetent male adult with autopsy proven acanthamoeba meningoencephalitis. The patient presented with a protracted febrile illness of 3 months duration with features of meningoencephalitis, this was followed by rapid deterioration while on anti tuberculous therapy and steroids and ended fatally. His magnetic resonance imaging showed features of hemorrhagic meningoencephalitis and magnetic resonance spectroscopy showed choline peak. Autopsy revealed necrotizing meningoencephalitis and intraocular colonization due to acanthamoeba. PMID- 24753676 TI - Clinical, hematological, and imaging observations in a 25-year-old woman with abetalipoproteinemia. AB - Abetalipoproteinemia is an uncommon cause of ataxia and retinitis pigmentosa (RP). Most of the neurological and ocular manifestations occur secondary to deficiency syndromes that is consequent to fat malabsorption from the small intestine. In this report, we have described the phenotype of a young adult female who manifested with recurrent diarrheal illness in her first decade, followed by anemia, RP, and neurological involvement with progressive deafness, cerebellar and sensory ataxia, and subclinical neuropathy in her second decade of life. While RP and sensory ataxia due to vitamin E deficiency are well-recognized features of abetalipoproteinemia, deafness is rarely described. In addition, we have highlighted the abnormal posterior column signal changes in the cervical cord in this patient. Early recognition avoids unnecessary investigations and has a potential to retard the disease progression by replacing some of the deficient vitamins. PMID- 24753677 TI - Intractable vomiting and hiccups as the presenting symptom of neuromyelitis optica. AB - Vomiting and hiccups can be due to peripheral or central causes. Neurological diseases causing vomiting and hiccups are due to lesions of medulla involving area postrema and nucleus tractus solitarius. Neuromyelitis optica (NMO) is one such disease which involves these structures. However refractory vomiting and hiccups as the presenting symptom of NMO is unusual. Here we report a patient with NMO in whom refractory vomiting and hiccups were the sole manifestation of the first attack. Diagnosis can be missed at this stage leading to delay in treatment and further complications. This case demonstrates the importance of considering NMO in any patient presenting with refractory vomiting and hiccups and with local and metabolic causes ruled out and linear medullary lesion on magnetic resonance imaging may indicate the diagnosis even when the classical clinical criteria are not met. Anti NMO antibody testing should be done and if positive appropriate treatment should be initiated to prevent further neurological damage. PMID- 24753678 TI - Pregnancy related symptomatic vertebral hemangioma. AB - Vertebral hemangiomas are benign vascular tumors of the spine that remain asymptomatic in most cases and incidentally encountered on imaging. Rarely, altered hemodynamic and hormonal changes during pregnancy may expand these benign lesions resulting in severe cord compression. The management of symptomatic vertebral hemangioma during pregnancy is controversial as modalities like radiotherapy and embolization are not suitable and surgery during pregnancy has a risk of preterm labor. Few cases of pregnancy related symptomatic vertebral hemangioma with marked epidural component have been reported in the literature. We report a case of 23-year-old primigravida who developed rapidly progressive paraparesis at 28 weeks of gestation and spine magnetic resonance imaging (MRI) revealed upper thoracic vertebral hemangioma with extensive extra-osseous extension and spinal cord compression. Laminectomy and surgical decompression of the cord was performed at 32 weeks of the pregnancy. There was significant improvement in muscle power after a week of surgery. Six weeks postoperatively she delivered a full term normal baby with subsequent improvement of neurologic deficit. Repeat MRI of dorsal spine performed at 3 months postoperatively showed reduced posterior and anterior epidural components of vertebral hemangioma. PMID- 24753679 TI - Glutamate-based magnetic resonance spectroscopy in neuroleptic malignant syndrome. AB - Glutamate neurotoxicity is implicated in a number of neurological diseases, including Neuroleptic Malignant syndrome. Therefore, functional magnetic resonance imaging can help in diagnosis and monitoring such conditions. However, reports of this application are scarce in the literature. In this manuscript, glutamate based imaging of the basal ganglia showed increased levels of the neurotransmitter bilaterally. In addition, a radon transform of the functional image was performed to look for any asymmetry in cerebral activation. Although no asymmetry was detected in this case, this novel analysis can be applied in physiological and pathological scenarios to visualize contribution of different brain structures. PMID- 24753680 TI - Multiple cerebral infarctions with severe multi-organ dysfunction following multiple wasp stings. AB - Wasp and bee sting are commonly encountered worldwide. Local reactions are more common, generally are self-limiting and settle within a few hours. Multiple stings can lead to various clinical manifestations like vomiting, diarrhea, dyspnea, generalized edema, hypotension, syncope, acute renal failure, and even death. Rarely, they can cause vasculitis, serum sickness, neuritis, and encephalitis. We are reporting a case of 40-year-old male who presented with stroke, right hemiparesis with severe multi-organ dysfunction due to multiple wasp stings. PMID- 24753681 TI - Vogt-Koyanagi-Harada syndrome presenting with encephalopathy. AB - Vogt-Koyanagi-Harada (VKH) is a rare syndrome affecting tissues containing melanocytes. The possibility of its autoimmune pathogenesis is supported by high frequent HLA-DR4 presentation, commonly associated with other autoimmune diseases. Eyes are the main affected organs, resulting in blindness. Brain disease is a late-onset event, and is extremely rare. Here, we are reporting a 57 year-old woman, a known case of VKH syndrome, presenting with brain encephalopathy several decades after the initial presentation. We think this long period between initial presentation and presentation of encephalopathy due to VKH syndrome has not been described before. She was treated with corticosteroids and discharged home with a good general condition. PMID- 24753682 TI - Cerebral tubercular thrombophlebitis presenting as venous infarct: Magnetic resonance imaging and pathologic correlation. AB - Central nervous system involvement by tuberculosis to produce basal meningitis, hydrocephalus, arteritis and infarcts is well-known, the brunt of the pathology being borne by the arterial vasculature to produce neurological sequelae. However, tuberculous thrombophlebitis causing venous infarction is exceedingly rare. We present imaging and pathological features of two autopsy proven cases of tuberculous thrombophlebitis with venous infarcts involving superficial venous system in one and deep venous system in the other. This is the first study presenting radiopathologic correlation of this rare complication. Tuberculous thrombophlebitis should be suspected if basal exudates and multiple white matter T2 hyperintensities are seen on neuroimaging and the imaging protocol should include both magnetic resonance arteriogram and venogram. PMID- 24753683 TI - Can residents diagnose this condition on X-ray? PMID- 24753684 TI - Death - My enemy. PMID- 24753685 TI - Mid life modifiable risk factors for late life Alzheimer's disease. PMID- 24753686 TI - Staphylococcus aureus tropical pyomyositis induced Guillain-Barre syndrome. PMID- 24753687 TI - Peripheral symmetrical gangrene in meningitis. PMID- 24753688 TI - Familial palmaris brevis spasm syndrome. PMID- 24753689 TI - A rare presentation of methanol toxicity. PMID- 24753690 TI - Reversible conduction failure in acute motor axonal neuropathy. PMID- 24753691 TI - National academy of medicine of Korea celebrates its 10th anniversary. PMID- 24753692 TI - Clinical application of adipose stem cells in plastic surgery. AB - Adipose stem cells (ASCs) are a type of adult stem cells that share common characteristics with typical mesenchymal stem cells. In the last decade, ASCs have been shown to be a useful cell resource for tissue regeneration. The major role of regenerative medicine in this century is based on cell therapy in which ASCs hold a key position. Active research on this new type of adult stem cell has been ongoing and these cells now have several clinical applications, including fat grafting, overcoming wound healing difficulties, recovery from local tissue ischemia, and scar remodeling. The application of cultured cells will increase the efficiency of cell therapy. However, the use of cultured stem cells is strictly controlled by government regulation to ensure patient safety. Government regulation is a factor that can limit more versatile clinical application of ASCs. In this review, current clinical applications of ASCs in plastic surgery are introduced. Future stem cell applications in clinical field including culturing and banking of ASCs are also discussed in this review. PMID- 24753693 TI - Evidence-based, pharmacological treatment guideline for depression in Korea, revised edition. AB - This paper aims to introduce, summarize, and emphasize the importance of the 'Evidence-Based, Pharmacological Treatment Guideline for Depression in Korea, Revised Edition'. The guideline broadly covers most aspects of the pharmacological treatment of patients in Korea diagnosed with moderate to severe major depression according to the DSM-IV TR. The guideline establishment process involved determining and answering a number of key questions, searching and selecting publications, evaluating recommendations, preparing guideline drafts, undergoing external expert reviews, and obtaining approval. A guideline adaptation process was conducted for the revised edition. The guideline strongly recommends pharmacological treatment considered appropriate to the current clinical situation in Korea, and should be considered helpful when selecting the appropriate pharmacological treatment of patients diagnosed with major depressive disorder. Therefore, the wide distribution of this guideline is recommended. PMID- 24753694 TI - The association between influenza treatment and hospitalization-associated outcomes among Korean children with laboratory-confirmed influenza. AB - There are limited data evaluating the relationship between influenza treatment and hospitalization duration. Our purpose assessed the association between different treatments and hospital stay among Korean pediatric influenza patients. Total 770 children <= 15 yr-of-age hospitalized with community-acquired laboratory-confirmed influenza at three large urban tertiary care hospitals were identified through a retrospective medical chart review. Demographic, clinical, and cost data were extracted and a multivariable linear regression model was used to assess the associations between influenza treatment types and hospital stay. Overall, there were 81% of the patients hospitalized with laboratory-confirmed influenza who received antibiotic monotherapy whereas only 4% of the patients received oseltamivir monotherapy. The mean treatment-related charges for hospitalizations treated with antibiotics, alone or with oseltamivir, were significantly higher than those treated with oseltamivir-only (P < 0.001). Influenza patients treated with antibiotics-only and antibiotics/oseltamivir combination therapy showed 44.9% and 28.2%, respectively, longer duration of hospitalization compared to those treated with oseltamivir-only. Patients treated with antibiotics, alone or combined with oseltamivir, were associated with longer hospitalization and significantly higher medical charges, compared to patients treated with oseltamivir alone. In Korea, there is a need for more judicious use of antibiotics, appropriate use of influenza rapid testing. PMID- 24753695 TI - Safety and immunogenicity assessment of an oral cholera vaccine through phase I clinical trial in Korea. AB - The safety, tolerability and immunogenicity of an oral cholera vaccine (OCV) was assessed in adult Korean male through an open-label, non-comparative clinical study. Two doses of vaccine with an interval of 2 weeks were given to 20 healthy subjects. A total of 7 adverse events occurred in 6 subjects. However, no clinically significant change was observed in electrocardiograms, vital signs, physical examinations, and clinical laboratory tests. The immunogenicity of OCV was evaluated by serum vibriocidal assay where anti-Vibrio cholerae O1 and O139 antibodies were measured at day 0, 14, and 28 of vaccine administration. The antibody titers ranged from < 2.5-5,120 for V. cholerae O1 Inaba, < 2.5-10,240 for V. cholerae O1 Ogawa and < 2.5-480 for V. cholerae O139. In addition, the fold increase in antibody titers ranged from 1-4,096 for O1 Inaba, 1-8,192 for O1 Ogawa, and 1-384 for O139. The seroconversion rate was 95% and 45% for O1 and O139 antibodies, respectively. Our study clearly shows that administration of two doses of OCV at a 2 week-interval increases an appropriate level of antibody titer in the serum of healthy Korean adult males (Clinical Trial Number, NCT01707537). PMID- 24753696 TI - Digital thermography of the fingers and toes in Raynaud's phenomenon. AB - The aim of this study was to determine whether skin temperature measurement by digital thermography on hands and feet is useful for diagnosis of Raynaud's phenomenon (RP). Fifty-seven patients with RP (primary RP, n = 33; secondary RP, n = 24) and 146 healthy volunteers were recruited. After acclimation to room temperature for 30 min, thermal imaging of palmar aspect of hands and dorsal aspect of feet were taken. Temperature differences between palm (center) and the coolest finger and temperature differences between foot dorsum (center) and first toe significantly differed between patients and controls. The area under curve analysis showed that temperature difference of the coolest finger (cutoff value: 2.2C) differentiated RP patients from controls (sensitivity/specificity: 67/60%, respectively). Temperature differences of first toe (cutoff value: 3.11C) also discriminated RP patients (sensitivity/specificity: about 73/66%, respectively). A combination of thermographic assessment of the coolest finger and first toe was highly effective in men (sensitivity/specificity : about 88/60%, respectively) while thermographic assessment of first toe was solely sufficient for women (sensitivity/specificity: about 74/68%, respectively). Thermographic assessment of the coolest finger and first toe is useful for diagnosing RP. In women, thermography of first toe is highly recommended. PMID- 24753697 TI - Prognostic significance of initial platelet counts and fibrinogen level in advanced non-small cell lung cancer. AB - Thrombocytosis and coagulation systems activation are commonly associated with disease progression and are suggested poor prognostic factors in patients with malignancies. This study aimed to investigate the prevalence and prognostic significance of thrombocytosis and elevated fibrinogen levels in patients with advanced non-small cell lung cancer (NSCLC). Initial platelet counts and fibrinogen levels were reviewed in 854 patients with histologically proven NSCLC. Thrombocytosis was defined as platelet counts > 450 * 10(9)/L. A serum fibrinogen level > 4.5 g/L was considered high. At the time of diagnosis, initial platelet counts and serum fibrinogen levels were evaluated before treatment. Clinicopathologic data including histological type, tumor, node, metastasis (TNM) stage, performance status, treatment method, and survival time were evaluated. Initial thrombocytosis was found in 6.9% of patients, and elevated fibrinogen levels were found in 55.1% of patients. Patients with thrombocytosis had a significantly poorer prognosis than patients with normal platelet counts (P < 0.001). In multivariate survival analysis, thrombocytosis was an independent prognostic factor (P < 0.001). An elevated serum fibrinogen level was associated with poor prognosis (P < 0.001). In conclusion, initial thrombocytosis and a high fibrinogen level are independent factors for predicting poor prognosis in patients with advanced NSCLC. PMID- 24753698 TI - The effect of preceding biopsy on complete endoscopic resection in rectal carcinoid tumor. AB - Biopsy of rectal carcinoid tumor is commonly taken before endoscopic resection. However the preceding biopsy can inhibit complete resection by causing blurred tumor border and fibrosis of the tissue. The objective of the study was to investigate the effect of preceding biopsy on complete endoscopic resection in rectal carcinoid tumor. It was also determined if rectal carcinoid tumors can be macroscopically distinguished by endoscopy. We reviewed retrospectively the records of patients with rectal carcinoid tumor who had undergone an endoscopic treatment at our hospital, during a 7-yr period. The resection margin was clear in 57 of 98 cases. The preceding biopsy was taken in 57 cases and the biopsy was significantly associated with the risk of incomplete tumor resection (OR, 3.696; 95% CI, 1.528-8.938, P = 0.004). In 95.9% of the cases, it was possible to suspect a carcinoid tumor by macroscopic appearance during initial endoscopy. The preceding biopsy may disturb complete resection of rectal carcinoid tumor. In most cases, the carcinoid tumor could be suspected by macroscopic appearance. Therefore the preceding biopsy is not essential, and it may be avoided for the complete resection. PMID- 24753699 TI - White blood cell, hemoglobin and platelet distribution width as short-term prognostic markers in patients with acute myocardial infarction. AB - The aim of this study was to assess the prognostic value of combined use of white blood cell (WBC), hemoglobin (Hb), and platelet distribution width (PDW) in patients with acute myocardial infarction (AMI). This study included 1,332 consecutive patients with AMI. Patients were categorized into complete blood cell (CBC) group 0 (n=346, 26.0%), 1 (n=622, 46.7%), 2 (n=324, 24.3%), and 3 (n=40, 3.0%) according to the sum of the value defined by the cut-off levels of WBC (1, >= 14.5 * 10(3)/uL; 0, <14.5 * 10(3)/uL), Hb (1, <12.7 g/dL; 0, >= 12.7 g/dL), and PDW (1, >= 51.2%; 0: <51.2%). In-hospital death occurred in 59 (4.4%) patients. Patients who died during index hospitalization had higher WBC and PDW and lower Hb. The patients could be stratified for in-hospital mortality according to CBC group; 1.2%, 2.7%, 9.0%, and 22.5% in CBC groups 0, 1, 2, and 3 (P<0.001), respectively. In multivariate logistic regression analysis, CBC group >= 2 (odds ratio, 3.604; 95% confidence interval, 1.040-14.484, P=0.043) was an independent predictor for in-hospital death. The prognostic impact of the combined use of CBC markers remained significant over 12 months. In conclusions, combination of WBC, Hb, and PDW, a cheap and simple hematologic marker, is useful in early risk stratification of patients with AMI. PMID- 24753700 TI - Characteristics, in-hospital and long-term clinical outcomes of nonagenarian compared with octogenarian acute myocardial infarction patients. AB - We compared clinical characteristics, management, and clinical outcomes of nonagenarian acute myocardial infarction (AMI) patients (n=270, 92.3 +/- 2.3 yr old) with octogenarian AMI patients (n=2,145, 83.5 +/- 2.7 yr old) enrolled in Korean AMI Registry (KAMIR). Nonagenarians were less likely to have hypertension, diabetes and less likely to be prescribed with beta-blockers, statins, and glycoprotein IIb/IIIa inhibitors compared with octogenarians. Although percutaneous coronary intervention (PCI) was preferred in octogenarians than nonagenarians, the success rate of PCI between the two groups was comparable. In hospital mortality, the composite of in-hospital adverse outcomes and one year mortality were higher in nonagenarians than in octogenarians. However, the composite of the one year major adverse cardiac events (MACEs) was comparable between the two groups without differences in MI or re-PCI rate. PCI improved 1 yr mortality (adjusted hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.36-0.69, P<0.001) and MACEs (adjusted HR, 0.47; 95% CI, 0.37-0.61, P<0.001) without significant complications both in nonagenarians and octogenarians. In conclusion, nonagenarians had similar 1-yr MACEs rates despite of higher in hospital and 1-yr mortality compared with octogenarian AMI patients. PCI in nonagenarian AMI patients was associated to better 1-yr clinical outcomes. PMID- 24753701 TI - The association of socioeconomic status with three-year clinical outcomes in patients with acute myocardial infarction who underwent percutaneous coronary intervention. AB - The aim of this study was to evaluate whether the clinical outcomes were associated with socioeconomic status (SES) in patients with acute myocardial infarction (AMI) who underwent percutaneous coronary intervention (PCI). The author analyzed 2,358 patients (64.9 +/- 12.3 yr old, 71.5% male) hospitalized with AMI between November 2005 and June 2010. SES was measured by the self reported education (years of schooling), the residential address (social deprivation index), and the national health insurance status (medical aid beneficiaries). Sequential multivariable modeling assessed the relationship of SES factors with 3-yr major adverse cardiovascular events (MACEs) and mortality after the adjustment for demographic and clinical factors. During the 3-yr follow up, 630 (26.7%) MACEs and 322 (13.7%) all-cause deaths occurred in 2,358 patients. In multivariate Cox proportional hazards regression modeling, the only lower education of SES variables was associated with MACEs (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.04-1.91) and mortality (HR, 1.93; 95% CI, 1.16-3.20) in the patients with AMI who underwent PCI. The study results indicate that the lower education is a significant associated factor to increased poor clinical outcomes in patients with AMI who underwent PCI. PMID- 24753702 TI - Trends in hospitalized acute myocardial infarction patients with heart failure in Korea at 1998 and 2008. AB - Heart failure (HF) complicating acute myocardial infarction (AMI) is common and is associated with poor clinical outcome. Limited data exist regarding the incidence and in-hospital mortality of AMI with HF (AMI-HF). We retrospectively analyzed 1,427 consecutive patients with AMI in the five major university hospitals in Korea at two time points, 1998 (n = 608) and 2008 (n = 819). Two hundred twenty eight patients (37.5%) in 1998 and 324 patients (39.5%) in 2008 of AMI patients complicated with HF (P = 0.429). AMI-HF patients in 2008 were older, had more hypertension, previous AMI, and lower systolic blood pressure than those in 1998. Regarding treatments, AMI-HF patients in 2008 received more revascularization procedures, more evidence based medical treatment and adjuvant therapy, such as mechanical ventilators, intra-aortic balloon pulsation compared to those in 1998. However, overall in-hospital mortality rates (6.4% vs 11.1%, P = 0.071) of AMI-HF patients were unchanged and still high even after propensity score matching analysis, irrespective of types of AMI and revascularization methods. In conclusion, more evidence-based medical and advanced procedural managements were applied for patients with AMI-HF in 2008 than in 1998. However the incidence and in-hospital mortality of AMI-HF patients were not significantly changed between the two time points. PMID- 24753703 TI - Seasonal variation in hemoglobin a1c in korean patients with type 2 diabetes mellitus. AB - A seasonal variation of glucose homeostasis in humans has been reported in various geographic regions. In this study, we examined seasonal variations in hemoglobin A1c (HbA1c) in patients with type 2 diabetes living in Korea. We analyzed 57,970 HbA1c values from 4,191 patients and the association of these values with ambient temperature for 3.5 yr. Overall, HbA1c exhibited its highest values from February to March and its lowest values from September to October (coefficient for cos t = -0.0743, P = 0.058) and the difference between the peak and nadir in a year was 0.16%-0.25%. A statistically significant seasonal variation was observed in the patients who were taking oral anti-diabetic drugs (OADs) without insulin treatment (coefficient for cos t = -0.0949, P < 0.05). The Spearman correlation coefficient between daily HbA1c values and the corresponding 3-month moving average ambient temperature was -0.2154 (95% confidence interval [CI]: -0.2711, -0.1580; P < 0.05). In conclusion, HbA1c values exhibited a seasonal variation in Korean patients with type 2 diabetes, with the highest values during the cold season, particularly in those who were treated with OADs, which should be taken into account in clinical practice for stable glucose control during the cold season. PMID- 24753704 TI - Effects of transglutaminase 2 inhibition on ventilator-induced lung injury. AB - This study was performed to examine the role of transglutaminase 2 (TG2) in ventilator-induced lung injury (VILI). C57BL/6 mice were divided into six experimental groups: 1) control group; 2) lipopolysaccharide (LPS) group; 3) lung protective ventilation (LPV) group; 4) VILI group; 5) VILI with cystamine, a TG2 inhibitor, pretreatment (Cyst+VILI) group; and 6) LPV with cystamine pretreatment (Cyst+LPV) group. Acute lung injury (ALI) score, TG2 activity and gene expression, inflammatory cytokines, and nuclear factor-kappaB (NF-kappaB) activity were measured. TG2 activity and gene expression were significantly increased in the VILI group (P < 0.05). Cystamine pretreatment significantly decreased TG2 activity and gene expression in the Cyst+VILI group (P < 0.05). Inflammatory cytokines were higher in the VILI group than in the LPS and LPV groups (P < 0.05), and significantly lower in the Cyst+VILI group than the VILI group (P < 0.05). NF-kappaB activity was increased in the VILI group compared with the LPS and LPV groups (P < 0.05), and significantly decreased in the Cyst+VILI group compared to the VILI group (P = 0.029). The ALI score of the Cyst+VILI group was lower than the VILI group, but the difference was not statistically significant (P = 0.105). These results suggest potential roles of TG2 in the pathogenesis of VILI. PMID- 24753705 TI - Phylogenetic analyses of HBV pre-s/s genes in mother-child pairs with long-term infection by presumed vertical transmission. AB - Vertical transmission from mother to child, the main route of chronic hepatitis B virus (HBV) infection in the East Asia, is considered one of the most important predictors for the response to antiviral therapies as well as its complications such as cirrhosis and hepatocellular carcinoma. Therefore, it is critical in both etiologic and prognostic aspects to confirm whether or not chronic HBV infection is acquired vertically. This study investigated whether mother-to-child infection could be proved by the phylogenetic analyses of HBV pre-S/S genes ever since several decades have elapsed in mother-child pairs with presumed vertical transmission. The pre-S and S regions of HBVs were compared and analyzed phylogenetically in a total of 36 adults (18 mother-child pairs) with chronic HBV infection. All of the isolates of HBV were genotype C and serotype adr. The divergence between mothers and offsprings was 0 to 1.5%. Phylogenetic trees revealed that 17 of 18 pairs (94%) with presumed vertical transmission were grouped into the same cluster. Vertical transmission from mother to child could be strongly suggested even in adults with a history of several decades of HBV infection using the phylogenetic analyses of pre-S and S genes. PMID- 24753706 TI - Assessment of hepatic fibrosis regression by transient elastography in patients with chronic hepatitis B treated with oral antiviral agents. AB - Transient elastography (TE) has been used as a non-invasive method for liver stiffness measurement (LSM) in patients with chronic liver disease. This study was performed to assess the change of LSM by TE and to assess its clinical usefulness during long-term oral antiviral therapy in patients with chronic hepatitis B (CHB). We retrospectively reviewed 83 CHB patients. The mean interval between two LSM was 411.5 +/- 149.5 days. Initial and follow-up LSM was 16.15 +/- 12.41 kPa and 11.26 +/- 7.36 kPa, respectively (P < 0.001). The degree of regression of liver stiffness was -2.03 +/- 0.36% per month. The fibrosis stage classified by LSM value improved in 37 (44.6%) patients during oral antiviral therapy. Of the 30 (36.1%) patients with LSM >= 14.1 kPa (cirrhosis) at 1st LSM, 12 (40%) proved to no longer have cirrhosis (>= 1 decrease in fibrosis stage) at 2nd LSM. LSM significantly decreased in both baseline high (> upper limit of normal [ULN] * 2) and low (<= ULN * 2) alanine aminotransferase groups during antiviral therapy (P < 0.001; P = 0.001, respectively). Long-term oral antiviral therapy resulted in the improvement of liver stiffness in a substantial portion of patients with CHB. TE may be used a useful clinical tool to assess disease progression in CHB patients. PMID- 24753707 TI - Achalasia in Korea: an epidemiologic study using a national healthcare database. AB - Owing to the rarity of the disease, epidemiologic information on achalasia is limited. This study aimed to investigate the epidemiology and treatment patterns of achalasia in the population of Korea using a national healthcare database. The diagnostic code K22.0 of the International Classification of Diseases was used to identify cases of achalasia between 2007 and 2011. Treatment modalities for achalasia were identified using the electronic data interchange codes Q7642 or Q7641 for balloon dilation and QA421 or QA422 for esophago-cardiomyotomy. A total of 3,105 patients with achalasia (1,447 men; mean age, 52.5 yr) were identified between 2007 and 2011, indicating a prevalence of 6.29/100,000 (95% confidence interval [CI], 4.94-7.66) during this 5-yr period. A total of 191 incident cases of achalasia (82 men; mean age, 49.5 yr), which were not diagnosed as achalasia in the previous 4 yr, were detected in 2011, indicating an incidence of 0.39/100,000 (95% CI, 0.15-0.63) for that year. During the study period, balloon dilation therapy was performed a total of 975 times in 719 patients, and surgical esophago-cardiomyotomy was performed once per patient in 17 patients. This is the first population-based epidemiologic study of achalasia in Korea. PMID- 24753708 TI - The timing of surgical ligation for patent ductus arteriosus is associated with neonatal morbidity in extremely preterm infants born at 23-25 weeks of gestation. AB - The purpose of this study was to evaluate prognostic factors associated with surgical ligation for patent ductus arteriosus (PDA) in extremely preterm infants born at the limits of viability. Ninety infants who were born at 23-25 weeks of gestation and who received surgical ligation were included and their cases were retrospectively reviewed. Infants were classified into two different groups: survivors with no major morbidity (N), and non-survivors or survivors with any major morbidity (M). Clinical characteristics were compared between the groups. Possible prognostic factors were derived from this comparison and further tested by logistic regression analysis. The mean gestational age and the mean birth weight of M were significantly lower than those of N. Notably, the mean postnatal age at time of ligation in N was significantly later than that of the other group (17 +/- 12 vs 11 +/- 8 days in N and M, respectively). An adjusted analysis showed that delayed ligation (>2 weeks) was uniquely associated with a significantly decreased risk for mortality or composite morbidity after surgical ligation (OR, 0.105; 95% CI, 0.012-0.928). In conclusion, delayed surgical ligation for PDA (>2 weeks) is associated with decreased mortality or morbidities in extremely preterm infants born at 23-25 weeks of gestation. PMID- 24753709 TI - Analysis on bilateral hindlimb mapping in motor cortex of the rat by an intracortical microstimulation method. AB - Intracortical microstimulation (ICMS) is a technique that was developed to derive movement representation of the motor cortex. Although rats are now commonly used in motor mapping studies, the precise characteristics of rat motor map, including symmetry and consistency across animals, and the possibility of repeated stimulation have not yet been established. We performed bilateral hindlimb mapping of motor cortex in six Sprague-Dawley rats using ICMS. ICMS was applied to the left and the right cerebral hemisphere at 0.3 mm intervals vertically and horizontally from the bregma, and any movement of the hindlimbs was noted. The majority (80%+/- 11%) of responses were not restricted to a single joint, which occurred simultaneously at two or three hindlimb joints. The size and shape of hindlimb motor cortex was variable among rats, but existed on the convex side of the cerebral hemisphere in all rats. The results did not show symmetry according to specific joints in each rats. Conclusively, the hindlimb representation in the rat motor cortex was conveniently mapped using ICMS, but the characteristics and inter-individual variability suggest that precise individual mapping is needed to clarify motor distribution in rats. PMID- 24753710 TI - Subchondral insufficiency fracture of the femoral head in elderly people. AB - We evaluated the clinical course of subchondral insufficiency fracture of the femoral head (SIFFH) and its characteristic findings with special regard to joint space narrowing (JSN). Thirty-one cases of SIFFH of mean age 68.9 yr initially underwent limited weight-bearing conservative treatment. During the follow-up period, the patients with intractable pain underwent total hip arthroplasty (THA). For radiographic evaluation, lateral center-edge angle, JSN and femoral head collapse (FHC) were documented, and the extent of FHC was classified as mild (<2 mm), moderate (2-4 mm), and severe (>4 mm). The progression or new development of FHC more than 2 mm was evaluated on sequential plain radiographs. The relationship between radiographic parameters and clinical outcomes were evaluated. THAs were performed in 15 cases (48.4%). There was no significant correlation between clinical outcomes and the extent of initial FHC. However, a significantly larger proportion of patients that underwent THA showed JSN and FHC progression compared to the symptom improvement group. The risk factor significantly associated with failed conservative treatment was JSN (P=0.038; OR, 11.8; 95% CI, 1.15-122.26). Clinical results of conservative treatment for SIFFH in elderly patients are relatively poor. The patients with JSN are at higher risk of failed conservative treatment. PMID- 24753711 TI - A case of IgG4-related disease with bronchial asthma and chronic rhinosinusitis in Korea. AB - IgG4-related disease (IgG4-RD) is characterized by a systemic involvement of tumor-like lesions with IgG4-positive plasmacytes. We experienced a case of IgG4 RD developed in a patient with bronchial asthma (BA) and chronic rhinosinusitis (CRS). A 55-yr-old female patient with BA and CRS complained of both eyes and neck swelling as well as a recurrent upper respiratory infection in recent 1 yr. The serum levels of IgG4, creatinine, and pancreatic enzymes were elevated. A biopsy of the submandibular gland showed an abundant infiltration of IgG4 positive plasmacytes. Her symptoms remarkably improved after the treatment of a systemic steroid that has been maintained without recurrence. We report a rare case of IgG4-RD developed in a patient with BA and CRS. PMID- 24753712 TI - A case of pulmonary arterial hypertension associated with congenital extrahepatic portocaval shunt. AB - Congenital extrahepatic portocaval shunt (CEPS) is a rare anomaly of the mesenteric vasculature in which the intestinal and splenic venous drainage bypasses the liver and drains directly into the inferior vena cava, the left hepatic vein or the left renal vein. This uncommon disease is frequently associated with other malformations and mainly affects females. Here we report a case of pulmonary arterial hypertension associated with CEPS (Abernethy type 1b shunt) in a 20-yr-old man who was incidentally diagnosed during evaluation of multiple nodules of the liver. The patient was treated by inhalation of iloprost (40 ug/day) with improved condition and walking test. Physicians should note that congenital portocaval shunt may cause pulmonary hypertension. PMID- 24753713 TI - Pneumonectomy case in a newborn with congenital pulmonary lymphangiectasia. AB - Congenital pulmonary lymphangiectasia (CPL) is a rare lymphatic pulmonary abnormality. CPL with respiratory distress has a poor prognosis, and is frequently fatal in neonates. We report a case of pneumonectomy for CPL in a newborn. An infant girl, born at 39 weeks' after an uncomplicated pregnancy, exhibited respiratory distress 1 hr after birth, which necessitated intubation and aggressive ventilator care. Right pneumonectomy was performed after her symptoms worsened. Histologic examination indicated CPL. She is currently 12 months old and developing normally. Pneumonectomy can be considered for treating respiratory symptoms for improving chances of survival in cases with unilateral CPL. PMID- 24753714 TI - Risk factors for suicidal ideation of the general population (J Korean Med Sci. 2013 Apr;28(4):602-607). PMID- 24753718 TI - Bayesian Sensitivity Analysis of Statistical Models with Missing Data. AB - Methods for handling missing data depend strongly on the mechanism that generated the missing values, such as missing completely at random (MCAR) or missing at random (MAR), as well as other distributional and modeling assumptions at various stages. It is well known that the resulting estimates and tests may be sensitive to these assumptions as well as to outlying observations. In this paper, we introduce various perturbations to modeling assumptions and individual observations, and then develop a formal sensitivity analysis to assess these perturbations in the Bayesian analysis of statistical models with missing data. We develop a geometric framework, called the Bayesian perturbation manifold, to characterize the intrinsic structure of these perturbations. We propose several intrinsic influence measures to perform sensitivity analysis and quantify the effect of various perturbations to statistical models. We use the proposed sensitivity analysis procedure to systematically investigate the tenability of the non-ignorable missing at random (NMAR) assumption. Simulation studies are conducted to evaluate our methods, and a dataset is analyzed to illustrate the use of our diagnostic measures. PMID- 24753719 TI - Optofluidic microcavities: Dye-lasers and biosensors. AB - Optofluidic microcavities are integrated elements of microfluidics that can be explored for a large variety of applications. In this review, we first introduce the physics basis of optical microcavities and microflow control. Then, we describe four types of optofluidic dye lasers developed so far based on both simple and advanced device fabrication technologies. To illustrate the application potential of such devices, we present two types of laser intracavity measurements for chemical solution and single cell analyses. In addition, the possibility of single molecule detection is discussed. All these recent achievements demonstrated the great importance of the topics in biology and several other disciplines. PMID- 24753720 TI - Quantifying the volume of single cells continuously using a microfluidic pressure driven trap with media exchange. AB - We demonstrate a microfluidic device capable of tracking the volume of individual cells by integrating an on-chip volume sensor with pressure-activated cell trapping capabilities. The device creates a dynamic trap by operating in feedback; a cell is periodically redirected back and forth through a microfluidic volume sensor (Coulter principle). Sieve valves are positioned on both ends of the sensing channel, creating a physical barrier which enables media to be quickly exchanged while keeping a cell firmly in place. The volume of individual Saccharomyces cerevisiae cells was tracked over entire growth cycles, and the ability to quickly exchange media was demonstrated. PMID- 24753721 TI - A perspective on optical developments in microfluidic platforms for Caenorhabditis elegans research. AB - Microfluidics offers unique ways of handling and manipulating microorganisms, which has particularly benefited Caenorhabditis elegans research. Optics plays a major role in these microfluidic platforms, not only as a read-out for the biological systems of interest but also as a vehicle for applying perturbations to biological systems. Here, we describe different areas of research in C. elegans developmental biology and behavior neuroscience enabled by microfluidics combined with the optical components. In particular, we highlight the diversity of optical tools and methods in use and the strategies implemented in microfluidics to make the devices compatible with optical techniques. We also offer some thoughts on future challenges in adapting advancements in optics to microfluidic platforms. PMID- 24753722 TI - Microfluidic electrical sorting of particles based on shape in a spiral microchannel. AB - Shape is an intrinsic marker of cell cycle, an important factor for identifying a bioparticle, and also a useful indicator of cell state for disease diagnostics. Therefore, shape can be a specific marker in label-free particle and cell separation for various chemical and biological applications. We demonstrate in this work a continuous-flow electrical sorting of spherical and peanut-shaped particles of similar volumes in an asymmetric double-spiral microchannel. It exploits curvature-induced dielectrophoresis to focus particles to a tight stream in the first spiral without any sheath flow and subsequently displace them to shape-dependent flow paths in the second spiral without any external force. We also develop a numerical model to simulate and understand this shape-based particle sorting in spiral microchannels. The predicted particle trajectories agree qualitatively with the experimental observation. PMID- 24753723 TI - Bubble-free and pulse-free fluid delivery into microfluidic devices. AB - The bubble-free and pulse-free fluid delivery is critical to reliable operation of microfluidic devices. In this study, we propose a new method for stable bubble free and pulse-free fluid delivery in a microfluidic device. Gas bubbles are separated from liquid by using the density difference between liquid and gas in a closed cavity. The pulsatile flow caused by a peristaltic pump is stabilized via gas compressibility. To demonstrate the proposed method, a fluidic chamber which is composed of two needles for inlet and outlet, one needle for a pinch valve and a closed cavity is carefully designed. By manipulating the opening or closing of the pinch valve, fluids fill up the fluidic chamber or are delivered into a microfluidic device through the fluidic chamber in a bubble-free and pulse-free manner. The performance of the proposed method in bubble-free and pulse-free fluid delivery is quantitatively evaluated. The proposed method is then applied to monitor the temporal variations of fluidic flows of rat blood circulating within a complex fluidic network including a rat, a pinch valve, a reservoir, a peristaltic pump, and the microfluidic device. In addition, the deformability of red blood cells and platelet aggregation are quantitatively evaluated from the information on the temporal variations of blood flows in the microfluidic device. These experimental demonstrations confirm that the proposed method is a promising tool for stable, bubble-free, and pulse-free supply of fluids, including whole blood, into a microfluidic device. Furthermore, the proposed method will be used to quantify the biophysical properties of blood circulating within an extracorporeal bypass loop of animal models. PMID- 24753724 TI - Elongated unique DNA strand deposition on microstructured substrate by receding meniscus assembly and capillary force. AB - Ordered deposition of elongated DNA molecules was achieved by the forced dewetting of a DNA solution droplet over a microstructured substrate. This technique allows trapping, uncoiling, and deposition of DNA fragments without the need of a physicochemical anchoring of the molecule and results in the combing of double stranded DNA from the edge of microwells on a polydimethylsiloxane (PDMS) substrate. The technique involves scanning a droplet of DNA solution caught between a movable blade and a PDMS substrate containing an array of microwells. The deposition and elongation appears when the receding meniscus dewets microwells, the latter acting here as a perturbation in the dewetting line forcing the water film to break locally. Thus, DNA molecules can be deposited in an ordered manner and elongated conformation based solely on a physical phenomenon, allowing uncoiled DNA molecules to be observed in all their length. However, the exact mechanism that governs the deposition of DNA strands is not well understood. This paper is an analysis of the physical phenomenon occurring in the deposition process and is based on observations made with the use of high frame/second rate video microscopy. PMID- 24753725 TI - Red blood cell dynamics in polymer brush-coated microcapillaries: A model of endothelial glycocalyx in vitro. AB - The confined flow of red blood cells (RBCs) in microvasculature is essential for oxygen delivery to body tissues and has been extensively investigated in the literature, both in vivo and in vitro. One of the main problems still open in microcirculation is that flow resistance in microcapillaries in vivo is higher than that in vitro. This discrepancy has been attributed to the glycocalyx, a macromolecular layer lining the inner walls of vessels in vivo, but no direct experimental evidence of this hypothesis has been provided so far. Here, we investigate the flow behavior of RBCs in glass microcapillaries coated with a polymer brush (referred to as "hairy" microcapillaries as opposed to "bare" ones with no coating), an experimental model system of the glycocalyx. By high-speed microscopy imaging and image analysis, a velocity reduction of RBCs flowing in hairy microcapillaries as compared to bare ones is indeed found at the same pressure drop. Interestingly, such slowing down is larger than expected from lumen reduction due to the polymer brush and displays an on-off trend with a threshold around 70 nm of polymer brush dry thickness. Above this threshold, the presence of the polymer brush is associated with an increased RBC deformation, and RBC velocity is independent on polymer brush thickness (at the same pressure drop). In conclusion, this work provides direct support to the hypothesis that the glycocalyx is the main factor responsible of the higher flow resistance found in microcapillaries in vivo. PMID- 24753726 TI - Impact of tortuous flow on bacteria streamer development in microfluidic system during filtration. AB - The way in which bacterial communities colonize flow in porous media is of importance, but basic knowledge on the dynamic of these phenomena is still missing. The aim of this work is to develop microfluidic experiments in order to progress in the understanding of bacteria capture in filters and membranes. PDMS microfluidic devices mimicking filtration processes have been developed to allow a direct dynamic observation of bacteria across 10 or 20 MUm width microchannels. When filtered in such devices, bacteria behave surprisingly: Escherichia coli, Pseudomonas aeruginosa or Staphylococcus aureus accumulate in the downstream zone of the filter and form large streamers which oscillate in the flow. In this study, streamer formation is put in evidence for bacteria suspension in non nutritive conditions in less than 1 h. This result is totally different from the one observed in same system with "inert" particles or dead bacteria which are captured in the bottleneck zone and are accumulated in the upstream zone. Observations within different flow geometries (straight channels, connected channels, and staggered row pillars) show that the bacteria streamer development is influenced by the flow configuration and, particularly by the presence of tortuosity within the microchannels zone. These results are discussed at the light of 3D flow simulations. In confined systems and in laminar flow, there is secondary flow (z-velocities) superimposed to the streamwise motion (in xy plane). The presence of the secondary flow in the microsystems has an effect on the bacterial adhesion. A scenario in three steps is established to describe the formation of the streamers and to explain the positive effect of tortuous flow on the development kinetics. PMID- 24753727 TI - Simulations of DNA stretching by flow field in microchannels with complex geometry. AB - Recently, we have reported the experimental results of DNA stretching by flow field in three microchannels (C. H. Lee and C. C. Hsieh, Biomicrofluidics 7(1), 014109 (2013)) designed specifically for the purpose of preconditioning DNA conformation for easier stretching. The experimental results do not only demonstrate the superiority of the new devices but also provides detailed observation of DNA behavior in complex flow field that was not available before. In this study, we use Brownian dynamics-finite element method (BD-FEM) to simulate DNA behavior in these microchannels, and compare the results against the experiments. Although the hydrodynamic interaction (HI) between DNA segments and between DNA and the device boundaries was not included in the simulations, the simulation results are in fairly good agreement with the experimental data from either the aspect of the single molecule behavior or from the aspect of ensemble averaged properties. The discrepancy between the simulation and the experimental results can be explained by the neglect of HI effect in the simulations. Considering the huge savings on the computational cost from neglecting HI, we conclude that BD-FEM can be used as an efficient and economic designing tool for developing new microfluidic device for DNA manipulation. PMID- 24753728 TI - Laminated microfluidic system for small sample protein analysis. AB - We describe a technology based on lamination that allows for the production of highly integrated 3D devices suitable for performing a wide variety of microfluidic assays. This approach uses a suite of microfluidic coupons ("microfloupons") that are intended to be stacked as needed to produce an assay of interest. Microfloupons may be manufactured in paper, plastic, gels, or other materials, in advance, by different manufacturers, then assembled by the assay designer as needed. To demonstrate this approach, we designed, assembled, and characterized a microfloupon device that performs sodium-dodecyl-sulfate polyacrylamide gel electrophoresis on a small sample of protein. This device allowed for the manipulation and transport of small amounts of protein sample, tight injection into a thin polyacrylamide gel, electrophoretic separation of the proteins into bands, and subsequent removal of the gel from the device for imaging and further analysis. The microfloupons are rugged enough to handle and can be easily aligned and laminated, allowing for a variety of different assays to be designed and configured by selecting appropriate microfloupons. This approach provides a convenient way to perform assays that have multiple steps, relieving the need to design highly sophisticated devices that incorporate all functions in a single unit, while still achieving the benefits of small sample size, automation, and high speed operation. PMID- 24753729 TI - Study of flow behaviors on single-cell manipulation and shear stress reduction in microfluidic chips using computational fluid dynamics simulations. AB - Various single-cell retention structures (SCRSs) were reported for analysis of single cells within microfluidic devices. Undesirable flow behaviors within micro environments not only influence single-cell manipulation and retention significantly but also lead to cell damage, biochemical heterogeneity among different individual cells (e.g., different cell signaling pathways induced by shear stress). However, the fundamentals in flow behaviors for single-cell manipulation and shear stress reduction, especially comparison of these behaviors in different microstructures, were not fully investigated in previous reports. Herein, flow distribution and induced shear stress in two different single-cell retention structures (SCRS I and SCRS II) were investigated in detail to study their effects on single-cell trapping using computational fluid dynamics (CFD) methods. The results were successfully verified by experimental results. Comparison between these two SCRS shows that the wasp-waisted configuration of SCRS II has a better performance in trapping and manipulating long cylinder shaped cardiac myocytes and provides a safer "harbor" for fragile cells to prevent cell damage due to the shear stress induced from strong flows. The simulation results have not only explained flow phenomena observed in experiments but also predict new flow phenomena, providing guidelines for new chip design and optimization, and a better understanding of the cell micro-environment and fundamentals of microfluidic flows in single-cell manipulation and analysis. PMID- 24753730 TI - A highly parallel microfluidic droplet method enabling single-molecule counting for digital enzyme detection. AB - Although digital detection of nucleic acids has been achieved by amplification of single templates in uniform microfluidic droplets and widely used for genetic analysis, droplet-based digital detection of proteins has rarely been reported, largely due to the lack of an efficient target amplification method for protein in droplets. Here, we report a key step towards digital detection of proteins using a highly parallel microfluidic droplet approach for single enzyme molecule detection in picoliter droplets via enzyme catalyzed signal amplification. An integrated microfluidic chip was designed for high throughput uniform droplet generation, monolayer droplet collection, incubation, detection, and release. Single beta-galatosidase (beta-Gal) molecules and the fluorogenic substrate fluorescein di-beta-D-galactopyranoside were injected from two separated inlets to form uniform 20 MUm droplets in fluorinated oil at a frequency of 6.6 kHz. About 200 000 droplets were captured as a monolayer in a capture well on-chip for subsequent imaging detection. A series of beta-Gal solutions at different concentrations were analyzed at the single-molecule level. With no enzyme present, no droplets were found to fluoresce, while brightly fluorescent droplets were observed under single-enzyme molecule conditions. Droplet fluorescence intensity distribution analysis showed that the distribution of enzyme molecules under single-molecule conditions matched well with theoretical prediction, further proving the feasibility of detecting single enzyme molecules in emulsion droplets. Moreover, the population of fluorescent droplets increased as the beta Gal concentration increased. Based on a digital counting method, the measured concentrations of the enzyme were found to match well with input enzyme concentration, establishing the accuracy of the digital detection method for the quantification of beta-Gal enzyme molecules. The capability of highly parallel detection of single enzyme molecules in uniform picoliter droplets paves the way to microdroplet based digital detection of proteins. PMID- 24753731 TI - Tandem array of nanoelectronic readers embedded coplanar to a fluidic nanochannel for correlated single biopolymer analysis. AB - We have developed a two-step electron-beam lithography process to fabricate a tandem array of three pairs of tip-like gold nanoelectronic detectors with electrode gap size as small as 9 nm, embedded in a coplanar fashion to 60 nm deep, 100 nm wide, and up to 150 MUm long nanochannels coupled to a world-micro nanofluidic interface for easy sample introduction. Experimental tests with a sealed device using DNA-protein complexes demonstrate the coplanarity of the nanoelectrodes to the nanochannel surface. Further, this device could improve transverse current detection by correlated time-of-flight measurements of translocating samples, and serve as an autocalibrated velocimeter and nanoscale tandem Coulter counters for single molecule analysis of heterogeneous samples. PMID- 24753732 TI - Coaxial flow focusing in poly(dimethylsiloxane) microfluidic devices. AB - We have developed a coaxial flow focusing geometry that can be fabricated using soft lithography in poly(dimethylsiloxane) (PDMS). Like coaxial flow focusing in glass capillary microfluidics, our geometry can form double emulsions in channels with uniform wettability and of a size much smaller than the channel dimensions. However, In contrast to glass capillary coaxial flow focusing, our geometry can be fabricated using lithographic techniques, allowing it to be integrated as the drop making unit in parallel drop maker arrays. Our geometry enables scalable formation of emulsions down 7 MUm in diameter, in large channels that are robust against fouling and clogging. PMID- 24753733 TI - Microfluidic device capable of medium recirculation for non-adherent cell culture. AB - We present a microfluidic device designed for maintenance and culture of non adherent mammalian cells, which enables both recirculation and refreshing of medium, as well as easy harvesting of cells from the device. We demonstrate fabrication of a novel microfluidic device utilizing Braille perfusion for peristaltic fluid flow to enable switching between recirculation and refresh flow modes. Utilizing fluid flow simulations and the human promyelocytic leukemia cell line, HL-60, non-adherent cells, we demonstrate the utility of this RECIR-REFRESH device. With computer simulations, we profiled fluid flow and concentration gradients of autocrine factors and found that the geometry of the cell culture well plays a key role in cell entrapping and retaining autocrine and soluble factors. We subjected HL-60 cells, in the device, to a treatment regimen of 1.25% dimethylsulfoxide, every other day, to provoke differentiation and measured subsequent expression of CD11b on day 2 and day 4 and tumor necrosis factor-alpha (TNF-alpha) on day 4. Our findings display perfusion sensitive CD11b expression, but not TNF-alpha build-up, by day 4 of culture, with a 1:1 ratio of recirculation to refresh flow yielding the greatest increase in CD11b levels. RECIR-REFRESH facilitates programmable levels of cell differentiation in a HL-60 non-adherent cell population and can be expanded to other types of non-adherent cells such as hematopoietic stem cells. PMID- 24753734 TI - Spatially variant red blood cell crenation in alternating current non-uniform fields. AB - Alternating-current (AC) electrokinetics involve the movement and behaviors of particles or cells. Many applications, including dielectrophoretic manipulations, are dependent upon charge interactions between the cell or particle and the surrounding medium. Medium concentrations are traditionally treated as spatially uniform in both theoretical models and experiments. Human red blood cells (RBCs) are observed to crenate, or shrink due to changing osmotic pressure, over 10 min experiments in non-uniform AC electric fields. Cell crenation magnitude is examined as functions of frequency from 250 kHz to 1 MHz and potential from 10 Vpp to 17.5 Vpp over a 100 MUm perpendicular electrode gap. Experimental results show higher peak to peak potential and lower frequency lead to greater cell volume crenation up to a maximum volume loss of 20%. A series of experiments are conducted to elucidate the physical mechanisms behind the red blood cell crenation. Non-uniform and uniform electrode systems as well as high and low ion concentration experiments are compared and illustrate that AC electroporation, system temperature, rapid temperature changes, medium pH, electrode reactions, and convection do not account for the crenation behaviors observed. AC electroosmotic was found to be negligible at these conditions and AC electrothermal fluid flows were found to reduce RBC crenation behaviors. These cell deformations were attributed to medium hypertonicity induced by ion concentration gradients in the spatially nonuniform AC electric fields. PMID- 24753735 TI - Using surface plasmon resonance imaging to study bacterial biofilms. AB - This paper describes the use of Surface Plasmon Resonance imaging (SPRi) as an emerging technique to study bacterial physiology in real-time without labels. The overwhelming majority of bacteria on earth exist in large multicellular communities known as biofilms. Biofilms are especially problematic because they facilitate the survival of pathogens, leading to chronic and recurring infections as well as costly industrial complications. Monitoring biofilm accumulation and removal is therefore critical in these and other applications. SPRi uniquely provides label-free, high-resolution images of biomass coverage on large channel surfaces up to 1 cm(2) in real time, which allow quantitative assessment of biofilm dynamics. The rapid imaging capabilities of this technique are particularly relevant for multicellular bacterial studies, as these cells can swim several body lengths per second and divide multiple times per hour. We present here the first application of SPRi to image Escherichia coli and Pseudomonas aeruginosa cells moving, attaching, and forming biofilms across a large surface. This is also the first time that biofilm removal has been visualized with SPRi, which has important implications for monitoring the biofouling and regeneration of fluidic systems. Initial images of the removal process show that the biofilm releases from the surface as a wave along the direction of the fluid flow. PMID- 24753736 TI - Euler force actuation mechanism for siphon valving in compact disk-like microfluidic chips. AB - Based on the Euler force induced by the acceleration of compact disk (CD)-like microfluidic chip, this paper presents a novel actuation mechanism for siphon valving. At the preliminary stage of acceleration, the Euler force in the tangential direction of CD-like chip takes the primary place compared with the centrifugal force to function as the actuation of the flow, which fills the siphon and actuates the siphon valving. The Euler force actuation mechanism is demonstrated by the numerical solution of the phase-field based mathematical model for the flow in siphon valve. In addition, experimental validation is implemented in the polymethylmethacrylate-based CD-like microfluidic chip manufactured using CO2 laser engraving technique. To prove the application of the proposed Euler force actuation mechanism, whole blood separation and plasma extraction has been conducted using the Euler force actuated siphon valving. The newly introduced actuation mechanism overcomes the dependence on hydrophilic capillary filling of siphon by avoiding external manipulation or surface treatments of polymeric material. The sacrifice for highly integrated processing in pneumatic pumping technique is also prevented by excluding the volume-occupied compressed air chamber. PMID- 24753737 TI - Study for optical manipulation of a surfactant-covered droplet using lattice Boltzmann method. AB - In this study, we simulated deformation and surfactant distribution on the interface of a surfactant-covered droplet using optical tweezers as an external source. Two optical forces attracted a single droplet from the center to both sides. This resulted in an elliptical shape deformation. The droplet deformation was characterized as the change of the magnitudes of surface tension and optical force. In this process, a non-linear relationship among deformation, surface tension, and optical forces was observed. The change in the local surfactant concentration resulting from the application of optical forces was also analyzed and compared with the concentration of surfactants subjected to an extensional flow. Under the optical force influence, the surfactant molecules were concentrated at the droplet equator, which is totally opposite to the surfactants behavior under extensional flow, where the molecules were concentrated at the poles. Lastly, the quasi-equilibrium surfactant distribution was obtained by combining the effects of the optical forces with the extensional flow. All simulations were executed by the lattice Boltzmann method which is a powerful tool for solving micro-scale problems. PMID- 24753739 TI - The efficacy of Yunnan Baiyao on haemostasis and antiulcer: a systematic review and meta-analysis of randomized controlled trials. AB - Yunnan Baiyao (YNBY) is widely used to treat rhexis haemorrhage and ulcer in China. This meta-analysis was conducted to determine the efficacy of YNBY on local haemostasis and antiulcer. Randomized controlled trials were included on condition that assessing the effects of YNBY with/without routine drugs versus the same routine drugs on haemorrhage or ulcer after searching major databases. Data were validated, extracted and synthesized using relative risk (RR) for dichotomous data using random effects models. Fifty-five studies involving 5,150 patients were identified. (1) YNBY alone for haemorrhage (RR = 1.16; 95% CI 1.06 to 1.28) (2) YNBY alone for antiulcer (RR = 1.26; 95% CI 1.03 to 1.53). We found certain effects on ulcerative colitis (RR = 1.22) and skin ulcer (RR = 1.20) in subgroup analysis. (3) YNBY plus routine haemostatic drugs for haemorrhage (RR = 1.23; 95% CI 1.17 to 1.29) with a significant funnel plot asymmetry (Begg's test, p = 0). (4) YNBY plus routine antiulcer drugs for antiulcer (RR = 1.18; 95% CI 1.05 to 1.33). Treatment effect in the 2(nd) and 4(th) group was unstable when RCTs at high risk of bias were excluded. Great heterogeneities and possible publication bias were found among the trials which preclude certain conclusions. The existing data showed that YNBY alone was helpful in treating uterine haemorrhage, ulcerative colitis and skin ulcer. YNBY plus routine antiulcer drugs was more effective in treating ulcerative colitis versus antiulcer drugs alone. PMID- 24753740 TI - Therapeutic effects of date fruits (Phoenix dactylifera) in the prevention of diseases via modulation of anti-inflammatory, anti-oxidant and anti-tumour activity. AB - The current mode of treatment of various diseases based on synthetic drugs is expensive, alters genetic and metabolic pathways and also shows adverse side effects. Thus, safe and effective approach is needed to prevent the diseases development and progression. In this vista, Natural products are good remedy in the treatment/management of diseases and they are affordable and effective without any adverse effects. Dates are main fruit in the Arabian Peninsula and are considered to be one of the most significant commercial crops and also have been documented in Holy Quran and modern scientific literatures. Earlier studies have shown that constituents of dates act as potent antioxidant, anti-tumour as well as anti-inflammatory, provide a suitable alternative therapy in various diseases cure. In this review, dates fruits has medicinal value are summarized in terms of therapeutic implications in the diseases control through anti-oxidant, anti-inflammatory, anti-tumour and ant-diabetic effect. PMID- 24753741 TI - Clinical and radiographic maxillofacial features of pycnodysostosis. AB - The aim of this study was to review of the literature to determine the radiographic and clinical maxillofacial features of pycnodysostosis emphasizing the main aspects of interest to the dentist in order to make them fit for the proper treatment of this population. It is important to make the diagnosis as early as possible in order to plan the treatment more suitable to provide a better life's quality to the patients. The most frequent clinical maxillofacial features were: grooved palate, midfacial hypoplasia, mandibular hypoplasia and enamel hypoplasia. The most common radiographic maxillofacial features were: obtuse mandibular angle, frontal/parietal/occiptal bossing, open fontanels and sutures, multiple impacted teeth. The earlier diagnostic of pycnodysostosis has a fundamental role in general health of the patients. We consider that is very important that the dentist know recognize the radiographic and clinical maxillofacial features of pycnodysostosis, which allows correct treatment planning avoiding risks and ensuring better life's quality to the patients. PMID- 24753743 TI - An MRI study of age-related changes in the dimensions related temporal lobe. AB - The aim of this study was to determine the effect age-related changes on the MRI based parameters related to several measurement of temporal lobe in the lifespan of adult persons. MRI scans of head (n=236) were reviewed retrospectively to identify abnormalities of temporal lobe, third ventricle, and temporal horn of lateral ventricle. Patients were divided into 3 study groups according to their age. Using axial and coronal views of the cerebral hemispheres, interuncal distance, thickness of temporal lobe, Evans' ratio, and the width of third ventricle, height of hippocampus, width of choroid fissure, and width of the temporal horn were measured. The mean age of study group was 44.2+/-17.7 (18 to 86). The gender ratio (F/M) of study group was 129/107. There is mild-moderate significant correlation between age and Evans' ratio (r=0.35, p<0.05). There is mild significant correlation between age and interuncal distances (r=0.24, p<0.05). There was no correlation between age and third ventricle widths, temporal lobe widths, and temporal horn widths of left and right sides of brain (p>0.05). A mild and significant correlation was present between these variables (r=0.14 and r=0.17, respectively; p<0.05). There was a mild and significant correlation between these variables. (r=-0.14 and r=-0.19, respectively; p<0.05). Although several parameters including our measurements were developed for the assessment of size and structure of temporal lobe. It is not ease to determine MRI-based markers for the prediction, diagnosis, and follow-up of mild cognitive impairment and Alzheimer's disease in the elderly. PMID- 24753742 TI - Short-term magnesium deficiency downregulates telomerase, upregulates neutral sphingomyelinase and induces oxidative DNA damage in cardiovascular tissues: relevance to atherogenesis, cardiovascular diseases and aging. AB - THE PRESENT WORK TESTED THE HYPOTHESES THAT: 1) short-term dietary deficiency of magnesium (Mg; 21 days) in rats (MgD) would result in a downregulation of telomerase in cardiac and aortic smooth muscle cells, 2) low levels of Mg(2+) added to drinking water (DW) would either prevent or greatly reduce the downregulation of telomerase in MgD, 3) MgD in rats would cause an upregulation of neutral-sphingomyelinase (N-SMAse) and p53, 4) short-term MgD would result in oxidation of DNA in diverse cardiac muscle and aortic smooth muscle cells as exemplified by measurement of 8-hydroxydeoxyguanosine (8-OH-dG), and 5) cross talk between telomerase, N-SMase, p53, and 8-OH-dG would be evident in left ventricular (LV), right ventricular (RV), atrial and aortic smooth muscle obtained from rats subjected to short-term MgD. The data indicated that short term MgD (10% normal dietary intake) resulted in downregulation of telomerase in LV, RV, atrial and aortic muscle cells; even very low levels of water-bourne Mg(2+) (e.g., 15-40 mg/lday) either prevented or ameliorated the downregulation of telomerase. Our experiments also showed that MgD resulted in a 7-10 fold increased formation of 8-OH-dG in the cardiac and aortic muscle cells. The experiments also confirmed that short-term dietary deficiency of Mg resulted in greatly increased upregulation of N-SMAse and p53 in the cardiac and aortic muscle tissues. These new experiments point to a sizeable cross-talk among telomerase, N-SMAse, and p53 in rat cardiac and peripheral vascular muscle exposed to a short-term MgD. These studies would be compatible with the idea that even short-term MgD could cause alterations of the genome in diverse cell types leading to mutations of cardiac, vascular, and endothelial cells seen in aging and atherogenesis. Since we have shown, previously, that activation of N-SMAse in MgD leads to synthesis and release of ceramide in cardiovascular tissues and cells, we believe this pathway, most likely, helps to result in downregulation of telomerase, upregulation of transcription factors (e.g., p53; NF-kB), cytokine release, mutations, transformations, and dysfunctional growth seen in the cardiac and vascular cells observed in the normal aging process, atherogenesis, hypertension, and cardiac failure. Lastly, we suggest ways in which this hypothesis can be tested. PMID- 24753744 TI - Exploratory study of oral mucosal colonization of human gastric Helicobacter pylori in mice. AB - In this study, human gastric Helicobacter pylori (Hp) was closely attached to the pre-treated mouse buccal mucosa by using artificial oral film to induce the growth and colonization of Hp on the buccal mucosa in mice. Sixty BALB/c mice were divided into three groups, in which Hp biofilm colonization was detected in three mice in Hp film group (Hp mesh biofilm accumulation under an optical microscope; Hp accumulated colonization under an electron microscope). There were no Hp biofilms detected in Hp smear group or the control group with black film. In this study, human gastric Hp was first used to artificially induce the growth and colonization of Hp on the buccal mucosa in mice. The mouse model of oral infection with Hp was initially established, providing animal experimental evidences for oral conditions of growth and colonization of Hp on the buccal mucosa in mice, and providing a workable animal modeling method for further research of joint infection of Hp on the mouth and stomach, as well as the relationship between oral Hp and gastric Hp. PMID- 24753745 TI - A multicenter randomized double-blind prospective study of the postoperative patient controlled intravenous analgesia effects of dezocine in elderly patients. AB - OBJECTIVE: The postoperative PCIA effects of dezocine in elderly patients were determined using a large multicenter randomized double-blind prospective study. METHODS: A total of 279 patients were randomized into four groups: (1) Control group (C): 2 MUg/kg sufentanil plus 10 mg metoclopramide. (2) Dezocine group 1 (D1): 1 MUg/kg sufentanil plus 0.1 mg/kg dezocine plus 10 mg metoclopramide. (3) Dezocine group 2 (D2): 1 MUg/kg sufentanil plus 0.2 mg/kg dezocine plus 10 mg metoclopramide. (4) Dezocine group 3 (D3): 1 MUg/kg sufentanil plus 0.3 mg/kg dezocine plus 10 mg metoclopramide. The index during operation including MAP, HR, SpO2, ETCO2, CVP, and BIS were determined. Analgesia effects including HR, MAP, RR, SpO2, pressing times of PCA demand, pressing times of PCR delivery, total amount of drug, additional sufentanil, VAS at rest and during moving, Ramsay sedation score, and BCS were repeated measured 1 h, 3 h, 6 h, 24 h, and 48 h after surgery. Overall satisfaction index and the side-effects including nausea, urinary retention, skin pruritus and respiratory depression were evaluated 1 h, 3 h, 6 h, 24 h, and 48 h after surgery. RESULTS: Dezocine combining with sufentanil is complement for sufentanil in PCIA at least in its analgesia effects after surgery. Dezocine at a dosage of 0.1 mg/kg or 0.2 mg/kg combining with sufentanil (1 MUg/kg) has limited side effects as sufentanil (2 MUg/kg) in PCIA. Sufentanil (1 MUg/kg) combining Dezocine at a dosage of 0.1 mg/kg or 0.2 mg/kg is better than combining Dezocine at a dosage of 0.3 mg/kg in PCIA at least in Overall satisfaction index. CONCLUSION: Dezocine combining with sufentanil is a complement drug for sufentanil in PCIA. Considering the side effects and overall satisfaction index, 0.1 mg/kg seems to be an ideal dosage for Dezocine using in the postoperative PCIA in elderly patients. PMID- 24753746 TI - Effect of Cbfa1 on osteogenic differentiation of mesenchymal stem cells under hypoxia condition. AB - OBJECTIVE: To observe the effect of Cbfa1 on biological characteristics of marrow mesenchymal stem cells under hypoxia. METHODS: The second passage of the MSCs were transfected with Cbfa1 and then cultured in 20% O2 and 3% O2 condition individually. The biological features of the cultured MSCs were assessed by the Real-time PCR. RESULTS: After transfected with Cbfa1, the morphology of MSCs was no significant difference between two oxygen concentrations; The RT-PCR examination revealed that the expression of Cbfa1, BMP, OPN and VEGF in MSCs was higher than those before Cbfa1 transfection (P<0.05), especial the expression of Cbfa1 (P<0.05). CONCLUSION: After transfected with Cbfa1, cell morphology or growth cycle of MSCs was not significantly affected, but its osteogenic differentiation potential enhanced, particularly its osteogenic differentiation potential under hypoxia enhanced. PMID- 24753747 TI - Effects of APP 5-mer peptide analogue P165 on the synaptic proteins and insulin signal transduction proteins. AB - Diabetic encephalopathy (DE) is one of risk factors for Alzheimer's disease (AD). Our previous findings indicated that DE animals had impairment of learning and memory and degeneration of hippocampal neurons, which could be improved by neurotrophic peptide. APP 17-mer peptide is a synthesized peptide sequenced from soluble amyloid precursor protein. APP 17-mer peptide has neural protective effect, but is susceptible to enzyme degradation. Soluble APP 5-mer peptide is the active form of APP 17-mer peptide, and composed of arginine, glutamic acid, arginine, methionine and serine. P165, an APP 5-mer peptide analog reconstructed by our lab, is resistant to enzyme degradation, and can be orally used to protect neurons. In the present study, high glucose and Abeta25-35 were used to cause injury to human neuroblastoma cell line SH-SY5Y in vitro, and streptozotocin was used to induce diabetes in mice in vivo. The changes in synaptic proteins and proteins of insulin signal transduction which closely correlate with learning and memory were detected in these cells and the brain of mice. Results showed that P165 could up-regulate the expression of alpha-synuclein and insulin receptor (IR), down-regulate the expression of insulin receptor substrate-1 (IRS-1), PSD 95, Shank1 and MAPK expression. All these findings suggest that nicorandil might be a potential drug used for the treatment of AD. PMID- 24753748 TI - MiRNA-26b inhibits cellular proliferation by targeting CDK8 in breast cancer. AB - OBJECTIVES: MicroRNA-26b (miR-26b) has been reported to be down-regulated in a wide range of malignant tumors, However, the mechanism by which miR-26b is implicated in breast cancer tumorigenesis is incompletely understood. This study was undertaken to evaluate the expression pattern of miR-26b and characterize its biological role in human breast cancer. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify the expression levels of miR-26b in breast cancer and adjacent non-cancerous breast tissues. MTT, colony formation assay and cell cycle assay were carried out to characterize the miR-26b function. Finally, to validate the target gene of miR-26b, luciferase reporter assay was employed, followed by RT-PCR and Western blot confirmation. RESULTS: Here, we found that miR-26b expression was relatively downregulated in breast cancer specimens (P<0.01). Overexpression of miR-26b dramatically suppressed cell proliferation, colony formation and induced G0/G1 cell cycle arrest of MDA-MB-231 and Mcf-7 cells. Luciferase assays revealed that miR-26b directly targeted the 3'UTR of CDK8. Overexpression of miR-26b led to the downregulation of CDK8 and beta-catenin expression. Similarly, CDK8 knockdown by siRNA suppressed cell growth and subsequent beta-catenin expression. CONCLUSIONS: These findings suggest that miR-26b exerts a tumor suppressive role in breast cancer and the miR 26b-mediated growth inhibition is achieved through suppression of a new target gene CDK8. PMID- 24753749 TI - Activation of circulated immune cells and inflammatory immune adherence are involved in the whole process of acute venous thrombosis. AB - OBJECTIVE: To investigate localization and distribution of integrin subunit beta1, beta2 and beta3 and morphological changes of ligand-recepter binding in thrombi of acute pulmonary embolism (PE) patients and explore activation of circulated immune cells, inflammatory immune adherence and coagulation response in acute venous thrombosis. METHODS: Thrombi were collected from patients with acute PE. Immunohistochemistry was done to detect the expression and distribution of integrin beta1, beta2 and beta3 in cells within thrombi, and ligands of integrin subunit beta1, beta2 and beta3 were also determined by immunohistochemistry within the thrombi. RESULTS: 1) Acute venous thrombi were red thrombi composed of skeletons and filamentous mesh containing large amounts of red blood cells and white blood cells; 2) Integrin subunit beta1, beta2 and beta3 were expressed on lymphocytes, neutrophils and platelets; 3) No expression of integrin beta1 ligands: Laminin, Fibronectin, Collagen I or Collagen-II on lymphocytes; integrin beta2 ligands including ICAM, factor X and iC3b are distributed on neutrophils, and ligand fibrinogen bound to neutrophils; integrin beta3 was expressed on platelets which form the skeleton of thrombi and bound to fibrinogen to construct mesh structure; 4) Factor Xa was expressed on the filamentous mesh; 5) Filamentous mesh was fully filled with red blood cell dominant blood cells. CONCLUSION: Acute venous thrombosis is an activation process of circulated lymphocytes, neutrophils and platelets mainly, and a whole process including integrin subunit beta2 and beta3 binding with their ligands. Activation of immune cells, inflammatory immune adherence and coagulation response are involved in the acute venous thrombosis. PMID- 24753750 TI - Contrast-enhanced ultrasonography of skeletal muscles for type 2 diabetes mellitus patients with microvascular complications. AB - PURPOSE: To explore the applicability of contrast-enhanced ultrasound (CEUS) as a new method to detect impaired microcirculation in type 2 diabetes mellitus patients with microvascular complications (DM+MC). METHODS: Ultrasound contrast agent was injected into peripheral vein of 28 patients with DM+MC, 30 uncomplicated type 2 diabetes mellitus (DM) patients, and 30 control subjects. Its appearance in the calf muscle was detected by contrast-enhanced ultrasound. Time-intensity curves were established based on mathematical modeling, particularly in small artery, muscular tissue and small vein. Times to peak intensity (TTPs), arrival times (ATs) and contrast transit times (CTTs) were analyzed. CTTs were calculated as the differences between arrival times. With patients under fasting conditions, plasma glucose and rheologic parameters of erythrocyte deformability and plasma viscosity were measured. RESULTS: DM and DM+MC groups tended to have longer TTPs than the control group, but without significant differences between DM group and DM+MC group. The median artery-vein and muscle-vein CTTs were statistically significantly highest in the DM+MC group (P < 0.05). Blood viscosity in the DM+MC group was higher than two other groups (P < 0.05). Blood viscosity correlated positively with both blood glucose and C reactive peptide (P < 0.01). CONCLUSION: CEUS is potentially reliable to detect changes in the microvascular bed. Abnormalities in capillary recruitment may be related to abnormal hemorheology. PMID- 24753751 TI - Bacterial contamination along implant-abutment interface in external and internal hex dental implants. AB - The aim of this research was to evaluate bacterial contamination along the implant-abutment interface in relation to the size of the interface. 80 brand name implants were used, 40 internal-hex and 40 external-hex. The implants were handled in a sterile atmosphere inside a box, where they were inoculated with 0.3 MUl of the Streptococcus sanguis ATCC10556 bacterium in the interior and the abutment was immediately installed with a torque of 30 Ncm for the external-hex and 20 Ncm for the internal-hex; the system was included in an Eppendorf control for 30 seconds and then placed in an Eppendorf control for 30 days. The implants were removed and assessed under a scanning electron microscope while the Eppendorf controls were bred in blood agar to analyze the colonies formed. The data were analyzed using the Chi-squared, Kruskal-Wallis and Mann-Whitney tests, considering a value of p<0.05 to obtain statistical significance. Five implants were excluded due to probable external contamination. Microspaces of up to 86.8 MUm were observed in the external-hex implants and up to 53.9 MUm in the internal hex implants with no significant differences between the different systems being observed (p>0.05). The contamination observed was produced mainly in the external hex implants and statistically significant differences were observed between the different hex systems from the same company. No significant differences were observed between interface size and bacterial contamination. Within our limitations, there was no relation between the size of the implant-abutment interface and bacterial contamination with Streptococcus sanguis ATCC10556. PMID- 24753752 TI - Gastroprotective effect of minocycline in experimentally induced gastric ulcers in rats. AB - Minocycline (MCN), a semi-synthetic tetracycline derivative possesses pleiotropic effects and provides protection against a number of disease models. However its effect on gastric ulcers has not been studied. The present investigation was undertaken, to study the gastro-protective potential of MCN in experimentally induced gastric ulcers in rats. MCN (10, 30, 100 mg/Kg) was tested for gastric secretion and antiulcer activity in different groups of Wistar rats. Gastric secretion and acidity studies were performed in pylorus ligated rats while indices of gastric ulcers were measured in ethanol (1 ml-100%) and indomethacin (30 mg/kg), induced gastric ulcers. Histological changes and the levels of gastric wall mucus, malondialdehyde (MDA), non-protein sulfhydryl (NP-SH), and myeloperoxidase (MPO), were used to assess ethanol induced gastric mucosal injuries. Exposure of rats to ulcerogens resulted in gastric mucosal injury and a significant increase in the indices of ulcer. MCN conferred a protective effect against ethanol, and indomethacin induced gastric mucosal injuries. Treatment with MCN, resulted in a significant decrease in the amount of gastric secretion, and total acidity and significantly (P<0.001), reduced the gastric lesions induced by ethanol and indomethacin. MCN also significantly attenuated the ethanol induced reduction in the levels of gastric wall mucus, and NP-SH (P<0.001). The histological changes and the increased MDA and MPO activity were also significantly (P<0.001) inhibited by MCN. Minocycline showed significant antiulcer and gastroprotective activity against experimentally induced gastric ulcers. The gastroprotective effects of minocycline may be due to its anti secretory, antioxidant and anti inflammatory action. PMID- 24753753 TI - Effect of Tianshengyuan-1 (TSY-1) on telomerase activity and hematopoietic recovery - in vitro, ex vivo, and in vivo studies. AB - Aplastic anemia is a heterogeneous disorder of bone marrow failure syndrome. Accumulating evidence indicates that both acquired and congenital aplastic anemia is linked to telomerase activity and telomere length. Chinese herbal medicine Tianshengyuan-1 (TSY-1), a liquid extraction of multiple Chinese herbs, appears to stimulate hematopoiesis in patients with bone marrow deficiencies; however, the exact mechanism of action remains unclear. In this study, we investigated the effect of TSY-1 on telomere length and telomerase activity. We first investigated the effects of TSY on in vitro cultured cell lines including CD34+ hepatic stem cells and CD4+/CD8- Jurkat cells. An immune-mediated murine aplastic anemia model and human samples, including peripheral blood samples of 4 healthy donors and bone marrow hematopoietic cells from 4 patients with hypocellular myelodysplastic syndrome (MDS), were also used to test the efficacy of TSY on hematopoiesis, telomerase activity and telomere length. Our results indicated that TSY-1 increased the telomerase activity and telomere length in a dose-response manner in vitro, in vivo, and in human samples including 3 of 4 healthy individuals and 3 of 4 bone marrow samples from MDS patients. In immune-mediated murine aplastic anemia model, TSY-1 activity on Telomere length was parallel to the significant increasing of the RBC, hemoglobin, hematocrit, and platelet count in peripheral blood, increasing of CD34+ cell count and hematopoiesis, and decreasing of fatty infiltration in bone marrow samples. Our study demonstrated that TSY-1 may exert its effects by modulating telomerase activity of hematopoietic cells. Further studies are warranted to explore the precise molecular mechanisms of how TSY-1 regulates telomerase activity and telomere length, and also to test the TSY-1 in randomized control trials. PMID- 24753754 TI - RNAi targeting GPR4 influences HMEC-1 gene expression by microarray analysis. AB - G-protein coupled receptor 4 (GPR4) belongs to a protein family comprised of 3 closely related G protein-coupled receptors. Recent studies have shown that GPR4 plays important roles in angiogenesis, proton sensing, and regulating tumor cells as an oncogenic gene. How GPR4 conducts its functions? Rare has been known. In order to detect the genes related to GPR4, microarray technology was employed. GPR4 is highly expressed in human vascular endothelial cell HMEC-1. Small interfering RNA against GPR4 was used to knockdown GPR4 expression in HMEC-1. Then RNA from the GPR4 knockdown cells and control cells were analyzed through genome microarray. Microarray results shown that among the whole genes and expressed sequence tags, 447 differentially expressed genes were identified, containing 318 up-regulated genes and 129 down-regulated genes. These genes whose expression dramatically changed may be involved in the GPR4 functions. These genes were related to cell apoptosis, cytoskeleton and signal transduction, cell proliferation, differentiation and cell-cycle regulation, gene transcription and translation and cell material and energy metabolism. PMID- 24753755 TI - A novel ureter dilatation method for replacing hydromantic perfusion pump during ureteroscopic lithotripsy in patients with ureteral calculi and ibroepithelial polyps. AB - This study aimed to evaluate the clinical value of a novel ureter dilatation method during ureteroscopic pneumatic lithotripsy in patients with ureteral calculi and polyps. Clinical information of 86 patients with ureter calculi and polyps who underwent ureteroscopic pneumatic lithotripsy was reviewed. A cavity distention machine was used in 44 cases to inject normal saline for keeping clear operation view (cavity-distention machine-assisted group). A high handled water bag with artificial water injection (traditional pneumatic lithotripsy group) was used in 42 cases. The total operation time, time of stone removal, stone clearance rate and surgery complications were compared between two groups. All operations were successful with no patients transferred to open surgery. No ureter breakage or avulsion occurred in two groups. Two patients in traditional pneumatic lithotripsy group suffered from ureter perforation. In cavity distention machine-assisted group and traditional pneumatic lithotripsy group, the total operation time was 30.1+/-4.8 min and 36.2+/-6.0 min, respectively (t= 5.22, P<0.01); the time of stone removal was 6.4+/-1.3 min and 9.3+/-1.5 min, respectively (t=-9.59, P<0.01); the stone clearance rate was 100% (44/44) and 95.2% (40/42; upper ureter stone immigrated to the renal pelvis in 2, and extraorgan shock wave lithotripsy was performed), respectively. Thus, intraoperative infusion of saline with a cavity-distention machine may replace the hydromantic perfusion pump to maintain a clear operation view and favor the stone removal in lesser time. This method has important clinical value in the treatment of ureteral calculi and polyps. PMID- 24753756 TI - Different effects of tetanic stimulation of facial nerve and ulnar nerve on transcranial electrical stimulation motor-evoked potentials. AB - OBJECTIVE: Our objective was to examine whether prior tetanic stimulation of cranial nerves enhances the amplitudes of transcranial motor-evoked potentials (MEPs). METHODS: Thirty patients undergoing elective craniotomy under propofol fentanyl anesthesia with partial neuromuscular blockade were enrolled. Both control and posttetanic MEPs (c-MEPs and p-MEPs) monitoring were performed with a train of five pulses delivered to C3 or C4. c-MEPs were recorded from target muscles and p-MEPs were obtained 1 s after tetanic stimulation to the ulnar nerves and facial nerves. The amplitudes of paired MEPs were compared with Wilcoxon's signed rank test. RESULTS: When tetanic stimulation was separately applied to the facial nerves, amplitudes of p-MEPs from abductor pollicis brevis, orbicularis oculi or oris were similar with those of c-MEPs. When tetanic stimulations were separately applied to the ulnar nerves, the amplitudes of p MEPs from the abductor pollicis brevis but not orbicularis oculi or oris were significantly enlarged compared with c-MEP. CONCLUSIONS: We found that only prior tetanic stimulation of ulnar nerve but not facial nerve could enlarge the amplitudes of trancranial hand MEPs. Augmentation of MEP amplitude via prior tetanic stimulation of peripheral nerve seems to originate from the subcortical level but not motor cortex. PMID- 24753757 TI - Effects of different types of hydroxyethyl starch (HES) on microcirculation perfusion and tissue oxygenation in patients undergoing liver surgery. AB - To compare the effects of hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5, which have different molecular weights and degrees of substitution, on microcirculation perfusion and tissue oxygenation in patients undergoing liver surgery. Thirty patients with an American Society of Anesthesiologists status I/II who were scheduled for liver surgery were randomly divided into two groups: one received an intraoperative HES 130/0.4 infusion equal to the amount of blood loss (HES 130/0.4 group, n=15), and the other received HES 200/0.5 equal to the amount of blood loss (HES 200/0.5 group, n=15). Gastric mucosal perfusion and tissue oxygenation were monitored by measuring the gastric mucosal pH (pHi), which was determined using a carbon dioxide tonometer inserted through a nasogastric tube. Gastric mucosal pHi , hemodynamic parameters, body temperature, and blood gas parameters were recorded upon entering the operating room, before skin incision, one hour and two hours after skin incision, and at the end of surgery. The intraoperative pHi decreased in both groups of patients, but the decline in the HES 130/0.4 group was smaller than that of the HES 200/0.5 group. The pHi of the HES 130/0.4 group was significantly higher than that of the HES 200/0.5 group two hours after skin incision and at the end of surgery (P<0.05). A multivariate analysis showed that the type of colloid used intraoperatively was the only variant that affected pHi (F=0.626, P<0.05). Moreover, there were good correlation between pHi at the end of surgery and the length of postoperative hospital stay (r=-0.536, P<0.05) and the time intervals from surgery to the passage of flatus (r=-0.547, P<0.05). Compared with HES 200/0.5, the use of HES 130/0.4 (with a relatively lower molecular weight and lower degree of substitution) could significantly improve internal organ perfusion and tissue oxygenation in patients undergoing liver surgery with a relatively large amount of blood loss. PMID- 24753758 TI - Hybrid PET/MR imaging in two sarcoma patients - clinical benefits and implications for future trials. AB - PET/MRI is an evolving hybrid imaging modality which combines the inherent strengths of MRIs soft-tissue and contrast resolution and PETs functional metabolic capabilities. Bone and soft-tissue sarcoma are a relatively rare tumor entity, relying on MRI for local staging and often on PET/CT for lymph node involvement and metastatic spread evaluation. The purpose of this article is to demonstrate the successful use of PET/MRI in two sarcoma patients. We also use these patients as a starting point to discuss how PET/MRI might be of value in sarcoma. Among its potential benefits are: superior TNM staging than either modality alone, decreased radiation dose, more sensitive and specific follow-up and better assessment of treatment response. These potentials need to be investigated in future PET/MRI soft-tissue sarcoma trials. PMID- 24753759 TI - Effect of carbodiimide cross-linking of decellularized porcine pulmonary artery valvular leaflets. AB - Decellularization provides low immunogenicity and is only slightly subject to calcification in tissue engineering. However, the mechanical properties of the tissues are weakened after decellularization. We adopted cross-linking agent 1 ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) to treat decellularized porcine pulmonary artery valvular leaflets to improve their mechanical properties. Twenty porcine pulmonary artery valvular leaflets were divided into three groups: the fresh control group A, group B treated with trypsin and Triton X-100 to remove cells, and group C cross-linked with EDC after decellularization. All samples were evaluated the physical and mechanical properties and were then subcutaneously embedded in rabbits. These valvular leaflets were removed after 1, 2, or 4 weeks and checked for pathological changes. The cells of the valvular leaflets were completely removed. The thickness of the valvular leaflets was thinner in group B than in group A (P<0.01). In the subcutaneous embedding of the group B samples, there was mild immunological response after 1-2 weeks, and parts of the scaffolds were degraded. After 4 weeks, fibroblasts had grown into the scaffolds. In group C, there was an increase in the tensile strength and thermal shrinkage temperature in group C compared with group B (P<0.01). In subcutaneous embedding of the group C samples, there was a mild immunological response after 1 2 weeks. The fibroblasts had grown into the samples. The EDC-based cross-linking procedure can enhance the tensile strength of decellularized pulmonary artery valvular leaflets and both decrease the valvular leaflets' rejection and promote tissue regeneration in vivo. PMID- 24753760 TI - Classification and surgical management for the axis fracture complicated with adjacent segment instability. AB - This study was to classify the axis fracture complicated with adjacent segment instability and to explore its significance to surgical management. 42 patients (25 males and 17 females) with axis fractures with an average age of 44.14 years (range, 23 to 65) who received surgery between January 2006 and June 2012 were analyzed retrospectively. Results suggest that all patients underwent surgery safely without spinal cord injury, cerebrospinal fluid leakage or vertebral artery injury. The average follow up was 18 months (12-48 months). There was significant difference (t = 2.339, P = 0.011) in JOA score between pre-operation (13.10 +/- 4.51) and post-operation time points (15.24 +/- 3.86). 1-2 degree improvement of neurofunction was achieved in all except 1 Frankel B. After operation, all patients were immobilized in a hard collar for 3 months. Fusion was achieved in all cases (mean 4.5 months). X-ray showed no malposition of the screws. No instrument failure was noted during follow up. Thus, axis fracture complicated with adjacent segment instability should be treated individually based on the fracture type and adjacent segment instability. Our classification can be used to guide the surgical management. PMID- 24753761 TI - APOBEC3G expression is correlated with poor prognosis in colon carcinoma patients with hepatic metastasis. AB - Increased expression of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) in human primary colorectal tumors and hepatic metastasis has been detected. However, the clinical relevance of APOBEC3G in colon carcinoma hepatic metastasis remains uncertain. The aim of this study was to assess the prognostic value of APOBEC3G in colon carcinoma patients with hepatic metastasis after hepatic resection. APOBEC3G expression was evaluated by immunohistochemistry in paraffin-embedded primary colon carcinoma and paired hepatic metastasis tissues from 136 patients with liver metastasis from colon carcinoma that underwent hepatic resection. The relation between APOBEC3G expression and clinicopathologic factors and long-term prognosis in these 136 patients was retrospectively examined. The prognostic significance of negative or positive APOBEC3G expression in colon carcinoma hepatic metastasis was assessed using Kaplan-Meier survival analysis and log-rank tests. Positive expression of APOBEC3G was correlated with liver metastasis of colon cancer. Univariate analysis indicated significantly worse overall survival (OS) for patients with a positive APOBEC3G expression in colon carcinoma hepatic metastasis than for patients with a negative APOBEC3G expression. Multivariate analysis showed positive-APOBEC3G in colon carcinoma hepatic metastasis to be an independent prognostic factor for OS after hepatic resection (P = 0.000). Positive expression of APOBEC3G was statistically significantly associated with poor prognosis of colon carcinoma patients with hepatic metastasis. APOBEC3G could be a novel predictor for poor prognosis of colon carcinoma patients with hepatic metastasis after hepatic resection. PMID- 24753762 TI - Effect of flumazenil on sevoflurane requirements for minimum alveolar anesthetic concentration-awake and recovery status. AB - OBJECTIVE: It is controversial that whether the GABA receptors contribute to the hypnotic action of volatile anesthetics. This study was to detect the effect of GABA receptors on the hypnotic action of volatile anesthetics by evaluation of the effect of intravenous flumazenil on sevoflurane minimum alveolar anesthetic concentration-awake (MAC-Awake) and emergence mental status. METHODS: This study included two steps. Firstly, 49 healthy patients, aged 20-40 years scheduled for elective surgeries, were randomly assigned to two groups, a flumazenil group (n=24) and a saline group (n=25). The flumazenil group received 0.006 mg/Kg IV, and the control group received the same volume of saline 20 min before induction. The flumazenil group and the control group were compared with regard to MAC-Awake (anesthetic concentration achieving 50% probability of eye opening in response to a verbal command). We used the mask inhalation to measure the MAC-Awake by up-and down method. The second steps, 60 patients undergoing lower abdomen surgeries were randomly divided into two groups, a experimental group (n=30) and a saline group (n=30). All patients were anesthetized with sevoflurane/sulfentanil. The experimental group received flumazenil at 0.006 mg/Kg IV, and the control group received the same volume of saline at the end of surgery. We recorded the time to awake and extubation. After extubation, the patients' recovery status was scored with the Mini-Mental state examination (MMSE) system in post anesthesia care unit (PACU). RESULTS: The MAC-Awake was 0.65% in the control group and 0.82% in the flumazenil group (p=0.34). After extubation, the recovery time and time to extubation showed no difference between the flumazenil group and the saline group (p>0.05). But the 10 min and 15 min MMSE scores after extubation were better in the flumazenil group than those in the saline group (p<0.05). There was no difference for MMSE scores after 30 min between two groups. CONCLUSION: We found that an IV flumazenil (0.006 mg/Kg) has no effect on sevoflurane MAC-Awake in humans. A single intravenous injection of flumazenil (0.006 mg/Kg) can partially reverse the hypnotic effect of sevoflurane/sulfentanil but do not contribute to reduction in the time to recovery and extubation. PMID- 24753763 TI - Perineural administration of dexmedetomidine in combination with ropivacaine prolongs axillary brachial plexus block. AB - To evaluate the hypothesis that adding dexmedetomidine to ropivacaine prolongs axillary brachial plexus block. Forty-five patients of ASA I~II and aged 25-60 yr who were scheduled for elective forearm and hand surgery were randomly divided into 3 equal groups and received 40 ml of 0.33% ropivacaine + 1 ml dexmedetomidine (50 MUg) (Group DR1), 40 ml of 0.33% ropivacaine + 1 ml dexmedetomidine (100 MUg) (group DR2) or 40 ml of 0.33% ropivacaine + 1 ml saline (group R) in a double-blind fashion. The onset and duration of sensory and motor blocks and side effects were recorded. The demographic data and surgical characteristics were similar in each group. Sensory and motor block onset times were the same in the three groups. Sensory and motor blockade durations were longer in group DR2 than in group R (P < 0.05). There was no significant difference in the sensory blockade duration between group DR1 and group R. Bradycardia, hypertension and hypotension were not observed in group R and occurred more often in group DR2 than in group DR1. Dexmedetomidine added to ropivacaine for an axillary brachial plexus block prolongs the duration of the block. However, dexmedetomidine may also lead to side effects such as bradycardia, hypertension, and hypotension. PMID- 24753764 TI - Prevalence and risk factors of urinary incontinence among Chinese women in Shanghai. AB - OBJECTIVE: A group of healthy females were randomly sampled in Shanghai for the purpose of evaluating the prevalence of urinary incontinence (UI) among Chinese women and its associated risk factors. METHODS: 5,467 registered female residents aged from 20 years were randomly sampled from four communities in Shanghai, and the Bristol Female Lower Urinary Tract Symptoms Questionnaire (the International Consultation Incontinence Questionnaire) was adopted. Detailed information regarding pregnancy, menstruation, and several demographic variables was also collected. Data were subsequently analyzed using McNemar's test, univariate analysis, multinomial logistic regression models, and binary logistic regression models. RESULTS: The prevalence rate of UI was estimated to be 23.3%. The rate of stress UI (SUI) was 14.0% (761/5433), which was more prevalent than the rate of urgency UI (UUI) and mixed UI (MUI), which were 3.0% (164/5433) and 6.3% (341/5433), respectively. The risk factors associated with developing UI included aging, lack of education, poor living environment (specifically in the rural area), intense manual labor, the absence of physical exercise, hyperlipemia, diabetes, nocturia, consumption of greasy food, divorce or widowing, chronic pelvic pain (CPP), pelvic organ prolapse (POP), frequent urinary tract infection, and vaginal delivery without episiotomy. We also observed that most Chinese women were not aware of UI, which prevented them from seeking early treatment. CONCLUSIONS: Urinary incontinence is a common disorder among Chinese women in Shanghai, and many risk factors contribute to the development of UI. Most Chinese women were not aware of UI, which prevented them from seeking early treatment. PMID- 24753765 TI - Methylenetetrahydrofolate reductase (MTHFR) 677C>T gene polymorphism as a possible factor for reducing clinical severity of psoriasis. AB - Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme in homocysteine/methionine metabolism. It catalysis the formation of 5 methyltetrahydrofolate (5-methyl-THF), which is the methyl donor for synthesis of methionine from homocysteine (Hcy). Decreases in folate consumption due to MTHFR polymorphism may affect production rate of keratinocytes of which had faster reproduction rates with a continuous DNA turnover and this may affect the clinical picture of psoriasis. This study aimed to investigate correlation of C677T polymorphisms in the MTHFR gene with severity of psoriasis and to evaluate the status of plasma Hcy, folate and vitamin B12 levels in patient with chronic plaque psoriasis. The study included 60 patients with chronic plaque psoriasis. The C677T polymorphisms were genotyped using PCR (Qiagen). Psoriasis Area and Severity Index (PASI) score below 7 was defined as mild, between 7 and 12 as moderate, and above 12 as severe disease. There was a significant difference between the severity of disease classification (p<0.05) with respect to the C677T polymorphism in the MTHFR gene. Severe involvement (PASI score >12) was observed in 38.46% of wild type (CC), but only 12.50% of homozygote (TT) and 7.69% of heterozygote (CT) patients. Significant differences between gene polymorphism and Hcy levels were noted in TT and CT genotypes respectively (p=0.025 and p=0.040). Plasma Hcy, folate and vitamin B12 levels were not correlated with the PASI score. Our data indicate a possible correlation of MTHFR polymorphism with severity of psoriasis. PMID- 24753766 TI - Assessment of numerical chromosomal abnormalities of the sperms before and after radiotherapy in seminoma patient. AB - OBJECTIVE: To assess numerical sex chromosomal abnormalities of the sperms before and after radiotherapy in seminoma patients and to evaluate their reproduction risks. METHODS: Three color Fluorescence in situ hybridization (FISH) was performed on sperms harvested from one seminoma patient before and after radiotherapy and before surgery. The numerical sex chromosomal abnormalities were compared. RESULTS: The ratio of 18-X and 18-Y sperm cells among the counted 40944 ones was close to 1:1 at three time points. The incidence of chromosome aneuploidy and diploid rate (18, X, Y) significantly increased after radiotherapy when compared with that before surgery and before radiotherapy. However, no significance was observed in the aneuploid and diploid rate between pre-operation group and pre-radiotherapy (post-operation) group except for the 18-YY karyotype (0.095% vs 0.026%, p<0.05). CONCLUSION: Our study shows increased incidence of numerical sex chromosomal abnormalities and high risk for reproductive and genetic diseases in patients treated with radiotherapy. Three colored FISH test is recommended to evaluate the rate of numerical chromosomal abnormalities; PGD and prenatal diagnosis are advised to improve the likelihood of a successful pregnancy. PMID- 24753767 TI - Long-term results of surgical treatment of aortic and mitral regurgitation with enlarged left ventricle. AB - Mitral valve and aortic valve regurgitation associated with enlarged left ventricle remains difficult to manage and the long-term results following surgical treatment is uncertain. Between April 1988 and September 2000, 82 patients with aortic and mitral regurgitation associated with enlarged left ventricle underwent valve replacement at Anzhen Hospital. The valve disease was rheumatic in origin in 75 patients (91.5%) and congenital in 7 (8.5%). Twenty eight patients were in New York heart Association Functional (NYHA) class II and 39 in class III and 15 in class IV. Echocardiogram showed severe aortic insufficiency associated with mild to moderate mitral regurgitation in 66 patients and severe mitral regurgitation associated with mild to moderate AI in 16 patients. The mean left ventricular diastole diameter (LVDD) was 77.8 +/- 5.2 mm. Valve replacement was performed under hypothermic cardiopulmonary bypass (CPB). Early hospital mortality was 7.3%. Two weeks after surgery the echocardiogram showed a reduction of LVDD. Follow up was completed in 69 patients with mean of 13.5 years. 20 patients were in NYHA class I; 26 in Class II and 3 in Class III and 2 in class IV. The follow-up survival rate was 73.9%, and follow up mortality was 26.1%. LVDD reduced from 77.8 +/- 5.2 mm to 58.3 +/- 4.5 mm (P < 0.001). In 24 patients, the LVDD was less than 50 mm. Double valve replacement and/or repair carried out an acceptable early and Long-term clinical outcomes in patients with MR and AI with associated LV great enlargement. Both LVDD and NYHA improved following surgical treatment in survival patients. PMID- 24753768 TI - Curcumin regulates hepatoma cell proliferation and apoptosis through the Notch signaling pathway. AB - Curcumin has become a compound of interest for its antioxidant and anti neoplastic properties. This study sought to determine the effect of curcumin administration on cell proliferation and apoptosis in hepatoma cells. SMMC-7721 hepatoma cells were treated with 10, 30, or 90 MUM curcumin solution, with DMEM alone (negative control), or with 20 mg/L fluorouracil (positive control). MTT colorimetry detected significant differences in the rates of cell proliferation inhibition following curcumin treatment, with increasing inhibition accompanying increasing doses of curcumin (P < 0.05), compared to the negative control. Similarly, flow cytometry revealed significant differences in the numbers of apoptotic cells following curcumin treatment: increasing doses of curcumin produced increases in the numbers of apoptotic cells (P < 0.05). To determine whether curcumin exerts these effects by altering the Notch signaling pathway, a phenomenon reported for other cancers, relative expression of Notch1 mRNA and protein were determined in curcumin-treated cells. Both mRNA and protein expression of Notch1 decreased with increasing curcumin dose (P < 0.05). Thus, curcumin appears to inhibit proliferation and induce apoptosis in hepatoma cells by altering the Notch signaling pathway. PMID- 24753769 TI - Evaluation of heart function with impedance cardiography in acute myocardial infarction patients. AB - To evaluate the capability of impedance cardiography (ICG) in reflecting the cardiac functions of acute myocardial infarction (AMI) patients. METHODS: 99 inpatients with initial AMI were recruited. Venous blood was obtained for detection of N-terminal brain-type natriuretic peptide (NT-proBNP), B-Type natriuretic peptide (BNP) and c troponin-T (cTnT) followed by ICG. Thorax fluid capacity (TFC), pre-ejection period (PEP), left ventricular ejection fraction (LVEF), cardiac output (CO), stroke volume (SV), stroke index (SI), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI), cardiac index (CI), end-diastolic volume (EDV) and systolic time ratio (STR) were measured. All these patients underwent ICG and echocardiography 2 days after surgery. RESULTS: Our results indicated NT-proBNP and BNP were associated with SVR, SVRI, PEP and STR, independently (P < 0.05). cTnT was associated with SVR and SVRI (P < 0.05). And the outcomes showed correlation between ICG and echocardiography in SV, SI, EDV, LEVT, STR, LVEF (P < 0.01), CO and CI (P < 0.05). However, no correlation was noted in PEP. In addition, changes were also found in the blood pressure and heart rate 7 days after PCI. CONCLUSION: May be ICG data could reflect the early cardiac functions of AMI patients, but the accuracy of ICG in evaluating cardiac functions should be combined with detection of blood NT-proBNP, BNP and cTnT and echocardiography. PMID- 24753770 TI - Gastro-esophageal reflux induced cough with airway hyperresponsiveness. AB - To investigate the characteristics of gastroesophageal reflux induced cough (GERC) with airway hyperresponsiveness (AHR). Compared to patients with GERC alone and healthy subjects, cough sensitivity, multi-channel intraluminal impedance combined with pH monitoring and airway inflammation were evaluated in patients with GERC and AHR. 23 patients were definitely diagnosed as acid reflux induced GERC, 9 patients developed AHR concomitantly. When compared with GERC patients, patients with AHR had significantly increased number of proximal extent episodes (21.5 (28.6) vs. 7.5 (1.8), Z = -2.038, P = 0.042) and increased proportion of proximal extent episodes to total refluxes episodes (24.5 (13.5)% vs. 4.2 (7.3)%, Z = -2.138, P = 0.032), and the level of IL-8 in the airway of these patients was significantly higher than that in healthy subjects (71.1 (64.0) vs. 24.3 (35.2) pg/ml, Z = -2.013, P = 0.044). Gastroesophageal reflux may cause neutrophilic airway inflammation due to the acid reflux into the airway, which results in AHR. However, AHR is not definitely able to cause chronic cough. Thus differential diagnosis is required in clinical practice. PMID- 24753771 TI - Clinical analysis of endometrial cancer patients with obesity, diabetes, and hypertension. AB - The purpose of our study was to study the postoperation outcome and incidence of deep vein thrombosis (DVT) in endometrial cancer (EC) patients with or without hypertension, diabetes, and obesity. This analysis included 219 patients with endometrial carcinoma who were treated between 2002 and 2012 at the Department of Obstetrics and Gynecology, Yangzhou University Hospital. Patients were divided into five groups based on the comorbidities. Group 1 EC & Diabetes, Group 2 EC & Hypertension, Group 3 EC & Obesity, Group 4 EC Combined two, Group 5 no combined. Then the five groups were analyzed in postoperation outcomes and DVT incidence using one-way analysis of variance or Pearson chi(2) tests. we found that there was no significant difference in pelvic lymph node metastasis (P=0.102), aortic lymph node metastasis (P=0.221), and operative time (P=0.503). But there was significant difference in blood loss (P<0.01), hospital stay (P<0.01). No significant difference (P>0.05) in treatment outcome between surgical operation, surgical operation+ radiotherapy and radiotherapy. Deep vein thrombosis and pulmonary embolism have some significantly (P<0.01) (P<0.01), respectively. Compared to patients who simply suffer from endometrial cancer, diabetes make patients easy bleeding in surgery and increase hospitalization time in corresponding. VTE is a common complication of EC surgery with comorbidities, such as diabetes and hypertension, and it's a remarkable proportion of events occurring late after surgery. PMID- 24753772 TI - Elevated serum level of carbohydrate antigen 19-9 in benign biliary stricture diseases can reduce its value as a tumor marker. AB - Although carbohydrate antigen (CA19-9) level is frequently upregulated in pancreatobiliary cancer, it is also elevated in some benign diseases. This study aimed to determine whether CA19-9 levels could be used to distinguish between benign obstructive jaundice and pancreatobiliary cancer. Fifty-seven patients with obstructive jaundice were studied retrospectively. Endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, stone extraction, or stent placement were used to treat patients with benign bile duct stricture or inoperable malignant biliopancreatic diseases, whilst surgery was performed in suitable cases. Serum CA19-9 levels and some additional biochemical parameters were evaluated before and after treatment. CA19-9 levels were elevated in most patients, along with levels of total bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGT), and 10 patients with benign disorders had extraordinarily high levels of these markers (> 1000 U/mL). The mean CA19-9 level in the malignant group was greater than that in the benign group (826.83 +/- 557.34 vs. 401.92 +/- 483.92 U/mL, P = 0.005), and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for CA19-9 were 100%, 7.69%, 33.33% and 47.47%, respectively. CA19-9 levels in the whole cohort were correlated with ALP (r = 0.77, P < 0.001), GGT (r = 0.83, P < 0.001), bilirubin (r = 0.69, P < 0.001), and CRP (r = 0.37, P = 0.004). The reduction in serum level of CA19-9 after treatment in the malignant group was remarkably less than that observed in the benign group (97.26 +/- 123.24 U/mL vs. 352.71 +/- 397.29 U/mL, P < 0.001). CA19-9 levels may not be sufficient to distinguish between malignant and benign obstructive jaundice diseases. PMID- 24753773 TI - Evaluation of cytokines as Th1/Th2 markers in pathogenesis of children with Crimean-Congo hemorrhagic fever. AB - Cytokine networks play a key role in the pathogenesis of the disease in Crimean Congo Hemorrhagic Fever (CCHF) patients. Therefore, our aim was to study the effects of cytokine levels on the pathogenesis and severity of the disease in children with CCHF. Fifty-two patients diagnosed with CCHF and 34 healthy controls (HC) were included in the study. The patients with CCHF were divided into two groups (severe and non-severe). The levels of the Interleukin-10 (IL 10), IL-12, IL-6, Endothelin-1 (ET-1) and tumor necrosis factor-alpha (TNF-alpha) were measured in all groups. IL-12 levels did not show any difference between the CCHF and HC groups and among the severe, non-severe and HC groups. IL-10 and ET-1 levels were significantly higher in the severe group when compared to the non severe group and the HC group. Moreover, IL-10 and ET-1 levels were significantly higher in the non-severe group when compared to the HC group. In terms of IL-6 and TNF-alpha levels, there was no difference between the severe and non-severe groups while the said levels were significantly higher in the severe group when compared to the HC group. The results of the present study showing significantly higher IL-10 and ET-1 levels in the severe group suggest that Th2-mediated humoral immunity is more effective in the pathogenesis and severity of CCHF in children. PMID- 24753774 TI - Development of a diabetes education program based on modified AADE diabetes education curriculum. AB - To assess the feasibility and acceptability of a diabetes education program tailored to patients with type 2 diabetes in communities and the preliminary outcomes of the intervention. METHODS: Two-phase, one group, mixed-method study design was used. Modified American Association of Diabetes Educators (AADE) diabetes education curriculum was used as the framework for the program. Patients with diabetes participated in classes and diabetes conversation map discussion. Feasibility and acceptability of the program were evaluated by the ability to recruit and retain participants and their satisfaction with the program. Diabetes knowledge test and the summary of diabetes self-care activities (SDSCA) were used to evaluate the knowledge and behavior changes of the patients. RESULTS: 40 patients completed the program and the attrition rate was 11.1%. All participants were "very satisfied" with the program. Significant improvement in diabetes knowledge and blood glucose monitoring and foot care were reported. CONCLUSION: The diabetes education program based on modified AADE diabetes education curriculum combined with diabetes conversation map may be effective in patients with type 2 diabetes. PRACTICE IMPLICATIONS: Flexible time schedule and a control group should be designed in the future study. PMID- 24753775 TI - Comparison of transvaginal ultrasonography and hysteroscopy in the diagnosis of uterine pathologies. AB - A thorough evaluation of the uterine cavity is frequently required in gynecology practice. The aim of this study was to compare the diagnostic values of transvaginal ultrasound examination and hysteroscopy in detecting uterine abnormalities in a group of patients within a range of menopausal status and symptomatology. This study included 285 patients admitted with complaints of abnormal uterine bleeding, postmenopausal bleeding, lower abdominal pain, abnormal vaginal discharge or for a routine gynecological examination. All patients had available transvaginal ultrasonography and hysteroscopy data for evaluation. A biopsy was obtained from all patients during the hysteroscopy session. Sensitivity, specificity, positive predictive value, negative predictive value and likelihood ratio were calculated for both methods and compared, considering the histopathological diagnosis as the gold standard. The mean age of the patients was 49.5+/-12.9 years (range, 24-89 y). Majority of the patients admitted for abnormal uterine bleeding (n=198, 69.4%). For the diagnosis of polyps of any size, hysteroscopy had better sensitivity (p<0.001), however, specificities did not differ (p=1.0). On the other hand, hysteroscopy did not have a sensitivity advantage over TVU in diagnosing polyps greater than 1 cm (p=0.077), although this time hysteroscopy had better specificity (p<0.001). Combined approach did not offer diagnostic advantage for any of the specific pathologies. Although TVU represents a practical approach for the initial evaluation of uterine pathologies, hysteroscopy seems to offer better diagnostic value for uterine pathologies in general, and uterine polyps in particular. PMID- 24753776 TI - Influence of Tai Chi exercise cycle on the senile respiratory and cardiovascular circulatory function. AB - OBJECTIVE: Observe the improvement effect of different cycles of Tai Chi exercise on the senile respiratory and cardiovascular circulatory function. METHODS: Select 180 elderly men who don't usually do the fitness exercise and then ask them to do Tai Chi exercise. Test their related indicators respectively prior to exercise and upon exercise for 3 months, 6 months and 12 months. 1 The cardiac pump function indicator: "Stroke Volume", "Ejection Fraction" and "Heart Rate"; 2 Rheoencephalogram (REG) indicator: "Inflow time", "Wave Amplitude"; 3 Pulmonary ventilation indicator: "Vital Capacity" (VC), "Maximum Minute Ventilation" (MMV). RESULTS: 1 Compared with the indicators before exercise, each indicator has no significant difference after 3 months of exercise and a part of indicators are improved after 6 months of exercise, but most indicators have no significant differences; 2 After 12 months of the exercise, compared with those indicators before exercise, the tested indicators are obviously improved. Specific data indicates that stroke volume (mL) is increased to 71.82 +/- 10.93 from 66.21 +/- 11.35 and the ejection fraction (%) is improved to 67.89 +/- 4.94 from 60.54 +/- 5.02, but the heart rate (times/min) is reduced to 67.15 +/- 8.39 from 76.62 +/- 8.40, mean P<0.05; inflow time (s) is shortened to 0.13 +/- 0.04 from 0.17 +/- 0.05; the amplitude (Omega) is increased to 1.19 +/- 0.23 from 0.97 +/- 0.21 before exercise and mean P<0.05; the vital capacity (L) is increased to 3.57 +/- 1.39 from 2.84 +/- 0.32; maximum minute ventilation (L/min) is improved to 117.25 +/- 14.86 from 97.26 +/- 14.71, mean P<0.05. CONCLUSION: The short-term Tai Chi exercise that is less than six months the following 6 months has no significant effect on the senile respiratory and cardiovascular circulatory function, however, with the longer exercise duration, after 12 months' exercise, it can significantly improve the effect. PMID- 24753777 TI - TMJ function after partial condylectomy in active mandibular condylar hyperplasia. AB - Condylar hyperplasia is a frequent pathology that causes severe facial asymmetries. The partial condylectomy generally halts the disease. The aim of this research was to examine post-condylectomy TMJ function; 14 patients were included in this study, 6 male and 8 female. The average age was 21 years old. In all, the partial condylectomy was performed with preauricular or endaural access and the osteotomy were performed with drills, saw or an ultrasonic system. The patients were assessed with 3 or more time after surgery and were considering maximum mouth opening, right and left lateralities, presence of pain, noises, alterations in the facial nerve (VII) and esthetic alteration from the scar. The analysis was performed with the visual analog scale (VAS) and with a 7 cm metallic rule. Data analysis was descriptive plus chi-square test considering p value < 0.05 for statistical differences. With an average of 11 month after surgery, the results showed that the open mouth (over 35 mm) and lateralities (average 9 mm for the both right and left side) were normal and without statistical differences between the right or left side. Noise was observed in 3 patients and pain was observed in two patients with level 2 and 1 (VAS score). Scar was not related to problem with patient and the temporal branch of facial nerve was observed with limitations but without problem for patients. It can be concluded that the condylectomy is a safe and effective procedure with low morbidity for patients. PMID- 24753778 TI - Isolated avulsion fractures of lesser tuberosity humerus: a case report and review of the literature. AB - In this case, a 31 year-old female was diagnosed of isolated fractures of lesser tuberosity humerus. The patient could take early functional training of shoulder joint two days after operation. Although isolated fractures of lesser tuberosity humerus are rare, when pain of anterior shoulder joint after trauma, doctors should consider isolated fractures of lesser tuberosity humerus. As for the therapy methods, they should be chosen according to time length after injury. Most of the patients had no obvious residual functional disability after treatments. PMID- 24753779 TI - Cutaneous metastasis of gastric cardia adenocarcinoma in a patient: a case report. AB - A large proportion of gastric cardia adenocarcinoma (GCA) present initially in an advanced stage in China. Skin metastasis of primary GCA rarely occurs and the incidence of it is still unclear yet. Here we report one case of skin metastasis from GCA in a 58-year-old male patient who underwent gastric cardia resection in 2002 and did not undergo chemotherapy. However, he was diagnosed with anastomotic stoma adenocarcinoma by gastroscopy and histological biopsy in 2012.4. Then he underwent four cycles of "XELOX" regimen chemotherapy and the evaluation was PR. Upper gastrointestinal bleeding occurred and he was administered hemostatic therapy in 2012.9; meanwhile, he suffered from severe pains all over the body and received slow-release morphine. However, he was found to have dozens of cutaneous metastasizes in the skin of abdominal and back. Then, he underwent best supportive care and died of cachexia in 2013.5. GCA cutaneous metastasis indicates a highly invasive potential of tumors, poor chemo-radiotherapy efficacy and poor prognosis. The patient may survive just for another several months without the treatment of anti-tumor agents. Appropriate treatment may prolong patient survival. PMID- 24753780 TI - Gunshot wound to the upper cervical spine leading to instability. AB - Gunshot wounds (GSW) to the cervical spine leading to instability are rare. Also, the presence of vital vascular and neurological structures in the surround area lead to death or severe disability in the vast majority of cases. In this brief report, we present a rare case of C1 fracture due to GSW leading to instability of the atlanto-occipital joint in a neurologically intact patient. PMID- 24753781 TI - Gross intraoperative evaluation (GIE): a reliable method for the evaluation of surgical margins at partial nephrectomy. AB - To determine the efficacy of a new method called by us as "gross intra-operative evaluation (GIE)" for the assessment of surgical margin (SM) status. A total of 26 consecutive patients operated with cT1a-b renal tumors at a single center were included in this study. After the excision, the tumors were uniformly divided into two halves in the longitudinal axis ex vivo. In this way, margins were exposed for GIE for the evaluation of the safety of SMs. Findings of GIE were compared with the permanent section analysis in terms of SM status. Mean patient age, tumor size and margin thickness was 59 (38-79), 3.1 (1.5-6) cm and 3.7 (0.1 12) mm, respectively. In all patients, GIE showed intact margins and none of the patients had positive SM in the final pathological examination. There was no evidence of local recurrence or distant metastasis with a mean follow-up of 25 (4 104) months. All patients are alive. GIE of resected specimen without FS analysis is a safe and effective method for the evaluation of SMs in partial nephrectomy patients. PMID- 24753782 TI - Clinical and angiographic findings in Moya Moya. AB - PATIENT: Female, 40 FINAL DIAGNOSIS: Moya-Moya Disease Symptoms: Blurred vision * headache * lethargy MEDICATION: - Clinical Procedure: - Specialty: Neurology. OBJECTIVE: Rare disease. BACKGROUND: Moya Moya is a cerebrovasculopathy of the terminal internal carotid arteries and the proximal anterior and middle cerebral arteries. It is comparatively more common in Japan compared to Western countries. CASE REPORT: We present a patient of South-East Asian origin diagnosed with Moya Moya, confirmed on magnetic resonance angiography and later computerized tomography angiography. She was managed conservatively through medical management and lifestyle advice, and has now been enlisted into the national Moya Moya database in the UK. CONCLUSIONS: We believe this report will help advance our understanding on Moya Moya and help to elucidate the importance of a combined medical and radiological approach to this condition. PMID- 24753783 TI - The potent synergistic effects of the combination of liraglutide and canagliflozin on glycemic control and weight loss. AB - PATIENT: Male, 57 FINAL DIAGNOSIS: Diabetes mellitus type 2 SYMPTOMS: Weight loss Medication: - Clinical Procedure: - Specialty: Endocrinology and Metabolic. OBJECTIVE: Unusual or unexpected effect of treatment. BACKGROUND: Studies of the efficacy of the combination of the incretin mimetic liraglutide and the SGLT2 inhibitor canagliflozin or indeed studies of the combination of any incretin mimetic with an SGLT2 inhibitor have neither been performed nor published. Pharmacologically, the combination of an incretin-mimetic and an SGLT2-receptor blocker should result in a more significant weight loss and a greater reduction in postprandial glucose and HbA1c. CASE REPORT: An insulin-dependent type 2 diabetic patient with multiple diabetic complications was placed on the combination of liraglutide and canagliflozin and 4 weeks later was able to discontinue insulin. In addition, in spite of discontinuing insulin, his HbA1c dropped from 7.0% to 6.8%, and he had reductions in body (weight from 247 to 218 lbs), BMI (from 34 to 29.5 Kg/m(2)), waist circumference (from 47 to 44 1/2 inches), and neck circumference (from 19 1/2 to 18 1/4 inches). CONCLUSIONS: The combination of an SGLT2 inhibitor and an incretin mimetic/analog results in improved glycemic control accompanied by significant weight loss. This combination needs to be studied in a prospective randomized trial because the effect of each of the components of this combination is synergistically magnified by the addition of the partner drug. PMID- 24753784 TI - Bird fanciers' lung induced by exposure to duck and goose feathers. AB - PATIENT: Female, 60 FINAL DIAGNOSIS: Bird fanciers' lung Symptoms: Cough productive * hypoxia * short of breath * substernal chest pain MEDICATION: - Clinical Procedure: - Specialty: - OBJECTIVE: Rare disease. BACKGROUND: Hypersensitivity pneumonitis (HP) is a group of inflammatory interstitial lung diseases caused by hypersensitivity reactions from repeated insults of inhalation of fine particulate organic dusts derived from environmental sources. Bird fanciers' lung (BFL) is the most common form of HP, with an estimated prevalence of 0.5-7.5% and is observed in individuals who develop a hypersensitivity response to avian droppings or antigens on bird feathers. CASE REPORT: A 60-year old woman presented to our care with shortness of breath with exertion. She was hypoxic with oxygen saturation of 70% on room air. The CTA of the chest revealed a diffuse bilateral ground glass density in the lung parenchyma with a mosaic attenuation pattern. On further questioning she explained that she collected many duck and goose feathers she found on the ranch and placed them in a vase at home. Transbronchial lung biopsy revealed non-caseating granulomas, aggregates of epithelioid macrophages, and patchy mononuclear cell infiltration with lymphocytes and fibrotic tissue. The patient clinically improved and was discharged home on the 6(th) hospital day with prednisone 20 mg daily, with clinical improvement noted on subsequent follow up visits. CONCLUSIONS: There is no specific clinical manifestation; abnormal laboratory test results help establish a definitive diagnosis. The best diagnostic tool is the correlation of symptom onset with the environmental exposure. The prognosis is excellent after a single episode of HP, but continuous re-exposure carries the risk of progressive pulmonary impairment. PMID- 24753785 TI - Bem3: Filling the GAP between cell polarity and secretion. AB - A highly conserved member of the Rho family of small GTPases, Cdc42 functions as the "master regulator of cell polarity." It has been reported that for proper establishment and maintenance of cell polarity, Cdc42 regulates and requires vesicle trafficking. Importantly, we recently discovered that in budding yeast, vesicle trafficking also controls the localization and function of Bem3, a GTPase activating protein for Cdc42. Specifically, we observed that Bem3 partitioned between the plasma membrane and an internal membrane-bound compartment. This Bem3 containing compartment was present during extended periods of apical growth, required actin tracks for trafficking to polarized sites and functioned as a recycling station that was positioned at the junction of endocytic and secretory pathways. Strikingly, many of these features are reminiscent of the Spitzenkorper, a dynamic structure involved in polarized growth during hyphal development in several filamentous fungi. Furthermore, Bem3 was not merely a passive cargo but actively recruited the secretory Rab GTPase Sec4 to this Spitzenkorper-like compartment. Importantly, this function of Bem3 was independent of its GAP activity. Our work demonstrates the existence of a complementary regulation between Bem3, a regulator of Cdc42 signaling and Sec4, a key component of the secretory machinery. PMID- 24753786 TI - SCAR/WAVE: A complex issue. AB - The SCAR/WAVE complex drives the actin polymerisation that underlies protrusion of the front of the cell and thus drives migration. However, it is not understood how the activity of SCAR/WAVE is regulated to generate the infinite range of cellular shape changes observed during cell motility. What are the relative roles of the subunits of the SCAR/WAVE complex? What signaling molecules do they interact with? And how does the complex integrate all this information in order to control the temporal and spatial polymerisation of actin during protrusion formation? Unfortunately, the interdependence of SCAR complex members has made genetic dissection hard. In our recent paper,(1) we describe stabilization of the Dictyostelium SCAR complex by a small fragment of Abi. Here we summarize the main findings and discuss how this approach can help reveal the inner workings of this impenetrable complex. PMID- 24753787 TI - The magnetic compass of domestic chickens. AB - In a recent paper, we showed that domestic chickens can be trained to search for a social stimulus in specific magnetic directions. Chickens can hardly fly and have only small home ranges, hence their having a functional magnetic compass may seem rather surprising. Yet considering the natural habitat of their ancestors and their lifestyle until recently, the advantages of a magnetic compass become evident. PMID- 24753788 TI - Interactions between intercellular adhesion molecule-5 positive elements and their surroundings in the rodent visual cortex. AB - The telencephalon-associated intercellular adhesion molecule 5 (Telencephalin; ICAM-5) regulates dendritic maturation, a process dependent on extracellular proteases in the developing brain. Using transmission electron microscopy, we have reported previously that ICAM-5 is localized primarily in dendritic protrusions during a period of robust synaptogenesis (P14 in mouse visual cortex). As dendritic protrusions mature (P28), ICAM-5 immuno-reactivity shifts from dendritic protrusions into dendritic shafts. ICAM-5 immuno-reactivity does not shift in animals lacking the matrix metalloproteinase-9 (MMP-9), a protease shown to regulate ICAM-5 cleavage. Cleaved ICAM-5 (soluble fraction; sICAM-5) has been shown to bind to a number of receptors located in neighboring structures, resulting in a variety of downstream signaling events, including enhanced neurotransmission. Here, we investigated the potential MMP-regulated ICAM-5 signaling by examining the relationship between ICAM-5 immuno-positive elements and the structures that directly neighbor them. PMID- 24753789 TI - Stigmergy: A key driver of self-organization in bacterial biofilms. AB - Bacterial biofilms are complex multicellular communities that are often associated with the emergence of large-scale patterns across the biofilm. How bacteria self-organize to form these structured communities is an area of active research. We have recently determined that the emergence of an intricate network of trails that forms during the twitching motility mediated expansion of Pseudomonas aeruginosa biofilms is attributed to an interconnected furrow system that is forged in the solidified nutrient media by aggregates of cells as they migrate across the media surface. This network acts as a means for self organization of collective behavior during biofilm expansion as the cells following these vanguard aggregates were preferentially confined within the furrow network resulting in the formation of an intricate network of trails of cells. Here we further explore the process by which the intricate network of trails emerges. We have determined that the formation of the intricate network of furrows is associated with significant remodeling of the sub-stratum underlying the biofilm. The concept of stigmergy has been used to describe a variety of self organization processes observed in higher organisms and abiotic systems that involve indirect communication via persistent cues in the environment left by individuals that influence the behavior of other individuals of the group at a later point in time. We propose that the concept of stigmergy can also be applied to describe self-organization of bacterial biofilms and can be included in the repertoire of systems used by bacteria to coordinate complex multicellular behaviors. PMID- 24753790 TI - The sense is in the fingertips: The distal end controls filopodial mechanics and dynamics in response to external stimuli. AB - Small hair-like cell protrusions, called filopodia, often establish adhesive contacts with the cellular surroundings with a subsequent build up of retraction force. This process seems to be important for cell migration, embryonic development, wound healing, and pathogenic infection pathways. We have shown that filopodial tips are able to sense adhesive contact and, as a consequence, locally reduce actin polymerization speed. This induces filopodial retraction via forces generated by the cell membrane tension and by the filopodial actin shaft that is constantly pulled rearwards via the retrograde flow of actin at the base. The tip is also the weakest point of actin-based force transduction. Forces higher than 15 pN can disconnect the actin shaft from the membrane, which increases actin polymerization at the tip. Together, this points toward the tip as a mechano chemical sensing and steering unit for filopodia, and it calls for a better understanding of the molecular mechanisms involved. PMID- 24753791 TI - Membrane rafts regulate phospholipase B activation in murine sperm. AB - It is intuitive that fertilization-the start of life-involves communication between a sperm cell and an egg. It has been known that to become able to fertilize an egg, a sperm must first communicate with stimuli in the female tract. For example, sterol removal from the plasma membrane is required for sperm to undergo membrane fusion during acrosome exocytosis (AE). However, how membrane lipid changes were transduced into initiation of AE remained unclear. Recently, we found that sperm phospholipase B (PLB) is activated in response to sterol removal and released into the extracellular fluid by proteolytic cleavage. The resultant active PLB fragment can stimulate initiation of AE without other physiological stimulation. These results provide a possible mechanism for how AE is triggered, a critical question given recent data from others that show that AE is induced prior to contact with the egg's extracellular covering, the zona pellucida. PMID- 24753792 TI - NAADP/TPC2/Ca(2+) Signaling Inhibits Autophagy. AB - Nicotinic adenine acid dinucleotide phosphate (NAADP) is one of the most potent endogenous Ca(2+) mobilizing messengers. NAADP mobilizes Ca(2+) from an acidic lysosome-related store, which can be subsequently amplified into global Ca(2+) waves by calcium-induced calcium release (CICR) from ER/SR via Ins(1,4,5)P 3 receptors or ryanodine receptors. A body of evidence indicates that 2 pore channel 2 (TPC2), a new member of the superfamily of voltage-gated ion channels containing 12 putative transmembrane segments, is the long sought after NAADP receptor. Activation of NAADP/TPC2/Ca(2+) signaling inhibits the fusion between autophagosome and lysosome by alkalizing the lysosomal pH, thereby arresting autophagic flux. In addition, TPC2 is downregulated during neural differentiation of mouse embryonic stem (ES) cells, and TPC2 downregulation actually facilitates the neural lineage entry of ES cells. Here we propose the mechanism underlying how NAADP-induced Ca(2+) release increases lysosomal pH and discuss the role of TPC2 in neural differentiation of mouse ES cells. PMID- 24753793 TI - Salivary glucose concentration and daily variation in the oral fluid of healthy patients. AB - AIM: The aim of this study was to determine the concentration and the variations of salivary glucose in healthy patients who were sampled at five different intervals during the day. MATERIALS AND METHODS: Samples of un-stimulated saliva have been collected from 21 healthy patients using the drooling technique and they were divided into two categories. In the first category, patients were asked not to toothbrush their teeth in the 8 hours prior to collection of the salivary sample. Patients in the second category were instead asked to toothbrush 90 minutes before the collection of the first sample of saliva. The glucose concentration was measured in all patients via an enzymatic spectrophotometry. Patients have been selected following a strict inclusion criteria, which included <5% of plaque presence e according to the plaque Index and a total absence of oral disease that could possibly interfere with sample taking or oral fluid analysis. The average age of patients was 22,4+/-2,6 years old of which 45% were female and 55% were male. Samples were collected five times between 8 am and 12 pm, before and after breakfast. Data was statistically analyzed using the Skewness/Kurtosis Test, Shapiro-Wilk Test, Kruskal Wallis Test and Linear Regression Model, considering values of p<0,05 to be significant. RESULTS: The average rate of un-stimulated salivary flow was 0,53+/-0,21 ml/min. There were no significant differences between salivary glucose values and salivary flow in female and male patients. However, we observed a typical trend which recurred for each patient and resembled a "pseudo-glycemic curve". CONCLUSIONS: The collected data suggests that glucose concentration results did not show statistically significant differences (p>0,078) which could however be due to the little number of patients assessed, nonetheless there is a trend, recalling a "pseudo-glycemic curve" not referable to changes in flow rates, probably due to glucose catabolism and shunt. PMID- 24753796 TI - Evaluation capability of surgical difficulty in the extraction of impacted mandibular third molars: a retrospective study from a post-graduate institution. AB - INTRODUCTION: The first aim of the present study was to analyze if any correlation exists between the post-graduate's and the tutor's difficulty evaluation of the same tooth to be extracted. Secondly, the study aimed to verify whether, and possibly which, anatomical/topographic characteristics of the impacted lower third molar influence the post-graduate's difficulty evaluation. Thirdly, patient's age and gender were studied for any influence either on the post-graduate's and tutor's extraction difficulty evaluation or on surgical time. Lastly, the possible effect of the post-graduate's difficulty evaluation on the incidence of surgical accidents was also studied. MATERIALS AND METHODS: Eighty four impacted mandibular third molars have been retrospectively reviewed. For each molar, pre- and operative information have been collected. The Pearson's Product Moment Correlation, the general linear model with backward stepwise procedure, the variance analysis and the logistic regression were used for inferential statistics. MAIN RESULTS: Correlation between the post-graduate's and tutor's difficulty evaluation of each lower third molar to be extracted as well as between difficulty evaluation and operative time were statistically significant. Tooth position, impaction depth and relationship with the inferior alveolar nerve influenced operative times. Pre-surgical difficult degree had a positive significant effect on accident occurrence. CONCLUSIONS: The pre operative post-graduates' difficulty evaluation did not differ from their post operative evaluation although their judgement differed from that given by the tutor and did not correlate with the operative time. Lower third molar extraction difficulty seems to be influenced by some topographic factors such as tooth position, impaction depth and relationship between inferior alveolar nerve and impacted tooth. PMID- 24753797 TI - Effects of dentin surface treatments on shear bond strength of glass-ionomer cements. AB - AIM: The aim of this in vitro study was to evaluate the effect of different surface treatments on shear bond strength of a conventional glass-ionomer cement (GIC) and a resin-modified glass-ionomer cement (RMGIC) to dentin. MATERIALS AND METHODS: 80 bovine permanent incisors were used. 40 cylindrical specimens of a GIC (Fuji IX GP Extra) and 40 cylindrical specimens of a RMGIC (Fuji II LC) were attached to the dentin. The teeth were then randomly assigned to 8 groups of equal size (n=10), 4 for every type of glass-ionomer cement, corresponding to type of dentin surface treatments. Group 1: GC Cavity Conditioner; Group 2: 37% phosphoric acid gel; Group 3: Clearfil SE Bond; Group 4: no dentin conditioning (control). The specimens were placed in a universal testing machine (Model 3343, Instron Corp., Canton, Mass., USA) and subsequently tested for shear bond strength (MPa). RESULTS: ANOVA showed the presence of significant differences among the various groups. Post hoc Tukey test showed different values of shear bond strength for Fuji IX GP Extra and for Fuji II LC. The different conditioners variably influence the adhesion of the glass-ionomer cements tested. Conclusions. RMGIC shear bond to dentin was higher than GIC. The use of a Self-etch adhesive system improved the shear bond strength values of RMGIC and lowered the shear bond strength values of GIC significantly. PMID- 24753798 TI - Characterizing scientific production of Italian Oral Surgery professionals through evaluation of bibliometric indices. AB - The aim of this study was to characterize the scientific production of Italian Oral Surgery professionals by evaluating different bibliometric indices. The bibliometric evaluation was conducted on the Scopus Database upon all the Active Members joining three important Italian scientific societies in Oral Surgery (SIdCO, SIO, and SICOI). The scientific production was analysed by considering the number of total publications, number of total citations, h-index, and hc index. Moreover, the overall sample was divided into two groups (Academics and Not Academics), according to the fact the professionals had or not a university position, and then into sub-groups according to the different career lengths. Statistical analyses were performed to compare the scientific productivity amongst groups. For all the considered parameters a lack of homogeneity between groups was reported, and significantly greater mean values were recorded for the Academics compared to the Not Academics Group. Moreover, the h-index values increased more regularly as the career length progressed than the hc-index values, even if the last seemed to be less variable. h- and hc-indices are both stable bibliometric parameters, but as the hc-index values are related not only to the number of citation but also to their age, it seems to be less influenced by the authors' career length. Bibliometric analysis of the scientific production in dentistry may facilitate the recognition of factors that may further enhance research activity and clinical performance and be useful for a comparative assessment of authors or research groups in terms of quality and quantity of the scientific production. PMID- 24753799 TI - Onlay bone grafting simultaneous with facial soft tissue augmentation in a hemifacial microsomia patient using de-epithelialized orthograde submental flap: a technical note. AB - Soft tissue augmentation in hemifacial microsomia patients is a challenging procedure. Free microvascular flap transfer is considered usually as the most accepted choice. On the other hand, bone grafting, simultaneous with facial soft tissue augmentation using de-epithelialized orthograde submental flap, is a suggested procedure. Moreover, preoperative evaluation of facial artery and anterior belly of the digastric muscle are essential steps for success in such flaps. Furthermore, bone suture technique helps achieve more predictable results and reduces the need for postoperative bulky dressing. PMID- 24753800 TI - Resolution of endodontic issues linked to complex anatomy. AB - Anatomical abnormalities of the root canal system are frequently seen in specialist endodontic practice, and represent a challenge to be faced with skill and thoroughness, beginning with an accurate diagnostic phase and devising the most appropriate treatment plan. Fortunately, much progress has been made in endodontic research thanks to technological advances and the evolution of higher performance instruments, which now consent even very complex cases to be resolved with relative ease. Below are described the salient features of recent progress in endodontics, along with a description of several clinical cases in which the operator has encountered numerous difficulties due to peculiar tooth morphology, overcome successfully thanks to the application of modern tools and consolidated clinical experience in the field. PMID- 24753801 TI - Exercise echocardiography in asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction. AB - The management of asymptomatic patients with severe aortic stenosis (AS) remains controversial. Recent series reported that early aortic valve replacement might be associated with improved clinical outcomes. However, the risk-benefit ratio should be carefully evaluated and early surgery only be proposed to a subset of asymptomatic patients considered at higher risk. Exercise echocardiography can help unmask symptomatic patients combined with assessment of the hemodynamic consequences of AS. Recent studies have demonstrated that exercise echocardiography can provide incremental prognostic value to identify patients who may benefit most from early surgery. In "truly" asymptomatic patients, an increase in mean aortic gradient >= 18-20 mmHg, a limited left ventricular contractile reserve or a pulmonary hypertension during exercise are predictive parameters of adverse cardiac events. Exercise echocardiography is low-cost, safe and available in many referral centers, and does not expose patients to radiation. The purpose of this article is to describe the role of exercise testing and echocardiography in the management of asymptomatic patients with severe AS and preserved left ventricular ejection fraction. PMID- 24753802 TI - Incidence and fate of the abnormal septal motion after open heart surgeries. PMID- 24753803 TI - Echocardiographic investigation of the mechanism underlying abnormal interventricular septal motion after open heart surgery. AB - BACKGROUND: Abnormal interventricular septal motion (ASM) is frequently observed after open heart surgery (OHS). The aim of this study was to investigate the incidence and temporal change of ASM, and its underlying mechanism in patients who underwent OHS using transthoracic echocardiography (TTE). METHODS: In total, 165 patients [60 +/- 13 years, 92 (56%) men] who underwent coronary bypass surgery or heart valve surgery were consecutively enrolled in a prospective manner. TTE was performed preoperatively, at 3--6-month postoperatively, and at the 1-year follow-up visit. Routine TTE images and strain analysis were performed using velocity vector imaging. RESULTS: ASM was documented in 121 of 165 patients (73%) immediately after surgery: 26 patients (17%) presented concomitant expiratory diastolic flow reversal of the hepatic vein, 11 (7%) had inferior vena cava plethora, and 11 (7%) had both. Only 2 patients (1%) showed clinically discernible constriction. ASM persisted 3--6 months after surgery in 38 patients (25%), but only in 23 (15%) after 1 year. There was no difference in preoperative and postoperative peak systolic strain of all segments of the left ventricle (LV) between groups with or without ASM. However, systolic radial velocity (VRad) of the mid anterior-septum and anterior wall of the LV significantly decreased in patients with ASM. CONCLUSION: Although ASM was common (74%) immediately after OHS, it disappeared over time without causing clinically detectable constriction. Furthermore, we consider that ASM might not be caused by myocardial ischemia, but by the decreased systolic VRad of the interventricular septum after pericardium incision. PMID- 24753804 TI - Estimating the Myocardium's Angle of Three-Dimensional Trajectory, Using the Tracking of Sequential Two-Dimensional Echocardiography Images. AB - BACKGROUND: In this study, the angle of the myocardium's trajectory in three dimensions (f) was estimated by simultaneous use of long-axis and short-axis views of left ventricle septum two-dimensional images. Then correlation of three dimensional trajectory's angle with the rotation angle from the long (chi) and short (theta) axis views was estimated and compared at the three levels of base, mid and apex of the interventricular septum wall. METHODS: Two-dimensional echocardiography images of long- and short-axis views of 19 healthy men were recorded and analyzed. Using an electrocardiogram of each individual, the images of the two views were synchronized. The interventricular septum wall motion at the three levels of base, mid and apex were estimated, using a block matching algorithm throughout three cardiac cycles. Considering the defined system of coordinates and the position vectors in long and short-axis views, the 3 dimensional angle of the trajectory was calculated. RESULTS: Maxima of the f, theta, and chi angles were extracted at 16.33 +/- 3.01, 10.61 +/- 3.38, and 15.11 +/- 3.30 degrees at base level, 22.77 +/- 4.95, 7.78 +/- 2.96, and 16.72 +/- 2.66 degrees at mid level and 14.60 +/- 5.81, 10.37 +/- 5.48, and 8.79 +/- 3.32 degrees at apex level, respectively, of the septum wall, respectively. This study shows significant correlation between the angle of 3-dimensional trajectory (f) with the angle in short axis view (theta) of the septum wall at the apex level; and also with the angle in long axis view (chi) of the septum wall at base and mid levels. CONCLUSION: Due to the motion of the wall of the left ventricle in three dimensions, and the non-isotropic structure of myofibers, the angle of 3 dimensional trajectory was estimated using the speckle tracking method of 2 dimentional echocardiography images. PMID- 24753805 TI - The tissue Doppler imaging derived post-systolic velocity notch originates at the aortic annulus. AB - BACKGROUND: A distinct velocity pattern represented by a "notch" is observed during the time interval between the end of the systolic and the onset of the early diastolic velocity wave on longitudinal myocardial velocity curve. The origin of the post-systolic velocity notch (PSN) has not been resolved. METHODS: The high frame rate color tissue Doppler imaging of the apical longitudinal axis was performed in 32 healthy subjects. RESULTS: The time delays of the PSN onset at the posterior aortic wall (AW), the mid anteroseptal wall (MAS) and the posterior mitral annulus (MA) relatively to the anterior aortic annulus (AA) were found to be significantly longer than zero (5.1 +/- 2.2, 6.0 +/- 2.3, 6.8 +/- 2.8 ms; p < 0.001). The amplitude was the highest at the AA when compared to the AW, the MAS and the MA (4.77 +/- 1.28 vs. 2.88 +/- 1.11, 2.15 +/- 0.73, 2.44 +/- 1.17 cm/s; p < 0.001). A second PSN spike was identifiable in 10/32 (31%) of the studied subjects at the AA. Of these, 9 (28%) exhibited a second PSN spike at the AW, 3 (9%) at the MAS and no one at the MA. CONCLUSION: The AA represents the site of the earliest onset and maximal amplitude of the PSN on the longitudinal velocity curve suggesting its mechanism to be that of an energy release at the instant of the aortic valve closure causing an apically directed acceleration of the myocardium. A substantial number of healthy subjects exhibit a second PSN spike predominantly at the level of the AA. Its mechanism remains to be elucidated. PMID- 24753806 TI - Coronary artery fistula draining into the left ventricle. AB - We present a case of 48-year-old male who presented with coronary artery fistula draining into left ventricle. Transthoracic echocardiography showed abnormal blood flow draining into left ventricle, with enlarged coronary arteries and multiple vascular structures around ventricular myocardium. Coronary computed tomography revealed dilatation of entire left coronary artery which was wrapping around left ventricle, and draining into the posterior side of left ventricle. He did not undergo any invasive treatment, because he was not symptomatic. PMID- 24753807 TI - Dilated cardiomyopathy secondary to hypothyroidism: case report with a review of literatures. AB - To date, it has been well documented that there is a relationship between alterations in thyroid hormones and cardiac dysfunction. We experienced a case of a 36-year-old man with dilated cardiomyopathy (DCM) accompanied by undiagnosed primary hypothyroidism. In the current case, there was a significant improvement in the cardiac function following heart failure management and thyroid hormone replacement. Our case highlights that clinicians should consider the possibility of hypothyroidism as a cause of DCM. PMID- 24753808 TI - Congenital absence of the pericardium. AB - Congenital absence of the pericardium is a rare cardiac malformation and is most often asymptomatic. It is usually discovered as an incidental finding. Physical examination, chest radiography, and electrocardiogram are often unremarkable. Echocardiography provides valuable information, and sometimes computed tomography or magnetic resonance imaging is needed for subsequent confirmation. PMID- 24753809 TI - Multiple papillary fibroelastomas and thrombus in the left heart. AB - Cardiac papillary fibroelastomas (CPF) are benign cardiac tumors and usually discovered incidentally during echocardiography. This report describes the case of a 68-year-old man, referred to cardiology for multiple masses of the left ventricle and left atrium. The transthoracic echocardiography revealed multiple oscillating masses in the left ventricle and aortic valve, non-mobile mass in the left atrium with severe mitral stenosis and moderate aortic regurgitation. The patient underwent surgical resection of the masses with valve replacements. Histopathologic examination confirmed the diagnosis of CPF in the left ventricle and aortic valve, thrombus in the left atrium. PMID- 24753810 TI - Unique congenital malformation of the mitral valve associated with anomalous coronary arteries and stroke. AB - A 55-year-old male presented with stroke. Transesophageal echocardiogram and cardiac computed tomography revealed an unrecognized congenital malformation of the anterior mitral leaflet associated with anomalous left coronary circumflex artery, arising from the right coronary artery, diagnosed first by echocardiogram. This case represents a unique unforeseen mitral valve anomaly that might be considered as potential cardiac source of embolism. This finding broadens the spectrum of known mitral valve anomalies. PMID- 24753811 TI - Similar morphology, but different function: acute improvement of myocardial longitudinal strain after percutaneous transcatheter aortic valve implantation therapy in a severe aortic stenosis patient. PMID- 24753812 TI - Metabolism of very long-chain Fatty acids: genes and pathophysiology. AB - Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are called very long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipids but also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallel with the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis, macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFA metabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolic pathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology. PMID- 24753813 TI - Conformation and Linkage Studies of Specific Oligosaccharides Related to H1N1, H5N1, and Human Flu for Developing the Second Tamiflu. AB - The interaction between viral HA (hemagglutinin) and oligosaccharide of the host plays an important role in the infection and transmission of avian and human flu viruses. Until now, this interaction has been classified by sialyl(alpha2-3) or sialyl(alpha2-6) linkage specificity of oligosaccharide moieties for avian or human virus, respectively. In the case of H5N1 and newly mutated flu viruses, classification based on the linkage type does not correlate with human infection and human-to-human transmission of these viruses. It is newly suggested that flu infection and transmission to humans require high affinity binding to the extended conformation with long length sialyl(alpha2-6)galactose containing oligosaccharides. On the other hand, the avian flu virus requires folded conformation with sialyl(alpha2-3) or short length sialyl(alpha2-6) containing trisaccharides. This suggests a potential future direction for the development of new species-specific antiviral drugs to prevent and treat pandemic flu. PMID- 24753814 TI - The Inhibitory Effect of Apigenin on the Agonist-Induced Regulation of Vascular Contractility via Calcium Desensitization-Related Pathways. AB - Apigenin, a natural flavonoid found in a variety of vegetables and fruits, has been shown to possess many biological functions. The present study was undertaken to investigate the influence of apigenin on vascular smooth muscle contractility and to determine the mechanism involved. Denuded aortic rings from male rats were used and isometric contractions were recorded and combined with molecular experiments. Apigenin significantly relaxed fluoride-, thromboxane A2 mimetic- or phorbol ester-induced vascular contraction, which suggests that apigenin could be an anti-hypertensive that reduces agonist-induced vascular contraction regardless of endothelial nitric oxide synthesis. Furthermore, apigenin significantly inhibited fluoride-induced increases in pMYPT1 levels and phorbol ester-induced increases in pERK1/2 levels, which suggests the mechanism involving the inhibition of Rho-kinase and MEK activity and the subsequent phosphorylation of MYPT1 and ERK1/2. This study provides evidence regarding the mechanism underlying the relaxation effect of apigenin on agonist-induced vascular contraction regardless of endothelial function. PMID- 24753815 TI - Enhanced Anti-Cancer Effect of Snake Venom Activated NK Cells on Lung Cancer Cells by Inactivation of NF-kappaB. AB - In the present study, we investigated anti-cancer effect of snake venom activated NK cells (NK-92MI) in lung cancer cell lines. We used snake venom (4 MUg/ml) treated NK-92MI cells to co-culture with lung cancer cells. There was a further decrease in cancer cell growth up to 65% and 70% in A549 and NCI-H460 cell lines respectively, whereas 30-40% was decreased in cancer cell growth by snake venom or NK-92MI alone treatment. We further found that the expression of various apoptotic proteins such as that Bax, and cleaved caspase-3 as well as the expression of various death receptor proteins like DR3, DR4 and Fas was also further increased. Moreover, consistent with cancer cell growth inhibition, the DNA binding activity of NF-kappaB was also further inhibited after treatment of snake venom activated NK-92MI cells. Thus, the present data showed that activated NK cells could further inhibit lung cancer cell growth. PMID- 24753816 TI - Vesicular Stomatitis Virus G Glycoprotein and ATRA Enhanced Bystander Killing of Chemoresistant Leukemic Cells by Herpes Simplex Virus Thymidine Kinase/Ganciclovir. AB - Refractoriness of acute myeloid leukemia (AML) cells to chemotherapeutics represents a major clinical barrier. Suicide gene therapy for cancer has been attractive but with limited clinical efficacy. In this study, we investigated the potential application of herpes simplex virus thymidine kinase/ganciclovir (HSV TK/GCV) based system to inhibit chemoresistant AML cells. We first generated Ara C resistant K562 cells and doxorubicin-resistant THP-1 cells. We found that the HSV-TK/GCV anticancer system suppressed drug resistant leukemic cells in culture. Chemoresistant AML cell lines displayed similar sensitivity to HSV-TK/GCV. Moreover, HSV-TK/GCV killing of leukemic cells was augmented to a mild but significant extent by all-trans retinoic acid (ATRA) with concomitant upregulation of Connexin 43, a major component of gap junctions. Interestingly, HSV-TK/GCV killing was enhanced by expression of vesicular stomatitis virus G glycoprotein (VSV-G), a fusogenic membrane protein, which also increased leukemic cell fusion. Co-culture resistant cells expressing HSV-TK and cells stably transduced with VSV-G showed that expression of VSV-G could promote the bystander killing effect of HSV-TK/GCV. Furthermore, combination of HSV-TK/GCV with VSV-G plus ATRA produced more pronounced antileukemia effect. These results suggest that the HSV-TK/GCV system in combination with fusogenic membrane proteins and/or ATRA could provide a strategy to mitigate the chemoresistance of AML. PMID- 24753817 TI - 12-O-Tetradecanoylphorbol-13-Acetate Induces Keratin 8 Phosphorylation and Reorganization via Expression of Transglutaminase-2. AB - The stiffness of cancer cells is attributable to intermediate filaments such as keratin. Perinuclear reorganization via phosphorylation of specific serine residue in keratin is implicated in the deformability of metastatic cancer cells including the human pancreatic carcinoma cell line (PANC-1). 12-O Tetradecanoylphorbol-13-acetate (TPA) is a potent tumor promoter and protein kinase C (PKC) activator. However, its effects on phosphorylation and reorganization of keratin 8 (K8) are not well known. Therefore, we examined the underlying mechanism and effect of TPA on K8 phosphorylation and reorganization. TPA induced phosphorylation and reorganization of K8 and transglutaminase-2 (Tgase-2) expression in a time- and dose-dependent manner in PANC-1 cells. These effects peaked after 45 min and 100 nM of TPA treatment. We next investigated, using cystamine (CTM), Tgase inhibitor, and Tgase-2 gene silencing, Tgase-2's possible involvement in TPA-induced K8 phosphorylation and reorganization. We found that Tgase-2 gene silencing inhibited K8 phosphorylation and reorganization in PANC-1 cells. Tgase-2 gene silencing, we additionally discovered, suppressed TPA-induced migration of PANC-1 cells and Tgase-2 overexpression induced migration of PANC-1 cells. Overall, these results suggested that TPA induced K8 phosphorylation and reorganization via Tgase-2 expression in PANC-1 cells. PMID- 24753818 TI - Action and Signaling of Lysophosphatidylethanolamine in MDA-MB-231 Breast Cancer Cells. AB - Previously, we reported that lysophosphatidylethanolamine (LPE), a lyso-type metabolite of phosphatidylethanolamine, can increase intracellular Ca(2+) ([Ca(2+)]i) via type 1 lysophosphatidic acid (LPA) receptor (LPA1) and CD97, an adhesion G-protein-coupled receptor (GPCR), in MDA-MB-231 breast cancer cells. Furthermore, LPE signaling was suggested as like LPA1/CD97-Gi/o proteins phospholipase C-IP3-Ca(2+) increase in these cells. In the present study, we further investigated actions of LPE not only in the [Ca(2+)]i increasing effect but also in cell proliferation and migration in MDA-MB-231 breast cancer cells. We utilized chemically different LPEs and a specific inhibitor of LPA1, AM-095 in comparison with responses in SK-OV3 ovarian cancer cells. It was found that LPE induced Ca(2+) response in MDA-MB-231 cells was evoked in a different manner to that in SK-OV3 cells in terms of structural requirements. AM-095 inhibited LPE induced Ca(2+) response and cell proliferation in MDA-MB-231 cells, but not in SK OV3 cells, supporting LPA1 involvement only in MDA-MB-231 cells. LPA had significant effects on cell proliferation and migration in MDA-MB-231 cells, whereas LPE had less or no significant effect. However, LPE modulations of MAPKs (ERK1/2, JNK and p38 MAPK) was not different to those by LPA in the cells. These data support the involvement of LPA1 in LPE-induced Ca(2+) response and cell proliferation in breast MDA-MB-231 cells but unknown GPCRs (not LPA1) in LPE induced responses in SK-OV3 cells. Furthermore, although LPE and LPA utilized LPA1, LPA utilized more signaling cascades than LPE, resulting in stronger responses by LPA in proliferation and migration than LPE in MDA-MB-231 cells. PMID- 24753820 TI - Analysis of disease progression-associated gene expression profile in fibrillin-1 mutant mice: new insight into molecular pathogenesis of marfan syndrome. AB - Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder caused by mutations in the gene encoding fibrillin-1 (FBN1) and is characterized by aortic dilatation and dissection, which is the primary cause of death in untreated MFS patients. However, disease progression-associated changes in gene expression in the aortic lesions of MFS patients remained unknown. Using a mouse model of MFS, FBN1 hypomorphic mouse (mgR/mgR), we characterized the aortic gene expression profiles during the progression of the MFS. Homozygous mgR mice exhibited MFS-like phenotypic features, such as fragmentation of elastic fibers throughout the vessel wall and were graded into mgR1-4 based on the pathological severity in aortic walls. Comparative gene expression profiling of WT and four mgR mice using microarrays revealed that the changes in the transcriptome were a direct reflection of the severity of aortic pathological features. Gene ontology analysis showed that genes related to oxidation/reduction, myofibril assembly, cytoskeleton organization, and cell adhesion were differentially expressed in the mgR mice. Further analysis of differentially expressed genes identified several candidate genes whose known roles were suggestive of their involvement in the progressive destruction of aorta during MFS. This study is the first genome-wide analysis of the aortic gene expression profiles associated with the progression of MFS. Our findings provide valuable information regarding the molecular pathogenesis during MFS progression and contribute to the development of new biomarkers as well as improved therapeutic strategies. PMID- 24753819 TI - The Polyphenol Chlorogenic Acid Attenuates UVB-mediated Oxidative Stress in Human HaCaT Keratinocytes. AB - We investigated the protective effects of chlorogenic acid (CGA), a polyphenol compound, on oxidative damage induced by UVB exposure on human HaCaT cells. In a cell-free system, CGA scavenged 1,1-diphenyl-2-picrylhydrazyl radicals, superoxide anions, hydroxyl radicals, and intracellular reactive oxygen species (ROS) generated by hydrogen peroxide and ultraviolet B (UVB). Furthermore, CGA absorbed electromagnetic radiation in the UVB range (280-320 nm). UVB exposure resulted in damage to cellular DNA, as demonstrated in a comet assay; pre treatment of cells with CGA prior to UVB irradiation prevented DNA damage and increased cell viability. Furthermore, CGA pre-treatment prevented or ameliorated apoptosis-related changes in UVB-exposed cells, including the formation of apoptotic bodies, disruption of mitochondrial membrane potential, and alterations in the levels of the apoptosis-related proteins Bcl-2, Bax, and caspase-3. Our findings suggest that CGA protects cells from oxidative stress induced by UVB radiation. PMID- 24753821 TI - Protective Effects of Diallyl Sulfide against Thioacetamide-Induced Toxicity: A Possible Role of Cytochrome P450 2E1. AB - Effects of diallyl sulfide (DAS) on thioacetamide-induced hepatotoxicity and immunotoxicity were investigated. When male Sprague-Dawley rats were treated orally with 100, 200 and 400 mg/kg of DAS in corn oil for three consecutive days, the activity of cytochrome P450 (CYP) 2E1-selective p-nitrophenol hydroxylase was dose-dependently suppressed. In addition, the activities of CYP 2B-selective benzyloxyresorufin O-debenzylase and pentoxyresorufin O-depentylase were significantly induced by the treatment with DAS. Western immunoblotting analyses also indicated the suppression of CYP 2E1 protein and/or the induction of CYP 2B protein by DAS. To investigate a possible role of metabolic activation by CYP enzymes in thioacetamide-induced hepatotoxicity, rats were pre-treated with 400 mg/kg of DAS for 3 days, followed by a single intraperitoneal treatment with 100 and 200 mg/kg of thioacetamide in saline for 24 hr. The activities of serum alanine aminotransferase and aspartate aminotransferase significantly elevated by thioacetamide were protected in DAS-pretreated animals. Likewise, the suppressed antibody response to sheep erythrocytes by thioacetamide was protected by DAS pretreatment in female BALB/c mice. Taken together, our present results indicated that thioacetamide might be activated to its toxic metabolite(s) by CYP 2E1, not by CYP 2B, in rats and mice. PMID- 24753822 TI - A Comparison of the In Vitro Inhibitory Effects of Thelephoric Acid and SKF-525A on Human Cytochrome P450 Activity. AB - Thelephoric acid is an antioxidant produced by the hydrolysis of polyozellin, which is isolated from Polyozellus multiplex. In the present study, the inhibitory effects of polyozellin and thelephoric acid on 9 cytochrome P450 (CYP) family members (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4) were examined in pooled human liver microsomes (HLMs) using a cocktail probe assay. Polyozellin exhibited weak inhibitory effects on the activities of all 9 CYPs examined, whereas thelephoric acid exhibited dose- and time-dependent inhibition of all 9 CYP isoforms (IC50 values, 3.2-33.7 MUM). Dixon plots of CYP inhibition indicated that thelephoric acid was a competitive inhibitor of CYP1A2 and CYP3A4. In contrast, thelephoric acid was a noncompetitive inhibitor of CYP2D6. Our findings indicate that thelephoric acid may be a novel, non-specific CYP inhibitor, suggesting that it could replace SKF 525A in inhibitory studies designed to investigate the effects of CYP enzymes on the metabolism of given compounds. PMID- 24753823 TI - A novel in situ gel formulation of ranitidine for oral sustained delivery. AB - The main purpose of this study was to develop a novel, in situ gel system for sustained delivery of ranitidine hydrochloride. Ranitidine in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of preparation, viscosity and in vitro release. The viscosity of the gellan gum formulations in solution increased with increasing concentrations of gellan gum. In vitro study showed that the release of ranitidine from these gels was characterized by an initial phase of high release (burst effect) and translated to the second phase of moderate release. Single photon emission computing tomography technique was used to evaluate the stomach residence time of gel containing (99m)Tc tracer. The animal experiment suggested in situ gel had feasibility of forming gels in stomach and sustained the ranitidine release from the gels over the period of at least 8 h. In conclusion, the in situ gel system is a promising approach for the oral delivery of ranitidine for the therapeutic effects improvement. PMID- 24753824 TI - Main complications of mild induced hypothermia after cardiac arrest: a review article. AB - The aim of the present study is to assess the complications of mild induced hypothermia (MIH) in patients with cardiac arrest. Presently, based on the guidelines of the American heart Association, MIH following successful cardiopulmonary resuscitation (CPR) in unconscious adult patients due to ventricular fibrillation (VF) with out-of-hospital cardiac arrest (OOHCA) is essential and required. However, MIH could be associated with complications in Patients with cardiac arrest. Studies conducted on the precautions and care following cardiac arrest and MIH were included. Valid scientific data bases were used for data collection. The obtained results from different studies revealed that mild MIH could be associated with numerous complications and the knowledge and awareness of the medical staff from the complications is required to guarantee successful therapeutic approaches in MIH following cardiac arrest which is a novel medical facility with different styles and complications. Overall, further future studies are required to improve the quality of MIH, to increase survival and to decrease complications rates. PMID- 24753825 TI - Electrocardiographic P-wave Indices as a Useful Tool to Predict Successful Percutaneous Balloon Mitral Valvotomy in Patients with Mitral Stenosis. AB - Introduction : Patients with hemodynamically significant mitral stenosis (MS) have prolonged P-wave duration and increased P-wave dispersion (PWD) that decrease after successful percutaneous balloon mitral valvotomy (PBMV). The purpose of this study was to investigate if the changes in these indices may predict a successful procedure. Methods : Fifty two patients with MS in sinus rhythm underwent PBMV (90.4% female; mean age 38+/-10 years). Mitral valve area (MVA), valve score, mean diastolic mitral gradient (mMVG), mitral regurgitation severity, and systolic pulmonary artery pressure (sPAP) were evaluated by echocardiography before PBMV and repeated after one month. P-wave duration (Pmax /Pmin) and PWD were measured before and immediately after PBMV, at discharge, and at the end of the first month after discharge. Results : Among all procedures, 38 (73.1%) were defined as successful. Mean age, valve score, mMVG, and MVA before PBMV were similar for both groups. MVA was significantly greater in the successful PBMV group (1.65+/-0.27 vs. 1.41+/-0.22; P= 0.003). sPAP was reduced after PBMV in all patients and there were no significant differences in the mean sPAP before and after PBMV in both successful and unsuccessful groups. Pmax and PWD were significantly decreased immediately after the procedure (P= 0.035), the next day (P= 0.005) and at one month (P= 0.002) only in patients with successful PBMV. Pmin did not change significantly in either group. Conclusion : Only is successful PBMV associated with a decrease in Pmax and PWD. These simple electrocardiographic indices may predict the success of the procedure immediately after PBMV. PMID- 24753826 TI - Predisposing factors to premature coronary artery disease in young (age <= 45 years) smokers: a single center retrospective case control study from India. AB - INTRODUCTION: The role of the conventional risk factors in premature coronary artery disease (CAD) after eliminating the confounding variability of smoking has not been evaluated. This study was conducted to identify role of traditional risk factors in smokers with premature CAD. METHODS: The case records of patients presenting acutely with premature CAD during the period 2007-2010 were analyzed retrospectively. Age, sex and smoking matched controls were selected from same time period. Data records were obtained for family history, alcohol, waist size, blood pressure, hypertension, blood sugar, lipid profile and presence of cutaneous markers for both groups and analyzed using statistical software. RESULTS: 234 smokers with CAD and 122 smokers without CAD were included in groups 1 and 2, respectively. The patients in group 1 had significantly increased prevalence of hypertension, diabetes mellitus, metabolic syndrome, dyslipidemia and central obesity. There was no difference in prevalence of family history of CAD, arcus juvenilis and baldness. We found statistically significant association of hypertension, DM and metabolic syndrome in young smokers with premature acute CAD in Indian population as compared to young smokers without CAD. CONCLUSION: In young smokers, presence of hypertension, central obesity, diabetes mellitus and metabolic syndrome identifies a subset at increased risk for future acute CAD requiring more rigorous follow up and treatment. PMID- 24753827 TI - Electrocardiographic changes in mitral valve prolapse syndrome. AB - INTRODUCTION: Mitral valve prolapse syndrome (MVP) is the most common valvular abnormalityin the young and is correlated with increased frequency of cardiac dysrhythmias and sudden death.The aim of this study was to compare frequency of "early repolarization" in electrocardiogram(ECG) between MVP patients and healthy adults. METHODS: In this cross-sectional study, we compared ECG presentations of early repolarizationincluding notch in descending arm of QRS and J-point and/or ST segment changes in 100 patientswith MVP with 100 healthy individuals. MVP patients were referred to cardiology clinic withsymptoms of palpitation, chest pain or anxiety. RESULTS: The mean age in patients with MVP was significantly less than healthy subjects (29.5 +/-9.3 years versus 31.0 +/- 6.9 years in control group, P= 0.1967). We detected early repolarizationas a prevalent sign in ECG of patients which was a notch in descending arm of QRS and/or STsegment or J point elevation seen in 74% of patients ( 51% in inferior leads and 23% in I and aVLleads) , whilst the same findings were seen in 8 men (8%) in control group (P= 0.0001). CONCLUSION: Early repolarization in ECG presented as a notch in descending arm of QRS and/or ST segment or J-point elevation is more frequent in in young patients with MVP syndrome. PMID- 24753828 TI - Laryngeal ultrasonography versus cuff leak test in predicting postextubation stridor. AB - INTRODUCTION: Although cuff leak test has been proposed as a simple method of predicting the occurrence of postextubation stridor, cut-off point of cuff-leak volume substantially differs between previous studies. In addition, laryngeal ultrasonography including measurement of air column width could predict postextubation stridor. The aim of the present study was to evaluate the value of laryngeal ultrasonography versus cuff leak test in predicting postextubation stridor. METHODS: In a prospective study, all patients intubated for a minimum of 24 h for acute respiratory failure, airway protection and other causes were included. Patients were evaluated for postextubation stridor and need for reintubation after extubation. The cuff leak volume was defined as a difference between expiratory tidal volumes with the cuff inflated and deflated. Laryngeal air column width was defined as the width of air passed through the vocal cords as determined by laryngeal ultrasonography. The air-column width difference was the width difference between balloon-cuff inflation and deflation. RESULTS: Forty one intubated patients with the mean age of 57.16+/-20.07 years were included. Postextubation stridor was observed in 4 patients (9.75%). Cuff leak test (cut off point: 249 mL) showed sensitivity and specificity of 75% and 59%, respectively. In addition, laryngeal ultrasonography (cut off point for air column width: 10.95 mm) resulted in sensitivity and specificity of 50% and 54%, respectively. Positive predictive value of both methods were <20%. CONCLUSION: Both cuff leak test and laryngeal ultrasonography have low positive predictive value and sensitivity in predicting postextubation stridor and should be used with caution in this regard. PMID- 24753829 TI - Cost-effectiveness of cardiac biomarkers as screening test in acute chest pain. AB - INTRODUCTION: Acute chest pain is an important and frequently occurring symptom in patients. Chest pain is often a sign of ischemic heart disease. Associated findings of electrocardiograph (ECG) are rather heterogeneous, and traditional cardiac biomarkers such as Creatine Kinase-MB (CK-MB) suffer from low cardiac specificity and sensitivity. In this study cost effectiveness of cardiac biomarkers single quantitative measurement was examined. METHODS: The present descriptive-analytic study conducted on patients who were asked for troponin I and CK-MB. All patients who referred to Emergency unit of Tabriz Imam Reza educational-medical center during January 2012 to July the 2013 were included in study. All patients included in the study were documented in terms of age, sex, working shift of referring, main complaint of patient, symptoms in referring, ECG findings, and results of troponin I and CK-MB tests. RESULTS: In this study, 2900 patients were studied including 1440 (49.7%) males and 1460 (50.3%) females. Mean age of patients was 62.91 (SD=14.36). Of all patients 1880 (64.8%) of patients referred during 8 a.m. to 8 p.m. and 1020 (35.2%) patients were referred during 8 p.m. to 8 a.m. The sensitivity of cardiac biomarkers' test in diagnosing Acute Coronary Syndrome (ACS) disease was calculated as 44.8% and its specificity was 86.6%. For diagnosing Acute Myocardial Infarction (AMI), sensitivity of cardiac biomarkers' test was 72.2% and its specificity was 86%. None of patients who were finally underwent unstable angina diagnosis showed increase in cardiac enzymes. CONCLUSION: In conclusion, cardiac biomarkers can be used for screening acute chest pains, also cost effectiveness of cardiac biomarkers, appropriate specificity and sensitivity can guarantee their usefulness in emergency room. PMID- 24753830 TI - The predictive Value of Total Neutrophil Count and Neutrophil/Lymphocyte Ratio in Predicting In-hospital Mortality and Complications after STEMI. AB - INTRODUCTION: Leukocytosis, predominantly neutrophilia, has previously been described following ST elevation myocardial infarction (STEMI). The exact contribution of this phenomenon to the clinical outcome of STEMI is yet to be shown. We examined cellular inflammatory response to STEMI in the blood and its association with in-hospital mortality and/or adverse clinical events. METHODS: In this cross-sectional study, 404 patients who were admitted with the diagnosis of acute STEMI at Madani Heart Hospital from March 2010 to March 2012 were studied. The complete blood cell count (CBC) was obtained from all patientswithin12-24 hours of the onset of symptoms. Total leukocytes were counted and differential count was obtained for neutrophils, lymphocytes and neutrophil/lymphocyte ratio (NLR) were evaluated. Association of cellular response with the incidence of post-MI mortality/complications was assessed by multiple logistic regression analyses. RESULTS: In-hospital mortality and post STEMI complication rate were 3.7% and 43.6%, respectively. Higher age (P=0.04), female gender (0.002), lower ejection fraction (P<0.001) and absolute neutrophil count (P=0.04) were predictors of mortality. Pump failure in the form of acute pulmonary edema or cardiogenic shock occurred in 35 (8.9%) of patients. Higher leukocyte (P<0.03) and neutrophil counts (P<0.03) and higher NLR (P=0.01) were predictors of failure. The frequency of ventricular tachyarrhythmias (VT/VF) at the first day was associated with higher neutrophil count (P<0.001) and higher NLR level (P<0.001). In multivariate analysis neutrophil count was an independent predictor of mortality (OR=2.94; 1.1-8.4, P=0.04), and neutrophil count [OR=1.1, CI (1.01-1.20), P=0.02], female gender [OR=2.34, CI (1.02-4.88), P=0.04] and diabetes [OR=2.52, CI (1.21-5.2), P=0.003] were independent predictors of heart failure. CONCLUSION: A single CBC analysis may help to identify STEMI patients at risk for mortality and heart failure, and total neutrophil count is the most valuable in predicting both. PMID- 24753831 TI - Percutaneous dilatational tracheostomy and surgically created thracheostomy in ICU patients. AB - INTRODUCTION: Following advances of Intensive Care medicine and widespread administration of mechanical ventilation, tracheostomy has become one of the indispensable surgical procedures. During this research we tried to assess and compare two main strategies for doing tracheostomy: Surgically Created Tracheostomy (SCT) and Percutaneous Dilatational Tracheostomy (PDT). METHODS: In a randomized clinical trial, 60 cases of patients who were admitted in Intensive Care Unit (ICU) and needed tracheostomy during their stay were enrolled. Patients were randomly divided into two groups. SCT technique was considered for the first group and PDT for the second one. Demographic characteristics, associated and underlying diseases, type and duration of procedure, duration of receiving mechanical ventilation and ICU stay, expenses and complications of tracheostomy including bleeding, subcutaneous emphysema, pneumothorax, stomal infection and airway loss were all recorded during study and compared between both groups. RESULTS: There were significant differences between two groups of patients in terms of duration of receiving mechanical ventilation (P=0.04), duration of tracheostomy procedure (P=0.001) and procedure expenses (P=0.04). There was no significant difference between two groups in terms of age and gender of patients, duration of ICU stay and complications of tracheostomy including copious bleeding, stomal infection, subcutaneous emphysema and airway. CONCLUSION: According to the results of our study and similar researches, it can be concluded that PDT can be considered as the preferred procedure in cautiously selected patients during their ICU stay. PMID- 24753832 TI - Vocal cord paralysis and its etiologies: a prospective study. AB - INTRODUCTION: Vocal cord paralysis is a common symptom of numerous diseases and it may be due to neurogenic or mechanical fixation of the cords. Paralysis of the vocal cords is just a symptom of underlying disease in some cases; so, clinical diagnosis of the underlying cause leading to paralysis of the vocal cords is important. This study evaluates the causes of vocal cord paralysis. METHODS: In a prospective study, 45 patients with paralyzed vocal cord diagnosis were examined by tests such as examination of the pharynx, larynx, esophagus, thyroid, cervical, lung, and mediastinum, brain and heart by diagnostic imaging to investigate the cause vocal cord paralysis. The study was ended by diagnosing the reason of vocal cord paralysis at each stage of the examination and the clinical studies. RESULTS: The mean duration of symptoms was 18.95+/-6.50 months. The reason for referral was phonation changes (97.8%) and aspiration (37.8%) in the subjects. There was bilateral paralysis in 6.82%, left paralysis in 56.82% and right in 63.36% of subjects. The type of vocal cord placement was midline in 52.8%, paramedian in 44.4% and lateral in 2.8% of the subjects. The causes of vocal cords paralysis were idiopathic paralysis (31.11%), tumors (31.11%), surgery (28.89%), trauma, brain problems, systemic disease and other causes (2.2%). CONCLUSION: An integrated diagnostic and treatment program is necessary for patients with vocal cord paralysis. Possibility of malignancy should be excluded before marking idiopathic reason to vocal cord paralysis. PMID- 24753833 TI - Non-modifiable Factors of Coronary Artery Stenosis in Late Onset Patients with Coronary Artery Disease in Southern Iranian Population. AB - INTRODUCTION: Coronary Artery disease (CAD) is influenced by genetic factors, environment and culture behavior. The aim of the present study was to evaluate some non-modifiable risk factors of coronary heart disease such as sex, age, family history and consanguineous marriage. METHODS: This is a case-control study. The study population consisted of 200 fifteen or more years old. Data were collected on 200 patients with positive angiography and 200 control subjects with negative angiography. Positive angiography was defined as coronary diameter cut greater than 50%. Statistical analysis was conducted using SPSS 11.5. In this study, data were collected through a checklist. Logistic regression and stratification were used to determine the impact of age, gender, family history, and consanguinity on the risk of stenosis. RESULTS: The percentage of men in patients and controls were 89% and 29%, respectively. As to gender, a significant association was found between patients and controls of CAD (CI 95%, 4.014-10.052, OR 6.352). Gender was determined as a risk factor for CAD. Family history of myocardial infarction did not show a significant effect on the artery stenosis. As to consanguinity of the parents, there was no significant association between patients and controls of CAD (P> 0.05). CONCLUSION: These researches show that ageing increases the risk of coronary heart stenosis; also, females are more than men protected against this disease. The impact of family history of myocardial infarction and consanguineous marriage were not associated with of CAD. PMID- 24753834 TI - Evaluation of sternal closure with absorbable polydioxanone sutures in children. AB - INTRODUCTION: Sternal dehiscence, sternal wound infection and mediastinitis are troublesome complications following median sternotomy which are major causes of morbidity and mortality of patients. Synthetic polydioxanone absorbable suture seems effective in prevention of these complications in children undergoing open heart surgery. METHODS: During 2 years period, 620 patients who underwent median sternotomy were studied. The efficacy of absorbable polydioxanone suture was tested on patients using figure-of-eight suture technique. The patients' age ranged from newborn to 15 years old. All surgical interventions were performed according to a standard protocol. RESULTS: No sternal sutures were broken during the sternal closure and no case of mediastinitis was seen. Two patients experienced sternal dehiscence (0.32%). Follow-up period of patients were established between 1 to 132 months after open heart surgery. CONCLUSION: Sternal closure with the polydioxanone suture in combination with figure-of-eight technique is a safe and suitable method in children with good clinical results. PMID- 24753835 TI - Rheumatic aortic regurgitation in a patient with large congenital fenestrations in all three leaflets. AB - Fenestrations of the aortic valve rarely produce significant valvular regurgitation. These are typically described as incidental findings with little clinical significance because they generally lie above their closing edges. Rarely however, when unusually large or multiple, they can lead to massive aortic regurgitation (AR), mostly in patients with chronic hypertension and/or aortic annular dilation. We operated a 52 year old normotensive male with chronic rheumatic AR and found large fenestrations in all three aortic cusps, hardly ever reported in rheumatic valvular involvement in the literature. PMID- 24753836 TI - Misdiagnosis of bland-white-garland syndrome: report of two cases with different presentations. AB - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) or Bland-White-Garland syndrome is usually an isolated cardiac anomaly but, in rare incidences, has been described with patent ductus arteriosus, ventricular septal defect, and tetralogy of Fallot. This syndrome may cause sudden death in infants and young people but in this case report we present two different types of presentation. First case was a 3 year old girl diagnosed with dilated cardiomyopathy since her infancy. Her electrocardiography showed prominent Q wave in lateral leads. Dilated right coronary artery was revealed by echocardiography. The second case was a girl with prolapsed mitral valve and chest pain but similar to first case she had prominent Q wave in lateral leads at her electrocardiography and dilated right coronary artery but without heart failure. ALCAPA in children may present with ambiguous presentations differing from dilated cardiomyopathy and full blown heart failure to an atypical chest pain attributed to prolapsed mitral valve. PMID- 24753837 TI - High Creatine Kinase (CK)-MB and Lactate Dehydrogenase in the Absence of Myocardial Injury or Infarction: A Case Report. AB - Acute myocardial infarction (AMI) is a life threatening condition that needs emergency diagnosis and early treatment in the emergency room. Rapid laboratory testing for creatine kinase (CK)-MB greatly revolutionized the diagnosis and management of acute myocardial infarction. We report a case with chest pain that referred to the emergency department (ED). Laboratory data showed high serum levels of creatine kinase and lactate dehydrogenase. With diagnosis of acute myocardial infarction, he was hospitalized and angiography was performed which showed three vessels disease; the patient was referred to surgical ward for coronary artery bypass graft. Surgery was performed after one week; during the operation there was no sign of infarction over the heart. Our observation suggests that false positive laboratory result may be due to other condition which must be evaluated. PMID- 24753841 TI - Editorial. PMID- 24753838 TI - Social networking in health system for knowledge translation. PMID- 24753842 TI - "One-Stop" fertility assessment using advanced ultrasound technology. PMID- 24753843 TI - Trisomy 13, 18, 21, Triploidy and Turner syndrome: the 5T's. Look at the hands. AB - First trimester spontaneous abortions occur in 15 to 20% of all clinically recognized pregnancies. Chromosomal -anomalies are responsible for more than 50% of spontaneous abortions. The majority (90%) of these chromosomal anomalies are numerical, particularly autosomal trisomies (involving chromosomes 13,16, 18, 21, 22), polyploidy and monosomy X. At birth chromosomal anomalies are still an important cause of congenital malformations occurring in 0,55% of newborns (autosomal: 0,40%, sex chromosomal: 0,15%). Autosomal trisomies result from maternal -meiotic nondisjunction of gametogenesis and the risk increases with maternal age. Polyploidy (triploidy (3n = 69) or tetraploidy (4n = 92)), results from a contribution of one or more extra haploid chromosome sets at fertilization. Unlike the risk for autosomal trisomies, the risk for polyploidies and for monosomy X (Turner syndrome) does not increase with maternal age. In the prenatal period the ultrasonographic diagnosis of some autosomal trisomies such as trisomy 13 and 18 is feasible based on the frequently seen major malformations while the diagnosis of trisomy 21 often remains challenging due to the absence of major malformations in > 50% of cases. For Turner syndrome (monosomy X), the lethal form will present with cystic hygroma colli and hydrops but the non lethal form is difficult to recognize by -ultrasound in the second trimester. The 5 frequently encountered chromosomal anomalies (Trisomy 13, 18, 21, Turner syndrome and Triploidy) referred here as the 5T's have specific hand features which will be discussed. PMID- 24753845 TI - A tribute to Robert Edwards and Howard Jones Jr. AB - "2010 was a fascinating year. Robert Edwards finally received the Nobel prize for Medicine and his friend in the United States, Howard W. Jones Jr. was honored in Denver by the American Society of Reproductive -Medicine (ASRM) upon his Centennial Birthday. He turned 100 on December 30(th)" PMID- 24753844 TI - The fetal respiratory system as target for antenatal therapy. AB - The widespread use of prenatal ultrasound has made the fetus a patient. A number of conditions diagnosed as such may require therapy prior to birth. Herein we describe past, current and potential future procedures designed to treat pulmonary conditions in the antenatal period. When congenital cystic adenomatoid malformation (CCAM) is -associated with fetal hydrops, treatment is required. Prior to viability this may be in utero resection of the pathologic lung lobe or shunting of cystic lesions. More recently, fetuses with isolated congenital diaphragmatic hernia (CDH) with lethal lung hypoplasia have been offered percutaneous fetal tracheal occlusion to provoke lung growth. A very rare condition is laryngeal atresia, which requires peripartum re-establishment of the airways. As we get more -experience with access to the fetal airways, this may open the doors for novel therapies. One of these is gene delivery to treat fetuses with serious monogenic disorders or to induce transient overexpression of certain proteins. We review the individual hurdles that are being met by researchers when designing fetal gene therapeutic strategies, in particular for the fetal lung. Also the use of stem cells for pulmonary disorders is currently explored. PMID- 24753846 TI - Spermatogonial stem cells: What does the future hold? AB - Spermatogonial stem cells (SSCs) are responsible for the preservation of spermatogenesis throughout a man's adult reproductive life. Like other stem cells in the body, SSCs can either self-renew or differentiate. Recent research has shown that SSCs can be considered as multipotent stem cells which can differentiate into cell types other than exclusively gametes. SSC proliferation is a well regulated mechanism and is mainly orchestrated by the Sertoli cells. In the future, SSCs may offer clinically relevant options for preservation and re establishment of the reproductive potential in patients suffering from spermatogonial stem cell loss, i.e. after gonadotoxic treatments for cancer or haematological diseases. However, one day, differentiation in-vitro of SSCs may also become an important strategy in other fields of -regenerative medicine. PMID- 24753847 TI - OHSS Free Clinic. AB - If ovarian stimulation is performed accordingly to new strategies available, the occurrence of ovarian hyperstimulation syndrome will be eradicated. The strategy is to stimulate all women with GnRH antagonist and in case of need to -induce final egg maturation with GnRH agonist. PMID- 24753848 TI - European Working Time Directive: Implementation across -Europe and consequences upon training in obstetrics and -gynaecology. AB - OBJECTIVE: To review the compliance of the European Working Time Directive (EWTD) in different teaching hospitals across Europe and its consequences upon training. STUDY DESIGN: It is an observational, descriptive, cross-sectional study. The sample is constituted by the answers from trainees selected by the representatives of 29 European Network of Trainees in Ob/Gyn (ENTOG) member countries to a survey designed by ENTOG Executive. The survey content was based on a joint survey by the Royal College of Obstetricians and Gynaecologists (RCOG) and the Royal College for Paediatrics (RCP), carried out in 2008, but adapted for use on a European level. RESULTS: An answer rate of 75% was obtained. Only 5 countries out of 29 were compliant with EWTD two months before the compulsory adherence. Countries needed to introduce 1 to 4 changes to the system to make the rotas -compliant. Positive effect on work and private life balance was noticed in 87% from all responses. Trainees notice the need to further improve training programmes in order to have the same quality of training and continuous care of patients. CONCLUSIONS: Steps forward to implement EWTD are being made. Trainees should be involved with the introduction to optimize training conditions under the EWTD. Countries that still struggle to introduce the directive may learn from countries that already are compliant. It is suggested to organize a survey on senior society level to gain additional information to further investigate the effects on training quality and patient care. PMID- 24753849 TI - Negotiating boundaries: Accessing donor gametes in India. AB - BACKGROUND: This paper documents how couples and providers access donor materials for conception in the Indian context and perceptions about using them. The objective is to facilitate understanding of critical issues and relevant concerns. METHODS: A postal survey was conducted with a sample of 6000 gynaecologists and in-depth interviews were -conducted with 39 gynaecologists in four cities. RESULTS: Donor gametes are relatively more acceptable than a few years ago, especially if confidentiality can be -maintained, though lack of availability of donor materials is sometimes an impediment to infertility treatment. Donor sperms are usually accessed from in-house or commercial sperm banks, pathology laboratories, IVF centres, -professional donors, relatives or friends. There is scepticism about screening procedures of sperm banks. Donor eggs are usually accessed from voluntary donors, friends, relatives, egg sharing programmes, donation from other patients, advertising and commercial donors. There are several concerns regarding informed consent for using donated gametes, using -relatives and friends gametes, the unregulated use of gametes and embryos, record keeping and documentation, -unethical and corrupt practices and commercialisation. CONCLUSION: These issues need to be addressed by patients, providers and regulatory authorities by providing -information, counselling, ensuring informed consent, addressing exploitation and commercialisation, ensuring -monitoring, proper documentation and transparency. PMID- 24753851 TI - An old men's dream. PMID- 24753850 TI - Editorial: a sentimental journey. PMID- 24753852 TI - De doelen declaration april 8, 2011. PMID- 24753853 TI - Clinical, epidemiological and socio-cultural aspects of -infertility in resource poor settings. Evidence from Rwanda. AB - Infertility is a serious but entirely neglected public health problem in resource poor countries. Most of the infertility is caused by infections and therefore potentially preventable. The problem of infertility in Rwanda has not been researched so far. We examined predictors for infertility and treatment-seeking behaviour in an unmatched case-control. We performed infertility investigations in all infertile couples and discussed consequences of infertility in focus group discussions. HSV-2 and HIV infection and sexual violence were the most important determinants of infertility. We found a higher HIV prevalence among couples in secondary and not primary infertile relationships with at least one HIV infected partner in 45% of these couples. Men in infertile relationships reported more frequently concurrent partners over the last year than fertile men. We found a high prevalence of tubal factor (70%) and male factor infertility (64%). Pregnancy rates (16%) were low after conventional therapy. Both men and women are unlikely to attribute infertility to the male partner. Participants reported a wide array of treatments they received in the past, often including ineffective or even harmful interventions. We demonstrated severe suffering as a consequence of infertility for both men and women but with women carrying the largest burden, similar to what is reported in other resource-poor countries. Overall, we can conclude that there is an urgent need for a more holistic approach towards reproductive health services in SSA, one that recognises the -importance of reproductive failure. The link with HIV has important consequences for both HIV and reproductive health programs. PMID- 24753854 TI - Wilms' Tumour gene 1 (WT1) as an immunotherapeutic target. AB - High grade uterine sarcoma and recurrent endometrial carcinoma are aggressive cancers with limited treatment options, resulting in a poor prognosis. In this research we focused in the first place on the detection of a highly immunogenic tumour-associated antigen Wilms' tumour gene 1 (WT1) in uterine tumours. We were able to reveal its overexpression in the tumour cells of high grade sarcomas and carcinosarcomas . Moreover, patients with WT1 positive tumours had a significantly worse prognosis than patients who were WT1 negative. For carcinomas, WT1 was present in only a minority of tumour cells, but in the majority of intratumoural blood vessels. Small blood vessels in the normal tissue surrounding the carcinoma were also WT1 positive, suggesting a role for WT1 in angiogenesis. WT1 was hardly expressed or absent in the non-tumour or benign tumoural uterus (myoma, polyp). The next step was to develop a targeted treatment against WT1. We opted for dendritic cell (DC) based immunotherapy. Nevertheless a basal expression of WT1 in monocytes and in vitro cultured unloaded DC was observed, the electroporation of in vitro cultured DC with WT1-mRNA resulted in a higher expression of WT1 by the DC. WT1-mRNA loaded DC were used for in vivo stimulations of T cells, resulting in the rise of WT1-specific T cells and a transient molecular response (decrease of CA125) in an end stage endometrial carcinoma patient. No toxic side effects were reported. Future in vivo research, carried out in a phase I clinical trial in our center, will reveal the ability of this new therapy to induce an immunological and possible clinical response in WT1 positive uterine cancer patients. PMID- 24753855 TI - Poor responders in in vitro fertilization (IVF) therapy: the challenge continues. AB - Poor responders represent more than a third of women undergoing assisted reproduction. Typically they are patients with advanced maternal age and low ovarian reserve. However, there is a younger group that unexpectedly demonstrates impaired response to controlled ovarian hyperstimulation. The etiologies in many of these cases are still unclear. In our program, the determination of basal cycle day 3 serum FSH, LH and E2 levels, measurement of AMH, and the estimation of the basal antral follicular count by transvaginal ultrasonography, are the preferred screening tests for ovarian reserve in all IVF patients, and together with the woman's age, determine the ovarian stimulation regimen to be chosen for the cycle treatment. In spite of a -variety of protocols and adjuvant therapies of unproven benefit, these patients have compromised outcomes and continue to represent a challenge to reproductive endocrinologists. PMID- 24753856 TI - Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause. AB - Perimenopause, women's normal midlife reproductive transition, is highly symptomatic for about 20% of women who are currently inaccurately counseled and inappropriately treated with oral contraceptives, menopausal hormone therapy or hysterectomy. About 80% of perimenopausal women experience vasomotor symptoms (VMS), 25% have menorrhagia, and about 10% experience mastalgia. The majority of women describe varying intensities of sleep, -coping or mood difficulties. Women are more symptomatic because common knowledge inaccurately says that estradiol (E2) levels are dropping/deficient. Evidence shows that with disturbed brain ovary feedbacks, E2 levels average 26% higher and soar erratically - some women describe feeling pregnant! Also, ovulation and progesterone (P4) levels become insufficient or absent. The most symptomatic women have higher E2 and lower P4 levels. Because P4 and E2 complement/counterbalance each other's tissue effects, oral micronized P4 (OMP4 300 mg at -bedtime) is a physiological therapy for treatment-seeking, symptomatic perimenopausal women. Given cyclically (cycle d 14 27, or 14 on/off) in menstruating midlife women, OMP4 decreases cyclic VMS, improves sleep and premenstrual mastalgia. Menorrhagia is treated with ibuprofen 200mg/6h plus OMP4 cycle d 4-28. For insulin resistance, metformin plus cyclic or daily OMP4 decreases insulin resistance and weight gain. Non-responsive migraines need daily OMP4 plus usual therapies. VMS and insomnia in late perimenopause respond to daily OMP4. In summary, OMP4 is a physiology-based therapy that improves sleep, treats VMS, does not increase breast proliferation or cancer risk, increases bone formation and has beneficial cardiovascular effects. A controlled trial is testing OMP4 for perimenopausal VMS - more evidence-based data are needed. PMID- 24753857 TI - Correlates of Occurrence of Obstetric Fistula among Women in Selected States of India: An Analysis of DLHS-3 Data. AB - Obstetric fistula is the most devastating form of maternal morbidity. It is an opening in the wall of vagina connecting to bladder or to rectum due to prolonged obstructed labour without timely medical assistance. A few research studies carried out in India and recently conducted DLHS-3 survey (2007-08) has information on obstetric fistula that gives scope for further research. This paper examines prevalence of obstetric fistula and its correlates using DLHS-3 data for selected states in India. Ever experience of obstetric fistula among women in these states ranges from 0.3 percent to 3.4 percent, being highest in Uttarakhand. Women living in rural areas have higher chance of obstetric fistula. Age and physical maturity is important factor in the occurrence of fistula and it is found that those women who were below 18 years at the time of their first birth have higher risk of fistula in comparison to those who had child at 18 or above years. In addition to this, those having problems at the time of delivery are around two times more likely to have fistula. Auxulary Nurse Midwife can be key players in the early detection and referral of cephalo-pelvic disproportion, malpresentation and prolonged, obstructed labour cases. PMID- 24753858 TI - Unicornuate uterus and ectopic (undescended) ovary. PMID- 24753860 TI - Laparoscopic sacrocolpopexy. AB - Laparoscopy offers great exposure and surgical detail, reduces blood loss and the need for excessive abdominal packing-- and bowel manipulation making it an excellent modality to perform pelvic floor surgery. Laparoscopic repair of level I or apical vaginal prolapse may be challenging, due to the need for extensive dissection and advanced suturing skills. However, it offers the efficacy of open abdominal sacrocolpopexy, such as lower recurrence rates and less dyspareunia-- than sacrospinous fixation, as well as the reduced morbidity of a laparoscopic approach. PMID- 24753861 TI - The role of magnetic resonance imaging in the diagnostic work-up of fetal ventriculomegaly. AB - The indication for fetal magnetic resonance imaging (MRI) remains a subject of debate, partly because of questions concerning its diagnostic accuracy compared to ultrasound, partly because of practical factors such as accessibility, high costs and available expertise. Most studies advocate an added value for MRI in cases diagnosed with central nervous system pathology. MRI is a good modality to detect small foci of brain hemorrhage, to depict callosal anomalies, to add information about normal and pathological cortical development, and is a more sensitive imaging method to detect white matter pathology. This manuscript discusses the role of MRI as an adjunct to ultrasound for cases diagnosed-- with cerebral ventriculomegaly. PMID- 24753859 TI - Imaging the fetal central nervous system. AB - The low prevalence of fetal central nervous system anomalies results in a restricted level of exposure and limited experience-- for most of the obstetricians involved in prenatal ultrasound. Sonographic guidelines for screening the fetal brain in a systematic way will probably increase the detection rate and enhance a correct referral to a tertiary care center, offering the patient a multidisciplinary approach of the condition. This paper aims to elaborate on prenatal sonographic and magnetic resonance imaging (MRI) diagnosis and outcome of various central nervous system malformations. Detailed neurosonographic investigation has become available through high resolution vaginal ultrasound probes and the development of a variety of 3D ultrasound modalities e.g. ultrasound tomographic imaging. In addition, fetal MRI is particularly helpful in the detection of gyration and neurulation-- anomalies and disorders of the gray and white matter. PMID- 24753862 TI - Prenatal diagnosis of congenital renal and urinary tract malformations. AB - Congenital abnormalities of the kidneys and the urinary tract are the most common sonographically identified -malformations in the prenatal period. Obstructive uropathies account for the majority of cases. The aim of prenatal diagnosis and management is to detect those anomalies having impact on the prognosis of the affected child and -requiring early postnatal evaluation or treatment to minimize adverse outcomes. In this paper, we summarize the embryology of kidneys and urinary tract, the normal sonographic appearance through-out pregnancy and the prenatal diagnosis of their congenital malformations. PMID- 24753863 TI - Evaluation of fetal cerebral blood flow perfusion using power Doppler ultrasound angiography (3D-PDA) in growth-restricted fetuses. AB - OBJECTIVE: to explore the potential of 3D Power Doppler Angiography (3D PDA) to evaluate the cerebral circulation in normal and growth restricted fetuses (IUGR). STUDY DESIGN: in a pilot study, we enrolled 51 appropriate for gestational age (AGA) pregnancies and 17 singleton pregnancies presenting IUGR, all between 22 and 38 weeks of gestation. Using 3D power Doppler ultrasound, a -volume acquisition of the fetal brain was performed. Two regions of interest (ROI) were defined within the fetal brain. Zone 1 is anterior to the cavum septi pellucidi (CSP). Zone 2 is defined by a rectangle obtained tracing a contour -between the temporal bones as wide as the CSP, corresponding to the area of the middle cerebral artery. The Flow Index (FI), the Vascularization Index (VI), the Vascularization and Flow Index (VFI) were determined in both areas in both IUGR and AGA fetuses by a single operator. IUGR fetuses were divided into three groups: Group 1, with normal pulsatility index (PI) of umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV); Group 2, IUGR fetuses with abnormal UA PI, normal MCA PI, normal DV PI; in Group 3, IUGR fetuses with abnormal UA PI, MCA PI and DV PI. RESULTS: FI and VFI values of zone 1 were increased in Group 1.Values of VFI in zone 2 were increased in Group 2. CONCLUSIONS: Our findings are in line with recent studies in growth-restricted fetuses suggesting that the anterior -cerebral artery shows Doppler signs of vasodilatation before these are observed in the MCA, demonstrating the "frontal brain sparing effect". PMID- 24753864 TI - Postpartum breast cancer behaves differently. AB - BACKGROUND AND AIM: Previous studies suggest a worse prognosis for postpartum breast cancer (PPBC) diagnosed within the first 12 months following delivery. We investigated this hypothesis in our setting through a retrospective pilot study. METHODS: A retrospective multicentre paired case-control study of breast cancer patients diagnosed under age 45 from the UZ Leuven database or affiliated centres. We compared disease outcome of women with a PPBC and those without a pregnancy associated breast cancer (PABC). They were matched for the following prognostic markers: age at diagnosis, tumour type, characteristics and stage. Kaplan-Meier statistics were applied for overall and disease free survival. RESULTS: 53 PPBC cases were matched with 103 controls. All PPBC patients were diagnosed with an invasive ductal carcinoma. Axillary lymph nodes were involved in 56.6% of cases and 13% were primary metastasized at diagnosis. A third was triple-negative and another third was HER-2-positive.The 5-year overall survival was 60% and 84% respec-tively for PPBC cases and control group. 5-year disease free survival was respectively 53% and 68%. CONCLUSIONS: We confirm that postpartum breast cancer behaves more aggressively than the matched non-PABC group. Longer follow-up and extension of the study group are necessary to confirm these findings. PMID- 24753865 TI - Clinicopathologic study in uterine cancer. AB - Patients with primary advanced or recurrent endometrial cancer are relatively uncommon and deserve better treatment options. Current treatment options are surgery, radiotherapy, and systemic therapy. Since the outcome is still poor, there is a need to improve our knowledge on molecular markers in order to personalize treatment. In addition, we need to continue the search for new treatment strategies with a better balance between efficacy and toxicity. In this doctoral thesis, we documented that among molecular and histological markers, blood vessel space involvement and chemotherapy induced regressive changes are new prognostic markers in endometrial cancer. We demonstrated that the tumour biology changes during tumour evolution. The optimal moment to decide on tumour biology is therefore the recurrent setting. A biopsy of the recurrent tumour is the best guarantee to characterize the tumour correctly. Furthermore, this study showed that neoadjuvant chemotherapy followed by interval debulking is a valuable treatment option for endometrial cancer with transperitoneal spread since optimal cytoreduction was achieved in 78% with a low morbidity. Future studies should look into new biomarkers that predict antitumoral activity and should search for mutations in endometrial cancer and analyse which mutation is sensitive for therapy. PMID- 24753866 TI - Fetal and maternal hemodynamics in pregnancy: new insights in the cardiovascular adaptation to uncomplicated pregnancy, twin-to-twin transfusion syndrome and congenital diaphragmatic hernia. AB - The fetal and the maternal cardiovascular compartment undergo dramatic functional changes during pregnancy. In this thesis we examined the heart of fetuses with twin-to-twin transfusion syndrome (TTTS) and congenital diaphragmatic hernia (CDH) using two new ultrasound parameters of ventricular function : the myocardial performance index and speckle tracking derived myocardial strain. Fetal cardiac function was grossly abnormal in recipient fetus of TTTS, yet normalized within 6 weeks after therapy. Ultrasound based cardiac function assessment could not predict short term fetal survival after therapy, nor could it predict eventual further progression to full-blown TTTS in a pre-disease stage. Fetuses with CDH on the other hand, have normal myocardial function, yet smaller left ventricles leading to decreased left ventricular output. We showed that the lower output leads to decreased cerebral perfusion, yet without apparent impact on brain and cranial growth. On the maternal side, plasma volume strongly increases in pregnancy, in parallel with an increase in insulin-like-growth factor(IGF) II which is secreted at the level of the placenta. Experimental administration of IGF-II by continuous infusion leads to increases in plasma volume whereas decreasing IGF-II by reduction of the feto-placental mass leads to decreased plasma volumes. In contrast to IGF-II, the highly vasoactive peptide apelin decreases near term due to a faster elimination as a consequence of an increase in placental angiotensin-converting-enzyme 2. Our experiments with IGF II and apelin substantiate an important role for the feto-placental unit in regulating maternal plasma volume expansion and (auto)regulating uterine perfusion and fetal growth. PMID- 24753867 TI - Judicious use of antenatal glucocorticoids: putting the risks into the balance. AB - The administration of a course of antenatal glucocorticoids (AG) to improve neonatal outcome after preterm birth is a prime example of evidence-based medicine, but the current clinical application of AG is too broad. AG override the glucocorticoid enzymatic placental barrier in order to elicit fetal lung maturation at a pre-physiological gestational age. Yet the maturation benefit is accompanied by a number of undesirable phenomena, most of which are transient (lasting for at least 24-48 h after the last injection). These include metabolic effects in both mother and fetus and signs of reduced fetal wellbeing. In addition, the fetal growth rate slows down depending on the number of AG courses. Multiple courses may increase the risk of cerebral palsy, as neonatal dexamethasone treatment does. There are no randomised trials on the benefit-risk balance of AG in pregnancies complicated by diabetes or intra-uterine growth restriction (IUGR). Animal studies indicate that AG are associated with an inadequate response to acute hypoxaemia and different brain development. Judicious use of AG includes avoidance of multiple courses, and a case-based approach in pregnancies with (pre)gestational diabetes, IUGR or equivocal fetal condition, until more data become available. In addition, better prediction models of preterm birth are needed. PMID- 24753869 TI - L'Amour des Moules - A Documentary about Passion, Struggle and Life. PMID- 24753868 TI - The fetal patient -- ethical aspects of fetal therapy. AB - The pregnant patient is a vulnerable subject, and even more so when a serious fetal condition is diagnosed. (Invasive) fetal therapy should only be offered when there is a good chance that the life of the fetus will be saved, or irreversible damage by the disease or disability is prevented. Following diagnosis of a potentially treatable condition, the patient needs to be referred to a center with sufficient expertise in diagnosis and all therapeutic options. Preferences of the physician towards one or another antenatal intervention is not at stake prior to that moment. When fetal therapy is justified--, it should be offered with full respect for maternal choice and individual assessment and perception of potential-- risks, and should be at the location where there is sufficient expertise. For therapies of unproven benefit, the absence of evidence must be disclosed, and therapy should only be undertaken with full voluntary consent of the mother. These ought to be undertaken within well designed and approved trials and only by experts in the treatment modality. Potential risks and eventual morbidities in case of therapeutic failure should be part of the counselling, neither-- should fetal therapy be presented as an alternative to termination of pregnancy. PMID- 24753870 TI - Editorial. PMID- 24753871 TI - The legacy of Archibald Cochrane: from authority based towards evidence based medicine. PMID- 24753872 TI - Progress in evidence based reproductive surgery. AB - The Consolidated Standards of Reporting Trials (CONSORT) was introduced in 1996 to improve the methodological quality of published reports of randomised controlled trials. By doing a systematic review of randomised controlled trials on reproductive surgery, our group can demonstrate that the overall quality of the published reports of randomised studies on reproductive surgical interventions has improved after CONSORT. Nevertheless, some problems still remain. By discussing the benefits and pitfalls of randomised trials in reproductive surgery, our opinion paper aims to stimulate the reader's further interest in evidence-based practice in reproductive surgery. PMID- 24753873 TI - Imagine a world where no woman is denied her right to health- Seven propositions. PMID- 24753874 TI - The Walking Egg non-profit organisation. AB - The Walking Egg non-profit organisation (npo) was founded in 2010 by scientists and an artist to realise the Arusha Project which strives to implement accessible infertility programmes in resource-poor countries. Right from the start The Walking Egg has opted for a multidisciplinary and global approach towards the problem of infertility and in cooperation with the Special Task Force (STF) on "Developing countries and infertility" of the European Society of Human reproduction and Embryology (ESHRE) and the WHO, it gathers medical, social and economical scientists and experts along with artists to discuss and work together towards its goal. The project aims to raise awareness -surrounding childlessness in resource-poor countries and to make infertility care in all its aspects, including assisted reproductive technologies, available and accessible for a much larger part of the population. PMID- 24753875 TI - Global access to infertility care in developing countries: a case of human rights, equity and social justice. AB - According to WHO data more than 180 million couples in developing countries suffer from primary or secondary infertility. The social stigma of childlessness still leads to isolation and abandonment in many developing countries. Differences between the developed and developing world are emerging because of the different availability in infertility care and different socio-cultural value surrounding procreation and childlessness. Although reproductive health education and prevention of infertility are number one priorities, the need for accessible diagnostic procedures and new reproductive technologies (ART) is very high. The success and sustainability of ART in resource-poor settings will depend to a large extend on our ability to optimise these techniques in terms of availability, affordability and effectiveness. Accessible infertility treatment can only be successfully introduced in developing countries if socio-cultural and economic prerequisites are fulfilled and governments can be persuaded to support their introduction. We have to liaise with the relevant authorities to discuss the strengthening of infertility services, at the core of which lies the integration of infertility, contraceptive and maternal health services within public health care structures. After a fascinating period of more than 30 years of IVF, only a small part of the world population benefits from these new technologies. Time has come to give equitable access to effective and safe infertility care in resource-poor countries as well. PMID- 24753876 TI - Menstrual-like vaginal bleeding in prepubertal girls: an unexplained condition. AB - Unexplained menstrual-like cyclic vaginal bleeding, lasting for several days and without any uterine and vaginal anomaly, is a rare condition in prepubertal girls. Only small series (containing four to eleven cases) have been described in literature. We report our in nine girls presenting with vaginal bleeding without any abnormality at gynaecological, hormonal and echographic examination. PMID- 24753877 TI - Statistical flaws in design and analysis of fertility treatment -studies on cryopreservation raise doubts on the conclusions. AB - Decisions about pharmacotherapy are being taken by medical doctors and authorities based on comparative studies on the use of medications. In studies on fertility treatments in particular, the methodological quality is of utmost importance in the application of evidence-based medicine and systematic reviews. Nevertheless, flaws and omissions appear quite regularly in these types of studies. Current study aims to present an overview of some of the typical statistical flaws, illustrated by a number of example studies which have been published in peer reviewed journals. Based on an investigation of eleven studies at random selected on fertility treatments with cryopreservation, it appeared that the methodological quality of these studies often did not fulfil the required statistical criteria. The following statistical flaws were identified: flaws in study design, patient selection, and units of analysis or in the definition of the primary endpoints. Other errors could be found in p-value and power calculations or in critical p-value definitions. Proper -interpretation of the results and/or use of these study results in a meta analysis should therefore be conducted with care. PMID- 24753878 TI - Identification of neonatal near miss by systematic screening for metabolic acidosis at birth. AB - AIMS: To evaluate the relevance of systematic screening for neonatal metabolic acidosis at birth as part of perinatal audit. METHODS: For every baby, born in Ziekenhuis Oost Limburg, Genk Belgium between 1/1/2010 and 31/12/2010, cord blood was analysed to diagnose metabolic acidosis, defined as arterial or venous pH <= 7.05 or 7.17 respectively, in association with base excess of <= -10 mmol/L. Three observers identified indicators for suboptimal peripartal care with likely contribution to metabolic acidosis. In a multidisciplinary consensus meeting, these indicators were classified into 5 categories : (a) fetal monitoring error (b) labour management error, (c) instrumental vaginal delivery for fetal distress within 2 h of second stage, (d) non-obstetric medical complications, (e) preterm births or accidental cases at term. RESULTS: In a total of 2117 neonates, there were 11 intra-uterine, 1 intrapartum and 3 early neonatal deaths, bringing early perinatal mortality rate at 7.10/00. Metabolic acidosis was identified in 23 (1.1%) babies, of which 21 (91.3%) left hospital in good clinical condition. Two babies (0.90/00), born in category c, had chronic neurologic symptoms. DISCUSSION: Systematic screening for neonatal metabolic acidosis caused a 2.5 fold increase of case identifications eligible for perinatal audit and opened perspectives towards rationalised improvement of perinatal care, in addition to the information obtained from cases of perinatal mortality. Next to indicators of perinatal mortality, perinatal audit programs should include neonatal metabolic acidosis as an extra parameter for quality assessment of perinatal care. CONCLUSION: Adding cases of near-miss neonatal morbidity to perinatal mortalities in perinatal audit programs increases opportunities for improvement of perinatal care. PMID- 24753879 TI - Understanding rising caesarean section trends: relevance of inductions and prelabour obstetric interventions at term. AB - AIMS: Single center 10-years audit on the relation between labour ward management and caesarean section rate, with special emphasis on the impact of reduced induction rate and the use of strict criteria for the diagnosis of onset of spontaneous labour and the indication for induction of labour. METHODS: Retrospective classification of all deliveries between 1st January 2001 and 31st December 2010 in Ziekenhuis Oost Limburg, Genk Belgium, into the 10- group classification according to Robson. Numbers and rate of caesarean sections were defined for primiparous and multiparous women in spontaneous labour (groups 1 and 3 respectively), after induced labour (groups 2 and 4 respectively), with caesarean scar uterus (group 5) or with other gestational complications (groups 6 to 10). For these groups, a 10-years evolution was evaluated. RESULTS: In a total of 19.675 deliveries, the overall caesarean section rate increased from 20% (380/1937) in 2001 to 25% (534/2121) in 2007 (p < 0.001), and decreased again to 20% in 2010 (415/2068) (p < 0.001). The increase of caesarean sections before 2007 was associated with an increase of inductions in singleton cephalic pregnancies at term from 28.5% (410/1437) in 2003 to 35.9% (551/1536) in 2006 (p < 0.001). The decrease of caesarean sections after 2007 occurred both in induced labours, as a direct consequence of rationalised reduction of induction rate, and in spontaneous labours, following introduction of strict criteria for diagnosis of labour. Despite a similar caesarean section rate of 20% in 2001 and 2010, the 6.6% (136/2068) repeat caesarean section rate in 2010 was higher than 4.2% (81/1937) in 2001 (p = 0.001). CONCLUSION: This single centre audit illustrates that increased induction rate is associated with increased caesarean section rate. This evolution can be reverted through a rationalised management aiming for reduction of induced labours and improved diagnosis of labour. PMID- 24753880 TI - Decisions on embryo disposition in cross-border reproductive care: differences between Belgian and Dutch patients at a Belgian fertility center. AB - Empirical research into cross-border reproductive care is scarce and many facets of the phenomenon are unexplored. The objective of this study was to compare Belgian and Dutch patients regarding the way they perceived the treatment they received and regarding the embryo disposition decisions (EDDs) they made. A questionnaire was sent to patients for whom embryos were cryopreserved at the Ghent University Hospital, Belgium. The response rate was 79%. Of those who replied the questionnaire, 70.9% was Belgian (n = 231) and 29.1% was from The Netherlands (n = 95). Dutch patients were on average three years older (38.22 years) than Belgian patients (35.30 years). Belgian patients more often considered their last treatment both physically and emotionally burdensome compared to Dutch patients (36.0% versus 25.5%). Half of the Dutch patients wanted to continue the storage of their embryos compared to a third of the Belgian patients. Dutch patients less often considered the EDD difficult to make compared to the local patients and they less often experienced stress or tension regarding the decision. In conclusion, Dutch cross-border patients had more positive experiences regarding to the treatment and the EDD compared to -Belgian patients. However, they wanted to hold on longer to their cryopreserved embryos. PMID- 24753882 TI - Editorial. PMID- 24753883 TI - The global health financing revolution: why maternal health is missing the boat. AB - The first decade of the new millennium saw an upsurge in global financing for health. When the world took stock of progress on the Millennium Development Goals in mid-2010 the one addressing maternal health showed the least progress. Did maternal health miss the boat? In mid-2010 the Secretary-General of the United Nations launched a "Global Strategy for Women's and Children's Health", also known as the "Every Woman Every Child" initiative. Has the tide now turned in favour of maternal health? The authors try to answer this question by first examining whether maternal health really missed out with respect to increased global funding and why this may have occurred. They then assess whether the new initiative will make a difference by comparing several elements of the approach taken by HIV/AIDS activist to that of maternal health activists. They suggest that real progress requires international financing, thus pledges must become robust and reliable commitments. They conclude that the absence of an organisational structure in the current initiative means the global maternal health financing revolution will probably not happen. PMID- 24753881 TI - Strategies for fertility preservation and restoration in the male. AB - INTRODUCTION: Patients faced with infertility due to spermatogonial stem cell loss have currently semen cryobanking as only option for fertility preservation. A growing group of patients cannot benefit from this strategy as they are devoid of spermatozoa or even of any spermatogenic cell at the time of diagnosis. We therefore aimed at investigating alternative strategies to preserve or restore fertility. METHODS: As fertility preservation strategies, we investigated the reintroduction of spermatogonial stem cells by spermatogonial stem cell transplantation (SCCT) or grafting of testicular tissue pieces. To restore fertility, we explored the germ cell differentiation capacity of human embryonic stem cells (hESC). Moreover, to avoid embryo destruction during hESC derivation, we aimed to derive hESC from single blastomeres of human embryos Results: For the SSCT, we showed that selection protocols based on magnetic and fluorescent cell sorting or selective-- matrix adhesion result in high germ cell-enriched fractions for transplantation. However, they are not sufficiently efficient to attain a pure germ cell fraction. After xenografting of human testicular testis tissue to immunodeficient mice, we observed long-term survival of spermatogonia within the grafts. In the fertility restoration part, we demonstrated the inductive capacity of sertoli cell-conditioned medium on germ cell differentiation from hESC. Finally, we derived two hESC from single blastomeres of two distinct four-cell stage human embryos. DISCUSSION AND CONCLUSIONS: The fertility preservation strategies that we investigated are currently on the edge of a clinical application. In the fertility restoration path, however, more extended research will be necessary. PMID- 24753884 TI - Dealing with trainees in difficulty. AB - Doctors are highly valued in every society as they are expected to serve humanity with dedication, commitment and motivation within professional boundaries. Those working within acute specialities are increasingly coming under public microscope. As the public expectations of a quality assured high quality services delivered by the doctors-- is increasing, so does the pressure on doctors to deliver these services. Our doctors in training are on the front line to deal with the initial assessment of acutely sick women and therefore may be exposed to stressful situations with little support. All doctors in training require support from their trainers and clinical supervisors but more support is needed for trainees who are struggling to cope with the pressure and are in difficulty. This paper examines underlying factors which need to be clearly understood before planning a remedial strategy for this group of doctors. They should be handled sensitively but pro actively. PMID- 24753885 TI - A call for a family planning surge. AB - In 1994, the International Conference on Population and Development (ICPD) held in Cairo, Egypt, laid out in its Programme of Action an impressive and ambitious set of goals for improving sexual and reproductive health and rights (SRHR) all over the world, by the target date of 2015 (International Conference on Population and Development 1994). One of these goals was the provision of universal access to a full range of safe and reliable family-planning methods. However, notwithstanding increases in budgets for family planning during the years following the ICPD (Organisation for Economic Co-operation and Development), there has been an alarming neglect from the international community for the topic since the year 2000. As a result, the progress made during the second half of the nineties slowed down considerably between 2000 and 2010; in a sense, one could say that ten years were almost wasted! This is astonishing, the more since meeting the need for family planning would have beneficial impacts on public health, environmental sustainability and social and economic development. In this paper, we explore these impacts and urge for a strong renewed commitment of the global community in the form of a global family planning decade. PMID- 24753887 TI - The impact of menopause and hormone therapy on voice and nasal resonance. AB - In an initial study it was shown that (without hormonal influences) middle-aged (premenopausal) women show a smaller frequency and intensity range and a lower fundamental frequency of the voice compared to young women. To investigate the impact of menopause on voice and nasal resonance a cross-sectional non-randomized study design was used. Vocal characteristics and nasal resonance in premenopausal and postmenopausal women without hormone therapy (HT) were compared. Postmenopausal women without HT showed a significantly lower speaking fundamental frequency (SFF) and were able to phonate lower compared to postmenopausal women with HT. The mean difference in SFF was 14 Hz. HT can also counteract the menopausal changes in SFF. The lower SFF did not result in vocal complaints. Further research about the impact of menopause and HT on voice should concentrate on elite professional voice users. PMID- 24753886 TI - Soy consumption during menopause. AB - In developed countries, the life expectancy of women is currently extending more than 30 years beyond the age of menopause. The menopausal transition is often associated with complaints. The conflicting results on the effectivity of phytoestrogens to alleviate menopausal symptoms. This discrepancy in treatment effect may be due to the large interindividual variation in isoflavone bioavailability in general and equol production in particular. Equol, a microbial metabolite of daidzein, has been hypothesized as a clue to the effectiveness of soy and its isoflavones, but only about 30-50% of the population harbor an intestinal microbial ecosystem supporting the conversion of daidzein into equol. There is much concern on breast cancer, since this incidence of this disease increases with age. There is indication that soy phytoestrogens may decrease this breast cancer incidence. In order to evaluate the estrogenic potential of these exposure levels, we studied the isoflavone-derived E2alpha- and E2beta equivalents (i.e. 17beta-estradiol (E2)-equivalents towards ERalpha and ERbeta, respectively) in human breast tissue. Total isoflavones showed a breast adipose/glandular tissue distribution of 40/60 and their derived E2beta equivalents exceeded on average 21 +/- 4 and 40 +/- 10 times the endogenous E2 concentrations in corresponding adipose and glandular biopsies, respectively, whereas the E2alpha/E2 ratios were 0.4 +/- 0.1 and 0.8 +/- 0.2 in adipose and glandular breast tissue, respectively. These calculations suggest that, at least in this case, soy consumption could elicit partial ERbeta agonistic effects in human breast tissue. We are currently characterizing the differential activation of estrogen-responsive genes between dietary isoflavones, the chemopreventive selective ER modulators tamoxifen and raloxifene and exogenous estrogens in a controlled dietary intervention trial that integrates data on the exposure to estrogenically active compounds, expression of isoflavone and estrogen target genes, and epigenetic events. During the menopause, there is a close relation between the drop in serum estrogen and negative metabolic changes such as the increase in bone resorption and negative change in the serum lipid profile. Randomized controlled trials measuring bone turnover markers in menopausal women revealed that soy isoflavone supplements significantly but moderately decrease the bone resorption marker urinary deoxypyridinoline without significant effects on the bone formation markers serum bone alkaline phosphatase and osteocalcin. PMID- 24753888 TI - Birth weight for gestational age among Flemish twin population. AB - OBJECTIVE: The aim of this study was to develop birth weight references for twins. Mean birth weights of individual twins are lower than those of singletons, hence singleton birth weight curves may not be suitable to assess twin birth weights. STUDY DESIGN: Twin birth weight curves were developed according to gestational age, gender, parity and mode of -conception. The curves are based on population-based data of 40,494 twins born in Flanders, Belgium between 1987 and 2007. RESULTS: A different growth potential was found comparing the birth weights of twins and singletons. Twins deviate from the singleton curve from 30 weeks gestational age on. CONCLUSION: Our study underlines that singleton birth weight curves differ from twin birth weight curves. We developed specific twin birth weight curves can be used in clinical practice in order to follow growth patterns of twins in utero. PMID- 24753889 TI - Does transferring three or more embryos make sense for a well-defined population of infertility patients undergoing IVF/ICSI? AB - Recently, there has been a marked increase in the use of Single Embryo Transfer (SET) subsequent to In Vitro Fertili-zation (IVF) and Intracytoplasmic Sperm Injection (ICSI), with the aim of reducing the risk of multiple gestations. However, critics have stated that by reducing the number of embryos transferred, a group of women with an a priori reduced chance of pregnancy are at particular greater risk of undertreatment. This group includes women who are of a certain age (>= 40 years) or have already received a number of - failed - IVF attempts. We wanted to study whether the practice of three or more embryos being transferred would be of added value to these patients and whether the strategy of Heavy Load Transfer (HLT) is likely to boost the pregnancy rates to an acceptable level. We performed both a literature study and a retrospective cohort analysis of 7,850 IVF/ICSI cycles of early cleavage stage embryo transfer. Notwithstanding the limitations associated with this approach, we contend that HLT in the group of patients with poor prognosis should be recommended. This article outlines a suggested protocol within the legal framework relevant to Belgium. PMID- 24753890 TI - Prevalence of chromosomal abnormalities and timing of karyotype analysis in patients with recurrent implantation failure (RIF) following assisted reproduction. AB - AIMS: To analyze the prevalence and type of karyotype abnormalities in RIF patients and to evaluate the adequate timing for analysis and the presence of possible risk factors. METHODS: 615 patients (317 women and 298 men) with RIF, having undergone at least 3 sequential failed IVF/ICSI cycles prior to karyotype analysis, were included in this study. Anomaly rates found were compared with published series. RESULTS: Chromosomal abnormalities were diagnosed in 2.1% of patients (13/615): 8 females (2.5%) and 5 males (1.7%) which is significantly higher for the females than in unselected newborns (0.8%) and normo-ovulatory women (0.6%) but lower than in women with high-order implantation failure (10.8%). No significant differences were found with couples at the start of IVF/ICSI (2.0%). Karyotyping all patients prior to IVF/ICSI results in a higher cost than selecting RIF patients. Two subgroups showed an increased prevalence of abnormalities: secondary infertile women with a history of only miscarriages (9.1%) and women with female infertility (6.0%). CONCLUSION: A karyotype analysis is indicated in all women with RIF. Nulliparous women with a history of mis carriage and women with documented infertility are at greater risk of CA and are to be advised to undergo -karyotyping. PMID- 24753892 TI - Editorial. PMID- 24753891 TI - Use of Non-invasive Uterine Electromyography in the Diagnosis of Preterm Labour. AB - Predictive values of methods currently used in the clinics to diagnose preterm labour are low. This leads to missed opportunities to improve neonatal outcomes and, on the other hand, to unnecessary hospitalizations and treatments. In addition, research of new and potentially more effective preterm labour treatments is hindered by the inability to include only patients in true preterm labour into studies. Uterine electromyography (EMG) detects changes in cell excitability and coupling required for labour and has higher predictive values for preterm delivery than currently available methods. This methodology could also provide a better means to evaluate various therapeutic interventions for preterm labour. Our manuscript presents a review of uterine EMG studies examining the potential clinical value that this technology possesses over what is available to physicians currently. We also evaluated the impact that uterine EMG could have on investigation of preterm labour treatments by calculating sample sizes for studies using EMG vs. current methods to enrol women. Besides helping clinicians to make safer and more cost-effective decisions when managing patients with preterm contractions, implementation of uterine EMG for diagnosis of preterm labour would also greatly reduce sample sizes required for studies of treatments. PMID- 24753893 TI - High susceptibility to cytomegalovirus infection of pregnant women in Flanders, Belgium. AB - Maternal antibodies against cytomegalovirus (CMV) infection offer, to some extent, protection against congenital CMV infection. This study describes the seroprevalence of CMV-specific IgG in 220 parturient women during pregnancy, at delivery, at 3 months after delivery and in their cord blood (Flanders, Belgium, 2006-2008). ELISA was used to measure IgG. Of this population, 30% had positive IgG titres. Active transplacental transport was confirmed with a ratio 1.15/1. Elevated maternal IgG titre and increased parity, but not age, were significantly associated with higher seroprevalence of CMV-specific IgG in the cord blood. These data indicate a high susceptibility to CMV among fertile women. Prenatal prevention and other strategies to prevent intra-uterine infection are of critical importance in a highly susceptible population. PMID- 24753894 TI - A prospective randomised study comparing a GnRH-antagonist versus a GnRH-agonist short protocol for ovarian stimulation in patients referred for IVF. AB - OBJECTIVE: To compare two short protocols for ovarian stimulation in IVF cycles using an antagonist and an agonist short protocol. The outcomes studied were dosis rec FSH needed, days of stimulation, number of oocytes retrieved and pregnancy outcome. METHODS: A prospective randomised study design. INCLUSION CRITERIA: first or second IVF attempt in women younger than 40 years. In the agonist protocol (Suprefact(r)) nasal spray was used. In the antagonist protocol (Orgalutran)(r) was started as soon as at least 1 follicle of 12 mm was visualized on ultrasound. RESULTS: 160 cycles were included in the study: 80 in the antagonist group and 80 in the agonist group. A higher dosis of recombinant FSH (rec FSH) was used for stimulation in the antagonist group (1897 IU versus 1655 IU). Pregnancy rate per ET in the antagonist group was 37% with an ongoing pregnancy rate of 21%/ET and an -implantation rate of 22%; versus respectively 39%, 20% and 22% in the agonist treated group. Live birth rate per started cylce was 19% in the antagonist group versus 20% in the agonist group. CONCLUSION: This study shows that implantation rates, ongoing pregnancy rates and live birth rates are equal in both groups. An identical number of oocytes was retrieved, with no difference in duration of the stimulation although a higher dosis of rec FSH was needed in the antagonist group. PMID- 24753895 TI - Is 48 hours enough for Obstetrics and Gynaecology training in Europe? AB - The European Working Time Directive, implemented by the European Union (EU) in 1993, was adopted in the medical profession to improve patient safety as well as the working lives of doctors. The Directive reduced the average amount of hours trainee doctors worked to 48 hours per week. However, its adoption has varied throughout the EU. Its potential effect on both the quality and total amount of hours of -training has caused concern. This monograph presents data on Obstetrics and Gynaecology training in Europe obtained from several of the European Network of Trainees in Obstetrics & Gynaecology's (ENTOG) surveys. The monograph demonstrates large variations in training and explains the difficulties in ascertaining whether 48 hours of training a week is sufficient to become an Obstetrics and Gynaecology specialist in Europe. PMID- 24753896 TI - Are you good enough for your patients? The European certification model in laparoscopic surgery. AB - Quality control, training and education in gynaecological surgery are challenged and urgent measures are emerging. The implementation of a structured and validated program for training and quality control seems the most urgent measurement to be taken. The European Academy of Gynaecological Surgery has made a first attempt to do so. Through a practical and theoretical tests system, the skills of an individual surgeon is measured and the conditions to enter the different level of expertise are clearly defined. This certification system based on the best possible level of scientific evidence provides a first practical tool, universally implementable for a decent quality control and structured training program in Gynaecological laparoscopic surgery. PMID- 24753897 TI - The economic impact of infertility on women in developing countries - a systematic review. AB - BACKGROUND: It is the responsibility of health systems to provide quality health care and to protect consumers against impoverishing health costs. In the case of infertility in developing countries, quality care is often lacking and treatment costs are usually covered by patients. Additional financial hardship may be caused by various social consequences. The economic implications of infertility and its treatment have not been systematically explored. METHODS: A systematic MEDLINE search was conducted to identify English language publications providing original data from developing countries on out-of-pocket payment (OoPP) for infertility treatment and on other economic consequences of involuntary childlessness. FINDINGS: Twenty one publications were included in this review. Information on OoPP was scant but suggests that infertility treatment is associated with a significant risk of catastrophic expenditure, even for basic or ineffective interventions. Other economic disadvantages, which may be profound, are caused by loss of access to child labour and support, divorce, as well as customary laws or negative attitudes which discriminate against infertile individuals. Women in particular are affected. CONCLUSION: Pertinent data on OoPP and other economic disadvantages of infertility in developing countries are limited. According to the evidence available, infertility may cause impoverishing health costs as well as economic instability or deprivation secondary to social consequences. Health systems in developing countries do not appear to meet their responsibilities vis-a-vis infertile patients. PMID- 24753898 TI - Actions of progestins for the inhibition of cervical ripening and uterine contractions to prevent preterm birth. AB - The importance of progesterone (P4) for maintenance of pregnancy, its role in cervical ripening and uterine contractions is at least partly established and therefore, not surprisingly, the basis for the concept to use P4 as a treatment for preterm birth. Due to the complexity of the condition of preterm birth there are still questions concerning the optimal population that might benefit, timing of treatment, dosage, vehicle and route of administration. Recently vaginal P4 and intramuscular 17-alpha-hydroxyprogesterone caproate (17P) have been used to prevent preterm birth in patients with a high risk for early delivery. The aim of this study was to assess cervical changes throughout pregnancy in rats and the timing of term and preterm delivery after various progestin treatments given by different routes and vehicles in hope of identifying better treatment regimens. This paper presents results that suggest that there are better routes of treatment than the vaginal route (e.g. topical), that the vehicle used in many of the clinical studies (Replens(r)) is not appropriate due to a low release of the steroid and consequently low uptake of P4, and that inhibition of birth is primarily due to inhibition of uterine contractility that can be achieved by supplementation of P4 but not with 17P. PMID- 24753899 TI - An exploration of the psycho-sexual experiences of women who have undergone female genital cutting: a case of the Maasai in Kenya. AB - The research explored the link between type II Female Genital Cutting (FGC) and sexual functioning. This thesis summary thus draws from an exploratory ethnographic field study carried out among the Maasai people of Kenya where type II FGC is still being practiced. A purposely sample consisting of 28 women and 19 men, within the ages of 15-80 years took part in individual interviews and 5 focus group discussions. Participants responded to open-ended questions, a method deemed appropriate to elicit insider's in-depth information. The study found out that one of the desired effects of FGC ritual among the Maasai was to reduce women's sexual desire, embodied as tamed sexuality. This consequence was however not experienced as an impediment to sexual function. The research established that esteeming transformational processes linked with the FGC 'rite of passage' are crucial in shaping a woman's femininity, identity, marriageable status and legitimating sexuality. In turn, these elements are imperative in inculcating and nurturing a positive body-self image and sex appeal and consequently, positive sexual self actualization. These finding brings to question the validity of conventional sexuality theory, particularly those that subscribe to bio-physical models as universal bases for understanding the subject of female sexual functioning among women with FGC. Socio-cultural-symbolic nexus and constructions of sexuality should also be considered when investigating psychosexual consequences of FGC. PMID- 24753900 TI - Therapeutic hypothermia in neonatal asphyxia. AB - Hypoxic ischemic encephalopathy is a serious condition affecting newborn infants which can result in death and disability. There is now strong clinical evidence that moderate post-asphyxial total body cooling or hypothermia in full term neonates results in long-term neuroprotection, allowing us to proclaim this innovative therapy as "standard of care." The treatment is a time-critical emergency and should be started within 6 hours after the insult. Such -requires optimal collaboration among local hospitals, transport teams and the closest neonatal intensive care unit. The technique is only safe when applied according to published clinical trial protocols, and with admission of these patients to a neonatal intensive care unit. Future studies should be aimed at optimizing the onset, duration, and depth of hypothermia. Combination of hypothermia and drugs may further improve neuroprotection in asphyxiated full term neonates. PMID- 24753901 TI - Increasing prevalence of macrosomia in Flanders, Belgium: an indicator of population health and a burden for the future. AB - Macrosomia, defined as birth weight > 4 kg, increased in Flanders from 7.3% (4899/67143) in 1991 to 8.63% (6034/69924) in 2010 (p < 0.0001) in singleton pregnancies at term. There are at least 3 important factors contributing to this evolution. (1) Increase of maternal stature and length: during the last century, mean length of Belgian women increased with approximately 10cm to the current value of 1.66 m. (2) Increase of maternal age: the proportion of pregnant women aged 35 years or more increased significantly from 6.1% in 1991 to 14.3% in 2010. (3) Increase of maternal overweight or obesity: between 1994 and 2000, there was an increase of 4% for both overweight and obesity in women and today, 44% of Belgians are overweight (BMI > 25 kg/m2), and 12% are obese (BMI > 30 kg/m2). From these data, rate and increase of macrosomia can be -considered indirect indicators of general public health. Next to the risks for obstetrical complications, neonates > 4 kg are at risk for development of adult obesity and type 2 diabetes with related diseases, such as hypertension and metabolic syndrome. As adults, they also tend to deliver macrosomic baby's themselves. As such, macrosomia at birth is a burden for a community's future health status, health care and related costs. Prenatal health care workers should be aware of the relevance to prevent macrosomia in the first generation by -implementing guidelines on nutrition, physical activity and appropriate weight gain into routine preconceptional and prenatal care, screening for gestational diabetes with strict monitoring of blood sugar levels in affected -individuals, and promotion of breastfeeding. PMID- 24753903 TI - Editorial. PMID- 24753902 TI - Progesterone action in the myometrium and decidua in preterm birth. AB - Progesterone is central to many reproductive processes and is critical in regulating the menstrual cycle and maintaining pregnancy. We discuss here similarities in the molecular mechanisms that regulate the process of decidualisation in endometrial stromal cells and uterine quiescence in myometrial smooth muscle cells. We discuss recent evidence that the decidua may be an important mediator of progesterone actions in the onset of labor in mammalian species lacking progesterone withdrawal. These observations have relevance to recent clinical observations of the effect of progesterone administration in the prevention of preterm labor. We suggest that further research is required to understand the role of progesterone in maintaining the decidua in late pregnancy and particular focus should be given to the mechanisms that increase prostaglandin production in the uterus at term. PMID- 24753904 TI - Invisible women in Bangladesh: Stakeholders' views on infertility services. PMID- 24753905 TI - Counselling on disclosure of gamete donation to donor offspring:a search for facts. AB - BACKGROUND: High quality counseling of potential parents is needed in the process of disclosure to donor offspring, which is important for the child and for family relationships. We performed a search for facts to identify the role of counseling in couples undergoing gamete donation. METHODS: We systematically searched Pubmed, EMBASE and Psychinfo. Studies were included if they reported on counseling in gamete donation. RESULTS: A total of 20 studies were included. Twelve studies stated that counselling was offered. The reported studies reflected no consensus about when and how counselling in gamete donation should be offered and no theoretical background of the disclosure/ secrecy issue. About 50% of the parents expressed the need for guidance and support of a counsellor. Special concerns were the disclosure issue and the future contact with the donor. Parents did not receive the guidance and support they needed in the disclosure process after treatment. CONCLUSION: Empirical knowledge on counselling is lacking. This review demonstrates the need to know more precisely at what moments couples should be counselled, and which specific information and guidelines couples need to receive to be more confident in the disclosure process to donor offspring. PMID- 24753907 TI - Stem cell therapy: facts and fiction. AB - This opinion paper is a brief overview of the current state of the translation of stem cell therapy from the bench to the clinic. The hype generated by the great medical potential of stem cells has lead to hundreds of clinics worldwide claiming to have the cure for every imaginable condition. This fraudulent practice is far from the reality of scientists and bona fide companies. Much effort is put into addressing all the hurdles we have been encountering for the safe use of stem cells in therapy. By now, a significant number of clinical trials are booking very exciting progress, opening a realistic path to the use of these amazing cells in regenerative medicine. PMID- 24753908 TI - Facts and myths in serological screening of ART couples. AB - Serological screening of couples attending for ART therapy is now common practice. The frequency of such screening is a topic of debate as few publications have addressed this question. Emerging evidence shows that the ART population has similar prevalence of infectious diseases compared with the general EU population. The need to pursue repeat screening is mainly related to the risk of seroconversion in this highly selected population. The -evidence presented here shows that seroconversion among cohabitating ART couples is negligible. Even if a -theoretical risk of seroconversion during therapy exists, with correct laboratory practice the risk of cross--contamination is negligible as laboratory processing eliminates the infective risk. As such ART laboratory processing of contaminated samples becomes an indication rather than a risk. To strengthen the evidence it is recommended that data on prevalence and incidence should be prospectively collected by all ART units. PMID- 24753906 TI - Postterm pregnancy. AB - Postterm pregnancy is a pregnancy that extends to 42 weeks of gestation or beyond. Fetal, neonatal and maternal complications associated with this condition have always been underestimated. It is not well understood why some women become postterm although in obesity, hormonal and genetic factors have been implicated. The management of postterm pregnancy constitutes a challenge to clinicians; knowing who to induce, who will respond to induction and who will require a caesarean section (CS). The current definition and management of postterm pregnancy have been challenged in several studies as the emerging evidence demonstrates that the incidence of complications associated with postterm pregnancy also increase prior to 42 weeks of gestation. For example the incidence of stillbirth increases from 39 weeks onwards with a sharp rise after 40 weeks of gestation. Induction of labour before 42 weeks of gestation has the potential to prevent these complications; however, both patients and clinicians alike are concerned about risks associated with induction of labour such as failure of induction and increases in CS rates. There is a strong body of evidence however that demonstrates that induction of labour at term and prior to 42 weeks of gestation (particularly between 40 & 42 weeks) is associated with a reduction in perinatal complications without an associated increase in CS rates. It seems therefore that a policy of induction of labour at 41 weeks in postterm women could be beneficial with potential improvement in perinatal outcome and a reduction in maternal complications. PMID- 24753909 TI - Optimisation of the follicular phase in IVF/ICSI. AB - In reproductive medicine, the aim is to establish an optimal balance between cost effectiveness, success rate and safety for the patient. In this thesis, a series of clinical studies are presented that all revolve around the optimisation of ovarian stimulation with GnRH antagonist co-treatment. Basal hormonal levels at the start of ovarian stimulation are mandatory to obtain acceptable pregnancy rates. In view of this, we focused on the impact of cycle day 2 progesterone levels on treatment outcome. By interfering in the early follicular phase, we tried to synchronise the follicular cohort and to increase the number of retrieved oocytes. Innovative treatment protocols based on GnRH antagonists should lead to a more flexible and better controlled schedule of oocyte retrievals. The inability to program the start of gonadotrophin stimulation and hence to minimise weekend oocyte retrievals is a major impediment to the widespread implementation of the GnRH antagonist protocol in fertility clinics. Because treatment schedule is important both for the patients, who wish to undergo reproductive treatment at their own convenience, and for the ART clinic, to organise the workload, we attempted to bring the schedule of egg retrievals in a GnRH antagonist protocol under improved control. Another important aim of our clinical research was to diminish patient discomfort and reduce side effects by a simplification of GnRH antagonist ovarian stimulation protocols. We also focused on significant reduction of FSH consumption by substitution of FSH by low dosages of hCG during the mid-late follicular phase, without impairing outcome in terms of oocyte yield and ongoing pregnancy rate or live birth rate. PMID- 24753911 TI - Editorial. PMID- 24753910 TI - Paratesticular leiomyoma in an azoospermic patient and -successful testicular sperm extraction (TESE) for intracytoplasmic sperm injection (ICSI) with an ongoing pregnancy. AB - Leiomyomata of the urinary and male genital tract are extremely rare. They have been reported throughout the genitourinary male tract and the most common localization is the renal capsule. However, leiomyomas of the epididimis, spermatic cord, tunica albuginea and testis have been reported. We report diagnostic confirmation of a paratesticular leiomyoma in an azoospermic patient undergoing a testicular sperm extraction for intracytoplasmic sperm injection (TESE/ICSI) procedure. PMID- 24753912 TI - Barriers to access to infertility care and assisted reproductive technology within the public health sector in Brazil. AB - BACKGROUND: In Brazil, access to infertility care, including assisted reproductive technologies (ARTs), is restricted. This is the third report of a study on access to infertility care and ARTs within the public sector, focusing on the barriers to these services. METHODS: The study was anchored on quantitative and qualitative methods. For the quantitative study interviews were conducted with health authorities in each of the 26 states, the Federal District, the state capitals and 16 cities with >= 500,000 inhabitants and directors of infertility referral centres within the public sector. Qualitative case studies-- were conducted in five ART centres. RESULTS: Overall, 63.5% of the authorities reported that complex infertility treatments were unavailable. Barriers identified consisted of "lack of political decision to implement them", and "lack of financial resources". In addition, 75% reported to have "no plans to implement them over the next 12 months". At the facilities offering ART, the barriers to these procedures were the high costs, long waiting times, complex scheduling processes and lack of initiative to implement low cost ARTs. CONCLUSIONS: Infertile couples' access to ART procedures is restricted due to the insufficient services and lack of political commitment to support existing and new services.. PMID- 24753913 TI - The role of oxytocin antagonists in repeated implantation -failure. AB - A prospective cohort study has been performed to find out if the administration of an oxytocin antagonist (Atosiban) at the occasion of embryo transfer has an effect on the pregnancy rate in patients with repeated failure of implantation. A total of 52 women with repeated failure of implantation after IVF/ICSI were included in this study. The ongoing pregnancy rate (OPR) in the total group of patients was 12 out of 52 (23.1%). Based on embryo quality all cases were categorized in two groups. One with good embryo quality (Group A) and one with poor quality embryos (Group B). Of all patients who became pregnant, 11 belonged to the group of 26 patients with good quality embryos (OPR 42.3 %) and only one to the group of 26 patients with poor quality embryos (OPR 3.8 %). Our results indicate that when good quality embryos can be obtained, the use of Atosiban at the occasion of embryo transfer might offer a significant better implantation rate in women with repeated implantation failure after IVF/ICSI. PMID- 24753914 TI - Difficult prenatal diagnosis: fetal coarctation. AB - The prenatal diagnosis of fetal coarctation is still challenging. It is mainly suspected by ventricular disproportion (smaller left ventricle than right ventricle). The sensitivity of ventricular discrepancy is however moderate for the diagnosis of coarctation and there is a high false positive rate. Prenatal diagnosis of coarctation is important because the delivery can be arranged in a centre with a pediatric cardiac intensive careand this reduces postnatal complications and longterm morbidity. For many years the prenatal diagnosis of coarctation has been investigated to improve specificity and sensitivity by several of measurements. This article reviews all relevant articles from 2000 until 2011 searching pubmed and the reference list of interesting articles. An overview of specific measurements and techniques that can improve the diagnosis of coarctation has been made, such as the isthmus diameter, ductal diameter, isthmus/ductal ratio, z-scores derived from measurements of the distal aortic isthmus and arterial duct, the presence of a shelf andisthmal flow disturbance. Also 3-dimensional (3D) and 4-dimensional (4D) imaging with or without STIC has been -suggested to be used as newer techniques to improve diagnosis of coarctation in fetal life. Although more methods regarding prenatal diagnosis of coarctationare being investigated, the ultrasound specialist remains challenged to correctly diagnose this cardiac anomaly in prenatal life. PMID- 24753915 TI - Use of progesterone and progestin analogs for inhibition of preterm birth and other uterine contractility disorders. AB - In this paper we focus on preterm birth as a uterine contractility disorder caused by hypercontractility of the -myometrium. We describe changes in uterine function during term and preterm labor and delivery. We also examine the usefulness of measurement of uterine electromyographic (EMG) activity, noninvasively monitored from the -abdominal surface of pregnant patients. The use of progesterone treatment for preterm birth is discussed and we conclude that present therapies with progesterone could be improved by changing the route of administration. -Finally we show the results of recent studies that show that progesterone injections completely inhibit uterine EMG activity when given several days to hours before normal delivery. These studies illustrate how progesterone suppresses labor at term or preterm, probably through repression of genes which control excitability and conduction of electrical activity. However, direct profusion of soluble progesterone into the uterine cavity has little immediate inhibitory action and this may demonstrate that progesterone has no direct, nongenomic effects, at least in the rat model used. Further studies are required to determine the effects of progesterone on human uterine EMG activity and whether progesterone treatments will prevent preterm birth. PMID- 24753917 TI - Is there any reproductive future left for men? PMID- 24753916 TI - Preterm Cervical Ripening in humans. AB - Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Despite the current treatment procedures, the incidence of PTB has not changed in the past thirty years. Incomplete understanding of the biological and patophysiological mechanisms underlying preterm delivery is the major obstacle to prevent PTB. Cervical ripening is necessary for vaginal delivery and understanding of preterm cervical ripening is required for developing new treatment strategies. Several important substances such as HMGB1 and its receptors, CRH and its receptors and numerous cytokines are localized in the cervix and undergo distinct changes in labour. Other important -molecules, such as CRH, CRH-BP, CRH-R1, CRH-R2, HMGB1, TLR2, TLR4, IL-10, IL-12, are localized in the cervical epithelium, also indicating their role in the process of cervical ripening during labour. Furthermore, CRH stimulates IL-8 secretion from both preterm and term cervical fibroblasts. Recent studies from our group show that major -inflammatory changes occur in the cervix at labour irrespective of gestational age. This indicates that cervical ripening at both term and preterm is an inflammatory process even if no infection is present. However, preterm cervical ripening still entails some differences from term cervical ripening, for example in the down-regulation of mRNA expression of Toll-like receptors (TLR-2 and TLR-4) and IL-12, higher levels of IL-10 in cervical epithelium, and presents different secretion patterns of cervical fibroblasts. Moreover, preterm cervical ripening, like preterm delivery itself, is a multifactorial disorder with pathways which are partly different from those involved in PPROM and infected preterm labour. PMID- 24753918 TI - Teaching professionalism - Why, What and How. AB - Due to changes in the delivery of health care and in society, medicine became aware of serious threats to its professionalism. Beginning in the mid-1990s it was agreed that if professionalism was to survive, an important step would be to teach it explicitly to students, residents, and practicing physicians. This has become a requirement for medical schools and training programs in many countries. There are several challenges in teaching professionalism. The first challenge is to agree on the definition to be used in imparting knowledge of the subjects to students and faculty. The second is to develop means of encouraging students to consistently demonstrate the behaviors characteristic of a professional - essentially to develop a professional identity. Teaching of professionalism must be both explicit and implicit. The cognitive base consisting of definitions and attributes and medicine's social contract with society must be taught and evaluated explicitly. Of even more -importance, there must be an emphasis on experiential learning and reflection on personal experience. The general principles, which can be helpful to an institution or program of teaching professionalism, are presented, along with the experience of McGill University, an institution which has established a comprehensive program on the teaching of professionalism. PMID- 24753919 TI - The art of medical education. AB - Is the art of medical education just making sure to provide sufficient up to date medical knowledge and a lot of clinical experience? It is much more. The art of medical education is about a teaching program that is designed to serve the community of the near future. The program is the result of a thorough evaluation of societal needs and is capable of influencing the properties of future care. New care professionals who are trained in the program will -become instrumental in solving complex problems in health systems. The art of medical education is about the change of traditional ideas of how to cope with these health systems. This change will raise anger and resistance. Effective change management is essential to survive attacks from laggards and to maintain enthusiasm to invest in the health care of the future. Educationalist science provides several important insights that help us find the optimal shape of the program. Good role models and a learning environment that is an example of the intended professional and organisational behaviour, learning by doing, simulation programs, educational tools like e-learning systems, a good assessment and feedback system, and a portfolio to prove and discuss professional progress are all pivotal components of the ideal program. To achieve mastery within the art of medical education, a quality improvement program will be the crown of the process. Medical education is a multifaceted process and so the quality improvement should be. The art of medical education is a great challenge. The health care of your future deserves it. PMID- 24753920 TI - From fresh heterologous oocyte donation to autologous oocyte banking. AB - INTRODUCTION: Today, oocyte donation has become well established, giving rise to thousands of children born worldwide annually. The introduction of oocyte cryopreservation through vitrification allows the introduction of egg banking, improving the efficiency and comfort of oocyte donation. Moreover, the vitrification technique can now enable autologous donation of oocytes to prevent future infertility. METHODS: We evaluated fresh heterologous oocyte donation in terms of obstetrical and perinatal outcome as well as of the reproductive outcome of past donors. We then evaluated the efficiency of a closed vitrification device and its clinical applications within ART. Thirdly, we evaluated the opinion of women with regard to preventive egg freezing and the efficiency of a human oocyte in relation to age. RESULTS: Oocyte donation is associated with an increased risk of first trimester bleeding and pregnancy induced hypertension. Donating oocytes does not seem to increase the likelihood for a later need of fertility treatment. The chance of an oocyte to result in live birth (utilization rate) in women <37 years old remains constant with a mean of 4.47%. A significant proportion of young women would consider safeguarding their reproductive potential through egg freezing or are at least open to the idea. DISCUSSION AND CONCLUSION: The introduction of efficient oocyte cryopreservation has revolutionized oocyte donation through the establishment of eggbank donation. The technique also enables women to perform autologous donation after preventive oocyte storage in order to circumvent their biological clock. PMID- 24753921 TI - Same-sex sexual behavior of men in Kenya: Implications for HIV prevention, programs, and policy. AB - Unprotected anal sex has long been recognized as a risk factor for HIV transmission among men who have sex with men (MSM). In Africa, however, general denial of MSM existence and associated stigma discouraged research. To address this gap in the literature, partners conducted the first behavioral surveys of MSM in Kenya. The first study was to assess HIV risk among MSM in Nairobi, and the second study a pre-post intervention study of male sex workers in Mombasa. The 2004 behavioral survey of 500 men in Mombasa revealed that MSM were having multiple sexual partners and failed to access appropriate prevention counseling and care at Kenya clinics. A 2006 capture-recapture enumeration in Mombasa estimated that over 700 male sex workers were active, after which a pre intervention baseline survey of 425 male sex workers was conducted. Awareness of unprotected anal sex as an HIV risk behavior and consistent condom use with clients was low, and use of oil-based lubricants high. Based on this information, peer educators were trained in HIV prevention, basic counseling skills, and distribution of condoms and lubricants. To assess impact of the interventions, a follow-up survey of 442 male sex workers was implemented in 2008. Exposure to peer educators was significantly associated with increased consistent condom use, improved HIV knowledge, and increased use of water-based lubricants. These results have provided needed information to the Government of Kenya and have informed HIV prevention interventions. PMID- 24753922 TI - Editorial. PMID- 24753923 TI - Vitamin D levels in maternal serum and umbilical cord blood in a multi-ethnic population in Antwerp, Belgium. AB - OBJECTIVE: To describe the status of vitamin D levels in maternal and umbilical cord blood in term pregnant woman in a mixed ethnic population in an inner-city European maternity. METHODS: A single centre prospective cohort descriptive study including all uncomplicated singleton term pregnancies from April 1, 2011 until May 31, 2011. Plasma 25-hydroxy vitamin D level was determined in maternal and umbilical cord blood and data on age, previous obstetric history, ethnicity, nutritional intake and use of vitamin supplements were registered. RESULTS: Complete data were collected in 94 patients. Mean maternal serum vitamin D was 16.6 ng/mL. Using a cut-off of 20 ng/mL, 66% of women were classified as deficient. Deficiency was present in all ethnic groups, but lower levels were noted in North-African, Central-African and Asian women. A strong correlation between maternal and umbilical cord levels was noted (R = 0.91). Number of previous pregnancies and intake of supplements had no influence. CONCLUSION: The majority of low risk pregnant women showed vitamin D deficiency which was strongly correlated with umbilical cord levels. The prevalence was highest in the immigrant non-European population and was not influenced by intake of vitamin supplements. It can therefore be questioned whether the proposed cut-off values are appropriate. PMID- 24753924 TI - Validation of 3D power Doppler and VOCAL software in the sonographic assessment of hepatic venous flow. AB - AIM: To evaluate the reproducibility of three-dimensional power Doppler ultrasonography (3D-PDU) and the repeatability of Virtual Organ Computer-aided AnaLysis (VOCAL) software in the assessment of hepatic venous flow in ten healthy non-pregnant individuals. METHODS: Visualization of hepatic veins was performed using both intra- and subhepatic approaches; These examinations were repeated twice. Vascular indices were obtained for each examination in a reference point using both small and large volume samples (3 times per type of volume sample). Intraclass Correlation Coefficients and Pearson's Product-Moment Correlation Coefficient were calculated to assess reproducibility and repeatability, respectively. RESULTS: Intraclass Correlation Coefficients were more than 0.60 in small volumes, but variable in large volumes for both approaches. However, re identification of the reference point failed in 30% using the subhepatic approach. Repeatability was high for all VOCAL analyses (Pearson's Product-Moment Correlation Coefficient > 0.98). CONCLUSIONS: These results indicate reliable use of intrahepatic small volume samples in clinical application and invite to explore the role of this technology in the assessment of hepatic venous hemodynamics. PMID- 24753925 TI - Preconceptional care: a systematic review of the current situation and recommendations for the future. AB - OBJECTIVE: To review the current knowledge and implementation of preconceptional care (PCC) in the Western world, focusing both on health care workers and the general population, and to analyze pathways to disseminate the influence of preconceptional care on pregnancy outcome. METHODS: A systematic literature study was performed using OvidSP and Pubmed, searching for articles about PCC and its implementation, published between 1966 and October 2012. Only randomized controlled trials and systematic reviews dealing with PCC in the Western world were retained. RESULTS: Forty-six articles were identified for review. PCC might result in better pregnancy outcomes, including e.g. a reduction of congenital abnormalities. There are no proven disadvantages of PCC. Health care workers are in favor of the implementation of PCC, but claim that they don't have enough knowledge to do so. The general population shows interest in receiving PCC. The implementation of PCC should be improved by e.g. the development of guidelines and checklists. CONCLUSIONS: As PCC might improve pregnancy outcomes and is considered important by health care workers and the general population, its implementation should be improved, e.g. by the development of guidelines and checklists. PMID- 24753926 TI - Benchmarking and audit of breast units improves quality of care. AB - Quality Indicators (QIs) are measures of health care quality that make use of readily available hospital inpatient administrative data. Assessment quality of care can be performed on different levels: national, regional, on a hospital basis or on an individual basis. It can be a mandatory or voluntary system. In all cases development of an adequate database for data extraction, and feedback of the findings is of paramount importance. In the present paper we performed a Medline search on "QIs and breast cancer" and "benchmarking and breast cancer care", and we have added some data from personal experience. The current data clearly show that the use of QIs for breast cancer care, regular internal and external audit of performance of breast units, and benchmarking are effective to improve quality of care. Adherence to guidelines improves markedly (particularly regarding adjuvant treatment) and there are data emerging showing that this results in a better outcome. As quality assurance benefits patients, it will be a challenge for the medical and hospital community to develop affordable quality control systems, which are not leading to excessive workload. PMID- 24753927 TI - Pelvic Girdle Pain during or after Pregnancy: a review of recent evidence and a clinical care path proposal. AB - PROBLEM STATEMENT: Pelvic girdle pain (PGP) is a common condition during or after pregnancy with pain and disability as most important symptoms. These symptoms have a wide range of clinical presentation. Most doctors perceive pregnancy related pelvic girdle pain (PPGP) as 'physiologic' or 'expected during pregnancy', where no treatment is needed. As such women with PPGP mostly experience little recognition. However, many scientific literature describes PPGP as being severe with considerable levels of pain and disability and socio economic consequences in about 20% of the cases. OBJECTIVES: We aimed to (1) inform the gynecologist/obstetrician about the etiology, diagnosis, risk factors, and treatment options of PPGP and (2) to make a proposition for an adequate clinical care path. METHODS: A systematic search of electronic databases and a check of reference lists for recent researches about the diagnosis, etiology, risk factors and treatment of PPGP. RESULTS: Adequate treatment is based on classification in subgroups according to the different etiologic factors. The various diagnostic tests can help to make a differentiation in the several pelvic girdle pain syndromes and possibly reveal the underlying biomechanical problem. This classification can guide appropriate multidimensional and multidisciplinary management. A proposal for a clinical care path starts with recognition of gynecologist and midwife for this disorder. Both care takers can make a preliminary diagnosis of PPGP and should refer to a physiatrist, who can make a definite diagnosis. Together with a physiotherapist, the latter can determine an individual tailored exercise program based on the influencing bio-psycho-social factors. PMID- 24753928 TI - In search of the most efficient fertility preservation strategy for prepubertal boys. AB - Fertility preservation strategies are currently being developed for boys facing spermatogonial stem cell (SSC) loss. However, it is not clear yet which transplantation strategy would be the best choice. Therefore, the aim of the work presented in this thesis was both to compare these strategies and to study how to improve their efficiency. The efficiency to restore spermatogenesis after transplantation of SSCs or testicular tissue was evaluated. In addition, we investigated the potential of transplanted adult bone marrow stem cells (BMSCs) to repopulate the testis. We aimed to improve the efficiency of human intratesticular xenografting by exogenous administration of FSH. Since spermatogonial loss was observed in human intratesticular xenografts, we finally evaluated whether early cell death was the cause of this loss. Compared to SSC transplantation, more donor-derived spermatogenesis was observed after intratesticular tissue grafting. Human SSCs were able to survive for at least 12 months inside the mouse testis and meiotic activity was observed. However, the attempt to improve germ cell survival and induce full differentiation by the exogenous administration of FSH failed. Spermatogonia-specific apoptosis could not explain the SSC loss. Differentiation towards the germ line was not observed after intra-testicular injection of BMSCs, neither did we observe any protective effect for SSC loss. Intra-testicular tissue grafting seems to be the most efficient fertility preservation strategy. However, this strategy can not be applied in patients at risk of malignant contamination. For these patients SSC transplantation should be performed after decontamination of the cell suspension. PMID- 24753929 TI - Postgraduate cadaver surgery: An educational course which aims at improving surgical skills. AB - OBJECTIVE: To describe the postgraduate surgical skills training programme of the Flemish Society of Obstetrics and Gynaecology (VVOG*). Laparoscopic surgical techniques and indications have increased substantially during the past two decades. From surgeons it is expected that they keep up with all techniques and should be able to perform all relevant procedures. Learning new procedures in daily practice is hazardous and difficult to achieve. A training experience with cadaver surgery could improve the course and outcome of surgery on patients. We present the objective, structure, and outcome of the endoscopic postgraduate training course. STRUCTURE: The overall objective of the endoscopic postgraduate training course is to refresh anatomical knowledge and improve general gynaecological laparoscopic surgical skills. The VVOG endoscopic training programme is based on black box training, followed by pig surgery. New is the possibility to perform surgical procedures on specifically prepared human cadavers. The course consists of an anatomical teaching session followed by lectures with videotaped procedures on the anatomical exploration of the pelvis, laparoscopic hysterectomy and pelvic lymphadenectomy. During the hands-on session the participant performs the surgical procedures in a controlled, nonthreatening and interactive way under the guidance of an experienced trainer. CONCLUSIONS: All participants provided feedback on their experiences. The evaluation of the workshop revealed that this course is an opportunity to practise and improve clinical laparoscopic skills of gynaecological procedures and anatomy. Attending the course was regarded as of genuine additional value for surgical practice. PMID- 24753930 TI - Use of progestagens during early pregnancy. AB - The term "progestagens" covers a group of molecules including both the natural female sex hormones Progesterone and 17-hydroxy Progesterone as well as several synthetic forms, all displaying the ability to bind Progesterone receptors. Several studies have used Progesterone and related steroids in the attempt to prevent spontaneous miscarriage, and treat recurrent miscarriage. The present paper aims to provide a comprehensive review of the literature on progestagens effects during early pregnancy. We looked only at the results from randomized controlled trials. We found and analyzed 15 trials on the prevention of recurrent miscarriage and 2 trials on the treatment of miscarriage. The results demonstrated that there is no evidence to support the routine use of progestagens for the treatment of threatened miscarriage. PMID- 24753932 TI - Editorial. PMID- 24753931 TI - The uterine myocyte as a target for prevention of preterm birth. AB - Preterm birth (PTB) remains the most common cause of neonatal morbidity and mortality as well as long-term disability. Current strategies to prevent or arrest spontaneous preterm labor (SPTL) have limited success. For almost three decades, there have been no novel pharmacological agents used clinically to address this important obstetrical complication. In this review, we focus on the uterine myocyte as a target for prevention of spontaneous PTB. After presenting an overview of intracellular signaling pathways that are important in regulation of smooth muscle contractility, we discuss previous and current pharmacological approaches to manage SPTL. We also present recent evidence from our own laboratories suggesting a potentially novel and uterine-specific approach to maintain or impose uterine relaxation. Finally, we briefly discuss extrinsic systems that might affect uterine activity and reinforce the concept that SPTL represents a syndrome that is the end result of a variety of pathophysiologic etiologies leading to PTB. We conclude by emphasizing the need for much more research to provide sufficient understanding of the mechanisms of SPTL and to make inroads towards reducing the incidence and adverse consequences of this common and serious syndrome. PMID- 24753933 TI - Improving external cephalic version for foetal breech presentation. AB - OBJECTIVES: If success rate of external cephalic version (ECV) increases, the rate of primary caesarean sections -declines. The aims of this retrospective cohort study were to evaluate the ECV and to identify factors associated with the success rate of ECV for breech presentation at term. The second aim of this study was to analyse the outcome of labour of all patients with a foetus in breech near term. METHODS: All women with a foetus in breech near or at term were included. Logistic regression analyses were -performed to identify the association between patient characteristics and success rate of ECV. RESULTS: The overall rate of successful ECV's was 19%. Foetal and maternal complications after ECV were negligible. BMI, type of breech and amount of amniotic fluid were significantly correlated with a successful ECV. The rate of primary caesarean sections for the group of patients who underwent an ECV was lower than the rate in the group who did not (52.9% vs. 79.6%). The rate of spontaneous deliveries was increased after ECV (36% versus 12%). After successful ECV the rate of spontaneous deliveries was 75%; after unsuccessful ECV 26.8%. CONCLUSION: The overall rate of successful ECV was low (19%). BMI, type of breech and amount of amniotic fluid were significantly correlated with a successful ECV. The rate of primary caesarean sections was significantly lower in patients with ECV (52.9% versus 79.6%). The rate of spontaneous deliveries was significantly higher (36% -versus 12%). PMID- 24753934 TI - ART in South Africa: The price to pay. AB - In developing countries especially in Sub-Saharan Africa, human immunodeficiency virus (HIV) infection -together with limited resources adds to the hindrances in becoming a parent. Although the South African's Bill of Rights proclaim that South Africans can "make decisions concerning reproduction"; access to and the use of Assisted Reproduction Technology (ART) are viewed in general as excessively expensive, accessible only to the privileged few. A dissection of cost-drivers within an ART laboratory, such as procedures; sperm preparations; laboratory supplies including embryo culture media and cryopreservation are discussed in the current overview. Subject to the nature of an ART practice, i.e. private vs. public/tertiary, the structure of a unit will vary with regards to patient demographics, costs and services offered. The average fees per procedure for 20 practices in the private sector in South Africa are: (i) IUI: ? 542 +/- ?159, (ii) IVF: ? 3,255 +/- ? 576 and (iii) ICSI: ?3,302 +/- ? 625. Laboratory costs can contribute between 35 and 48% of ART fees payable in the private sector. Low-cost public ART services are available to citizens of the country at a few tertiary academic units. Some private practices also cater specifically for middle-income citizens. ART procedures need not be propelled towards the must have and cannot-do without approach, but providers should also reflect on the validity of the techniques and equipment, without compromising treatment virtue. PMID- 24753935 TI - Semen analysis workshops in India and Africa: the vital role of training and external quality control programmes. AB - Two hundred and fifty seven individuals from 16 African and Indian andrology laboratories attended several -semenology workshops from 1997 to 2013. The external quality control programme in Africa indicated the ability of participants to maintain the technology skills following a hands-on training. The pre-training sessions of the workshops indicated a total lack of knowledge how to perform a semen analysis according to the WHO manual. This was the case for morphology, motility and concentration. The results of this report underline the vital role of training as well as external quality control programmes. PMID- 24753936 TI - Systematic review of breast cancer related lymphoedema: making a balanced decision to perform an axillary clearance. AB - AIM: Breast cancer-related lymphoedema (BCRL) is a disabling complication developing after breast cancer treatment in a proportion of patients. Its impact on quality of life becomes more substantial as survival after breast cancer diagnosis increases. The incidence of BCRL following breast cancer treatment varies due to a lack of -uniform definition and measurement criteria. This review aims to determine the prevalence of BCRL following axillary lymph node dissection (ALND) as a benchmark to be used in a risk-benefit medical decision whether to proceed with ALND or not. The risk of leaving unresected non-sentinel metastatic lymph nodes with a presumed inherent risk of local recurrence will be balanced against the risk of BCRL following a potentially unnecessary ALND. METHODS: Pubmed and Embase databases were searched for all publications on BCRL in order to estimate its -incidence and to decide on the most appropriate measurement method to use in clinical practice. RESULTS: 51 articles were identified on BCRL incidence and measurement technique. Most studies measured BCRL based on differences in arm circumference (n = 18) or by self-reported symptoms (n = 18). The weighted average of BCRL incidence following ALND measured by self-report and circumference method was 28% and 16%, respectively. CONCLUSION: The importance of ALND and irradiation as part of the treatment of operable breast carcinoma is well established, but its morbidity is less well documented. We argue self-report as the most appropriate method to -establish a diagnosis of BCRL. Therefore a 28% risk of finding non-sentinel lymph node metastases in a completion ALND will be regarded as the cut-off in a medical decision to proceed with ALND. PMID- 24753937 TI - The maternal venous system: the ugly duckling of obstetrics. AB - In pregnancy, both maternal vascular tone and cardiac function are considered key players to reach a normal outcome for both mother and child. This complex story of maternal hemodynamics is intensely discussed in current scientific literature, however the role of the maternal veins has been strongly underestimated. We developed and evaluated a set of measurable objective parameters which give an indication of venous function, i.e. the venous impedance index and the venous pulse transit time. These parameters turned out to be subject to changes throughout normal pregnancy and in preeclampsia enabling their use in gestational hemodynamic -studies. From our studies, we concluded that the venous system is a crucial determinant of cardiac output, which can be estimated by impedance cardiography. The introduction of these non-invasive techniques in obstetrics enables profiling the maternal cardiovascular system, integrating both arteries and veins, as well as maternal cardiac -function. Studying the cascade of cardiovascular changes throughout pregnancy using such non-invasive, easily applicable, and highly accessible methods opens perspectives to introduce this maternal cardiovascular profile in several -clinical settings. The early discrimination between low and high risk patients, together with the classification of different pregnancy disorders may help guiding the clinical work-up of the pregnant population regarding both prevention and treatment, as well as follow-up. We illustrate that the venous system, being an "ugly duckling" at first neglected by the medical world, transforms and matures into a beautiful swan, accepted by the obstetric world. We are confident that this is the beginning of many other studies regarding the maternal venous system, an important piece of the gestational physiology puzzle. PMID- 24753938 TI - Delayed diagnosis of an Ewing sarcoma of the knee during pregnancy. PMID- 24753939 TI - The portrayal of healthy women requesting oocyte cryo-preservation. AB - The possibility to cryopreserve oocytes to be used in IVF treatment later in life has not only enlarged the reproductive options of cancer patients who are faced with gonadotoxic treatments, but also holds the promise of enlarging the reproductive options of healthy women whose personal circumstances (most often the absence of a partner) do not allow them to reproduce in their most fertile years. Opinions for and against this application of the cryopreservation technology are often based on different portrayals of the women who might use it. Three different portrayals can be discerned in the debate about the ethics of so called 'social egg freezing' or 'non medical egg freezing'. First, these women have been portrayed as selfish career-pursuing women. Second, healthy women who might benefit from oocyte cryopreservation have been portrayed as victims of a male-oriented society that makes it difficult for women to combine motherhood with a good education or professional responsibilities. Third, healthy women opting to cryopreserve oocytes have been portrayed as wise, proactive women who will not have to depend on -oocyte donors should they suffer from age-related infertility by the time they are ready to reproduce. Each of these three portrayals has its own shortcomings that one should be wary of, as they lead to an oversimplification of the ethical debate. PMID- 24753942 TI - Editorial. PMID- 24753940 TI - Hormonal anticonception anno 2013: a clinician's view. AB - Hormonal contraception has recently drawn the attention of both national and international Health Organizations mainly because of new data on the risk of venous and arterial thrombosis. This has, fortunately, not led to a 'pill scare' as happened in 1996 when controversy arose with respect to the thrombotic risk of third versus second -generation pills. This time, evidence on the thrombotic risk of pills with the newer progestogens is gathering, -leading to a re-evaluation of guidelines. In this paper, we summarize this evidence and try to present a clinician's view of the indications and contraindications of hormonal contraception and situate them in the perspective of the numerous non contraceptive health benefits of hormonal contraception. PMID- 24753941 TI - The Walking Egg Project: Universal access to infertility care - from dream to reality. AB - Childlessness and infertility care are neglected aspects of family planning in resource-poor countries, although the consequences of involuntary childlessness are much more dramatic and can create more wide ranging societal problems compared to Western societies, particularly for women. Because many families in developing countries completely depend on children for economic survival, childlessness has to be regarded as a social and public health issue and not only as an individual medical problem. In the Walking Egg Project we strive to raise awareness surrounding childlessness in resource-poor countries and to make infertility care in all its aspects, including assisted reproductive technologies, available and accessible for a much larger part of the world population. We hope to achieve this goal through innovation and research, advocacy and networking, training and capacity building and service delivery. The Walking Egg non-profit organization has chosen a holistic approach of reproductive health and therefore strengthening infertility care should go together with strengthening other aspects of family planning and mother care. Right from the start The Walking Project has approached the problem of infertility in a multidisciplinary and global manner. It gathers medical, social, ethical, epidemiological, juridical and economical scientists and experts along with artists and philosophers to discuss and work together towards its goal. We recently developed a simplified tWE lab IVF culture system with excellent results. According to our first cost calculation, the price of a single IVF cycle using the methodologies and protocols we described, seems to be less than 200 Euros. We realize that universal access to infertility care can only be achieved when good quality but affordable infertility care is linked to effective family planning and safe motherhood programmes. Only a global project with respect to sociocultural, ethical, economical and political differences can be successful. PMID- 24753943 TI - Factors predicting recurrent endometrial cancer. AB - OBJECTIVES: The aim of this study was to identify (prognostic) factors that may predict the development of recurrent endometrial cancer and may improve the choice of adjuvant therapy subsequently. METHODS: Data of all patients, diagnosed with primary endometrial cancer in Orbis Medical Center Sittard between 2002 and 2010, were analyzed retrospectively. Cox regression analysis was performed for identification of independent prognostic factors; survival was calculated by using the Kaplan-Meier method. STUDY DESIGN: Data of all patients, diagnosed with primary endometrial cancer in Orbis Medical Center Sittard between 2002 and 2010, were analyzed retrospectively. Cox regression analysis was performed for identification of independent prognostic factors; survival was calculated by using the Kaplan-Meier method. Multiple factors were associated with recurrence. Age, histological type and progesteron receptor expression (PR) were identified as independent prognostic factors. Risk profile (according to the PORTEC-1 study) and PR were also independent prognostic factors. Furthermore, PR (p < 0.001) and histological type (p = 0.013) were associated with disease specific survival after recurrence. CONCLUSION: Although the survival of endometrial cancer is good, the prognosis of recurrent disease is poor. Recurrence- of endometrial cancer and disease free survival rates are associated with several (independent) factors. The effect of adjuvant treatment may improve through more sufficient selection of patients by using the new prognostic- factors and through better selection of the type of adjuvant therapy. KEY WORDS: Endometrial cancer, recurrence, survival, prognostic factors, progesterone receptor expression. PMID- 24753944 TI - Pheromones and their effect on women's mood and sexuality. AB - Pheromones are substances which are secreted to the outside by an individual and received by a second individual of the same species. Many examples exist in animals but their role in humans remains uncertain since adults have no functioning vomeronasal organ, which processes pheromone signals in animals. Yet pheromones can be detected by the olfactory system although humans under develop and underrate their smelling sense. Pheromones may be present in all bodily secretions but most attention has been geared toward axillary sweat which contains the odorous 16-androstenes. One of these steroidal compounds, androstadienone, is present at much higher concentrations in male sweat and can be detected by women, albeit with wide variation in sensitivity. Upper-lip application of a pharmacological dose of androstadienonein women results in improved mood and heightened focus - particularly to capture emotional information. A positive mood is known to facilitate women's sexual response, and increased focus improves sexual satisfaction. Indeed, some studies showed a beneficial effect of androstadienone on sexual desire and arousal. However, these effects were dependent on the context of the experiment, for example, on the presence of a male attendant. Pheromones may also play a role in mate selection which is "disassortative" regarding the human leukocyte antigen (HLA)-genotype. Preliminary evidence suggests that exposure to androstadienone in women promotes attractiveness ratings of potential mates. In conclusion, some data indicate that 16-androstene pheromones, in particular androstadienone, play a beneficial role in women's mood, focus and sexual response, and perhaps also in mate selection. PMID- 24753945 TI - Limited effectiveness of HIV prevention for young people in sub-Saharan Africa: studying the role of intervention and evaluation. AB - On average, 2,500 young people (15-24 years) get -infected with HIV every day; 80% of which live in sub-Saharan Africa. Since no cure or vaccine is available, reducing sexual risk behaviour in this group is crucial in tackling the epidemic. The general objective of this doctoral study was to improve the effectiveness of HIV prevention interventions for young people in sub-Saharan Africa. First, we assessed the overall effectiveness of such interventions (systematic literature review, meta-analysis). Secondly, we evaluated a school-based peer-led HIV prevention interventions in Rwanda (longitudinal, non-randomized controlled trial), to get insight into how interventions are developed, implemented and evaluated. While the first two objectives demonstrated limited effectiveness, the third objective aimed to identify reasons for this limited effectiveness: a) baseline characteristics of -respondents that predict participation were identified (using data from objective 2); b) we studied determinants of young people's sexual behavior using a qualitative 'mailbox study' that assessed the spontaneous thoughts of Rwandan adolescents on sexuality; c) we assessed the role of one specific structural factor: -education (literature review and analysis of existing datasets); d) we assessed the theoretical underpinnings of existing HIV prevention interventions for young people in sub-Saharan Africa (literature review). Based on these studies, we discuss two main reasons for the observed limited effectiveness: factors associated with the intervention (strong focus on cognitions and moral, and implementation issues), and with evaluation (design, power, indicators). Recommendations for improving interventions, evaluations and for further research are provided. PMID- 24753946 TI - Imaging in gynaecological disease: clinical and ultrasound characteristics of mucocele of the appendix. A pictorial essay. AB - The aim of this pictorial essay is to describe the ultrasound characteristics of the mucocele of the appendix (MA) by transvaginal ultrasound. The databases of the pathology and gynaecology departments of two Belgian hospitals were retrospectively searched for all cases of MA. Only patients who received a pre operative transvaginal ultrasound scan by an experienced ultrasound examiner following the IOTA protocol were included. Ultrasound -characteristics were described and pattern recognition was applied in order to find morphological characteristics typical for MA. Thirty-one cases were found of which five underwent a transvaginal ultrasound. In three out of these five cases a mucocele was described. All three masses had a similar morphology, i.e. a para-ovarian uni locular tubular mass with a color score of 1. A typical characteristic was the aspect of the cyst content, which resembled whipped cream. Although MA is seldom diagnosed by gynaecologists, transvaginal ultrasound is able to make an accurate diagnosis. MA is a -para-ovarian, unilocular tubular mass that typically has a cyst content that resembles whipped cream. PMID- 24753947 TI - A short history of sonography in obstetrics and gynaecology. AB - The history of sonography in Obstetrics and Gynaecology dates from the classic 1958 Lancet paper of Ian Donald and his team from Glasgow. Fifty years on it is impossible to conceive of practising Obstetrics and Gynaecology without one of the many forms of ultrasound available today. Technological developments such as solid state circuitry, real time imaging, colour and power Doppler, transvaginal sonography and 3/4D imaging have been seized by clinical researchers to enhance the investigation and management of patients in areas as diverse as assessment of fetal growth and wellbeing, screening for fetal anomalies, prediction of pre eclampsia and preterm birth, detection of ectopic gestation, evaluation of pelvic masses, screening for ovarian cancer and fertility management. Ultrasound guided procedures are now essential components of fetal therapy and IVF treatment. This concise history is written by someone who has witnessed each of these advances throughout the ultrasound era and is able to give perspective to these momentous happenings. PMID- 24753948 TI - Evidence-based reproductive medicine: a critical appraisal. AB - Evidence-based medicine has become the golden standard of good medical practice. I analysed meta-analyses and systematic reviews, the cornerstones of evidence based medicine, pertaining to two important problems in in vitro fertilization: failed implantation and poor ovarian response to ovarian stimulation. Numerous interventions and procedures have been tried to facilitate implantation and to enhance the ovarian response to stimulation. Notwithstanding the fact that many clinical trials have been performed, very few procedures can as yet stand the critical test of evidence-based medicine. A plea is made for co-ordination between clinicians and reviewers and co-operation between infertility centres to combine their efforts to set up sufficiently powered clinical trials to arrive at more solid evidence for a number of interventions in in vitro fertilization programmes. PMID- 24753949 TI - The importance of being fertile. A call for a more balanced approach towards reproductive health. AB - The core business of reproductive health care in developing countries is HIV/AIDS, contraception and maternal care and not one single reproductive health care program is dealing with couples unable to reproduce. How strange to have on the one hand the reproductive medicine clinics in the resource rich countries focusing mainly on infertility care and on the other hand reproductive health care programs in resource poor countries not giving one single penny to infertility care. In this paper I am exploring the reasons for this unbalanced situation. It is clear from the facts and figures that infertility affects - often with devastating consequences - the lives of roughly one tenth of couples in developing countries. I argue that the neglect of infertility in the public health debate is caused by a mixture of ignorance (mainly by the international aid community) and tunnel vision, opportunism and a non--enlightened attitude of contempt for individual human rights. The prohibitive cost of IVF is contributing to this neglect as well. At present promising low cost IVF techniques are being developed and could potentially make IVF available at a cost accessible for a much larger part of the world population. With the latter becoming available, there should be no impediment for infertility care to become integrated into mainstream reproductive health care in developing nations. Reproductive rights advocates can no longer justify the systematic exclusion of one tenth of couples from the right to decide freely if, when and how to reproduce. KEY WORDS: Reproductive health, reproductive rights, infertility care, developing countries, public health, simplified IVF. PMID- 24753951 TI - Editorial. PMID- 24753950 TI - We may not have it all together, but together we have it all. The importance of intra- and interdisciplinary collaboration. AB - The tremendous development of knowledge, the accumulation of clinical experience, and the enriching of everyday practice with the results of basic and clinical research created the need for splitting medicine in specialities and sub specialities. Although this evolution is inevitable in order to meet the complex needs and demands of patients, we have to be aware of the risk of neglecting the holistic approach of a person in distress. Indeed, the organ-focused and pathology-centred approach of a patient may not exempt us of the rudiments of care such as the notion that a human being is more than the sum of its parts. This involves the absolute obligation for intra and inter-disciplinary cooperation. Recently, the European leading societies in Gynaecology, the European Board Obstetricians and Gynaecologists (EBCOG), the European Society of Human reproduction and Embryology (ESHRE), the European Society for Gynaecological Endoscopy (ESGE) and the European Academy for Gynaecological Surgery (+he Academy), have established some common impressive initiatives to improve women's health care. As a result of an intensive research programme coordinated by +he Academy with a multidisciplinary team of gynaecologists and surgeons a unique structured training and certification programme in endoscopic surgery is established. This project is a fine example making the dream of multidisciplinary approach reality and achieving some most impressive results. It is without any doubt a major step forwards in the improvement of the quality assurance in endoscopic surgery in benefit of the patients care and has been accepted by our leading European and national societies. Recently, ESGE and ESHRE developed a new classification on female genital anomalies. An evidence-based updated new classification published in the official journal of both societies was the ended result. THIS CREATIVE, SUCCESSFUL AND UNEVENTFUL COLLABORATION UNDERLINES THE NEED FOR RESPECTING SOME CRUCIAL POINTS: to clearly outline the topic of common action, to find the working platform, to define the method and to respect -independence of each society by clarifying the borders and the responsibilities. Keeping the window of the collaboration open is crucial for keeping the window to medicine of the future unlocked. PMID- 24753952 TI - A novel radiographic technique to asses grafts in the female -pelvis: a comparison of the Inside-Out and the Outside-In trans-obturator mid urethral sling positioning. AB - The three-dimensional configuration of mid-urethral sling tapes is difficult to demonstrate in traditional anatomical dissections or imaging studies. The aim of this study was to test the utility of a novel technique using mesh tapes to assess spatial differences between the in-out and out-in transobturator mid urethral slings. Two independent surgeons performed their usual transobturator mid-urethral sling placement on 10 fresh thawed cadavers, alternating sides in the consecutive cadavers. Tantalum wires threaded through the polypropylene-tapes rendered them radio-opaque. Following placement, CT scans were obtained to generate 3-D and MIPS images for analysis. Results showed that the mean angle formed by the in-out sling measured 122o (95%CI: 107o-136o); versus 144o (95%CI: 131o-151o) for the out-in sling (p = 0.02). The paired differences between the tapes' inner angles were significantly different; with a mean difference of 20o (median 19.0o), (p = 0.008). There was no significant correlation between either approach and BMI or angle of the pubic arch. The images revealed that the tapes lie as a band posterior/dorsal to the urethra rather than inferior. IN CONCLUSION: marking mesh with -Tantalum wire, in combination with 3-D and MIPS CT scan reconstruction images, provided a unique method to visualize the entire sling trajectory. The clinical implications of the more horizontal positioning after the out-in approach remain to be determined. PMID- 24753953 TI - Donor-conceived children looking for their sperm donor: what do they want to know? AB - OBJECTIVE: This paper aims to gain in-depth understanding of why some donor conceived offspring want to know the identity of their sperm donor. METHODS: Step by-step inductive thematic analysis was performed on first-hand quotes from donor conceived offspring selected from a wide range of sources (including empirical studies and donor conception networks, registries and support groups). RESULTS: We found that at least 7 different objectives can underlie the wish to know one's donor: to avoid medical risks and consanguineous relationships; to connect with one's roots; to complete one's life (hi-)story; to understand where one's traits come from; to discover or assess one's defining characteristics and capabilities; to rectify a wrong-doing, and to map out one's ancestral history. CONCLUSION: The analysis shows that there is great variance among identity-seekers in the weight they attribute to wanting to know their donor. It is also clear that they have very different assumptions about the role and importance of genetics in terms of establishing 'who they are' or 'can become', including deterministic misconceptions. Rather than treat all donor-conceived offspring's needs as of equal concern, this analysis should help distinguish between and assess the relevance of the various motivations. PMID- 24753954 TI - Does ovulation induction increase the risk of gynecological cancer? AB - The risk of developing gynaecological cancer following ovulation induction therapy in infertile patients is not easy to determine due to many confounding factors. These include the fact that infertility in itself is a known risk factor for some of these cancers, that these patients are subjected to increased surveillance compared to the general population and that the drugs used for ovulation induction are sometimes used in combination. Notwithstanding these limitations, most of the studies have not confirmed a link between these drugs and invasive ovarian cancers, although some studies have suggested that the risk of borderline ovarian tumors may be increased. Investigations regarding breast cancer risk have produced inconsistent results and more information on the subject is warranted. On the contrary, many studies suggest that drugs used for ovulation induction may increase the risk of uterine cancers. More large well designed studies are still needed to further clarify the effects on cancer risk of these drugs and will allow more in-depth subgroup analysis based on both patient and disease characteristics. PMID- 24753955 TI - Life and death in the Philippines. AB - In a country in which contraception is controversial, abortion illegal and in which reproductive rights are limited, IVF is an unaffordable dream for most couples. But things are slowly changing in the only Christian democracy in Asia: the Philippines. In December 2012 the Senate passed the Reproductive Health bill and president Benigno Aquino III signed the measure into a law which is still not implemented due to the opposition of the ultra-orthodox Roman Catholic Church. However, the more liberal perspective of pope Francis on sexuality and human reproduction may have an positive impact on this issue. While government funding for contraceptives is still being opposed, the IVF market is estimated to grow considerable. This creates promising opportunities. PMID- 24753956 TI - The world population explosion: causes, backgrounds and -projections for the future. AB - At the beginning of the nineteenth century, the total world population crossed the threshold of 1 billion people for the first time in the history of the homo sapiens sapiens. Since then, growth rates have been increasing -exponentially, reaching staggeringly high peaks in the 20th century and slowing down a bit thereafter. Total world population reached 7 billion just after 2010 and is expected to count 9 billion by 2045. This paper first charts the differences in population growth between the world regions. Next, the mechanisms behind unprecedented population growth are explained and plausible scenarios for future developments are discussed. Crucial for the long term trend will be the rate of decline of the number of births per woman, called total fertility. Improvements in education, reproductive health and child survival will be needed to speed up the decline of total fertility, particularly in Africa. But in all scenarios, world population will continue to grow for some time due to population momentum. Finally, the paper outlines the debate about the consequences of the population explosion, involving poverty and food security, the impact on the natural environment, and migration flows. KEY WORDS: Fertility, family planning, world population, population growth, demographic transition, urbanization, population momentum, population projections. PMID- 24753957 TI - Incessant ovulation and ovarian cancer - a hypothesis re-visited. AB - Ovarian cancer continues to be a silent killer. Most women have advanced disease at the time of diagnosis. Intensive efforts to develop effective screening strategies have not so far met with success. There is a need to re-visit the potential of prevention strategies. In 1971, the author submitted a hypothesis for a possible relationship between incessant ovulation and development of epithelial ovarian cancer. Subsequent research from different disciplines opened new frontiers to be explored for prevention in the general population and in high risk groups, and for opportunistic interventions. The protective effect of oral contraceptive pills has been well documented. Widespread use of the pill in the past several decades is credited with a fall in the incidence of ovarian cancer in the general population, countering the effect of low parity. Removing the barriers against contraceptive access and satisfying the still unmet contraceptive need could expand the protective coverage. Enhanced understanding of the biological mechanisms involved in process of ovulation offers the promise of non-hormonal pharmacologic suppression of follicle rupture for women who have risk factors and do not need contraception. The evidence for a possible origin of epithelial cancer in the fimbria of the Fallopian tube presents an opportunity for preventive intervention, during hysterectomy, where salpingectomy alone may provide protection while one or both ovaries are conserved. Finally, the incessant ovulator egg-laying hen has demonstrated its potential as an experimental model for chemoprevention of epithelial ovarian cancer. PMID- 24753958 TI - Early stage management of ovarian endometrioma to prevent infertility. AB - There are now convincing data showing that cystectomy of the endometrioma is not only no cure of infertility, but may harm follicle reserve. The question arises why is cystectomy for an endometrioma, in contrast with other -benign cysts, a risk for follicle reserve and how can ovarian damage be prevented. Surgical specimens of ovaries with endometrioma in situ show in the majority of cases manifestly a combined -extra-ovarian and intra-ovarian pathology with the cortex invaginated to form a pseudocyst. The extra-ovarian pathology includes endometrial lining of the cortex, bleeding and adhesions with surrounding tissues. The intra-ovarian pathology is characterized by microscopic stromal implants, fibrosis, smooth muscle metaplasia and -arteriosclerosis, all affecting follicle reserve in the endometrioma bed. Clinically, ovarioscopy allows differential diagnosis (e.g. luteal cyst) and evaluation of the degree of fibrosis and darkening of the cortical wall. Transvaginal colour Doppler sonography can demonstrate the presence and extent of devascularisation in the endometrioma bed. Given this reality, surgery should be based on evaluation of the pathology of the endometrioma bed, but not on the mere size of the chocolate cyst. The main clinical problem is indeed the delayed diagnosis and consequently advanced irreversible cortical damage. Therefore, the sooner endometriomas are diagnosed, the better, because it increases the chances that vascularisation of the endometrioma bed is preserved. Finally, ablation, but not excision is the treatment of choice. The diagnosis of endometriosis is traditionally based on laparoscopy, but in a sexually active adolescent transvaginal endoscopy can be proposed. PMID- 24753959 TI - Letter to the editor. PMID- 24753960 TI - Photoactivation of neurons by laser-generated local heating. AB - We present a method for achieving temporally and spatially precise photoactivation of neurons without the need for genetic expression of photosensitive proteins. Our method depends upon conduction of thermal energy via absorption by chemically inert carbon particles and does not require the presence of voltage-gated channels to create transmembrane currents. We demonstrate photothermal initiation of action potentials in Hirudo verbana neurons within an intact ganglion and of transmembrane currents in Xenopus oocytes. Thermal energy is delivered by focused 50 ms, 650 nm laser pulses with total pulse energies between 250 and 3500 MUJ. We document an optical delivery system for targeting specific neurons that can be expanded for multiple target sites. Our method achieves photoactivation reliably (70 - 90% of attempts) and can issue multiple pulses (6-9) with minimal changes to cellular properties as measured by intracellular recording. Direct photoactivation presents a significant step towards all-optical analysis of neural circuits in animals such as Hirudo verbana where genetic expression of photosensitive compounds is not feasible. PMID- 24753961 TI - Assessing the usability of MAX 2008 encounter data for comprehensive managed care. AB - BACKGROUND: As growing numbers of Medicaid enrollees receive health benefits through comprehensive managed care, researchers and policymakers seeking to understand the service use of these enrollees must rely on encounter data. OBJECTIVE: To assess the availability, completeness, and quality of physician, clinic, and outpatient service (OT), inpatient (IP), and prescription drug (RX) encounter claims to judge the usability of the 2008 Medicaid Analytical eXtract (MAX) encounter data. DATA: 2008 MAX encounter data, which are derived from the state-submitted Medicaid Statistical Information System (MSIS) files. METHODS: For each basis of eligibility (BOE) group in each state that had at least ten percent participation in comprehensive managed care and submitted at least 200 encounter claims, the completeness and quality of the OT, IP, and RX encounter data were evaluated using comparison metrics created from the full-benefit, non dual fee-for-service (FFS) population across all states with substantial FFS participation. Data that met both the completeness and quality criteria were considered usable. RESULTS: The completeness and the quality of the encounter data were high. The encounter data were considered usable for a least one BOE category for 22 of the 25 states that submitted OT encounter data, 20 of the 24 states that submitted IP data, and 13 of the 15 states that submitted RX data. CONCLUSIONS: Most states that have comprehensive managed care plans are reporting OT, IP, and RX encounter data. Of those data, the majority are complete and of comparable quality to FFS data for adults, children, the disabled, and aged populations. PMID- 24753962 TI - The effect of the children's health insurance program on pediatricians' work hours. AB - OBJECTIVE: Our study examines changes in physicians' work hours in response to a coverage expansion. METHODS: We use as a natural experiment the Children's Health Insurance Program (CHIP), which was established in 1997 and significantly expanded children's eligibility for public health insurance coverage. The magnitude of the CHIP expansion varied across states and over time, allowing its effects to be identified using a state-year fixed effects model. We focus on pediatricians, and we measure their self-reported work hours using multiple waves (pre- and post-CHIP) of the physician survey component of the Community Tracking Study. To address endogeneity concerns, we instrument for CHIP enrollment using key program features (income eligibility cutoffs and waiting times). RESULTS: We find a large negative relationship between the magnitude of a state's CHIP expansion and trends in pediatricians' work hours. This relationship could be due to key supply-side features of CHIP, including relatively low provider reimbursements and heavy use of managed care tools. PMID- 24753963 TI - Medicare Part D roulette: potential implications of random assignment and plan restrictions. AB - BACKGROUND: Dual-eligible (Medicare/Medicaid) beneficiaries are randomly assigned to a benchmark plan, which provides prescription drug coverage under the Part D benefit without consideration of their prescription drug profile. To date, the potential for beneficiary assignment to a plan with poor formulary coverage has been minimally studied and the resultant financial impact to beneficiaries unknown. OBJECTIVE: We sought to determine cost variability and drug use restrictions under each available 2010 California benchmark plan. METHODS: Dual eligible beneficiaries were provided Part D plan assistance during the 2010 annual election period. The Medicare Web site was used to determine benchmark plan costs and prescription utilization restrictions for each of the six California benchmark plans available for random assignment in 2010. A standardized survey was used to record all de-identified beneficiary demographic and plan specific data. For each low-income subsidy-recipient (n = 113), cost, rank, number of non-formulary medications, and prescription utilization restrictions were recorded for each available 2010 California benchmark plan. Formulary matching rates (percent of beneficiary's medications on plan formulary) were calculated for each benchmark plan. RESULTS: Auto-assigned beneficiaries had only a 34% chance of being assigned to the lowest cost plan; the remainder faced potentially significant avoidable out-of-pocket costs. Wide variations between benchmark plans were observed for plan cost, formulary coverage, formulary matching rates, and prescription utilization restrictions. CONCLUSIONS: Beneficiaries had a 66% chance of being assigned to a sub-optimal plan; thereby, they faced significant avoidable out-of-pocket costs. Alternative methods of beneficiary assignment could decrease beneficiary and Medicare costs while also reducing medication non-compliance. PMID- 24753964 TI - Forecasting the use of electronic health records: an expert opinion approach. AB - BACKGROUND: To promote the widespread adoption and use of electronic health records (EHRs), in 2011, CMS started making Medicare and Medicaid incentive payments to providers who demonstrate that they are "meaningful users" of certified EHR systems. DATA AND METHODS: This paper combines an expert opinion method, a modified Delphi technique, with a technological diffusion framework to create a forecast of the percent of office-based physicians who will become adopters and "meaningful users" of health information technology from 2012 to 2019. The panel consisted of 18 experts from industry, academia, and government who are knowledgeable about the adoption and use of EHRs in office-based settings and are recognized as opinion leaders in their respective professions. RESULTS: Overall, the expert panel projected that primary care physicians in large group practices are more likely to achieve the meaningful use of EHRS relative to primary care physicians in small group practices and all other specialists: the group projected that 65 percent of primary care physicians in large group practices, 45 percent of primary care physicians in small group practices, and 44 percent of all other specialists could achieve meaningful use by 2015. In 2019, these projections increase to 80 percent, 65 percent, and 66 percent for these three groups, respectively. CONCLUSIONS AND POLICY IMPLICATIONS: The information from this study is especially valuable when there is a lack of data and a high degree of uncertainty in a new policy environment and could help inform and evaluate government programs, such as the Regional Extension Centers (REC), by providing data from leading experts. PMID- 24753965 TI - The impact of electronic health records on ambulatory costs among Medicaid beneficiaries. AB - BACKGROUND: Broad adoption of electronic health records (EHRs) is a potential strategy for curbing healthcare cost growth, which is particularly vital for Medicaid. Despite limited evidence for EHR-related cost savings, the 2009 HITECH Act included incentives for providers to become meaningful users of EHRs. We evaluated a large Massachusetts EHR pilot to obtain early insight into the potential for the national strategy to reduce short-run healthcare costs in the Medicaid population. METHODS: We calculated monthly ambulatory cost and visit measures from Medicaid claims data for beneficiaries receiving the majority of their care in the three Massachusetts eHealth Collaborative (MAeHC) pilot communities or in six matched control communities. Using a difference-in differences of slope analysis, we assessed whether cost and visit trajectories differed in the pre-implementation period compared to the post-implementation period for intervention and control community members. RESULTS: We found evidence that EHR adoption impacted ambulatory medical cost in two of the three communities, but the effects were in opposite directions. Ambulatory medical costs increased more slowly in one intervention compared to its control communities in the pre-to-post period (difference-in-differences=-1.98%, p<0.001; PMPM savings of $41.60). In contrast, for a second pilot community, ambulatory medical cost increased more slowly in the control communities (difference-in differences=2.56%, p=0.005; PMPM increase of $43.34). CONCLUSIONS: As a stand alone approach, adoption of commercially-available EHRs in community practices did not consistently impact Medicaid costs in the short-run. This suggests that future meaningful use criteria may need to specifically target cost savings and coordinate with payment reform efforts. PMID- 24753966 TI - Medicare readmission rates showed meaningful decline in 2012. AB - OBJECTIVE: Descriptive analysis of 30-day, all-cause hospital readmission rate patterns from 2007-2012. POPULATION: Medicare FFS beneficiaries experiencing at least one acute inpatient hospital stay. METHODS: Using Chronic Condition Data Warehouse claims, we estimate unadjusted, monthly, readmission rates for the nation, within the Dartmouth Hospital Referral Regions (HRR), and compare participating and non-participating hospitals in the Partnership for Patients (P4P) program (overall and by number of inpatient beds at each facility). RESULTS: From 2007 through 2011, the national 30-day, all-cause, hospital readmission rate averaged 19 percent. During calendar year 2012, the readmission rate averaged 18.4 percent. Of the 306 HRRs, rates in 166 HRRs fell by between 1 and 5 percent, while rates dropped by more than 5 percent in 73 HRRs, with the largest reduction in Longview, Texas. Rates increased by more than 1 percent in only 30 HRRs, with the largest increase in Bloomington, Illinois. Readmission rates at hospitals participating in the P4P program have been, on average, consistently lower than the rates at non-participating hospitals within all size categories except for the very smallest and largest hospitals, but rates at both participant and non-participant hospitals fell in 2012. DISCUSSION: Although claims data are not yet final for 2012, our analysis indicates that hospital readmission rates for all Medicare FFS beneficiaries dropped noticeably during the year. The reasons behind the apparent reduction are not yet clear and merit further investigation. PMID- 24753967 TI - Medicare payments: how much do chronic conditions matter? AB - OBJECTIVE: Analyze differences in Medicare Fee-for-Service utilization (i.e., program payments) by beneficiary characteristics, such as gender, age, and prevalence of chronic conditions. METHODS: Using the 2008 and 2010 Chronic Conditions Public Use Files, we conduct a descriptive analysis of enrollment and program payments by gender, age categories, and eleven chronic conditions. RESULTS: We find that the effect of chronic conditions on Medicare payments is dramatic. Average Medicare payments increase significantly with the number of chronic conditions. Finally, we quantify the effect of individual conditions and find that "Stroke / Transient Ischemic Attack" and "Chronic Kidney Disease" are the costliest chronic conditions for Part A, and "Cancer" and "Chronic Kidney Disease" are the costliest for Part B. PMID- 24753968 TI - Expansion of Medicaid covered smoking cessation services: maternal smoking and birth outcomes. AB - OBJECTIVE: To assess whether Medicaid coverage of smoking cessation services reduces maternal smoking and improves birth outcomes. METHODS: Pooled, cross sectional data for 178,937 women with live births from 1996 to 2008, who were insured by Medicaid in 34 states plus New York City, were used to analyze self reported smoking before pregnancy (3 months), smoking during the last 3 months of pregnancy, smoking after delivery (3-4 months), infant birth weight, and gestational age at delivery. Maternal socio-demographic and behavior variables from survey data and birth outcomes from vital records were merged with annual state data on Medicaid coverage for nicotine replacement therapies (NRT), medications and cessation counseling. Probit and OLS regression models were used to test for effects of states' Medicaid cessation coverage on mother's smoking and infant outcomes relative to mothers in states without coverage. RESULTS: Medicaid coverage of NRT and medications is associated with 1.6 percentage point reduction (p<.05) in smoking before pregnancy among Medicaid insured women relative to no coverage. Adding counseling coverage to NRT and medication coverage is associated with a 2.5 percentage point reduction in smoking before pregnancy (p<.10). Medicaid cessation coverage during pregnancy was associated with a small increase (<1 day) in infant gestation (p<.05). CONCLUSIONS: In this sample, Medicaid coverage of smoking cessation only affected women enrolled prior to pregnancy. Expansions of Medicaid eligibility to include more women prior to pregnancy in participating states, and mandated coverage of some cessation services without co-pays under the Affordable Care Act (ACA) should reduce the number of women smoking before pregnancy. PMID- 24753969 TI - State variability in children's Medicaid/CHIP crowd-out estimates. AB - BACKGROUND: Health insurance crowd-out occurs when individuals enrolled in a public health insurance plan would have enrolled in a private plan but for the public option. The crowding-out of private insurance is often used to criticize state Medicaid and Children's Health Insurance Program (CHIP) expansion, as already insured children move their coverage to the states at the public's expense. A difficulty in discussing crowd-out comes from inconsistent estimates. Previous work focusing on the expansion of public programs has led to estimates ranging from 0% to 50% of the children newly insured on public plans being crowded-out. METHODS: We apply a regression discontinuity approach to estimate how many children near the state Medicaid/CHIP threshold are crowded-out of private insurance. This approach allows estimates of crowd-out near the eligibility threshold independent of any expansion. Data from the American Community Survey's yearly survey of American households allows for state-level estimates of crowd-out. RESULTS: We find considerable heterogeneity in the crowd out that occurs in each state, ranging from no crowd-out to over 18% in states with similar eligibility thresholds. Additionally, we found that as state eligibility thresholds increase, children are less likely to be crowded-out. DISCUSSION: This research indicates that national estimates of crowd-out are inappropriate, as state-specific Medicaid and CHIP programs have state-specific crowd-out. Additionally, it indicates that wealthier families that are eligible for public insurance are less likely to switch from private to public coverage than families earning less. Future work should identify reasons for the heterogeneity among states. PMID- 24753970 TI - Bundling post-acute care services into MS-DRG payments. AB - OBJECTIVE: A bundled hospital payment system that encompasses both acute and post acute care has been proposed as a means of creating financial incentives in the Medicare fee-for-service system to foster care coordination and to improve the current disorganized system of post care. The objective of this study was to evaluate the statistical stability of alternative designs of a hospital payment system that includes post-acute care services to determine the feasibility of using a combined hospital and post-acute care bundle as a unit of payment. METHODS: The Medicare Severity-Diagnosis Related Groups (MS-DRGs) were subdivided into clinical subclasses that measured a patient's chronic illness burden to test whether a patient's chronic illness burden had a substantial impact on post-acute care expenditures. Using Medicare data the statistical performance of the MS-DRGs with and without the chronic illness subclasses was evaluated across a wide range of post-acute care windows and combinations of post-acute care service bundles using both submitted charges and Medicare payments. RESULTS: The statistical performance of the MS-DRGs as measured by R(2) was consistently better when the chronic illness subclasses are included indicating that MS-DRGs by themselves are an inadequate unit of payment for post-acute care payment bundles. In general, R(2) values increased as the post-acute care window length increased and decreased as more services were added to the post-acute care bundle. DISCUSSION: The study results suggest that it is feasible to develop a payment system that incorporates significant post-acute care services into the MS-DRG inpatient payment bundle. This expansion of the basic DRG payment approach can provide a strong financial incentive for providers to better coordinate care potentially leading to improved efficiency and outcome quality. PMID- 24753971 TI - Effect of long-term care use on Medicare and Medicaid expenditures for dual eligible and non-dual eligible elderly beneficiaries. AB - BACKGROUND: Dual eligible Medicare and Medicaid beneficiaries consume disproportionate shares of both programs. OBJECTIVES: To compare Medicare and Medicaid expenditures of elderly dual eligible beneficiaries with non-dual eligible beneficiaries based on their long-term care (LTC) use. RESEARCH DESIGN: Secondary analysis of linked MAX and Medicare data in seven states. SUBJECTS: Dual eligible adults (65+) receiving LTC in institutions, in the community, or not at all; and Medicare non-dual eligibles. MEASURES: Medicaid acute medical and LTC expenditures per beneficiary year, Medicare expenditures. RESULTS: Among dual eligibles and non-dual eligibles, the average number of diseases and case mix scores are higher for LTC users. Adjusting for case mix virtually eliminates the difference for medical costs, but not for LTC expenditures. Adjusting for LTC status reduces the difference in LTC costs, but increases the difference in medical costs. CONCLUSIONS: Efforts to control costs for dual eligibles should target those in LTC while better coordinating medical and LTC expenditures. PMID- 24753972 TI - Standardizing Medicare payment information to support examining geographic variation in costs. AB - OBJECTIVES: Examination of efficiency in health care requires that cost information be normalized. Medicare payments include both geographic and policy based facility type differentials (e.g., wage index and disproportionate share hospital), which can bias cost comparisons of hospitals and averages across geographic areas. Standardizing payment information to remove the area- and policy-based payment differentials should normalize much of the observed geographic variability in payments, allowing for a more accurate comparison of resource use between providers and across geographic regions. Use of standardized payments will ensure that observed payment variation is due to differences in practice patterns and service use, rather than Medicare payment differences over which the providers have no control. This paper describes a method for standardizing claim payments, and demonstrates the difference in actual versus standardized payments by geographic region. STUDY DESIGN AND METHODS: We used a nationwide cohort of Medicare patients hospitalized with an acute myocardial infarction (AMI) in 2007, then limited our study to those with Medicare Part A and Part B fee-for-service (FFS), and Part D coverage (n = 143,123). Standardized payment amounts were calculated for each Part A and Part B claim; standardized and actual payments were summed for all services for each patient beginning with the index hospitalization through 12 months post discharge. PRINCIPAL FINDINGS: Without standardization of payments, certain areas of the country are mischaracterized as either high or low healthcare resource-consuming areas. The difference between actual and standardized payments varies by care setting. CONCLUSIONS: Standardized payment amounts should be calculated when comparing Medicare resource use across geographic areas. PMID- 24753973 TI - Episode-based payment: evaluating the impact on chronic conditions. AB - BACKGROUND: Policy makers are interested in aggregating fee-for-service reimbursement into episode-based bundle payments, hoping it will lead to greater efficiency in the provision of care. The focus of bundled payment initiatives has been upon surgical or discrete procedures. Relatively little is known about calculating and implementing episode-based payments for chronic conditions. OBJECTIVE: Compare the differences in two different episode-creation algorithms for two common chronic conditions: diabetes and coronary artery disease (CAD). STUDY DESIGN: We conducted a retrospective evaluation using enrollees with continuous coverage in a self-funded plan from 2003 to 2006, meeting Healthcare Effectiveness Data and Information Set (HEDIS) criteria for diabetes or CAD. For each condition, an annual episode-based payment was assessed using two algorithms: Episode Treatment Groups (ETGs) and the Prometheus model. PRINCIPAL FINDINGS: We began with 1,580 diabetes patients with a 4-year total payment mean of $67,280. ETGs identified 1,447 (92%) as having diabetes with 4-year episode based mean payments of $12,731; while the Prometheus model identified 1,512 (96%) as having diabetes, but included only 1,195 of them in the Prometheus model with mean diabetes payments of $23,250. Beginning with 1,644 CAD patients with a 4 year total payment mean of $65,661, ETGs identified 983 patients (60%) with a 4 year episode-based mean of $24,362. The Prometheus model identified 1,135 (69%) as CAD patients with 948 CAD patients having a mean of $26,536. CONCLUSIONS: The two episode-based methods identify different patients with these two chronic conditions. In addition, there are significant differences in the episode-based payment estimates for diabetes, but similar estimates for CAD. Implementing episode-based payments for chronic conditions is challenging, and thoughtful discussions are needed to determine appropriate payments. PMID- 24753974 TI - Medicare non-payment of hospital-acquired infections: infection rates three years post implementation. AB - BACKGROUND: Medicare ceased payment for some hospital-acquired infections beginning October 1, 2008, following provisions in the Medicare Modernization Act of 2003 and the Deficit Reduction Act of 2005. OBJECTIVE: We examined the association of this policy with declines in rates of vascular catheter-associated infections (VCAI) and catheter-associated urinary tract infection (CAUTI). DATA: Discharge data from the Florida Agency for Healthcare Administration from 2007 to 2011. STUDY DESIGN: We compared rates of hospital-acquired vascular catheter associated infections (HA-VCAI) and catheter-associated urinary tract infections (HA-CAUTI) before and after implementation of the new policy (January 2007 to September 2008 vs. October 2008 to September 2011). This pre-post, retrospective, interrupted time series study was further analyzed with a generalized hierarchical logistic regression, by estimating the probability of a patient acquiring these infections in the hospital, post-policy compared to pre-policy. PRINCIPAL FINDINGS: Pre-policy, 0.12% of admitted patients were diagnosed with CAUTI; of these, 32% were HA-CAUTI. Similarly, 0.24% of admissions were diagnosed as VCAI; of these, 60% were HA-VCAI. Post-policy, 0.16% of admissions were CAUTIs; of these, 31% were HA-CAUTI. Similarly, 0.3% of admissions were VCAIs and, of these, 45% were HA-VCAI. There was a statistically significant decrease in HA-VCAIs (OR: 0.571 (p < 0.0001)) post-policy, but the reduction in HA-CAUTI (OR: 0.968 (p < 0.4484)) was not statistically significant. CONCLUSIONS: The results suggest Medicare non payment policy is associated with both a decline in the rate of hospital-acquired VCAI (HA-VCAI) per quarter, and the probability of acquiring HA-VCAI post- policy. The strength of the association could be overestimated, because of concurrent ongoing infection control interventions. PMID- 24753975 TI - Increased use of dental services by children covered by Medicaid: 2000-2010. AB - This report analyzes the use of dental services by children enrolled in Medicaid from federal fiscal years (FFY) 2000 to 2010. The number and percent of children receiving dental services under Medicaid climbed continuously over the decade. In FFY 2000, 6.3 million children ages 1 to 20 were reported to receive some form of dental care (either preventive or treatment); the number more than doubled to 15.4 million by FFY 2010. Part of the increase was because the overall number of children covered by Medicaid rose by 12 million (50%), but the percentage of children who received dental care climbed appreciably from 29.3% in FFY 2000 to 46.4% in FFY 2010. In that same time period, the number of children ages 1 to 20 receiving preventive dental services climbed from a reported 5.0 million to 13.6 million, while the percentage of children receiving preventive dental services rose from 23.2% to 40.8%. For children ages 1 to 20 who received dental treatment services, the reported number rose from 3.3 million in FFY 2000 to 7.6 million in FFY 2010. The percentage of children who obtained dental treatment services increased from 15.3% to 22.9%. In FFY 2010, about one sixth of children covered by Medicaid (15.7%) ages 6-14 had a dental sealant placed on a permanent molar. While most states have made steady progress in improving children's access to dental care in Medicaid over the past decade, there is still substantial variation across states and more remains to be done. PMID- 24753976 TI - Multiple chronic conditions among Medicare beneficiaries: state-level variations in prevalence, utilization, and cost, 2011. AB - OBJECTIVES: Individuals with multiple (>2) chronic conditions (MCC) present many challenges to the health care system, such as effective coordination of care and cost containment. To assist health policy makers and to fill research gaps on MCC, we describe state-level variation of MCC among Medicare beneficiaries, with a focus on those with six or more conditions. METHODS: Using Centers for Medicare & Medicaid Services administrative data for 2011, we characterized a beneficiary as having MCC by counting the number of conditions from a set of fifteen conditions, which were identified using diagnosis codes on the claims. The study population included fee-for-service beneficiaries residing in the 50 U.S. states and Washington, DC. RESULTS: Among beneficiaries with six or more chronic conditions, prevalence rates were lowest in Alaska and Wyoming (7%) and highest in Florida and New Jersey (18%); readmission rates were lowest in Utah (19%) and highest in Washington, DC (31%); the number of emergency department visits per beneficiary were lowest in New York and Florida (1.6) and highest in Washington, DC (2.7); and Medicare spending per beneficiary was lowest in Hawaii ($24,086) and highest in Maryland, Washington, DC, and Louisiana (over $37,000). CONCLUSION: These findings expand upon prior research on MCC among Medicare beneficiaries at the national level and demonstrate considerable state-level variation in the prevalence, health care utilization, and Medicare spending for beneficiaries with MCC. State-level data on MCC is important for decision making aimed at improved program planning, financing, and delivery of care for individuals with MCC. PMID- 24753977 TI - Using the National Provider Identifier for health care workforce evaluation. AB - The establishment in recent years of a National Provider Identifier (NPI) offers a new method for counting and categorizing physicians and other health care professionals involved in clinical care. In this paper, I describe how the NPI is assigned, the information collected in association with assigning the NPI, potential ways to enhance information on health professionals through data linkages using the NPI, and how the assessment of the health care workforce could be improved by requiring health care professionals to update their information as a part of maintaining their NPI. PMID- 24753978 TI - Utilization of dental services among Medicaid-enrolled children. AB - OBJECTIVE: To assess what characteristics of children and their communities are associated with lower dental service use rates, to support development of strategies to target subgroups of children with lower utilization. DATA SOURCE: The Medicaid Analytic Extract (MAX) 5-percent sample file, known as Mini- MAX 2008. METHODS: Multivariate logistic regression was used to assess the association between enrollee and county characteristics and dental preventive and treatment service utilization. PRINCIPAL FINDINGS: There is substantial variation in service use by age. Relative to a 9-year-old, a 2-year-old is 28 percentage points less likely, and a 15-year-old is 15 percentage points less likely, to receive a preventive dental service. Children enrolled in Medicaid for only part of the year were significantly less likely to receive a preventive or a treatment service relative to children covered by Medicaid for the full year. For preventive care, children enrolled for nine months were 15 percentage points less likely to have a service. Those enrolled for six months were 30 points less likely; those enrolled for three months were 41 points less likely. Children eligible for Medicaid based on disability were 9 and 6 percentage points less likely to receive a preventive or treatment service, respectively, than their counterparts who were eligible based on income alone. CONCLUSIONS: This study identifies some subgroups of children who are particularly underserved and for whom states may need to devote more attention. PMID- 24753980 TI - Multiplexing SERS nanotags for the imaging of differentiated mouse embryonic stem cells (mESC) and detection of teratoma in vivo. AB - Herein, we report fifty four membered, a new set of novel NIR Raman reporters and CyRLA-572 has been selected to be the best among them considering the signal intensity and stability. This new reporter molecule is an excellent partner with our in house Raman reporters (Cy7LA and Cy7.5LA). These three NIR Raman reporters are adsorbed on the gold nanoparticles to obtain their corresponding unique SERS fingerprints in which three individual characteristic peaks are capable to multiplex among them. These multiplexed Raman reporters are applied to develop biocompatible and specific targeting SERS nanotags after tagging with specific antibodies. These multiplex targeted SERS nanotags are applied to detect three targeting receptors in differentiated mouse embryonic stem cells (mESCs) consisting three germ layers such as ectoderm, mesoderm and endoderm. After successful recognition of cells by SERS techniques, we detect simultaneously three germ layers in teratoma which is a monster tumor formed from mESC cells in animal xenograft model. PMID- 24753979 TI - Bioorthogonal chemistry: implications for pretargeted nuclear (PET/SPECT) imaging and therapy. AB - Due to their rapid and highly selective nature, bioorthogonal chemistry reactions are attracting a significant amount of recent interest in the radiopharmaceutical community. Over the last few years, reactions of this type have found tremendous utility in the construction of new radiopharmaceuticals and as a method of bioconjugation. Furthermore, reports are beginning to emerge in which these reactions are also being applied in vivo to facilitate a novel pretargeting strategy for the imaging and therapy of cancer. The successful implementation of such an approach could lead to dramatic improvements in image quality, therapeutic index, and reduced radiation dose to non-target organs and tissues. This review will focus on the potential of various bioorthogonal chemistry reactions to be used successfully in such an approach. PMID- 24753982 TI - Probabilistic atlas-based segmentation of combined T1-weighted and DUTE MRI for calculation of head attenuation maps in integrated PET/MRI scanners. AB - We present a new MRI-based attenuation correction (AC) approach for integrated PET/MRI systems that combines both segmentation- and atlas-based methods by incorporating dual-echo ultra-short echo-time (DUTE) and T1-weighted (T1w) MRI data and a probabilistic atlas. Segmented atlases were constructed from CT training data using a leave-one-out framework and combined with T1w, DUTE, and CT data to train a classifier that computes the probability of air/soft tissue/bone at each voxel. This classifier was applied to segment the MRI of the subject of interest and attenuation maps (MU-maps) were generated by assigning specific linear attenuation coefficients (LACs) to each tissue class. The MU-maps generated with this "Atlas-T1w-DUTE" approach were compared to those obtained from DUTE data using a previously proposed method. For validation of the segmentation results, segmented CT MU-maps were considered to the "silver standard"; the segmentation accuracy was assessed qualitatively and quantitatively through calculation of the Dice similarity coefficient (DSC). Relative change (RC) maps between the CT and MRI-based attenuation corrected PET volumes were also calculated for a global voxel-wise assessment of the reconstruction results. The MU-maps obtained using the Atlas-T1w-DUTE classifier agreed well with those derived from CT; the mean DSCs for the Atlas-T1w-DUTE based MU-maps across all subjects were higher than those for DUTE-based MU-maps; the atlas-based MU-maps also showed a lower percentage of misclassified voxels across all subjects. RC maps from the atlas-based technique also demonstrated improvement in the PET data compared to the DUTE method, both globally as well as regionally. PMID- 24753983 TI - Multi-radionuclide digital autoradiography of the intra-aortic atherosclerotic plaques using a monoclonal antibody targeting oxidized low-density lipoprotein. AB - The aim of this study was to use multi-radionuclide autoradiography to compare the different distributions of three radiolabelled tracers in an atherosclerotic mouse model. This method, along with immunohistochemistry, was applied to investigate the intra-aortic distribution of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG), (131)I/(125)I labeled anti-oxidized Low Density Lipoprotein (oxLDL), and non-binding control antibodies. Aortas were isolated from a total of 12 apoB 100/LDL receptor deficient mice 73 h post injection of radioiodine-labeled anti oxLDL and control antibody and 1 h post injection of (18)F-FDG. A solid-state real-time digital autoradiography system was used to image the slide mounted aortas. Contributions from each radionuclide were separated by half-life and emission energy and the aortas were subsequently stained with Oil Red O for plaque to aorta contrast ratios. Immunohistochemical staining was performed to detect anti-oxLDL and control antibody localization. Radiolabeled anti-oxLDL showed increased total activity uptake in the aorta over control antibody and immunohistochemical analysis of plaques indicated increased binding of the specific antibody compared to control. The intra-aortic activity distribution of the anti-oxLDL antibody was however very similar to that of the control antibody although both had higher atherosclerotic plaques to aorta wall ratios than (18)F FDG. Given the right choice of radionuclides, multi-radionuclide digital autoradiography can be employed to compare several tracers ex vivo in the same animal. The distribution of anti-oxLDL antibodies did not significantly differ from the control antibody but it did appear to have a better plaque to aorta contrast at 73 h post injection than (18)F-FDG at 1 h post injection. PMID- 24753981 TI - Modeling and imaging cardiac sympathetic neurodegeneration in Parkinson's disease. AB - Parkinson's disease (PD) is currently recognized as a multisystem disorder affecting several components of the central and peripheral nervous system. This new understanding of PD helps explain the complexity of the patients' symptoms while challenges researchers to identify new diagnostic and therapeutic strategies. Cardiac neurodegeneration and dysautonomia affect PD patients and are associated with orthostatic hypotension, fatigue, and abnormal control of electrical heart activity. They can seriously impact daily life of PD patients, as these symptoms do not respond to classical anti-parkinsonian medications and can be worsened by them. New diagnostic tools and therapies aiming to prevent cardiac neurodegeneration and dysautonomia are needed. In this manuscript we critically review the relationship between the cardiovascular and nervous system in normal and PD conditions, current animal models of cardiac dysautonomia and the application of molecular imaging methods to visualize cardiac neurodegeneration. Our goal is to highlight current progress in the development of tools to understand cardiac neurodegeneration and dysautonomia and monitor the effects of novel therapies aiming for global neuroprotection. PMID- 24753984 TI - Phase I trial to evaluate the tumor and normal tissue uptake, radiation dosimetry and safety of (111)In-DTPA-human epidermal growth factor in patients with metastatic EGFR-positive breast cancer. AB - The safety, pharmacokinetics, biodistribution and radiation dosimetry of (111)In DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, were evaluated in a first-in-human trial. Dose escalation was performed in patients with EGFR positive metastatic breast cancer who had received >=2 prior courses of systemic treatment. (111)In-DTPA-hEGF (0.25 mg) was administered once intravenously (i.v.). Blood was collected for biochemistry/hematology testing and pharmacokinetic and immunogenicity analyses at selected times post injection (p.i.). Whole body planar images were acquired at 1, 4-6, 24 and 72 h p.i. and SPECT images at 24 and/or 72 h p.i. Macrodosimetry (MIRD) for the whole body and organs was estimated using OLINDA. Correlative radiological imaging was obtained at baseline, 1 and 3 months and then 6 monthly. Toxicity was scored using Common Terminology Criteria for Adverse Events (CTCAE)v2.0. Sixteen patients, median age 47 yr (range, 35-59), received (111)In-DTPA-hEGF as follows: 357-434 MBq (7), 754 805 MBq (3), 1,241-1,527 MBq (3) and 2,030-2,290 MBq (3). Fifteen were evaluable for toxicity. The commonest adverse events (AE) were flushing, chills, nausea, and vomiting occurring during or immediately p.i. One patient experienced Grade 3 thrombocytopenia (attributed to bone marrow infiltration by cancer). There were no other Grade 3 or 4 AEs. Maximum tolerated dose was not reached. Clear accumulation of radiopharmaceutical in at least one known site of disease was observed in 47% of patients. (111)In-DTPA-hEGF was cleared biexponentially from the blood with alpha-phase T1/2 of 0.16 +/- 0.03 h and beta-phase T1/2 of 9.41 +/ 1.93 h. (111)In-DTPA-hEGF was not immunogenic. The mean radiation dose estimates in mGy/MBq for whole body, liver, kidneys, spleen and thyroid were 0.08, 0.86, 0.74, 0.37 and 0.30, respectively. No objective antitumor responses were observed at the doses studied. In summary, administered amounts of up to 2,290 MBq (0.25 mg) of (111)In-DTPA-hEGF were well tolerated as a single i.v. injection. PMID- 24753985 TI - FDG-PET/CT can rule out malignancy in patients with vocal cord palsy. AB - The aim was to investigate the performance of (18)F-fluorodeoxyglucose PET/CT to rule out malignancy in patients with confirmed vocal cord palsy (VCP). Between January 2011 and June 2013, we retrospectively included consecutive patients referred to PET/CT with paresis or paralysis of one or both vocal cords. PET/CT results were compared to clinical workup and histopathology. The study comprised 65 patients (32 females) with a mean age of 66+/-12 years (range 37-89). Eleven patients (17%) had antecedent cancer. Twenty-seven (42%) were diagnosed with cancer during follow-up. The palsy was right-sided in 24 patients, left-sided in 37, and bilateral in 4. Median follow-up was 7 months (interquartile range 4-11 months). Patients without cancer were followed for at least three months. PET/CT suggested a malignancy in 35 patients (27 true positives, 8 false positives) and showed none in 30 (30 true negatives, 0 false negatives). Thus, the sensitivity, specificity, positive and negative predictive values, and accuracy were (95% confidence intervals in parenthesis): 100% (88%-100%), 79% (64%-89%), 77% (61% 88%), 100% (89%-100%), and 88% (78%-94%), respectively. Sixteen patients had palliative treatment, while 11 were treated with curative intent, emphasising the severity of VCP and the need for a rapid and accurate diagnostic work-up. In this retrospective survey, biopsy proven malignancy (whether newly diagnosed or relapsed) was the cause of VCP in almost half of patients (42%). PET/CT had a high sensitivity (100%) with a relatively high false positive rate, but was excellent in ruling out malignancy (negative predictive value 100%). PMID- 24753987 TI - An allogeneic NK cell line engineered to express chimeric antigen receptors: A novel strategy of cellular immunotherapy against cancer. PMID- 24753988 TI - Looking back, looking forward. PMID- 24753986 TI - Clinical oncologic applications of PET/MRI: a new horizon. AB - Positron emission tomography/magnetic resonance imaging (PET/MRI) leverages the high soft-tissue contrast and the functional sequences of MR with the molecular information of PET in one single, hybrid imaging technology. This technology, which was recently introduced into the clinical arena in a few medical centers worldwide, provides information about tumor biology and microenvironment. Studies on indirect PET/MRI (use of positron emission tomography/computed tomography (PET/CT) images software fused with MRI images) have already generated interesting preliminary data to pave the ground for potential applications of PET/MRI. These initial data convey that PET/MRI is promising in neuro-oncology and head & neck cancer applications as well as neoplasms in the abdomen and pelvis. The pediatric and young adult oncology population requiring frequent follow-up studies as well as pregnant woman might benefit from PET/MRI due to its lower ionizing radiation dose. The indication and planning of therapeutic interventions and specifically radiation therapy in individual patients could be and to a certain extent are already facilitated by performing PET/MRI. The objective of this article is to discuss potential clinical oncology indications of PET/MRI. PMID- 24753989 TI - The science of connection. PMID- 24753990 TI - Pathways to Healing: Person-centered Responses to Complementary Services. AB - OBJECTIVES: This research study assessed perceived changes in quality-of-life measures related to participation in complementary services consisting of a variety of nontraditional therapies and/or programs at Pathways: A Health Crisis Resource Center in Minneapolis, Minnesota. DESIGN: Survey data were used to assess perceived changes participants ascribed to their experience with complementary services at Pathways. Quantitative data analysis was conducted using participant demographics together with participant ratings of items from the "Self-Assessment of Change" (SAC) measure developed at the University of Arizona, Tucson. Qualitative data analysis was conducted on written responses to an additional survey question: "To what extent has your participation at Pathways influenced your healing process?" SETTING/LOCATION: Pathways offers a variety of services, including one-to-one sessions using nontraditional healing therapies, support groups, educational classes, and practice groups such as yoga and meditation for those facing serious health challenges. These services are offered free of charge through community financial support using volunteer practitioners. PARTICIPANTS: People (126) diagnosed with serious health challenges who used Pathways services from 2007 through 2009. INTERVENTIONS: Participation in self selected Pathways services. MEASURES: Responses to items on the SAC measure plus written responses to the question, "To what extent has your participation at Pathways influenced your healing process?" RESULTS: QUANTITATIVE FINDINGS: Participants reported experiencing significant changes across all components of the SAC measure. Qualitative findings: Responses to the open-ended survey question identified perspectives on the culture of Pathways and a shift in participants' perceptions of well-being based on their experience of Pathways services. CONCLUSIONS: Participation in services provided by the Pathways organization improved perceptions of quality of life and well-being and led to more active involvement in the experience of a healing process. PMID- 24753992 TI - Adverse effects of high doses of intravenous alpha lipoic Acid on liver mitochondria. AB - Alpha lipoic acid (ALA, thioctic acid), among other actions, is an essential coenzyme in the conversion of pyruvate to acetyl co-enzyme A. Therefore, it is necessary for the production of energy for aerobic organisms. Scientists have found that it can be used medically to help regenerate liver tissue, reverse the complications of diabetes mellitus, slow or stop the growth of cancer cells, and chelate heavy metals, among other actions. In this article, the authors describe the cellular mitochondrial damage from excessively high doses of this beneficial agent. PMID- 24753991 TI - Patterns of complementary and alternative medicine use in children with common neurological conditions. AB - BACKGROUND: Recent literature suggests that one in nine children in the United States uses some type of complementary and alternative medicine (CAM). Children with challenging neurological conditions such as headache, migraine, and seizures may seek CAM in their attempts at self-care. Our objective was to describe CAM use in children with these conditions. METHODS: We compared use of CAM among children aged 3 to 17 years with and without common neurological conditions (headaches, migraines, seizures) where CAM might plausibly play a role in their self-management using the 2007 National Health Interview Survey (NHIS) data. RESULTS: Children with common neurological conditions reported significantly more CAM use compared to the children without these conditions (24.0% vs 12.6%, P<.0001). Compared to other pediatric CAM users, children with neurological conditions report similarly high use of biological therapies and significantly higher use of mind-body techniques (38.6% vs 20.5%, P<.007). Of the mind-body techniques, deep breathing (32.5%), meditation (15.1%), and progressive relaxation (10.1%) were used most frequently. CONCLUSIONS: About one in four children with common neurological conditions use CAM. The nature of CAM use in this population, as well as its risks and benefits in neurological disease, deserve further investigation. PMID- 24753993 TI - A Pilot Feasibility Study of Whole-systems Ayurvedic Medicine and Yoga Therapy for Weight Loss. AB - OBJECTIVE: To develop and test the feasibility of a whole-systems lifestyle intervention for obesity treatment based on the practices of Ayurvedic medicine/ Yoga therapy. DESIGN: A pre-post weight loss intervention pilot study using conventional and Ayurvedic diagnosis inclusion criteria, tailored treatment within a standardized treatment algorithm, and standardized data collection instruments for collecting Ayurvedic outcomes. PARTICIPANTS: A convenience sample of overweight/obese adult community members from Tucson, Arizona interested in a "holistic weight loss program" and meeting predetermined inclusion/exclusion criteria. INTERVENTION: A comprehensive diet, activity, and lifestyle modification program based on principles of Ayurvedic medicine/yoga therapy with significant self-monitoring of lifestyle behaviors. The 3-month program was designed to change eating and activity patterns and to improve self-efficacy, quality of life, well-being, vitality, and self-awareness around food choices, stress management, and barriers to weight loss. PRIMARY OUTCOME MEASURES: Changes in body weight, body mass index; body fat percentage, fat/lean mass, waist/hip circumference and ratio, and blood pressure. SECONDARY OUTCOME MEASURES: Diet and exercise self-efficacy scales; perceived stress scale; visual analog scales (VAS) of energy, appetite, stress, quality of life, well-being, and program satisfaction at all time points. RESULTS: Twenty-two adults attended an in-person Ayurvedic screening; 17 initiated the intervention, and 12 completed the 3-month intervention. Twelve completed follow-up at 6 months and 11 completed follow-up at 9 months. Mean weight loss at 3 months was 3.54 kg (SD 4.76); 6 months: 4.63 kg, (SD 6.23) and 9 months: 5.9 kg (SD 8.52). Self-report of program satisfaction was more than 90% at all time points. CONCLUSIONS: An Ayurveda-/yoga-based lifestyle modification program is an acceptable and feasible approach to weight management. Data collection, including self-monitoring and conventional and Ayurvedic outcomes, did not unduly burden participants, with attrition similar to that of other weight loss studies. PMID- 24753995 TI - Overview of the Publications From the Anthroposophic Medicine Outcomes Study (AMOS): A Whole System Evaluation Study. AB - Anthroposophic medicine is a physician-provided complementary therapy system that was founded by Rudolf Steiner and Ita Wegman. Anthroposophic therapy includes special medicinal products, artistic therapies, eurythmy movement exercises, and special physical therapies. The Anthroposophic Medicine Outcomes Study (AMOS) was a prospective observational multicenter study of 1631 outpatients starting anthroposophic therapy for anxiety disorders, asthma, attention deficit hyperactivity disorder, depression, low back pain, migraine, and other chronic indications under routine conditions in Germany. AMOS INCORPORATED TWO FEATURES PROPOSED FOR THE EVALUATION OF INTEGRATIVE THERAPY SYSTEMS: (1) a sequential approach, starting with the whole therapy system (use, safety, outcomes, perceived benefit), addressing comparative effectiveness and proceeding to the major system components (physician counseling, anthroposophic medicinal products, art therapy, eurythmy therapy, rhythmical massage therapy) and (2) a mix of different research methods to build an information synthesis, including pre-post analyses, prospective comparative analyses, economic analyses, and safety analyses of individual patient data. AMOS fostered two methodological innovations for the analysis of single-arm therapy studies (combined bias suppression, systematic outcome comparison with corresponding cohorts in other studies) and the first depression cost analysis worldwide comparing primary care patients treated for depression vs depressed patients treated for another disorder vs nondepressed patients. A total of 21 peer-reviewed publications from AMOS have resulted. This article provides an overview of the main research questions, methods, and findings from these publications: anthroposophic treatment was safe and was associated with clinically relevant improvements in symptoms and quality of life without cost increase; improvements were found in all age, diagnosis, and therapy modality groups and were retained at 48-month follow-up; nonrespondent bias, natural recovery, regression to the mean, and adjunctive therapies together could explain a maximum of 37% of the improvement. PMID- 24753996 TI - A single case study: treating migraine headache with acupuncture, chinese herbs, and diet. AB - BACKGROUND: Acupuncture is an often sought-out treatment modality for migraine. The World Health Organization lists headache as one of the several conditions treated effectively by acupuncture. CASE DESCRIPTION: This single case reports on a 32-year-old woman who presented with a 10-year history of migraine. METHODS: The patient was treated with acupuncture, dietary modifications, and Chinese herbal medicine enemas over a course of 2 months. RESULTS: The patient experienced pain relief that resulted in several months without any migraine. CONCLUSION: This article may aid in expanding practitioners' treatment options to include a more diverse set of modalities such as Chinese herbal enemas. More research is needed to investigate the role of Oriental medicine and Chinese herbal enemas in the treatment of pain conditions. PMID- 24753997 TI - Ayurvedic therapy (shirodhara) for insomnia: a case series. AB - BACKGROUND: Insomnia is one of the most common complaints faced by primary care practitioners after pain. Non-pharmacological management of Insomnia that is noninvasive is gaining interest among patients with insomnia. PURPOSE: To determine the feasibility of recruiting and retaining participants in a clinical trial on shirodhara, Ayurvedic oil dripping therapy, for insomnia in the United States and also to investigate the therapeutic usefulness of Shirodhara for insomnia using standardized outcome measures. DESIGN: Case series. STUDY INTERVENTION AND DATA COLLECTION: Shirodhara with Brahmi oil was done for 45 minutes on each participant for 5 consecutive days. Insomnia Severity Index (ISI) was used to evaluate the severity of insomnia as well as to determine the response to Shirodhara therapy. Data were collected at baseline, end of the treatment (day 5) and 1 week after the treatment ended (follow-up). RESULTS: Two males and eight females with a mean age of 40 years (range 23 to 72), SD +/- 14.2, were enrolled in the study. One dropped out of the study, but all remaining nine participants experienced improvement at the end of treatment. The percentage of improvement range varied from 3.85% to 69.57%. At follow-up, most participants continued to improve. Comparison of means between baseline and day 5 indicated an overall significant improvement (P < .005), but in a comparison of baseline vs 1 week posttreatment the improvement was not significant (P < .089). No adverse events were reported during the study. CONCLUSION: Shirodhara with Brahmi oil may be beneficial for moderate to severe insomnia. It is feasible to recruit and retain participants for such therapies in the United States. It is important to validate these findings and investigate the mechanism of action using a larger sample and rigorous research design. PMID- 24753994 TI - Integrative nanomedicine: treating cancer with nanoscale natural products. AB - Finding safer and more effective treatments for specific cancers remains a significant challenge for integrative clinicians and researchers worldwide. One emerging strategy is the use of nanostructured forms of drugs, vaccines, traditional animal venoms, herbs, and nutraceutical agents in cancer treatment. The recent discovery of nanoparticles in traditional homeopathic medicines adds another point of convergence between modern nanomedicine and alternative interventional strategies. A way in which homeopathic remedies could initiate anticancer effects includes cell-to-cell signaling actions of both exogenous and endogenous (exosome) nanoparticles. The result can be a cascade of modulatory biological events with antiproliferative and pro-apoptotic effects. The Banerji Protocols reflect a multigenerational clinical system developed by homeopathic physicians in India who have treated thousands of patients with cancer. A number of homeopathic remedy sources from the Banerji Protocols (eg, Calcarea phosphorica; Carcinosin-tumor-derived breast cancer tissue prepared homeopathically) overlap those already under study in nonhomeopathic nanoparticle and nanovesicle tumor exosome cancer vaccine research. Past research on antineoplastic effects of nano forms of botanical extracts such as Phytolacca, Gelsemium, Hydrastis, Thuja, and Ruta as well as on homeopathic remedy potencies made from the same types of source materials suggests other important overlaps. The replicated finding of silica, silicon, and nano-silica release from agitation of liquids in glassware adds a proven nonspecific activator and amplifier of immunological effects. Taken together, the nanoparticulate research data and the Banerji Protocols for homeopathic remedies in cancer suggest a way forward for generating advances in cancer treatment with natural product-derived nanomedicines. PMID- 24753998 TI - The academy of integrative health & medicine: a conversation with mimi guarneri, president of the american board of integrative holistic medicine. PMID- 24753999 TI - C9ORF72 hexanucleotide repeats in behavioral and motor neuron disease: clinical heterogeneity and pathological diversity. AB - Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia (FTD), a predominantly behavioral disease, and amyotrophic lateral sclerosis (ALS), a disease of motor neurons. The primary objectives of this review are to highlight the clinical heterogeneity associated with C9ORF72 pathogenic expansion and identify potential molecular mechanisms underlying selective vulnerability of distinct neural populations. The proposed mechanisms by which C9ORF72 expansion causes behavioral and motor neuron disease highlight the emerging role of impaired RNA and protein homeostasis in a spectrum of neurodegeneration and strengthen the biological connection between FTD and ALS. PMID- 24754000 TI - Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue. AB - In a collaboration involving 11 groups with research interests in cerebral amyloid angiopathy (CAA), we used a two-stage process to develop and in turn validate a new consensus protocol and scoring scheme for the assessment of CAA and associated vasculopathic abnormalities in post-mortem brain tissue. Stage one used an iterative Delphi-style survey to develop the consensus protocol. The resultant scoring scheme was tested on a series of digital images and paraffin sections that were circulated blind to a number of scorers. The scoring scheme and choice of staining methods were refined by open-forum discussion. The agreed protocol scored parenchymal and meningeal CAA on a 0-3 scale, capillary CAA as present/absent and vasculopathy on 0-2 scale, in the 4 cortical lobes that were scored separately. A further assessment involving three centres was then undertaken. Neuropathologists in three centres (Bristol, Oxford and Sheffield) independently scored sections from 75 cases (25 from each centre) and high inter rater reliability was demonstrated. Stage two used the results of the three centre assessment to validate the protocol by investigating previously described associations between APOE genotype (previously determined), and both CAA and vasculopathy. Association of capillary CAA with or without arteriolar CAA with APOE epsilon4 was confirmed. However APOE epsilon2 was also found to be a strong risk factor for the development of CAA, not only in AD but also in elderly non demented controls. Further validation of this protocol and scoring scheme is encouraged, to aid its wider adoption to facilitate collaborative and replication studies of CAA. PMID- 24754001 TI - Identification of microRNAs involved in Alzheimer's progression using a rabbit model of the disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by the presence of extracellular plaques of beta-amyloid peptides and intracellular tangles of hyperphosphorylated tau proteins in the brain. The vast majority of cases are late onset AD (LOAD), which are genetically heterogeneous and occur sporadically. High blood cholesterol is suggested to be a risk factor for this disease. Several neuropathological changes of LOAD can be reproduced by supplementing a rabbit's diet with 2% cholesterol for 12 weeks. Accumulating data in the literature suggest that microRNAs (miRNA) participate in the development of AD pathology. The present study focuses on the survey of changes of miRNA expression in rabbit brains during the progression of AD-like pathology using microarray followed by Taq-Man qRT-PCR analyses. Out of 1769 miRNA probes used in the experiments, 99 miRNAs were found to be present in rabbit brain, 57 were newly identified as miRNAs from rabbit brain. Eleven miRNAs showed significant changes over AD-like pathology progression. Among them, the changes of miR-125b, miR-98, miR-107, miR-30, along with 3 members of the let-7 family were similar to those observed in human AD samples, whereas the expression patterns of miR-15a, miR-26b, miR-9 and miR-576-3p were unique to this rabbit LOAD model. The significant up regulation of miR-26b is consistent with the decrease of leptin levels in the brains of cholesterol fed rabbit model for AD, confirming that miR-26b is indeed regulated by leptin and that both leptin and miR-26b may be involved in cholesterol induced AD-like pathology. PMID- 24754002 TI - Neuropathologic correlates of trial-related instruments for Alzheimer's disease. AB - To advance disease-modifying therapies, it is critical to understand the relationship between the neuropathological changes of Alzheimer's Disease (AD) and the clinical measures used in therapeutic trials. We reviewed neuropathologically proven cases of AD from the National Alzheimer's Coordinating Center (NACC) and examined correlations between neuropathological changes and clinical-trial related instruments collected as part of the Uniform Dataset (UDS). We explored the relationships between neurofibrillary tangles, neuritic plaques, and total pathology burden with immediate and delayed recall, Clinical Dementia Rating-Sum of Boxes, Functional Activity Questionnaire, Neuropsychiatric Inventory Questionnaire, and Mini-Mental State Examination scores. 169 patients in NACC database had appropriate neuropathological and clinical data. All instruments correlated highly with neuritic plaques, Braak staging, and total pathology. Correlation coefficients for the relationships were relatively modest, suggesting that the pathologic burden examined accounts for between 13 and 40% of the variance of each of the instruments assessed. We conclude that there is a strong correlation between clinical trial-related measures and neuropathology identified at autopsy in AD. The amount of variance explained by the pathology is limited and other factors, both disease- and measurement-related, contribute to the variability observed in clinical measurements. PMID- 24754003 TI - The prelude on novel receptor and ligand targets involved in the treatment of diabetes mellitus. AB - Metabolic disorders are a group of disorders, due to the disruption of the normal metabolic process at a cellular level. Diabetes Mellitus and Tyrosinaemia are the majorly reported metabolic disorders. Among them, Diabetes Mellitus is a one of the leading metabolic syndrome, affecting 5 to 7 % of the population worldwide and mainly characterised by elevated levels of glucose and is associated with two types of physiological event disturbances such as impaired insulin secretion and insulin resistance. Up to now, various treatment strategies are like insulin, alphaglucosidase inhibitors, biguanides, incretins were being followed. Concurrently, various novel therapeutic strategies are required to advance the therapy of Diabetes mellitus. For the last few decades, there has been an extensive research in understanding the metabolic pathways involved in Diabetes Mellitus at the cellular level and having the profound knowledge on cell-growth, cell-cycle, and apoptosis at a molecular level provides new targets for the treatment of Diabetes Mellitus. Receptor signalling has been involved in these mechanisms, to translate the information coming from outside. To understand the various receptors involved in these pathways, we must have a sound knowledge on receptors and ligands involved in it. This review mainly summarises the receptors and ligands which are involved the Diabetes Mellitus. Finally, researchers have to develop the alternative chemical moieties that retain their affinity to receptors and efficacy. Diabetes Mellitus being a metabolic disorder due to the glucose surfeit, demands the need for regular exercise along with dietary changes. PMID- 24754004 TI - Reduced ABCB1 Expression and Activity in the Presence of Acrylic Copolymers. AB - PURPOSE: P-glycoprotein (P-gp; ABCB1), an integral membrane protein in the apical surface of human intestinal epithelial cells, plays a crucial role in the intestinal transport and efflux leading to changes in the bioavailability of oral pharmaceutical compounds. This study was set to examine the potential effects of three Eudragits RL100, S100 and L100 on the intestinal epithelial membrane transport of rhodammine-123 (Rho-123), a substrate of P-gp using a monolayer of human colon cancer cell line (Caco-2). METHODS: The least non-cytotoxic concentrations of the excipients were assessed in Caco-2 cells by the MTT assay. Then the transepithelial transport of Rho-123 across Caco-2 monolayers was determined with a fluorescence spectrophotometer. Besides, the expression of the P-gp in cells exposed to the polymers was demonstrated using Western-blotting analysis. RESULTS: Treatment of cells with Eudragit RL100 and L100 led to a very slight change while Eudragit S100 showed 61% increase in Rho-123 accumulation (P<0.001) and also reduced transporter expression. CONCLUSION: Our studies suggest that using proper concentrations of the Eudragit S100 in drug formulation would improve intestinal permeability and absorption of p-gp substrate drugs. PMID- 24754005 TI - Evolutionary Origin and Conserved Structural Building Blocks of Riboswitches and Ribosomal RNAs: Riboswitches as Probable Target Sites for Aminoglycosides Interaction. AB - PURPOSE: Riboswitches, as noncoding RNA sequences, control gene expression through direct ligand binding. Sporadic reports on the structural relation of riboswitches with ribosomal RNAs (rRNA), raises an interest in possible similarity between riboswitches and rRNAs evolutionary origins. Since aminoglycoside antibiotics affect microbial cells through binding to functional sites of the bacterial rRNA, finding any conformational and functional relation between riboswitches/rRNAs is utmost important in both of medicinal and basic research. METHODS: Analysis of the riboswitches structures were carried out using bioinformatics and computational tools. The possible functional similarity of riboswitches with rRNAs was evaluated based on the affinity of paromomycin antibiotic (targeting "A site" of 16S rRNA) to riboswitches via docking method. RESULTS: There was high structural similarity between riboswitches and rRNAs, but not any particular sequence based similarity between them was found. The building blocks including "hairpin loop containing UUU", "peptidyl transferase center conserved hairpin A loop"," helix 45" and "S2 (G8) hairpin" as high identical rRNA motifs were detected in all kinds of riboswitches. Surprisingly, binding energies of paromomycin with different riboswitches are considerably better than the binding energy of paromomycin with "16S rRNA A site". Therefore the high affinity of paromomycin to bind riboswitches in comparison with rRNA "A site" suggests a new insight about riboswitches as possible targets for aminoglycoside antibiotics. CONCLUSION: These findings are considered as a possible supporting evidence for evolutionary origin of riboswitches/rRNAs and also their role in the exertion of antibiotics effects to design new drugs based on the concomitant effects via rRNA/riboswitches. PMID- 24754006 TI - Testosterone replacement attenuates haloperidol-induced catalepsy in male rats. AB - PURPOSE: Parkinson's disease (PD) is a progressive neurodegenerative disease. Recent studies have indicated a higher prevalence of PD in male gender. Furthermore testosterone deficiency is more common among male parkinsonians in compare to healthy men. This study was aimed to investigate the effect of testosterone on catalepsy, in male rats. METHODS: The study carried out on male Wistar rats. To induce catalepsy, haloperidol (1 mg/kg, i.p) as D2 antagonist was administered before testing animals via Bar test. Animals were gonadectomized to investigate testosterone elimination effect on catalepsy, and also the androgen receptor blocker, flutamide, and the aromatase inhibitor, letrozole, were administered in certain groups of animals. The bar test method was used to evaluate haloperidol-induced catalepsy. RESULTS: Haloperidol 1 mg/kg, i.p, was able to induce catalepsy. Gonadectomy worsened the catalepsy and subchronic testosterone replacement could restore this effect to the level of normal animals. While low dose of flutamide administration represented an improvement in cataleptic symptoms, higher doses worsened catalepsy. Letrozole(4mg/kg,sc) administered animals represented nearly the same cataleptic symptoms as the control group. CONCLUSION: Testosterone deficiency increases catalepsy and testosterone replacement can significantly be effective in catalepsy remission. It seems that the anticataleptic effect of testosterone is exerted through affecting on androgenic receptors. PMID- 24754007 TI - Therapeutic Effects of Myeloid Cell Leukemia-1 siRNA on Human Acute Myeloid Leukemia Cells. AB - PURPOSE: Up-regulation of Mcl-1, a known anti-apoptotic protein, is associated with the survival and progression of various malignancies including leukemia. The aim of this study was to explore the effect of Mcl-1 small interference RNA (siRNA) on the proliferation and apoptosis of HL-60 acute myeloid leukemia (AML) cells. METHODS: siRNA transfection was performed using LipofectamineTM2000 reagent. Relative mRNA and protein expressions were quantified by quantitative real-time PCR and Western blotting, respectively. Trypan blue assay was performed to assess tumor cell proliferation after siRNA transfection. The cytotoxic effect of Mcl-1 siRNA on leukemic cells was measured using MTT assay. Apoptosis was detected using ELISA cell death assay. RESULTS: Mcl-1 siRNA clearly lowered both Mcl-1 mRNA and protein levels in a time-dependent manner, leading to marked inhibition of cell survival and proliferation. Furthermore, Mcl-1 down-regulation significantly enhanced the extent of HL-60 apoptotic cells. CONCLUSION: Our results suggest that the down-regulation of Mcl-1 by siRNA can effectively trigger apoptosis and inhibit the proliferation of leukemic cells. Therefore, Mcl 1 siRNA may be a potent adjuvant in AML therapy. PMID- 24754008 TI - Protective Effects of N-acetylcysteine Against the Statins Cytotoxicity in Freshly Isolated Rat Hepatocytes. AB - PURPOSE: Hepatotoxicity is one of the most important side effects of the statins therapy as lipid-lowering agents. However, the mechanism(s) of hepatotoxicity induced by these drugs is not clearly understood yet, and no hepatoprotective agent has been developed against this complication. METHODS: The protective effect of N-acetylcysteine (NAC) against statins-induced cytotoxicity was evaluated by using freshly isolated rat hepatocytes. Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. This technique is based on liver perfusion with collagenase after removal of calcium ion (Ca2+) with a chelator (ethylene glycol tetra acetic acid (EGTA) 0.5 mM). The level of parameters such as cell death, ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) in the statins-treated hepatocytes were determined. Additionally, the mentioned markers were assessed in the presence of NAC. RESULTS: Incubation of hepatocytes with the statins resulted in cytotoxicity characterized by an elevation in cell death, increasing ROS generation and consequently lipid peroxidation and impairment of mitochondrial function. Administration of NAC caused reduction in amount of ROS formation, lipid peroxidation and finally, cell viability and mitochondrial membrane potential (MMP) were improved. CONCLUSION: This study confirms that oxidative stress and consequently mitochondrial dysfunction is one of the mechanisms underlying the statins-induced liver injury and treating hepatocytes by NAC (200 MUM) attenuates this cytotoxicity. PMID- 24754009 TI - Induction of Apoptosis and Cytotoxic Activities of Iranian Orthodox Black Tea Extract (BTE) Using in vitro Models. AB - PURPOSE: Plant-derivate therapeutic agents can perform cancer chemotherapeutic activity through triggering apoptotic cell death. Our aim was to investigate the cytotoxic effects, induction of apoptosis, and the mechanism of cell death of Iranian orthodox black tea extracts (BTEs) and hydro methanolic purified fractions (40, 60, 80 and 100%) in KB cells (oral squamous cell carcinoma). METHODS: In order to analyze the cytotoxic activity of the BTEs, MTT (3-(4, 5- dimetylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide) and Trypan-blue assays were performed in oral squamous cell carcinoma (KB). Furthermore, the apoptosis inducing action of the extracts was determined by TUNEL, DNA fragmentation and cell death detection analysis. RESULTS: Dichloromethane BTE and hydro methanol fractions (40 and 60%) extract showed no cytotoxic effects; however, hydro methanol crude and hydro methanol fractions of BTE (80 and 100%) significantly inhibited cell growth and viability in a dose and time dependent manner. In addition, Cell death assay, TUNEL, and DNA fragmentation indicated induction of apoptosis by hydro methanol 80 and 100% fractions of BTE in KB cells. Statistical significance was determined by analysis of variance (ANOVA), followed by Duncan test and p value <=0.05 was considered significant. CONCLUSION: The results from the present study suggests that the hydro methanol crude and hydro methanol fractions of BTE (80 and 100%) are significant source of compounds with the anti proliferative and cytotoxic activities, and this may be useful for developing potential chemo preventive substances. PMID- 24754010 TI - Optimized condition for enhanced soluble-expression of recombinant mutant anabaena variabilis phenylalanine ammonia lyase. AB - PURPOSE: Recently discovered Anabaena variabilis phenylalanine ammonia lyase (AvPAL) proved to be a good candidate for enzyme replacement therapy of phenylketonuria. Outstanding stability properties of a mutant version of this enzyme, produced already in our laboratory, have led us to the idea of culture conditions optimization for soluble expression of this therapeutically valuable enzyme in E. coli. METHODS: In the present study, the gene encoding mutant version of AvPAL was cloned into the pET28a expression vector. Different concentrations of IPTG, induction period, growth temperature, shaking speed, as well as different types of culture media were examined with respect to the amount of recombinant protein produced and specific activity of the enzyme. RESULTS: Based upon our findings, maximum amount of active mutant enzyme was attained by addition of 0.5 mM IPTG at 150 rpm to the TB culture media. The yield of active enzyme at cluture tempreature of 25 degrees C and induction period of 18 hour was the highest. CONCLUSION: The results of this study indicated that the yield of mutant AvPAL production in E. coli can be affected mainly by culture temperature and inducer concentration. PMID- 24754011 TI - Chiral separation of indapamide enantiomers by capillary electrophoresis. AB - PURPOSE: Indapamide is probably the most frequently prescribed diuretic drug, generally being used for the treatment of hypertension. It contains a chiral center in its molecule; is marketed as a racemic mixture; but there are rather few studies regarding the pharmacokinetic and the pharmacological effect differences of the two enantiomers. Our aim was the development of a simple, rapid and precise analytical procedure for the chiral separation of indapamide enantiomers. METHODS: In this study capillary zone electrophoresis was used for the enantiomeric separation of indapamide using a systematic screening approach involving different native and derivatized; neutral and charged cyclodextrines as chiral selectors. The effects of pH value and composition of the background electrolyte, capillary temperature, running voltage and injection parameters have been investigated. RESULTS: After preliminary analysis a charged derivatized CD, sulfobuthyl ether- beta-CD, proved to be the optimum chiral selector for the enantioseparation. Using a buffer solution containing 25 mM disodium hydrogenophosphate - 25 mM sodium didydrogenophosphate and 5 mM sulfobuthyl ether beta-CD as chiral selector at a pH - 7, a voltage of + 25 kV, temperature 15 degrees C and UV detection at 242 nm, we succeeded in the separation of the two enantiomers in approximately 6 minutes, with a resolution of 4.30 and a separation factor of 1.08. CONCLUSION: Capillary zone electrophoresis using cyclodextrines as chiral selectors proved to be a suitable method for the enantioseparation of indapamide. Our method is rapid, specific, reliable, and cost-effective and can be proposed for laboratories performing indapamide routine analysis. PMID- 24754012 TI - HPLC-Analysis of Polyphenolic Compounds in Gardenia jasminoides and Determination of Antioxidant Activity by Using Free Radical Scavenging Assays. AB - PURPOSE: Gardenia jasminoides is a traditional medicinal plant rich in anti inflammatory flavonoids and phenolic compounds and used for the treatment of inflammatory diseases and pain. In this present study, antioxidant potential of Gardenia jasminoides leaves extract was evaluated by using various antioxidant assays. METHODS: Various antioxidant assays such as 1, 1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging assay, reducing power and total antioxidant capacity expressed as equivalent to ascorbic acid were employed. Moreover, phenolic compounds were detected by high-performance liquid chromatography (HPLC) coupled with diode-array detection. RESULTS: The methanol extract showed significant free radical scavenging activities in DPPH radical scavenging antioxidant assays compared to the reference antioxidant ascorbic acid. Total antioxidant activity was increased in a dose dependent manner. The extract also showed strong reducing power. The total phenolic content was determined as 190.97 mg/g of gallic acid equivalent. HPLC coupled with diode array detection was used to identify and quantify the phenolic compounds in the extracts. Gallic acid, (+)-catechin, rutin hydrate and quercetin have been identified in the plant extracts. Among the phenolic compounds, catechin and rutin hydrate are present predominantly in the extract. The accuracy and precision of the presented method were corroborated by low intra- and inter-day variations in quantitative results in leaves extract. CONCLUSION: These results suggest that phenolic compounds and flavonoids might contribute to high antioxidant activities of Gardenia jasminoides leaves. PMID- 24754013 TI - Thermal analysis study of antihypertensive drugs telmisartan and cilazapril. AB - PURPOSE: The aim of the present work is to study the thermal analysis of telmisartan and cilazapril. METHODS: Thermogravimetry (TGA), derivative thermogravimetry (DTG) and differential thermal analysis (DTA) were used through the work to achieve the thermal analysis study of some antihypertensive drugs, telmisartan and cilazapril. RESULTS: The results led to thermal stability data and also to the interpretation concerning the thermal decomposition. Thermogravimetry data allowed determination of the kinetic parameters such as, activation energy and frequency factor. CONCLUSION: The simplicity, speed and low operational costs of thermal analysis justify its application in the quality control of pharmaceutical compounds for medications. PMID- 24754015 TI - Formulation and physicochemical characterization of buccoadhesive microspheres containing diclofenac sodium. AB - PURPOSE: The present study involves preparation and evaluation of diclofenac buccal-mucoadhesive microparticles for prolongation of buccal residence time. METHODS: The microparticles were prepared by modified double-emulsion dehydration method (O1/W/O2) using sodium carboxymethylcellulose (CMC-Na) as mucoadhesive polymer. Calcium chloride was used as a cross-linking agent. Buccal-mucoadhesive microparticles with different drug to polymers ratios were prepared and characterized by encapsulation efficiency, particle size, DSC (Differential Scanning Calormetric), flowability, degree of swelling, surface pH, mucoadhesive property and drug release studies. RESULTS: The best drug to polymer ratio in microparticles was 1:5 (F3) with CMC-Na. F1 microparticles showed loading efficiency 51.43% and mean particle size 1013.92 MUm. The DSC showed stable character of drug in microparticles and revealed amorphous form. Microparticles had slower release than the commercial tablet (p50 min). Histopathological studies revealed no buccal mucosal damage. CONCLUSION: It may be concluded that drug loaded buccal-mucoadhesive microparticles are a suitable delivery system for DS. PMID- 24754014 TI - Selenium effect on oxidative stress factors in septic rats. AB - PURPOSE: Severe oxidative stress is an important event that occurs in patients with sepsis. The body has extensive and multiple defense mechanisms against the reactive oxygen species (ROS) produced during inflammation and sepsis. One of these mechanisms includes a group of enzymes that utilize selenium as their cofactor. The purpose of this study is investigating of Selenium effect on oxidative stress factors in animal model of sepsis. METHODS: Sepsis was induced by caecal ligation and puncture (CLP) method. 30 Male Wistar rats were divided into following groups: sham group; CLP group; 100 MUg/kg Selenium- treated CLP group. 12 hours after inducing sepsis animals were killed and lungs were removed. One of the lungs was frozen in liquid nitrogen and kept at -70 degrees C for enzymatic activity analysis and the other was kept in formalin 10% until tissue section preparation performed for histopathological studies. RESULTS: The Myeloperoxidase (MPO) activity was decreased in Selenium- treated CLP group. Inflammation score of lung tissue was lowered in Selenium- treated CLP group, but it wasn't statically significant. Level of glutathione peroxidase (GPx) was higher in CLP and Selenium- treated CLP groups. CONCLUSION: It seems that Selenium has protective effect on lung inflammation during acute lung injury. Also it may improve some stress oxidative profile during CLP model of sepsis. PMID- 24754016 TI - Hypolipidemic activity of a natural mineral water rich in calcium, magnesium, and bicarbonate in hyperlipidemic adults. AB - PURPOSE: This study compared the effects of a mineral water rich in calcium, magnesium, bicarbonate, and sulfate and a marketed mineral water with a composition similar to that of urban water on the lipid profile of dyslipidemic adults. METHODS: In a randomized controlled trial, 32 adults received one liter of "rich mineral water" daily for one month, and 37 adults drank the same amount of normal mineral water for the same period. Changes in lipid profiles were compared separately in each studied group at the end of one month. RESULTS: RESULTS showed that mean cholesterol and low density lipoprotein LDL levels were significantly decreased in both studied groups after one month of drinking mineral water (P<0.05); however, no significant differences in high density lipoprotein (HDL) and triglyceride (TG) levels were seen in either group one month after drinking. There were no statistically significant differences between the "rich mineral water" and the normal mineral water groups in any of the above mentioned lipid levels ( P>0.05). CONCLUSION: A one-month intake of mineral water rich in calcium, magnesium bicarbonate, and sulfate decreased cholesterol and LDL levels but not TG or HDL levels in dyslipidemic adults. PMID- 24754017 TI - Drug-Drug/Drug-Excipient Compatibility Studies on Curcumin using Non-Thermal Methods. AB - PURPOSE: Curcumin is a hydrophobic polyphenol isolated from dried rhizome of turmeric. Clinical usefulness of curcumin in the treatment of cancer is limited due to poor aqueous solubility, hydrolytic degradation, metabolism, and poor oral bioavailability. To overcome these limitations, we proposed to fabricate curcumin piperine, curcumin-quercetin and curcumin-silibinin loaded polymeric nanoformulation. However, unfavourable combinations of drug-drug and drug excipient may result in interaction and rises the safety concern. Hence, the present study was aimed to assess the interaction of curcumin with excipients used in nanoformulations. METHODS: Isothermal stress testing method was used to assess the compatibility of drug-drug/drug-excipient. RESULTS: The combination of curcumin-piperine, curcumin-quercetin, curcumin-silibinin and the combination of other excipients with curcumin, piperine, quercetin and silibinin have not shown any significant physical and chemical instability. CONCLUSION: The study concludes that the curcumin, piperine, quercetin and silibinin is compatible with each other and with other excipients. PMID- 24754018 TI - Plasmodium knowlesi and other blood parasites. PMID- 24754019 TI - Ethics of sponsored research. AB - The combined effort of private sponsors and academic researchers will undoubtedly bring in the forms of clinical trials is expected to usher in tremendous progress in science. Unfortunately, if not monitored, such trials can deviate from the humanitarian goals. Hence, registration in a common platform of such trials is mandatory and monitoring of such platforms is also necessary. Furthermore, caution should be exercised at all levels during the conduct of a trial. PMID- 24754020 TI - Drug resistance in leishmaniasis: Newer developments. AB - Leishmaniasis is a vector borne protozoan disease and it remains a major public health problem world-wide. Lack of an effective vaccine and vector control program makes the chemotherapy as the primary tool for leishmaniasis. Antimonials were used as the first line of treatment for many years. Emergence of resistance against this drug has become a major concern. Literatures and studies published on anti-leishmanial drug resistance, newer drug discovery for leishmanial resistance etc., in PubMed, Medline and Google search and reviewed thoroughly. Various newer drugs have been identified but, are in limited use because of high cost, toxicity, resistance etc., Recently, many newer mechanisms of drug resistance have been identified which may boost in future designing and development of drugs. PMID- 24754021 TI - The lost hope of elimination of Kala-azar (visceral leishmaniasis) by 2010 and cyclic occurrence of its outbreak in India, blame falls on vector control practices or co-infection with human immunodeficiency virus or therapeutic modalities? AB - The Kala-azar/visceral leishmaniasis (VL) turns epidemic form once in every 15 years in the endemic regions of Indian subcontinent. The goal of elimination of Kala-azar from India by 2010 was lost despite paramount efforts taken by the Government of India and World Health Organization and Regional Office for South East Asia. The main objective of this review was to elucidate the possible reason for the failure of Kala-azar elimination program and to suggest possible remedial measures to achieve the goal in future. The annual numbers of VL cases and deaths recorded in India since 1977 were plotted on a graph, to see if the temporal trends could be associated with changes in the vector control practices or co infection with human immunodeficiency virus (HIV) or therapeutic modalities used against VL. The VL cases flares up whenever the effect of dichlorodiphenyltrichloroethane (DDT) diminished after the withdrawal of spray. The fading effectiveness was clearly correlated with an increasing number of VL cases. Therapeutic modalities were found to be highly correlating with VL mortality not with VL morbidity. The diminishing efficacy of first and second line drugs and the introduction of new drugs and drugs combination were responsible for ups and downs in the VL mortality. The VL mortality is constantly declining since 1993, but cases started increasing from 2003 to 2007 and then recently again from 2010 to 2011. This shows a serious lacuna in the vector control practices applied. The extent of HIV co-infection did not show any correlation with number/trend of VL cases or death over the study period. It is concluded that, by strict vector control practices, the VL cases can be reduced and by applying proper therapeutic strategies, the VL mortality can be reduced. HIV-VL co-infection does not seem to be in a worried stage. PMID- 24754022 TI - Molecular epidemiology of the emerging human malaria parasite "Plasmodium knowlesi". AB - Malaria is the most important parasitic disease with global concern. Plasmodium knowlesi recently has emerged from its natural simian host as a significant cause of human malaria, particularly in Malaysian Borneo. Therefore, it has been added as the fifth human Plasmodium specie which is widely distributed in Southeast Asia. Recent developments of new molecular tools enhanced our understanding about the key features of this malaria parasite. Here, we review some of the ways in which molecular approaches might be used for epidemiology of P. knowlesi and finally lead to an efficient control of malaria. PMID- 24754023 TI - Challenges in diagnosis of Plasmodium knowlesi infections. AB - Plasmodium knowlesi is the fifth species of Plasmodium recently identified to cause human malaria. Infections with P. knowlesi are currently being reported from South-East Asian countries and the incidence is on the rise with a possibility of spread to the geographically contiguous countries. P. knowlesi infections can result in a high degree of parasitemia causing severe malaria in a larger proportion of infected individuals. If detected early and treated with appropriate antimicrobials, these infections show a significant clinical improvement. The widely used microscopic methods usually misidentify P. knowlesi as the less pathogenic Plasmodium malariae leading to inadequate therapy and adverse clinical outcomes. The currently popular rapid immuno-chromatographic card tests have a very low sensitivity in diagnosing knowlesi malaria and can erroneously report P. knowlesi as other Plasmodia and vice-versa. At present molecular methods are the most efficacious in diagnosing P. knowlesi infections, but these tests can produce a false positive report in Plasmodium vivax infections and require expensive equipment and trained personnel. An ideal diagnostic test for P. knowlesi infections, which is potent, cost-effective and practically feasible in the resource limited setting is yet to be developed. PMID- 24754024 TI - Recent advances in the management of Plasmodium knowlesi infection. AB - Plasmodium knowlesi (P. knowlesi) has been detected to be the fifth malarial parasite that can cause malaria in human beings. The parasite is known to commonly infect macaque monkeys. The infection is highly prevalent in South-East Asia. It has morphologic similarities to Plasmodium malariae and Plasmodium falciparum. P. knowlesi is known to replicate every 24 h in the human host and hence, causes "quotidian malaria." It causes a wide spectrum of clinical manifestations and sometimes can cause fatal illness. Chloroquine is effective in the treatment of uncomplicated P. knowlesi infection. Severe and complicated P. knowlesi malaria can be managed with artemisinin combination therapy. PMID- 24754025 TI - Molecular technique for detection of Leishmania infantum isolates in Iran. AB - INTRODUCTION: Leishmania infantum is the causative agent of autochthonous cutaneous and visceral cases of leishmaniasis and transmitted by female sandflies. The dogs are considered the main reservoir hosts; however, there are the reports on Leishmania infection in other animals. In this study, occurrence types of L. infantum isolates have been analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. MATERIALS AND METHODS: In this experimental study, 77 samples were cultured and prepared for microscopic study and examined through PCR-RFLP. The samples were used for both deoxyribonucleic acid (DNA) and smear-slide preparations. The DNAs were amplified by PCR for the detection of Leishmania subgenus and PCR products were restricted with HaeIII for the species differentiation. RESULTS: The visceral Leishmania parasites were genotyped as L. infantum. It was also determined sensitivity in PCR (100%) was higher than microscopic examination. CONCLUSION: PCR-RFLP technique appears to be most sensitive for the detection and differentiation of L. infantum. There exists a relationship between genetic heterogeneousness and clinical manifestation and geographical regions of this disease in human. PMID- 24754026 TI - Differentiating Schistosoma haematobium from Schistosoma magrebowiei and other closely related schistosomes by polymerase chain reaction amplification of a species specific mitochondrial gene. AB - INTRODUCTION: Schistosoma haematobium infection afflicts about 150 million people in 53 countries in Africa and the Middle East. In many endemic areas, S. haematobium is sympatric with Schistosoma bovis, Schistosoma mattheei, Schistosoma curassoni, Schistosoma intercalatum and Schistosoma magrebowiei, its closely related species. In addition, they also develop in the same intermediate snail hosts. Since these schistosome species often infect snails inhabiting the same bodies of water, examining cercariae or infected snails for estimating transmission of S. haematobium is always confounded by the need to differentially identify S. haematobium from these other species. Recently, differentiating S. haematobium by polymerase chain reaction (PCR) from S. bovis, S. mattheei, S. curassoni and S. intercalatum, but not from S. magrebowiei was reported. However, to be able to evaluate residual S. haematobium transmission after control interventions in areas where S. haematobium may be sympatric with S. magrebowiei, a differential tool for accurate monitoring of infected snails is needed. MATERIALS AND METHODS: Thus in this study, we developed a new PCR assay using a pair of primers, ShND-1/ShND-2, to amplify a target sequence of 1117 bp (GenBank accession number KF834975) from S. haematobium mitochondrion complete genome (GenBank accession number DQ157222). Sensitivity of the assay was determined by PCR amplification of different concentrations of S. haematobium gDNA serially diluted from 10ng to 0.1pg. For assay specificity, different concentrations of gDNA from S. haematobium and the other schistosome species, 20 positive urine samples and five controls as well as 20 infected snails were subjected to PCR amplification, while some of the PCR products were sequenced. RESULTS: The assay detected up to 1pg of S. haematobium gDNA, while a differential identification of S. haematobium DNA content from other closely related species was achieved when applied to urine and naturally infected snails. When a protein-protein blast search was carried out using Blastp, the amplified sequence was found to encode a protein that shows a 100% similarity with S. haematobium nicotinamide adenine dinucleotide dehydrogenase subunit 3 (GenBank accession number YP_626524.1). CONCLUSION: The PCR assay was sensitive, specific and was able to successfully differentiate S. haematobium from S. magrebowiei, in addition to its other closely related animal infective schistosome species. PMID- 24754028 TI - A rare case of urinary balantidiasis in an elderly renal failure patient. AB - Balantidium coli is the largest ciliated protozoa infecting humans by the feco oral transmission from pigs. Large gut is the most common site of involvement. Symptomatology varies from asymptomatic carrier to invasive dysentery. Extra intestinal infections can occur in liver, lung and urogenital tract. There are very few case reports of urinary balantidiasis. We present a case of urinary balantidiasis in an elderly farmer having diabetes and chronic kidney disease. This case is reported for its rarity and future references. PMID- 24754027 TI - Performance of polymerase chain reaction for the diagnosis of cystic echinococcosis using serum, urine, and cyst fluid samples. AB - INTRODUCTION: Cystic echinococcosis (CE) is a chronic zoonosis which presents with variable clinical manifestations. Currently the diagnosis of this disease is based on radiological findings and serological tests which lack specificity. Although antigen detection from the cyst fluid is the most specific, it is seldom done due to the complications involved. Detecting the presence of Echinococcus granulosus specific deoxyribonucleic acid (DNA) by the polymerase chain reaction (PCR) could provide a definitive diagnosis of CE. MATERIALS AND METHODS: An in house PCR assay was devised to detect E. granulosus specific DNA in serum, urine and hydatid cyst fluid. The ability of the PCR to detect E. granulosus in the above mentioned samples were observed in comparison with other antigen and antibody detection tests. RESULTS: Serum samples from surgically confirmed patients of CE with ruptured cysts contained the corresponding DNA while the in the majority of cases who had an intact cyst had no DNA of E. granulosus in their serum. DNA of E. granulosus was not found to be excreted in urine. PCR performed equal to antigen detection ELISA while testing hydatid cyst fluid samples. CONCLUSIONS: Serum and urine might not serve as useful samples for the molecular diagnosis of cystic echinococcosis. However, PCR can be useful on serum samples to detect ruptured hydatid cysts and on hydatid cyst fluid to confirm the parasitic diagnosis. PMID- 24754029 TI - First reported cases of diffuse cutaneous leishmaniasis in human immunodeficiency virus positive patients in Jaipur District of Rajasthan, India. AB - Diffuse cutaneous leishmaniasis (DCL) is characterized by the presence of a large number of lesions at several anatomic sites (head, limbs and trunk). The lesions include papules, nodules and areas of diffuse infiltration that do not ulcerate and reveal abundant parasites on histopathological examination. DCL and human immunodeficiency virus (HIV) co-infections are seldom reported. We report two cases of DCL in HIV positive patients without visceral involvement. DCL is emerging as a new opportunistic infection associated with HIV/acquired immunodeficiency syndrome. PMID- 24754030 TI - The basic rules and methods of mosquito rearing (Aedes aegypti). AB - The rearing of Aedes mosquitoes is complex and demanding for several reasons. Aedes larvae are affected by temperature, density and available nutrition, mating is not necessarily accomplished naturally and females need a blood meal to develop eggs. The climate chambers where the mosquitoes are kept are warm and sweaty. Due to these tropical conditions the larvae develop fast and need to be cared for daily. The Laboratory of Entomology in National Institute of Malaria Research Bangalore has cultured different colonies of different vectors successfully. In this paper, we discuss different aspects off the rearing process which affect mosquito fitness and are of importance for the quality of fundamental and applied research. PMID- 24754031 TI - Unusual presentation of acute pancreatitis in falciparum malaria. AB - Malaria is known for its protean manifestations and multi systemic complications. Acute pancreatitis as a consequence of falciparum malaria is rare in the literature. We report a case of falciparum malaria complicated by acute pancreatitis. PMID- 24754032 TI - Detection of microfilaria on needle aspiration from breast mass: An uncommon finding. PMID- 24754033 TI - A simple and rapid staining method for detection of hemozoin pigment by methylene blue stain. PMID- 24754035 TI - An interview with Dr. T. M. Mohapatra. PMID- 24754034 TI - A case of mixed infection with filariasis and visceral leishmaniasis. PMID- 24754036 TI - Retraction notice. PMID- 24754037 TI - Retraction notice. PMID- 24754038 TI - Flexible and stretchable thin-film transistors based on molybdenum disulphide. AB - The outstanding physical and chemical properties of two-dimensional materials, which include graphene and transition metal dichalcogenides, have allowed significant applications in next generation electronics. In particular, atomically thin molybdenum disulphide (MoS2) is attracting widespread attention because of its large bandgap, effective carrier mobility, and mechanical strength. In addition, recent developments in large-area high-quality sample preparation methods via chemical vapour deposition have enabled the use of MoS2 in novel functional applications, such as flexible and stretchable electronic devices. In this perspective, we focus on the current progress in generating MoS2 based flexible and stretchable thin-film transistors. The reported virtues and novelties of MoS2 provide significant advantages for future flexible and stretchable electronics. PMID- 24754039 TI - Fabrication of N-doped TiO2 coatings on nanoporous Si nanopillar arrays through biomimetic layer by layer mineralization. AB - Si/N-doped TiO2 core/shell nanopillar arrays with a nanoporous structure are fabricated through a simple protein-mediated TiO2 deposition process. The Si nanopillar arrays are used as templates and alternatively immersed in aqueous solutions of catalytic molecules (protamine, PA) and the titania precursor (titanium(iv) bis(ammonium lactato)dihydroxide, Ti-BALDH) for the layer by layer mineralization of a PA/TiO2 coating. After a subsequent calcination, a N-doped TiO2 layer is formed, and its thickness could be controlled by varying the cycles of deposition. Moreover, the nanoporous structure of the Si nanopillars strongly affects the formation of the TiO2 layer. The obtained Si/TiO2 nanocomposites show significantly improved solar absorption compared with commercially purchased TiO2 nanoparticles. PMID- 24754040 TI - Unexpected bond activations promoted by palladium nanoparticles. AB - Thioether-phosphines, 1 and 2, were applied for the stabilisation of palladium nanoparticles (PdNPs) synthesised by a bottom-up methodology, using [Pd2(dba)3] as an organometallic precursor. For the phenyl containing ligand 1, small (d(mean) = 1.6 nm), well-defined and dispersed nanoparticles were obtained; however, ligand 2 involving a long alkyl chain led to agglomerates. NMR and GC-MS analyses throughout the synthesis of the nanomaterials revealed partial cleavage of ligands by C-S and C-P bond activations, and XPS spectra of the isolated nanoparticles indicated the presence of both thioether-phosphines and their fragments on the metallic surface. Reactivity studies of molecular palladium systems as well as on extended palladium surfaces pointed out that cluster entities are responsible for C-heteroatom activations, triggering structure modifications of stabilisers during the synthesis of PdNPs. PMID- 24754041 TI - The paradoxical evolution of agriculture. PMID- 24754042 TI - Policy: Bring sustainable energy to the developing world. PMID- 24754043 TI - Biology of telomeres: lessons from budding yeast. AB - Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes and thereby protect their stability and integrity. Telomeres play central roles in maintaining the genome's integrity, distinguishing between the natural chromosomal ends and unwanted double-stranded breaks. In addition, telomeres are replicated by a special reverse transcriptase called telomerase, in a complex mechanism that is coordinated with the genome's replication. Telomeres also play an important role in tethering the chromosomes to the nuclear envelope, thus helping in positioning the chromosomes within the nucleus. The special chromatin configuration of telomeres affects the expression of nearby genes; nonetheless, telomeres are transcribed, creating noncoding RNA molecules that hybridize to the chromosomal ends and seem to play regulatory roles. The yeast Saccharomyces cerevisiae, with its sophisticated genetics and molecular biology, has provided many fundamental concepts in telomere biology, which were later found to be conserved in all organisms. Here, we present an overview of all the aspects of telomere biology investigated in yeast, which continues to provide new insights into this complex and important subject, which has significant medical implications, especially in the fields of aging and cancer. PMID- 24754044 TI - Exercise improves sexual function in women taking antidepressants: results from a randomized crossover trial. AB - BACKGROUND: In laboratory studies, exercise immediately before sexual stimuli improved sexual arousal of women taking antidepressants [1]. We evaluated if exercise improves sexual desire, orgasm, and global sexual functioning in women experiencing antidepressant-induced sexual side effects. METHODS: Fifty-two women who were reporting antidepressant sexual side effects were followed for 3 weeks of sexual activity only. They were randomized to complete either three weeks of exercise immediately before sexual activity (3*/week) or 3 weeks of exercise separate from sexual activity (3*/week). At the end of the first exercise arm, participants crossed to the other. We measured sexual functioning, sexual satisfaction, depression, and physical health. RESULTS: Exercise immediately prior to sexual activity significantly improved sexual desire and, for women with sexual dysfunction at baseline, global sexual function. Scheduling regular sexual activity significantly improved orgasm function; exercise did not increase this benefit. Neither regular sexual activity nor exercise significantly changed sexual satisfaction. CONCLUSIONS: Scheduling regular sexual activity and exercise may be an effective tool for the behavioral management of sexual side effects of antidepressants PMID- 24754045 TI - Meeting of the International Task Force for Disease Eradication, January 2014. PMID- 24754046 TI - Severe atypical pneumonia outbreak associated with influenza A(H1N1)pdm09 in Egypt, 2013-2014 season. PMID- 24754047 TI - Altered frequencies of dendritic cells and IFN-gamma-secreting T cells with granulocyte colony-stimulating factor (G-CSF) therapy in acute-on- chronic liver failure. AB - BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a serious hepatic ailment with impaired immunity and poor treatment options resulting high mortality. Treatment with granulocyte colony-stimulating factor(G-CSF) mobilizes CD34(+) cells in ACLF patients; however its effect on impaired immune responses remains to be elucidated. To analyse the effect of G-CSF in immune modulation in ACLF. METHODS: We have analysed the frequencies of circulating and intrahepatic myeloid (mDCs) and plasmacytoid(pDCs) dendritic cells (DCs) and T cells in ACLF patients treated with G-CSF (Group A; n = 23) and placebo (Group B; n = 24) using flow cytometry. IFN-c production was compared in both groups following stimulation of PBMCs with phorbol myristate acetate (PMA). RESULTS: In Group A, circulating and intrahepatic mDCs, pDCs (P < 0.04, P < 0.02) and T cells(CD3, CD4 and CD8) increased significantly post-G-CSF treatment in comparison to placebo group. Importantly in Group A, IFN-c-producing CD8 T cells were significantly decreased (P > 0.05) along with decreased serum bilirubin and international normalized ratio (INR). Intrahepatic DCs and IFN-clevel were compared in survivor and non-survivor. Non-survivors from both groups, showed decreased DCs, high IFN c level and no improvement in clinical parameters including s-bilirubin and INR. CONCLUSIONS: G-CSF therapy increased the frequencies of dendritic cells and reduced IFN-c secreting CD8 T cells with improved clinical severity indices. Decreased IFN- c production may contribute to reduced hepatocellular damage in ACLF patients.Our observations support the basis for further use of G-CSF therapy as immune modulator in these patients. PMID- 24754048 TI - Early clearance of Mycobacterium tuberculosis: a new frontier in prevention. AB - Early clearance (EC) is the successful eradication of inhaled Mycobacterium tuberculosis before an adaptive immune response develops. Evidence for EC comes from case contact studies that consistently show that a proportion of heavily exposed individuals do not develop M. tuberculosis infection. Further support for the existence of this phenotype comes from genetic loci associated with tuberculin reactivity. In this review we discuss aspects of the innate response that may underpin EC and hypotheses that can be tested through field laboratory link studies in M. tuberculosis case contacts. Specifically, we consider mechanisms whereby alveolar macrophages recognize and kill intracellular M. tuberculosis, and how other cell types, such as neutrophils, natural killer T cells, mucosa-associated invariant T cells and cd T cells may assist. How EC may be impaired by HIV infection or vitamin D deficiency is also explored. As EC is a form of protective immunity, further study may advance the development of vaccines and immunotherapies to prevent M. tuberculosis infection. PMID- 24754049 TI - Regulation of pancreatic inflammation by connective tissue growth factor (CTGF/CCN2). AB - Pancreatitis is caused by long-term heavy alcohol consumption, which results in injury and death of pancreatic acinar cells (PAC). The PAC play a pivotal role in mediating early inflammatory responses but the underlying mechanisms remain poorly understood. Treatment of C57BL/6 mice with ethanol and cerulein resulted in increased staining for acinar interleukin- 1b (IL-1b), chemokine (C-C motif) ligand 3 (CCL3), or connective tissue growth factor (CTGF/CCN2) by Day 16 and this was associated with increased infiltration of F4/80-positive macrophages and increased expression of pancreatic CTGF/CCN2 mRNA. Compared with wild-type Swiss Webster mice, ethanol treatment of pan-green fluorescent protein (GFP)-CTGF/CCN2 transgenic mice caused enhanced acinar staining for GFP or CTGF/CCN2 and a significant increase in pancreatic infiltration of F4/80-positive macrophages or NIMP-R14-positive neutrophils. Treatment of primary mouse PAC or the rat AR42J PAC line with ethanol or CTGF/CCN2 resulted in enhanced expression of IL-1b or CCL3. Conditioned medium from CTGF/CCN2-treated AR42J cells induced chemotaxis in NR8383 macrophages and this response was abrogated in a dose dependent manner by addition of BX471, an inhibitor of chemokine (C-C motif) receptor 1. These results reveal that acinar CTGF/CCN2 plays a novel role in alcohol-induced inflammatory processes in the pancreas by increasing infiltration of macrophages and neutrophils and increasing acinar production of inflammatory mediators such as IL-1b or CCL3. The early production of CTGF/CCN2 by PAC to drive inflammation is distinct from its previously reported production by pancreatic stellate cells to drive fibrosis at later stages of pancreatic injury. PMID- 24754050 TI - Effect of age and maternal antibodies on the systemic and mucosal immune response after neonatal immunization in a porcine model. AB - Newborn mammals are highly susceptible to respiratory infections. Although maternal antibodies (MatAb) offer them some protection, they may also interfere with their systemic immune response to vaccination. However, the impact of MatAb on the neonatal mucosal immune response remains incompletely described. This study was performed to determine the effect of ovalbumin (OVA) -specific MatAb on the anti- OVA antibody response in sera, nasal secretions and saliva from specific pathogen-free Vietnamese miniature piglets immunized at 7 or 14 days of age. Our results demonstrated that MatAb increased antigen-specific IgA and IgG responses in sera, and transiently enhanced an early secretory IgA response in nasal secretions of piglets immunized at 7 days of age. In contrast, we detected a lower mucosal (nasal secretion and saliva) anti- OVA IgG response in piglets with MatAb immunized at 14 days of age, compared with piglets with no MatAb, suggesting a modulatory effect of antigen-specific maternal factors on the isotype transfer to the mucosal immune exclusion system. In our porcine model, we demonstrated that passive maternal immunity positively modulated the systemic and nasal immune responses of animals immunized early in life. Our results, therefore, open the possibility of inducing systemic and respiratory mucosal immunity in the presence of MatAb through early vaccination. PMID- 24754051 TI - Testing search strategies for systematic reviews in the Medline literature database through PubMed. AB - BACKGROUND: A high-quality electronic search is essential in ensuring accuracy and completeness in retrieved records for the conducting of a systematic review. OBJECTIVE: We analysed the available sample of search strategies to identify the best method for searching in Medline through PubMed, considering the use or not of parenthesis, double quotation marks, truncation and use of a simple search or search history. METHODS: In our cross-sectional study of search strategies, we selected and analysed the available searches performed during evidence-based medicine classes and in systematic reviews conducted in the Botucatu Medical School, UNESP, Brazil. RESULTS: We analysed 120 search strategies. With regard to the use of phrase searches with parenthesis, there was no difference between the results with and without parenthesis and simple searches or search history tools in 100% of the sample analysed (P = 1.0). The number of results retrieved by the searches analysed was smaller using double quotations marks and using truncation compared with the standard strategy (P = 0.04 and P = 0.08, respectively). CONCLUSIONS: There is no need to use phrase-searching parenthesis to retrieve studies; however, we recommend the use of double quotation marks when an investigator attempts to retrieve articles in which a term appears to be exactly the same as what was proposed in the search form. Furthermore, we do not recommend the use of truncation in search strategies in the Medline via PubMed. Although the results of simple searches or search history tools were the same, we recommend using the latter. PMID- 24754052 TI - Author response. PMID- 24754053 TI - Author response. PMID- 24754054 TI - Expression of concern. PMID- 24754055 TI - Clinical practice and research in rehabilitation. PMID- 24754056 TI - Elevating the quality of disability and rehabilitation research: mandatory use of the reporting guidelines. PMID- 24754057 TI - Motor rehabilitation research. PMID- 24754058 TI - A thermodynamic approach to alamethicin pore formation. AB - The structure and energetics of alamethicin Rf30 monomer to nonamer in cylindrical pores of 5 to 11A radius are investigated using molecular dynamics simulations in an implicit membrane model that includes the free energy cost of acyl chain hydrophobic area exposure. Stable, low energy pores are obtained for certain combinations of radius and oligomeric number. The trimer and the tetramer formed 6A pores that appear closed while the larger oligomers formed open pores at their optimal radius. The hexamer in an 8A pore and the octamer in an 11A pore give the lowest effective energy per monomer. However, all oligomers beyond the pentamer have comparable energies, consistent with the observation of multiple conductance levels. The results are consistent with the widely accepted "barrel stave" model. The N terminal portion of the molecule exhibits smaller tilt with respect to the membrane normal than the C terminal portion, resulting in a pore shape that is a hybrid between a funnel and an hourglass. Transmembrane voltage has little effect on the structure of the oligomers but enhances or decreases their stability depending on its orientation. Antiparallel bundles are lower in energy than the commonly accepted parallel ones and could be present under certain experimental conditions. Dry aggregates (without an aqueous pore) have lower average effective energy than the corresponding aggregates in a pore, suggesting that alamethicin pores may be excited states that are stabilized in part by voltage and in part by the ion flow itself. PMID- 24754059 TI - Retraction: Sophocleous, M. (2012). On understanding and predicting groundwater response time. Ground Water, 50: 528-540. doi: 10.1111/j.1745-6584.2011.00876.x. AB - The above article, published online on October 24, 2011 on Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the author's sponsoring institution, the journal Editor in Chief, Franklin W. Schwartz, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation by the Kansas Geological Survey (a research and service division of the University of Kansas), which identified unattributed areas of overlap with a number of other publications. PMID- 24754060 TI - Retraction: Sophocleous, M. (2012). Conserving and extending the useful life of the largest aquifer in North America: The future of the High Plains/Ogallala aquifer. Ground Water , 50: 831-839. doi: 10.1111/j.1745-6584.2012.00965.x. AB - The above article, published online on July 23, 2012 on Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the author's sponsoring institution, the journal Editor in Chief, Franklin W. Schwartz, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation by the Kansas Geological Survey (a research and service division of the University of Kansas), which identified unattributed areas of overlap with a number of other publications. PMID- 24754061 TI - Effective strategies by any other name. PMID- 24754062 TI - [The contribution of current investigations to understanding the nature of type 2 diabetes mellitus, and treatment perspectives]. AB - The paper discusses the key issues of modern diabetology: a concept of pathogenesis, genetic aspects, novel drugs and devices for the therapy of diabetes mellitus, and its treatment perspectives. PMID- 24754063 TI - [Estimation of immune response parameters in patients with frequent premature ventricular contractions without signs of organic pathology of the cardiovascular system]. AB - AIM: To study the specific features of an immune response and the role of infectious pathogens in the occurrence, development, and maintenance of ventricular ectopic activity in patients without signs of organic disease of the cardiovascular system (CVS). SUBJECTS AND METHODS: The investigation enrolled 91 patients (27 men and 64 women with a mean age of 36.5 +/- 11.5 years) with premature ventricular contractions (PVC) without signs of organic CVS pathology. A control group comprised 31 healthy volunteers. In addition to standard physical examination, a study of N-terminal pro-brain natriuretic peptide (NT-proBNP) and cellular and humoral immune parameters was performed and the serological and molecular genetic markers of infections were determined in all the patients. RESULTS: The persons with PVC, as compared to the control group, were recorded to have a higher NT-proBNP level (49.2 pg/ml versus 25.4 pg/ml; p = 0.001) accompanied by an increase in both the total number of PVC and the number of coupled PVC and the episodes of ventricular tachycardia. They were also found to have elevated CD3(+)HLA-DR+ (2.4% versus 1.56%) and CD3(+)CD95+ (27.6% versus 18.8%) counts (p = 0.001). In patients with a C-reactive protein level of more than 2 mg/l, the total number of PVC was larger than that in the other patients (p = 0.065). The patients with PVC did not show a statistically significant difference from the controls in the levels of antiviral and antibacterial antibodies. The people with PVC displayed a number of relationships between the infectious pathogen antibody titers and the ECG Holter monitoring and echocardiography readings. CONCLUSION: In the patients with PVC without signs of organic CVS pathology, the parameters of an immune response were not different from those obtained in the control group, which was likely to be associated with the involvement of the immune system in the development and maintenance of ventricular arrhythmias. PMID- 24754064 TI - [The clinical manifestations of atherosclerosis in familial hypercholesterolemia]. AB - AIM: To study the specific features of manifestations of atherosclerosis in Karelia dwellers with familial hypercholesterolemia (FH). SUBJECTS AND METHODS: The examination of 196 patients with FH involved laboratory tests, electrocardiography, echocardiography, triplex scanning of the arteries, exercise testing, and coronarography as indicated. Genetic examination was performed in 109 (55.6%) patients. RESULTS: The examinees' mean age was 48 +/- 2.3 years; there was a female predominance (68.7%). All the patients were found to have significant hypercholesterolemia due to elevated low-density lipoprotein levels. There was arcus lipoides corneae in 26% of cases, tendinous xanthomas in 17%, and xanthelasma palpebrarum in 34.9%. Carotid stenosis and lower extremity atherosclerosis obliterans were detected in 26.3 and 4.6%, respectively. 27.5% of the patients were diagnosed with coronary heart disease (CHD) (mean age at onset 45 years): exertional angina pectoris (10.2%), acute myocardial infarction (AMI) (14.8%), and an arrhythmic form (5.6%). 65.5% of the patients who had developed the first AMI were aged younger than 55 years. The most common site of AMI was the anterior wall of the left ventricle (55%); 51.7% of cases had transmural AMI. 24.1% of the patients sustained recurrent AMI. Complicated AMI was noted in 13.8% of cases. One third of the patients could achieve target blood lipid levels. CONCLUSION: The characteristics of the patients with FH in Karelia are a mean age of 48 years and a female predominance; the main criterion for the diagnosis of FH is significant dyslipidemia while its stigmas are rarely encountered. The specific features of CHD in the patients with FH are as follows: the age at onset is 45 years; AMI develops at the ages of less than 55 and 40 years in 65.5 and 26.3%, respectively; the rate of recurrent AMI is as high as 24%; transmural AMIs occur in 51.7% of the patients; 26.3% had signs of brachiocephalic artery stenotic lesion; 4.6% present with lower extremity atherosclerosis obliterans; one third of the patients could achieve target blood lipid levels. PMID- 24754065 TI - [A home exercise training program after acute coronary syndrome and/or endovascular coronary intervention: efficiency and a patient motivation problem]. AB - AIM: To analyze the impact of a home exercise training (ET) program on quality of life, motor activity (MA), dietary habit, functional and biochemical parameters, and clinical course of the disease in patients who have experienced acute coronary syndrome (ACS) and/or endovascular coronary intervention (ECI). SUBJECTS AND METHOD: The trial included 100 patients after ECL who were randomized into 2 groups: those who had gone through Patient School (PS) and received a 6-week course of controlled ET (a study group (Group S)) and those who had gone through PS only (a control group (Group C). The patients of both groups were recommended a home ET program and, according to its implementation, they formed 2 subgroups: Subgroup A (home ET+) comprising 51 patients who had trained themselves at home) and Subgroup B (home ET-) consisting of 46 patients who had not. The follow-up lasted 1 year. Quality of life, risk factors, lifestyle and clinical parameters were assessed. RESULTS: As time elapsed, the patients' motivation to perform home ET; and, accordingly, the proportion of those who had trained themselves decreased in Group S to 67 and 61% and in Group C to 39 and 40% after 6 and 12 months, respectively. Among the reasons for refusal to perform home ET, disease was reported by only 5.6% of the patients (by all from Group C). The comprehensive physical rehabilitation program (RP) (controlled ET in combination with home ET) produced the best effect in raising the level of daily MA, exercise performance with a 21.3-fold increase in cardiac performance (p < 0.05) and a 14.3-fold decrease in heart rate increment in response to exercises. Group C patients who had refused the home ET program, as compared to those in the same group who had trained themselves at home, showed the worst daily MA levels, none body mass index reduction, and a rise in the low-density lipoprotein cholesterol (by 20.3%; p < 0.05) and in the number of angina attacks (by 1.9 times; p < 0.05). CONCLUSION: RP in the early-stage, which encompasses an educational program (PS), a short-term course of controlled ET and home ET used in patients with ACS, including in those after ECI, has clear clinical benefits. The participation of patients with coronary heart disease (CHD) in the home ET programs increases their motivation and, hence, the proportion of those who participate in therapeutic and rehabilitation measures. Home patient physical rehabilitation is one of the important components of different rehabilitation and prevention programs in patients with CHD after ACS and ECI. PMID- 24754066 TI - [The course of coronary heart disease concurrent with peptic ulcer disease: clinical and pathogenetic aspects]. AB - AIM: To make a comprehensive evaluation of the efficiency of eradication therapy in patients with coronary heart disease (CHD) concurrent with peptic ulcer disease (PUD). SUBJECTS AND METHODS: The results of treatment were studied in 112 patients with CHD concurrent with PUD who were randomized into 3 groups: 1) adequate eradication therapy during treatment for CHD; 2) antisecretory therapy; 3) treatment for CHD only. The trend in the clinical symptoms of the diseases and the results of an exercise test were assessed. RESULTS: After eradication therapy, Group 1 patients displayed a reduction in the frequency of angina attacks by 62.6% and weekly nitroglycerin needs by 70.4% and an increase in exercise tolerance by 45.3%. In Group 2 patients on antisecretory therapy, the similar indicators changed by 30.7, 21.2, and 26.5%, respectively. Group 3 patients showed no significant change in the study indicators. CONCLUSION: The findings suggest that eradication therapy has a positive impact on the course of CHD, which manifests itself as an antianginal effect and hence a change in the clinical picture. PMID- 24754067 TI - [Prognostic factors for progression of mitral regurgitation in patients with coronary heart disease after aortocoronary bypass surgery alone and in combination with surgical left ventricular reconstruction]. AB - AIM: To identify risk and prognostic factors for mitral regurgitation (MR) progression after aortocoronary bypass surgery (ACBS) alone and in combination with surgical left ventricular (LV) reconstruction. SUBJECTS AND METHODS: Data on 101 patients with coronary heart disease who had undergone surgical treatment: ACBS alone in 57 (56%) patients and that in combination with surgical LV reconstruction in 44 (44%). RESULTS: In the late periods after ACBS alone, there was reduced or no MR in 18% of the patients; no substantial changes in MR in 52%, the latter being moderate; progression to significant mitral insufficiency (MI) in 30%. In the same periods after ACBS in combination with surgical LV reconstruction, there was a reduction in MR to its minimum or complete absence in 14% of the patients; no substantial change in the degree of MR in 54%, and progression to significant MI in 32%. The prognostic factors of MI progression after ACBs alone and in combination with surgical LV reconstruction were a more than 32-mm fibrous ring of the mitral valve (MV) (chi2 = 11.62; p = 0.0001); a LV sphericity index of more than 0.65 cm (chi2 = 3.38; p = 0.06); a myocardial scar lesion extent of more than 30% of the LV segments (chi2 = 4.7; p = 0.03); a myocardial reserve of less than 25% (chi2 = 3.1; p = 0.07) (when taking low-dose dobutamine). CONCLUSION: Myocardial revascularization should be combined with MV intervention in patients with moderate MR and risk factors for its progression, such as significant LV remodeling (LV sphericity index of more than 0.65 cm), extensive LV scar lesion (more than 30% of the segments), a low myocardial reserve (less than 25%) during dobutamine test, and a MV fibrous ring of more than 32 mm). PMID- 24754068 TI - [Adipokines and the metabolism of key nutrients in patients with obesity]. AB - AIM: To study the effect of adipokines on the metabolism of key nutrients in patients with obesity. SUBJECTS AND METHODS: Ninety patients aged 18 to 66 years old who were treated at the Department of Preventive and Rehabilitative Nutrition, Research Institute of Nutrition, Russian Academy of Medical Sciences, were examined. Carbohydrate and lipid metabolisms were assessed by turbidimetry and spectrophotometry. The levels of adipokines, insulin, and oxidized low density lipoproteins (LDL) were measured by ELISA. Insulin resistance was assessed with HOMA-IR in all the patients. RESULTS: It was found that there were discoordinated changes in the content of adipokines. The patients with Grade 1 obesity, as compared to the control group, had a statistically significant decrease in the serum concentrations of adiponectin (5.94 +/- 0.90 and 15.34 +/- 0.45 microg/ml; p < 0.05) and ghrelin (215.50 +/- 104.50 and 540.67 +/- 0.76 pg/ml; (p < 0.05) and resistin levels above the normal values (7.34 +/- 1.24 and 5.12 +/- 0.22 ng/ml; p < 0.05; respectively). There was an inverse correlation between the content of adiponectin and ghrelin, and body mass index in obese patients (r1 = -0.25, r2 = -0.15; p < 0.05). There was evidence that there was also an inverse correlation between the levels of adiponectin, triglycerides, LDL, particularly oxidized LDL (p < 0.05). Adipokine-induced insulin resistance appeared as increases in the concentrations of glucose, insulin, and HOMA-IR, as compared to those in the control group. CONCLUSION: A comprehensive approach to evaluating metabolic disorders and adipokine synthesis in obese patients makes it possible to optimize the diagnosis of type 2 diabetes mellitus and cardiovascular diseases and to personalize diet therapy. PMID- 24754069 TI - [Association of leptin with obesity and hypertension in an ethnic Kyrgyz group]. AB - AIM: To study an association of the level of leptin, obesity, and hypertension in a group of ethnic Kyrgyz. SUBJECTS AND METHODS: Three hundred and twenty-two Kyrgyz people (145 men and 177 women) who were aged above 30 years and resided in the Kyrgyz Republic were examined. They underwent physical examination involving the collection of complaints and medical history data, objective examination, and anthropometric (height, weight, waist and hip circumference (WC and HC), body mass index (BMI)) and blood pressure (BP) measurements. The persons filled out the Finnish Diabetes Risk Assessment Form including data on vegetable consumption (daily or every other day) and exercise (more or less than 30 min per day). Fasting plasma glucose and serum leptin levels were determined. RESULTS: All the study participants were allocated to 4 groups according the quartile of leptin levels: < 2.2, 2.2-4.2, 4.3-6.34, and > 6.34 ng/ml for men and < 8.05, 8.05-13.4; 13.5-19.09, and > 19.09 ng/ml for women. The persons in the highest leptin quartile were found to have higher BMI, WC, systolic and diastolic BP (SBP and DBP), and blood glucose levels than those in the lowest quartile. Elevated leptin levels were associated with the higher risk of hypertension. Leptin levels correlated with BMI (r = 0.719; p < 0.001 for men and r = 0.74; p < 0.001 for women) and WC (r = 0.684; p < 0.001 for men; and r = 0.649; p < 0.001 for women). There was also a correlation of leptin levels with SBP (r = 0.355; p < 0.001 and r = 0.277; p < 0.001) and DBP (r = 0.426; p < 0.001 and r = 0.228; p < 0.01) in men and women, respectively. CONCLUSION: Leptin levels were associated with obesity and hypertension in the group of ethnic Kyrgyz people. PMID- 24754070 TI - [Role of pFox inhibitors in the treatment of patients with acute myocardial ischemia]. AB - AIM: To evaluate the anti-ischemic and anti-anginal efficacy of meldonium (Idrinol) in its short-term use as part of combination therapy in patients with chronic heart failure in the early post-infarction period. SUBJECTS AND METHODS: The investigation enrolled 60 patients (men and women) aged 45 to 75 years at weeks 3-4 after postmyocardial infarction with symptoms of Functional Class II III heart failure. All the patients underwent physical examination, 24-hour ECG monitoring, heart rate variability (HRV) study, and quality of life assessment using the Seattle questionnaire. After randomization of the patients into 2 groups, Group 1 (a study group) (n = 30) was given intravenous Idrinol 1000 mg/day in addition to the basic therapy of coronary heart disease. The study and control (Group 2; n = 30) groups were matched for age, gender, disease severity, and basic therapy pattern. RESULTS: Following 10-14 days of treatment, both groups showed clinical improvement and the autonomically normalizing effect of meldonium (Idrinol), which were more pronounced in Group 1 patients. CONCLUSION: Meldonium (Idrinol) was effective when parenterally administered in a dose of 1000 mg/day for 10-14 days as part of combination therapy in the early post infarction period, which showed up as clinical improvement, a significant reduction in the frequency of angina attacks and in the need to use nitroglycerin, a decrease in the number of arrhythmia episodes, and its normalizing effect of HRV. PMID- 24754071 TI - [Current possibilities of correcting subchondral bone resorption as a major pathogenetic factor for progressive osteoarthrosis]. AB - The paper considers the current pathogenesis, by choosing the actual targets of pharmacotherapy with available drugs. It reflects the cytokine mechanisms responsible for lesion of the synovial membranes, cartilage, and subchondral bone. Particular emphasis is laid on the role of chondroitin sulfate, glucosamine, vitamin D3 as drugs that affect the key components of pathogenesis, including the volume of resorptive cavities in the subchondral bone. PMID- 24754072 TI - [Creation of a Russian Federation's register for assessing the physician adherence to the guidelines for the diagnosis and treatment of chronic heart failure]. AB - The paper reviews existing chronic heart failure (CHF) registers, a number of randomized trials, and meta-analyses on CHF. It provides a rationale for the need to create a CHF register in the Russian Federation, which will be able to assess the physician adherence to the guidelines for the guidelines for and the quality of medical care. PMID- 24754073 TI - [Role of atrial structural and functional changes in the development and progression of atrial fibrillation]. AB - Atrial fibrillation (AF) is one of the most common reasons for decreased life quality and increased mortality rates. Experimental and clinical data show that atrial structural and functional changes contribute to the development and progression of AF. The survey article considers the role of the systemic and local activities of the renin-angiotensin-aldosterone system and inflammatory mediators in the development of atrial structural remodeling, which may be a cause and a consequence of AF. PMID- 24754074 TI - [Peroxisome proliferator-activated receptors-alpha (PPAR-alpha) and chronic heart failure: is there a reason to discuss the metabolic strategy of treatment?]. AB - Despite improved prognosis in patients with heart failure (HF) treated with neurohumoral activation-suppressing drugs (such as angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, beta-adrenergic receptor antagonists, aldosterone receptor antagonists), mortality from heart failure remains high, myocardial contractile dysfunction progresses, and the left ventricle becomes enlarged. This leads to the need to elaborate novel approaches to treating HF. The latter is obviously due to impaired myocardial energy substrate metabolism. The mechanisms underlying this phenomenon are numerous and complex. These include reduced myocardial expression and activity of key free fatty acid oxidative enzymes. The expression of these enzymes is controlled by peroxisome proliferator-activated receptors-alpha (PPAR-alpha). Thus, PPAR-alpha activation is a direct method to regulate myocardial fatty acid metabolism. Evidence for the efficiency of therapeutic strategies based on the fact that fatty acid metabolism may be modulated is controversial, which indicates that there may be more complex molecular/biochemical changes than supposed before. The data available in the literature suggest the promises of the above strategy and its serious therapeutic potential. PMID- 24754075 TI - [The therapeutic efficacy of cycloferon and the pharmacological activity of interferon inducers]. AB - The review describes endogenous interferon inductors that belong to antiviral drugs and contain different chemical compounds. Among the groups identified by the authors, there are promising and most effective medicines inducing different types of interferon in the body, as well as their mechanism of action. The paper shows the synthesis of endogenous interferon and the level of its accumulation in the organs and tissues. The clinical effects of methylglucamine acridonacetate (cycloferon) are depicted in patients with major viral (influenza, acute respiratory viral and arboviral infections, and viral hepatitis) and bacterial (brucellosis, tuberculosis) infections, or endometrial hyperplastic processes. Cycloferon is shown to be used as an etiotropic and antipathogenic drug. PMID- 24754076 TI - [Some aspects of the treatment of adult patients with Epstein-Barr virus infection]. AB - The review analyzes the basic aspects of treatment policy in patients with different forms of Epstein-Barr virus infection. Practical recommendations are given on the basis of the extensive literature data published in the past 20 years. PMID- 24754077 TI - [The significance of natriuretic peptides in the evaluation of water-salt metabolism in chronic kidney disease]. AB - The paper discusses the molecular, biochemical, and physiological properties of natriuretic peptides, including the clinical applications of their synthetic formulations, as well as the renal and extrarenal mechanisms of water-salt metabolism in chronic kidney disease. PMID- 24754078 TI - [Pain treatment in patients with hemophilia]. AB - Pain in patients with hemophilia is an urgent problem. The possibilities of using analgesic drugs are interesting by virtue of the specific features of pain syndrome and the problems of treatment in these patients. Foreign and Russian trials using current analgesics are analyzed; difficulties in choosing analgesic therapy and in performing anesthesia mode in patients with congenital hypocoagulation and hyperalgesia are discussed. PMID- 24754079 TI - The production of hydroxyl radical by bleomycin and iron (ii). PMID- 24754080 TI - The kinetics of the reaction of superoxide radical with Fe(III) complexes of EDTA, DETAPAC and HEDTA. AB - To gain an understanding of the mechanism by which the hydroxyl free radical can arise in superoxide generating systems and learn how different chelaters of iron can inhibit this reaction, a pulse radiolysis kinetic study of the reaction of O; with Fe(III)EDTA, Fe(III)HEDTA and Fe(III)DETAPAC (or DTPA)was undertaken. Superoxide reacts readily with Fe(III)EDTA and Fe(III)HEDTA with a pH-dependent second-order rate constant having values of 1.9 x lo6 M-l. s-' and 7.6 x 16 M-'. s-' at pH 7,respectively. However, the rate constant for the reaction of O;- with Fe(III)DETAPAC was found to be much slower, the upper limit for the rate constant being 104 M-l. s-l. These results in conjunction with spin-trapping experiments with Fe(II)EDTA, Fe(II)HEDTA, Fe(II)DETAPAC and Hz02 suggests that DETAPAC inhibits the formation of 'OH by slowing the reduction of Fe(II1) to Fe(I1) and not by inhibiting the Fenton reaction. PMID- 24754081 TI - Building the evidence, block by block. PMID- 24754082 TI - [Adhere to the scientific and strive for excellence]. PMID- 24754083 TI - [New advances in liver cancer research: a review of 2013]. PMID- 24754084 TI - [Recent advances in our understanding of the molecular mechanisms of liver fibrosis]. PMID- 24754085 TI - [Chinese expert consensus guidelines for the diagnosis and treatment of cholestatic liver disease reached in 2013]. PMID- 24754086 TI - [Explanation of the 2013 Chinese expert consensus guidelines for the diagnosis and treatment of cholestatic liver disease]. PMID- 24754087 TI - [Expression and implication of the augmenter of liver regeneration protein in acute-on-chronic liver failure]. PMID- 24754088 TI - [Colorectal adenomatous polyps and non-alcoholic fatty liver disease]. PMID- 24754089 TI - [Ratio analysis of HBV-related liver disease and primary liver carcinoma development over 10 years in patients who received no antiviral therapy versus those treated with antiviral therapy]. PMID- 24754090 TI - [Preventing paclitaxel-induced toxicity by reducing glutathione]. PMID- 24754091 TI - [A case report of multiple spontaneous bone fractures in a patient with alcoholic liver disease and metabolic bone disease]. PMID- 24754092 TI - [Liver cirrhosis with factor VII deficiency: a case report and literature review]. PMID- 24754093 TI - [Progression of hepatic osteodystrophy: pathogenesis, diagnosis and treatment]. PMID- 24754094 TI - [Advances in understanding the pathogenesis of hepatogenic diabetes]. PMID- 24754095 TI - Medical devices; ophthalmic devices; classification of the eyelid weight. Final rule. AB - The Food and Drug Administration (FDA or Agency) is classifying the eyelid weight into class II (special controls). The Agency is exempting the external eyelid weight from premarket notification, but continuing to require premarket notification for implantable eyelid weights in order to provide a reasonable assurance of safety and effectiveness of the device. Both external and implantable eyelid weight devices are subject to special controls. The eyelid weight may be adhered to the outer skin of the upper eyelid (external eyelid weight) or implanted into the upper eyelid (implantable eyelid weight), and is intended for the gravity assisted treatment of lagophthalmos (incomplete eyelid closure). PMID- 24754096 TI - Breast conserving surgery using volume replacement with oxidized regenerated cellulose: a cosmetic outcome analysis. AB - We evaluated the cosmetic outcome of volume replacement with oxidized regenerated cellulose (ORC) after breast-conserving surgery (BCS) and also examined factors that may have influenced the results. Ninety-four patients who underwent BCS with ORC replacement between January 2010 and August 2012 participated in this study. The cosmetic outcomes of these patients were evaluated using scores based on the criteria of the Japan Breast Cancer Society. We evaluated cosmetic scores with regards to several clinical factors and the occurrence of complications after this procedure. The mean score of the cosmetic outcome of all patients was 9.5 points of 12 points. Thirty-seven patients were categorized as "Excellent," 34 were "Good," 22 were "Fair," and 1 was "Poor." Patient age, body mass index, weight of the specimen, and ORC amount were not significantly different between patients with favorable cosmetic scores and those without. However, the weight of the removed specimen was slightly higher in patients with an unfavorable cosmetic score. Although acute dermatitis and eczema was observed in 15% and 3% of patients, all of them were improved with conservative treatment. Cosmetic scores were significantly higher in patients without complications than in patients with complications. In conclusion, ORC replacement after BCS is a simple and reliable procedure. The selection of indication and prevention of complications are important for obtaining a better cosmetic outcome. This is the first report to cosmetically evaluate a relatively large number of patients that have undergone ORC replacement after BCS. PMID- 24754097 TI - [Hydrolyzed wheat protein]. PMID- 24754098 TI - [Sublingual immunotherapy]. PMID- 24754099 TI - Chronic kidney disease and the aging population. PMID- 24754100 TI - "It's time to end the understaffing scandals". PMID- 24754101 TI - Trusts in breach of sharps rules. PMID- 24754102 TI - "Revalidation will provide an opportunity to reflect on practice". PMID- 24754103 TI - "When tasks overwhelm, the human touch will be missing". PMID- 24754104 TI - Diagnosis and treatment of prostate cancer. AB - Nurses are often key workers for patients with prostate cancer and are responsible for ensuring men have the support they need throughout their cancer journey. This article provides an overview of the patient pathway. PMID- 24754105 TI - Incontinence following prostate cancer surgery. AB - I am a nurse with 25 years' experience in continence care. This case study describes my personal experience of managing urinary incontinence after my husband's radical prostatectomy for prostate cancer. The management of incontinence, alongside the treatment regimen, motivational strategies, dignity and the desire to regain bladder control, are described. PMID- 24754106 TI - Continence care for people with dementia at home. AB - The majority of people with dementia live in their own homes. Difficulties with using the toilet and incontinence can lead to them moving into care homes. This report summarises a systematic review by Drennan et al (2012) that investigated the evidence for conservative interventions for the prevention or management of incontinence in people with dementia living at home. PMID- 24754107 TI - Patients' views on a nurse-led prostate clinic. AB - Nurse-led clinics are being established in a number of specialties including urology. Men attending a nurse-led clinic for suspected prostate cancer were surveyed to investigate their perception of and satisfaction with a nurse-led clinic and to establish whether this model of care met expectations. The results showed that patients were satisfied with the service. This adds to the growing body of evidence supporting nurse-led services. PMID- 24754108 TI - Drug treatments for Alzheimer's disease. AB - This article discusses the development and progress of treatment for Alzheimer's disease. Medical treatments have not changed since the late 1990s and have limited effects. They treat the symptoms patients experience but do not reverse the effects or repair neurological damage caused by Alzheimer's disease. Updated NICE guidance and likely future advances in treatment are also PMID- 24754109 TI - 60 seconds with Catherine Walshe. PMID- 24754110 TI - From script to screening. PMID- 24754112 TI - [There's a urgent need to improve nursing in psychiatry]. PMID- 24754111 TI - Ensure you have a recipe for success. PMID- 24754113 TI - [Professional meeting with the President of nurses's international council]. PMID- 24754114 TI - [National health plan cancer 3 is about reducing inequalities]. PMID- 24754115 TI - [Operating room nursing diploma soon to be accessible through competence validation]. PMID- 24754116 TI - [What will become of the Clinical Sciences Nursing Master degree?]. PMID- 24754117 TI - [Crohn's disease and ulcerative colitis]. AB - Extremely variable in their clinical expression, inflammatory bowl diseases evolve by flare-ups interspersed with phases of remission. Complications can be severe, sometimes requiring surgery. While treatments have evolved considerably, therapeutic patient education plays an important role in the therapeutic approach. PMID- 24754118 TI - [Surgical treatment of ulcerative colitis]. AB - Surgery for patients suffering from inflammatory bowel diseases is an option when medication-based treatment fails. Sometimes complex and carried out in several stages, the procedures require the nurses to be involved in the education of the patient, monitoring prevention and identification of complications. PMID- 24754119 TI - [Nutritional recommendations in cases of IBD]. AB - During flare-ups as well as periods of remission, diet is a concern for people suffering from inflammatory bowel disease. Hence the importance of dietary advice given by dietetic specialists to whom patients can freely direct their questions about their diets. PMID- 24754120 TI - [Preventing the emotional and social isolation of patients suffering from IBD]. AB - Inflammatory bowel diseases can remain invisible even though they are very disabling. Every aspect of the patient's life is affected with particular repercussions for teenagers. Psychological treatment can help to prevent emotional and social isolation. PMID- 24754121 TI - [Therapeutic education, a factor of compliance and autonomy]. AB - Improving the daily life of patients suffering from inflammatory bowel disease is one of the objectives of the gastroenterological team of Nice general hospital. Therapeutic patient education has been developed in the hospital, through the Edu MICI programme. The practice of this multi-disciplinary team gives nurses the opportunity to fully express their unique role. PMID- 24754122 TI - [Art as a complement to TPE]. AB - Seeking to enrich the support process developed by therapeutic education, a team in Nantes proposes innovative mediation actions to favour the adaptability of patients suffering from inflammatory bowel diseases. PMID- 24754123 TI - [IBD and increased risk of cancer: what is the reality?]. AB - Inflammatory bowel diseases can favour the occurrence of colon cancer while their treatments can increase the risk of certain other cancers. The doctor's skill lies in striking the right benefit-risk balance of the treatments. PMID- 24754124 TI - [Promoting occupational health in a Parisian department store]. AB - Astrid Tellier has found her professional footing within the occupational health department of a Parisian department store. The coordinator of the nursing team, she feels fulfilled in this practice which combines various missions of organisation, prevention and care. PMID- 24754125 TI - [The nurse and the clinical examination of the nervous system]. AB - The clinical examination of the neurological system provides valuable information regarding a person's health status. The nurse, in her daily practice, must be able to identify certain signs which may reveal situations requiring urgent treatment. Others are regularly assessed to monitor the evolution of the patient's condition. PMID- 24754126 TI - [Workshop for the prevention of blood exposure accidents]. AB - In the framework of the Stop Risk programme, presented by the centre for the coordination of the fight against hospital-acquired infections (CClin) in the south east of France, a workshop on the prevention of accidents through exposure to blood combined with improvement actions was offered to the nursing staff of Sartene general hospital. This approach is based on existing programmes and encourages the application of standard precautions. PMID- 24754127 TI - [Self-dialysis nursing practice in Mayotte]. AB - Mayotte's first self-dialysis centre was created in January 2012 in Mamoudzou, the island's capital. The cultural approach of Mahorais patients gives rise to the need for a specific care management and adapted care for haemodialysis patients. Sabine, a nurse, works in Mayotte in a multi-disciplinary environment, as these student nurses who went to meet her describe. PMID- 24754128 TI - [Nurses in telehealth]. AB - The development of telehealth is gathering pace. Advice, telemonitoring, support, as well as teleconsultations or even telediagnosis help to improve access to care across the health territories. The nursing team of a telehealth platform based in Lorraine presents this new area of practice. PMID- 24754129 TI - [Shared resistance to the transfer to a palliative care unit]. AB - The transfer to a palliative care unit requires the acceptance of the patient and their family. Resistance to the transfer can arise and both the patient and their family have to relinquish certain things. PMID- 24754130 TI - [Role of diet hygiene in diabetes treatment]. PMID- 24754131 TI - [The nurse role, facing a traffic accident]. PMID- 24754132 TI - [A health promotion class organized by nursing students]. PMID- 24754133 TI - [Performing a percutaneous tracheotomy]. PMID- 24754134 TI - [Discussion about operative treatment for acromioclavicular joint dislocation]. PMID- 24754135 TI - [Case-control study on therapeutic effects between modified Weaver-Dunn surgery and clavicular hook plate fixation in the treatment of acromioclavicular joint dislocation]. AB - OBJECTIVE: To study therapeutic effects between hook plate fixation and modified Weaver-Dunn surgery for the treatment of acromioclavicular joint dislocation. METHODS: Forty patients with fresh acromioclavicular joint dislocations of type III according to Rockwood classification were reviewed. All the patients were divided into two groups: hook plate fixation group and modified surgery group. There were 20 patients in hook plate fixation group, including 13 males and 7 females, with an average age of (37.45 +/- 14.29) years old; 12 patients had injuries in the left and 8 patients had injuries in the right; preoperative Constant-Murley score was 40.75 +/- 10.40. And there were 20 patients in modified surgery group,including 11 males and 9 females, with an average age of (41.65 +/- 14.83) years old; 11 patients had injuries in the left and 9 patients had injuries in the right; preoperative Constant-Murley score was 42.75 +/- 8.18. The Lazzcano standard, Constant-Murley score and imaging changes were used to evaluate shoulder joint function before and after surgery. RESULTS: All the patients were followed up,and the duration ranged from 7 to 32 months,with an average of 24 months. According to Lazzcano evaluation, 16 patients got an excellent result,3 good and 1 poor in modified surgery group with no re dislocation, and 1 patient had pain more than middle degree; while in hook plate fixation group, 9 patients got an excellent result, 7 good and 4 poor, 1 patient had re-dislocation, and 3 patients got pain more than middle degree. The therapeutic effects of modified surgery group were better than those of hook plate fixation group. Constant-Murley scores:preoperative 42.75 +/- 8.18 vs 93.40 +/- 4.04 at the latest follow-up in modified surgery group; preoperative 40.75 +/ 10.40 vs postoperative 88.40 +/- 4.81 and 92.05 +/- 4.49 at the latest follow-up in hook plate fixation group. The postoperative scores all improved compared to preoperative scores in two groups. And there was no statistical difference of scores at the latest follow-up between two groups. CONCLUSION: The surgery of allograft tendon transplantation combined with anchor fixation to strengthen coracoclavicular ligament, as well as part transposition of acromiocoracoid ligament and resection at the distal part of clavicle may got safety fixation and less postoperative complications compared with hook plate internal fixation. PMID- 24754136 TI - [Analysis on the long-term effects of modified double endobutton technique in the treatment of Tossy type III acromioclavicular joint dislocations]. AB - OBJECTIVE: To investigate the long-term clinical effects of modified double Endobutton technique for the treatment of acromioclavicular joint dislocations of Tossy type III. METHODS: A retrospective study was done in 42 patients with acromioclavicular joint dislocations of Tossy type III treated with modified double Endobutton technique from December 2008 to December 2010. There were 24 males and 18 females, ranging in age from 21 to 56 years old (averaged, 32.5 years old). All the patients were treated with open reduction, coracoclavicular ligament reconstruction using double Endobutton technique, and repair of acromioclavicular ligament. The Karlsson system was used to evaluate therapeutic effects. The distance from coracoid to clavicle was measured to evaluate reduction loss. RESULTS: All the patients were followed up, and the duration ranged from 2.0 to 3.2 years (averaged,2.4 years). According to Karlsson system, 32 patients got an A degree and 10 patients got a B degree at three months post operatively; 26 patients got an A degree and 16 patients got a B degree at the latest follow-up; 6 patients got an A degree at 3 months after operation lowered to B degree at the latest follow-up. The coracoid-clavicle distance increased from (26.91 +/- 0.91) mm at 3 months after operation to (27.41 +/- 1.10) mm at the latest follow-up. Te patients treated with over-reduction during operation or with heavy physical labour work after operation had obvious widened coracoid clavicle distance. Bone absorption was found around the plate in most cases, mainly in the clavicular side. CONCLUSION: Treatment for acromioclavicular joint dislocations of Tossy type III with modified double Endobutton technique has satisfactory early clinical results. But with time passing, loss of reduction and bone absorption around the plate could be observed, and clinical outcomes of some cases downgrade during the long-term follow-up. PMID- 24754137 TI - [Case-control study on measurement of coracoclavicular and acromioclavicular ligament injuries during internal fixation operation for the treatment of fresh acromioclavicular joint dislocation of Tossy type III]. AB - OBJECTIVE: To study measurement methods of acromioclavicular and coracoclavicular ligament injuries,its therapeutic effects and complications during internal fixation operation for the treatment of fresh acromioclavicular joint dislocations of Tossy type III. METHODS: From July 2003 to May 2012,127 patients with acromioclavicular joint dislocations of Tossy type III were treated with wire fixation from coracoid process to clavicle or hook-plate fixation. The patients were divided into group A (63 cases) and group B (64 cases) according to whether acromioclavicular ligament and coracoclavicular ligament were repaired or not. In group A (ligaments repaired), there were 39 males and 24 females with an average age of (33.25 +/- 8.46) years old (ranged from 17 to 59 years). And in group B (no ligaments repaired), there were 41 males and 23 females with an average age of (34.10 +/- 7.19) years (ranged from 19 to 57 years). The operation times, intraoperative blood loss, postoperative infections, internal fixation failure, recurrence and other complications, together with therapeutic effects were compared between two groups. RESULTS: The outcome was analyzed according to Karlsson standard. In group A, 54 patients got an excellent result and 9 good according to Karlsson standard;the average operative time was (55.90 +/- 26.56) min; the average intraoperative bleeding amount was (99.80 +/- 50.30) ml; 1 patient had wire broken without re-dislocation at 16 weeks after operation, 3 patients got wound fat liquefaction and recovered after treatment, 1 patient had pain after shoulder joint motion and pain disappeared after implants were taken out. In group B, 52 patients got an excellent result and 12 good according to Karlsson standard; the average operative time was (49.50 +/- 23.14) min; the average intraoperative bleeding amount was (87.30 +/- 46.41) ml; 2 patients got wound fat liquefaction, and 2 patients had pain after shoulder joint motion. All the patients were followed up, and the duration ranged from 9 to 16 months. All internal steel-wire or hook plate were taken out during 4 to 9 months without acromioclavicular joint re dislocation. There were no significant difference in the average operative time, the average intraoperative blood less, complication recurrence rates of fixation failure, wound fat liquefaction, postoperative infection, acromioclavicular joint re-dislocation, and therapeutic effects between two groups. CONCLUSION: Both wire and clavicular hook plate fixation, performed for fresh acromioclavicular joint dislocation with Tossy type III, are simple, effective, less invasive method with less blood loss. In addition, the treatment without ligaments repaired could not increase incidence of complications. PMID- 24754138 TI - [Soft tissue changes observed through musculoskeletal ultrasound in the treatment of knee osteoarthritis with needle-knife]. AB - OBJECTIVE: To study soft tissue changes observed through musculoskeletal ultrasound (MSUS) in the treatment of knee osteoarthritis with needle-knife, so as to provide MSUS basis for needle-knife in the treatment of knee osteoarthritis. METHODS: Forty patients with knee osteoarthritis treated in the Third Affiliated Hospital of Beijing University of Chinese Medicine from December 2011 to December 2012 were selected according to inclusion and exclusion criteria. All the patients were treated with needle-knife release method. The VAS scores and knee joint circumference were recorded before treatment and 2 weeks after treatment. The changes of knee joint hydrops articuli and joint synovial thickness were measured through MSUS. RESULTS: The knee pain index was 6.850 +/- 1.417 before treatment and 2.790 +/- 1.299 after treatment;the index after treatment was lower than that of before treatment. The knee joint circumference was 407.320 +/- 45.151 mm before treatment and 391.240 +/- 41.129 mm after treatment; the knee joint circumference decreased after treatment. The amount of hydrops articuli observed by musculoskeletal ultrasound showed that 47 knees were cured, 19 knees improved and 2 knees failed. The synovial membrane thickness: 43 knees cured, 17 knees improved and 8 knees failed. CONCLUSION: The hydrops articuli and synovial thickness of knee joint of patients with knee osteoarthritis observed under the MSUS is consistent with the main symptoms and signs, which suggests that MSUS observation on soft tissue changes before and after needle knife in the treatment of knee osteoarthritis with high reliability. PMID- 24754139 TI - [Study on distribution features of tender points in patients with knee osteoarthritis by cluster analysis]. AB - OBJECTIVE: To observe the distribution features of tender points in knee of patients with knee osteoarthritis in order to provide evidences for the treatment and diagnosis. METHODS: From November 2011 to December 2012,86 patients with knee osteoarthritis were recruited, including 21 males and 65 females, ranging in age from 45 to 85 years old, with an average of (59.98 +/- 8.23) years old. The course of disease ranged from 3 months to 15 years. The tender points and its distributions were determined by finger press carefully on their knees. Data of studying was analyzed by frequency statistics and Hierachical cluster analysis. RESULTS: The distribution of tender points in the knee osteoarthritis was mainly in the interior region and anterior area such as in apex of patella, adductor tubercle and et al. According to the results of hierachical cluster analysis, the tender points could be divided into two categories the first cluster was in the interior region of knee, the second cluster was in the lateral region. CONCLUSION: The findings demonstrated that cluster analysis statistical method can be used for classification of the distribution of tender points. The distribution features of tender points in knee osteoarthritis are related to the anatomic site in knee. PMID- 24754140 TI - [Surgical strategy for the treatment of thoracolumbar metastatic tumor and its clinical outcomes]. AB - OBJECTIVE: To evaluate surgical strategy and clinical outcomes for the treatment of thoracolumbar metastatic tumor. METHODS: From January 2009 to December 2010,42 patients with thoracolumbar metastatic tumor were treated surgically. Among the patients, 30 patients were male, and 12 patients were female, ranging in age from 28 to 76 years old, with an average age of 56.8 years old. Twenty-five patients had metastatic tumor in thoracic vertebraes, and 17 patients had metastatic tumor in lumbar vertebraes. Thirty-four patients had metastatic tumor in 1 segment, 6 patients had metastatic tumor in 2 segments and 2 patients had metastatic tumor in 3 segments. Two patients had no symptoms and 40 patients had back or leg pain. Eighteen patients had neurologic deficits, and 5 patients had injuries of A degree, 3 patients had injuries of B degree, 4 patients had injuries of C degree, 6 patients had injuries of D degree according to ASIA grading system. The operation goal was made according to Tomita evaluation. The surgical procedures included pallative decompression, tumor curettage and total vertebrectomy, which were decided based on Tomita classification. The pain, spinal cord function,part control of tumor,survival rate and conditions of internal fixation were evaluated at 1 week, 3 months, 6 months, 1 year and 2 years after operation. RESULTS: One patient died in the operation. Pain relief was obtained in 38 patients after operation. Among 18 patients suffering from spinal cord compromise, 17 patients improved 1 to 4 grades after surgery according to the ASIA grading system. All the patients were followed up and the duration ranged from 24 to 48 months, with a mean time of 34.2 months. Five patients got recurrence. The postoperative survival rates at 3 months, 6 months, 1 year and 2 years were 95.2%, 85.7%, 58.2%, 37.6% respectively. CONCLUSION: According to Tomita system, the different surgical treatments can be selected for patients with spinal metastatic tumors, which can relieve pain, improve the neurological status and spine stabilization, maintain local control, improve quality of life. PMID- 24754141 TI - [Case-control study on effects of external fixation combined with limited internal fixation for the treatment of Pilon fractures of Ruedi-Allgower type III]. AB - OBJECTIVE: To analyze the effects of three surgical operations in the treatment of Pilon fracture of Ruedi-Allgower type III, and put forward the best therapeutic method. METHODS: The clinical data of 33 patients with Pilon fracture who received surgical operations (plaster immobilization group, 10 cases; distal tibia anatomical plate group, 11 cases; external fixation with limited internal fixation group, 12 cases) from October 2009 to January 2012 were analyzed. There were 5 males and 5 females, ranging in age from 24 to 61 years in the plaster immobilization group. There were 7 males and 4 females, ranging in age from 21 to 64 years in the distal tibia anatomical plate group. There were 7 males and 5 females, ranging in age from 23 to 67 years in the external fixation with limited internal fixation group. The Ankle X-ray of Pilon fracture after operation, ankle score, early and late complications were collected. Bourne system was used to evaluate ankle joint function. RESULTS: After 8 months to 3 years follow-up, it was found that three kinds of treatment had significant differences in the outcomes and complications (P < 0.05): the external fixation with limited internal fixation group got the best results. The number of anatomic reduction cases in the external fixation with limited internal fixation group (7 cases) and the distal tibia anatomical plate group (8 cases) was more than the plaster immobilization group (2 cases). According to the ankle score, 8 patients got an excellent result, 3 good and 1 poor in the limited internal fixation group ,which was better than those of distal tibia anatomical plate group (5 excellent, 4 good and 2 poor) and the plaster immobilization group (3 excellent, 4 good and 3 poor). The number of early and late complications in the external fixation with limited internal fixation group was more than those in the plaster immobilization group and the distal tibia anatomical plate group (P< 0.05). CONCLUSION: Treatment of external fixation with limited internal fixation in the treatment of Pilon fracture of Ruedi-Allgower type III is effective and safe. PMID- 24754142 TI - [Case-control study on effect of rivaroxaban on the risk of hidden bleeding after total hip arthroplasty]. AB - OBJECTIVE: To investigate the risk of hidden blood loss about applying rivaroxaban after total hip arthroplasty. METHODS: From October 2009 to May 2012,88 patients with femoral head necrosis were treated with primary total hip arthroplasty. All the patients were divided into Rivaroxaban group(44 cases)and control group(44 cases). There were 25 males and 19 females in the Rivaroxaban group, with an average age of (58.48 +/- 15.19) years old; in the control group,24 patients were male and 20 patients were female, with an average age of (61.11 +/- 13.54) years old. The patients in the Rivaroxaban group took Rivaroxaban orally from the first day after operation with a dose of 10 mg each day, and treatment course was 14 days. The patients in the control group took placebo orally at the same time. Dominant blood loss and transfusion were recorded, blood routine examinations were taken before operation and at 3 days after operation. The total blood loss and hidden blood loss were calculated according to the formula. RESULTS: The mean total blood loss was (1509.56 +/- 325.23) ml and the hidden blood loss was(581.47 +/- 215.01) ml, accounting for (37.88 +/- 10.42)% in the Rivaroxaban group. The mean total blood loss was (1262.30 +/- 397.95) ml and the hidden blood loss was (395.59 +/- 97.33) ml, accounting for (30.62 +/- 0.20)% in the control group. The total blood loss, hidden blood loss and transfusion in the Rivaroxaban group was significantly more than those in control group,b ut there was no significant difference on dominant blood loss between two groups. CONCLUSION: Rivaroxaban increased the overall bleeding risk of total hip arthroplasty, especially hidden bleeding risk, which should be careful used. PMID- 24754143 TI - [Case-control study on locking plates fixation for the treatment of Neer 3-and 4 part proximal humerus fractures]. AB - OBJECTIVE: To compare therapeutic effects of locking plates for the treatment of Neer 3-and 4-part proximal humerus fractures. METHODS: From January 2009 to June 2011, 64 patients with Neer 3-and 4-part proximal humerus fractures were treated with locked plate fixation. There were 39 patients in the 3-part group including 16 males and 23 females, with an average age of (55.12 +/- 12.52) years old; and 25 patients in the 4-part fractures group including 9 males and 16 females,with an average age of (57.92 +/- 13.14) years old. The American Shoulder and Elbow Surgeons score (ASES), visual analogue scale (VAS) and complications were documented for analysis before and after treatment. RESULTS: All the patients had incision healing at the first stage. All the patients were followed up, and the duration ranged from 12 to 30 months, with a mean of 16.5 months. Comparably better shoulder function recovery was achieved in the 3-part fractures group with regard to the ASES (76.14 +/- 14.10 in the 3-part fractures group vs. 65.93 +/- 11.82 in the 4-part fractures group, P < 0.05). Moreover,a statistical difference (P < 0.05) was observed regarding the VAS pain score (2.12 +/- 1.63 in the 3-part fractures group vs. 3.90 +/- 2.21 in the 4-part fractures group). For the complications rate,no statistical difference was noted between 3-part fractures group and 4-part fractures group (20.51% vs. 36.00%). CONCLUSION: The clinical outcomes of the 3-part proximal humerus fractures is better than the 4-part fractures proximal humerus fractures treated with locking plate. Complex proximal humeral fractures treated with locking plates can be achieved a satisfactory outcome when attention is paid to anatomic reduction, stable fixation, proper screws and plate placement, and reasonable functional exercise postoperative. PMID- 24754144 TI - [Case-control study on the operative treatment for terrible triad of the elbow]. AB - OBJECTIVE: To retrospectively analyze therapy comparison between hinged external fixator combining with internal fixation, soft tissue repair and plaster fixation after routine surgery for terrible triad of the elbow. METHODS: From January 2003 to June 2011,26 patients with terrible triad of the elbow (posterior dislocation associated with fracture of both the radial head and the ulnar coronoid process) were treated respectively by unilateral hinged external fixator and plaster fixation. Fourteen patients were treated with external fixator combining with internal fixation, soft tissue repair and reconstruction, including 8 males and 6 females,ranging in age from 20 to 62 years with an average of (33.60 +/- 8.53) years. The mean time of fixation was 7.5 weeks (ranged, 6 to 8 weeks), and forearm rotation exercise was performed after the first day of operation, elbow flexion and extension activities after 4 to 6 days. Twelve patients were treated with plaster external fixation combining with open reduction and internal fixation,including 8 males and 4 females,ranging in age from 21 to 63 years with an average of (34.80 +/- 7.41) years. The mean time of plaster fixation was 30.4 days, and functional exercise was carried out after 4 to 6 weeks of plaster removal. JOA assessment score were used to evaluate the elbow joint function. RESULTS: All the patients were followed up, and the duration ranged from 12 to 36 months,with an average of 18.6 months. The mean time of fracture healing was (8.6 +/- 3.1) weeks in plaster group and (9.0 +/- 2.7) weeks in fixator group, with no statistical difference between the two groups (t =1.47, P > 0.05). The function and are of motion in plaster group and fixator group showed significant difference. While the pain, articular instability and deformity showed no statistical difference. The total assessment score between two groups indicated markedly difference (t = -2.66, P < 0.01). CONCLUSION: Hinged external fixator can enhance lateral stability of elbows,benefit the reduction of fracture dislocation, guarantee early and safe functional exercise, prevent elbow stiffness, and reduce heterotopic ossification. In treating terrible triad of the elbow, the hinged external fixator is superior to other therapies with respect of improving the function of elbow joint. PMID- 24754145 TI - [Synovial osteochondromatosis misdiagnosed as avulsion fracture of tibial tubercle: a case report]. PMID- 24754146 TI - [Study on bone mesenchymal stem cells transfected by polyethylene glycol/bone morphogenetic protein-2]. AB - OBJECTIVE: Polyethylene glycol/bone morphogenetic protein-2 (PEG/BMP-2) nanoparticles were transfected into Rabbit bone mesenchymal stem cells (rBMSCs) and the expression of BMP-2 was detected. METHODS: Dissociated rBMSCs were primarily cultured in vitro and BMP-2 gene was transfected into rBMSCs by PEG/BMP 2 nanoparticals and lipofectamine, respectively. The efficiency of transfection was detected by flow cytometry and the expression of BMP-2 was detected by Western Blot and real time RT-PCR. RESULTS: PEG/BMP-2 nanoparticals were successfully synthesized and transfected into rBMSCs. Compared with the lipofectamine transfection group, PEG/BMP-2 transfection group had higher efficiency and higher BMP-2 expression. CONCLUSION: PEG/BMP-2 nanoparticals transfected rBMSCs highly expressed BMP-2,which provided novel strategies for the treatment of bone defect. PMID- 24754147 TI - [Expression of lipoprotein related genes in subchondral bone of early experimental osteoarthritis]. AB - OBJECTIVE: To study the expression of lipoprotein related genes in subchondral bone of early experimental os-teoarthritis, which may play an important role in the pathogenesis of osteoarthritis. METHODS: Animals are equally divided into two groups: experimental group and control group, both of which contain fifteen rats of similar weight. The right knee joints of experimental group underwent surgery,which involved in both medial collateral ligament(MCL) transaction and medial meniscectomy, while the control group was only carried out with a sham operation. Rats were killed at 1, 2 and 4 weeks postsurgery to obtain the right knee joints. Total RNA of the subchondral bone was extracted,and then hybridized to Agilent Whole Rat Genome Microarray. Differentially expressed genes analysis was used to study the chemokine signaling pathway. RESULTS: Apoa5 expression was down-regulated at 1, 2 weeks post-surgery, Apoc2 expression was up-regulated at 1 week after surgery, Apol3 expression was up-regulated at 1 and down-regulated at 4 weeks post-surgery, Lrp1 expression was down-regulated at 1, 2 weeks after surgery. Lrp5 was down-regulated at 2 weeks after surgery. Gpihbp1, Lpl, Tfpi and Vldlr were up-regulated at 1 weeks after surgery. Lrpap1 and RGD1309808 were down regulated at 4 weeks after surgery. CONCLUSION: Dysregulation of lipoprotein related genes plays an important role in pathogenesis of early experimental osteoarthritis. PMID- 24754148 TI - [Clinical apprehension on application of Tri-lock BPS total hip arthroplasty]. AB - OBJECTIVE: To study short-term results and clinical application of Tri-lock BPS in total hip arthoplasty. METHODS: From May 2010 to July 2011, 32 hips in 31 patients (18 males and 13 females, ranging in age from 50 to 77 years old, with an average of 60.5 years old) were treated by total hip arthroplasty with Tri lock BPS, including 8 patients with osteonecrosis (ON), 13 patients with fresh femoral neck fracture, 10 patients with developmental dysplasia of the hip (DDH). The therapeutic effects were evaluated by self assessment form, preoperative and postoperative Harris hip score, radiographs, Engh score and bone in growth of femoral side described by Gruen. Based on the short-term results,its design characteristic and clinical properties were analyzed. RESULTS: All the incisions healed well and there were no complications such as femoral fracture, infection, dislocation and neurovascular injuries. All the patients were followed up with an average time of 12.2 months (ranged, 10 to 14 months). All the joints had good or excellent clinical results. The Harris score increased from preoperative 38.3 +/- 4.9 to 92.5 +/- 11.2 at the latest follow-up (t = 27.53, P < 0.01). Radiographically, the positions of the prostheses were normal,the average limbs length and femoral eccentricity recovered to normal. X-ray of the hips showed that the femoral stem prosthesis was in line with good initial fixed standard. At 3 months after surgery, X-ray of the hips showed that bone in growth in Gruen II and VI of femoral side. CONCLUSION: Short-term results show that the design of Tri-lock BPS is more in line with human anatomy, and has the advantages in rapid recovery of hip function and retains more bone mass. It offers a newly valuable technology for the treatment of osteonecrosis, femoral neck fracture and DDH and so on. PMID- 24754149 TI - [Triple-Endobutton plates for the treatment of rockwood type III to V acromioclavicular joint dislocation]. AB - OBJECTIVE: To evaluate the clinical results of Triple-Endobutton plates for the treatment of Rockwood type III to V acromioclavicular joint dislocation. METHODS: From March 2008 to June 2010,28 patients with Rockwood type II to V acromioclavicular joint dislocations were treated with Triple-Endobutton plates. There were 18 males and 10 females,ranging in age from 20 to 60 years old (averaged 38 years old). Twenty patients had dislocations in the left and 8 patients had dislocations in the right. All the patients had close injury. The Constant criterion was used to evaluate shoulder joint function. RESULTS: All the patients were followed up,and the duration ranged from 18 to 24 months,with an average of 20 months. All the patients got good shoulder joint function,and no re dislocation and pain occurred. The X-ray showed all acromioclavicular joints got good reduction. According to Constant criterion,preoperative score was 25.4 +/- 2.0, postoperative scores were 65.9 +/- 3.0, 87.2 +/- 3.2 and 95.7+/- 1.6 at 1 month,3 months and 6 months separately. CONCLUSION: Treatment of Rockwood type III to V acromioclavicular joint dislocation with Triple-Endobutton plates has satisfactory clinical outcome, simple operation, few complications, without secondary operation and early functional exercise postoperatively. PMID- 24754150 TI - [Three-column reconstruction via posterior approach for the treatment of unstable thoracolumbar fracture accompanied by posterior column injury]. AB - OBJECTIVE: To investigate clinical effects of three-column reconstruction via single posterior approach for the treatment of unstable thoracolumbar fractures accompanied by posterior column injury. METHODS: From December 2008 to May 2010,three-column reconstruction via posterior approach was implemented to 21 patients with unstable thoracolumbar fractures accompanied by posterior column injuries. There were 13 males and 8 females, ranging in age from 23 to 54 years old(averaged,35.5 years old). Injured vertebrae: 1 patient had injury in T11, 4 patients had injuries in T12, 8 patients had injuries in L1, 5 patients had injuries in L2, 3 patients had injuries in L3. The Cobb angle was (25.34 +/- 3.42) degrees. The operation time,blood loss during operation, Cobb angle and the bony fusion were observed. RESULTS: Twenty-one patients were followed up, and the duration ranged from 24 to 27 years old, with an average of 25.6 months. The operation time ranged from 135 to 275 min, with a mean of 185 min. The blood loss during operation ranged from 700 to 1 650 ml (averaged, 870 ml). All the patients had complete decompression. Postoperative Cobb angle was (4.01 +/- 2.03) degrees, and (4.34 +/- 2.38) degrees at the latest follow-up. All the patients got bony fusion. CONCLUSION: To the patients with unstable thoracolumbar fractures accompanied by posterior column injuries, three-column reconstruction via single posterior approach has both anterior approach and posterior approach advantages, which can obtain excellent clinical outcomes. PMID- 24754151 TI - [Minimally invasive percutaneous osteosynthesis with intramedullary nail and close reduction by manipulation for the treatment of femoral shaft fractures]. AB - OBJECTIVE: To explore the technique and clinical results of close reduction by manipulation and minimally invasive percutaneous osteosynthesis with intramedullary nail for the treatment of femur shaft fractures. methods: A retrospective study was conducted to analyze 96 patients with the femur shaft fractures who had been treated with close reduction by manipulation and minimally invasive percutaneous osteosynthesis with intramedullary nail. There were 67 males and 29 females. The average age of patients was 39 years old (ranging from 16 to 88). According to AO fracture classification for the femur shaft fractures,there were 29 cases of type A,46 type B,21 type C. RESULTS: All the patients were followed up and the duration ranged from 12 to 24 months (averaged, 15 months). All the fractures showed union. The time required for the bony union ranged from 3 to 10 months (averaged,4 months). The clinical results were evaluated by Thorsen classification system. At the latest follow-up, 87 patients obtained excellent results, 7 good, 2 fair. CONCLUSION: This treatment method combines advantages of intramedullary nail with close manipulative reduction, so can get satisfactory clinical results for the treatment of femoral shaft fracture with minimal trauma. PMID- 24754152 TI - [Posttraumatic osteosarcoma: a case report and review of relative literatures]. PMID- 24754153 TI - [Missed diagnosis of hiding posterior marginal fracture of ankle with pronation external rotation type and its treatment]. AB - OBJECTIVE: To analyze causes of missed diagnosis of hiding post-malleolar fractures in treating ankle joint fractures of pronation-external rotation type according to Lauge-Hansen classification and assess its medium-term outcomes. METHODS: Among 103 patients with ankle joint fracture of pronation-external rotation type treated from March 2002 to June 2010,9 patients were missed diagnosis,including 6 males and 3 females,with a mean age of 35.2 years old (ranged, 18 to 55 years old) . Four patients were diagnosed during operation, 2 patients were diagnosed 2 or 3 days after first surgery and 3 patients came from other hospital. All the patients were treated remedially with lag screws and lock plates internal fixation. After operation,ankle joint function was evaluated according to American Orthopaedic Foot and Ankle Society (AOFAS). RESULTS: All the 9 patients were followed up, and the duration ranged from 14 to 30 months (averaged, 17 months). No incision infection was found, and all incision healed at the first stage. At the latest follow-up, AOFAS was 83.0 +/- 4.4, the score of 4 patients diagnosed during operation was 85.0 +/- 2.9, and the score of 5 patients treated by secondary operation was 81.0 +/- 5.3. All the patients got fracture union observed by X-ray at a mean time of 2.2 months after operation. There were no complications such as internal fixation loosing, broken and vascular or nerve injuries. CONCLUSION: Ankle joint fracture of pronation external rotation type may be combined with hiding post-malleolar fractures. So to patients with ankle joint fracture of pronation-external rotation type, lateral X-ray should be read carefully, and if necessary, CT or MRI examination should be performed. If adding lateral X-ray examination after reduction of exterior and interior ankle joint fixation, the missed diagnosis may be avoided. PMID- 24754154 TI - [Value of MRI in the diagnosis of radial head fracture with forearm interosseous membrane injury]. AB - OBJECTIVE: To investigate the diagnostic value of MRI in radial head fracture with forearm interosseous membrane injuries. METHODS: From December 2011 to December 2012,26 patients with fractures of capitulum radial in our hospital were collected. There were 15 males and 11 females, ranging in age from 21 to 53 years old,with an average of 37.6 years old. All the patients visited hospital within 72 hours after injuries. X-ray radiography of full ulnar radial length in injured side, CT in injured side (three-dimensional reconstruction if necessary) and MRI (including the elbow and wrist joints) were performed within a week after the injury. The MRI manifestations of the forearm interosseous membrane (with or without damage, the injured location and the injury degree ) and the fractures degree of radial head were observed and compared for the relativity. RESULTS: Radial head fracture from Mason type I to III was associated with the forearm interosseous membrane injury. Radial head fracture degree was positive correlated with forearm interosseous membrane injury degree (P < 0.05). CONCLUSION: Radial head fracture with suspicious forearm interosseous membrane injury is necessary to take MRI for checking for any interosseous membrane injury and injury degree, then choose the right treatment for radial capitulum fracture, only in this way can be helpful for the functional recovery of elbow and forearm. PMID- 24754155 TI - [Pull with manipulation in the treatment of anterior dislocation of the shoulder]. PMID- 24754156 TI - [Review and selection of the approach of total elbow arthroplasty]. AB - Total elbow arthroplasty was initially used to manage the rheumatoid arthritis of elbow. With the developement of technology in recent decades, the indication of total elbow arthroplasty include the trauma associated unstable joint, traumatic arthritis and distal humerus fractures in elderly. But the high risk of complications, which includes infection, ulnar nerve deficit and tricep insufficiency, is still an unsolved issue. The most widely used approach nowadays is the Bryan-Morrey approach, while some authors also report triceps on approach recently. This article is an overview in approaches and biomechanical researches of total elbow arthroplasy by reviewing the domestic and overseas involved literatures. PMID- 24754157 TI - [Advances and new ideas of neurobiology scaffold in repair of nerve injury]. AB - Nerve injury including peripheral nerve injury and central nerve injury has been a global problem. With the development of technology, many innovative approaches for nerve repair have been tested and some of the results are meaningful. It becomes a hot point that repair nerve injured by biological scaffold (nerve conduit). This article reviewed and analyzed several kinds of biological scaffold materials and microenvironment with better effect in recent years. Some new ideas were raised from the three aspects: appropriate materials, microstructure, and bionic microenvironment. It is better to combine multiple measures and achieve the best effect. In addition, nerve scaffold have a bright future in repair of central nervous system. PMID- 24754158 TI - [Specificity of traditional Chinese medicine's clinical re-evaluation]. AB - Clinical re-evaluation is to verify the drug's safety and effectiveness again,while the drug itself has not been improved. However, due to the complexity of traditional Chinese medicine, ingredients in bulk drugs, prescription, productive processes, quality standards and other aspects need to be enhanced. So improving the quality, safety and effectiveness of traditional Chinese medicine by clinical re-evaluation is also very necessary. Therefore, except for achieving those basic requirements of medicine, it should also be improved on itself and pay full attention to the particularity, then traditional Chinese medicine's clinical re-evaluation will play its due role. PMID- 24754159 TI - [Identification and early diagnosis for traditional Chinese medicine-induced liver injury based on translational toxicology]. AB - Recently traditional Chinese medicine (TCM)-induced liver injury has been an unresolved critical issue which impacts TCM clinical safety. The premise and key step to reduce or avoid drug-induced liver injury (DILI) is to identify the drug source of liver injury in early stage. Then the timely withdrawal of drug and treatment can be done. However, the current diagnosis of DILI is primarily governed by exclusive method relying on administering history supplied by patients and experience judgment from doctors, which lacks objective and reliable diagnostic indices. It is obvious that diagnosis of TCM-induced liver injury is especially difficult due to the complicated composition of TCM medication, as well the frequent combination of Chinese and Western drugs in clinic. In this paper, we proposed construction of research pattern and method for objective identification of TCM-related DILI based on translational toxicology, which utilizes clinical specimen to find specific biomarkers and characteristic blood entering constituents, as well the clinical biochemistry and liver biopsy. With integration of diagnosis marker database, bibliographic database, medical record database and clinical specimen database, an integrative diagnosis database for TCM-related DILI can be established, which would make a transformation of clinical identification pattern for TCM-induced liver injury from subjective and exclusive to objective and index-supporting mode. This would be helpful to improve rational uses of TCM and promote sustainable development of TCM industry. PMID- 24754160 TI - [Analysis of projects funded by NSFC in field of pharmacology of traditional Chinese medicine between 2010 to 2013 fiscal years]. AB - Projects which supported by National Natural Science Foundation of China (NSFC) in discipline of pharmacology of Chinese medicine between 2010 to 2013 financial years were reviewed. Based on these research items, new features and problems were summarized in this field. PMID- 24754161 TI - [Progress of diagnosis and treatment of hypertensive renal damage by Chinese medicine]. AB - Hypertensive renal damage is based on the extent and duration of hypertension, renal damage caused by varying severity. Hypertensive renal damage due to various causes imbalance of vascular active substances, renal arteriosclerosis, so that the abnormal renal hemodynamic, renal ischemia, low specific gravity of urine, low osmotic pressure and urine. The rapidly increasing incidence of hypertensive renal damage has become one of the most important reasons of end stage renal disease (ESRD). Effective treatment of hypertension is limited by poor compliance and significant adverse reaction of antihypertensive drugs. Therefore, some patients have turned to Chinese medicine (CM), hoping that such treatments might improve the efficiency. The author reviews relevant theory and the latest researches, on the basis of combining diseases and syndrome, discusses state and achievement of hypertensive renal damage with Chinese herbal medicines from fundamental and clinical research and action mechanism from standpoints of Chinese herbal compound and herbal effective chemical composition to take future research for important reference. PMID- 24754162 TI - [Study on material base of corydalis rhizoma]. AB - Corydalis Rhizoma, the dried tuber of Corydalis yanhusuo (Papaveraceae) distributed traditionally mainly in south-eastern and now cultivated in northwestern and other district in China, is one of the commonly used and well known traditional Chinese medicine. It has been widely used to treat spastic pain, abdominal pain, pain due to injury, and promote blood circulation. Its main chemical constituents were alkaloids, which were divided into the two types of protoberberines and aporphines. Among them, some alkaloids were found to elicit profound effects on the dopaminergic system in the central nervous system, which plays an important role in regulating nociception. In this article, the chemical composition and structure-types, new methods of qualitative and quantitative analysis as well as characteristics of biotransformation, absorption, distribution, metabolism, excretion, pharmacokinetic, and drug-drug interaction for the alkaloids were revealed. These results would greatly contribute to the establishment of bioactive material base of Corydalis Rhizoma. PMID- 24754163 TI - [Research status of natural compounds combine with antifungal agents against drug resistent Candida albicans]. AB - To against the emergence of drug-resistent candidiasis, the studys of synergism of natural compounds combine with antifungal agents in vitro showed a continuous growth in recent years. The paper reviewed recent progresses to compare the synergetic effect by FICI method, and to conclude the synergetic mechanisms which have been confirmed as a reference for futher study. PMID- 24754164 TI - [Effect of exogenous calcium on seed germination and seedling physiological characteristics of Lycium ruthenium]. AB - OBJECTIVE: In order to get the method for improving the salt resistance of Lycium ruthenium seeds and seedlings under NaCl stress, the seed germination and physiological characteristics of L. ruthenium seedlings was studied. METHOD: Several physiological indexes of L. ruthenium seeds under NaCl stress, such as the germination rate (Gr), germination vigor (Gv), germination index (Gi), vigor index (Vi), and relative salt damage rate were measured. Other indexes of the seedlings like relative water contents (RWC) , chlorophyll contents, soluble protein contents, electrolyte leakage, the contents of malondialdehyde (MDA), and peroxidase (POD) were also measured. RESULT: NaCl at lower concentration could promote the seed germination but inhibit the seed germination at higher concentration. After the treatment by CaCl2 at the different concentrations, all germination indexes were increased. With the increase of salt concentration, the relative water contents and the contents of chlorophyll were decreased, the content of MDA and electrolyte leakage were increased. The change trend of POD activity showed the first increase and then decrease with the increase of salt concentration, which was similar to that of the soluble protein. After the treatment by CaCl2, relative water contents, chlorophyll and POD activities were decreased more slowly, and also electrolyte leakage and MDA contents increased slowly. CONCLUSION: The CaCl2 could significantly alleviate the damages to the seeds and seedlings of L. ruthenium under NaCl stress, and promote the salt resistance to the seeds and seedlings of L. ruthenium. PMID- 24754165 TI - [Physicochemical properties of medicinal fungus Polyporus umbellatus sclerotial exudate]. AB - This study was conducted to investigate the physicochemical properties of Polyporus umbellatus sclerotial exudate. Morphological characteristics of the sclerotia and its exudate were observed during different stages of sclerotial formation. The pH of the exudate was detected at different time during cultivation. A phenol-sulfuric acid method was employed to determine the polysaccharide content of P. umbellatus sclerotial exudate during cultivating time. Additionally, the protein content was measured by means of BCA protein assay. Furthermore, CAT content was detected using ultraviolet absorption method. That the protein content of the exudate and CAT specific activity rose gradually during the passage of the cultivating time indicated a high level of oxidative stress during P. umbellatus sclerotial exudate formation. The results showed that the pH of the exudate increased gradually and then dropped down during sclerotial formation. That the pH of the exudate maintained the acidity state during the cultivation indirectly indicated that acidic environment would help sclerotial formation. The exudate produced gradually and was absorbed by the sclerotia itself. PMID- 24754166 TI - [Studies on methods of in vitro evaluation of soft rot-resistance in jinxianlian]. AB - Compared with living spray method, it focused on the investigation of different inoculation methods, various inoculation concentration and the influence of different seeding age on soft rot-resistance in Jinxianlian. The results showed that (1) Inoculated with dropping connection, the difference of disease index between A. roxburghii and A. formosanus was grate, so that the disease-resistance could be obviously distinguished. (2) When the inoculation concentration was 1.0 x 10(7) cfu x mL(-1), the difference of disease index was relatively obvious and the disease-resistance could be differentiated well. (3) At the moment of 4-month seeding inoculation, a certain difference of the disease index between A. roxburghii and A. formosanus was existed, so, relatively, it could accurately reflect the resistance difference between various species. With the inoculation of dropping connection, A. roxburghii and A. formosanus of 4-month seeding age was put in the bacteria suspension of inoculation concentration of 1.0 x 10(7) cfu x mL(-1). The identification was taken up after 5 days in the incubator under the condition of 14 h daylight and 28 degrees C. The identification result was conformed with that of the living spray method. To investigate the identification method of in vitro evaluation of soft rot-resistance of Jinxianlian so as to provide the foundation for germplasm utilization and excellent cultivars breeding. PMID- 24754167 TI - [Morphological character of growth cycle for Epimedium acuminatim and icariin content analysis]. AB - OBJECTIVE: To study the relationship between morphological characteristics of growth cycle for Epimedium acuminatium and accumulation level of secondary metabolites. METHOD: After making habitat clear, methods of morphology observation, specimen preparation, organism charting were applied to record morphological characteristics of E. acuminatium at different stages. HPLC was employed to detect icariin content of different parts of the plant at the stage of vegetative growth and sexual reproduction. RESULT: The growth cycle of E. acuminatium was divided into vegetative growth stage and sexual and asexual reproduction coexistence stage. Seven to eight years were needed for the plants flowering and seeding of E. acuminatimcan in open land of forest edge, but within good nutrition conditions, growth cycle is shortened into three to four years. The difference of icariin content in two growth stages was not significant. CONCLUSION: Morphological change of lower and foliar organ can be utilized to estimate growth age. But after applying sexual propagation for both root and stem of grown plants, it's been difficult to determine their growth year. If individual biomass or yield is economical, plants can be harvested in both vegetative growth and sexual reproduction stages. PMID- 24754168 TI - [Expression pattern of genes involved in tropane alkaloids biosynthesis and tropane alkaloids accumulation in Atropa belladonna]. AB - Atropa belladonna is a medicinal plant and main commercial source of tropane alkaloids (TAs) including scopolamine and hyoscyamine, which are anticholine drugs widely used clinically. Based on the high throughput transcriptome sequencing results, the digital expression patterns of UniGenes representing 9 structural genes (ODC, ADC, AIH, CPA, SPDS, PMT, CYP80F1, H6H, TRII) involved in TAs biosynthesis were constructed, and simultaneously expression analysis of 4 released genes in NCBI (PMT, CYP80F1, H6H, TRII) for verification was performed using qPCR, as well as the TAs contents detection in 8 different tissues. Digital expression patterns results suggested that the 4 genes including ODC, ADC, AIH and CPA involved in the upstream pathway of TAs, and the 2 branch pathway genes including SPDS and TRII were found to be expressed in all the detected tissues with high expression level in secondary root. While the 3 TAs-pathway-specific genes including PMT, CYP80F1, H6H were only expressed in secondary roots and primary roots, mainly in secondary roots. The qPCR detection results of PMT, CYP80F1 and H6H were consistent with the digital expression patterns, but their expression levels in primary root were too low to be detected. The highest content of hyoscyamine was found in tender stems (3.364 mg x g(-1)), followed by tender leaves (1.526 mg x g(-1)), roots (1.598 mg x g(-1)), young fruits (1.271 mg x g(-1)) and fruit sepals (1.413 mg x g(-1)). The highest content of scopolamine was detected in fruit sepals (1.003 mg x g(-1)), then followed by tender stems (0.600 mg x g(-1)) and tender leaves (0.601 mg x g(-1)). Both old stems and old leaves had the lowest content of hyoscyamine and scopolamine. The gene expression profile and TAs accumulation indicated that TAs in Atropa belladonna were mainly biosynthesized in secondary root, and then transported and deposited in tender aerial parts. Screening Atropa belladonna secondary root transcriptome database will facilitate unveiling the unknown enzymatic reactions and the mechanisms of transcriptional control. PMID- 24754169 TI - [Study of pretreatment on microfiltration of huanglian jiedu decoction with ceramic membranes based on solution environment regulation theory]. AB - To optimize the pretreatment of Huanglian Jiedu decoction before ceramic membranes and verify the effect of different pretreatments in multiple model system existed in Chinese herb aqueous extract. The solution environment of Huanglian Jiedu decoction was adjusted by different pretreatments. The flux of microfiltration, transmittance of the ingredients and removal rate of common polymers were as indicators to study the effect of different solution environment It was found that flocculation had higher stable permeate flux, followed by vacuuming filtration and adjusting pH to 9. The removal rate of common polymers was comparatively high. The removal rate of protein was slightly lower than the simulated solution. The transmittance of index components were higher when adjust pH and flocculation. Membrane blocking resistance was the major factor in membrane fouling. Based on the above indicators, the effect of flocculation was comparatively significant, followed by adjusting pH to 9. PMID- 24754170 TI - [Impact of directly compressed auxiliary materials on powder property of fermented cordyceps powder]. AB - To investigate such physical indexes as hygroscopicity, angle of repose, bulk density, fillibility of compression of mixed powder of directly compressed auxiliary materials and fermented cordyceps powder by using micromeritic study methods. The results showed that spray-dried lactose Flowlac100 and microcrystalline cellulose Avicel PH102 had better effect in liquidity and compressibility on fermented cordyceps powder than pregelatinized starch. The study on the impact of directly compressed auxiliary materials on the powder property of fermented cordyceps powder had guiding significant to the research of fermented cordyceps powder tablets, and could provide basis for the development of fermented cordyceps powder tablets. PMID- 24754171 TI - [Preparation of baicalin colon-specific solid dispersion and evaluation on its in vitro release]. AB - OBJECTIVE: To prepare pH-dependent baicalin colon-specific solid dispersion, with the aim of colon-specific delivery and rapid drug release. METHOD: Baicalin eudragit S100 solid dispersion was prepared by using the solvent method. The microscopic structure and physicochemical properties were analyzed by using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X ray powder diffraction (XRD) and infrared spectroscopy (IR). And its in vitro release was also investigated. RESULT: The results of DSC and XRD analysis suggested that baicalin may be dispersed in solid dispersion in the amorphous state. IR results indicated a non-covalent bond effect may exist between baicalin and eudragit S100. The results of in vitro release determination showed that very few baicalins in pH 1.2 diluted hydrochloric acid solution for 2 h at the baicalin-eudragit S100 ratio of 1 : 6. The accumulated dissolution rate was less than 15% in pH 6.8 phosphate buffer solution for 4 h, but exceeding 90% in pH 7.6 phosphate buffer solution for 1 h. CONCLUSION: The prepared baicalin-eudragit S100 solid dispersion could achieve the objective of colon-specific delivery and rapid drug release, and helps increase the concentration of baicalin in colons. PMID- 24754172 TI - [Technological parameter optimization method for washing of coarse bear gall powder extracts based on NIR spectroscopy]. AB - During the washing process of coarse bear gall powder extracts, it is necessary to adjust the amount of ethyl acetate according to the properties of raw materials, which aims to improving the yield and purity of the final product. In the research, using NIR spectra to reflect the comprehensive properties of coarse bear gall powder extracts, the process is optimized in a flexible way. Forty batches experiments are designed according to the weight ratio of ethyl acetate and coarse extracts of bear gall powder. The NIR spectra of the coarse extracts of bear gall powder are collected and processed using principal component analysis (PCA) method. The first 8 principal components combined with the amount of the ethyl acetate are used as the input variables, and calibration models are established to predict the yield and purity of the final product 30 batches are used as calibration set, which is used to establish the models, and other 10 batches are used as validation set, which is used for the performance appraisal of the established models. The correlation coefficients of the calibration, inner cross-validation and external validation for the purity model are 0.902, 0.896 and 0.883, respectively, and the RMSEC, RMSECV and RMSEP are 1.22%, 1.48% and 1.59%, respectively. The correlation coefficients of the calibration, inner cross validation and external validation for the yield model are 0.921, 0.859 and 0.916, respectively, and the RMSEC, RMSECV and RMSEP are 1.39%, 1.65% and 1.53% respectively. This work demonstrated that NIR spectra combined with technology parameter could be used to predict the yield and purity of the final product. Using the established models, the most appropriate amount of the ethyl acetate can be determined according to the properties of the coarse bear gall powder extracts, and the yield and purity of the final product can be improved. PMID- 24754173 TI - [A new phthalide from angelicae sinensis radix]. AB - Angelicae Sinensis Radix, dried roots of Angelicae sinensis, is a well-known traditional Chinese medicine. Six compounds were isolated and purified by silica gel and preparative HPLC. According to physicochemical properties and spectral data, the compounds were identified as senkyunolide H-7-acetate (1), o-phthalic acid (2), diisobutyl phthalate (3), p-hydroxyphenylethanol ferulate (4), ferulic acid (5) and coniferylferulate (6). Compound 1 was a new one. PMID- 24754174 TI - [Anti-inflammatory constituents from Inula japonica]. AB - Chemical constituents of Inula japonica were isolated and purified by repeated column chromatographies, over silica gel, and Toyopearl HW-40, and preparative HPLC. On the basis of spectral data analysis, including NMR and MS data, the structures of the isolates were elucidated and their anti-inflammatory activities were assayed. Fifteen compounds were isolated from the ethyl acetate extract of I. japonica, and their structures were elucidated as dihydrosyringenin (1), (3S, 5R, 6S, 7E)-5,6-epoxy-3-hydroxy-7-megastigmen-9-one (2), (6R, 7E) -9-hydroxy-4,7 megastigmadien-3-one (3), arnidiol (4), taraxasterol acetate (5), 8,9,10 trihydroxythymol (6), taxifolin (7), luteolin (8), napetin (9), eupatin (10), spinacetin (11), quercetin (12), p-hydroxycinnamic acid (13), caffeic acid (14), and caffeoyl acetate (15). Compounds 1, 2, 7, 13 and 15 were isolated from the genus Inula for the first time, and compounds 3, 4, 9-11 and 14 were isolated from this plant for the first time. The anti-inflammatory activity result showed that compounds 3, 6-12 and 14 exhibited inhibition effect against leukotriene C4 (LTC4) synthesis and degranulation definitely in c-Kit Ligand (KL) induced mast cells, and compound 8 and 12 also had the suppression effect against lipopolysacharide(LPS) induced nitric oxide (NO) activity in RAW264.7 macrophages. It is firstly reported that compounds 7 and 9-11 possessed potent inhibition activities against LTC4 generation and degranulation in mast cells. PMID- 24754175 TI - [Chemical structural features and anti-complementary activity of polysaccharide HPS1-D from Hedysarum polybotrys]. AB - HPS1-D, an active polysaccharide,was isolated and purified from Hedysarum polybotrys. HPS1-D was obtained after treated with Savage method and H2O2, and purified with DEAE-cellulose 52 and Sephadex G-100 gel filtration chromatography. Then physicochemical property analysis, GC, methylation, partial acid hydrolysis, and NMR method were used to study chemical structural of HPS1-D. The conformation was primarily analyzed with GPC-MALLS method and Congo red reaction. The anti complementary activity of HPS1-D was evaluated with the hemolysis assay. HPS1-D was a heteropolysaccharide and consisted of D-glucose, L-arabinose, (7.2:1.3). HPS1-D proved to be a neutral sugar, with 1, 4-and 1, 4, 6-alpha-D-glucopyranosyl residues in backbone ,and 1, 5-and 1, 3, 5-alpha-L-arabinofuranosyl residues in branches. HPS1-D has a random coil state conformation with monodisperse mass distribution in 0.9% NaCl solution. And HPS1-D had triple-helix conformation in concentrate of NaOH solution. Anti-complementary activity of HPS1-D was closed to its positive control heparin. PMID- 24754176 TI - [Quality standard study on Vigna radiata]. AB - In order to control the quality of Vigna radiata, the quality control method and standard were established in this study. The tests of water content, ash and ethanol-soluble extractives of V. radiata were carried out according to the methods recoded in appendix of Chinese Pharmacopeia (2010 edition, volume 1). The TLC method was established by using vitexin and isovitexin as references, and a mixture of acetate-method-water (10: 1.7 : 1.3) as the developing solvent system on GF254 thin layer plate. The contents of vitexin and isovitexin were determined by HPLC on a Prevail C18 (4.6 mm x 250 mm, 5 microm) column, using acetonitrile: water (23 : 77) as mobile phase at a flow rate of 1.0 mL x min(-1). The column temperature is 30 degrees C and the detection wavelength is 337 nm. As a result, vitexin, isovitexin and the other constituents were well separated on TLC detected under the UV light (254 nm). The methodology validation for the assay of vitexin and isovitexin presented that they were in good linear correlation in the ranges of 6.12-98 mg x L(-1) and 6.85-109.6 mg x L(-1), with the regression equations of Y = 46.213X - 7.100 (r = 1.000) and Y = 54.515X + 6.829 (r = 1.000), and the average recoveries were 98.2% (RSD 1.9%) and 97.2% (RSD 0.79%), respectively. The content ranges of vitexin and isovitexin from 25 different batches of V. radiata were 1.076-2.062 mg x g(1) and 1.127-2.303 mg x g(-1), respectively. suggesting that the qualities of V. radiata are relatively stable. The ethanol-soluble extractives, water content and total ash of 25 samples varied in the ranges of 13.27% - 18.46%, 9.59% - 12.43% and 2.63% - 3.53%, respectively. All of the above data proved that the established quality of control method V. radiata is specific and accurate, which can be used for the quality control of this drug. PMID- 24754177 TI - [Effect of pure total flavonoids from citrus on hepatic SIRT1/PGC-1alpha pathway in mice with NASH]. AB - OBJECTIVE: To observe the effect of pure total flavonoids from Citrus (PTFC) on the hepatic fatty degeneration, inflammation, oxidative stress and SIRT1/PGC 1alpha expressions in mice with non-alcohol steatohepatitis (NASH), and discuss the action mechanism of PTFC on NASH. METHOD: Mice were given high-fat diet for 16 weeks to induce the NASH model. Since the seventh week after the model establishment, the mice were intervened with 100, 50 and 25 mg x kg(-1) x d(-1) PTFC for 10 weeks. The pathologic changes in hepatic tissues were observed with HE staining. The contents of TG, CHOL in hepatic tissue, as well as the levels of AST, ALT in serum were detected by using the biochemical process. The expression of SIRT1, PGC-1alpha and MnSOD mRNA in hepatic tissues were detected with Real time PCR assay. SIRT1, PGC-1alpha protein and 8-OHdG expressions were determined with the immunohistochemical method. The SOD level in hepatic tissues was tested by the xanthine oxidase method. The MDA content in hepatic tissues was examined by the thiobarbituric acid method. RESULT: The contents of TG, CHOL, NAFLD activity scores and ALT level in serum in hepatic tissues of mice in the model induced by fat-rich diet were obviously higher than that of the normal group (P < 0.010. The SIRT1, PGC-1alpha, MnSOD mRNA and protein expression in hepatic tissues were significantly lower than that of the normal group (P < 0.01). The expression of 8-OHdG and the content of MDA in hepatic tissues were obviously higher than that of the normal group (P < 0.01). After the intervention with different doses of PTFC, the NAFLD activity scores, the content of TG and the level of AST in serum were notably lower than that of the normal group (P < 0.01, P < 0.05); whereas the SIRT1, PGC-1alpha, MnSOD mRNA and protein expression were obviously higher than that of the normal group (P < 0.01, P < 0.05), with the significant decrease in the expression of 8-OHdG and the content of MDA (P < 0.01). CONCLUSION: Oxidative stress/lipid peroxidation enhancement in in NASH mice induced by high-fat diet may be related to the changes in SIRT1/PGC-1alpha signal transduction pathway. PTFC could enhance the anti-oxidant capacity in liver, relieve the damage of reactive oxygen during the fatty acid metabolic process, and prevent NASH from the occurrence and development by regulating the SIRT1/PGC-1alpha signal pathway. PMID- 24754178 TI - [Effect of chaperone-mediated autophagy in MPP(+) -induced SH-SY5Y cells and interventional effect of puerarin]. AB - OBJECTIVE: To study the protective effect of puerarin on MPP(+) -induced SH-SY5Y cells by chaperone-mediated autophagy (CMA). METHOD: The Parkinson's disease cell model was established by injuring SH-SY5Y cells with 1 mmol x L(-1) MPP+. The CCK 8 staining was adopted to detect the effect the puerarin of different concentrations on the survival rate of MPP(+)-induced SH-SYSY cells. The autophagosome formation was observed under transmission electron microscope. The AO staining showed the changes in the lysosome activity. RT-PCR was used to detect the changes in Lamp2a and Hsc70 mRNA expressions. The western blotting was adopted to test the expressions of Lamp2a, Hsc70 and alpha-synuclein protein in cells. RESULT: Within the concentration range of 12. 5-50.0 micromol x L(-1), the pretreatment with puerain for 30 minutes could protect the injury of MPP+ in SH SY5Y cells, and showed a certain dose-effect relationship. The AO staining and electron microscope showed the effect of puerain within the concentration range of 12.5-50.0 micromol x L(-1) on 1 mmol x L(-1) MPP(+)-induced SH-SY5Y cells; autophagosomes emerged in cells, and increased along with the rise in the puerarin dose. The results of the flow cytometry revealed that 50.0 micromol x L( 1) of puerarin could protect against the increase of the ROS level in 1 mmol x L( 1) MPP(+) -induced SH-SY5Y cells and prevent the oxidative injury. The results of RT-PCR and western blotting indicated that puerain within the concentration range of 12.5-50.0 micromol x L(-1) alleviated the MPP(+)-induced SH-SY5Y cell injury, and inhibited the accumulation of alpha-synuclein proteins in MPP(+) -induced SH SY5Y cells by up-regulating Hsc70, Lamp2a mRNA and protein level. CONCLUSION: Puerarin could protect against the MPP(+) -induced cell injury, whose protective mechanism may be related to the chaperone-mediated autophagy pathway of interventional molecules. PMID- 24754179 TI - [Network pharmacology study on major active compounds of siwu decoction analogous formulae for treating primary dysmenorrhea of gynecology blood stasis syndrome]. AB - OBJECTIVE: To explore the molecular mechanisms of main active ingredients of Siwu decoction analogous formulae for treating primary dysmenorrhea of gynecology blood stasis syndrome by network pharmacology study, and to investigate the correlations between multi-compounds, multi targets and multi pathways. METHOD: Major active compounds from Siwu decoction analogous formulae, including ligustilide, butylidene phthalide, senkyunolide, ferulic acid, gallic acid, peoniflorin, jioglutin A, catalpol, transanethole, zingiberone, commiphoric acid, eugenol, isorhamnetin-3-O-neohesperidoside, wulingzhic acid, alpha-cyperone, cyperene, costunolide, costic acid, tetrahydropalmatine, protopine, amygdalin, 24 methylene cycloartanol, oleic acid, linoleic acid, 3-p-coumaroylquinic acid, hydroxysafflor yellow A, coptisine, berberine, jatrorrhizine, baicalein, baicalin, wogonin were collected to build component-protein networks based on PharmMapper database. The targets information access was used to construct and visualize components-targets-pathways network model using the kyoto encyclopedia of genes and genomes (KEGG) pathway database and Cytoscape software. RESULT AND CONCLUSION: Serine threonine protein kinases play an important role in the process of cells. They were potential targets in the effect of Siwu decoction analogous formulae. The effect of main active ingredients involved 51 the pathway. Besides the same ones, Shaofu Zhuyu decoction had more effect on lipid metabolism, Xiangfu Siwu decoction on amino acid metabolism pathways, Taohong Siwu decoction on carbohydrate metabolism, while, Qinlian Siwu decoction on ErbB, VEGF signal transduction pathway. Siwu decoction and its derived formulae not only had common targets and pathways, but also had their own emphasis. This reflected the formulae effect mode of multi-ingredients, multi-targets and multi pathways. It may provide clues to deeper study of molecular mechanism of Siwu decoction analogous formulae action. PMID- 24754180 TI - [Effect of combined administration of Angelica polysaccharide and cytarabine on liver of human leukemia NOD/SCID mouse model]. AB - Leukemia is a type of malignant tumors of hematopoietic system with the abnormal increased immature leukemia cells showing metastasis and invasion ability. Liver is one of the main targets of the leukemia cells spread to, where they may continue to proliferate and differentiate and cause liver function damage, even liver failure. Our previous studies showed that Angelica polysscharides (APS), the main effective components in Angelica sinensis of Chinese traditional medicine, was able to inhibit the proliferation and induced differentiation of the leukemia cells, however, its effect on the liver during the treatment remains elucidated. In the present study, the human leukemia NOD/SCID mouse model were established by implantation human leukemia K562 cells line, then the leukemia mouse were treated with APS, Ara-c or APS + Ara-c respectively by peritoneal injection for 14 days, to explore the effect and mechanism of the chemicals on the mouse liver. Compared to the human leukemia NOD/SCID mouse model group with the treatments of APS, Ara-c and APS + Ara-c, We found that severe liver damage and pathological changes of the liver were able to alleviate: First, the number of white blood cells in the peripheral blood was significantly lower and with less transplanted K562 leukemia cells; Second, liver function damage was alleviated as liver function tests showed that alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBiL) were significantly reduced, while the albumin (Alb) was notably increased; Third, liver antioxidant ability was improved as the activities of the antioxidant enzymes glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were significantly increased, and the contents of GSH and malonaldehyde (MDA) were decreased significantly in the liver; Fourth, the inflammation of the liver was relieved as the level of IL 1beta and IL-6, the inflammatory cytokines, were decreased significantly in the liver. Fifth, liver index was increased as the pathological observation showed that leukemia cells with diffused infiltration into the liver lobules were significantly reduced and with a remarkable increase of apoptotic positive cell rate by TUNEL test. Furthermore, the APS + Ara-c combined administration showed an even more significant positive effect. In conclusion, the APS, Ara-c therapy reduced the accumulation of leukemia cells within the liver, reduced the liver function damage and levels of inflammatory factors, improved antioxidant capacity of the liver tissue and thus alleviate the pathological changes of the liver. Moreover, the APS + Ara-c combination therapy may have an additive effect. PMID- 24754181 TI - [Study on pharmacological ingredients of wuzhuyu tang treating migraine by correlating absorption ingredients in everted intestinal sac and pharmacodynamics]. AB - Wuzhuyu Tang is a classical formula for treating migraine, but its' pharmacological ingredients is unclear yet. Present study employed the everted intestinal sac model to collect the absorption samples of 10 kinds of Wuzhuyu decoction, and then analyzed the contents of 9 ingredients in Wuzhuyu Tang and absorption samples quantitatively or semi-quantitatively by HPLC-DAD method. Reserpine was used to establish the mice model of migraine, and then the contents and activities of 5-hydroxytryptamine, noradrenaline, dopamine, nitric oxide and nitricoxide synthase in brain tissues and serums were determined respectively after oral administration of Wuzhuyu Tang. Using the partial least squares regression method to correlate the total absorption quantity of 9 ingredients and pharmacodynamics. The result shows that limocitrin-3-O-beta-D-glucoside, ginsenoside Rg1 and Rb1, rutaevine, limonin, evodiamine and rutaecarpine are the main ingredients influenced the effects in absorption samples in everted intestinal sacs, especially ginsenoside Rg1, rutaevine, evodiamine and rutaecarpine among them have obvious improving effects to most pharmacodynamics index, might be the pharmacological ingredients influenced the therapeutical effects of Wuzhuyu Tang treating migraine. PMID- 24754182 TI - [Intervention effects of qingre jiangya capsule on brain hippocampus of spontaneously hypertensive rats based on metabonomic research]. AB - Thirty SHRs were obtained randomly to hypertension, model group, captopril group and Qingre jiangya capsule group. Ten Wistar rats were used as control group. The hippocampus tissue was removed to explore the damage of spontaneously hypertensive rats (SHR) and the protective effect of Qingre jiangya capsule after continuously administered for 14 days. And then the data were processed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). The research results revealed captopril group was significantly different from the other three groups. The classification of other three groups is also very clear after captopril group removed. This suggested that Qingre jiangya capsule could improve the overall metabolism compared with captopril. Four metabolites were identified: dimethylglycine, glycerophosphocholine, aldosterone and noradrenaline. Hypertension hippocampus damage may mainly be expressed in tyrosine metabolism, aldosterone-regulated sodium, vascular smooth muscle contraction reabsorption, and Qingre jiangya capsule could reverse the hippocampus tissue damage of SHR. PMID- 24754183 TI - [Clinical efficacy observation on therapy ovulation failure infertility caursed by PCOS with reinforcing kidney, activating blood circulation and ovarian stimulation compound recipe]. AB - To investigate the clinical effect of tonifying the kidney and promoting blood circulation to promote oocyte decoction in the treatment of anovulatory infertility caused by polycystic ovary syndrome. Sixty cases were selected from the out-patient department of Xiyuan hospital of China academy of Chinese medical sciences and the Chinese academy of traditional Chinese medicine, Chinese medicine out-patient department. Sixty patients with PCOS patients were randomly divided into the treatment group and the control group, with 30 cases and 30 cases respectively. The treatment group was given decoction of the reinforcing kidney, activating blood circulation and ovarian stimulation compound recipe. The control group was treated with clomiphene. Through the treatment of 1-2 courses, in the treatment group the pregnancy rate was 56.67%, the ovulation rate 61%; in control group of clomiphene citrate ovulation ratepregnancy rate was 30% , 72.84% of ovulation rate. The difference was significant between two groups (P < 0.05), the pregnancy rate in the treatment group was higher than the control group. The treatment group has regulatory effect on FSH, LH and their ratio, and increase E2 level, decrease T, PRL, INS and other hormone levels, contributing to the mature development of the follicles and endometrium growth, increase the ovulation rate and pregnancy rate. The control group on FSH, E2 increased, LH, T, PRL and INS showed no obvious effect. PMID- 24754184 TI - [Prudent use price controls in Chinese medicines market: based on statistical data analysis]. AB - A dispute about the decreasing-price problem of traditional Chinese medicine (TCM) has recently arisen. This article analyzes the statistical data of 1995 2011 in China, the results showed that the main responsibility of expensive health care has no direct relationship with the drug price. The price index of TCM rose significantly slower than the medicine prices, the production margins of TCM affected by the material prices has been diminishing since 1995, continuous price reduction will further depress profits of the TCM industry. Considering the pros and cons of raw materials vary greatly in price, decreasing medicine price behavior will force enterprises to use inferior materials in order to maintain corporate profits. The results have the guiding meaning to medicine price management. PMID- 24754185 TI - [Application of traditional Chinese medicine reference standards in quality control of Chinese herbal pieces]. AB - Traditional Chinese medicine (TCM) reference standards plays an important role in the quality control of Chinese herbal pieces. This paper overviewed the development of TCM reference standards. By analyzing the 2010 edition of Chinese pharmacopoeia, the application of TCM reference standards in the quality control of Chinese herbal pieces was summarized, and the problems exiting in the system were put forward. In the process of improving the quality control level of Chinese herbal pieces, various kinds of advanced methods and technology should be used to research the characteristic reference standards of Chinese herbal pieces, more and more reasonable reference standards should be introduced in the quality control system of Chinese herbal pieces. This article discussed the solutions in the aspect of TCM reference standards, and future development of quality control on Chinese herbal pieces is prospected. PMID- 24754186 TI - [Preliminary study on general regulations for processing of different processing procedures of prepared slices of Chinese crude drugs in China]. AB - General regulations for the processing are the important part of processing procedures of prepared slices of Chinese crude drugs. It has an important significance on enhancing the operability of actual production, regulating production of prepared slices of Chinese crude drugs, improving quality and establishing drug safety. The article could provides suggestions and reference for future compilation work on "National processing procedures of prepared slices of Chinese crude drugs" by comparative analysis and summary on general regulations for the processing of different processing procedures of prepared slices of Chinese crude drugs in China. PMID- 24754187 TI - [Temporal rotation skin flap combined with cartilage plasty for correcting cryptotia]. AB - OBJECTIVE: To explore the therapeutic effect of the temporal rotation flap combined with cartilage plasty for cryptotia correction. METHODS: From January 2009 to June 2012, 8 cases with cryptotia (10 ears) were treated. After complete dissection of the cartilage adhesion, the cartilage was reshaped by suture to restore its appearance. Then the temporal triangular rotation flap was transferred to cover the wound. RESULTS: No hematoma, infection or flap necrosis happened. The follow-up period ranged from 3 months to 1 year, with an average of (6.88 +/- 2.85) months. The ear appearance kept stable with no recurrence and inconspicuous scar. Satisfactory result was achieved. CONCLUSION: Temporal rotation flap combined with cartilage plasty is a good option for correction of mild or moderate cryptotia. PMID- 24754188 TI - [Expanded post-auricular skin flap combined with autologous rib cartilage framework for correction of concha-type microtia]. AB - OBJECTIVE: To explore the clinical effect of the method by using an expanded post auricular skin flap combined with autologous rib cartilage framework for correction of concha-type microtia. METHODS: The operation were performed in three stages. The expander was implanted under post-auricular skin at the first stage and expanded skin flap was formed. At the second stage, the expander was taken out and the expanded skin flap was transferred with autologous rib cartilage framework and skin graft for correction of microtia. At the third stage, the reconstructed ear was revised and new concha was formed. RESULTS: From August 2008 to August 2011, 108 cases with 113 concha-type microtia were corrected by this method. All patients healed primarily and were followed up for 6 months to 3 years. The reconstructed ears had a good appearance and position, and were symmetric to ear on the healthy sides. CONCLUSIONS: Using expanded post auricular skin flap combined with autologous rib cartilage framework is a reliable method for concha-type microtia. PMID- 24754189 TI - [Treatment of auricular keloids with surgery and intralesional injection of compound betamethasone]. AB - OBJECTIVE: To investigate the treatment of auricular keloid with dinuclear surgery and intralesional injection of compound Betamethasone. METHODS: From Jan. 2008 to Jan. 2012, a total of 186 cases of ear keloid were treated by surgery only (22 cases), or intralesional injection of compound Betamethasone (34 cases), or combined dinuclear surgery with compound Betamethasone (130 cases). All the patients were followed up for one year. SPSS 16.0 software was used for statistical processing and analysis, and GraphPad inspection method for inspection. RESULTS: The effective rate was 54.55% (12/ 22) in surgery group and 55.88% (19/34)in injection group. The recurrence was obvious in injection group during the follow-up period. The effective rate was as high as 96.92% (126/130) in combined group with recurrence in 4 cases, which was significantly higher than that in other 2 groups (P < 0. 01). CONCLUSION: Combined dinuclear surgery and compound Betamethasone injection has a good therapeutic effect on auricular keloids. PMID- 24754190 TI - [The keystone design perforator island flap in reconstructive surgery]. AB - OBJECTIVE: To introduce the experience in skin defects reconstruction using keystone design perforator island flap. METHODS: Since June 2012 to June 2013, the flaps have been used in 14 patients. The size of defects ranged from 1 cm x 1 cm to 5 cm x 9 cm at the extremities, trunk and facial region. The trapezoidal shaped flap has the same width as the defect. The flap is designed along the edge of the defect with 90 degree angle at the ends of the island flap. This curvilinear- and trapezoidal-shaped flap essentially consists of two conjoined V Y advancement flaps at the proximal and distal end. The vascular supply is supported by the subcutaneous vascular network and fascial/muscular perforators. Perforators should be detected by Doppler techniques when large size flaps are used. RESULTS: Primary wound healing and satisfactory result was achieved in 13 patients except for one with partial flap necrosis. CONCLUSION: The technique offers a simple and effective method of wound closure in situations that would otherwise have required complex flap closure or skin grafting. PMID- 24754191 TI - [Nipple reduction by using a modified Z-shaped incision technique]. AB - OBJECTIVE: To explore an ideal surgical method for nipple hypertrophy correction. METHODS: From July 2008 to June 2011, 44 nipple reductions were performed for 22 women (44 sides) by using the modified Z-shaped incision technique. The incision consists of two circles, one quadrangle and one triangle located on the top, body and base of the nipple. The nipple's height was decreased and the nipple diameter and base area were reduced. Bilateral nipples were designed symmetrically. RESULTS: 22 cases(44 sides) were treated with primary healing. The mean diameter of the nipple was reduced to (9.8 +/- 1.6) mm from (17.6 +/- 3.4) mm, the average height from (18.8 +/- 3.6) mm to (8.2 +/- 1.4) mm, with the patient supine. All the patients were followed up for 14 months to 4 years with satisfactory results. No nipple necrosis, infection and numb happened. 20 patients completed the self designed survey scale 1 year after operation, of which 4 cases achieved normal lactation, and the remaining patients didn't have childbirth and breastfeeding yet. CONCLUSIONS: The modified Z-shaped incision technique could reduce the height, diameter, and most importantly, reduce the basal shape of all types of hypertrophic nipple to create a desired new cylindrical nipple without affection of nipple sensation and function. PMID- 24754192 TI - [Reconstruction of facial defects with frontal expanded flaps bipedicled by superficial temple vessels and supraorbital/supratrochlear neurovascular bundles]. AB - OBJECTIVE: To investigate the therapeutic effect of reconstruction of facial defects with frontal expanded flaps bipedicled by superficial temple vessels and supraorbital/supratrochlear neurovascular bundles. METHODS: From June 2006 to Mar. 2013, the patients with mostly unilateral facial defects which affected temple area and crossed the facial midline, were treated with frontal expanded flaps. The expanders were implanted at first stage and the expanded frontal flaps were transferred at second stage. At third stage, pedicle division was performed and the pedicle skin tissue was used to repair the residue defect. RESULT: All the 18 flaps survived completely with satisfactory color and texture. Good results were achieved during the follow-up period of one year. CONCLUSION: The bipedicled frontal expanded flap has a reliable blood supply which is very suitable for large facial defect. PMID- 24754193 TI - [The hemodynamics study and application of the reversed descending branch of lateral circumflex femoral artery]. AB - OBJECTIVE: To investigate the hemodynamics evidence of the descending branch of lateral circumflex femoral artery in a reversed way. To explore the clinical result of using the reversed descending branch of the lateral circumflex femoral artery as the receipt artery for free flaps for reconstruction of the leg soft tissue defect. METHODS: From October 2005 to February 2012, 38 patients with severe leg soft-tissue defects were treated. The proximal antegrade and retrograde mean artery pressure of the descending branch of the lateral circumflex femoral artery in 16 of 38 patients were recorded during operation. All wounds had osteomyelitis, bone and tendon exposure requiring coverage reconstruction. And there was no recipient artery in the injured lower leg for free flaps in all 38 patients. Reversed descending branches of lateral femoral circumflex arteries were used as recipient arteries for free flaps (free latissimus dorsi flap, free thoracoumbilical flap, and free anterolateral thigh flap) in all patients. The flap donor site was closed directly or with the skin graft. RESULTS: The proximal antegrade mean artery pressure of the descending branch of lateral circumflex femoral artery was(81.6 +/- 12.4) mmHg. The proximal retrograde pressure was(48.2 +/- 10.7) mmHg. The proximal retrograde mean artery pressure was 59.07 percent of the proximal antegrade pressure. The donor skin graft survived and wound healed primarily. After operation, 2 flaps had distal partial necrosis and healing was achieved after dressing change. All the other flaps survived completely without vascular problems. All the patients were followed up for 11 months to 2.5 years (mean, 1.6 years). The flap appearance was satisfactory. The texture and color of flaps in all cases were good. CONCLUSIONS: The reverse descending branch of lateral circumflex femoral artery is a reliable recipient artery for the free flaps. It is an easy and simple technique that can be used for reconstruction of the defects in the lower leg, with the reversed descending branch of lateral circumflex femoral artery as recipient artery. PMID- 24754194 TI - [Reconstruction of donor site defect after harvesting anterolateral thigh flap by V-Y flap pedicled with the lateral superior genicular perforator]. AB - OBJECTIVE: To investigate the clinical application of V-Y flap pedicled with the lateral superior genicular perforator for donor site defect after harvesting anterolateral thigh flap. METHODS: From June 2011 to June 2012, 9 cases with defects at hands and feet were treated with anterolateral thigh flaps. The defects left at the donor sites were consequently reconstructed with V-Y flap pedicled with the lateral superior genicular perforator. The defects left by V-Y flap were closed directly. RESULTS: All the 9 anterolateral thigh flap survived completely. 5 flaps underwent thinning surgery 6-8 months after operation. The flaps had a good appearance, texture, color and elasticity. The 8 perforator flaps survived completely with partial necrosis in 1 flap at the proximal end. The average healing time was 17 days. There was no obvious depression at donor sites with normal function. CONCLUSIONS: The method is easily performed with optional therapeutic effect. It is a modified improvement for the anterolateral thigh flap. PMID- 24754195 TI - [An alternative model of composite tissue transplantation in rat: the femur osteomyocutaneous flap]. AB - OBJECTIVE: To reconstruct a simpler and reliable composite tissue transplantation model-the femur osteomyocutaneous flap for the replacement of hindlimb transplantation. METHODS: Ten femur osteomyocutaneous flaps from 5 Lewis rats were transplanted into 10 syngeneic recipients' inguinal region. Their nutrient vessels were anastomosed with recipients vessels. The graft of this model was consisted of the groin flap and partial femur. To verify the feasibility of this model, gross and histological appearance were studied after transplantation to evaluate the viability of grafts. RESULTS: The operative time was (159.0 +/- 8.3) min with the harvesting time of (68.0 +/- 4.8) min and the ischemia time of (55. 8 +/- 6.8) min. The methylene blue injection showed rich blood supply of transplanted femur osteomyocutaneous flap. All the 10 flaps survived completely with pink skin color and hair regrowth. The histologic examination of the flaps also revealed the normal appearance of the viable skin and bone marrow. CONCLUSIONS: The femur osteomyocutaneous flap is a simple and reliable model for composite tissue transplantation, and its establishment will provide a new tool for the study of composite tissue allografts. PMID- 24754196 TI - [Comparison study of tissue engineered cartilage constructed with chondrocytes derived from porcine auricular and articular cartilage]. AB - OBJECTIVE: To compare the tissue engineered cartilage constructed with chondrocytes derived from auricular and articular cartilage. METHODS: Chondrocytes were isolated from porcine auricular and articular cartilage, and BMSCs were obtained from bone marrow aspirate and cultured. Each kind of chondrocytes were resuspended alone or mixed with BMSCs at a ratio of 1:1, and seeded onto PGA/PLA scaffolds to construct tissue engineered cartilage (n = 4). The constructs were cultured for 8 weeks in vitro and then subcutaneously implanted into nude mice for 6 weeks. The differences between chondrocytes monoculture from articular and auricular cartilage or between each of them co cultured with BMSCs were evaluated by gross view, measurement of thickness and wet weight, histological examinations including H&E, Safranin O, type II collagen, and Ponceau's & Victoria blue staining, and gene expression analysis of cartilage related genes. RESULTS: No obvious differences were found histologically among the complexes constructed in vitro 8 weeks except for few elastic fibers secreted in the auricular chondrocytes + BMSCs co-culture group. Neo-cartilage is thicker in the groups of articular chondrocytes (38. 1% than the group of auricular chondrocytes, P < 0.05) and articular chondrocytes + BMSCs co culture (19.3% than the group of auricular chondrocytes + BMSCs, P < 0.05). However, after 6 weeks in vivo the elastic fibers were found positive in the complexes constructed by auricular chondrocytes, and its staining was even stronger and more homogenous in the group of auricular chondrocytes + BMSCs co culture. The tissues generated by articular chondrocytes alone and co-cultured with BMSCs both formed the characteristic features of three-layer structure of hyaline cartilage and ossified in vivo with significant up-regulation of COL10A1 and MMP-13. To summarize, auricular chondrocytes formed the elastic cartilage while articular chondrocytes formed the hyaline cartilage during the development of tissue engineered cartilage either by monoculture or the co-culture with BMSCs. CONCLUSIONS: The chondrogenic response of chondrocytes from different cartilage origins demonstrates that an initial chondrocyte and cartilage type recapitulates the same in later tissue-engineered development. PMID- 24754197 TI - [A perforator-based dorsal flap's experimental research in the rat]. AB - OBJECTIVE: To develop a new experimental animal model of different a single perforating vessel as its pedicle, and to investigate this vessel can captures how many adjacent angiosomes in different directions. METHODS: Thirty-six Sprague Dawly rats of both sexes were used. The rats were divided into group A, group B and group C. Group A: the unilateral deep circumflex iliac perforator artery- based flap. Group B: the unilateral posterior intercostal perforator artery-based flap. Group C: the unilateral lateral thoracic perforator artery-based flap. An extended dorsal perforator flap measuring up to 13 cm x 6 cm was designed in 36 rats to assess the viability of the flap. The upper margin was located at the level of the tip of the scapula and the lower margin at a level 1 cm below the iliac crest. All flaps were observed for 7 days postoperatively, 72 hours after flap elevation, observe flap dyeing conditions through the vivo fluorescein injection, the surviving flap area was calculated as a percentage of total flap dimensions and the angiosome's structure of the flap was displayed by radiopaque microangiography. RESULTS: No fluorescence was visible in the distal flap of groups A and C, the whole flap show bright fluorescence in group B. Survival rate of C, A, B were improved in order. Statistic difference is significant (P < 0.01) between group and group. In group A, lead oxide-gelatin angiography shows the cephalic flap necrosis occurred in the bilateral lateral thoracic territories, and the vascular architecture partly disappeared in the necrotic area. In group B, the vascular architecture of flap is unbroken. In group C, the caudal flap necrosis occurred in the bilateral deep circumflex iliac perforator artery territories, and the vascular architecture partly disappeared and disordered in the necrotic area. CONCLUSIONS: The perforator flap is based centrally on a single perforator, this vessel can capture multiple the second vascular territory. In a direction, the longest distance that the blood supply can reach is the point of the third perforator vessel puncture into skin, which can provide certain theoretical guidance for designing of perforator flap. PMID- 24754198 TI - [Study of the effects of integrin-linked kinase on proliferation and differentiation of fibroblast in hypertrophic scar]. AB - OBJECTIVE: To study the role of integrin-linked kinase (ILK) on the proliferation and differentiation of human fibroblast in hypertrophic scar and its effect on the scar formation. METHODS: The human scar fibroblasts were isolated and cultured in vitro. The cells were divided into 4 groups. (1) control group: only contains DMEM; (2) jetPRIME group: DMEM with 200 microl jetPRIME buffer and 4 microl jetPRIME; (3) ILK siRNA group: DMEM and ILK siRNA; (4) ILK cDNA group: DMEM and ILK cDNA. The cell proliferation was detected by XTT assay and the mRNA and protein expressions of ILK and alpha-SMA were detected by Real-time qPCR and Western blot. RESULTS: (1) XTT results showed that the cellular proliferation level after 48 h in four groups were 0.820 +/- 0.065, 0.873 +/- 0.041, 0.554 +/- 0.013 and 1.296 +/- 0.094, respectively. The cellular proliferation curve showed that the cellular proliferation level was very flat in ILK siRNA group while the cellular proliferation level gradually increased from 12 h. 48 h after transfection, the cellular proliferation level in ILK siRNA group was significant lower than those in other groups (P value were 0.021, 0.034, 0), while the cellular proliferation level in ILK cDNA group was the highest among all 4 groups (P value were 0.017, 0.009, 0). (2) The Real-time qPCR showed that the expressions of ILK mRNA and alpha-SMA mRNA were 0.693 +/- 0.412 and 0.422 +/- 0.037 in control group, were 0.621 +/- 0.183 and 0.388 +/- 0.005 in jetPRIME group, were 0.052 +/- 0.019 and 0.073 +/- 0.023 in ILK siRNA group, were 240.193 +/- 35.170 and 138.056 +/- 24.060 in ILK cDNA group. The expressions of ILK mRNA and alpha-SMA mRNA in ILK siRNA group were significantly lower than those in other three groups (P < 0.05). And the expressions of ILK mRNA and alpha-SMA mRNA in ILK cDNA group were significantly higher than those in other three groups (P < 0.05). (3) The Western blot also showed that the expression of ILK and alpha-SMA proteins were decreased in ILK siRNA group and increased in ILK cDNA group. CONCLUSION: ILK may promote the proliferation and differentiation of human scar fibroblast. It may play an important role in scar formation and contracture. PMID- 24754199 TI - [Anatomical studying of the tear trough area]. AB - OBJECTIVE: To explore the mechanism of the aging deformity of tear trough through the anatomic study of the tear trough region. METHODS: 13 adult cadaveric heads (26 sides), including 9 male heads (18 sides) and 4 female heads (8 sides), aged 22-78 years old, were used. Anatomic study was performed around the orbital, especially tear trough region, with microsurgery instrument under microscope( x 10 times). The lower orbicularis retaining ligament was dissected and exposed. The anatomic location was recorded and photographed. RESULTS: (1) The anatomic layers of the tear trough region contains skin, subcutaneous tissue, orbicularis oculi muscle, periosteal membrane. There is no subcutaneous fat above the tear trough, while it exists below the tear trough, called malar fat pad. (2) There is a natural boundary between the septal and the orbital portions of the orbicularis oculi muscle of lower eyelid at surface of the orbital bone. The natural boundary, projected on the body surface corresponds to tear trough. The width of boundary is (2.06 +/- 0.15) mm on the vertical line through inner canthus and (3.25 +/- 0.12) mm on the vertical line through the lateral margin of the ala. The septal portion and the orbital portion of the orbicularis oculi muscle began to merge in (16.56 +/- 0.51) mm to inner canthus. (3) There is ligament attachment in the medial, upper and lower orbital and no ligament attachment in the lateral orbital. Orbicularis retaining ligament of lower eyelid is divided into two layers. (4) The medial of the upper layer of the orbicularis retaining ligament in lower eyelid originates from orbital margin and from preorbital walls laterally in (16.10 +/- 0.43) mm to the medial of lateral orbital margin, through orbicularis oculi muscle and ends at the skin. The lower layer of the orbicularis retaining ligament of lower eyelid originates from preorbital walls through orbicularis oculi muscle and its superficial fat, then ends at the skin. CONCLUSIONS: The length of tear trough is (16.56 +/- 0.51) mm, the width of tear trough is (2.06 +/- 0.15) mm and (3.25 +/- 0.12) mm on the vertical line through inner canthus and the lateral margin of the ala nasi respectively. The main reason of the aging deformity of tear trough attributes to the increased distance between the upper and lower layers of the orbicularis retaining ligament in lower eyelid, which is caused by loose of the orbicularis retaining ligament and its underlying fat atrophy or decline. PMID- 24754200 TI - Acceleration endurance with pressure breathing during G with and without a counterpressure vest. AB - INTRODUCTION: The purpose of this study was to test whether pressure breathing during G (PBC) without a counterpressure vest negatively influences G endurance or increases breathing fatigue during extended duration high-G exposures. METHODS: While using PBG, 10 subjects underwent 2 trials of +3 Gz exposures: once when wearing a counterpressure vest and once without. The exposures consisted of a relaxed, gradual G onset run until peripheral or central light loss, a straining rapid onset GC run to +6 Gz for 15 s, and a simulated aerial combat maneuver (SACM) G profile consisting of 10-s periods varying between +5 Gz and +9 Gz, during which subjects executed a hand-eye tracking task. The SACM endpoint was light loss or exhaustion. Subjects provided ratings of subjective effort and discomfort after the SACM. RESULTS: Significant differences were found between the vest and no-vest conditions for only 3 of 19 measures: heart rate under G and two measures of tracking ability. The vast majority of data indicated no difference between the vest and no-vest conditions for performance under G. DISCUSSION: This experiment supports previous studies and expands those previous results by increasing the duration of PBG exposure shown to not be influenced by wearing of the vest. We conclude that there is likely no practical advantage to wearing a counterpressure vest during PBG. PMID- 24754202 TI - Cardiovascular models of simulated moon and mars gravities: head-up tilt vs. lower body unweighting. AB - INTRODUCTION: In this study we compare two models [head-up tilt (HUT) vs. body unweighting using lower body positive pressure (LBPP)] to simulate Moon, Mars, and Earth gravities. A literature search did not reveal any comparisons of this type performed previously. We hypothesized that segmental fluid volume shifts (thorax, abdomen, upper and lower leg), cardiac output, and blood pressure (BP), heart rate (HR), and total peripheral resistance to standing would be similar in the LBPP and HUT models. METHODS: There were 21 subjects who were studied while supine (simulation of spaceflight) and standing at 100% (Earth), 40% (Mars), and 20% (Moon) bodyweight produced by LBPP in Alter-G and while supine and tilted at 80 degrees, 20 degrees, and 10 degrees HUT (analogues of Earth, Mars, and Moon gravities, respectively). RESULTS: Compared to supine, fluid shifts from the chest to the abdomen, increases in HR, and decreases in stroke volume were greater at 100% bodyweight than at reduced weights in response to both LBPP and HUT. Differences between the two models were found for systolic BP, diastolic BP, mean arterial BP, stroke volume, total peripheral resistance, and thorax and abdomen impedances, while HR, cardiac output, and upper and lower leg impedances were similar. CONCLUSIONS: Bodyweight unloading via both LBPP and HUT resulted in cardiovascular changes similar to those anticipated in actual reduced gravity environments. The LBPP model/Alter-G has the advantage of providing an environment that allows dynamic activity at reduced bodyweight; however, the significant increase in blood pressures in the Alter-GC may favor the HUT model. PMID- 24754201 TI - Simulations of gravitational stress on normovolemic and hypovolemic men and women. AB - BACKGROUND: Earth-based simulations of physiologic responses to space mission activities are needed to develop prospective countermeasures. To determine whether upright lower body positive pressure (LBPP) provides a suitable space mission simulation, we investigated the cardiovascular responses of normovolemic and hypovolemic men and women to supine and orthostatic stress induced by head-up tilt (HUT) and upright LBPP, representing standing in lunar, Martian, and Earth gravities. METHODS: Six men and six women were tested in normovolemic and hypovolemic (furosemide, intravenous, 0.5 mg x kg(-1)) conditions. Continuous electrocardiogram, blood pressure, segmental bioimpedance, and stroke volume (echocardiography) were recorded supine and at lunar, Martian, and Earth gravities (10 degrees, 20 degrees, and 80 degrees HUT vs. 20%, 40%, and 100% bodyweight upright LBPP), respectively. Cardiovascular responses were assessed from mean values, spectral powers, and spontaneous baroreflex parameters. RESULTS: Hypovolemia reduced plasma volume by approximately 10% and stroke volume by approximately 25% at supine, and increasing orthostatic stress resulted in further reductions. Upright LBPP induced more plasma volume losses at simulated lunar and Martian gravities compared with HUT, while both techniques induced comparable central hypovolemia at each stress. Cardiovascular responses to orthostatic stress were comparable between HUT and upright LBPP in both normovolemic and hypovolemic conditions; however, hypovolemic blood pressure was greater during standing at 100% bodyweight compared to 80 degree HUT due to a greater increase of total peripheral resistance. CONCLUSIONS: The comparable cardiovascular response to HUT and upright LBPP support the use of upright LBPP as a potential model to simulate activity in lunar and Martian gravities. PMID- 24754204 TI - +Gz tolerance, with and without muscle tensing, following loss of anti-G trouser pressure. AB - BACKGROUND: Fast jet aircrew are heavily reliant on anti-G trousers (AGT) and failure of the garment or its pressure supply would expose them to high levels of +Gz acceleration without protection. A previous study demonstrated the severity of this event at high +Gz, but no data exists as to the maximum +Gz level which could be tolerated. METHODS: : While relaxed and with lower body muscle tensing, 10 experienced centrifuge subjects had their AGT deflated after 5 and 30 s of +Gz exposure. Discrete +Gz exposures of increasing intensity were performed until deflation resulted in central light loss (CLL). Visual symptoms, eye-level systolic BP (SBPeye), and mean blood flow velocity in the middle cerebral artery (MCAVmean) were recorded. RESULTS: The mean +Gz level at CLL following AGT deflation was comparable to that without AGT inflation (+4.07 Gz) and increased by muscle tensing (+0.53 G) independent of exposure duration. Initial visual symptoms occurred more rapidly in the shorter +Gz exposures, while progression to CLL was quicker with muscle tensing compared with relaxed, but never less than 6.7 s. At CLL, the nadir in SBPeye was higher (+17 mmHg) with muscle tensing compared with relaxed, while MCAVmean was decreased by about 50% in all conditions. DISCUSSION: +Gz tolerance following AGT deflation is comparable to that without inflation and only modestly increased by muscle tensing. Although vision is maintained for several seconds following AGT deflation, progression of light loss symptoms can be rapid, possibly resulting in insufficient time to respond before G-induced loss of conciousness (G-LOC) ensues. PMID- 24754203 TI - Postural control and shoulder steadiness in F-16 pilots: a randomized controlled study. AB - BACKGROUND: During maneuvering, fighter pilots experience loads of up to 50-70 kg on their necks. Neck disorders are common and have been linked to impairment in muscle control. We conducted an intervention study introducing targeted training for 24 wk that reduced neck pain. The current study reports the results of the secondary objective, which was to increase the understanding of possible mechanisms underlying such neck pain and its intervention-related relief. METHODS: In a parallel, single-blinded, randomized controlled study, 55 F-16 pilots were evaluated at baseline and randomized to a control group (CG; N = 28) or training group (TG; N = 27). Postural control was tested in four different settings: Romberg with open and closed eyes, unilateral stance, and perturbation. Maximal voluntary contraction and force steadiness was measured for shoulder elevation. RESULTS: At follow-up, there was a significant between-group difference in the Romberg test with closed eyes only (95% confidence ellipse area; CG: 761 +/- 311 mm2; TG: 650 +/- 405 mm2). Prior to randomization, there were no significant differences in postural control and steadiness between 30 pilots who experienced neck pain within the previous 3 mo and 25 pilots without such pain. DISCUSSION: Impaired postural control and steadiness may only be quantifiable in individuals experiencing acute neck pain of certain intensity, and there may be a ceiling effect in the ability to improve these parameters. For individuals with highly developed physiological capacity, a battery of tests with more stringent demands should be considered, e.g., increased number of repetitions, prolonged duration of the tests, or testing with eyes closed. PMID- 24754205 TI - Common mental disorders among civil aviation flight attendants. AB - INTRODUCTION: The purpose of the current study was to estimate the prevalence of common mental disorders (CMDs) among Brazilian civil aviation flight attendants and to investigate associations between CMDs and sociodemographic and work related variables. METHODS: This was a quantitative cross-sectional study conducted between October 2009-October 2010 using a self-reporting questionnaire about sociodemographic and work-related data and a screening instrument for the detection of psychiatric morbidity. RESULTS: A total of 453 flight attendants were evaluated. The prevalence of CMDs was found to be 29.8% (N = 135/453; 95% CI 25.7-34.10%). Female flight attendants presented higher prevalence (36.0%) than male flight attendants (19.7%). The prevalence among individuals who had completed their training more than 5 yr earlier was 35.7% versus 19.2% among those who had qualified less than 5 yr earlier. In the final adjusted model, only the following variables maintained a statistically significant association: sex (OR 2.83); regular physical activity practice (OR 1.68); time since completion of training (OR 2.56); involvement with religious belief (OR 1.66); and type of flight route (OR 1.71). DISCUSSION: Flight attendants are subjected to stressful situations determined both by specific occupational risks and by the form of work organization. Studies with civil aviation pilots found lower values for CMD prevalence (6.7%). This shows that although both categories are classified as aircrew members and share various similarities of occupational risks, they are also, at the same time, profoundly different regarding their professional profiles. PMID- 24754206 TI - Helicopter crashes into water: warning time, final position, and other factors affecting survival. AB - INTRODUCTION: According to 40 yr of data, the fatality rate for a helicopter crash into water is approximately 25%. Does warning time and the final position of the helicopter in the water influence the survival rate? METHODS: The National Transportation Safety Board (NTSB) database was queried to identify helicopter crashes into water between 1981 and 2011 in the Gulf of Mexico and Hawaii. Fatality rate, amount of warning time prior to the crash, and final position of the helicopter were identified. RESULTS: There were 133 helicopters that crashed into water with 456 crew and passengers. Of these, 119 occupants (26%) did not survive; of those who did survive, 38% were injured. Twelve died after making a successful escape from the helicopter. Crashes with < 15 s warning had a fatality rate of 22%, compared to 12% for 16-60 s warning and 5% for > 1 min. However, more than half of fatalities (57%) came from crashes for which the warning time could not be determined. DISCUSSION: Lack of warning time and how to survive in the water after the crash should be a topic for study in all marine survival/aircraft ditching courses. Investigators should be trained to provide estimates of warning time when investigating helicopter crashes into water. PMID- 24754207 TI - Heat removal using microclimate foot cooling: a thermal foot manikin study. AB - BACKGROUND: It has been proposed that microclimate cooling systems exploit the peripheral extremities because of more efficient heat transfer. The purpose of this study was to quantify, using a patented microclimate cooling technique, the heat transfer from the plantar surface of the foot for comparison to other commonly cooled body regions. METHODS: A military boot was fitted with an insole embedded with a coiled, 1.27 m length of hollow tubing terminating in inlet and outlet valves. A thermal foot manikin with a surface temperature of 34 degrees C was placed in the boot and the valves were connected to a system that circulated water through the insole at a temperature of 20 degrees C and flow rate of 120 ml x min(-1). The manikin foot served as a constant heat source to determine heat transfer provided by the insole. Testing was done with the foot model dry and sweating at a rate of 500 ml x h(- 1) x m(-2). Climatic chamber conditions were 30 degrees C with 30% RH. RESULTS: Heat loss was approximately 4.1 +/- 0.1 and approximately 7.7 +/- 0.3 W from the dry and sweating foot models, respectively. On a relative scale, the heat loss was 3.0 W and 5.5 W per 1% (unit) body surface area, respectively, for the dry and sweating conditions. DISCUSSION: The relative heat loss afforded by plantar foot cooling was similar compared to other body regions, but the absolute amount of heat removal is unlikely to make an impact on whole body heat balance. PMID- 24754208 TI - Bungee force level, stiffness, and variation during treadmill locomotion in simulated microgravity. AB - INTRODUCTION: Crewmembers performing treadmill exercise on the International Space Station must wear a harness with an external gravity replacement force that is created by elastomer bungees. The quantification of the total external force, displacement, stiffness, and force variation is important for understanding the forces applied to the crewmember during typical exercise. METHODS: Data were collected during static trials in the laboratory from a single subject and four subjects were tested while walking at 1.34 m x s(-1) and running at 2.24 m x s( 1) and 3.13 m x s(-1) on a treadmill during simulated microgravity in parabolic flight. The external force was provided by bungees and carabiner clips in configurations commonly used by crewmembers. Total external force, displacement, and force variation in the bungee system were measured, from which stiffness was computed. RESULTS: Mean external force ranged from 431 to 804 N (54-131% bodyweight) across subjects and conditions. Mean displacement was 4 to 8 cm depending upon gait speed. Mean stiffness was affected by bungee configuration and ranged from 1.73 to 29.20 N x cm(-1). Force variation for single bungee configurations was 2.61-4.48% of total external force and between 4.30-57.5% total external force for two-bungee configurations. CONCLUSIONS: The external force supplied to crewmembers by elastomer bungees provided a range of loading levels with variations that occur throughout the gait cycle. The quantification of bungee-loading characteristics is important to better define the system currently used by crewmembers during exercise. PMID- 24754209 TI - Complex collaborative problem-solving processes in mission control. AB - INTRODUCTION: NASA's Mission Control Center (MCC) is responsible for control of the International Space Station (ISS), which includes responding to problems that obstruct the functioning of the ISS and that may pose a threat to the health and well-being of the flight crew. These problems are often complex, requiring individuals, teams, and multiteam systems, to work collaboratively. Research is warranted to examine individual and collaborative problem-solving processes in this context. Specifically, focus is placed on how Mission Control personnel-each with their own skills and responsibilities-exchange information to gain a shared understanding of the problem. The Macrocognition in Teams Model describes the processes that individuals and teams undertake in order to solve problems and may be applicable to Mission Control teams. METHOD: Semistructured interviews centering on a recent complex problem were conducted with seven MCC professionals. In order to assess collaborative problem-solving processes in MCC with those predicted by the Macrocognition in Teams Model, a coding scheme was developed to analyze the interview transcriptions. RESULTS: Findings are supported with excerpts from participant transcriptions and suggest that team knowledge-building processes accounted for approximately 50% of all coded data and are essential for successful collaborative problem solving in mission control. Support for the internalized and externalized team knowledge was also found (19% and 20%, respectively). DISCUSSION: The Macrocognition in Teams Model was shown to be a useful depiction of collaborative problem solving in mission control and further research with this as a guiding framework is warranted. PMID- 24754210 TI - An unusual case of ventricular ectopy in a military pilot. AB - BACKGROUND: Congenital left ventricular diverticula are an uncommon cardiac malformation. Although they may be asymptomatic, their presence is important to note as they are associated with systemic embolization of mural thrombus, valvular regurgitation, heart failure, focal ventricular arrhythmias, and sudden death. CASE REPORT: We describe a case of an asymptomatic pilot with a significant burden of ventricular ectopy. The diagnosis of a large left ventricular diverticulum was made by cardiac CT and confirmed by cardiac magnetic resonance imaging. No specific treatment was warranted; however, regular on-going follow up was required. DISCUSSION: It is important to seek out a structural cause for frequent ventricular ectopy even in the absence of symptoms. Transthoracic echocardiography is not always able to delineate the entire left ventricular cavity and other imaging modalities such as ECG-gated cardiac CT or gated MRI may need to be used in conjunction to permit assessment for the presence of structural heart disease in the whole heart. Aircrew with a high burden of ectopy require regular follow-up for complications such as more malignant dysrhythmias or LV impairment. In some cases, pharmacological or even surgical treatment is warranted, which may have a significant bearing for the future licensing of aircrew. PMID- 24754211 TI - Physiological consequences of rapid or prolonged aircraft decompression: evaluation using a human respiratory model. AB - BACKGROUND: Aircraft passengers and crew may be subjected to rapid or prolonged decompression to high cabin altitude when an aircraft develops a hole in the fuselage. The accepted measure of neurological damage due to the hypobaric hypoxia produced is the subjective 'time of useful consciousness' (TUC) measure, which is appropriate for pilots and crew who perform their given tasks, however, TUC is measured under conditions different than the decompression scenarios that passengers undergo in today's aircraft. METHODS: Ernsting proposed that prolonged exposure to alveolar O2 pressures less than 30 mmHg (P30) causes neurological damage. The current study proposes that a critical value of arterial O2 saturation of 70% (S70) can be used in place of P30 and that this physiological measure is more suited for determination of hypobaric hypoxia in passengers. RESULTS: The study shows the equivalence of model-predicted P30 and S70 values in the Ernsting-decompression scenarios. The model is also used to predict values of these physiological measures in actual aircraft-decompression scenarios. DISCUSSION: The model can be used by others to quantitatively predict the degree of hypobaric hypoxia for virtually any kind of decompression scenario, including those where supplemental O2 is used. Use of this tool avoids the prohibitive costs of human-subject testing for new aircraft and the potential danger inherent in such tests. PMID- 24754212 TI - Safe-to-fly test and evaluation of fatigue research study test devices. AB - INTRODUCTION: The U.S. Air Force (USAF) School of Aerospace Medicine is conducting a fatigue research study titled "Assessment of Fatigue in Deployed Critical Care Air Transport Team (CCATT) Crews" using two electronic devices onboard USAF aircraft during actual CCATT missions. Both devices were subjected to testing to support a safe-to-fly (STF) recommendation prior to their use in flight. The purpose of the test and evaluation process was to ensure the devices can be safely operated in flight without posing a hazard to the research participant, crewmembers, or aircraft during an actual mission. The goal of this article is to outline the key factors involved in the STF certification process. METHODS: This paper discusses the test and evaluation process for making STF recommendation and presents the rationale for selecting the applicable tests and test susceptibilities. The following STF tests were conducted: baseline assessment, vibration, electromagnetic interference, altitude, rapid decompression, and explosive atmosphere. Acceleration testing, environmental (temperature and humidity) testing, and in-flight assessments were deemed not required for the STF certification of these devices. RESULTS: Based on the results of this study, the devices were deemed safe to the flight crew and aircraft. CONCLUSIONS: The outcome of this study was subsequent approval letters issued by the respective airframe system program offices to allow use of these devices onboard USAF C-130 E/H/J, C-17, and KC-135 aircraft. PMID- 24754213 TI - Managing acute coronary syndrome during medical air evacuation from a remote location at sea. PMID- 24754214 TI - Managing acute coronary syndrome during medical air evacuation from a remote location at sea. PMID- 24754215 TI - Bioinformatics tools available for K-12 students to engage in research. PMID- 24754216 TI - You're the flight surgeon: mixed connective tissue disease. PMID- 24754217 TI - You're the flight surgeon: Wolff-Parkinson-White. PMID- 24754218 TI - This month in aerospace medicine history. PMID- 24754219 TI - Implications of an exemplar-theoretic model of phoneme genesis: a velar palatalization case study. AB - Diachronic velar palatalization is taken as the case study for modeling the emergence of a new phoneme category. The spread of a palatalized variant through the lexicon is treated as a stochastic classification task for the listener/learner. The model combines two measures of similarity to determine classification within an exemplar-theoretic framework: acoustic distance and phonotactic expectation. There are three model outcomes: contrast, allophony, or contextual neutralization between the plain and palatalized velars. It is shown, through a series of simulations, that these can be predicted from the distribution of sounds within the pre-change lexicons, namely, the ratio of the /k-vowel/ sequences containing naturally palatalizing vowels (i, I, e), to those containing non-palatalizers. "Unnatural" phonotactic associations can arise in individual lexicons, but are sharply limited due to the large size of the lexicon and the local nature of the phoneme changes. "Anti-natural" distributions, which categorically violate the proposed implicational relationship between palatalization and frontness/height, are absent. This work provides an explicit and restrictive model of phoneme change. The results also serve as an existence proof for an outcome-blind mechanism of avoiding over-generation. PMID- 24754220 TI - Phonological variant recognition: representations and rules. AB - The current research explores the role of lexical representations and processing in the recognition of phonological variants. Two alternative approaches for variant recognition are considered: a representational approach that posits frequency-graded lexical representations for variant forms and inferential processes that mediate between the spoken variant and the lexical representation. In a lexical decision task (Experiment 1) and in a phoneme identification task (Experiment 2) using real words, low-frequency variants, but not high-frequency variants, show improved recognition rates following additional experience with the variants. This knowledge generalized to novel variant forms. Experiment 3 replicated these results using an artificial lexicon and showed that recognition of low-frequency variants was influenced by similarity to a high-frequency variant form. Similarity to a high-frequency variant alone, however, was insufficient to explain recognition of the infrequent variants (Experiments 4 and 5). The results support a hybrid account of variant recognition that relies on both multiple frequency-graded representations and inference processes. PMID- 24754221 TI - Use of syntax in perceptual compensation for phonological reduction. AB - Listeners resolve ambiguity in speech by consulting context. Extensive research on this issue has largely relied on continua of sounds constructed to vary incrementally between two phonemic endpoints. In this study we presented listeners instead with phonetic ambiguity of a kind with which they have natural experience: varying degrees of word-final /t/-reduction. In two experiments, Dutch listeners decided whether or not the verb in a sentence such as Maar zij ren(t) soms 'But she sometimes run(s)' ended in /t/. In Dutch, presence versus absence of final /t/ distinguishes third- from first-person singular present tense verbs. Acoustic evidence for /t/ varied from clear to absent, and immediately preceding phonetic context was consistent with more versus less likely deletion of /t/. In both experiments, listeners reported more /t/s in sentences in which /t/ would be syntactically correct. In Experiment 1, the disambiguating syntactic information preceded the target verb, as above, while in Experiment 2, it followed the verb. The syntactic bias was greater for fast than for slow responses in Experiment 1, but no such difference appeared in Experiment 2. We conclude that syntactic information does not directly influence pre-lexical processing, but is called upon in making phoneme decisions. PMID- 24754222 TI - Children's expression of uncertainty in collaborative and competitive contexts. AB - We studied the effect of two social settings (collaborative versus competitive) on the visual and auditory expressions of uncertainty by children in two age groups (8 and 11). We conducted an experiment in which children played a quiz game in pairs. They either had to collaborate or compete with each other. We found that the Feeling-of-Knowing of eight-year-old children did not seem to be affected by the social setting, contrary to the Feeling-of-Knowing of 11-year-old children. In addition, we labelled children's expressions in clips taken from the experiment for various visual and auditory features. We found that children used some of these features to signal uncertainty and that older children exhibited clearer cues than younger children. In a subsequent perception test, adults rated children's certainty in clips used for labelling. It appeared that older children and children in competition expressed their confidence level more clearly than younger children and children in collaboration. PMID- 24754223 TI - On the intonation of German intonation questions: the role of the prenuclear region. AB - German questions and statements are distinguished not only by lexical and syntactic but also by intonational means. This study revisits, for Northern Standard German, how questions are signalled intonationally in utterances that have neither lexical nor syntactic cues. Starting from natural productions of such 'intonation questions', two perception experiments were run. Experiment 1 is based on a gating paradigm, which was applied to naturally produced questions and statements. Experiment 11 includes two indirect-identification tasks. Resynthesized stimuli were judged in relation to two context utterances, each of which was compatible with only one sentence mode interpretation. Results show that utterances with a finally falling nuclear pitch-accent contour can also trigger question perception. An utterance-final rise is not mandatory. Also, question and statement cues are not restricted to the intonational nucleus. Rather, listeners can refer to shape, slope, and alignment differences of the preceding prenuclear pitch accent to identify sentence mode. These findings are in line with studies suggesting that the utterance-final rise versus fall contrast is not directly related to sentence modality, but represents a separate attitudinal meaning dimension. Moreover, the findings support that both prenuclear and nuclear fundamental frequency (F0) patterns must be taken into account in the analysis of tune meaning. PMID- 24754224 TI - PDMS-based triboelectric and transparent nanogenerators with ZnO nanorod arrays. AB - Vertically-grown ZnO nanorod arrays (NRAs) on indium tin oxide (ITO)-coated polyethylene terephthalate (PET), as a top electrode of nanogenerators, were investigated for the antireflective property as well as an efficient contact surface in bare polydimethysiloxane (PDMS)-based triboelectric nanogenerators. Compared to conventional ITO-coated PET (i.e., ITO/PET), the ZnO NRAs considerably suppressed the reflectance from 20 to 9.7% at wavelengths of 300 1100 nm, creating a highly transparent top electrode, as demonstrated by theoretical analysis. Also, the interval time between the peaks of generated output voltage under external pushing forces was significantly decreased from 1.84 to 0.19 s because the reduced contact area of the PDMS by discrete surfaces of the ZnO NRAs on ITO/PET causes a rapid sequence for triboelectric charge generation process including rubbing and separating. Therefore, the use of this top electrode enabled to operate the transparent PDMS-based triboelectric nanogenerator at high frequency of external pushing force. Under different external forces of 0.3-10 kgf, the output voltage and current were also characterized. PMID- 24754225 TI - Dynamics of WD-repeat containing proteins in SSU processome components. AB - Nine WD-repeat containing proteins in human SSU processome components have been found in a HeLa cell nuclear matrix fraction. In these proteins, t-UTP sub complex components, i.e., CIRH1A, UTP15, and WDR43, were shown to be immobilized in the fibrillar centers of nucleoli in living cells. In this study, the dynamics of the remaining six proteins fused with green fluorescent protein (GFP), i.e., PWP2-GFP, TBL3-GFP, GFP-UTP18, GFP-NOL10, GFP-WDR46, and GFP-WDSOF1, were examined in living cells. The findings were as follows. (i) The majority of UTP-B sub-complex components, i.e., PWP2-GFP, TBL3-GFP, and GFP-UTP18, are localized to the dense fibrillar component and granular component regions in nucleoli; (ii) When rRNA transcription is suppressed, the majority of GFP-fused UTP-B sub complex components are localized in the cap and body regions of nucleoli. (iii) The mobility of these proteins except for GFP-WDSOF1, and half of GFP-UTP18 and GFP-WDR46, respectively, is very low in living cells. (iv) When rRNA transcription is suppressed, the mobility of these proteins except for GFP-WDSOF1 is accelerated but still slow. These findings and others suggest that these WD repeat proteins other than GFP-WDSOF1 found in the nuclear matrix fraction bind tightly to some macro-protein complexes and act as a scaffold or a core for the complexes in nucleoli. PMID- 24754226 TI - Predictive modeling for growth of non- and cold-adapted Listeria monocytogenes on fresh-cut cantaloupe at different storage temperatures. AB - The aim of this study was to determine the growth kinetics of Listeria monocytogenes, with and without cold-adaption, on fresh-cut cantaloupe under different storage temperatures. Fresh-cut samples, spot inoculated with a 4 strain cocktail of L. monocytogenes (~3.2 log CFU/g), were exposed to constant storage temperatures held at 10, 15, 20, 25, or 30 degrees C. All growth curves of L. monocytogenes were fitted to the Baranyi, modified Gompertz, and Huang models. Regardless of conditions under which cells grew, the time needed to reach 5 log CFU/g decreased with the elevated storage temperature. Experimental results showed that there were no significant differences (P > 0.05) in the maximum growth rate k (log CFU/g h(-1) ) and lag phase duration lambda (h) between the cultures of L. monocytogenes with or without previous cold-adaption treatments. No distinct difference was observed in the growth pattern among 3 primary models at various storage temperatures. The growth curves of secondary modeling were fitted on an Arrhenius-type model for describing the relationship between k and temperature of the L. monocytogenes on fresh-cut cantaloupe from 10 to 30 degrees C. The root mean square error values of secondary models for non- and cold-adapted cells were 0.018, 0.021, and 0.024, and 0.039, 0.026, and 0.017 at the modified Gompertz, Baranyi, and Huang model, respectively, indicating that these 3 models presented the good statistical fit. This study may provide valuable information to predict the growth of L. monocytogenes on fresh-cut cantaloupes at different storage conditions. PRACTICAL APPLICATION: Listeriosis has occurred and increased along with the increased demand of fresh and fresh-cut fruits and vegetables. This study was conducted to predict the growth of non- and cold-adapted L. monocytogenes on fresh-cut cantaloupe at different temperature using mathematical model. These results can be helpful for risk assessments of L. monocytogenes in fresh-cut cantaloupe. This study provides valuable information to food handlers to choose proper storage temperatures for extending the shelf life of fresh-cut cantaloupe. PMID- 24754227 TI - Concerns about bilateral radiosurgical treatment of a patient with bilateral temporal lobe epilepsy. PMID- 24754228 TI - DNA damage by histone radicals in nucleosome core particles. AB - Although DNA binding proteins shield the genetic material from diffusible reactive oxygen species by reacting with them, the resulting protein (peroxyl) radicals can oxidize the bound DNA. To explore this possible DNA damage by protein radicals, histone H4 proteins containing an azoalkane radical precursor at defined sites were prepared. Photolysis of a nucleosome core particle containing the modified protein produces DNA damage that is consistent with selective C4'-oxidation. The nucleotide(s) damaged is highly dependent on proximity to the protein radical. These experiments provide insight into the effects of oxidative stress on protein-bound DNA, revealing an additional layer of complexity concerning nucleic acid damage. PMID- 24754230 TI - Beyond personal responsibility: effects of causal attributions for overweight and obesity on weight-related beliefs, stigma, and policy support. AB - OBJECTIVE: The objective of this research was to compare the effects of different causal attributions for overweight and obesity, among individuals with overweight and obesity, on weight-related beliefs, stigmatising attitudes and policy support. DESIGN: In Study 1, an online sample of 95 US adults rated the extent to which they believed various factors caused their own weight status. In Study 2, 125 US adults read one of three randomly assigned online passages attributing obesity to personal responsibility, biology, or the 'food environment.' All participants in both studies were overweight or obese. MAIN OUTCOME MEASURES: All participants reported beliefs about weight loss, weight-stigmatising attitudes, and support for obesity-related policies. RESULTS: In Study 1, biological attributions were associated with low weight-malleability beliefs and blame, high policy support, but high internalised weight bias. 'Food environment' attributions were not associated with any outcomes, while 'personal responsibility' attributions were associated with high prejudice and blame. In Study 2, participants who received information about the food environment reported greater support for food-related policies and greater self-efficacy to lose weight. CONCLUSION: Emphasising the role of the food environment in causing obesity may promote food policy support and health behaviours without imposing the negative consequences associated with other attributions. PMID- 24754229 TI - Total pancreatectomy for the treatment of pancreatic neoplasms. AB - BACKGROUND: Total pancreatectomy (TP) is an operation that has long been associated with high morbidity and mortality, and rarely advocated for treatment of pancreatic tumours. Because of the improvements in diabetes management, there has been renewed interest in TP for treatment of pancreatic neoplasm, with a need to reassess outcomes. METHODS: Fifteen patients (9%) underwent TP in a single Australian high-volume tertiary institution between August 2005 and January 2012. Pancreaticoduodenectomy (PD) was performed in 150 patients during the same time period. Indications and peri-operative outcomes of patients were compared. RESULTS: TP was performed for treatment of malignancy in 13 (87%) cases, for tumours involving the pancreatic neck. Complete tumour clearance achieved. Portal vein resections were more frequently required than in the PD group (5 (33%) versus 9 (6%); P = 0.004), as were blood transfusions (11 (73%) versus 28 (19%); P < 0.001), and median operative times were longer (10.5 versus 7.0 h; P < 0.001). Overall, complications were significantly greater in the TP group compared with the PD group (13 (87%) versus 86 (57%); P = 0.029), but the difference was mainly as a result of high grade I complications, in particular symptomatic hypoglycaemia (4 (27%) versus 0 (0%): P < 0.001) that could be easily managed. The overall lengths of stay and readmission rates were similar between groups. CONCLUSION: TP should be considered in selective cases for treatment of pancreatic neoplasm if it allows complete clearance. The procedure does not appear to be associated with significant increases in serious complications compared with PD. PMID- 24754231 TI - Suppression of tumor necrosis factor receptor-associated protein 1 expression induces inhibition of cell proliferation and tumor growth in human esophageal cancer cells. AB - Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a molecular chaperone involved in multidrug resistance and antiapoptosis in some human tumors, but its regulatory mechanisms have not been revealed in esophageal squamous cell carcinoma (ESCC). In this study, 138 specimens of ESCC were analyzed. TRAP1 was overexpressed in ESCC, particularly in poorly differentiated tumors. To further explore the molecular regulatory mechanism, we constructed specific small interfering RNA-expressing vectors targeting Trap1, and knocked down Trap1 expression in the esophageal cancer cell lines ECA109 and EC9706. Knockdown of Trap1 induced increases in reactive oxygen species and mitochondrial depolarization, which have been proposed as critical regulators of apoptosis. The cell cycle was arrested in G2/M phase, and in vitro inhibition of cell proliferation was confirmed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and bromodeoxyuridine assays. Furthermore, re-expression of TRAP1 in Trap1 small interfering RNA-transfected ESCC cells restored cell proliferation and cell apoptosis. Bioluminescence of subcutaneously xenografted ESCC tumor cells demonstrated significant inhibition of in vivo tumor growth by Trap1 knockdown. This study shows that TRAP1 was overexpressed in most patients with ESCC, and caused an increase in antiapoptosis potency. TRAP1 may be regarded as a target in ESCC biotherapy. PMID- 24754232 TI - Barriers for poor cataract surgery uptake among patients with operable cataract in a program of outreach screening and low-cost surgery in rural China. AB - AIMS: To identify the reasons for poor uptake of cataract surgery in a program of outreach screening and low-cost surgery in Pucheng County, a rural area in northwestern China. METHODS: Detailed interviews with a semi-structured questionnaire were conducted by telephone or face-to-face for participants who had been advised to attend a low-cost cataract surgery program but did not schedule the surgery within 3 months after the initial screening. RESULTS: Among 432 eligible subjects, 355 (82.2%) were interviewed (mean age 70.6 +/- 6.6 years, 73.8% female). A total of 138 subjects (38.9%) were interviewed by phone and 217 (61.1%) were interviewed face-to-face. Lack of family support (n = 106, 29.9%) and failure to understand the need for surgery (n = 96, 27.0%) were the two main reasons for not undergoing cataract surgery. Other factors included fear of surgery (n = 62, 17.5%), lack of faith in doctors (n = 36, 10.1%), financial constraints (n = 25, 7.0%) and lack of transportation (n = 4, 1.1%). CONCLUSION: The principal barriers to low-cost cataract surgery uptake in rural China included lack of family support and failure to understand the need for surgery. Education targeting entire families to eliminate these barriers and development of community support systems at the family level are required to achieve greater uptake of low-cost cataract surgery programs in rural China. PMID- 24754233 TI - Review article: 2014 UK consensus guidelines - hepatitis C management and direct acting anti-viral therapy. AB - BACKGROUND: Therapeutic options for the management of hepatitis C virus (HCV) infection have evolved rapidly over the past two decades, with a consequent improvement in cure rates. Novel therapeutic agents are an area of great interest in the research community, with a number of these agents showing promise in the clinical setting. AIMS: To assess and present the available evidence for the use of novel therapeutic agents for the treatment of HCV, updating previous guidelines. METHODS: All Phase 2 and 3 studies, as well as abstract presentations from international Hepatology meetings were identified and reviewed for suitable inclusion, based on studies of new therapies in HCV. Treatment-naive and experienced individuals, as well as cirrhotic and co-infected individuals were included. RESULTS: Sofosbuvir, simeprevir and faldaprevir, along with pegylated interferon and ribavirin, have a role in the treatment of chronic HCV infection. The precise regimens are largely dependent on the patient characteristics, patient and physician preferences, and cost implication. CONCLUSIONS: Therapies for chronic HCV have evolved dramatically in recent years. Interferon-free regimens are now possible without compromise in the rate of sustained viral response. The decision as to which regimen is most appropriate is multifactorial, and based on efficacy, safety and cost. PMID- 24754234 TI - Mild and phosphine-free iron-catalyzed cross-coupling of nonactivated secondary alkyl halides with alkynyl Grignard reagents. AB - A simple protocol for iron-catalyzed cross-coupling of nonactivated secondary alkyl bromides and iodides with alkynyl Grignard reagents at room temperature has been developed. A wide range of secondary alkyl halides and terminal alkynes are tolerated to afford the substituted alkynes in good yields. A slight modification of the reaction protocol also allows for cross-coupling with a variety of primary alkyl halides. PMID- 24754235 TI - Impact of Al2O3 on the aggregation and deposition of graphene oxide. AB - To assess the environmental behavior and impact of graphene oxide (GO) on living organisms more accurately, the aggregation of GO and its deposition on Al2O3 particles were systematically investigated using batch experiments across a wide range of solution chemistries. The results indicated that the aggregation of GO and its deposition on Al2O3 depended on the solution pH and the types and concentrations of electrolytes. MgCl2 and CaCl2 destabilized GO because of their effective charge screening and neutralization, and the presence of NaH2PO4 and poly(acrylic acid) (PAA) improved the stability of GO with the increase in pH values as a result of electrostatic interactions and steric repulsion. Specifically, the dissolution of Al2O3 contributed to GO aggregation at relatively low pH or high pH values. Results from this study provide critical information for predicting the fate of GO in aquatic-terrestrial transition zones, where aluminum (hydro)oxides are present. PMID- 24754236 TI - Dendritic changes in rat visual pathway associated with experimental ocular hypertension. AB - PURPOSE: Increasing evidence shows that structural changes in dendrites play an important role in neuronal degenerative processes. The aims of this study were to characterize and delineate morphological changes of dendrites in retinal ganglion cells (RGCs) and their central target neurons in the superior colliculus (SC) and lateral geniculate nucleus (LGN) in experimental rat glaucoma. METHODS: Chronic ocular hypertension (OHT) was surgically induced in rats and animals were sacrificed at 1, 4, 8, 16 and 32 weeks following IOP elevation. Animals without IOP elevation served as normal control. Dendritic morphology of neurons was visualized by ex vivo DiI labelling using confocal microscopy and dendritic length and number was quantified using Image J. RESULTS: We found significant dendritic shrinkage (p < 0.001) and loss (p < 0.001) in RGCs and neurons in the SC and LGN in OHT animals compared to age-matched controls. Analysis of the temporal morphological profiles among them revealed the RGCs to have the earliest changes compared to the SC and LGN although the most prominent changes occurred in the SC. CONCLUSION: Our study has demonstrated that OHT results in dendritic changes of the neurons throughout the visual pathways, from RGCs to SC cells and LGN cells, suggesting that both the retina and the brain should be targeted when considering diagnosis and therapeutic strategies for glaucoma. PMID- 24754237 TI - A prospective study on the effect of photoselective vaporization of prostate by 120-W high-performance system laser on sexual function. AB - INTRODUCTION: Photoselective vaporization of prostate (PVP) by 120W HPS laser emerged as an efficient, bloodless, and durable first line alternative to transurethral resection of prostate for treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE). In this study, we assessed effects of PVP by HPS laser on erectile function. MATERIAL AND METHODS: Between January 2012 and February 2014, 143 consecutive patients presenting with LUTS secondary to BPE, who underwent PVP by 120W HPS laser, were prospectively enrolled in the study. Patient's (Group A: International Index of Erectile Function-5 (IIEF-5) >=19; Group B: IIEF <19) preoperative, perioperative and follow-up data were recorded. IIEF-5 was used to assess preoperative and postoperative erectile function at 1, 3, 6, and 12 months. Recorded data was analyzed statistically. RESULTS: Preoperative and perioperative data of the two groups were comparable. Significant improvement in IPSS, Qmax, QoL, and post void residual urine at 1, 3, 6 and 12 months were observed in both groups with no significant difference between them. Although IIEF-5 scores declined in both groups postoperatively (Group A: 21.06+/-1.21 to 19.84+/-1.55, P=0.43; Group B: 14.67+/-2.05 to 12.79+/-1.42, P=0.53), it was not statistically significant in either group. No significant difference was noted in IIEF-5 score between patients with or without indwelling catheter in either of the two groups. CONCLUSIONS: In patients undergoing PVP by 120W HPS laser for LUTS secondary to BPE, no significant effect was observed in sexual function at 1 year follow-up. PMID- 24754238 TI - Endoscopic diagnosis of early Barrett's neoplasia: perspectives for advanced endoscopic technology. AB - Barrett's esophagus (BE) is a metaplastic condition that occurs secondary to gastroesophageal reflux disease. BE is also a precursor to esophageal adenocarcinoma, which, although still rare in Japan, is one of the most rapidly increasing cancers in Western countries. However, the prevalence of gastroesophageal reflux disease has increased significantly over the past few decades in Japan, possibly leading to an incremental rise in BE and the associated inherent risk of adenocarcinoma. Given the poor prognosis of advanced stage Barrett's adenocarcinoma, endoscopic surveillance is recommended for subjects with BE to detect early neoplasias including dysplasia. However, endoscopic identification of dysplastic lesions is still not sufficiently reliable or subjective, making targeted therapy extremely difficult. Over the past few years, improvements in image resolution, image processing software, and optical filter technology have enabled identification of dysplasia and early cancer in BE patients. We retrieved as many studies on advanced endoscopic technologies in BE as possible from MEDLINE and PubMed. The present review focuses on the emergent clinically available technologies to provide an overview of the technologies, their practical applicability, current status, and future challenges. PMID- 24754239 TI - Does the AIMS65, a new risk score for upper gastrointestinal bleeding, work in Japan? PMID- 24754240 TI - Is endoscopic ultrasonography-guided biliary drainage really that wonderful? PMID- 24754241 TI - Seeing is believing. PMID- 24754244 TI - Secreted mucosal antimicrobials in the female reproductive tract that are important to consider for HIV prevention. AB - The mucosal microenvironment of the female reproductive tract (FRT) is rich in secreted endogenous antimicrobials that provide the first line of defense against pathogens. This review focuses on the spectrum of secreted antimicrobials found in the FRT that have anti-HIV functions and are regulated by the natural hormonal changes in women's life cycle. Understanding the complex nature of FRT, mucosal microenvironment will enable us to better design therapeutic interventions for women against sexually transmitted pathogens. PMID- 24754245 TI - Management of a pemphigus with IgA and IgG antibodies and coexistent lung cancer. AB - Immunoglobulin A (IgA) pemphigus is a clinically distinct variant of pemphigus characterized by intercellular IgA deposition in the epidermis. Recently, an IgA/Immunoglobulin G (IgG) subset of pemphigus with IgA and IgG anti-keratinocyte cell surface antibodies has been described. Both IgA and IgA/IgG pemphigus have been associated with internal malignancies. Above all, monoclonal IgA gammopathy in patients with IgA pemphigus has been reported, and lung cancers in association with IgA/IgG pemphigus have been described. IgA pemphigus can be successfully treated with dapsone, whereas therapeutic management of IgG/IgA pemphigus is not well established yet. We report a rare case of a patient, who developed atypical pemphigus with both IgA and IgG autoantibodies and an underlying lung cancer, successfully treated with corticosteroids and dapsone. PMID- 24754246 TI - Expression of CD24 is associated with HER2 expression and supports HER2-Akt signaling in HER2-positive breast cancer cells. AB - Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is treated with HER2-targeted agents, such as trastuzumab and lapatinib, that suppress signaling by phosphatidylinositol 3-kinase (PI3K)-Akt and MAPK pathways. However, resistance to HER2-targeted therapy remains a major clinical problem. Overexpression of CD24 has been detected in many cancers and is associated with a poor prognosis in women with breast cancer. HER2-positive breast tumors are predominantly positive for CD24, suggesting that the expression of the two molecules is related. To investigate the relation between HER2 and CD24, we overexpressed HER2 in breast cancer cells that were triple-negative for the estrogen receptor, progesterone receptor and HER2. We found that expression of CD24 was increased by stable overexpression of HER2. Flow cytometry thus revealed that the percentage of CD24-positive cells was markedly higher in the HER2 positive fraction than in the HER2-negative fraction. Knockdown of CD24 in breast cancer cells positive for endogenous HER2 downregulated HER2 expression, whereas knockdown of HER2 did not affect the expression of CD24. Knockdown of CD24 also suppressed the phosphorylation of Akt, which functions downstream of HER2 and PI3K to promote cell survival. Moreover, knockdown of CD24 increased the sensitivity of HER2-positive breast cancer cells to lapatinib treatment. Our results thus indicate that CD24 supports both the expression of HER2 and the consequent activation of PI3K-Akt signaling. Furthermore, CD24 may contribute to resistance to HER2-targeted therapy and, therefore, is itself a potential therapeutic target in HER2-positive breast cancer. PMID- 24754247 TI - Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3. AB - Digitalis-like compounds (DLCs) such as digoxin, digitoxin, and ouabain, also known as cardiac glycosides, are among the oldest pharmacological treatments for heart failure. The compounds have a narrow therapeutic window, while at the same time, DLC pharmacokinetics is prone to drug-drug interactions at the transport level. Hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and Na(+)-dependent taurocholate co-transporting polypeptide (NTCP) influence the disposition of a variety of drugs by mediating their uptake from blood into hepatocytes. The interaction of digoxin, digitoxin, and ouabain with hepatic uptake transporters has been studied before. However, here, we systematically investigated a much wider range of structurally related DLCs for their capability to inhibit or to be transported by these transporters in order to better understand the relation between the activity and chemical structure of this compound type. We studied the uptake and inhibitory potency of a series of 14 structurally related DLCs in Chinese hamster ovary cells expressing NTCP (CHO NTCP) and human embryonic kidney cells expressing OATP1B1 and OATP1B3 (HEK OATP1B1 and HEK-OATP1B3). The inhibitory effect of the DLCs was measured against taurocholic acid (TCA) uptake in CHO-NTCP cells and against uptake of beta estradiol 17-beta-d-glucuronide (E217betaG) in HEK-OATP1B1 and HEK-OATP1B3 cells. Proscillaridin A was the most effective inhibitor of NTCP-mediated TCA transport (IC50 = 22 MUM), whereas digitoxin and digitoxigenin were the most potent inhibitors of OATP1B1 and OAPTP1B3, with IC50 values of 14.2 and 36 MUM, respectively. Additionally, we found that the sugar moiety and hydroxyl groups of the DLCs play different roles in their interaction with NTCP, OATP1B1, and OATP1B3. The sugar moiety decreases the inhibition of NTCP and OATP1B3 transport activity, whereas it enhances the inhibitory potency against OATP1B1. Moreover, the hydroxyl group at position 12 reinforces the inhibition of NTCP but decreases the inhibition of OATP1B1 and OATP1B3. To investigate whether DLCs can be translocated, we quantified their uptake in transporter-expressing cells by LC MS. We demonstrated that convallatoxin, ouabain, dihydroouabain, and ouabagenin are substrates of OATP1B3. No transport was observed for the other compounds in any of the studied transporters. In summary, this work provides a step toward an improved understanding of the interaction of DLCs with three major hepatic uptake transporters. Ultimately, this can be of use in the development of DLCs that are less prone to transporter-mediated drug-drug interactions. PMID- 24754248 TI - Prevalence and risk factors for age-related macular degeneration: Korean National Health and Nutrition Examination Survey 2008-2011. AB - PURPOSE: To evaluate the prevalence of and risk factors for age-related macular degeneration (AMD) in a representative Korean population. MATERIALS AND METHODS: A nationwide population-based cross-sectional study was conducted among the civilian, noninstitutionalized Korean population aged 40 and older (mean age, 55.7 years; 95% confidence interval [CI], 55.4-56.0). A total of 16,109 older (>=40 years of age) subjects participated in the Korean National Health and Nutrition Survey 2008-2011. All participants underwent standardized interviews and comprehensive ophthalmic examinations. Using physiologic mydriasis, a 45 degrees digital fundus photograph was taken of both eyes of each participant. All fundus photographs were graded according to an international classification and grading system. Main outcome measures consisted of prevalence of early- and late-AMD. RESULTS: Of the 16,109 subjects, fundus photographs were gradable for 14,352 (89.1%). The prevalence of early- and late-AMD in the Korean population was 6.0 and 0.6%, respectively. The prevalence of early-AMD increased from 1.5% in those aged 40-49 years to 16.2% in those aged >=70 years. After adjusting for confounders, the prevalence of early-AMD increased with increasing age (odds ratio [OR], 1.08; CI, 1.06-1.09). For late-AMD, old age (OR, 1.09; CI, 1.04 1.14), male gender (OR, 2.45; CI, 1.11-5.37), high systolic blood pressure (OR, 1.03; CI, 1.00-1.06) and high fasting glucose level (OR, 0.97; CI, 0.94-0.99) were significant risk factors. Smoking was not associated with either early- or late-AMD in this Korean population. CONCLUSIONS: The present study provides the first population-based data on the prevalence of and risk factors for AMD in a representative Korean population. The prevalences of early- and late-AMD in this population were 6.0 and 0.6%, respectively. The prevalence of AMD in Koreans is higher than for those in other Asian countries and similar to that of Caucasians in Western countries. PMID- 24754249 TI - Polymorphism of GST and FTO Genes in Risk Prediction of Cataract among a North Indian Population. AB - BACKGROUND: The present study was carried out to investigate the association of GST and FTO gene polymorphisms with cataract cases and controls. MATERIALS AND METHODS: The study included 131 cases and 126 controls. GST and FTO gene polymorphisms were evaluated by PCR-RFLP. RESULTS: The frequency of the GSTM1 positive and GSTT1-positive in cataract cases were 62.13% and 86.40% while in the controls it was 46.39% and 95.87% with odds ratios of 1.9 (95% CI, 1.08-3.32; p value 0.025) and 0.27 (95% CI, 0.09-0.86; p value, 0.019) respectively. There was a statistically significant association between the GSTM1 null genotype and the risk of cataract development with an odds ratio of 0.43 (95% CI, 0.24-0.76; p value, 0.003). Significant differences were obtained in the frequencies of FTO AA and TT genotype (p = 0.023 and 0.023) between cases and controls. CONCLUSION: The present study suggested that GSTM1, GSTT1 and FTO gene polymorphisms are associated with increased risk for cataract in North Indian populations. Due to the limited sample size, the finding on GST and FTO gene polymorphisms need further investigation. PMID- 24754250 TI - Metal nanoparticles: The protective nanoshield against virus infection. AB - Re-emergence of resistance in different pathogens including viruses are the major cause of human disease and death, which is posing a serious challenge to the medical, pharmaceutical and biotechnological sectors. Though many efforts have been made to develop drug and vaccines against re-emerging viruses, researchers are continuously engaged in the development of novel, cheap and broad-spectrum antiviral agents, not only to fight against viruses but also to act as a protective shield against pathogens attack. Current advancement in nanotechnology provides a novel platform for the development of potential and effective agents by modifying the materials at nanolevel with remarkable physicochemical properties, high surface area to volume ratio and increased reactivity. Among metal nanoparticles, silver nanoparticles have strong antibacterial, antifungal and antiviral potential to boost the host immunity against pathogen attack. Nevertheless, the interaction of silver nanoparticles with viruses is a largely unexplored field. The present review discusses antiviral activity of the metal nanoparticles, especially the mechanism of action of silver nanoparticles, against different viruses such HSV, HIV, HBV, MPV, RSV, etc. It is also focused on how silver nanoparticles can be used in therapeutics by considering their cytotoxic level, to avoid human and environmental risks. PMID- 24754251 TI - Bacterial collagenases - A review. AB - Bacterial collagenases are metalloproteinases involved in the degradation of the extracellular matrices of animal cells, due to their ability to digest native collagen. These enzymes are important virulence factors in a variety of pathogenic bacteria. Nonetheless, there is a lack of scientific consensus for a proper and well-defined classification of these enzymes and a vast controversy regarding the correct identification of collagenases. Clostridial collagenases were the first ones to be identified and characterized and are the reference enzymes for comparison of newly discovered collagenolytic enzymes. In this review we present the most recent data regarding bacterial collagenases and overview the functional and structural diversity of bacterial collagenases. An overall picture of the molecular diversity and distribution of these proteins in nature will also be given. Particular aspects of the different proteolytic activities will be contextualized within relevant areas of application, mainly biotechnological processes and therapeutic uses. At last, we will present a new classification guide for bacterial collagenases that will allow the correct and straightforward classification of these enzymes. PMID- 24754252 TI - Type D personality and cardiovascular reactivity to an ecologically valid multitasking stressor. AB - Previous research investigating the influence of Type D personality on cardiovascular reactivity to stress in healthy young adults is somewhat mixed. The present study sought to investigate this question using an ecologically valid laboratory stressor. Beat-to-beat blood pressure and heart rate were measured in 77 healthy young adults during exposure to multitasking stress. Mood and background stress were both associated with Type D personality when Type D was conceptualised as a dimensional construct, with less robust findings observed using the traditional dichotomous typological approach. However, the continuous Type D construct added limited predictive value of the self-report measures above that of its constituent components, negative affectivity (NA) and social inhibition (SI). Further, an inverse relationship between the continuous Type D construct and blood pressure reactivity to multitasking stress was observed. In summary, our findings suggest that Type D personality is predictive of blunted cardiovascular reactivity to stress in healthy individuals when Type D is considered as a dimensional construct and the independent influence of NA and SI is controlled for. Further, our findings suggest that Type D does not predict additional variance in mood and background stress above that of NA and SI when these constituent factors are considered independently. PMID- 24754253 TI - Technologies and mechanisms for safety control of ready-to-eat muscle foods: an updated review. AB - Ready-to-eat (RTE) muscle foods refer to a general category of meat and poultry products that are fully cooked and consumable without reheating. These products, including whole and sliced pork, beef, turkey, chicken, and variety of meats, in the forms of ham, roast, rolls, sausage, and frankfurter, are widely available in the delicatessen section of retail stores or various food service outlets. However, difficulties in avoidance of contamination by foodborne pathogens, notably Listeria monocytogenes, during product postlethality repackaging render RTE meats labile to outbreaks. Accordingly, the USDA-FSIS has established processing guidelines and regulations, which are constantly updated, to minimize foodborne pathogens in RTE products. Technologies that complement good manufacturing practice have been developed to control RTE meat safety. Among them, various antimicrobial product formulations, postpackaging pasteurization (thermal and nonthermal), and antimicrobial packaging are being used. Through these efforts, outbreaks linked to RTE meat consumption have substantially reduced in recent years. However, the pervasive and virulent nature of L. monocytogenes and the possible presence of other cold-tolerant pathogens entail continuing developments of new intervention technologies. This review updates existing and emerging physical and chemical methods and their mode of action to inactivate or inhibit threatening microorganisms in RTE muscle foods. PMID- 24754255 TI - Receiver-operating characteristics analysis: a new approach to predicting the presence of pathogens in surface waters. AB - Fecal indicator microbes are used to monitor the public health risks of recreating in surface waters. However, the importance of indicator tests as predictors of waterborne pathogens has been unclear. Numerous studies have also shown that the survival and growth of indicator organisms may depend on location specific factors that cannot be broadly generalized. We used receiver-operating characteristic (ROC) methods to determine whether fecal indicator species are capable of predicting the presence of Giardia and Cryptosporidium in fresh surface waters in the Chicago area. We also derived recreational water quality criteria specific to our location with respect to this end point. We considered five fecal indicators: enterococci measured by culture and quantitative polymerase chain reaction (qPCR), Escherichia coli measured by culture, somatic coliphage, and F+ coliphage. All fecal indicators were found to predict the presence and absence of protozoan pathogens. The test for enterococci measured by culture was the poorest predictor of the presence of pathogens. The test for enterococci measured by qPCR was the best predictor of the presence of Giardia, but not an important predictor of the presence of Cryptosporidium. The test for somatic coliphage was a relatively strong predictor of the presence of both pathogens. This analysis supports the use of qPCR-based assays over culture-based assays for predicting the presence of Giardia in fresh surface water. Our criteria were optimized for the prediction of the presence of Giardia and Cryptosporidium in our location and were closely aligned with criteria of the U.S. Environmental Protection Agency derived from epidemiological risk assessment. The ROC approach is flexible and can inform location-specific interpretation of water quality monitoring data and decision making. PMID- 24754254 TI - Bipolar transurethral resection versus monopolar transurethral resection for benign prostatic hypertrophy: a systematic review and meta-analysis. AB - PURPOSE: To evaluate the efficacy and safety of monopolar (M-TURP) and bipolar (B TURP) transurethral resection of the prostate in benign prostatic hypertrophy (BPH) patients. MATERIALS AND METHODS: Eligible randomized controlled trials (RCTs) were identified from electronic databases without language restrictions. Database search, quality assessment, and data extraction were independently performed. The primary postoperative outcomes of topical M-TURP and B-TURP were maximum flow rate (Qmax) and/or International Prostate Symptom Score (IPSS). Safety was estimated by TUR syndrome; need for transfusion; clot retention; bladder neck contracture (BNC); urethral stricture (US); and catheter removal time. Efficacy and safety were investigated using the Review Manager. RESULTS: Thirty-one trials met the inclusion criteria. Pooled analysis revealed significant difference in efficacy between the M-TURP and B-TURP groups. Safety analysis revealed significant improvement in the TUR syndrome with B-TURP than with M-TURP. Pooled analysis revealed that clot retention was significantly higher in M-TURP than in B-TURP. Moreover, pooled analysis revealed no significant difference between both groups in the blood transfusion frequency or late complications (urethral strictures) and bladder neck constriction. CONCLUSIONS: This systematic review indicates that B-TURP was significantly better in the result of Qmax and for decreasing the incidence of TUR syndrome and clot retention. No significant differences were observed in the nature of adverse events such as transfusions, retention after catheter removal, and urethral complications between both groups. Thus, B-TURP is the next generation "gold standard" for benign prostatic obstruction (BPO) because it is associated with a lower rate of clinically relevant complications such as TUR syndrome and clot retention. PMID- 24754256 TI - Expression and regulation of the proton-coupled oligopeptide transporter PhT2 by LPS in macrophages and mouse spleen. AB - Membrane transporter PhT2 (SLC15A3), which belongs to the proton-coupled oligopeptide transporter family, mediates the transport of di/tripeptides and histidine utilizing an inwardly directed proton gradient and negative membrane potential. The aim of this study was to elucidate the molecular expression of PhT2 in macrophages and mouse tissues and to explore the regulation of PhT2 by lipopolysaccharide (LPS). The results showed relatively high expression of PhT2 in J774A.1 and THP-1 macrophage cells, mouse spleen, and lung. Using an LPS induced inflammatory cell model, we found that hPhT2 mRNA expression was up regulated in THP-1 cells and that the up-regulation was suppressed by pyrrolidine dithiocarbamate, a specific inhibitor of NF-kappaB. Similar results were observed in mouse spleen during LPS-induced acute inflammation. Using dual-labeling immunofluorescence and confocal laser scanning microscopy, we confirmed that mPhT2 was colocalizing with lysosome-associated membrane protein 1 in transfected HEK293 cells. These results suggested that PhT2, a lysosomal membrane transporter, was up-regulated by LPS via the NF-kappaB signaling pathway. PMID- 24754257 TI - Australian and New Zealand Audit of Surgical Mortality: concordance between reported and audited clinical events and delays in management in surgical mortality patients. AB - BACKGROUND: The Australian and New Zealand Audit of Surgical Mortality (ANZASM) is a nationwide confidential peer review of deaths associated with surgical care. This study assesses the concordance between treating surgeons and peer reviewers in reporting clinical events and delays in management. METHODS: This is a retrospective cross-sectional analysis of deaths in 2009 and 2010. Cases that went through the process of submission of details by the surgeon in a structured surgical case form (SCF), first-line assessment (FLA) and a more detailed second line assessment (SLA) were included. Significant clinical events reported for these patients were categorized and analysed for concordance. RESULTS: Of the 11,303 notifications of death to the ANZASM, 6507 (57.6%) were audited and 685 (10.5%) required the entire review process. Nationally, the most significant events were post-operative complications, poor preoperative assessment and delay to surgery or diagnosis. The SCF submissions reported 338 events, as compared with 1009 and 985 events reported through FLA and SLA, respectively (P = 0.01). Treating surgeons and assessors attributed 29-30% of events to factors outside the surgeon's control. Surgeons felt that delay to surgery or diagnosis was a significant event in 6.6% of cases, in contrast to 20% by assessors (P = 0.01). Preoperative management could be improved in 19% of cases according to surgeons, compared with 45 and 36% according to the assessors (P < 0.001). CONCLUSION: There is significant discordance between treating surgeons and assessors. This suggests the need for in-depth analysis and possible refinement of the audit process. PMID- 24754258 TI - Experiences of mothers of infants with neonatal abstinence syndrome in the neonatal intensive care unit. AB - OBJECTIVE: To describe the experiences of mothers of infants with neonatal abstinence syndrome (NAS) in the neonatal intensive care unit (NICU). DESIGN: Qualitative description. SETTING: We recruited participants from community-based, out-patient, addiction treatment facilities in a large urban city in the southwestern region of the United States. PARTICIPANTS: A convenience sample of 15 Hispanic, substance addicted mothers of infants with NAS participated. METHODS: We conducted semistructured, individual, interviews and analyzed the data using qualitative content analysis. First, we analyzed the data independently and then discussed the themes until a consensus was reached. RESULTS: We identified four themes: (a) understanding addiction, (b) watching the infant withdraw, (c) judging, and (d) trusting the nurses. The participants felt there was a lack of understanding concerning addiction that was particularly noted when interacting with the nurses. They shared their feelings of guilt and shame when observing their infants withdrawing. The participants felt judged by the nurses for having used illicit drugs during pregnancy. Feeling judged interfered with the participants' ability to trust the nurses. CONCLUSION: These findings provide nurses with a better understanding of the experiences of mothers who have addiction problems and may lead to more customized nursing care for this high-risk population of mothers and their infants. PMID- 24754260 TI - Improvement in survival associated with embolisation of spontaneous portosystemic shunt in patients with recurrent hepatic encephalopathy. AB - BACKGROUND: Spontaneous portosystemic shunt (SPSS) is a frequent cause of recurrent hepatic encephalopathy (HE) in patients with cirrhosis. AIM: To assess the effectiveness and optimal candidate selection for embolisation of SPSS, for the treatment of recurrent HE in patients with cirrhosis. METHODS: This retrospective cohort study compared 17 patients with recurrent HE who achieved complete occlusion of SPSS by angiographic embolisation and 17 control patients. RESULTS: Most baseline characteristics were similar in the two groups. The 2-year HE recurrence rate was significantly lower in the embolisation than in the control group (39.9% vs. 79.9%, P = 0.02), whereas their 2-year overall survival rates were similar (64.7% vs. 53.4%, P = 0.98). Model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) score were significant predictors of 2-year patient mortality in the embolisation group. Analysis of patients with MELD <15 in the absence of hepatocellular carcinoma (HCC) showed that 2-year overall survival rate was significantly higher in the embolisation group than in the control group (100% vs. 60%, P = 0.03). The median changes in MELD (-1.6 vs. 2.5, P < 0.01), CTP score (-3 vs. 0, P < 0.01), and liver volume (61 mL vs. -117 mL; P = 0.046) at 1 year significantly favoured the embolisation group. Serious clinical complications after embolisation occurred only in patients who had MELD >=15 and/or HCC at baseline, with all six dying within 1 year. CONCLUSIONS: Embolisation of a large spontaneous portosystemic shunt may be associated with improved survival and liver function, as well as prevention of hepatic encephalopathy in cirrhotic patients with recurrent hepatic encephalopathy and modestly preserved liver function. PMID- 24754261 TI - Transiently produced hypochlorite is responsible for the irreversible inhibition of chlorite dismutase. AB - Chlorite dismutases (Clds) are heme b-containing prokaryotic oxidoreductases that catalyze the reduction of chlorite to chloride with the concomitant release of molecular oxygen. Over time, they are irreversibly inactivated. To elucidate the mechanism of inactivation and investigate the role of the postulated intermediate hypochlorite, the pentameric chlorite dismutase of "Candidatus Nitrospira defluvii" (NdCld) and two variants (having the conserved distal arginine 173 exchanged with alanine and lysine) were recombinantly produced in Escherichia coli. Exchange of the distal arginine boosts the extent of irreversible inactivation. In the presence of the hypochlorite traps methionine, monochlorodimedone, and 2-[6-(4-aminophenoxy)-3-oxo-3H-xanthen-9-yl]benzoic acid, the extent of chlorite degradation and release of molecular oxygen is significantly increased, whereas heme bleaching and oxidative modifications of the protein are suppressed. Among other modifications, hypochlorite-mediated formation of chlorinated tyrosines is demonstrated by mass spectrometry. The data obtained were analyzed with respect to the proposed reaction mechanism for chlorite degradation and its dependence on pH. We discuss the role of distal Arg173 by keeping hypochlorite in the reaction sphere for O-O bond formation. PMID- 24754262 TI - Gastroduodenal stenting with Niti-S stent: long-term benefits and additional stent intervention. AB - BACKGROUND AND AIM: Self-expandable metallic stents have mainly been used for the palliation of malignant gastric outlet obstruction (GOO). However, their use in long-term survivors and the feasibility, safety and benefit of additional intervention for stent dysfunction remain controversial. The present study examined the long-term benefits of endoscopic gastroduodenal stenting. METHODS: We reviewed 61 patients treated with Niti-S stents at several hospitals and estimated the efficacy of stent intervention, stent patency, eating period and factors related to poor effectiveness. RESULTS: All 61 first stent interventions and 14 additional stent interventions (11 second interventions and 3 third interventions) were successfully carried out. Clinical success rates were 83.6% and 85.7%, and median stent patency was 214 days and 146 days (P = 0.47), respectively. Fifty patients could be treated with a first stent only, and 11 patients received additional stents. At the time of study termination or death, 70.0% of the former group and 63.6% of the latter group maintained oral intake (P = 0.71), and each 86% and 100% among the group could maintain oral intake for a period exceeding half of their remaining lives after first stent intervention. Karnofsky performance status <=50 (P = 0.03), ascites (P = 0.009), and peritoneal dissemination (P = 0.001) appeared to be factors related to poor effectiveness. CONCLUSIONS: Despite the presence of factors related to poor effectiveness, endoscopic gastroduodenal stenting would be the first treatment of choice for GOO and provide long-term benefits. If stent dysfunction occurs, additional stent intervention enables continued oral intake safely. PMID- 24754263 TI - Progesterone and its downstream molecules as blastocyst implantation essential factors. AB - This review is to update the previous review (Am J Reprod Immunol, 63, 2010 and 413) on the research on blastocyst implantation essential factors (BIEFs). Focus of the current review is on progesterone and its downstream molecules in the process of blastocyst implantation. To understand the process of implantation, we need to know where and when the BIEFs are expressed and what they do. Progress in this research area is rapid, and its update is indeed necessary. The basic concept of BIEFs is that they have dual functions, one physiological and the other immunological (J Reprod Dev, 58, 2012 and 196). As we are still exploring the mechanism of implantation, available data are incomplete and human data are few. Thus, I will use information obtained through research on animal models, in vitro studies, cell lines, and some human studies where available. The ultimate goal of the review is to understand human blastocyst implantation. PMID- 24754264 TI - Both low-dose arotinoid ethylester and acitretin are effective in the treatment of familial erythrokeratodermia variabilis. AB - We previously reported a large Chinese pedigree of erythrokeratodermia variabilis (EKV). A unique feature was that some of the affected members experienced transitory pustules on the border of classic lesions. Here we prescribed oral arotinoid ethylester and acitretin to two of the affected members in the pedigree, at starting dosage of 0.03 mg/day for arotinoid ethylester and 30 mg/day for acitretin, maintenance dosage of 0.03 mg every other day and 20 mg/day, respectively. Both patients reached complete clearance of the lesions during the treatment period. Side effect was negligible for the case on arotinoid ethylester. The patient on acitretin experienced elevated level of serum triglyceride and alanine aminotransferase that restrained further use. PMID- 24754265 TI - Skull vibration-induced nystagmus test in unilateral superior canal dehiscence and otosclerosis: a vestibular Weber test. AB - CONCLUSIONS: The skull vibration-induced nystagmus test (SVINT) acts as a vestibular Weber test and reveals a vibration-induced nystagmus (VIN), elicited mainly on the vertex location, with a horizontal or torsional component beating more often toward the side of the lesion in superior canal dehiscence (SCD) than in otosclerosis (OS). In SCD, the VIN vertical component is most often up beating. These results suggest more a global vestibular contribution than the sole stimulation of the superior semicircular canal. OBJECTIVES: This study aimed to evaluate the possible occurrence of nystagmus during SVINT in unilateral conductive hearing loss related to SCD or OS. METHODS: The slow-phase velocities (SPVs) of the VIN horizontal, torsional, and vertical components were recorded in patients with a unilateral otologic lesion (17 SCD, 38 OS) and 12 control subjects. Vibratory stimulations (60 Hz, 100 Hz) were applied on the vertex and on each mastoid. RESULTS: In SCD, VIN was observed in 82% of patients with a primarily torsional, horizontal, and vertical (up-beating) component in 40%, 30%, and 30%, respectively. Horizontal and torsional components beat toward the side of the lesion more often than in OS. Higher SPVs were observed after vertex stimulation. In OS, VIN was sparse with low amplitude and was not systematically lateralized to a specific side. PMID- 24754266 TI - Current status of the use of single-nucleotide polymorphisms in forensic practices. AB - Forensic geneticists often use short tandem repeats (STRs) to solve cases. However, STRs can be insufficient when DNA samples are degraded due to environmental exposure and mass disasters, alleged and real relatives are genetically related in paternity or kinship analyses, or a suspect is lacking. In such cases, single-nucleotide polymorphisms (SNPs) can provide valuable information and thus should be seriously considered as a tool to help resolve challenging cases. In this review, the current status of SNP analyses in forensic applications and the comparative advantages and disadvantages of SNPs with other biomarkers are discussed. PMID- 24754269 TI - The increasing price of dyes and pigments-short and long term issues. PMID- 24754268 TI - Behavioural, metabolic, and endothelial effects of the TNF-alpha suppressor thalidomide on rats subjected to chronic mild stress and fed an atherogenic diet. AB - There is accumulating evidence suggesting that depression is a risk factor for cardiovascular diseases. This study aimed to examine the hypothesis that the proinflammatory cytokine TNF-alpha would partially explain the link between depression and atherosclerotic endothelial changes. Rats were distributed among 6 groups: (i) control group; (ii) group subjected to chronic mild stress (CMS); (iii) group fed a cholesterol-cholic acid-thiouracil (CCT diet); and (iv) CMS group fed the CCT diet and treated with the vehicle for 8 weeks. The last 2 groups were subjected to CMS-CCT and received thalidomide (THAL) or imipramine (IMIP). Rats were assessed behaviorally (sucrose preference, open field, and forced-swimming tests). TNF-alpha protein was assessed from the serum, aorta, and liver. Aortic TNF-alpha gene expression (assessed using RT-PCR), serum lipid profile, and insulin levels were measured. Endothelial function was assessed in isolated aortic rings. The THAL and IMIP groups showed ameliorated CMS-CCT related behavioral changes. CMS-CCT-induced metabolic and endothelial dysfunctions were improved in the THAL group but were worsened in the IMIP group. RT-PCR showed a significant reduction of aortic TNF-alpha mRNA expression in the THAL and IMIP treatment groups. These data paralleled the findings for aortic immunohistochemistry. The THAL group, but not the IMIP group, showed improved CMS CCT-induced changes in the vascular reactivity of the aortic rings. Thus, TNF alpha provides a target link between depression, metabolic syndrome, and endothelial dysfunction. This could open a new therapeutic approach to address the comorbidities of depression. PMID- 24754267 TI - Functional polymorphisms in the NPAS2 gene are associated with overall survival in transcatheter arterial chemoembolization-treated hepatocellular carcinoma patients. AB - The functional abnormality of circadian regulation genes is involved in the development and progression of hepatocellular carcinoma (HCC). However, the association between functional single nucleotide polymorphisms (SNPs) in circadian gene NPAS2 and the overall survival of HCC patients treated with transcatheter arterial chemoembolization (TACE) has never been investigated. Six functional SNPs in the NPAS2 gene were genotyped using the Sequenom iPLEX genotyping system in a cohort of 448 unresectable Chinese patients with HCC treated with TACE. Multivariate Cox proportional hazards model and Kaplan-Meier curves were used for the prognosis analysis. We found that two SNPs, rs1053096 and rs2305160, in the NPAS2 gene showed significant associations with overall death risk in HCC patients in the recessive model (hazard ratio [HR] = 1.48; 95% confidence interval [CI], 1.13-1.94; P = 0.004) and in the dominant model (HR = 1.63; 95% CI, 1.29-2.07; P < 0.001), respectively. Moreover, we observed a cumulative effect of these two SNPs on HCC overall survival, indicating a significant trend of increasing death risk with increasing number of unfavorable genotypes (P for trend < 0.001). Compared with the patients without any unfavorable genotypes, the HRs for patients with one and two unfavorable genotypes were 1.41 (95% CI, 1.10-1.82; P = 0.007) and 2.09 (95% CI, 1.46-2.97, P < 0.001), respectively. The haplotype and diplotype analyses further characterized the association between NPAS2 genotype and survival of HCC patients. Our results for the first time suggest that NPAS2 gene polymorphisms may serve as an independent prognostic marker for HCC patients treated with TACE. PMID- 24754270 TI - Our epilepsy story: SUDEP Aware. PMID- 24754271 TI - Rapid progression to cardiac tamponade in Erdheim-Chester disease despite treatment with interferon alpha. AB - Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis with heterogeneous clinical manifestations. The most common presentation is bone pains typically involving the long bones. Approximately 75% of the patients develop extraskeletal involvement. Cardiac involvement is seen in up to 45% of the patients, and although, pericardial involvement is the most common cardiac pathology of this rare disease, cardiac tamponade due to ECD has been very rarely reported. We describe a case of a patient found to have ECD with multi-organ involvement and small pericardial effusion, which progressed to cardiac tamponade despite treatment with interferon alpha. PMID- 24754272 TI - Successful therapy of macrophage activation syndrome with dexamethasone palmitate. AB - Macrophage activation syndrome (MAS) is a severe and potential life-threatening complication of childhood systemic inflammatory disorders. Corticosteroids are commonly used as the first-line therapy for MAS. We report four patients with MAS who were successfully treated with dexamethasone palmitate (DexP), a liposome incorporated dexamethasone, much more efficient than free corticosteroids. DexP effectively inhibited inflammation in MAS patients in whom the response to pulse methylprednisolone was not sufficient to manage their diseases. DexP was also effective as the first-line therapy for MAS. Based on these findings, DexP is an effective therapy in treating MAS patients. PMID- 24754273 TI - Phase III, multicenter, open-label, long-term study of the safety of abatacept in Japanese patients with rheumatoid arthritis and an inadequate response to conventional or biologic disease-modifying antirheumatic drugs. AB - OBJECTIVES: To examine the long-term safety of intravenous (IV) abatacept treatment in Japanese patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) or other conventional or biologic disease modifying antirheumatic drugs. METHODS: This Phase III, open-label, long-term study (NCT00484289) comprised Japanese patients with RA who had completed abatacept Phase I or Phase II studies, and new patients intolerant to MTX. Patients from Phase I and Phase II studies received a weight-tiered dosing equivalent of 10 mg/kg abatacept, with MTX at doses up to 8 mg/week; newly enrolled patients received weight-tiered 10 mg/kg abatacept monotherapy. Safety and efficacy were assessed. RESULTS: A total of 217 patients (Phase I, n = 13; Phase II, n = 178; newly enrolled, n = 26) were treated with IV abatacept for a mean of 3 years. Serious adverse events occurred in 67/217 (30.9%) patients. Most adverse events were mild or moderate. For all cohorts combined, American College of Rheumatology 20% response rates ranged from 61.3 to 81.8% for as-observed and last observation carried forward analyses over 192 weeks. Following initial response, clinical and functional outcomes were maintained for up to 3 years. CONCLUSIONS: In Japanese patients with RA, IV abatacept with and without background MTX showed tolerable safety and sustained efficacy over 3 years. PMID- 24754274 TI - Clinical features of patients with IgG4-related disease complicated with perivascular lesions. AB - OBJECTIVE: To define the clinical features of IgG4-related disease (IgG4-RD) complicated with perivascular lesions. METHODS: The clinical features of seven patients with IgG4-RD and perivascular lesions diagnosed at the University of Tsukuba Hospital between October 2008 and October 2013, were analyzed, including clinical background, results of imaging studies, satisfaction of the 2011 comprehensive diagnostic criteria (CDC) for IgG4-RD, laboratory data, distribution of perivascular lesions, involvement of other organs, and response to steroid therapy. RESULTS: We studied six men and one woman with a mean age of 66.9 +/- 6.7 years (+/- SD). Six of seven patients were diagnosed as definite IgG4-RD, while the seventh was considered possible IgG4-RD, based on the CDC for IgG4-RD. Serum IgG4 levels at diagnosis were higher than 135 mg/dl in all seven patients (mean, 933 +/- 527). Serum C-reactive protein (CRP) levels were elevated in two only (mean, 1.42 +/- 3.56 mg/dl). The perivascular lesions were located in the pulmonary artery (n = 1), thoracic aorta (n = 2), abdominal aorta (n = 6), coronary (n = 1), celiac (n = 1), superior mesenteric (n = 1), renal (n = 2), inferior mesenteric (n = 5), and iliac (n = 3) arteries. In addition to perivascular lesions, six patients showed involvement of other organs. All seven patients were treated with prednisolone (0.6 mg/kg/day), which rapidly improved the perivascular and other organ lesions in six patients (the other one patient have not yet been evaluated due to the short follow-up). CONCLUSION: Perivascular lesions show wide distribution in patients with IgG4-RD. Serum CRP levels are not necessarily elevated in these patients. Steroid therapy is effective in IgG4-RD and results in resolution of lesions. PMID- 24754275 TI - Association of polymorphisms in SPARC and NLRP2 genes with rheumatoid arthritis in a Chinese Han population. AB - OBJECTIVES: To investigate the association of the polymorphisms in SPARC and NLRP2 with rheumatoid arthritis (RA) in a Chinese Han population. METHODS: Four single nucleotide polymorphisms (SNPs) covering SPARC and three SNPs covering NLRP2 were investigated in 624 Chinese Han RA patients and 1920 healthy controls. RESULTS: The A allele at SPARC rs3210714, SPARC rs11950384, NLRP2 rs2217659, and NLRP2 rs703468 were linked to reduced risk of RA (p = 0.0016, p = 0.0051, p < 0.0001, and p = 0.0033, respectively). Under the recessive model, the A/A genotype of rs3210714, rs11950384, rs2217659, and rs703468 were relevant with RA (p = 0.0071, p = 0.017, p < 0.0001 and p = 0.0066, respectively). Haplotype analysis identified the SPARC GGCG haplotype, AAAA haplotype were associated with the risk for RA (p < 0.0001 and p = 0.0015, respectively), while the risk of RA was lower for carriers of the GAAA haplotype (p < 0.0001), AACG haplotype (p < 0.0001), and the AGCG haplotype (p < 0.0001). The NLRP2 GG haplotype was a risk factor (p < 0.0001), while the GA haplotype and the AG haplotype were associated with lower risk of RA (p < 0.0001 and p = 0.0017, respectively). There was no significant difference between the RA patients and the controls in polymorphisms of rs7719521, rs1978707, and rs269913. CONCLUSION: This study indicates that polymorphisms in SPARC and NLRP2 are related to RA susceptibility in a Chinese Han population. PMID- 24754276 TI - Renal denervation for hypertension refractory to renal artery stenting. AB - PURPOSE: To investigate the effect of renal denervation (RDN) on blood pressure and renal function in refractory hypertension after renal artery recanalization and optimal medical therapy. METHODS: Ten patients (6 women; mean age 70.0+/-5.1 years) with an office systolic blood pressure >160 mmHg despite taking >=3 antihypertensive drugs and uni- or bilateral renal artery stenting were treated with RDN. Radiofrequency (RF) energy was delivered to the native segment of the artery keeping a 5-mm safe distance from the stented segments. Standardized office (OBP) and ambulatory (ABP) blood pressure measurements, medication, and renal assessment, including renal duplex ultrasound and renal function, were determined at baseline and on follow-up to 12 months. RESULTS: OBP (systolic/diastolic) at baseline was 190.0+/-20.4 / 84.2+/-10.1 mmHg. It decreased to 171.1+/-28.7* / 82.2+/-8.7, 165.5+/-28.4(?) / 76.1+/-7.4, and 158.3+/-14.2(?) / 75.5+/-9.5(?) mmHg (*p<0.001; (?)p<0.01) at 3, 6, and 12 months after RDN, respectively. Average ABP (systolic/diastolic) after 6 and 12 months decreased by -7.6(?) / -3.1 and -11.3(?) / -5.1(?) mmHg ((?)p<0.05). There was no renal artery (re)stenosis, dissection, or aneurysm within 12 months. Creatinine, cystatin C, and glomerular filtration rate remained unchanged. Urine albumin excretion decreased in 4/10 patients. Renal resistive indices improved in native, but not in stented renal arteries within the follow-up period. CONCLUSION: This proof-of-concept study demonstrates that RF-based RDN can be safely and effectively delivered in patients with resistant hypertension and previous renal artery stenting. PMID- 24754277 TI - Is an abnormal vascular response after renal sympathetic denervation predictive of permanent damage? An unusual case of late renal artery stenosis after energy delivery. AB - PURPOSE: To describe the effect of renal sympathetic denervation (RDN) on renal arteries immediately after the procedure and at follow-up. CASE REPORT: A 52-year old woman with severe resistant hypertension underwent RDN. A transient spasm occurred in the left renal artery immediately after radiofrequency energy delivery, with subsequent complete resolution without any additional therapy. At 6-month follow-up, the blood pressure increased, and imaging revealed a tight stenosis in the left renal artery, which was successfully treated with a stent. In the next days, there was an immediate significant blood pressure reduction. CONCLUSION: Renal denervation can be complicated by local tissue injury at the ablation sites that could be a possible trigger of late arterial disease. PMID- 24754278 TI - Commentary: transcatheter renal sympathetic denervation for resistant arterial hypertension: when sham brings shame? PMID- 24754280 TI - The EPIC nitinol stent system in the treatment of iliac artery lesions: one-year results from the ORION clinical trial. AB - PURPOSE: To report the 1-year results of a pivotal study for a new-generation nitinol stent for the treatment of iliac atherosclerotic lesions. METHODS: The ORION trial (ClinicalTrials.gov identifier NCT00896337) was a single-arm, non randomized, prospective, multicenter clinical trial that enrolled 125 patients (81 men; mean age 61.1+/-9.3 years) implanted with the EPIC self-expanding nitinol stent system in 166 de novo or restenotic iliac artery lesions <=13 cm long. The primary endpoint was the 9-month major adverse event rate [i.e., device or procedure-related death within 30 days, myocardial infarction during the index hospitalization, target vessel revascularization (TVR), or index limb amputation]. Follow-up occurred at hospital discharge and at 1, 9, and 12 months. An independent core laboratory evaluated ultrasound results at 1, 9, and 12 months. RESULTS: The primary endpoint met the prespecified performance goal, with only 3.4% (4/117) of patients experiencing a major adverse event by 9 months (p<0.0001). By 12 months, 6 (5.4%) of 111 patients had TVR; none had an index limb amputation. The ankle-brachial index, Walking Impairment Questionnaire, and Rutherford classifications all showed sustained improvements through 12 months. Primary patency was 94.4% with comparable results for lesions classified as complex (TASC II C/D 95.5%) or non-complex (TASC II A/B 95.0%). CONCLUSION: The EPIC stent system demonstrated safety and effectiveness through 12 months, including improvements for complex lesions. The EPIC stent is a viable alternative to surgery for patients with either complex or non-complex lesions. PMID- 24754279 TI - Nitinol stent implantation in the superficial femoral artery and proximal popliteal artery: twelve-month results from the complete SE multicenter trial. AB - PURPOSE: To determine the safety and efficacy of a new-generation nitinol stent with enhanced flexibility in arterial lesions in the superficial femoral artery (SFA) and proximal popliteal artery (PPA). METHODS: The Complete Self-Expanding (SE) Multicenter Trial (ClinicalTrials.gov identifier NCT00814970) enrolled 196 patients (124 men; mean age 68.7+/-10.5 years) from 28 centers in the United States and Europe. The patients presented with intermittent claudication (193/196) or ischemic rest pain (3/196) and were treated with nitinol stents for obstructive lesions of the SFA or PPA. Over a quarter of lesions (29.9%) were chronic total occlusions. The mean lesion length was 60.7 mm. Moderate to severe calcification was present in 91.0% of lesions. RESULTS: A total of 225 stents were successfully implanted in 213 (99.5%) of 214 lesions. Acute lesion success (<30% residual stenosis) was achieved in 90.0%. There were no in-hospital major adverse events. Primary patency (defined as a peak systolic velocity ratio <2.0) at 12 months was 72.6%. Clinically-driven target lesion revascularization (TLR) was required in 8.4% of patients at 12 months. The mean ankle-brachial index increased from 0.7 at baseline to 0.9, and there was sustained improvement in the Rutherford category, with 83% of patients classified as Rutherford category 0 or 1 at 12-month follow-up. No stent fractures were detected through 12 months. CONCLUSION: In this multicenter trial, primary implantation of a new-generation self-expanding nitinol stent in the SFA and PPA was associated with a low rate of TLR and sustained clinical benefit at 12 months without stent fracture. PMID- 24754281 TI - Endovascular treatment of external iliac artery occlusive disease: midterm results. AB - PURPOSE: To report midterm outcomes for endovascular treatment of external iliac artery (EIA) occlusive disease and assess possible factors affecting patency. METHODS: A retrospective analysis was conducted of 99 consecutive patients (91 men; mean age 67.3 years) with claudication (n=70) or critical limb ischemia (n=29) owing to occlusive EIA disease treated at our center from January 2005 to June 2012. The majority of lesions (79/108) were TASC A/B. Lesions were a mean 42.2 mm long (range 10-125); 43/108 affected the distal third of the EIA. Balloon angioplasty alone was performed in 7 limbs, while the remaining 101 lesions were stented (65 self-expanding, 24 balloon-expandable, and 12 covered). Clinical and hemodynamic follow-up was performed at 1, 3, 6, and 12 months after therapy and yearly thereafter. The factors examined were procedure characteristics and patency rates. RESULTS: Over a median follow-up of 27.5 months (range 1-89), there were 2 (1.9%) early occlusions followed by a successful reintervention, 4 late occlusions, and 5 hemodynamic failures followed by 7 reinterventions. These events led to primary and secondary patency rates at 30 months of 89.7% and 94.1%, respectively. No differences in patency rates were detected according to age, clinical state, or comorbidity. Use of covered stents (p=0.006) was the only variable associated with lower primary patency rates. CONCLUSION: Endovascular therapy to treat TASC A/B lesions of the EIA yielded good short and midterm patency and low early morbidity and mortality. Lesions involving the distal third of the EIA treated by simple angioplasty +/- stenting fared worse. No clinical factors could be correlated with patency. PMID- 24754282 TI - Corrosion resistance, surface evaluation, and geometric design comparison of five self-expanding nitinol stents used in clinical practice. AB - PURPOSE: To investigate the corrosion resistance properties of 5 commercially available nitinol stents used to treat peripheral artery disease and compare their surface quality, elemental composition, and geometrical design. METHODS: Samples of 5 different designs of nitinol peripheral stents [LifeStent (n=4), Philon (n=6), Epic (n=6), S.M.A.R.T. Control (n=7), and Complete SE (n=7)] were examined using stereomicroscopy, environmental scanning electron microscopy, and x-ray photoelectron spectroscopy. Corrosion resistance testing was performed in accordance with ASTM International Standard F2129-08. RESULTS: Thirteen (43%) of 30 stents corroded during this experiment. Stent fracture was observed in 12 (92%) of these corroded stents. Mean breakdown potentials ranged from 517 to 835 mV (vs. Ag/AgCl) for the Philon, Complete SE, S.M.A.R.T. Control, Epic, and LifeStent models from lowest to highest. A statistically significant difference in breakdown potential was observed between the LifeStent vs. Philon stents (835 vs. 517 mV, p=0.01) and Epic vs. Philon stents (833 vs. 517 mV, p=0.03). Stents with lower breakdown potential and relative breakdown potentials were associated with a higher fracture frequency (Spearman correlation coefficient -0.44, p=0.015 and -0.869, p<0.01, respectively). CONCLUSION: In this in vitro study, corrosion led independently to stent fracture. There is a significant association between lower mean breakdown/relative breakdown potentials and stent fracture. PMID- 24754283 TI - Commentary: nitinol stent designs need to adhere to the 3Bs: biofunctionality, biodurability, and biocompatibility. PMID- 24754284 TI - Propensity score analysis of clinical outcome after bypass surgery vs. endovascular therapy for infrainguinal artery disease in patients with critical limb ischemia. AB - PURPOSE: To compare endovascular therapy (EVT) outcomes to those of bypass surgery (BSG) for infrainguinal artery disease in patients with critical limb ischemia (CLI). METHODS: A retrospective review was conducted of 1053 CLI patients (1053 first treated limbs) who underwent BSG (n=230) or EVT (n=823) for de novo infrainguinal lesions between January 2004 and December 2009 at 14 Japanese centers. Propensity score analysis was used for risk adjustment in multivariate analysis and for one-to-one matching (n=200 in each group). Amputation-free survival, overall survival, limb salvage, and freedom from major adverse limb events (any repeat revascularization or major amputation) were calculated. RESULTS: Mean follow-up was 30+/-16 months. In the overall series, there was no significant difference at 3 years between the EVT and BSG groups in amputation-free survival (60.5% vs. 62.1%, p=0.84), limb salvage (88.7% vs. 85.4%, p=0.24), or overall survival (65.8% vs. 69.2%, p=0.40). However, freedom from adverse limb events was significantly lower in the EVT group (56.6% vs. 69.2%, p=0.02) at 3 years. In the matched pairs analysis, there was no significant difference in any outcome between BSG and EVT at 3 years: amputation free survival 66.3% vs. 62.0 (p=0.44), limb salvage 88.8% vs. 84.8% (p=0.44), survival 73.8% vs. 68.8% (p=0.61), and freedom from adverse limb events 61.3% vs. 69.1% (p=0.27). CONCLUSION: Our cohort suggested that the frequency of serious adverse events after EVT was comparable to that after BSG in CLI patients who underwent their first infrainguinal revascularization. PMID- 24754285 TI - Commentary: on the silver jubilee of subintimal angioplasty, how successful are contemporary endovascular therapies in the management of critical limb ischemia? PMID- 24754286 TI - Pooled analysis of the CONFIRM registries: safety outcomes in diabetic patients treated with orbital atherectomy for peripheral artery disease. AB - PURPOSE: To compare the acute outcomes of orbital atherectomy treatment in diabetic vs. non-diabetic patients with peripheral artery disease (PAD). METHODS: The CONFIRM registry series contained 1842 diabetic patients (1111 men; mean age 70.6+/-10.2 years) with 2819 lesions and 1247 non-diabetic patients (732 men; mean age 72.9+/-10.7 years) with 1885 lesions. The composite rate of procedure related complications, including dissection, perforation, slow flow, vessel closure, spasm, embolism, and thrombus formation, was analyzed for the diabetic and non-diabetic groups. RESULTS: Diabetics were younger but had a higher prevalence of coronary artery disease (p<0.001), renal disease (p<0.001), hypertension (p<0.001), hyperlipidemia (p<0.001), and lower ankle-brachial index scores (p=0.007). Diabetics had more severe PAD (Rutherford category 4-6; p<0.001), longer lesions (p<0.001), more infrapopliteal lesions (58% vs. 46%, p<0.001), and more lesions with severe and moderate calcium (86% vs. 78%, p<0.001). Diabetic and non-diabetic patients had the same (21.8%) composite rate of procedure-related complications, as well as similar rates of dissection (11.4% vs. 10.8%, p=0.68), embolism (2.2% vs. 2.4%, p=0.67), and thrombus formation (1.3% vs. 1.1%, p=0.75). However, diabetics had lower rates of perforation (0.5% vs. 1.1%, p=0.03) and spasm (5.5% vs. 7.6%, p=0.005), but a higher rate of slow flow (5.0% vs. 3.5%, p=0.02) and a tendency toward increased vessel closure (1.7% vs. 0.9%, p=0.06). CONCLUSION: Plaque modification with orbital atherectomy resulted in similar low procedure-related complication rates in both the diabetic and non-diabetic groups, despite diabetics having more unfavorable baseline clinical and lesion characteristics. This study suggests that orbital atherectomy is a safe and effective treatment modality in both the diabetic and the non diabetic populations. PMID- 24754287 TI - Contemporary crossing techniques for infrapopliteal chronic total occlusions. AB - The synergism of technical refinement and advanced technology has significantly increased the popularity of infrapopliteal intervention. Since chronic total occlusion (CTO) is a common disorder among patients with symptomatic infrapopliteal artery disease, infrapopliteal CTO intervention is now evolving rapidly in the field of endovascular intervention. Guidewire crossing through the CTO is essential for a successful procedure. We review up-to-date infrapopliteal CTO crossing techniques based on the current literature. PMID- 24754288 TI - Endovascular treatment of infrainguinal chronic total occlusions using the TruePath device: features, handling, and 6-month outcomes. AB - PURPOSE: To report experience with a recently approved peripheral chronic total occlusion (CTO) crossing device in the superficial femoral (SFA), popliteal, and below-the-knee (BTK) arteries. METHODS: Thirteen patients (all men; mean age 68.6+/-7.9 years) from the XLPAD registry (ClinicalTrials.gov identifier NCT01904851) were treated between April 2012 and August 2013 with the TruePath device after an unsuccessful guidewire crossing attempt. More than half of the patients had diabetes mellitus. Most lesions were TASC classification type C (n=5) or D (n=6), with mean lesion length 169.8+/-83.3 mm; 12 lesions were de novo and severely calcified. Procedure success was defined as successful revascularization of the CTO. Technical success was placement of a guidewire beyond the distal CTO cap into the true lumen without the need for a re-entry device. RESULTS: All CTOs were successfully crossed using the TruePath, but 3 subintimal recanalizations required the use of a re-entry device (77% technical success). Eight lesions were stented, while the remaining were treated with balloon angioplasty and/or atherectomy. Average fluoroscopy time was 41.1+/-18.3 minutes, during which a mean 200.0+/-46.2 mL of iodinated contrast were used (radiation dose area product 211.2+/-202.6 Gy*cm(2)). There were no periprocedural complications. Significant improvement was seen in the 6-month ankle-brachial index (p=0.018) and Rutherford class (p=0.019). The 6-month clinically indicated target vessel revascularization rate was 8%. CONCLUSION: TruePath facilitated successful crossing of infrainguinal CTOs following an unsuccessful guidewire recanalization, with significant improvement in symptoms and no complications. PMID- 24754289 TI - A sheathless retrograde approach via the popliteal artery is useful and safe for treating chronic total occlusions in the superficial femoral artery. AB - PURPOSE: To compare the safety and success of a retrograde approach using a microcatheter vs. a sheath in the treatment of superficial femoral artery (SFA) chronic total occlusions (CTOs). METHODS: From April 2007 to December 2012, 188 consecutive patients underwent EVT for 229 de novo SFA CTOs using the retrograde approach in 68 patients (35 men; mean age 72 years). This cohort was divided into cases performed with a 4-F or 6-F sheath (n=28, 36 limbs) and those with a 2.1-F microcatheter (n=35, 49 limbs). The primary outcomes were mean time to hemostasis and number of intra- and postoperative puncture site complications, as well as the success of popliteal artery puncture, lesion crossing, and reperfusion. RESULTS: There were no significant differences between two groups in baseline characteristics. PA puncture was successful in all limbs, and the success in crossing the lesion with the wire was not significantly different (91.9% in the sheath group vs. 89.8% in the microcatheter group). Mean time to hemostasis was 8.9+/-8.8 minutes in the microcatheter group vs. 47.7+/-13 minutes in the sheath group (p<0.0001). There was a significant difference in intraoperative and postoperative complications (22.2% in the sheath group vs. 2.0% in the microcatheter group, p=0.002). CONCLUSION: Based on this retrospective analysis, the use of a microcatheter for SFA CTO retrograde access appears to be superior to 4-F or 6-F sheaths in terms of shorter time to hemostasis and fewer complications. PMID- 24754290 TI - Hospital reimbursement for carotid stenting and endarterectomy. AB - PURPOSE: To investigate the cost-effectiveness of carotid endarterectomy (CEA) vs. carotid artery stenting (CAS) in terms of hospital reimbursement. METHODS: A retrospective analysis was conducted of hospital reimbursement for patients undergoing CEA and CAS from 1 January 2008 through 30 September 2010 at a single tertiary referral institution. Hospital cost and reimbursement were assessed using patient-specific data gathered by the institution's cost accounting system. Professional fees were excluded. RESULTS: Hospital reimbursement data were extracted for a total of 301 cases (169 CEA and 132 CAS). Mean hospital reimbursement was 16% higher for CAS ($12,000+/-$7372) vs. CEA ($10,160+/-$6840, p=0.02). However, because of the significantly higher cost of materials necessary to perform CAS, the net revenue for the hospital was 29% greater in patients undergoing CEA ($3487) vs. CAS ($2603). The differences in hospital reimbursement and net revenue were consistent in asymptomatic (n=183), symptomatic (n=123), and urgent (n=36) subgroups. When focusing on cases by diagnosis-related group (DRG) codes vs. current procedural terminology (CPT) codes, the data shifted. Several patients were coded as an outpatient procedure (DRG 0): 28 (21%) of the 132 CAS patients and 7 (4%) of the 169 CEA patients, reducing their mean reimbursement to $4046 and $2513, respectively. If these patients were excluded, the mean hospital reimbursement differential widened between and CEA ($10,515) and CAS ($13,825). CONCLUSION: Hospital reimbursement for CAS is significantly higher than that for CEA. While both procedures created net positive income for the hospital, CEA was associated with a 29% higher net revenue due to the 40% cost premium of CAS when looking at all carotid procedures. However, proper DRG coding of CAS cases would have likely resulted in similar net revenue. Asymptomatic patients had the lowest cost and highest net revenue of all the subgroups. Per capita, significantly more healthcare resources were expended with CAS when compared to CEA. Given the lack of improved clinical outcome in most cases, CAS cannot be considered cost effective for most patients. PMID- 24754291 TI - Commentary: carotid artery stenting: still not as cost-effective as carotid endarterectomy, but the contest continues. PMID- 24754292 TI - Challenging carotid intervention after total arch rerouting and hybrid zone 0 elephant trunk repair for a complicated type A aortic dissection. AB - PURPOSE: To report a challenging carotid intervention after total arch rerouting and hybrid zone 0 elephant trunk repair. CASE REPORT: A 54-year-old man developed symptomatic left carotid artery restenosis 2 weeks after total arch rerouting and hybrid zone 0 elephant trunk repair for acute retrograde type A aortic dissection with left carotid malperfusion. Because the origins of the 3 supra-aortic branches were already transected and rerouted to the proximal end of the reconstructed ascending aortic graft, the peripheral access routes for carotid intervention were deemed difficult, with little chance of success due to acute angles between these rerouted supra-aortic branches and the ascending aortic graft. Emergent carotid artery stenting was therefore performed via sternal reentry with successful restoration of cerebral perfusion. CONCLUSION: Total arch rerouting, facilitating hybrid endovascular repair for extensive thoracic aortic disease, creates an extremely deformed arch anatomy that renders subsequent carotid intervention a challenging task. PMID- 24754293 TI - Chimney technique for aortic arch pathologies: an 11-year single-center experience. AB - PURPOSE: To report our single-center experience with the chimney technique for aortic arch pathologies and the mid- to long-term results in these patients. METHODS: From June 2002 to May 2013, 26 patients (18 men; mean age 71.2 years, 53 86) underwent thoracic endovascular aortic repair (TEVAR) combined with chimney technique. Indications for treatment were: a proximal landing zone <15 mm long distal to the left subclavian artery (LSA), thoracic aortic aneurysm (n=13), complicated type B aortic dissection (n=10), type I endoleak after previous TEVAR (n=2), and penetrating aortic ulcer (n=1). Treatment was performed in the emergency setting in 7 cases. The 28 chimney stent-grafts (double chimneys in 2 patients) were deployed in the innominate artery (n=7), left common carotid artery (n=10), and LSA (n=11). All patients underwent computed tomography before discharge, at 1, 6, and 12 months, and yearly thereafter. RESULTS: Technical success was 100%. One (3.8%) perioperative death was due to a cerebral hemorrhage. No major stroke was registered, but 3 (11.5%) minor strokes occurred (all resolved). Paraparesis developed in 2 (7.7%) patients. Median follow-up was 36.8 months (range 1-131), during which an additional 4 (15.4%) patients died, but only 1 death was aneurysm-related. Chimney graft patency was 89.3% (25/28); an asymptomatic fracture was found in a patent chimney stent-graft at the 18 month follow-up. The type I endoleak rate was 23% (n=6); 3 endoleaks associated with aneurysm sac enlargement were treated. CONCLUSION: The chimney technique for aortic arch pathologies is safe and feasible and may be an option in patients considered at high risk for surgery or who are ineligible for conventional TEVAR, especially in the emergency setting. Concern persists regarding type I endoleak, and long-term follow-up remains mandatory. PMID- 24754294 TI - Endovascular treatment of isolated abdominal aortic dissections: long-term results. AB - PURPOSE: To examine long-term survival and freedom from reintervention after endovascular treatment of patients with isolated abdominal aortic dissections (IAAD). METHODS: A retrospective review was conducted of 21 patients (18 men; mean age 72+/-18 years, range 34-90) with an IAAD who underwent endovascular treatment between January 2000 and December 2012. Fourteen patients had spontaneous abdominal dissections, while 7 dissections were iatrogenic in origin. Thirteen patients with symptomatic acute (n=9) or subacute (n=4) lesions underwent analgesic therapy and medical management of systolic blood pressure for at least 5 days; persistent pain was an indication for endovascular treatment. Eight patients with chronic dissections were treated by endovascular means for co existent (1) abdominal aortic aneurysm (AAA) that was >5 cm in diameter or had expanded >5 mm in 6 months (n=6) or (2) rupture-threatening penetrating aortic ulcer (PAU, n=2) even with a diameter <5 cm. Mean dissection length was 45+/-12 mm (range 18-98). Ten patients received tube stent-grafts, 9 had bifurcated endografts, one had an aortouni-iliac (AUI) endoprosthesis, and one patient was treated with a bare metal stent. Follow-up included computed tomographic angiography within 1 month postoperatively, duplex ultrasound at 3 and 6 months, CTA at 12 months, and then annual duplex scans. RESULTS: Early (30-day) mortality was 0%; no major adverse events occurred during hospitalization. Patients with co existent AAA/PAU had complete exclusion of the aneurysm sac. The patient with an AUI graft suffered from an early stent-graft thrombosis in the abdominal aorta; flow was restored after transfemoral thrombectomy and balloon angioplasty of the common iliac artery. During a mean 73+/-22-month follow-up (range 19-144), 3 patients died due to unrelated causes (95% survival at a median 67 months estimated by Kaplan-Meier analysis). All patients showed full aortic remodeling over a period of 12 years. One patient with AAA underwent surgical conversion due to persistent type II endoleak (95% freedom from reintervention at a median 67 months). CONCLUSION: In this series, long-term evaluation of endovascular IAAD treatment found no mortality, few complications, and rare need for secondary interventions. PMID- 24754295 TI - Commentary: abdominal aortic dissection: a shift to endovascular treatment is probably justified. PMID- 24754296 TI - Technical challenges encountered during deployment of the ovation abdominal aortic stent-graft system. AB - PURPOSE: To describe technical challenges encountered using the Ovation endograft for abdominal aortic aneurysms and suggest tips and maneuvers for successful management. TECHNIQUE: Deployment of the Ovation's unsupported main body is often associated with the anteroposterior arrangement of the limb gates instead of the usual side-by-side configuration, rendering contralateral catheterization challenging. Successful catheterization of the contralateral limb can be confirmed by lateral deviation of the ipsilateral stiff guidewire caused by balloon inflation within the contralateral limb. Moreover, failure to cannulate the contralateral limb gate due to persistent impingement of the guidewire or compromise of the inflated rings can be overcome using the transbrachial antegrade approach. CONCLUSION: Awareness of certain aspects associated with the use of the Ovation device and adoption of the adjunctive techniques herein described helps the interventionist avoid unexpected challenges or manage technical difficulties to maximize the device's safety and effectiveness. PMID- 24754297 TI - Evaluation of visceral artery displacement by endograft delivery system insertion. AB - PURPOSE: To assess the displacement of the aorta and its visceral branch ostia after insertion of a rigid system including a stiff guidewire and endograft delivery system during endovascular aneurysm repair (EVAR). METHODS: Between January and May 2013, 20 consecutive patients (19 men; mean age 67.2 years, range 61-83) undergoing EVAR (n=13) or fenestrated EVAR (FEVAR, n=7) were prospectively enrolled. Each patient underwent an intraoperative contrast-enhanced cone beam computed tomography (ceCBCT) acquisition after the insertion of the endograft delivery system. Each ceCBCT was loaded on a workstation and manually registered with the preoperative computed tomographic angiogram (CTA) in a way that optimized superposition of the spine from both images. The locations of the superior mesenteric artery (SMA) and of both renal artery ostia were depicted in 3D multiplanar reconstructions by 3 independent operators on the CTA and on the ceCBCT. Motion of the aortic segment at the level of the visceral arteries was estimated by the barycenter of the origin of the SMA and both renal arteries. RESULTS: The ostium displacement between the CTA and ceCBCT images was 6.7 mm (range 2.2-13.5) for the SMA; 6.2 mm (2.5-13.5) and 6.4 mm (1.9-14.5) for the right and the left renal arteries, respectively; and 5.5 mm (2.3-11.4) for the aortic segment. The displacement was mostly posterosuperior and to the left (65%). The radiation dose and contrast volume required to perform the ceCBCT were 30% and 41%, respectively, of the amounts used in the EVAR procedures. CONCLUSION: This study demonstrates a significant displacement of the main aortic branches after rigid material insertion. Image fusion applications aimed at providing intraoperative guidance must allow an easy and rapid repositioning of the overlay during the procedure to match the deformation of the aortic anatomy during the procedure. PMID- 24754298 TI - Back-table modification of a bifurcated infrarenal stent-graft to aortomonoiliac for emergencies. AB - PURPOSE: To describe a simple and quick technique for converting a Zenith bifurcated stent-graft to an aortouni-iliac device for emergency treatment of hemorrhage when a suitable marketed stent-graft is not readily available. TECHNIQUE: The technique is described in an emergent case involving a 72-year-old man presenting with an aortoduodenal fistula and acute gastrointestinal bleeding. The Zenith device was prepared and flushed in the typical fashion. An extra stiff Lunderquist wire was advanced through the graft for better stability during the modification. The peel-away sheath was advanced beyond the hemostatic valve to allow partial release of the graft from the back then the grey positioner was retracted while the sheath was held firmly on the table, partially deploying the iliac limbs from the back side of the sheath. An occluding non-absorbable braided suture was placed at the short limb of the bifurcated graft close to the middle of the contralateral limb stent, through the webbing connecting both limbs below the flow divider of the bifurcated Zenith device. The graft was then resheathed using manual pinching of the graft or compression with umbilical tape. In the illustrated case, the stent-graft was intentionally deployed with the uncovered stents below the renal arteries to facilitate easier explantation later on. CONCLUSION: Back-table modification of stent-grafts is feasible in emergencies for operators familiar with all technical aspects and potential risks of the modifications. PMID- 24754299 TI - Acute type B dissection complicated by infrarenal aortic stent-graft collapse with spontaneous re-expansion. PMID- 24754300 TI - Atherectomy for superficial femoral artery in-stent restenosis: can lasers light the way to a better outcome? PMID- 24754301 TI - Hydrophobic poly (amino acid)-modified PEI-mediated delivery of single-chain antibody scFv1C9 inhibits HepG2 cell cycle process and xenograft growth in nude mice. AB - The safe and effective gene delivery vector remains the key step for gene therapy. Hydrophobic-modified Phe-PEI (PP80) was exhibited in advantage with biocompatibility and gene delivery with smaller size and easier penetration into cells and tissues. PP80 delivery of rev-casp-3 gene was demonstrated effectively to inhibit HeLa xenograft growth in our previous work. However, it was necessary to evaluate its applicability in other cells or tissues as gene carrier. Here, we quantitatively optimized the complex ratio of PP80 and plasmid DNA (pDNA) and evaluated the potential pyrogenicity by rabbit pyrogen test. In addition, PP80 mediated expression of scFv1C9 gene blocked HepG2 cell cycle progress in vitro. Subsequently, PP80-scFv1C9 was injected into HepG2 xenograft and significantly inhibited the xenograft growth in nude mice. Further investigation indicated that PP80 was an effective gene carrier and possible for entering hepatic xenograft. These features of PP80 made it attractive as a potential gene carrier for cancer therapy. PMID- 24754302 TI - Toward tailored functional design of multi-walled carbon nanotubes (MWNTs): electrochemical and antimicrobial activity enhancement via oxidation and selective reduction. AB - Multiwalled carbon nanotubes (MWNTs) are utilized in a number of sectors as a result of their favorable electronic properties. In addition, MWNT antimicrobial properties can be exploited or considered a potential liability depending on their intended application and handling. The ability to tailor electrochemical and antimicrobial properties using economical and conventional treatment processes introduces the potential to significantly enhance product performance. Oxygen functional groups are known to influence several MWNT properties, including redox activity. Here, MWNTs were functionalized with oxygen groups using standard acid treatments followed by selective reduction via annealing. Chemical derivatization coupled to X-ray photoelectron spectroscopy was utilized to quantify specific surface oxygen group concentration after variable treatment conditions, which were then correlated to observed trends in electrochemical and antimicrobial activities. These activities were evaluated as the potential for MWNTs to participate in the oxygen reduction reaction and to have the ability to promote the oxidation of glutathione. The compiled results strongly suggest that the reduction of surface carboxyl groups and the redox activity of carbonyl groups promote enhanced MWNT reactivity and elucidate the opportunity to design functional MWNTs for enhanced performance in their intended electrochemical or antimicrobial application. PMID- 24754304 TI - Ab initio molecular crystal structures, spectra, and phase diagrams. AB - Conspectus Molecular crystals are chemists' solids in the sense that their structures and properties can be understood in terms of those of the constituent molecules merely perturbed by a crystalline environment. They form a large and important class of solids including ices of atmospheric species, drugs, explosives, and even some organic optoelectronic materials and supramolecular assemblies. Recently, surprisingly simple yet extremely efficient, versatile, easily implemented, and systematically accurate electronic structure methods for molecular crystals have been developed. The methods, collectively referred to as the embedded-fragment scheme, divide a crystal into monomers and overlapping dimers and apply modern molecular electronic structure methods and software to these fragments of the crystal that are embedded in a self-consistently determined crystalline electrostatic field. They enable facile applications of accurate but otherwise prohibitively expensive ab initio molecular orbital theories such as Moller-Plesset perturbation and coupled-cluster theories to a broad range of properties of solids such as internal energies, enthalpies, structures, equation of state, phonon dispersion curves and density of states, infrared and Raman spectra (including band intensities and sometimes anharmonic effects), inelastic neutron scattering spectra, heat capacities, Gibbs energies, and phase diagrams, while accounting for many-body electrostatic (namely, induction or polarization) effects as well as two-body exchange and dispersion interactions from first principles. They can fundamentally alter the role of computing in the studies of molecular crystals in the same way ab initio molecular orbital theories have transformed research practices in gas-phase physical chemistry and synthetic chemistry in the last half century. In this Account, after a brief summary of formalisms and algorithms, we discuss applications of these methods performed in our group as compelling illustrations of their unprecedented power in addressing some of the outstanding problems of solid-state chemistry, high-pressure chemistry, or geochemistry. They are the structure and spectra of ice Ih, in particular, the origin of two peaks in the hydrogen-bond-stretching region of its inelastic neutron scattering spectra, a solid-solid phase transition from CO2-I to elusive, metastable CO2-III, pressure tuning of Fermi resonance in solid CO2, and the structure and spectra of solid formic acid, all at the level of second-order Moller-Plesset perturbation theory or higher. PMID- 24754303 TI - Rh(III)-catalyzed oxidative coupling of 1,2-disubstituted arylhydrazines and olefins: a new strategy for 2,3-dihydro-1H-indazoles. AB - A rhodium(III)-catalyzed oxidative olefination of 1,2-disubstituted arylhydrazines with alkenes via sp(2) C-H bond activation followed by an intramolecular aza-Michael reaction is described. This strategy allows the direct and efficient construction of highly substituted 2,3-dihydro-1H-indazole scaffolds. PMID- 24754305 TI - Cohort efficacy study of natural family planning among perimenopause age women. AB - OBJECTIVE: To determine the efficacy of using natural family planning (NFP) methods to avoid unintended pregnancy among women of perimenopause age (i.e., age 40-55 years). DESIGN: A secondary analysis of subset data from two prospective observational cohort studies. SETTING: A university based in-person and online NFP service program. PARTICIPANTS: One hundred and sixty couples who used either a website or an in-person NFP service to learn how to avoid pregnancy from January 2001 to November 2012. METHODS: A prospective 12-month effectiveness study among 160 women (between ages 40-55) who used NFP to avoid pregnancy. The women used either a hormonal fertility monitor, cervical mucus monitoring, or both to estimate the fertile phase of their menstrual cycles. Survival analysis was used to determine the pregnancy rate over 12 months of use. RESULTS: There were a total of five unintended pregnancies among the participants. The typical use pregnancy rate was six per 100 women over 12 months. The monitor alone participants (n = 35) had a 12-month pregnancy rate of three, the participants (n = 73) who used mucus alone had a pregnancy rate of four, and the participants (n = 42) who used the fertility monitor plus mucus had a pregnancy rate of six. CONCLUSION: Natural family planning methods can be effective for older women to avoid an unintended pregnancy with correct use and adequate instructions. The pregnancy rate most likely was affected by diminished fertility and motivation to limit family size. PMID- 24754306 TI - Endoscopic submucosal dissection for rectal carcinoid tumour using the Clutch Cutter. AB - BACKGROUND: To reduce the risk of complications related to endoscopic submucosal dissection (ESD) using knives, we developed the Clutch Cutter (CC), which can grasp and incise the target tissue similarly to biopsy techniques using an electrosurgical current. The aim of this study was to evaluate the efficacy and safety of ESD using the CC for removal of rectal carcinoid tumours. METHODS: Between December 2009 and December 2011, we prospectively enrolled seven patients (seven lesions) on 7 different days. Patients were endoscopically diagnosed with rectal subepithelial lesions (upper rectum, n = 3; lower rectum, n = 4) within the level 3 layer and without lymph node involvement, with the diagnosis confirmed by preliminary endoscopy, endoscopic ultrasound and endoscopic biopsies. ESD using the CC was performed in all cases, and the therapeutic efficacy, safety and tumour recurrence were assessed. RESULTS: All lesions were treated easily and safely, and there were no inadvertent incisions. En bloc resection was obtained in all cases, and histologic tumour-free lateral/basal margins were obtained in six of the seven patients. No delayed haemorrhage, perforation or tumour recurrence occurred. CONCLUSION: ESD using the CC appears to be an easy, safe and technically efficient method for resecting rectal carcinoid tumour. PMID- 24754307 TI - Transient depletion of specific immune cell populations to improve adenovirus mediated transgene expression in the liver. AB - BACKGROUND & AIMS: Adenoviral (Ad) vectors are currently one of the most efficient tools for in vivo gene transfer to the liver. However, anti-Ad immune responses limit the safety and efficacy of these vectors. The initial inflammatory reaction is a concern in terms of toxicity, and it favours the development of cellular and humoral responses leading to short transgene persistence and inefficient vector re-administrations. Therefore, safe and simple ways to interfere with these processes are needed. Study ways to deplete specific immune cell populations and their impact on liver-directed gene transfer. METHODS: First-generation Ad vectors encoding reporter genes (luciferase or beta galactosidase) were injected intravenously into Balb/c mice. Kupffer cells and splenic macrophages were depleted by intravenous administration of clodronate liposomes. B lymphocytes, CD4(+) , CD8(+) T lymphocytes or NK cells were depleted by intraperitoneal injection of anti-M plus anti-D, anti-CD4, anti-CD8 or anti asialo-GM1 antibodies respectively. Long-term evolution of luciferase expression in the liver was monitored by bioluminescence imaging. RESULTS: The anti-CD4 monoclonal antibody impaired cellular and humoral immune responses, leading to efficient vector re-administration. Clodronate liposomes had no impact on humoral responses but caused a 100-1000 fold increase in liver transduction, stabilized transgene expression, reduced the concentration of inflammatory cytokines, and inhibited lymphocyte activation. CONCLUSIONS: Transient CD4(+) T-cell depletion using antibodies is a clinically feasible procedure that allows efficient Ad redosing. Systemic administration of clodronate liposomes may further increase the safety and efficacy of vectors. PMID- 24754308 TI - Diagnostic value of MRI in dogs with inflammatory nasal disease. AB - OBJECTIVES: To determine the value of low-field magnetic resonance imaging in differentiating sino-nasal aspergillosis from lymphoplasmacytic rhinitis in dogs. METHODS: A retrospective study of 41 dogs (25 with lymphoplasmacytic rhinitis and 16 with sino-nasal aspergillosis) that underwent magnetic resonance imaging scan of the nasal cavity was conducted. On magnetic resonance imaging, turbinate destruction was classified as mild, moderate or severe. The cribriform plate and vomer destruction were classified as present or absent. The intensity of fluid accumulation and turbinates was classified on T1-weighted and T2-weighted images as hypointense, hyperintense and isointense based on the brightest area on the same slice. RESULTS: Turbinate destruction was significantly (P=0.005) associated with sino-nasal aspergillosis. On T1-weighted images, sino-nasal aspergillosis was associated with turbinate hyperintensity, while lymphoplasmacytic rhinitis was significantly (P=0.007) associated with hypointensity. On T2-weighted images, this feature was shown not to be relevant. CLINICAL SIGNIFICANCE: This study has demonstrated that turbinate destruction is the most reliable feature to differentiate sino-nasal aspergillosis from lymphoplasmacytic rhinitis and that T1-weighted image was the most useful sequence. PMID- 24754309 TI - Newly synthesized anticancer drug HUHS1015 is effective on malignant pleural mesothelioma. AB - The newly synthesized naftopidil analogue HUHS1015 reduced cell viability in malignant pleural mesothelioma cell lines MSTO-211H, NCI-H28, NCI-H2052, and NCI H2452, with the potential greater than that for the anticancer drugs paclitaxel or cisplatin at concentrations higher than 30 MUM. HUHS1015 induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. HUHS1015 upregulated expression of mRNAs for Puma, Hrk, and Noxa in MSTO-211H and NCI-H2052 cells, suggesting HUHS1015-induced mitochondrial apoptosis. HUHS1015 clearly suppressed tumor growth in mice inoculated with NCI-H2052 cells. Taken together, the results of the present study indicate that HUHS1015 could be developed as an effective anticancer drug for treatment of malignant pleural mesothelioma. PMID- 24754310 TI - Optimal medical therapy and percutaneous coronary intervention for stable angina: why patients should 'be taking' and 'keep taking' the tablets. AB - WHAT IS KNOWN AND OBJECTIVE: Cardioprotective drug regimens improve outcomes in patients with stable coronary artery disease. Revascularization is recommended for the persistence of symptoms despite optimal medical therapy (OMT) or in patients likely to derive prognostic benefit. Our objective is to comment on recent evidence that initiation of OMT is suboptimal in patients undergoing percutaneous coronary intervention (PCI) but conversely adherence to medication may be higher in patients treated with PCI. COMMENT: Large randomized controlled trials demonstrate that the risk of death or myocardial infarction is similar in patients treated by OMT alone and those treated with PCI and OMT. Despite the recommendations of international practice guidelines, OMT remains underutilized in recent analyses of patients referred for PCI. Notwithstanding the underutilization of proven therapies, a recent study suggests that adherence to medication is significantly higher in patients treated with PCI than in those treated with OMT alone. We discuss the potential factors that may contribute to underprescription of OMT and predict adherence in patients undergoing PCI. WHAT IS NEW AND CONCLUSION: Contemporary studies continue to demonstrate underutilization of OMT in patients referred for PCI but increased medication adherence in patients treated by PCI. We argue for increased recognition of OMT as the definitive treatment for stable angina, so that we can be sure those patients who require PCI 'are taking' and 'keep taking' the tablets. PMID- 24754311 TI - Electrochemotherapy as a novel treatment for primary cutaneous marginal zone B cell lymphomas. AB - In the present study, we describe the use of electrochemotherapy as alternative therapy for primary cutaneous marginal zone B-cell lymphomas in patients unsuitable for surgery or radiotherapy. Our experience refers to three patients with primary cutaneous marginal zone B-cell lymphomas related to Borrelia burgdorferi infection, treated with specific antimicrobial therapy and electrochemotherapy. PMID- 24754312 TI - Transgastric endoscopic biliary drainage in an old patient with complete ligation of the common bile duct at cholecystectomy. PMID- 24754313 TI - Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver selective thyroid hormone receptor agonist eprotirome. AB - BACKGROUND: Liver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. METHODS: We performed a multicentre, randomized, placebo controlled, double-blind study to evaluate the efficacy and safety of eprotirome, a liver-selective thyroid hormone receptor agonist, in 98 patients with primary hypercholesterolaemia. After previous drug wash-out and dietary run-in, patients received 100 or 200 MUg day(-1) eprotirome or placebo for 12 weeks. The primary end-point was change in serum LDL cholesterol; secondary end-points included changes in other lipid parameters and safety measures. RESULTS: Eprotirome treatment at 100 and 200 MUg daily reduced serum LDL cholesterol levels by 23 +/- 5% and 31 +/- 4%, respectively, compared with 2 +/- 6% for placebo (P < 0.0001). Similar reductions were seen in non-HDL cholesterol and apolipoprotein (apo) B, whereas serum levels of HDL cholesterol and apo A-I were unchanged. There were also considerable reductions in serum triglycerides and lipoprotein(a), in particular in patients with elevated levels at baseline. There was no evidence of adverse effects on heart or bone and no changes in serum thyrotropin or triiodothyronine, although the thyroxine level decreased. Low-grade increases in liver enzymes were evident in most patients. CONCLUSION: In hypercholesterolaemic patients, the liver-selective thyromimetic eprotirome decreased serum levels of atherogenic lipoproteins without signs of extra-hepatic side effects. Selective stimulation of hepatic thyroid hormone receptors may be an attractive way to modulate lipid metabolism in hyperlipidaemia. PMID- 24754314 TI - Onset and persistence of efficacy by symptom domain with long-acting injectable paliperidone palmitate in patients with schizophrenia. AB - INTRODUCTION: Several long-acting injectable (LAI) second-generation antipsychotics are now available for the management of schizophrenia. As patients with schizophrenia frequently present with diverse and challenging symptoms, it is important to understand the effects of antipsychotics in treating these different symptom subgroups and the timing of these responses. AREAS COVERED: For this review, data from two randomized, double-blind trials were analyzed in respect to the onset and persistence of effects on several measures of psychopathology (as measured by the Positive and Negative Syndrome Scale [PANSS]) after treatment with LAI paliperidone palmitate (PP) (NCT00590577 and NCT00589914). EXPERT OPINION: Symptom reductions from baseline with PP were significant by day 4 for all five PANSS factors in both studies. Some effects may have been driven by the presence or absence of a placebo response. A significant effect for PP versus placebo was observed for all major symptom domains for one or more doses of PP during the first month of treatment. Once established, most (but not all) significant responses persisted to the end point. Similar improvements were observed in PANSS scores with PP and oral risperidone. Dose dependent trends were observed for the effect of PP on positive, negative and uncontrolled hostility/excitement symptoms. PMID- 24754315 TI - Dolutegravir, abacavir and lamivudine as HIV therapy. AB - INTRODUCTION: Antiretroviral therapy has evolved dramatically and more potent, safer and convenient drugs have replaced former compounds. Dolutegravir (DTG) is the most recently approved integrase inhibitor. It displays attractive properties such as one pill once daily (QD) dosing, high barrier to resistance and clean safety profile. Moreover, it is planned to be marketed, co-formulated with abacavir (ABC) and lamivudine (3TC) as a single-tablet regimen (STR). The availability of this QD single pill represents a significant step further for a large number of HIV-infected persons. AREAS COVERED: Updated summary of evidence based information on efficacy and safety of DTG along with ABC and 3TC. All information available on antiretrovirals in the most advanced stages of clinical development reported in peer-reviewed journals or at international meetings has been reviewed. EXPERT OPINION: The combination of DTG, ABC and 3TC displays a high efficacy, superior to many other antiretroviral combinations, including other convenient STR. The good safety profile, low potential for drug interactions and high resistance barrier of DTG- ABC-3TC are unique features than make this co-formulation the preferred choice as HIV therapy in multiple clinical scenarios, including most treatment-naive and treatment-experienced patients, as part of switch strategies, and in patients with underlying serious medical conditions such as kidney abnormalities, liver disease, metabolic disturbances or neuropsychiatric conditions. PMID- 24754318 TI - The long-term effect of vagus nerve stimulation on quality of life in patients with pharmacoresistant focal epilepsy: the PuLsE (Open Prospective Randomized Long-term Effectiveness) trial. AB - OBJECTIVE: To evaluate whether vagus nerve stimulation (VNS) as adjunct to best medical practice (VNS + BMP) is superior to BMP alone in improving long-term health-related quality of life (HRQoL). METHODS: PuLsE (Open Prospective Randomized Long-term Effectiveness) was a prospective, randomized, parallel group, open-label, and long-term effectiveness study (conducted at 28 sites in Europe and Canada). Adults with pharmacoresistant focal seizures (n = 112) received VNS + BMP or BMP (1:1 ratio). Medications and VNS parameters could be adjusted as clinically indicated for optimal seizure control while minimizing adverse effects. Primary endpoint was mean change from baseline HRQoL (using Quality of Life in Epilepsy Inventory-89 total score; QOLIE-89). Secondary endpoints included changes in seizure frequency, responder rate (>=50% decrease in seizure frequency), Centre for Epidemiologic Studies Depression scale (CES-D), Neurological Disorders Depression Inventory-Epilepsy scale (NDDI-E), Clinical Global Impression-Improvement scale (CGI-I), Adverse Event Profile (AEP), and antiepileptic drug (AED) load. The study was prematurely terminated due to recruitment difficulties prior to completing the planned enrollment of n = 362. Results for n = 96 who had baseline and at least one follow-up QOLIE-89 assessment (from months 3-12) were included in this analysis. Mixed model repeated measures (MMRM) analysis of variance was performed on change from baseline for the primary and secondary endpoints. RESULTS: Significant between group differences in favor of VNS + BMP were observed regarding improvement in HRQoL, seizure frequency, and CGI-I score (respective p-values < 0.05, 0.03, and 0.01). More patients in the VNS + BMP group (43%) reported adverse events (AEs) versus BMP group (21%) (p = 0.01), a difference reflecting primarily mostly transient AEs related to VNS implantation or stimulation. No significant difference between treatment groups was observed for changes in CES-D, NDDI-E, AEP, and AED load. SIGNIFICANCE: VNS therapy as a treatment adjunct to BMP in patients with pharmacoresistant focal seizures was associated with a significant improvement in HRQoL compared with BMP alone. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24754319 TI - Effects of pyruvate on the energetics of rat ventricles stunned by ischemia reperfusion. AB - Pyruvate (Pyr) was proposed as an additive to cold high-K(+)-low-Ca(2+) cardioplegia (CPG) to protect the heart during surgery. We explored whether Pyr and CPG would work synergistically to protect rat hearts from stunning during ischemia-reperfusion (I/R). We measured the heat release and contractility of perfused ventricles during I/R, and the cytosolic and mitochondrial [Ca(2+)] in cardiomyocytes by confocal microscopy. We found that under cold-CPG (30 degrees C), 10 mmol.L(-1) Pyr reduced the post-ischemic contractile recovery (PICR) as well as muscle economy, when added either before ischemia or during I/R, which was reversed by blockade of UCam. In noncardioplegic hearts, Pyr was cardioprotective when it was present during I/R, more so at 37 degrees C than at 30 degrees C, with improved economy. In cardiomyocytes, the addition of Pyr to CPG slightly increased the mitochondrial [Ca(2+)] but decreased cytosolic [Ca(2+)]. The results suggest that Pyr only protects hearts from stunning when present before ischemia and during reperfusion, and that it dampens the cardioprotective properties of CPG. The mechanisms underlying such different behavior depend on the dynamic balance between Pyr stimulation of the energetic state and mitochondrial Ca(2+) uptake. Our results support the use of Pyr in stunned hearts, but not in cold high-K(+) cardioplegia. PMID- 24754320 TI - Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications. AB - Toll-like receptors (TLRs) form the major family of pattern recognition receptors (PRRs) that are involved in innate immunity. Innate immune responses against microorganisms at the maternal-fetal interface may have a significant impact on the success of pregnancy, as intrauterine infections have been shown to be strongly associated with certain complications of pregnancy. At the maternal fetal interface, TLRs are expressed not only in the immune cells but also in non immune cells such as trophoblasts and decidual cells; moreover, their expression patterns vary according to the stage of pregnancy. Here, we will update potential functions of TLRs in these cells, their recognition and response to microorganisms, and their involvement in the innate immunity. The impact of TLR mediated innate immune response will be discussed via animal model studies, as well as clinical observations. PMID- 24754321 TI - Competency-based medical education--is it being followed through? PMID- 24754322 TI - Biofilm community dynamics in bench-scale annular reactors simulating arrestment of chloraminated drinking water nitrification. AB - Annular reactors (ARs) were used to study biofilm community succession and provide ecological insight during nitrification arrestment through simultaneously increasing monochloramine (NH2Cl) and chlorine to nitrogen mass ratios, resulting in four operational periods (I-IV). Analysis of 16S rRNA-encoding gene sequence reads (454-pyrosequencing) examined viable and total biofilm communities and found total samples were representative of the underlying viable community. Bacterial community structure showed dynamic changes corresponding with AR operational parameters. Period I (complete nitrification and no NH2Cl residual) was dominated by Bradyrhizobium (total cumulative distribution: 38%), while environmental Legionella-like phylotypes peaked (19%) during Period II (complete nitrification and minimal NH2Cl residual). Nitrospira moscoviensis (nitrite oxidizing bacteria) was detected in early periods (2%) but decreased to <0.02% in later periods, corresponding to nitrite accumulation. Methylobacterium (19%) and members of Nitrosomonadaceae (42%) dominated Period III (complete ammonia and partial nitrite oxidation and low NH2Cl residual). An increase in Afipia (haloacetic acid-degrading bacteria) relative abundance (<2% to 42%) occurred during Period IV (minimal nitrification and moderate to high NH2Cl residual). Microbial community and operational data provided no evidence of taxa-time relationship, but rapid community transitions indicated that the system had experienced ecological regime shifts to alternative stable states. PMID- 24754323 TI - Electrospinning of poly(lactic acid)/polyhedral oligomeric silsesquioxane nanocomposites and their potential in chondrogenic tissue regeneration. AB - The study was conducted to evaluate the cytocompatibility and hydrolytic degradability of the new poly(lactic acid)/polyethylene glycol-polyhedral oligomeric silsesquioxane (peg-POSS/PLLA) nanocomposite as potential material for cartilage regeneration. PLLA scaffolds containing 0 to 5% of peg-POSS were fabricated by electrospinning. Human mesenchymal stem cells (hMSC's) were cultured in vitro to evaluate the cytocompatibility of the new nanocomposite material. Hydrolytic degradation studies were also carried out to analyze the mass loss rate of the nanocomposites through time. The addition of the peg-POSS to the PLLA did not affect the processability of the nanocomposite by electrospinning. It was also observed that peg-POSS did not show any relevant change in fibers morphology, concluding that it was well dispersed. However, addition of peg-POSS caused noticeable decrease in mean fiber diameter, which made the specific surface area of the scaffold to rise. hMSC's were able to attach, to proliferate, and to differentiate into chondrocytes in a similar way onto the different types of electrospun peg-POSS/PLLA and pure PLLA scaffolds, showing that the peg-POSS as nano-additive does not exhibit any cytotoxicity. The hydrolytic degradation rate of the material was lower when peg-POSS was added, showing a higher durability of the nanocomposites through time. Results demonstrate that the addition of peg-POSS to the PLLA scaffolds does not affect its cytocompatibility to obtain hyaline cartilage from hMSC's. PMID- 24754324 TI - Trust, commitment, love and sex: HIV, monogamy, and gay men. AB - Research on gay men's relationships has neglected monogamy. Instead, it has tended to (a) emphasize HIV risk and relationship agreements between partners regarding sex and condom use with outside partners or (b) focus on nonmonogamous relationships as emblematic of relationship innovation. On the basis of qualitative interviews with 36 gay Australian men who favored a monogamous relationship as ideal, this article explores the meaning and practice of monogamy and its association with HIV risk. The authors present themes that include men's use of condoms in monogamous relationships, expectations of fidelity, and understandings of trust and security as the basis to meaningful and satisfying relationships. PMID- 24754325 TI - Are polyploids really evolutionary dead-ends (again)? A critical reappraisal of Mayrose et al. (). PMID- 24754326 TI - In vivo reflectance confocal microscopy assessment of the therapeutic follow-up of cutaneous T-cell lymphomas causing scalp alopecia. AB - Cutaneous T-cell lymphomas involving the scalp and determining scarring alopecias are difficult to be followed up during treatment because of the peculiar anatomical site of onset. In vivo reflectance confocal microscopy has already been reported to be useful for cutaneous T-cell lymphoma evaluation and for therapeutic follow-up in inflammatory skin conditions. We describe a case of a 26 year-old man affected by cutaneous T-cell lymphoma affecting the scalp in which reflectance confocal microscopy demonstrated to be useful for in vivo evaluation of the therapeutic response to topical and systemic treatment. PMID- 24754327 TI - Resin bond to indirect composite and new ceramic/polymer materials: a review of the literature. AB - STATEMENT OF THE PROBLEM: Resin bonding is essential for clinical longevity of indirect restorations. Especially in light of the increasing popularity of computer-aided design/computer-aided manufacturing-fabricated indirect restorations, there is a need to assess optimal bonding protocols for new ceramic/polymer materials and indirect composites. PURPOSE OF THE STUDY: The aim of this article was to review and assess the current scientific evidence on the resin bond to indirect composite and new ceramic/polymer materials. MATERIALS AND METHODS: An electronic PubMed database search was conducted from 1966 to September 2013 for in vitro studies pertaining the resin bond to indirect composite and new ceramic/polymer materials. RESULTS: The search revealed 198 titles. Full-text screening was carried out for 43 studies, yielding 18 relevant articles that complied with inclusion criteria. No relevant studies could be identified regarding new ceramic/polymer materials. Most common surface treatments are aluminum-oxide air-abrasion, silane treatment, and hydrofluoric acid-etching for indirect composite restoration. Self-adhesive cements achieve lower bond strengths in comparison with etch-and-rinse systems. Thermocycling has a greater impact on bonding behavior than water storage. CONCLUSIONS: Air particle abrasion and additional silane treatment should be applied to enhance the resin bond to laboratory-processed composites. However, there is an urgent need for in vitro studies that evaluate the bond strength to new ceramic/polymer materials. CLINICAL SIGNIFICANCE: This article reviews the available dental literature on resin bond of laboratory composites and gives scientifically based guidance for their successful placement. Furthermore, this review demonstrated that future research for new ceramic/polymer materials is required. PMID- 24754328 TI - Feasibility of oral prenatal probiotics against maternal group B Streptococcus vaginal and rectal colonization. AB - OBJECTIVE: To examine the effect of an oral prenatal probiotic on group B Streptococcus (GBS) colonization and to demonstrate the feasibility of a larger randomized controlled trial. DESIGN: This pilot study was an open-label, two group quasi-experiment. SETTING: An urban central city nurse-midwifery and wellness center serving a diverse population. PARTICIPANTS: Ten pregnant participants received the oral probiotic (Florajen3) taken once daily, and 10 participants served as controls. METHODS: A questionnaire on dietary practices, vaginal cleansing, sexual history, and symptoms and GBS colony count samples were taken at 28-, 32-, and 36-weeks gestation. RESULTS: Participants in the probiotic group reported no adverse events or minor side effects; one half reported improved gastrointestinal symptoms. Although two women in each group had positive qualitative prenatal GBS cultures at 36 weeks, the probiotic group participants had lower quantitative GBS colony counts. The eight GBS negative averaged 90% probiotic adherence compared with two GBS positive women who averaged 68%. Yogurt ingestion was inversely related (p = .02) to GBS colonization. CONCLUSIONS: Prenatal probiotic therapy has the potential to reduce GBS colonization. The potential of the probiotic intervention appears to be linked to daily adherence. A controlled clinical trial with a larger, adequately powered sample is feasible and justified. PMID- 24754329 TI - Prevalence of female sexual dysfunction in urban chinese women based on cutoff scores of the Chinese version of the female sexual function index: a preliminary study. AB - INTRODUCTION: The Female Sexual Function Index (FSFI) remains the most widely used scale for screening female sexual dysfunction (FSD), and the Chinese Version of the FSFI (CVFSFI) has been validated, but cutoff scores for the CVFSFI to distinguish between cases and noncases have not been developed, so the real prevalence of FSD in China is unknown. AIM: To establish clinical cutoff scores for the CVFSFI and to evaluate the prevalence of FSD in urban Chinese women. METHODS: A cross-sectional study was conducted between June and December 2011. A total of 586 (age range of 22-60 years) women participated in the study. Receiving operating characteristic curve and classification and regression trees methodology were combined to establish clinical cutoff scores for the CVFSFI. The cutoff scores we developed were used to determine the prevalence of FSD in urban Chinese women. MAIN OUTCOME MEASURES: The prevalence of FSD based on cutoff scores developed herein. RESULTS: The optimal CVFSFI cutoff score for the FSFI total score was 23.45 (sensitivity = 66.9%; specificity = 72.7%; area under curve [AUC] = 0.75). The cutoff score for each domain was also established as follows: <=2.7 low desire (sensitivity = 55.2%; specificity = 78.3%; AUC = 0.73); <=3.15 arousal disorder (sensitivity = 62.1%; specificity = 76.9%; AUC = 0.74); <=4.05 lubrication disorder (sensitivity = 86.4%; specificity = 69.8%; AUC = 0.85); <=3.8 orgasm disorder (sensitivity = 83.3%; specificity = 74.2%; AUC = 0.85); and <=3.8 sexual pain (sensitivity = 65.4%; specificity = 80.6%; AUC = 0.79). Using these cutoff scores, we determined the prevalence for FSD, low desire, arousal disorder, lubrication disorder, orgasm disorder, and sexual pain to be 37.6%, 23.6%, 25.4%, 36.8%, 30.6%, and 21.8% in urban Chinese women, respectively. CONCLUSIONS: The present data may suggest that urban Chinese women might have a lower FSD prevalence than women from some other countries; however, further study to achieve a better understanding of its epidemiology in China is a high necessity. PMID- 24754330 TI - Powerful relaxation of phosphodiesterase type 4 inhibitor rolipram in the pig and human bladder neck. AB - INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors act as effective drugs for the treatment of lower urinary tract symptom (LUTS). There is a poor information, however, about the role of the PDE4 inhibitors on the bladder outflow region contractility. AIM: To investigate PDE4 expression and the relaxation induced by the PDE4 inhibitor rolipram versus that induced by the PDE5 blockers sildenafil and vardenafil, in the pig and human bladder neck. METHODS: Immunohistochemistry for PDE4 expression, myographs for isometric force recordings and fura-2 fluorescence for simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i ) and tension for rolipram in bladder neck samples were used. MAIN OUTCOME MEASURES: PDE4 expression and relaxations to PDE4 and PDE5 inhibitors and simultaneous measurements of [Ca2+]i and tension. RESULTS: PDE4 expression was observed widely distributed in the smooth muscle layer of the pig and human bladder neck. On urothelium-denuded phenylephrine (PhE) precontracted strips of pig and human, rolipram, sildenafil and vardenafil produced concentration-dependent relaxations with the following order of potency: rolipram> > sildenafil>vardenafil. In pig, the adenylyl cyclase activator forskolin potentiated rolipram-elicited relaxation, whereas protein kinase A (PKA) blockade reduced such effect. On potassium-enriched physiological saline solution (KPSS)-precontracted strips, rolipram evoked a lower relaxation than that obtained on PhE-stimulated preparations. Inhibition of large (BKCa ) and intermediate (IKCa ) conductance Ca2+ -activated K+ channels, neuronal voltage gated Ca2+ channels, nitric oxide (NO) and hydrogen sulfide (H2 S) synthases reduced rolipram responses. Rolipram inhibited the contractions induced by PhE without reducing the PhE-evoked [Ca2+]i increase. CONCLUSIONS: PDE4 is present in the pig and human bladder neck smooth muscle, where rolipram exerts a much more potent relaxation than that elicited by PDE5 inhibitors. In pig, rolipram-induced response is produced through the PKA pathway involving BKCa and IKCa channel activation and [Ca2+]i desensitization-dependent mechanisms, this relaxation also being due to neuronal NO and H2S release. PMID- 24754331 TI - Impact of iron supplementation on sexual dysfunction of women with iron deficiency anemia in short term: a preliminary study. AB - INTRODUCTION: Iron deficiency anemia (IDA) is a common micronutrient deficiency worldwide. It is an important health problem especially in women of reproductive age. IDA may cause anxiety, which is the major factor for female sexual dysfunction (FSD). AIM: The aim of the present study was to determine the impact of IDA on FSD in women of reproductive age. METHODS: In total, 207 women were enrolled. Women with IDA who were admitted in an outpatient clinic of family medicine were asked to complete Beck Anxiety Inventory (BAI), Female Sexual Function Index (FSFI), and Quality of Life (QoL) questionnaires. Questionnaires were completed before and after IDA treatments. Blood samples were obtained for measurements of hemoglobin, hematocrit, levels of serum iron, and iron-binding capacity. MAIN OUTCOME MEASURES: Outcomes of blood samples were used for diagnosing of IDA. BAI, FSFI, and QoL scores were evaluated. Paired samples t tests and Pearson correlation analyses were used to assess relationship between findings of IDA treatments and other parameters. RESULTS: The mean age was 33.6 +/- 8.4 years. There were statistical significant differences between pre- and posttreatment in terms of hemoglobin, hematocrit, serum iron, and serum iron binding capacity. BAI scores were decreased and FSFI scores, which were statistically significant, increased after IDA treatments (P < 0.001). However, QoL scores were developed without statistical significance. CONCLUSION: There is a risk for anxiety as well as FSD in IDA women of reproductive age. Treatment of IDA can significantly improve sexual functions and QoL in these women population in short term. PMID- 24754332 TI - Attachment styles in transsexual patients and clinical and nonclinical control groups: comment on Colizzi et al. PMID- 24754333 TI - Attachment styles in transsexual patients and clinical and nonclinical control groups: a response. PMID- 24754334 TI - Visual function and compensatory mechanisms for hemianopia after hemispherectomy in children. AB - OBJECTIVE: Little is known about the functional visual outcome of children after hemispherectomy. Several case reports have described an anomalous head posture (AHP) and exotropia (XT) contralateral to the side of early brain damage, as possible compensatory mechanisms (CMs) for homonymous hemianopia (HH). The aim of this study was to determine visual outcome and the prevalence of such CMs in hemispherectomized children. METHODS: Patient files from all children who underwent hemispherectomy and had a postoperative ophthalmologic examination in the University Medical Center (UMC) Utrecht up to October 2012 were retrospectively reviewed. Preoperative and postoperative clinical information on visual fixation, visual acuity, visual fields, optic discs, head posturing, ocular alignment, and cognitive development was collected. Clinical characteristics were compared between children who developed CMs and those who did not. RESULTS: Forty-five children (21 male) underwent a hemispherectomy (22 right) at a median age of 2.1 years. Median ophthalmologic follow-up was 2.3 years. After hemispherectomy, visual fixation was present in all children, and 87% of the examined children had a normal visual acuity or a mild visual impairment. All children who underwent a visual field measurement had an HH. Anomalous head posturing and continuous or intermittent XT contralateral to the side of hemispherectomy were found in 53% and 38% of children, respectively. Children with CMs had more frequently right-sided surgery and earlier onset of epilepsy, and they tended to be younger when they underwent hemispherectomy than children without. SIGNIFICANCE: Despite HH, the majority of children who undergo hemispherectomy have a good visual outcome. Furthermore, they frequently develop AHP and continuous or intermittent XT contralateral to the hemispherectomy as part of a coping strategy to optimize the functional visual field. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24754335 TI - Variants in the circle of Willis and white matter disease in Ecuadorian Mestizos. AB - BACKGROUND AND PURPOSE: Studies on Whites and Asians have shown contradictory results on the association between an incomplete circle of Willis (CoW) and white matter disease (WMD). We evaluated such relationship in Ecuadorian Mestizos. METHODS: Ecuadorian Mestizos aged >=40 years were evaluated with MRI and MRA. WMD was graded according to the modified Fazekas' scale, and the CoW was classified as complete or incomplete according to the presence or absence of one A1 segment of the anterior cerebral artery or one or both P1 segments of posterior cerebral arteries. RESULTS: A total of 315 persons (mean age 64.7 +/- 13.4 years, 56.5% women) were prospectively enrolled over 6 months. MRAs revealed a complete CoW in 65.1%, and MRIs showed WMD in 62.5% of cases. Irrespective of age and sex, incompleteness of the CoW was not associated with a higher prevalence or severity of WMD. In contrast, age was an independent risk factor for the occurrence of WMD. CONCLUSIONS: In the Ecuadorian Mestizo population, WMD occurrence and severity do not seem to be related to incompleteness of the CoW. PMID- 24754336 TI - CD10 is useful to identify gastrointestinal contamination in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology from pancreatic ductal adenocarcinoma. AB - OBJECTIVE: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology is an effective tool to diagnose pancreatic ductal adenocarcinoma (PDA). Standard morphological criteria are usually reliable. When contaminating gastrointestinal (GI) epithelial cells are prevalent among neoplastic cells, these can be highlighted by carcinoembryonic antigen (CEA) staining. CD10 is a cell-surface metallopeptidase normally expressed by the GI epithelial apical border, whose expression is decreased or lost in PDA. We included CD10 in a panel, together with CEA, to discriminate the GI contaminant cells from PDA cells on cell blocks. METHODS: Eight cases of EUS-FNA of PDA, featuring both contaminating GI cells and neoplastic cells, whose corresponding cell blocks were available for immunostaining, were selected. CD10 and CEA were stained on cell blocks by standard methods. RESULTS: CD10 strongly labelled only the GI cells, with a well defined apical membrane signal; conversely, GI cells did not show CEA staining; benign duodenal cells were faintly labelled in only one case. Malignant cells were positive for CEA and negative for CD10, with the exception of one case with labelled neoplastic cells with weak diffuse cytoplasmic positivity. CD10 apical membrane staining was a feature only seen in benign GI cells. CONCLUSIONS: As a loss of CD10 is a consistent feature of PDA, this marker can be useful, together with CEA, to aid the cytopathologist to identify neoplastic cells in a background rich in GI contaminant cells. PMID- 24754337 TI - Effect of a Mediterranean diet during pregnancy on fetal growth and preterm delivery: results from a French Caribbean Mother-Child Cohort Study (TIMOUN). AB - BACKGROUND: Recent studies suggest that a Mediterranean dietary pattern during pregnancy may influence pregnancy outcomes. The aim of this study was to evaluate the effect of adherence to a Mediterranean diet (MD) during pregnancy on fetal growth restriction (FGR) and preterm delivery (PTD) in a French Caribbean island where the population is largely of African descent and presents dietary patterns similar to MD. METHODS: Using data from the TIMOUN Mother-Child Cohort Study conducted in Guadeloupe (French West Indies) between 2004 and 2007, we analysed data for 728 pregnant women who delivered liveborn singletons without any major congenital malformations. Degree of adherence to MD during pregnancy was evaluated with a semi-quantitative food frequency questionnaire based on nine dietary criteria. Multiple logistic regression models were used to analyse birth outcomes while taking potential confounders into account. RESULTS: Overall there was no association between MD adherence during pregnancy and the risk of PTD or FGR. However, pre-pregnancy body mass index was a strong effect modifier, and MD adherence was associated with a decreased risk of PTD specifically in overweight and obese women (adjusted odds ratio 0.7, 95% confidence interval 0.6, 0.9) (P heterogeneity <0.01). CONCLUSIONS: These results suggest that Caribbean diet during pregnancy may carry some benefits of MD and may contribute to reduce the risk of PTD in overweight and obese pregnant women. PMID- 24754338 TI - Amphipathic homopolymers for siRNA delivery: probing impact of bifunctional polymer composition on transfection. AB - In this study, we systematically explore the influence of the lipophilic group on the siRNA transfection properties of the polycationic-based delivery vectors. For this, a novel and modular synthetic strategy was developed for the preparation of polymers carrying a cationic site and a lipophilic group at each polymer repeat unit. These bifunctional polymers could form a complex with siRNA and deliver it to human colon carcinoma cells (HT-29-luc). In general, transfection capability increased with an increase in the chain length of the lipophilic moiety. The best transfection agent, a polymer containing ammonium groups and pentyl side chains, exhibited lower toxicity and higher transfection efficiency than branched and linear polyethylenimines (PEI). Moreover, as opposed to PEI, the transfection efficiency of polymer/siRNA complexes remained unchanged in the presence of bafilomycin A1, a proton pump inhibitor, suggesting that the present system did not rely on the "proton sponge" effect for siRNA delivery. PMID- 24754339 TI - Ecological traits influence the phylogenetic structure of bird species co occurrences worldwide. AB - The extent to which species' ecological and phylogenetic relatedness shape their co-occurrence patterns at large spatial scales remains poorly understood. By quantifying phylogenetic assemblage structure within geographic ranges of >8000 bird species, we show that global co-occurrence patterns are linked - after accounting for regional effects - to key ecological traits reflecting diet, mobility, body size and climatic preference. We found that co-occurrences of carnivorous, migratory and cold-climate species are phylogenetically clustered, whereas nectarivores, herbivores, frugivores and invertebrate eaters tend to be more phylogenetically overdispersed. Preference for open or forested habitats appeared to be independent from the level of phylogenetic clustering. Our results advocate for an extension of the tropical niche conservatism hypothesis to incorporate ecological and life-history traits beyond the climatic niche. They further offer a novel species-oriented perspective on how biogeographic and evolutionary legacies interact with ecological traits to shape global patterns of species coexistence in birds. PMID- 24754340 TI - Managing student anxiety during curriculum change. PMID- 24754341 TI - Template-based lymphadenectomy in urothelial carcinoma of the renal pelvis: a prospective study. AB - OBJECTIVES: Recent studies showed the therapeutic benefit of lymphadenectomy in advanced stage urothelial carcinoma of the upper urinary tract, but there is still a lack of prospective studies and standardization of the extent of lymphadenectomy. The aim of this multi-institutional study was to examine the role of lymphadenectomy in urothelial carcinoma of the upper urinary tract. METHODS: From January 2005 to September 2012, 77 patients undergoing nephroureterectomy and lymphadenectomy for non-metastatic (cN0M0) urothelial carcinoma of the upper urinary tract were included in a prospective study at two Japanese institutions(lymphadenectomy group). Lymphadenectomies were carried out according to definite anatomical template. Results from this group were compared with those from a control group of 89 patients who did not receive lymphadenectomy during the study period (no lymphadenectomy group). RESULTS: In patients with urothelial carcinoma of the upper urinary tract in the renal pelvis of pathological stage 2 or higher, template-based lymphadenectomy resulted in significantly higher cancer-specific survival (89.8% and 51.7%, P = 0.01) and overall survival (86.1% and 48.0%, P = 0.01). Disease-free survival tended to be higher in the lymphadenectomy group(77.8% and 50.0%, P = 0.06). Template-based lymphadenectomy was a significant independent factor for reducing the risk of cancer death in patients with renal pelvic cancer of >= pT2 by multivariate analysis. In contrast, cancer-specific survival of patients with ureteral urothelial carcinoma of the upper urinary tract was not significantly different between the lymphadenectomy and no lymphadenectomy groups. CONCLUSIONS: This multi-institutional prospective study further supports the therapeutic role of template-based lymphadenectomy in patients with advanced-stage urothelial carcinoma of the upper urinary tract in the renal pelvis. This is not the case for patients with ureteral urothelial carcinoma of the upper urinary tract. PMID- 24754342 TI - Tuning of automatic exposure control strength in lumbar spine CT. AB - OBJECTIVE: To investigate the impact of tuning the automatic exposure control (AEC) strength curve (specific to Care Dose 4D(r); Siemens Healthcare, Forchheim, Germany) from "average" to "strong" on image quality, radiation dose and operator dependency during lumbar spine CT examinations. METHODS: Two hospitals (H1, H2), both using the same scanners, were considered for two time periods (P1 and P2). During P1, the AEC curve was "average" and radiographers had to select one of two protocols according to the body mass index (BMI): "standard" if BMI <30.0 kg m( 2) (120 kV-330 mAs) or "large" if BMI >30.0 kg m(-2) (140 kV-280 mAs). During P2, the AEC curve was changed to "strong", and all acquisitions were obtained with one protocol (120 kV and 270 mAs). Image quality was scored and patients' diameters calculated for both periods. RESULTS: 497 examinations were analysed. There was no significant difference in mean diameters according to hospitals and periods (p > 0.801) and in quality scores between periods (p > 0.172). There was a significant difference between hospitals regarding how often the "large" protocol was assigned [13 (10%)/132 patients in H1 vs 37 (28%)/133 in H2] (p < 0.001). During P1, volume CT dose index (CTDIvol) was higher in H2 (+13%; p = 0.050). In both hospitals, CTDIvol was reduced between periods (-19.2% in H1 and 29.4% in H2; p < 0.001). CONCLUSION: An operator dependency in protocol selection, unexplained by patient diameters or highlighted by image quality scores, has been observed. Tuning the AEC curve from average to strong enables suppression of the operator dependency in protocol selection and related dose increase, while preserving image quality. ADVANCES IN KNOWLEDGE: CT acquisition protocols based on weight are responsible for biases in protocol selection. Using an appropriate AEC strength curve reduces the number of protocols to one. Operator dependency of protocol selection is thereby eliminated. PMID- 24754343 TI - Closed incision management with negative pressure wound therapy. AB - Post-sternotomy mediastinitis is the most severe surgical site infection after sternotomy with an incidence between 1-4% related to the patient co-morbidity. This complication will increase morbidity and mortality and may also have an economic impact. There are guidelines to prevent surgical site infections; however, age and co-morbidities increase and therefore it is important to develop new tools to improve wound healing. This manuscript will give an overview of a new concept using negative pressure wound therapy over a closed incision (so called, closed incision management) after surgery and will include the principles of negative pressure wound therapy and the positively applied mechanical forces as a permutation of Wolff's law. The use and indication of this therapy is supported by experimental studies divided into physiological and biomechanical property studies. Finally, an overview of clinical studies is given based on the evidence rating scale for therapeutic studies. PMID- 24754344 TI - Erection of Ceratonova n. gen. (Myxosporea: Ceratomyxidae) to encompass freshwater species C. gasterostea n. sp. from threespine stickleback (Gasterosteus aculeatus) and C. shasta n. comb. from salmonid fishes. AB - Ceratonova gasterostea n. gen. n. sp. is described from the intestine of freshwater Gasterosteus aculeatus L. from the Klamath River, California. Myxospores are arcuate, 22.4 +/- 2.6 MUm thick, 5.2 +/- 0.4 MUm long, posterior angle 45 degrees +/- 24 degrees , with 2 sub-spherical polar capsules, diameter 2.3 +/- 0.2 MUm, which lie adjacent to the suture. Its ribosomal small subunit sequence was most similar to an intestinal parasite of salmonid fishes, Ceratomyxa shasta (97%, 1,671/1,692 nucleotides), and distinct from all other Ceratomyxa species (<85%), which are typically coelozoic parasites in the gall bladder or urinary system of marine fishes. We propose erection of genus Ceratonova to contain both intestinal, freshwater species and reassign the salmonid parasite as Ceratonova shasta n. comb. PMID- 24754345 TI - Total syntheses of leuconoxine, leuconodine B, and melodinine E by oxidative cyclic aminal formation and diastereoselective ring-closing metathesis. AB - Total syntheses of leuconodine B, melodinine E, and leuconoxine were accomplished via a divergent route. The [5.5.6.6]diazafenestrane skeleton was constructed from an indole-3-acetamide derivative via DMDO oxidation to hydroxylindolenine, TMSOTf/2,6-lutidine mediated cyclic aminal formation, and diastereoseletive ring closing metathesis of a triene derivative. PMID- 24754346 TI - Nanopesticides: guiding principles for regulatory evaluation of environmental risks. AB - Nanopesticides or nano plant protection products represent an emerging technological development that, in relation to pesticide use, could offer a range of benefits including increased efficacy, durability, and a reduction in the amounts of active ingredients that need to be used. A number of formulation types have been suggested including emulsions (e.g., nanoemulsions), nanocapsules (e.g., with polymers), and products containing pristine engineered nanoparticles, such as metals, metal oxides, and nanoclays. The increasing interest in the use of nanopesticides raises questions as to how to assess the environmental risk of these materials for regulatory purposes. Here, the current approaches for environmental risk assessment of pesticides are reviewed and the question of whether these approaches are fit for purpose for use on nanopesticides is addressed. Potential adaptations to existing environmental risk assessment tests and procedures for use with nanopesticides are discussed, addressing aspects such as analysis and characterization, environmental fate and exposure assessment, uptake by biota, ecotoxicity, and risk assessment of nanopesticides in aquatic and terrestrial ecosystems. Throughout, the main focus is on assessing whether the presence of the nanoformulation introduces potential differences relative to the conventional active ingredients. The proposed changes in the test methodology, research priorities, and recommendations would facilitate the development of regulatory approaches and a regulatory framework for nanopesticides. PMID- 24754347 TI - Management of a facial talon cusp on a maxillary permanent central incisor: a case report and review of the literature. AB - BACKGROUND: A talon cusp is a morphologically well-delineated accessory cusp. This case report discusses the unusual appearance of a talon cusp on the facial surface of the maxillary right permanent central incisor, which was conservatively treated and followed up for a period of 1 year. METHODS: A 21-year old female was referred for the treatment of a maxillary right central incisor that caused an esthetic problem. Intraoral examination and radiographic and computerized tomographic investigation indicated that there was no connection between the pulp chamber, a "V"-shaped radiopaque structure, and three radiolucent globe areas. The accessory cusp was treated by selective cuspal grinding, followed by resin-based composite placement. The restoration was clinically evaluated 1 week after placement, as a baseline, and after 1 year. The restoration did not exhibit postoperative sensitivity at the 1-year evaluation. No difference was observed in the color match, marginal discoloration, marginal adaptation, or anatomic form compared with the baseline evaluation. CONCLUSION: The management and treatment outcome of a talon cusp depends on its size, presenting complications and patient cooperation. The present case report outlines the conservative management of a talon cusp. CLINICAL SIGNIFICANCE: This paper outlines a viable esthetic treatment option and a review of the relevant literature with regards to managing a facial talon cusp. PMID- 24754348 TI - Silver nanoparticle-embedded poly(vinyl pyrrolidone) hydrogel dressing: gamma-ray synthesis and biological evaluation. AB - Silver nanoparticle (nAg)-embedded poly(vinyl pyrrolidone) (PVP) hydrogels, to be used as antibacterial wound dressings, were prepared by gamma-irradiation at various doses: 25, 35, and 45 kGy. The formation and characteristics of the silver nanoparticles were investigated with a UV-vis spectrophotometer, transmission electron microscopy, and scanning electron microscopy with energy dispersive X-ray. The hydrogels were characterized for physical and biological properties. Based on the antibacterial determination, the 1 and 5 mM nAg-embedded PVP hydrogels were effective, with 99.99% bactericidal activity at 12 and 6 h, respectively. The indirect cytotoxicity evaluation based on 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated that both the neat and the nAg-embedded PVP hydrogels were non-toxic to mouse fibroblasts (L929). The 5 mM nAg-embedded PVP hydrogels not only provided a clean, moist environment for wound healing, but also effectively prevented bacterial infection and enhanced wound recovery. PMID- 24754349 TI - Healthcare resource use and relapses with fingolimod versus natalizumab for treating multiple sclerosis: a retrospective US claims database analysis. AB - OBJECTIVE: Healthcare resource utilization in patients with multiple sclerosis (MS) is linked to relapses and disease progression. This retrospective cohort database analysis compared healthcare resource use and proxy measures of relapse outcomes in patients with active disease who switched to fingolimod or natalizumab. METHODS: Using administrative claims data from the US PharMetrics Plus database, we identified patients with an MS diagnosis and a claim for fingolimod or natalizumab between 1 October 2010 and 30 June 2012 (index period) who had experienced a relapse (identified using a claims-based algorithm) and used other disease-modifying therapies (DMTs) in the previous year. Patients in the fingolimod and natalizumab cohorts were propensity score matched (1:1). MS related inpatient stays, corticosteroid use and the proportion of patients experiencing claims-based relapses were assessed in the pre-index and post-index persistence periods. Time to first claims-based relapse in the post-index persistence period was assessed using a Kaplan-Meier curve. RESULTS: The study included 623 unmatched patients (299 and 324 patients in the fingolimod and natalizumab cohorts, respectively) and 370 matched patients (185 in each cohort). In the matched analysis, MS-related inpatient stays and corticosteroid use were similar in the fingolimod and natalizumab cohorts during the post-index persistence period, and were significantly reduced versus the pre-index period (p < 0.01). A similar proportion of patients in the fingolimod and natalizumab cohorts were free from claims-based relapses in the persistence period (68.1% and 68.6%, respectively). There was no significant difference in the likelihood of experiencing a claims-based relapse (p = 0.8696). LIMITATION: Identification of relapses is based on database claims rather than on clinical assessment. CONCLUSIONS: In analyses of patients with MS with a history of relapse and DMT use, fingolimod and natalizumab reduce healthcare resource utilization and have similar effectiveness in a real-world setting. PMID- 24754350 TI - Early botulinum toxin treatment for spastic pes equinovarus--a randomized double blind placebo-controlled study. AB - BACKGROUND AND PURPOSE: Spastic pes equinovarus is a frequent pathological posture of the lower extremity. Botulinum toxin (BoNT/A) has been successfully applied to treat lower limb spasticity. However, the best time to initiate treatment remains unclear. A beneficial effect of an early treatment has been suggested in previous studies. METHODS: A single-centre double-blind randomized placebo-controlled trial was performed to investigate the efficacy of BoNT/A to reduce muscle hypertonicity at the ankle. Fifty-two patients with unilateral or bilateral spastic pes equinovarus with a modified Ashworth score (mAS) of at least 1+ after stroke, traumatic brain injury or hypoxic encephalopathy were allocated to receive either BoNT/A or placebo treatment. A second, open injection was optional at week 12. Patients received unilateral or bilateral injections with 230 or 460 U onabotulinumtoxinA, respectively. The course of the mAS was explored during the open study phase. RESULTS: Patients who had received BoNT/A treatment had lower mAS compared with placebo at week 12 (P < 0.01). During the open label phase, patients from the placebo group showed further deterioration of muscle tone despite starting from a similar baseline and receiving BoNT treatment. Spastic feet that had received BoNT/A in the first cycle had comparatively lower mAS scores over all follow-up data and at week 24 (P < 0.01). CONCLUSIONS: The study demonstrates a reduction of muscular hypertonicity in spastic pes equines with BoNT/A treatment given during the first 3 months after the lesion. Exploratory analyses of the course of muscular hypertonicity during the open phase favour earlier to later treatment. PMID- 24754351 TI - Association between penile dynamic contrast-enhanced MRI-derived quantitative parameters and self-reported sexual function in patients with newly diagnosed prostate cancer. AB - INTRODUCTION: The high incidence of prostate cancer, coupled with excellent prostate cancer control rates, has resulted in growing interest in nononcological survivorship issues such as sexual function. Multiparametric magnetic resonance imaging (MRI) is increasingly being performed for local staging of prostate cancer, and due to the close anatomical relationship to the prostate, penile enhancement is often depicted in prostate MRI. AIM: To evaluate the associations between quantitative perfusion-related parameters derived from dynamic contrast enhanced (DCE)-MRI of the penis and self-reported sexual function in patients with newly diagnosed prostate cancer. METHODS: This retrospective study included 50 patients who underwent DCE-MRI for prostate cancer staging before prostatectomy. The following perfusion-related parameters were calculated: volume transfer constant (K(trans)), rate constant (k(ep)), extracellular-extravascular volume fraction (v(e)), contrast enhancement ratio (CER), area under the gadolinium curve after 180 seconds (AUC180), and slope of the time/signal intensity curve of the corpora cavernosa. Associations between perfusion-related parameters and self-reported sexual function were evaluated using the Wilcoxon Rank-Sum test. MAIN OUTCOME MEASURES: Patient responses to the sexual function domain of the Prostate Quality of Life survey. RESULTS: Five of the six DCE-MRI parameters (K(trans), v(e), CER, AUC180, and slope) were significantly associated with the overall score from the sexual domain of the survey (P = 0.0020-0.0252). CER, AUC180, and slope were significantly associated with the answers to all six questions (P = 0.0020-0.0483), ve was significantly associated with the answers to five of six questions (P = 0.0036-0.1029), and K(trans) was significantly associated with the answers to three of six questions (P = 0.0252-0.1023). k(ep) was not significantly associated with the overall survey score (P = 0.7665) or the answers to any individual questions (P = 0.4885-0.8073). CONCLUSION: Penile DCE-MRI parameters were significantly associated with self-reported sexual function in patients with prostate cancer. These parameters are readily available when performing prostate MRI for staging and may be relevant to the management of patients considering prostate cancer therapies. PMID- 24754352 TI - A proteomic approach reveals new actors of nodule response to drought in split root grown pea plants. AB - Drought is considered the more harmful abiotic stress resulting in crops yield loss. Legumes in symbiosis with rhizobia are able to fix atmospheric nitrogen. Biological nitrogen fixation (SNF) is a very sensitive process to drought and limits legumes agricultural productivity. Several factors are known to regulate SNF including oxygen availability to bacteroids, carbon and nitrogen metabolisms; but the signaling pathways leading to SNF inhibition are largely unknown. In this work, we have performed a proteomic approach of pea plants grown in split-root system where one half of the root was well-irrigated and the other was subjected to drought. Water stress locally provoked nodule water potential decrease that led to SNF local inhibition. The proteomic approach revealed 11 and 7 nodule proteins regulated by drought encoded by Pisum sativum and Rhizobium leguminosarum genomes respectively. Among these 18 proteins, 3 proteins related to flavonoid metabolism, 2 to sulfur metabolism and 3 RNA-binding proteins were identified. These proteins could be molecular targets for future studies focused on the improvement of legumes tolerance to drought. Moreover, this work also provides new hints for the deciphering of SNF regulation machinery in nodules. PMID- 24754353 TI - A common microdeletion affecting a hippocampus- and amygdala-specific isoform of tryptophan hydroxylase 2 is not associated with affective disorders. AB - OBJECTIVES: Copy number variants (CNVs) have been shown to affect susceptibility for neuropsychiatric disorders. To date, studies implicating the serotonergic system in complex conditions have just focused on single nucleotide polymorphisms (SNPs). We therefore sought to identify novel common genetic copy number polymorphisms affecting genes of the serotonergic system, and to assess their putative role in bipolar affective disorder (BPAD) and major depressive disorder (MDD). METHODS: A selection of 41 genes of the serotonergic system encoding receptors, the serotonin transporter, metabolic enzymes and chaperones were investigated using a paired-end mapping (PEM) approach on next-generation sequencing data from the pilot project of the 1000 Genomes Project. For association testing, 593 patients with MDD, 1,145 patients with BPAD, and 1,738 healthy controls were included in the study. RESULTS: PEM led to the identification of a microdeletion in the gene encoding tryptophan hydroxylase 2 (TPH2), affecting an amygdala- and hippocampus-specific isoform. It was not associated with BPAD or MDD using a case-control association approach. CONCLUSIONS: We did not find evidence for a role of the TPH2 microdeletion in the pathoetiology of affective disorders. Further studies examining its putative role in behavioral traits regulated by the limbic system are warranted. PMID- 24754354 TI - Copper(II) and gallium(III) complexes of trans-bis(2-hydroxybenzyl) cyclen derivatives: absence of a cross-bridge proves surprisingly more favorable. AB - Two cyclen (1,4,7,10-tetraazacyclododecane) derivatives bearing trans-bis(2 hydroxybenzyl) arms, the 1,7-(2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane (H2do2ph) and its cross-bridged counterpart (H2cb-do2ph), have been synthesized, aiming toward the possible use of their copper(II) and gallium(III) complexes in nuclear medicine. The protonation of both compounds was studied in aqueous solution as well as their complexes with Cu(2+) and Ga(3+) cations. The complexes of both ligands with Ca(2+) and Zn(2+) metal ions were also studied due to the abundance of these cations in biological media. In mild conditions the complexes of Ca(2+) and Ga(3+) with H2cb-do2ph did not form. The behavior of the two ligands and their complexes was compared by the values of the equilibrium constants, the data of varied spectroscopic techniques, the values of redox potentials of their copper(II) complexes, and the resistance of the complexes to acid dissociation. It was expected that, as found for related pairs of cyclen and cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives, the cross-bridged macrocyclic derivative could be an excellent ligand for the complexation of copper(II). Additionally, the N-2-hydroxybenzyl groups were chosen due to their known ability to coordinate the gallium(III) cation. Due to the small size of the latter cation and its particular propensity to form hexacoordinate complexes, it was also expected that there would be a good ability of both ligands for the uptake of Ga(3+). Surprisingly, the results revealed that the cyclen derivative H2do2ph is the best ligand for the coordination of Cu(2+) and Ga(3+) cations, not only from their thermodynamic stability as expected but also from their kinetic inertness, when compared with its cross-bridged counterpart. PMID- 24754355 TI - Dermatological conditions presenting at the Emergency Department in Siena University Hospital from 2006 to 2011. AB - BACKGROUND: Published studies on emergency dermatology consultations are few because there are few dermatology emergency units in the world. No study has yet described the Italian situation. OBJECTIVES: To quantify and characterize patients evaluated in our dermatology emergency unit from 2006 to 2011. METHODS: We studied personal details, diagnosis, annual trend of cases, emergency level and hospitalization of dermatology cases over the 6-year period. RESULTS: A total of 12,226 patients were evaluated. The most numerous diagnostic group was infections (27.1%), followed by non-specific and descriptive diagnosis (22.5%), skin conditions caused by mechanical or physical agents (13.1%), eczematous diseases (10.5%), insect bites (9.5%) and urticaria/angio-oedema (8.8%). The most common indications for admission to hospital were skin conditions caused by mechanical or physical agents (33.3%), infections (27.5%), drug eruption (15.9%) and autoimmune or inflammatory disorders (7.4%). Emergency dermatology cases followed a variable annual trend, with more consultations in the summer months. CONCLUSION: This is the first long-term retrospective analysis of a large series of dermatology emergency patients. It provides useful quantitative and qualitative information on cases for physicians and the national health system for the purposes of improving patient care and cost-effectiveness. PMID- 24754356 TI - On "heredity of restless legs syndrome in a pregnant population". PMID- 24754357 TI - Review articles about special interest groups: difficult but rewarding. PMID- 24754358 TI - Interventions to reduce sexual prejudice: a study-space analysis and meta analytic review. AB - Sexual prejudice is an important threat to the physical and mental well-being of lesbians, gay men, and bisexual people. Therefore, we reviewed the effectiveness of interventions designed to reduce such prejudice. A study-space analysis was performed on published and unpublished papers from all over the world to identify well-studied and underexplored issues. Most studies were conducted with North American undergraduates and were educational in nature. Dissertations were often innovative and well designed but were rarely published. We then performed meta analyses on sets of comparable studies. Education, contact with gay people, and combining contact with education had a medium-size effect on several measures of sexual prejudice. The manipulation of social norms was effective in reducing antigay behavior. Other promising interventions, such as the use of entertainment media to promote tolerance, need further investigation. More research is also needed on populations other than American students, particularly groups who may have higher levels of sexual prejudice. PMID- 24754359 TI - A systematic review of instruments to measure sexual functioning in patients using antipsychotics. AB - Sexual dysfunction is a frequent side effect of antipsychotics, but information is scant regarding the psychometric properties and clinical usefulness of currently existing questionnaires. This systematic review compares the psychometric properties and content of questionnaires for assessment of sexual functioning in patients using antipsychotics. A systematic literature search was performed using three electronic databases (PubMed, Embase, and PsycINFO) with predefined search terms. We identified six validated instruments for assessment of sexual functioning in patients using antipsychotics: the Antipsychotic Non Neurological Side Effects Rating Scale (ANNSERS), the Arizona Sexual Experience Scale (ASEX), the Antipsychotics and Sexual Functioning Questionnaire (ASFQ), the Changes in Sexual Function Questionnaire-14 (CSFQ-14), the Nagoya Sexual Function Questionnaire (NSFQ), and the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ). The ASFQ, CSFQ-14, and PRSexDQ cover all stages of sexual functioning, which makes these questionnaires preferable to the other three questionnaires described. The ASFQ and PRSexDQ are clinician-administered and ask for a change in sexual functioning related to medication. The ASFQ assesses improvement as well as deterioration of sexual functioning, and includes items about hyperprolactinemia. The CSFQ-14 is useful when self-report is desired but contains more items. PMID- 24754361 TI - Psychological and physical health of mostly heterosexuals: a systematic review. AB - We reviewed whether mostly heterosexuals, a sexual orientation group characterized by a small amount of same-sex sexuality, differ from heterosexuals and bisexuals on a variety of mental and physical health outcomes (e.g., internalizing problems, body dissatisfaction and disordered eating, obesity, sexual/reproductive health, physical health), health risk behaviors (e.g., substance use, sexual risk taking), and risk and protective factors (e.g., victimization, stressful/risky environment, socioeconomic status, personal and social relationships, gender nonconformity). A narrative and quantitative literature review was conducted of 60 papers covering 22 samples from five Western countries. Individual, mean, and median effect sizes (Cohen ds) were calculated whenever possible. Mostly heterosexuals reported higher levels of risk in most reviewed outcomes compared to heterosexuals (unweighted mean effect sizes ranged from 0.20 to 0.50) but typically somewhat lower than bisexuals (unweighted mean effect sizes ranged from -0.10 to -0.30). Various risk factors frequently reduced, but rarely eliminated, health disparities between mostly heterosexuals and heterosexuals. Findings are discussed through the lens of three potential explanations of elevated health risks among nonheterosexuals: minority stress, nonheterosexual lifestyles, and common causes. Because data on many outcomes were scarce or missing, particularly for men and in comparison with bisexuals, further research is needed. PMID- 24754363 TI - Surface morphology of superficial cells in irradiated oral mucosa. PMID- 24754360 TI - Gay and bisexual men's use of the Internet: research from the 1990s through 2013. AB - We document the historical and cultural shifts in how gay and bisexual men have used the Internet for sexuality between the 1990s and 2013-including shifting technology as well as research methods to study gay and bisexual men online. Gay and bisexual men have rapidly taken to using the Internet for sexual purposes: for health information seeking, finding sex partners, dating, cybersex, and pornography. Men have adapted to the ever-evolving technological advances that have been made in connecting users to the Internet-from logging on via dial-up modem on a desktop computer to geo-social-sexual networking via handheld devices. In kind, researchers have adapted to the Internet to study gay and bisexual men. Studies have carefully considered the ethics, feasibility, and acceptability of using the Internet to conduct research and interventions. Much of this work has been grounded in models of disease prevention, largely as a result of the ongoing HIV/AIDS epidemic. The need to reduce HIV in this population has been a driving force to develop innovative research and Internet-based intervention methodologies. The Internet, and specifically mobile technology, is an environment gay and bisexual men are using for sexual purposes. These innovative technologies represent powerful resources for researchers to study and provide outreach. PMID- 24754364 TI - SUDEP and epilepsy-related mortality in pregnancy. AB - Although data are limited, research in 2004 estimated a 10-fold increase in mortality in pregnancy in the United Kingdom in women with epilepsy (WWE) compared to women without epilepsy. We highlight epilepsy mortality in pregnancy based on the 2011 report of the United Kingdom Confidential Enquiries into Maternal Deaths, relating its findings to previous reports and epilepsy-rates in pregnancy. Among 2,291,493 maternities (2006-2008), we estimated 0.6% or 13,978 were in WWE. Fourteen deaths were epilepsy-related, of which 11 (79%) were sudden and unexpected (SUDEP). Nine occurred during pregnancy and five were postpartum. Nine (64%) were in women taking lamotrigine, seven as monotherapy. We estimated that 1:1,000 women died from epilepsy (mostly SUDEP) during or shortly after pregnancy. Epilepsy-related mortality is a significant risk in pregnancy. Antiepileptic drug-related factors may be relevant. The high proportion of women taking lamotrigine may reflect United Kingdom prescribing practice. Recent observations from the European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), whereby women on lamotrigine, the levels of which significantly decrease in pregnancy, had more difficulties with epilepsy control, argue against this being the sole explanation. Given the potential risks, every attempt should be made to prevent seizures, particularly convulsive, during pregnancy and postpartum. This, we believe, includes being proactive in maintaining lamotrigine levels during pregnancy. PMID- 24754365 TI - Multigroup confirmatory factor analysis and structural invariance with age of the Behavior Rating Inventory of Executive Function (BRIEF)--French version. AB - The parent and teacher forms of the French version of the Behavioral Rating Inventory of Executive Function (BRIEF) were used to evaluate executive function in everyday life in a large sample of healthy children (N = 951) aged between 5 and 18. Several psychometric methods were applied, with a view to providing clinicians with tools for score interpretation. The parent and teacher forms of the BRIEF were acceptably reliable. Demographic variables (such as age and gender) were found to influence the BRIEF scores. Confirmatory factor analysis was then used to test five competing models of the BRIEF's latent structure. Two of these models (a three-factor model and a two-factor model, both based on a nine-scale structure) had a good fit. However, structural invariance with age was only obtained with the two-factor model. The French version of the BRIEF provides a useful measure of everyday executive function and can be recommended for use in clinical research and practice. PMID- 24754366 TI - Understanding tDCS effects in schizophrenia: a systematic review of clinical data and an integrated computation modeling analysis. AB - Although recent clinical studies using transcranial direct current stimulation (tDCS) for schizophrenia showed encouraging results, several tDCS montages were employed and their current flow pattern has not been investigated. We performed a systematic review to identify clinical tDCS studies in schizophrenia. We then applied computer head modeling analysis for prediction of current flow. Out of 41 references, we identified 12 relevant studies. The most employed montage was anode and cathode over the left dorsolateral prefrontal and temporoparietal cortex, respectively. Computational model analysis predicted activation and under activation under the anode and the cathode, respectively, occurring in areas respectively associated with negative and positive symptoms. We also identified tDCS-induced electrical currents in cortical areas between the electrodes (frontoparietal network) and, to a lesser extent, in deeper structures involved in schizophrenia pathophysiology. Mechanisms of tDCS effects in schizophrenia and the usefulness of computer modeling techniques for planning tDCS trials in schizophrenia are discussed. PMID- 24754368 TI - Twin infant with lymphatic dysplasia diagnosed with Noonan syndrome by molecular genetic testing. AB - Noonan Syndrome is an autosomal dominant disorder characterized by short stature, congenital heart defects, developmental delay, dysmorphic facial features and occasional lymphatic dysplasias. The features of Noonan Syndrome change with age and have variable expression. The diagnosis has historically been based on clinical grounds. We describe a child that was born with congenital refractory chylothorax and subcutaneous edema suspected to be secondary to pulmonary lymphangiectasis. The infant died of respiratory failure and anasarca at 80 days. The autopsy confirmed lymphatic dysplasia in lungs and mesentery. The baby had no dysmorphic facial features and was diagnosed postmortem with Noonan syndrome by genomic DNA sequence analysis as he had a heterozygous mutation for G503R in the PTPN11 gene. PMID- 24754367 TI - Autoimmune hepatitis and primary sclerosing cholangitis in children and adolescents. AB - Clinical presentation and histopathology of autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) overlap syndrome (OS) are similar, but their management is different. We conducted a pediatric retrospective cross-sectional study of 34 patients with AIH and PSC. AIH had female predominance (74%) and was lower in PSC (45%). There was a trend toward higher frequency of blacks in PSC/OS (55%) compared to Caucasians (36%) and Hispanics (9%), but not race differences in AIH. Inflammatory bowel disease (IBD) was present in 75% of PSC/OS. Plasma cells were not specific for AIH (found in 42% of PSC). Concentric fibrosis was not reliable for PSC as was found in 46% of AIH. CONCLUSION: A combination of clinical history, laboratory tests, imaging studies and liver biopsy are required to confirm and properly treat AIH and PSC. Liver biopsy should be used to grade severity and disease progression, but cannot be used alone to diagnose these conditions. PMID- 24754369 TI - Death due to perforation of solitary rectal ulcer: case report. AB - Presented case was 57-year-old male reported to be found dead in the watchman cabin in his workplace. At the autopsy, in abdominal cavity dirty green-brown colored fluid with a few particles of intestinal contents and yellow-green colored membranes on abdominal organs were observed, on the anterior wall of the rectum, 2x1.5 cm size perforation area was observed. We aimed to present the rare case of solitary rectal ulcer perforation. KEYWORDS: solitary rectal ulcer - death - autopsy. PMID- 24754370 TI - [Ultrastruktural diagnosis of hypertrophic kardiomyopathy with beta-aktin mutation in sudden death - case report]. AB - INTRODUCTION: Light microscopy and electron microscopy rank among methods to diagnose of cardiomyopathy in forensic medicine, and, recently, the methods of molecular biology. METHODS: Investigation of 27 year old man who collapsed on his way to work. The Rescuers did not succeed resuscitation of vital function. Samples were H-E stained and processed for the electron microscopy. RNA was isolated from the tissue for the alpha, beta, gama actine primer investigation. RESULTS: By H-E staining we proved irregular hypertrophic cardiomyocytes (disarray) with the links and loci patches of thin fibrosis. Ultrastructurally we diagnosed a disarray of Z-bands, accumulation of mitochondria, rectangular nuclei of cardiomyocytes. We have detected rare plasmocytes and leucocytes with specific granules in cytoplasma. In the electronogrames we can see myofibriles oriented longitudinally and transversally. A genetic examination demonstrated beta actin mutation. CONCLUSION: Cardiomyopathy can be a cause of sudden and unexpected death in young individuals and its diagnostics requires an interdisciplinary collaboration. KEYWORDS: Sudden and unexpected death - hypertrophic cardiomyopathy - ultrastructure of cardiomyocyte - gene mutation. PMID- 24754371 TI - Relationship between the stature and the length of long bones measured from the X rays; modified trotter and gleser formulae in iranian population: A preliminary report. AB - BACKGROUND: We aimed to determine specific formulae by which we are able to estimate the body stature from the length of ulna and tibia calculated from the X rays in order to be a reference for skeletal remains-based identification in Iranian population. METHODS: The length of right ulna and tibia of 49 male and 52 female adults, who were anatomically healthy, were measured on the antero posterior X-rays. Body height of each subject was also recorded. RESULTS: Mean stature of the male and female adults was reported to be 171 +/- 3.6 and 160 +/- 3.9 centimeters (cm), respectively. Four single linear regression equations and 2 multiple regression equations were obtained. CONCLUSIONS: Lengths of ulna and tibia measured on the X-rays may be useful for estimation of the stature in cases of forensic personal identification. KEYWORDS: stature - length of long bones - ulna - tibia - radiological evaluation - skeletal remains. PMID- 24754372 TI - UV-triggerable alginate beads decorated with basic proteinoid-coumarin conjugates. AB - UV-triggerable bead was prepared by coating the surface of alginate bead with a photo-responsive proteinoid. Epoxypropoxy coumarin (EPC) was covalently attached to a basic proteinoid composed of lysine and serine (PLS), and the PLS-EPC conjugate was used as a photo-responsive coat of the bead. EPC residues of PLS EPC conjugate on the bead surface were photo-cross-linked upon the irradiation of lambda = 365 nm, and then FITC-dextran was loaded as a fluorescence dye in the bead coated with photo-cross-linked PLS-EPC conjugate. Upon the irradiation of lambda = 254 nm, the degree of release from the bead was enhanced possibly because the cross-linked network of PLS-EPC conjugate coating layer is photo cleaved. The UV-triggerable bead developed in the present study could be applied to a UV-responsive drug carrier. PMID- 24754373 TI - Compositional equivalency of RNAi-mediated virus-resistant transgenic soybean and its nontransgenic counterpart. AB - RNA silencing or RNA interference (RNAi), which is triggered by double-stranded RNA (dsRNA), is an evolutionarily conserved process that is active in a wide variety of eukaryotic organisms. Engineering plants with hairpin construct in which the viral gene is arranged in inverted repeats (IR) renders plants resistant to plant virus infection. However, there is no report on whether biologically important changes occurred by the insertion of IR, which confer transgenic plants virus resistance. In the present study, the compositions of virus-resistant transgenic soybean seeds developed by insertion of three short IRs, each containing the specific, highly conserved sequences derived from one virus, were compared with those of nontransgenic counterparts by applying the principle of substantial equivalence to determine whether significant undesirable biological changes occurred by IR insertion. The results revealed that the nutrient components as well as antinutrient contents of these virus-resistant soybean lines are substantially equivalent to those of the nontransgenic counterparts, and the majority of the measured amounts of nutritional components and antinutrient contents are well within the range of values reported for other commercial soybean lines. The results imply that no biologically important changes occurred by the insertion of IRs in the RNAi-mediated virus-resistant transgenic soybeans. The results can serve as baseline information for developing RNAi-mediated transgenic soybean cultivars or other crops with broader spectrum virus resistance. PMID- 24754374 TI - Esthetic treatment of a diffuse amelogenesis imperfecta using pressed lithium disilicate and feldspathic ceramic restorations: 5-year follow up. AB - OBJECTIVE: The treatment of a diffuse and severe case of amelogenesis imperfecta represents a challenge for the dental team and in particular for the dentist who perform the prosthetic restorations. CLINICAL CONSIDERATIONS: The enamel alterations, which are characteristic of the disease, determine different problems that need to be carefully planned and solved before the beginning of the treatment, with particular regard to the materials used to perform the restorations. In order to create the best conditions to perform the prosthetic restoration, the treatment plan should be multidisciplinary. In addition, the young age of the patients usually affected by the disease imposes a very conservative and cautious approach. The main goals of the therapy are represented by the need to protect the occlusal dental surfaces from the abrasion and provide a satisfactory esthetic result. In particular, dental abrasions if not treated may determine the loss of the vertical dimension as well as a diffuse and marked dentinal hypersensitivity. CONCLUSIONS: A correct treatment plan and the use of the new adhesive ceramic materials made it possible to obtain good results both from a functional and esthetic point of view with a much more conservative approach compared with the traditional one. CLINICAL SIGNIFICANCE: This clinical report describes the prosthetic rehabilitation of an adult female patient with a diffuse amelogenesis imperfecta using feldspathic ceramics for the esthetic regions and monolithic lithium disilicate material for the posterior areas. PMID- 24754375 TI - Association of genetic variants of membrane receptors related to recognition and induction of immune response with Helicobacter pylori infection in Ecuadorian individuals. AB - Helicobacter pylori (Hp) has a worldwide distribution showing its higher prevalence of infection in developing countries. Toll-like receptors (TLRs) and C type lectin receptors (CLRs) are proteins that recognize pathogen-associated molecular patterns (PAMPs) and initiate an innate immune response by promoting growth and differentiation of specialized hematopoietic cells for host defense. Gastric infections led by Hp induce a Th-1 cellular immune response, regulated mainly by the expression of IFN-gamma. In this retrospective case-control study, we evaluated the TLR1 1805T/G, TLR2 2029C/T, TLR4 896A/G, CD209 -336A/G and IFNGR1 -56C/T polymorphisms and their relationship with susceptibility to Hp infection. TLR1 1805T/G showed statistical differences when the control (Hp-) and infected (Hp+) groups (P = 0.041*) were compared; the TLR1 1805G allele had a protective effect towards infection (OR = 0.1; 95% CI = 0.01-0.88, P = 0.033*). Similarly, the IFNGR1 -56C/T polymorphism showed statistical differences between Hp+ and Hp- (P = 0.018*), and the IFNGR1 -56TT genotype exhibited significant risk to Hp infection (OR = 2.9, 95% CI = 1.27-6.54, P = 0.018*). In conclusion, the pro-inflammatory TLR1 1805T and IFNGR1 -56T alleles are related with susceptibility to Hp infection in Ecuadorian individuals. The presence of these polymorphisms in individuals with chronic infection increases the risk of cellular damage and diminishes the cellular immune response efficiency towards colonizing agents. PMID- 24754376 TI - Seroprevalence of occult hepatitis B among Egyptian paediatric hepatitis C cancer patients. AB - Occult hepatitis B infection is characterized by the presence of hepatitis B virus (HBV) DNA in the serum in the absence of hepatitis B surface antigen (HBsAg). Prevalence of hepatitis C virus (HCV) infections in Egypt is among the highest in the world. In this study, we aim at analysing the rates of occult HBV infections among HCV paediatric cancer patients in Egypt. The prevalence of occult HBV was assessed in two groups of paediatric cancer patients (HCV positive and HCV negative), in addition to a third group of paediatric noncancer patients, which was used as a general control. All groups were negative for HBsAg and positive for HCV antibody. HBV DNA was detected by nested PCR and real-time PCR. HCV was detected by real-time PCR. Sequencing was carried out in order to determine HBV genotypes to all HBV patients as well as to detect any mutation that might be responsible for the occult phenotype. Occult hepatitis B infection was observed in neither the non-HCV paediatric cancer patients nor the paediatric noncancer patients but was found in 31% of the HCV-positive paediatric cancer patients. All the detected HBV patients belonged to HBV genotype D, and mutations were found in the surface genome of HBV leading to occult HBV. Occult HBV infection seems to be relatively frequent in HCV-positive paediatric cancer patients, indicating that HBsAg negativity is not sufficient to completely exclude HBV infection. These findings emphasize the importance of considering occult HBV infection in HCV-positive paediatric cancer patients especially in endemic areas as Egypt. PMID- 24754377 TI - Alzheimer's disease research and development: a call for a new research roadmap. AB - Epidemiological projections of the prevalence of Alzheimer's disease (AD) and related dementias, the rapidly expanding population over the age of 65, and the enormous societal consequence on health, economics, and community foretell of a looming global public health crisis. Currently available treatments for AD are symptomatic, with modest effect sizes and limited impact on longer term disease outcomes. There have been no newly approved pharmaceutical treatments in the last decade, despite enormous efforts to develop disease-modifying treatments directed at Alzheimer's-associated pathology. An unprecedented collaborative effort of government, regulators, industry, academia, and the community at-large is needed to address this crisis and to develop an actionable plan for rapid progress toward successfully developing effective treatments. Here, we map out a course of action in four key priority areas, including (1) addressing the fundamental mechanisms of disease, with the goal of developing a core set of research tools, a framework for data sharing, and creation of accessible validated and replicated disease models; (2) developing translational research that emphasizes rapid progress in disease model development and better translation from preclinical to clinical stages, deploying leading technologies to more accurately develop predictive models; (3) preventing AD through the development of robust methods and resources to advance trials and creating fundamental resources such as continuous adaptive trials, registries, data repositories, and instrument development; and (4) innovating public/private partnerships and global collaborations, with mechanisms to incentivize collaborations and investments, develop larger precompetitive spaces, and more rapid data sharing. PMID- 24754378 TI - Ni3Cl2.1(OH)3.9.4H2O, the Ni analogue to Mg3Cl2(OH)4.4H2O. AB - For the first time a basic transition-metal hydrate, Ni3Cl2.1(OH)3.9.4H2O, is found to be isostructural to a main-group metal phase, Mg3Cl2.0(OH)4.0.4H2O. The Ni phase was found as crystalline solid in the course of investigations into the formation of basic nickel(II) chloride phases at 25 and 40 degrees C in alkaline, concentrated nickel(II) chloride solutions. Ni3Cl2.1(OH)3.9.4H2O was characterized by thermal analysis, IR spectroscopy, scanning electron microscopy, and X-ray powder diffraction. The crystal structure was determined from high resolution laboratory X-ray powder diffraction data. Ni3Cl2.1(OH)3.9.4H2O crystallizes in space group C2/m (12) with Z = 2, a = 14.9575(4) A, b = 3.1413(1) A, c = 10.4818(5) A, beta = 101.482(1) degrees , and V = 482.50(3) A(3). The main building unit of the structure is an infinite triple chain of edge-linked distorted NiO6 octahedra. These chains are separated by interstitial one dimensional zigzag chains of disordered Cl(-) ions and H2O molecules. The crystal structures of Ni3Cl2.1(OH)3.9.4H2O and the isostructural magnesium salt hydrate Mg3Cl2(OH)4.4H2O (2-1-4 phase) are compared in detail. PMID- 24754379 TI - A multicentre, randomized, placebo-controlled trial establishing the treatment effect of TDT 068, a topical formulation containing drug-free ultra-deformable phospholipid vesicles, on the primary features of erythematotelangiectatic rosacea. AB - BACKGROUND: Rosacea subtype 1 (erythematotelangiectatic) is an inflammatory skin disease with limited treatment options. TDT 068, a topical drug-free gel containing ultra-deformable Sequessome vesicles, is registered for use in inflammatory skin conditions, but has not been investigated in rosacea. OBJECTIVE: This postmarketing study aimed to substantiate the effects of TDT 068 in rosacea subtype 1. METHODS: Patients aged 18-85 scoring 6-15/30 for the primary and secondary features of the rosacea standard grading system (RSGS) were enrolled. Following stratification (four females/one male) patients were randomized (2:1) to receive TDT 068 or vehicle gel for 4 weeks. Efficacy was evaluated using the patient-rated rosacea-specific quality of life (R-QOL) instrument and investigator-rated RSGS. Adverse events (AEs) were monitored throughout. RESULTS: Of the 61 randomized patients, 58 were eligible for the full analysis set per protocol. Baseline characteristics were balanced across the groups. R-QOL symptom construct scores improved slightly from baseline to Week 4 in both groups (-0.04 +/- 0.51 TDT 068 vs. -0.22 +/- 0.59 vehicle; P = 0.1990). Changes in R-QOL total, function and emotion construct scores at Week 4 were similar with TDT 068 and vehicle, but TDT 068 yielded numerically greater increases in total RSGS scores (-1.55 +/- 1.83 vs. -0.75 +/- 2.38 vehicle; P = 0.105). Non-transient erythema improved significantly with TDT 068 at Week 4 ( 0.34 +/- 0.63 vs. -0.05 +/- 0.51 vehicle; P = 0.044), with >=1 grade improvement in 35% of patients (vs. 15% vehicle; P = 0.039). Numerically greater improvements in transient erythema and telangiectasia were also seen with TDT 068. Three treatment-related AEs were reported but no serious AEs occurred. CONCLUSION: These data, based on investigator assessment, provide evidence for the good tolerability of drug-free TDT 068 as well as modest improvements in the symptoms of erythematotelangiectatic rosacea. PMID- 24754380 TI - Metabolic inflexibility and insulin resistance in obese adolescents with non alcoholic fatty liver disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a comorbidity of childhood obesity. OBJECTIVE: We examined whole-body substrate metabolism and metabolic characteristics in obese adolescents with vs. without NAFLD. SUBJECTS: Twelve obese (BMI >= 95th percentile) adolescents with and without NAFLD [intrahepatic triglyceride (IHTG) >=5.0% vs. <5.0%] were pair-matched for race, gender, age and % body fat. METHODS: Insulin sensitivity (IS) was assessed by a 3 h hyperinsulinemic-euglycemic clamp and whole-body substrate oxidation by indirect calorimetry during fasting and insulin-stimulated conditions. RESULTS: Adolescents with NAFLD had increased (p < 0.05) abdominal fat, lipids, and liver enzymes compared with those without NAFLD. Fasting glucose concentration was not different between groups, but fasting insulin concentration was higher (p < 0.05) in the NAFLD group compared with those without. Fasting hepatic glucose production and hepatic IS did not differ (p > 0.1) between groups. Adolescents with NAFLD had higher (p < 0.05) fasting glucose oxidation and a tendency for lower fat oxidation. Adolescents with NAFLD had lower (p < 0.05) insulin stimulated glucose disposal and lower peripheral IS compared with those without NAFLD. Although respiratory quotient (RQ) increased significantly from fasting to insulin-stimulated conditions in both groups (main effect, p < 0.001), the increase in RQ was lower in adolescents with NAFLD vs. those without (interaction, p = 0.037). CONCLUSION: NAFLD in obese adolescents is associated with adverse cardiometabolic profile, peripheral insulin resistance and metabolic inflexibility. PMID- 24754381 TI - Nucleophilic phosphine-catalyzed intramolecular Michael reactions of N-allylic substituted alpha-amino nitriles: construction of functionalized pyrrolidine rings via 5-endo-trig cyclizations. AB - Pyrrolidine rings are common moieties for pharmaceutical candidates and natural compounds, and the construction of these skeletons has received much attention. alpha-Amino nitriles are versatile intermediates in synthetic chemistry and have been widely used in the generation of multiple polyfunctional structures. Herein, a novel nucleophilic phosphine-catalyzed intramolecular Michael reaction of N allylic substituted alpha-amino nitriles has been developed for the efficient construction of functionalized 2,4-disubstituted pyrrolidines (N-heterocyclic alpha-amino nitriles) via 5-endo-trig cyclization. Furthermore, the one-pot sequence of the synthesis of pyrrolidine and the subsequent transformations of the functionalized products have also been demonstrated. PMID- 24754382 TI - Non-nutritive sucking for preterm infants in Egypt. AB - OBJECTIVE: To assess how non-nutritive sucking (NNS) using a pacifier affected physiological and behavioral outcomes of preterm infants. DESIGN: Short-term longitudinal, experimental design. SETTING: The study took place at the neonatal intensive care unit at Al-Mansoura, Egypt. METHODS: Forty-seven preterm infants were divided into intervention and control groups. Preterm infants in the intervention group received NNS during nasogastric tube feeding while infants in the control group never received NNS. During 10 days, behavioral responses were videotaped and physiological responses were monitored. RESULTS: Significantly higher oxygen saturation occurred during and after nasogastric feeding for the intervention infants as compared to the control group. No significant group differences occurred in heart rate. The NNS group showed an accelerated transition to nipple feeding and had better weight gain and earlier discharge. CONCLUSION: Non-nutritive sucking was found to improve physiological and behavioral responses of preterm infants. PMID- 24754383 TI - Factors associated with colorectal cancer in the context of the Mediterranean diet: a case-control study. AB - Recent evidence demonstrates that increased adherence to the Mediterranean diet (MD) may prevent colorectal cancer (CRC). The aim of this study was to evaluate the association between health-related characteristics and CRC in the context of the MD. This was a case-control study conducted on a sample of 338 consecutive patients with a first diagnosis of CRC recruited in an urban facility in the city of Catania, southern Italy, and matched with 676 apparently healthy subjects without clinical symptoms or signs of any type of cancer. Data regarding sociodemographic, clinical, and lifestyle characteristics were collected, and adherence to the Mediterranean diet pattern was assessed using the MedDietScore. A significant association between a greater adherence to the MD and lower odds of having cancer (odds ratio = 0.46, 95% confidence interval: 0.28-0.75) was found. Also, smoking status, family history of CRC, obesity, diabetes, physical activity, and high intake of alcohol were significantly associated with CRC, but only among subjects less adherent to the MD. MD was associated with a less detrimental effects of several health-related characteristics associated with CRC, suggesting potential benefits of adherence to this dietary pattern with regards to CRC risk factors. PMID- 24754384 TI - Laboratory features of common causes of fever in returned travelers. AB - BACKGROUND: There can be considerable overlap in the clinical presentation and laboratory features of dengue, malaria, and enteric fever, three important causes of fever in returned travelers. Routine laboratory tests including full blood examination (FBE), liver function tests (LFTs), and C-reactive protein (CRP) are frequently ordered on febrile patients, and may help differentiate between these possible diagnoses. METHODS: Adult travelers returning to Australia who presented to the Royal Melbourne Hospital with confirmed diagnosis of dengue, malaria, or enteric fever between January 1, 2000 and March 1, 2013 were included in this retrospective study. Laboratory results for routine initial investigations performed within the first 2 days were extracted and analyzed. RESULTS: There were 304 presentations including 58 with dengue fever, 187 with malaria, and 59 with enteric fever, comprising 56% of all returned travelers with a febrile systemic illness during the study period. Significant findings included 9-fold and 21-fold odds of a normal CRP in dengue compared with malaria and enteric fever, respectively. The odds of an abnormally low white cell count (WCC) were also significantly greater in dengue versus malaria or enteric fever. Approximately one third of dengue presentations and almost half of the malaria presentations had platelet counts <100 * 10(9) /L. A normal CRP with leukopenia and/or thrombocytopenia occurred in 21% to 30% of dengue presentations, but not in malaria or enteric fever presentations. CONCLUSIONS: There is a wide differential diagnosis for imported fever, but the non-specific findings of a normal CRP with a low WCC and/or low platelet count may provide useful information in addition to clinical clues to suggest dengue over malaria or enteric fever. Further systematic prospective studies among travelers could help define the potential clinical utility of these results in assisting the clinician when deciding for or against commencement of empiric antimicrobial therapy while awaiting confirmatory tests. PMID- 24754385 TI - 4th Norwegian Environmental Toxicology Symposium: Emerging challenges and threats in the Arctic. PMID- 24754386 TI - Relationships between persistent organic pollutants and circulating immunoglobulin-Y in black-legged kittiwakes and Atlantic puffins. AB - Have Although persistent organic pollutants (POPs) may affect the immune system, few field studies actually examined this effect. There are indications that POP exert effects on the immune system; however, in the Arctic ecosystem data are scarce. The aim of this study was to examine immune functions in two medium trophic-positioned seabirds, the black-legged kittiwakes (Rissa tridactyla) and Atlantic puffins (Fratercula arctica). Overall POP concentrations were higher in kittiwakes than puffins and males had significantly higher concentrations than females. Mean concentrations of total polychlorinated biphenyls (SigmaPCB9) were 4700 +/- 200 and 9600 +/- 1400 ng/g lipid weight and 2800 +/- 180 and 3900 +/- 200 ng/g lipid weight in female and male kittiwake and puffin blood, respectively. Levels of immunoglobulin-Y (IgY) in blood of kittiwakes were not markedly affected by concentrations of POP. Similarly, the primary IgY response to tetanus toxoid was not affected by POP concentrations in a subsample of immunized kittiwakes. In puffins, there were significant correlations between the IgY-response and some of the POPs, but with low explanatory values. These results suggest that POPs concentrations were lower than, or just at the threshold level for effects of the proposed IgY biomarker. It is also conceivable that the IgY levels are not a suitable endpoint for evaluating perturbation of the immune system in free-living seabirds. PMID- 24754387 TI - Acute toxicity of eight oil spill response chemicals to temperate, boreal, and Arctic species. AB - The objectives of this study were to (1) determine the acute toxicity of selected shoreline washing agents (SWA) and dispersants, and (2) assess interspecies differences in sensitivity to the products. Eight shoreline washing agents (Hela saneringsvaeske, Bios, Bioversal, Absorrep K212, and Corexit 9580) and chemical dispersants (Corexit 9500, Dasic NS, and Gamlen OD4000) were tested on five marine species, algae Skeletonema costatum, planktonic copepod species Acartia tonsa (temperate species), Calanus finmarchicus (boreal species) and Calanus glacialis (Arctic species), and benthic amphipod Corophium volutator. For most products, A. tonsa was the most sensitive species, whereas C. volutator was the least sensitive; however, these species were exposed through different media (water/sediment). In general, all copepod species displayed a relatively similar sensitivity to all products. However, A. tonsa was somewhat more sensitive than other copepods to most of the tested products. Thus, A. tonsa appears to be a candidate species for boreal and Arctic copepods for acute toxicity testing, and data generated on this species may be used as to provide conservative estimates. The benthic species (C. volutator) had a different sensitivity pattern relative to pelagic species, displaying higher sensitivity to solvent-based SWA than to water-based SWA. Comparing product toxicity, the dispersants were in general most toxic while the solvent-based SWA were least toxic to pelagic species. PMID- 24754388 TI - Endocrine and AhR-CYP1A pathway responses to the water-soluble fraction of oil in zebrafish (Danio rerio Hamilton). AB - Crude oil is a complex mixture of compounds of which the water-soluble fraction (WSF) is considered to be bioavailable and potentially toxic to aquatic biota. Containing numerous compounds, WSF becomes a source of multiple chemical stressors to wildlife when introduced into the environment. To study the combined effects of WSF components on aquatic biota, the model species zebrafish (Danio rerio Hamilton) was exposed for 24 or 72 h to 10 or 50% WSF solution of known composition, generated from artificially weathered North Sea crude oil. Hepatic expression of genes involved in the aryl hydrocarbon receptor-cytochrome P-450 1A (AhR-CYP1A) pathway (AhR2, AhRR1, CYP1A1) and steroidogenesis (StAR, CYP11A, 3beta-HSD, CYP19A, CYP19B) was measured, as well as estrogen receptors ERalpha and ERbeta1. Induction of CYP1A and particularly of AhRR1 was observed while ERalpha and steroidogenic enzymes CYP11A and 3beta-HSD were downregulated. Regression analysis demonstrated a negative relationship between AhR-CYP1A pathway and endocrine transcript levels, although causality remains to be established. These findings indicate that exposure to WSF of oil disrupts steroidogenesis and may therefore constitute a potential risk for reproductive ability of aquatic organisms. In addition, it is proposed that hepatic gene expression of AhRR1 may serve as a novel biomarker of WSF exposure. PMID- 24754389 TI - Exposure to the three structurally different PCB congeners (PCB 118, 153, and 126) results in decreased protein expression and altered steroidogenesis in the human adrenocortical carcinoma cell line H295R. AB - Polychlorinated biphenyls (PCB), synthetic, persistent organic pollutants (POP), are detected ubiquitously, in water, soil, air, and sediments, as well as in animals and humans. PCB are associated with range of adverse health effects, such as interference with the immune system and nervous system, reproductive abnormalities, fetotoxicity, carcinogenicity, and endocrine disruption. Our objective was to determine the effects of three structurally different PCB congeners, PCB118, PCB 126, and PCB 153, each at two concentrations, on the steroidogenic capacity and proteome of human adrenocortical carcinoma cell line cultures (H295R) . After 48 h of exposure, cell viability was monitored and estradiol, testosterone, cortisol and progesterone secretion measured to quantify steroidogenic capacity of the cells. Two-dimensional (2D) gel-based proteomics was used to screen for proteome alterations in H295R cells in response to the PCB. Exposure to PCB 118 increased estradiol and cortisol secretion, while exposure to PCB 153 elevated estradiol secretion. PCB 126 was the most potent congener, increasing estradiol, cortisol, and progesterone secretion in exposed H295R cells. Seventy-three of the 711 spots analyzed showed a significant difference in normalized spot volumes between controls (vehicle only) and at least one exposure group. Fourteen of these protein spots were identified by liquid chromatography with mass spectroscopy (LC-MS/MS). Exposure to three PCB congeners with different chemical structure perturbed steroidogenesis and protein expression in the H295R in vitro model. This study represents an initial analysis of the effects on proteins and hormones in the H295R cell model, and additional studies are required in order to obtain a more complete understanding of the pathways disturbed by PCB congeners in H295R cells. Overall, alterations in protein regulation and steroid hormone synthesis suggest that exposure to PCB disturbs several cellular processes, including protein synthesis, stress response, and apoptosis. PMID- 24754390 TI - Effects of elevated carbon dioxide (CO2) concentrations on early developmental stages of the marine copepod Calanus finmarchicus Gunnerus (Copepoda: Calanoidae). AB - Ocean acidification poses an ongoing threat to marine organisms, and early life stages are believed to be particularly sensitive. The boreal calanoid copepod Calanus finmarchicus seasonally dominates the standing stock of zooplankton in the northern North Sea and North Atlantic, and due to its size and abundance is considered an ecological key species linking energy from primary producers to higher trophic levels. To examine whether the early stages of C. finmarchicus are particularly vulnerable to elevated levels of CO2, eggs and nauplii were subjected to different levels of CO2-acidified seawater for 1 wk. The first experiment, with eggs as the starting point, revealed no marked effect on hatching success, but a significant reduction in nauplii survival during incubation at 8800 ppm CO2. In addition, a significant decrease in ontogenetic development rate during incubation at 8800 ppm CO2 was observed in this experiment. In the second experiment, where third-stage nauplii represented the starting point, no significant effects on ontogenetic development and survival following exposure to pCO2 >= 7700 ppm were observed. Data suggest that the two first nauplii stages, which are fed endogenously, may be more vulnerable and therefore likely to represent the "bottleneck" for this species in a more acidic ocean. However, the absence of significant effects in the most sensitive stages during exposure to 2800 ppm CO2, a level that is well above worst-case scenario predictions for year 2300 (approximately 2000 ppm CO2), suggests that this species may be generally robust to direct effects of ocean acidification. PMID- 24754391 TI - Aryl hydrocarbon receptor agonists in European herring gull (Larus argentatus) eggs from Norway. AB - Herring gull eggs from two locations in Norway, an island situated in the north (Musvaer, 69.88 degrees N, 18.55 degrees E) and an island in the southeast (Reiaren, 59.15 degrees N, 10.46 degrees E) of the country, were analyzed for the presence of aryl hydrocarbon receptor (AhR) agonists. AhR agonist activity was determined using the dioxin-responsive chemically activated luciferase expression (DR-CALUX) assay to calculate the toxic equivalent quotient (TEQ)CALUX. TEQCALUX ranged from 16 to 401 pg TEQ/g lipid in the samples from the north (n = 11) and between 6 and 360 pg TEQ/g lipid (n = 12) in the southeastern samples. The large variance between the individual samples is postulated to be due to different feeding habits of individual birds. The levels of AhR agonists detected might lead to adverse effects for the developing embryo or to a significant increase of contaminant load for human consumers of eggs. PMID- 24754392 TI - In vivo effects of environmental concentrations of produced water on the reproductive function of polar cod (Boreogadus saida). AB - Offshore oil and gas drilling processes generate operational discharges such as produced water (PW), a complex mixture of seawater with polycyclic aromatic hydrocarbons (PAH) and alkylphenols (AP). Some of these compounds may interact with the endocrine system of marine organisms and alter reproductive functions. In this study, polar cod were exposed for up to 28 d to a mixture of PAH, alkylated PAH, and AP simulating the composition of North Sea PW, at low and high concentrations (1:2000 and 1:1000 dilution of the original concentrate, respectively). Potential adverse effects of PW on polar cod physiology were investigated through biomarkers of biotransformation (hepatic ethoxyresorufin O deethylase [EROD] activity and bile PAH metabolites), endocrine disruption (plasma vitellogenin [VTG] levels and sex steroid concentrations), and gonad histology. Plasma sexual steroid levels in fish were not markedly affected by PW exposure, while higher plasma VTG concentrations were measured in females exposed to the high PW treatment for 7 and 28 d. In males exposed to the higher PW concentration, inhibition of spermatogenesis was observed after 28 d in addition to increase of melano-macrophage occurrence in testis. Females exposed to the high PW treatment for 21 d showed a significant increase of atresia incidence. Finally, a significant decrease in oocyte number was observed in high PW exposed female ovaries after 28 d of exposure. PMID- 24754393 TI - Effects on development, growth responses and thyroid-hormone systems in eyed-eggs and yolk-sac larvae of Atlantic salmon (Salmo salar) continuously exposed to 3,3',4,4'-tetrachlorobiphenyl (PCB-77). AB - Thyroid hormones (triiodothyronine, T3; and thyroxine, T4) play significant roles in development, metamorphosis, metabolism, homeostasis, cellular proliferation, and differentiation, for which the effects are mediated through thyroid hormone receptors (TRalpha and TRbeta). Similarly, the insulin-like growth factor (IGF) is involved in growth and development through regulation of somatic growth. This study was designed to examine the effects of the dioxin-like 3,3',4,4' tetrachlorobiphenyl (PCB-77) on responses related to growth and thyroid hormone system in eyed eggs and yolk-sac larvae of Atlantic salmon. Salmon eggs were continuously exposed to two waterborne concentrations of PCB-77 (1 or 10 ng/L) over a period of 50 d covering hatching and through yolk-sac absorption stages. Sampling was performed regularly throughout the exposure period and at different time intervals. Gene expression patterns were performed on whole-body homogenate at age 500, 548, 632, 674, and 716 dd (dd: day degrees) using quantitative polymerase chain reaction (PCR). Total T3 (TT3) and total T4 (TT4) were measured using radioimmunoassay (RIA). Data showed that 10 ng PCB-77 increased dioiodinase 2 (Dio2) at 500 dd and both PCB-77 concentrations decreased dio2 expression at 548 dd. PCB-77 elevated cellular TT3 at 500 dd and was lowered at 548 dd only at 10 ng. Otherwise, time-related reduction was not affected by PCB-77 exposure as observed for the rest of the exposure period. For TT4, 1 ng PCB-77 produced a rise at 500 dd, and an apparent concentration decrease at 548 dd, before a total inhibition at 632 dd. The IGF-1 and IGF-1R were variably affected by PCB-77. For IGF-2, PCB-77 produced a concentration-dependent increase at 548 dd, and thereafter an elevation (1 ng) and fall (10 ng) at 632 dd. TRbeta mRNA demonstrated PCB-77 related increases during the exposure period, and this effect returned to control levels at 716 dd. For TRalpha, a rise was noted only after exposure to 10 ng PCB-77 at 500 dd. Overall, the present study demonstrates some possible growth and developmental consequences following exposure to PCB-77 during early life stages of Atlantic salmon. PMID- 24754395 TI - Toxicity screening of produced water extracts in a zebrafish embryo assay. AB - Produced water is the largest effluent discharge from oil and gas/condensate production facilities in the North Sea. There is concern that contaminants originating from the reservoir and chemicals used in the production process may affect marine organisms. Developmental toxicity of extractable organic compounds in produced water effluents from oil and gas/condensate production platforms in the Norwegian sector of the North Sea was assessed in a temporal and spatial manner using zebrafish (Danio rerio) embryos. Large-scale solid-phase extraction (SPE) and on-column fractionation of water-soluble fraction (WSF) and an oil/particulate fraction was used in a rapid screening bioassay for embryotoxicity. Exposure to produced water extracts increased rate of mortality and reduced pigmentation and heart rate, as well as delaying time to hatch. The oil/particulate fraction was 10-fold less toxic than WSF, indicating that toxicity was predominantly produced by moderately polar and bioavailable compounds. Large spatial and temporal variation in produced water toxicity was observed, displaying considerable variability in the reservoir, oil well, and effluent composition over time. The noted toxicity did not correlate well with either reported produced water composition or parameters such as total hydrocarbons, thus challenging chemical measurements as a reliable source of information for predicting complex effects. Although embryotoxicity was observed following exposure to the extracts, dilution and transformation of produced water in the recipient are expected to rapidly reduce the concentrations of compounds in the effluents to levels below the thresholds of observed effects. PMID- 24754394 TI - Development of a screening system for the detection of chemically induced DNA methylation alterations in a zebrafish liver cell line. AB - Early molecular events with correlation to disease, such as aberrant DNA methylation, emphasize the importance of DNA methylation as a potential environmental biomarker. Currently, little is known regarding how various environmental contaminants and mixtures alter DNA methylation in aquatic organisms, and testing is both time- and labor-consuming. Therefore, the potential of an in vitro screening method was evaluated by exposing zebrafish liver cells (ZF-L) for 96 h to the nonmutagenic model substance 5'-azacytidine (AZA), as well as a selection of environmental pollutants such as sodium arsenite (NAS), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 17alpha-ethinylestradiol (EE2), and diethylstilbestrol (DES). Six single genes with reported and anticipated importance in cancer were selected for analysis. Methylation of gene promoter areas was monitored by bisulfite conversion and high-resolution melt (HRM) analysis after exposure to sublethal concentrations of the test compounds. Subsequently, results were validated with direct bisulfite sequencing. Exposure of ZF-L cells to 0.5 MUM AZA for 96 h led to hypomethylation of genes with both low and high basal methylation indicating similarity to mechanism of action in mammals. Further, NAS, EE2, and DES were shown to induce significant alterations in methylation, whereas TCDD did not. It was concluded that cell line exposure in combination with HRM may provide an initial contaminant screening assay by quantifying DNA methylation alterations with high throughput capacity. In addition, the rapid determination of effects following contaminant exposure with this in vitro system points to the possibility for new in vivo applications to be useful for environmental monitoring. PMID- 24754396 TI - Enantiomer-selective and quantitative trace analysis of selected persistent organic pollutants (POP) in traditional food from western Greenland. AB - Enantiomeric fractions (EF) are today considered a powerful tool to elucidate selective uptake processes of chiral contaminants in biota. In this study, concentration levels and EF were determined by gas chromatograph-mass spectrometer (GC/MS) for alpha-hexachlorocyclohexane (alpha-HCH) and trans-, cis , and oxychlordane in selected Greenlandic traditional food items, collected at the local market in Nuuk in 2010. The food items selected were raw and smoked fish (salmon and halibut, n = 6), whale meat (n = 8), seal meat (n = 2) and narwhal mattak (skin and blubber, n = 6). The EF were nonracemic (?0.5) for all samples except for alpha-HCH in narwhal, trans-chlordane in whale and smoked salmon, and cis- and oxychlordane in seal. The EF for alpha-HCH were significant for all fish samples, but not for mammalian samples. Data indicate that different uptake and/or transformation mechanisms may be responsible for nonracemic distributions of chiral pesticides in mammals and fish species analyzed. There were no general enantiomer-selective transformation/accumulation trends found for chlordanes. Data indicate that enantiomer-specific properties are an important prerequisite for interaction of chiral contaminant with internal metabolic processes. However, marked differences within these groups were identified. The EF in ringed seals were racemic for most of the analyzed pesticides (i.e., chlordanes). However, narwhal were characterized by nonracemic EF for all chiral pesticides analyzed. Median levels of alpha-HCH ranged from 2 to 24 ng/g lw and from 15.1 to 626.6 ng/g lw for trans-nonachlor, with lowest levels observed in smoked salmon and highest levels in narwhal mattak. This study confirmed that concentration levels of analyzed pesticides in the investigated food items were below the tolerable daily intake (TDI) threshold. PMID- 24754397 TI - In utero exposure to environmentally relevant concentrations of PCB 153 and PCB 118 disrupts fetal testis development in sheep. AB - Polychlorinated biphenyls (PCB) are environmental pollutants linked to adverse health effects including endocrine disruption and disturbance of reproductive development. This study aimed to determine whether exposure of pregnant sheep to three different mixtures of PCB 153 and PCB 118 affected fetal testis development. Ewes were treated by oral gavage from mating until euthanasia (d 134), producing three groups of fetuses with distinct adipose tissue PCB levels: high PCB 153/low PCB 118 (n = 13), high PCB 118/low PCB 153 (n = 14), and low PCB 153/low PCB 118 (n = 14). Fetal testes and blood samples were collected for investigation of testosterone, testis morphology, and testis proteome. The body weight of the offspring was lower in the high PCB compared to the low PCB group, but there were no significant differences in testis weight between groups when corrected for body weight. PCB exposure did not markedly affect circulating testosterone. There were no significant differences between groups in number of seminiferous tubules, Sertoli cell only tubules, and ratio between relative areas of seminiferous tubules and interstitium. Two-dimensional (2D) gel-based proteomics was used to screen for proteomic alterations in the high exposed groups relative to low PCB 153/low PCB 118 group. Twenty-six significantly altered spots were identified by liquid chromatography (LC)-mass spectroscopy (MS)/MS. Changes in protein regulation affected cellular processes as stress response, protein synthesis, and cytoskeleton regulation. The study demonstrates that in utero exposure to different environmental relevant PCB mixtures exerted subtle effects on developing fetal testis proteome but did not significantly disturb testis morphology and testosterone production. PMID- 24754398 TI - Alterations in the Atlantic cod (Gadus morhua) hepatic thiol-proteome after methylmercury exposure. AB - Proteomic studies in general have demonstrated that the most effective and thorough analysis of biological samples requires subfractionation and/or enrichment prior to downstream processing. In the present study, Atlantic cod (Gadus morhua) liver samples were fractionated using activated thiol sepharose to isolate hepatic proteins containing free/reactive cysteines. This subset of proteins is of special interest when studying the physiological effects attributed to methylmercury (MeHg) exposure. Methylmercury is a persistent environmental contaminant that has a potent affinity toward thiol groups, and can directly bind proteins via available cysteine residues. Further, alterations in the cod thiol-proteome following MeHg exposure (2 mg/kg body weight) were explored with two-dimensional gel electrophoresis combined with downstream mass spectrometry analyses for protein identifications. Thirty-five protein spots were found to respond to MeHg exposure, and 13 of these were identified when searching cod-specific databases with acquired mass spectrometry data. Among the identified thiol-containing proteins, some are known to respond to MeHg treatment, including constituents of the cytoskeleton, and proteins involved in oxidative stress responses, protein synthesis, protein folding, and energy metabolism. Methylmercury also appeared to affect cod heme metabolism/turnover, producing significantly altered levels of hemoglobin and hemopexin in liver following metal exposure. The latter finding suggests that MeHg may also affect the hematological system in Atlantic cod. PMID- 24754399 TI - Zwitteration: coating surfaces with zwitterionic functionality to reduce nonspecific adsorption. AB - Coating surfaces with thin or thick films of zwitterionic material is an effective way to reduce or eliminate nonspecific adsorption to the solid/liquid interface. This review tracks the various approaches to zwitteration, such as monolayer assemblies and polymeric brush coatings, on micro- to macroscopic surfaces. A critical summary of the mechanisms responsible for antifouling shows how zwitterions are ideally suited to this task. PMID- 24754401 TI - Genotype/phenotype in tuberous sclerosis complex: associations with clinical and radiologic manifestations. AB - OBJECTIVES: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC. METHODS: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance). RESULTS: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention deficit/hyperactive disorder, or major depressive disorder. SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD. PMID- 24754400 TI - Complementary assessments of executive function in preterm and full-term preschoolers. AB - Executive functions (EFs) are interrelated cognitive processes that have been studied in relation to behavior, attention, academic achievement, and developmental disorders. Studies of EF skills assessed through parent report and performance-based measures show correlations between them ranging from none to modest. Few studies have examined the relationship between EF skills measured through parent report and performance-based measures in relation to adaptive function. The present study included preschool children born preterm as a population at high risk for EF impairments. Preschool children (N = 149) completed a battery of EF tasks that assess working memory, response inhibition, idea generation, and attention shifting or cognitive flexibility. Parents reported on children's EF and adaptive skills. Preterm children showed more parent-rated and performance-based EF impairments than did full-term children. The combined use of either parent report or performance-based measures resulted in the identification of a large number of children at risk for EF impairment, especially in the preterm group. Both parent report and performance-based EF measures were associated with children's adaptive function. EF skills are measurable in young child'ren, and we suggest that EF skills may serve as targets for intervention to improve functional outcomes. We recommend the use of both parent report and performance-based measures to characterize children's EF profiles and to customize treatment. PMID- 24754402 TI - Noncompliance is an impact factor in the treatment of gastroesophageal reflux disease. AB - The basis of pharmacological treatment of the gastroesophageal reflux disease is the use of proton pump inhibitors (PPIs) which provide effective gastric acid secretion blockade. However, PPI therapy failure may occur in up to 42% of patients. The main causes for therapeutic failure are non-acid or weakly acid reflux, genotypic differences, presence of comorbidities, wrong diagnosis and lack of treatment compliance. Noncompliance is an important issue and should be carefully observed. Several studies addressed patient compliance and 20-50% of patients may present lack of compliance to the PPI prescribed. When symptoms persist depite adherence has been confirmed, it is recommended to substitute the prescribed PPI to another of the same class or alternatively, prescription of a double dose of the same drug. When even so the symptoms persist, other causes of failure should be assigned. In particular cases of PPI failure, fundoplication surgery may be indicated. PMID- 24754403 TI - A correlation study applied to biomarkers of internal and effective dose for acrylonitrile and 4-aminobiphenyl in smokers. AB - The urinary metabolites 2-cyanoethylmercapturic acid and 4-aminobiphenyl have been correlated with tobacco smoke exposure. Similarly, 2-cyanoethylvaline and 4 aminobiphenyl haemoglobin adducts have been used as biomarkers of effective dose for the exposure to acrylonitrile and 4-aminobiphenyl, respectively. Each pair of biomarkers is derived from the same parent chemical; however, the correlation between the urinary and the haemoglobin biomarkers has not been investigated. Using clinical study samples, we report a weak correlation between urinary and haemoglobin biomarkers due to different accumulation and elimination rates. Time course analysis showed that a reduction in exposure was paralleled by a delayed reduction in haemoglobin adducts. PMID- 24754404 TI - Are urinary PAHs biomarkers of controlled exposure to diesel exhaust? AB - Urinary polycyclic aromatic hydrocarbons (PAHs) were evaluated as possible biomarkers of exposure to diesel exhaust (DE) in two controlled-chamber studies. We report levels of 14 PAHs from 28 subjects in urine that were collected before, immediately after and the morning after exposure. Using linear mixed-effects models, we tested for effects of DE exposure and several covariates (time, age, gender and urinary creatinine) on urinary PAH levels. DE exposures did not significantly alter urinary PAH levels. We conclude that urinary PAHs are not promising biomarkers of short-term exposures to DE in the range of 106-276 ug/m(3). PMID- 24754405 TI - The centipede Strigamia maritima possesses a large complement of Wnt genes with diverse expression patterns. AB - The genes of the Wnt family play important roles in the development of many animals. In the arthropods, these genes are known to have multiple functions, including roles in posterior development and segmentation. Despite this, secondary loss of Wnt genes is common among the Arthropoda. Unlike many arthropods, Strigamia maritima, a geophilomorph centipede, possesses a large complement of Wnt ligands, with 11 Wnt genes present. In this study, the expression of each of these genes was examined across a range of stages during embryonic development. The expression of Wnt genes in Strigamia displays much variability. Most Wnt genes are expressed in segmental stripes in the trunk; near the proctodeum; and in the head region. However, despite this overall broad similarity, there are many differences between the various Wnt genes in their exact patterns of expression. These data should be considered in the context of different hypotheses regarding the functional relationships between the Wnt genes and the degree of redundancy present in this system. The findings of this study are consistent with one particular model of Wnt activity, the combinatorial model, whereby the combination of Wnt ligands present in a particular region defines its identity. These findings should also be useful in attempts to reconstruct the evolutionary history of Wnt signaling in arthropods. PMID- 24754406 TI - Effect of intracameral carbachol in phacoemulsification surgery on macular morphology and retinal vessel caliber. AB - OBJECTIVE: To investigate the effects of intracameral carbachol in phacoemulsification surgery on central macular thickness (CMT), total macular volume (TMV) and retinal vessel caliber (RVC). MATERIALS AND METHODS: In this prospective consecutive case series, 82 patients underwent uneventful phacoemulsification and in-the-bag intraocular lens implantation. Unlike patients in the control group (43 eyes), patients in the study group (42 eyes) were injected with intracameral 0.01% carbachol during surgery. Spectral-domain optical coherence tomography (OCT) was used to analyze the parameters of CMT, TMV and RVC. RESULTS: On the first postoperative day, mean CMT and TMV decreased markedly in the carbachol group, though these values did not change significantly in the control group. During follow-up visits, no statistically significant differences between the groups occurred regarding changes in mean CMT (p = 0.25, first day; p = 0.80, first week; p = 0.95, first month). However, change in mean TMV between groups on the first postoperative day was statistically significant (p = 0.01, first day; p = 0.96, first week; p = 0.68, first month). RVC values were similar on the preoperative and postoperative first days in both groups (p > 0.05). DISCUSSION: Results suggest that the effect of intracameral carbachol on macular OCT is related to pharmacological effects, as well as optic events (e.g. miosis). CONCLUSION: Intracameral carbachol given during cataract surgery decreases macular thickness and volume in the early postoperative period but does not exert any gross effect on RVC. PMID- 24754407 TI - Inhibitory effects of the platelet-activating factor receptor antagonists, CV 3988 and Ginkgolide B, on alkali burn-induced corneal neovascularization. AB - PURPOSE: Platelet-activating factor (PAF) has been found in various ocular tissues; the activity of PAF depends on the binding to its specific receptor, PAF receptor. We investigated the therapeutic effects of PAF-receptor antagonists (CV 3988 and Ginkgolide B) on alkali burn-induced corneal neovascularization (CNV). METHODS: CNV was induced by applying a 0.2 N sodium hydroxide (3 ul, NaOH) solution directly on mice corneas. CV-3988 (1 mM/10 ul) and Ginkgolide B (1 mM/10 ul) were administered topically on the corneas three times daily for three consecutive days. CNV was evaluated under a slit-lamp microscope. Corneas were processed for histological, immunohistochemical and reverse transcription polymerase chain reaction analysis. Human umbilical vein endothelial cells were used for the migration and tube formation assay. RESULTS: Application of CV-3988 and Ginkgolide B inhibited CNV caused by alkali burn. CV-3988 and Ginkgolide B attenuated the expression of PAF-receptor mRNA. Alkali injury induced a massively increased intraocular mRNA expression of an angiogenic factor in cornea tissues, whereas these increments were attenuated by the application of CV-3988 and Ginkgolide B. CONCLUSIONS: CV-3988 and Ginkgolide B reversed opacity and neovascularization in alkali burn-induced corneas. Our findings suggest that CV 3988 and Ginkgolide B may be therapeutically useful in the treatment of CNV and inflammation. PMID- 24754408 TI - Prolonged mydriasis after inadvertent topical administration of the calcium channel antagonist amlodipine: implications for glaucoma drug development. AB - CONTEXT: Calcium channel inhibitors are being investigated as potential therapeutic adjuncts to reduce painful ciliary muscle spasm and control intraocular pressure in glaucoma. Relatively little is known about the effect of topical administration of calcium channel blockers in humans. OBJECTIVE: (1) To describe prolonged fixed pupil dilation resulting from exposure to topical amlodipine (2) to review the evidence that links calcium channel blockers with mydriasis and (3) to discuss the implications for glaucoma pharmacotherapy. DESIGN: Single interventional case report, literature review (including human and animal studies) and analysis of reported adverse drug reactions (ADRs) records in the USA and UK. CASE: A 35-year-old female doctor presented to eye casualty with blurred vision and bilateral, fixed, dilated pupils. A history of exposure to liquid amlodipine while preparing a paediatric chemotherapy regimen for a neuroblastoma patient was elicited. The patient was reassured and observed. RESULTS: Pupil function returned to normal within 48 h. A multi-national review of adverse drug reactions reports was conducted, as well as an extensive literature search for case reports and experimental studies. To the authors' knowledge this is the first report of amlodipine causing mydriasis and we discuss the potential molecular mechanism. CONCLUSIONS: This case is the first to suggest that calcium channel blockers can cause prolonged mydriasis. These agents have been investigated as potential adjuncts in glaucoma therapy. As accidental topical exposure to amlodipine can cause prolonged pupil dilation, it could precipitate angle closure in predisposed patients. PMID- 24754409 TI - Dermatotoxicologic clinical solutions: hair dying in hair dye allergic patients? AB - This article describes how to identify allergic contact dermatitis resulting from hair dye, and outlines interventions and prevention principles for those who wish to continue dyeing their hair despite being allergic. Hair dye chemicals thought to be the most frequent sensitizers are discussed with instructions for health care providers on how to counsel patients about techniques to minimize exposure to allergenic substances. This framework should allow many patients to continue dyeing their hair without experiencing adverse side effects. PMID- 24754410 TI - In vitro skin penetration of acetyl hexapeptide-8 from a cosmetic formulation. AB - There is a concern that peptides in cosmetic creams marketed as anti-aging/anti wrinkle may penetrate into the deep layers of the skin and potentially stimulate biological activity. Claims for one cosmetic peptide, acetyl hexapeptide-8 (Ac EEMQRR-amide), suggest interference with neuromuscular signaling as its anti wrinkle mechanism of action. Therefore, the skin penetration of commercially available Ac-EEMQRR-amide from a cosmetic formulation (oil-in-water (O/W) emulsion) was determined in hairless guinea pig (HGP) and human cadaver skin assembled into in vitro diffusion cells. An O/W emulsion containing 10% Ac-EEMQRR amide was applied to skin at a dose of 2 mg/cm(2). After a 24-h exposure, the skin surface was washed to remove unabsorbed peptide. Skin disks were tape stripped to determine the amount of peptide in the stratum corneum. Removal of the stratum corneum layers was verified by confocal microscopy. The epidermis was heat separated from the dermis and each skin fraction was homogenized. Skin penetration of Ac-EEMQRR-amide was measured in skin layers by hydrophilic interaction liquid chromatography with tandem mass spectrometry using electrospray ionization (ESI) in the positive mode. Stable isotopically labeled hexapeptides were used as internal standards for the quantitation of native hexapeptides to correct for matrix effects associated with ESI. The results (percent of applied dose) showed that the majority of the Ac-EEMQRR-amide was washed from the surface of both HGP and human skin. Ac-EEMQRR-amide that penetrated skin remained mostly in the stratum corneum of HGP (0.54%) and human (0.22%) with the peptide levels decreasing as each layer was removed by tape stripping. Total Ac-EEMQRR-amide found in the epidermis of HGP and human skin was similar at 0.01%. No peptide was detected in the dermis or buffer collected underneath the skin for both human and HGP. There was no hexapeptide metabolite (H2N-EEMQRR-amide) detected in any layers of HGP skin, human skin or buffer collected underneath the skin. This skin penetration data will be useful for evaluating the safety of cosmetic products containing small peptide cosmetic ingredients. PMID- 24754411 TI - Development and evaluation of a novel in situ gel of sparfloxacin for sustained ocular drug delivery: in vitro and ex vivo characterization. AB - Conventional eye drops are the most popular delivery systems in the treatment of various eye infections. However, the major problem encountered in these dosage forms is precorneal elimination of the drug, resulting in poor bioavailability and therapeutic response. To overcome the side effects of pulsed dosing, an attempt has been made to formulate and evaluate a novel in situ gelling system of Sparfloxacin for sustained ocular drug delivery (ion and pH triggered gelling system). These gelling systems involve the use of sodium alginate (ion sensitive polymer) used as gelling agent and methylcellulose as viscosity-enhancing agent. The developed formulations were evaluated for clarity, pH, gelling capacity, rheological study, in vitro release study, ex vivo corneal permeation study, ocular irritation studies (HET-CAM test) and histopathological study using isolated goat corneas. The formulations were found to be stable, non-irritant and showed sustained release of the drug for a period up to 24 h with no ocular damage. In situ gel of sparfloxacin could be prepared successfully promising their use in ophthalmic delivery. PMID- 24754412 TI - Design and evaluation of novel barrier layer technologies for controlling venlafaxine hydrochloride release from tablet dosage form. AB - CONTEXT: Venlafaxine Hydrochloride (VH) is a highly soluble and highly permeable antidepressant compound. Thus controlling VH release from tablet dosage form over a prolonged period is a challenge. OBJECTIVE: The objective of this work was to study the effect of various barrier layer formulation compositions, its orientations and manufacturing technology on release profile of highly soluble VH. MATERIALS AND METHODS: Different barrier compositions and orientations were established on the same extended release formulations of VH using compression as well as film coating technologies. Barrier effectiveness in reducing the VH release was verified through in vitro dissolution studies. RESULTS AND DISCUSSION: The "belly band" portion of the tablets was successfully oriented in different ways to develop bilayer as well as trilayer tablets. The compression technology had substantially reduced the VH release up to 16% in various compositions and orientation as compared to core tablet. The film coating technology had reduced the VH release up to 14% effectively; thereby shifting the dissolution curve to downside. CONCLUSION: The explored "belly band" portion of the tablets had reduced the VH release substantially. These innovatively created different barrier orientation technologies hold the great promise of commercialization in future. PMID- 24754413 TI - Development of eye drops containing antihypertensive drugs: formulation of aqueous irbesartan/gammaCD eye drops. AB - Aqueous nanoparticulated eye drop formulations based on gamma-cyclodextrin (gammaCD) complexes were developed and tested in vitro. Three antihypertensive drugs, i.e. enalapril maleate, irbesartan and verapamil HCl, that have been shown to possess IOP-lowering activity were selected for this study. All three drugs displayed Bs-type phase-solubility diagrams in aqueous gammaCD solutions and had relatively low affinity for gammaCD. Irbesartan was selected for further formulation development. The drug was relatively stable at pH 4.5 but somewhat less stable at physiologic pH. However, presence of gammaCD in the aqueous media enhanced the chemical stability of irbesartan. Aqueous gammaCD-based eye drop formulations containing 1% and 2% (w/v) irbesartan were prepared and the effect of pH on the particles size distribution and drug release investigated. Only ~2% of the drug was in solution in the pH 4.5 formulations but up to 45% in the pH 7 formulations. The pH 7 formulations, where larger fraction of the drug was in solution, displayed somewhat greater drug permeation flux but much lower drug permeation coefficients than the pH 4.5 formulations. Dynamic light scattering studies indicated the faster permeation was due to formation of smaller particles in presence tyloxapol. PMID- 24754414 TI - Assessment of left ventricular diastolic function by radionuclide ventriculography in patients with chronic heart failure and reduced ejection fraction. AB - STUDY OBJECTIVE: To compare parameters of diastolic function as assessed by radionuclide ventriculography (RNVG) and Doppler echocardiography (ECHO) in the patients with chronic heart failure and reduced ejection fraction (HF REF). PATIENTS AND METHODS: RNVG and ECHO were performed on the same day in 40 patients with systolic chronic HF, NYHA II and III, with LV EF < 50 % and sinus rhythm, followed at tertiary HF clinic. Diastolic function was assessed by RNVG using parameters: PFR (peak filling rate [% SV/sec]), TFR - time to peak filling rate (ms), and by ECHO using pulse Doppler parameters: the peak Doppler velocities of early (E) and late diastolic flow (A), the E/A ratio, the calculated mean of the early (E') diastolic velocity of septal and lateral mitral annulus measured by tissue Doppler imaging, and the E/E' ratio. RESULTS: The mean PFR was 421.7 (median 371.0) % SV/sec and TPF was 198.7 ms (median 169.5), the mean E/A ratio was 1.21 (median 0.85) and the E/E' ratio was 9.0 (median 8.40). TPF correlated significantly (inverse correlation) with the E/A ratio (r = -0.34, p = 0.030), and not significantly with E' (r = -0.27, p = 0.082), the PFR/age ratio correlated with the E/E' ratio (r = -0.31, p = 0.05). CONCLUSION: Significant correlations of parame-ters of diastolic function as assessed by radionuclide and Doppler studies were identified in the HF REF patients. PMID- 24754415 TI - [Dynamics of interleukin 6 levels in the patients with cardiogenic and septic shock and in a control group of patients with uncomplicated AMI]. AB - INTRODUCTION: Cardiogenic shock (CS) is the leading cause of mortality in patients with acute myocardial infarction (AMI). Inflammatory response seems to be common response in patients with AMI, especially those with CS. We have therefore conducted a study to determine diagnostic and prognostic utility of interleukin 6 (IL6) levels in the cohort of patients with cardiogenic and septic shock (SS) and in a control group of patients with uncomplicated AMI. METHODS: In this prospective study 71 patients fulfilled the inclusion criteria: 30 patients with cardiogenic shock, 21 patients with septic shock and 20 patients with ST elevation myocardial infarction (STEMI). Plasma levels of IL6 were measured at 8 time points. The main endpoint was 3 month mortality. RESULTS: We have shown that the highest IL6 levels during the first week were recorded in patients with septic shock with peak value at admission. The maximum level of IL6 was detected between 12 to 24 hours after the onset of MI among patients with cardiogenic shock. According to Receiver operating characteristic (ROC) statistics levels of IL6 > 357 pg/ml at admission (AUC 0.730, p = 0.031) were typical for patients with CS in comparison with control group of STEMI patients. Values of IL6 > 1 237 pg/ml at admission and > 1 071 pg/ml at 24 hours (after admission?) were typical for thouse in septic shock in comparison with CS patients. We found only a non significant trend of IL6 for the prediction of mortality in the cohort of CS patients for levels 1 854 pg/ml (AUC 0.769, p = 0.066) sampled 12 hours after admission. There was no association of plasma levels of IL6 with mortality in septic shock patients. CONCLUSIONS: Patients with cardiogenic shock demonstrated more pronounced cytokine response as evidenced by increased levels of IL6 compared to patients with uncomplicated STEMI. Levels of IL6 peaked in SS patients at admission, in CS patients 12-24 hours after admission. In daily clinical practice routine measurement of IL6 levels for prediction of prognosis both in cardiogenic and septic shock are of little value mainly due to significant interindividual variability of IL6 values. PMID- 24754416 TI - [MRI compatible cardiac pacemakers and implantable cardioverter defibrillators]. AB - Implanted cardiac pacemaker (PM) or implantable cardioverter defibrillator (ICD) has been so far considered a contra-indication to magnetic resonance imaging (MRI). In the last few years MRI conditional cardiac implantable electronic devices have been marketed enabling patients undergo MRI under specific conditions. We present current state of the art and provide overview of available MRI conditional devices. Magnetic resonance imaging in these patients should be performed only in cases where the requested information can not be obtained using alternative imaging technique. PMID- 24754417 TI - [Oral infection and rheumatic diseases]. AB - Periodontitis (PD) is one of the most common infectious diseases of dental attachment. From epidemiological studies there is known association of periodontitis with chronic diseases as for example diabetes mellitus, cardiovacular diseases, atherosclerosis or Crohn disease. In last decade there is an increasing evidence for association of rheumatoid arthritis (RA) and periodontitis also. RA and PD have some common genetic, environmental and immunopathological characters. Important aspect of reciprocal relationship is also ability to citrullination, which is innate to one of most important oral patogen - Porphyromonas gingivalis. Citrullination and production of autoantibodies against this modified proteins is one the important pathophysiological actions in course of RA. Recently, there has been published papers drawing attention to potential influence of periodontitis therapy to course and activity of RA. Furthermore there appear some information pointing to possible association between PD and other rheumatic diseases as for exam-ple spondyloarthritis. Interrelationship between PD and rheumatic diseases thus stay important and still open question in research of pathophysiology, course and therapeutic possibilities of rheumatic diseases. PMID- 24754418 TI - [Renal denervation for treatment of arterial hypertension - the unanswered questions]. AB - Despite the extensive armamentarium of antihypertensive medication available, the control of hypertension remains poor. Therefore any possibilities of non pharmacological treatment of resistant hypertension are welcome. Recently, close attention was paid to renal denervation. Present work summarizes the scientific reports and clinical trials related to this topic published so far and addresses the unanswered questions. Moreover, it also contains brief summary of authors own experience with the method. PMID- 24754419 TI - [Therapy of Waldenstrom's macroglobulinaemia in the year 2014]. AB - Therapy of Waldenstrom's macroglobulinaemia (WM) is indicated in patients with clinically relevant symptoms. Therapeutic plasmapheresis should be performed in cases with hyperviscosity. The intensity of chemotherapy should be adjusted to the degree of cytopenia. Monotherapy with rituximab is recommended in cases with severe cytopenia, also combination of rituximab with dexamethasone should be possible. Patients with symptomatic WM without severe cytopenia should received a rituximab-containing regimens, optimal variant is combination of rituximab + dexamethasone + alkylation drug (such as cyclophosphamide or bendamustine). Possible treatment combinations are for instance R-CHOP (rituximab, cyclophosphamide, vincristine, and prednisone), R-COP (rituximab, cyclophosphamide, and prednisone), or RCD (rituximab, cyclophosphamide, and dexamethasone). The choice of regimen in individual patients will take into consideration performance status, clinical features including renal function, comorbidities and potential candidacy for stem cell transplantation.Chlorambucil and rituximab is possible treatment options for older patients. The choice of treatment of WM relapse depends on the time of treatment response. Retreatment with primary therapy may be appropriate in patients with duration of treatment response at least 2 years. Other treatment possibilities for WM relapse are regimens containing fludarabine, cladribine or bortezomib. Autologous transplantation of peripheral blood stem cells is feasible therapeutic option for relapsed WM in younger, fitter patients with aggressive chemosensitive disease. PMID- 24754420 TI - [The place of JAK2 inhibitors in the treatment of myelofibrosis. An amendment to the recommendations for diagnosis and treatment of Ph negative myeloproliferations of the Czech group for Ph- myeloproliferative disorders (CZEMP)]. AB - Primary myelofibrosis (PMF) belongs to Ph- myeloproliferative diseases. The only curative treatment is hematopoietic stem cell transplantation (HSCT). Conservative treatment options comprise supportive care, especially administration of red blood cell and platelet transfusions, and medication. Hydroxyurea, interferon alpha, anagrelide, corticosteroids, androgens, or inhibitors of angiogenesis (thalidomide, lenalidomide, pomalidomide) may be used for treatment of PMF, depending on the clinical stage and disease symptoms present. Also splenectomy or radiotherapy of enlarged spleen have palliative potential. JAK2 kinase inhibitors represent a novel class of drugs with a very dynamic development. Ruxolitinib, an oral selective inhibitor of JAK1 and JAK2 kinases, has shown high efficacy in patients with high-risk PMF (or with myelofibrosis following polycythemia vera or essential thrombocythemia) to ameliorate disease symptoms and to reduce splenomegaly in randomized trials COMFORT-I and COMFORT-II. Long-term monitoring of the enrolled patients demonstated prolongation of overall survival. The drug is well-tolerated, the most common side effects of treatment with ruxolitinib being deepening of thrombocytopenia and temporary worsening of anemia. The current review deals with the place of JAK2 inhibitors (and the only drug already approved for clinical use - ruxolitinib) in the management of PMF, as an addendum to the Summary of recommendations for the diagnosis and therapy of BCR/ABL-negative myeloproliferations of the Czech Hematological Societys CZEMP. PMID- 24754421 TI - [Isolated ventricular non-compaction: review article with a case-report example]. AB - Isolated ventricular non-compaction (IVNC) is rare, genetically determined disorder characterized by prominent trabecularization of luminal side of the ventricular wall with deep recesses. The disease is believed to arise due to an in utero arrest of the compaction of the former loose meshwork of myocardial trabeculations. The symptoms of the disease include: heart failure, thromboembolic complications and arrhythmias. The course of the disease is variable ranging from patients with IVNC diagnosis as an incidental finding, to cases of severe heart failure and sudden cardiac death. This article brings an overview of the current state of knowledge on the disease and finally presents a short case-report of patient with IVNC. PMID- 24754422 TI - [Catheter related septic central venous thrombosis of the superior vena cava and right atrium]. AB - Catheter related septic central venous thrombosis (CR-SCVT) is an uncommon but serious complication related to central venous catheter use. Prolonged sepsis, late detection of the right diagnosis, difficult, long and costly treatment (and its own complications) threaten patients with further, potentially lethal complications. By the patients with an evidence of catheter sepsis, which persists despite targeted antibiotic therapy, it is important to think of this possible complication. Diagnosis can be determined by a combination of clinical, laboratory, microbiological and imaging techniques, from which is transesophageal echocardiography the most useful diagnostic test. Treatment of CR-SCVT consists of long-term targeted antibiotic therapy, the role of anticoagulation is not clearly solved. The article presents case studies of four patients diagnosed and treated in our clinic for infected thrombus in the superior vena cava and right atrium in relation with a central venous catheter. It also compares our diagnostic and therapeutic strategies with the similar cases described in literature. PMID- 24754423 TI - Pathological gambling and alcohol dependence: neural disturbances in reward and loss avoidance processing. AB - Pathological gambling (PG) shares clinical characteristics such as craving and loss of control with substance use disorders and is thus considered a behavioral addiction. While functional alterations in the mesolimbic reward system have been correlated with craving and relapse in substance use disorders, only a few studies have examined this brain circuit in PG, and no direct comparison has been conducted so far. Thus, we investigated the neuronal correlates of reward processing in PG in contrast to alcohol-dependent (AD) patients and healthy subjects. Eighteen PG patients, 15 AD patients and 17 controls were investigated with a monetary incentive delay task, in which visual cues predict the consequence (monetary gain, avoidance of loss, none) of a fast response to a subsequent target stimulus. Functional magnetic resonance imaging data were analyzed to account for possible confounding factors such as local gray matter volume. Activity in the right ventral striatum during loss anticipation was increased in PG patients compared with controls and AD patients. Moreover, PG patients showed decreased activation in the right ventral striatum and right medial prefrontal cortex during successful loss avoidance compared with controls, which was inversely associated with severity of gambling behavior. Thus, despite neurobiological similarities to substance use disorders in reward processing, as reported by previous studies, we found relevant differences with respect to the anticipation of loss as well as its avoidance (negative reinforcement), which further contributes to the understanding of PG. PMID- 24754424 TI - AP1S1 defect causing MEDNIK syndrome: a new adaptinopathy associated with defective copper metabolism. AB - MEDNIK (mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia) syndrome has been recently described as a new disorder of copper metabolism. This multisystem disease combines clinical and biochemical signs of both Menkes and Wilson's diseases, in which liver copper overload is treatable using zinc acetate therapy. MEDNIK syndrome is caused by mutation of the AP1S1 gene, which codes for the sigma1A subunit of adaptor protein complex 1, and directs intracellular trafficking of copper pumps ATP7A and ATP7B. Adaptor protein complexes regulate clathrin-coated vesicle assembly, protein cargo sorting, and vesicular trafficking between organelles in eukaryotic cells. A growing number of diseases have been associated with mutations in genes coding for adaptor protein complexes subunits and we propose for them the term adaptinopathies, as a new organic category of disorders of intracellular trafficking, which offers the opportunity to dissect the mechanisms involved in the crosstalk between the Golgi apparatus and the other organelles. PMID- 24754425 TI - Mixed-ligand approach to design of heterometallic single-source precursors with discrete molecular structure. AB - Heterometallic single-source precursors for the Pb/Fe = 1:1 oxide materials, PbFe(beta-dik)4 (beta-dik = hexafluoroacetylacetonate (hfac, 1), acetylacetonate (acac, 2), and trifluoroacetylacetonate (tfac, 4)), have been isolated by three different solid-state synthetic methods. The crystal structures of heterometallic diketonates 1, 2, and 4 were found to contain polymeric chains built on alternating [Fe(beta-dik)2] and [Pb(beta-dik)2] units that are held together by bridging M-O interactions. Heterometallic precursors are highly volatile, but soluble only in coordinating solvents, in which they dissociate into solvated homometallic fragments. In order to design the heterometallic precursor with a proper metal/metal ratio and with a discrete molecular structure, we used a combination of two different diketonate ligands. Heteroleptic complex Pb2Fe2(hfac)6(acac)2 (5) has been obtained by optimized stoichiometric reaction of an addition of homo-Fe(acac)2 to heterometallic Pb2Fe(hfac)6 (3) diketonate that can be run in solution on a high scale. The combination of two ligands with electron-withdrawing and electron-donating groups allows changing the connectivity pattern within the heterometallic assembly and yields the precursor with a discrete tetranuclear structure. In accord with its molecular structure, heteroleptic complex 5 is soluble even in noncoordinating solvents and was found to retain its heterometallic structure in solution. Thermal decomposition of heterometallic precursors in air at 750 degrees C resulted in the target Pb2Fe2O5 oxide, a prospective multiferroic material. Prolonging the annealing time or increasing the decomposition temperature leads to another phase-pure lead iron oxide PbFe12O19 that is a representative of the important family of magnetic hexaferrites. PMID- 24754426 TI - Protective effects of dimethyl sulfoxide on labile protein interactions during electrospray ionization. AB - Electrospray ionization mass spectrometry is a valuable tool to probe noncovalent interactions. However, the integrity of the interactions in the gas-phase is heavily influenced by the ionization process. Investigating oligomerization and ligand binding of transthyretin (TTR) and the chaperone domain from prosurfactant protein C, we found that dimethyl sulfoxide (DMSO) can improve the stability of the noncovalent interactions during the electrospray process, both regarding ligand binding and the protein quaternary structure. Low amounts of DMSO can reduce in-source dissociation of native protein oligomers and their interactions with hydrophobic ligands, even under destabilizing conditions. We interpret the effects of DMSO as being derived from its enrichment in the electrospray droplets during evaporation. Protection of labile interactions can arise from the decrease in ion charges to reduce the contributions from Coulomb repulsions, as well as from the cooling effect of adduct dissociation. The protective effects of DMSO on labile protein interactions are an important property given its widespread use in protein analysis by electrospray ionization mass spectrometry (ESI-MS). PMID- 24754427 TI - Sleep disturbances, anxiety and depression in patients with oral lichen planus: a case-control study. AB - BACKGROUND: The psychological factors and their association with chronic inflammatory disease, aren't well recognized, yet their importance in oral lichen planus is still debated. AIMS: The aim of this study was to investigate the prevalence of sleep disturbances, anxiety, depression and their association in patient with oral lichen planus. MATERIALS AND METHODS: 50 patients with oral lichen planus vs. equal number of age and sex-matched healthy controls were enrolled. Questionnaires examining insomnia symptoms, excessive daytime sleepiness (Pittsburgh sleep quality index and Epworth aleepiness scale) depression and anxiety (The Hamilton rating scale for Depression and Anxiety) were used. RESULTS: The patients with oral lichen planus had statistically higher scores in all items of the Pittsburgh sleep quality index, the Hamilton rating scale for depression and anxiety and Epworth sleepiness scale than the healthy controls. The median and inter-quartile range of the Pittsburgh sleep quality index was 5-2 and for the oral lichen planus patients and 4-2 for the healthy controls (P < 0.011). In the study group, a depressed mood and anxiety correlated positively with sleep disturbances. The Pearson correlations were 0.76 for Pittsburgh sleep quality Index vs. Hamilton rating scale for depression (P < 0.001) and 0.77 for Pittsburgh sleep quality Index vs. Hamilton rating scale for anxiety (P < 0.001). DISCUSSION: Oral lichen planus patients report a greater degree of sleep problems, depressed mood and anxiety as compared with controls. CONCLUSION: We suggest to screen sleep disturbances in patients with oral lichen planus because they could be considered a prodromal symptoms of mood disorders. PMID- 24754428 TI - Step-along power vector method for astigmatic wavefront propagation. AB - PURPOSE: To propose both a new algebraic solution and a graphical monitoring method for astigmatic wavefront propagation in the framework provided by power vectors. METHODS: The generalised propagation equation describing the propagation of astigmatic wavefronts from one plane to another is adapted to the power vectors formalism using a novel algorithm based on a step-along method. The step along procedure is directly applied to the tuple of power vectors [M, J0 , J45 ] representing an arbitrary astigmatic wavefront and it permits the calculation of the tuple of power vectors [M', J'0 , J'45 ] after a given propagation distance. This is achieved mathematically first by temporarily rotating the astigmatic wavefront so that one of the principal meridians is horizontal, then propagating the wavefront, and finally rotating the propagated wavefront back to its original orientation. RESULTS: A transfer rule for power vectors representing astigmatic wavefronts is analytically obtained. The new algorithm provides an algebraic solution for the propagation of astigmatic wavefronts using power vectors in a homogeneous medium. In addition, the new step-along procedure allows 2D as well as 3D graphical monitoring of the astigmatic wavefront being referred to the X-Y conventional reference framework by virtue of the trajectories of the power vector coordinates. The proposed solution has been validated through several numerical examples. CONCLUSIONS: A new step-along method for astigmatic wavefront propagation using power vectors has been presented and validated for classical as well as new numerical examples. The method provides algebraic calculation as well as graphical monitoring of the wavefront vergence during propagation. PMID- 24754429 TI - Theoretical model of the contributions of corneal asphericity and anterior chamber depth to peripheral wavefront aberrations. AB - PURPOSE: The purpose of this study was to theoretically model the contributions of corneal asphericity (Q) and anterior chamber depth to peripheral wavefront aberrations. METHODS: Ray-tracing was performed on a model eye using a customised MatLab program to calculate Zernike aberrations up to the 5th order across +/-60 degrees of the horizontal visual field. The corneal Q was varied from -0.5 to 0.8, and the anterior chamber depth was changed from 2.05 to 4.05 mm while axial length was held constant. Spherical equivalent refractive error derived from Zernike defocus was used to estimate peripheral refraction. RESULTS: Relative to axial Zernike aberrations, both defocus and astigmatism in the peripheral field increased with the corneal Q value, but the increases in relative peripheral astigmatism were much smaller in amplitude than relative peripheral defocus. Anterior chamber depth shortening caused the relative peripheral defocus and astigmatism to increase toward more positive values, although the changes in relative peripheral astigmatism with anterior chamber depth were small. Combination of the variations in both corneal Q and anterior chamber depth does not produce linear sum of the changes in relative peripheral defocus. The relative peripheral refractive error was more myopic when either the corneal Q was increased or the anterior chamber depth was shortened. The changes in relative peripheral x-axis coma, trefoil and spherical aberration with corneal Q value were complex but were barely changed with anterior chamber depth within the central 60 degrees visual field. CONCLUSIONS: Both corneal asphericity and anterior chamber depth play important roles in determining peripheral wavefront aberrations. The two factors nonlinearly interact to affect peripheral aberrations. Higher corneal Q and/or shorter anterior chamber depth tend to produce relatively more myopic peripheral refraction. Increasing the Q value of the anterior surface of a contact lens might provide an interesting intervention to slow myopia progression. PMID- 24754430 TI - The impact of postgraduate training on UK optometrists' clinical decision-making in glaucoma. AB - PURPOSE: To investigate the impact of a postgraduate training module on optometrists' clinical decision-making in relation to the diagnosis and management of primary open-angle glaucoma. METHODS: A group of United Kingdom community optometrists (n = 53) were assessed immediately before and again 3 months after completing a 3-day didactic postgraduate university module on the diagnosis and management of glaucoma. A smaller control cohort (n = 20), who did not receive the intervention, was recruited and completed the same assessments on two occasions, separated by approximately 3 months. The assessments comprised: knowledge of five key features of the optic disc in glaucoma, performance on a computer program (Discus) that assessed the ability to differentiate normal from glaucomatous discs and a clinical decision-making exercise using case-based scenarios. RESULTS: The scores for the knowledge of important disc features for the intervention cohort significantly increased from a median of 2/5 to 5/5 post intervention (p < 0.001). For the control cohort, the difference in median scores between the two tests was not significant. Analysing the performance of the intervention cohort using the Discus program showed no significant improvement in ability to diagnose a glaucomatous disc following the intervention [mean area under the receiver operating characteristic curve pre-intervention = 0.85 (95% CI: 0.76-0.91), post-intervention = 0.84 (95% CI: 0.76-0.91)]. Similarly, there were no statistically significant differences in mean areas under the receiver operating characteristic curve between tests for the control cohort, although both cohorts compared favourably with a previously published Discus data set from a panel of experts in disc analysis (mean area = 0.87). For the clinical decision making exercise the median test score for the intervention cohort was unchanged pre- and post-intervention. CONCLUSION: The results of the present study suggest that a traditional didactic approach, in isolation, is unlikely to be suited to training optometrists to achieve or develop the clinical competencies required for glaucoma detection and management. Consideration should be given to the development of specialist postgraduate training that is more practice-based, provides opportunities for active learning and includes strategies for feedback and reinforcement. PMID- 24754431 TI - Annual conference 2013 highlights. PMID- 24754432 TI - Genetic diseases, immunology, viruses, and gene therapy. PMID- 24754435 TI - Catalytic asymmetric aza-ene reaction of 3-indolylmethanols with cyclic enaminones: enantioselective approach to C3-functionalized indoles. AB - The catalytic asymmetric aza-ene reactions of 3-indolylmethanols with cyclic enaminones and the highly enantioselective aza-ene reactions utilizing cyclic aza ene components have been established, which directly assemble isatin-derived 3 indolylmethanols and dimedone-derived enaminones into C3-functionalized chiral indoles with one all-carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 99% yield, up to 95:5 er). PMID- 24754436 TI - A new call for the prevention of primary cesarean delivery. PMID- 24754437 TI - IL-1beta associations with posttraumatic epilepsy development: a genetics and biomarker cohort study. AB - OBJECTIVE: Posttraumatic epilepsy (PTE) is a significant complication following traumatic brain injury (TBI), yet the role of genetic variation in modulating PTE onset is unclear. We hypothesized that TBI-induced inflammation likely contributes to seizure development. We assessed whether genetic variation in the interleukin-1beta (IL-1beta) gene, IL-1beta levels in cerebrospinal fluid (CSF) and serum, and CSF/serum IL-1beta ratios would predict PTE development post-TBI. METHODS: We investigated PTE development in 256 Caucasian adults with moderate-to severe TBI. IL-1beta tagging and functional single nucleotide polymorphisms (SNPs) were genotyped. Genetic variance and PTE development were assessed. Serum and CSF IL-1beta levels were collected from a subset of subjects (n = 59) during the first week postinjury and evaluated for their associations with IL-1beta gene variants, and also PTE. Temporally matched CSF/serum IL-1beta ratios were also generated to reflect the relative contribution of serum IL-1beta to CSF IL-1beta. RESULTS: Multivariate analysis showed that higher CSF/serum IL-1beta ratios were associated with increased risk for PTE over time (p = 0.008). Multivariate analysis for rs1143634 revealed an association between the CT genotype and increased PTE risk over time (p = 0.005). The CT genotype group also had lower serum IL-1beta levels (p = 0.014) and higher IL-1beta CSF/serum ratios (p = 0.093). SIGNIFICANCE: This is the first report implicating IL-1beta gene variability in PTE risk and linking (1) IL-1beta gene variation with serum IL 1beta levels observed after TBI and (2) IL-1beta ratios with PTE risk. Given these findings, we propose that genetic and IL-1beta ratio associations with PTE may be attributable to biologic variability with blood-brain barrier integrity during TBI recovery. These results provide a rationale for further studies (1) validating the impact of genetic variability on IL-1beta production after TBI, (2) assessing genetically mediated signaling mechanisms that contribute to IL 1beta CSF/serum associations with PTE, and (3) evaluating targeted IL-1beta therapies that reduce PTE. PMID- 24754439 TI - Advances in research of the neuroprotective mechanisms of cerebral ischemic postconditioning. AB - Ischemic postconditioning refers to controlling reperfusion blood flow during reperfusion after ischemia, which can induce an endogenous neuroprotective effect and reduce ischemia-reperfusion injury. Activation of endogenous neuroprotective mechanisms plays a key role in protecting against brain ischemia-reperfusion injury. The mechanisms of cerebral ischemic postconditioning are not completely clear, and the following aspects may be involved: downregulation of oxidative stress, attenuating mitochondrial dysfunction, attenuating endoplasmic reticulum stress, accelerating the elimination of glutamate, increasing rCBF, inhibiting apoptosis, inhibiting autophagy, and regulating signal transduction. PMID- 24754438 TI - Berberine ameliorates renal interstitial fibrosis induced by unilateral ureteral obstruction in rats. AB - AIM: To investigate the potential effects of berberine on renal interstitial fibrosis (RIF) of obstructed kidneys in a unilateral ureteral obstruction (UUO) rat model. METHODS: Forty-eight rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and berberine-treated UUO. Rats were gavaged with berberine (200 mg/kg per day) or vehicle. Eight randomly chosen rats in each group were kiled and specimens were collected at day 14 after UUO. Physiological parameters and histological changes were assessed, RIF was evaluated using Masson's trichrome and Sirius red staining, oxidative stress and inflammation markers were determined, transforming growth factor beta1 (TGF-beta1), phosphorylated Smad3 (pSmad3) and alpha-smooth muscle actin (alpha-SMA) were measured using immunohistochemistry or western blotting analysis. The obstruction was relieved at day 14 by percutaneous nephrostomy in the remaining UUO rats. The resistive index of left kidneys was undertaken by coloured Doppler flow imaging at day 14 before nephrostomy and day 7 after the relief. RESULTS: Berberine treatment significantly attenuated RIF induced by UUO. The UUO-induced reduction in kidney superoxide dismutase and catalase activities increased, whereas elevated kidney malondialdehyde level markedly decreased. Berberine treatment significantly ameliorated UUO-induced inflammation, and decreased TGF-beta1, pSmad3 and alpha-SMA expression of UUO kidneys. Moreover, berberine treatment significantly suppressed the increase of resistive index compared with UUO group at day 14 after UUO as well as day 7 after the relief of obstruction. CONCLUSION: Berberine treatment ameliorates RIF in a UUO rat model by inhibition of oxidative stress, inflammatory responses, and TGF-beta1/pSmad3 signalling. PMID- 24754440 TI - A mixed-methods pilot study of the acceptability and effectiveness of a brief meditation and mindfulness intervention for people with diabetes and coronary heart disease. AB - Mindfulness-based interventions can successfully target negative perseverative cognitions such as worry and thought suppression, but their acceptability and effectiveness in people with long-term conditions is uncertain. We therefore pilot tested a six-week meditation and mindfulness intervention in people (n = 40) with diabetes mellitus and coronary heart disease. We used a sequential mixed methods approach that measured change in worry and thought suppression and qualitatively explored acceptability, feasibility, and user experience with a focus group (n = 11) and in-depth interviews (n = 16). The intervention was highly acceptable, with 90% completing >=5 sessions. Meditation and mindfulness skills led to improved sleep, greater relaxation, and more-accepting approaches to illness and illness experience. At the end of the six-week meditation course, worry, and thought suppression were significantly reduced. Positive impacts of mindfulness-based interventions on psychological health may relate to acquisition and development of meta-cognitive skills but this needs experimental confirmation. PMID- 24754441 TI - The GHQ-12 for the assessment of psychological distress of family caregivers. AB - This study examined the utility of the 12-item General Health Questionnaire (GHQ 12) to assess the psychological distress of family caregivers. To accomplish this goal, a sample of 172 caregivers, 25 men and 147 women, aged 56.6 (SD = 13.7) completed self-report questionnaires and provided data on demographic factors. Univariate and bivariate models adjust adequately, although the two-factor model (anxiety/depression and social dysfunction) presented a better fit. Relative caregivers scored higher in psychological distress (anxiety and depression levels) on the GHQ-12 than did the normal population. In conclusion, the GHQ-12 is a sensitive instrument to detect the presence of anxiety and depression in relative caregivers, and the external validity of the instrument is generally adequate. The GHQ-12 seems particularly appropriate for research and clinical and health intervention in caregivers. Implications and limitations of these results are discussed, along with suggestions for future research. PMID- 24754442 TI - Outcomes of patients with prior coronary artery bypass graft who present with acute coronary syndrome. AB - Generally, patients with prior coronary artery bypass graft (CABG) are often under-represented in acute coronary syndrome (ACS) clinical trials. Nevertheless, there is growing global attention concerning their short- and long-term prognosis. Some reports suggest prior CABG as an independent risk factor for increased mortality, while others report an equal or a more favorable prognosis despite their adverse baseline clinical characteristics. The reasons for this 'risk-mortality paradox' need to be further evaluated. More recent reports showed a significant reduction in in-hospital morbidity and mortality over a 20-year period of follow up that may be attributed to the improvement in surgical CABG techniques and increased use of evidence-based therapies over the past two decades. In the current review we discuss the available literature regarding outcomes of prior CABG patients who are presenting with ACS. PMID- 24754443 TI - Advances in the chemistry of oxaziridines. PMID- 24754444 TI - The oldest known priapulid-like scalidophoran animal and its implications for the early evolution of cycloneuralians and ecdysozoans. AB - Morphological phylogenetic analyses suggest that scalidophorans (priapulids, loriciferans, and kinorhynchs) and nematoids (nematodes and nematomorphs) form the ecdysozoan clade Cycloneuralia, which is a sister group to panarthropods. It has been proposed that extant priapulids and Cambrian priapulid-like scalidophorans, because of their conserved evolution, have the potential to illuminate the ancestral morphology, ecology, and developmental biology of highly derived ecdysozoans such as nematods and arthropods. As such, Cambrian fossils, particularly Markuelia and possibly olivooids, can inform the early evolution of scalidophorans, cycloneuralians, and ecdysozoans. However, the scalidophoran Markuelia is known exclusively as embryo fossils, and the olivooids have been alternatively interpreted as cnidarians or cycloneuralians. Here, we describe a post-embryonic scalidophoran fossil Eopriapulites sphinx new genus and species, which represents the oldest known scalidophoran, from the early Cambrian Period (~535 Ma) in South China. E. sphinx is similar to modern scalidophorans in having an introvert armed with hollow scalids, a collar with coronal scalids, and a pharynx with pharyngeal teeth, but its scalids and pharyngeal teeth are arranged in a hexaradial pattern. Phylogenetically resolved as a stem-group scalidophoran, E. sphinx shares a hexaradial pattern with the hexaradial arrangement of certain anatomical structures in kinorhynchs, loriciferans, nematoids, and Cambrian fossils such as Eolympia pediculata, which could also be a scalidophoran. Thus, the bodyplan of ancestral cycloneuralians may have had a component of hexaradial symmetry (i.e., some but not necessarily all anatomical parts are hexaradially arranged). If panarthropods are nested within paraphyletic cycloneuralians, as several molecular phylogenetic analyses suggest, the ancestral ecdysozoans may have been a legless worm possibly with a component of hexaradial symmetry. PMID- 24754445 TI - Single-crystal growth and size control of three novel polar intermetallics: Eu2.94(2)Ca6.06In8Ge8, Eu3.13(2)Ca5.87In8Ge8, and Sr3.23(3)Ca5.77In8Ge8 with crystal structure, chemical bonding, and magnetism studies. AB - Three new quaternary polar intermetallic compounds of Eu2.94(2)Ca6.06In8Ge8, Eu3.13(2)Ca5.87In8Ge8, and Sr3.23(3)Ca5.77In8Ge8 have been synthesized by a metal flux method using molten indium metal as a reactive flux, and the novel isotypic crystal structures have been characterized by both powder and single-crystal X ray diffractions. All compounds crystallize in the orthorhombic space group Pmmn (Z = 2, Pearson symbol oP50) with 14 crystallographically unique atomic positions in the asymmetric unit. The lattice parameters are refined as follows: a = 36.928(2) A, b = 4.511(1) A, and c = 7.506(1) A for Eu2.94(2)Ca6.06In8Ge8; a = 37.171(19) A, b = 4.531(2) A, and c = 7.560(4) A for Eu3.13(2)Ca5.87In8Ge8; and a = 37.350(2) A, b = 4.550(3) A, and c = 7.593(4) A for Sr3.23(3)Ca5.77In8Ge8. In particular, single crystals of two Eu-containing compounds are obtained as bundles of bar/needle-shaped crystals, and the thicknesses of those crystals can be controlled in the range between ca. 300 MUm and ca. <10 MUm by adjusting several reaction conditions, including the reaction cooling rate and the centrifugation temperature. The overall crystal structure is illustrated as an assembly of (1) the three-dimensional anionic framework, which is formed by the chains of edge-sharing InGe4 tetrahedra and the annulene-like "12-membered anionic rings" connected via Ge2 dimers, and (2) the cationic mixed sites embedded in the space between the anionic frameworks. Theoretical investigations based on tight-binding linear muffin-tin orbital (TB-LMTO) calculations provide a comprehesive understanding of the overall electronic structure and chemical bonding observed among anionic components and between anions and cations. Electron localization function (ELF) and electron density map present chemical bond strengths and polarization within the anionic framework. Magnetic susceptibility measurement proves an antiferromagnetic (AFM) ordering of Eu atoms below 4 K with a reduced effective magnetic moment of 7.12 MUB for the Eu atom. PMID- 24754446 TI - The roles of the shikimate pathway genes, aroA and aroB, in virulence, growth and UV tolerance of Burkholderia glumae strain 411gr-6. AB - Burkholderia glumae is the major causal agent of bacterial panicle blight of rice, which is a growing disease problem for rice growers worldwide. In our previous study, some B. glumae strains showed pigmentation phenotypes producing at least two (yellow-green and purple) pigment compounds in casein-peptone glucose agar medium. The B. glumae strains LSUPB114 and LSUPB116 are pigment deficient mutant derivatives of the virulent and pigment-proficient strain 411gr 6, having mini-Tn5gus insertions in aroA encoding 3-phosphoshikimate 1 carboxyvinyltransferase and aroB encoding 3-dehydroquinate synthase, respectively. Both enzymes are known to be involved in the shikimate pathway, which leads to the synthesis of aromatic amino acids. Here, we demonstrate that aroA and aroB are required for normal virulence in rice and onion, growth in M9 minimal medium and tolerance to UV light, but are dispensable for the production of the phytotoxin toxoflavin. These results suggest that the shikimate pathway is involved in bacterial pathogenesis by B. glumae without a significant role in the production of toxoflavin, a major virulence factor of this pathogen. PMID- 24754447 TI - A small structural change resulting in improved properties for product development. AB - AZD9343 is a water-soluble gamma amino butyric acid (GABAB) agonist intended for symptomatic relief in gastroesophageal reflux disease (GERD) patients. The compound has good chemical stability in aqueous solutions, as well as in the solid state. Only one crystal modification has been observed to date. This polymorph is slightly hygroscopic (1.5% water uptake at 80% relative humidity (RH)), which is an improvement compared to the structurally similar agonist lesogaberan (AZD3355) which liquefies at 65% RH. Since the substance is very polar and lacks a UV chromophore, conventional separation and detection techniques cannot be used to characterize the substance and its impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for assay and purity, the liquid chromatographic method for enantiomeric separation with derivatization with UV chromophore and three complementary nuclear magnetic resonance (NMR) approaches ((31)P-NMR, (13)C-NMR and (1)H-NMR) for impurities. For oral solutions, it was important to select the right concentration of phosphate buffer for the specific drug concentration and routinely use small additions of EDTA. I.V. solutions containing physiological saline as tonicity modifier could not be stored frozen at -20 degrees C. Properties of AZD9343 will be discussed in light of experiences from the structurally similar lesogaberan and (2R)-(3-amino-2 fluoropropyl)sulphinic acid (AFPSiA). PMID- 24754448 TI - Microbial production of specialty organic acids from renewable and waste materials. AB - Microbial production of organic acids has become a fast-moving field due to the increasing role of these compounds as platform chemicals. In recent years, the portfolio of specialty fermentation-derived carboxylic acids has increased considerably, including the production of glyceric, glucaric, succinic, butyric, xylonic, fumaric, malic, itaconic, lactobionic, propionic and adipic acid through innovative fermentation strategies. This review summarizes recent trends in the use of novel microbial platforms as well as renewable and waste materials for efficient and cost-effective bio-based production of emerging high-value organic acids. Advances in the development of robust and efficient microbial bioprocesses for producing carboxylic acids from low-cost feedstocks are also discussed. The industrial market scenario is also reviewed, including the latest information on the stage of development for producing these emerging bio-products via large scale fermentation. PMID- 24754449 TI - Advances in the biotechnology of hydrogen production with the microalga Chlamydomonas reinhardtii. AB - Biological hydrogen production is being evaluated for use as a fuel, since it is a promising substitute for carbonaceous fuels owing to its high conversion efficiency and high specific energy content. The basic advantages of biological hydrogen production over other "green" energy sources are that it does not compete for agricultural land use, and it does not pollute, as water is the only by-product of the combustion. These characteristics make hydrogen a suitable fuel for the future. Among several biotechnological approaches, photobiological hydrogen production carried out by green microalgae has been intensively investigated in recent years. A select group of photosynthetic organisms has evolved the ability to harness light energy to drive hydrogen gas production from water. Of these, the microalga Chlamydomonas reinhardtii is considered one of the most promising eukaryotic H2 producers. In this model microorganism, light energy, H2O and H2 are linked by two excellent catalysts, the photosystem 2 (PSII) and the [FeFe]-hydrogenase, in a pathway usually referred to as direct biophotolysis. This review summarizes the main advances made over the past decade as an outcome of the discovery of the sulfur-deprivation process. Both the scientific and technical barriers that need to be overcome before H2 photoproduction can be scaled up to an industrial level are examined. Actual and theoretical limits of the efficiency of the process are also discussed. Particular emphasis is placed on algal biohydrogen production outdoors, and guidelines for an optimal photobioreactor design are suggested. PMID- 24754450 TI - ATP7A trafficking and mechanisms underlying the distal motor neuropathy induced by mutations in ATP7A. AB - Diverse mutations in the gene encoding the copper transporter ATP7A lead to X linked recessive Menkes disease or occipital horn syndrome. Recently, two unique ATP7A missense mutations, T994I and P1386S, were shown to cause isolated adult onset distal motor neuropathy. These mutations induce subtle defects in ATP7A intracellular trafficking resulting in preferential accumulation at the plasma membrane compared to wild-type ATP7A. Immunoprecipitation assays revealed abnormal interaction between ATP7A(T994I) and p97/VCP, a protein mutated in two autosomal dominant forms of motor neuron disease. Small-interfering RNA knockdown of valosin-containing protein corrected ATP7A(T994I) mislocalization. For ATP7A(P1386S) , flow cytometry documented that nonpermeabilized fibroblasts bound a C-terminal ATP7A antibody, suggesting unstable insertion of the eighth transmembrane segment due to a helix-breaker effect of the amino acid substitution. This could sabotage interaction of ATP7A(P1386S) with adaptor protein complexes. These molecular events appear to selectively disturb normal motor neuron function and lead to neurologic illness that takes years and sometimes decades to develop. PMID- 24754452 TI - Size-to-charge dispersion of collision-induced dissociation product ions for enhancement of structural information and product ion identification. AB - Ion mobility is used to disperse product ions formed by collision-induced dissociation (CID) on the basis of charge state and size-to-charge ratio. We previously described an approach for combining CID with ion mobility mass spectrometry (IM-MS) for dispersing fragment ions along charge state specific trend lines (Zinnel, N. F.; Pai, P. J.; Russell, D. H. Anal. Chem. 2012, 84, 3390; Sowell, R. A.; Koeniger, S. L.; Valentine, S. J.; Moon, M. H.; Clemmer, D. E. J. Am. Soc. Mass Spectrom. 2004, 15, 1341; McLean, J. A.; Ruotolo, B. T.; Gillig, K. J.; Russell, D. H. Int. J. Mass Spectrom. 2005, 240, 301), and this approach was used to assign metal ion binding sites for human metallothionein protein MT-2a (Chen, S. H.; Russell, W. K.; Russell, D. H. Anal. Chem. 2013, 85, 3229). Here, we use this approach to distinguish b-type N-terminal fragment ions from both internal fragment ions and y-type C-terminal fragment ions. We also show that in some cases specific secondary structural elements, viz., extended coils or helices, can be obtained for the y-type fragment ions series. The advantage of this approach is that product ion identity can be correlated to gas phase ion structure, which provides rapid identification of the onset and termination of extended coil structure in peptides. PMID- 24754451 TI - Cumulative gains enhance striatal response to reward opportunities in alcohol dependent patients. AB - Substance use disorder is characterized by a transition from volitional to compulsive responding for drug reward. A possible explanation for this transition may be that alcohol-dependent patients (ADP) show a general propensity for a history of rewarded instrumental responses, and these rewarded responses may boost the activation of motivational neurocircuitry for additional reward. Brain imaging studies of decision-making have demonstrated that ADP relative to controls (CON) often show altered neural activation in response to anticipating and receiving rewards, but the majority of studies have not investigated how past performance affects activation. A potential exists for ADP to show increased sensitivity to reward as a function of reward delivery history. In the current study, we used functional magnetic resonance imaging to investigate the neural correlates of risky decision-making in ADP (n = 18) and CON (n = 18) while they played a two-choice monetary risk-taking game. In addition to investigating general neural recruitment by risky decision-making, we also modeled each participant's running total of monetary earnings in order to determine areas of activation that correlated with cumulative reward. We found that ADP and CON showed few differences in behavior or in mesolimbic activation by choice for, and receipt of, risky gains. However, when including a cumulative-earnings covariate, ADP exhibited heightened striatal activation that correlated with total earnings during the choice event in the task. The heightened contextual sensitivity of striatal responses to cumulative earnings in ADP may represent a general neurobiological affective substrate for development of automatized instrumental behavior. PMID- 24754453 TI - Pituitary-tumour-transforming-gene 1 expression in testicular cancer. AB - Genomic instability is a feature of germ cell tumours. The pituitary-tumour transforming-gene 1 (PTTG1) is the major effector of chromosome segregation during mitosis, protecting the cell from aneuploidy. The protein expression of this gene has been evaluated in testicular tumours by immunohistochemistry. Formalin-fixed and paraffin-embedded specimens of testicular tissues from 83 patients undergoing therapeutic orchidectomy for seminomas (n = 53), embryonal carcinoma (n = 10), yolk sac tumour (n = 10) and teratoma (n = 10) were examined. Seminoma was associated with in situ carcinoma (CIS) in 23 samples. PTTG1 immunostaining was performed using rabbit anti-PTTG1 as a primary antibody. In CIS, only isolated cells showed nuclear staining for PTTG1. In the peripheral area of seminoma, PTTG1 was mostly detected as localised in the nucleus; in the central area of seminoma, PTTG1 staining was more intense in cytoplasm. PTTG1 positive cells were also present in the areas of seminoma infiltration. On the other hand, in embryonal carcinoma, cells had a diffuse positive immunostaining, mainly cytoplasmatic, while we did not observe an expression of PTTG1 in yolk sac tumour and mature teratoma. We firstly identified the PTTG1 expression pattern in normal testis, CIS and testicular cancer. Further investigation is needed to clarify the functional activity of PTTG1 in testicular oncogenesis. PMID- 24754454 TI - Direct comparison between negative wound pressure therapy and negatively charged polystyrene microspheres in wound bed preparation for split skin grafting in two large symmetric whole circumference leg ulcers, a single patient experience. PMID- 24754455 TI - A Quasi-experimental outcomes analysis of a psychoeducation intervention for pregnant women with abuse-related posttraumatic stress. AB - OBJECTIVE: To test the effectiveness of a trauma-specific, psychoeducational intervention for pregnant women with a history of childhood maltreatment on six intrapartum and postpartum psychological outcomes. DESIGN: Quasi-experimental study comparing women from a single-group, pretest-posttest pilot intervention study with women matched from a prospective observational study. SETTING: Rural and university-based prenatal clinics. PARTICIPANTS: Pregnant women entered the study by responding to an advertisement or by referral from a maternity care provider. Women could take part whether or not they met posttraumatic stress disorder diagnostic criteria. Outcomes data exist for 17 pilot intervention study participants and 43 matched observational study participants. INTERVENTIONS: Participants in the observational study received usual care. Participants in the pilot intervention study received usual care plus the intervention, a fully manualized, self-study program supported by weekly phone tutoring sessions with a health professional. MAIN OUTCOME MEASURES: The National Women's Study PTSD Module, the Peritraumatic Dissociation Experience Questionnaire, the Perception of Care Questionnaire, the Postpartum Depression Screening Scale, the Postpartum Bonding Questionnaire, and a semantic differential appraisal of the labor experience. RESULTS: Participants in the intervention study had better scores on all measures. Differences in means between participants in the intervention study and participants in the observational study equated to medium effect sized for dissociation during labor, rating of labor experience, and perception of care in labor and small effect sizes for postpartum posttraumatic stress disorder (PTSD) symptoms, postpartum depression symptoms, and motherinfant bonding. CONCLUSION: This trauma-specific intervention reaches and benefits pregnant women with a history of childhood maltreatment. PMID- 24754456 TI - Direct beta-alkylation of aldehydes via photoredox organocatalysis. AB - Direct beta-alkylation of saturated aldehydes has been accomplished by synergistically combining photoredox catalysis and organocatalysis. Photon induced enamine oxidation provides an activated beta-enaminyl radical intermediate, which readily combines with a wide range of Michael acceptors to produce beta-alkyl aldehydes in a highly efficient manner. Furthermore, this redox-neutral, atom-economical C-H functionalization protocol can be achieved both inter- and intramolecularly. Mechanistic studies by various spectroscopic methods suggest that a reductive quenching pathway is operable. PMID- 24754457 TI - Focus on Feeding! Evaluation of a framework for maximizing mealtime in aged care facilities. AB - Unintentional weight loss is a health risk for residents of aged care facilities, a concern for families and places demands on nursing staff. An existing weight loss framework to assess and manage residents' weight developed by a multidisciplinary team was implemented and evaluated with nurses and residents in aged care facilities within an area health service of Sydney, Australia. Thematic analysis generated seven binary concepts relating to relational, procedural, behavioural, physical, psychological, environmental and temporal aspects of feeding assistance provided by nurses to residents. Theoretical sampling was applied to the literature confirming those concepts which were organized as a model of feeding assistance labelled the Focus on Feeding! Decision Model. Nurses can play a pivotal role in the assessment of feeding difficulty and implementation of innovative mealtime programs. The Model aims to promote nurses' critical thinking and decision-making to improve nutritional intake of residents and avoid preventable weight loss. PMID- 24754458 TI - C3 and C4 are strongly related to adipose tissue variables and cardiovascular risk factors. AB - BACKGROUND: In several reports, C3 and C4 have been linked to diabetes and cardiovascular disease (CVD). Here, we investigate this link and the degree of C3 activation in elderly individuals. METHODS: In this study, C3 and C4 and the activation fragment C3a-desArg were analysed in 1016 subjects aged 70, in which blood pressure, lipid variables and fasting blood glucose were assessed. RESULTS: C3 levels were related to all the investigated classical cardiovascular risk factors and the metabolic syndrome (BMI, waist circumference, fat distribution, blood pressure, blood glucose levels, TG) except total cholesterol and LDL cholesterol in a highly significant fashion (Spearman up to 0,5; P < 0.0001). C4 and C3a-desArg were associated in the same fashion but less significantly, while the ratios C4/C3 or C3a-desArg/C3 were not, indicating that the association was not directly related to complement activation. The levels C3 and to a lesser degree C4 and C3a-desArg were associated particularly with CRP, but also with E selectin and ICAM-1. In addition, C3 and C4 levels were shown to decline significantly in 15 female subjects enrolled in a weight-reduction programme over 4 months. CONCLUSION: A strong relation between C3, C4 and C3a-desArg levels, adipose tissue and risk factors of CVD was established. The data support that the adipose tissue produces complement components and generates initiators of inflammation, such as C3a and C5a, able to trigger a cyto/chemokine response, in proportion to the amount of adipose tissue. This corroborates the concept that complement contributes to the low-grade inflammation associated with obesity. PMID- 24754459 TI - The ICF core sets for hearing loss project: International expert survey on functioning and disability of adults with hearing loss using the international classification of functioning, disability, and health (ICF). AB - OBJECTIVE: To identify relevant aspects of functioning, disability, and contextual factors for adults with hearing loss (HL) from hearing health professional perspective summarized using the ICF classification as reference tool. DESIGN: Internet-based cross-sectional survey using open-ended questions. Responses were analysed using a simplified content analysis approach to link concept to ICF categories according to linking rules. STUDY SAMPLE: Hearing health professionals (experts) recruited through e-mail distribution lists of professional organizations and personal networks of ICF core set for hearing loss steering committee members. Stratified sampling according to profession and world region enhanced the international and professional representation. RESULTS: Sixty three experts constituted the stratified sample used in the analysis. A total of 1726 meaningful concepts were identified in this study, resulting in 209 distinctive ICF categories, with 106 mentioned by 5% or more of respondents. Most categories in the activities & participation component related to communication, while the most frequent environmental factors related to the physical environment such as hearing aids or noise. Mental functions, such as confidence or emotional functions were also frequently highlighted. CONCLUSIONS: More than half (53.3%) of the entire ICF classification categories were included in the expert survey results. This emphasizes the importance of a multidimensional tool, such as the ICF, for assessing persons with hearing loss. PMID- 24754460 TI - Hypervalent iodine mediated synthesis of C-2 deoxy glycosides and amino acid glycoconjugates. AB - A simple, efficient, and practical method for the synthesis of C-2 deoxy-2-iodo glycoconjugates in self-assembled structures was found using PhI(OCOR)2. 2-Iodo glycoserinyl esters were intramolecularly converted into 2-iodo serinyl glycosides which upon dehalogenation gave C-2 deoxy amino acid glycoconjugates. PMID- 24754461 TI - Cardiac magnetic resonance for prognostic assessment: present applications and future directions. AB - Cardiac magnetic resonance is increasingly used in clinical practice for both diagnostic and prognostic purposes. In the field of ischemic heart disease, perfusion imaging permits the assessment of ischemia, which is strongly related to future cardiac events and mortality. Late gadolinium enhancement is also associated with the prognosis and can be used as a marker of functional recovery. Cardiac magnetic resonance also permits the detection of microvascular obstruction and infarct hemorrhage, both related to an adverse outcome. In non ischemic heart disease, the presence of late gadolinium enhancement is linked to mortality and hard events. Finally, coronary angiography, as well as new techniques, such as T1 mapping, may also have a prognostic role. PMID- 24754462 TI - Clinician outreach to improve the quality of rabies postexposure prophylaxis administration: Maryland's experience, 2010-2011. AB - Errors in the administration of rabies postexposure prophylaxis (PEP) are known to occur despite guidelines promulgated by the Advisory Committee on Immunization Practices (ACIP). In addition to elevating a patient's PEP failure risk, errors in administration increase medical expenses. A record review conducted at a local health department in Maryland revealed that ~8% of reported PEPs deviated from ACIP guidelines. Physicians surveyed at a local hospital also demonstrated knowledge gaps concerning use of rabies immune globulin and special indications for the five-dose PEP series. In response, we implemented an intervention to raise clinician awareness and adherence to recommended protocols. Activities included development of a patient fact sheet, hospital-based poster, and online training course targeted to a diverse group of healthcare providers. We also explored the use of hospital informatics in delivering PEP guidance. Clinician outreach by using a multipronged approach might increase adherence to recommended protocols. PMID- 24754464 TI - Titanium oxide nanosheets: graphene analogues with versatile functionalities. PMID- 24754465 TI - Variable framework structures and centricities in alkali metal yttrium selenites, AY(SeO3)2 (A = Na, K, Rb, and Cs). AB - Pure samples of a series of yttrium selenites, AY(SeO3)2 (A = Na, K, Rb, and Cs), were prepared through hydrothermal reactions using A2CO3, Y(NO3)3.6H2O, and SeO2. All four materials have 3D framework structures; however, they exhibit different channel geometries. The three-dimensional framework of NaY(SeO3)2 consists of zigzag chains of vertex-shared YO7 polyhedra and SeO3 linkers. KY(SeO3)2 and RbY(SeO3)2 reveal channels composed of corner-shared YO6 octahedra and SeO3 polyhedra. CsY(SeO3)2 exhibits a highly symmetric cage structure with radially spreading linkages of YO6 and SeO3 groups. Close structural examinations suggest that the cation size and coordination environment significantly influence the backbone architectures and their centricities. Second-harmonic generation (SHG) measurements on the powder sample of NaY(SeO3)2 reveal that the NCS selenite possesses a similar SHG efficiency to that of NH4H2PO4 (ADP). PMID- 24754463 TI - Estimation of insulin sensitivity in children: methods, measures and controversies. AB - Insulin resistance is defined as a state where insulin produces a diminished biological response, primarily in its capacity as a glucose-regulating hormone. Insulin resistance is commonly diagnosed by pediatric clinicians, but is rarely measured directly in children or adolescents. This review provides an overview of the techniques that can be used to assess insulin sensitivity in children, summarizing the methods involved, the assumptions, pitfalls, and appropriate uses of each technique, as well as their validation and reproducibility in pediatric samples. PMID- 24754466 TI - Drop-out from a psychodynamic group psychotherapy outpatient unit. AB - BACKGROUND. Drop-out from psychotherapy is common and represents a considerable problem in clinical practice and research. Aim. To explore pre-treatment predictors of early and late drop-out from psychodynamic group therapy in a public outpatient unit for non-psychotic disorders in Denmark. Methods. Naturalistic design including 329 patients, the majority with mood, neurotic and personality disorders referred to 39-session group therapy. Predictors were socio demographic and clinical variables, self-reported symptoms (Symptom Check List-90 Revised) and personality style (Millon Clinical Multiaxial Inventory-II). Drop out was classified into early and late premature termination excluding patients who dropped out for external reasons. Results. Drop-out comprised 20.6% (68 patients) of the sample. Logistic regression revealed social functioning, vocational training, alcohol problems and antisocial behavior to be related to drop-out. However, early drop-outs had prominent agoraphobic symptoms, lower interpersonal sensitivity and compulsive personality features, and late drop-outs cognitive and somatic anxiety symptoms and antisocial personality features. Clinical and psychological variables accounted for the major part of variance in predictions of drop-out, which ranged from 15.6% to 19.5% (Nagelkerke Pseudo R Square). Conclusion. Social functioning was consistently associated with drop out, but personality characteristics and anxiety symptoms differentiated between early and late drop-out. Failure to discriminate between stages of premature termination may explain some of the inconsistencies in the drop-out literature. Clinical implications. Before selection of patients to time-limited psychodynamic groups, self-reported symptoms should be thoroughly considered. Patients with agoraphobic symptoms should be offered alternative treatment. Awareness of and motivation to work with interpersonal issues may be essential for compliance with group therapy. PMID- 24754467 TI - Risk factors and study designs used in research of youths' suicide behaviour-an epidemiological discussion with focus on level of evidence. AB - Abstract Introduction: Many different epidemiology study designs have been used to analyse risk factors for suicide behaviour. The purpose of this study was to obtain an insight into the current study design used in research on youths' risk factors for suicide behaviour and to rank the studies according to level of evidence (LoE). METHODS: We searched PubMed and psycINFO in order to identify relevant individual studies. RESULTS: We included 36 studies of children and youth on suicidal behaviour and ideation-many rank low on LoE. For suicide, cohort design was often used, and mental illness (depression, substance abuse and severity of mental illness) was the most common risk factor. Cohort studies are ranked 2b, which is high according to LoE. For suicide attempts, survey was often used, and psychopathology, substance abuse and being exposed to suicidal behaviour were the most common risk factors. For suicidal ideation, survey was the only design used, and substance abuse and psychopathology the most common risk factors. Surveys are ranked 4, which are low according to LoE. Many risk factors were broad and unspecific, and standard definitions of outcome and exposure were rarely used. CONCLUSION: A good study of risk factors for suicidal behaviour would need a high LoE, as a high-powered longitudinal epidemiological study (cohort or case-control) of very specific risk factors. The factors would have high prevention potential, compared with more broad and unspecific risk factors, to which many people are exposed. We would recommend a cohort design (in high-risk populations) or a case-control design to identify risk factors, using clinical and/or register data instead of self-reported information, reporting adjusted estimates and using standard definition of suicidal outcome and risk factors. PMID- 24754469 TI - Pre-treatment child and family characteristics as predictors of outcome in cognitive behavioural therapy for youth anxiety disorders. AB - BACKGROUND: Cognitive behavioural therapy (CBT) has been found to be effective for children and adolescents (6-18 years) with anxiety disorders, but the non response rate is high-a fact that may argue for the importance of studies on pre treatment characteristics of children and their families that predict treatment outcome. AIMS: To provide a systematic review of clinical and demographic pre treatment child and family predictors of treatment outcome in CBT for anxiety disorders in youth. METHOD: A systematic literature search was conducted based on electronic databases (PsycINFO, Embase and PubMed), and retrieved studies were analysed according to the box-score method of counting significant findings. RESULTS: 24 studies with a sample size >= 60 were located. Most studies dealt with the following predictors: child age, gender, comorbidity, symptom severity and parental psychopathology. There was some evidence that a higher degree of pre treatment symptomatic severity and non-anxiety comorbidity predicted higher end state severity, but not a lesser degree of improvement. There was some but inconsistent support for a negative influence of parental psychopathology. CONCLUSION: Studies on pre-treatment child and family predictors of outcome in CBT for youth anxiety disorders have until now resulted in few findings of clinical or theoretical significance. PMID- 24754468 TI - Consumption of psychotropic drugs among adults who were in societal care during their childhood-A Swedish national cohort study. AB - BACKGROUND: Previous studies have demonstrated greatly increased risks of severe psychiatric morbidity for former child welfare clients. We investigated psychotropic medication in this population as a proxy indicator of less severe mental health problems. METHODS: This register-based cohort study comprises the Swedish birth cohorts between 1973 and 1981, 765,038, including 16,986 former children from societal care and 1296 national adoptees. Estimates of risk of retrieval of prescribed psychotropic medications during 2009 were calculated in four categories (any such drug, neuroleptics, antidepressants and anxiolytics/hypnotics) as hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression analysis, adjusting for birth parental background including psychiatric morbidity. RESULTS: 17-25% of men and 25-32% of the women with childhood experiences of societal care retrieved at least one prescription of a psychotropic drug, equivalent to age-adjusted HRs of between 2.1 and 3.3, compared with the general population. Adjusting the analysis for birth parental confounders attenuated risks to between 1.5 and 2.7, depending on subgroup and sex. Men-especially those that entered care settings during their teens-tended to have higher risks of all outcomes. Adjusted HRs for national adoptees were similar to former children in care. CONCLUSIONS: Former residents of societal care are a high-risk group for mental health problems well into mature adult age, demonstrating the need for systematic screening and implementation of effective prevention/treatment during time in care. PMID- 24754470 TI - Botrytis species: relentless necrotrophic thugs or endophytes gone rogue? AB - Plant pathology has a long-standing tradition of classifying microbes as pathogens, endophytes or saprophytes. Lifestyles of pathogens are categorized as biotrophic, necrotrophic or hemibiotrophic. Botrytis species are considered by many to be archetypal examples of necrotrophic fungi, with B. cinerea being the most extensively studied species because of its broad host range and economic impact. In this review, we discuss recent work which illustrates that B. cinerea is capable of colonizing plants internally, presumably as an endophyte, without causing any disease or stress symptoms. The extent of the facultative endophytic behaviour of B. cinerea and its relevance in the ecology and disease epidemiology may be vastly underestimated. Moreover, we discuss the recent discovery of a novel Botrytis species, B. deweyae, which normally grows as an endophyte in ornamental daylilies (Hemerocallis), but displays facultative pathogenic behaviour, and is increasingly causing economic damage. We propose that the emergence of endophytes 'gone rogue' as novel diseases may be related to increased inbreeding of hybrid lines and reduced genetic diversity. These observations lead us to argue that the sometimes inflexible classification of pathogenic microbes by their lifestyles requires serious reconsideration. There is much more variety to the interactions of Botrytis with its hosts than the eye (or the plant pathologist) can see, and this may be true for other microbes interacting with plants. PMID- 24754472 TI - The success of cone beam CT. PMID- 24754471 TI - Statistical iterative reconstruction for streak artefact reduction when using multidetector CT to image the dento-alveolar structures. AB - OBJECTIVES: When metallic prosthetic appliances and dental fillings exist in the oral cavity, the appearance of metal-induced streak artefacts is not avoidable in CT images. The aim of this study was to develop a method for artefact reduction using the statistical reconstruction on multidetector row CT images. METHODS: Adjacent CT images often depict similar anatomical structures. Therefore, reconstructed images with weak artefacts were attempted using projection data of an artefact-free image in a neighbouring thin slice. Images with moderate and strong artefacts were continuously processed in sequence by successive iterative restoration where the projection data was generated from the adjacent reconstructed slice. First, the basic maximum likelihood-expectation maximization algorithm was applied. Next, the ordered subset-expectation maximization algorithm was examined. Alternatively, a small region of interest setting was designated. Finally, the general purpose graphic processing unit machine was applied in both situations. RESULTS: The algorithms reduced the metal-induced streak artefacts on multidetector row CT images when the sequential processing method was applied. The ordered subset-expectation maximization and small region of interest reduced the processing duration without apparent detriments. A general-purpose graphic processing unit realized the high performance. CONCLUSIONS: A statistical reconstruction method was applied for the streak artefact reduction. The alternative algorithms applied were effective. Both software and hardware tools, such as ordered subset-expectation maximization, small region of interest and general-purpose graphic processing unit achieved fast artefact correction. PMID- 24754473 TI - Ultrasensitive detection of human liver hepatocellular carcinoma cells using a label-free aptasensor. AB - Liver cancer is one of the most common cancers in the world and has no effective cure, especially in later stages. The development of a tangible protocol for early diagnosis of this disease remains a major challenge. In the present manuscript, an aptamer-based, label-free electrochemical biosensor for the sensitive detection of HepG2, a hepatocellular carcinoma cell line, is described. The target cells are captured in a sandwich architecture using TLS11a aptamer covalently attached to a gold surface and a secondary TLS11a aptamer. The application of TLS11a aptamer as a recognition layer resulted in a sensor with high affinity for HepG2 cancer cells in comparison with control cancer cells of human prostate, breast, and colon tumors. The aptasensor delivered a wide linear dynamic range over 1 * 10(2) to 1 * 10(6) cells/mL, with a detection limit of 2 cells/mL. This protocol provides a precise method for sensitive detection of liver cancer with significant advantages in terms of simplicity, low cost, and stability. PMID- 24754474 TI - Vitamin D receptor agonists' anti-inflammatory properties. AB - One century after its discovery, vitamin D has been shown to be, in fact, a pleiotropic steroid hormone, which, besides regulation of calcium homeostasis and bone turnover, has antiproliferative, prodifferentiation, antibacterial, immunomodulatory, and anti-inflammatory properties in various cells and tissues. D hormone (1alpha,25(OH)2 D), regulated in an endocrine, autocrine, and paracrine manner, must be bound to the specific nuclear vitamin D receptor (VDR) to exert epigenetic and genetic effects, acting as a connection between extracellular stimuli and genomic responses of the cells. Since only high doses of hormone, provoking hypercalcemia, can achieve immunomodulatory effects, more than 3000 VDR agonists have been synthesized. Numerous experimental trials have been performed in animal models, evidencing the preventive and therapeutic potential of VDR agonists for chronic inflammatory diseases and cancer. Considering the selective anti-inflammatory effects of VDR agonists compared to glucocorticoids, sparing microbicidal functions, the fear of hypercalcemia as their only frequent side effect becomes a questionable reason for the lack of clinical studies. PMID- 24754475 TI - Force measurement tools to explore cadherin mechanotransduction. AB - Cell-cell adhesions serve to mechanically couple cells, allowing for long-range transmission of forces across cells in development, disease, and homeostasis. Recent work has shown that such contacts also play a role in transducing mechanical cues into a wide variety of cellular behaviors important to tissue function. As such, understanding the mechanical regulation of cells through their adhesion molecules has become a point of intense focus. This review will highlight the existing and emerging technologies and models that allow for exploration of cadherin-based adhesions as sites of mechanotransduction. PMID- 24754476 TI - Successful treatment of ustekinumab in a severe psoriasis patient with human immunodeficiency virus infection. PMID- 24754477 TI - Korean immigrant women's lived experience of childbirth in the United States. AB - OBJECTIVE: To understand Korean immigrant women's common experiences and practices of utilizing health care services in the United States during childbirth. DESIGN: A qualitative interpretive phenomenological research design. SETTING: Recruitment was conducted through advertisement on the MissyUSA.com website, which is the largest online community for married Korean women who live in North America. PARTICIPANTS: A purposive sample of 15 Korean immigrant women who experienced childbirth in the United States within the past 5 years was recruited. METHODS: Data were collected using semistructured telephone interviews and were analyzed using the Heideggerian hermeneutical methodology. RESULTS: During childbirth in the United States, participants faced multifaceted barriers in unfamiliar sociocultural contexts yet maintained their own cultural heritages. They navigated the unfamiliar health care system and developed their own strategies to overcome barriers to health care access. Korean immigrant women actively sought health information on the Internet and through social networking during childbirth. CONCLUSIONS: Korean immigrant women selectively accepted new cultural beliefs with some modifications from their own cultural contexts and developed their own distinct birth cultures. Understanding a particular culture and respecting women's traditions, beliefs, and practices about their childbirth could help nurses to provide culturally sensitive care. PMID- 24754478 TI - Neuropeptide S receptor gene variant and environment: contribution to alcohol use disorders and alcohol consumption. AB - The functional polymorphism Asn(107) Ile (rs324981, A > T) of the neuropeptide S receptor (NPSR1) gene is involved in the modulation of traits that affect alcohol use. Hence, we have examined whether the NPSR1 A/T polymorphism is associated with alcohol use disorders (AUD) and alcohol use in a population-representative sample. Lifetime AUD were assessed by the MINI psychiatric interview (n = 501) in the older cohort of the longitudinal Estonian Children Personality Behaviour and Health Study at age 25. Alcohol use, environmental adversities and personality were reported by both the younger (original n = 583) and the older cohort (original n = 593) in three study waves. NPSR1 associations with AUD and alcohol use differed by sex. In females, both AUD [odds ratio (OR) = 7.20 (0.94-55.0), P = 0.029] and harmful alcohol use were more prevalent in A-allele carriers. In contrast, in males, AUD was more frequent in T-allele carriers [OR = 2.75 (1.19 6.36), P = 0.017], especially if exposed to adverse environments at age 15 [OR = 10 (1.18-84.51), P = 0.019]. Alcohol use was higher in male T-allele carriers at ages 15 and 18 as well. Similarly to females, however, the risk allele for higher alcohol use for males at age 25 was the A-allele. Many of the effects on alcohol use were explained by genotype effects on measures of personality. In the general population, the NPSR1 Asn(107) Ile polymorphism is associated with AUD and alcohol consumption, dependent on sex, environment and age. The results are in line with the impulsivity and personality regulating role of the NPSR1. PMID- 24754479 TI - Prophylaxis and treatment of HIV-1 infection in pregnancy: Swedish recommendations 2013. AB - Prophylaxis and treatment with antiretroviral drugs and elective caesarean section delivery have resulted in very low mother-to-child transmission of HIV during recent years. Updated general treatment guidelines and increasing knowledge about mother-to-child transmission have necessitated regular revisions of the recommendations for the prophylaxis and treatment of HIV-1 infection in pregnancy. The Swedish Reference Group for Antiviral Therapy (RAV) updated the recommendations from 2010 at an expert meeting on 11 September 2013. The most important revisions are the following: (1) ongoing efficient treatment at confirmed pregnancy may, with a few exceptions, be continued; (2) if treatment is initiated during pregnancy, the recommended first-line therapy is essentially the same as for non-pregnant women; (3) raltegravir may be added to achieve rapid reduction in HIV RNA; (4) vaginal delivery is recommended if at > 34 gestational weeks and HIV RNA is < 50 copies/ml and no obstetric contraindications exist; (5) if HIV RNA is < 50 copies/ml and delivery is at > 34 gestational weeks, intravenous zidovudine is not recommended regardless of the delivery mode; (6) if HIV RNA is > 50 copies/ml close to delivery, it is recommended that the mother should undergo a planned caesarean section, intravenous zidovudine, and oral nevirapine, and the infant should receive single-dose nevirapine at 48-72 h of age and post-exposure prophylaxis with 2 drugs; (7) if delivery is preterm at < 34 gestational weeks, a caesarean section delivery should if possible be performed, with intravenous zidovudine and oral nevirapine given to the mother, and single-dose nevirapine given to the infant at 48-72 h of age, as well as post exposure prophylaxis with 2 additional drugs. PMID- 24754480 TI - Joint failure after steroid therapy in tuberculous encephalitis. AB - We report a case of multifocal avascular osteonecrosis (AVN) following steroid administration in a case of tuberculous encephalitis in a young patient. The risk of joint-related AVN as a side effect of adjunctive steroid therapy should be taken into consideration when evaluating the dosage and treatment duration in tuberculous encephalitis. PMID- 24754481 TI - Mn-catalyzed three-component reactions of imines/nitriles, Grignard reagents, and tetrahydrofuran: an expedient access to 1,5-amino/keto alcohols. AB - An expedient Mn-catalyzed three-component synthesis of 1,5-amino/keto alcohols from Grignard reagents, imines/nitriles, and tetrahydrofuran (THF) is described, which deviates from the classic Grignard addition to imines/nitriles in THF solvent. THF is split and "sewn" in an unprecedented manner in the reaction, leading to the formation of two geminal C-C bonds via C-H and C-O cleavage. Mechanistic experiments and DFT calculations reveal radical and organo-Mn intermediates in the catalytic cycle and the alpha-arylative ring-opening of THF as the key reaction step. PMID- 24754482 TI - A fatal case of peripartum cardiomyopathy. AB - Peripartum cardiomyopathy is a life-threatening cardiac condition affecting pregnant women either late in pregnancy or early in the post-partum period. The latest studies show a dramatic improvement in the mortality rates of women affected with this disorder, which has been correlated with advances in medical therapy for heart failure. However, patients continue to die of this condition. The following case report describes a typical patient with peripartum cardiomyopathy diagnosed on clinical grounds, along with echocardiogram findings of severe systolic dysfunction and global hypokinesis consistent with dilated cardiomyopathy. Emergency cesarean delivery had to be performed for fetal distress. There was significant improvement of the patient's condition with standard pharmacological management for heart failure at the time of discharge. However, five weeks after discharge, fatal cardiac arrest occurred. It is hoped that this article will raise awareness about this rare but potentially fatal condition and promote understanding of its main clinical features, diagnostic criteria, and conventional pharmacological management. PMID- 24754483 TI - Stress, sleep quality and unplanned Caesarean section in pregnant women. AB - This study examines the relationship among prenatal maternal stress, sleep quality and unplanned Caesarean delivery. For this research, we adopted a prospective survey design and a sample of 200 women in the early stages of labour. The findings were as follows: (i) 11.5% of the participants underwent unplanned Caesarean sections; (ii) based on a Pittsburg Sleep Quality Index split point of 5, approximately 90.5% of the participants experienced poor sleep quality; and (iii) the odds ratio for primiparas undergoing an unplanned Caesarean section was 4.183 times that for multiparas (95% confidence interval (CI) = 1.177 to 14.864), indicating a statistically significant difference. The results also showed that stress was a significant factor related to unplanned Caesarean sections; a 1-point increase on the Pregnancy Stress Rating Scale was associated with a 1.033-fold higher probability of undergoing an unplanned Caesarean section (95% CI = 1.002 to 1.065). Furthermore, prenatal stress was a significant variable that can be used to predict unplanned Caesarean deliveries. PMID- 24754484 TI - Computational screening and selection of cyclic peptide hairpin mimetics by molecular simulation and kinetic network models. AB - Designing peptidomimetic compounds to have a preorganized structure in solution is highly nontrivial. To show how simulation-based approaches can help speed this process, we performed an extensive simulation study of designed cyclic peptide mimics of a beta-hairpin from bacterial protein LapD involved in a protein protein interaction (PPI) pertinent to bacterial biofilm formation. We used replica exchange molecular dynamics (REMD) simulation to screen 20 covalently cross-linked designs with varying stereochemistry and selected the most favorable of these for massively parallel simulation on Folding@home in explicit solvent. Markov state models (MSMs) built from the trajectory data reveal how subtle chemical modifications can have a significant effect on conformational populations, leading to the overall stabilization of the target structure. In particular, we identify a key steric interaction between a methyl substituent and a valine side chain that acts to allosterically shift population between native and near-native states, which could be exploited in future designs. Visualization of this mechanism is aided considerably by the tICA method, which identifies degrees of freedom most important in slow conformational transitions. The combination of quantitative detail and human comprehension provided by MSMs suggests such approaches will be increasingly useful for design. PMID- 24754485 TI - Chance, purpose, and progress in evolution and christianity. AB - Evolutionary biology has a complex relationship with ideas of chance, purpose, and progress. Probability plays a subtle role; strikingly, founding figures in statistics were motivated by evolutionary questions. The findings of evolutionary biology have been used both in support of narratives of progress, and in their deconstruction. Likewise, professional biologists bring to their scientific work a set of preconceptions about chance and progress, grounded in their philosophical, religious, and/or political views. From the religious side, questions of purpose are ever-present. We explore this interplay in five broad categories: chance, progress, intelligence, eugenics, and the evolution of religious practices, each the subject of a semester long symposium. The intellectual influence of evolutionary biology has had a broad societal impact in these areas. Based on our experience, we draw attention to a number of relevant facts that, while accepted by experts in their respective fields, may be unfamiliar outside them. We list common areas of miscommunication, including specific examples and discussing causes: sometimes semantics and sometimes more substantive knowledge barriers. We also make recommendations for those attempting similar dialogue. PMID- 24754486 TI - Multifocal epithelial hyperplasia (Heck disease) in a patient with chronic lymphocytic leukemia. PMID- 24754487 TI - Shear-stress-induced conformational changes of von Willebrand factor in a water glycerol mixture observed with single molecule microscopy. AB - The von Willebrand factor (VWF) is a human plasma protein that plays a key role in the initiation of the formation of thrombi under high shear stress in both normal and pathological situations. It is believed that VWF undergoes a conformational transition from a compacted, globular to an extended form at high shear stress. In this paper, we develop and employ an approach to visualize the large-scale conformation of VWF in a (pressure-driven) Poiseuille flow of water glycerol buffers with wide-field single molecule fluorescence microscopy as a function of shear stress. Comparison of the imaging results for VWF with the results of a control with lambda-phage double-stranded DNA shows that the detection of individual VWF multimers in flow is feasible. A small fraction of VWF multimers are observed as visibly extended along one axis up to lengths of 2.0 MUm at high applied shear stresses. The size of this fraction of molecules seems to exhibit an apparent dependency on shear stress. We further demonstrate that the obtained results are independent of the charge of the fluorophore used to label VWF. The obtained results support the hypothesis of the conformational extension of VWF in shear flow. PMID- 24754488 TI - Trifluoromethyltrimethylsilane: nucleophilic trifluoromethylation and beyond. PMID- 24754489 TI - GPs, medications and older people: A qualitative study of general practitioners' approaches to potentially inappropriate medications in older people. AB - AIM: To explore the prescribing, and the rationale for this prescribing, of potentially inappropriate medications (PIMs) in older persons by Australian general practitioners (GPs). METHODS: This was a qualitative study employing semistructured interviews and thematic analysis. GPs who had patients taking at least one PIM were invited to participate. PIMs were defined by the Beers criteria. RESULTS: Twenty-two GPs from four regions in three Australian states participated. While none were aware of the Beers criteria, participant GPs displayed good knowledge of the potential adverse effects of these medications. They were comfortable with the continued prescription of the medications. This was based on often quite complex harm-benefit considerations of the biopsychosocial contexts of individual patients. CONCLUSIONS: The concept of 'appropriate' versus 'inappropriate' medications implicit in classification systems such as the Beers criteria is at odds with complex considerations informing decision-making prescribing PIMs in older persons. PMID- 24754490 TI - Cross-sequence interactions between human and rat islet amyloid polypeptides. AB - Human islet amyloid polypeptide (hIAPP) can assemble into toxic oligomers and fibrils, which are associated with cell degeneration and the pathogenesis of type 2 diabetes. Cross-interaction of hIAPP with rat IAPP (rIAPP)--a non-amyloidogenic peptide with high sequence similarity to hIAPP--might influence the aggregation and toxicity of hIAPP. However, the exact role of rIAPP in hIAPP aggregation and toxicity still remains unclear. In this work, we investigated the effect of cross sequence interactions between full-length hIAPP(1-37) and rIAPP(1-37) on hybrid amyloid structures, aggregation kinetics, and cell toxicity using combined computational and experimental approaches. Experimental results indicate a contrasting role of rIAPP in hIAPP aggregation, in which rIAPP initially inhibits the early aggregation and nuclei formation of hIAPP, but hIAPP seeds can also recruit both hIAPP and rIAPP to form more hybrid fibrils, thus promoting amyloid fibrillation ultimately. The coincubation of hIAPP and rIAPP also decreases cell viability, presumably due to the formation of more toxic hybrid oligomers at the prolonged lag phase. Comparative MD simulations confirm that the cross-sequence interactions between hIAPP and rIAPP stabilize beta-sheet structure and thus likely promote their fibrillization. This work provides valuable insights into a critical role of cross-amyloid interactions in protein aggregation. PMID- 24754491 TI - Catalytic formal [4 + 2] cycloadditions between unactivated allenes and N hydroxyaniline catalyzed by AuCl3/CuCl2/O2. AB - AuCl3-catalyzed formal [4 + 2]-cycloadditions between substituted allenes and N hydroxyanilines are described. This reaction sequence comprises initial isomerizations of allenes to butadienes under N2 and subsequent oxidations of N hydroxyanilines to nitrosoarenes under O2. CuCl2 (5 mol %) was added in the second step to increase the oxidation efficiency. The reactions are compatible with various 1,1-di- and 1,1,3-trisubstituted allenes and N-hydroxyaniline derivatives. Our experimental data reveal that the roles of AuCl3 are 3-fold, including catalytic oxidations of N-hydroxyaniline derivatives to nitrosoarenes, isomerizations of alkyl-substituted allenes to dienes, and final nitroso/butadiene [4 + 2] cycloadditions. PMID- 24754492 TI - Epidemiology of injuries in metropolitan Tehran, Iran: a household survey. AB - A household survey was conducted to determine the epidemiological characteristics of injuries among people living in Tehran, the mega capital of Iran. Using cluster random sampling in April 2007, survey was conducted seeking information about injuries occurred within families in past Persian year. All injury patterns and causes were classified according to ICD-10 and analysed using SPSS version 16. Out of 9173 household participants, 765 ones (8.3%) had injuries during the past Persian year, frequently open wounds and burns with a male to female ratio of 0.54 : 1. They occurred mostly due to 'exposure to the inanimate mechanical forces', followed by 'contact with heat or hot substances' and 'falls'. The common locations were home, and then streets. Approximately 15% of injuries required medical attention and the incidence rate was 175.5 per 10,000 person year with male to female ratio of 2.37 : 1. They were frequently fractures and open wounds and mostly associated with falls and transport accidents that had been transpired on streets or at workplace. This study evidences the high rate of injuries in Tehran city and prevention priorities should be given to traffic and home injuries. PMID- 24754494 TI - A new perspective on the importance of glycine conjugation in the metabolism of aromatic acids. AB - A number of endogenous and xenobiotic organic acids are conjugated to glycine, in animals ranging from mosquitoes to humans. Glycine conjugation has generally been assumed to be a detoxification mechanism, increasing the water solubility of organic acids in order to facilitate urinary excretion. However, the recently proposed glycine deportation hypothesis states that the role of the amino acid conjugations, including glycine conjugation, is to regulate systemic levels of amino acids that are also utilized as neurotransmitters in the central nervous systems of animals. This hypothesis is based on the observation that, compared to glucuronidation, glycine conjugation does not significantly increase the water solubility of aromatic acids. In this review it will be argued that the major role of glycine conjugation is to dispose of the end products of phenylpropionate metabolism. Furthermore, glucuronidation, which occurs in the endoplasmic reticulum, would not be ideal for the detoxification of free benzoate, which has been shown to accumulate in the mitochondrial matrix. Glycine conjugation, however, prevents accumulation of benzoic acid in the mitochondrial matrix by forming hippurate, a less lipophilic conjugate that can be more readily transported out of the mitochondria. Finally, it will be explained that the glycine conjugation of benzoate, a commonly used preservative, exacerbates the dietary deficiency of glycine in humans. Because the resulting shortage of glycine can negatively influence brain neurochemistry and the synthesis of collagen, nucleic acids, porphyrins, and other important metabolites, the risks of using benzoate as a preservative should not be underestimated. PMID- 24754493 TI - Coronary artery plaque volume and obesity in patients with diabetes: the factor 64 study. AB - PURPOSE: To determine the relationship between coronary plaque detected with coronary computed tomographic (CT) angiography and clinical parameters and cardiovascular risk factors in asymptomatic patients with diabetes. MATERIALS AND METHODS: All patients signed institutional review board-approved informed consent forms before enrollment. Two hundred twenty-four asymptomatic diabetic patients (121 men; mean patient age, 61.8 years; mean duration of diabetes, 10.4 years) underwent coronary CT angiography. Total coronary artery wall volume in all three vessels was measured by using semiautomated software. The coronary plaque volume index (PVI) was determined by dividing the wall volume by the coronary length. The relationship between the PVI and cardiovascular risk factors was determined with multivariable analysis. RESULTS: The mean PVI (+/-standard deviation) was 11.2 mm(2) +/- 2.7. The mean coronary artery calcium (CAC) score (determined with the Agatston method) was 382; 67% of total plaque was noncalcified. The PVI was related to age (standardized beta = 0.32, P < .001), male sex (standardized beta = 0.36, P < .001), body mass index (BMI) (standardized beta = 0.26, P < .001), and duration of diabetes (standardized beta = 0.14, P = .03). A greater percentage of soft plaque was present in younger individuals with a shorter disease duration (P = .02). The soft plaque percentage was directly related to BMI (P = .002). Patients with discrepancies between CAC score and PVI rank quartiles had a higher percentage of soft and fibrous plaque (18.7% +/- 3.3 vs 17.4% +/- 3.5 [P = .008] and 52.2% +/- 7.2 vs 47.2% +/- 8.8 [P < .0001], respectively). CONCLUSION: In asymptomatic diabetic patients, BMI was the primary modifiable risk factor that was associated with total and soft coronary plaque as assessed with coronary CT angiography. PMID- 24754495 TI - Renal artery stenosis as the cause of resistant arterial hypertension: an unusual technique for revascularization. PMID- 24754496 TI - An acoustofluidic micromixer via bubble inception and cavitation from microchannel sidewalls. AB - During the deep reactive ion etching process, the sidewalls of a silicon mold feature rough wavy structures, which can be transferred onto a polydimethylsiloxane (PDMS) microchannel through the soft lithography technique. In this article, we utilized the wavy structures of PDMS microchannel sidewalls to initiate and cavitate bubbles in the presence of acoustic waves. Through bubble cavitation, this acoustofluidic approach demonstrates fast, effective mixing in microfluidics. We characterized its performance by using viscous fluids such as poly(ethylene glycol) (PEG). When two PEG solutions with a resultant viscosity 54.9 times higher than that of water were used, the mixing efficiency was found to be 0.92, indicating excellent, homogeneous mixing. The acoustofluidic micromixer presented here has the advantages of simple fabrication, easy integration, and capability to mix high-viscosity fluids (Reynolds number: ~0.01) in less than 100 ms. PMID- 24754497 TI - Dermoscopy and reflectance confocal microscopy of pigmented actinic keratoses: a morphological study. AB - BACKGROUND: Actinic keratoses (AKs) are very common lesions on sun damaged skin and, when pigmented, represent a challenge in the differential diagnosis with early melanoma. Non-invasive diagnostic methods, such as dermoscopy and reflectance confocal microscopy (RCM) have been shown to improve the diagnostic accuracy of melanoma and non-melanoma skin cancer, however, only one case report described confocal findings of pigmented AKs up to now. OBJECTIVES: The aim of our retrospective morphological study was to analyse dermoscopic and confocal images of a series of histopathologically proven pigmented AKs, located on the face and other body sites, to define peculiar features of these "difficult to diagnose" lesions. METHODS: Clinical, dermoscopic and RCM images of 17 histopathologically confirmed pigmented AKs were retrospectively collected from the databases of four skin lesion clinics in Italy and USA. Dermoscopic and RCM images were analysed for prevalent morphological features. RESULTS: The majority of the lesions were located on the face (n = 8); followed by scalp (n = 4) and trunk (n = 4); and one lesion was located on the lower limbs. On dermoscopy the majority of lesions were characterized by grey dots/globules/granularity and structureless brown pigmentation. The main RCM feature of pigmented AKs was as follows: (i) the presence of epidermal changes (atypical keratinocytes, parakeratosis, scaling); (ii) increased epidermal thickness; (iii) bright, small, dermal papillae with enlarged interpapillary space; and (iv) intraepidermal dendritic cells referrable to Langherans cells. Features suggestive of melanocytic lesions, such as nesting, meshwork pattern or atypical cells infiltrating the junction, were never detected in our case series at the dermal epidermal junction (DEJ) level. CONCLUSION: Larger case series with adequate control population are warranted to validate these findings and to test their value in clinical setting. PMID- 24754498 TI - Desmosomes in the heart: a review of clinical and mechanistic analyses. AB - Desmosomes have long been appreciated as intercellular junctions that are vital for maintaining the structural integrity of stratified epithelia. More recent clinical investigations of patients with diseases such as arrhythmogenic cardiomyopathy have further highlighted the importance of desmosomes in cardiac tissue, where they help to maintain coordination of cardiac myocytes. Here, we review clinical and mechanistic studies that provide insight into the functions of desmosomal proteins in skin and heart during homeostasis and in disease. While intercellular junctions are organized differently in cardiac and epithelial tissues, studies conducted in epithelial systems may inform our understanding of cardiac desmosomes. We explore traditional and non-traditional roles of desmosomal proteins, ranging from adhesive capacities to nuclear functions. Finally, we discuss how these studies can guide future investigations focused on determining the molecular mechanisms by which desmosomal mutations promote the development of cardiac diseases. PMID- 24754499 TI - Engineering cardiac cell junctions in vitro to study the intercalated disc. AB - This review article discusses a recent work using engineered cardiac cells to study the function of the intercalated disc putting emphasis on mechanical and electrical coupling. PMID- 24754500 TI - Metal-to-metal charge transfer in AWO4 (A = Mg, Mn, Co, Ni, Cu, or Zn) compounds with the wolframite structure. AB - Using a combination of UV-visible spectroscopy and electronic structure calculations, we have characterized the electronic structures and optical properties of AWO4 (A = Mn, Co, Ni, Cu, Zn, or Mg) tungstates with the wolframite structure. In MgWO4 and ZnWO4, the lowest energy optical excitation is a ligand to metal charge transfer (LMCT) excitation from oxygen 2p nonbonding orbitals to antibonding W 5d orbitals. The energy of the LMCT transition in these two compounds is 3.95 eV for ZnWO4 and 4.06 eV for MgWO4. The charge transfer energies observed for the other compounds are significantly smaller, falling in the visible region of the spectrum and ranging from 2.3 to 3.0 eV. In these compounds, the partially occupied 3d orbitals of the A(2+) ion act as the HOMO, rather than the O 2p orbitals. The lowest energy charge transfer excitation now becomes a metal-to-metal charge transfer (MMCT) excitation, where an electron is transferred from the occupied 3d orbitals of the A(2+) ion to unoccupied antibonding W 5d states. The MMCT value for CuWO4 of 2.31 eV is the lowest in this series due to distortions of the crystal structure driven by the d(9) configuration of the Cu(2+) ion that lower the crystal symmetry to triclinic. The results of this study have important implications for the application of these and related materials as photocatalysts, photoanodes, pigments, and phosphors. PMID- 24754501 TI - Recovery from neuromuscular block in dogs: restoration of spontaneous ventilation does not exclude residual blockade. AB - OBJECTIVE: To evaluate if return of spontaneous ventilation to pre-relaxation values indicates complete recovery from neuromuscular blockade. STUDY DESIGN: Prospective, with each individual acting as its own control. ANIMALS: Ten healthy adult female Beagle dogs weighing 6.2-9.4 kg. METHODS: Dogs were anesthetized with propofol, dexemedetomidine and isoflurane. Spontaneous ventilation was assessed by measuring end-tidal CO2 , expired tidal volume, peak inspiratory flow, respiratory rate and minute ventilation. Vecuronium 25 MUg kg(-1) IV was administered and neuromuscular block was evaluated by measuring the train-of-four (TOF) ratio with acceleromyography in the hind limb. During spontaneous recovery from neuromuscular block, the TOF ratio when each ventilatory variable returned to baseline was recorded. RESULTS: This dose of vecuronium produced moderate neuromuscular block in all dogs, with TOF ratio values of 0-18% at maximal block. Expired tidal volume, peak inspiratory flow and minute ventilation returned to pre-relaxation values when the median TOF ratio was <= 20%. The median TOF ratio was 42% when the end-tidal CO2 returned to pre-relaxation values. CONCLUSIONS AND CLINICAL RELEVANCE: Significant residual neuromuscular block could be measured at the hind limb with acceleromyography when ventilation had spontaneously returned to pre-vecuronium values. Monitoring spontaneous ventilation, including end-tidal CO2 , expired tidal volume, peak inspiratory flow or minute ventilation cannot be used as a surrogate for objective neuromuscular monitoring, and this practice may increase the risk of postoperative residual paralysis. PMID- 24754502 TI - Current resources for evidence-based practice, May/June 2014. PMID- 24754503 TI - Suppression of lithium dendrite growth using cross-linked polyethylene/poly(ethylene oxide) electrolytes: a new approach for practical lithium-metal polymer batteries. AB - Solid polymer electrolyte (SPE) membranes are a critical component of high specific energy rechargeable Li-metal polymer (LMP) batteries. SPEs exhibit low volatility and thus increase the safety of Li-based batteries compared to current state-of-the-art Li-ion batteries that use flammable small-molecule electrolytes. However, most SPEs exhibit low ionic conductivity at room temperature, and often allow the growth of lithium dendrites that short-circuit the batteries. Both of these deficiencies are significant barriers to the commercialization of LMP batteries. Herein we report a cross-linked polyethylene/poly(ethylene oxide) SPE with both high ionic conductivity (>1.0 * 10(-4) S/cm at 25 degrees C) and excellent resistance to dendrite growth. It has been proposed that SPEs with shear moduli of the same order of magnitude as lithium could be used to suppress dendrite growth, leading to increased lifetime and safety for LMP batteries. In contrast to the theoretical predictions, the low-modulus (G' ~ 1.0 * 10(5) Pa at 90 degrees C) cross-linked SPEs reported herein exhibit remarkable dendrite growth resistance. These results suggest that a high-modulus SPE is not a requirement for the control of dendrite proliferation. PMID- 24754504 TI - Do women with premenopausal-onset rheumatoid arthritis have relative insufficiency or imbalance of adrenocortical steroids? AB - Adrenocortical steroids may influence susceptibility to rheumatoid arthritis (RA). Serum levels of adrenocortical steroids in female RA patients not previously treated with glucocorticoids were reviewed in this paper, as were controlled cohort studies of predisease (pre-RA) and control (CN) women. Serum dehydroepiandrosterone sulfate (DHEAS) levels were lower in most reports of premenopausal-onset RA patients not treated with glucocorticoids and in the baseline levels in one cohort study of pre-RA females compared with CN subjects. The pre-RA versus CN cohort difference was confirmed in an independent laboratory. Basal DHEAS and cortisol levels correlated oppositely in pre-RA versus CN women, suggesting relative adrenocortical androgenic insufficiency in case subjects. Clinical observations of lower androstenedione levels in premenopausal RA patients were also reported in pre-RA versus CN subjects who had lower DHEAS and cortisol values. In summary, a minority of premenopausal-onset RA females had decreased adrenocortical androgenic steroid levels and exhibited an adrenal androgen-to-cortisol steroid imbalance. PMID- 24754505 TI - Suicide among young Alaska Native men: community risk factors and alcohol control. AB - OBJECTIVES: I examined community risk factors that explained variation in suicide rates among young rural Alaska Native men, evaluating the effectiveness of local alcohol control as a public health policy to reduce this population's historically high vulnerability. METHODS: I compiled suicide data, alcohol control status, and community-level social, cultural, and economic characteristics for Alaska Native men aged 15 to 34 years in 178 small Alaska communities from 1980 to 2007. Poisson regression equations explained variation in suicide rates as a function of endogenous alcohol control and community characteristics. RESULTS: Suicide rates were higher in communities prohibiting alcohol importation under state law, but the effect was not significant after controlling for other community characteristics. More remote communities, those with fewer non-Natives, and those with evidence of cultural divides had higher suicide risks. Communities with higher incomes, more married couples, and traditional elders had lower risks. CONCLUSIONS: Alcohol control is ineffective in preventing suicide among Alaska Natives; suicide instead appears related to particular complex community characteristics that are either protective or increase risk. Communities have limited means to pursue economic and cultural development strategies that might offer more protection. PMID- 24754506 TI - Fermi resonance as a tool for probing peridinin environment. AB - In the present paper, we provide an extended study of the vibrational signature of a butenolide carotenoid, peridinin, in various solvents by combining resonance Raman spectroscopy (RRS) with theoretical calculations. The presence of a Fermi resonance due to coupling between the lactonic C?O stretching and the overtone of the wagging of the C-H in the lactonic ring provides a spectroscopic way of differentiating between peridinins lying in different environments. This is a significant achievement, given that simultaneous presence of several peridinins (each with a peculiar photophysical role) in different environments occurs in the most important peridinin containing proteins, the peridinin-chlorophyll proteins (PCPs) and the Chl a-c2-peridinin binding proteins. In RRS, small modifications of solvent polarity can give rise to large differences in the intensity and splitting between the two bands, resulting from the Fermi resonance. By changing the polarity, we can tune the frequency of stretching of the C?O and, while the C H wagging frequency is almost always constant in different solvents, move the system from a perfect resonance condition to off-resonance ones. We have corroborated our spectroscopic findings with a quasi-classical dynamical model of two coupled oscillators, and DFT calculations on peridinin in different solvents; we have also used calculations to complete the peridinin vibrational mode assignments in the 800-1600 cm(-1) region of RRS spectra, corresponding to polyene chain motion. Finally, the presence of Fermi resonance has been used to reinterpret previous vibrational spectroscopic experiments in PCPs. PMID- 24754507 TI - A nursing care classification system for assessing workload and determining optimal nurse staffing in a teaching hospital in China: A pre-post intervention study. AB - We aimed to evaluate the effectiveness of a nursing care classification system for re-assessing nurse workload and determining staffing needs. Adequate bed nurse ratios help manage hospital cost-efficiency, quality of care and patient safety. A prospective pre-post intervention study was conducted from January 2010 to December 2012 in 16 medical-surgical units of a tertiary teaching hospital. Nursing tasks were classified into four grades of care reflecting actual workload. Units were re-staffed accordingly and bed-nurse ratios compared with government-authorized bed-nurse ratios. Patient satisfaction, hospital stays and mortality were evaluated pre- and poststaffing changes. Average bed-nurse ratio (1:0.41) exceeded the national standard (1:0.40) in 16 units, but was inadequate in five units. Re-staffing increased average bed-nurse ratio from 1:0.41 to 1:0.48. Patients' satisfaction increased from 96.9% to 97.6%, and hospital stays decreased significantly. Nursing care classification effectively distributes nurse staffing to match patients' care levels, improving patient outcomes. PMID- 24754508 TI - Nurses' knowledge about venous leg ulcer care: a literature review. AB - INTRODUCTION: There is an increasing prevalence of venous leg ulcers coinciding with increasing older people populations. They are therefore important health problems, which restrict daily activities and incur high costs. BACKGROUND: Efficient and comprehensive nursing care for people with venous leg ulcers requires knowledge of causes, presentations and characteristics, the effects that venous leg ulcers have on individuals and nursing care with evidence-based treatment. AIM: To identify the gaps between nurses' demonstrated knowledge of venous leg ulcers and the related nursing care treatment with evidence-based nursing care. METHOD: A computerized search using MEDLINE, CINAHL the COCHRANE LIBRARY was conducted. RESULTS: The initial search yielded 174 citations from which 16 relevant articles were included in this review. Four themes in venous leg ulcer nursing care emerged demonstrating nurses' knowledge gaps: assessment, physiology and the healing process, nursing care and dressings, and compression treatment. CONCLUSION: This review suggests that there is a lack of knowledge related to venous leg ulcer physiology, the healing process and how this influences care and treatment. Nurses may not be using the evidence base sufficiently well to support ulcer healing and patient well-being. IMPLICATIONS FOR NURSING AND HEALTH POLICY: There is a need for a positive work culture development and ongoing educational programmes aimed at improving nurses' knowledge of venous leg ulcer treatment and care, which address the themes within the results of this review. PMID- 24754509 TI - Anticytomegalovirus antibody titres are not associated with caregiving burden in younger caregivers. AB - OBJECTIVE: This analysis examines whether or not younger caregivers, parents of children with developmental disabilities, differed from controls in terms of cytomegalovirus (CMV) seropositivity and CMV-specific antibody titre. Secondly, it examined whether any particular socio-demographics, health behaviours, or psychological/caregiving variables were associated with a higher CMV antibody titre among caregivers. DESIGN: Young caregivers and age- and sex-matched controls were compared with respect to their reported health behaviour and psychosocial status as well as latent virus control. METHODS: One hundred and seventeen parents of children with developmental disabilities and 52 control parents completed standard measures of health behaviours, socio-demographics, perceived stress, depression and anxiety, caregiver burden, child problem behaviours. They also provided a blood sample assayed for the presence of CMV specific antibody. RESULTS: Caregivers were no more likely to be CMV positive than controls and did not have higher antibody titres against CMV. In addition, there was no association between CMV antibody titre in seropositive caregivers and any of the psychological/caregiving variables. However, higher CMV antibody titres were significantly associated with a higher BMI, lower exercise levels, smoking, and lower fruit and vegetable and fat intake among seropositive caregivers. CONCLUSIONS: These data suggest that in the absence of immunosenescence, the chronic stress of caregiving is not sufficient to compromise the immune response to persistent CMV infection. However, an indirect mechanism to poorer health in caregivers might be via adoption of disadvantageous health behaviours in response to stress. Statement of contribution What is already known on this subject? Older caregivers of spouses with dementia show a poorer immune response against latent viruses when compared to age- and sex matched controls. Younger parental caregivers of children with developmental disabilities show a poorer antibody response to vaccination. What does this study add? The study showed no association between caregiving stress and CMV antibody titre in young caregivers. There were higher CMV antibody titres in the caregivers who engage in unhealthy behaviours. PMID- 24754510 TI - Immunomodulatory effect of tea saponin in immune T-cells and T-lymphoma cells via regulation of Th1, Th2 immune response and MAPK/ERK2 signaling pathway. AB - The anti-cancer activity of saponins and phenolic compounds present in green tea was previously reported. However, the immunomodulatory and adjuvanticity activity of tea saponin has never been studied. In this study, we investigated the immunomodulatory effect of tea saponin in T-lymphocytes and EL4 cells via regulation of cytokine response and mitogen-activated protein kinases (MAPK) signaling pathway. Quantitative analysis of mRNA expression level of cytokines were performed by reverse transcription polymerase chain reaction following stimulation with tea saponin, ovalbumin (OVA) alone or tea saponin in combination with OVA. Tea saponin inhibited the proliferation of EL4 cells measured in a dose dependent manner. No cytotoxicity effect of tea saponin was detected in T lymphocytes; rather, tea saponin enhanced the proliferation of T-lymphocytes. Tea saponin with OVA increased the expression of interleukin (IL)-1, IL-2, IL-12, interferon-gamma and tumor necrosis factor (TNF)-alpha and decreased the expression level of IL-10 and IL-8 in T-lymphocytes. Furthermore, tea saponin, in the presence of OVA, downregulated the MAPK signaling pathway via inhibition of IL-4, IL-8 and nuclear factor kappaB (NF-kappaB) in EL4 cells. Th1 cytokines enhancer and Th2 cytokines and NF-kappaB inhibitor, tea saponin can markedly inhibit the proliferation and invasiveness of T-lymphoma (EL4) cells, possibly due to TNF-alpha- and NF-kappaB-mediated regulation of MAPK signaling pathway. PMID- 24754511 TI - The immunomodulatory effects induced by dietary Zearalenone in pregnant rats. AB - CONTEXT: Zearalenone (ZEN) is a common contaminant that is present in feedstuff of high humidity and high temperatures. OBJECTIVE: The aim of this study was to investigate the effects of diets contaminated with different concentrations of ZEN on immunomodulation in early pregnant rats. MATERIALS AND METHODS: Forty eight pregnant Sprague Dawley (SD) rats were randomly divided into four treatment groups fed on a diet supplemented with one of four concentrations of ZEN: 0 mg/kg (ZEN 0), 50 mg/kg (ZEN 50), 100 mg/kg (ZEN 100) and 150 mg/kg (ZEN 150). The pregnant rats were fed ZEN-treated diets from gestation days 0 to 7 and a basal diet from gestation days 8 to 20. RESULTS: ZEN exposure (ZEN 100 and 150) caused significant decreases in splenic coefficients, viability of splenocyte and T-cell proliferation and induced histopathological damage in the spleen of early pregnant rats compared with other groups. Levels of IgG and IgA were decreased, while IgM was increased, in high doses of ZEN (ZEN 100 and ZEN 150) compared with other groups. ZEN 150 caused increases in white blood cells and hemoglobin and induced a significant decrease in platelets in blood of the pregnant rats compared with other groups. ZEN 150 increased the mRNA expression levels of interleukin (IL)-6, IL-18 and IL-1beta and decreased the mRNA expression levels of interferon-gamma, tumor necrosis factor-alpha and IL-10 in the spleen of pregnant rats compared with ZEN 0. CONCLUSION: High doses of ZEN-induced immunomodulatory effects on early pregnant rats by altering immunological parameters. PMID- 24754512 TI - Surface-specific deposition of catalytic metal nanocrystals on hollow carbon nanospheres via galvanic replacement reactions of carbon-encapsulated MnO nanoparticles. AB - This paper reports the findings of our efforts toward gaining a more complete understanding and utilization of galvanic replacement reactions involving manganese oxide with noble metals. It was revealed that the site of metal deposition is significantly affected by the variable oxidation state of manganese oxide. The use of carbon-encapsulated MnO nanoparticles as a reaction template led to metal growth specifically on the outermost surfaces of the carbon shells rather than on the MnO cores, which allowed for the selective decoration of the external surfaces of hollow carbon nanospheres with catalytic nanocrystals of various noble metals, including Pt, Pd, Rh, and Ir. By rearranging the sequence between carbon-shell coating and galvanic replacement processes, the deposited metal nanocrystals could be placed on the interior surfaces of hollow carbon nanospheres and, moreover, separately on the internal and the external surfaces, which may enable the respective control of the catalytic functionalities of each specific surface. PMID- 24754513 TI - The role of apolipoprotein E in neurodegeneration and cardiovascular disease. AB - Apolipoprotein E (ApoE) is an abundant plasma protein that interacts with low density lipoprotein receptors and other proteins, participating in the transport of cholesterol and lipids. Research has revealed many other roles for this multifunctional protein. ApoE is polymorphic and exists in three major isoforms: ApoE2, ApoE3 (the most common isoform) and ApoE4, which differ by only one amino acid, at positions 112 and 158. The altered binding to lipids and receptors by ApoE isoforms E2 and E4 results in an elevated risk for neurological, cerebrovascular and cardiovascular pathologies. Most notably, ApoE4 is associated with an elevated risk (relative to E3) for Alzheimer's disease. The application of mass spectrometry for genotyping and also direct measurement of ApoE protein isoforms is a recent development and is well suited to high-throughput applications. The precise quantification of protein isoforms will allow better characterization of effects resulting from heterozygous APOE genotypes. PMID- 24754514 TI - Isolation and characterization of microglia from adult mouse brain: selected applications for ex vivo evaluation of immunotoxicological alterations following in vivo xenobiotic exposure. AB - Microglia play a dual role in neuroprotection as well as in neurodegeneration and thus occupy the focal interest in neurodegenerative disease research. In vitro studies either by using cell lines or neonatal mouse primary microglia correlated xenobiotic induced microglial activation and neuronal death. However, these in vitro studies cannot portray the in vivo scenario. Therefore, environmental pollutant induced in vivo alteration in microglial function can be best assessed by ex vivo analysis, which is not in use because of limitations in the isolation procedure. Therefore, in the first part of the study we describe an optimized isolation procedure and characterization of isolated cells. The second part of the study demonstrates the utility of the isolated cells in evaluation of immunotoxicological alterations following arsenic, as a model xenobiotic, exposure. Purity of the isolated microglia was checked by immunostaining of microglial (CD11b and CD68) and nonmicroglial (GFAP) markers. Immunostaining of activation marker Iba1 proves that cells were not activated during the isolation procedure. Microglia yield and viability from the treated group shows no significant alterations compared to that of the control group. Proinflammatory cytokines (IL-6 and TNF-alpha) were upregulated following arsenic treatment as in the case of the LPS stimulated group without alterations in anti-inflammatory IL 10. Phagocytic potential was affected significantly following arsenic exposure without alteration in viability. Thus, our protocol can be proficiently used for quick isolation of primary microglia from adult mouse brain without altering their activation status, and most importantly, the isolated cells can be of aid to the ex vivo evaluation of immunotoxicological alterations. PMID- 24754515 TI - Evaluating the effects of a large increase in off-sale alcohol outlets on motor vehicle crashes: a time-series analysis. AB - This study examined the effects on motor vehicle crashes of a policy change that led to the introduction of a very large number of off-sale alcohol outlets in Lubbock, Texas. Times-series analysis of total crashes and single-vehicle nighttime (SVN) crashes was used to compare the periods before and after the policy change in Lubbock and in a comparison area. The results of the analysis revealed some weak effects on total crashes, but no statistically significant effects were found for SVN crashes. Possible reasons for the essentially null findings of the current study regarding the effects of the policy change on motor vehicle crashes are discussed. These include the fact that there were a small number of off-sale outlets already present in the community and that motor vehicle travel immediately following alcohol consumption is less likely to occur with alcohol purchased from an off-sale outlet compared to an on-sale outlet. PMID- 24754516 TI - Ultrathin hybrid films of polyoxohydroxy clusters and proteins: layer-by-layer assembly and their optical and mechanical properties. AB - The hierarchical assembly of inorganic and organic building blocks is an efficient strategy to produce high-performance materials which has been demonstrated in various biomaterials. Here, we report a layer-by-layer (LBL) assembly method to fabricate ultrathin hybrid films from nanometer-scale ionic clusters and proteins. Two types of cationic clusters (hydrolyzed aluminum clusters and zirconium-glycine clusters) were assembled with negatively charged bovine serum albumin (BSA) protein to form high-quality hybrid films, due to their strong electrostatic interactions and hydrogen bonding. The obtained hybrid films were characterized by scanning electron microscope (SEM), UV-vis, Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray fluorescence (XRF), and X-ray diffraction (XRD). The results demonstrated that the cluster protein hybrid films exhibited structural homogeneity, relative transparency, and bright blue fluorescence. More importantly, these hybrid films displayed up to a 70% increase in hardness and up to a 100% increase in reduced Young's modulus compared to the pure BSA film. These hybrid cluster-protein films could be potentially used as biomedical coatings in the future because of their good transparency and excellent mechanical properties. PMID- 24754517 TI - Intestinal involvement in toxic epidermal necrolysis. A case report and review of literature. PMID- 24754518 TI - Age-related trends in late mortality following traumatic brain injury: A multicentre inception cohort study. AB - AIM: To investigate age-related mortality risk following traumatic brain injury (TBI). METHODS: Review of 2545 consecutive discharges from three metropolitan rehabilitation centres in New South Wales, between 1 January 1990 and 1 October 2007. Survival status was censored on 1 October 2009. Between-group differences were assessed for older/younger patients. Multivariate Cox hazard regression was used to evaluate age-related mortality risk. Crude mortality rates, standardised mortality ratios and cause of death data were derived for each age decade. RESULTS: After controlling for known mortality risk factors, older patients were three times more likely to die than younger patients. Crude mortality rates increased exponentially with advancing age. However, when compared to normative population data, younger adults with TBI (<50 years) had the highest risk of death relative to their non-injured peers. CONCLUSIONS: Crude mortality rates, which do not account for the naturally increasing rate of death associated with ageing, artificially inflate estimates of age-related mortality risk following TBI. PMID- 24754519 TI - Magnetic nanoparticles as contrast agents in biomedical imaging: recent advances in iron- and manganese-based magnetic nanoparticles. AB - Improvements in diagnostic measures for biomedical applications have been investigated in various studies for better interpretations of biological abnormalities and several medical conditions. The use of imaging techniques, such as magnetic resonance imaging (MRI), is widespread and becoming a standard procedure for such specialized applications. A major avenue being studied in MRI is the use of magnetic nanoparticles (NPs) as contrast agents (CAs). Among various approaches, current research also incorporates use of superparamagnetic iron oxide NPs and manganese-based NPs with biocompatible coatings for improved stability and reduced biodegradation when exposed to a biological environment. In this review, recent advances with these types of magnetic NPs and their potential use as CAs in MRI are reported, as well as new insights into the selectivity and cellular transport mechanism that occurs following injection. PMID- 24754520 TI - Does investment in home visitors lead to better psychological health for HIV affected families? Results from a quasi-experimental evaluation in South Africa. AB - Children and families affected by HIV are at considerable risk for psychological distress. Community-based home visiting is a common mechanism for providing basic counseling and other services to HIV-affected families. While programs emphasize home visitor training and compensation as means to promote high-quality service delivery, whether these efforts result in measurable gains in beneficiaries' well being remains largely unanswered. This study employs a longitudinal quasi experimental design to explore whether these kinds of investments yield concomitant gains in psychological outcomes among beneficiaries. Baseline and follow-up data were collected over a two-year period from children aged 10-17 at the time of program enrollment and their caregivers, with 80% retention. In this sample of 1487 children and 918 caregivers, the psychological health outcomes of those enrolled in programs with home visitors who receive intensive training, organizational support, and regular compensation (termed "paraprofessional") were compared to those enrolled in programs offering limited home visiting services from lay volunteers. Applying multilevel logistic regression, no measurable improvements were found among paraprofessional enrollees, and three outcomes were significantly worse at follow-up regardless of program model. Children's behavior problems became more prevalent even after adjusting for other factors, increasing from 29% to 35% in girls and from 28% to 43% in boys. Nearly one-quarter of girl and boys reported high levels of depression at follow-up, and this was a significant rise over time for boys. Rates of poor family functioning also significantly worsened over time, rising from 30% to 59%. About one-third of caregivers reported high levels of negative feelings at follow-up, with no improvements observed in the paraprofessional group. Results highlight that children's and caregivers' psychological outcomes may be relatively impervious to change even in paraprofessional home visiting models. Findings underscore the need for programs serving HIV-affected families to add focused evidence-based psychological interventions to supplement traditional home visiting. PMID- 24754521 TI - Radical model of arsenic(III) toxicity: theoretical and EPR spin trapping studies. AB - Arsenic is one of the most environmentally significant pollutants and a great global health concern. Although a growing body of evidence suggests that reactive oxygen species (ROS) mediate the mechanism of arsenic toxicity, the exact mechanism remains elusive. In this study, we examine the capacity of trivalent arsenic species arsenous acid (iAs(III)), monomethylarsonous acid (MMA(III)), and dimethylarsinous acid (DMA(III)) to generate ROS through a theoretical analysis of their structures, redox properties, and their reactivities to various ROS using a density functional theory (DFT) approach at the B3LYP/6-31+G**//B3LYP/6 31G* level of theory and by employing electron paramagnetic resonance (EPR) spin trapping studies using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap. Results show that the oxidized forms (As(IV)) are structurally more stable compared to the reduced forms (As(II)) that impart elongated As-O bonds leading to the formation of As(III) and hydroxide anion. Enthalpies of one-electron reduction and oxidation indicate that increasing the degree of methylation makes it harder for As(III) to be reduced but easier to be oxidized. The order of increasing favorability for arsenical activation by ROS is O2 < O2(*-) < HO(*), and the oxidation of DMA(III) to DMA(V) is highly exoergic in multiple redox pathways with concomitant generation of radicals. This is followed by MMA(III) and by iAs(III) being the least favorable. Spin trapping studies showed a higher propensity for methylated arsenicals to generate radicals than iAs(III) upon treatment with H2O2. However, in the presence of Fe(II,III), all showed radical generation where MMA(III) gave predominantly C-centered adducts, while acidified iAs (III) and DMA(III) gave primarily HO-adducts, and their formation was affected in the presence of SOD suggesting a As(III)-OO/OOH radical intermediate. Therefore, our results suggest a basis for the increased redox activity of methylated arsenicals that can be applied to the observed trends in arsenic methylation and toxicity in biological systems. PMID- 24754522 TI - A novel form of the human manganese superoxide dismutase protects rat and human livers undergoing ischaemia and reperfusion injury. AB - Hepatic microcirculatory dysfunction due to cold storage and warm reperfusion (CS+WR) injury during liver transplantation is partly mediated by oxidative stress and may lead to graft dysfunction. This is especially relevant when steatotic donors are considered. Using primary cultured liver sinusoidal endothelial cells (LSECs), liver grafts from healthy and steatotic rats, and human liver samples, we aimed to characterize the effects of a new recombinant form of human manganese superoxide dismutase (rMnSOD) on hepatic CS+WR injury. After CS+WR, the liver endothelium exhibited accumulation of superoxide anion (O2 ) and diminished levels of nitric oxide (NO); these detrimental effects were prevented by rMnSOD. CS+WR control and steatotic rat livers exhibited markedly deteriorated microcirculation and acute endothelial dysfunction, together with liver damage, inflammation, oxidative stress, and low NO. rMnSOD markedly blunted oxidative stress, which was associated with a global improvement in liver damage and microcirculatory derangements. The addition of rMnSOD to CS solution maintained its antioxidant capability, protecting rat and human liver tissues. In conclusion, rMnSOD represents a new and highly effective therapy to significantly upgrade liver procurement for transplantation. PMID- 24754523 TI - Conformational flexibility of mephenesin. AB - The mephenesin molecule (3-(2-methylphenoxy)propane-1,2-diol) serves as a test bank to explore several structural and dynamical issues, such as conformational flexibility, the orientation of the carbon linear chain relative to the benzene plane, or the effect of substituent position on the rotational barrier of a methyl group. The molecule has been studied by rotational spectroscopy in the 4 18 GHz frequency range by Fourier-transform methods in a supersonic expansion. The experiment has been backed by a previous conformational search plus optimization of the lowest energy structures by ab initio and density functional quantum calculations. The three lowest-lying conformers that can interconvert to each other by simple bond rotations have been detected in the jet. Rotational parameters for all structures have been obtained, and methyl torsional barriers have been determined for the two lowest-lying rotamers. The lowest-lying structure of mephenesin is highly planar, with all carbon atoms lying nearly in the benzene ring plane, and is stabilized by the formation of cooperative intramolecular hydrogen bonding. An estimation of the relative abundance of the detected conformers indicates that the energetically most stable conformer will have an abundance near 80% at temperatures relevant for biological activity. PMID- 24754524 TI - Measuring mass of nanoparticles and viruses in liquids with nanometer-scale pores. AB - Nanopores have recently been developed for the detection and physical characterization of nanoparticles, viruses, proteins, nucleic acids, and other macromolecules in liquids. The method provides the ability to rapidly estimate the size and electrical charge of analytes over a wide range of concentration, potentially with small sample volumes and low cost. Here, we use the technique to measure the mass of nanoparticles and viruses and their sedimentation. The analyte sedimentation-time measurement provides an estimate for the nanoparticle mass-density. We also show that the method can be used with samples at low concentration and in small volumes. PMID- 24754525 TI - Biomimetic oxidative dimerization of anodically generated stilbene radical cations: effect of aromatic substitution on product distribution and reaction pathways. AB - A systematic study of the electrochemical oxidation of 1,2-diarylalkenes was carried out with the focus on detailed product studies and variation of product type as a function of aromatic substitution. A reinvestigation of the electrochemical oxidation of 4,4'-dimethoxystilbene under various conditions was first carried out, and all products formed were fully characterized and quantitated. This was followed by a systematic investigation of the effect of aromatic substitution on the nature and distribution of the products. The aromatic substituents were found to fall into three main categories, viz., substrates in which the nature and position of the aromatic substituents gave rise to essentially the same products as 4,4'-dimethoxystilbene, for example, tetraaryltetrahydrofurans, dehydrotetralins, and aldehydes (p-MeO or p-NMe2 on one ring and X on the other ring, where X = o-MeO or p-alkyl, or m- or p-EWG; e.g., 4-methoxy-4'-trifluoromethylstilbene); those that gave rise to a mixture of indanyl (or tetralinyl) acetamides and dehydrotetralins (or pallidols) (both or one ring substituted by alkyl groups, e.g., 4,4'-dimethylstilbene); and those where strategic placement of donor groups, such as OMe and OH, led to the formation of ampelopsin F and pallidol-type carbon skeletons (e.g., 4,3',4' trimethoxystilbene). Reaction pathways to rationalize the formation of the different products are presented. PMID- 24754526 TI - Sequencing the threat and recommendation components of persuasive messages differentially improves the effectiveness of high- and low-distressing imagery in an anti-alcohol message in students. AB - OBJECTIVES: Distressing imagery is often used to improve the persuasiveness of mass-reach health promotion messages, but its effectiveness may be limited because audiences avoid attending to content. Prior self-affirmation or self efficacy inductions have been shown to reduce avoidance and improve audience responsiveness to distressing messages, but these are difficult to introduce into a mass-reach context. Reasoning that a behavioural recommendation may have a similar effect, we reversed the traditional threat-behavioural recommendation health promotion message sequence. DESIGN: 2 * 2 experimental design: Factor 1, high- and low-distress images; Factor 2, threat-recommendation and recommendation threat sequences. METHODS: Ninety-one students were exposed to an identical text message accompanied by high- or low-distress imagery presented in threat recommendation and recommendation-threat sequences. RESULTS: For the high distress message, greater persuasion was observed for the recommendation-threat than the threat-recommendation sequence. This was partially mediated by participants' greater self-exposure to the threat component of the message, which we attribute to the effect of sequence in reducing attentional avoidance. For the low-distress message, greater persuasion was observed for the threat recommendation sequence, which was not mediated by reading time allocated to the threat. CONCLUSIONS: Tailoring message sequence to suit the degree of distress that message developers wish to induce provides a tool that could improve persuasive messages. These findings provide a first step in this process and discuss further steps needed to consolidate and expand these findings. Statement of contribution What is already known on this subject? Health promotion messages accompanied by distressing imagery might, under some circumstances, persuade individuals to engage in healthier behaviour. Audiences can respond defensively to distressing imagery, but may be less inclined to do so when an easily followed behavioural recommendation is presented before imagery. Current literature is divided on whether presenting a behavioural recommendation before a threat component accompanied by distressing images will improve the persuasiveness of messages. What does this study add? We show that, when a behavioural recommendation precedes a threat containing distressing images, persuasiveness of a threatening message is stronger than a threat-recommendation sequence. We show that a recommendation-threat sequence improves persuasiveness of distressing imagery because it reduces attentional avoidance. PMID- 24754527 TI - Postoperative ileus: mechanisms and future directions for research. AB - Postoperative ileus (POI) is an abnormal pattern of gastrointestinal motility characterized by nausea, vomiting, abdominal distension and/or delayed passage of flatus or stool, which may occur following surgery. Postoperative ileus slows recovery, increases the risk of developing postoperative complications and confers a significant financial load on healthcare institutions. The aim of the present review is to provide a succinct overview of the clinical features and pathophysiological mechanisms of POI, with final comment on selected directions for future research.Terminology used when describing POI is inconsistent, with little differentiation made between the obligatory period of gut dysfunction seen after surgery ('normal POI') and the more clinically and pathologically significant entity of a 'prolonged POI'. Both normal and prolonged POI represent a fundamentally similar pathophysiological phenomenon. The aetiology of POI is postulated to be multifactorial, with principal mediators being inflammatory cell activation, autonomic dysfunction (both primarily and as part of the surgical stress response), agonism at gut opioid receptors, modulation of gastrointestinal hormone activity and electrolyte derangements. A final common pathway for these effectors is impaired contractility and motility and gut wall oedema. There are many potential directions for future research. In particular, there remains scope to accurately characterize the gastrointestinal dysfunction that underscores an ileus, development of an accurate risk stratification tool will facilitate early implementation of preventive measures and clinical appraisal of novel therapeutic strategies that target individual pathways in the pathogenesis of ileus warrant further investigation. PMID- 24754528 TI - Neural basis of new clinical vestibular tests: otolithic neural responses to sound and vibration. AB - Extracellular single neuron recording and labelling studies of primary vestibular afferents in Scarpa's ganglion have shown that guinea-pig otolithic afferents with irregular resting discharge are preferentially activated by 500 Hz bone conducted vibration (BCV) and many also by 500 Hz air-conducted sound (ACS) at low threshold and high sensitivity. Very few afferent neurons from any semicircular canal are activated by these stimuli and then only at high intensity. Tracing the origin of the activated neurons shows that these sensitive otolithic afferents originate mainly from a specialized region, the striola, of both the utricular and saccular maculae. This same 500 Hz BCV elicits vestibular dependent eye movements in alert guinea-pigs and in healthy humans. These stimuli evoke myogenic potentials, vestibular-evoked myogenic potentials (VEMPs), which are used to test the function of the utricular and saccular maculae in human patients. Although utricular and saccular afferents can both be activated by BCV and ACS, the differential projection of utricular and saccular afferents to different muscle groups allows for differentiation of the function of these two sensory regions. The basic neural data support the conclusion that in human patients in response to brief 500 Hz BCV delivered to Fz (the midline of the forehead at the hairline), the cervical VEMP indicates predominantly saccular function and the ocular VEMP indicates predominantly utricular function. The neural, anatomical and behavioural evidence underpins clinical tests of otolith function in humans using sound and vibration. PMID- 24754529 TI - Photodynamic therapy vs. imiquimod 5% cream as skin cancer preventive strategies in patients with field changes: a randomized intraindividual comparison study. AB - BACKGROUND: Actinic damage is responsible for the development of multiple, recurrent non-melanoma skin cancers (NMSCs), including actinic keratoses (AKs). Photodynamic therapy (PDT) and imiquimod cream (IMIQ) 5% are recommended as field directed treatment options. OBJECTIVES: To compare efficacy and safety of methyl aminolevulinate (MAL)-PDT vs. IMIQ 5% in the prevention of new NMSCs development patients with field changes. METHODS: Patients with field cancerization of the face or scalp were randomized to receive MAL-PDT on one side, and IMIQ 5% on the mirror field. The primary endpoint was the number of new lesions on the treated fields during a 12-month follow-up period. Secondary assessments included adverse events and patient preference. RESULTS: Forty-four patients completed the study. MAL-PDT and IMIQ did not differ concerning the primary endpoint, as there was no statistically significant difference in terms of development of new NMSCs at any point of follow-up. Both treatment regimens were safe and well tolerated. Patients' preference based on the procedure, response rates and future choice favoured MAL-PDT. CONCLUSIONS: MAL-PDT and IMIQ 5% are safe and well-tolerated treatments that equally prevent development of new AKs in patients suffering from field changes. MAL-PDT treatment appears to be superior in terms of patients' preference. PMID- 24754531 TI - Serum adiponectin and leptin levels in psoriatic patients according to topical treatment. AB - OBJECTIVES: Psoriasis has been considered as a systemic disease associated with obesity, cardiovascular diseases and metabolic syndrome. Adipokines have influence on many metabolic processes. Aim of this study was to evaluate the effect of conventional topical treatment on serum adiponectin and leptin levels in patients with psoriasis. METHODS: Forty-nine patients with relapse of plaque type psoriasis and 16 healthy controls were examined. Blood samples were collected before therapy and after 14 days of application. Serum adiponectin and leptin concentrations were examined by enzyme-linked immunosorbent assay for correlations with effectiveness of topical treatment. RESULTS: Adiponectin and leptin serum levels were significantly decreased in psoriatic patients in comparison to the controls. As a result of the topical treatment, serum adiponectin level did not significantly change. Serum leptin level increased significantly, still remaining lower than in the controls. CONCLUSIONS: Leptin might be a useful marker in assessing the efficacy of the treatment for psoriasis. PMID- 24754530 TI - The efficacy of alfaxalone for immersion anesthesia in koi carp (Cyprinus carpio). AB - OBJECTIVE: To characterize the physiologic and behavioral effects of a single induction dose and two maintenance doses of alfaxalone delivered by water immersion in the anesthesia of koi (Cyprinus carpio). STUDY DESIGN: Prospective, within-subject complete crossover design. ANIMALS: Six adult koi (Cyprinus carpio) with a median body weight of 344.5 g (range 292.0-405.0 g). METHODS: Koi were immersed in water containing 10 mg L(-1) alfaxalone until immobile and then maintained with alfaxalone at either 1 or 2.5 mg L(-1) via a recirculating water system. Times for anesthetic induction and recovery periods were recorded. Physiologic and blood gas parameters were evaluated before, during and after the anesthetic trial. Response to noxious stimuli was also assessed. RESULTS: Median anesthesia induction time for all fish was 5.4 minutes. Median recovery time was 11.8 and 26.4 minutes in the 1.0 and 2.5 mg L(-1) doses, respectively, which were significantly different (p = 0.04). Cessation of opercular movement occurred in 0/6 and 4/6 fish exposed to 1.0 and 2.5 mg L(-1) dose respectively. No difference was observed in median heart rate over the duration of the anesthetic events. Response to noxious stimulation was 4/6 and 0/6 in the 1.0 and 2.5 mg L(-1) doses respectively. Oxygenation and ventilation did not change during the experiment, but there was a significant decrease in blood pH along with an increase in blood lactate concentration. CONCLUSION AND CLINICAL RELEVANCE: Administration of alfaxalone, via water immersion, as an induction and maintenance anesthesia agent provided rapid and reliable anesthesia of koi with no mortality. The maintenance dose of 2.5 mg L(-1) was sufficient to prevent response to noxious stimuli but was associated with a clinically relevant depression in opercular rate. PMID- 24754532 TI - Clinical considerations for an effective medical therapy in Wilson's disease. AB - Wilson's disease is an autosomal recessively inherited copper overload disorder that leads to hepatic and/or neurologic symptoms. More than a century after the first description of Wilson's disease, the available medical treatment options have not been standardized. The efficacy of the commonly used drugs is satisfactory for hepatic disease, but disappointing in the neurologic patients, including the risk of neurologic deterioration after the initiation of chelation therapy. An approach to overcome this problem is the careful and systematic assessment of biochemical response patterns and the quantitative monitoring of symptoms using validated rating scales. Standardized dosage strategies that address changes in copper pools might improve adherence and reduce side effects. Such an approach may reduce long-term morbidity. In this paper, we discuss considerations for an effective medical treatment and requirements for future studies in Wilson's disease. PMID- 24754533 TI - Job-related stress and sickness absence among belgian nurses: a prospective study. AB - PURPOSE: The purpose of this study was to investigate the influence of job stress on sickness absence of nurses and determine the predictive power of the Demand Control-Support (DCS) model, the Effort-Reward Imbalance-Overcommitment (ERI-OC) model, and a combination of both. DESIGN: A survey was conducted to measure job stress in a sample of 527 Belgian nurses, followed by prospective data collection of sickness absence (long-term, short-term, and multiple episodes). FINDINGS: Perceptions of job strain and ERI increased the odds for long-term (adjusted odds ratio [OR] = 2.26; 99% confidence interval [CI; 1.27-4.04]) and multiple episodes of sickness absence (adjusted OR = 1.64; 95% CI [1.01-2.65]). Iso-strain and ERI OC increased the odds for long-term (OR = 1.75; 95% CI [0.98-3.11]), multiple episode (adjusted OR = 1.93; 95% CI [1.14-3.26]), and short-term (adjusted OR = 1.69; 95% CI [1.03-2.76]) sickness absence. CONCLUSIONS: The combined model of DCS and ERI-OC predicts the odds for long-term and short-term sickness absence and multiple episodes. CLINICAL RELEVANCE: This study has implications for human resources management in nursing organizations. Nursing administrators are advised to monitor and balance nurses' job demands and efforts. They should recognize the importance of social support, job control, job rewards, and overcommitment in order to reduce the job stress of nurses. PMID- 24754534 TI - Two distinct allosteric active sites regulate guest binding within a Fe8Mo1216+ cubic receptor. AB - The binding of phosphine ligands to molybdenum sites on the faces of a supramolecular cube served to inhibit allosterically the encapsulation of a neutral or anionic guest. The edges of the cube also provided a distinct second allosteric site, where the binding of tetraphenylborate also allosterically inhibited anion binding in the cube's cavity. The two allosteric sites were shown to regulate the binding of an anionic guest either independently or in concert. The use of a tertiary amine as an allosteric effector also enabled a phosphine guest to be ejected from the cube's cavity into solution, to generate phosphine complexes with other metal ions. PMID- 24754535 TI - The pediatric sepsis biomarker risk model: potential implications for sepsis therapy and biology. AB - Sepsis remains a major cause of morbidity and mortality in adult and pediatric intensive care units. Heterogeneity of demographics, comorbidities, biological mechanisms, and severity of illness leads to difficulty in determining which patients are at highest risk of mortality. Determining mortality risk is important for weighing the potential benefits of more aggressive interventions and for deciding whom to enroll in clinical trials. Biomarkers can be used to parse patients into different risk categories and can outperform current methods of patient risk stratification based on physiologic parameters. Here we review the Pediatric Sepsis Biomarker Risk Model that has also been modified and applied to estimate mortality risk in adult patients. We compare the two models and speculate on the biological implications of the biomarkers in patients with sepsis. PMID- 24754536 TI - Neuroprotective effect of oral choline administration after global brain ischemia in rats. AB - Choline - now recognized as an essential nutrient - is the most common polar group found in the outer leaflet of the plasma membrane bilayer. Brain ischemia reperfusion causes lipid peroxidation triggering multiple cell death pathways involving necrosis and apoptosis. Membrane breakdown is, therefore, a major pathophysiologic event in brain ischemia. The ability to achieve membrane repair is a critical step for survival of ischemic neurons following reperfusion injury. The availability of choline is a rate-limiting factor in phospholipid synthesis and, therefore, may be important for timely membrane repair and cell survival. This work aimed at verifying the effects of 7-day oral administration with different doses of choline on survival of CA1 hippocampal neurons following transient global forebrain ischemia in rats. The administration of 400 mg/kg/day divided into two daily doses for 7 consecutive days significantly improved CA1 pyramidal cell survival, indicating that the local availability of this essential nutrient may limit postischemic neuronal survival. PMID- 24754537 TI - DNA amplification in neutral liposomes for safe and efficient gene delivery. AB - In general, traditional gene carriers contain strong cationic charges to efficiently load anionic genes, but this cationic character also leads to destabilization of plasma membranes and causes severe cytotoxicity. Here, we developed a PCR-based nanofactory as a safe gene delivery system. A few template plasmid DNA can be amplified by PCR inside liposomes about 200 nm in diameter, and the quantity of loaded genes highly increased by more than 8.8-fold. The liposome membrane was composed of neutral lipids free from cationic charges. Consequently, this system is nontoxic, unlike other traditional cationic gene carriers. Intense red fluorescent protein (RFP) expression in CHO-K1 cells showed that the amplified genes could be successfully transfected to cells. Animal experiments with the luciferase gene also showed in vivo gene expression by our system without toxicity. We think that this PCR-based nanofactory system can overcome the toxicity problem that is the critical limitation of current gene delivery to clinical application. PMID- 24754538 TI - PhiC31 integrase induces efficient site-specific recombination in the Capra hircus genome. AB - Streptomyces phage phiC31 integrase induces efficient site-specific recombination capable of integrating exogenous genes at pseudo attP sites in human, mouse, rat, rabbit, sheep, Drosophila, and bovine genomes. However, the phiC31-mediated recombination between attB and the corresponding pseudo attP sites has not been investigated in Capra hircus. Here, we identified eight pseudo attP sites located in the intron or intergenic regions of the C. hircus genome, and demonstrated different levels of foreign gene expression after phiC31 integrase-mediated integration. These pseudo attP sites share similar sequences with each other and with pseudo attP sites in other mammalian genomes, and these are associated with a neighboring consensus motif found in other genomes. The application of the phiC31 integrase system in C. hircus provides a new option for genetic engineering of this economically important goat species. PMID- 24754539 TI - International Federation of Nurse Anesthetists' anesthesia program approval process. AB - The International Federation of Nurse Anesthetists is improving anaesthesia patient care through a voluntary Anesthesia Program Approval Process (APAP) for schools and programmes. It is the result of a coordinated effort by anaesthesia leaders from many nations to implement a voluntary quality improvement system for education. These leaders firmly believe that meeting international education standards is an important way to improve anaesthesia, pain management and resuscitative care to patients worldwide. By 2013, 14 anaesthesia programmes from France, Iceland, Indonesia, Philippines, Sweden, Switzerland, Netherlands, Tunisia and the USA had successfully completed the process. Additional programmes were scheduled for review in 2014. Faculty from these programmes, who have successfully completed APAP, show how anaesthesia educators throughout the world seek to continually improve education and patient care by pledging to meet common education standards. As national governments, education ministers and heads of education institutions work to decrease shortages of healthcare workers, they would benefit from considering the value offered by quality improvement systems supported by professional organizations. When education programmes are measured against standards developed by experts in a profession, policy makers can be assured that the programmes have met certain standards of quality. They can also be confident that graduates of approved programmes are appropriately trained healthcare workers for their citizens. PMID- 24754540 TI - Singlet-singlet exciton recombination: theoretical insight into the influence of high density regime of excitons in conjugated polymers. AB - Using a modified version of the Su-Schrieffer-Heeger (SSH) model combined with the extended Hubbard model (EHB), the recombination between a singlet exciton pair is investigated under the influence of an external electric field, electron electron interactions, and temperature effects in the scope of a nonadiabatic evolution method. The excitons are positioned very close to each other in a way to mimic a high-density region in monomolecular conjugated polymer systems. Results show that there are mainly three possible channels resulting from singlet singlet exciton recombination: (1) forming an excited negative polaron and an excited positive bipolaron, (2) forming two free and excited oppositely charged polarons, and (3) forming a biexciton. These results suggest that the recombination processes critically depends on the condition imposed to the system. The description of this dependence, as carried out in the present work, may provide guidance to improve the generation of free charge carriers in organic optoelectronic devices. PMID- 24754541 TI - Review of community facilities in Australian retirement villages: A content analysis. AB - AIM: Facilities in retirement villages form a supportive environment for older residents. The purpose of this paper is to investigate the provision of these facilities in retirement villages, which are regarded as a viable accommodation option for the increasing ageing population in Australia. METHODS: A content analysis of facilities in 124 retirement villages operated by 22 developers in Queensland and South Australia was conducted. RESULTS: The most widely provided facilities are community centres, libraries, barbeque facilities, hairdressers/salons and billiards/snooker/pool tables. Commercial operators provide more facilities than not-for-profit organisations, and larger retirement villages normally have more facilities due to the economies of scale involved. CONCLUSIONS: The results of the study provide a useful reference for providing facilities within retirement villages that may support the quality lifestyles of older residents. PMID- 24754542 TI - Relationship between menopausal symptoms and sexual dysfunction among married Turkish women in 40-65 age group. AB - This was a cross-sectional study to analyse the relationship between menopausal symptoms and sexual dysfunction among 229 married Turkish women in the 40-65 age group. The study was carried out at a menopause clinic of a state hospital between 1 October and 31 December 2010. Data were collected with Personal Characteristics Form, Menopause Rating Scale (MRS) and the Arizona Sexual Experience Scale (ASEX). The average age of the women was 52.33 (SD = 4.80) years. The average MRS total score was 20.13(SD = 9.20). The ASEX mean score was 19.97 (SD = 5.44). It was determined that there is a positive meaningful relationship between ASEX mean score, MRS total mean score and the sub-score of women. From the results obtained from this study, it can be said that women have differing levels of menopausal symptoms, and as the severity of menopausal symptoms increases, there is an increase in sexual dysfunction. PMID- 24754543 TI - CD4 count outperforms World Health Organization clinical algorithm for point-of care HIV diagnosis among hospitalised HIV-exposed Malawian infants. AB - OBJECTIVE: To determine, for the WHO algorithm for point-of-care diagnosis of HIV infection, the agreement levels between paediatricians and non-physician clinicians, and to compare sensitivity and specificity profiles of the WHO algorithm and different CD4 thresholds against HIV PCR testing in hospitalised Malawian infants. METHODS: In 2011, hospitalised HIV-exposed infants <12 months in Lilongwe, Malawi, were evaluated independently with the WHO algorithm by both a paediatrician and clinical officer. Blood was collected for CD4 and molecular HIV testing (DNA or RNA PCR). Using molecular testing as the reference, sensitivity, specificity and positive predictive value (PPV) were determined for the WHO algorithm and CD4 count thresholds of 1500 and 2000 cells/mm(3) by paediatricians and clinical officers. RESULTS: We enrolled 166 infants (50% female, 34% <2 months, 37% HIV infected). Sensitivity was higher using CD4 thresholds (<1500, 80%; <2000, 95%) than with the algorithm (physicians, 57%; clinical officers, 71%). Specificity was comparable for CD4 thresholds (<1500, 68%, <2000, 50%) and the algorithm (paediatricians, 55%, clinical officers, 50%). The positive predictive values were slightly better using CD4 thresholds (<1500, 59%, <2000, 52%) than the algorithm (paediatricians, 43%, clinical officers 45%) at this prevalence. CONCLUSION: Performance by the WHO algorithm and CD4 thresholds resulted in many misclassifications. Point-of-care CD4 thresholds of <1500 cells/mm(3) or <2000 cells/mm(3) could identify more HIV-infected infants with fewer false positives than the algorithm. However, a point-of-care option with better performance characteristics is needed for accurate, timely HIV diagnosis. PMID- 24754544 TI - Agreement between self-reported and registered colorectal cancer screening: a meta-analysis. AB - This random-effects meta-analysis investigates the accuracy of self-reported colorectal cancer screening history as a function of screening mode (colonoscopy, flexible sigmoidoscopy, faecal occult blood testing - FOBT, double-contrast barium enema - DCBE) and survey mode (written, telephone, face-to-face). Summary estimates of sensitivity, specificity, positive predictive value (PPV) and area under the receiver operating characteristic curve (AUC) were calculated. Medical record data were used as reference. We included 23 studies comprising 11,592 subjects. Colonoscopy yielded higher AUC [0.948, 95% confidence interval (CI) = 0.918, 0.968] than flexible sigmoidoscopy (0.883, 95% CI = 0.849, 0.911) and FOBT (0.869, 95% CI = 0.833, 0.898). Colonoscopy showed the highest sensitivity (0.888, 95% CI = 0.835, 0.931), whereas specificity was comparable between screening modes (ranging from 0.802 for FOBT to 0.904 for DCBE). AUC was not significantly different between survey modes. Prevalence of screening history correlated positively with sensitivity and negatively with specificity, possibly because of errors in the medical records. In conclusion, the accuracy of self reported cancer screening is generally moderate, and higher for colonoscopy than for sigmoidoscopy and FOBT. PMID- 24754545 TI - Promoting reflection by using contextual activity sampling: a study on students' interprofessional learning. AB - Students' engagement and reflection on learning activities are important during interprofessional clinical practice. The contextual activity sampling system (CASS) is a methodology designed for collecting data on experiences of ongoing activities by frequent distribution of questionnaires via mobile phones. The aim of this study was to investigate if the use of the CASS methodology affected students' experiences of their learning activities, readiness for interprofessional learning, academic emotions and experiences of interprofessional team collaboration. Student teams, consisting of 33 students in total from four different healthcare programs, were randomized into an intervention group that used CASS or into a control group that did not use CASS. Both quantitative (questionnaires) and qualitative (interviews) data were collected. The results showed that students in the intervention group rated teamwork and collaboration significantly higher after than before the course, which was not the case in the control group. On the other hand, the control group reported experiencing more stress than the intervention group. The qualitative data showed that CASS seemed to support reflection and also have a positive impact on students' experiences of ongoing learning activities and interprofessional collaboration. In conclusion, the CASS methodology provides support for students in their understanding of interprofessional teamwork. PMID- 24754546 TI - Multiple anterior tibial stress fractures complicated by acute complete fracture of the distal tibia. PMID- 24754547 TI - Can viscosupplementation be used in the hip? PMID- 24754549 TI - Will total ankle arthroplasty become the new standard for end-stage ankle arthritis? PMID- 24754550 TI - Current indications for and the technique of wrist arthroscopy. AB - Since its introduction more than 30 years ago, wrist arthroscopy has become an essential diagnostic and therapeutic tool in hand surgery. This procedure minimizes exposures and allows access to otherwise remotely located anatomic regions with minimal morbidity. Advances in anatomic understanding and wrist scope technology have standardized the procedure and expanded indications. Current applications are diagnostic staging of various wrist pathologies where arthroscopy allows for a direct, magnified, and tactile-assisted examination. This includes injuries to the triangular fibrocartilage complex (TFCC), osteochondral lesion of the carpus, and dynamic assessment of carpal instability and radiocarpal arthritis. Therapeutic applications have continued to expand and include arthroscopic-assisted fracture reductions, treatment of radiocarpal synovitis and arthritis, TFCC repairs, and arthroscopic management of soft tissue pathologies such as ganglion excisions and release of contractures. PMID- 24754551 TI - Serum high-mobility group box 1 protein correlates with cognitive decline after gastrointestinal surgery. AB - BACKGROUND: Accumulating evidence has indicated that inflammation may act as a potential mechanism underlying post-operative cognitive dysfunction (POCD). High mobility group box 1 (HMGB1), as a known late mediator of inflammation, is involved in the development of post-operative complications. Thus, we sought to determine the role of HMGB1 in reflecting POCD following major gastrointestinal surgery. METHODS: Fifty-three elderly patients undergoing gastrointestinal surgery were recruited, and 50 patients completed the study. Serum HMGB1 and interleukin (IL)-6 levels were measured pre-operatively and at 6 h, day 1 and day 3 post-operatively. Neuropsychological tests were administered before and 1 week after surgery. POCD was determined using a Z score >= 1.96. RESULTS: Seventeen (34%, 17/50) patients developed POCD at 1 week. The POCD group had higher serum HMGB1 levels at day 1 (12.15 +/- 3.12 vs. 9.91 +/- 3.15 ng/ml, P = 0.021) and day 3 (11.04 +/- 2.88 vs. 8.52 +/- 3.31 ng/ml, P = 0.011). IL-6 levels at 6 h (51.18 +/- 15.22 vs. 39.20 +/- 14.32 pg/ml, P = 0.009) and day 1 (41.59 +/- 11.08 vs. 33.81 +/- 11.42 pg/ml, P = 0.026) were significantly higher in POCD patients. Serum values of IL-6 at 6 h, HMGB1 at day 1 and levels of education showed positive correlations with Z scores. HMGB1 at day 3 and IL-6 at 6 h were independent risk factors. CONCLUSIONS: Serum HMGB1 and IL-6 levels increase significantly after major gastrointestinal surgery in elderly patients and such elevations are associated with the occurrence of cognitive decline after surgery. PMID- 24754552 TI - Effect of waveform of ac voltage on the morphology and crystallinity of electrochemically assembled platinum nanowires. AB - Here we present electrochemically grown ultrathin platinum nanowires and demonstrate that their morphology and crystalline structure can be tuned by the waveform of the alternating voltage applied to the microelectrodes. The structure of the nanowires was analyzed by scanning and transmission electron microscopy. The voltage signal, applied to grow the nanowires, consisted of several Fourier components of a square-shaped wave. We observed that, depending on the number of Fourier components, the morphology of the nanowires changed from branched dendritic-like patterns to straight wires and the wire crystallinity changed from polycrystalline to highly oriented growth with the [111] direction of platinum crystallites along the nanowire axis. We propose a simple model to explain this intriguing observation. PMID- 24754553 TI - Period life tables for the non-Hispanic American Indian and Alaska Native population, 2007-2009. AB - OBJECTIVES: We estimated complete period life tables for the non-Hispanic American Indian and Alaska Native (AI/AN) population residing in Contract Health Service Delivery Area (CHSDA) counties for the period 2007-2009. METHODS: We used National Vital Statistics System mortality data files for years 2007-2009 corrected for AI/AN misclassification on death certificates, midyear 2008 revised census bridged race intercensal population estimates, and National Vital Statistics System birth data for years 2006-2009. We used the same methodology as that used to estimate official US annual life tables, with some minor modifications. RESULTS: For the period 2007-2009, the non-Hispanic AI/AN population in CHSDA counties had the lowest life expectancy at birth (71.1 years) of any racial/ethnic group for which official US life tables are estimated. By comparison, in 2008, life expectancy at birth was 73.9 years for the non-Hispanic Black population, 78.4 years for the non-Hispanic White population, and 80.8 years for the Hispanic population. CONCLUSIONS: The life tables showed a clear mortality disadvantage for the non-Hispanic AI/AN population in CHSDA counties relative to other national populations. The findings suggested that further research is necessary to explore the causes behind these disadvantages. PMID- 24754554 TI - Leading causes of death and all-cause mortality in American Indians and Alaska Natives. AB - OBJECTIVES: We present regional patterns and trends in all-cause mortality and leading causes of death in American Indians and Alaska Natives (AI/ANs). METHODS: US National Death Index records were linked with Indian Health Service (IHS) registration records to identify AI/AN deaths misclassified as non-AI/AN. We analyzed temporal trends for 1990 to 2009 and comparisons between non-Hispanic AI/AN and non-Hispanic White persons by geographic region for 1999 to 2009. Results focus on IHS Contract Health Service Delivery Area counties in which less race misclassification occurs. RESULTS: From 1990 to 2009 AI/AN persons did not experience the significant decreases in all-cause mortality seen for Whites. For 1999 to 2009 the all-cause death rate in CHSDA counties for AI/AN persons was 46% more than that for Whites. Death rates for AI/AN persons varied as much as 50% among regions. Except for heart disease and cancer, subsequent ranking of specific causes of death differed considerably between AI/AN and White persons. CONCLUSIONS: AI/AN populations continue to experience much higher death rates than Whites. Patterns of mortality are strongly influenced by the high incidence of diabetes, smoking prevalence, problem drinking, and social determinants. Much of the observed excess mortality can be addressed through known public health interventions. PMID- 24754555 TI - Effectiveness of Circle of Life, an HIV-preventive intervention for American Indian middle school youths: a group randomized trial in a Northern Plains tribe. AB - OBJECTIVES: We assessed the effectiveness of Circle of Life (COL), an HIV preventive intervention developed specifically for American Indian and Alaska Native (AI/AN) middle school youths. METHODS: By partnering with a tribal community, we conducted a longitudinal wait-listed group randomized trial with 635 seventh and eighth graders in 13 schools of a Northern Plains tribe. We surveyed participants at baseline, 3 months, and 12 months from 2006 to 2007. RESULTS: COL was found to increase HIV knowledge in the short term, but had no effect on sexual activity compared with those who did not receive it. However, COL was found to be effective for delaying the onset of sexual activity, with the greatest reduction in risk occurring for those receiving COL at early ages. CONCLUSIONS: Community partnership was key to successful project design, implementation, and analysis. The project confirmed the importance of the timing of interventions in early adolescence. COL may be a key resource for reducing sexual risk among AI/AN youths. PMID- 24754556 TI - Trends and disparities in heart disease mortality among American Indians/Alaska Natives, 1990-2009. AB - OBJECTIVES: We evaluated heart disease death rates among American Indians and Alaska Natives (AI/ANs) and Whites after improving identification of AI/AN populations. METHODS: Indian Health Service (IHS) registration data were linked to the National Death Index for 1990 to 2009 to identify deaths among AI/AN persons aged 35 years and older with heart disease listed as the underlying cause of death (UCOD) or 1 of multiple causes of death (MCOD). We restricted analyses to IHS Contract Health Service Delivery Areas and to non-Hispanic populations. RESULTS: Heart disease death rates were higher among AI/AN persons than Whites from 1999 to 2009 (1.21 times for UCOD, 1.30 times for MCOD). Disparities were highest in younger age groups and in the Northern Plains, but lowest in the East and Southwest. In AI/AN persons, MCOD rates were 84% higher than UCOD rates. From 1990 to 2009, UCOD rates declined among Whites, but only declined significantly among AI/AN persons after 2003. CONCLUSIONS: Analysis with improved race identification indicated that AI/AN populations experienced higher heart disease death rates than Whites. Better prevention and more effective care of heart disease is needed for AI/AN populations. PMID- 24754557 TI - Methods for improving the quality and completeness of mortality data for American Indians and Alaska Natives. AB - OBJECTIVES: We describe methods used to mitigate the effect of race misclassification in mortality records and the data sets used to improve mortality estimates for American Indians and Alaska Natives (AI/ANs). METHODS: We linked US National Death Index (NDI) records with Indian Health Service (IHS) registration records to identify AI/AN deaths misclassified as non-AI/AN deaths. Analyses excluded decedents of Hispanic origin and focused on Contract Health Service Delivery Area (CHSDA) counties. We compared death rates for AI/AN persons and Whites across 6 US regions. RESULTS: IHS registration records merged to 176,137 NDI records. Misclassification of AI/AN race in mortality data ranged from 6.3% in the Southwest to 35.6% in the Southern Plains. From 1999 to 2009, the all-cause death rate in CHSDA counties for AI/AN persons varied by geographic region and was 46% greater than that for Whites. Analyses for CHSDA counties resulted in higher death rates for AI/AN persons than in all counties combined. CONCLUSIONS: Improving race classification among AI/AN decedents strengthens AI/AN mortality data, and analyzing deaths by geographic region can aid in planning, implementation, and evaluation of efforts to reduce health disparities in this population. PMID- 24754558 TI - Perspectives on mortality data from the Indian Health Service. PMID- 24754559 TI - Modeling cell survival after irradiation with Ultrasoft X rays using the giant loop binary lesion model. AB - We present an application of the Giant LOop Binary LEsion (GLOBLE) model to the case of cell killing after irradiation with ultrasoft X rays. The model is based on the analysis of DSB clustering on the level of chromatin organization on a megabase pair length scale; it distinguishes between two classes of damage, characterized by either an isolated, single DSB (iDSB) or multiple, clustered DSB (cDSB) within a single giant loop. These corresponding fractions of iDSB and cDSB depend on the total number of DSB and thus on the dose as well as the yield of DSB per Gy per cell. Based on the increased yield of DSB with decreasing photon energy as reported in the literature, we demonstrate that according to the model this increased yield of DSB is sufficient to explain the increased RBE of ultrasoft X rays. Further assumptions as e.g., a higher lethality of individual DSB induced by ultrasoft X rays compared to high-energy photons, which might be a consequence of the more localized energy deposition, seem not to be a prerequisite. Since the model is also suitable to take into account local dose variations within the cell nucleus, we further analyze the impact of attenuation of low-energy photon radiation when penetrating a cell layer. We show that the inhomogenous dose distribution resulting from attenuation further increases the effectiveness and particularly affects the beta-term of the corresponding dose response curve. Finally, we compare and discuss the mechanisms of increased RBE as observed after ultrasoft X-ray irradiation with those observed after high-LET ion beam irradiation. PMID- 24754560 TI - Skin cancer incidence among atomic bomb survivors from 1958 to 1996. AB - The radiation risk of skin cancer by histological types has been evaluated in the atomic bomb survivors. We examined 80,158 of the 120,321 cohort members who had their radiation dose estimated by the latest dosimetry system (DS02). Potential skin tumors diagnosed from 1958 to 1996 were reviewed by a panel of pathologists, and radiation risk of the first primary skin cancer was analyzed by histological types using a Poisson regression model. A significant excess relative risk (ERR) of basal cell carcinoma (BCC) (n = 123) was estimated at 1 Gy (0.74, 95% confidence interval (CI): 0.26, 1.6) for those age 30 at exposure and age 70 at observation based on a linear-threshold model with a threshold dose of 0.63 Gy (95% CI: 0.32, 0.89) and a slope of 2.0 (95% CI: 0.69, 4.3). The estimated risks were 15, 5.7, 1.3 and 0.9 for age at exposure of 0-9, 10-19, 20-39, over 40 years, respectively, and the risk increased 11% with each one-year decrease in age at exposure. The ERR for squamous cell carcinoma (SCC) in situ (n = 64) using a linear model was estimated as 0.71 (95% CI: 0.063, 1.9). However, there were no significant dose responses for malignant melanoma (n = 10), SCC (n = 114), Paget disease (n = 10) or other skin cancers (n = 15). The significant linear radiation risk for BCC with a threshold at 0.63 Gy suggested that the basal cells of the epidermis had a threshold sensitivity to ionizing radiation, especially for young persons at the time of exposure. PMID- 24754561 TI - Effect of temperature on the low-linear energy transfer radiolysis of the ceric cerous sulfate dosimeter: a Monte Carlo simulation study. AB - The stochastic modeling of the (60)Co gamma/fast-electron radiolysis of the ceric cerous chemical dosimeter has been performed as a function of temperature from 25 350 degrees C. The system used is a dilute solution of ceric sulfate and cerous sulfate in aqueous 0.4 M sulfuric acid. In this system, H(*) (or HO2(*) in the presence of dissolved oxygen) and H2O2 produced by the radiolytic decomposition of water both reduce Ce(4+) ions to Ce(3+) ions, while (*)OH radicals oxidize the Ce(3+) present in the solution back to Ce(4+). The net Ce(3+) yield is given by G(Ce(3+)) = g(H(*)) + 2 g(H2O2) - g((*)OH), where the primary (or "escape") yields of H(*), H2O2 and (*)OH are represented by lower case g's. At room temperature, G(Ce(3+)) has been established to be 2.44 +/- 0.8 molecules/100 eV. In this work, we investigated the effect of temperature on the yield of Ce(3+) and on the underlying chemical reaction kinetics using Monte Carlo track chemistry simulations. The simulations showed that G(Ce(3+)) is time dependent, a result of the differences in the lifetimes of the reactions that make up the radiolysis mechanism. Calculated G(Ce(3+)) values were found to decrease almost linearly with increasing temperature up to about 250 degrees C, and are in excellent agreement with available experimental data. In particular, our calculations confirmed previous estimated values by Katsumura et al. (Radiat Phys Chem 1988; 32:259-63) showing that G(Ce(3+)) at ~250 degrees C is about one third of its value at room temperature. Above ~250 degrees C, our model predicted that G(Ce(3+)) would drop markedly with temperature until, instead of Ce(4+) reduction, Ce(3+) oxidation is observed. This drop is shown to occur as a result of the reaction of hydrogen atoms with water in the homogeneous chemical stage. PMID- 24754562 TI - Metformin exhibits radiation countermeasures efficacy when used alone or in combination with sulfhydryl containing drugs. AB - Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4 fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use. PMID- 24754563 TI - Associations of unprotected anal intercourse with Grindr-met partners among Grindr-using young men who have sex with men in Los Angeles. AB - Grindr, a geosocial smartphone application, is a networking medium for men who have sex with men. Although three quarters of young men who have sex with men (YMSM) Grindr users report having sex with a Grindr-met partner, the correlates of risky sexual behavior with Grindr-met partners are unknown. A randomly selected sample of 18- to 24-year-old, Grindr-using YMSM completed an anonymous online questionnaire assessing patterns of Grindr use and sexual behavior with their last Grindr-met partners. Of the 146 YMSM who reported having sex with Grindr-met partners, 20% had unprotected anal intercourse (UAI) at last sex with their Grindr-met partner. In the multivariable model, YMSM who used Grindr for at least one year showed naked chest/abs in their profile photo, and reported more past month Grindr-met partners were more likely to report UAI. These findings suggest that familiarity with the app was associated with YMSM's UAI with Grindr met partners. Moreover, sexualized profile photos (i.e., naked chest/abs) may be associated with sexual risk-taking behaviors. HIV prevention interventions delivered or linked through such apps should target individuals who are longer/frequent users and who present sexualized profiles. PMID- 24754564 TI - Tacrolimus dose requirements in African-American and Caucasian kidney transplant recipients on mycophenolate and prednisone. AB - Racial differences among kidney transplant recipients may impact the total daily tacrolimus dose required to achieve therapeutic tacrolimus concentrations. Previous studies suggest that African Americans require higher doses to achieve similar therapeutic drug concentrations compared with Caucasians. Data were collected on a total of 147 de novo kidney transplant recipients. Tacrolimus total daily dose (TDD) requirements (mg/kg/d) and tacrolimus concentrations were retrospectively reviewed at discharge and at days 30, 60, and 90 after transplant. TDD requirements in African-American and Caucasian patients were 0.14 mg/kg/d and 0.11 mg/kg/d, respectively (p = 0.005), at day 30. TDD requirements at day of hospital discharge and days 60 and 90 following transplant were significantly higher in African-American patients vs. Caucasian patients, with similar tacrolimus concentrations at all time points. This study suggests that when compared to Caucasians, African Americans require significantly higher TDD of tacrolimus to achieve similar tacrolimus concentrations. These findings provide transplant clinicians with a sense of certainty to more rapidly titrate daily tacrolimus doses in African-American patients to achieve therapeutic concentrations. PMID- 24754565 TI - Translating cell-based regenerative medicines from research to successful products: challenges and solutions. AB - The Tissue Engineering & Regenerative Medicine International Society-Europe (TERMIS-EU) Industry Committee as well as its TERMIS-Americas (AM) counterpart intend to address the specific challenges and needs facing the industry in translating academic research into commercial products. Over the last 3 years, the TERMIS-EU Industry Committee has worked with commercial bodies to deliver programs that encourage academics to liaise with industry in proactive collaborations. The TERMIS-EU 2013 Industry Symposium aimed to build on this commercial agenda by focusing on two topics: Operations Management (How to move a process into the good manufacturing practice [GMP] environment) and Clinical Translation (Moving a GMP process into robust trials). These topics were introduced by providing the synergistic business perspective of partnering between the multiple regenerative medicine stakeholders, throughout the life cycle of product development. Seven industry leaders were invited to share their experience, expertise, and strategies. Due to the complex nature of regenerative medicine products, partnering for their successful commercial development seems inevitable to overcome all obstacles by sharing experiences and expertise of all stakeholders. When ideally implemented, the "innovation quotient" of a virtual team resulting from the combination of internal and external project teams can be maximized through maximizing the three main dimensions: core competences, technology portfolio, and alliance management. PMID- 24754566 TI - Boron carboxylate catalysis of homoallylboration. AB - Boron tris(trifluoroacetate) is identified as the first effective catalyst for the homoallyl- and homocrotylboration of aldehydes by cyclopropylcarbinylboronates. NMR spectroscopic studies and theoretical calculations of key intermediates and transition states both suggest that a ligand-exchange mechanism, akin to our previously reported PhBCl2-promoted homoallylations, is operative. Our experimental and theoretical results also suggest that the catalytic activity of boron tris(trifluoroacetate) might originate from more facile catalytic turnover of the trifluoroacetate ligands (in agreement with DFT calculations) or from a lower propensity for formation of off pathway reservoir intermediates (as observed by (1)H NMR). This work shows that carboxylates are viable catalytic ligands for homoallyl- and homocrotylations of carbonyl compounds and opens the door to the development of catalytic asymmetric versions of this transformation. PMID- 24754568 TI - Acute hospital admission for nursing home residents without cognitive impairment with a diagnosis of cancer. AB - Studies of hospitalisation of cognitively intact nursing home (NH) residents with cancer are scarce. Knowledge about associations between socio-demographic, medical and social support variables and hospital admissions aids in preventing unnecessary admissions. This is part of a prospective study from 2004 to 2005 with follow-up to 2010 for admission rates. We studied whether residents with cancer have more admissions and whether socio-demographic and medical variables and social support subdimensions are associated with admission among cognitively intact NH residents with (n = 60) and without (n = 167) cancer aged >=65 years scoring <=0.5 on the Clinical Dementia Rating Scale and residing >=6 months. We measured social support by face-to-face interview. We identified all respondents through NH medical records for hospital admission, linking their identification numbers to the hospital record system to register all admissions. We examined whether socio-demographic and medical variables (medical records) and social support subscales were associated with the time between inclusion and first admission. Residents with cancer had more admissions (25/60) than those without (53/167) (odds ratio 1.7). Social integration was correlated with admission (P = 0.04) regardless of cancer diagnosis. Residents with cancer had more hospital admissions than those without. Higher social integration gave more admissions independent of cancer diagnosis. PMID- 24754567 TI - Selective uptake and imaging of aptamer- and antibody-conjugated hollow nanospheres targeted to epidermal growth factor receptors overexpressed in head and neck cancer. AB - The purpose of this study was to compare the binding affinity and selective targeting of aptamer- and antibody-coated hollow gold nanospheres (HAuNS) targeted to epidermal growth factor receptors (EGFR). EGFR-targeting aptamers were conjugated to HAuNS (apt-HAuNS) by attaching a thiol-terminated single stranded DNA to the HAuNS and then adding the complementary RNA targeted to EGFR. Apt-HAuNS was characterized in terms of size, surface charge, absorption, and number of aptamers per particle. The in vivo pharmacokinetics, in vivo biodistribution, and micro-SPECT/CT imaging of (111)In-labeled apt-HAuNS and anti EGFR antibody (C225)-conjugated HAuNS were evaluated in nude mice bearing highly malignant human OSC-19 oral tumors. (111)In-labeled PEG-HAuNS was used as a control (n = 5/group). Apt-HAuNS did not have an altered absorbance profile or size (lambdamax = 800 nm; diameter = 55 nm) compared to C225-HAuNS or PEG-HAuNS. The surface charge became more negative upon conjugation of the aptamer (-51.4 vs -19.0 for PEG-HAuNS and -25.0 for C225-HAuNS). The number of aptamers/particle was ~250. In vitro cell binding and in vivo biodistribution showed selective binding of the apt-HAuNS to EGFR. MUSPECT/CT imaging confirmed that there was more tumor uptake of apt-HAuNS than C225-HAuNS. Aptamer is a promising ligand for image-guided delivery of nanoparticles for treatment of tumor cells overexpressing EGFR. PMID- 24754569 TI - Retrospective clinical evaluation of ultrasound guided transverse abdominis plane block in dogs undergoing mastectomy. AB - HISTORY: Eleven female dogs of different breeds undergoing unilateral radical (n = 7) or regional abdominal mastectomy (n = 4) received an ultrasound guided transverse abdominis plane block (TAP-block). PHYSICAL EXAMINATION: Subjects showed single or multiple mammary tumours. Serum biochemistry, CBC and electrocardiogram were unremarkable. Eight animals were classified as ASA physical status II and 3 as ASA III. MANAGEMENT: Dogs were premedicated with methadone [0.1 or 0.2 mg kg(-1) intravenously (IV) or intramuscularly respectively] or fentanyl (2.5 MUg kg(-1) IV). Anaesthesia was induced with propofol and maintained with isoflurane or sevoflurane. Unilateral ultrasound guided TAP blocks were performed in the caudal and cranial abdomen with bupivacaine 0.25% (0.3 to 0.35 mL kg(-1) ). Intercostal nerve blocks (T4 to T11 ) with bupivacaine 0.25% (0.013 to 0.04 mL kg(-1) ) completed the blocked area in dogs undergoing radical mastectomy. FOLLOW UP: The median (range) of end-expired isoflurane and sevoflurane necessary to maintain anaesthesia was 1.15 (1.07-1.22) and 2.07 (2.05-2.2) vol% respectively. A single administration of fentanyl (2.5 MUg kg(-1) , IV) was administered to control nociception (defined as an increased heart rate or mean arterial blood pressure above 20% of the pre-incisional value) in four of 11 dogs. All dogs received carprofen (2 mg kg(-1) subcutaneously) at the end of surgery. Post-operative pain, assessed for 120 minutes using the short form of Glasgow Composite Pain Scale (0-24), was always lower than 3. No rescue analgesia (allowed by the protocol) was required in this time. CONCLUSION: Transverse abdominis plane block combined with intercostal nerve blocks may be useful to produce intraoperative anti-nociception and short term post-operative analgesia in dogs undergoing unilateral mastectomy. PMID- 24754570 TI - Nanocrystals of a metal-organic complex exhibit remarkably high conductivity that increases in a single-crystal-to-single-crystal transformation. AB - Ag(I) is used to form a pi-stacked metal-organic solid that exhibits remarkably high electrical conductivity. The solid undergoes a single-crystal-to-single crystal [2+2] photodimerization to generate a 1D coordination polymer with over 40% higher conductivity. The Ag(I) complex represents the first example of an increase in conductivity resulting from a [2+2] photodimerization. Density of states calculations show a higher contribution from Ag(I) ions to the valence band in the photodimerized solid, supporting the increase in conductivity. PMID- 24754574 TI - Interaction of the rattlesnake toxin crotamine with model membranes. AB - Crotamine is one of the main constituents of the venom of the South American rattlesnake Crotalus durissus terrificus. A common gene ancestry and structural similarity with the antimicrobial beta-defensins (identical disulfide bond pattern and highly positive net charge) suggested potential antimicrobial activities for this snake toxin. Although crotamine demonstrated low activity against both Gram-positive and Gram-negative bacteria, a pronounced antifungal activity was observed against Candida spp., Trichosporon spp., and Cryptococcus neoformans. Crotamine's selective antimicrobial properties, with no observable hemolytic activity, stimulated us to evaluate the potential applications of this polypeptide as an antiyeast or candicidal agent for medical and industrial application. Aiming to understand the mechanism(s) of action underlying crotamine antimicrobial activity and its selectivity for fungi, we present herein studies using membrane model systems (i.e., large unilamellar vesicles, LUVs, and giant unilamellar vesicles, GUVs), with different phospholipid compositions. We show here that crotamine presents a higher lytic activity on negatively charged membranes compared with neutral membranes, with or without cholesterol or ergosterol content. The vesicle burst was not preceded by membrane permeabilization as is generally observed for pore forming peptides. Although such a property of disrupting lipid membranes is very important to combat multiresistant fungi, no inhibitory activity was observed for crotamine against biofilms formed by several Candida spp. strains, except for a limited effect against C. krusei biofilm. PMID- 24754575 TI - Health education needs of incarcerated women. AB - PURPOSE: This study identifies the healthcare education needs of incarcerated women in a state corrections facility. METHODS: This was a naturalistic qualitative study. Focus groups included two groups of adult women incarcerated in a state corrections facility. One group consisted of women housed in maximum security, and one group consisted of women housed in medium security. Data were analyzed using a constant comparison approach. FINDINGS: Three guiding questions provided the foundation for the identified themes. Themes included six healthcare education topics important to incarcerated women and three related to health education strategies best suited for incarcerated women. CONCLUSIONS: Trust, respect and empowerment are key concepts in educating incarcerated women about their personal health and health of their families. CLINICAL RELEVANCE: With over 200,000 women incarcerated in the United States today, creating policies and practices that focus on the healthcare education needs of women that are woman focused may enhance knowledge and skills and may ultimately lead to reduced recidivism. PMID- 24754577 TI - Breast cancer prevention for BRCA1 and BRCA2 mutation carriers: is there a role for tamoxifen? PMID- 24754576 TI - Age-related dermal collagen changes during development, maturation and ageing - a morphometric and comparative study. AB - The tissue organisation of dermal collagen is gaining importance as a contributing factor both in development and ageing, as well as in skin maturation processes. In this work we aim to study different representative parameters of this structural organisation in 45 human skin samples of assorted ages, by means of image analysis. The variation of these parameters on the basis of age was assessed using several regression models (linear, quadratic and cubic). The area occupied by collagen was significantly reduced as a function of age in the papillary dermis (R(2) = 0.437, P < 0.0001), as well as the thickness of the collagen bundles (R(2) = 0.461, P < 0.0001), following statistical models of cubic and quadratic regression, respectively. The width of the papillary dermis increased in a significant manner over a linear regression model (R(2) = 0.26, P < 0.0001). In the reticular dermis, the cubic regression indicated a significant decline (R(2) = 0.392, P = 0.002) of the area filled with collagen according to the age. Both collagen thickness and bundle orientation parameters fit a quadratic regression over the age in a significant way (R(2) = 0.433 and R(2) = 0.334, respectively, both P < 0.0001). The width of the reticular dermis followed also a significant quadratic distribution according to age (R(2) = 0.193, P = 0.011). These parameters could partially explain the lifelong functional changes taking place in the skin and propose a baseline providing a useful entry point for future investigation. PMID- 24754578 TI - Will there be enough medical oncologists in the EU come 2020? PMID- 24754579 TI - A superior strategy for single-cell mutational screening via multiplex-targeted QPCR using the BioMark HD microfluidic platform. AB - A major challenge in cancer therapy lies in its complexity and heterogeneity, with increasing recognition of many tumor subtypes that have different biological characteristics and responses to therapies. To effectively address this challenge, personalized medicine has been the 'vogue' currently. Dissecting the detailed clonal architecture of cancer by cancer genomics, which holds the promise of personalized medicine, has significant clinical implications. Substantial advances have been made in DNA-based, high-throughput genomic technologies. However, current methods are still in its infancy, significantly limited by error rates, low cell throughput, high cost and labor intensive. The study under evaluation develops a superior strategy for a comprehensive interrogation of the complex genomics of cancer cells by using multiplex-targeted DNA amplification from flow-sorted single cells followed by high-throughput quantitative PCR using the BioMark HD microfluidic platform. The platform demonstrated a successful rate of approximately 75%, a highly efficient single cell sorting rate of 96-98%, a high-throughput analysis of 200-300 leukemic cells, and was able to simultaneously detected chimeric fusion genes, copy number alterations and single-nucleotide variants in a single cell sample. PMID- 24754580 TI - 36th San Antonio Breast Cancer Symposium: focus on clinical trial results. AB - The 2013 San Antonio Breast Cancer Symposium, held under the auspices of the San Antonio Cancer Therapy & Research Center, the AACR, and Baylor College of Medicine, took place in San Antonio (TX, USA) on 10-14 December 2013. This international Symposium was attended by more than 7000 academic and private physicians and researchers from more than 90 countries, involved in all the fields of breast cancer (BC) research and treatment, including basic, translational and clinical research. Topics of discussion covered all aspects of BC research, from basic science to clinical practice, from prevention to targeted therapies. This report will focus on some of the most important results that were presented during the meeting. PMID- 24754581 TI - Novel approaches to the diagnosis and treatment of breast cancer. AB - 36th San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 10-14 December 2013 Progress in the treatment of breast cancer continues to require the thoughtful planning of new clinical trials and patient participation in those trials. During the 2013 San Antonio Breast Cancer Symposium (SABCS), the results of several clinical trials with practice-changing implications were presented. Additionally, the results of numerous interesting and provocative observational studies were reported. There were also several plenary lectures during the 2013 SABCS that addressed timely and controversial topics. The SABCS is a global forum for clinicians and scientists who are committed to eradicating the burden of breast cancer mortality worldwide. In this report, we highlight only a few of the many important studies and plenary talks presented during the 2013 SABCS. PMID- 24754582 TI - Opportunities and challenges of using technology to address health disparities. AB - During a panel presentation at the American Association for Cancer Research Cancer Health Disparities Conference titled 'Opportunities and challenges of using technology to address health disparities', the latest scientific advances in the application and utilization of mobile technology and/or mobile-health (mHealth) interventions to address cancer health disparities were discussed. The session included: an examination of overall population trends in the uptake of technology and the potential of addressing health disparities through such media; an exploration of the conceptual issues and challenges in the construction of mHealth interventions to address disparate and underserved populations; and a presentation of pilot study findings on the acceptability and feasibility of using mHealth interventions to address prostate cancer disparities among African American men. PMID- 24754583 TI - Long-term survival in small cell lung cancer: a case report and review of the literature. AB - Small cell lung cancer (SCLC) represents approximately 13% of all newly diagnosed lung cancers. SCLC is a very aggressive disease characterized by early locoregional and distant metastases. The median survival is 14-16 months for patients with limited disease and 8-11 months for those with extensive disease, with 20-40% of patients with limited disease and 5% of patients with extensive disease alive at 2 years. This report discusses the case of a long-term SCLC survivor treated with radiotherapy, several lines of chemotherapy and long-acting somatostatin analogs who is alive 7 years after diagnosis, with no evidence of further relapse. In the near future, better identification of prognostic and predictive factors based on models that integrate clinical data and multiple gene expression profiles and the use of novel treatments could increase the number of long-term SCLC survivors. PMID- 24754584 TI - Combined point mutation in KRAS or EGFR genes and EML4-ALK translocation in lung cancer patients. AB - A total of three cases with novel constellations regarding mutation patterns in non-small-cell lung cancer (NSCLC) are reported. The mutation patterns that are observed are novel and unexpected. First, a combined simultaneous KRAS mutation and EML4-ALK translocation, both in the main tumor and a bone metastasis, were observed, these mutations are assumed to mutually exclude each other. A further two cases include a father and a daughter, both of whom are suffering from NSCLC with different EGFR mutation patterns. A common cause was assumed; however, could not be deduced to mutations in the KRAS, BRAF and EGFR genes. The aforementioned cases are important, as it must be taken into account that mutations previously assumed to be exclusive can occur in combination, may influence the clinical outcome and may require different therapy compared with single mutated tumors. It has to be discussed whether diagnostic algorithms need to be adapted. The cases of father and daughter show that further unknown factors can influence development of NSCLC. PMID- 24754585 TI - LUX-Lung 3: redundancy, toxicity or a major step forward? Afatinib as front-line therapy for patients with metastatic EGFR-mutated lung cancer. AB - Mutant EGF receptor (EGFR) is an attractive therapeutic target in patients with metastatic non-small cell lung cancer (NSCLC). A new paradigm has been defined using ATP-competitive EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, as the most effective first-line treatment. However, clinical benefit of EGFR-TKI is only transient and limited by primary or acquired resistance. Afatinib has been developed as a highly potent, irreversible inhibitor of EGFR, HER2 and ErbB4, as well as transphosphorylation of ErbB3. The clinical activity of afatinib in lung cancer has been extensively studied in the LUX-Lung series of trials. LUX-Lung 3 was a pivotal randomized Phase III study that recently led to the approval of afatinib (Gilotrif) in several countries for treatment of patients with metastatic NSCLC harboring somatic EGFR gene mutations. Here, we review the rationale, study design including end points, results and implications of this trial for current and future EGFR genotype-directed lung cancer therapies. PMID- 24754586 TI - Vintafolide: a novel targeted agent for epithelial ovarian cancer. AB - Vintafolide (EC145) is a novel folate-conjugated vinca alkaloid (desacetylvinblastine hydrazide; DAVBLH) that binds with high affinity to the folate receptor (FR), expressed in a majority of epithelial ovarian cancers. In preclinical studies, vintafolide had significant antiproliferative activity and tolerability. Phase I studies demonstrated an acceptable safety profile, with constipation being the dose-limiting toxicity. A Phase II study of vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with platinum-resistant ovarian cancer showed a statistically significant improvement in progression-free survival with combination therapy. (99m)Tc-etarfolatide, a diagnostic radiopharmaceutical, determines FR status, which allows determination of those patients most likely to benefit from treatment with vintafolide. A Phase III study evaluating vintafolide plus PLD versus PLD alone in patients with platinum-resistant ovarian cancer is currently underway. PMID- 24754587 TI - Autotransplantation of cryopreserved ovarian tissue in oncological patients: recovery of ovarian function. AB - AIM: To present preliminary results of autotransplantation of cryopreserved ovarian tissue performed at Sant'Orsola-Malpighi Hospital, Bologna, Italy. MATERIALS & METHODS: Orthotopic transplantation was performed in two women with colorectal and breast cancer, and heterotopic transplantation was performed in one Hodgkin's lymphoma woman. The presence of micrometastasis in the ovarian tissue was checked, and morphological features of ovarian tissue were evaluated before transplantation. Ovarian function was monitored by hormonal and ultrasound color Doppler examination after transplantation. RESULTS: In all three women, no micrometastasis was found; light and transmission electron microscopy showed well preserved thawed ovarian tissue. Ovarian function recovery was observed 2-4 months after transplantation. Spontaneous menstrual cycles occurred in two women with normal follicular densities. No periods occurred in the woman with low follicular density at the time of tissue collection. CONCLUSION: Ovarian tissue cryopreservation and transplantation is a promising approach for preserving ovarian function in women with cancer. PMID- 24754588 TI - The quality frontier. AB - Quality is gaining increased attention in medicine including oncology. This heightened focus on quality is long overdue, as noted by the Institute of Medicine over a decade ago. Unfortunately, medical practice including the numerous disciplines of oncology continues to fall short of its 'quality frontier', an analogous concept to the productivity frontier in business. Diverse but inter-related forces including culture, transparency, personalized medicine, economics and informatics are together driving the practice of oncology closer to its quality frontier. Examples of initial progress in relation to each of these forces are reviewed and their implications for future impact on quality discussed. PMID- 24754589 TI - CT-on-rails-guided HDR brachytherapy: single-room, rapid-workflow treatment delivery with integrated image guidance. AB - Brachytherapy is an important component of multidisciplinary cancer care for a variety of solid tumors. Most systems require moving the patient to multiple locations for treatment planning and delivery after the applicator is placed. A dedicated computed tomography (CT)-on-rails brachytherapy suite was installed at our institution to allow image-guided brachytherapy and a rapid scan-plan-treat workflow that is well suited to a busy quaternary care medical center. The suite consists of an OR couch with CT-compatible insert, a CT-on-rails imaging unit, a Varian Varisource iX HDR afterloader and full anesthesia capabilities. The explicit goal was to provide the ability to perform applicator placement, CT guided treatment planning, and treatment delivery efficiently and without moving the patient. The dedicated CT-on-rails suite for high-dose-rate brachytherapy offers image-guided brachytherapy capabilities with a rapid workflow that lends itself well to efficient, high-quality care that can meet the demands of a large volume referral center capable of high patient throughput. PMID- 24754590 TI - Sentinel lymph node biopsy and neoadjuvant chemotherapy in breast cancer patients. AB - Patient selection and timing of sentinel lymph node (SLN) in the context of primary chemotherapy continues to evolve; there is some evidence that primary chemotherapy may modify lymphatic drainage patterns and cause differential downstaging between SLNs and non-SLNs. SLN biopsy undertaken prior to chemotherapy will minimize the risk of a false-negative result, may allow more accurate initial staging and provides important information on prognostication which can guide decisions about adjuvant radiotherapy. However, quantification of regional metastatic load is incomplete and some advocate SLN biopsy after primary chemotherapy to take advantage of nodal downstaging and avoidance of axillary dissection in up to 40% of patients. Initial reports on false-negative rates for SLN biopsy after primary chemotherapy in patients who had proven axillary node metastases at presentation based on needle core biopsy were relatively high and a cause for clinical concern. However, more recent data suggest that SLN biopsy is as accurate when performed post- as pre-neochemotherapy and current practice incorporates both approaches. PMID- 24754591 TI - Resection and transplantation for hepatocellular carcinoma: factors influencing surgical options. AB - The management of hepatocellular carcinoma within the Milan criteria and with well-compensated cirrhosis is a topic of debate. Recent surveillance programs in patients with hepatitis C and cirrhosis have allowed some patients to be diagnosed with early, potentially curable, disease via liver resection (LR), liver transplantation (LT) or liver ablation. LT has excellent outcomes with 5 year survival rates >70% for patients within the Milan criteria. However, its utilization is limited by increasing organ shortages. LR is also effective with 5 year survival outcomes between 50-70% and safe in light of advances in surgical technique, preresection optimization and patient selection. Patients with solitary tumors and well-preserved liver function are good candidates for LR, whereas LT is best reserved for patients with compromised liver function and multifocal disease. LT and LR should not be viewed as competing tools but as complementary tools in the current armamentarium to treat early hepatocellular carcinoma. PMID- 24754592 TI - Monoclonal antibodies as therapeutics in human malignancies. AB - Monoclonal antibodies (mAbs) are a proven effective therapeutic modality in human malignancy. Several mAbs are approved to targets critical in aberrant oncogenic signaling within tumors and their microenvironment. These targets include secreted ligands (e.g., VEGF and HGH), their receptors (e.g., HER2 and VEGFR2), cell surface counter receptors and their receptor-bound ligands (e.g., PD1 and PD1L, respectively). The ability to genetically engineer the structure and/or functions of mAbs has significantly improved their effectiveness. Furthermore, advances in gene expression profiling, proteomics, deep sequencing and deciphering of complex signaling networks have revealed novel therapeutic targets. We review target selection, approved indications and the rationale for mAb utilization in solid and hematologic malignancies. We also discuss novel mAbs in early- and late-phase clinical trials that are likely to change the natural history of disease and improve survival. The future challenge is to design mAb based novel trial designs for diagnostics and therapeutics for human malignancies. PMID- 24754593 TI - The biologic era of childhood medulloblastoma and clues to novel therapies. AB - Currently, the treatment of childhood medulloblastoma (MB) is tailored to risk groups defined by clinical parameters. Growing evidence of tumoral heterogeneity is apparent as response remains varied and unpredictable based on current treatment strategies, indicating the lack of understanding of the elusive biology that drives oncogenesis of these tumors. Advances in genomic technologies are revealing newer insights into the molecular pathogenesis of MB. Utilization of the genomic machinery has enabled the definition of new molecular markers and signaling pathways, resulting in a paradigm shift in the classification of childhood MB. Recent focus into the postgenomic era has revealed varied perturbations in the epigenetic machinery in these subtypes as likely predictive biomarkers and potential therapeutic targets. Ahead lies the task and challenge in the ability to comprehensively evaluate all these data, which could provide clues to profile the next-generation clinical trials combining conventional with molecularly targeted novel therapies. PMID- 24754594 TI - Use of artemisinin and its derivatives to treat HPV-infected/transformed cells and cervical cancer: a review. AB - Cervical cancer and HPV-related diseases remain a burden in the developing world. While much progress has been gained in the detection of HPV and preneoplastic cervical lesions, the rate-limiting step in the prevention of cervical cancer is management of these women. A natural compound, artemisinin, and its derivatives appear to hold promise as a simple means of treatment. Laboratory studies have shown that this compound, and its derivatives, have activity against HPV-infected and -transformed cells and cervical cancer cells. In situations of compassionate use, studies have also demonstrated efficacy in clinical situations. Well designed clinical trials relating to its use should be undertaken. PMID- 24754595 TI - Cellular communication via microparticles: role in transfer of multidrug resistance in cancer. AB - Multidrug resistance (MDR) continues to be a major impediment to the successful treatment of cancer. The two efflux transporters, P-glycoprotein (P-gp) and MRP1 are major contributors to cancer MDR clinically. The upregulation of P-gp leading to MDR was initially understood to occur via pre- and post-transcriptional mechanisms only. However, we demonstrated that microparticles mediate the intercellular exchange and trafficking of bioactive material, including functional P-gp and selected modulatory miRNAs. This exchange of P-gp leads to the dissemination of MDR within a cancer cell population. These findings have significant implications in understanding the cellular basis governing the intercellular acquisition of deleterious traits in cancers, serving to substantially advance our understanding of the molecular basis of the emergence of MDR in cancer clinically. PMID- 24754596 TI - Dark side of the exosome: the role of the exosome in cancer metastasis and targeting the exosome as a strategy for cancer therapy. AB - Cell-cell communication is essential for the regulation of various biological phenomena in multicellular organisms, including development and homeostasis. Deregulation of these interactions leads to inappropriate cell-cell communication, resulting in disease development. Cancer cells communicate closely with the cells in their microenvironment, and this communication promotes malignancy via abnormal growth, invasion, drug resistance and metastasis. Understanding cell-cell interactions in cancer is essential for the development of novel anticancer agents. As a result, discovering the communication tools used by cancer cells is important to understanding these interactions. In this review, we summarize the recent findings regarding exosome-mediated cancer development. In addition, we propose that targeting the exosome represents a novel strategy for cancer therapy. PMID- 24754597 TI - Next-generation sequencing and DNA replication in human cells: the future has arrived. AB - Accurate regulation of DNA replication ensures faithful transmission of eukaryotic genomes and maintenance of genomic stability and chromatin organization. However, by itself the replication process is a threat for both DNA and chromatin integrity. This becomes particularly relevant in cancer cells, where activated oncogenes induce replication-stress, including unscheduled initiation, fork stalling and collapse and, ultimately, genomic instability. Studies addressing the relationship between (epi)genome integrity and disease have been hampered by our poor knowledge of the mechanisms regulating where and when eukaryotic replication initiates. Recently developed genome-scale methods for the analysis of DNA replication in mammals will contribute to the identification of missing links between replication, chromatin regulation and genome stability in normal and cancer cells. PMID- 24754598 TI - Exploring use of the ICF in health education. AB - PURPOSE: Currently, little is known regarding use of the International Classification of Functioning, Disability and Health (ICF) in health education applications. Therefore, this review sought to examine the scope of work that has been conducted regarding the application of the ICF in health education. METHODS: A review of the current literature related to use of the ICF in health education programs was conducted. Twelve electronic databases were searched in accordance with a search protocol developed by a health sciences librarian. In total, 17,878 records were reviewed, and 18 articles met the criteria for inclusion in this review. RESULTS: Current evidence regarding use of the ICF in healthcare education revealed that program and participant properties can be essential facilitators or barriers to successful education programs. In addition, gaps in comprehensive outcome measurement were revealed as areas for future attention. Educational applications of the ICF are very much a work in progress as might be expected given the ICF's existence for only a little over a decade. CONCLUSIONS: To advance use of the ICF in education, it is important to incorporate the measurement of both knowledge acquisition and behavior change related to ICF based programs. Ultimately, widespread implementation of the ICF represents not only a substantial opportunity but also poses a significant challenge. PMID- 24754599 TI - Psychosocial outcomes and coping after complete avulsion traumatic brachial plexus injury. AB - PURPOSE: To understand psychosocial outcomes, coping and adjustment after complete avulsion traumatic brachial plexus injury (BPI). METHOD: We conducted a grounded theory analysis of 12 semi-structured patient interviews exploring psychosocial outcomes, augmented by quantitative evaluation of self-reported mental health and social functioning, body image and coping strategies obtained via three questionnaires (SF-36, Brief COPE and modified SWAP). RESULTS: Subjects' main sources of psychological stress were chronic pain, unemployment, decreased self-efficacy and social-emotional consequences of poor body image. One third of participants reported depression, half experienced anger and frustration and two-thirds were dissatisfied with the appearance of their affected limbs. Acceptance, active coping, planning and emotional support were the most frequently used coping strategies. CONCLUSIONS: Patients encounter high levels of physical and psychological stress after complete avulsion BPI and must find ways to cope to adjust to their injuries. They face similar challenges to patients with spinal cord injuries, for whom many models describing coping and adjustment exist. Similar models could facilitate more complete adjustment and rehabilitation of BPI patients and help to reduce the prevalence of negative stress responses, including anger and depression. Future patients would benefit from a multidisciplinary treatment program, involving medical and mental health services. PMID- 24754600 TI - A follow-up study on the relationship among participation, activity and motor function in survivors of stroke following constraint-induced therapy. AB - PURPOSE: The aim of this follow-up study was to examine the relationships among motor function, activity and participation following constraint-induced therapy (CIT). METHODS: In this correlational study, 12 individuals who had previously participated in CIT completed the Fugl Meyer Assessment for the Upper Extremity and Wolf Motor Function Test (motor assessments), the Motor Activity Log (activity measure) and the Daily Experiences of Pleasure, Productivity and Restoration Profile (participation measure). Motor and activity changes over time were assessed using repeated measures ANOVA and Friedman's tests. Spearman's correlations were used to examine the associations between the participation measure and motor and activity measures were analyzed using Spearman's correlations. RESULTS: No statistically significant correlations were found among motor and activity scores and the amount of time spent in activity categories (e.g. self-care, leisure). Yet, moderate to strong correlations were found between motor assessments and time spent with others versus alone. CONCLUSION: The lack of significant correlations between motor, activity and participation measures challenges assumptions that improved motor abilities will translate to greater participation. Correlations found between motor and activity measures and the context of participation suggests participation post-stroke is complex, and survivors of stroke may benefit from rehabilitation practices that encompass more than motor therapy. PMID- 24754602 TI - Deformation and fracture incidence of Reciproc instruments: a clinical evaluation. AB - AIM: To investigate the incidence of fracture and deformation observed on Reciproc instruments after clinical use. METHODOLOGY: A total of 1696 Reciproc NiTi instruments that were discarded after normal clinical usage over 30 months were collected. Of these 1580 instruments were R25 (93%), 76 were R40 (5%), and 40 were R50 (2%). The treatments included 3780 root canal preparations, 3023 primary treatments and 757 retreatments. Root canal preparation was standardized and followed the manufacturer's directions for the use of Reciproc files without creating prior glide path with hand instruments. In retreatment cases, Reciproc R25 instrument was used to remove all filling material and to complete the preparation. Each instrument was used for shaping only one tooth. All the instruments used were inspected under a microscope to detect signs of fracture or deformation and, if any fracture existed, the length of the files was measured. Data were analysed using a chi-square test with a level of significance set at P < .05. RESULTS: A total of 8 Reciproc R25 instruments fractured during treatment, which represents 0.47% of the number of instruments used and 0.21% of the root canals treated. Five instruments fractured in primary treatment cases and three instruments during retreatments. Six Reciproc R25 deformed during clinical use (0.35% of the number of instruments used and 0.15% of the root canals treated), four during retreatments and two during primary treatments. The deformation reported was unwinding of the blades, one at 1 mm from the tip and five between 2 and 3 mm from the tip. No deformations or fracture were registered for the Reciproc R40 and R50 instruments. CONCLUSIONS: Root canal instrumentation following the manufacturer's instructions can be performed with Reciproc instruments with a very low incidence of instrument fracture and deformation. PMID- 24754603 TI - Tacrolimus exposure in the real world: an analysis from the Mycophenolic acid Observational REnal transplant study. AB - Tacrolimus exposure and renal function data to 36 months post-transplant were analyzed from the prospective, observational Mycophenolic acid Observational REnal transplant (MORE) registry in which de novo kidney transplant patients were managed according to local practice. Tacrolimus trough (C0 ) concentration at month 12 was stratified as low (<6 ng/mL), moderate (6-8 ng/mL), or high (>8 ng/mL) in 724 patients. Estimated glomerular filtration rate (eGFR) was stratified as low (<60 mL/min/1.73 m(2) ) or high (>=60 mL/min/1.73 m(2) ). High tacrolimus C0 (>8 ng/mL) was observed in 47.7%, 34.1%, 26.8%, and 26.7% of patients at baseline and months 12, 24, and 36, respectively. Biopsy-proven acute rejection was similar to month 36 regardless of tacrolimus C0 category at month 12. Tacrolimus C0 >8 ng/mL vs. <6 ng/mL at month 12 was predictive of low eGFR at month 24 (p = 0.023) with a nonsignificant trend at month 36 (p = 0.085). Infections (p < 0.013) and BK virus infection (p < 0.001) were most frequent in the low tacrolimus C0 cohort. Neutropenia was most frequent in the high tacrolimus C0 category (p = 0.010). In conclusion, over a quarter of patients were exposed to high tacrolimus C0 to 36 months post-transplant. Tacrolimus exposure did not affect rejection risk, but tacrolimus C0 >8 ng/mL at month 12 was predictive of subsequent low eGFR compared to C0 <6 ng/mL. PMID- 24754604 TI - Examination time. PMID- 24754605 TI - Cerebral perfusion pressure in women with preeclampsia is elevated even after treatment of elevated blood pressure. AB - Cerebral perfusion pressure (CPP) is elevated in preeclampsia, and may predispose to cerebrovascular complications and progression to eclampsia. We estimated zero flow pressure (ZFP) and CPP using simultaneously obtained arterial blood pressure and middle cerebral artery blood flow velocity in 10 women with preeclampsia, all treated with methyldopa with or without nifedipine, and 18 healthy pregnant controls. Mean +/- SD ZFP was lower in women with preeclampsia than in controls (16.8 +/- 10.9 vs. 31.7 +/- 15.0 mmHg, p = 0.01) whereas CPP was considerably higher (82.3 +/- 17.7 vs. 55.0 +/- 11.7 mmHg, p < 0.001), as was the cerebral flow index (41.9 +/- 18.0 vs. 25.6 +/- 11.2, p = 0.02). There was a significant correlation between blood pressure and CPP in women with preeclampsia, but not in controls. Women with preeclampsia may have an increased cerebral perfusion due to a reduced ZFP and increased CPP despite treatment with antihypertensive medication. More rigorous antihypertensive therapy, aimed at reducing CPP, could result in a decrease in cerebral complications in women with preeclampsia. PMID- 24754606 TI - The descent of the fetal head is not modified by mobile epidural analgesia: a controlled sonographic study. AB - The aim of our study was to assess the sonographic indices of fetal head progression obtained by three-dimensional ultrasound during the second stage of labor in women with and without mobile epidural analgesia. Sonographic volume data sets were obtained with a transperineal approach every 20 min from the beginning of the active second stage until delivery. The ultrasound parameters were calculated off-line from each volume and compared between women with and without epidural analgesia. All the sonographic measurements of the fetal head descent were comparable at each time interval between the two groups. This observation suggests that mobile epidural analgesia is not likely to affect the dynamics of the second stage of labor. PMID- 24754607 TI - Comparing hands-on and video training for postpartum hemorrhage management. AB - The objective was to compare two teaching methods for postpartum hemorrhage management: interactive hands-on training and non-interactive video training. In a controlled intervention study at a secondary health care center in Kenya, the two training methods, based on the Advanced Life Support in Obstetrics curriculum, were evaluated utilizing structured observation of a standardized scenario before and after training. Both intervention groups significantly increased in performance scores after receiving hands-on training: 40% (95% CI 29.5-47.0) and video training: 34.5% (95% CI 25.0-42.0); likewise, pass rates improved significantly. No significant differences in performance score or pass rates were found between the two methods. The findings indicate that postpartum hemorrhage management training by mobile media might be just as effective as conventional hands-on training and a feasible way to overcome the outreach gap in sub-Saharan Africa's rural areas, where peripheral health facilities are generally difficult to reach with conventional training programs. PMID- 24754608 TI - Bubble-propelled micromotors for enhanced transport of passive tracers. AB - Fluid convection and mixing induced by bubble-propelled tubular microengines are characterized using passive microsphere tracers. Enhanced transport of the passive tracers by bubble-propelled micromotors, indicated by their mean squared displacement (MSD), is dramatically larger than that observed in the presence of catalytic nanowires and Janus particle motors. Bubble generation is shown to play a dominant role in the effective fluid transport observed in the presence of tubular microengines. These findings further support the potential of using bubble-propelled microengines for mixing reagents and accelerating reaction rates. The study offers useful insights toward understanding the role of the motion of multiple micromotors, bubble generation, and additional factors (e.g., motor density and fuel concentration) upon the observed motor-induced fluid transport. PMID- 24754609 TI - Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase gamma. AB - Phosphoinositide 3-kinase gamma (PI3Kgamma) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kgamma, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region. PMID- 24754611 TI - Arterial hypertension in nursing personnel of an emergency hospital. AB - Risk factors related to the workplace environment are being studied to identify positive associations with hypertension disorders. Hypertension is considered as one of the main modifiable risk factors and most important public health issues. The study aims to describe the prevalence of hypertension and associate it with sociodemographic, labour and health aspects, in the health-care nursing staff of an emergency hospital.Cross-sectional study enrolled 606 nursing workers. The data were collected from February to June, and the analysis was conducted in November 2010. Arterial blood pressure, body mass index (BMI), waist-to-hip ratio (WHR) were assessed, and sociodemographic and labour variables were investigated by means of a questionnaire. The data were analysed by descriptive statistics, univariate and multivariate analysis. The prevalence of hypertension was 32% (n = 388), with positive associations with age > 49 years (OR = 2.55 (CI: 1.19 to 5.43)), ethnicity (non-white) (odds ratio (OR) = 2.22, confidence interval (CI) 1.16 to 1.24), BMI (OR = 2.24 (CI: 1.25 to 4.01)) and WHR (OR = 2.65 (CI: 1.95 to 7.763)). Arterial hypertension was frequent in the nursing staff of this emergency hospital. Further studies are needed to better understand the relationship between occupational aspects and arterial hypertension. PMID- 24754610 TI - Cognitive control moderates early childhood temperament in predicting social behavior in 7-year-old children: an ERP study. AB - Behavioral inhibition (BI) is a temperament associated with heightened vigilance and fear of novelty in early childhood, and social reticence and increased risk for anxiety problems later in development. However, not all behaviorally inhibited children develop signs of anxiety. One mechanism that might contribute to the variability in developmental trajectories is the recruitment of cognitive control resources. The current study measured N2 activation, an ERP (event related potential) associated with cognitive control, and modeled source-space activation (LORETA; Low Resolution Brain Electromagnetic Tomography) at 7 years of age while children performed a go/no-go task. Activation was estimated for the entire cortex and then exported for four regions of interest: ventromedial prefrontal cortex (VMPFC), ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dorsal ACC), and dorsal lateral prefrontal cortex (DLPFC). BI was measured in early childhood (ages 2 and 3 years). Anxiety problems and social reticence were measured at 7 years of age to ascertain stability of temperamental style. Results revealed that BI was associated with increased performance accuracy, longer reaction times, greater (more negative) N2 activation, and higher estimated dorsal ACC and DLPFC activation. Furthermore, early BI was only associated with social reticence at age 7 at higher (more negative) levels of N2 activation or higher estimated dorsal ACC or DLPFC activation. Results are discussed in the context of overcontrolled behavior contributing to social reticence and signs of anxiety in middle childhood. PMID- 24754612 TI - Genotyping of infectious bronchitis viruses identified in Canada between 2000 and 2013. AB - Infectious bronchitis virus (IBV) was detected in 185 samples originating from chicken flocks of various commodity groups in Canada. Flocks with clinical signs such as respiratory challenge, sudden death, egg production problems, or nephropathogenic conditions, and randomly selected flocks sampled at slaughter as part of an Ontario broiler surveillance project, were included. Most samples were from Ontario and Quebec; however, a small number from British Columbia, Nova Scotia, and Newfoundland and Labrador were also analysed. The nucleotide sequence of the spike (S) protein gene was compared with sequences available in GenBank. Based on their S gene sequence similarities, Canadian IBVs could be divided into nine genotypes belonging to four groups: Canadian variant virus, strain Qu_mv; the classic, vaccine-like viruses, Connecticut and Massachusetts; US variant-like virus strains, California 1734/04, California 99, CU_82792, Pennsylvania 1220/98 and Pennsylvania Wolg/98; and non-Canadian, non-US virus, strain 4/91. Based on the field situation, the effectiveness of current vaccination practices mostly based on Massachusetts and Connecticut-type vaccines appeared generally satisfactory for minimizing the damage due to infection with Canadian variant and US variant-like viruses. However, the recent outbreaks of severe respiratory disease and production problems in Ontario chicken flocks related to the incursion of IBV strain 4/91 were not prevented by standard vaccination protocols. It appears that IBV strain 4/91 has now become endemic in Ontario and the need for 4/91-type vaccines must be evaluated. PMID- 24754613 TI - Lung cancer deaths among American Indians and Alaska Natives, 1990-2009. AB - OBJECTIVES: We examined regional differences in lung cancer among American Indians/Alaska Natives (AI/ANs) using linked data sets to minimize racial misclassification. METHODS: On the basis of federal lung cancer incidence data for 1999 to 2009 and deaths for 1990 to 2009 linked with Indian Health Service (IHS) registration records, we calculated age-adjusted incidence and death rates for non-Hispanic AI/AN and White persons by IHS region, focusing on Contract Health Service Delivery Area (CHSDA) counties. We correlated death rates with cigarette smoking prevalence and calculated mortality-to-incidence ratios. RESULTS: Lung cancer death rates among AI/AN persons in CHSDA counties varied across IHS regions, from 94.0 per 100,000 in the Northern Plains to 15.2 in the Southwest, reflecting the strong correlation between smoking and lung cancer. For every 100 lung cancers diagnosed, there were 6 more deaths among AI/AN persons than among White persons. Lung cancer death rates began to decline in 1997 among AI/AN men and are still increasing among AI/AN women. CONCLUSIONS: Comparison of regional lung cancer death rates between AI/AN and White populations indicates disparities in tobacco control and prevention interventions. Efforts should be made to ensure that AI/AN persons receive equal benefit from current and emerging lung cancer prevention and control interventions. PMID- 24754614 TI - Linkages to improve mortality data for American Indians and Alaska Natives: a new model for death reporting? AB - Racial misclassification is a well-documented weakness of mortality data taken from death certificates. As a result, mortality statistics for American Indians and Alaska Natives (AI/ANs) present, at best, an inaccurate and misleading assessment of mortality in this population. Studies evaluating the quality of race/ethnicity reporting on death certificates have linked data from death certificates to other data sources collected when the decedent was still alive (e.g., Census, Current Population Survey). Such studies have shown substantial misclassification of AI/AN decedents. Despite limitations, linking mortality data from death certificates with data from other sources collected when decedents were living provides opportunities to evaluate and correct misclassification of populations such as AI/AN persons and facilitates the calculation and presentation of more accurate mortality statistics. PMID- 24754615 TI - Adapting to the effects of climate change on Inuit health. AB - Climate change will have far-reaching implications for Inuit health. Focusing on adaptation offers a proactive approach for managing climate-related health risks one that views Inuit populations as active agents in planning and responding at household, community, and regional levels. Adaptation can direct attention to the root causes of climate vulnerability and emphasize the importance of traditional knowledge regarding environmental change and adaptive strategies. An evidence base on adaptation options and processes for Inuit regions is currently lacking, however, thus constraining climate policy development. In this article, we tackled this deficit, drawing upon our understanding of the determinants of health vulnerability to climate change in Canada to propose key considerations for adaptation decision-making in an Inuit context. PMID- 24754616 TI - Mortality caused by chronic liver disease among American Indians and Alaska Natives in the United States, 1999-2009. AB - OBJECTIVES: We compared chronic liver disease (CLD) mortality from 1999 to 2009 between American Indians and Alaska Natives (AI/ANs) and Whites in the United States after improving CLD case ascertainment and AI/AN race classification. METHODS: We defined CLD deaths and causes by comprehensive death certificate based diagnostic codes. To improve race classification, we linked US mortality data to Indian Health Service enrollment records, and we restricted analyses to Contract Health Service Delivery Areas and to non-Hispanic populations. We calculated CLD death rates (per 100,000) in 6 geographic regions. We then described trends using linear modeling. RESULTS: CLD mortality increased from 1999 to 2009 in AI/AN persons and Whites. Overall, the CLD death rate ratio (RR) of AI/AN individuals to Whites was 3.7 and varied by region. The RR was higher in women (4.7), those aged 25 to 44 years (7.4), persons residing in the Northern Plains (6.4), and persons dying of cirrhosis (4.0) versus hepatocellular carcinoma (2.5), particularly those aged 25 to 44 years (7.7). CONCLUSIONS: AI/AN persons had greater CLD mortality, particularly from premature cirrhosis, than Whites, with variable mortality by region. Comprehensive prevention and care strategies are urgently needed to stem the CLD epidemic among AI/AN individuals. PMID- 24754617 TI - Racial misclassification of American Indians and Alaska Natives by Indian Health Service Contract Health Service Delivery Area. AB - OBJECTIVES: We evaluated the racial misclassification of American Indians and Alaska Natives (AI/ANs) in cancer incidence and all-cause mortality data by Indian Health Service (IHS) Contract Health Service Delivery Area (CHSDA). METHODS: We evaluated data from 3 sources: IHS-National Vital Statistics System (NVSS), IHS-National Program of Cancer Registries (NPCR)/Surveillance, Epidemiology and End Results (SEER) program, and National Longitudinal Mortality Study (NLMS). We calculated, within each data source, the sensitivity and classification ratios by sex, IHS region, and urban-rural classification by CHSDA county. RESULTS: Sensitivity was significantly greater in CHSDA counties (IHS NVSS: 83.6%; IHS-NPCR/SEER: 77.6%; NLMS: 68.8%) than non-CHSDA counties (IHS NVSS: 54.8%; IHS-NPCR/SEER: 39.0%; NLMS: 28.3%). Classification ratios indicated less misclassification in CHSDA counties (IHS-NVSS: 1.20%; IHS-NPCR/SEER: 1.29%; NLMS: 1.18%) than non-CHSDA counties (IHS-NVSS: 1.82%; IHS-NPCR/SEER: 2.56%; NLMS: 1.81%). Race misclassification was less in rural counties and in regions with the greatest concentrations of AI/AN persons (Alaska, Southwest, and Northern Plains). CONCLUSIONS: Limiting presentation and analysis to CHSDA counties helped mitigate the effects of race misclassification of AI/AN persons, although a portion of the population was excluded. PMID- 24754618 TI - Community-based surveillance and case management for suicide prevention: an American Indian tribally initiated system. AB - The National Strategy for Suicide Prevention highlights the importance of improving the timeliness, usefulness, and quality of national suicide surveillance systems, and expanding local capacity to collect relevant data. This article describes the background, methods, process data, and implications from the first-of-its-kind community-based surveillance system for suicidal and self injurious behavior developed by the White Mountain Apache Tribe with assistance from Johns Hopkins University. The system enables local, detailed, and real-time data collection beyond clinical settings, with in-person follow-up to facilitate connections to care. Total reporting and the proportion of individuals seeking treatment have increased over time, suggesting that this innovative surveillance system is feasible, useful, and serves as a model for other communities and the field of suicide prevention. PMID- 24754619 TI - American Indian and Alaska Native infant and pediatric mortality, United States, 1999-2009. AB - OBJECTIVES: We described American Indian/Alaska Native (AI/AN) infant and pediatric death rates and leading causes of death. METHODS: We adjusted National Vital Statistics System mortality data for AI/AN racial misclassification by linkage with Indian Health Service (IHS) registration records. We determined average annual death rates and leading causes of death for 1999 to 2009 for AI/AN versus White infants and children. We limited the analysis to IHS Contract Health Service Delivery Area counties. RESULTS: The AI/AN infant death rate was 914 (rate ratio [RR] = 1.61; 95% confidence interval [CI] = 1.55, 1.67). Sudden infant death syndrome, unintentional injuries, and influenza or pneumonia were more common in AI/AN versus White infants. The overall AI/AN pediatric death rates were 69.6 for ages 1 to 4 years (RR = 2.56; 95% CI = 2.38, 2.75), 28.9 for ages 5 to 9 years (RR = 2.12; 95% CI = 1.92, 2.34), 37.3 for ages 10 to 14 years (RR = 2.22; 95% CI = 2.04, 2.40), and 158.4 for ages 15 to 19 years (RR = 2.71; 95% CI = 2.60, 2.82). Unintentional injuries and suicide occurred at higher rates among AI/AN youths versus White youths. CONCLUSIONS: Death rates for AI/AN infants and children were higher than for Whites, with regional disparities. Several leading causes of death in the AI/AN pediatric population are potentially preventable. PMID- 24754620 TI - Pneumonia and influenza mortality among American Indian and Alaska Native people, 1990-2009. AB - OBJECTIVES: We compared pneumonia and influenza death rates among American Indian/Alaska Native (AI/AN) people with rates among Whites and examined geographic differences in pneumonia and influenza death rates for AI/AN persons. METHODS: We adjusted National Vital Statistics Surveillance mortality data for racial misclassification of AI/AN people through linkages with Indian Health Service (IHS) registration records. Pneumonia and influenza deaths were defined as those who died from 1990 through 1998 and 1999 through 2009 according to codes for pneumonia and influenza from the International Classification of Diseases, 9th and 10th Revision, respectively. We limited the analysis to IHS Contract Health Service Delivery Area counties, and compared pneumonia and influenza death rates between AI/ANs and Whites by calculating rate ratios for the 2 periods. RESULTS: Compared with Whites, the pneumonia and influenza death rate for AI/AN persons in both periods was significantly higher. AI/AN populations in the Alaska, Northern Plains, and Southwest regions had rates more than 2 times higher than those of Whites. The pneumonia and influenza death rate for AI/AN populations decreased from 39.6 in 1999 to 2003 to 33.9 in 2004 to 2009. CONCLUSIONS: Although progress has been made in reducing pneumonia and influenza mortality, disparities between AI/AN persons and Whites persist. Strategies to improve vaccination coverage and address risk factors that contribute to pneumonia and influenza mortality are needed. PMID- 24754621 TI - Diabetes-related mortality among American Indians and Alaska Natives, 1990-2009. AB - OBJECTIVES: We assessed diabetes-related mortality for American Indians and Alaska Natives (AI/ANs) and Whites. METHODS: Study populations were non-Hispanic AI/AN and White persons in Indian Health Service (IHS) Contract Health Service Delivery Area counties; Hispanics were excluded. We used 1990 to 2009 death certificate data linked to IHS patient registration records to identify AI/AN decedents aged 20 years or older. We examined disparities and trends in mortality related to diabetes as an underlying cause of death (COD) and as a multiple COD. RESULTS: After increasing between 1990 and 1999, rates of diabetes as an underlying COD and a multiple COD subsequently decreased in both groups. However, between 2000 and 2009, age-adjusted rates of diabetes as an underlying COD and a multiple COD remained 2.5 to 3.5 times higher among AI/AN persons than among Whites for all age groups (20-44, 45-54, 55-64, 65-74, and >= 75 years), both sexes, and every IHS region except Alaska. CONCLUSIONS: Declining trends in diabetes-related mortality in both AI/AN and White populations are consistent with recent improvements in their health status. Reducing persistent disparities in diabetes mortality will require developing effective approaches to not only control but also prevent diabetes among AI/AN populations. PMID- 24754622 TI - Infectious disease mortality among American Indians and Alaska Natives, 1999 2009. AB - OBJECTIVES: We described death rates and leading causes of death caused by infectious diseases (IDs) in American Indian/Alaska Native (AI/AN) persons. Methods. We analyzed national mortality data, adjusted for AI/AN race by linkage with Indian Health Service registration records, for all US counties and Contract Health Service Delivery Area (CHSDA) counties. The average annual 1999 to 2009 ID death rates per 100,000 persons for AI/AN persons were compared with corresponding rates for Whites. RESULTS: The ID death rate in AI/AN populations was significantly higher than that of Whites. A reported 8429 ID deaths (rate 86.2) in CHSDA counties occurred among AI/AN persons; the rate was significantly higher than the rate in Whites (44.0; rate ratio [RR] = 1.96; 95% confidence interval [CI] = 1.91, 2.00). The rates for the top 10 ID underlying causes of death were significantly higher for AI/AN persons than those for Whites. Lower respiratory tract infection and septicemia were the top-ranked causes. The greatest relative rate disparity was for tuberculosis (RR = 13.51; 95% CI = 11.36, 15.93). CONCLUSIONS: Health equity might be furthered by expansion of interventions to reduce IDs among AI/AN communities. PMID- 24754623 TI - All-cause, cardiovascular, and cancer mortality in western Alaska Native people: western Alaska Tribal Collaborative for Health (WATCH). AB - OBJECTIVES: We determined all-cause, cardiovascular disease (CVD), and cancer mortality in western Alaska Native people and examined agreement between death certificate information and adjudicated cause of deaths. METHODS: Data from 4 cohort studies were consolidated. Death certificates and medical records were reviewed and adjudicated according to standard criteria. We compared adjudicated CVD and cancer deaths with death certificates by calculating sensitivity, specificity, predictive values, and kappa statistics. RESULTS: Men (n = 2116) and women (n = 2453), aged 18 to 95 years, were followed an average of 6.7 years. The major cause of death in men was trauma (25%), followed by CVD (19%) and cancer (13%). The major cause of death in women was CVD (24%), followed by cancer (19%) and trauma (8%). Stroke rates in both genders were higher than those of US Whites. Only 56% of deaths classified as CVD by death certificate were classified as CVD by standard criteria; discordance was higher among men (55%) than women (32%; kappas = 0.4 and 0.7). CONCLUSIONS: We found lower rates for coronary heart disease death but high rates of stroke mortality. Death certificates overestimated CVD mortality; concordance between the 2 methods is better for cancer mortality. The results point to the importance of cohort studies in this population in providing data to assist in health care planning. PMID- 24754624 TI - Unintentional injury mortality among American Indians and Alaska Natives in the United States, 1990-2009. AB - OBJECTIVES: We describe the burden of unintentional injury (UI) deaths among American Indian and Alaska Native (AI/AN) populations in the United States. METHODS: National Death Index records for 1990 to 2009 were linked with Indian Health Service registration records to identify AI/AN deaths misclassified as non AI/AN deaths. Most analyses were restricted to Contract Health Service Delivery Area counties in 6 geographic regions of the United States. We compared age adjusted death rates for AI/AN persons with those for Whites; Hispanics were excluded. RESULTS: From 2005 to 2009, the UI death rate for AI/AN people was 2.4 times higher than for Whites. Death rates for the 3 leading causes of UI death motor vehicle traffic crashes, poisoning, and falls-were 1.4 to 3 times higher among AI/AN persons than among Whites. UI death rates were higher among AI/AN males than among females and highest among AI/AN persons in Alaska, the Northern Plains, and the Southwest. CONCLUSIONS: AI/AN persons had consistently higher UI death rates than did Whites. This disparity in overall rates coupled with recent increases in unintentional poisoning deaths requires that injury prevention be a major priority for improving health and preventing death among AI/AN populations. PMID- 24754625 TI - Charging the quantum capacitance of graphene with a single biological ion channel. AB - The interaction of cell and organelle membranes (lipid bilayers) with nanoelectronics can enable new technologies to sense and measure electrophysiology in qualitatively new ways. To date, a variety of sensing devices have been demonstrated to measure membrane currents through macroscopic numbers of ion channels. However, nanoelectronic based sensing of single ion channel currents has been a challenge. Here, we report graphene-based field effect transistors combined with supported lipid bilayers as a platform for measuring, for the first time, individual ion channel activity. We show that the supported lipid bilayers uniformly coat the single layer graphene surface, acting as a biomimetic barrier that insulates (both electrically and chemically) the graphene from the electrolyte environment. Upon introduction of pore-forming membrane proteins such as alamethicin and gramicidin A, current pulses are observed through the lipid bilayers from the graphene to the electrolyte, which charge the quantum capacitance of the graphene. This approach combines nanotechnology with electrophysiology to demonstrate qualitatively new ways of measuring ion channel currents. PMID- 24754626 TI - Oxidative stress and autonomic dysregulation contribute to the acute time dependent myocardial depressant effect of ethanol in conscious female rats. AB - BACKGROUND: The molecular mechanisms of the acute hypotensive and indirectly assessed cardiac depressant effect of ethanol (EtOH)-evoked myocardial depression and hypotension in female rats are not known. We tested the hypothesis that a time-dependent myocardial depression caused by EtOH is initiated by its direct and indirect (cardiac vagal dominance) effects and is exacerbated by gradual development of oxidative stress. METHODS: In conscious female rats, we directly measured left ventricular developed pressure (LVDP), the maximal rise of ventricular pressure over time (dP/dtmax ), blood pressure (BP), heart rate (HR), and sympathovagal activity following intragastric EtOH (1 g/kg) or water over 90 minutes. Catalytic activity of acetaldehyde (ACA)-generating (alcohol dehydrogenase [ADH] and catalase) and eliminating aldehyde dehydrogenase [ALDH2] enzymes along with mediators of oxidative stress were measured in myocardial tissues collected at 30, 60, or 90 minutes after EtOH or water. RESULTS: EtOH reduced myocardial function (LVDP and dP/dtmax ) within 5 to 10 minutes before the steady fall in BP in conscious proestrus rats. Further, EtOH shifted the sympathovagal balance, analyzed by spectral analysis of high frequency and low frequency of interbeat intervals, toward vagal dominance. Prior vagal blockade (atropine) or antioxidant (tempol) treatment attenuated EtOH-evoked myocardial depression and hypotension. Ex vivo studies revealed time-dependent: (i) enhancement of ADH, but not ALDH2 activity (indicative of elevated ACA levels), (ii) increases in phosphorylated Akt and ERK1/2, NADPH-oxidase activity, reactive oxygen species, malondialdehyde, and 4-hydroxy-2-nonenal-modified proteins. These molecular responses along with reduced myocardial catalase activity were most evident at 90 minutes post-EtOH when the reductions in cardiac function and BP reached their nadir. CONCLUSIONS: Vagal dominance and time-dependent myocardial oxidative stress along with the accumulation of cardiotoxic aldehydes mediate EtOH-evoked myocardial dysfunction and hypotension in conscious proestrus female rats. PMID- 24754627 TI - Renal nurses' views of the potential role of pharmacists in outpatient dialysis centres: a qualitative study. AB - OBJECTIVES: The aim of this study was to explore the differences in the views of Australian and Portuguese renal nurses on the provision of clinical pharmacy services in outpatient dialysis centres. METHODS: Semi-structured interviews were conducted with Australian and Portuguese renal nurses. The interviews were recorded and thematically content-analysed. KEY FINDINGS: Three main themes were identified: nurses' opinions towards pharmacists' current role; nurses' opinions towards pharmacists' future role; and future clinical pharmacy services to be provided. While Australian nurses appeared to be aware of pharmacists' competencies and viewed a role for pharmacists within the team, Portuguese nurses showed low expectations of pharmacists and regarded them as external to the team. CONCLUSIONS: Previous or lack of exposure to pharmacists' clinical skills and the existence of health policies that promote interprofessional collaboration appear to influence nurses' views. PMID- 24754628 TI - Ectopic phytocystatin expression leads to enhanced drought stress tolerance in soybean (Glycine max) and Arabidopsis thaliana through effects on strigolactone pathways and can also result in improved seed traits. AB - Ectopic cystatin expression has long been used in plant pest management, but the cysteine protease, targets of these inhibitors, might also have important functions in the control of plant lifespan and stress tolerance that remain poorly characterized. We therefore characterized the effects of expression of the rice cystatin, oryzacystatin-I (OCI), on the growth, development and stress tolerance of crop (soybean) and model (Arabidopsis thaliana) plants. Ectopic OCI expression in soybean enhanced shoot branching and leaf chlorophyll accumulation at later stages of vegetative development and enhanced seed protein contents and decreased the abundance of mRNAs encoding strigolactone synthesis enzymes. The OCI-expressing A. thaliana showed a slow-growth phenotype, with increased leaf numbers and enhanced shoot branching at flowering. The OCI-dependent inhibition of cysteine proteases enhanced drought tolerance in soybean and A. thaliana, photosynthetic CO2 assimilation being much less sensitive to drought-induced inhibition in the OCI-expressing soybean lines. Ectopic OCI expression or treatment with the cysteine protease inhibitor E64 increased lateral root densities in A. thaliana. E64 treatment also increased lateral root densities in the max2-1 mutants that are defective in strigolactone signalling, but not in the max3-9 mutants that are defective in strigolactone synthesis. Taken together, these data provide evidence that OCI-inhibited cysteine proteases participate in the control of growth and stress tolerance through effects on strigolactones. We conclude that cysteine proteases are important targets for manipulation of plant growth, development and stress tolerance, and also seed quality traits. PMID- 24754629 TI - The endometrium of cycling cows contains populations of putative mesenchymal progenitor cells. AB - Endometrial stem cells have been identified in humans, mice and pigs. This study was designed to determine whether the uterine endometrium of cycling cows contains such cells, to identify markers of stemness and ultimately to isolate putative stem/progenitor cell and evaluate their capability to differentiate into mesodermal derivatives. Uteri from healthy cows in the early (days 1-5) and late luteal phases (days 13-18) of the oestrous cycle were collected. Total RNA and proteins were isolated and searched for gene markers of embryonic (OCT4, NANOG, SOX2) and mesenchymal (CD44, STAT3, CD-117) stem cells and for protein markers (Oct4, Sox2, Cd44) in Western blots or immunostaining of paraffin-embedded tissue. Primary cell cultures were isolated; characterized in terms of morphology, colony formation and gene/protein expression; and induced osteogenic and chondrogenic differentiation. We identified expression of embryonic (OCT4 and SOX2, but not NANOG) and mesenchymal (STAT3, CD44 and c-KIT) gene markers in the endometrium of cycling cows and the encoded proteins (Oct4, Sox2 and Cd44) in both stages of the oestrous cycle. Derived cell lines displayed essentially the same gene expression pattern; however, at the protein level, Oct4 was not detected. No clear influence of the stage of the oestrous cycle was found. Cell lines from late luteal phase displayed osteogenic and chondrogenic differentiation potential upon chemical stimulation. In this research, we demonstrated the presence of mesenchymal progenitor cell populations of apparently mesenchymal origin in the endometrium of cycling cows, in both the early and late phases of the oestrous cycle. The cells isolated from the late luteal phase were more acquiescent to differentiate into mesodermal derivatives than cells in the early luteal phase. Our findings might have implications for the understanding of uterine stem cell biology in cows and other farm animal species. PMID- 24754630 TI - Downhill walking to improve lower limb strength in healthy young adults. AB - Walking is the most natural physical activity to maintain and improve fitness and health. Walking downhill is usefully adopted to plan training programmes to improve the strength, particularly in older adults. The present research was aimed to evaluate the influence of downhill walking on leg strength in young adult. A total of 32 females (age 26 +/- 4 years; height 1.64 +/- 0.05 m; body mass 57.6 +/- 5.6 kg) were divided into four groups and they carried out an exercise intervention consisting of three sessions per week for 6 weeks, each lasting 30 minutes. Groups were defined at several workloads characterised by treadmill inclination (%) and walking speed (m . s(-1)): Level Walking at treadmill inclination 0% and walking speed 1.0; Uphill Walking at +20%, 0.75; Downhill Walking (DW) at -20%, 1.36; and Mixed Walking at +20%, 0.75 and -20%, 1.36 each lasting 15 minutes. Maximum voluntary contraction (MVC) developed by the Quadriceps Femoris and Endurance Time at 60% MVC were evaluated before and after experimental period. At the end of each session, Borg's scale and Visual Analogue Scale (VAS) were adopted in order to evaluate perception of rate exertion and pain. Statistical analysis showed significant only in MVC for DW in both right and left legs. Borg's scale and VAS described light activity free of pain. Present findings showed how an eccentric exercise, short lasting and at a low workload, can be useful in inducing improvements in leg strength. PMID- 24754631 TI - Phenolic constituents from the roots of Phyllodium pulchellum. AB - Three new phenolic constituents 1-3 were obtained from the 95% ethanol extract of the roots of Phyllodium pulchellum (Leguminosae). Their structures were elucidated on the basis of spectroscopic analyses, such as NMR, UV, IR, HR-ESI MS, and CD. Furthermore, in an in vitro bioassay, all compounds were tested for inhibitory effects against the proliferation of acetaldehyde-stimulated HSC-T6 cells, and compound 3 exhibited potent inhibitory activity with the IC50 value of 7.6 MUM. PMID- 24754632 TI - Comorbidity is an independent prognostic factor in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP: a population-based cohort study. AB - An observational population-based cohort study was performed to investigate the role of comorbidity on outcome and treatment-related toxicity in patients with newly diagnosed advanced-stage diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Data for the clinical characteristics of 154 patients (median age 69 years), including Charlson Comorbidity Index (CCI), treatment, toxicity and outcome were evaluated. Forty-five percent of the patients had an International Prognistic index >=3 and 16% had a CCI >=2. The planned R-CHOP schedule was completed by 84% and 75% reached complete remission (CR). In those with CCI >=2, 67% completed treatment with 46% CR. In patients with a CCI <2, overall survival (OS) after 1, 2 and 5 years was 84%, 79% and 65% respectively and it was 64%, 48% and 48% for those with CCI >=2. Grade III/IV toxicity was documented in 53%, most frequently febrile neutropenia (27%) and infections (23%). In multivariate analysis CCI >=2 and IPI >=3 were independent risk indicators for OS and grade III/IV toxicity. In conclusion, comorbidity is an independent risk indicator for worse OS in patients with advanced DLBCL treated with R-CHOP by interference with intensive treatment schedules and more grade III/IV toxicity. Future studies are warranted to determine the optimal treatment approach in patients with significant comorbidities. PMID- 24754633 TI - Treatment outcome in children and adolescents with relapsed Hodgkin lymphoma- results of the UK HD3 relapse treatment strategy. AB - The purpose of this national retrospective study was to evaluate the outcome in children with relapsed or primary refractory Hodgkin lymphoma [HL] after a primary chemotherapy alone treatment strategy. Between 2000 and 2005, 80 children with relapsed [n = 69] or primary refractory [n = 11] HL were treated on a standardized treatment protocol of 4-6 cycles of EPIC [etoposide, prednisolone, ifosfamide and cisplatin] chemotherapy. Radiotherapy was recommended to all relapsed sites. High dose therapy with stem cell rescue [SCT] was recommended for patients with poor response. The 5-year overall survival [OS] and progression free survival from relapse was 75.8% [64.8-83.9] and 59.9% [48.3-69.7] respectively. Duration of first remission was strongly associated with OS; risk of death was decreased by 53% [Hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.19-1.18] for those with a time from end of treatment to relapse of 3-12 months (compared to <3 months) and reduced by 80% (HR 0.20, 95% CI: 0.04-0.90) for those >12 months after end of treatment. Other poor prognostic factors included advanced stage disease at relapse and B symptoms at first diagnosis. The most important factor associated with salvage failure was time to relapse. Survival outcome in children with primary refractory HL is poor. PMID- 24754634 TI - Adenosine A2B and A3 receptor location at the mouse neuromuscular junction. AB - To date, four subtypes of adenosine receptors have been cloned (A(1)R, A(2A)R, A(2B)R, and A(3)R). In a previous study we used confocal immunocytochemistry to identify A(1)R and A(2A)R receptors at mouse neuromuscular junctions (NMJs). The data shows that these receptors are localized differently in the three cells (muscle, nerve and glia) that configure the NMJs. A(1)R localizes in the terminal teloglial Schwann cell and nerve terminal, whereas A(2A)R localizes in the postsynaptic muscle and in the axon and nerve terminal. Here, we use Western blotting to investigate the presence of A(2B)R and A(3)R receptors in striated muscle and immunohistochemistry to localize them in the three cells of the adult neuromuscular synapse. The data show that A(2B)R and A(3)R receptors are present in the nerve terminal and muscle cells at the NMJs. Neither A(2B)R nor A(3)R receptors are localized in the Schwann cells. Thus, the four subtypes of adenosine receptors are present in the motor endings. The presence of these receptors in the neuromuscular synapse allows the receptors to be involved in the modulation of transmitter release. PMID- 24754635 TI - Tunable heptamethine-azo dye conjugate as an NIR fluorescent probe for the selective detection of mitochondrial glutathione over cysteine and homocysteine. AB - Although a lot of mitochondria-targeting biothiol probes have been developed and applied to cellular imaging through thiol-induced disulfide cleavage or Michael addition reactions, relatively few probes assess mitochondrial GSH with high selectivity over Cys and Hcy and with NIR fluorescence capable of noninvasive imaging in biological samples. In order to monitor mitochondrial GSH with low background autofluorescence, we designed a heptamethine-azo conjugate as an NIR fluorescent probe by introducing a tunable lipophilic cation unit as the biomarker for mitochondria and a nitroazo group as the GSH-selective reaction site as well as the fluorescence quencher. The probe exhibited a dramatic off-on NIR fluorescence response toward GSH with high selectivity over other amino acids including Cys and Hcy. Further application to cellular imaging indicated that the probe was highly responsive to the changes of mitochondrial GSH in cells. PMID- 24754636 TI - dependence of melt behavior of star polystyrene/POSS composites on the molecular weight of arm chains. AB - Rheological behavior of three-arm and six-arm star polystyrene (SPS) with a small amount of polyhedral oligosilsesquioxane (POSS) was studied. Both linear oscillatory frequency sweep and steady state shear results of SPS/POSS composites showed the reduction of melt viscosity in the unentangled SPS matrix and the increase of viscosity in the entangled SPS matrix. In particular, when molecular weight of the arm (Ma) of SPS was smaller than the critical molecular weight for entanglement (Mc) of PS, the melt viscosity of SPS/POSS composites with low content of POSS was lower than that of pure SPS. The abnormal phenomenon of reduced melt viscosity in SPS/POSS composites was in coincidence with the melt viscosity behavior of SPS/C60 composites reported in our previous work ( Soft Matter 2013 , 9 , 6282 - 6290 ), although the diameters of two nanoparticles and their interaction with SPS matrix were different. A possible mechanism behind the melt viscosity behavior was discussed. Furthermore, the time-temperature superposition principle (TTS) was applied in SPS and SPS/POSS composites. The Cox Merz empirical relationship was verified to be valid for SPS/POSS composites when the content of POSS was low (1 wt %). PMID- 24754637 TI - Measuring rehabilitation outcome in post-acute hip fractured patients. AB - PURPOSE: To present our experience in measuring rehabilitation achievements of post-acute hip fractured patients with the FIM instrument; assess its appropriateness as to the patients' various disability levels and describe our experience with other measuring tools in patients less sensitive to changes in the FIM instrument. METHODS: A retrospective study performed in a post-acute geriatric rehabilitation center. Three hundred and eighty-seven hip fractured patients admitted from January 2010 to May 2012 were included in this study. Patients were evaluated by the Functional Independence Measure (FIM), the Timed Get Up and Go (TUG) test and "bed to chair" transfer FIM parameter. The study population was divided into three disability groups according to their admission disability level: high (admission FIM score <40), moderate (FIM 40-79) and low (FIM >= 80). The Mann-Whitney U, ANOVA and Chi square tests analyzed the data. RESULTS: The FIM instrument was found most sensitive in identifying functional change in patients with moderate disability. Low disability patients received more physio- and occupational-therapy treatment time, yet achieved a lower mean FIM score change compared to moderately disabled patients. The smallest real difference (SRD = 13) for the FIM score was achieved by 60% of patients with moderate disability. When assessed by the TUG test, most patients (94%) improved their score. The SRD% of 31% was achieved by 71.7% of the patients. Nineteen patients (35.9%) achieved a discharge score of <20 s. The high disability group achieved the lowest mean FIM score change. On admission, 52/64 (81%) patients required considerable help in transferring from bed to chair (FIM 1-2), however, upon discharge, the majority (69.2%) improved to the level of a one man transfer (FIM >= 3). Forty-one (64.1%) patients were discharged home. CONCLUSION: Post acute hip fracture patients exhibit variable functional ability. Assessing rehabilitation achievements with a disability measure is limited; therefore, it is advisable to use an instrument most suitable to the patients' disability level. PMID- 24754638 TI - Fast gait speed and self-perceived balance as valid predictors and discriminators of independent community walking at 6 months post-stroke--a preliminary study. AB - PURPOSE: To determine the validity of walking speed, muscle strength, function of the hemiparetic lower limb and self-perceived balance to predict and discriminate independent community walkers (ICW) within the first 6 months post-stroke. METHODS: Inpatients with a first ischemic stroke (<3 months), able to walk, were evaluated (T0) and re-evaluated after 6 months post-stroke (T1). Comfortable, fast speed and the difference between fast and comfortable speed, muscle strength of knee flexors and extensors, sensory-motor function of the hemiparetic lower limb and self-perceived balance were assessed at T0 and T1. At T1, a self reported question was used to discriminate ICW versus Dependent Community Walkers (DCW). ROC curve analysis was used to determine valid predictive (T0) and discriminative (T1) cut-offs of ICW. RESULTS: Only 25.7% of the 35 participants were ICW at T1. Valid predictive cut-offs at T0 were found for fast speed (>=0.42 m/s) and Falls Efficacy Scale (<57). Valid discriminators were found at T1 for fast speed (>0.84 m/s) and FES (<18.50). CONCLUSION: Fast speed and self perceived balance appear to be important characteristics of ICW at 6 months and may be useful early predictors of the potential for patients to achieve this. Further research is needed to ensure the precision of these functional cut-offs. PMID- 24754639 TI - Covalent deposition of zwitterionic polymer and citric acid by click chemistry enabled layer-by-layer assembly for improving the blood compatibility of polysulfone membrane. AB - Development of blood compatible membranes is critical for biomedical applications. Zwitterionic polymers have been proved to be resistant to nonspecific protein adsorption and platelet adhesion. In this work, two kinds of zwitterionic copolymers bearing alkynyl and azide groups are synthesized by atom transfer radical polymerization (ATRP) and subsequent reactions, namely alkynyl poly(sulfobetaine methacrylate) (alkynyl-PSBMA) and azide-poly(sulfobetaine methacrylate) (azide-PSBMA). The copolymers are directly used to modify azido functionalized polysulfone (PSf-N3) membrane via click chemistry-enabled layer-by layer (LBL) assembly. Alkynyl-citric acid is then clicked onto the membrane when the outermost layer was azide-PSBMA. The chemical compositions, surface morphologies, and hydrophilicity of the zwitterionic polymer and citric acid multilayer modified membranes are characterized. The composite multilayer is resistant to protein adsorption and platelet adhesion and also prolongs clotting times, indicating that the blood compatibility is improved. Moreover, after clicking the small molecule anticoagulant alkynyl-citric acid onto the outermost of the zwitterionic multilayer, the membrane shows further improved anticoagulant property. The deposition of zwitterionic polymer and citric acid via click chemistry-enabled LBL assembly can improve the blood compatibility of the PSf membrane. PMID- 24754640 TI - New 5-unsubstituted dihydropyridines with improved CaV1.3 selectivity as potential neuroprotective agents against ischemic injury. AB - C5-unsubstituted-C6-aryl-1,4-dihydropyridines were prepared by a CAN-catalyzed multicomponent reaction from chalcones, beta-dicarbonyl compounds, and ammonium acetate. These compounds were able to block Ca(2+) entry after a depolarizing stimulus and showed an improved Cav1.3/Cav1.2 selectivity in comparison with nifedipine. Furthermore, they were able to protect neuroblastoma cells against Ca(2+) overload and oxidative stress models. Their selectivity ratio makes them highly interesting for the treatment of neurological disorders where Ca(2+) dyshomeostasis and high levels of oxidative stress have been demonstrated. Furthermore, their low potency toward the cardiovascular channel subtype makes them safer by reducing their probable side effects, in comparison to classical 1,4-dihydropyridines. Some compounds afforded good protective profile in a postincubation model that simulates the real clinical situation of ictus patients, offering a therapeutic window of opportunity of great interest for patient recovery after a brain ischemic episode. Good activities were also found in acute ischemia/reperfusion models of oxygen and glucose deprivation. PMID- 24754641 TI - Achievement in mathematics and language is linked to regular physical activity: a population study in Chilean youth. AB - We examined the association between the allocation of time to regular physical activity (PA) and achievement in mathematics and language in Chilean adolescents after controlling for confounders. In a random sample of 620 ninth graders (15.6 +/- 0.7 years old), we measured regular PA, including physical education and sports extracurricular activities, and academic performance, using national standardised tests. Bivariate and multivariate regression analyses modelled the relation between academic and health-related behaviours. Sufficiency and proficiency in mathematics and language were used as outcome variables. Only 18% of adolescents had >4 h.week(-1) of regular PA. Devoting >4 h . week(-1) to regular PA significantly increased the odds of sufficiency and proficiency in both domains. After full adjustment, the odds of sufficiency and proficiency in mathematics increased by 1.9 (95% CI: 1.1-3.5) and 2.7 (95% CI: 1.7-4.3), respectively. Similarly, the odds of sufficiency and proficiency in language increased by 3.3 (95% CI: 1.7-9.7) and 2.6 (95% CI: 1.6-4.1), respectively. Adolescents with the highest allocation of time to regular PA performed much better in mathematics and language than inactive students. The academic benefits associated with PA can help to promote sustained behaviour changes regarding lifestyles. They can be more easily perceived as gains than health benefits alone. PMID- 24754642 TI - Unacknowledged threats proffered "in a manner of speaking": recognizing workplace bullying as shaming. AB - PURPOSE: The purpose of this study was to examine workplace bullying victims' perceptions of what they heard their bully counterparts say through their use of prosody. DESIGN: From a sampling frame of 89 manuscripts referenced in the authors' previous studies, we identified a subset (n = 10) that included quotes regarding bullying victims' perceptions of communication experiences with their bully perpetrators. METHODS: We used hermeneutics and a recursive metasynthesis to interpret quotes embedded in the manuscripts chosen for this study. FINDINGS: Two-thirds of language is expressed nonverbally through prosody or "manner of speaking"-rhythm, stress, intonation, and vocabulary choice. We found that as bullies communicated with their intended victims over time, they used prosody across subtle, linked communications, or boldly and openly in public venues, to establish a context-embedded, one-way communication process of "doublespeak." CONCLUSIONS: Bullies' confusing prosodic communication processes served to recontexualize victims' situations and, through mechanisms largely unacknowledged by the victims, to subtly demean their personhood, and to shame them and render them voiceless. CLINICAL RELEVANCE: This study directs formal attention to the language of workplace bullying. Further study might strengthen opportunities to effectively address and curtail the long-term personal, professional, and organizational injuries deriving from workplace bullying. PMID- 24754643 TI - Lung transplantation following hematopoietic stem cell transplantation: report of two cases and systematic review of literature. AB - BACKGROUND: Non-infectious pulmonary complications following hematopoietic stem cell transplantation (HSCT) are major cause of morbidity and mortality with limited treatment options. Lung transplantation (LT) has been rarely reported as a treatment option for selected HSCT recipients with these problems. OBJECTIVE: Describe the outcome of HSCT recipients who underwent LT. METHODS: Two cases of LT following HSCT from our institution are presented. Cases reported in literature were identified using English language PubMed/MEDLINE with keywords hematopoietic stem cell transplantation, bone marrow transplantation, or bronchiolitis obliterans cross-referenced with lung transplantation. We extracted data on baseline characteristics and survival data following LT. RESULTS: Total of 84 patients are analyzed. Age at time of LT was median of 22 yr (range 1-66). Seventy-nine patients were recipients of allogeneic HSCT. The indications for LT were bronchiolitis obliterans syndrome (BOS; 63 patients), pulmonary fibrosis (13 patients), BOS/pulmonary fibrosis (five patients), and graft-versus-host-disease (GVHD) of lung (three patients). The median time between HSCT and LT was 52.3 months (range 6-240). The median follow-up after LT was 36 months (range 0-168). During this time, BOS was documented in 25 patients. Relapse of hematological malignancy was reported in two patients, and new malignancy developed in four patients. At the end of follow-up, 60 patients were alive and 24 patients died. The probability of survival following LT at 24 and 36 months was 0.88 (95% CI 0.78-0.93) and 0.79 (95% CI 0.67-0.87), respectively. CONCLUSION: LT is a potential therapeutic option in selected patients with severe chronic pulmonary disease following HSCT. Further studies are needed to determine the appropriate timing and the outcome of this approach. PMID- 24754644 TI - Exploring cyclopentadienone antiaromaticity: charge density studies of various tetracyclones. AB - A systematic study of six tetracyclones has been carried out using experimental and theoretical charge density analysis. A three pronged approach based on quantum theory of atoms in molecules (QTAIM), nucleus independent chemical shifts (NICS) criterion, and source function (SF) contributions has been performed to establish the degree of antiaromaticity of the central five-membered ring in all the derivatives. Electrostatic potentials mapped on the isodensity surface show that electron withdrawing substituents turn both C and O atoms of the carbonyl group more electropositive while retaining the direction of polarity. PMID- 24754645 TI - Metastasis of an undifferentiated fetal soft tissue sarcoma to the maternal compartment of the placenta: maternal aspects, pathology findings and review of the literature on fetal malignancies with placenta metastases. PMID- 24754646 TI - Use of a validated algorithm to estimate the annual cost of effective biologic treatment for rheumatoid arthritis. AB - OBJECTIVES: To estimate biologic cost per effectively treated patient with rheumatoid arthritis (RA) using a claims-based algorithm for effectiveness. METHODS: Patients with RA aged 18-63 years in the IMS PharMetrics Plus database were categorized as effectively treated if they met all six criteria: (1) a medication possession ratio >=80% (subcutaneous) or at least as many infusions as specified in US labeling (intravenous); (2) no biologic dose increase; (3) no biologic switch; (4) no new non-biologic disease-modifying anti-rheumatic drug; (5) no new or increased oral glucocorticoid; and (6) <=1 glucocorticoid injection. Biologic cost per effectively treated patient was defined as total cost of the index biologic (drug plus intravenous administration) divided by the number of patients categorized by the algorithm as effectively treated. Similar methods were used for the index biologic in the second year and for a second biologic after a switch. RESULTS: Rates that the index biologic was categorized as effective in the first year were 31.0% etanercept (2243/7247), 28.6% adalimumab (1426/4991), 28.6% abatacept (332/1160), 27.2% golimumab (71/261), and 20.2% infliximab (474/2352). Mean biologic cost per effectively treated patient, per the algorithm, was $50,141 etanercept, $53,386 golimumab, $56,942 adalimumab, $73,516 abatacept, and $114,089 infliximab. Biologic cost per effectively treated patient, using this algorithm, was lower for patients who continued the index biologic in the second year and higher after switching. CONCLUSIONS: When a claims-based algorithm was applied to a large commercial claims database, etanercept was categorized as the most effective and had the lowest estimated 1 year biologic cost per effectively treated patient. This proxy for effectiveness from claims databases was validated against a clinical effectiveness scale, but analyses of the second year or the year after a biologic switch were not included in the validation. Costs of other medications were not included in cost calculations. PMID- 24754647 TI - Trevor John Bagust (1944-2014). PMID- 24754648 TI - Profiling nurses' job satisfaction, acculturation, work environment, stress, cultural values and coping abilities: A cluster analysis. AB - This study aimed to determine whether definable profiles existed in a cohort of nursing staff with regard to demographic characteristics, job satisfaction, acculturation, work environment, stress, cultural values and coping abilities. A survey was conducted in one hospital in Singapore from June to July 2012, and 814 full-time staff nurses completed a self-report questionnaire (89% response rate). Demographic characteristics, job satisfaction, acculturation, work environment, perceived stress, cultural values, ways of coping and intention to leave current workplace were assessed as outcomes. The two-step cluster analysis revealed three clusters. Nurses in cluster 1 (n = 222) had lower acculturation scores than nurses in cluster 3. Cluster 2 (n = 362) was a group of younger nurses who reported higher intention to leave (22.4%), stress level and job dissatisfaction than the other two clusters. Nurses in cluster 3 (n = 230) were mostly Singaporean and reported the lowest intention to leave (13.0%). Resources should be allocated to specifically address the needs of younger nurses and hopefully retain them in the profession. Management should focus their retention strategies on junior nurses and provide a work environment that helps to strengthen their intention to remain in nursing by increasing their job satisfaction. PMID- 24754649 TI - American Indian health policy: historical trends and contemporary issues. AB - The United States has a trust responsibility to provide services to American Indians and Alaska Native (AI/AN) persons. However, a long-standing history of underfunding of the Indian Health Service (IHS) has led to significant challenges in providing services. Twentieth century laws, including the Snyder Act, Transfer Act, Indian Self-Determination and Education Assistance Act, and Indian Health Care Improvement Act (IHCIA) have had an effect on the way health services are provided. IHCIA was reauthorized as part of the Patient Protection and Affordable Care Act (ACA). Several provisions in ACA allow for potential improvements in access to services for AI/AN populations and are described herein. Although policy developments have been promising, IHS underfunding must be resolved to ensure improved AI/AN health. PMID- 24754650 TI - Cervical cancer incidence and mortality among American Indian and Alaska Native women, 1999-2009. AB - OBJECTIVES: We analyzed cervical cancer incidence and mortality data in American Indian and Alaska Native (AI/AN) women compared with women of other races. METHODS: We improved identification of AI/AN race, cervical cancer incidence, and mortality data using Indian Health Service (IHS) patient records; our analyses focused on residents of IHS Contract Health Service Delivery Area (CHSDA) counties. Age-adjusted incidence and death rates were calculated for AI/AN and White women from 1999 to 2009. RESULTS: AI/AN women in CHSDA counties had a death rate from cervical cancer of 4.2, which was nearly twice the rate in White women (2.0; rate ratio [RR] = 2.11). AI/AN women also had higher incidence rates of cervical cancer compared with White women (11.0 vs 7.1; RR = 1.55) and were more often diagnosed with later-stage disease (RR = 1.84 for regional stage and RR = 1.74 for distant stage). Death rates decreased for AI/AN women from 1990 to 1993 (-25.8%/year) and remained stable thereafter. CONCLUSIONS: Although rates decreased over time, AI/AN women had disproportionately higher cervical cancer incidence and mortality. The persistently higher rates among AI/AN women compared with White women require continued improvements in identifying and treating cervical cancer and precancerous lesions. PMID- 24754651 TI - Historical trends and regional differences in all-cause and amenable mortality among American Indians and Alaska Natives since 1950. AB - American Indian and Alaska Native (AI/AN) death rates declined over most of the 20th century, even before the Public Health Service became responsible for health care in 1956. Since then, rates have declined further, although they have stagnated since the 1980s. These overall patterns obscure substantial regional differences. Most significant, rates in the Northern and Southern Plains have declined far less since 1949 to 1953 than those in the East, Southwest, or Pacific Coast. Data for Alaska are not available for the earlier period, so its trajectory of mortality cannot be ascertained. Socioeconomic measures do not adequately explain the differences and rates of change, but migration, changes in self-identification as an AI/AN person, interracial marriage, and variations in health care effectiveness all appear to be implicated. PMID- 24754652 TI - A systematic review of community interventions to improve Aboriginal child passenger safety. AB - We evaluated evidence of community interventions to improve Aboriginal child passenger safety (CPS) in terms of its scientific merit and cultural relevance. We included studies if they reported interventions to improve CPS in Aboriginal communities, compared at least pre- and postintervention conditions, and evaluated rates and severity of child passenger injuries, child restraint use, or knowledge of CPS. We also appraised quality and cultural relevance of studies. Study quality was associated with community participation and cultural relevance. Strong evidence showed that multicomponent interventions tailored to each community improves CPS. Interventions in Aboriginal communities should incorporate Aboriginal views of health, involve the community, and be multicomponent and tailored to the community's circumstances and culture. PMID- 24754653 TI - Trends and disparities in stroke mortality by region for American Indians and Alaska Natives. AB - OBJECTIVES: We evaluated trends and disparities in stroke death rates for American Indians and Alaska Natives (AI/ANs) and White people by Indian Health Service region. METHODS: We identified stroke deaths among AI/AN persons and Whites (adults aged 35 years or older) using National Vital Statistics System data for 1990 to 2009. We used linkages with Indian Health Service patient registration data to adjust for misclassification of race for AI/AN persons. Analyses excluded Hispanics and focused on Contract Health Service Delivery Area (CHSDA) counties. RESULTS: Stroke death rates among AI/AN individuals were higher than among Whites for both men and women in CHSDA counties and were highest in the youngest age groups. Rates and AI/AN:White rate ratios varied by region, with the highest in Alaska and the lowest in the Southwest. Stroke death rates among AI/AN persons decreased in all regions beginning in 2001. CONCLUSIONS: Although stroke death rates among AI/AN populations have decreased over time, rates are still higher for AI/AN persons than for Whites. Interventions that address reducing stroke risk factors, increasing awareness of stroke symptoms, and increasing access to specialty care for stroke may be more successful at reducing disparities in stroke death rates. PMID- 24754654 TI - Addressing disparities in the health of American Indian and Alaska Native people: the importance of improved public health data. PMID- 24754655 TI - Kidney cancer incidence and mortality among American Indians and Alaska Natives in the United States, 1990-2009. AB - OBJECTIVES: We describe rates and trends in kidney cancer incidence and mortality and identify disparities between American Indian/Alaska Native (AI/AN) and White populations. METHODS: To improve identification of AI/AN race, incidence and mortality data were linked with Indian Health Service (IHS) patient records. Analysis focused on residents of IHS Contract Health Service Delivery Area counties; Hispanics were excluded. We calculated age-adjusted kidney cancer incidence (2001-2009) and death rates (1990-2009) by sex, age, and IHS region. RESULTS: AI/AN persons have a 1.6 times higher kidney cancer incidence and a 1.9 times higher kidney cancer death rate than Whites. Despite a significant decline in kidney cancer death rates for Whites (annual percentage change [APC] = -0.3; 95% confidence interval [CI] = -0.5, 0.0), death rates for AI/AN persons remained stable (APC = 0.4; 95% CI = -0.7, 1.5). Kidney cancer incidence rates rose more rapidly for AI/AN persons (APC = 3.5; 95% CI = 1.2, 5.8) than for Whites (APC = 2.1; 95% CI = 1.4, 2.8). CONCLUSIONS: AI/AN individuals have greater risk of developing and dying of kidney cancers. Incidence rates have increased faster in AI/AN populations than in Whites. Death rates have decreased slightly in Whites but remained stable in AI/AN populations. Racial disparities in kidney cancer are widening. PMID- 24754656 TI - Survival on dialysis among American Indians and Alaska Natives with diabetes in the United States, 1995-2010. AB - OBJECTIVES: We assessed survival in American Indians and Alaska Natives (AI/ANs) with end-stage renal disease attributed to diabetes who initiated hemodialysis between 1995 and 2009. METHODS: Follow-up extended from the first date of dialysis in the United States Renal Data System until December 31, 2010, kidney transplantation, or death. We used the Kaplan-Meier method to compute survival on dialysis by age and race/ethnicity and Cox regression analysis to compute adjusted hazard ratios (HRs). RESULTS: Our study included 510,666 persons-48% Whites, 2% AI/AN persons, and 50% others. Median follow-up was 2.2 years (interquartile range = 1.1-4.1 years). At any age, AI/AN persons survived longer on hemodialysis than Whites; this finding persisted after adjusting for baseline differences. Among AI/AN individuals, those with full Indian blood ancestry had the lowest adjusted risk of death compared with Whites (HR = 0.58; 95% confidence interval = 0.55, 0.61). The risk increased with declining proportion of AI/AN ancestry. CONCLUSIONS: Survival on dialysis was better among AI/AN than White persons with diabetes. Among AI/AN persons, the inverse relationship between risk of death and level of AI/AN ancestry suggested that cultural or hereditary factors played a role in survival. PMID- 24754657 TI - Geographic variation in colorectal cancer incidence and mortality, age of onset, and stage at diagnosis among American Indian and Alaska Native people, 1990-2009. AB - OBJECTIVES: We characterized estimates of colorectal cancer (CRC) in American Indians/Alaska Natives (AI/ANs) compared with Whites using a linkage methodology to improve AI/AN classification in incidence and mortality data. METHODS: We linked incidence and mortality data to Indian Health Service enrollment records. Our analyses were restricted to Contract Health Services Delivery Area counties. We analyzed death and incidence rates of CRC for AI/AN persons and Whites by 6 regions from 1999 to 2009. Trends were described using linear modeling. RESULTS: The AI/AN colorectal cancer incidence was 21% higher and mortality 39% higher than in Whites. Although incidence and mortality significantly declined among Whites, AI/AN incidence did not change significantly, and mortality declined only in the Northern Plains. AI/AN persons had a higher incidence of CRC than Whites in all ages and were more often diagnosed with late stage CRC than Whites. CONCLUSIONS: Compared with Whites, AI/AN individuals in many regions had a higher burden of CRC and stable or increasing CRC mortality. An understanding of the factors driving these regional disparities could offer critical insights for prevention and control programs. PMID- 24754658 TI - Breast cancer mortality among American Indian and Alaska Native women, 1990-2009. AB - OBJECTIVES: We compared breast cancer death rates and mortality trends among American Indian/Alaska Native (AI/AN) and White women using data for which racial misclassification was minimized. METHODS: We used breast cancer deaths and cases linked to Indian Health Service (IHS) data to calculate age-adjusted rates and 95% confidence intervals (CIs) by IHS-designated regions from 1990 to 2009 for AI/AN and White women; Hispanics were excluded. Mortality-to-incidence ratios (MIR) were calculated for 1999 to 2009 as a proxy for prognosis after diagnosis. RESULTS: Overall, the breast cancer death rate was lower in AI/AN women (21.6 per 100,000) than in White women (26.5). However, rates in AI/ANs were higher than rates in Whites for ages 40 to 49 years in the Alaska region, and ages 65 years and older in the Southern Plains region. White death rates significantly decreased (annual percent change [APC] = -2.1; 95% CI = -2.3, -2.0), but regional and overall AI/AN rates were unchanged (APC = 0.9; 95% CI = 0.1, 1.7). AI/AN women had higher MIRs than White women. CONCLUSIONS: There has been no improvement in death rates among AI/AN women. Targeted screening and timely, high quality treatment are needed to reduce mortality from breast cancer in AI/AN women. PMID- 24754659 TI - Prostate cancer deaths and incident cases among American Indian/Alaska Native men, 1999-2009. AB - OBJECTIVES: We linked databases to improve identification of American Indians/Alaska Natives (AI/ANs) in determining prostate cancer death and incidence rates. METHODS: We linked prostate cancer mortality and incidence data with Indian Health Service (IHS) patient records; analyses focused on residents of IHS Contract Health Service Delivery Area (CHSDA) counties. We calculated age adjusted incidence and death rates for AI/AN and White men for 1999 to 2009; men of Hispanic origin were excluded. RESULTS: Prostate cancer death rates were higher for AI/AN men than for White men. Death rates declined for White men ( 3.0% per year) but not for AI/AN men. AI/AN men had lower prostate cancer incidence rates than White men. Incidence rates declined among Whites (-2.2% per year) and AI/ANs (-1.9% per year). CONCLUSIONS: AI/AN men had higher prostate cancer death rates and lower prostate cancer incidence rates than White men. Disparities in accessing health care could contribute to mortality differences, and incidence differences could be related to lower prostate-specific antigen testing rates among AI/AN men. PMID- 24754660 TI - Disparities in cancer mortality and incidence among American Indians and Alaska Natives in the United States. AB - OBJECTIVES: We used improved data on American Indian and Alaska Native (AI/AN) ancestry to provide an updated and comprehensive description of cancer mortality and incidence among AI/AN populations from 1990 to 2009. METHODS: We linked the National Death Index and central cancer registry records independently to the Indian Health Service (IHS) patient registration database to improve identification of AI/AN persons in cancer mortality and incidence data, respectively. Analyses were restricted to non-Hispanic persons residing in Contract Health Service Delivery Area counties in 6 geographic regions of the United States. We compared age-adjusted mortality and incidence rates for AI/AN populations with White populations using rate ratios and mortality-to-incidence ratios. Trends were described using joinpoint analysis. RESULTS: Cancer mortality and incidence rates for AI/AN persons compared with Whites varied by region and type of cancer. Trends in death rates showed that greater progress in cancer control was achieved for White populations compared with AI/AN populations over the last 2 decades. CONCLUSIONS: Spatial variations in mortality and incidence by type of cancer demonstrated both persistent and emerging challenges for cancer control in AI/AN populations. PMID- 24754661 TI - Alcohol-attributable mortality among American Indians and Alaska Natives in the United States, 1999-2009. AB - OBJECTIVES: We describe the relative burden of alcohol-attributable death among American Indians/Alaska Natives (AI/ANs) in the United States. METHODS: National Death Index records were linked with Indian Health Service (IHS) registration records to identify AI/AN deaths misclassified as non-AI/AN. We calculated age adjusted alcohol-attributable death rates from 1999 to 2009 for AI/AN and White persons by sex, age, geographic region, and leading causes; individuals of Hispanic origin were excluded. RESULTS: AI/AN persons had a substantially higher rate of alcohol-attributable death than Whites from 2005 to 2009 in IHS Contract Health Service Delivery Area counties (rate ratio = 3.3). The Northern Plains had the highest rate of AI/AN deaths (123.8/100,000), and the East had the lowest (48.9/100,000). For acute causes, the largest relative risks for AI/AN persons compared with Whites were for hypothermia (14.2) and alcohol poisoning (7.6). For chronic causes, the largest relative risks were for alcoholic psychosis (5.0) and alcoholic liver disease (4.9). CONCLUSIONS: Proven strategies that reduce alcohol consumption and make the environment safer for excessive drinkers should be further implemented in AI/AN communities. PMID- 24754662 TI - Health behaviors and risk factors among American Indians and Alaska Natives, 2000 2010. AB - OBJECTIVES: We provided contextual risk factor information for a special supplement on causes of death among American Indians and Alaska Natives (AI/ANs). We analyzed 11 years of Behavioral Risk Factor Surveillance System (BRFSS) data for AI/AN respondents in the United States. METHODS: We combined BRFSS data from 2000 to 2010 to determine the prevalence of selected risk factors for AI/AN and White respondents residing in Indian Health Service Contract Health Service Delivery Area counties. Regional prevalence estimates for AI/AN respondents were compared with the estimates for White respondents for all regions combined; respondents of Hispanic origin were excluded. RESULTS: With some regional exceptions, AI/AN people had high prevalence estimates of tobacco use, obesity, and physical inactivity, and low prevalence estimates of fruit and vegetable consumption, cancer screening, and seatbelt use. CONCLUSIONS: These behavioral risk factors were consistent with observed patterns of mortality and chronic disease among AI/AN persons. All are amenable to public health intervention. PMID- 24754663 TI - Ovarian and uterine cancer incidence and mortality in American Indian and Alaska Native women, United States, 1999-2009. AB - OBJECTIVES: We examined geographic differences and trends in incidence and mortality of ovarian and uterine cancer in American Indian/Alaska Native (AI/AN) women. METHODS: We linked mortality data (1990-2009) and incidence data (1999 2009) to Indian Health Service (IHS) records. Death (and incidence) rates for ovarian and uterine cancer were examined for AI/AN and White women; Hispanics were excluded. Analyses focused on Contract Health Service Delivery Area (CHSDA) counties. RESULTS: AI/AN and White women had similar ovarian and uterine cancer death rates. Ovarian and uterine cancer incidence and death rates were higher for AI/ANs residing in CHSDA counties than for all US counties. We also observed geographic differences, regardless of CHSDA residence, in ovarian and uterine cancer incidence and death rates in AI/AN women by IHS region; Pacific Coast and Southern Plains women had higher ovarian cancer death rates and Northern Plains women had higher uterine cancer death rates. CONCLUSIONS: Regional differences in the incidence and mortality of ovarian and uterine cancers among AI/AN women in the United States were significant. More research among correctly classified AI/AN women is needed to understand these differences. PMID- 24754664 TI - Death rates from human immunodeficiency virus and tuberculosis among American Indians/Alaska Natives in the United States, 1990-2009. AB - OBJECTIVES: We used race-corrected data and comprehensive diagnostic codes to better compare HIV and tuberculosis (TB) mortality from 1999 to 2009 between American Indian/Alaska Natives (AI/ANs) and Whites. METHODS: National Vital Statistics Surveillance System mortality data were adjusted for AI/AN racial misclassification through linkage with Indian Health Service registration records. We compared average annual 1990 to 2009 HIV and TB death rates (per 100,000 people) for AI/AN persons with those for Whites; Hispanics were excluded. RESULTS: Although death rates from HIV in AI/AN persons were significantly lower than those in Whites from 1990 to 1998 (4.2 vs 7.0), they were significantly higher than those in Whites from 1999 to 2009 (3.6 vs 2.0). Death rates from TB in AI/AN persons were significantly higher than those in Whites, with a significant disparity during both 1990 to 1998 (3.3 vs 0.3) and 1999 to 2009 (1.5 vs 0.1). CONCLUSIONS: The decrease in death rates from HIV and TB was greater among Whites, and death rates remained significantly higher among AI/AN individuals. Public health interventions need to be prioritized to reduce the TB and HIV burden and mortality in AI/AN populations. PMID- 24754665 TI - Suicide mortality among American Indians and Alaska Natives, 1999-2009. AB - OBJECTIVES: We assessed national and regional suicide mortality for American Indian and Alaska Native (AI/AN) persons. METHODS: We used 1999 to 2009 death certificate data linked with Indian Health Service (IHS) patient registration data to examine death rates from suicide in AI/AN and White persons. Analysis focused primarily on residents of IHS Contract Health Service Delivery Area counties; Hispanics were excluded. We used age-adjusted death rates per 100,000 population and stratified our analyses by age and IHS region. RESULTS: Death rates from suicide were approximately 50% higher among AI/AN persons (21.2) than Whites (14.2). By region, rates for AI/AN people were highest in Alaska (rates = 65.4 and 19.3, for males and females, respectively) and in the Northern Plains (rates = 41.6 and 11.9 for males and females, respectively). Disparities between AI/AN and White rates were also highest in these regions. CONCLUSIONS: A coordinated, multidisciplinary effort involving federal, state, local, and tribal health officials is needed to address this important public health issue. PMID- 24754666 TI - Core-spun carbon nanotube yarn supercapacitors for wearable electronic textiles. AB - Linear (fiber or yarn) supercapacitors have demonstrated remarkable cyclic electrochemical performance as power source for wearable electronic textiles. The challenges are, first, to scale up the linear supercapacitors to a length that is suitable for textile manufacturing while their electrochemical performance is maintained or preferably further improved and, second, to develop practical, continuous production technology for these linear supercapacitors. Here, we present a core/sheath structured carbon nanotube yarn architecture and a method for one-step continuous spinning of the core/sheath yarn that can be made into long linear supercapacitors. In the core/sheath structured yarn, the carbon nanotubes form a thin surface layer around a highly conductive metal filament core, which serves as current collector so that charges produced on the active materials along the length of the supercapacitor are transported efficiently, resulting in significant improvement in electrochemical performance and scale up of the supercapacitor length. The long, strong, and flexible threadlike supercapacitor is suitable for production of large-size fabrics for wearable electronic applications. PMID- 24754667 TI - Learning to imitate individual finger movements by the human neonate. AB - Imitation in human neonates, unlike imitation in young infants, is still regarded as controversial. Four studies with 203 newborns are presented to examine the imitation of index finger, two- and three-finger movements in human neonates. Results found differential imitations of all three modelled gestures, a left handed pattern, and a rapid learning mechanism. The lateralized behavioural pattern suggests the involvement of a right lateralized neural network, and the mechanisms described in this study - (i) the accurate imitation of all aspects of the model's movements, (ii) the rapid learning component, and the (iii) the early sensitive period might fulfil the criteria for filial imprinting. PMID- 24754668 TI - Forster resonance energy transfer studies of luminescent gold nanoparticles functionalized with ruthenium(II) and rhenium(I) complexes: modulation via esterase hydrolysis. AB - A number of ruthenium(II) and rhenium(I) bipyridine complexes functionalized with lipoic acid moieties have been synthesized and characterized. Functionalization of gold nanoparticles with these chromophoric ruthenium(II) and rhenium(I) complexes has resulted in interesting supramolecular assemblies with Forster resonance energy transfer (FRET) properties that could be modulated via esterase hydrolysis. The luminescence of the metal complex chromophores was turned on upon cleavage of the ester bond linkage by esterase to reduce the efficiency of FRET quenching. The prepared nanoassembly conjugates have been characterized by transmission electron microscopy (TEM), energy-dispersive X-ray analysis (EDX), Fourier transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), UV-visible spectroscopy, and emission spectroscopy. The quenching mechanism has also been studied by transient absorption and time-resolved emission decay measurements. The FRET efficiencies were found to vary with the nature of the chromophores and the length of the spacer between the donor (transition metal complexes) and the acceptor (gold nanoparticles). PMID- 24754669 TI - The effect of the intracervical application of follicle-stimulating hormone or luteinizing hormone on the pattern of expression of gonadotrophin receptors in the cervix of non-pregnant ewes. AB - During the periovulatory period, the cervix relaxes in response to changes in circulating concentrations of reproductive hormones. The present study investigated the role of gonadotrophins in cervical function by examining the expression of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) and their mRNAs following intracervical treatment with either FSH or LH. Eighteen ewes were assigned to four groups, and they were then treated with progestagen sponges and PMSG to synchronize their oestrous cycles. Intracervical treatments were given 24 h after sponge removal as follows: Group 1: FSH 2 mg; Group 2: LH 2 mg; Group 3: Vehicle and Group 4: Control. Cervices were collected 54 h after sponge removal and then divided into three regions. The expression of FSHR and LHR was determined by immunohistochemistry and FSHR mRNA and LH mRNA by in situ hybridization. The expression of LHR, FSHR and their respective mRNAs was compared in six tissue layers (luminal epithelium, subepithelial stroma, circular, longitudinal and transverse muscle and serosa) and in three cervical regions (vaginal, mid and uterine). The results showed that FSH increased transcription of the FSHR gene and the levels of its receptor, but only in subepithelial stroma of the cervix. FSH also increased the levels of LHR in the cervix, but only in the muscle layers. LH had no effect on the levels of FSHR despite the fact that it did increase the level of transcription of the FSHR gene and LH also increased the levels of its own receptor in the cervix, but only in the muscle layers, and this action was independent of increased levels of transcription of the LHR gene. These findings suggest multiple levels of regulation of cervical LH and FSH receptors and that the gonadotrophins may have a role in relaxation of the cervix during oestrus by regulating their own receptors. PMID- 24754670 TI - How I determine if and when to recommend stopping tyrosine kinase inhibitor treatment for chronic myeloid leukaemia. AB - Treatment-free remission (TFR) has recently emerged as a goal of treatment in chronic myeloid leukaemia (CML). Molecular remission is sustained in around 30% of imatinib-treated patients who stop treatment after >=2 years with undetectable minimal residual disease (UMRD) by conventional real-time reverse transcription polymerase chain reaction. An additional 20-30% of patients will lose UMRD, but remain in stable major molecular remission off treatment. Most patients with molecular recurrence have a significant increase in BCR-ABL1 within the first 6 months off treatment, but there are also rare late relapses. As re-treatment with imatinib restores control, a trial of TFR is safe so long as careful molecular monitoring is provided to enable prompt re-treatment. The minimum eligibility criteria for a trial of TFR are not yet defined, but the available data support a MRD level of around a molecular response of 4.5 log for at least 2 years. Factors associated with a higher probability of TFR include low risk Sokal score, prior interferon treatment, longer total duration of imatinib treatment and higher numbers of natural killer cells at the time of imatinib discontinuation. Preliminary data suggest that the rate of TFR in patients treated with more potent tyrosine kinase inhibitors will probably be higher. The biology that underlies TFR is an area of active investigation. PMID- 24754671 TI - Three-dimensional kinematic correlates of ball velocity during maximal instep soccer kicking in males. AB - Achieving a high ball velocity is important during soccer shooting, as it gives the goalkeeper less time to react, thus improving a player's chance of scoring. This study aimed to identify important technical aspects of kicking linked to the generation of ball velocity using regression analyses. Maximal instep kicks were obtained from 22 academy-level soccer players using a 10-camera motion capture system sampling at 500 Hz. Three-dimensional kinematics of the lower extremity segments were obtained. Regression analysis was used to identify the kinematic parameters associated with the development of ball velocity. A single biomechanical parameter; knee extension velocity of the kicking limb at ball contact Adjusted R(2) = 0.39, p <= 0.01 was obtained as a significant predictor of ball-velocity. This study suggests that sagittal plane knee extension velocity is the strongest contributor to ball velocity and potentially overall kicking performance. It is conceivable therefore that players may benefit from exposure to coaching and strength techniques geared towards the improvement of knee extension angular velocity as highlighted in this study. PMID- 24754672 TI - The effect of non-surgical weight loss interventions on urinary incontinence in overweight women: a systematic review and meta-analysis. AB - Although the aetiology of urinary incontinence can be multifactorial, in some cases weight loss could be considered as a part of the therapeutic approach for urinary incontinence in people who are overweight. The objective of this study was to review and meta-analyse the effect of non-surgical weight loss interventions on urinary incontinence in overweight women. Web of Science, PubMed, Pedro, SPORTDiscus and Cochrane were systematically searched for clinical trials that met the a priori set criteria. Data of women who participated in non surgical weight loss interventions (diet, exercise, medication or a combination) were included in the meta-analysis. After removing duplicates, 62 articles remained for screening on title, abstract and full text. Six articles (totalling 2,352 subjects in the intervention groups) were included for meta-analysis. The mean change in urinary incontinence (reported as frequency or quantity, depending on the study) after a non-surgical weight loss intervention, expressed as standardized effect size and corrected for small sample sizes (Hedges' g), was 0.30 (95%CI = -0.47 to -0.12). This systematic review and meta-analysis shows evidence that a non-surgical weight loss intervention has the potential to improve urinary incontinence and should be considered part of standard practice in the management of urinary incontinence in overweight women. PMID- 24754674 TI - Kinetic analysis of the thermal processing of silica and organosilica. AB - The incorporation of an organic group into sol-gel-derived silica causes significant changes in the structure and properties of these materials. Therefore, the thermal treatment of organosilica materials may require a different approach. In the present paper, kinetic parameters (activation energy, pre-exponential constant, and reaction models) have been determined from mass loss data for the dehydration, dehydroxylation, and decomposition reactions that take place upon heating silica and organosilica. Parameters were obtained by employing model-free isoconversional methods to data obtained under multiple heating rates as well as by multivariate analysis of the kinetics using a multistep reaction model with distributed activation energy. For silica, it can be concluded that the reaction atmosphere (i.e., inert or thermo-oxidative) has no influence on the reaction rate of the dehydration and dehydroxylation reactions that are responsible for the densification of the material. Under inert atmosphere, full dehydration can be reached without affecting the organic moiety. Achieving complete dehydroxylation of the organosilica is practically impossible as decomposition does manifest itself under commonly employed calcination temperatures. This indicates that prudence is required in designing a heat treatment program for these hybrid materials. To aid in optimizing the thermal treatment, a predictive model was developed, which can be used to forecast the extent of dehydration, dehydroxylation, and decomposition reactions under a multitude of temperature programs. PMID- 24754673 TI - Comparative study of the shell development of hard- and soft-shelled turtles. AB - The turtle shell provides a fascinating model for the investigation of the evolutionary modifications of developmental mechanisms. Different conclusions have been put forth for its development, and it is suggested that one of the causes of the disagreement could be the differences in the species of the turtles used - the differences between hard-shelled turtles and soft-shelled turtles. To elucidate the cause of the difference, we compared the turtle shell development in the two groups of turtle. In the dorsal shell development, these two turtle groups shared the gene expression profile that is required for formation, and shared similar spatial organization of the anatomical elements during development. Thus, both turtles formed the dorsal shell through a folding of the lateral body wall, and the Wnt signaling pathway appears to have been involved in the development. The ventral portion of the shell, on the other hand, contains massive dermal bones. Although expression of HNK-1 epitope has suggested that the trunk neural crest contributed to the dermal bones in the hard-shelled turtles, it was not expressed in the initial anlage of the skeletons in either of the types of turtle. Hence, no evidence was found that would support a neural crest origin. PMID- 24754675 TI - Advances in quantitative structure-activity relationship models of anti Alzheimer's agents. AB - INTRODUCTION: Alzheimer's disease (AD) is one of the lethal diseases, mainly affecting older people. The unclear root cause and involvement of various enzymes in the pathological conditions confirm the complexity of the disease. Quantitative structure-activity relationship (QSAR) techniques are of great significance in the design of drugs against AD. AREAS COVERED: In the present review, the authors provide a basic background about AD and QSAR techniques. Furthermore, they review the various QSAR studies reported against various targets of AD. The information provided for each QSAR study includes chemical scaffold and target enzyme under study, applied QSAR technique and outcomes of the respective study. EXPERT OPINION: In silico techniques like QSAR hold great potential in designing leads against a complex disease like AD. In combination with other in silico techniques, QSAR can provide more useful and rational insight to facilitate the discovery of novel compounds. Only few QSAR studies on imaging agents have been reported; hence, more QSAR studies are recommended to explore the biomarker or imaging agents for improving diagnosis. Again, for proper symptomatic treatment, multi-target drugs acting on more than one target are required. Hence, more multi-target QSAR studies are recommended in future to achieve this goal. PMID- 24754676 TI - Natural selection and the genetic basis of osmoregulation in heteromyid rodents as revealed by RNA-seq. AB - One adaptation of ecological and evolutionary interest is the extraordinary ability of desert rodents to retain water during waste production. Much is known regarding the unique kidney physiology of kangaroo rats (Dipodomys spp.) and their ability to retain water during waste production, yet the genetic basis of these physiological adaptations is relatively unknown. Herein, we utilized RNA seq data to conduct a comparative study to identify osmoregulatory genes expressed in heteromyid rodents. We sequenced kidney tissue from two temperate desert species (Dipodomys spectabilis and Chaetodipus baileyi) from two separate subfamilies of the Heteromyidae and compared these transcriptomes to a tropical mesic species (Heteromys desmarestianus) from a third subfamily. The evolutionary history of these subfamilies provided a robust phylogenetic control that allowed us to separate shared evolutionary history from convergence. Using two methods to detect differential expression (DE), we identified 1890 genes that showed consistent patterns of DE between the arid and mesic species. A three-species reciprocal BLAST analysis revealed 3511 sets of putative orthologues that, upon comparison to known Mus musculus sequences, revealed 323 annotated and full length genic regions. Selection tests displayed evidence of positive selection (dn/ds > 1) on six genes in the two desert species and remained significant for one of these genes after correction for multiple testing. Thus, our data suggest that both the coding sequence and expression of genes have been shaped by natural selection to provide the genetic architecture for efficient osmoregulation in desert-adapted heteromyid rodents. PMID- 24754677 TI - Identification of type II and III DDR2 inhibitors. AB - Discoidin domain-containing receptors (DDRs) exhibit a unique mechanism of action among the receptor tyrosine kinases (RTKs) because their catalytic activity is induced by extracellular collagen binding. Moreover, they are essential components in the assimilation of extracellular signals. Recently, DDRs were reported to be significantly linked to tumor progression in breast cancer by facilitating the processes of invasion, migration, and metastasis. Here, we report the successful development of a fluorescence-based, direct binding assay for the detection of type II and III DFG-out binders for DDR2. Using sequence alignments and homology modeling, we designed a DDR2 construct appropriate for fluorescent labeling. Successful assay development was validated by sensitive detection of a reference DFG-out binder. Subsequent downscaling led to convenient application to high-throughput screening formats. Screening of a representative compound library identified high-affinity DDR2 ligands validated by orthogonal activity-based assays, and a subset of identified compounds was further investigated with respect to DDR1 inhibition. PMID- 24754679 TI - Surfaces energies of monoliths by inverse liquid chromatography and contact angles. AB - Seven porous chromatographic columns, termed monoliths, and seven nonporous sheets were produced from polymethacrylates. Their surfaces were activated by different densities of butyl and phenyl ligands. We determined the retention times of highly dilute molecular probes in monoliths and accessed contact angles of pure molecular probes of sheets. We calculated surface energies for both systems. We applied theories of Young, Dupre, and van Oss and compared the results of both types of experiments with respect to Lifshitz-van der Waals and Lewis acid and Lewis base contributions and find agreement but an additive constant. PMID- 24754680 TI - pi-Electron ring-currents and bond-currents in some conjugated altan-structures. AB - Ring-currents and bond-currents calculated using the Huckel-London-Pople-McWeeny (HLPM) method are reported for a series of altan-structures recently explored by Monaco et al. and to which these authors have applied the ab initio ipso-centric formalism in order to calculate the structures' pi-electron current-density maps. Two aspects of the conclusions of their ab initio study are confirmed by means of the much more simplistic HLPM formalism adopted here: namely (a) that the inner core in these altan-structures generally displays similar current patterns to those previously reported for the parent fragments, and (b) that the unexpected diamagnetic circulation in the outer [4n]-perimeter of altan-kekulene reported by Monaco et al. is not an artifact of their method but appears to be confirmed. Attention is drawn to the conceptual advantages of discussing bond currents rather than just (equivalent) ring currents. PMID- 24754678 TI - Spectroscopic and mechanistic studies of heterodimetallic forms of metallo-beta lactamase NDM-1. AB - In an effort to characterize the roles of each metal ion in metallo-beta lactamase NDM-1, heterodimetallic analogues (CoCo-, ZnCo-, and CoCd-) of the enzyme were generated and characterized. UV-vis, (1)H NMR, EPR, and EXAFS spectroscopies were used to confirm the fidelity of the metal substitutions, including the presence of a homogeneous, heterodimetallic cluster, with a single atom bridge. This marks the first preparation of a metallo-beta-lactamase selectively substituted with a paramagnetic metal ion, Co(II), either in the Zn1 (CoCd-NDM-1) or in the Zn2 site (ZnCo-NDM-1), as well as both (CoCo-NDM-1). We then used these metal-substituted forms of the enzyme to probe the reaction mechanism, using steady-state and stopped-flow kinetics, stopped-flow fluorescence, and rapid-freeze-quench EPR. Both metal sites show significant effects on the kinetic constants, and both paramagnetic variants (CoCd- and ZnCo NDM-1) showed significant structural changes on reaction with substrate. These changes are discussed in terms of a minimal kinetic mechanism that incorporates all of the data. PMID- 24754681 TI - An NRAS mutation in a case of Erdheim-Chester disease. PMID- 24754683 TI - A good death in hospital. PMID- 24754682 TI - Gastrointestinal side effects in liver transplant recipients taking enteric coated mycophenolate sodium vs. mycophenolate mofetil. AB - In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric-coated mycophenolate sodium (EC-MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC-MPS to MMF in liver transplant patients in a de novo study (Study I randomized, prospective, double-blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC-MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC-MPS instead of MMF. PMID- 24754684 TI - Cardiovascular disease in human immunodeficiency virus. AB - With widespread access to high-quality medical care as in Australia, human immunodeficiency virus (HIV) is now considered a chronic, treatable condition, with a good life expectancy. The use of combined highly active antiretroviral therapy has enabled effective suppression of the virus, but has also been associated with increased cardiac morbidity and mortality. Over representation of traditional cardiac risk factors, such as hyperlipidaemia and diabetes, as well as an increased incidence of ischaemic and non-ischaemic heart disease is now considered a major concern of treatment with antiretroviral therapy. Therefore, a contemporary management strategy for patients with HIV must include active prevention and treatment of cardiovascular risk. This review will outline the complex interplay between HIV infection, antiretroviral drug regimens and accelerated cardiovascular disease, with a particular focus on screening, prevention and treatment options in a contemporary Australian HIV population. PMID- 24754686 TI - Robust reflections and radical thoughts: perspectives of a medical journal editor. PMID- 24754687 TI - Journal and college: thanks from a former editor. PMID- 24754688 TI - Medicine's inconvenient truth: the placebo and nocebo effect. AB - Placebo and nocebo effects are often regarded by clinicians as either a quaint reminiscence from the pre-therapeutic era, or simply as a technique for establishing the efficacy of therapeutic interventions within the locus of evidence-based practice. However, neither of these explanations sufficiently account for their complexity or their persistence and impact in clinical medicine. Placebo and nocebo effects are embedded in the very fabric of therapeutic relationships and are both a manifestation and outcome of the rituals that characterise clinical practice. They are also a stark reminder of the many personal and environmental factors, including the attitudes, beliefs and expectations of both doctor and patient, that shape the outcomes of health professional-patient interactions. We describe how recent biological and neuropsychiatric data have clarified the operation of placebo and nocebo effects in clinical practice - demonstrating the ability of the therapeutic context to modulate endogenous biological processes in a targeted manner. This, in turn, illustrates the potent philosophical and sociocultural aspects of medical praxis. PMID- 24754689 TI - Knowledge and attitudes regarding the personally controlled electronic health record: an Australian national survey. AB - The personally controlled electronic health record (PCHER) was designed to bring important information together to facilitate effective communication between clinicians and so improve patient care. This national cross-sectional survey of 405 healthcare providers and consumers found that they had relatively low awareness and knowledge about the PCEHR; that 62% of respondents believed that healthcare providers with access to the PCEHR would be able to provide better quality of care but only 50% of respondents would sign up to have a PCEHR. PMID- 24754690 TI - Complete recovery from paraparesis in spinal cord compression due to extramedullary haemopoiesis in beta-thalassaemia by emergency radiation therapy. AB - Extramedullary haemopoiesis (EMH) is a complication commonly associated with beta thalassaemia intermedia; it is frequently asymptomatic but can sometimes lead to symptomatic tumour-like masses. No guidelines or common consensus are available in literature regarding the different treatment strategies and only single cases have been reported. We describe a case of spinal cord compression due to intrathoracic EMH masses treated with combined radiotherapy and hydroxyurea. PMID- 24754691 TI - Novel inactivating mutation of the calcium-sensing receptor in a young woman with mild hypercalcaemia. AB - A young woman with mild hypercalcaemia and an inappropriately normal serum parathyroid hormone had parathyroid scintigraphy suggestive of an active ectopic parathyroid tissue in the superior mediastinum. Urinary calcium to creatinine clearance ratio was low, and a subsequent genetic analysis confirmed a novel mutation (Q164K) in the calcium sensing receptor gene, consistent with familial hypocalciuric hypercalcaemia. We propose that this mutation accounts for her clinical and investigational findings, although a double pathology of Q164K and an ectopic parathyroid adenoma is also conceivable. PMID- 24754692 TI - CD5-positive follicular lymphoma: prognostic significance of this aberrant marker? AB - Follicular lymphomas are the most common of the clinically indolent non-Hodgkin lymphomas. The immunophenotypic pattern of follicular lymphoma classically demonstrates the B-cell markers CD19, CD20, CD22, CD79a, surface immunoglobulin and CD10. The tumour cells are usually negative for CD5. We described two cases of CD5-positive follicular lymphoma. This finding has rarely been described. Our aim was to discuss two cases of CD5-positive follicular lymphoma and review the published literature on the significance of CD5 expression. Bone marrow biopsies showing involvement with follicular lymphoma at our institution over the past 34 months were evaluated for the presence of CD5 positivity by flow cytometry and immunohistochemistry. Two of eight cases (25%) of the follicular lymphomas with marrow involvement at our institution were found to be CD5-positive. Only 36 cases of CD5-positive follicular lymphoma have previously been described in the literature. The clinical and therapeutic significance of this remains uncertain. More research into such cases may establish whether the presence of this aberrant marker bears prognostic significance. PMID- 24754693 TI - Fatal quinine-induced thrombocytopenia from pulmonary haemorrhage. AB - Severe drug-induced thrombocytopenia is a well known but rare complication of quinine. This paper presents a discussion on quinine-induced thrombocytopenia based on a patient who developed fatal thrombocytopenia and pulmonary haemorrhage. PMID- 24754694 TI - Fatal graft-versus-host disease after unrelated cadaveric liver transplantation due to donor/recipient human leucocyte antigen matching. PMID- 24754695 TI - Transfusion in gastrointestinal haemorrhage: time to change? PMID- 24754696 TI - Cavernous sinus syndrome: a rare complication of neurosyphilis. PMID- 24754697 TI - Author reply: To PMID 24020346. PMID- 24754698 TI - Drug shortages and medication quality: integrally related. PMID- 24754699 TI - Early recovery experience of patients with injury in Taiwan. AB - PURPOSE: To fill out the gaps in the existing research on the early recovery experiences of patients who have suffered moderate to severe injuries. DESIGN: Exploratory phenomenology was applied in this study. METHODS: Data were collected at a hospital in Taiwan from a purposive sample of 14 participants who were interviewed before hospital discharge. Semi-structured and audio-taped interviews were conducted. Colaizzi's methods were applied to analyze data. Four criteria were applied to establish the rigors of this study. FINDINGS: The patients expressed that during the early stages following their injury, several aspects of the traumatic event caused them concern. Six themes were delineated: "experience of acute pain after the injury," "inability to fulfill daily needs," "concerns with impacts caused by the injury," "perceiving that time is needed to recover," "applying multiple methods to restore one's health," and "perceiving fate as the cause of the accident." CONCLUSIONS: The findings identify that injuries bring several problems for patients. Some culture-related issues such as Chinese diets, Chinese medicine, and karmic causation have emerged. Clinicians should better understand patient care needs in the early stages of recovery after an injury. CLINICAL RELEVANCE: Findings from this study could lead to new interventions, and finally improve care outcomes for patients with injuries. PMID- 24754702 TI - Epoxy nanocomposites with two-dimensional transition metal dichalcogenide additives. AB - Emerging two-dimensional (2D) materials such as transition metal dichalcogenides offer unique and hitherto unavailable opportunities to tailor the mechanical, thermal, electronic, and optical properties of polymer nanocomposites. In this study, we exfoliated bulk molybdenum disulfide (MoS2) into nanoplatelets, which were then dispersed in epoxy polymers at loading fractions of up to 1% by weight. We characterized the tensile and fracture properties of the composite and show that MoS2 nanoplatelets are highly effective at enhancing the mechanical properties of the epoxy at very low nanofiller loading fractions (below 0.2% by weight). Our results show the potential of 2D sheets of transition metal dichalcogenides as reinforcing additives in polymeric composites. Unlike graphene, transition metal dichalcogenides such as MoS2 are high band gap semiconductors and do not impart significant electrical conductivity to the epoxy matrix. For many applications, it is essential to enhance mechanical properties while also maintaining the electrical insulation properties and the high dielectric constant of the polymer material. In such applications, conductive carbon based fillers such as graphene cannot be utilized. This study demonstrates that 2D transition metal dichalcogenide additives offer an elegant solution to such class of problems. PMID- 24754700 TI - A UK analysis of the cost of switching renal transplant patients from an immediate-release to a prolonged-release formulation of tacrolimus based on differences in trough concentration variability. AB - BACKGROUND AND AIMS: Randomized controlled trials have shown that a once-daily prolonged-release (PR) tacrolimus formulation (PR tacrolimus; Advagraf * ), is non-inferior to a twice-daily immediate-release (IR) tacrolimus formulation (IR tacrolimus; Prograf ? ) in terms of biopsy-proven acute rejection, graft failure and mortality in renal transplant recipients. However, relative to IR tacrolimus, PR tacrolimus exhibits reduced tacrolimus trough concentration variability, which has been associated with reduced graft failure. Based on these data, the present study evaluated the cost of switching UK renal transplant patients from IR tacrolimus to PR tacrolimus. METHODS: UK-specific data on acute rejection, graft failure, and mortality were used to construct a budget impact model to assess the costs of switching from IR tacrolimus to PR tacrolimus on a 1:1 mg:mg basis. The model assumed that 3.1% of patients on PR tacrolimus had high tacrolimus trough concentration variability compared with 17.4% on IR tacrolimus, based on a study comparing PR tacrolimus and IR tacrolimus pharmacokinetics. A relative graft failure risk of 2.38 was applied to high variability patients based on data from a tacrolimus variability study in which 10/148 patients with low variability experienced graft failure, compared with 24/149 in the high variability group. Cost data were taken from the British National Formulary and 2012-2013 NHS tariff information. RESULTS: The mean per-patient cost (including tacrolimus, concomitant immunosuppressive medications, dialysis after graft failure, and treatment for acute rejection) was GBP 26,941 (standard deviation [SD] = GBP 2765) with PR tacrolimus vs GBP 30,356 (SD = GBP 3085) for IR tacrolimus over a 5 year period, corresponding to a saving of GBP 3415 (SD = GBP 516) per patient or GBP 341,500 in a hypothetical 100-patient transplant center. Cost savings were driven primarily by lower dialysis costs resulting from the lower proportion of PR tacrolimus patients with high tacrolimus trough concentration variability (leading to lower graft failure risk). LIMITATIONS: The main limitation of the study was the use of heterogeneous data sources to capture the effect of within patient variability on graft failure. The most important difference between the studies was the definition of the threshold between low and high within-patient variability. This was explored in sensitivity analyses in which the inter-arm difference in the inter-arm proportions of patients with high and low variability was abolished. CONCLUSIONS: Converting UK renal transplant recipients from IR tacrolimus to PR tacrolimus was associated with lower pharmacy and dialysis costs. PMID- 24754703 TI - From challenges to advanced practice registered nursing role development: Qualitative interview study. AB - The aim of this study is to describe the factors hindering and facilitating the implementation of the advanced practice registered nurses role at Finnish university hospitals, and to examine the implications for its future development. A descriptive qualitative approach, using thematic individual interviews, was conducted in 2011 with a sample of 11 advanced practice registered nurses. The data were analysed using qualitative content analysis. The advanced practice registered nurses role barriers had an impact on the role development needs. In turn, the facilitating factors helped encounter the challenges of the role, therefore having an impact on both the current role achievement, as well as contributing to the future role development. The factors hindering and facilitating the advanced practice registered nurses role need to be acknowledged to support the role implementation and planning of the future of the role. PMID- 24754705 TI - Does a water-training macrocycle really create imbalances in swimmers' shoulder rotator muscles? AB - The continuous execution of swimming techniques may cause muscle imbalances in shoulder rotators leading to injury. However, there is a lack of published research studies on this topic. The aim of this study was to analyze the influence of a competitive swim period on the shoulder rotator-cuff balance in young swimmers. A randomized controlled pretest-posttest design was used, with two measurements performed during the first macrocycle of the swimming season (baseline and 16 weeks). Twenty-seven young male swimmers (experimental group) and 22 male students who were not involved in swim training (control group) with the same characteristics were evaluated. Peak torque of shoulder internal and external rotators was assessed. Concentric action at 1.04 rad s(-1) (3 repetitions) and 3.14 rad s(-1) (20 repetitions) was measured using an isokinetic dynamometer (Biodex System 3). External/internal rotators strength ratios were also obtained. For both protocols, there were significant training effects on internal rotator strength and external/internal rotator ratios (p <= .05). This trend was the same for both shoulders. Within-group analysis showed significant changes from baseline to 16 weeks for internal rotators strength and unilateral ratios of the experimental group. Swimmers' internal rotator strength levels increased significantly. In contrast, a significant decrease of the unilateral ratios was observed. Findings suggest that a competitive swim macrocycle leads to an increase in muscular imbalances in the shoulder rotators of young competitive swimmers. Swimming coaches should consider implementing a compensatory strength training program. PMID- 24754706 TI - Natural resilience in Arctic charr Salvelinus alpinus: life history, spatial and dietary alterations along gradients of interspecific interactions. AB - The Arctic charr Salvelinus alpinus species complex has been shown to be exceptionally vulnerable to rapid abiotic and biotic changes. Salvelinus alpinus, however, inhabit environmental extremes ranging from lakes and rivers in the High Arctic to deep multi-fish species lakes far outside the polar region. Long-term responses to post-glacial environmental variations and successively increased interspecific interactions reveal an essential degree of natural ecological resilience and phenotypic flexibility. Case studies in Scandinavia and Newfoundland illustrate the alternate trophic roles of S. alpinus, and its flexible niche use and life-history changes in order to regain or maintain body size in gradients of lakes with increasing fish species diversity. While allopatric in northern low-productive upland lakes, landlocked populations are commonly structured by cannibalism. In sympatry with other fish species, S. alpinus mostly serve as prey, with their decreasing growth and body size reflecting the successive diet shift from littoral macro-benthos to zooplankton and profundal microbenthos as interspecific competition for food and habitat intensifies. Interactions with natural and introduced superior zooplankton feeders and ultimate predators finally become detrimental. Consequently, the niche of S. alpinus is increasingly compressed in lakes along latitudinal and altitudinal gradients, although certain natural key conditions offer S. alpinus temporary asylum in the inescapable process towards local and regional extinction. The water temperature drop during winter allows S. alpinus to temporarily resume the richer littoral dietary and spatial niche use in low diversity lakes. In southern lowland and coastal lakes with more complex fish communities, access to key prey species such as profundal macro-crustaceans and smelt Osmerus spp. allow S. alpinus to regain its original niche space and characteristics as a large piscivore. In conclusion, S. alpinus along its evolutionary landscape demonstrates associated alterations of life-history characteristics, such as body size and longevity, and thus reproductive traits demonstrating similarities between northern cannibals and southern piscivores. Although including a high degree of natural resilience, obviously differing among S. alpinus populations along its range, differences seen in extreme marginal populations may have been adaptive and the product of an evolutionary response with optimized growth resulting from natural selection due to ultimate intra or inter-specific competition and predation. PMID- 24754704 TI - Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling. AB - Chronic N-methyl-d-aspartate receptor (NMDAR) hypofunction has been proposed as a contributing factor to symptoms of schizophrenia. However, it is unclear how sustained NMDAR hypofunction throughout development affects other neurotransmitter systems that have been implicated in the disease. Dopamine neuron biochemistry and activity were examined to determine whether sustained NMDAR hypofunction causes a state of hyperdopaminergia. We report that a global, genetic reduction in NMDARs led to a remodeling of dopamine neurons, substantially affecting two key regulators of dopamine homeostasis, i.e., tyrosine hydroxylase and the dopamine transporter. In NR1 knockdown mice, dopamine synthesis and release were attenuated, and dopamine clearance was increased. Although these changes would have the effect of reducing dopamine transmission, we demonstrated that a state of hyperdopaminergia existed in these mice because dopamine D2 autoreceptors were desensitized. In support of this conclusion, NR1 knockdown dopamine neurons have higher tonic firing rates. Although the tonic firing rates are higher, phasic signaling is impaired, and dopamine overflow cannot be achieved with exogenous high-frequency stimulation that models phasic firing. Through the examination of several parameters of dopamine neurotransmission, we provide evidence that chronic NMDAR hypofunction leads to a state of elevated synaptic dopamine. Compensatory mechanisms to attenuate hyperdopaminergia also impact the ability to generate dopamine surges through phasic firing. PMID- 24754707 TI - Teaching moral reasoning through gesture. AB - Stem-cell research. Euthanasia. Personhood. Marriage equality. School shootings. Gun control. Death penalty. Ethical dilemmas regularly spark fierce debate about the underlying moral fabric of societies. How do we prepare today's children to be fully informed and thoughtful citizens, capable of moral and ethical decisions? Current approaches to moral education are controversial, requiring adults to serve as either direct ('top-down') or indirect ('bottom-up') conduits of information about morality. A common thread weaving throughout these two educational initiatives is the ability to take multiple perspectives - increases in perspective taking ability have been found to precede advances in moral reasoning. We propose gesture as a behavior uniquely situated to augment perspective taking ability. Requiring gesture during spatial tasks has been shown to catalyze the production of more sophisticated problem-solving strategies, allowing children to profit from instruction. Our data demonstrate that requiring gesture during moral reasoning tasks has similar effects, resulting in increased perspective taking ability subsequent to instruction. A video abstract of this article can be viewed at http://www.youtube.com/watch?v/gAcRIClU_GY. PMID- 24754708 TI - Increasing use of antibiotics in pregnancy during the period 2000-2010: prevalence, timing, category, and demographics. AB - OBJECTIVE: The aim of this study was to describe the use of antibiotics in a national population-based cohort of pregnant Danish women between 2000 and 2010. DESIGN: Register-based, population-wide, cohort study. SETTING: Denmark, from 2000 to 2010. POPULATION: All pregnancies among Danish residents during the period 2000-2010 were included for analysis. METHODS: Data were obtained from the Danish Medical Birth Registry, the Danish National Patient Registry, and the Registry of Medicinal Product Statistics. The filled prescriptions for systemic antibacterial, antimycotic, and antiviral drugs, as well as intravaginally applied antibiotics, were analysed. Associations with demographic variables were assessed using multivariate analysis. MAIN OUTCOME MEASURES: Filled prescriptions for antibiotic drugs during pregnancy. RESULTS: We included 987 973 pregnancies in Denmark from 2000 to 2010; 38.9% of women with a delivery and 14.8% of women with a miscarriage or termination of pregnancy had one or more antibiotic treatments during pregnancy. Systemic antibacterial drugs were the most frequently used drug group, with filled prescriptions for 33.4% of all deliveries and 12.6% of all abortions. This proportion increased from 28.4% in 2000 to 37.0% in 2010 among deliveries. The biggest change was seen for pivmecillinam, which increased among deliveries from 6.3% in 2000 to 19.5% in 2010. Obese (odds ratio 1.51; 95% CI 1.47-1.56), young (odds ratio 1.35; 95% CI 1.30-1.39), and low educated women (odds ratio 1.37; 95% CI 1.35-1.1.39) tended to fill more prescriptions of antibiotics during pregnancy. CONCLUSIONS: Overall, the number of women who filled prescriptions of antibiotics increased during the 11-year study period. In 2010, at least 41.5% of all deliveries were exposed to antibiotic therapy during pregnancy. PMID- 24754709 TI - Evaluation of the reticulocyte counting by the Mindray BC 6800 automated hematology analyzer: comparison with ABX Pentra 120, Coulter LH 750, and microscopy. PMID- 24754710 TI - Effects of oxidative stress on red blood cell rheology in sickle cell patients. AB - Sickle cell anaemia (SS) and sickle cell-haemoglobin C disease (SC) patients exhibit severe red blood cell (RBC) rheological alterations involved in the development of several complications. The contribution of oxidative stress in these haemorheological abnormalities is still unknown. We compared RBC reactive oxygen species (ROS) and glutathione (GSH) content, and the haemorheological profile of SS (n = 11), SC (n = 11) and healthy subjects (n = 12) at baseline and after in-vitro treatment with t-butyl hydroperoxide (TBHP). We showed: (i) higher RBC ROS content in SS and SC patients, with the highest level observed in SS patients; (ii) lower RBC GSH content in sickle syndrome patients, especially in SS patients; (iii) TBHP increased RBC ROS production and decreased RBC GSH content in all groups; (iv) TBHP decreased RBC aggregation and increased the strength of RBC aggregates in all groups but the increase in RBC aggregates strength was greater in sickle cell patients; (v) TBHP decreased RBC deformability in the three groups but with a higher magnitude in sickle cell patients. These data suggest that RBCs from sickle cell patients have an exaggerated response to oxidative stress, which is accompanied by a profound abnormal haemorheological profile, with greater alterations in SS than in SC patients. PMID- 24754712 TI - The future is now--using personal cellphones to gather data on substance use and related factors. PMID- 24754711 TI - Syntheses, radiolabelings, and in vitro evaluations of fluorinated PET radioligands of 5-HT6 serotoninergic receptors. AB - The 5-HT6 receptors are potent therapeutic targets for psychiatric and neurological diseases (schizophrenia, Alzheimer's disease, etc.). However, with lack of specific radiopharmaceuticals, their pharmacology is still incomplete and their exploration is limited to animal models. In this context, we have designed a fluorinated PET radiotracer, [(18)F]2FNQ1P, that possesses a high affinity and selectivity for 5-HT6. In vitro PET autoradiographies in rat brain sections with this radiotracer were in accordance with the 5-HT6 distribution pattern. PMID- 24754713 TI - Fukushima's forgotten radionuclides: a review of the understudied radioactive emissions. AB - In environmental monitoring campaigns for anthropogenic radionuclides released in the course of the Fukushima nuclear accident (2011), most focus had been on gamma emitting radionuclides. More than 99% of the released activity was due to radionuclides of the elements Kr, Te, I, Xe, and Cs. However, little work had been done on the monitoring of radionuclides other than (131)I, (132)Te, (134)Cs, (136)Cs, and (137)Cs. Radionuclides such as those of less volatile elements (e.g., (89)Sr, (90)Sr, (103)Ru, (106)Ru, plutonium), pure beta-emitters ((3)H, (14)C, (35)S), gaseous radionuclides ((85)Kr, (133)Xe, (135)Xe) or radionuclides with very long half-lives (e.g., (36)Cl, (99)Tc, (129)I, some actinides such as (236)U) have been understudied by comparison. In this review, we summarize previous monitoring work on these "orphan" radionuclides in various environmental media and outline further challenges for future monitoring campaigns. Some of the understudied radionuclides are of radiological concern, others are promising tracers for environmental, geochemical processes such as oceanic mixing. Unfortunately, the shorter-lived nuclides of radioxenon, (103)Ru, (89)Sr and (35)S will no longer exhibit detectable activities in the environment. Activity concentrations of other radionuclides such as tritium, (14)C, or (85)Kr will become blurred in the significant background of previous releases (nuclear explosions and previous accidents). Isotope ratios such as (240)Pu/(239)Pu will allow for the identification of Fukushima plutonium despite the plutonium background. PMID- 24754714 TI - Animal models of chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a leading global cause of mortality and chronic morbidity. Inhalation of cigarette smoke is the principal risk factor for development of this disease. COPD is a progressive disease that is typically characterised by chronic pulmonary inflammation, mucus hypersecretion, airway remodelling and emphysema that collectively reduce lung function. There are currently no therapies that effectively halt or reverse disease progression. It is hoped that the development of animal models that develop the hallmark features of COPD, in a short time frame, will aid in the identifying and testing of new therapeutic approaches. AREAS COVERED: The authors review the recent developments in mouse models of chronic cigarette smoke-induced COPD as well as the principal findings. Furthermore, the authors discuss the use of mouse models to understand the pathogenesis and the contribution of infectious exacerbations. They also discuss the investigations of the systemic co morbidities of COPD (pulmonary hypertension, cachexia and osteoporosis). EXPERT OPINION: Recent advances in the field mark a point where animal models recapitulate the pathologies of COPD patients in a short time frame. They also reveal novel insights into the pathogenesis and potential treatment of this debilitating disease. PMID- 24754716 TI - Three-year clinical evaluation of different restorative resins in class I restorations. AB - The aim of the present study was to evaluate the three-year clinical performance of a nanofilled resin composite, a packable resin composite, and silorane-based resin restorations in Class I occlusal cavities. Twenty-eight patients with at least three similar-sized occlusal lesions in molar teeth participated in the study. A total of 84 Class I occlusal restorations were placed: 28 with nanofilled resin composite (Filtek Supreme), 28 with packable resin composite (P60), and 28 with silorane-based resin (Filtek Silorane). Filtek Supreme and P60 were used with their respective etch-and-rinse adhesive system, Adper Single Bond 2, and Filtek Silorane was used with its respective self-etch adhesive, Filtek Silorane Adhesive. All restorations were placed by the same operator. The restorations were evaluated at baseline, at six months, and annually for three years according to modified US Public Health Service criteria by two calibrated examiners who did not know which restorative resin had been used. The three restorative materials for each category were compared using the chi (2) test at a significance level of 0.05. Cochran's Q test was used to compare the changes across the five time points for each restorative material. McNemar's test followed by Bonferroni adjustment was used when significance differences were found. At the end of the three years, 60 restorations were evaluated in 20 patients, with a recall rate of 71.4%. The retention rate was 100% for all restorative resins. Eight restorations from the P60 group, ten from the Filtek Supreme group, and nine from the Filtek Silorane group were rated Bravo for marginal discoloration. For marginal adaptation, three P60, five Filtek Supreme, and 11 Filtek Silorane restorations were rated Bravo. No statistically significant differences in overall clinical performance were found between the restorative materials except for marginal adaptation. P60 showed the best marginal adaptation at the end of the three years. No differences were observed between the restorative resins for any of the evaluation criteria tested (p>0.05). None of the restorations showed postoperative sensitivity, secondary caries, or loss of anatomic form. All restorative resins performed equally well in clinical conditions during the three-year evaluation, and no significant differences were found among them, except for marginal adaptation, in which P60 showed superior results. PMID- 24754721 TI - Hyperporphyrin effects in the spectroscopy of protonated porphyrins with 4 aminophenyl and 4-pyridyl meso substituents. AB - Spectrophotometric titrations for a full series of 4-aminophenyl/4-pyridyl meso substituted porphyrins were carried out using methanesulfonic acid in DMSO to study the hyperporphyrin effect across different substitution patterns. The series included zero, one, two (cis and trans), three, and four meso(4 aminophenyl) groups, with the remaining meso substituents being 4-pyridyl groups. The peripheral pyridyl groups consistently protonate before the interior porphyrin pyrrole nitrogens, which protonate before the aminophenyl groups. Aminophenyl substituents increase the basicity of the pyrrole nitrogens and lead to distinctive hyperporphyrin spectra with a broad Soret band and a strong red absorption. The structure proposed to give rise to these spectra is the previously proposed charge-transfer interaction between the aminophenyl and the protonated pyrrole. A novel hyperporphyrin structure involving charge-transfer interactions between two peripheral substituents is also proposed in one case, the triply protonated (+3) porphyrin with three aminophenyls and one pyridyl substituent; two of the aminophenyl groups delocalize the charges on the interior nitrogens, while the third aminophenyl group delocalizes with the protonated pyridyl. PMID- 24754722 TI - All two-dimensional, flexible, transparent, and thinnest thin film transistor. AB - In this article, we report only 10 atomic layer thick, high mobility, transparent thin film transistors (TFTs) with ambipolar device characteristics fabricated on both a conventional silicon platform as well as on a flexible substrate. Monolayer graphene was used as metal electrodes, 3-4 atomic layers of h-BN were used as the gate dielectric, and finally bilayers of WSe2 were used as the semiconducting channel material for the TFTs. The field effect carrier mobility was extracted to be 45 cm(2)/(V s), which exceeds the mobility values of state of the art amorphous silicon based TFTs by ~100 times. The active device stack of WSe2-hBN-graphene was found to be more than 88% transparent over the entire visible spectrum and the device characteristics were unaltered for in-plane mechanical strain of up to 2%. The device demonstrated remarkable temperature stability over 77-400 K. Low contact resistance value of 1.4 kOmega-MUm, subthreshold slope of 90 mv/decade, current ON-OFF ratio of 10(7), and presence of both electron and hole conduction were observed in our all two-dimensional (2D) TFTs, which are extremely desirable but rarely reported characteristics of most of the organic and inorganic TFTs. To the best of our knowledge, this is the first report of all 2D transparent TFT fabricated on flexible substrate along with the highest mobility and current ON-OFF ratio. PMID- 24754723 TI - Factors associated with health-related quality of life among patients with implantable cardioverter defibrillator: identification of foci for nursing intervention. AB - AIM: To explore factors associated with health-related quality of life of patients with implantable cardioverter defibrillators. BACKGROUND: Substantial evidence indicates that implantable cardioverter defibrillator is proven to increase survival rate by terminating life-threatening arrhythmia. However, this device can negatively affect health-related quality of life. Little is known about factors associated with health-related quality of life of patients with implantable cardioverter defibrillators, particularly in Asian population. DESIGN: A transversal descriptive design was used. METHODS: Data were collected from a convenience sample of 139 adult patients with implantable cardioverter defibrillators from 4 January-30 April 2012 using the structured questionnaires administered by the researcher and medical record reviews. The Short Form-36 Health Survey version 2 was used to measure health-related quality of life. RESULTS: A total of 139 Chinese patients, including 107 (77.0%) males with a mean age of 63.0 (14.6) years, were selected. The physical component summary was relatively lower, whereas the mental component summary was relatively higher than that of the general Hong Kong Chinese population. Multivariable regression analysis revealed gender, self-care dependence, educational level, atrial fibrillation, diabetes mellitus, anxiety and depression significantly associated with physical or mental quality of life. CONCLUSIONS: Depression was a common factor affecting physical and mental quality of life. Self-care dependence, atrial fibrillation, diabetes mellitus, depression and anxiety could be improved. Our findings expand existing knowledge on identifying at-risk patients for having lower quality of life, thus allowing development of appropriate interventions targeting risk factors for improving health-related quality of life of patients with implantable cardioverter defibrillator. PMID- 24754724 TI - Childhood appendicitis: a surgical challenge. PMID- 24754725 TI - Adjunct ultrasonography in children with suspected acute appendicitis: identifying the optimal target group. AB - BACKGROUND: Role of ultrasonography in diagnosis of acute appendicitis in children is being debated. This study was conducted ahead of a clinical trial and aimed to evaluate the adjunctive role of ultrasonography in this group. METHODS: Retrospective chart review of consecutive children undergoing appendicectomy in an Australian tertiary children's hospital over 24 months. Two study groups were: clinical assessment and clinical assessment plus ultrasonography. The accuracy of diagnosis was compared by generating estimates for sensitivity and positive predictive value using histopathology of the appendix as the reference standard. The incremental value of ultrasonography was evaluated in subgroups of gender, age and clinical severity. RESULTS: Two hundred ninety-five children (170 boys, median age 10 years) were included in the study. Negative appendicectomy rate was 17.3%; 10.4% in the clinical assessment group (n = 134) and 23% in the ultrasonography group (n = 161). Overall sensitivity for diagnosis by clinical assessment (71.4%, 95% confidence interval (CI) 63.3-79.5) was not significantly different to that using adjunct ultrasonography (77.7%, 95% CI 69.7-85.7; P = 0.29). Adjunct ultrasonography was more sensitive between 7 and 11 years (81% versus 68%, P = 0.002) and possibly in girls (86% versus 73%, P = 0.1), but did not increase the sensitivity of the diagnosis in children who presented with milder symptoms and signs. CONCLUSIONS: Adjunct ultrasonography may not increase the overall accuracy of diagnosis of acute appendicitis in children but holds promise in certain subgroups viz. between 7 and 11 years and in girls. There is an increase in negative appendicectomies following a 'non-targeted' use of ultrasonography. Future prospective trials should take cognizance of these findings in designing the subgroup analysis. PMID- 24754726 TI - Hypogenesis of the right hepatic lobe and associated Chilaiditi sign. PMID- 24754727 TI - Continuous mass closure of the abdominal wall for the unassisted surgeon: 'the pinkie technique'. PMID- 24754728 TI - Testicular torsion in a 65-year-old male identified using Doppler ultrasound. PMID- 24754729 TI - Non-operative management for ruptured splenule in haemodynamically stable patients previously splenectomized. PMID- 24754730 TI - Enhancement of the cytotoxicity and selectivity of doxorubicin to hepatoma cells by synergistic combination of galactose-decorated gamma-poly(glutamic acid) nanoparticles and low-intensity ultrasound. AB - Specific drug delivery to solid tumors remains one of the challenges in cancer therapy. The aim of this study was to combine three drug-targeting strategies, polymer-drug conjugate, ligand presentation and ultrasound treatment, to enhance the efficacy and selectivity of doxorubicin (DXR) to hepatoma cells. The conjugation of DXR to gamma-poly(glutamic acids) (gamma-PGA) decreased the cytotoxicity of DXR, while the conjugation of galactosamine (Gal) to the gamma PGA-DXR conjugate restored the cytotoxic efficacy of DXR on hepatoma cells due to increased uptake of DXR. Furthermore, low-intensity ultrasound treatment increased the cell-killing ability of gamma-PGA-DXR conjugates by 20%. The in vitro results showed the potential of the gamma-PGA-DXR-Gal conjugate for future clinical applications. PMID- 24754731 TI - Nebulized colistin for non-cystic fibrosis bronchiectasis: deja vu all over again? PMID- 24754732 TI - Using nursing intervention classification in an advance practice registered nurse led preventive model for adults aging with developmental disabilities. AB - PURPOSE: To describe the most frequently reported and the most central nursing interventions in an advance practice registered nurse (APRN)-led in-home preventive intervention model for adults aging with developmental disabilities using the Nursing Intervention Classification (NIC) system. METHODS: A descriptive data analysis and a market basket analysis were conducted on de identified nominal nursing intervention data from two home visits conducted by nurse practitioners (NPs) from October 2010 to June 2012 for 80 community dwelling adults with developmental disabilities, ages 29 to 68 years. RESULTS: The mean number of NIC interventions was 4.7 in the first visit and 6.0 in the second visit and last visit. NPs reported 45 different intervention types as classified using a standardized language, with 376 in Visit One and 470 in Visit Two. Approximately 85% of the sample received the Health education intervention. The market basket analysis revealed common pairs, triples, and quadruple sets of interventions in this preventive model. The NIC nursing interventions that occurred together repeatedly were: Health education, Weight management, Nutrition management, Health screening, and Behavior management. CONCLUSIONS: Five NIC interventions form the basis of an APRN-led preventive intervention model for individuals aging with lifelong disability, with health education as the most common intervention, combined with interventions to manage weight and nutrition, promote healthy behaviors, and encourage routine health screening. Less frequently reported NIC interventions suggest the need to tailor prevention to individual needs, whether acute or chronic. CLINICAL RELEVANCE: APRNs employing prevention among adults aging with developmental disabilities must anticipate the need to focus on health education strategies for health promotion and prevention as well as tailor and target a patient-centered approach to support self management of health to promote healthy aging in place. These NIC interventions serve not only as a guide for planning preventive interventions, but for designing nursing curricula to reduce health disparities among people with varying learning needs. PMID- 24754733 TI - Vaginal fluid IL-6 and IL-8 levels in pregnancies complicated by preterm prelabor membrane ruptures. AB - OBJECTIVE: To determine the vaginal fluid interleukin (IL)-6 and IL-8 concentrations in pregnancies complicated by preterm prelabor rupture of membranes and their correlation to microbial invasion of the amniotic cavity (MIAC) as well as histological chorioamnionitis (HCA). METHODS: Sixty-eight women with singleton pregnancies were included in this study. Vaginal fluid was collected at the time of admission. IL-6 and IL-8 concentrations in the vaginal fluid were determined using ELISA. RESULT: Women with MIAC had higher vaginal fluid IL-6 levels compared to those without MIAC (with MIAC: median 374 pg/mL versus without MIAC: median 174 pg/mL; p = 0.03). IL-8 levels were higher in women with MIAC only in the crude analysis but not after adjustment for gestational age. There was no difference in the IL-6 and IL-8 concentrations between those with and without HCA. Women with both MIAC and HCA had higher IL-6 vaginal fluid levels than those without both MIAC and HCA (with MIAC and HCA: median 466 pg/mL versus without MIAC and HCA: median 178 pg/mL; p = 0.02). IL-8 levels were higher in women with MIAC and HCA only in the crude analysis but not after adjustment for gestational age. CONCLUSIONS: Vaginal fluid IL-6 but not IL 8 levels reflect the presence of MIAC and both MIAC and HCA. PMID- 24754734 TI - Relevance of labor room fetal autopsy in increasing its acceptance. AB - BACKGROUND: Fetal autopsy is included in the basic protocol of investigating a perinatal death, parental refusal is the main reason for its low rate. AIM: To increase acceptance of fetal autopsy and to provide better counselling to the couple regarding risk of recurrence in future pregnancies. MATERIALS AND METHODS: All cases with antenatally diagnosed congenital anomaly resulting in stillbirth or termination before 20 weeks were offered fetal autopsy and it was performed in labor room itself by the fetal medicine specialist after consents. External and internal examination, photograph, infantogram and karyotyping were done, and relevant tissue was sent for histopathology. Correlation between the ultrasound and autopsy finding was done. RESULTS: Total 674 cases of antenatally detected major congenital anomaly were included in the study. Out of 403 cases of stillbirth and abortion, consent for autopsy was given in 312. Most common defect was cranio-vertebral defect followed by genitourinary anomaly. The autopsy finding correlated with USG findings fully in 63.5% cases, there were additional findings altering diagnosis in 24.7% cases, the diagnosis completely changed in 11.8% cases. CONCLUSION: Autopsy if done in labor room increases its acceptance by the couple. Additional findings on autopsy helped in reaching at diagnosis and counseling accordingly. PMID- 24754736 TI - VEGF, VEGFR3, and PDGFRB protein expression is influenced by RAS mutations in medullary thyroid carcinoma. AB - BACKGROUND: Tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical results in medullary thyroid carcinoma (MTC) patients. However, the considerable variability in patient response to treatment with TKIs remains largely unexplained. There is evidence that it could be due, at least in part, to alterations in genes associated with the disease via their effect on the expression of TKI targets. The objective of this study was to evaluate the influence of RAS mutations on the expression levels in MTC tumors of eight key TKI target proteins. METHODS: We assessed by immunohistochemistry the expression of EGFR, KIT, MET, PDGFRB, VEGF, VEGFR1, VEGFR2, and VEGFR3 in a series of 84 primary MTC tumors that had previously been molecularly characterized, including 14 RAS-positive, 18 RET(M918T)-positive, and 24 RET(C634)-positive tumors, as well as 15 wild-type tumors with no mutations in the RET or RAS genes. RESULTS: In contrast to RET-positive tumors, RAS-positive tumors expressed neither PDGFRB nor MET (p=0.0060 and 0.047, respectively). Similarly, fewer RAS-positive than RET-related tumors expressed VEGFR3 (p=0.00062). Finally, wild-type tumors expressed VEGF more often than both RAS- and RET-positive tumors (p=0.0082 and 0.011, respectively). CONCLUSIONS: This is the first study identifying that the expression of TKI targets differs according to the presence of RAS mutations in MTC. This information could potentially be used to select the most beneficial TKI treatment for these patients. PMID- 24754735 TI - Design considerations of iron-based nanoclusters for noninvasive tracking of mesenchymal stem cell homing. AB - Stem-cell-based therapies have attracted considerable interest in regenerative medicine and oncological research. However, a major limitation of systemic delivery of stem cells is the low homing efficiency to the target site. Here, we report a serendipitous finding that various iron-based magnetic nanoparticles (MNPs) actively augment chemokine receptor CXCR4 expression of bone-marrow derived mesenchymal stem cells (MSCs). On the basis of this observation, we designed an iron-based nanocluster that can effectively label MSCs, improve cell homing efficiency, and track the fate of the cells in vivo. Using this nanocluster, the labeled MSCs were accurately monitored by magnetic resonance imaging and improved the homing to both traumatic brain injury and glioblastoma models as compared to unlabeled MSCs. Our findings provide a simple and safe method for imaging and targeted delivery of stem cells and extend the potential applications of iron-based MNPs in regenerative medicine and oncology. PMID- 24754737 TI - Terminal hypothermic Tau.P301L mice have increased Tau phosphorylation independently of glycogen synthase kinase 3alpha/beta. AB - The microtubule-associated protein Tau is responsible for a large group of neurodegenerative disorders, known as tauopathies, including Alzheimer's disease. Tauopathy result from augmented and/or aberrant phosphorylation of Tau. Besides aging and various genetic and epigenetic defects that remain largely unknown, an important non-genetic agent that contributes is hypothermia, eventually caused by anesthesia. Remarkably, tauopathy in brains of hibernating mammals is not pathogenic, and, because it is fully reversible, is even considered to be neuroprotective. Here, we assessed the terminal phase of Tau.P301L mice and bigenic crosses with mice lacking glycogen synthase kinase 3 (GSK3)alpha completely, or GSK3beta specifically in neurons. We also analysed biGT bigenic mice that co-express Tau.P301L with GSK3beta.S9A and develop severe forebrain tauopathy with age. We found that the precocious mortality of Tau.P301L mice was typified by hypothermia that aggravated Tau phosphorylation, but, surprisingly, independently of GSK3alpha/beta. The important contribution of hypothermia at the time of death of mice with tauopathy suggests that body temperature should be included as a parameter in the analysis of pre-clinical models, and, by extension, in patients suffering from tauopathy. PMID- 24754738 TI - Solubility of fructose in water-ethanol and water-methanol mixtures by using H bonding models. AB - The solubility of fructose in water-ethanol and water-methanol mixtures and the saturated density of each solution at 20, 30, and 40 degrees C over a range of water mass percentage have been measured. Also, a new modification of the Wilson model has been proposed to describe solubility data satisfactorily. The H-UNIQUAC and H-NRTL models were applied and a comparison between these 3 models was carried out. These 3 models were used to estimate the experimental data which was reported in this study. The comparison of the results showed that the H-Wilson model has the lowest AAD% between these 3 models in correlating the solubility data and the saturated density. PMID- 24754739 TI - Electrospun doping of carbon nanotubes and platinum nanoparticles into the beta phase polyvinylidene difluoride nanofibrous membrane for biosensor and catalysis applications. AB - A novel beta-phase polyvinylidene difluoride (PVDF) nanofibrous membrane decorated with multiwalled carbon nanotubes (MWCNTs) and platinum nanoparticles (PtNPs) was fabricated by an improved electrospinning technique. The morphology of the fabricated PVDF-MWCNT-PtNP nanofibrous membrane was observed by scanning electron microscopy, and the formation of high beta-phase in the hybrid nanofibrous membrane was investigated by Fourier transform infrared spectroscopy and differential scanning calorimetry. The uniform dispersion of MWCNTs and PtNPs in the PVDF hybrid nanofibrous membrane and their interaction were explored by transmission electron microscopy and X-ray diffraction. For the first time, we utilized this created PVDF-MWCNT-PtNP nanofibrous membrane for biosensor and catalysis applications. The nonenzymatic amperometric biosensor with highly stable and sensitive, and selective detection of both H2O2 and glucose was successfully fabricated based on the electrospun PVDF-MWCNT-PtNP nanofibrous membrane. In addition, the catalysis of the hybrid nanofibrous membrane for oxygen reduction reaction was tested, and a good catalysis performance was found. We anticipate that the strategies utilized in this work will not only guide the further design of functional nanofiber-based biomaterials and biodevices but also extend the potential applications in energy storage, cytology, and tissue engineering. PMID- 24754740 TI - Human proteins with target sites of multiple post-translational modification types are more prone to be involved in disease. AB - Many proteins can be modified by multiple types of post-translational modifications (Mtp-proteins). Although some post-translational modifications (PTMs) have recently been found to be associated with life-threatening diseases like cancers and neurodegenerative disorders, the underlying mechanisms remain enigmatic to date. In this study, we examined the relationship of human Mtp proteins and disease and systematically characterized features of these proteins. Our results indicated that Mtp-proteins are significantly more inclined to participate in disease than proteins carrying no known PTM sites. Mtp-proteins were found significantly enriched in protein complexes, having more protein partners and preferred to act as hubs/superhubs in protein-protein interaction (PPI) networks. They possess a distinct functional focus, such as chromatin assembly or disassembly, and reside in biased, multiple subcellular localizations. Moreover, most Mtp-proteins harbor more intrinsically disordered regions than the others. Mtp-proteins carrying PTM types biased toward locating in the ordered regions were mainly related to protein-DNA complex assembly. Examination of the energetic effects of PTMs on the stability of PPI revealed that only a small fraction of single PTM events influence the binding energy of >2 kcal/mol, whereas the binding energy can change dramatically by combinations of multiple PTM types. Our work not only expands the understanding of Mtp proteins but also discloses the potential ability of Mtp-proteins to act as key elements in disease development. PMID- 24754741 TI - Comparison of search strategies in systematic reviews of adverse effects to other systematic reviews. AB - BACKGROUND: Research indicates that the methods used to identify data for systematic reviews of adverse effects may need to differ from other systematic reviews. OBJECTIVES: To compare search methods in systematic reviews of adverse effects with other reviews. METHODS: The search methodologies in 849 systematic reviews of adverse effects were compared with other reviews. RESULTS: Poor reporting of search strategies is apparent in both systematic reviews of adverse effects and other types of systematic reviews. Systematic reviews of adverse effects are less likely to restrict their searches to MEDLINE or include only randomised controlled trials (RCTs). The use of other databases is largely dependent on the topic area and the year the review was conducted, with more databases searched in more recent reviews. Adverse effects search terms are used by 72% of reviews and despite recommendations only two reviews report using floating subheadings. CONCLUSIONS: The poor reporting of search strategies in systematic reviews is universal, as is the dominance of searching MEDLINE. However, reviews of adverse effects are more likely to include a range of study designs (not just RCTs) and search beyond MEDLINE. PMID- 24754742 TI - Lactobacillus salivarius Ren prevent the early colorectal carcinogenesis in 1, 2 dimethylhydrazine-induced rat model. AB - AIMS: The objective of this study was to investigate the impact of Lactobacillus salivarius Ren (LS) on modulating colonic micro flora structure and influencing host colonic health in a rat model with colorectal precancerous lesions. METHODS AND RESULTS: Male F344 rats were injected with 1, 2-dimethylhydrazine (DMH) and treated with LS of two doses (5 * 10(8) and 1 * 10(10) CFU kg(-1) body weight) for 15 weeks. The colonic microflora profiles, luminal metabolites, epithelial proliferation and precancerous lesions [aberrant crypt foci (ACF)] were determined. A distinct segregation of colonic microflora structures was observed in LS-treated group. The abundance of one Prevotella-related strain was increased, and the abundance of one Bacillus-related strain was decreased by LS treatment. These changes were accompanied by increased short-chain fatty acid levels and decreased azoreductase activity. LS treatment also reduced the number of ACF by c. 40% and suppressed epithelial proliferation. CONCLUSIONS: Lactobacillus salivarius Ren improved the colonic microflora structures and the luminal metabolisms in addition preventing the early colorectal carcinogenesis in DMH-induced rat model. SIGNIFICANCE AND IMPACT OF THE STUDY: Colonic microflora is an important factor in colorectal carcinogenesis. Modulating the structural shifts of microflora may provide a novel option for preventing colorectal carcinogenesis. This study suggested a potential probiotic-based approach to modulate the intestinal microflora in the prevention of colorectal carcinogenesis. PMID- 24754743 TI - Influence of phosphate and silica on U(VI) precipitation from acidic and neutralized wastewaters. AB - Uranium speciation and physical-chemical characteristics were studied in solids precipitated from synthetic acidic to circumneutral wastewaters in the presence and absence of dissolved silica and phosphate to examine thermodynamic and kinetic controls on phase formation. Composition of synthetic wastewater was based on disposal sites 216-U-8 and 216-U-12 Cribs at the Hanford site (WA, USA). In the absence of dissolved silica or phosphate, crystalline or amorphous uranyl oxide hydrates, either compreignacite or meta-schoepite, precipitated at pH 5 or 7 after 30 d of reaction, in agreement with thermodynamic calculations. In the presence of 1 mM dissolved silica representative of groundwater concentrations, amorphous phases dominated by compreignacite precipitated rapidly at pH 5 or 7 as a metastable phase and formation of poorly crystalline boltwoodite, the thermodynamically stable uranyl silicate phase, was slow. In the presence of phosphate (3 mM), meta-ankoleite initially precipitated as the primary phase at pH 3, 5, or 7 regardless of the presence of 1 mM dissolved silica. Analysis of precipitates by U LIII-edge extended X-ray absorption fine structure (EXAFS) indicated that "autunite-type" sheets of meta-ankoleite transformed to "phosphuranylite-type" sheets after 30 d of reaction, probably due to Ca substitution in the structure. Low solubility of uranyl phosphate phases limits dissolved U(VI) concentrations but differences in particle size, crystallinity, and precipitate composition vary with pH and base cation concentration, which will influence the thermodynamic and kinetic stability of these phases. PMID- 24754744 TI - Impact of iron deficiency on hemoglobin A2% in obligate beta-thalassemia heterozygotes. AB - INTRODUCTION: The potential impact of concomitant iron deficiency on hemoglobin A2 (HbA2)-based identification of beta-thalassemia trait (betaTT) is a worrisome issue for screening laboratories. This is especially true for resource constrained settings where iron deficiency is widespread and molecular confirmatory tests for borderline low HbA2 values may be unavailable. METHODS: Obligate betaTT carrier individuals (n = 752) were identified during screening studies on the parents of thalassemia major patients. HbA2%, complete blood counts and serum iron, ferritin and transferrin saturation were studied. Iron deficient individuals (n = 135) with normal range HbA2% were taken as controls. RESULTS: Concomitant iron deficiency (defined as ferritin <=15 ng/mL and/or transferrin saturation <=15%) was present in 20.7% (156/752) betaTT cases, that is, 33.3% females (122/366) and 8.8% males with betaTT (34/386). Mean HbA2 in iron-replete betaTT was 5.4 +/- 0.8 (range 3.1-7.9) and in iron-deficient betaTT was 5.4 +/- 0.9 (range 3.3-7.6). HbA2 < 4.0% was found in 23/752 (3.1%) betaTT: 13/595 iron-replete (2.2%) and 10/157 (6.4%) iron-deficient betaTT individuals. However, five of the 10 iron-deficient betaTT cases carried the silent CAP+1 (A>C) beta-thalassemia allele accounting for the borderline HbA2%. On a separate analysis, all five severely anemic betaTT (Hb < 80 g/L) and 16/17 betaTT with severe hypoferritinemia (<5 ng/mL) had HbA2 > 4.5%. The single case with serum ferritin 4.8 ng/mL and HbA2 3.3% showed a CAP+1 (A>C) mutation. CONCLUSIONS: Iron deficiency was prevalent among north Indian betaTT individuals, especially women. After adjusting for other causes of low HbA2 in betaTT, iron deficiency, even when very severe, was very unlikely to interfere significantly with HbA2-based identification of betaTT. PMID- 24754745 TI - Thromboembolism in inflammatory bowel disease: results from a prospective, population-based European inception cohort. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) have proven an increased risk of venous thromboembolism (VTE), particularly when hospitalized. The estimate of the true risk varies considerably between studies, primarily due to differences in methodology. We set out to determine the incidence of VTE in a population-based European inception cohort. METHODS: IBD patients were incepted into a cohort that was prospectively followed from the early 1990s to the early 2000s. A total of 1145 patients were followed for a total of 10,634 patient-years (p.y.). RESULTS: A total of 19 thromboembolic events were identified - 13 deep vein thrombosis and 6 with pulmonary embolism. The incidence rate of VTE was 1.8 per 1000 p.y. CONCLUSION: The risk of VTE was elevated in this IBD cohort but lower than previously reported. The highest risk was seen in hospitalized patients, but corticosteroids-requiring disease in outpatients also conferred some risk. PMID- 24754746 TI - Allelic variants of PRDM9 associated with high hyperdiploid childhood acute lymphoblastic leukaemia. PMID- 24754747 TI - Refining stability and dissolution rate of amorphous drug formulations. AB - INTRODUCTION: Poor aqueous solubility of active pharmaceutical ingredients (APIs) is one of the main challenges in the development of new small molecular drugs. Additionally, the proportion of poorly soluble drugs among new chemical entities is increasing. The transfer of a crystalline drug to its amorphous counterpart is often seen as a potential solution to increase the solubility. However, amorphous systems are physically unstable. Therefore, pharmaceutical formulations scientists need to find ways to stabilise amorphous forms. AREAS COVERED: The use of polymer-based solid dispersions is the most established technique for the stabilisation of amorphous forms, and this review will initially focus on new developments in this field. Additionally, newly discovered formulation approaches will be investigated, including approaches based on the physical restriction of crystallisation and crystal growth and on the interaction of APIs with small molecular compounds rather than polymers. Finally, in situ formation of an amorphous form might be an option to avoid storage problems altogether. EXPERT OPINION: The diversity of poorly soluble APIs formulated in an amorphous drug delivery system will require different approaches for their stabilisation. Thus, increased focus on emerging techniques can be expected and a rational approach to decide the correct formulation is needed. PMID- 24754748 TI - Asymmetric catalysis with substitutionally labile yet stereochemically stable chiral-at-metal iridium(III) complex. AB - A metal-coordination-based high performance asymmetric catalyst utilizing metal centrochirality as the sole element of chirality is reported. The introduced substitutionally labile chiral-at-metal octahedral iridium(III) complex exclusively bears achiral ligands and effectively catalyzes the enantioselective Friedel-Crafts addition of indoles to alpha,beta-unsaturated 2-acyl imidazoles (19 examples) with high yields (75%-99%) and high enantioselectivities (90-98% ee) at low catalyst loadings (0.25-2 mol %). Counterintuitively, despite its substitutional lability, which is mechanistically required for coordination to the 2-acyl imidazole substrate, the metal-centered chirality is maintained throughout the catalysis. This novel class of reactive chiral-at-metal complexes will likely be of high value for a large variety of asymmetric transformations. PMID- 24754749 TI - Medicines' management: a public health problem on nursing's agenda. PMID- 24754750 TI - Nurses' spontaneous reporting of adverse drug reactions: expert review of routine reports. AB - AIM: The aims of this study were to analyse spontaneously reported adverse drug reactions according to their previous description, seriousness, causality and the reporting professional. BACKGROUND: Previous findings showed that fewer nurses than physicians and pharmacists report adverse drug reactions. This is not attributed to any lack of ability in identifying adverse drug reactions. METHOD: Adverse drug reactions received by the Central Portugal Regional Pharmacovigilance Unit, between 2001 and 2011, were studied. Certain and probable adverse drug reactions were included to test differences between professional groups for serious and non-serious adverse drug reactions. RESULTS: The Central Portugal Regional Pharmacovigilance Unit received 1014 adverse drug reactions. Fifty-four nurses reported 66 adverse drug reactions, whereas 232 physicians and 145 pharmacists reported 589 and 357 adverse drug reactions, respectively. Considering the number of practising professionals, it was estimated that 0.55% of nurses, 3.96% of physicians and 7.08% of pharmacists have reported an adverse drug reaction. Of the 633 adverse drug reactions assessed as certain or probable, 46 (21 serious), 387 (192 serious) and 198 (77 serious) were reported from nurses, physicians and pharmacists, respectively. There were no differences in the reporting of serious adverse drug reactions among nurses, physicians and pharmacists. CONCLUSIONS: Nurses are able to identify serious adverse drug reactions although they report less than other professionals. IMPLICATIONS FOR NURSING MANAGEMENT: Nurses need to increase their involvement in spontaneous reporting schemes by taking responsibility for routinely reporting suspected adverse drug reactions. PMID- 24754751 TI - In regard to 'Nurse manager succession planning: synthesis of evidence'. PMID- 24754752 TI - Response to Warshawsky et al. PMID- 24754753 TI - Mutualistic fungal endophytes in the Triticeae - survey and description. AB - Grasses of the tribe Triticeae were screened to determine the presence of mutualistic epichloae fungal endophytes. Over 1500 accessions, from more than 250 species, encompassing 22 genera within the Triticeae were screened using immunodetection and direct staining/microscopy techniques. Only two genera, Elymus and Hordeum, were identified as harbouring epichloae endophytes with accessions native to a range of countries including Canada, China, Iran, Kazakhstan, Kyrgyzstan, Mongolia, Russia and the USA. Genetic analysis based on simple sequence repeat data revealed that the majority of endophytes cluster according to geographical regions rather than to host species; many strains isolated from Hordeum grouped with those derived from Elymus, and amongst the Elymus-derived strains, there was no clear correspondence between clustering topology and host species. This is the first detailed survey demonstrating the genetic diversity of epichloae endophytes within the Triticeae and highlights the importance of germplasm centres for not only preserving the genetic diversity of plant species but also the beneficial microorganisms they may contain. PMID- 24754754 TI - Concerted or stepwise mechanism? New insight into the water-mediated neutral hydrolysis of carbonyl sulfide. AB - The water-mediated neutral hydrolysis mechanism of carbonyl sulfide (OCS) has been re-examined using the hybrid supramolecule/continuum models with n = 2-8 explicit water cluster at the level of MP2(fc)(CPCM)/6 311++G(d,p)//MP2(fc)(CPCM)/6-31+G(d). Present calculations indicate that the potential energy surface in water solution is different from the one in the gas phase, and only stepwise mechanism is observed in aqueous solution, i.e., monothiocarbonic acid (H2CO2S) is formed via monothiocarbonate (OCSOH(-), MTC) and its counterion, protonated water cluster, (H2O)nH3O(+). The predicted rate determining step (RDS) barrier for the stepwise mechanism in water solution, about 90 kJ/mol, shows good agreement with the experimental values, 83.7-96.2 kJ/mol using six- or eight-water model including two cooperative water molecules. Moreover, two reaction pathways, the nucleophilic addition of water molecule across the C?O or the C?S bond of OCS are competitive. PMID- 24754755 TI - Dynamic nuclear spin polarization of liquids and gases in contact with nanostructured diamond. AB - Optical pumping of spin polarization can produce almost complete spin order but its application is restricted to select atomic gases and condensed matter systems. Here, we theoretically investigate a novel route to nuclear spin hyperpolarization in arbitrary fluids in which target molecules are exposed to polarized paramagnetic centers located near the surface of a host material. We find that adsorbed nuclear spins relax to positive or negative polarization depending on the average paramagnetic center depth and nanoscale surface topology. For the particular case of optically pumped nitrogen-vacancy centers in diamond, we calculate strong nuclear spin polarization at moderate magnetic fields provided the crystal surface is engineered with surface roughness in the few-nanometer range. The equilibrium nuclear spin temperature depends only weakly on the correlation time describing the molecular adsorption dynamics and is robust in the presence of other, unpolarized paramagnetic centers. These features could be exploited to polarize flowing liquids or gases, as we illustrate numerically for the model case of a fluid brought in contact with an optically pumped diamond nanostructure. PMID- 24754757 TI - Introduction to this special issue: The Gaps and Pathways Project for medically at-risk older drivers. PMID- 24754758 TI - Screening and assessment tools for determining fitness to drive: a review of the literature for the pathways project. AB - With a brief introduction, 10 tables summarize the findings from the literature describing screening and assessment tools used with older adults to identify risk or determine fitness to drive. With a focus on occupational therapy's duty to address driving as a valued activity, this paper offers information about tools used by occupational therapy practitioners across practice settings and specialists in driver rehabilitation. The tables are organized into groups of key research studies of assessment tools, screening batteries, tools used in combination (i.e., as a battery), driving simulation as an assessment tool, and screening/assessment for individuals with stroke, vision impairment, Parkinson's disease, dementia, and aging. Each table has a summary of important concepts to consider as occupational therapists choose the methods and tools to evaluate fitness to drive. PMID- 24754759 TI - Driving experts address expanding access through pathways to older driver rehabilitation services: expert meeting results and implications. AB - As one of the first papers in this special issue, this paper describes the expert meeting that established the goals of the Gaps and Pathways Project. Through a unique Audience response system (ARS), this expert panel established over 60 consensus statements grounded in evidence of either research literature or expert clinical practice. The paper describes the process and identifies the outcomes of the panel including gaps of need for occupational therapy service and potential ideas for future research. PMID- 24754760 TI - Consensus statements for screening and assessment tools. AB - Occupational therapists, both generalists and specialists, have a critical role in providing services to senior drivers. These services include evaluating fitness-to-drive, developing interventions to support community mobility, and facilitating the transition from driving to non-driving when necessary for personal and community safety. The evaluation component and decision-making process about fitness-to-drive are highly dependent on the use of screening and assessment tools. The purpose of this paper is to briefly present the rationale and context for 12 consensus statements about the usefulness and appropriateness of screening and assessment tools to determine fitness-to-drive, within the occupational therapy clinical setting, and their implications on community mobility. PMID- 24754761 TI - Consensus statements on driving for persons with dementia. AB - The presence of dementia can have a profound effect on a person's capacity for driving, and will lead to eventual cessation of driving and reliance on alternative transportation options. This paper offers evidence and discussion that affirm eight consensus statements related to drivers with dementia and the impact of dementia on the driving task. These statements offer guidance for occupational therapy practitioners when addressing driving and community mobility, a valued instrumental task of daily living. PMID- 24754762 TI - Consensus statements on driving in people with Parkinson's disease. AB - Parkinson's disease (PD) is a complex neurodegenerative disorder leading to motor and non-motor impairments, all of which can affect fitness to drive. The literature suggest that on-road and simulated driving performances are impaired in people with PD, as compared to healthy control drivers. Clear associations exist between impaired driving performance and contrast sensitivity, visual processing speed, and psychomotor speed. Prior to this review and expert panel process, no evidence-based guidelines have existed to help occupational therapy practitioners determining fitness to drive in those with PD. Three consensus statements are presented in this work to enable occupational therapy practitioners and other driver rehabilitation specialists to make fitness to drive determinations in people with PD. PMID- 24754763 TI - Driving for adults with acquired physical disabilities. AB - The purpose of this paper is to document and give context to consensus statements for drivers with physical disabilities, and specifically chronic obstructive pulmonary disease, by expert clinicians in driver rehabilitation and researchers in the area of driver assessment. A brief introduction to the profession of driver rehabilitation sets the context for how individuals with physically based impairments have facilitated the development of the specialty area. PMID- 24754764 TI - Driving simulators for occupational therapy screening, assessment, and intervention. AB - Simulation technology provides safe, objective, and repeatable performance measures pertaining to operational (e.g., avoiding a collision) or tactical (e.g., lane maintenance) driver behaviors. Many occupational therapy researchers and others are using driving simulators to test a variety of applications across diverse populations. A growing body of literature provides support for associations between simulated driving and actual on-road driving. One limitation of simulator technology is the occurrence of simulator sickness, but management strategies exist to curtail or mitigate its onset. Based on the literature review and a consensus process, five consensus statements are presented to support the use of driving simulation technology among occupational therapy practitioners. The evidence suggests that by using driving simulators occupational therapy practitioners may detect underlying impairments in driving performance, identify driving errors in at-risk drivers; differentiate between driving performance of impaired and healthy controls groups; show driving errors with absolute and relative validity compared to on-road studies; and mitigate the onset of simulator sickness. Much progress has been made among occupational therapy researchers and practitioners in the use of driving simulation technology; however, empirical support is needed to further justify the use of driving simulators in clinical practice settings as a valid, reliable, clinical useful, and cost effective tool for driving assessment and intervention. PMID- 24754765 TI - Consensus statements on occupational therapy ethics related to driving. AB - As part of an expert panel convened to examine evidence and practice related to diverse aspects of driving evaluation and rehabilitation, consensus statements were developed on ethics. This paper provides context for the ethical obligation of practitioners to assess and make recommendations about the ability of clients to safely perform the activity of driving. It highlights key articles from the literature as well as principles from the Occupational Therapy Code of Ethics and Ethics Standards (2010). The statements support the importance of identifying impairments affecting driving, which could result in harm to the client as well as to the public. The ethical and professional obligation of practitioners to evaluate, make recommendations, and possibly report and/or refer to a driver rehabilitation specialist for further services is reinforced. PMID- 24754766 TI - Consensus statements on occupational therapy education and professional development related to driving and community mobility. AB - Professional and postprofessional education for occupational therapy practitioners in the area of driving and community mobility has been inconsistent and not sufficient to meet the growing community mobility needs of the aging population. This article reviews the current expectations of entry-level occupational therapy education, the postprofessional credentialing opportunities, and the professional development path for occupational therapy practitioners. Finally, consensus statements are presented to move both entry-level and professional education forward in the area of driving and community mobility. PMID- 24754767 TI - Note from editor. PMID- 24754768 TI - Driver rehabilitation programs: defining program models, services, and expertise. AB - This paper highlights the critical need for a diverse span of services targeted at older drivers that is clear and understandable to health care professionals, service providers, and consumers. The paper describes how a panel of expert driver rehabilitation specialists and researchers on older drivers affirmed consensus statements addressing the need for clarification of terms and services. It also presents a new document that describes a spectrum of driver services from education to specific driver rehabilitation services. The document will provide consumers, referral sources, payers, and stakeholders invested in older drivers' services, with the information to refer the right people to the right service at the right time. PMID- 24754769 TI - Can clinicians, researchers, and driver licensing officials build a shared vocabulary? AB - Communication through a shared understanding is essential with multidisciplinary groups. The objective of this paper is to discuss and illustrate how licensing authorities, researchers, practitioners (clinicians), and consumers do not share the same understanding of key terminology related to safe and competent driving. Ongoing and planned work that aims to develop a resource to promote shared understanding of terms relating to driver testing, evaluation, and rehabilitation is then highlighted. PMID- 24754770 TI - Decision tool for clients with medical issues: a framework for identifying driving risk and potential to return to driving. AB - This paper offers occupational therapy generalists and specialists a new framework by which to consider clinical evaluation data and an older adult's driving risk and potential to resume this previously learned skill. Based on Michon's model describing the hierarchy of driving levels, clinical questions identify the factors that may affect a client's fitness to drive. The first part is intended to support clinical judgment of whether a client needs a driving evaluation by a driver rehabilitation specialist. The second part offers a framework to organize clinical data that are already known and determine what other evaluation information is justified and necessary to make a driving recommendation. Methods and rational for use are discussed. PMID- 24754771 TI - Gaps and Pathways Project: driving pathways by diagnosis sheets. AB - This paper describes the development and use of information sheets for occupational therapy practitioners to use as guides for evaluation and intervention planning to address their client's driving and community mobility needs. Called Driving Pathways by Diagnosis Sheets, the information assists therapists with direction to connect impairment to driving risk and incorporate intervention to client goals and priorities related to driving and community mobility. An example of one of the sheets for the diagnosis of arthritis is highlighted and implications for use are discussed. PMID- 24754772 TI - Documentation and reimbursable for driver rehabilitation services. AB - Driving is the method of choice to maintain independent community mobility for most older adults. Therefore, occupational therapy practitioners need to evaluate and provide intervention for driver rehabilitation services. Since reimbursement is often seen as a barrier to providing these services, this paper underscores the value of occupational therapy practitioners providing driver rehabilitation services. Appropriate documentation and guidelines for reimbursement from Medicare are addressed with examples of how occupational therapy driver rehabilitation services can be funded by third party payers. PMID- 24754773 TI - Summary of an evidence based review on interventions for medically at risk older drivers. AB - This paper offers a summary based on the findings of an evidence-based review previously conducted to determine the effectiveness of interventions for medically at risk drivers with stroke, visual deficits, or cognitive decline. Specifically, this work offers occupational therapy practitioners clinically applicable recommendations and intervention strategies. Because driving is a key instrumental activity of daily living for continued independence, autonomy, and quality of life, the recommendations provided in this review may enable the clinical reasoning and decision-making skills of occupational therapists working with medically at risk older drivers. PMID- 24754776 TI - Abstracts of the RACS Annual Scientific Congress and ANZCA Annual Scientific Meeting, 5-9 May 2014, Singapore. PMID- 24754775 TI - Submersion and hypoxia inhibit ciliated cell differentiation in a notch-dependent manner. AB - The epithelium that lines the conducting airways is composed of several distinct cell types that differentiate from common progenitor cells. The signals that control fate selection and differentiation of ciliated cells, a major component of the epithelium, are not completely understood. Ciliated cell differentiation can be accomplished in vitro when primary normal human bronchial epithelial (NHBE) cells are cultured at an air-liquid interface, but is inhibited when NHBE cells are cultured under submerged conditions. The mechanism by which submersion prevents ciliogenesis is not understood, but may provide clues to in vivo regulation of ciliated cell differentiation. We hypothesized that submersion creates a hypoxic environment that prevents ciliated cell differentiation by blocking the gene expression program required for ciliogenesis. This was confirmed by showing that expression of multicilin and Forkhead box J1, key factors needed for ciliated cell differentiation, was inhibited when NHBE cells were cultured in submerged and hypoxic conditions. Multicilin and Forkhead box J1 expression and ciliated cell differentiation were restored in submerged and hypoxic cells upon treatment with the gamma-secretase inhibitor, N-[(3,5 difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT), which suggested that Notch signaling was involved. Overexpression of Notch intracellular domain inhibited differentiation in the presence of DAPT, confirming the role of Notch signaling. These results indicate that submersion and hypoxia prevent ciliated cell differentiation by maintaining Notch signaling, which represses genes necessary for ciliogenesis. These data provide new insights into the molecular mechanisms that control human bronchial differentiation. PMID- 24754778 TI - Perception of spanish nursing staff on the use of physical restraints. AB - PURPOSE: To examine the perception of registered nurses and nursing assistants regarding the use of physical restraints with residents of nursing homes located in four of the regions of Spain; and to evaluate the relationship of these perceptions to the staff respondents' level of training. DESIGN: Cross-sectional multicenter and correlational study. The research was conducted in 2013 in 19 Spanish nursing homes with 2,940 residential beds. A total of 785 nurses (170 registered nurses and 615 nursing assistants) participated in the study. METHODS: The Perception of Restraint Use Questionnaire (PRUQ), consisting of 17 of the most cited reasons for using these devices, was used, as was a questionnaire capturing the sociodemographic characteristics and educational or experience level of staff respondents. FINDINGS: Nurses reported the most important uses for restraints as prevention of falls and avoidance of medical device interference. As indicated by an average PRUQ score of 3.47, staff respondents supported restraint use, especially nursing assistants (3.59) as compared to registered nurses (3.00). With regard to training: 83.7% had participated in little, if any, training and only 29.2% had read three or more documents related to restraint use; 66.6% believed that their training was inadequate. No correlation was found between the results of the PRUQ and the respondents' sociodemographic characteristics or participation in training activities. No differences were found among nurses by region. CONCLUSIONS: In contrast to papers published in other countries, nurses in this study still consider it necessary to apply restraints in everyday practice. The education of nursing staff regarding restraint and knowledge of alternatives is needed; they should at least be aware of international standards of care regarding physical restraint use. CLINICAL RELEVANCE: Most of the staff perceived their training related to the use of these devices as insufficient. Nursing assistants considered the use of restraints more important than did the registered nurses. PMID- 24754779 TI - Characterization by electrochemical and X-ray photoelectron spectroscopic measurements and quantum chemical calculations of N-containing functional groups introduced onto glassy carbon electrode surfaces by electrooxidation of a carbamate salt in aqueous solutions. AB - The present paper deals with characterization of an aminated glassy carbon electrode (GCE) surface obtained by electrooxidation of ammonium carbamate in its aqueous solution (amination reaction) using electrochemical and XPS methods. From the XPS analysis, it was found that not only the primary amine group (i.e., aniline-like aromatic amine moiety) but also other N-containing functional groups (i.e., the secondary amine-like moieties containing pyrrole-type nitrogen and quaternary amine-like moieties containing graphitic quaternary nitrogen) are introduced onto the GCE surface during the amination reaction. Moreover, the presence of the primary and secondary amine groups was ascertained based on the difference in the reactivity of a Michael reaction-type addition reaction of amine groups introduced onto the GCE surface with quinone compounds having a carbonyl group and a C?C double bond (i.e., in this case, 1,2-benzoquinone which is in situ prepared by the electrooxidation of catechol) and on the electrochemical redox response of the introduced benzoquinones. This electrochemical treatment of aminated GCE with catechol led to catechol-grafted aminated GCE which indicated two surface redox couples (i.e., the Ia/Ic and IIa/IIc couples with formal potentials of E(0)'(Ia/Ic) = ca. 0.17 V and E(0)'(IIa/IIc) = ca. 0.03 V vs Ag|AgCl|KCl(sat.) in phosphate buffer solution (pH 7)). From the electrochemical behavior of catechols grafted onto the maleimide treated aminated GCE and on the methylamine-treated GCE, it was found that the catechol associated with the primary amine groups gave the IIa/IIc redox peaks, while the catechol bound to the secondary amine groups gave the Ia/Ic redox peaks. Further electrochemical measurements and quantum chemical calculations concluded that the IIa/IIc redox peaks are ascribed to the surface-redox reaction of the 1,2-dihydroxybenzene/1,2-benzoquinone couple, while those of the 1,2 dihydroxybenzene/1,2-benzoquinone and the N-(4'-hydroxyphenyl)-p aminophenol/indophenol couples can be associated with the Ia/Ic redox peaks. PMID- 24754780 TI - How good is post-biopsy multiparametric magnetic resonance imaging in detecting and characterising the index lesion of localised prostate cancer? AB - OBJECTIVE: The aim of this study was to evaluate the accuracy of multiparametric endorectal magnetic resonance imaging (mp-MRI) in detecting and characterising the largest tumour lesion, which is defined as the index tumour of prostate cancer. MATERIAL AND METHODS: A total of 55 patients with proven histological prostate cancer underwent post-biopsy MRI at 1.5 T and subsequent radical prostatectomy. The maximum tumour diameter (MTD) of the index lesion was determined independently by MRI and histopathology in a prospective manner. The detection rate of the index lesion, the MTD and volume by pathology, and the pathological tumour (pT) stage were correlated with the MTD by MRI using Pearson's correlation. RESULTS: Pathohistology revealed 158 cancer foci. MRI detected 55 foci. The sensitivity, specificity, accuracy, and negative and positive predictive values of mp-MRI for index lesion detection were 89%, 100%, 90%, 44% and 100%, respectively. Three positive correlations were found: one between the MTD of the index lesion by MRI and the MTD by pathology (Pearson coefficient = 0.890, p < 0.01), a second between the MTD by MRI and the index tumour volume at pathology (Pearson coefficient = 0.786, p < 0.01), and a third between the MTD and the pT stage (Pearson coefficient = 0.678, p < 0.01). CONCLUSION: mp-MRI can accurately detect the index lesion and estimate the TVP of localised prostate cancer. PMID- 24754781 TI - An array of ferromagnetic nanoislands nondestructively patterned via a local phase transformation by low-energy proton irradiation. AB - Low-energy proton irradiation was applied to pattern an array of metallic, ferromagnetic nanoislands through the local phase transformation of an oxidic, paramagnetic phase in a complex superlattice composed of repetitions of an oxidic and metallic layer. The irradiation inflicted minimal damage on the structure, resulting in the absence of unwanted defects and side effects. This nondestructive pattern transfer was clearly confirmed by the contrast between irradiated and unirradiated regions in electrical, chemical, and magnetic images. Simulation based on the magnetic properties suggests that this low-energy proton irradiation can nondestructively pattern an array of ferromagnetic islands with 8.2 nm in diameter and 7.4 nm in spacing between islands, which means it can achieve an areal density of ~3 Tb/in.(2) with a thermal stability of over 80 kBT. Such an array is strong enough to overcome the so-called superparamagnetism limit in magnetic recording. The attributes demonstrated here corroborate that proton irradiation can be applied to design and pattern devices on a nanometer scale not only for magnetic but also for electric and optical materials systems in all such systems in which a local phase transformation is available. PMID- 24754782 TI - Ipsilateral corticomotor excitability is associated with increased gait variability in unilateral transtibial amputees. AB - Ipsilateral primary motor cortex (M1) reorganisation after unilateral lower-limb amputation may degrade function of the amputated limb. We hypothesised unilateral lower-limb amputees would have a bilateral increase in corticomotor excitability, and increased excitability of ipsilateral M1 would be associated with increased step-time variability during gait. Twenty transtibial amputees (16 male) aged 60.1 years (range 45-80 years), and 20 age- and gender-matched healthy adult controls were recruited. Single-pulse transcranial magnetic stimulation assessed corticomotor excitability. Two indices of corticomotor excitability were calculated. An index of corticospinal excitability (ICE) determined relative excitability of ipsilateral and contralateral corticomotor projections to alpha motoneurons innervating the quadriceps muscle (QM) of the amputated limb. A laterality index (LI) assessed relative excitability of contralateral projections from each hemisphere. Spatial-temporal gait analysis was performed to calculate step-time variability. Amputees had lower ICE values, indicating relatively greater excitability of ipsilateral corticomotor projections than controls (P = 0.04). A lower ICE value was associated with increased step-time variability for amputated (P = 0.04) and non-amputated limbs (P = 0.02). This association suggests corticomotor projections from ipsilateral M1 to alpha-motoneurons innervating the amputated limb QM may interfere with gait. Cortical excitability in amputees was not increased bilaterally, contrary to our hypothesis. There was no difference in excitability of contralateral M1 between amputees and controls (P = 0.10), and no difference in LI (P = 0.71). It appears both hemispheres control one QM, with predominance of contralateral corticomotor excitability in healthy adults. Following lower-limb amputation, putative ipsilateral corticomotor excitability is relatively increased in some amputees and may negatively impact on function. PMID- 24754783 TI - Conjugated linoleic acid (CLA) formation in edible oils by photoisomerization: a review. AB - Conjugated linoleic acid (CLA) that is commonly found in dairy and ruminant fats, is geometrical and positional isomer of linoleic acid (LA). Edible oils are not good sources of CLA. Attempts have been made to generate CLA in edible oils through photoisomerization procedures. CLA isomers have several proven health benefits. This article reviews procedures for producing CLA containing edible oils by photoisomerization approach and applications of photoisomerized oils for food uses. The article reviews (1) the photoisomerized production of CLA containing oils on lab scale, with customized equipment, at pilot plant scale; (2) the effects of iodine content, photoisomerization time, refining, interference from minor components of oils, efficacy of different edible oils containing LA, interference from antioxidants; (3) the chemical kinetics, oxidative stability; and (4) photoisomerized oils for frying oils and as drying oils.The review also briefly covers methods of measurement of CLA. PMID- 24754785 TI - Choosing and using methodological search filters: searchers' views. AB - BACKGROUND: Search filters or hedges are search strategies developed to assist information specialists and librarians to retrieve different types of evidence from bibliographic databases. The objectives of this project were to learn about searchers' filter use, how searchers choose search filters and what information they would like to receive to inform their choices. METHODS: Interviews with information specialists working in, or for, the National Institute for Health and Care Excellence (NICE) were conducted. An online questionnaire survey was also conducted and advertised via a range of email lists. RESULTS: Sixteen interviews were undertaken and 90 completed questionnaires were received. The use of search filters tends to be linked to reducing a large amount of literature, introducing focus and assisting with searches that are based on a single study type. Respondents use numerous ways to identify search filters and can find choosing between different filters problematic because of knowledge gaps and lack of time. CONCLUSIONS: Search filters are used mainly for reducing large result sets (introducing focus) and assisting with searches focused on a single study type. Features that would help with choosing filters include making information about filters less technical, offering ratings and providing more detail about filter validation strategies and filter provenance. PMID- 24754786 TI - Characterization of proapoptotic compounds from the bark of Garcinia oblongifolia. AB - Twenty compounds from Garcinia oblongifolia were screened for proapoptotic activity using FRET-based HeLa-C3 sensor cells. Among them, oblongifolins F and G (1 and 2), 1,3,5-trihydroxy-13,13-dimethyl-2H-pyran[7,6-b]xanthone (3), nigrolineaxanthone T (4), and garcicowin B (5) showed significant proapoptotic activity at a concentration of 10 MUM. Bioassessments were then performed to evaluate the potential of these compounds for therapeutic application. All five compounds showed significant cytotoxicity and caspase-3-activating ability in cervical cancer HeLa cells, with compounds 1 and 2 having the highest potencies. All five compounds specifically induced caspase-dependent apoptosis, which could be prevented by the pan-caspase inhibitor zVAD-fmk. In particular, 3 induced apoptosis through mitotic arrest. Compounds 1-5 displayed similar IC50 values (3.9-16.5 MUM) against the three cancer cell lines HeLa, MDA-MB-435, and HepG2. In addition, compounds 1, 2, and 4 exhibited similar and potent IC50 values (2.4 5.1 MUM) against several breast and colon cancer cell lines, including those overexpressing either HER2 or P-glycoprotein. HER2 and P-glycoprotein are known factors that confer resistance to anticancer drugs in cancer cells. This is the first study on the cytotoxicity, caspase-3-activing ability, and specificity of proapoptotic compounds isolated from G. oblongifolia in HeLa cells. The potential application of these compounds against HER2- or P-glycoprotein-overexpressing cancer cells was investigated. PMID- 24754787 TI - Accounting for nitrogen fixation in simple models of lake nitrogen loading/export. AB - Coastal eutrophication, an important global environmental problem, is primarily caused by excess nitrogen and management efforts consequently focus on lowering watershed N export (e.g., by reducing fertilizer use). Simple quantitative models are needed to evaluate alternative scenarios at the watershed scale. Existing models generally assume that, for a specific lake/reservoir, a constant fraction of N loading is exported downstream. However, N fixation by cyanobacteria may increase when the N loading is reduced, which may change the (effective) fraction of N exported. Here we present a model that incorporates this process. The model (Fixation and Export of Nitrogen from Lakes, FENL) is based on a steady-state mass balance with loading, output, loss/retention, and N fixation, where the amount fixed is a function of the N/P ratio of the loading (i.e., when N/P is less than a threshold value, N is fixed). Three approaches are used to parametrize and evaluate the model, including microcosm lab experiments, lake field observations/budgets and lake ecosystem model applications. Our results suggest that N export will not be reduced proportionally with N loading, which needs to be considered when evaluating management scenarios. PMID- 24754784 TI - Protein-centric N-glycoproteomics analysis of membrane and plasma membrane proteins. AB - The advent of proteomics technology has transformed our understanding of biological membranes. The challenges for studying membrane proteins have inspired the development of many analytical and bioanalytical tools, and the techniques of glycoproteomics have emerged as an effective means to enrich and characterize membrane and plasma-membrane proteomes. This Review summarizes the development of various glycoproteomics techniques to overcome the hurdles formed by the unique structures and behaviors of membrane proteins with a focus on N-glycoproteomics. Example contributions of N-glycoproteomics to the understanding of membrane biology are provided, and the areas that require future technical breakthroughs are discussed. PMID- 24754788 TI - ADMET: ADipocyte METabolism mathematical model. AB - White fat cells have an important physiological role in maintaining triglyceride and free fatty acid levels due to their fundamental storage property, as well as determining insulin resistance. ADipocyte METabolism is a mathematical model that mimics the main metabolic pathways of human white fat cell, connecting inputs (composition of culture medium) to outputs (glycerol and free fatty acid release). It is based on a set of nonlinear differential equations, implemented in Simulink(r) and controlled by cellular energetic state. The validation of this model is based on a comparison between the simulation results and a set of experimental data collected from the literature. PMID- 24754789 TI - Evaluation of the validity of Hb A2 and mean corpuscular haemoglobin action values in antenatal screening for beta thalassaemia carriers in England. AB - National antenatal screening of all pregnant women in England is carried out using standards and guidelines produced by the National Health Service Sickle Cell and Thalassaemia Screening Programme. The algorithms for detection of beta thalassaemia carrier status rely on action criteria, which are set using the percentage Hb A2 and mean corpuscular haemoglobin (MCH) values. Three groups of samples: MCH <27 pg and Hb A2 3.5-3.9%, MCH >=27 pg and Hb A2 4-4.3% and MCH >=27 pg and Hb A2 3.5-3.9% were selected from a sample population of 59 500 to assess the validity and predictive value of the action criteria - 25 false positives (0.042% of total) and nine false negatives (0.015% of total) were detected. These findings support the continuation of the current action values. PMID- 24754791 TI - Numerical study of mode excitation in a partially illuminated silver rod. AB - Using electrodynamics theory, we numerically demonstrated that when the incident light polarization direction is parallel to a silver rod axis, the modes that are forbidden in a fully illuminated silver rod can be excited when the rod is partially illuminated. The modes are excited due to the symmetry breaking of the rod when it is partially illuminated. They are characterized by the even number of nodes in the excited surface plasmons and quadrupole pattern of the scattered light in the space. These modes are different from the allowed modes in a fully illuminated rod, which shows an odd number of nodes in the excited surface plasmons and a dipole pattern of the scattered light. The conclusion was further supported by the calculation results when the illuminated spot was moved from the rod end to its center and when the illuminated length was varied. We also demonstrated dark modes when the incident light polarization is perpendicular to the rod axis. Contrary to the hypothesis that a dark mode will be an efficient waveguide mode, the dark mode shows very poor waveguide applications when the incident polarization is perpendicular to the rod axis. PMID- 24754790 TI - Cyclopamine: from cyclops lambs to cancer treatment. AB - In the late 1960s, the steroidal alkaloid cyclopamine was isolated from the plant Veratrum californicum and identified as the teratogen responsible for craniofacial birth defects including cyclops in the offspring of sheep grazing on mountain ranges in the western United States. Cyclopamine was found to inhibit the hedgehog (Hh) signaling pathway, which plays a critical role in embryonic development. More recently, aberrant Hh signaling has been implicated in several types of cancer. Thus, inhibitors of the Hh signaling pathway, including cyclopamine derivatives, have been targeted as potential treatments for certain cancers and other diseases associated with the Hh signaling pathway. A brief history of cyclopamine and cyclopamine derivatives investigated for the treatment of cancer is presented. PMID- 24754792 TI - Route less travelled? Ambulance use for children with high-acuity acute illness. AB - AIM: Ambulance transportation offers important supportive care and treatment en route to definitive treatment. However, children may be at risk of under utilising ambulance transportation, where private vehicle is possible. This study aims to determine how many of the sickest children present to hospitals in Auckland via ambulance and whether certain population groups are lower users of ambulance services. METHODS: Transportation, demographic and outcome data were collected and analysed for children presenting to Starship Children's Health (Starship) from 1 January to 31 December 2011), who were 'self referrals' to hospital, less than 15 years of age, and assigned triage category 1 and 2 on presentation. RESULTS: There were 1047 presentations to Starship identified that met inclusion criteria. Of these, 256 of the 341 triage one presentations (75.1%) and 217 of the 706 triage two presentations (30.7%) were transported by ambulance.Ambulance use was higher among older children (P < 0.001). Severity of illness or injury, as estimated by admission rates (56.7% vs. 43.3%, P = 0.21) and length of hospital stay (median = 1 day, P = 0.92), did not differ significantly by mode of transportation. There was no observed relationship with gender, ethnicity or area deprivation index score. CONCLUSION: A significant proportion of acutely unwell children presenting to hospital were not transported by ambulance, particularly those aged less than 1 year. This has the potential to result in worse health outcomes. There were no identified associations with patient demographics, and further research is required to better understand this problem and develop solutions. PMID- 24754793 TI - Treatment of periorbital infantile haemangiomas: a systematic literature review on propranolol or steroids. AB - AIM: The aim of this study was to compare the efficacy and safety of propranolol versus corticosteroids for the treatment of periorbital infantile haemangiomas (IHs). METHODS: A literature review using PubMed, Ovid Medline, EBSCO, Springer, Web of Knowledge, Cochrane Library, CNKI and associated references before 2 March 2013 was conducted. The main outcomes were distribution of locations, response rate, rebound growth rate, spherical and cylinder power before and after treatment, amblyopia rate and adverse events. RESULTS: Thirty-one studies including 425 patients met the inclusion criteria. A total of 70.6% of patients were female, 89.6% of the periorbital IHs were located in the upper or lower eyelid area. The most common administration routes involved oral propranolol and intralesional injection of corticosteroids. The mean response rate was 94.0% for propranolol and 82.3% for corticosteroid (P = 0.001). The rebound growth rate was 13.9% for propranolol and 12.0% for steroids (P = 0.71). Astigmatism was reduced in both propranolol and steroid studies (P < 0.0001, P < 0.0001), but a significant reduction in spherical power was only demonstrated in propranolol studies (P = 0.005). A total of 31.1% of patients treated with corticosteroids developed post-operative amblyopia compared with 16.7% of patients treated with propranolol (P = 0.04). Oral propranolol seemed to induce more temporary adverse events than intralesional corticosteroids administration (24.0% vs. 9.6%, P = 0.006). CONCLUSION: Propranolol may represent an effective therapy for periorbital IHs compared with the use of corticosteroids; however, further randomised control studies are needed to compare adverse events. PMID- 24754794 TI - Factors affecting virus dynamics and microbial host-virus interactions in marine environments. AB - Marine microorganisms constitute the largest percentage of living biomass and serve as the major driving force behind nutrient and energy cycles. While viruses only comprise a small percentage of this biomass (i.e., 5%), they dominate in numerical abundance and genetic diversity. Through host infection and mortality, viruses affect microbial population dynamics, community composition, genetic evolution, and biogeochemical cycling. However, the field of marine viral ecology is currently limited by a lack of data regarding how different environmental factors regulate virus dynamics and host-virus interactions. The goal of the present minireview was to contribute to the evolution of marine viral ecology, through the assimilation of available data regarding the manner and degree to which environmental factors affect viral decay and infectivity as well as influence latent period and production. Considering the ecological importance of viruses in the marine ecosystem and the increasing pressure from anthropogenic activity and global climate change on marine systems, a synthesis of existing information provides a timely framework for future research initiatives in viral ecology. PMID- 24754795 TI - Cell-penetrating nanobiosensors for pointillistic intracellular Ca2+-transient detection. AB - Small-molecule chemical calcium (Ca(2+)) indicators are invaluable tools for studying intracellular signaling pathways but have severe shortcomings for detecting local Ca(2+) entry. Nanobiosensors incorporating functionalized quantum dots (QDs) have emerged as promising alternatives but their intracellular use remains a major challenge. We designed cell-penetrating FRET-based Ca(2+) nanobiosensors for the detection of local Ca(2+) concentration transients, using commercially available CANdot565QD as a donor and CaRuby, a custom red-emitting Ca(2+) indicator, as an acceptor. With Ca(2+)-binding affinities covering the range of 3-20 MUM, our CaRubies allow building sensors with a scalable affinity for detecting intracellular Ca(2+) transients at various concentrations. To facilitate their cytoplasmic delivery, QDs were further functionalized with a small cell-penetrating peptide (CPP) derived from hadrucalcin (HadUF1-11: H11), a ryanodine receptor-directed scorpion toxin identified within the venom of Hadrurus gertschi. Efficient internalization of QDs doubly functionalized with PEG5-CaRuby and H11 (in a molar ratio of 1:10:10, respectively) is demonstrated. In BHK cells expressing a N-methyl-d-aspartate receptor (NMDAR) construct, these nanobiosensors report rapid intracellular near-membrane Ca(2+) transients following agonist application when imaged by TIRF microscopy. Our work presents the elaboration of cell-penetrating FRET-based nanobiosensors and validates their function for detection of intracellular Ca(2+) transients. PMID- 24754796 TI - A call for policy action in sub-Saharan Africa to rethink diagnostics for pregnancy affected by sickle cell disease: differential views of medical doctors, parents and adult patients predict value conflicts in Cameroon. AB - Sickle cell disease (SCD) is a debilitating illness that affects the life expectancy of patients. It is possible to test for SCD before birth, to allow for reproductive options to parents. However, under Cameroonian Law, voluntary abortion is a criminal offense and medical abortion is permitted only "...if it is done by an authorized professional and justified by the need to save the mother from grave health jeopardy." The objective of the present study was to compare the views of Cameroonian doctors, parents with at least one living SCD affected child, and adult SCD patients, regarding prenatal genetic diagnosis and termination of SCD-affected pregnancy. We conducted a quantitative sociological survey of 110 doctors, 130 parents, and 89 adult patients. The majority accepted the prenatal genetic diagnosis for SCD (78.7%, 89.8%, and 89.2%, respectively). Parents (62.5%) were more in favor of termination of SCD-affected pregnancy, than doctors and adults patients (36.1% and 40.9% acceptance, respectively). Parents and patients who found medical abortion acceptable cited fear to have a SCD affected child (98.1 and 88.9%) and the poor quality of the affected child's health (92.6% and 81.5%). The data underscore the urgency of policy action to place emphasis on: premarital screening, early detection and care of SCD, socio economic measures to assist SCD-affected families, appropriateness to consider maternal distress due to fetal anomalies in medical abortion legislation. These novel findings signal potential value-based conflicts on the horizon, and can usefully inform the future policy actions in the African continent as OMICS biotechnologies are increasingly employed in global health. To the best of our knowledge, the present study is the first attempt in sub-Saharan Africa to attempt to triangulate the views of multiple stakeholders towards prenatal diagnosis of SCD and termination of an affected pregnancy. PMID- 24754797 TI - Effects of different types of tooth movement and force magnitudes on the amount of tooth movement and root resorption in rats. AB - OBJECTIVE: To investigate differences in the amount of tooth movement and root resorption that occurred after tipping and bodily movement of the maxillary first molar in rats. MATERIALS AND METHODS: Ten-week-old female Wistar rats were divided into two groups according to type of tooth movement and subdivided into four subgroups according to the magnitude of applied force. Nickel-titanium closed-coil springs exerting forces of 10, 25, 50, or 100 g were applied to the maxillary left first molars to induce mesial tooth movement. We designed a novel orthodontic appliance for bodily tooth movement. Tooth movement distance and root resorption were measured using microcomputed tomography and scanning electron and scanning laser microscopy. RESULTS: The amount of tooth movement in the bodily tooth movement group was less than half that in the tipping tooth movement group. The greatest amount of tooth movement occurred in the 10-g tipping and 50-g bodily tooth movement subgroups, and the amount of tooth movement decreased with the application of an excessive magnitude of force. Conversely, root resorption increased when the heavier orthodontic force was applied in both groups. Root resorption in the tipping tooth movement group was approximately twice that in the bodily tooth movement group. CONCLUSIONS: Root resorption in the tipping tooth movement group was more pronounced than that in the bodily tooth movement group. Although the amount of tooth movement decreased when extremely heavy forces were applied, root resorption increased in both the tipping and bodily tooth movement groups in rats. PMID- 24754798 TI - To infiltrate or not? Acute effects of local anaesthetic in breast surgery. AB - BACKGROUND: There is limited evidence to support use of local anaesthetic (LA) wound infiltration in breast surgery. This study seeks to examine whether wound infiltration of bupivacaine (0.25%) decreases post-operative pain and analgesic use, without increasing post-operative complications. METHODS: A prospective single-blind study was undertaken of 90 patients undergoing breast lump excision, wide local excision and mastectomy with or without axillary surgery. Patients were randomized to receive infiltration with bupivacaine (0.25%) into the surgical wound (Group LA) or no infiltration (Group No LA). Data on post operative analgesia use was collected. Pain scores were assessed at 1, 24, 48 h and 1 week with a visual analogue scale. Complications associated with wound healing were documented at the first post-operative visit. RESULTS: Forty-five patients received infiltration and 34 patients received none. There were no significant differences in baseline characteristics between patient groups or surgical details. Analysis revealed Group LA used significantly less opioids than Group No LA during the first 48 h post-op (3.42 mg versus 7.33 mg; P = 0.02). Overall, Group LA used half the total average opioid equivalent amount (5.04 mg versus 10.08 mg; P = 0.069). There were no significant differences in post operative pain scores or complications. Overall pain scores were low, suggesting effective analgesic use by nursing staff. DISCUSSION: LA infiltration during breast surgery has a marked opioid sparing effect, which has significant patient benefits as well as reducing nursing workload and drug costs. PMID- 24754799 TI - Food insecurity and dental caries in schoolchildren: a cross-sectional survey in the western Brazilian Amazon. AB - We analyzed the association between food insecurity and dental caries in 7- to 9 yr-old schoolchildren. We performed a cross-sectional survey nested in a population-based cohort study of 203 schoolchildren. The participants lived in the urban area of a small town within the western Brazilian Amazon. Dental examinations were performed according to criteria recommended by the World Health Organization. The number of decayed deciduous and permanent teeth as a count variable was the outcome measure. Socio-economic status, food security, behavioral variables, and child nutritional status, measured by Z-score for body mass index (BMI), were investigated, and robust Poisson regression models were used. The results showed a mean (SD) of 3.63 (3.26) teeth affected by untreated caries. Approximately 80% of schoolchildren had at least one untreated decayed tooth, and nearly 60% lived in food-insecure households. Sex, household wealth index, mother's education level, and food-insecurity scores were associated with dental caries in the crude analysis. Dental caries was 1.5 times more likely to be associated with high food-insecurity scores after adjusting for socio-economic status and sex. A significant dose-response relationship was observed. In conclusion, food insecurity is highly associated with dental caries in 7- to 9-yr old children and may be seen as a risk factor. These findings suggest that food security policies could reduce dental caries. PMID- 24754800 TI - Workplace violence and occupational stress in healthcare workers: a chicken-and egg situation-results of a 6-year follow-up study. AB - OBJECTIVES: Violence at work (WV) is an important occupational hazard for health care workers (HCWs). A number of surveys addressing the causes and effects of WV have shown that it is associated with work-related stress. However, it is not clear what direction this relationship takes, that is, whether job strain facilitates aggression against HCWs or WV is the cause of job strain. METHODS: From 2003 to 2009, HCWs from a public health care unit were asked to self-assess their level of work-related stress and to report aggression that occurred in the 12-month period preceding their routine medical examination. In 2009, physical and mental health and job satisfaction were also assessed. A total of 698 out of 723 HCWs (96.5%) completed the study. FINDINGS: Job strain and lack of social support were predictors of the occurrence of nonphysical aggression during the ensuing year. HCWs who experienced WV reported high strain and low support at work in the following year. The experience of nonphysical violence and a prolonged state of strain and social isolation were significant predictors of psychological problems and bad health at follow-up. CONCLUSIONS AND IMPLICATIONS: The relationship between work-related distress and WV is bidirectional. The monitoring of workers through questionnaires distributed before their periodic examination is a simple and effective way of studying WV and monitoring distress. CLINICAL RELEVANCE: The findings of the present study may facilitate the subsequent design of participatory intervention for the prevention of violence in healthcare facilities. This should always be accompanied by measures designed to reduce strain and improve social support. PMID- 24754801 TI - Age-related distance esotropia--fusional amplitudes and clinical course. AB - BACKGROUND: Age-related distance esotropia (ARDET) is a form of acquired strabismus that affects elderly patients and manifests as an esotropia greater with distance fixation. Limited information exists regarding fusional amplitudes and deficient divergence in this disorder. METHODS: In this retrospective study, patient characteristics, ocular alignment and motility, and clinical course of patients with ARDET were recorded. Fusional amplitudes were analyzed to assess whether deficient divergence was present in patients with ARDET. RESULTS: Twenty patients with ARDET were identified. Median age was 77.5 years (range, 59 to 89 years) and median best-corrected visual acuity was 20/25. Median esotropia angle with distance fixation was 5.5Delta (range, 2 to 18Delta); median angle with near fixation was esotropia 2.5Delta (range, exotropia 3Delta to esotropia 13Delta). Fusional divergence amplitudes were decreased in all but two patients. The median amplitude with distance fixation was 4.5Delta for break (range, 1 to 11Delta) and 2Delta for recovery (range, 0 to 9Delta). In 5 patients, the fusional divergence amplitude was as large or larger than the esotropia angle. Most patients remained stable throughout a mean follow-up of 18 months (range, 3 to 37 months). Nineteen patients were managed with prisms. Strabismus surgery was performed in one patient. CONCLUSIONS: Fusional divergence amplitude was deficient in most but not all patients with ARDET. In this study, most patients with ARDET remained stable and free of diplopia with prism treatment. PMID- 24754802 TI - The physiologist Ewald Hering (1834-1918): curriculum vitae. PMID- 24754803 TI - Reduction of rat brain CD8+ T-cells by levodopa/benserazide treatment after experimental stroke. AB - The activation of inflammatory cascades in the ischemic hemisphere impairs mechanisms of tissue reorganization with consequences for recovery of lost neurological function. Recruitment of T-cell populations to the post-ischemic brain occurs and represents a significant part of the inflammatory response. This study was conducted to investigate if treatment with levodopa, potentially acting as an immunomodulator, affects the T-cell accumulation in the post-ischemic brain. Male Sprague-Dawley rats were subjected to transient occlusion of the middle cerebral artery (tMCAO) for 105 min followed by levodopa/benserazide treatment (20 mg/kg/15 mg/kg) for 5 days initiated on day 2 post-stroke. One week after tMCAO, T-cell populations were analysed from brains, and levels of interleukin (IL)-1beta, chemokine (C-X-C motif) ligand 1, IL-4, IL-5, interferon gamma and IL-13 were analysed. After levodopa/benserazide treatment, we found a significant reduction of cytotoxic T-cells (CD3+ CD8+ ) in the ischemic hemisphere together with reduced levels of T-cell-associated cytokine IL-5, while other T-cell populations (CD3+, CD3+ CD4+, CD3+ CD4+ CD25+) were unchanged compared with vehicle-treated rats. Moreover, a reduced number of cells was associated with reduced levels of intercellular adhesion molecule 1, expressed in endothelial cells, in the infarct core of levodopa/benserazide-treated animals. Together, we provide the first evidence that dopamine can act as a potential immunomodulator by attenuating inflammation in the post-ischemic brain. PMID- 24754804 TI - Increased facial width-to-height ratio and perceived dominance in the faces of the UK's leading business leaders. AB - The relative proportion of the internal features of a face (the facial width-to height ratio, FWH) has been shown to be related to individual differences in behaviour in males, specifically competitiveness and aggressiveness. In this study, we show that the Chief Executive Officers (CEOs) of the leading UK businesses have greater FWHs than age- and sex-matched controls. We demonstrate that perceivers, naive as to the nature of the stimuli, rate the faces of CEOs as higher in dominance or success, and that ratings of dominance or success are themselves correlated with the FWH ratio. We find no association with other inferred traits such as trustworthiness, attraction or aggression. The latter is surprising given previous research demonstrating a link between FWH and ratings of aggression. We speculate that the core association may be between FWH and drive for dominance or power, but this can be interpreted as aggression only in particular circumstances (e.g., when the stimuli are comprised of faces of young, as opposed to middle-aged, men). PMID- 24754805 TI - Sexual distractors boost younger and older adults' visual search RSVP performance. AB - Do sexual words have high attentional priority? How does the ability to ignore sexual distractors evolve with age? To answer these questions, two experiments using Rapid Serial Visual Presentation (RSVP) were conducted. Experiment 1 showed that both younger and older participants were better at identifying a target (the name of a colour) when it was preceded by 336 ms by a sexual word rather than by a musical word. Strikingly, the sexual-word advantage was more pronounced for older adults than for younger adults. Experiment 2 showed that introducing a variable delay between the distractor and the target eliminated the sexual-word advantage. This finding suggests that the sexual-word advantage found in Experiment 1 was due to learning to utilize the sexual word as a temporal cue with a fixed duration between the distractor and the target. Contrary to previous research [Arnell et al., 2007, Emotion, 7, 465), neither experiment showed that sexual words produce an attentional blink. PMID- 24754806 TI - Communal and agentic behaviour in response to facial emotion expressions. AB - Facial emotions are important for human communication. Unfortunately, traditional facial emotion recognition tasks do not inform about how respondents might behave towards others expressing certain emotions. Approach-avoidance tasks do measure behaviour, but only on one dimension. In this study 81 participants completed a novel Facial Emotion Response Task. Images displaying individuals with emotional expressions were presented in random order. Participants simultaneously indicated how communal (quarrelsome vs. agreeable) and how agentic (dominant vs. submissive) they would be in response to each expression. We found that participants responded differently to happy, angry, fearful, and sad expressions in terms of both dimensions of behaviour. Higher levels of negative affect were associated with less agreeable responses specifically towards happy and sad expressions. The Facial Emotion Response Task might complement existing facial emotion recognition and approach-avoidance tasks. PMID- 24754807 TI - Sub-threshold autism traits: the role of trait emotional intelligence and cognitive flexibility. AB - Theory and research suggests that features of autism are not restricted to individuals diagnosed with autism spectrum disorders (ASDs), and that autism-like traits vary throughout the general population at lower severities. The present research first investigated the relationship of autism traits with trait emotional intelligence and empathy in a sample of 163 adults aged between 18 and 51 years (44% male). It then examined performance on a set of tasks assessing social cognition and cognitive flexibility in 69 participants with either high or low scores on ASD traits. Results confirm that there is pronounced variation within the general population relating to ASD traits, which reflect similar (though less severe) social-cognitive and emotional features to those observed in ASDs. PMID- 24754808 TI - Stress in telephone helpline nurses is associated with failures of concentration, attention and memory, and with more conservative referral decisions. AB - Nurses working for telephone-based medical helplines must maintain attentional focus while quickly and accurately processing information given by callers to make safe and appropriate treatment decisions. In this study, both higher levels of general occupational stress and elevated stress levels on particular shifts were associated with more frequent failures of attention, memory, and concentration in telephone nurses. Exposure to a stressful shift was also associated with a measurable increase in objectively assessed information processing errors. Nurses who experienced more frequent cognitive failures at work made more conservative decisions, tending to refer patients on to other health professionals more often than other nurses. As stress is associated with cognitive performance decrements in telephone nursing, stress-reduction interventions could improve the quality and safety of care that callers to medical helplines receive. PMID- 24754809 TI - Chewing gum moderates the vigilance decrement. AB - We examine the impact of chewing gum on a Bakan-type vigilance task that requires the continual updating of short-term order memory. Forty participants completed a 30-min auditory Bakan-task either with, or without, the requirement to chew gum. Self-rated measures of mood were taken both pre- and post-task. As expected, the vigilance task produced a time-dependent performance decrement indexed via decreases in target detections and lengthened correct reaction times (RTs), and a reduction in post-task self-rated alertness scores. The declines in both performance and subjective alertness were attenuated in the chewing-gum group. In particular, correct RTs were significantly shorter following the chewing of gum in the latter stages of the task. Additionally, the gradients of decline for target detection and incline for correct RTs were both attenuated for the chewing gum group. These findings are consistent with the data of Tucha and Simpson (2011), Appetite, 56, 299-301, who showed beneficial effects of chewing gum in the latter stages of a 30 min visual attention task, and extend their data to a task that necessitates the continuous updating of order memory. It is noteworthy that our data contradict the claim (Kozlov, Hughes, & Jones, 2012, Q. J. Exp. Psychology, 65, 501-513) that chewing gum negatively impacts short-term memory task performance. PMID- 24754810 TI - Binding and content updating in working memory tasks. AB - Working memory updating can involve processing of either a specific memory content or a binding. So far, research has focused mainly on single contents as objects of updating, via recall accuracy measures. Here, we have addressed more direct measurement of the updating process (i.e., response times), assessing individually the role of single contents, as well as bindings. To this end, we compared two updating tasks from separate research traditions: a RT-based computer task and a classical accuracy-based task. The former consisted of trials where measures of content and binding updating were obtained, allowing a dissociation between these two components. The latter measured recall accuracy and intrusion rate for lists of words under different conditions of maintenance/inhibition. These results enable a better understanding of the updating process for the dual components of binding and content updating, and their potential role in an accuracy-based task. An overlap between the underlying components of updating tasks was demonstrated, specifically between binding updating RT and intrusion rate. Notably, binding updating appears to be a more sensitive measure in explaining results in the classical updating task. PMID- 24754811 TI - Intelligence, gender, and assessment method affect the accuracy of self-estimated intelligence. AB - Self-estimates of intelligence (SEI), which influence to what extent people engage in and how well they perform at a task, are subject to distortion. Here, the distortion effects of individual differences in intelligence (IQ), gender, and proximal (with reference to test performance) and distal (with reference to IQ score distributions) assessments of SEI were tested in a sample of 200 British adults. The results showed that (1) people with lower IQ misestimated their SEI to a greater extent than people with high IQ; (2) this effect was more pronounced in distal than proximal measures of SEI; (3) SEI means did not differ significantly across gender but the IQ-related level of SEI distortion did; (4) this effect was greater for distal than proximal measurement; and (5) proximal SEI were on average less distorted than distal SEI scores and also correlated more closely with IQ. Overall, the findings suggest that the distal SEI assessment method resulted in greater gender- and IQ-related distortions of SEI. PMID- 24754813 TI - Is grammatical gender considered arbitrary or semantically motivated? Evidence from young adult monolinguals, second language learners, and early bilinguals. AB - It is generally assumed that speakers of grammatical gender languages consider grammatical gender arbitrary, but this assumption has never been tested. Research shows that the grammatical gender of nouns can affect perceptions of the masculinity or femininity of the noun's referent in speakers of languages with masculine and feminine noun classes. However, bilingualism facilitates the development of lexical arbitrariness awareness, and could therefore affect awareness of grammatical gender arbitrariness. This study then compared three groups of young adult speakers of a grammatical gender language: monolinguals, early bilinguals, and instructed second language learners. Participants evaluated the gender assignments of 25 nouns of entities (animals, abstract concepts, natural kinds, and artefacts), and answered open and closed questions about grammatical gender. Participants considered grammatical gender as semantically motivated and mostly related gender assignments to perceived masculine or feminine connotations of referents. Knowledge of an additional grammatical gender language was linked to increased awareness of the arbitrariness of first language gender assignments in both early bilinguals and later instructed learners. It is argued that grammatical gender awareness deserves further investigation. Knowing more than one grammatical gender language can increase awareness of grammatical gender arbitrariness. Implications are discussed for language teaching and language reform. PMID- 24754812 TI - Women are more sensitive than men to prior trial events on the Stop-signal task. AB - Sexual dimorphism in the brain and cognition is a topic of widespread interest. Many studies of sex differences have focused on visuospatial and verbal abilities, but few studies have investigated sex differences in executive functions. We examined two key components of executive function - response inhibition and response monitoring - in healthy men (n = 285) and women (n = 346) performing the Stop-signal task. In this task, participants are required to make a key press to a stimulus, unless a tone is presented at some delay following the initial stimulus presentation; on these infrequent trials, participants are instructed to inhibit their planned response. Response inhibition was assessed with an estimate of the latency needed to inhibit a response (stop-signal reaction time), and response monitoring was measured by calculating the degree to which participants adjusted their reaction times based on the immediately preceding trial (e.g., speeding following correct trials and slowing following errors). There were no sex differences in overall accuracy or response inhibition, but women showed greater sensitivity to trial history. Women sped up more than men following correct 'Go' trials, and slowed down more than men following errors. These small but statistically significant effects (Cohen's d = 0.25-0.3) suggest more flexible adjustments in speed-accuracy trade-offs in women and greater cognitive flexibility associated with the responsive control of action. PMID- 24754814 TI - Flexible dosing with fesoterodine 4 and 8 mg: a systematic review of data from clinical trials. AB - AIMS: To systematically review dose-escalation data from flexible-dose studies of fesoterodine and summarise factors associated with dose-escalation decisions. METHODS: A PubMed search was conducted using the terms (fesoterodine AND flexible dose), with no limits. Articles were included if they contained fesoterodine dose escalation data for efficacy or safety outcomes or factors associated with dose escalation decisions. RESULTS: Of 13 articles identified by the search, 10 articles (six clinical studies) met inclusion criteria. In flexible-dose trials of fesoterodine, 51-63% of subjects initially receiving fesoterodine 4 mg opted for dose escalation to fesoterodine 8 mg. Escalators generally reported significantly more severe overactive bladder (OAB) symptoms, greater OAB symptom bother and worse health-related quality of life at baseline than non-escalators. Escalators demonstrated less treatment benefit with fesoterodine 4 mg than non escalators. Non-escalators generally had a higher rate of dry mouth and constipation with fesoterodine 4 mg than escalators. The decision to escalate appeared to be determined by the efficacy/tolerability responses; fesoterodine escalators demonstrated a lower sensitivity (less efficacy and fewer adverse events) before their decision to escalate. By study end (8-11 weeks after escalation decision), the efficacy and tolerability profiles were similar in escalators and non-escalators. CONCLUSIONS: Data from flexible-dose studies provide strong evidence that fesoterodine provides treatment benefit to individual subjects with OAB because of its true dose-response effect. In clinical practice, it can be worthwhile to escalate to fesoterodine 8 mg in individual subjects who require additional efficacy benefit. PMID- 24754815 TI - Carpatamides A-C, cytotoxic arylamine derivatives from a marine-derived Streptomyces sp. AB - Three new acylated arylamine derivatives (1-3), carpatamides A-C, were isolated from a marine-derived Streptomyces sp. based on activity screening against non small-cell lung cancer (NSCLC). The structures of 1-3 were established on the basis of comprehensive spectroscopic analyses and chemical methods. Compounds 1 and 3 showed moderate cytotoxicity against NSCLC cell lines HCC366, A549, and HCC44 with IC50 values ranging from 2.2 to 8.4 MUM. PMID- 24754816 TI - Drivers of the growth in global greenhouse gas emissions. AB - Greenhouse gas emissions increased by 8.9 Gigatons CO2 equivalent (Gt) in the period 1995-2008. A phenomenon that has received due attention is the upsurge of emission transfers via international trade. A question that has remained unanswered is whether trade changes have affected global emissions. For each of five factors (one of which is trade changes) in 40 countries we quantify its contribution to the growth in global emissions. We find that the changes in the levels of consumption per capita have led to an enormous growth in emissions (+14.0 Gt). This effect was partly offset by the changes in technology (-8.4 Gt). Smaller effects are found for population growth (+4.2 Gt) and changes in the composition of the consumption (-1.5 Gt). Changes in the trade structure had a very moderate effect on global emissions (+0.6 Gt). Looking at the geographical distribution, changes in the emerging economies (Brazil, Russia, India, Indonesia and China) have caused 44% of emission growth whereas the increase in their national emissions accounted for 59% of emission growth. This means that 15% (1.4 Gt) of all extra GHG emissions between 1995 and 2008 have been emitted in emerging countries but were caused by changes in other countries. PMID- 24754817 TI - Hemodynamic outcomes of transcatheter aortic valve implantation with the CoreValve system: an early assessment. AB - BACKGROUND AND AIMS: Transcatheter aortic valve implantation (TAVI) is an established method for the treatment of high-risk patients with aortic stenosis (AS). The beneficial effects of TAVI in cardiac hemodynamics have been described in recent studies, but those investigations were mostly performed after an interval of more than 6 months following aortic valve implantation. The aim of this study is to investigate the acute and short-term alterations in hemodynamic conditions using the echocardiography outcomes in patients undergoing TAVI. METHODS AND RESULTS: A total of 60 patients (26 males, 34 females; age 84.7 +/- 5.8) who underwent TAVI with CoreValve system were included in the study. Echocardiography was performed before hospital discharge and at 3 months follow up. As expected, TAVI was associated with an immediate significant improvement in aortic valve area (AVA) (from 0.64 +/- 0.16 cm(2) to 1.67 +/- 0.41 cm(2) , P value<0.001) and mean gradient (from 51.9 +/- 15.4 mmHg to 8.8 +/- 3.8 mmHg, P value<0.001). At 3-month follow-up, systolic LV function was augmented (EF: 50 +/ 14% to 54 +/- 11%, P-value = 0.024). Left ventricle (LV) mass and left atrium (LA) volume were significantly reduced (LV mass index from 126.5 +/- 30.5 g m(-2) to 102.4 +/- 32.4 g m(-2) ; LA index from 42.9 +/- 17.3 ml m(-2) to 33.6 +/- 10.6 ml m(-2) ; P-value<0.001 for both). Furthermore, a decrement in systolic pulmonary artery pressure (SPAP) from 47.5 +/- 13.5 mmHg to 42.5 +/- 11.2 mmHg, P value = 0.02 was also observed. Despite the high incidence of paravalvular regurgitation (PVR) (80%), most of the patients presented mild or trace PVR and no significant progress of the regurgitation grade was seen after 3 months. CONCLUSION: This study demonstrates that the beneficial effects of TAVI in cardiac function and hemodynamics occur already after a short period following aortic valve implantation. PMID- 24754818 TI - Antimicrobial N-halamine modified polyethylene: characterization, biocidal efficacy, regeneration, and stability. AB - Development of antimicrobial materials that regenerate antimicrobial activity represents a novel technology in preventing microbial cross-contamination. We report a method for the application of regenerably antimicrobial N-halamines onto the surface of polyethylene (PE) materials through layer-by-layer (LbL) assembly of polyethyleneimine and poly(acrylic acid). A total of 5, 10, 15, and 20 bilayers were applied. Modified PE had from 49.3 to 293.5 nmol cm(-2) antimicrobial N-halamines from 5 to 20 bilayers after 10 min of chlorination. Each variant of N-halamine modified PE was able to reduce by >5 logarithmic cycles Listeria monocytogenes. The stability of N-halamine modified PE was characterized after extended exposure to chlorine, acidic solutions, and an alkaline cleaner. After an initial conditioning period, materials generated more than double the quantity of N-halamines present on as prepared materials, retaining regenerability for up to 100 chlorination cycles. After the equivalent of 300 washing cycles by buffers (pH values 3, 5, and 7) or a commercial alkaline detergent, there was no change in the number of antimicrobial N-halamines on the modified materials. These results indicate that the reported LbL deposition technique results in antimicrobial N-halamine materials capable of long-term reuse and exposure to harsh chemicals as expected in a food-processing environment. Such robust, regenerably antimicrobial materials could be an effective technology in the food industry to prevent cross-contamination of pathogenic and spoilage microorganisms. PRACTICAL APPLICATION: The food contact surface of polyethylene was modified by layer-by-layer deposition of 2 polymers, resulting in a rechargeably antimicrobial surface. Repeated exposure to chlorine regenerated its antimicrobial activity, resulting in greater than 99.999% reduction in Listeria monocytogenes. Materials were stable against repeated washing and exposure to acidic environments. These food contact materials could support current cleaning and sanitization protocols in improving food safety in the processing environment. PMID- 24754819 TI - Purpose of the meeting: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. PMID- 24754820 TI - Executive Summary: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. PMID- 24754821 TI - Promotion of lung health: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. AB - Lung-related research primarily focuses on the etiology and management of diseases. In recent years, interest in primary prevention has grown. However, primary prevention also includes "health promotion" (actions in a population that keep an individual healthy). We encourage more research on population-based (public health) strategies that could not only maximize lung health but also mitigate "normal" age-related declines-not only for spirometry but across multiple measures of lung health. In developing a successful strategy, a "life course" approach is important. Unfortunately, we are unable to achieve the full benefit of this approach until we have better measures of lung health and an improved understanding of the normal trajectory, both over an individual's life span and possibly across generations. We discuss key questions in lung health promotion, with an emphasis on the upper (healthier) end of the distribution of lung functioning and resiliency and briefly summarize the few interventions that have been studied to date. We conclude with suggestions regarding the most promising future research for this important, but largely neglected, area of lung research. PMID- 24754822 TI - Asthma: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. AB - Asthma is a common disease with enormous public health costs, and its primary prevention is an ambitious and important goal. Understanding of how host and environmental factors interact to cause asthma is incomplete, but persistent questions about mechanisms should not stop clinical research efforts aimed at reducing the prevalence of childhood asthma. Achieving the goal of primary prevention of asthma will involve integrated and parallel sets of research activities in which mechanism-oriented studies of asthma inception proceed alongside clinical intervention studies to test biologically plausible prevention ideas. For example, continued research is needed, particularly in young children, to uncover biomarkers that identify asthma risk and provide potential targets of intervention, and to improve understanding of the role of microbial factors in asthma risk and disease initiation. In terms of clinical trials that could be initiated now or in the near future, we recommend three interventions for testing: (1) preventing asthma through prophylaxis against respiratory syncytial virus and human rhinovirus infections of the airway; (2) immune modulation, using prebiotics, probiotics, and bacterial lysates; and (3) prevention of allergen sensitization and allergic inflammation, using anti-IgE. These interventions should be tested while other, more universal prevention measures that may promote lung health are also investigated. These potential universal lung health measures include prevention of preterm delivery; reduced exposure of the fetus and young infant to environmental pollutants, including tobacco smoke; prevention of maternal and child obesity; and management of psychosocial stress. PMID- 24754823 TI - Bronchopulmonary dysplasia: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. AB - Bronchopulmonary dysplasia (BPD) is the most common complication of extreme preterm birth. Infants who develop BPD manifest aberrant or arrested pulmonary development and can experience lifelong alterations in cardiopulmonary function. Despite decades of promising research, primary prevention of BPD has proven elusive. This workshop report identifies current barriers to the conduct of primary prevention studies for BPD and causal pathways implicated in BPD pathogenesis. Throughout, we highlight promising areas for research to improve understanding of normal and aberrant lung development, distinguish BPD endotypes, and ascertain biomarkers for more targeted therapeutic approaches to prevention. We conclude with research recommendations and priorities to accelerate discovery and promote lung health in infants born preterm. PMID- 24754824 TI - Chronic obstructive pulmonary disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. AB - Chronic obstructive pulmonary disease (COPD) is a complex set of conditions with multiple risk factors, disease mechanisms, and clinical manifestations. These characteristics make primary prevention of COPD challenging. Semantic issues related to prevalent and incident disease (e.g., the use of specific cut points on a continuous range) should not derail development of primary prevention initiatives. Potential targets for COPD prevention occur along the spectrum of disease development. Understanding risk factors early in life, whether specific to COPD or not, allows for study of interventions to optimize lung function at birth and to prolong the lung function plateau, potentially reducing the development of COPD. It is necessary to identify noninvasive ways to screen for early COPD in those at risk before progression to clinically significant disease. Identification of specific COPD subgroups, such as individuals with chronic bronchitis, those with alpha1-antitrypsin deficiency, or early radiographic changes with normal spirometry, may offer specific opportunities for primary prevention. A better understanding of why COPD progresses despite smoking cessation is needed. Future research initiatives should also focus on identifying the underlying mechanisms and relevant interventions for nonsmokers with COPD, a currently poorly studied group. Ultimately, preventing the development of COPD will serve to reduce the tremendous burden of this chronic disease worldwide. PMID- 24754825 TI - Cystic fibrosis: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. AB - Cystic fibrosis (CF) is a life-limiting, monogenic disorder characterized by chronic sinopulmonary and gastrointestinal involvement. Progressive pulmonary disease leads to death in the majority of patients. Despite its well-defined molecular basis related to defects in the cystic fibrosis transmembrane conductance regulator anion transport channel, there are large gaps in our understanding of the origin of CF lung disease. Disease has been shown to be present in infancy, and there is mounting evidence that abnormalities begin in utero. Heterogeneity of clinical presentations and severity suggest that many factors involved in lung disease have yet to be fully elucidated. Although new advances in therapeutic treatments have shown promise in delaying disease progression, the prevention of pulmonary disease at its origin (primary prevention) should be a key goal of CF care. The objective of this workshop was to (1) review our understanding of the origins of CF lung disease, (2) determine gaps in the knowledge base that are most significant and most likely to enable prevention of CF lung disease, and (3) prioritize new research questions that will promote pulmonary health in both CF and other childhood lung diseases. The goal of this report is to provide recommendations for future research that will improve our understanding of pulmonary development in health and disease, improve outcome measures and biomarkers for early lung disease, and determine therapeutic targets and strategies to prevent the development of lung disease in children with CF. PMID- 24754827 TI - Pulmonary hypertension: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. AB - Pulmonary vascular dysfunction (PVD) precedes the onset of clinical signs and symptoms of pulmonary arterial hypertension (PAH). PAH is defined by the elevation of pulmonary arterial pressure, which often progresses to right ventricular (RV) dysfunction and failure. PAH affects subjects of all ages, and is associated with diverse medical conditions, most of which are rare. Several factors pose immediate challenges to the development of strategies for primary prevention of PAH, including: (1) the idiopathic or primary form of the disease is extremely rare, limiting screening practicality; (2) methods for the detection of preclinical PVD are currently not established; (3) the understanding of determinants of pulmonary vascular growth, structure, and function in normal and PAH states is insufficient; (4) relatively small numbers of "at-risk" subjects are available for long-term studies to accurately assess disease development; and (5) preventative therapies for PVD are lacking. Despite these limitations, leveraging known at-risk patient populations for study, as well as growing progress across multiple disciplines, ranging from systems biology to advanced and more sensitive functional imaging modalities, may facilitate the opportunity to significantly improve primary prevention research and implementation over the next decade. PMID- 24754828 TI - Optimizing scan parameters for antibody microarray experiments: accelerating robust systems diagnostics for life sciences. AB - Microarray experiments are a centerpiece of postgenomics life sciences and the current efforts to develop systems diagnostics for personalized medicine. The majority of antibody microarray experiments are fluorescence-based, which utilizes a scanner to convert target signals into image files for subsequent quantification. Certain scan parameters such as the laser power and photomultiplier tube gain (PMT) can influence the readout of fluorescent intensities and thus may affect data quantitation. To date, however, there is no consensus of how to determine the optimal settings of microarray scanners. Here we show that different settings of the laser power and PMT not only affect the signal intensities but also the accuracy of antibody microarray experiments. More importantly, we demonstrate an experimental approach using two fluorescent dyes to determine optimal settings of scan parameters for microarray experiments. These measures provide added quality control of microarray experiments, and thus help to improve the accuracy of quantitative outcome in microarray experiments in the above contexts. PMID- 24754826 TI - Interstitial lung disease: NHLBI Workshop on the Primary Prevention of Chronic Lung Diseases. AB - Population-based, longitudinal studies spanning decades linking risk factors in childhood, adolescence and early adulthood to incident clinical interstitial lung disease (ILD) events in late adulthood have not been performed. In addition, no observational or randomized clinical trials have been conducted; therefore, there is presently no evidence to support the notion that reduction of risk factor levels in early life prevents ILD events in adult life. Primary prevention strategies are host-directed interventions designed to modify adverse risk factors (i.e., smoking) with the goal of preventing the development of ILD, whereas primordial prevention for ILD can be defined as the elimination of external risk factors (i.e., environmental pollutants). As no ILD primary prevention studies have been previously conducted, we propose that research studies that promote implementation of primary prevention strategies could, over time, make a subset of ILD preventable. Herein, we provide a number of initial steps required for the future implementation of prevention strategies; this statement discusses the rationale and available evidence that support potential opportunities for primordial and primary prevention, as well as fertile areas for future research of preventive intervention in ILD. PMID- 24754829 TI - Possible association of maternal factors with the higher risk of isolated true undescended testis: A population-based case-control study. AB - The objective of the study was to evaluate the possible association of maternal factors with the risk of isolated true undescended testis (ITUT) diagnosed at the third postnatal month because our knowledge is limited regarding the origin of ITUT. Acute and chronic diseases with related drug treatments were compared in the mothers of 2052 cases with ITUT, 24,814 male controls without any defects and 12,082 malformed male controls with other isolated defects in the population based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Prospective medically recorded endometriosis before conception of the study pregnancy in the mothers of 39 cases was associated with a higher risk of ITUT in their sons (odds ratio (OR) with 95% confidence interval [CI]: 2.42, 1.71-3.42). Dihydrogesterone treatment in the first trimester of pregnancy also showed association with the higher risk of ITUT but based on only five pregnant women. In conclusion, endometriosis before pregnancy may have a role in the origin of ITUT. PMID- 24754830 TI - Plasmonic DNA-origami nanoantennas for surface-enhanced Raman spectroscopy. AB - We report that plasmonic nanoantennas made by DNA origami can be used as reliable and efficient probes for surface-enhanced Raman spectroscopy (SERS). The nanoantenna is built up by two gold nanoparticles that are linked together by a three-layered DNA origami block at a separation distance of 6 nm in order to achieve plasmonic coupling and the formation of a plasmonic "hot spot". The plasmonic properties of the hybrid structure are optically characterized by dark field imaging and polarization-dependent spectroscopy. SERS measurements on molecules that are embedded in the DNA origami that bridges the nanoantenna gap were performed in order to demonstrate the excellent performance of these structures for enhancing spectroscopic signals. A strong enhancement of the Raman signal was recorded from measurements on single hot spots compared to measurements in bulk. Finally, we show that the laser polarization with respect to the dimer orientation has a strong impact on the SERS performance. PMID- 24754831 TI - Oesophageal haematoma masquerading as cardiac ischaemia. PMID- 24754832 TI - Pseudomonas biofilms: possibilities of their control. AB - Genus Pseudomonas includes a large number of species that can be encountered in biotechnological processes as well as in the role of serious human or plant pathogens. Pseudomonads easily form biofilms on various types of surfaces. The biofilm phenotype is characterized by an increased resistance to environmental influences including resistance to antibiotics and other disinfectants, causing a number of problems in health care, food industry, and other areas. Considerable attention is therefore paid to the possibilities of eradication/destruction of pseudomonads biofilms both in terms of understanding the mechanisms of biofilm formation and at the level of finding suitable antibiofilm tools applicable in practice. The first part of this review is devoted to an overview of the regulatory mechanisms that are directly or indirectly involved in the formation of biofilm. The most effective approaches to suppressing the formation of biofilm that do not cause the development of resistance are based on the application of substances that interfere with the regulatory molecules or block the appropriate regulatory mechanisms involved in biofilm development by the cells. Pseudomonads biofilm formation is, similar to other microorganisms, a sophisticated process with many regulatory elements. The suppression of this process therefore also requires multiple antibiofilm tools. PMID- 24754833 TI - Calcium phosphate particles induce interleukin-8 expression in a human gingival epithelial cell line via the nuclear factor-kappaB signaling pathway. AB - BACKGROUND: Dental calculus is calcified plaque composed primarily of calcium phosphate mineral salts, and there is a clear association between the presence of calculus and the initiation/progression of periodontitis. However, it is still inconclusive whether dental calculus can be a direct causative factor. The authors examined the effect of nano/microsized calcium phosphate particles, which may be generated in the process of early precipitation and/or dissolution of calcium phosphate mineral, on the expression of interleukin (IL)-8 in human gingival epithelial cells. METHODS: Primary human gingival epithelial cells and/or a human gingival carcinoma cell line (Ca9-22) were stimulated with calcium phosphate particles. Gene and protein levels were assessed by real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay, respectively. The activity of nuclear factor (NF)-kappaB signaling was measured by an immunofluorescence assay to evaluate NF-kappaB p65 nuclear translocation. RESULTS: The results show that nano/microsized particles stimulate IL-8 expression in human gingival epithelial cells at gene and protein levels. The activity to induce IL-8 expression depends on the particle size: particles with a diameter of 200 nm are more effective than those of 40-nm and 5-MUm diameters. Calcium phosphate particles (diameter 200 nm) stimulated NF-kappaB activity. Pretreatment with BMS-345541, an NF-kappaB signaling inhibitor, inhibited the particle-mediated IL-8 gene induction, suggesting a requirement for the NF-kappaB signaling pathway. CONCLUSION: These findings suggest that calcium phosphate particles, which may be related to calculus development, may act as a direct causative factor in the pathogenesis of gingival epithelium. PMID- 24754834 TI - Modeling neuroendocrine stress reactivity in salivary cortisol: adjusting for peak latency variability. AB - In this report, we present growth curve modeling (GCM) with landmark registration as an alternative statistical approach for the analysis of time series cortisol data. This approach addresses an often-ignored but critical source of variability in salivary cortisol analyses: individual and group differences in the time latency of post-stress peak concentrations. It allows for the simultaneous examination of cortisol changes before and after the peak while controlling for timing differences, and thus provides additional information that can help elucidate group differences in the underlying biological processes (e.g., intensity of response, regulatory capacity). We tested whether GCM with landmark registration is more sensitive than traditional statistical approaches (e.g., repeated measures ANOVA--rANOVA) in identifying sex differences in salivary cortisol responses to a psychosocial stressor (Trier Social Stress Test--TSST) in healthy adults (mean age 23). We used plasma ACTH measures as our "standard" and show that the new approach confirms in salivary cortisol the ACTH finding that males had longer peak latencies, higher post-stress peaks but a more intense post peak decline. This finding would have been missed if only saliva cortisol was available and only more traditional analytic methods were used. This new approach may provide neuroendocrine researchers with a highly sensitive complementary tool to examine the dynamics of the cortisol response in a way that reduces risk of false negative findings when blood samples are not feasible. PMID- 24754835 TI - The TIR-domain-containing adapter inducing interferon-beta-dependent signaling cascade plays a crucial role in ischemia-reperfusion-induced retinal injury, whereas the contribution of the myeloid differentiation primary response 88 dependent signaling cascade is not as pivotal. AB - Toll-like receptor 4 (Tlr4) plays an important role in ischemia-reperfusion (IR) induced retinal inflammation and damage. However, the role of two Tlr4-dependent signaling cascades, myeloid differentiation primary response 88 (Myd88) and TIR domain-containing adapter inducing interferon-beta (Trif), in retinal IR injury is poorly understood. In this study, we investigated the contribution of the Myd88-dependent and Trif-dependent signaling cascades in retinal damage and inflammation triggered by IR, by using Myd88 knockout (Myd88KO) and Trif knockout (TrifKO) mice. Retinal IR injury was induced by unilateral elevation of intraocular pressure for 45 min by direct corneal cannulation. To study IR induced retinal ganglion cell (RGC) death in vitro, we used an oxygen and glucose deprivation (OGD) model. Our data suggested that Myd88 was present in many retinal layers of sham-operated and ischemic mice, whereas Trif was mainly present in the ganglion cell layer (GCL). The level of Myd88 was increased in the retina after IR. We found that retinas of TrifKO mice had a significantly reduced neurotoxic pro-inflammatory response and significantly increased survival of the GCL neurons after IR. Although Myd88KO mice had relatively low levels of inflammation in ischemic retinas, their levels of IR-induced retinal damage were notably higher than those of TrifKO mice. We also found that Trif-deficient RGCs were more resistant to death induced by OGD than were RGCs isolated from Myd88KO mice. These data suggested that, as compared with the Myd88-dependent signaling cascade, Trif signaling contributes significantly to retinal damage after IR. PMID- 24754837 TI - A 3D biomimetic model of tissue stiffness interface for cancer drug testing. AB - Contrary to oversimplified preclinical drug screens that derive treatment responses of cancer cells grown on plastic cell culturing surfaces, the actual in vivo scenario for cancer cell invasion is confronted with a diversity of tissue stiffness. After all, the packing of organs and tissues in the body translates to the abundant presence of tissue stiffness interfaces. The invasive dissemination of cancer cells in vivo might be encouraged by favorable tissue stiffness gradients, likely explaining the preferential spread of cancer cells which is subjective to the cancer type and origin of the primary site. Yet these critical tumor microenvironmental influences cannot be recapitulated in 2D preclinical drug screens, hence omitting potentially invaluable in vivo patterns of drug responses that may support safer clinical dosage implementation of cancer drugs. Current attempts to study stiffness implications on cancer cells are largely confined to 2D surfaces of tunable stiffness. While these studies collectively show that cancer cells migrate better on a stiffer matrix, the generation of a biomimetic 3D tissue stiffness interface for cancer cell migration would clearly give a more definitive understanding on the probable push and pull influences of the 3D ECM. Herein, we developed a biomimetic platform which enables the precise placement of spheroids at tissue stiffness interfaces constructed with natural ECM collagen type I. This enables a standardized comparison of spheroid invasion under a 3D stiffness gradient influence. We found that cancer cells in 3D infiltrated more extensively into a softer matrix of 300 Pa while showing significantly reduced invasion into stiffer matrix of 1200 and 6000 Pa. These biomimetic spheroid cultures postinvasion were suitably subjected to paclitaxel treatment and subsequent daily live quantification of apoptotic cells to evaluate the implications of tissue stiffness on chemotherapeutic treatment. We importantly found that cancer cells which more extensively infiltrated the 300 Pa matrix also succumbed to paclitaxel induced apoptosis earlier than cells in stiffer matrices of 1200 and 6000 Pa respectively. This suggests that reduced invasion of cancer cells attributed to increased tissue stiffness barriers may favor their reduced apoptotic susceptibility to chemotherapeutic treatment. PMID- 24754836 TI - A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers. AB - Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis driven research, especially in the context of 'phenotypic expansion' driven by next-generation sequencing. PMID- 24754839 TI - Oral colchicine for prevention of proliferative vitreoretinopathy: a randomized clinical trial. PMID- 24754838 TI - OnabotulinumtoxinA 100U provides significant improvements in overactive bladder symptoms in patients with urinary incontinence regardless of the number of anticholinergic therapies used or reason for inadequate management of overactive bladder. AB - INTRODUCTION: A prespecified pooled analysis of two placebo-controlled, phase 3 trials evaluated whether the number of prior anticholinergics used or reason for their discontinuation affected the treatment response to onabotulinumtoxinA 100U in overactive bladder (OAB) patients with urinary incontinence (UI). METHODS: Patients with symptoms of OAB received intradetrusor injections of onabotulinumtoxinA 100U or placebo, sparing the trigone. Change from baseline at week 12 in UI episodes/day, proportion of patients reporting a positive response ('greatly improved' or 'improved') on the treatment benefit scale (TBS), micturition and urgency were evaluated by number of prior anticholinergics (1, 2 or >= 3) and reason for their discontinuation (insufficient efficacy or side effects). Adverse events (AE) were assessed. RESULTS: Patients had taken an average of 2.4 anticholinergics before study enrolment. OnabotulinumtoxinA reduced UI episodes/day from baseline vs. placebo, regardless of the number of prior anticholinergics (-2.82 vs. -1.52 for one prior anticholinergic; -2.58 vs. 0.58 for two prior anticholinergics; and -2.92 vs. -0.73 for three or more prior anticholinergics; all p < 0.001). The proportion of TBS responders was higher with onabotulinumtoxinA vs. placebo (69.0% vs. 37.2% for one prior anticholinergic; 58.8% vs. 24.8% for two prior anticholinergics and 56.4% vs. 22.5% for three or more prior anticholinergics; all p < 0.001). Similar results were observed regardless of the reason for discontinuation. OnabotulinumtoxinA reduced the episodes of urgency and frequency of micturition vs. placebo in all groups. AEs were well tolerated, with a comparable incidence in all groups. CONCLUSION: In patients with symptoms of OAB who were inadequately managed by one or more anticholinergics, onabotulinumtoxinA 100U provided significant and similar treatment benefit and safety profile regardless of the number of prior anticholinergics used or reason for inadequate management of OAB. ClinicalTrials.gov: NCT00910845, NCT00910520. PMID- 24754840 TI - Implications of shale gas development for climate change. AB - Advances in technologies for extracting oil and gas from shale formations have dramatically increased U.S. production of natural gas. As production expands domestically and abroad, natural gas prices will be lower than without shale gas. Lower prices have two main effects: increasing overall energy consumption, and encouraging substitution away from sources such as coal, nuclear, renewables, and electricity. We examine the evidence and analyze modeling projections to understand how these two dynamics affect greenhouse gas emissions. Most evidence indicates that natural gas as a substitute for coal in electricity production, gasoline in transport, and electricity in buildings decreases greenhouse gases, although as an electricity substitute this depends on the electricity mix displaced. Modeling suggests that absent substantial policy changes, increased natural gas production slightly increases overall energy use, more substantially encourages fuel-switching, and that the combined effect slightly alters economy wide GHG emissions; whether the net effect is a slight decrease or increase depends on modeling assumptions including upstream methane emissions. Our main conclusions are that natural gas can help reduce GHG emissions, but in the absence of targeted climate policy measures, it will not substantially change the course of global GHG concentrations. Abundant natural gas can, however, help reduce the costs of achieving GHG reduction goals. PMID- 24754841 TI - Aerobic capacity and its correlates in patients with ankylosing spondylitis. AB - AIM: To evaluate aerobic capacity in patients with ankylosing spondylitis (AS) and determine possible relationships between aerobic capacity, pulmonary function, and disease-related variables. METHOD: Forty-two patients with AS and 42 healthy controls were recruited in the study. Descriptive data, disease related variables (grip strength, lumbosacral mobility, occiput-to-wall distance, chest expansion, finger-to-floor distance, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Global Score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and hemoglobin), and chest and thoracic spine x-rays were collected in each patient with AS. All subjects took standard pulmonary function and exercise tolerance tests, and forced vital capacity (FVC) and aerobic capacity were recorded. RESULTS: Both aerobic capacity and FVC in patients with AS were significantly lower than those in normal subjects (P < 0.05). AS patients with BASFI scores of < 3 or BASDI scores of < 4 had a higher aerobic capacity. There was significant correlation between aerobic capacity, vital capacity, chest expansion, Schober's test, cervical range of motion, and BASFI in patients with AS. Neither aerobic capacity nor vital capacity correlated with disease duration, ESR, CRP, and hemoglobin. CONCLUSIONS: Significantly reduced aerobic capacity and FVC were observed in patients with AS, and there was significant correlation between aerobic capacity, vital capacity, chest expansion, and BASFI. PMID- 24754843 TI - Application of oxidized starch in bake-only chicken nuggets. AB - There is a need to reduce the fat content in fried foods because of increasing health concerns from consumers. Oxidized starches have been utilized in many coating applications for their adhesion ability. However, it is not known if they perform similarly in bake-only products. This study investigated the application of oxidized starch in bake-only chicken nuggets. Oxidized starches were prepared from 7 starches and analyzed for gelatinization and pasting properties. Chicken nuggets were prepared using batter containing wheat flour, oxidized starch, salt, and leavening agents prior to steaming, oven baking, freezing, and final oven baking for sensory evaluation. All nuggets were analyzed for hardness by a textural analyzer, crispness by an acoustic sound, and sensory characteristics by a trained panel. The oxidation level used in the study did not alter the gelatinization temperature of most starches, but increased the peak pasting viscosity of both types of corn and rice starches and decreased that of tapioca and potato starches. There were slight differences in peak force and acoustic reading between some treatments; however, the differences were not consistent with starch type or amylose content. There was no difference among the treatments as well as between the control with wheat flour and the treatments partially replaced with oxidized starches in all sensory attributes of bake-only nuggets evaluated by the trained panel. PRACTICAL APPLICATION: There is a need to reduce the fat content in fried food, such as chicken nuggets, because of increasing childhood obesity. Oxidized starches are widely used in coating applications for their adhesion ability. This study investigated the source of oxidized starches in steam-baked coated nuggets for their textural and sensorial properties. The findings from this research will provide an understanding of the contributions of starch source and oxidation to the texture and sensory attributes of bake-only nuggets, and future directions to improve the batter formulation for bake-only nuggets. PMID- 24754846 TI - Management of recurrent miscarriage. AB - Recurrent miscarriage is classically defined as three or more consecutive pregnancy losses. Many researchers have now revised this definition to two or more pregnancy losses because of the recent increase in the prevalence of childless couples. Established causes of recurrent miscarriage are antiphospholipid antibodies, uterine anomalies and abnormal chromosomes in either partner, particularly translocations. Antiphospholipid syndrome is the most important treatable cause of recurrent miscarriage. However, it is not yet established as to what kind of testing should be conducted in patients with recurrent pregnancy loss. Standardization of tests for antiphospholipid antibodies is needed. On the other hand, embryonic aneuploidy is the most frequent cause of recurrent miscarriage. Chromosome analysis of the embryo is important, because it has good predictive value for subsequent live birth. It is not necessary to give any medications for unexplained cases of recurrent miscarriage, and provision of psychological support may be the most important to encourage the couples to continue to conceive until a live birth results. PMID- 24754844 TI - Patterns and associates of cognitive function, psychosocial wellbeing and health in the Lothian Birth Cohort 1936. AB - BACKGROUND: Cognitive function, psychosocial wellbeing and health are important domains of function. Consistencies and inconsistencies in patterns of wellbeing across these domains may be informative about wellbeing in old age and the ways it is manifested amongst individuals. In this study we investigated whether there were groups of individuals with different profiles of scores across these domains. We also aimed to identify characteristics of any evident groups by comparing them on variables that were not used in identifying the groups. METHODS: The sample was the Lothian Birth Cohort 1936, which included 1091 participants born in 1936. They are a community-dwelling, narrow-age-range sample of 70-year-olds. Most had taken part in the Scottish Mental Survey 1947 at an average age of 11, making available a measure of childhood intelligence. We used latent class analysis (LCA) to explore possible profiles using 9 variables indicating cognitive functioning, psychosocial wellbeing and health status. Demographic, personality, and lifestyle variables - none of which were used in the LCA - were used to characterize the resulting profile groups. RESULTS: We accepted a 3-group solution, which we labeled High Wellbeing (65.3%), Low Cognition (20.3%), and Low Bio-Psychosocial (14.5%). Notably, the High Wellbeing group had significantly higher childhood IQ, lower Neuroticism scores, and a lower percentage of current smokers than the other 2 groups. CONCLUSION: The majority of individuals were functioning generally well; however, there was evidence of the presence of groups with different profiles, which may be explained in part in terms of cognitive ability differences. Results suggested that higher life-long intelligence, personality traits associated with less mental distress, and basic health practices such as avoiding smoking are important associates of wellbeing in old age. PMID- 24754845 TI - Patient selection for whole brain radiotherapy (WBRT) in a large lung cancer cohort: Impact of a new Dutch guideline on brain metastases. AB - BACKGROUND: Median survival after diagnosis of brain metastases is, depending on the Recursive Partitioning Analysis (RPA) classes, 7.1 (class I) to 2.3 months (class III). In 2011 the Dutch guideline on brain metastases was revised, advising to withhold whole brain radiotherapy (WBRT) in RPA class III. In this large retrospective study, we evaluated the guideline's use in daily practice. MATERIAL AND METHODS: Data of 428 lung cancer patients undergoing WBRT for brain metastases (2004-2012) referred from three Dutch hospitals were retrospectively analyzed. Details on Karnofsky performance score (KPS), age, control of primary tumor, extracranial metastases, histology, and survival after diagnosis of brain metastases were collected. RPA class was determined using the first four items. RESULTS: In total 327 patients had non-small cell lung cancer (NSCLC) and 101 small cell lung cancer (SCLC). For NSCLC, 6.1%, 71.9%, and 16.2% were classified as RPA I, II, and III, respectively, and 5.8% could not be classified. For SCLC this was 8.9%, 66.3%, 14.9%, and 9.9%, respectively. Before the revised guideline was implemented, 11.3-21.3% of WBRT patients were annually classified as RPA III. In the year thereafter, this was 13.0% (p = 0.646). Median survival (95% CI) for NSCLC RPA class I, II, and III was 11.4 (9.9-12.9), 4.0 (3.4-4.7), and 1.7 (1.3 2.0) months, respectively. For SCLC this was 7.9 (4.1-11.7), 4.7 (3.3-6.1), and 1.7 (1.5-1.8) months. CONCLUSIONS: Although it is advised to withhold WBRT in RPA class III patients, in daily practice 11.3-21.3% of WBRT-treated patients were classified as RPA III. The new guideline did not result in a decrease. Reasons for referral of RPA III patients despite a low KPS were not found. Despite WBRT, survival of RPA III patients remains poor and this poor outcome should be stressed in practice guidelines. Therefore, better awareness amongst physicians would prevent some patients from being treated unnecessarily. PMID- 24754847 TI - Regulation of decidualization and angiogenesis in the human endometrium: mini review. AB - AIM: The human endometrium is a dynamic tissue that undergoes regular cycles of menstruation, menstrual repair, proliferation and secretory differentiation in response to hypoxia and the female sex hormones. METHODS: We identified new target genes that are regulated by progesterone during the decidualization of human endometrial stromal cells (ESC), including interleukin-15 (IL-15), fibulin 1 (FBLN-1), and heart and neural crest derivatives expressed transcript 2 (HAND2). RESULTS: IL-15 is deeply involved in the hormonal control of the human endometrium by progesterone and may be important in embryo implantation. FBLN-1 has been shown to be an important extracellular matrix that mediates progesterone action in human ESC differentiation toward implantation. Moreover, progestin induced HAND2 is a transcription factor that contributes to the increased levels of FBLN-1 in human ESC. Several mediators, including vascular endothelial growth factor (VEGF), angiopoietin (ANGPT) and stromal cell-derived factor 1 (SDF-1), regulate human endometrial angiogenesis. Hypoxia increased the expression of VEGF and decreased the expression of SDF-1 in ESCs. Furthermore, hypoxia reduced ANGPT1 levels in ESC; however, ANGPT2 levels were unaffected. Estradiol simultaneously induced the expressions of VEGF and SDF-1, suppressing ANGPT1 production. Therefore, hypoxia and estradiol caused an increase in the ANGPT2/ANGPT1 ratio. CONCLUSION: Hypoxia and female sex hormones are involved in the regulation of angiogenic factors in an independent manner in human ESC. Analysis of the process of decidualization and angiogenesis in the human endometrium would provide useful information for the fields of reproductive biology, regenerative medicine and tissue engineering. PMID- 24754848 TI - Letrozole versus clomiphene citrate for unexplained infertility: a systematic review and meta-analysis. AB - The objective of this study is to investigate and compare the effectiveness of letrozole and clomiphene citrate for improving fertility outcomes, including pregnancy rate, miscarriage rate, multiple pregnancy rate, and incidence rate of adverse events, number of dominant follicles, endometrial thickness at hCG day and serum E2 on hCG day. MEDLINE, EMBASE, CENTRAL, CNKI and CBMdisc databases were searched up to March 2013. Randomized controlled trials comparing letrozole with clomiphene in women with unexplained infertility were included. Pooled relative risk, mean difference and 95% confidence intervals were calculated. We found that there are no differences in pregnancy, miscarriage and multiple pregnancy rates, incidence rate of adverse events, number of dominant follicles (>18 mm) and endometrial thickness at hCG day in women with unexplained infertility between letrozole and clomiphene regimens. The mean (+/-standard deviation) concentration of serum E2 on hCG day was lower in those treated with letrozole than those with clomiphene. The subgroup of 2.5 mg letrozole displayed a statistically significant higher rate of clinical pregnancy as compared with 100 mg of clomiphene. The results of this study conclude that letrozole is as effective as clomiphene in women with unexplained infertility. Letrozole at a dose of 2.5 mg seems more effective. Further high-quality studies assessing the possible effectiveness of letrozole in selected groups of patients are warranted. PMID- 24754849 TI - Polymorphism in the epidermal growth factor gene is associated with pre-eclampsia and low birthweight. AB - AIM: We have previously reported that polymorphism in the epidermal growth factor (EGF) gene is associated with pre-eclampsia and birthweight based on case-control association studies involving two single nucleotide polymorphisms (SNP). We extended that work to investigate other SNP in the EGF gene for their association with pre-eclampsia and the weight of babies at birth. MATERIAL AND METHODS: A population-based DNA collection was genotyped to determine whether the selected SNP were polymorphic in the study population. In total, 175 women with pre eclampsia and 171 matched normotensive controls were genotyped for the polymorphic SNP using polymerase chain reaction/restriction fragment length polymorphism and MassARRAY Sequenom iPLEX methodology. RESULTS: The rs3756261A, rs4444903G, rs2237051G haplotype was associated with the highest increased risk of pre-eclampsia (odds ratio: 3.70, 95% confidence interval: 1.38-9.94; P = 0.016). The rs3756261A allele was the one that contributed to this high degree of significance. The same allele was present in the haplotype rs3756261A, rs11568943G, rs2237051G, rs11569017A, rs4698803T (likelihood ratio statistic = 20.4671, d.f. = 3, P-value = 0.0001), which was associated with the lower birthweight. CONCLUSIONS: In this study we found further evidence for the association of polymorphism in the EGF gene with pre-eclampsia and the weight of babies at birth and identified rs3756261A>G as the SNP that makes the most significant contribution to this association. Bioinformatic analysis showed that this effect may be mediated by caudal type homeohox-2, a transcriptional repressor expressed in the trophoblast, for which a binding site is created at this polymorphic site when the rs3756261A allele is present. PMID- 24754850 TI - Establishing measurements of subcutaneous and visceral fat area ratio in the early second trimester by magnetic resonance imaging in obese pregnant women. AB - AIM: Our aim was to establish measurements of subcutaneous fat area ratio (SFAR) and visceral fat area ratio (VFAR) in the early second trimester using magnetic resonance imaging (MRI) in an obese pregnant cohort. METHODS: Obesity was defined as pre-pregnancy body mass index of 25.0 or more. One hundred and twelve obese pregnant women with a singleton pregnancy gave written informed consent between April 2007 and April 2010. For determining the most suitable MRI slice level, four women lacking MRI slices at the level of L2-3 or L3-4, and two women upon whom MRI was performed at 14 and 19 weeks were excluded, and the remaining 106 women were analyzed. We developed a novel method for calculating SFAR and VFAR at 15-18 weeks using a T1-weighted spin echo sequence with fluid-attenuated inversion recovery for MRI where fat shows high signal intensity. RESULTS: MRI slices just above the uterine fundus at 15-18 weeks of gestation never included either the fundus or liver, but the other three slices always included either the liver or the uterus. In addition, the mean value of VFAR just above the uterine fundus was significantly larger than those at L2-3, L3-4 and navel position (47.3 +/- 1.1% vs 37.3 +/- 1.0%, 45.1 +/- 1.2%, 45.6 +/- 1.2%, respectively [P < 0.001]). CONCLUSION: The most suitable MRI slice level for calculating SFAR and VFAR may be just above the uterine fundus in pregnant women at 15-18 weeks of gestation. The evaluation of clinical significance of visceral adiposity for gestational diabetes mellitus is warranted. PMID- 24754851 TI - Additional surgical risk factors and patient characteristics for mesh erosion after abdominal sacrocolpopexy. AB - AIM: The aim of this study is to determine the risk factors of mesh exposures following abdominal sacral colpopexy (ASC) in which polypropylene mesh is used. METHODS: This is a retrospective cohort study of patients who underwent ASC and were subsequently followed for development of mesh exposure for vaginal/vault prolapse between 2002 and 2012. Demographics and risk factors of the patients who did develop mesh exposure after ASC and the ones who did not were compared. RESULTS: In 42 months of survey, 19 of the 292 patients who underwent ASC developed mesh exposure. It was found that rates of patients with stage 3-4 prolapse were significantly greater in the mesh exposure group than in the control group (P = 0.04). Rates of mesh exposure were lower in patients with previous hysterectomy (P = 0.03). Also, it was found that concomitant hysterectomy or three or more additional procedures increased the risk of mesh exposure (P = 0.03 and P = 0.02). CONCLUSION: In abdominal sacrocolpopexy operations in which polypropylene meshes are used, stage 3 or 4 prolapse, concomitant hysterectomy and three or more additional procedures increase the risk of mesh exposure development. PMID- 24754852 TI - Successful pregnancy in a woman with uterine scarring by transverse fundal cesarean section. AB - There has been only one case to date of pregnancy outcome after fundal transverse cesarean section (FTC). We report a pregnancy established after FTC. The FTC was performed at gestational week (GW) 24 in this patient's first pregnancy, but the uterus was preserved. Magnetic resonance imaging studies performed four times in her second pregnancy consistently showed part of the uterine fundus in which the muscle layer was interrupted. Concern regarding spontaneous uterine rupture in the absence of labor pains prompted us to interrupt her pregnancy at GW 31(+5) , delivering a premature, but otherwise healthy female infant, weighing 1832 g. The infant required transient intratracheal intubation for respiratory distress syndrome (for less than 1 h), but had an otherwise uneventful clinical course. Two cases, including ours, suggest that successful pregnancy outcome is feasible at least in some women with uterine scarring due to FTC. PMID- 24754853 TI - Concomitant ovarian drilling and oocyte retrieval by laparoendoscopic single-site surgery led to live birth using in vitro maturation of oocyte and transfer of frozen-thawed blastocyst in woman with polycystic ovary syndrome. AB - This case report describes a case of concomitant ovarian drilling and retrieval of oocytes using laparoendoscopic single-site surgery and the resultant birth of a healthy infant after transfer of frozen-thawed blastocyst from in vitro matured oocyte in a woman with polycystic ovary syndrome. A 33-year-old woman presented with anovulatory, clomiphene-resistant polycystic ovary syndrome, and 1-year history of infertility. Thirty-seven immature oocytes were retrieved and multiperforation of ovaries was performed at the same time by laparoendoscopic single-site surgery. Twenty-three oocytes reached metaphase II after 24-h culture in in vitro maturation medium, which was followed by intracytoplasmic sperm injection. Eventually, seven embryos were vitrified and spontaneous ovulation was restored after the operation. Although the first single frozen-thawed blastocyst transferred in a natural cycle ended up a biochemical pregnancy, the second frozen-thawed blastocyst transfer resulted in successful pregnancy, followed by live birth of a healthy male infant. PMID- 24754854 TI - Unusual ectopic pregnancies: a retrospective analysis of 65 cases. PMID- 24754855 TI - Response to unusual ectopic pregnancies: a retrospective analysis of 65 cases. PMID- 24754856 TI - Seeking genes responsible for developmental origins of health and disease from the fetal mouse liver following maternal food restriction. AB - Low birthweight resulting from a non-optimal fetal environment is correlated epidemiologically to a higher risk of adult diseases, and which has also been demonstrated using animal models for maternal undernutrition. In this study, we subjected pregnant mice to 50% food restriction (FR), and profiled gene expression and promoter DNA methylation genome-wide using the fetal livers. The fact that effect of food restriction is opposite between before and after birth encouraged us to hunt for genes that are expressed oppositely to adult calorie restriction (CR) using the maternal livers. Among oppositely regulated genes, we identified trib1 (tribbles homolog 1). Using genetically modified mice, trib1 has been shown to have a demonstrable contribution to a risk of hypertriglyceridaemia and insulin resistance. Our data showed that the trib1 expression and its promoter DNA methylation could be affected physiologically (by maternal nutrition), and therefore might be a strong candidate gene for developmental origins of adult diseases. Furthermore, lepr (leptin receptor) gene was downregulated by maternal FR, indicating its potential role in induction of obesity and diabetes. Gene expression as well as promoter DNA methylation profiling revealed that glucocorticoid receptor target genes were regulated by maternal FR. This supports previous studies that suggest an important role of fetal glucocorticoid exposure in the mechanism of developmental origins of diseases. Our transcriptomics profiling data also suggested that maternal FR impaired development of the immune system. An inventory of candidate genes responsible for developmental origins of health and disease is presented and discussed in this study. PMID- 24754857 TI - Arylative cyclization of 2-isocyanobiphenyls with anilines: one-pot synthesis of 6-arylphenanthridines via competitive reaction pathways. AB - A transition-metal-free method for the synthesis of C6 phenanthridine derivatives by arylative cyclization of 2-isocyanobiphenyls with arylamines in one pot was developed. Mechanistic studies suggest that electrophilic aromatic substitution (SEAr) of a nitrilium intermediate and homolytic aromatic substitution (HAS) of an imidoyl radical intermediate are two competitive reaction pathways involved in the annulation step. PMID- 24754858 TI - Diversity, social justice, and intersectionality trends in C/MFT: a content analysis of three family therapy journals, 2004-2011. AB - In this study, we analyzed the amount of attention given to diversity, social justice, and an intersectional approach to social inequalities over an 8-year period (769 articles) in three family therapy journals. Overall, 28.1% of articles addressed at least one diversity issue, and a social justice framework was utilized in 48.1% of diversity articles. A systemic, intersectional approach to conceptualizing and analyzing multiple social inequalities was utilized in 17.6% of diversity articles. The most common goals addressed in diversity articles, articles using a social justice framework, and articles using an intersectional approach are also identified. Findings indicate that, despite important work being carried out, more work remains to further identify how addressing diversity issues can improve client outcomes. PMID- 24754859 TI - The alliance in relationship education programs. AB - Couple relationship education (CRE) programs are associated with positive romantic relationship outcomes; however, the mechanisms by which these gains occur are less understood. The current study (122 couples) utilized actor-partner modeling to examine the association between the therapeutic alliance and dedication and negative and positive communication for racial/ethnic minority couples. Additionally, we examined whether gender and delivery format moderated these relationships. Results demonstrated that both men's and women's alliance scores were significantly related to their own outcomes. Higher ratings of alliance were related to partner outcomes for men only. The association between partners' alliance and dedication outcomes was stronger within the group format as compared to the couple format. Implications for leaders of CRE programs are offered. PMID- 24754867 TI - Breast reconstruction using de-epithelialized dermal flap after vertical-pattern skin-sparing mastectomy in macromastia. AB - INTRODUCTION: Prophylactic mastectomy is performed to reduce the risk of breast cancer in high-risk conditions, and expectations about reconstruction are too high. Implant coverage with healthy tissue and skin reducing as an envelope are two concerns in the treatment of macromastia cases. We present our results obtained with a prosthetic reconstruction technique using an inferior pedicled de epithelialized dermal flap after vertical-pattern skin-sparing mastectomy in this retrospective study. METHODS: Fourteen patients with macromastia and with a high risk of breast malignancy were treated with breast prosthesis using an inferior pedicled de-epithelialized dermal flap after vertical-pattern skin-sparing mastectomy, and were followed for 6 months to 2 years. RESULTS: Good aesthetic results were obtained in all of the patients with increased patient satisfaction. There were no serious complications and the patients were all satisfied. DISCUSSION: Since there is no dangerous T-point in vertical-pattern skin-sparing mastectomy in contrast to an inverted-T wise-pattern technique, where flaps are connected under great tension and susceptible to separation, it can be used safely in macromastia cases, as in smaller breasts. In addition, a de epithelialized dermal flap is quite useful to cover the inferior pole of the prosthesis and it eliminates the need for an acellular dermal matrix. PMID- 24754868 TI - Angiogenesis in bone regeneration: tailored calcium release in hybrid fibrous scaffolds. AB - In bone regeneration, silicon-based calcium phosphate glasses (Bioglasses) have been widely used since the 1970s. However, they dissolve very slowly because of their high amount of Si (SiO2 > 45%). Recently, our group has found that calcium ions released by the degradation of glasses in which the job of silicon is done by just 5% of TiO2 are effective angiogenic promoters, because of their stimulation of a cell-membrane calcium sensing receptor (CaSR). Based on this, other focused tests on angiogenesis have found that Bioglasses also have the potential to be angiogenic promoters even with high contents of silicon (80%); however, their slow degradation is still a problem, as the levels of silicon cannot be decreased any lower than 45%. In this work, we propose a new generation of hybrid organically modified glasses, ormoglasses, that enable the levels of silicon to be reduced, therefore speeding up the degradation process. Using electrospinning as a faithful way to mimic the extracellular matrix (ECM), we successfully produced hybrid fibrous mats with three different contents of Si (40, 52, and 70%), and thus three different calcium ion release rates, using an ormoglass-polycaprolactone blend approach. These mats offered a good platform to evaluate different calcium release rates as osteogenic promoters in an in vivo subcutaneous environment. Complementary data were collected to complement Ca(2+) release analysis, such as stiffness evaluation by AFM, zeta-potential, morphology evaluation by FESEM, proliferation and differentiation analysis, as well as in vivo subcutaneous implantations. Material and biological characterization suggested that compositions of organic/inorganic hybrid materials with a Si content equivalent to 40%, which were also those that released more calcium, were osteogenic. They also showed a greater ability to form blood vessels. These results suggest that Si-based ormoglasses can be considered an efficient tool for calcium release modulation, which could play a key role in the angiogenic promoting process. PMID- 24754869 TI - Medical students as hospice volunteers: reflections on an early experiential training program in end-of-life care education. AB - BACKGROUND: Despite an increase in the content of palliative medicine curricula in medical schools, students are rarely exposed to end-of-life (EOL) care through real-patient experiences during their preclinical education. OBJECTIVE: To evaluate the utility and impact of exposure to EOL care for first year medical students (MS-1s) through a hospice volunteer experience. METHODS: Patients and Families First (PFF), a hospice volunteer training program in EOL care, was piloted on three cohorts of MS-1s as an elective. Fifty-five students received 3 hours of volunteer training, and were then required to conduct at least two consecutive hospice visits on assigned patients to obtain course credit. Students' reflective essays on their experiences were analyzed using qualitative methodology and salient themes were extracted by two investigators independently and then collaboratively. RESULTS: The following five themes were identified from students' reflective essays: perceptions regarding hospice patients; reactions regarding self; normalcy of EOL care at home; impact of witnessing death and dying; and suggestions for improving EOL care education for medical students. CONCLUSION: Hospice volunteering during preclinical years may provide valuable experiential training for MS-1s in caring for seriously ill patients and their families by fostering personal reflection and empathic skills, thereby providing a foundation for future patient encounters during clinical training. PMID- 24754871 TI - Synthetic polyglutamylation of dual-functional MTX ligands for enhanced combined cytotoxicity of poly(I:C) nanoplexes. AB - The antifolate drug methotrexate (MTX) can serve as a dual-functional ligand in antitumoral drug delivery, inducing both a folate receptor mediated cellular uptake and an intracellular cytotoxic action. Bioactivity of MTX however changes by conjugation; the activity can be affected by the hampered intracellular conversion to more potent poly-gamma-glutamyl derivatives. Therefore, in a cancer combination therapy approach for the codelivery of cytotoxic dsRNA polyinosinic polycytidylic acid poly(I:C), a set of molecularly precise oligo(ethanamino)amides were synthesized comprising poly(ethylene glycol) conjugated MTX ligands. The conjugates differed in the number of additional glutamic acid residues to investigate the effect of different degrees of synthetic "a priori" polyglutamylation. The bioactivity of these compounds concerning dihydrofolate reductase (DHFR) inhibition, cytotoxicity, nucleic acid binding potency, cellular uptake of poly(I:C) polyplexes, and combined antifolate/poly(I:C) toxicity was investigated. Synthetic polyglutamylation had a crucial impact on several stages of efficient poly(I:C) delivery and combined MTX cytotoxicity. DHFR inhibition of the conjugates significantly increased with increasing polyglutamate chain length. The library member with highest glutamylation degree even outperformed free MTX in direct comparison. Studies in KB cells showed the corresponding enhanced cytotoxicity by polyglutamylation. Also poly(I:C) polyplexes of the glutamylated MTX variants exhibited higher cellular uptake in the folate receptor positive cell line. Finally, a synergistic combined cytotoxicity of polyglutamylated MTX ligands and complexed poly(I:C) cargo was observed in transfected KB cells. The present structure-activity relationship study of MTX-based ligands pinpoints the concept of synthetic polyglutamylation as a promising approach for optimizing bioactivity of antifolate conjugates, which might be considered as a useful tool also in context of other drug delivery systems. PMID- 24754870 TI - Prevalence and predictors of adult hypertension in Kabul, Afghanistan. AB - BACKGROUND: The prevalence of hypertension is rising worldwide with an estimated one billion people now affected globally and is of near epidemic proportions in many parts of South Asia. Recent turmoil has until recently precluded estimates in Afghanistan so we sought, therefore, to establish both prevalence predictors in our population. METHODS: We conducted a cross-sectional study of adults >=40 years of age in Kabul from December 2011-March 2012 using a multistage sampling method. Additional data on socioeconomic and lifestyle factors were collected as well as an estimate of glycaemic control. Bivariate and multivariable analyses were undertaken to explore the association between hypertension and potential predictors. RESULTS: A total of 1183 adults (men 396, women 787) of >= 40years of age were assessed. The prevalence of hypertension was 46.2% (95% CI 43.5 - 49.3). Independent predictors of hypertension were found to be: age >=50 (OR = 3.86, 95% CI: 2.86 - 5.21); illiteracy (OR = 1.90, 1.05 - 1.90); the consumption of rice >3 times per week (OR = 1.43, 1.07 - 1.91); family history of diabetes (OR = 2.20, 1.30 - 3.75); central obesity (OR = 1.67, 1.23 - 2.27); BMI >= 30 Kg/meter squared (OR = 2.08, 1.50 - 2.89). The consumption of chicken and fruit more than three times per week were protective with ORs respectively of 0.73 (0.55-0.97) and 0.64 (0.47 - 0.86). CONCLUSIONS: Hypertension is a major public health problem in Afghan adults. We have identified a number of predictors which have potential for guiding interventions. PMID- 24754872 TI - Health coaching for low back pain: a systematic review of the literature. AB - OBJECTIVE: To systematically review the evidence for health coaching for patients with low back pain and describe the diversity of health coach training and interventions. METHODS: Electronic databases Medline, CINAHL, EMBASE, PsycINFO, AMED and the Cochrane Central Register of Controlled Trials were searched to 24 June 2013 using individually devised strategies. Randomised or quasi randomised controlled trials (RCTs) of health coaching for adults with low back pain of any duration were considered. The overall quality of the body of evidence was assessed using the GRADE approach. Treatment effects were presented as the difference in mean scores with 95% confidence intervals and standardised mean difference at follow-up between health coaching and control groups. Health coaching interventions were compared narratively by their theoretical principles and the training and assessment of heath coaches. RESULTS: Five publications describing three RCTs and one cluster RCT met the criteria for review. A rating of very low was assigned to the body of evidence using the GRADE approach. One RCT found significant improvements in lifting capacity and exercise compliance in favour of the health coaching group at both follow-up points with a large and moderate standardised mean difference. All included studies based health coaching interventions on the transtheoretical model of change however, the content of counselling programmes varied between studies and measures of treatment fidelity were inconclusive. DISCUSSION: Variability in health coaching interventions and a lack of assessment of treatment fidelity in addition to the very low rating of the overall body of evidence identified in the current review renders any estimates of the effect of health coaching on low back pain uncertain. Well designed RCTs of patients with sub-acute low back pain are required that incorporate clearly described protocols for health coaching interventions and include standardised measures of treatment fidelity. PMID- 24754874 TI - Characterization of food-grade titanium dioxide: the presence of nanosized particles. AB - Titanium dioxide (TiO2) is widely used in food products, which will eventually enter wastewater treatment plants and terrestrial or aquatic environments, yet little is known about the fraction of this TiO2 that is nanoscale, or the physical and chemical properties of TiO2 that influence its human and environmental fate or toxicity. Instead of analyzing TiO2 properties in complex food or environmental samples, we procured samples of food-grade TiO2 obtained from global food suppliers and then, using spectroscopic and other analytical techniques, quantified several parameters (elemental composition, crystal structure, size, and surface composition) that are reported to influence environmental fate and toxicity. Another sample of nano-TiO2 that is generally sold for catalytic applications (P25) and widely used in toxicity studies, was analyzed for comparison. Food-grade and P25 TiO2 are engineered products, frequently synthesized from purified titanium precursors, and not milled from bulk scale minerals. Nanosized materials were present in all of the food-grade TiO2 samples, and transmission electron microscopy showed that samples 1-5 contained 35, 23, 21, 17, and 19% of nanosized primary particles (<100 nm in diameter) by number, respectively (all primary P25 particles were <100 nm in diameter). Both types of TiO2 aggregated in water with an average hydrodynamic diameter of >100 nm. Food-grade samples contained phosphorus (P), with concentrations ranging from 0.5 to 1.8 mg of P/g of TiO2. The phosphorus content of P25 was below inductively coupled plasma mass spectrometry detection limits. Presumably because of a P-based coating detected by X-ray photoelectron spectroscopy, the zeta potential of the food-grade TiO2 suspension in deionized water ranged from -10 to -45 mV around pH 7, and the iso-electric point for food grade TiO2 (= 20% decrease in the post-exercise Peak Expiratory Flow Rate (PEFR) values was the criterion for diagnosing exercise-induced asthma. RESULTS: The mean age of participants was 16.8 (+/-1.8) years. The prevalence of wheeze in the past 12 months was 12.1% in Bagamoyo district and 23.1% in Ilala district (p < 0.001). Self-reported asthma was found in 17.6% and 6.4% of pupils in Ilala and Bagamoyo districts, respectively (p < 0.001). The prevalence of exercise-induced asthma was 2.4% in Bagamoyo, and 26.3% in Ilala (P < 0.002). In both districts, most information on asthma came from parents, and there was variation in symptoms and triggers of asthma reported by the pupils. Non-asthmatic pupils feared sleeping, playing, and eating with their asthmatic peers. CONCLUSION: The prevalence rates of self-reported asthma, wheezing in the past 12 months, and exercise-induced asthma were significantly higher among urban than rural pupils. Although bronchial asthma is a common disease, pupils' perceptions about asthma were associated with fear of contact with their asthmatic peers in both rural and urban schools. PMID- 24754896 TI - Sentinel lymph node biopsy before mastectomy and immediate breast reconstruction does not significantly delay surgery in early breast cancer. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) before mastectomy and immediate breast reconstruction (IBR) may help to avoid the negative cosmetic effects of radiotherapy on reconstructed breasts in lymph node-positive patients. Concerns have been raised regarding possible delays whilst awaiting the SLNB result prior to definitive surgery, which needs to be performed within 31 days of cancer diagnosis. The aim was to investigate whether initial SLNB delays mastectomy and IBR. METHODS: All patients who had IBR between January 2005 and 2007 were reviewed retrospectively. Before October 2005 axillary staging was performed simultaneously with mastectomy and IBR (Group I). After October 2005, SLNB was performed as an initial procedure and patients with positive SLNB were only offered a temporary tissue expander to be replaced by autogenous reconstruction after completing the cancer treatment (Group II). Date of diagnosis and waiting times were recorded and the two groups were compared. Different reasons for delays in treatment were studied. RESULTS: One hundred and thirty-nine IBR (123 patients) were included in the statistical analysis (67 IBR in Group I and 72 IBR in Group II). Seventy-one patients (57.7%) had no delay (mean waiting time of 23 days). Fifty-two patients (42.3%) had delay longer than 31 days (mean waiting time of 66 days). Group I patients had a mean waiting time (standard deviation) of 38.8 (38) days and Group II patients 42.7 (24) days (p = 0.51). CONCLUSIONS: In this group of patients, SLNB before mastectomy and IBR does not significantly delay definitive breast cancer surgery. PMID- 24754897 TI - PEG-stabilized bilayer nanodisks as carriers for doxorubicin delivery. AB - Spherical nanoparticles as a classic delivery vehicle for anticancer drugs have been extensively investigated, but study on the shape of nanoparticles has received little attention until now. Here, a nonspherical poly(ethylene glycol) (PEG)-stabilized bilayer nanodisk consisting of 1,2-distearyl-sn-glycero-3 phosphocholine (DSPC) and PEG5000-glyceryl distearate (PEG5K-GCDS) was prepared for doxorubicin delivery, called DOX-Disks. The prepared disks were open bilayer structures, with a hydrophobic discoid center built by DSPC and a hydrophilic PEG edge. Mean particle diameter of the disk was 80.14 nm, and the disk height was about 6 nm with aspect ratio about 12. Encapsulation efficiency of DOX-Disks was as high as 96.1%, and DOX release from DOX-Disks was pH-dependent (25.6% of total DOX released at 24 h in pH 7.4). The pharmacokinetic performances showed that DOX Disks demonstrated long circulation time in blood and larger AUC (11.7-fold of t1/2 and 31.7-fold of AUC) in rats compared with DOX solutions (DOX-Sol). Tissue distribution in H22 tumor bearing mice demonstrated higher tumor accumulation (9.7-fold) and lower heart toxicities (25.7-fold) at 48 h after iv administration, in comparison with DOX-Sol. In addition, DOX-Disks exhibited much effectiveness in inhibiting tumor cell growth, and the IC50 values were 2.03, 0.85, and 0.86 MUg/mL for DOX-Sol and 0.23, 0.24, and 0.20 MUg/mL for DOX-Disks after treatment for 48, 72, and 96 h against MCF-7/Adr cells, respectively. DOX Disks were taken up into MCF-7/Adr cells via energy-dependent endocytosis processes, involved in clathrin-mediated, macropinocytosis-mediated, and non clathrin- and non-caveolae-mediated endocytosis pathways. In summary, such PEG stabilized bilayer nanodisks could be one of the promising carriers for antitumor drugs via extended blood circulation and improved tumor distribution. PMID- 24754898 TI - Evaluation of genetic introgression from domesticated pigs into the Ryukyu wild boar population on Iriomote Island in Japan. AB - We evaluated genetic introgression from domesticated pigs into the Ryukyu wild boar (RWB) population on Iriomote Island based on their genetic structure and diversity. We used a combination of mitochondrial DNA D-loop region (596 bp) polymorphisms and 23 microsatellite markers. RWBs (n = 130) were collected from 18 locations on Iriomote Island and compared with 66 reference samples of European and Asian domestic pigs. We identified six distinct haplotypes, involving 22 single nucleotide polymorphisms (including one insertion) in the RWB population. The phylogenetic tree had two branches: the RWB group and domestic lineage. Fourteen of 130 RWBs (10.8%) belonged to the European domestic lineage, including 11 RWBs from the Panari Islands, northwest of Iriomote Main Island (IMI). The heterozygosity values, total number of alleles, number of effective alleles and polymorphism information content of the RWB groups were lower than those of the European domestic groups. The RWB population on IMI had a lower heterozygous deficiency index (FIS = 0.059) than did the other populations, which indicates that this population was more inbred. There was a large genetic distance (FST = 0.560) between RWBs on IMI and the Meishan populations. Structure analysis using the 23 microsatellite markers revealed that 16 RWBs had an admixture pattern between RWB and domesticated pig breeds. These results suggest that gene flow may have occurred from domestic pigs to RWBs and demonstrate that there was low genetic variation in the IMI population. PMID- 24754899 TI - Laparoscopic partial nephrectomy for multilocular cystic renal cell carcinoma: a potential gold standard treatment with excellent perioperative outcomes. AB - BACKGROUND: To report on the perioperative outcomes of laparoscopic partial nephrectomy (LPN) for multilocular cystic renal cell carcinoma (MCRCC) and evaluate the feasibility of this minimally invasive technique as a potential gold standard treatment for MCRCC. METHODS: We retrospectively reviewed the database of surgically pathological findings of patients who were diagnosed with MCRCC at Peking University First Hospital and Chinese PLA General Hospital (Beijing, China) between May 2009 and January 2013. A total of 42 patients with an average age of 48.3 years who were treated with LPN were collected. The patients' perioperative outcomes were reported and analyzed. RESULTS: All operations were performed successfully without massive hemorrhage or open conversion. None of patients received lymph node dissection or metastasectomy. Two patients required postoperative transfusion with a mean amount of 175 cc packed red blood cells. Only three patients experienced mild postoperative complications. The mean operative time was 2.4 +/- 1.2 hours, including the mean warm ischemia time (WIT) of 23.2 +/- 5.7 minutes. The mean estimated blood loss was 72.0 +/- 49.6 ml. The mean retroperitoneal drainage was 4.4 +/- 1.7 days. The mean postoperative hospital stay was 6.1 +/- 1.9 days. Pathologically, 40 (95.2%) of the tumors presented as stage pT1abN0M0, while the remaining two (4.8%) presented as stage pT2aN0M0. No recurrences or new lesions occurred in these patients at a mean follow-up time of 30.0 months. CONCLUSIONS: Although the effective option of LPN is not yet the gold standard treatment for conventional renal cell carcinoma, it should be strongly recommended as a potential gold standard treatment for MCRCC due to the benign nature of MCRCC and the excellent perioperative outcomes provided by LPN. PMID- 24754900 TI - Neurotoxocarosis: marked preference of Toxocara canis for the cerebrum and T. cati for the cerebellum in the paratenic model host mouse. AB - BACKGROUND: Infective larvae of the worldwide occurring zoonotic roundworm T. canis exhibit a marked affinity to the nervous tissues of paratenic hosts. In humans, most cases of neurotoxocarosis are considered to be caused by larvae of T. canis as T. cati larvae have rarely been found in the CNS in previous studies. However, direct comparison of studies is difficult as larval migration depends on a variety of factors including mouse strains and inoculation doses. Therefore, the present study aims to provide a direct comparison of both roundworm species in mice as a model for paratenic hosts with specific focus on the CNS during the acute and chronic phase of disease to provide a basis for further studies dealing with neurotoxocarosis. METHODS: C57Bl/6J mice were infected with 2000 embryonated T. canis and T. cati eggs, respectively as well as Balb/c mice infected with T. cati eggs only. On 8 time points post infection, organs were removed and microscopically examined for respective larvae. Special focus was put on the CNS, including analysis of larval distribution in the cerebrum and cerebellum, right and left hemisphere as well as eyes and spinal cord. Additionally, brains of all infection groups as well as uninfected controls were examined histopathologically to characterize neurostructural damage. RESULTS: Significant differences in larval distribution were observed between and within the infection groups during the course of infection. As expected, significantly higher recovery rates of T. canis than T. cati larvae were determined in the brain. Surprisingly, significantly more T. canis larvae could be found in cerebra of infected mice whereas T. cati larvae were mainly located in the cerebellum. Structural damage in brain tissue could be observed in all infection groups, being more severe in brains of T. canis infected mice. CONCLUSIONS: The data obtained provides an extensive characterization of migrational routes of T. canis and T. cati in the paratenic host mouse in direct comparison. Even though to a lesser extent, structural damage in the brain was also caused by T. cati larvae and therefore, the potential as pathogenic agents should not be underestimated. PMID- 24754901 TI - Identification of B-cell lymphoma subsets by plasma protein profiling using recombinant antibody microarrays. AB - B-cell lymphoma (BCL) heterogeneity represents a key issue, often making the classification and clinical management of these patients challenging. In this pilot study, we outlined the first resolved view of BCL disease heterogeneity on the protein level by deciphering disease-associated plasma biomarkers, specific for chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma, using recombinant antibody microarrays targeting mainly immunoregulatory proteins. The results showed the BCLs to be heterogeneous, and revealed potential novel subgroups of each BCL. In the case of diffuse large B-cell lymphoma, we also indicated a link between the novel subgroups and survival. PMID- 24754902 TI - Combined DaT imaging and olfactory testing for differentiating parkinsonian disorders. AB - OBJECTIVE: Dopamine transporter (DaT) imaging with single photon emission computed tomography (SPECT) detects loss of striatal dopaminergic innervation with very high sensitivity. It cannot readily distinguish idiopathic Parkinson's disease (iPD) and dementia with Lewy bodies (DLB) from atypical disorders (aPD). However, most iPD/DLB patients are hyposmic, whereas the majority of aPD patients were reported to have intact olfaction. For this reason, we conducted a longitudinal follow-up study to investigate the power of combined DaT imaging and olfactory testing to predict the final diagnosis of the patients. MATERIALS AND METHODS: A total of 129 patients received [123I]FP-CIT SPECT and olfactory testing at baseline assessment. Clinical follow-up 30 +/- 12 months later was the diagnostic standard of truth. A normative dataset of 24 healthy controls was used for comparison. RESULTS: Baseline DaT imaging predicted a dopamine-deficient diagnosis with 98% sensitivity and 98% specificity. The combined DaT/olfactory testing correctly classified 91% of patients as iPD/DLB (PPV 91%). The PPV rose to 97% or greater in anosmic patients. In contrast, only 45% of aPD patients were categorised correctly by combined DaT/olfactory testing - mainly because of the presence of normosmic iPD patients. CONCLUSIONS: In patients with an abnormal DaT SPECT, hyposmia yields an a posteriori likelihood of iPD/DLB of > 90%. In contrast, a finding of normosmia only increases the a posteriori likelihood of aPD to approximately the 50%. PMID- 24754903 TI - Clinical and inflammatory response to bloodstream infections in octogenarians. AB - BACKGROUND: Given the increasing incidence of bacteraemia causing significant morbidity and mortality in older patients, this study aimed to compare the clinical features, laboratory findings and mortality of patients over the age of 80 to younger adults. METHODS: This study was a retrospective, observational study. Participants were taken to be all patients aged 18 and above with confirmed culture positive sepsis, admitted to a large metropolitan hospital in the year 2010. Measurements taken included patient demographics (accommodation, age, sex, comorbidities), laboratory investigations (white cell count, neutrophil count, C-reactive protein, microbiology results), clinical features (vital signs, presence of localising symptoms, complications, place of acquisition). RESULTS: A total of 1367 patient episodes were screened and 155 met study inclusion criteria. There was no statistically significant difference between likelihood of fever or systolic blood pressure between younger and older populations (p-values of 0.81 and 0.64 respectively). Neutrophil count was higher in the older cohort (p = 0.05). Higher Charlson (J Chronic Dis 40(5):373-383, 1987) comorbidity index, greater age and lower systolic blood pressure were found to be statistically significant predictors of mortality (p-values of 0.01, 0.02 and 0.03 respectively). CONCLUSION: The findings of this study indicate older patients are more likely to present without localising features. However, importantly, there is no significant difference in the likelihood of fever or inflammatory markers. This study also demonstrates the importance of the Charlson Index of Comorbidities (J Chronic Dis 40(5):373-383, 1987) as a predictive factor for mortality, with age and hypotension being less important but statistically significant predictive factors of mortality. PMID- 24754904 TI - Human placenta-derived neurospheres are susceptible to transformation after extensive in vitro expansion. AB - INTRODUCTION: The cancer stem cell model links neoplastic cells with normal stem cell biology, but little is known on how normal stem cells are transformed into cancer stem cells. METHODS: To investigate the processes underlying the transformation of normal stem cells we developed in vitro a cancer stem cell model from human amniotic and chorionic placenta membranes. In this model we studied the expression of specific stem cell molecules by flow cytometry, and genes, by real time RT-PCR. Microscopy immunfluorescence was employed to investigate the proliferative and differentiation patterns. Fluorescence microscopy and FACS were employed to investigate the proliferative and differentiation patterns. To evaluate the tumorigenic potential of our model we injected the cells into NOD.CB17-Prkdcscid/NCrHsd mice. RESULTS: Normal human stem cells from amniotic and chorionic placenta membranes were converted into neural cell lineages, under specific conditions, to form secondary neurospheres with a capacity for self-renewal. After extensive in vitro culture, these cells underwent spontaneous transformations and acquired a neuroblastoma (NB)-like phenotype with an elevated proliferative potential that is comparable to established neuroblastoma cell lines. The ability of these cells to transform their phenotype was evidenced by increased clonogenic ability in vitro; by augmented expression level of certain proliferation- and transformation-related genes (e.g., CCNA2, MYCN, ENPP2, GRIA3, and KIT); by the presence of multinucleated and hyperdiploid cells. We further demonstrated that the transformed phenotype is an NB by measuring the expression of NB-specific markers, disialoganglioside GD2 and N-Myc proteins. CONCLUSIONS: We have developed a cancer stem cell model starting from normal human stem cells derived from amniotic and chorionic placenta membranes. These cells are able to differentiate into neural cell lineages and to undergo spontaneous transformations and acquire an NB-like phenotype. PMID- 24754905 TI - Snacking patterns, diet quality, and cardiovascular risk factors in adults. AB - BACKGROUND: The relationship of snacking patterns on nutrient intake and cardiovascular risk factors (CVRF) in adults is unknown. The aim of this study was to examine the associations of snacking patterns with nutrient intake, diet quality, and a selection of CVRF in adults participating in the 2001-2008 National Health and Nutrition Examination Survey. METHODS: 24-hour dietary recalls were used to determine intake and cluster analysis was used to identify the snacking patterns. Height and weight were obtained and the health indices that were evaluated included diastolic and systolic blood pressure, high density lipoprotein-cholesterol, low density lipoprotein cholesterol, triacylglycerides, blood glucose, and insulin. RESULTS: The sample was participants (n = 18,988) 19+ years (50% males; 11% African-Americans; 72% white, 12% Hispanic-Americans, and 5% other). Cluster analyses generated 12 distinct snacking patterns, explaining 61% of the variance in snacking. Comparisons of snacking patterns were made to the no snack pattern. It was found that miscellaneous snacks constituted the most common snacking pattern (17%) followed by cakes/cookies/pastries (12%) and sweets (9%). Most snacking patterns were associated with higher energy intakes. Snacking patterns cakes/cookies/pastries, vegetables/legumes, crackers/salty snacks, other grains and whole fruit were associated with lower intakes of saturated fatty acids. Added sugars intakes were higher in the cakes/cookies/pastries, sweets, milk desserts, and soft drinks patterns. Five snack patterns (cakes/cookies/pastries, sweets, vegetable/legumes, milk desserts, soft drinks) were associated with lower sodium intakes. Several snack patterns were associated with higher intakes of potassium, calcium, fiber, vitamin A, and magnesium. Five snacking patterns (miscellaneous snacks; vegetables/legumes; crackers/salty snacks; other grains; and whole fruit) were associated with better diet quality scores. Alcohol was associated with a lower body mass index and milk desserts were associated with a lower waist circumference. No snack patterns were associated with other CVRF studied. CONCLUSIONS: Overall, several snacking patterns were associated with better diet quality than those consuming no snacks. Yet, the majority of the snacking patterns were not associated with CVRF. Education is needed to improve snacking patterns in terms of nutrients to limit in the diet along with more nutrient-dense foods to be included in snacks. PMID- 24754907 TI - Emotion regulation predicts symptoms of depression over five years. AB - Deficits in emotion regulation have been identified as an important risk and maintaining factor for depression. The aim of this study was to examine the long term effects of emotion regulation on symptoms of depression. Moreover, we investigated which specific emotion regulation skills were associated with subsequent symptoms of depression. Participants were 116 individuals (78% women, average age 35.2 years) who registered for an online-based assessment of depression and its risk-factors and reported at least some symptoms of depression. Successful application of emotion regulation skills and depressive symptom severity were assessed twice over a 5-year period. We utilized cross lagged panel analyses to assess whether successful skills application would be negatively associated with subsequent depressive symptom severity. Cross-lagged panel analyses identified successful skills application as a significant predictor for depressive symptom severity even when controlling for the effects of initial symptoms of depression. A comparison of the effect sizes for different emotion regulation skills on subsequent depressive symptoms suggests that most of the skills included have similar predictive value. These findings provide preliminary evidence for the hypotheses that deficits in emotion regulation may contribute to the development of depression and that interventions systematically enhancing adaptive emotion regulation skills may help prevent and treat depressive symptoms. PMID- 24754908 TI - Catalyst-free synthesis of Si-SiOx core-shell nanowire anodes for high-rate and high-capacity lithium-ion batteries. AB - Si-SiOx core-shell nanowires (NWs) ranging from 10 to 30 nm in diameter are prepared by a simple evaporation of silicon monoxide and control of substrate temperatures without any catalyst. The Si-SiOx NWs grown at 735 and 955 degrees C are strongly anchored to the Cu current collector by forming copper silicide at the interface between Si and Cu, and subsequently used as anodes in lithium-ion batteries, in which no binder or conducting materials are used. The Si-SiOx NWs anodes show excellent electrochemical performances in terms of capacity retention and rate capability. In particular, the Si-SiOx NW anode grown at 955 degrees C shows a reversible capacity of ~1000 mAh g(-1) even at a high-rate of 50 C. This catalyst-free synthetic route of Si-SiOx NWs that are strongly anchored to the Cu current collector opens up an effective process for fabricating other high capacity anodes in lithium-ion batteries (LIBs). PMID- 24754906 TI - All-atomic molecular dynamic studies of human CDK8: insight into the A-loop, point mutations and binding with its partner CycC. AB - The Mediator, a conserved multisubunit protein complex in eukaryotic organisms, regulates gene expression by bridging sequence-specific DNA-binding transcription factors to the general RNA polymerase II machinery. In yeast, Mediator complex is organized in three core modules (head, middle and tail) and a separable 'CDK8 submodule' consisting of four subunits including Cyclin-dependent kinase CDK8 (CDK8), Cyclin C (CycC), MED12, and MED13. The 3-D structure of human CDK8-CycC complex has been recently experimentally determined. To take advantage of this structure and the improved theoretical calculation methods, we have performed molecular dynamic simulations to study dynamics of CDK8 and two CDK8 point mutations (D173A and D189N), which have been identified in human cancers, with and without full length of the A-loop, as well as the binding between CDK8 and CycC. We found that CDK8 structure gradually loses two helical structures during the 50-ns molecular dynamic simulation, likely due to the presence of the full length A-loop. In addition, our studies showed the hydrogen bond occupation of the CDK8 A-loop increases during the first 20-ns MD simulation and stays stable during the later 30-ns MD simulation. Four residues in the A-loop of CDK8 have high hydrogen bond occupation, while the rest residues have low or no hydrogen bond occupation. The hydrogen bond dynamic study of the A-loop residues exhibits three types of changes: increasing, decreasing, and stable. Furthermore, the 3-D structures of CDK8 point mutations D173A, D189N, T196A and T196D have been built by molecular modeling and further investigated by 50-ns molecular dynamic simulations. D173A has the highest average potential energy, while T196D has the lowest average potential energy, indicating that T196D is the most stable structure. Finally, we calculated theoretical binding energy of CDK8 and CycC by MM/PBSA and MM/GBSA methods, and the negative values obtained from both methods demonstrate stability of CDK8-CycC complex. Taken together, these analyses will improve our understanding of the exact functions of CDK8 and the interaction with its partner CycC. PMID- 24754910 TI - How good are ensembles in improving QSAR models? The case with eCoRIA. AB - A conceptually new idea in quantitative structure-activity relationships (QSAR) which makes use of ensembles from molecular dynamics (MD) trajectories and information retrieved from enzyme-inhibitor binding thermodynamics is presented in this study. This new methodology, termed ensemble comparative residue interaction analysis (eCoRIA), attempts to overcome the current one chemical-one structure-one parameter value dogma in computational chemistry by modeling the biological activity as a function of molecular descriptors derived from an ensemble of conformers of enzyme-inhibitor complexes. The approach is distinctly different from the standard QSAR methodology which uses a single low-energy conformation or the properties averaged over a set of conformers to correlate with the activity. Each conformational ensemble derived from MD simulations is analyzed for the distribution of the non-bonded interaction energies (steric, electrostatic, and hydrophobic) along with solvation, strain, and entropic energy of the inhibitors with the individual amino acid residues in the receptor and these are correlated to the activity through a QSAR model. The scope of the new method is demonstrated with three diverse enzyme-inhibitor data-sets - glycogen phosphorylase b, human immunodeficiency virus-1 protease and cyclin-dependent kinase 2. The QSAR equations derived from the methodology have revealed all the structure activity relationships previously reported for these classes of molecules as well as uncovered some features that were hitherto unknown and may have a hidden role in driving the ligand-receptor-binding process. Impressive improvements in the predictions of affinity have been achieved compared to other QSAR formalisms namely CoMFA, CoMSIA (receptor-independent QSAR techniques), and CoRIA (a receptor-dependent QSAR technique). eCoRIA could provide an understanding of the thermodynamic properties influencing the ligand-receptor binding over a time scale as sampled by the MD simulation. The advantage of analyzing enzyme-inhibitor interaction energies in a statistical domain is that the noise due to inaccuracies in the potential energy functions can be reduced and mechanistically important interaction terms related to protein-ligand binding specificity can be identified which can assist the medicinal chemists in designing new molecules and biologists in studying the influence of position specific mutations in the receptor on ligand binding. PMID- 24754912 TI - Behavioral and anticonvulsant effects of the standardized extract of Ficus platyphylla stem bark. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Decoctions of Ficus platyphylla Del.-Holl (Family: Moraceae) are used in Nigeria's folk medicine for the management of epilepsy and their efficacies are widely acclaimed among the rural communities of northern Nigeria. The aim of the study is to examine the behavioral and anticonvulsant properties of the standardized methanol extract of Ficus platyphylla (FP) stem bark, in order to scientifically describe its potential values in the management of convulsive disorders. MATERIALS AND METHODS: High performance liquid chromatography (HPLC) and preliminary phytochemical analysis of the methanol extract were utilized and the intraperitoneal median lethal dose (LD50) determined in mice. The effects of FP were investigated on some murine models of behavior and its anticonvulsant effects studied on pentylenetetrazole (PTZ)-, strychnine (STN)-, picrotoxin (PCT)-, isoniazid (INH)-, aminophylline (AMI)- and maximal electroshock (MES)-induced seizures in mice. RESULTS: The intraperitoneal oral LD50 of FP was estimated to be 5000mg/kg. FP significantly reduced the locomotor activities including the total distance covered, speed, active time and rearing counts. It shortened the onset and prolonged the duration of diazepam-induced sleep, but had no effect on motor coordination on the rota rod treadmill or beam-walking assay in mice at the doses tested. The extract protected the mice against PTZ- and STN-induced seizures and significantly delayed the latencies of myoclonic jerks and tonic seizures induced by all the standard convulsant agents (PTZ, PCT, INH, STN and AMI) used in this study, but failed to protect the mice against MES seizures at the doses tested. The HPLC fingerprint of the extract shows a spectrum profile characteristic of Ficus platyphylla, while the preliminary phytochemical screening revealed the presence of saponins, flavonoids and tannins. CONCLUSION: Our study provides scientific evidence that FP may contain psychoactive principles with potential anticonvulsant properties, thus supporting further development of the psychoactive components of this plant as anticonvulsant agents. PMID- 24754911 TI - Plasma fatty acid changes following consumption of dietary oils containing n-3, n 6, and n-9 fatty acids at different proportions: preliminary findings of the Canola Oil Multicenter Intervention Trial (COMIT). AB - BACKGROUND: The Canola Oil Multicenter Intervention Trial (COMIT) was a randomized controlled crossover study designed to evaluate the effects of five diets that provided different oils and/or oil blends on cardiovascular disease (CVD) risk factors in individuals with abdominal obesity. The present objective is to report preliminary findings on plasma fatty acid profiles in volunteers with abdominal obesity, following the consumption of diets enriched with n-3, n-6 and n-9 fatty acids. METHODS: COMIT was conducted at three clinical sites, Winnipeg, Manitoba, Canada, Quebec City, Quebec, Canada and University Park, Pennsylvania, United States. Inclusion criteria were at least one of the followings: waist circumference (>=90 cm for males and >=84 cm for females), and at least one other criterion: triglycerides >=1.7 mmol/L, high density lipoprotein cholesterol <1 mmol/L (males) or <1.3 mmol/L (females), blood pressure >=130 mmHg (systolic) and/or >=85 mmHg (diastolic), and glucose >=5.5 mmol/L. Weight-maintaining diets that included shakes with one of the dietary oil blends were provided during each of the five 30-day dietary phases. Dietary phases were separated by four-week washout periods. Treatment oils were canola oil, high oleic canola oil, high oleic canola oil enriched with docosahexaenoic acid (DHA), flax oil and safflower oil blend, and corn oil and safflower oil blend. A per protocol approach with a mixed model analysis was decided to be appropriate for data analysis. RESULTS: One hundred and seventy volunteers were randomized and 130 completed the study with a dropout rate of 23.5%. The mean plasma total DHA concentrations, which were analyzed among all participants as a measure of adherence, increased by more than 100% in the DHA-enriched phase, compared to other phases, demonstrating excellent dietary adherence. CONCLUSIONS: Recruitment and retention strategies were effective in achieving a sufficient number of participants who completed the study protocol to enable sufficient statistical power to resolve small differences in outcome measures. It is expected that the study will generate important data thereby enhancing our understanding of the effects of n-3, n-6, and n-9 fatty acid-containing oils on CVD risks. TRIAL REGISTRATION: ClinicalTrials.gov NCT01351012. PMID- 24754913 TI - The genus Inula and their metabolites: from ethnopharmacological to medicinal uses. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Inula comprises more than one hundred species widespread in temperate regions of Europe and Asia. Uses of this genus as herbal medicines have been first recorded by the Greek and Roman ancient physicians. In the Chinese Pharmacopoeia, from the 20 Inula spp. distributed in China, three are used as Traditional Chinese medicines, named Tumuxiang, Xuanfuhua and Jinfeicao. These medicines are used as expectorants, antitussives, diaphoretics, antiemetics, and bactericides. Moreover, Inula helenium L. which is mentioned in Minoan, Mycenaean, Egyptian/Assyrian pharmacotherapy and Chilandar Medical Codex, is good to treat neoplasm, wound, freckles and dandruff. Many other Inula spp. are used in Ayurvedic and Tibetan traditional medicinal systems for the treatment of diseases such as bronchitis, diabetes, fever, hypertension and several types of inflammation. This review is a critical evaluation of the published data on the more relevant ethnopharmacological and medicinal uses of Inula spp. and on their metabolites biological activities. This study allows the identification of the ethnopharmacological knowledge of this genus and will provide insight into the emerging pharmacological applications of Inula spp. facilitating the prioritirization of future investigations. The corroboration of the ethnopharmacological applications described in the literature with proved biological activities of Inula spp. secondary metabolites will also be explored. MATERIALS AND METHODS: The major scientific databases including ScienceDirect, Medline, Scopus and Web of Science were queried for information on the genus Inula using various keyword combinations, more than 180 papers and patents related to the genus Inula were consulted. The International Plant Name Index was also used to confirm the species names. RESULTS: Although the benefits of Inula spp. are known for centuries, there are insufficient scientific studies to certify it. Most of the patents are registered by Chinese researchers, proving the traditional use of these plants in their country. Although a total of sixteen Inula species were reported in the literature to have ethnopharmacological applications, the species Inula cappa (Buch.-Ham. ex D.Don) DC., Inula racemosa Hook.f., Inula viscosa (L.) Aiton [actually the accepted name is Dittrichia viscosa (L.) Greuter], Inula helenium, Inula britannica L. and Inula japonica Thunb. are the most frequently cited ones since their ethnopharmacological applications are vast. They are used to treat a large spectrum of disorders, mainly respiratory, digestive, inflammatory, dermatological, cancer and microbial diseases. Fifteen Inula spp. crude extracts were investigated and showed interesting biological activities. From these, only 7 involved extracts of the reported spp. used in traditional medicine and 6 of these were studied to isolate the bioactive compounds. Furthermore, 90 bioactive compounds were isolated from 16 Inula spp. The characteristic compounds of the genus, sesquiterpene lactones, are involved in a network of biological effects, and in consequence, the majority of the experimental studies are focused on these products, especially on their cytotoxic and anti-inflammatory activities. The review shows the chemical composition of the genus Inula and presents the pharmacological effects proved by in vitro and in vivo experiments, namely the cytotoxic, anti-inflammatory (with focus on nitric oxide, arachidonic acid and NF-kappaB pathways), antimicrobial, antidiabetic and insecticidal activities. CONCLUSIONS: Although there are ca. 100 species in the genus Inula, only a few species have been investigated so far. Eight of the sixteen Inula spp. with ethnopharmacological application had been subjected to biological evaluations and/or phytochemical studies. Despite Inula royleana DC. and Inula obtusifolia A. Kerner are being used in traditional medicine, as far as we are aware, these species were not subjected to phytochemical or pharmacological studies. The biological activities exhibited by the compounds isolated from Inula spp., mainly anti-inflammatory and cytotoxic, support some of the described ethnopharmacological applications. Sesquiterpene lactone derivatives were identified as the most studied class, being britannilactone derivatives the most active ones and present high potential as anti-inflammatory drugs, although, their pharmacological effects, dose-response relationship and toxicological investigations to assess potential for acute or chronic adverse effects should be further investigated. The experimental results are promising, but the precise mechanism of action, the compound or extract toxicity, and the dose to be administrated for an optimal effect need to be investigated. Also human trials (some preclinical studies proved to be remarkable) should be further investigated. The genus Inula comprises species useful not only in medicine but also in other domains which makes it a high value added plant. PMID- 24754914 TI - Single stage surgery for contouring the prominent mandibular angle with a broad chin deformity: en-bloc Mandibular Angle-Body-Chin Curved Ostectomy (MABCCO) and Outer Cortex Grinding (OCG). AB - BACKGROUND: Various surgical options are reported to address the Asian 'squared face', characterized by a prominent mandibular angle (PMA) associated with an oversized chin deformity; but shortcomings lie in the requirement of multi-stage procedures with the risk of further revision surgery. We have developed a single stage "Mandibular Angle-Body-Chin Curved Ostectomy (MABCCO) and Outer Cortex Grinding (OCG)" surgical technique to shorten the period of the surgical treatment and minimize the inherent surgical risks in the multi-staged procedures. METHODS: A retrospective study involving patients (n = 36) presented with prominent mandibular angle and an oversized chin who underwent the operation described from 2010 to 2012 with at least 12 months of follow-up. The surgical and aesthetic outcomes were evaluated through clinical assessment, photography, imaging analysis including preoperative and post-operative patient satisfaction rates. RESULTS: All the patients were satisfied with the improvement in their appearance following surgery; specifically the 'smoothness' of the mandibular inferior border with no 'second mandibular angle'. The width of the mandible was reduced with G-G distance reduced from 119.9 mm +/- 3.9-109.7 mm +/- 3.5 (p < 0.05). A significant preoperative and post-operative gonial angle (G-A) was found at the left (110.7 degrees +/- 9.6 vs 139.9 degrees +/- 11.5, p < 0.05) and right side of mandible (111.3 degrees +/- 10.7 vs 140.7 degrees +/- 11.8, p < 0.05). There was no iatrogenic inferior alveolar nerve or mental nerve injury and a stable aesthetic outcome beyond the first year. CONCLUSION: We demonstrated favourable surgical and aesthetic outcomes with our single-stage en-bloc curved osteotomy surgical technique to reshape the prominent mandibular angle with a broad chin deformity with no increased in surgical risks but a high satisfaction rate and stable outcomes. PMID- 24754915 TI - Normal emotion regulation in adults with cleft lip and palate: an exploratory study. AB - INTRODUCTION: Cleft lip and palate (CLP) represent the most common congenital malformations of the midfacial region. Although these patients show differences in their facial appearance, we hypothesize that CLP-affected individuals do not show an alteration in their emotion regulation abilities compared to unaffected individuals. This is because of the strong biological basis of facial emotion and expression that is inherent and receives little influence from external factors. MATERIAL AND METHODS: The present study evaluated various aspects of emotion regulation in 25 adults with CLP and an equally sized control group of unaffected volunteers. The study was divided into three parts. First, we investigated emotion regulation strategies. Here, each participant was asked to complete the Emotion Regulation Questionnaire (ERQ) and Ambivalence over Emotional Expressiveness Questionnaire G 18 (AEQ-G18). Second, we examined the recognition of facially expressed basic emotions (FEEL test). Third, we evaluated the expression of an emotion induced by an odor sample. RESULTS: Habitual emotion regulation, measured by ERQ and AEQ-G18, was not different between CLP and controls subjects for all of the sub-scales. Recognition of facially expressed basic emotions was also the same for both groups. Facial emotion encoding did not differ for both groups. CONCLUSIONS: To summarize, the findings suggest that individuals with an orofacial cleft show undisturbed emotion regulation and recognition. This may be explained by the strong biological basis of facial emotion recognition and regulation as well as by the healthy emotional resilience and social functioning of CLP patients. PMID- 24754916 TI - Failure of open reduction internal fixation of acute scaphoid fractures. PMID- 24754917 TI - A scoping study on task shifting; the case of Uganda. AB - BACKGROUND: Task shifting has been implemented in Uganda for decades with little documentation. This study's objectives were to; gather evidence on task-shifting experiences in Uganda, establish its acceptability and perceptions among health managers and policymakers, and make recommendations. METHODS: This was a qualitative study. Data collection involved; review of published and gray literature, and key informant interviews of stakeholders in health policy and decision making in Uganda. Data was analyzed by thematic content analysis. RESULTS: Task shifting was the mainstay of health service delivery in Uganda. Lower cadre of health workers performed duties of specialized health workers. However, Uganda has no task shifting policy and guidelines, and task shifting was practiced informally. Lower cadre of health workers were deemed to be incompetent to handle shifted roles and already overworked, and support supervision was poor. Advocates of task shifting argued that lower cadre of health workers already performed the roles of highly trained health workers. They needed a supporting policy and support supervision. Opponents argued that lower cadre of health workers were; incompetent, overworked, and task shifting was more expensive than recruiting appropriately trained health workers. CONCLUSIONS: Task shifting was unacceptable to most health managers and policy makers because lower cadres of health workers were; incompetent, overworked and support supervision was poor. Recruitment of existing unemployed well trained health workers, implementation of human resource motivation and retention strategies, and government sponsored graduates to work for a defined mandatory period of time were recommended. PMID- 24754918 TI - Malignant peritoneal mesothelioma with lymph node metastasis that originated in the transverse colon. AB - BACKGROUND: We report an extremely rare case of resection of localized biphasic malignant peritoneal mesothelioma of the transverse colon. CASE REPORT: Computed tomography and magnetic resonance imaging in a 72-year-old man showed a tumor with enhanced borders consistent with the transverse colon. Colonoscopy showed ulcerative lesions in the transverse colon, but histological examination showed no malignancy. A gastrointestinal stromal tumor was strongly suspected, so an extended right hemicolectomy was performed. Histopathological examination showed that the tumor was a localized malignant peritoneal mesothelioma of the transverse colon. The patient did not receive postoperative chemotherapy and died 18 months after surgery. CONCLUSIONS: The number of patients with malignant mesotheliomas is predicted to increase in the future both in Japan and in western countries. We report this case due to its probable usefulness in future studies pertaining to the diagnosis and treatment of malignant mesotheliomas. PMID- 24754919 TI - Prevalence of Haplorchis taichui among humans and fish in Luang Prabang Province, Lao PDR. AB - This study confirmed the prevalence of the intestinal fluke Haplorchis taichui (Trematoda: Heterophyidae) among people and fish in Luang Prabang Province, Lao PDR. Fecal specimens were collected from 559 riparian people (229 males and 330 females), residing in 4 Districts (Luang Prabang, Xieng Ngeun, Pak Ou, and Nam Bak) and were examined by the Kato-Katz fecal smear technique. The overall helminth egg positive rate was 64.9%. The positive rate for small trematode eggs (STE), which may include H. taichui and other heterophyids, Opisthorchis viverrini, and lecithodendriids, was 15.2%. For recovery of adult helminths, 10 STE-positive people were treated with 40mg/kg praziquantel and 15mg/kg pyrantel pamoate, and then purged. Mixed infections with 3 Haplorchis species (H. taichui, H. pumilio, and H. yokogawai), a species of cestode (Taenia saginata), and several species of nematodes including Enterobius vermicularis and hookworms were found. The worm load for trematodes was exclusively high for H. taichui with an average of 7691 specimens per infected person, followed by H. yokogawai (8.3 specimens) and H. pumilio (4.1 specimens). Out of 207 freshwater fish (17 species) purchased in a market in Luang Prabang District, 138 (67%) harboured H. taichui metacercariae (metacercarial burden per fish; 520). Lower prevalence of fish and lower metacercarial density were observed for H. yokogawai (52% and 50 per fish, respectively) and H. pumilio (18% and 3 per fish, respectively). STE found in the surveyed population of Luang Prabang Province were verified to be those of intestinal fukes, particularly H. taichui. PMID- 24754920 TI - Sarconesiopsis magellanica (Diptera: Calliphoridae) excretions and secretions have potent antibacterial activity. AB - The most important mechanism for combating infection using larval therapy depends on larval excretions and secretions (ES). The present work was aimed at evaluating Sarconesiopsis magellanica (Diptera: Calliphoridae) ES antibacterial activity in six bacterial strains (three Gram-positive and three Gram-negative) and comparing this to the effect of Lucilia sericata-derived ES. Antibacterial activity at 50MUg/mL minimum inhibitory concentration (MIC) was observed for Staphylococcus epidermidis ATCC-12228 and Staphylococcus aureus ATCC-29213 strains, when the turbidimetry test involving S. magellanica ES was used; the rest of the bacterial strains (Staphylococcus aureus ATCC-6538, Pseudomonas aeruginosa ATCC-10145, Pseudomonas aeruginosa ATCC-9027 and Pseudomonas aeruginosa ATCC-27853) were inhibited at a 100MUg/mL MIC. Twice the amount was required to inhibit the aforementioned bacteria with L. sericata-derived ES using this same technique; a similar trend was observed when the agar diffusion method was used instead. Furthermore, when the previously established MIC for each bacterial strain was used, their colonies became reduced following 1-6h incubation with S. magellanica derived ES, whilst the reduction occurred from 2 to 6hours with those from L. sericata. Although the MIC for each strain obtained with ciprofloxacin was lower than those established when using either blowfly derived-ES, the gradual reduction of the colonies occurred at a longer incubation time (6h or more). The results showed that S. magellanica ES antibacterial activity was more potent and effective, compared to that of L. sericata-derived ES. PMID- 24754921 TI - Combining cattle and wound-derived synthetic attractants, POC and Bezzilure B, for sampling Chrysomya bezziana in Indonesia. AB - The myiasis fly Chrysomya bezziana Villeneuve (Diptera: Calliphoridae) is an obligate parasite of body orifices and unnatural openings or wounds of vertebrates. It is a major pest of livestock and responsible for economic losses throughout the Old World. Two chemical lures were tested in the present study to assess their effectiveness at trapping Ch. bezziana. Bezzilure B contains a synthetic lure of 2-mercaptoethanol originally identified from cattle wound volatiles. POC is a synthetic lure comprising 4-methyl phenol, 3-propyl phenol and racemic 1-octen-3-ol, originally identified from volatiles of ox odour and now used to control tsetse flies (Diptera: Glossina). Bezzilure B and POC lures were tested alone, and in combination, in a laboratory free flight room bioassay and in a field trial. Sticky traps were used to capture males and females of Ch. bezziana and to determine the efficacy of the lures. In the laboratory, Bezzilure B caught significantly more male and female flies than Bezzilure B+POC (p<0.001). Similarly, in the field, treatment significantly affected the total number of Ch. bezziana caught (p<0.001) but, contrastingly, Bezzilure B+POC caught significantly more flies than Bezzilure B (p<0.05). The differing results between the laboratory and field may simply reflect the different assays and could suggest different roles of semiochemicals at different operational distances. Although ineffective on its own, POC has a synergistic effect with Bezzilure B to increase fly catches in the field: by proportion, Bezzilure B+POC was 2.17 times as efficient as Bezzilure B for Ch. bezziana, and 1.16-2.68 times as efficient for other flies depending on the species collected. PMID- 24754922 TI - MAP1B rescues LRRK2 mutant-mediated cytotoxicity. AB - Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of dominant and sporadic Parkinson's disease (PD), a common neurodegenerative disorder. Yeast-two-hybrid screening using human LRRK2 kinase domain as bait identified microtubule associated protein 1B (MAP1B) as a LRRK2 interactor. The interacting domains were LRRK2 kinase and the light chain portion of MAP1B (LC1). LRRK2 + LC1 interaction resulted in LRRK2 kinase inhibition. LRRK2 mutants (R1441C, G2019S and I2020T) exhibited decreased endogenous LC1 expression and its co-expression with LC1 rescued LRRK2 mutant-mediated toxicity. This study presented the first data on the effects of LRRK2 + LC1 interaction and also suggested that LCI possibly rescued LRRK2 mutant-induced cytotoxicity by inhibiting LRRK2 kinase activity. Compounds that upregulate LC1 expression may therefore hold therapeutic potential for LRRK2-linked diseases. PMID- 24754923 TI - Using the NHS's market monopoly to reduce waste by suppliers and increase sustainability. PMID- 24754924 TI - Effect of addition of FSH, LH and proteasome inhibitor MG132 to in vitro maturation medium on the developmental competence of yak (Bos grunniens) oocytes. AB - BACKGROUND: The competence for embryonic development after IVF is low in the yak, therefore, we investigated the effects of supplementation of FSH, LH and the proteasome inhibitor MG132 in IVM media on yak oocyte competence for development after IVF. METHODS: In Experiment 1, yak cumulus-oocyte complexes (COCs) were in vitro matured (IVM) in TCM-199 with 20% fetal calf serum (FCS), 1 microg/mL estradiol-17beta, and different combinations of LH (50 or 100 IU/mL) and FSH (0, 1, 5, 10 microg/mL) at 38.6 degrees C, 5% CO2 in air for 24 h. Matured oocytes were exposed to frozen-thawed, heparin-capacitated yak sperm. Presumptive zygotes were cultured in SOF medium containing 6 mg/ml BSA, 0.5 mg/mL myoinositol, 3% (v/v) essential amino acids, 1% nonessential amino acids and 100 MUg/mL L glutamine (48 h, 38.5 degrees C, 5% CO2, 5% O2, and 90% N2). In Experiment 2, cumulus cells were collected at the end of IVM to determine FSHR and LHR mRNA expression by real-time PCR. In Experiment 3 and 4, COCs were cultured in the presence or absence of the proteasomal inhibitor MG132 from either 0-6 h or 18-24 h after initiation of maturation. RESULTS: The optimum concentration of FSH and LH in IVM media was 5 microg/mL FSH and 50 IU/mL LH which resulted in the greatest cleavage (79.1%) and blastocyst rates (16.1%). Both FSHR and LHR mRNA were detected in yak cumulus cells after IVM. Treatment with MG132 early in maturation reduced (P<0.05) cleavage and blastocyst rates. Conversely, treatment with MG132 late in maturation improved (P<0.05) blastocyst rate. Optimal results with MG132 were achieved at a concentration of 10 microM. CONCLUSIONS: An optimum concentration of FSH and LH in IVM medium, and treatment with MG132 late in maturation can improve yak oocytes competence for development after IVF. PMID- 24754925 TI - Comparison of the vasodilator responses of isolated human and rat middle meningeal arteries to migraine related compounds. AB - BACKGROUND: Migraine attacks occur spontaneously in those who suffer from the condition, but migraine-like attacks can also be induced artificially by a number of substances. Previously published evidence makes the meninges a likely source of migraine related pain. This article investigates the effect of several vasodilators on meningeal arteries in order to find a connection between the effect of a substance on a meningeal vessel and its ability to artificially induce migraine. METHODS: A myograph setup was used to test the vasodilator properties of the substances acetylcholine (ACh), sodium nitroprusside (SNP), sildenafil, prostaglandin E2 (PGE2), pituitary adenylate cyclase activating peptide-38 (PACAP-38), calcitonin gene-related peptide (CGRP) and NaCl buffer on meningeal arteries from human and rat. An unpaired t-test was used to statistically compare the mean Emax(%) at the highest concentration of each substance to the Emax(%) of NaCl buffer. RESULTS: In the human experiments, all substances except PACAP-38 had an Emax (%) higher than the NaCl buffer, but the difference was only significant for SNP and CGRP. For the human samples, clinically tested antimigraine compounds (sumatriptan, telcagepant) were applied to the isolated arteries, and both induced a significant decrease of the effect of exogenously administrated CGRP. In experiments on rat middle meningeal arteries, pre-contracted with PGF2alpha, similar tendencies were seen. When the pre-contraction was switched to K+ in a separate series of experiments, CGRP and sildenafil significantly relaxed the arteries. CONCLUSIONS: Still no definite answer can be given as to why pain is experienced during an attack of migraine. No clear correlation was found between the efficacy of a substance as a meningeal artery vasodilator in human and the ability to artificially induce migraine or the mechanism of action. Vasodilatation could be an essential trigger, but only in conjunction with other unknown factors. The vasculature of the meninges likely contributes to the propagation of the migrainal cascade of symptoms, but more research is needed before any conclusions can be drawn about the nature of this contribution. PMID- 24754926 TI - Distribution of the phosphatidylinositol 3-kinase inhibitors Pictilisib (GDC 0941) and GNE-317 in U87 and GS2 intracranial glioblastoma models-assessment by matrix-assisted laser desorption ionization imaging. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and the limited available treatment options have not meaningfully impacted patient survival in the past decades. Such poor outcomes can be at least partly attributed to the inability of most drugs tested to cross the blood-brain barrier and reach all areas of the glioma. The objectives of these studies were to visualize and compare by matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry the brain and tumor distribution of the phosphatidylinositol 3-kinase (PI3K) inhibitors pictilisib (GDC-0941, 2-(1H indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl thieno[3,2-d]pyrimidine) and GNE-317 [5-(6-(3-methoxyoxetan-3-yl)-7-methyl-4 morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine] in U87 and GS2 orthotopic models of GBM, models that exhibit differing blood-brain barrier characteristics. Following administration to tumor-bearing mice, pictilisib was readily detected within tumors of the contrast-enhancing U87 model whereas it was not located in tumors of the nonenhancing GS2 model. In both GBM models, pictilisib was not detected in the healthy brain. In contrast, GNE-317 was uniformly distributed throughout the brain in the U87 and GS2 models. MALDI imaging revealed also that the pictilisib signal varied regionally by up to 6 fold within the U87 tumors whereas GNE-317 intratumor levels were more homogeneous. Liquid chromatography coupled with tandem mass spectrometry (LC MS/MS) analyses of the nontumored half of the brain showed pictilisib had brain to-plasma ratios lower than 0.03 whereas they were greater than 1 for GNE-317, in agreement with their brain penetration properties. These results in orthotopic models representing either the contrast-enhancing or invasive areas of GBM clearly demonstrate the need for whole-brain distribution to potentially achieve long-term efficacy in GBM. PMID- 24754927 TI - [Genome-wide association studies: methodology and interpretation for clinicians]. AB - Genome-wide association studies (GWAS) are performed to find associations between genetic variants (i.e. single-nucleotide polymorphisms) and diseases. This review describes the basic principles of GWAS. To date, GWAS have identified thousands of genetic variants associated with complex diseases and biological characteristics such as LDL cholesterol levels. GWAS can provide important insights into the underlying mechanisms of complex diseases and biological characteristics, thereby aiding the development of biomarkers and potentially pinpointing novel drug targets. PMID- 24754928 TI - [TNF inhibitors: the role of drug levels]. AB - There is a variation in the pharmacokinetics of TNF inhibitors. Measurement of drug levels may help to identify patients in whom treatment can be optimised. Various factors influence the pharmacokinetics of TNF inhibitors; one of the most important factors is immunogenicity. There is inter-patient variation in the TNF inhibitor dose needed to achieve clinical effectiveness, as well as variation in the dose needed to maintain clinical effectiveness. Immunosuppressive co medication plays an important role in the optimisation of TNF inhibitor therapy via an effect on inflammation and immunogenicity. PMID- 24754929 TI - [School absenteeism as a signal for psychological problems]. AB - CASE DESCRIPTION: We present two patients with frequent school absences. Patient A is a 12-year-old boy, diagnosed with developmental coordination disorder. When his mother visits the youth community health doctor, he shows signs of an anxiety disorder with stress-related physical symptoms. Patient B is a 15-year-old boy whose teacher suspects a gaming and internet addiction. After consulting the youth community health doctor, he is referred to a psychologist for further diagnosis of a social anxiety disorder. CONCLUSION: Frequent school absenteeism is associated with psychological problems. After excluding physical causes referral for further psychiatric assessment is recommended. As the medical advisor of the school, the youth community health doctor can play a role in this process. PMID- 24754930 TI - [Pregnancy and fertility in schizophrenia]. AB - Pregnancy and childbirth are risky periods for developing psychotic dysregulation in patients with schizophrenia. Antipsychotic treatment significantly reduces the risk, but also implies possible adverse effects on the neonate, such as neonatal adaptation symptoms and a slightly increased risk of congenital defects. Patients with schizophrenia are at higher risk of obstetric complications. Optimal care for these patients requires coordination between multiple disciplines. Timely counselling with the patient on lifestyle, sexual side effects and contraception yields many health benefits. PMID- 24754932 TI - [Proactive monitoring of sickness absence for psychosocial problems]. AB - Psychosocial problems are common in daily practice. These problems are the cause of 30% of absence from work due to sickness. Almost one third of workers with common mental disorders experience recurrent sickness absence. Although general practitioner (GP) and occupational physician (OP) guidelines have suggested monitoring these patients, these doctors are not used to doing this. Dutch researchers studied a problem-solving intervention (SHARP-at work) for evaluating the effectiveness of preventing recurrent sickness absence. Although the researchers found a decrease in recurrent sickness absence, it is not clear whether this effect was caused by the intervention or by the extra contacts between doctor and employee. Support and empathy are non-specific factors which could explain these positive findings in themselves. Given the findings in this study, GPs and OPs should be more aware of the importance of proactive monitoring of patients with common mental disorders after they have returned to work. PMID- 24754933 TI - [An individual 'traffic light system' for children with fever?]. AB - Fever in children is very common, and is usually caused by self-limiting upper respiratory-tract infections. The low incidence of serious infections makes it a challenge to identify children that do have a serious infection and need treatment or observation. The Dutch Society of Paediatrics (NVK) recently presented their guideline for febrile children in secondary care. This is an important, science-based guideline. However, the diagnostic schemes presented, which are based on tests that are not available in primary care, in combination with a different prior chance of serious infections between the primary and secondary care settings make it difficult to translate this guideline to primary care. Nevertheless, the 'traffic light system' presented is a promising potential safety net tool for providing advice for parents in the general practitioner's consultation room. A traffic light system especially developed for primary care should be considered. PMID- 24754934 TI - [The effects of ceruloplasmin in PI3K/PTEN cell signaling pathway change induced by silica]. AB - OBJECTIVE: To investigate the roles of ceruloplasmin (Cp) in PI3K/PTEN cell signaling pathway change in human embryonic lung fibroblasts (HELFs) induced by silica. METHODS: HELFs transfected with pGenesil1.1 plasmid and pGenesil1.1 with PTEN shRNA (PT) plasmid were successfully established. 100 ug/ml silica and different concentrations of Cp (10, 20, 30 ug/ml) were used in this experiment and Cp were treated cells after exposed to silica for 1h. Three different cell lines (including HELFs, PT and cells were transfected with p85 dominant negative mutant plasmid (DN-p85)) were divided into control groups, silica groups and silica+different concentrations of Cp groups. MTT assay was used to detect the effects of Cp on silica-induced cell proliferation after inhibiting PTEN and p85. When suppressing the expression of PTEN and p85, western blot assay was performed to detect the levels of p85, p110, AKT308, AKT473 and ERK, JNK and their phosphorylated levels. RESULTS: After inhibition of PTEN, the high levels of p85 induced by 100 ug/ml silica with 30 ug/ml Cp were markedly decreased (P<0.05). When suppressing p85, the increased cell proliferation was not observed. And the high levels of AKT308, AKT473, ERK and phosphorylated JNK and ERK stimulated by 100 ug/ml silica with 30 ug/ml Cp were decrease (P < 0.05). CONCLUSION: Cp could further strengthened silica-induced cell proliferation by PI3K/AKT/MAPK cell signaling pathway, of which the level of p85 was regulated by PTEN. PMID- 24754935 TI - [Study on genetic toxicity of gaseous benzene to mouse bone marrow cells]. AB - OBJECTIVE: To investigate the mechanism of genetic toxicity of gaseous benzene to mouse bone marrow cells and to provide an experimental basis for the discovery of early biomarkers among benzene-exposed population. METHODS: Male mice were randomly divided into control group and three benzene-exposed groups (6 mice per group). The control group was exposed to ambient air, and the three benzene exposed groups were exposed to different concentrations of benzene (400, 800, and 1 600 mg/m(3)) for 15 days, 2 hours per day, in static inhalation chambers. At the end of the 15-day experimental period, the mice were killed. Bone marrow cells were separated from sacrificed mice, and superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-Px) activity, myeloperoxidase (MPO) activity, and malondialdehyde (MDA) content were determined by biochemical methods. DNA damage was evaluated by micronucleus assay and single cell gel electrophoresis (SCGE). The expression of MPO protein was determined by immunocytochemistry. RESULTS: The SOD activities in different dose groups (88.67 +/- 13.58, 73.64 +/- 4.50, and 67.63 +/- 5.42 U/mg prot) were significantly decreased as compared with the control group (119.98+/-9.42 U/mg prot) (P<0.01). Moreover, the SOD activities in medium- and high-dose groups were significantly lower than that of the low-dose group (P < 0.05). The GSH-Px activities in medium and high-dose groups (705.07 +/- 93.75 and 674.77 +/- 86.80 U/mg prot) were significantly decreased as compared with that of the control group (940.25 +/- 82.63 U/mg prot) (P < 0.01), and the high-dose group had a significantly lower GSH-Px activity than the low-dose group (674.77 +/- 86.80 U/mg prot vs 833.98 +/- 130.64 U/mg prot, P < 0.05). The MDA content of low-, medium-, and high-dose groups (22.42+/-2.67, 22.38+/-3.02, and 27.66+/-2.89 nmol/mg prot) were significantly higher than that of the control group (12.35+/-1.58 nmol/mg prot) (P < 0.01), and MDA content was significantly higher in the high-dose group than in the medium- and low-dose groups (P < 0.05). The micronucleus assay showed that the micronucleus rates in different dose groups (4.67+/-0.820/00, 5.00+/ 0.890/00, and 5.33+/-1.030/00) were significantly higher than that of the control group (2.50+/-0.550/00) (P < 0.01). The SCGE demonstrated that the DNA damage rates of medium- and high-dose groups (22.08% and 25.68%) were significantly higher than that of the control group (7.00%) (P < 0.01), and the DNA damage rate of high-dose group was significantly higher than that of the low-dose group (11.24%) (P < 0.05). MPO activity increased with the dose of benzene in all three benzene-treated groups (16.79+/-2.16, 19.46+/-2.28, and 22.53+/-2.76 U/g prot) and was significantly higher than that of the control group (12.89+/-0.74 U/g prot) (P < 0.01). The positive rates of MPO protein expression in low-, medium-, and high-dose groups (13.20+/-2.28%, 30.80+/-3.35%, and 40.20+/-1.92%) were significantly higher than that of the control group (6.60+/-1.14%) (P < 0.01). The MPO activity in high-dose group and the positive rates of MPO protein expression in medium- and high-dose groups were all significantly higher than those of the low-dose group (P < 0.01). CONCLUSION: Gaseous benzene exposure has toxic effect on genetics of mouse bone marrow cells. It leads to chromosome breakage and DNA damage, enhances the activity and protein expression of MPO, and induces lipid peroxidation. Lipid peroxidation damage is a potential mechanism by which gaseous benzene exerts toxic effect on mouse bone marrow cells. PMID- 24754936 TI - [Effects of electromagnetic pulses on apoptosis and TGF-beta3 expression of mouse testis tissue]. AB - OBJECTIVE: To investigate the effects of electromagnetic pulses (EMP) on the apoptosis and transforming growth factor beta 3 (TGF-beta3) expression of mouse testis tissue. METHODS: Thirty-two male BALB/c mice were randomly and equally divided into one control group and three EMP treated groups, which were whole body exposed to EMP at 200 kV/m with 100, 200, and 400 pulses, respectively. The control group received no treatment. The pathological changes and cell apoptosis in testis tissue were analyzed by TUNEL assay. The mRNA expression of TGF-beta3 in testis tissue was determined by RT-PCR, and the protein expression of TGF beta3 was determined by immunohistochemistry and Western blot. RESULTS: No obvious pathological changes were found in testis tissue after EMP exposure at 200 kV/m with 100 and 200 pulses. However, after EMP exposure with 400 pulses, degeneration and shedding of testis tissue, accompanied by significant increase in apoptosis rate (P < 0.05), was observed. The RT-PCR, immunohistochemistry, and Western blot showed that the expression of TGF-beta3 mRNA and protein increased significantly after EMP exposure with 400 pulses as compared with that of the control group (P < 0.05). CONCLUSION: EMP exposure at 200 kV/m with 400 pulses increases the incidence of apoptosis and expression of TGF-beta3 in mouse testis tissue, which is potentially one of the mechanisms by which EMP increases blood testis barrier permeability in mice. PMID- 24754937 TI - [Study on occupational safety climate in different types of enterprises and its relationship with occupational accidental injury]. AB - OBJECTIVE: To evaluate the occupational safety climate in different types of enterprises and its relationship with occupational accidental injury. METHODS: A cross-sectional survey based on self-report questionnaires was performed among 3311 front-line workers from 54 medium and small-sized manufacturing enterprises of different types in Zhongshan, China to investigate the socio-demographic characteristics, safety climate experience in workplace, and incidence of occupational accidental injury in the past year. RESULTS: Analysis of the data revealed that employees in different types of companies perceived different levels of safety climate, according to the scores on four subscales; the European and American enterprises had significantly better safety climate than the Hong Kong and Chinese private enterprises (P < 0.01). The self-reported rates of occupational injury were 3.38%, 4.76%, and 6.72%, respectively, for European and American, Hong Kong, and Chinese private enterprises (chi(2) = 6.78, P < 0.05). After control of such factors as age, sex, income, education level, and marriage, the logistic regression analysis showed that the risk of occupational accidental injury in the European and American enterprises was significantly lower than that in the Chinese private enterprises (OR = 0.57, 95%CI = 0.35-0.91). CONCLUSION: The type of enterprise influences the occupational safety climate and incidence of occupational injury among workers. PMID- 24754938 TI - [Establishment of a rat model of subacute toxic encephalopathy induced by 1, 2 dichloroethane]. AB - OBJECTIVE: To establish a rat model of 1,2-dichloroethane (DCE)-induced subacute toxic encephalopathy. METHODS: Sixty Sprague-Dawley rats were randomly divided into five groups: negative control, positive control, low-dose DCE (1 472 mg/m(3)), middle-dose DCE (2 550 mg/m(3)), and high-dose DCE (4 418 mg/m(3)). The three DCE groups received static inhalation of DCE 6 hours a day for 6 consecutive days. The positive control group received intraperitoneal injection of lipopolysaccharide (5 mg/kg) and were sacrificed 8 hours after injection. Blood and brain tissue were collected, followed by determination of brain water content and HE staining for pathological examination of brain tissue. RESULTS: The rats in DCE groups suffered decreased body weight with increasing DCE dose (P < 0.01), and brain water content rose with increasing DCEdose. The brain water content of middle-dose DCE group (80.09 +/- 0.14%) and high-dose DCE group (80.28+/-0.10%) increased significantly as compared with that of the negative control group (79.46+/-0.23%) (P < 0.001). Optical microscopy discovered loose structure and vasodilation in the brain tissue of middle-dose DCE group, indicating obvious brain edema; the high-dose DCE group and positive control group had spongiform and vacuolated brain tissues with severe vascular dilation, indicating severe brain edema. CONCLUSION: A rat model of subacute toxic encephalopathy induced by 1, 2-dichloroethane has been successfully established. PMID- 24754939 TI - [Follow-up assessment of "Technical specifications for occupational health surveillance"]. AB - OBJECTIVE: To investigate the possession of occupational health examination qualification among occupational health examination institutions in Zhejiang province, China and the application of GBZ188-2007 "Technical specifications for occupational health surveillance" among related government departments, and to provide a basis for revising and improving the specifications. METHODS: A questionnaire survey was carried out among occupational health inspection agencies, health supervision authorities, and enterprises of different sizes, which possessed provincial-level occupation health inspection qualifications and had engaged in occupational health examination for more than 2 years. The investigation included awareness, using frequency, and revision suggestion about GBZ 188-2007 "Technical specifications for occupational health surveillance". RESULTS: Medical institutions and centers for disease control and prevention (CDCs)showed a high rate of occupational health examination qualification possession in chemical substances, dust, noise, and high temperature and a low rate of qualification possession in physical factors, biological factors, special operations, and other aspects. These institutions showed high awareness of chemical substances, dust, and physical factors in GBZ 188-2007 "Technical specifications for occupational health surveillance" and low awareness of other factors. Medical institutions, CDCs, and provincial and municipal health supervision authorities used these specifications more frequently than county level authorities and enterprises. More than 80% investigated units believed that the following issues required further optimization: occupational health care, emergency health examination regulations, classification of occupational health inspection reports, and special operation monitoring. It is consistently stressed that for exposure to chemical compounds that may bring harm to various organs of the body, explicit specifications should be made concerning health examination before, during, and after service. Conflicting opinions existed concerning the following issues: satisfaction with GBZ 188-2007 specifications, whether to add contents for care of personnel exposed to biological factors (such as forest encephalitis), the threshold of noise intensity to perform health care, and whether to add health care for exposure to compounds such as benzene and phenols. CONCLUSION: The occupational health inspection agencies in Zhejiang province have a high rate of qualification possession in health examination concerning chemicals, dust, noise, and high temperature. The medical institutions, CDCs, and health supervision departments above the county level often use the specifications at work. It is consistently recommended that more kinds of harmful substances should be included, and related specifications and issues should be further optimized, in order to better meet the requirement of occupational health care in the new era. PMID- 24754940 TI - [Occupational hazards survey of specially supervised enterprises during 2011-2012 in one district of Shenzhen, China]. AB - OBJECTIVE: To analyze the results of an occupational hazards survey of specially supervised enterprises (156 enterprise-times) during 2011-2012 in one district of Shenzhen, China and find out the changes in occupational hazards in these enterprises, and to put forward countermeasures for the prevention and control of occupational hazards. METHODS: Occupational hazards monitoring results for specially supervised enterprises (156 enterprise-times) during 2011-2012 were included. Comparison and analysis were performed between different years, different industries, different occupational hazards, and different sizes of enterprises. RESULTS: A total of 1274 monitoring sites from these specially supervised enterprises were included, of which qualification rate was 73.55% (937/1274), and the noise monitoring sites showed the lowest qualification rate. The overall qualification rate in 2012 (70.37%) was significantly lower than that in 2011 (80.94%) (chi(2) = 15.38, P < 0.01). In electronics industry, the qualification rate in 2012 was significantly lower than that in 2011 (chi2 = 11.27, P = 0.001). Comparison of various hazards in different industries indicated that electronic enterprises and furniture enterprises had the lowest qualification rate in noise monitoring, printing enterprises had the lowest qualification rate in organic solvent monitoring, and furniture enterprises had the lowest qualification rate in dust monitoring. Comparison between different sizes of enterprises indicated that the qualification rate of large and medium enterprises in 2012 was significantly lower than that in 2011, while the qualification rate of small enterprises in 2012 was significantly higher than that in 2011 (P < 0.01 or P < 0.05). CONCLUSION: In the prevention and control of occupational hazards in specially supervised enterprises, special attention should be paid to the control of organic solvents in printing enterprises and noise and dust in furniture enterprises. PMID- 24754941 TI - [Health survey of painting and coating workers in an automobile manufacturing enterprise in Guangzhou, China]. AB - OBJECTIVE: To investigate the health status of painting and coating workers in an automobile manufacturing enterprise in Guangzhou, China and analyze the influential factors for the health status of these workers, and to provide health intervention measures and strategies. METHODS: Typical sampling was used to select an automobile manufacturing enterprise; according to whether the subjects were in contact with paint and coatings, paint spraying workers in the painting workshop were selected as the exposed group, and the staff in the administration, procurement, and marketing departments as the control group. Physical examination was performed by doctors among these subjects. RESULTS: The exposed group had significantly higher positive rates of dizziness, headache, bleeding gums, chest tightness, and skin itching than the control group (P < 0.05). The exposed group had a nonsignificantly higher rate of abnormal ECG than the control group (P > 0.05), but the exposed group had a significantly higher incidence of various blocks (P = 0.020) and significantly lower leukocyte count, erythrocyte count, and male workers' hemoglobin level (P < 0.05), as compared with the control group. CONCLUSION: Volatile organic solvents have adverse effect on the health of paint spraying workers in the automobile manufacturing enterprise, so regular physical examination should be performed to strengthen health interventions and improve health. PMID- 24754942 TI - [Analysis of use of personal protective equipment among rural-to-urban migrant workers in small and medium enterprises in Zhongshan and Shenzhen, China]. AB - OBJECTIVE: To investigate the current supply and use of personal protective equipment (PPE) among rural-to-urban migrant workers in small and medium enterprises (SMEs) in Zhongshan and Shenzhen, China and the influential factors for the use of PPE, and to provide a basis for better occupational health services and ensuring the health of migrant workers. METHODS: Multi-stage sampling was used to select 856 migrant workers from 27 SMEs in Zhongshan and Shenzhen, and face-to-face questionnaire survey was conducted in these subjects. Statistical analysis was performed by one-way analysis of variance, chi-square test, and logistic regression. RESULTS: Of all migrant workers, 38.67%were supplied with free PPE by the factory, and this rate varied across industries (furniture industry: 45.81%; electronic industry: 31.46%) and SMEs (medium enterprises: 42.13%; small enterprises: 39.20%; micro enterprises: 22.16%); 22.43% insisted on the use of PPE. The logistic regression analysis showed that factors associated with the use of PPE included sex, age, awareness of occupational health knowledge, and the size of enterprise. CONCLUSION: The rates of supply and use of PPE among migrant workers are low. The larger the enterprise, the better the supply of PPE. Male gender, being elder, and high occupational health knowledge score were favorable factors for the use of PPE, while small enterprise size was the unfavorable factor for the use of PPE. PMID- 24754943 TI - [Effect of combined exposure to organic solvents in oil paint on health of painters]. PMID- 24754945 TI - [Blood lead levels in lead-exposed workers in storage battery industry: a survey from 2011 to 2012 in Hangzhou, China]. PMID- 24754944 TI - [Effects of dichloromethane exposure on neuro-behavior, neurotransmitter, and biochemical indices]. PMID- 24754946 TI - [Current status and risk assessment of occupational hazards among 4S automobile store workers in Guangzhou, China]. PMID- 24754947 TI - [Death after exposure to dimethylformamide: a case report]. PMID- 24754948 TI - [Effect of welding dust on pulmonary function in exposed workers]. PMID- 24754949 TI - [Effect of acetamide on histopathology in cerebral cortex of rats with tetramine poisoning]. AB - OBJECTIVE: To observe the effect of different doses of acetamide on the histopathology in the cerebral cortex of rats with tetramine (TET) poisoning and to provide a basis for the treatment of fluoroacetamide poisoning with acetamide. METHODS: Eighty clean Sprague-Dawley rats were randomly divided into five groups: saline control group,dimethylsulfoxide water solution control group,TET poisoning group, acetamide (2.88 g/kg/d) treatment group, and acetamide (5.68 g/kg/d) treatment group, with 16 rats in each group. Rats in the poisoning group and treatment groups were poisoned with TET by intragastric administration after fasting; then, saline was injected intramuscularly into rats of the poisoning group, and different doses of acetamide were injected intramuscularly into rats of treatment groups; the course of treatment was 5 d. At 3 h, 12 h, 48 h, and 7 d after treatment, the cerebral cortex was harvested from rats in each group, and the histopathological changes in the cerebral cortex were evaluated under light and electron microscopes. RESULTS: The light microscopy showed that the TET poisoning group had hypoxia changes in the cerebral cortex, which worsened over time; the treatment groups had reduced hypoxia changes, and the acetamide (2.88 g/kg/d) treatment group had more reduction than the acetamide (5.68 g/kg/d) treatment group. The electron microscopy showed that the apoptosis of neuronal cells were the main pathological changes in the TET poisoning group; the treatment groups had reduced apoptotic changes, and the acetamide (2.88 g/kg/d) treatment group had more reduction than the acetamide (5.68 g/kg/d) treatment group. CONCLUSION: No pathological changes associated with the synergistic toxic effect of acetamide and TET are found in the cerebral cortex. Acetamide (2.88 g/kg/d) could reduce central nervous lesions, but the efficacy is not improved after increasing the dose. For patients who cannot be identified with TET or fluoroacetamide poisoning, acetamide could be considered for treatment. PMID- 24754950 TI - [Application of nutritional support therapy and noninvasive positive pressure ventilation in pneumoconiosis patients with respiratory failure]. PMID- 24754951 TI - [Acute occupational phosgene poisoning: a case report]. PMID- 24754952 TI - [Determination of ester compounds in the air by tubular passive sampling]. PMID- 24754953 TI - [Simultaneous determination of butene and butadiene in workplace air by gas chromatography]. PMID- 24754954 TI - [Applicability of occupational health and safety protection package for small and medium enterprises of International Labour Organization and significance of its popularization and application]. PMID- 24754955 TI - [Calibration methods and influencing factors in random determination of urinary toxins]. PMID- 24754956 TI - [Experience and thinking concerning occupational health reexamination]. PMID- 24754957 TI - [Problems and proposal concerning evaluation and measurement of hand-transmitted vibration in workplace]. PMID- 24754958 TI - [Quantitative classification-based occupational health management for electroplating enterprises in Baoan District of Shenzhen, China]. AB - OBJECTIVE: To improve the occupational health management levels in electroplating enterprises with quantitative classification measures and to provide a scientific basis for the prevention and control of occupational hazards in electroplating enterprises and the protection of workers' health. METHODS: A quantitative classification table was created for the occupational health management in electroplating enterprises. The evaluation indicators included 6 items and 27 sub items, with a total score of 100 points. Forty electroplating enterprises were selected and scored according to the quantitative classification table. These electroplating enterprises were classified into grades A, B, and C based on the scores. RESULTS: Among 40 electroplating enterprises, 11 (27.5%) had scores of >85 points (grade A), 23 (57.5%) had scores of 60~85 points (grade B), and 6 (15.0%) had scores of <60 points (grade C). CONCLUSION: Quantitative classification management for electroplating enterprises is a valuable attempt, which is helpful for the supervision and management by the health department and provides an effective method for the self-management of enterprises. PMID- 24754960 TI - On-site visual detection of hydrogen sulfide in air based on enhancing the stability of gold nanoparticles. AB - We have described a simple and low-cost visual method for on-site detection of hydrogen sulfide (H2S) in air based on the antiaggregation of gold nanoparticles (AuNPs). The bubbling of H2S into a weak alkaline buffer solution leads to the formation of HS-, which can stabilize the AuNPs and ensure the AuNPs maintain their red color even in a Tris buffer solution containing 80 mM NaCl with the presence of Tween 80. The stabilization of the AuNPs is attributed to the adsorption of negatively charged S2- on the AuNPs surface. In contrast, without the bubbling of H2S, AuNPs aggregate and change color from red to blue. Under optimal conditions, the proposed method exhibits excellent visual sensitivity with a naked-eye detectable limit of 0.5 ppm (v/v), making the on-site detection of H2S possible. This method also possesses good selectivity toward H2S over other gases by using a simple SO2 removal device. The successful determination of the concentrations of H2S in local air indicates the potential application of this cost-effective method. PMID- 24754959 TI - Farmers' knowledge, practices and injuries associated with pesticide exposure in rural farming villages in Tanzania. AB - BACKGROUND: Pesticides in Tanzania are extensively used for pest control in agriculture. Their usage and unsafe handling practices may potentially result in high farmer exposures and adverse health effects.The aim of this study was to describe farmers' pesticide exposure profile, knowledge about pesticide hazards, experience of previous poisoning, hazardous practices that may lead to Acute Pesticide Poisoning (APP) and the extent to which APP is reported. METHODS: The study involved 121 head- of-household respondents from Arumeru district in Arusha region. Data collection involved administration of a standardised questionnaire to farmers and documentation of storage practices. Unsafe pesticide handling practices were assessed through observation of pesticide storage, conditions of personal protective equipment (PPE) and through self-reports of pesticide disposal and equipment calibration. RESULTS: Past lifetime pesticide poisoning was reported by 93% of farmers. The agents reported as responsible for poisoning were Organophosphates (42%) and WHO Class II agents (77.6%).Storage of pesticides in the home was reported by 79% of farmers. Respondents with higher education levels were significantly less likely to store pesticides in their home (PRR High/Low = 0.3; 95% CI = 0.1-0.7) and more likely to practice calibration of spray equipment (PRR High/Low = 1.2; 95% CI = 1.03-1.4). However, knowledge of routes of exposure was not associated with safety practices particularly for disposal, equipment wash area, storage and use of PPE . The majority of farmers experiencing APP in the past (79%) did not attend hospital and of the 23 farmers who did so in the preceding year, records could be traced for only 22% of these cases. CONCLUSIONS: The study found a high potential for pesticide exposure in the selected community in rural Tanzania, a high frequency of self-reported APP and poor recording in hospital records. Farmers' knowledge levels appeared to be unrelated to their risk. Rather than simply focusing on knowledge-based strategies, comprehensive interventions are needed to reduce both exposure and health risks, including training, improvements in labeling, measures to reduce cost barriers to the adoption of safe behaviours, , promotion of control measures other than PPE and support for Integrated Pest Management (IPM). PMID- 24754961 TI - One or two trainees per workplace in a structured multimodality training curriculum for laparoscopic surgery? Study protocol for a randomized controlled trial - DRKS00004675. AB - BACKGROUND: Laparoscopy training courses have been established in many centers worldwide to ensure adequate skill learning before performing operations on patients. Different training modalities and their combinations have been compared regarding training effects. Multimodality training combines different approaches for optimal training outcome. However, no standards currently exist for the number of trainees assigned per workplace. METHODS: This is a monocentric, open, three-arm randomized controlled trial. The participants are laparoscopically naive medical students from Heidelberg University. After a standardized introduction to laparoscopic cholecystectomy (LC) with online learning modules, the participants perform a baseline test for basic skills and LC performance on a virtual reality (VR) trainer. A total of 100 students will be randomized into three study arms, in a 2:2:1 ratio. The intervention groups participate individually (Group 1) or in pairs (Group 2) in a standardized and structured multimodality training curriculum. Basic skills are trained on the box and VR trainers. Procedural skills and LC modules are trained on the VR trainer. The control group (Group C) does not receive training between tests. A post-test is performed to reassess basic skills and LC performance on the VR trainer. The performance of a cadaveric porcine LC is then measured as the primary outcome using standardized and validated ratings by blinded experts with the Objective Structured Assessment of Technical Skills. The Global Operative Assessment of Laparoscopic Surgical skills score and the time taken for completion are used as secondary outcome measures as well as the improvement of skills and VR LC performance between baseline and post-test. Cognitive tests and questionnaires are used to identify individual factors that might exert influence on training outcome. DISCUSSION: This study aims to assess whether workplaces in laparoscopy training courses for beginners should be used by one trainee or two trainees simultaneously, by measuring the impact on operative performance and learning curves. Possible factors of influence, such as the role of observing the training partner, exchange of thoughts, active reflection, model learning, motivation, pauses, and sympathy will be explored in the data analysis. This study will help optimize the efficiency of laparoscopy training courses. TRIAL REGISTRATION NUMBER: DRKS00004675. PMID- 24754962 TI - Heritable GATA2 mutations associated with familial AML-MDS: a case report and review of literature. AB - A 50-year-old woman was diagnosed with acute myeloid leukemia (AML). She has history of thrombocytopenia for 25 years and a significant family history of thrombocytopenia, affecting her mother, siblings and their children, as well as her own children. Both her mother and maternal aunt died from myelodysplastic syndrome (MDS). Additional genetic analysis was performed and identified two heterozygous missence mutations in the second zinc finger domain of GATA2 gene (p.Thr358Lys, and p.Leu359Val), occurring in cis on the same allele. Given the patient's family history and clinical manifestation, this was interpreted as an acute myeloid leukemia with heritable GATA2 mutations associated with familial AML-MDS. Germline GATA2 mutations are involved in a group of complex syndromes with overlapping clinical features of immune deficiency, lymphedema and propensity to acute myeloid leukemia or myelodysplastic syndrome (AML-MDS). Here we reported a case of familial AML-MDS with two novel GATA2 mutations. This case illustrates the importance of recognizing the clinical features for this rare category of AML-MDS and performing the appropriate molecular testing. The diagnosis of heritable gene mutations associated familial AML-MDS has significant clinical implication for the patients and affected families. Clinical trials are available to further investigate the role of allogeneic hematopoietic stem cell transplant in managing these patients. PMID- 24754963 TI - Intra-abdominal aortic graft infection: prognostic factors associated with in hospital mortality. AB - BACKGROUND: Mortality associated with aortic graft infection is considerable. The gold standard for surgical treatment remains explantation of the graft. However, prognostic factors associated with early mortality due to this surgical procedure are not well-known. METHODS: Retrospective analysis of patients admitted in our center between January 2006 and October 2011 for aortic graft infection. The primary endpoint was in-hospital mortality. A bivariate analysis of characteristics of patients associated with in-hospital outcome was performed. RESULTS: Twenty five evaluable patients were studied. All patients were male. Their mean age was 67 +/- 8.4 years. Most of them (92%) had severe underlying diseases. An in situ prosthetic graft replacement, mainly using cryopreserved arterial allografts, was performed in all patients, excepted one who underwent extra-anatomic bypass. Causative organisms were identified in 23 patients (92%). The in-hospital mortality rate was 48%. Among pre-operative characteristics, age >= 70 years, creatinine >= 12 mg/L and C reactive protein >= 50 mg/L were significantly associated with in-hospital mortality. Hospital mortality rates increased with the number of risk factor present on ICU admission, and were 0%, 14.3%, 85.7% and 100% for 0, 1, 2 and 3 factors, respectively. The only intra operative factor associated with prognosis was an associated intestinal procedure due to aorto-enteric fistula. SAPS II, SOFA score and occurrence of medical or surgical complications were postoperative characteristics associated with in hospital mortality. CONCLUSION: Morbidity and mortality associated with surgical approach of aortic graft infections are considerable. Age and values of creatinine and C Reactive protein on hospital admission appear as the most important determinant of in hospital mortality. They could be taken into account for guiding the surgical strategy. PMID- 24754965 TI - Physician tracking in sub-Saharan Africa: current initiatives and opportunities. AB - BACKGROUND: Physician tracking systems are critical for health workforce planning as well as for activities to ensure quality health care - such as physician regulation, education, and emergency response. However, information on current systems for physician tracking in sub-Saharan Africa is limited. The objective of this study is to provide information on the current state of physician tracking systems in the region, highlighting emerging themes and innovative practices. METHODS: This study included a review of the literature, an online search for physician licensing systems, and a document review of publicly available physician registration forms for sub-Saharan African countries. Primary data on physician tracking activities was collected as part of the Medical Education Partnership Initiative (MEPI) - through two rounds over two years of annual surveys to 13 medical schools in 12 sub-Saharan countries. Two innovations were identified during two MEPI school site visits in Uganda and Ghana. RESULTS: Out of twelve countries, nine had existing frameworks for physician tracking through licensing requirements. Most countries collected basic demographic information: name, address, date of birth, nationality/citizenship, and training institution. Practice information was less frequently collected. The most frequently collected practice fields were specialty/degree and current title/position. Location of employment and name and sector of current employer were less frequently collected. Many medical schools are taking steps to implement graduate tracking systems. We also highlight two innovative practices: mobile technology access to physician registries in Uganda and MDNet, a public-private partnership providing free mobile-to-mobile voice and text messages to all doctors registered with the Ghana Medical Association. CONCLUSION: While physician tracking systems vary widely between countries and a number of challenges remain, there appears to be increasing interest in developing these systems and many innovative developments in the area. Opportunities exist to expand these systems in a more coordinated manner that will ultimately lead to better workforce planning, implementation of the workforce, and better health. PMID- 24754966 TI - Microfat Grafting in Nasal Surgery. AB - BACKGROUND: Injectable fillers are sometimes necessary to correct slight skin irregularities. However, there have been reports of necrosis after injection of alloplastic materials and heterogeneous transplants. On the other hand, the advantages of autogenous tissue grafts over those fillers are well established. Volumetric reshaping of the face with autologous tissue injection is a popular and reliable method with good long-term results. However, procedures performed on the fragile skin of the nose are prone to complications. OBJECTIVES: The author conducted a study of injectable autologous microfat grafting to the nose in patients with secondary nasal deformities. METHODS: During a 5-year period, 313 patients who had secondary nasal deformities with slight skin irregularities or severe nasal skin damage were treated with microfat grafting. At each patient's first injection session, excess harvested fat was cryopreserved for subsequent injection. To correct minor irregularities, 0.3 to 0.8 mL of microfat was injected during each session; for major irregularities or defects, 1 to 6 mL was required for each session. RESULTS: One to 3 injections of microfat provided satisfactory results in all patients who had minor irregularities. For patients with multiple and severe irregularities, 3 to 6 injections were necessary and resulted in high patient satisfaction. In another group of patients, with severe traumatic skin damage, 6 to 16 injections were necessary for reconstruction. After repeated injections, each patient's skin damage was repaired. CONCLUSIONS: Autologous microfat injection appears to be safe and effective for correcting slight irregularities of the nose. LEVEL OF EVIDENCE: 4. PMID- 24754967 TI - The higher sensitivity of PSI to ROS results in lower chilling-light tolerance of photosystems in young leaves of cucumber. AB - The development of PSII tolerance to stress and photoprotection mechanisms during leaf growth has been widely studied, however, knowledge about PSI photoinhibition and interaction between PSI and PSII under stress during leaf growth is still lacking. This study showed that during the chilling-light treatment, the photoinhibitions of PSI and PSII were more severe in young leaves than in fully expanded leaves of cucumber, but the inhibition of CO2 assimilation and the accumulation of reactive oxygen species (ROS) were similar in leaves at different development stages. During the chilling-light treatment, PSII photoinhibition was positive correlated to PSI photoinhibition in leaves, however, this correlation no longer existed in leaves pretreated with DCMU, an inhibitor of electron transport from PSII to PSI. Although the photoinhibitions of PSII and PSI in young leaves were more severe, the sensitivity of PSII to excitation pressure was lower in young leaves. The above results demonstrate that, the lower chilling light tolerance of photosystems in young leaves was due to the higher sensitivity of PSI to ROS and the higher PSII excitation pressure caused by PSI photoinhibition in young leaves, rather than the difference of ROS content and sensitivity of PSII to excitation pressure between the young and fully-expanded leaves. PMID- 24754968 TI - Negative biopsies, deadly disease: metastatic angiosarcoma. PMID- 24754970 TI - Literary fiction and medical care: a Perfect example. PMID- 24754969 TI - A deficiency of nutrition education in medical training. PMID- 24754971 TI - A bitter effect: thrombocytopenia induced by a quinidine-containing beverage. PMID- 24754972 TI - Takotsubo syndrome (stress cardiomyopathy): an intriguing clinical condition in search of its identity. AB - Takotsubo syndrome is a relatively frequent clinical entity presenting typically as an acute coronary syndrome in the absence of obstructive coronary artery disease and characterized angiographically by transient left ventricular systolic dysfunction, sparing the basal segments of the left ventricle ("apical ballooning"). Takotsubo syndrome characteristically affects peri- or postmenopausal women, albeit recent series show that men also are at risk. Takotsubo syndrome is characteristically triggered by severe emotional or physical stress, which suggests a pathogenic role for increased sympathetic activity leading to myocardial perfusion abnormalities and ventricular dysfunction. The reasons why severe emotional and physical stress result in the development of takotsubo syndrome in certain individuals but not others is still a matter of speculation, but strongly suggests the existence of predisposing factors/mechanisms in certain subjects. The present article reviews the different factors that can play a role in the development of takotsubo syndrome in different patients. We propose that triggers (ie, emotional stressors, physical stressors, iatrogenic stressors, and neurologic triggers), pathogenic mechanisms (ie, increased catecholamine levels, coronary vasomotor abnormalities leading to myocardial ischemia), and predisposing factors (ie, cardiovascular risk factors, endothelial dysfunction, comorbidities) all interact in a complex fashion and possibly differently in different patients to cause takotsubo syndrome. Identifying these factors may help in preventing and managing the condition more effectively. PMID- 24754973 TI - Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss. AB - The mechanism of action of the combination therapy, naltrexone/bupropion (NB), for obesity has not been fully described to date. Weight loss attempts rarely result in long-term success. This is likely a result of complex interactions among multiple peripheral and CNS systems that defend against weight loss, and may explain the overwhelming lack of effective obesity treatments. NB is an investigational combination therapy for obesity that was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behavior that affect body weight. We review the individual actions of naltrexone and bupropion in brain hypothalamic and reward systems, and describe the current in vitro, in vivo, and clinical evidence for how NB influences food intake and produces weight loss. PMID- 24754974 TI - Feedback versus no feedback in improving patient outcome in group psychotherapy for eating disorders (F-EAT): protocol for a randomized clinical trial. AB - BACKGROUND: Continuous feedback on patient improvement and the therapeutic alliance may reduce the number of dropouts and increase patient outcome. There are, however, only three published randomized trials on the effect of feedback on the treatment of eating disorders, showing inconclusive results, and there are no randomized trials on the effect of feedback in group therapy. Accordingly the current randomized clinical trial, initiated in September 2012 at the outpatient clinic for eating disorders at Stolpegaard Psychotherapy Centre, aims to investigate the impact of continuous feedback on attendance and outcome in group psychotherapy. METHODS/DESIGN: The hypothesis is that continuous feedback to both patient and therapist on treatment progress and alliance will increase attendance and treatment outcome. The trial is set up using a randomized design with a minimum of 128 patients allocated to either an experimental or control group at a ratio of 1:1. The experimental group will receive standard treatment (systemic and narrative group psychotherapy) with feedback intervention, whereas the control group will receive standard treatment only. The participants are diagnosed with bulimia nervosa, binge eating disorder, or an eating disorder not otherwise specified, according to the DSM-IV. In the experimental group feedback to the participants, based on the Outcome Rating Scale (ORS) and the Group Session Rating Scale (GSRS), is actively added to standard treatment. The ORS assesses areas of life functioning known to change as a result of therapeutic intervention. The GSRS assesses key dimensions of effective therapeutic relationships. In the control group, the patients fill out the Outcome Rating Scale only, and feedback is not provided.The primary outcome is the rate of attendance to treatment sessions. The secondary outcome is the severity of eating disorder symptoms. Exploratory outcomes are the level of psychological and social functioning, and suicide or self-harm. This is measured with the ORS, Symptom Check List, WHO-Five Wellbeing Index, Sheehan Disability Scale and a modified version of the Self-Harm Inventory. DISCUSSION: If the results will confirm the hypothesis, this trial will support feedback as a way to improve group treatment attendance for outpatients with eating disorders. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01693237. PMID- 24754975 TI - HIV serostatus and disclosure: implications for infant feeding practice in rural south Nyanza, Kenya. AB - BACKGROUND: The World Health Organization (WHO) recommends that HIV-infected women practice exclusive breastfeeding (EBF) for the first 6 months postpartum to reduce HIV transmission. The aim of this study was to determine the effects of HIV/AIDS knowledge and other psychosocial factors on EBF practice among pregnant and postpartum women in rural Nyanza, Kenya, an area with a high prevalence of HIV. METHODS: Data on baseline characteristics and knowledge during pregnancy, as well as infant feeding practices 4-8 weeks after the birth were obtained from 281 pregnant women recruited from nine antenatal clinics. Factors examined included: fear of HIV/AIDS stigma, male partner reactions, lack of disclosure to family members, knowledge of prevention of mother-to-child transmission (PMTCT) and mental health. In the analysis, comparisons were made using chi-squared and t test methods as well as logistic multivariate regression models. RESULTS: There were high levels of anticipated stigma 171(61.2%), intimate partner violence 57(20.4%) and postpartum depression 29(10.1%) and low levels of disclosure among HIV positive women 30(31.3%). The most significant factors determining EBF practice were hospital delivery (aOR = 2.1 95% CI 1.14-3.95) HIV positive serostatus (aOR 2.5 95% CI 1.23-5.27), and disclosure of HIV-positive serostatus (aOR 2.9 95% CI 1.31-6.79). Postpartum depression and PMTCT knowledge were not associated with EBF (aOR 1.1 95% CI 0.47-2.62 and aOR 1.2 95% CI 0.64-2.24) respectively. CONCLUSIONS: Health care workers and counselors need to receive support in order to improve skills required for diagnosing, monitoring and managing psychosocial aspects of the care of pregnant and HIV positive women including facilitating disclosure to male partners in order to improve both maternal and child health outcomes. PMID- 24754976 TI - Protective effect of CD4(+)CD25(high)CD127(low) regulatory T cells in renal ischemia-reperfusion injury. AB - Ischemia reperfusion injury (IRI) is critical in the pathogenesis of acute renal failure and graft rejection. Regulatory T cells (Tregs) suppress excessive immune responses in IRI. We investigated the role of CD4(+)CD25(high)CD127(low) Tregs in the early phase of renal IRI pathogenesis in a mouse model. CD4(+)CD25(high)CD127(low) Tregs in the kidney, tubular necrosis scores, and renal function were measured 24 or 72 h after reperfusion. PC61, an anti-CD25 monoclonal antibody, was used to deplete Tregs before renal ischemia to confirm the effect of these Tregs. CD4(+)CD25(high)CD127(low) Tregs were expanded 24 and 72 h after reperfusion. Depletion of CD4(+)CD25(high)CD127(low) Tregs was associated with worsening of renal function and histology, particularly at 72 h after reperfusion. These results indicated that expansion of CD4(+)CD25(high)CD127(low) Tregs in the early phase of renal IRI may participate in tissue repair. These data reveal new insights into the pathogenesis of ischemic acute renal failure and a novel therapeutic approach. PMID- 24754977 TI - Electrochemical properties of VPO4/C nanosheets and microspheres as anode materials for lithium-ion batteries. AB - VPO4/C nanosheets and microspheres are successfully synthesized via a hydrothermal method followed by calcinations. The XRD results reveal that the obtained products both have an orthorhombic VPO4 phase. The SEM and TEM images demonstrate that nanosheets and spherical morphology can be obtained by controlling the synthesis conditions. The samples are both uniformly coated by amorphous carbon. The electrochemical test results show that the sample with a nanosheet structure has a better electrochemical performance than the microsphere samples. The VPO4/C nanosheets can deliver an initial discharge capacity of 788.7 mAh g(-1) at 0.05 C and possessed a favorable capacity at the rates of 1, 2, and 4 C. The nanosheet structure can effectively improve the electrochemical performances of VPO4/C anode materials. PMID- 24754978 TI - An examination of family caregiver experiences during care transitions of older adults. AB - This study explored informal family caregiver experiences in supporting care transitions between hospital and home for medically complex older adults. Using a qualitative, grounded-theory approach, in-depth semi-structured interviews were conducted with community and resource case managers, as well as with informal caregivers of older hip-fracture and stroke patients, and of those recovering from hip replacement surgery. Six properties characterizing caregiver needs in successfully transitioning care between hospital and home were integrated into a theory addressing both a transitional care timeline and the emotional journey. The six properties were (1) assessment of unique family situation; (2) practical information, education, and training; (3) involvement in planning process; (4) agreement between formal and informal caregivers; (5) time to make arrangements in personal life; and (6) emotional readiness. This work will support research and clinical efforts to develop more well-informed and relevant interventions to most appropriately support patients and families during transitional care. PMID- 24754979 TI - [Improve the diagnosis and treatment of sleep apnea to develop sleep medicine in China]. PMID- 24754980 TI - [Association between serum lipoprotein lipase level and dyslipidemia in patients with obstructive sleep apnea syndrome]. AB - OBJECTIVE: To explore the association between serum lipoprotein lipase (LPL) level and dyslipidemia in patients with obstructive sleep apnea syndromes (OSAS). METHODS: Overnight polysomnography (PSG) was performed for 158 patients with snoring at our Sleep Center from June 2011 to April 2013. Based on the results of apnea-hypopnea index (AHI) assessment, they were divided into 4 groups: primary snoring (AHI<5/h, n = 26), mild (5/h <= AHI <= 15/h, n = 23), moderate (15/h < AHI <= 30/h, n = 31) and severe (AHI>30/h, n = 78) OSAS. According to body mass index (BMI), primary snoring group was further divided into normal BMI and overweight (obese) groups. The level of LPL was determined by enzyme-linked immunosorbent assay (ELISA) and the correlations were observed with OSAS, blood total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL).In normal weight OSAS patients, the relationship was analyzed between different conditions, plasma lipid and serum LPL.In 49 OSAS groups, the level of LPL was observed after 6-month continuous positive airflow pressure (CPAP). RESULTS: From a comparison of four groups, it was found that AHI, night blood lowest oxygen saturation (L SaO2) and time ratio of lowest SaO2<90% (TS90%) had statistical significance (all P < 0.01). The serum LPL gradually decreased in four groups. Compared with primary snoring group, there was a significant increase of serum LPL level in severe OSAS group ((37 +/- 15) vs (45 +/- 17) ug/L, P = 0.022). And severe OSAS group had significantly higher serum levels of TC, TG and LDL (P = 0.025,0.001,0.049).HDL of OSAS group was significantly lower than that of primary snoring group (all P < 0.05). Additionally, after adjustment for BMI and age, serum LPL levels showed significant negative correlations with TC and LDL (r = 0.221,0.199) .Serum LPL level was negative correlated with AHI and TS90 % and oxygen decrease index (ODI) (r = 0.231,0.228,0.184). Compared with normal BMI patients, there was a significant increase of VLDL ((0.77 +/- 0.30) vs (0.46 +/- 0.23) mmol/L, P = 0.034) and decrease of LPL ((37 +/- 10) vs (523 +/- 23) ug/L, P = 0.047) in weight (obesity) in primary snoring group. Compared with primary snoring group in normal BMI groups, there was a significant increase of TG,VLDL and decrease of LPL, HDL in OSAS group (all P < 0.05). The level of LPL significantly increased after 6-month CPAP ((60 +/- 6) vs (38 +/- 3) ug/L, P = 0.001). CONCLUSIONS: Serum LPL and plasma lipid decrease in OSAS patients. And serum LPL level is correlated significantly with the severity of OSAS and nocturnal hypoxia. Thus LPL may play some roles in dyslipidemia of OSAS patients. PMID- 24754981 TI - [Value of transcutaneous monitoring of CO2 pressure in the diagnosis and treatment of sleep and breathing disorders]. AB - OBJECTIVE: To evaluate the clinical value of transcutaneous carbon dioxide (TcPCO2) measurement during sleep respiratory monitoring. METHODS: A total of 29 patients were prospectively recruited. Their age range was (49.5 +/- 12.9) years and body mass index (BMI) (28.2 +/- 3.6) kg/m(2). All of them underwent polysomnography (PSG) at Sleep Center, Peking University People's Hospital during the period of January-August 2013. TcPCO2 signal was entered into PSG systems and TcPCO2 (TCM4, Radiometer,Demark) measured simultaneously. Arterial blood gas (ABG) analysis for arterial pressure of CO2 (PaCO2) was undertaken to validate TcPCO2 measurement. The data were statistically analyzed by Pearson's product moment correlation. Dynamic change of TcPCO2 was monitored during rapid eye movement (REM) and non-rapid eye movement (NREM) sleep stages. The effect of noninvasive positive airway pressure ventilation (NPPV) treatment on TcPCO2 during sleep was also observed. RESULTS: TcPCO2 (44.2 +/- 4.0) mmHg (1 mmHg = 0.133 kPa) was highly correlated with PaCO2 (43.2 +/- 4.7) mmHg (Pearson's correlation, r = 0.896, P = 0.000), TcPCO2 (45.8 +/- 5.4) mmHg level during wakefulness correlated significantly with that during N1, N2, N3 and REM sleep stages (r = 0.658, 0.871, 0.898,0.775; P = 0.009, 0.000, 0.003, 0.000). TcPCO2 levels during different sleep stages were all higher than that of wakefulness.However, TcPCO2 levels did not differ between two sleep stages. During both NREM and REM, elevated TcPCO2 returned to the level during wakefulness on NPPV treatment. CONCLUSIONS: Continuous monitoring of PCO2 is well tolerated during PSG testing. And the signal is stable. During whole night sleep, TcPCO2 monitoring provides more accurate and clinically acceptable estimation of PaCO2 so that it helps to titrate the NPPV pressure levels. PMID- 24754982 TI - [Effects of continuous positive airway pressure on daytime sleepiness in patients with severe obstructive sleep apnea syndrome]. AB - OBJECTIVE: To evaluate the effects of continuous positive airway pressure (CPAP) on daytime sleepiness in patients with severe obstructive sleep apnea syndrome (OSAS). METHODS: Retrospective evaluations were performed for 70 consecutive patients at the medical sleep center, West China Hospital, Sichuan University from May 2013 to October 2013. They were all diagnosed with severe OSAS and underwent overnight CPAP titration. Their mean age and body mass index (BMI) were (42.7 +/- 8.4) years and (29.2 +/- 4.2) kg/m(2) respectively. The sleep structure, hypoxia and objective sleepiness was compared between baseline and CPAP titration. And correspondence analysis was performed between multiple sleep latency tests (MSLT) and other sleep and expiratory parameters. RESULTS: Comparing to the baseline polysomnogram (PSG) levels, CPAP titration significantly decreased apnea hypopnea index (AHI) ((4.4 +/- 2.7) vs (67.7 +/- 18.9)/h), significantly shortened the longest apnea time (24.0 (16.5, 29.6) vs 61.3(51.0, 74.8) s) and raised the lowest oxygen saturation ((84.8 +/- 8.8)% vs (54.4 +/- 18.7)%).Furthermore, the percentage of stage 3 (N3%) (18.2(12.5, 25.6)% vs 2.4 (0.1, 8.2)%), the percentage of stage rapid eye movement (REM) sleep (REM%) ((22.3 +/- 7.7)% vs (12.7 +/- 5.8)%) and sleep perception improved significantly (89.1(88.3, 91.2)% vs 82.7(82.7, 87.0)%, all P < 0.05).Furthermore, CPAP also significantly improved their mean sleep latency of multiple sleep latency test (MSLT) ((8.5 +/- 3.8) vs (4.8 +/- 2.3) min, P < 0.05); the mean sleep latency of MSLT was negatively correlated with AHI, the percentage of stage 1 (N1%) and the longest apnea (r = -0.501,-0.308,-0.309,-0.501, all P < 0.01); but positively correlated with REM%, N3%, mean oxygen saturation and minimal oxygen saturation during CPAP titration (r = 0.235,0.394,0.398,0.440, all P < 0.05). CONCLUSION: CPAP significantly improves nocturnal oxygen desaturation, sleep architecture and objective sleepiness in patients with severe OSAS. PMID- 24754983 TI - [Effects of continuous positive airway pressure treatment of inflammatory factors in patients with overlap syndrome]. AB - OBJECTIVE: To explore the effects of continuous positive airway pressure (CPAP) treatment on the serum levels of associated inflammatory factors in patients with overlap syndrome (OS). METHODS: Seventy-four patients with obstructive sleep apnea syndrome (OSAS) or chronic obstructive pulmonary disease (COPD) or overlap syndrome (OS) were recruited from Department of Respirology and Affiliated Sleep Center of our hospital from March 2012 to September 2013. They were divided into OSAS (n = 25), COPD (n = 26) and OS (n = 23) groups according to the results of polysomnography (PSG) and spirometry. By enzyme linked immunosorbent assay (ELISA), the serum levels of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha) and asymmetric dimethylarginine (ADMA) were measured and compared before and at Day 30 post-CPAP in OSAS and OS groups. RESULTS: At pre CPAP, there was no statistical difference in serum levels of CRP ((7.2 +/- 6.6),(8.4 +/- 6.8),(8.5 +/- 7.9) mg/L) and TNF-alpha ((33 +/- 13),(52 +/- 34),(41 +/- 33) ng/L) among OSAS, COPD and OS groups (all P > 0.05).However, serum ADMA level in OSAS group were significantly lower than those in COPD group ((0.50 +/- 0.08) vs (0.71 +/- 0.31) umol/L, P = 0.002). Compared with before and at Day 30 post-CPAP, although no significant difference existed in serum levels of ADMA (all P > 0.05), at Day 30 post-CPAP there were significantly lower serum levels of CRP ((4.5 +/- 4.2) and (5.5 +/- 4.1) mg/L) and TNF-alpha levels ((31 +/- 9) and (35 +/- 24) ng/L) than those pre-CPAP in OSAS and OS groups respectively (all P < 0.05).No significant difference existed between OSAS and OS groups (all P > 0.05). CONCLUSION: CPAP treatment significantly reduces the serum levels of CRP and TNF-alpha so as to improve inflammation responses in OS and OSAS patients. PMID- 24754984 TI - [Efficacy of BAHA softband in young children with bilateral congenital aural atresia]. AB - OBJECTIVE: To retrospectively analyze the auditory and speech development of young children with bilateral congenital aural atresia after using bone-anchored hearing aid (BAHA) softband. METHODS: From August 2010 to January 2013, a total of 12 patients aged at a range of 3 months to 6 years with bilateral aural atresia using BAHA softband were divided into under 4-year-old group (n = 7, an average age of 14 months) and over 4-year-old group (n = 5, an average age of 77 months). The air and bone auditory thresholds of the under 4-year-old group were assessed by auditory brainstem response (ABR). The Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) was used to evaluate early auditory development.Soundfield pure tone audiometry (PTA) was applied in the over 4-year old group. The Standard Chinese lexical neighborhood test (LNT) was conducted to evaluate the speech discrimination scores unaided and aided for 6, 12 and 24 months. RESULTS: For the under 4-year-old group, the unaided air and bone conduction hearing thresholds were 70-90(73 +/- 12) and 15-25(21 +/- 4) dB nHL respectively.IT-MAIS score improved significantly after using softband for 6 months in comparisons with unaided situations. The average hearing threshold of patients in the over 4-year-old group was (63 +/- 6) dB HL unaided versus (31 +/- 4)dB HL aided. The average decline in pure-tone threshold was (32 +/- 3)dB HL with BAHA softbands and LNT demonstrated improvements in the speech discrimination score. The differences of paired comparison were significant (all P < 0.05). CONCLUSIONS: The hearing ability of children with bilateral congenital aural atresia improves significantly after using BAHA softband. And its application at a young age can guarantee a relatively normal hearing development and avoid oral communication impairment. PMID- 24754985 TI - [Infection in lupus nephritis: risk factors and significance of immune cell functional assay]. AB - OBJECTIVE: To explore the risk factors for infection in lupus nephritis (LN) and identify the correlation of ImmuKnow adenosine triphosphate (ATP) value with the development of infections. METHODS: We respectively followed up 96 patients from January 2006 to December 2012 and all infectious episodes were recorded. The amount of ATP produced by CD4(+)T cells was measured by ImmuKnow assay and compared with the results of 27 healthy controls. Multivariate Logistic regression analysis was used to evaluate possible risk factors associated with infection in LN patients. RESULTS: Among them, the incidence of infection was 22.68%. The mean CD4(+)T cell ATP level was significantly lower in LN patients with infection (258 +/- 112) mg/L compared to both healthy controls (521 +/- 257) mg/L (P < 0.01) and LN patients without infection (437 +/- 193) mg/L (P < 0.05). A cutoff CD4(+)T cell ATP value of 300 mg/L predicted infection in LN patients with a specificity of 77% and a sensitivity of 77%. Multivariate Logistic analysis revealed that lower CD4(+)T cell ATP level (<300 mg/L), higher prednisone dosage ( >= 20 mg/d) and hyperglycemia (>10 mmol/L) were the independent predictors of infection. And the corresponding OR values were 3.47(P < 0.01), 1.17(P = 0.03) and 1.33 (P = 0.02) respectively. CONCLUSIONS: ImmuKnow assay may be effective in identifying the elevated risk of infection in LN patients. And larger studies are required to establish the clinical advantages of this assay in LN treatment. PMID- 24754986 TI - [Risk factors for interstitial cystitis/painful bladder syndrome in patients with lower urinary tract symptoms presenting for urologic care]. AB - OBJECTIVE: To identify the risk factors in interstitial cystitis/painful bladder syndrome (IC/PBS) patients with lower urinary tract symptoms (LUTS) without urinary tract infection or benign prostate hyperplasia in China. METHODS: A total of 954 outpatients with LUTS presenting for care to urology clinics at 8 hospitals throughout China from November 20, 2008 to August 24, 2012 were surveyed with a standardized questionnaire and validated outcome measures. The definitions for IC/PBS based on the O'Leary-Sant interstitial cystitis symptom and problem indices were used. The possible risk factors was analyzed with the Fisher's exact and Pearson chi-square tests. And multivariate predictive models were developed with binary Logistic regression methods. RESULTS: There were 491 females and 463 males. And 44.7% (427/954) met the criteria for IC/PBS. There was significant gender difference (51.7% (254/491) vs 37.4% (173/463), P < 0.05) . After adjusting for confounding factors, bladder pain was significantly associated with stimulatory foods (OR: 81.16, 95%CI: 11.50-590.00, P = 0.001) and anorectal disease (OR: 54.90, 95%CI: 9.52-401.00, P = 0.001) in females. Caffeine beverage intake (OR: 4.29, 95%CI: 1.86-9.86, P = 0.001) was the only modifiable association according to multivariate analysis of males. CONCLUSIONS: Stimulatory foods, anorectal disease and caffeine beverages are potential risk factors for IC/PBS.Further studies are necessary to determine their roles in the pathogenesis of this disorder. PMID- 24754987 TI - [Long-term follow up after colonoscopy screening and polypectomy of male health care population with age >= 50 years]. AB - OBJECTIVE: To analyze the trends of colorectal polyps for age >= 50 years male healthcare patients during a long-term colonoscopic follow-up. METHODS: Endoscopic and pathological reports of age >= 50 years male healthcare patients undergoing colonoscopy from April 1983 to April 2013 were retrospectively reviewed and their general data collected. The proportion of different histological types, the distribution at different anatomic sites and the trends of size and number of colorectal polyps during different follow-up years were analyzed. RESULTS: A total of 3 746 colonoscopy reports of 501 age >= 50 years healthcare cases were collected. After initial colonoscopic screening and polypectomy, 501, 371, 251 and 106 cases were followed up to the 5(th), 10(th), 15(th) and 20(th) years. Their mean age was (74 +/- 9) years. And their mean age of initial colonoscopic screening and polypectomy was (66 +/- 8) years. During a follow-up period of 54-348 months, each of them underwent (7 +/- 5) colonoscopies. A total of 9 006 polyps were detected and 3 986 polyps confirmed pathologically. And 2 608 polyps(65.43%) belonged to adenomas. Among them, 4 638 (51.50%) polyps were located in descending colon and rectum while 1 314 (14.59%) in ascending colon and cecum.In a descending trend, the sizes of initial colonoscopy, 5(th), 10(th), 15(th) and 20(th) year were 0.44 +/- 0.03, 0.07 +/- 0.01, 0.07 +/- 0.01, 0.12 +/- 0.03 and 0.07 +/- 0.01 respectively during the follow-up period (all P < 0.05). Also the numbers were in a descending trend, initial colonoscopy, 5(th), 10(th) and 20(th) year were 3.08 +/- 0.19, 0.77 +/- 0.09, 0.83 +/- 0.10 and 1.03 +/- 0.20 respectively during the follow-up period (all P < 0.05). The numbers of four different pathological types of polyps were all in a descending trend compared with initial colonoscopy. And the numbers peaked around 2(nd), 5(th), 7(th), 10(th), 11(th), 15(th), 18(th) and 19(th) year of follow-up. Statistical differences existed between tubular adenoma and tubule villous adenoma, inflammatory polyps and hyperplastic polyps in mean number in the same follow-up year (all P < 0.05). The number of colorectal polyps in different anatomic sites was different in the same follow-up year (all P < 0.05). CONCLUSIONS: The mean age of initial colonoscopic screening and polypectomy is 66 years. And the main histological type of colorectal polyps is adenoma.Rectum, sigmoid and descending colon are the major sites of colorectal polyps. During the follow-up, the size and number of colorectal polyps are both in a descending trend and the number changes with years. The recurrence of colorectal polyps has pathological and anatomical disparities during follow-up years. PMID- 24754988 TI - [Influence and analysis of seven kinds of hemoglobin variants on HbA1c detection]. AB - OBJECTIVE: To explore the effects of seven kinds of hemoglobin variants on two HbA1c detection methods. METHODS: Twenty-five hemoglobin variant samples (Hb D, S, Q, G, J, E & F) and 40 control samples were from February 2012 to April 2013 collected. All samples were tested by ion exchange-high performance liquid chromatography system (IE-HPLC) and affinity chromatograghy high performance liquid chromatography (AC-HPLC) respectively.We compared the coincidence between HbA1c results of two instruments and blood glucose and observed the difference between variant and control groups for two methods using statistic software SPSS 19.0. RESULTS: A high consistency existed between IE-HPLC and AC-HPLC in the control group with no hemoglobin variants (6.68% +/- 1.87% vs 6.64% +/- 1.99%, P > 0.05) . For the hemoglobin variants group, the results of HbA1c via IE-HPLC were interfered by hemoglobin variants (3.57% +/- 3.51% than 4.95% +/- 0.57%, P < 0.05). However, HbA1c detection of AC-HPLC had no interference with hemoglobin variants and it demonstrated an excellent correlation with blood glucose. CONCLUSIONS: The results of HbA1c in blood samples containing common hemoglobin variants may be interfered on IE-HPLC to be falsely lower or higher.Only detecting glycated hemoglobin with strong specificity,AC-HPLC is well-correlated with blood glucose and its results are not interfered by common variant hemoglobin. PMID- 24754989 TI - [Pancreatic cystic neoplasms: a report of 139 cases]. AB - OBJECTIVE: To review our experience in the diagnosis and treatment of pancreatic cystic neoplasms (PCN). METHODS: The clinicopathological data of PCN were retrospectively analyzed and the relevant medical literatures reviewed. RESULTS: A total of 139 cases were treated at our hospital. There were serous cystic neoplasm (n = 38, SCN), mucinous cystic neoplasm (n = 32, MCN), intraductal papillary mucinous neoplasm (n = 9, IPMN) and solid pseudopapillary neoplasms (n = 60, SPN). The male-to-female ratio was 1: 3.63. The average age of disease onset was 46.1 years old. And 46.3% of them had no symptom at diagnosis. Among symptomatic ones, there were stomach ache (43.4%), location in body and tail of pancreas (58.2%) and solitary (99.5%). The accuracy of ultrasound type B, computed tomography (CT) and magnetic resonance imaging (MRI) were above 80%. The 5-year survival rate of benign PCNs was 100%. The 1, 3, 5-year survival rates of resected malignant PCNs were 70.2%, 47.9% and 39.5% respectively. However, the 5 year survival rate of those undergoing palliative surgery was only 16.7%. CONCLUSIONS: PCNs are more common in females. And the most common clinical presentation is stomach ache. Most PCNs are solitary tumors located in body and tail of pancreas and may be detected by imaging examinations. The prognosis is excellent for benign PCNs and malignant ones undergoing radical resection. However, the prognosis of those undergoing palliative surgery remains poor. PMID- 24754990 TI - [Clinical analysis of 105 extremely low birth weight infants]. AB - OBJECTIVE: To explore the changes of outcome and morbidity in extremely low birth weight (ELBW) infants. METHODS: A retrospective study was performed for ELBW infants admitted into Children's Hospital, Fudan University within 24 hours after birth from January 2007 to December 2011. The maternal and neonatal data were collected by reviewing the medical charts and entered into the dataset. RESULTS: A total of 105 ELBW infants (54 males, 51 females) were enrolled. The average gestational age was (28.4 +/- 2.6)weeks and birth weight was (860 +/- 121)g. Neonatal respiratory syndrome (NRDS) (n = 89, 84.8%), apnea(n = 58, 55.2%), sepsis (n = 47, 44.8%) and patent ductus arteriosus (n = 46, 43.8%) remained their major complications.Sepsis was the commonest cause of mortality (7/17) excluding social factors. The incidence of extrauterine growth restriction (46/51, 90.2%) was significantly high at discharge. And the use of antenatal steroids was merely 40.8% (42/103) in ELBW infants at a gestation age under 34 weeks. CONCLUSIONS: The number of ELBW infants has increased dramatically. Antenatal steroids, noninvasive respiratory support, prevention of infections and optimal nutrition supports are key factors of improving the survival rate, short and long-term outcomes of ELBW infants. PMID- 24754991 TI - [Computed tomographic diagnosis of intrahepatic cholangiocarcinoma]. AB - OBJECTIVE: To explore the computed tomographic (CT) manifestations and their values in the diagnosis of intrahepatic cholangiocarcinoma (IHC) and improve the understanding of IHC. METHODS: A total of 58 IHC patients confirmed pathologically from January 2006 to December 2012 were reviewed. RESULTS: On plain CT scans, all lesions were of low density with lower density region (n = 37), retraction of liver capsule (n = 11), dilation of intrahepatic biliary duct (n = 22), bile duct calculus (n = 13) and atrophy of liver lobe (n = 14).On enhanced scans, most tumor showed obvious circular enhancement on arterial phase, stripe and network enhancement of internal region on portal phase and obvious enhancement on delayed phase. CONCLUSION: CT manifestations of intrahepatic cholangiocarcinoma are specific for its diagnosis. PMID- 24754992 TI - [Clinical experiences of semi-sitting astride position for extracorporeal shock wave lithotripsy treatment of urethral calculi]. AB - OBJECTIVE: To explore the therapeutic feasibility, safety and efficacy of semi sitting astride position for extracorporeal shock wave lithotripsy (SWL) of urethral calculi. METHODS: A total of 7 male cases of urethral calculi from November 1997 to August 2013 were enrolled. Their age range was 24-52 years. There were anterior (n = 1) and posterior (n = 6) urethral calculi. The diameter range of stone was 0.5 cm*0.5 cm to 1.0 cm*2.0 cm. BH-VG twin-pulse low-energy SWL was employed with a semi-sitting astride position. The average frequency was 2 500 (1 800-3 500) times. And the treatment voltage was 3-8 kV. RESULTS: Both stone fragmentation rate and stone-free rate 1 hour post-SWL was 100%.No severe complications occurred. CONCLUSION: Semi-sitting astride position SWL is simple, safe, effective and feasible for posterior urethral calculi. PMID- 24754993 TI - [Relationship between mesenchymal stem cells and liver cancer recurrence after liver transplantation in mice]. AB - OBJECTIVE: To explore the relationship between mesenchymal stem cells (MSCs) and liver cancer recurrence after liver transplantation in mice. METHODS: The recurrent murine model of hepatocellular carcinoma (HCC) after liver transplantation was established by transplanting tumor cells of hind paw pads. MSCs labeled with green fluorescent protein (GFP) were injected into the marrow cavity of 615 mice after successful modeling. And the proliferation of MSCs in marrow cavity was observed under stereoscopic fluorescence microscope. MSCs labeled with red fluorescent protein (RFP) were injected into tail vein of mice during tumor dissection. The migration of GFP and RFP- labeled MSCs were tracked before and after tumor recurrence. After recurrence, the mice were sacrificed and the recurrent lesions harvested for conforming pathological type by biopsy. RESULTS: The rate of success modeling was 37.5%. Both gross morphology and pathological examination corresponded to typical HCC manifestations. Thirty mice were detected by GFP/RFP fluorescence for a recurrence of HCC. The outcomes were GFP+RFP (n = 4), GFP (n = 1) and neither (n = 25). CONCLUSIONS: The presence of MSCs in host may be one of important reasons for recurrent HCC after liver transplantation.It helps to support the traditional view of residual tumor cells mediating the relapse and metastasis of HCC. PMID- 24754994 TI - [Effects of liraglutide on the expression of local renin-angiotensin system, transforming growth factor-beta1 and collagen type III in pulmonary tissue of diabetic rats]. AB - OBJECTIVE: To explore the effects of GLP-1 receptor analog liraglutide on the expression of local renin-angiotensin system (RAS), TGF-beta1 and collagen type III in pulmonary tissue of diabetic rats. METHODS: Thirty male Wistar rats were divided into normal (N), diabetic (DM) and liraglutide treatment (LR) groups according to the table of random number. Diabetes mellitus was induced by feeding with a high-sugar and high-fat diet and a low-dose injection of streptozotocin into caudal vein for 8 weeks. After successful modeling, liraglutide (400 ug*kg( 1)*d(-1)) was administered by a subcutaneous injection for 12 weeks in LR group. At Week 12, the mRNA expression levels of AT1R and TGF-beta1 were detected by real-time quantitative polymerase chain reaction (RT-qPCR), the protein expression of AngII was detected by enzyme-linked immunosorbent assay (ELISA) and the protein expression levels of AT1R and transforming growth factor-beta 1 (TGF beta1) were detected by Western blotting (WB). Collagen type III was detected by immunohistochemistry. RESULTS: The expressions of AT1R,AngII, TGF-beta1 and collagen type III increased in DM group than those of N group (P < 0.05). The expressions of AT1R, AngII, TGF-beta1 and collagen type III were lower in LR group than those of DM group (RT-qPCR of AT1R: 0.08 +/- 0.04 vs 0.32 +/- 0.16, WB of AT1R: 1.20 +/- 0.11 vs 1.32 +/- 0.05; ELISA of AngII: (2.78 +/- 0.56) vs (4.04 +/- 0.13) ng/L; RT-qPCR of TGF-beta1: 0.21 +/- 0.11 vs 0.64 +/- 0.16, WB of TGF beta1:1.01 +/- 0.15 vs 1.19 +/- 0.13; mean optical density of Col III:0.11 +/- 0.04 vs 0.27 +/- 0.04, positive area ratio of Col III:0.056 +/- 0.023 vs 0.090 +/ 0.026, all P < 0.05). CONCLUSIONS: Liraglutide plays a role of organ protection by inhibiting the expression of TGF-beta1 of pulmonary tissue of diabetic rats. And it may be related with a down-regulation of local RAS. PMID- 24754995 TI - [Expression change and significance of homebox gene-A10 in rat cryptorchidism]. AB - OBJECTIVE: To explore the effects of HOXA10 gene expression in undescended and descended testis. METHODS: Twenty-four male Sprague Dawley rats were surgically prepared for unilateral cryptorchidism model. Their undescended and descended testes were removed at days 7 (infancy period, group B7) and 60 (sexual maturity period, group B60) post-operation. And contralateral descended testis served as controls (group A7, group A60). The expression of HOXA10 with histologic changes in experimental cryptorchidism were detected with one-step real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. RESULTS: Compared with the control group, the levels of HOXA10 gene for groups B7 and B60 decreased markedly to 0.78 +/- 0.11 (P < 0.01) and 0.56 +/- 0.03 (P < 0.01) respectively.However the levels of HOXA10 gene and protein in group B60 were significantly lower than those in group B7 (P < 0.01). CONCLUSIONS: There is a lower expression of HOXA10 in undescended testes than in normally developed counterparts. And the expression of HOXA10 decreases with the elapsing time of cryptorchidism. PMID- 24754996 TI - Persistence of pulmonary tertiary lymphoid tissues and anti-nuclear antibodies following cessation of cigarette smoke exposure. AB - Formation of pulmonary tertiary immune structures is a characteristic feature of advanced COPD. In the current study, we investigated the mechanisms of tertiary lymphoid tissue (TLT) formation in the lungs of cigarette smoke-exposed mice. We found that cigarette smoke exposure led to TLT formation that persisted following smoking cessation. TLTs consisted predominantly of IgM positive B cells, while plasma cells in close proximity to TLTs expressed IgM, IgG, and IgA. The presence of TLT formation was associated with anti-nuclear autoantibody (ANA) production that also persisted following smoking cessation. ANAs were observed in the lungs, but not the circulation of cigarette smoke-exposed mice. Similarly, we observed ANA in the sputum of COPD patients where levels correlated with disease severity and were refractory to steroid treatment. Both ANA production and TLT formation were dependent on interleukin-1 receptor 1 (IL-1R1) expression. Contrary to TLT and ANA, lung neutrophilia resolved following smoking cessation. These data suggest a differential regulation of innate and B cell-related immune inflammatory processes associated with cigarette smoke exposure. Moreover, our study further emphasizes the importance of interleukin-1 (IL-1) signaling pathways in cigarette smoke-related pulmonary pathogenesis. PMID- 24754997 TI - Diffusion of e-health innovations in 'post-conflict' settings: a qualitative study on the personal experiences of health workers. AB - BACKGROUND: Technological innovations have the potential to strengthen human resources for health and improve access and quality of care in challenging 'post conflict' contexts. However, analyses on the adoption of technology for health (that is, 'e-health') and whether and how e-health can strengthen a health workforce in these settings have been limited so far. This study explores the personal experiences of health workers using e-health innovations in selected post-conflict situations. METHODS: This study had a cross-sectional qualitative design. Telephone interviews were conducted with 12 health workers, from a variety of cadres and stages in their careers, from four post-conflict settings (Liberia, West Bank and Gaza, Sierra Leone and Somaliland) in 2012. Everett Roger's diffusion of innovation-decision model (that is, knowledge, persuasion, decision, implementation, contemplation) guided the thematic analysis. RESULTS: All health workers interviewed held positive perceptions of e-health, related to their beliefs that e-health can help them to access information and communicate with other health workers. However, understanding of the scope of e-health was generally limited, and often based on innovations that health workers have been introduced through by their international partners. Health workers reported a range of engagement with e-health innovations, mostly for communication (for example, email) and educational purposes (for example, online learning platforms). Poor, unreliable and unaffordable Internet was a commonly mentioned barrier to e-health use. Scaling-up existing e-health partnerships and innovations were suggested starting points to increase e-health innovation dissemination. CONCLUSIONS: Results from this study showed ICT based e-health innovations can relieve information and communication needs of health workers in post-conflict settings. However, more efforts and investments, preferably driven by healthcare workers within the post-conflict context, are needed to make e health more widespread and sustainable. Increased awareness is necessary among health professionals, even among current e-health users, and physical and financial access barriers need to be addressed. Future e-health initiatives are likely to increase their impact if based on perceived health information needs of intended users. PMID- 24754998 TI - Double strand break (DSB) repair in heterochromatin and heterochromatin proteins in DSB repair. AB - Chromosomal translocations are a hallmark of cancer cells and they represent a major cause of tumorigenesis. To avoid chromosomal translocations, faithful repair of DNA double strand breaks (DSBs) has to be ensured in the context of high ordered chromatin structure. However, chromatin compaction is proposed to represent a barrier for DSB repair. Here we review the different mechanisms cells use to alleviate the heterochromatic barrier for DNA repair. At the same time, we discuss the activating role of heterochromatin-associated proteins in this process, therefore proposing that chromatin structure, more than being a simple barrier, is a key modulator of DNA repair. PMID- 24755000 TI - Protein ADP-ribosylation and the cellular response to DNA strand breaks. AB - DNA strand breaks arise continuously in cells and can lead to chromosome rearrangements and genome instability or cell death. The commonest DNA breaks are DNA single-strand breaks, which arise at a frequency of tens-of-thousands per cell each day and which can block the progression of RNA/DNA polymerases and disrupt gene transcription and genome duplication. If not rapidly repaired, SSBs can be converted into DNA double-strand breaks (DSBs) during genome duplication, eliciting a complex series of DNA damage responses that attempt to protect cells from irreversible replication fork collapse. DSBs are the most cytotoxic and clastogenic type of DNA breaks, and can also arise independently of DNA replication, albeit at a frequency several orders of magnitude lower than SSBs. Here, I discuss the evidence that DNA single- and double -strand break repair pathways, and cellular tolerance mechanisms for protecting replication forks during genome duplication, utilize signalling by protein ADP-ribosyltransferases to protect cells from the harmful impact of DNA strand breakage. PMID- 24755001 TI - Longitudinal analysis of antibody responses to trachoma antigens before and after mass drug administration. AB - BACKGROUND: Blinding trachoma, caused by the bacteria Chlamydia trachomatis, is a neglected tropical disease targeted for elimination by 2020. A major component of the elimination strategy is mass drug administration (MDA) with azithromycin. Currently, program decisions are made based on clinical signs of ocular infection, but we have been investigating the use of antibody responses for post MDA surveillance. In a previous study, IgG responses were detected in children lacking clinical evidence of trachoma, suggesting that IgG responses represented historical infection. To explore the utility of serology for program evaluation, we compared IgG and IgA responses to trachoma antigens and examined changes in IgG and IgA post-drug treatment. METHODS: Dried blood spots and ocular swabs were collected with parental consent from 264 1-6 year olds in a single village of Kongwa District, central Tanzania. Each child also received an ocular exam for detection of clinical signs of trachoma. MDA was given, and six months later an additional blood spot was taken from these same children. Ocular swabs were analyzed for C. trachomatis DNA and antibody responses for IgA and total IgG were measured in dried bloods spots. RESULTS: Baseline antibody responses showed an increase in antibody levels with age. By age 6, the percentage positive for IgG (96.0%) was much higher than for IgA (74.2%). Antibody responses to trachoma antigens declined significantly six months after drug treatment for most age groups. The percentage decrease in IgA response was much greater than for IgG. However, no instances of seroreversion were observed. CONCLUSIONS: Data presented here suggest that focusing on concordant antibody responses in children will provide the best serological surveillance strategy for evaluation of trachoma control programs. PMID- 24754999 TI - The cutting edges in DNA repair, licensing, and fidelity: DNA and RNA repair nucleases sculpt DNA to measure twice, cut once. AB - To avoid genome instability, DNA repair nucleases must precisely target the correct damaged substrate before they are licensed to incise. Damage identification is a challenge for all DNA damage response proteins, but especially for nucleases that cut the DNA and necessarily create a cleaved DNA repair intermediate, likely more toxic than the initial damage. How do these enzymes achieve exquisite specificity without specific sequence recognition or, in some cases, without a non-canonical DNA nucleotide? Combined structural, biochemical, and biological analyses of repair nucleases are revealing their molecular tools for damage verification and safeguarding against inadvertent incision. Surprisingly, these enzymes also often act on RNA, which deserves more attention. Here, we review protein-DNA structures for nucleases involved in replication, base excision repair, mismatch repair, double strand break repair (DSBR), and telomere maintenance: apurinic/apyrimidinic endonuclease 1 (APE1), Endonuclease IV (Nfo), tyrosyl DNA phosphodiesterase (TDP2), UV Damage endonuclease (UVDE), very short patch repair endonuclease (Vsr), Endonuclease V (Nfi), Flap endonuclease 1 (FEN1), exonuclease 1 (Exo1), RNase T and Meiotic recombination 11 (Mre11). DNA and RNA structure-sensing nucleases are essential to life with roles in DNA replication, repair, and transcription. Increasingly these enzymes are employed as advanced tools for synthetic biology and as targets for cancer prognosis and interventions. Currently their structural biology is most fully illuminated for DNA repair, which is also essential to life. How DNA repair enzymes maintain genome fidelity is one of the DNA double helix secrets missed by James Watson and Francis Crick, that is only now being illuminated though structural biology and mutational analyses. Structures reveal motifs for repair nucleases and mechanisms whereby these enzymes follow the old carpenter adage: measure twice, cut once. Furthermore, to measure twice these nucleases act as molecular level transformers that typically reshape the DNA and sometimes themselves to achieve extraordinary specificity and efficiency. PMID- 24755003 TI - Role of multiple cusps in tooth fracture. AB - The role of multiple cusps in the biomechanics of human molar tooth fracture is analysed. A model with four cusps at the bite surface replaces the single dome structure used in previous simulations. Extended finite element modelling, with provision to embed longitudinal cracks into the enamel walls, enables full analysis of crack propagation from initial extension to final failure. The cracks propagate longitudinally around the enamel side walls from starter cracks placed either at the top surface (radial cracks) or from the tooth base (margin cracks). A feature of the crack evolution is its stability, meaning that extension occurs steadily with increasing applied force. Predictions from the model are validated by comparison with experimental data from earlier publications, in which crack development was followed in situ during occlusal loading of extracted human molars. The results show substantial increase in critical forces to produce longitudinal fractures with number of cuspal contacts, indicating a capacity for an individual tooth to spread the load during mastication. It is argued that explicit critical force equations derived in previous studies remain valid, at the least as a means for comparing the capacity for teeth of different dimensions to sustain high bite forces. PMID- 24755002 TI - Low sensitivity of the metabolic syndrome to identify adolescents with impaired glucose tolerance: an analysis of NHANES 1999-2010. AB - BACKGROUND: The presence of impaired glucose tolerance (IGT) and metabolic syndrome (MetS) are two risk factors for Type 2 diabetes. The inter-relatedness of these factors among adolescents is unclear. METHODS: We evaluated the sensitivity and specificity of MetS for identifying IGT in an unselected group of adolescents undergoing oral glucose tolerance tests (OGTT) in the National Health and Nutrition Evaluation Survey 1999-2010. We characterized IGT as a 2-hour glucose >=140 mg/dL and MetS using ATP-III-based criteria and a continuous sex- and race/ethnicity-specific MetS Z-score at cut-offs of +1.0 and +0.75 standard deviations (SD) above the mean. RESULTS: Among 1513 adolescents, IGT was present in 4.8%, while ATP-III-MetS was present in 7.9%. MetS performed poorly in identifying adolescents with IGT with a sensitivity/specificity of 23.7%/92.9% for ATP-III-MetS, 23.6%/90.8% for the MetS Z-score at +1.0 SD and 35.8%/85.0 for the MetS Z-score at +0.75 SD. Sensitivity was higher (and specificity lower) but was still overall poor among overweight/obese adolescents: 44.7%/83.0% for ATP III-MetS, 43.1%/77.1% for the MetS Z-score at +1.0 SD and 64.3%/64.3% for MetS Z score at +0.75 SD. CONCLUSION: This lack of overlap between MetS and IGT may indicate that assessment of MetS is not likely to be a good indicator of which adolescents to screen using OGTT. These data further underscore the importance of other potential contributors to IGT, including Type 1 diabetes and genetic causes of poor beta-cell function. Practitioners should keep these potential causes of IGT in mind, even when evaluating obese adolescents with IGT. PMID- 24755004 TI - Core-shell silver nanoparticles for optical labeling of cells. AB - Silver nanoparticles have been modified with self-assembled monolayers of hydroxyl-terminated long chain thiols and encapsulated with a silica shell. The resulting core-shell nanoparticles were used as optical labels for cell analysis using flow cytometry and microscopy. The excitation of plasmon resonances in nanoparticles results in strong depolarized scattering of visible light, permitting detection at the single nanoparticle level. The nanoparticles were modified with neutravidin via epoxide-azide coupling chemistry, to which biotinylated antibodies targeting cell surface receptors were bound. The nanoparticle labels exhibited long-term stability in solutions with high salt concentrations without aggregation or silver etching. Labeled cells exhibited two orders of magnitude enhancement of the scattering intensity compared with unlabeled cells. PMID- 24755005 TI - Proposed lexicon for anatomic landmarks in normal posterior segment spectral domain optical coherence tomography: the IN*OCT consensus. AB - PURPOSE: To develop a consensus nomenclature for the classification of retinal and choroidal layers and bands visible on spectral-domain optical coherence tomography (SD-OCT) images of a normal eye. DESIGN: An international panel with expertise in retinal imaging (International Nomenclature for Optical Coherence Tomography [IN * OCT] Panel) was assembled to define a consensus for OCT imaging terminology. PARTICIPANTS: A panel of retina specialists. METHODS: A set of 3 B scan images from a normal eye was circulated to the panel before the meeting for independent assignment of nomenclature to anatomic landmarks in the vitreous, retina, and choroid. The outputs were scrutinized, tabulated, and used as the starting point for discussions at a roundtable panel meeting. The history of anatomic landmark designations over time was reviewed for the various cellular layers of the ocular structures that are visible by SD-OCT. A process of open discussion and negotiation was undertaken until a unanimous consensus name was adopted for each feature. MAIN OUTCOME MEASURES: Definitions of normal eye features showed by SD-OCT. RESULTS: Definitions for various layers changed frequently in the literature and were often inconsistent with retinal anatomy and histology. The panel introduced the term "zone" for OCT features that seem to localize to a particular anatomic region that lacks definitely proven evidence for a specific reflective structure. Such zones include the myoid, ellipsoid, and the interdigitation zones. CONCLUSIONS: A nomenclature system for normal anatomic landmarks seen on SD-OCT outputs has been proposed and adopted by the IN * OCT Panel. The panel recommends this standardized nomenclature for use in future publications. The proposed harmonizing of terminology serves as a basis for future OCT research studies. PMID- 24755006 TI - Paradoxical low-flow, low-gradient aortic stenosis despite preserved left ventricular ejection fraction: new insights from weights of operatively excised aortic valves. AB - AIMS: We reported that patients with small aortic valve area (AVA) and low flow despite preserved left ventricular ejection fraction (LVEF), i.e. 'paradoxical' low flow (PLF), have worse outcomes compared with patients with normal flow (NF), although they generally have a lower mean gradient (MG). The aortic valve weight (AVW) excised at the time of valve replacement is a flow-independent marker of stenosis severity. The objective of this study was to compare the AVW of patients with PLF and MG<40 mmHg with the AVW of patients with NF and MG>=40 mmHg. METHODS AND RESULTS: We recruited 250 consecutive patients undergoing valve replacement (Cohort A) for severe stenosis. Among them, 33 (13%) were in PLF [LVEF > 50% but stroke volume index (SVi) <= 35 mL/m(2)] with MG < 40 mmHg (PLF-LG group) and 105 (42%) were in NF (LVEF > 50% and SVi > 35 mL/m(2)) with MG >= 40 mmHg (NF-HG group). Despite a much lower MG (29 +/- 7 vs. 53 +/- 10 mmHg; P < 0.0001), patients in the PLF-LG group had a similar AVA (0.73 +/- 0.12 vs. 0.69 +/- 0.13; P = 0.19) compared with those in the NF-HG group. The AVW [median (interquartile): 1.90 (1.63-2.50) vs. 2.60 (1.66-3.32)] and prevalence of bicuspid phenotype (15 vs. 42%) were lower in the PLF-LG group than in the NF-HG group. However, AVWs analysed separately in the tricuspid and bicuspid valves were similar in both groups [tricuspid valves: 1.80 (1.63-2.50) vs. 2.30 (1.58 3.00) g; P = 0.26 and bicuspid valves: 2.72 (1.73-3.61) vs. 2.60 (2.10-3.55) g; P = 0.93]. When using cut-point values of AVW established in another series of non consecutive patients (n = 150, Cohort B) with NF and concordant Doppler echocardiographic findings, we found that the percentage of patients with evidence of severe stenosis in Cohort A was 70% in patients with PLF-LG and 86% in patients with NF-HG. CONCLUSION: The aortic valve weight data reported in this study provide evidence that a large proportion of patients with PLF and low gradient have a severe stenosis and that the gradient may substantially underestimate stenosis severity in these patients. A multi-parametric approach including all Doppler-echocardiographic parameters of valve function as well as other complementary diagnostic tests may help correctly identify these patients. PMID- 24755007 TI - Prospective validation of the Bleeding Academic Research Consortium classification in the all-comer PRODIGY trial. AB - AIMS: The Bleeding Academic Research Consortium (BARC) classification has been proposed by consensus to standardize bleeding endpoint definition and reporting in cardiovascular clinical trials. There are no prospective studies on its prognostic impact. METHODS AND RESULTS: We explored the association of BARC defined bleeding with mortality and compared its prognostic value against two validated bleeding scales: the Thrombolysis in Myocardial Infarction (TIMI) and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) scales. Non-coronary artery bypass graft (CABG)-related bleedings within the PRODIGY trial were prospectively adjudicated by a blinded Clinical Event Committee and analysed according to multiple statistical modelling. At 2 years, bleeding occurred in 143 patients (7.1%) according to BARC Type 2, 3, or 5; in 50 patients (2.5%) according to TIMI minor or major; and in 61 patients (3.1%) according to GUSTO moderate or severe. One hundred sixty-three patients died (8.1%). After multivariable modelling, BARC Type 2, 3, or 5 bleeding was associated with increased 2-year mortality [hazard ratio (HR): 3.77; 95% confidence interval (CI): 2.37-5.98]. Bleeding Academic Research Consortium Type 3 or 5 was associated with an increased mortality rate at 2 years (adjusted HR: 7.72; 95% CI: 4.75-12.54) similar to that provided by TIMI (HR: 7.64, 95% CI: 4.53-12.87) or GUSTO (HR: 7.36, 95% CI: 4.38-12.34) criteria. CONCLUSIONS: In a contemporary, all-comer percutaneous coronary intervention trial actionable BARC bleedings were associated with increased risk of mortality with BARC Type 3 or 5 bleedings providing a similar mortality risk to that posed by TIMI or GUSTO scales. PMID- 24755008 TI - Vitamin D status is poor in the UK. PMID- 24755009 TI - A prospective study on ambulatory care provided by primary care pediatricians during influenza season. AB - Aim of this study was to obtain a picture of the nature of the primary care pediatricians' visits during a winter season. We investigated reasons for visits, diagnosis, and pattern of prescription in 284 children. The reason for visit was a planned visit in 54% of cases, a well-being examination in 26%, and an urgent visit for an acute problem in 20% of cases. Cough was the most common symptom reported (61%). The most common pediatricians' diagnosis was flu-like syndrome (47%). No disease was found by pediatrician in 27% of children with a symptom reported by caregivers. Antibiotics were prescribed in 25% of children, the vast majority of which affected by viral respiratory infections. The unjustified access to physician's visit may lead to a inappropriate prescription of drugs. PMID- 24755010 TI - Stress and cardiometabolic manifestations among Saudi students entering universities: a cross-sectional observational study. AB - BACKGROUND: In this observational study, we aimed to see whether transition in Saudi students entering university life could be a breeding stage for cardiometabolic risk factor emergence and clustering. METHODS: A total of 1878 apparently healthy Saudi students of the Preparatory Year, King Saud University, Riyadh, KSA (1112 men and 766 women) spanning 2 academic years were included. They were divided into 2 groups based on the validated perceived stress test (PST). Anthropometrics were obtained and fasting blood samples were collected for measurement of fasting blood glucose and a lipid profile. RESULTS: PST score (>27) considered indicative of stress was noted in 44.4% of students. The prevalence of this score was higher in women than in men (49.7% versus 40.7%). The prevalence of obesity, hypertension and dyslipidemia was significantly higher in men than women (p < 0.01), and this was even more apparent among stressed men, who had a significantly higher prevalence of all the above cardiometabolic factors than the non-stressed ones (p < 0.01). CONCLUSION: Perceived stress is alarmingly high among Saudi students entering universities. This study sheds light on the social responsibility of universities in promoting a healthy lifestyle, particularly in this age group, when exposure to different kinds of stressors may result in body weight and metabolic changes. PMID- 24755012 TI - Clinical translation of nuclear export inhibitors in cancer. AB - Clinical targeting of multi-dimensional proteins such as the proteasome has been efficacious in recent years. Inhibitors such as bortezomib and carfilzomib have been used successfully to treat multiple myeloma despite early skepticism surrounding unsubstantiated toxic side effects. Another target of this magnitude is ready to emerge as a clinically viable option for targeting various neoplasias. This target, XPO1 (exportin-1 also known as Chromosome Region Maintenance 1 (CRM1)), is the transport protein responsible for nuclear export of many of the major tumor suppressor proteins and cell growth regulators. Up regulation of XPO1 protein, a common occurrence in a variety of cancers, can lead to aberrant cytoplasmic localization and degradation of tumor suppressors such as p53 and FOXO. Therefore, inhibition of XPO1 using specific small molecules collectively called Selective Inhibitors of Nuclear Export (SINE) could potentially restore normal tumor suppressor function and have universal application for the treatment of cancer. This review will discuss the current pre clinical data on SINE compounds in both hematological and solid malignancies. Cancer treatment through direct inhibition of the proteasome and the nuclear export machinery should instill optimism for further targeting of critical cellular pathways. PMID- 24755013 TI - Cell response to nanocrystallized metallic substrates obtained through severe plastic deformation. AB - Cell-substrate interface is known to control the cell response and subsequent cell functions. Among the various biophysical signals, grain structure, which indicates the repeating arrangement of atoms in the material, has also proved to play a role of significant importance in mediating the cell activities. Moreover, refining the grain size through severe plastic deformation is known to provide the processed material with novel mechanical properties. The potential application of such advanced materials as biomedical implants has recently been evaluated by investigating the effect of different substrate grain sizes on a wide variety of cell activities. In this review, recent advances in biomedical applications of severe plastic deformation techniques are highlighted with special attention to the effect of the obtained nano/ultra-fine-grain size on cell-substrate interactions. Various severe plastic deformation techniques used for this purpose are discussed presenting a brief description of the mechanism for each process. The results obtained for each treatment on cell morphology, adhesion, proliferation, and differentiation, as well as the in vivo studies, are discussed. Finally, the advantages and challenges regarding the application of these techniques to produce multifunctional bio-implant materials are addressed. PMID- 24755011 TI - The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies. AB - BACKGROUND: Adjustment for prognostic covariates can lead to increased power in the analysis of randomized trials. However, adjusted analyses are not often performed in practice. METHODS: We used simulation to examine the impact of covariate adjustment on 12 outcomes from 8 studies across a range of therapeutic areas. We assessed (1) how large an increase in power can be expected in practice; and (2) the impact of adjustment for covariates that are not prognostic. RESULTS: Adjustment for known prognostic covariates led to large increases in power for most outcomes. When power was set to 80% based on an unadjusted analysis, covariate adjustment led to a median increase in power to 92.6% across the 12 outcomes (range 80.6 to 99.4%). Power was increased to over 85% for 8 of 12 outcomes, and to over 95% for 5 of 12 outcomes. Conversely, the largest decrease in power from adjustment for covariates that were not prognostic was from 80% to 78.5%. CONCLUSIONS: Adjustment for known prognostic covariates can lead to substantial increases in power, and should be routinely incorporated into the analysis of randomized trials. The potential benefits of adjusting for a small number of possibly prognostic covariates in trials with moderate or large sample sizes far outweigh the risks of doing so, and so should also be considered. PMID- 24755014 TI - [2012 ranking in research in Spanish public universities]. AB - 2012 ranking in research in Spanish public universities. BACKGROUND: In order to guarantee the usefulness of promotion policies for the investigation of educational institutions, in recent years studies analyzing different indicators have been developed, with the intention of valuing possible changes in the future. The objective of this work is to update the research production and productivity ranking of Spanish public universities, using data from 2012. METHOD: The same methodology as previous years has been followed. Seven indicators have been evaluated: articles from journals indexed in the JCR, research lines, R+D projects, doctoral theses, Spanish research and training grants, doctorate courses awarded a mention of excellence and patents. RESULTS: Amongst the results obtained in the global ranking there are differences between the universities with a higher production (University of Barcelona, Complutense University of Madrid and the University of Granada) and those with a higher productivity (Pompeu Fabra, Pablo de Olavide and Miguel Hernández de Elche). CONCLUSIONS: When comparing the results to those of 2011, it can be observed that the three most productive universities remain in the same positions. PMID- 24755015 TI - Personality disorders among patients with panic disorder and individuals with high anxiety sensitivity. AB - BACKGROUND: No studies have been found that compared the psychopathology features, including personality disorders, of Panic Disorder (PD) and Panic Disorder with Agoraphobia (PDA), and a nonclinical sample with anxiety vulnerability. METHOD: The total sample included 152 participants, 52 in the PD/PDA, 45 in the high anxiety sensitivity (AS) sample, and 55 in the nonclinical sample. The participants in PD/PDA sample were evaluated with the structured interview ADIS-IV. The Brief Symptom Inventory and the MCMI-III were used in all three samples. RESULTS: Statistically significant differences were found between the PD/PDA and the nonclinical sample in all MCMI-III scales except for antisocial and compulsive. No significant differences were found between PD/PDA and the sample with high scores in AS. Phobic Anxiety and Paranoid Ideation were the only scales where there were significant differences between the PD/PDA sample and the high AS sample. CONCLUSIONS: Our findings showed that people who scored high on AS, despite not having a diagnosis of PD/PDA, were similar in regard to psychopathology features and personality to individuals with PD/PDA. PMID- 24755016 TI - Cognitive executive performance influences functional outcome in euthymic type I bipolar disorder outpatients. AB - BACKGROUND: There is a debate about the influence of executive functioning impairment in the functionality of Bipolar Disorder Type I, even when euthymic (EutBDI). The aim of this study was to explore this relationship, taking functional outcome from a multidimensional point of view. METHODS: An extended neuropsychological battery of executive tests and measures of social functioning were administered to 31 EutBDI and 25 non-psychiatric patients. Percentage of patients scoring lower than -1.64 SD was calculated for each executive measure. This was compared in terms of clinical features to those with normal performance. Partial correlations and ANCOVA were applied between psychosocial and executive variables within the EutBDI-group. RESULTS: Patients reached poorer scores in mental flexibility, plan implementing, set-shifting, and fluency (p<0.05). 76% of patients performed poorly on some of the executive tests, although only around 1/3 reached a clinical deficit (<-1.64SD). Executive functioning was related to some clinical, evolution, and treatment variables. A better use of leisure time, higher competence for independent living and holding a skilled type of profession were significantly associated with a better performance on planning, set shifting, and fluency tasks. CONCLUSIONS: Persistent executive deficits in EutBDI may be related to their frequently reported difficulties in personaland occupational adjustment. PMID- 24755017 TI - Obsessive Compulsive Inventory-Child Version (OCI-CV) in a Spanish community sample of children and adolescents. AB - BACKGROUND: There is a growing interest in designing instruments to assess obsessive-compulsive symptoms in children. The Obsessive-Compulsive Inventory Child Version (OCI-CV) has showed to be a valid in the evaluation of OCD in clinical and nonclinical populations. The main goal in this study was to analyze factor structure and psychometric properties of the OCI-CV in a community Spanish sample. METHOD: Data were collected from 914 children/adolescents with a mean age of 13.01 (SD = 1.96; Males = 51.3%). Exploratory factor analysis was carried out in order to study the internal structure of the OCI-CV Spanish version. Further, internal consistency, test-retest reliability, and convergent and discriminant validity of the total score and the factors obtained were examined. Finally, age and gender differences were also explored. RESULTS: Exploratory factor analysis yielded a similar structure to the original OCI-CV with the following six factors: Washing/Checking, Obsession, Ordering, Doubting, Neutralizing, and Hoarding. The internal consistency was strong for the total score, but moderate for the subscales. The Spanish version of the OCI-CV showed evidences of test retest reliability and convergent and discriminant validity. CONCLUSION: The Spanish version of the OCI-CV is an instrument with adequate psychometric properties to assess obsessions and compulsions in Spanish children/adolescents. PMID- 24755018 TI - Validation of the Spanish version of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). AB - BACKGROUND: To evaluate the psychometric properties of the Spanish version of the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and its effectiveness as a screening tool for problematic alcohol, tobacco and other psychoactive substance use in groups of low, moderate, and high risk users. METHODS: A test battery including the ASSIST and several standardized screening, assessment, and diagnostic instruments was administered to 485 patients recruited in different primary health-care facilities and specialized addiction treatment units from Health Area 11 in Madrid. RESULTS: ASSIST cut-off scores show a good sensitivity and specificity for discrimination between substance use and abuse and between abuse and dependence. Concurrent validity was demonstrated by significant correlations between ASSIST scores and scores from the Mini International Neuropsychiatric Interview (MINI-Plus), the Alcohol Use Disorders Identification Test (AUDIT), the Revised Fagerstrom Tolerance Questionnaire (RTQ) and the Severity of Dependence Scale (SDS). CONCLUSIONS: Psychometric properties of the Spanish version of the ASSIST indicate that is a valid screening test for identifying substance use disorders in various health-care settings. PMID- 24755019 TI - Advances in the indirect, descriptive, and experimental approaches to the functional analysis of problem behavior. AB - BACKGROUND: Experimental functional analysis is an assessment methodology to identify the environmental factors that maintain problem behavior in individuals with developmental disabilities and in other populations. Functional analysis provides the basis for the development of reinforcement-based approaches to treatment. METHODS: This article reviews the procedures, validity, and clinical implementation of the methodological variations of functional analysis and function-based interventions. RESULTS: We present six variations of functional analysis methodology in addition to the typical functional analysis: brief functional analysis, single-function tests, latency-based functional analysis, functional analysis of precursors, and trial-based functional analysis. We also present the three general categories of function-based interventions: extinction, antecedent manipulation, and differential reinforcement. CONCLUSIONS: Functional analysis methodology is a valid and efficient approach to the assessment of problem behavior and the selection of treatment strategies. PMID- 24755020 TI - Psychological intervention in the Spanish military deployed on international operations. AB - BACKGROUND: Spain was one of the first countries to recognize the importance of psychological aspects in the planning and development of international military operations, and also to include military psychologists in contingents deployed abroad. METHOD: This paper describes the psychological intervention model used by Spanish military psychologists involved in military operations abroad. RESULTS: This model is comprised of a systematic set of interventions and actions carried out in the different phases of any military operation (concentration, deployment and post-mission). It also contemplates the intervention not only in personnel who integrate the military contingents, but also with their families and, at certain times of the mission, with the local population of the area in which the operation is carried out. CONCLUSIONS: The model presented has a preventive orientation, based on the selection and psychological preparation of contingents before deployment, and supplemented by support in the area of operations for personnel who need it, and the psychological care of their families in Spain. Whereas this model has been effective so far, in this work, we present a series of measures aimed at improving the psychological well-being of our troops deployed outside our country. PMID- 24755021 TI - Satisfaction with life and with food-related life in central Chile. AB - BACKGROUND: Eating is one of the most frequent human behaviors, but there are few studies that relate eating and subjective well-being. Typologies of people were distinguished and characterized according to their level of satisfaction with life and food in central Chile. METHOD: A survey was applied to a sample of 1,277 people in the main municipalities of this area, distributed proportionally by municipality. The questionnaire included the SWLS scales (Satisfaction with Life Scale), SWFL (Satisfaction with Food-related Life), Health-Related Quality of Life Index (HRQOL), Subjective Happiness Scale (SHS), and respondents' demographic characteristics and eating habits were also ascertained. RESULTS: Using hierarchical cluster analysis, three typologies were distinguished with significant differences in the scores on the SWLS, SWFL, SHS, self-perception of health, days with physical or mental problems in the last month, sociodemographic characteristics and frequency with which the family eats together. CONCLUSIONS: The results suggest that a higher level of general subjective well-being, and eating is associated with better health, greater family interaction around meals, higher levels of happiness, and with some sociodemographic characteristics. PMID- 24755022 TI - Development and validation of the Occupational Hardiness Questionnaire. AB - BACKGROUND: One of the most traditional approaches to the positive study of personality has been the research on Hardiness or Hardy Personality. However, studies about this construct have systematically suffered from a lack of sufficient psychometric guarantees of the measures. METHOD: This paper presents the Occupational Hardiness Questionnaire (OHQ), the result of a research line on the subject and its measurement with a total sample of 1,647 participants. RESULTS: Four studies show the results of exploratory factor analysis (EFA), confirmatory factor analysis (CFA), consistency, temporal reliability and construct validity. CONCLUSIONS: Results indicate that the OHQ has satisfactory psychometric characteristics and can be used in the study of Occupational Health and in the area of Positive Personality. PMID- 24755023 TI - Development and psychometric properties of the Resistance to Trauma Test (TRauma). AB - BACKGROUND: The Resistance to trauma Test: TRauma is an instrument designed to assess six dimensions involving personal strengths or resources that promote coping with difficult life situations. In addition, an overall score is obtained that is conceptually equivalent to the concept of resilience. The aim of this study was to analyze the psychometric properties and factorial structure of the TRauma in a sample of subjects affected by a traumatic event. METHOD: Participants were 222 people affected by a traumatic life event (36.5% males), with ages ranging between 18 and 71 years. RESULTS: Confirmatory factor analysis supports the theoretical internal structure proposed for the instrument. Moreover, the reliability coefficients of the six scales and the total score are both acceptable. CONCLUSIONS: Overall, the findings of this study support the use of the TRauma to measure factors of personal strengths and resilience. However, these results do not exhaust the validation process of the TRauma, and it is necessary to continue to seek empirical evidence. PMID- 24755024 TI - Working in direct contact with the public as a predictor of burnout in the banking sector. AB - BACKGROUND: This study investigated the presence of the burnout syndrome amongst employees of the banking sector. This topic is of particular interest owing to recent changes in working conditions and the controversial commercial strategies employed in this sector in recent years. METHOD: A total of 1,341 professionals, 883 men and 458 women took part in the study. A Spanish version of the Maslach Burnout Inventory-General Survey was used, via electronic mail. RESULTS: The results revealed that at least 55.78% of the sample showed a high risk of burnout in at least two of the dimensions. The workers in commercial branch offices dealing with the general public showed a greater risk of burnout than those working in central services. CONCLUSIONS: The risk of burnout was higher than in other professions considered to be at risk and appears to be more closely associated with work-related stress and the controversial commercial strategies employed in the sector in recent years than with the possibility of cuts in salary. Psychological intervention programs aimed at stress management would be a recommendable way of helping employees address problems of this kind. PMID- 24755025 TI - Multivariate analysis of burnout syndrome in Latin-American priests. AB - BACKGROUND: Burnout syndrome is a highly prevalent disorder in a wide range of professional groups, and is associated with substantial psychophysiological alterations. Nevertheless, this syndrome has not been analyzed in depth among the clergy, a group which fulfils a fundamental social function and has to deal with numerous stressors that increase the risk of burnout onset. METHOD: In the present study, the authors assessed 881 Catholic priests from Latin America. The Maslach Burnout Inventory-22, the General Health Questionnaire-28 and the CAGE were applied; we also recorded the priests' rates of cigarette-smoking. Specific cut-off points were set for burnout syndrome in priests. RESULTS: The original factor structures of the questionnaires are confirmed in the clerical sample, and the reliability is adequate. As regards the dimensions of the syndrome as a function of the countries studied, no statistically significant differences were found, except for the exhaustion dimension. CONCLUSIONS: The authors established the typology that defines the relevance and effect of each dimension, as well as its prevalence in this group, with a figure of 25.39%. Furthermore, burnout shows a clear relationship with general health and may be associated with addiction to substances such as alcohol or tobacco. PMID- 24755026 TI - An updated review on burden on caregivers of schizophrenia patients. AB - BACKGROUND: Schizophrenia is a debilitating mental illness that has a significant impact not only in the patient but also in the entire family as well. Caregivers assume almost the totality of the patient care. This responsibility exposes caregivers to an intense burden with negative consequences for them and the rest of the family system. This is an updated review of existing literature about burden on families with schizophrenia patients. METHOD: An electronic search of articles from MEDLINE, EMBASE, APA, EBSCO, and Cochrane databases was conducted for articles published between 2008 and 2013. RESULTS: A systematization of information and frequency analysis revealed the existence of eight factors related to burden that were present in almost all the reviewed literature: Programs of family treatment, Ethnic group, Expressed Emotion, Stress and Burden, Preoccupations of the caregiver, Kind of caregiver, Social networks, Social support, Finances and Coping Strategies. CONCLUSIONS: This study supports the statements of different theories reflecting the complexity of schizophrenia caregivers' burden and these, in turn, may be related to the above factors. PMID- 24755027 TI - Explicit and implicit assessment of gender roles. AB - BACKGROUND: Gender roles have been assessed by explicit measures and, recently, by implicit measures. In the former case, the theoretical assumptions have been questioned by empirical results. To solve this contradiction, we carried out two concatenated studies based on a relatively well-founded theoretical and empirical approach. METHOD: The first study was designed to obtain a sample of genderized activities of the domestic sphere by means of an explicit assessment. Forty-two raters (22 women and 20 men, balanced on age, sex, and level of education) took part as raters. In the second study, an implicit assessment of gender roles was carried out, focusing on the response time given to the sample activities obtained from the first study. A total of 164 adults (90 women and 74 men, mean age = 43), with experience in living with a partner and balanced on age, sex, and level of education, participated. RESULTS: Taken together, results show that explicit and implicit assessment converge. The current social reality shows that there is still no equity in some gender roles in the domestic sphere. CONCLUSIONS: These consistent results show considerable theoretical and empirical robustness, due to the double implicit and explicit assessment. PMID- 24755028 TI - Classical and causal inference approaches to statistical mediation analysis. AB - BACKGROUND: Although there is a broad consensus on the use of statistical procedures for mediation analysis in psychological research, the interpretation of the effect of mediation is highly controversial because of the potential violation of the assumptions required in application, most of which are ignored in practice. METHOD: This paper summarises two currently independent procedures for mediation analysis, the classical/SEM and causal inference/CI approaches, together with the statistical assumptions required to estimate unbiased mediation effects, in particular the existence of omitted variables or confounders. A simulation study was run to test whether violating the assumptions changes the estimation of mediating effects. RESULTS: The simulation study showed a significant overestimation of mediation effects with latent confounders. CONCLUSIONS: We recommend expanding the classical with the causal inference approach, which generalises the results of the first approach to mediation using a common estimation method and incorporates new tools to evaluate the statistical assumptions. To achieve this goal, we compare the distinguishing features of recently developed software programs in R, SAS, SPSS, STATA and Mplus. PMID- 24755029 TI - Psychometric properties of the Looming Maladaptive Style Questionnaire (LMSQ-R) in young Spanish adults. AB - BACKGROUND: The looming cognitive style (LCS) is a specific putative cognitive vulnerability to anxiety but not to depression. LCS is assessed by the Looming Maladaptive Style Questionnaire (LMSQ-R), which assesses a tendency to generate, maintain, and attend to internally generated scenarios of threats as rapidly increasing and headed in one's direction. This study investigated the structure, measurement invariance across subsamples, concurrent validity, consistency, and stability of a Spanish translation of the LMSQ-R. METHOD: LMSQ-R was examined in a large sample of Spanish students (n = 1,128, 56.47% women). A subsample of 675 was followed-up six months later. The participants also completed measures of social anxiety, generalized anxiety, and depression. RESULTS: The results provide evidence from factor analyses confirming two second-order factors (social and physical threat). Multiple-group analysis indicated the measurement invariance of the model for men and women and for groups that displayed clinically significant generalized social anxiety and those that did not. Women scored higher on the LMSQ-R. Partial correlation analyses indicated that LMSQ-R scales were independently associated with symptoms of generalized and social anxiety but they were not independently associated with depression. CONCLUSIONS: The Spanish version of the LMSQ-R has shown good psychometric properties. PMID- 24755030 TI - Psychometric characteristics of the Spanish version of the Sport Imagery Questionnaire. AB - BACKGROUND: The aim of this study was to examine the psychometric properties of the Spanish version of the Sport Imagery Questionnaire (SIQ), which assesses cognitive and motivational functions of imagery use. METHOD: Participants were 361 athletes (234 male and 127 female) with a mean of age of 24.29 +/- 7.76 yrs. Athletes were recruited from 31 sports across three competitive levels (i.e., regional, national, and international). RESULTS: Confirmatory factor analyses of the 30-item five factor SIQ model revealed adequate fit to the data, c2(378) = 694.6, CFI = .91, TLI = .90, RMSEA= .05, SRMR= .05. Multivariate analyses of variance revealed that athletes of higher competitive level reported significantly higher levels of cognitive general and cognitive specific imagery. CONCLUSIONS: Overall, these results provide further support for the claim that the SIQ has a reproducible factor structure and internal consistency for measuring imagery use in Spanish athletes. PMID- 24755031 TI - Spanish adaptation of the internal functioning of the Work Teams Scale (QFI-22). AB - BACKGROUND: The aim of this article is to develop the Spanish adaptation of the internal functioning of Work Teams Scale (QFI-22). METHODS: The scale was adapted from the French version, and was applied to a sample of 1,055 employees working for firms operating in Spain. The article analyses the internal structure (exploratory and confirmatory factor analysis) and internal consistency, and provides convergent validity evidence of the scale. RESULTS: The QFI-22 scale shows the same internal structure as the original. Factor analysis confirmed the existence of two factors: interpersonal support and team work management, with good internal consistency coefficients (alpha1 = .93, alpha2 = .92). Regarding validity evidence, the QFI-22 scale has significant correlations with other correlates and alternative scales used for comparison purposes. The two factors correlated positively with team vision, participation safety, task orientation and support for innovation (Team Climate Inventory, TCI scale), with progressive culture (Organisational Culture, X-Y scale), and with creating change, customer focus and organisational learning (Denison Organizational Culture Survey, DOCS scale). In contrast, the two factors correlated negatively with traditional culture (X-Y scale). CONCLUSION: The QFI-22 scale is a useful instrument for assessing the internal functioning of work teams. PMID- 24755032 TI - The effect of skewness and kurtosis on the Kenward-Roger approximation when group distributions differ. AB - BACKGROUND: This study examined the independent effect of skewness and kurtosis on the robustness of the linear mixed model (LMM), with the Kenward-Roger (KR) procedure, when group distributions are different, sample sizes are small, and sphericity cannot be assumed. METHODS: A Monte Carlo simulation study considering a split-plot design involving three groups and four repeated measures was performed. RESULTS: The results showed that when group distributions are different, the effect of skewness on KR robustness is greater than that of kurtosis for the corresponding values. Furthermore, the pairings of skewness and kurtosis with group size were found to be relevant variables when applying this procedure. CONCLUSIONS: With sample sizes of 45 and 60, KR is a suitable option for analyzing data when the distributions are: (a) mesokurtic and not highly or extremely skewed, and (b) symmetric with different degrees of kurtosis. With total sample sizes of 30, it is adequate when group sizes are equal and the distributions are: (a) mesokurtic and slightly or moderately skewed, and sphericity is assumed; and (b) symmetric with a moderate or high/extreme violation of kurtosis. Alternative analyses should be considered when the distributions are highly or extremely skewed and samples sizes are small. PMID- 24755033 TI - Psychometric properties of the School Anxiety Inventory-Short Version in Spanish secondary education students. AB - BACKGROUND: The School Anxiety Inventory (SAI) can be applied in different fields of psychology. However, due to the inventory's administration time, it may not be useful in certain situations. To address this concern, the present study developed a short version of the SAI (the SAI-SV). METHOD: This study examined the reliability and validity evidence drawn from the scores of the School Anxiety Inventory-Short Version (SAI-SV) using a sample of 2,367 (47.91% boys) Spanish secondary school students, ranging from 12 to 18 years of age. To analyze the dimensional structure of the SAI-SV, exploratory and confirmatory factor analyses were applied. Internal consistency and test-retest reliability were calculated for SAI-SV scores. RESULTS: A correlated three-factor structure related to school situations (Anxiety about Aggression, Anxiety about Social Evaluation, and Anxiety about Academic Failure) and a three-factor structure related to the response systems of anxiety (Physiological Anxiety, Cognitive Anxiety, and Behavioral Anxiety) were identified and supported. The internal consistency and test-retest reliability were determined to be appropriate. CONCLUSIONS: The reliability and validity evidence based on the internal structure of SAI-SV scores was satisfactory. PMID- 24755034 TI - Reconstruction of soft tissue necrosis secondary to cryoglobulinaemia. AB - Cryoglobulinaemia is an uncommon immunological disorder that can lead to extensive areas of skin and soft-tissue necrosis. The reconstructive surgeon may be faced with the wound complications of cryoglobulinaemia but there are few case reports in the literature to help guide the reconstructive approach. Moreover, the literature suggests that these wounds are refractory to conventional wound care principles and routine reconstructive practices, and can signify a high risk of morbidity and mortality. We present a case of cryoglobulinaemia leading to severe bilateral lower limb ulceration with necrosis extending through subcutaneous tissues and muscle to the level of bone. Faced with the possibility of above knee amputation, these wounds with exposed bone denuded of periosteum were successfully reconstructed with the dermal regeneration template Pelnac(r) (Gunze Corp., Kyoto, Japan) and secondary split skin grafting. As far as we are aware, this is the first case reported in the literature where reconstruction was successful, disease remission was achieved, and significant morbidity or mortality did not ensue. We discuss caveats to the reconstruction of soft tissue loss secondary to cryoglobulinaemia, and highlight the multimodal approach to treatment. PMID- 24755035 TI - Impact of serum omentin-1 levels on cardiac prognosis in patients with heart failure. AB - BACKGROUND: Various adipokines are reported to be associated with the development of heart failure (HF) through insulin resistance and chronic inflammation. Omentin-1 is a novel adipokine and is associated with incident coronary artery disease. However, it remains unclear whether serum omentin-1 levels are associated with cardiac prognosis in patients with HF. METHODS: We measured serum omentin-1 levels at admission in 136 consecutive patients with HF, and 20 control subjects without signs of significant heart disease. We prospectively followed patients with HF to endpoints of cardiac death or re-hospitalization for worsening HF. RESULTS: Serum omentin-1 levels were markedly lower in HF patients with cardiac events compared with to without. The patients who were in New York Heart Association (NYHA) functional class IV showed significantly lower serum omentin-1 levels compared to those in class II and III, whereas serum omentin-1 levels did not correlate with serum brain natriuretic peptide levels (r = 0.217, P = 0.011). We divided the HF patients into three groups based on the tertiles of serum omentin-1 level (low T1, middle T2, and high T3). Multivariate Cox hazard analysis showed that the lowest serum omentin-1 level (T1) was independently associated with cardiac events after adjustment for confounding factors (hazard ratio 5.78, 95% confidence interval 1.20-12.79). We divided the HF patients into two groups according to the median serum omentin-1 levels. Kaplan-Meier analysis revealed that the patients with low serum omentin-1 levels had a higher risk of cardiac events compared with those with high serum omentin-1 levels (log-rank test p < 0.001). CONCLUSION: Decreased serum omentin-1 levels were associated with a poor cardiac outcome in patients with HF. PMID- 24755036 TI - Enhanced circulating PCSK9 concentration by berberine through SREBP-2 pathway in high fat diet-fed rats. AB - BACKGROUND: Berberine (BBR), a natural plant extract, has been shown to improve lipid metabolism. However, its effects on PCSK9, a key factor involving in the lipid metabolism, have not yet been evaluated in vivo. The aim of the present study was to investigate the effect of BBR on PCSK9 expression in high fat diet fed (HFD) rats. METHODS: Thirty-two male Sprague Dawley (SD) rats were randomized into the four groups (n = 8): normal diet (Control), HFD, HFD + simvastatin (Sim, 2 mg/kg/d) and HDF + BBR (400 mg/kg/d) for 6 weeks. The following parameters were determined: 1) body weight; 2) serum lipid profile; 3) serum PCSK9 measured by enzyme-linked immuno sorbent assay (ELISA) ; 4) hepatic expressions of low density lipoprotein receptor (LDLR), sterol regulatory element binding protein-2 (SREBP-2) and hepatocyte nuclear factor 1 (HNF1) were examined by real time quantitative polymerase chain reaction (RT-PCR) and western blotting analysis. RESULTS: Compared with HFD rats, Sim and BBR significantly reduced body weight gain and improved lipid profile (P < 0.05 respectively). In addition, either of drug treatment for 6 weeks could increase serum concentration of PCSK9 in HFD rats (P < 0.05). This enhanced PCSK9 expression was demonstrated to be associated with the up-regulation of hepatic expression of LDLR and SREBP-2 and the down regulation of hepatic expression of HNF1 (P < 0.05 respectively). CONCLUSIONS: The data provided the first line of the evidence that BBR, similar to the Sim, could increase the expression of PCSK9 levels in HFD rats through SREBP-2 activation, suggesting that impacts of BBR on lipid profile may also be linked to SREBP-2 pathway. PMID- 24755037 TI - Differences in outpatient care and treatment utilization for patients with HIV/HCV coinfection, HIV, and HCV monoinfection, a cross-sectional study. AB - BACKGROUND: Few studies have explored how utilization of outpatient services differ for HIV/HCV coinfected patients compared to HIV or HCV monoinfected patients. The objectives of this study were to (1) compare annual outpatient clinic visit rates between coinfected and monoinfected patients, (2) to compare utilization of HIV and HCV therapies between coinfected and monoinfected patients, and (3) to identify factors associated with therapy utilization. METHODS: Data were from the 2005-2010 U.S. National Hospital Ambulatory Medical Care Surveys. Clinic visits with a primary or secondary ICD-9-CM codes for HIV or HCV were included. Coinfection included visits with codes for both HIV and HCV. Monoinfection only included codes for HIV or HCV, exclusively. Patients <15 years of age at time of visit were excluded. Predictors of HIV and HCV therapy were determined by logistic regressions. Visits were computed using survey weights. RESULTS: 3,021 visits (11,352,000 weighted visits) met study criteria for patients with HIV/HCV (8%), HIV (70%), or HCV (22%). The HCV subgroup was older in age and had the highest proportion of females and whites as compared to the HIV/HCV and HIV subgroups. Comorbidities varied significantly across the three subgroups (HIV/HCV, HIV, HCV): current tobacco use (40%, 27%, 30%), depression (32%, 23%, 24%), diabetes (9%, 10%, 17%), and chronic renal failure (<1%, 3%, 5%), (p < 0.001 for all variables). Annual visit rates were highest in those with HIV, followed by HIV/HCV, but consistently lower in those with HCV. HIV therapy utilization increased for both HIV/HCV and HIV subgroups. HCV therapy utilization remained low for both HIV/HCV and HCV subgroups for all years. Coinfection was an independent predictor of HIV therapy, but not of HCV therapy. CONCLUSION: There is a critical need for system-level interventions that reduce barriers to outpatient care and improve uptake of HCV therapy for patients with HIV/HCV coinfection. PMID- 24755038 TI - Association between source-specific particulate matter air pollution and hs-CRP: local traffic and industrial emissions. AB - BACKGROUND: Long-term exposures to particulate matter air pollution (PM2.5 and PM10) and high traffic load have been associated with markers of systemic inflammation. Epidemiological investigations have focused primarily on total PM, which represents a mixture of pollutants originating from different sources. OBJECTIVE: We investigated associations between source-specific PM and high sensitive C-reactive protein (hs-CRP), an independent predictor of cardiovascular disease. METHODS: We used data from the first (2000-2003) and second examination (2006-2008) of the Heinz Nixdorf Recall study, a prospective population-based German cohort of initially 4,814 participants (45-75 years of age). We estimated residential long-term exposure to local traffic- and industry-specific fine particulate matter (PM2.5) at participants' residences using a chemistry transport model. We used a linear mixed model with a random participant intercept to estimate associations of source-specific PM and natural log-transformed hs CRP, controlling for age, sex, education, body mass index, low- and high-density lipoprotein cholesterol, smoking variables, physical activity, season, humidity, and city (8,204 total observations). RESULTS: A 1-MUg/m3 increase in total PM2.5 was associated with a 4.53% increase in hs-CRP concentration (95% CI: 2.76, 6.33%). hs-CRP was 17.89% (95% CI: 7.66, 29.09%) and 7.96% (95% CI: 3.45, 12.67%) higher in association with 1-MUg/m3 increases in traffic- and industry-specific PM2.5, respectively. RESULTS for PM10 were similar. CONCLUSIONS: Long-term exposure to local traffic-specific PM (PM2.5, PM10) was more strongly associated with systemic inflammation than total PM. Associations of local industry-specific PM were slightly stronger but not significantly different from associations with total PM. PMID- 24755039 TI - Physical complaints in girls with major depression--a controlled study. AB - Major depression is a frequent affective disorder in young adolescents. Patients do not only suffer from severe psychological but also from physical impairments. Aim of the present study is a description of physical complaints in girls with major depression. Seventy-three patients fulfilling DSM-IV criteria for major depression were compared to 72 controls. Physical complaints were assessed by a standardised and validated German questionnaire (Giessen Scale of Physical Complaints in Children and Adolescents). Patients reported significantly more complaints, in particular exhaustion and circulation problems. Physical problems are more likely to be a consequence rather than a cause of depression. Treatment of adolescents' depression should consider coping with body dysfunction during depressive episodes. PMID- 24755040 TI - Sleep disturbances and suicidal ideation in a sample of treatment-seeking Canadian Forces members and veterans. AB - This study examines the association between suicidal ideation and sleep disturbances in a sample of treatment-seeking Canadian Forces members and veterans, after controlling for probable posttraumatic stress disorder (PTSD), major depressive disorder (MDD), generalised anxiety disorder (GAD), and alcohol use disorder (AUD). Subjects included members and veterans of Canadian Forces seeking treatment at a hospital-based Operational Stress Injury Clinic (n=404). Sleep disturbances and nightmares were measured using individual items on the PTSD Checklist - Military Version (PCL - M), while the suicidality item of the Patient Health Questionnaire (PHQ-9) was used as a stand-alone item to assess presence or absence of suicidal ideation. Regression analyses were used to determine the respective impact of (1) insomnia and (2) nightmares on suicidal ideation, while controlling for presence of probable PTSD, MDD, GAD, and AUD. We found that 86.9% of patients reported having problems falling or staying asleep and 67.9% of patients reported being bothered by nightmares related to military specific traumatic events. Neither sleep disturbances nor nightmares significantly predicted suicidal ideation; instead, probable MDD emerged as the most significant predictor. The clinical implications of these findings and their potential impact on treatment guidelines are discussed. PMID- 24755041 TI - Exploratory analysis of social cognition and neurocognition in individuals at clinical high risk for psychosis. AB - Neurocognition and social cognition are separate but related constructs known to be impaired in schizophrenia. The aim of this study was to extend the current knowledge of the relationship between social cognition and neurocognition in individuals at clinical high risk (CHR) of developing psychosis by examining, in a large sample, the associations between a wide range of neurocognitive tasks and social cognition. Participants included 136 young people at CHR. Specific domains within neurocognition and social cognition were compared using Spearman correlations. Results showed that poor theory of mind correlated with low ratings on a wide range of neurocognitive tasks. Facial affect was more often associated with low ratings on spatial working memory and attention. These results support a link between neurocognition and social cognition even at this early stage of potential psychosis, with indication that poorer performance on social cognition may be associated with deficits in attention and working memory. Understanding these early associations may have implications for early intervention. PMID- 24755042 TI - Social anhedonia and work and social functioning in the acute and recovered phases of eating disorders. AB - Interpersonal difficulties are proposed to maintain eating disorders (EDs). This study explored whether social anhedonia (SA) was an additional social emotional maintenance factor which might also explain work/social problems in EDs. Additionally, the study explored SA and work and social adjustment in recovered participants. Women with anorexia nervosa (AN; n=105), bulimia nervosa (BN; n=46), recovered from AN (RAN; n=30) and non-ED controls (n=136) completed the Work and Social Adjustment Scale (WSAS) and the Revised Social Anhedonia Scale. ED participants reported greater SA and WSAS scores than non-ED controls; the RAN group reported an intermediate profile. AN participants had poorer work/social adjustment than BN participants. SA was associated with longer illness duration. SA, current severity (BMI) and lifetime severity (lowest adult BMI) significantly predicted work/social difficulties. Recovered participants scoring in the clinical range for SA experienced significantly greater work/social difficulties than recovered participants scoring outside the clinical range for SA. EDs are associated with clinical levels of SA and poor work/social functioning which reduce in recovery. SA may maintain the interpersonal functioning difficulties. PMID- 24755043 TI - Kallikrein 3 and vitamin D receptor polymorphisms: potentials environmental risk factors for prostate cancer. AB - OBJECTIVE: To investigate the relationship and interaction of the single nucleotide polymorphisms (SNPs) of KLK3 and VDR and environmental factors with the predisposition to prostate cancer within Chinese population. METHODS: The comparison between 108 patients and 242 healthy people was carried out by using the TaqMan/MGB Probe Technology to determine the genotypes of KLK3(rs2735839 is located between KLK2 and KLK3) and VDR (rs731236 is located exon 9). Univariate and multivariate logistic regression model were used to assess the connection of genetic polymorphisms and environmental risk factors with PCa by collecting demographic information, as well as BMI, consumption of cigarettes, alcohol, and tea, exercise, and other environmental risk factors. RESULTS: The appearing frequencies of AA, AG, and GG genotypes at the SNPs rs2735839 (A/G) for KLK3 were 13.89%, 62.96% and 23.15% in PCa and 37.19%, 44.63%, 18.18% in control, respectively; these two groups are statistically different (P=0.00). While the appearing frequencies of TT, TC, and CC genotypes at the SNPs rs731236 (T/C) for VDR were 88.89%, 9, 26%, 1.85% and 90.50%, 9.10%, 0.40% in control, respectively, with no significant statistical difference between the two group. The study confirmed decreasing risk in tea drinkers (OR=0.58, 95% CI=0.35-0.96). CONCLUSIONS: Our studies indicate that environmental factor-tea drinking is associated with the development of PCa. The habit of drinking tea is a protective factor against PCa. The SNPs rs2735839 for KLK3 is strongly related to the development of PCa, while the SNPs rs731236 for VDR is not. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9759981571058803. PMID- 24755044 TI - The phenotypic predisposition of the parent in F1 hybrid is correlated with transcriptome preference of the positive general combining ability parent. AB - BACKGROUND: Sprague and Tatum (1942) introduced the concepts of general combining ability (GCA) and specific combining ability (SCA) to evaluate the breeding parents and F1 hybrid performance, respectively. Since then, the GCA was widely used in cross breeding for elite parent selection. However, the molecular basis of GCA remains to unknown. RESULTS: We studied the transcriptomes of three varieties and three F1 hybrids using RNA-Sequencing. Transcriptome sequence analysis revealed that the transcriptome profiles of the F1s were similar to the positive GCA-effect parent. Moreover, the expression levels of most differentially expressed genes (DEGs) were equal to the parent with a positive GCA effect. Analysis of the gene expression patterns of gibberellic acid (GA) and flowering time pathways that determine plant height and flowering time in rice validated the preferential transcriptome expression of the parents with positive GCA effect. Furthermore, H3K36me3 modification bias in the Pseudo-Response Regulators (PRR) gene family was observed in the positive GCA effect parents and demonstrated that the phenotype and transcriptome bias in the positive GCA effect parents have been epigenetically regulated by either global modification or specific signaling pathways in rice. CONCLUSIONS: The results revealed that the transcriptome profiles and DEGs in the F1s were highly related to phenotype bias to the positive GCA-effect parent. The transcriptome bias toward high GCA parents in F1 hybrids attributed to H3K36me3 modification both on global modification level and specific signaling pathways. Our results indicated the transcriptome profile and epigenetic modification level bias to high GCA parents could be the molecular basis of GCA. PMID- 24755046 TI - Comparison of metabolic cost and cardiovascular response to stair ascending and descending with walkers and canes in older adults. AB - OBJECTIVE: To compare oxygen cost (mL.kg(-1).m(-1)) and cardiovascular response (beats/m) and oxygen consumption (mL.kg(-1).min(-1)) and heart rate (beats/min) to stair ascending and descending with walkers, with canes, and without assistive devices (ADs) in older adults. DESIGN: Descriptive, repeated measures. SETTING: Indoor stairway. PARTICIPANTS: Convenience sample of able-bodied volunteers, non AD users (N=14; mean age, 63.71 +/- 11.7 y; mean body mass, 72.7 +/- 14.1 kg; mean height, 165.7 +/- 9.2 cm). INTERVENTIONS: Participants performed 4 randomized trials of stair ascending and descending at their own self-selected speed with 3 ADs: single-point cane, standard walker (SW), and wheeled walker (WW). They also performed unassisted stair ascending and descending. Each trial consisted of a 5-minute steady-state session followed by a 2-minute data collection period. Steady-state expired ventilations were collected in Douglas bags for metabolic analysis. MAIN OUTCOME MEASURES: Oxygen cost (mL.kg(-1).m( 1)), heart rate (HR) response (beats/m), oxygen consumption (mL.kg(-1).min(-1)), and HR (beats/min) were compared for each trial of stair ascending and descending using analysis of variance repeated measures (P<.05). RESULTS: Greater oxygen cost (per meter) was found for stair ascending and descending using the single point cane (121%), SW (217%), and WW (232%) compared with unassisted stair ascending and descending (P<.05). Increased HR response (per meter) was found for stair ascending and descending using the single-point cane (116%), SW (126%), and WW (147%) compared with unassisted stair ascending and descending (P<.05). However, oxygen consumption (per minute) and HR (per minute) were not significantly increased during stair ascending and descending with the ADs compared with unassisted stair ascending and descending. Participants stair ascended and descended at significantly (P<.05) reduced speeds during trials with the ADs. CONCLUSIONS: This research should aid clinicians by providing evidence to base recommendations on regarding AD usage when encountering stairs during home and community ambulation. PMID- 24755045 TI - Recovery of paretic lower extremity loading ability and physical function in the first six months after stroke. AB - OBJECTIVES: To evaluate poststroke recovery of paretic lower extremity loading, walking ability, and self-reported physical function; and to identify subject characteristics associated with recovery. DESIGN: Inception cohort study, with testing at monthly intervals from 1 to 6 months poststroke. SETTING: Medical center and research laboratory. PARTICIPANTS: Volunteer sample of individuals with first-ever, unilateral, noncerebellar stroke (N=33). A total of 78 individuals underwent screening, and 45 were found to be eligible. Of these, 8 declined participation, 2 were excluded because of deteriorating cognitive status, and 2 were lost to follow-up. The remaining 33 individuals enrolled in the study, and 30 (91%) completed the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcomes were loading of the paretic lower extremity when standing up from a chair, self-selected gait speed (GS), and Physical Functioning Index. RESULTS: Data analyses using linear mixed models indicated that subjects improved over time for all outcomes. Baseline Fugl-Meyer (FM) lower extremity motor scale score was a predictor of immediate poststroke performance for paretic lower extremity loading and self-selected GS, and a predictor of recovery rate for paretic lower extremity loading. Factors identified as having significant effects on performance at 6 months poststroke were baseline FM lower extremity motor scale score for paretic lower extremity loading and self-selected GS and baseline star cancellation score (from the Behavioral Inattention Test) for paretic lower extremity loading. CONCLUSIONS: Individuals with better baseline paretic lower extremity motor function have better ability to load that extremity during functional activities and faster walking speeds, and these advantages are still present at 6 months poststroke. Individuals with severe visuospatial neglect demonstrate less ability to load the paretic leg during functional activities at 6 months poststroke. PMID- 24755047 TI - Utilization of behavioral therapy services long-term after traumatic brain injury in young children. AB - OBJECTIVE: To examine associations of clinical need, defined by elevated parent ratings of child behavior problems and utilization of behavioral health services in young children with traumatic brain injury (TBI) and an orthopedic injury (OI) comparison group. DESIGN: Parents completed outcome measures 18 months after injury and at an extended follow-up conducted an average of 38 months postinjury. SETTING: Children's hospitals and a general hospital. PARTICIPANTS: Participants included parents of 3 groups of children injured between 3 and 7 years of age (N=139): 47 children with complicated mild to moderate TBI, 18 with severe TBI, and 74 with OI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Parents completed ratings of child behavior, mental health symptomology, and family functioning at both visits; at the extended follow-up, they reported utilization of behavior therapy or counseling services since the 18-month follow-up visit. RESULTS: Children with TBI had more behavior problems than those with OI. Although clinical need at both follow-ups was associated with greater service utilization at the extended follow-up, all groups had unmet needs as defined by a clinical need in the absence of services. Lower socioeconomic status was associated with higher rates of unmet need across groups. CONCLUSIONS: The results document unmet long-term behavioral health needs after both TBI and OI in children and underscore the importance of monitoring and treatment of postinjury behavior problems. PMID- 24755048 TI - Comparative chest computed tomography findings of non-tuberculous mycobacterial lung diseases and pulmonary tuberculosis in patients with acid fast bacilli smear positive sputum. AB - BACKGROUND: Early diagnosis and treatment of nontuberculous mycobacterial lung diseases (NTM-LD) and pulmonary tuberculosis (PTB) are important clinical issues. The present study aimed to compare and identify the chest CT characteristics that help to distinguish NTM lung disease from PTB in patients with acid-fast bacilli (AFB) smear-positive sputum. METHODS: From January 2009 to April 2012, we received 467 AFB smear-positive sputum specimens. A total of 95 CT scans obtained from the 159 patients were analyzed, 75 scans were from patients with PTB and 20 scans from NTM-LD. The typical chest CT findings of mycobacterial diseases were analyzed. RESULTS: In patients with PTB, the prevalence of pleural effusion (38.7% vs. 15.0%; P = 0.047), nodules < 10 mm in size (76.0% vs. 25.0%; P < 0.001), tree-in-bud pattern (81.3% vs. 55.0%; P = 0.021), and cavities (31.1% vs. 5.0%; P = 0.018) were significantly higher than patients with NTM. Of the 20 patients with NTM lung diseases, bronchiectasis and cystic changes were significantly higher than patients with PTB (20.0% vs. 4.0%; P = 0.034). In multivariate analysis, CT scan findings of nodules was independently associated with patients with diagnoses of PTB (odds ratio [OR], 0.07; 95% confidence interval [CI], 0.02-0.30). Presence of bronchiectasis and cystic changes in CT scans was strongly associated with patients with NTM-LD (OR, 33.04; 95% CI, 3.01 362.55). CONCLUSIONS: The CT distinction between NTM-LD and PTB may help radiologists and physicians to know the most likely diagnoses in AFB-smear positive patients and avoid unnecessary adverse effects and the related costs of anti-TB drugs in endemic areas. PMID- 24755049 TI - Diffusion-weighted imaging of the sellar region: a comparison study of BLADE and single-shot echo planar imaging sequences. AB - PURPOSE: The purpose of this study is to compare BLADE diffusion-weighted imaging (DWI) with single-shot echo planar imaging (EPI) DWI on the aspects of feasibility of imaging the sellar region and image quality. METHODS: A total of 3 healthy volunteers and 52 patients with suspected lesions in the sellar region were included in this prospective intra-individual study. All exams were performed at 3.0T with a BLADE DWI sequence and a standard single-shot EP-DWI sequence. Phantom measurements were performed to measure the objective signal-to noise ratio (SNR). Two radiologists rated the image quality according to the visualisation of the internal carotid arteries, optic chiasm, pituitary stalk, pituitary gland and lesion, and the overall image quality. One radiologist measured lesion sizes for detecting their relationship with the image score. RESULTS: The SNR in BLADE DWI sequence showed no significant difference from the single-shot EPI sequence (P>0.05). All of the assessed regions received higher scores in BLADE DWI images than single-shot EP-DWI. PMID- 24755050 TI - The Content, Quality and Impact of Cognitive Behavioural Case Formulation During Treatment of Obsessive Compulsive Disorder. AB - BACKGROUND: Case formulation (CF) is considered a core component of cognitive behavioural therapy (CBT). Despite this, few studies have explored the content and quality of CFs in routine practice and any associated impact on treatment outcome. AIMS: This study investigated (1) the content, timing and quality of CF for patients (N = 29) with Obsessive Compulsive Disorder; (2) the impact of CF on symptoms, distress and therapeutic alliance; and (3) the relationship between CF quality and treatment outcome. METHOD: CF content and quality were assessed from audiotapes of routine CBT sessions using a validated coding manual and evaluated against treatment outcomes at different stages of therapy. RESULTS: CFs were developed early during treatment and contained strong behavioural and cognitive components, with a focus on symptoms and maintaining factors. CF quality ratings ranged from rudimentary to excellent. A significant improvement in distress and the therapeutic alliance occurred following the introduction of CF, but no significant relationship was found between CF quality and outcome at any stage of treatment. CONCLUSION: CF may be valuable in reducing patient attrition, due to its impact early in treatment. Further research is needed to explore the most important components of CF. Theoretically sound and disorder specific measurement tools for evaluating CFs are required. PMID- 24755051 TI - Femtogram level detection of nitrate ester explosives via an 8-pyrenyl substituted fluorene dimer bridged by a 1,6-hexanyl unit. AB - Compared with nitroaromatic explosives detection, nitrate esters are far from wide attention possibly because of their shortage of aromatic ring and difficulty in being detected. Three fluorescent chemical probes for trace nitrate ester detection: an intramolecular dimer (P3) of 8-pyrenyl-substituted fluorenes bridged by a 1,6-hexanyl unit as well as its counterparts 2PR-F (P1) and 2PR-Cz (P2) has been synthesized and characterized. Their chemical structures and photophysical and electrochemical properties show that the dimer P3 film has a higher molar extinction coefficient, larger steric hindrance, higher area-to volume ratio, and matching energy level with nitrate ester explosives, which contributes to higher sensitivity and moderate selectivity for sensing of nitrate ester explosives such as nitroglycerin (NG). The fluorescence of the P3 film is rapidly about 90% quenched upon exposure to a saturated vapor of NG for 50 s and almost 100% quenched for 300 s at room temperature due to photoinduced electron transfer between the probe and analyte. In addition, a very sensitive, rapid, simple, and low-cost surface-sensing method by disposable filter-paper-based test strips is demonstrated. The contact-mode approach exhibits a detection limit as low as 0.5 fg/cm(2) for NG. These results reveal that the multiple-pyrenyl-unit substituted fluorene dimer P3 is suitable for preparing a highly sensitive and efficient thin-film device for detecting nitrate esters. PMID- 24755052 TI - Minority report: how the UK's treatment of foreign and ethnic minority doctors needs to change. PMID- 24755053 TI - Model predictive control for a class of systems with isolated nonlinearity. AB - The paper is concerned with an overall convergent nonlinear model predictive control design for a kind of nonlinear mechatronic drive systems. The proposed nonlinear model predictive control results in the improvement of regulatory capacity for reference tracking and load disturbance rejection. The design of the nonlinear model predictive controller consists of two steps: the first step is to design a linear model predictive controller based on the linear part of the system at each sample instant, then an overall convergent nonlinear part is added to the linear model predictive controller to combine a nonlinear controller using error driven. The structure of the proposed controller is similar to that of classical PI optimal regulator but it also bears a set-point feed forward control loop, thus tracking ability and disturbance rejection are improved. The proposed method is compared with the results from recent literature, where control performance under both model match and mismatch cases are enlightened. PMID- 24755054 TI - Non-union in forearm fractures. AB - Non-union in forearm fractures is an uncommon but complex problem. This is especially given the unique anatomical structure and function of the forearm, making treatment distinctly different to that of other long bone fractures. Anatomical restoration of length, alignment, rotation and the radial bow maintains the optimal stabilising effects of the forearm muscles and interosseous membrane, as well as maximising the range of movement, particularly pronation and supination. Contemporary plate osteosynthesis using variations of the dynamic compression plate (DCP) developed by the AO group combined with established techniques of internal fixation have revolutionised the treatment of diaphyseal forearm fractures. Non-union rates have been minimised to below 5% and good to excellent functional outcomes are achieved. Non-union of the forearm is also intimately associated with a significant pain experience, marked pre-operative functional disability and physical and psychosocial morbidity. This review examines the literature and presents a guide to management as well as the current controversies and future directions related to this challenging problem. PMID- 24755055 TI - [Effect of sterilisation with formaldehyde, gamma irradiation and ethylene oxide on the properties of polyethylene joint replacement components]. AB - PURPOSE OF THE STUDY: Each method of sterilisation has some effect on the structure and properties of UHMWPE and thus also on joint replacement longevity. This study was designed to compare, using objective methods of measurement, several kinds of sterilisation and to recommend the one which has the best prospect for making joint replacements last longer. MATERIAL AND METHODS: Two groups of UHMWPE samples were tested. Group 1 included virgin GUR 1020 polyethylene, non-modified and non-sterilised (Meditech, Germany). Group 2 comprised of three sets of samples sterilised with formaldehyde, gamma irradiation and ethylene oxide, respectively. In both groups, physicochemical properties were assessed by infrared spectroscopy (IR), and the oxidation (OI) and trans-vinyl (VI) indices, which show the degree of oxidation of a material, were determined. Free-radical concentrations were measured by the method of electron spin resonance (ESR). The mechanical properties of each sample were studied using small punch tests (SPT) and testing microhardness (MH). Any change in mechanical properties can affect, to various degrees, the quality and longevity of a prosthetic joint. RESULTS: The samples sterilised by gamma irradiation showed higher values of both the OI (0.37) and the VI index (0.038) than the other samples (OI, 0.02 to 0.05 and VI, 0). Also, the free-radical concentration was detectable only in the gamma-sterilised sample. Values obtained for mechanical properties were as follows: peak load in the range of 58.48 N (gamma irradiation) to 59.60 N (ethylene oxide); ultimate load in the range of 46.69 N (gamma irradiation) to 57.50 N (ethylene oxide); ultimate displacement in the range of 4.29 mm (gamma irradiation) to 4.58 mm (virgin polyethylene and formaldehyde); and work to failure in the range of 185.18 mJ (gamma irradiation) to 205.89 mJ (virgin polyethylene). Microhardness values were obtained in the following ranges: 41.2 to 44.6 MPa (virgin polyethylene); 40.2 to 44.1 MPa (formaldehyde); 46.1 to 49.3 MPa (gamma irradiation); and 40.3 to 44.2 MPa (ethylene oxide). DISCUSSION: The samples sterilised with formaldehyde and ethylene oxide have mechanical properties very similar to virgin polyethylene, they are not damaged by oxidation and do not contain free radicals. Owing to these characteristics, the immediate and long-term oxidation stability of the three samples is higher. The sample sterilised by gamma irradiation showed the presence of free radicals and immediate and long-term oxidative degradation. This results in the deterioration of mechanical properties and the growth of crystallinity due to enhanced oxidation and leads to higher polyethylene microhardness. CONCLUSIONS: Sterilisation with gamma irradiation results in oxidative degradation and mechanical property deterioration, which is one of the potential risks of a shorter life span of joint replacements. The use of ethylene oxide or formaldehyde does not change polymer properties nor has any effect on oxidation of materials. Therefore, a longer life expectancy of the joint replacements sterilised with ethylene oxide can be expected. The life span of their joint replacements is a key issue for the patients. Prosthetic joint loosening is painful and the patient often requires re-implantation. A higher number of re-implantations is associated with higher costs for the institution involved and, consequently, for the whole health care system. Although this study basically deals with chemical issues, it informs the surgeon of the latest developments leading to the improvement of implanted materials, which can increase the life expectancy of joint replacements and patients' satisfaction. PMID- 24755056 TI - [Anatomical ACL reconstruction by a double- versus a single-bundle technique. Prospective randomised study of short-term clinical results]. AB - PURPOSE OF THE STUDY: The aim of the study is to present a comparison of short term results of double- versus single-bundle anatomical reconstruction of the anterior cruciate ligament (ACL) using hamstring endons and their fixation with absorbable interference screws. MATERIAL AND METHODS: A total of 110 patients with an isolated ACL lesion and the healthy contralateral knee who met the indication criteria for ACL double bundle reconstruction (TISL, 14 mm; ICNW, 12 mm) were intra-operatively allocated at random to either double-bundle group (DB, n=55) or single-bundle group (SB, n=55). At 12 months after surgery, 97 patients (DB group, n=49; SB group, n=48), comprising 68 men and 29 women, were evaluated; the average age was 29.1 years and the injury-to-surgery interval was 15.9 weeks. Pre- and post-operative subjective criteria involved the IKDC and Lysholm score. Objectively, the occurrence of graft failure, range of motion deficit, return to pre-injury sports activity, side-to-side difference in anterior laxity of both knees in 20 degrees flexion on a GNRB laximeter at an applied pressure of 124 N and 250 N, and pivot shift phenomenon were assessed. RESULTS: No statistically significant difference was found in pre-operative values between the two groups. Post-operatively, there were no significant differences in the occurrence of complete graft failure (p=0.0755; DB group, n=0; SB group, n=3), range-of-motion deficit (p=0.2277-0.9788) or return to pre-operative sports activity (p=0.2322). In the DB group, side-to-side anterior tibial shifts at a pressure of 124 N (medians=1.3 mm and 2.1 mm for DB and SB groups, respectively; p=0.0007) and at a pressure of 250 N (DB group =2.1 mm; SB group = 3.1 mm; p<0.0001) were significantly different from the corresponding values in the SB group. Positive results for the pivot shift test (PST) were significantly less frequent in the DB than the SB group (Chi-square test =0.0112). The SB group patients had a 2.9 times (odds ratio, 2.8704) higher risk of positive postoperative PST results than the DB group patients. In both groups, a comparison of pre- and post-operative criteria showed significant improvement in both the subjective and the objective results. DISCUSSION: The results of this study, in accordance with other authors' conclusions, suggest that the double-bundle technique provides better control over rotational and anterior knee laxity and therefore restores knee biomechanics better. However, other literature data do not confirm any significantly better outcomes of this method. Since only short-term results have been obtained so far, the study will continue because only the long-term results can provide conclusive evidence of an advantage of one technique over the other. CONCLUSIONS: Our study showed significantly better restoration of knee rotational and anterior laxity in the patients undergoing anatomical reconstruction of the ACL by the double-bundle technique. The other evaluated criteria did not differ in relation to the technique used. PMID- 24755057 TI - [Arthroscopic stabilisation of the shoulder. Risk factors for its failure]. AB - PURPOSE OF THE STUDY: Shoulder instability adversely affects the quality of life and restricts the functional capacity of the upper extremity involved. Today stabilisation surgery is almost always performed arthroscopically. The aim of this study was to present our experience with arthroscopic stabilisation of the shoulder and to identify risk factors responsible for its failure. MATERIAL AND METHODS: The group of 110 patients with recurrent anterior dislocation of the shoulder, who were treated between January 2007 and December 2010, consisted of 19 women and 91 men with an average age of 27 years (range, 14 to 56) at the time of surgery. Patients who had a concomitant tear of the rotator cuff or of the long head tendon of the biceps were excluded from the study. The minimum follow up period was 2 years. The patients were evaluated for signs of clinical instability. Function was evaluated using WOSI, Constant-Murley and Rowe-Zarins. Statistical methods were used to assess factors leading to failed arthroscopic stabilisation. RESULTS: At final follow-up, 17 patients (17 shoulders, 15.3%) had re-dislocation or subluxation of the joint treated. Age over 20 years reduced the probability of re-dislocation (odds ratio, OR=0.87; p=0.021) while the finding of an engaging Hill-Sachs lesion increased the risk of re-dislocation (OR=5.53; p=0.0028). The presence of a bony Bankart lesion had only a marginal effect on the probability of re-dislocation (p=0.0512). In stable shoulders the average pre operative values improved to the final follow-up values as follows: WOSI index, 53.65 +/- 5.6 to 94.8 +/- 5.2 (p<0.0001); Constant-Murley score, 78.9 +/- 6.1 to 95.6 +/- 4.4 (p<0.0001); and Rowe-Zarins score, 53.3 +/- 6.7 to 92.9 +/- 7.8 (p<0.0001). No peri-operative complication was recorded. DISCUSSION: Our study confirmed the role of 3D CT examination before arthroscopic stabilisation of the shoulder joint. The exact identification of bone injury and its extent is of prognostic importance. At the same time special attention should be paid to surgical and post-operative tactics in patients operated on before their 20 years of age. On the other hand, no risks were found to be associated with gender, sports activities, the number of previous dislocations, types of anchors, suture material or knot tying. CONCLUSIONS: Arthroscopic stabilisation of the shoulder significantly relieves pain and improves shoulder function in 85% of the patients with anterior shoulder dislocation. The risk that this stabilisation surgery will fail increases with lower age of the patient and the presence of an engaging Hill Sachs lesion. PMID- 24755058 TI - [Failure of the primary treatment of displaced supracondylar humerus fractures in children]. AB - PURPOSE OF THE STUDY: The aim of the study was to retrospectively evaluate the treatment outcomes of displaced supracondylar humerus fractures, including potential complications, in children treated at the Department of Paediatric General Surgery, Orthopaedics and Trauma Surgery of the Faculty of Medicine in Brno between 2000 and 2011. MATERIAL AND METHODS: The study comprised 564 children, 321 (57%) boys and 243 (43%) girls, who were allocated to two groups according to the method of primary treatment. The average age at the time of injury was 6.8 years (range, 1 to 16). In group 1, all 499 patients were indicated for primary closed reduction and percutaneous osteosynthesis with crossed K-wires under general anaesthesia. In group 2, all 65 patients underwent closed reduction under general anaesthesia and immobilisation in a high plaster cast. The per cent failure of primary treatment requiring either repeat surgery or a change in treatment strategy was evaluated. The duration of follow-up ranged from 14 to 150 months. RESULTS: Open fractures were recorded in eight (1.4%) patients. Twenty-five (4.4%) children had further injury to the ipsilateral limb. Three (0.5%) patients underwent open reduction because it was not possible to achieve adequate reduction by the closed method. In group 1, percutaneous osteosynthesis was performed using two crossed K-wires in 484, three K-wires in 13 and four K-wires in two patients. Re-displacement of fracture fragments requiring repeat reduction and percutaneous osteosynthesis occurred in 10 (2%) patients. One patient had two re-operations. In group 2, the primary treatment failed in 13 (20%) children who needed repeat reduction and conversion to percutaneous osteosynthesis. The difference in the occurrence of failure between the two groups was significant (p<0.001). Nerve injury was recorded in 92 patients (16.3% of all children and 18% of those treated with percutaneous osteosynthesis). Neurosurgical intervention was necessary for injury to the ulnar nerve in five patients and to the radial nerve in one patient. Three children had vascular injury requiring vascular surgery. Two patients underwent corrective osteotomy of the distal humerus for cubitus varus deformity. Volkmann's contracture as a complication was not recorded. DISCUSSION: Minimally displaced fractures can be treated by closed reduction and plaster cast immobilisation but this method fails in up to 20% of cases. A poor result is related to the extent of dorsal displacement before reduction; on the other hand, degrees of flexion in a plaster cast have no effect. The most frequent technical errors resulting in re displacement after primary osteosynthesis include incomplete reduction and primary fixation in displacement, or failure of both K-wires to pass through the opposite cortex or to fix both fragments firmly. A K-wire diameter smaller than 1.6 mm may also be a reason for failure. The main problem of the method of two crossed K-wires is a frequent injury to the ulnar nerve. CONCLUSIONS: Supracondylar humerus fracture is, regardless of advancements in therapy, an injury with an uncertain treatment outcome and a high percentage of complications. Since primary osteosynthesis failed in 20% of the patients treated by simple reduction under general anaesthesia and plaster cast immobilisation, for the patients requiring fracture reduction under general anaesthesia, the authors recommend one-stage primary treatment including K-wire transfixation. Re displacement after primary osteosynthesis was always due to a technical error during the surgical procedure and can, therefore, be avoided by a precise operative technique. PMID- 24755059 TI - [Anatomy notes on minimally invasive plate osteosynthesis of the proximal humerus. A cadaver study]. AB - PURPOSE OF THE STUDY: The aim of the study was to assess the average length of a proximal and a distal incision, to verify the location of the axillary nerve and to identify risk factors for nerve injury during minimally invasive plate osteosynthesis. MATERIAL AND METHODS: During cadaver study a total of 24 implantations using the Philos angular stable plate were performed from the minimally invasive anterolateral approach. A five-hole plate inserted with the aid of new Philos aiming device was used in all cases. The plate was fixed with four screws proximally and with three screws to the diaphysis. After implantation either of the incisions were joined and the axillary nerve was exposed on the lateral side of the arm. RESULTS: The nerve was not found to be injured during plate implantation in any of the cases. The average length of the proximal incision was 56 +/- 2.8 mm (52-64 mm) and that of the distal incision was 32 +/- 2.5 mm (28-35 mm). The middle free part covering the axillary nerve was on average 45 +/- 4.3 mm (38-54) long. The average width of the nerve was 1.9 +/- 0.35 mm (1.4-2.8 mm). The average distance of the axillary nerve was 39 +/- 2.9 mm (37-44 mm) from the superior facet of the greater tubercle and 53 +/- 3.9 mm (48-60) from the lower edge of the acromial process. In 80% of the cases the nerve was located in the area determined for the screws going to the medial calcar region; in 20% it was over a hole for the screw directed towards the centre of humeral head. Nerve location above the first six most proximally placed screws was not recorded in any of the cases. DISCUSSION: The minimally invasive anterolateral approach is an alternative technique for osteosynthesis of proximal humerus fractures using angular stable plates. Advantages reported by a number of authors include lower incidence of avascular necrosis of the humeral head, an easier way of reduction and a better view of the rotator cuff. On the other hand, this approach is associated with a higher risk of damage to the axillary nerve. Distance of axillary nerve from acromion is very variable. It may be located in the range of 30 to 85 mm from the acromial edge. CONCLUSION: The anterolateral approach is, when respecting the anatomical position of the axillary nerve, a safe alternative to the conventional deltoideopectoral approach. PMID- 24755060 TI - [Our experience with the metha short hip stem]. AB - PURPOSE OF THE STUDY: The aim of the study was to evaluate the clinical and radiographic results of total hip arthroplasty (THA) with the Metha short hip stem and their comparison with the outcomes of THA using a conventional cementless stem. MATERIAL AND METHODS: A total of 30 Metha stems and 30 standard Biocontact stems implanted in the period from 2007 to 2012 were evaluated. The Metha patient group comprised 22 women and six men, with the mean age of 58.9 +/- SD 8.7 years (43-75), mean height of 164.2 +/- 6.3 cm (156-178), mean body mass of 68.2 +/- 12 (48-91) and mean BMI of 25 +/- 3.9 (19-32). The Biocontact group included 19 women and 11 men, with the mean age of 63.6 +/- 10.8 years (45-77), mean height of 166.6 +/- 6.6 cm (152-175), mean body mass of 77.6 +/- 13.1 (46 104) and mean BMI of 27.6 +/- 4.3 (20-37). The evaluation was based on plain X ray findings and clinical status assessed using the Harris hip score and 10-point visual analogue scale (VAS) for pain before surgery and at final follow-up. RESULTS: In the Metha group the mean pre- and post-operative Harris hip scores were 41.7 +/- 9.9 (28-57) and 94.4 +/- 5.1 (82-100), respectively. In the Biocontact group the values were 41.5 +/- 11.9 (32-64) and 89.3 +/- 11.2 (57 100), respectively. The mean VAS for low back and thigh pain improved from the pre-operative value of 7.41 +/- 2.1 (4-9) to 0.56 +/- 1.0 (0-3) in the Metha group and from 7.29 +/- 2.2 (4-9) to 1.64 +/- 1.8 (0-5) in the Biocontact group. The post-operative results in both rating systems were significantly better (p<0.05) in the Metha than the Biocontact group patients. All stems showed radiographic evidence of good osteointegration. Stem subsidence and calcar atrophy were recorded in one patient of the Metha group. In the Biocontact group stem subsidence was found in two patients and signs of stress shielding in 14 patients. DISCUSSION: Short hip stems have been introduced in THA implantation with the aim to restore physiological biomechanics as much as possible and to ensure good long-term functioning of the joint replacement as well as to save the proximal femoral bone tissue for potential THA re-implantation. Our results of short hip stem implantation presented in this study are compared with the results of relevant recently published literature. CONCLUSIONS: Short hip stems show adequate osteointegration without need for diaphyseal fixation and allow for more natural weightbearing distribution in the proximal femur. The short- and mid-term clinical results are better than with the use of conventional cementless stems. They can be recommended as an optimal choice for use in younger patients with good bone quality who are expected to require THA re-implantation. PMID- 24755061 TI - [The effect of anticoagulation and anti-aggregation treatment on the extent, development and prognosis of acute craniocerebral injury]. AB - PURPOSE OF THE STUDY: A retrospective analysis of the effect of anticoagulation and anti-aggregation treatments on the post-injury clinical status, frequency of necessary surgical interventions including re-operations, course of intracranial haemorrhage dynamics and treatment outcome in patients with acute traumatic intracranial haematoma. MATERIAL AND METHODS: The group consisted of 328 patients with acute post-traumatic intracranial haemorrhage treated at the author's institution from 2008 to 2012. Fifteen patients with anticoagulation therapy (warfarin; 8 females, 7 males; median age, 72.0 years) and 46 patients with anti aggregation treatment (21 females, 25 males; median age, 75.5 years ; 37 with acetylsalicylic acid, 5 with thienopyridines, 2 with new antithrombotics and 2 taking dual anti-aggregation therapy), all older than 55 years, were included in statistical analysis. The post-injury clinical condition (Glasgow Coma Scale), incidence of haemorrhagic contusions, intracranial haematoma progression, particularly when surgery was indicated, incidence of re-operations and treatment outcome (Glasgow Outcome Scale - GOS) were the study parameters. The control group included 77 patients with post-traumatic intracranial haematoma with normal coagulation who were older than 55 years (27 females, 50 males; median age, 67 years). Patients younger than 55 years and those with normal coagulation were not included in the statistical analysis. The treatment of all patients with anti aggregation or anticoagulation therapy was consulted with the haematology specialist. RESULTS: The median age and initial status evaluated by the Glasgow Coma Scale were similar in the groups of anti-aggregated and anticoagulated patients and the control group. The number of good treatment outcomes, as evaluated by the GOS, was significantly higher in the anti-aggregated patients than in those on warfarin. A comparison of anti-aggregated, anticoagulated and normal coagulation patients did not show any statistically significant differences in the incidence of patients operated on, in the incidence of haemorrhagic contusions requiring surgery as a marker of the severity of brain parenchyma injury, intracranial haemorrhage progression with time, particularly when requiring surgery, and the rate of re-operations. However, when comparing the group of anti-aggregated patients with the control group, the higher incidence of haemorrhagic contusions and the lower number of patients requiring surgery were found to be close to the level of statistical significance. DISCUSSION: The positive effect of anti-aggregation and anticoagulation treatment on the morbidity and mortality from cardiovascular diseases should be regarded in relation to a higher risk of haemorrhagic complications. If a bleeding complication occurs, the possibility of neutralising this treatment should be considered, but this is particularly difficult in new agents. The relationship between anti-aggregation or anticoagulation treatment and the treatment results in the patients with head injury is particularly important from the neurosurgical point of view, because the relevant literature data are ambiguous. CONCLUSIONS: The results did not confirm any statistically significant adverse effects of anticoagulation or anti-aggregation treatment on the severity of post-injury status and risk of intracranial bleeding progression. The incidence of poor outcomes is higher in anticoagulated patients than in anti-aggregated patients. Although not reaching the level of statistical significance, the results also indicate higher risk of significant haemorrhagic brain contusions in anti aggregated patients. PMID- 24755062 TI - Lower limb salvage: indication and decision making for replantation, revascularisation and amputation. AB - Defining reproducible criteria for lower extremity salvage following severe high energy trauma continues to be one of the most challenging and controversially discussed fields in orthopaedic surgery. At present, however, the difficult performance, limited availability and number of valid reconstructive options for complex injury types, i. e. simultaneous osteoligamentous trauma with neurovascular lesions and severe soft tissue defects ("composite/compound multilayer defects") represent the decisive prognostic injury components triggering and determining the fate of the limb. Consequently, due to the complex injury pattern of the extremity and the overall situation of multiple injured patient the treatment and decision making has to be made in a priority-adapted algorithm. In this treatment algorithm interdisciplinary cooperation with vascular and plastic surgeons is of tremendous importance. Although the number of severely injured patients remains stable in the last decade, changes in the treatment algorithms result from increased survival rates of multiple injured patients and improved modern reconstructive options leading to continuously increasing rates of salvaged limbs. This paper aimed to systematically review the current literature for lower extremity injuries in order to unravel the different surgical treatment options and provide guidelines for decision making with corresponding treatment algorithms for limb salvage. Furthermore, the experiences in the management of mangled extremities in our centre are presented and illustrated/underscored with different cases. PMID- 24755063 TI - Cloning, purification, and characterization of inorganic pyrophosphatase from the hyperthermophilic archaea Pyrococcus horikoshii. AB - The gene encoding inorganic pyrophosphatase (PPiase) from the hyperthermophilic archaea Pyrococcus horikoshii (Pho PPiase) was cloned in the Escherichia coli strain BL21/pET15b, and the recombinant PPiase was purified by Ni-chelating chromatography in only an one-step procedure. The PPiase showed optimal activity at 88 degrees C and pH of 10.3. Kinetic analysis revealed Km, kcat, Vm of 14.27MUM, 3436s(-1), and 34.35MUmol/min/mg protein, respectively. Pho PPiase was stable against denaturant chemicals as well as heat. It retained 19.61% of the original activity after incubation at 100 degrees C for 12h and 25.96% of the original activity in the presence of 8M urea after incubation at 50 degrees C for 120h. Pho PPiase showed high specificity for inorganic pyrophosphate but low reactivity to sodium tripolyphosphate and sodium tetrapolyphosphate. ADP and ATP could not serve as substrates. PMID- 24755064 TI - Purification and partial characterization of a novel fibrinogenase from the venom of Deinagkistrodon acutus: inhibition of platelet aggregation. AB - A novel fibrinogenase, DAnase, was purified from the venom of Deinagkistrodon acutus by a combination of anion and cation exchange chromatography. Unlike other fibrinogenases which are usually single polypeptide chain proteins, the enzyme was a disulfide-linked dimer with an isoelectric point of 6.03 and an apparent molecular weight of 25kDa on SDS-polyacrylamide gel electrophoresis. DAnase showed alpha-fibrinogenase activity devoid of fibrinolytic activity. It hydrolyzed rapidly the Aalpha-chain of fibrinogen and followed by the Bbeta-chain and did not cleave the gamma-chain. It also exhibited arginine esterase activity. The fibrinogenolytic and arginine esterase activities were completely inhibited by phenylmethanesulfonyl fluoride or tris-(2-carboxyethyl)phosphine hydrochloride, but not by EDTA, indicating that DAnase is a serine protease requiring disulfide bridge(s) for its activity. The protease strongly inhibited ADP-induced platelet aggregation in human platelet-rich plasma but was lack of ADPase activity, indicating that its fibrinogenolytic activity is involved in its inhibition of ADP-induced platelet aggregation. DAnase was devoid of hemorrhagic activity and Factor XIII activation activity. DAnase may have a potential clinical application for the therapy of thrombosis disease. PMID- 24755065 TI - Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment. AB - BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterized, in part, by increased fatigue following minimal exertion, cognitive impairment, poor recovery to physical and other stressors, in addition to other symptoms. Unlike healthy subjects and other diseased populations who reproduce objective physiological measures during repeat cardiopulmonary exercise tests (CPETs), ME/CFS patients have been reported to fail to reproduce results in a second CPET performed one day after an initial CPET. If confirmed, a disparity between a first and second CPET could serve to identify individuals with ME/CFS, would be able to document their extent of disability, and could also provide a physiological basis for prescribing physical activity as well as a metric of functional impairment. METHODS: 22 subjects diagnosed with ME/CFS completed two repeat CPETs separated by 24 h. Measures of oxygen consumption (VO2), heart rate (HR), minute ventilation (Ve), workload (Work), and respiratory exchange ratio (RER) were made at maximal (peak) and ventilatory threshold (VT) intensities. Data were analyzed using ANOVA and Wilcoxon's Signed-Rank Test (for RER). RESULTS: ME/CFS patients showed significant decreases from CPET1 to CPET2 in VO2peak (13.8%), HRpeak (9 bpm), Ve peak (14.7%), and Work@peak (12.5%). Decreases in VT measures included VO2@VT (15.8%), Ve@VT (7.4%), and Work@VT (21.3%). Peak RER was high (>=1.1) and did not differ between tests, indicating maximum effort by participants during both CPETs. If data from only a single CPET test is used, a standard classification of functional impairment based on VO2peak or VO2@VT results in over-estimation of functional ability for 50% of ME/CFS participants in this study. CONCLUSION: ME/CFS participants were unable to reproduce most physiological measures at both maximal and ventilatory threshold intensities during a CPET performed 24 hours after a prior maximal exercise test. Our work confirms that repeated CPETs warrant consideration as a clinical indicator for diagnosing ME/CFS. Furthermore, if based on only one CPET, functional impairment classification will be mis identified in many ME/CFS participants. PMID- 24755066 TI - Brain mass estimation by head circumference and body mass methods in neonatal glycaemic modelling and control. AB - INTRODUCTION: Hyperglycaemia is a common complication of stress and prematurity in extremely low-birth-weight infants. Model-based insulin therapy protocols have the ability to safely improve glycaemic control for this group. Estimating non insulin-mediated brain glucose uptake by the central nervous system in these models is typically done using population-based body weight models, which may not be ideal. METHOD: A head circumference-based model that separately treats small for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) infants is compared to a body weight model in a retrospective analysis of 48 patients with a median birth weight of 750g and median gestational age of 25 weeks. Estimated brain mass, model-based insulin sensitivity (SI) profiles, and projected glycaemic control outcomes are investigated. SGA infants (5) are also analyzed as a separate cohort. RESULTS: Across the entire cohort, estimated brain mass deviated by a median 10% between models, with a per-patient median difference in SI of 3.5%. For the SGA group, brain mass deviation was 42%, and per-patient SI deviation 13.7%. In virtual trials, 87-93% of recommended insulin rates were equal or slightly reduced (Delta<0.16mU/h) under the head circumference method, while glycaemic control outcomes showed little change. CONCLUSION: The results suggest that body weight methods are not as accurate as head circumference methods. Head circumference-based estimates may offer improved modelling accuracy and a small reduction in insulin administration, particularly for SGA infants. PMID- 24755067 TI - Systematic review and evidence integration for literature-based environmental health science assessments. AB - BACKGROUND: Systematic-review methodologies provide objectivity and transparency to the process of collecting and synthesizing scientific evidence in reaching conclusions on specific research questions. There is increasing interest in applying these procedures to address environmental health questions. OBJECTIVES: The goal was to develop a systematic-review framework to address environmental health questions by extending approaches developed for clinical medicine to handle the breadth of data relevant to environmental health sciences (e.g., human, animal, and mechanistic studies). METHODS: The Office of Health Assessment and Translation (OHAT) adapted guidance from authorities on systematic-review and sought advice during development of the OHAT Approach through consultation with technical experts in systematic review and human health assessments, as well as scientific advisory groups and the public. The method was refined by considering expert and public comments and through application to case studies. RESULTS AND DISCUSSION: Here we present a seven-step framework for systematic review and evidence integration for reaching hazard identification conclusions: 1) problem formulation and protocol development, 2) search for and select studies for inclusion, 3) extract data from studies, 4) assess the quality or risk of bias of individual studies, 5) rate the confidence in the body of evidence, 6) translate the confidence ratings into levels of evidence, and 7) integrate the information from different evidence streams (human, animal, and "other relevant data" including mechanistic or in vitro studies) to develop hazard identification conclusions. CONCLUSION: The principles of systematic review can be successfully applied to environmental health questions to provide greater objectivity and transparency to the process of developing conclusions. PMID- 24755068 TI - TGF-beta2 induces transdifferentiation and fibrosis in human lens epithelial cells via regulating gremlin and CTGF. AB - Transforming growth factor (TGF)-beta2, gremlin and connective tissue growth factor (CTGF) are known to play important roles in the induction of epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) synthesis. However, the complex functional relationship among gremlin, CTGF and TGF-beta2 in the induction of EMT and ECM synthesis in human lens epithelial cells (HLECs) has not been reported. In this study, we found that TGF-beta2, CTGF and gremlin can individually induce the expression of alpha-smooth muscle actin (alpha-SMA), fibronectin (Fn), collagen type I (COL-I), Smad2 and Smad3 in HLECs. Blockade of CTGF and gremlin effectively inhibited TGF-beta2-induced expression of alpha-SMA, Fn, COL-I, Smad2, and Smad3 in HLECs. Furthermore blockade of Smad2 and Smad3 effectively inhibited CTGF and gremlin induced expression of alpha-SMA, Fn, COL-I in HLECs. In conclusion, TGF-beta2, CTGF and gremlin are all involved in EMT and ECM synthesis via activation of Smad signaling pathway in HLECs. Specifically silencing CTGF and gremlin can effectively block the TGF-beta2-induced EMT, ECM synthesis due to failure in activation of Smad signaling pathway in HLECs. PMID- 24755069 TI - Establishment of a signal peptide with cross-species compatibility for functional antibody expression in both Escherichia coli and Chinese hamster ovary cells. AB - Signal peptides are short peptides located at the N-terminus of secreted proteins. They characteristically have three domains; a basic region at the N terminus (n-region), a central hydrophobic core (h-region) and a carboxy-terminal cleavage region (c-region). Although hundreds of different signal peptides have been identified, it has not been completely understood how their features enable signal peptides to influence protein expression. Antibody-derived signal peptides are often used to prepare recombinant antibodies expressed by eukaryotic cells, especially Chinese hamster ovary (CHO) cells. However, when prokaryotic Escherichia coli (E. coli) are utilized in drug discovery processes, such as for phage display selection or antibody humanization, signal peptides have been selected separately due to the differences in the expression systems between the species. In this study, we successfully established a signal peptide that enables a functional antibody to be expressed in both prokaryotic and eukaryotic cells by focusing on the importance of having an Ala residue in the c-region of the signal sequence. We found that changing Ser to Ala at only two positions significantly augmented the anti-HER2 antigen binding fragment (Fab) expression in E. coli. In addition, this altered signal peptide also retained the ability to express functional anti-HER2 antibody in CHO cells. Taken together, the present findings indicate that the signal peptide can promote functional antibody expression in both prokaryotic E. coli and eukaryotic CHO cells. This finding will contribute to the understanding of signal peptides and accelerate therapeutic antibody research. PMID- 24755070 TI - Differentiation, polarization, and migration of human induced pluripotent stem cell-derived neural progenitor cells co-cultured with a human glial cell line with radial glial-like characteristics. AB - Here we established a unique human glial cell line, GDC90, derived from a human glioma and demonstrated its utility as a glial scaffold for the polarization and differentiation of human induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs). When co-cultured with GDC90 cells, iPSC-NPCs underwent rapid polarization and neurite extension along the radially spreading processes of the GDC90 cells, and showed migratory behavior. This method is potentially useful for detailed examination of neurites or for controlling neurites behavior for regenerative medicine. PMID- 24755071 TI - Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression. AB - INTRODUCTION: Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages. METHODS AND RESULTS: Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-alpha. IH led to a robust increase in NF-kappaB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-kappaB response of adipocytes to both IH and TNF-alpha was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-kappaB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-alpha with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes. CONCLUSION: Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA. PMID- 24755073 TI - Superoxide dismutase as a target of clioquinol-induced neurotoxicity. AB - Subacute myelo-optico-neuropathy (SMON) is a progressive neurological disorder affecting the spinal cord, peripheral nerves and optic nerves. Although it has been assumed that SMON was caused by intoxication of clioquinol, the mechanism underlying clioquinol-induced neurotoxicity is not fully understood. This study aimed to clarify the relevance of oxidative stress to clioquinol-induced neurotoxicity and the cause of the enhanced oxidative stress. Clioquinol induced cell death in human-derived neuroblastoma cell line, SH-SY5Y, in a dose-dependent manner. This process was accompanied by activation of caspase-3 and enhanced production of reactive oxygen species (ROS). We examined whether clioquinol inhibited the activity of superoxide dismutase-1 (SOD1), based on its metal chelating properties. Clioquinol inhibited activities of purified SOD1 in a dose dependent manner. Cytosolic SOD activities were also inhibited in SH-SY5Y cells treated with clioquinol. Finally, addition of exogenous SOD1 to the culture significantly reduced enhanced ROS production and cell death induced by clioquinol in SH-SY5Y cells. These findings suggested that enhanced oxidative stress caused by inhibition of SOD1 undelay clioquinol-induced neurotoxicity and was relevant to the pathogenesis of SMON. PMID- 24755072 TI - Activation of SIRT1 by curcumin blocks the neurotoxicity of amyloid-beta25-35 in rat cortical neurons. AB - As one of the most important hallmarks of Alzheimer's disease (AD), beta-amyloid (Abeta) plays important roles in inducing reactive oxygen species (ROS) generation, mitochondrial dysfunction and apoptotic cell death in neurons. Curcumin extracted from the yellow pigments spice plant turmeric shows multiplied bioactivities such as antioxidant and anti-apoptosis properties in vitro and in vivo. In the present study, the neuroprotective effect of curcumin against Abeta25-35-induced cell death in cultured cortical neurons was investigated. We found that pretreatment of curcumin prevented the cultured cortical neurons from Abeta25-35-induced cell toxicity. In addition, curcumin improved mitochondrial membrane potential (DeltaPsim), decreased ROS generation and inhibited apoptotic cell death in Abeta25-35 treated neurons. Furthermore, we found that application of curcumin activated the expression of SIRT1 and subsequently decreased the expression of Bax in the presence of Abeta25-35. The protective effect of curcumin was blocked by SIRT1 siRNA. Taken together, our results suggest that activation of SIRT1 is involved in the neuroprotective action of curcumin. PMID- 24755074 TI - Glutaminase catalyzes reaction of glutamate to GABA. AB - Here, for the first time, we report an NMR spectroscopy study of l-Glutamine (Gln) conversion by Glutaminase (Glnase), which shows that the reaction involves two distinct steps. In the first step, Glnase rapidly hydrolyzes Gln to Glutamate (Glu) (~16.87 MUmol of Gln/min/mg of Glnase) and in the second step, Glu generated in the first step is decarboxylated into gamma-amino butyric acid (GABA) with a much slower rate (~0.185 MUmol/min/mg). When Glnase was added to the sample containing l-Glu alone, it was also converted to GABA, at a similar rate as in the second step mentioned above. The rate of Glu decarboxylation into GABA by Glnase is about an order of magnitude lower than that by commonly known enzyme, Glutamate decarboxylase. Potential impact of these findings, on the mechanistic aspects of Gln-Glu shuttle in neuroscience and glutaminolysis in tumors, is discussed. PMID- 24755075 TI - Valproic acid downregulates Cdk5 activity via the transcription of the p35 mRNA. AB - The cyclin-dependent kinase 5 (Cdk5) is a neuron-specific Ser/Thr kinase that is activated by the regulatory subunit p35. Overactivation of Cdk5, which is induced by the cleavage of p35 by calpain, is implicated in neuronal death in various neurodegenerative diseases. In contrast, depletion of the Cdk5 activity renders neurons vulnerable to stresses. Recent reports suggest the involvement of Cdk5 in mental disorders. We hypothesized that perturbation of Cdk5 activity is related to mental conditions. To verify this hypothesis, we investigated the effect of valproic acid (VPA), which is a drug of choice for psychiatric disorders, on Cdk5 activity. VPA decreased the expression of p35 at both the protein and mRNA levels in cultured neurons, resulting in a decrease of Cdk5 activity. VPA decreased the p35 mRNA via histone deacetylase inhibition. The chronic administration of VPA also downregulated p35 in mouse brains. These results indicate that VPA regulates Cdk5 activity in neurons via p35 transcription mediated by HDAC inhibition. PMID- 24755076 TI - Molecular cloning and characterization of a novel SK3-type dehydrin gene from Stipa purpurea. AB - Stipa purpurea, an endemic forage of the grass family in the Tibetan Plateau, is highly resistant to drought. Dehydrins (DHNs) are stress proteins involved in plant protective reactions against environmental stress. In this study, the full length DHN open reading frame (ORF) cloned from S. purpurea, named SpDHN1, was 816 nucleotides length and encoded a protein of 271 amino acids. Phylogenetic and sequence characterization analysis revealed that the DHN gene was an SK3-type DHNs. Subcellular localization analysis indicated that SpDHN1 was localized in the cytoplasm and the plasma membrane. SpDHN1 function analysis provided new evidence to support the antioxidation of SpDHN1 in plant responses drought stress. Ectopic expression of SpDHN1 in Arabidopsis thaliana plants showed more resistance to drought stress than the wild-type, indicating that SpDHN1 may be a potential candidate gene for genetic improvement of crops to improve stress tolerance. PMID- 24755077 TI - Dysfunction of mitochondrial dynamics in the brains of scrapie-infected mice. AB - Mitochondrial dysfunction is a common and prominent feature of many neurodegenerative diseases, including prion diseases; it is induced by oxidative stress in scrapie-infected animal models. In previous studies, we found swelling and dysfunction of mitochondria in the brains of scrapie-infected mice compared to brains of controls, but the mechanisms underlying mitochondrial dysfunction remain unclear. To examine whether the dysregulation of mitochondrial proteins is related to the mitochondrial dysfunction associated with prion disease, we investigated the expression patterns of mitochondrial fusion and fission proteins in the brains of ME7 prion-infected mice. Immunoblot analysis revealed that Mfn1 was up-regulated in both whole brain and specific brain regions, including the cerebral cortex and hippocampus, of ME7-infected mice compared to controls. Additionally, expression levels of Fis1 and Mfn2 were elevated in the hippocampus and the striatum, respectively, of the ME7-infected brain. In contrast, Dlp1 expression was significantly reduced in the hippocampus in the ME7-infected brain, particularly in the cytosolic fraction. Finally, we observed abnormal mitochondrial enlargement and histopathological change in the hippocampus of the ME7-infected brain. These observations suggest that the mitochondrial dysfunction, which is presumably caused by the dysregulation of mitochondrial fusion and fission proteins, may contribute to the neuropathological changes associated with prion disease. PMID- 24755078 TI - A site-directed mutagenesis study of the MdmX RING domain. AB - Mdm2 and MdmX are important negative regulators of the tumor suppressor p53. Structurally homologous Mdm2 and MdmX inhibit p53 by directly blocking p53 transcriptional activation. Mdm2 also modifies and targets p53 for 26S proteasome dependent protein degradation through E3 ligase activity mediated by its C terminal RING domain. However, MdmX lacks intrinsic E3 ligase activity and fails to catalyze ubiquitination of p53 despite containing a conserved RING domain. Thus, a comparative structural analysis between the Mdm2 and MdmX RING domains offers a unique way to elucidate the distinct functions of the two proteins in ubiquitination. We performed site-directed mutagenesis of the MdmX RING domain and found that the substitution of the residue N448 for cysteine and the substitution of the residue K478 for arginine granted MdmX RING domain ubiquitination activity. The structural analysis of the Mdm2 and MdmX RING domains revealed that the residue C449 of Mdm2 (structurally homologous to MdmX RING N448) located at the Mdm2 RING dimer interface is critical for the stability of the RING dimer structure, while the residue R479 (structurally homologous to MdmX RING K478) plays a role in recruiting and activating the ubiquitin E2 conjugating enzyme. This study provides new insight into the molecular mechanism of Mdm2 RING domain mediated ubiquitination. PMID- 24755079 TI - Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes. AB - AIMS: Calmodulin (CaM) plays a key role in modulating channel gating in ryanodine receptor (RyR2). Here, we investigated (a) the pathogenic role of CaM in the channel disorder in CPVT and (b) the possibility of correcting the CPVT-linked channel disorder, using knock-in (KI) mouse model with CPVT-associated RyR2 mutation (R2474S). METHODS AND RESULTS: Transmembrane potentials were recorded in whole cell current mode before and after pacing (1-5 Hz) in isolated ventricular myocytes. CaM binding was assessed by incorporation of exogenous CaM fluorescently labeled with HiLyte Fluor((r)) in saponin-permeabilized myocytes. In the presence of cAMP (1 MUM) the apparent affinity of CaM binding to the RyR decreased in KI cells (Kd: 140-400 nM), but not in WT cells (Kd: 110-120 nM). Gly Ser-His-CaM (GSH-CaM that has much higher RyR-binding than CaM) restored normal binding to the RyR of cAMP-treated KI cells (140 nM). Neither delayed afterdepolarization (DAD) nor triggered activity (TA) were observed in WT cells even at 5Hz pacing, whereas both DAD and TA were observed in 20% and 12% of KI cells, respectively. In response to 10nM isoproterenol, only DAD (but not TA) was observed in 11% of WT cells, whereas in KI cells the incidence of DAD and TA further increased to 60% and 38% of cells, respectively. Addition of GSH-CaM (100 nM) to KI cells decreased both DADs and TA (DAD: 38% of cells; TA: 10% of cells), whereas CaM (100 nM) had no appreciable effect. Addition of GSH-CaM to saponin permeabilized KI cells decreased Ca(2+) spark frequency (+33% of WT cells), which otherwise markedly increased without GSH-CaM (+100% of WT cells), whereas CaM revealed much less effect on the Ca(2+) spark frequency (+76% of WT cells). Then, by incorporating CaM or GSH-CaM to intact cells (with protein delivery kit), we assessed the in situ effect of GSH-CaM (cytosolic [CaM]=~240 nM, cytosolic [GSH CaM]=~230 nM) on the frequency of spontaneous Ca(2+) transient (sCaT, % of total cells). Addition of 10nM isoproterenol to KI cells increased sCaT after transient 5 Hz pacing (37%), whereas it was much more attenuated by GSH-CaM (9%) than by CaM (26%) (P<0.01 vs CaM). CONCLUSIONS: Several disorders in the RyR channel function characteristic of the CPVT-mutant cells (increased spontaneous Ca(2+) leak, delayed afterdepolarization, triggered activity, Ca(2+) spark frequency, spontaneous Ca(2+) transients) can be corrected to a normal function by increasing the affinity of CaM binding to the RyR. PMID- 24755080 TI - Ablation of cereblon attenuates myocardial ischemia-reperfusion injury. AB - Cereblon (CRBN) was originally identified as a target protein for a mild type of mental retardation in humans. However, recent studies showed that CRBN acts as a negative regulator of AMP-activated protein kinase (AMPK) by binding directly to the AMPK catalytic subunit. Because AMPK is implicated in myocardial ischemia reperfusion (I-R) injury, we reasoned that CRBN might play a role in the pathology of myocardial I-R through regulation of AMPK activity. To test this hypothesis, wild-type (WT) and crbn knockout (KO) mice were subjected to I-R (complete ligation of the coronary artery for 30 min followed by 24h of reperfusion). We found significantly smaller infarct sizes and less fibrosis in the hearts of KO mice than in those of WT mice. Apoptosis was also significantly reduced in the KO mice compared with that in WT mice, as shown by the reduced numbers of TUNEL-positive cells. In parallel, AMPK activity remained at normal levels in KO mice undergoing I-R, whereas it was significantly reduced in WT mice under the same conditions. In rat neonatal cardiomyocytes, overexpression of CRBN significantly reduced AMPK activity, as demonstrated by reductions in both phosphorylation levels of AMPK and the expression of its downstream target genes. Collectively, these data demonstrate that CRBN plays an important role in myocardial I-R injury through modulation of AMPK activity. PMID- 24755081 TI - KIN enhances stem cell-like properties to promote chemoresistance in colorectal carcinoma. AB - Chemotherapy is widely used in colorectal cancer (CRC) treatment, especially in advanced stage patients. However, it is inevitable to develop chemoresistance. Recently, cancer cells acquired stem cell-like properties or cancer stem cells (CSC) were proved to attribute to chemoresistance. Here, we found that KIN protein was elevated in CRC cell lines and tissue specimens as compared to normal controls. Upregulation of KIN positively correlates with the metastatic status of CRC patients. Patients with high KIN expression showed poor prognosis and were with a short survival time. Overexpression of KIN enhanced, while silencing KIN impaired, chemoresistance to oxaliplatin (Ox) or 5-fluorouracil (5-FU) in CRC cell lines. Further investigation demonstrated that overexpression of KIN rendered CRC cells enriching CSC markers and CSC phenotype, and silencing KIN reduced CSC markers and CSC phenotype. Our findings suggest that the KIN level may be a suitable marker for predicting chemotherapy response in CRC, and silencing KIN plus chemotherapy may be a novel therapy for CRC treatment. PMID- 24755082 TI - Regulation of hemeoxygenase-1 gene expression by Nrf2 and c-Jun in tertiary butylhydroquinone-stimulated rat primary astrocytes. AB - Hemeoxygenase-1 (HO-1) is a phase II antioxidant enzyme that is primarily involved in detoxification and cytoprotection in a variety of tissues. However, the mechanism underlying HO-1 gene expression remains unclear. In the present study, we investigated the regulation of HO-1 expression in primary cultured astrocytes by using the natural antioxidant compound tertiary butylhydroquinone (tBHQ). We found that tBHQ increased HO-1 mRNA and protein levels. Promoter analysis revealed that tBHQ enhanced HO-1 gene transcription in an antioxidant response element (ARE)-dependent manner. In addition, tBHQ increased the nuclear translocation and DNA binding of Nrf2 and c-Jun to ARE. Small interfering RNA (siRNA) experiments demonstrated that Nrf2 and c-Jun are involved in the differential modulation of HO-1 expression. Thus, Nrf2 knockdown reduced the basal level of HO-1 expression but did not affect the fold induction by tBHQ. On the other hand, knockdown of c-Jun diminished tBHQ-mediated induction of HO-1 without affecting basal expression. The data suggest that Nrf2 generally modulates the basal expression of HO-1, while c-Jun mediates HO-1 induction in response to tBHQ. The results of co-immunoprecipitation assays demonstrated a physical interaction between Nrf2 and c-Jun in tBHQ-treated astrocytes. The results suggest that Nrf2 and c-Jun regulate HO-1 expression via their coordinated interaction in tBHQ-treated rat primary astrocytes. PMID- 24755083 TI - Orai1 and STIM1 are critical for cell migration and proliferation of clear cell renal cell carcinoma. AB - The intracellular Ca(2+) regulation has been implicated in tumorigenesis and tumor progression. Notably, store-operated Ca(2+) entry (SOCE) is a major Ca(2+) entry mechanism in non-excitable cells, being involved in cell proliferation and migration in several types of cancer. However, the expression and biological role of SOCE have not been investigated in clear cell renal cell carcinoma (ccRCC). Here, we demonstrate that Orai1 and STIM1, not Orai3, are crucial components of SOCE in the progression of ccRCC. The expression levels of Orai1 in tumor tissues were significantly higher than those in the adjacent normal parenchymal tissues. In addition, native SOCE was blunted by inhibiting SOCE or by silencing Orai1 and STIM1. Pharmacological blockade or knockdown of Orai1 or STIM1 also significantly inhibited RCC cell migration and proliferative capability. Taken together, Orai1 is highly expressed in ccRCC tissues illuminating that Orai1-mediated SOCE may play an important role in ccRCC development. Indeed, Orai1 and STIM1 constitute a native SOCE pathway in ccRCC by promoting cell proliferation and migration. PMID- 24755084 TI - Protective effects of exogenous beta-hydroxybutyrate on paraquat toxicity in rat kidney. AB - In this study, we demonstrated the protective effects of beta-hydroxybutyrate (beta-HB) against paraquat (PQ)-induced kidney injury and elucidated the underlying molecular mechanisms. By histological examination and renal dysfunction specific markers (serum BUN and creatinine) assay, beta-HB could protect the PQ-induced kidney injury in rat. PQ-induced kidney injury is associated with oxidative stress, which was measured by increased lipid peroxidation (MDA) and decreased intracellular anti-oxidative abilities (SOD, CAT and GSH). beta-HB pretreatment significantly attenuated that. Caspase-mediated apoptosis pathway contributed importantly to PQ toxicity, as revealed by the activation of caspase-9/-3, cleavage of PARP, and regulation of Bcl-2 and Bax, which were also effectively blocked by beta-HB. Moreover, treatment of PQ strongly decreased the nuclear Nrf2 levels. However, pre-treatment with beta-HB effectively suppressed this action of PQ. This may imply the important role of beta-HB on Nrf2 pathway. Taken together, this study provides a novel finding that beta-HB has a renoprotective ability against paraquat-induced kidney injury. PMID- 24755085 TI - Selective arterial embolization with ethylene-vinyl alcohol copolymer for control of massive lower gastrointestinal bleeding: feasibility and initial experience. AB - PURPOSE: To evaluate the efficacy, safety, and clinical outcomes of superselective embolization using ethylene-vinyl alcohol copolymer (Onyx Liquid Embolic System; ev3 Neurovascular, Irvine, California) as the primary treatment for acute and massive lower gastrointestinal bleeding (LGIB). MATERIALS AND METHODS: Between January 2008 and October 2013, all patients with focal massive LGIB who were treated by embolization were retrospectively analyzed. The study was approved by the hospital's ethics committee; informed consent was obtained in all cases. Onyx was chosen as the embolic agent in all cases in an intention-to treat fashion. Embolization was indicated in 31 consecutive patients (mean age, 80 y +/- 11.1). Multidetector computed tomography and digital subtraction angiography were performed in all patients. RESULTS: Active bleeding was detected in all cases. A colonoscopy was performed in 11 patients. The correlation between multidetector computed tomography and angiography findings was 96.7%. The causes of bleeding were diverticula in 15 patients, iatrogenic in 7 patients, neoplasia in 3 patients, hemorrhoids in 2 patients, angiodysplasia in 2 patients, and unknown in 2 patients. Embolization was not possible in one patient, who required urgent left hemicolectomy. The technical success rate was 93.5%. The embolic material refluxed in one patient, causing an undesired embolization, without any clinical consequences. In the 30 patients who received embolization, the immediate bleeding control rate was 100%. Rebleeding at 30 days occurred in three patients (10%). There were no major complications, intestinal ischemia, or deaths attributable to the treatment. No patient needed surgery or new embolization during a mean follow-up period of 23.7 months (range, 1-71 mo). CONCLUSIONS: Control of massive LGIB using superselective embolization with Onyx is feasible and safe. PMID- 24755086 TI - Transcatheter CT arterial portography and CT hepatic arteriography for liver tumor visualization during percutaneous ablation. AB - PURPOSE: To evaluate the feasibility of combining transcatheter computed tomography (CT) arterial portography or transcatheter CT hepatic arteriography with percutaneous liver ablation for optimized and repeated tumor exposure. MATERIALS AND METHODS: Study participants were 20 patients (13 men and 7 women; mean age, 59.4 y; range, 40-76 y) with unresectable liver-only malignancies--14 with colorectal liver metastases (29 lesions), 5 with hepatocellular carcinoma (7 lesions), and 1 with intrahepatic cholangiocarcinoma (2 lesions)--that were obscure on nonenhanced CT. A catheter was placed within the superior mesenteric artery (CT arterial portography) or in the hepatic artery (CT hepatic arteriography). CT arterial portography or CT hepatic arteriography was repeatedly performed after injecting 30-60 mL 1:2 diluted contrast material to plan, guide, and evaluate ablation. The operator confidence levels and the liver to-lesion attenuation differences were assessed as well as needle-to-target mismatch distance, technical success, and technique effectiveness after 3 months. RESULTS: Technical success rate was 100%; there were no major complications. Compared with conventional unenhanced CT, operator confidence increased significantly for CT arterial portography or CT hepatic arteriography cases (P < .001). The liver-to-lesion attenuation differences between unenhanced CT, contrast-enhanced CT, and CT arterial portography or CT hepatic arteriography were statistically significant (mean attenuation difference, 5 HU vs 28 HU vs 70 HU; P < .001). Mean needle-to-target mismatch distance was 2.4 mm +/- 1.2 (range, 0-12.0 mm). Primary technique effectiveness at 3 months was 87% (33 of 38 lesions). CONCLUSIONS: In patients with technically unresectable liver-only malignancies, single-session CT arterial portography-guided or CT hepatic arteriography-guided percutaneous tumor ablation enables repeated contrast enhanced imaging and real-time contrast-enhanced CT fluoroscopy and improves lesion conspicuity. PMID- 24755087 TI - Endovascular procedures versus intravenous thrombolysis in stroke with tandem occlusion of the anterior circulation. AB - PURPOSE: Stroke with tandem occlusion within the anterior circulation presents a lower probability of recanalization and good clinical outcome after intravenous (IV) thrombolysis than stroke with single occlusion. The present study describes the impact of endovascular procedures (EPs) compared with IV thrombolysis alone on recanalization and clinical outcome. MATERIALS AND METHODS: Thirty patients with symptom onset less than 4.5 hours and tandem occlusion within the anterior circulation were analyzed retrospectively. Recanalization was assessed per Thrombolysis In Cerebral Infarction (TICI) classification on computed tomography, magnetic resonance imaging, or digital subtraction angiography within 24 hours. Infarct size was detected on follow-up imaging as a dichotomized variable, ie, more than one third of the territory of the middle cerebral artery. Clinical outcomes were major neurologic improvement, independent outcome (90-d modified Rankin Scale [mRS] score), symptomatic intracerebral hemorrhage (sICH; per European Cooperative Acute Stroke Study criteria), and death within 7 days. RESULTS: Patients treated with EPs (n = 14) were significantly younger and had a history of arterial hypertension more frequently than patients treated with IV thrombolysis alone (n = 16). Recanalization (ie, TICI score 2b/3; EP, 64%; IV, 19%; P = .01), major neurologic improvement (EP, 64%; IV, 19%; P = .01), and independent outcome (mRS score <= 2; EP, 54% IV, 13%; P = .02) occurred more often in the EP group, whereas infarct sizes greater than one third of the MCA territory (EP, 43%; IV, 81%; P = .03) were observed less often. Rates of sICH (P = .12) and death within 7 days (P = .74) did not differ significantly. CONCLUSIONS: Higher recanalization rate, smaller infarct volume, and better clinical outcome in the EP group should encourage researchers to include this subgroup of patients in prospective randomized trials comparing IV thrombolysis versus EP in stroke. PMID- 24755088 TI - Preparations for Severe Winter Conditions by Emergency Health Personnel in Turkey. AB - OBJECTIVE: Emergency and core ambulance personnel work under all environmental conditions, including severe weather condtions. We evaluated emergency medical personnel in Canakkale, Turkey, for their degree of preparedness. METHODS: A descriptive study was conducted in Canakkale, Turkey, within 112 emergency service units and their 17 district stations. Surveys were developed to measure the level of preparedness for serious winter conditions that individual workers made for themselves, their homes, and their cars. RESULTS: Of the 167 survey participants, the mean age was 29.8 +/- 7.9 years; 52.7% were women; more than half (54.75%) were emergency medical technicians; and 53.3% were married. Only 10.4% of those who heated their homes with natural gas had carbon monoxide detectors. Scores relating to household and individual preparation for severe winter conditions increased by participants' age (P < .003), being married (P < .000) and working in the city center (P < .021); and for men whose cars were equipped with tow ropes, extra clothing, and snow tires (P < .05). Absenteeism was higher for central-city personnel than district workers because they were less prepared for harsh winter conditions (P = .016). CONCLUSION: Many of the surveyed emergency health personel demonstrated insufficient preparations for serious winter conditions. To increase the safety and efficiency of emergency medical personnel, educational training programs should be rountinely conducted. (Disaster Med Public Health Preparedness. 2014;0:1-4). PMID- 24755091 TI - Impact of nanocrystal spray deposition on inorganic solar cells. AB - Solution-synthesized inorganic cadmium telluride nanocrystals (~4 nm; 1.45 eV band gap) are attractive elements for the fabrication of thin-film-based low-cost photovoltaic (PV) devices. Their encapsulating organic ligand shell enables them to be easily dissolved in organic solvents, and the resulting solutions can be spray-cast onto indium-tin oxide (ITO)-coated glass under ambient conditions to produce photoactive thin films of CdTe. Following annealing at 380 degrees C in the presence of CdCl2(s) and evaporation of metal electrode contacts (glass/ITO/CdTe/Ca/Al), Schottky-junction PV devices were tested under simulated 1 sun conditions. An improved PV performance was found to be directly tied to control over the film morphology obtained by the adjustment of spray parameters such as the solution concentration, delivery pressure, substrate distance, and surface temperature. Higher spray pressures produced thinner layers (<60 nm) with lower surface roughness (<200 nm), leading to devices with improved open-circuit voltages (Voc) due to decreased surface roughness and higher short-circuit current (Jsc) as a result of enhanced annealing conditions. After process optimization, spray-cast Schottky devices rivaled those prepared by conventional spin-coating, showing Jsc = 14.6 +/- 2.7 mA cm(-2), Voc = 428 +/- 11 mV, FF = 42.8 +/- 1.4%, and Eff. = 2.7 +/- 0.5% under 1 sun illumination. This optimized condition of CdTe spray deposition was then applied to heterojunction devices (ITO/CdTe/ZnO/Al) to reach 3.0% efficiency after light soaking under forward bias. The film thickness, surface morphology, and light absorption were examined with scanning electron microscopy, optical profilometry, and UV/vis spectroscopy. PMID- 24755090 TI - Internet access and use by COPD patients in the National Emphysema/COPD Association Survey. AB - BACKGROUND: Technology offers opportunities to improve healthcare, but little is known about Internet use by COPD patients. We tested two hypotheses: Internet access is associated with socio-demographic disparities and frequency of use is related to perceived needs. METHODS: We analyzed data from a 2007-2008 national convenience sample survey of COPD patients to determine the relationship between Internet access and frequency of use with demographics, socio-economic status, COPD severity, and satisfaction with healthcare. RESULTS: Among survey respondents (response rate 7.2%; n = 914, 59.1% women, mean age 71.2 years), 34.2% reported lack of Internet access, and an additional 49% had access but used the Internet less than weekly. Multivariate models showed association between lack of access and older age (OR 1.10, 95% CI 1.07, 1.13), lower income (income below $30,000 OR 2.47, 95% CI 1.63, 3.73), less education (high school highest attainment OR 2.30, 95% CI 1.54, 3.45), comorbid arthritis or mobility-related disease (OR 1.56, 95% CI 1.05, 2.34). More frequent use (at least weekly) was associated with younger age (OR 0.95, 95% CI 0.93, 0.98), absence of cardiovascular disease (OR 0.48, 95% CI 0.29, 0.78), but with perception of needs insufficiently met by the healthcare system, including diagnostic delay (OR 1.72, 95% CI 1.06, 2.78), feeling treated poorly (OR 2.46, 95% CI 1.15, 5.24), insufficient physician time (OR 2.29, 95% CI 1.02, 5.13), and feeling their physician did not listen (OR 3.14, 95% CI 1.42, 6.95). CONCLUSIONS: An analysis of the characteristics associated with Internet access and use among COPD patients identified two different patient populations. Lack of Internet access was a marker of socioeconomic disparity and mobility-associated diseases, while frequent Internet use was associated with less somatic disease but dissatisfaction with care. PMID- 24755089 TI - Prevalence and trends of markers of hepatitis B virus, hepatitis C virus and human Immunodeficiency virus in Argentine blood donors. AB - BACKGROUND: Transfusion-transmitted infections are a major problem associated with blood transfusion. The aim of this study was to determine prevalence and trends of HBV, HCV and HIV in blood donors in Argentina. METHODS: A retrospective study was carried out in blood donors of 27 transfusion centers covering the whole country over a period of eight years (2004-2011). Serologic screening assays for HBsAg, anti-HBc, anti-HCV, and anti-HIV were performed in all centers and nucleic acid amplification testing (NAT) was performed in 2 out of the 27 centers. RESULTS: The 2,595,852 samples tested nationwide from 2004 to 2011 showed that the prevalence of HBsAg decreased from 0.336% to 0.198% (p < 0.0001), that of anti-HBc from 2.391% to 2.007% (p < 0.0001), that of anti-HCV from 0.721% to 0.460%, (p < 0.0001) and that of anti-HIV from 0.208% to 0.200 (p = 0.075). The prevalence of HBV, HCV and HIV was unevenly distributed among the different regions of the country. Two out of 74,838 screening- negative samples were positive in NAT assays (1 HIV-RNA and 1 HCV-RNA); moreover, HBV-DNA, HCV-RNA and HIV-RNA were detected in 60.29, 24.54 and 66.67% of screening-positive samples of the corresponding assays. As regards donors age, positive HBV-DNA and HCV-RNA donors were significantly older than healthy donors (46.6, 50.5 and 39.5 y respectively, p < 0.001). CONCLUSIONS: Argentina has a low prevalence of HBsAg, anti-HCV and anti-HIV in blood donors, with a decreasing trend for HBsAg, anti HBc and anti-HCV but not for anti-HIV over the last 8 years. The uneven distribution of transfusion-transmitted infections prevalence among the different regions of the country highlights the need to implement regional awareness campaigns and prevention. The discrepancy between samples testing positive for screening assays and negative for NAT assays highlights the problem of blood donors who test repeatedly reactive in screening assays but are not confirmed as positive upon further testing. The uneven distribution of age between healthy donors and NAT-positive donors could be related to changes in risks of these pathogens in the general population and might be attributed to a longer exposure to transmission risk factors in elderly people. PMID- 24755092 TI - Cotranslational protein-RNA associations predict protein-protein interactions. AB - BACKGROUND: Most cellular proteins function as part of stable protein complexes. We recently showed that around 38% of proteins associate with mRNAs that encode interacting proteins, reflecting the cotranslational formation of the complex between the bait protein and the nascent peptides encoded by the interacting mRNAs. Here we hypothesise that these cotranslational protein-mRNA associations can be used to predict protein-protein interactions. RESULTS: We found that the fission yeast Exo2 protein, which encodes an exonuclease of the XRN1 family, coimmunoprecipitates with the eti1 mRNA, which codes for a protein of unknown function and uninformative sequence. Based on this protein-mRNA association, we predicted that the Exo2 and Eti1 protein are part of the same complex, and confirmed this hypothesis by coimmunoprecipitation and colocalization of the proteins. Similarly, we show that the cotranslational interaction between the Sty1 MAP kinase and the cip2 mRNA, which encodes an RNA-binding protein, predicts a complex between Sty1 and Cip2. CONCLUSIONS: Our results demonstrate that cotranslational protein-mRNA associations can be used to identify new components of protein complexes. PMID- 24755093 TI - The effect of New Neonatal Porcine Diarrhoea Syndrome (NNPDS) on average daily gain and mortality in 4 Danish pig herds. AB - BACKGROUND: The study evaluated the effect of New Neonatal Porcine Diarrhoea Syndrome (NNPDS) on average daily gain (ADG) and mortality and described the clinical manifestations in four herds suffering from the syndrome. NNPDS is a diarrhoeic syndrome affecting piglets within the first week of life, which is not caused by enterotoxigenic Escherichia coli (ETEC), Clostridium perfringens (C. perfringens) type A/C, Clostridium difficile (C. difficile), rotavirus A, coronavirus, Cystoisospora suis, Strongyloides ransomi, Giardia spp or Cryptosporidium spp. RESULTS: Piglets were estimated to have a negative ADG of 9 and 14 g when diarrhoeic for 1 day and >1 day respectively. However, if only diarrhoeic on the day of birth, no negative effect on ADG was seen. Piglets originating from severely affected litters were estimated to have a reduced ADG of 38 g. The study did not show an overall effect of diarrhoea on mortality, but herd of origin, sow parity, birth weight, and gender were significantly associated with mortality. In one of the herds, approximately 25% of the diarrhoeic piglets vs. 6% of the non-diarrhoeic piglets died, and 74% of necropsied piglets were diagnosed with enteritis. These findings indicate that the high mortality seen in this herd was due to diarrhoea. CONCLUSIONS: NNPDS negatively affected ADG in piglets, and even piglets that were diarrhoeic for one day only experienced a reduction in ADG. However, the study showed that diarrhoea restricted to the day of birth did not affect ADG and suggested this phenomenon to be unrelated to the syndrome. Since the diarrhoeal status of the litter had important effects on ADG, future research on NNPDS probably ought to focus on piglets from severely affected litters.The study showed important dissimilarities in the course of diarrhoea between the herds, and one herd was considerably more affected than the others. Within this herd, NNPDS seemed to be associated with a higher mortality, whereas in general the study did not show lethal effects of NNPDS. PMID- 24755095 TI - Usefulness of F-18-fluorodeoxyglucose positron emission tomography to confirm suspected pancreatic cancer: a meta-analysis. AB - INTRODUCTION: Pancreatic cancer is among the five most lethal malignancies in the world. Unfortunately, many malignant tumors go undetected by the current primary diagnostic tools. (18)FDG-PET and (18)FDG-PET/CT might be useful to confirm suspected pancreatic cancer. METHODS: A meta-analysis was performed using all major search engines. Methodological quality of included studies was assessed as well as quality of the PET-protocol. The following pooled estimates served as primary outcome measures: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. RESULTS: Thirty-five studies were included. Pooled estimates for (18)FDG-PET were: sensitivity 90%, specificity 76%, PPV 90%, NPV 76% and accuracy 86%. Pooled estimates for (18)FDG PET/CT were: sensitivity 90%, specificity 76%, PPV 89%, NPV 78% and accuracy 86%. The pooled sensitivity and specificity for (18)FDG-PET to differentiate between pancreatic cancer and chronic pancreatitis were 90% and 84%, respectively. CONCLUSION: Both (18)FDG-PET and (18)FDG-PET/CT offer no benefit over the current primary diagnostic tools in diagnosing pancreatic cancer. However, the (18)FDG PET/CT systems are still improving. We should investigate the sensitivity and specificity of these new systems while reevaluating the tradeoff between false positive and false negative results. Yet, (18)FDG-PET/CT may have a role in the staging of pancreatic cancer, in survival prediction, and may add to other diagnostic information, like histology. PMID- 24755094 TI - Exercise reduces diet-induced cognitive decline and increases hippocampal brain derived neurotrophic factor in CA3 neurons. AB - BACKGROUND: Previous studies have shown that a western diet impairs, whereas physical exercise enhances hippocampus-dependent learning and memory. Both diet and exercise influence expression of hippocampal brain-derived neurotrophic factor (BDNF), which is associated with improved cognition. We hypothesized that exercise reverses diet-induced cognitive decline while increasing hippocampal BDNF. METHODS: To test the effects of exercise on hippocampal-dependent memory, we compared cognitive scores of Sprague-Dawley rats exercised by voluntary running wheel (RW) access or forced treadmill (TM) to sedentary (Sed) animals. Memory was tested by two-way active avoidance test (TWAA), in which animals are exposed to a brief shock in a specific chamber area. When an animal avoids, escapes or has reduced latency to do either, this is considered a measure of memory. In a second experiment, rats were fed either a high-fat diet or control diet for 16 weeks, then randomly assigned to running wheel access or sedentary condition, and TWAA memory was tested once a week for 7 weeks of exercise intervention. RESULTS: Both groups of exercised animals had improved memory as indicated by reduced latency to avoid and escape shock, and increased avoid and escape episodes (p<0.05). Exposure to a high-fat diet resulted in poor performance during both the acquisition and retrieval phases of the memory test as compared to controls. Exercise reversed high-fat diet-induced memory impairment, and increased brain-derived neurotrophic factor (BDNF) in neurons of the hippocampal CA3 region. CONCLUSIONS: These data suggest that exercise improves memory retrieval, particularly with respect to avoiding aversive stimuli, and may be beneficial in protecting against diet induced cognitive decline, likely via elevated BDNF in neurons of the CA3 region. PMID- 24755096 TI - Reply to: Extralevator abdomino-perineal excision (ELAPE) or abdomino-sacral amputation of the rectum (ASAR): revitalised approach for low rectal carcinoma described by Tadeusz Koszarowski in the 50s. PMID- 24755097 TI - Radiation recall reaction causing cardiotoxicity. AB - Radiation recall phenomenon is a tissue reaction that develops within a previously irradiated area, precipitated by the subsequent administration of certain chemotherapeutic agents. It commonly affects the skin, but can also involve internal organs with functional consequences. To our best knowledge, this phenomenon has never been reported as a complication on the heart and should be consider as a potential cause of cardiotoxicity. PMID- 24755098 TI - Avoiding thoughtless waste: consider the energy cost of emails in the NHS. PMID- 24755099 TI - Sardine cycles, krill declines, and locust plagues: revisiting 'wasp-waist' food webs. AB - 'Wasp-waist' systems are dominated by a mid trophic-level species that is thought to exert top-down control on its food and bottom-up control on its predators. Sardines, anchovy, and Antarctic krill are suggested examples, and here we use locusts to explore whether the wasp-waist concept also applies on land. These examples also display the traits of mobile aggregations and dietary diversity, which help to reduce the foraging footprint from their large, localised biomasses. This suggests that top-down control on their food operates at local aggregation scales and not at wider scales suggested by the original definition of wasp-waist. With this modification, the wasp-waist framework can cross fertilise marine and terrestrial approaches, revealing how seemingly disparate but economically important systems operate. PMID- 24755100 TI - Single-position, minimally invasive Ivor Lewis oesophagectomy for lower thoracic oesophageal cancer. AB - Although several surgical approaches exist for lower thoracic oesophageal cancer, standardized techniques for minimally invasive oesophageal resection and intrathoracic anastomosis have not yet been established. Thus, optimization of the approach and identification of the ideal anastomosis technique are needed. Seven consecutive patients with lower thoracic oesophageal cancer were treated using a single-position, minimally invasive surgical technique with laparoscopy and thoracoscopy. In the present article, we describe this technique in detail and discuss the outcomes of these patients. No adverse events occurred intraoperatively, no failures in the intrathoracic oesophagogastrostomy were detected and favourable short-term outcomes were obtained. Thus, the procedure described is safe and technically feasible and appears to be promising as an alternative approach for the treatment of patients with lower thoracic oesophageal cancer. PMID- 24755101 TI - Mitral valve repair with loop technique via median sternotomy in 180 patients. AB - OBJECTIVES: Artificial chordal reconstruction technique uses several expanded polytetrafluoroethylene loops to achieve mitral valve repair. METHODS: We studied retrospectively 180 patients who underwent mitral valve repair using the loop technique via median sternotomy: 86 for posterior leaflet prolapse, 48 for anterior leaflet prolapse and 26 for bileaflet prolapse. RESULTS: Of the 180 patients, 138 required 1 loop set; 40 patients required 2 and 2 patients with Barlow's disease required 3. Loop sets contained two to nine loops ranging in length from 14 to 26 mm. Additional techniques required to ensure complete repair using the loop technique included commissural edge-to-edge suture in 78 patients, loop-in-loop technique for extension of the artificial loop in 18 and use of needle-side sutures in 18. Systolic anterior leaflet motion was observed in only 2 patients (1.1%). One patient with immune deficiency died of sepsis. Predischarge echocardiograms showed no or trace mitral regurgitation (MR) in 160 patients (89%), mild MR in 17 patients (9.4)% and mild-to-moderate MR in 3 patients (1.7%). Only 1 patient required redo operation due to recurrent MR freedom from MR greater than moderate was seen in 98.0 +/- 1.4% of patients at 1 year, 91.5 +/- 2.8% of patients at 3 years, and 91.5 +/- 2.8% at 5 years postoperatively. No significant difference was seen in the rate of recurrence of MR among the sites of prolapsing leaflets. CONCLUSIONS: The loop technique via median sternotomy to treat posterior, anterior and, especially, bileaflet prolapse provided satisfactory mid-term outcomes. PMID- 24755102 TI - An expansible aortic ring to preserve aortic root dynamics after aortic valve repair. AB - OBJECTIVES: Aortic annuloplasty and preservation of root dynamics have been described as factors for durability of aortic valve repair. The objective of this study is to document the first clinical analysis of root dynamics after a standardized valve-sparing procedure for root aneurysms associating a calibrated expansible external aortic ring annuloplasty with a physiological remodelling of the aortic root (CAVIAAR technique: Conservative Aortic Valve surgery for aortic Insufficiency and Aneurysm of the Aortic Root). METHODS: Of the 600 patients operated on with the CAVIAAR technique, 60 consecutive patients from a single team underwent double independent reading of the echocardiographic analysis performed in the operative period and yearly after discharge until a maximum of 5 year follow-up. Forty-four patients had preoperative aortic insufficiency (AI) >=grade 2 (73.3%) and 29 patients (48%) had bicuspid valves. RESULTS: The expansible aortic ring (median size 27 (25-27) mm) significantly reduced the aortic annular base diameter (from 28 (25-29) mm to 23 (21-24) mm) (P < 0.001) without a significant median transvalvular gradient increase (P = 0.545). Cusp repair was performed in 55 patients (91.7%). Operative mortality was 1.7% (1). During the median 19-month (95% confidential interval [11-26]) follow-up, annular diameter and cusp effective height remained stable. There were no valve-related reoperations. One patient died at 6 months postoperatively from congestive heart failure. Freedom from AI >=grade 2 was 100% at 1-year follow-up and 96.8% +/- 3.2% at 3-year follow-up. Systolic root expansibility of the four echocardiographic diameters (aortic annular base, sinuses of Valsalva level, sino tubular junction and tubular aorta) was maintained, throughout the follow-up period with the aortic annular base expansibility coefficient having consistently higher values than the three other levels. CONCLUSIONS: The expansible aortic ring achieved a complete calibrated external annuloplasty and maintained dynamics of the aortic root at mid-term follow-up. Whether this could be a factor for durability of aortic valve repair is currently under evaluation through the CAVIAAR study 10-year follow-up. PMID- 24755103 TI - Impact of right ventricular dysfunction on the outcome of heart failure patients undergoing surgical ventricular reconstruction?. AB - OBJECTIVES: The aim was to assess the impact of right ventricular dysfunction (RVD) on the outcome of heart failure (HF) patients undergoing surgical ventricular reconstruction (SVR). METHODS: A total of 324 patients (65 +/- 9 years) with previous myocardial infarction had an echocardiographic assessment of right ventricular (RV) function before and after SVR. RV function was assessed measuring the tricuspid annular plane systolic excursion (TAPSE) and RV dysfunction was defined by a TAPSE < 16 mm. RESULTS: RV dysfunction was detected in 69 patients (Group A, mean age 64 +/- 11 years), while 255 patients (Group B, mean age 65 +/- 9 years) had a preserved RV function. Patients in Group A showed a higher New York Heart Association (NYHA) class (P = 0.01), larger left ventricular (LV) end-diastolic and end-systolic volumes (P = 0.01), a lower EF (P = 0.01), a higher percentage of moderate-to-severe mitral regurgitation (P = 0.01) and a higher systolic pulmonary artery pressure (PAPs; P = 0.01). Propensity score matching was applied in order to adjust for baseline differences. In the fully matched population, low-output syndrome (P = 0.01), inotropic support (P = 0.01) and intra-aortic balloon pump insertion (P = 0.03) were significantly more frequent in Group A compared with Group B. However, 30 day mortality was not significantly different between the two groups (P = 0.18). Kaplan-Meier 5- and 8-year survival rate (log-rank: P = 0.01) as well as freedom from cardiac events (log-rank: P = 0.02) were significantly lower in patients with RV dysfunction. At Cox regression analysis, preoperative RVD (P = 0.01) and NYHA class at admission >II (P = 0.02) resulted in independent predictor of late mortality. CONCLUSIONS: RV dysfunction correlates with LV dysfunction and it is an important predictor of long-term outcome in HF patients undergoing SVR. PMID- 24755104 TI - Diffusion-weighted magnetic resonance imaging lesions after repair of acute type A aortic dissection: association with neurocognitive outcomes??. AB - OBJECTIVES: We sought to analyse the preoperative status of arch vessels by postoperative diffusion-weighted magnetic resonance imaging (DWI) as a potential surrogate marker for cerebral thromboembolism and its relationship to neurocognitive outcomes. METHODS: Preoperative computed tomography (CT) and postoperative DWI were available for 50 patients who received surgery for acute type A aortic dissection. Two radiologists evaluated CT and DWI scans. Mini mental status examinations (MMSE) were performed on the same day with DWI. RESULTS: Mean age of participants was 57 +/- 14 years. MMSE and DWI were performed 6 +/- 3 days after surgery. New cerebral embolisms were evident in 35 of 50 patients (70%) and often occurred as multiple lesions (28/35, 80%; range 2 21). Among patients with multiple lesions, 23 (66%) were clinically silent. Pathological lesions at the origin of the arch vessels correlated with the number and volume of new DWI lesions (P < 0.05). Degree of neurocognitive dysfunction tested by MMSE was negatively associated with age (r = -0.48, P < 0.0001) and left-sided DWI lesion number and volume (r = -0.74, P < 0.0001; r = -0.707, P < 0.0001). CONCLUSIONS: DWI revealed new cerebral embolisms in 70% of patients following surgery for acute type A aortic dissection. Lesion number and volume significantly correlated with pathological status of arch vessels. MMSE was representative of left-sided lesions. PMID- 24755105 TI - Activation of mTOR contributes to foam cell formation in the radial arteries of patients with end-stage renal disease. AB - BACKGROUND: Our previous in-vivo and in-vitro studies demonstrated that inflammation accelerated the progression of atherosclerosis via the dysregulation of the low-density lipoprotein receptor (LDLr) pathway. The current study aimed to investigate the effects and their underlying mechanisms of inflammation on lipid accumulation in the radial arteries of endstage renal disease (ESRD) patients with arteriovenostomy. METHODS: 30 ESRD patients with arteriovenostomy were included. The patients were divided into two groups based on their plasma levels of C-reactive protein: a control (n = 16) and an inflamed group (n = 14). The expression of tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein-1 of the radial arteries were increased in the inflamed group. Foam cell formation and lipid droplet accumulation were examined by hematoxylin and eosin (H & E) and Oil Red O staining. Intracellular cholesterol trafficking-related proteins were examined by immunohistochemistry and immunofluorescent staining. RESULTS: There was significant lipid accumulation in the radial arteries of the inflamed group compared with the control. Further analysis demonstrated that this accumulation was correlated with the increased protein expression of LDLr, sterol regulatory element-binding protein-2 (SREBP 2), and SREBP cleavageactivating protein (SCAP). Confocal microscopy showed that inflammation enhanced the translocation of SCAP escorting SREBP-2 from the endoplasmic reticulum to the Golgi, thereby activating LDLr gene transcription. Interestingly, upregulated LDLr expression was positively associated with the increased protein expression of mammalian target of rapamycin (mTOR), which had enhanced coexpression with SREBP-2. This finding suggests that the activation of mTOR may be involved in LDLr pathway disruption through the upregulation of SREBP 2 expression. CONCLUSION: Inflammation contributed to foam cell formation in the radial arteries of ESRD patients via the dysregulation of the LDLr pathway, which could be modulated by the activation of the mTOR pathway. PMID- 24755106 TI - Problem-solving therapy to improve depression scores among older hemodialysis patients: a pilot randomized trial. AB - AIMS: Depression is common among dialysis patients and is associated with adverse outcomes. Problem-solving therapy (PST) is effective for treating depression in older patients with chronic illness, but its effectiveness has never been reported in hemodialysis (HD) patients. We investigated the feasibility and satisfaction of PST and its impact on depression scores among older HD patients. METHODS: Patients at least 60 years of age receiving maintenance HD at a single outpatient dialysis center were eligible for the study. Randomized patients received either 6 weeks of PST from a licensed renal social worker or usual care. This study modeled the staff-patient ratio standard of most dialysis clinics, and therefore only one social worker provided the interventions. Study outcomes included feasibility (successful completion of 6 weekly sessions) and patient satisfaction with PST as well as impact on depression scores (between-group comparison of mean Beck depression inventory (BDI) and Patient health questionnaire-9 (PHQ-9) scores at 6 weeks, and of mean change-from-baseline scores). RESULTS: The recruitment rate was 92% (35/38). All subjects randomized to the intervention arm (n = 17) and who initiated PST (n = 15) completed the study, and all reported overall satisfaction with the intervention. 87% reported that PST helped them to better solve problems and improved their ability to cope with their medical condition. At 6 weeks, there were no significant differences in mean BDI and PHQ scores between the usual care and the intervention group (BDI 11.3 vs. 9.3, p = 0.6; PHQ 5.7 vs. 3.3, p = 0.1). Mean change-from-baseline depression scores were significantly improved in the intervention group relative to the control group (change in BDI 6.3 vs.- 0.6, p = 0.004; change in PHQ 7.2 vs. 0.3, p < 0.001). CONCLUSIONS: The results demonstrate that PST is feasible in the dialysis unit setting, acceptable to patients, and may positively impact depression among maintenance hemodialysis patients. PMID- 24755107 TI - Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis. AB - BACKGROUND: Sporotrichosis is a chronic subcutaneous mycosis of humans and animals, which is typically acquired by traumatic inoculation of plant material contaminated with Sporothrix propagules, or via animals, mainly felines. Sporothrix infections notably occur in outbreaks, with large epidemics currently taking place in southeastern Brazil and northeastern China. Pathogenic species include Sporothrix brasiliensis, Sporothrix schenckii s. str., Sporothrix globosa, and Sporothrix luriei, which exhibit differing geographical distribution, virulence, and resistance to antifungals. The phylogenetically remote species Sporothrix mexicana also shows a mild pathogenic potential. METHODS: We assessed a genetically diverse panel of 68 strains. Susceptibility profiles of medically important Sporothrix species were evaluated by measuring the MICs and MFCs for amphotericin B (AMB), fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), posaconazole (PCZ), flucytosine (5FC), and caspofungin (CAS). Haplotype networks were constructed to reveal interspecific divergences within clinical Sporothrix species to evaluate genetically deviant isolates. RESULTS: ITC and PCZ were moderately effective against S. brasiliensis (MIC90 = 2 and 2 MUg/mL, respectively) and S. schenckii (MIC90 = 4 and 2 MUg/mL, respectively). PCZ also showed low MICs against the rare species S. mexicana. 5FC, CAS, and FLC showed no antifungal activity against any Sporothrix species. The minimum fungicidal concentration ranged from 2 to >16 MUg/mL for AMB against S. brasiliensis and S. schenckii, while the MFC90 was >16 MUg/mL for ITC, VRC, and PCZ. CONCLUSION: Sporothrix species in general showed high degrees of resistance against antifungals. Evaluating a genetically diverse panel of strains revealed evidence of multidrug resistant phenotypes, underlining the need for molecular identification of etiologic agents to predict therapeutic outcome. PMID- 24755108 TI - High burden of malaria following scale-up of control interventions in Nchelenge District, Luapula Province, Zambia. AB - BACKGROUND: Malaria control interventions have been scaled-up in Zambia in conjunction with a malaria surveillance system. Although substantial progress has been achieved in reducing morbidity and mortality, national and local information demonstrated marked heterogeneity in the impact of malaria control across the country. This study reports the high burden of malaria in Nchelenge District, Luapula Province, Zambia from 2006 to 2012 after seven years of control measures. METHODS: Yearly aggregated information on cases of malaria, malaria deaths, use of malaria diagnostics, and malaria control interventions from 2006 to 2012 were obtained from the Nchelenge District Health Office. Trends in the number of malaria cases, methods of diagnosis, malaria positivity rate among pregnant women, and intervention coverage were analysed using descriptive statistics. RESULTS: Malaria prevalence remained high, increasing from 38% in 2006 to 53% in 2012. Increasing numbers of cases of severe malaria were reported until 2010. Intense seasonal malaria transmission was observed with seasonal declines in the number of cases between April and August, although malaria transmission continued throughout the year. Clinical diagnosis without accompanying confirmation declined from 95% in 2006 to 35% in 2012. Intervention coverage with long-lasting insecticide-treated nets and indoor residual spraying increased from 2006 to 2012. CONCLUSIONS: Despite high coverage with vector control interventions, the burden of malaria in Nchelenge District, Zambia remained high. The high parasite prevalence could accurately reflect the true burden, perhaps in part as a consequence of population movement, or improved access to care and case reporting. Quality information at fine spatial scales will be critical for targeting effective interventions and measurement of progress. PMID- 24755109 TI - Dexmedetomidine improves the histological and neurological outcomes 48 h after transient spinal ischemia in rats. AB - Dexmedetomidine, an alpha2 adrenoceptor agonist, provides neuroprotection against various cerebral ischemia models through its anti-apoptotic effects. Dexmedetomidine also improves paraplegia induced by intrathecal morphine after short-term spinal ischemia. However, there are no reports regarding dexmedetomidine's ability to provide neuroprotection solely against transient spinal ischemia. We investigated whether dexmedetomidine would provide spinal protection following transient spinal ischemia in rats. Adult male Sprague Dawley rats were randomly assigned to one of the following five groups: (1) intravenous infusion of 0.9% NaCl at the rate of 0.5 mL/h (control), (2) dexmedetomidine 0.1 ug/kg/h, (3) dexmedetomidine 1 ug/kg/h, (4) dexmedetomidine 10 ug/kg/h, or (5) intravenous infusion of 0.9% NaCl without spinal ischemia (sham). The rats received saline solution or dexmedetomidine from 30 min before spinal cord ischemia to 48 h after ischemia. Spinal cord ischemia was induced by intraaortic balloon occlusion combined with proximal arterial hypotension for 10 min. Ischemic injury was assessed by neurological deficit scores and the number of viable motor nerve cells in the anterior spinal cord at 48 h after reperfusion. Neurological deficit scores in the dexmedetomidine-treated rats were significantly lower than the scores in the control group at 24 and 48 h after ischemia (P<0.05). The number of viable motor nerve cells was significantly larger in the dexmedetomidine-treated rats than in the control rats (P<0.05), but the number of motor nerve cells in the dexmedetomidine group was significantly smaller than the sham group. Our results indicate that the continuous administration of dexmedetomidine improves neurological and histological outcomes 48 h after transient spinal ischemia in rats. PMID- 24755110 TI - Atrial arrhythmias after lung transplant: underlying mechanisms, risk factors, and prognosis. AB - BACKGROUND: Atrial arrhythmias (AAs) early after lung transplant are frequent and have a significant impact on morbidity and mortality. However, the pathogenesis of AAs after lung transplant remains incompletely understood. In this study we aimed to determine the prevalence of atrial fibrillation (AF) and other AAs, as well as risk factors, clinical outcomes and possible underlying mechanisms associated with AAs after lung transplant. METHODS: A retrospective analysis was performed on 382 patients who underwent lung transplantation from 2000 to 2010. A 12-lead electrocardiogram (ECG) was obtained and AAs classified as AF and other AAs (atrial flutter [AFL] and supraventricular tachycardia [SVT]). Multivariate logistic regression analysis was performed to determine predictors, and Kaplan Meier survival curves were constructed. RESULTS: The incidence of AAs was 25%; 17.8% developed AF and 7.6% other AAs (AFL/SVT). The major indication for transplant was idiopathic pulmonary fibrosis (IPF, 35%). Significant predictors of AF were as follows: age; IPF; left atrial enlargement; diastolic dysfunction; and history of coronary artery disease (CAD). Risk factors for other AAs (AFL/SVT) were: age; right ventricle dysfunction; right ventricular enlargement; and elevated right atrial pressure (RAP). One-year mortality was higher in the arrhythmia group (21.5% arrhythmia vs 15.7% no-arrhythmia group; p < 0.05). In addition, patients treated with anti-arrhythmic medications had higher mortality (p < 0.05). CONCLUSIONS: AAs are common after lung transplantation. Risk factors for developing either AF or other AAs (AFL/SVT) are different. The development of early AAs post-transplant is associated with prolonged post-operative stay and increased mortality. A rate-control strategy should be used as first-line therapy and anti-arrhythmic agents reserved for those patients who do not respond to the initial treatment. PMID- 24755111 TI - Alveolar epithelial cells undergo epithelial-mesenchymal transition in acute interstitial pneumonia: a case report. AB - BACKGROUND: Acute interstitial pneumonia is a rare interstitial lung disease that rapidly progresses to respiratory failure or death. Several studies showed that myofibroblast plays an important role in the evolution of diffuse alveolar damage, which is the typical feature of acute interstitial pneumonia. However, no evidence exists whether alveolar epithelial cells are an additional source of myofibroblasts via epithelial-mesenchymal transition in acute interstitial pneumonia. CASE PRESENTATION: In this report, we present a case of acute interstitial pneumonia in a previously healthy 28-year-old non-smoking woman. Chest high-resolution computed tomography scan showed bilateral and diffusely ground-glass opacification. The biopsy was performed on the fifth day of her hospitalization, and results showed manifestation of acute exudative phase of diffuse alveolar damage characterized by hyaline membrane formation. On the basis of the preliminary diagnosis of acute interstitial pneumonia, high-dose glucocorticoid was used. However, this drug showed poor clinical response and could improve the patient's symptoms only during the early phase. The patient eventually died of respiratory dysfunction. Histological findings in autopsy were consistent with the late form of acute interstitial pneumonia. CONCLUSIONS: The results in this study revealed that alveolar epithelial cells underwent epithelial-mesenchymal transition and may be an important origin of myofibroblasts in the progression of acute interstitial pneumonia. Conducting research on the transformation of alveolar epithelial cells into myofibroblasts in the lung tissue of patients with acute interstitial pneumonia may be beneficial for the treatment of this disease. However, to our knowledge, no research has been conducted on this topic. PMID- 24755112 TI - Role of season, temperature and humidity on the incidence of epistaxis in Alberta, Canada. AB - BACKGROUND: Classical dogma holds that epistaxis is more common in winter months but there is significant variability reported in the literature. No study has yet examined the effect of season, humidity and temperature on epistaxis in a location with as severe weather extremes as seen in Alberta, Canada. The objective of the study is to evaluate for an effect of these meteorological factors on the incidence of epistaxis in Alberta. METHOD: A retrospective review of consecutive adult patients presenting to the Emergency room (ER) in Edmonton and Calgary, Alberta over a three-year period was performed. Daily temperature and humidity data was recorded from the respective airports. Statistical analysis with Pearson's correlation coefficient was performed. RESULTS: 4315 patients presented during the study period. Mean daily temperatures ranged from a low of 40 degrees C to a high of +23 degrees C. A significant negative correlation was found for mean monthly temperature with epistaxis (Pearson's r = -0.835, p = 0.001). A significant correlation was also present for daily temperature and epistaxis presentation (Pearson's r = -0.55, p = 0.018, range 1.8 to 2.2 events/day). No correlation was identified with humidity and no significant seasonal variation was present. CONCLUSIONS: A negative correlation was found to exist for both daily and mean monthly temperature with rates of epistaxis. A seasonal variation was seen in Edmonton but not in Calgary. No correlation was found for humidity when compared to both presentation rates and admissions. PMID- 24755113 TI - Two-steps extraction of essential oil, polysaccharides and biphenyl cyclooctene lignans from Schisandra chinensis Baill fruits. AB - A method for two-steps extraction of essential oil, polysaccharides and lignans from Schisandra chinensis Baill had been established. Firstly, S. chinensis was extracted by hydro-distillation, the extracted solution was separated from the water-insoluble residue and precipitated by adding dehydrated alcohol after the essential oil was collected, and then the precipitate as polysaccharide was collected. Finally, second extraction was performed to obtained lignans from the water-insoluble residue with ultrasonic-microwave assisted extraction (UMAE) method. Response surface methodology was employed to optimize the UMAE parameters, the optimal conditions were as follows: microwave power 430W, ethanol concentration 84%, particle size of sample 120-mesh sieves, ratio of water to raw material 15 and extraction time 2.1min. Under these optimized conditions, the total extraction yields of five lignans (Schisandrol A, Schisantherin A, Deoxyschisandrin, Schisandrin B and Schisandrin C) had reached 14.22+/-0.135mg/g. Compared with the traditional method of direct extraction of different bioactive components in respective procedure, the extraction yields of polysaccharides and the five lignans had reached 99% and 95%, respectively. The mean recoveries of the 5 lignan compounds and polysaccharides were 97.75-101.08% and their RSD value was less than 3.88%.The approach proposed in this study not only improved the extraction yield of lignans, but also elevated the utilization of Schisandra resources. PMID- 24755114 TI - Ventriculoperitoneal shunt infection caused by Bifidobacterium breve. AB - Bifidobacterium breve is a rare cause of human infections. Previously, bacteremia and meningitis caused by this organism linked to probiotic use have been reported in a neonate. We report the first case of a ventriculoperitoneal shunt infection caused by B. breve in an adult without a history of probiotic use. PMID- 24755115 TI - Identification and characterization of transcript polymorphisms in soybean lines varying in oil composition and content. AB - BACKGROUND: Variation in seed oil composition and content among soybean varieties is largely attributed to differences in transcript sequences and/or transcript accumulation of oil production related genes in seeds. Discovery and analysis of sequence and expression variations in these genes will accelerate soybean oil quality improvement. RESULTS: In an effort to identify these variations, we sequenced the transcriptomes of soybean seeds from nine lines varying in oil composition and/or total oil content. Our results showed that 69,338 distinct transcripts from 32,885 annotated genes were expressed in seeds. A total of 8,037 transcript expression polymorphisms and 50,485 transcript sequence polymorphisms (48,792 SNPs and 1,693 small Indels) were identified among the lines. Effects of the transcript polymorphisms on their encoded protein sequences and functions were predicted. The studies also provided independent evidence that the lack of FAD2-1A gene activity and a non-synonymous SNP in the coding sequence of FAB2C caused elevated oleic acid and stearic acid levels in soybean lines M23 and FAM94 41, respectively. CONCLUSIONS: As a proof-of-concept, we developed an integrated RNA-seq and bioinformatics approach to identify and functionally annotate transcript polymorphisms, and demonstrated its high effectiveness for discovery of genetic and transcript variations that result in altered oil quality traits. The collection of transcript polymorphisms coupled with their predicted functional effects will be a valuable asset for further discovery of genes, gene variants, and functional markers to improve soybean oil quality. PMID- 24755116 TI - Highly conductive freestanding graphene films as anode current collectors for flexible lithium-ion batteries. AB - The electrodes in lithium-ion batteries (LIBs) are typically films that are arranged on metal foil current collectors with a thickness of several tens of MUm. Here, we report on the preparation of a thick free-standing graphene film synthesized by CVD as an alternative to Cu foil as an anode current collector. As a model system, MoS2 anodes with a flower-like morphology were anchored onto the surface of the thick graphene film. A hybrid and binder free anode without a conventional metal current collector exhibited an excellent capacity value of around 580 mAh/g (@50 mA/g) and reasonable charge/discharge cyclability. The work presented here may stimulate the use of graphene films as replacements for conventional current collectors and additive free electrode in LIBs. PMID- 24755117 TI - Nonsteroidal anti-inflammatory drugs and antihypertensives: how do they relate? AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available as over-the counter medications, despite their numerous side effects and drug interactions. The aim of this article is to increase awareness of the hypertensive potential of NSAIDs and their interference with antihypertensives. Patients with hypertension appear to be more susceptible than normotensive individuals to the blood pressure increasing effect of NSAIDs. Most studies have found that short-term use of NSAIDs does not pose a major risk for hypertension or increase in cardiovascular disease in healthy individuals. The calcium channel blockers and beta-blockers seem to be least affected by the concomitant use of NSAIDs. A dentist must weigh the benefits and disadvantages of using NSAIDs in patients taking antihypertensive drugs. For those who may be at greater risk, such as patients with hypertension and the elderly, careful selection of the class of NSAID and close monitoring are appropriate measures, especially if long-term use is anticipated. PMID- 24755118 TI - Molecular and serological surveillance of canine enteric viruses in stray dogs from Vila do Maio, Cape Verde. AB - BACKGROUND: Infections caused by canine parvovirus, canine distemper virus and canine coronavirus are an important cause of mortality and morbidity in dogs worldwide. Prior to this study, no information was available concerning the incidence and prevalence of these viruses in Cape Verde archipelago. RESULTS: To provide information regarding the health status of the canine population in Vila do Maio, Maio Island, Cape Verde, 53 rectal swabs were collected from 53 stray dogs during 2010 and 93 rectal swabs and 88 blood samples were collected from 125 stray dogs in 2011. All rectal swabs (2010 n = 53; 2011 n = 93) were analysed for the presence of canine parvovirus, canine distemper virus and canine coronavirus nucleic acids by quantitative PCR methods. Specific antibodies against canine distemper virus and canine parvovirus were also assessed (2011 n = 88).From the 2010 sampling, 43.3% (23/53) were positive for canine parvovirus DNA, 11.3% (6/53) for canine distemper virus RNA and 1.9% (1/53) for canine coronavirus RNA. In 2011, the prevalence values for canine parvovirus and canine coronavirus were quite similar to those from the previous year, respectively 44.1% (41/93), and 1.1% (1/93), but canine distemper virus was not detected in any of the samples analysed (0%, 0/93). Antibodies against canine parvovirus were detected in 71.6% (63/88) blood samples and the seroprevalence found for canine distemper virus was 51.1% (45/88). CONCLUSIONS: This study discloses the data obtained in a molecular and serological epidemiological surveillance carried out in urban populations of stray and domestic animals. Virus transmission and spreading occurs easily in large dog populations leading to high mortality rates particularly in unvaccinated susceptible animals. In addition, these animals can act as disease reservoirs for wild animal populations by occasional contact. Identification of susceptible wildlife of Maio Island is of upmost importance to evaluate the risk of pathogen spill over from domestic to wild animals in Cape Verde and to evaluate the associated threat to the wild susceptible species. PMID- 24755119 TI - Additive enhancement of apoptosis by TRAIL and fenretinide in metastatic breast cancer cells in vitro. AB - Successful management of metastatic breast cancer still needs better chemotherapeutic approaches. The combination of fenretinide (4-HPR), a synthetic retinoid inducing apoptosis by ROS generation, and TRAIL, a cell death ligand inducing caspase-dependent apoptosis, might result in more powerful cytotoxic activity. We therefore investigated the cytotoxic activity and resulting cell death mode of this combination in MDA-MB-231 cell line as a representative of metastatic state. Cytotoxicity was assessed by the ATP viability assay while the mode of cell death was determined both morphologically using fluorescence microscopy and biochemically using Western blotting and ELISA. The combination resulted in an additive cytotoxic effect at the doses used. Fragmented and/or pyknotic nuclei, which is a feature of apoptosis, were observed after treatment with fenretinide or TRAIL. However, the combinatorial treatment further increased apoptotic figures. Confirming apoptosis, active caspase-3 and cleaved PARP were increased by fenretinide or TRAIL in both western blotting and ELISA. Again, apoptosis was further increased by the combination. The combination warrants further studies due to its superior cytotoxic activity in the metastatic setting of breast cancer. PMID- 24755121 TI - A systematic review of outcome data for dermatofibrosarcoma protuberans with and without fibrosarcomatous change. AB - BACKGROUND: To our knowledge, no systematic review of dermatofibrosarcoma protuberans (DFSP) outcomes based on the presence or absence of fibrosarcomatous (FS) change has been performed. OBJECTIVE: We sought to compare available outcome data for DFSP versus DFSP-FS. METHODS: The literature was searched for DFSP and DFSP-FS reports with outcome data (local recurrence, metastasis, or death from disease). Chi-square tests were calculated to determine whether DFSP and DFSP-FS significantly differed in risk of local recurrence, metastasis, and death from disease. RESULTS: In all, 24 reports containing 1422 patients with DFSP and 225 with DFSP-FS are summarized. Risk of local recurrence, metastasis, and death from disease in DFSP-FS was significantly higher as compared with DFSP (local recurrence 29.8% vs 13.7%, risk ratio 2.2 [95% confidence interval 1.7-2.9]; metastasis 14.4% vs 1.1%, risk ratio 5.5 [95% confidence interval 4.3-7.0]; and death from disease 14.7% vs 0.8%, risk ratio 6.2 [95% confidence interval 5.0 7.8]). There was no significant difference in DFSP-FS outcomes based on proportion of FS change within tumors. LIMITATIONS: This study is based on previously reported data from different hospitals with no uniform process for reporting FS change. The impact of confounders (age, immune status, tumor location, treatment) could not be evaluated because of limited data. CONCLUSION: Based on available retrospective data, risk of metastasis and death is elevated in DFSP-FS as compared with DFSP. Even a low degree of FS involvement portends worse outcomes. PMID- 24755120 TI - Effect of high altitude exposure on the hemodynamics of the bidirectional Glenn physiology: modeling incremented pulmonary vascular resistance and heart rate. AB - The considerable blood mixing in the bidirectional Glenn (BDG) physiology further limits the capacity of the single working ventricle to pump enough oxygenated blood to the circulatory system. This condition is exacerbated under severe conditions such as physical activity or high altitude. In this study, the effect of high altitude exposure on hemodynamics and ventricular function of the BDG physiology is investigated. For this purpose, a mathematical approach based on a lumped parameter model was developed to model the BDG circulation. Catheterization data from 39 BDG patients at stabilized oxygen conditions was used to determine baseline flows and pressures for the model. The effect of high altitude exposure was modeled by increasing the pulmonary vascular resistance (PVR) and heart rate (HR) in increments up to 80% and 40%, respectively. The resulting differences in vascular flows, pressures and ventricular function parameters were analyzed. By simultaneously increasing PVR and HR, significant changes (p <0.05) were observed in cardiac index (11% increase at an 80% PVR and 40% HR increase) and pulmonary flow (26% decrease at an 80% PVR and 40% HR increase). Significant increase in mean systemic pressure (9%) was observed at 80% PVR (40% HR) increase. The results show that the poor ventricular function fails to overcome the increased preload and implied low oxygenation in BDG patients at higher altitudes, especially for those with high baseline PVRs. The presented mathematical model provides a framework to estimate the hemodynamic performance of BDG patients at different PVR increments. PMID- 24755122 TI - DNA copy number changes in tumors within the spectrum of cellular, atypical, and metastasizing fibrous histiocytoma. AB - BACKGROUND: Cutaneous fibrous histiocytoma (FH) is a common mesenchymal neoplasm. Metastasis is rare, disproportionately occurring among the aneurysmal, cellular, atypical, and deep variants. OBJECTIVE: We determined whether DNA copy number changes occurred in atypical FH (AFH), and whether they were similar to those in metastasizing FH (MetFH) and benign cellular FH (CFH). METHODS: Five primary tumors of MetFH were evaluated by array-based comparative genomic hybridization analysis, with tissue from local recurrences and lung metastases in 2 and 2 patients, respectively. Seven indolent AFH and 5 CFH were identified for comparison. RESULTS: Substantial differences between the groups were found both in the frequency of chromosomal aberrations (higher among MetFH and absent or solitary in CFH) and array-based comparative genomic hybridization profiles (frequent gains of 7 and 8q and losses of Xq in MetFH; recurrent losses of chromosomes 9 and 22 in AFH; isolated loss of 5q and gain in chromosome 20 in 2 CFH). Fatal MetFH cases (2 of 5 cases) exhibited the highest rate of chromosomal aberrations. LIMITATIONS: This study included a small sample size with a short term follow-up. CONCLUSIONS: Benign CFH, indolent AFH, and MetFH represent distinct biological entities within the spectrum of FH; array-based comparative genomic hybridization may be a tool in recognizing FH cases with metastatic potential and increasingly aggressive behavior. PMID- 24755123 TI - Linagliptin fixed-dose combination with metformin is bioequivalent to co administration of linagliptin and metformin as individual tablets. AB - OBJECTIVE: To demonstrate bioequivalence of linagliptin/metformin fixed-dose combination (FDC) tablets and the corresponding combination of individual tablets taken together, i.e., free-pill (FP) treatment. METHODS: Three dosing combinations were evaluated in three separate randomized studies: linagliptin 2.5 mg with 500 mg, 850 mg, or 1,000 mg metformin. These studies used a prospective, open-label, randomized, two-way crossover design to evaluate bioequivalence in healthy volunteers (n = 287). After an overnight fast, participants received an FDC tablet once, and on a separate visit received the corresponding FP treatment. The two possible treatment sequences (FDC/FP and FP/FDC) were randomly allocated to the participants. A washout period of 35 days separated the two study treatments. The primary endpoints were maximum plasma concentration (Cmax) of linagliptin and metformin, area under the plasma concentration time curve from 0 to 72 hours (AUC0-72) for linagliptin, and from 0 to infinity (AUC0-inf) for metformin. RESULTS: The 90% confidence intervals of the adjusted geometric mean ratios of Cmax and AUC (calculated as FDC/ FP) were within the bioequivalence acceptance limits of 80 - 125%. The number of participants reporting at least one adverse event following FDC treatments was comparable to, or less than, that following FP treatments. Evaluation of vital signs and clinical laboratory tests revealed no safety issues. CONCLUSIONS: FDC tablets of linagliptin and metformin are bioequivalent to individual tablets of respective dose strengths taken together. Both treatments were well tolerated. PMID- 24755124 TI - Effect of food and tablet-dissolution characteristics on the bioavailability of linagliptin fixed-dose combination with metformin: evidence from two randomized trials. AB - OBJECTIVE: The objectives of the studies reported here were to determine the relative bioavailability of linagliptin and metformin when administered in a fixed-dose combination (FDC) tablet with and without food, and to investigate the relative bioavailability of linagliptin and metformin FDC tablets from two treatment batches with different dissolution behavior. METHODS: These studies were open-label, single-dose, randomized, two-way crossover trials. After an overnight fast, healthy volunteers received an FDC tablet once (with/without food in the food-effect study; or from one of two batches with differing dissolution behavior in the tablet-dissolution study). On a separate visit, following a washout period of 35 days, participants received the alternative treatment. In the food-effect study the primary endpoints were maximum measured concentration in plasma (C(max)) for linagliptin and metformin, area under the plasma concentration-time curve from 0 to 72 hours (AUC(0-72)) for linagliptin and from 0 to infinity (AUC(0-inf)) for metformin. In the tablet-dissolution study the primary endpoints were Cmax for both analytes, AUC(0-72) for linagliptin, and from 0 to the time of the last quantifiable data point (AUC(0-t)) for metformin. RESULTS: The administration of the FDC tablet with food had no influence on the relative bioavailability of linagliptin and metformin with regard to the extent of exposure as determined by AUC(0-72) (linagliptin) and AUC(0-inf) (metformin) compared with FDC tablet administration while fasting. After food intake, peak plasma concentrations of linagliptin were slightly lowered (from 4.99 to 4.56 nmol L-1), but the 90% confidence interval (CI) of the geometric mean test/reference ratio was still located within the generally applied bioequivalence acceptance limits of 80 - 125%. The median time from dosing to the maximum concentration of linagliptin in plasma (t(max)) was similar under both conditions. Administration with food reduced the rate of absorption of metformin indicated by a prolongation in median tmax (from 2 to 4 hours) and a decrease in Cmax by ~ 18%. There were no notable differences between the two treatment groups with respect to safety and tolerability. In the tablet-dissolution study, bioequivalence was demonstrated between linagliptin/metformin FDC tablets with normal and slower dissolution characteristics. For both linagliptin and metformin, the 90% CI of all pharmacokinetic (PK) parameters were well within the bioequivalence acceptance limits of 80 - 125%. Tablets from both batches were well tolerated with no unexpected adverse events. CONCLUSIONS: Food did not have a relevant impact on the bioavailability of linagliptin from the FDC tablet. The effect of food on the metformin component was comparable to that previously demonstrated. Furthermore, differences in tablet-dissolution characteristics did not have an impact on the bioavailability of linagliptin or metformin from the FDC tablet. PMID- 24755125 TI - Absence of clinically relevant cardiovascular interaction upon add-on of mirabegron or tamsulosin to an established tamsulosin or mirabegron treatment in healthy middle-aged to elderly men. AB - OBJECTIVE: Tamsulosin and mirabegron may be used concomitantly in patients with lower urinary tract symptoms. Since alpha1-adrenoceptor antagonists are associated with cardiovascular side effects, potential pharmacokinetic and cardiovascular interactions were evaluated. MATERIALS AND METHODS: This was an open-label, randomized, 2-arm, 2-sequence study in 48 healthy men (24/arm) aged 44 - 72 years. In arm 1, subjects received single-dose tamsulosin hydrochloride modified release capsules (0.4 mg) alone and with steady-state mirabegron oral controlled absorption system tablets (100 mg once daily) in random sequence. In arm 2, subjects received single-dose mirabegron alone and with steady-state tamsulosin. Samples for mirabegron and tamsulosin plasma concentrations were collected. Blood pressure (BP) and pulse rate (PR) were measured and orthostatic stress tests were performed. RESULTS: Mirabegron increased tamsulosin C(max) to 159% (90% confidence interval (CI) 143 - 177%), AUC(infinity) to 161% (90% CI 149 - 173%), and t(1/2) to 116%. Tamsulosin reduced mirabegron C(max) to 85% (90% CI 71 - 103%) and AUC(infinity) to 84% (90% CI 74 - 95%) without effect on t1/2. Mirabegron and tamsulosin co-treatment caused no statistically significant changes (p > 0.05) in PR or systolic BP versus mono-treatment up to 12 hours post dose. Mean diastolic BP decreases of -2.1 (95% CI -4.1, -0.1) to -4.2 (-7.5, 0.9) mmHg in arm 1 and -3.0 (-5.7, -0.3) to -4.2 (-7.4, -1.0) mmHg in arm 2 were observed, statistically significant (p < 0.05) at several time points, not accompanied by orthostatic symptoms or increases in positive orthostatic stress tests. Adverse and orthostatic events were balanced across treatments. CONCLUSIONS: The observed pharmacokinetic interactions upon add-on of mirabegron or tamsulosin to existing tamsulosin or mirabegron therapy did not cause clinically relevant changes in cardiovascular safety or safety profiles. PMID- 24755126 TI - Warfarin compared with aspirin for older Chinese patients with stable coronary heart diseases and atrial fibrillation complications. AB - OBJECTIVE: To compare the therapeutic warfarin and aspirin efficacies for treatments of atrial fibrillation (AF) complicated with stable coronary heart disease particularly in older Chinese patients. METHODS: In our prospective study 101 patients with AF and stable coronary heart disease older than 80 years were randomized into two groups. One group (n = 51) basically received 1.25 mg/day warfarin per os, followed by addition of 0.5 - 1.0 mg/day from day 3 - 5 if the international normalized ratio (INR) was initially < 1.5 and in order to achieve a maintained INR between 1.6 and 2.5 (warfarin group). The second group (n = 50) received 100 mg aspirin per day (control group). All patients were medicated and monitored for a period of 2 years. The primary endpoint was the occurrence of ischemic stroke or systemic embolism, and the composite secondary endpoint was non-fatal myocardial infarction and all causes of death. For safety evaluation, the hemorrhage rates were recorded. RESULTS: The warfarin medication was superior regarding the overall occurrence of ischemic stroke or systemic embolism as well as non-fatal myocardial infarction and all causes of death outcomes compared to aspirin administration during the 2 years of medication (17.6% vs. 36.0%, p = 0.03), while there was no significant difference of mild (5 vs. 4), severe (2 vs. 1), and fatal (1 vs. 1) hemorrhage incidences between the warfarin and aspirin groups (p > 0.05). CONCLUSION: Warfarin was found to be more efficacious than aspirin for an anticoagulation therapy of older Chinese patients with AF and stable coronary heart disease. PMID- 24755127 TI - Integrating disease progression models, non-clinical pharmacokinetic data and treatment response endpoints to optimize intravitreal dosing regimens. AB - OBJECTIVE: To rapidly identify patients who will ultimately respond to 1 year of therapy, and optimize their inter dose interval. MATERIALS AND METHODS: An intravitreal (IVT) ophthalmic dosing paradigm was designed based on clinical efficacy, nonclinical pharmacokinetics (PK), and disease progression modeling. Relevant non-clinical PK models were used to extrapolate IVT drug concentrations to patients. RESULTS: Modeling predicted that > 80% of patients who would respond to 1 year of IVT treatment with an improvement in best-corrected visual acuity (BCVA) could be identified after the first 2 doses of treatment. These 2 initial doses produced ~ 75% of the maximum improvement in BCVA attainable. Moreover, the models also predicted those patients who responded after 1 year of treatment may tolerate an extension of the inter dose interval to 12 weeks without significant deterioration of BCVA. In contrast, > 70% of responsive patients who did not respond to 1 year of treatment showed inadequate responses after 2 doses. CONCLUSIONS: These models use data from 2 doses to identify those patients likely to benefit after 1 year of treatment, and thereafter can lengthen their inter dose interval without deleterious effects. This method identifies potential treatment responders early, and lengthens the inter dose interval during long term administration while allowing non-responders to pursue alternative therapies earlier, thereby minimizing risk to the patient. PMID- 24755128 TI - C5 variant is associated with decreased risk of coronary artery disease in outpatients with severe hypercholinesterasemia. AB - OBJECTIVE: Although the C5 variant of cholinesterase is known to be a cause of hypercholinesterasemia, the pathophysiological significance of the C5 variant and the C5 variant-related hypercholinesterasemia in cardiovascular diseases remain unclear. The present study aimed to clarify the pathophysiological significance of the C5 variant as a risk or protective factor for coronary artery disease (CAD) in patients with severe hypercholinesterasemia. METHODS: Severe hypercholinesterasemia was defined as serum cholinesterase (ChE) activity >= 450 IU/L (>= 2.0 SD). We screened 11,648 consecutive outpatients between 2005 and 2011 at Toho University, Sakura Medical Center. In patients with severe hypercholinesterasemia, phenotyping of the C5 variant was conducted using polyacrylamide gel electrophoresis and alpha-naphthyl butyrate staining. RESULTS: 157 subjects (1.4% of 11,648 outpatients screened) were diagnosed with severe hypercholinesterasemia (mean serum ChE activity 574 +/- 109 IU/L), and the frequency of the C5 variant was 45.2%. Subjects with the C5 variant had higher age, lower body mass index, milder dyslipidemia and liver dysfunction, and lower rates of hypertension and CAD compared with subjects without the C5 variant. Multivariate logistic regression model demonstrated that the presence of C5 variant independently lowered the risk of CAD, with odds ratio 0.071 (95% confidence interval (CI) 0.007 - 0.763, p = 0.029). CONCLUSION: The prevalence of the C5 variant was relatively high, and the C5 variant is associated with decreased risk of CAD in outpatients with severe hypercholinesterasemia. PMID- 24755129 TI - Pharmacokinetics, pharmacodynamics, and tolerability of single and multiple doses of ticagrelor in Japanese and Caucasian volunteers. AB - OBJECTIVES: Two studies assessing ticagrelor pharmacokinetics, pharmacodynamics, and tolerability in healthy Japanese and Caucasian volunteers. MATERIALS AND METHODS: Single-ascending dose (SAD) study: Japanese (n = 20) and Caucasians (n = 20) received single doses of ticagrelor (50, 100, 200, 300, 400, and 600 mg) or placebo. Multiple-ascending dose (MAD) study: Japanese (n = 36) and Caucasians (n = 36) received single doses of 100 mg or 300 mg ticagrelor (day 1), twice-daily 100 mg or 300 mg ticagrelor, or placebo (days 4 a?? 9), and single doses of 100 mg or 300 mg ticagrelor (day 10). RESULTS: Exposure to ticagrelor and its active metabolite, AR-C124910XX, was generally higher in Japanese vs. Caucasians. In the SAD study, area under the plasma concentration-time curve (AUC) values were 33% (ticagrelor) and 55% (AR-C124910XX) greater in Japanese vs. Caucasians following 600 mg ticagrelor. In the MAD study, AUC values of ticagrelor and AR-C124910XX following multiple doses of ticagrelor 100 mg and 300 mg were statistically significantly greater (33 - 48%) in Japanese vs. Caucasians. In both groups, mean peak inhibition of platelet aggregation was > 86% after single doses (>= 100 mg ticagrelor) and > 84% after multiple doses. Bleeding times were >= 60 minutes in more Japanese than Caucasians with multiple dosing of 100 mg and 300 mg ticagrelor Adverse events were similar between groups (mild-to-moderate intensity). CONCLUSIONS: The pharmacokinetics and tolerability of ticagrelor were broadly similar in Japanese and Caucasians, although exposure was slightly greater in Japanese volunteers. Ticagrelor was generally well tolerated. PMID- 24755130 TI - Flurbiprofen improves dysfunction of T-lymphocyte subsets and natural killer cells in cancer patients receiving post-operative morphine analgesia. AB - OBJECTIVE: Acute pain can lead to immune dysfunction, which can be partly ameliorated by successful pain management. Opioids, which are widely used for analgesia, can result in the deterioration of immune function. This study aimed to investigate the influence of morphine with or without flurbiprofen as post operative analgesics on the immune systems of patients undergoing gastric cancer surgery. METHODS: 60 patients undergoing gastric cancer surgery were equally randomized into two groups. They received post-operative patient-controlled intravenous (IV) analgesia using morphine either with or without flurbiprofen. Visual analogue scale (VAS) scores, Bruggemann comfort scale (BCS) scores, morphine consumption, time of first flatus, incidence of nausea/vomiting, and T lymphocyte subsets (CD3+, CD4+, and CD8+) and natural killer cells (CD3 CD16+CD56+) were evaluated. RESULTS: No significant difference was observed in the VAS scores, BCS scores, and nausea/vomiting incidence between groups. Less morphine was consumed and the time of first flatus was earlier in patients receiving morphine with flurbiprofen than morphine alone. The expression of CD3+, CD4+, CD4+/CD8+, and CD3-CD16+CD56+ decreased at 2 hours after incision and, except for CD3-CD16+CD56+, returned to baseline at 120 hours after surgery. Moreover, the expression of CD3-CD16+CD56+ at 2 hours after incision and the expression of CD3+, CD4+, CD4+/CD8+, and CD3-CD16+CD56+ at 24 hours after surgery were higher in patients receiving morphine with flurbiprofen than morphine alone. CONCLUSION: The combination of morphine and flurbiprofen ameliorates the immune depression in Tlymphocyte subsets and natural killer cells and provides a similar analgesic efficacy to morphine alone in patients undergoing gastric cancer surgery. PMID- 24755131 TI - Prolonged profound hypotension complicating severe methyldopa overdose. AB - OBJECTIVE: Methyldopa, a centrally acting antihypertensive drug, has been in use since the 1960s, but reports of (severe) overdose are rare. We present a case of severe methyldopa overdose with prolonged profound hypotension. CASE SUMMARY: A 50-year-old woman developed sinus bradycardia, prolonged profound hypotension, and drowsiness after ingesting over 300 tablets (> 75 g) of methyldopa. At presentation, her blood pressure was 59/27 mmHg, heart rate 49 beats/minute, and Glasgow Coma Scale Score 14. She needed intensive care unit (ICU) care and intravenous infusion of a large amount of fluids and GelofusineA(r), injections of ephedrine sulphate, and intravenous infusion of norepinephrine for 41 hours followed by dopamine for 21 hours to maintain her systolic blood pressure at ~ 100 mmHg. She was observed for 3 more days in the general ward before discharge. CONCLUSION: Severe methyldopa overdose can be complicated by prolonged profound hypotension. The management of these patients should include close monitoring of vital functions and administration of intravenous fluids, colloids, and vasopressor agents. PMID- 24755132 TI - Bioequivalence study of two commercial amoxicillin suspension formulations in healthy human volunteers. AB - PURPOSE: To compare the pharmacokinetic profiles and to evaluate the bioequivalence of two commercial amoxicillin suspension formulations (500 mg/5 mL AMOXIL(r), reference formulation and AMOXI-PED(r), test formulation) in healthy Brazilian volunteers. METHODS: Under fasting condition, 25 volunteers (13 males and 12 females) were included in this randomized, open-label, two-period crossover (1-week washout interval) bioequivalence study. Blood samples were collected at pre-dose (0 hour) and 0.5, 1, 1.33, 1.66, 2, 2.5, 3, 4, 6, 8, and 12 hours after drug ingestion. Pharmacokinetic parameters (Cmax, tmax, t1/2, AUC0 tlast, and AUC0-infinity) were calculated from plasma concentrations for both formulations in each subject. RESULTS: Arithmetic mean values of the pharmacokinetic parameters were: Cmax = 12.004 (+/- 2.824) MUg*mL-1; tmax = 1.118 (+/- 0.396) h; t1/2 = 1.226 (+/- 0.179) h; AUC0-tlast = 29.297 (+/- 6.007) MUg*h*mL-1; and AUC0-infinity = 29.299 (+/- 6.007) MUg*h*mL-1 for reference formulation and Cmax = 11.456 (+/- 2.825) MUg*mL-1; tmax = 1.331 (+/- 0.509) h; t1/2 = 1.141 (+/- 0.133) h; AUC0-tlast = 28.672 (+/- 5.778) MUg*h*mL-1; and AUC0 infinity = 28.693 (+/- 5.796) MUg*h*mL-1 for test formulation. The confidence intervals (90% CI) for reference and test formulations were, respectively, 90.74 100.46% for Cmax and 93.62 - 103.61% for AUC0-t. CONCLUSION: Based on the results, both formulations of amoxicillin evaluated in this study were considered bioequivalent according to FDA and ANVISA/Brazil criteria. PMID- 24755133 TI - Lower-dose warfarin delays renal progression and prolongs patient survival in patients with stage 3 - 5 chronic kidney disease and nonvalvular atrial fibrillation: a 12-year follow-up study. AB - BACKGROUND: Anticoagulants are used to reduce the risk of stroke in patients with atrial fibrillation (Af) and chronic kidney disease (CKD). Warfarin is one of the commonly used anticoagulants; however, its effect on renal function remains unclear. METHODS: In a retrospective cohort study (January 2001 - July 2013), we surveyed data charts from 2,450 patients with stage 3 - 5 CKD, and enrolled 159 patients with Af. In total, 104 patients had a CHADS2 score of >= 2 (congestive heart failure, hypertension, >= 75 years old, diabetes, 1 point; prior stroke or transient ischemic attack or thromboembolism, 2 points). These patients were categorized into groups A and B based on warfarin treatment. Group A included 73 patients and was not undergoing warfarin treatment and group B included 31 patients undergoing warfarin treatment. The baseline demographic and biochemical data as well as changes in estimated glomerular filtration rate (eGFR) after 6, 12, and 18 months of warfarin treatment were analyzed. We also studied censored patient survival over 12 years using Kaplan-Meier model. RESULTS: The mean international normalization ratio (INR) of warfarin treatment in group B was 1.92 +/- 1.04. Moreover, group B showed a significant increase in eGFR. The maximum improvement was at 6 months (mean eGFR increased from 25.97 to 31.12 mL/min; p = 0.01) and lasted for up to 18 months (eGFR 28.65 mL/min). Despite higher initial CHADS2 scores, group B showed a superior survival rate compared with group A (p = 0.02). CONCLUSION: Lower doses of warfarin may protect against renal dysfunction and could be beneficial for treatment of stage 3 - 5 CKD with Af. PMID- 24755134 TI - Why did the FDA approve efavirenz 800 mg when co-administered with rifampin? AB - OBJECTIVES: Literature reports regarding the efficacy of efavirenz (EFV) 600 mg with rifampin (RIF) are not consistent. Evaluation of a drug-drug interaction (DDI) study and supportive semi-mechanistic population pharmacokinetic (PK) analyses were undertaken to help delineate this issue. DESIGN/METHODS: DDI study and supportive semi-mechanistic population PK analyses were provided by BMS. Population PK analysis was based on six studies with intensive EFV PK sampling. An ACTG study with sparse PK sampling was used for model evaluation. Simulations compared EFV exposure at various doses in combination with RIF to EFV exposures at 600 mg once daily (QD). Effects of CYP2B6 genotypes on the magnitude of EFV RIF interaction were also explored. RESULTS: In DDI study, co-administering EFV 600 mg QD and RIF reduced mean EFV exposure by ~ 30%. Population PK model provided acceptable predictive performance of central tendency and variability for EFV C0, Cmax, and AUC. Simulations predicted that increasing EFV to 800 mg QD with RIF would result in EFV AUC and Cmax similar to EFV 600 mg QD alone. EFV AUC and Cmax were ~ 2 times higher in subjects with reduced function CYP2B6 genotypes. However, the RIF effect was consistent across all genotypes. EFV dose adjustment to 800 mg QD did not increase the risk of overexposure compared to 600 mg EFV QD within each genotype. CONCLUSION: Dose adjustment based on matching systemic exposure was recommended to mitigate the potential for sub-therapeutic EFV exposures. Our review did not reveal any safety concerns in subjects receiving EFV 800 mg QD with RIF. PMID- 24755135 TI - A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development. AB - OBJECTIVE: To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy. MATERIALS: Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 a?? 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 A? daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated. RESULTS: 60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling "drunk", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance. CONCLUSIONS: Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA. PMID- 24755136 TI - The effect of experimentally induced sleep disturbance on the pharmacokinetics of lorazepam in healthy volunteers. AB - The aim of this study was to evaluate the effect of sleep disturbance on the pharmacokinetics, especially on the absorption, of lorazepam in humans. Eight healthy male volunteers received a single oral dose of lorazepam 1 mg before sleep on two occasions in a cross-over design. In either of the two doses, subjects were intermittently exposed to noise for 1.5 hours after oral lorazepam administration. Plasma lorazepam concentrations were measured by HPLC. The exposure to noise significantly prolonged tmax (control vs. noise: 2.0 vs. 3.0 hours) and significantly decreased AUC of lorazepam in the absorption phase. The reduction was 54% (95% CI, 15 - 75%) and 24% (3 - 40%) for AUC (0 - 1 hours) and AUC (0 - 3 hours), respectively. No significant changes were observed in other pharmacokinetic parameters. The results of this study suggest that the onset of drug action after oral lorazepam administration can be altered by sleep disturbance. PMID- 24755137 TI - Tacrolimus reversibly reduces insulin secretion, induces insulin resistance, and causes islet cell damage in rats. AB - OBJECTIVE: To investigate the diabetogenic effects of the immunosuppressive agent tacrolimus, the reversibility of these effects upon treatment discontinuation, and the underlying mechanisms in a rat model. MATERIALS AND METHODS: 60 healthy male rats were randomly divided into three groups for intragastric administration of tacrolimus either at 4 mg/kg/d or 2 mg/kg/d or an equal volume of normal saline (control). The treatment was administered for 5 months, followed by a 5 month period of no intervention. Fasting plasma glucose and insulin levels were used to calculate the homeostasis model assessment of beta-cell function (HOMA beta) and insulin sensitivity index (ISI). RESULTS: Tacrolimus treatment significantly increased blood glucose concentrations (p < 0.05) and lowered HOMA beta and ISI (p < 0.01) in a time- and dose-dependent manner. Five months after tacrolimus treatment, significant islet cell injury was observed. However, 5 months after tacrolimus discontinuation, blood glucose concentrations significantly declined, HOMA-I2 and ISI levels significantly increased, and islet cell morphology noticeably improved. CONCLUSIONS: In conclusion, tacrolimus treatment of healthy rats increased blood glucose concentrations in a time- and concentration-dependent manner. Development of tacrolimus-induced diabetes and reversibility after tacrolimus discontinuation may involve factors of and interactions between the insulin secretion pathway, local and/or systemic insulin resistance, and islet cell damage. PMID- 24755138 TI - Postoperative meningitis after spinal surgery: a review of 21 cases from 20,178 patients. AB - BACKGROUND: Postoperative bacterial meningitis is a rare complication of spinal surgery and is considered to be a complication related to intraoperative incidental durotomy. A high index of suspicion for meningitis is essential in patients who have the clinical triad of fever, neck stiffness and consciousness disturbance during the postoperative period. A delay in diagnosis or treatment can lead to morbidity and mortality. Due to the low incidence of postoperative meningitis, very few studies have reported this complication. The purpose of this study was to report the clinical features, laboratory evaluations, treatment course and prognosis of 21 patients with post spinal surgery meningitis. METHODS: We retrospectively reviewed 21 patients (13 male, 8 female) with the diagnosis of postoperative meningitis after lumbar spinal surgery between January 2001 and Aug 2011. The median age of the patients was 67 years old (range 27 to 82 years) at the time of surgery. We recorded the preoperative diagnosis, operative methods, amount of drainage, clinical manifestations, laboratory evaluations, cerebrospinal fluid study, and infectious organisms. All patients diagnosed with postoperative meningitis received at least two weeks of antibiotic treatment. Clinical outcomes were assessed after at least two years of follow-up. RESULTS: From January 2001 to August 2011, 20,178 spinal operations were performed in our institution, and 21 patients (0.10%) were diagnosed with postoperative meningitis. Eighteen patients (85.7%) had fever, 19 (90.5%) had neck stiffness, and 16 (76.2%) had consciousness disturbance. All patients had at least two of the classic triad. In addition, 9 patients (42.9%) had headache, 3 (14.3%) had focal neurological deficits, and 2 (9.5%) had seizure attacks. There was no mortality in this series. Postoperative meningitis showed no adverse effect on the results of spinal surgery after follow-up for at least two years. CONCLUSIONS: Postoperative meningitis is a rare complication after spinal lumbar surgery. A high index of suspicion for meningitis should be maintained in patients with the clinical triad of fever, neck stiffness, and consciousness disturbance after spinal surgery. Intraoperative incidental durotomy is the most important predictor. An early diagnosis and appropriate antibiotic treatment can lead to a good outcome. PMID- 24755139 TI - Dietary supplementation with rice bran fermented with Lentinus edodes increases interferon-gamma activity without causing adverse effects: a randomized, double blind, placebo-controlled, parallel-group study. AB - BACKGROUND: The purpose of this study was to investigate the hypothesis that dietary supplementation with rice bran fermented with Lentinus edodes (rice bran exo-biopolymer, RBEP), a substance known to contain arabinoxylan, enhances natural killer (NK) cell activity and modulates cytokine production in healthy adults. METHODS: This study was designed in a randomized, double-blind, placebo controlled, and parallel-group format. Eighty healthy participants with white blood cell counts of 4,000-8,000 cells/MUL were randomly assigned to take six capsules per day of either 3 g RBEP or 3 g placebo for 8 weeks. Three participants in the placebo group were excluded after initiation of the protocol; no severe adverse effects from RBEP supplementation were reported. NK cell activity of peripheral blood mononuclear cells was measured using nonradioactive cytotoxicity assay kits and serum cytokine concentrations included interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, IL-10, and IL-12 were measured by Bio-Plex cytokine assay kit. This study was registered with the Clinical Research Information Service (KCT0000536). RESULTS: Supplementation of RBEP significantly increased IFN-gamma production compared with the placebo group (P = 0.012). However, RBEP supplementation did not affect either NK cell activity or cytokine levels, including IL-2, IL-4, IL-10, IL-12, and TNF-alpha, compared with the placebo group. CONCLUSIONS: The data obtained in this study indicate that RBEP supplementation increases IFN-gamma secretion without causing significant adverse effects, and thus may be beneficial to healthy individuals. This new rice bran-derived product may therefore be potentially useful to include in the formulation of solid and liquid foods designed for treatment and prevention of pathological states associated with defective immune responses. PMID- 24755140 TI - Parents as moderators of longitudinal associations between sexual peer norms and Dutch adolescents' sexual initiation and intention. AB - PURPOSE: The present study investigated how parents and peers interact in promoting or delaying Dutch adolescents' sexual initiation and intention and focused specifically on parents as moderators of peer influence. METHODS: Using a longitudinal design, two waves of online questionnaire data were collected among 900 Dutch adolescents (M = 13.8 years at T1), who were sexually inexperienced at baseline. At T1, participants reported on three types of perceived sexual peer norms: friends' sexual behaviors (descriptive norms), friends' sexual attitudes (injunctive norms), and experienced peer pressure to have sex. They also rated two parenting aspects at T1: the general quality of their relationship with parents and the frequency of sexuality-specific communication with their parents. Six months later, the participants reported on their experience with different sexual behaviors ranging from naked touching or caressing to intercourse and their intention to have sex in the next school year. RESULTS: Relationship quality with parents was significantly associated with both outcomes, with a higher relationship quality predicting smaller odds of sexual initiation and less intention to have sex. Two significant interaction effects showed that frequent sexual communication with parents significantly reduced the effects of sexually active friends and experienced peer pressure on adolescents' intention to have sex. CONCLUSIONS: Our findings show that different types of sexual peer norms and both general and sexuality-specific parenting play an important role in the early stages of Dutch adolescents' sexual trajectories. Moreover, parent-adolescent communication about sexuality can function as a buffer for the sex-stimulating effects of sexual peer norms. PMID- 24755141 TI - Predictors of co-occurring risk behavior trajectories among economically disadvantaged African-American youth: contextual and individual factors. AB - PURPOSE: African-American youth, particularly those from low-income backgrounds, evidence high rates of negative outcomes associated with three problem behaviors, conduct problems, risky sexual behavior, and substance use. This study used a contextually tailored version of problem behavior theory (PBT) to examine predictors of the simultaneous development of problem behaviors in this specific cultural group. METHODS: Sociocontextual and individual variables representing four PBT predictor categories, controls protection, support protection, models risk, and vulnerability risk, were examined as predictors of co-occurring problem behaviors among economically disadvantaged African-American adolescents (n = 949). Specifically, the likelihood of following three classes of multiple problem behavior trajectories spanning ages 12-18, labeled the "early experimenters," "increasing high risk-takers," and "adolescent-limited" classes, as opposed to a "normative" class, was examined. RESULTS: Among other findings, controls protection in the form of a more stringent household curfew at age 12 was related to a lower likelihood of being in the "early experimenters" and "increasing high risk-takers" classes. Conversely, vulnerability risk manifested as stronger attitudes of violence inevitability was associated with a higher likelihood of being in the "early experimenters" class. However, the PBT category of support protection was not associated with risk trajectory class. More distal neighborhood-level manifestations of PBT categories also did not predict co occurring behavior problems. CONCLUSION: Guided by an incorporation of contextually salient processes into PBT, prevention programs aiming to decrease co-occurring problem behaviors among low-income African-American adolescents would do well to target both proximal systems and psychological constructs related to perceived security throughout adolescence. PMID- 24755142 TI - In-situ electrochemical transmission electron microscopy for battery research. AB - The recent development of in-situ liquid stages for (scanning) transmission electron microscopes now makes it possible for us to study the details of electrochemical processes under operando conditions. As electrochemical processes are complex, care must be taken to calibrate the system before any in situ/operando observations. In addition, as the electron beam can cause effects that look similar to electrochemical processes at the electrolyte/electrode interface, an understanding of the role of the electron beam in modifying the operando observations must also be understood. In this paper we describe the design, assembly, and operation of an in-situ electrochemical cell, paying particular attention to the method for controlling and quantifying the experimental parameters. The use of this system is then demonstrated for the lithiation/delithiation of silicon nanowires. PMID- 24755143 TI - Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel. AB - Chlorpromazine (CPZ) is a well-known antipsychotic drug, still widely being used to treat symptoms of schizophrenia, psychotic depression and organic psychoses. We have previously reported that CPZ activates the BKCa (KCa1.1) channel at whole cell level. In the present study, we demonstrated that CPZ increased the single channel open probability of the BKCa channels without changing its single channel amplitude. As BKCa channel is one of the molecular targets of brain ischemia, we explored a possible new use of this old drug on ischemic brain injury. In middle cerebral artery occlusion (MCAO) focal cerebral ischemia, a single intraperitoneal injection of CPZ at several dosages (5mg/kg, 10mg/kg and 20mg/kg) could exert a significant neuroprotective effect on the brain damage in a dose- and time-dependent manner. Furthermore, blockade of BKCa channels abolished the neuroprotective effect of CPZ on MCAO, suggesting that the effect of CPZ is mediated by activation of the BKCa channel. These results demonstrate that CPZ could reduce focal cerebral ischemic damage through activating BKCa channels and merits exploration as a potential therapeutic agent for treating ischemic stroke. PMID- 24755144 TI - Cardiovascular stimulant actions of bupropion in comparison to cocaine in the rat. AB - Stimulants are banned in competition by the World Anti-Doping Agency, except for a small number of therapeutic agents subject to monitoring, including bupropion. We have examined the potency of bupropion in comparison with two agents banned in competition, adrafinil and modafinil, and with cocaine and desipramine as blockers of the noradrenaline re-uptake transporter in peripheral tissues of the rat. For studies in vivo, the pressor response to noradrenaline in the anaesthetized rat was studied. Cocaine, desipramine and bupropion at doses of 0.1, 0.3 and 1mg/kg, respectively, significantly increased the pressor response to noradrenaline. Overall, cocaine and desipramine were approximately 2-5 times more potent than bupropion in vivo in the rat. Adrafinil and modafinil (both 3mg/kg) did not significantly affect the pressor response. Bupropion was chosen for further study. In 1Hz paced rat right ventricular strips, bupropion (30MUM) significantly increased the potency of noradrenaline at increasing the force of contraction. In rat vas deferens, bupropion and cocaine produced concentration dependent increases in the contractile response to nerve stimulation, and cocaine was 11 times more potent than bupropion. Since bupropion is used clinically in doses of up to 300mg, it is likely that bupropion has actions at the noradrenaline transporter, and thus cardiovascular stimulant actions, in clinical doses. This may explain findings of increased exercise performance with bupropion. PMID- 24755145 TI - Attenuation of collagen induced arthritis via suppression on Th17 response by activating cholinergic anti-inflammatory pathway with nicotine. AB - The cholinergic anti-inflammatory pathway can inhibit the inflammation of collagen induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA). However, the immunologic mechanisms that provide a therapeutic effect against the auto-inflammatory disease are not yet elucidated. The present study explores the effect of cholinergic anti-inflammatory pathway on CD4+ T cell responses in CIA. Forty DBA/1 mice were divided into 4 groups: a control group, a CIA group, a vagotomy group, and a nicotine group. The degree of arthritis was measured by arthritis score and hematoxylin and eosin. ELISA was used to detect the serum concentration of IFN-gamma, IL-4 and IL-17A. Flow cytometry was used to detect the cytokines and transcription factors (TFs) (the TFs of Th1, Th2, and Th17 cells are T-bet, RORgammatau and GATA3 respectively) in the spleen. Immunohistochemistry was used to analyze RORgammatau expression in the joint synovium. Arthritis in the nicotine group was significantly lightened compared with that in the CIA group and in the vagotomy group. Nicotine attenuated Th17 lineage by reducing IL-17A production and RORgammatau expression. The expressions of IL-4 and GATA3 were increased in the same setting. However, the expressions of IFN-gamma and T-bet had no difference between the nicotine and the CIA group. Nicotine may induce a shift to the Th2 lineage and improve the Th1/Th2 imbalance. Activating the cholinergic anti-inflammatory pathway with nicotine can inhibit Th17 cell responses and may improve the Th1/Th2 imbalance in CIA, providing a new justification for its application in the treatment of rheumatoid arthritis. PMID- 24755146 TI - Dioscin induced activation of p38 MAPK and JNK via mitochondrial pathway in HL-60 cell line. AB - Saponins have shown promise in cancer prevention and therapy; however, little is known about the detailed signaling pathways underlying their anticancer activities. In the present study, we examined the mechanisms of action of dioscin, a glucosides saponin isolated from Polygonatum zanlanscianense pump, in human myeloblast leukemia HL-60 cells. Dioscin suppressed HL-60 cell growth in a dose-dependent manner. This inhibition was due to the induction of apoptosis as revealed by the externalization of phosphatidylserine, and cleavages of lamin A/C and PARP-1. Treatment with dioscin induced apoptosis through activation of caspases 3, 7, 8, 9, and 10. Phosphorylation of p38 MAPK and JNK contributed to dioscin-induced apoptosis upstream of caspase activation. Using various inhibitors and antioxidant agents, we found that mitochondrial derived reactive oxygen species and depletion of mitochondrial transmembrane potential lead to the phosphorylation of p38 MAPK and JNK. Taken together, our results demonstrated that dioscin induces apoptosis by activation of p38 MAPK and JNK through the caspase-dependent mitochondrial death pathway. This work suggests that dioscin may be used as a drug lead for the treatment of myeloblast leukemia. PMID- 24755147 TI - Bisphenol A increases atherosclerosis in pregnane X receptor-humanized ApoE deficient mice. AB - BACKGROUND: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA has recently been associated with increased risk of cardiovascular disease (CVD) in multiple large-scale human population studies, but the underlying mechanisms remain elusive. We previously reported that BPA activates the pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism and has pro-atherogenic effects in animal models upon activation. Interestingly, BPA is a potent agonist of human PXR but does not activate mouse or rat PXR signaling, which confounds the use of rodent models to evaluate mechanisms of BPA-mediated CVD risk. This study aimed to investigate the atherogenic mechanism of BPA using a PXR-humanized mouse model. METHODS AND RESULTS: A PXR-humanized ApoE deficient (huPXR*ApoE(-/-)) mouse line was generated that respond to human PXR ligands and feeding studies were performed to determine the effects of BPA exposure on atherosclerosis development. Exposure to BPA significantly increased atherosclerotic lesion area in the aortic root and brachiocephalic artery of huPXR*ApoE(-/-) mice by 104% (P<0.001) and 120% (P<0.05), respectively. By contrast, BPA did not affect atherosclerosis development in the control littermates without human PXR. BPA exposure did not affect plasma lipid levels but increased CD36 expression and lipid accumulation in macrophages of huPXR*ApoE(-/-) mice. CONCLUSION: These findings identify a molecular mechanism that could link BPA exposure to increased risk of CVD in exposed individuals. PXR is therefore a relevant target for future risk assessment of BPA and related environmental chemicals in humans. PMID- 24755148 TI - Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial. AB - BACKGROUND: Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons. METHODS AND RESULTS: TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger-stick point-of-care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non-central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower-risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non-major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values. CONCLUSIONS: The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR. PMID- 24755149 TI - Outcomes of out-of-hospital cardiac arrest by public location in the public access defibrillation era. AB - BACKGROUND: The strategy to place public-access automated external defibrillators (AEDs) has not yet been established in real settings. METHODS AND RESULTS: This, prospective, population-based observational study in Osaka, Japan, included consecutive out-of-hospital cardiac arrest (OHCA) patients with resuscitation attempts during 7 years, from January 2005 through December 2011. The trends in the proportion of public-access AED use and 1-month survival with neurologically favorable outcome were evaluated by location. Factors associated with neurologically favorable outcome (defined as cerebral performance category 1 or 2) after ventricular fibrillation were also assessed using multiple logistic regression analysis. A total of 9453 bystander-witnessed OHCAs of cardiac origin were documented and 894 (9.5%) of them occurred at public places. The proportion of public-access AED use significantly increased from 0.0% (0/20) in 2005 to 41.2% (7/17) in 2011 at railway stations and from 0.0% (0/7) to 56.5% (13/23) at sports facilities. Mean time from collapse to shock was 5.0 minutes among those who received shocks with public-access AEDs. The proportion of neurologically favorable outcome was 28.0% (33/118) at railway stations, 51.6% (48/93) at sports facilities, 23.3% (20/86) in public buildings, and 41.9% (13/31) in schools. In multivariate analysis, early defibrillation, irrespective of bystander or emergency medical service (EMS) personnel, was significantly associated with neurologically favorable outcome (adjusted odds ratio for 1-minute increment, 0.89; 95% confidence interval, 0.87 to 0.92). CONCLUSIONS: This large, population based OHCA registry demonstrated that earlier shock, irrespective the shock provider (bystander or EMS personnel), contributed to improving outcome, and a public-access defibrillation program was successfully implemented so that shocks with public-access AEDs were delivered to over 40% of bystander-witnessed OHCAs and time to shock was shortened in some kinds of public places. PMID- 24755150 TI - Association of physical activity in childhood and early adulthood with carotid artery elasticity 21 years later: the cardiovascular risk in Young Finns Study. AB - BACKGROUND: Decreased arterial elasticity is a risk factor for several cardiovascular outcomes. Longitudinal data on the effect of physical activity in youth on adult arterial elasticity are limited. The aim of this study was to determine the long-term effects of physical activity in children and young adults on carotid artery elasticity after 21 years of follow-up. METHODS AND RESULTS: Participants were 1417 children (aged 9 to 15 years) and 999 young adults (aged 18 to 24 years) from the prospective Cardiovascular Risk in Young Finns Study. Participants had questionnaire measures of leisure-time physical activity available from 1986 and ultrasound-derived indices of carotid artery elasticity measured in 2007. Carotid artery elasticity indices were distensibility (%/10 mm Hg), Young's elastic modulus (kPa), and stiffness index (unitless). Physical activity at age 18 to 24 years was directly associated with distensibility (beta=0.068, P=0.014) and inversely with Young's elastic modulus (beta=-0.057, P=0.0037) and indirectly with stiffness index (beta=-0.050, P=0.0028) 21 years later in males and females. The associations remained after adjustment for age, sex, body mass index, smoking, systolic blood pressure, serum lipids and insulin, and 21-year change in physical activity. At age 9 to 15 years, the favorable association, remaining after adjustment, was found in males (distensibility [beta=0.097, P=0.010], Young's elastic modulus [beta=-0.060, P=0.028], and stiffness index [beta=-0.062, P=0.007]) but not in females (P=0.70, P=0.85, and P=0.91, respectively). CONCLUSIONS: Leisure-time physical activity in boys and young adults is associated with carotid artery elasticity later in life, suggesting that higher levels of physical activity in youth may benefit future cardiovascular health. PMID- 24755152 TI - CD3 antibody and IL-2 complex combination therapy inhibits atherosclerosis by augmenting a regulatory immune response. AB - BACKGROUND: Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti-CD3 antibody (CD3-Ab) and IL-2/anti-IL-2 monoclonal antibody complex (IL-2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice. METHODS AND RESULTS: We treated apolipoprotein E deficient mice fed a high-cholesterol diet with vehicle, CD3-Ab, IL-2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with CD3-Ab or IL-2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C(high) inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions. CONCLUSIONS: Our results indicate that in addition to suppressing Teff responses, enhancing Treg-mediated immune responses is more efficacious in preventing atherosclerosis, suggesting a novel therapeutic approach for atherosclerosis. PMID- 24755151 TI - Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies. PMID- 24755154 TI - Narrowing sex differences in lipoprotein cholesterol subclasses following mid life: the very large database of lipids (VLDL-10B). AB - BACKGROUND: Women have less risk of atherosclerotic cardiovascular disease compared with men up until midlife (ages 50 to 60), after which the gap begins to narrow post menopause. We hypothesized that the average lipid profile of women undergoes unfavorable changes compared with men after midlife. METHODS AND RESULTS: We examined lipids by sex and age in the Very Large Database of Lipids 10B (VLDL 10B) study. The analysis included 1 350 908 unique consecutive patients clinically referred for lipoprotein testing by density gradient ultracentrifugation from 2009 to 2011. Ratio variables were created for density subclasses of LDL-C, HDL-C, and VLDL-C (LLDR, LHDR, LVDR, respectively). Men showed higher median LDL-C values than women for ages 20 to 59, with the greatest difference in their 30s: 146 mg/dL in men versus 130 mg/dL in women. In contrast, women consistently had higher values after midlife (age 60), for example ages 70 to 79: 129 mg/dL in women versus 112 mg/dL in men. After age 50, women had higher LDL-C each decade, for example 14% higher from their 30s to 50s, while HDL-C concentrations did not differ. Women had more buoyant LDL-C and HDL-C (lower LLDR and LHDR) than men at all ages but the gap closed in higher age groups. In contrast, women had a generally denser VLDL-C (higher LVDR) leading into midlife, with the gap progressively closing in higher age groups, approximating that of men in their 60s and 70s. CONCLUSION: The narrowing sex differential in cardiovascular disease risk after midlife is mirrored by a higher total atherogenic lipoprotein cholesterol burden in women and a closer approximation of the less favorable density phenotype characteristic of men. PMID- 24755153 TI - Glutathionylation mediates angiotensin II-induced eNOS uncoupling, amplifying NADPH oxidase-dependent endothelial dysfunction. AB - BACKGROUND: Glutathionylation of endothelial nitric oxide synthase (eNOS) "uncouples" the enzyme, switching its function from nitric oxide (NO) to O2(*-) generation. We examined whether this reversible redox modification plays a role in angiotensin II (Ang II)-induced endothelial dysfunction. METHODS AND RESULTS: Ang II increased eNOS glutathionylation in cultured human umbilical vein endothelial cells (HUVECs), rabbit aorta, and human arteries in vitro. This was associated with decreased NO bioavailability and eNOS activity as well as increased O2(*-) generation. Ang II-induced decrease in eNOS activity was mediated by glutathionylation, as shown by restoration of function by glutaredoxin-1. Moreover, Ang II-induced increase in O2(*-) and decrease in NO were abolished in HUVECs transiently transfected, with mutant eNOS rendered resistant to glutathionylation. Ang II effects were nicotinamide adenine dinucleotide phosphate (NADPH) oxidase dependent because preincubation with gp 91ds-tat, an inhibitor of NADPH oxidase, abolished the increase in eNOS glutathionylation and loss of eNOS activity. Functional significance of glutathionylation in intact vessels was supported by Ang II-induced impairment of endothelium-dependent vasorelaxation that was abolished by the disulfide reducing agent, dithiothreitol. Furthermore, attenuation of Ang II signaling in vivo by administration of an angiotensin converting enzyme (ACE) inhibitor reduced eNOS glutathionylation, increased NO, diminished O2(*-), improved endothelium dependent vasorelaxation and reduced blood pressure. CONCLUSIONS: Uncoupling of eNOS by glutathionylation is a key mediator of Ang II-induced endothelial dysfunction, and its reversal is a mechanism for cardiovascular protection by ACE inhibition. We suggest that Ang II-induced O2(*-) generation in endothelial cells, although dependent on NADPH oxidase, is amplified by glutathionylation dependent eNOS uncoupling. PMID- 24755155 TI - Risk factors and outcome of Fontan-associated plastic bronchitis: a case-control study. AB - BACKGROUND: The onset of plastic bronchitis (PB) can be debilitating in survivors of Fontan surgery. The rarity of this complication makes designing studies to understand risk factors for PB challenging. This 2-center case-control study aimed to describe patient outcomes and to assess the association of antecedent patient factors with PB development. METHODS AND RESULTS: Using center registries, PB patients (n=25) were matched 1:2 to non-PB Fontans (n=43) by date of Fontan surgery and center. The groups were compared for baseline characteristics. Association of patient characteristics with PB was assessed using logistic regression and of potential risk factors with onset of PB using time-to-event analyses. The median time from Fontan to PB diagnosis was 2.5 years. Overall, 12/25 PB patients died or underwent heart transplant; the median transplant-free survival was 8.3 years after diagnosis. Factors associated with developing PB included post-surgical chylothorax (44% PB versus 10% control; odds ratio [OR] 7.3; P=0.003), chest tube (CT) duration at stage 2 (P=0.04) and Fontan (P=0.004), and postoperative ascites (36% PB versus 12% control; OR 4.2; P=0.003). CT drainage >13 days at Fontan was associated with earlier PB onset (P=0.04). Early-onset PB was associated with an increased risk of death (OR 5.0; P=0.002). CONCLUSIONS: PB is a life-threatening disorder. A longer duration of CT drainage after surgery, chylothorax, and development of ascites are all associated with developing PB. Understanding the pathophysiology of peri operative complications in individual patients and using targeted interventions may delay the onset of the PB phenotype. PMID- 24755156 TI - How old are your arteries? Exercise-mediated protection from age-associated vascular stiffness. PMID- 24755157 TI - It's Always Something... PMID- 24755158 TI - Back pain in seniors: the Back pain Outcomes using Longitudinal Data (BOLD) cohort baseline data. AB - BACKGROUND: Back pain represents a substantial burden globally, ranking first in a recent assessment among causes of years lived with disability. Though back pain is widely studied among working age adults, there are gaps with respect to basic descriptive epidemiology among seniors, especially in the United States. Our goal was to describe how pain, function and health-related quality of life vary by demographic and geographic factors among seniors presenting to primary care providers with new episodes of care for back pain. METHODS: We examined baseline data from the Back pain Outcomes using Longitudinal Data (BOLD) registry, the largest inception cohort to date of seniors presenting to a primary care provider for back pain. The sample included 5,239 patients >= 65 years old with a new primary care visit for back pain at three integrated health systems (Northern California Kaiser-Permanente, Henry Ford Health System [Detroit], and Harvard Vanguard Medical Associates [Boston]). We examined differences in patient characteristics across healthcare sites and associations of patient sociodemographic and clinical characteristics with baseline patient-reported measures of pain, function, and health-related quality of life. RESULTS: Patients differed across sites in demographic and other characteristics. The Detroit site had more African-American patients (50%) compared with the other sites (7-8%). The Boston site had more college graduates (68%) compared with Detroit (20%). Female sex, lower educational status, African-American race, and older age were associated with worse functional disability as measured by the Roland-Morris Disability Questionnaire. Except for age, these factors were also associated with worse pain. CONCLUSIONS: Baseline pain and functional impairment varied substantially with a number of factors in the BOLD cohort. Healthcare site was an important factor. After controlling for healthcare site, lower education, female sex, African-American race, and older age were associated with worse physical disability and all of these factors except age were associated with worse pain. TRIAL REGISTRATION: Clinical Trials.gov NCT01776242; Registration date: June 13, 2012. PMID- 24755159 TI - Fiber-optic endoscopic evaluation of swallowing to assess swallowing outcomes as a function of head position in a normal population. AB - BACKGROUND: Head position practice has been shown to influence pill-swallowing ability, but the impact of head position on measures of swallowing outcomes has not yet been studied with fiber-optic endoscopic evaluation of swallowing (FEES). The primary purpose of this study was to determine whether head position impacts penetration-aspiration scale scores and/or post-swallow pharyngeal residue as assessed by FEES. Documenting the incidence of pharyngeal residue and laryngeal penetration and aspiration in a normal population was a secondary goal. METHODS: Adults without swallowing difficulties (N = 84) were taught a pill swallowing technique based on learning five head positions and were asked to practice with small, hard candies (e.g., TicTacs) for two weeks. Then they demonstrated swallowing in each of the head positions for two conditions, liquid and puree, while undergoing FEES. RESULTS: Out of 840 examined swallows, one event of aspiration and 5 events of penetration occurred. During practice >50% participants found positions they preferred over the center position for swallowing but head position was not associated with penetration-aspiration scores assessed by FEES. Significant associations and non-significant trends were found between pharyngeal residue and three variables: age, most preferred head position, and least preferred head position. CONCLUSION: Head position during swallowing (head up) and age greater than 40 years may result in increased pharyngeal residue but not laryngeal penetration or aspiration. PMID- 24755161 TI - How should tissue Doppler tracings be measured? PMID- 24755160 TI - Streptococcus sanguinis-induced cytokine and matrix metalloproteinase-1 release from platelets. AB - BACKGROUND: Streptococcus sanguinis (S.sanguinis), a predominant bacterium in the human oral cavity, has been widely associated with the development of infective endocarditis. Platelets play both a haemostatic function and can influence both innate and adaptive immune responses. Previous studies have shown that S.sanguinis can interact with, and activate, platelets. RESULTS: The aim of this study was to determine whether S.sanguinis stimulates the release of matrix metalloproteinases (MMPs) 1, 2 and 9 and the pro-inflammatory mediators SDF-1, VEGF and sCD40L, from platelets and to subsequently pharmacologically address the release mechanism (s). S.sanguinis stimulated the release of MMP-1, SDF-1, VEGF and sCD40L from platelets and inhibitors of cyclooxygenase and phosphatidylinositol 3-kinase, and antagonists of the alphaIIbbeta3 integrin and glycoprotein Ib, each inhibited the secretion of all factors. CONCLUSIONS: Therefore the release of MMP-1, SDF-1, VEGF and sCD40L occurs late in the platelet response to S.sanguinis and highlights the complex intracellular signalling pathways stimulated in response to S.sanguinis which lead to haemostasis, MMP and pro-inflammatory mediator secretion. PMID- 24755162 TI - Transthoracic echocardiography for non-invasive assessment of coronary vasodilator function after DES implantation. AB - AIMS: Coronary vasodilator dysfunction has been reported after drug-eluting stent (DES) implantation. Recent ESC guidelines suggest that transthoracic echocardiography (TTE) may be considered for assessment of coronary flow reserve (CFR) and microvascular disease in patients with stable angina, but its reliability has not been tested in patients with DES. We sought to assess the agreement between TTE (CFRTTE) and invasive thermodilution-derived CFR (CFRThermodilution) as well as their association with index of microcirculatory resistance (IMR) in mid-term follow-up after percutaneous coronary intervention for acute coronary syndrome. METHODS AND RESULTS: CFRTTE and CFRThermodilution were assessed 3 months after DES implantation in the left anterior descending artery in 24 patients. Patients with haemodynamically significant epicardial stenosis (fractional flow reserve <0.75) were excluded. Correlation between the two methods was good (r = 0.71, P < 0.001), but CFRThermodilution (mean +/- SD) tended to be higher (3.17 +/- 1.00 vs. 2.87 +/- 0.72; mean difference 0.29, 95% confidence interval -0.06 to 0.59). In Bland-Altman analysis, there was a trend towards a greater difference in the range of higher invasive values. Nevertheless, TTE was successful in discriminating moderately impaired CFR (<=2.5) (P = 0.001) and severely impaired CFR (<=2.0) (P < 0.001) when compared with an invasive method. No association between either CFR measurements vs. IMR measurement was detected, suggesting that in addition to microcirculatory function, CFR also accounts for epicardial vasodilator function in the absence of haemodynamically significant stenosis. CONCLUSION: TTE is a feasible and reliable method for the assessment of CFR and vasodilator dysfunction after DES implantation. Values obtained with this method successfully find abnormal CFR confirmed with the invasive thermodilution method. PMID- 24755163 TI - Nanostructured (Co, Ni)-based compounds coated on a highly conductive three dimensional hollow carbon nanorod array (HCNA) scaffold for high performance pseudocapacitors. AB - The electrochemical performance of the pseudocapacitive materials is seriously limited by poor electron and ions transport. Herein, an advanced integrated electrode has been designed by growing the pseudocapacitive materials, including Co(x)Ni(1-x)(OH)2, Co(x)Ni(1-x)O, and (Co(x)Ni(1-x))9S8, on a three-dimensional hollow carbon nanorod arrays (HCNA) scaffold. The HCNA scaffold not only can provide large surface area for increasing the mass loading of the pseudocapacitive materials, but also is with good electrical conductivity and hollow structure for facilitating fast electron and electrolyte ions transport, and thus improve the electrochemical performance. Particularly, in comparison with Co(x)Ni(1-x)(OH)2 and Co(x)Ni(1-x)O nanosheets, (Co(x)Ni(1-x))9S8 nanosheets on the HCNA scaffold exhibit better electrochemical performance. The discharge areal capacitance of the (CoxNi1-x)9S8/HCNA electrode can be achieved to 1.32 F cm(-2) at 1 mA cm(-2), ~1.5 times as that of the Co(x)Ni(1-x)(OH)2/HCNA electrode. The rate capability performance is also improved. 71.8% of the capacitance is retained with increasing the discharge current density from 1 to 10 mA cm(-2), in contrast to ~59.9% for the Co(x)Ni(1-x)(OH)2/HCNA electrode. Remarkably, the cycling stability is significantly enhanced. ~111.2% of the initial capacitance is gained instead of decaying after the 3000 cycles at 8 mA cm(-2), while there is ~11.5% loss for the Co(x)Ni(1-x)(OH)2/HCNA electrode tested under the same condition. Such good electrochemical performance can be ascribed by that (Co(x)Ni(1-x))9S8 exhibits the similar energy storage mechanism as Co(x)Ni(1-x)(OH)2 and Co(x)Ni(1-x)O, and more importantly, is with better electrical conductivity. PMID- 24755164 TI - Primary care physicians' familiarity, beliefs, and perceived barriers to practice guidelines in non-diabetic CKD: a survey study. AB - BACKGROUND: Most non-dialysis dependent chronic kidney disease (CKD) patients are cared for by their primary care physicians (PCPs). Studies suggest many CKD patients receive suboptimal care. Recently, CKD clinical practice guidelines were updated with additional emphasis on albuminuria. METHODS: We performed an internet-based, cross-sectional survey of active PCPs in the United States using the American Medical Association Physician Masterfile. We explored CKD guideline familiarity, self-reported practice behaviors, and attitudinal and external barriers to implementing guideline recommendations, including albuminuria testing. RESULTS: Of 12,034 PCPs targeted, 848 opened a study email, 165 (19.5%) responded. Most respondents (88%) spent >=50% of their time in clinical care. Respondents were generally in private practice (46%). Most PCPs (96%) felt that eGFR values were helpful. Approximately, 75% and 91% of PCPs reported testing for albuminuria in non-diabetic hypertensive patients with an eGFR > 60 ml/min/1.73 m2 and < 60 ml/min/1.73 m2, respectively. Barriers to albuminuria testing included a lack of effect on management, limited time, and the perceived absence of guidelines recommending testing. While PCPs expressed high levels of agreement with the definition of CKD, 30% were concerned with overdiagnosis in older adults with an eGFR in the CKD stage 3a range. Most PCPs felt that angiotensin converting enzyme inhibitor (ACEi)/ angiotensin II receptor blockers (ARBs) improved outcomes in CKD, though agreement was lower with severe vs. moderate albuminuria (78% vs. 85%, respectively, p = 0.03). Many PCPs (51%) reported being unfamiliar with CKD guidelines, but were receptive to systematic interventions to improve their CKD care. CONCLUSIONS: PCPs generally agree with CKD clinical practice guidelines regarding CKD definition and albuminuria testing. However, future interventions are necessary to improve PCPs' familiarity with CKD guidelines, overcome barriers to albuminuria testing and, assist PCPs in targeting ACEi/ARBs to the patients most likely to benefit. PMID- 24755165 TI - Nuclear envelope proteins in health and diseases. PMID- 24755167 TI - Editorial. Cancer models in Drosophila. PMID- 24755168 TI - Acoustic parameters for classification of breathiness in continuous speech according to the GRBAS scale. AB - OBJECTIVES: The purpose of this study was to classify objectively breathiness in continuous speech according to a subjective evaluation of voice based on the GRBAS scale. STUDY DESIGN: A retrospective, experimental study. METHODS: A total of 593 records with read text were twice evaluated by five experts according to the GRBAS scale within two sessions with a time delay of at least 2 weeks. The records were subsequently subjected to acoustic analysis using parameters which do not rely on the accurate estimation of fundamental frequency: Glottal-to-Noise Excitation ratio, Cepstral Peak Prominence Pearson r at autocorrelation peak, Breathiness Index, and the ratio of high- to mid/low-frequency energy. These parameters were subsequently analyzed and a total of 92 features were created for each record. After feature space reduction based on Correlation Feature Selection and Information Gain, the feature space was reduced to four parameters. These four parameters were used for classification of breathiness. RESULTS: In the final set of four, the acoustic parameters have significantly different mean ranks in every grade of breathiness according to the GRBAS scale (Kruskal-Wallis test [P < 0.001]). The accuracy of classifier for objective evaluation of level of breathiness based on the discrete scale of breathiness reached 77%. Assuming continuous grades of breathiness, the classifier reached rho = 0.92 (P < 0.001). CONCLUSIONS: The level of breathiness in continuous speech can be effectively described by automatic system-based analysis of acoustic measures. The proposed automatic system is able to determine the level of breathiness in continuous speech with sufficient precision. PMID- 24755169 TI - [Introduction and welcome messages]. PMID- 24755166 TI - Regulation of spermatogenesis by small non-coding RNAs: role of the germ granule. AB - The spermatogenic process relays in highly regulated gene expression mechanisms at the transcriptional and post-transcriptional levels to generate the male gamete that is needed for the perpetuation of the species. Small non-coding RNA pathways have been determined to participate in the post-transcriptional regulatory processes of germ cells. The most important sncRNA molecules that are critically involved in spermatogenesis belong to the miRNA and piRNAs pathways as illustrated by animal models where ablation of specific protein components displays male infertility. Several elements of these regulatory pathways have been found in the nuage or germ granule, a non-membranous cytoplasmatic structure that can be seen in spermatocytes and spermatids. This notion suggests that germ granules may act as organizer centers for silencing pathways in the germline. In general, miRNAs regulate spermatogenesis through targeting and down-regulation of specific transcripts to eventually promote sperm development. However, piRNAs are powerful repressors of transposon elements expression in the spermatogenic process. Here we describe the suggested functions that miRNA and piRNAs pathways execute in the regulation of spermatogenesis and include some recent studies in the field. Despite major strides on the detailed molecular mechanisms of sncRNAs in relation to spermatogenesis, there is plenty to discover on this fascinating regulatory program. PMID- 24755170 TI - [Inaugural conference - what stakes face rare diseases in the French health care system]. PMID- 24755171 TI - [Round table 1. PNMR 2011-2014: point of view of the stakeholders]. PMID- 24755172 TI - [Round table 2. The evolutions following the implementation of the law for health and sanitary security]. PMID- 24755173 TI - [Conference 1. An economic observatory for orphan drugs: myth or reality?]. PMID- 24755174 TI - [Conference 2. Evolution of criteria for evaluating drugs use in France and in Europe]. PMID- 24755175 TI - [Conference 3. European directive on the cross-border health care: implementation in reference European network]. PMID- 24755176 TI - [Round table 3. How to improve French competitiveness in clinical research]. PMID- 24755177 TI - [Workshops A1 to A5]. PMID- 24755178 TI - [Mediterranean region debate-what are the existing partnerships? What are the ones missing?]. PMID- 24755179 TI - [Round table 4. Speeding new therapeutic approaches for rare diseases: do we need new economical models or financial tools?]. PMID- 24755180 TI - [Round table 5. Will a third PNMR be needed?]. PMID- 24755181 TI - [Conclusions of the meeting]. PMID- 24755182 TI - [Public partners voices-why do communities support this dynamic?]. PMID- 24755183 TI - Automatic method for the dermatological diagnosis of selected hand skin features in hyperspectral imaging. AB - INTRODUCTION: Hyperspectral imaging has been used in dermatology for many years. The enrichment of hyperspectral imaging with image analysis broadens considerably the possibility of reproducible, quantitative evaluation of, for example, melanin and haemoglobin at any location in the patient's skin. The dedicated image analysis method proposed by the authors enables to automatically perform this type of measurement. MATERIAL AND METHOD: As part of the study, an algorithm for the analysis of hyperspectral images of healthy human skin acquired with the use of the Specim camera was proposed. Images were collected from the dorsal side of the hand. The frequency lambda of the data obtained ranged from 397 to 1030 nm. A total of 4'000 2D images were obtained for 5 hyperspectral images. The method proposed in the paper uses dedicated image analysis based on human anthropometric data, mathematical morphology, median filtration, normalization and others. The algorithm was implemented in Matlab and C programs and is used in practice. RESULTS: The algorithm of image analysis and processing proposed by the authors enables segmentation of any region of the hand (fingers, wrist) in a reproducible manner. In addition, the method allows to quantify the frequency content in different regions of interest which are determined automatically. Owing to this, it is possible to perform analyses for melanin in the frequency range lambdaE?(450,600) nm and for haemoglobin in the range lambdaH?(397,500) nm extending into the ultraviolet for the type of camera used. In these ranges, there are 189 images for melanin and 126 images for haemoglobin. For six areas of the left and right sides of the little finger (digitus minimus manus), the mean values of melanin and haemoglobin content were 17% and 15% respectively compared to the pattern. CONCLUSIONS: The obtained results confirmed the usefulness of the proposed new method of image analysis and processing in dermatology of the hand as it enables reproducible, quantitative assessment of any fragment of this body part. Each image in a sequence was analysed in this way in no more than 100 ms using Intel Core i5 CPU M460 @2.5 GHz 4 GB RAM. PMID- 24755184 TI - Preparative separation of two subsidiary colors of FD&C Yellow No. 5 (Tartrazine) using spiral high-speed counter-current chromatography. AB - Specifications in the U.S. Code of Federal Regulations for the color additive FD&C Yellow No. 5 (Color Index No. 19140) limit the level of the tetrasodium salt of 4-[(4',5-disulfo[1,1'-biphenyl]-2-yl)hydrazono]-4,5-dihydro-5-oxo-1-(4 sulfophenyl)-1H-pyrazole-3-carboxylic acid and that of the trisodium salt of 4,4' [4,5-dihydro-5-oxo-4-[(4-sulfophenyl)hydrazono]-1H-pyrazol-1,3 diyl]bis[benzenesulfonic acid], which are subsidiary colors abbreviated as Pk5 and Pk7, respectively. Small amounts of Pk5 and Pk7 are needed by the U.S. Food and Drug Administration for confirmatory analyses and for development of analytical methods. The present study describes the use of spiral high-speed counter-current chromatography (HSCCC) to separate the closely related minor components Pk5 and Pk7 from a sample of FD&C Yellow No. 5 containing ~3.5% Pk5 and ~0.7% Pk7. The separations were performed with highly polar organic/high ionic strength aqueous two-phase solvent systems that were chosen by applying the recently introduced method known as graphic optimization of partition coefficients (Zeng et al., 2013). Multiple ~1.0g portions of FD&C Yellow No. 5 (totaling 6.4g dye) were separated, using the upper phase of the solvent system 1 butanol/abs. ethanol/saturated ammonium sulfate/water, 1.7:0.3:1:1, v/v/v/v, as the mobile phase. After removing the ammonium sulfate from the HSCCC-collected fractions, these separations resulted in an enriched dye mixture (~160mg) of which Pk5 represented ~46% and Pk7, ~21%. Separation of the enriched mixture, this time using the lower phase of that solvent system as the mobile phase, resulted in ~61mg of Pk5 collected in fractions whose purity ranged from 88.0% to 92.7%. Pk7 (20.7mg, ~83% purity) was recovered from the upper phase of the column contents. Application of this procedure also resulted in purifying the major component of FD&C Yellow No. 5 to >99% purity. The separated compounds were characterized by high-resolution mass spectrometry and several (1)H and (13)C nuclear magnetic resonance spectroscopic techniques. PMID- 24755185 TI - Immunolocalization of nitric oxide synthase (NOS) isoforms in ovarian follicles of the catfish, Clarias batrachus and its relation with ovarian activity. AB - Nitric oxide, a gaseous molecule, is produced during the conversion of arginine to citrulline by the action of NOS isoforms (eNOS, iNOS or nNOS). Role of NO in regulation of mammalian reproduction is well established; however, practically no report is available on fishes. Hence, in the present study, expression of all three isoforms of NOS was worked out in the ovary of Clarias batrachus immunohistochemically during different phases of its reproductive cycle and its relation with ovarian activities. No immunoreactivity of eNOS was observed in the ovary of C. batrachus during the late-quiescence and early-recrudescence phases. While during the recrudescence phase (April and May) it expressed intensely in thecal and granulosa cells of the oocyte-II and III, but immune-intensity decreased in the late-recrudescence and spawning phases (June and July). Similar pattern of immunoprecipitation was also observed in case of iNOS. However, the immunoreactivity pattern of nNOS was quite varied, it expressed moderately only in the nucleus and cytoplasm of perinuclear and oocyte-I stages during late quiescence phase. While during the early recrudescence phase, the expression of nNOS disappeared completely from the nucleus and cytoplasm, rather it expressed intensely in the thecal and granulosa cells, which declined in the late recrudescence and spawning phases. Moderate immunoreactivity of iNOS could also be localized in the zona radiata of ovulated oocyte. The intense NOS immunoreactivity in the thecal and granulosa cells coincided with increased levels of ovarian NO and 17beta-estradiol content. They exhibited statistically significant positive correlation amongst themselves, suggesting the involvement of ovarian NOS/NO system in oogenesis and steroidogenesis in the catfish. PMID- 24755186 TI - Secretagogue induction of GH release in QNR/D cells: prevention of cell death. AB - Retinal ganglion cells (RGCs) in the chick embryonic neural retina are extrapituitary sites of growth hormone (GH) synthesis and release. The regulation of GH secretion by these cells is largely unknown, although we recently discovered several of the hypothalamic releasing factors involved in pituitary GH regulation (including GH-releasing hormone (GHRH) and thyrotropin releasing hormone, TRH) to be present in the cytoplasm of immortalized quail RGCs (QNR/D cells). QNR/D cells may therefore provide an experimental model for studies on GH regulation in the chick neural retina. The possibility that GHRH and TRH might stimulate GH secretion in QNR/D cells was therefore investigated. Both peptides acutely depleted the GH content of the QNR/D cells, as demonstrated by immunocytochemistry and ELISA, whilst increasing the GH content in incubation media. Both peptides also increased the immunochemical and ELISA content of the QNR/D cells and the content of GH in the incubation media after long-term incubation. Cell survival, determined by metabolic activity of the QNR/D cells and by TUNEL-labeling, was reduced when the endogenous GH content was reduced by GH immunoneutralization, even in the presence of exogenous GHRH or TRH. Cell survival was also reduced when endogenous GHRH was blocked by GHRH immunoneutralization, although the immunoneutralization of endogenous TRH did not affect QNR/D cell survival. In summary, these results demonstrate secretagogue actions of exogenous GHRH and TRH on the secretion of GH from QNR/D cells. They also suggest that endogenous GHRH, but not endogenous TRH, prevents cell death by increasing endogenous GH secretion in QNR/D cells. PMID- 24755187 TI - Understanding factors associated with the translation of cardiovascular research: a multinational case study approach. AB - BACKGROUND: Funders of health research increasingly seek to understand how best to allocate resources in order to achieve maximum value from their funding. We built an international consortium and developed a multinational case study approach to assess benefits arising from health research. We used that to facilitate analysis of factors in the production of research that might be associated with translating research findings into wider impacts, and the complexities involved. METHODS: We built on the Payback Framework and expanded its application through conducting co-ordinated case studies on the payback from cardiovascular and stroke research in Australia, Canada and the United Kingdom. We selected a stratified random sample of projects from leading medical research funders. We devised a series of innovative steps to: minimize the effect of researcher bias; rate the level of impacts identified in the case studies; and interrogate case study narratives to identify factors that correlated with achieving high or low levels of impact. RESULTS: Twenty-nine detailed case studies produced many and diverse impacts. Over the 15 to 20 years examined, basic biomedical research has a greater impact than clinical research in terms of academic impacts such as knowledge production and research capacity building. Clinical research has greater levels of wider impact on health policies, practice, and generating health gains. There was no correlation between knowledge production and wider impacts. We identified various factors associated with high impact. Interaction between researchers and practitioners and the public is associated with achieving high academic impact and translation into wider impacts, as is basic research conducted with a clinical focus. Strategic thinking by clinical researchers, in terms of thinking through pathways by which research could potentially be translated into practice, is associated with high wider impact. Finally, we identified the complexity of factors behind research translation that can arise in a single case. CONCLUSIONS: We can systematically assess research impacts and use the findings to promote translation. Research funders can justify funding research of diverse types, but they should not assume academic impacts are proxies for wider impacts. They should encourage researchers to consider pathways towards impact and engage potential research users in research processes. PMID- 24755188 TI - Epidemiology and outcomes of community-acquired Clostridium difficile infections in Medicare beneficiaries. AB - BACKGROUND: The incidence of community-acquired Clostridium difficile (CACD) is increasing in the United States. Many CACD infections occur in the elderly, who are predisposed to poor outcomes. We aimed to describe the epidemiology and outcomes of CACD in a nationally representative sample of Medicare beneficiaries. STUDY DESIGN: We queried a 5% random sample of Medicare beneficiaries (2009-2011 Part A inpatient and Part D prescription drug claims; n = 864,604) for any hospital admission with a primary ICD-9 diagnosis code for C difficile (008.45). We examined patient sociodemographic and clinical characteristics, preadmission exposure to oral antibiotics, earlier treatment with oral vancomycin or metronidazole, inpatient outcomes (eg, colectomy, ICU stay, length of stay, mortality), and subsequent admissions for C difficile. RESULTS: A total of 1,566 (0.18%) patients were admitted with CACD. Of these, 889 (56.8%) received oral antibiotics within 90 days of admission. Few were being treated with oral metronidazole (n = 123 [7.8%]) or vancomycin (n = 13 [0.8%]) at the time of admission. Although 223 (14%) patients required ICU admission, few (n = 15 [1%]) underwent colectomy. Hospital mortality was 9%. Median length of stay among survivors was 5 days (interquartile range 3 to 8 days). One fifth of survivors were readmitted with C difficile, with a median follow-up time of 393 days (interquartile range 129 to 769 days). CONCLUSIONS: Nearly half of the Medicare beneficiaries admitted with CACD have no recent antibiotic exposure. High mortality and readmission rates suggest that the burden of C difficile on patients and the health care system will increase as the US population ages. Additional efforts at primary prevention and eradication might be warranted. PMID- 24755189 TI - Surgeon, not disease severity, often determines the operation for acute complicated diverticulitis. AB - BACKGROUND: The "best" operation in the setting of acute complicated diverticulitis has been debated for decades. Multiple studies, including a recent prospective randomized trial, have reported improved outcomes with primary anastomosis. The aim of this study was to determine whether surgeon or patient specific factors drives the choice of operative procedure. STUDY DESIGN: Consecutive adult patients with sigmoid diverticulitis, requiring emergent operative treatment for acute complicated diverticulitis, from 1997 to 2012 at an academic medical center, were identified from a prospectively maintained complications database. Patient characteristics, surgeon, choice of operation, and outcomes including postoperative complications and stoma reversal were noted. The use of primary anastomosis and associated outcomes between colorectal and noncolorectal surgeons were compared. RESULTS: There were 151 patients who underwent urgent resection during the study period, and 136 met inclusion criteria. Eighty-two resections (65.1%) were performed by noncolorectal surgeons and 44 by colorectal surgeons (34.9%). Noncolorectal surgeons performed more Hartmann procedures (68.3% vs 40.9%, p = 0.01) despite similar demographics, American Society of Anesthesiologists (ASA) classification, and Hinchey stage. Length of stay, time to stoma reversal, ICU days, and postoperative complications were lower in the colorectal group (43.2% vs 16.7, p = 0.02). CONCLUSIONS: Although patient-specific factors are important, surgeon is a potent predictor of operation performed in the setting of severe acute diverticulitis. A more aggressive approach to primary anastomosis may lower the complication rate after surgical treatment for severe acute diverticulitis. PMID- 24755190 TI - A bariatric surgery center of excellence: operative trends and long-term outcomes. AB - BACKGROUND: Surgery remains the most effective intervention for obesity and its comorbidities. However, the long-term efficacy of bariatric procedures is rarely reported. This study addresses operative trends, efficiency, and long-term outcomes from a large bariatric program. STUDY DESIGN: Data were prospectively collected on 3,460 patients undergoing 3,503 operations from January 2004 to March 2013. Primary procedures included Roux-en-Y gastric bypass (RY; n = 2,966), adjustable band (AB; n = 352), and sleeve gastrectomy (SG; n = 118). There were 67 revisional procedures (RP). Mean operative time, hospital length of stay, major 30-day morbidity/mortality, follow-up compliance, and weight loss per procedure at follow-up were recorded. RESULTS: Mean operative times decreased to the following: RY, 53 minutes; AB, 35 minutes; SG, 46 minutes; and RP, 71 minutes. Mean length of stay was reduced to the following: RY, 1.53 days; AB, 0.97 days; SG, 2.12 days; and RP, 2.68 days. Major complications were mortality, 0.09%; leak, 0.51%; bleed, 2.37%; pneumonia, 0.63%; venous thromboembolism, 0.40%; and reoperation, 2.34%. The complication rate was lowest for AB and highest for SG (p < 0.05). Adjustable band was the initial procedure in 73% of cases requiring RP. Follow-up compliance was 93% at 1 year, 79% at 3 years, 71% at 5 years, and 33% at 9 years. Adjustable band offered significant weight loss at 1 and 3 years (p < 0.0001), but less than RY or SG (p < 0.0001). Excess weight loss was not significantly different between RY and SG at 1 year. Significant weight loss with RY persisted at 7 to 9 years (p < 0.0001). CONCLUSIONS: Our bariatric program experienced an increase in SG and RP and a decrease in AB. Optimization of care reduced operative time and length of stay. All procedures achieved significant weight loss in the first year. Adjusted band had the lowest morbidity, but inferior weight loss and greater need for revision. Long-term weight-loss data are only available for RY. PMID- 24755191 TI - Fast and economic immobilization methods described for non-commercial Pseudomonas lipases. AB - BACKGROUND: There is an increasing interest to seek new enzyme preparations for the development of new products derived from bioprocesses to obtain alternative bio-based materials. In this context, four non-commercial lipases from Pseudomonas species were prepared, immobilized on different low-cost supports, and examined for potential biotechnological applications. RESULTS: To reduce costs of eventual scaling-up, the new lipases were obtained directly from crude cell extracts or from growth culture supernatants, and immobilized by simple adsorption on Accurel EP100, Accurel MP1000 and Celite(r)545. The enzymes evaluated were LipA and LipC from Pseudomonas sp. 42A2, a thermostable mutant of LipC, and LipI.3 from Pseudomonas CR611, which were produced in either homologous or heterologous hosts. Best immobilization results were obtained on Accurel EP100 for LipA and on Accurel MP1000 for LipC and its thermostable variant. Lip I.3, requiring a refolding step, was poorly immobilized on all supports tested (best results for Accurel MP1000). To test the behavior of immobilized lipases, they were assayed in triolein transesterification, where the best results were observed for lipases immobilized on Accurel MP1000. CONCLUSIONS: The suggested protocol does not require protein purification and uses crude enzymes immobilized by a fast adsorption technique on low-cost supports, which makes the method suitable for an eventual scaling up aimed at biotechnological applications. Therefore, a fast, simple and economic method for lipase preparation and immobilization has been set up. The low price of the supports tested and the simplicity of the procedure, skipping the tedious and expensive purification steps, will contribute to cost reduction in biotechnological lipase-catalyzed processes. PMID- 24755192 TI - Regression of cardiac growth in kidney transplant recipients using anti-m-TOR drugs plus RAS blockers: a controlled longitudinal study. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is common in kidney transplant (KT) recipients. LVH is associated with a worse outcome, though m-TOR therapy may help to revert this complication. We therefore conducted a longitudinal study to assess morphological and functional echocardiographic changes after conversion from CNI to m-TOR inhibitor drugs in nondiabetic KT patients who had previously received RAS blockers during the follow-up. METHODS: We undertook a 1-year nonrandomized controlled study in 30 non-diabetic KT patients who were converted from calcineurin inhibitor (CNI) to m-TOR therapy. A control group received immunosuppressive therapy based on CNIs. Two echocardiograms were done during the follow-up. RESULTS: Nineteen patients were switched to SRL and 11 to EVL. The m TOR group showed a significant reduction in LVMi after 1 year (from 62 +/- 22 to 55 +/- 20 g/m2.7; P=0.003, paired t-test). A higher proportion of patients showing LVMi reduction was observed in the m-TOR group (53.3 versus 29.3%, P=0.048) at the study end. In addition, only 56% of the m-TOR patients had LVH at the study end compared to 77% of the control group (P=0.047). A significant change from baseline in deceleration time in early diastole was observed in the m TOR group compared with the control group (P=0.019). CONCLUSIONS: Switching from CNI to m-TOR therapy in non-diabetic KT patients may regress LVH, independently of blood pressure changes and follow-up time. This suggests a direct non hemodynamic effect of m-TOR drugs on cardiac mass. PMID- 24755194 TI - Developing monitoring techniques for the invasive goldspotted oak borer (Coleoptera: Buprestidae) in California. AB - The goldspotted oak borer, Agrilus auroguttatus Schaeffer (Coleoptera: Buprestidae), is an invasive species that has colonized oak woodlands in southern California. To better define its seasonal flight activity, assist with forest and integrated pest management activities, and define the current distribution in California, an effective monitoring technique for A. auroguttatus is necessary. We assessed the efficacy of two colors of flight-intercept prism traps, the placement of these traps at three heights, and several commercially available lures [Manuka oil, Phoebe oil, and a green leaf volatile, (3Z)-hexenol] for monitoring the flight of adult A. auroguttatus. Landing rates and the densities of D-shaped emergence holes of A. auroguttatus adults were assessed on the lower stems of coast live oak, Quercus agrifolia Nee, of varying size and crown health classes. Purple flight-intercept prism traps placed at heights of 3 m and 4.5 m caught significantly more female A. auroguttatus than green prism traps. In one experiment, males also responded at a significantly higher level to purple than to green prism traps placed at 3 m height. The addition of commercially available lures significantly enhanced male, but not female, A. auroguttatus trap catch when compared with unbaited control traps. There were no differences among male flight responses to the three lures. A. auroguttatus landing rates and emergence hole densities were significantly greater on the largest-diameter trees (>76.2 cm diameter at breast height) and on trees with severe crown thinning or complete crown collapse. The annual increment in emergence hole densities was also significantly greater on trees with severe crown thinning or complete crown collapse. In three trapping studies over multiple years in southern California, the adult flight period began as early as mid-May, peaked in mid-June to early July, and ended in early- to mid-September. To demonstrate the efficacy of the detection method for A. auroguttatus (unbaited purple traps at 3 m height), a delimitation survey conducted from 2009 to 2012 confirmed that the species was only present in San Diego Co., but that the distribution was expanding northward. PMID- 24755193 TI - L-alanine-induced germination in Bacillus licheniformis -the impact of native gerA sequences. AB - BACKGROUND: L-alanine, acting through the GerA receptor, was recently found to be an efficient germinant in Bacillus licheniformis ATCC14580/DSM13. RESULTS: In this study, we show that several of 46 examined B. licheniformis strains germinate remarkably slower than the type strain when exposed to L-alanine. These strains are not necessarily closely related, as determined by MLST (multi-locus sequence typing). Three of the slow-germinating strains were further examined in order to see whether nucleotide substitutions in the gerA sequences were responsible for the slow L-alanine germination. This was performed by complementing the transformable type strain derivate MW3DeltagerAA with gerA variants from the three slow-germinating strains; NVH1032, NVH1112 and NVH800. CONCLUSIONS: A wide selection of B. licheniformis strains was evaluated for L alanine-induced germination efficiency. Our results show that gerA substitutions could only partially explain why spores of some B. licheniformis strains responded slower than others in the presence of L-alanine. PMID- 24755195 TI - Feasibility and acceptability of a volunteer-mediated diversional therapy program for older patients with cognitive impairment. AB - Understanding the perceptions of stakeholders is critical for determining acceptability and feasibility of volunteer-mediated programs. This study evaluated the feasibility and acceptability for staff, volunteers, patients and their carers, of a volunteer diversional therapy program for patients with cognitive impairment undergoing inpatient rehabilitation. Post-program structured interviews were conducted with the volunteers (n = 10), patients (n = 30) and their carers (n = 3); and nursing staff (n = 6) participated in a focus group. Thematic analysis identified five themes (values, attitudes, knowledge, purpose, support) in two dimensions (personal, team culture). Overall, patients, carers, staff and volunteers were satisfied with the volunteer program and perceived benefits for quality of care. Recommendations for improvements to the program related to staff engagement with the program and the volunteers' education and training. The volunteer diversional therapy pilot program for patients with cognitive impairment on a sub-acute ward was acceptable and feasible for patients, carers, staff and volunteers. PMID- 24755196 TI - Effective elimination of contaminants after oral care in elderly institutionalized individuals. AB - After mechanical cleaning in oral care, eliminating residual oral contaminants has an important role in preventing their aspiration, especially in individuals with weak airway protection. We examined the effectiveness of wiping the oral cavity after oral care on eliminating contaminants in 31 patients who were hospitalized in our neurology inpatient unit. The amount of bacteria on the tongue, palate, and buccal vestibule was counted before and just after oral care, after eliminating contaminants either by rinsing with water and suction or by wiping with mouth wipes, and 1 h after oral care. Oral bacteria amounts were decreased significantly by both elimination procedures after oral care. These findings suggest that wiping with mouth wipes is as effective as mouth rinsing to decrease bacteria following oral care. With a lower risk of contaminant aspiration, wiping may be a suitable alternative to rinsing, especially in dysphagic individuals. PMID- 24755197 TI - A pragmatic definition of therapeutic synergy suitable for clinically relevant in vitro multicompound analyses. AB - For decades, the standard procedure when screening for candidate anticancer drug combinations has been to search for synergy, defined as any positive deviation from trivial cases like when the drugs are regarded as diluted versions of each other (Loewe additivity), independent actions (Bliss independence), or no interaction terms in a response surface model (no interaction). Here, we show that this kind of conventional synergy analysis may be completely misleading when the goal is to detect if there is a promising in vitro therapeutic window. Motivated by this result, and the fact that a drug combination offering a promising therapeutic window seldom is interesting if one of its constituent drugs can provide the same window alone, the largely overlooked concept of therapeutic synergy (TS) is reintroduced. In vitro TS is said to occur when the largest therapeutic window obtained by the best drug combination cannot be achieved by any single drug within the concentration range studied. Using this definition of TS, we introduce a procedure that enables its use in modern massively parallel experiments supported by a statistical omnibus test for TS designed to avoid the multiple testing problem. Finally, we suggest how one may perform TS analysis, via computational predictions of the reference cell responses, when only the target cell responses are available. In conclusion, the conventional error-prone search for promising drug combinations may be improved by replacing conventional (toxicology-rooted) synergy analysis with an analysis focused on (clinically motivated) TS. PMID- 24755198 TI - A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas: a road map for the study of genes with potential clinical relevance. AB - Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209). Tumors with none of these mutations are termed "pan negative." We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies. First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS-driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS. Second, we found that the 69 "pan negative" melanoma genomes harbored alternate infrequent mutations in the five known driver genes along with many mutations in genes encoding guanine nucleotide binding protein alpha-subunits. Third, we identified 12 significantly mutated genes in "pan-negative" samples (ALK, STK31, DGKI, RAC1, EPHA4, ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR), including five genes (RAC1, ADAMTS18, EPHA7, TAF1L, and NF1) with a recurrent mutation in at least two "pan-negative" tumor samples. This meta-analysis provides a road map for the study of additional potentially actionable genes in both driver mutation-positive and pan-negative melanomas. PMID- 24755199 TI - Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer. AB - The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (P < 0.05). Individual as well as combination therapies showed significant antiangiogenic, antiproliferative, and proapoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer. PMID- 24755200 TI - Generation of a canine anti-EGFR (ErbB-1) antibody for passive immunotherapy in dog cancer patients. AB - Passive immunotherapy with monoclonal antibodies represents a cornerstone of human anticancer therapies, but has not been established in veterinary medicine yet. As the tumor-associated antigen EGFR (ErbB-1) is highly conserved between humans and dogs, and considering the effectiveness of the anti-EGFR antibody cetuximab in human clinical oncology, we present here a "caninized" version of this antibody, can225IgG, for comparative oncology studies. Variable region genes of 225, the murine precursor of cetuximab, were fused with canine constant heavy gamma and kappa chain genes, respectively, and transfected into Chinese hamster ovary (CHO) DUKX-B11 cells. Of note, 480 clones were screened and the best clones were selected according to productivity and highest specificity in EGFR-coated ELISA. Upon purification with Protein G, the recombinant cetuximab-like canine IgG was tested for integrity, correct assembly, and functionality. Specific binding to the surface of EGFR-overexpressing cells was assessed by flow cytometry and immunofluorescence; moreover, binding to canine mammary tissue was demonstrated by immunohistochemistry. In cell viability and proliferation assays, incubation with can225IgG led to significant tumor cell growth inhibition. Moreover, this antibody mediated significant tumor cell killing via phagocytosis in vitro. We thus present here, for the first time, the generation of a canine IgG antibody and its hypothetical structure. On the basis of its cetuximab-like binding site, on the one hand, and the expression of a 91% homologous EGFR molecule in canine cancer, on the other hand, this antibody may be a promising research compound to establish passive immunotherapy in dog patients with cancer. PMID- 24755202 TI - Impact of clustered depression and anxiety on mortality and rehospitalization in patients with heart failure. AB - BACKGROUND: Anxiety is often present in patients with depression. The aim of this study was to evaluate the impact of clustered depression and anxiety on mortality and rehospitalization in hospitalized patients with heart failure (HF). METHODS: A total of 221 hospitalized patients with HF, who completed the questionnaires, were analyzed in this prospective study (mean age 62+/-13 years; 28% female). One third patients had implanted cardiac devices. Depression was defined as a Zung Self-Rating Depression Scale index score of >=60 and anxiety was defined as a State-Trait Anxiety Inventory score of >=40 (male) or >=42 (female). The primary outcome was the composite of death from any cause or rehospitalization due to worsened HF and refractory arrhythmia. RESULTS: Of the 221 HF patients, 29 (13%) had depression alone, 80 (36%) had anxiety alone, and 46 patients (21%) had both depression and anxiety. During an average follow-up of 41+/-21 months, patients with depression alone and those with clustered depression and anxiety were at an increased risk of the primary outcome [hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.17-4.28, p=0.01 and HR 2.75, 95% CI: 1.51-4.99, p=0.01, respectively] compared to patients with no symptoms. Multivariate analysis after adjusting for age, gender, New York Heart Association functional class, B-type natriuretic peptide, device implantation, renal dysfunction, and left ventricular dysfunction showed clustered depression and anxiety, but not depression alone or anxiety alone, was an independent predictor of the primary outcome (HR 1.96, 95% CI: 1.00-3.27, p=0.04). CONCLUSIONS: Our results showed that clustered depression and anxiety were associated with worse outcomes in patients with HF. PMID- 24755201 TI - Frequency of deep vein thrombosis among hospitalized non-surgical Japanese patients with congestive heart failure. AB - PURPOSE: Congestive heart failure (CHF) is one of the risk factors for deep vein thrombosis (DVT) according to the Japanese guidelines for DVT treatment and prevention. The purpose of this study is to estimate the frequency of DVT among hospitalized CHF patients, since there have been only limited DVT data in Japanese CHF patients. METHODS: Patients enrolled in the study were with risk factors for DVT listed in the guidelines as well as with acute exacerbation of CHF, bed rest for at least 4 days, and aged 60 or above. Patients treated by physical prophylaxis or anti-platelet medication were included, while patients treated by any anticoagulant medicines were excluded. Patients with surgery or injury within 3 months before the hospitalization or diagnosed clinically or with obvious past history as having DVT at hospitalization were excluded. The presence of DVT in the eligible patients was determined by ultrasonography and the images were evaluated by an independent central evaluation committee. RESULTS: Forty four patients were enrolled in the study including 19 males and 25 females. The mean age was 79.0+/-10.6 years, and the mean duration of bed rest was 8.9+/-3.2 days. Out of these 44 patients, DVT was detected in 15 (34%) patients. Eight patients were on treatment with physical prophylaxis but DVT was still detected in two patients. Furthermore, 12 out of the rest of the patients were treated by anti-platelet agents and were still with DVT in 3 patients. CONCLUSION: When evaluated ultrasonographically, the frequency of DVT in hospitalized non-surgical Japanese patients with CHF was approximately 35%. DVT occurred in 25% of patients treated by physical prophylaxis or anti-platelet agents. The results suggest that Japanese hospitalized patients with CHF have a high risk of DVT and thus can be recognized to have potential benefit by preventing and treating DVT according to the guidelines. PMID- 24755203 TI - Arterial stiffness, antiphospholipid antibodies, and pulmonary arterial hypertension in systemic lupus erythematosus. AB - BACKGROUND: The aim of this study is to evaluate the role of arterial stiffness in pulmonary arterial hypertension (PAH) in systemic lupus erythematosus (SLE) patients and its relationship with antiphospholipid antibody (aPL). METHODS: Measurement of brachial ankle pulse wave velocity (baPWV), carotid arterial stiffness, and pulmonary vascular resistance (PVR) was performed in 51 patients with SLE. PAH was diagnosed if the pulmonary artery systolic pressure was >40mmHg. Information concerning SLE duration, medication, and serum autoantibodies was recorded. SLE activity was assessed by the SLE disease activity index (SLEDAI). RESULTS: aPL was present in 10 patients (20%), and PAH was detected in 6 patients (12%). The prevalence of Raynaud's phenomenon, baPWV, positive aPL, and titers of IgG anticardiolipin antibody (aCL) were increased in SLE with PAH; however, no difference was found in inflammatory markers, disease duration, and SLEDAI compared to SLE without PAH. Carotid artery deformation and right ventricular function were reduced in patients with PAH (all p<0.05). Carotid artery circumferential strain (r=0.34, p=0.021), radial strain (r=-0.30, p=0.045), and baPWV (r=0.46, p=0.001) showed significant correlation between IgG aCL. Univariate and multiple regression analysis revealed that the only significant independent predictors of the presence of PAH were baPWV, carotid artery stiffness, and IgG aCL. CONCLUSION: Arterial stiffness might contribute to the pathogenesis of PAH related to SLE as well as aPLs. Furthermore, the significant association of aPL with arterial stiffness suggests its important role in PAH with SLE. PMID- 24755205 TI - Ternary bulk heterojunction solar cells: addition of soluble NIR dyes for photocurrent generation beyond 800 nm. AB - The incorporation of a tert-butyl-functionalized silicon 2,3-naphthalocyanine bis(trihexylsilyloxide) dye molecule as a third component in a ternary blend bulk heterojunction (BHJ) organic solar cell containing P3HT (donor) and PC60BM (acceptor) results in increased NIR absorption. This absorption yields an increase of up to 40% in the short-circuit current and up to 19% in the power conversion efficiency (PCE) in photovoltaic devices. Two-dimensional grazing incidence wide-angle X-ray scattering (2-D GIWAXS) experiments show that compared to the unfunctionalized dye the tert-butyl functionalization enables an increase in the volume fraction of the dye molecule that can be incorporated before the device performance decreases. Quantum efficiency and absorption spectra also indicate that, at dye concentrations above about 8 wt %, there is an approximately 30 nm red shift in the main silicon naphthalocyanine absorption peak, allowing further dye addition to contribute to added photocurrent. This peak shift is not observed in blends with unfunctionalized dye molecules, however. This simple approach of using ternary blends may be generally applicable for use in other unoptimized BHJ systems towards increasing PCEs beyond current levels. Furthermore, this may offer a new approach towards OPVs that absorb NIR photons without having to design, synthesize, and purify complicated donor acceptor polymers. PMID- 24755204 TI - AP39, a novel mitochondria-targeted hydrogen sulfide donor, stimulates cellular bioenergetics, exerts cytoprotective effects and protects against the loss of mitochondrial DNA integrity in oxidatively stressed endothelial cells in vitro. AB - The purpose of the current study was to investigate the effect of the recently synthesized mitochondrially-targeted H2S donor, AP39 [(10-oxo-10-(4-(3-thioxo-3H 1,2-dithiol-5yl)phenoxy)decyl) triphenylphosphonium bromide], on bioenergetics, viability, and mitochondrial DNA integrity in bEnd.3 murine microvascular endothelial cells in vitro, under normal conditions, and during oxidative stress. Intracellular H2S was assessed by the fluorescent dye 7-azido-4-methylcoumarin. For the measurement of bioenergetic function, the XF24 Extracellular Flux Analyzer was used. Cell viability was estimated by the combination of the MTT and LDH methods. Oxidative protein modifications were measured by the Oxyblot method. Reactive oxygen species production was monitored by the MitoSOX method. Mitochondrial and nuclear DNA integrity were assayed by the Long Amplicon PCR method. Oxidative stress was induced by addition of glucose oxidase. Addition of AP39 (30-300 nM) to bEnd.3 cells increased intracellular H2S levels, with a preferential response in the mitochondrial regions. AP39 exerted a concentration dependent effect on mitochondrial activity, which consisted of a stimulation of mitochondrial electron transport and cellular bioenergetic function at lower concentrations (30-100 nM) and an inhibitory effect at the higher concentration of 300 nM. Under oxidative stress conditions induced by glucose oxidase, an increase in oxidative protein modification and an enhancement in MitoSOX oxidation was noted, coupled with an inhibition of cellular bioenergetic function and a reduction in cell viability. AP39 pretreatment attenuated these responses. Glucose oxidase induced a preferential damage to the mitochondrial DNA; AP39 (100 nM) pretreatment protected against it. In conclusion, the current paper documents antioxidant and cytoprotective effects of AP39 under oxidative stress conditions, including a protection against oxidative mitochondrial DNA damage. PMID- 24755207 TI - Benzodiazepine treatment can impair or spare extinction, depending on when it is given. AB - BACKGROUND: Benzodiazepines reduce the effectiveness of fear extinction in rodents and of exposure therapy in people suffering from anxiety disorders if given concomitantly with the behavioral treatment from its onset. The present experiments used rats to examine whether benzodiazepines had the same detrimental effect when given after some initial extinction had been conducted drug-free. METHODS: Rats were trained to fear a context (Experiments 1 and 2) or discrete cue (Experiment 3) and were extinguished to the context or cue under a benzodiazepine (midazolam) or vehicle. Extinction occurred either continuously in one session, with the drug or vehicle administered prior to the onset, or divided into two sessions, with the drug or vehicle administered prior to the second session. Rats were then tested, drug-free, for fear of the context or CS. RESULTS: Midazolam disrupted context and cue extinction when administered prior to the initial session but failed to disrupt extinction when given prior to the second session. CONCLUSIONS: The results in an animal model confirm that the effectiveness of extinction can be reduced when combined with benzodiazepines. They also suggest that the effectiveness of extinction will not be reduced when combined with a benzodiazepine if the patient has undergone some initial extinction drug-free. PMID- 24755206 TI - A randomized trial of peer-delivered self-management support for hypertension. AB - BACKGROUND: Peer-led interventions to improve chronic disease self-management can improve health outcomes but are not widely used. Therefore, we tested a peer-led hypertension self-management intervention delivered at regular meetings of community veterans' organizations. METHODS: We randomized 58 organizational units ("posts") of veterans' organizations in southeast Wisconsin to peer-led vs. professionally delivered self-management education. Volunteer peer leaders at peer-led posts delivered monthly presentations regarding hypertension self management during regular post meetings. Volunteer post representatives at seminar posts encouraged post members to attend 3 didactic seminars delivered by health professionals at a time separate from the post meeting. Volunteers in both groups encouraged members to self-monitor using blood pressure cuffs, weight scales, and pedometers. Our primary outcome was change in systolic blood pressure (SBP) at 12 months. RESULTS: We measured SBP in 404 participants at baseline and in 379 participants at 12 months. SBP decreased significantly (4.4mm Hg; P < 0.0001) overall; the decrease was similar in peer-led and seminar posts (3.5mm Hg vs. 5.4mm Hg; P = 0.24). Among participants with uncontrolled BP at baseline, SBP decreased by 10.1mm Hg from baseline to 12 months but was again similar in the 2 groups. This pattern was also seen at 6 months and with diastolic blood pressure. CONCLUSIONS: Our peer-led educational intervention was not more effective than didactic seminars for SBP control. Although peer-led educational programs have had important impacts in a number of studies, we did not find our intervention superior to a similar intervention delivered by healthcare professionals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00571038. PMID- 24755208 TI - Phonological markers of sentence stress in ataxic dysarthria and their relationship to perceptual cues. AB - A wide range of literature is available on the features of ataxic dysarthria, investigating segmental and prosodic characteristics by acoustic and perceptual means. However, very few studies have been published that look closely at the relationship between the observed phonetic disturbances and their perceptual sequelae, particularly in the area of prosody. The aim of the current study was therefore to examine the stress production of eight individuals with ataxic dysarthria and matched healthy controls, and to relate the results of phonological and perceptual evaluations to phonetic performances to better understand the relationship between these three components for speech outcomes. Speakers performed a sentence stress task which was analysed phonologically in terms of inventory, distribution, implementation and function of pitch accentuation. These data were then evaluated in relation to previously published phonetic and perceptual results on the same speaker group by the authors. Results indicated that the speakers with ataxia used a wide range of pitch patterns, but pitch-accented a higher number of words, and produced shorter phrases. The increased number of pitch accents per phrase was furthermore reflected in a reduced percentage of de-accented words in post-focal position. Perceptual results established this pattern as the main cause for listener errors in identifying the intended stressed item in an utterance. In addition, the performances of two speakers are discussed in greater detail. Although they were unable to de-accent, they nevertheless marked stress appropriately through phonetic compensatory strategies. LEARNING OUTCOMES: After reading this article the reader will be able to (1) explain the relevance of phonology and phonetics in the perception of stress production in ataxic dysarthria; (2) describe the different levels of intonational analysis; and (3) understand the observed intonation patterns in ataxic dysarthria as well as the compensatory mechanisms speakers may adopt to produce stress. PMID- 24755209 TI - Correlations of skin fold thickness and validation of prediction equations using DEXA as the gold standard for estimation of body fat composition in Pakistani children. AB - OBJECTIVE: To determine the correlation between dual energy X-ray absorptiometry (DEXA) and skin fold thickness (SKF) equations for estimation of body fat (BF) composition in secondary school children and validation of prediction equations by Slaughter, Goran and Dezenberg. DESIGN: Cross sectional analytical study. SETTING: Joint Commission for International Accredited (JCIA) tertiary care hospital of Karachi, Pakistan from January 2010 to May 2010. PARTICIPANTS: The study was approved by the Hospital's ethical review committee. Written and verbal consents were obtained from principals of two schools and parents of 99 children (mean age of 14+/-1.89 years; min-max 9-19 years; 54 men and 45 women) accrued in study. DEXA scan was acquired and SKF was measured at angle of the scapula, iliac crest and mid-arm for bicep and tricep skin folds using Holtain Callipers. Correlations were established between estimated fat mass (FM) and per cent BF (%BF) calculated by DEXA and those predicted by prediction equations. On obtaining significant correlation of >0.5, overall accuracy, precision and bias was calculated. RESULTS: There was an overall increased adiposity in females with FM of 3.57 kg and %BF 6.2% higher than male counterparts (p<0.05). Slaughter equation predicted %BF accurately with overall high accuracy, minimal bias and with good precision with DEXA. Dezenberg and Goran equations had significant bias in prediction of FM which was statistically significant with low level of accuracy of the Goran equation. CONCLUSIONS: We conclude that Slaughter equation for estimating %BF showed reasonable validation with DEXA. Nevertheless further studies with consideration for maturity and ethnicity are warranted for better results. However, for estimation of FM, previously formulated equations by Goran and Dezenberg showed significant difference in our population. We do recommend further studies for developing and validation of skin fold equations specific to Pakistani paediatric population. PMID- 24755210 TI - Maltreatment or violence-related injury in children and adolescents admitted to the NHS: comparison of trends in England and Scotland between 2005 and 2011. AB - OBJECTIVE: Legislation to safeguard children from maltreatment by carers or violence by others was advanced in England and Scotland around 2004-2005 and resulted in different policies and services. We examined whether subsequent trends in injury admissions to hospital related to maltreatment or violence varied between the two countries. SETTING AND PARTICIPANTS: We analysed rates of all unplanned injury admission to National Health Service (NHS) hospitals in England and Scotland between 2005 and 2011 for children and adolescents aged less than 19 years. OUTCOMES: We compared incidence trends for maltreatment or violence-related (MVR) injury and adjusted rate differences between 2005 and 2011 using Poisson or negative binomial regression models to adjust for seasonal effects and secular trends in non-MVR injury. Infants, children 1-10 years and adolescents 11-18 years were analysed separately. RESULTS: In 2005, MVR rates were similar in England and Scotland for infants and 1-10-year-olds, but almost twice as high in Scotland for 11-18-year-olds. MVR rates for infants increased by similar amounts in both countries, in line with rising non-MVR rates in England but contrary to declines in Scotland. Among 1-10-year-olds, MVR rates increased in England and declined in Scotland, in line with increasing non-MVR rates in England and declining rates in Scotland. Among 11-18-year-olds, MVR rates declined more steeply in Scotland than in England along with declines in non-MVR trends. CONCLUSIONS: Diverging trends in England and Scotland may reflect true changes in the occurrence of MVR injury or differences in the way services recognise and respond to these children, record such injuries or a combination of these factors. Further linkage of data from surveys and services for child maltreatment and violence could help distinguish the impact of policies. PMID- 24755211 TI - Is density of neighbourhood restaurants associated with BMI in rural Chinese adults? A longitudinal study from the China Health and Nutrition Survey. AB - OBJECTIVES: The neighbourhood availability of restaurants has been linked to the weight status. However, little is known regarding the relation between access to restaurant and obesity among the Chinese population. This study aims to explore the relationship between neighbourhood restaurant density and body mass index (BMI) in rural China. DESIGN: A longitudinal study using data from the China Health and Nutrition Survey (CHNS) was conducted. Participants aged 18 and older from the 2004, 2006, 2009 and 2011 CHNS were recruited Separate sex-stratified random intercept-slope growth models of repeated BMI observations were estimated in the study. SETTING: The data were derived from rural communities in nine provinces in China. PARTICIPANTS: There were 11 835 male and 12 561 female person years assessed in this study. OUTCOMES: The primary outcome of this study was weight status. It is defined as a BMI value, a continuous variable which is calculated by dividing weight (kg) by the square of height (m(2)). RESULTS: The study indicated that among men an increase of one indoor restaurant in the neighbourhood was associated with a 0.01 kg/m(2) increase in BMI, and an increase of one fixed outdoor food stall was associated with a 0.01 kg/m(2) decrease in BMI, whereas among women, an increase of one indoor restaurant in the neighbourhood was associated with a 0.005 kg/m(2) increase in BMI, and an increase of one fast-food restaurant and one fixed outdoor food stall was associated with a 0.02 and 0.004 kg/m(2) decline in BMI, respectively. CONCLUSIONS: The density of neighbourhood restaurants was found to be significantly related to BMI in rural China. The results indicated that providing healthy food choices and developing related public health policies are necessary to tackle obesity among rural Chinese adults. PMID- 24755212 TI - Clinical predictors of 2-year outcome of resective epilepsy surgery in adults with refractory epilepsy: a cohort study. AB - OBJECTIVES: Resective epilepsy surgery is currently a standard treatment for intractable epilepsy. Seizure freedom and discontinuation of antiepileptic drugs are the ultimate goals of epilepsy treatment. This study was carried out to delineate (1) possible differences in the success rate of epilepsy surgery 6 and 24 months after surgery; and (2) the clinical predictors of a good response to surgery. SETTING: This is a cohort study performed at a tertiary care unit of a university hospital. PARTICIPANTS: In this cohort study, 189 adults with intractable epilepsy who underwent epilepsy surgery were included. We collected clinical data at three time points, that is, preoperative and 6 and 24 months after surgery. PRIMARY AND SECONDARY OUTCOME MEASURES: Engel class I-IV classification was the primary outcome measure of epilepsy surgery. The authors statistically adjusted Engel class I-IV classification for postoperative changes in antiepileptic drugs and used this new classification as a secondary outcome variable. RESULTS: The success rate was 78.8% 6 months after surgery and increased to 88.3% 24 months after surgery. This success rate was reflected not only by the reduced number of seizures postsurgery, but also by a reduced dosage and use of antiepileptic drugs. Logistic regression analysis showed that a successful outcome of surgery is predicted by having temporal rather than extratemporal lobe epilepsy and less than nine presurgery seizures per month, while a positive familial history of epilepsy, younger age and dysphoric symptoms, the first 3 months after surgery, significantly worsened the outcome of surgery. Duration of illness, age at onset, epilepsy location, type of lesions and the presence of psychosis were not significant in predicting treatment outcome. CONCLUSIONS: These findings have clinical relevance in that a better selection of patients based on the significant clinical predictors will increase the success rate of epilepsy surgery and treatment. PMID- 24755213 TI - Automatic method of analysis of OCT images in the assessment of the tooth enamel surface after orthodontic treatment with fixed braces. AB - INTRODUCTION: Fixed orthodontic appliances, despite years of research and development, still raise a lot of controversy because of its potentially destructive influence on enamel. Therefore, it is necessary to quantitatively assess the condition and therein the thickness of tooth enamel in order to select the appropriate orthodontic bonding and debonding methodology as well as to assess the quality of enamel after treatment and clean-up procedure in order to choose the most advantageous course of treatment. One of the assessment methods is computed tomography where the measurement of enamel thickness and the 3D reconstruction of image sequences can be performed fully automatically. MATERIAL AND METHOD: OCT images of 180 teeth were obtained from the Topcon 3D OCT-2000 camera. The images were obtained in vitro by performing sequentially 7 stages of treatment on all the teeth: before any interference into enamel, polishing with orthodontic paste, etching and application of a bonding system, orthodontic bracket bonding, orthodontic bracket removal, cleaning off adhesive residue. A dedicated method for the analysis and processing of images involving median filtering, mathematical morphology, binarization, polynomial approximation and the active contour method has been proposed. RESULTS: The obtained results enable automatic measurement of tooth enamel thickness in 5 seconds using the Core i5 CPU M460 @ 2.5GHz 4GB RAM. For one patient, the proposed method of analysis confirms enamel thickness loss of 80 MUm (from 730 +/- 165 MUm to 650 +/- 129 MUm) after polishing with paste, enamel thickness loss of 435 MUm (from 730 +/- 165 MUm to 295 +/- 55 MUm) after etching and bonding resin application, growth of a layer having a thickness of 265 MUm (from 295 +/- 55 MUm to 560 +/- 98 MUm after etching) which is the adhesive system. After removing an orthodontic bracket, the adhesive residue was 105 MUm and after cleaning it off, the enamel thickness was 605 MUm. The enamel thickness before and after the whole treatment decreased by about 125 MUm. CONCLUSIONS: This paper presents an automatic quantitative method for the assessment of tooth enamel thickness. This method has proven to be an effective diagnostic tool that allows evaluation of the surface and cross section of tooth enamel after orthodontic treatment with fixed thin arched braces and proper selection of the methodology and course of treatment. PMID- 24755214 TI - De-implementation of expensive blood saving measures in hip and knee arthroplasties: study protocol for the LISBOA-II cluster randomized trial. AB - BACKGROUND: Despite evidence that erythropoietin and intra- and postoperative blood salvage are expensive techniques considered to be non-cost-effective in primary elective total hip and knee arthroplasties in the Netherlands, Dutch medical professionals use them frequently to prevent the need for allogeneic transfusion. To actually change physicians' practice, a tailored strategy aimed at barriers that hinder physicians in abandoning the use of erythropoietin and perioperative blood salvage was systematically developed. The study aims to examine the effectiveness, feasibility and costs of this tailored de implementation strategy compared to a control strategy. METHODS/DESIGN: A cluster randomized controlled trial including an effect, process and economic evaluation will be conducted in a minimum of 20 Dutch hospitals. Randomisation takes place at hospital level. The hospitals in the intervention group will receive a tailored de-implementation strategy that consists of four components: interactive education, feedback in educational outreach visits, electronically sent reports on hospital performance (all aimed at orthopedic surgeons and anesthesiologists), and information letters or emails aimed at other involved professionals within the intervention hospital (transfusion committee, OR-personnel, pharmacists). The hospitals in the control group will receive a control strategy (i.e., passive dissemination of available evidence). Outcomes will be measured at patient level, using retrospective medical record review. This will be done in all hospitals at baseline and after completion of the intervention period. The primary outcome of the effect evaluation is the percentage of patients undergoing primary elective total hip or knee arthroplasty in which erythropoietin or perioperative blood salvage is applied. The actual exposure to the tailored strategy and users' experiences will be assessed in the process evaluation. In the economic evaluation, the costs of the tailored strategy and the control strategy in relation to the difference in their effectiveness will be compared. DISCUSSION: This study will show whether a systematically developed tailored strategy is more effective for de-implementation of non-cost-effective blood saving measures than the control strategy. This knowledge can be used in national and international initiatives to make healthcare more efficient. It also provides more generalized knowledge regarding de-implementation strategies. TRIAL REGISTRATION: This trial is registered at the Dutch Trial Register NTR4044. PMID- 24755215 TI - Endoplasmic reticulum stress triggers gametocytogenesis in the malaria parasite. AB - The malaria parasite experiences a significant amount of redox stress during its growth in human erythrocytes and heavily relies on secretory functions for pathogenesis. Most certainly, the parasite is equipped with machinery to tackle perturbations in the secretory pathway, like the unfolded protein response pathway in higher eukaryotes. Our bioinformatics analysis revealed the complete absence of genes involved in the canonical unfolded protein response pathway in Plasmodium falciparum. Accordingly, the parasite was unable to up-regulate endoplasmic reticulum (ER) chaperones or ER-associated degradation in response to DTT-mediated ER stress. Global profiling of gene expression upon DTT treatment revealed a network of AP2 transcription factors and their targets being activated. The overall outcome was up-regulation of genes involved in protein export and the sexual stage of the parasite life cycle culminating in gametocytogenesis. Our results suggest that the malaria parasite uses ER stress as a cue to switch to the transmissible sexual stages. PMID- 24755216 TI - Involvement of Neisseria meningitidis lipoprotein GNA2091 in the assembly of a subset of outer membrane proteins. AB - GNA2091 of Neisseria meningitidis is a lipoprotein of unknown function that is included in the novel 4CMenB vaccine. Here, we investigated the biological function and the subcellular localization of the protein. We demonstrate that GNA2091 functions in the assembly of outer membrane proteins (OMPs) because its absence resulted in the accumulation of misassembled OMPs. Cell fractionation and protease accessibility experiments showed that the protein is localized at the periplasmic side of the outer membrane. Pulldown experiments revealed that it is not stably associated with the beta-barrel assembly machinery, the previously identified complex for OMP assembly. Thus, GNA2091 constitutes a novel outer membrane-based lipoprotein required for OMP assembly. Furthermore, its location at the inner side of the outer membrane indicates that protective immunity elicited by this antigen cannot be due to bactericidal or opsonic activity of antibodies. PMID- 24755217 TI - The novel alpha4B murine alpha4 integrin protein splicing variant inhibits alpha4 protein-dependent cell adhesion. AB - Integrins affect the motility of multiple cell types to control cell survival, growth, or differentiation, which are mediated by cell-cell and cell extracellular matrix interactions. We reported previously that the alpha9 integrin splicing variant, SFalpha9, promotes WT alpha9 integrin-dependent adhesion. In this study, we introduced a new murine alpha4 integrin splicing variant, alpha4B, which has a novel short cytoplasmic tail. In inflamed tissues, the expression of alpha4B, as well as WT alpha4 integrin, was up-regulated. Cells expressing alpha4B specifically bound to VCAM-1 but not other alpha4 integrin ligands, such as fibronectin CS1 or osteopontin. The binding of cells expressing WT alpha4 integrin to alpha4 integrin ligands is inhibited by coexpression of alpha4B. Knockdown of alpha4B in metastatic melanoma cell lines results in a significant increase in lung metastasis. Expression levels of WT alpha4 integrin are unaltered by alpha4B, with alpha4B acting as a regulatory subunit for WT alpha4 integrin by a dominant-negative effect or inhibiting alpha4 integrin activation. PMID- 24755218 TI - Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor-alpha and interleukin-1beta but suppresses that by interleukin-17A: importance of proteolytic degradation of osteoprotegerin by lysine gingipain. AB - Periodontitis is a chronic inflammatory disease accompanied by alveolar bone resorption by osteoclasts. Porphyromonas gingivalis, an etiological agent for periodontitis, produces cysteine proteases called gingipains, which are classified based on their cleavage site specificity (i.e. arginine (Rgps) and lysine (Kgps) gingipains). We previously reported that Kgp degraded osteoprotegerin (OPG), an osteoclastogenesis inhibitory factor secreted by osteoblasts, and enhanced osteoclastogenesis induced by various Toll-like receptor (TLR) ligands (Yasuhara, R., Miyamoto, Y., Takami, M., Imamura, T., Potempa, J., Yoshimura, K., and Kamijo, R. (2009) Lysine-specific gingipain promotes lipopolysaccharide- and active-vitamin D3-induced osteoclast differentiation by degrading osteoprotegerin. Biochem. J. 419, 159-166). Osteoclastogenesis is induced not only by TLR ligands but also by proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) 1beta, and IL-17A, in inflammatory conditions, such as periodontitis. Although Kgp augmented osteoclastogenesis induced by TNF-alpha and IL-1beta in co-cultures of mouse osteoblasts and bone marrow cells, it suppressed that induced by IL-17A. In a comparison of proteolytic degradation of these cytokines by Kgp in a cell free system with that of OPG, TNF-alpha and IL-1beta were less susceptible, whereas IL-17A and OPG were equally susceptible to degradation by Kgp. These results indicate that the enhancing effect of Kgp on cytokine-induced osteoclastogenesis is dependent on the difference in degradation efficiency between each cytokine and OPG. In addition, elucidation of the N-terminal amino acid sequences of OPG fragments revealed that Kgp primarily cleaved OPG in its death domain homologous region, which might prevent dimer formation of OPG required for inhibition of receptor activator of nuclear factor kappaB ligand. Collectively, our results suggest that degradation of OPG by Kgp is a crucial event in the development of osteoclastogenesis and bone loss in periodontitis. PMID- 24755219 TI - Galiellalactone is a direct inhibitor of the transcription factor STAT3 in prostate cancer cells. AB - The transcription factor STAT3 is constitutively active in several malignancies including castration-resistant prostate cancer and has been identified as a promising therapeutic target. The fungal metabolite galiellalactone, a STAT3 signaling inhibitor, inhibits the growth, both in vitro and in vivo, of prostate cancer cells expressing active STAT3 and induces apoptosis of prostate cancer stem cell-like cells expressing phosphorylated STAT3 (pSTAT3). However, the molecular mechanism of this STAT3-inhibiting effect by galiellalactone has not been clarified. A biotinylated analogue of galiellalactone (GL-biot) was synthesized to be used for identification of galiellalactone target proteins. By adding streptavidin-Sepharose beads to GL-biot-treated DU145 cell lysates, STAT3 was isolated and identified as a target protein. Confocal microscopy revealed GL biot in both the cytoplasm and the nucleus of DU145 cells treated with GL-biot, appearing to co-localize with STAT3 in the nucleus. Galiellalactone inhibited STAT3 binding to DNA in DU145 cell lysates without affecting phosphorylation status of STAT3. Mass spectrometry analysis of recombinant STAT3 protein pretreated with galiellalactone revealed three modified cysteines (Cys-367, Cys 468, and Cys-542). Here we demonstrate with chemical and molecular pharmacological methods that galiellalactone is a cysteine reactive inhibitor that covalently binds to one or more cysteines in STAT3 and that this leads to inhibition of STAT3 binding to DNA and thus blocks STAT3 signaling without affecting phosphorylation. This further validates galiellalactone as a promising direct STAT3 inhibitor for treatment of castration-resistant prostate cancer. PMID- 24755220 TI - Structural basis of pilus anchoring by the ancillary pilin RrgC of Streptococcus pneumoniae. AB - Pili are surface-attached, fibrous virulence factors that play key roles in the pathogenesis process of a number of bacterial agents. Streptococcus pneumoniae is a causative agent of pneumonia and meningitis, and the appearance of drug resistance organisms has made its treatment challenging, especially in developing countries. Pneumococcus-expressed pili are composed of three structural proteins: RrgB, which forms the polymerized backbone, RrgA, the tip-associated adhesin, and RrgC, which presumably associates the pilus with the bacterial cell wall. Despite the fact that the structures of both RrgA and RrgB were known previously, structural information for RrgC was still lacking, impeding the analysis of a complete model of pilus architecture. Here, we report the structure of RrgC to 1.85 A and reveal that it is a three-domain molecule stabilized by two intradomain isopeptide bonds. RrgC does not depend on pilus-specific sortases to become attached to the cell wall; instead, it binds the preformed pilus to the peptidoglycan by employing the catalytic activity of SrtA. A comprehensive model of the type 1 pilus from S. pneumoniae is also presented. PMID- 24755221 TI - Delay in apoptosome formation attenuates apoptosis in mouse embryonic stem cell differentiation. AB - Differentiation is an inseparable process of development in multicellular organisms. Mouse embryonic stem cells (mESCs) represent a valuable research tool to conduct in vitro studies of cell differentiation. Apoptosis as a well known cell death mechanism shows some common features with cell differentiation, which has caused a number of ambiguities in the field. The research question here is how cells could differentiate these two processes from each other. We have investigated the role of the mitochondrial apoptotic pathway and cell energy level during differentiation of mESCs into the cardiomyocytes and their apoptosis. p53 expression, cytochrome c release, apoptosome formation, and caspase-3/7 activation are observed upon induction of both apoptosis and differentiation. However, remarkable differences are detected in time of cytochrome c appearance, apoptosome formation, and caspase activity upon induction of both processes. In apoptosis, apoptosome formation and caspase activity were observed rapidly following the cytochrome c release. Unlike apoptosis, the release of cytochrome c upon differentiation took more time, and the maximum caspase activity was also postponed for 24 h. This delay suggests that there is a regulatory mechanism during differentiation of mESCs into cardiomyocytes. The highest ATP content of cells was observed immediately after cytochrome c release 6 h after apoptosis induction and then decreased, but it was gradually increased up to 48 h after differentiation. These observations suggest that a delay in the release of cytochrome c or delay in ATP increase attenuate apoptosome formation, and caspase activation thereby discriminates apoptosis from differentiation in mESCs. PMID- 24755222 TI - Ligand-induced homotypic and heterotypic clustering of apolipoprotein E receptor 2. AB - ApoE Receptor 2 (ApoER2) and the very low density lipoprotein receptor (VLDLR) are type I transmembrane proteins belonging to the LDLR family of receptors. They are neuronal proteins found in synaptic compartments that play an important role in neuronal migration during development. ApoER2 and VLDLR bind to extracellular glycoproteins, such as Reelin and F-spondin, which leads to phosphorylation of adaptor proteins and subsequent activation of downstream signaling pathways. It is thought that ApoER2 and VLDLR undergo clustering upon binding to their ligands, but no direct evidence of clustering has been shown. Here we show strong clustering of ApoER2 induced by the dimeric ligands Fc-RAP, F-spondin, and Reelin but relatively weak clustering with the ligand apoE in the absence of lipoproteins. This clustering involves numerous proteins besides ApoER2, including amyloid precursor protein and the synaptic adaptor protein PSD-95. Interestingly, we did not observe strong clustering of ApoER2 with VLDLR. Clustering was modulated by both extracellular and intracellular domains of ApoER2. Together, our data demonstrate that several multivalent ligands for ApoER2 induce clustering in transfected cells and primary neurons and that these complexes included other synaptic molecules, such as APP and PSD-95. PMID- 24755223 TI - RNA protein granules modulate tau isoform expression and induce neuronal sprouting. AB - The neuronal microtubule-associated protein Tau is expressed in different variants, and changes in Tau isoform composition occur during development and disease. Here, we investigate a potential role of the multivalent tau mRNA binding proteins G3BP1 and IMP1 in regulating neuronal tau expression. We demonstrate that G3BP1 and IMP1 expression induces the formation of structures, which qualify as neuronal ribonucleoprotein (RNP) granules and concentrate multivalent proteins and mRNA. We show that RNP granule formation leads to a >30 fold increase in the ratio of high molecular weight to low molecular weight tau mRNA and an ~12-fold increase in high molecular weight to low molecular weight Tau protein. We report that RNP granule formation is associated with increased neurite formation and enhanced process growth. G3BP1 deletion constructs that do not induce granule formation are also deficient in inducing neuronal sprouting or changing the expression pattern of tau. The data indicate that granule formation driven by multivalent proteins modulates tau isoform expression and suggest a morphoregulatory function of RNP granules during health and disease. PMID- 24755224 TI - Two p90 ribosomal S6 kinase isoforms are involved in the regulation of mitotic and meiotic arrest in Artemia. AB - There are multiple isoforms of p90 ribosomal S6 kinase (RSK), which regulate diverse cellular functions such as cell growth, proliferation, maturation, and motility. However, the relationship between the structures and functions of RSK isoforms remains undetermined. Artemia is a useful model in which to study cell cycle arrest because these animals undergo prolonged diapauses, a state of obligate dormancy. A novel RSK isoform was identified in Artemia, which was termed Ar-Rsk2. This isoform was compared with an RSK isoform that we previously identified in Artemia, termed Ar-Rsk1. Ar-Rsk2 has an ERK-docking motif, whereas Ar-Rsk1 does not. Western blot analysis revealed that Ar-Rsk1 was activated by phosphorylation, which blocked meiosis in oocytes. Knockdown of Ar-Rsk1 reduced the level of phosphorylated cdc2 and thereby suppressed cytostatic factor activity. This indicates that Ar-Rsk1 regulates the cytostatic factor in meiosis. Expression of Ar-Rsk2 was down-regulated in Artemia cysts in which mitosis was arrested. Knockdown of Ar-Rsk2 resulted in decreased levels of cyclin D3 and phosphorylated histone H3, and the production of pseudo-diapause cysts. This indicates that Ar-Rsk2 regulates mitotic arrest. PLK and ERK RNAi showed that Ar Rsk2, but not Ar-Rsk1, could be activated by PLK-ERK in Artemia. This is the first study to report that RSK isoforms with and without an ERK-docking motif regulate mitosis and meiosis, respectively. This study provides insight into the relationship between the structures and functions of RSK isoforms. PMID- 24755225 TI - (R)-mevalonate 3-phosphate is an intermediate of the mevalonate pathway in Thermoplasma acidophilum. AB - The lack of a few conserved enzymes in the classical mevalonate pathway and the widespread existence of isopentenyl phosphate kinase suggest the presence of a partly modified mevalonate pathway in most archaea and in some bacteria. In the pathway, (R)-mevalonate 5-phosphate is thought to be metabolized to isopentenyl diphosphate via isopentenyl phosphate. The long anticipated enzyme that catalyzes the reaction from (R)-mevalonate 5-phosphate to isopentenyl phosphate was recently identified in a Cloroflexi bacterium, Roseiflexus castenholzii, and in a halophilic archaeon, Haloferax volcanii. However, our trial to convert the intermediates of the classical and modified mevalonate pathways into isopentenyl diphosphate using cell-free extract from a thermophilic archaeon Thermoplasma acidophilum implied that the branch point intermediate of these known pathways, i.e. (R)-mevalonate 5-phosphate, is unlikely to be the precursor of isoprenoid. Through the process of characterizing the recombinant homologs of mevalonate pathway-related enzymes from the archaeon, a distant homolog of diphosphomevalonate decarboxylase was found to catalyze the phosphorylation of (R)-mevalonate to yield (R)-mevalonate 3-phosphate. The product could be converted into isopentenyl phosphate, probably through (R)-mevalonate 3,5 bisphosphate, by the action of unidentified T. acidophilum enzymes fractionated by anion-exchange chromatography. These findings demonstrate the presence of a third alternative "Thermoplasma-type" mevalonate pathway, which involves (R) mevalonate 3-phosphotransferase and probably both (R)-mevalonate 3-phosphate 5 phosphotransferase and (R)-mevalonate 3,5-bisphosphate decarboxylase, in addition to isopentenyl phosphate kinase. PMID- 24755227 TI - Domain contributions to signaling specificity differences between Ras-guanine nucleotide releasing factor (Ras-GRF) 1 and Ras-GRF2. AB - Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity. They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras activating domains. Nevertheless, they regulate different forms of synaptic plasticity. Although both GRF proteins transduce calcium signals emanating from NMDA-type glutamate receptors in the CA1 region of the hippocampus, GRF1 promotes LTD, whereas GRF2 promotes theta-burst stimulation-induced LTP (TBS-LTP). GRF1 can also mediate high frequency stimulation-induced LTP (HFS-LTP) in mice over 2 months of age, which involves calcium-permeable AMPA-type glutamate receptors. To add to our understanding of how proteins with similar domains can have different functions, WT and various chimeras between GRF1 and GRF2 proteins were tested for their abilities to reconstitute defective LTP and/or LTD in the CA1 hippocampus of Grf1/Grf2 double knock-out mice. These studies revealed a critical role for the GRF2 CDC25 domain in the induction of TBS-LTP by GRF proteins. In contrast, the N-terminal pleckstrin homology and/or coiled-coil domains of GRF1 are key to the induction of HFS-LTP by GRF proteins. Finally, the IQ motif of GRF1 determines whether a GRF protein can induce LTD. Overall, these findings show that for the three forms of synaptic plasticity that are regulated by GRF proteins in the CA1 hippocampus, specificity is encoded in only one or two domains, and a different set of domains for each form of synaptic plasticity. PMID- 24755226 TI - Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2 mediated cell migration. AB - Eya proteins are essential co-activators of the Six family of transcription factors and contain a unique tyrosine phosphatase domain belonging to the haloacid dehalogenase family of phosphatases. The phosphatase activity of Eya is important for the transcription of a subset of Six1-target genes, and also directs cells to the repair rather than apoptosis pathway upon DNA damage. Furthermore, Eya phosphatase activity has been shown to mediate transformation, invasion, migration, and metastasis of breast cancer cells, making it a potential new drug target for breast cancer. We have previously identified a class of N arylidenebenzohydrazide compounds that specifically inhibit the Eya2 phosphatase. Herein, we demonstrate that these compounds are reversible inhibitors that selectively inhibit the phosphatase activity of Eya2, but not Eya3. Our mutagenesis results suggest that this class of compounds does not bind to the active site and the binding does not require the coordination with Mg(2+). Moreover, these compounds likely bind within a site on the opposite face of the active site, and function as allosteric inhibitors. We also demonstrate that this class of compounds inhibits Eya2 phosphatase-mediated cell migration, setting the foundation for these molecules to be developed into chemical probes for understanding the specific function of the Eya2 phosphatase and to serve as a prototype for the development of Eya2 phosphatase specific anti-cancer drugs. PMID- 24755228 TI - Caveolin-1 alters the pattern of cytoplasmic Ca2+ oscillations and Ca2+-dependent gene expression by enhancing leukotriene receptor desensitization. AB - Cytoplasmic Ca(2+) oscillations constitute a widespread signaling mode and are often generated in response to stimulation of G protein-coupled receptors that activate phospholipase C. In mast cells, repetitive Ca(2+) oscillations can be evoked by modest activation of cysteinyl leukotriene type I receptors by the physiological trigger, leukotriene C4. The Ca(2+) oscillations arise from regenerative Ca(2+) release from inositol 1,4,5-trisphosphate-sensitive stores followed by Ca(2+) entry through store-operated Ca(2+) channels, and the latter selectively activate the Ca(2+)-dependent transcription factor NFAT. The cysteinyl leukotriene type I receptors desensitize through negative feedback by protein kinase C, which terminates the oscillatory Ca(2+) response. Here, we show that the scaffolding protein caveolin-1 has a profound effect on receptor-driven Ca(2+) signals and downstream gene expression. Overexpression of caveolin-1 increased receptor-phospholipase C coupling, resulting in initially larger Ca(2+) release transients of longer duration but which then ran down quickly. NFAT activated gene expression, triggered in response to the Ca(2+) signal, was also reduced by caveolin-1. Mutagenesis studies revealed that these effects required a functional scaffolding domain within caveolin-1. Mechanistically, the increase in Ca(2+) release in the presence of caveolin-1 activated protein kinase C, which accelerated homologous desensitization of the leukotriene receptor and thereby terminated the oscillatory Ca(2+) response. Our results reveal that caveolin-1 is a bimodal regulator of receptor-dependent Ca(2+) signaling, which fine-tunes the spatial and temporal profile of the Ca(2+) rise and thereby its ability to activate the NFAT pathway. PMID- 24755229 TI - Visuo-spatial ability in individuals with Down syndrome: is it really a strength? AB - Down syndrome (DS) is associated with extreme difficulty in verbal skills and relatively better visuo-spatial skills. Indeed, visuo-spatial ability is often considered a strength in DS. However, it is not clear whether this strength is only relative to the poor verbal skills, or, more impressively, relative to cognitive ability in general. To answer this question, we conducted an extensive literature review of studies on visuo-spatial abilities in people with Down syndrome from January 1987 to May 2013. Based on a general taxonomy of spatial abilities patterned after Lohman, Pellegrino, Alderton, and Regian (1987) and Carroll (1993) and existing studies of DS, we included five different domains of spatial abilities - visuo-spatial memory, visuo-spatial construction, mental rotation, closure, and wayfinding. We evaluated a total of 49 studies including 127 different comparisons. Most comparisons involved a group with DS vs. a group with typical development matched on mental age and compared on a task measuring one of the five visuo-spatial abilities. Although further research is needed for firm conclusions on some visuo-spatial abilities, there was no evidence that visuo-spatial ability is a strength in DS relative to general cognitive ability. Rather, the review suggests an uneven profile of visuo-spatial abilities in DS in which some abilities are commensurate with general cognitive ability level, and others are below. PMID- 24755230 TI - A comparison of family financial and employment impacts of fragile X syndrome, autism spectrum disorders, and intellectual disability. AB - This study compares the family financial and employment impacts of having a child with fragile X syndrome (FXS), autism spectrum disorder (ASD), or intellectual disabilities (ID). Data from a 2011 national survey of families of children with FXS were matched with data from the National Survey of Children with Special Health Care Needs 2009-2010 to form four analytic groups: children with FXS (n=189), children with special health care needs with ASD only (n=185), ID only (n=177), or both ASD and ID (n=178). Comparable percentages of parents of children with FXS (60%) and parents of children with both ASD and ID (52%) reported that their families experienced a financial burden as a result of the condition, both of which were higher than the percentages of parents of children with ASD only (39%) or ID only (29%). Comparable percentages of parents of children with FXS (40%) and parents of children with both ASD and ID (46%) reported quitting employment because of the condition, both of which were higher than the percentages of parents of children with ID only (25%) or ASD only (25%). In multivariate analyses controlling for co-occurring conditions and functional difficulties and stratified by age, adjusted odds ratios for the FXS group aged 12-17 years were significantly elevated for financial burden (2.73, 95% CI 1.29 5.77), quitting employment (2.58, 95% CI 1.18-5.65) and reduced hours of work (4.34, 95% CI 2.08-9.06) relative to children with ASD only. Among children aged 5-11 years, the adjusted odds ratios for the FXS group were elevated but statistically insignificant for financial burden (1.63, 95% CI 0.85-3.14) and reducing hours of work (1.34, 95% CI 0.68-2.63) relative to children with ASD only. Regardless of condition, co-occurring anxiety or seizures, limits in thinking, reasoning, or learning ability, and more irritability were significantly associated with more caregiver financial and employment impacts. Proper management of anxiety or seizures and functional difficulties of children with FXS or other developmental disabilities may be important in alleviating adverse family caregiver impacts. PMID- 24755231 TI - NQO1 gene rs1800566 variant is not associated with risk for multiple sclerosis. AB - BACKGROUND: A possible role of oxidative stress in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis has been suggested. The detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1) has been found up-regulated in MS lesions. A previous report described an association between the SNP rs1800566 in the NQO1 gene and the risk for MS in the Greek population. The aim of this study was to replicate a possible influence of the. SNP rs1800566 in the NQO1 gene in the risk for MS in the Spanish Caucasian population. METHODS: We analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays. RESULTS: NQO1 rs1800566 allelic and genotypic frequencies did not differ significantly between MS patients and controls, and were unrelated with age of onset of MS, gender, and clinical type of MS. CONCLUSIONS: Our results indicate that NQO1 rs1800566 does not have an effect on MS disease risk. PMID- 24755232 TI - On the influence of the culture conditions in bacterial antifouling bioassays and biofilm properties: Shewanella algae, a case study. AB - BACKGROUND: A variety of conditions (culture media, inocula, incubation temperatures) are employed in antifouling tests with marine bacteria. Shewanella algae was selected as model organism to evaluate the effect of these parameters on: bacterial growth, biofilm formation, the activity of model antifoulants, and the development and nanomechanical properties of the biofilms.The main objectives were: 1) To highlight and quantify the effect of these conditions on relevant parameters for antifouling studies: biofilm morphology, thickness, roughness, surface coverage, elasticity and adhesion forces. 2) To establish and characterise in detail a biofilm model with a relevant marine strain. RESULTS: Both the medium and the temperature significantly influenced the total cell densities and biofilm biomasses in 24-hour cultures. Likewise, the IC50 of three antifouling standards (TBTO, tralopyril and zinc pyrithione) was significantly affected by the medium and the initial cell density. Four media (Marine Broth, MB; 2% NaCl Mueller-Hinton Broth, MH2; Luria Marine Broth, LMB; and Supplemented Artificial Seawater, SASW) were selected to explore their effect on the morphological and nanomechanical properties of 24-h biofilms. Two biofilm growth patterns were observed: a clear trend to vertical development, with varying thickness and surface coverage in MB, LMB and SASW, and a horizontal, relatively thin film in MH2. The Atomic Force Microscopy analysis showed the lowest Young modulii for MB (0.16 +/- 0.10 MPa), followed by SASW (0.19 +/- 0.09 MPa), LMB (0.22 +/- 0.13 MPa) and MH2 (0.34 +/- 0.16 MPa). Adhesion forces followed an inverted trend, being higher in MB (1.33 +/- 0.38 nN) and lower in MH2 (0.73 +/- 0.29 nN). CONCLUSIONS: All the parameters significantly affected the ability of S. algae to grow and form biofilms, as well as the activity of antifouling molecules. A detailed study has been carried out in order to establish a biofilm model for further assays. The morphology and nanomechanics of S. algae biofilms were markedly influenced by the nutritional environments in which they were developed. As strategies for biofilm formation inhibition and biofilm detachment are of particular interest in antifouling research, the present findings also highlight the need for a careful selection of the assay conditions. PMID- 24755233 TI - Antioxidant effect of Phyllanthus emblica extract prevents contrast-induced acute kidney injury. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) occurs after the administration of intravenous iodinated contrast agents. Oxidative stress has been proposed as one of the most important mechanisms in the pathogenesis of CI AKI. The objective of this study was to investigate the antioxidant effect of the extract from Phyllanthus emblica (PE) in preventing CI-AKI. METHODS: Male Sprague Dawley rats were subjected into eight groups, were given water (control) or PE extract (125 or 250 or 500 mg/kg/day) for 5 days before the induction of CI-AKI. Renal function and oxidative stress markers; malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase (CAT) activity were determined in plasma and renal tissue. Kidney sections were performed for histopathological examination. RESULTS: In the contrast media (CM) group, increases in blood urea nitrogen and serum creatinine were demonstrated which correlated with severity of tubular necrosis, peritubular capillary congestion and interstitial edema. Moreover, an increase in MDA and a decrease in TAC SOD and CAT activity in CM group were significantly changed when compared with the control (P<0.05). In contrast, CI-AKI-induced rats administrated with PE extract 250 and 500 mg/kg/day significantly preserved renal function and attenuated the severity of pathological damage (P<0.05) as well as significantly lower MDA and higher TAC, SOD and CAT than the CM group (P<0.05). CONCLUSIONS: This study demonstrated the protective role of PE extract against CI-AKI. PMID- 24755234 TI - Hemodynamic changes during posterior epilepsies: an EEG-fNIRS study. AB - Posterior epilepsies are mainly characterized clinically by visual symptoms. Functional near-infrared spectroscopy (fNIRS) is an emerging non-invasive imaging technique that has the potential to monitor hemodynamic changes during epileptic activity. Combined with electroencephalography (EEG), 9 patients with posterior epilepsies were recorded using EEG-fNIRS with large sampling (19 EEG electrodes and over 100 fNIRS channels). Spikes and seizures were carefully marked on EEG traces, and convolved with a standard hemodynamic response function for general linear model (GLM) analysis. GLM results for seizures (in 3 patients) and spikes (7 patients) were broadly sensitive to the epileptic focus in 7/9 patients, and specific in 5/9 patients with fNIRS deoxyhemoglobin responses lateralized to the correct lobe, and to plausible locations within the occipital or parietal lobes. This work provides evidence that EEG-fNIRS is a sensitive technique for monitoring posterior epileptic activity. PMID- 24755235 TI - Bedside measures of malnutrition and association with mortality in hospitalized adults. AB - BACKGROUND & AIMS: The impact of malnutrition on the outcomes of hospitalized adults in resource-limited settings such as sub-Saharan Africa (SSA) is not fully described. We aimed to determine the association between malnutrition and mortality in adults admitted to hospital in the resource-limited setting of Southwestern Uganda. METHODS: We performed a cohort study of adults admitted to the medical ward of Mbarara Regional Referral Hospital. Measures of nutritional status included: 1) body mass index (BMI), 2) the mini-nutritional assessment short form (MNA-sf), and 3) mid-upper arm circumference (MUAC). Subjects were followed until death or 30 days from admission. We used proportional hazards regression to assess associations between malnutrition and in-hospital and 30-day mortality. RESULTS: We enrolled 318 subjects. The prevalence of malnutrition was 25-59% depending on the measure used. In-hospital and 30-day mortality were 18% and 37% respectively. In the adjusted analysis, subjects with MNA-sf score 0-7 had a 2.7-fold higher risk of in-hospital mortality (95% CI: 1.3-5.9, p = 0.011) than those with a score of 8-14, and subjects with malnutrition determined by MUAC (<20 cm for males, and <19 cm for females) had a 1.8-fold higher risk of in hospital mortality (95% CI: 0.98-3.4, p = 0.06) than those normally nourished. MNA-sf (HR 1.6, 95% CI: 1.02-2.6, p = 0.039) and MUAC (HR 1.6, 95% CI: 1.0-2.3, p = 0.048) were independently predictive of 30-day mortality. BMI <18.5 was not associated with in-hospital or 30-day mortality. CONCLUSIONS: Malnutrition was common and simple measures of nutritional status predicted in-hospital and 30-day mortality. Further research is needed to understand the pathophysiology of malnutrition during acute illness and mitigate its effects. PMID- 24755236 TI - Nutritional risk screening in hospitalized patients with heart failure. AB - BACKGROUND & AIMS: Malnutrition is an important issue in patient outcome. Screening tools to find risk patients need to be evaluated. This study looks at the validity and reliability of nutritional risk screening (named NRS-2002) in hospitalized patients with chronic heart failure. METHODS: In this cross sectional study nutritional screening was performed using NRS-2002 in 131 patients with chronic heart failure. The predictive validity was evaluated in relation to whether NRS-2002 predicted the incidence of complications and length of hospital stay. NRS-2002's ability to locate nutritional risk in patients with edema was evaluated. The inter-rater reliability was measured between three investigators screening 45 patients each. RESULTS: The prevalence of nutritional risk was 57%. The incidence of complications and the median length of hospital stay were significantly higher in patients at nutritional risk compared to patients not at nutritional risk. Only the component of severity of disease in NRS-2002 and not the component of the nutritional status was associated with increased length of hospital stay in multivariate analysis. Patients with edema were classified correctly regarding nutritional risk status by NRS-2002 in all but one occasion. The inter-rater reliability was documented, kappa >0.60. CONCLUSION: NRS-2002 was a reliable screening tool in an in-patient sample with chronic heart failure. The validity of NRS-2002 needs further investigation in a larger sample of hospitalized patients with chronic heart failure. PMID- 24755237 TI - Diagnostic effectiveness of quantitative [18F]flutemetamol PET imaging for detection of fibrillar amyloid beta using cortical biopsy histopathology as the standard of truth in subjects with idiopathic normal pressure hydrocephalus. AB - INTRODUCTION: PET imaging of amyloid-beta (Abeta) in vivo holds promise for aiding in earlier diagnosis and intervention in Alzheimer's disease (AD) and mild cognitive impairment. AD-like Abeta pathology is a common comorbidity in patients with idiopathic normal pressure hydrocephalus (iNPH). Fifty patients with iNPH needing ventriculo-peritoneal shunting or intracranial pressure monitoring underwent [18F]flutemetamol PET before (N = 28) or after (N = 22) surgery. Cortical uptake of [18F]flutemetamol was assessed visually by blinded reviewers, and also quantitatively via standard uptake value ratio (SUVR) in specific neocortical regions in relation to either cerebellum or pons reference region: the cerebral cortex of (prospective studies) or surrounding (retrospective studies) the biopsy site, the contralateral homolog, and a calculated composite brain measure. Abeta pathology in the biopsy specimen (standard of truth [SoT]) was measured using Bielschowsky silver and thioflavin S plaque scores, percentage area of grey matter positive for monoclonal antibody to Abeta (4G8), and overall pathology impression. We set out to find (1) which pair(s) of PET SUVR and pathology SoT endpoints matched best, (2) whether quantitative measures of [18F]flutemetamol PET were better for predicting the pathology outcome than blinded image examination (BIE), and (3) whether there was a better match between PET image findings in retrospective vs. prospective studies. RESULTS: Of the 24 possible endpoint/SoT combinations, the one with composite-cerebellum SUVR and SoT based on overall pathology had the highest Youden index (1.000), receiver operating characteristic area under the curve (1.000), sensitivity (1.000), specificity (1.000), and sum of sensitivity and specificity for the pooled data as well as for the retrospective and prospective studies separately (2.00, for all 3). The BIE sum of sensitivity and specificity, comparable to that for quantitation, was highest using Bielschowsky silver as SoT for all SUVRs (ipsilateral, contralateral, and composite, for both reference regions). The composite SUVR had a 100% positive predictive value (both reference regions) for the overall pathology diagnosis. All SUVRs had a 100% negative predictive value for the Bielschowsky silver result. CONCLUSION: Bielschowsky silver stain and overall pathology judgment showed the strongest associations with imaging results. PMID- 24755238 TI - Biotransformation of dianabol with the filamentous fungi and beta-glucuronidase inhibitory activity of resulting metabolites. AB - Biotransformation of the anabolic steroid dianabol (1) by suspended-cell cultures of the filamentous fungi Cunninghamella elegans and Macrophomina phaseolina was studied. Incubation of 1 with C. elegans yielded five hydroxylated metabolites 2 6, while M. phaseolina transformed compound 1 into polar metabolites 7-11. These metabolites were identified as 6beta,17beta-dihydroxy-17alpha-methylandrost-1,4 dien-3-one (2), 15alpha,17beta-dihydroxy-17alpha-methylandrost-1,4-dien-3-one (3), 11alpha,17beta-dihydroxy-17alpha-methylandrost-1,4-dien-3-one (4), 6beta,12beta,17beta-trihydroxy-17alpha-methylandrost-1,4-dien-3-one (5), 6beta,15alpha,17beta-trihydroxy-17alpha-methylandrost-1,4-dien-3-one (6), 17beta hydroxy-17alpha-methylandrost-1,4-dien-3,6-dione (7), 7beta,17beta,-dihydroxy 17alpha-methylandrost-1,4-dien-3-one (8), 15beta,17beta-dihydroxy-17alpha methylandrost-1,4-dien-3-one (9), 17beta-hydroxy-17alpha-methylandrost-1,4-dien 3,11-dione (10), and 11beta,17beta-dihydroxy-17alpha-methylandrost-1,4-dien-3-one (11). Metabolite 3 was also transformed chemically into diketone 12 and oximes 13, and 14. Compounds 6 and 12-14 were identified as new derivatives of dianabol (1). The structures of all transformed products were deduced on the basis of spectral analyses. Compounds 1-14 were evaluated for beta-glucuronidase enzyme inhibitory activity. Compounds 7, 13, and 14 showed a strong inhibition of beta glucuronidase enzyme, with IC50 values between 49.0 and 84.9 MUM. PMID- 24755239 TI - A fish tale worth telling: enteral fat for management of short gut syndrome. PMID- 24755240 TI - A fixed-dose ketamine protocol for adolescent sedations in a pediatric emergency department. AB - OBJECTIVES: To assess provider and patient satisfaction with a fixed-dose ketamine protocol for procedural sedation of adolescent subjects. We further compared data for normal weight (body mass index [BMI] <= 25 kg/m(2)) vs overweight/obese subjects (BMI >25 kg/m(2)). STUDY DESIGN: Prospective, observational cohort study of adolescent patients undergoing procedural sedation in a pediatric emergency department. Adequate sedation was defined as a Ramsay Sedation Score (RSS) >= 5. Subjects received an initial 50 mg intravenous ketamine dose followed by 25 mg intravenous doses to maintain an RSS >= 5. The sedating physician, procedural physician, and sedating nurse independently rated the sedations on a 100 mm visual analog scale (0 = "very unsatisfied", 100 = "very satisfied"). Subjects and their guardians were contacted 12-24 hours postsedation. RESULTS: Forty-three subjects (26 normal weight, 17 overweight/obese), aged 12-17 years, were enrolled in the study. An RSS >= 5 was observed in 35 (81.4%) of the subjects following the initial 50 mg ketamine dose and in the remaining 8 subjects following the first additional 25 mg dose. The median combined provider satisfaction score for the sedations was 92.7 (IQR 83.7 95.0) and was similar for the normal weight and overweight/obese groups (93.1 [IQR 84.6-95.9] vs 89.7 [IQR 83.7-93.5], respectively, P = .27). Subjects and guardians in both groups reported high rates of satisfaction. CONCLUSION: The fixed-dose ketamine protocol resulted in an adequate level of sedation and high provider/patient satisfaction for the majority of patients regardless of weight or BMI status. PMID- 24755241 TI - TRAF6 is upregulated in colon cancer and promotes proliferation of colon cancer cells. AB - TNF receptor associated factor 6 (TRAF6) plays a critical role in the regulation of innate immune responses and adaptive immune responses. Though recent studies indicate that TRAF6 is involved in cancer, its precise role in cancer including colon cancer has not been extensively investigated and remains largely unknown. The purpose of this work is to determine the expression of TRAF6 in colon cancer as well as the possible role of it in proliferation and apoptosis of colon cancer cells. Fifty colon cancer tissues paired with their adjacent non-cancerous tissues were analyzed. TRAF6 expression is upregulated in cancers (P=0.000), which is correlated with tumor grades (P=0.012). The tumor tissue-array analysis also indicates that expression of TRAF6 is upregulated in colon cancer (P=0.000), but the TRAF6 upregulation has no association with patients' survival rate (P=0.055). We found that knockdown of TRAF6 blocks proliferation of colon cancer cells through cyclin D1. Different from other reports, in our experiments knockdown of TRAF6 alone has little effect on survival of colon cancer cells examined. Knockdown of TRAF6 sensitizes the cells to treatment of the conventional anti-cancer drugs 5-fluorouracil and etoposide. Thus, inhibition of TRAF6 may improve the therapeutic treatment of these drugs. Together, our data suggest that TRAF6 promotes proliferation of colon cancer cells and it may serve as a potential target for therapy of colon cancer. PMID- 24755242 TI - Development and performance of a new prosthesis system using ultrasonic sensor for wrist movements: a preliminary study. AB - BACKGROUND: The design and performance of a new development prosthesis system known as biomechatronics wrist prosthesis is presented in this paper. The prosthesis system was implemented by replacing the Bowden tension cable of body powered prosthesis system using two ultrasonic sensors, two servo motors and microcontroller inside the prosthesis hand for transradial user. METHODS: The system components and hand prototypes involve the anthropometry, CAD design and prototyping, biomechatronics engineering together with the prosthetics. The modeler construction of the system develop allows the ultrasonic sensors that are placed on the shoulder to generate the wrist movement of the prosthesis. The kinematics of wrist movement, which are the pronation/supination and flexion/extension were tested using the motion analysis and general motion of human hand were compared. The study also evaluated the require degree of detection for the input of the ultrasonic sensor to generate the wrist movements. RESULTS: The values collected by the vicon motion analysis for biomechatronics prosthesis system were reliable to do the common tasks in daily life. The degree of the head needed to bend to give the full input wave was about 45 degrees -55 degrees of rotation or about 14 cm-16 cm. The biomechatronics wrist prosthesis gave higher degree of rotation to do the daily tasks but did not achieve the maximum degree of rotation. CONCLUSION: The new development of using sensor and actuator in generating the wrist movements will be interesting for used list in medicine, robotics technology, rehabilitations, prosthetics and orthotics. PMID- 24755243 TI - Contribution of predator identity to the suppression of herbivores by a diverse predator assemblage. AB - Studies manipulating predator diversity and measuring the impact on herbivore abundance have found that enhancing predator species richness often increases the strength of prey suppression. This relationship may be due to mechanisms such as complementarity or facilitation, which are considered "true" benefits of diversity because greater prey suppression is an emergent property of the multispecies predator community. Or it may be due to an identity effect, an "apparent" benefit of diversity that results from the greater likelihood of including one particularly voracious predator species as the total number of predator species increases. In separate greenhouse and field experiments, we simultaneously manipulated the species richness and species composition of predators attacking bird cherry-oat aphids (Rhopalosiphum padi) (L.) on wheat (Triticum aestivum L.). We found that on average aphid suppression by species rich predator assemblages was greater than suppression by single-species monocultures. However, the performance of individual predator species varied and the species-rich assemblages did not outperform all single-species compositions, suggesting an identity effect. In particular, single-species compositions of the lady beetle Coleomegilla maculata (DeGeer) exhibited high performance across experiments, and on average predator assemblages that contained a lady beetle predator had lower overall aphid abundance than compositions where lady beetles were absent. Taken together, these results provide evidence for the dominant role of lady beetles, especially C. maculata, in natural pest suppression and suggest that predator species composition and identity are important factors to consider in efforts to conserve this valuable ecosystem service. PMID- 24755244 TI - The effect of drainage tube on bleeding and prognosis after total knee arthroplasty: a prospective cohort study. AB - BACKGROUND: To evaluate the effect of drainage tube on prognosis after total knee arthroplasty (TKA) and explore an effective treatment with favorable prognosis. METHODS: In a prospective study, 18 patients with TKA for the first time were included and randomly divided into three groups, group A (no placement of drainage tube), group B (negative pressure drainage), and group C (4 h clamping drainage). Intraoperative and postoperative blood loss, operation time, and the drainage volume were recorded and analyzed. Arthrocele, ecchymosis, and range of motion (ROM) were examined postoperatively. The degree of pain was scored by Visual Analog Scale (VAS) after 6, 12, and 24 h of operation. The complications were examined and HSS (hospital for special surgery) knee score was taken during the follow-up period. RESULTS: There was no significant difference in operation time, total blood loss, intraoperative blood loss, and VAS score among three groups. Meanwhile, the hidden blood loss in group B was significantly decreased compared with group A (P = 0.0015). The postoperative drainage volume of group B was significantly increased compared with group C (P = 0.0002). No drainage increased the rate of arthrocele and ecchymosis. Compared with group A, ROM after 3 days of operation in groups B and C was significantly increased (P = 0.0357, P = 0.0372, respectively). During follow-up study, no deep infection or deep venous thrombosis was found. CONCLUSION: After TKA, early clamping of the drainage tube reduced the bleeding loss without adverse effect on prognosis, which might be useful for clinical application in future. PMID- 24755245 TI - Unusual variability of PRRT2 linked phenotypes within a family. AB - BACKGROUND: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene on chromosome 16p11.2 have recently been identified as a cause of paroxysmal kinesigenic dyskinesias (PKD), infantile convulsions and choreoathetosis (ICCA) syndrome or infantile convulsions (IC). AIMS: Here, we describe a family with four affected members. They all suffer from different diseases: febrile convulsion, epileptic seizures, PKD or headache. METHODS: The whole coding region of PRRT2 gene has been analyzed. RESULTS: Molecular testing revealed the PRRT2 gene mutation c649.delC in exon 2 for all three sibs as well as for the mother. CONCLUSION: Our presented family case shows the great variability within PRRT2 linked phenotypes even within the same family. Further and more detailed studies will be needed before genetic findings enter into the daily diagnostic and the daily genetic counseling with all its consequences. PMID- 24755246 TI - The representation of visual depth perception based on the plenoptic function in the retina and its neural computation in visual cortex V1. AB - BACKGROUND: How it is possible to "faithfully" represent a three-dimensional stereoscopic scene using Cartesian coordinates on a plane, and how three dimensional perceptions differ between an actual scene and an image of the same scene are questions that have not yet been explored in depth. They seem like commonplace phenomena, but in fact, they are important and difficult issues for visual information processing, neural computation, physics, psychology, cognitive psychology, and neuroscience. RESULTS: The results of this study show that the use of plenoptic (or all-optical) functions and their dual plane parameterizations can not only explain the nature of information processing from the retina to the primary visual cortex and, in particular, the characteristics of the visual pathway's optical system and its affine transformation, but they can also clarify the reason why the vanishing point and line exist in a visual image. In addition, they can better explain the reasons why a three-dimensional Cartesian coordinate system can be introduced into the two-dimensional plane to express a real three-dimensional scene. CONCLUSIONS: 1. We introduce two different mathematical expressions of the plenoptic functions, Pw and Pv that can describe the objective world. We also analyze the differences between these two functions when describing visual depth perception, that is, the difference between how these two functions obtain the depth information of an external scene.2. The main results include a basic method for introducing a three dimensional Cartesian coordinate system into a two-dimensional plane to express the depth of a scene, its constraints, and algorithmic implementation. In particular, we include a method to separate the plenoptic function and proceed with the corresponding transformation in the retina and visual cortex.3. We propose that size constancy, the vanishing point, and vanishing line form the basis of visual perception of the outside world, and that the introduction of a three-dimensional Cartesian coordinate system into a two dimensional plane reveals a corresponding mapping between a retinal image and the vanishing point and line. PMID- 24755248 TI - Transcatheter valve-in-valve implantation in the tricuspid position. AB - AIMS: Transcatheter implantation of valved stents (Melody and Edwards valves) for replacement of the pulmonary valve is currently an established procedure. We reviewed our experience on implantation of such valves in the tricuspid valve position. METHODS AND RESULTS: Transcatheter valve implantation in the tricuspid position was attempted in five patients. Four patients had predominantly tricuspid valve regurgitation, two of whom also had tricuspid valve stenosis. All patients had severely symptomatic right heart failure. Patient median age and weight were 12 years and 50 kg (range six-43 years and 13-68 kg, respectively). All patients had a bioprosthetic valve already in place. The mean gradient across the tricuspid valve decreased from 12 to 3 mmHg after the procedure. Median procedure time and fluoroscopy time were 100 and 39 min (range 60-180 and 30-57 min, respectively). The patients' functional class improved from NYHA Class III to II in three and from Class III to I in two patients during a follow-up period of 15-22 months. CONCLUSIONS: Transcatheter replacement of malfunctioning bioprosthetic valves in the tricuspid position using valved stents is an attractive alternative to repeat surgery in high-risk or multi-operated patients. Longer follow-up and a larger number of patients are required to establish the long-term benefit of the procedure and freedom from reinterventions. PMID- 24755247 TI - Discovery and characterization of a G protein-biased agonist that inhibits beta arrestin recruitment to the D2 dopamine receptor. AB - A high-throughput screening campaign was conducted to interrogate a 380,000+ small-molecule library for novel D2 dopamine receptor modulators using a calcium mobilization assay. Active agonist compounds from the primary screen were examined for orthogonal D2 dopamine receptor signaling activities including cAMP modulation and beta-arrestin recruitment. Although the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate beta-arrestin recruitment. One such compound (MLS1547; 5-chloro-7-[(4-pyridin-2-ylpiperazin-1-yl)methyl]quinolin 8-ol) is a highly efficacious agonist at D2 receptor-mediated G protein-linked signaling, but does not recruit beta-arrestin as demonstrated using two different assays. This compound does, however, antagonize dopamine-stimulated beta-arrestin recruitment to the D2 receptor. In an effort to investigate the chemical scaffold of MLS1547 further, we characterized a set of 24 analogs of MLS1547 with respect to their ability to inhibit cAMP accumulation or stimulate beta-arrestin recruitment. A number of the analogs were similar to MLS1547 in that they displayed agonist activity for inhibiting cAMP accumulation, but did not stimulate beta-arrestin recruitment (i.e., they were highly biased). In contrast, other analogs displayed various degrees of G protein signaling bias. These results provided the basis to use pharmacophore modeling and molecular docking analyses to build a preliminary structure-activity relationship of the functionally selective properties of this series of compounds. In summary, we have identified and characterized a novel G protein-biased agonist of the D2 dopamine receptor and identified structural features that may contribute to its biased signaling properties. PMID- 24755249 TI - Isotonic sodium bicarbonate-triggered emodin release from borate stabilized emodin nanoparticles-loaded polymeric microgel films. AB - Hydrosoluble emodin-borate (EmB) nanoparticles (NPs) were fabricated by a simple solvent exchange method to address emodin's poor water solubility. As the result, negative charges were introduced in the surface of EmB NPs. In addition, layer-by layer assembled multilayer films containing cation-rich polymeric microgels (named PAHD) and sodium carboxymethyl cellulose (NaCMC) were employed as drug carrier. Anionic EmB can be loaded into the PAHD/CMC multilayer films. The influences of various experimental parameters on cargo capacity of the PAHD/CMC film were studied in detail. The loaded EmB can be released in the form of emodin molecule in presence of isotonic sodium bicarbonate (ISB) solution. Gratifyingly, EmB did not almost release in presence of water, PBS buffer solution, 0.9% normal saline, and 5% glucose solution. PMID- 24755250 TI - Morus alba L. suppresses the development of atopic dermatitis induced by the house dust mite in NC/Nga mice. AB - BACKGROUND: Morus alba, a medicinal plant in Asia, has been used traditionally to treat diabetes mellitus and hypoglycemia. However, the effects of M. alba extract (MAE) on atopic dermatitis have not been verified scientifically. We investigated the effects of MAE on atopic dermatitis through in vitro and in vivo experiments. METHODS: We evaluated the effects of MAE on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7, as well as thymus and activation regulated chemokine (TARC/CCL17) in HaCaT cells. In an in vivo experiment, atopic dermatitis was induced by topical application of house dust mites for four weeks, and the protective effects of MAE were investigated by measuring the severity of the skin reaction on the back and ears, the plasma levels of immunoglobulin E (IgE) and histamine, and histopathological changes in the skin on the back and ears. RESULTS: MAE suppressed the production of NO and PGE2 in RAW 264.7 cells, as well as TARC in HaCaT cells, in a dose-dependent manner. MAE treatment of NC/Nga mice reduced the severity of dermatitis and the plasma levels of IgE and histamine. MAE also reduced the histological manifestations of atopic dermatitis like skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration in the skin on the back and ears. CONCLUSION: Our results suggest that MAE has potent inhibitory effects on atopic dermatitis-like lesion and may be a beneficial natural resource for the treatment of atopic dermatitis. PMID- 24755252 TI - MRI Anatomy of the Tibial ACL Attachment and Proximal Epiphysis in a Large Population of Skeletally Immature Knees: Reference Parameters for Planning Anatomic Physeal-Sparing ACL Reconstruction. AB - BACKGROUND: To aid in performing anatomic physeal-sparing anterior cruciate ligament (ACL) reconstruction, it is important for surgeons to have reference data for the native ACL attachment positions and epiphyseal anatomy in skeletally immature knees. PURPOSE: To characterize anatomic parameters of the ACL tibial insertion and proximal tibial epiphysis at magnetic resonance imaging (MRI) in a large population of skeletally immature knees. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The ACL tibial attachment site and proximal epiphysis were examined in 570 skeletally immature knees with an intact ACL (age, 6-15 years) using 1.5-T proton density-weighted sagittal MRI; also measured were the tibial anteroposterior diameter; anterior, central, and posterior ACL attachment positions; vertical height of the epiphysis; and maximum oblique epiphyseal depth extending from the ACL tibial attachment center to the tibial tuberosity. RESULTS: In adolescents (11-15 years of age), the center of the ACL's tibial attachment was 51.5% +/- 5.7% of the anteroposterior diameter of the tibia, with no significant differences between sexes or age groups (P > .05 in all cases). Mean vertical epiphyseal height was 15.9 +/- 1.7 mm in the adolescent group, with significant differences between 11-year-olds (15.2 +/- 1.5 mm) and 15 year-olds (16.6 +/- 1.6 mm), P < .001, and between males (16.6 +/- 1.5 mm) and females (14.8 +/- 1.4), P < .001. Mean maximum oblique depth was 30.0 +/- 5.3 mm, with a significant difference between 11-year-olds (26.7 +/- 4.9 mm) and 15-year olds (32.7 +/- 5.1 mm), P < .001, and between males (29.7 +/- 6.4 mm) and females (27.8 +/- 5.2 mm), P < .001. The maximum oblique depth occurred at a mean angle of ~50 degrees , and this angle did not change with age or sex. There was a significant moderate correlation (r = 0.39, P < .001) between epiphyseal vertical height and maximum oblique depth. CONCLUSION: The center of the ACL tibial attachment was consistently near 51% of the anteroposterior diameter, regardless of age or sex. The vertical depth of the tibial epiphysis was ~16 mm in adolescents. Maximum oblique depth from ACL attachment was ~30 mm, occurring at a mean angle ~50 degrees regardless of age or sex. The normative values for tibial ACL attachment and epiphyseal anatomy presented here may be helpful in selecting candidates for surgery and in planning surgical approaches for pediatric ACL reconstruction. PMID- 24755251 TI - Expression microarray identifies the unliganded glucocorticoid receptor as a regulator of gene expression in mammary epithelial cells. AB - BACKGROUND: While glucocorticoids and the liganded glucocorticoid receptor (GR) have a well-established role in the maintenance of differentiation and suppression of apoptosis in breast tissue, the involvement of unliganded GR in cellular processes is less clear. Our previous studies implicated unliganded GR as a positive regulator of the BRCA1 tumour suppressor gene in the absence of glucocorticoid hormone, which suggested it could play a similar role in the regulation of other genes. METHODS: An shRNA vector directed against GR was used to create mouse mammary cell lines with depleted endogenous levels of this receptor in order to further characterize the role of GR in breast cells. An expression microarray screen for targets of unliganded GR was performed using our GR-depleted cell lines maintained in the absence of glucocorticoids. Candidate genes positively regulated by unliganded GR were identified, classified by Gene Ontology and Ingenuity Pathway Analysis, and validated using quantitative real time reverse transcriptase PCR. Chromatin immunoprecipitation and dual luciferase expression assays were conducted to further investigate the mechanism through which unliganded GR regulates these genes. RESULTS: Expression microarray analysis revealed 260 targets negatively regulated and 343 targets positively regulated by unliganded GR. A number of the positively regulated targets were involved in pro-apoptotic networks, possibly opposing the activity of liganded GR targets. Validation and further analysis of five candidates from the microarray indicated that two of these, Hsd11b1 and Ch25h, were regulated by unliganded GR in a manner similar to Brca1 during glucocorticoid treatment. Furthermore, GR was shown to interact directly with and upregulate the Ch25h promoter in the absence, but not the presence, of hydrocortisone (HC), confirming our previously described model of gene regulation by unliganded GR. CONCLUSION: This work presents the first identification of targets of unliganded GR. We propose that the balance between targets of liganded and unliganded GR signaling is responsible for controlling differentiation and apoptosis, respectively, and suggest that gene regulation by unliganded GR may represent a mechanism for reducing the risk of breast tumourigenesis by the elimination of abnormal cells. PMID- 24755253 TI - Genotoxic evaluation of five Angiotesin II receptor blockers: in vivo and in vitro micronucleus assay. AB - Angiotensin II receptor blockers (ARBs) are a new class of drugs for the treatment of hypertension. In this study, we studied the potential genotoxic effects of five ARBs in vivo and in vitro in human peripheral blood lymphocytes (PBLs) by means of the cytokinesis-block micronucleous (CBMN) assay in combination with fluorescence in situ hybridization (FISH) with a centromeric probe. The nuclear division index (NDI) was used as a measure of cytotoxicity. We also analyzed the association between sex, age, duration of treatment and MN formation. The in vivo study was carried out in 55 hypertensive patients. The in vitro study was performed in 10 control individuals by adding the drugs to the culture medium at a final concentration similar to the levels found in plasma in patients. Our results showed a significant increase in the frequencies of MN and binucleated cells with MN (BNMN) in vivo and especially in vitro. We observed variability in the mean frequency of MN and BNMN among the five drugs analyzed. In vivo, patients treated with Candesartan, Telmisartan and Valsartan showed a statistical significant increase in these parameters, while Olmesartan showed the highest effect in vitro. We also found that the drugs inhibit the NDI in vitro and that Eprosartan, Olmesartan and Telmisartan are the ARBs studied with the highest effect in decreasing the proliferation of the cells. FISH analysis revealed no significant difference between patients and controls in the frequency of centromeric signals. A slight variability, without statistical significance, in the frequency of micronuclei with a centromere signal (CN(+)MN) was found among the different ARBs analyzed, ruling out an aneugenic potential. When accounting for risk factors, we found that in patients there is a positive correlation between MN, BNMN and sex and a negative correlation with duration of treatment. PMID- 24755254 TI - Protective effect of apigenin against N-nitrosodiethylamine (NDEA)-induced hepatotoxicity in albino rats. AB - A number of pharmacological properties have been attributed to apigenin. In the present study the effect of apigenin was investigated with respect to hepatotoxicity induced by N-nitrosodiethylamine (NDEA), a compound that is present in many food stuffs and has been reported to be a hepatocarcinogen. Male rats were exposed to NDEA (0.1mg/ml) dissolved in drinking-water separately, and with 10, 20, or 40mg/ml of apigenin for 21 days. The activity of glutamic oxaloacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) was measured in blood serum. Lipid peroxidation, protein carbonyl content and micronucleus frequency were determined in hepatocytes. To assess the effect on DNA damage, the comet assay was performed on hepatocytes, blood lymphocytes and bone-marrow cells of the exposed rats. The results of the study reveal that the treatment of NDEA together with apigenin showed a significant dose-dependent decrease in the serum concentration of the enzymes SGOT, SGPT, ALP and LDH (p<0.05). Histological sections of the liver also showed a protective effect of apigenin. A significant dose-dependent reduction in lipid peroxidation and protein carbonyl content was observed in rats exposed to NDEA (0.1mg/ml) together with apigenin (p<0.05). The results obtained for the comet assay in rat hepatocytes, blood lymphocytes and bone-marrow cells showed a significant dose-dependent decrease in the mean tail length (p<0.05). The present study supports the role of apigenin as an anti genotoxic and hepatoprotective agent. PMID- 24755255 TI - 3D graphene foams decorated by CuO nanoflowers for ultrasensitive ascorbic acid detection. AB - When the in vitro research works of biosensing begin to mimic in vivo conditions, some certain three-dimensional (3D) structures of biosensors are needed to accommodate biomolecules, bacteria or even cells to resemble the in vivo 3D environment. To meet this end, a novel method of synthesizing CuO nanoflowers on the 3D graphene foam (GF) was first demonstrated. The 3DGF/CuO nanoflowers composite was used as a monolithic free-standing 3D biosensor for electrochemical detection of ascorbic acid (AA). The 3D conductive structure of the GF is favorable for current collection, mass transport and loading bioactive chemicals. And CuO nanoflowers further increase the active surface area and catalyze the redox of AA. Thus, all these features endows 3DGF/CuO composite with outstanding biosensing properties such as an ultrahigh sensitivity of 2.06 mA mM(-1) cm(-2) to AA at 3 s response time. PMID- 24755256 TI - Au nanoparticles/PAMAM dendrimer functionalized wired ethyleneamine-viologen as highly efficient interface for ultra-sensitive alpha-fetoprotein electrochemical immunosensor. AB - In this work, a novel electrochemical immunoassay system is developed for ultrasensitive detection of cancer biomarker, alpha-fetoprotein (AFP). This immunosensor is constructed by covalent immobilization of polyamidoamine (PAMAM) dendrimer-encapsulated gold nanoparticles (Au-PAMAM) sensing interface on a Au electrode surface, followed by sequential covalent immobilization of ethyleneamineviologen (Vio) electrochemical redox marker and AFP monoclonal antibody (mAb) on the surface of Au-PAMAM. The Au-PAMAM nanocomposite not only led to increase the electrode surface area and accelerate the electron transfer kinetics, but also it could provide a highly stable matrix for the convenient conjugation of biomolecules. Upon immunorecognition of the immobilized AFP to its antibody, the Vio peak current decreased due to the hindered electron transfer reaction on the electrode surface. Through the differential pulse voltammetry (DPV) experiments, it is found that the proposed method could detect AFP antigen at a wide linear range (0.001-45 ng mL(-1)) and a detection limit down to 130 fg mL(-1). The immunosensor exhibited high specificity for AFP detection, extremely short incubation time (5 min), good stability and acceptable reproducibility. Moreover, the fabricated immunosensor could accurately detect AFP concentration in human serum samples demonstrated by excellent correlations with standard ELISA immunoassay. In addition, electrochemical impedance spectroscopy technique was used as an efficient alternative detection system for AFP measurement with detection limit 0.5ngmL(-1) and concentration range up to 40 ng mL(-1). The present protocol is shown to be quite promising for clinical screening of cancer biomarkers and point-of-care diagnostics applications. PMID- 24755257 TI - Anger problems and posttraumatic stress disorder in male and female National Guard and Reserve Service members. AB - Anger is a common problem among veterans and has been associated with posttraumatic stress disorder (PTSD). This study aimed to improve understanding of how anger and PTSD co-occur by examining gender differences and differences by whether the triggering traumatic event is deployment-related vs. civilian-related in current service members. A representative cohort of Reserve and National Guard service personnel (n = 1293) were interviewed to assess for deployment- or civilian-related traumas, PTSD, and anger. The prevalence of self-reported anger problems was estimated among male (n = 1036) and female (n = 257) service members. Log Poisson regression models with robust standard errors were used to estimate the associations of problems with anger with PTSD and PTSD symptom severity for men and women. Self-reported anger problems were common among male (53.0%) and female (51.3%) service members. Adjusted prevalence ratios (PR) showed associations between anger and PTSD connected to both civilian- and deployment-related traumas (PR were 1.77 (95% CI 1.52-2.05) and 1.85 (95% CI 1.62 2.12), respectively). PTSD symptom severity was also associated with anger. This study was cross-sectional and so a causal relationship between PTSD and anger cannot be established. Problems with anger are common among male and female current Guard and Reserve members. These findings suggest that anger treatment should be made available to current service members and that clinicians should assess anger problems irrespective of gender. Future research should examine the effectiveness of anger treatment protocols by gender. PMID- 24755258 TI - The impact of alcohol and tobacco use on in vivo glutathione in youth with bipolar disorder: an exploratory study. AB - Risky alcohol consumption and tobacco smoking is highly prevalent in bipolar disorder (BD) and is associated with increased formation of neural reactive oxygen species. Proton magnetic resonance spectroscopy ((1)H-MRS) is an in vivo imaging modality that allows quantification of glutathione (GSH) concentration, the brains primary antioxidant. Sixty-four patients with BD and 49 controls (18 30 years) completed self-report questionnaires regarding alcohol and tobacco use and underwent (1)H-MRS. Levels of GSH in the hippocampus and anterior cingulate cortex (ACC) were determined. Within-group Pearson's correlations were used to explore the relationship between alcohol use and GSH concentration for BD and controls, covarying for age, gender, family history of alcohol dependence and smoking status. Relationships between GSH and presence/severity of alcohol induced blackouts were determined using Spearman's correlations. In BD, reduced hippocampal-GSH associated with higher alcohol use (R = -0.489, p < 0.021). Reduction of ACC-GSH with increased drinking was non-significant when controlling for tobacco use. Independent samples t-test revealed a significantly decreased ACC-GSH in smokers with BD (t (53) = 4.162, p < 0.001). In controls, alcohol use was not correlated to GSH in either region. In both patients and controls, reduced hippocampal-GSH was associated with blackout presence/severity, supporting a role for the hippocampus in the continuum of alcohol-induced memory impairments. Our preliminary findings suggest that in youth with BD reduced hippocampal-GSH is associated with risky alcohol use and alcohol and tobacco use is associated with reduced ACC-GSH, highlighting the role of these substances as modifiable risk factors for decreased anti-oxidant capacity in BD. PMID- 24755259 TI - In-vitro release of acyclovir loaded Eudragit RLPO((r)) nanoparticles for sustained drug delivery. AB - In this present study the possibility to develop Eudragit RLPO((r)) based nanoparticles of acyclovir was investigated in order to increase its efficacy because acyclovir has oral bioavailability of only 10-20% thus showing erratic absorption and bioavailability behaviour. The nanoparticles were prepared by nanoprecipitation technique. Pluronic F68 was used as stabilizer. The nanoparticles were characterized by particle size, entrapment efficiency, DSC, SEM, FTIR and in-vitro drug release. It was found that as drug:polymer (Acyclovir:Eudragit RLPO((r))) ratio increased from 1:1.5 to 1:2, particle size was increased significantly and drug entrapment also increased but thereafter, further increase in drug: polymer ratio showed reduced or insignificant change in the drug entrapment efficiency. DSC results showed that in the prepared nanoaprticles, the drug was present in the amorphous phase and may have been homogeneously dispersed in the polymer matrix. In vitro drug release study of formulations showed release in 24h in the range 71.62+/-1.72 to 93.25+/-1.02%. The release was found to follow Higuchi model with non-Fickian diffusion mechanism for all batches. These preliminary results indicate that acyclovir loaded Eudragit RLPO((r)) nanoparticles could be effective in sustaining drug release for a prolonged period. PMID- 24755260 TI - Auricularia polytricha polysaccharides induce cell cycle arrest and apoptosis in human lung cancer A549 cells. AB - In the present study, the anticancer activity of Auricularia polytricha polysaccharides (APPs) towards A549 human lung cancer cells and its underlying mechanisms were investigated. APPs significantly inhibited the proliferation and DNA synthesis of A549 cells in a concentration-dependent manner. The compound also induced apoptosis in A549 cells by arresting cell cycle progression at the G0/G1 phase. Western blotting assay demonstrated that APPs significantly increased the expression of cyclin-dependent kinase (CDK) inhibitors p53 and p21, whereas the expression of cyclin A, cyclin D, and CDK2 were decreased by treatment with APPs. This apoptotic induction in APPs-treated A549 cells was also associated with the release of cytochrome c from mitochondria to cytosol, which in turn resulted in the activation of caspase-9 and -3, and the cleavage of poly (ADP-ribose) polymerase (PARP). Furthermore, the inhibitory effect of APPs on the growth in BALB/c-nu nude mice bearing A549 cells was also proven. These findings suggested that APPs might be a useful chemotherapeutic agent for lung cancer. PMID- 24755261 TI - Monoolein production by triglycerides hydrolysis using immobilized Rhizopus oryzae lipase. AB - Lipase extracted from Rhizopus oryzae was immobilized in alginate gel beads. The effects of the immobilization conditions, such as, alginate concentration, CaCl2 concentration and amount of initial enzyme on retained activity (specific activity ratio of entrapped active lipase to free lipase) were investigated. The optimal conditions for lipase entrapment were determined: 2% (w/v) alginate concentration, 100mM CaCl2 and enzyme ratio of 2000IU/mL.In such conditions, immobilized lipase by inclusion in alginate showed a highest stability and activity, on olive oil hydrolysis reaction where it could be reused for 10 cycles. After 15min of hydrolysis reaction, the mass composition of monoolein, diolein and triolein were about 78%, 10% and 12%. Hydrolysis' products purification by column chromatography lead to a successful separation of reaction compounds and provide a pure fraction of monoolein which is considered as the widest used emulsifier in food and pharmaceutical industries. PMID- 24755263 TI - [Promotion of environmental health: close up of two fields. The case of Mexico]. PMID- 24755262 TI - Piloting the promotion of bamboo skirt barriers to prevent Nipah virus transmission through date palm sap in Bangladesh. AB - Drinking raw date palm sap contaminated with infected fruit bat saliva or urine is an important mode of Nipah virus transmission to humans in Bangladesh. Bamboo skirts are an effective way to interrupt bat access to the sap. We conducted a study from November 2008 to March 2009 to explore the effectiveness of higher- and lower-intensity interventions by promoting bamboo skirt preparation and use among sap harvesters (gachhis). We spent 280 person-hours in two villages for the higher-intensity intervention and half that amount of time in two other villages for the lower-intensity intervention. To evaluate the interventions we followed up all gachhis once a month for three months. A high percentage of gachhis (83% in higher-, 65% in lower-intensity interventions) prepared and used a skirt of bamboo or other materials - jute stalk, dhoincha (Sesbania aculeata), or polythene - at least once after intervention. In general, 15% of gachhis consistently used skirts throughout the sap collection season. The intensive nature of this intervention is very expensive for a large-scale programme. Future efforts should focus on developing a low-cost behaviour change intervention and evaluate if it reduces the human exposure to potentially contaminated fresh date palm sap. PMID- 24755264 TI - [Community campaigns to promote HIV testing and counseling in West Africa: Perceptions of users in Burkina Faso]. PMID- 24755265 TI - Verbal autopsy as a tool for identifying children dying of sickle cell disease: a validation study conducted in Kilifi district, Kenya. AB - BACKGROUND: Sickle cell disease (SCD) is common in many parts of sub-Saharan Africa (SSA), where it is associated with high early mortality. In the absence of newborn screening, most deaths among children with SCD go unrecognized and unrecorded. As a result, SCD does not receive the attention it deserves as a leading cause of death among children in SSA. In the current study, we explored the potential utility of verbal autopsy (VA) as a tool for attributing underlying cause of death (COD) in children to SCD. METHODS: We used the 2007 WHO Sample Vital Registration with Verbal Autopsy (SAVVY) VA tool to determine COD among child residents of the Kilifi Health and Demographic Surveillance System (KHDSS), Kenya, who died between January 2008 and April 2011. VAs were coded both by physician review (physician coded verbal autopsy, PCVA) using COD categories based on the WHO International Classification of Diseases 10th Edition (ICD-10) and by using the InterVA-4 probabilistic model after extracting data according to the 2012 WHO VA standard. Both of these methods were validated against one of two gold standards: hospital ICD-10 physician-assigned COD for children who died in Kilifi District Hospital (KDH) and, where available, laboratory confirmed SCD status for those who died in the community. RESULTS: Overall, 6% and 5% of deaths were attributed to SCD on the basis of PCVA and the InterVA-4 model, respectively. Of the total deaths, 22% occurred in hospital, where the agreement coefficient (AC1) for SCD between PCVA and hospital physician diagnosis was 95.5%, and agreement between InterVA-4 and hospital physician diagnosis was 96.9%. Confirmatory laboratory evidence of SCD status was available for 15% of deaths, in which the AC1 against PCVA was 87.5%. CONCLUSIONS: Other recent studies and provisional data from this study, outlining the importance of SCD as a cause of death in children in many parts of the developing world, contributed to the inclusion of specific SCD questions in the 2012 version of the WHO VA instruments, and a specific code for SCD has now been included in the WHO and InterVA-4 COD listings. With these modifications, VA may provide a useful approach to quantifying the contribution of SCD to childhood mortality in rural African communities. Further studies will be needed to evaluate the generalizability of our findings beyond our local context. PMID- 24755266 TI - Essential roles of zebrafish rtn4/Nogo paralogues in embryonic development. AB - BACKGROUND: As a consequence of gene/genome duplication, the RTN4/Nogo gene has two counterparts in zebrafish: rtn4a and rtn4b. The shared presence of four specific amino acid motifs-M1 to M4-in the N-terminal region of mammalian RTN4, and zebrafish Rtn4b suggests that Rtn4b is the closest homologue of mammalian Nogo-A. RESULTS: To explore their combined roles in zebrafish development, we characterized the expression patterns of rtn4a and rtn4b in a comparative manner and performed morpholino-mediated knockdowns. Although both genes were coexpressed in the neural tube and developing brain at early stages, they progressively acquired distinct expression domains such as the spinal cord (rtn4b) and somites (rtn4a). Downregulation of rtn4a and rtn4b caused severe brain abnormalities, with rtn4b knockdown severely affecting the spinal cord and leading to immobility. In addition, the retinotectal projection was severely affected in both morphants, as the retina and optic tectum appeared smaller and only few retinal axons reached the abnormally reduced tectal neuropil. The neuronal defects were more persistent in rtn4b morphants. Moreover, the latter often lacked pectoral fins and lower jaws and had malformed branchial arches. Notably, these defects led to larval death in rtn4b, but not in rtn4a morphants. CONCLUSIONS: In contrast to mammalian Nogo-A, its zebrafish homologues, rtn4a and particularly rtn4b, are essential for embryonic development and patterning of the nervous system. PMID- 24755267 TI - Metastatic lung carcinoma to the lower anterior gingiva. PMID- 24755268 TI - Multimodality treatment of anaplastic thyroid cancer with nearly resolved effect. PMID- 24755269 TI - Prescription antibiotics for outpatients in Bangladesh: a cross-sectional health survey conducted in three cities. AB - BACKGROUND: Antibiotics prescribing by physicians have gained due importance across the globe, mainly because of an increase in antibiotic usage, prevalence of infections and drug resistances. The present study is aimed to evaluate the physicians prescribing pattern of antibiotics, their usages by outpatients and disease conditions for which the antibiotics are prescribed in three cities of Bangladesh. METHODS: This cross sectional health survey was carried out with a self designed standard questionnaire by manual data collection over a three months period (20.03.2013 to 20.06.2013) at three adjacent cities Jessore Sadar, Monirampur and Keshabpur upazila respectively. The data were collected from the patient's prescription and by directly interviewing the patients who were prescribed at least one antibiotic during the study period. WHO Anatomical Therapeutic Chemical (ATC) classifications for antibiotics was used and descriptive statistics were applied to the collected data and analyzed using Microsoft Excel software. Modified Wald method was applied to calculate 95% CI. RESULTS: A total of 900 prescriptions were analyzed during the study period. It was found that the prescriber prescribed antibiotics to the patients who were suffering mainly from cold and fever, infections, diarrhea and gonorrhea. The highest prescribed antibiotic groups were cephalosporins (31.78%), macrolides (27.33%), quinolones (16.33%), penicillins (7.11%), and metronidazoles (6.78%) respectively. Two or more antibiotics were prescribed in 25.44% of prescriptions. A total of 66.89% prescriptions had complete information on dosage form, 57% had complete direction for antibiotics use and 64.22% patients completed full course of antibiotics. Although 83% prescriptions have no clinical test for using antibiotics, even though the percentages of patients' disease recovery were 61.78% and in compliance were 38.22%. CONCLUSION: From this research, it is observed that physicians prescribed antibiotics rationally in some cases but needs to ensure in all cases of prescription. Because irrational use leads to the spread of bacterial resistance to antibiotics and related health problems, our findings have important implications for public education and the enforcement of regulations regarding the prescription of antibiotics in Bangladesh. PMID- 24755270 TI - Differential regulation of MMPs by E2F1, Sp1 and NF-kappa B controls the small cell lung cancer invasive phenotype. AB - BACKGROUND: E2F1 transcription factor plays a vital role in the regulation of diverse cellular processes including cell proliferation, apoptosis, invasion and metastasis. E2F1 overexpression has been demonstrated in small cell lung cancer (SCLC), and extensive metastasis in early phase is the most important feature of SCLC. In this study, we investigated the involvement of E2F1 in the process of invasion and metastasis in SCLC by regulating the expression of matrix metalloproteinases (MMPs). METHODS: Immunohistochemistry was performed to evaluate the expression of E2F1 and MMPs in SCLC samples in a Chinese Han population. The impact of E2F1 on invasion and metastasis was observed by transwell and wound healing experiments with depletion of E2F1 by specific siRNA. The target genes regulated by E2F1 were identified by chromatin immunoprecipitation (ChIP)-to-sequence, and the expressions of target genes were detected by real time PCR and western blotting. The dual luciferase reporter system was performed to analyze the regulatory relationship between E2F1 and MMPs. RESULTS: E2F1 is an independent and adverse prognosis factor that is highly expressed in SCLC in a Chinese Han population. Knockdown of E2F1 by specific siRNA resulted in the downregulation of migration and invasion in SCLC. The expressions of MMP-9 and -16 in SCLC were higher than other MMPs, and their expressions were most significantly reduced after silencing E2F1. ChIP-to sequence and promoter-based luciferase analysis demonstrated that E2F1 directly controlled MMP-16 expression via an E2F1 binding motif in the promoter. Although one E2F1 binding site was predicted in the MMP-9 promoter, luciferase analysis indicated that this binding site was not functionally required. Further study demonstrated that E2F1 transcriptionally controlled the expression of Sp1 and p65, which in turn enhanced the MMP-9 promoter activity in SCLC cells. The associations between E2F1, Sp1, p65, and MMP-9 were validated by immunohistochemistry staining in SCLC tumors. CONCLUSIONS: E2F1 acts as a transcriptional activator for MMPs and directly enhances MMP transcription by binding to E2F1 binding sequences in the promoter, or indirectly activates MMPs through enhanced Sp1 and NF-kappa B as a consequence of E2F1 activation in SCLC. PMID- 24755271 TI - [Evaluation of the Andalusia Public Health System hospital websites in the period 2010-2012]. AB - OBJECTIVES: Evaluate the quality, accessibility and presence of Web 2.0 tools in the Andalusia Public Health System hospitals websites METHODS: Observational, descriptive study carried out between 2010 and 2012. The variables analyzed were: quality, accessibility and innovation. The quality was evaluated using a Bermudez Tamayo questionnaire. Accessibility was measured using the Web Accessibility Test (TAW) tool. Web 2.0 tools were identified by direct observation. RESULTS: A total of 31 of the 45 hospitals (68.9%) had a website in the year 2010, increasing to 34 (75.5%) in 2012. The average score+standard deviation (SD) of the Bermudez Tamayo quality questionnaire was 11.1+3.8 points in 2010, and 12.3+3.9 points in 2012, observing a statistically significant difference of 0.25 being observed between the means (P=.007), 95% CI; 0.00 to 0.50) In the accessibility evaluation only 7 websites (n=31) in 2010, and 10 (n=34) in 2012, fulfilled the legal criteria for accessibility. The use of Web 2.0 tools has increased throughout the study. In 2010, 19.4% (n=6) of the hospital websites had this type of tool, in comparison to 58.8% (n=20) in 2012. CONCLUSIONS: In general, the quality of the websites studied is good. However, current legislation regarding accessibility is not fulfilled and must be revised and adapted to the current legal rules. There is an incipient use of Web 2.0 resources as education and communication strategies with regard to health. PMID- 24755272 TI - How should I treat a challenging case of MitraClip implantation? AB - BACKGROUND: A 71-year-old woman affected by idiopathic dilated cardiomyopathy with normal coronary arteries and permanent atrial fibrillation was found to have severe mitral regurgitation at transthoracic echocardiography (TTE), due to annular dilatation and restricted motion of the posterior leaflet. Because of poor quality of life, high functional class (NYHA Class III) and the high risk of surgery, the patient agreed to undergo the implantation of a MitraClip device. During the procedure, the transoesophageal echocardiographic (TEE) images were of a poor quality since the view of the mitral valve in the mid-oesophageal and transgastric projections did not accurately show the valve leaflets and the convergence area of the regurgitation at colour Doppler, which is indispensable for the correct positioning of the clip. INVESTIGATION: Physical examination, transthoracic echocardiography, transoesophageal echocardiography. DIAGNOSIS: Severe mitral regurgitation suitable for MitraClip implantation. MANAGEMENT: Transthoracic, and not transoesophageal, echocardiography approach during MitraClip procedure. PMID- 24755273 TI - DYNC1H1 mutation alters transport kinetics and ERK1/2-cFos signalling in a mouse model of distal spinal muscular atrophy. AB - Mutations in the gene encoding the heavy chain subunit (DYNC1H1) of cytoplasmic dynein cause spinal muscular atrophy with lower extremity predominance, Charcot Marie-Tooth disease and intellectual disability. We used the legs at odd angles (Loa) (DYNC1H1(F580Y)) mouse model for spinal muscular atrophy with lower extremity predominance and a combination of live-cell imaging and biochemical assays to show that the velocity of dynein-dependent microtubule minus-end (towards the nucleus) movement of EGF and BDNF induced signalling endosomes is significantly reduced in Loa embryonic fibroblasts and motor neurons. At the same time, the number of the plus-end (towards the cell periphery) moving endosomes is increased in the mutant cells. As a result, the extracellular signal-regulated kinases (ERK) 1/2 activation and c-Fos expression are altered in both mutant cell types, but the motor neurons exhibit a strikingly abnormal ERK1/2 and c-Fos response to serum-starvation induced stress. These data highlight the cell-type specific ERK1/2 response as a possible contributory factor in the neuropathological nature of Dync1h1 mutations, despite generic aberrant kinetics in both cell types, providing an explanation for how mutations in the ubiquitously expressed DYNC1H1 cause neuron-specific disease. PMID- 24755275 TI - Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism. AB - The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE 084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma 1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma 1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease. PMID- 24755274 TI - Longitudinal changes in cortical thickness in autism and typical development. AB - The natural history of brain growth in autism spectrum disorders remains unclear. Cross-sectional studies have identified regional abnormalities in brain volume and cortical thickness in autism, although substantial discrepancies have been reported. Preliminary longitudinal studies using two time points and small samples have identified specific regional differences in cortical thickness in the disorder. To clarify age-related trajectories of cortical development, we examined longitudinal changes in cortical thickness within a large mixed cross sectional and longitudinal sample of autistic subjects and age- and gender matched typically developing controls. Three hundred and forty-five magnetic resonance imaging scans were examined from 97 males with autism (mean age = 16.8 years; range 3-36 years) and 60 males with typical development (mean age = 18 years; range 4-39 years), with an average interscan interval of 2.6 years. FreeSurfer image analysis software was used to parcellate the cortex into 34 regions of interest per hemisphere and to calculate mean cortical thickness for each region. Longitudinal linear mixed effects models were used to further characterize these findings and identify regions with between-group differences in longitudinal age-related trajectories. Using mean age at time of first scan as a reference (15 years), differences were observed in bilateral inferior frontal gyrus, pars opercularis and pars triangularis, right caudal middle frontal and left rostral middle frontal regions, and left frontal pole. However, group differences in cortical thickness varied by developmental stage, and were influenced by IQ. Differences in age-related trajectories emerged in bilateral parietal and occipital regions (postcentral gyrus, cuneus, lingual gyrus, pericalcarine cortex), left frontal regions (pars opercularis, rostral middle frontal and frontal pole), left supramarginal gyrus, and right transverse temporal gyrus, superior parietal lobule, and paracentral, lateral orbitofrontal, and lateral occipital regions. We suggest that abnormal cortical development in autism spectrum disorders undergoes three distinct phases: accelerated expansion in early childhood, accelerated thinning in later childhood and adolescence, and decelerated thinning in early adulthood. Moreover, cortical thickness abnormalities in autism spectrum disorders are region-specific, vary with age, and may remain dynamic well into adulthood. PMID- 24755276 TI - A qualitative assessment of internal medicine resident perceptions of graduate medical education following implementation of the 2011 ACGME duty hour standards. AB - BACKGROUND: In 2011, the Accreditation Council of Graduate Medical Education implemented updated guidelines for medical resident duty hours, further limiting continuous work hours for first-year residents. We sought to investigate the impact of these restrictions on graduate medical education among internal medicine residents. METHODS: We conducted eight focus groups with internal medicine residents at the University of Alabama at Birmingham in 06/2012-07/2012. Discussion questions included, "How do you feel the 2011 ACGME work hour restrictions have impacted your graduate medical education?" Transcripts of the focus groups were reviewed and themes identified using a deductive/inductive approach. Participants completed a survey to collect demographic information and future practice plans. RESULTS: Thirty-four residents participated in our focus groups. Five themes emerged: decreased teaching, decreased experiential learning, shift-work mentality, tension between residency classes, and benefits and opportunities. Residents reported that since implementation of the guidelines, teaching was often deferred to complete patient-care tasks. Residents voiced concern that PGY-1 s were not receiving adequate clinical experience and that procedural and clinical reasoning skills are being negatively impacted. PGY-1 s reported being well-rested and having increased time for independent study. CONCLUSIONS: Residents noted a decline in teaching and are concerned with the decrease in "hands-on" clinical education that is inevitably impacted by fewer hours in the hospital, though some benefits were also reported. Future studies are needed to further elucidate the impact of decreased resident work hours on graduate medical education. PMID- 24755277 TI - Variations in mismatch repair genes and colorectal cancer risk and clinical outcome. AB - DNA mismatch repair (MMR) deficiency is one of the best understood forms of genetic instability in colorectal cancer (CRC). CRC is routinely cured by 5 fluorouracil (5-FU)-based chemotherapy, with a prognostic effect and resistance to such therapy conferred by MMR status. In this study, we aimed to analyse the effect of genetic variants in classical coding regions or in less-explored predicted microRNA (miRNA)-binding sites in the 3' untranslated region (3'UTR) of MMR genes on the risk of CRC, prognosis and the efficacy of 5-FU therapy. Four single nucleotide polymorphisms (SNPs) in MMR genes were initially tested for susceptibility to CRC in a case-control study (1095 cases and 1469 healthy controls). Subsequently, the same SNPs were analysed for their role in survival on a subset of patients with complete follow-up. Two SNPs in MLH3 and MSH6 were associated with clinical outcome. Among cases with colon and sigmoideum cancer, carriers of the CC genotype of rs108621 in the 3'UTR of MLH3 showed a significantly increased survival compared to those with the CT + TT genotype (log rank test, P = 0.05). Moreover, this polymorphism was also associated with an increased risk of relapse or metastasis in patients with heterozygous genotype (log-rank test, P = 0.03). Patients carrying the CC genotype for MSH6 rs1800935 (D180D) and not undergoing 5-FU-based chemotherapy showed a decreased number of recurrences (log-rank test, P = 0.03). No association with CRC risk was observed. We provide the first evidence that variations in potential miRNA target-binding sites in the 3'UTR of MMR genes may contribute to modulate CRC prognosis and predictivity of therapy. PMID- 24755278 TI - Bundle-sheath leakiness in C4 photosynthesis: a careful balancing act between CO2 concentration and assimilation. AB - Crop species with the C4 photosynthetic pathway are generally characterized by high productivity, especially in environmental conditions favouring photorespiration. In comparison with the ancestral C3 pathway, the biochemical and anatomical modifications of the C4 pathway allow spatial separation of primary carbon acquisition in mesophyll cells and subsequent assimilation in bundle-sheath cells. The CO2-concentrating C4 cycle has to operate in close coordination with CO2 reduction via the Calvin-Benson-Bassham (CBB) cycle in order to keep the C4 pathway energetically efficient. The gradient in CO2 concentration between bundle-sheath and mesophyll cells facilitates diffusive leakage of CO2. This rate of bundle-sheath CO2 leakage relative to the rate of phosphoenolpyruvate carboxylation (termed leakiness) has been used to probe the balance between C4 carbon acquisition and subsequent reduction as a result of environmental perturbations. When doing so, the correct choice of equations to derive leakiness from stable carbon isotope discrimination (Delta(13)C) during gas exchange is critical to avoid biased results. Leakiness responses to photon flux density, either short-term (during measurements) or long-term (during growth and development), can have important implications for C4 performance in understorey light conditions. However, recent reports show leakiness to be subject to considerable acclimation. Additionally, the recent discovery of two decarboxylating C4 cycles operating in parallel in Zea mays suggests that flexibility in the transported C4 acid and associated decarboxylase could also aid in maintaining C4/CBB balance in a changing environment. In this paper, we review improvements in methodology to estimate leakiness, synthesize reports on bundle-sheath leakiness, discuss different interpretations, and highlight areas where future research is necessary. PMID- 24755279 TI - Phylogeny and the inference of evolutionary trajectories. AB - Most important organismal adaptations are not actually single traits, but complex trait syndromes that are evolutionarily integrated into a single emergent phenotype. Two alternative photosynthetic pathways, C4 photosynthesis and crassulacean acid metabolism (CAM), are primary plant adaptations of this sort, each requiring multiple biochemical and anatomical modifications. Phylogenetic methods are a promising approach for teasing apart the order of character acquisition during the evolution of complex traits, and the phylogenetic placement of intermediate phenotypes as sister taxa to fully optimized syndromes has been taken as good evidence of an 'ordered' evolutionary trajectory. But how much power does the phylogenetic approach have to detect ordered evolution? This study simulated ordered and unordered character evolution across a diverse set of phylogenetic trees to understand how tree size, models of evolution, and sampling efforts influence the ability to detect an evolutionary trajectory. The simulations show that small trees (15 taxa) do not contain enough information to correctly infer either an ordered or unordered trajectory, although inference improves as tree size and sampling increases. However, even when working with a 1000-taxon tree, the possibility of inferring the incorrect evolutionary model (type I/type II error) remains. Caution is needed when interpreting the phylogenetic placement of intermediate phenotypes, especially in small lineages. Such phylogenetic patterns can provide a line of evidence for the existence of a particular evolutionary trajectory, but they should be coupled with other types of data to infer the stepwise evolution of a complex character trait. PMID- 24755280 TI - Life and death under salt stress: same players, different timing? AB - Salinity does not only stress plants but also challenges human life and the economy by posing severe constraints upon agriculture. To understand salt adaptation strategies of plants, it is central to extend agricultural production to salt-affected soils. Despite high impact and intensive research, it has been difficult to dissect the plant responses to salt stress and to define the decisive key factors for the outcome of salinity signalling. To connect the rapidly accumulating data from different systems, treatments, and organization levels (whole-plant, cellular, and molecular), and to identify the appropriate correlations among them, a clear conceptual framework is required. Similar to other stress responses, the molecular nature of the signals evoked after the onset of salt stress seems to be general, as with that observed in response to many other stimuli, and should not be considered to confer specificity per se. The focus of the current review is therefore on the temporal patterns of signals conveyed by molecules such as Ca(2+), H(+), reactive oxygen species, abscisic acid, and jasmonate. We propose that the outcome of the salinity response (adaptation versus cell death) depends on the timing with which these signals appear and disappear. In this context, the often-neglected non-selective cation channels are relevant. We also propose that constraining a given signal is as important as its induction, as it is the temporal competence of signalling (signal on demand) that confers specificity. PMID- 24755281 TI - Oxidative and pro-inflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is smoking reduced or nicotine-free products really safe? AB - BACKGROUND: Both active and passive tobacco smoke (TS) potentially impair the vascular endothelial function in a causative and dose-dependent manner, largely related to the content of reactive oxygen species (ROS), nicotine, and pro inflammatory activity. Together these factors can compromise the restrictive properties of the blood-brain barrier (BBB) and trigger the pathogenesis/progression of several neurological disorders including silent cerebral infarction, stroke, multiple sclerosis and Alzheimer's disease. Based on these premises, we analyzed and assessed the toxic impact of smoke extract from a range of tobacco products (with varying levels of nicotine) on brain microvascular endothelial cell line (hCMEC/D3), a well characterized human BBB model. RESULTS: Initial profiling of TS showed a significant release of reactive oxygen (ROS) and reactive nitrogen species (RNS) in full flavor, nicotine-free (NF, "reduced-exposure" brand) and ultralow nicotine products. This release correlated with increased oxidative cell damage. In parallel, membrane expression of endothelial tight junction proteins ZO-1 and occludin were significantly down regulated suggesting the impairment of barrier function. Expression of VE cadherin and claudin-5 were also increased by the ultralow or nicotine free tobacco smoke extract. TS extract from these cigarettes also induced an inflammatory response in BBB ECs as demonstrated by increased IL-6 and MMP-2 levels and up-regulation of vascular adhesion molecules, such as VCAM-1 and PECAM 1. CONCLUSIONS: In summary, our results indicate that NF and ultralow nicotine cigarettes are potentially more harmful to the BBB endothelium than regular tobacco products. In addition, this study demonstrates that the TS-induced toxicity at BBB ECs is strongly correlated to the TAR and NO levels in the cigarettes rather than the nicotine content. PMID- 24755282 TI - Toll-like receptor 4 signaling contributes to Paclitaxel-induced peripheral neuropathy. AB - This paper tests the contribution of the toll-like receptors, TLR4 in particular, in the initiation and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. TLR4 and its immediate downstream signaling molecules myeloid differentiation primary response gene 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter-inducing interferon-beta (TRIF)-were found to be increased in the dorsal root ganglion (DRG) using Western blot by day 7 of paclitaxel treatment. The behavioral phenotype, the increase of both TLR4 and MyD88, was blocked by cotreatment with the TLR4 antagonist lipopolysaccharide Rhodobacter sphaeroides during chemotherapy. A similar, but less robust, behavioral effect was observed using intrathecal treatment of MyD88 homodimerization inhibitory peptide. DRG levels of TLR4 and MyD88 reduced over the next 2 weeks, whereas these levels remained increased in spinal cord through day 21 following chemotherapy. Immunohistochemical analysis revealed TLR4 expression in both calcitonin gene-related peptide-positive and isolectin B4 positive small DRG neurons. MyD88 was only found in calcitonin gene-related peptide-positive neurons, and TRIF was found in both calcitonin gene-related peptide-positive and isolectin B4-positive small DRG neurons as well as in medium and large-size DRG neurons. In the spinal cord, TLR4 was only found colocalized to astrocytes but not with either microglia or neurons. Intrathecal treatment with the TLR4 antagonist lipopolysaccharide-R. sphaeroides transiently reversed preestablished chemotherapy-induced peripheral neuropathy mechanical hypersensitivity. These results strongly implicate TLR4 signaling in the DRG and the spinal cord in the induction and maintenance of paclitaxel-related chemotherapy-induced peripheral neuropathy. PERSPECTIVE: The toll-like receptor TLR4 and MyD88 signaling pathway could be a new potential therapeutic target in paclitaxel-induced painful neuropathy. PMID- 24755284 TI - Tissue factor predicts response to chemotherapy in esophageal cancer. AB - BACKGROUND: Neoadjuvant chemotherapy (NACT) improves the prognosis of patients with esophageal cancer who respond, but it is not effective in nonresponders. Therefore, it is crucial to establish a reliable method of predicting response before initiation of chemotherapy. Hypercoagulability, which is thought to be because of upregulation of tissue factor (TF) in cancer cells, was reported to be associated with chemoresistance. The aim of this study was to investigate the association between TF expression and response to NACT in esophageal cancer. METHODS: In 67 patients with advanced esophageal cancer, TF expression in pretreatment biopsy samples was evaluated immunohistochemically and correlated with clinicopathologic factors and response to chemotherapy. RESULTS: TF was expressed by 43.3% of the tumors, but there were no correlations observed with any clinicopathologic parameters examined. Clinical and histologic responses to chemotherapy were significantly worse in TF-positive patients compared with TF negative patients. Multivariate analysis revealed that TF expression was significantly associated with a poor clinical response (P = 0.0431). TF expression was also independently associated with poor progression-free survival (P = 0.0353). CONCLUSIONS: TF expression levels in pretreatment biopsy samples are useful for predicting response to NACT in advanced esophageal cancer. Further studies of mechanisms underlying the relationship between TF expression and chemosensitivity are needed. PMID- 24755283 TI - Screening the role of pronociceptive molecules in a rodent model of endometriosis pain. AB - Chronic pain is a major symptom in patients with endometriosis, a common gynecologic condition affecting women in their reproductive years. Although many proalgesic substances are produced by endometriosis lesions, experimental evidence supporting their relative roles is still lacking. Furthermore, it is unclear whether these proalgesic agents directly activate nociceptors to induce endometriosis pain. To determine their relative contribution to pain associated with endometriosis, we evaluated the intrathecal administration of oligodeoxynucleotides (ODNs) antisense to messenger RNA for receptors for 3 pronociceptive mediators known to be produced by the ectopic endometrium. Two weeks after the implant of autologous uterine tissue onto the gastrocnemius muscle, local mechanical hyperalgesia was observed in operated rats. Intrathecal antisense ODN targeting messenger RNA for the interleukin 6 receptor-signaling complex subunit glycoprotein 130 and the nerve growth factor tyrosine kinase receptor A, but not their mismatch ODNs, reversibly attenuated mechanical hyperalgesia at the implant site. In contrast, intrathecal antisense ODN targeting the tumor necrosis factor receptor 1, at a dose that markedly inhibited intramuscularly injected tumor necrosis factor alpha, had only a small antihyperalgesic effect in this model. These results indicate the relative contribution of pronociceptive mediators produced by ectopic endometrial tissue to endometriosis pain. The experimental approach presented here provides a novel method to evaluate for the differential contribution of mediators produced by other painful lesions as well as endometriosis lesions as targets for novel treatment of pain syndromes. PERSPECTIVE: This article presents evidence for the relative contribution of proalgesic mediators to primary hyperalgesia displayed by rats submitted to a model of endometriosis pain. This approach can be used to identify potential targets for the treatment of endometriosis pain. PMID- 24755285 TI - Gene structure, cDNA characterization and RNAi-based functional analysis of a myeloid differentiation factor 88 homolog in Tenebrio molitor larvae exposed to Staphylococcus aureus infection. AB - Myeloid differentiation factor 88 (MyD88), an intracellular adaptor protein involved in Toll/Toll-like receptor (TLR) signal processing, triggers activation of nuclear factor-kappaB (NF-kappaB) transcription factors. In the present study, we analyzed the gene structure and biological function of MyD88 in a coleopteran insect, Tenebrio molitor (TmMyD88). The TmMyD88 gene was 1380 bp in length and consisted of five exons and four introns. The 5'-flanking sequence revealed several putative transcription factor binding sites, such as STAT-4, AP-1, cJun, cfos, NF-1 and many heat shock factor binding elements. The cDNA contained a typical death domain, a conservative Toll-like interleukin-1 receptor (TIR) domain, and a C-terminal extension (CTE). The TmMyD88 TIR domain showed three significantly conserved motifs for interacting with the TIR domain of TLRs. TmMyD88 was grouped within the invertebrate cluster of the phylogenetic tree and shared 75% sequence identity with the TIR domain of Tribolium castaneum MyD88. Homology modeling of the TmMyD88 TIR domain revealed five parallel beta-strands surrounded by five alpha-helices that adopted loop conformations to function as an adaptor. TmMyD88 expression was upregulated 7.3- and 4.79-fold after 12 and 6h, respectively, of challenge with Staphylococcus aureus and fungal beta-1,3 glucan. Silencing of the TmMyD88 transcript by RNA interference led to reduced resistance of the host to infection by S. aureus. These results indicate that TmMyD88 is required for survival against Staphylococcus infection. PMID- 24755286 TI - Regulation of branching dynamics by axon-intrinsic asymmetries in Tyrosine Kinase Receptor signaling. AB - Axonal branching allows a neuron to connect to several targets, increasing neuronal circuit complexity. While axonal branching is well described, the mechanisms that control it remain largely unknown. We find that in the Drosophila CNS branches develop through a process of excessive growth followed by pruning. In vivo high-resolution live imaging of developing brains as well as loss and gain of function experiments show that activation of Epidermal Growth Factor Receptor (EGFR) is necessary for branch dynamics and the final branching pattern. Live imaging also reveals that intrinsic asymmetry in EGFR localization regulates the balance between dynamic and static filopodia. Elimination of signaling asymmetry by either loss or gain of EGFR function results in reduced dynamics leading to excessive branch formation. In summary, we propose that the dynamic process of axon branch development is mediated by differential local distribution of signaling receptors. DOI: http://dx.doi.org/10.7554/eLife.01699.001. PMID- 24755287 TI - SIR-2.1 integrates metabolic homeostasis with the reproductive neuromuscular excitability in early aging male Caenorhabditis elegans. AB - The decline of aging C. elegans male's mating behavior is correlated with the increased excitability of the cholinergic circuitry that executes copulation. In this study, we show that the mating circuits' functional durability depends on the metabolic regulator SIR-2.1, a NAD(+)-dependent histone deacetylase. Aging sir-2.1(0) males display accelerated mating behavior decline due to premature hyperexcitability of cholinergic circuits used for intromission and ejaculation. In sir-2.1(0) males, the hypercontraction of the spicule-associated muscles pinch the vas deferens opening, thus blocking sperm release. The hyperexcitability is aggravated by reactive oxygen species (ROS). Our genetic, pharmacological, and behavioral analyses suggest that in sir-2.1(0) and older wild-type males, enhanced catabolic enzymes expression, coupled with the reduced expression of ROS scavengers contribute to the behavioral decline. However, as a compensatory response to reduce altered catabolism/ROS production, anabolic enzymes expression levels are also increased, resulting in higher gluconeogenesis and lipid synthesis. DOI: http://dx.doi.org/10.7554/eLife.01730.001. PMID- 24755288 TI - Transgressions of compartment boundaries and cell reprogramming during regeneration in Drosophila. AB - Animals have developed mechanisms to reconstruct lost or damaged tissues. To regenerate those tissues the cells implicated have to undergo developmental reprogramming. The imaginal discs of Drosophila are subdivided into distinct compartments, which derive from different genetic programs. This feature makes them a convenient system to study reprogramming during regeneration. We find that massive damage inflicted to the posterior or the dorsal compartment of the wing disc causes a transient breakdown of compartment boundaries, which are quickly reconstructed. The cells involved in the reconstruction often modify their original identity, visualized by changes in the expression of developmental genes like engrailed or cubitus interruptus. This reprogramming is mediated by up regulation of the JNK pathway and transient debilitation of the epigenetic control mechanism. Our results also show that the local developmental context plays a role in the acquisition of new cell identities: cells expressing engrailed induce engrailed expression in neighbor cells. DOI: http://dx.doi.org/10.7554/eLife.01831.001. PMID- 24755289 TI - RGS7/Gbeta5/R7BP complex regulates synaptic plasticity and memory by modulating hippocampal GABABR-GIRK signaling. AB - In the hippocampus, the inhibitory neurotransmitter GABA shapes the activity of the output pyramidal neurons and plays important role in cognition. Most of its inhibitory effects are mediated by signaling from GABAB receptor to the G protein gated Inwardly-rectifying K+ (GIRK) channels. Here, we show that RGS7, in cooperation with its binding partner R7BP, regulates GABABR-GIRK signaling in hippocampal pyramidal neurons. Deletion of RGS7 in mice dramatically sensitizes GIRK responses to GABAB receptor stimulation and markedly slows channel deactivation kinetics. Enhanced activity of this signaling pathway leads to decreased neuronal excitability and selective disruption of inhibitory forms of synaptic plasticity. As a result, mice lacking RGS7 exhibit deficits in learning and memory. We further report that RGS7 is selectively modulated by its membrane anchoring subunit R7BP, which sets the dynamic range of GIRK responses. Together, these results demonstrate a novel role of RGS7 in hippocampal synaptic plasticity and memory formation. DOI: http://dx.doi.org/10.7554/eLife.02053.001. PMID- 24755290 TI - Gating of neural error signals during motor learning. AB - Cerebellar climbing fiber activity encodes performance errors during many motor learning tasks, but the role of these error signals in learning has been controversial. We compared two motor learning paradigms that elicited equally robust putative error signals in the same climbing fibers: learned increases and decreases in the gain of the vestibulo-ocular reflex (VOR). During VOR-increase training, climbing fiber activity on one trial predicted changes in cerebellar output on the next trial, and optogenetic activation of climbing fibers to mimic their encoding of performance errors was sufficient to implant a motor memory. In contrast, during VOR-decrease training, there was no trial-by-trial correlation between climbing fiber activity and changes in cerebellar output, and climbing fiber activation did not induce VOR-decrease learning. Our data suggest that the ability of climbing fibers to induce plasticity can be dynamically gated in vivo, even under conditions where climbing fibers are robustly activated by performance errors. DOI: http://dx.doi.org/10.7554/eLife.02076.001. PMID- 24755291 TI - Requirement for highly efficient pre-mRNA splicing during Drosophila early embryonic development. AB - Drosophila syncytial nuclear divisions limit transcription unit size of early zygotic genes. As mitosis inhibits not only transcription, but also pre-mRNA splicing, we reasoned that constraints on splicing were likely to exist in the early embryo, being splicing avoidance a possible explanation why most early zygotic genes are intronless. We isolated two mutant alleles for a subunit of the NTC/Prp19 complexes, which specifically impaired pre-mRNA splicing of early zygotic but not maternally encoded transcripts. We hypothesized that the requirements for pre-mRNA splicing efficiency were likely to vary during development. Ectopic maternal expression of an early zygotic pre-mRNA was sufficient to suppress its splicing defects in the mutant background. Furthermore, a small early zygotic transcript with multiple introns was poorly spliced in wild-type embryos. Our findings demonstrate for the first time the existence of a developmental pre-requisite for highly efficient splicing during Drosophila early embryonic development and suggest in highly proliferative tissues a need for coordination between cell cycle and gene architecture to ensure correct gene expression and avoid abnormally processed transcripts. DOI: http://dx.doi.org/10.7554/eLife.02181.001. PMID- 24755293 TI - A new spanner in the works of bacterial transcription. AB - A promising molecular target that is unlikely to develop antibiotic resistance has been identified in bacteria. PMID- 24755292 TI - GE23077 binds to the RNA polymerase 'i' and 'i+1' sites and prevents the binding of initiating nucleotides. AB - Using a combination of genetic, biochemical, and structural approaches, we show that the cyclic-peptide antibiotic GE23077 (GE) binds directly to the bacterial RNA polymerase (RNAP) active-center 'i' and 'i+1' nucleotide binding sites, preventing the binding of initiating nucleotides, and thereby preventing transcription initiation. The target-based resistance spectrum for GE is unusually small, reflecting the fact that the GE binding site on RNAP includes residues of the RNAP active center that cannot be substituted without loss of RNAP activity. The GE binding site on RNAP is different from the rifamycin binding site. Accordingly, GE and rifamycins do not exhibit cross-resistance, and GE and a rifamycin can bind simultaneously to RNAP. The GE binding site on RNAP is immediately adjacent to the rifamycin binding site. Accordingly, covalent linkage of GE to a rifamycin provides a bipartite inhibitor having very high potency and very low susceptibility to target-based resistance. DOI: http://dx.doi.org/10.7554/eLife.02450.001. PMID- 24755294 TI - A high sensitive biosensor based on FePt/CNTs nanocomposite/N-(4-hydroxyphenyl) 3,5-dinitrobenzamide modified carbon paste electrode for simultaneous determination of glutathione and piroxicam. AB - This study describes the development, electrochemical characterization and utilization of novel modified N-(4-hydroxyphenyl)-3,5-dinitrobenzamide-FePt/CNTs carbon paste electrode for the electrocatalytic determination of glutathione (GSH) in the presence of piroxicam (PXM) for the first time. The synthesized nanocomposite was characterized with different methods such as TEM and XRD. The modified electrode exhibited a potent and persistent electron mediating behavior followed by well-separated oxidation peaks of GSH and PXM. The peak currents were linearly dependent on GSH and PXM concentrations in the range of 0.004-340 and 0.5-550 umol L(-1), with detection limits of 1.0 nmol L(-1) and 0.1 umolL(-1), respectively. The modified electrode was successfully used for the determination of the analytes in real samples with satisfactory results. PMID- 24755295 TI - MicroRNA-181a promotes tumor growth and liver metastasis in colorectal cancer by targeting the tumor suppressor WIF-1. AB - BACKGROUND: Given the emerging role of microRNA in tumor disease progression, we investigated the association between microRNA expression, liver metastasis and prognosis of colorectal cancer. METHODS: Colorectal cancer tissues from patients with or without liver metastases were profiled to identify differentially expressed microRNA. Expression profile was further assessed using quantitative reverse transcription PCR and in situ hybridization. Correlation between miR-181a expression, the most differentially expressed microRNA, between patients with and without liver metastasis, and its downstream target genes were investigated using qRT-PCR. Luciferase reporter assay was conducted to establish functional association between miR-181a and its target genes. Manipulation of miR-181a expression and its consequences in tumor growth and metastasis were demonstrated in various in vitro and in vivo models. RESULTS: miR-181a was revealed being the most elevated in CRC with liver metastases. miR-181a expression correlated with advanced stage, distant metastasis, and served as an independent prognostic factor of poor overall survival. Stable transfection of CRC cell lines with miR 181a promoted cell motility and invasion, as well as tumor growth and liver metastasis,while silencing its expression resulted in reduced migration and invasion. Additionally, we identified WIF-1 as direct and functional targets of miR-181a. Ectopic expression of miR-181a suppressed the epithelial markers E cadherin and beta-catenin, while enhanced the mesenchymal markers vimentin. CONCLUSION: Our data demonstrate that miR-181a expression is associated with CRC liver metastasis and survival. miR-181a has strong tumor-promoting effects through inhibiting the expression of WIF-1, and its potential role in promoting epithelial-mesenchymal transition. PMID- 24755296 TI - Capecitabine in combination with oxaliplatin and bevacizumab (AXELOX) as 1st line treatment for fit and vulnerable elderly patients (aged >70 years) with metastatic colorectal cancer (mCRC): a multicenter phase II study of the Hellenic Oncology Research Group (HORG). AB - BACKGROUND: Colorectal cancer (CRC) is a disease of the elderly. However, geriatric patients are often excluded from clinical trials. The combination of capecitabine, oxaliplatin and bevacizumab (XELOX/BEV) has not been assessed in an elderly population. METHODS: We conducted a phase II study of XELOX plus bevacizumab combination as first line treatment in elderly patients with metastatic CRC. Treatment consisted of capecitabine 750 mg/m2 twice a day during days 1-7, oxaliplatin 85 mg/m2 and bevacizumab 5 mg/kg on day 1. Treatment was repeated every 14 days. The primary endpoint was overall response rate. RESULTS: In the 48 enrolled patients response rate according was 46.8% (95% CI: 32.54% 61.07%), while 13 patients had stable disease, for an overall disease control rate of 74.4% (95% CI: 57.8-91.2). Progression free survival was 7.9 months (95% CI: 5.9-9.8 months) and the median overall survival 20.1 months (95% CI: 15.6 25.7 months). Response rate and progression free survival has been correlated with baseline albumin and haemoglobin levels. There was one treatment-related death. Grade 3-4 toxicities were asthenia (4.2%), neurotoxicity (2.1%) and diarrhea 6.3%). CONCLUSIONS: The combination of capecitabine, oxaliplatin and bevacizumab is an effective and safe combination for the treatment of elderly patients with metastatic CRC. TRIAL REGISTRATION: Clinical trials NCT01024504, 26 November 2010. PMID- 24755297 TI - Mesoderm is required for coordinated cell movements within zebrafish neural plate in vivo. AB - BACKGROUND: Morphogenesis of the zebrafish neural tube requires the coordinated movement of many cells in both time and space. A good example of this is the movement of the cells in the zebrafish neural plate as they converge towards the dorsal midline before internalizing to form a neural keel. How these cells are regulated to ensure that they move together as a coherent tissue is unknown. Previous work in other systems has suggested that the underlying mesoderm may play a role in this process but this has not been shown directly in vivo. RESULTS: Here we analyze the roles of subjacent mesoderm in the coordination of neural cell movements during convergence of the zebrafish neural plate and neural keel formation. Live imaging demonstrates that the normal highly coordinated movements of neural plate cells are lost in the absence of underlying mesoderm and the movements of internalization and neural tube formation are severely disrupted. Despite this, neuroepithelial polarity develops in the abnormal neural primordium but the resulting tissue architecture is very disorganized. CONCLUSIONS: We show that the movements of cells in the zebrafish neural plate are highly coordinated during the convergence and internalization movements of neurulation. Our results demonstrate that the underlying mesoderm is required for these coordinated cell movements in the zebrafish neural plate in vivo. PMID- 24755299 TI - University hospitals as drivers of career success: an empirical study of the duration of promotion and promotion success of hospital physicians. AB - BACKGROUND: German hospitals have a well-defined career structure for clinicians. In this hierarchical career system university hospital are stepping stones for career advancement. This longitudinal study investigates the impact of working in university hospitals on the career success of junior physicians and senior physicians. METHODS: Consideration of the career trajectories of 324 hospital physicians. Discrete-time event history analysis is used to study the influence of working in university hospitals on the chance of promotion from junior physician to senior physician and senior physician to chief physician. A comparison of medians provides information about the impact of working in university hospitals on the duration of promotion to senior and chief physician positions. RESULTS: Working in university hospitals has a negative impact for advancement to a senior physician position in terms of promotion duration (p = 0.005) and also in terms of promotion success, where a short time span of just 1 2 years in university hospitals has a negative effect (OR = 0.38, p < 0.01), while working there for a medium or long term has no significant effect. However, working in universities has a positive effect on the duration of promotion to a chief physician position (p = 0.079), and working in university hospitals for 3-4 years increases the chance of promotion to a chief physician position (OR = 4.02, p < 0.05), while working there > =7 years decreases this chance (OR = 0.27, p < 0.05). In addition, physicians have a higher chance of promotion to a chief physician position through career mobility when they come to the position from a university hospital. CONCLUSION: Working at university hospitals has a career enhancing effect for a senior physician with ambitions to become a chief physician. For junior physicians on the trajectory to a senior physician position, however, university hospitals are not drivers of career success. PMID- 24755298 TI - Putative role of protein kinase C in neurotoxic inflammation mediated by extracellular heat shock protein 70 after ischemia-reperfusion. AB - BACKGROUND: Sterile inflammation occurs in the absence of live pathogens and is an unavoidable consequence of ischemia-reperfusion (IR) injury in the central nervous system (CNS). It is known that toll-like receptor 4 (Tlr4) contributes to damage and sterile inflammation in the CNS mediated by IR. However, the mechanism of Tlr4 activation under sterile conditions in ischemic tissue is poorly understood. We performed this study to clarify the mechanism. To this end, we focused on the extracellular heat shock protein 70 (Hsp70), the prototypic Tlr4 ligand. METHODS: Tlr4-, Myd88- and Trif-knockout animals, as well as C57BL/6 mice, were used for the wild type control. For the in vivo study, we used a mouse model of retinal IR injury. To test the role of protein kinase C (PKC) in IR injury, IR retinas were treated with the PKC inhibitors (polymyxin B and Go6976) and retinal damage was evaluated by directly counting neurons in the ganglion cell layer of flat-mounted retinas seven days after IR. Primary retinal neurons (retinal ganglion cells) and glial cells were used for in vitro experiments. Quantitative RT-PCR, ELISA and western blot analysis were used to study the production of pro-inflammatory factors in IR retinas and in primary cell cultures. RESULTS: We found significant accumulation of extracellular Hsp70 in a model of retinal IR injury. We noted that PKC was involved in Tlr4 signaling, and found that PKC inhibitors promoted neuroprotection by reducing pro-inflammatory activity in ischemic tissue. To put all of the pieces in the signaling cascade together, we performed an in vitro study. We found that PKC was critical to mediate the Hsp70-dependent pro-inflammatory response. At the same time, the contamination of Hsp70 preparations with low-dose endotoxin was not critical to mediate the production of pro-inflammatory factors. We found that extracellular Hsp70 can promote neuronal death at least, by mediating production of cytotoxic levels of tumor necrosis factor alpha, predominantly due to the Tlr4/Myd88 signaling cascade. CONCLUSIONS: Our findings suggest that PKC acts as a switch to amplify the pro-inflammatory activity of Hsp70/Tlr4 signaling, which is sufficient to mediate neuronal death. PMID- 24755300 TI - Enhanced degradation of textile effluent in constructed wetland system using Typha domingensis and textile effluent-degrading endophytic bacteria. AB - Textile effluent is one of the main contributors of water pollution and it adversely affects fauna and flora. Constructed wetland is a promising approach to remediate the industrial effluent. The detoxification of industrial effluent in a constructed wetland system may be enhanced by applying beneficial bacteria that are able to degrade contaminants present in industrial effluent. The aim of this study was to evaluate the influence of inoculation of textile effluent-degrading endophytic bacteria on the detoxification of textile effluent in a vertical flow constructed wetland reactor. A wetland plant, Typha domingensis, was vegetated in reactor and inoculated with two endophytic bacterial strains, Microbacterium arborescens TYSI04 and Bacillus pumilus PIRI30. These strains possessed textile effluent-degrading and plant growth-promoting activities. Results indicated that bacterial inoculation improved plant growth, textile effluent degradation and mutagenicity reduction and were correlated with the population of textile effluent-degrading bacteria in the rhizosphere and endosphere of T. domingensis. Bacterial inoculation enhanced textile effluent-degrading bacterial population in rhizosphere, root and shoot of T. domingensis. Significant reductions in COD (79%), BOD (77%) TDS (59%) and TSS (27%) were observed by the combined use of plants and bacteria within 72 h. The resultant effluent meets the wastewater discharge standards of Pakistan and can be discharged into the environment without any risks. This study revealed that the combined use of plant and endophytic bacteria is one of the approaches to enhance textile effluent degradation in a constructed wetland system. PMID- 24755301 TI - Autotrophic denitrification of nitrate and nitrite using thiosulfate as an electron donor. AB - This study was carried out to determine the possibility of autotrophic denitritation using thiosulfate as an electron donor, compare the kinetics of autotrophic denitrification and denitritation, and to study the effects of pH and sulfur/nitrogen (S/N) ratio on the denitrification rate of nitrite. Both nitrate and nitrite were removed by autotrophic denitrification using thiosulfate as an electron donor at concentrations up to 800 mg-N/L. Denitrification required a S/N ratio of 5.1 for complete denitrification, but denitritation was complete at a S/N ratio of 2.5, which indicated an electron donor cost savings of 50%. Also, pH during denitrification decreased but increased with nitrite, implying additional alkalinity savings. Finally, the highest specific substrate utilization rate of nitrite was slightly higher than that of nitrate reduction, and biomass yield for denitrification was relatively higher than that of denitritation, showing less sludge production and resulting in lower sludge handling costs. PMID- 24755302 TI - Left ventricular contrast injection with rotational C-arm CT improves accuracy of aortic annulus measurement during cardiac catheterisation. AB - AIMS: Introduction of a novel contrast injection protocol during rotational C-arm CT (RCT) in cardiac catheterisation of patients with aortic stenosis for aortic root assessment. METHODS AND RESULTS: Fifty-two patients underwent RCT imaging with contrast injection performed either into the aorta (Ao-RCT, n=25) or into the left ventricle (LV-RCT, n=27). Aortic annulus diameters were assessed in a multiplanar reconstruction view and compared with corresponding multidetector computed tomography (MDCT). LV contrast injection additionally enabled measurement of the left ventricular outflow tract (LVOT). LV-RCT improved the accuracy of annulus measurements and correlated well with MDCT data in comparison with Ao-RCT and MDCT (r=0.91, r=0.76, respectively). The Bland-Altman analysis showed smaller differences in MDCT and LV-RCT annulus measurements than between MDCT and Ao-RCT (LV-RCT: mean=0.4 mm, limits of agreement -1.5-2.3 mm vs. Ao-RCT: mean=0.1 mm, limits of agreement -3.4-3.6 mm). The inter-observer agreement for the annulus measurements was significantly increased for LV-RCT as calculated by the intra-class coefficient (ICC=0.85) in comparison with Ao-RCT (ICC=0.52). CONCLUSIONS: Cardiac catheterisation including LV-RCT offers complementary assessment of left ventricular function, aortic valve anatomy, coronary angiography and arterial access routes. LV-RCT for aortic root measurements shows better correlation to MDCT than standard Ao-RCT protocols. PMID- 24755303 TI - A power set-based statistical selection procedure to locate susceptible rare variants associated with complex traits with sequencing data. AB - MOTIVATION: Existing association methods for rare variants from sequencing data have focused on aggregating variants in a gene or a genetic region because of the fact that analysing individual rare variants is underpowered. However, these existing rare variant detection methods are not able to identify which rare variants in a gene or a genetic region of all variants are associated with the complex diseases or traits. Once phenotypic associations of a gene or a genetic region are identified, the natural next step in the association study with sequencing data is to locate the susceptible rare variants within the gene or the genetic region. RESULTS: In this article, we propose a power set-based statistical selection procedure that is able to identify the locations of the potentially susceptible rare variants within a disease-related gene or a genetic region. The selection performance of the proposed selection procedure was evaluated through simulation studies, where we demonstrated the feasibility and superior power over several comparable existing methods. In particular, the proposed method is able to handle the mixed effects when both risk and protective variants are present in a gene or a genetic region. The proposed selection procedure was also applied to the sequence data on the ANGPTL gene family from the Dallas Heart Study to identify potentially susceptible rare variants within the trait-related genes. AVAILABILITY AND IMPLEMENTATION: An R package 'rvsel' can be downloaded from http://www.columbia.edu/~sw2206/ and http://statsun.pusan.ac.kr. PMID- 24755304 TI - The cell behavior ontology: describing the intrinsic biological behaviors of real and model cells seen as active agents. AB - MOTIVATION: Currently, there are no ontologies capable of describing both the spatial organization of groups of cells and the behaviors of those cells. The lack of a formalized method for describing the spatiality and intrinsic biological behaviors of cells makes it difficult to adequately describe cells, tissues and organs as spatial objects in living tissues, in vitro assays and in computational models of tissues. RESULTS: We have developed an OWL-2 ontology to describe the intrinsic physical and biological characteristics of cells and tissues. The Cell Behavior Ontology (CBO) provides a basis for describing the spatial and observable behaviors of cells and extracellular components suitable for describing in vivo, in vitro and in silico multicell systems. Using the CBO, a modeler can create a meta-model of a simulation of a biological model and link that meta-model to experiment or simulation results. Annotation of a multicell model and its computational representation, using the CBO, makes the statement of the underlying biology explicit. The formal representation of such biological abstraction facilitates the validation, falsification, discovery, sharing and reuse of both models and experimental data. AVAILABILITY AND IMPLEMENTATION: The CBO, developed using Protege 4, is available at http://cbo.biocomplexity.indiana.edu/cbo/ and at BioPortal (http://bioportal.bioontology.org/ontologies/CBO). PMID- 24755305 TI - Production of cecropin A antimicrobial peptide in rice seed endosperm. AB - BACKGROUND: Cecropin A is a natural antimicrobial peptide that exhibits rapid, potent and long-lasting lytic activity against a broad spectrum of pathogens, thus having great biotechnological potential. Here, we report a system for producing bioactive cecropin A in rice seeds. RESULTS: Transgenic rice plants expressing a codon-optimized synthetic cecropin A gene drived by an endosperm specific promoter, either the glutelin B1 or glutelin B4 promoter, were generated. The signal peptide sequence from either the glutelin B1 or the glutelin B4 were N-terminally fused to the coding sequence of the cecropin A. We also studied whether the presence of the KDEL endoplasmic reticulum retention signal at the C-terminal has an effect on cecropin A subcellular localization and accumulation. The transgenic rice plants showed stable transgene integration and inheritance. We show that cecropin A accumulates in protein storage bodies in the rice endosperm, particularly in type II protein bodies, supporting that the glutelin N-terminal signal peptides play a crucial role in directing the cecropin A to this organelle, independently of being tagged with the KDEL endoplasmic reticulum retention signal. The production of cecropin A in transgenic rice seeds did not affect seed viability or seedling growth. Furthermore, transgenic cecropin A seeds exhibited resistance to infection by fungal and bacterial pathogens (Fusarium verticillioides and Dickeya dadantii, respectively) indicating that the in planta-produced cecropin A is biologically active. CONCLUSIONS: Rice seeds can sustain bioactive cecropin A production and accumulation in protein bodies. The system might benefit the production of this antimicrobial agent for subsequent applications in crop protection and food preservation. PMID- 24755307 TI - Animals with a schizophrenia-like phenotype are differentially sensitive to the motivational effects of cannabinoid agonists in conditioned place preference. AB - Cannabis is the most consumed illicit drug worldwide, but among patients with a diagnosis of schizophrenia, this consumption is higher suggesting that they are differentially sensitive to cannabis. We chose to study this problematic using a neurodevelopmental model of schizophrenia: neonatal ventral hippocampus lesions (NVHL). In a first study, we compared the locomotor response to novelty, a mild stress and two doses of amphetamine (0.75 and 1.5 mg/kg) in sham and NVHL rats at post-natal day 35 (PD35) or 56 (PD56). In a second study, we investigated the valence of the motivational effect of Delta-9-tetrahydrocannabinnol (THC, 0.5 mg/kg, i.p.) and the cannabinoid receptor agonist, WIN55,212-2 (WIN, 1 mg/kg, i.p.), using the conditioned place preference paradigm; we used a biased procedure that comprised 12 days of testing with 3 paired-conditioning. The effects of this dose of WIN were also measured on locomotor activity. Results confirmed that the adult NVHL animals displayed a stronger locomotor response to the two doses of amphetamine, but not to novelty and a mild stress. In adult NVHL, but not sham animals, WIN stimulated locomotor activity and produced a conditioned place aversion. At the dose tested, THC tended to produce an aversion in adult sham but not NVHL animals. Taken together these findings show that adult animals with a schizophrenia-like phenotype are differentially sensitive to the motivational effect of cannabinoids. PMID- 24755306 TI - Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson's disease rat model. AB - Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD) and treatment with drugs modulating glutamatergic activity may have beneficial effects. Ceftriaxone has been reported to increase glutamate uptake by increasing glutamate transporter expression. The aim of this study was to determine the effects of ceftriaxone on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced PD rat model. MPTP was stereotaxically injected into the substantia nigra pars compacta (SNc) of male Wistar rats. Then, starting the next day (day 1), the rats were injected daily with either ceftriaxone (200 mg/kg/day, i.p.) or saline for 14 days and underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test. The treatment of ceftriaxone decreased the above MPTP-induced cognitive deficits. Furthermore, this study provides evidence that ceftriaxone inhibits MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area. In conclusion, these data support the idea that hyperactivity of the glutamatergic system is involved in the pathophysiology of PD and suggest that ceftriaxone may be a promising pharmacological tool for the development of new treatments for the dementia associated with PD. PMID- 24755308 TI - Influence of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine-induced conditioned place preference in rats. AB - The influence of systemic administration of cholinesterase inhibitors, donepezil and rivastigmine on the acquisition, expression, and reinstatement of morphine induced conditioned place preference (CPP) was examined in rats. Additionally, this study aimed to compare the effects of donepezil, which selectively inhibits acetylcholinesterase, and rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase on morphine reward. Morphine-induced CPP (unbiased method) was induced by four injections of morphine (5 mg/kg, i.p.). Donepezil (0.5, 1, and 3 mg/kg, i.p.) or rivastigmine (0.03, 0.5, and 1 mg/kg, i.p.) were given 20 min before morphine during conditioning phase and 20 min before the expression or reinstatement of morphine-induced CPP. Our results indicated that both inhibitors of cholinesterase attenuated the acquisition and expression of morphine CPP. The results were more significant after rivastigmine due to a broader inhibitory spectrum of this drug. Moreover, donepezil (1 mg/kg) and rivastigmine (0.5 mg/kg) attenuated the morphine CPP reinstated by priming injection of 5mg/kg morphine. These properties of both cholinesterase inhibitors were reversed by mecamylamine (3 mg/kg, i.p.), a nicotinic acetylcholine receptor antagonist but not scopolamine (0.5 mg/kg, i.p.), a muscarinic acetylcholine receptor antagonist. All effects of cholinesterase inhibitors were observed at the doses that had no effects on locomotor activity of animals. Our results suggest beneficial role of cholinesterase inhibitors in reduction of morphine reward and morphine-induced seeking behavior. Finally, we found that the efficacy of cholinesterase inhibitors in attenuating reinstatement of morphine CPP provoked by priming injection may be due to stimulation of nicotinic acetylcholine receptors. PMID- 24755310 TI - A nationwide survey on Marinesco-Sjogren syndrome in Japan. AB - BACKGROUND: Marinesco-Sjogren syndrome (MSS) is an autosomal recessive multisystem disorder characterized by the tetralogy of cerebellar ataxia, congenital cataracts, intellectual disability, and progressive muscle weakness due to myopathy. MSS is extremely rare, and its clinical, pathological, and genetic features are not yet fully understood. METHODS: We conducted a nationwide, questionnaire-based survey on MSS in Japan and carefully reviewed the medical records of 36 patients suspected of having this disease. In addition, pathological examinations of muscles, sequence and haplotype analysis in SIL1 were performed. RESULTS: The patients had been examined between the ages of 2 and 52 years. Delayed psychomotor development and cataracts from early childhood were observed in all patients, whereas no life-threatening events were observed. Mutations in SIL1 were identified in 24 of the 27 patients tested, and 43 of the 48 chromosomes possessed the SIL1 c.936dupG (p.Leu313fs) mutation. The haplotype analysis revealed that 31 of the 32 chromosomes (96.9%) with the c.936dupG mutation had the same haplotype. CONCLUSIONS: The results of haplotype analysis suggested the presence of a founder effect. The clinical features of patients without SIL1 mutations were indistinguishable from those with SIL1 mutations, suggesting the genetic heterogeneity of MSS. PMID- 24755309 TI - Effects of dopamine D1 receptor blockade in the prelimbic prefrontal cortex or lateral dorsal striatum on frontostriatal function in Wistar and Spontaneously Hypertensive Rats. AB - Attention Deficit Hyperactivity Disorder (ADHD) is associated with dysfunctional prefrontal and striatal circuitry and dysregulated dopamine neurotransmission. Spontaneously Hypertensive Rats (SHR), a heuristically useful animal model of ADHD, were evaluated against normotensive Wistar (WIS) controls to determine whether dopamine D1 receptor blockade of either prelimbic prefrontal cortex (plPFC) or lateral dorsal striatum (lDST) altered learning functions of both interconnected sites. A strategy set shifting task measured plPFC function (behavioral flexibility/executive function) and a reward devaluation task measured lDST function (habitual responding). Prior to tests, rats received bilateral infusions of SCH 23390 (1.0 MUg/side) or vehicle into plPFC or lDST. Following vehicle, SHR exhibited longer lever press reaction times, more trial omissions, and fewer completed trials during the set shift test compared to WIS, indicating slower decision-making and attentional/motivational impairment in SHR. After reward devaluation, vehicle-treated SHR responded less than WIS, indicating relatively less habitual responding in SHR. After SCH 23390 infusions into plPFC, WIS expressed the same behavioral phenotype as vehicle-treated SHR during set shift and reward devaluation tests. In SHR, SCH 23390 infusions into plPFC exacerbated behavioral deficits in the set shift test and maintained the lower rate of responding in the reward devaluation test. SCH 23390 infusions into lDST did not modify set shifting in either strain, but produced lower rates of responding than vehicle infusions after reward devaluation in WIS. This research provides pharmacological evidence for unidirectional interactions between prefrontal and striatal brain regions, which has implications for the neurological basis of ADHD and its treatment. PMID- 24755311 TI - A high efficiency gene disruption strategy using a positive-negative split selection marker and electroporation for Fusarium oxysporum. AB - The Fusarium oxysporum species complex consists of fungal pathogens that cause serial vascular wilt disease on more than 100 cultivated species throughout the world. Gene function analysis is rapidly becoming more and more important as the whole-genome sequences of various F. oxysporum strains are being completed. Gene disruption techniques are a common molecular tool for studying gene function, yet are often a limiting step in gene function identification. In this study we have developed a F. oxysporum high-efficiency gene-disruption strategy based on split marker homologous recombination cassettes with dual selection and electroporation transformation. The method was efficiently used to delete three RNA-dependent RNA polymerase (RdRP) genes. The gene-disruption cassettes of three genes can be constructed simultaneously within a short time using this technique. The optimal condition for electroporation is 10MUF capacitance, 300Omega resistance, 4kV/cm field strength, with 1MUg of DNA (gene-disruption cassettes). Under these optimal conditions, we were able to obtain 95 transformants per MUg DNA. And after positive-negative selection, the transformants were efficiently screened by PCR, screening efficiency averaged 85%: 90% (RdRP1), 85% (RdRP2) and 77% (RdRP3). This gene-disruption strategy should pave the way for high throughout genetic analysis in F. oxysporum. PMID- 24755312 TI - Women's experience with postpartum intrauterine contraceptive device use in India. AB - BACKGROUND: Postpartum intrauterine contraceptive devices (PPIUCD) are increasingly included in many national postpartum family planning (PPFP) programs, but satisfaction of women who have adopted PPIUCD and complication rates need further characterization. Our specific aims were to describe women who accepted PPIUCD, their experience and satisfaction with their choice, and complication of expulsion or infection. METHODS: We studied 2,733 married women, aged 15-49 years, who received PPIUCD in sixteen health facilities, located in eight states and the national capital territory of India, at the time of IUCD insertion and six weeks later. The satisfaction of women who received IUCD during the postpartum period and problems and complications following insertion were assessed using standardized questionnaires. RESULTS: Mean (SD) age of women accepting PPIUCD was 24 (4) years. Over half of women had parity of one, and nearly one-quarter had no formal schooling. Nearly all women (99.6%) reported that they were satisfied with IUCD at the time of insertion and 92% reported satisfaction at the six-week follow-up visit. The rate of expulsion of IUCD was 3.6% by six weeks of follow-up. There were large variations in rates of problems and complications that were largely attributable to the individual hospitals implementing the study. CONCLUSIONS: Women who receive PPIUCD show a high level of satisfaction with this choice of contraception, and the rates of expulsion were low enough such that the benefits of contraceptive protection outweigh the potential inconvenience of needing to return for care for that subset of women. PMID- 24755313 TI - Short- and long-term lung cancer risk associated with noncalcified nodules observed on low-dose CT. AB - Chemoprevention is an important potential tool in reducing lung cancer incidence. Noncalcified nodules (NCN) observed on low-dose computed tomography (LDCT) have been proposed as intermediate endpoints in chemoprevention trials, but whether NCNs represent cancer precursors is unclear. We analyzed data from subjects in the LDCT arm of the National Lung Screening Trial (NLST) to examine short- and long-term lung cancer risks associated with NCNs and to elucidate whether some NCNs may be cancer precursors. NLST subjects received a baseline and two additional LDCT screens and were followed for a median of 6.5 years. We examined lung cancer incidence over three distinct periods from baseline-0-23 months (short-term), 24-59 months (medium-term), and 60-84 months (long-term)-in relation to baseline NCN characteristics. Spatially, lung cancer incidence was analyzed at the person, lung, and lobe levels relative to NCN location. A total of 26,272 subjects received the baseline LDCT screen, with 468, 413, and 190 lung cancers observed in the three periods. The presence of an NCN gave significantly elevated long-term lung cancer risk ratios (RR) of 1.8, 2.4, and 3.5 at the person, lung, and lobe levels; corresponding short-term RRs were 10.3, 16.8, and 38.0. Ground-glass attenuation was positively associated with long-term lung cancer risk but inversely associated with short-term risk; NCN size was positively associated with short-term risk but not significantly associated with long-term risk. That NCNs convey significantly elevated excess long-term of lung cancer lends evidence to the hypothesis that some NCNs may be cancer precursors. PMID- 24755314 TI - Stability of human alpha-salivary amylase in aged forensic samples. AB - The unequivocal tissue identification in forensic casework samples is a key step for crime scene reconstruction. Just knowing the origin of a fluid can sometimes be enough to either prove or disprove a fact in court. Despite the importance of this test, very few data are available in literature concerning human saliva identification in old forensic caseworks. In this work the stability of human alpha-amylase activity in aged samples is described by using three different methods integrated with DNA profiling techniques. This analytical protocol was successfully applied on 26-years old samples coming from anonymous threat letters sent to prosecutors who were working on "the Monster of Florence", a case of serial murders happened around Florence (Italy) between 1968 and 1985. PMID- 24755315 TI - Vascular measurements correlate with estrogen receptor status. AB - BACKGROUND: Breast carcinoma can be classified as either Estrogen Receptor (ER) positive or negative by immunohistochemical phenotyping, although ER expression may vary from 1 to 100% of malignant cells within an ER + tumor. This is similar to genetic variability observed in other tumor types and is generally viewed as a consequence of intratumoral evolution driven by random genetic mutations. Here we view cellular evolution within tumors as a classical Darwinian system in which variations in molecular properties represent predictable adaptations to spatially heterogeneous environmental selection forces. We hypothesize that ER expression is a successful adaptive strategy only if estrogen is present in the microenvironment. Since the dominant source of estrogen is blood flow, we hypothesized that, in general, intratumoral regions with higher blood flow would contain larger numbers of ER + cells when compared to areas of low blood flow and in turn necrosis. METHODS: This study used digital pathology whole slide image acquisition and advanced image analysis algorithms. We examined the spatial distribution of ER + and ER- cells, vascular density, vessel area, and tissue necrosis within histological sections of 24 breast cancer specimens. These data were correlated with the patients ER status and molecular pathology report findings. RESULTS: ANOVA analyses revealed a strong correlation between vascular area and ER expression and between high fractional necrosis and absent ER expression (R(2) = 39%; p < 0.003 and R(2) = 46%; p < 0.001), respectively). ER expression did not correlate with tumor grade or size. CONCLUSION: We conclude that ER expression can be understood as a Darwinian process and linked to variations in estrogen delivery by temporal and spatial heterogeneity in blood flow. This correlation suggests strategies to promote intratumoral blood flow or a cyclic introduction of estrogen in the treatment schedule could be explored as a counter-intuitive approach to increase the efficacy of anti-estrogen drugs. PMID- 24755317 TI - Investigation of fatty acid accumulation in the engineered Saccharomyces cerevisiae under nitrogen limited culture condition. AB - In this study, the Saccharomyces cerevisiae wild type strain and engineered strain with an overexpressed heterologous ATP-citrate lyase (acl) were cultured in medium with different carbon and nitrogen concentrations, and their fatty acid production levels were investigated. The results showed that when the S. cerevisiae engineered strain was cultivated under nitrogen limited culture condition, the yield of mono-unsaturated fatty acids showed higher than that under non-nitrogen limited condition; with the carbon concentration increased, the accumulation become more apparent, whereas in the wild type strain, no such correlation was found. Besides, the citrate level in the S. cerevisiae under nitrogen limited condition was found to be much higher than that under non nitrogen limited condition, which indicated a relationship between the diminution of nitrogen and accumulation of citrate in the S. cerevisiae. The accumulated citrate could be further cleaved by acl to provide substrate for fatty acid synthesis. PMID- 24755316 TI - Fibrates ameliorate the course of bacterial sepsis by promoting neutrophil recruitment via CXCR2. AB - Bacterial sepsis results in high mortality rates, and new therapeutics to control infection are urgently needed. Here, we investigate the therapeutic potential of fibrates in the treatment of bacterial sepsis and examine their effects on innate immunity. Fibrates significantly improved the survival from sepsis in mice infected with Salmonella typhimurium, which was paralleled by markedly increased neutrophil influx to the site of infection resulting in rapid clearance of invading bacteria. As a consequence of fibrate-mediated early control of infection, the systemic inflammatory response was repressed in fibrate-treated mice. Mechanistically, we found that fibrates preserve chemotaxis of murine neutrophils by blocking LPS-induced phosphorylation of ERK. This results in a decrease of G protein-coupled receptor kinase-2 expression, thereby inhibiting the LPS-mediated downregulation of CXCR2, a chemokine receptor critical for neutrophil recruitment. Accordingly, application of a synthetic CXCR2 inhibitor completely abrogated the protective effects of fibrates in septicemia in vivo. Our results unravel a novel function of fibrates in innate immunity and host response to infection and suggest fibrates as a promising adjunct therapy in bacterial sepsis. PMID- 24755318 TI - Synergistic effect of delignification and treatment with the ionic liquid 1-ethyl 3-methylimidazolium acetate on enzymatic digestibility of poplar wood. AB - This study examined the effects of removing key recalcitrance factors by ionic liquid (IL) treatment on the cellulase digestibility of poplar wood. Ground biomass was subjected to chlorite delignification and IL (1-ethyl-3 methylimidazolium acetate) treatment alone or in combination. The compositional and structural features of differentially treated biomass samples and their hydrolysis performance at various cellulase loadings were investigated. IL treatment caused minor compositional changes but drastically decreased cellulose crystallinity; in particular, when administered after delignification, an X-ray diffractogram similar to that of cellulose II polymorph was observed, suggesting that in the absence of lignin, the cellulose was dissolved in the IL and regenerated in water with a polymorphic transformation. The structural changes induced by the combined delignification-IL treatment facilitated the enzymatic hydrolysis of cellulose; the biomass could be fully degraded within 72 h by 4 FPU of cellulase per gram glucan, with cellobiose degradation being the rate-limiting step. PMID- 24755319 TI - Influence of dilute acid and alkali pretreatment on reducing sugar production from corncobs by crude enzymatic method: a comparative study. AB - In the present study, two commonly used catalysts in chemical pretreatment, sulfuric acid and sodium hydroxide, were tested to evaluate the effect of solid to-liquid ratio on pretreatment and enzymatic hydrolysis. Solid to liquid ratio (S/L) was influential on sugars released with an increase in the S/L ratio between 0.03 and 0.2. Enzymatic digestibility of 0.25 M H2SO4 pretreated corncobs were released more sugars (415.12 mg/mL); whereas, corncobs pretreated with NaOH released 350.12 mg/mL of reducing sugars at S/L 0.05. Further, in comparison with NaOH pretreated corncobs, acid treated material substantially increased the accessibility and digestibility of cellulose during crude enzymatic hydrolysis (28.96 FPU) and released 398.95 mg/mL reducing sugars. PMID- 24755320 TI - Dynamic modelling of mixotrophic microalgal photobioreactor systems with time varying yield coefficient for the lipid consumption. AB - Microalgae have been suggested as a promising feedstock for producing biofuel because of their potential for lipid production. In this study, microalgal photobioreactor systems under mixotrophic conditions were investigated, for the purpose of developing a mathematical model that predicts biomass and lipid production. The model was developed based on the Droop model, and the optimal input design using D-optimality criterion was performed to compute the system input profile, to estimate parameters more accurately. From the experimental observations, the newly defined yield coefficient was suggested to represent the consumption of lipid and nitrogen within the cell, which reduces the number of parameters with more accurate prediction. Furthermore, the lipid consumption rate was introduced to reflect the experimental results that lipid consumption is related to carbon source concentration. The model was validated with experiments designed with different initial conditions of nutrients and input changes, and showed good agreement with experimental observations. PMID- 24755321 TI - Isolation of high quality lignin as a by-product from ammonia percolation pretreatment of poplar wood. AB - A two-step process combining percolation-mode ammonia pretreatment of poplar sawdust with mild organosolv purification of the extracted lignin produced high quality, high purity lignin in up to 31% yield and 50% recovery. The uncondensed fraction of the isolated lignin was up to 34%, close to that the native lignin (40%). Less lignin was recovered after pretreatment in batch mode, apparently due to condensation during the longer residence time of the solubilised lignin at elevated temperature. The lignin recovery was directly correlated with its molecular weight and its nitrogen content. Low nitrogen incorporation, observed at high ammonia concentration, may be explained by limited homolytic cleavage of beta-O-4 bonds. Ammonia concentrations from 15% to 25% (w/w) gave similar results in terms of lignin structure, yield and recovery. PMID- 24755322 TI - Tumor necrosis factor inhibitor therapy but not standard therapy is associated with resolution of erosion in the sacroiliac joints of patients with axial spondyloarthritis. AB - INTRODUCTION: Radiography is an unreliable and insensitive tool for the assessment of structural lesions in the sacroiliac joints (SIJ). Magnetic resonance imaging (MRI) detects a wider spectrum of structural lesions but has undergone minimal validation in prospective studies. The Spondyloarthritis Research Consortium of Canada (SPARCC) MRI Sacroiliac Joint (SIJ) Structural Score (SSS) assesses a spectrum of structural lesions (erosion, fat metaplasia, backfill, ankylosis) and its potential to discriminate between therapies requires evaluation. METHODS: The SSS score assesses five consecutive coronal slices through the cartilaginous portion of the joint on T1-weighted sequences starting from the transitional slice between cartilaginous and ligamentous portions of the joint. Lesions are scored dichotomously (present/absent) in SIJ quadrants (fat metaplasia, erosion) or halves (backfill, ankylosis). Two readers independently scored 147 pairs (baseline, 2 years) of scans from a prospective cohort of patients with SpA who received either standard (n = 69) or tumor necrosis factor alpha (TNFalpha) inhibitor (n = 78) therapy. Smallest detectable change (SDC) was calculated using analysis of variance (ANOVA), discrimination was assessed using Guyatt's effect size, and treatment group differences were assessed using t-tests and the Mann-Whitney test. We identified baseline demographic and structural damage variables associated with change in SSS score by univariate analysis and analyzed the effect of treatment by multivariate stepwise regression adjusted for severity of baseline structural damage and demographic variables. RESULTS: A significant increase in mean SSS score for fat metaplasia (P = 0.017) and decrease in mean SSS score for erosion (P = 0.017) was noted in anti-TNFalpha treated patients compared to those on standard therapy. Effect size for this change in SSS fat metaplasia and erosion score was moderate (0.5 and 0.6, respectively). Treatment and baseline SSS score for erosion were independently associated with change in SSS erosion score (beta = 1.75, P = 0.003 and beta = 0.40, P < 0.0001, respectively). Change in ASDAS (beta = -0.46, P = 0.006), SPARCC MRI SIJ inflammation (beta = -0.077, P = 0.019), and baseline SSS score for fat metaplasia (beta = 0.085, P = 0.034) were independently associated with new fat metaplasia. CONCLUSION: The SPARCC SSS method for assessment of structural lesions has discriminative capacity in demonstrating significantly greater reduction in erosion and new fat metaplasia in patients receiving anti TNFalpha therapy. PMID- 24755323 TI - Use of an electrocardiographic screening tool to determine candidacy for a subcutaneous implantable cardioverter-defibrillator. AB - BACKGROUND: An electrocardiographic (ECG) screening test has been developed to identify patients being considered for a totally subcutaneous implantable cardioverter-defibrillator (S-ICD) at risk for T-wave oversensing. OBJECTIVE: The purpose of this study was to determine the proportion of potential S-ICD recipients who fail the ECG screening test and to identify predictors of failure. METHODS: Patients who already have an ICD but are not receiving antibradycardia pacing are representative of patients who might be considered for an S-ICD. One hundred such outpatients were enrolled in the study. Surface rhythm strips were recorded along the sensing vectors of the S-ICD system and the screening template applied. Clinical and standard ECG characteristics of patients who failed the test were compared to those who passed. RESULTS: Patients had the following characteristics: 72% male, age 57 +/- 16 years, body mass index 29 +/- 6 kg/m(2), left ventricular ejection fraction 43% +/- 17%, QRS duration 109 +/- 23 ms, QTc interval 447 +/- 39 ms, 44% had coronary disease, and 55% had heart failure. Among the 100 patients, 8% failed the screening test. There were no differences in patient clinical characteristics and most standard ECG measurements. However, patients with T-wave inversions in standard ECG leads I, II, and aVF had a 45% chance of failing. CONCLUSION: Eight percent of potential S-ICD patients were not eligible for the S-ICD after failing the screening test designed to identify patients susceptible to T-wave oversensing. Patients with T-wave inversions in leads I, II, and aVF on a standard ECG were 23 times more likely to fail. More work is needed in S-ICD sensing algorithms to increase patient eligibility for the S-ICD. PMID- 24755324 TI - Biomarkers: more than just markers! AB - In the strive for optimal indicators of kidney damage, nephrologists may at times feel entangled in a molecular jungle. Contrary to cardiologists that succeeded in establishing highly sensitive biomarker molecules for hypoxic cellular damage, nephrologists await well-performing 'damage' indicators. Reasons for this are ample and mostly relate to the complex composition of the functional units along the nephrons and the diverse cellular phenotypes that may be affected by different insults (hypoxia, direct and indirect cell toxicity, autoimmunity, apoptosis and necrosis). Besides elegant studies that confirm the appropriateness of biomarkers to indicate, early and adequately, kidney damage and putatively predict outcome for kidney function, there is a need to understand the (patho )physiological roles that these molecules play in health and disease. In this respect, a recent study by Humphreys et al. (J Clin Invest, 2013; 123: 4023) shed some light on the (patho-)physiological role that kidney injury molecule 1 (KIM 1) may play. By establishing transgenic mouse models with confined KIM-1 overexpression in proximal tubular cells, the authors are able to dissect cause and consequence, and link KIM-1 expression per se with interstitial inflammation and fibrosis. This study is remarkable for several reasons, given the profound insights into the pleiotropic functions of a single molecule, the simplicity of its design and the inclusion of adequately performed control experiment. PMID- 24755325 TI - Predictive validity of a new integrated selection process for medical school admission. AB - BACKGROUND: This paper is an evaluation of an integrated selection process utilising previous academic achievement [Universities Admission Index (UAI)], a skills test [Undergraduate Medicine and Health Sciences Admission Test (UMAT)], and a structured interview, introduced (in its entirety) in 2004 as part of curriculum reform of the undergraduate Medicine Program at the University of New South Wales (UNSW), Australia. Demographic measures of gender, country of birth, educational background and rurality are considered. METHOD: Admission scores and program outcomes of 318 students enrolled in 2004 and 2005 were studied. Regression analyses were undertaken to determine whether selection scores predicted overall, knowledge-based and clinical-based learning outcomes after controlling for demographics. RESULTS: UAI attained the highest values in predicting overall and knowledge-based outcomes. The communication dimension of the interview achieved similar predictive values as UAI for clinical-based outcomes, although predictive values were relatively low. The UMAT did not predict any performance outcome. Female gender, European/European-derived country of birth and non-rurality were significant predictors independent of UAI scores. CONCLUSION: Results indicate promising validity for an integrated selection process introduced for the Medicine Program at UNSW, with UAI and interview predictive of learning outcomes. Although not predictive, UMAT may have other useful roles in an integrated selection process. Further longitudinal research is proposed to monitor and improve the validity of the integrated student selection process. PMID- 24755326 TI - An extreme case of aortic root pseudoaneurysm after allograft root replacement: a technical challenge. PMID- 24755327 TI - Mobile right ventricular myxoma traversing chambers during cardiac cycle. PMID- 24755328 TI - High basal level of autophagy in high-altitude residents attenuates myocardial ischemia-reperfusion injury. AB - OBJECTIVE: Hypoxia can induce autophagy, which plays an important role in cardioprotection. The present study tested the hypothesis that patients with congenital heart disease living at a high altitude could resist ischemia reperfusion injury better than those at a low altitude, through elevated basal autophagy by chronic hypoxia. METHODS: Twelve Tibetan patients residing at a high altitude of >3000 m and 12 Han patients residing at a low altitude of <500 m with simple atrial or ventricular septal defects were prospectively recruited. All patients underwent cardiopulmonary bypass, maintaining a flow rate of approximately 2.4 to 2.8 L/min/m2 and mean arterial pressure of >=40 to 60 mm Hg. Myocardial ischemia-reperfusion injury between the 2 groups was compared using cardiac troponin I, brain natriuretic peptide, hematoxylin eosin staining, and the terminal deoxynucleotidyl transferase dUTP nick end labeling test. Autophagy related proteins microtubule-associated protein 1 light chain 3 II (LC3II), Beclin1, and lysosomal-associated membrane protein 2 (LAMP2) and their upstream protein BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) were evaluated with Western blotting. RESULTS: The maximal cardiac troponin I concentration and increasing x-fold of brain natriuretic peptide in the high altitude group were obviously lower than those in the low-altitude group (3.10+/ 0.77 vs 7.10+/-2.28 ng/mL and 2.51+/-0.94 vs 14.66+/-6.83, respectively). The preoperative and postoperative levels of LC3II, LAMP2, and upstream Bnip3 in the high-altitude group were obviously greater. No difference was found in the Beclin1 level between the 2 groups at baseline or ischemia-reperfusion. CONCLUSIONS: Patients living at a high altitude with congenital heart disease resisted ischemia-reperfusion injury during cardiac surgery better than those at a low altitude, possibly through elevated basal autophagy induced by chronic hypoxia. PMID- 24755329 TI - Very long-term durability of the edge-to-edge repair for isolated anterior mitral leaflet prolapse: up to 21 years of clinical and echocardiographic results. AB - OBJECTIVE: To assess the very long-term clinical and echocardiographic results of the edge-to-edge repair for mitral regurgitation (MR) due to isolated prolapse or flail of the anterior leaflet. METHODS: From 1991 to 2004, 139 patients (age, 54+/-14.4 years; left ventricular ejection fraction 56%+/-7.8%, New York Heart Association class I-II in 68.9%, atrial fibrillation in 20.1%) with severe degenerative MR due to isolated segmental prolapse or flail of the anterior leaflet were treated with the EE technique combined with annuloplasty. MR had resulted from prolapse or flail of the central scallop of the anterior leaflet (A2) in 105 patients (75.5%) and scallops A1 or A3 in 34 (24.4%). RESULTS: No hospital deaths occurred. At hospital discharge, MR was absent or mild in 130 patients (93.5%) and moderate (2+/4+) in 9 (6.4%). The clinical and echocardiographic follow-up data were 97.1% complete (mean length, 11.5+/-3.73 years; median, 11; longest duration, 21.5). At 17 years, the actuarial survival was 72.4%+/-7.89%, freedom from cardiac death was 90.8%+/-4.77%, and freedom from reoperation was 89.6%+/-2.74%. At the last echocardiographic examination, recurrence of MR grade>=3+ was documented in 17 patients (17 of 135, 12.5%). Freedom from MR grade>=3+ at 17 years was 80.2%+/-5.86%. At multivariate analysis, the predictors of MR recurrence grade>=3+ were residual MR greater than mild at hospital discharge (hazard ratio, 7.4; 95% confidence interval, 2.5-21.2; P=.0001) and the use of posterior pericardial rather than prosthetic ring annuloplasty, which was very close to statistical significance (hazard ratio, 2.8; 95% confidence interval, 0.9-8.7; P=.06). CONCLUSIONS: In patients with MR due to segmental anterior leaflet prolapse, the very long-term results of the edge-to-edge repair combined with annuloplasty were excellent. PMID- 24755330 TI - Effect of aortic aneurysm replacement on outcomes after bicuspid aortic valve surgery: validation of contemporary guidelines. AB - OBJECTIVE: Bicuspid aortic valve (BAV) disease is associated with aortic dilatation and aneurysm (AN) formation. The American College of Cardiology/American Heart Association (ACC/AHA) 2006 guidelines recommend replacement of the ascending aorta for an aortic diameter (AD)> 45 mm in patients undergoing aortic valve replacement (AVR). We evaluated the outcomes of AVR and AVR with aortic replacement (AVR/AN). METHODS: We retrospectively reviewed (2004 2011) the data from 456 patients with BAV and compared the morbidity and mortality between the AVR and AVR/AN groups and 3 subgroups: AVR with an AD<45 mm; AVR/AN with an AD of 45 to 49 mm; and AVR/AN with an AD of >=50 mm. Propensity score matching was used to reduce bias. RESULTS: Of the 456 patients, 250 (55%) underwent AVR and 206 (45%) AVR/AN, with 98% compliance with the current guidelines. The overall 30-day mortality was 0.9%. The AVR AD<45-mm group had adjusted short- and medium-term survival similar to that of the AVR/AN AD 45- to 49-mm and AVR/AN AD>=50-mm groups, with a 30-day mortality of 0.8%, 0%, and 1.9%, respectively (P=.41). The propensity score-matched AVR/AN AD>=50-mm group had significantly greater rates of reintubation than either the AVR AD<45-mm (P=.012) or AVR/AN AD 45- to 49-mm (P=.04) group and greater rates of prolonged ventilation (P=.022) than the AVR AD<45-mm group. No significant differences were found in reoperation or myocardial infarction among the subgroups. CONCLUSIONS: In patients with undergoing AVR, no increase was seen in morbidity or mortality when adding aortic replacement with an AD of 45 to 49 mm, in accordance with the 2006 ACC/AHA guidelines, although the AVR/AN AD>=50-mm group had a greater risk of respiratory complications. Our findings indicate that compliance with the ACC/AHA guidelines is safe in select centers. PMID- 24755331 TI - Perioperative factors associated with in-hospital mortality or retransplantation in pediatric heart transplant recipients. AB - OBJECTIVE: Despite improved long-term survival after pediatric heart transplantation, perioperative mortality has remained high. We sought to understand the factors associated with perioperative graft loss after pediatric heart transplantation. METHODS: The factors associated with primary heart transplant mortality and retransplantation before hospital discharge in 226 pediatric heart transplant recipients (1995-2010) at a single-center institution were analyzed using multivariable logistic regression models adjusted for age at surgery and year of surgery. RESULTS: A total of 26 patients died (n = 21) or underwent retransplantion (n = 5) before hospital discharge secondary to primary graft failure (n = 10), multisystem organ failure (n = 5), infection (n = 4), rejection (n = 2), and perioperative complications (n = 5). United Network for Organ Sharing status 1 (vs status 2) at transplantation was associated with an increased odds of death from noncardiac causes (odd ratio [OR], 4.7; 95% confidence level [CI], 1.2-22.3; P = .002). The factors associated with increased odds of perioperative mortality or retransplant were pre- and post-transplant extracorporeal membrane oxygenation (OR, 5.3; 95% CI, 1.5-18.7; P = .01; and OR, 25.9; 95% CI, 7.0-95.9; P < .001), longer ischemic times (OR, 1.4 per 30 minutes; 95% CI, 1.0-2.0; P = .04), reoperation after transplantation (OR, 3.5; 95% CI, 1.2-10.4; P = .02), and transplantation before 2002 (OR, 4.5; 95% CI, 1.4-14.9; P = .01), respectively. CONCLUSIONS: The use of extracorporeal membrane oxygenation (both before and after transplantation), a longer ischemic time, and reoperation were key factors associated with perioperative graft loss, with noncardiac mortality closely related to United Network for Organ Sharing status at heart transplantation. Knowledge of the perioperative risk factors and how they affect graft survival will help guide difficult decisions around eligibility, timing of primary listing, and appropriateness for retransplantation, and potentially affect long-term survival. PMID- 24755332 TI - "Triplet" polycistronic vectors encoding Gata4, Mef2c, and Tbx5 enhances postinfarct ventricular functional improvement compared with singlet vectors. AB - OBJECTIVE: The in situ reprogramming of cardiac fibroblasts into induced cardiomyocytes by the administration of gene transfer vectors encoding Gata4 (G), Mef2c (M), and Tbx5 (T) has been shown to improve ventricular function in myocardial infarction models. The efficacy of this strategy could, however, be limited by the need for fibroblast targets to be infected 3 times--once by each of the 3 transgene vectors. We hypothesized that a polycistronic "triplet" vector encoding all 3 transgenes would enhance postinfarct ventricular function compared with use of "singlet" vectors. METHODS: After validation of the polycistronic vector expression in vitro, adult male Fischer 344 rats (n=6) underwent coronary ligation with or without intramyocardial administration of an adenovirus encoding all 3 major vascular endothelial growth factor (VEGF) isoforms (AdVEGF-All6A positive), followed 3 weeks later by the administration to AdVEGF-All6A-positive treated rats of singlet lentivirus encoding G, M, or T (1*10(5) transducing units each) or the same total dose of a GMT "triplet" lentivirus vector. RESULTS: Western blots demonstrated that triplet and singlet vectors yielded equivalent GMT transgene expression, and fluorescence activated cell sorting demonstrated that triplet vectors were nearly twice as potent as singlet vectors in generating induced cardiomyocytes from cardiac fibroblasts. Echocardiography demonstrated that GMT triplet vectors were more effective than the 3 combined singlet vectors in enhancing ventricular function from postinfarct baselines (triplet, 37%+/-10%; singlet, 13%+/-7%; negative control, 9%+/-5%; P<.05). CONCLUSIONS: These data have confirmed that the in situ administration of G, M, and T induces postinfarct ventricular functional improvement and that GMT polycistronic vectors enhance the efficacy of this strategy. PMID- 24755333 TI - Early failures of Trifecta aortic bioprosthesis. PMID- 24755334 TI - Driveline insulation as a conduit for left ventricular assist device pocket infection. PMID- 24755335 TI - Meta-analysis of minimally invasive coronary artery bypass versus drug-eluting stents for isolated left anterior descending coronary artery disease. AB - OBJECTIVE: To compare the outcomes between minimally invasive coronary artery bypass (MINI-CAB) and drug-eluting stent (DES) implantation for isolated left anterior descending artery disease. METHODS: Randomized and observational comparative publications were identified using MEDLINE and Google Scholar databases (January 2003 to December 2013). Studies without outcomes data, without DES use, or using conventional bypass surgery were excluded. The outcomes of interest were cardiac death, myocardial infarction, target vessel revascularization, and periprocedural stroke. Data were compared using the Mantel Haenszel methods and are presented as odds ratios (ORs), 95% confidence intervals (CIs), and number needed to treat. RESULTS: From 230 publications, we identified 4 studies (2 randomized and 2 observational) with 941 patients (478 had undergone MINI-CAB and 463 DES implantation). The incidence of target vessel revascularization at maximum follow-up (range, 6-60 months) was significantly lower in the MINI-CAB group (OR, 0.16; 95% CI, 0.08-0.30; P<.0001; number needed to treat, 13). The incidence of cardiac mortality and MI was similar between the MINI-CAB and DES groups during follow-up (OR, 1.05; 95% CI, 0.44-2.47; and OR, 0.83; 95% CI, 0.43-1.58, respectively). In addition, a similar incidence of periprocedural death (OR, 0.85; 95% CI, 0.21-3.47; P=.82), myocardial infarction (OR, 0.98; 95% CI, 0.38-2.58; P=.97), and stroke (OR, 1.36; 95% CI, 0.28-6.70; P=.70) was observed between the 2 treatment modalities. CONCLUSIONS: Given the available evidence, MINI-CAB will result in lower target vessel revascularization rates but otherwise similar clinical outcomes compared with DESs in patients with left anterior descending artery disease. PMID- 24755336 TI - Metabolic switching of central carbon metabolism in response to nitrate: application to autofermentative hydrogen production in cyanobacteria. AB - Nitrate removal from culture media is widely used to enhance autofermentative hydrogen production in cyanobacteria during dark anaerobiosis. Here we have performed a systematic inventory of carbon and nitrogen metabolites, redox pools, and excreted product fluxes which show that addition of nitrate to cultures of Synechococcus sp. PCC 7002 has no influence on glycogen catabolic rate, but shifts the distribution of excreted products from predominantly lactate and H2 to predominantly CO2 and nitrite, while increasing the total consumption of intracellular reducing equivalents (mainly glycogen) by 3-fold. Together with LC MS derived metabolite pool sizes these data show that glycogen catabolism is redirected from the upper-glycolytic (EMP) pathway to the oxidative pentose phosphate (OPP) pathway upon nitrate addition. This metabolic switch in carbon catabolism is shown to temporally correlate with the pyridine nucleotide redox poise (NAD(P)H/NAD(P)(+)) and demonstrates the reductant availability controls H2 evolution in cyanobacteria. PMID- 24755337 TI - Idiopathic desmoid-type fibromatosis of the pancreatic head: case report and literature review. AB - Desmoid-type fibromatosis (DTF) is an uncommon nonmetastatic fibrous neoplasm. Sporadic intraperitoneal DTF is rarely described in current literature. We herein report a case of DTF of unknown cause involving the pancreatic head. A 41-year old man presented with recurrent epigastric pain and weight loss. An abdominal computed tomography scan showed a well-delineated solid cystic mass inside the pancreatic head. Pylorus-preserving pancreaticoduodenectomy was performed due to the patient's debilitating symptoms and suspected malignancy. The pathological examination revealed massive fibroblastic proliferation arising from the musculoaponeurotic tissues, consistent with a diagnosis of DTF. Immunohistochemical phenotyping determined positive immunoreactivity to vimentin and beta-catenin, but negative immunoreactivity to smooth muscle actin, CD117, CD34, or S-100, confirming the diagnosis of DTF. No local recurrence or distant metastasis was found during a 24-month follow-up. Radical resection is recommended as first-line treatment for pancreatic DTF. Long-term follow-up studies are required to establish the prognosis of pancreatic DTF. PMID- 24755339 TI - The plasma level and biomarker value of neutrophil gelatinase-associated lipocalin in critically ill patients with acute kidney injury are not affected by continuous venovenous hemofiltration and anticoagulation applied. AB - INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI), and levels reflect severity of disease in critically ill patients. However, continuous venovenous hemofiltration (CVVH) may affect plasma levels by clearance or release of NGAL by activated neutrophils in the filter, dependent on the anticoagulation regimen applied. We therefore studied handling of NGAL by CVVH in patients with AKI. METHODS: Immediately before initiation of CVVH, prefilter blood was drawn. After 10, 60, 180, and 720 minutes of CVVH, samples were collected from pre- and postfilter (in- and outlet) blood and ultrafiltrate. CVVH with the following anticoagulation regimens was studied: no anticoagulation in case of a high bleeding tendency (n = 13), unfractionated heparin (n = 8), or trisodium citrate (n = 21). NGAL levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: Concentrations of NGAL at inlet and outlet were similar, and concentrations did not change over time in any of the anticoagulation groups; thus no net removal or production of NGAL occurred. Concentrations of NGAL at inlet correlated with disease severity at initiation of CVVH and at the end of a CVVH run. Concentrations of NGAL in the ultrafiltrate were lower with citrate-based CVVH (P = 0.03) and decreased over time, irrespective of anticoagulation administered (P < 0.001). The sieving coefficient and clearance of NGAL were low and decreased over time (P < 0.001). CONCLUSIONS: The plasma level and biomarker value of NGAL in critically ill patients with AKI are not affected by CVVH, because clearance by the filter was low. Furthermore, no evidence exists for intrafilter release of NGAL by neutrophils, irrespective of the anticoagulation method applied. PMID- 24755340 TI - Cavitation technology - a greener processing technique for the generation of pharmaceutical nanoemulsions. AB - Novel nanoemulsion-based drug delivery systems (DDS) have been proposed as alternative and effective approach for the delivery of various types of poorly water-soluble drugs in the last decade. This nanoformulation strategy significantly improves the cell uptake and bioavailability of numerous hydrophobic drugs by increasing their solubility and dissolution rate, maintaining drug concentration within the therapeutic range by controlling the drug release rate, and reducing systemic side effects by targeting to specific disease site, thus offering a better patient compliance. To date, cavitation technology has emerged to be an energy-efficient and promising technique to generate such nanoscale emulsions encapsulating a variety of highly potent pharmaceutical agents that are water-insoluble. The micro-turbulent implosions of cavitation bubbles tear-off primary giant oily emulsion droplets to nano-scale, spontaneously leading to the formation of highly uniform drug contained nanodroplets. A substantial body of recent literatures in the field of nanoemulsions suggests that cavitation is a facile, cost-reducing yet safer generation tool, remarkably highlighting its industrial commercial viability in the development of designing novel nanocarriers or enhancing the properties of existing pharmaceutical products. In this review, the fundamentals of nanoemulsion and the principles involved in their formation are presented. The underlying mechanisms in the generation of pharmaceutical nanoemulsion under acoustic field as well as the advantages of using cavitation compared to the conventional techniques are also highlighted. This review focuses on recent nanoemulsion-based DDS development and how cavitation through ultrasound and hydrodynamic means is useful to generate the pharmaceutical grade nanoemulsions including the complex double or submicron multiple emulsions. PMID- 24755338 TI - Genome-wide identification of WRKY family genes and their response to cold stress in Vitis vinifera. AB - BACKGROUND: WRKY transcription factors are one of the largest families of transcriptional regulators in plants. WRKY genes are not only found to play significant roles in biotic and abiotic stress response, but also regulate growth and development. Grapevine (Vitis vinifera) production is largely limited by stressful climate conditions such as cold stress and the role of WRKY genes in the survival of grapevine under these conditions remains unknown. RESULTS: We identified a total of 59 VvWRKYs from the V. vinifera genome, belonging to four subgroups according to conserved WRKY domains and zinc-finger structure. The majority of VvWRKYs were expressed in more than one tissue among the 7 tissues examined which included young leaves, mature leaves, tendril, stem apex, root, young fruits and ripe fruits. Publicly available microarray data suggested that a subset of VvWRKYs was activated in response to diverse stresses. Quantitative real-time PCR (qRT-PCR) results demonstrated that the expression levels of 36 VvWRKYs are changed following cold exposure. Comparative analysis was performed on data from publicly available microarray experiments, previous global transcriptome analysis studies, and qRT-PCR. We identified 15 VvWRKYs in at least two of these databases which may relate to cold stress. Among them, the transcription of three genes can be induced by exogenous ABA application, suggesting that they can be involved in an ABA-dependent signaling pathway in response to cold stress. CONCLUSIONS: We identified 59 VvWRKYs from the V. vinifera genome and 15 of them showed cold stress-induced expression patterns. These genes represented candidate genes for future functional analysis of VvWRKYs involved in the low temperature-related signal pathways in grape. PMID- 24755341 TI - Abdominal pain, fever, and unrelenting melena. PMID- 24755342 TI - Unusual cause of abdominal pain. PMID- 24755343 TI - A rapidly enlarging gastric subepithelial lesion. PMID- 24755344 TI - Abdominal pain and bloating in an auto mechanic. PMID- 24755345 TI - Postural threat during walking: effects on energy cost and accompanying gait changes. AB - BACKGROUND: Balance control during walking has been shown to involve a metabolic cost in healthy subjects, but it is unclear how this cost changes as a function of postural threat. The aim of the present study was to determine the influence of postural threat on the energy cost of walking, as well as on concomitant changes in spatiotemporal gait parameters, muscle activity and perturbation responses. In addition, we examined if and how these effects are dependent on walking speed. METHODS: Healthy subjects walked on a treadmill under four conditions of varying postural threat. Each condition was performed at 7 walking speeds ranging from 60-140% of preferred speed. Postural threat was induced by applying unexpected sideward pulls to the pelvis and varied experimentally by manipulating the width of the path subjects had to walk on. RESULTS: Results showed that the energy cost of walking increased by 6-13% in the two conditions with the largest postural threat. This increase in metabolic demand was accompanied by adaptations in spatiotemporal gait parameters and increases in muscle activity, which likely served to arm the participants against a potential loss of balance in the face of the postural threat. Perturbation responses exhibited a slower rate of recovery in high threat conditions, probably reflecting a change in strategy to cope with the imposed constraints. The observed changes occurred independent of changes in walking speed, suggesting that walking speed is not a major determinant influencing gait stability in healthy young adults. CONCLUSIONS: The current study shows that in healthy adults, increasing postural threat leads to a decrease in gait economy, independent of walking speed. This could be an important factor in the elevated energy costs of pathological gait. PMID- 24755346 TI - Removal of sulfamethoxazole and ciprofloxacin from aqueous solutions by graphene oxide. AB - As a promising nanomaterial, graphene-oxide (GO) has shown great sorption potential for environmental contaminants. This study evaluated the ability and mechanism of GO to remove sulfamethoxazole (SMX) and ciprofloxacin (CIP) from aqueous solution. Experimental and modeling results showed that GO effectively sorbed both CIP and SMX with maximum sorption capacity of 379 and 240 mg g(-1), respectively. The sorption of CIP was mainly controlled by the electrostatic attractions; while SMX sorption was mainly though pi-pi EDA attraction on the basal planes of the GO. Solution pH showed strong effect on the sorption ability of GO to the two antibiotics: at pH of 2, GO sorption ability decreased for both CIP and SMX; at pH of 9, GO completely lost SMX sorption ability but still showed strong sorption to CIP. Both NaCl and CaCl2 decreased CIP sorption onto GO and CaCl2 showed high efficiency even at low ionic strength. The effect of NaCl and CaCl2 on SMX sorption was weaker, but higher ionic strength also reduced the sorption of SMX onto GO. At solution pH of 2, sorption of CIP destabilized GO suspension to form aggregates. Results obtained from this work demonstrated that GO can be used as an effective adsorbents to removal antibiotics from water. PMID- 24755347 TI - Primary diffuse large B-cell lymphoma of the chest wall: a case report. AB - Reports of primary diffuse large B-cell lymphomas of the chest wall are extremely rare in the literature. We report the case of a 62-year-old Chinese woman presenting with left-sided chest pain. A computed tomography scan showed a solid, round mass in the left anterior chest wall, involving the second and third costal cartilages. Complete resection and reconstruction of the chest wall was performed. The histological and immunohistochemical features of the mass were used to diagnose a primary diffuse large B-cell lymphoma. PMID- 24755348 TI - Expression of a single prominin homolog in the embryo of the model chordate Ciona intestinalis. AB - Prominins are a family of pentaspan transmembrane glycoproteins, expressed in various types of cells, including stem and cancer stem cells in mammals. Prominin 1 is critical in generating and maintaining the structure of the photoreceptors in the eye since mutations in the PROM1 gene are associated with retinal and macular degeneration in human. In this study, we identified a single prominin homolog, Ci-prom1/2, in the model chordate the ascidian Ciona intestinalis and characterized Ci-prom1/2 expression profile in relation to photoreceptor differentiation during Ciona embryonic development. In situ hybridization experiments show Ci-prom1/2 transcripts localized in the developing central nervous system, predominantly in photoreceptor cell precursors as early as neurula stage and expression is maintained through larva stage in photoreceptor cells around the simple eye. We also isolated the regulatory region responsible for the specific spatio-temporal expression of the Ci-prom1/2 in photoreceptor cell lineage. Collectively, we report that Ci-prom1/2 is a novel molecular marker for ascidian photoreceptor cells and might represent a potential source to enlarge the knowledge about the function of prominin family in photoreceptor cell evolution and development. PMID- 24755349 TI - PKA regulatory subunit expression in tooth development. AB - Protein kinase A (PKA) plays critical roles in many biological processes including cell proliferation, cell differentiation, cellular metabolism and gene regulation. Mutation in PKA regulatory subunit, PRKAR1A has previously been identified in odontogenic myxomas, but it is unclear whether PKA is involved in tooth development. The aim of the present study was to assess the expression of alpha isoforms of PKA regulatory subunit (Prkar1a and Prkar2a) in mouse and human odontogenesis by in situ hybridization. PRKAR1A and PRKAR2A mRNA transcription was further confirmed in a human deciduous germ by qRT-PCR. Mouse Prkar1a and human PRKAR2A exhibited a dynamic spatio-temporal expression in tooth development, whereas neither human PRKAR1A nor mouse Prkar2a showed their expression in odontogenesis. These isoforms thus showed different expression pattern between human and mouse tooth germs. PMID- 24755350 TI - Associations between genes for killer immunoglobulin-like receptors and their ligands in patients with epithelial ovarian cancer. AB - Killer immunoglobulin-like receptors (KIRs) regulate function of NK cells and subsets of T cells. HLA class I molecules are ligands for inhibitory KIRs while specificity of activating KIRs is mainly unknown. Both KIR and HLA genotypes are highly polymorphic. In this study we analyzed associations of KIR and KIR ligand genes with the incidence and clinical course of epithelial ovarian cancer. DNA of 142 patients was analyzed for KIR genes and 103 samples were typed for HLA class I. Control group consisted of 200 healthy individuals, including 83 women, analyzed separately. The frequency of KIR genes in patients and controls were comparable. HLA-C group 1 (ligand for KIR2DL2/3) was more frequent in patients than in controls (86.4% vs. 67.5%, p=0.002). The frequency of KIR2DS4fl was higher in patients with endometrioid cancer (72.3%) compared with other histological subtypes (36.5%, p=0.004) and controls (29.5%, p=0.0001). KIR and KIR ligand genotype did not influence significantly the clinical course of the disease. We conclude that the genotype of KIR ligands is strongly associated with the incidence of epithelial ovarian cancer while KIR2DS4fl confers susceptibility to endometrioid subtype of the disease. PMID- 24755351 TI - T-cell epitope discovery technologies. AB - Despite tremendous potential utility in clinical medicine and research, the discovery and characterization of T-cell antigens has lagged behind most other areas of health research in joining the high-throughput '-omics' revolution. Partially responsible for this is the complex nature of the interactions between effector T cells and antigen-presenting cells. Further contributing to the challenge is the vastness of both the T-cell repertoire and the large number of potential T-cell epitopes. In this review, we trace the development of various discovery strategies, the technical platforms used to carry them out, and we assess the level of success achieved in the field today. PMID- 24755352 TI - Killer cell immunoglobulin-like receptors in Thai patients with leukemia and diffuse large B-cell lymphoma. AB - Natural killer (NK) cells are key components of the innate immune system that have been implicated in the immune response against tumor cells. Killer cell immunoglobulin-like receptors (KIR) regulate NK cell activity by interaction with specific human leukocyte antigen (HLA) class I. In this study, KIR gene polymorphisms and their HLA ligands were investigated in Thai patients with chronic myelogenous leukemia (CML) (n=60), acute myelogenous leukemia (AML) (n=60), acute lymphoblastic leukemia (ALL) (n=55), and diffuse large B-cell lymphoma (DLBCL) (n=60) compared with 150 healthy controls. The frequency of KIR3DL1 with HLA-Bw4 was significantly lower in DLBCL patients than in controls (P=0.0006, Pc=0.02), whereas no significant differences were seen in KIR gene frequencies and their ligands between leukemia patients and controls. This study suggest a role of inhibitory KIR with its ligand in the protection against DLBCL. PMID- 24755353 TI - Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP. AB - Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA. PMID- 24755354 TI - Spectral domain optical coherence tomography in children: normative data and biometric correlations. AB - BACKGROUND: The aim was to report normative values of retinal nerve fiber layer (RNFL) and macular parameters in children using spectral domain optical coherence tomography (OCT) and to perform correlations with age, refractive error and axial length. METHODS: This was an observational cross-sectional study recruiting 113 healthy children aged 6 to 17 years with no ocular abnormality except refractive error. After a comprehensive eye examination and axial length measurement, RNFL and macular thickness measurements were performed using the Cirrus OCT machine. Main outcome measures were macular volume, macular thickness and RNFL thickness values as well as their correlations with age, refractive error and axial length. Right eyes of all subjects were selected for analysis. RESULTS: One hundred and eight children were included in the study, 65 females and 43 males. Mean age was 10.7+/-3.1 years, average spherical equivalent refraction (SE) was -0.02+/-1.77( 4.25 to +5.00) diopters and average axial length was 23.5+/-1.0 (21.5 to 25.8)mm. Mean RNFL thickness was 95.6+/-8.7 MUm, average macular thickness was 279.6+/ 12.5 MUm, central macular thickness was 249.1+/-20.2 MUm, and mean macular volume was 10.1+/-0.5 mm(3). Central macular thickness values were significantly higher in males (p < 0.001). RNFL measurements did not correlate with age but did show a positive correlation with SE. All macular parameters were consistently positively correlated with age and most of them were positively correlated with SE. When controlling for axial length, only the macular inner circle thickness was positively correlated with age. CONCLUSIONS: Using Cirrus OCT, normative RNFL and macular parameters in healthy children below 18 years of age were established; measurements varied by age and gender. PMID- 24755355 TI - Predictors of first-year GPA of medical students: a longitudinal study of 1285 matriculates in China. AB - BACKGROUND: Although medical education has developed rapidly in the last decade, and the National College Entrance Examination (NCEE) is used as the "gold standard" for admission to medical college in mainland China, there is a lack of literature regarding the influence of NCEE score and other factors on the academic performance of medical students. This study aimed to examine potential predictors of first-year grade point average (GPA) for medical students. METHODS: This study included 1,285 students who matriculated at a first-tier medical university in mainland China in 2011. The precollege motivational attitudes for each matriculate were investigated via questionnaire. A hierarchical linear model was fitted to regress first-year GPA on a 100-point scale on NCEE score and other student-level and major-level characteristics. RESULTS: NCEE score was a significant predictor of both within-major and between-major variation of first year GPA for medical students. Majors with higher mean NCEE scores had higher mean GPAs, and higher GPAs were observed among those individuals with higher NCEE scores after controlling for major-level characteristics. First-year GPA differed by certain individual socio-demographic variables. Female students had a 2.44 higher GPA on average than did male students. NCEE repeaters had a 1.55-lower GPA than non-repeaters. First-year GPA was associated negatively with parental income but positively with academic self-concept. CONCLUSIONS: NCEE score is an important predictor of the first-year GPA of medical students, but it is not the sole determinant. Individual socio-demographic characteristics and major-level characteristics should be taken into account to understand better and improve the first-year GPA of medical students. PMID- 24755356 TI - Mitigation of methane emission from an old unlined landfill in Klintholm, Denmark using a passive biocover system. AB - Methane generated at landfills contributes to global warming and can be mitigated by biocover systems relying on microbial methane oxidation. As part of a closure plan for an old unlined landfill without any gas management measures, an innovative biocover system was established. The system was designed based on a conceptual model of the gas emission patterns established through an initial baseline study. The study included construction of gas collection trenches along the slopes of the landfill where the majority of the methane emissions occurred. Local compost materials were tested as to their usefulness as bioactive methane oxidizing material and a suitable compost mixture was selected. Whole site methane emission quantifications based on combined tracer release and downwind measurements in combination with several local experimental activities (gas composition within biocover layers, flux chamber based emission measurements and logging of compost temperatures) proved that the biocover system had an average mitigation efficiency of approximately 80%. The study showed that the system also had a high efficiency during winter periods with temperatures below freezing. An economic analysis indicated that the mitigation costs of the biocover system were competitive to other existing greenhouse gas mitigation options. PMID- 24755357 TI - What is the acceptable margin of error for the oxygen uptake method in evaluating the reactivity of organic waste? AB - The acceptable margin of error for the organic waste reactivity measured by the oxygen uptake method was assessed. Oxygen uptake was determined by the Dynamic Respiration Index (DRI) (mgO2/kgVS h). The composed uncertainty (uC) of the experimental set up used for the DRI test was evaluated and the uncertainty (u) of all the components of the apparatus was evaluated. A procedure for calculating the uC of the apparatus is proposed. The components affecting the uC of the DRI to a more significant extent were the one of the oxygen mass rate and the u of the amount of VS in the sample analyzed. For a confidence level of 99.73%, the extended uC (UC) interval for a DRI = 1024 mgO2/kgVS h was +/- 440 mgO2/kgVS h, whereas for a DRI = 3,489 mgO2/kgVS h, the UC interval was +/- 1288 mgO2/kgVS h. When oxygen consumption and VS content become lower than 600 mgO2/h and 0.9 kg, respectively, the UC interval is similar to the measured DRI. PMID- 24755358 TI - Trauma exposure, posttraumatic stress disorder and the effect of explanatory variables in paramedic trainees. AB - BACKGROUND: Emergency healthcare workers, including trainees and individuals in related occupations are at heightened risk of developing posttraumatic stress disorder (PTSD) and depression owing to work-related stressors.We aimed to investigate the type, frequency, and severity of direct trauma exposure, posttraumatic stress symptoms and other psychopathology amongst paramedic trainees. In order to create a risk profile for individuals who are at higher occupational risk of developing PTSD, we examined risk and resilience factors that possibly contributed to the presence and severity of posttraumatic symptomatology. METHODS: Paramedic trainees (n = 131) were recruited from a local university. A logistic regression analysis was conducted using the explanatory variables age, gender, population group, trauma exposure, depression, alcohol abuse, alcohol dependence, resilience and social support. RESULTS: 94% of paramedic trainees had directly experienced trauma, with 16% meeting PTSD criteria. A high rate of depression (28%), alcohol abuse (23%) and chronic perceived stress (7%) and low levels of social support was found. The number of previous trauma exposures, depression, resilience and social support significantly predicted PTSD status and depression had a mediating effect. CONCLUSION: There is a need for efficient, ongoing screening of depressive and PTSD symptomatology in trauma exposed high risk groups so that early psychological supportive interventions can be offered. PMID- 24755359 TI - Extra-gastrointestinal stromal tumor of the pancreas: case report and review of the literature. AB - Primary extra-gastrointestinal stromal tumor (EGISTs) arising in the pancreas is extremely rare: only 20 cases have previously been reported in the English literature from 2000 to 2013. We reported a case of EGIST of the pancreas in a 69 year-old woman who presented with abdominal pain and with a solid, heterogeneously enhancing neoplasm in the uncinate process of the pancreas, revealed preoperatively by an abdominal computed tomography scan. A diagnosis of neuroendocrine tumor was suggested. Positron emission tomography with 68Ga DOTATOC did not show pathological accumulation of the tracer in the pancreas. The patient underwent enucleation, under ultrasonic guidance, of the pancreatic tumor that emerged to the surface of the pancreas. Histopathology and immunohistochemical examination confirmed the final diagnosis of EGIST of the pancreas (CD117+), with one mitosis per 50 high-power fields. Although rarely, GIST can involve the pancreas as a primary site, and this tumor should be considered in the differential diagnosis of pancreatic neoplasms. PMID- 24755360 TI - Effective microorganisms enhance the scavenging capacity of the ascorbate glutathione cycle in common bean (Phaseolus vulgaris L.) plants grown in salty soils. AB - No information is available regarding effective microorganisms (EM) influence on the enzymatic and non-enzymatic antioxidant defence system involved in the ascorbate-glutathione cycle under saline conditions. Therefore, as a first approach, this article focuses on the contribution of EM to the scavenging capacity of the ascorbate-glutathione cycle in salt-stressed plants. It investigates some mechanisms underlying alleviation of salt toxicity by EM application. Phaseolus vulgaris cv. Nebraska plants were grown under non-saline or saline conditions (2.5 and 5.0 dSm(-1)) with and without EM application. Lipid peroxidation and H2O2 content were significantly increased in response to salinity, while they decreased with EM application in both stressed and non stressed plants. Activities of ascorbate peroxidase (APX; EC 1.11.1.11) and glutathione reductase (GR; EC 1.6.4.2) increased under saline conditions; these increases were more significant in salt-stressed plants treated by EM. Activities of monodehydroascorbate reductase (MDHAR; EC 1.6.5.4) and dehydroascorbate reductase (DHAR; EC 1.8.5.1) decreased in response to salinity; however, they were significantly increased in stressed plants treated with EM. Ascorbate and glutathione contents were increased with the increasing salt concentration; moreover they further increased in stressed plants treated with EM. Ratios of AsA/DHA and GSH/GSSG decreased under saline conditions, whereas they were significantly increased with EM treatment in the presence or in the absence of soil salinization. The EM treatment detoxified the stress generated by salinity and significantly improved plant growth and productivity. Enhancing the H2O2 scavenging capacity of the ascorbate-glutathione cycle in EM-treated plants may be an efficient mechanism to attenuate the activation of plant defences. PMID- 24755361 TI - Molecular characterisation of human hepatitis E virus from Italy: comparative analysis of five reverse transcription-PCR assays. AB - BACKGROUND: Hepatitis E (HEV) is an important public-health concern as a major cause of enterically transmitted hepatitis worldwide. In industrialised countries it is considered rare, and largely confined to travellers returning from endemic areas. However, autochthonous (locally acquired) HEV infection is also emerging in these regions. The infection is caused by different genotypes, depending on whether it is travel-related or autochthonous. Conventional RT-PCR followed by sequencing of PCR products can identify HEV genotype and, depending on the region, the subtype, thus helping in defining the origin of infection and tracing the source of contamination. METHODS: We re-analysed a collection of serum samples previously confirmed as hepatitis E positive by anti-HEV IgM and IgG assays as well as by Real-Time PCR, with the aim to compare the performances of five different broad range RT-PCR assays that could be provided for molecular characterisation of HEV. This approach is certainly valuable to investigate the molecular epidemiology of acute hepatitis E in countries where co-circulation of different genotypes occurs, like Italy. RESULTS: Samples were analyzed by five assays targeting the ORF1, ORF2, and ORF2/3 regions. The sensitivity of these assays varied significantly, depending on the target region. Only 46% of samples tested positive by nested PCR; moreover, no single method was able to detect all positive samples. Most sequences originated from patients who had travelled to endemic areas (genotype 1), while the minority originated from Italian patients with no travel history (genotype 3). CONCLUSION: Broad range methods for molecular characterization of HEV still need to be improved to detect all circulating strains. PMID- 24755362 TI - Concepts of mental capacity for patients requesting assisted suicide: a qualitative analysis of expert evidence presented to the Commission on Assisted Dying. AB - BACKGROUND: In May 2013 a new Assisted Dying Bill was tabled in the House of Lords and is currently scheduled for a second reading in May 2014. The Bill was informed by the report of the Commission on Assisted Dying which itself was informed by evidence presented by invited experts.This study aims to explore how the experts presenting evidence to the Commission on Assisted Dying conceptualised mental capacity for patients requesting assisted suicide and examine these concepts particularly in relation to the principles of the Mental Capacity Act 2005. METHODS: This study was a secondary qualitative analysis of 36 transcripts of oral evidence and 12 pieces of written evidence submitted by invited experts to the Commission on Assisted Dying using a framework approach. RESULTS: There was agreement on the importance of mental capacity as a central safeguard in proposed assisted dying legislation. Concepts of mental capacity, however, were inconsistent. There was a tendency towards a conceptual and clinical shift toward a presumption of incapacity. This appeared to be based on the belief that assisted suicide should only be open to those with a high degree of mental capacity to make the decision.The 'boundaries' around the definition of mental capacity appeared to be on a continuum between a circumscribed legal 'cognitive' definition of capacity (in which most applicants would be found to have capacity unless significantly cognitively impaired) and a more inclusive definition which would take into account wider concepts such as autonomy, rationality, voluntariness and decision specific factors such as motivation for decision making. CONCLUSION: Ideas presented to the Commission on Assisted Dying about mental capacity as it relates to assisted suicide were inconsistent and in a number of cases at variance with the principles of the Mental Capacity Act 2005. Further work needs to be done to establish a consensus as to what constitutes capacity for this decision and whether current legal frameworks are able to support clinicians in determining capacity for this group. PMID- 24755363 TI - miRNAs and aging: a genetic perspective. AB - A growing body of evidence shows that microRNA expression changes with age in animals ranging from nematode to human. Genetic studies of microRNA function in vivo provide the means to move beyond correlation and to explore cause-effect relationships. Genetic studies in Caenorhabditis elegans and Drosophila have identified cellular pathways involved in organismal aging. Here, we review the evidence that microRNAs act in vivo as regulators of aging pathways, with emphasis on Drosophila. PMID- 24755364 TI - Collision-induced light scattering in a thin xenon layer between graphite slabs - MD study. AB - The collision-induced light scattering many-body correlation functions and their spectra in thin xenon layer located between two parallel graphite slabs have been investigated by molecular dynamics computer simulations. The results have been obtained at three different distances (densities) between graphite slabs. Our simulations show the increased intensity of the interaction-induced light scattering spectra at low frequencies for xenon atoms in confined space, in comparison to the bulk xenon sample. Moreover, we show substantial dependence of the interaction-induced light scattering correlation functions of xenon on the distances between graphite slabs. The dynamics of xenon atoms in a confined space was also investigated by calculating the mean square displacement functions and related diffusion coefficients. The structural property of confined xenon layer was studied by calculating the density profile, perpendicular to the graphite slabs. Building of a fluid phase of xenon in the innermost part of the slot was observed. The nonlinear dependence of xenon diffusion coefficient on the separation distance between graphite slabs has been found. PMID- 24755365 TI - New challenges and opportunities in nonclinical safety testing of biologics. AB - New challenges and opportunities in nonclinical safety testing of biologics were discussed at the 3rd European BioSafe Annual General Membership meeting in November 2013 in Berlin: (i)Approaches to refine use of non-human primates in non clinical safety testing of biologics and current experience on the use of minipigs as alternative non-rodent species.(ii)Tissue distribution studies as a useful tool to support pharmacokinetic/pharmacodynamic (PKPD) assessment of biologics, in that they provide valuable mechanistic insights at drug levels at the site of action.(iii)Mechanisms of nonspecific toxicity of antibody drug conjugates (ADC) and ways to increase the safety margins.(iv)Although biologics toxicity typically manifests as exaggerated pharmacology there are some reported case studies on unexpected toxicity.(v)Specifics of non-clinical development approaches of noncanonical monoclonal antibodies (mAbs), like bispecifics and nanobodies. PMID- 24755366 TI - Variation in classification of live birth with newborn period death versus fetal death at the local level may impact reported infant mortality rate. AB - BACKGROUND: To better understand factors that may impact infant mortality rates (IMR), we evaluated the consistency across birth hospitals in the classification of a birth event as either a fetal death or an early neonatal (infant) death using natality data from North Carolina for the years 1995-2000. METHODS: A database consisting of fetal deaths and infant deaths occurring within the first 24 hours after birth was constructed. Bivariate, followed by multivariable regression, analyses were used to control for relevant maternal and infant factors. Based upon hospital variances, adjustments were made to evaluate the impact of the classification on statewide infant mortality rate. RESULTS: After controlling for multiple maternal and infant factors, birth hospital remained a factor related to the classification of early neonatal versus fetal death. Reporting of early neonatal deaths versus fetal deaths consistent with the lowest or highest hospital strata would have resulted in an adjusted IMR varying from 7.5 to 10.64 compared with the actual rate of 8.95. CONCLUSIONS: Valid comparisons of IMR among geographic regions within and between countries require consistent classification of perinatal deaths. This study demonstrates that local variation in categorization of death events as fetal death versus neonatal death within the first 24 hours after delivery may impact a state-level IMR in a meaningful magnitude. The potential impact of this issue on IMRs should be examined in other state and national populations. PMID- 24755367 TI - Editorial overview: Genome architecture and expression: the nucleus, top and bottom. PMID- 24755368 TI - Identifying factors associated with the uptake of prevention of mother to child HIV transmission programme in Tigray region, Ethiopia: a multilevel modeling approach. AB - BACKGROUND: Prevention of mother to child HIV transmission (PMTCT) remains a challenge in low and middle-income countries. Determinants of utilization occur- and often interact--at both individual and community levels, but most studies do not address how determinants interact across levels. Multilevel models allow for the importance of both groups and individuals in understanding health outcomes and provide one way to link the traditionally distinct ecological- and individual level studies. This study examined individual and community level determinants of mother and child receiving PMTCT services in Tigray region, Ethiopia. METHODS: A multistage probability sampling method was used for this 2011 cross-sectional study of 220 HIV positive post-partum women attending child immunization services at 50 health facilities in 46 districts. In view of the nested nature of the data, we used multilevel modeling methods and assessed macro level random effects. RESULTS: Seventy nine percent of mothers and 55.7% of their children had received PMTCT services. Multivariate multilevel modeling found that mothers who delivered at a health facility were 18 times (AOR = 18.21; 95% CI 4.37,75.91) and children born at a health facility were 5 times (AOR = 4.77; 95% CI 1.21,18.83) more likely to receive PMTCT services, compared to mothers delivering at home. For every addition of one nurse per 1500 people, the likelihood of getting PMTCT services for a mother increases by 7.22 fold (AOR = 7.22; 95% CI 1.02,51.26), when other individual and community level factors were controlled simultaneously. In addition, district-level variation was low for mothers receiving PMTCT services (0.6% between districts) but higher for children (27.2% variation between districts). CONCLUSIONS: This study, using a multilevel modeling approach, was able to identify factors operating at both individual and community levels that affect mothers and children getting PMTCT services. This may allow differentiating and accentuating approaches for different settings in Ethiopia. Increasing health facility delivery and HCT coverage could increase mother-child pairs who are getting PMTCT. Reducing the distance to health facility and increasing the number of nurses and laboratory technicians are also important variables to be considered by the government. PMID- 24755369 TI - Identifying unusual performance in Australian and New Zealand intensive care units from 2000 to 2010. AB - BACKGROUND: The Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) collects voluntary data on patient admissions to Australian and New Zealand intensive care units (ICUs). This paper presents an in depth statistical analysis of risk-adjusted mortality of ICU admissions from 2000 to 2010 for the purpose of identifying ICUs with unusual performance. METHODS: A cohort of 523,462 patients from 144 ICUs was analysed. For each ICU, the natural logarithm of the standardised mortality ratio (log-SMR) was estimated from a risk adjusted, three-level hierarchical model. This is the first time a three-level model has been fitted to such a large ICU database anywhere. The analysis was conducted in three stages which included the estimation of a null distribution to describe usual ICU performance. Log-SMRs with appropriate estimates of standard errors are presented in a funnel plot using 5% false discovery rate thresholds. False coverage-statement rate confidence intervals are also presented. The observed numbers of deaths for ICUs identified as unusual are compared to the predicted true worst numbers of deaths under the model for usual ICU performance. RESULTS: Seven ICUs were identified as performing unusually over the period 2000 to 2010, in particular, demonstrating high risk-adjusted mortality compared to the majority of ICUs. Four of the seven were ICUs in private hospitals. Our three stage approach to the analysis detected outlying ICUs which were not identified in a conventional (single) risk-adjusted model for mortality using SMRs to compare ICUs. We also observed a significant linear decline in mortality over the decade. Distinct yearly and weekly respiratory seasonal effects were observed across regions of Australia and New Zealand for the first time. CONCLUSIONS: The statistical approach proposed in this paper is intended to be used for the review of observed ICU and hospital mortality. Two important messages from our study are firstly, that comprehensive risk-adjustment is essential in modelling patient mortality for comparing performance, and secondly, that the appropriate statistical analysis is complicated. PMID- 24755370 TI - Testicular sex cord-stromal tumor in a boy with 2q37 deletion syndrome. AB - BACKGROUND: 2q37 deletion syndrome is a rare congenital disorder that is characterized by facial dysmorphism, obesity, vascular and skeletal malformations, and a variable degree of intellectual disability. To date, common but variable phenotypes, such as skeletal or digit malformations and obesity, have been associated with the deleted size or affected genes at chromosome 2q37. However, it remains elusive whether 2q37 deletion per se or other genetic factors, such as copy number variations (CNVs), may confer the risk for the tumorigenic condition. CASE PRESENTATION: We report a two-year-old Japanese boy with 2q37 deletion syndrome who exhibited the typical facial appearance, coarctation of the aorta, and a global developmental delay, while lacking the symptoms of brachydactyly and obesity. He developed a sex cord-stromal tumor of the right testis at three months of age. The array comparative genome hybridization analysis identified an 8.2-Mb deletion at 2q37.1 (chr2:234,275,216 242,674,807) and it further revealed two additional CNVs: duplications at 1p36.33 p36.32 (chr1:834,101-2,567,832) and 20p12.3 (chr20:5,425,762-5,593,096). The quantitative PCRs confirmed the heterozygous deletion of HDAC4 at 2q37.3 and duplications of DVL1 at 1q36 and GPCPD1 at 20p12.3. CONCLUSION: This study describes the unique phenotypes in a boy with 2q37 deletion and additional CNVs at 1p36.33-p36.32 and 20p12.3. The data provide evidence that the phenotypic variations and unusual complications of 2q37 deletion syndrome are not simply explained by the deleted size or genes located at 2q37, but that external CNVs may account at least in part for their variant phenotypes. Accumulating the CNV data for chromosomal disorders will be beneficial for understanding the genetic effects of concurrent CNVs on the syndromic phenotypes and rare complications. PMID- 24755371 TI - Metastasis of distal esophageal carcinoma to the thyroid with presentation simulating primary thyroid carcinoma: a case report and review of the literature. AB - Metastasis to the thyroid is extremely rare. There is a lack of awareness of and adequate preparation for this situation, especially in an individual without a past history of malignancy. We describe a rare case of a 61-year-old man in whom a primary distal esophageal carcinoma gave rise to a metastatic palpable mass in the thyroid gland. Palliative bilateral near-total thyroidectomy was performed with pathology showing squamous cell carcinoma and tracheostomy was carried out simultaneously due to airway compression with related symptoms. A review of the literature only reveals 4 similar cases. Secondary neoplasm of the thyroid mimicking a primary malignant lesion is seldom encountered, however, in order to make appropriate treatment, the most critical problem is to distinguish the difference between the above two and the final diagnosis can only be confirmed on pathologic examination. Although the prognosis of thyroid metastasis is commonly felt to be poor, improvement of living quality and prolongation of survival may be obtained in such patients through correct diagnosis and treatment. PMID- 24755372 TI - Rapid detection of porcine kobuvirus in feces by reverse transcription loop mediated isothermal amplification. AB - BACKGROUND: PKV is a new emerging pathogen detected in diarrhea pigs. At present, no more detection methods were reported except RT-PCR method. this study was to develop a fast diagnostic method based on the LAMP reaction for rapid detection of PKV nucleic acid in fecal samples. FINDINGS: Two pairs of primers were designed to amplify the conservative 3D gene of PKV genome. The PKV RT-LAMP method possessed well specificity and had 100 times higher sensitivity than common reverse transcription PCR (RT-PCR), which could detect up to 10 RNA copies of the target gene. CONCLUSIONS: The results showed that the optimal reaction condition for RT-LAMP was achieved at 64 degrees C for 50 min. Furthermore, the RT-LAMP procedure does not demand special equipment and is time-saving. PMID- 24755374 TI - Inhibitors of the peptidoglycan biosynthesis enzymes MurA-F. AB - The widespread emergence of resistant bacterial strains is becoming a serious threat to public health. This thus signifies the need for the development of new antibacterial agents with novel mechanisms of action. Continuous efforts in the design of novel antibacterials remain one of the biggest challenges in drug development. In this respect, the Mur enzymes, MurA-F, that are involved in the formation of UDP-N-acetylmuramyl-pentapeptide can be genuinely considered as promising antibacterial targets. This review provides an in-depth insight into the recent developments in the field of inhibitors of the MurA-F enzymes. Special attention is also given to compounds that act as multiple inhibitors of two, three or more of the Mur enzymes. Moreover, the reasons for the lack of preclinically successful inhibitors and the challenges to overcome these hurdles in the next years are also debated. PMID- 24755373 TI - Prevalence and course of somatic symptoms in patients with stress-related exhaustion: does sex or age matter. AB - BACKGROUND: Both mental and somatic symptoms are commonly reported in patients with stress-related problems. We have explored the prevalence of somatic symptoms in patients seeking medical care for stress-related mental health problems and followed the course of illness alongside with that the patients receive multimodal treatment. METHOD: This study comprises data from 228 patients (69% women, mean age 43 years) who fulfilled the criteria for Exhaustion Disorder (ED). Somatic symptoms were assessed at baseline and after 3, 6, 12 and 18 months using the one-page questionnaire Primary Care Evaluation of Mental Disorders. Prevalence of different symptoms was compared between men and women and patients, over and below 40 years of age, and possible predictors of recovery were explored. RESULTS: Tiredness and low energy are the core symptom reported by the patients. Almost all (98%) reported at least one somatic symptom and 45% reported six symptoms or more, which was similar for men and women. Nausea, gas or indigestion are the most common symptoms (67%) followed by headaches (65%) and dizziness (57%). The number of symptoms reported was significantly related to the severity of mental health problems. The only difference between the sexes was that "chest pain" and "pain or problems during sexual intercourse" were more common among males. Patients over forty more often reported "pain in arms, legs or joints, knees, hips" and this was also the only symptom that did not significantly decline during treatment. Neither sex, age, symptom duration before seeking medical care, education or any other predictor tested was shown to predict recovery in patients reporting six symptoms or more. CONCLUSION: A heavy burden of somatic symptoms was generally seen in most patients with stress related exhaustion. Somatic symptoms are equally common in males and females and in younger and older patients. The somatic symptoms seem to be mostly stress related since all symptoms, except musculoskeletal pain, reduce with individualised treatment designed for stress-related mental problems. This study brings to attention the complicated burden of both somatic and mental symptoms in patients with stress-related exhaustion, raising several clinical implications of interest to discuss. PMID- 24755375 TI - Bacterial cell division proteins as antibiotic targets. AB - Proteins involved in bacterial cell division often do not have a counterpart in eukaryotic cells and they are essential for the survival of the bacteria. The genetic accessibility of many bacterial species in combination with the Green Fluorescence Protein revolution to study localization of proteins and the availability of crystal structures has increased our knowledge on bacterial cell division considerably in this century. Consequently, bacterial cell division proteins are more and more recognized as potential new antibiotic targets. An international effort to find small molecules that inhibit the cell division initiating protein FtsZ has yielded many compounds of which some are promising as leads for preclinical use. The essential transglycosylase activity of peptidoglycan synthases has recently become accessible to inhibitor screening. Enzymatic assays for and structural information on essential integral membrane proteins such as MraY and FtsW involved in lipid II (the peptidoglycan building block precursor) biosynthesis have put these proteins on the list of potential new targets. This review summarises and discusses the results and approaches to the development of lead compounds that inhibit bacterial cell division. PMID- 24755376 TI - Program theory-driven evaluation science in a youth development context. AB - Program theory-driven evaluation science (PTDES) provides a useful framework for uncovering the mechanisms responsible for positive change resulting from participation in youth development (YD) programs. Yet it is difficult to find examples of PTDES that capture the complexity of such experiences. This article offers a much-needed example of PTDES applied to Project K, a youth development program with adventure, service-learning and mentoring components. Findings from eight program staff focus groups, 351 youth participants' comments, four key program documents, and results from six previous Project K research projects were integrated to produce a theory of change for the program. A direct logic analysis was then conducted to assess the plausibility of the proposed theory against relevant research literature. This demonstrated that Project K incorporates many of the best practice principles discussed in the literature that covers the three components of the program. The contributions of this theory-building process to organizational learning and development are discussed. PMID- 24755377 TI - Evaluating complex community-based health promotion: addressing the challenges. AB - Community-based health promotion is poorly theorised and lacks an agreed evidence base. This paper examines characteristics of community-based health promotion and the challenges they present to evaluation. A review of health promotion evaluation leads to an exploration of more recent approaches, drawing on ideas from complexity theory and developmental evaluation. A reflexive analysis of three program evaluations previously undertaken as an evaluation consultant is used to develop a conceptual model to help in the design and conduct of health promotion evaluation. The model is further explored by applying it retrospectively to one evaluation. Findings suggest that the context-contingent nature of health promotion programs; turbulence in the community context and players; multiple stakeholders, goals and strategies; and uncertainty of outcomes all contribute to the complexity of interventions. Bringing together insights from developmental evaluation and complexity theory can help to address some evaluation challenges. The proposed model emphasises recognising and responding to changing contexts and emerging outcomes, providing rapid feedback and facilitating reflexive practice. This will enable the evaluator to gain a better understanding of the influence of context and other implementation factors in a complex setting. Use of the model should contribute to building cumulative evidence and knowledge in order to identify the principles of health promotion effectiveness that may be transferable to new situations. PMID- 24755378 TI - Innovation: "It's about the people you have!". PMID- 24755379 TI - South America: a land of innovators and innovation. PMID- 24755380 TI - Intricacies in the analysis and interpretation of optical coherence tomography findings. PMID- 24755381 TI - The new Nurses and Technicians committee of the EAPCI: towards the common objective of the best care for our patients. PMID- 24755382 TI - First-in-man randomised comparison of a novel sirolimus-eluting stent with abluminal biodegradable polymer and thin-strut cobalt-chromium alloy: INSPIRON-I trial. AB - AIMS: The INSPIRON-I trial is a first-in-man evaluation of the safety and efficacy of the Inspiron drug-eluting stent, a sirolimus-eluting stent with abluminal biodegradable polymer coating and thin cobalt-chromium alloy. METHODS AND RESULTS: This is a randomised, multicentre comparison between Inspiron and a stent with the same metallic structure but without polymer coating or drug elution (Cronus). The primary objective was to evaluate the in-segment late loss (LLL) at six months. Secondary endpoints included percent in-stent obstruction as measured by intravascular ultrasound (IVUS) at six months and major adverse cardiac events (MACE). Fifty-eight patients were enrolled (60 lesions), 39 for Inspiron and 19 for Cronus. Baseline clinical and angiographic characteristics of both groups were similar. At six months, the in-segment LLL was reduced in the Inspiron group compared to the control group (0.19+/-0.16 mm vs. 0.58+/-0.4 mm, respectively; p<0.001), as well as the percent neointimal obstruction (7.8+/-7.1% vs. 26.5+/-11.4%; p<0.001). At two-year follow-up, incidence of MACE was similar between groups (7.9 vs. 21.1%, respectively; p=0.20), with lower target lesion revascularisation for Inspiron (0 vs. 21.1%, respectively; p=0.01) and no stent thrombosis. CONCLUSIONS: Sirolimus eluted from an abluminal biodegradable polymer on a cobalt-chromium alloy proved effective in reducing restenosis at six months. PMID- 24755384 TI - Stent deformation, physical stress, and drug elution obtained with provisional stenting, conventional culotte and Tryton-based culotte to treat bifurcations: a virtual simulation study. AB - AIMS: This study sought to investigate the possible influence of different bifurcation stenting techniques on stent deformation, physical stress, and drug elution using a virtual tool that includes structural, fluid dynamics and drug eluting numerical models. METHODS AND RESULTS: A virtual bench test based on explicit dynamics modelling was used to simulate procedures on bifurcated coronary vessels performed according to three different stenting techniques: provisional side branch stenting, culotte, and Tryton-based culotte. Geometrical configurations obtained after virtual stenting simulations were used to perform fluid dynamics and drug elution analyses. The results showed that substantially different patterns of mechanical deformation, shear stress and theoretical drug elution were obtained using the different techniques. Compared with conventional culotte, the dedicated Tryton seems to facilitate the intervention in terms of improved access to the main branch and to lower its biomechanical influence on the coronary bifurcation in terms of mechanical and haemodynamic parameters. However, since the Tryton stent is a bare metal stent, the drug elution obtained is lower. CONCLUSIONS: Numerical models might successfully complement the information on stenting procedures obtained with traditional approaches such as in vitro bench testing or clinical trials. Devices dedicated to bifurcations may facilitate procedure completion and may result in specific patterns of mechanical stress, regional blood flow and drug elution. PMID- 24755383 TI - Increased hyperaemic coronary microvascular resistance adds to the presence of myocardial ischaemia. AB - AIMS: It has been argued that hyperaemic microvascular resistance (HMR), defined as the ratio of mean distal coronary pressure to flow velocity, is overestimated in the presence of a coronary stenosis compared to actual microvascular resistance (MR), due to neglecting collateral flow. We aimed to test the hypothesis that HMR allows accurate identification of microvascular functional abnormalities by evaluating the association between high or low HMR and the presence of myocardial ischaemia on non-invasive stress testing. METHODS AND RESULTS: Myocardial perfusion scintigraphy was performed in 228 patients, with 299 lesions to identify reversible myocardial ischaemia. Intracoronary distal pressure and flow velocity were assessed during adenosine-induced hyperaemia (20 40 ug, intracoronary) to determine hyperaemic stenosis resistance (HSR) and HMR. HMR >1.9 mmHg/cm/s was defined as high. The diagnostic odds ratio (OR) for myocardial ischaemia for lesions associated with high compared to low HMR was 2.6 (95% confidence interval [CI]: 1.5-4.4; p<0.001) overall, 3.3 (95% CI: 1.2-9.0; p=0.02) for lesions with HSR >0.8 mmHg/cm/s, and 1.3 (95% CI: 0.6-2.9; p=0.52) for lesions with HSR <=0.8 mmHg/cm/s. CONCLUSIONS: The increased risk of myocardial ischaemia in the presence of high HMR, uncorrected for collateral flow, demonstrates that HMR is reflective of an increase in actual MR, identifying pertinent pathophysiological alterations in the microvasculature. PMID- 24755385 TI - Longitudinal compression behaviour of coronary stents: a bench-top comparative study. AB - AIMS: The aim of this study was to characterise the coronary stent longitudinal resistance of new coronary stents under worst case clinical crossing simulated configurations. METHODS AND RESULTS: Six coronary balloon-expandable stents were evaluated using two different tests. The first was a direct parallel plates longitudinal crush resistance test: it was conducted on stents deployed to 3 mm diameter, and three samples of each model were used. The second was performed by tracking over the wire and deploying the stents in two types of coronary model: good and malapposition models. Two samples of each model were used for this test. After deployment, a PTCA balloon was advanced over the wire. For each stent, the force required for balloon tracking and the stent shortening were recorded. In the first crush test, three out of six stent models demonstrated higher longitudinal crush rates compared to the Resolute Integrity (Medtronic, Minneapolis, MN, USA): PROMUS ElementTM (Boston Scientific, Natick, MA, USA) p<0.0001, Coroflex(r) Blue (B. Braun, Melsungen, Germany) p<0.0001, and Orsiro (Biotronik, Berlin, Germany) p=0.038. In the simulation test, there were no statistical differences when comparing all good and malapposition groups. CONCLUSIONS: Lower resistance to mechanical longitudinal compression of some stents did not correlate to significantly higher crush rates in simulated clinical conditions. Nevertheless, it would be useful for cardiologists to be aware of the actual mechanical characteristics of new stents to take them into account and thus minimise longitudinal compression during difficult stent implantations. PMID- 24755386 TI - Cardiac remote ischaemic preconditioning reduces periprocedural myocardial infarction for patients undergoing percutaneous coronary interventions: a meta analysis of randomised clinical trials. AB - AIMS: To establish the cardioprotective effect of remote ischaemic preconditioning (RIPC) in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Pubmed (MEDLINE), Cochrane and Embase were systematically searched for randomised controlled trials of RIPC in patients undergoing PCI. Periprocedural myocardial infarction (PMI) was the primary endpoint (defined as troponin elevation >3 times upper reference limit) and C reactive protein (CRP) was a secondary endpoint. Five studies with 731 patients were included. The median age of the patients was 62 (59-68) years old, 25% were female (23-33), 29% (25-33) had diabetes mellitus, and 26.5% (19-31) presented with multivessel disease. RIPC significantly reduced the incidence of PMI (odds ratio: 0.58 [0.36, 0.93]; I2 43%), with a greater benefit when performed using the lower limb (0.21 [0.07-0.66]) compared to the upper limb (0.67 [0.46-0.99]). This reduction was enhanced for patients with multivessel disease (beta -0.05 [ 0.09;-0.01], p=0.01) and with type C lesion (beta -0.014 [-0.04;-0.010], p=0.01) and did not vary according to age, female gender, diabetes mellitus, use of beta blockers and of angiotensin converting enzyme inhibitors. Absolute risk difference was -0.10 [-0.19, -0.02], with a number needed to treat of 10 [6-50] patients to avoid one event. CRP -0.69 [-1.69, 0.31] was not significantly reduced by RIPC. CONCLUSIONS: RIPC reduced the incidence of PMI following PCI, especially when performed in the lower limb and for patients with multivessel disease and complex lesions. PMID- 24755387 TI - Tools and techniques--statistics: how many variables are allowed in the logistic and Cox regression models? PMID- 24755388 TI - How should I treat a patient with a stenosed bicuspid aortic valve and an unexpected finding during TAVI? PMID- 24755389 TI - How should I treat critical stenosis of a saphenous venous graft to the posterior descending artery on the bifurcation site? PMID- 24755390 TI - Efficacy of 360-degree three-dimensional rotational pulmonary angiography to guide percutaneous transluminal pulmonary angioplasty. PMID- 24755391 TI - Coronary wedge pressure and collateral flow contribution: not a dichotomy! PMID- 24755393 TI - Central role of Nix in the autophagic response to ochratoxin A. AB - Nephrotoxicity is the most prominent toxicological effects of ochratoxin A (OTA). We have previously shown that autophagy might be involved in OTA-induced early renal cytotoxicity, but the mechanisms of action are unknown. Since OTA is known to induce mitochondrial damage and Nix is a selective autophagy receptor for mitochondrial clearance, the objective of this study was to investigate whether Nix mediates autophagic response to OTA-induced renal cytotoxicity. Our results showed that OTA induced autophagic and mitophagic activitits. Nix shRNA HEK 293 cells were more sensitive than scrambled shRNA cells to OTA-induced cell death, and differentially affect the mRNA expression of SDHA, AIFM1, and Bad and protein expression of AIF, VDAC, SDHA and LONP1 after OTA treatment. In particular, up regulation of the pro-apoptotic Bad and AIF after OTA treatment was prominent only in Nix shRNA cells, which might explain the higher ratio of cell death. These results might indicate that Nix plays a critical role in the cellular protection against OTA toxicity through autophagy and mitochondria. PMID- 24755394 TI - Environmental neurotoxins beta-N-methylamino-l-alanine (BMAA) and mercury in shark cartilage dietary supplements. AB - Shark cartilage products are marketed as dietary supplements with claimed health benefits for animal and human use. Shark fin and cartilage products sold as extracts, dry powders and in capsules are marketed based on traditional Chinese medicine claims that it nourishes the blood, enhances appetite, and energizes multiple internal organs. Shark cartilage contains a mixture of chondroitin and glucosamine, a popular nutritional supplement ingested to improve cartilage function. Sharks are long-lived apex predators, that bioaccumulate environmental marine toxins and methylmercury from dietary exposures. We recently reported detection of the cyanobacterial toxin beta-N-methylamino-l-alanine (BMAA) in the fins of seven different species of sharks from South Florida coastal waters. Since BMAA has been linked to degenerative brain diseases, the consumption of shark products may pose a human risk for BMAA exposures. In this report, we tested sixteen commercial shark cartilage supplements for BMAA by high performance liquid chromatography (HPLC-FD) with fluorescence detection and ultra performance liquid chromatography/mass spectrometry/mass spectrometry (UPLC MS/MS). Total mercury (Hg) levels were measured in the same shark cartilage products by cold vapor atomic fluorescence spectrometry (CVAFS). We report here that BMAA was detected in fifteen out of sixteen products with concentrations ranging from 86 to 265MUg/g (dry weight). All of the shark fin products contained low concentrations of Hg. While Hg contamination is a known risk, the results of the present study demonstrate that shark cartilage products also may contain the neurotoxin BMAA. Although the neurotoxic potential of dietary exposure to BMAA is currently unknown, the results demonstrate that shark cartilage products may contain two environmental neurotoxins that have synergistic toxicities. PMID- 24755392 TI - Intracluster correlation coefficients for the Brazilian Multicenter Study on Preterm Birth (EMIP): methodological and practical implications. AB - BACKGROUND: Cluster-based studies in health research are increasing. An important characteristic of such studies is the presence of intracluster correlation, typically quantified by the intracluster correlation coefficient (ICC), that indicate the proportion of data variability that is explained by the way of clustering. The purpose of this manuscript was to evaluate ICC of variables studied in the Brazilian Multicenter Study on Preterm Birth. METHODS: This was a multicenter cross-sectional study on preterm births involving 20 referral hospitals in different regions of Brazil plus a nested case-control study to assess associated factors with spontaneous preterm births. Estimated prevalence rates or means, ICC with 95% confidence intervals, design effects and mean cluster sizes were presented for more than 250 maternal and newborn variables. RESULTS: Overall, 5296 cases were included in the study (4,150 preterm births and 1,146 term births). ICC ranged from <0.001 to 0.965, with a median of 0.028. For descriptive characteristics (socio-demographic, obstetric history and perinatal outcomes) the median ICC was 0.014, for newborn outcomes the median ICC was 0.041 and for process variables (clinical management and delivery), it was 0.102. ICC was <0.1 in 78.4% of the variables and <0.3 for approximately 95% of them. Most of ICC >0.3 was found in some clinical management aspects well defined in literature such as use of corticosteroids, indicating there was homogeneity in clusters for these variables. CONCLUSIONS: Clusters selected for Brazilian Multicenter Study on Preterm Birth had mainly heterogeneous findings and these results can help researchers estimate the required sample size for future studies on maternal and perinatal health. PMID- 24755395 TI - Effective anaerobic biodegradation of municipal solid waste fresh leachate using a novel pilot-scale reactor: comparison under different seeding granular sludge. AB - A novel integrated internal and external circulation (IIEC) reactor was developed for anaerobic biodegradation of municipal solid waste (MSW) fresh leachate with chemical oxygen demand (COD) between 40,000 and 60,000mg/l. The pilot-scale IIEC reactor was inoculated with two kinds of granular sludge from paper mill (SPM) and from citric acid factory (SCF), respectively. The bio-treating capacity in contaminant removal and biogas production performed much superior to others' results, principally attributed to appropriate configuration modification. Compared to SCF, much higher organic loading rate (40.5 vs 23.0kgCOD/m(3)d) and COD removal efficiency (>80% vs 60-75%) were achieved for the reactor with SPM. For methane production, 11.77 or ~6m(3)STP/m(3)d of rate and 66-85% of content were observed with SPM or SCF, respectively. Due to better sludge concentrations and methanogenic activity, these findings indicate the anaerobic reactor could effectively bio-treat MSW leachate for methane generation, especially inoculated with granular sludge derived from leachate-like-wastewater. PMID- 24755396 TI - Acid-catalyzed hot-water extraction of docosahexaenoic acid (DHA)-rich lipids from Aurantiochytrium sp. KRS101. AB - In this study, acid-catalyzed hot-water extraction of docosahexaenoic acid (DHA) rich lipids from Aurantiochytrium sp. was performed, and its yield-enhancing effects were investigated. The total fatty acid content of the Aurantiochytrium sp. was 482.5mg/g cell, of which 141.7mg/g cell (29.4% of total fatty acids) was DHA. The lipid-extraction yield by acid-catalyzed hot-water treatment was compared with those by organic solvents. Among the various acid-catalyzed hot water treatment conditions, the most optimal were 1.00% H2SO4 concentration, 100 degrees C, 30min, under which the lipid-extraction yield was 472.4mg/g cell, and most of the DHA was extracted (29.2% of total fatty acids). Acid-catalyzed hot water extraction treatment markedly improved the lipid-extraction yield of Aurantiochytrium sp. PMID- 24755398 TI - Momentary negative moods and being with friends precede cigarette use among Korean American emerging adults. AB - INTRODUCTION: The objective of this study was to determine contextual antecedents to smoking among Korean American emerging adult (KAEA) smokers using ecological momentary assessment. Based on extant theory and data documenting the importance of negative affect (NA) and social context, we examined the extent to which being with friends and NA independently and concomitantly were associated with the likelihood of subsequent smoking, over and beyond other known situational correlates of smoking. METHODS: Twenty-two KAEA daily smokers recorded their smoking events in real time and participated in short surveys implemented on mobile phones for 7 days. Individual, interpersonal, and situational contexts immediately preceding and during smoking events were examined in comparison to nonsmoking events using a within-subject modeling approach. RESULTS: Both NA and being with friends independently were correlated with increased likelihood of smoking. We also found an interaction showing that the effects of NA on smoking were significant only in presence of friends. CONCLUSIONS: Unlike more established smokers, these younger smokers may be strongly influenced by peer contexts as well as unpleasant affect. The interaction between social contexts and NA highlights a potential window for intervention for the population of KAEA smokers. PMID- 24755397 TI - How U.S. adults find out about electronic cigarettes: implications for public health messages. AB - INTRODUCTION: Electronic cigarettes (e-cigarettes) are battery-powered nicotine delivery systems that have become increasingly popular in the United States. We sought to understand how U.S. adults hear about e-cigarettes. METHODS: A national sample of 17,522 U.S. adults (>= 18 years old) completed an online survey in March 2013 assessing their awareness of and sources of information about e cigarettes. RESULTS: Most respondents (86%) had heard of e-cigarettes. Current and former smokers were more likely to be aware of e-cigarettes than non-smokers. Males, younger adults, non-Hispanic Whites, and those with higher education were also more likely to have heard of e-cigarettes. The most commonly reported sources of information were another person, ads on television, and seeing e cigarettes being sold, although the relative frequency of these sources differed for current, former, and never-smokers. Former and current smokers were more likely to have heard about e-cigarettes from e-cigarette users than were never smokers. Adults age 30 years or younger were more likely than adults older than 30 years to have heard about e-cigarettes online. CONCLUSIONS: Nearly all U.S. adults had heard of e-cigarettes in 2013. By focusing on the most common channels of information, public health campaigns can more efficiently communicate information about e-cigarette safety and consider necessary regulations should companies use these channels for marketing that targets youth, non-tobacco users, and other at-risk groups. PMID- 24755399 TI - Non-degree allopathic practitioners as first contact points for acute illness episodes: insights from a qualitative study in rural northern India. AB - BACKGROUND: In 2005, the Indian government launched the National Rural Health Mission (NRHM) to improve the quality of and access to rural public health care. Despite these efforts, recent evidence shows that the rural poor continue to primarily consult private non-degree allopathic practitioners (NDAPs) for acute illness episodes. To examine this phenomenon, we explore the rural poor's perception and utilization of the rural health care system and the role and accessibility of NDAPs therein. METHODS: Our study is based on qualitative data from focus group discussions conducted in three rural districts in Bihar and Uttar Pradesh, two high-focus states of the NRHM in northern India, in 2009/2010. Our study population consists of female micro-credit self-help group members and their male household heads. We apply a directed content analysis and use a theoretical framework to differentiate between physical, financial and cultural access to care. RESULTS: Our study population distinguishes between "home treatment" (informal self-care), "local treatment" (formally unqualified care) and "outside treatment" (formally qualified care). Because of their proximity, flexible payment options and familiarity with patients' belief systems, among other things, local NDAPs are physically, financially and culturally accessible. They are usually the first contact points for patients before turning to qualified practitioners, and treat minor illnesses, provide first relief, refer patients to other providers and administer formally prescribed treatments. CONCLUSION: Our findings are similar for all three study sites and reinforce recent findings from southern and eastern India. The poor's understanding and utilization of the rural health system deviates from governmental ideas. Because of their embeddedness in the community, private NDAPs are the most accessible medical providers and first contact points for acute illness episodes. Thus, they de-facto fulfill the role envisaged by the Indian government for accredited social health activists introduced as part of the NRHM. We conclude that instead of trying to replace NDAPs with public initiatives, the Indian government should regulate, qualify and integrate them as part of the existing public health care system. This way, we argue, India can improve the rural poor's access to formally qualified practitioners. PMID- 24755400 TI - Socioeconomic impact of children's burns-a pilot study. AB - OBJECTIVE: This pilot study aimed to gain empirical data on the social and economic impacts of child burns on children and parents, in the context of the outpatient setting. METHOD: A questionnaire was completed by 52 parents of paediatric patients attending the burns outpatient department at Queen Victoria Hospital (QVH), East Grinstead, for at least the third time. Children's medical notes were used to extract demographic and medical data. Quantitative data was analyzed statistically and qualitative data was analyzed manually using content analysis. RESULTS: The financial burden related to the injury posed the greatest impact on parents, and was mainly associated with making the journey to the hospital, with lower income households being most affected. Self-employed parents and those who had to attend more than 6 hospital appointments also ran into difficulties. On the whole, there was not a considerable social impact on the burn-injured child, which may reflect the minor nature of burns in this study (mean depth partial thickness, median TBSA 1.0%). CONCLUSION: Parents were shown to perceive a greater impact from their child's burn injury than their child. Certain groups of parents were identified as requiring additional support following the burn injury. PMID- 24755401 TI - Francisella tularensis subsp. tularensis group A.I, United States. AB - We used whole-genome analysis and subsequent characterization of geographically diverse strains using new genetic signatures to identify distinct subgroups within Francisella tularensis subsp. tularensis group A.I: A.I.3, A.I.8, and A.I.12. These subgroups exhibit complex phylogeographic patterns within North America. The widest distribution was observed for A.I.12, which suggests an adaptive advantage. PMID- 24755402 TI - Characterization of alpha-1,3-glucanase isozyme from Paenibacillus glycanilyticus FH11 in a new subgroup of family 87 alpha-1,3-glucanase. AB - Two alpha-1,3-glucanase isozymes, designated as alpha-1,3-glucanase 1 (Agl-FH1) and alpha-1,3-glucanase 2 (Agl-FH2), were purified from the culture medium of Paenibacillus glycanilyticus FH11. Agl-FH1 and Agl-FH2 exhibited similar characteristics such as optimal pH, pH stability, optimal temperature, thermostability, and molecular masses on SDS-PAGE. However, their hydrolysis products of alpha-1,3-glucan varied somewhat. Agl-FH1 hydrolyzed alpha-1,3-glucan into a mixture of maltotriose and maltotetraose, and maltotetraose was the major hydrolysis product of Agl-FH2. N-terminal amino acid sequence analysis and LC MS/MS analysis of trypsin digested fragments revealed several differences between the amino acid sequences of Agl-FH1 and Agl-FH2. Genes of Agl-FH1 and Agl-FH2 were subcloned into an expression plasmid, and both enzymes were successfully expressed in Escherichia coli. The recombinant Agl-FH1 and Agl-FH2 exhibited the same enzymatic properties as those of each wild-type enzyme, and both of the recombinants showed the activity on the protoplast formation of Schizophyllum commune mycelia. A great diversity was detected in the C-terminal region of family 87 alpha-1,3-glucanases. Compared with Agl-FH2 which is highly sequence related to the known alpha-1,3-glucanases, the C-terminal region of Agl-FH1 has only slight similarity to them (approximately 20% identity). Our analysis revealed that Agl-FH1 was the first member of a new subgroup of family 87 alpha 1,3-glucanases. PMID- 24755403 TI - Characterization of miRNomes in acute and chronic myeloid leukemia cell lines. AB - Myeloid leukemias are highly diverse diseases and have been shown to be associated with microRNA (miRNA) expression aberrations. The present study involved an in-depth miRNome analysis of two human acute myeloid leukemia (AML) cell lines, HL-60 and THP-1, and one human chronic myeloid leukemia (CML) cell line, K562, via massively parallel signature sequencing. mRNA expression profiles of these cell lines that were established previously in our lab facilitated an integrative analysis of miRNA and mRNA expression patterns. miRNA expression profiling followed by differential expression analysis and target prediction suggested numerous miRNA signatures in AML and CML cell lines. Some miRNAs may act as either tumor suppressors or oncomiRs in AML and CML by targeting key genes in AML and CML pathways. Expression patterns of cell type-specific miRNAs could partially reflect the characteristics of K562, HL-60 and THP-1 cell lines, such as actin filament-based processes, responsiveness to stimulus and phagocytic activity. miRNAs may also regulate myeloid differentiation, since they usually suppress differentiation regulators. Our study provides a resource to further investigate the employment of miRNAs in human leukemia subtyping, leukemogenesis and myeloid development. In addition, the distinctive miRNA signatures may be potential candidates for the clinical diagnosis, prognosis and treatment of myeloid leukemias. PMID- 24755404 TI - Community perception on biomedical research: A case study of malariometric survey in Korogwe District, Tanga Region, Tanzania. AB - BACKGROUND: Community perception in biomedical research remains critical in Africa with many participants being driven by different motives. The objective of this study was to explore the perceived motives for women or females guardians to volunteer for their children to participate in biomedical research and to explore experiences and challenges faced by Community Owned Resource Persons (CORPs) when mobilizing community members to participate in biomedical research. METHODS: This cross sectional study was conducted in Korogwe district, in north-eastern Tanzania. Qualitative methods combining random and purposive sampling techniques were used for data collection. A randomly selected sample using random table method from the existing list of households in the ward office was used to select participants for Focus Group Discussions (FGDs). A purposive sampling technique was used for In-Depth Interviews (IDIs) with CORPs. Thematic framework analysis was used to analyze the data. RESULTS: Need for better health services, availability of qualified clinicians, and better access to services provided at the research points were reported as main motives for community members to participate in biomedical research. With regard to experience and challenges faced by CORPs, the main reasons for mothers and guardians not participating in biomedical research were linked to misconception of the malariometric surveys, negative perception of the validity and sensitivity of rapid diagnostic tests, fear of knowing Human Immunodeficiency Virus Infection (HIV)/Acquired Immune Deficiency Syndrome (HIV/AIDS) sero status, and lack of trust for the medical information provided by the CORPs. Challenges reported by CORPs included lack ofawareness of malariometric surveys among participants, time consumption in mobilization of the community, difficulties in identifying individual results, and family responsibilities. CONCLUSION: This study has shown that majority of community members had positive perceptions of the about malariometric surveys services provided. The availability of free health services was the major determining factor for community members' participation in malariometric surveys. CORPs are instrumental in mobilizing community members participation during malariometric surveys, despite their experiences and the challenges they face. PMID- 24755405 TI - Long-term survival of a patient with metachronous rectal metastasis from primary cecal cancer who underwent repetitive resection and chemotherapy: a case report. AB - There are few reported cases of colorectal metastasis from cancers of other organs, particularly other segments of the colon. Here we describe the long-term survival of a 68-year-old male patient with metachronous rectal metastasis from cecal cancer who underwent repetitive resection and chemotherapy. The patient underwent ileocecal resection and hepatectomy for cecal cancer with liver metastasis (T3, N1a, M1a, Stage IVA) in 2006. The patient subsequently underwent splenectomy for splenic metastasis in 2007. In August 2008, barium enema revealed compression of the rectal wall, and abdominal computed tomography (CT) detected a mass along the rectum extending into the pelvis. Rectal metastasis from cecal cancer was suspected and Hartmann's operation with bilateral seminal vesicle dissection was performed. Histological examination of the excised tumor revealed moderately differentiated adenocarcinoma formed in the muscularis propria of the rectum and infiltrating the connective tissue between the seminal vesicle and rectum. However, no tumor was detected in the rectal mucosa or submucosa. These histological findings supported the diagnosis of rectal metastasis from cecal cancer. The patient has been monitored at our clinic for 60 months after surgical removal of the rectal metastasis. The findings from this case should alert oncologists to the potential danger of rectal metastasis from primary colon cancer and the benefits of timely complete resection in terms of improved patient outcomes. PMID- 24755406 TI - The covariation of independent and dependant variables in neurofeedback: a proposal framework to identify cognitive processes and brain activity variables. AB - This methodological article proposes a framework for analysing the relationship between cognitive processes and brain activity using variables measured by neurofeedback (NF) carried out by functional Magnetic Resonance Imagery (fMRI NF). Cognitive processes and brain activity variables can be analysed as either the dependant variable or the independent variable. Firstly, we propose two traditional approaches, defined in the article as the "neuropsychological" approach (NP) and the "psychophysiology" approach (PP), to extract dependent and independent variables in NF protocols. Secondly, we suggest that NF can be inspired by the style of inquiry used in neurophenomenology. fMRI NF allows participants to experiment with his or her own cognitive processes and their effects on brain region of interest (ROI) activations simultaneously. Thus, we suggest that fMRI NF could be improved by implementing "the elicitation interview method", which allows the investigator to gather relevant verbatim from participants' introspection on subjective experiences. PMID- 24755407 TI - Proof of principle: quality control of therapeutic cell preparations using senescence-associated DNA-methylation changes. AB - BACKGROUND: Tracking of replicative senescence is of fundamental relevance in cellular therapy. Cell preparations - such as mesenchymal stromal cells (MSCs) - undergo continuous changes during culture expansion, which is reflected by impaired proliferation and loss of differentiation potential. This process is associated with epigenetic modifications: during in vitro culture, cells acquire senescence-associated DNA methylation (SA-DNAm) changes at specific sites in the genome. We have recently described an Epigenetic-Senescence-Signature that facilitates prediction of the state of cellular aging by analysis of DNAm at six CpG sites (associated with the genes GRM7, CASR, PRAMEF2, SELP, CASP14 and KRTAP13-3), but this has not yet been proven over subsequent passages and with MSCs isolated under good manufacturing practice (GMP) conditions. FINDINGS: MSCs were isolated from human bone marrow and GMP-conform expanded for up to 11 passages. Cumulative population doublings (cPDs) and long-term growth curves were calculated based on cell numbers at each passage. Furthermore, 32 cryopreserved aliquots of these cell preparations were retrospectively analyzed using our Epigenetic-Senescence-Signature: DNAm-level was analyzed at six specific CpGs, and the results were used to estimate cPDs, time of culture expansion, and passage numbers. Overall, predicted and real parameters revealed a good correlation, particularly in cPDs. Based on predicted cPDs we could reconstruct long-term growth curves and demonstrated the continuous increase in replicative senescence on molecular level. CONCLUSION: Epigenetic analysis of specific CpG sites in the genome can be used to estimate the state of cellular aging for quality control of therapeutic cell products. PMID- 24755408 TI - Bitter taste receptor (TAS2R) agonists inhibit IgE-dependent mast cell activation. PMID- 24755409 TI - The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells. AB - Previous studies demonstrated that imatinib mesylate (IM) induces autophagy in chronic myeloid leukemia (CML) and that this process is critical to cell survival upon therapy. However, it is not known if the autophagic process differs at basal levels between CML patients and healthy individuals and if pretreatment CML cells harbor unique autophagy characteristics that could predict patients' clinical outcomes. We now demonstrate that several key autophagy genes are differentially expressed in CD34(+) hematopoietic stem/progenitor cells, with the highest transcript levels detected for ATG4B, and that the transcript and protein expression levels of ATG4 family members, ATG5 and BECLIN-1 are significantly increased in CD34(+) cells from chronic-phase CML patients (P < .05). Importantly, ATG4B is differentially expressed in pretreatment CML stem/progenitor cells from subsequent IM responders vs IM nonresponders (P < .05). Knockdown of ATG4B suppresses autophagy, impairs the survival of CML stem/progenitor cells and sensitizes them to IM treatment. Moreover, deregulated expression of ATG4B in CD34(+) CML cells inversely correlates with transcript levels of miR-34a, and ATG4B is shown to be a direct target of miR-34a. This study identifies ATG4B as a potential biomarker for predicting therapeutic response in treatment-naive CML stem/progenitor cells and uncovers ATG4B as a possible drug target in these cells. PMID- 24755411 TI - Frede S, Freitag P, Geuting L, Konietzny R, Fandrey J. Oxygen-regulated expression of the erythropoietin gene in the human renal cell line REPC. Blood. 2011;117(18):4905-4914. PMID- 24755410 TI - Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. AB - Viral infections have been associated with reduced platelet counts, the biological significance of which has remained elusive. Here, we show that infection with encephalomyocarditis virus (EMCV) rapidly reduces platelet count, and this response is attributed to platelet Toll-like receptor 7 (TLR7). Platelet TLR7 stimulation mediates formation of large platelet-neutrophil aggregates, both in mouse and human blood. Intriguingly, this process results in internalization of platelet CD41-fragments by neutrophils, as assessed biochemically and visualized by microscopy, with no influence on platelet prothrombotic properties. The mechanism includes TLR7-mediated platelet granule release, translocation of P selectin to the cell surface, and a consequent increase in platelet-neutrophil adhesion. Viral infection of platelet-depleted mice also led to increased mortality. Transfusion of wild-type, TLR7-expressing platelets into TLR7 deficient mice caused a drop in platelet count and increased survival post EMCV infection. Thus, this study identifies a new link between platelets and their response to single-stranded RNA viruses that involves activation of TLR7. Finally, platelet-TLR7 stimulation is independent of thrombosis and has implications to the host immune response and survival. PMID- 24755412 TI - Awareness, agreement, adoption and adherence to type 2 diabetes mellitus guidelines: a survey of Indonesian primary care physicians. AB - BACKGROUND: To assess the degree of awareness, agreement, adoption and adherence of physicians in Indonesia to type 2 diabetes mellitus guidelines, and their association with characteristics of the responders. METHODS: Questionnaire survey among General Practitioners (GPs) attending the Indonesian Association of Family Practitioners annual conference in November 2012. The proportion of GPs who were aware of, agreed with, adopted and adhered to the seven recommendations in the guidelines (screening for diabetes, diagnosis, lifestyle modification, use of sulfonylurea, target blood glucose, target blood pressure and use of statin) were calculated in the total number of responders. RESULTS: Of the 399 GPs participating, 383 (89%) were aware of the existence of Indonesian type 2 diabetes guidelines. Awareness for each recommendation varied from 66 to 91%. The recommendation to use a random blood glucose test for diagnosing patients with classic diabetes symptoms had the least awareness (265/399, 66%) and least agreement (163/399, 41%). The recommendation on statin use was the least adopted (192/399, 48%), while the least adherence (7/399, 2%) was found for the recommendation on screening for diabetes for patients with risk factors. Years of practice experience and proportion of diabetes patients seen in their practice were independently related with adherence to statin prescription. CONCLUSIONS: High awareness of the Indonesian type 2 diabetes guideline does not necessary lead to adoption or adherence to recommendations important for outcomes and quality of care. The awareness-to-adherence model helps in identifying barriers for the use of guidelines. PMID- 24755413 TI - Commentary on: Defining the fat compartments in the neck: a cadaver study. PMID- 24755414 TI - The Sunshine Act: even SPF 100 won't help. PMID- 24755415 TI - The FACE-Q: the importance of full disclosure and sound methodology in outcome studies. PMID- 24755416 TI - Response to "The FACE-Q: the importance of full disclosure and sound methodology in outcomes studies". PMID- 24755417 TI - Was the surgeon a satisfactory informant? How to minimize room for claims. PMID- 24755418 TI - Reduction mammaplasty and mastopexy in previously irradiated breasts: notes on safety and pitfalls. PMID- 24755419 TI - Response to "Reduction mammaplasty and mastopexy in previously irradiated breasts: notes on safety and pitfalls". PMID- 24755420 TI - Dynamin-related protein Drp1 and mitochondria are important for Shigella flexneri infection. AB - Shigella infection in epithelial cells induces cell death which is accompanied by mitochondrial dysfunction. In this study the role of the mitochondrial fission protein, Drp1 during Shigella infection in HeLa cells was examined. Significant lactate dehydrogenase (LDH) release was detected in the culture supernatant when HeLa cells were infected with Shigella at a high multiplicity of infection. Drp1 inhibition with Mdivi-1 and siRNA knockdown significantly reduced LDH release. HeLa cell death was also accompanied by mitochondrial fragmentation. Tubular mitochondrial networks were partially restored when Drp1 was depleted with either siRNA or inhibited with Mdivi-1. Surprisingly either Mdivi-1 treatment or Drp1 siRNA-depletion of HeLa cells also reduced Shigella plaque formation. The effect of Mdivi-1 on Shigella infection was assessed using the murine Sereny model, however it had no impact on ocular inflammation. Overall our results suggest that Drp1 and the mitochondria play important roles during Shigella infection. PMID- 24755421 TI - Differential intracellular signalling properties of the growth hormone receptor induced by the activation of an anti-GHR antibody. AB - A series of studies have reported that anti-GHR antibody can function as a GHR agonist and may serve as an attractive tool for studying the mechanisms of GHR activation. However, to date, there is relatively little information about intracellular signalling triggered by anti-GHR antibody. Therefore, in this work, we have developed a panel of monoclonal antibodies to GHBP, among which one Mab, termed CG-172, was selected for further characterisation because of its signalling properties. The results from FACS assays, receptor binding and immunoprecipitation assays and western blotting demonstrated that CG-172 specifically binds to GHR expressed on target cells. Subsequently, epitope mapping studies that used receptor binding analysis showed that CG-172 specifically binds subdomain 1 of GHR ECD. We next examined the resulting signal transduction pathways triggered by this antibody in CHO-GHR638 cells and rat hepatocytes. We found that CG-172 can activate JAK2, AKT, ERK1/2 and STAT1/3 but not STAT5. The phosphorylation kinetics of STAT1/3, AKT and ERK1/2 induced by either GH or CG-172 were analysed in dose-response and time course experiments. Our observations demonstrated that an anti-GHR monoclonal antibody (CG-172) can serve as an attractive tool to study the mechanism(s) of GHR-mediated intracellular signalling pathways and may lead to the production of signal specific molecules that are capable of inducing different biochemical responses. PMID- 24755422 TI - Elevated hypothalamic aromatization at the onset of precocious puberty in transgenic female mice hypersecreting human chorionic gonadotropin: effect of androgens. AB - Transgenic female mice overexpressing the alpha- and beta- subunits of human chorionic gonadotropin (hCGalphabeta+) exhibited precocious puberty, as evidenced by early vaginal opening. Chronically elevated hCG in 21-day-old hCGalphabeta+ females stimulated gonadal androgen production, which exerted negative feedback over the endogenous gonadotropin synthesis, and activated the hypothalamic GnRH pulsatility and gene expression. Transgenic females also exhibited elevated hypothalamic aromatization in the preoptic area (POA), which is the sexually differentiated area that controls the LH surge in adulthood. Ovariectomy at 14 days of age was unable to rescue this phenotype. However, the blockade of androgen action by flutamide from postnatal day 6 onwards reduced the aromatase levels in the POA of hCGalphabeta+ females. Our results suggest that early exposure of females to androgen action during a critical period between postnatal days 6-14 induces sex-specific organizational changes of the brain, which affect the aromatase expression in the POA at the onset of precocious puberty. PMID- 24755423 TI - Tend-and-befriend is a beacon for change in stress research: a reply to Tops. PMID- 24755424 TI - Oxytocin and the familiarization-habituation response: Commenting on: Cardoso, C., Ellenbogen, M.A., Serravalle, L., Linnen, A.M., 2013. Stress-induced negative mood moderates the relation between oxytocin administration and trust: evidence for the tend-and-befriend response to stress? Psychoneuroendocrinology 38, 2800 2804. PMID- 24755425 TI - Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists. AB - Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles. PMID- 24755426 TI - Structure-based design and synthesis of bicyclic fused-pyridines as MEK inhibitors. AB - The MAPK pathway is identified as one of the most important pathways involved in cell proliferation and differentiation. A key kinase in the pathway, the Mitogen activated protein kinase kinase (MEK) is recognized as a promising target for antitumor drugs. Structure-based design and optimization of known MEK inhibitors resulted in identification of compound 10a as a potent non-ATP competitive MEK inhibitor in both in vitro and in vivo tests. PMID- 24755427 TI - The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation. AB - We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands. PMID- 24755428 TI - Inhibition of biofilm formation by conformationally constrained indole-based analogues of the marine alkaloid oroidin. AB - Herein, we describe indole-based analogues of oroidin as a novel class of 2 aminoimidazole-based inhibitors of methicillin-resistant Staphylococcus aureus biofilm formation and, to the best of our knowledge, the first reported 2 aminoimidazole-based inhibitors of Streptococcus mutans biofilm formation. This study highlighted the indole moiety as a dibromopyrrole mimetic for obtaining inhibitors of S. aureus and S. mutans biofilm formation. The most potent compound in the series, 5-(trifluoromethoxy)indole-based analogue 4b (MBIC50 = 20 MUM), emerged as a promising hit for further optimisation of novel inhibitors of S. aureus and S. mutans biofilms. PMID- 24755429 TI - A chiral benzoylthiourea-pyrrolidine catalyst for the highly enantioselective Michael addition of ketones to chalcones. AB - A benzoylthiourea-pyrrolidine catalyst was developed for the asymmetric Michael addition of ketones to chalcones. The corresponding products were obtained in high yields with high level of diastereoselectivities (up to 99:1 dr) and high level of enantioselectivities (up to 94% ee) under mild conditions. PMID- 24755430 TI - Discovery of novel bacterial elongation condensing enzyme inhibitors by virtual screening. AB - The elongation condensing enzymes in the bacterial fatty acid biosynthesis pathway represent desirable targets for the design of novel, broad-spectrum antimicrobial agents. A series of substituted benzoxazolinones was identified in this study as a novel class of elongation condensing enzyme (FabB and FabF) inhibitors using a two-step virtual screening approach. Structure activity relationships were developed around the benzoxazolinone scaffold showing that N substituted benzoxazolinones were most active. The benzoxazolinone scaffold has high chemical tractability making this chemotype suitable for further development of bacterial fatty acid synthesis inhibitors. PMID- 24755432 TI - Secondary bacterial infection following first viral or fungal hit: could granulocyte-macrophage colony-stimulating factor help? PMID- 24755431 TI - The discovery of diazepinone-based 5-HT3 receptor partial agonists. AB - Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7-87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold-Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication. PMID- 24755433 TI - Increased susceptibility to vaginal simian/human immunodeficiency virus transmission in pig-tailed macaques coinfected with Chlamydia trachomatis and Trichomonas vaginalis. AB - BACKGROUND: Sexually transmitted infections (STIs) are associated with an increased risk of human immunodeficiency virus (HIV) infection, but their biological effect on HIV susceptibility is not fully understood. METHODS: Female pig-tailed macaques inoculated with Chlamydia trachomatis and Trichomonas vaginalis (n = 9) or medium (controls; n = 7) were repeatedly challenged intravaginally with SHIVSF162p3. Virus levels were evaluated by real-time polymerase chain reaction, plasma and genital cytokine levels by Luminex assays, and STI clinical signs by colposcopy. RESULTS: Simian/HIV (SHIV) susceptibility was enhanced in STI-positive macaques (P = .04, by the log-rank test; relative risk, 2.5 [95% confidence interval, 1.1-5.6]). All STI-positive macaques were SHIV infected, whereas 3 controls (43%) remained uninfected. Moreover, relative to STI-negative animals, SHIV infections occurred earlier in the menstrual cycle in STI-positive macaques (P = .01, by the Wilcoxon test). Levels of inflammatory cytokines (interferon gamma, interleukin 6, and granulocyte colony-stimulating factor [G-CSF]) were higher in STI-positive macaques during STI inoculation and SHIV exposure periods (P <= .05, by the Wilcoxon test). CONCLUSIONS: C. trachomatis and T. vaginalis infection increase the susceptibility to SHIV, likely because of prolonged genital tract inflammation. These novel data demonstrate a biological link between these nonulcerative STIs and the risk of SHIV infection, supporting epidemiological associations of HIV and STIs. This study establishes a macaque model for studies of high-risk HIV transmission and prevention. PMID- 24755435 TI - Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation. AB - BACKGROUND: Vitamin D, an important modulator of the immune system, has been shown to protect mucosal barrier homeostasis. This study investigates the effects of vitamin D deficiency on infection-induced changes in intestinal epithelial barrier function in vitro and on Citrobacter rodentium-induced colitis in mice. METHODS: Polarized epithelial Caco2-bbe cells were grown in medium with or without vitamin D and challenged with enterohemorrhagic Escherichia coli O157:H7. Barrier function and tight junction protein expression were assessed. Weaned C57BL/6 mice were fed either a vitamin D-sufficient or vitamin D-deficient diet and then infected with C. rodentium. Disease severity was assessed by histological analysis, intestinal permeability assay, measurement of inflammatory cytokine levels, and microbiome analysis. RESULTS: 1,25(OH)2D3 altered E. coli O157:H7-induced reductions in transepithelial electrical resistance (P < .01), decreased permeability (P < .05), and preserved barrier integrity. Vitamin D deficient mice challenged with C. rodentium demonstrated increased colonic hyperplasia and epithelial barrier dysfunction (P < .0001 and P < .05, respectively). Vitamin D deficiency resulted in an altered composition of the fecal microbiome both in the absence and presence of C. rodentium infection. CONCLUSIONS: This study demonstrates that vitamin D is an important mediator of intestinal epithelial defenses against infectious agents. Vitamin D deficiency predisposes to more-severe intestinal injury in an infectious model of colitis. PMID- 24755434 TI - Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. AB - BACKGROUND: While inflammation predicts mortality in treated human immunodeficiency virus (HIV) infection, the prognostic significance of gut barrier dysfunction and phenotypic T-cell markers remains unclear. METHODS: We assessed immunologic predictors of mortality in a case-control study within the Longitudinal Study of the Ocular Complications of AIDS (LSOCA), using conditional logistic regression. Sixty-four case patients who died within 12 months of treatment-mediated viral suppression were each matched to 2 control individuals (total number of controls, 128) by duration of antiretroviral therapy-mediated viral suppression, nadir CD4(+) T-cell count, age, sex, and prior cytomegalovirus (CMV) retinitis. A similar secondary analysis was conducted in the SCOPE cohort, which had participants with less advanced immunodeficiency. RESULTS: Plasma gut epithelial barrier integrity markers (intestinal fatty acid binding protein and zonulin-1 levels), soluble CD14 level, kynurenine/tryptophan ratio, soluble tumor necrosis factor receptor 1 level, high-sensitivity C-reactive protein level, and D-dimer level all strongly predicted mortality, even after adjustment for proximal CD4(+) T-cell count (all P <= .001). A higher percentage of CD38(+)HLA DR(+) cells in the CD8(+) T-cell population was a predictor of mortality before (P = .031) but not after (P = .10) adjustment for proximal CD4(+) T-cell count. Frequencies of senescent (defined as CD28(-)CD57(+) cells), exhausted (defined as PD1(+) cells), naive, and CMV-specific T cells did not predict mortality. CONCLUSIONS: Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions. PMID- 24755436 TI - Reply to Roux and Ricard. PMID- 24755438 TI - Rapid synthesis of water-dispersible superparamagnetic iron oxide nanoparticles by a microwave-assisted route for safe labeling of endothelial progenitor cells. AB - We synthesize highly crystalline citrate-coated iron oxide superparamagnetic nanoparticles that are stable and readily dispersible in water by an extremely fast microwave-assisted route and investigate the uptake of magnetic nanoparticles by endothelial cells. Nanoparticles form large aggregates when added to complete endothelial cell medium. The size of the aggregates was controlled by adjusting the ionic strength of the medium. The internalization of nanoparticles into endothelial cells was then investigated by transmission electron microscopy, magnetometry and chemical analysis, together with cell viability assays. Interestingly, a sevenfold more efficient uptake was found for systems with larger nanoparticle aggregates, which also showed significantly higher magnetic resonance imaging effectiveness without compromising cell viability and functionality. We are thus presenting an example of a straightforward microwave synthesis of citrate-coated iron oxide nanoparticles for safe endothelial progenitor cell labeling and good magnetic resonance cell imaging with potential application for magnetic cell guidance and in vivo cell tracking. PMID- 24755437 TI - The lacdiNAc-specific adhesin LabA mediates adhesion of Helicobacter pylori to human gastric mucosa. AB - Adhesion of Helicobacter pylori to the gastric mucosa is a necessary prerequisite for the pathogenesis of H. pylori-related diseases. In this study, we investigated the GalNAcbeta1-4GlcNAc motif (also known as N,N' diacetyllactosediamine [lacdiNAc]) carried by MUC5AC gastric mucins as the target for bacterial binding to the human gastric mucosa. The expression of LacdiNAc carried by gastric mucins was correlated with H. pylori localization, and all strains tested adhered significantly to this motif. Proteomic analysis and mutant construction allowed the identification of a yet uncharacterized bacterial adhesin, LabA, which specifically recognizes lacdiNAc. These findings unravel a target of adhesion for H. pylori in addition to moieties recognized by the well characterized adhesins BabA and SabA. Localization of the LabA target, restricted to the gastric mucosa, suggests a plausible explanation for the tissue tropism of these bacteria. These results pave the way for the development of alternative strategies against H. pylori infection, using adherence inhibitors. PMID- 24755439 TI - Full-genome analysis of avian influenza A(H5N1) virus from a human, North America, 2013. AB - Full-genome analysis was conducted on the first isolate of a highly pathogenic avian influenza A(H5N1) virus from a human in North America. The virus has a hemagglutinin gene of clade 2.3.2.1c and is a reassortant with an H9N2 subtype lineage polymerase basic 2 gene. No mutations conferring resistance to adamantanes or neuraminidase inhibitors were found. PMID- 24755440 TI - Use of antiarrhythmic drug therapy and clinical outcomes in older patients with concomitant atrial fibrillation and coronary artery disease. AB - AIMS: Atrial fibrillation (AF) and coronary artery disease (CAD) are common in older patients. We aimed to describe the use of antiarrhythmic drug (AAD) therapy and clinical outcomes in these patients. METHODS AND RESULTS: We analysed AAD therapy and outcomes in 1738 older patients (age >=65) with AF and CAD in the Duke Databank for cardiovascular disease. The primary outcomes were mortality and rehospitalization at 1 and 5 years. Overall, 35% of patients received an AAD at baseline, 43% were female and 85% were white. Prior myocardial infarction (MI, 31%) and heart failure (41%) were common. Amiodarone was the most common AAD (21%), followed by pure Class III agents (sotalol 6.3%, dofetilide 2.2%). Persistence of AAD was low (35% at 1 year). After adjustment, baseline AAD use was not associated with 1-year mortality [adjusted hazard ratio (HR) 1.23, 95% confidence interval (CI) 0.94-1.60] or cardiovascular mortality (adjusted HR 1.27, 95% CI 0.90-1.80). However, AAD use was associated with increased all-cause rehospitalization (adjusted HR 1.20, 95% CI 1.03-1.39) and cardiovascular rehospitalization (adjusted HR 1.20, 95% CI 1.01-1.43) at 1 year. This association did not persist at 5 years; however, these patients were at very high risk of death (55% for those >75 and on AAD) and all-cause rehospitalization (87% for those >75 and on AAD) at 5 years. CONCLUSIONS: In older patients with AF and CAD, antiarrhythmic therapy was associated with increased rehospitalization at 1 year. Overall, these patients are at high risk of longer-term hospitalization and death. Safer, better-tolerated, and more effective therapies for symptom control in this high-risk population are warranted. PMID- 24755441 TI - Surgical treatment of a solitary pulmonary metastasis from eyelid sebaceous carcinoma: report of a case. AB - BACKGROUND: Ocular sebaceous carcinoma is an uncommon, aggressive ocular neoplasm with potential for regional and distant metastasis. CASE PRESENTATION: A 77-year old woman was found to have a solitary pulmonary lesion 6 years after the initial treatment of sebaceous carcinoma of the eyelid. Video-assisted lung wedge resection of an undetermined pulmonary nodule was carried out successfully. Microscopically, the tumor showed foamy cytoplasm and atypical nuclei, consistent with metastasis of eyelid sebaceous carcinoma. CONCLUSION: This is the first case report of resected solitary pulmonary metastasis of eyelid sebaceous carcinoma. Pulmonary resection is a good option for the treatment and diagnosis of metastatic eyelid sebaceous carcinoma. PMID- 24755442 TI - Development and characterization of 16 polymorphic microsatellite markers from Taiwan cow-tail fir, Keteleeria davidiana var. formosana (Pinaceae) and cross species amplification in other Keteleeria taxa. AB - BACKGROUND: Keteleeria davidiana var. formosana (Pinaceae), Taiwan cow-tail fir, is an endangered species listed on the IUCN Red List of Threatened Species and only two populations remain, both on the Taiwan Island. Sixteen polymorphic microsatellite loci were developed in an endangered and endemic gymnosperm species, Keteleeria davidiana var. formosana, and were tested in an additional 6 taxa, K. davidiana var. calcarea, K. davidiana var. chienpeii, K. evelyniana, K. fortunei, K. fortunei var. cyclolepis, and K. pubescens, to evaluate the genetic variation available for conservation management and to reconstruct the phylogeographic patterns of this ancient lineage. FINDINGS: Polymorphic primer sets were developed from K. davidiana var. formosana using the modified AFLP and magnetic bead enrichment method. The number of alleles ranged from 3 to 16, with the observed heterozygosity ranging from 0.28 to 1.00. All of the loci were found to be interspecifically amplifiable. CONCLUSIONS: These polymorphic and transferable loci will be potentially useful for future studies that will focus on identifying distinct evolutionary units within species and establishing the phylogeographic patterns and the process of speciation among closely related species. PMID- 24755443 TI - Source of hepatitis A outbreak in Europe may be frozen berries. PMID- 24755444 TI - Molecular and immunological approaches in quantifying the air-borne food allergen tropomyosin in crab processing facilities. AB - Tropomyosin is a cross-reactive allergenic protein present in ingested shellfish species. Exposure and sensitization to this protein via inhalation is particularly important in the crustacean processing industry where workers are continuously exposed to the aerosolized form of this allergen. The aim of this study was to develop an antibody-based immunoassay to enable the specific and sensitive quantification of aerosolized tropomyosin present in the environment of two crab processing facilities. Anti-tropomyosin antibody was generated in rabbits against tropomyosins from four different crustacean species. These antibodies were purified using recombinant tropomyosin using an immuno-affinity column. The recombinant tropomyosin was also used as an allergen standard for the sandwich ELISA. In order to quantify aerosolized tropomyosin, air collection was performed in the personal breathing zone of 80 workers during two crab processing activities, edible crab (Cancer pagurus) and king crab (Paralithodes camtschaticus) using polytetrafluoroethylene filters. The purified antibody was able to detect tropomyosin selectively from different crustaceans but not from vertebrate sources. The limit of detection (LOD) for the developed sandwich ELISA was 60 picogram/m(3) and limit of quantitation (LOQ) 100 picogram/m(3). Immunoassay validation was based on linearity (R(2) 0.999), matrix interference test (78.8+/-6.5%), intra-assay CV (9.8%) and inter-assay CV (11%). The novel immunoassay was able to successfully identify working activities, which generated low, medium or high concentrations of the aerosolized food allergen. We describe an IgG antibody-based immunoassay for quantification of the major food allergen tropomyosin, with high sensitivity and specificity. This modified immunological approach can be adapted for the detection of other aerosolized food allergens, assisting in the identification of high-risk allergen exposure areas in the food industry. PMID- 24755445 TI - An unsual symptomatic case of mediastinal myelolipoma treated by VATS approach. AB - Symptomatic mediastinal location of an extra-adrenal myelolipoma is extremely rare. We describe a 56-year-old female with unusual pain in the right lower posterior chest radiated to the neck and to the upper abdomen. Chest CT showed a lesion of 3.5 x 2.2 cm in the posterior mediastinum. Video-assisted resection was performed and the final pathologic examination revealed the presence of a myelolipoma. Herein we discuss the clinical presentation, the differential diagnosis and treatment of mediastinal myelolipoma. PMID- 24755446 TI - [Decision making for termination of pregnancies and the pre-abortion period in the context of women's mental health]. AB - Based on statistical figures of the past 30 years, the number of induced abortions in Hungary is constantly decreasing. However, compared to the number of live births, even today approximately one third of pregnancies conceived eventuate in termination. Various international studies confirm the negative consequences of the intervention exerting influence on women's mental health. The aim of this publication is to give a summary on the psychological aspects of the decision making process in the pre-abortion period, from the diagnosis of pregnancy to the surgical intervention. The authors present a detailed overview on the background for the reasons of the decision, the stages of the period from conception until termination, as well as factors related to difficulties in decision making, and possible psychological consequences. PMID- 24755447 TI - [Treatment of acute myeloid leukemia -- a single center experience (2007-2013)]. AB - INTRODUCTION: Mortality of acute myeloid leukemia is still 60-70% in young (<60 years) adults and 90% in elderly (>=60 years) patients. AIM: The aim of the authors was to analyse the outcome of treatment in their patients with acute myeloid leukemia. METHOD: From 2007 to 2013, 173 patients with acute myeloid leukemia were treated. Patients were classified according to the European LeukemiaNet prognostic guideline. Association between mortality and the type of acute myeloid leukemia (secondary or primary), dose of daunoblastin at induction of treatment, and the rate of minimal residual disease were investigated. RESULTS: The 5-year survival probability was 25% in young adults and 2% in the elderly. The survival was significantly influenced by these prognostic factors. The 5-year survival rate was 50% in the young, favorable prognostic group. The 90 mg/m2 daunoblastin dose was found to be beneficial. Addition of bortezomib to the standard induction protocol had an additional beneficial effect. CONCLUSIONS: The speed and depth of the response to induction therapy, and the initial white blood cell count had an apparent effect on survival. PMID- 24755448 TI - [Vitamin D supply of patients with hip fracture]. AB - INTRODUCTION: Vitamin D deficiency is an important risk factor for fractures. However, there are few data available only on the relationship between serum 25 hydroxyvitamin D levels and recovery after surgery for hip fracture. AIM: The authors investigate the vitamin D supply of patients with hip fractures. METHOD: Between February and September 2013, serum 25-hydroxyvitamin D and parathyroid hormone levels were determined in 203 patients with hip fracture (74.8+/-11.5 ys; 67 men and 136 women) and in 74 control subjects. RESULTS: Vitamin D deficiency and secondary hyperparathyroidism occurred significantly more frequently in patients with hip fracture than in control subjects (72% vs. 45%, and 33% vs. 17%, respectively). Patients with better condition after surgery showed higher 25 hydroxyvitamin D levels (p<0.001) than those with poor condition. Serum 25 hydroxyvitamin D were lower in the 31 patients who died [median of survival time: 19 (5-52) days] compared to those who survived [22.6 (9.5-45.0) vs. 33.0 (16.5 56.6) nmol/l]. CONCLUSIONS: The association between vitamin-D deficiency and mortality as well as the positive correlation between serum 25-hydroxyvitamin D levels and better postoperative condition confirm the importance of proper vitamin D supply in the prevention and cure of hip fractures, what is more in the increase of the chance of survival. PMID- 24755449 TI - [Lipid-lowering therapy and patient adherence in the MULTI GAP 2013 trial]. AB - INTRODUCTION: Dyslipidemia is a well-known cardiovascular risk factor. To achieve lipid targets patient adherence is a particularly important issue. AIM: To assess adherence and persistence to statin therapy in patients with atherosclerotic disease who participated in the MULTI Goal Attainment Problem 2013 (MULTI GAP 2013) study. Patient adherence was assessed using estimation by the physicians in charge and analysis of pick up rate of prescribed statins in 319 patients based on data of National Health Insurance Fund Administration of Hungary. METHOD: In the MULTI GAP 2013 study, data from standard and structured questionnaires of 1519 patients were processed. Serum lipid values of patients treated by different healthcare professionals (general practitioners, cardiologists, diabetologists, neurologists, and internists), treatment adherence of patients assessed by doctors and treatment adherence based on data of National Health Insurance Fund Administration of Hungary were analysed. Satisfaction of doctors with results of statin therapy and the relationship between the level of adherence and serum lipid values were also evaluated. RESULTS: Considering the last seven years of survey data, the use of more effective statins became more prevalent with an about 70% increase of prescriptions of atorvastatin and rosuvastatin from 49% to 83%. Patients with LDL-cholesterol level below 2.5 mmol/l had 8 prescriptions per year. In contrast, patients who had LDL-cholesterol levels above 2.5 mmol/l had only 5.3-6.3 prescriptions per year. Patients who picked up their statins 10-12 or 7-9 times per year had significantly lower LDL-cholesterol level than those who had no or 1-3 pick up. The 100% persistence assessed by doctors was significantly lower (74%) based on data from the National Health Insurance Fund Administration of Hungary. About half of the patients were considered to display 100% adherence to lipid-lowering therapy by their doctors, while data from the National Health Insurance Fund Administration of Hungary showed only 36%. In patients with better adherence (90-100%) LDL-cholesterol levels below 2.5 mmol/l were more frequent (59.5%) compared to those with worse adherence. Satisfaction of doctors with lipid targets achieved was 69-80% in patients with total cholesterol between 4.5 and 6 mmol/l, and satisfaction with higher cholesterol values was also high (53-54%). CONCLUSIONS: The results show that doctors may overestimate patient adherence to lipid-lowering treatment. Based on data from the National Health Insurance Fund Administration of Hungary, satisfaction of doctors with high lipid level appears to be high. There is a need to optimize not only patient adherence, but adherence of doctors to lipid guidelines too. PMID- 24755450 TI - [De Quervain thyroiditis. Corner points of the diagnosis]. AB - Inflammatory disorders of the thyroid gland are divided into three groups according to their duration (acute, subacute and chronic). De Quervain's thyroiditis (also termed giant cell or granulomatous thyroiditis) is a subacute inflammation of the thyroid, which accounts for 5% of thyroid disorders. The etiology is unknown, it usually appears two weeks after an upper viral respiratory infection. The clinical feature includes neck pain, which is aggravated during swallowing, and radiates to the ear. On palpation, the thyroid is exquisitely tender. The erythrocyte sedimentation rate is markedly elevated, the leukocyte count, C-reactive protein are normal or slightly elevated. The natural history of granulomatous thyroiditis involves four phases: the destructive inflammation results temporarily in hyperthyroidism followed by euthyroidism. After a transient hypothyroidism the disease becomes inactive and the thyroid function is normalised. Ultrasonographic findings are diffuse hypoechogenic structures, but nodules may also occur. The disease often remains unrecognised, or the first phase of the disease is diagnosed and treated as hyperthyroidism. The diagnosis can be confirmed by the presence of the thyroid autoantibodies, radioiodine uptake and fine needle aspiration cytology. There is no special treatment, non-steroid anti-inflammatory drugs or steroid should be given to relieve the pain. The aim of the authors is to shed light the key points of diagnosis and differential diagnosis by the presentation of four slightly different cases. PMID- 24755453 TI - Regulation of miR-23b expression and its dual role on ROS production and tumour development. AB - Among the wide family of microRNAs, microRNA 23b (miR-23b) intriguingly assumes opposite roles on regulation of reactive oxygen species (ROS) and on the development of human cancers. In this review we describe novel findings concerning the molecular events involved in miR-23b gene activation or repression and in both ROS regulation and tumour development. In particular, we define the molecular targets of miR-23b that determine its function as either a tumour suppressor or oncomir in different cell types. Finally, we analyze the involvement of miR-23b in cancer cell metabolism, including autophagy, and in biomarker signatures of microRNAs allowing a prognostic and therapeutic evaluation in various human cancers. PMID- 24755454 TI - Orange Carotenoid Protein Quenches Excess Energy and Singlet Oxygen. PMID- 24755452 TI - Rotavirus vaccines: current status and future considerations. AB - Rotavirus is the leading cause of severe diarrhea among children<5 years worldwide. Currently licensed rotavirus vaccines have been efficacious and effective, with many countries reporting substantial declines in diarrheal and rotavirus-specific morbidity and mortality. However, the full public health impact of these vaccines has not been realized. Most countries, including those with the highest disease burden, have not yet introduced rotavirus vaccines into their national immunization programs. Research activities that may help inform vaccine introduction decisions include (1) establishing effectiveness, impact, and safety for rotavirus vaccines in low-income settings; (2) identifying potential strategies to improve performance of oral rotavirus vaccines in developing countries, such as zinc supplementation; and (3) pursuing alternate approaches to oral vaccines, such as parenteral immunization. Policy- and program level barriers, such as financial implications of new vaccine introductions, should be addressed to ensure that countries are able to make informed decisions regarding rotavirus vaccine introduction. PMID- 24755455 TI - Clathrin and Membrane Microdomains Cooperatively Regulate RbohD Dynamics and Activity in Arabidopsis. AB - Arabidopsis thaliana respiratory burst oxidase homolog D (RbohD) functions as an essential regulator of reactive oxygen species (ROS). However, our understanding of the regulation of RbohD remains limited. By variable-angle total internal reflection fluorescence microscopy, we demonstrate that green fluorescent protein (GFP)-RbohD organizes into dynamic spots at the plasma membrane. These RbohD spots have heterogeneous diffusion coefficients and oligomerization states, as measured by photobleaching techniques. Stimulation with ionomycin and calyculin A, which activate the ROS-producing enzymatic activity of RbohD, increases the diffusion and oligomerization of RbohD. Abscisic acid and flg22 treatments also increase the diffusion coefficient and clustering of GFP-RbohD. Single-particle analysis in clathrin heavy chain2 mutants and a Flotillin1 artificial microRNA line demonstrated that clathrin- and microdomain-dependent endocytic pathways cooperatively regulate RbohD dynamics. Under salt stress, GFP-RbohD assembles into clusters and then internalizes into the cytoplasm. Dual-color fluorescence cross-correlation spectroscopy analysis further showed that salt stress stimulates RbohD endocytosis via membrane microdomains. We demonstrate that microdomain-associated RbohD spots diffuse at the membrane with high heterogeneity, and these dynamics closely relate to RbohD activity. Our results provide insight into the regulation of RbohD activity by clustering and endocytosis, which facilitate the activation of redox signaling pathways. PMID- 24755457 TI - Is there any effect of bolus and/or infusion 5-fluorouracil treatment on microalbuminuria in immediate or long term? AB - 5-Fluorouracil is a widely used cytotoxic chemotherapeutic agent in the treatment settings particularly in patients with gastrointestinal cancer. Various studies on the cardiac adverse effects of 5-fluorouracil, reported the likelihood of altered myocardial contractility and vascular endothelial damage caused by this agent. However, the mechanism underlying 5-fluorouracil-related cardiotoxicity is not clear. In certain experimental studies, thrombotic processes occurring in microvascular field were supposed to play a role in this condition. In the light of this knowledge, the administration of 5-fluorouracil may be considered to cause renal vascular endothelial damage that may result in the altered endothelial permeability. As a result of endothelial dysfunction, increased urinary albumin excretion may be in question and no study investigating this potential direct relationship has been available in medical literature. Based on this evidence, the hypothesis of that 5-fluorouracil might cause renal vascular dysfunction and microalbuminuria, was discussed in this article along with the basic knowledge. PMID- 24755456 TI - The Rice Basic Helix-Loop-Helix Transcription Factor TDR INTERACTING PROTEIN2 Is a Central Switch in Early Anther Development. AB - In male reproductive development in plants, meristemoid precursor cells possessing transient, stem cell-like features undergo cell divisions and differentiation to produce the anther, the male reproductive organ. The anther contains centrally positioned microsporocytes surrounded by four distinct layers of wall: the epidermis, endothecium, middle layer, and tapetum. Here, we report that the rice (Oryza sativa) basic helix-loop-helix (bHLH) protein TDR INTERACTING PROTEIN2 (TIP2) functions as a crucial switch in the meristemoid transition and differentiation during early anther development. The tip2 mutants display undifferentiated inner three anther wall layers and abort tapetal programmed cell death, causing complete male sterility. TIP2 has two paralogs in rice, TDR and EAT1, which are key regulators of tapetal programmed cell death. We revealed that TIP2 acts upstream of TDR and EAT1 and directly regulates the expression of TDR and EAT1. In addition, TIP2 can interact with TDR, indicating a role of TIP2 in later anther development. Our findings suggest that the bHLH proteins TIP2, TDR, and EAT1 play a central role in regulating differentiation, morphogenesis, and degradation of anther somatic cell layers, highlighting the role of paralogous bHLH proteins in regulating distinct steps of plant cell-type determination. PMID- 24755458 TI - Mechanical tension as a driver of connective tissue growth in vitro. AB - We propose the progressive mechanical expansion of cell-derived tissue analogues as a novel, growth-based approach to in vitro tissue engineering. The prevailing approach to producing tissue in vitro is to culture cells in an exogenous "scaffold" that provides a basic structure and mechanical support. This necessarily pre-defines the final size of the implantable material, and specific signals must be provided to stimulate appropriate cell growth, differentiation and matrix formation. In contrast, surgical skin expansion, driven by increments of stretch, produces increasing quantities of tissue without trauma or inflammation. This suggests that connective tissue cells have the innate ability to produce growth in response to elevated tension. We posit that this capacity is maintained in vitro, and that order-of-magnitude growth may be similarly attained in self-assembling cultures of cells and their own extracellular matrix. The hypothesis that growth of connective tissue analogues can be induced by mechanical expansion in vitro may be divided into three components: (1) tension stimulates cell proliferation and extracellular matrix synthesis; (2) the corresponding volume increase will relax the tension imparted by a fixed displacement; (3) the repeated application of static stretch will produce sustained growth and a tissue structure adapted to the tensile loading. Connective tissues exist in a state of residual tension, which is actively maintained by resident cells such as fibroblasts. Studies in vitro and in vivo have demonstrated that cellular survival, reproduction, and matrix synthesis and degradation are regulated by the mechanical environment. Order-of-magnitude increases in both bone and skin volume have been achieved clinically through staged expansion protocols, demonstrating that tension-driven growth can be sustained over prolonged periods. Furthermore, cell-derived tissue analogues have demonstrated mechanically advantageous structural adaptation in response to applied loading. Together, these data suggest that a program of incremental stretch constitutes an appealing way to replicate tissue growth in cell culture, by harnessing the constituent cells' innate mechanical responsiveness. In addition to offering a platform to study the growth and structural adaptation of connective tissues, tension-driven growth presents a novel approach to in vitro tissue engineering. Because the supporting structure is secreted and organised by the cells themselves, growth is not restricted by a "scaffold" of fixed size. This also minimises potential adverse reactions to exogenous materials upon implantation. Most importantly, we posit that the growth induced by progressive stretch will allow substantial volumes of connective tissue to be produced from relatively small initial cell numbers. PMID- 24755459 TI - An investigation of the value of tridimensional kinematic analysis in functional diagnosis of lumbar spinal stenosis. AB - Diagnosis of lumbar spinal stenosis (LSS) is based on clinical examination and imaging. The aim of this study was to evaluate the influence of 3D gait analysis as a tool in the differential diagnosis of LSS. Fourteen patients participated in the study that consisted of three phases: (1) capture six gait cycles after rest, (2) walk on a treadmill for a maximum of 20 min, (3) capture six gait cycles after effort. From these data, the kinematic variables were compared with the perception of pain and the cross sectional area of the spinal canal as measured by magnetic resonance. Most of correlations were weak and showed that the most significant results are reported by the Gait Deviation Index (GDI). The Gait Deviation Index demonstrated moderate negative correlation with the perception of pain after effort was made by both limbs. This means that there is a significant decrease in the overall function of the lower limbs according to the increase in pain symptoms. This situation may be reflected in decreased cadence and speed beyond the times of single support for the left limb, and the balance of the right limb, as part of a strategy to protect against pain and imbalance. We found no correlation between gait and pain in the cross-sectional area of the spinal canal. Therefore, we believe that there is no advantage for the patient to make a 3-D gait analysis because the analysis does not add relevant information to clinical diagnosis. PMID- 24755460 TI - An ethnographic study of barriers to cancer pain management and opioid availability in India. AB - The world's global cancer burden disproportionally affects lower income countries, where 80% of patients present with late-stage disease and have limited access to palliative care and effective pain-relieving medications, such as morphine. Consequently, millions die each year with unrelieved pain. Objective. The objective of this study was to examine barriers to opioid availability and cancer pain management in India, with an emphasis on the experiences of nurses, who are often the front-line providers of palliative care. Methods. Fifty-nine participants were recruited using a purposive, snowball sampling strategy. Ethnographic data collection included in-depth, semistructured interviews (n = 54), 400+ hours of participant observation, and review of documents over 9 months at a government cancer hospital in South India. Systematic qualitative analysis led to identification of key barriers that are exemplified by representative quotes. Results. Morphine is more available at this study site than in most of India, but access is limited to patients seen by the palliative care service, and significant gaps in supply still occur. Systems to measure and improve pain outcomes are largely absent. Key barriers related to pain management include the role of nursing, opioid misperceptions, bureaucratic hurdles, and sociocultural/infrastructure challenges. Implications. Interventions must streamline process details of morphine procurement, work within the existing sociocultural infrastructure to ensure opioids reach patients most in need, target unexpected audiences for symptom management education, and account for role expectations of health care providers. Conclusion. Macro- and micro-level policy and practice changes are needed to improve opioid availability and cancer pain management in India. PMID- 24755461 TI - 10% Tumor diameter shrinkage on the first follow-up computed tomography predicts clinical outcome in patients with advanced renal cell carcinoma treated with angiogenesis inhibitors: a follow-up validation study. AB - Vascular endothelial growth factor (VEGF)-targeted agents are standard therapies for metastatic renal cell carcinoma (mRCC), associated with variable tumor shrinkage. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting, and other imaging changes are sought to reliably predict outcome early. We aim to validate 10% tumor shrinkage as the best early indicator of outcome. Methods. In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study, 66 mRCC patients with 165 lesions on clinical trials of VEGF-targeted agents underwent thoracic and abdominal computed tomography at baseline and at first follow-up after therapy. Measurements were performed according to RECIST and tumor shrinkage of >=10% decrease in sum of the longest diameter (-10%SLD). Correlation with time-to treatment failure (TTF) and overall survival (OS) were compared and stratified by response to the radiologic criteria. Receiver-operating characteristics (ROC) analysis yielded the optimal threshold change in SLD, defining patients with prolonged survival. Results. More than -10%SLD significantly differentiated responders from nonresponders (median TTF 8.4 vs. 4.1 months, p = .001), whereas partial response by RECIST did not (median TTF 6.9 vs. 5.5 months in responders vs. nonresponders, p = .34). -10%SLD was also significantly predictive of OS (median OS 35.1 vs. 15.0 months in responders vs. nonresponders, p = .003). ROC curve analysis yielded -9.3% in SLD as the optimal threshold for response/no response. Conclusion. Ten percent tumor shrinkage is validated as a reliable early predictor of outcome in mRCC patients receiving VEGF-targeted therapies and may provide a practical measure to guide therapeutic decisions. PMID- 24755462 TI - Are we ready for the 10% solution? PMID- 24755463 TI - Rural and urban hospitals' role in providing inpatient care, 2010. AB - KEY FINDINGS: Data from the National Hospital Discharge Survey, 2010. In 2010, 12% of the 35 million U.S. hospitalizations were in rural hospitals. A higher percentage of inpatients in rural hospitals were aged 65 and over (51%) compared with inpatients in urban hospitals (37%). The average number of diagnoses for rural and urban inpatients was similar, as was the average length of stay. Sixty four percent of rural hospital inpatients, compared with 38% of urban hospital inpatients, had no procedures performed while in the hospital. Following their hospitalization, a higher percentage of rural inpatients (7%) than urban inpatients (3%) were transferred to other short-term hospitals, and a higher percentage of rural (14%) than urban (11%) inpatients were discharged to long term care institutions. PMID- 24755464 TI - Solitary lateral neck node metastasis in papillary thyroid carcinoma. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) is associated with a high incidence of regional node metastasis, but the patterns of lateral neck node metastasis (LNM) vary. Occasionally, a solitary LNM (SLNM) is seen in PTC patients. We therefore assessed whether selective single level node dissection is appropriate in PTC patients with SLNM. METHODS: We retrospectively reviewed the medical records of 241 PTC patients who underwent total thyroidectomy with central neck dissection plus ipsilateral internal jugular node dissection (level II to IV) between January 2010 and December 2011. Of these patients, 51 had SLNM and 190 had multiple LNM (MLNM). The clinicopathologic characteristics of the two groups were compared. RESULTS: Age, gender ratio, and numbers of lateral neck nodes harvested (29.4+/-11.0 versus 30.3+/-9.5; P=0.574) were similar in the SLNM and MLNM groups. Mean primary tumor size was significantly smaller in the SLNM than in the MNLM group (1.03 cm versus 1.35 cm; P=0.037). The proportion of patients with primary tumor<=1 cm was significantly greater in the SLNM group (60.8% versus 38.4%; P=0.006), whereas the proportion with maximal node size<=0.7 cm (28.9% versus 73.3%; P<0.001) and the proportion with capsular invasion (62.7% versus 83.7%, P=0.002) were significantly lower in the SLNM than in the MLNM group. CONCLUSIONS: Selective single level neck dissection can be considered as an alternative to systemic lateral neck dissection in PTC patients with SLNM, maximal metastatic node size<=0.7 cm, and no extrathyroidal invasion. PMID- 24755465 TI - Eye movement abnormalities after a ruptured intracranial aneurysm. AB - OBJECTIVE: Overlooking eye movement abnormalities associated with aneurysmal subarachnoid hemorrhage (aSAH) is common, although these abnormalities may greatly affect quality of life. Their prevalence remains undetermined. The aim of the study was to assess preoperative and postoperative eye movement abnormalities and their recovery in follow-up of patients with aSAH and their association with age, gender, and aSAH severity. METHODS: Patients admitted to Helsinki University Central Hospital who underwent surgery or endovascular treatment for a ruptured intracranial aneurysm during 2011 were participants in this prospective study. A neuro-ophthalmic examination was performed on admission, and 3 days, 14 days, 2-4 months, and 6 months postoperatively. For those patients with third, fourth, or sixth nerve palsies or brainstem vascular syndromes, follow-up was 12 months. Associations between neuro-ophthalmic findings and relevant clinical, radiologic, and demographic data were studied. Two intraoperative videos were selected to show rare cases of aneurysms causing cranial nerve palsies. RESULTS: Of 121 participants, 11 (9%) presented on admission and 16 (13%) postoperatively showed signs of third, fourth, or sixth nerve palsy. Most of these palsies resolved; leaving 2.5% of all patients presenting with a partial palsy at 1 year. We also evaluated the frequencies of horizontal gaze pareses (n = 9) and Parinaud's syndromes (n = 3). No statistically significant associations emerged between neuro-ophthalmic findings and other clinical variables. CONCLUSIONS: Eye movement abnormalities are a quite common finding in the acute stage of aSAH. Within 1 year, however, marked improvement occurs. Identifying these neuro-ophthalmic findings can assist in localization of the underlying pathology. PMID- 24755466 TI - Statistics on the use of cardiac electronic devices and electrophysiological procedures in 55 ESC countries: 2013 report from the European Heart Rhythm Association (EHRA). PMID- 24755467 TI - NADPH oxidase NOX4 supports renal tumorigenesis by promoting the expression and nuclear accumulation of HIF2alpha. AB - Most sporadically occurring renal tumors include a functional loss of the tumor suppressor von Hippel Lindau (VHL). Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor-2alpha (HIF2alpha), a master transcriptional regulator of genes that drive diverse processes, including angiogenesis, proliferation, and anaerobic metabolism. In determining the critical functions for HIF2alpha expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here, we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation, and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF2alpha in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade. PMID- 24755469 TI - Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes. AB - Cancer genomes maintain a complex array of somatic alterations required for maintenance and progression of the disease, posing a challenge to identify driver genes among this genetic disorder. Toward this end, we mapped regions of recurrent amplification in a large collection (n=392) of primary human cancers and selected 620 genes whose expression is elevated in tumors. An RNAi loss-of function screen targeting these genes across a panel of 32 cancer cell lines identified potential driver genes. Subsequent functional assays identified SHMT2, a key enzyme in the serine/glycine synthesis pathway, as necessary for tumor cell survival but insufficient for transformation. The 26S proteasomal subunit, PSMB4, was identified as the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo. Elevated expression of SHMT2 and PSMB4 was found to be associated with poor prognosis in human cancer, supporting the development of molecular therapies targeting these genes or components of their pathways. PMID- 24755468 TI - Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein. AB - Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2alpha (HIF2alpha) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2alpha and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2alpha. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2alpha, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL R167Q or similar missense mutations. PMID- 24755470 TI - Influence of drug formulation on OATP1B-mediated transport of paclitaxel. AB - Taxane antineoplastic agents are extensively taken up into hepatocytes by OATP1B type transporters before metabolism and excretion. Because the biodistributional properties imposed upon these agents by different solubilizers drive clinically important pharmacodynamic endpoints, we tested the hypothesis that the in vitro and in vivo interaction of taxanes with OATP1B transporters is affected by the choice of drug delivery system. Transport of paclitaxel, docetaxel, and cabazitaxel was studied in vitro using various cell lines transfected with OATP1B1, OATP1B3, or the rodent equivalent OATP1B2. Pharmacokinetic studies were done in wild-type and OATP1B2-knockout mice in the presence or absence of polysorbate 80 (PS80) or Kolliphor EL (formerly Cremophor EL; CrEL). Paclitaxel and docetaxel, but not cabazitaxel, were transported substrates of OATP1B1, OATP1B3, and OATP1B2, and these in vitro transport processes were strongly reduced in the presence of clinically relevant concentrations of PS80 and CrEL. When paclitaxel was administered without any solubilizers, deficiency of OATP1B2 in mice was associated with a significantly decreased systemic clearance because of a liver distribution defect (P=0.000484). However, this genotype dependence of paclitaxel clearance was masked in the presence of PS80 or CrEL because of significant inhibition of OATP1B2-mediated hepatocellular uptake of the drug (P<0.05). Our findings confirm the importance of OATP1B-type transporters in the hepatic elimination of taxanes and indicate that this process can be inhibited by PS80 and CrEL. These results suggest that the likelihood of drug-drug interactions mediated by these transporters is strongly dependent on the selected taxane solubilizer. PMID- 24755471 TI - Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. AB - Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase epsilon proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFbeta, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses. PMID- 24755472 TI - G protein-coupled receptor kinase GRK5 phosphorylates moesin and regulates metastasis in prostate cancer. AB - G protein-coupled receptor kinases (GRK) regulate diverse cellular functions ranging from metabolism to growth and locomotion. Here, we report an important contributory role for GRK5 in human prostate cancer. Inhibition of GRK5 kinase activity attenuated the migration and invasion of prostate cancer cells and, concordantly, increased cell attachment and focal adhesion formation. Mass spectrometric analysis of the phosphoproteome revealed the cytoskeletal-membrane attachment protein moesin as a putative GRK5 substrate. GRK5 regulated the subcellular distribution of moesin and colocalized with moesin at the cell periphery. We identified amino acid T66 of moesin as a principal GRK5 phosphorylation site and showed that enforcing the expression of a T66-mutated moesin reduced cell spreading. In a xenograft model of human prostate cancer, GRK5 silencing reduced tumor growth, invasion, and metastasis. Taken together, our results established GRK5 as a key contributor to the growth and metastasis of prostate cancer. PMID- 24755474 TI - Insulin, estrogen, inflammatory markers, and risk of benign proliferative breast disease. AB - Women with benign proliferative breast disease (BPBD) are at increased risk for developing breast cancer. Evidence suggests that accumulation of adipose tissue can influence breast cancer development via hyperinsulinemia, increased estrogen, and/or inflammation. However, there are limited data investigating these pathways with respect to risk of BPBD. We evaluated serologic markers from these pathways in a case-control study of postmenopausal women nested within the Women's Health Initiative Clinical Trial. Cases were the 667 women who developed BPBD during follow-up, and they were matched to 1,321 controls. Levels of insulin, estradiol, C-reactive protein (CRP), and adiponectin were measured in fasting serum collected at baseline. Conditional logistic regression models were used to estimate ORs for the association of each factor with BPBD risk. Among nonusers of hormone therapy, fasting serum insulin was associated with a statistically significant increase in risk of BPBD (OR for highest vs. lowest quartile = 1.80; 95% confidence interval, CI, 1.16-2.79; Ptrend = 0.003) as were levels of estradiol (OR for highest vs. lowest tertile = 1.89; 95% CI, 1.26-2.83; Ptrend = 0.02) and CRP (OR for highest vs. lowest quartile = 2.46; 95% CI, 1.59-3.80; Ptrend < 0.001). Baseline adiponectin level was inversely associated with BPBD risk (OR for highest vs. lowest quartile = 0.47; 95% CI, 0.31-0.71; Ptrend < 0.001). These associations persisted after mutual adjustment, but were not observed among users of either estrogen alone or of estrogen plus progestin hormone therapy. Our results indicate that serum levels of estrogen, insulin, CRP, and adiponectin are independent risk factors for BPBD and suggest that the estrogen, insulin, and inflammation pathways are associated with the early stages of breast cancer development. PMID- 24755473 TI - IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. AB - Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation. PMID- 24755475 TI - Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study. AB - BACKGROUND: Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study. CASE PRESENTATION: On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 MUM. Over the next three days, although blood cultures remained negative, the patient's condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity. CONCLUSIONS: After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided. PMID- 24755476 TI - Computer-assisted direct observation of behavioral agitation, engagement, and affect in long-term care residents. AB - OBJECTIVES: The objectives of the current research were (1) to test and evaluate the investigator-designed Behavior, Engagement, and Affect Measure (BEAM) touchpad direct observational data collection tool, and (2) to implement this tool to investigate residents' patterns of behavioral agitation, engagement, affect, behaviors associated with positive mood, general time-activity use, and social interactions within long-term care. DESIGN: Raters collected cross sectional observational data and conducted semistructured interviews with participants of the Sydney Multisite Intervention of LaughterBosses and ElderClowns (SMILE) Study. Researchers tested the BEAM's reliability and validity and evaluated the instrument's discriminate validity for sampling resident behaviors. SETTING: Data were collected in 36 long-term care homes. The sample included low-care hostels, high-care nursing homes, and residential facilities offering aging-in-place. PARTICIPANTS: Participants were 406 residents aged 52 to 105 years, with and without dementia. MEASUREMENTS: Researchers collected direct observational data using the BEAM and operationalized behavioral domains based largely on concepts from Kitwood's model of person-centered care. Care staff reported on resident behavior using standardized measures of agitation, depression, quality of life, and social engagement. RESULTS: The BEAM showed moderate-to-substantial interrater reliability and slight-to-moderate correlations with staff-report data gathered through standardized questionnaire measures. Observations showed that residents spent the greatest amount of time stationary and expressing little emotion, although actively engaged with their environment. Residents were observed to be coping adequately and experiencing a positive social and/or positive care interaction in approximately half of observations; however, close to a third of ratings identified "ill-being." Residents showed more positive behavior, appeared happier and less anxious, and exhibited higher "well-being" during structured activity than during free time or meals. CONCLUSION: The BEAM is a reliable and valid observational tool for measuring behavior in long-term care. Long-term care residents expressed little emotion and experienced limited positive social interaction in their daily routine. Increased provision of structured activities may increase resident experiences of positive behavior, affect, and well-being. PMID- 24755477 TI - Antihypertensive treatment in people with dementia. AB - BACKGROUND: The range and magnitude of potential benefits and harms of antihypertensive treatment in people with dementia has not been previously established. METHODS: A scoping review to identify potential domains of benefits and harms of antihypertensive therapy in people with dementia was undertaken. Systematic reviews of these domains were undertaken to examine the magnitude of the benefits or harms. RESULTS: Potential outcome domains identified in the 155 papers in the scoping review were cardiovascular events, falls, fractures and syncope, depression, orthostatic hypotension, behavioral disturbances, polypharmacy risks, kidney problems, sleep problems, interactions with cholinesterase inhibitors, and pain. The systematic reviews across these domains identified relatively few studies done in people with dementia, and no convincing evidence of safety, benefit, or harm across any of them. DISCUSSION: Given the lack of firm evidence of benefits or harm from antihypertensive therapy in people with dementia and the weak evidence for benefits in people over 80 years of age, the current presumption that the favorable evidence drawn from the treatment of nondemented people should be extrapolated to those with dementia is contentious. There is sufficient evidence to warrant particular caution and further research into treatment in this group of patients. PMID- 24755478 TI - New reference values for body composition by bioelectrical impedance analysis in the general population: results from the UK Biobank. AB - BACKGROUND: Low fat-free mass (FFM) is a risk factor for morbidity and mortality in elderly and patient populations. Therefore, measurement of FFM is important in nutritional assessment. Bioelectrical impedance analysis (BIA) is a convenient method to assess FFM and FFM index (FFMI; FFM/height(2)). Although reference values have been established for individuals with normal body weight, no specific cutoff values are available for overweight and obese populations. Also, limited studies accounted for the age-related decline in FFM. OBJECTIVE: To determine BMI and age-specific reference values for abnormal low FFM(I) in white-ethnic men and women free of self-reported disease from the general population. DESIGN: The UK Biobank is a prospective epidemiological study of the general population from the United Kingdom. Individuals in the age category 45 to 69 years were analyzed. In addition to body weight, FFM and FFMI were measured using a Tanita BC-418MA. Also, self-reported chronic conditions and ethnic background were registered, and lung function was assessed using spirometry. RESULTS: After exclusion of all individuals with missing data, nonwhite ethnicity, self-reported disease, body mass index (BMI) less than 14 or 36 kg/m(2) or higher, and/or an obstructive lung function, reference values for FFM and FFMI were derived from 186,975 individuals (45.9% men; age: 56.9 +/- 6.8 years; BMI: 26.5 +/- 3.6 kg/m(2); FFMI 18.3 +/- 2.4 kg/m(2)). FFM and FFMI were significantly associated with BMI and decreased with age. Percentiles 5, 10, 25, 50, 75, 90, and 95 were calculated for FFM, FFMI, and fat mass (index), after stratification for gender, age, and BMI. CONCLUSIONS: Using the UK Biobank dataset, new reference values for body composition assessed with BIA were determined in white-ethnic men and women aged 45 to 69 years. Because these reference values are BMI specific, they are of broad interest for overweight and obese populations. PMID- 24755479 TI - Impact of throughput optimization on intensive care unit occupancy. AB - Intensive care unit (ICU) resources are scarce, yet demand is increasing at a rapid rate. Optimizing throughput efficiency while balancing patient safety and quality of care is of utmost importance during times of high ICU utilization. Continuous improvement methodology was used to develop a multidisciplinary workflow to improve throughput in the ICU while maintaining a high quality of care and minimizing adverse outcomes. The research team was able to decrease ICU occupancy and therefore ICU length of stay by implementing this process without increasing mortality or readmissions to the ICU. By improving throughput efficiency, more patients were able to be provided with care in the ICU. PMID- 24755480 TI - Consumers' understanding of and interest in provider- versus practice-level quality characteristics: findings from a focus group study. AB - Quality measures are currently reported almost exclusively at the facility level. Forthcoming physician quality data are expected to be reported primarily at the level of the group practice. Little is known about consumers' understanding of and interest in practice-level measures. The research team conducted 4 focus groups, half with individuals who had a chronic illness and half with individuals who did not. Most consumers correctly understand the concept of a physician practice. However, consumers exhibit little interest in practice-level characteristics, preferring information about their personal doctor. Understanding of and interest in practice-level quality does not differ by chronic disease status. Additional work must be done to design, develop, and test promotional and educational materials to accompany the planned reports to highlight the relevance of practice-level characteristics for consumer decision making. PMID- 24755481 TI - Implementation of Pharmacy to Dose: Reducing Near Miss Medication Errors. PMID- 24755483 TI - Vitamin D deficiency in Scotland. PMID- 24755484 TI - Involvement of ERK1/2 pathway in neuroprotective effects of pyrroloquinoline quinine against rotenone-induced SH-SY5Y cell injury. AB - Pyrroloquinoline quinone (PQQ), a redox cofactor in the mitochondrial respiratory chain, has been shown to protect neurons against glutamate-induced damage both in vitro and in vivo. In this study, specific inhibitors to each of the mitochondrial complexes were used to find out which reactive oxygen species (ROS) generating sites could be affected by PQQ. Then we established an in vitro model of Parkinson's disease (PD) by exposing cultured SH-SY5Y dopaminergic cells to rotenone, a complex I inhibitor. The neuroprotective effects of PQQ were observed by pretreatment of SH-SY5Y cells with PQQ before rotenone injury, and the possible involvement of certain signaling pathways were investigated. PQQ pretreatment prevented SH-SY5Y cells from rotenone-induced apoptosis in a concentration-dependent manner. PQQ neuroprotection was associated with inhibition of intracellular ROS production, modulation of the expression of apoptosis-related Bcl-2 and Bax, and regulation of the level of superoxide dismutase, glutathione, and malondialdehyde. Meanwhile, PQQ up-regulated the gene expression of Ndufs 1, 2, and 4 (complex I subunits), and increased mitochondrial viability and mitochondrial DNA content. Furthermore, PQQ pretreatment activated ERK1/2 phosphorylation in rotenone-injured SH-SY5Y cells, while ERK1/2 inhibition suppressed PQQ neuroprotection. All the results suggested that PQQ could protect SH-SY5Y cells against rotenone injury by reducing ROS production and maintaining mitochondrial functions through activation of ERK1/2 pathway. PMID- 24755486 TI - High-frequency electrical stimulation of the subthalamic nucleus excites target structures in a model using c-fos immunohistochemistry. AB - Deep-brain stimulation at high frequencies (HFS) directed to the subthalamic nucleus (STN) is used increasingly to treat patients with Parkinson's disease. However, the mechanism of action by which HFS of the STN achieves its therapeutic effects remains unresolved. Insofar as lesions of the STN have similar therapeutic benefit, a favored hypothesis is that HFS acts by suppressing neural activity in the STN. The purpose of the present study was to exploit prior observations that exposure to ether anesthesia in a rodent model evokes c-fos expression (a marker of neural activation) in the STN and its efferent structures, the globus pallidus, entopeduncular nucleus and substantia nigra. We showed first that exposure to ether induced a profound oscillatory pattern of neural activity in the STN and SNr, which could explain the marked induction of c fos immunoreactivity in these structures. Secondly, inhibition of the STN by local injections of the GABA agonist, muscimol, suppressed ether-evoked c-fos expression in all target structures. This showed that excitation of target structures in the ether model originated, at least in part, from the STN. Thirdly, and contrary to expectation, HFS of the STN increased further the expression of c-fos in the STN target structures of animals treated with ether. Finally, we demonstrated, in the absence of ether treatment, that HFS and chemical stimulation of the STN with local injections of kainic acid both induced c-fos expression in the globus pallidus, entopeduncular nucleus and substantia nigra. Together these results suggest that the principal action of STN stimulation at high frequencies is to excite rather than inhibit its efferent targets. Given that Parkinsonism has been associated with increased levels of inhibitory output activity from the basal ganglia, it is unlikely that excitation of output structures revealed in this study provides a basis for deep-brain stimulation's therapeutic action. PMID- 24755485 TI - N-type calcium current, Cav2.2, is enhanced in small-diameter sensory neurons isolated from Nf1+/- mice. AB - Major aspects of neuronal function are regulated by Ca(2+) including neurotransmitter release, excitability, developmental plasticity, and gene expression. We reported previously that sensory neurons isolated from a mouse model with a heterozygous mutation of the Nf1 gene (Nf1+/-) exhibited both greater excitability and evoked release of neuropeptides compared to wildtype mice. Furthermore, augmented voltage-dependent sodium currents but not potassium currents contribute to the enhanced excitability. To determine the mechanisms giving rise to the enhanced release of substance P and calcitonin gene-related peptide in the Nf1+/- sensory neurons, the potential differences in the total voltage-dependent calcium current (ICa) as well as the contributions of individual Ca(2+) channel subtypes were assessed. Whole-cell patch-clamp recordings from small-diameter capsaicin-sensitive sensory neurons demonstrated that the average peak ICa densities were not different between the two genotypes. However, by using selective blockers of channel subtypes, the current density of N-type (Cav2.2) ICa was significantly larger in Nf1+/- neurons compared to wildtype neurons. In contrast, there were no significant differences in L-, P/Q- and R-type currents between the two genotypes. Quantitative real-time polymerase chain reaction measurements made from the isolated but intact dorsal root ganglia indicated that N-type (Cav2.2) and P/Q-type (Cav2.1) Ca(2+) channels exhibited the highest mRNA expression levels although there were no significant differences in the levels of mRNA expression between the genotypes. These results suggest that the augmented N-type (Cav2.2) ICa observed in the Nf1+/- sensory neurons does not result from genomic differences but may reflect post-translational or some other non-genomic modifications. Thus, our results demonstrate that sensory neurons from Nf1+/- mice, exhibit increased N-type ICa and likely account for the increased release of substance P and calcitonin gene-related peptide that occurs in Nf1+/- sensory neurons. PMID- 24755487 TI - A novel synthetic 1,3-phenyl bis-thiourea compound targets microtubule polymerization to cause cancer cell death. AB - Microtubules are essential cytoskeletal components with a central role in mitosis and have been particularly useful as a cancer chemotherapy target. We synthesized a small molecule derivative of a symmetrical 1,3-phenyl bis-thiourea, (1,1'-[1,3 phenylene]bis[3-(3,5-dimethylphenyl)thiourea], named "41J"), and identified a potent effect of the compound on cancer cell survival. 41J is cytotoxic to multiple cancer cell lines at nanomolar concentrations. Cell death occurred by apoptosis and was preceded by mitotic arrest in prometaphase. Prometaphase arrest induced by 41J treatment was accompanied by dissociation of cyclin B1 levels from the apparent mitotic stage and by major spindle abnormalities. Polymerization of purified tubulin in vitro was directly inhibited by 41J, suggesting that the compound works by directly interfering with microtubule function. Compound 41J arrested the growth of glioblastoma multiforme xenografts in nude mice at doses that were well-tolerated, demonstrating a relatively specific antitumor effect. Importantly, 41J overcame drug resistance due to beta-tubulin mutation and P glycoprotein overexpression. Compound 41J may serve as a useful new lead compound for anticancer therapy development. PMID- 24755489 TI - We have recently received and handled three cases in which complaints were made regarding plagiarism. Introduction. PMID- 24755490 TI - Paternalism reigns!: Assessing capacity to consent to treatment. PMID- 24755488 TI - Heparan sulfate signaling in cancer. AB - Heparan sulfate (HS) is a biopolymer consisting of variably sulfated repeating disaccharide units. The anticoagulant heparin is a highly sulfated intracellular variant of HS. HS has demonstrated roles in embryonic development, homeostasis, and human disease via non-covalent interactions with numerous cellular proteins, including growth factors and their receptors. HS can function as a co-receptor by enhancing receptor-complex formation. In other contexts, HS disrupts signaling complexes or serves as a ligand sink. The effects of HS on growth factor signaling are tightly regulated by the actions of sulfyltransferases, sulfatases, and heparanases. HS has important emerging roles in oncogenesis, and heparin derivatives represent potential therapeutic strategies for human cancers. Here we review recent insights into HS signaling in tumor proliferation, angiogenesis, metastasis, and differentiation. A cancer-specific understanding of HS signaling could uncover potential therapeutic targets in this highly actionable signaling network. PMID- 24755491 TI - The importance of performing a sentinel node biopsy in case of recurrent vulval cancer. PMID- 24755492 TI - Risk factors for ovarian cancers with and without microsatellite instability. AB - OBJECTIVE: In a population-based sample of epithelial ovarian cancers, the objective of this study was to evaluate the association between microsatellite instability (MSI) status and the following factors: (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes. PATIENTS AND METHODS: Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer; tumor DNA was analyzed using 5 standardized microsatellite markers to assess the MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSI-stable) according to the National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. RESULTS: A total of 917 ovarian cancer patients were included. One hundred twenty-seven cases of cancer (13.8%) were MSI-high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significance differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 patients with BRCA2 mutations. The proportions of different ovarian cancer histologies among the various MSI subgroups were similar. CONCLUSIONS: The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without MSI. The distributions of MSI do not differ significantly among ovarian cancers with different histologies. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors compared with 6% among patients with BRCA2 mutations, but this difference was not statistically significant. PMID- 24755493 TI - Reconsolidation of human memory: brain mechanisms and clinical relevance. AB - The processes of memory formation and storage are complex and highly dynamic. Once memories are consolidated, they are not necessarily fixed but can be changed long after storage. In particular, seemingly stable memories may re-enter an unstable state when they are retrieved, from which they must be re-stabilized during a process known as reconsolidation. During reconsolidation, memories are susceptible to modifications again, thus providing an opportunity to update seemingly stable memories. While initial demonstrations of memory reconsolidation came mainly from animal studies, evidence for reconsolidation in humans is now accumulating as well. Here, we review recent advances in our understanding of human memory reconsolidation. After a summary of findings on the reconsolidation of human fear and episodic memory, we focus particularly on recent neuroimaging data that provide first insights into how reconsolidation processes are implemented in the human brain. Finally, we discuss the implications of memory modifications during reconsolidation for the treatment of mental disorders such as posttraumatic stress disorder and drug addiction. PMID- 24755494 TI - [Telemedicine as a useful supplement]. PMID- 24755495 TI - [Primary immune thrombocytopenia]. PMID- 24755497 TI - [Gastroenterology. What is your diagnosis? Large Zenker diverticulum]. PMID- 24755498 TI - [Psychiatric emergencies in the outpatient setting]. AB - Psychiatric emergencies are stressful and time-consuming for physicians. Comprehensive diagnostic assessment is often not feasible in psychiatric emergency situations. Primary interventions target symptoms and syndromes. Treatments for psychiatric emergencies often lack an evidence base and rely on expert opinions and good clinical practice. Target symptoms for interventions in emergency situations are agitation, aggressive behavior, delirious states, psychotic symptoms and anxiety (psychotic or non-psychotic). Pharmacological treatments are indicated due to their sedative, antipsychotic, and anxiolytic effects. It is important to look for possible medical causes and comorbidity (differential diagnosis). The treatment of delirium should always focus on any underlying medical conditions. Psychiatric emergencies require immediate action by a physician, although the options available are often limited. If an emergency situation can be converted into a crisis situation by means of a successful intervention, additional time is gained and the range of options for action may be widened. PMID- 24755499 TI - [Words before actions- the significance of counselling in the Praena-Test era]. AB - Due to new offers in prenatal diagnostics pregnant women are forced to make choices. In Switzerland physicians are obliged to inform previous to prenatal tests and to obtain informed consent. Considering the complexity of this information and the consequences of a positive result, counselling is challenging, especially in an intercultural context. A questionnaire-based study compared information processing, test interpretation and emotional response of pregnant women from Switzerland and adjacent countries with Turkish women. Knowledge of the latter was significantly lower and they found counselling more unsettling, but their acceptance of prenatal tests was significantly higher. An empathetic approach and the right words are decisive, and counselling will even gain importance when considering the increase in options patients are confronted with. PMID- 24755500 TI - [Interventional decentralized telemonitoring: possible indications and perspectives of a new method in telemedicine]. AB - Telemedicine comprises different concepts aiming to close a spatial distance between practitioner, medical staff and patient. Its functionality can include mere data transmission but extend as well to triggering alarms or enable consultation and therapy suggestions. A special form of telemedicinal application is interventional decentralized telemonitoring. Here practitioner-patient communication is characterized by telemedicinal data collection driven therapy control and -optimization. To identify feasible indications for the employment of telemonitoring a detailed definition of communicated parameters, alarm rules and algorithms of intervention are required as well as a benefit-cost analysis. The quality of the telemedical application is determined by the medical quality of the resulting actions. PMID- 24755501 TI - [A heart without overspeed trip unit]. AB - We report the case of a 38-year patient who presented in our outpatient clinic for cardiac evaluation and assessment as volunteer firefighter. The patient had an asymptomatic sinustachycardia, which was diagnosed at the age of 15. After we excluded secondary etiologies, as well as a postural orthostatic tachycardia syndrome (POTS) diagnosis of inappropriate sinus tachycardia (IST) was confirmed. A metoprolol therapy was established, however to resistant tachycardia, we suggested a combined therapy of Bisoprolol and Ivabradin, which resulted successfully in normocard sinus rhythm. PMID- 24755504 TI - [Inhaled steroids increase the risk of severe pneumonia in varying degrees]. PMID- 24755505 TI - [Vitamin B12 deficiency and acid blockers - connection is there, causality remains unclear]. PMID- 24755507 TI - [CME ORL 11. Right sided cervical space occupying lesion with left sided hemianopsia. Diffuse large cell B-cell lymphoma with multiple organ manifestations]. PMID- 24755510 TI - Malakoplakia of liver: report of two cases. AB - Malakoplakia is an unusual chronic inflammatory condition characterized by the presence of Michaelis-Gutmann bodies. Patients with malakoplakia often have an immunodeficiency state. It is believed that malakoplakia results from a defective macrophage response to phagocytosed bacteria. Malakoplakia most commonly affects the genitourinary tract. Cases confined to the liver are rare, with only five cases described in the literature. We report two cases of malakoplakia of liver; both were incidental autopsy findings. The first case involves a 53-year-old man with systemic lupus erythematosus and chronic refractory pancytopenia who presented with febrile neutropenia. His blood culture was positive for Stenotrophomonas maltophilia and Enterococcus faecium, and he subsequently developed invasive pulmonary aspergillosis. The second case involves a 60-year old man who presented with a mass in periorbital tissue which, on biopsy, showed inflammation and Treponema-like spirochetes. He died unexpectedly at home. Autopsy revealed adrenal gland chronic inflammation and abscess. Both cases had grossly normal livers with microscopic findings of calcified targetoid structures consistent with Michaelis-Gutmann bodies. In these cases, malakoplakia was an incidental finding confined to liver. Although asymptomatic in these cases, diagnosis in the liver may be useful to initiate a search for hepatic or non hepatic infections. PMID- 24755511 TI - Comparison of in-home collection of physical measurements and biospecimens with collection in a standardized setting: the health measures at home study. AB - OBJECTIVES: Collection of physical measurements and biospecimens in the home may be an efficient way to obtain objective health measurements. This study assesses differences between collection in the home and a standardized setting. METHODS: Participants had physical measurements and biospecimens taken in the National Health and Nutrition Examination Survey mobile examination center (MEC). Then, they had height and weight measured in the MEC using portable equipment. In the home, participants had height, weight, and blood pressure measured and dried blood spots collected using portable equipment. Two complete examinations were done in the home: one by a health technician and one by a field interviewer. RESULTS: Home environments were less standardized and presented more challenges to examiners. Correlations between all four height measurements and all four weight measurements were higher than 99%. Mean differences in height (0.3 cm) and weight (0.4 kg) were small but statistically significant. The home measurements perfectly or near-perfectly classified participants as obese relative to the standardized MEC examination. CONCLUSIONS: The selected physical measurements can be collected in the home by field interviewers using portable equipment. Before adding home collection of physical measurements to household interview surveys, further research should be done to examine the impact of these changes on interviewer training, participant recruitment, and participant response rates. PMID- 24755512 TI - Contrasting Roles of the Apoplastic Aspartyl Protease APOPLASTIC, ENHANCED DISEASE SUSCEPTIBILITY1-DEPENDENT1 and LEGUME LECTIN-LIKE PROTEIN1 in Arabidopsis Systemic Acquired Resistance. AB - Systemic acquired resistance (SAR) is an inducible immune response that depends on ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1). Here, we show that Arabidopsis (Arabidopsis thaliana) EDS1 is required for both SAR signal generation in primary infected leaves and SAR signal perception in systemic uninfected tissues. In contrast to SAR signal generation, local resistance remains intact in eds1 mutant plants in response to Pseudomonas syringae delivering the effector protein AvrRpm1. We utilized the SAR-specific phenotype of the eds1 mutant to identify new SAR regulatory proteins in plants conditionally expressing AvrRpm1. Comparative proteomic analysis of apoplast-enriched extracts from AvrRpm1 expressing wild-type and eds1 mutant plants led to the identification of 12 APOPLASTIC, EDS1-DEPENDENT (AED) proteins. The genes encoding AED1, a predicted aspartyl protease, and another AED, LEGUME LECTIN-LIKE PROTEIN1 (LLP1), were induced locally and systemically during SAR signaling and locally by salicylic acid (SA) or its functional analog, benzo 1,2,3-thiadiazole-7-carbothioic acid S methyl ester. Because conditional overaccumulation of AED1-hemagglutinin inhibited SA-induced resistance and SAR but not local resistance, the data suggest that AED1 is part of a homeostatic feedback mechanism regulating systemic immunity. In llp1 mutant plants, SAR was compromised, whereas the local resistance that is normally associated with EDS1 and SA as well as responses to exogenous SA appeared largely unaffected. Together, these data indicate that LLP1 promotes systemic rather than local immunity, possibly in parallel with SA. Our analysis reveals new positive and negative components of SAR and reinforces the notion that SAR represents a distinct phase of plant immunity beyond local resistance. PMID- 24755513 TI - Interventions for attention problems after pediatric traumatic brain injury: what is the evidence? AB - OBJECTIVE: To gain an understanding of the current state of the evidence for management of attention problems after traumatic brain injury (TBI) in children, determine gaps in the literature, and make recommendations for future research. TYPE: Focused systematic review. LITERATURE SURVEY: PubMed/Medline and PsychINFO databases were searched for relevant articles published in English during the last 20 years. Keywords included "attention" "attention deficit and disruptive behavior disorders," and "brain injuries." Studies were limited to children. METHODOLOGY: Titles were examined first and eliminated based on lack of relevancy to attention problems after brain injury in children. This was followed by an abstract and full text review. Article quality was determined based on the US Preventative Services Task Force recommendations for evidence grading. SYNTHESIS: Four pharmacologic and 10 cognitive therapy intervention studies were identified. These studies varied in level of evidence quality but were primarily nonrandomized or cohort studies. CONCLUSIONS: There are studies that demonstrate benefits of varying pharmacologic and cognitive therapies for the management of attention problems after TBI. However, there is a paucity of evidence available to definitively guide management of attention problems after pediatric TBI. Larger randomized, controlled trials and multicenter studies are needed to elucidate optimal treatment strategies in this population. PMID- 24755514 TI - Trainee involvement in transforaminal epidural steroid injections associated with increased incidence of vasovagal reactions. AB - OBJECTIVES: To evaluate whether trainee involvement (resident and fellow) during transforaminal epidural steroid injections (TFESI) results in greater rates of vasovagal reactions. DESIGN: Retrospective study on consecutive patients. SETTING: Single academic medical center with multiple attending physicians and trainees. PARTICIPANTS: A total of 2642 consecutive subjects undergoing 4482 TFESI were analyzed from March 8, 2004, to January 30, 2009. MAIN OUTCOME MEASURES: The Pearson chi(2) test was used to determine the relationship between vasovagal reactions and level of trainee involvement. RESULTS: A total of 4482 TFESIs were performed, with 157 (3.5%) of procedures complicated by a vasovagal reaction. An attending physician performed 2884 (64.3%) procedures without trainee involvement, with only 79 (2.7%) vasovagal reaction noted. A fellow was involved in 723 (16.1%) procedures, with 30 (4.1%) noted to have a vasovagal reaction. A resident was involved in 875 (19.5%) procedures, with 48 (5.5%) having a vasovagal reaction. Overall, trainees were involved in 1598 (35.7%) cases, of which 78 (4.9%) were complicated by vasovagal reaction. When a trainee was involved in the case, there was a greater incidence of vasovagal episodes (P < .001, chi(2) = 16.047). Although there was a trend towards greater vasovagal rates with residents over fellows, this did not reach statistical difference. CONCLUSIONS: Vasovagal reactions can occur with spine injection procedures and may result in premature procedure termination or other adverse events. Although this retrospective study has significant potential for bias, it appears that trainee involvement in a TFESI is associated with a greater incidence of vasovagal reaction (P < .001, chi(2) = 16.047). PMID- 24755515 TI - Different modes of TiO2 uptake by Ceriodaphnia dubia: relevance to toxicity and bioaccumulation. AB - The extensive environmental exposure of engineered metal oxide nanoparticles (NPs) may result in their bioaccumulation in aquatic organisms leading to their biotransfer in a food chain through various routes in a freshwater ecosystem. The present study focuses on the possible modes of TiO2 NP trophic transfer to Ceriodaphnia dubia, in presence and/absence of its diet, Scenedesmus obliquus (primary producer). The acute exposure studies (48h) were designed to have daphnids exposed to (i) the free NPs, (ii) both the free and the algae-borne NPs; and (iii) only the algae-borne NPs in separate tests to understand the possible routes of NP transfer. The dietary uptake of TiO2 NPs (algae-borne) was found to be the primary route for NP biotransfer with ~70% of total NP uptake. Interestingly, in a separate study it was noticed that the NPs coated with algal exudates were easily taken up by daphnids as compared to pristine NPs of same concentrations, leading to their higher bioaccumulation. A chronic toxicity study, where daphnids were exposed to both free and algae-borne NPs for 21 days was undertaken to comprehend the TiO2 NP effect on daphnia growth and reproduction upon chronic exposure and also the bioaccumulation potential. Both acute and chronic exposure studies suggested higher bioaccumulation of TiO2 in daphnids when the particles were less toxic to the diet (algae). PMID- 24755517 TI - Applications of micro/nanoparticles in microfluidic sensors: a review. AB - This paper reviews the applications of micro/nanoparticles in microfluidics device fabrication and analytical processing. In general, researchers have focused on two properties of particles--electric behavior and magnetic behavior. The applications of micro/nanoparticles could be summarized on the chip fabrication level and on the processing level. In the fabrication of microfluidic chips (chip fabrication level), particles are good additives in polydimethylsiloxane (PDMS) to prepare conductive or magnetic composites which have wide applications in sensors, valves and actuators. On the other hand, particles could be manipulated according to their electric and magnetic properties under external electric and magnetic fields when they are travelling in microchannels (processing level). Researchers have made a great progress in preparing modified PDMS and investigating the behaviors of particles in microchannels. This article attempts to present a discussion on the basis of particles applications in microfluidics. PMID- 24755518 TI - Response of a new low-coherence Fabry-Perot sensor to hematocrit levels in human blood. AB - In this paper, a low-coherence Fabry-Perot sensor with a spectrally measured signal processing response to the refractive index of liquids is presented. Optical fiber sensors are potentially capable of continuous measuring hematocrit levels in blood. Low-coherence Fabry-Perot interferometric sensors offer a robust solution, where information about the measurand is encoded in the full spectrum of light reflected from the sensing interferometer. The first step in the research on such sensor is the assessment of its performance under favorable conditions, i.e., using blood samples from healthy volunteers tested in vitro. Such an experiment was conducted using a sensor comprising a superluminescent diode source, an optical spectrum analyzer working as the detection setup and a sensing Fabry-Perot interferometer providing high interference contrast. The response of this sensor was recorded for several samples and compared with the reference laboratory method. The coefficient of determination (R2) for a linear relationship between the results given by both methods was 0.978 and the difference between these results was less than 1%. The presented results suggest that further research into the performance of the sensor is merited. PMID- 24755519 TI - Applications of nuclear magnetic resonance sensors to cultural heritage. AB - In recent years nuclear magnetic resonance (NMR) sensors have been increasingly applied to investigate, characterize and monitor objects of cultural heritage interest. NMR is not confined to a few specific applications, but rather its use can be successfully extended to a wide number of different cultural heritage issues. A breakthrough has surely been the recent development of portable NMR sensors which can be applied in situ for non-destructive and non-invasive investigations. In this paper three studies illustrating the potential of NMR sensors in this field of research are reported. PMID- 24755520 TI - An internet of things example: classrooms access control over near field communication. AB - The Internet of Things is one of the ideas that has become increasingly relevant in recent years. It involves connecting things to the Internet in order to retrieve information from them at any time and from anywhere. In the Internet of Things, sensor networks that exchange information wirelessly via Wi-Fi, Bluetooth, Zigbee or RF are common. In this sense, our paper presents a way in which each classroom control is accessed through Near Field Communication (NFC) and the information is shared via radio frequency. These data are published on the Web and could easily be used for building applications from the data collected. As a result, our application collects information from the classroom to create a control classroom tool that displays access to and the status of all the classrooms graphically and also connects this data with social networks. PMID- 24755521 TI - Measurement of Cerenkov radiation induced by the gamma-rays of Co-60 therapy units using wavelength shifting fiber. AB - In this study, a wavelength shifting fiber that shifts ultra-violet and blue light to green light was employed as a sensor probe of a fiber-optic Cerenkov radiation sensor. In order to characterize Cerenkov radiation generated in the developed wavelength shifting fiber and a plastic optical fiber, spectra and intensities of Cerenkov radiation were measured with a spectrometer. The spectral peaks of light outputs from the wavelength shifting fiber and the plastic optical fiber were measured at wavelengths of 500 and 510 nm, respectively, and the intensity of transmitted light output of the wavelength shifting fiber was 22.2 times higher than that of the plastic optical fiber. Also, electron fluxes and total energy depositions of gamma-ray beams generated from a Co-60 therapy unit were calculated according to water depths using the Monte Carlo N-particle transport code. The relationship between the fluxes of electrons over the Cerenkov threshold energy and the energy depositions of gamma-ray beams from the Co-60 unit is a near-identity function. Finally, percentage depth doses for the gamma-ray beams were obtained using the fiber-optic Cerenkov radiation sensor, and the results were compared with those obtained by an ionization chamber. The average dose difference between the results of the fiber-optic Cerenkov radiation sensor and those of the ionization chamber was about 2.09%. PMID- 24755523 TI - Extracellular activation of Wnt signaling through epigenetic dysregulation of Wnt inhibitory factor-1 (Wif-1) is associated with pathogenesis of adrenocortical tumor. AB - Wnt/beta-catenin signaling is considered to be an essential regulator of adrenocortical oncogenesis. Wnt inhibitory factor-1 (Wif-1), an extracellular regulator of Wnt signaling, is frequently down-regulated by hypermethylation of the promoter CpG. We investigated epigenetic regulation of Wif-1 and its association with adrenocortical (AC) tumor pathogenesis in light of Wnt activation. The AC tumors showed a high prevalence of Wif-1 promoter methylation and low prevalence of Wif-1 mRNA transcription as compared to the normal adrenal (NA) samples. Furthermore, a significant correlation was found between Wif-1 promoter methylation and mRNA transcription in the tumors. Either intracellular beta-catenin accumulation or beta-catenin mRNA transcription was significantly elevated in the AC tumors, which also showed an inverse correlation with Wif-1 mRNA transcription. Cyclin D1, a target gene of Wnt signaling, was also up regulated in the AC tumors as compared with the NA samples. In addition, down regulation of Wif-1 was correlated with increased cyclin D1 at both mRNA and protein levels. However, despite the proposed activation of Wnt signaling in AC tumors, only 2 of 20 with intracellular beta-catenin accumulation showed beta catenin mutations. Thus, genetic alterations of beta-catenin and epigenetics related Wif-1 promoter hypermethylation may be important mechanisms underlying AC tumor formation though aberrant canonical Wnt/beta-catenin signaling activation. PMID- 24755524 TI - Design, synthesis and preliminary evaluation of alpha-sulfonyl gamma-(glycinyl amino)proline peptidomimetics as matrix metalloproteinase inhibitors. AB - A series of novel alpha-sulfonyl gamma-(glycinyl-amino)proline peptidomimetic derivatives were designed, synthesized and assayed for their activities against matrix metalloproteinase-2 (MMP-2), aminopeptidase N (APN)/CD13 and HDACs. The results indicated that all the compounds exhibited highly selective inhibition against MMP-2 as compared with APN and HDACs. The antiproliferative activities of some compounds against SKOV3, HL60 and A549 cells were also investigated. Comparing with the control LY52, compound 12u, with excellent activity both in the enzymatic inhibition assay and cell-based assay, could be used as lead compound for the further development of MMP inhibitors. PMID- 24755522 TI - DNA topology and transcription. AB - Chromatin is a complex assembly that compacts DNA inside the nucleus while providing the necessary level of accessibility to regulatory factors conscripted by cellular signaling systems. In this superstructure, DNA is the subject of mechanical forces applied by variety of molecular motors. Rather than being a rigid stick, DNA possesses dynamic structural variability that could be harnessed during critical steps of genome functioning. The strong relationship between DNA structure and key genomic processes necessitates the study of physical constrains acting on the double helix. Here we provide insight into the source, dynamics, and biology of DNA topological domains in the eukaryotic cells and summarize their possible involvement in gene transcription. We emphasize recent studies that might inspire and impact future experiments on the involvement of DNA topology in cellular functions. PMID- 24755525 TI - Identifying structural determinants of potency for analogs of apelin-13: integration of C-terminal truncation with structure-activity. AB - Apelin peptides function as endogenous ligands of the APJ receptor and have been implicated in a number of important biological processes. While several apelinergic peptides have been reported, apelin-13 (Glu-Arg-Pro-Arg-Leu-Ser-His Lys-Gly-Pro-Met-Pro-Phe) remains the most commonly studied and reported ligand of APJ. This study examines the effect of C-terminal peptide truncations and comprehensive structure-activity relationship (SAR) for a series of analogs based on apelin-13 in an attempt to develop more potent and stable analogs. C-terminal truncation studies identified apelin-13 (N-acetyl 2-11) amide (9) as a potent agonist (EC50=4.4 nM). Comprehensive SAR studies also determined that Arg-2, Leu 5, Lys-8, Met-11, were key positions for determining agonist potency, whereas the hydrophobic volume of Lys-8 was a specific determinate of activity. Plasma stability studies on the truncated 10-mer peptide 28 (EC50=33 nM) indicated the primary sites of cleavage occurred between Nle-3 and Leu-4 and also between Ala-5 and Ala-6. These new ligands represent the shortest known apelin peptides with good functional potency. PMID- 24755526 TI - A composite demineralized bone matrix--self assembling peptide scaffold for enhancing cell and growth factor activity in bone marrow. AB - The need for suitable bone grafts is high; however, there are limitations to all current graft sources, such as limited availability, the invasive harvest procedure, insufficient osteoinductive properties, poor biocompatibility, ethical problems, and degradation properties. The lack of osteoinductive properties is a common problem. As an allogenic bone graft, demineralized bone matrix (DBM) can overcome issues such as limited sources and comorbidities caused by invasive harvest; however, DBM is not sufficiently osteoinductive. Bone marrow has been known to magnify osteoinductive components for bone reconstruction because it contains osteogenic cells and factors. Mesenchymal stem cells (MSCs) derived from bone marrow are the gold standard for cell seeding in tissue-engineered biomaterials for bone repair, and these cells have demonstrated beneficial effects. However, the associated high cost and the complicated procedures limit the use of tissue-engineered bone constructs. To easily enrich more osteogenic cells and factors to DBM by selective cell retention technology, DBM is modified by a nanoscale self-assembling peptide (SAP) to form a composite DBM/SAP scaffold. By decreasing the pore size and increasing the charge interaction, DBM/SAP scaffolds possess a much higher enriching yield for osteogenic cells and factors compared with DBM alone scaffolds. At the same time, SAP can build a cellular microenvironment for cell adhesion, proliferation, and differentiation that promotes bone reconstruction. As a result, a suitable bone graft fabricated by DBM/SAP scaffolds and bone marrow represents a new strategy and product for bone transplantation in the clinic. PMID- 24755527 TI - A comparison of neuroinflammation to implanted microelectrodes in rat and mouse models. AB - Rat models have emerged as a common tool to study neuroinflammation to intracortical microelectrodes. While a number of studies have attempted to understand the factors resulting in neuroinflammation using rat models, a complete understanding of key mechanistic pathways remains elusive. Transgenic mouse models, however, could facilitate a deeper understanding of mechanistic pathways due to an ease of genetic alteration. Therefore, the goal of the present study is to compare neuroinflammation following microelectrode implantation between the rat and the mouse model. Our study suggests that subtle differences in the classic neuroinflammatory markers exist between the animal models at both two and sixteen weeks post implantation. Most notably, neuronal densities surrounding microelectrodes were significantly lower in the rat model at two weeks, while similar densities were observed between the animal models at sixteen weeks. Physiological differences between the species and slight alterations in surgical methods are likely key contributors to the observed differences. Moving forward, we propose that differences in the time course of neuroinflammation between the animal models should be considered when trying to understand and prevent intracortical microelectrode failure. PMID- 24755529 TI - Abstracts of the 11th Annual Conference of the Asian Australasian Federation of Interventional and Therapeutic Neuroradiology, March 26-28, 2014, Da Nang City, Vietnam. PMID- 24755528 TI - The influence of linker length on the properties of cathepsin S cleavable (177)Lu labeled HPMA copolymers for pancreatic cancer imaging. AB - N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymers have shown promise for application in the detection and staging of cancer. However, non-target accumulation, particularly in the liver and spleen, hinders the detection of resident or nearby metastatic lesions thereby decreasing diagnostic effectiveness. Our laboratory has pursued the development of cathepsin S susceptible linkers (CSLs) to reduce the non-target accumulation of diagnostic/radiotherapeutic HPMA copolymers. In this study, we ascertain if the length of the linking group impacts the cleavage and clearance kinetics, relative to each other and a non-cleavable control, due to a reduction in steric inhibition. Three different CSLs with linking groups of various lengths (0, 6 and 13 atoms) were conjugated to HPMA copolymers. In vitro cleavage studies revealed that the longest linking group (13 atoms) led to more rapid cleavage when challenged with cathepsin S. The CSL incorporated HPMA copolymers demonstrated significantly higher levels of excretion and a significant decrease in long-term hepatic and splenic retention relative to the non-cleavable control. Contrary to in vitro observations, the length of the linking group did not substantially impact the non-target in vivo clearance. In the case of HPAC tumor retention, the CSL with the null (0 atom) linker demonstrated significantly higher levels of retention relative to the other CSLs. Given these results, we find that the length of the linking group of the CSLs did not substantially impact non-target clearance, but did influence tumor retention. Overall, these results demonstrate that the CSLs can substantially improve the non-target clearance of HPMA copolymers thereby enhancing clinical potential. PMID- 24755530 TI - Optimal evidence in difficult settings: improving health interventions and decision making in disasters. AB - Martin Gerdin and colleagues argue that disaster health interventions and decision-making can benefit from an evidence-based approach Please see later in the article for the Editors' Summary. PMID- 24755531 TI - Factors predicting the capacity of Los Angeles city-region recreation programs to promote energy expenditure. AB - An audit of recreation programs with moderate or higher levels of physical activity (PA) in Los Angeles area cities (N=82) was conducted using internet, telephone, and survey methods. Metabolic Equivalents (METs) were used to code programs' physical activity intensity. MET-hours per recreation program was associated with required age for enrollment, percent of residents >64 years of age, and fiscal capacity of cities. Capacity to promote energy expenditure may depend on targeted age groups, age of population, and municipal fiscal capacity. Cities with lower fiscal capacity might offer those higher MET-hour activities which require less specialized equipment and seek outside funding to offer higher MET programs. PMID- 24755532 TI - Decreased DNA repair activity in bone marrow due to low expression of DNA damage repair proteins. AB - The bone marrow (BM) is one of the organs that is sensitive to acute exposure of ionizing radiation (IR); however, the mechanism of its high sensitivity to IR remains to be elucidated. BM is differentiated into dendritic cells (DC) with granulocyte macrophage-colony stimulating factor (GM-CSF). Using this in vitro model, we studied whether radiosensitivity is distinctly regulated in undifferentiated and differentiated BM. We discovered that levels of DNA damage repair (DDR) proteins are extremely low in BM, and they are markedly increased upon differentiation to DC. Efficiency of both homologous recombination (HR)- and non-homologous end joining (NHEJ)-mediated repair of DNA double strand breaks (DSBs) is much lower in BM compared with that of DC. Consistent with this, immunofluorescent gammaH2AX is highly detected in BM after IR. These results indicate that increased radiosensitivity of BM is at least due to low expression of the DNA repair machinery. PMID- 24755533 TI - Variability of target and normal structure delineation using multimodality imaging for radiation therapy of pancreatic cancer. AB - PURPOSE: To explore the potential of multimodality imaging (dynamic contrast enhanced magnetic resonance imaging [DCE-MRI], apparent diffusion-coefficient diffusion-weighted imaging [ADC-DWI], fluorodeoxyglucose positron emission tomography [FDG-PET], and computed tomography) to define the gross tumor volume (GTV) and organs at risk in radiation therapy planning for pancreatic cancer. Delineated volumetric changes of DCE-MRI, ADC-DWI, and FDG-PET were assessed in comparison with the finding on 3-dimensional/4-dimensional CT with and without intravenous contrast, and with pathology specimens for resectable and borderline resectable cases of pancreatic cancer. METHODS AND MATERIALS: We studied a total of 19 representative patients, whose DCE-MRI, ADC-DWI, and FDG-PET data were reviewed. Gross tumor volume and tumor burden/active region inside pancreatic head/neck or body were delineated on MRI (denoted GTVDCE, and GTVADC), a standardized uptake value (SUV) of 2.5, 40%SUVmax, and 50%SUVmax on FDG-PET (GTV2.5, GTV40%, and GTV50%). Volumes of the pancreas, duodenum, stomach, liver, and kidneys were contoured according to CT (VCT), T1-weighted MRI (VT1), and T2 weighted MRI (VT2) for 7 patients. RESULTS: Significant statistical differences were found between the GTVs from DCE-MRI, ADC-DW, and FDG-PET, with a mean and range of 4.73 (1.00-9.79), 14.52 (3.21-25.49), 22.04 (1.00-45.69), 19.10 (4.84 45.59), and 9.80 (0.32-35.21) cm(3) for GTVDCE, GTVADC, GTV2.5, GTV40%, and GTV50%, respectively. The mean difference and range in the measurements of maximum dimension of tumor on DCE-MRI, ADC-DW, SUV2.5, 40%SUVmax, and 50%SUVmax compared with pathologic specimens were -0.84 (-2.24 to 0.9), 0.41 (-0.15 to 2.3), 0.58 (-1.41 to 3.69), 0.66 (-0.67 to 1.32), and 0.15 (-1.53 to 2.38) cm, respectively. The T1- and T2-based volumes for pancreas, duodenum, stomach, and liver were generally smaller compared with those from CT, except for the kidneys. CONCLUSIONS: Differences exists between DCE-, ADC-, and FDG-PET-defined target volumes for RT of pancreatic cancer. Organ at risk volumes based on MRI are generally smaller than those based on CT. Further studies combined with pathologic specimens are required to identify the optimal imaging modality or sequence to define GTV. PMID- 24755534 TI - Is Biblioleaks inevitable? AB - In 2014, the vast majority of published biomedical research is still hidden behind paywalls rather than open access. For more than a decade, similar restrictions over other digitally available content have engendered illegal activity. Music file sharing became rampant in the late 1990s as communities formed around new ways to share. The frequency and scale of cyber-attacks against commercial and government interests has increased dramatically. Massive troves of classified government documents have become public through the actions of a few. Yet we have not seen significant growth in the illegal sharing of peer-reviewed academic articles. Should we truly expect that biomedical publishing is somehow at less risk than other content-generating industries? What of the larger threat- a "Biblioleaks" event--a database breach and public leak of the substantial archives of biomedical literature? As the expectation that all research should be available to everyone becomes the norm for a younger generation of researchers and the broader community, the motivations for such a leak are likely to grow. We explore the feasibility and consequences of a Biblioleaks event for researchers, journals, publishers, and the broader communities of doctors and the patients they serve. PMID- 24755535 TI - Comparison of strength, consistency, and speed of COR-KNOT versus manually hand tied knots in an ex vivo minimally invasive model. AB - OBJECTIVE: This study compared the strength, consistency, and speed of prosthetic attachment sutures secured with automated fasteners with those of manual knots using an ex vivo porcine mitral valve annuloplasty model. A novel miniature pressure transducer system was developed to quantify pressures between sutured prosthetic rings and underlying cardiac tissue. METHODS: Sixteen mitral annuloplasty rings were sewn into ex vivo pig hearts. Eight rings were secured with the COR-KNOT device; and eight rings, with hand-tied knots using a knot pusher. A cardiac surgeon and a surgery resident each completed four manually tied rings and four COR-KNOT rings via a thoracotomy trainer. The total time to knot and cut each ring's sutures was recorded. Suture attachment pressures were measured within (intrasuture) and between (extrasuture) each suture loop using a 0.5 * 2.0-mm microtransducer probe system. RESULTS: The suture holding pressures for the COR-KNOT fasteners were significantly greater than for the manually tied knots (median, 1008.9 vs 415.8 mm Hg, P < 0.001). All automated fasteners measured greater than 500 mm Hg, whereas 56% of the hand-tied knots were less than 500 mm Hg, and 14% were less than 75 mm Hg. There was less variation in attachment pressures for the COR-KNOT fasteners than for the hand-tied knots (SD, 401.6 vs 499.3 mm Hg, P = 0.04). Significant time savings occurred with the use of the COR-KNOT compared with manual tying (12.4 vs 71.1 seconds per knot, P = 0.001). CONCLUSIONS: The novel microtransducer technology provided an innovative means of evaluating cardiac prosthetic anchoring sutures. In this model, mitral annuloplasty ring sutures secured with the COR-KNOT device were stronger, more consistent, and faster than with manually tied knots. PMID- 24755536 TI - Innate immune responses after resection for lung cancer via video-assisted thoracoscopic surgery and thoracotomy. AB - OBJECTIVE: Innate immune responses to pulmonary resection may be critical in the pathogenesis of important postoperative pulmonary complications and potentially longer-term survival. We sought to compare innate immunity of patients undergoing major pulmonary resection for bronchogenic carcinoma via video-assisted thoracoscopic surgery (VATS) and thoracotomy. METHODS: Bronchoalveolar lavage was conducted in the contralateral lung before staging bronchoscopy and mediastinoscopy and immediately after lung resection. Blood and exhaled nitric oxide were sampled preoperatively and at 6, 24, and 48 hours postoperatively. RESULTS: Forty patients were included (26 VATS and 14 thoracotomy). There was a lower systemic cytokine response from lung resection undertaken by VATS compared with thoracotomy [interleukin 6 (IL-6), analysis of variance (ANOVA) P = 0.026; IL-8, ANOVA P = 0.018; and IL-10, ANOVA P = 0.047]. The VATS patients had higher perioperative serum albumin levels (ANOVA P = 0.001). Lower levels of IL-10 were produced by lipopolysaccharide-stimulated blood monocytes from the VATS patients compared with the thoracotomy patients at 6 hours postoperatively (geometric mean ratio, 1.16; 95% confidence interval, 1.08-1.33; P = 0.011). No statistically significant differences in the neutrophil phagocytic capacity, overall leukocyte count, or differential leukocyte count were found between the surgical groups (ANOVA P > 0.05). No statistically significant differences in bronchoalveolar lavage fluid parameters were found. Exhaled nitric oxide levels fell postoperatively, which reached statistical significance at 48 hours (geometric mean ratio, 1.2; 95% confidence interval, 1.02-1.46; P = 0.029). There were no significant differences found between the surgical groups (ANOVA P = 0.331). CONCLUSIONS: Overall, a trend toward greater proinflammatory and anti inflammatory responses is seen with lung resection performed via thoracotomy compared with VATS. PMID- 24755537 TI - Experience with thoracoscopic pneumonectomies at a single institution. AB - OBJECTIVE: The aim of this study was to review a single-institution experience with video-assisted thoracoscopic pneumonectomy (VATP). METHODS: From July 2008 through December 2012, the medical records of all patients undergoing pneumonectomy (total and completion) for lung cancer were reviewed. Clinical parameters were recorded and analyzed. RESULTS: During this period, 16% (7/45) of pneumonectomies for malignancy were performed thoracoscopically. Patient selection was performed in the context of a multidisciplinary tumor board. Of the seven VATPs, five were standard (Video 1, available at http://links.lww.com/INNOV/A40) and two were completion pneumonectomies (Video 2, available at http://links.lww.com/INNOV/A41). Indications were primary lung cancer in six (three adenocarcinoma, one squamous carcinoma, one large cell neuroendocrine carcinoma, and one mixed adenocarcinoma cell and small cell lung carcinoma) and metastatic esophageal cancer in one patient. Preoperative selection was based on unfavorable location of the primary tumor, which excluded the possibility of a lesser resection such as sleeve resection while permitting an R0 resection by pneumonectomy. Pathologic staging was consistent with clinical staging except for one patient who was upstaged. There were four complications: atrial fibrillation, pneumonia, and two bronchopleural fistulas. The median length of stay was 4 days (excluding one outlier). Distant disease recurrence occurred in one patient. Kaplan-Meier survival at 24 months was 75%. CONCLUSIONS: Introduction of VATP into the armamentarium of the experienced thoracoscopic surgeon is feasible with acceptable outcomes and a complication profile that is not dissimilar to the open pneumonectomy experience. Greater experience with this approach should provide additional data to more objectively evaluate the merits of this approach. PMID- 24755538 TI - Video-assisted thoracoscopic resection of recurrent intrapulmonary bronchogenic cyst after thoracotomy. AB - Intrapulmonary bronchogenic cysts are typically treated surgically by lobectomy to completely excise the cyst to minimize risk for recurrence. Video-assisted thoracoscopic surgery is being used with increasing frequency to manage intrathoracic pathology. We present a patient who underwent resection of a bronchogenic cyst 20 years before. She developed a symptomatic recurrence, and video-assisted thoracoscopic surgery was used to lyse adhesions from her previous posterolateral thoracotomy and perform an intraparenchymal dissection to resect the pathologic lesion while sparing the remaining parenchyma of her right upper lobe. At 2 years of follow-up, the patient is without evidence of recurrence. PMID- 24755539 TI - Use of pledgeted sutures in mitral annuloplasty. AB - Annuloplasty ring or band dehiscence is a possible complication of mitral valve repair surgery. It may be due to increased tension on the annuloplasty sutures, especially in ischemic mitral pathology in which a circumferential ring is used. Herein, we describe a technique for alternative suture placement in mitral annuloplasty using pledgeted sutures that may reduce the risk for ring or band dehiscence. PMID- 24755542 TI - Examination bar for overseas doctors must rise, researchers say. PMID- 24755540 TI - Reductive methylation and mutation of an anthrax toxin fusion protein modulates its stability and cytotoxicity. AB - We characterized an anti-cancer fusion protein consisting of anthrax lethal factor (LF) and the catalytic domain of Pseudomonas exotoxin A by (i) mutating the N-terminal amino acids and by (ii) reductive methylation to dimethylate all lysines. Dimethylation of lysines was achieved quantitatively and specifically without affecting binding of the fusion protein to PA or decreasing the enzymatic activity of the catalytic moiety. Ubiquitination in vitro was drastically decreased for both the N-terminally mutated and dimethylated variants, and both appeared to be slightly more stable in the cytosol of treated cells. The dimethylated variant showed greatly reduced neutralization by antibodies to LF. The two described modifications offer unique advantages such as increased cytotoxic activity and diminished antibody recognition, and thus may be applicable to other therapeutic proteins that act in the cytosol of cells. PMID- 24755543 TI - Will cetuximab-induced follicular rash get worse with moisturizers containing liquid paraffinum? PMID- 24755545 TI - Cancer incidence trends in India. AB - During the last 20 years, India has emerged as a fast growing economy with changes in lifestyle-related behavior partially responsible for the increasing cancer burden. While cancer incidence rates are lower than many western countries some changes over recent decades have emerged. This paper examines the time trends in cancer-specific incidence from six population-based cancer registries in India and review articles published on cancer trends in the country. The results are examined in light of their implications to cancer prevention and cancer control. PMID- 24755544 TI - Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma. AB - OBJECTIVE: Cholangiocarcinoma is a refractory cancer whose incidence has been increasing worldwide in recent years. Neoangiogenesis plays an important role in the growth of various solid cancers, including cholangiocarcinoma. Vascular endothelial growth factor plays an important role in tumor-induced angiogenesis and its expression is associated with the progression and prognosis of cholangiocarcinoma. This study examined whether axitinib (AG-013736, INLYTA((r))), a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3, could be a potentially useful therapeutic agent for cholangiocarcinoma. METHODS: We performed expression profiling of angiogenesis-related molecules in eight cholangiocarcinoma cell lines and found that three of them showed high vascular endothelial growth factor expression. Among them, we examined the in vivo anti-tumor effect of axitinib on NCC-BD1 (a gemcitabine-sensitive extra-hepatic cholangiocarcinoma cell line) and TKKK (a gemcitabine-resistant intra-hepatic cholangiocarcinoma cell line) using subcutaneous xenograft models. RESULTS: Oral administration of axitinib significantly inhibited the growth of TKKK xenografts at a dose of 6 mg kg(-1) day(-1) (P<0.05), and the growth of NCC-BD1 xenografts at 30 mg kg(-1)day(-1) (P<0.05). Treated tumors showed a significant decrease of microvessel density and the tumor cell proliferation index and a mild but significant increase of the apoptotic index in comparison with untreated tumors. CONCLUSIONS: Our results suggest that axitinib should be a promising therapy for vascular endothelial growth factor-expressing cholangiocarcinoma, irrespective of tumor origin and gemcitabine sensitivity. PMID- 24755546 TI - Clinical efficacy of alternating chemoradiotherapy by conformal radiotherapy combined with intracavitary brachytherapy for high-risk cervical cancer. AB - OBJECTIVE: The purpose of this study was to assess the outcome of alternating chemoradiotherapy in patients with high-risk cervical cancer. METHODS: We performed definitive alternating chemoradiotherapy in cervical cancer patients with at least one high-risk factor such as International Federation of Gynecology and Obstetrics III or IVA disease, primary tumor diameter >=50 mm, positive pelvic node, and positive para-aortic node. Our chemoradiotherapy protocol was as follows: (i) alternating chemoradiotherapy with 5-fluorouracil and nedaplatin; (ii) whole pelvic radiotherapy with the dynamic conformal technique combined with intracavitary brachytherapy; (iii) prophylactic irradiation to the para-aortic region for International Federation of Gynecology and Obstetrics III/IVA or positive pelvic node and full-dose radiotherapy for positive para-aortic node. Between 1998 and 2010, 121 patients were treated with this protocol. RESULTS: The median follow-up period was 53.7 months (7.6-162.2). International Federation of Gynecology and Obstetrics stages were IB; (9.1%), IIA; 6 (5.0%), IIB; 53 (43.8%), IIIA; 7 (5.8%), IIIB; 37 (30.6%) and IVA; 7 (5.8%), respectively. Nodal involvement was reported in 77 patients (63.6%) at the pelvis and 25 (20.7%) at the para-aortic region. The 5-year overall survival and progression-free survival rates were 80.0 and 63.4%, respectively. Regarding Grade >=3 late toxicities, three patients developed urinary and three developed intestinal toxicities. We encountered no treatment-related death. CONCLUSIONS: The clinical results of our alternating chemoradiotherapy protocol for high-risk cervical cancer are promising. PMID- 24755547 TI - The drug discovery by nanomedicine and its clinical experience. AB - It is expected that the incidence of various adverse effects of anticancer agents maybe decreased owing to the reduced drug distribution in normal tissue. Anticancer agent incorporating nanoparticles including micelles and liposomes can evade non-specific capture by the reticuloendothelial system because the outer shell of the nanoparticles is covered with polyethylene glycol. Consequently, the micellar and liposomal carrier can be delivered selectively to a tumor by utilizing the enhanced permeability and retention effect. Presently, several anticancer agent-incorporating nano-carrier systems are under preclinical and clinical evaluation. Several drug delivery system formulations have been approved worldwide. Regarding a pipeline of clinical development of anticancer agent incorporating micelle carrier system, several clinical trials are now underway not only in Japan but also in other countries. A Phase 3 trial of NK105, a paclitaxel incorporating micelle is now underway. In this paper, preclinical and clinical studies of NK105, NC-6004, cisplatin incorporating micelle, NC-6300, epirubicin incorporating micelle and the concept of cancer stromal targeting therapy using nanoparticles and monoclonal antibodies against cancer related stromal components are reviewed. PMID- 24755548 TI - Prevalence and clinicopathologic characteristics of the molecular subtypes in malignant glioma: a multi-institutional analysis of 941 cases. AB - BACKGROUND: Glioblastoma can be classified into four distinct molecular subtypes (Proneural, Neural, Classical and Mesenchymal), based on gene expression profiling. This study aimed to investigate the prevalence, clinicopathologic features and overall survival (OS) of the four molecular subtypes among all malignant gliomas. METHODS: A total of 941 gene expression arrays with clinical data were obtained from the Rembrandt, GSE16011 and CGGA datasets. Molecular subtypes were predicted with a prediction analysis of microarray. RESULTS: Among 941 malignant gliomas, 32.73% were Proneural, 15.09% Neural, 19.77% Classical and 32.41% Mesenchymal. The Proneural and Neural subtypes occurred largely in low grade gliomas, while the Classical and Mesenchymal subtypes were more frequent in high-grade gliomas. A survival analysis showed that the Proneural subtype displayed a good prognosis, Neural had an intermediate correlation with overall survival, Mesenchymal had a worse prognosis than Neural, and Classical had the worst clinical outcome. Furthermore, oligodendrocytomas were preferentially assigned to the Proneural subtype, while the Mesenchymal subtype included a higher percentage of astrocytomas, compared with oligodendrocytomas. Additionally, nearly all classical gliomas harbored EGFR amplifications. Classical anaplastic gliomas have similar clinical outcomes as their glioblastoma counterparts and should be treated more aggressively. CONCLUSIONS: Molecular subtypes exist stably in all histological malignant gliomas subtypes. This could be an important improvement to histological diagnoses for both prognosis evaluations and clinical outcome predictions. PMID- 24755549 TI - Estimating the sizes of populations at high risk for HIV: a comparison study. AB - OBJECTIVES: Behavioral interventions are effective strategies for HIV/AIDS prevention and control. However, implementation of such strategies relies heavily on the accurate estimation of the high-risk population size. The multiplier method and generalized network scale-up method were recommended to estimate the population size of those at high risk for HIV by UNAIDS/WHO in 2003 and 2010, respectively. This study aims to assess and compare the two methods for estimating the size of populations at high risk for HIV, and to provide practical guidelines and suggestions for implementing the two methods. METHODS: Studies of the multiplier method used to estimate the population prevalence of men who have sex with men in China published between July 1, 2003 and July 1, 2013 were reviewed. The generalized network scale-up method was applied to estimate the population prevalence of men who have sex with men in the urban district of Taiyuan, China. RESULTS: The median of studies using the multiplier method to estimate the population prevalence of men who have sex with men in China was 4-8 times lower than the national level estimate. Meanwhile, the estimate of the generalized network scale-up method fell within the range of national level estimate. CONCLUSIONS: When high-quality existing data are not readily available, the multiplier method frequently yields underestimated results. We thus suggest that the generalized network scale-up method is preferred when sampling frames for the general population and accurate demographic information are available. PMID- 24755551 TI - ARF sees Pdgfrbeta through the miR. PMID- 24755550 TI - Fetal growth and risk of stillbirth: a population-based case-control study. AB - BACKGROUND: Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. METHODS AND FINDINGS: We conducted a population based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non missing variables showed similar findings. CONCLUSIONS: Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary. PMID- 24755552 TI - The Ca2+ channel beta2 subunit is selectively targeted to the axon terminals of supraoptic neurons. AB - The assembly of high voltage-activated Ca(2+) channels with different beta subunits influences channel properties and possibly subcellular targeting. We studied beta subunit expression in the somata and axon terminals of the magnocellular neurosecretory cells, which are located in the supraoptic nucleus (SON) and neurohypophysis, respectively. Antibodies directed against the 4 Ca(V)beta subunits (Ca(V)beta(1)-Ca(V)beta(4)) were used for immunoblots and for immunostaining of slices of these two tissues. We found that all 4 beta subunits are expressed in both locations, but that Ca(V)beta(2) had the highest relative expression in the neurohypophysis. These data suggest that the Ca(V)beta(2) subunit is selectively targeted to axon terminals and may play a role in targeting and/or regulating the properties of Ca(2+) channels. PMID- 24755553 TI - Transcriptional changes in canine distemper virus-induced demyelinating leukoencephalitis favor a biphasic mode of demyelination. AB - Canine distemper virus (CDV)-induced demyelinating leukoencephalitis in dogs (Canis familiaris) is suggested to represent a naturally occurring translational model for subacute sclerosing panencephalitis and multiple sclerosis in humans. The aim of this study was a hypothesis-free microarray analysis of the transcriptional changes within cerebellar specimens of five cases of acute, six cases of subacute demyelinating, and three cases of chronic demyelinating and inflammatory CDV leukoencephalitis as compared to twelve non-infected control dogs. Frozen cerebellar specimens were used for analysis of histopathological changes including demyelination, transcriptional changes employing microarrays, and presence of CDV nucleoprotein RNA and protein using microarrays, RT-qPCR and immunohistochemistry. Microarray analysis revealed 780 differentially expressed probe sets. The dominating change was an up-regulation of genes related to the innate and the humoral immune response, and less distinct the cytotoxic T-cell mediated immune response in all subtypes of CDV leukoencephalitis as compared to controls. Multiple myelin genes including myelin basic protein and proteolipid protein displayed a selective down-regulation in subacute CDV leukoencephalitis, suggestive of an oligodendrocyte dystrophy. In contrast, a marked up-regulation of multiple immunoglobulin-like expressed sequence tags and the delta polypeptide of the CD3 antigen was observed in chronic CDV leukoencephalitis, in agreement with the hypothesis of an immune-mediated demyelination in the late inflammatory phase of the disease. Analysis of pathways intimately linked to demyelination as determined by morphometry employing correlation-based Gene Set Enrichment Analysis highlighted the pathomechanistic importance of up-regulated genes comprised by the gene ontology terms "viral replication" and "humoral immune response" as well as down-regulated genes functionally related to "metabolite and energy generation". PMID- 24755554 TI - The diverse roles of RNA polymerase II C-terminal domain phosphatase SCP1. AB - RNA polymerase II carboxyl-terminal domain (pol II CTD) phosphatases are a newly emerging family of phosphatases that are members of DXDX (T/V). The subfamily includes Small CTD phosphatases, like SCP1, SCP2, SCP3, TIMM50, HSPC129 and UBLCP. Extensive study of SCP1 has elicited the diversified roles of the small C terminal domain phosphatase. The SCP1 plays a vital role in various biological activities, like neuronal gene silencing and preferential Ser5 dephosphorylation, acts as a cardiac hypertrophy inducer with the help of its intronic miRNAs, and has shown a key role in cell cycle regulation. This short review offers an explanation of the mechanism of action of small CTD phosphatases, in different biological activities and metabolic processes. PMID- 24755555 TI - Upregulation of Fas in epithelial ovarian cancer reverses the development of resistance to cisplatin. AB - This study was to investigate the role of Fas in the development of Cisplatin resistant ovarian cancer. On the cellular level, Fas expression was significantly reduced in Cisplatin resistant A2780 (A2780/CP) cells compared with A2780 cells. Fas silence with siRNA would promote tumor cell lines proliferation, facilitate tumor cell cycle transition of G1/S, prevent cell apoptosis, and promote cell migration. Expression of drug resistance gene was negatively correlated to Fas. In nude mice metastasis model of human ovarian carcinoma by subcutaneous transplantation, after Ad-Fas injected intratumorly, we found that upregulation of Fas could inhibit transplantation tumor tissue growth and reduce the expression of drug resistance gene. Our results indicated that upregulation of Fas in epithelial ovarian cancer reversed the development of resistance to Cisplatin. In conclusion, our findings suggested that Fas might act as a promising therapeutic target for improvement of the sensibility to Cisplatin in ovarian cancer. PMID- 24755556 TI - The effect of intracellular trafficking of CD1d on the formation of TCR repertoire of NKT cells. AB - CD1 molecules belong to non-polymorphic MHC class I-like proteins and present lipid antigens to T cells. Five different CD1 genes (CD1a-e) have been identified and classified into two groups. Group 1 include CD1a-c and present pathogenic lipid antigens to alphabeta T cells reminiscence of peptide antigen presentation by MHC-I molecules. CD1d is the only member of Group 2 and presents foreign and self lipid antigens to a specialized subset of alphabeta T cells, NKT cells. NKT cells are involved in diverse immune responses through prompt and massive production of cytokines. CD1d-dependent NKT cells are categorized upon the usage of their T cell receptors. A major subtype of NKT cells (type I) is invariant NKT cells which utilize invariant Valpha14-Jalpha18 TCR alpha chain in mouse. The remaining NKT cells (type II) utilize diverse TCR alpha chains. Engineered CD1d molecules with modified intracellular trafficking produce either type I or type II NKT cell-defects suggesting the lipid antigens for each subtypes of NKT cells are processed/generated in different intracellular compartments. Since the usage of TCR by a T cell is the result of antigen-driven selection, the intracellular metabolic pathways of lipid antigen are a key in forming the functional NKT cell repertoire. PMID- 24755557 TI - Therapeutic implications of microRNAs in pulmonary arterial hypertension. AB - microRNAs (miRNAs) are a class of small, non-coding RNAs that play critical posttranscriptional regulatory roles typically through targeting of the 3' untranslated region of messenger RNA (mRNA). Mature miRNAs are known to be involved in global cellular processes, such as differentiation, proliferation, apoptosis, and organogenesis, due to their capacity to target multiple mRNAs. Thus, imbalances in the expression and/or activity of miRNAs are involved in the pathogenesis of numerous diseases, including pulmonary arterial hypertension (PAH). PAH is a progressive disease characterized by vascular remodeling due to excessive proliferation of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs). Recently, studies have evaluated the roles of miRNAs involved in the pathogenesis of PAH in these pulmonary vascular cells. This review provides an overview of recent discoveries on the role of miRNAs in the pathogenesis of PAH and discusses the potential for miRNAs as therapeutic targets and biomarkers of PAH. PMID- 24755558 TI - Noise properties in the ideal Kirchhoff-Law-Johnson-Noise secure communication system. AB - In this paper we determine the noise properties needed for unconditional security for the ideal Kirchhoff-Law-Johnson-Noise (KLJN) secure key distribution system using simple statistical analysis. It has already been shown using physical laws that resistors and Johnson-like noise sources provide unconditional security. However real implementations use artificial noise generators, therefore it is a question if other kind of noise sources and resistor values could be used as well. We answer this question and in the same time we provide a theoretical basis to analyze real systems as well. PMID- 24755559 TI - miR-200c regulates IL8 expression by targeting IKBKB: a potential mediator of inflammation in leiomyoma pathogenesis. AB - We have previously reported that leiomyoma expressed lower levels of miR-200c and elevated IL8 as compared to paired myometrium. Here we addressed the regulatory functions of miR-200c on the expression of inflammatory mediators and cellular viability using leiomyomas and paired myometrium and their isolated primary smooth muscle cells. Our results indicated that gain-of function or knockdown of miR-200c in leiomyoma smooth muscle cells (LSMC) regulated IL8 mRNA and protein expression through direct targeting of IKBKB and alteration of NF-kB activity. Additionally, leiomyoma expressed higher levels of phosphorylated IKBKB with no significant difference in the level of IKBKB mRNA and protein as compared to matched myometrium. Gain-of function of miR-200c in LSMC resulted in decreased IkBalpha phosphorylation and p65 nuclear translocation, which led to decreased p65 transcriptional activity of IL8 promoter, and increased caspase 3/7 activity which was not reversible following IL8 restoration. Collectively, our results suggest that NF-kappaB signaling pathway is a target of miR-200c regulatory function, and low level of miR-200c expression in leiomyoma by transcriptional regulation of inflammatory mediators such as IL8, in part account for development of leiomyomas. PMID- 24755560 TI - Human spotted fever group rickettsioses are underappreciated in southern Taiwan, particularly for the species closely-related to Rickettsia felis. AB - BACKGROUND: Despite increased identification of spotted fever group rickettsioses (SFGR) in animals and arthropods, human SFGR are poorly characterized in Taiwan. METHODS: Patients with suspected Q fever, scrub typhus, murine typhus, leptospirosis, and dengue fever from April 2004 to December 2009 were retrospectively investigated for SFGR antibodies (Abs). Sera were screened for Rickettsia rickettsii Abs by indirect immunofluorescence antibody assay (IFA), and those with positive results were further examined for Abs against R. rickettsii, R. typhi, R. felis, R. conorii, and R. japonica using micro immunofluorescence (MIF) tests. Polymerase chain reaction (PCR) for detection of SFGR DNA was applied in those indicated acute infections. Case geographic distribution was made by the geographic information system software. RESULTS: A total of 413 cases with paired serum, including 90 cases of Q fever, 47 cases of scrub typhus, 12 cases of murine typhus, 6 cases of leptospirosis, 3 cases of dengue fever, and 255 cases of unknown febrile diseases were investigated. Using IFA tests, a total of 49 cases with 47 (11.4%) and 4 (1.0%) cases had sera potentially positive for R. rickettsii IgG and IgM, respectively. In the 49 cases screened from IFA, MIF tests revealed that there were 5 cases of acute infections (3 possible R. felis and 2 undetermined SFGR) and 13 cases of past infections (3 possible R. felis and 10 undetermined SFGR). None of the 5 cases of acute infection had detectable SFGR DNA in the blood specimen by PCR. Possible acute infection of R. felis was identified in both one case of Q fever and scrub typhus. The geographic distribution of SFGR cases is similar with that of scrub typhus. CONCLUSIONS: Human SFGR exist and are neglected diseases in southern Taiwan, particularly for the species closely-related to R. felis. PMID- 24755561 TI - Expression of Gadd45alpha in human early placenta and its role in trophoblast invasion. AB - OBJECTIVES: Well-controlled trophoblast migration and invasion at the maternal foetal interface are crucial events for normal placentation and successful pregnancy. Growing evidence has revealed that growth arrest and DNA damage inducible 45 alpha (Gadd45alpha) participates in tumour migration and invasion as a tumour suppressor. However, the expression and function of Gadd45alpha in trophoblasts is unknown. This study aimed to determine the Gadd45alpha expression and function in the human first trimester placenta and identify the underlying mechanisms. METHODS: The expression of Gadd45alpha in human first trimester placenta was determined using immunohistochemistry. HTR8/SVneo cell line was used to investigate the effects of Gadd45alpha on proliferation, apoptosis, migration/invasion, matrix metalloproteinase (MMP)2/9 activities, and tissue inhibitor of metalloproteinase (TIMP)1/2 expression using cell proliferation assays, flow cytometric analysis, transwell migration/invasion assays, gelatin gel zymography, and western blotting, respectively. Moreover, a placental villous explant model was employed to verify its functions in placentation. RESULTS: Gadd45alpha was strongly expressed in syncytiotrophoblasts and trophoblast columns of human placental villi, extravillous trophoblast cells and glandular epithelium within the maternal decidua. Gadd45alpha knockdown significantly promoted migration and invasion of HTR8/SVneo cells, whereas it did not affect cell proliferation or apoptosis. Silencing Gadd45alpha also enhanced trophoblast outgrowth and migration in placental explants. These effects were related to increased activities of MMP2/9 and the decreased expression of TIMP1/2. DISCUSSION AND CONCLUSION: Gadd45alpha may be involved in human trophoblast migration and invasion and may function as an important negative regulator at the foetal-maternal interface during early pregnancy by directly or indirectly regulating MMP2/9 activities. PMID- 24755562 TI - miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression. AB - Non-small-cell lung cancer (NSCLC) is one of the most leading causes of cancer related deaths worldwide. Paclitaxel based combination therapies have long been used as a standard treatment in aggressive NSCLCs. But paclitaxel resistance has emerged as a major clinical problem in combating non-small-cell lung cancer and autophagy is one of the important mechanisms involved in this phenomenon. In this study, we used microRNA (miRNA) arrays to screen differentially expressed miRNAs between paclitaxel sensitive lung cancer cells A549 and its paclitaxel-resistant cell variant (A549-T24). We identified miR-17-5p was one of most significantly downregulated miRNAs in paclitaxel-resistant lung cancer cells compared to paclitaxel sensitive parental cells. We found that overexpression of miR-17-5p sensitized paclitaxel resistant lung cancer cells to paclitaxel induced apoptotic cell death. Moreover, in this report we demonstrated that miR-17-5p directly binds to the 3'-UTR of beclin 1 gene, one of the most important autophagy modulator. Overexpression of miR-17-5p into paclitaxel resistant lung cancer cells reduced beclin1 expression and a concordant decease in cellular autophagy. We also observed similar results in another paclitaxel resistant lung adenosquamous carcinoma cells (H596-TxR). Our results indicated that paclitaxel resistance of lung cancer is associated with downregulation of miR-17-5p expression which might cause upregulation of BECN1 expression. PMID- 24755563 TI - High-level systemic expression of conserved influenza epitope in plants on the surface of rod-shaped chimeric particles. AB - Recombinant viruses based on the cDNA copy of the tobacco mosaic virus (TMV) genome carrying different versions of the conserved M2e epitope from influenza virus A cloned into the coat protein (CP) gene were obtained and partially characterized by our group previously; cysteines in the human consensus M2e sequence were changed to serine residues. This work intends to show some biological properties of these viruses following plant infections. Agroinfiltration experiments on Nicotiana benthamiana confirmed the efficient systemic expression of M2e peptides, and two point amino acid substitutions in recombinant CPs significantly influenced the symptoms and development of viral infections. Joint expression of RNA interference suppressor protein p19 from tomato bushy stunt virus (TBSV) did not affect the accumulation of CP-M2e-ser recombinant protein in non-inoculated leaves. RT-PCR analysis of RNA isolated from either infected leaves or purified TMV-M2e particles proved the genetic stability of TMV-based viral vectors. Immunoelectron microscopy of crude plant extracts demonstrated that foreign epitopes are located on the surface of chimeric virions. The rod-shaped geometry of plant-produced M2e epitopes is different from the icosahedral or helical filamentous arrangement of M2e antigens on the carrier virus-like particles (VLP) described earlier. Thereby, we created a simple and efficient system that employs agrobacteria and plant viral vectors in order to produce a candidate broad-spectrum flu vaccine. PMID- 24755565 TI - Glyphosate: its effects on humans. PMID- 24755566 TI - A randomized, controlled trial of acupuncture for chronic low-back pain. AB - BACKGROUND: Chronic low-back pain (cLBP) is a common condition throughout the world, and acupuncture is widely sought for treatment. As clinical evidence for the benefits of acupuncture grows, acupuncture for cLBP is receiving increased recognition and acceptance by both patients and professionals. Time method acupuncture has been previously researched with respect to chronic gastritis. OBJECTIVE: For individuals with cLBP in the current study, the research team examined the efficacy of adding confluent acupoints, related to the daytime period in time method acupuncture, to regular acupuncture and also evaluated the persistence of the benefits of such acupuncture in comparison with regular acupuncture. DESIGN: The study was a randomized, controlled trial (RCT). SETTING: The setting was an outpatient clinic of the Dongzhimen Hospital in Beijing, China. PARTICIPANTS: Participants were Chinese men and women with cLBP. INTERVENTION: Sixty participants were randomly divided into 2 groups to receive acupuncture. The control group received a treatment that followed a routine acupuncture (RA) protocol, while the intervention group received a treatment that followed an RA protocol plus acupuncture in confluent points related to time (TA). OUTCOME MEASURES: The research team measured the change in participants' scores using the visual analogue scale (VAS), the number of therapy sessions needed, the number of days that participants were absent from work during the treatment period and at 12 wk posttreatment, and the number of pain relapses between the end of treatment and the 4- and 12-wk follow-ups. RESULTS: VAS scores decreased from 69.6 +/- 7.9 to 11.8 +/- 4.9 in the intervention group compared with a decrease from 69.2 +/- 8.0 to 15.7 +/- 10.0 in the control group (P = .001). The intervention group received fewer therapy sessions (8.1 +/- 2.0) than did the control group (10.1 +/- 2.0, P < .001). Compared with the controls, the intervention group showed fewer days absent from work (0.5 vs 1.4; P = .03) and fewer pain relapses (4.0 vs 7.0; P = .04) at the 12-wk follow-up. In the 2 groups combined, VAS decreased from 69.4 +/- 7.9 before the first session of acupuncture to 13.8 +/- 8.0 after the last session (P < .001), and the number of therapy sessions needed for pain relief was 9.1 +/- 2.2. CONCLUSION: Accompanying routine acupuncture with time method acupuncture can enhance the efficacy of treatment and the persistence of its benefits in individuals with cLBP. PMID- 24755564 TI - Hantavirus Gn and Gc envelope glycoproteins: key structural units for virus cell entry and virus assembly. AB - In recent years, ultrastructural studies of viral surface spikes from three different genera within the Bunyaviridae family have revealed a remarkable diversity in their spike organization. Despite this structural heterogeneity, in every case the spikes seem to be composed of heterodimers formed by Gn and Gc envelope glycoproteins. In this review, current knowledge of the Gn and Gc structures and their functions in virus cell entry and exit is summarized. During virus cell entry, the role of Gn and Gc in receptor binding has not yet been determined. Nevertheless, biochemical studies suggest that the subsequent virus membrane fusion activity is accomplished by Gc. Further, a class II fusion protein conformation has been predicted for Gc of hantaviruses, and novel crystallographic data confirmed such a fold for the Rift Valley fever virus (RVFV) Gc protein. During virus cell exit, the assembly of different viral components seems to be established by interaction of Gn and Gc cytoplasmic tails (CT) with internal viral ribonucleocapsids. Moreover, recent findings show that hantavirus glycoproteins accomplish important roles during virus budding since they self-assemble into virus-like particles. Collectively, these novel insights provide essential information for gaining a more detailed understanding of Gn and Gc functions in the early and late steps of the hantavirus infection cycle. PMID- 24755567 TI - Comparison of functional fitness outcomes in experienced and inexperienced older adults after 16-week tai chi program. AB - CONTEXT: The positive effects of physical activity on the well-being of older adults have been well documented. Tai chi is a suitable form of physical activity, with known physical and psychological benefits for older adults. OBJECTIVE: The objective of the current study was to compare the effects of participation in a 16-wk tai chi program on the functional fitness of older adults with and without previous tai chi experience. DESIGN: The research team designed a prospective cohort study. Participants who had practiced tai chi previously for >=1 y at baseline were classified as experienced; all others were considered inexperienced. SETTING: The study took place at 2 community centers in 2 locations in the Greater Toronto area of Ontario, Canada. PARTICIPANTS: Participants were residents of the 2 communities. INTERVENTION: Participants were instructed to attend two 1-h sessions of Yang-style tai chi per wk. OUTCOME MEASURES: Data on functional fitness- strength, endurance, speed, and flexibility were collected at baseline and after completion of the tai chi program. RESULTS: Of the 143 participants who completed the study, 20.5% were classified as experienced. Experienced participants had significantly higher ratings on functional fitness tests at baseline compared with the inexperienced group. At the end of the study, inexperienced participants had experienced significant improvements in all measures of functional fitness, although experienced participants had shown significant improvements only in measures of endurance and speed. CONCLUSION: Tai chi appears to be an optimal mode of physical activity for older adults regardless of previous experience with tai chi. PMID- 24755568 TI - Effect of palladium alpha-lipoic acid complex on energy in the brain mitochondria of aged rats. AB - CONTEXT: According to the mitochondrial mutation theory of aging, the impairment of mitochondrial functions and decline of cellular bioenergetics are induced by highly reactive oxygen species (ROS). Supplementation with antioxidants may protect mitochondria against respiration-linked oxidative stress and reduce decay by preserving genomic and structural integrity. Several clinical studies have reported beneficial effects of alpha-lipoic acid (LA) administration in individuals with Alzheimer's disease, particularly improving their spatial orientation; however, no studies have been reported on the effects of palladium alpha-lipoic acid (Pd-LA). OBJECTIVE: The current study examined the effects of the Pd-LA complex on mitochondrial energy status in the brains of aged rats. DESIGN: The study used male Wistar rats, some that were older than 24 mo and weighed approximately 350 +/- 50 g and some that were younger than 24 mo and weighed approximately 175 +/- 25 g. The research team divided the rats into 5 groups of 6 rats. SETTING: The study was conducted at the Amala Cancer Research Centre in Amala Nagar, Thrissur, Kerala, India. INTERVENTION: Three groups of rats were controls: (1) young controls administered no solution, (2) aged controls administered 1 mL/kg of a 0.25% solution (PO) of sodium hydroxide (NaOH), and (3) positive aged controls treated with LA (7.6 mg/kg, PO) dissolved in an alkaline saline (0.25% NaOH, w/v). Two groups were intervention groups: (1) aged rats treated with 1.2 mg/kg of Pd-LA (PO) and (2) aged rats treated with 23.5 mg/kg of Pd-LA (PO). The research team administered the solutions once daily for 30 d. After 30 d, all animals were sacrificed. OUTCOME MEASURES: The research team evaluated serum transaminases, lactate dehydrogenase (LDH), serum urea, and creatinine. The activities of superoxide dismutase (SOD), catalase (CAT), and the levels of reduced glutathione (GSH) were determined in the blood samples. Krebs cycle dehydrogenases were evaluated in the brain mitochondria. Furthermore, the activities of the respiratory chain complexes I, III and IV as well as adenosine triphosphate (ATP) levels were estimated in the mitochondrial fraction. RESULTS: The study found that Pd-LA elevated the mitochondrial ATP levels in the brains of aged rats by enhancing the activity of not only the Krebs cycle dehydrogenases but also complexes I and IV. Furthermore, Pd-LA improved the body weight and blood antioxidant status of aged rats without affecting the functions of liver or renal cells. CONCLUSIONS: The results of the current study demonstrate that Pd-LA improves mitochondrial energy status in the brains of aged rats. The effects can be attributed to the enhancing effect on the Krebs cycle dehydrogenase and the activities of complexes I, III, and IV. The results further support the possible use of Pd-LA as an adjuvant treatment, together with the standard cholinesterase inhibitors, in individuals with mild or moderate dementia caused by Alzheimer's disease (AD). PMID- 24755570 TI - The pharmacodynamics of L-arginine. AB - L-Arginine is a precursor for nitric oxide (NO) synthesis. NO is a ubiquitous mediator that is formed by a family of enzymes called NO synthases (NOSs). In the brain, NO acts as a neurotransmitter; in the immune system, it acts as a mediator of host defense; and in the cardiovascular system, it mediates the protective effects of the intact endothelium, acting as a vasodilator and endogenous, antiatherogenic molecule. About 5 g of L-arginine are ingested each day in a normal Western diet. Plasma levels of L-arginine are not significantly reduced in most diseases, except in end-stage renal failure during hemodialysis treatment. Nonetheless, intravenous or dietary (oral) administration of relatively large doses of L-arginine has been shown to result in enhanced NO formation in individuals with impaired endothelial function at baseline. In several controlled clinical trials, long-term administration of L-arginine has been shown to improve the symptoms of cardiovascular disease. However, in other trials, L-arginine was not beneficial, and in a recent study, the authors reported higher mortality for participants receiving L-arginine than for those receiving placebo. Recently, it became clear that endogenous levels of asymmetric dimethylarginine (ADMA), a competitive inhibitor of L-Arginine metabolism by NOS, may determine an individual's response to L-arginine supplementation. L-Arginine appears to exert no effect in individuals with low ADMA levels, whereas in those with high levels, L-arginine restores the L-arginine/ADMA ratio to normal and, thereby, normalizes endothelial function. In conclusion, the effects of L-arginine supplementation on human physiology appear to be multicausal and dose-related. Doses of 3-8 g/d appear to be safe and not to cause acute pharmacologic effects in humans. PMID- 24755569 TI - Yoga for improving sleep quality and quality of life for older adults. AB - CONTEXT: The aging process is associated with physiological changes that affect sleep. In older adults, undiagnosed and untreated insomnia may cause impaired daily function and reduced quality of life (QoL). Insomnia is also a risk factor for accidents and falls that are the main cause of accidental deaths in older adults and, therefore, is associated with higher morbidity and mortality rates in older populations. OBJECTIVES: The research team aimed to (1) examine the efficacy of a yoga intervention (YI) for the treatment of insomnia in older adults, (2) determine the ability of yoga to enhance the QoL of older adults, and (3) establish the applicability of yoga practice for older people in a Western cultural setting. DESIGN: A waiting-list controlled trial. Settings * The study took place in Jerusalem, Israel, from 2008-2009. PARTICIPANTS: Participants were older men and women (age >= 60 y) with insomnia. INTERVENTION: The YI group participated in 12 wk of classes, held 2 */wk, incorporating yoga postures, meditative yoga, and daily home practice of meditative yoga. OUTCOME MEASURES: The study used self-report assessments of sleep quality using the following: (1) sleep quality-the Karolinska Sleepiness Scale (KSS), the Epworth Sleepiness Scale (ESS), and the Pittsburgh Sleep Quality Index (PSQI), and daily sleep and practice logs; (2) mood states-the Depression Anxiety Stress Scale long form (DASS-42) and the Profile of Mood States short form (POMS-SF); (3) a health survey (SF-36); and (4) mobile at-home sleep studies. RESULTS: Compared with controls, the YI group showed significant improvements in a range of subjective factors, including overall sleep quality; sleep efficiency; sleep latency and duration; self-assessed sleep quality; fatigue; general well-being; depression; anxiety; stress; tension; anger; vitality; and function in physical, emotional, and social roles. CONCLUSIONS: Yoga was shown to be safe and improved sleep and QoL in a group of older adults with insomnia. Outcomes depended on practice compliance. PMID- 24755571 TI - L. Terry Chappell, MD: considering the past and promise of chelation therapy. PMID- 24755573 TI - Chance performance and floor effects: threats to the validity of the Wechsler Memory Scale--fourth edition designs subtest. AB - The Designs subtest allows for accumulation of raw score points by chance alone, creating the potential for artificially inflated performances, especially in older patients. A random number generator was used to simulate the random selection and placement of cards by 100 test naive participants, resulting in a mean raw score of 36.26 (SD = 3.86). This resulted in relatively high-scaled scores in the 45-54, 55-64, and 65-69 age groups on Designs II. In the latter age group, in particular, the mean simulated performance resulted in a scaled score of 7, with scores 1 SD below and above the performance mean translating to scaled scores of 5 and 8, respectively. The findings indicate that clinicians should use caution when interpreting Designs II performance in these age groups, as our simulations demonstrated that low average to average range scores occur frequently when patients are relying solely on chance performance. PMID- 24755572 TI - The root hair assay facilitates the use of genetic and pharmacological tools in order to dissect multiple signalling pathways that lead to programmed cell death. AB - The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of PCD. PMID- 24755574 TI - Estimating seasonal nitrogen removal and biomass yield by annuals with the extended logistic model. AB - The Extended Logistic Model (ELM) has been previously shown to adequately describe seasonal biomass production and N removal with respect to applied N for several types of annuals and perennials. In this analysis, data from a corn (Zea mays L.) study with variable applied N were analyzed to test hypotheses that certain parameters in the ELM are invariant with respect to site specific attributes, like environmental conditions and soil type. Invariance to environmental conditions suggests such parameters may be functions of the crop characteristics and certain other management practices alone (like plant population, planting date, harvest date). The first parameter analyzed was Deltab, the difference between the N uptake shifting parameter and the biomass shifting parameter. The second parameter tested was N(cm), the maximum N concentration. Both parameters were shown to be statistically invariant, despite soil and site differences. This was determined using analysis of variance with normalized nonlinear regression of the ELM on the data from the study. This analysis lends further evidence that there are common parameters involved in the ELM that do not rely on site-specific or situation-specific factors. More insight into the derivation of, definition of, and logic behind the various parameters involved in the model are also given in this paper. PMID- 24755575 TI - Alterations of high endothelial venules in primary and metastatic tumors are correlated with lymph node metastasis of oral and pharyngeal carcinoma. PMID- 24755576 TI - E-cigarette companies target youth, US congressional study finds. PMID- 24755577 TI - The living lab. PMID- 24755583 TI - Proton-coupled electron transfer: Free radicals under control. PMID- 24755584 TI - Protein folding: When ribosomes pick the structure. PMID- 24755585 TI - Synthetic biology: Two-for-one designer labels. PMID- 24755586 TI - Polymer mechanochemistry: Flex, release and repeat. PMID- 24755587 TI - Cycloparaphenylenes: Closing the loop. PMID- 24755588 TI - Solar energy: Packing heat. PMID- 24755589 TI - Unusual structure, bonding and properties in a californium borate. AB - The participation of the valence orbitals of actinides in bonding has been debated for decades. Recent experimental and computational investigations demonstrated the involvement of 6p, 6d and/or 5f orbitals in bonding. However, structural and spectroscopic data, as well as theory, indicate a decrease in covalency across the actinide series, and the evidence points to highly ionic, lanthanide-like bonding for late actinides. Here we show that chemical differentiation between californium and lanthanides can be achieved by using ligands that are both highly polarizable and substantially rearrange on complexation. A ligand that suits both of these desired properties is polyborate. We demonstrate that the 5f, 6d and 7p orbitals are all involved in bonding in a Cf(III) borate, and that large crystal-field effects are present. Synthetic, structural and spectroscopic data are complemented by quantum mechanical calculations to support these observations. PMID- 24755590 TI - Optimized orthogonal translation of unnatural amino acids enables spontaneous protein double-labelling and FRET. AB - The ability to introduce different biophysical probes into defined positions in target proteins will provide powerful approaches for interrogating protein structure, function and dynamics. However, methods for site-specifically incorporating multiple distinct unnatural amino acids are hampered by their low efficiency. Here we provide a general solution to this challenge by developing an optimized orthogonal translation system that uses amber and evolved quadruplet decoding transfer RNAs to encode numerous pairs of distinct unnatural amino acids into a single protein expressed in Escherichia coli with a substantial increase in efficiency over previous methods. We also provide a general strategy for labelling pairs of encoded unnatural amino acids with different probes via rapid and spontaneous reactions under physiological conditions. We demonstrate the utility of our approach by genetically directing the labelling of several pairs of sites in calmodulin with fluorophores and probing protein structure and dynamics by Forster resonance energy transfer. PMID- 24755591 TI - Efficient room-temperature synthesis of a highly strained carbon nanohoop fragment of buckminsterfullerene. AB - Warped carbon-rich molecules have captured the imagination of scientists across many disciplines. Owing to their promising materials properties and challenging synthesis, strained hydrocarbons are attractive targets that push the limits of synthetic methods and molecular design. Herein we report the synthesis and characterization of [5]cycloparaphenylene ([5]CPP), a carbon nanohoop that can be envisaged as an open tubular fragment of C60, the equator of C70 fullerene and the unit cycle of a [5,5] armchair carbon nanotube. Given its calculated 119 kcal mol(-1) strain energy and severely distorted benzene rings, this synthesis, which employs a room-temperature macrocyclization of a diboronate precursor, single electron reduction and elimination, is remarkably mild and high yielding (27% over three steps). Single-crystal X-ray diffraction data were obtained to confirm its geometry and previously disputed benzenoid character. First and second pseudoreversible oxidation and reduction events were observed via cyclic voltammetry. The ease of synthesis, high solubility and narrowest optical HOMO/LUMO gap of any para-polyphenylene synthesized make [5]CPP a desirable new material for organic electronics. PMID- 24755592 TI - Ultra stable self-assembled monolayers of N-heterocyclic carbenes on gold. AB - Since the first report of thiol-based self-assembled monolayers (SAMs) 30 years ago, these structures have been examined in a huge variety of applications. The oxidative and thermal instabilities of these systems are widely known, however, and are an impediment to their widespread commercial use. Here, we describe the generation of N-heterocyclic carbene (NHC)-based SAMs on gold that demonstrate considerably greater resistance to heat and chemical reagents than the thiol based counterparts. This increased stability is related to the increased strength of the gold-carbon bond relative to that of a gold-sulfur bond, and to a different mode of bonding in the case of the carbene ligand. Once bound to gold, NHCs are not displaced by thiols or thioethers, and are stable to high temperatures, boiling water, organic solvents, pH extremes, electrochemical cycling above 0 V and 1% hydrogen peroxide. In particular, benzimidazole-derived carbenes provide films with the highest stabilities and evidence of short-range molecular ordering. Chemical derivatization can be employed to adjust the surface properties of NHC-based SAMs. PMID- 24755593 TI - Self-powered enzyme micropumps. AB - Non-mechanical nano- and microscale pumps that function without the aid of an external power source and provide precise control over the flow rate in response to specific signals are needed for the development of new autonomous nano- and microscale systems. Here we show that surface-immobilized enzymes that are independent of adenosine triphosphate function as self-powered micropumps in the presence of their respective substrates. In the four cases studied (catalase, lipase, urease and glucose oxidase), the flow is driven by a gradient in fluid density generated by the enzymatic reaction. The pumping velocity increases with increasing substrate concentration and reaction rate. These rechargeable pumps can be triggered by the presence of specific analytes, which enables the design of enzyme-based devices that act both as sensor and pump. Finally, we show proof of-concept enzyme-powered devices that autonomously deliver small molecules and proteins in response to specific chemical stimuli, including the release of insulin in response to glucose. PMID- 24755594 TI - A bioinspired redox relay that mimics radical interactions of the Tyr-His pairs of photosystem II. AB - In water-oxidizing photosynthetic organisms, light absorption generates a powerfully oxidizing chlorophyll complex (P680(*+)) in the photosystem II reaction centre. This is reduced via an electron transfer pathway from the manganese-containing water-oxidizing catalyst, which includes an electron transfer relay comprising a tyrosine (Tyr)-histidine (His) pair that features a hydrogen bond between a phenol group and an imidazole group. By rapidly reducing P680(*+), the relay is thought to mitigate recombination reactions, thereby ensuring a high quantum yield of water oxidation. Here, we show that an artificial reaction centre that features a benzimidazole-phenol model of the Tyr His pair mimics both the short-internal hydrogen bond in photosystem II and, using electron paramagnetic resonance spectroscopy, the thermal relaxation that accompanies proton-coupled electron transfer. Although this artificial system is much less complex than the natural one, theory suggests that it captures the essential features that are important in the function of the relay. PMID- 24755595 TI - Switchable enantioseparation based on macromolecular memory of a helical polyacetylene in the solid state. AB - In the chromatographic separation of enantiomers the order of elution is determined by the strength of diasteromeric interactions between the components of the mixture and a chiral stationary phase. For analytical purposes, it is ideal to have the minor component elute first, whereas in the preparative mode a faster elution of the major component is desirable. Here we describe a stationary phase constructed from a polyacetylene that bears 2,2'-bisphenol-derived side chains in which chirality can be switched in the solid state prior to use. Both the macromolecular helicity of the polymer backbone and the axial chirality of the side chains can be switched in the solid state by interaction with a chiral alcohol, but importantly are maintained after removal of the chiral alcohol because of a memory effect. The chiral stationary phase thus prepared was used to separate the enantiomers of trans-stilbene oxide with the enantiomer elution order determined by the preseparation treatment. PMID- 24755596 TI - Quantitative sequencing of 5-formylcytosine in DNA at single-base resolution. AB - Recently, the cytosine modifications 5-hydroxymethylcytosine (5hmC) and 5 formylcytosine (5fC) were found to exist in the genomic deoxyribonucleic acid (DNA) of a wide range of mammalian cell types. It is now important to understand their role in normal biological function and disease. Here we introduce reduced bisulfite sequencing (redBS-Seq), a quantitative method to decode 5fC in DNA at single-base resolution, based on a selective chemical reduction of 5fC to 5hmC followed by bisulfite treatment. After extensive validation on synthetic and genomic DNA, we combined redBS-Seq and oxidative bisulfite sequencing (oxBS-Seq) to generate the first combined genomic map of 5-methylcytosine, 5hmC and 5fC in mouse embryonic stem cells. Our experiments revealed that in certain genomic locations 5fC is present at comparable levels to 5hmC and 5mC. The combination of these chemical methods can quantify and precisely map these three cytosine derivatives in the genome and will help provide insights into their function. PMID- 24755597 TI - Templated assembly of photoswitches significantly increases the energy-storage capacity of solar thermal fuels. AB - Large-scale utilization of solar-energy resources will require considerable advances in energy-storage technologies to meet ever-increasing global energy demands. Other than liquid fuels, existing energy-storage materials do not provide the requisite combination of high energy density, high stability, easy handling, transportability and low cost. New hybrid solar thermal fuels, composed of photoswitchable molecules on rigid, low-mass nanostructures, transcend the physical limitations of molecular solar thermal fuels by introducing local sterically constrained environments in which interactions between chromophores can be tuned. We demonstrate this principle of a hybrid solar thermal fuel using azobenzene-functionalized carbon nanotubes. We show that, on composite bundling, the amount of energy stored per azobenzene more than doubles from 58 to 120 kJ mol(-1), and the material also maintains robust cyclability and stability. Our results demonstrate that solar thermal fuels composed of molecule-nanostructure hybrids can exhibit significantly enhanced energy-storage capabilities through the generation of template-enforced steric strain. PMID- 24755598 TI - Structural complexity through multicomponent cycloaddition cascades enabled by dual-purpose, reactivity regenerating 1,2,3-triene equivalents. AB - Multicomponent reactions allow for more bond-forming events per synthetic operation, enabling more step- and time-economical conversion of simple starting materials to complex and thus value-added targets. These processes invariably require that reactivity be relayed from intermediate to intermediate over several mechanistic steps until a termination event produces the final product. Here, we report a multicomponent process in which a novel 1,2,3-butatriene equivalent (TMSBO: TMSCH2C=CCH2OH) engages chemospecifically as a two-carbon alkyne component in a metal-catalysed [5 + 2] cycloaddition with a vinylcyclopropane to produce an intermediate cycloadduct. Under the reaction conditions, this intermediate undergoes a remarkably rapid 1,4-Peterson elimination, producing a reactive four-carbon diene intermediate that is readily intercepted in either a metal-catalysed or thermal [4 + 2] cycloaddition. TMSBO thus serves as an yne-to diene transmissive reagent coupling two powerful and convergent cycloadditions- the homologous Diels-Alder and Diels-Alder cycloadditions--through a vinylogous Peterson elimination, and enabling flexible access to diverse polycycles. PMID- 24755602 TI - Poisonous polonium. PMID- 24755603 TI - National profile and treatment outcomes of patients with extrapulmonary tuberculosis in Benin. AB - BACKGROUND: In sub-Saharan Africa, there is a dearth of published literature on extrapulmonary tuberculosis (EPTB). OBJECTIVE: To describe demographic, diagnostic and HIV-status characteristics of patients with EPTB in Benin, their treatment outcomes, and among those who completed their treatment in the Centre National Hospitalier de Pneumo-Phtisiologie (CNHP-P), the proportion whose bodyweight increased during treatment. MATERIAL AND FINDINGS: This was a retrospective cohort study with comparisons made between EPTB and new smear positive pulmonary tuberculosis (NPTB) patients diagnosed in the country from January to December 2011. There were 383 EPTB patients (9% of all TB cases) with a mean age of 35 years, male/female ratio of 1.3 and important regional variation. There were significantly more females (p = 0.001), children <15 years (p<0.001) and HIV-positive patients (p = 0.005) with EPTB compared with NPTB. Pleural effusion, spinal and lymph node tuberculosis accounted for 66% of all EPTB. Children <15 years represented 16% of cases, with lymph node disease being most common among them (p<0.001). Of 130 EPTB patients registered in CNHP-P, 7% had a confirmed bacteriological/histological diagnosis. There were 331 (86%) patients who successfully completed treatment. More patients with EPTB were lost to-follow-up compared with NPTB (p<0.001) with all these patients from one region. The best treatment completion rates were in children <15 years (OR:3.5, 95%CI:1.0-14.8) while patients with pleural effusion and ascites had the worst outcomes. Of 72 HIV-coinfected patients, 88% were on antiretroviral therapy (ART). HIV-positive status was associated with poor outcomes while those on ART fared better. In the CNHP-P, more than 80% who completed their treatment showed an increase in bodyweight and this was more evident in HIV-positive compared with HIV-negative patients (p = 0.03). CONCLUSION: Patients with EPTB generally do well in Benin, although the TB Programme would benefit through more attention to accurate diagnosis and earlier start of ART in HIV-infected patients. PMID- 24755604 TI - Preparation of modified long-mer RNAs and analysis of FMN binding to the ypaA aptamer from B. subtilis. AB - In recent years, RNA has been shown to fulfil a number of cellular functions. This has led to much interest in elucidation of the structure of functional RNA molecules, and thus, in the preparation of suitably functionalized RNAs. The chemical synthesis of RNAs allows for the site-specific modification; however, is limited to sequences of about 60-70 nucleotides in length. At the example of the flavine mononucleotide (FMN) responsive aptamer of the ypaA riboswitch from B. subtilis, we demonstrate the highly efficient preparation of site-specifically modified long-mer RNAs. Our strategy consists of the chemical synthesis of fragments followed by enzymatic or chemical ligation. Splint ligation with T4 RNA ligase turned out to be most successful among the enyzymatic protocols. Highly efficient chemical ligation was performed by azide-alkyne cycloaddition of suitably modified RNA fragments. Wild-type and 2-aminopurine (2-AP)-modified variants of the ypaA aptamer were prepared. FMN binding to all synthesized ypaA aptamer variants is demonstrated. However, dissociation of FMN from its binding site by reduction of the isoalloxazin unit as demonstrated before for a small hairpin-derived aptazyme could not be shown. This implies that either FMN is less accessible to reduction when it is bound to its natural aptamer; that reduced FMN remains bound to the aptamer; or that FMN upon reduction indeed is released from its binding site, without the aptamer folding back in the natural ligand-free state. The results of this study are of general interest to the preparation of site-specifically modified RNAs for investigation into structure and function. PMID- 24755605 TI - Wnt signaling in form deprivation myopia of the mice retina. AB - BACKGROUND: The canonical Wnt signaling pathway plays important roles in cellular proliferation and differentiation, axonal outgrowth, cellular maintenance in retinas. Here we test the hypothesis that elements of the Wnt signaling pathway are involved in the regulation of eye growth and prevention of myopia, in the mouse form-deprivation myopia model. METHODOLOGY/PRINCIPAL FINDINGS: (1) One hundred twenty-five C57BL/6 mice were randomly distributed into form-deprivation myopia and control groups. Form-deprivation myopia (FDM) was induced by suturing the right eyelid, while the control group received no treatment. After 1, 2, and 4 weeks of treatment, eyes were assessed in vivo by cycloplegic retinoscopic refraction and axial length measurement by photography or A-scan ultrasonography. Levels of retinal Wnt2b, Fzd5 and beta-catenin mRNA and protein were evaluated using RT-PCR and western blotting, respectively. (2) Another 96 mice were divided into three groups: control, drugs-only, and drugs+FDM (by diffuser). Experimentally treated eyes in the last two groups received intravitreal injections of vehicle or the proteins, DKK-1 (Wnt-pathway antagonist) or Norrin (Wnt-pathway agonist), once every three days, for 4 injections total. Axial length and retinoscopic refraction were measured on the 14th day of form deprivation. Following form-deprivation for 1, 2, and 4 weeks, FDM eyes had a relatively myopic refractive error, compared with contralateral eyes. There were no significant differences in refractive error between right and left eye in control group. The amounts of Wnt2b, Fzd5 and beta-catenin mRNA and protein were significantly greater in form-deprived myopia eyes than in control eyes.DKK-1 (antagonist) reduced the myopic shift in refractive error and increase in axial elongation, whereas Norrin had the opposite effect in FDM eyes. CONCLUSIONS/SIGNIFICANCE: Our studies provide the first evidence that the Wnt2b signaling pathway may play a role in the development and progression of form deprivation myopia, in a mammalian model. PMID- 24755606 TI - Molecular characterization of Cryptosporidium spp. in children from Mexico. AB - Cryptosporidiosis is a parasitic disease caused by Cryptosporidium spp. In immunocompetent individuals, it usually causes an acute and self-limited diarrhea; in infants, infection with Cryptosporidium spp. can cause malnutrition and growth retardation, and declined cognitive ability. In this study, we described for the first time the distribution of C. parvum and C. hominis subtypes in 12 children in Mexico by sequence characterization of the 60-kDa glycoprotein (GP60) gene of Cryptosporidium. Altogether, 7 subtypes belonging to 4 subtype families of C. hominis (Ia, Ib, Id and Ie) and 1 subtype family of C. parvum (IIa) were detected, including IaA14R3, IaA15R3, IbA10G2, IdA17, IeA11G3T3, IIaA15G2R1 and IIaA16G1R1. The frequency of the subtype families and subtypes in the samples analyzed in this study differed from what was observed in other countries. PMID- 24755607 TI - Prevalence, associated factors and predictors of depression among adults in the community of Selangor, Malaysia. AB - INTRODUCTION: Depression is one of the most common mental health disorders and is an emerging public health problem. The objectives of this paper were to determine the prevalence of depression, its associated factors and the predictors of depression among adults in the community of Selangor. METHODS: A cross sectional study was conducted in three districts in Selangor, from 11th June to 30th December 2012. The sampling frame was obtained from the Department of Statistics Malaysia (DOS) in May 2012, using the National Population and Housing Census 2010. Adults aged 18 years and above, living in the selected living quarters were approached to participate in the study and requested to complete a set of questionnaires. RESULTS: A total of 1,556 out of 2,152 participants participated in this study, giving an overall study response rate of 61.90%. Patient Health Questionnaire 9 (PHQ-9) was used to determine the presence of depression. The prevalence of depression was 10.3%, based on the PHQ-9 cut off point of 10 and above. Based on multiple logistic regression analysis, the predictors of depression were presence of anxiety, serious problems at work, unhappy relationship with children, high perceived stress, domestic violence, unhappy relationship with spouse, low self-esteem, unhappy relationship with family, serious financial constraint and presence of chronic diseases. When reanalyzed after removing anxiety, high perceived stress and low self-esteem, additional predictors of depression were found to be serious marital problems and religiosity. CONCLUSION: The prevalence of depression in this study is similar to that found in other studies. Findings from this study are being used as baseline data to develop an effective program to assist in the management of common mental health disorders in the community, in particular depression. The identification of predictors of depression in the community is important to identify the target population for the program. PMID- 24755608 TI - Enabling an integrated rate-temporal learning scheme on memristor. AB - Learning scheme is the key to the utilization of spike-based computation and the emulation of neural/synaptic behaviors toward realization of cognition. The biological observations reveal an integrated spike time- and spike rate-dependent plasticity as a function of presynaptic firing frequency. However, this integrated rate-temporal learning scheme has not been realized on any nano devices. In this paper, such scheme is successfully demonstrated on a memristor. Great robustness against the spiking rate fluctuation is achieved by waveform engineering with the aid of good analog properties exhibited by the iron oxide based memristor. The spike-time-dependence plasticity (STDP) occurs at moderate presynaptic firing frequencies and spike-rate-dependence plasticity (SRDP) dominates other regions. This demonstration provides a novel approach in neural coding implementation, which facilitates the development of bio-inspired computing systems. PMID- 24755609 TI - Risk of Budd-Chiari syndrome associated with factor V Leiden and G20210A prothrombin mutation: a meta-analysis. AB - BACKGROUND: Various studies have demonstrated that factor V Leiden (FVL) and G20210A prothrombin mutation contribute to the risk of Budd-Chiari syndrome (BCS), while other studies provided conflicting findings. In order to derive more precise estimations of the relationships, a meta-analysis was performed. METHODS: Eligible articles were identified through search of databases including Pubmed, Chinese Biomedical Database (CBM, Chinese), and Chinese National Knowledge Infrastructure (CNKI, Chinese). Odd ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed- model. RESULTS: Finally, twelve studies were included for FVL and nine studies were included for G20210A prothrombin mutation. With respect to FVL, significantly increased BCS risk was found in the overall population (OR = 6.29, 95%CI = 4.23-9.36). Subgroup analyses suggested that FVL was associated with an increased risk of BCS in the population with high background mutation prevalence (>1% in the normal population). No significant association was found between BCS and G20210A prothrombin mutation (OR = 1.78, 95%CI = 0.77-4.11). CONCLUSION: The presence of FVL should be evaluated in patients with BCS. Conversely, G20210A prothrombin mutation is not significantly associated with risk of BCS. Large-scale well designed studies are necessary to be conducted to further confirm or refute the observed association. PMID- 24755610 TI - Evidence that p-cresol and IL-6 are adsorbed by the HFR cartridge: towards a new strategy to decrease systemic inflammation in dialyzed patients? AB - INTRODUCTION: Hemodialysis (HD) and hemodiafiltration clear only with a low efficiency the plasma from interleukin-6 and p-cresol, two protein-bound uremic toxins associated with high cardiovascular risk in end stage renal disease. HFR Supra is a double-chamber hemodiafiltration system in which the ultrafiltrate returns to the patient after its regeneration through a resin cartridge that binds hydrophobic and protein-bound solutes. In the present study, we evaluated whether the HFR cartridge can also bind total p-cresol and IL-6 and remove them from the ultrafiltrate. METHODS: We compared the levels of IL-6 and p-cresol in ultrafiltrate samples collected at the inlet (UFin) and at the outlet (UFout) of the cartridge at the start or at the end of a 240 min HFR session in 12 inflamed chronic HD patients. The pro-inflammatory activity of the ultrafiltrate samples was also determined by evaluating the changes that they induced in IL-6 mRNA expression and protein release in peripheral blood mononuclear cells from 12 healthy volunteers. IL-6 and p-cresol circulating levels were also assessed in peripheral plasma blood samples collected before and after HFR and, for comparison, a control HD. RESULTS: p-Cresol and IL-6 were lower in UFout than in UFin both at the start and at the end of the HFR session, suggesting that they were retained by the cartridge. IL-6 mRNA expression and release were lower in PBMC incubated with UFout collected at the end than with UFin collected at the start of HFR, suggesting that passage through the cartridge reduced UF pro inflammatory activity. Plasma total p-cresol decreased by about 53% after HFR, and 37% after HD. IL-6 circulating values were unmodified by either these dialysis procedures. CONCLUSIONS: This study shows that the HFR-Supra cartridge retains total p-cresol and IL-6 in the ultrafiltrate and lowers plasma total p cresol but not IL-6 levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT01865773. PMID- 24755611 TI - A temporal dimension to the influence of pollen rewards on bee behaviour and fecundity in Aloe tenuior. AB - The net effect of pollen production on fecundity in plants can range from negative--when self-pollen interferes with fecundity due to incompatibility mechanisms, to positive--when pollen availability is associated with increased pollinator visitation and fecundity due to its utilization as a reward. We investigated the responses of bees to pollen and nectar rewards, and the effects of these rewards on pollen deposition and fecundity in the hermaphroditic succulent shrub Aloe tenuior. Self-pollinated plants failed to set fruit, but their ovules were regularly penetrated by self-pollen tubes, which uniformly failed to develop into seeds as expected from ovarian self-incompatibility (or strong early inbreeding depression). Bees consistently foraged for pollen during the morning and early afternoon, but switched to nectar in the late afternoon. As a consequence of this differential foraging, we were able to test the relative contribution to fecundity of pollen- versus nectar-collecting flower visitors. We exposed emasculated and intact flowers in either the morning or late afternoon to foraging bees and showed that emasculation reduced pollen deposition by insects in the morning, but had little effect in the afternoon. Despite the potential for self-pollination to result in ovule discounting due to late-acting self sterility, fecundity was severely reduced in artificially emasculated plants. Although there were temporal fluctuations in reward preference, most bee visits were for pollen rewards. Therefore the benefit of providing pollen that is accessible to bee foragers outweighs any potential costs to fitness in terms of gender interference in this species. PMID- 24755612 TI - Toll-like receptor 4 mediates inflammatory cytokine secretion in smooth muscle cells induced by oxidized low-density lipoprotein. AB - Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-beta (IL1-beta), tumor necrosis factor-alpha (TNFalpha), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4-/ ). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFkappaB was also inhibited in TLR4-/- primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL induced inflammatory cytokine expression and secretion, and p38 and NFkappaB activation. PMID- 24755613 TI - Vemurafenib and panitumumab combination tailored therapy in BRAF-mutated metastatic colorectal cancer: a case report. AB - As the knowledge on cancer genetic alterations progresses, it fosters the need for more personalized therapeutic intervention in modern cancer management. Recently, mutations in KRAS, BRAF, and PIK3CA genes have emerged as important mechanisms of resistance to EGFR-targeted therapy in metastatic colorectal cancer (mCRC). Here we report the first case of a mCRC patient whose disease had progressed on standard lines of treatment and for which we devised a personalized therapeutic approach consisting of vemurafenib (Zelboraf) and panitumumab (Vectibix), based on the following molecular profile: BRAF(V600E)-mutant, amplified EGFR (double positive) and WT KRAS, WT PIK3CA, not-amplified HER2 (triple negative). This new combination therapy was well tolerated and resulted in a strong control of the disease. In particular, the vemurafenib-panitumumab combination appears to limit the typical toxicity of single agents, since no cutaneous toxic effects typically associated with vemurafenib were observed. Here we report the first clinical evidence that the combination of an anti-EGFR (panitumumab) and an inhibitor of BRAF(V600E) (vemurafenib) is well tolerated and results in a strong disease control in an extensively pretreated mCRC patient. PMID- 24755614 TI - Long-distance dispersal by sea-drifted seeds has maintained the global distribution of Ipomoea pes-caprae subsp. brasiliensis (Convolvulaceae). AB - Ipomoea pes-caprae (Convolvulaceae), a pantropical plant with sea-drifted seeds, is found globally in the littoral areas of tropical and subtropical regions. Unusual long-distance seed dispersal has been believed to be responsible for its extraordinarily wide distribution; however, the actual level of inter-population migration has never been studied. To clarify the level of migration among populations of I. pes-caprae across its range, we investigated nucleotide sequence variations by using seven low-copy nuclear markers and 272 samples collected from 34 populations that cover the range of the species. We applied coalescent-based approaches using Bayesian and maximum likelihood methods to assess migration rates, direction of migration, and genetic diversity among five regional populations. Our results showed a high number of migrants among the regional populations of I. pes-caprae subsp. brasiliensis, which suggests that migration among distant populations was maintained by long-distance seed dispersal across its global range. These results also provide strong evidence for recent trans-oceanic seed dispersal by ocean currents in all three oceanic regions. We also found migration crossing the American continents. Although this is an apparent land barrier for sea-dispersal, migration between populations of the East Pacific and West Atlantic regions was high, perhaps because of trans isthmus migration via pollen dispersal. Therefore, the migration and gene flow among populations across the vast range of I. pes-caprae is maintained not only by seed dispersal by sea-drifted seeds, but also by pollen flow over the American continents. On the other hand, populations of subsp. pes-caprae that are restricted to only the northern part of the Indian Ocean region were highly differentiated from subsp. brasiliensis. Cryptic barriers that prevented migration by sea dispersal between the ranges of the two subspecies and/or historical differentiation that caused local adaptation to different environmental factors in each region could explain the genetic differentiation between the subspecies. PMID- 24755615 TI - A novel microfluidic chip electrophoresis strategy for simultaneous, label-free, multi-protein detection based on a graphene energy transfer biosensor. AB - A new type of high-throughput and parallel optical sensing platform with a single color probe based on microfluidic chip electrophoresis combined with aptamer carboxyfluorescein/graphene oxide energy transfer is reported here. Label-free protein multi-targets were detected, even in challenging complex samples without any pre-treatment. PMID- 24755616 TI - Translational control of small heat shock genes in mesophilic and thermophilic cyanobacteria by RNA thermometers. AB - Cyanobacteria constitute a heterogeneous phylum of oxygen-producing, photosynthetic prokaryotes. They are susceptible to various stress conditions like heat, salt, or light stress, all inducing the cyanobacterial heat shock response (HSR). Cyanobacterial small heat shock proteins (sHsps) are known to preserve thylakoid membrane integrity under stress conditions, thereby protecting the photosynthesis machinery. In Synechocystis sp PCC 6803, synthesis of the sHsp Hsp17 is regulated by an RNA thermometer (RNAT) in the 5'-untranslated region (5' UTR) of the hsp17 mRNA. RNATs are direct temperature sensors that control expression of many bacterial heat shock and virulence genes. They hinder translation at low temperatures by base pairing, thus blocking ribosome access to the mRNA. To explore the temperature range in which RNATs act, we studied various RNAT candidates upstream of sHsp genes from mesophilic and thermophilic cyanobacteria. The mesophilic cyanobacteria Anabaena variabilis and Nostoc sp chromosomally encode two sHsps each. Reporter gene studies suggested RNAT mediated post-transcriptional regulation of shsp expression in both organisms. Detailed structural analysis of the two A. variabilis candidates revealed two novel RNAT types. The first, avashort, regulates translation primarily by masking of the AUG translational start codon. The second, featuring an extended initial hairpin, thus named avalong, presumably makes use of complex tertiary interaction. The 5'-UTR of the small heat shock gene hspA in the thermophile Thermosynechococcus elongatus is predicted to adopt an extended secondary structure. Structure probing revealed that the ribosome binding site was blocked at temperatures below 55 degrees C. The results of this study demonstrate that cyanobacteria commonly use RNATs to control expression of their small heat shock genes. PMID- 24755617 TI - Increased amygdala and visual cortex activity and functional connectivity towards stimulus novelty is associated with state anxiety. AB - Novel stimuli often require a rapid reallocation of sensory processing resources to determine the significance of the event, and the appropriate behavioral response. Both the amygdala and the visual cortex are central elements of the neural circuitry responding to novelty, demonstrating increased activity to new as compared to highly familiarized stimuli. Further, these brain areas are intimately connected, and thus the amygdala may be a key region for directing sensory processing resources to novel events. Although knowledge regarding the neurocircuit of novelty detection is gradually increasing, we still lack a basic understanding of the conditions that are necessary and sufficient for novelty specific responses in human amygdala and the visual cortices, and if these brain areas interact during detection of novelty. In the present study, we investigated the response of amygdala and the visual cortex to novelty, by comparing functional MRI activity between 1st and 2nd time presentation of a series of emotional faces in an event-related task. We observed a significant decrease in amygdala and visual cortex activity already after a single stimulus exposure. Interestingly, this decrease in responsiveness was less for subjects with a high score on state anxiety. Further, novel faces stimuli were associated with a relative increase in the functional coupling between the amygdala and the inferior occipital gyrus (BA 18). Thus, we suggest that amygdala is involved in fast sensory boosting that may be important for attention reallocation to novel events, and that the strength of this response depends on individual state anxiety. PMID- 24755618 TI - Changes in the organics metabolism in the hepatopancreas induced by eyestalk ablation of the Chinese mitten crab Eriocheir sinensis determined via transcriptome and DGE analysis. AB - BACKGROUND: To understand the regulation mechanism of eyestalk ablation on the activities of hepatopancreas, Illumina RNA-Seq and digital gene expression (DGE) analyses were performed to investigate the transcriptome of the eyestalk, Y organ, and hepatopancreas of E. sinensis and to identify the genes associated with the hepatopancreas metabolism that are differentially expressed under eyestalk ablation conditions. RESULTS: A total of 58,582 unigenes were constructed from 157,168 contigs with SOAPdenovo. A BlastX search against the NCBI Nr database identified 21,678 unigenes with an E-value higher than 10-5. Using the BLAST2Go and BlastAll software programs, 6,883 unigenes (11.75% of the total) were annotated to the Gene Ontology (GO) database, 7,386 (12.6%) unigenes were classified into 25 Clusters of Orthologous Groups of Proteins (COGs), 16,200 (27.7%) unigenes were assigned to 242 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and 1,846 unigenes were matched to "metabolism pathways". The DGE analysis revealed that 1,416 unigenes were significantly differentially expressed in the hepatopancreas, of which 890 unigenes were up-regulated and 526 unigenes were down-regulated. Of the differentially expressed genes, 382 unigenes were annotated and 63 were classified into metabolism pathways. The results of the real-time polymerase chain reaction (PCR) analysis of four unigenes related to carbohydrate metabolism were consistent with those obtained from the DGE analysis, which demonstrates that the sequencing data were satisfactory for further gene expression analyses. CONCLUSION: This paper reported the transcriptom of the eyestalk, Y-organ, and hepatopancreas from E. sinensis. DGE analysis provided the different expressed genes of the metabolism processes in hepatopancreas that are affected by eyestalk ablation. These findings will facilitate further investigations on the mechanisms of the metabolism of organic substances during development and reproduction in crustaceans. PMID- 24755619 TI - Insights into persistence mechanisms of a zoonotic virus in bat colonies using a multispecies metapopulation model. AB - Rabies is a worldwide zoonosis resulting from Lyssavirus infection. In Europe, Eptesicus serotinus is the most frequently reported bat species infected with Lyssavirus, and thus considered to be the reservoir of European bat Lyssavirus type 1 (EBLV-1). To date, the role of other bat species in EBLV-1 epidemiology and persistence remains unknown. Here, we built an EBLV-1-transmission model based on local observations of a three-cave and four-bat species (Myotis capaccinii, Myotis myotis, Miniopterus schreibersii, Rhinolophus ferrumequinum) system in the Balearic Islands, for which a 1995-2011 serological dataset indicated the continuous presence of EBLV-1. Eptesicus serotinus was never observed in the system during the 16-year follow-up and therefore was not included in the model. We used the model to explore virus persistence mechanisms and to assess the importance of each bat species in the transmission dynamics. We found that EBLV-1 could not be sustained if transmission between M. schreibersii and other bat species was eliminated, suggesting that this species serves as a regional reservoir. Global sensitivity analysis using Sobol's method revealed that following the rate of autumn-winter infectious contacts, M. schreibersii's incubation- and immune-period durations, but not the infectious period length, were the most relevant factors driving virus persistence. PMID- 24755621 TI - Exploring empirical rank-frequency distributions longitudinally through a simple stochastic process. AB - The frequent appearance of empirical rank-frequency laws, such as Zipf's law, in a wide range of domains reinforces the importance of understanding and modeling these laws and rank-frequency distributions in general. In this spirit, we utilize a simple stochastic cascade process to simulate several empirical rank frequency distributions longitudinally. We focus especially on limiting the process's complexity to increase accessibility for non-experts in mathematics. The process provides a good fit for many empirical distributions because the stochastic multiplicative nature of the process leads to an often observed concave rank-frequency distribution (on a log-log scale) and the finiteness of the cascade replicates real-world finite size effects. Furthermore, we show that repeated trials of the process can roughly simulate the longitudinal variation of empirical ranks. However, we find that the empirical variation is often less that the average simulated process variation, likely due to longitudinal dependencies in the empirical datasets. Finally, we discuss the process limitations and practical applications. PMID- 24755622 TI - Antimicrobial and immunomodulatory activities of PR-39 derived peptides. AB - The porcine cathelicidin PR-39 is a host defence peptide that plays a pivotal role in the innate immune defence of the pig against infections. Besides direct antimicrobial activity, it is involved in immunomodulation, wound healing and several other biological processes. In this study, the antimicrobial- and immunomodulatory activity of PR-39, and N- and C-terminal derivatives of PR-39 were tested. PR-39 exhibited an unexpected broad antimicrobial spectrum including several Gram positive strains such as Bacillus globigii and Enterococcus faecalis. Of organisms tested, only Staphylococcus aureus was insensitive to PR 39. Truncation of PR-39 down to 15 (N-terminal) amino acids did not lead to major loss of activity, while peptides corresponding to the C-terminal part of PR-39 were hampered in their antimicrobial activity. However, shorter peptides were all much more sensitive to inhibition by salt. Active peptides induced ATP leakage and loss of membrane potential in Bacillus globigii and Escherichia coli, indicating a lytic mechanism of action for these peptides. Finally, only the mature peptide was able to induce IL-8 production in porcine macrophages, but some shorter peptides also had an effect on TNF-alpha production showing differential regulation of cytokine induction by PR-39 derived peptides. None of the active peptides showed high cytotoxicity highlighting the potential of these peptides for use as an alternative to antibiotics. PMID- 24755624 TI - Plane wave diffraction by a finite plate with impedance boundary conditions. AB - In this study we have examined a plane wave diffraction problem by a finite plate having different impedance boundaries. The Fourier transforms were used to reduce the governing problem into simultaneous Wiener-Hopf equations which are then solved using the standard Wiener-Hopf procedure. Afterwards the separated and interacted fields were developed asymptotically by using inverse Fourier transform and the modified stationary phase method. Detailed graphical analysis was also made for various physical parameters we were interested in. PMID- 24755623 TI - Economics and financing of vaccines for diarrheal diseases. AB - The considerable burden of infectious disease-caused diarrhea around the world has motivated the continuing development of a number of vaccine candidates over the past several decades with some reaching the market. As with all major public health interventions, understanding the economics and financing of vaccines against diarrheal diseases is essential to their development and implementation. This review focuses on each of the major infectious pathogens that commonly cause diarrhea, the current understanding of their economic burden, the status of vaccine development, and existing economic evaluations of the vaccines. While the literature on the economics and financing of vaccines against diarrhea diseases is growing, there is considerable room for more inquiry. Substantial gaps exist for many pathogens, circumstances, and effects. Economics and financing studies are integral to vaccine development and implementation. PMID- 24755625 TI - Secondary structure changes in ApoA-I Milano (R173C) are not accompanied by a decrease in protein stability or solubility. AB - Apolipoprotein A-I (apoA-I) is the main protein of high-density lipoprotein (HDL) and a principal mediator of the reverse cholesterol transfer pathway. Variants of apoA-I have been shown to be associated with hereditary amyloidosis. We previously characterized the G26R and L178H variants that both possess decreased stability and increased fibril formation propensity. Here we investigate the Milano variant of apoAI (R173C; apoAI-M), which despite association with low plasma levels of HDL leads to low prevalence of cardiovascular disease in carriers of this mutation. The R173C substitution is located to a region (residues 170 to 178) that contains several fibrillogenic apoA-I variants, including the L178H variant, and therefore we investigated a potential fibrillogenic property of the apoAI-M protein. Despite the fact that apoAI-M shared several features with the L178H variant regarding increased helical content and low degree of ThT binding during prolonged incubation in physiological buffer, our electron microscopy analysis revealed no formation of fibrils. These results suggest that mutations inducing secondary structural changes may be beneficial in cases where fibril formation does not occur. PMID- 24755626 TI - Calcium binding to beta-2-microglobulin at physiological pH drives the occurrence of conformational changes which cause the protein to precipitate into amorphous forms that subsequently transform into amyloid aggregates. AB - Using spectroscopic, calorimetric and microscopic methods, we demonstrate that calcium binds to beta-2-microglobulin (beta2m) under physiological conditions of pH and ionic strength, in biological buffers, causing a conformational change associated with the binding of up to four calcium atoms per beta2m molecule, with a marked transformation of some random coil structure into beta sheet structure, and culminating in the aggregation of the protein at physiological (serum) concentrations of calcium and beta2m. We draw attention to the fact that the sequence of beta2m contains several potential calcium-binding motifs of the DXD and DXDXD (or DXEXD) varieties. We establish (a) that the microscopic aggregation seen at physiological concentrations of beta2m and calcium turns into actual turbidity and visible precipitation at higher concentrations of protein and beta2m, (b) that this initial aggregation/precipitation leads to the formation of amorphous aggregates, (c) that the formation of the amorphous aggregates can be partially reversed through the addition of the divalent ion chelating agent, EDTA, and (d) that upon incubation for a few weeks, the amorphous aggregates appear to support the formation of amyloid aggregates that bind to the dye, thioflavin T (ThT), resulting in increase in the dye's fluorescence. We speculate that beta2m exists in the form of microscopic aggregates in vivo and that these don't progress to form larger amyloid aggregates because protein concentrations remain low under normal conditions of kidney function and beta2m degradation. However, when kidney function is compromised and especially when dialysis is performed, beta2m concentrations probably transiently rise to yield large aggregates that deposit in bone joints and transform into amyloids during dialysis related amyloidosis. PMID- 24755627 TI - A combination of serological assays to detect human antibodies to the avian influenza A H7N9 virus. AB - Human infection with avian influenza A H7N9 virus was first identified in March 2013 and represents an ongoing threat to public health. There is a need to optimize serological methods for this new influenza virus. Here, we compared the sensitivity and specificity of the hemagglutinin inhibition (HI), microneutralization (MN), and Western blot (WB) assays for the detection of human antibodies against avian influenza A (H7N9) virus. HI with horse erythrocytes (hRBCs) and a modified MN assay possessed greater sensitivity than turkey erythrocytes and the standard MN assay, respectively. Using these assays, 80% of tested sera from confirmed H7N9 cases developed detectable antibody to H7N9 after 21 days. To balance sensitivity and specificity, we found serum titers of >=20 (MN) or 160 (HI) samples were most effective in determining seropositive to H7N9 virus. Single serum with HI titers of 20-80 or MN titer of 10 could be validated by each other or WB assay. Unlike serum collected from adult or elderly populations, the antibody response in children with mild disease was low or undetectable. These combinations of assays will be useful in case diagnosis and serologic investigation of human cases. PMID- 24755628 TI - Validating a scoring system for the diagnosis of smear-negative pulmonary tuberculosis in HIV-infected adults. AB - BACKGROUND: The challenge of diagnosing smear-negative pulmonary TB (tuberculosis) in people living with HIV justifies the use of instruments other than the smear test for diagnosing the disease. Considering the clinical radiological similarities of TB amongst HIV-infected adults and children, the proposal of this study was to assess the accuracy of a scoring system used to diagnose smear-negative pulmonary TB in children and adolescents, in HIV-infected adults suspected of having smear-negative pulmonary TB. METHODS: A Phase III validation study aiming to assess the diagnostic accuracy of a scoring system for diagnosing smear-negative pulmonary TB in HIV-infected adults. The study assessed sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values of the scoring system. Three versions of the scoring system were tested. RESULTS: From a cohort of 2,382 (HIV-infected adults), 1276 were investigated and 128 were diagnosed with pulmonary TB. Variables associated with the diagnosis of TB were: coughing, weight loss, fever, malnutrition, chest X-ray, and positive tuberculin test. The best diagnostic performance occurred with the scoring system with new scores, with sensitivity = 81.2% (95%-CI 74.5% -88%), specificity = 78% (75.6% -80.4%), PPV = 29.2% (24.5% 33.9%) and NPV = 97.4% (96.4% -98.4%), LR+ = 3.7 (3.4-4.0) and LR- = 0.24 (0.2 0.4). CONCLUSION: The proposed scoring system (with new scores) presented a good capacity for discriminating patients who did not have pulmonary TB, in the studied population. Further studies are necessary in order to validate it, thus permitting the assessment of its use in diagnosing smear-negative pulmonary TB in HIV-infected adults. PMID- 24755620 TI - Overrepresentation of glutamate signaling in Alzheimer's disease: network-based pathway enrichment using meta-analysis of genome-wide association studies. AB - Genome-wide association studies (GWAS) have successfully identified several risk loci for Alzheimer's disease (AD). Nonetheless, these loci do not explain the entire susceptibility of the disease, suggesting that other genetic contributions remain to be identified. Here, we performed a meta-analysis combining data of 4,569 individuals (2,540 cases and 2,029 healthy controls) derived from three publicly available GWAS in AD and replicated a broad genomic region (>248,000 bp) associated with the disease near the APOE/TOMM40 locus in chromosome 19. To detect minor effect size contributions that could help to explain the remaining genetic risk, we conducted network-based pathway analyses either by extracting gene-wise p-values (GW), defined as the single strongest association signal within a gene, or calculated a more stringent gene-based association p-value using the extended Simes (GATES) procedure. Comparison of these strategies revealed that ontological sub-networks (SNs) involved in glutamate signaling were significantly overrepresented in AD (p<2.7*10(-11), p<1.9*10(-11); GW and GATES, respectively). Notably, glutamate signaling SNs were also found to be significantly overrepresented (p<5.1*10(-8)) in the Alzheimer's disease Neuroimaging Initiative (ADNI) study, which was used as a targeted replication sample. Interestingly, components of the glutamate signaling SNs are coordinately expressed in disease-related tissues, which are tightly related to known pathological hallmarks of AD. Our findings suggest that genetic variation within glutamate signaling contributes to the remaining genetic risk of AD and support the notion that functional biological networks should be targeted in future therapies aimed to prevent or treat this devastating neurological disorder. PMID- 24755629 TI - Development of a multiplex autoantibody test for detection of lung cancer. AB - Lung cancer is the leading cause of cancer-related deaths for both men and women. Early diagnosis of lung cancer has a 5-year survival rate of 48.8%, however, nearly 35% of stage I patients relapses after surgical resection, thus portending a poor prognosis. Therefore, detecting lung cancer in early stage and further identifying the high-risk patients would allow the opportunity to provide adjuvant therapy and possibly increase survival. There is considerable evidence that the immune system produces an autoantibody response to neoplastic cells. The detection of such autoantibodies has been shown to have diagnostic and prognostic value. Here we took advantage of the high-throughput Luminex technique to multiplex a total of 14 tumor-associated autoantigens to detect the autoantibody from the patients sera. The 14 antigens were expressed by in vitro transcription/translation system with HaloTag at N-terminus. The fusion proteins were then covalently immobilized onto the Luminex microspheres conjugated by the halo-link ligand, thus eliminating the protein purification procedure. Sera samples from cancer patients and healthy controls were interacted with the microsphere-antigen complex to measure the autoantibodies. We have developed a quick multiplex detection system for measuring autoantibody signature from patient sera with minimal cross-reaction. A panel of seven autoantibody biomarkers has generated an AUC>80% in distinguishing the lung cancers from healthy controls. This study is the first report by combining Luminex platform and HaloTag technology to detect humoral immune response in cancer patients. Due to the flexibility of the Luminex technology, this approach can be applied to others conditions such as infectious, neurological, and metabolic diseases. One can envision that this multiplex Luminex system as well as the panel of seven biomarkers could be used to screen the high-risk population with subsequent CT test based on the blood test result. PMID- 24755631 TI - Replacement of HA-MRSA by CA-MRSA infections at an academic medical center in the midwestern United States, 2004-5 to 2008. AB - We noted anecdotally that infections designated as health care-associated (HA-) MRSA by epidemiologic criteria seemed to be decreasing in incidence at the University of Chicago Medical Center (UCMC) after 2004. We compared MRSA patients seen at any site of clinical care at UCMC and the isolates that caused their infections in 2004-5 (n = 545) with those in 2008 (n = 135). The percent of patients with MRSA infections cultured > 2 days after hospital admission decreased from 19.5% in 2004-5 to 7.4% in 2008 (p = 0.001). The percent in 2004-5 compared with 2008 who had a hospitalization (49.1% to 26.7%, p = 0.001) or surgery (43.0% to 14.1%, p<0.001) in the previous year decreased. In 2008 a greater percent of patients was seen in the emergency department (23.1% vs. 39.3%) and a smaller percent both in intensive care units (15.6% vs. 6.7%) and in other inpatient units (40.7% vs. 32.6%) (p<0.001). The percent of patients with CA-MRSA infections by the CDC epidemiologic criteria increased from 36.5% in 2004 5 to 62.2% in 2008 (p<0.001). The percent of MRSA isolates sharing genetic characteristics of USA100 decreased from 27.9% (152/545) to 12.6% (17/135), while the percent with CA-MRSA (USA300) characteristics increased from 53.2% (290/545) to 66.7% (90/135). The percent of infections that were invasive did not change significantly. Our data suggest that HA-MRSA infections, both by epidemiologic and microbiologic criteria, relative to CA-MRSA, decreased between 2004-5 and 2008 at UCMC. PMID- 24755632 TI - Understanding the dangers of synthetic cannabinoids. PMID- 24755630 TI - Transcriptional profiling of Mycobacterium tuberculosis replicating ex vivo in blood from HIV- and HIV+ subjects. AB - Hematogenous dissemination of Mycobacterium tuberculosis (M. tb) occurs during both primary and reactivated tuberculosis (TB). Although hematogenous dissemination occurs in non-HIV TB patients, in ~80% of these patients, TB manifests exclusively as pulmonary disease. In contrast, extrapulmonary, disseminated, and/or miliary TB is seen in 60-70% of HIV-infected TB patients, suggesting that hematogenous dissemination is likely more common in HIV+ patients. To understand M. tb adaptation to the blood environment during bacteremia, we have studied the transcriptome of M. tb replicating in human whole blood. To investigate if M. tb discriminates between the hematogenous environments of immunocompetent and immunodeficient individuals, we compared the M. tb transcriptional profiles during replication in blood from HIV- and HIV+ donors. Our results demonstrate that M. tb survives and replicates in blood from both HIV- and HIV+ donors and enhances its virulence/pathogenic potential in the hematogenous environment. The M. tb blood-specific transcriptome reflects suppression of dormancy, induction of cell-wall remodeling, alteration in mode of iron acquisition, potential evasion of immune surveillance, and enhanced expression of important virulence factors that drive active M. tb infection and dissemination. These changes are accentuated during bacterial replication in blood from HIV+ patients. Furthermore, the expression of ESAT-6, which participates in dissemination of M. tb from the lungs, is upregulated in M. tb growing in blood, especially during growth in blood from HIV+ patients. Preliminary experiments also demonstrate that ESAT-6 promotes HIV replication in U1 cells. These studies provide evidence, for the first time, that during bacteremia, M. tb can adapt to the blood environment by modifying its transcriptome in a manner indicative of an enhanced-virulence phenotype that favors active infection. Additionally, transcriptional modifications in HIV+ blood may further accentuate M. tb virulence and drive both M. tb and HIV infection. PMID- 24755634 TI - Self-administration of ethanol, cocaine, or nicotine does not decrease the soma size of ventral tegmental area dopamine neurons. AB - Our previous observations show that chronic opiate administration, including self administration, decrease the soma size of dopamine (DA) neurons in the ventral tegmental area (VTA) of rodents and humans, a morphological change correlated with increased firing rate and reward tolerance. Given that a general hallmark of drugs of abuse is to increase activity of the mesolimbic DA circuit, we sought to determine whether additional drug classes produced a similar morphological change. Sections containing VTA were obtained from rats that self-administered cocaine or ethanol and from mice that consumed nicotine. In contrast to opiates, we found no change in VTA DA soma size induced by any of these other drugs. These data suggest that VTA morphological changes are induced in a drug-specific manner and reinforce recent findings that some changes in mesolimbic signaling and neuroplasticity are drug-class dependent. PMID- 24755633 TI - Stimulant dependence and stimulant-associated psychosis: clinical characteristics and age of onset in a native American community sample. AB - OBJECTIVES: Native Americans experience some of the highest rates of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) stimulant dependence (SD) of all US ethnic groups. The present report examined the clinical characteristics and age of onset of stimulant use, SD, remission from SD, and stimulant-associated psychosis (SAP) in a Native American community sample. METHODS: Demographic information, stimulant (methamphetamine or cocaine) use, and lifetime Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) psychiatric disorder diagnoses were assessed in 858 Native Americans. Logistic regression was used to assess the associations of demographic, stimulant use, and psychiatric disorder variables with SD, remission from SD, and SAP. Kaplan-Meier survival analyses were used to assess time from first use to the onset of SD. RESULTS: The overall rate of SD was 33%, of remission from SD 73%, and of SAP 17%. Stimulant dependence was associated with older age, less current annual household income, fewer lifetime years of education, intravenous stimulant use, and earlier age of first stimulant use. Remission from SD was associated with older age, currently being married, and never having used stimulants intravenously. Attention-deficit/hyperactivity disorder (assessed as a lifetime disorder), increased number of years of daily stimulant use, and intravenous use were independently associated with SAP. Younger age at first use was significantly associated with shorter survival to the onset of SD. CONCLUSIONS: Stimulant dependence is prevalent in this population and is associated with less income and education and an earlier age at first use. Intravenous stimulant use adds additional risk for SD, nonremission, and psychosis. PMID- 24755635 TI - Effects of age, adipose percent, and reproduction on PCB concentrations and profiles in an extreme fasting North Pacific marine mammal. AB - Persistent organic pollutants, including polychlorinated biphenyls (PCBs), are widely distributed and detectable far from anthropogenic sources. Northern elephant seals (Mirounga angustirostris) biannually travel thousands of kilometers to forage in coastal and open-ocean regions of the northeast Pacific Ocean and then return to land where they fast while breeding and molting. Our study examined potential effects of age, adipose percent, and the difference between the breeding and molting fasts on PCB concentrations and congener profiles in blubber and serum of northern elephant seal females. Between 2005 and 2007, we sampled blubber and blood from 58 seals before and after a foraging trip, which were then analyzed for PCBs. Age did not significantly affect total PCB concentrations; however, the proportion of PCB congeners with different numbers of chlorine atoms was significantly affected by age, especially in the outer blubber. Younger adult females had a significantly greater proportion of low-chlorinated PCBs (tri-, tetra-, and penta-CBs) than older females, with the opposite trend observed for hepta-CBs, indicating that an age-associated process such as parity (birth) may significantly affect congener profiles. The percent of adipose tissue had a significant relationship with inner blubber PCB concentrations, with the highest mean concentrations observed at the end of the molting fast. These results highlight the importance of sampling across the entire blubber layer when assessing contaminant levels in phocid seals and taking into account the adipose stores and reproductive status of an animal when conducting contaminant research. PMID- 24755636 TI - Spectroscopic and density functional theory studies of trans-3-(trans-4 imidazolyl)acrylic acid. AB - The structural parameters, thermodynamic properties and vibrational frequencies of the optimised geometry of trans-3-(trans-4-imidazolyl)acrylic acid have been determined from B3LYP methods with 6-311++G(**) and cc-pVTZ basis sets. The effects of substituents (acrylyl group) on the imidazole vibrational frequencies are analysed. The vibrational frequencies of the fundamental modes of trans-3 (trans-4-imidazolyl)acrylic acid have been precisely assigned and analysed and the theoretical results are compared with the experimental vibrations. (1)H and (13)C NMR isotropic chemical shifts are calculated and the assignments made are compared with the experimental values. The energies of important MO's of the compound are also determined from DFT method. The total electron density and electrostatic potential of the compound are determined by natural bond orbital analysis. Various reactivity and selectivity descriptors such as chemical hardness, chemical potential, softness, electrophilicity, nucleophilicity and the appropriate local quantities employing natural population analysis (NPA) are calculated. PMID- 24755637 TI - Crystal structure and vibrational spectral studies of a new organic-inorganic crystal: 4-Benzylpiperidinium trioxonitrate. AB - Single crystals of a new organic-inorganic crystal, 4-benzylpiperidinium trioxonitrate (4-BPPN) were grown by slow evaporation at room temperature and were characterized by X-ray diffraction, DTA-TG measurement, FT-IR and FT-Raman spectroscopies. The title compound crystallizes in the monoclinic system P21/c at room temperature with the following parameters: a=12.787(8)A, b=9.007(5)A, c=11.120(5)A, beta=95.974(2) degrees and Z=4. Its crystal structure is packing of alternated inorganic and organic layers parallel to (a, c) planes. The different components are connected by a bi-dimensional network of N-H?O hydrogen bonds. The ability of ions to form spontaneous three-dimensional structure through N-H?O hydrogen bond is fully utilized. These hydrogen bonds give notable vibrational effects. The optimized molecular structure and the vibrational spectra were calculated by the Density Functional Theory (DFT) method using the B3LYP function with the 6-31G(d) basis set. All observed vibrational bands have been discussed and assigned to normal mode or to combinations on the basis of our DFT calculations as a primary source of attribution and also by comparison with the previous results for similar compounds. Good consistency is found between the calculated results and the experimental structure, IR, and Raman spectra. PMID- 24755639 TI - Synthesis, spectral, SHG efficiency and computational studies of some newly synthesized unsymmetrical azines of 4-biphenylcarboxaldehyde. AB - A series of novel unsymmetrical azines 2-8 are prepared and characterized by FT IR, (1)H, (13)C NMR, Mass and UV spectral studies. The Gaussian-03 B3LYP/6 311+G(d,p) calculations on these azines are used to evaluate the heat of formation of the different conformers, identify the stable conformation, to determine dipole moment (MU), polarizability (alpha0), first hyperpolarizability (betatot), selected geometrical parameters, MEP surface, frontier molecular orbital energies (HOMO-LUMO) and their energy gap. The MU, alpha0, betatot values clearly depict that the unsymmetrical azine 8 is found to have a good NLO property compared to other azines 1-7. The SHG measurement of unsymmetrical azine 8 was performed by Kurtz and Perry powder method and the results indicated that the azine 8 is having comparable efficiency as that of potassium dihydrogen phosphate (KDP) crystal. The natural bond orbital (NBO) analysis of the unsymmetrical azines 2-8 are also made using B3LYP/6-31G(d,p) basis set. PMID- 24755638 TI - Spectroscopic investigations, antimicrobial, and cytotoxic activity of green synthesized gold nanoparticles. AB - The gold nanoparticles (AuNPs) were synthesized by using naturally available Punica Granatum fruit extract as reducing and stabilizing agent. The biosynthesized AuNPs was characterized by using UV-Vis, fluorescence, high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), Fourier transform infrared (FTIR) and thermogravimetric (TGA) analysis. The surface plasmon resonance (SPR) band at 585nm confirmed the reduction of auric chloride to AuNPs. The crystalline nature of the biosynthesized AuNPs was confirmed from the HRTEM images, XRD and selected area electron diffraction (SAED) pattern. The HRTEM images showed the mixture of triangular and spherical like AuNPs having size between 5 and 20nm. The weight loss of the AuNPs was measured by TGA as a function of temperature under a controlled atmosphere. The biomolecules are responsible for the reduction of AuCl4(-) ions and the formation of stable AuNPs which was confirmed by FTIR measurement. The synthesized AuNPs showed an excellent antibacterial activity against Candida albicans (ATCC 90028), Aspergillus flavus (ATCC 10124), Staphylococcus aureus (ATCC 25175), Salmonella typhi (ATCC 14028) and Vibrio cholerae (ATCC 14033). The minimum inhibitory concentration (MIC) of AuNPs was recorded against various microorganisms. Further, the synthesized AuNPs shows an excellent cytotoxic result against HeLa cancer cell lines at different concentrations. PMID- 24755640 TI - The mucosal adjuvant cyclic di-AMP exerts immune stimulatory effects on dendritic cells and macrophages. AB - The cyclic di-nucleotide bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di AMP) is a candidate mucosal adjuvant with proven efficacy in preclinical models. It was shown to promote specific humoral and cellular immune responses following mucosal administration. To date, there is only fragmentary knowledge on the cellular and molecular mode of action of c-di-AMP. Here, we report on the identification of dendritic cells and macrophages as target cells of c-di-AMP. We show that c-di-AMP induces the cell surface up-regulation of T cell co stimulatory molecules as well as the production of interferon-beta. Those responses were characterized by in vitro experiments with murine and human immune cells and in vivo studies in mice. Analyses of dendritic cell subsets revealed conventional dendritic cells as principal responders to stimulation by c-di-AMP. We discuss the impact of the reported antigen presenting cell activation on the previously observed adjuvant effects of c-di-AMP in mouse immunization studies. PMID- 24755642 TI - p-type Mesoscopic nickel oxide/organometallic perovskite heterojunction solar cells. AB - In this article, we present a new paradigm for organometallic hybrid perovskite solar cell using NiO inorganic metal oxide nanocrystalline as p-type electrode material and realized the first mesoscopic NiO/perovskite/[6,6]-phenyl C61 butyric acid methyl ester (PC61BM) heterojunction photovoltaic device. The photo induced transient absorption spectroscopy results verified that the architecture is an effective p-type sensitized junction, which is the first inorganic p-type, metal oxide contact material for perovskite-based solar cell. Power conversion efficiency of 9.51% was achieved under AM 1.5 G illumination, which significantly surpassed the reported conventional p-type dye-sensitized solar cells. The replacement of the organic hole transport materials by a p-type metal oxide has the advantages to provide robust device architecture for further development of all-inorganic perovskite-based thin-film solar cells and tandem photovoltaics. PMID- 24755641 TI - Microsecond time-resolved absorption spectroscopy used to study CO compounds of cytochrome bd from Escherichia coli. AB - Cytochrome bd is a tri-heme (b558, b595, d) respiratory oxygen reductase that is found in many bacteria including pathogenic species. It couples the electron transfer from quinol to O2 with generation of an electrochemical proton gradient. We examined photolysis and subsequent recombination of CO with isolated cytochrome bd from Escherichia coli in one-electron reduced (MV) and fully reduced (R) states by microsecond time-resolved absorption spectroscopy at 532-nm excitation. Both Soret and visible band regions were examined. CO photodissociation from MV enzyme possibly causes fast (tau<1.5 us) electron transfer from heme d to heme b595 in a small fraction of the protein, not reported earlier. Then the electron migrates to heme b558 (tau~16 us). It returns from the b-hemes to heme d with tau~180 us. Unlike cytochrome bd in the R state, in MV enzyme the apparent contribution of absorbance changes associated with CO dissociation from heme d is small, if any. Photodissociation of CO from heme d in MV enzyme is suggested to be accompanied by the binding of an internal ligand (L) at the opposite side of the heme. CO recombines with heme d (tau~16 us) yielding a transient hexacoordinate state (CO-Fe2+-L). Then the ligand slowly (tau~30 ms) dissociates from heme d. Recombination of CO with a reduced heme b in a fraction of the MV sample may also contribute to the 30-ms phase. In R enzyme, CO recombines to heme d (tau~20 us), some heme b558 (tau~0.2-3 ms), and finally migrates from heme d to heme b595 (tau~24 ms) in ~5% of the enzyme population. Data are consistent with the recent nanosecond study of Rappaport et al. conducted on the membranes at 640-nm excitation but limited to the Soret band. The additional phases were revealed due to differences in excitation and other experimental conditions. PMID- 24755643 TI - The relation between thematic role computing and semantic relatedness processing during on-line sentence comprehension. AB - Sentence comprehension involves timely computing different types of relations between its verbs and noun arguments, such as morphosyntactic, semantic, and thematic relations. Here, we used EEG technique to investigate the potential differences in thematic role computing and lexical-semantic relatedness processing during on-line sentence comprehension, and the interaction between these two types of processes. Mandarin Chinese sentences were used as materials. The basic structure of those sentences is "Noun+Verb+'le'+a two-character word", with the Noun being the initial argument. The verb disambiguates the initial argument as an agent or a patient. Meanwhile, the initial argument and the verb are highly or lowly semantically related. The ERPs at the verbs revealed that: relative to the agent condition, the patient condition evoked a larger N400 only when the argument and verb were lowly semantically related; however, relative to the high-relatedness condition, the low-relatedness condition elicited a larger N400 regardless of the thematic relation; although both thematic role variation and semantic relatedness variation elicited N400 effects, the N400 effect elicited by the former was broadly distributed and reached maximum over the frontal electrodes, and the N400 effect elicited by the latter had a posterior distribution. In addition, the brain oscillations results showed that, although thematic role variation (patient vs. agent) induced power decreases around the beta frequency band (15-30 Hz), semantic relatedness variation (low-relatedness vs. high-relatedness) induced power increases in the theta frequency band (4-7 Hz). These results suggested that, in the sentence context, thematic role computing is modulated by the semantic relatedness between the verb and its argument; semantic relatedness processing, however, is in some degree independent from the thematic relations. Moreover, our results indicated that, during on-line sentence comprehension, thematic role computing and semantic relatedness processing are mediated by distinct neural systems. PMID- 24755644 TI - Human survivin and Trypanosoma cruzi calreticulin act in synergy against a murine melanoma in vivo. AB - Immune-based anti-tumor or anti-angiogenic therapies hold considerable promise for the treatment of cancer. The first approach seeks to activate tumor antigen specific T lymphocytes while, the second, delays tumor growth by interfering with blood supply. Tumor Associated Antigens are often employed to target tumors with therapeutic drugs, but some are also essential for tumor viability. Survivin (Surv) is a member of the inhibitor of apoptosis protein family that is considered a Tumor Associated Antigen important for cancer cell viability and proliferation. On the other hand, Trypanosoma cruzi (the agent of Chagas' disease) calreticulin (TcCRT) displays remarkable anti-angiogenic properties. Because these molecules are associated with different tumor targets, we reasoned that immunization with a Surv-encoding plasmid (pSurv) and concomitant TcCRT administration should generate a stronger anti-tumor response than application of either treatment separately. To evaluate this possibility, C57BL/6 mice were immunized with pSurv and challenged with an isogenic melanoma cell line that had been pre-incubated with recombinant TcCRT (rTcCRT). Following tumor cell inoculation, mice were injected with additional doses of rTcCRT. For the combined regimen we observed in mice that: i). Tumor growth was impaired, ii). Humoral anti-rTcCRT immunity was induced and, iii). In vitro rTcCRT bound to melanocytes, thereby promoting the incorporation of human C1q and subsequent macrophage phagocytosis of tumor cells. These observations are interpreted to reflect the consequence of the following sequence of events: rTcCRT anti-angiogenic activity leads to stress in tumor cells. Murine CRT is then translocated to the external membrane where, together with rTcCRT, complement C1 is captured, thus promoting tumor phagocytosis. Presentation of the Tumor Associated Antigen Surv induces the adaptive anti-tumor immunity and, independently, mediates anti-endothelial cell immunity leading to an important delay in tumor growth. PMID- 24755646 TI - Prediction models discriminating between nonlocomotive and locomotive activities in children using a triaxial accelerometer with a gravity-removal physical activity classification algorithm. AB - The aims of our study were to examine whether a gravity-removal physical activity classification algorithm (GRPACA) is applicable for discrimination between nonlocomotive and locomotive activities for various physical activities (PAs) of children and to prove that this approach improves the estimation accuracy of a prediction model for children using an accelerometer. Japanese children (42 boys and 26 girls) attending primary school were invited to participate in this study. We used a triaxial accelerometer with a sampling interval of 32 Hz and within a measurement range of +/-6 G. Participants were asked to perform 6 nonlocomotive and 5 locomotive activities. We measured raw synthetic acceleration with the triaxial accelerometer and monitored oxygen consumption and carbon dioxide production during each activity with the Douglas bag method. In addition, the resting metabolic rate (RMR) was measured with the subject sitting on a chair to calculate metabolic equivalents (METs). When the ratio of unfiltered synthetic acceleration (USA) and filtered synthetic acceleration (FSA) was 1.12, the rate of correct discrimination between nonlocomotive and locomotive activities was excellent, at 99.1% on average. As a result, a strong linear relationship was found for both nonlocomotive (METs = 0.013*synthetic acceleration +1.220, R2 = 0.772) and locomotive (METs = 0.005*synthetic acceleration +0.944, R2 = 0.880) activities, except for climbing down and up. The mean differences between the values predicted by our model and measured METs were -0.50 to 0.23 for moderate to vigorous intensity (>3.5 METs) PAs like running, ball throwing and washing the floor, which were regarded as unpredictable PAs. In addition, the difference was within 0.25 METs for sedentary to mild moderate PAs (<3.5 METs). Our specific calibration model that discriminates between nonlocomotive and locomotive activities for children can be useful to evaluate the sedentary to vigorous PAs intensity of both nonlocomotive and locomotive activities. PMID- 24755645 TI - Evaluating new therapies in gastrointestinal stromal tumor using in vivo molecular optical imaging. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the US. The majority (~85%) of GISTs possess gain-of-function mutations in KIT or PDGFRA, causing constitutive activation of the kinase receptor. GIST management has been transformed by the identification of tumor driver mutations leading to unprecedented disease control of advanced GIST with the introduction of imatinib mesylate (IM). Despite IM's efficacy, most patients experience primary and/or secondary resistance within 2 y of treatment. Additional therapies and methods to optimize screening of novel approaches in preclinical studies are warranted. Clinically, treatment efficacy is typically assessed using Response Evaluation Criteria In Solid Tumors (RECIST) guidelines or Choi criteria. Both require a period of time on therapy before changes indicative of response can be observed. In addition, neither informs directly about cell death. We evaluated the use of molecular imaging technology in an animal model using near-infrared (NIR) imaging probes together with three-dimensional fluorescence molecular tomography (FMT) for assessing therapeutic response and ultimately optimizing our understanding of the biologic effects of these agents. We determined the potential of NIR probes (PSVue(TM) 794 and cell-penetrating KcapQ647) for detecting distinct markers of apoptosis and compare this to tumor size measured by MRI in response to IM treatment in GIST-T1 xenografts. Our studies revealed statistically significant increases in apoptosis due to IM treatment using both probes as early as 24 h post IM treatment which was confirmed by IHC. Molecular imaging will allow for faster and more effective screening of novel therapies in preclinical GIST models. PMID- 24755647 TI - 1H NMR-based lipidomics of rodent fur: species-specific lipid profiles and SCD1 inhibitor-related dermal toxicity. AB - A method is described that allows noninvasive identification and quantitative assessment of lipid classes present in sebaceous excretions in rodents. The method relies on direct high-field proton NMR analysis of common group lipid protons in deuterated organic solvent extracts of fur. Extracts from as little as 15 mg of fur from rat, mouse, and hamster provided acceptable results on a 600 MHz NMR equipped with a cryogenically cooled proton-observe probe. In rats, sex- and age-related differences in lipid composition are larger than differences in fur collected from various body regions within an individual and much larger than interanimal differences in age- and sex-matched specimens. The utility of this method to noninvasively monitor drug-induced sebaceous gland atrophy in rodents is demonstrated in rats dosed with a stearoyl-CoA desaturase 1 (SCD1) inhibitor. In this model, a 35% reduction in sebum lipids, extracted from fur, was observed. Finally, structural elucidation of cholesta-7,24-dien-3beta-ol ester as the most prominent, previously unidentified sebum sterol ester in male Syrian hamsters is described. The utility of this method for drug and cosmetic safety and efficacy assessment is discussed. PMID- 24755648 TI - The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis. AB - Liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IGF2BP2-2 induces a fatty liver, which highly expresses IGF2 Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These findings underline the detrimental role of p62 in liver disease. PMID- 24755649 TI - The rainbow trout genome provides novel insights into evolution after whole genome duplication in vertebrates. AB - Vertebrate evolution has been shaped by several rounds of whole-genome duplications (WGDs) that are often suggested to be associated with adaptive radiations and evolutionary innovations. Due to an additional round of WGD, the rainbow trout genome offers a unique opportunity to investigate the early evolutionary fate of a duplicated vertebrate genome. Here we show that after 100 million years of evolution the two ancestral subgenomes have remained extremely collinear, despite the loss of half of the duplicated protein-coding genes, mostly through pseudogenization. In striking contrast is the fate of miRNA genes that have almost all been retained as duplicated copies. The slow and stepwise rediploidization process characterized here challenges the current hypothesis that WGD is followed by massive and rapid genomic reorganizations and gene deletions. PMID- 24755650 TI - The mitochondrial permeability transition pore is a dispensable element for mitochondrial calcium efflux. AB - The mitochondrial permeability transition pore (mPTP) has long been known to have a role in mitochondrial calcium (Ca(2+)) homeostasis under pathological conditions as a mediator of the mitochondrial permeability transition and the activation of the consequent cell death mechanism. However, its role in the context of mitochondrial Ca(2+) homeostasis is not yet clear. Several studies that were based on PPIF inhibition or knock out suggested that mPTP is involved in the Ca(2+) efflux mechanism, while other observations have revealed the opposite result. The c subunit of the mitochondrial F1/FO ATP synthase has been recently found to be a fundamental component of the mPTP. In this work, we focused on the contribution of the mPTP in the Ca(2+) efflux mechanism by modulating the expression of the c subunit. We observed that forcing mPTP opening or closing did not impair mitochondrial Ca(2+) efflux. Therefore, our results strongly suggest that the mPTP does not participate in mitochondrial Ca(2+) homeostasis in a physiological context in HeLa cells. PMID- 24755651 TI - An improved procedure for subcellular spatial alignment during live-cell CLEM. AB - Live-cell correlative light and electron microscopy (CLEM) offers unique insights into the ultrastructure of dynamic cellular processes. A critical and technically challenging part of CLEM is the 3-dimensional relocation of the intracellular region of interest during sample processing. We have developed a simple CLEM procedure that uses toner particles from a laser printer as orientation marks. This facilitates easy tracking of a region of interest even by eye throughout the whole procedure. Combined with subcellular fluorescence markers for the plasma membrane and nucleus, the toner particles allow for precise subcellular spatial alignment of the optical and electron microscopy data sets. The toner-based reference grid is printed and transferred onto a polymer film using a standard office printer and laminator. We have also designed a polymer film holder that is compatible with most inverted microscopes, and have validated our strategy by following the ultrastructure of mitochondria that were selectively photo irradiated during live-cell microscopy. In summary, our inexpensive and robust CLEM procedure simplifies optical imaging, without limiting the choice of optical microscope. PMID- 24755652 TI - Prenatal alcohol exposure modifies glucocorticoid receptor subcellular distribution in the medial prefrontal cortex and impairs frontal cortex-dependent learning. AB - Prenatal alcohol exposure (PAE) has been shown to impair learning, memory and executive functioning in children. Perseveration, or the failure to respond adaptively to changing contingencies, is a hallmark on neurobehavioral assessment tasks for human fetal alcohol spectrum disorder (FASD). Adaptive responding is predominantly a product of the medial prefrontal cortex (mPFC) and is regulated by corticosteroids. In our mouse model of PAE we recently reported deficits in hippocampal formation-dependent learning and memory and a dysregulation of hippocampal formation glucocorticoid receptor (GR) subcellular distribution. Here, we examined the effect of PAE on frontal cortical-dependent behavior, as well as mPFC GR subcellular distribution and the levels of regulators of intracellular GR transport. PAE mice displayed significantly reduced response flexibility in a Y-maze reversal learning task. While the levels of total nuclear GR were reduced in PAE mPFC, levels of GR phosphorylated at serines 203, 211 and 226 were not significantly changed. Cytosolic, but not nuclear, MR levels were elevated in the PAE mPFC. The levels of critical GR trafficking proteins, FKBP51, Hsp90, cyclophilin 40, dynamitin and dynein intermediate chain, were altered in PAE mice, in favor of the exclusion of GR from the nucleus, indicating dysregulation of GR trafficking. Our findings suggest that there may be a link between a deficit in GR nuclear localization and frontal cortical learning deficits in prenatal alcohol-exposed mice. PMID- 24755654 TI - Design strategy for photoinduced electron transfer-based small-molecule fluorescent probes of biomacromolecules. AB - As the cardinal support of innumerable biological processes, biomacromolecules such as proteins, nucleic acids and polysaccharides are of importance to living systems. The key to understanding biological processes is to realize the role of these biomacromolecules in thte localization, distribution, conformation and interaction with other molecules. With the current development and adaptation of fluorescent technologies in biomedical and pharmaceutical fields, the fluorescence imaging (FLI) approach of using small-molecule fluorescent probes is becoming an up-to-the-minute method for the detection and monitoring of these imperative biomolecules in life sciences. However, conventional small-molecule fluorescent probes may provide undesirable results because of their intrinsic deficiencies such as low signal-to-noise ratio (SNR) and false-positive errors. Recently, small-molecule fluorescent probes with a photoinduced electron transfer (PET) "on/off" switch for biomacromolecules have been thoroughly considered. When recognized by the biomacromolecules, these probes turn on/off the PET switch and change the fluorescence intensity to present a high SNR result. It should be emphasized that these PET-based fluorescent probes could be advantageous for understanding the pathogenesis of various diseases caused by abnormal expression of biomacromolecules. The discussion of this successful strategy involved in this review will be a valuable guide for the further development of new PET-based small-molecule fluorescent probes for biomacromolecules. PMID- 24755653 TI - Mutations in BIN1 associated with centronuclear myopathy disrupt membrane remodeling by affecting protein density and oligomerization. AB - The regulation of membrane shapes is central to many cellular phenomena. Bin/Amphiphysin/Rvs (BAR) domain-containing proteins are key players for membrane remodeling during endocytosis, cell migration, and endosomal sorting. BIN1, which contains an N-BAR domain, is assumed to be essential for biogenesis of plasma membrane invaginations (T-tubules) in muscle tissues. Three mutations, K35N, D151N and R154Q, have been discovered so far in the BAR domain of BIN1 in patients with centronuclear myopathy (CNM), where impaired organization of T tubules has been reported. However, molecular mechanisms behind this malfunction have remained elusive. None of the BIN1 disease mutants displayed a significantly compromised curvature sensing ability. However, two mutants showed impaired membrane tubulation both in vivo and in vitro, and displayed characteristically different behaviors. R154Q generated smaller membrane curvature compared to WT N BAR. Quantification of protein density on membranes revealed a lower membrane bound density for R154Q compared to WT and the other mutants, which appeared to be the primary reason for the observation of impaired deformation capacity. The D151N mutant was unable to tubulate liposomes under certain experimental conditions. At medium protein concentrations we found 'budding' structures on liposomes that we hypothesized to be intermediates during the tubulation process except for the D151N mutant. Chemical crosslinking assays suggested that the D151N mutation impaired protein oligomerization upon membrane binding. Although we found an insignificant difference between WT and K35N N-BAR in in vitro assays, depolymerizing actin in live cells allowed tubulation of plasma membranes through the K35N mutant. Our results provide insights into the membrane-involved pathophysiological mechanisms leading to human disease. PMID- 24755656 TI - US agency warns against morcellation in hysterectomies and myomectomies. PMID- 24755655 TI - Development of an HbA1c-based conversion equation for estimating glycated albumin in a Korean population with a wide range of glucose intolerance. AB - BACKGROUND: Compared to the golden standard glycation index of HbA1c, glycated albumin (GA) has potentials for assessing insulin secretory dysfunction and glycemic fluctuation as well as predicting diabetic vascular complications. However, the reference ranges of GA and a conversion equation need to be clearly defined. We designed this study to determine the reference ranges in patients with normal glucose tolerance (NGT) based on conventional measures of glycemic status and to devise a conversion equation for calculating HbA1c and GA in a Korean population. METHODOLOGY/PRINCIPAL FINDINGS: In this multicenter, retrospective, cross-sectional study, we recruited antidiabetic drug-naive patients with available glycemic variables including HbA1c, GA, and fasting plasma glucose regardless of glucose status. For the reference interval of serum GA, 5th to 95th percentile value of GA in subjects with NGT was adopted. The conversion equation between HbA1c and GA was devised using an estimating regression model with unknown break-points method. The reference range for GA was 9.0-14.0% in 2043 subjects. The 95th percentile responding values for FPG, and HbA1c were approximately 5.49 mmol/l, and 5.6%, respectively. The significant glycemic turning points were 5.868% HbA1c and 12.2% GA. The proposed conversion equation for below and above the turning point were GA (%) = 6.960+0.8963 * HbA1c (%) and GA (%) = -9.609+3.720 * HbA1c (%), respectively. CONCLUSIONS/SIGNIFICANCE: These results should be helpful in future studies on the clinical implications of high GA relative to HbA1c and the clinical implementation of diabetes management. PMID- 24755657 TI - PcExl1 a novel acid expansin-like protein from the plant pathogen Pectobacterium carotovorum, binds cell walls differently to BsEXLX1. AB - Microbial expansins act on plant cell walls similarly to plant expansins, albeit their loosening activity levels are tenfold lesser compared to plant expansins. We report the characterization of an expansin-like gene from the plant pathogen Pectobacterium carotovorum, named exl1. PcExl1 is an acidic protein that binds cellulose (Avicel), and weakens filter paper. The acidic nature of PcExl1 confers different binding properties when compared to Bacillus subtilis BsEXLX1, which is a basic protein. PcExl1 binding to wheat cell wall increased when acidic components were depleted, reaching a similar level to the binding to Avicel, indicating that cellulose is the target of PcExl1. PMID- 24755658 TI - A hyperoxic lung injury model in premature rabbits: the influence of different gestational ages and oxygen concentrations. AB - BACKGROUND: Many animal models have been developed to study bronchopulmonary dysplasia (BPD). The preterm rabbit is a low-cost, easy-to-handle model, but it has a high mortality rate in response to the high oxygen concentrations used to induce lung injury. The aim of this study was to compare the mortality rates of two models of hyperoxia-induced lung injury in preterm rabbits. METHODS: Pregnant New Zealand white rabbits were subjected to caesarean section on gestational day 28 or 29 (full term = 31 days). The premature rabbits in the 28-day gestation group were exposed to room air or FiO2 >=95%, and the rabbits in the 29-day gestation group were exposed to room air or FiO2 = 80% for 11 days. The mean linear intercept (Lm), internal surface area (ISA), number of alveoli, septal thickness and proportion of elastic and collagen fibers were quantified. RESULTS: The survival rates in the 29-day groups were improved compared with the 28-day groups. Hyperoxia impaired the normal development of the lung, as demonstrated by an increase in the Lm, the septal thickness and the proportion of elastic fibers. Hyperoxia also decreased the ISA, the number of alveoli and the proportion of collagen fibers in the 28-day oxygen-exposed group compared with the control 28 day group. A reduced number of alveoli was found in the 29-day oxygen exposed animals compared with the control 29-day group. CONCLUSIONS: The 29-day preterm rabbits had a reduced mortality rate compared with the 28-day preterm rabbits and maintained a reduction in the alveoli number, which is comparable to BPD in humans. PMID- 24755659 TI - The aryl hydrocarbon receptor is constitutively active in advanced prostate cancer cells. AB - BACKGROUND: Distant prostate cancers are commonly hormone refractory and exhibit increased growth no longer inhibited by androgen deprivation therapy. Understanding all molecular mechanisms contributing to uncontrolled growth is important to obtain effective treatment strategies for hormone refractory prostate cancers (HRPC). The aryl hydrocarbon receptor (AhR) affects a number of biological processes including cell growth and differentiation. Several studies have revealed that exogenous AhR ligands inhibit cellular proliferation but recent evidence suggests AhR may possess intrinsic functions that promote cellular proliferation in the absence of exogenous ligands. METHODS/RESULTS: qRT PCR and western blot analysis was used to determine AhR mRNA and protein expression in hormone sensitive LNCaP cells as well as hormone refractory DU145, PC3 and PC3M prostate cancer cell lines. LNCaP cells express AhR mRNA and protein at a much lower level than the hormone refractory cell models. Cellular fractionation and immunocytochemistry revealed nuclear localization of AhR in the established hormone refractory cell lines while LNCaP cells are devoid of nuclear AhR protein. qRT-PCR analysis used to assess basal CYP1B1 levels and a xenobiotic responsive element binding assay confirmed ligand independent transcriptional activity of AhR in DU145, PC3 and PC3M cells. Basal CYP1B1 levels were decreased by treatment with specific AhR inhibitor, CH223191. An in vitro growth assay revealed that CH223191 inhibited growth of DU145, PC3 and PC3M cells in an androgen depleted environment. Immunohistochemical staining of prostate cancer tissues revealed increased nuclear localization of AhR in grade 2 and grade 3 cancers compared to the well differentiated grade 1 cancers. CONCLUSIONS: Together, these results show that AhR is constitutively active in advanced prostate cancer cell lines that model hormone refractory prostate cancer. Chemical ablation of AhR signaling can reduce the growth of advanced prostate cancer cells, an effect not achieved with androgen receptor inhibitors or growth in androgen depleted media. PMID- 24755660 TI - The effect of antifibrotic drugs in rat precision-cut fibrotic liver slices. AB - Two important signaling pathways in liver fibrosis are the PDGF- and TGFbeta pathway and compounds inhibiting these pathways are currently developed as antifibrotic drugs. Testing antifibrotic drugs requires large numbers of animal experiments with high discomfort. Therefore, a method to study these drugs ex vivo was developed using precision-cut liver slices from fibrotic rat livers (fPCLS), representing an ex vivo model with a multicellular fibrotic environment. We characterized the fibrotic process in fPCLS from rat livers after 3 weeks of bile duct ligation (BDL) during incubation and tested compounds predominantly inhibiting the TGFbeta pathway (perindopril, valproic acid, rosmarinic acid, tetrandrine and pirfenidone) and PDGF pathway (imatinib, sorafenib and sunitinib). Gene expression of heat shock protein 47 (Hsp47), alpha smooth muscle actin (alphaSma) and pro-collagen 1A1 (Pcol1A1) and protein expression of collagens were determined. During 48 hours of incubation, the fibrosis process continued in control fPCLS as judged by the increased gene expression of the three fibrosis markers, and the protein expression of collagen 1, mature fibrillar collagen and total collagen. Most PDGF-inhibitors and TGFbeta inhibitors significantly inhibited the increase in gene expression of Hsp47, alphaSma and Pcol1A1. Protein expression of collagen 1 was significantly reduced by all PDGF-inhibitors and TGFbeta-inhibitors, while total collagen was decreased by rosmarinic acid and tetrandrine only. However, fibrillar collagen expression was not changed by any of the drugs. In conclusion, rat fPCLS can be used as a functional ex vivo model of established liver fibrosis to test antifibrotic compounds inhibiting the PDGF- and TGFbeta signalling pathway. PMID- 24755661 TI - Hospital Case Volume Is Associated With Improved Survival for Patients With Metastatic Melanoma. AB - OBJECTIVES: Hospital case volume has been shown to be a predictor of patient mortality for treatment for various cancers. The influence of hospital case volume on malignant melanoma survival and treatment utilization is unknown. METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare linked databases to identify patients aged 65 years or older diagnosed with metastatic melanoma between 2000 and 2009. We analyzed claims data to ascertain cancer treatment variation by hospital case volume. Overall survival was evaluated using propensity score methods. RESULTS: Among 1438 patients, 612 (42.6%) were treated in low-volume hospitals (<=5 patients) after receiving their diagnosis, 479 (33.3%) were treated in intermediate-volume hospitals (6 to 10 patients), and 347 (24.1%) were treated in high-volume hospitals (>10 patients). In Cox proportional hazards models, treatment in a high-volume hospital after propensity score adjustment was associated with a significant improvement in survival when adjusting for other characteristics (intermediate volume: hazard ratio [HR]=0.70, P=0.0007; high volume: HR=0.63, P<0.0001). Patients treated in high-volume hospitals were less likely to receive chemotherapy, surgery, and/or radiation therapy after a metastatic melanoma diagnosis. CONCLUSIONS: For patients diagnosed with metastatic melanoma, being treated in a high-volume hospital was associated with an improvement in survival and lower utilization of chemotherapy, immunotherapy, surgery, and radiation therapy. PMID- 24755662 TI - Prognostic Significance of Nodal Ratio in Patients Undergoing Adjuvant Chemoradiotherapy After Curative Resection for Ampullary Cancer. AB - OBJECTIVES: To analyze the outcome of patients with ampullary cancer who had undergone curative surgery followed by adjuvant chemoradiotherapy and to identify the prognostic factors for these patients METHODS: : Between January 1991 and August 2006, 71 patients with ampullary cancer underwent curative resection followed by adjuvant radiotherapy. There were 38 males and 33 females, and median age was 56 years (range, 28 to 77 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 to 50 Gy at 2 Gy/fraction; 67 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 72 months for survivors. RESULTS: There were 5 isolated locoregional recurrences, 20 isolated distant metastases, and 11 combined locoregional and distant relapses. The 5-year locoregional relapse-free and overall survival rates were 76.2% and 64.5%, respectively. On multivariate analysis, nodal ratio and histologic differentiation were significant prognostic factors for overall survival (P=0.0382 and 0.0331, respectively). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival rate in patients with ampullary cancer. Nodal ratio and histologic differentiation are independent prognostic factors for these patients. PMID- 24755663 TI - Outcomes Following Hypofractionated Stereotactic Radiotherapy in the Management of Brain Metastases. AB - OBJECTIVE: To evaluate the outcomes of patients treated with hypofractionated stereotactic radiotherapy (HSRT) for radiosensitive and radioresistant brain metastases. METHODS: Between August 2006 and July 2013, a total of 56 lesions in 44 patients with brain metastases were treated with HSRT. Twenty-three (41.1%) lesions were radioresistant. Patients were treated to a total dose of 24 to 30 Gy in 3 to 5 fractions. Median planning target volume was 6.18 cm. The primary endpoint for this study was local control with secondary endpoints of overall survival, distant failure, performance status, and treatment toxicity. RESULTS: The median follow-up for all patients was 5 months (range, 0.4 to 58.3 mo). Six- and 12-month Kaplan-Meier estimates of local control for all lesions were 85.6% and 79.4%, respectively. Radioresistant tumors had a 6- and 12-month local control rate of 87.0%, whereas radiosensitive tumors had a 6- and 12-month local control rate of 82.5% and 72.2%, respectively (P=0.41). Six- and 12-month distant brain control rates were 56.8% and 46.9%, respectively. Overall survival was significantly associated with recursive partitioning analysis classes I, II, and III (P=0.0003) and graded prognostic assessment classes 2 to 3 and 1 to 1.5 (P=0.041). CONCLUSIONS: HSRT is a safe and feasible alternative to single-session stereotactic radiosurgery for brain metastases. No difference was observed in local control rates between radioresistant and radiosensitive tumors. PMID- 24755664 TI - Long-term Outcomes After Gamma Knife Radiosurgery for Meningiomas. AB - BACKGROUND: Gamma knife stereotactic radiosurgery (SRS) has become an important management strategy for patients with meningiomas. Although prior reports have studied early tumor control, neurological response, and associated morbidity, our purpose was to use clinical and imaging studies to determine whether long-term outcomes remain stable over time. MATERIALS AND METHODS: We studied 290 consecutive patients (92 men and 198 women) who underwent gamma knife SRS for a meningioma between 1987 and 1997. The median tumor margin dose was 15 Gy and the median tumor volume was 5.5 mL. Target definition was performed using contrast enhanced computed tomography in 72 patients and magnetic resonance imaging in 218 patients. The median patient age at radiosurgery was 61 years. Twenty patients had a history of fractionated radiation therapy, 136 patients had undergone a subtotal resection, and 22 patients had recurrences after initial gross total resection. RESULTS: The overall tumor control rate was 91%. Twenty-six patients (9%) had evidence of delayed local tumor growth and 44 (15%) had regional tumor progression, which occurred at a median of 38 months. The 10- and 20-year actuarial rates of freedom from tumor progression of the targeted tumor were 87.7%+/-2.5% and 87.2%+/-4.2%. Of 234 patients who had symptoms before SRS (n=62, 26%) improved, 126 (54%) had no change in symptoms and 46 (20%) gradually worsened. Thirty-two of 34 (94%) asymptomatic patients remained asymptomatic. We found no difference in long-term tumor control rates between patients who had undergone craniotomy before radiosurgery (89%) and patients who underwent primary radiosurgery (93.1%). Adverse radiation effects were detected in 3.1% of patients. Factors associated with worse progression-free survival included prior radiation therapy (P<0.0001) and higher grade meningioma (P<0.0001). At a median of 8.7 years after SRS, 137 patients were dead at a median age of 77 years. CONCLUSIONS: We found that gamma knife SRS provided durable tumor control with low morbidity in meningioma patients. PMID- 24755665 TI - Social accountability of medical schools and academic primary care training in Latin America: principles but not practice. AB - BACKGROUND: Latin America has one of the highest rates of health disparities in the world and is experiencing a steep increase in its number of medical schools. It is not clear if medical school authorities consider social responsibility, defined as the institutional commitment to contribute to the improvement of community well-being, as a priority and if there are any organizational strategies that could reduce health disparities. OBJECTIVE: To study the significance and relevance of social responsibility in the academic training of medical schools in Latin America. METHODS: The study combined a qualitative thematic literature review of three databases with a quantitative design based on a sample of nine Latin American and non-Latin American countries. RESULTS: The thematic analysis showed high agreement among academic groups on considering medical schools as 'moral agents', part of a 'social contract' and with an institutional responsibility to reduce health disparities mainly through the implementation of strong academic primary care programs. The quantitative analysis showed a significant association between higher development of academic primary care programs and lower level of health disparities by country (P = 0.028). However, the data showed that most Latin American medical schools did not prioritize graduate primary care training. CONCLUSIONS: The study shows a discrepancy between the importance given to social responsibility and academic primary care training in Latin America and the practices implemented by medical schools. It highlights the need to refocus medical education policies in the region. PMID- 24755666 TI - Evaluation of mycobactericidal activity of selected chemical disinfectants and antiseptics according to European standards. AB - BACKGROUND: The history of the investigation of standardized mycobactericidal activity of disinfectants and antiseptics is not very long. There is growing interest among the manufacturers of disinfectants in carrying out research on the antimicrobial activities in accordance with European standards (EN). This research could facilitate the introduction of high-quality disinfectants to the market. The aim of this study was to evaluate the mycobactericidal activity of selected chemical disinfectants and antiseptics used in the medical and veterinary fields. MATERIAL AND METHODS: This study included 19 products submitted to the National Medicines Institute in Poland for evaluation of mycobactericidal activity. These products contain in their composition active substances belonging to different chemical groups, including aldehydes, alcohols, amines, quaternary ammonium compounds, phenols, guanidine, and oxidizing compounds. This study, conducted according to the manufacturers' description of the preparations, was carried out in accordance with European standards, which also met the Polish standards: PN-EN 14204: 2013, PN-EN 14348: 2006, and PN-EN 14563: 2012. RESULTS: Tested products for disinfection and antiseptics containing active substances from different chemical groups showed high mycobactericidal activity and met the requirements of the appropriate European standards in most cases. In the case of products containing guanidine and amine compounds, the concentration of active ingredients used in the test and the test conditions specified by the manufacturer did not provide the mycobactericidal activity required by the standards. CONCLUSIONS: Prior to the launch of a new product on the market, it is important to establish the appropriate usage and testing conditions of the preparation, such as its practical concentration, contact time, and environment condition (clean or dirty). PMID- 24755667 TI - Positive airway pressure in patients with coronary artery disease and obstructive sleep apnea syndrome. AB - AIMS: We designed a prospective nonrandomized study aiming at assessing the impact of continuous positive airway pressure (CPAP) after a new diagnosis of obstructive sleep apnea syndrome (OSAS) in patients with coronary artery disease (CAD). METHODS: Consecutive patients referred to coronary angiography underwent an overnight sleep study during their hospital stay. Among those with angiographically confirmed CAD and a new diagnosis of moderate or severe OSAS, we compared the 3-year major adverse cardiac or cerebrovascular event (MACCE)-free survival stratified by CPAP at discharge. RESULTS: Of 496 patients undergoing an overnight sleep study, 129 had angiographically confirmed CAD and presented with moderate or severe OSAS. The incidence of 3-year MACCE was significantly lower in the CPAP-treated group (n = 17) than in the untreated group (n = 112; 12 vs. 44%, P = 0.02). After adjusting for differences in baseline characteristics, CPAP was significantly associated with a decreased risk of MACCE [adjusted hazard ratio 0.18, 95% confidence interval (CI) 0.04-0.78, P = 0.02]. Among men, CPAP was associated with a significant 3-year risk reduction in MACCE (adjusted hazard ratio 0.12, 95% CI 0.02-0.87, P = 0.04), whereas no significant benefit of CPAP was seen in women (adjusted hazard ratio 2.1, 95% CI 0.10-41.6, P = 0.63). The statistical interaction between CPAP and sex trended to be significant (adjusted P for interaction = 0.10). CONCLUSION: In patients with OSAS and CAD, the initiation of CPAP is associated with a significant reduction in MACCE compared with patients left untreated. PMID- 24755668 TI - On the fate of pumice rafts formed during the 2012 Havre submarine eruption. AB - Pumice rafts are floating mobile accumulations of low-density pumice clasts generated by silicic volcanic eruptions. Pumice in rafts can drift for years, become waterlogged and sink, or become stranded on shorelines. Here we show that the pumice raft formed by the impressive, deep submarine eruption of the Havre caldera volcano (Southwest Pacific) in July 2012 can be mapped by satellite imagery augmented by sailing crew observations. Far from coastal interference, the eruption produced a single >400 km(2) raft in 1 day, thus initiating a gigantic, high-precision, natural experiment relevant to both modern and prehistoric oceanic surface dispersal dynamics. Observed raft dispersal can be accurately reproduced by simulating drift and dispersal patterns using currents from an eddy-resolving ocean model hindcast. For future eruptions that produce potentially hazardous pumice rafts, our technique allows real-time forecasts of dispersal routes, in addition to inference of ash/pumice deposit distribution in the deep ocean. PMID- 24755669 TI - Candida albicans suppresses nitric oxide generation from macrophages via a secreted molecule. AB - Macrophages and neutrophils generate a potent burst of reactive oxygen and nitrogen species as a key aspect of the antimicrobial response. While most successful pathogens, including the fungus Candida albicans, encode enzymes for the detoxification of these compounds and repair of the resulting cellular damage, some species actively modulate immune function to suppress the generation of these toxic compounds. We report here that C. albicans actively inhibits macrophage production of nitric oxide (NO). NO production was blocked in a dose dependent manner when live C. albicans were incubated with either cultured or bone marrow-derived mouse macrophages. While filamentous growth is a key virulence trait, yeast-locked fungal cells were still capable of dose-dependent NO suppression. C. albicans suppresses NO production from macrophages stimulated by exposure to IFN-gamma and LPS or cells of the non-pathogenic Saccharomyces cerevisiae. The NO inhibitory activity was produced only when the fungal cells were in direct contact with macrophages, but the compound itself was secreted into the culture media. LPS/IFNgamma stimulated macrophages cultured in cell-free conditioned media from co-cultures showed reduced levels of iNOS enzymatic activity and lower amounts of iNOS protein. Initial biochemical characterization of this activity indicates that the inhibitor is a small, aqueous, heat-stable compound. In summary, C. albicans actively blocks NO production by macrophages via a secreted mediator; these findings expand our understanding of phagocyte modulation by this important fungal pathogen and represent a potential target for intervention to enhance antifungal immune responses. PMID- 24755670 TI - Effects of core self-evaluations on the job burnout of nurses: the mediator of organizational commitment. AB - OBJECTIVE: To explore the impact of Core self-evaluations on job burnout of nurses, and especially to test and verify the mediator role of organizational commitment between the two variables. METHOD: Random cluster sampling was used to pick up participants sample, which consisted of 445 nurses of a hospital in Shanghai. Core self-evaluations questionnaire, job burnout scale and organizational commitment scale were administrated to the study participants. RESULTS: There are significant relationships between Core self-evaluations and dimensions of job burnout and organizational commitment. There is a significant mediation effect of organizational commitment between Core self-evaluations and job burnout. CONCLUSIONS: To enhance nurses' Core self-evaluations can reduce the incidence of job burnout. PMID- 24755671 TI - Characterization of nitrite degradation by Lactobacillus casei subsp. rhamnosus LCR 6013. AB - Nitrites are potential carcinogens. Therefore, limiting nitrites in food is critically important for food safety. The nitrite degradation capacity of Lactobacillus casei subsp. rhamnosus LCR 6013 was investigated in pickle fermentation. After LCR 6013 fermentation for 120 h at 37 degrees C, the nitrite concentration in the fermentation system was significantly lower than that in the control sample without the LCR 6013 strain. The effects of NaCl and Vc on nitrite degradation by LCR 6013 in the De Man, Rogosa and Sharpe (MRS) medium were also investigated. The highest nitrite degradations, 9.29 mg/L and 9.89 mg/L, were observed when NaCl and Vc concentrations were 0.75% and 0.02%, respectively in the MRS medium, which was significantly higher than the control group (p <= 0.01). Electron capture/gas chromatography and indophenol blue staining were used to study the nitrite degradation pathway of LCR 6013. The nitrite degradation products contained N2O, but no NH4(+). The LCR 6013 strain completely degraded all NaNO2 (50.00 mg/L) after 16 h of fermentation. The enzyme activity of NiR in the periplasmic space was 2.5 times of that in the cytoplasm. Our results demonstrated that L. casei subsp. rhamnosus LCR 6013 can effectively degrade nitrites in both the pickle fermentation system and in MRS medium by NiR. Nitrites are degraded by the LCR 6013 strain, likely via the nitrate respiration pathway (NO2(-)>NO->N2O->N2), rather than the aammonium formation pathway (dissimilatory nitrate reduction to ammonium, DNRA), because the degradation products contain N2O, but not NH4(+). PMID- 24755672 TI - The soul-sucking wasp by popular acclaim--museum visitor participation in biodiversity discovery and taxonomy. AB - Taxonomy, the science of describing and naming of the living world, is recognized as an important and relevant field in modern biological science. While there is wide agreement on the importance of a complete inventory of all organisms on Earth, the public is partly unaware of the amount of known and unknown biodiversity. Out of the enormous number of undescribed (but already recognized) species in natural history museum collections, we selected an attractive example of a wasp, which was presented to museum visitors at a special museum event. We asked 300 visitors to vote on a name for the new species and out of four preselected options, Ampulex dementor Ohl n. sp. was selected. The name, derived from the 'soul sucking' dementors from the popular Harry Potter books is an allusion to the wasps' behavior to selectively paralyze its cockroach prey. In this example, public voting on a scientific name has been shown to be an appropriate way to link museum visitors emotionally to biodiversity and its discovery. PMID- 24755673 TI - Apolipoprotein E gene polymorphism and risk for coronary heart disease in the Chinese population: a meta-analysis of 61 studies including 6634 cases and 6393 controls. AB - BACKGROUND: Numerous studies have evaluated the association between the apolipoprotein E (apoE) gene polymorphisms in coronary heart disease (CHD). However, the results remain uncertain. We carried out a meta-analysis to derive a more comprehensive estimation of the association in Chinese population. METHODS: Case-control studies in Chinese and English publications were identified by searching databases of PubMed, EMBASE, Web of Science, CNKI, CBM, Wanfang, VIP and hand searching of relevant journals and the reference lists of retrieved articles. Odds ratio (OR) and 95% confidence interval (CI) were applied to assess the strength of the associations. Subgroup analysis and sensitivity analysis were performed to explore the between-study heterogeneity. RESULTS: We finally identified 61 relevant studies which comprised 6634 case-patients and 6393 controls. The pooled OR for epsilon4 carriers was 96% higher than the epsilon3/3 genotype for CHD (OR, 1.96; 95% CI, 1.70 to 2.24; P<0.001). However, there was no evidence of statistically significant association between epsilon2 carriers and risk of CHD (OR, 1.02; 95% CI, 0.91 to 1.13; P = 0.729). In the subgroup analysis, different endpoints may partially account for the heterogeneity. No publication bias was found. CONCLUSIONS: Our meta-analysis suggests that the apoE epsilon4 allele may be a risk factor for CHD in the Chinese population, however, epsilon2 allele has no significant association. PMID- 24755675 TI - The secretome of endothelial progenitor cells promotes brain endothelial cell activity through PI3-kinase and MAP-kinase. AB - BACKGROUND: Angiogenesis and vascular remodelling are crucial events in tissue repair mechanisms promoted by cell transplantation. Current evidence underscores the importance of the soluble factors secreted by stem cells in tissue regeneration. In the present study we investigated the effects of paracrine factors derived from cultured endothelial progenitor cells (EPC) on rat brain endothelial cell properties and addressed the signaling pathways involved. METHODS: Endothelial cells derived from rat brain (rBCEC4) were incubated with EPC-derived conditioned medium (EPC-CM). The angiogenic response of rBCEC4 to EPC CM was assessed as effect on cell number, migration and tubular network formation. In addition, we have compared the outcome of the in vitro experiments with the effects on capillary sprouting from rat aortic rings. The specific PI3K/AKT inhibitor LY294002 and the MEK/ERK inhibitor PD98059 were used to study the involvement of these two signaling pathways in the transduction of the angiogenic effects of EPC-CM. RESULTS: Viable cell number, migration and tubule network formation were significantly augmented upon incubation with EPC-CM. Similar findings were observed for aortic ring outgrowth with significantly longer sprouts. The EPC-CM-induced activities were significantly reduced by the blockage of the PI3K/AKT and MEK/ERK signaling pathways. Similarly to the outcome of the rBCEC4 experiments, inhibition of the PI3K/AKT and MEK/ERK pathways significantly interfered with capillary sprouting induced by EPC-CM. CONCLUSION: The present study demonstrates that EPC-derived paracrine factors substantially promote the angiogenic response of brain microvascular endothelial cells. In addition, our findings identified the PI3K/AKT and MEK/ERK pathways to play a central role in mediating these effects. PMID- 24755674 TI - Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer. AB - This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAK(Y397) were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P<0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P<0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P<0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors. PMID- 24755676 TI - Multi-modal assessment of long-term erythropoietin treatment after neonatal hypoxic-ischemic injury in rat brain. AB - Erythropoietin (EPO) has been recognized as a neuroprotective agent. In animal models of neonatal brain injury, exogenous EPO has been shown to reduce lesion size, improve structure and function. Experimental studies have focused on short course treatment after injury. Timing, dose and length of treatment in preterm brain damage remain to be defined. We have evaluated the effects of high dose and long-term EPO treatment in hypoxic-ischemic (HI) injury in 3 days old (P3) rat pups using histopathology, magnetic resonance imaging (MRI) and spectroscopy (MRS) as well as functional assessment with somatosensory-evoked potentials (SEP). After HI, rat pups were assessed by MRI for initial damage and were randomized to receive EPO or vehicle. At the end of treatment period (P25) the size of resulting cortical damage and white matter (WM) microstructure integrity were assessed by MRI and cortical metabolism by MRS. Whisker elicited SEP were recorded to evaluate somatosensory function. Brains were collected for neuropathological assessment. The EPO treated animals did not show significant decrease of the HI induced cortical loss at P25. WM microstructure measured by diffusion tensor imaging was improved and SEP response in the injured cortex was recovered in the EPO treated animals compared to vehicle treated animals. In addition, the metabolic profile was less altered in the EPO group. Long-term treatment with high dose EPO after HI injury in the very immature rat brain induced recovery of WM microstructure and connectivity as well as somatosensory cortical function despite no effects on volume of cortical damage. This indicates that long-term high-dose EPO induces recovery of structural and functional connectivity despite persisting gross anatomical cortical alteration resulting from HI. PMID- 24755677 TI - NF-kappa B modulation is involved in celastrol induced human multiple myeloma cell apoptosis. AB - Celastrol is an active compound extracted from the root bark of the traditional Chinese medicine Tripterygium wilfordii Hook F. To investigate the effect of celastrol on human multiple myeloma cell cycle arrest and apoptosis and explore its molecular mechanism of action. The activity of celastrol on LP-1 cell proliferation was detected by WST-8 assay. The celastrol-induced cell cycle arrest was analyzed by flow cytometry after propidium iodide staining. Nuclear translocation of the nuclear factor kappa B (NF-kappaB) was observed by fluorescence microscope. Celastrol inhibited cell proliferation of LP-1 myeloma cell in a dose-dependent manner with IC50 values of 0.8817 uM, which was mediated through G1 cell cycle arrest and p27 induction. Celastrol induced apoptosis in LP 1 and RPMI 8226 myeloma cells in a time and dose dependent manner, and it involved Caspase-3 activation and NF-kappaB pathway. Celastrol down-modulated antiapoptotic proteins including Bcl-2 and survivin expression. The expression of NF-kappaB and IKKa were decreased after celastrol treatment. Celastrol effectively blocked the nuclear translocation of the p65 subunit and induced human multiple myeloma cell cycle arrest and apoptosis by p27 upregulation and NF kB modulation. It has been demonstrated that the effect of celastrol on NF-kB was HO-1-independent by using zinc protoporphyrin-9 (ZnPPIX), a selective heme oxygenase inhibitor. From the results, it could be inferred that celastrol may be used as a NF-kB inhibitor to inhibit myeloma cell proliferation. PMID- 24755679 TI - Regulation of endothelial-specific transgene expression by the LacI repressor protein in vivo. AB - Genetically modified mice have played an important part in elucidating gene function in vivo. However, conclusions from transgenic studies may be compromised by complications arising from the site of transgene integration into the genome and, in inducible systems, the non-innocuous nature of inducer molecules. The aim of the present study was to use the vascular system to validate a technique based on the bacterial lac operon system, in which transgene expression can be repressed and de-repressed by an innocuous lactose analogue, IPTG. We have modified an endothelium specific promoter (TIE2) with synthetic LacO sequences and made transgenic mouse lines with this modified promoter driving expression of mutant forms of connexin40 and an independently translated reporter, EGFP. We show that tissue specificity of this modified promoter is retained in the vasculature of transgenic mice in spite of the presence of LacO sequences, and that transgene expression is uniform throughout the endothelium of a range of adult systemic and cerebral arteries and arterioles. Moreover, transgene expression can be consistently down-regulated by crossing the transgenic mice with mice expressing an inhibitor protein LacI(R), and in one transgenic line, transgene expression could be de-repressed rapidly by the innocuous inducer, IPTG. We conclude that the modified bacterial lac operon system can be used successfully to validate transgenic phenotypes through a simple breeding schedule with mice homozygous for the LacI(R) protein. PMID- 24755680 TI - Electroporation and microinjection successfully deliver single-stranded and duplex DNA into live cells as detected by FRET measurements. AB - Forster resonance energy transfer (FRET) technology relies on the close proximity of two compatible fluorophores for energy transfer. Tagged (Cy3 and Cy5) complementary DNA strands forming a stable duplex and a doubly-tagged single strand were shown to demonstrate FRET outside of a cellular environment. FRET was also observed after transfecting these DNA strands into fixed and live cells using methods such as microinjection and electroporation, but not when using lipid based transfection reagents, unless in the presence of the endosomal acidification inhibitor bafilomycin. Avoiding the endocytosis pathway is essential for efficient delivery of intact DNA probes into cells. PMID- 24755681 TI - Community-based network study of protein-carbohydrate interactions in plant lectins using glycan array data. AB - Lectins play major roles in biological processes such as immune recognition and regulation, inflammatory responses, cytokine signaling, and cell adhesion. Recently, glycan microarrays have shown to play key roles in understanding glycobiology, allowing us to study the relationship between the specificities of glycan binding proteins and their natural ligands at the omics scale. However, one of the drawbacks in utilizing glycan microarray data is the lack of systematic analysis tools to extract information. In this work, we attempt to group various lectins and their interacting carbohydrates by using community based analysis of a lectin-carbohydrate network. The network consists of 1119 nodes and 16769 edges and we have identified 3 lectins having large degrees of connectivity playing the roles of hubs. The community based network analysis provides an easy way to obtain a general picture of the lectin-glycan interaction and many statistically significant functional groups. PMID- 24755682 TI - DPP-4 inhibitor attenuates toxic effects of indoxyl sulfate on kidney tubular cells. AB - Diabetic nephropathy is a common causative factor of chronic kidney disease (CKD). DPP-4 inhibitor has the ability to improve kidney function and renal microvasculature. In the present study, we investigate the deleterious effects of IS on proximal tubular cells and the protective role of DPP-4 inhibitor. Human kidney 2 (HK-2) cells were exposed to IS in the presence or absence of DPP-4 inhibitor. Effects of DPP-4 inhibitor on viability of HK-2 cells were determined by MTT assay. Reactive oxygen species (ROS) production was examined using fluorescent microscopy. Levels of cleaved caspase-3, transforming growth factor beta (TGF-beta), alpha-smooth muscle actin (alpha-SMA) and NF-kappaB p65 and phosphorylation of AKT and extracellular signal-regulated kinase (ERK) were detected by immunoblotting. Production of ROS and level of cleaved caspase-3 were increased by IS in a dose-dependent manner. The phosphorylation of AKT and ERK p65 were decreased alongside activation of NF-kappaB. Expression of TGF-beta and alpha-SMA, were upregulated in IS-treated HK-2 cells. Treatment with DPP-4 inhibitor resulted in a significant increase in cell viability and a decrease of ROS production in IS-treated HK-2 cells. DPP-4 inhibitor restored IS-induced deactivations of AKT and ERK and inhibited activation of NF-kappaB in IS-treated HK-2 cells. Moreover, DPP-4 inhibitor could also attenuate IS-induced up regulation of TGF-beta and alpha-SMA expression. These findings suggest that DPP 4 inhibitor possesses anti-apoptotic activity to ameliorate the IS-induced renal damage, which may be partly attributed to regulating ROS/p38MAPK/ERK and PI3K-AKT pathways as well as downstream NF-kappaB signaling pathway. PMID- 24755683 TI - Superior tensile ductility in bulk metallic glass with gradient amorphous structure. AB - Over centuries, structural glasses have been deemed as a strong yet inherently 'brittle' material due to their lack of tensile ductility. However, here we report bulk metallic glasses exhibiting both a high strength of ~2 GPa and an unprecedented tensile elongation of 2-4% at room temperature. Our experiments have demonstrated that intense structural evolution can be triggered in theses glasses by the carefully controlled surface mechanical attrition treatment, leading to the formation of gradient amorphous microstructures across the sample thickness. As a result, the engineered amorphous microstructures effectively promote multiple shear banding while delay cavitation in the bulk metallic glass, thus resulting in superior tensile ductility. The outcome of our research uncovers an unusual work-hardening mechanism in monolithic bulk metallic glasses and demonstrates a promising yet low-cost strategy suitable for producing large sized, ultra-strong and stretchable structural glasses. PMID- 24755684 TI - Dietary flaxseed modulates the miRNA profile in irradiated and non-irradiated murine lungs: a novel mechanism of tissue radioprotection by flaxseed. AB - INTRODUCTION: Dietary flaxseed (FS) displays antioxidant and anti-inflammatory properties in preclinical models of lung disease including radiation-induced pneumonopathy, however the mechanisms of lung radioprotection are incompletely understood. MicroRNAs (miRNAs) are short oligonucleotides that act as important posttranscriptional regulators of diverse networks including inflammatory response networks. Responses of miRNA profiles to diet and radiation exposure have been reported, but the potential contribution of miRNAs to diet-related radioprotection has never been tested. METHODS: In this exploratory pilot study, mice were fed 10% FS or a 0% FS isocaloric control diet and exposed to a single fraction 13.5 Gy thoracic X-ray radiation treatment (XRT). Lung RNA was extracted 48 h post-XRT and small RNAs profiled by OpenArray. RESULTS: FS significantly modulated expression of multiple miRNAs, including 7 with P<0.001. miR-150 was downregulated approximately 2.9-fold in the FS groups and is disproportionately integrated into immune response-related networks. Although few miRNAs were significantly changed by radiation, interaction between diet and radiation was observed. For example, miR-29c was greatly downregulated in the FS/Control group (10- to 50-fold) but slightly upregulated in the FS/radiation group. Compared with FS/control, the FS/radiation group experienced a 50% decrease of the p53 responsive miR-34a, which regulates senescence- and apoptosis-related factors. CONCLUSIONS: FS induced significant changes in lung miRNA profile suggesting that modulation of small RNA by dietary supplements may represent a novel strategy to prevent adverse side-effects of thoracic radiotherapy. This pilot study provides insight into a potential mechanism of flaxseed's radioprotection and provides a useful model-system to further explore and optimize such small RNA-based therapies. PMID- 24755685 TI - The diagnostic importance of matrix metalloproteinase-7 and nestin in gastrointestinal stromal tumors. AB - BACKGROUND: The importance of the matrix metalloproteinase-7 (MMP-7) and nestin immunomarkers, C-kit proto-oncogene (CD117), and the efficiency of the Ki-67 proliferation index for gastrointestinal stromal tumors were evaluated. MATERIAL AND METHODS: This study was conducted by examining the microscope slides of 72 patients with gastrointestinal stromal tumors that were sent to the pathology laboratory between 2007 and 2012. Immunohistochemical staining for CD117, MMP-7, nestin, and marker of proliferation Ki-67 was performed. The correlations between the positive results for Ki-67, CD117, MMP-7, and nestin were evaluated relative to the tumor characteristics of size, localization, grade, cellular type, cellularity, cytology type, growth pattern, ulceration, necrosis, hemorrhage, invasion depth, and lymph node metastasis. RESULTS: The tumor was localized in the stomach in 42 of the patients, the intestines in 19, the colon in 7, and the rectum in 4. Comparisons among the groups showed that MMP-7 was correlated with the tumor grade (p<0.001), cellularity (p<0.009), cytologic atypia (p<0.001), ulceration (p=0.002), necrosis (p<0.001), and tumor size (p=0.001). Nestin was correlated with the tumor grade (p=0.013), and tumor size (p=0.024). Correlations among CD117, MMP-7, nestin, and Ki-67 were examined. Nestin and Ki-67 were both significantly correlated with CD117 and MMP-7 [(r=0.279, p=0.018), (r=0.322, p=0.006), (r=0.386, p=0.001), (r=0.386, p=0.002)], respectively. CONCLUSIONS: MMP 7 and nestin may be beneficial as markers, given their sensitivity to gastrointestinal stromal tumors. PMID- 24755686 TI - Spatial/temporal variations and source apportionment of VOCs monitored at community scale in an urban area. AB - This study aimed to characterize spatial/temporal variations of ambient volatile organic compounds (VOCs) using a community-scale monitoring approach and identify the main sources of concern in Paterson, NJ, an urban area with mixed sources of VOCs. VOC samples were simultaneously collected from three local source-dominated (i.e., commercial, industrial, and mobile) sites in Paterson and one background site in Chester, NJ (located ~58 km southwest of Paterson). Samples were collected using the EPA TO-15 method from midnight to midnight, one in every sixth day over one year. Among the 60 analyzed VOCs, ten VOCs (acetylene, benzene, dichloromethane, ethylbenzene, methyl ethyl ketone, styrene, toluene, m,p-xylene, o-xylene, and p-dichlorobenzene) were selected to examine their spatial/temporal variations. All of the 10 VOCs in Paterson were significantly higher than the background site (p<0.01). Ethylbenzene, m,p-xylene, o-xylene, and p-dichlorobenzene measured at the commercial site were significantly higher than the industrial/mobile sites (p<0.01). Seven VOCs (acetylene, benzene, dichloromethane, methyl ethyl ketone, styrene, toluene, and p-dichlorobenzene) were significantly different by season (p<0.05), that is, higher in cold seasons than in warm seasons. In addition, dichloromethane, methyl ethyl ketone, and toluene were significantly higher on weekdays than weekend days (p<0.05). These results are consistent with literature data, indicating the impact of anthropogenic VOC sources on air pollution in Paterson. Positive Matrix Factorization (PMF) analysis was applied for 24-hour integrated VOC measurements in Paterson over one year and identified six contributing factors, including motor vehicle exhausts (20%), solvents uses (19%), industrial emissions (16%), mobile+stationery sources (12%), small shop emissions (11%), and others (22%). Additional locational analysis confirmed the identified sources were well matched with point sources located upwind in Paterson. The study demonstrated the community-scale monitoring approach can capture spatial variation of VOCs in an urban community with mixed VOC sources. It also provided robust data to identify major sources of concern in the community. PMID- 24755687 TI - Acute liver failure in rats activates glutamine-glutamate cycle but declines antioxidant enzymes to induce oxidative stress in cerebral cortex and cerebellum. AB - BACKGROUND AND PURPOSE: Liver dysfunction led hyperammonemia (HA) causes a nervous system disorder; hepatic encephalopathy (HE). In the brain, ammonia induced glutamate-excitotoxicity and oxidative stress are considered to play important roles in the pathogenesis of HE. The brain ammonia metabolism and antioxidant enzymes constitute the main components of this mechanism; however, need to be defined in a suitable animal model. This study was aimed to examine this aspect in the rats with acute liver failure (ALF). METHODS: ALF in the rats was induced by intraperitoneal administration of 300 mg thioacetamide/Kg. b.w up to 2 days. Glutamine synthetase (GS) and glutaminase (GA), the two brain ammonia metabolizing enzymes vis a vis ammonia and glutamate levels and profiles of all the antioxidant enzymes vis a vis oxidative stress markers were measured in the cerebral cortex and cerebellum of the control and the ALF rats. RESULTS: The ALF rats showed significantly increased levels of ammonia in the blood (HA) but little changes in the cortex and cerebellum. This was consistent with the activation of the GS-GA cycle and static levels of glutamate in these brain regions. However, significantly increased levels of lipid peroxidation and protein carbonyl contents were consistent with the reduced levels of all the antioxidant enzymes in both the brain regions of these ALF rats. CONCLUSION: ALF activates the GS-GA cycle to metabolize excess ammonia and thereby, maintains static levels of ammonia and glutamate in the cerebral cortex and cerebellum. Moreover, ALF induces oxidative stress by reducing the levels of all the antioxidant enzymes which is likely to play important role, independent of glutamate levels, in the pathogenesis of acute HE. PMID- 24755688 TI - Dobutamine in paediatric population: a systematic review in juvenile animal models. AB - OBJECTIVE: Although dobutamine is widely used in neonatal clinical practice, the evidence for its use in this specific population is not clear. We conducted a systematic review of the use of dobutamine in juvenile animals to determine whether the evidence from juvenile animal experiments with dobutamine supported the design of clinical trials in neonatal/paediatric population. METHODS: Studies were identified by searching MEDLINE (1946-2012) and EMBASE (1974-2012). Articles retrieved were independently reviewed by three authors and only those concerning efficacy and safety of the drug in juvenile animals were included. Only original articles published in English and Spanish were included. RESULTS: Following our literature search, 265 articles were retrieved and 24 studies were included in the review: 17 focused on neonatal models and 7 on young animal models. Although the aims and design of these studies, as well as the doses and ages analysed, were quite heterogeneous, the majority of authors agree that dobutamine infusion improves cardiac output in a dose dependent manner. Moreover, the cardiovascular effects of dobutamine are influenced by postnatal age, as well as by the dose used and the duration of the therapy. There is inadequate information about the effects of dobutamine on cerebral perfusion to draw conclusions. CONCLUSION: There is enough preclinical evidence to ensure that dobutamine improves cardiac output, however to better understand its effects in peripheral organs, such as the brain, more specific and well designed studies are required to provide additional data to support the design of clinical trials in a paediatric population. PMID- 24755689 TI - Parameters of gait among community-dwelling older adults. AB - BACKGROUND: Functional fitness is the ability of an older adult to perform activities of daily living. Stair-climb power is a well-documented marker of functional fitness among older adults. Gait velocity and parameters of gait are related to functional fitness but have been understudied to date. PURPOSE: The purpose of this observational study was to determine differences in parameters of gait between high- and low-functioning older adults. METHODS: Twenty high functioning older adults, mean age (SD)=71.6 (5.6), volunteered for the cross sectional observational study. Functional fitness was determined by a stair-climb performance test. Parameters of gait included velocity, step length, swing and stance phase, double support time, ground reaction forces, impulse, and propulsion during habitual walking. Analysis of variance was performed to determine differences in the dependent variables between groups. RESULTS: Individuals with high levels of functional fitness walked 13.1% faster than the lower-functioning group (P=.01). No significant differences (P>.05) were detected for any other measure; however, all gait parameters were more favorable in the higher-functioning group. CONCLUSION: Functional fitness is imperative for older adults as declines could hinder mobility. Thus, earlier detection of declines in gait parameters may reduce the risk of falling. The results suggest that gait velocity was slower among older adults with lower levels of functional fitness. PMID- 24755690 TI - Contribution of age and balance confidence to functional mobility test performance: diagnostic accuracy of L test and normal-paced timed up and go. AB - BACKGROUND AND PURPOSE: Falls are a public health priority. Contribution of age and balance confidence to functional mobility is unknown. Appropriate cutoff scores for normal-paced Timed Up and Go (TUG) and L test may improve ability to determine fall risk. Purposes were to determine the contribution of age and balance confidence to functional mobility, determine the association between balance confidence and fall risk, and propose cutoffs. METHODS: A prospective, descriptive study was conducted in the community with 105 apparently healthy adults at the age of 60 to 96 years. Participants provided fall history. Examiners administered the Activities-Specific Balance Confidence Scale, Dynamic Gait Index (DGI), Functional Gait Assessment, TUG, and L test. Linear regression determined the balance confidence contribution. Multivariate analysis of covariance determined differences between participants with high and low confidence. Sensitivity, specificity, overall diagnostic accuracy, and receiver operating characteristics curves were used to estimate cutoffs. RESULTS: Performance across functional mobility tests declined with age. A total of 46 participants had low balance confidence. Depending on the outcome measure, 16% to 30% of participants' balance confidence and physical performance did not match. Regression analysis revealed that the best model combines age and balance confidence. Regardless of age, participants with high and low balance confidence differed on the basis of multivariate analysis of covariance. Receiver operating characteristics curves supported the diagnostic accuracy of 12 or more seconds (normal-paced TUG) and 25.5 or more seconds (L test) cutoffs. DISCUSSION: We confirmed that functional mobility, as measured by the L test, declines with age similar to other outcome measures. Balance confidence contributes to functional mobility performance, and the 2 constructs do not match about 25% of the time. Because these constructs may not match, the need to formally assess balance confidence is warranted when concerned about fall risk. Cutoff scores to predict fall risk for the L test and normal-paced TUG are proposed using the DGI cutoff (<=19) as the reference standard. The proposed cutoff scores merit further testing with prospective fall data as the reference standard. CONCLUSIONS: Older adults would benefit if clinicians would assess balance confidence. PMID- 24755691 TI - Balance and gait of adults with very mild Alzheimer disease. AB - BACKGROUND AND PURPOSE: Studies have shown that adults with Alzheimer disease (AD) have gait and balance deficits; however, the focus has been on those with mild to severe disease. The purpose of this study was to determine whether balance and gait deficits are present in those with very mild AD. METHODS: Thirteen adults (72.9+/-4.7 years old) with very mild AD and 13 age-matched (72.6+/-4.6 years old) and sex-matched (10 males and 3 females) participants in a control group without AD performed balance and gait tests. All participants were living in the community and independent in community ambulation. RESULTS: Participants with very mild AD had shorter times in tandem stance with eyes open (P<0.001) and with eyes closed (P=0.007) compared with participants in the control group. Those with AD also took longer to complete the Timed "Up & Go" Test (P<0.001). Gait deficits were found for those with AD as demonstrated by slower velocities in the 10-m walk at a comfortable pace (P=0.029) and on an instrumented walkway (P<0.001). Stance times were longer for those with AD (P<0.001) and step length was shorter (P=0.001). There were no group differences in the 10-m walk at a fast pace. The gait velocity of participants in the control group was faster on the instrumented walkway than in the 10-m walk at a comfortable pace (P=0.031). In contrast, the gait velocity of those with AD was significantly slower on the instrumented walkway than in the 10-m walk at a comfortable pace (P=0.024). DISCUSSION: Balance and gait deficits may be present in those in the very early stages of AD. Novel surfaces may affect gait speed in those with very mild AD. Identifying mobility deficits early in the progression of AD may provide an opportunity for early physical therapy intervention, thus promoting continued functional independence. CONCLUSIONS: Adults in the very early stages of AD may show signs of balance and gait deficits. Recognition of these problems early with subsequent physical therapy may slow the progression of further balance and gait dysfunction. PMID- 24755692 TI - Targeted NGF siRNA delivery attenuates sympathetic nerve sprouting and deteriorates cardiac dysfunction in rats with myocardial infarction. AB - Nerve growth factor (NGF) is involved in nerve sprouting, hyper-innervation, angiogenesis, anti-apoptosis, and preservation of cardiac function after myocardial infarction (MI). Positively modulating NGF expression may represent a novel pharmacological strategy to improve post-infarction prognosis. In this study, lentivirus encoding NGF short interfering RNA (siRNA) was prepared, and MI was modeled in the rat using left anterior descending coronary artery ligation. Rats were randomly grouped to receive intramyocardial injection of lentiviral solution containing NGF-siRNA (n = 19, MI-SiNGF group), lentiviral solution containing empty vector (n = 18, MI-GFP group) or 0.9% NaCl solution (n = 18, MI control group), or to receive thoracotomy and pericardiotomy (n = 17, sham operated group). At 1, 2, 4, and 8 wk after transduction, rats in the MI-control group had higher levels of NGF mRNA and protein than those in the sham-operated group, rats in the MI-GFP group showed similar levels as the MI-control group, and rats in the MI-SiNGF group had lower levels compared to the MI-GFP group, indicating that MI model was successfully established and NGF siRNA effectively inhibited the expression of NGF. At 8 wk, echocardiographic and hemodynamic studies revealed a more severe cardiac dysfunction in the MI-siRNA group compared to the MI-GFP group. Moreover, rats in the MI-siRNA group had lower mRNA and protein expression levels of tyrosine hydroxylase (TH) and growth-associated protein 43-positive nerve fibers (GAP-43) at both the infarcted border and within the non-infarcted left ventricles (LV). NGF silencing also reduced the vascular endothelial growth factor (VEGF) expression and decreased the arteriolar and capillary densities at the infarcted border compared to the MI-GFP group. Histological analysis indicated a large infarcted size in the MI-SiNGF group. These findings suggested that endogenous NGF silencing attenuated sympathetic nerve sprouting and angiogenesis, enlarged the infarct size, aggravated cardiac dysfunction, and potentially contributed to an unfavorable prognosis after MI. PMID- 24755693 TI - Heterologous prime-boost vaccination with MF59-adjuvanted H5 vaccines promotes antibody affinity maturation towards the hemagglutinin HA1 domain and broad H5N1 cross-clade neutralization. AB - In an open label clinical study (2007), MF59-adjuvanted hemagglutinin (HA) vaccine from H5N1-A/Vietnam/1194/2004 (clade 1) was administered to subjects previously vaccinated (primed) with clade 0 H5N3 (A/duck/Singapore/97) vaccine at least 6 years earlier (in 1999 or 2001). The primed individuals responded rapidly and generated high neutralizing antibody titers against the H5N1-Vietnam strain within 7 days of a single booster vaccination. Furthermore, significant cross neutralization titers were measured against H5N1 clade 0, 1, and 2 viruses. In the current study, the impact of MF59 adjuvant during heterologous priming on the quality of humoral polyclonal immune response in different vaccine arms were further evaluated using real time kinetics assay by surface plasmon resonance (SPR). Total anti-H5N1 HA1 polyclonal sera antibody binding from the heterologous prime-boost groups after a single MF59-H5N1 boost was significantly higher compared with sera from unprimed individuals that received two MF59-H5N1 vaccinations. The antigen-antibody complex dissociation rates (surrogate for antibody affinity) of the polyclonal sera against HA1 of H5N1-A/Vietnam/1194/2004 from the MF59-H5N3 primed groups were significantly higher compared to sera from unadjuvanted primed groups or unprimed individuals that received two MF59-H5N1 vaccines. Furthermore, strong inverse correlations were observed between the antibody dissociation off-rates of the immune sera against HA1 (but not HA2) and the virus neutralization titers against H5 vaccine strains and heterologous H5N1 strains. These findings supports the use of oil-in-water-adjuvanted pandemic influenza vaccines to elicit long term memory B cells with high affinity BCR capable of responding to potential variant pandemic viruses likely to emerge and adapt to human transmissions. PMID- 24755695 TI - Clinical presentation and outcome of mesenteric vein thrombosis: a single-center experience. AB - Mesenteric venous thrombosis (MVT) is an uncommon event. We retrospectively analyzed data for patients who were admitted with MVT between June 2005 and May 2012 in Qatar. The study included 35 patients with a mean age of 45 +/- 11 years. The risk of MVT was significantly high among males who smoked and females of Arab ethnicity. The main manifestations of MVT were abdominal distension and vomiting. The major etiological factors included deficiency in protein C and S, homocysteinemia, and prior abdominal surgery. Computed tomography (CT) findings were helpful in 80% of the patients. Bowel resection with primary anastomosis was performed in 25 (71%) patients. The overall mortality rate was 17%. High index of suspicion, detection of risk factors, CT imaging, and timely intervention are essential for better prognosis. PMID- 24755696 TI - The effect of radiotherapy on aortic stiffness in patients with breast cancer: role of antihypertensive drugs and statins. PMID- 24755694 TI - Influence of tea consumption on acute myocardial infarction in China population: the INTERHEART China study. AB - We assessed the association between tea consumption and acute myocardial infarction (AMI) using INTERHEART China data. Cases (n = 2909) and controls (n = 2947) were randomly selected and frequency matched by age and sex. Participants who drank tea >=4 cups/d had a significantly higher risk of AMI than tea nondrinkers; odds ratio (OR) was 1.29 (95% confidence interval [CI]: 1.03-1.61) compared with tea nondrinkers. A similar trend was found in green tea drinkers; OR was 1.52 (95% CI: 1.13-2.05) in the participants who drank 3 cups/d and 1.73 (95% CI: 1.35-2.22) in the participants who drank >=4 cups/d compared with tea nondrinkers. We also found that green tea consumption had a greater effect on females; OR was 2.80 (95% CI: 1.43-5.50) in females. In conclusion, we found that the risk of AMI increases as tea consumption increases. Further studies are needed to confirm this association. PMID- 24755697 TI - How long do your angiographically normal coronary arteries remain normal? A pilot study. AB - Coronary atherosclerosis is a progressive disease. We sought to determine whether this fact also applies to patients at an advanced age with normal coronary arteries (NCAs) undergoing repeat catheterization at least 5 years later. Of the 189 patients who were found to have NCAs, 154 (81%) remained with NCAs and 35 (19%) developed obstructive coronary artery disease (OCAD). Development of OCAD was observed at all ages. Isolated risk factors were not associated with the appearance of OCAD, but the combination of diabetes mellitus with age >65 years or with smoking was associated with the appearance of OCAD (P = .04 for both). In conclusion, the finding of angiographically NCAs in elderly individuals does not prevent the later development of OCAD. PMID- 24755698 TI - Towards a better understanding and more efficient treatment of in-stent restenosis. PMID- 24755699 TI - Pathophysiology of superficial femoral artery in-stent restenosis. AB - Peripheral artery disease (PAD) is an emerging problem especially with aging population and increase in the incidence of diabetes and metabolic syndrome. The disease is histologically characterized by the presence of moderate to severe calcification and fibrous plaques as compared to coronary and carotid atherosclerotic disease, which are richer in necrotic core. Endovascular therapy for the superficial femoral artery (SFA), at least in the United States, has been largely limited to balloon angioplasty and stenting and these are considered safe and relatively effective therapies. However, the patency rates remain low even at one year and restenosis is a growing and challenging problem. Recently the development of newer devices, i.e., drug-eluting stent, and drug coated balloon are showing greater efficacy and are being adopted into daily practice. In this review, we will present the morphologic characteristics of the underlying SFA atherosclerotic disease and discuss in-stent restenosis and the mechanisms that may be involved in the induction of excessive smooth muscle cell proliferation and deposition of proteoglycans and collagen, that lead to restenosis. PMID- 24755700 TI - Femoropopliteal in-stent restenosis: current treatment strategies. AB - Nitinol self-expanding stents are increasingly used to treat symptomatic peripheral arterial disease. Despite reduction in procedural complications and rates of stent fracture, femoropopliteal in-stent restenosis (FP-ISR) remains a common and important clinical problem. Due to heterogenous patient and angiographic characteristics, treatment of FP-ISR continues to evolve. Multiple modalities have been evaluated including standard balloon angioplasty, cutting or scoring balloon angioplasty, repeat stenting (nitinol stent vs. stent-graft vs. drug eluting stent), excisional or laser atherectomy, drug coated balloon angioplasty, and atherectomy followed by drug coated balloon angioplasty. This review highlights the clinical evidence for the currently available modalities in the treatment of FP-ISR. Future studies should utilize uniform classification schemes and assess similar outcomes to help determine the optimal approach for endovascular treatment of FP-ISR. PMID- 24755701 TI - Management of in-stent restenosis in peripheral arteries: are DEBs sufficient as stand-alone treatment for femoro-popliteal in-stent restenosis? AB - The treatment of in-stent restenosis (ISR) in the femoro-popliteal artery (FPA) is one of the major challenges of endovascular therapy, occurring in up to 40% of femoro-popliteal lesions treated with bare-metal stents within 1 year of treatment. Drug-eluting technologies, involving local delivery of paclitaxel, are providing a new paradigm for the treatment of ISR. Preliminary experience shows promising results compared to other techniques such as cutting balloon angioplasty and debulking strategies. Based on available data, drug-eluting balloons (DEBs) seem sufficient as stand-alone treatment of FPA-ISR. However, larger evidence from randomized studies is warranted to identify the clinical and/or anatomical setting in which they could fail. PMID- 24755702 TI - Role of laser atherectomy for the management of in-stent restenosis in the peripheral arteries. AB - The prevalence of PAD is expected to increase as the population ages and the treatment for chronic disease becomes more sophisticated. The safety, efficacy, and lower cost of endovascular treatment for peripheral vascular disease of the lower extremities when compared with surgical revascularization are well known. Despite the clinical improvements and advances in endovascular techniques over the past decade, in-stent restenosis of peripheral arteries remains a challenge for the endovascular specialist. The use of excimer laser atherectomy has been shown to be safe and effective for the revascularization of complex, critical de novo peripheral lesions and offers promise in the treatment and prevention of in stent restenosis. PMID- 24755703 TI - Combination of mechanical atherectomy and drug-eluting balloons for femoropopliteal in-stent restenosis. AB - Mechanical atherectomy for instent restenosis (ISR) seems to be limited by a low patency rate. This might be due to the mechanical trauma that induces an inflammatory response leading to recurrent ISR. Addition of drug eluting balloon angioplasty could overcome these challenges while preserving the advantages of a better acute result. Due to lack of clinical data combination of atherectomy and DEB remains an experimental procedure for ISR treatment. PMID- 24755704 TI - Laser debulking and DEB for in-stent restenosis: technique and review of the literature. AB - This paper will describe the technique of the treatment of in-stent restenosis of the infrainguinal arteries, using a combined technique of laser debulking followed by drug-eluting balloon angioplasty. The results of this technique from the literature will be discussed, and a comparison with other techniques that are currently used will be made. PMID- 24755705 TI - The use fibrinogen/thrombin-coated equine collagen patch in children requiring reoperations for congenital heart disease. A single center clinical experience. AB - AIM: The aim of this study was to evaluate the efficacy and cost-effectiveness of fibrinogen/thrombin-coated collagen patch (FTCCP)(TachoSil(r)) during intraoperative hemostasis in patients with congenital heart disease, who required a reoperation during childhood. METHODS: We reviewed data on the intraoperative blood product requirements and hospital costs of children (age <16 years) who underwent a reoperation for treating their congenital heart disease between January 2009 and December 2011. RESULTS: One-hundred and seventeen patients were included. Median age at surgery was 2.1 years (range 3 days-14.1 years). Main causes of intraoperative bleeding were: 1) reinforcement of suture lines (106 patients, 90.6%); 2) lung lesions (5 patients, 4.2%); 3) epicardial lesions (3 patients, 2.6%); and 4) chest wall lesions (3 patients, 2.6%). At logistic regression the amount of packed red blood cells (PRBC) requirement was significantly higher in patients with preoperative cyanosis (P=0.008, OR=3.85) and in patients who required the use of cardiopulmonary bypass (P=0.005, OR=21.19). The use of FTCCP (N.=90 patients) as first line treatment was significantly associated with a lower PRBC requirement (P=0.0003, OR=0.1) which in addition to the avoidance of other hemostatic/sealant agents, leads to lower hospital cost. CONCLUSION: FTCCP is an effective hemostatic agent which can be safely used during the hemostasis of children requiring reoperations for their congenital heart malformations. When used as first line treatment, with specific indications, FTCCP limited the intraoperative PRBC requirement and the use of other hemostatic/sealant agents thus reducing hospital costs. PMID- 24755706 TI - One-stage coronary, carotid, aortobifemoral, and femoropoliteal surgery for concomitant critical ischemia in three vascular beds. PMID- 24755709 TI - Eternal Sunshine of the Spotless Machine: Protecting Privacy with Ephemeral Channels. AB - Modern systems keep long memories. As we show in this paper, an adversary who gains access to a Linux system, even one that implements secure deallocation, can recover the contents of applications' windows, audio buffers, and data remaining in device drivers-long after the applications have terminated. We design and implement Lacuna, a system that allows users to run programs in "private sessions." After the session is over, all memories of its execution are erased. The key abstraction in Lacuna is an ephemeral channel, which allows the protected program to talk to peripheral devices while making it possible to delete the memories of this communication from the host. Lacuna can run unmodified applications that use graphics, sound, USB input devices, and the network, with only 20 percentage points of additional CPU utilization. PMID- 24755707 TI - Differential expression of miR200a-3p and miR21 in grade II-III and grade IV gliomas: evidence that miR200a-3p is regulated by O6-methylguanine methyltransferase and promotes temozolomide responsiveness. AB - Glioblastoma multiforme (GBM) is the most common primary brain tumor and is among the deadliest of human cancers. Dysregulation of microRNAs (miRNAs) expression is an important step in tumor progression as miRNAs can act as tumor suppressors or oncogenes and may affect cell sensitivity to chemotherapy. Whereas the oncogenic miR21 has been shown to be overexpressed in gliomas, the expression and function of the tumor-supressor miR200a in GBMs remains unknown. In this study, we show that miR21 is upregulated in grade IV (GBMs) vs. grade II-III (LGs) gliomas, confirming that miR21 expression level is correlated with tumor grade, and that it may be considered as a marker of tumor progression. Conversely, miR200a is demonstrated for the first time to be downregulated in GBMs compared with LGs, and overexpression of miR200a in GBM cells is shown to promote TMZ-sensitivity. Interestingly, miR200a but not miR21 expression level is significantly higher in TMZ-responsive vs. -unresponsive tumoral glial cells in primary culture. Furthermore, miR200a appears negatively correlated with the expression of the DNA repair enzyme O (6)-methylguanine methyltransferase (MGMT), and the inhibition of MGMT activity results in an increase of miR200a expression in GBM cells. Taken together, these data strongly suggest that miR200a is likely to act as a crucial antitumoral factor regarding glioma progression. Interplay between miR200a and MGMT should be considered as potential mechanism involved in therapeutic response. PMID- 24755708 TI - Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors. AB - Genetically encoded fluorescence voltage sensors offer the possibility of directly visualizing neural spiking dynamics in cells targeted by their genetic class or connectivity. Sensors of this class have generally suffered performance limiting tradeoffs between modest brightness, sluggish kinetics and limited signalling dynamic range in response to action potentials. Here we describe sensors that use fluorescence resonance energy transfer (FRET) to combine the rapid kinetics and substantial voltage-dependence of rhodopsin family voltage sensing domains with the brightness of genetically engineered protein fluorophores. These FRET-opsin sensors significantly improve upon the spike detection fidelity offered by the genetically encoded voltage sensor, Arclight, while offering faster kinetics and higher brightness. Using FRET-opsin sensors we imaged neural spiking and sub-threshold membrane voltage dynamics in cultured neurons and in pyramidal cells within neocortical tissue slices. In live mice, rates and optical waveforms of cerebellar Purkinje neurons' dendritic voltage transients matched expectations for these cells' dendritic spikes. PMID- 24755710 TI - Arterial blood pressure is closely related to ascites development in compensated HCV-related cirrhosis. AB - BACKGROUND: Arterial blood pressure (BP) is a reliable marker of circulatory dysfunction in cirrhotic patients. There are no prospective studies evaluating the association between different levels of arterial BP and ascites development in compensated cirrhotic patients. Therefore, we evaluated the relationship between arterial BP and ascites development in compensated cirrhotic patients. MATERIALS AND METHODS: A total of 402 patients with compensated HCV-related cirrhosis were prospectively followed during 6 years to identify ascites development. At baseline, patients underwent systolic, diastolic and mean arterial pressure (MAP) measurements. Any history of arterial hypertension was also recorded. The occurrence of events such as bleeding, hepatocellular carcinoma, death and liver transplantation prior to ascites development were considered as competing risk events. RESULTS: Over a median of 156 weeks, ascites occurred in 54 patients (13%). At baseline, MAP was significantly lower in patients with ascites development (75.9 mm/Hg [95%CI, 70.3-84.3]) than those without ascites (93.6 mm/Hg [95% CI: 86.6-102.3]). After adjusting for covariates, the 6-year cumulative incidence of ascites was 40% (95%CI, 34%-48%) for patients with MAP<83.32 mm/Hg. In contrast, cumulative incidences of ascites were almost similar among patients with MAP values between 83.32 mm/Hg and 93.32 mm/Hg (7% [95% CI: 4%-12%]), between 93.32 mm/Hg and 100.31 mm/Hg (5% [95% CI: 4% 11%]) or higher than 100.31 mm/Hg (3% [95% CI: 1%-6%]). The MAP was an independent predictor of ascites development. CONCLUSIONS: The MAP is closely related to the development of ascites in compensated HCV-related cirrhosis. The risk of ascites development increases in 4.4 fold for subjects with MAP values <83.32 mm/Hg. PMID- 24755712 TI - Evidence that the lung Adenocarcinoma EML4-ALK fusion gene is not caused by exposure to secondhand tobacco smoke during childhood. AB - BACKGROUND: The EML4-ALK fusion gene is more frequently found in younger, never smoking patients with lung cancer. Meanwhile, never smokers exposed to secondhand tobacco smoke (SHS) during childhood are diagnosed at a younger age compared with never smoking patients with lung cancer who are not exposed. We, therefore, hypothesized that SHS, which can induce DNA damage, is associated with the EML4 ALK fusion gene. METHODS: We compared the frequency of the EML4-ALK fusion gene among 197 never smoker patients with lung cancer with and without a history of exposure to SHS during childhood at Mayo Clinic. RESULTS: The EML4-ALK fusion gene was detected in 33% of cases from never smokers with a history of SHS exposure during childhood, whereas 47% of never smoking lung cancer cases without a history of childhood SHS exposure tested positive for the fusion gene. CONCLUSIONS: The EML4-ALK fusion gene is not enriched in tumors from individuals exposed to SHS during childhood. IMPACT: These data suggest that childhood exposure to SHS is not a significant etiologic cause of the EML4-ALK fusion gene in lung cancer. PMID- 24755711 TI - GPBAR1/TGR5 mediates bile acid-induced cytokine expression in murine Kupffer cells. AB - GPBAR1/TGR5 is a novel plasma membrane-bound G protein-coupled bile acid (BA) receptor. BAs are known to induce the expression of inflammatory cytokines in the liver with unknown mechanism. Here we show that without other external stimuli, TGR5 activation alone induced the expression of interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in murine macrophage cell line RAW264.7 or murine Kupffer cells. The TGR5-mediated increase of pro-inflammatory cytokine expression was suppressed by JNK inhibition. Moreover, the induced pro inflammatory cytokine expression in mouse liver by 1% cholic acid (CA) diet was blunted in JNK-/- mice. TGR5 activation by its ligands enhanced the phosphorylation levels, DNA-binding and trans-activities of c-Jun and ATF2 transcription factors. Finally, the induced pro-inflammatory cytokine expression in Kupffer cells by TGR5 activation correlated with the suppression of Cholesterol 7alpha-hydroxylase (Cyp7a1) expression in murine hepatocytes. These results suggest that TGR5 mediates the BA-induced pro-inflammatory cytokine production in murine Kupffer cells through JNK-dependent pathway. This novel role of TGR5 may correlate to the suppression of Cyp7a1 expression in hepatocytes and contribute to the delicate BA feedback regulation. PMID- 24755713 TI - Intervention completion rates among African Americans in a randomized effectiveness trial for diet and physical activity changes. AB - BACKGROUND: The intervention completion rate is an important metric in behavioral and intervention research; trials with limited intervention completion rates may have reduced internal validity. We examined intervention completion rates among 530 African Americans who had been randomized to an integrated (INT) or disease specific (DSE) risk education protocol as part of a comparative effectiveness trial from September 2009 to August 2012. METHODS: The interventions were developed by an academic-community partnership using community-based participatory research. Intervention completion rates were determined based on attendance at all four intervention sessions. Intervention completers were participants who completed all four sessions and noncompleters were those who did not complete any session or only completed one to three sessions following randomization. RESULTS: Seventy-three percent of participants were intervention completers and 27% were noncompleters. There were no differences in intervention completion based on randomization to INT (72%) or DSE (75%), sociodemographic factors, or body mass index (BMI) in the total sample. Different factors were associated significantly with intervention completion within study groups. Among participants randomized to INT, the odds of intervention completion were greater with higher levels of intrinsic motivation, less exposure to information about diet and cardiovascular disease, and greater BMI. Among participants randomized to DSE, the odds of completing the intervention were associated significantly with older age and greater dietary self-efficacy. CONCLUSIONS: Many African Americans are likely to complete risk education interventions. IMPACT: Psychologic characteristics should be considered when determining intervention completion rates following randomization in behavioral and intervention trials. PMID- 24755714 TI - Risk of breast cancer recurrence associated with carbohydrate intake and tissue expression of IGFI receptor. AB - BACKGROUND: The insulin-like growth factor-I (IGFI) receptor is a potential target for breast cancer treatment and may be influenced by dietary intake. METHODS: Nested, case-control study of 265 postmenopausal breast cancer survivors; primary breast cancer tissue was stained to determine IGFI receptor status. Change in carbohydrate intake from baseline to year 1 of study was estimated from 24-hour dietary recalls. Breast cancer recurrence cases (91) were matched to two controls (n = 174) on disease and study characteristics and counter matched on change in carbohydrate intake. Weighted conditional logistic regression models fit the risk of recurrence on IGFI receptor status and dietary change. RESULTS: Half of the tumors were IGFI receptor positive. Increased risk of recurrence was associated with IGFI receptor-positive status [HR 1.7; 95% confidence interval (CI), 1.2-2.5] and, separately, with a stable/increased intake of carbohydrates (HR 2.0; 95% CI, 1.3-5.0). There was a borderline significant interaction between those two variables (P = 0.11). Specifically, carbohydrate intake had no significant impact on risk of recurrence among women who were receptor negative, yet increased the risk of recurrence by more than 5 fold among women who were receptor positive (HR 5.5; 95% CI, 1.8-16.3). CONCLUSIONS: Among women whose tumor tissue is positive for the IGFI receptor, reducing carbohydrate intake after diagnosis could reduce the risk of breast cancer recurrence. These findings need replication in a larger sample. IMPACT: This is the first study to suggest that it may be possible to personalize dietary recommendations for breast cancer survivors based on molecular characteristics of their primary tumor tissue. . PMID- 24755716 TI - Neuropathological evaluation of an 84-year-old man after 422 ECT treatments. AB - Concern remains among many that electroconvulsive therapy (ECT) causes "brain damage." This ambiguous term presumably refers to lesions that could, in principle, be observed either grossly or microscopically in postmortem studies, and the assertion that it occurs appears to be based largely on old reports with dubious relevance to modern practice. Fortunately, using modern technique, ECT is so safe that mortality around the time of treatment is extraordinarily rare and as a result there has been little opportunity for postmortem examination of individuals who had recently had ECT. We report a case in which postmortem brain examination was performed roughly a month after the patient's last treatment. PMID- 24755715 TI - Serum hepatic enzyme activity and alcohol drinking status in relation to the prevalence of metabolic syndrome in the general Japanese population. AB - BACKGROUND: Studies on the combined associations of elevated serum hepatic enzyme activity and alcohol drinking with metabolic syndrome are rare. Our objectives were to evaluate the associations of elevated serum hepatic enzyme activity with the prevalence of metabolic syndrome in the general Japanese population and whether alcohol drinking had a modifying effect on these associations. METHODS: We conducted a cross-sectional study with 1,027 men and 1,152 women throughout Japan during 2002-2010. Biochemical factors including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were determined in overnight fasting blood, and a survey on lifestyle was conducted by questionnaire. Serum ALT and GGT levels were divided into tertiles in men and women, and their associations with the prevalence of metabolic syndrome were evaluated by logistic regressions. RESULTS: Elevated serum ALT and GGT, even within the reference range, were independently associated with increased metabolic syndrome prevalence and were associated with most of its components in both sexes, except for the association between GGT and low high-density lipoprotein (HDL) cholesterol in men. Stratified analyses by alcohol drinking status revealed that within the same tertile category of serum ALT and GGT, subjects classified as alcohol abstainers showed higher adjusted odds ratios for metabolic syndrome prevalence than those classified as regular alcohol drinkers in both sexes. The interaction effects of serum GGT with alcohol drinking status on metabolic syndrome prevalence were significant in both sexes. CONCLUSIONS: These results suggest that elevated serum ALT and GGT, even within the reference range, are independently associated with increased metabolic syndrome prevalence, especially in alcohol abstainers, in Japanese men and women. PMID- 24755717 TI - Maintenance electroconvulsive therapy for depression with catatonia in a young woman with Down syndrome. AB - OBJECTIVES: To describe and discuss the use of maintenance electroconvulsive therapy (ECT) in a young woman with Down syndrome and depression with catatonia. METHODS: Clinical case report. RESULTS: A 23-year-old woman with Down syndrome (mosaic type) and a 4-year history of depressed mood triggered by adverse life events presented with mutism, psychomotor retardation, and compromised oral intake. Multiple trials of antidepressant medications were either ineffective or complicated by adverse reactions. She improved rapidly with a course of bilateral ECT but required maintenance ECT to sustain recovery. A series of premorbid, morbid, and post-treatment drawings by the young woman highlight the efficacy of treatment. CONCLUSION: Electroconvulsive therapy was found to be a safe and effective treatment for life-threatening mental illness in a young woman with Down syndrome who had failed multiple trials of antidepressant medications. This case highlights the importance of considering catatonia as a diagnosis in persons with Down syndrome and the effectiveness of electroconvulsive treatment. PMID- 24755718 TI - Transient Babinski sign after electroconvulsive therapy (ECT). PMID- 24755719 TI - Searching for the mechanism(s) of ECT's therapeutic effect. AB - The exact therapeutic mechanism of action of electroconvulsive therapy (ECT) remains unresolved. Numerous psychological theories from decades ago have been proven untrue. In the ensuing years, ECT has been proven to have numerous reproducible effects on brain chemistry, regional brain activity, electroencephalographic sleep stages, and neurogenesis. Clinically, ECT has been shown to have antidepressant, antipsychotic, antimanic, antiparkinsonian, and anticonvulsive effects. It is possible that different biological effects of ECT are responsible for different clinical effects or that several biological effects in concert work together to produce a given clinical effect. This paper comments on the array of possible mechanisms and points toward the future of mechanistic research in ECT. PMID- 24755720 TI - The immune system and electroconvulsive therapy for depression. AB - BACKGROUND: Electroconvulsive therapy (ECT) remains the most effective and fast acting treatment option for several psychiatric conditions, including treatment resistant depression. Although ECT has been in use for 75 years, the mechanism of action is unknown. There is emerging evidence that modulation of the hypothalamic pituitary-adrenal axis may mediate, in part, the therapeutic action of ECT. A growing body of evidence points to links between disturbances in the immune system and depression. However, the impact of ECT on immune functioning and the possible role of alterations in the immune system as a mechanism of action of ECT remain elusive. OBJECTIVES: To provide a literature overview on the effects of ECT on the immune system. METHODS: Relevant articles and abstracts in English were retrieved from PubMed/Medline using search terms related to ECT, inflammation, and immune system. The results of studies examining ECT-induced changes in immune functioning as well as the degree to which these represent possible mechanisms mediating the therapeutic action of ECT were summarized. RESULTS: Our search identified only a limited number of studies. The findings suggest that a single session of ECT induces an acute, transient immune activation, whereas repetitive ECT treatment results in long-term down-regulation of immune activation. However, inconsistency in findings and methodological issues, including sample size and lack of consideration of confounding factors affecting cytokine concentrations, precludes definitive conclusion. CONCLUSIONS: To elucidate the possible role of immunological changes mediating the effect of ECT, more prospective controlled studies with larger sample sizes are required. PMID- 24755721 TI - Celebrating 80 years of inducing brain seizures as psychiatric treatment. PMID- 24755723 TI - Retrograde autobiographical amnesia after electroconvulsive therapy: on the difficulty of finding the baby and clearing murky bathwater. PMID- 24755722 TI - Post-electroconvulsive therapy recovery and reorientation time with methohexital and ketamine: a randomized, longitudinal, crossover design trial. AB - OBJECTIVES: Methohexital, a barbiturate anesthetic commonly used for electroconvulsive therapy (ECT), possesses dose-dependent anticonvulsant properties, and its use can interfere with effective seizure therapy in patients with high seizure thresholds. Ketamine, an N-methyl-d-aspartate antagonist with epileptogenic properties not broadly used for ECT inductions, is a commonly used induction agent for general anesthesia. Recent studies suggest that the use of ketamine is effective in allowing successful ECT treatment in patients with high seizure thresholds without an increase in adverse effects. In this preliminary study, we directly compared the recovery and reorientation times of subjects receiving ketamine and methohexital for ECTs. METHODS: Twenty patients were randomized in a crossover design to receive methohexital and ketamine for ECT inductions in alternating fashion in 6 trials. Primary outcome measures were recovery time (voluntary movement, respiratory effort, blood pressure, consciousness, and O2 saturation) and reorientation time. Secondary outcome measures were individual recovery variables, adverse effect occurrence, and seizure duration. RESULTS: Overall recovery time was not significantly different between the 2 treatment arms (F(1, 17) = 0.72; P = 0.41). Reorientation time was faster in the methohexital arm (F(1, 17) = 9.23; P = 0.007). CONCLUSION: Ketamine inductions resulted in higher number of adverse effects, higher subject dropout rates, and a longer reorientation time with respect to methohexital inductions. No significant difference in postanesthesia recovery time was found between the ketamine and methohexital arms. Intolerability to ketamine affected a significant proportion of subjects and suggests that ketamine should remain as an alternative or adjunctive agent for patients with high seizure thresholds. PMID- 24755725 TI - Optimal dose of landiolol for preventing abrupt changes in both cardiac output and middle cerebral artery flow velocity after electroconvulsive therapy. AB - The purpose of this study was to examine the dose-dependent effects of landiolol on systemic hemodynamics, cardiac output, and cerebral artery blood flow. Eight patients undergoing electroconvulsive therapy (ECT) received 1 of the 3 drugs/doses (saline, 0.125 mg/kg of landiolol, 0.25 mg/kg of landiolol), in turn, for 3 ECT sessions, immediately after the administration of succinylcholine. In the case of 0.25 mg/kg of landiolol, heart rate, mean arterial pressure, and cardiac output remained unchanged throughout the study period.We believe that 0.25 mg/kg of landiolol may be suitable for preventing the increase in systemic hemodynamics, including cardiac output after ECT. PMID- 24755726 TI - Impedance testing on cochlear implants after electroconvulsive therapy. AB - OBJECTIVE: Cochlear implants (CI) are neural prostheses that restore hearing to individuals with profound sensorineural hearing loss. The surgically implanted component consists of an electrode array, which is threaded into the cochlea, and an electronic processor, which is buried under the skin behind the ear. The Food and Drug Administration and CI manufacturers contend that electroconvulsive therapy (ECT) is contraindicated in CI recipients owing to risk of damage to the implant and/or the patient. We hypothesized that ECT does no electrical damage to CIs. METHODS: Ten functional CIs were implanted in 5 fresh cadaveric human heads. Each head then received a consecutive series of 12 unilateral ECT sessions applying maximum full pulse-width energy settings. Electroconvulsive therapy was delivered contralaterally to 5 CIs and ipsilaterally to 5 CIs. Electrical integrity testing (impedance testing) of the electrode array was performed before and after CI insertion, and after the first, third, fifth, seventh, ninth, and 12th ECT sessions. Electroconvulsive therapy was performed by a staff psychiatrist experienced with the technique. Explanted CIs were sent back to the manufacturer for further integrity testing. RESULTS: No electrical damage was identified during impedance testing. Overall, there were statistically significant decreases in impedances (consistent with no electrical damage) when comparing pre-ECT impedance values to those after 12 sessions. There was no statistically significant difference (P > 0.05) in impedance values comparing ipsilateral to contralateral ECT. Manufacturer testing revealed no other electrical damage to the CIs. CONCLUSION: Electroconvulsive therapy does not seem to cause any detectable electrical injury to CIs. PMID- 24755727 TI - Autobiographical memory and electroconvulsive therapy: do not throw out the baby. AB - Retrograde amnesia for autobiographical information is the most critical adverse effect of electroconvulsive therapy (ECT). Much, if not most, modern research demonstrating long-term autobiographical amnesia after ECT has used either the Columbia University Autobiographical Memory Interview (CUAMI) or the short form of this scale (CUAMI-SF). Semkovska and McLoughlin claimed that studies using these instruments should be dismissed and the findings ignored owing to a lack of normative data, as well as concerns about the reliability and validity of these instruments. In this commentary, the development and use of these scales is reviewed. It is shown that Semkovska and McLoughlin's critique is factually incorrect, as normative data were simultaneously collected in virtually all studies using these instruments. Furthermore, there is substantial evidence supporting the reliability and validity of these scales. Indeed, these instruments are the only neuropsychological tests repeatedly shown to covary with patient self-evaluations of ECT's effects on memory and have repeatedly demonstrated long-term differences in the magnitude of amnesia as a function of ECT technique. Findings with the CUAMI and CUAMI-SF provide key evidence regarding ECT's adverse cognitive effect profile. It is inaccurate and inadvisable to continue to deny that ECT can exert long-term adverse effects in this domain. PMID- 24755728 TI - Effect of atropine dose on heart rate during electroconvulsive therapy. AB - INTRODUCTION: Transient bradycardia during the stimulation phase of electroconvulsive therapy (ECT) is a well-known clinical observation. The optimal dose of atropine needed to prevent bradycardia has not been determined. This study was designed to investigate the effect of low doses of atropine on heart rate during ECT. METHODS: Patients who received at least 2 different doses of atropine over their series of right unilateral ECT were included in the analysis. The anesthetic consisted of 0, 0.2, 0.3, or 0.4 mg of atropine, methohexital, and succinylcholine. Heart rate was measured by the RR interval, the time between sequential R waves on the electrocardiogram. Analysis was performed using logistic multivariate regression and repeated-measures multivariate analysis of variance. RESULTS: One hundred eighteen ECT sessions were identified from 19 patients. Patients were grouped into 4 groups by atropine dose (0, 0.2, 0.3, or 0.4 mg) with 9, 33, 13, and 63 ECT sessions identified for each dose, respectively. Patients who received atropine had significantly less bradycardia after electrical stimulus and a faster heart rate through the seizure than patients who did not receive atropine. There was no significant difference in heart rate between patients receiving 0.2, 0.3, and 0.4 mg of atropine at any time point. There was no significant difference in heart rate at time points after the seizure conclusion in any group of patients. CONCLUSION: Low-dose atropine results in significantly less bradycardia after electrical stimulus. There was no significant difference in heart rate across low doses of atropine. PMID- 24755729 TI - Transcranial magnetic stimulation in the treatment of chronic widespread pain: a randomized controlled study. AB - OBJECTIVE: Our objective was to assess transcranial magnetic stimulation (TMS) in the treatment of chronic widespread pain. METHODS: Nineteen participants were randomized into 2 groups: one group receiving active TMS (n = 7) and another group receiving sham stimulation (n = 11) applied to the left dorsolateral prefrontal cortex. During sham stimulation, subjects heard a sound similar to the sound heard by those receiving the active treatment and received an active electrical stimulus to the scalp. The stimulation protocol consisted of 15 sessions completed within a 4-week period. Blind assessments were done at baseline and after each 5 sessions followed by blind assessments at 1 week, 1 month, and 3 months after the last TMS sessions. The primary outcome variable was a pain measure, the Gracely Box Intensity Scale (BIRS). RESULTS: The percentage of subjects who guessed that they were receiving TMS was similar in the 2 groups. Both the TMS group and the sham group showed a statistically significant reduction in the BIRS scores from baseline during the acute phase of treatment and the follow-up phase. However, the TMS and sham groups did not differ in the change in the BIRS scores. DISCUSSION: Although some previous clinical studies and basic science studies of TMS in treating pain are promising, this study found no difference in the analgesic effect of TMS and sham stimulation. Future studies should use a sham condition that attempts to simulate the sound and sensation of the TMS stimulation. Stimulus location and other stimulus parameters should be explored in future studies. PMID- 24755730 TI - Unique epitopes recognized by antibodies induced in Chikungunya virus-infected non-human primates: implications for the study of immunopathology and vaccine development. AB - Chikungunya virus (CHIKV) is an Alphavirus that causes chronic and incapacitating arthralgia in humans. Although patient cohort studies have shown the production of CHIKV specific antibodies, the fine specificity of the antibody response against CHIKV is not completely defined. The macaque model of CHIKV infection was established due to limitations of clinical specimens. More importantly, its close relation to humans will allow the study of chronic infection and further identify important CHIKV targets. In this study, serum samples from CHIKV-infected macaques collected at different time-points post infection were used to characterize the antibody production pattern and kinetics. Results revealed that anti-CHIKV antibodies were neutralizing and the E2 glycoprotein, Capsid, nsP1, nsP3 and nsP4 proteins were targets of the anti-CHIKV antibody response in macaques. Furthermore, linear B-cell epitopes recognized by these anti-CHIKV antibodies were identified, and mapped to their structural localization. This characterizes the specificity of anti-CHIKV antibody response in macaques and further demonstrates the importance of the different regions in CHIKV-encoded proteins in the adaptive immune response. Information from this study provides critical knowledge that will aid in the understanding of CHIKV infection and immunity, vaccine design, and pre-clinical efficacy studies. PMID- 24755732 TI - Gallstones. PMID- 24755731 TI - The association of 5-HT2A, 5-HTT, and LEPR polymorphisms with obstructive sleep apnea syndrome: a systematic review and meta-analysis. AB - OBJECTIVE: A consensus has not been reached regarding the association of several different gene polymorphisms and susceptibility to obstructive sleep apnea syndrome (OSAS). We performed a meta-analysis to better evaluate the associations between 5-HT2A, 5-HTT, and LEPR polymorphisms, and OSAS. METHOD: 5-HT2A, 5-HTT, and LEPR polymorphisms and OSAS were identified in PubMed and EMBASE. The pooled odd rates (ORs) with 95%CIs were estimated using a fixed-effect or random-effect models. The associations between these polymorphisms and OSAS risk were assessed using dominant, recessive and additive models. RESULTS: Twelve publications were included in this study. The -1438 "A" allele of 5-HT2A was identified as a candidate genetic risk factor for OSAS (OR: 2.33, 95%CI 1.49-3.66). Individuals carrying the -1438 "G" allele had a nearly 70% reduced risk of OSAS when compared with AA homozygotes (OR: 0.30, 95%CI 0.23-0.40). There was no significant association between 5-HT2A 102C/T and OSAS risk, using any model. The "S" allele of 5-HTTLPR conferred protection against OSAS (OR: 0.80, 95%CI 0.67-0.95), while the "10" allele of 5-HTTVNTR contributed to the risk of OSAS (OR: 2.08, 95%CI: 1.58-2.73). The "GG" genotype of LEPR was associated with a reduced risk of OSAS (OR: 0.39, 95%CI 0.17-0.88). CONCLUSION: The meta-analysis demonstrated that 5 HTR-1438 "A" and 5-HTTVNTR "10" alleles were significantly associated with OSAS. The "S" allele of 5-HTTLPR and the "GG" genotype of LEPR conferred protection against OSAS. Further studies, such as Genome-Wide Association study (GWAS), should be conducted in a large cohort of OSAS patients to confirm our findings. PMID- 24755733 TI - Nanocrystalline, ultra-degradation-resistant zirconia: its grain boundary nanostructure and nanochemistry. AB - Y2O3-stabilized tetragonal ZrO2 polycrystal (Y-TZP) has been known to be an excellent structural material with high strength and toughness since the pioneering study by Garvie et al. in 1975. However, Y-TZP is not considered an environmental or biomedical material because it undergoes an inherent tetragonal to-monoclinic (T -> M) phase transformation in humid or aqueous environment, which leads to premature failure, so-called low-temperature degradation (LTD). In this study, we demonstrate for the first time that this fatal shortcoming of Y TZP can be resolved by controlling the grain boundary nanostructure and chemical composition distribution in Y-TZP. Nanocrystalline Y-TZP doped with Al(3+) and Ge(4+) ions exhibits no LTD for more than 4 years in hot water at 140 degrees C, whereas 70% of the tetragonal phase in conventional TZP transforms to the monoclinic phase within only 15 h. This innovative Y-TZP can be fabricated by pressureless sintering at 1200 degrees C; far below the sintering temperature for conventional Y-TZP. The developed TZP ceramics will be useful in numerous environmental-proofing applications, particularly in the biomedical engineering field. PMID- 24755734 TI - A method enabling high-throughput sequencing of human cytomegalovirus complete genomes from clinical isolates. AB - Human cytomegalovirus (HCMV) is a ubiquitous virus that can cause serious sequelae in immunocompromised patients and in the developing fetus. The coding capacity of the 235 kbp genome is still incompletely understood, and there is a pressing need to characterize genomic contents in clinical isolates. In this study, a procedure for the high-throughput generation of full genome consensus sequences from clinical HCMV isolates is presented. This method relies on low number passaging of clinical isolates on human fibroblasts, followed by digestion of cellular DNA and purification of viral DNA. After multiple displacement amplification, highly pure viral DNA is generated. These extracts are suitable for high-throughput next-generation sequencing and assembly of consensus sequences. Throughout a series of validation experiments, we showed that the workflow reproducibly generated consensus sequences representative for the virus population present in the original clinical material. Additionally, the performance of 454 GS FLX and/or Illumina Genome Analyzer datasets in consensus sequence deduction was evaluated. Based on assembly performance data, the Illumina Genome Analyzer was the platform of choice in the presented workflow. Analysis of the consensus sequences derived in this study confirmed the presence of gene-disrupting mutations in clinical HCMV isolates independent from in vitro passaging. These mutations were identified in genes RL5A, UL1, UL9, UL111A and UL150. In conclusion, the presented workflow provides opportunities for high throughput characterization of complete HCMV genomes that could deliver new insights into HCMV coding capacity and genetic determinants of viral tropism and pathogenicity. PMID- 24755735 TI - Papillary thyroid microcarcinoma: proposal of treatment based on histological prognostic factors evaluation. AB - BACKGROUND: Papillary thyroid cancer accounts for approximately 80% of thyroid tumors and its incidence has increased over the past decades. Papillary thyroid microcarcinomas (PMCs), defined by the World Health Organization as less than 1.0 cm in size, are identified with greater frequency. The majority of patients with PMCs follows a benign clinical course, however a subgroup of these carcinomas is as aggressive as bigger tumors. Risk factors related with poor outcome have not been defined and the optimal treatment has not been proved. The authors investigated histologic prognostic factors predicting high risk patients considered for more aggressive treatment and propose reviewed therapeutic guidelines based on analysis of histopathologic features which determined the recurrence rate. STUDY DESIGN: One hundred forty nine patients with PMC who underwent surgery were retrospectively analyzed. Clinical and histopathologic parameters potentially predicting patient outcome and recurrent disease were statistically investigated, after a minimum follow-up of 5 years. RESULTS: After a median follow-up of 5.4 years 28 of 149 patients experienced recurrent disease. All of them were reoperated on and newly treated with radioiodine administration. The multivariate statistical analysis identified extrathyroidal invasion (Odds Ratio, OR, 58.54; P=0.013), the solid pattern (OR,25.77; P>0.001), the tumor multifocality (OR, 15.80; P= 0.005), and the absence of tumor capsule (OR, 9.74; P=0.015) as significant and indipendent risk factors for the appearance of PMCs recurrences. Of note, none of the PMC "incidentally" discovered at histopathological examination alone experienced recurrent disease during follow up. CONCLUSIONS: Although most PMC have favourable long-term prognosis, some patients (19% in our series) presented aggressive clinical course strongly correlated with some histopathologic features (extrathyroidal invasion, tumor multifocality, solid pattern and absence of capsule) who need to be investigated and for whom a radical therapeutic approach is recommended based on total thyroidectomy and regional lymphadenectomy followed by radioiodine administration. PMID- 24755736 TI - Tumor-free iPS stem cells for heart cells. PMID- 24755737 TI - A theoretically based model of rat personality with implications for welfare. AB - As animal personality research becomes more central to the study of animal behavior, there is increasing need for theoretical frameworks addressing its causes and consequences. We propose that regulatory focus theory (RFT) could serve as one such framework while also providing insights into how animal personality relates to welfare. RFT distinguishes between two types of approach motivation: promotion, the motivation to approach gains, and prevention, the motivation to approach or maintain safety. Decades of research have established the utility of RFT as a model of human behavior and recent evidence from zoo housed primates and laboratory rats has suggested that it may be applicable to nonhuman animal behavior as well. Building on these initial studies, we collected data on 60 rats, Rattus norvegicus, navigating an automated maze that allowed individuals to maintain darkness (indicative of prevention/safety-approach motivation) and/or activate food rewards (indicative of promotion/gain-approach motivation). As predicted, both behaviors showed stable individual differences (Ps <0.01) and were inversely associated with physiological signs of chronic stress, possibly indicating poor welfare (Ps <0.05). Subsequently, half the rats were exposed to a manageable threat (noxious novel object) in the homecage. Re testing in the maze revealed that threat exposure increased darkness time achieved (P<0.05), suggesting a mechanism by which prevention motivation may be enhanced. These results point toward the potential utility of RFT as a model for animal behavior and welfare. PMID- 24755738 TI - Outcomes of patients with mild to moderate ischemic mitral regurgitation after coronary artery bypass graft surgery alone. AB - AIM: Mitral regurgitation (MR) is considered as an independent factor in determining prognosis of patients with myocardial infarction and impacts of untreated insufficiency on long-term results of patients undergoing CABG is well recognized. Regarding proper treatment of mild to moderate regurgitation of mitral valve is controversial and there is little research in this field in our country, we attempted to examine this issue by planning and executing the present study. METHODS: 40 patients were studied in Mazandaran Heart Center, Sari, Iran in 2012. Echocardiography was done before surgery and ones with mild to moderate ischemic mitral regurgitation were studied. Patients were underwent echocardiography 3 times after surgery. RESULTS: Average score of LVEF in the studied patients increased from 21+/-2.4% to 32.3+/-4.8% in a manner that average increasing variation of LVEF in patients, 2 months after surgery was 3.8+/-10.8%, not showing significant statistic difference, but 6 months after surgery it was increased by 9.2+/-11.2%. Also, average classification score of NYHA class in the patients decreased from 3.4+/-0.2 to 1.5+/-0.9 (p=0.09) and average decreasing score of NYHA class in the studied group, 2 months after surgery was 1.8+/- 0.5 and at the end of 6 months after surgery, it decreased by about 2.1+/-0.3. CONCLUSION: Average grade of Mitral regurgitation in patients undergoing CABG decreased as compared with baseline state significantly. With due attention to complications and mortality of patients in this study, one can understand that ideal treatment results can be obtained through correct selection of patients before CABG, although more studies with wider statistical sample volume is recommended. PMID- 24755739 TI - Ravens notice dominance reversals among conspecifics within and outside their social group. AB - A core feature of social intelligence is the understanding of third-party relations, which has been experimentally demonstrated in primates. Whether other social animals also have this capacity, and whether they can use this capacity flexibly to, for example, also assess the relations of neighbouring conspecifics, remains unknown. Here we show that ravens react differently to playbacks of dominance interactions that either confirm or violate the current rank hierarchy of members in their own social group and of ravens in a neighbouring group. Therefore, ravens understand third-party relations and may deduce those not only via physical interactions but also by observation. PMID- 24755740 TI - Environmental heat stress induces epigenetic transgenerational inheritance of robustness in parthenogenetic Artemia model. AB - The notion that phenotypic traits emerging from environmental experiences are heritable remains under debate. However, the recent report of nonmendelian transgenerational epigenetic inheritance, i.e., the inheritance of traits not determined by the DNA sequence, might make such a phenomenon plausible. In our study, by carrying out common garden experiments, we could provide clear evidences that, on exposure to nonlethal heat shocks, a parental population of parthenogenetic (all female) Artemia (originating from one single female) experiences an increase in levels of Hsp70 production, tolerance toward lethal heat stress, and resistance against pathogenic Vibrio campbellii. Interestingly, these acquired phenotypic traits were transmitted to three successive generations, none of which were exposed to the parental stressor. This transgenerational inheritance of the acquired traits was associated with altered levels of global DNA methylation and acetylated histones H3 and H4 in the heat shocked group compared to the control group, where both the parental and successive generations were reared at standard temperature. These results indicated that epigenetic mechanisms, such as global DNA methylation and histones H3 and H4 acetylation, have particular dynamics that are crucial in the heritability of the acquired adaptive phenotypic traits across generations. PMID- 24755742 TI - Whole-mount MeFISH: a novel technique for simultaneous visualization of specific DNA methylation and protein/RNA expression. AB - To understand the spatiotemporal changes in cellular status that occur during embryonic development, it is desirable to detect simultaneously the expression of genes, proteins, and epigenetic modifications in individual embryonic cells. A technique termed methylation-specific fluorescence in situ hybridization (MeFISH) was developed recently that can visualize the methylation status of specific DNA sequences in cells fixed on a glass slide. Here, we adapted this glass slide based MeFISH to the study of intact embryos, and established a method called whole-mount MeFISH. This method can be applied to any DNA sequences in theory and, as a proof-of-concept experiment, we examined the DNA methylation status of satellite repeats in developing mouse primordial germ cells, in which global DNA demethylation is known to take place, and obtained a result that was consistent with previous findings, thus validating the MeFISH method. We also succeeded in combining whole-mount MeFISH with immunostaining or RNA fluorescence in situ hybridization (RNA-FISH) techniques by adopting steps to retain signals of RNA FISH or immunostaining after harsh denaturation step of MeFISH. The combined methods enabled the simultaneous visualization of DNA methylation and protein or RNA expression at single-cell resolution without destroying embryonic and nuclear structures. This whole-mount MeFISH technique should facilitate the study of the dynamics of DNA methylation status during embryonic development with unprecedented resolution. PMID- 24755741 TI - Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. AB - Reduced AMP kinase (AMPK) activity has been shown to play a key deleterious role in increased hepatic gluconeogenesis in diabetes, but the mechanism whereby this occurs remains unclear. In this article, we document that another AMP-dependent enzyme, AMP deaminase (AMPD) is activated in the liver of diabetic mice, which parallels with a significant reduction in AMPK activity and a significant increase in intracellular glucose accumulation in human HepG2 cells. AMPD activation is induced by a reduction in intracellular phosphate levels, which is characteristic of insulin resistance and diabetic states. Increased gluconeogenesis is mediated by reduced TORC2 phosphorylation at Ser171 by AMPK in these cells, as well as by the up-regulation of the rate-limiting enzymes PEPCK and G6Pc. The mechanism whereby AMPD controls AMPK activation depends on the production of a specific AMP downstream metabolite through AMPD, uric acid. In this regard, humans have higher uric acid levels than most mammals due to a mutation in uricase, the enzyme involved in uric acid degradation in most mammals, that developed during a period of famine in Europe 1.5 * 10(7) yr ago. Here, working with resurrected ancestral uricases obtained from early hominids, we show that their expression on HepG2 cells is enough to blunt gluconeogenesis in parallel with an up-regulation of AMPK activity. These studies identify a key role AMPD and uric acid in mediating hepatic gluconeogenesis in the diabetic state, via a mechanism involving AMPK down-regulation and overexpression of PEPCK and G6Pc. The uricase mutation in the Miocene likely provided a survival advantage to help maintain glucose levels under conditions of near starvation, but today likely has a role in the pathogenesis of diabetes. PMID- 24755743 TI - Differences in nicotine metabolism of two Nicotiana attenuata herbivores render them differentially susceptible to a common native predator. AB - BACKGROUND: Nicotiana attenuata is attacked by larvae of both specialist (Manduca sexta) and generalist (Spodoptera exigua) lepidopteran herbivores in its native habitat. Nicotine is one of N. attenuata's important defenses. M. sexta is highly nicotine tolerant; whether cytochrome P450 (CYP)-mediated oxidative detoxification and/or rapid excretion is responsible for its exceptional tolerance remains unknown despite five decades of study. Recently, we demonstrated that M. sexta uses its nicotine-induced CYP6B46 to efflux midgut nicotine into the hemolymph, facilitating nicotine exhalation that deters predatory wolf spiders (Camptocosa parallela). S. exigua's nicotine metabolism is uninvestigated. METHODOLOGY/PRINCIPAL FINDINGS: We compared the ability of these two herbivores to metabolize, tolerate and co-opt ingested nicotine for defense against the wolf spider. In addition, we analyzed the spider's excretion to gain insights into its nicotine metabolism. Contrary to previous reports, we found that M. sexta larvae neither accumulate the common nicotine oxides (cotinine, cotinine N-oxide and nicotine N-oxide) nor excrete them faster than nicotine. In M. sexta larvae, ingestion of nicotine as well as its oxides increases the accumulation of CYP6B46 transcripts. In contrast, S. exigua accumulates nicotine oxides and exhales less (66%) nicotine than does M. sexta. Spiders prefer nicotine-fed S. exigua over M. sexta, a preference reversed by topical or headspace nicotine supplementation, but not ingested or topically-coated nicotine oxides, suggesting that externalized nicotine but not the nicotine detoxification products deter spider predation. The spiders also do not accumulate nicotine oxides. CONCLUSIONS: Nicotine oxidation reduces S. exigua's headspace-nicotine and renders it more susceptible to predation by spiders than M. sexta, which exhales unmetabolized nicotine. These results are consistent with the hypothesis that generalist herbivores incur costs of detoxification, which include the ecological costs of greater predation risks, in addition to the previously demonstrated energetic, physiological and metabolic costs. PMID- 24755744 TI - [Gender-specific colorectal cancer: epidemiologic difference and role of estrogen]. AB - Gender difference in the incidence of colorectal cancer is well known and has been supported by various epidemiologic studies. In Korea, women have lower incidence of colorectal cancer and adenoma, and the incidence in men has recently increased. Hormone replacement therapy in menopausal women is preventive of colorectal cancer but can cause cardiovascular diseases and breast cancer. Estrogen exerts diverse effects through estrogen receptors, ERalpha and ERbeta. ERbeta is associated with anti-proliferation and apoptosis. The ratio of ERalpha/ERbeta is important in the protection and tumorigenesis of colorectal cancer. Therefore ERbeta modulation has been investigated for preventing or treating colorectal cancer and avoiding adverse effects of estrogen at the same time. In addition, the gender-difference in the incidence of colorectal cancer should be taken into account when making guidelines on colorectal surveillance for Korean population. PMID- 24755746 TI - [A single institution's experience of infundibulotomy in patients taking antiplatelet agents: outcomes, safety and complications]. AB - BACKGROUND/AIMS: The diagnostic and therapeutic utility of endoscopic retrograde cholangiopancreatography (ERCP) has been well demonstrated for biliary and pancreatic diseases. Biliary access can be allowed by infundibulotomy if failed by using the standard cannulation methods. However, no data are available regarding ERCP-related complications in patients taking antiplatelet agents who are undergoing infundibulotomy. Therefore, we aimed to assess the frequency of ERCP-related complications after infundibulotomy in patients taking antiplatelet agents. METHODS: We performed a retrospective study, and enrolled 835 patients who underwent ERCP at Pusan National University Hospital from January 2011 to December 2012. Seventy-two patients had been taking antiplatelet agents prior to the procedure. Patients were classified into two groups according to the utilization of infundibulotomy: 20 patients underwent infundibulotomy (group 1), and 52 patients did not undergo infundibulotomy (group 2). Complications after ERCP were defined as bleeding, post-ERCP pancreatitis, and perforation according to Cotton's criteria. RESULTS: Between group 1 and 2, there were no significant differences in baseline characteristics. ERCP was successfully performed in all cases. Clinically significant bleeding was observed in one patient in group 1 (5%, 1/20) versus none in group 2. Post-ERCP pancreatitis was observed in 2 patients (10.0%, 2/20) in group 1, and 7 patients (13.5%, 7/52) in group 2 (p=0.691). However, none of these differences were statistically significant. No perforation occurred in both groups. CONCLUSIONS: Considering the low incidence of bleeding after infundibulotomy in patients taking antiplatelet agents, infundibulotomy may be safely performed in this group of patients. PMID- 24755745 TI - Prognostic factors for metastatic colorectal cancer after first-line chemotherapy with FOLFOX-4 or FOLFIRI regimen. AB - BACKGROUND/AIMS: Information on prognostic factors for metastatic colorectal cancer is an important basis for planning the treatment and predicting the outcomes of the patients; however, it has not been well established. The aim of this study was to identify factors that predict results of chemotherapy and to establish a plan for treatment of patients whose tumors are inoperable due to metastatic colorectal cancer. METHODS: We conducted a retrospective review of records from 75 patients treated for colorectal cancer in Kosin University Gospel Hospital, from October 2004 to September 2008. Patients with inoperable tumors due to metastasis at the time of diagnosis who were treated with oxaliplatin or irinotecan as the first-line treatment were included in this study. We investigated the factors that might have an effect on overall survival. RESULTS: A total of 75 patients were included in this study. Results of univariate analysis showed that hemoglobin (Hb) >=10 g/dL at the time of diagnosis, no increase in CEA on the follow-up examination after chemotherapy, chemotherapy plus surgery, and better response to chemotherapy were significant prognostic factors. Results of multivariate analysis showed that Hb >=10 g/dL at the time of diagnosis (p<0.001), surgery after chemotherapy (p=0.001), and better response to chemotherapy (p=0.014) were significant prognostic factors. CONCLUSIONS: In this study, Hb >=10 g/dL at the time of diagnosis, surgery after chemotherapy, and better response to chemotherapy were significant prognostic factors for metastatic colorectal cancer. PMID- 24755747 TI - Diagnostic accuracy of brush cytology with direct smear and cell-block techniques according to preparation order and tumor characteristics in biliary strictures. AB - BACKGROUND/AIMS: There are few data supporting the diagnostic yield of brush cytology depending on the order of cytologic preparation method or the location or shape of tumors in biliary strictures. We investigated diagnostic yields and variations in brush cytology with direct smear and cell-block preparations according to sampling preparation sequence and tumor location and shape in biliary strictures. METHODS: Patients who had undergone ERCP with tissue sampling between August 2009 and April 2013 were analyzed retrospectively. Group A was examined using brush cytology with direct smear followed by cell-block with or without biopsy, while the reverse order was performed for group B. RESULTS: Among 138 enrolled patients, 92 patients (A: 36, B: 56) underwent both brush cytology with direct smear and cell-block preparations. No differences in sensitivity, specificity, or accuracy were observed according to the sampling preparation method and the location or shape of tumors in biliary strictures. The cellularity observed from brush cytology with direct smear was better than that from cell block according to the location of the tumor (p<0.01). The diagnostic yield was increased in both groups with addition of an endobiliary biopsy. CONCLUSIONS: No difference in diagnostic accuracy was observed between the sequences of preparation for brush cytology with direct smear and cell-block techniques. Brush cytology showed better cellularity for diagnosis. PMID- 24755748 TI - [Safety and effectiveness of successive extracorporeal shock wave lithotripsy for pancreatolithiasis under intravenous bolus pethidine administration alone]. AB - BACKGROUND/AIMS: A retrospective analysis was performed to evaluate the safety and effectiveness of extracorporeal shock wave lithotripsy (ESWL) for pancreatolithiasis on successive days under intravenous bolus of pethidine alone. METHODS: Ninety patients with calcified pancreatic stones (>=5 mm) presenting with abdominal pain were selected for ESWL. ESWL was performed with an electroconductive lithotripter under fluoroscopic target systems. Fragmented calculi after ESWL were removed by endotherapy. RESULTS: A mean of 4.2 ESWL sessions were performed for each patient, with a mean of 2,984 shocks at a mean power setting of 12.8 kV. Eighty-four (89.3%) patients underwent ESWL for three or more days in a row. Fragmentation of the stones were achieved in 83/90 (92.2%) patients. Complete clearance of the main pancreatic duct was achieved in 54/90 (60.0%) patients, and partial clearance was achieved in 27 (30.0%) patients. The mean dose of pethidine used during ESWL was 53.5+/-20.7 mg per session. As ESWL related complications, four (4.3%) patients developed mild acute pancreatitis. CONCLUSIONS: In case of endoscopically difficult-to-treat pancreatic duct stones, combined therapy with ESWL is an effective method, and treatment with multiple sessions of ESWL on successive days under intravenous bolus of pethidine alone is safe and well tolerated. PMID- 24755749 TI - Primary aortoenteric fistula to the sigmoid colon in association with intra abdominal abscess. AB - Primary aortoenteric fistula (PAEF) is a rare but catastrophic cause of massive gastrointestinal bleeding. Diagnosis of PAEF is difficult to make and is frequently delayed without strong clinical suspicion. Timely surgical intervention is essential for patient's survival. We report on a case of an 86 year-old woman with no history of abdominal surgery, who presented with abdominal pain. Initially, computed tomography scan showed an intra-abdominal abscess, located anterior to the aortic bifurcation. However, she was discharged without treatment because of spontaneous improvement on a follow-up computed tomography scan, which showed a newly developed right common iliac artery aneurysm. One week later, she was readmitted due to recurrent abdominal pain. On the second day of admission, sudden onset of gastrointestinal bleeding occurred for the first time. After several endoscopic examinations, an aortoenteric fistula bleeding site was found in the sigmoid colon, and aortography showed progression of a right common iliac artery aneurysm. We finally concluded that intra-abdominal abscess induced an infected aortic aneurysm and enteric fistula to the sigmoid colon. This case demonstrated an extremely rare type of PAEF to the sigmoid colon caused by an infected abdominal aortic aneurysm, which has rarely been reported. PMID- 24755750 TI - A case of plummer-vinson syndrome associated with Crohn's disease. AB - Plummer-Vinson syndrome manifests as cervical dysphagia, iron deficiency anemia, an upper esophageal web, and atrophic glossitis. The cause of the esophageal web is thought to be iron deficiency anemia; however, the cause of Plummer-Vinson syndrome has not been established. Crohn's disease is usually accompanied by malnutrition and iron deficiency anemia; however, no case of concomitant Crohn's disease and Plummer-Vinson syndrome with aggravated malnutrition and anemia has been previously reported. Here, we report on a rare case of Plummer-Vinson syndrome in a Crohn's disease patient, which caused malnutrition and constipation. PMID- 24755751 TI - Long-term successful treatment of massive distal duodenal variceal bleeding with balloon-occluded retrograde transvenous obliteration. AB - Duodenal variceal bleeding in patients with portal hypertension due to cirrhosis or other causes is uncommon. We report on a case of a 55-year-old male with an ectopic variceal rupture at the distal fourth part of the duodenum who presented with massive hematochezia and shock. Shortly after achievement of hemodynamic stability, due to the limitation of an endoscopic procedure, we initially attempted to find the bleeding focus by abdominal computed tomography, which showed tortuous duodenal varices that drained into the left gonadal vein. He was treated with first-line balloon-occluded retrograde transvenous obliteration (BRTO), resulting in a favorable long-term outcome without rebleeding three years later. This case suggests that BRTO may be a first-line therapeutic option for control of ruptured duodenal varices, especially at a distal location. PMID- 24755752 TI - [A case of alpha-cell nesidioblastosis and hyperplasia with multiple glucagon producing endocrine cell tumor of the pancreas]. AB - Nesidioblastosis is a term used to describe pathologic overgrowth of pancreatic islet cells. It also means maldistribution of islet cells within the ductules of exocrine pancreas. Generally, nesidioblastosis occurs in beta-cell and causes neonatal hyperinsulinemic hypoglycemia or adult noninsulinoma pancreatogenous hypoglycemia syndrome. Alpha-cell nesidioblastosis and hyperplasia is an extremely rare disorder. It often accompanies glucagon-producing marco- and mircoadenoma without typical glucagonoma syndrome. A 35-year-old female was referred to our hospital with recurrent acute pancreatitis. On radiologic studies, 1.5 cm sized mass was noted in pancreas tail. Cytological evaluation with EUS-fine-needle aspiration suggested serous cystadenoma. She received distal pancreatectomy. The histologic examination revealed a 1.7 cm sized neuroendocrine tumor positive for immunohistochemical staining with glucagon antibody. Multiple glucagon-producing micro endocrine cell tumors were scattered next to the main tumor. Additionally, diffuse hyperplasia of pancreatic islets and ectopic proliferation of islet cells in centroacinar area, findings compatible to nesidioblastosis, were seen. These hyperplasia and almost all nesidioblastic cells were positive for glucagon immunochemistry. Even though serum glucagon level still remained higher than the reference value, she has been followed-up without any evidence of recurrence or hormone related symptoms. Herein, we report a case of alpha-cell nesidioblastosis and hyperplasia combined with glucagon producing neuroendocrine tumor with literature review. PMID- 24755753 TI - Terrorist attacks escalate in frequency and fatalities preceding highly lethal attacks. AB - Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates--both in the number of people killed per attack and in the frequency of attacks--leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack. PMID- 24755763 TI - Abnormal bispectral index values associated with the presence of periodic lateralized epileptiform discharges. PMID- 24755764 TI - Intractable nausea and vomiting following balloon occlusion of carotico-cavernous fistula. PMID- 24755754 TI - Parkinson-related changes of activation in visuomotor brain regions during perceived forward self-motion. AB - Radial expanding optic flow is a visual consequence of forward locomotion. Presented on screen, it generates illusionary forward self-motion, pointing at a close vision-gait interrelation. As particularly parkinsonian gait is vulnerable to external stimuli, effects of optic flow on motor-related cerebral circuitry were explored with functional magnetic resonance imaging in healthy controls (HC) and patients with Parkinson's disease (PD). Fifteen HC and 22 PD patients, of which 7 experienced freezing of gait (FOG), watched wide-field flow, interruptions by narrowing or deceleration and equivalent control conditions with static dots. Statistical parametric mapping revealed that wide-field flow interruption evoked activation of the (pre-)supplementary motor area (SMA) in HC, which was decreased in PD. During wide-field flow, dorsal occipito-parietal activations were reduced in PD relative to HC, with stronger functional connectivity between right visual motion area V5, pre-SMA and cerebellum (in PD without FOG). Non-specific 'changes' in stimulus patterns activated dorsolateral fronto-parietal regions and the fusiform gyrus. This attention-associated network was stronger activated in HC than in PD. PD patients thus appeared compromised in recruiting medial frontal regions facilitating internally generated virtual locomotion when visual motion support falls away. Reduced dorsal visual and parietal activations during wide-field optic flow in PD were explained by impaired feedforward visual and visuomotor processing within a magnocellular (visual motion) functional chain. Compensation of impaired feedforward processing by distant fronto-cerebellar circuitry in PD is consistent with motor responses to visual motion stimuli being either too strong or too weak. The 'change' related activations pointed at covert (stimulus-driven) attention. PMID- 24755766 TI - EEG as a surrogate to brain imaging for diagnosing stroke in morbidly obese patients. PMID- 24755765 TI - Apnea during awake epilepsy surgery: an unusual cause for a rare complication. PMID- 24755767 TI - Hacking on decoy-state quantum key distribution system with partial phase randomization. AB - Quantum key distribution (QKD) provides means for unconditional secure key transmission between two distant parties. However, in practical implementations, it suffers from quantum hacking due to device imperfections. Here we propose a hybrid measurement attack, with only linear optics, homodyne detection, and single photon detection, to the widely used vacuum + weak decoy state QKD system when the phase of source is partially randomized. Our analysis shows that, in some parameter regimes, the proposed attack would result in an entanglement breaking channel but still be able to trick the legitimate users to believe they have transmitted secure keys. That is, the eavesdropper is able to steal all the key information without discovered by the users. Thus, our proposal reveals that partial phase randomization is not sufficient to guarantee the security of phase encoding QKD systems with weak coherent states. PMID- 24755768 TI - The effect of MUC1 rs4072037 functional polymorphism on cancer susceptibility: evidence from published studies. AB - Genome-wide association studies have identified a susceptibility variation MUC1 rs4072037 for gastric cancer in Chinese population. Subsequent case-control studies have reported this association in other populations. However, the results remain controversial and ambiguous. The aim of this study is to provide a precise quantification for the association between MUC1 rs4072037 variation and the risk of cancer. We performed pooled analysis of 10 case-control designed studies including 4,220 cases and 6,384 controls. Odds ratios (OR) and 95% confidence interval (95%CI) were calculated to assess strength of association in overall studies and in subgroup analysis stratified by ethnicity and cancer types. All statistical analyses were performed by Manager 5.0 and Stata 12.0 software. Overall, the MUC1 rs4072037 polymorphism was associated with risk of cancer in all genetic models (G vs A: OR = 0.71, 95%CI: 0.63-0.80, p<0.01; GA vs AA: OR = 0.61, 95%CI:0.55-0.67, p<0.01; GG vs AA: OR = 0.58, 95%CI: 0.47-0.71, p<0.01; AG+AA vs GG: OR = 0.60, 95%CI: 0.55-0.60, p<0.01; GG vs AG+AA: OR = 0.70, 95%CI: 0.58-0.85, p<0.01). Further, subgroup analysis based on ethnicity suggested MUC1 rs4072037 polymorphism had a subtly reduced cancer risk among Asian population, and stratified analysis by cancer types showed significantly decreased risk of gastric cancer in all genetic models. In conclusion, MUC1 rs4072037 polymorphism may be used as potential biomarker for cancer susceptibility particularly for gastric cancer and for Asian population. PMID- 24755769 TI - Emergence of collective territorial defense in bacterial communities: horizontal gene transfer can stabilize microbiomes. AB - Multispecies bacterial communities such as the microbiota of the gastrointestinal tract can be remarkably stable and resilient even though they consist of cells and species that compete for resources and also produce a large number of antimicrobial agents. Computational modeling suggests that horizontal transfer of resistance genes may greatly contribute to the formation of stable and diverse communities capable of protecting themselves with a battery of antimicrobial agents while preserving a varied metabolic repertoire of the constituent species. In other words horizontal transfer of resistance genes makes a community compatible in terms of exoproducts and capable to maintain a varied and mature metagenome. The same property may allow microbiota to protect a host organism, or if used as a microbial therapy, to purge pathogens and restore a protective environment. PMID- 24755770 TI - Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. AB - Medical research is developing an ever greater need for comprehensive high quality data generation to realize the promises of personalized health care based on molecular biomarkers. The nucleic acid proximity-based methods proximity ligation and proximity extension assays have, with their dual reporters, shown potential to relieve the shortcomings of antibodies and their inherent cross reactivity in multiplex protein quantification applications. The aim of the present study was to develop a robust 96-plex immunoassay based on the proximity extension assay (PEA) for improved high throughput detection of protein biomarkers. This was enabled by: (1) a modified design leading to a reduced number of pipetting steps compared to the existing PEA protocol, as well as improved intra-assay precision; (2) a new enzymatic system that uses a hyper thermostabile enzyme, Pwo, for uniting the two probes allowing for room temperature addition of all reagents and improved the sensitivity; (3) introduction of an inter-plate control and a new normalization procedure leading to improved inter-assay precision (reproducibility). The multiplex proximity extension assay was found to perform well in complex samples, such as serum and plasma, and also in xenografted mice and resuspended dried blood spots, consuming only 1 uL sample per test. All-in-all, the development of the current multiplex technique is a step toward robust high throughput protein marker discovery and research. PMID- 24755772 TI - The pasting and gel textural properties of corn starch in glucose, fructose and maltose syrup. AB - The pasting and gel textural properties of corn starch in syrup at different concentrations were investigated by Rapid Visco Analyzer (RVA) and Texture profile analysis (TPA) tests. The results showed that the pasting temperatures of corn starch greatly increased, especially at higher sugar concentration. Increasing concentration of syrup caused an increase in peak, trough and final viscosity of corn starch. Peak viscosity and the disintegration rate of starch increased in the following order: fructose syrup> maltose syrup> glucose syrup. Increasing syrup concentration to 13%, 25% and 50% resulted in a lower retrogradation rate than the control. When the maltose syrup concentration increased to 50%, the retrogradation rate decreased to 14.30% from 33.38%. The highest hardness was observed when the syrup concentration was 25%. There was a particular low hardness when the concentration of syrup was 50%. The springiness of starch gels in syrup was similar at different concentrations. PMID- 24755771 TI - Lens oscillations in the human eye. Implications for post-saccadic suppression of vision. AB - The eye changes gaze continuously from one visual stimulus to another. Using a high speed camera to record eye and lens movements we demonstrate how the crystalline lens sustains an inertial oscillatory decay movement immediately after every change of gaze. This behavior fit precisely with the movement of a classical damped harmonic oscillator. The time course of the oscillations range from 50 to 60 msec with an oscillation frequency of around 20 Hz. That has dramatic implications on the image quality at the retina on the very short times (~50 msec) that follow the movement. However, it is well known that our vision is nearly suppressed on those periods (post-saccadic suppression). Both phenomenon follow similar time courses and therefore might be synchronized to avoid the visual impairment. PMID- 24755773 TI - Internet-based home training is capable to improve balance in multiple sclerosis: a randomized controlled trial. AB - BACKGROUND: Balance disorders are common in multiple sclerosis. AIM: Aim of the study is to investigate the effectiveness of an Internet-based home training program (e-Training) to improve balance in patients with multiple sclerosis. DESIGN: A randomized, controlled study. SETTING: Academic teaching hospital in cooperation with the therapeutic riding center Gut Uttingshof, Bad Mergentheim. POPULATION: Eighteen multiple sclerosis patients (mean EDSS 3,5) took part in the trial. Outcome of patients using e-Training (N.=9) was compared to the outcome of patients receiving hippotherapy (N.=9), which can be considered as an advanced concept for the improvement of balance and postural control in multiple sclerosis. METHODS: After simple random allocation patients received hippotherapy or Internet-based home training (balance, postural control and strength training) twice a week for 12 weeks. Assessments were done before and after the intervention and included static and dynamic balance (primary outcome). Isometric muscle strength of the knee and trunk extension/flexion (dynamometer), walking capacity, fatigue and quality of life served as secondary outcome parameters. RESULTS: Both intervention groups showed comparable and highly significant improvement in static and dynamic balance capacity, no difference was seen between the both intervention groups. However looking at fatigue and quality of life only the group receiving hippotherapy improved significantly. CONCLUSION: Since e-Training shows even comparable effects to hippotherapy to improve balance, we believe that the established Internet-based home training program, specialized on balance and postural control training, is feasible for a balance and strength training in persons with multiple sclerosis. CLINICAL REHABILITATION IMPACT: We demonstrated that Internet-based home training is possible in patients with multiple sclerosis. PMID- 24755774 TI - Is vestibular rehabilitation as effective in bilateral vestibular dysfunction as in unilateral vestibular dysfunction? AB - BACKGROUND: Bilateral vestibular dysfunction causes serious disabilities and handicaps. Patients with bilateral dysfunction often restrict their activities and tend to be unsocial. AIM: To compare the effects of vestibular rehabilitation on disability, balance, and postural stability in patients with unilateral and bilateral vestibular dysfunction. DESIGN: Retrospective study. SETTING: Outpatient rehabilitation center. POPULATION: Patients with unilateral (group 1, N.=42) and bilateral vestibular dysfunction (group 2, N.=19). METHODS: All patients were evaluated before and after eight weeks of customized vestibular rehabilitation for disability (Dizziness Handicap Inventory [DHI], Activities specific Balance Confidence Scale [ABC]), dynamic balance (Timed Up and Go Test [TUG], Dynamic Gait Index [DGI]), and postural stability (static posturography). RESULTS: The differences between DHI, TUG, DGI, and falling index (as assessed by static posturography) scores before and after the exercise program were statistically significant in both groups (P<0.05). There were no significant intergroup differences in any of the parameters evaluated (P>0.05). CONCLUSION: In this study, vestibular rehabilitation was found to be equally effective in unilateral and bilateral vestibular dysfunction patients for improving disability, dynamic balance, and postural stability. CLINICAL REHABILITATION IMPACT: Patients with bilateral dysfunction, causing more disability and greater handicap may indeed regain their functions as in patients with unilateral vestibular dysfunction by receiving appropriate and adequate vestibular rehabilitation. PMID- 24755775 TI - Expectations for treatment outcomes in neck/back patients regarding improvements in pain and function. A cross-sectional pilot study. AB - BACKGROUND: Literature has suggested that patients' pretreatment expectations may influence both prognosis and outcome. Investigation of these possible benefits requires knowledge about what is actually expected among these patients. AIM: To investigate neck/back patients' expectations for treatment outcomes (pain and functional improvement) prior to their first meetings with specialists in physical medicine and rehabilitation (PMR). DESIGN: Cross-sectional pilot study. SETTING: PMR Neck/Back Outpatient Clinic, Oslo University Hospital. POPULATION: Patients with neck/back pain and/or functional problems referred for the first time to a neck/back PMR outpatient clinic. METHODS: Questionnaires were completed prior to an appointment with a PMR specialist. The forms consisted of one earlier designed instrument (PSOE) and one self-constructed part with six 11-point numeric rating scales (11-NRS). Eligible patients were randomly selected between January and June 2012. RESULTS: Approximately 42 % expected their status to remain un-changed. A total of 17 % expected exacerbation of their status. No differences were found between expectations regarding pain and function. Full recovery was not expected. Highly educated patients, and those reporting high usage of analgesics, had higher expectations for improvement. CONCLUSION: Few of the selected patients seemed to expect improvement. These expectations are quite pessimistic, in our opinion. More elaborate studies are needed to confirm these results. PMID- 24755776 TI - Postural control and balance self-efficacy in women with fibromyalgia: are there differences? AB - BACKGROUND: Fibromyalgia (FM) is a rheumatic disease characterized by chronic widespread pain and symptoms such as fatigue, sleep disturbances, cognitive difficulties, and depression. Postural instability is a debilitating disorder increasingly recognized as part of FM. OBJECTIVE: To assess and compare postural control and balance self-efficacy in women with and without FM and verify the association of these variables with pain, symptom severity, and strength. DESIGN: Case-control study SETTING: Physiotherapeutic Clinical Research and Electromyography Laboratory Department of Physical Therapy, Speech Therapy, and Occupational Therapy, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil. POPULATION: Case-control study of 117 women ranging from age 35 to 60 years. Of these, 67 had FM. METHODS: Posture control was assessed with the modified clinical test of sensory interaction on balance with patients in forceplates, balance self-efficacy with the Activities-specific Balance Confidence Scale, pain severity with the Visual Analog Scale, tender point pain threshold with digital algometry, symptom severity with the fibromyalgia impact questionnaire, and lower limb strength with a dynamometer. RESULTS: Individuals with FM had impaired postural control showing increased speed of oscillation of the center of gravity (P=0.004) and decreased balance self-efficacy (P<0.001). They had moderate to excellent correlations of balance self-efficacy with pain (r=0.7, P<0.01), muscle strength (r=0.52, P<0.01), and symptom severity (r=0.78, P<0.10) compared with the control group. Correlation of postural control with the same variables was weak. CONCLUSIONS: Patients with FM have impaired postural control and low balance self-efficacy that are associated with pain, muscle strength, and symptom severity. CLINICAL REHABILITATION IMPACT: Postural control and balance self-efficacy needs to be assessed in patients with FM and the treatment goals should be the improvement of postural control and balance self efficacy. PMID- 24755777 TI - Intuitive logic revisited: new data and a Bayesian mixed model meta-analysis. AB - Recent research on syllogistic reasoning suggests that the logical status (valid vs. invalid) of even difficult syllogisms can be intuitively detected via differences in conceptual fluency between logically valid and invalid syllogisms when participants are asked to rate how much they like a conclusion following from a syllogism (Morsanyi & Handley, 2012). These claims of an intuitive logic are at odds with most theories on syllogistic reasoning which posit that detecting the logical status of difficult syllogisms requires effortful and deliberate cognitive processes. We present new data replicating the effects reported by Morsanyi and Handley, but show that this effect is eliminated when controlling for a possible confound in terms of conclusion content. Additionally, we reanalyze three studies (n = 287) without this confound with a Bayesian mixed model meta-analysis (i.e., controlling for participant and item effects) which provides evidence for the null-hypothesis and against Morsanyi and Handley's claim. PMID- 24755778 TI - Development of an adverse drug reaction risk assessment score among hospitalized patients with chronic kidney disease. AB - BACKGROUND: Adverse drug reactions (ADRs) represent a major burden on the healthcare system. Chronic kidney disease (CKD) patients are particularly vulnerable to ADRs because they are usually on multiple drug regimens, have multiple comorbidities, and because of alteration in their pharmacokinetics and pharmacodynamic parameters. Therefore, one step towards reducing this burden is to identify patients who are at increased risk of an ADR. OBJECTIVE: To develop a method of identifying CKD patients who are at increased risk for experiencing ADRs during hospitalisation. MATERIALS AND METHODS: Factors associated with ADRs were identified by using demographic, clinical and laboratory variables of patients with CKD stages 3 to 5 (estimated glomerular filtration rate, 10-59 ml/min/1.73 m2) who were admitted between January 1, 2012, and December 31, 2012, to the renal unit of Dubai Hospital. An ADR risk score was developed by constructing a series of logistic regression models. The overall model performance for sequential models was evaluated using Akaike Information Criterion for goodness of fit. Odd ratios of the variables retained in the best model were used to compute the risk scores. RESULTS: Of 512 patients (mean [SD] age, 60 [16] years), 62 (12.1%) experienced an ADR during their hospitalisation. An ADR risk score included age 65 years or more, female sex, conservatively managed end-stage renal disease, vascular disease, serum level of C-reactive protein more than 10 mg/L, serum level of albumin less than 3.5 g/dL, and the use of 8 medications or more during hospitalization. The C statistic, which assesses the ability of the risk score to predict ADRs, was 0.838; 95% CI, 0.784-0.892). CONCLUSION: A score using routinely available patient data can be used to identify CKD patients who are at increased risk of ADRs. PMID- 24755779 TI - Nuclear localization of SALL4: a stemness transcription factor. PMID- 24755781 TI - A. L. Parker's broadside: laughing "gas" for Littleton. PMID- 24755780 TI - High-fidelity optical reporting of neuronal electrical activity with an ultrafast fluorescent voltage sensor. AB - Accurate optical reporting of electrical activity in genetically defined neuronal populations is a long-standing goal in neuroscience. We developed Accelerated Sensor of Action Potentials 1 (ASAP1), a voltage sensor design in which a circularly permuted green fluorescent protein is inserted in an extracellular loop of a voltage-sensing domain, rendering fluorescence responsive to membrane potential. ASAP1 demonstrated on and off kinetics of ~ 2 ms, reliably detected single action potentials and subthreshold potential changes, and tracked trains of action potential waveforms up to 200 Hz in single trials. With a favorable combination of brightness, dynamic range and speed, ASAP1 enables continuous monitoring of membrane potential in neurons at kilohertz frame rates using standard epifluorescence microscopy. PMID- 24755782 TI - Transforming high risk to high yield. PMID- 24755783 TI - A.L. Parker's broadside: "any... painless" anesthetic for Penacook. PMID- 24755785 TI - The Wachter chloroform dropper. PMID- 24755784 TI - GNAS gene variants affect beta-blocker-related survival after coronary artery bypass grafting. AB - BACKGROUND: Cardiac overexpression of the beta-adrenoreceptor (betaAR)-coupled stimulatory G-protein subunit Galphas enhances inotropic responses to adrenergic stimulation and improves survival in mice under betaAR blockade. The authors recently identified three common haplotypes in the GNAS gene encoding Galphas, with the greatest Galphas protein expression and signal transduction in haplotype *3 carriers and less in haplotype *2 and *1 carriers. The authors tested the hypothesis that these GNAS variants result in altered mortality in patients after coronary artery bypass graft surgery, particularly in those receiving betaAR blockade. METHODS: This prospective analysis included 1,627 European ancestry patients undergoing primary coronary artery bypass graft surgery. Patients were genotyped for two GNAS haplotype tagging single-nucleotide polymorphisms defining three major haplotypes. Up to 5-yr all-cause mortality was estimated using a Cox proportional hazard model; hazard ratios and 95% CIs were calculated while adjusting for demographics, clinical covariates, and the new EuroSCORE II. RESULTS: Univariate analysis revealed haplotype-dependent 5-yr mortality rates (*1/*1: 18.9%, *2/*1: 13.7%, *2/*2: 9.3%, *3/*1: 10.6%, *3/*2: 9.1%, and *3/*3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype *1 carriers showed a doubled risk for death (hazard ratio, 2.2; 95% CI, 1.2 to 3.8; P = 0.006). Considering only patients receiving betaAR blockers (n = 1,267), the adjusted risk of death even tripled (hazard ratio, 3.0; 95% CI, 1.5 to 6.1; P = 0.002). CONCLUSIONS: GNAS haplotypes independently associate with an increased risk of death after primary coronary artery bypass graft surgery. These results are most pronounced in patients receiving betaAR blockers, strengthening the rationale for personalized treatment, to decrease medication side effects and improve outcomes. PMID- 24755787 TI - "HANSGEN" amber bottle for the Wachter chloroform dropper. PMID- 24755788 TI - Laterality of motor control and breathing share the same hemisphere: considerations regarding neuroaxial anesthesia in cases with intracranial pathology. PMID- 24755786 TI - Predicting risk of postoperative lung injury in high-risk surgical patients: a multicenter cohort study. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) remains a serious postoperative complication. Although ARDS prevention is a priority, the inability to identify patients at risk for ARDS remains a barrier to progress. The authors tested and refined the previously reported surgical lung injury prediction (SLIP) model in a multicenter cohort of at-risk surgical patients. METHODS: This is a secondary analysis of a multicenter, prospective cohort investigation evaluating high-risk patients undergoing surgery. Preoperative ARDS risk factors and risk modifiers were evaluated for inclusion in a parsimonious risk-prediction model. Multiple imputation and domain analysis were used to facilitate development of a refined model, designated SLIP-2. Area under the receiver operating characteristic curve and the Hosmer-Lemeshow goodness-of-fit test were used to assess model performance. RESULTS: Among 1,562 at-risk patients, ARDS developed in 117 (7.5%). Nine independent predictors of ARDS were identified: sepsis, high risk aortic vascular surgery, high-risk cardiac surgery, emergency surgery, cirrhosis, admission location other than home, increased respiratory rate (20 to 29 and >=30 breaths/min), FIO2 greater than 35%, and SpO2 less than 95%. The original SLIP score performed poorly in this heterogeneous cohort with baseline risk factors for ARDS (area under the receiver operating characteristic curve [95% CI], 0.56 [0.50 to 0.62]). In contrast, SLIP-2 score performed well (area under the receiver operating characteristic curve [95% CI], 0.84 [0.81 to 0.88]). Internal validation indicated similar discrimination, with an area under the receiver operating characteristic curve of 0.84. CONCLUSIONS: In this multicenter cohort of patients at risk for ARDS, the SLIP-2 score outperformed the original SLIP score. If validated in an independent sample, this tool may help identify surgical patients at high risk for ARDS. PMID- 24755789 TI - In reply. PMID- 24755790 TI - Association of intraoperative hypotension with postoperative acute kidney and myocardial injuries in noncardiac surgery patients. PMID- 24755791 TI - In reply. PMID- 24755792 TI - Cerebral and renal blood flow autoregulation. PMID- 24755793 TI - In reply. PMID- 24755794 TI - Not all injections are the same. PMID- 24755795 TI - Evaluation of effect on nonsteroid epidural injections. PMID- 24755796 TI - In reply. PMID- 24755797 TI - Does beta selectivity really affect outcome? PMID- 24755798 TI - In reply. PMID- 24755799 TI - Thoracic epidural anesthesia in abdominal aortic surgery: use and advantages. PMID- 24755800 TI - Sevoflurane--compared with propofol-based anesthesia reduces the need for inotropic support in patients undergoing abdominal aortic aneurysm repair: evidence of cardioprotection by volatile anesthetics in noncardiac surgery. PMID- 24755801 TI - Comparing cardioprotective effects of anesthesia methods in patients undergoing elective abdominal aortic surgery. PMID- 24755802 TI - In reply. PMID- 24755803 TI - Predicting postoperative morbidity: in what procedures and what patients? PMID- 24755804 TI - In reply. PMID- 24755805 TI - Is perioperative intravenous lidocaine for complex spine surgery a more complex issue? PMID- 24755806 TI - In reply. PMID- 24755812 TI - Complex information for anesthesiologists presented quickly and clearly: vasopressor variation: intra- and international variation in perioperative utilization of vasopressors and inotropes in cardiac surgery. PMID- 24755813 TI - Outcomes in polytrauma: comparison between the results achieved in the Cesena Trauma Centre and in the Regional Registry of a (RRGT) of Emilia Romagna, Italy. AB - AIM: The aim of this retrospective study is to compare the outcomes achieved in the Trauma Centre of Cesena to those of the Regional Registry of Major Trauma (RRGT) of Emilia-Romagna, where a coordinated trauma care network has been implemented since 2001, based on the hub & spoke model. MATERIAL OF STUDY: A group of 747 patients were compared to 3.803 cases of the RRGT. The most serious patients, who arrived to the emergency room with a red or yellow emergency code, were sorted into 3 groups according to their haemodynamic response after the primary survey. Each group of patients was treated following a determined diagnostic and therapeutic protocol. Outcome indicators as well as diagnostic and therapeutic resources were examined. RESULTS: Mortality at discharge from Intensive Care was 10.6%. A drop of 2.2% mortality in ICU was recorded as well as reductions in the ICU average stay (13.6%) and in the use of CT (3.9%). On the other hand, surgeries increased by 17% in the Trauma Centre of Cesena as well as the use of angiographies (3.8%) compared to the RRGT regional register. DISCUSSION: The most important data is a sensible reduction in mortality among the group of patients who were hospitalized in ICU. These results can be compared to those which have recently been published by Scalea [1] concerning a retrospective analysis studying a 12-year period. CONCLUSIONS: A significant improvement of some indicators, with respect to the RRGT, was registered within the last three years among the group of the analyzed major traumas. It is therefore arguable that these protocols may represent a viable and clear reference point for all trauma care providers. PMID- 24755814 TI - [Observational study on urinary status following HoLEP]. AB - We assessed the safety, and postoperative urinary status of holmium laser enucleation of the prostate (HoLEP) for the treatment of benign prostatic hyperplasia (BPH). Of the initial 117 patients who underwent HoLEP from November 2004 to March 2011, 49 were followed up for two yearsor longer. These 49 patients were evaluated once preoperatively, and at the 3rd, 6th, 12th, 24th, 48th, and 60th month postoperatively using International Prostate Symptom Scores (I-PSS) total and sub-score, quality of life score (QOL), maximum flow rate (Qmax), and post-voiding residual urine volume (PVR). The median estimated transition zone and enucleated volume were 45. 1 and 47. 9 g, respectively. Evaluation scores showed significant improvementsthroughout the follow-up. I-PSS total scoresimproved from 21 points(before surgery) to 6 points(12 monthsafter surgery), QOL scoresimproved from 5 pointsto 2 points, Qmax improved from 6.8 ml/s to 17.4 ml/s, and PVR improved from 101 ml to 26 ml, respectively. Transient urinary incontinence was noted in 14 patients (28.5%). One case showed a Clavien grade 3 complication of postoperative bleeding. No blood transfusion or re surgery for BPH was required. In conclusion, HoLEP proved to be a safe and effective therapy, with potential to become a new gold standard for treating BPH. PMID- 24755815 TI - [Additional administration of dutasteride in patients with benign prostatic hyperplasia who did not respond sufficiently to alpha1-adrenoceptor antagonist : investigation of clinical factors affecting the therapeutic effect of dutasteride]. AB - We performed additional administration of dutasteride in patients who did not respond sufficiently to alpha1-adrenoceptor antagonist treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) (LUTS/BPH). Among 76 registered patients, efficacy was analyzed in 58 patients. International Prostate Symptom Score (IPSS), subscores for voiding and storage symptoms and quality of life (QOL) on the IPSS, and Overactive Bladder Symptom Score (OABSS) were all significantly improved from the third month of administration compared to the time of initiating additional administration of dutasteride. Additional administration of dutasteride also significantly reduced prostate volume, and residual urine with the exception of the sixth month after administration. Age at initiation of administration and voiding symptom subscore on the IPSS were clinical factors affecting the therapeutic effects of dutasteride. The rate of improvement with treatment decreased with increasing age at initiation of dutasteride administration, and increased as voiding symptom subscore on the IPSS increased. Therefore, additional administration of dutasteride appears useful for cases of LUTS/BPH in which a sufficient response is not achieved with alpha1-adrenoceptor antagonist treatment. Because patients who have severe voiding symptoms or begin dutasteride at an early age may be expected to respond particularly well to dutasteride in terms of clinical efficacy, they were considered to be suitable targets for additional administration. PMID- 24755816 TI - [Port site recurrence after retroperitoneoscopic nephrectomy for renal cell carcinoma : a case report]. AB - A 61-year-old woman was diagnosed with left renal cell carcinoma. Clinical stage was cT1bN0M0. She underwent retroperitoneoscopic radical nephrectomy. The pathological diagnosis was clear cell carcinoma, pT1b, G1>G2, INFalpha, v(+). At 33 months postoperatively CT demonstrated an enhancing tumor just under the port site for evacuation route of the kidney. The tumor was removed by surgery. The pathological diagnosis was clear cell carcinoma. The patient had no recurrence or metastasis 21 months after the surgery. PMID- 24755817 TI - [A case of pneumatosis cystoides intestinalis secondary to sunitinib treatment for renal cell carcinoma]. AB - A 78-year-old man was diagnosed as having right renal cell carcinoma (RCC) with metastasis to the right lung. He received sunitinib and the treatment reduced the size of both RCC and lung metastasis. Then he received right radical nephrectomy. The pathological diagnosis was clear cell RCC. After the initial surgery, he was diagnosed with polymyalgia rheumatic and steroid therapy was started. During follow-up, local recurrence was discovered and sunitinib was then started at a dose of 25 mg/day. Two months after the treatment, abdominal computed tomography (CT) revealed colonic pneumatosis cystoides intestinalis. Administration of sunitinib was stopped and the patient was observed carefully without pursuing surgical intervention. A follow-up CT demonstrated resolution of the colonic pnumatosis. PMID- 24755818 TI - [A case of adrenal metastasectomy in renal cell carcinoma after neoadjuvant therapy with sunitinib]. AB - A 58-year-old man had undergone laparoscopic radical nephrectomy for right renal cell carcinoma. The histopathological diagnosis was clear cell carcinoma, grade 2>3, pT1b. Two years and 10 months postoperatively, computed tomography scans demonstrated an enhanced mass on the right adrenal gland. As we could not detect other metastatic lesions, it was diagnosed as solitary adrenal metastasis of renal cell carcinoma. Albeit metastasectomy was planned with curative intent, right hemihepatectomy was also required for surgical removal because the tumor was adherent to the right lobe of the liver broadly and had indistinct margins. So we started neoadjuvant therapy with sunitinib. Eight courses of treatment shrunk the metastatic tumor enough to allow it to be removed completely without partial hepatectomy. Neoadjuvant therapy with the molecular targeted drugs may provide an effective option for metastasectomy in renal cell carcinoma regarding increased curability and decreased the risk of an operation. PMID- 24755819 TI - [An intravesical foreign body by migration of remnant gauze into the bladder: a case report]. AB - A 35-year-old female, who had undergone Caesarean sections in 2000 and 2001, presented with repeated candida vaginitis and cystitis. She reported that a piece of gauze was excreted through the urethra in 2005. The patient visited an outpatient clinic, but no foreign body was identified by cystoscopy. She again visited the clinic in 2012 complaining of miction pain, and a calcified mass was identified in the bladder. The patient was then referred to our hospital. During a transurethral operation, crushed stones, which included the gauze, were removed from the bladder. We concluded that remnant gauze left in the abdominal cavity during the previous pelvic surgery, had migrated into the bladder and formed a calcified mass. PMID- 24755820 TI - [Four cases of urinary dysfunction associated with sacral herpes zoster]. AB - Herpes zoster is caused by the infection of Varicella-Zoster virus. The anatomical distribution of herpes zoster in the sacral area is only 6. 9%1). Moreover, the onset rate of herpes zoster with urinary dysfunction is 0.6%1). The lesion sites of herpes zoster which cause urinary dysfunction are almost lumber and sacral areas. We describe four cases of sacral herpes zoster with urinary dysfunction in this report. All patients were elderly people (66-84 years old), and all patients were administered anti-virus drugs and alpha 1-adrenergic receptor blockers. Because of urinary retention, three patients have performed clean intermittent self-catheterization (CIC) for several weeks. As the lesions of herpes zoster healed, each patient recovered from urinary dysfunction. PMID- 24755821 TI - [Urinary schistosomiasis: report of a case]. AB - A 20-year-old unmarried Ghanaian man complaining of macroscopic hematuria and cystitis symptom was admitted to our institute. Abdominal ultrasound revealed a hyper echoic lesion in the entire bladder wall. Computed tomography showed a calcification of the whole bladder wall and of the left lower ureter. Flexible cystoscopy revealed many nodular masses, so-called 'bilharzial tubercles', at the trigone and posterior wall of the urinary bladder, and there was partial bleeding. Pathological examination revealed granuloma with many calcified eggs of schistosome haematobium. He was diagnosed with Bilharzial schistosomiasis and was treated with 1,500 mg of praziquantel for two days. However the therapeutic effect was insufficient. Therefore, he was treated with 2,400 mg of praziquantel for two days, and the symptoms disappeared. PMID- 24755822 TI - [Neoadjuvant and adjuvant chemotherapy with paclitaxel, cisplatin and 5 fluorouracil for advanced penile cancer: a case report]. AB - 54-year-old male was introduced to our hospital in January 2012 for surgical treatment and chemotherapy. The pathological examination revealed well differentiated squamous cell carcinoma of the penis. Computed tomography and magnetic resonance imaging indicated right inguinal and pelvic lymphadenopathy. We diagnosed the tumor to be unresectable radically and administered paclitaxel, cisplatin and 5-fluorouracil (TPF) as neoadjuvant chemotherapy. After 3 courses of chemotherapy, the size of lymphadenopathy had become small enough to allow curative surgical treatment. Partial penectomy and lymph node dissection were performed after neoadjuvant chemotherapy. For 12 months after this radical treatment, the patient has been healthy with no local resurrence and no distant metastatic lesion. TPF chemotherapy for unresectable nodal metastasis from squamous cell carcinoma of penis was suggested to be effective. PMID- 24755823 TI - A rapid and robust selection procedure for generating drug-selectable marker-free recombinant malaria parasites. AB - Experimental genetics have been widely used to explore the biology of the malaria parasites. The rodent parasites Plasmodium berghei and less frequently P. yoelii are commonly utilised, as their complete life cycle can be reproduced in the laboratory and because they are genetically tractable via homologous recombination. However, due to the limited number of drug-selectable markers, multiple modifications of the parasite genome are difficult to achieve and require large numbers of mice. Here we describe a novel strategy that combines positive-negative drug selection and flow cytometry-assisted sorting of fluorescent parasites for the rapid generation of drug-selectable marker-free P. berghei and P. yoelii mutant parasites expressing a GFP or a GFP-luciferase cassette, using minimal numbers of mice. We further illustrate how this new strategy facilitates phenotypic analysis of genetically modified parasites by fluorescence and bioluminescence imaging of P. berghei mutants arrested during liver stage development. PMID- 24755824 TI - Liver stiffness by transient elastography predicts liver-related complications and mortality in patients with chronic liver disease. AB - BACKGROUND: Liver stiffness measurement (LSM) by transient elastography (TE, FibroScan) is a validated method for noninvasively staging liver fibrosis. Most hepatic complications occur in patients with advanced fibrosis. Our objective was to determine the ability of LSM by TE to predict hepatic complications and mortality in a large cohort of patients with chronic liver disease. METHODS: In consecutive adults who underwent LSM by TE between July 2008 and June 2011, we used Cox regression to determine the independent association between liver stiffness and death or hepatic complications (decompensation, hepatocellular carcinoma, and liver transplantation). The performance of LSM to predict complications was determined using the c-statistic. RESULTS: Among 2,052 patients (median age 51 years, 65% with hepatitis B or C), 87 patients (4.2%) died or developed a hepatic complication during a median follow-up period of 15.6 months (interquartile range, 11.0-23.5 months). Patients with complications had higher median liver stiffness than those without complications (13.5 vs. 6.0 kPa; P<0.00005). The 2-year incidence rates of death or hepatic complications were 2.6%, 9%, 19%, and 34% in patients with liver stiffness <10, 10-19.9, 20-39.9, and >=40 kPa, respectively (P<0.00005). After adjustment for potential confounders, liver stiffness by TE was an independent predictor of complications (hazard ratio [HR] 1.05 per kPa; 95% confidence interval [CI] 1.03-1.06). The c statistic of liver-stiffness for predicting complications was 0.80 (95% CI 0.75 0.85). A liver stiffness below 20 kPa effectively excluded complications (specificity 93%, negative predictive value 97%); however, the positive predictive value of higher results was sub-optimal (20%). CONCLUSIONS: Liver stiffness by TE accurately predicts the risk of death or hepatic complications in patients with chronic liver disease. TE may facilitate the estimation of prognosis and guide management of these patients. PMID- 24755825 TI - Bacteria and genes involved in arsenic speciation in sediment impacted by long term gold mining. AB - The bacterial community and genes involved in geobiocycling of arsenic (As) from sediment impacted by long-term gold mining were characterized through culture based analysis of As-transforming bacteria and metagenomic studies of the arsC, arrA, and aioA genes. Sediment was collected from the historically gold mining impacted Mina stream, located in one of the world's largest mining regions known as the "Iron Quadrangle". A total of 123 As-resistant bacteria were recovered from the enrichment cultures, which were phenotypically and genotypically characterized for As-transformation. A diverse As-resistant bacteria community was found through phylogenetic analyses of the 16S rRNA gene. Bacterial isolates were affiliated with Proteobacteria, Firmicutes, and Actinobacteria and were represented by 20 genera. Most were AsV-reducing (72%), whereas AsIII-oxidizing accounted for 20%. Bacteria harboring the arsC gene predominated (85%), followed by aioA (20%) and arrA (7%). Additionally, we identified two novel As transforming genera, Thermomonas and Pannonibacter. Metagenomic analysis of arsC, aioA, and arrA sequences confirmed the presence of these genes, with arrA sequences being more closely related to uncultured organisms. Evolutionary analyses revealed high genetic similarity between some arsC and aioA sequences obtained from isolates and clone libraries, suggesting that those isolates may represent environmentally important bacteria acting in As speciation. In addition, our findings show that the diversity of arrA genes is wider than earlier described, once none arrA-OTUs were affiliated with known reference strains. Therefore, the molecular diversity of arrA genes is far from being fully explored deserving further attention. PMID- 24755827 TI - Palestinian doctors can sit exam to practise in Israel, court rules. PMID- 24755826 TI - Multi-parametric spinal cord MRI as potential progression marker in amyotrophic lateral sclerosis. AB - OBJECTIVE: To evaluate multimodal MRI of the spinal cord in predicting disease progression and one-year clinical status in amyotrophic lateral sclerosis (ALS) patients. MATERIALS AND METHODS: After a first MRI (MRI1), 29 ALS patients were clinically followed during 12 months; 14/29 patients underwent a second MRI (MRI2) at 11+/-3 months. Cross-sectional area (CSA) that has been shown to be a marker of lower motor neuron degeneration was measured in cervical and upper thoracic spinal cord from T2-weighted images. Fractional anisotropy (FA), axial/radial/mean diffusivities (lambda?, lambda//, MD) and magnetization transfer ratio (MTR) were measured within the lateral corticospinal tract in the cervical region. Imaging metrics were compared with clinical scales: Revised ALS Functional Rating Scale (ALSFRS-R) and manual muscle testing (MMT) score. RESULTS: At MRI1, CSA correlated significantly (P<0.05) with MMT and arm ALSFRS-R scores. FA correlated significantly with leg ALFSRS-R scores. One year after MRI1, CSA predicted (P<0.01) arm ALSFSR-R subscore and FA predicted (P<0.01) leg ALSFRS-R subscore. From MRI1 to MRI2, significant changes (P<0.01) were detected for CSA and MTR. CSA rate of change (i.e. atrophy) highly correlated (P<0.01) with arm ALSFRS-R and arm MMT subscores rate of change. CONCLUSION: Atrophy and DTI metrics predicted ALS disease progression. Cord atrophy was a better biomarker of disease progression than diffusion and MTR. Our study suggests that multimodal MRI could provide surrogate markers of ALS that may help monitoring the effect of disease-modifying drugs. PMID- 24755828 TI - MiR-21 expression in the tumor stroma of oral squamous cell carcinoma: an independent biomarker of disease free survival. AB - Oral squamous cell carcinoma (OSCC) patients have a high mortality rate; thus, new clinical biomarkers and therapeutic options are needed. MicroRNAs (miRNAs) are short noncoding RNAs that regulate posttranscriptional gene expression and are commonly deregulated in OSCC and other cancers. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several types of cancer, and it might be a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in OSCC, paraffin-embedded tumor tissue samples from 86 patients with primary OSCC were analyzed by in situ hybridization. We found that miR-21 was primarily expressed in the tumor stroma and in some tumor-associated blood vessels with no expression in the adjacent normal epithelia or stroma. Using image analysis, we quantitatively estimated miR-21 expression levels specifically in the stroma of a cohort of OSCC samples. These miR-21 levels significantly correlated with disease free survival with the highest levels being located in the stroma. Stromal miR-21 expression was independently associated with a poorer prognosis, even after adjusting for clinical parameters (perineural invasion and N-stage) in a multivariate analysis. In summary, we have shown that miR-21 is located in the carcinoma cells, stroma and blood vessels of tumors, and its expression specifically in the stromal compartment has a negative prognostic value in OSCC. PMID- 24755829 TI - Pathophysiology of chronic venous disease. AB - Chronic venous disease (CVD) is a debilitating condition with a prevalence between 60-70%. The disease pathophysiology is complex and involves genetic susceptibility and environmental factors, with individuals developing visible telengiectasias, reticular veins, and varicose veins. Patient with significant lower extremity symptoms have pain, dermal irritation, swelling, skin changes, and are at risk of developing debilitating venous ulceration. The signature of CVD is an increase in venous pressure referred to as venous hypertension. The various symptoms presenting in CVD and the clinical signs that are observed indicate that there is inflammation, secondary to venous hypertension, and it leads to a number of inflammatory pathways that become activated. The endothelium and glycocalyx via specialized receptors are critical at sensing changes in shear stress, and expression of adhesion molecules allows the activation of leukocytes leading to endothelial attachment, diapedisis, and transmigration into the venous wall/valves resulting in venous wall injury and inflammatory cells in the interstitial tissues. There is a complex of cytokines, chemokines, growth factors, proteases and proteinases, produced by activated leukocytes, that are expressed and unbalanced resulting in an environment of persistent inflammation with the clinical changes that are commonly seen, consisting of varicose veins to more advanced presentations of skin changes and venous ulceration. The structural integrity of protein and the extracellular matrix is altered, enhancing the progressive events of CVD. Work focusing on metabolic changes, miRNA regulation, inflammatory modulation and the glycocalyx will further our knowledge in the pathophysiology of CVD, and provide answers critical to treatment and prevention. PMID- 24755830 TI - Quinolone resistance mechanisms among extended-spectrum beta-lactamase (ESBL) producing Escherichia coli isolated from rivers and lakes in Switzerland. AB - Sixty extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolated from rivers and lakes in Switzerland were screened for individual strains additionally exhibiting a reduced quinolone susceptibility phenotype. Totally, 42 such isolates were found and further characterized for their molecular (fluoro)quinolone resistance mechanisms. PCR and sequence analysis were performed to identify chromosomal mutations in the quinolone resistance-determining regions (QRDR) of gyrA, gyrB, parC and parE and to describe the occurrence of the following plasmid-mediated quinolone resistance genes: qepA, aac-6'-Ib-cr, qnrA, qnrB, qnrC, qnrD and qnrS. The contribution of efflux pumps to the resistance phenotype of selected strains was further determined by the broth microdilution method in the presence and absence of the efflux pump inhibitor phe-arg-beta naphthylamide (PAbetaN). Almost all strains, except two isolates, showed at least one mutation in the QRDR of gyrA. Ten strains showed only one mutation in gyrA, whereas thirty isolates exhibited up to four mutations in the QRDR of gyrA, parC and/or parE. No mutations were detected in gyrB. Most frequently the amino-acid substitution Ser83->Leu was detected in GyrA followed by Asp87->Asn in GyrA, Ser80->Ile in ParC, Glu84->Val in ParC and Ser458->Ala in ParE. Plasmid-mediated quinolone resistance mechanisms were found in twenty isolates bearing QnrS1 (4/20), AAC-6'-Ib-cr (15/20) and QepA (1/20) determinants, respectively. No qnrA, qnrB, qnrC and qnrD were found. In the presence of PAbetaN, the MICs of nalidixic acid were decreased 4- to 32-fold. (Fluoro) quinolone resistance is due to various mechanisms frequently associated with ESBL-production in E. coli from surface waters in Switzerland. PMID- 24755832 TI - The Homans family in American surgery. AB - Within the Homans family is a display of duty to country and service to humanity that is as old as our country, and the contributions of this American family should not go unappreciated. In addition to the Homans' sign, 5 generations of John Homans have contributed much to our current understanding and practice of surgery. Herein we briefly outline the contributions that the Homans family has made to American surgery. PMID- 24755831 TI - A novel genetic score approach using instruments to investigate interactions between pathways and environment: application to air pollution. AB - Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999-2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (p(interaction) = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (p(interaction) = 0.12), CRP (p(interaction) = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications. PMID- 24755833 TI - A vectorial semantics approach to personality assessment. AB - Personality assessment and, specifically, the assessment of personality disorders have traditionally been indifferent to computational models. Computational personality is a new field that involves the automatic classification of individuals' personality traits that can be compared against gold-standard labels. In this context, we introduce a new vectorial semantics approach to personality assessment, which involves the construction of vectors representing personality dimensions and disorders, and the automatic measurements of the similarity between these vectors and texts written by human subjects. We evaluated our approach by using a corpus of 2468 essays written by students who were also assessed through the five-factor personality model. To validate our approach, we measured the similarity between the essays and the personality vectors to produce personality disorder scores. These scores and their correspondence with the subjects' classification of the five personality factors reproduce patterns well-documented in the psychological literature. In addition, we show that, based on the personality vectors, we can predict each of the five personality factors with high accuracy. PMID- 24755834 TI - Isolated late CNS relapse in a young adult 10 years after initial treatment for neuroblastoma. PMID- 24755835 TI - Pyomyositis Causing Temporary Quadriparesis During Induction Therapy for Acute Lymphoblastic Leukemia: Case Report and Review of the Literature. AB - Pyomyositis (PM) is a purulent infection of skeletal muscle. It is often associated with immunosuppression in temperate climates. Herein, we report a case of PM causing temporary quadriparesis in a 14-year-old girl undergoing induction therapy for acute lymphoblastic leukemia and we review the reported pediatric cases associated with induction therapy for hematologic malignancies. Early symptoms of PM can be mistaken for the side effects of chemotherapeutic agents. Greater awareness of the clinical picture of PM will aid in early diagnosis and treatment. With appropriate medical therapy and timely abscess drainage, morbidity and mortality is greatly reduced. PMID- 24755836 TI - Comparison of APACHE II, P-POSSUM and SAPS II scoring systems in patients underwent planned laparotomies due to secondary peritonitis. AB - BACKGROUND: The first aim of this study was to discuss the factors affecting mortality rate in patients with severe intraabdominal sepsis treated with planned relaparotomy. The second aim was to compare APACHEE II, P-POSSUM and SAPS II scoring systems to allow identification of high-risk patients. MATERIAL AND METHODS: A series of 34 patients who had intra-abdominal sepsis and treated with planned relaparotomy between January 2009 and January 2012 were included the study. The source of the peritonitis, type and number of surgical procedures, number of planned relaparatomies, microbiology surveillance, total intensive care unit (ICU) and hospital stay duration, number of intubated days, morbidity and mortality were analyzed. APACHEE II, SAPS II, P-POSSUM scores and estimated mortality ranges at admission were compared. RESULTS: The mean age was 46 (16-76 years) and 73.5 % (n=25) were male. A total of 119 operations and 50 surgical procedures were performed. The overall mortality rate was 20.6% (n=7). Complications developed in %53 (n=18) of the patients. Mortality was higher in upper GIS leaks (6/20 versus 1/14 patients). Areas under the curve calculated by ROC curve analysis for APACHE II, SAPS II and P-POSSUM were 0.958, 0.955 and 0.931, respectively. The highest values for sensitivity (100%) and specivity (85.2%) together were reached in APACHE II, when cut off value for it was set to 20.5. The SAPS II and P-POSSUM physiology scores were correlated with overall hospital stay (p=0.022 r=0.438 and p=0.001 r=0.609 respectively), but this correlation was not found for APACHEE II score (p=0.085 r=0.337). However, all three scoring systems provided clear estimation of ICU stay duration. CONCLUSION: We suggest that, in secondary peritonitis patients reserved for planned relaparotomy, APACHE II is more reliable for prediction of mortality and P-POSSUM scoring system is more reliable for prediction of overall hospital stay duration. PMID- 24755837 TI - Characterization of LGALS3 (galectin-3) as a player in DNA damage response. AB - DNA damage repair (DDR) is an orchestrated process encompassing the injury detection to its complete resolution. DNA double-strand break lesions are repaired mainly by two distinct mechanisms: the error-free homologous recombination (HR) and the error-prone non-homologous end-joining. Galectin-3 (GAL3) is the unique member of the chimeric galectins subfamily and is reported to be involved in several cancer development and progression related events. Recently our group described a putative protein interaction between GAL3 and BARD1, the main partner of breast and ovarian cancer susceptibility gene product BRCA1, both involved in HR pathway. In this report we characterized GAL3/BARD1 protein interaction and evaluated the role of GAL3 in DDR pathways using GAL3 silenced human cells exposed to different DNA damage agents. In the absence of GAL3 we observed a delayed DDR response activation, as well as a decrease in the G 2/M cell cycle checkpoint arrest associated with HR pathway. Moreover, using a TAP-MS approach we also determined the protein interaction network of GAL3. PMID- 24755838 TI - Is DNA barcoding actually cheaper and faster than traditional morphological methods: results from a survey of freshwater bioassessment efforts in the United States? AB - Taxonomic identification accounts for a substantial portion of cost associated with bioassessment programs across the United States. New analytical approaches, such as DNA barcoding have been promoted as a way to reduce monitoring costs and improve efficiency, yet this assumption has not been thoroughly evaluated. We address this question by comparing costs for traditional morphology-based bioassessment, the standard Sanger sequencing-based DNA barcoding approach, and emerging next-generation (NGS) molecular methods. Market demand for molecular approaches is also assessed through a survey of the level of freshwater bioassessment effort in the United States across multiple habitat types (lakes, streams, wetlands) and indicators (benthic invertebrates, fish, algae). All state and regional level programs administered by public agencies and reported via agency web sites were included in the survey. Costs were based on surveys of labs and programs willing to provide such information. More than 19,500 sites are sampled annually across the United States, with the majority of effort occurring in streams. Benthic invertebrates are the most commonly used indicator, but algae and fish comprise between 35% and 21% of total sampling effort, respectively. We estimate that between $104 and $193 million is spent annually on routine freshwater bioassessment in the United States. Approximately 30% of the bioassessment costs are comprised of the cost to conduct traditional morphology based taxonomy. Current barcoding costs using Sanger sequencing are between 1.7 and 3.4 times as expensive as traditional taxonomic approaches, excluding the cost of field sampling (which is common to both approaches). However, the cost of NGS methods are comparable (or slightly less expensive) than traditional methods depending on the indicator. The promise of barcoding as a cheaper alternative to current practices is not yet realized, although molecular methods may provide other benefits, such as a faster sample processing and increased taxonomic resolution. PMID- 24755840 TI - Genetic and ecotypic differentiation in a Californian plant polyploid complex (Grindelia, Asteraceae). AB - Studies of ecotypic differentiation in the California Floristic Province have contributed greatly to plant evolutionary biology since the pioneering work of Clausen, Keck, and Hiesey. The extent of gene flow and genetic differentiation across interfertile ecotypes that span major habitats in the California Floristic Province is understudied, however, and is important for understanding the prospects for local adaptation to evolve or persist in the face of potential gene flow across populations in different ecological settings. We used microsatellite data to examine local differentiation in one of these lineages, the Pacific Coast polyploid complex of the plant genus Grindelia (Asteraceae). We examined 439 individuals in 10 different populations. The plants grouped broadly into a coastal and an inland set of populations. The coastal group contained plants from salt marshes and coastal bluffs, as well as a population growing in a serpentine grassland close to the coast, while the inland group contained grassland plants. No evidence for hybridization was found at the single location where adjacent populations of the two groups were sampled. In addition to differentiation along ecotypic lines, there was also a strong signal of local differentiation, with the plants grouping strongly by population. The strength of local differentiation is consistent with the extensive morphological variation observed across populations and the history of taxonomic confusion in the group. The Pacific Clade of Grindelia and other young Californian plant groups warrant additional analysis of evolutionary divergence along the steep coast-to-inland climatic gradient, which has been associated with local adaptation and ecotype formation since the classic studies of Clausen, Keck, and Hiesey. PMID- 24755841 TI - UK doctors commonly face fitness to practise hearings without legal representation. PMID- 24755839 TI - Protection of pyruvate against glutamate excitotoxicity is mediated by regulating DAPK1 protein complex. AB - The neuroprotective activity of pyruvate has been confirmed in previous in vivo and in vitro studies. Here, we report a novel mechanism that pyruvate prevents SH SY5Y cells from glutamate excitotoxicity by regulating death-associated protein kinase 1 (DAPK1) protein complex. Our results showed pyruvate regulated DAPK1 protein complex to protect cells by two ways. First, pyruvate induced the dissociation of DAPK1 with NMDA receptors. The disruption of the DAPK1-NMDA receptors complex resulted in a decrease in NMDA receptors phosphorylation. Then the glutamate-stimulated Ca2+ influx was inhibited and intracellular Ca2+ overload was alleviated, which blocked the release of cytochrome c and cell death. In addition, increased Bcl-xL induced by pyruvate regulated Bax/Bak dependent death by inhibiting the release of cytochrome c from the mitochondrial inter-membrane space into the cytosol. As a result, the cytochrome c-initiated caspase cascade, including caspase-3 and caspase-9, was inhibited. Second, pyruvate promoted the association between DAPK1 and Beclin-1, which resulted in autophagy activation. The autophagy inhibitor 3-methyladenine reversed the protection afforded by pyruvate. Furthermore, the attenuation of mitochondrial damage induced by pyruvate was partly reduced by 3-methyladenine. This suggested autophagy mediated pyruvate protection by preventing mitochondrial damage. Taken together, pyruvate protects cells from glutamate excitotoxicity by regulating DAPK1 complexes, both through dissociation of DAPK1 from NMDA receptors and association of DAPK1 with Beclin-1. They go forward to protect cells by attenuating Ca2+ overload and activating autophagy. Finally, a convergence of the two ways protects mitochondria from glutamate excitotoxicity, which leads to cell survival. PMID- 24755842 TI - Population dynamics of the critically endangered golden lancehead pitviper, Bothrops insularis: stability or decline? AB - Little is known about vital rates of snakes generally because of the difficulty in collecting data. Here we used a robust design mark-recapture model to estimate survival, behavioral effects on capture probability, temporary emigration, abundance and test the hypothesis of population decline in the golden lancehead pitviper, Bothrops insularis, an endemic and critically endangered species from southeastern Brazil. We collected data at irregular intervals over ten occasions from 2002 to 2010. Survival was slightly higher in the wet season than in the dry season. Temporal emigration was high, indicating the importance of accounting for this parameter both in the sampling design and modeling. No behavioral effects were detected on capture probability. We detected an average annual population decrease (lambda = 0.93, CI = 0.47-1.38) during the study period, but estimates included high uncertainty, and caution in interpretation is needed. We discuss the potential effects of the illegal removal of individuals and the implications of the vital rates obtained for the future persistence and conservation of this endemic, endangered species. PMID- 24755843 TI - The reporting of observational clinical functional magnetic resonance imaging studies: a systematic review. AB - INTRODUCTION: Complete reporting assists readers in confirming the methodological rigor and validity of findings and allows replication. The reporting quality of observational functional magnetic resonance imaging (fMRI) studies involving clinical participants is unclear. OBJECTIVES: We sought to determine the quality of reporting in observational fMRI studies involving clinical participants. METHODS: We searched OVID MEDLINE for fMRI studies in six leading journals between January 2010 and December 2011.Three independent reviewers abstracted data from articles using an 83-item checklist adapted from the guidelines proposed by Poldrack et al. (Neuroimage 2008; 40: 409-14). We calculated the percentage of articles reporting each item of the checklist and the percentage of reported items per article. RESULTS: A random sample of 100 eligible articles was included in the study. Thirty-one items were reported by fewer than 50% of the articles and 13 items were reported by fewer than 20% of the articles. The median percentage of reported items per article was 51% (ranging from 30% to 78%). Although most articles reported statistical methods for within-subject modeling (92%) and for between-subject group modeling (97%), none of the articles reported observed effect sizes for any negative finding (0%). Few articles reported justifications for fixed-effect inferences used for group modeling (3%) and temporal autocorrelations used to account for within-subject variances and correlations (18%). Other under-reported areas included whether and how the task design was optimized for efficiency (22%) and distributions of inter-trial intervals (23%). CONCLUSIONS: This study indicates that substantial improvement in the reporting of observational clinical fMRI studies is required. Poldrack et al.'s guidelines provide a means of improving overall reporting quality. Nonetheless, these guidelines are lengthy and may be at odds with strict word limits for publication; creation of a shortened-version of Poldrack's checklist that contains the most relevant items may be useful in this regard. PMID- 24755845 TI - Adsorption of SF6 decomposed gas on anatase (101) and (001) surfaces with oxygen defect: a density functional theory study. AB - The detection of partial discharge by analyzing the components of SF6 gas in gas insulated switchgears is important to the diagnosis and assessment of the operational state of power equipment. A gas sensor based on anatase TiO2 is used to detect decomposed gases in SF6. In this paper, first-principle density functional theory calculations are adopted to analyze the adsorption of SO2, SOF2, and SO2F2, the primary decomposition by-products of SF6 under partial discharge, on anatase (101) and (001) surfaces. Simulation results show that the perfect anatase (001) surface has a stronger interaction with the three gases than that of anatase (101), and both surfaces are more sensitive and selective to SO2 than to SOF2 and SO2F2. The selection of a defect surface to SO2, SOF2, and SO2F2 differs from that of a perfect surface. This theoretical result is corroborated by the sensing experiment using a TiO2 nanotube array (TNTA) gas sensor. The calculated values are analyzed to explain the results of the Pt-doped TNTA gas sensor sensing experiment. The results imply that the deposited Pt nanoparticles on the surface increase the active sites of the surface and the gas molecules may decompose upon adsorption on the active sites. PMID- 24755844 TI - Acute undifferentiated febrile illness in rural Cambodia: a 3-year prospective observational study. AB - In the past decade, malaria control has been successfully implemented in Cambodia, leading to a substantial decrease in reported cases. Wide-spread use of malaria rapid diagnostic tests (RDTs) has revealed a large burden of malaria negative fever cases, for which no clinical management guidelines exist at peripheral level health facilities. As a first step towards developing such guidelines, a 3-year cross-sectional prospective observational study was designed to investigate the causes of acute malaria-negative febrile illness in Cambodia. From January 2008 to December 2010, 1193 febrile patients and 282 non-febrile individuals were recruited from three health centers in eastern and western Cambodia. Malaria RDTs and routine clinical examination were performed on site by health center staff. Venous samples and nasopharyngeal throat swabs were collected and analysed by molecular diagnostic tests. Blood cultures and blood smears were also taken from all febrile individuals. Molecular testing was applied for malaria parasites, Leptospira, Rickettsia, O. tsutsugamushi, Dengue- and Influenza virus. At least one pathogen was identified in 73.3% (874/1193) of febrile patient samples. Most frequent pathogens detected were P. vivax (33.4%), P. falciparum (26.5%), pathogenic Leptospira (9.4%), Influenza viruses (8.9%), Dengue viruses (6.3%), O. tsutsugamushi (3.9%), Rickettsia (0.2%), and P. knowlesi (0.1%). In the control group, a potential pathogen was identified in 40.4%, most commonly malaria parasites and Leptospira. Clinic-based diagnosis of malaria RDT-negative cases was poorly predictive for pathogen and appropriate treatment. Additional investigations are needed to understand their impact on clinical disease and epidemiology, and the possible role of therapies such as doxycycline, since many of these pathogens were seen in non-febrile subjects. PMID- 24755846 TI - Inhibition of voltage-gated Na+ channels by the synthetic cannabinoid ajulemic acid. AB - BACKGROUND: The synthetic cannabinoid ajulemic acid has been demonstrated to alleviate pain in patients suffering from chronic neuropathic pain. Cannabinoids interact with several molecules within the pain circuit, including a potent inhibition of voltage-gated sodium channels. In this study, we closely characterized this property on neuronal and nonneuronal sodium channels. METHODS: The inhibition of sodium inward currents by ajulemic acid was studied in vitro. Human embryonic kidney 293t cells were used as the expression system for Nav1.2, 1.3, 1.4, 1.5, 1.5N406K, 1.5F1760A, and 1.7; Nav1.8 was transiently expressed in ND7/23 cells. Nav1.2, Nav1.3, and Nav 1.8 were from rats, and Nav1.4, Nav1.5, and Nav1.7 were of human origin. Sodium currents were analyzed by means of the whole cell patch-clamp technique. The investigated concentrations of ajulemic acid were 0.1, 0.3, 1, 3, 10, and 30 MUmol/L. RESULTS: Ajulemic acid reversibly and concentration-dependently inhibited all voltage-gated sodium channel (Nav) isoforms investigated in this study, including Nav1.2, 1.3, 1.4, 1.5, 1.7, and 1.8. Tonic block of resting channels yielded half-maximal inhibitory concentration values between 2 and 9 MUmol/L and was strongly enhanced on inactivated channels, suggesting state-dependent inhibition by ajulemic acid. Tonic block did not differ significantly when comparing Nav1.2 and Nav1.3, Nav1.4 and Nav1.5, and Nav1.7 and Nav1.8. Statistical analysis of other combinations of subunits (e.g., Nav1.2 and Nav1.4) by analysis of variance yielded a significant difference in block. Although we did not observe any relevant use-dependent block, ajulemic acid induced a strong hyperpolarizing shift of the voltage dependency of fast inactivation and modest shift of slow inactivation. The local anesthetic-insensitive Nav1.5 constructs N406K and F1760A displayed a preserved sensitivity to block by ajulemic acid. Finally, we found that low concentrations of ajulemic acid efficiently inhibited Navbeta4 peptide-mediated resurgent currents in Nav1.5. CONCLUSIONS: Our data suggest that block of sodium channels can be a relevant mechanism by which ajulemic acid alleviates neuropathic pain. The potent inhibition of resurgent currents and the preserved block on local anesthetic-insensitive channels indicates that ajulemic acid interacts with a conserved but yet unknown site of sodium channels. PMID- 24755847 TI - Curcumin treatment attenuates pain and enhances functional recovery after incision. AB - BACKGROUND: Acute pain after surgery remains moderate to severe for 20% to 30% of patients despite advancements in the use of opioids, adjuvant drugs, and regional anesthesia. Depending on the type of surgery, 10% to 50% of patients experience persistent pain postoperatively, and there are no established methods for its prevention. Curcumin (diferuloylmethane) is one of the phenolic constituents of turmeric that has been used in Eastern traditional medicine as an antiseptic, antioxidant, anti-inflammatory, and analgesic agent. It may be effective for treating postoperative pain. METHODS: We used the hindpaw incision model with C57BL/6 mice. Sensitization to mechanical and thermal stimuli as well as effects on edema and temperature were measured up to 7 days after surgery. Spontaneous pain after incision was assessed by using conditioned place preference (CPP), and alterations in gait function were assessed using multiparameter digital gait analysis. RESULTS: Curcumin (50 mg/kg) significantly reduced the intensity of mechanical and heat sensitization after hindpaw incision in mice. No effects of curcumin on baseline nociceptive thresholds were observed. Curcumin also reduced hindpaw swelling after incision, suggesting an anti-inflammatory effect. In addition, perioperative curcumin treatment attenuated hyperalgesic priming due to incision when mice were subsequently challenged with hindpaw prostaglandin E2 application. Furthermore, while vehicle-treated mice had evidence of spontaneous pain 48 hours after incision in the CPP paradigm, no evidence of ongoing pain was observed in the mice treated with curcumin. Likewise, hindpaw incision caused changes in several gait-related indices, but most of these were normalized in the curcumin-treated animals. The peri-incisional levels of several pronociceptive immune mediators including interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha, and macrophage inflammatory protein-1alpha were either not reduced or were even augmented 1 and 3 days after incision in curcumin-treated mice. The anti inflammatory cytokine IL-10 was unchanged, while transforming growth factor-beta levels were enhanced under the same conditions. CONCLUSIONS: Our studies suggest that curcumin treatment is effective in alleviating incision-induced inflammation, nociceptive sensitization, spontaneous pain, and functional gait abnormalities. Augmented transforming growth factor-beta production provides one possible mechanism. These preclinical findings demonstrate curcumin's potential as a preventative strategy in postoperative pain treatment. PMID- 24755848 TI - A Bayesian geostatistical Moran Curve model for estimating net changes of tsetse populations in Zambia. AB - For the first time a Bayesian geostatistical version of the Moran Curve, a logarithmic form of the Ricker stock recruitment curve, is proposed that is able to give an estimate of net change in population demographic rates considering components such as fertility and density dependent and density independent mortalities. The method is applied to spatio-temporally referenced count data of tsetse flies obtained from fly-rounds. The model is a linear regression with three components: population rate of change estimated from the Moran curve, an explicit spatio-temporal covariance, and the observation error optimised within a Bayesian framework. The model was applied to the three main climate seasons of Zambia (rainy--January to April, cold-dry--May to August, and hot-dry--September to December) taking into account land surface temperature and (seasonally changing) cattle distribution. The model shows a maximum positive net change during the hot-dry season and a minimum between the rainy and cold-dry seasons. Density independent losses are correlated positively with day-time land surface temperature and negatively with night-time land surface temperature and cattle distribution. The inclusion of density dependent mortality increases considerably the goodness of fit of the model. Cross validation with an independent dataset taken from the same area resulted in a very accurate estimate of tsetse catches. In general, the overall framework provides an important tool for vector control and eradication by identifying vector population concentrations and local vector demographic rates. It can also be applied to the case of sustainable harvesting of natural populations. PMID- 24755849 TI - Radiographic and functional evaluation of the iliac bone graft in the treatment of adolescent idiopathic scoliosis. AB - This study aimed to assess the impact of the use of an additional iliac bone graft on functional and radiographic results after thoracic spine arthrodesis with pedicle screws in patients with adolescent idiopathic scoliosis. Participants were divided into two groups: a control group that received only local bone (n=19) and a second group that, in addition to this procedure, received an iliac graft (n=22). The evaluations were performed on preoperative, immediate postoperative, and last follow-up (mean 29.7 months; minimum 12 months). Radiographic evaluations included the loss of correction and the presence of nonunion. The functional outcome was evaluated using the Scoliosis Research Society-30 questionnaire. Surgical complications and the presence of iliac donor site pain were also described. There were no significant differences between groups in the pseudoarthrosis rate, loss of correction over time, and quality of life. We concluded that the addition of bone graft from the iliac yielded no benefit in terms of the fusion rate and functional outcomes. The appropriate facetectomy, bed preparation, and filling with a local bone graft must be adequate to achieve an adequate fusion on surgical treatment of adolescent idiopathic scoliosis. PMID- 24755850 TI - Risk factors for venous thromboembolism in hospitalized children and adolescents: a systemic review and pooled analysis. AB - We performed a systematic review of published studies that evaluated the potential risk factors and outcomes of venous thromboembolism (VTE) in hospitalized children. A total of 761 VTE patients from six published studies were identified. The mean prevalence of VTE in children admitted to the hospital was 9.7/10 000 admissions. The presence of a central venous catheter was found to be the single most important predisposing cause of VTE, with a pooled percentage of 29%. Infection was the second most common cause of the disease (20%). Pulmonary embolism occurred in 15% (113/745) of the patients. The overall recurrence rate of VTE was 16% (74/464) and the mortality rate was 8% (59/704). Although uncommon, orthopedic surgeons need to be aware of the unique risk factors for VTE among pediatric inpatients. Hospitalized children and adolescents with known risk factors for VTE should be considered candidates for VTE screening or prophylaxis. PMID- 24755851 TI - Medial patellar subluxation without previous lateral release: a case report. AB - Medial patellar subluxation (MPS) is normally described following a lateral release. We report on a 14-year-old girl with MPS without previous lateral release. Arthroscopic examination demonstrated MPS at 0 and 30 degrees of flexion, and the patella was tight in flexion on the lateral side. A low lateral release with a tibial tubercle transfer was performed, followed by repair of the lateral release with an iliotibial band flap, and lateral patellofemoral ligament reconstruction. Excellent functional outcome was achieved. This type of patellar instability is often overlooked and a high index of suspicion is needed for appropriate diagnosis and treatment. PMID- 24755853 TI - New insights into cell signaling. PMID- 24755854 TI - CaMKIIalpha and caveolin-1 cooperate to drive ATP-induced membrane delivery of the P2X3 receptor. AB - The P2X3 receptor plays a vital role in sensory processing and transmission. The assembly and trafficking of the P2X3 receptor are important for its function in primary sensory neurons. As an important inflammation mediator, ATP is released from different cell types around primary sensory neurons, especially under pathological pain conditions. Here, we show that alpha, beta-MeATP dramatically promoted membrane delivery of the P2X3 receptor both in HEK293T cells expressing recombinant P2X3 receptor and in rat primary sensory neurons. alpha, beta-MeATP induced P2X3 receptor-mediated Ca2+ influx, which further activated Ca2+/calmodulin-dependent protein kinase IIalpha (CaMKIIalpha). The N terminus of the P2X3 receptor was responsible for CaMKIIalpha binding, whereas Thr388 in the C terminus was phosphorylated by CaMKIIalpha. Thr388 phosphorylation increased P2X3 receptor binding to caveolin-1. Caveolin-1 knockdown abrogated the alpha, beta-MeATP-induced membrane insertion of the P2X3 receptor. Moreover, alpha, beta MeATP drove the CaMKIIalpha-mediated membrane coinsertion of the P2X2 receptor with the P2X3 receptor. The increased P2X3 receptors on the cell membrane that are due to Thr388 phosphorylation facilitated P2X3 receptor-mediated signal transduction. Together, our data indicate that CaMKIIalpha and caveolin-1 cooperate to drive ligand-induced membrane delivery of the P2X3 receptor and may provide a mechanism of P2X3 receptor sensitization in pain development. PMID- 24755855 TI - TRIM4 modulates type I interferon induction and cellular antiviral response by targeting RIG-I for K63-linked ubiquitination. AB - RIG-I is a pivotal cytoplasmic sensor that recognizes different species of viral RNAs. This recognition leads to activation of the transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and innate antiviral response. In this study, we identified the TRIM family protein TRIM4 as a positive regulator of RIG-I-mediated IFN induction. Overexpression of TRIM4 potentiated virus-triggered activation of IRF3 and NF-kappaB, as well as IFN-beta induction, whereas knockdown of TRIM4 had opposite effects. Mechanistically, TRIM4 associates with RIG-I and targets it for K63-linked polyubiquitination. Our findings demonstrate that TRIM4 is an important regulator of the virus-induced IFN induction pathways by mediating RIG-I for K63-linked ubiquitination. PMID- 24755856 TI - Conversion of female germline stem cells from neonatal and prepubertal mice into pluripotent stem cells. AB - Pluripotent stem cells derived from neonatal or adult testes are a useful tool to examine the mechanisms of pluripotency and a resource for cell-based therapies. However, therapies using these cells will only benefit males but not females. Recently, female germline stem cells (FGSCs) were discovered in ovaries. Whether FGSCs can be converted into pluripotent stem cells, similar to spermatogonial stem cells, is unknown. Here, we demonstrate that female embryonic stem-like cells (fESLCs) can be generated within 1 month from the stably proliferating FGSCs cultured in embryonic stem cell (ESC) medium. fESLCs exhibit properties similar to those of ESCs in terms of marker expression and differentiation potential. Thus, our findings suggest that generation of patient-specific fESLCs is feasible and provides a foundation for personalized regenerative applications. PMID- 24755857 TI - Development and validation of a clinical model to predict the presence of beta lactam resistance in viridans group streptococci causing bacteremia in neutropenic cancer patients. AB - BACKGROUND: Concern for serious infection due to beta-lactam-resistant viridans group streptococci (VGS) is a major factor driving empiric use of an anti-gram positive antimicrobial in patients with febrile neutropenia. We sought to develop and validate a prediction model for the presence of beta-lactam resistance in VGS causing bloodstream infection (BSI) in neutropenic patients. METHODS: Data from 569 unique cases of VGS BSI in neutropenic patients from 2000 to 2010 at the MD Anderson Cancer Center were used to develop the clinical prediction model. Validation was done using 163 cases from 2011 to 2013. In vitro activity of beta lactam agents was determined for 2011-2013 VGS bloodstream isolates. RESULTS: In vitro resistance to beta-lactam agents commonly used in the empiric treatment of febrile neutropenia was observed only for VGS isolates with a penicillin minimum inhibitory concentration (MIC) of >= 2 ug/mL. One hundred twenty-nine of 732 patients (17%) were infected with VGS strains with a penicillin MIC >= 2 ug/mL. For the derivation and validation cohorts, 98% of patients infected by VGS with a penicillin MIC of >= 2 ug/mL had at least 1 of the following risk factors: current use of a beta-lactam as antimicrobial prophylaxis, receipt of a beta lactam antimicrobial in the previous 30 days, or nosocomial VGS BSI onset. Limiting empiric anti-gram-positive therapy to neutropenic patients having at least 1 of these 3 risk factors would have reduced such use by 42%. CONCLUSIONS: Simple clinical criteria can assist with targeting of anti-gram-positive therapy to febrile neutropenic patients at risk of serious beta-lactam-resistant VGS infection. PMID- 24755859 TI - Viridans group streptococci in febrile neutropenic cancer patients: what should we fear? PMID- 24755858 TI - Prevalence and risk factors for asymptomatic Clostridium difficile carriage. AB - BACKGROUND: Clostridium difficile infection (CDI) incidence has increased dramatically over the last decade. Recent studies suggest that asymptomatic carriers may be an important reservoir of C. difficile in healthcare settings. We sought to identify the prevalence and risk factors for asymptomatic C. difficile carriage on admission to the hospital. METHODS: Patients admitted to Barnes Jewish Hospital without diarrhea were enrolled from June 2010 through October 2011. Demographic information and healthcare and medication exposures 90 days prior to admission were collected. Stool specimens or rectal swabs were collected within 48 hours of admission and stored at -30 degrees C until cultured. Clostridium difficile isolates were typed and compared with isolates from patients with CDI. RESULTS: A stool/swab specimen was obtained for 259 enrolled subjects on admission. Two hundred four (79%) were not colonized, 40 (15%) had toxigenic C. difficile (TCD), and 15 (6%) had nontoxigenic C. difficile. There were no differences between TCD-colonized and -uncolonized subjects for age (mean, 56 vs 58 years; P = .46), comorbidities, admission from another healthcare facility (33% vs 24%; P = .23), or recent hospitalization (50% vs 50%; P = .43). There were no differences in antimicrobial exposures in the 90 days prior to admission (55% vs 56%; P = .91). Asymptomatic carriers were colonized with strains similar to strains from patients with CDI, but the relative proportions were different. CONCLUSIONS: There was a high prevalence of TCD colonization on admission. In contrast to past studies, TCD colonization was not associated with recent antimicrobial or healthcare exposures. Additional investigation is needed to determine the role of asymptomatic TCD carriers on hospital-onset CDI incidence. PMID- 24755862 TI - Cigarette smoke and calcium conspire to impair CFTR function in airway epithelia. AB - To maintain health and function in response to inhaled environmental irritants and toxins, the lungs and airways depend upon an innate defense system that involves the secretion of mucus (i.e., mucin, salts, and water) by airway epithelium onto the apical surface to trap foreign particles. Airway mucus is then transported in an oral direction via ciliary beating and coughing, which helps to keep the airways clear. CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP-regulated Cl(-) channel in the apical membrane of epithelium that contributes to salt and water secretion onto the luminal surface of airways, thereby ensuring that secreted mucus is sufficiently hydrated for movement along the epithelial surface. Dehydration of airway mucus, as occurs in cystic fibrosis, results in a more viscous, less mobile secretion that compromises the lung's innate defense system by facilitating a build-up of foreign particles and bacterial growth. Related to this situation is chronic obstructive pulmonary disease (COPD), which is a leading cause of death globally. A major cause of COPD is cigarette smoking, which has been reported to decrease the cellular levels of CFTR in airway epithelia. In their recent article, Rasmussen and coworkers now report that exposure to cigarette smoke elevates cytosolic free Ca(2+) in airway epithelium, leading to decreased surface localization and cellular expression of CFTR and reduced levels of secreted airway surface liquid. Blocking this increase in cytosolic Ca(2+) largely prevented CFTR loss in airway epithelium and surprisingly, cellular lysosomes appear to be a major source for smoke-induced Ca(2+) elevation. PMID- 24755860 TI - Lymphoma immune reconstitution inflammatory syndrome in the center for AIDS research network of integrated clinical systems cohort. AB - BACKGROUND: Lymphoma incidence is increased among human immunodeficiency virus (HIV)-infected individuals soon after antiretroviral therapy (ART), perhaps due to unmasking immune reconstitution inflammatory syndrome (IRIS). Clinical characteristics and survival for unmasking lymphoma IRIS have not been described. METHODS: We studied lymphoma patients in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) from 1996 until 2011. Unmasking lymphoma IRIS was defined as lymphoma within 6 months after ART accompanied by a >= 0.5 log10 copies/mL HIV RNA reduction. Differences in presentation and survival were examined between IRIS and non-IRIS cases. RESULTS: Of 482 lymphoma patients, 56 (12%) met criteria for unmasking lymphoma IRIS. Of these, 12 (21%) had Hodgkin lymphoma, 22 (39%) diffuse large B-cell lymphoma, 5 (9%) Burkitt lymphoma, 10 (18%) primary central nervous system lymphoma, and 7 (13%) other non-Hodgkin lymphoma. Median CD4 cell count at lymphoma diagnosis among IRIS cases was 173 cells/uL (interquartile range, 73-302), and 48% had suppressed HIV RNA <400 copies/mL. IRIS cases were similar overall to non-IRIS cases in histologic distribution and clinical characteristics, excepting more frequent hepatitis B and C (30% vs 19%, P = .05), and lower HIV RNA at lymphoma diagnosis resulting from the IRIS case definition. Overall survival at 5 years was similar between IRIS (49%; 95% confidence interval [CI], 37%-64%) and non-IRIS (44%; 95% CI, 39% 50%), although increased early mortality was suggested among IRIS cases. CONCLUSIONS: In a large HIV-associated lymphoma cohort, 12% of patients met a uniformly applied unmasking lymphoma IRIS case definition. Detailed studies of lymphoma IRIS might identify immunologic mechanisms of lymphoma control. PMID- 24755863 TI - Hyperosmolar therapy in severe traumatic brain injury: a survey of emergency physicians from a large Canadian province. AB - INTRODUCTION: Worldwide, severe traumatic brain injury is a frequent pathology and is associated with high morbidity and mortality. Mannitol and hypertonic saline are therapeutic options for intracranial hypertension occurring in the acute phase of care. However, current practices of emergency physicians are unknown. METHODS: We conducted a self-administered survey of emergency physicians in the province of Quebec, Canada, to understand their attitudes surrounding the use of hyperosmolar solutions in patients with severe traumatic brain injury. Using information from a systematic review of hypertonic saline solutions and experts' opinion, we developed a questionnaire following a systematic approach (items generation and reduction). We tested the questionnaire for face and content validity, and test-retest reliability. Physicians were identified through the department head of each eligible level I and II trauma centers. We administered the survey using a web-based interface and planned email reminders. RESULTS: We received 210 questionnaires out of 429 potentials respondents (response rate 49%). Most respondents worked in level II trauma centers (69%). Fifty-three percent (53%) of emergency physicians stated using hypertonic saline to treat severe traumatic brain injury. Most reported using hyperosmolar therapy in the presence of severe traumatic brain injury and unilateral reactive mydriasis, midline shift or cistern compression on brain computed tomography. CONCLUSION: Hyperosmolar therapy is believed being broadly used by emergency physicians in Quebec following severe traumatic brain injury. Despite the absence of clinical practice guidelines promoting the use of hypertonic saline, a majority of them said to use these solutions in specific clinical situations. PMID- 24755865 TI - Similarity ratio analysis for early stage fault detection with optical emission spectrometer in plasma etching process. AB - A Similarity Ratio Analysis (SRA) method is proposed for early-stage Fault Detection (FD) in plasma etching processes using real-time Optical Emission Spectrometer (OES) data as input. The SRA method can help to realise a highly precise control system by detecting abnormal etch-rate faults in real-time during an etching process. The method processes spectrum scans at successive time points and uses a windowing mechanism over the time series to alleviate problems with timing uncertainties due to process shift from one process run to another. A SRA library is first built to capture features of a healthy etching process. By comparing with the SRA library, a Similarity Ratio (SR) statistic is then calculated for each spectrum scan as the monitored process progresses. A fault detection mechanism, named 3-Warning-1-Alarm (3W1A), takes the SR values as inputs and triggers a system alarm when certain conditions are satisfied. This design reduces the chance of false alarm, and provides a reliable fault reporting service. The SRA method is demonstrated on a real semiconductor manufacturing dataset. The effectiveness of SRA-based fault detection is evaluated using a time series SR test and also using a post-process SR test. The time-series SR provides an early-stage fault detection service, so less energy and materials will be wasted by faulty processing. The post-process SR provides a fault detection service with higher reliability than the time-series SR, but with fault testing conducted only after each process run completes. PMID- 24755864 TI - Advanced beamformers for cochlear implant users: acute measurement of speech perception in challenging listening conditions. AB - OBJECTIVE: To investigate the performance of monaural and binaural beamforming technology with an additional noise reduction algorithm, in cochlear implant recipients. METHOD: This experimental study was conducted as a single subject repeated measures design within a large German cochlear implant centre. Twelve experienced users of an Advanced Bionics HiRes90K or CII implant with a Harmony speech processor were enrolled. The cochlear implant processor of each subject was connected to one of two bilaterally placed state-of-the-art hearing aids (Phonak Ambra) providing three alternative directional processing options: an omnidirectional setting, an adaptive monaural beamformer, and a binaural beamformer. A further noise reduction algorithm (ClearVoice) was applied to the signal on the cochlear implant processor itself. The speech signal was presented from 0 degrees and speech shaped noise presented from loudspeakers placed at +/ 70 degrees , +/-135 degrees and 180 degrees . The Oldenburg sentence test was used to determine the signal-to-noise ratio at which subjects scored 50% correct. RESULTS: Both the adaptive and binaural beamformer were significantly better than the omnidirectional condition (5.3 dB+/-1.2 dB and 7.1 dB+/-1.6 dB (p<0.001) respectively). The best score was achieved with the binaural beamformer in combination with the ClearVoice noise reduction algorithm, with a significant improvement in SRT of 7.9 dB+/-2.4 dB (p<0.001) over the omnidirectional alone condition. CONCLUSIONS: The study showed that the binaural beamformer implemented in the Phonak Ambra hearing aid could be used in conjunction with a Harmony speech processor to produce substantial average improvements in SRT of 7.1 dB. The monaural, adaptive beamformer provided an averaged SRT improvement of 5.3 dB. PMID- 24755866 TI - Effects of three different stretching techniques on vertical jumping performance. AB - The aim of this study was to evaluate 3 different flexibility techniques: (a) ballistic stretching (BS), (b) proprioceptive neuromuscular facilitation stretching (PNF) + BS, and (c) PNF + static stretching (SS) on vertical jump (VJ) performance and to determine the most appropriate stretching method during warm up period before explosive force disciplines. One hundred voluntary male athletes participated in this study. All subjects performed aerobic warm-up (5-minute jog) followed by BS (5 seconds for each stretching exercise), PNF + BS (PNF performed followed by 5 seconds of BS), and PNF + SS (PNF performed followed by 30 seconds of SS) treatment protocol, respectively in the same day. Each stretching treatment was applied for 4 sets bilaterally. In all stretching treatments, lumbar extensor, gluteus maximus, and hamstring muscles were stretched with a single stretching exercise. After a 2-minute brief rest period, participants performed 3 trials of VJ test followed by one of the treatment protocols. Vertical jump performance was evaluated by countermovement jump (CMJ). Participants were divided into 3 groups according to their flexibility and prejump performances after warm-up. For each individual group and the whole group, after all treatments, differences in CMJ values were obtained (p <= 0.05). Ballistic stretching increased the VJ performance in the groups with low and average flexibility, poor prejumping performance, and also in the whole group (p <= 0.05). Proprioceptive neuromuscular facilitation stretching + BS affected VJ performance in the group of participants with high flexibility (p <= 0.05). Proprioceptive neuromuscular facilitation + SS decreased VJ performance in groups of participants with high flexibility, moderate, and high prejumping performance and in whole group (p <= 0.05). Ballistic stretching method increased VJ height, therefore seems to be more suitable than PNF + SS and PNF + BS before events that rely on explosive power as a part of warm-up period. PMID- 24755867 TI - Clinical measures associated with dynamic balance and functional movement. AB - Decreased balance and impaired functional movement have been linked with increased injury risk. The purpose of our study was to determine the association between specific measures of power, strength, flexibility, balance, and endurance compared with more global measures of dynamic balance, using the Y-Balance Test (YBT), and functional movement, using the functional movement screen (FMS), in healthy soldiers. Our participants (n = 64; 53 men, 11 women) were healthy active duty service members (25.2 +/- 3.8 years, 25.1 +/- 3.1 kg.m(-2)). Seventeen tests with 38 associated measures of strength, power, flexibility, endurance, balance, and functional measures were assessed. A significant Pearson product moment correlation (r > 0.2 and p < 0.01) was used to narrow the number of variables of interest. Two hierarchical stepwise regression analyses were performed to determine the most parsimonious set of variables associated with the YBT and FMS performance scores. Our results included a 4 variable model (F = 13.4, p < 0.001) that was associated with YBT scores (R = 0.72, R2 = 0.51). Superior performance on the YBT was associated with better performance on the FMS lunge and upper trunk mobility tests, decreased number of hops during a 6-m hop test, and greater gastrocnemius flexibility. A second 4 variable model (F = 11.813, p < 0.001) was associated with FMS scores (R = 0.70, R2 = 0.50). Superior performance on the FMS was associated with greater anterior reach on the YBT, greater distance on the crossover hop test, increased hamstring flexibility, and higher levels of self reported function through the lower-extremity functional scale. Physical fitness leaders and clinicians could use these models to inform decision making when developing and assessing the outcomes of a personalized intervention program for those with low FMS and YBT scores. PMID- 24755868 TI - Development, test-retest reliability, and construct validity of the resistance training skills battery. AB - The aim of this study was to describe the development and assess test-retest reliability and construct validity of the Resistance Training Skills Battery (RTSB) for adolescents. The RTSB provides an assessment of resistance training skill competency and includes 6 exercises (i.e., body weight squat, push-up, lunge, suspended row, standing overhead press, and front support with chest touches). Scoring for each skill is based on the number of performance criteria successfully demonstrated. An overall resistance training skill quotient (RTSQ) is created by adding participants' scores for the 6 skills. Participants (44 boys and 19 girls, mean age = 14.5 +/- 1.2 years) completed the RTSB on 2 occasions separated by 7 days. Participants also completed the following fitness tests, which were used to create a muscular fitness score (MFS): handgrip strength, timed push-up, and standing long jump tests. Intraclass correlation (ICC), paired samples t-tests, and typical error were used to assess test-retest reliability. To assess construct validity, gender and RTSQ were entered into a regression model predicting MFS. The rank order repeatability of the RTSQ was high (ICC = 0.88). The model explained 39% of the variance in MFS (p <= 0.001) and RTSQ (r = 0.40, p <= 0.001) was a significant predictor. This study has demonstrated the construct validity and test-retest reliability of the RTSB in a sample of adolescents. The RTSB can reliably rank participants in regards to their resistance training competency and has the necessary sensitivity to detect small changes in resistance training skill proficiency. PMID- 24755869 TI - Test-retest reliability and sensitivity of the Concept2 Dyno dynamometer: practical applications. AB - Strength assessment is often part of the objective periodical observation of teams, squads, or large groups of athletes. Equipment that provides assessment that is mobile and is easy to use will reduce the impact on the athletes' training and competitive calendar. However, any equipment used must be reliable to allow accurate monitoring of performance. The aim of this study was to examine the reliability of the Concept2 Dyno dynamometer. Forty-six competitive athletes (males: n = 36, age 23.3 +/- 6.8 years, height 1.80 +/- 0.09 m, body mass 82.3 +/ 15.6 kg; females, n = 10, age 20.7 +/- 1.4 years, height 1.65 +/- 0.09 m, body mass 62.7 +/- 11.8 kg), with a strength training background of more than 2 years, performed a familiarization session and 3 experimental sessions with 1 week intervening each. Each experimental session consisted of 3 maximal efforts of seated chest press (CPress), seated row (SRow), and seated leg press (LPress) exercises. Reliability was assessed examining systematic bias, intraclass correlation coefficient, coefficient of variation (CV), and 95% limits of agreement (95% LoA) between sessions. No systematic bias was found for any of the exercises. Intraclass correlation coefficients were high (0.89-0.98) with relatively low CV (6.2-4.3%). Finally, 95% LoA indicated that subsequent testing could underestimate by a factor of 0.87 or overestimate by a factor of 1.17, on average. These results indicate that Concept2 Dyno dynamometer is reliable and can be used in the field to efficiently monitor strength performance. Coaches and researchers should use "analytical goals" to help decide as to the use of Concept2 Dyno for their purposes. PMID- 24755870 TI - A comparison of training and physical performance of police students at the start and the end of three-year police education. AB - The purpose was to compare male and female police students exercise and physical performances at the beginning and the end of a 3-year police education. Two hundred thirty-five subjects answered the survey about exercise and 85 subjects (58 men: age = 23.7 +/- 2.8 years, body mass = 82.1 +/- 7.8 kg, height = 1.83 +/- 0.06 m; 27 women: age = 24.9 +/- 3.1 years, body mass = 66 +/- 8.5 kg, height = 1.70 +/- 0.09 m) participated in the 4 physical exercises (bench press, pull-ups, standing long jump, and 3,000-m run). It was found that the priority of maximum strength training increased (p < 0.001), whereas the priority of endurance and sprint training decreased during the 3-year period, with no differences between gender (p >= 0.28). The performances in the strength-related physical tests, bench press, and pull-ups also increased in the same period. These changes were the same for both genders. Findings showed a discrepancy between what is reported as necessary physical skills in police work and what actually is trained during the police education. This discrepancy was caused by the large focus upon maximal strength in the physical examination program in the police education. PMID- 24755871 TI - The importance of stimulus noise analysis for self-motion studies. AB - Motion simulators are widely employed in basic and applied research to study the neural mechanisms of perception and action during inertial stimulation. In these studies, uncontrolled simulator-introduced noise inevitably leads to a disparity between the reproduced motion and the trajectories meticulously designed by the experimenter, possibly resulting in undesired motion cues to the investigated system. Understanding actual simulator responses to different motion commands is therefore a crucial yet often underestimated step towards the interpretation of experimental results. In this work, we developed analysis methods based on signal processing techniques to quantify the noise in the actual motion, and its deterministic and stochastic components. Our methods allow comparisons between commanded and actual motion as well as between different actual motion profiles. A specific practical example from one of our studies is used to illustrate the methodologies and their relevance, but this does not detract from its general applicability. Analyses of the simulator's inertial recordings show direction dependent noise and nonlinearity related to the command amplitude. The Signal-to Noise Ratio is one order of magnitude higher for the larger motion amplitudes we tested, compared to the smaller motion amplitudes. Simulator-introduced noise is found to be primarily of deterministic nature, particularly for the stronger motion intensities. The effect of simulator noise on quantification of animal/human motion sensitivity is discussed. We conclude that accurate recording and characterization of executed simulator motion are a crucial prerequisite for the investigation of uncertainty in self-motion perception. PMID- 24755873 TI - Could single-slice quantitative computerized tomography image analysis at the midpoint of the third lumbar region accurately predict total body skeletal muscle? PMID- 24755872 TI - Effects of magnetic fields of up to 9.4 T on resolution and contrast of PET images as measured with an MR-BrainPET. AB - Simultaneous, hybrid MR-PET is expected to improve PET image resolution in the plane perpendicular to the static magnetic field of the scanner. Previous papers have reported this either by simulation or experiment with simple sources and detector arrangements. Here, we extend those studies using a realistic brain phantom in a recently installed MR-PET system comprising a 9.4 T MRI-scanner and an APD-based BrainPET insert in the magnet bore. Point and line sources and a 3D brain phantom were filled with 18F (low-energy positron emitter), 68Ga (medium energy positron emitter) or 120I, a non-standard positron emitter (high positron energies of up to 4.6 MeV). Using the BrainPET insert, emission scans of the phantoms were recorded at different positions inside and outside the magnet bore such that the magnetic field was 0 T, 3 T, 7 T or 9.4 T. Brain phantom images, with the 'grey matter' compartment filled with 18F, showed no obvious resolution improvement with increasing field. This is confirmed by practically unchanged transaxial FWHM and 'grey/white matter' ratio values between at 0T and 9.4T. Field-dependent improvements in the resolution and contrast of transaxial PET images were clearly evident when the brain phantom was filled with 68Ga or 120I. The grey/white matter ratio increased by 7.3% and 16.3%, respectively. The greater reduction of the FWTM compared to FWHM in 68Ga or 120I line-spread images was in agreement with the improved contrast of 68Ga or 120I images. Notwithstanding elongations seen in the z-direction of 68Ga or 120I point source images acquired in foam, brain phantom images show no comparable extension. Our experimental study confirms that integrated MR-PET delivers improved PET image resolution and contrast for medium- and high-energy positron emitters even though the positron range is reduced only in directions perpendicular to the magnetic field. PMID- 24755874 TI - Author response. PMID- 24755875 TI - JPEN Journal Club 4. Using surrogate outcomes. PMID- 24755877 TI - Enhanced antitumor efficacy of an oncolytic herpes simplex virus expressing an endostatin-angiostatin fusion gene in human glioblastoma stem cell xenografts. AB - Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin-angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo-angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin-angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development. PMID- 24755878 TI - Job strain, health and sickness absence: results from the Hordaland Health Study. AB - OBJECTIVES: While it is generally accepted that high job strain is associated with adverse occupational outcomes, the nature of this relationship and the causal pathways involved are not well elucidated. We aimed to assess the association between job strain and long-term sickness absence (LTSA), and investigate whether any associations could be explained by validated health measures. METHODS: Data from participants (n = 7346) of the Hordaland Health Study (HUSK), aged 40-47 at baseline, were analyzed using multivariate Cox regression to evaluate the association between job strain and LTSA over one year. Further analyses examined whether mental and physical health mediated any association between job strain and sickness absence. RESULTS: A positive association was found between job strain and risk of a LTSA episode, even controlling for confounding factors (HR = 1.64 (1.36-1.98); high job strain exposure accounted for a small proportion of LTSA episodes (population attributable risk 0.068). Further adjustments for physical health and mental health individually attenuated, but could not fully explain the association. In the fully adjusted model, the association between high job strain and LTSA remained significant (HR = 1.30 (1.07-1.59)). CONCLUSION: High job strain increases the risk of LTSA. While our results suggest that one in 15 cases of LTSA could be avoided if high job strain were eliminated, we also provide evidence against simplistic causal models. The impact of job strain on future LTSA could not be fully explained by impaired health at baseline, which suggests that factors besides ill health are important in explaining the link between job strain and sickness absence. PMID- 24755879 TI - A method for estimating intracellular sodium concentration and extracellular volume fraction in brain in vivo using sodium magnetic resonance imaging. AB - In this feasibility study we propose a method based on sodium magnetic resonance imaging (MRI) for estimating simultaneously the intracellular sodium concentration (C1, in mM) and the extracellular volume fraction (alpha) in grey and white matters (GM, WM) in brain in vivo. Mean C1 over five healthy volunteers was measured ~11 mM in both GM and WM, mean alpha was measured ~0.22 in GM and ~0.18 in WM, which are in close agreement with standard values for healthy brain tissue (C1 ~ 10-15 mM, alpha ~ 0.2). Simulation of 'fluid' and 'solid' inclusions were accurately detected on both the C1 and alpha 3D maps and in the C1 and alpha distributions over whole GM and WM. This non-invasive and quantitative method could provide new biochemical information for assessing ion homeostasis and cell integrity in brain and help the diagnosis of early signs of neuropathologies such as multiple sclerosis, Alzheimer's disease, brain tumors or stroke. PMID- 24755881 TI - Response to 'Comment on external multicentre validation of a nomogram predicting the risk of relapse in patients with borderline ovarian tumours'. PMID- 24755880 TI - Bioinformatics of prokaryotic RNAs. AB - The genome of most prokaryotes gives rise to surprisingly complex transcriptomes, comprising not only protein-coding mRNAs, often organized as operons, but also harbors dozens or even hundreds of highly structured small regulatory RNAs and unexpectedly large levels of anti-sense transcripts. Comprehensive surveys of prokaryotic transcriptomes and the need to characterize also their non-coding components is heavily dependent on computational methods and workflows, many of which have been developed or at least adapted specifically for the use with bacterial and archaeal data. This review provides an overview on the state-of-the art of RNA bioinformatics focusing on applications to prokaryotes. PMID- 24755882 TI - A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies. AB - BACKGROUND: Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours. METHODS: Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose limiting toxicities (DLT) in the first treatment course. RESULTS: Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ~135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile. CONCLUSIONS: These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients. PMID- 24755883 TI - Breast cancer risk after radiotherapy for heritable and non-heritable retinoblastoma: a US-UK study. AB - BACKGROUND: Retinoblastoma is a rare childhood eye cancer caused by germline or somatic mutations in the RB1 gene. Previous studies observed elevated breast cancer risk among retinoblastoma survivors. However, there has been no research on breast cancer risk in relation to radiation (primarily scatter radiation from the primary treatment) and genetic susceptibility of retinoblastoma survivors. METHODS: Two groups of retinoblastoma survivors from the US and UK were selected, and breast cancer risk analysed using a case-control methodology, nesting within the respective cohorts, matching on heritability (that is to say, having bilateral retinoblastoma or being unilateral cases with at least one relative with retinoblastoma), and using exact statistical methods. There were a total of 31 cases and 77 controls. RESULTS: Overall there was no significant variation of breast cancer risk with dose (P>0.5). However, there was a pronounced and significant (P=0.047) increase in the risk of breast cancer with increasing radiation dose for non-heritable retinoblastoma patients and a slight and borderline significant (P=0.072) decrease in risk of breast cancer with increasing radiation dose for heritable retinoblastoma patients, implying significant (P=0.024) heterogeneity in radiation risk between the heritable and non-heritable retinoblastoma groups; this was unaffected by the blindness status. There was no significant effect of any type of alkylating-agent chemotherapy on breast cancer risk (P>0.5). CONCLUSIONS: There is significant radiation-related risk of breast cancer for non-heritable retinoblastoma survivors but no excess risk for heritable retinoblastoma survivors, and no significant risk overall. However, these results are based on very small numbers of cases; therefore, they must be interpreted with caution. PMID- 24755884 TI - Oncogenic KRAS signalling in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future. PMID- 24755885 TI - HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer. AB - BACKGROUND: HAGE protein is a known immunogenic cancer-specific antigen. METHODS: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. RESULTS: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGE+) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGE+expression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+residual disease (P=0.0003). CONCLUSIONS: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC. PMID- 24755886 TI - Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. AB - Trabectedin is the first marine-derived anti-neoplastic drug approved for the treatment of advanced soft tissue sarcoma and, in combination with pegylated liposomal doxorubicin, for the treatment of patients with relapsed platinum sensitive ovarian cancer. From the beginning of its development, trabectedin showed some peculiar properties that clearly distinguished it from other anti cancer drugs. In this mini-review, we will outline the current state of knowledge regarding the mode of action of trabectedin, which appears to represent a new class of anti-neoplastic drugs acting both on cancer cells and on the tumour microenvironment. PMID- 24755887 TI - Tumour-initiating capacity is independent of epithelial-mesenchymal transition status in breast cancer cell lines. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are considered to be crucial for cancer biology. The purpose of this study was to determine whether EMT directly led to the acquisition of tumour-initiating capacity in breast cancer cell lines. METHODS: Epithelial-mesenchymal transition was induced in five breast cancer cell lines and one normal breast cell line by EMT-related cytokine stimulation. Mesenchymal-epithelial transition (MET) was induced by stably overexpressing miR-200c in three mesenchymal-like breast cancer cell lines. Molecular expression and cell function analysis were performed to evaluate the effect of EMT or MET on tumour-initiating capacity and other biological characteristics. RESULTS: The induction of EMT did not enhance tumour initiating capacity but, instead, conferred a CD44(+)/CD24(-/low) phenotype as well as cell proliferation, migration, and resistance to doxorubicin and radiation on breast cancer cell lines. Furthermore, MET did not lead to inhibition or loss of the tumour-initiating capacity in mesenchymal-like breast cancer cell lines, but it markedly attenuated other malignant properties, including proliferation, invasion, and resistance to therapy. CONCLUSIONS: Epithelial-mesenchymal transition does not alter tumour-initiating capacity of breast cancer cells but some other biological characteristics. Therefore, EMT and tumour-initiating capacity may not be directly linked in breast cancer cell lines. PMID- 24755888 TI - A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer. AB - Current pemetrexed/platinum chemotherapy does not produce a satisfactory therapeutic response in advanced lung cancer patients. The aim of this study was to determine whether the administration of gefitinib, a tyrosine kinase inhibitor (TKI), intercalated with pemetrexed/platinum could improve the efficacy in chemotherapy-naive patients with advanced non-squamous NSCLC without subsequent gefitinib maintenance therapy. Treatment-naive patients with stage IIIB or IV NSCLC were randomly assigned to receive pemetrexed (500 mg/m (2) d1) and either cisplatin (75 mg/m (2) d1) or carboplatin (AUC = 5 d1) plus gefitinib (250 mg/d on days 3 to 16 of a 3-week cycle) (PC-G) or pemetrexed-platinum (PC) alone. Randomization was stratified according to the tobacco smoking status and EGFR mutational status of the patients. The primary endpoint was the non-progression rate (NPR) at 12 weeks. Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and biosafety. The NPR at 12 weeks was 84.5% for the PC-G treatment arm and 83.1% for the PC treatment arm (P = 0.87). Median PFS was 7.9 months for the PC-G arm and 7.0 months for the PC arm (P = 0.57). The ORR was 50.0% for the PC-G arm and 47.4% for the PC arm (P = 0.78). Median survival was 25.4 mo for the PC-G arm and 20.8 mo for the PC arm (P = 0.54). The incidence of adverse events was similar between the two treatment arms, except for a higher incidence of skin rash with PC-G. Predefined subgroup analyses demonstrated that PC-G significantly increased the PFS compared with the PC regimen in patients with EGFR mutations (P = 0.017). Although gefitinib intercalated with pemetrexed/platinum chemotherapy did not improve the NPR at 12 weeks compared with chemotherapy, an improvement in the PFS for the intercalated treatment arm was seen in the subgroup of patients with EGFR mutations. PMID- 24755889 TI - Adenosinergic regulation of striatal clock gene expression and ethanol intake during constant light. AB - Circadian rhythm and sleep disruptions occur frequently in individuals with alcohol use disorders (AUD) and present significant barriers to treatment. Recently, a variant of adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), was associated with the co-occurrence of sleep problems and AUD. We have previously shown that mice lacking ENT1 (ENT1 KO) have reduced adenosine levels in the striatum and drink more alcohol compared with wild types (WT). However, it is unknown whether ENT1 deletion disrupts circadian rhythms, which may contribute to alcohol preference in ENT1 KO mice. Here we used these mice to determine whether endogenous adenosine regulates circadian genetic and behavioral rhythms and influences alcohol intake during chronodisruption. We examined circadian locomotor activity in ENT1 KO vs WT littermates and found that ENT1 KO mice were both active earlier and hyperactive compared with WT mice at night. We used real-time PCR and immunohistochemistry to estimate striatal clock gene levels and found that PER2 expression in the striatum was blunted by ENT1 deletion or A2A receptor (A2AR) antagonism. Next, we exposed ENT1 KO and WT mice to constant light (LL) and found further elevation in ethanol intake in ENT1 KO, but not in WT mice, supporting the notion that circadian dysfunction may contribute to increased alcohol intake in ENT1 KO mice. Finally, we showed that A2AR agonist administration normalized PER1 and PER2 expression and circadian locomotor activity in ENT1 KO mice. Together, our results demonstrate that adenosine signaling regulates cellular and behavioral circadian timing and influences alcohol intake during chronodisruption. PMID- 24755891 TI - Inhibition of apomorphine-induced behavioral sensitization in rats pretreated with fluoxetine. AB - Despite a number of clinically useful effects, there is growing evidence that psychosis and impulse control disorders develop in patients on apomorphine therapy. Evidence suggests a critical role of serotonin-1A receptors in psychosis, drug abuse, and in the mechanism of action of the prototypical selective serotonin reuptake inhibitor fluoxetine. We investigated whether fluoxetine can prevent apomorphine-induced behavioral sensitization in a rat model of psychosis. Animals treated with fluoxetine (5 and 10 mg/kg) for 2 weeks were subsequently cotreated with apomorphine (1.0 mg/kg) for 7 days. A single injection of apomorphine increased motor activity, whereas repeated daily injections produced a progressive sensitization of motor behavior. The sensitization effects of apomorphine did not occur in fluoxetine-pretreated and subsequently cotreated animals. To further elucidate the mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-treated animals, we found that apomorphine-induced motor behavior was much greater in repeated apomorphine-treated than repeated saline-treated animals. It was also greater in apomorphine and fluoxetine-cotreated animals, but not in animals pretreated and cotreated with fluoxetine. The mechanism involved in the inhibition of apomorphine sensitization in fluoxetine-pretreated animals is discussed. The findings introduce an innovative approach for extending the therapeutic use of apomorphine and classical psychostimulant drugs. PMID- 24755890 TI - Evidence for linkage and association of GABRB3 and GABRA5 to panic disorder. AB - Panic disorder (PD) is a debilitating anxiety disorder characterized by episodes of intense fear with autonomic and psychological symptoms that lead to behavioral impairment. A convergence of genetic and biological evidence implicates gamma aminobutyric acid type A receptor subunits on chromosome 15q12 as candidate genes for PD. This study investigated 120 Caucasian, multiplex PD pedigrees using regional microsatellites (chr15q11-13) and found support for linkage (logarithm of odds (LOD) ?2), with a prominent parent-of-origin effect. Genotyping with 10 single-nucleotide polymorphisms (SNPs) showed linkage to GABRB3 (rs11631421, LOD=4.6) and GABRA5 (rs2075716, LOD=2.2), and allelic association to GABRB3 (rs8024564, p=0.005; rs8025575, p=0.02) and GABRA5 (rs35399885, p=0.05). Genotyping of an independent Sardinian PD trio sample also supported association in the region, again with a parent-of-origin effect. These findings provide genetic evidence for the involvement of the genes GABRB3 and GABRA5 in the susceptibility to PD. PMID- 24755892 TI - Human collective intelligence under dual exploration-exploitation dilemmas. AB - The exploration-exploitation dilemma is a recurrent adaptive problem for humans as well as non-human animals. Given a fixed time/energy budget, every individual faces a fundamental trade-off between exploring for better resources and exploiting known resources to optimize overall performance under uncertainty. Colonies of eusocial insects are known to solve this dilemma successfully via evolved coordination mechanisms that function at the collective level. For humans and other non-eusocial species, however, this dilemma operates within individuals as well as between individuals, because group members may be motivated to take excessive advantage of others' exploratory findings through social learning. Thus, even though social learning can reduce collective exploration costs, the emergence of disproportionate "information scroungers" may severely undermine its potential benefits. We investigated experimentally whether social learning opportunities might improve the performance of human participants working on a "multi-armed bandit" problem in groups, where they could learn about each other's past choice behaviors. Results showed that, even though information scroungers emerged frequently in groups, social learning opportunities reduced total group exploration time while increasing harvesting from better options, and consequentially improved collective performance. Surprisingly, enriching social information by allowing participants to observe others' evaluations of chosen options (e.g., Amazon's 5-star rating system) in addition to choice-frequency information had a detrimental impact on performance compared to the simpler situation with only the choice-frequency information. These results indicate that humans groups can handle the fundamental "dual exploration-exploitation dilemmas" successfully, and that social learning about simple choice-frequencies can help produce collective intelligence. PMID- 24755896 TI - What midlife women should know about menopause and sleep. PMID- 24755895 TI - Menopause and sleep. AB - CLINICAL SCENARIO: An obese, 50-year-old woman complains of hot flashes, poor sleep, snoring, and daytime sleepiness. She states that these problems have bothered her for about 4 years. Her partner recently complained about her snoring and restlessness, prompting this visit. She has become hypertensive. What should she do? PMID- 24755897 TI - What does it really mean? PMID- 24755893 TI - A three dimensional study of upper airway in adult skeletal Class II patients with different vertical growth patterns. AB - OBJECTIVE: The study was performed to compare the 3D pharyngeal airway dimensions in adult skeletal Class II patients with different vertical growth patterns (low, normal, and high angle) and to investigate whether the upper airway dimensions of untreated skeletal Class II adults were affected by vertical skeletal variables. METHODS: Cone-beam computed tomography (CBCT) records of 64 untreated adult skeletal Class II patients (34 male and 30 female) were collected to evaluate the pharyngeal airway dimensions. Subjects were divided into three subgroups according to the GoGn-SN angle (low angle, normal angle or high angle). All subgroups were matched for sex. ANOVA and SNK-q tests were used to identify differences within and among groups (p<0.05). Coefficient of product-moment correlation (Pearson correlation coefficient) was used to analyze the association between pharyngeal airway dimensions and vertical growth patterns. RESULTS: The results showed that pharyngeal airway measurements were statistically significantly less (p<0.05) in high angle group as compared to normal angle or low angle group. CONCLUSIONS: Adult skeletal Class II subjects with vertical growth patterns have significantly narrower pharyngeal airways than those with normal or horizontal growth patterns, confirming an association between pharyngeal airway measurements and a vertical skeletal pattern. PMID- 24755898 TI - Is early menopause a risk factor for heart failure? PMID- 24755899 TI - Save the ovaries in reproductive years... and maybe the uterus, too? PMID- 24755900 TI - Sleep in midlife women: effects of menopause, vasomotor symptoms, and depressive symptoms. AB - OBJECTIVE: This study aims to evaluate subjective sleep quality in premenopausal and postmenopausal women and to study its association with night sweats, hot flashes, and depressive symptoms. METHODS: A total of 158 healthy women were recruited; 107 were premenopausal (44-48 y) and 51 were postmenopausal (53-58 y). Sleep quality was evaluated with the Basic Nordic Sleep Questionnaire, night sweats and hot flashes were evaluated with a specific symptom questionnaire, and depressive symptoms were evaluated with the Beck Depression Inventory. RESULTS: Postmenopausal women had poorer general sleep quality (P < 0.001), slept more restlessly (P = 0.020), and had more nocturnal awakenings (P = 0.015). However, the frequency of difficulty falling asleep, snoring, witnessed apnea, or use of sleep medication was similar between the groups. Furthermore, sleep latency, morning tiredness, or daytime tiredness did not differ between the groups. Postmenopausal women did not report more unintentional falling asleep at work or during leisure time; however, when not active, they dozed off more easily than premenopausal women (P < 0.001). Postmenopausal women had more night sweats (P < 0.001), hot flashes (P < 0.001), and depressive symptoms (P < 0.001). Even a low frequency of night sweats disturbed sleep in postmenopausal women, whereas only frequent night sweats were disturbing in premenopausal women. Depressive symptoms disturbed sleep regardless of menopause status. CONCLUSIONS: Maintenance insomnia, most evidently because of night sweats and hot flashes, seems to be the major type of insomnia in postmenopausal women and has to be considered when choosing insomnia treatment for this group. Initiation of sleep and daytime vitality are not, in general, affected by menopause. PMID- 24755902 TI - Amorphous effect on the advancing of wide-range absorption and structural-phase transition in gamma-In2Se3 polycrystalline layers. AB - The exploitation of potential functions in material is crucial in materials research. In this study, we demonstrate a III-VI chalcogenide, polycrystalline gamma-In2Se3, which simultaneously possesses the capabilities of thickness dependent optical gaps and wide-energy-range absorption existed in the polycrystalline layers of gamma-In2Se3. Transmission electron microscopy and Raman measurement show a lot of gamma-phase nanocrystals contained in the disordered and polycrystalline state of the chalcogenide with medium-range order (MRO). The MRO effects on the gamma-In2Se3 layers show thickness-dependent absorption-edge shift and thickness-dependent resistivities. The amorphous effect of MRO also renders a structural-phase transition of gamma -> alpha occurred inside the gamma-In2Se3 layer with a heat treatment of about 700 degrees C. Photo-voltage-current (Photo V-I) measurements of different-thickness gamma In2Se3 layers propose a wide-energy-range photoelectric conversion unit ranging from visible to ultraviolet (UV) may be achieved by stacking gamma-In2Se3 layers in a staircase form containing dissimilar optical gaps. PMID- 24755901 TI - Efficient de novo assembly of highly heterozygous genomes from whole-genome shotgun short reads. AB - Although many de novo genome assembly projects have recently been conducted using high-throughput sequencers, assembling highly heterozygous diploid genomes is a substantial challenge due to the increased complexity of the de Bruijn graph structure predominantly used. To address the increasing demand for sequencing of nonmodel and/or wild-type samples, in most cases inbred lines or fosmid-based hierarchical sequencing methods are used to overcome such problems. However, these methods are costly and time consuming, forfeiting the advantages of massive parallel sequencing. Here, we describe a novel de novo assembler, Platanus, that can effectively manage high-throughput data from heterozygous samples. Platanus assembles DNA fragments (reads) into contigs by constructing de Bruijn graphs with automatically optimized k-mer sizes followed by the scaffolding of contigs based on paired-end information. The complicated graph structures that result from the heterozygosity are simplified during not only the contig assembly step but also the scaffolding step. We evaluated the assembly results on eukaryotic samples with various levels of heterozygosity. Compared with other assemblers, Platanus yields assembly results that have a larger scaffold NG50 length without any accompanying loss of accuracy in both simulated and real data. In addition, Platanus recorded the largest scaffold NG50 values for two of the three low heterozygosity species used in the de novo assembly contest, Assemblathon 2. Platanus therefore provides a novel and efficient approach for the assembly of gigabase-sized highly heterozygous genomes and is an attractive alternative to the existing assemblers designed for genomes of lower heterozygosity. PMID- 24755903 TI - Are we changing our inclusion criteria for the minimally invasive videoassisted thyroidectomy? AB - AIM: The first cases treated with Minimally Invasive videoassisted thyroidectomy (MIVAT) were characterized by inclusion and exclusion criteria that are changing with the experience. MATERIALS AND METHODS: We have analyzed the patients treated from july 2005 to december 2010 with MIVAT All these cases were treated in accord with Miccoli's technique with a minicervicotomy of 1.5-2 cm above the sternal notch. We have divided the cases on the surgical period highlighting changing in the inclusion criteria and the adverse events (0-211 cases; 212-300 cases). All the cases treated were followed up at days 7 (ambulatory visit) and days 30-12 months (ambulatory visit or telephone contatct). The patients classified in the II degrees period were chracterized by the exclusion of the clinical thyroiditis. We have related these cases with the cases treated with conventional thyroidectomy(CT). RESULTS: No differences in postoperative pain,nerve palsy and hypocalcemia in MIVAT group and CT group. We have registered a postoperative pain at 24 hours lower in MIVAT group. The percentage of transitory nerve palsy in the MIVAT group in the first period was 2,84 % versus 1,12 % in the second period. CONCLUSION: MIVAT technique is safe and reproducible, with an excellent cosmetic results. In our experience MIVAT remains the better surgical options for the patients that meet the inclusion criteria.These cases are 15% of patients treated with thyroidectomy in our Endocrine surgery Unit. PMID- 24755904 TI - Synthesis of NASICON-type structured NaTi2(PO4)3-graphene nanocomposite as an anode for aqueous rechargeable Na-ion batteries. AB - A new solvothermal strategy combined with calcination has been developed to synthesize NaTi2(PO4)3-graphene nanocomposites. X-ray diffraction, thermogravimetric analysis, field-emission scanning electron microscopy and transmission electron microscopy were performed to characterize their microstructures and morphologies. It was found that NASICON-type structured NaTi2(PO4)3 nanoparticles with highly crystallinity were homogeneously anchored on the surface of conducting graphene nanosheets, forming a two-dimensional hybrid nanoarchitecture. A possible growth mechanism was also discussed based on time-dependent experiments. When used as anode materials for Na-ion batteries, the nanocomposites exhibited excellent electrochemical performance with high-rate capability and excellent cycling stability in 1 M Na2SO4 aqueous electrolyte. The electrode delivered high specific capacities of 110, 85, 65, 40 mA h g(-1) at 2, 5, 10 and 20 C, respectively, and still retained 90% of the initial capacity after 100 cycles at 2 C. PMID- 24755905 TI - Comparison of five major trichome regulatory genes in Brassica villosa with orthologues within the Brassicaceae. AB - Coding sequences for major trichome regulatory genes, including the positive regulators GLABRA 1(GL1), GLABRA 2 (GL2), ENHANCER OF GLABRA 3 (EGL3), and TRANSPARENT TESTA GLABRA 1 (TTG1) and the negative regulator TRIPTYCHON (TRY), were cloned from wild Brassica villosa, which is characterized by dense trichome coverage over most of the plant. Transcript (FPKM) levels from RNA sequencing indicated much higher expression of the GL2 and TTG1 regulatory genes in B. villosa leaves compared with expression levels of GL1 and EGL3 genes in either B. villosa or the reference genome species, glabrous B. oleracea; however, cotyledon TTG1 expression was high in both species. RNA sequencing and Q-PCR also revealed an unusual expression pattern for the negative regulators TRY and CPC, which were much more highly expressed in trichome-rich B. villosa leaves than in glabrous B. oleracea leaves and in glabrous cotyledons from both species. The B. villosa TRY expression pattern also contrasted with TRY expression patterns in two diploid Brassica species, and with the Arabidopsis model for expression of negative regulators of trichome development. Further unique sequence polymorphisms, protein characteristics, and gene evolution studies highlighted specific amino acids in GL1 and GL2 coding sequences that distinguished glabrous species from hairy species and several variants that were specific for each B. villosa gene. Positive selection was observed for GL1 between hairy and non-hairy plants, and as expected the origin of the four expressed positive trichome regulatory genes in B. villosa was predicted to be from B. oleracea. In particular the unpredicted expression patterns for TRY and CPC in B. villosa suggest additional characterization is needed to determine the function of the expanded families of trichome regulatory genes in more complex polyploid species within the Brassicaceae. PMID- 24755908 TI - Association between Down syndrome and in-hospital death among children undergoing surgery for congenital heart disease: a US population-based study. AB - BACKGROUND: The prevalence of Down syndrome (DS)-affected births has increased during the past 30 years; moreover, children with DS have a higher incidence of congenital heart disease compared with their peers. Whether children with DS have better or worse outcomes after repair of congenital heart disease is unclear. We sought to identify differences in in-hospital mortality after cardiac surgery in pediatric patients with and without DS using a large national database. METHODS AND RESULTS: Children aged <18 years who underwent surgical intervention for congenital heart disease were identified using the Kids' Inpatient Database (2000, 2003, 2006, and 2009). Patients were stratified using the Risk Adjustment for Congenital Heart Surgery algorithm. A total of 4231 (8.2%) of the 51 309 patients studied had a diagnosis of DS. In-hospital death for patients with DS was significantly lower than that for patients without DS overall (1.9% versus 4.3%; P<0.05) as well as within risk categories 2 (1.0% versus 1.8%; P<0.05) and 3 (2.3% versus 5.1%; P<0.05). Multivariable logistic regression showed a lower odds of death among children with DS (odds ratio=0.60; 95% confidence interval, 0.47-0.76; P<0.05) after adjusting for Risk Adjustment for Congenital Heart Surgery risk category, premature birth, major noncardiac structural anomaly, and age. CONCLUSIONS: In this large national study, children with DS who underwent repair of congenital heart disease were more likely to survive to discharge than children without DS. Future work is needed to better understand the factors underlying these differences. PMID- 24755906 TI - Impact of metformin on endothelial ischemia-reperfusion injury in humans in vivo: a prospective randomized open, blinded-endpoint study. AB - INTRODUCTION: Large prospective studies in patients with type 2 diabetes mellitus have demonstrated that metformin treatment improves cardiovascular prognosis, independent of glycemic control. Administration of metformin potently limits infarct size in murine models of myocardial infarction. This study examined, for the first time in humans, whether metformin limits ischemia-reperfusion (IR) injury in vivo using a well-validated forearm model of endothelial IR-injury. METHODS: Twenty-eight healthy volunteers (age 41+/-6 years, 10 male/16 female) were randomized between pretreatment with metformin (500 mg three times a day for 3 days) or no treatment in a Prospective Randomized Open Blinded Endpoint study. Brachial artery flow mediated dilation (FMD) was measured before and after 20 minutes of forearm ischemia and 20 minutes of reperfusion. FMD analysis was performed offline by investigators blinded for the treatment arm. RESULTS: Baseline FMD did not differ between metformin pretreatment and no pretreatment (6.9+/-3.6% and 6.1+/-3.5%, respectively, p = 0.27, n = 26). FMD was significantly lower after forearm IR in both treatment arms (4.4+/-3.3% and 4.3+/ 2.8%, respectively, P<0.001 in both conditions). A linear mixed model analysis revealed that metformin treatment did not prevent the decrease in FMD by IR. CONCLUSION: A 3 day treatment with metformin in healthy, middle-aged subjects does not protect against endothelial IR-injury, measured with brachial artery FMD after forearm ischemia. Further studies are needed to clarify what mechanism underlies the cardiovascular benefit of metformin treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01610401. PMID- 24755909 TI - Validity of deterministic record linkage using multiple indirect personal identifiers: linking a large registry to claims data. AB - BACKGROUND: Linking patient registries with administrative databases can enhance the utility of the databases for epidemiological and comparative effectiveness research. However, registries often lack direct personal identifiers, and the validity of record linkage using multiple indirect personal identifiers is not well understood. METHODS AND RESULTS: Using a large contemporary national cardiovascular device registry and 100% Medicare inpatient data, we linked hospitalization-level records. The main outcomes were the validity measures of several deterministic linkage rules using multiple indirect personal identifiers compared with rules using both direct and indirect personal identifiers. Linkage rules using 2 or 3 indirect, patient-level identifiers (ie, date of birth, sex, admission date) and hospital ID produced linkages with sensitivity of 95% and specificity of 98% compared with a gold standard linkage rule using a combination of both direct and indirect identifiers. CONCLUSIONS: Ours is the first large scale study to validate the performance of deterministic linkage rules without direct personal identifiers. When linking hospitalization-level records in the absence of direct personal identifiers, provider information is necessary for successful linkage. PMID- 24755907 TI - Transcriptomic and functional analysis of NaCl-induced stress in Enterococcus faecalis. AB - The robust physiology of Enterococcus faecalis facilitates tolerance to various stresses. We here report the transcriptional response of E. faecalis V583 to growth in the presence of 6.5% NaCl. Among the early responses observed was an immediate down-regulation of mscL, accompanied by an up-regulation of genes predicted to be involved in uptake of extracellular potassium and glycine betaine. The high NaCl concentration also induced expression of chaperons and cell envelope related traits, such as the enterococcal polysaccharide antigen (epa) locus. Functional genetic analysis revealed reduced salt stress resistance in both epaB and epaE mutants. The reduced salt resistance phenotype associated with the epaB mutant was restored by complementation, hence demonstrating a role of Epa in the physiological robustness of E. faecalis. Furthermore, we demonstrate that Epa confers increased resistance towards multiple cell envelope stress-inducing factors. Accordingly, these findings delineate a potential link between the robust nature of E. faecalis and its ability to perform as a human pathogen, and provide a new perspective on the mechanisms by which Epa contributes to virulence. Notably, the high NaCl concentration also resulted in strict repression of the gelE-sprE operon and impaired gelatinase activity. We demonstrate that NaCl antagonize the GBAP-pheromone dependent induction in a concentration dependent manner. PMID- 24755910 TI - Islet1 and its co-factor Ldb1 are expressed in quiescent cells of mouse intestinal epithelium. AB - Islet1 belongs to Lim homeobox (Lhx) gene family which encodes transcription factors that have been conserved in evolution. They form complexes with other transcriptional regulators, among them obligatory co-factors encoded by Ldb genes. Isl1 (Islet1), Lhx and Ldb1 genes play a crucial role in organ patterning, cell fate determination and cell differentiation in both embryonic and adult tissues. In this study we analyzed expression pattern of Isl1 and its co-factor Ldb1 in small intestine. We also studied the biological role of Ldb1 in gut endoderm. Quantitative PCR analysis revealed a relatively high level of expression of Lhx1, Isl1, Isl2, Lmx1a, Ldb1 and Ldb2 mRNAs in the gut tissue as compared to the level of less abundant detectable Lmx1b mRNA. Immunohistochemical studies demonstrated a unique pattern of Ldb1 and Islet1 proteins in the crypt compartment. Ldb1 is produced at a low level in majority of crypt cells; but, its abundant expression was demonstrated for some single cells. Islet1 is also expressed in single cells of the crypt. Double staining experiments with Ldb1 and Isl1 antibodies showed that both genes are co-expressed in certain cells of the crypt. Further analysis revealed the Ldb1-expressing cells in the gut are both of endodermal and mesodermal origin. Proliferation studies using antibodies to phospho-histone H3 and Ki-67 antigens, as well as long-term BrdU labeling, showed that cells prominently expressing Ldb1/Islet1 are quiescent but do not belong to any known terminally differentiated cell lineages. They may represent a group of stem-like cells in the crypt. Further experiments by cell lineage tracing should be performed to better characterize this cell population. Functional studies of mice with Ldb1 gene ablated in gut endoderm revealed no specific role of Ldb1 in that tissue. PMID- 24755911 TI - Investigation of avian influenza infections in wild birds, poultry and humans in Eastern Dongting Lake, China. AB - We investigated avian influenza infections in wild birds, poultry, and humans at Eastern Dongting Lake, China. We analyzed 6,621 environmental samples, including fresh fecal and water samples, from wild birds and domestic ducks that were collected from the Eastern Dongting Lake area from November 2011 to April 2012. We also conducted two cross-sectional serological studies in November 2011 and April 2012, with 1,050 serum samples collected from people exposed to wild birds and/or domestic ducks. Environmental samples were tested for the presence of avian influenza virus (AIV) using quantitative PCR assays and virus isolation techniques. Hemagglutination inhibition assays were used to detect antibodies against AIV H5N1, and microneutralization assays were used to confirm these results. Among the environmental samples from wild birds and domestic ducks, AIV prevalence was 5.19 and 5.32%, respectively. We isolated 39 and 5 AIVs from the fecal samples of wild birds and domestic ducks, respectively. Our analysis indicated 12 subtypes of AIV were present, suggesting that wild birds in the Eastern Dongting Lake area carried a diverse array of AIVs with low pathogenicity. We were unable to detect any antibodies against AIV H5N1 in humans, suggesting that human infection with H5N1 was rare in this region. PMID- 24755912 TI - Proton channel models filling the gap between experimental data and the structural rationale. AB - Voltage-gated proton channels are integral membrane proteins with the capacity to permeate elementary particles in a voltage- and pH-dependent manner. These proteins have been found in several species and are involved in various physiological processes. Although their primary topology is known, lack of details regarding their structures in the open conformation has limited analyses toward a deeper understanding of the molecular determinants of their function and regulation. Consequently, the function-structure relationships have been inferred based on homology models. In the present work, we review the existing proton channel models, their assumptions, predictions, and the experimental facts that support them. Modeling proton channels is not a trivial task due to the lack of a close homolog template. Hence, there are important differences between published models. This work attempts to critically review existing proton channel models toward the aim of contributing to a better understanding of the structural features of these proteins. PMID- 24755913 TI - Response to "evaluation of pharmacogenetic markers to predict the risk of Cisplatin-induced ototoxicity". PMID- 24755914 TI - Inflammation-related genetic variations and survival in patients with advanced non-small cell lung cancer receiving first-line chemotherapy. AB - Accurate prognostic prediction is challenging for patients with advanced-stage non-small cell lung cancer (NSCLC). We systematically investigated genetic variants within inflammation pathways as potential prognostic markers for advanced-stage NSCLC patients treated with first-line chemotherapy. A discovery phase in 502 patients and an internal validation phase in 335 patients were completed at the MD Anderson Cancer Center. External validation was performed in 371 patients at Harvard University. A missense single-nucleotide polymorphism (SNP) in the gene encoding the major histocompatibility complex class II, DO-beta chain (HLA-DOB:rs2071554), predicted to influence protein function, was significantly associated with poor survival in the discovery (hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02-2.09), internal validation (HR: 1.51; 95% CI: 1.02-2.25), and external validation (HR: 1.52; 95% CI: 1.01-2.29) populations. KLRK1:rs2900420 was associated with reduced risk in the discovery (HR: 0.76; 95% CI: 0.60-0.96), internal validation (HR: 0.77; 95% CI: 0.61-0.99), and external validation (HR: 0.80; 95% CI: 0.63-1.02) populations. A strong cumulative effect on overall survival was observed for these SNPs. Genetic variations in inflammation-related genes could have potential to complement prediction of prognosis. PMID- 24755915 TI - Coronary artery disease: Use of ACE inhibitors in stable CAD--what is the truth? PMID- 24755917 TI - Coronary artery disease: Similar 5-year outcomes with CABG surgery or PCI for left main disease. PMID- 24755916 TI - Comprehensive plaque assessment by coronary CT angiography. AB - Most acute coronary syndromes are caused by sudden luminal thrombosis due to atherosclerotic plaque rupture or erosion. Preventing such an event seems to be the only effective strategy to reduce mortality and morbidity of coronary heart disease. Coronary lesions prone to rupture have a distinct morphology compared with stable plaques, and provide a unique opportunity for noninvasive imaging to identify vulnerable plaques before they lead to clinical events. The submillimeter spatial resolution and excellent image quality of modern computed tomography (CT) scanners allow coronary atherosclerotic lesions to be detected, characterized, and quantified. Large plaque volume, low CT attenuation, napkin ring sign, positive remodelling, and spotty calcification are all associated with a high risk of acute cardiovascular events in patients. Computation fluid dynamics allow the calculation of lesion-specific endothelial shear stress and fractional flow reserve, which add functional information to plaque assessment using CT. The combination of morphologic and functional characteristics of coronary plaques might enable noninvasive detection of vulnerable plaques in the future. PMID- 24755918 TI - Systematic design of 18S rRNA gene primers for determining eukaryotic diversity in microbial consortia. AB - High-throughput sequencing of ribosomal RNA gene (rDNA) amplicons has opened up the door to large-scale comparative studies of microbial community structures. The short reads currently produced by massively parallel sequencing technologies make the choice of sequencing region crucial for accurate phylogenetic assignments. While for 16S rDNA, relevant regions have been well described, no truly systematic design of 18S rDNA primers aimed at resolving eukaryotic diversity has yet been reported. Here we used 31,862 18S rDNA sequences to design a set of broad-taxonomic range degenerate PCR primers. We simulated the phylogenetic information that each candidate primer pair would retrieve using paired- or single-end reads of various lengths, representing different sequencing technologies. Primer pairs targeting the V4 region performed best, allowing discrimination with paired-end reads as short as 150 bp (with 75% accuracy at genus level). The conditions for PCR amplification were optimised for one of these primer pairs and this was used to amplify 18S rDNA sequences from isolates as well as from a range of environmental samples which were then Illumina sequenced and analysed, revealing good concordance between expected and observed results. In summary, the reported primer sets will allow minimally biased assessment of eukaryotic diversity in different microbial ecosystems. PMID- 24755920 TI - Unmet needs in food protein-induced enterocolitis syndrome. PMID- 24755919 TI - Etoposide-loaded immunoliposomes as active targeting agents for GD2-positive malignancies. AB - Systemic chemotherapeutics remain the standard of care for most malignancies even though they frequently suffer from narrow therapeutic index, poor serum solubility, and off-target effects. In this study, we have encapsulated etoposide, a topoisomerase inhibitor effective against a wide range of cancers, in surface-modified liposomes decorated with anti-GD2 antibodies. We characterized the properties of the liposomes using a variety of methods including dynamic light scattering, electron microscopy, and Fourier transformed infrared spectroscopy. We examined whether these immunoliposomes were able to target cell lines expressing varying levels of surface GD2 and affect cellular proliferation. Anti-GD2 liposomes were generally targeted in a manner that correlated with GD2 expression and inhibited proliferation in cell lines to which they were efficiently targeted. The mechanism by which the immunoliposomes entered targeted cells appeared to be via clathrin-dependent uptake as demonstrated using flow cytometry and confocal microscopy. These studies suggest that anti-GD2-targeted, etoposide-loaded liposomes represent a potential strategy for more effective delivery of anti-cancer drugs that could be used for GD2 positive tumors. PMID- 24755921 TI - Seeking data and the implicit order that grounds a chaotic world. PMID- 24755923 TI - Haemorrhoids are associated with internal iliac vein reflux in up to one-third of women presenting with varicose veins associated with pelvic vein reflux. AB - OBJECTIVES: To determine the prevalence of haemorrhoids in women with pelvic vein reflux, identify which pelvic veins are associated with haemorrhoids and assess if extent of pelvic vein reflux influences the prevalence of haemorrhoids. METHODS: Females presenting with leg varicose veins undergo duplex ultrasonography to assess all sources of venous reflux. Those with significant reflux arising from the pelvis are offered transvaginal duplex ultrasound (TVS) to evaluate reflux in the ovarian veins and internal Iliac veins and associated pelvic varices in the adnexa, vulvar/labial veins and haemorrhoids. Patterns and severity of reflux were evaluated. RESULTS: Between January 2010 and December 2012, 419 female patients with leg or vulvar varicose vein patterns arising from the pelvis underwent TVS. Haemorrhoids were identified on TVS via direct tributaries from the internal Iliac veins in 152/419 patients (36.3%) and absent in 267/419 (63.7%). The prevalence of the condition increased with the number of pelvic trunks involved. CONCLUSION: There is a strong association between haemorrhoids and internal Iliac vein reflux. Untreated reflux may be a cause of subsequent symptomatic haemorrhoids. Treatment with methods proven to work in conditions caused by pelvic vein incompetence, such as pelvic vein embolisation and foam sclerotherapy, could be considered. PMID- 24755924 TI - CHIVA strategy in chronic venous disease treatment: instructions for users. AB - Along the years, scientific clinical data have been collected concerning the possible saphenous flow restoration without any ablation and according with the CHIVA strategy. Moreover, in 2013 a Cochrane review highlighted the smaller recurrence risk following a CHIVA strategy rather than a saphenous stripping. Nevertheless, the saphenous sparing strategy surely remains a not-so-worldwide spread and accepted therapeutic option, also because considered not so immediate and easy to perform. Aim of this paper is to provide an easily accessible guide to an everyday use of a saphenous sparing strategy for chronic venous disease, highlighting how even apparently too complicated reflux patterns classifications can be fastly and successfully managed and exploited for a hemodynamic correction. PMID- 24755922 TI - Activation of silenced cytokine gene promoters by the synergistic effect of TBP TALE and VP64-TALE activators. AB - Recent work has shown that the combinatorial use of multiple TALE activators can selectively activate certain cellular genes in inaccessible chromatin regions. In this study, we aimed to interrogate the activation potential of TALEs upon transcriptionally silenced immune genes in the context of non-immune cells. We designed a unique strategy, in which a single TALE fused to the TATA-box binding protein (TBP-TALE) is coupled with multiple VP64-TALE activators. We found that our strategy is significantly more potent than multiple TALE activators alone in activating expression of IL-2 and GM-CSF in diverse cell origins in which both genes are otherwise completely silenced. Chromatin analysis revealed that the gene activation was due in part to displacement of a distinctly positioned nucleosome. These studies provide a novel epigenetic mechanism for artificial gene induction and have important implications for targeted cancer immunotherapy, DNA vaccine development, as well as rational design of TALE activators. PMID- 24755925 TI - Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA. AB - Hepatitis C virus (HCV) infection affects more than 170 million people. The high genetic variability of HCV and the rapid development of drug-resistant strains are driving the urgent search for new direct-acting antiviral agents. A new class of agents has recently been developed that are believed to target the HCV protein NS5A although precisely where they interact and how they affect function is unknown. Here we describe an in vitro assay based on microscale thermophoresis and demonstrate that two clinically relevant inhibitors bind tightly to NS5A domain 1 and inhibit RNA binding. Conversely, RNA binding inhibits compound binding. The compounds bind more weakly to known resistance mutants L31V and Y93H. The compounds do not affect NS5A dimerisation. We propose that current NS5A inhibitors act by favouring a dimeric structure of NS5A that does not bind RNA. PMID- 24755926 TI - The dark truth about vitamin D licensing: food or drug? PMID- 24755927 TI - The effects of Ramadan fasting on endothelial function in patients with cardiovascular diseases. AB - BACKGROUND/OBJECTIVES: Endothelial dysfunction, which can be manifested by loss of nitric oxide bioavailability, is an increasingly recognized cause of cardiovascular diseases. Previous studies showed that diets affect endothelial function and modify cardiovascular risks. This study aimed to assess the effects of Ramadan fasting, as a diet intervention, on endothelial function. SUBJECTS/METHODS: The study population consisted of 21 male patients (mean age: 52+/-9 years) with cardiovascular risks (coronary artery disease, cerebrovascular or peripheral arterial diseases). The biochemical variables in serum of patients were measured 2 days before and after Ramadan fasting. The levels of asymmetric dimethylarginine (ADMA) and vascular endothelial growth factor (VEGF) were evaluated using the enzyme-linked immunosorbent assay. Nitric oxide (NO) and Malondialdehyde (MDA) levels were measured by the Griess and thiobarbituric acid reaction substances assay, respectively. RESULTS: NO levels in patients after Ramadan fasting were significantly higher compared with the baseline value (85.1+/-11.54 vs 75.8+/-10.7 MUmol/l) (P<0.05). Post-Ramadan levels of ADMA decreased significantly in comparison with pre-Ramadan levels (802.6+/-60.9 vs 837.6+/-51.0 nmol/l) (P<0.05). In addition, the levels of VEGF and MDA changed during Ramadan fasting, but these changes were not statistically significant (228.1+/-27.1 vs 222.7+/-22.9 pg/ml and 3.2+/-0.7 vs 3.6+/-1.1 MUmol/l, respectively). CONCLUSIONS: Ramadan fasting may have beneficial effects on endothelial function and can modulate cardiovascular risks. Further studies are needed to confirm the clinical significance of Ramadan fasting on cardiovascular health. PMID- 24755928 TI - Prevalence of neonatal hypothyroidism in Kangra Valley, Himachal Pradesh. AB - Iodine deficiency (ID) is an endemic health problem in Kangra District, Himachal Pradesh (HP). ID in pregnant mothers leads to neonatal hypothyroidism (NH), mental retardation, deaf mutism, squint, dwarfism, spastic dysplasia, neurological defects and congenital anomalies. NH can be assessed by estimating the thyroid stimulating hormone (TSH) in cord blood samples. The present study was conducted with an objective to assess the prevalence of NH in district Kangra, HP. In district Kangra, all the hospitals providing obstetric services were enlisted. Three hospitals conducting more than 100 deliveries per year were selected randomly. A total of 613 umbilical cord blood samples of neonates were collected on filter papers and analyzed for TSH. TSH was estimated by enzyme linked immunosorbent assay method. Neonates with TSH levels ?20 mIU/l were recalled for reassessment of TSH for confirmation of NH. Prevalence of NH was found to be 4.4%. This finding suggests the need for the implementation of a neonatal screening program for early detection of children with ID. PMID- 24755929 TI - Development of a single-frequency bioimpedance prediction equation for fat-free mass in an adult Indigenous Australian population. AB - BACKGROUND/OBJECTIVES: To describe the development of a single-frequency bioimpedance prediction equation for fat-free mass (FFM) suitable for adult Aboriginal and Torres Strait Islander peoples with and without diabetes or indicators of chronic kidney disease (CKD). SUBJECTS/METHODS: FFM was measured by whole-body dual-energy X-ray absorptiometry in 147 adult Indigenous Australians. Height, weight, body circumference and resistance were also measured. Adults with and without diabetes and indicators of CKD were examined. A random split sample with internal cross-validation approach was used to predict and subsequently validate FFM using resistance, height, weight, age and gender against measured FFM. RESULTS: Among 147 adults with a median body mass index of 31 kg/m(2), the final model of FFM was FFM (kg)=0.432 (height, cm(2)/resistance, ohm)-0.086 (age, years)+0.269 (weight, kg)-6.422 (if female)+16.429. Adjusted R(2) was 0.94 and the root mean square error was 3.33 kg. The concordance was high (rc=0.97) between measured and predicted FFM across a wide range of FFM (31-85 kg). CONCLUSIONS: In the context of the high burden of diabetes and CKD among adult Indigenous Australians, this new equation for FFM was both accurate and precise and based on easily acquired variables (height, weight, age, gender and resistance) among a heterogeneous adult cohort. PMID- 24755935 TI - Seasonal patterns of nitrogen and phosphorus limitation in four German lakes and the predictability of limitation status from ambient nutrient concentrations. AB - To identify the seasonal pattern of nitrogen (N) and phosphorus (P) limitation of phytoplankton in four different lakes, biweekly experiments were conducted from the end of March to September 2011. Lake water samples were enriched with N, P or both nutrients and incubated under two different light intensities. Chlorophyll a fluorescence (Chla) was measured and a model selection procedure was used to assign bioassay outcomes to different limitation categories. N and P were both limiting at some point. For the shallow lakes there was a trend from P limitation in spring to N or light limitation later in the year, while the deep lake remained predominantly P limited. To determine the ability of in-lake N:P ratios to predict the relative strength of N vs. P limitation, three separate regression models were fit with the log-transformed ratio of Chla of the P and N treatments (Response ratio = RR) as the response variable and those of ambient total phosphorus:total nitrogen (TN:TP), dissolved inorganic nitrogen:soluble reactive phosphorus (DIN:SRP), TN:SRP and DIN:TP mass ratios as predictors. All four N:P ratios had significant positive relationships with RR, such that high N:P ratios were associated with P limitation and low N:P ratios with N limitation. The TN:TP and DIN:TP ratios performed better than the DIN:SRP and TN:SRP in terms of misclassification rate and the DIN:TP ratio had the highest R2 value. Nitrogen limitation was predictable, frequent and persistent, suggesting that nitrogen reduction could play a role in water quality management. However, there is still uncertainty about the efficacy of N restriction to control populations of N2 fixing cyanobacteria. PMID- 24755933 TI - Plant and animal stem cells: similar yet different. AB - The astonishingly long lives of plants and their regeneration capacity depend on the activity of plant stem cells. As in animals, stem cells reside in stem cell niches, which produce signals that regulate the balance between self-renewal and the generation of daughter cells that differentiate into new tissues. Plant stem cell niches are located within the meristems, which are organized structures that are responsible for most post-embryonic development. The continuous organ production that is characteristic of plant growth requires a robust regulatory network to keep the balance between pluripotent stem cells and differentiating progeny. Components of this network have now been elucidated and provide a unique opportunity for comparing strategies that were developed in the animal and plant kingdoms, which underlie the logic of stem cell behaviour. PMID- 24755934 TI - What are memories made of? How Polycomb and Trithorax proteins mediate epigenetic memory. AB - In any biological system with memory, the state of the system depends on its history. Epigenetic memory maintains gene expression states through cell generations without a change in DNA sequence and in the absence of initiating signals. It is immensely powerful in biological systems - it adds long-term stability to gene expression states and increases the robustness of gene regulatory networks. The Polycomb group (PcG) and Trithorax group (TrxG) proteins can confer long-term, mitotically heritable memory by sustaining silent and active gene expression states, respectively. Several recent studies have advanced our understanding of the molecular mechanisms of this epigenetic memory during DNA replication and mitosis. PMID- 24755937 TI - Climate change and the distribution of neotropical red-bellied toads (Melanophryniscus, Anura, Amphibia): how to prioritize species and populations? AB - We used species distribution modeling to investigate the potential effects of climate change on 24 species of Neotropical anurans of the genus Melanophryniscus. These toads are small, have limited mobility, and a high percentage are endangered or present restricted geographical distributions. We looked at the changes in the size of suitable climatic regions and in the numbers of known occurrence sites within the distribution limits of all species. We used the MaxEnt algorithm to project current and future suitable climatic areas (a consensus of IPCC scenarios A2a and B2a for 2020 and 2080) for each species. 40% of the species may lose over 50% of their potential distribution area by 2080, whereas 28% of species may lose less than 10%. Four species had over 40% of the currently known occurrence sites outside the predicted 2080 areas. The effect of climate change (decrease in climatic suitable areas) did not differ according to the present distribution area, major habitat type or phylogenetic group of the studied species. We used the estimated decrease in specific suitable climatic range to set a conservation priority rank for Melanophryniscus species. Four species were set to high conservation priority: M. montevidensis, (100% of its original suitable range and all known occurrence points potentially lost by 2080), M. sp.2, M. cambaraensis, and M. tumifrons. Three species (M. spectabilis, M. stelzneri, and M. sp.3) were set between high to intermediate priority (more than 60% decrease in area predicted by 2080); nine species were ranked as intermediate priority, while eight species were ranked as low conservation priority. We suggest that monitoring and conservation actions should be focused primarily on those species and populations that are likely to lose the largest area of suitable climate and the largest number of known populations in the short term. PMID- 24755936 TI - Rapamycin and dietary restriction induce metabolically distinctive changes in mouse liver. AB - Dietary restriction (DR) is the gold standard intervention used to delay aging, and much recent research has focused on the identification of possible DR mimetics. Energy sensing pathways, including insulin/IGF1 signaling, sirtuins, and mammalian Target of Rapamycin (mTOR), have been proposed as pathways involved in the antiaging actions of DR, and compounds that affect these pathways have been suggested to act as DR mimetics, including metformin (insulin/IGF1 signaling), resveratrol (sirtuins), and rapamycin (mTOR). Rapamycin is a promising DR mimetic because it significantly increases both health span and life span in mice. Unfortunately, rapamycin also leads to some negative effects, foremost among which is the induction of insulin resistance, potentially limiting its translation into humans. To begin clarifying the mechanism(s) involved in insulin resistance induced by rapamycin, we compared several aspects of liver metabolism in mice treated with DR or rapamycin for 6 months. Our data suggest that although both DR and rapamycin inhibit lipogenesis, activate lipolysis, and increased serum levels of nonesterified fatty acids, only DR further activates beta-oxidation of the fatty acids leading to the production of ketone bodies. PMID- 24755938 TI - Aortic unfolding determined using non-contrast cardiac computed tomography: correlations with age and coronary artery calcium score. AB - OBJECTIVE: Aortic unfolding occurs with aging and reflects proximal aortic dilation, aortic arch widening, and decreased curvature. This study 1) evaluated the relationship between aortic unfolding measured using non-contrast cardiac gated computed tomography (CT) and age, 2) assessed factors influencing aortic unfolding, and 3) determined the association of this measurement with coronary artery calcium (CAC) score. METHODS: We reviewed the charts of 219 subjects (142 men, 77 women; mean age 54.2+/-9.3 years) who underwent coronary artery calcium scanning during routine health screening from December 2010 to May 2011. Multivariate regression analysis according to cardiovascular risk factors was performed. We also analyzed the relationship between aortic unfolding measurements and CAC score using stepwise multiple linear regression. RESULTS: Mean aortic unfolding was 103.7+/-13.9 mm (men, 106.5+/-13.5 mm; women, 98.4+/ 12.9 mm). Age, body surface area, and hypertension were exclusively associated with aortic unfolding. The association between aortic unfolding and CAC score was significant after adjustment for age and gender (beta = 1.89, p = 0.017) and for Framingham risk score (beta = 2.83, p<0.001). CONCLUSIONS: Aortic unfolding defined by measuring aortic width was a reproducible and practical method with non-contrast cardiac CT and associated with age, body surface area, and hypertension. CAC score, a well-established surrogate marker of cardiovascular disease, is positively associated with aortic unfolding. Further study to evaluate aortic unfolding as a potential predictor of cardiovascular risk is warranted. PMID- 24755939 TI - Breaking symmetry in multimeric ATPase motors. PMID- 24755940 TI - Novel insights on the role of CD8+ T cells and cytotoxic responses during Helicobacter pylori infection. AB - Helicobacter pylori chronically persists in 50% of the human population and causes serious gastric and duodenal pathologies in 15% of infected people. Research on the immune response to the infection has mainly focused on the induction of CD4+ T cell responses. Human studies emphasize the potential clinical relevance of CD8+ cytotoxic T lymphocytes, however this cell type has barely been reported in studies employing mouse or gerbil models. Traditionally characterized as an extracellular bacterium, H. pylori has been identified inside epithelial and immune cells. Similarly to other intracellular bacteria, H. pylori infection of macrophages can alter autophagy and phagosome processing. A novel animal model of H. pylori infection demonstrates for the first time the induction of cytotoxic CD8+ T cell responses in pigs and localization of intracellular H. pylori within lymphoid aggregates. Here, we discuss novel mechanisms of host-H. pylori interactions that could lead to the induction of cytotoxic responses. PMID- 24755941 TI - Transport of particles in intestinal mucus under simulated infant and adult physiological conditions: impact of mucus structure and extracellular DNA. AB - The final boundary between digested food and the cells that take up nutrients in the small intestine is a protective layer of mucus. In this work, the microstructural organization and permeability of the intestinal mucus have been determined under conditions simulating those of infant and adult human small intestines. As a model, we used the mucus from the proximal (jejunal) small intestines of piglets and adult pigs. Confocal microscopy of both unfixed and fixed mucosal tissue showed mucus lining the entire jejunal epithelium. The mucus contained DNA from shed epithelial cells at different stages of degradation, with higher amounts of DNA found in the adult pig. The pig mucus comprised a coherent network of mucin and DNA with higher viscosity than the more heterogeneous piglet mucus, which resulted in increased permeability of the latter to 500-nm and 1-um latex beads. Multiple-particle tracking experiments revealed that diffusion of the probe particles was considerably enhanced after treating mucus with DNase. The fraction of diffusive 500-nm probe particles increased in the pig mucus from 0.6% to 64% and in the piglet mucus from ca. 30% to 77% after the treatment. This suggests that extracellular DNA can significantly contribute to the microrheology and barrier properties of the intestinal mucus layer. To our knowledge, this is the first time that the structure and permeability of the small intestinal mucus have been compared between different age groups and the contribution of extracellular DNA highlighted. The results help to define rules governing colloidal transport in the developing small intestine. These are required for engineering orally administered pharmaceutical preparations with improved delivery, as well as for fabricating novel foods with enhanced nutritional quality or for controlled calorie uptake. PMID- 24755942 TI - Cost benefit analysis of two policy options for cannabis: status quo and legalisation. AB - AIMS: To date there has been limited analysis of the economic costs and benefits associated with cannabis legalisation. This study redresses this gap. A cost benefit analysis of two cannabis policy options the status quo (where cannabis use is illegal) and a legalised-regulated option was conducted. METHOD: A cost benefit analysis was used to value the costs and benefits of the two policies in monetary terms. Costs and benefits of each policy option were classified into five categories (direct intervention costs, costs or cost savings to other agencies, benefits or lost benefits to the individual or the family, other impacts on third parties, and adverse or spill over events). The results are expressed as a net social benefit (NSB). FINDINGS: The mean NSB per annum from Monte Carlo simulations (with the 5 and 95 percentiles) for the status quo was $294.6 million AUD ($201.1 to $392.7 million) not substantially different from the $234.2 million AUD ($136.4 to $331.1 million) for the legalised-regulated model which excludes government revenue as a benefit. When government revenue is included, the NSB for legalised-regulated is higher than for status quo. Sensitivity analyses demonstrate the significant impact of educational attainment and wellbeing as drivers for the NSB result. CONCLUSION: Examining the percentiles around the two policy options, there appears to be no difference between the NSB for these two policy options. Economic analyses are essential for good public policy, providing information about the extent to which one policy is substantially economically favourable over another. In cannabis policy, for these two options this does not appear to be the case. PMID- 24755943 TI - Acute stress modulates feedback processing in men and women: differential effects on the feedback-related negativity and theta and beta power. AB - Sex-specific prevalence rates in mental and physical disorders may be partly explained by sex differences in physiological stress responses. Neural networks that might be involved are those underlying feedback processing. Aim of the present EEG study was to investigate whether acute stress alters feedback processing, and whether stress effects differ between men and women. Male and female participants performed a gambling task, in a control and a stress condition. Stress was induced by exposing participants to a noise stressor. Brain activity was analyzed using both event-related potential and time-frequency analyses, measuring the feedback-related negativity (FRN) and feedback-related changes in theta and beta oscillatory power, respectively. While the FRN and feedback-related theta power were similarly affected by stress induction in both sexes, feedback-related beta power depended on the combination of stress induction condition and sex. FRN amplitude and theta power increases were smaller in the stress relative to the control condition in both sexes, demonstrating that acute noise stress impairs performance monitoring irrespective of sex. However, in the stress but not in the control condition, early lower beta-band power increases were larger for men than women, indicating that stress effects on feedback processing are partly sex-dependent. Our findings suggest that sex specific effects on feedback processing may comprise a factor underlying sex specific stress responses. PMID- 24755944 TI - Searching for effective forces in laboratory insect swarms. AB - Collective animal behaviour is often modeled by systems of agents that interact via effective social forces, including short-range repulsion and long-range attraction. We search for evidence of such effective forces by studying laboratory swarms of the flying midge Chironomus riparius. Using multi-camera stereoimaging and particle-tracking techniques, we record three-dimensional trajectories for all the individuals in the swarm. Acceleration measurements show a clear short-range repulsion, which we confirm by considering the spatial statistics of the midges, but no conclusive long-range interactions. Measurements of the mean free path of the insects also suggest that individuals are on average very weakly coupled, but that they are also tightly bound to the swarm itself. Our results therefore suggest that some attractive interaction maintains cohesion of the swarms, but that this interaction is not as simple as an attraction to nearest neighbours. PMID- 24755946 TI - Driving human-mouse avatars to understand the HSC niche. PMID- 24755945 TI - Anchoring linkage groups of the Rosa genetic map to physical chromosomes with tyramide-FISH and EST-SNP markers. AB - In order to anchor Rosa linkage groups to physical chromosomes, a combination of the Tyramide-FISH technology and the modern molecular marker system based on High Resolution Melting (HRM) is an efficient approach. Although, Tyramide-FISH is a very promising technique for the visualization of short DNA probes, it is very challenging for plant species with small chromosomes such as Rosa. In this study, we successfully applied the Tyramide-FISH technique for Rosa and compared different detection systems. An indirect detection system exploiting biotinylated tyramides was shown to be the most suitable technique for reliable signal detection. Three gene fragments with a size of 1100 pb-1700 bp (Phenylalanine Ammonia Lyase, Pyrroline-5-Carboxylate Synthase and Orcinol O-Methyl Transferase) have been physically mapped on chromosomes 7, 4 and 1, respectively, of Rosa wichurana. The signal frequency was between 25% and 40%. HRM markers of these 3 gene fragments were used to include the gene fragments on the existing genetic linkage map of Rosa wichurana. As a result, three linkage groups could be anchored to their physical chromosomes. The information was used to check for synteny between the Rosa chromosomes and Fragaria. PMID- 24755947 TI - Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease. AB - Alexander disease (AxD) is an astrogliopathy that primarily affects the white matter of the central nervous system (CNS). AxD is caused by mutations in a gene encoding GFAP (glial fibrillary acidic protein). The GFAP mutations in AxD have been reported to act in a gain-of-function manner partly because the identified mutations generate practically full-length GFAP. We found a novel nonsense mutation (c.1000 G>T, p.(Glu312Ter); also termed p.(E312*)) within a rod domain of GFAP in a 67-year-old Korean man with a history of memory impairment and leukoencephalopathy. This mutation, GFAP p.(E312*), removes part of the 2B rod domain and the whole tail domain from the GFAP. We characterized GFAP p.(E312*) using western blotting, in vitro assembly and sedimentation assay, and transient transfection of human adrenal cortex carcinoma SW13 (Vim(+)) cells with plasmids encoding GFAP p.(E312*). The GFAP p.(E312*) protein, either alone or in combination with wild-type GFAP, elicited self-aggregation. In addition, the assembled GFAP p.(E312*) aggregated into paracrystal-like structures, and GFAP p.(E312*) elicited more GFAP aggregation than wild-type GFAP in the human adrenal cortex carcinoma SW13 (Vim(+)) cells. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of GFAP that is associated with AxD and paracrystal formation. PMID- 24755948 TI - Positional cloning and next-generation sequencing identified a TGM6 mutation in a large Chinese pedigree with acute myeloid leukaemia. AB - An inherited predisposition to acute myeloid leukaemia (AML) is exceedingly rare, but the investigation of these families will aid in the delineation of the underlying mechanisms of the more common, sporadic cases. Three AML predisposition genes, RUNX1, CEBPA and GATA2, have been recognised, but the culprit genes in the majority of AML pedigrees remain obscure. We applied a combined strategy of linkage analysis and next-generation sequencing (NGS) technology in an autosomal-dominant AML Chinese family with 11 cases in four generations. A genome-wide linkage scan using a 500K SNP genotyping array was conducted to identify a previously unreported candidate region on 20p13 with a maximum multipoint heterogeneity LOD (HLOD) score of 3.56 (P=0.00005). Targeted NGS within this region and whole-exome sequencing (WES) revealed a missense mutation in TGM6 (RefSeq, NM_198994.2:c.1550T>G, p.(L517W)), which cosegregated with the phenotype in this family, and was absent in 530 healthy controls. The mutated amino acid was located in a highly conserved position, which may be deleterious and affect the activation of TGM6. Our results strongly support the candidacy of TGM6 as a novel familial AML-associated gene. PMID- 24755949 TI - Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome. AB - First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations. PMID- 24755950 TI - Brain tumor risk according to germ-line variation in the MLLT10 locus. AB - Genome-wide association studies have recently identified a cancer susceptibility locus at 10p12 mapping to MLLT10 associated with the onset of diverse tumors. We genotyped two tightly linked single-nucleotide polymorphisms (SNPs) at MLLT10 associated with meningioma (rs12770228) or ovarian cancer (rs1243180), and tested for associations among 295 meningioma cases, 606 glioma cases and 646 noncancer controls, all of European descent. The variant 'A' allele in MLLT10 rs12770228 was associated with an increased risk of meningioma (per allele odds ratio: 1.25; 95% confidence interval: 1.02, 1.53; P=0.031). Similar associations were observed for rs1243180. MLLT10 variants were unrelated to glioma. Functional investigation identified 22 candidate functional SNPs mapping to this region. The present study further validates 10p12 as a meningioma risk locus. PMID- 24755951 TI - Parental expression is overvalued in the interpretation of rare inherited variants. PMID- 24755952 TI - Possible technical and biological explanations for the 'parental telomere length inheritance discrepancy' enigma. PMID- 24755953 TI - Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had >11 D4Z4 repeats. SMCHD1 c.1040+1G>A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G>T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD. PMID- 24755954 TI - An environmental data set for vector-borne disease modeling and epidemiology. AB - Understanding the environmental conditions of disease transmission is important in the study of vector-borne diseases. Low- and middle-income countries bear a significant portion of the disease burden; but data about weather conditions in those countries can be sparse and difficult to reconstruct. Here, we describe methods to assemble high-resolution gridded time series data sets of air temperature, relative humidity, land temperature, and rainfall for such areas; and we test these methods on the island of Madagascar. Air temperature and relative humidity were constructed using statistical interpolation of weather station measurements; the resulting median 95th percentile absolute errors were 2.75 degrees C and 16.6%. Missing pixels from the MODIS11 remote sensing land temperature product were estimated using Fourier decomposition and time-series analysis; thus providing an alternative to the 8-day and 30-day aggregated products. The RFE 2.0 remote sensing rainfall estimator was characterized by comparing it with multiple interpolated rainfall products, and we observed significant differences in temporal and spatial heterogeneity relevant to vector borne disease modeling. PMID- 24755955 TI - Protective effects of the polyphenol sesamin on allergen-induced T(H)2 responses and airway inflammation in mice. AB - Allergic asthma is a lifelong airway condition that affects people of all ages. In recent decades, asthma prevalence continues to increase globally, with an estimated number of 250,000 annual deaths attributed to the disease. Although inhaled corticosteroids and beta-adrenergic receptor agonists are the primary therapeutic avenues that effectively reduce asthma symptoms, profound side effects may occur in patients with long-term treatments. Therefore, development of new therapeutic strategies is needed as alternative or supplement to current asthma treatments. Sesamin is a natural polyphenolic compound with strong anti oxidative effects. Several studies have reported that sesamin is effective in preventing hypertension, thrombotic tendency, and neuroinflammation. However, it is still unknown whether sesamin can reduce asthma-induced allergic inflammation and airway hyperresponsiveness (AHR). Our study has revealed that sesamin exhibited significant anti-inflammatory effects in ovalbumin (OVA)-induced murine asthma model. We found that treatments with sesamin after OVA sensitization and challenge significantly decreased expression levels of interleukin-4 (IL-4), IL 5, IL-13, and serum IgE. The numbers of total inflammatory cells and eosinophils in BALF were also reduced in the sesamin-treated animals. Histological results demonstrated that sesamin attenuated OVA-induced eosinophil infiltration, airway goblet cell hyperplasia, mucus occlusion, and MUC5AC expression in the lung tissue. Mice administered with sesamin showed limited increases in AHR compared with mice receiving vehicle after OVA challenge. OVA increased phosphorylation levels of IkappaB-alpha and nuclear expression levels of NF-kappaB, both of which were reversed by sesamin treatments. These data indicate that sesamin is effective in treating allergic asthma responses induced by OVA in mice. PMID- 24755956 TI - Which models are appropriate for six subtropical forests: species-area and species-abundance models. AB - The species-area relationship is one of the most important topic in the study of species diversity, conservation biology and landscape ecology. The species-area relationship curves describe the increase of species number with increasing area, and have been modeled by various equations. In this paper, we used detailed data from six 1-ha subtropical forest communities to fit three species-area relationship models. The coefficient of determination and F ratio of ANOVA showed all the three models fitted well to the species-area relationship data in the subtropical communities, with the logarithm model performing better than the other two models. We also used the three species-abundance distributions, namely the lognormal, logcauchy and logseries model, to fit them to the species abundance data of six communities. In this case, the logcauchy model had the better fit based on the coefficient of determination. Our research reveals that the rare species always exist in the six communities, corroborating the neutral theory of Hubbell. Furthermore, we explained why all species-abundance figures appeared to be left-side truncated. This was due to subtropical forests have high diversity, and their large species number includes many rare species. PMID- 24755957 TI - Oxygenation and hemodynamics do not underlie early muscle fatigue for patients with work-related muscle pain. AB - Patients suffering from work-related muscle pain (WRMP) fatigue earlier during exercise than healthy controls. Inadequate oxygen consumption and/or inadequate blood supply can influence the ability of the muscles to withstand fatigue. However, it remains unknown if oxygenation and hemodynamics are associated with early fatigue in muscles of WRMP patients. In the present study we applied near infrared spectroscopy (NIRS) on the extensor carpi radialis (ECR) and trapezius (TD) muscles of patients with WRMP (n = 18) and healthy controls (n = 17). Our objective was to determine if there were group differences in endurance times for a low-level contraction of 15% maximal voluntary contraction (MVC)--sustained for 12-13 min, and to see if these differences were associated with differences in muscle oxygenation and hemodynamics. At baseline, oxygen saturation (StO2%) was similar between groups for the ECR, but StO2% was significantly lower for TD for the WRMP patients (76%) compared to controls (85%) (P<0.01). Also, baseline ECR blood flow was similar in the two groups. For both muscles there were a larger number of patients, compared to controls, that did not maintain the 15% MVC for the allotted time. Consequently, the endurance times were significantly shorter for the WRMP patients than controls (medians, ECR: 347 s vs. 582 s; TD: 430 s vs. 723 s respectively). Responses in StO2% during the contractions were not significantly different between groups for either muscle, i.e. no apparent difference in oxygen consumption. Overall, we interpret our findings to indicate that the early fatigue for our WRMP patients was not associated with muscle oxygenation and hemodynamics. PMID- 24755958 TI - Circulating endothelial progenitor cells in castration resistant prostate cancer: a randomized, controlled, biomarker study. AB - BACKGROUND: Endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients. PATIENTS AND METHODS: Chemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m2) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy. RESULTS: A total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p<0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6-3.6 months, 95% CI) and 6.2 months (4.9-7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable. CONCLUSION: In summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel/sunitinib therapy resulted in a better response in terms of PSA decline and a trend towards improved PFS. TRIAL REGISTERY: clinicaltrialsregister.eu EudraCT 2007-003705-27. PMID- 24755961 TI - Microbial mediated formation of Fe-carbonate minerals under extreme acidic conditions. AB - Discovery of Fe-carbonate precipitation in Rio Tinto, a shallow river with very acidic waters, situated in Huelva, South-western Spain, adds a new dimension to our understanding of carbonate formation. Sediment samples from this low-pH system indicate that carbonates are formed in physico-chemical conditions ranging from acid to neutral pH. Evidence for microbial mediation is observed in secondary electron images (Fig. 1), which reveal rod-shaped bacteria embedded in the surface of siderite nanocrystals. The formation of carbonates in Rio Tinto is related to the microbial reduction of ferric iron coupled to the oxidation of organic compounds. Herein, we demonstrate for the first time, that Acidiphilium sp. PM, an iron-reducing bacterium isolated from Rio Tinto, mediates the precipitation of siderite (FeCO3) under acidic conditions and at a low temperature (30 degrees C). We describe nucleation of siderite on nanoglobules in intimate association with the bacteria cell surface. This study has major implications for understanding carbonate formation on the ancient Earth or extraterrestrial planets. PMID- 24755959 TI - Small regulatory RNAs in Archaea. AB - Small regulatory RNAs (sRNAs) are universally distributed in all three domains of life, Archaea, Bacteria, and Eukaryotes. In bacteria, sRNAs typically function by binding near the translation start site of their target mRNAs and thereby inhibit or activate translation. In eukaryotes, miRNAs and siRNAs typically bind to the 3'-untranslated region (3'-UTR) of their target mRNAs and influence translation efficiency and/or mRNA stability. In archaea, sRNAs have been identified in all species investigated using bioinformatic approaches, RNomics, and RNA-Seq. Their size can vary significantly between less than 50 to more than 500 nucleotides. Differential expression of sRNA genes has been studied using northern blot analysis, microarrays, and RNA-Seq. In addition, biological functions have been unraveled by genetic approaches, i.e., by characterization of designed mutants. As in bacteria, it was revealed that archaeal sRNAs are involved in many biological processes, including metabolic regulation, adaptation to extreme conditions, stress responses, and even in regulation of morphology and cellular behavior. Recently, the first target mRNAs were identified in archaea, including one sRNA that binds to the 5'-region of two mRNAs in Methanosarcina mazei Go1 and a few sRNAs that bind to 3'-UTRs in Sulfolobus solfataricus, three Pyrobaculum species, and Haloferax volcanii, indicating that archaeal sRNAs appear to be able to target both the 5'-UTR or the 3'-UTRs of their respective target mRNAs. In addition, archaea contain tRNA-derived fragments (tRFs), and one tRF has been identified as a major ribosome-binding sRNA in H. volcanii, which downregulates translation in response to stress. Besides regulatory sRNAs, archaea contain further classes of sRNAs, e.g., CRISPR RNAs (crRNAs) and snoRNAs. PMID- 24755962 TI - We call it football! PMID- 24755960 TI - High-throughput identification and dendritic cell-based functional validation of MHC class I-restricted Mycobacterium tuberculosis epitopes. AB - Emergence of drug-resistant strains of the pathogen Mycobacterium tuberculosis (Mtb) and the ineffectiveness of BCG in curtailing Mtb infection makes vaccine development for tuberculosis an important objective. Identifying immunogenic CD8+ T cell peptide epitopes is necessary for peptide-based vaccine strategies. We present a three-tiered strategy for identifying and validating immunogenic peptides: first, identify peptides that form stable complexes with class I MHC molecules; second, determine whether cytotoxic T lymphocytes (CTLs) raised against the whole protein antigen recognize and lyse target cells pulsed with peptides that passed step 1; third, determine whether peptides that passed step 2, when administered in vivo as a vaccine in HLA-A2 transgenic mice, elicit CTLs that lyse target cells expressing the whole protein antigen. Our innovative approach uses dendritic cells transfected with Mtb antigen-encoding mRNA to drive antigen expression. Using this strategy, we have identified five novel peptide epitopes from the Mtb proteins Apa, Mtb8.4 and Mtb19. PMID- 24755963 TI - Effects of domestic air travel on technical and tactical performance and recovery in soccer. AB - The current study examined the effects of short-haul air travel on competition performance and subsequent recovery. Six male professional Australian football (soccer) players were recruited to participate in the study. Data were collected from 12 matches, which included 6 home and away matches against the same 4 teams. Together with the outcome of each match, data were obtained for team technical and tactical performance indicators and individual player-movement patterns. Furthermore, sleep quantity and quality, hydration, and perceptual fatigue were measured 2 days before, the day of, and 2 days after each match. More competition points were accumulated (P > .05, d = 1.10) and fewer goals were conceded (P > .05, d = 0.93) in home than in away matches. Furthermore, more shots on goal (P > .05, d = 1.17) and corners (P > .05, d = 1.45) and fewer opposition shots on goal (P > .05, d = 1.18) and corners (P < .05, d = 2.32) occurred, alongside reduced total distance covered (P > .05, d = 1.19) and low-intensity activity (P < .05, d = 2.25) during home than during away matches. However, while oxygen saturation was significantly lower during than before and after outbound and return travel (P < .01), equivocal differences in sleep quantity and quality, hydration, and perceptual fatigue were observed before and after competition away compared with home. These results suggest that, compared with short-haul air travel, factors including situational variables, territoriality, tactics, and athlete psychological state are more important in determining match outcome. Furthermore, despite the potential for disrupted recovery patterns, return travel did not impede player recovery or perceived readiness to train. PMID- 24755966 TI - Motion characteristics of women's college soccer matches: Female Athletes in Motion (FAiM) study. AB - PURPOSE: To quantify the locomotor demands of college female soccer matches and compare the relative proportion of distances in specified velocity bands between players completing an entire half with substitutes. METHODS: College female soccer players (n = 113) were assessed during a regular-season match using global positioning system technology. An ANCOVA was used to compare the locomotor characteristics for positions and substitutes, adjusting for duration played. Paired t tests compared the proportion of distances for players substituted out and back into the second half. RESULTS: Defenders covered less total absolute distance than midfielders (first half) and midfielders and forwards (second half) with concomitantly lower work rates. Moderate- and high-intensity running were similar between positions within each half. Midfielders substituted into the match had a lower proportion of moderate-intensity running than those substituted out (15% +/- 1.8% vs 19% +/- 0.9%), and defenders completing an entire first half had a lower proportion of high-intensity running than defenders substituted in or out (6% +/- 1.0% vs 11% +/- 1.0% and 16% +/- 2.8%). There were no differences in the proportion of distances covered within each velocity band for any position in the second half or for the players substituted out and then back in during the second half. CONCLUSIONS: The current findings provide novel insight linking the developmental progression between youth and high-level matches for overall demands and work rates. Moderate- and high-intensity distances cumulatively range from 2100 to 2600 m (26-28% total distance) in female college matches. The high amount of consistency observed for the proportions of distance covered suggest that substitution patterns have little impact on locomotor distribution. PMID- 24755978 TI - Bridging the gap between empirical results, actual strategies, and developmental programs in soccer. AB - Being one of the most prominent globalized sports, soccer played at club, national, and continental levels has a relevant societal role. At present, the specific competencies, interests, and languages of the different actors involved in the selection, development, and support of long-lasting careers of players might limit opportunities for potential talented players. Unless the cultural environment of soccer resolves the gaps between empirical results and actual soccer strategies, scientific discussion relating to the effectiveness of talent selection and development remains limited. This commentary is intended to highlight the need for developmental programs to prepare soccer personnel for a transdisciplinary dialogue, which could foster a future development of this sport. Finally, in considering the wide soccer-related employment opportunities at local, national, and international levels, the need for a clear qualification framework is crucial. PMID- 24755979 TI - Long-range correlations and complex regulation of pacing in long-distance road racing. AB - PURPOSE: To analyze time-domain, spectral, and fractal properties of speed regulation during half-marathon racing. METHODS: In 21 male experienced runners, high-resolution data on speed (V), stride frequency (SF), and stride length (SL) were assessed during half-marathon competition (21,098 m). Performance times, time- and frequency-domain variability, spectral-scaling exponent (beta), and fractal dimension (FD) of V, SF, and SL were analyzed. RESULTS: V of 3.65 +/- 0.41 m/s, SF of 1.41 +/- 0.05 Hz, and SL of 2.58 +/- 0.25 m occurred with higher (P < .05) individual variability in V and SL than in SF. Beta and FD were always 1.04-1.88 and 1.56-1.99, respectively. Beta and FD differed (P < .05) in SF and SL compared with V and were correlated in V and SL (r = .91, P < .05). Spectral peaks of V, SF, and SL occurred at wavelengths of 3-35 min, and those of V and SL were interrelated (r = .56, P < .05). Mean SF and mean SL were significantly correlated with performance (r = .59 and r = .95, P < .05). SL accounted for 84% +/- 6% and SF for 16% +/- 6% of speed variability. CONCLUSIONS: The observed nonrandom fluctuations in V, SF, and SL correspond to nonstationary fractional Brownian motion with inherent long-range correlations. This indicates a similar complex regulation process in experienced runners that is primarily mediated via SL. PMID- 24755982 TI - Care.data doesn't care enough about consent. PMID- 24755983 TI - The evolution of genomic imprinting: theories, predictions and empirical tests. AB - The epigenetic phenomenon of genomic imprinting has motivated the development of numerous theories for its evolutionary origins and genomic distribution. In this review, we examine the three theories that have best withstood theoretical and empirical scrutiny. These are: Haig and colleagues' kinship theory; Day and Bonduriansky's sexual antagonism theory; and Wolf and Hager's maternal-offspring coadaptation theory. These theories have fundamentally different perspectives on the adaptive significance of imprinting. The kinship theory views imprinting as a mechanism to change gene dosage, with imprinting evolving because of the differential effect that gene dosage has on the fitness of matrilineal and patrilineal relatives. The sexual antagonism and maternal-offspring coadaptation theories view genomic imprinting as a mechanism to modify the resemblance of an individual to its two parents, with imprinting evolving to increase the probability of expressing the fitter of the two alleles at a locus. In an effort to stimulate further empirical work on the topic, we carefully detail the logic and assumptions of all three theories, clarify the specific predictions of each and suggest tests to discriminate between these alternative theories for why particular genes are imprinted. PMID- 24755984 TI - Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis. AB - RATIONALE: The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown. OBJECTIVE: To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis. METHODS AND RESULTS: Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis. CONCLUSIONS: Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17. PMID- 24755985 TI - Hemodynamic disturbed flow induces differential DNA methylation of endothelial Kruppel-Like Factor 4 promoter in vitro and in vivo. AB - RATIONALE: Hemodynamic disturbed flow (DF) is associated with susceptibility to atherosclerosis. Endothelial Kruppel-Like Factor 4 (KLF4) is an important anti inflammatory atheroprotective transcription factor that is suppressed in regions of DF. OBJECTIVE: The plasticity of epigenomic KLF4 transcriptional regulation by flow-mediated DNA methylation was investigated in vitro and in arterial tissue. METHODS AND RESULTS: To recapitulate dominant flow characteristics of atheroprotected and atherosusceptible arteries, human aortic endothelial cells were subjected to pulsatile undisturbed flow or oscillatory DF containing a flow reversing phase. Differential CpG site methylation was measured by methylation specific polymerase chain reaction, bisulfite pyrosequencing, and restriction enzyme-polymerase chain reaction. The methylation profiles of endothelium from disturbed and undisturbed flow sites of adult swine aortas were also investigated. In vitro, DF increased DNA methylation of CpG islands within the KLF4 promoter that significantly contributed to suppression of KLF4 transcription; the effects were mitigated by DNA methyltransferase (DNMT) inhibitors and knockdown of DNMT3A. Contributory mechanisms included DF-induced increase of DNMT3A protein (1.7-fold), DNMT3A enrichment (11-fold) on the KLF4 promoter, and competitive blocking of a myocyte enhancer factor-2 binding site in the KLF4 promoter near the transcription start site. DF also induced DNMT sensitive propathological expression of downstream KLF4 transcription targets nitric oxide synthase 3, thrombomodulin, and monocyte chemoattractant protein-1. In support of the in vitro findings, swine aortic endothelium isolated from DF regions expressed significantly lower KLF4 and nitric oxide synthase 3, and bisulfite sequencing of KLF4 promoter identified a hypermethylated myocyte enhancer factor-2 binding site. CONCLUSIONS: Hemodynamics influence endothelial KLF4 expression through DNMT enrichment/myocyte enhancer factor-2 inhibition mechanisms of KLF4 promoter CpG methylation with regional consequences for atherosusceptibility. PMID- 24755986 TI - A novel photocatalytic material for removing microcystin-LR under visible light irradiation: degradation characteristics and mechanisms. AB - BACKGROUND AND PURPOSE: Microcystin-LR (MC-LR), a common toxic species in contaminated aquatic systems, persists for long periods because of its cyclic structure. Ag3PO4 is an environment-friendly photocatalyst with relatively good degradation capacity for hazardous organic pollutants. This study aimed to investigate the degradation capacity of Ag3PO4 for MC-LR under visible light. METHODS: An Ag3PO4 photocatalyst was synthesized by the ion-exchange method and characterized by X-ray diffraction, field-emission scanning electron microscope, and UV-Vis spectrophotometer. MC-LR was quantified in each sample through high performance liquid chromatograph. The degradation efficiency of MC-LR was affected by initial pH, initial Ag3PO4 concentration, initial MC-LR concentration, and recycle experiments. The degradation intermediates of MC-LR were examined by liquid chromatography-mass spectrometry (LC/MS). RESULTS: The degradation process can be well fitted with the pseudo-first-order kinetic model. The maximum MC-LR degradation rate of 99.98% can be obtained within 5 h under the following optimum conditions: pH of 5.01, Ag3PO4 concentration of 26.67 g/L, and MC-LR concentration of 9.06 mg/L. Nine intermediates were detected and analyzed by LC/MS. Three main degradation pathways were proposed based on the molecular weight of the intermediates and the reaction mechanism: (1) hydroxylation on the aromatic ring of Adda, (2) hydroxylation on the diene bonds of Adda, and (3) internal interactions on the cyclic structure of MC-LR. CONCLUSION: Ag3PO4 is a highly efficient catalyst for MC-LR degradation in aqueous solutions. PMID- 24755987 TI - Toxic megacolon in ulcerative rectocolitis. Current trends in clinical evaluation, diagnosis and treatment. AB - Toxic megacolon is a clinical condition associated to high risk of colonic perforation, that significantly increases--even triplicates--the megacolon related mortality when causing diffuse peritonitis. Abdominal and pelvic helical CT scan proved to be a fundamental diagnostic tool, in defining the colic dilatation and perforation. Conservative treatment is initially indicated in the event of toxic megacolon arising at the onset of a severe or toxic colitis. However it should be avoided when the toxic megacolon appears on corticosteroid therapy. Non operative management must not exceed 48 hours. The rationale of this strategy lies on the fact that early surgery is burdened by a mortality rate that, although moderate, is still higher than medical treatment. Nevertheless, successful conservative management does not exempt from surgery, which must be performed as soon as possible, in an elective setting, to prevent the recurrence of toxic megacolon. In emergency total colectomy and end ileostomy is the gold standard procedure. Bowel continuity will be restored, evaluating case by case, by performing an ileorectal anastomosis or proctectomy and ileoanal pouch anastomosis. Primary ileorectal anastomosis should be reserved to selected cases. In the elective setting, after proper therapy and regression of toxic megacolon, proctocolectomy and ileoanal pouch anastomosis is indicated. PMID- 24755988 TI - Inhibition of Notch signaling alters the phenotype of orthotopic tumors formed from glioblastoma multiforme neurosphere cells but does not hamper intracranial tumor growth regardless of endogene Notch pathway signature. AB - BACKGROUND: Brain cancer stem-like cells (bCSC) are cancer cells with neural stem cell (NSC)-like properties found in the devastating brain tumor glioblastoma multiforme (GBM). bCSC are proposed a central role in tumor initiation, progression, treatment resistance and relapse and as such present a promising target in GBM research. The Notch signaling pathway is often deregulated in GBM and we have previously characterized GBM-derived bCSC cultures based on their expression of the Notch-1 receptor and found that it could be used as predictive marker for the effect of Notch inhibition. The aim of the present project was therefore to further elucidate the significance of Notch pathway activity for the tumorigenic properties of GBM-derived bCSC. METHODS: Human-derived GBM xenograft cells previously established as NSC-like neurosphere cultures were used. Notch inhibition was accomplished by exposing the cells to the gamma-secretase inhibitor DAPT prior to gene expression analysis and intracranial injection into immunocompromised mice. RESULTS: By analyzing the expression of several Notch pathway components, we found that the cultures indeed displayed different Notch pathway signatures. However, when DAPT-treated neurosphere cells were injected into the brain of immunocompromised mice, no increase in survival was obtained regardless of Notch pathway signature and Notch inhibition. We did however observe a decrease in the expression of the stem cell marker Nestin, an increase in the proliferative marker Ki-67 and an increased number of abnormal vessels in tumors formed from DAPT-treated, high Notch-1 expressing cultures, when compared with the control. CONCLUSION: Based on the presented results we propose that Notch inhibition partly induces differentiation of bCSC, and selects for a cell type that more strongly induces angiogenesis if the treatment is not sustained. However, this more differentiated cell type might prove to be more sensitive to conventional therapies. PMID- 24755989 TI - LMKB/MARF1 localizes to mRNA processing bodies, interacts with Ge-1, and regulates IFI44L gene expression. AB - The mRNA processing body (P-body) is a cellular structure that regulates the stability of cytoplasmic mRNA. MARF1 is a murine oocyte RNA-binding protein that is associated with maintenance of mRNA homeostasis and genomic stability. In this study, autoantibodies were used to identify Limkain B (LMKB), the human orthologue of MARF1, as a P-body component. Indirect immunofluorescence demonstrated that Ge-1 (a central component of the mammalian core-decapping complex) co-localized with LMKB in P-bodies. Two-hybrid and co immunoprecipitation assays were used to demonstrate interaction between Ge-1 and LMKB. The C-terminal 120 amino acids of LMKB mediated interaction with Ge-1 and the N-terminal 1094 amino acids of Ge-1 were required for interaction with LMKB. LMKB is the first protein identified to date that interacts with this portion of Ge-1. LMKB was expressed in human B and T lymphocyte cell lines; depletion of LMKB increased expression of IFI44L, a gene that has been implicated in the cellular response to Type I interferons. The interaction between LMKB/MARF1, a protein that contains RNA-binding domains, and Ge-1, which interacts with core decapping proteins, suggests that LMKB has a role in the regulation of mRNA stability. LMKB appears to have different functions in different cell types: maintenance of genomic stability in developing oocytes and possible dampening of the inflammatory response in B and T cells. PMID- 24755990 TI - Heteroatom-enriched and renewable banana-stem-derived porous carbon for the electrochemical determination of nitrite in various water samples. AB - For the first time, high-surface-area (approximately 1465 m(2) g(-1)), highly porous and heteroatom-enriched activated carbon (HAC) was prepared from banana stems (Musa paradisiaca, Family: Musaceae) at different carbonization temperatures of 700, 800 and 900 degrees C (HAC) using a simple and eco-friendly method. The amounts of carbon, hydrogen, nitrogen and sulfur in the HAC are 61.12, 2.567, 0.4315, and 0.349%, respectively. Using X-ray diffraction (XRD), CHNS elemental analysis, X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy, the prepared activated carbon appears amorphous and disordered in nature. Here, we used HAC for an electrochemical application of nitrite (NO2(-)) sensor to control the environmental pollution. In addition, HAC exhibits noteworthy performance for the highly sensitive determination of nitrite. The limit of detection (LODs) of the nitrite sensor at HAC-modified GCE is 0.07 MUM. In addition, the proposed method was applied to determine nitrite in various water samples with acceptable results. PMID- 24755991 TI - Effects of silver nitrate and silver nanoparticles on a planktonic community: general trends after short-term exposure. AB - Among metal pollutants silver ions are one of the most toxic forms, and have thus been assigned to the highest toxicity class. Its toxicity to a wide range of microorganisms combined with its low toxicity to humans lead to the development of a wealth of silver-based products in many bactericidal applications accounting to more than 1000 nano-technology-based consumer products. Accordingly, silver is a widely distributed metal in the environment originating from its different forms of application as metal, salt and nanoparticle. A realistic assessment of silver nanoparticle toxicity in natural waters is, however, problematic and needs to be linked to experimental approaches. Here we apply metatranscriptome sequencing allowing for elucidating reactions of whole communities present in a water sample to stressors. We compared the toxicity of ionic silver and ligand free silver nanoparticles by short term exposure on a natural community of aquatic microorganisms. We analyzed the effects of the treatments on metabolic pathways and species composition on the eukaryote metatranscriptome level in order to describe immediate molecular responses of organisms using a community approach. We found significant differences between the samples treated with 5 ug/L AgNO3 compared to the controls, but no significant differences in the samples treated with AgNP compared to the control samples. Statistical analysis yielded 126 genes (KO-IDs) with significant differential expression with a false discovery rate (FDR) <0.05 between the control (KO) and AgNO3 (NO3) groups. A KEGG pathway enrichment analysis showed significant results with a FDR below 0.05 for pathways related to photosynthesis. Our study therefore supports the view that ionic silver rather than silver nanoparticles are responsible for silver toxicity. Nevertheless, our results highlight the strength of metatranscriptome approaches for assessing metal toxicity on aquatic communities. PMID- 24755992 TI - Effect of proline analogues on activity of human prolyl hydroxylase and the regulation of HIF signal transduction pathway. AB - Hypoxia inducible factor 1 (HIF-1) plays a pivotal role in cellular responses to hypoxia. Prolyl hydroxylase 3 (PHD3) degrades HIF-1alpha under normoxic conditions through the hydroxylation of HIF-1alpha for proteolysis. Inhibiting PHD3 activity is crucial for up-regulating HIF-1alpha, thereby acting as a potential target for treating hypoxia-related diseases. In this study, two proline analogues (PA1 and PA2) were screened as PHD3 inhibitors with apparent EC50 values of 1.53 and 3.17 uM respectively, indicating good inhibition potency. Nine proteins, significantly regulated by PA1, were identified using 2-DE coupled with MALDI-TOF/TOF MS. Pyruvate kinase isozymes M1/M2 (PKM) and alpha-enolase 1 (ENO1), which are key modulators of glycolysis, are directly regulated by HIF 1alpha. Moreover, VEGF, a signal protein stimulating angiogenesis, was strongly promoted by PA1. Our findings suggest that PA1 stabilized HIF-1alpha as well as up-regulated glycolysis and angiogenesis proteins. Herein, for the first time, we systematically studied proline analogue PA1 as a PHD3 inhibitor, which provides innovative evidence for the treatment of HIF-related diseases. PMID- 24755993 TI - Therapygenetics in mindfulness-based cognitive therapy: do genes have an impact on therapy-induced change in real-life positive affective experiences? AB - Positive affect (PA) has an important role in resilience against depression and has been shown to increase with mindfulness-based cognitive therapy (MBCT). To elucidate the underlying mechanisms of change in PA as well as develop insights that may benefit personalized medicine, the current study examined the contribution of genetic variation to individual differences in change in PA in response to MBCT. Individuals (n=126) with residual depressive symptoms were randomized to either an MBCT group or treatment as usual. PA was assessed using experience sampling methodology (ESM). Single-nucleotide polymorphisms (SNPs) in genes known to be involved in reward functioning were selected. SNPs in the genes for brain-derived neurotrophic factor (BDNF), the muscarinic acetylcholine receptor M2 (CHRM2), the dopamine receptor D4 (DRD4) and the MU1 opioid receptor (OPRM1) significantly moderated the impact of treatment condition over time on PA. Genetic variation in the genes for CHRM2 and OPRM1 specifically had an impact on the level of PA following MBCT. The current study shows that variation in response to MBCT may be contingent on genetic factors associated with the regulation of PA. These findings contribute to our understanding of the processes moderating response to treatment and prediction of treatment outcome. PMID- 24755994 TI - Sustained AAV-mediated overexpression of CRF in the central amygdala diminishes the depressive-like state associated with nicotine withdrawal. AB - Smoking cessation leads to a dysphoric state and this increases the risk for relapse. Animal studies indicate that the dysphoric state associated with nicotine withdrawal is at least partly mediated by an increase in corticotropin releasing factor (CRF) release in the central nucleus of the amygdala (CeA). In the present study, we investigated whether a sustained overexpression of CRF in the CeA affects the dysphoric-like state associated with nicotine withdrawal. To study brain reward function, rats were prepared with intracranial self stimulation (ICSS) electrodes in the medial forebrain bundle. An adeno-associated virus (AAV, pseudotype 2/5) was used to overexpress CRF or green fluorescent protein (GFP, control) in the CeA and minipumps were used to induce nicotine dependence. The AAV2/5-CRF vector induced a 40% increase in CRF protein and mRNA levels in the CeA. Administration of the nicotinic receptor antagonist mecamylamine (precipitated withdrawal) or nicotine pump removal (spontaneous withdrawal) led to elevations in ICSS thresholds. Elevations in ICSS thresholds are indicative of a dysphoric-like state. The overexpression of CRF did not affect baseline ICSS thresholds but diminished the elevations in ICSS thresholds associated with precipitated and spontaneous nicotine withdrawal. The real-time reverse transcriptase (RT)-PCR analysis showed that the overexpression of CRF led to a decrease in CRF1 mRNA levels and an increase in CRF2 mRNA levels in the CeA. In conclusion, the overexpression of CRF in the CeA diminishes the dysphoric-like state associated with nicotine withdrawal and this might be driven by neuroadaptive changes in CRF1 and CRF2 receptor gene expression. PMID- 24755995 TI - Roles of interleukin-9 in the growth and cholecystokinin-induced intracellular calcium signaling of cultured interstitial cells of Cajal. AB - Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract and loss of ICC is associated with many GI motility disorders. Previous studies have shown that ICC have the capacity to regenerate or restore, and several growth factors are critical to their growth, maintenance or regeneration. The present study aimed to investigate the roles of interleukin-9 (IL-9) in the growth, maintenance and pacemaker functions of cultured ICC. Here, we report that IL-9 promotes proliferation of ICC, and culturing ICC with IL-9 enhances cholecystokinin-8-induced Ca2+ transients, which is probably caused by facilitating maintenance of ICC functions under culture condition. We also show co-localizations of cholecystokinin-1 receptor and IL-9 receptor with c-kit by double-immunohistochemical labeling. In conclusion, IL-9 can promote ICC growth and help maintain ICC functions; IL-9 probably performs its functions via IL-9 receptors on ICC. PMID- 24755996 TI - Association of veterinary third-generation cephalosporin use with the risk of emergence of extended-spectrum-cephalosporin resistance in Escherichia coli from dairy cattle in Japan. AB - The use of extended-spectrum cephalosporins in food animals has been suggested to increase the risk of spread of Enterobacteriaceae carrying extended-spectrum beta lactamases to humans. However, evidence that selection of extended-spectrum cephalosporin-resistant bacteria owing to the actual veterinary use of these drugs according to criteria established in cattle has not been demonstrated. In this study, we investigated the natural occurrence of cephalosporin-resistant Escherichia coli in dairy cattle following clinical application of ceftiofur. E. coli isolates were obtained from rectal samples of treated and untreated cattle (n = 20/group) cultured on deoxycholate-hydrogen sulfide-lactose agar in the presence or absence of ceftiofur. Eleven cefazoline-resistant isolates were obtained from two of the ceftiofur-treated cattle; no cefazoline-resistant isolates were found in untreated cattle. The cefazoline-resistant isolates had mutations in the chromosomal ampC promoter region and remained susceptible to ceftiofur. Eighteen extended-spectrum cephalosporin-resistant isolates from two ceftiofur-treated cows were obtained on ceftiofur-supplemented agar; no extended spectrum cephalosporin-resistant isolates were obtained from untreated cattle. These extended-spectrum cephalosporin-resistant isolates possessed plasmid mediated beta-lactamase genes, including bla(CTX-M-2) (9 isolates), bla(CTX-M-14) (8 isolates), or bla(CMY-2) (1 isolate); isolates possessing bla(CTX-M-2) and bla(CTX-M-14) were clonally related. These genes were located on self transmissible plasmids. Our results suggest that appropriate veterinary use of ceftiofur did not trigger growth extended-spectrum cephalosporin-resistant E. coli in the bovine rectal flora; however, ceftiofur selection in vitro suggested that additional ceftiofur exposure enhanced selection for specific extended spectrum cephalosporin-resistant beta-lactamase-expressing E. coli clones. PMID- 24755997 TI - Current and emerging therapies for Addison's disease. AB - PURPOSE OF REVIEW: The purpose of this article is to review the current therapy of Addison's disease and to highlight recent developments in this field. RECENT FINDINGS: Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone; however, new treatment modalities such as modified-released hydrocortisone and continuous subcutaneous hydrocortisone infusion have recently been developed. These offer the potential for closer simulation of the physiological serum cortisol rhythm. Two studies have also looked at modifying the natural history of adrenal failure using adrenocorticotropic hormone (ACTH) stimulation and immunomodulatory therapies, leading to the concept of residual adrenal function in some Addison's disease patients. SUMMARY: Following more than 60 years with no significant innovation in the management of Addison's disease, these new approaches hold promise for improved patient health and better quality of life in the future. PMID- 24755998 TI - Management of female-to-male transgender persons: medical and surgical management, life expectancy. AB - PURPOSE OF REVIEW: Hormonal treatment of transgender people is becoming a normal part of medicine, though numbers of subjects remain small because of low prevalence. Information on treatment is scattered and this review brings together the latest information on treatment goals and potential side-effects of androgen treatment of female-to-male transsexual subjects. RECENT FINDINGS: Androgen treatment of female-to-male transsexuals is usually uneventful, with a good patient compliance. Goals of hormonal treatment are elimination of secondary sex characteristics of the female sex and induction of those of the male sex. Completion takes approximately 2 years. Hormonal treatment is eventually followed by surgical ablation of breasts and removal of uterus and ovaries. Phalloplasty may be considered. Concerns are the sequelae of hypogonadism following surgery, such as loss of bone mass. Contrary to earlier expectations, there is no increase in cardiovascular disease. (Hormone-related) cancers are rare, but vaginal, cervical, endometrial carcinomas have been reported. Cancers of the breasts are of greater concern and have been found in residual mammary tissue after breast ablation. So far, androgen treatment has not raised major safety concerns. Regrets about changing sex have not been reported. SUMMARY: Testosterone treatment of female-to-male transsexuals is effective and well tolerated. PMID- 24755999 TI - Developmental changes in mismatch responses to mandarin consonants and lexical tones from early to middle childhood. AB - The purpose of this study was to use mismatch responses (MMRs) to explore the dynamic changes of Mandarin speech perception abilities from early to middle childhood. Twenty preschoolers, 18 school-aged children, and 26 adults participated in this study. Two sets of synthesized speech stimuli varying in Mandarin consonant (alveolo-palatal affricate vs. fricative) and lexical tone features (rising vs. contour tone) were used to examine the developmental course of speech perception abilities. The results indicated that only the adult group demonstrated typical early mismatch negativity (MMN) responses, suggesting that the ability to discriminate specific speech cues in Mandarin consonant and lexical tone is a continuing process in preschool- and school-aged children. Additionally, distinct MMR patterns provided evidence indicating diverse developmental courses to different speech characteristics. By incorporating data from the two speech conditions, we propose using MMR profiles consisting of mismatch negativity (MMN), positive mismatch response (p-MMR), and late discriminative negativity (LDN) as possible brain indices to investigate speech perception development. PMID- 24756000 TI - Risk factors for vitamin D deficiency among HIV-infected and uninfected injection drug users. AB - INTRODUCTION: Vitamin D deficiency is highly prevalent and is associated with bone disease, cardiovascular disease, metabolic syndrome and malignancy. Injection drug users (IDUs), with or without HIV infection, are at risk for these conditions; however, limited data on vitamin D deficiency exist in this population. We determined the prevalence and correlates of vitamin D deficiency among urban IDUs in the AIDS Linked to the IntraVenous Experience (ALIVE) Study cohort. METHODS: For this cross-sectional sub-study, vitamin D deficiency was defined as a serum 25(OH)-vitamin D level <20 ng/mL. Multivariable logistic regression was used to identify factors independently associated with vitamin D deficiency. RESULTS: Of 950 individuals analyzed, 29% were HIV-infected. The median age was 49 years; 65% were male, and 91% were black. The median vitamin D level was 13.5 ng/mL (IQR, 9.0-20.3); 74% were deficient (68% in HIV-infected vs. 76% in HIV-uninfected, p = 0.01). Non-black race, fall/winter season, multivitamin intake, higher serum albumin, HCV seropositivity and HIV-infection were associated with significantly lower odds of vitamin D deficiency. CONCLUSIONS: Vitamin D deficiency is prevalent among IDUs. Notably, HIV-infected IDUs were less likely to be vitamin D deficient. Higher vitamin D levels were associated with multivitamin intake and with higher albumin levels, suggesting that nutritional status contributes substantially to deficiency. The association between HCV serostatus and vitamin D level remains unclear. Further investigation is needed to define the clinical implications of the heavy burden of vitamin D deficiency in this high-risk, aging population with significant co-morbidities. PMID- 24756001 TI - Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model. AB - Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 ug and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures. PMID- 24756003 TI - Getting the facts right about the law and female genital mutilation. PMID- 24756002 TI - Correlation of DNA methylation levels in blood and saliva DNA in young girls of the LEGACY Girls study. AB - Many epidemiologic studies of environmental exposures and disease susceptibility measure DNA methylation in white blood cells (WBC). Some studies are also starting to use saliva DNA as it is usually more readily available in large epidemiologic studies. However, little is known about the correlation of methylation between WBC and saliva DNA. We examined DNA methylation in three repetitive elements, Sat2, Alu, and LINE-1, and in four CpG sites, including AHRR (cg23576855, cg05575921), cg05951221 at 2q37.1, and cg11924019 at CYP1A1, in 57 girls aged 6-15 years with blood and saliva collected on the same day. We measured all DNA methylation markers by bisulfite-pyrosequencing, except for Sat2 and Alu, which were measured by the MethyLight assay. Methylation levels measured in saliva DNA were lower than those in WBC DNA, with differences ranging from 2.8% for Alu to 14.1% for cg05575921. Methylation levels for the three repetitive elements measured in saliva DNA were all positively correlated with those in WBC DNA. However, there was a wide range in the Spearman correlations, with the smallest correlation found for Alu (0.24) and the strongest correlation found for LINE-1 (0.73). Spearman correlations for cg05575921, cg05951221, and cg11924019 were 0.33, 0.42, and 0.79, respectively. If these findings are replicated in larger studies, they suggest that, for selected methylation markers (e.g., LINE 1), methylation levels may be highly correlated between blood and saliva, while for others methylation markers, the levels may be more tissue specific. Thus, in studies that differ by DNA source, each interrogated site should be separately examined in order to evaluate the correlation in DNA methylation levels across DNA sources. PMID- 24756005 TI - Combined hepatocellular-cholangiocarcinoma (cHCC-CC): a distinct entity. AB - Patients with hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, display a highly variable clinical course, suggesting that HCC encompasses several biologically distinct subtypes. This heterogeneity has the potential to impede both treatment decisions and prognostic predictions for patients with HCC. One distinct, albeit rare, subtype of HCC is combined hepatocellular-cholangiocarcinoma (cHCC-CC), which overall carries a poorer prognosis than HCC and cholangiocarcinoma (CC) alone. This review discusses predominantly the histopathologic and pathogenetic intricacies of this tumor and highlights the need for an accurate diagnosis of this specific HCC subtype. PMID- 24756006 TI - An update on management of Budd-Chiari syndrome. AB - The topic of this paper is to report an update on management of Budd-Chiari syndrome (BCS). Actually, the flow-chart of BCS management comes from experts opinion and is not evidence-based due to the rarity of BCS. Management of BCS follows a step-wise strategy. Anticoagulation and medical therapy should be the first line treatment. Revascularization or TIPS in case of no response to medical therapy. OLT as a rescue therapy. Surgery has limited but important space, especially in cases with high inferior vena cava obstruction not suitable for endovascular treatment. However, no clear indication can actually be given about the timing of different treatments. Moreover, there is some concern about treatment of some subgroup of patients, especially regarding the risk of recurrence after liver transplantation. This paper propose a new algorithm of BCS management suggesting an earlier therapeutic approach when clinical signs are evident. PMID- 24756007 TI - Efficacy and safety of long term entecavir in chronic hepatitis B treatment naive patients in clinical practice. AB - BACKGROUND AND AIMS: Entecavir (ETV) is effective and safe in patients with chronic hepatitis B in the short term, but its long term efficacy and safety has not been established. MATERIAL AND METHODS: We evaluated HBV DNA clearance, HBeAg/antiHBe and HBsAg/antiHBs seroconversion rates in HBeAg-positive and negative NUC naive HBV patients treated with ETV for more than 6 months, and predictors of response. RESULTS: A hundred and sixty nine consecutive patients were treated with ETV for a median of 181 weeks. 61% were HBeAg positive, 23% were cirrhotics, and mean HBV-DNA levels were 6,88 +/- 1,74 log10 IU/mL. Overall, 156 (92%) patients became HBV DNA undetectable, 92 (88%) HBeAg positive and 64 (98%) HBeAg negative patients. Seventy four (71%) patients cleared HBeAg after a median of 48 weeks of treatment, 23 (14%) patients cleared HBsAg (19 HBeAg positive and 4 HBeAg negative, p 0.025) after a median of 96 weeks of treatment, and 22 (13%) patients developed protective titers of anti-HBs. At the end of the study, 35 (20%) patients had discontinued therapy: 33 HBeAg positive and 2 HBeAg negative; 9 of them (26%) developed virological relapse after a median of 48 weeks of stopping treatment. None of the patients had primary non response and one patient developed breakthrough. Two patients developed HCC, three underwent liver transplantation and 3 deaths were attributable to liver-related events. No serious adverse events were reported. CONCLUSION: Long term ETV treatment showed high virological response rates, and a favorable safety profile for NUC-naive HBeAg-positive and negative patients treated in clinical practice. PMID- 24756008 TI - Comparison of two diagnostic algorithms for the identification of patients with HCV viremia using a new HCV antigen test. AB - BACKGROUND: Patients exposed to hepatitis C virus (HCV) may develop chronic infection with viremia. The diagnosis of this condition requires the use of several laboratory tests in algorithms tailored to the population and resources available for each laboratory. AIM: We compared the diagnostic efficacy of two diagnostic algorithms for the identification of viremic patients with HCV. One based on confirmation of reactive antibody results with molecular techniques (reverse transcription polymerase chain reaction, RTPCR) and the other based on the use of a new HCV core antigen test (HCV Ag). Material and methods. We measured levels of anti-HCV, HCV Ag and viral load (trough RT-PCR) in parallel, in 211 samples (53 antibody positive, 158 antibody negative). Using the three results available for each sample we simulated the diagnostic performance of the two algorithms and compared them to the results of RT-PCR as gold standard. RESULTS: Both algorithms showed a high degree of concordance for viremic patients. The percentage of correctly classified patients was 99.05% for the algorithm based on RT-PCR and 98.10% for the HCV Ag algorithm. The HCV core Ag test showed a clinical sensitivity of 0.917 and showed a good correlation to the results of molecular biology. Spearman rank correlation coefficient (rho) of 0.97 (95% CI 0.95 to 0.99, p < 0.0001). CONCLUSION: An algorithm incorporating HCV Ag as confirmatory test for anti-HCV results is a feasible alternative to the use of molecular techniques in laboratories that do not have access to them or require faster turn around times. PMID- 24756009 TI - Treatment with metadoxine and its impact on early mortality in patients with severe alcoholic hepatitis. AB - BACKGROUND & AIM: Despite treatment with glucocorticoids, mortality remains high in patients with severe alcoholic hepatitis. Oxidative stress and depletion of mitochondrial glutathione are implicated factors in liver injury. The aim of this study was to evaluate the impact of the addition of metadoxine, a drug which possesses a multifactorial mechanism of action, including antioxidant properties, to standard treatment with glucocorticoids in patients with severe alcoholic hepatitis. MATERIAL AND METHODS: This randomized open label clinical trial was performed in Mexico's General Hospital (Registry Key DIC/10/107/03/043). We randomized 70 patients with severe alcoholic hepatitis. The first group received prednisone (40 mg/day), and the second group received prednisone (40 mg/day) plus metadoxine tablets (500 mg three times daily). The duration of treatment in both groups was 30 days. Survival at 30 and 90 days, development of complications, adverse events and response to treatment (Lille model) were assessed. RESULTS: In the group receiving metadoxine, significant improvements were observed, as follows: survival at 30 days (74.3 vs. 45.7%, P = 0.02); survival at 90 days (68.6 vs. 20.0%, P = 0.0001). There was less development or progression of encephalopathy (28.6 vs. 60.0%, P = 0.008) and hepatorenal syndrome (31.4 vs. 54.3%, P = 0.05), and the response to treatment (Lille model) was higher in the metadoxine group (0.38 vs. 0.63, P = 0.001; 95% CI 0.11 to 0.40). There were no differences between groups regarding the development or progression of variceal hemorrhage or infection. The incidence of adverse events, mainly gastrointestinal, was similar in both groups. CONCLUSIONS: Addition of metadoxine to glucocorticoid treatment improves the short-term survival of patients with severe alcoholic hepatitis and diminishes the development or progression of encephalopathy and hepatorenal syndrome. PMID- 24756010 TI - Inflammation is not the cause of an elevated serum ferritin in non-alcoholic fatty liver disease. AB - BACKGROUND: In non-alcoholic fatty liver disease (NALFD), it has often been assumed that an elevation in serum ferritin is likely related to inflammation rather than iron overload. MATERIAL AND METHODS: Patients referred with NAFLD were entered into a clinical study of phlebotomy therapy. A liver biopsy with liver iron concentration was done at entry and 6 months after phlebotomy (n = 56) until the patient had a low serum ferritin or developed anemia. Serum ferritin was compared to liver iron concentration, ESR, CRP, BMI and grade of inflammation on liver biopsy. RESULTS: Iron removed by phlebotomy in NAFLD correlated with the decrease in serum ferritin (r = 0.57, p = 0.0014) and liver iron concentration (r = 0.57, p = 0.0013). There was no significant correlations between serum ferritin and ESR, CRP or grade of liver inflammation. CONCLUSIONS: Serum ferritin is related to liver iron storage in NAFLD and decreasing body iron stores by phlebotomy is reflected by an appropriate decrease in serum ferritin. Inflammation is not the cause of the elevated serum ferritin in fatty liver disease. PMID- 24756011 TI - Evaluation of tumor markers for the differential diagnosis of benign and malignant ascites. AB - INTRODUCTION: The diagnosis of malignant ascites is a challenging problem in clinical practice, non-invasive techniques should be developed to improve diagnostic accuracy. The diagnostic performances of tumor markers in malignant ascites remained unsettled. Our aim was to evaluate diagnostic performance of tumor markers in differential diagnosis of benign and malignant ascites. MATERIAL AND METHODS: A total of 437 patients were enrolled, and the relevant parameters of the patients were analyzed for the differentiation of benign ascites from malignant ascites. RESULTS: At the predetermined cutoff values of tumor makers, tumor markers in ascitic fluid showed better diagnostic performance than those in serum. Combined use of tumor markers and the cytology increased the diagnostic yield of the latter by 37%. In cytologically negative malignant ascites, tumor markers provided assistance in differentiating malignant ascites from benign ascites, and the combination of ascitic tumor markers yielded 86% sensitivity, 97% specificity. CONCLUSION: Use of a panel of tumor markers exhibited excellent diagnostic performance in diagnosing malignant ascites, which indicated the detection of tumor markers may represent a beneficial adjunct to cytology, thus guiding the selection of patients who might benefit from further invasive procedures. PMID- 24756012 TI - The effect of bacterial infections in cirrhotic patients with esophageal variceal bleeding. AB - BACKGROUND: Cirrhotic patients are prone to having bacterial infections due to impaired innate immunity. This nationwide population-based study aimed to identify the effect of bacterial infections on the mortality of the cirrhotic patients with esophageal variceal bleeding (EVB). MATERIAL AND METHODS: The Taiwan National Health Insurance Database was used to collect data about the cirrhotic patients receiving endoscopic procedures for EVB between January 1, 2004 and December 31, 2004. The enrolled patients were followed up individually for one year to identify their 6-week and 1-year mortalities. RESULTS: Of the 2,053 cirrhotic patients with EVB, 318 (15.5 %) were diagnosed with bacterial infections. Compared to non-infection group, the adjusted hazard rations (HRs) of bacterial infection for 6-week and 1-year mortalities were 2.69 (2.06-3.52) and 1.89 (1.56-2.28), respectively. Compared to non-infection group, the HRs of pneumonia, spontaneous bacterial peritonitis, urinary tract infection, and sepsis without specific focus (SWSF) were 3.54, 1.91, 1.04, and 3.95 for 6-week mortality, and 3.18, 1.52, 1.15, and 2.23 for 1-year mortality of cirrhotic patients with EVB. CONCLUSIONS: In cirrhotic patients with EVB, bacterial infections increase 2.7 folds of 6-week mortality and 1.9 folds of 1-year mortality. Of all infections, pneumonia and SWSF contributed higher risks for mortality. PMID- 24756013 TI - Antioxidant effect of N-acetylcysteine on prehepatic portal hypertensive gastropathy in rats. AB - BACKGROUND: Portal hypertension is a clinical syndrome associated with the development of a hyperdynamic circulation and gastroesophageal varices. Aim. To evaluate the antioxidant effect of N-acetylcysteine on portal hypertensive rats. MATERIAL AND METHODS: Portal hypertension was induced by partial portal vein ligation (PPVL). Oxidative damage in the stomach was measured by lipoperoxidation trough thiobarbituric acid reactive substances (TBARS) and antioxidant enzyme activity; we also evaluated nitrates and nitrites level and histology stained by hematoxylin-eosin. We performed evaluation of portal pressure and measurement of vessels diameter. Liver damage was evaluated by measuring hepatic enzymes. The animals were divided in four experimental groups (n = 6): Sham-operated (SO), SO + NAC, Partial portal vein ligation (PPVL) and PPVL + NAC. N-acetylcysteine (10 mg/kg ip) was administered daily for 7 days and started 8 days after surgery. RESULTS: The portal hypertensive group showed an increase in portal pressure, vessels diameter, levels of TBARS and nitrates and nitrites when compared to SO group. These values were accompanied by a decrease in superoxide dismutase (SOD) and glutathione peroxidase (GPx) antioxidant enzyme activity. Histology showed dilated vessels in the gastric mucosa in the PPVL group. NAC was able to decrease portal pressure values, vessels diameter, TBARS and also nitrates and nitrites levels when compared to PPVL group. Furthermore, PPVL+NAC group presented an increase in SOD and GPx activity. N-acetylcysteine attenuated damage in gastric mucosa. CONCLUSION: Oxidative stress is associated with portal hypertension and that antioxidant NAC is able to minimize damages of PPVL in rats. PMID- 24756014 TI - Capsulorrhaphy in the management of liver hydatid cyst. AB - INTRODUCTION: Hydatid disease is a major health problem in some parts of the world. There are several nonoperative and operative ways to treat hydatic disease. The aim of this retrospective study is to assess the rate of postoperative complications, mortality rate, hospitalization period, and recurrence for capsulorrhaphy method, and to compare it with other hydatic cyst management techniques. MATERIAL AND METHODS: An open surgical procedure using capsulorrhaphy technique was performed on 250 patients (130 men and 120 women) with uncomplicated hydatic cysts in the Northwest of Iran, between 1989 and 2011. RESULTS: The patients stayed in the hospital between 4 and 10 days, with an average of 5 days. Of the patients, 233 (93.2%) were discharged without any complications, 9 (3.6%) developed a wound infection in the abdominal wall, and 7 (2.8%) developed pulmonary atelectasis. Those who developed an infection or an atelectasis stayed in the hospital for few more days for conservative treatments. One of the patients (0.4%) had external biliary fistula and bile leak, which was treated with surgery and Roux-en-Y cystojejunostomy. During follow-ups (13.2 +/- 8.5 months), incisional hernias occurred in 5 (2%) patients and hydatid cyst recurrence affected 7 (2.8) patients. The mortality rate was zero amongst the studied patients. CONCLUSION: Compared to other techniques in the literature, the results presented in the current work indicate that capsulor-rhaphy is an efficient method in terms of decreased postoperative complications, recurrence, and hospitalization period, and is a safe method with low morbidity and zero mortality rates. PMID- 24756015 TI - Association between serum IgE level and adverse clinical endpoints in primary sclerosing cholangitis. AB - INTRODUCTION: Primary sclerosing cholangitis (PSC) is an idiopathic hepatobiliary disorder associated with an increased risk for cholangiocarcinoma (CCA) and a median survival time of 12 years. Reliable predictors of CCA and other major adverse events in PSC are currently lacking. Recently, serum IgE was found to be associated with CCA in a Japanese cohort of PSC patients. Our aim in this study was to determine whether IgE levels predict time to CCA, liver transplantation, or death in a Western (USA-based) cohort of PSC patients. MATERIAL AND METHODS: Thirty-eight patients with PSC and IgE levels were identified and categorized into low or high IgE groups based on the sample median. Groups were compared with respect to clinical characteristics and adverse endpoint-free survival, and the association between IgE and endpoints was assessed with multivariate proportional hazards models. RESULTS: The median sample age at PSC diagnosis was 41 years, and median serum IgE level was 47.6 kU/L. Low and high IgE groups differed significantly only with respect to IgG subclasses, which were higher among the latter (p < 0.05). There were no significant differences in composite endpoint free (p = 0.83) or CCA-free survival (p = 0.20). In multivariate analyses, only Mayo PSC risk score and MELD score were significant predictors of endpoint-free survival (p < 0.05). CONCLUSIONS: Serum IgE level is associated with several IgG subclass levels but not time to CCA, liver transplantation, or death among PSC patients in a USA-based cohort. While Mayo PSC risk score and MELD score can predict these outcomes, more specific predictors of CCA are needed. PMID- 24756016 TI - Akin criteria as a predictor of mortality in cirrhotic patients after spontaneous bacterial peritonitis. AB - BACKGROUND AND AIMS: Spontaneous bacterial peritonitis (SBP) often triggers acute on-chronic liver failure (ACLF). Acute kidney injury (AKI) is frequent and correlates with higher mortality in such cases. The aim of this study is to evaluate the Acute Kidney Injury Network (AKIN) criteria in the prediction of death in cirrhotic patients after an episode of SBP. MATERIAL AND METHODS: Forty six cirrhotic patients with SBP were included in a cohort study. Renal injury was estimated by AKIN criteria (grades 1, 2 or 3) to examine the association between AKI severity and mortality. Patients were followed-up for a mean of 13.22 months. Kaplan-Meier survival curve and the hazard ratio of mortality by Cox regression model were calculated accordingly to the AKIN criteria. RESULTS: The mean age of the included patients was 56.94 +/- 9.49; 29 (63%) were male. Mean MELD score was 19.46 +/- 6.16; 78.3% were Child-Pugh C. AKI occurred in 43.5% of patients (8.7, 17.4 and 17.4% respectively for AKIN criteria 1, 2 and 3). Inpatient mortality for AKIN 1, 2 and 3 was 50, 37.5 and 62.5 vs. 3.8% for patients without renal injury (p = 0.002, 0.001 and < 0.001 respectively). Patients with AKIN grades 1, 2 or 3 had no significant differences regarding MELD score (p = 0.893). The hazard ratio and 95% confidence interval of mortality for patients with AKI (AKIN grades 1, 2 and 3 grouped) were 3.41 (1.58-7.36). CONCLUSIONS: AKIN criteria are useful to predict mortality in patients with SBP. PMID- 24756017 TI - Severe mixed-type iron overload in alcoholic cirrhosis related to advanced spur cell anemia. PMID- 24756018 TI - A modified heterotopic auxiliary living donor liver transplantation: report of a case. AB - Liver transplantation is regarded as an effective treatment for Wilson's disease (WD), and recently has been shown to improve not only hepatic but also neurologic manifestations. Conventional auxiliary liver transplantation for WD is orthotopic liver transplantation and heterotopic liver transplantation. But the conventional procedure could not avoid the problem of space, functional competition, hemodynamic variation. Here we report a case of heterotopic auxiliary living donor liver transplantation (HALDLT) to treat WD. We modified the operation to have a splenectomy, implant graft into the splenic fossa. The patient recovered well after the transplantation and has been symptom-free during a 5-year follow up. This modified operation is more safe and simple. HALDLT might be an effective treatment for WD patients with splenomegaly. PMID- 24756019 TI - Molecular surveillance of hepatitis A virus in Argentina: first subgenotype IB detected in a traveler. AB - By using molecular surveillance of hepatitis A virus, we characterized for the first time a subgenotype IB imported case in Argentina, a country with universal vaccination since 2005. The case was a crew member of a cruise ship. We consider this a case alert because of its multiple implications. PMID- 24756020 TI - Patients with hyponatremic cirrhosis have low-grade cerebral edema and poor quality-of-life. PMID- 24756021 TI - New strategies for treating hepatic encephalopathy. PMID- 24756023 TI - Variation in fetal outcome, viral load and ORF5 sequence mutations in a large scale study of phenotypic responses to late gestation exposure to type 2 porcine reproductive and respiratory syndrome virus. AB - In spite of extensive research, the mechanisms of reproductive disease associated with Porcine Reproductive and Respiratory Syndrome virus (PRRSv) are still poorly understood. The objectives of this large scale study were to evaluate associations between viral load and fetal preservation, determine the impact of type 2 PRRSv on fetal weights, and investigate changes in ORF5 PRRSv genome in dams and fetuses during a 21-day period following challenge. At gestation day 85 (+/-1), 114 gilts were experimentally infected with type 2 PRRSv, while 19 gilts served as reference controls. At necropsy, fetuses were categorized according to their preservation status and tissue samples were collected. PRRSv RNA concentrations were measured in gilt serum collected on days 0, 2, 6, and 21 post infection, as well as in gilt and fetal tissues collected at termination. Fetal mortality was 41+/-22.8% in PRRS infected litters. Dead fetuses appeared to cluster in some litters but appeared solitary or random in others. Nine percent of surviving piglets were meconium-stained. PRRSv RNA concentration in fetal thymus, fetal serum and endometrium differed significantly across preservation category and was greatest in tissues of meconium-stained fetuses. This, together with the virtual absence of meconium staining in non-infected litters indicates it is an early pathological condition of reproductive PRRS. Viral load in fetal thymus and in fetal serum was positively associated with viral load in endometrium, suggesting the virus exploits dynamic linkages between individual maternal-fetal compartments. Point mutations in ORF5 sequences from gilts and fetuses were randomly located in 20 positions in ORF5, but neither nucleotide nor amino acid substitutions were associated with fetal preservation. PRRSv infection decreased the weights of viable fetuses by approximately 17%. The considerable variation in gilt and fetal outcomes provides tremendous opportunity for more detailed investigations of potential mechanisms and single nucleotide polymorphisms associated with fetal death. PMID- 24756024 TI - DNA sequence heterogeneity of Campylobacter jejuni CJIE4 prophages and expression of prophage genes. AB - Campylobacter jejuni carry temperate bacteriophages that can affect the biology or virulence of the host bacterium. Known effects include genomic rearrangements and resistance to DNA transformation. C. jejuni prophage CJIE1 shows sequence variability and variability in the content of morons. Homologs of the CJIE1 prophage enhance both adherence and invasion to cells in culture and increase the expression of a specific subset of bacterial genes. Other C. jejuni temperate phages have so far not been well characterized. In this study we describe investigations into the DNA sequence variability and protein expression in a second prophage, CJIE4. CJIE4 sequences were obtained de novo from DNA sequencing of five C. jejuni isolates, as well as from whole genome sequences submitted to GenBank by other research groups. These CJIE4 DNA sequences were heterogenous, with several different insertions/deletions (indels) in different parts of the prophage genome. Two variants of a 3-4 kb region inserted within CJIE4 had different gene content that distinguished two major conserved CJIE4 prophage families. Additional indels were detected throughout the prophage. Detection of proteins in the five isolates characterized in our laboratory in isobaric Tags for Relative and Absolute Quantitation (iTRAQ) experiments indicated that prophage proteins within each of the two large indel variants were expressed during growth of the bacteria on Mueller Hinton agar plates. These proteins included the extracellular DNase associated with resistance to DNA transformation and prophage repressor proteins. Other proteins associated with known or suspected roles in prophage biology were also expressed from CJIE4, including capsid protein, the phage integrase, and MazF, a type II toxin-antitoxin system protein. Together with the results previously obtained for the CJIE1 prophage these results demonstrate that sequence variability and expression of moron genes are both general properties of temperate bacteriophages in C. jejuni. PMID- 24756025 TI - A Randomized Controlled Trial of EEG-Based Motor Imagery Brain-Computer Interface Robotic Rehabilitation for Stroke. AB - Electroencephalography (EEG)-based motor imagery (MI) brain-computer interface (BCI) technology has the potential to restore motor function by inducing activity dependent brain plasticity. The purpose of this study was to investigate the efficacy of an EEG-based MI BCI system coupled with MIT-Manus shoulder-elbow robotic feedback (BCI-Manus) for subjects with chronic stroke with upper-limb hemiparesis. In this single-blind, randomized trial, 26 hemiplegic subjects (Fugl Meyer Assessment of Motor Recovery After Stroke [FMMA] score, 4-40; 16 men; mean age, 51.4 years; mean stroke duration, 297.4 days), prescreened with the ability to use the MI BCI, were randomly allocated to BCI-Manus or Manus therapy, lasting 18 hours over 4 weeks. Efficacy was measured using upper-extremity FMMA scores at weeks 0, 2, 4 and 12. ElEG data from subjects allocated to BCI-Manus were quantified using the revised brain symmetry index (rBSI) and analyzed for correlation with the improvements in FMMA score. Eleven and 15 subjects underwent BCI-Manus and Manus therapy, respectively. One subject in the Manus group dropped out. Mean total FMMA scores at weeks 0, 2, 4, and 12 weeks improved for both groups: 26.3+/-10.3, 27.4+/-12.0, 30.8+/-13.8, and 31.5+/-13.5 for BCI-Manus and 26.6+/-18.9, 29.9+/-20.6, 32.9+/-21.4, and 33.9+/-20.2 for Manus, with no intergroup differences (P=.51). More subjects attained further gains in FMMA scores at week 12 from BCI-Manus (7 of 11 [63.6%]) than Manus (5 of 14 [35.7%]). A negative correlation was found between the rBSI and FMMA score improvement (P=.044). BCI-Manus therapy was well tolerated and not associated with adverse events. In conclusion, BCI-Manus therapy is effective and safe for arm rehabilitation after severe poststroke hemiparesis. Motor gains were comparable to those attained with intensive robotic therapy (1,040 repetitions/session) despite reduced arm exercise repetitions using EEG-based MI-triggered robotic feedback (136 repetitions/session). The correlation of rBSI with motor improvements suggests that the rBSI can be used as a prognostic measure for BCI based stroke rehabilitation. PMID- 24756026 TI - The exploration-exploitation dilemma: a multidisciplinary framework. AB - The trade-off between the need to obtain new knowledge and the need to use that knowledge to improve performance is one of the most basic trade-offs in nature, and optimal performance usually requires some balance between exploratory and exploitative behaviors. Researchers in many disciplines have been searching for the optimal solution to this dilemma. Here we present a novel model in which the exploration strategy itself is dynamic and varies with time in order to optimize a definite goal, such as the acquisition of energy, money, or prestige. Our model produced four very distinct phases: Knowledge establishment, Knowledge accumulation, Knowledge maintenance, and Knowledge exploitation, giving rise to a multidisciplinary framework that applies equally to humans, animals, and organizations. The framework can be used to explain a multitude of phenomena in various disciplines, such as the movement of animals in novel landscapes, the most efficient resource allocation for a start-up company, or the effects of old age on knowledge acquisition in humans. PMID- 24756027 TI - Antimicrobial activity of cefepime-tazobactam combination tested against clinical isolates of Enterobacteriaceae. PMID- 24756029 TI - Evolution: why all plumes and jets evolve to round cross sections. AB - Turbulent curtains of smoke rise initially as flat plumes and, above a certain height, they become round plumes. The same evolution of cross-sectional shape is exhibited by jets issuing from flat nozzles. Here we predict based on principle that all such flows should evolve their cross-sectional shapes from flat to round (and not the other way) at a critical distance downstream, which is predictable. The principle is that the prevailing flow architecture provides greater access to the flow of momentum from the moving core (plume, jet) to the still surroundings. For turbulent plumes and jets, the transition distance scales with the long dimensions (L) of the two-dimensional (flat) heat sources and nozzles that drive them. For laminar jets, the transition distance scales with L Re, where Re is the Reynolds number based on nozzle velocity and the smaller dimension of the nozzle cross section. These predictions are confirmed by full numerical experiments of the three-dimensional flow fields of turbulent and laminar jets covering the Re range 10-10(4). PMID- 24756030 TI - Collaborative working between pediatric speech and language therapy and ENT colleagues: what is good practice? AB - PURPOSE OF REVIEW: This article considers current evidence pertaining to good practice in joint paediatric speech and language therapy (SLT) and ear, nose and throat (ENT) assessment and management in the general hospital clinic. Because of space limitations, this review excludes those cases that are typically referred into highly specialist clinics dealing with cleft palate or profound hearing loss and cochlear implant. It will instead focus on children with the types of communication difficulties that are related to physical anomalies and conditions impacting on speech, nasal resonance, voice and those cases with a history of fluctuating or mild hearing loss. The value of the multidisciplinary team in appropriate decision making has to be considered in terms of outcomes and related cost-effectiveness. RECENT FINDINGS: Research into the dynamic between paediatric ENT and SLT outcomes remains relatively sparse. Evidence continues to show that multiple factors impact on any decision regarding surgical or SLT interventions. SLT opinion across a range of perceptual, physical and social parameters aids the medical consultation on a case-by-case basis. Current evidence for speech therapy interventions shows that environmental management and family involvement are crucial, and any direct intervention should be well timed and regular to be effective. SUMMARY: The development of communication and listening is easily disrupted because of ENT disease or abnormality. The child's relationship with the ENT consultant and SLT may span several years, and communication difficulties may persist after any apparent physical problem has resolved. It is essential to jointly consider the optimum timing for any surgical and speech interventions so that services are better targeted and cost-effective. PMID- 24756031 TI - Treatment outcomes in acute invasive fungal rhinosinusitis. AB - PURPOSE OF REVIEW: Acute invasive fungal rhinosinusitis (AIFR) is an aggressive and often fatal infection with wide variability of both presentation and survival rate across several published case reports and small case series. This review discusses treatment outcomes for this challenging disease. RECENT FINDINGS: For several decades, the use of medical therapy (consisting primarily of intravenous antifungals) combined with surgical resection and/or debridement has been widely recommended for the treatment of AIFR. Unfortunately, because of the rarity of AIFR, few large-scale studies have evaluated 'best options' for disease management. Most recent studies show few changes in either survival outcomes or management over time. SUMMARY: Although overall survival rates remain below about 60%, outcomes are significantly more favorable for those patients undergoing surgical/endoscopic resection and who have reversible predisposing factors that can be rapidly managed (e.g., diabetes). The indications for orbital exenteration remain unclear, but recent studies suggest that this procedure may not change outcome in most patients. PMID- 24756028 TI - Structural, kinetic and proteomic characterization of acetyl phosphate-dependent bacterial protein acetylation. AB - The emerging view of Nepsilon-lysine acetylation in eukaryotes is of a relatively abundant post-translational modification (PTM) that has a major impact on the function, structure, stability and/or location of thousands of proteins involved in diverse cellular processes. This PTM is typically considered to arise by the donation of the acetyl group from acetyl-coenzyme A (acCoA) to the epsilon-amino group of a lysine residue that is reversibly catalyzed by lysine acetyltransferases and deacetylases. Here, we provide genetic, mass spectrometric, biochemical and structural evidence that Nepsilon-lysine acetylation is an equally abundant and important PTM in bacteria. Applying a recently developed, label-free and global mass spectrometric approach to an isogenic set of mutants, we detected acetylation of thousands of lysine residues on hundreds of Escherichia coli proteins that participate in diverse and often essential cellular processes, including translation, transcription and central metabolism. Many of these acetylations were regulated in an acetyl phosphate (acP)-dependent manner, providing compelling evidence for a recently reported mechanism of bacterial Nepsilon-lysine acetylation. These mass spectrometric data, coupled with observations made by crystallography, biochemistry, and additional mass spectrometry showed that this acP-dependent acetylation is both non-enzymatic and specific, with specificity determined by the accessibility, reactivity and three-dimensional microenvironment of the target lysine. Crystallographic evidence shows acP can bind to proteins in active sites and cofactor binding sites, but also potentially anywhere molecules with a phosphate moiety could bind. Finally, we provide evidence that acP-dependent acetylation can impact the function of critical enzymes, including glyceraldehyde-3-phosphate dehydrogenase, triosephosphate isomerase, and RNA polymerase. PMID- 24756032 TI - Improving access to psychological therapies in voice disorders: a cognitive behavioural therapy model. AB - PURPOSE OF REVIEW: The improving access to psychological therapies initiative has highlighted the importance of managing mental health problems effectively, and research has shown excellent outcomes from cognitive behavioural therapy (CBT) interventions. Patients presenting with functional dysphonia will often also describe psychological distress including anxiety, depression and reduced general well-being, and it is felt that effective voice therapy needs to include the management of psychological well-being. The evidence for the use of CBT enhanced voice therapy is limited to date. Recent research has only started to identify the benefits of this approach and questions regarding how to achieve and maintain competence are essential. RECENT FINDINGS: Voice therapy outcomes are positive and patients receiving CBT with voice therapy have shown more improvement in their general well-being and distress. SUMMARY: CBT is a very well evidenced therapy and recommended by The National Institute for Health and Care Excellence (NICE) as the treatment of choice for mental health difficulties and medically unexplained symptoms. Allied health professionals are increasingly being trained to use CBT skills in the management of a number of symptoms/illnesses, and this should be considered for the management of functional dysphonia. However, there is a need for more research and detailed consideration of how therapists should be trained and supervised and how cost-effective this approach may be. PMID- 24756034 TI - Results of intravitreal ranibizumab with a prn regimen in the treatment of extrafoveal and juxtafoveal neovascular membranes in age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy of intravitreal ranibizumab with a "pro re nata" regimen in the treatment of nonsubfoveal neovascular membranes secondary to age-related macular degeneration. METHODS: Retrospective noncomparative case series. Thirty-one eyes with naive nonsubfoveal neovascularization secondary to age-related macular degeneration were consecutively enrolled and treated with ranibizumab intravitreal injections according to a pro re nata regimen. The follow-up was performed monthly up to 6 months and quarterly up to 2 years (25 patients). Early treatment diabetic retinopathy study best-corrected visual acuity and lesion size analysis with fluorescein angiography were recorded. RESULTS: The mean baseline early treatment diabetic retinopathy study best corrected visual acuity worsened from 20/40 (0.28 logMAR) at baseline to 20/50 (0.42 logMAR) at 1-year follow-up and 20/60 (0.53 logMAR) at 2-year follow-up. The mean lesions size nearly doubled from baseline at the 2-year follow up (1.19 2.47 mm). Twenty-two patients had one or more recurrences at 1-year follow-up. All 25 patients developed a recurrence at 2 years with 7 cases developing a recurrence by 12 months. Twelve cases progressed to subfoveal lesions by the 24 month visit. CONCLUSION: Other regimens described in the literature might result in a more the satisfactory outcome using more frequent follow-up and more frequent intravitreal injections. PMID- 24756033 TI - Effect of antiprogesterone RU486 on VEGF expression and blood vessel remodeling on ovarian follicles before ovulation. AB - BACKGROUND: The success of ovarian follicle growth and ovulation is strictly related to the development of an adequate blood vessel network required to sustain the proliferative and endocrine functions of the follicular cells. Even if the Vascular Endothelial Growth Factor (VEGF) drives angiogenesis before ovulation, the local role exerted by Progesterone (P4) remains to be clarified, in particular when its concentration rapidly increases before ovulation. AIM: This in vivo study was designed to clarify the effect promoted by a P4 receptor antagonist, RU486, on VEGF expression and follicular angiogenesis before ovulation, in particular, during the transition from pre to periovulatory follicles induced by human Chorionic Gonadotropins (hCG) administration. MATERIAL AND METHODS: Preovulatory follicle growth and ovulation were pharmacologically induced in prepubertal gilts by combining equine Chorionic Gonadotropins (eCG) and hCG used in the presence or absence of RU486. The effects on VEGF expression were analyzed using biochemical and immunohistochemical studies, either on granulosa or on theca layers of follicles isolated few hours before ovulation. This angiogenic factor was also correlated to follicular morphology and to blood vessels architecture. RESULTS AND CONCLUSIONS: VEGF production, blood vessel network and follicle remodeling were impaired by RU486 treatment, even if the cause-effect correlation remains to be clarified. The P4 antagonist strongly down regulated theca VEGF expression, thus, preventing most of the angiogenic follicle response induced by hCG. RU486-treated follicles displayed a reduced vascular area, a lower rate of endothelial cell proliferation and a reduced recruitment of perivascular mural cells. These data provide important insights on the biological role of RU486 and, indirectly, on steroid hormones during periovulatory follicular phase. In addition, an in vivo model is proposed to evaluate how periovulatory follicular angiogenesis may affect the functionality of the corpus luteum (CL) and the success of pregnancy. PMID- 24756035 TI - Mini-cognitive testing in patients with age-related macular degeneration. AB - PURPOSE: To compare Mini-Cognitive (Mini-Cog) Screening test results between patients with age-related macular degeneration (AMD) and age-matched controls. PARTICIPANTS: Two hundred and twenty-nine patients were included in the study. Patients were divided into 3 groups: 56 patients with exudative AMD, mean age of 76 +/- 8 years; 82 patients with dry AMD, mean age of 77 +/- 9 years; and 91 controls, mean age of 75 +/- 8 years. METHODS: The Mini-Cog test, used to screen patients with early cognitive impairment, was introduced to the three groups of patients at the settings of an ophthalmology outpatient clinic. Test scores were compared between the groups. RESULTS: The mean for the Mini-Cog test scores was 3.5 (95% confidence interval, 3.15-3.85) for the dry AMD group, 3.95 (95% confidence interval, 3.51-4.39) for the exudative AMD group, and 4.63 (95% confidence interval, 4.45-4.80) for the control group. There was no statistically significant difference between the scores of AMD groups, however, both AMD groups received significantly lower scores than controls (P < 0.0001). CONCLUSION: Patients with age-related macular degeneration in this study demonstrated lower mean scores in the Mini-Cog test than age-matched controls. The Mini-Cog test may be easily applied at an office setting of ophthalmology outpatient clinics, and may help in the early diagnosis of cognitive impairment in the patients with AMD. PMID- 24756036 TI - Prevalence and spatial distribution of cystoid spaces in retinitis pigmentosa: investigation with spectral domain optical coherence tomography. AB - PURPOSE: To investigate the prevalence and spatial distribution of cystoid spaces (CS) in retinitis pigmentosa patients with spectral domain optical coherence tomography. METHODS: A total of 529 eyes of 275 patients with retinitis pigmentosa were examined with spectral domain optical coherence tomography. The presence or absence of CS was judged for each eye. Retinal layer and outer retinal status where the CS existed were also investigated. Statistical analysis was performed using 1 eye per 1 patient. RESULTS: Cystoid spaces were present in 119 of 529 eyes (22.5%) of 74 of 275 patients (26.9%). There were no significant differences between the cases with and without CS except for central foveal thickness (P < 0.001). Cystoid spaces were noted in the inner nuclear layer in almost all eyes (98.6%), and outer nuclear layer/outer plexiform layer was also involved in many eyes (27.8%). Cystoid spaces were sometimes seen in ganglion cell layer (6.9%). Cystoid spaces were predominantly (78.9%) distributed in the relatively preserved retina where external limiting membrane was retained. The presence of epiretinal membrane or posterior vitreous adhesion was associated with the presence of CS (P < 0.001) but showed no relationship with the spatial location of CS (P = 1.000). CONCLUSION: The prevalence of CS in patients with retinitis pigmentosa was 26.9% and contrary to previous reports, most CS were present in inner nuclear layer. In addition, most CS were observed in relatively retained retina, which is compatible to the prevailing notion. Epiretinal membrane or posterior vitreous adhesion was also associated with the development of CS. The distribution of CS in inner and preserved retina may provide insight for the pathogenesis of CS in retinitis pigmentosa. PMID- 24756037 TI - Tripartite motif-containing protein 30 modulates TCR-activated proliferation and effector functions in CD4+ T cells. AB - To avoid excessive activation, immune signals are tightly controlled by diverse inhibitory proteins. TRIM30, a tripartite motif (TRIM)-containing protein is one of such inhibitors known to function in macrophages. To define the roles of TRIM30, we generated Trim30 knockout (Trim30-/-) mice. Trim30 deletion caused no major developmental defects in any organs, nor showed any discernable defect in the activation of macrophages. But, Trim30-/- mice showed increased CD4/CD8 ratio when aged and Trim30-/- CD4+ T cells exhibited an abnormal response upon TCR activation, in particular in the absence of a costimulatory signal. Adoptive transfer of wild-type and Trim30-/- CD4+ T cells together into lymphopenic hosts confirmed higher proliferation of the Trim30-/- CD4+ T cells in vivo. Despite the enhanced proliferation, Trim30-/- T cells showed decreased levels of NF-kappaB activation and IL-2 production compared to wild-type cells. These results indicate a distinct requirement for TRIM30 in modulation of NF-kappaB activation and cell proliferation induced by TCR stimulation. PMID- 24756039 TI - Emergency peripartum hysterectomy and risk factors by mode of delivery and obstetric history: a 10-year review from Helsinki University Central Hospital. AB - OBJECTIVE: This study aims to estimate the occurrence of emergency peripartum hysterectomy (EPH) and to quantify its risk factors in connection with the mode of delivery and the obstetric history of patients at the Helsinki University Central Hospital, Finland. METHODS: In a retrospective, matched case-control study we identified 124 cases of EPH from 2000 to 2010 at our hospital. These were matched with 248 control patients. RESULTS: The incidence rate of EPH was 9.9/10,000. Patients whose current delivery was vaginal, and had a cesarean section (CS) in their history had a six-fold risk for EPH. Women who underwent their first CS had a nine times higher risk, while patients who currently underwent CS and had a history of previous CS, had a 22 times higher risk. Those who experienced prostaglandin-E1 induction had a five-fold risk. Maternal age >35 years, previous curettage, and twin pregnancy were identified as significant risk factors. In 41 cases, interventions to reduce bleeding were performed. CONCLUSION: Obstetric emergency training and guidelines for massive hemorrhage should be established in any delivery department. Moreover, all possible precautions should be taken to avoid the first CS if it is obstetrically unnecessary. Induction with prostaglandin-E1, maternal age >35 years, previous curettage, twin pregnancies, and early gestation were identified as risk factors for EPH. PMID- 24756038 TI - Separate and combined effects of DNMT and HDAC inhibitors in treating human multi drug resistant osteosarcoma HosDXR150 cell line. AB - Understanding the molecular mechanisms underlying multi-drug resistance (MDR) is one of the major challenges in current cancer research. A phenomenon which is common to both intrinsic and acquired resistance, is the aberrant alteration of gene expression in drug-resistant cancers. Although such dysregulation depends on many possible causes, an epigenetic characterization is considered a main driver. Recent studies have suggested a direct role for epigenetic inactivation of genes in determining tumor chemo-sensitivity. We investigated the effects of the inhibition of DNA methyltransferase (DNMT) and hystone deacethylase (HDAC), considered to reverse the epigenetic aberrations and lead to the re-expression of de novo methylated genes in MDR osteosarcoma (OS) cells. Based on our analysis of the HosDXR150 cell line, we found that in order to reduce cell proliferation, co treatment of MDR OS cells with DNMT (5-Aza-dC, DAC) and HDAC (Trichostatin A, TSA) inhibitors is more effective than relying on each treatment alone. In re expressing epigenetically silenced genes induced by treatments, a very specific regulation takes place which suggests that methylation and de-acetylation have occurred either separately or simultaneously to determine MDR OS phenotype. In particular, functional relationships have been reported after measuring differential gene expression, indicating that MDR OS cells acquired growth and survival advantage by simultaneous epigenetic inactivation of both multiple p53 independent apoptotic signals and osteoblast differentiation pathways. Furthermore, co-treatment results more efficient in inducing the re-expression of some main pathways according to the computed enrichment, thus emphasizing its potential towards representing an effective therapeutic option for MDR OS. PMID- 24756040 TI - Justified skepticism about Apgar scoring in out-of-hospital birth settings. AB - BACKGROUND: The Apgar score is used worldwide to assess the newborn infant shortly after birth. Apgar scores, including mean scores and those with high cut off scores, have been used to support claims that planned home birth is as safe as hospital birth. The purpose of this study was to determine the distribution of 5 min Apgar scores among different birth settings and providers in the USA. METHODS: We obtained data from the National Center for Health Statistics of the US Centers for Disease Control birth certificate data for 2007-2010 for all singleton, term births of infants weighing >=2500 g (n=13,830,531). Patients were then grouped into six categories by birth setting and birth attendant: hospital based physician, hospital-based midwife, freestanding birth center with either certified nurse midwife and/or other midwife, and home-based delivery with either certified nurse midwife or other midwife. The distribution of each Apgar score from 0 to 10 was assessed for each group. RESULTS: Newborns delivered by other midwives or certified nurse midwives (CNMs) in a birthing center or at home had a significantly higher likelihood of a 5 min maximum Apgar score of 10 than those delivered in a hospital [52.63% in birthing centers, odds ratio (OR) 29.19, 95% confidence interval (CI): 28.29-30.06, and 52.44% at home, OR 28.95, 95% CI: 28.40-29.50; CNMs: 16.43% in birthing centers, OR 5.16, 95% CI: 4.99-5.34, and 36.9% at home births, OR 15.29, 95% CI: 14.85-15.73]. CONCLUSIONS: Our study shows an inexplicable bias of high 5 min Apgar scores of 10 in home or birthing center deliveries. Midwives delivering at home or in birthing centers assigned a significantly higher proportion of Apgar scores of 10 when compared to midwives or physicians delivering in the hospital. Studies that have claimed the safety of out-of-hospital deliveries by using higher mean or high cut-off 5 min Apgar scores and reviews based on these studies should be treated with skepticism by obstetricians and midwives, by pregnant women, and by policy makers. The continued use of studies using higher mean or high cut-off 5 min Apgar scores, and a bias of high Apgar score, to advocate the safety of home births is inappropriate. PMID- 24756041 TI - Hypophosphatemic rickets caused by a novel PHEX gene mutation in an Indian girl. AB - We report a girl who presented with clinical and biochemical features of hypophosphatemic rickets. Mutational analysis detected a heterozygous nonsynonymous sequence variation in exon 11 of the PHEX gene (NM_000444.4:c.1216T>C, NP_000435.3:p.Cys406Arg). This previously undescribed PHEX mutation is probably the cause of renal phosphate wasting in our patient that resulted in rickets. PMID- 24756042 TI - Clinical features at diagnosis and responses to antithyroid drugs in younger children with Graves' disease compared with adolescent patients. AB - OBJECTIVE: The aim of this study was to evaluate clinical manifestations, laboratory findings, and effects of antithyroid drugs in younger children with Graves' disease (GD). DESIGN: A retrospective and collaborative study. SETTING: Nine facilities in Chiba prefecture, Japan. PATIENTS: We analyzed 132 children and adolescents with GD. The subjects were divided according to the median age into a group of young children (group I, 4.1-12.4 years, n=66) and an adolescent group (group II, 12.5-15.9 years, n=66). MAIN OUTCOME MEASURES: Clinical manifestations, laboratory findings, incidence of adverse effects, and remission rates 5 years after initial therapy were assessed. RESULTS: The mean height SD score of group I (1.0) was higher than that of group II (0.3, p<0.001). The mean BMI SD score of group I (-0.7) was lower than that of group II (-0.3, p<0.05). The most common presentations were goiter, sweating, and hyperactivity in group I, whereas the most common presentations were goiter, sweating, and easy fatigability in group II. Hyperactivity was more frequent in group I (56.7%) than in group II (37.9%, p<0.05). Liver dysfunction appeared more often in group I (14.3%) than in group II (1.9%, p<0.05). There was no difference in the appearance of adverse effects between the two groups. The remission rate was slightly lower in group I (23.1%) than in group II (31.3%), but was not significant. CONCLUSIONS: Thyrotoxicosis had more influence on the growth and liver function in younger children. PMID- 24756043 TI - Evaluation of epicardial adipose tissue, carotid intima-media thickness and ventricular functions in obese children and adolescents. AB - BACKGROUND: Childhood obesity is a cardiovascular risk factor. OBJECTIVE: Epicardial adipose tissue (EAT) thickness, carotid intima-media thickness (IMT) and cardiac functions of obese children and their correlations were evaluated. SUBJECTS: Five hundred obese children and 150 age- and sex-matched healthy controls. METHODS: Anthropometric, laboratory data and echocardiographic measurements of IMT, EAT and cardiac functions were determined. RESULTS: Increased M-mode echocardiographic measurements, E/e' ratios, Tei index values and decreased E/A and e'/a' ratios (where E and A are early and late mitral/tricuspid diastolic velocities, respectively, and e' and a' are peak early diastolic and peak atrial systolic myocardial velocities, respectively), were determined in the obese group. Also, carotid artery IMT and EAT thickness were significantly higher in obese children. Carotid artery IMT, EAT thickness and left ventricular mass (LVM) were found to be strongly associated with Tei index values. CONCLUSION: Obesity is a major risk factor for cardiovascular diseases. In our study, we showed that obese children have early subclinical systolic and diastolic dysfunctions. Also, these cardiac impairments are correlated with the increase in IMT, EAT thickness and LVM. PMID- 24756044 TI - Muscle strength and body composition during the transition phase in patients treated with recombinant GH to final height. AB - We assessed body composition and muscle strength during the transition phase in 18 growth hormone (GH) deficient males treated with recombinant GH to final height and 18 controls. According to peak-stimulated GH and basal insulin-like growth factor-1 (IGF-1) during the transition phase, patients were subdivided into GH deficient (GHD-TP, n=9) and GH sufficient (GHS-TP, n=9) groups. Assessments included lean and fat body mass and bone mineral density (BMD), all measured by dual-energy X-ray absorptiometry, and dynamic knee muscle strength, assessed by isokinetic dynamometer. Total body and lumbar spine BMD and muscle strength were lower in GHD-TP patients when compared with GHS-TP and controls (all p<0.05), whereas lean and fat body mass were lower in both GHD-TP and GHS-TP patients when compared with controls (p<0.05). These findings suggest that administration of recombinant GH to final height is not sufficient to provide normal body composition and muscle strength in young male patients with GH deficiency. PMID- 24756045 TI - A rare case of hypoglycaemia due to insulinoma in an adolescent with acutely altered mental status. AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is an inherited neoplasia syndrome that generally presents with hypercalcaemia due to hyperparathyroidism. Insulin-producing tumours are less common components of the syndrome that emerge later during the course of the disease. We report here a case of an adolescent who presented with symptomatic hypoglycaemia as the first indication of MEN1. CASE: A 14-year-old boy, known to use illicit drugs, was brought to the hospital with altered mental status. He was hypoglycaemic and further investigations revealed two pancreatic insulinomas. Despite having no relevant family history, genetic evaluation showed a mutation consistent with MEN1. CONCLUSION: Insulinomas in adolescents are generally rare and even less common as a first presentation of MEN1. This diagnosis carries implications for potential future neoplasms, both benign and malignant. While intoxication is a more common case of altered mental status in adolescents, clinicians must maintain a high index of suspicion for organic disease. PMID- 24756046 TI - The natural course of Hashimoto's thyroiditis in children and adolescents. AB - OBJECTIVE: Hashimoto's thyroiditis (HT) is the most common cause of thyroid disease in children and adolescents, but little is known about the long-term follow-up of HT. The aim of this study was to analyze the clinical and laboratory characteristics and to observe the natural course of HT in children and adolescents. METHODS: We retrospectively reviewed 153 patients with HT diagnosed before 18 years of age. Subjects were grouped into euthyroid, subclinical hypothyroidism, overt hypothyroidism, and hyperthyroidism on the basis of the thyroid function test. Of the 153 subjects, 133 were followed up (range 6~181 months) at our clinic every 6 months for evaluation of goiter size, thyroid function, thyroid peroxidase antibodies (TPO Ab), and thyroglobulin antibodies (TG Ab) serum concentration. RESULTS: Thyroid function tests at the time of presentation revealed euthyroid in 72 patients (47.1%), subclinical hypothyroidism in 48 (31.4%), overt hypothyroidism in 22 (14.4%), and hyperthyroidism in 11 (7.2%). Serum TPO Ab and TG Ab significantly decreased in the subclinical hypothyroidism group with levothyroxine treatment. Also, there was a significant decrease in the mean serum TG Ab levels among the overt hypothyroid patients during the follow-up period, although TPO Ab levels were not significantly different when compared to their baseline TPO Ab levels. CONCLUSION: Most children with HT were euthryoid and remained euthyroid during follow-up. However, thyroid function should still be monitored periodically for early detection and treatment of overt hypothyroidism. Our data also showed that levothyroxine treatment may have beneficial effects on the thyroid antibody titers. PMID- 24756047 TI - Association between vitamin D level and cardiovascular risk in obese children and adolescents. AB - BACKGROUND: The aim of our study was to evaluate the associations between vitamin D deficiency, the atherosclerosis and metabolic syndrome. METHODS: Two hundred and forty-seven obese children and adolescents, 8-16 years of age (body mass index>95 p) were included in the study. Anthropometric measurements, blood pressure measurements, lipid profile, vitamin D level and carotid intima media thickness (c-IMT) were measured. MS was diagnosed according to IDF criteria. RESULTS: The prevalance of vitamin D deficieny in obese children and adolescent was 46.6%. Low levels of vitamin D were associated with increased carotis intima media thickness and metabolic syndrome (p=0.03, p=0.04, respectively). For clinical cardiovascular risk factors, mutivariable regression analyses showed that low vitamin D level was best predictor of c-IMT. CONCLUSIONS: In this study we showed an association between low vitamin D status and atherosclerosis independent of traditional risk factors in obese children and adolescents. PMID- 24756048 TI - Exhaled carbon monoxide in adolescents with diabetic cardiovascular autonomic neuropathy. AB - The aim of the study was to determine if cardiovascular autonomic neuropathy (CAN) is associated with changed concentration of exhaled carbon monoxide (eCO) in adolescents with type 1 diabetes (T1D). A total of 46 T1D patients and 25 healthy controls (15-19 years) were enrolled. The parameters eCO and carboxyhemoglobin (HbCO) were established using a MICRO-4 Smokerlyser. CAN was examined by standard cardiovascular tests. Adolescents with T1D did not significantly differ in eCO compared to healthy subjects. eCO and HbCO were significantly lower in CAN-positive subjects (n=19) (1.36 +/- 1.65 ppm vs. 3.09 +/- 2.31, p=0.01 and 0.58 +/- 0.49% vs. 1.04 +/- 0.44, p<0.01, respectively) compared to CAN-negative subjects (n=27), whereas no significant difference was found in other measured parameters. By multivariate logistic regression, eCO and HbCO were associated with higher risk of CAN (OR=1.824, p<0.05 and OR=10.989, p<0.01). Our results indicate that eCO is decreased in CAN-positive diabetic subjects. Further studies are necessary to investigate the possible role of eCO as a marker for CAN. PMID- 24756049 TI - Influence of hormonal parameters, bone mineral density and bone turnover on fracture risk in healthy male adolescents: a case control study. AB - OBJECTIVE: The aim of this study was to assess possible associations between potential risk factors for fractures and their occurrence in otherwise healthy Greek male adolescents. SUBJECTS: A total of 63 male adolescents participated in the study, 21 males with a history of at least one fracture and 42 healthy male controls. METHODS: Each participant was assessed for physical and pubertal status, hormonal profile, bone mineral density, bone turnover indices, and dietary habits. RESULTS: The lower bone mineral density-z scores and increasing testosterone and serum collagen type 1 cross-linked C-telopeptide levels were related to fracture risk, whereas increased insulin-like growth factor-1, soluble receptor activator of nuclear factor kappa-B (factor-kappaB) ligand, and soluble receptor activator of nuclear factors-kappaB ligand/osteoprotegerin levels were protective for fractures. CONCLUSIONS: The findings indicate a potential 'added value' of hormonal parameters and bone markers to bone mineral density for evaluating fracture risk in healthy male adolescents. PMID- 24756050 TI - Benign vaginal bleeding in 24 prepubertal patients: clinical, biochemical and imaging features. AB - OBJECTIVE: Premature menarche is an uncommon, benign condition characterized by isolated or recurrent menstrual bleeding in the absence of secondary sexual characteristics. METHODS: We performed an observational retrospective study to further characterize the clinical, biochemical and imaging features of benign prepubertal vaginal bleeding (BPVB). Out of 1037 girls evaluated for precocious puberty over a 5-year period, 24 girls with BPVB were identified based on >=1 episodes of vaginal bleeding, Tanner I or non-progressive Tanner II breast development, and lack of physical findings suggesting genital infection, trauma or foreign body. RESULTS: Age at presentation ranged from 3 years 2 months to 9 years 11 months. Ten patients (42%) had one episode of vaginal bleeding, six (25%) had two episodes and eight patients (33%) had three or more. First bleeding episode lasted 3 days (range; 1-30 days). Six girls had intermittent spotting for up to 1 year. No breast development was noted in 19 (79%) patients. Minimal breast was present in five girls; early pubic hair was present in 2. LH and FSH were prepubertal; estradiol was >20 pg/mL in two girls. Pelvic ultrasound, performed in 11 patients, showed pre-pubertal uterus and ovaries without adnexal masses. CONCLUSION: Isolated prepubertal vaginal bleeding is typically benign and self-limited, in the absence of sexual precocity signs or other vaginal pathology. Laboratory and imaging studies are generally unrevealing. PMID- 24756051 TI - An association of hypochondroplasia and immune deficiency. AB - A 4-year-old boy with hypochondroplasia was admitted to our clinic with complaints of bronchopneumonia. He also had immune deficiency characterized by low CD3, CD4 T-lymphocyte subsets and a low level of serum immunoglobulin A (IgA). The diagnosis of hypochondroplasia was made on clinical, radiological, and laboratory findings by the pediatric endocrinology department. The focus of our study is hypochondroplasia associated with immune deficiency which was unpublished in English medical literature previously. PMID- 24756052 TI - Outcome analysis of aromatase inhibitor therapy to increase adult height in males with predicted short adult stature and/or rapid pubertal progress: a retrospective chart review. AB - BACKGROUND: Aromatase inhibitors (AIs) have been used off-label to increase adult height in short adolescent males. Studies have shown that AIs increase the predicted adult height (PAH) while delaying bone age (BA) maturation. We sought to determine whether AI therapy increases PAH in boys with short stature or rapid pubertal progression, and to evaluate any untoward effects. METHODS: The charts of 27 boys with BA >= 13 and short stature [height >= 2 standard deviation (SD) below the mean or >= 2 SD below mid-parental target height (MPTH)] or rapid pubertal progress, treated with anastrozole were reviewed. Outcome measures included anthropomorphic, hormonal, and metabolic data. RESULTS: The AI therapy averaged 21 months (range 14-30 months) for all, with Rx group 1 receiving <18 months therapy (n=7) and Rx group 2 receiving 18-30 months therapy (n=20). Post therapy, in Rx group 1 and all subjects, there was no significant change in the PAH, height SDS, or BA/chronological age (CA). In Rx group 2, there was a small, nonsignificant increase in PAH, no change in height SDS, and a small decrease in BA/CA. Post-therapy PAH was different from MPTH in all and in both Rx groups 1 and 2, p<0.02. Eight of them achieved near-final height, averaging 6.73 +/- 1.40 cm less than MPTH and 1.91 +/- 0.86 cm less than the pre-therapy PAH. Post therapy, the initially decreased estradiol did not persist but mildly increased testosterone and decreased high-density lipoprotein were noted, as was an increase in hematocrit, and decrease in growth velocity. CONCLUSIONS: We suggest that although bone age progression may be slightly delayed with longer duration of therapy, an overall short-term AI therapy does not lead to a final height that is greater than the predicted pre-therapy height. PMID- 24756053 TI - Persistent congenital hyperinsulinism in two patients with Beckwith-Wiedemann syndrome due to mosaic uniparental disomy 11p. AB - Congenital hyperinsulinism (CHI) is a rare metabolic disease characterized by inappropriate insulin secretion in the presence of hypoglycemia. We describe the clinical presentation and management of congenital hyperinsulinism and persistent hypoglycemia in two infants. Both patients had an initial clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) but normal methylation analysis for LIT1 and H19 status. Both patients were eventually found to have mosaic uniparental disomy 11p diagnosed by single nucleotide polymorphism (SNP) array in DNA isolated from lymphoblasts and fibroblasts, respectively. We report that patients with mosaic BWS are at increased risk for both transient and refractory hypoglycemia that may need aggressive management with diazoxide, octreotide, high glucose infusion rates, and a frequent feeding regime. Our patient experience supports the case for pursuing further testing in patients with features of BWS with normal methylation studies, karyotype, and SNP arrays on blood. The next logical step is SNP array on skin biopsy to rule out mosaicism. PMID- 24756054 TI - Identification of a combined missense/splice-site mutation in FAH causing tyrosinemia type 1. AB - Tyrosinemia type I (HT1) is a genetic metabolic disorder characterized by progressive liver disease, kidney disease, and rickets. The disease is caused by mutations in the FAH gene that results in deficiency of fumarylacetoacetase, an enzyme that is involved in the tyrosine degradation pathway. We investigated the clinical characteristics and molecular cause of HT1 in an affected family from Iran. Molecular analysis identified a homozygous combined missense (c.G1009G>A, p.Gly337Ser) and aberrant splicing mutation removing the first 50 nucleotides of exon 12. This mutation was only described in HT1 patients from Scandinavian countries and this is the first report from another population. Although failure to thrive is one of the typical features in HT1, our proband, similar to the reported Scandinavian patients, had normal growth and development. The results of this study have applications in patient screening and genetic counselling. PMID- 24756056 TI - Importance of ABC transporters in different tissues. PMID- 24756055 TI - Frequency of CYP450 enzyme gene polymorphisms in the Greek population: review of the literature, original findings and clinical significance. AB - The cytochrome P450 (CYP450) enzyme family is involved in the oxidative metabolism of many therapeutic drugs and various endogenous substrates. These enzymes are highly polymorphic. Prevalence of CYP450 enzyme gene polymorphisms vary among different populations and substantial inter- and intra-ethnic variability in frequency of CYP450 enzyme gene polymorphisms has been reported. This paper provides an overview and investigation of CYP450 genotypic and phenotypic reports published in the Greek population. PMID- 24756057 TI - Anti-inflammatory and antinociceptive activities of the aqueous leaf extract of Phyllanthus amarus Schum (Euphorbiaceae) in some laboratory animals. AB - BACKGROUND: Phyllanthus amarus has a history of use in Ayurvedic medicine for over 2000 years as well as a wide variety of traditional applications and has gained popularity in many continents as a herbal remedy; hence, it is being assessed for its safety potential and anti-inflammatory and analgesic properties in some laboratory animals. METHODS: Standard phytochemical methods were used to test for the presence of phytoactive compounds in the plant. Acute toxicity testing was carried out in mice to determine safe doses for the extract. The anti inflammatory activity of the leaf extract of this plant was assessed using carrageenan-induced and histamine-induced paw edema. The analgesic effect was determined using the acetic acid writhing method as well as formalin test. RESULTS: The extract at 100 and 200 mg/kg body weight reduced significantly, the formation of edema induced by carrageenan and histamine. In the acetic acid induced writhing model, the extract showed a good analgesic effect characterized by reduction in the number of writhes when compared to the control. The extract caused dose-dependent decrease of licking time in rats injected with 2.5% formalin, signifying its analgesic effect. These results were also comparable to those of ibuprofen, the reference drug used in this study. CONCLUSIONS: The plant extract reduced significantly the formation of edema induced by carrageenan and histamine as well as reducing the number of writhes in acetic acid-induced writhing models and dose-dependent decrease of licking time in rats injected with 2.5% formalin. The results have validated the basis for the traditional use of P. amarus as a medicinal plant. PMID- 24756058 TI - Neuroprotective effect of N-acetyl cysteine against streptozotocin-induced memory dysfunction and oxidative damage in rats. AB - BACKGROUND: Growing evidences indicate that endogenous oxidants and antioxidant defense interact in a vicious cycle, which plays a critical role in the pathogenesis of cognitive dysfunction. In this study, we examined the effect of N acetyl cysteine (NAC) against the intracerebroventricular infusion of streptozotocin (ICV STZ)-induced cognitive impairment and mitochondrial oxidative damage in rats. METHODS: Male adult Wistar rats were injected with STZ (3 mg/kg) bilaterally through ICV. NAC (50 and 100 mg/kg) was administered for 3 weeks post surgery. The rats were sacrificed on the 21st day following the last behavioral test, and cytoplasmic fractions of the hippocampus and cortex were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes, inflammatory mediators and caspase-3 activity. RESULTS: ICV STZ resulted in poor retention of memory in Morris water maze. It also increased the mito-oxidative damage and tumor necrosis factor-alpha, interleukin 6 and caspase-3 levels in the hippocampus and cortex compared to sham animals. NAC significantly improved memory retention and attenuated oxidative damage parameters, inflammatory markers in STZ-treated rats. CONCLUSIONS: The results of the present study strongly indicate the effectiveness of NAC in preventing cognitive impairment as well as mito-oxidative stress and may be considered as a potential agent in the management of cognitive-related disorders. PMID- 24756059 TI - Gastroprotective activity of essential oils from turmeric and ginger. AB - BACKGROUND: Turmeric (Curcuma longa) and ginger (Zingiber officianale) are widely used in Asian countries as traditional medicine and food ingredients. In the present study, we have evaluated the gastroprotective activity of turmeric essential oil (TEO) and ginger essential oil (GEO) in rats. METHODS: Turmeric and ginger were evaluated for their antiulcer activity against ethanol-induced ulcers in male Wistar rats at different doses: 100, 500 and 1000 mg/kg body weight. Ethanol was used to induce gastric ulcer in Wistar rats. Parameters such as ulcer index, histopathology and levels of antioxidant enzymes such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase and glutathione (GSH) levels were measured to assess the degree of protection produced by the essential oils. RESULTS: TEO and GEO inhibited ulcer by 84.7% and 85.1%, respectively, as seen from the ulcer index. Reduced antioxidant enzymes such as GPx, SOD, catalase and GSH produced by alcohol administration were significantly (p<0.001) increased by simultaneous administration of TEO and GEO. Histopathological examination showed that ethanol-induced lesions such as necrosis, erosion and hemorrhage of the stomach wall were significantly reduced after oral administration of essential oils. CONCLUSIONS: RESULTS suggest that TEO and GEO could reduce the gastric ulcer in rat stomach as seen from the ulcer index and histopathology of the stomach. Moreover, oxidative stress produced by ethanol was found to be significantly reduced by TEO and GEO. PMID- 24756060 TI - Lactase persistence genotyping: rapid detection of seven sequence variants in a single tube with melting curve analyses. AB - BACKGROUND: Lactase persistence is an inherited autosomal dominant trait that confers the ability to digest lactose after weaning. Lactose persistence is caused by single nucleotide variants in a regulatory element for the lactase gene (LCT). In Europeans, lactase persistence is associated with the nucleotide variant LCT -13910C>T. Ethnic groups from Africa and the Arabian Peninsula have other lactase persistence variants in close proximity to the -13910C>T variant. Current hybridisation probe analysis methods have been limited by the inability to detect all the known nucleotide variants. The aim of this study was to devise a method based on hybridisation probes and melting curve analysis for rapidly detecting LCT variants. METHODS: We designed hybridisation probes for producing melting curve profiles that could identify seven LCT nucleotide variants: 13907C>G, -13910C>T, -13913T>C, -13914G>A, -13915T>G, -14009T>G, and -14010G>C. To validate the assay, we generated plasmid standards of all the alleles and mixed them to create artificial heterozygote samples. RESULTS: All genotypes could be detected in a single tube assay. Rare genotypes were confirmed in a second assay with probes that had different complementary sequences. CONCLUSIONS: This assay can be used for rapidly genotyping lactase persistence in multi-ethnic populations. PMID- 24756061 TI - How galectin-3 changes acute heart failure decision making in the emergency department. AB - When considering the appropriate disposition plan in a patient presenting to the emergency department (ED) with acute heart failure (HF), the range of options includes discharge home to intensive care unit (ICU) admission. Unfortunately, there are few objective measures to insure optimal choices, and the currently available science is scant at best. The consequences of a lack of a standardized approach are nowhere more evident than as demonstrated by the worldwide 90-day heart failure rehospitalization rate that exceeds 25%. New strategies to address this important gap in clinical care are sorely needed. The measurement of galectin-3 may represent a new alternative to the historical standard of gestalt based clinical disposition decisions. Elevated galectin-3 can identify patients at very high risk for short-term adverse outcomes, while low levels identify a population with essentially no 90-day revisits. This prospective objective measure of illness severity may aid in clinical decision making and thus represent a future where rehospitalization after HF is an unusual event. PMID- 24756062 TI - Novel biomarkers in acute heart failure: MR-pro-adrenomedullin. AB - First isolated from human pheochromocytoma cells, adrenomedullin (ADM) is a peptide hormone with natriuretic, vasodilatory, and hypotensive effects mediated by cyclic adenosine monophosphate (cAMP), nitric oxide, and renal prostaglandin systems. ADM expression occurs in many tissues and organ systems, including cardiovascular, renal, pulmonary, cerebrovascular, gastrointestinal, and endocrine tissues where it acts as a circulating hormone and a local autocrine and paracrine hormone. ADM plasma concentrations are increased in hypertension, chronic renal disease, and heart failure. As ADM is unstable in vitro, it is necessary to measure its mid-regional pro-hormone fragment, the levels of which correspond to ADM concentration (MR-proADM). The prognostic potential of MR proADM was recently demonstrated in the Biomarkers in Acute Heart Failure (BACH) trial. In this trial of 568 acute heart failure patients, MR-proADM was superior to both brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality within 14 days. MR-proADM also provided significant additive incremental predictive value for 90-day mortality when added to BNP and NT-proBNP. PMID- 24756063 TI - Accelerated degeneration of a bovine pericardial bioprosthetic aortic valve in children and young adults. AB - BACKGROUND: Experience with aortic valve replacement (AVR) with current generation pericardial bioprostheses in young patients is limited. The death of a child with accelerated bioprosthetic aortic stenosis prompted enhanced surveillance of all such patients at our institution. METHODS AND RESULTS: We reviewed records of 27 patients who had undergone AVR (median follow-up, 13.7 months) with a bovine pericardial bioprosthesis at <=30 years of age. In the Mitroflow LXA valve group (n=15), freedom from valve failure was 100% at 1 year, 53% (95% confidence interval, 12-82) at 2 years, and 18% (95% confidence interval, 1-53) at 3 years. No Magna/Magna Ease valves (n=12) failed by 3 years. Among valve failure patients, median age at AVR was 12 years (range, 10-21 years). Life-threatening prosthetic aortic stenosis was detected at a median of 6 months after prior echocardiograms showing mild or less gradients. Patients with Mitroflow LXA compared with Magna/Magna Ease valves were smaller (median body surface area, 1.42 versus 1.93 m(2); P=0.002) and younger (median age, 13.0 versus 20.9 years; P=0.02) at AVR. Pathology demonstrated diffuse intrinsic leaflet calcification, not associated with inflammation or infection, and virtually immobile leaflets in closed position. CONCLUSIONS: Young patients undergoing AVR with Mitroflow LXA pericardial valves are at high risk for rapid progression from mild or less to severe aortic stenosis over months, highlighting their need for heightened echocardiographic surveillance and suggesting that this aortic bioprosthesis should not be implanted in the young. Current data are insufficient to assess the safety of AVR with other pericardial bioprostheses in children and the youngest adults. PMID- 24756065 TI - The pace of transradial procedural learning. PMID- 24756064 TI - The learning curve for transradial percutaneous coronary intervention among operators in the United States: a study from the National Cardiovascular Data Registry. AB - BACKGROUND: Adoption of transradial percutaneous coronary intervention (TRI) in the United States is low and may be related to challenges learning the technique. We examined the relationships between operator TRI volume and procedural metrics and outcomes. METHODS AND RESULTS: We used CathPCI Registry data from July 2009 to December 2012 to identify new radial operators, defined by an exclusively femoral percutaneous coronary intervention approach for 6 months after their first percutaneous coronary intervention in the database and >=15 total TRIs thereafter. Primary outcomes of fluoroscopy time, contrast volume, and procedure success were chosen as markers of technical proficiency. Secondary outcomes included in-hospital mortality, bleeding, and vascular complications. Adjusted outcomes were analyzed by using operator TRI experience as a continuous variable with generalized linear mixed models. Among 54 561 TRI procedures performed at 704 sites, 942 operators performed 1 to 10 procedures, 942 operators performed 11 to 50 procedures, 375 operators performed 51 to 100 procedures, and 148 operators performed 101 to 200 procedures. As radial caseload increased, more TRIs were performed in women, in patients presenting with ST-segment elevation myocardial infarction, and for emergency indications. Decreased fluoroscopy time and contrast use were nonlinearly associated with greater operator TRI experience, with faster reductions observed for newer (<30-50 cases) compared with more experienced (>30-50 cases) operators. Procedure success was high, whereas mortality, bleeding, and vascular complications remained low across TRI volumes. CONCLUSIONS: As operator TRI volume increases, higher-risk patients are chosen for TRI. Despite this, operator proficiency improves with greater TRI experience, and safety is maintained. The threshold to overcome the learning curve appears to be approximately 30 to 50 cases. PMID- 24756066 TI - Downregulation of GRHL2 inhibits the proliferation of colorectal cancer cells by targeting ZEB1. AB - Previous reports have associated GRHL2 with tumor progression. However, the biological role of GRHL2 in human colorectal cancer (CRC) has not been explored. We examined the expression of GRHL2 in 75 CRC samples, as well as the paired non tumor tissues, by immunohistochemistry, qRT-PCR, and western blot analysis. The association between GRHL2 expression and various clinicopathological parameters including Ki-67, a marker of proliferative activity, was also evaluated. We performed lentivirus-mediated shRNA transfection to knock down GRHL2 gene expression in HT29 and HCT116 CRC cells. Cell proliferation was examined by the CCK-8 (Cell Counting Kit-8) assay, colony formation, and cell cycle assay in vitro. Tumorigenesis in vivo was assessed using a mouse xenograft model. Moreover, we transiently silenced ZEB1 expression in GRHL2-knockdown CRC cells using specific shRNA, and then examined the effects on GRHL2 and E-cadherin expression, as well as cell proliferation. Herein, we demonstrated that enhanced GRHL2 expression was detected in CRC, and correlated with higher levels of Ki-67 staining, larger tumor size, and advanced clinical stage. Knocking down GRHL2 in HT29 and HCT116 CRC cells significantly inhibited cell proliferation by decreasing the number of cells in S phase and increasing that in the G 0/G 1 phaseof the cell cycle. This resulted in inhibition of tumorigenesis in vivo, as well as increased expression of ZEB1. Furthermore, transient ZEB1 knockdown dramatically enhanced cell proliferation and increased GRHL2 and E-cadherin expression. Collectively, our study has identified ZEB1 as a target of GRHL2 and suggested a reciprocal GRHL2-ZEB1 repressive relationship, providing a novel mechanism through which proliferation may be modulated in CRC cells. PMID- 24756067 TI - Validation of a dumbbell body sway test in olympic air pistol shooting. AB - We present and validate a test able to provide reliable body sway measurements in air pistol shooting, without the use of a gun. 46 senior male pistol shooters who participated in Spanish air pistol championships participated in the study. Body sway data of two static bipodal balance tests have been compared: during the first test, shooting was simulated by use of a dumbbell, while during the second test the shooters own pistol was used. Both tests were performed the day previous to the competition, during the official training time and at the training stands to simulate competition conditions. The participants performance was determined as the total score of 60 shots at competition. Apart from the commonly used variables that refer to movements of the shooters centre of pressure (COP), such as COP displacements on the X and Y axes, maximum and average COP velocities and total COP area, the present analysis also included variables that provide information regarding the axes of the COP ellipse (length and angle in respect to X). A strong statistically significant correlation between the two tests was found (with an interclass correlation varying between 0.59 and 0.92). A statistically significant inverse linear correlation was also found between performance and COP movements. The study concludes that dumbbell tests are perfectly valid for measuring body sway by simulating pistol shooting. PMID- 24756068 TI - Tackling climate change: SMART objectives for health workers. PMID- 24756069 TI - Dehydrogenation of a tertiary amine-borane by a rhenium complex. AB - Photolysis of CpRe(CO)3 in the presence of H3BNEt3 yields the trans-CpRe(CO)2(H)2 complex. This preliminary finding presents a rare example of transition metal mediated dehydrogenation of a tertiary amine-borane and suggests that the abstracted hydrogens may be stored in the form of metal hydride complexes. PMID- 24756070 TI - Investigating microRNA-target interaction-supported tissues in human cancer tissues based on miRNA and target gene expression profiling. AB - Recent studies have revealed that a small non-coding RNA, microRNA (miRNA) down regulates its mRNA targets. This effect is regarded as an important role in various biological processes. Many studies have been devoted to predicting miRNA target interactions. These studies indicate that the interactions may only be functional in some specific tissues, which depend on the characteristics of an miRNA. No systematic methods have been established in the literature to investigate the correlation between miRNA-target interactions and tissue specificity through microarray data. In this study, we propose a method to investigate miRNA-target interaction-supported tissues, which is based on experimentally validated miRNA-target interactions. The tissue specificity results by our method are in accordance with the experimental results in the literature. AVAILABILITY AND IMPLEMENTATION: Our analysis results are available at http://tsmti.mbc.nctu.edu.tw/ and http://www.stat.nctu.edu.tw/hwang/tsmti.html. PMID- 24756072 TI - A galactic view of nature's decontamination squad. PMID- 24756071 TI - Psychometric properties of the Hebrew short version of the Zimbardo Time Perspective Inventory. AB - The purpose of this study was to develop a short Hebrew version of the Zimbardo Time Perspective Inventory that can be easily administered by health professionals in research, therapy, and counseling. First, the empirical links of time perspective (TP) to subjective well-being and health protective and health risk behaviors are reviewed. Then, a brief account of the instrument's previous modifications is provided. Results of confirmatory factor analysis (N = 572) verified the five-factor structure of the short version and yielded acceptable internal consistency reliability for each factor. The correlation coefficients between the five subscales of the short (20 items) and the original (56 items) instruments were all above .79, indicating the suitability of the short version for assessing the five TP factors. Support for the discriminant and concurrent validity was also achieved, largely in agreement with previous findings. Finally, limitations and future directions are addressed, and potential applications in therapy and counseling are offered. PMID- 24756073 TI - High throughput immunosenor based on multi-label strategy and a novel array electrode. AB - Accurate prediction of a particular cancer can be achieved by measuring multiplex biomarkers. Traditional methods for multi-biomarkers detection are either multi spots assay with chip or multi-label assay with one detection spot. However, the detection throughput of these two approaches is limited by the substrate area and the numbers of available label respectively. To solve this problem, in the present study, an immunoassay was firstly prepared by combining multi-label strategy and multi-spot assay with a novel array electrode for simultaneous detection of six biomarkers for hepatocellular carcinoma (HCC). The detection throughput of the proposed method was doubled in comparison with traditional multi-spots assay (one target protein was detected on each analytic spot), which could greatly enhance the sensitivity and specificity of HCC diagnosis. This detection model may serve as the starting point for high throughput of multianalyte assay. PMID- 24756074 TI - Rat experimental model of myocardial ischemia/reperfusion injury: an ethical approach to set up the analgesic management of acute post-surgical pain. AB - RATIONALE: During the past 30 years, myocardial ischemia/reperfusion injury in rodents became one of the most commonly used model in cardiovascular research. Appropriate pain-prevention appears critical since it may influence the outcome and the results obtained with this model. However, there are no proper guidelines for pain management in rats undergoing thoracic surgery. Accordingly, we evaluated three analgesic regimens in cardiac ischemia/reperfusion injury. This study was strongly focused on 3R's ethic principles, in particular the principle of Reduction. METHODS: Rats undergoing surgery were treated with pre-surgical tramadol (45 mg/kg intra-peritoneal), or carprofen (5 mg/kg sub-cutaneous), or with pre-surgical administration of carprofen followed by 2 post-surgery tramadol injections (multi-modal group). We assessed behavioral signs of pain and made a subjective evaluation of stress and suffering one and two hours after surgery. RESULTS: Multi-modal treatment significantly reduced the number of signs of pain compared to carprofen alone at both the first hour (61+/-42 vs 123+/-47; p<0.05) and the second hour (43+/-21 vs 74+/-24; p<0.05) post-surgery. Tramadol alone appeared as effective as multi-modal treatment during the first hour, but signs of pain significantly increased one hour later (from 66+/-72 to 151+/-86, p<0.05). Carprofen alone was more effective at the second hour post-surgery when signs of pain reduced to 74+/-24 from 113+/-40 in the first hour (p<0.05). Stress behaviors during the second hour were observed in only 20% of rats in the multimodal group compared to 75% and 86% in the carprofen and tramadol groups, respectively (p<0.05). CONCLUSIONS: Multi-modal treatment with carprofen and tramadol was more effective in preventing pain during the second hour after surgery compared with both tramadol or carprofen. Our results suggest that the combination of carprofen and tramadol represent the best therapy to prevent animal pain after myocardial ischemia/reperfusion. We obtained our results accordingly with the ethical principle of Reduction. PMID- 24756075 TI - Endothelial glycocalyx on brain endothelial cells is lost in experimental cerebral malaria. AB - We hypothesized that the glycocalyx, which is important for endothelial integrity, is lost in severe malaria. C57BL/6 mice were infected with Plasmodium berghei ANKA, resulting in cerebral malaria, or P. chabaudi AS, resulting in uncomplicated malaria. We visualized the glycocalyx with transmission electron microscopy and measured circulating glycosaminoglycans by dot blot and ELISA. The glycocalyx was degraded in brain vasculature in cerebral and to a lesser degree uncomplicated malaria. It was affected on both intact and apoptotic endothelial cells. Circulating glycosaminoglycan levels suggested that glycocalyx disruption preceded cerebral manifestations. The contribution of this loss to pathogenesis should be studied further. PMID- 24756076 TI - Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits. AB - Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration. PMID- 24756077 TI - Snapshot MR technique to measure OEF using rapid frequency mapping. AB - Magnetic resonance (MR)-based oxygen extraction fraction (OEF) measurement techniques that use blood oxygen level-dependent (BOLD)-based approaches require the measurement of the R2' decay rate and deoxygenated blood volume to derive the local oxygen saturation in vivo. We describe here a novel approach to measure OEF using rapid local frequency mapping. By modeling the MR decay process in the static dephasing regime as two separate dissipative and oscillatory effects, we calculate the OEF from local frequencies measured across the brain by assuming that the biophysical mechanisms causing OEF-related frequency changes can be determined from the oscillatory effects. The Parameter Assessment by Retrieval from Signal Encoding (PARSE) technique was used to acquire the local frequency change maps. The PARSE images were taken on 11 normal volunteers, and 1 patient exhibiting hemodynamic stress. The mean MR-OEF in 11 normal subjects was 36.66+/ 7.82%, in agreement with positron emission tomography (PET) literature. In regions of hemodynamic stress induced by vascular steal, OEF exhibits the predicted focal increases. These preliminary results show that it is possible to measure OEF using a rapid frequency mapping technique. Such a technique has numerous advantages including speed of acquisition, is noninvasive, and has sufficient spatial and temporal resolution. PMID- 24756078 TI - Developmental programming by high fructose decreases phosphorylation efficiency in aging offspring brain mitochondria, correlating with enhanced UCP5 expression. AB - Fructose has recently been observed to affect brain metabolism and cognitive function in adults. Yet, possible late-onset effects by gestational fructose exposure have not been examined. We evaluated mitochondrial function in the brain of aging (15 months) male offspring of Fischer F344 rat dams fed a high-fructose diet (50% energy from fructose) during gestation and lactation. Maternal fructose exposure caused a significantly lower body weight of the offspring throughout life after weaning, while birth weight, litter size, and body fat percentage were unaffected. Isolated brain mitochondria displayed a significantly increased state 3 respiration of 8%, with the substrate combinations malate/pyruvate, malate/pyruvate/succinate, and malate/pyruvate/succinate/rotenone, as well as a significant decrease in the P/O2 ratio, compared with the control. Uncoupling protein 5 (UCP5) protein levels increased in the fructose group compared with the control (P=0.03) and both UCP5 mRNA and protein levels were inversely correlated with the P/O2 ratio (P=0.008 and 0.03, respectively), suggesting that UCP5 may have a role in the observed decreased phosphorylation efficiency. In conclusion, maternal high-fructose diet during gestation and lactation has long-term effects (fetal programming) on brain mitochondrial function in aging rats, which appears to be linked to an increase in UCP5 protein levels. PMID- 24756079 TI - Cortical microinfarcts on 7T MRI in patients with spontaneous intracerebral hemorrhage. AB - In patients with spontaneous intracerebral hemorrhage (ICH) coexisting abnormalities on brain imaging can provide clues on the etiology of the underlying small vessel disease. We examined cortical cerebral microinfarcts as a novel marker of coexistent vascular damage in ICH. Twelve patients with spontaneous ICH and 15 controls underwent 7Tesla magnetic resonance imaging (MRI). Microinfarcts were present in 9 of 12 patients with spontaneous ICH, and in 5 of 15 controls. This explorative study shows, for the first time, that microinfarcts appear to be a very common vascular comorbidity in spontaneous ICH. Future larger studies should further assess the etiological significance of these lesions. PMID- 24756080 TI - Prdm9 incompatibility controls oligospermia and delayed fertility but no selfish transmission in mouse intersubspecific hybrids. AB - PR-domain 9 (Prdm9) is the first hybrid sterility gene identified in mammals. The incompatibility between Prdm9 from Mus musculus domesticus (Mmd; the B6 strain) and the Hstx2 region of chromosome (Chr) X from M. m. musculus (Mmm; the PWD strain) participates in the complete meiotic arrest of mouse intersubspecific (PWD*B6)F1 hybrid males. Other studies suggest that also semisterile intersubspecific hybrids are relevant for mouse speciation, but the genes responsible remain unknown. To investigate the causes of this semisterility, we analyzed the role of Prdm9 and Chr X in hybrids resulting from the crosses of PWK, another Mmm-derived inbred strain. We demonstrate that Prdm9 and Chr X control the partial meiotic arrest and reduced sperm count in (PWK*B6)F1 males. Asynapsis of heterosubspecific chromosomes and semisterility were partially suppressed by removal of the B6 allele of Prdm9. Polymorphisms between PWK and PWD on Chr X but not in the Prdm9 region were responsible for the modification of the outcome of Prdm9-Chr X F1 hybrid incompatibility. Furthermore, (PWK*B6)F1 hybrid males displayed delayed fertility dependent on the Prdm9 incompatibility. While the Drosophila hybrid sterility gene Overdrive causes both delayed fertility and increased transmission of its own chromosome to the offspring, the segregation of Chr X and the Prdm9 region from the mouse (PWK*B6)F1 males was normal. Our results indicate extended functional consequences of Prdm9-Chr X intersubspecific incompatibility on the fertility of hybrids and should influence the design of fertility analyses in hybrid zones and of laboratory crosses between Mmm and Mmd strains. PMID- 24756081 TI - Interactions of ionic liquids with hydration layer of poly(N isopropylacrylamide): comprehensive analysis of biophysical techniques results. AB - Here, we report comprehensive analysis of biophysical technique results for the influence of ionic liquids (ILs) containing the same cation, 1-butyl-3 methylimidazolium (Bmim(+)), and commonly used anions such as SCN(-), BF4(-), I( ), Br(-), Cl(-), CH3COO(-) and HSO4(-) on the phase transition temperature of poly(N-isopropylacrylamide) (PNIPAM) aqueous solution. Further, the effect of these ILs on bovine serum albumin (BSA) has also been studied. The modulations in UV-visible (UV-vis) absorption spectra, fluorescence intensity spectra, viscosity (eta), hydrodynamic diameter (dH), Fourier transform infrared (FTIR) spectra and scanning electron microscopy (SEM) micrographs clearly reflect the change in the hydration state of PNIPAM in the presence of ILs. The observed single phase transition of PNIPAM aqueous solution at higher concentration of IL is the result of weak ion-ion pair interactions in IL. PMID- 24756082 TI - Refinement of an instrument for assessing incontinent-associated dermatitis and its severity for use with darker-toned skin. AB - PURPOSE: The purpose of this study was to refine an instrument for assessing incontinence-associated dermatitis (IAD) and its severity for use on lighter- and darker-toned skin, the Incontinence-Associated Dermatitis and its Severity Instrument-D (IADS-D), and to test its validity and reliability among WOC nurses. METHODS: Revisions to the existing instrument included examples of colors of normal and IAD-damaged skin that would be observed on light-, medium-, and dark toned skin using pixels from patient photographs, additional photographs of IAD manifestations on different skin tones, and training materials. Four certified WOC nurse consultants and 2 WOC nurse clinical experts assessed the face and content validity of the IADS-D instrument. The IADS-D instrument was tested for criterion validity and interrater reliability using photo cases by attendees at the Wound, Ostomy, and Continence Nurses Society 2012 conference. RESULTS: The IADS-D instrument had good face and content validity. The overall average intraclass correlation coefficient (ICC) of IADS-D scores for all photo cases of testers (n = 266, 95% female, age 53.0 +/- 7.9 years, mean +/- SD) and those of investigators, experts, and consultants serving as the criterion was 0.90. The overall ICC for interrater reliability between all nurse testers was 0.99 and the ICC for tester skin tone was 0.99. CONCLUSION: The IADS-D instrument has excellent validity and interrater reliability among WOC nurses. Its refinement for use with lighter- and darker-toned skin addresses the lack of a much-needed instrument in nursing practice and research. Results support continued development and evaluation of the instrument's use in clinical and research settings. PMID- 24756085 TI - NICE's role in further developing the Quality and Outcomes Framework is in question. PMID- 24756084 TI - Overall and allele-specific expression of the SMC1A gene in female Cornelia de Lange syndrome patients and healthy controls. AB - Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder characterized by facial dysmorphisms, limb anomalies, and growth and cognitive deficits. Mutations in genes encoding subunits (SMC1A, SMC3, RAD21) or regulators (NIPBL, HDAC8) of the cohesin complex account for approximately 65% of clinically diagnosed CdLS cases. The SMC1A gene (Xp11.22), responsible for 5% of CdLS cases, partially escapes X chromosome inactivation in humans and the allele on the inactive X chromosome is variably expressed. In this study, we evaluated overall and allele specific SMC1A expression. Real-time PCR analysis conducted on 17 controls showed that SMC1A expression in females is 50% higher than in males. Immunoblotting experiments confirmed a 44% higher protein level in healthy females than in males, and showed no significant differences in SMC1A protein levels between controls and patients. Pyrosequencing was used to assess the reciprocal level of allelic expression in six female carriers of different SMC1A mutations and 15 controls who were heterozygous at a polymorphic transcribed SMC1A locus. The two alleles were expressed at a 1:1 ratio in the control group and at a 2:1 ratio in favor of the wild type allele in the test group. Since a dominant negative effect is considered the pathogenic mechanism in SMC1A-defective female patients, the level of allelic preferential expression might be one of the factors contributing to the wide phenotypic variability observed in these patients. An extension of this study to a larger cohort containing mild to borderline cases could enhance our understanding of the clinical spectrum of SMC1A-linked CdLS. PMID- 24756086 TI - Low back pain in the paediatric athlete. AB - BACKGROUND: This study was designed to provide an overview of the epidemiology and clinical findings in children presenting to a sports injury clinic with 'low back pain' (LBP). OBJECTIVES: The aim of this study was to determine the pattern of presentation, management and outcome of children and adolescents presenting with back pain to a specialist paediatric sports injury clinic. MATERIALS AND METHODS: A retrospective descriptive review of patients aged 8-16 years presenting with LBP to a specialist at sports injury clinic between January 2004 and December 2010 was performed. Epidemiological variables, historical points and examination features, including several 'red flags', were evaluated in each patient and the findings related to the diagnosis made from the consultant radiologist reported imaging at that time. RESULTS: A total of 174 patients were analysed. LBP constituted 30% of presentations to the clinic. The median patient age in the study group was 14.0 years, with the male to female ratio of the population analysed being almost 1 : 1. For males, the most prevalent primary sport was rugby and for females, swimming was the most prevalent primary sport. Biomechanical back pain was most frequently diagnosed with spondylolysis, the most prevalent radiological diagnosis. CONCLUSION: No consistent demonstrable association was established between clinical presentation and final diagnosis. It was found that red flags could not be relied upon for the inclusion or the exclusion of a significant radiological finding. This study therefore suggests that, in this population group, a significant diagnosis cannot always be reliably excluded from clinical assessment alone. PMID- 24756089 TI - A new approach for mechanisms of ferroelectric crystalline phase formation in PVDF nanocomposites. AB - This paper proposes a new mechanism for ferroelectric polymorph formation of poly(vinylidene fluoride) (PVDF) nanocomposites. Utilizing time-resolved Fourier transform infrared spectroscopy (FTIR), the real-time investigation of the conformational changes of the PVDF chain segment during crystallization of neat PVDF and the corresponding nanocomposite was performed. Whilst PVDF-clay nanocomposites exhibited mainly the beta crystal phase coexisting with the gamma phase at low Tc (Tc < 155 degrees C), the coexistence of gamma and beta crystalline phases was found at a high Tc temperature range (Tc > 155 degrees C). Experimental results were compared with predictions of the Lauritzen and Hoffman (LH) model and discrepancies were observed between model predictions and experiments. We then recalled the Brochard-de Gennes (BD) model and proposed that different crystalline polymorph formation should be inferred as a transition in the reeling-in rate dependence of the friction coefficient on nanocomposites rather than as a change in the relative rates of secondary nucleation and substrate completion. Combining LH and BD models we proposed a new mechanism to answer the contradictory questions associated with nanocomposite polymorphism. The coexistence of different polymorphs in nanocomposites was proposed to be associated with the coexistence of fast and slow moving chains, which were recognized as the free and adsorbed chains by nanofillers. PMID- 24756087 TI - Ectopic expression of a maize hybrid down-regulated gene ZmARF25 decreases organ size by affecting cellular proliferation in Arabidopsis. AB - Heterosis is associated with differential gene expression between hybrids and their parental lines, and the genes involved in cell proliferation played important roles. AtARF2 is a general cell proliferation repressor in Arabidopsis. In our previous study, two homologues (ZmARF10 and ZmARF25) of AtARF2 were identified in maize, but their relationship with heterosis was not elucidated. Here, the expression patterns of ZmARF10 and ZmARF25 in seedling leaves of maize hybrids and their parental lines were analyzed. The results of qRT-PCR exhibited that ZmARF25 was down-regulated in leaf basal region of hybrids. Moreover, overexpression of ZmARF25 led to reduced organ size in Arabidopsis, which was mainly due to the decrease in cell number, not cell size. In addition, the cell proliferation related genes AtANT, AtGIF1 and AtGRF5 were down-regulated in 35S::ZmARF25 transgenic lines. Collectively, we proposed that the down-regulation of ZmARF25 in maize hybrid may accelerate cell proliferation and promote leaf development, which, in turn, contributes to the observed leaf size heterosis in maize. PMID- 24756090 TI - Proteomic analysis of etiolated juvenile tetraploid Robinia pseudoacacia branches during different cutting periods. AB - The propagation of hard-branch cuttings of tetraploid Robinia pseudoacacia (black locust) is restricted by the low rooting rate; however, etiolated juvenile tetraploid black locust branches result in a significantly higher rooting rate of cuttings compared with non-etiolated juvenile tetraploid branches. To identify proteins that influence the juvenile tetraploid branch rooting process, two dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectra (MALDI-TOF/TOF MS) were used to analyze proteomic differences in the phloem of tetraploid R. pseudoacacia etiolated and non-etiolated juvenile branches during different cutting periods. A total of 58 protein spots differed in expression level, and 16 protein spots were only expressed in etiolated branches or non-etiolated ones. A total of 40 highly expressed protein spots were identified by mass spectrometry, 14 of which were accurately retrieved. They include nucleoglucoprotein metabolic proteins, signaling proteins, lignin synthesis proteins and phyllochlorin. These results help to reveal the mechanism of juvenile tetraploid R. pseudoacacia etiolated branch rooting and provide a valuable reference for the improvement of tetraploid R. pseudoacacia cutting techniques. PMID- 24756091 TI - Functional identification of Proteus mirabilis eptC gene encoding a core lipopolysaccharide phosphoethanolamine transferase. AB - By comparison of the Proteus mirabilis HI4320 genome with known lipopolysaccharide (LPS) phosphoethanolamine transferases, three putative candidates (PMI3040, PMI3576, and PMI3104) were identified. One of them, eptC (PMI3104) was able to modify the LPS of two defined non-polar core LPS mutants of Klebsiella pneumoniae that we use as surrogate substrates. Mass spectrometry and nuclear magnetic resonance showed that eptC directs the incorporation of phosphoethanolamine to the O-6 of L-glycero-D-mano-heptose II. The eptC gene is found in all the P. mirabilis strains analyzed in this study. Putative eptC homologues were found for only two additional genera of the Enterobacteriaceae family, Photobacterium and Providencia. The data obtained in this work supports the role of the eptC (PMI3104) product in the transfer of PEtN to the O-6 of L,D HepII in P. mirabilis strains. PMID- 24756092 TI - Polymorphisms in DNA repair genes and MDR1 and the risk for non-Hodgkin lymphoma. AB - The damage caused by oxidative stress and exposure to cigarette smoke and alcohol necessitate DNA damage repair and transport by multidrug resistance-1 (MDR1). To explore the association between polymorphisms in these genes and non-Hodgkin lymphoma risk, we analyzed 15 polymorphisms of 12 genes in a population-based study in Korea (694 cases and 1700 controls). Four genotypes of DNA repair pathway genes (XRCC1 399 GA, OGG1 326 GG, BRCA1 871 TT, and WRN 787 TT) were associated with a decreased risk for NHL [odds ratio (OR)XRCC1 GA=0.80, p=0.02; OROGG1 GG=0.70, p=0.008; ORBRCA1 TT=0.71, p=0.048; ORWRN TT=0.68, p=0.01]. Conversely, the MGMT 115 CT genotype was associated with an increased risk for NHL (OR=1.25, p=0.04). In the MDR1 gene, the 1236 CC genotype was associated with a decreased risk for NHL (OR=0.74, p=0.04), and the 3435 CT and TT genotypes were associated with an increased risk (OR3435CT=1.50, p<0.0001; OR3435TT=1.43, p=0.02). These results suggest that polymorphisms in the DNA repair genes XRCC1, OGG1, BRCA1, WRN1, and MGMT and in the MDR1 gene may affect the risk for NHL in Korean patients. PMID- 24756093 TI - Towards personalized medicine mediated by in vitro virus-based interactome approaches. AB - We have developed a simple in vitro virus (IVV) selection system based on cell free co-translation, using a highly stable and efficient mRNA display method. The IVV system is applicable to the high-throughput and comprehensive analysis of proteins and protein-ligand interactions. Huge amounts of genomic sequence data have been generated over the last decade. The accumulated genetic alterations and the interactome networks identified within cells represent a universal feature of a disease, and knowledge of these aspects can help to determine the optimal therapy for the disease. The concept of the "integrome" has been developed as a means of integrating large amounts of data. We have developed an interactome analysis method aimed at providing individually-targeted health care. We also consider future prospects for this system. PMID- 24756094 TI - Supercritical carbon dioxide extraction of carotenoids from pumpkin (Cucurbita spp.): a review. AB - Carotenoids are well known for their nutritional properties and health promoting effects representing attractive ingredients to develop innovative functional foods, nutraceutical and pharmaceutical preparations. Pumpkin (Cucurbita spp.) flesh has an intense yellow/orange color owing to the high level of carotenoids, mainly alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin. There is considerable interest in extracting carotenoids and other bioactives from pumpkin flesh. Extraction procedures able to preserve nutritional and pharmacological properties of carotenoids are essential. Conventional extraction methods, such as organic solvent extraction (CSE), have been used to extract carotenoids from plant material for a long time. In recent years, supercritical carbon dioxide (SC-CO2) extraction has received a great deal of attention because it is a green technology suitable for the extraction of lipophylic molecules and is able to give extracts of high quality and totally free from potentially toxic chemical solvents. Here, we review the results obtained so far on SC-CO2 extraction efficiency and quali-quantitative composition of carotenoids from pumpkin flesh. In particular, we consider the effects of (1) dehydration pre treatments; (2) extraction parameters (temperature and pressure); the use of water, ethanol and olive oil singularly or in combination as entrainers or pumpkin seeds as co-matrix. PMID- 24756095 TI - Design, synthesis and bioactivity of N-glycosyl-N'-(5-substituted phenyl-2 furoyl) hydrazide derivatives. AB - Condensation products of 5-substituted phenyl-2-furoyl hydrazide with different monosaccharides D-glucose, D-galactose, D-mannose, D-fucose and D-arabinose were prepared. The anomerization and cyclic-acyclic isomers were investigated by 1H NMR spectroscopy. The results showed that, except for the d-glucose derivatives, which were in the presence of beta-anomeric forms, all derivatives were in an acyclic Schiff base form. Their antifungal and antitumor activities were studied. The bioassay results indicated that some title compounds showed superior effects over the commercial positive controls. PMID- 24756097 TI - Downregulation of the ACE2/Ang-(1-7)/Mas axis in transgenic mice overexpressing GH. AB - The renin-angiotensin system (RAS) plays a crucial role in the regulation of physiological homeostasis and diseases such as hypertension, coronary artery disease, and chronic renal failure. In this cascade, the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/AT1 receptor axis induces pathological effects, such as vasoconstriction, cell proliferation, and fibrosis, while the ACE2/Ang-(1-7)/Mas receptor axis is protective for end-organ damage. The altered function of the RAS could be a contributing factor to the cardiac and renal alterations induced by GH excess. To further explore this issue, we evaluated the consequences of chronic GH exposure on the in vivo levels of Ang II, Ang-(1-7), ACE, ACE2, and Mas receptor in the heart and the kidney of GH-transgenic mice (bovine GH (bGH) mice). At the age of 7-8 months, female bGH mice displayed increased systolic blood pressure (SBP), a high degree of both cardiac and renal fibrosis, as well as increased levels of markers of tubular and glomerular damage. Angiotensinogen abundance was increased in the liver and the heart of bGH mice, along with a concomitant increase in cardiac Ang II levels. Importantly, the levels of ACE2, Ang-(1-7), and Mas receptor were markedly decreased in both tissues. In addition, Ang-(1-7) administration reduced SBP to control values in GH-transgenic mice, indicating that the ACE2/Ang-(1-7)/Mas axis is involved in GH mediated hypertension. The data indicate that the altered expression profile of the ACE2/Ang-(1-7)/Mas axis in the heart and the kidney of bGH mice could contribute to the increased incidence of hypertension, cardiovascular, and renal alterations observed in these animals. PMID- 24756098 TI - Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice. AB - Angiotensin II (Ang II) is involved in induction and progression of renal damage in diabetes. Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and has been shown to be renoprotective by degrading Ang II to Ang-(1-7). A disintegrin and metalloproteinase 17 (ADAM17)-mediated shedding of renal ACE2 contribute to diabetic nephropathy pathogenesis. Lifestyle modification and metformin are recommended as initial therapies for most patients with type 2 diabetes. The aim of this study was to investigate whether exercise training and/or metformin improve glucose homeostasis and albuminuria and downregulate renal ADAM17 and ACE2 shedding in db/db mice. Seven-week-old normal and db/db mice were subjected either to a sedentary existence or exercise training with and without metformin (150 mg/kg per day) for 10 weeks. Exercise training significantly lowered blood glucose, urinary albumin and ACE2 excretion in db/db mice. ADAM17 and ACE2 proteins were co-localized in cortical tubules of the kidney, indicating a possible interaction. Metformin treatment was effective in lowering hyperglycemia only during the first 2 weeks of treatment. Increased renal ADAM17 in 17-week-old db/db mice was corrected by physical exercise but not metformin. In addition, exercise training reduced plasma triglycerides and enhanced insulin levels of db/db mice. In conclusion, exercise training alone and in combination with metformin prevented shedding of renal ACE2 by decreasing ADAM17 protein. Urinary ACE2 could serve as a prognostic tool for the progression of kidney damage and its attenuation by exercise may partially contribute to its renal protection. PMID- 24756099 TI - Antenatal corticosteroids alter insulin signaling pathways in fetal baboon skeletal muscle. AB - We hypothesize that prenatal exposure to glucocorticoids (GCs) negatively alters the insulin signal transduction pathway and has differing effects on the fetus according to gestational age (GA) at exposure. Twenty-three fetal baboons were delivered from 23 healthy, nondiabetic mothers. Twelve preterm (0.67 GA) and 11 near-term (0.95 GA) baboons were killed immediately after delivery. Half of the pregnant baboons at each gestation received two doses of i.m. betamethasone 24 h apart (170 MUg/kg) before delivery, while the other half received no intervention. Vastus lateralis muscle was obtained from postnatal animals to measure the protein content and gene expression of insulin receptor beta (IRbeta; INSR), IRbeta Tyr 1361 phosphorylation (pIRbeta), IR substrate 1 (IRS1), IRS1 tyrosine phosphorylation (pIRS1), p85 subunit of PI3-kinase, AKT (protein kinase B), phospho-AKT Ser473 (pAKT), AKT1, AKT2, and glucose transporters (GLUT1 and GLUT4). Skeletal muscle from preterm baboons exposed to GCs had markedly reduced protein content of AKT and AKT1 (respectively, 73 and 72% from 0.67 GA control, P<0.001); IRbeta and pIRbeta were also decreased (respectively, 94 and 85%, P<0.01) in the muscle of premature GC-exposed fetuses but not in term fetuses. GLUT1 and GLUT4 tended to increase with GC exposure in preterm animals (P=0.09), while GLUT4 increased sixfold in term animals after exposure to GC (P<0.05). In conclusion, exposure to a single course of antenatal GCs during fetal life alters the insulin signaling pathway in fetal muscle in a manner dependent on the stage of gestation. PMID- 24756100 TI - Assessment of chemical coexposure patterns based upon phthalate biomonitoring data within the 2007/2008 National Health and Nutrition Examination Survey. AB - As regulatory initiatives increasingly call for an understanding of the cumulative risks from chemical mixtures, evaluating exposure data from large biomonitoring programs, which may inform these cumulative risk assessments, will improve the understanding of occurrence and patterns of coexposures. Here we have analyzed the urinary metabolite data for six phthalates (di-butyl phthalate; di isobutyl phthalate; butyl-benzyl phthalate; bis(2-ethylhexyl) phthalate; di isononyl phthalate; and di-isodecyl phthalate) in the 2007/2008 National Health and Nutrition Examination Survey (NHANES) data set. For the total data set (N=2604), the co-occurrence of multiple phthalates at the upper percentile of exposure was infrequent. There were no individuals in the NHANES sample who were exposed to >95th percentiles for all six phthalates. For 75% of individuals, none of the six phthalates were above the 95th percentile of their respective exposure distributions. These data suggest that high exposure to multiple phthalates is infrequent in the NHANES population. This analysis solely focused on the pattern of contribution of individual phthalates to total exposure. It did not address the pattern of contribution to potential risk. The approach presented could potentially be used to provide insight into understanding the coexposure patterns for other chemicals. PMID- 24756101 TI - Multiple pathway asbestos exposure assessment for a Superfund community. AB - Libby, MT, USA, was the home to workers at a historical vermiculite mining facility and served as the processing and distribution center for this industrial product that was contaminated with amphibole asbestos. Several pathways of environmental asbestos exposure to the general population have been identified. The local clinic and health screening program collects data from participants on past occupational and environmental exposures to vermiculite and asbestos. Health studies among this population have demonstrated associations between amphibole exposure and health outcomes, but critical questions regarding the nature and level of exposure associated with specific outcomes remain unanswered. The objective of this study was to develop a comprehensive exposure assessment approach that integrates information on individuals' contact frequency with multiple exposure pathways. For 3031 participants, we describe cumulative exposure metrics for environmental exposures, occupational exposures, and residents' contact with carry-home asbestos from household workers. As expected, cumulative exposures for all three occupational categories were higher among men compared with women, and cumulative exposures for household contact and environmental pathways were higher among women. The comprehensive exposure assessment strategies will advance health studies and risk assessment approaches in this population with a complex history of both occupational and environmental asbestos exposure. PMID- 24756103 TI - 2'-Epi-uscharin from the latex of Calotropis gigantea with HIF-1 inhibitory activity. AB - Two stereoisomeric cardenolides, uscharin (1) and a new compound, 2'-epi-uscharin (2), were isolated from the latex of Calotropis gigantea (Asclepiadaceae). Their structures were fully elucidated based on their spectroscopic data, X-ray crystallographic data and chemical evidences. Both epimers (1 and 2) exhibited strong inhibitory effects on HIF-1 activity with different magnitudes. Compound 1 showed much more potent activity than 2 and digoxin, a well-known HIF-1 inhibitor. Discrepancy in potencies between 1 and 2 revealed the contribution of a beta-configuration of 2' hydroxyl moiety for HIF-1 inhibitory activity. This is a first report of the activity of HIF-1 inhibition of thiazoline ring-containing cardenolides. PMID- 24756102 TI - Placental transfer and concentrations of cadmium, mercury, lead, and selenium in mothers, newborns, and young children. AB - There is an emerging hypothesis that exposure to cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se) in utero and early childhood could have long-term health consequences. However, there are sparse data on early life exposures to these elements in US populations, particularly in urban minority samples. This study measured levels of Cd, Hg, Pb, and Se in 50 paired maternal, umbilical cord, and postnatal blood samples from the Boston Birth Cohort (BBC). Maternal exposure to Cd, Hg, Pb, and Se was 100% detectable in red blood cells (RBCs), and there was a high degree of maternal-fetal transfer of Hg, Pb, and Se. In particular, we found that Hg levels in cord RBCs were 1.5 times higher than those found in the mothers. This study also investigated changes in concentrations of Cd, Hg, Pb, and Se during the first few years of life. We found decreased levels of Hg and Se but elevated Pb levels in early childhood. Finally, this study investigated the association between metal burden and preterm birth and low birthweight. We found significantly higher levels of Hg in maternal and cord plasma and RBCs in preterm or low birthweight births, compared with term or normal birthweight births. In conclusion, this study showed that maternal exposure to these elements was widespread in the BBC, and maternal-fetal transfer was a major source of early life exposure to Hg, Pb, and Se. Our results also suggest that RBCs are better than plasma at reflecting the trans-placental transfer of Hg, Pb, and Se from the mother to the fetus. Our study findings remain to be confirmed in larger studies, and the implications for early screening and interventions of preconception and pregnant mothers and newborns warrant further investigation. PMID- 24756104 TI - The importance of gender of patients and general practitioners in relation to treatment practices for overweight. AB - BACKGROUND: Several studies suggest that men and women are treated differently for similar disease including diabetes and cardiovascular disease. Differences in attitudes and treatment practices towards men and women with obesity are not well recognized. OBJECTIVE: To investigate the attitudes and treatment practices among Danish general practitioners (GPs), in relation to treatment of overweight, while taking gender of both the patients and practitioners into account. DESIGN: Questionnaire inventory covertly examining attitudes and practices among Danish general practitioners towards treatment of overweight. All 3.637 general practitioners from the Danish Medical Association register were invited to participate in the survey. In total 1.136 participated. RESULTS: The GPs found weight loss to be more important for overweight male than overweight female patients. They also treated complications to overweight more rigorously among male than female patients, and recommended lipid lowering medicine more often to male than female overweight patients. In addition, the younger female GPs and older male GPs more often said that they would treat an overweight patient with lipid lowering medicine. CONCLUSION: Among general practitioners in Denmark, treatment for weight loss is more often practiced for overweight male than overweight female patients presenting with same symptoms. In addition, hyperlipidemia among overweight males is also more often treated with lipid lowering medicine than hyperlipidemia among overweight females. PMID- 24756105 TI - Five-coordinate M(II)-semiquinonate (M = Fe, Mn, Co) complexes: reactivity models of the catechol dioxygenases. AB - A series of five-coordinate M(II)-semiquinonate (M = Fe, Mn, Co) complexes were synthesized and characterized, including the first example of a mononuclear Fe(II)-semiquinonate. Intermediates were observed in the reactions of M(II) phenSQ (M = Fe, Co) with O2. Evidence for the relevance of these intermediates to the intradiol catechol dioxygenases was obtained by characterization of the oxidized semiquinone-derived product, muconic anhydride, resulting from the reaction of [PhTt(tBu)]Co(II)(3,5-DBSQ) with O2. PMID- 24756106 TI - ERM/ETV5 and RUNX1/AML1 expression in endometrioid adenocarcinomas of endometrium and association with neoplastic progression. AB - The majority of endometrioid endometrial carcinomas (EEC) is diagnosed at stage I. Among these, 30% present myometrial invasion (stage IB), which is associated with tumor spread and relapse after primary treatment. Although an increased expression of RUNX1/AML1 and ERM/ETV5 in EEC have been suggested to be associated with early events of myometrial infiltration, there is no data regarding its expression along the evolution of EEC and possible associations with other clinicopathological parameters. Therefore, ERM/ETV5 and RUNX1/AML1 protein and gene expression profiles were assessed in different EEC stages to evaluate their role in endometrial carcinogenesis. RUNX1/AML1 and ERM/ETV5 proteins were analyzed by immunohistochemistry in 219 formalin fixed paraffin embedded endometrioid tumors and in 12 normal atrophic and proliferative endometrium samples. RUNX1/AML1 and ERM/ETV5 genes expression were analyzed by RT-qPCR. RUNX1/AML1 and ERM/ETV5 expression were decreased with increasing EEC stage, with a positive correlation between protein and gene expression for ERM/ETV5, but not for RUNX1/AML1. Both proteins were present in the nucleus of the tumor cells, whereas RUNX1/AML1, but not ERM/ETV5, was expressed in 7 out of 12 normal endometrial samples, with its expression being restricted to the cytoplasm of the positive cells. We concluded that there is a higher expression of ERM/ETV5 in early stages of EEC, whereas there seems to be a RUNX1/AML1 translocation from cytoplasm to nucleus in EEC neoplastic transformation. PMID- 24756107 TI - Large-scale determination of sequence, structure, and function relationships in cytosolic glutathione transferases across the biosphere. AB - The cytosolic glutathione transferase (cytGST) superfamily comprises more than 13,000 nonredundant sequences found throughout the biosphere. Their key roles in metabolism and defense against oxidative damage have led to thousands of studies over several decades. Despite this attention, little is known about the physiological reactions they catalyze and most of the substrates used to assay cytGSTs are synthetic compounds. A deeper understanding of relationships across the superfamily could provide new clues about their functions. To establish a foundation for expanded classification of cytGSTs, we generated similarity-based subgroupings for the entire superfamily. Using the resulting sequence similarity networks, we chose targets that broadly covered unknown functions and report here experimental results confirming GST-like activity for 82 of them, along with 37 new 3D structures determined for 27 targets. These new data, along with experimentally known GST reactions and structures reported in the literature, were painted onto the networks to generate a global view of their sequence structure-function relationships. The results show how proteins of both known and unknown function relate to each other across the entire superfamily and reveal that the great majority of cytGSTs have not been experimentally characterized or annotated by canonical class. A mapping of taxonomic classes across the superfamily indicates that many taxa are represented in each subgroup and highlights challenges for classification of superfamily sequences into functionally relevant classes. Experimental determination of disulfide bond reductase activity in many diverse subgroups illustrate a theme common for many reaction types. Finally, sequence comparison between an enzyme that catalyzes a reductive dechlorination reaction relevant to bioremediation efforts with some of its closest homologs reveals differences among them likely to be associated with evolution of this unusual reaction. Interactive versions of the networks, associated with functional and other types of information, can be downloaded from the Structure-Function Linkage Database (SFLD; http://sfld.rbvi.ucsf.edu). PMID- 24756108 TI - IL-18, but not IL-12, induces production of IFN-gamma in the immunosuppressive environment of HPV16 E7 transgenic hyperplastic skin. AB - IFN-gamma has a central role in the defense against infections and cancer. More recently, however, IFN-gamma has also been reported to have immunosuppressive effects in models of autoimmune disease, melanoma, and premalignant skin disease. Although IL-12 and IL-18 are critical inducers of IFN-gamma during infection, the mechanisms that induce IFN-gamma in an immunosuppressive context are unknown. Previously, we identified a key role for IFN-gamma in mediating the suppression of antigen-specific immune responses in a transgenic mouse model of human papillomavirus (HPV)-associated epidermal hyperplasia, driven by the expression of the HPV16 E7 oncoprotein from a keratin 14 promoter (K14E7). We now demonstrate elevated production of IFN-gamma, IL-18, and IL-12 by K14E7 transgenic skin compared with nontransgenic skin. IFN-gamma in K14E7 transgenic skin was produced predominantly by CD8(+) and CD4(+) T cells, which were present in greater numbers in K14E7 transgenic skin. Production of IFN-gamma in K14E7 skin required IL-18 but not IL-12. Our findings show that IL-18 contributes to inducing IFN-gamma in an immunosuppressive cutaneous environment caused by viral oncogene-driven hyperplasia. PMID- 24756109 TI - Inhibition of melanogenesis by the antidiabetic metformin. AB - Several reports have demonstrated the inhibitory effect of metformin, a widely used drug in the treatment of type 2 diabetes, on the proliferation of many cancers including melanoma. Recently, it has been shown that metformin is able to modulate the cAMP level in the liver. As cAMP has a crucial role in melanin synthesis and skin pigmentation, we investigated the effect of metformin on melanogenesis both in vitro and in vivo. We showed that metformin led to reduced melanin content in melanoma cells and in normal human melanocytes by decreasing cAMP accumulation and cAMP-responsive element-binding protein phosphorylation. This inhibitory effect is correlated with decreased expression of master genes of melanogenesis, microphthalmia-associated transcription factor, tyrosinase, dopachrome tautomerase, and tyrosinase-related protein 1. Furthermore, we demonstrated that the antimelanogenic effect of metformin is independent of the AMPK pathway. Interestingly, topical application of metformin induced tail whitening in mice. Finally, we confirmed the antimelanogenic effect of metformin on reconstituted human epidermis and on human skin biopsies. These data emphasize the depigmenting effect of metformin and suggest a clinical strategy for using metformin in the topical treatment of hyperpigmentation disorders. PMID- 24756110 TI - Natural killer T cells are essential for the development of contact hypersensitivity in BALB/c mice. AB - Contact hypersensitivity (CHS) has been widely used to study cutaneous immune responses, as a prototype of delayed-type hypersensitivity. Although natural killer T (NKT) cells have been assumed to have an important role in CHS, their role is controversial. Here, we report the role of NKT cells in the sensitization phase of CHS, by promoting the survival and maturation of dendritic cells (DCs) in the draining lymph nodes (LNs). The CHS response was attenuated with Cd1d1(-/ ) and Traj18(-/-) BALB/c mice in which NKT cells were absent. In the draining LNs, the number of effector T cells and cytokine production were significantly reduced with NKT cell-deficient mice. NKT cells activated and colocalized with DCs in the draining LNs after sensitization. The number of migrated and mature DCs was reduced in NKT cell-deficient mice 72 hours after FITC application. In in vitro experiments, activated NKT cells enhanced bone marrow-derived DC (BMDC) survivability via tumor necrosis factor (TNF) production from BMDCs. In addition, TNF production from BMDCs was partially suppressed by the neutralizing anti-CD54 or CD154 antibodies. Our data demonstrate that DC-NKT interaction has a pivotal role in the sensitization phase of CHS. PMID- 24756111 TI - Exploring the IL-21-STAT3 axis as therapeutic target for Sezary syndrome. AB - Sezary syndrome is an aggressive cutaneous T-cell lymphoma. The malignant cells (Sezary cells) are present in skin, lymph nodes, and blood, and express constitutively activated signal transducer and activator of transcription (STAT)3. STAT3 can be activated by IL-21 in vitro and the IL-21 gene itself is a STAT3 target gene, thereby creating an autocrine positive feedback loop that might serve as a therapeutic target. Sezary cells underwent apoptosis when incubated with Stattic, a selective STAT3 inhibitor. STAT3 activation in Sezary cells did not affect expression of the supposed anti-apoptotic STAT3 target genes BCL2, BCL-xL, and SURVIVIN, whereas expression of (proto)oncogenes miR-21, TWIST1, MYC, and PIM1 was significantly increased. CD3/CD28-mediated activation of Sezary cells induced IL-21 expression, accompanied by STAT3 activation and increased proliferation. Blocking IL-21 in CD3/CD28-activated cells had no effects, whereas Stattic abrogated IL-21 expression and cell proliferation. Thus, specific inhibition of STAT3 is highly efficient in the induction of apoptosis of Sezary cells, likely mediated via the regulation of (proto)oncogenes. In contrast, blocking IL-21 alone seems insufficient to affect STAT3 activation, cell proliferation, or apoptosis. These data provide further insights into the pathogenic role of STAT3 in Sezary syndrome and strengthen the notion that STAT3 represents a promising therapeutic target in this disease. PMID- 24756116 TI - Plantar Static Pressure Distribution in Healthy Individuals: Percentiles for the Evaluation of Forefoot Loading. AB - : In literature, one finds little scientific statements regarding plantar static pressure distribution in healthy individuals. Miscellaneous studies, however, characterize pathologies of feet and associate those with abnormal static or dynamic plantar load sharing. Our study reveals that healthy individuals show significant age-dependent differences in forefoot and rear foot load measured in standing position. The forefoot and rear foot load of 238 female and 193 male individuals aged between 2 and 69 years were measured. Using a pressure distribution measurement platform, the measurements were taken barefooted in standing position. Those measurements are presented as percentage of the overall load. The measurements within the age groups A1 (2-6 years), A2 (7-10 years), and A3 (11-69 years) showed significantly different forefoot loading means of the left foot (A1, 19.9%; A2, 28.2%; A3, 39.7%) and the right foot (A1, 22.6%; A2, 29.7%; A3, 39.6%). The forefoot loadings are graphically displayed as a function of the percentiles 5, 10, 25, 50, 75, 90, and 95. Forefoot loadings are referred to as "prominent" if the measured values lie off the interquartile range; if either below the percentile 10 or above 90 the loadings are referred to as "very prominent." Our study contains significant data regarding the extent of the static load sharing of the forefoot and rear foot of healthy individuals; the data are suited for being standard values to evaluate plantar load sharing. LEVELS OF EVIDENCE: Diagnostic Level IV: Case series. PMID- 24756113 TI - Apoptosis therapy in cancer: the first single-molecule co-activating p53 and the translocator protein in glioblastoma. AB - In the complex scenario of cancer, treatment with compounds targeting multiple cell pathways has been emerging. In Glioblastoma Multiforme (GBM), p53 and Translocator Protein (TSPO), both acting as apoptosis inducers, represent two attractive intracellular targets. On this basis, novel indolylglyoxylyldipeptides, rationally designed to activate TSPO and p53, were synthesized and biologically characterized. The new compounds were able to bind TSPO and to reactivate p53 functionality, through the dissociation from its physiological inhibitor, murine double minute 2 (MDM2). In GBM cells, the new molecules caused Deltapsim dissipation and inhibition of cell viability. These effects resulted significantly higher with respect to those elicited by the single target reference standards applied alone, and coherent with the synergism resulting from the simultaneous activation of TSPO and p53. Taken together, these results suggest that TSPO/MDM2 dual-target ligands could represent a new attractive multi-modal opportunity for anti-cancer strategy in GBM. PMID- 24756117 TI - Retrospective comparative study of operative repair of hammertoe deformity. AB - BACKGROUND: The purpose of this study was to compare the outcomes of patients with second hammertoe deformities who underwent correction using either joint resection arthroplasty, proximal interphalangeal joint (PIP) arthrodesis without osteotomy, or interpositional implant arthroplasty. METHODS: Medical records from patients who underwent second PIP correction from July 1999 to December 2008 were retrospectively reviewed. A total of 114 patients (136 second toes) were the basis for this retrospective comparative study. The average final follow-up with weight-bearing radiographs of the 136 procedures at the second toe was 53.8 months. RESULTS: All 3 groups had significantly reduced VAS scores postoperatively (P < .01). Also, all groups had significant radiographic correction in the average measured lateral angle of the second PIP joint (P < .01). However, the interpositional implant group had significantly corrected the second PIP joint in the axial plane, with an average postoperative anterior posterior (AP) angle of 2.9 degrees (P < .01). The postoperative AP angle was also significantly different compared with the postoperative AP angles of the other 2 groups (P < .01). DISCUSSION: Our study confirms that all 3 techniques provide adequate pain relief and radiographic sagittal plane correction. However, interpositional implant arthroplasty provides significant radiographic correction in the axial plane. LEVELS OF EVIDENCE: Therapeutic Level III, Retrospective comparative study. PMID- 24756118 TI - Surface roughness and refractive index changes in contact lens induced by lens care systems. AB - PURPOSE: The aim of this study was to analyze the influence of different lens care systems in surface roughness and refractive index (RI) of contact lenses (CL). This information provides us with a better understanding of how care solutions affect CL materials. METHODS: Several CL and three commercially available and appropriate lens care solutions were used (two polyhexamethylene biguanide and one hydrogen peroxide care systems). Lenses were immersed in the lens care systems, and then measurements with CLR 12-70 digital automated refractometer and atomic force microscopy analysis on Tapping mode were recorded. The measurements were performed before and after the lenses were immersed in each care solution. RESULTS: Significant changes were observed on the CL materials when exposed to lens care systems. All the materials changed, to a greater or lesser extent, their roughness and RI, after being immersed in the different solutions. The water content varied between 0% (Nelfilcon A in ReNu Multiplus, Senofilcon A in AOSEPT Plus, and Methafilcon A in Solocare Aqua) and 4.1% (Hilafilcon B in Solocare Aqua) The higher change in roughness was obtained with ReNu Multiplus in the lens Comfilcon A (with an increase of 27.2 nm) and Senofilcon A (with an increase of 16.7 nm). CONCLUSION: This study suggests that lens care systems play an important role in surface roughness and RI of CL. PMID- 24756119 TI - Risk factors for microbial bioburden during daily wear of silicone hydrogel contact lenses. AB - PURPOSE: To assess risk factors associated with substantial microbial bioburden of lids, conjunctivae, contact lenses, and storage cases during daily wear of silicone hydrogel contact lenses. METHODS: Two hundred eighteen patients were fit to lotrafilcon A lenses, randomized to use either a multipurpose solution or a hydrogen peroxide care system, and followed up for 1 year. Lenses, lens transport saline, lids, conjunctivae, and storage cases were cultured and considered to have substantial microbial bioburden when they harbored high levels of commensal or pathogenic organisms. Univariate and multivariate logistic regression analyses were conducted to examine which demographic covariates were associated with significant bioburden at each location while controlling for solution use. RESULTS: In multivariate analyses, smoking trended toward an association with lens bioburden (odds ratio [OR]=2.15, 95% confidence interval [CI]: 0.95-4.88). Clerical occupations were found to be associated with more frequent overall storage case contamination (OR=3.51, 95% CI: 1.15-10.70) and, specifically, higher gram-positive storage case contamination (OR=5.57, 95% CI: 1.82-17.06). The peroxide system was associated with more frequent storage case contamination (OR=7.6, 95% CI: 3.79-15.19). Coagulase-negative staphylococci (CNS) were the most frequently cultured organisms within storage cases, and in multivariate analyses, CNS were more frequently found in storage cases of peroxide users (OR=6.12, 95% CI: 2.91-13.09). CONCLUSIONS: Clerical occupations were associated with increased microbial bioburden of storage cases during daily wear of silicone hydrogel lenses. Smoking may increase the risk of lens contamination. Storage cases are most frequently contaminated with normal skin flora, and peroxide cases were associated with more frequent contamination. However, the solution type was not associated with lid or lens contamination nor with corneal infiltrative events in this study. PMID- 24756120 TI - Efficacy of multipurpose contact lens solutions against ESBL-positive Escherichia coli, MRSA, and Candida albicans clinical isolates. AB - OBJECTIVES: The antimicrobial effects of multipurpose contact lens solutions (MPSs) have been evaluated according to ISO 14729 standards. The aim of this study was to assess the efficacy of commercially available MPSs against extended spectrum beta lactamases (ESBL)-producing Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans clinical isolates. METHODS: Three commercially available contact lens solutions (Opti-Free Expresss, ReNu MultiPlus, and Solo Care Aqua) were tested against 18 ESBL-positive E. coli clinical strains, 20 MRSA clinical strains, and 20 C. albicans clinical strains. The stand-alone assays for bacteria and fungi were performed according to ISO 14729 criteria, and all samples were evaluated after 2, 4, and 24 hours of incubation. The numbers of viable microorganisms were evaluated by the plate counting method. RESULTS: All MPSs demonstrated at least 3 log reduction in colony-forming units (CFU) for all bacterial isolates and 1 log reduction in CFU for all yeast isolates, which meets ISO 14729 standards. Although no statistically significant differences were obtained among MPSs for bacterial isolates, variable responses were observed against clinical isolates: 5% povidone iodine was more effective compared with Solo Care Aqua for C. albicans clinical strains (P<0.05); and all solutions were effective after an incubation time of only 2 hrs. The MPSs showed good activity against S. aureus, E. coli, and C. albicans. CONCLUSIONS: Although effective log reductions were provided with all MPSs, the reduction was variable depending on the strains tested. Multipurpose contact lens solutions should be tested under ISO 14729 standards for both standard and clinical strains. PMID- 24756121 TI - Compliance study of contact lens wearers in Japan, part 1: internet survey of actual circumstances of lens use. AB - PURPOSE: To conduct a survey of contact lens (CL) wearers who use their CLs with satisfaction in Japan and to establish the actual circumstances of CL use. METHOD: An Internet survey was conducted in 1,000 CL wearers in Japan with questionnaires concerning CL purchase/change, compliance with the duration of wear, and occurrence of complications of CL use. RESULTS: Replies from 636 women (63.6%) and 364 men (36.4%) were received. The largest source of CL purchase was CL specialty stores (eyeglass chains, 41.3%). The most frequent CL types were 2 week frequent replacement (2WFR) soft CLs (SCLs) (32.1%), daily disposable (DD) (31.0%), and other lenses. The main determining factors of purchase were "price" (38.0%), "recommendation of a doctor/staff" (37.6%), and "comfort" (34.1%). The number of wearers who changed their CLs was 372 (37.2%), and the main reasons for change were "inexpensive" (34.9%) and "recommendation of a doctor/staff" (31.2%). In DD and 2WFR/planed replacement SCLs, 270 (42.7%) of 632 wearers were compliant with the recommended duration of use, and the remainder were self-identified as noncompliant. The main reason given for noncompliant behavior was "no harm in extending the duration of use" (60.3%). The number of wearers with eye complications related to lens was 373 (37.3%). CONCLUSIONS: The choice of CLs by wearers seems to be price driven rather than being safety focused. Despite being aware of noncompliant behaviors regarding CL use, there were many noncompliant wearers. Clearly, ophthalmologists, optometrists, CL manufacturers, and other CL related practitioners should cooperate and better educate patients to promote the importance of compliance with safe lens use. PMID- 24756122 TI - Monitor corneal epithelial healing under bandage contact lens using ultrahigh resolution optical coherence tomography after pterygium surgery. AB - OBJECTIVE: To monitor corneal epithelial healing under bandage contact lens (BCL) using ultrahigh-resolution optical coherence tomography (UHR-OCT) after pterygium surgery. METHODS: Thirty-nine eyes of 39 patients undergoing pterygium excision and conjunctival autografting were randomly allocated into 2 groups: 20 eyes were covered with silicone hydrogel BCLs at the end of surgery and 19 eyes served as a control. Ultrahigh-resolution optical coherence tomography scans of the cornea were performed sequentially at 1, 2, and 3 days, and then every other day until the end of re-epithelialization after surgery. Complete epithelial healing was verified with fluorescein staining examination after removal of BCLs. Postsurgery pain was evaluated using the visual analog scale. RESULTS: All BCLs were successfully fit without any contact lens-related complications. Ultrahigh resolution optical coherence images clearly revealed the architectural features of postoperative cornea with BCL in situ and showed epithelial healing process. Ultrahigh-resolution optical coherence tomography imaging agreed with the fluorescein staining examinations in detecting corneal epithelial defect. Based on the assessment by UHR-OCT, the average time course of re-epithelialization in the BCL group was 3.9+/-1.2 days, whereas in the control group, it was 5.7+/-1.8 days (P=0.001). Visual analog scale scoring showed lower pain levels in the BCL group comparing with the control group at each point of time (all P<0.05). CONCLUSIONS: Ultrahigh-resolution optical coherence tomography is an excellent tool in monitoring corneal epithelial healing under BCLs and determining the appropriate time for lens removal. Silicone hydrogel BCL is recommended as an adjuvant therapy after pterygium surgery for its efficacy in improving re epithelialization and postoperative comfort. PMID- 24756123 TI - Absolute electron total ionization cross-sections: molecular analogues of DNA and RNA nucleobase and sugar constituents. AB - Accurate ionization cross-sections for DNA and RNA constituents in the condensed or aqueous phase are important parameters for models simulating radiation damage to genetic material in living cells. In this work, absolute gas-phase electron total ionization cross-sections (TICSs) have been measured for a series of six aromatic and eight non-aromatic cyclic species that can be considered as prototype functional group analogues for the nucleobases and sugar backbone constituents of DNA and RNA. TICSs for water, hexane, and ethylacetamide (a peptide bond analogue) are also reported. The experimental apparatus utilizes a cylindrical ion collector that surrounds the ionization region, providing essentially unit detection efficiency. Two theoretical models, the polarizability correlation method and binary-encounter Bethe theory, are able to reproduce the measured maximum TICS well for all species studied. An empirical energy-dependent correction is found to yield improvement in the agreement between experimental energy-dependent cross sections and the predictions of the BEB model. Having characterised and optimised the performance of both models, they are then used to predict TICSs for gas-phase DNA and RNA nucleobases and sugars. Direct experimental determinations of TICSs for these species are difficult because of their low volatility, which makes it difficult to prepare suitable gas-phase samples for measurement. PMID- 24756124 TI - Total synthesis of (+)-kopsihainanine A. AB - Total synthesis of (+)-kopsihainanine A was accomplished on the basis of (i) Stoltz's enantioselective decarboxylative asymmetric allylation and (ii) the proposed biogenetic pathway from the related alkaloid, kopsihainanine B. In addition, HPLC analysis of the synthetic (+)-kopsihainanine A confirmed its ee to be 99% with [alpha] = 25.35. PMID- 24756125 TI - Effect of feeding palm oil by-products based diets on total bacteria, cellulolytic bacteria and methanogenic archaea in the rumen of goats. AB - Rumen microorganisms are responsible for digestion and utilization of dietary feeds by host ruminants. Unconventional feed resources could be used as alternatives in tropical areas where feed resources are insufficient in terms of quality and quantity. The objective of the present experiment was to evaluate the effect of diets based on palm oil (PO), decanter cake (DC) or palm kernel cake (PKC) on rumen total bacteria, selected cellulolytic bacteria, and methanogenic archaea. Four diets: control diet (CD), decanter cake diet (DCD), palm kernel cake diet (PKCD) and CD plus 5% PO diet (CPOD) were fed to rumen cannulated goats and rumen samples were collected at the start of the experimental diets (day 0) and on days 4, 6, 8, 12, 18, 24 and 30 post dietary treatments. Feeding DCD and PKCD resulted in significantly higher (P<0.05) DNA copy number of total bacteria, Fibrobacter succinogenes, Ruminococcus flavefeciens, and Ruminococcus albus. Rumen methanogenic archaea was significantly lower (P<0.05) in goats fed PKCD and CPOD and the trend showed a severe reduction on days 4 and 6 post experimental diets. In conclusion, results indicated that feeding DCD and PKC increased the populations of cellulolytic bacteria and decreased the density of methanogenic archaea in the rumen of goats. PMID- 24756127 TI - A novel side electrode configuration integrated in fused silica microsystems for synchronous optical and electrical spectroscopy. AB - We present a novel electrode configuration consisting of coplanar side electrode pairs integrated at the half height of the microchannels for the creation of a homogeneous electric field distribution as well as for synchronous optical and electrical measurements. For the integration of such electrodes in fused silica microsystems, a dedicated microfabrication method was utilized, whereby an intermediate bonding layer was applied to lower the temperature for fusion bonding to avoid thereby metal degradation and subsequently to preserve the electrode structures. Finally, we demonstrate the applicability of our devices with integrated electrodes for single cell electrical lysis and simultaneous fluorescence and impedance measurements for both cell counting and characterization. PMID- 24756126 TI - Modulation of STAT3 folding and function by TRiC/CCT chaperonin. AB - Signal transducer and activator of transcription 3 (Stat3) transduces signals of many peptide hormones from the cell surface to the nucleus and functions as an oncoprotein in many types of cancers, yet little is known about how it achieves its native folded state within the cell. Here we show that Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. TRiC binding to Stat3 was mediated, at least in part, by TRiC subunit CCT3. Stat3 binding to TRiC mapped predominantly to the beta-strand rich, DNA-binding domain of Stat3. Notably, enhancing Stat3 binding to TRiC by engineering an additional TRiC-binding domain from the von Hippel-Lindau protein (vTBD), at the N-terminus of Stat3, further increased its affinity for TRiC as well as its function, as determined by Stat3's ability to bind to its phosphotyrosyl-peptide ligand, an interaction critical for Stat3 activation. Thus, Stat3 levels and function are regulated by TRiC and can be modulated by manipulating its interaction with TRiC. PMID- 24756128 TI - Effect of delayed vs early umbilical cord clamping on iron status and neurodevelopment at age 12 months: a randomized clinical trial. AB - IMPORTANCE: Prevention of iron deficiency in infancy may promote neurodevelopment. Delayed cord clamping (DCC) can prevent iron deficiency during the first 6 months of life. However, no data are available on long-term effects on infant outcomes in relation to time for umbilical cord clamping. OBJECTIVE: To investigate effects of DCC, as compared with early cord clamping (ECC), on infant iron status and neurodevelopment at age 12 months in a European setting. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 382 full-term infants born after a low-risk pregnancy at a Swedish county hospital. Follow-up at 12 months included evaluation of iron status (ferritin level, transferrin saturation, transferrin receptor level, reticulocyte hemoglobin level, and mean cell volume) and parental assessment of neurodevelopment by the Ages and Stages Questionnaire, second edition (ASQ). INTERVENTIONS: Infants were randomized to DCC (>=180 seconds after delivery) or ECC (<=10 seconds after delivery). MAIN OUTCOMES AND MEASURES: The main outcome was iron status at age 12 months; the secondary outcome was ASQ score. RESULTS: In total, 347 of 382 infants (90.8%) were assessed. The DCC and ECC groups did not differ in iron status (mean ferritin level, 35.4 vs 33.6 ng/mL, respectively; P = .40) or neurodevelopment (mean ASQ total score, 229.6 vs 233.1, respectively; P = .42) at age 12 months. Predictors of ferritin levels were infant sex and ferritin in umbilical cord blood. Predictors of ASQ score were infant sex and breastfeeding within 1 hour after birth. For both outcomes, being a boy was associated with lower results. Interaction analysis showed that DCC was associated with an ASQ score 5 points higher among boys (mean [SD] score, 229 [43] for DCC vs 224 [39] for ECC) but 12 points lower among girls (mean [SD] score, 230 [39] for DCC vs 242 [36] for ECC), out of a maximum of 300 points (P = .04 for the interaction term). CONCLUSIONS AND RELEVANCE: Delayed cord clamping did not affect iron status or neurodevelopment at age 12 months in a selected population of healthy term-born infants. However, it may not be possible to demonstrate minor effects on neurodevelopment with the size of the study population and the chosen method for assessment. The current data indicate that sex may influence the effects on infant development after DCC in different directions. The magnitude and biological reason for this finding remain to be investigated. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01245296. PMID- 24756129 TI - Microsomal prostaglandin E synthase-1 deficiency exacerbates pulmonary fibrosis induced by bleomycin in mice. AB - Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2), plays an important role in a variety of diseases. So far, the role of mPGES-1 in idiopathic pulmonary fibrosis (IPF) remained unknown. The current study aimed to investigate the role of mPGES-1 in pulmonary fibrosis induced by bleomycin in mice. We found that mPGES-1 deficient (mPGES-1-/-) mice exhibited more severe fibrotic lesions with a decrease in PGE2 content in lungs after bleomycin treatment when compared with wild type (mPGES-1+/+) mice. The mPGES-1 expression levels and PGE2 content were also decreased in bleomycin-treated mPGES-1+/+ mice compared to saline treated mPGES-1+/+ mice. Moreover, in both mPGES-1-/- and mPGES-1+/+ mice, bleomycin treatment reduced the expression levels of E prostanoid receptor 2 (EP2) and EP4 receptor in lungs, whereas had little effect on EP1 and EP3. In cultured human lung fibroblast cells (MRC-5), siRNA-mediated knockdown of mPGES-1 augmented transforming growth factor-beta1 (TGF-beta1)-induced alpha-smooth muscle actin (alpha-SMA) protein expression, and the increase was reversed by treatment of PGE2, selective EP2 agonist and focal adhesion kinase (FAK) inhibitor. In conclusion, these findings revealed mPGES-1 exerts an essential effect against pulmonary fibrogenesis via EP2-mediated signaling transduction, and activation of mPGES-1-PGE2-EP2-FAK signaling pathway may represent a new therapeutic strategy for treatment of IPF patients. PMID- 24756130 TI - High efficiency acetylcholinesterase immobilization on DNA aptamer modified surfaces. AB - We report here the in vitro selection of DNA aptamers for electric eel acetylcholinesterase (AChE). One selected aptamer sequence (R15/19) has a high affinity towards the enzyme (Kd=157+/-42 pM). Characterization of the aptamer showed its binding is not affected by low ionic strength (~20 mM), however significant reduction in affinity occurred at high ionic strength (~1.2 M). In addition, this aptamer does not inhibit the catalytic activity of AChE that we exploit through immobilization of the DNA on a streptavidin-coated surface. Subsequent immobilization of AChE by the aptamer results in a 4-fold higher catalytic activity when compared to adsorption directly on to plastic. PMID- 24756131 TI - An enantioselective strategy for the total synthesis of (S)-tylophorine via catalytic asymmetric allylation and a one-pot DMAP-promoted isocyanate formation/Lewis acid catalyzed cyclization sequence. AB - A new asymmetric total synthesis of a phenanthroindolizidine alkaloid (S) tylophorine is reported, which features a catalytic asymmetric allylation of aldehydes and an unexpected one-pot DMAP promoted isocyanate formation and Lewis acid catalyzed intramolecular cyclization reaction. In addition, White's direct C H oxidation catalyst system converting monosubstituted olefins to linear allylic acetates was also employed for late-stage transformation. PMID- 24756135 TI - Leadership in the NHS: does the Emperor have any clothes? AB - In this essay, I explore the rise of the concept of 'leadership' in the English NHS, highlighting the similarity with a previous shift from (bad, old) 'administration' to (good, new) 'management'. I take a critical look at this discursive shift and highlight some of the overblown claims made for the value of 'clinical leadership'. I argue that, rather than turning all NHS staff into leaders, we should perhaps tone down the level of our rhetoric and instead emphasize the need for a service full of good followers who will maintain a relentless focus on care, quality and efficiency. PMID- 24756133 TI - In vivo therapeutic potential of Dicer-hunting siRNAs targeting infectious hepatitis C virus. AB - The development of RNA interference (RNAi)-based therapy faces two major obstacles: selecting small interfering RNA (siRNA) sequences with strong activity, and identifying a carrier that allows efficient delivery to target organs. Additionally, conservative region at nucleotide level must be targeted for RNAi in applying to virus because hepatitis C virus (HCV) could escape from therapeutic pressure with genome mutations. In vitro preparation of Dicer generated siRNAs targeting a conserved, highly ordered HCV 5' untranslated region are capable of inducing strong RNAi activity. By dissecting the 5'-end of an RNAi mediated cleavage site in the HCV genome, we identified potent siRNA sequences, which we designate as Dicer-hunting siRNAs (dh-siRNAs). Furthermore, formulation of the dh-siRNAs in an optimized multifunctional envelope-type nano device inhibited ongoing infectious HCV replication in human hepatocytes in vivo. Our efforts using both identification of optimal siRNA sequences and delivery to human hepatocytes suggest therapeutic potential of siRNA for a virus. PMID- 24756137 TI - The use of aprepitant in a case of refractory nausea and vomiting. AB - BACKGROUND: This case report describes a patient whose refractory nausea and vomiting significantly improved with the use of aprepitant, a neurokinin receptor antagonist currently only licensed for short-term use in chemotherapy-induced nausea and vomiting. CASE PRESENTATION: A patient with breast cancer and meningeal metastases had an 18-month history of nausea and vomiting refractory to a number of antiemetics commonly used in palliative care. The nausea and vomiting resolved after receiving two doses of the drug aprepitant. CASE MANAGEMENT AND OUTCOME: Maintenance antiemetic treatment with aprepitant was continued over a 5 month period with no recurrence of nausea and vomiting, and no observed side effects. CONCLUSIONS: Aprepitant has a potential role as an antiemetic for refractory symptoms within the palliative-care setting. PMID- 24756136 TI - Antiviral activity of ginseng extract against respiratory syncytial virus infection. AB - Panax ginseng has been known to have a number of immuno-modulatory effects. In this study, we investigated whether Panax Korean red ginseng extract (KRGE) has in vitro and in vivo antiviral effects on respiratory syncytial virus (RSV) infection. KRGE improved the survival of human lung epithelial cells against RSV infection and inhibited RSV replication. In addition, KRGE treatment suppressed the expression of RSV-induced inflammatory cytokine genes (IL-6 and IL-8) and the formation of reactive oxygen species in epithelial cell cultures. Oral administration of mice with KRGE resulted in lowering lung viral loads after RSV infection. Additionally, the in vivo effects of KRGE showed an enhanced level of interferon-gamma (IFN-gamma) producing dendritic cells subsequent to RSV infection. Taken together, these results suggested that KRGE has antiviral activity against RSV infection. PMID- 24756138 TI - Impact of different setup approaches in image-guided radiotherapy as primary treatment for prostate cancer: a study of 2940 setup deviations in 980 MVCTs. AB - AIM: The goal of this study was to assess the impact of different setup approaches in image-guided radiotherapy (IMRT) of the prostatic gland. METHODS: In all, 28 patients with prostate cancer were enrolled in this study. After the placement of an endorectal balloon, the planning target volume (PTV) was treated to a dose of 70 Gy in 35 fractions. A simultaneously integrated boost (SIB) of 76 Gy (2.17 Gy per fraction and per day) was delivered to a smaller target volume. All patients underwent daily prostate-aligned IGRT by megavoltage CT (MVCT). Retrospectively, three different setup approaches were evaluated by comparison to the prostate alignment: setup by skin alignment, endorectal balloon alignment, and automatic registration by bones. RESULTS: A total of 2,940 setup deviations were analyzed in 980 fractions. Compared to prostate alignment, skin mark alignment was associated with substantial displacements, which were >= 8 mm in 13%, 5%, and 44% of all fractions in the lateral, longitudinal, and vertical directions, respectively. Endorectal balloon alignment yielded displacements >= 8 mm in 3%, 19%, and 1% of all setups; and >= 3 mm in 27%, 58%, and 18% of all fractions, respectively. For bone matching, the values were 1%, 1%, and 2% and 3%, 11%, and 34%, respectively. CONCLUSION: For prostate radiotherapy, setup by skin marks alone is inappropriate for patient positioning due to the fact that, during almost half of the fractions, parts of the prostate would not be targeted successfully with an 8-mm safety margin. Bone matching performs better but not sufficiently for safety margins <= 3 mm. Endorectal balloon matching can be combined with bone alignment to increase accuracy in the vertical direction when prostate-based setup is not available. Daily prostate alignment remains the gold standard for high-precision radiotherapy with small safety margins. PMID- 24756140 TI - Atomic partitioning of M-H2 bonds in [NiFe] hydrogenase--a test case of concurrent binding. AB - The possibility of simultaneous addition of eta(2)-H2 to both the metals (Ni and Fe) in the active site of the as isolated state of the enzyme (Ni-SI) is examined here by an atom-by-atom electronic energy partitioning based on the QTAIM method. Results show that the 4LS state prefers H2 removal than addition. Destabilization of the atomic basins of the thiolate bridges and decrease of the electrophilicity of the Fe and Ni, resulting in poor back donation to the CO ligand, are the bottlenecks that hamper dihydrogen activation simultaneously. The study helps to understand why such states are seldom accessed in the activation of dihydrogen. Moreover, Ni has been found to be the natural choice for the dihydrogen binding. PMID- 24756139 TI - Early changes of parotid density and volume predict modifications at the end of therapy and intensity of acute xerostomia. AB - PURPOSE: To quantitatively assess the predictive power of early variations of parotid gland volume and density on final changes at the end of therapy and, possibly, on acute xerostomia during IMRT for head-neck cancer. MATERIALS AND METHODS: Data of 92 parotids (46 patients) were available. Kinetics of the changes during treatment were described by the daily rate of density (rDeltarho) and volume (rDeltavol) variation based on weekly diagnostic kVCT images. Correlation between early and final changes was investigated as well as the correlation with prospective toxicity data (CTCAEv3.0) collected weekly during treatment for 24/46 patients. RESULTS: A higher rDeltarho was observed during the first compared to last week of treatment (-0,50 vs -0,05HU, p-value = 0.0001). Based on early variations, a good estimation of the final changes may be obtained (Deltarho: AUC = 0.82, p = 0.0001; Deltavol: AUC = 0.77, p = 0.0001). Both early rDeltarho and rDeltavol predict a higher "mean" acute xerostomia score (>= median value, 1.57; p-value = 0.01). Median early density rate changes for patients with mean xerostomia score >= / < 1.57 were -0.98 vs -0.22 HU/day respectively (p = 0.05). CONCLUSIONS: Early density and volume variations accurately predict final changes of parotid glands. A higher longitudinally assessed score of acute xerostomia is well predicted by higher rDeltarho and rDeltavol in the first two weeks of treatment: best cut-off values were -0.50 HU/day and -380 mm(3)/day for rDeltarho and rDeltavol respectively. Further studies are necessary to definitively assess the potential of early density/volume changes in identifying more sensitive patients at higher risk of experiencing xerostomia. PMID- 24756141 TI - Oral chemotherapy food and drug interactions: a comprehensive review of the literature. AB - INTRODUCTION: Oral chemotherapy is rapidly becoming a popular dosage form for cancer treatment. These medications have a narrow therapeutic index, and their metabolism can be easily affected by food and/or drug interactions. These interactions can significantly reduce the effectiveness of oral chemotherapy, which could possibly result in harm to patients. METHODS: A systematic evaluation of 58 oral chemotherapeutics was conducted. Drug and food interactions were analyzed using US Food and Drug Administration-approved product labeling, primary literature, and tertiary databases. RESULTS: Our evaluation identified information about drug and food interactions. We present the recommended dose adjustments in our article. CONCLUSION: Oral chemotherapy is associated with a significant number of medication and food interactions. It is essential that health care providers evaluate patients' diet and concurrent medications to provide accurate patient education, therapeutic monitoring, and, if necessary, alternative recommendations whenever oral chemotherapy is prescribed. PMID- 24756142 TI - Patient-reported outcome performance measures in oncology. PMID- 24756143 TI - Population-based standardized symptom screening: Cancer Care Ontario's Edmonton Symptom Assessment System and performance status initiatives. PMID- 24756144 TI - Increasing use of advanced radiation therapy technologies in the last 30 days of life among patients dying as a result of cancer in the United States. AB - PURPOSE: We sought to analyze trends in radiation therapy (RT) technology use and costs in the last 30 days of life for patients dying as a result of cancer. METHODS: We used the Surveillance, Epidemiology, and End Results (SEER) -Medicare and Texas Cancer Registry-Medicare databases to analyze claims data for 13,488 patients dying as a result of lung, breast, prostate, colorectal, melanoma, and pancreas cancers from 2000 to 2009. Logistic regression modeling was used to conduct adjusted analyses regarding influence of demographic, clinical, and health services variables on receipt of types of RT. Costs were calculated in 2009 US dollars. RESULTS: The proportion of patients treated with two-dimensional RT decreased from 74.9% of those receiving RT in the last 30 days of life in 2000 to 32.7% in 2009 (P < .001). Those receiving three-dimensional RT increased from 27.2% in 2000 to 58.5% in 2009 (P < .001). The proportion of patients treated with intensity-modulated radiation therapy in the last 30 days of life increased from 0% in 2000 to 6.2% in 2009 (P < .001), and those undergoing stereotactic radiosurgery increased from 0% in 2000 to 5.0% in 2009 (P < .001). The adjusted mean costs of per-patient RT services delivered in the last 30 days of life were higher in the years 2007 to 2009. CONCLUSION: Among patients receiving RT in the last month of life, there was a shift away from the simplest technique toward more advanced RT technologies. Studies are needed to ascertain whether these technology shifts improve palliative outcomes and quality of life for patients dying as a result of cancer who receive RT services. PMID- 24756145 TI - Radiation oncology services in the modern era: evolving patterns of usage and payments in the office setting for medicare patients from 2000 to 2010. AB - PURPOSE: We evaluated long-term changes in the volume and payments for radiation oncology services in the intensity-modulated radiation therapy (IMRT) era from 2000 to 2010 using a database of Medicare claims. METHODS: We used the Medicare Physician/Supplier Procedure Summary Master File (PSPSMF) for each year from 2000 to 2010 to tabulate the volume and payments for radiation oncology services. This database provides a summary of each billing code submitted to Medicare part B. We identified all codes used in radiation oncology services and categorized billing codes by treatment modality and place of service. RESULTS: We focused our analysis on office-based practices. Total office-based patient volume increased 8.2% from 2000 to 2010, whereas total payments increased 217%. Increase in overall payments increased dramatically from 2000 to 2007, but subsequently plateaued from 2008 to 2010. Increases in complexity of care, and image guidance in particular, have also resulted in higher payments. CONCLUSION: The cost of radiation oncology services increased from 2000 to 2010, mostly due to IMRT, but also with significant contribution from increased overall complexity of care. A cost adjustment occurred after 2007, limiting further growth of payments. Future health policy studies should explore the potential for further cost containment, including differences in use between freestanding and hospital outpatient facilities. PMID- 24756147 TI - Primary non-adherence in general practice: a Danish register study. AB - PURPOSE: The aim of this study was to describe primary non-adherence (PNA) in a Danish general practitioner (GP) setting, i.e. the extent to which patients fail to fill the first prescription for a new drug. We also assessed the length of time between the issuing of a prescription by the GP and the dispensing of the drug by the pharmacist. Lastly, we sought to identify associations between PNA and the characteristics of the patient, the drug and the GP. METHODS: By linking data on issued prescriptions compiled in the Danish General Practice Database with data on redeemed prescriptions contained in the Danish National Prescription Registry, we calculated the rate of PNA among Danish patients from January 2011 through to August 2012. Characteristics associated with PNA were analysed using a mixed effects logistic regression model. RESULTS: A total of 146,959 unique patients were started on 307,678 new treatments during the study period. The overall rate of PNA was 9.3 %, but it varied according to the major groups of the Anatomical Therapeutic Chemical (ATC) Classification System, ranging from 16.9 % for "Blood and bloodforming organs" (ATC group B) to 4.7 % for "Cardiovascular system" (ATC group C). Most of the patients redeemed their prescriptions within the first week. Older age, high income and a diagnosis of chronic obstructive pulmonary disease were found to be significantly associated with lower rates of PNA, while polypharmacy and a diagnosis of ischaemic heart disease were associated with higher rates of PNA. CONCLUSIONS: The overall rate of PNA among Danish residents in a GP setting was 9.3 %. Certain drug classes and patient characteristics were associated with PNA. PMID- 24756148 TI - Therapeutic drug monitoring of once daily aminoglycoside dosing: comparison of two methods and investigation of the optimal blood sampling strategy. AB - PURPOSE: Therapeutic drug monitoring of patients receiving once daily aminoglycoside therapy can be performed using pharmacokinetic (PK) formulas or Bayesian calculations. While these methods produced comparable results, their performance has never been checked against full PK profiles. We performed a PK study in order to compare both methods and to determine the best time-points to estimate AUC0-24 and peak concentrations (C max). METHODS: We obtained full PK profiles in 14 patients receiving a once daily aminoglycoside therapy. PK parameters were calculated with PKSolver using non-compartmental methods. The calculated PK parameters were then compared with parameters estimated using an algorithm based on two serum concentrations (two-point method) or the software TCIWorks (Bayesian method). RESULTS: For tobramycin and gentamicin, AUC0-24 and C max could be reliably estimated using a first serum concentration obtained at 1 h and a second one between 8 and 10 h after start of the infusion. The two-point and the Bayesian method produced similar results. For amikacin, AUC0-24 could reliably be estimated by both methods. C max was underestimated by 10-20% by the two-point method and by up to 30% with a large variation by the Bayesian method. CONCLUSIONS: The ideal time-points for therapeutic drug monitoring of once daily administered aminoglycosides are 1 h after start of a 30-min infusion for the first time-point and 8-10 h after start of the infusion for the second time point. Duration of the infusion and accurate registration of the time-points of blood drawing are essential for obtaining precise predictions. PMID- 24756146 TI - Burden of total and cause-specific mortality related to tobacco smoking among adults aged >= 45 years in Asia: a pooled analysis of 21 cohorts. AB - BACKGROUND: Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest. METHODS AND FINDINGS: We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged >=45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan-accounting for ~71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged >=45 y in the seven countries/regions combined, with a total number of estimated deaths of ~1,575,500 (95% CI = 1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged >=45 y. CONCLUSIONS: Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged >=45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary. PMID- 24756149 TI - Clinical pharmacology and regulatory consequences of GnRH analogues in prostate cancer. AB - INTRODUCTION: GnRH (gonadotropin-releasing hormone) analogues are long-term known to be safe and effective in the clinical management of hormone-dependent advanced prostate cancer. However, their unusual mechanism of action of de-sensitizing pituitary receptors makes generic market entry challenging. In addition, safety aspects like initial flare-up, breakthrough escape, and miniflares render planning and organization of clinical registration trials a complex project. REGULATORY REQUIREMENTS THERAPEUTIC EQUIVALENCE: Regulatory requirements are high as these medicines are compared to bilateral surgical castration with a 100% success rate. GnRH analogues will be used probably even wider in the near future due to demographic development and extension of indications. However, they are challenged by their antagonistic counterparts, which are avoiding flare-up phenomena. The following article deals with regulatory requirements of GnRH analogues in regard to their clinical characteristics. PMID- 24756150 TI - Self-assembly of reconfigurable colloidal molecules. AB - The lock-and-key colloidal particles of Sacanna et al. are novel "dynamic" building blocks consisting of a central spherical colloidal particle (key) attached to a finite number of dimpled colloidal particles (locks) via depletion interactions strong enough to bind the particles together but weak enough that the locks are free to rotate around the key. This rotation imbues a mechanical reconfigurability to these colloidal "molecules". Here we use molecular simulation to predict that these lock-and-key building blocks can self-assemble into a wide array of complex crystalline structures that are tunable via a set of reconfigurability dimensions: the number of locks per building block, bond length, size ratio, confinement, and lock mobility. We demonstrate that, with reconfigurability, ordered structures - such as random triangle square tilings - assemble, despite being kinetically inaccessible with non-reconfigurable but similar building blocks. PMID- 24756151 TI - Factors associated with exclusive breastfeeding in Timor-Leste: findings from Demographic and Health Survey 2009-2010. AB - Exclusive breastfeeding is known to have nutritional and health benefits. This study investigated factors associated with exclusive breastfeeding among infants aged five months or less in Timor-Leste. The latest data from the national Demographic and Health Survey 2009-2010 were analyzed by binary logistic regression. Of the 975 infants included in the study, overall 49% (95% confidence interval 45.4% to 52.7%) were exclusively breastfed. The exclusive breastfeeding prevalence declined with increasing infant age, from 68.0% at less than one month to 24.9% at five months. Increasing infant age, mothers with a paid occupation, who perceived their newborn as non-average size, and residence in the capital city Dili, were associated with a lower likelihood of exclusive breastfeeding. On the other hand, women who could decide health-related matters tended to breastfeed exclusively, which was not the case for others whose decisions were made by someone else. The results suggested the need of breastfeeding promotion programs to improve the exclusive breastfeeding rate. Antenatal counseling, peer support network, and home visits by health workers could be feasible options to promote exclusive breastfeeding given that the majority of births occur at home. PMID- 24756152 TI - Targeting endothelin receptors A and B attenuates the inflammatory response and improves locomotor function following spinal cord injury in mice. AB - After spinal cord injury (SCI), the disruption of blood-spinal cord barrier by activation of the endothelin (ET) system is a critical event leading to leukocyte infiltration, inflammatory response and oxidative stress, contributing to neurological disability. In the present study, we showed that blockade of ET receptor A (ETAR) and/or ET receptor B (ETBR) prevented early inflammatory responses directly via the inhibition of neutrophil and monocyte diapedesis and inflammatory mediator production following traumatic SCI in mice. Long-term neurological improvement, based on a series of tests of locomotor performance, occurred only in the spinal cord-injured mice following blockade of ETAR and ETBR. We also examined the post-traumatic changes of the micro-environment within the injured spinal cord of mice following blockade of ET receptors. Oxidative stress reflects an imbalance between malondialdehyde and superoxide dismutase in spinal cord-injured mice treated with vehicle, whereas blockade of ETAR and ETBR reversed the oxidation state imbalance. In addition, hemeoxygenase-1, a protective protease involved in early SCI, was increased in spinal cord-injured mice following the blockade of ETAR and ETBR, or only ETBR. Matrix metalloproteinase-9, a tissue-destructive protease involved in early damage, was decreased in the injured spinal cord of mice following blockade of ETAR, ETBR or a combination thereof. The findings of the present study therefore suggested an association between ETAR and ETBR in regulating early pathogenesis of SCI and determining the outcomes of long-term neurological recovery. PMID- 24756153 TI - Label-free blood plasma test based on surface-enhanced Raman scattering for tumor stages detection in nasopharyngeal cancer. AB - This study aims to evaluate the feasibility of a label-free nanobiosensor based on blood plasma surface-enhanced Raman spectroscopy (SERS) method for exploring variability of different tumor (T) stages in nasopharyngeal cancer (NPC). Au nanoparticles as the SERS-active nanostructures were directly mixed with human blood plasma to enhance the Raman scattering signals. High quality SERS spectra can be acquired from blood plasma samples belong to 60 healthy volunteers, 25 NPC patients with T1 stage and 75 NPC patients with T2-T4 stage. A diagnostic accuracy of 83.5% and 93.3%, respectively, can be achieved for classification between early T (T1) stage cancer and normal; and advanced T (T2-T4) stage cancer and normal blood groups. This exploratory study demonstrates that the nanobiosensor based on SERS technique in conjunction with PCA-LDA has great potential as a clinical complement for different T stages detection in nasopharyngeal cancer. PMID- 24756154 TI - Flexible bonding between copper and nitric oxide: infrared photodissociation spectroscopy of copper nitrosyl cation complexes: [Cu(NO)n]+ (n = 1-5). AB - The infrared spectra of mass-selected mononuclear copper nitrosyl cation complexes [Cu(NO)n](+) with n = 1-5 and their argon tagged complexes are measured via infrared photodissociation spectroscopy in the nitrosyl stretching frequency region in the gas phase. The experimental spectra provide distinctive patterns allowing the determination of the geometries and electronic structures of these complexes by comparison with the predicted spectra from density functional theory computations. The argon tagged [Cu(NO)2Ar2](+) and [Cu(NO)3Ar](+) complexes as well as the higher n = 4 and 5 complexes each involve a bidentate (NO)2 dimer ligand, suggesting that ligand-ligand coupling plays an important role in the bonding of these cation systems. The results also show that argon tagging has a strong influence on the geometric and electronic structures of the n = 2 and 3 complexes. The [Cu(NO)4](+) cation is the most intense peak in the mass spectrum, which is characterized to be the fully coordinated ion with a D2d structure involving two (NO)2 units but with only 14-valence electrons on Cu. The [Cu(NO)5](+) cation complex is determined to involve a [Cu(NO)4](+) core ion that is coordinated by an external NO ligand. PMID- 24756158 TI - Vertically aligned ZnO@CuS@PEDOT core@shell nanorod arrays decorated with MnO2 nanoparticles for a high-performance and semi-transparent supercapacitor electrode. AB - Hybrid nano-architectures with high electrochemical performance for supercapacitors have been designed by growing hierarchical ZnO NRs@CuS@PEDOT@MnO2 core@shell heterostructured nanorod arrays on ITO/glass substrates. This hybrid nano-structured electrode exhibits excellent electrochemical performance, with a high specific areal capacitance of 19.85 mF cm(-2), good rate capability, cycling stability and diffused coloured transparency. PMID- 24756157 TI - Increased prevalence of celiac disease among pediatric patients with irritable bowel syndrome: a 6-year prospective cohort study. AB - IMPORTANCE: Recurrent abdominal pain is a prevalent health issue in childhood. Clinical criteria (ie, the Rome criteria) have been established to aid diagnosis. Studies of adults have shown an increased prevalence of celiac disease among patients with irritable bowel syndrome (IBS); few data are available with regard to children. OBJECTIVE: To assess the prevalence of celiac disease among children with abdominal pain-related functional gastrointestinal disorders classified according to the Rome criteria. DESIGN, SETTING, PARTICIPANTS: Six-year (2006 2012) prospective cohort study conducted in a tertiary referral center for the diagnosis and follow-up of gastrointestinal disorders in southern Italy (ie, Bari, Italy). A total of 992 children (42.8% male; median age, 6.8 years) consecutively referred for recurrent abdominal pain by their primary care physicians without previous investigation were evaluated. EXPOSURE: Patients were classified according to Rome III criteria as having IBS, functional dyspepsia, functional abdominal pain, or abdominal migraine. MAIN OUTCOMES AND MEASURES: Prevalence of celiac disease in each category of abdominal pain-related functional gastrointestinal disorder. Concentrations of IgA, IgA antitissue transglutaminase, and endomysial antibodies were measured, and a duodenal biopsy was performed in case of antibody positivity. RESULTS: A total of 992 children were evaluated: 270 were classified as having IBS, 201 as having functional dyspepsia, and 311 as having functional abdominal pain, and 210 children were excluded from the study because they had an organic disorder or some other functional gastrointestinal disorder (not related to abdominal pain). Serologic testing was performed for all 782 children included in the study, and 15 patients tested positive for celiac disease (12 of 270 patients with IBS [4.4%], 2 of 201 patients with functional dyspepsia [1%], and 1 of 311 patients with functional abdominal pain [0.3%]). Children presenting with IBS have a 4 times higher risk of having celiac disease than children without IBS (odds ratio, 4.19 [95% CI, 2.03-8.49]; P < .001). CONCLUSIONS AND RELEVANCE: The prevalence of celiac disease among children with IBS is 4 times higher than among the general pediatric population. Rome III classification of abdominal pain-related functional gastrointestinal disorders might help to select children who deserve screening for celiac disease. PMID- 24756159 TI - Chirped-Pulse millimeter-Wave spectroscopy for dynamics and kinetics studies of pyrolysis reactions. AB - A Chirped-Pulse millimeter-Wave (CPmmW) spectrometer is applied to the study of chemical reaction products that result from pyrolysis in a Chen nozzle heated to 1000-1800 K. Millimeter-wave rotational spectroscopy unambiguously determines, for each polar reaction product, the species, the conformers, relative concentrations, conversion percentage from precursor to each product, and, in some cases, vibrational state population distributions. A chirped-pulse spectrometer can, within the frequency range of a single chirp, sample spectral regions of up to ~10 GHz and simultaneously detect many reaction products. Here we introduce a modification to the CPmmW technique in which multiple chirps of different spectral content are applied to a molecular beam pulse that contains the pyrolysis reaction products. This technique allows for controlled allocation of its sensitivity to specific molecular transitions and effectively doubles the bandwidth of the spectrometer. As an example, the pyrolysis reaction of ethyl nitrite, CH3CH2ONO, is studied, and CH3CHO, H2CO, and HNO products are simultaneously observed and quantified, exploiting the multi-chirp CPmmW technique. Rotational and vibrational temperatures of some product molecules are determined. Subsequent to supersonic expansion from the heated nozzle, acetaldehyde molecules display a rotational temperature of 4 +/- 1 K. Vibrational temperatures are found to be controlled by the collisional cooling in the expansion, and to be both species- and vibrational mode-dependent. Rotational transitions of vibrationally excited formaldehyde in levels nu4, 2nu4, 3nu4, nu2, nu3, and nu6 are observed and effective vibrational temperatures for modes 2, 3, 4, and 6 are determined and discussed. PMID- 24756160 TI - Sequential one-pot enzymatic synthesis of oligo-N-acetyllactosamine and its multi sialylated extensions. AB - A simple and efficient protocol for the preparative-scale synthesis of various lengths of oligo-N-acetyllactosamine (oligo-LacNAc) and its multi-sialylated extensions is described. The strategy utilizes one thermophilic bacterial thymidylyltransferase (RmlA) coupled with corresponding sugar-1-phosphate kinases to generate two uridine diphosphate sugars, UDP-galactose and UDP-N acetylglucosamine. By incorporating glycosyltransferases, oligo-LacNAcs and their sialylated analogs were synthesized. PMID- 24756161 TI - "Legacy of Dr. Kazuo Moriwaki" (1930-2013). PMID- 24756162 TI - beta-Boomerang Antimicrobial and Antiendotoxic Peptides: Lipidation and Disulfide Bond Effects on Activity and Structure. AB - Drug-resistant Gram-negative bacterial pathogens and endotoxin- or lipopolysaccharide (LPS)-mediated inflammations are among some of the most prominent health issues globally. Antimicrobial peptides (AMPs) are eminent molecules that can kill drug-resistant strains and neutralize LPS toxicity. LPS, the outer layer of the outer membrane of Gram-negative bacteria safeguards cell integrity against hydrophobic compounds, including antibiotics and AMPs. Apart from maintaining structural integrity, LPS, when released into the blood stream, also induces inflammatory pathways leading to septic shock. In previous works, we have reported the de novo design of a set of 12-amino acid long cationic/hydrophobic peptides for LPS binding and activity. These peptides adopt beta-boomerang like conformations in complex with LPS. Structure-activity studies demonstrated some critical features of the beta-boomerang scaffold that may be utilized for the further development of potent analogs. In this work, beta boomerang lipopeptides were designed and structure-activity correlation studies were carried out. These lipopeptides were homo-dimerized through a disulfide bridge to stabilize conformations and for improved activity. The designed peptides exhibited potent antibacterial activity and efficiently neutralized LPS toxicity under in vitro assays. NMR structure of C4YI13C in aqueous solution demonstrated the conserved folding of the lipopeptide with a boomerang aromatic lock stabilized with disulfide bond at the C-terminus and acylation at the N terminus. These lipo-peptides displaying bacterial sterilization and low hemolytic activity may be useful for future applications as antimicrobial and antiendotoxin molecules. PMID- 24756163 TI - miR-181b increases drug sensitivity in acute myeloid leukemia via targeting HMGB1 and Mcl-1. AB - Multidrug resistance (MDR) remains the major cause of disease relapse and poor prognosis in adults with acute myeloid leukemia (AML). Emerging evidence shows that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to elucidate the mechanisms through which AML patients develop drug resistance. MicroRNAs have been shown to play an important role in regulating the chemotherapy resistance in AML. A detailed understanding of the mechanisms of microRNA that are clinically relevant in AML may enhance our ability to predict and overcome drug resistance. Here, we demonstrated, for the first time, that miR 181b was decreased significantly in human multidrug-resistant leukemia cells and relapsed/refractory AML patient samples. Overexpression of miR-181b increased the sensitivity of leukemia cells to cytotoxic chemotherapeutic agents and promoted drug-induced apoptosis. Moreover, miR-181b inhibited HMGB1 and Mcl-1 expression by direct binding to their 3'-untranslated regions. In addition, HMGB1 was expressed at high levels in relapsed/refractory AML patients and suppression of HMGB1 via RNA interference sensitized multidrug-resistant leukemia cells to chemotherapy and induced apoptosis. In conclusion, these results provide a strong rationale for the development of miR-181b-based therapeutic strategies for the enhancement of efficacy in AML treatment. PMID- 24756165 TI - Developmental venous anomaly in the newborn brain. AB - INTRODUCTION: Cerebral developmental venous anomaly (DVA) is considered a benign anatomical variant of parenchymal venous drainage; it is the most common vascular malformation seen in the adult brain. Despite its assumed congenital origin, little is known about DVA in the neonatal brain. We report here the first cohort study of 14 neonates with DVA. METHODS: Fourteen infants (seven preterm) with DVA diagnosed neonatally using cranial ultrasound (cUS) and magnetic resonance imaging (MRI) from three tertiary neonatal units over 14 years are reviewed. RESULTS: DVA was first detected on cUS in 6 and on MRI in 8 of the 14 infants. The cUS appearances of DVA showed a focal fairly uniform area of increased echogenicity, often (86 %) adjacent to the lateral ventricle and located in the frontal lobe (58 %). Blood flow in the dilated collector vein detected by Doppler ultrasound (US) varied between cases (venous flow pattern in ten and arterialized in four). The appearance on conventional MRI was similar to findings in adults. Serial imaging showed a fairly constant appearance to the DVAs in some cases while others varied considerably regarding anatomical extent and flow velocity. CONCLUSIONS: This case series underlines that a neonatal diagnosis of DVA is possible with carefully performed cUS and MRI and that DVA tends to be an incidental finding with a diverse spectrum of imaging appearances. Serial imaging suggests that some DVAs undergo dynamic changes during the neonatal period and early infancy; this may contribute to why diagnosis is rare at this age. PMID- 24756164 TI - Magnetic resonance imaging of anterior temporal lobe cysts in children: discriminating special imaging features in a particular group of diseases. AB - INTRODUCTION: We hypothesised that disorders with anterior temporal lobe (ATL) cysts might exhibit common peculiarities and distinguishable imaging features that could be useful for diagnosis. We reviewed a series of patients for neuroimaging contributions to specific diagnoses. METHODS: A literature search was conducted, and institutional imaging files were reviewed to identify MR examinations with ATL cysts in children. Patients were divided according to head size, calcifications, white matter and cortical abnormalities. Unsupervised hierarchical clustering of patients on the basis of their MR and CT items was performed. RESULTS: We identified 23 patients in our database in whom MR revealed ATL cysts. Our series included five patients with congenital muscular dystrophy (05/23=21.7 %), six with megalencephalic leukoencephalopathy with subcortical cysts (06/23=26.1 %), three with non-megalencephalic leukoencephalopathy with subcortical cysts (03/23=13.1 %), seven with congenital cytomegalovirus disease (07/23=30.4 %) and two with Aicardi-Goutieres syndrome (02/23=8.7 %). After analysis, 11 clusters resulted in the highest discriminative indices. Thereafter, patients' clusters were linked to their underlying diseases. The features that best discriminated between clusters included brainstem abnormalities, cerebral calcifications and some peculiar grey and white matter abnormalities. A flow chart was drafted to guide the radiologist in these diagnoses. CONCLUSIONS: The authors encourage the combined interpretation of these features in the herein proposed approach that confidently predicted the final diagnosis in this particular group of disorders associated with ATL cysts. PMID- 24756166 TI - Microguidewire protection of wide-necked aneurysms incorporating orifices of tortuous acute-angled vessels: a novel approach. AB - INTRODUCTION: Protective/remodeling techniques for treating wide-necked intracranial aneurysms are constantly sought. However, their utility may be limited in lesions that incorporate the orifice of acute-angled efferent branch vessels. Furthermore, passage of a protective microcatheter may be challenging if a small branch is extremely tortuous. This study was conducted to explore a novel method of treating wide-necked aneurysms, utilizing microguidewire protection. METHODS: A microcatheter is first passed into parent artery (proximal to aneurysm) to position a microguidewire proximally in the involved branch. A second microcatheter is then inserted into aneurysmal sac. Advancement of the first microcatheter forces the microguidewire to shift, thus covering aneurysmal neck. A framing coil may then be placed within aneurysmal sac, under microguidewire protection. After completing initial coil insertion, easing of tension on the microcatheter allows separation of protective microguidewire and frame coil, confirming stability of the initial coil. RESULTS: This technique was applied to 11 intracranial saccular aneurysms of M1 segment (n=6), middle cerebral artery bifurcation (n=4), and anterior communicating artery (n=1) with success, combining stent protection in two patients. Coil embolization was thus facilitated, resulting in excellent outcomes for all patients. No morbidity or mortality was directly related to microguidewire protection. CONCLUSION: Our small study suggests that microguidewire protection may be a safe alternative, if traditional remodeling or protective options are infeasible due to intrinsic vascular properties. This technique is particularly suited for treatment of wide necked aneurysms where passage of protective microcatheters into involved branches is not achievable. PMID- 24756167 TI - Learning strategies in table tennis using inverse reinforcement learning. AB - Learning a complex task such as table tennis is a challenging problem for both robots and humans. Even after acquiring the necessary motor skills, a strategy is needed to choose where and how to return the ball to the opponent's court in order to win the game. The data-driven identification of basic strategies in interactive tasks, such as table tennis, is a largely unexplored problem. In this paper, we suggest a computational model for representing and inferring strategies, based on a Markov decision problem, where the reward function models the goal of the task as well as the strategic information. We show how this reward function can be discovered from demonstrations of table tennis matches using model-free inverse reinforcement learning. The resulting framework allows to identify basic elements on which the selection of striking movements is based. We tested our approach on data collected from players with different playing styles and under different playing conditions. The estimated reward function was able to capture expert-specific strategic information that sufficed to distinguish the expert among players with different skill levels as well as different playing styles. PMID- 24756169 TI - Children's health care and the Patient Protection and Affordable Care Act: what's at stake? PMID- 24756170 TI - Flux-assisted synthesis of SnNb2O6 for tuning photocatalytic properties. AB - A flux-assisted method was used to synthesize SnNb2O6 as a visible-light responsive metal oxide photocatalyst. The role of flux was investigated in detail using different flux to reactant molar ratios (1 : 1, 3 : 1, 6 : 1, 10 : 1, and 14 : 1) and different reaction temperatures (300, 500, and 600 degrees C). The obtained products were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), diffuse reflectance UV-Vis spectroscopy, X-ray photoelectron spectroscopy (XPS), the Brunauer-Emmett-Teller method (BET), and high resolution scanning transmission electron microscopy (HRTEM). Flux-assisted synthesis led to tin niobate particles of platelet morphology with smooth surfaces. The synthesized crystal showed a 2D anisotropic growth along the (600) plane as the flux ratio increased. The particles synthesized with a high reactant to flux ratio (1 : 10 or higher) exhibited slightly improved photocatalytic activity for hydrogen evolution from an aqueous methanol solution under visible radiation (lambda > 420 nm). The photo-deposition of platinum and PbO2 was examined to gain a better understanding of electrons and hole migration pathways in these layered materials. The HR-STEM observation revealed that no preferential deposition of these nanoparticles was observed depending on the surface facets of SnNb2O6. PMID- 24756171 TI - Synthesis of dimesitylborane-substituted phenylcarbazoles as bipolar host materials and the variation of the green PHOLED performance with the substituent position of the boron atom. AB - Two structural isomers of the bipolar host material containing the dimesitylborane moiety were synthesized and their device performance was investigated. The quantum efficiency of the devices depends on the substituent position of the dimesitylborane moiety. The maximum external quantum efficiency of the device reached as high as 23.8% with a green color coordinate of (0.30, 0.63). PMID- 24756172 TI - The Efficacy of Computerized Cognitive Training in Adults With ADHD: A Randomized Controlled Trial. AB - OBJECTIVE: This is a randomized control trial examining the efficiency of computerized cognitive training (CCT) for adults with ADHD, comparing two training conditions with graded levels of executive cognitive demands. METHOD: Adults with ADHD (n = 60) were randomized into study (n = 34) and control (n = 26) groups. Training was conducted with the computerized AttenFocus program. Control group received a simple, non-hierarchical version with less executive demands. RESULTS: Significant positive changes in symptoms ratings, ecological measures of executive functions, and occupational performance were found in both groups. No significant changes were found in variables of neurocognitive performance battery and quality of life. No significant time by group interaction effects were found. CONCLUSION: No benefits of the intervention were found relative to the control. Lack of interaction effects may be due to insufficient power, non-specific cognitive training or placebo effects. Results demonstrate some positive findings for general CCT, yet do not support the inclusion of specific higher level executive training. PMID- 24756173 TI - Non-Medical Prescription Stimulant Use in Graduate Students: Relationship With Academic Self-Efficacy and Psychological Variables. AB - OBJECTIVE: The objective of this study was to examine graduate students' non medical use of prescription stimulant medication, and the relationship between non-medical use of prescription stimulants with academic self-efficacy, psychological factors (i.e., anxiety, depression, and stress), and internal restlessness. METHOD: The sample consisted of 807 graduate students from universities located in five geographic regions of the United States. RESULTS: Past-year rates of self-reported non-medical use were determined to be 5.9%, with overall lifetime prevalence of 17.5%. Observed self-reported non-medical use of prescription stimulant medications was significantly correlated with self reported levels of anxiety and stress, various aspects of internal restlessness, and perceived safety of the medications. CONCLUSION: Findings support graduate students' motivations of non-medical prescription stimulant use to be both academic and social in nature. Effective prevention and education efforts are needed to help address the non-medical use of prescription stimulants by graduate students on university campuses. PMID- 24756174 TI - School Maladjustment and External Locus of Control Predict the Daytime Sleepiness of College Students With ADHD. AB - OBJECTIVE: The primary aim of this study was to evaluate whether school maladjustment longitudinally predicts the daytime sleepiness of college students with ADHD above and beyond symptoms of ADHD and to determine whether internalizing dimensions mediate the relationship between maladjustment and sleepiness. METHOD: A prospective longitudinal study of 59 college students comprehensively diagnosed with ADHD who completed ratings at the beginning, middle, and end of the school year. RESULTS: School maladjustment at the beginning of the year significantly predicted daytime sleepiness at the end of the year above and beyond symptoms of ADHD. Locus of control mediated the relationship between maladjustment and daytime sleepiness. CONCLUSION: The significant school maladjustment difficulties that students with ADHD experience following the transition to college may lead to the development of problems with daytime sleepiness, particularly for those students with high external locus of control. This pattern is likely reciprocal, whereby sleep problems in turn result in greater school impairment, reinforcing the idea that life events are outside of one's control. PMID- 24756175 TI - Additional surgical procedure is a risk factor for surgical site infections after laparoscopic cholecystectomy. AB - PURPOSE: Surgical site infections (SSI) are associated with increased costs and length of hospital stay, readmission rates, and mortality. The aim of this study was to identify risk factors for SSI in patients undergoing laparoscopic cholecystectomy. METHODS: Analysis of 35,432 laparoscopic cholecystectomies of a prospective multicenter database was performed. Risk factors for SSI were identified among demographic data, preoperative patients' history, and operative data using multivariate analysis. RESULTS: SSIs after laparoscopic cholecystectomy were seen in 0.8 % (n = 291) of the patients. Multivariate analysis identified the following parameters as risk factors for SSI: additional surgical procedure (odds ratio [OR] 4.0, 95 % confidence interval [CI] 2.2-7.5), age over 55 years (OR 2.4 [1.8-3.2]), conversion to open procedure (OR 2.6 [1.9 3.6]), postoperative hematoma (OR 1.9 [1.2-3.1]), duration of operation >60 min (OR 2.5 [1.7-3.6], cystic stump insufficiency (OR 12.5 [4.2-37.2]), gallbladder perforation (OR 6.2 [2.4-16.1]), gallbladder empyema (OR 1.7 [1.1-2.7]), and surgical revision (OR 15.7 [10.4-23.7]. SSIs were associated with a significantly prolonged hospital stay (p < 0.001), higher postoperative mortality (p < 0.001), and increased rate of surgical revision (p < 0.001). CONCLUSIONS: Additional surgical procedure was identified as a strong risk factor for SSI after laparoscopic cholecystectomy. Furthermore, operation time >60 min, age >55 years, conversion to open procedure, cystic stump insufficiency, postoperative hematoma, gallbladder perforation, gallbladder empyema, or surgical revision were identified as specific risk factors for SSI after laparoscopic cholecystectomy. PMID- 24756176 TI - A genetically encoded aldehyde for rapid protein labelling. AB - Using a mutant pyrrolysyl-tRNA synthetase-tRNA(Pyl)(CUA) pair, 3-formyl phenylalanine is genetically incorporated into proteins at amber mutation sites in Escherichia coli. This non-canonical amino acid readily reacts with hydroxylamine dyes, leading to rapid and site-selective protein labelling. PMID- 24756177 TI - Is retrograde intrarenal surgery a viable treatment option for renal stones in patients with solitary kidney? AB - PURPOSE: To evaluate the effectiveness and safety of retrograde intrarenal surgery (RIRS) for stones up to 2 cm in diameter in patients with solitary kidney. METHODS: From January 2008 to January 2013, we prospectively enrolled all consecutive patients with solitary kidney and renal stones. Plain abdominal computed tomography scan was performed preoperatively and 1 month after the procedure to assess the stone-free rates (SFR). Serum creatinine levels were detected preoperatively, at day 1 postoperatively, at 1 month postoperatively, and then every 6 months postoperatively. RESULTS: During the study period, we prospectively enrolled a total of 29 patients. The mean age was 55.7 +/- 12.3 years; the mean stone size was 1.3 +/- 0.4 cm. The primary SFR was 72.4 %; the secondary SFR was 93.1 %. The mean number of procedures per patient was 1.24. The mean serum creatinine levels were 1.5 +/- 0.6, 1.6 +/- 0.7, 1.6 +/- 0.6, and 1.7 +/- 0.7 mg/dl preoperatively, at 1 day after RIRS, at 1 month after RIRS, and at 1 year after RIRS, respectively, without detection of any statistical difference (p = 0.76). Median follow-up time was 35.7 +/- 19.3 (12-72) months, but that was available for only 18 patients. The mean serum creatinine level at the last follow-up was 1.7 +/- 0.9 mg/dl. No major complications were recorded. Grade I complications occurred in eight patients (27.4 %). CONCLUSIONS: RIRS is safe and effective in the treatment of renal stones in patients with solitary kidney, without worsening renal function. PMID- 24756178 TI - Single perioperative dose of tranexamic acid in primary hip and knee arthroplasty. AB - INTRODUCTION: Tranexamic acid (TXA) is an antifibrinolytic agent that competitively inhibits the activation of plasminogen to plasmin. It has been shown to reduce blood loss in trauma and other haemorrhagic conditions and has recently been utilised in elective orthopaedic surgery. There are various methods of administering TXA described in the literature. METHODS: This retrospective cohort study reviews the effects of a single perioperative 1 g intravenous bolus on patients undergoing primary hip and knee arthroplasty and its effect on operative blood loss. After excluding patients who did not fulfil our inclusion criteria, a total of 110 patients were included in this study. Fifty underwent primary hip arthroplasty (30 treated with TXA; 60.0 %), and 60 underwent primary knee arthroplasty (29 treated with TXA; 48.3 %). The main outcome measure was red cell volume and total blood loss, and secondary measures were needed for blood transfusions, presence of thromboembolic events, and length of hospital stay. RESULTS: Both cohorts who received TXA showed a reduction in immediate postoperative red cell volume loss and total blood loss (p < 0.01). There was no association with the administration of TXA and the rate of postoperative blood transfusions (hip p = 0.36, knee p = 0.13), incidence of symptomatic deep vein thrombosis (hip p = 0.36, knee p = 0.31), or postoperative hospital length of stay (hip p = 0.70, knee p = 0.68). CONCLUSION: This study demonstrates that a single perioperative bolus of intravenous TXA may significantly reduce operative blood loss in both primary total hip and knee arthroplasty in a cost-effective manner, in combination with meticulous perioperative haemostasis. PMID- 24756179 TI - Surgical waiting times and patient choice: how much delay do patients really want? AB - BACKGROUND: The 18-week target to treatment government initiative was implemented in 2004. In order for this to work, patients need to accept operative dates provided, otherwise the pathway will fail. AIM: The aim of this prospective study was to identify the earliest time patients would accept surgical intervention following assessment at an outpatient clinic and to identify the reasons why some patients would choose to delay surgery. METHODS: This prospective study was carried out at an elective orthopaedic centre over a 5-month period. All new adult referrals to the department were asked to complete a seven-point questionnaire on waiting time preference and possible reasons for delaying surgery. No paediatric or spinal orthopaedics was carried out at the centre. RESULTS: A total of 73 % of the 797 questionnaires were completed. Up to 16 % of patients could not accept day-case/inpatient operation within 6 weeks. Work commitment was the most common reason for choosing to delay surgery, with nearly 50 % of employed patients citing it as a reason. No significant difference was identified between inpatient and day-case procedures. CONCLUSION: There is a risk that operative slots will be unfilled within the 18-week pathway. 18 % of patients will potentially refuse an operative date offered within 6 weeks of their outpatient visit. Work, holidays and care arrangements are important in uptake. A proactive strategy to improve the uptake of offered surgery is required to prevent operating slots being underutilised. PMID- 24756180 TI - Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer. AB - Myofibroblasts in the stroma of pancreatic cancers promote tumor proliferation, invasion and metastasis by increasing extracellular matrix and secretion of several growth factors. In contrast, the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer has not yet been determined. This study was designed to assess the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer. Three primary cultures of human peritoneal myofibroblasts (hPMFs) were established from disseminated sites of pancreatic cancer and their interactions with the SUIT-2 and CAPAN-1 human pancreatic cancer cell lines were analyzed in vitro. Using a model in BALB/c nu/nu mice, we compared the dissemination ability of intraperitoneally implanted pancreatic cancer cells, with and without hPMFs, and examined the presence of green fluorescent protein (GFP)-labeled hPMFs at peritoneally disseminated sites in mice. hPMFs significantly promoted the migration and invasion of pancreatic cancer cells (P<0.05), while the cancer cells significantly promoted the migration and invasion of hPMFs (P<0.05). In vivo, the number of peritoneally disseminated nodules, more than 3 mm in size, was significantly greater in mice implanted with cancer cells plus hPMFs compared to mice implanted with cancer cells alone, with GFP-labeled hPMFs surviving in the peritoneal cavity of the former. hPMFs promote the peritoneal dissemination of pancreatic cancer. The cancer-stromal cell interaction in the peritoneal cavity may be a new therapeutic target to prevent the dissemination of pancreatic cancer. PMID- 24756182 TI - Segregation effects on the properties of (AuAg)147. AB - AuAg nanoclusters are promising supported co-catalysts for photocatalytic hydrogen reduction. However, beyond the quantum regime (N > 100) little is known about how the electronic properties of these nanoparticles are affected by chemical ordering. We investigate the effects of chemical ordering on the properties of 147-atom cuboctahedral AuAg nanoclusters, using empirical potentials coupled with an atomic-swap basin-hopping search to optimise the elemental distribution, with the lowest energy arrangements then reminimised using Density Functional Theory (DFT). Force-field calculations show Au atoms preferentially occupy sub-surface positions in the bimetallic structures, which results in the formation of a pseudo-onion structure for Ag-rich compositions. At the DFT-level, however, an Ag core surrounded by an Au shell (Ag@Au) is energetically favoured, as electron density can be drawn more readily when Au atoms are positioned on the nanocluster surface, thus resulting in a partial negative charge. Core@shell configurations are analogous to structures that can be chemically synthesised, and further detailed electronic analysis is discussed in the context of nanocluster applications to co-catalysed photocatalysis. PMID- 24756181 TI - The role of fluoride in montmorillonite-catalyzed RNA synthesis. AB - The montmorillonite-catalyzed reactions of the 5'-phosphorimidazolide of adenosine in the presence of fluoride were investigated to complete our study on the effect of salts on this type of reaction. Both anions and cations have been found to influence the oligomerization reactions of the activated nucleotides, being used here as a model system for pre-biotic RNA synthesis. However, in total contrast to the behavior of the activated nucleotides in the presence of montmorillonite and other salts, alkali metal fluorides did not yield any detectable oligomerization products except in very dilute (<0.005 M) solutions of fluoride. Instead, 5'-phosphorofluoridates were formed. Their identity was confirmed by a combination of HPLC, mass spectrometry, synthesis, and NMR. PMID- 24756183 TI - Infantile spasms and hyperekplexia associated with isolated sulfite oxidase deficiency. AB - IMPORTANCE: Isolated sulfite oxidase deficiency (ISOD) causes severe intellectual disability, epilepsy, and shortened life expectancy. Intractable seizures are invariable in children with ISOD; however, to our knowledge, infantile spasms with a corresponding hypsarrhythmia pattern on electroencephalogram have never been reported. In addition, the nonepileptic paroxysmal movement disorder hyperekplexia has not previously been reported with ISOD. OBSERVATIONS: We describe an infant with ISOD who initially presented with neonatal seizures, diffusion restriction noted on magnetic resonance imaging, and elevated serum S sulfocysteine consistent with ISOD. A homozygous mutation in the SUOX gene was identified, confirming the diagnosis. Uniquely, this patient developed a profound accentuated startle response that did not have a corresponding electrographic change on electroencephalogram consistent with hyperekplexia. This was followed by a change in the child's electroencephalogram to the chaotic pattern of hypsarrhythmia and brief tonic seizures with attenuation of the hypsarrhythmia pattern characteristic of infantile spasms. CONCLUSIONS AND RELEVANCE: The evolution of seizures associated with ISOD is poorly characterized because of the small number of patients. We report what we believe to be the first case of a child with ISOD who developed infantile spasms and hyperekplexia. This expands the phenotypes associated with ISOD and also should caution clinicians to not assume that all abnormal movements are seizures. PMID- 24756184 TI - Emerging double helical nanostructures. AB - As one of the most important and land-mark structures found in nature, a double helix consists of two congruent single helices with the same axis or a translation along the axis. This double helical structure renders the deoxyribonucleic acid (DNA) the crucial biomolecule in evolution and metabolism. DNA-like double helical nanostructures are probably the most fantastic yet ubiquitous geometry at the nanoscale level, which are expected to exhibit exceptional and even rather different properties due to the unique organization of the two single helices and their synergistic effect. The organization of nanomaterials into double helical structures is an emerging hot topic for nanomaterials science due to their promising exceptional unique properties and applications. This review focuses on the state-of-the-art research progress for the fabrication of double-helical nanostructures based on 'bottom-up' and 'top down' strategies. The relevant nanoscale, mesoscale, and macroscopic scale fabrication methods, as well as the properties of the double helical nanostructures are included. Critical perspectives are devoted to the synthesis principles and potential applications in this emerging research area. A multidisciplinary approach from the scope of nanoscience, physics, chemistry, materials, engineering, and other application areas is still required to the well controlled and large-scale synthesis, mechanism, property, and application exploration of double helical nanostructures. PMID- 24756185 TI - Letter in response: breast cancer screening of women aged 70-74 years. AB - The purpose of this study is to critically appraise the claim by Nickson et al. [1] that they have evidence supporting the Australian Government's recent decision to extend the national free invitation for biennial mammography program (BreastScreen) to women aged 70-74 years. Since their claim was made on the basis of a significant difference in the incidence of larger primary breast cancers between women in this age group who are already participating in BreastScreen versus those who are not, an analysis of the stage at diagnosis of breast cancer in the USA versus mammographic screening over 30 years, evidence from breast cancer adjuvant endocrine and chemotherapy (adjuvant therapy) trials and data from an evaluation of BreastScreen and adjuvant therapy use in Australia were examined. By 1999, most Australian women aged 40-79 years were receiving adjuvant therapy that could cure breast cancer no matter what the size of the primary cancer. Further, the incidence primary breast cancers of all sizes had doubled in the USA during 30 years of mammographic screening, but the incidence of more advanced breast cancers had almost remained constant, indicating that adjuvant therapy, not mammographic screening, was the main cause of the 28 % reduction in breast cancer mortality that had been observed. In conclusion, the claim by Nickson et al. is not supported by available evidence. Further, BreastScreen should not have been extended to these older women before the UK trial, which is testing the efficacy of mammographic screening of women aged 70-74 years [8], had reported its results. PMID- 24756186 TI - Effect of melatonin on depressive symptoms and anxiety in patients undergoing breast cancer surgery: a randomized, double-blind, placebo-controlled trial. AB - Depression, anxiety and sleep disturbances are known problems in patients with breast cancer. The effect of melatonin as an antidepressant in humans with cancer has not been investigated. We investigated whether melatonin could lower the risk of depressive symptoms in women with breast cancer in a three-month period after surgery and assessed the effect of melatonin on subjective parameters: anxiety, sleep, general well-being, fatigue, pain and sleepiness. Randomized, double blind, placebo-controlled trial undertaken from July 2011 to December 2012 at a department of breast surgery in Copenhagen, Denmark. Women, 30-75 years, undergoing surgery for breast cancer and without signs of depression on Major Depression Inventory (MDI) were included 1 week before surgery and received 6 mg oral melatonin or placebo for 3 months. The primary outcome was the incidence of depressive symptoms measured by MDI. The secondary outcomes were area under the curve (AUC) for the subjective parameters. 54 patients were randomized to melatonin (n = 28) or placebo (n = 26) and 11 withdrew from the study (10 placebo group and 1 melatonin group, P = 0.002). The risk of developing depressive symptoms was significantly lower with melatonin than with placebo (3 [11 %] of 27 vs. 9 [45 %] of 20; relative risk 0.25 [95 % CI 0.077-0.80]), giving a NNT of 3.0 [95 % CI 1.7-11.0]. No significant differences were found between AUC for the subjective parameters. No differences in side effects were found (P = 0.78). Melatonin significantly reduced the risk of depressive symptoms in women with breast cancer during a three-month period after surgery. PMID- 24756187 TI - Patterns of chemotherapy, toxicity, and short-term outcomes for older women receiving adjuvant trastuzumab-based therapy. AB - Limited data are available regarding patterns of chemotherapy receipt and treatment-related toxicities for older women receiving adjuvant trastuzumab-based therapy. We used surveillance, epidemiology and end results (SEER)-Medicare data to identify patients >=66 years with stage I-III breast cancer treated during 2005-2009, who received trastuzumab-based therapy. We examined patterns of chemotherapy receipt, and using multivariable logistic regression, we examined associations of age and comorbidity with non-standard chemotherapy. In propensity weighted cohorts of women receiving standard and non-standard trastuzumab-based therapy, we also examined rates of (1) hospital events during the first 6 months of chemotherapy and (2) short-term survival. Among 2,106 women, 29.7 % were aged >=76 and 66 % had a comorbidity score = 0. Overall, 31.3 % of women received non standard chemotherapy. Compared to patients aged 66-70, older patients more often received non-standard chemotherapy [adjusted odds ratio (OR) = 4.1, 95 % confidence interval (CI) = 3.40-4.92 (ages 76-80); OR = 15.3, 95 %CI = 9.92-23.67 (age >= 80)]. However, comorbidity was not associated with receipt of non standard chemotherapy. After propensity score adjustment, hospitalizations were more frequent in the standard (vs. non-standard) group (adjusted OR = 1.7, 95 % CI = 1.29-2.24). With a median follow-up of 2.8 years, 276 deaths occurred; the adjusted hazard ratio (HR) for death was lower in standard versus non-standard treated women (HR = 0.69, 95 % CI = 0.52-0.91). Among a population-based cohort of older women receiving trastuzumab, nearly one-third received non-standard chemotherapy, with the highest rates among the oldest women. Non-standard chemotherapy was associated with fewer toxicity-related hospitalizations but worse survival. Further exploration of treatment toxicities and outcomes for older women with HER2-positive breast cancer is warranted. PMID- 24756188 TI - [Assessment and quality assurance of refractive surgical interventions by the DOG (German Society of Ophthalmology) and the BVA (Professional Association of German Ophthalmologists): Update January 2014]. PMID- 24756189 TI - [New therapeutic strategies for retinoblastoma: non-systemic chemotherapy]. AB - Retinoblastoma is the most common primary intraocular malignancy worldwide. The known established standard therapies for bilateral disease, such as external beam radiation therapy or systemic chemotherapy often lead to a higher morbidity and increased risk of secondary malignancies, especially with radiation therapy. Therefore, new non-systemic chemotherapy strategies, such as the intra-arterial or intravitreal administration of melphalan are being revised with the aim of reducing systemic side effects. PMID- 24756190 TI - [Pseudotumor cerebri syndrome]. AB - Pseudotumor cerebri is a non-tumor related idiopathic or secondary intracranial hypertension. It is typically associated with papilledema and headache and patients are typically female, young and obese. Diagnosis is established by neuroimaging by magnetic resonance imaging (MRI), cerebral MR venography (MRV) and lumbar puncture. Papilledema is assessed by ophthalmoscopy, ultrasound and optical coherence tomography. Ophthalmologists monitor visual function by measuring visual acuity and visual field testing. Therapy of patients not facing immediate visual loss encompasses weight reduction and administration of carbonic anhydrase inhibitors. In vision-threatening situations invasive procedures are necessary, such as repeated lumbar puncture, liquor drainage, optic nerve sheath fenestration and endovascular venous stenting. PMID- 24756191 TI - Wernekink commissure syndrome secondary to ischemic stroke: severe dysarthria is one of the main characteristics of this syndrome. PMID- 24756192 TI - Non-alcoholic fatty liver disease in patients with migraine. AB - Evidence suggests that migraine is associated with metabolic syndrome, which is also implicated in non-alcoholic fatty liver disease (NAFLD). Reported for the first time, we aimed to investigate the relationship between migraine and NAFLD in patients with migraine. A total of 90 consecutive migraine patients were enrolled in this cross-sectional study. The diagnosis of migraine was determined according to the International Classification of Headache Disorders-II diagnostic criteria. The diagnosis of NAFLD was based on abdominal ultrasonography findings. Anthropometric indices and the homeostasis model assessment of insulin resistance (HOMA-IR) were calculated, and serum insulin level measurements and other biochemical analyses were performed for each subject. The measurements of body mass index and waist circumference were significantly higher in migraine patients with NAFLD than in those without NAFLD (p < 0.001). Regarding the laboratory results, insulin (p = 0.024), alanine aminotransferase (p = 0.027), and triglyceride levels (p = 0.001) and the HOMA-IR (p = 0.039) were higher in migraineurs with NAFLD than in those without NAFLD. Among the headache characteristics, the presence of aura was higher, and disease and attack durations were significantly longer in migraineurs with NAFLD than in those without NAFLD (p = 0.005, p = 0.024, and p = 0.023; respectively). However, the headache characteristics did not correlate with either the hepatosteatosis grade or HOMA-IR in migraine patients (p > 0.05). Our results show that NAFLD may present in migraine patients with higher frequency of auras and longer disease and attack durations. PMID- 24756193 TI - Multiple sclerosis rebound after fingolimod discontinuation for lymphopenia. PMID- 24756194 TI - Christian VII of Denmark and Tourette syndrome: fact or fiction? PMID- 24756195 TI - Application of quasi-equilibrated thermodesorption of linear and di-branched paraffin molecules for detailed porosity characterization of the mono-layered zeolite MCM-56, in comparison with MCM-22 and ZSM-5. AB - The pore characteristics of zeolite samples including two kinds of ZSM-5 crystals as a base case and the unique mono-layered MCM-56 in different structural forms have been studied by the new method QE-TPDA (quasi-equilibrated temperature programmed desorption and adsorption) in comparison with the standard nitrogen adsorption. Both approaches produce consistent results in terms of micro- and meso-porous features as well as quantitative pore volume values. The benefits of QE-TPDA include fast data acquisition (hours) and small sample size (milligrams). It is very flexible in using various hydrocarbons as probe molecules, which may reveal additional details associated with pores, their internal environment and dimensions/shape of the sorbate molecules. Hence, QE-TPDA is a valuable complementary tool for porosity characterization of the ever increasing diversity of porous materials and their pore structures. This was demonstrated by the results for the desorption of nonane and 2,2-dimethyloctane (DMO). The latter showed an additional maximum in the intermediate temperature range (between 'micro-' and 'mesopore' regions) which could be attributed to adsorption in the subsurface micropores (i.e. the pore mouths) where DMO could be partially adsorbed with t-butyl groups remaining on the outside. This was also reflected in the discrepancy between apparent volumes of micro- and mesopores calculated from the nonane and DMO experiments. Pillared MCM-56 revealed visibly enhanced subsurface micropore adsorption compared to the parent (mono-layer MWW) and MCM 22 (multi-layered MWW) consistent with the expected increase in the content of external 12 ring surface cups. PMID- 24756196 TI - Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation. AB - Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca(2+)-activated K(+) channels and inward rectifier K(+) channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2 mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4 AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2. PMID- 24756197 TI - Cyclic AMP synthesis and hydrolysis in the normal and failing heart. AB - Cyclic AMP regulates a multitude of cellular responses and orchestrates a network of intracellular events. In the heart, cAMP is the main second messenger of the beta-adrenergic receptor (beta-AR) pathway producing positive chronotropic, inotropic, and lusitropic effects during sympathetic stimulation. Whereas short term stimulation of beta-AR/cAMP is beneficial for the heart, chronic activation of this pathway triggers pathological cardiac remodeling, which may ultimately lead to heart failure (HF). Cyclic AMP is controlled by two families of enzymes with opposite actions: adenylyl cyclases, which control cAMP production and phosphodiesterases, which control its degradation. The large number of families and isoforms of these enzymes, their different localization within the cell, and their organization in macromolecular complexes leads to a high level of compartmentation, both in space and time, of cAMP signaling in cardiac myocytes. Here, we review the expression level, molecular characteristics, functional properties, and roles of the different adenylyl cyclase and phosphodiesterase families expressed in heart muscle and the changes that occur in cardiac hypertrophy and failure. PMID- 24756198 TI - MicroRNA-23a has minimal effect on endurance exercise-induced adaptation of mouse skeletal muscle. AB - Skeletal muscles contain several subtypes of myofibers that differ in contractile and metabolic properties. Transcriptional control of fiber-type specification and adaptation has been intensively investigated over the past several decades. Recently, microRNA (miRNA)-mediated posttranscriptional gene regulation has attracted increasing attention. MiR-23a targets key molecules regulating contractile and metabolic properties of skeletal muscle, such as myosin heavy chains and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1alpha). In the present study, we analyzed the skeletal muscle phenotype of miR-23a transgenic (miR-23a Tg) mice to explore whether forced expression of miR 23a affects markers of mitochondrial content, muscle fiber composition, and muscle adaptations induced by 4 weeks of voluntary wheel running. When compared with wild-type mice, protein markers of mitochondrial content, including PGC 1alpha, and cytochrome c oxidase complex IV (COX IV), were significantly decreased in the slow soleus muscle, but not the fast plantaris muscle of miR-23a Tg mice. There was a decrease in type IId/x fibers only in the soleus muscle of the Tg mice. Following 4 weeks of voluntary wheel running, there was no difference in the endurance exercise capacity as well as in several muscle adaptive responses including an increase in muscle mass, capillary density, or the protein content of myosin heavy-chain IIa, PGC-1alpha, COX IV, and cytochrome c. These results show that miR-23a targets PGC-1alpha and regulates basal metabolic properties of slow but not fast twitch muscles. Elevated levels of miR 23a did not impact on whole body endurance capacity or exercise-induced muscle adaptations in the fast plantaris muscle. PMID- 24756200 TI - A tetranaphthoimidazolium receptor as a fluorescent chemosensor for phytate. AB - A new tetranaphthoimidazolium receptor was synthesized and reported to be a selective fluorescent chemosensor for phytate, myo-inositol hexakisphosphate (IP6). In a 100% aqueous solution at pH 7.4, chemosensor 1 showed a selective fluorescence enhancement for IP6 over IP3, phosphates, pyrophosphates, AMP, ADP and ATP. An excimer emission at 465 nm linearly increases in the range of 300 nM to 1 MUM with a detection limit of 2.28 * 10(-7) M. In addition, first live cell imaging of IP6 has been demonstrated by using a synthetic receptor. PMID- 24756201 TI - Assessment of genotoxic induction and deterioration of fish quality in commercial species due to heavy-metal exposure in an urban reservoir. AB - The aim of the study was to evaluate the effect of heavy-metal contamination on two fish species (Channa striatus and Heteropneustes fossilis) inhabiting a small freshwater body of northern India. After being captured, each specimen was weighed, measured, and analyzed for heavy metals (chromium [Cr], nickel [Ni], and lead [Pb]). Accumulation of heavy metals was found to be significantly greater (p < 0.05) in different tissues (gill, liver, kidney, and muscle) of fishes captured from the reservoir than from the reference site. Levels of heavy-metal contamination in Shah jamal water was Cr (1.51 mg/l) > Ni (1.22 mg/l) > Pb (0.38 mg/l), which is significantly greater than World Health Organization standards. Bioaccumulation factor was calculated, and it was observed that Pb was most detrimental heavy metal. Condition factor was also influenced. Micronucleus test of fish erythrocytes and comet assay of liver cells confirmed genotoxicity induced by heavy-metal contamination in fishes. Heavy metals (Cr, Ni, and Pb) were increased in both fish species as determined using recommended values of Federal Environmental Protection Agency for edible fishes. This raises a serious concern because these fishes are consumed by the local populations and hence would ultimately affect human health. PMID- 24756199 TI - Involvement of bradykinin in brain edema development after ischemic stroke. AB - Stroke is the third leading cause of death in the Western world. Ischemic stroke is characterized by a rapid loss of brain function due to disturbance in the blood supply to a part of the brain. Due to fixed intracranial space, any increase in intracranial fluid volume, or progressive brain edema formation, contributes to further deterioration of the already impaired brain function. Bradykinin increases blood-brain barrier permeability and raises intracranial capillary blood pressure by arterial dilatation and venous constriction leading to brain edema formation. The aim of this paper is to summarize the recent research in the field of bradykinin function (structure, synthesis, signaling pathways, mechanism of action) followed by characterization of different types of brain edema development related to ischemic brain injury, together with the involvement of bradykinin in edema formation. Since there is currently no causal treatment addressing brain edema after ischemic stroke, specific bradykinin receptor antagonists are proposed as a possible new therapeutic approach. PMID- 24756202 TI - Complex rostral neurovascular system in a giant pliosaur. AB - Pliosaurs were a long-lived, ubiquitous group of Mesozoic marine predators attaining large body sizes (up to 12 m). Despite much being known about their ecology and behaviour, the mechanisms they adopted for prey detection have been poorly investigated and represent a mystery to date. Complex neurovascular systems in many vertebrate rostra have evolved for prey detection. However, information on the occurrence of such systems in fossil taxa is extremely limited because of poor preservation potential. The neurovascular complex from the snout of an exceptionally well-preserved pliosaur from the Kimmeridgian (Late Jurassic, c. 170 Myr ago) of Weymouth Bay (Dorset, UK) is described here for the first time. Using computed tomography (CT) scans, the extensive bifurcating neurovascular channels could be traced through the rostrum to both the teeth and the foramina on the dorsal and lateral surface of the snout. The structures on the surface of the skull and the high concentrations of peripheral rami suggest that this could be a sensory system, perhaps similar to crocodile pressure receptors or shark electroreceptors. PMID- 24756203 TI - Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses. AB - Emerging evidence has unveiled a critical role for immunological parameters in predicting tumor prognosis and clinical responses to anticancer therapeutics. On the other hand, responsiveness to anticancer drugs greatly modifies the repertoires, phenotypes, and immunogenicity of tumor-infiltrating immune cells, serving as a critical factor to regulate tumorigenic activities and the emergence of therapy-resistant phenotypes. Tumor-associated immune functions are influenced by distinct or overlapping sets of therapeutic modalities, such as cytotoxic chemotherapy, radiotherapy, or molecular-targeted therapy, and various anticancer modalities have unique properties to influence the mode of cross-talk between tumor cells and immune cells in tumor microenvironments. Thus, it is critical to understand precise molecular machineries whereby each anticancer strategy has a distinct or overlapping role in regulating the dynamism of reciprocal communication between tumor and immune cells in tumor microenvironments. Such an understanding will open new therapeutic opportunities by harnessing the immune system to overcome resistance to conventional anticancer drugs. PMID- 24756204 TI - Expanded C9ORF72 hexanucleotide repeat in depressive pseudodementia. AB - IMPORTANCE: Expanded hexanucleotide repeats in C9ORF72 are a common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. Repeat expansions have also been detected infrequently in other disorders, including Alzheimer disease, dementia with Lewy bodies, and parkinsonian disorders. OBSERVATIONS: A consecutive series of 31 cases from the brain bank for neurodegenerative disorders at Mayo Clinic was screened to assess the incidence of the expanded C9ORF72 repeat in cases of depressive pseudodementia. The presence of the hexanucleotide repeat was established using immunohistochemistry with a highly disease-specific antibody (C9RANT), and was further validated in carriers using repeat-primed polymerase chain reaction and Southern blotting. Two individuals harbored the C9ORF72 repeat expansion. Both patients were men with refractory depression. One patient experienced drug-induced parkinsonism and sudden-onset dementia, while the other patient had a more insidious disease course suspected to be Alzheimer disease. CONCLUSIONS AND RELEVANCE: This report increases the range of clinicopathologic presentations of C9ORF72 expanded hexanucleotide repeat to include psychiatric disorders such as depressive pseudodementia. PMID- 24756207 TI - Online first publication. PMID- 24756205 TI - Investigating drug induced changes in single, living lymphocytes based on Raman micro-spectroscopy. AB - Raman spectroscopy is a powerful tool for label-free, single cell characterization. In many reported studies, a Raman spectrum is acquired from a fraction of the cell volume and used as a representative signature of the whole cell to identify and discriminate between cell populations. It has remained an open question whether this is the most suitable approach since the spectra may not truly represent the cell as a whole and critical biochemical information could therefore be lost. To address this question, we developed a line-scan Raman microscope to acquire Raman images of single lymphocytes exposed to the chemotherapeutic drug doxorubicin for 24 to 96 hours. Principal component analysis was able to separate cells based on their drug-exposure times. Difference spectra on the mean data for the different time-points revealed that changes are related to a decrease in mean nucleic acid content and an increase in mean protein and lipid content. Vertex component analysis was used to extract the pure component spectra of lipids, nucleic acids, and proteins. Quantitative analysis of the data revealed that biochemical changes occurred at both local subcellular (i.e. molecular density) and global cellular (i.e. total observable molecular content) levels. However, significant differences between the trends in the local and global changes were observed. While local nucleic acid content decreased with increasing drug exposure time, the total cellular nucleic acid content remained relatively constant. For protein, local content remained relatively constant for all exposure times while the total protein content in the cell increased ~3 fold. Lipid content in the entire cell increased ~5 fold, compared to a smaller increase in lipid at the local level. These results show that valuable information about the biochemical changes throughout the entire cell can be missed if only Raman spectra of localized cell regions are used. These findings are expected to have a major impact on the future development of Raman spectroscopy for cytometry applications. PMID- 24756208 TI - Erratum: journal of comparative physiology a (1999) 184: 481-488. PMID- 24756209 TI - Clinical and microbiological characteristics of Klebsiella pneumoniae from community-acquired recurrent urinary tract infections. AB - Understanding the pathogenesis of recurrent urinary tract infection (RUTI) and whether it is attributable to reinfection with a new strain or relapse with the primary infecting strain is of considerable importance. Because previous studies regarding community-acquired Klebsiella pneumoniae RUTI are inconclusive, we undertook this study to evaluate the characteristics of the host and the bacterial agent K. pneumoniae in RUTI. A prospective study was designed, using consecutive patients diagnosed with community-acquired K. pneumoniae-related UTI from January 2007 to December 2009. Of the total 468 consecutive episodes, we found 7 patients with RUTI. All the patients with RUTI were elderly (median, 74 years), with diabetes (100 %, 7 out of 7). Clinical K. pneumoniae isolates derived from the same patients with RUTI revealed identical genomic fingerprints, indicating that K. pneumoniae UTI relapsed despite appropriate antibiotic therapy. The antimicrobial resistance, growth curve and biofilm formation of the recurrent isolates did not change. K. pneumoniae strains causing RUTI had more adhesion and invasiveness than the colonization strains (p < 0.01). When we compared the recurrent strains with the community-acquired UTI strains, the prevalence of diabetes mellitus was significant (100 % vs 53.7 %, p = 0.03) in the RUTI group. Our data suggest that K. pneumoniae strains might be able to persist within the urinary tract despite appropriate antibiotic treatment, and the greater adhesion and invasiveness in the recurrent strains may play an important role in recurrent infections. PMID- 24756210 TI - Epidemiological analysis on two decades of hospitalisations for meningitis in the United States. AB - Bacterial meningitis is an important source of mortality and morbidity worldwide. Data exist on specific vaccines against Streptococcus pneumoniae and Neisseria meningitidis indicating that they reduce the incidence of meningitis, yet comprehensive information on the trend of bacterial meningitis is still lacking. We analysed the Kids' Inpatient Database and the National Inpatient Database considering all bacterial meningitides in the United States, excluding cases of tuberculosis and sexually transmitted diseases. We analysed the trend of meningitis incidence from 1993 to 2011 and in specific age groups before and after the introduction of the pneumococcal conjugate vaccine 7 (PCV-7) and the meningococcal conjugate vaccine 4 (MCV-4). Moreover, we analysed the prevalence of aetiological agents to assess their changes. We estimated 295,706 cases of meningitis having occurred in the United States and a reduction of the discharge rate of 21 %. We observed a significant reduction in cases of meningitis in children and elderly patients following the introduction of the PCV-7. We also found a reduction in subjects aged 10-14 years, an age span consistent with the introduction of MCV-4, although further analyses based on serotypes data are required to confirm this observation. By contrast, we observed an increased prevalence of cases of staphylococcal and streptococcal meningitides. The introduction of PCV-7 has reduced the incidence and changed significantly the aetiology of bacterial meningitis in the United States during the last two decades. PMID- 24756211 TI - Risk factors for bacterial vaginosis: results from a cross-sectional study having a sample of 53,652 women. AB - The aim of this study was to estimate the risk factors of bacterial vaginosis (BV) among rural married women of childbearing age in Anhui Province of China. A cross-sectional study was conducted and the method of stratified cluster sampling was used to identify a sample of 53,652 married women aged 18-49 years. All women were asked to complete an interviewer-administered standardized questionnaire, covering sociodemographic characteristics, history of menstruation, marriage and procreation, sexual life, personal hygienic behaviors, and reproductive tract infections (RTIs) knowledge, followed by the gynecological examination and laboratory inspection. A total of 53,286 married women aged 18-49 years were included in this analysis. The prevalence of BV was 11.99 % (6,391/53,286). Risk factors for BV included the minority nationality, women's lower education levels, husband's elder age, over 35 days of menstrual cycle, less than 3 days of menstruation, dysmenorrhea, usage of an intrauterine device (IUD), lack of RTIs knowledge, higher frequency of washing genitals before having sex with husband and changing underwear, lower frequency of sexual intercourse per month, and suffering from other RTIs. The results suggest that BV can be affected by many factors among rural married women of reproductive age, so comprehensive, scheduled programs at healthcare educations should be provided for women in order to prevent BV. PMID- 24756212 TI - Decline of IgG pertussis toxin measured in umbilical cord blood, and neonatal and early infant serum. AB - Maternal pertussis-specific antibodies are passively acquired by infants during pregnancy. An IgG pertussis toxin (IgG-PT) concentration of >20 U/ml is considered to protect neonates against pertussis. To evaluate the IgG concentration at birth and during the first two months of life, we examined the IgG-PT concentration in the umbilical cord blood and three times during the neonatal and early infant period. IgG-PT was measured by validated IgG-specific enzyme-linked immunosorbent assays (ELISA) in umbilical cord blood and in Guthrie card blood samples of umbilical cord blood in 2,790 children, born between 1 August 2006 and 1 December 2008. These measurements were comparable. All children with concentrations of IgG-PT >30 U/ml were included. IgG-PT was also measured in Guthrie card blood samples, when the neonates or early infants were 5 days, 1 month and 2 months old. The mean concentrations of IgG-PT were calculated. The mean concentration of IgG-PT in umbilical cord blood was 60.1 U/ml (LN 4.1; 0.6 SD; n = 103). At the age of 5 days, 1 month and 2 months, the mean concentration of IgG-PT was 40.6 U/ml (LN 3.7; 0.5 SD; n = 103), 20.7 U/ml (LN 3.0; 0.7 SD; n = 62) and 16.7 U/ml (LN 2.8; 0.9 SD; n = 61), respectively. Four percent of the neonates had a concentration of IgG-PT >30 U/ml in umbilical cord blood, which declined to levels around the concentration needed for protection against pertussis (>20 U/ml) in the first two months of life. Hence, it is of great importance to further investigate the safety of maternal immunisation during pregnancy to prevent life-threatening pertussis in newborns. PMID- 24756213 TI - Solvation dependence of valence electronic states of water diluted in organic solvents probed by soft X-ray spectroscopy. AB - Knowledge of hydrogen bonds is important in a wide range of scientific fields. However, information on the electronic state of hydrogen bonded molecules in liquids and solutions is still limited. We applied X-ray emission and absorption spectroscopy to observe the electronic state around oxygen of water and investigate the solvent dependence of occupied and unoccupied valence electronic states of water in acetonitrile, 3-methylpyridine, and ethylenediamine at room temperature under atmospheric pressure. Based on the direct comparison of the spectra, the pronounced variation of the unoccupied 2b2 state of water in acetonitrile and 3-methylpyridine was assigned to the difference of the dipole dipole interaction and the donor hydrogen bond. For ethylenediamine solution, an enhancement of the peak structure in the post-edge region of X-ray absorption spectra and an evident shoulder structure on the higher energy side of the occupied 1b1 state in X-ray emission spectra were observed. Although ethylenediamine has two amino groups that can form the hydrogen bonds as a proton donor, the obtained results indicate that the amino groups of ethylenediamine also act as a proton acceptor in the hydrogen bond between water molecules. A systematic peak intensity variation of the pre-edge peak corresponding to the lowest unoccupied molecular orbital, 4a1, was also found through the comparison of three organic solvents. Since the peak intensity tends to decrease with increasing number of hydrogen bonds, the results can be interpreted by the covalency of hydrogen bonds. PMID- 24756214 TI - Synthesis and in vitro assessment of a bifunctional closomer probe for fluorine ((19)F) magnetic resonance and optical bimodal cellular imaging. AB - The design, synthesis and in vitro assessment of a bifunctional imaging probe for dual fluorine ((19)F) magnetic resonance spectroscopy ((19)F-MRS) and fluorescence detection is reported. Eleven copies of 3,5 bis(trifluoromethyl)phenyl and a single copy of a sulforhodamine-B were covalently attached to a closo-B12(2-)-core via suitable linkers. The (19)F-MRS and fluorescence imaging shows that, this novel bimodal imaging probe was readily taken up by the cells in vitro after co-incubation. PMID- 24756215 TI - Absence of estrogen receptor alpha (ESR1) gene amplification in a series of breast cancers in Taiwan. AB - Immunohistochemical expression of ERalpha, encoded by the ESR1 (estrogen receptor 1) gene located at 6q25.1, is the most important determinant of responsiveness to endocrine therapy in breast cancer. The prevalence and significance of ESR1 amplification in breast cancer remain controversial. We set out to assess ESR1 status and its relevance in breast cancer in Taiwan. We tested tissue samples from 311 invasive carcinomas in a tissue microarray for ESR1 status by fluorescent in situ hybridization (FISH) and chromogenic in situ hybridization (CISH). In order to examine its association with ERalpha and ESR1 status, HER2 status was determined by FISH. Of the carcinomas, 58.8 % (183/311) was ERalpha positive. None of the carcinomas showed amplification of ESR1 by either method, whereas 24.1 % (75/311) of the carcinomas harbored HER2 amplification. Of the carcinomas, 9.6 % (26/301) showed ESR1 gain (1.3 <= ratio ESR1/chromosome 6 < 2) by FISH and 10 % (24/299) by CISH. FISH and CISH results showed a good correlation (kappa-coefficient = 0.786). ESR1 gain by FISH and CISH was significantly associated with high-grade (P = 0.0294 and 0.0417, respectively) but not with ERalpha expression, HER2 status, or overall survival. ERalpha positivity was significantly associated with better overall survival (P = 0.039). HER2 amplification was significantly related with poor overall survival (P = 0.002). Our data confirm that in breast cancer, HER2 amplification is a frequent genetic aberration and a negative prognostic factor, and show that ESR1 amplification is not a key genetic abnormality in the tumorigenesis of breast cancer in Taiwan. PMID- 24756216 TI - BUB1 mRNA is significantly co-expressed with AURKA and AURKB mRNA in advanced stage ovarian serous carcinoma. AB - The objective of this study was to investigate the expression and clinical role of the spindle checkpoint kinase budding uninhibited by benzimidazole 1 (Bub1) in primary and metastatic advanced-stage ovarian serous carcinoma. BUB1 mRNA expression was analyzed in 178 tumors (88 effusions, 38 primary carcinomas, and 52 solid metastases) from 144 patients with advanced-stage disease using quantitative real-time polymerase chain reaction (PCR). Bub1 protein expression by Western blotting was studied in 63 carcinomas (30 effusions and 33 solid lesions). BUB1 mRNA expression at different anatomic sites was studied for association with clinicopathologic parameters, including chemotherapy resistance and survival. BUB1 mRNA was universally expressed in serous carcinomas, irrespective of anatomic site. BUB1 mRNA levels were uniformly low in six ovarian surface epithelium specimens analyzed for comparative purposes. Bub1 protein was expressed in 22/30 effusions and 28/33 solid lesions. BUB1 mRNA expression was significantly higher in chemo-naive primary carcinomas and solid metastases compared to specimens obtained following neoadjuvant chemotherapy (p < 0.001) and was unrelated to chemotherapy exposure in effusions nor to chemoresponse or survival at any anatomic site. BUB1 mRNA levels in both effusions and solid lesions were strongly related to the mRNA levels of AURKA and AURKB previously studied in this cohort (p < 0.001 for both). Bub1 is widely expressed in primary and metastatic OC, suggesting a biological role in this cancer. BUB1 mRNA levels are lower following chemotherapy exposure in solid lesions, though its presence is unrelated to clinical behavior including response to chemotherapy and survival. BUB1 is co-expressed with AURKA and AURKB suggesting biological relationship between these spindle cell components. PMID- 24756218 TI - Dynamics of unidirectional drying of colloidal dispersions. AB - We investigate the dynamics of unidirectional drying of silica dispersions. For small colloids (radii a < 15 nm), the minute recession of the drying interface inside the growing solid leads to a slowing down of the evaporation rate, as recently proposed by Wallenstein and Russel [J. Phys.: Condens. Matter, 2011, 23, 194104]. We first propose that Kelvin's effect, i.e. the reduction of the partial pressure of water in the presence of highly curved nanomenisci at the drying air dispersion interface, has to be taken into account, notably for such small colloids. Our model can fit qualitatively the literature measurements, but with a crossover between the linear regime and the slowing down regime that scales as a(2), as compared to the model of Wallenstein and Russel that predicts a linear scaling. We then also present careful measurements of the dynamics of solidification, which clearly demonstrate that both models (taking into account or not Kelvin's effect) do not fit correctly the slowing down. This is consistent with a brief review of similar recent measurements. Nevertheless, the dynamics can be correctly estimated with a significantly lower effective permeability of the solid region. We suggest that this result may come from the polydispersity of the suspensions, and from the inhomogeneity of the flow within the fracturated solid region, as illustrated by infiltration experiments of a coloured dye. PMID- 24756217 TI - Rating scales and questionnaires for assessment of sleep disorders in Parkinson's disease: what they inform about? AB - Sleep disorders are very prevalent in Parkinson's disease (PD) and include a diversity of disturbances. Rating scales and questionnaires are widely used to assess the presence and severity of the sleep disorders. The objective is to review rating scales and questionnaires used for assessment of sleep disorders in PD. To this purpose, a description and update of the sleep scales reviewed by the ad hoc Movement Disorder Society task force (MDS-TF) and other sleep disorder assessments was performed. Two specific (Parkinson's Disease Sleep Scale and Scales for Outcomes in PD Sleep) and two generic scales (Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale) were "Recommended" by the MDS-TF as they were used in PD patients, by researchers others than their developers and properly validated. Two other generic scales (Inappropriate Sleep Composite Score and Stanford Sleepiness Scale), "Suggested" due to incomplete validation, are also reviewed. Other instruments included in this review are three comprehensive PD specific instruments for assessing multiple domains in addition to sleep problems (e.g., Non-Motor Symptoms Questionnaire, Non-Motor Symptoms Scale, MDS-UPDRS), and three generic instruments focused on particular disturbances (e.g., International Restless Legs Syndrome Study Group Rating Scale, REM behavioral disorders questionnaires), although these latter lack formal validation in PD populations. The "Recommended" instruments cover satisfactorily the needs for screening and evaluation of the nocturnal sleep disorders and daytime sleepiness in PD patients. It would be convenient to validate or complete the validation in PD populations of those instruments that cannot be recommended due to the lack of information on their clinimetric attributes. PMID- 24756219 TI - Supramolecular architectures with pyridine-amide based ligands: discrete molecular assemblies and their applications. AB - Recent years have seen a surge of interest in supramolecular architectures with the focus shifting towards generating discrete molecular assemblies and factors controlling their formation. Such molecular assemblies offer a wide range of applications which are often architecture-dependent. To construct such assemblies, nitrogen-donor ligands have been intensively employed to generate an assorted variety of topologies. Out of various nitrogen-donor ligands, pyridine amide based ligands stand out as they not only offer structural flexibility and their ability to adjust to the geometrical requirements of a metal ion but also offer dual functional groups: pyridine and amide. The present perspective will focus on recent developments in the design of discrete supramolecular assemblies utilizing pyridine-amide based ligands with a specific stress on the architectural aspects and subsequent applications of designed molecular assemblies. PMID- 24756220 TI - Is effective, person-centred, home-based palliative care truly achievable? PMID- 24756221 TI - In vivo construction of tissue-engineered cartilage using adipose-derived stem cells and bioreactor technology. AB - The present study aims to investigate the feasibility of tissue-engineered cartilage constructed in vivo and in vitro by dynamically culturing adipose derived stem cells (ADSCs) with an articular cartilage acellular matrix in a bioreactor and subsequently implanting the cartilage in nude mice. ADSCs were proliferated, combined with three dimensional scaffolds (cell density: 5 * 10(7)/mL) and subsequently placed in a bioreactor and culture plate for 3 weeks. In the in vivo study, complexes cultured for 1 week under dynamic or static states were subcutaneously implanted into nude mice and collected after 3 weeks. Indicators such as gross morphology, histochemistry and immunohistochemistry were examined. In the in vitro study, histological observation showed that most scaffolds in the dynamic group were absorbed, and cell proliferation and matrix secretion were significant. Positive staining of safranin-O and alcian blue II collagen stain in the dynamic group was significantly stronger than that in the static culture group. In the in vivo study, cartilage-like tissues formed in the specimens of the two groups. Histological examination showed that cell distribution in the dynamic group was relatively more uniform than in the static group, and matrix secretion was relatively stronger. Bioreactor culturing can promote ADSC proliferation and cartilage differentiation and is thus a suitable method for constructing tissue-engineered cartilage in vivo. PMID- 24756222 TI - The PTEN/PI3K/Akt and Wnt/beta-catenin signaling pathways are involved in the inhibitory effect of resveratrol on human colon cancer cell proliferation. AB - Colon cancer is one of the most common malignancies and the treatments for colon cancer have been developed substantially in the last decades, but there is still a great clinical need to explore new treatment regimens due to the undesirable prognosis. In this investigation, we demonstrated the anti-proliferative and apoptosis-inducing activities of resveratrol (Res) in human colon cancer cells, and the possible mechanisms underlying these effects. We used crystal violet staining, flow cytometry and western blotting to validate the anti-proliferative and apoptosis-inducing effects of Res on HCT116 cells. A xenograft tumor model was used to confirm the anti-proliferative effects of Res. We employed polymerase chain reaction, western blotting, recombinant adenovirus and luciferase reporter assay to explore the possible mechanism(s) of action. We found that Res inhibits significantly the proliferation and promotes apoptosis in HCT116 cells, as well as inhibits the xenograft tumor growth of colon cancer. Res upregulates the expression of phosphatase and tensin homolog (PTEN) and decreases the phosphorylation of Akt1/2. The exogenous expression of PTEN inhibits the PI3K/Akt signal and promotes the anti-proliferative effects of Res in HCT116 cells, while knockdown of PTEN increases PI3K/Akt signal but reduces the anti-proliferative function of Res. The protein and mRNA expression of beta-catenin are all decreased by Res concentration-dependently. Thus, our findings strongly suggest that the anti-proliferative effects of Res in human colon cancer cells may be mediated by regulating separately the PTEN/PI3K/Akt and Wnt/beta-catenin signaling. PMID- 24756223 TI - The influence of human leukocyte antigen matching on outcomes in pediatric heart transplantation. AB - Previous adult heart transplantation studies have demonstrated that donor recipient human leukocyte antigen (HLA) matching results in reduced graft failure and improved patient survival. No study has examined these effects in children. This study investigated the effect of HLA matching on outcomes in pediatric heart transplantation. All pediatric heart transplantation data for patients 0-18 years of age available from the United Network for Organ Sharing Transplant Registry from 1987 to 2009 were analyzed retrospectively. Donor-recipient HLA matching at loci A, B, and DR (0-6) was compared with graft survival and recipient survival. For this study, 3,751 pediatric cardiac transplantation events with complete HLA matching data were identified and grouped as having 0 to 2 matches (3,416 events) or 3 to 6 matches (335 events). The 3- to 6-match group had less graft failure than the 0- to 2-match group (28.7% vs 34.4%; p = 0.035) and greater patient survival by 5 years (81% vs 72%; p = 0.045) and 10 years (66% vs 55%; p = 0.005) after transplantation. The HLA-DR matching alone resulted in less graft failure (p = 0.038) and improved patient survival (p = 0.017). A higher degree of HLA matching in pediatric heart transplantation is associated with decreased graft failure and improved patient survival. In this study, decreased graft failure rates and superior survival also were seen with DR matching alone. PMID- 24756224 TI - Idiopathic intracranial hypertension: important questions answered with more to come. PMID- 24756225 TI - Microfluidic-SERS devices for one shot limit-of-detection. AB - Microfluidic sensing platforms facilitate parallel, low sample volume detection using various optical signal transduction mechanisms. Herein, we introduce a simple mixing microfluidic device, enabling serial dilution of introduced analyte solution that terminates in five discrete sensing elements. We demonstrate the utility of this device with on-chip fluorescence and surface-enhanced Raman scattering (SERS) detection of analytes, and we demonstrate device use both when combined with a traditional inflexible SERS substrate and with SERS-active nanoparticles that are directly incorporated into microfluidic channels to create a flexible SERS platform. The results indicate, with varying sensitivities, that either flexible or inflexible devices can be easily used to create a calibration curve and perform a limit of detection study with a single experiment. PMID- 24756226 TI - Variation in birth outcomes by mother's country of birth among non-Hispanic black women in the United States. AB - Rates of prematurity (PTB) and small-for-gestational age (SGA) were compared between US-born and foreign-born non-Hispanic black women. Comparisons were also made between Sub-Saharan African-born and Caribbean-born black women and by maternal country of birth within the two regions. Comparisons were adjusted for sociodemographic, health behavioral and medical risk factors available on the birth record. Birth record data (2008) from all states (n = 27) where mother's country of birth was recorded were used. These data comprised 58 % of all singleton births to non-Hispanic black women in that year. Pearson Chi square and logistic regression were used to investigate variation in the rates of PTB and SGA by maternal nativity. Foreign-born non-Hispanic black women had significantly lower rates of PTB (OR 0.727; CI 0. 726, 0.727) and SGA (OR 0.742; CI 0.739 0.745) compared to US-born non-Hispanic black women in a fully adjusted model. Sub-Saharan African-born black women compared to Caribbean-born black women had significantly lower rates of PTB and SGA. Within each region, the rates of PTB and SGA varied by mother's country of birth. These differences could not be explained by adjustment for known risk factors obtained from vital records. Considerable heterogeneity in rates of PTB and SGA among non-Hispanic black women in the US by maternal nativity was documented and remained unexplained after adjustment for known risk factors. PMID- 24756228 TI - Associations of general parenting and parent-child relationship with pediatric obesity: a meta-analysis. AB - OBJECTIVE: The objective of the meta-analysis is to integrate available results on associations of general parenting (not specific to feeding and activity promotion) and parent-child relations with child weight status, eating, and physical activity. METHODS: Searching in electronic databases and cross referencing identified 156 empirical studies. Random-effects meta-analysis was computed. RESULTS: A positive parent-child relationship and higher levels of parental responsiveness were associated with lower weight, healthier eating, and more physical activity of the child. Parental demandingness, overprotection, psychological control, inconsistency, and parenting styles showed associations with some of the assessed outcome variables. Most effect sizes were small and varied by study characteristics. CONCLUSIONS: The small effects do not support making general parenting styles, parental demandingness, responsiveness, and the quality of the parent-child relationship a main target of preventing and treating obesity. Reducing parental inconsistency may be a better target if available results are replicated in future studies. PMID- 24756229 TI - Immune response is required for the control of in vivo translocation and chronic toxicity of graphene oxide. AB - Graphene oxide (GO) shows great promise as a nanomaterial for medical applications; however, the mechanism for its long-term adverse effects is still largely unclear. Here, we show that chronic GO exposure not only caused damage on the function of both primary and secondary targeted organs but also induced severe accumulation of pathogenic microbial food (OP50) in the intestine of Caenorhabditis elegans, a non-mammalian alternative toxicity assay system. GO accumulated in the intestine could be largely co-localized with OP50 and induced decreased immune response of animals. In contrast, feeding with UV-treated OP50 suppressed GO toxicity and accumulation in the intestine and maintained the relatively normal immune response of animals. The severe accumulation of OP50 in the intestine might be partially due to the damage by GO on the development and function of AVL and DVB neurons controlling defecation behavior. Reduction of chronic GO toxicity by PEG surface modification largely resulted from the inhibition of OP50 accumulation in the intestine and the maintenance of normal immune response. Our results highlight the key role of innate immunity in regulating in vivo chronic GO toxicity, which will be helpful for our understanding of the interactions between nanomaterials and biological systems during the long-term development of animals. PMID- 24756230 TI - [Invasive procedure for clarification of pulmonary nodules]. AB - CLINICAL/METHODICAL ISSUE: The management of solitary lung nodules poses a common clinical problem and biopsy is oftten required. Several guidelines provide slightly different recommendations and there are no uniform recommendations regarding the ideal technique of puncture guidance (e.g. percutaneous versus bronchoscopic or thoracoscopic). STANDARD RADIOLOGICAL METHODS: Fine needle aspiration biopsy (FNA) and core biopsy are well established techniques. Both can be performed under CT and to some extent ultrasound guidance. PERFORMANCE: Diagnostic accuracies of FNA and core biopsy for malignant lesions are around 95 %. Core biopsy is superior to FNA for establishing a specific diagnosis with a diagnostic yield of 81-88 % versus 17-21 %. ACHIEVEMENTS: In clinical routine practice core biopsy is the superior tool when compared to FNA. PRACTICAL RECOMMENDATIONS: Central lesions in close proximity to bronchi may be biopsied with endobronchial ultrasound (EBUS)-guided bronchoscopy. In all other lesions percutaneous, ideally CT-guided biopsy should be the method of first choice. PMID- 24756231 TI - [Role of MRI for detection and characterization of pulmonary nodules]. AB - BACKGROUND: Due to physical and technical limitations, magnetic resonance imaging (MRI) has hitherto played only a minor role in image-based diagnostics of the lungs. However, as a consequence of important methodological developments during recent years, MRI has developed into a technically mature and clinically well proven method for specific pulmonary questions. OBJECTIVES AND METHODS: The purpose of this article is to provide an overview on the currently available sequences and techniques for assessment of pulmonary nodules and analyzes the clinical significance according to the current literature. The main focus is on the detection of lung metastases, the detection of primary pulmonary malignancies in high-risk individuals and the differentiation between pulmonary nodules of benign and malignant character. RESULTS AND CONCLUSION: The MRI technique has a sensitivity of approximately 80 % for detection of malignant pulmonary nodules compared to the reference standard low-dose computed tomography (CT) and is thus somewhat inferior to CT. Advantages of MRI on the other hand are a higher specificity in differentiating malignant and benign pulmonary nodules and the absence of ionizing radiation exposure. A systematic use of MRI as a primary tool for detection and characterization of pulmonary nodules is currently not recommended due to insufficient data. The diagnostic potential of MRI for early detection and staging of malignant pulmonary diseases, however, seems promising. Therefore, further evaluation of MRI as a secondary imaging modality in clinical trials is highly warranted. PMID- 24756232 TI - Subacute bioresorbable vascular scaffold thrombosis: a report of 2 cases. AB - Drug-eluting bioresorbable vascular scaffold (BVS) is a revolutionary treatment option for obstructive coronary artery disease in percutaneous coronary intervention. It restores blood flow to the myocardium but unlike permanent metallic stent, BVS dissolves in the body within 2 years. This allows the coronary vessel to regain its normal function and motion. The clinical efficacy and safety of BVS in the first-in-human trials have been reported with low major adverse cardiac event rates observed at short- and long-term follow-up. The incidence of BVS scaffold thrombosis (ST) in these studies was 0 %. There is limited data on the incidence of BVS ST in the real world. We report 2 cases of subacute ST involving BVS in our real-world practice and discuss on the possible mechanisms of these thrombotic episodes (with insights from intracoronary imaging studies). PMID- 24756234 TI - The synthesis route and the growth mechanism of aligned GaN nanobelts. AB - Crystallographically aligned GaN nanobelt arrays were synthesized through a hybrid process of Au-assisted nucleation followed by non-Au-assisted anisotropy vapor-solid growth on a (100) gamma-LiAlO2 substrate. To the best of our knowledge, this is the first report on aligned GaN nanobelts. PMID- 24756235 TI - alpha-Hydroxycyclopentanones via one-pot oxidation of the trimethylaluminum mediated Nazarov reaction with triplet oxygen. AB - Trimethylaluminum and molecular oxygen are used in tandem to interrupt the Nazarov cyclization. alpha-Hydroxycyclopentanones are produced in moderate to good yield as a mixture of epimers. This sequence is the first example of combined nucleophilic/electrophilic trapping of the Nazarov oxyallyl intermediate. PMID- 24756233 TI - Lipoprotein-associated phospholipase A2 is associated with postpartum hypertension in women with history of preeclampsia. AB - Both hypertension and preeclampsia (PE) are considered as inflammatory diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated with lipid metabolism. We aimed to study the correlation and predictive value of Lp-PLA2 in postpartum hypertension after PE. A group of 160 PE patients (PE group) and a separate group of 160 normal pregnant women (control group) were recruited from January 2010 to October 2011. The average age in the PE group was 28.4 +/- 4.5 years and the average gestational age was 34.7 +/- 1.1 weeks. The average age in the control group was 27.8 +/- 4.5 years and the average gestational age was 35.5 +/- 1.2 weeks. General information (including age, gestational age, parity, history of metabolic disease, family history of high blood pressure, height, body weight before childbirth, and blood pressure) and blood samples were collected for measuring Lp-PLA2 and lipid parameters. From February to April in 2013, 153 cases in the PE group and 132 in the control group were re-called. We assessed their postpartum health, pregnancy, height, weight, and blood pressure. Serum mass of Lp-PLA2 in the PE group (210.67 +/- 17.98 ng/mL) was significantly higher compared with that in the control group (174.72 +/- 30.26 ng/mL) (P < 0.01). The pro-gestation BMI, systolic blood pressure (SBP), diastolic blood pressure, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol (LDL-C) were also significantly higher. Correlation analysis showed that the level of Lp-PLA2 and SBP (r = 0.31), LDL-C (r = 0.37) were positively correlated. The incidence of postpartum hypertension in the PE group was higher than that in the normal control group. Logistic regression analysis showed that prenatal Lp-PLA2 mass was an independent risk factor for PE postpartum hypertension (OR 1.134,95 % CI 1.086-1.185). ROC curve analysis showed that the sensitivity of predicting postpartum hypertension was 73.2% and the specific degree was 86.6%, with Lp-PLA2 level of 217.75 ng/mL for boundary value. The onset of postpartum hypertension in PE patients may contribute to vascular inflammation, which is associated with antepartum lipid metabolism. PMID- 24756238 TI - Mechanisms of enhanced sulfur tolerance on samarium (Sm)-doped cerium oxide (CeO2) from first principles. AB - The role of samarium (Sm) 4f states and Sm-perturbed O 2p states in determining the sulfur tolerance of Sm-doped CeO2 was elucidated by using the density functional theory (DFT) + U calculation. We find that the sulfur tolerance of Sm doped CeO2 is closely related to the modification of O 2p states by the strong interaction between Sm 4f and O 2p states. In particular, the availability of unoccupied O 2p states near the Fermi level is responsible for enhancing the sulfur tolerance of Sm-doped CeO2 compared to the pure CeO2 by increasing the activity of the surface lattice oxygen toward sulfur adsorption, by weakening the interaction between Sm-O, and by increasing the migration tendency of the subsurface oxygen ion toward the surface. PMID- 24756239 TI - Lung abscess mimicking lung cancer developed around staples in a patient with permanent tracheostoma. AB - A 68-year-old male with a tracheostoma due to hypopharyngeal cancer was admitted because his chest computed tomography (CT) showed a small nodule in the right middle lobe. Following a partial resection of the right middle lobe, histopathological diagnosis of the resected sample was that of organizing pneumonia. Eleven months later, chest CT showed a mass with pleural indentation and spiculation in the right middle lobe. 18-Fluorodeoxyglucose-positron emission tomography showed significant accumulation in the middle lobe tumor mass shadow. The abnormal chest shadow that had developed around surgical staples suggested inadequate resection and tumor recurrence. As the abnormal radiological shadow was enlarging, middle lobectomy was carried out. Histological examination revealed that the tumor was a lung abscess without malignant features. This is a unique case of lung abscess mimicking lung cancer which developed around staples used during partial resection of the lung. PMID- 24756240 TI - Computational studies of the unusual water adduct [Cp2TiMe(OH2)](+): the roles of the solvent and the counterion. AB - The recently reported cationic titanocene complex [Cp2TiMe(OH2)](+) was subjected to detailed computational studies using density functional theory (DFT). The calculated NMR spectra revealed the importance of including the anion and the solvent (CD2Cl2) in order to calculate spectra which were in good agreement with the experimental data. Specifically, two organic solvent molecules were required to coordinate to the two hydrogens of the bound OH2 in order to achieve such agreement. Further elaboration of the role of the solvent led to Bader's QTAIM and natural bond order calculations. The zirconocene complex [Cp2ZrMe(OH2)](+) was simulated for comparison. PMID- 24756242 TI - The Ph-3 gene from Solanum pimpinellifolium encodes CC-NBS-LRR protein conferring resistance to Phytophthora infestans. AB - KEY MESSAGE: Ph-3 is the first cloned tomato gene for resistance to late blight and encodes a CC-NBS-LRR protein. Late blight, caused by Phytophthora infestans, is one of the most destructive diseases in tomato. The resistance (R) gene Ph-3, derived from Solanum pimpinellifolium L3708, provides resistance to multiple P. infestans isolates and has been widely used in tomato breeding programmes. In our previous study, Ph-3 was mapped into a region harbouring R gene analogues (RGA) at the distal part of long arm of chromosome 9. To further narrow down the Ph-3 interval, more recombinants were identified using the flanking markers G2-4 and M8-2, which defined the Ph-3 gene to a 26 kb region according to the Heinz1706 reference genome. To clone the Ph-3 gene, a bacterial artificial chromosome (BAC) library was constructed using L3708 and one BAC clone B25E21 containing the Ph-3 region was identified. The sequence of the BAC clone B25E21 showed that only one RGA was present in the target region. A subsequent complementation analysis demonstrated that this RGA, encoding a CC-NBS-LRR protein, was able to complement the susceptible phenotype in cultivar Moneymaker. Thus this RGA was considered the Ph-3 gene. The predicted Ph-3 protein shares high amino acid identity with the chromosome-9-derived potato resistance proteins against P. infestans (Rpi proteins). PMID- 24756243 TI - Diallyl disulfide inhibits proliferation and transdifferentiation of lung fibroblasts through induction of cyclooxygenase and synthesis of prostaglandin E2. AB - Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta1 (TGF-beta1) are critically involved in idiopathic pulmonary fibrosis by inducing the proliferation and transdifferentiation of lung fibroblasts. In the present study, we examined the impact of diallyl disulfide (DADS), a garlic-derived compound, on such pathological conditions. DADS showed profound inhibitory effects on the PDGF-BB-induced proliferation of human and mouse lung fibroblasts. DADS also abrogated the TGF-beta1-induced expression of alpha-smooth muscle actin, type I collagen and fibronectin. Following treatment with DADS, the expression of cyclooxygenase-2 (COX-2) and the synthesis of prostaglandin E2 (PGE2) were found to be markedly enhanced, which in turn led to elevated cAMP levels in lung fibroblasts. Notably, the effect of DADS was largely abolished in the presence of either COX inhibitor indomethacin or siRNA-targeting COX-2, or in the absence of the PGE2 receptor EP2, supporting an essential role for the COX-2 PGE2-cAMP autocrine loop. Furthermore, we demonstrated that the upregulated expression of COX-2 was a result of increased level of histone 3 acetylation at COX-2 locus in DADS-treated cells. Together, these results suggest that DADS, by inducing COX-2 expression, may have therapeutic potential in treating lung fibrosis. PMID- 24756244 TI - Decreased expression of RASSF1A and up-regulation of RASSF1C is associated with esophageal squamous cell carcinoma. AB - The Ras-Association Domain Family 1 (RASSF1) gene, which is located on the small arm of chromosome 3, contains two CpG islands and generates seven transcripts (RASSF1A-RASSF1G) by differential promoter usage and alternative splicing. As the main transcript, RASSF1A, B and C may play different roles in tumorigenesis. The present study was to detect the role of RASSF1A, B and C in esophageal squamous cell carcinoma (ESCC) and clarify the critical CpG sites of RASSF1A, in order to clarify more information on the role of RASSF1 with regard to the pathogenesis of ESCC. Frequent silencing of RASSF1A but not RASSF1B and RASSF1C were found in esophageal cancer cell lines and the silencing of RASSF1A may be reversed by 5 Aza-dC treatment. The aberrant promoter and exon 1 especially exon 1 methylation of RASSF1A induces silencing of its expression in TE13 cell line. Decreased mRNA and protein expression of RASSF1A was observed in ESCC tumor tissues and was associated with RASSF1A promoter and exon 1 methylation status. Unlike RASSF1A, methylation and expression variation of RASSF1B was not found in ESCC tissues. However, RASSF1C is highly expressed in ESCC tissues. RASSF1A methylation and protein expression were independently associated with ESCC patients' survival. These data indicated that the inactivation of RASSF1A through promoter and exon 1 methylation may play an important role in ESCC carcinogenesis and reactivation of RASSF1A gene may has therapeutic potential and may be used as a prognostic marker for ESCC patients. PMID- 24756245 TI - Osteopontin promotes the progression of gastric cancer through the NF-kappaB pathway regulated by the MAPK and PI3K. AB - To elucidate the biological functions of osteopontin (OPN) in gastric tumors and to better understand the molecular events of OPN responsible for the malignancy, the present studies were performed. Growth curve, apoptosis assay, invasion assay and migration assay revealed that OPN status significantly affected proliferation, apoptosis, invasion and migration in gastric cancer cell lines. In mouse xenograft models of human gastric cancer, OPN silencing significantly inhibited tumor growth and the incidence of metastasis compared with non-silenced control. Mechanistic investigations revealed that OPN silencing inhibited the mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase (NF-kappaB) pathways, and OPN-mediated NF-kappaB activity was reduced in the presence of MAPK or PI3K inhibitor. Our findings also indicated that OPN through the NF-kappaB pathway promotes the expression of matrix metalloproteinase 2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (uPA), the activation of MMP-2 and MMP-9, and the inhibition of caspase 3. Taken together, our results reveal that OPN promotes the progression of gastric cancer through the NF-kappaB pathway, which is regulated by the MAPK and PI3K pathways and leads to MMP-2, MMP-9 and uPA activation and caspase-3 inhibition. These findings identify OPN as a novel oncogene in gastric cancer and suggest that OPN is an attractive therapeutic target for this aggressive malignancy. PMID- 24756246 TI - Omission of axillary lymph node dissection for clinically node negative early stage breast cancer patients. AB - BACKGROUND: For clinically node negative (N0) breast cancer patients, sentinel node (SN) biopsy (SNB) is a standard technique and complete axillary lymph node dissection (ALND) remains the standard treatment when the SN is positive. However, the American College of Surgeons Oncology Group Z0011 trial and the International Breast Cancer Study Group 23-01 trial showed that SNB without ALND can offer excellent regional control and equal survival compared with ALND for limited macrometastatic and micrometastatic SN involvement, respectively. We retrospectively evaluated axillary control rates in clinically N0 patients who had no axillary surgical treatment. METHODS: Data on 158 patients who underwent breast-conserving therapy without any axillary surgical procedure between 1994 and 2010 were extracted. The last follow-up was on May 2013, and the overall median follow-up period was 119.0 months. RESULTS: Of all 158 patients, 10 (6.3 %) and 3 (1.9 %) developed locoregional and axillary recurrences, respectively. The 10-year locoregional and axillary recurrence rates were 5.8 and 2.1 %, respectively. The 5- and 10-year overall survival rates were 94.0 and 84.8 %, respectively. Cases with axillary recurrence tended to have common risk factors for recurrence. CONCLUSION: Even if SNB and ALND were omitted, local and regional recurrence rates were very low among clinically N0 patients and were at the same levels shown in recent trials. This suggests that at least ALND might be safely avoided in clinically N0 patients without any obvious risk factors regardless of axillary nodal status after SNB. PMID- 24756247 TI - Metabolic syndrome prevalence in psoriasis: a cross-sectional study in the Italian population. AB - BACKGROUND: The pathogenesis of psoriasis is complex, with a significant role suggested for pro-inflammatory mediators. There is strong evidence of an association between psoriasis and the metabolic syndrome (MetS), a cluster of cardiovascular risk factors, which impose a substantial disease burden. OBJECTIVE: This study aimed to evaluate the prevalence of MetS and to examine the implications of disease severity, type 2 diabetes mellitus, and cardiovascular disease in a large cohort of Italian psoriatic patients representative of the whole population. METHODS: This was a cross-sectional study involving 13 dermatological clinics in Italy. The primary study endpoint was a comparison of the prevalence of MetS between psoriatic patients and a non-psoriatic control group; secondary endpoints included the influence of psoriasis severity on the prevalence of MetS, and the relative prevalence and risk of type 2 diabetes mellitus and cardiovascular disorders. RESULTS: A total of 720 patients were enrolled (n = 360 per group). The prevalence of MetS was 26.84% in the psoriatic population and 15.16% in the control population (p = 0.0001; adjusted odds ratio 1.96). MetS was associated with a greater degree of psoriasis severity, and the prevalence and risk of diabetes tended to be higher in psoriatic patients than in the control group. CONCLUSION: In the Italian population, the prevalence of MetS and associated comorbidities is elevated in patients with psoriasis compared with non-psoriatic subjects, as has been demonstrated in other countries. Our findings reinforce the importance of considering the implications of metabolic comorbidities in treating patients with psoriasis. PMID- 24756248 TI - Impact of functional pruritus compared with mild psoriasis on quality of life: a cross-sectional questionnaire study in Turkey. AB - BACKGROUND: Functional pruritus (FP) is a type of chronic pruritus that is a somatoform disease in nature, triggered by psychogenic factors. Psoriasis is a chronic, inflammatory, and pruritic skin disease that causes significant cosmetic problems and psychological distress. OBJECTIVE: In this study, we aimed to investigate the effects of functional pruritus on quality of life and to compare these with the effects of mild psoriasis. METHODS: A total of 73 patients (40 with psoriasis and 33 with FP) were enrolled into the study. All the participants were asked to complete the Dermatology Life Quality Index (DLQI) and World Health Organization (WHO) Quality of Life, short form, Turkish version (WHOQOL-BREF-TR). Pruritus severity was evaluated subjectively with a visual analog scale (VAS) in both groups, and psoriasis severity was evaluated with the Psoriasis Area and Severity Index. Patients' age, gender, educational status, duration of disease, and medications were recorded. RESULTS: There was no significant difference in quality of life between the two groups. VAS values were significantly higher in the FP group. A negative correlation was found between age and the physical domain on the WHOQOL-BREF-TR, and also between the psychological domain on the WHOQOL-BREF-TR and the duration of the disease in FP patients. In psoriasis patients, a negative correlation was found between age and DLQI scores. CONCLUSION: FP has a negative impact on quality of life that is comparable to that of mild psoriasis. It seems that the visibility of psoriatic lesions and the cosmetic concerns in psoriasis patients do not result in a more severely impaired quality of life than in patients with FP. PMID- 24756249 TI - A practical approach to the diagnosis, evaluation, and management of cutaneous small-vessel vasculitis. AB - Cutaneous small-vessel vasculitis (CSVV) is a disorder characterized by neutrophilic inflammation predominantly limited to the superficial cutaneous postcapillary venules. CSVV may be idiopathic or may have a defined cause such as infection, medication, connective tissue disease, or malignancy. CSVV may also be associated with extracutaneous disease or systemic vasculitis. The most common clinical presentation of CSVV consists of symmetrically distributed palpable purpura of the lower extremities. In general, lesional skin biopsy samples should be examined with light microscopy and direct immunofluorescence for adult patients with suspected CSVV. A complete history, review of systems, physical examination, and selected laboratory studies also should be performed to assess for inciting causes or extracutaneous involvement of CSVV. Treatment varies and depends on the chronicity of CSVV, the severity of cutaneous involvement, and the presence or absence of both an underlying cause and extracutaneous involvement of CSVV. An isolated episode of CSVV associated with a known inciting factor may be managed by removal or treatment of the trigger, along with symptomatic measures. First-line systemic treatments for chronic, idiopathic CSVV include colchicine or dapsone, used singly or in combination. Recurrent, chronic, or severely symptomatic CSVV that does not respond to the aforementioned therapies may require initiation of an immunosuppressive agent such as azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, or rituximab. PMID- 24756250 TI - MRI anatomy of anteriorly displaced anus: what obstructs defecation? AB - BACKGROUND: Anteriorly displaced anus is an anomaly that is debated with regard to its nomenclature, diagnosis and management. OBJECTIVE: To describe MRI anatomy of the anal canal in children with anteriorly displaced anus and its impact on the process of defecation. MATERIALS AND METHODS: We prospectively examined ten children (7 girls, 3 boys; age range 7 months to 8 years, mean 3 years) with anteriorly displaced anus between August 2009 and April 2012. Noncontrast MRI examinations were performed on a 1.5-T magnet. T1- and T2-weighted turbo spin echo images were acquired in axial, sagittal and coronal planes of the pelvis. The anorectal angle and the relative hiatal distance were measured in mid sagittal images, and compared with those of a control group using the Mann Whitney test. RESULTS: In children with anteriorly displaced anus, no anatomical abnormality was depicted at the level of the proximal anal canal. However, the distal anal canal was displaced anteriorly, running out its external muscle cuff, which remained un-displaced at the usual site of the anus. This changes the orientation of the central axis of the anal canal by passing across instead of along the fibers of the longitudinal muscle coat. Children with anteriorly displaced anus had a more obtuse anorectal angle (mean 112.1 degrees ), which was significantly greater than that of the control group (mean 86.2 degrees ). CONCLUSION: MRI is a valuable tool in studying the anatomy of the anal canal in children with anteriorly displaced anus. The abnormal orientation of the longitudinal muscle across the anal canal can explain the obstructed defecation in these children. Based on this study, it might be of interest to use MRI in studying equivocal cases and children with unexplained constipation. PMID- 24756251 TI - An idiopathic case of pediatric retroperitoneal fibrosis with extensive magnetic resonance imaging and follow-up. AB - Retroperitoneal fibrosis has seldom been described in the pediatric literature. We present a child who presented with retroperitoneal fibrosis without any associated underlying vascular or inflammatory conditions. This is one of only a few cases of primary idiopathic retroperitoneal fibrosis in a pediatric patient to have been imaged extensively by MRI. PMID- 24756252 TI - Shrinking lung syndrome complicating pediatric systemic lupus erythematosus. AB - Systemic lupus erythematosis (SLE) can affect the lungs and pleura, usually manifesting with pleural effusions or diffuse parenchymal disease. A rare manifestation of SLE is shrinking lung syndrome, a severe restrictive respiratory disorder. While pleuropulmonary complications of pediatric SLE are common, shrinking lung syndrome is exceedingly rare in children. We present a case of a 13-year-old girl previously diagnosed with lupus, who developed severe dyspnea on exertion and restrictive pulmonary physiology. Her chest radiographs on presentation demonstrated low lung volumes, and CT showed neither pleural nor parenchymal disease. Fluoroscopy demonstrated poor diaphragmatic excursion. While shrinking lung syndrome is described and studied in adults, there is only sparse reference to shrinking lung syndrome in children. PMID- 24756253 TI - Reply to Raimondi et al.: Pediatric chest ultrasound versus conventional radiology: experimental evidence first. PMID- 24756254 TI - gamma-H2AX foci are increased in lymphocytes in vivo in young children 1 h after very low-dose X-irradiation: a pilot study. AB - BACKGROUND: Computed tomography (CT) is an imaging modality involving ionizing radiation. The presence of gamma-H2AX foci after low to moderate ionizing radiation exposure has been demonstrated; however it is unknown whether very low ionizing radiation exposure doses from CT exams can induce gamma-H2AX formation in vivo in young children. OBJECTIVE: To test whether very low ionizing radiation doses from CT exams can induce lymphocytic gamma-H2AX foci (phosphorylated histones used as a marker of DNA damage) formation in vivo in young children. MATERIALS AND METHODS: Parents of participating children signed a consent form. Blood samples from three children (ages 3-21 months) undergoing CT exams involving very low blood ionizing radiation exposure doses (blood doses of 0.22 1.22 mGy) were collected immediately before and 1 h post CT exams. Isolated lymphocytes were quantified for gamma-H2AX foci by a technician blinded to the radiation status and dose of the patients. Paired t-tests and regression analyses were performed with significance levels set at P < 0.05. RESULTS: We observed a dose-dependent increase in gamma-H2AX foci post-CT exams (P = 0.046) among the three children. Ionizing radiation exposure doses led to a linear increase of foci per cell in post-CT samples (102% between lowest and highest dose). CONCLUSION: We found a significant induction of gamma-H2AX foci in lymphocytes from post-CT samples of three very young children. When possible, CT exams should be limited or avoided by possibly applying non-ionizing radiation exposure techniques such as US or MRI. PMID- 24756256 TI - Touch spray mass spectrometry for in situ analysis of complex samples. AB - Touch spray, a spray-based ambient in situ ionization method, uses a small probe, e.g. a teasing needle to pick up sample and the application of voltage and solvent to cause field-induced droplet emission. Compounds extracted from the microsample are incorporated into the sprayed micro droplets. Performance tests include disease state of tissue, microorganism identification, and therapeutic drug quantitation. Chemical derivatization is performed simultaneously with ionization. PMID- 24756257 TI - Over-the-scope clip system is effective for the closure of post-endoscopic submucosal dissection ulcer, especially at the greater curvature. PMID- 24756258 TI - Proximal migration of pancreatic stent: placement of smaller stent within another stent for retrieval. PMID- 24756259 TI - Jejunal post-polypectomy syndrome. PMID- 24756260 TI - Pancreatic metastasis of a meningeal hemangiopericytoma: a rare cause of obstructive jaundice. PMID- 24756261 TI - Intraoropharyngeal U-turn method using transnasal esophagogastroduodenoscopy. PMID- 24756262 TI - Using a gastroscope to accomplish ERCP: a forward-viewing endoscope for cannulation of the intradiverticular papilla. PMID- 24756263 TI - Untying the knot: technique of unraveling a guidewire knot created during EUS guided biliary drainage. PMID- 24756264 TI - A rare case of migration of a T-tube into the duodenum. PMID- 24756265 TI - Gastroscopic snare polypectomy for cystic duct adenoma: a rare occurrence. PMID- 24756266 TI - Endoscopic treatment using a knife to correct complete anastomotic obstruction following rectal cancer surgery. PMID- 24756267 TI - Closure of a persistent gastric leak using a cardiac septal occluder. PMID- 24756268 TI - Are endoscopic mucosal resection and endoscopic submucosal dissection risky for patients with cirrhosis? PMID- 24756269 TI - Cerebral air embolism during endoscopic retrograde cholangiopancreatography: treatment with therapeutic hypothermia. PMID- 24756270 TI - Pyogenic granuloma mimicking a colon cancer. PMID- 24756271 TI - Vocal cord paralysis due to self-expandable metal stent in the proximal esophagus. PMID- 24756272 TI - Pancreatic hamartoma: a rare cause of obstructive jaundice. PMID- 24756273 TI - Stent-in-stent technique and endoscopic resection of granulation tissue to remove a migrated metal duodenal stent embedded in the colon. PMID- 24756274 TI - Massive hemobilia following transpapillary bile duct biopsy treated by using a covered self-expandable metal stent. PMID- 24756275 TI - Endoscopic drainage of gastric wall mycetoma. PMID- 24756276 TI - Endoscopic repair of a massive postoperative pancreatic juice leak through the bile duct stump due to pancreatobiliary maljunction. PMID- 24756277 TI - Isolated gastroduodenal Crohn's disease in a septuagenarian man. PMID- 24756278 TI - Colonic perforation caused by the inadvertent trapping of mucosa in a retrieval net. PMID- 24756279 TI - Minimally invasive treatment of a duodenal perforation associated with the EndoBarrier duodenal-jejunal bypass liner. PMID- 24756280 TI - Successful Hemospray treatment for recurrent diclofenac-induced severe diffuse lower gastrointestinal bleeding avoiding the need for colectomy. PMID- 24756281 TI - Severe colitis related to granulomatosis with polyangiitis (Wegener's granulomatosis). PMID- 24756282 TI - A new method using a polyglycolic acid monolayer patch to shield the mucosal defect after endoscopic submucosal dissection. PMID- 24756283 TI - Pancreatic pseudocyst with complicating colonic fistula successfully closed using the over-the-scope-clip system. PMID- 24756284 TI - Acute colonic intramural hematoma: a rare complication of colonoscopy. PMID- 24756285 TI - Treatment of unusual rectal foreign body using a Foley catheter. PMID- 24756286 TI - Transgastric and percutaneous transhepatic rendezvous maneuver for the treatment of difficult intrahepatic stones. PMID- 24756287 TI - Balloon extraction for the endoscopic removal of proximally migrated pancreatic stent. PMID- 24756288 TI - Tuberculous abscess formation with liver invasion after endoscopic ultrasound guided fine-needle aspiration for abdominal lymphadenopathy. PMID- 24756289 TI - Rectal perforation caused by mesalazine enema in a patient with ulcerative colitis. PMID- 24756290 TI - Giant liver cyst caused by tuberculosis infection and masquerading as malignant peritonitis. PMID- 24756291 TI - Esophageal perforation during endoscopic removal of food impaction in eosinophilic esophagitis: stent well spent? PMID- 24756292 TI - Endoscopic ultrasound diagnosis of pneumatosis cystoides coli initially misdiagnosed as colonic polyps. PMID- 24756293 TI - Calcified thrombosis in the portal system mimicking choledocholithiasis and diagnosed by endoscopic ultrasound. PMID- 24756294 TI - Pure transgastric NOTES ovarian cystectomy: the first human procedure. PMID- 24756295 TI - Esophageal duplication cyst causing megaesophagus in a young woman presenting with dysphagia. PMID- 24756296 TI - Esophageal hematoma caused by foreign body ingestion. PMID- 24756297 TI - Double-tunnel endoscopic submucosal tunnel dissection for circumferential superficial esophageal neoplasms. PMID- 24756298 TI - Successful closure of an endoscopic ultrasound-induced duodenal perforation using an over-the-scope-clip. PMID- 24756299 TI - Gastric compression due to a cystic liver metastasis of vulvar carcinoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration. PMID- 24756300 TI - Large nylon bag causing gastric outlet obstruction in a patient with schizophrenia. PMID- 24756301 TI - A minimally invasive technique utilizing percutaneous and endoscopic rendezvous for successful treatment of a proximal bile leak following partial hepatectomy. PMID- 24756303 TI - Structure of the LINGO-1-anti-LINGO-1 Li81 antibody complex provides insights into the biology of LINGO-1 and the mechanism of action of the antibody therapy. AB - Multiple sclerosis (MS) is an autoimmune-inflammatory disease of the central nervous system (CNS) with prominent demyelination and axonal injury. While most MS therapies target the immunologic response, there is a large unmet need for treatments that can promote CNS repair. LINGO-1 (leucine-rich repeat and Ig containing Nogo receptor interacting protein-1) is a membrane protein selectively expressed in the CNS that suppresses myelination, preventing the repair of damaged axons. We are investigating LINGO-1 antagonist antibodies that lead to remyelination as a new paradigm for treatment of individuals with MS. The anti LINGO-1 Li81 antibody,BIIB033, is currently in clinical trials and is the first MS treatment targeting CNS repair. Here, to elucidate the mechanism of action of the antibody, we solved the crystal structure of the LINGO-1-Li81 Fab complex and used biochemical and functional studies to investigate structure-function relationships. Li81 binds to the convex surface of the leucine-rich repeat domain of LINGO-1 within repeats 4-8. Fab binding blocks contact points used in the oligomerization of LINGO-1 and produces a stable complex containing two copies each of LINGO-1 and Fab that results from a rearrangement of contacts stabilizing the quaternary structure of LINGO-1. The formation of the LINGO-1-Li81 Fab complex masks functional epitopes within the Ig domain of LINGO-1 that are important for its biologic activity in oligodendrocyte differentiation. These studies provide new insights into the structure and biology of LINGO-1 and how Li81 monoclonal antibody can block its function. PMID- 24756304 TI - Quality of life in adults treated in infancy for hydrocephalus. AB - PURPOSE: The objective was to analyze quality of life in a very long-term follow up study of now adult individuals, treated for hydrocephalus (without spina bifida) during infancy. METHODS: The entire series was population-based, and the subgroup under study consisted of the 29 individuals without intellectual disability, who consented to participate. About one third had concomitant mild cerebral palsy or epilepsy or both. A Finnish validated questionnaire, the 15D, was used to measure quality of life. RESULTS: There was no significant difference between the study group and the controls with regard to the total quality of life score. Individuals with associated cerebral palsy and/or epilepsy had a lower total score compared with both those without associated impairments and controls. Most participants differed from controls in the dimension of mental/memory function which pertains to executive functions, an ability of considerable importance for daily life skills. CONCLUSION: It is important to follow children with hydrocephalus over time--due to the different etiological panorama, interventions, and associated impairments this group displays. This is the only way to learn more about critical factors that require attention and that predict quality of life in adulthood. PMID- 24756305 TI - Is microplegia really superior to standard blood cardioplegia? The results from a meta-analysis. AB - BACKGROUND: Microplegia (whole blood cardioplegia with reduced volume) retains all the advantages of blood cardioplegia (such as superior oxygen-carrying capacity, better osmotic properties and antioxidant capability, etc.) without the potential disadvantages of hemodilution (such as myocardial edema). We sought to perform a systematic review and meta-analysis to compare microplegia and standard blood cardioplegia on the cardioprotective effects for patients undergoing coronary artery bypass grafting (CABG). METHODS: MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for relevant controlled trials published in English, from their inception up to May 15th, 2013. Data on low output syndrome, spontaneous return to sinus rhythm, volume of cardioplegia and perioperative myocardial infarction were analyzed. RESULTS: Five studies, totaling 296 patients, were included out of 77 retrieved citations. The microplegia group used less volume of cardioplegia (WMD, -514.79 ml, 95%CI: 705.37 ml to -324.21 ml) when compared with the standard blood cardioplegia group. There were no statistical differences in the incidence of low output syndrome (RR, 0.95, 95%CI: 0.55 to 1.62), spontaneous return to sinus rhythm (RR, 1.64, 95%CI: 0.61 to 4.41) and perioperative myocardial infarction (RR, 0.62, 95%CI: 0.19 to 2.08). CONCLUSIONS: Microplegia was associated with less volume of cardioplegia, whereas the incidence of spontaneous return to sinus rhythm and perioperative myocardial infarction were similar, but large controlled randomized trials are still needed to confirm this. PMID- 24756306 TI - A Model for Identifying Patients Who May Not Need Neurologic Intensive Care Unit Admission: Resource Utilization Study. AB - PURPOSE: Limited resources, neurointensivists, and neurologic intensive care unit (neuro-ICU) beds warrant investigating models for predicting who will benefit from admission to neuro-ICU. This study presents a possible model for identifying patients who might be too well to benefit from admission to a neuro-ICU. METHODS: We retrospectively identified all patients admitted to our 16-bed neuro-ICU between November 2009 and February 2013. We used the Acute Physiology and Chronic Health Evaluation (APACHE) outcomes database to identify patients who on day 1 of neuro-ICU admission received 1 or more of 30 subsequent active life-supporting treatments. We compared 2 groups of patients: low-risk monitor (LRM; patients who did not receive active treatment [AT] on the first day and whose risk of ever receiving AT was <= 10%) and AT (patients who received at least 1 of the 30 ICU treatments on any day of their ICU admission). RESULTS: There were 873 (46%) admissions in the LRM group and 1006 (54%) admissions in the AT group. The ICU length of stay in days was 1.7 (+/- 1.9) for the LRM group versus 4.5 (+/- 5.5) for the AT group. The ICU mortality was 0.8% for the LRM group compared to 14% for the AT group (odds ratio [OR] = 17.6; 95% confidence interval [CI], 8.2-37.8, P < .0001). Hospital mortality was 1.9% for the LRM group compared to 19% for the AT group (OR = 9.7; 95% CI, 5.8-16.1, P < .0001). CONCLUSION: The outcome for LRM patients in our neuro-ICU suggests they may not require admission to neurologic intensive care. This may provide a measure of neuro-ICU resource use. Improved resource use and reduced costs might be achieved by strategies to provide care for these patients on floors or intermediate care units. This model will need to be validated in other neuro-ICUs and prospectively studied before it can be adopted for triaging admissions to neuro-ICUs. PMID- 24756307 TI - Systematic Review and Meta-Analysis of End-Tidal Carbon Dioxide Values Associated With Return of Spontaneous Circulation During Cardiopulmonary Resuscitation. AB - OBJECTIVE: End-tidal carbon dioxide (ETCO(2)) measurements during cardiopulmonary resuscitation (CPR) reflect variable cardiac output over time, and low values have been associated with decreased survival. The goals of this review are to confirm and quantify this relationship and to determine the mean ETCO(2) value among patients with return of spontaneous circulation (ROSC) as an initial step toward determining an appropriate target for intervention during resuscitation in the absence of prospective data. DATA SOURCES AND STUDY SELECTION: The PubMed database was searched for the key words "end-tidal carbon dioxide" or "capnometry" or "capnography" and "resuscitation" or "return of spontaneous circulation." Randomized controlled trials, cohort studies, or case-control studies that reported ETCO(2) values for participants with and without ROSC were included. DATA EXTRACTION AND SYNTHESIS: Twenty-seven studies met the inclusion criteria for qualitative synthesis. Twenty studies were included in determination of average ETCO(2) values. The mean ETCO(2) in participants with ROSC was 25.8 +/ 9.8 mm Hg versus 13.1 +/- 8.2 mm Hg (P = .001) in those without ROSC. Nineteen studies were included in a meta-analysis. The mean difference in ETCO(2) was 12.7 mm Hg (95% confidence interval: 10.3-15.1) between participants with and without ROSC (P < .001). The mean difference in ETCO(2) was not modified by the receipt of sodium bicarbonate, uncontrolled minute ventilation, or era of resuscitation guidelines. The overall quality of data by Grades of Recommendations, Assessment, Development and Evaluation criteria is very low, but no prospective data are currently available. CONCLUSIONS: Participants with ROSC after CPR have statistically higher levels of ETCO(2). The average ETCO(2) level of 25 mm Hg in participants with ROSC is notably higher than the threshold of 10 to 20 mm Hg to improve delivery of chest compressions. The ETCO(2) goals during resuscitation may be higher than previously suggested and further investigation into appropriate targets during resuscitation is needed to diminish morbidity and mortality after cardiorespiratory arrest. PMID- 24756308 TI - Prevalence of Ventilatory Conditions for Dynamic Fluid Responsiveness Prediction in 2 Tertiary Intensive Care Units. AB - BACKGROUND: Dynamic parameters for fluid responsiveness obtained from heart-lung interaction during invasive mechanical ventilation require specific conditions not always present in intensive care unit (ICU) patients. The aim of this study was to examine the prevalence of these conditions in critically ill patients. METHODS: We conducted a prospective observational study in 2 medical-surgical ICUs. We evaluated whether it would be possible to measure dynamic indices of fluid responsiveness when fluid expansion was administered. We recorded whether the patients were in controlled invasive mechanical ventilation with tidal volume >8 mL/kg and without arrhythmias. The proportion of patients who fulfilled these conditions was recorded. A post hoc subgroup analyses by terciles of Simplified Acute Physiology Score 3 (SAPS3) were performed. RESULTS: A total of 826 fluid challenges were undertaken in 424 patients during the study. The use of controlled mechanical ventilation with tidal volume > 8 mL/kg and without arrhythmias occurred in only 2.9% of the patients at the time of fluid challenge episodes. There was an increase in the prevalence of these conditions as the severity of the patients also increased: lower tercile of SAPS3 (0%), intermediate tercile (2%), and higher tercile (6.9%; P < .01 Pearson chi-square test). CONCLUSIONS: Respiratory-dependent dynamic parameters for predicting fluid responsiveness in ICU may have restricted applicability in daily practice, even in more severe patients, due to low prevalence of required conditions. PMID- 24756309 TI - Management of Acute Myeloid Leukemia in the Intensive Care Setting. AB - Patients with acute myeloid leukemia (AML) who are newly diagnosed or relapsed and those who are receiving cytotoxic chemotherapy are predisposed to conditions such as sepsis due to bacterial and fungal infections, coagulopathies, hemorrhage, metabolic abnormalities, and respiratory and renal failure. These conditions are common reasons for patients with AML to be managed in the intensive care unit (ICU). For patients with AML in the ICU, providers need to be aware of common problems and how to manage them. Understanding the pathophysiology of complications and the recent advances in risk stratification as well as newer therapy for AML are relevant to the critical care provider. PMID- 24756310 TI - Two Methods of Hemodynamic and Volume Status Assessment in Critically Ill Patients: A Study of Disagreement. AB - INTRODUCTION: The invasive nature and potential complications associated with pulmonary artery (PA) catheters (PACs) have prompted the pursuit of less invasive monitoring options. Before implementing new hemodynamic monitoring technologies, it is important to determine the interchangeability of these modalities. This study examines monitoring concordance between the PAC and the arterial waveform analysis (AWA) hemodynamic monitoring system. METHODS: Critically ill patients undergoing hemodynamic monitoring with PAC were simultaneously equipped with the FloTrac AWA system (both from Edwards Lifesciences, Irvine, California). Data were concomitantly obtained for hemodynamic variables. Bland-Altman methodology was used to assess CO measurement bias and kappa coefficent to show discrepancies in intravascular volume. RESULTS: Significant measurement bias was observed in both CO and intravascular volume status between the 2 techniques (mean bias, 1.055 +/- 0.263 liter/min, r = 0.481). There was near-complete lack of agreement regarding the need for intravenous volume administration (kappa = 0.019) or the need for vasoactive agent administration (kappa = 0.015). CONCLUSIONS: The lack of concordance between PAC and AWA in critically ill surgical patients undergoing active resuscitation raises doubts regarding the interchangeability and relative accuracy of these modalities in clinical use. Lack of awareness of these limitations can lead to errors in clinical decision making when managing critically ill patients. PMID- 24756302 TI - The idiopathic intracranial hypertension treatment trial: clinical profile at baseline. AB - IMPORTANCE: To our knowledge, there are no large prospective cohorts of untreated patients with idiopathic intracranial hypertension (IIH) to characterize the disease. OBJECTIVE: To report the baseline clinical and laboratory features of patients enrolled in the Idiopathic Intracranial Hypertension Treatment Trial. DESIGN, SETTING, AND PARTICIPANTS: We collected data at baseline from questionnaires, examinations, automated perimetry, and fundus photography grading. Patients (n = 165) were enrolled from March 17, 2010, to November 27, 2012, at 38 academic and private practice sites in North America. All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation between -2 dB and -7 dB. All but 4 participants were women. MAIN OUTCOMES AND MEASURES: Baseline and laboratory characteristics. RESULTS: The mean (SD) age of our patients was 29.0 (7.4) years and 4 (2.4%) were men. The average (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 39.9 (8.3). Headache was the most common symptom (84%). Transient visual obscurations occurred in 68% of patients, back pain in 53%, and pulse synchronous tinnitus in 52%. Only 32% reported visual loss. The average (SD) perimetric mean deviation in the worst eye was -3.5 (1.1) dB, (range, -2.0 to -6.4 dB) and in the best eye was -2.3 (1.1) dB (range, -5.2 to 0.8 dB). A partial arcuate visual field defect with an enlarged blind spot was the most common perimetric finding. Visual acuity was 85 letters or better (20/20) in 71% of the worst eyes and 77% of the best eyes. Quality of life measures, including the National Eye Institute Visual Function Questionnaire-25 and the Short Form-36 physical and mental health summary scales, were lower compared with population norms. CONCLUSIONS AND RELEVANCE: The Idiopathic Intracranial Hypertension Treatment Trial represents the largest prospectively analyzed cohort of untreated patients with IIH. Our data show that IIH is almost exclusively a disease of obese young women. Patients with IIH with mild visual loss have typical symptoms, may have mild acuity loss, and have visual field defects, with predominantly arcuate loss and enlarged blind spots that require formal perimetry for detection. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639. PMID- 24756311 TI - A conformation-selective IR-UV study of the dipeptides Ac-Phe-Ser-NH2 and Ac-Phe Cys-NH2: probing the SH...O and OH...O hydrogen bond interactions. AB - The conformational preferences of peptides are mainly controlled by the stabilizing effect of intramolecular interactions. In peptides with polar side chains, not only the backbone but also the side chain interactions determine the resulting conformations. In this paper, the conformational preferences of the capped dipeptides Ac-Phe-Ser-NH2 (FS) and Ac-Phe-Cys-NH2 (FC) are resolved under laser-desorbed jet cooling conditions using IR-UV ion dip spectroscopy and density functional theory (DFT) quantum chemistry calculations. As serine (Ser) and cysteine (Cys) only differ in an OH (Ser) or SH (Cys) moiety; this subtle alteration allows us to study the effect of the difference in hydrogen bonding for an OH and SH group in detail, and its effect on the secondary structure. IR absorption spectra are recorded in the NH stretching region (3200-3600 cm(-1)). In combination with quantum chemical calculations the spectra provide a direct view of intramolecular interactions. Here, we show that both FS as FC share a singly gamma-folded backbone conformation as the most stable conformer. The hydrogen bond strength of OH...O (FS) is stronger than that of SH...O (FC), resulting in a more compact gamma turn structure. A second conformer is found for FC, showing a beta turn interaction. PMID- 24756312 TI - Structure modulation of manganese coordination polymers consisting of 1,4 naphthalene dicarboxylate and 1,10-phenanthroline. AB - Three new manganese coordination polymers, {[Mn2(1,4-NDC)2(phen)2](H2O)}n (1), [Mn2(1,4-NDC)2(phen)(H2O)]n (2) and {[Mn4(1,4-NDC)4(phen)4](DMF)2}n (3) (1,4 H2NDC = 1,4-naphthalene dicarboxylic acid; phen = 1,10-phenanthroline; DMF = N,N dimethylformamide), have been synthesized solvo/hydrothermally. 1,4-NDC(2-) ligands adopt different coordination modes under different solvents and concentrations which promotes different crystal structure formation. X-ray crystal structural data reveal that compounds 1, 2 and 3 crystallize in monoclinic space groups C2/c, P21/c and C2/c, respectively. Compound 1 has Mn2 dimers connected by 1,4-NDC(2-) linkers, packing into a 2D structure in a grid pattern. Compound 2 has a three-dimensional (3D) structure which is constructed by Mn2 dimers and 1,4-NDC(2-) linkers. Each MnO4N2 node of compound 3 is linked to another by 1,4-NDC(2-) ligands to form a two-dimensional (2D) structure. Variable-temperature magnetic susceptibilities of compounds 1-3 exhibit overall weak antiferromagnetic coupling between the adjacent Mn(II) ions. PMID- 24756313 TI - Addressing fear of cancer recurrence among women with cancer: a feasibility and preliminary outcome study. AB - BACKGROUND: Evidence suggests that fear of cancer recurrence (FCR) is one of the most frequently cited unmet needs among cancer survivors and is associated with psychological distress, stress-response symptoms, and lower quality of life, as well as increased use of health care resources. Despite these factors, few manualized interventions exist to address FCR among cancer survivors. PURPOSE: To develop, manualize, and pilot test the feasibility and preliminary efficacy of a 6-week cognitive-existential (CE) group intervention designed to address FCR in women with breast or ovarian cancer. METHODS: This study was a single-arm multi site study with pre-, post-, and 3-month follow-up measurement occasions. RESULTS: A total of 56 breast or ovarian cancer survivors enrolled in the study; 44 completed the CE group intervention. Following the intervention, women experienced a reduction in the primary study outcome measure of FCR and secondary study outcome measures of cancer-specific distress and uncertainty. They also reported improvements in secondary study outcome measures of quality of life and coping. The effect sizes of the observed changes were for the most part in the medium to large effect range; furthermore, almost all changes were sustained at 3 month follow-up. CONCLUSION: This brief intervention appears feasible and has shown promising results in addressing FCR and related secondary outcomes of cancer-specific distress, uncertainty, quality of life, and coping; however, it should be further tested using a randomized controlled study design to more definitively assess its efficacy. IMPLICATIONS FOR CANCER SURVIVORS: FCR is a near-universal worry for cancer survivors that, when left unaddressed, tends to remain stable over time. This study has important implications for all cancer survivors as it is the first published intervention that provides preliminary evidence of its efficacy in decreasing fear of cancer recurrence. PMID- 24756315 TI - Colitis associated with biological agents. PMID- 24756314 TI - Myeloid-specific deletion of SIRT1 increases hepatic steatosis and hypothalamic inflammation in mice fed a high-fat diet. AB - Obesity-induced fatty liver disease is associated with increased hypothalamic inflammation. Previous reports have demonstrated that the deletion of SIRT1 in hepatocytes increases hepatic steatosis and inflammation. Using myeloid cell specific SIRT1 knockout (KO) mice, we investigated whether ablation of SIRT1 in macrophages plays a role in regulating hepatic steatosis and hypothalamic inflammation. When challenged with a high-fat diet (HFD) for 24 weeks, hyperleptinemia, hyperinsulinemia, hepatic steatosis and macrophage infiltrations in HFD-fed KO mice were increased compared with HFD-fed WT mice. Hypothalamic expression levels of iba1 were increased in HFD-fed KO mice compared with HFD-fed WT mice. In particular, the expression levels of choline acetyltransferase were decreased in the hypothalamus of HFD-fed KO mice compared with HFD-fed WT mice. Thus, our findings suggest that SIRT1 plays a key role for hepatic steatosis and hypothalamic inflammation and that anti-inflammatory effect of SIRT1 may be important for the prevention of obesity-induced metabolic syndromes. PMID- 24756316 TI - Endoscopic balloon dilation lithotripsy for difficult bile duct stones. AB - BACKGROUND/AIM: Endoscopic treatment for removal of large or impacted bile duct stones is challenging, and may not be successful. The aim of this study was to evaluate the safety and efficacy of endoscopic balloon dilation lithotripsy (EBDL) as a means of treating difficult extrahepatic bile duct stones refractory to failed conventional endoscopic treatments. PATIENTS AND METHODS: The patients were included in the indication of EBDL only if stones were confirmed as brown pigmented stones or recurrent. Balloon dilation was performed using a balloon dilation catheter in order to crush large and/or impacted stones at the common hepatic duct or common bile duct level in seven cases, and then fragmented stones were removed using a basket and/or an extraction balloon catheter. RESULTS: The median diameter of the balloons used for EBDL was 32.4 +/- 10.5 mm (range, 12.4 52.1). Balloon dilation was performed for 60 s per session. The mean number of EBDL sessions required to crush stones was two (range, 1-5), the mean number of ERCP sessions required for complete stone removal was 2.4 +/- 0.8 (range, 1-3), the overall procedure-related complication rate was 0% (0/7), and the success rate was 100% (7/7). CONCLUSION: EBDL might be a safe and effective option for the treatment of large and impacted extrahepatic bile duct stones refractory to conventional endoscopic treatments. PMID- 24756317 TI - Prophylactic use of endoclips post-polypectomy: to bleed or not to bleed? PMID- 24756318 TI - Healing defective CVD-graphene through vapor phase treatment. AB - Structural defects present on chemical vapor deposition (CVD)-graphene have usually originated from the growth stage and transfer process. They limit the electronic transport properties of graphene and degrade performance of related devices. Here we report that these inherent atomic defects could be selectively healed by a simple vapor phase treatment performed in equipment conventionally used for atomic layer deposition (ALD). The unique chemistry of Al2O3 ALD facilitated selective depositions of AlxOy compounds on the defects, which could be readily probed and visualized using AFM imaging. The healing agent, AlxOy, was observed to bind tightly to the defects and lead to doping of the CVD-graphene, which was reflected in the noticeable improvement in electrical sheet resistance. In contrast with the chemically doped graphene, the ALD-treated graphenes revealed notable long-term stability under environmental conditions. Our approach promises selective healing of defects present in most materials and possibly ensures considerable improvement in electrical and mechanical properties. ALD with a broad spectrum of material selection could be a versatile tool for upgrading properties of materials. PMID- 24756319 TI - Assessing medication adherence and healthcare utilization and cost patterns among hospital-discharged patients with schizoaffective disorder. AB - BACKGROUND: Hospital-discharged patients with schizoaffective disorder have a high risk of re-hospitalization. However, limited data exist evaluating critical post-discharge periods during which the risk of re-hospitalization is significant. OBJECTIVE: Among hospital-discharged patients with schizoaffective disorder, we assessed pharmacotherapy adherence and healthcare utilization and costs during sequential 60-day clinical periods before schizoaffective disorder related hospitalization and post-hospital discharge. METHODS: From the MarketScan((r)) Medicaid database (2004-2008), we identified patients (>=18 years) with a schizoaffective disorder-related inpatient admission. Study measures including medication adherence and healthcare utilization and costs were assessed during sequential preadmission and post-discharge periods. We conducted univariate and multivariable regression analyses to compare schizoaffective disorder-related and all-cause healthcare utilization and costs (in 2010 US dollars) between each adjacent 60-day post-discharge periods. No adjustment was made for multiplicity. RESULTS: We identified 1,193 hospital-discharged patients with a mean age of 41 years. The mean medication adherence rate was 46% during the 60-day period prior to index inpatient admission, which improved to 80% during the 60-day post-discharge period. Following hospital discharge, schizoaffective disorder-related healthcare costs were significantly greater during the initial 60-day period compared with the 61- to 120-day post-discharge period (mean US$2,370 vs US$1,765; p < 0.001), with rehospitalization (36%) and pharmacy (40%) accounting for over three-fourths of the initial 60-day period costs. Compared with the initial 60-day post-discharge period, both all-cause and schizoaffective disorder-related costs declined during the 61- to 120-day post discharge period and remained stable for the remaining post-discharge periods (days 121-365). CONCLUSIONS: We observed considerably lower (46%) adherence during 60 days prior to the inpatient admission; in comparison, adherence for the overall 6-month period was 8% (54%) higher. Our study findings suggest that both short-term (e.g., 60 days) and long-term (e.g., 6-12 months) medication adherence likely are important characteristics to examine among patients with schizoaffective disorder and help provide a more holistic view of patients' adherence patterns. Furthermore, we observed a high rate of rehospitalization and greater healthcare costs during the initial 60-day period post-discharge among patients with schizoaffective disorder. Further research is required to better understand and manage transitional care after discharge (e.g., monitor adherence), which may help reduce the likelihood of rehospitalization and the associated downstream costs. PMID- 24756321 TI - Autodisplay of an archaeal gamma-lactamase on the cell surface of Escherichia coli using Xcc_Est as an anchoring scaffold and its application for preparation of the enantiopure antiviral drug intermediate (-) vince lactam. AB - At present, autotransporter protein mediated surface display has opened a new dimension in the development of whole-cell biocatalysts. Here, we report the identification of a novel autotransporter Xcc_Est from Xanthomonas campestris pv campestris 8004 by bioinformatic analysis and application of Xcc_Est as an anchoring motif for surface display of gamma-lactamase (Gla) from thermophilic archaeon Sulfolobus solfataricus P2 in Escherichia coli. The localization of gamma-lactamase in the cell envelope was monitored by Western blot, activity assay and flow cytometry analysis. Either the full-length or truncated Xcc_Est could efficiently transport gamma-lactamase to the cell surface. Compared with the free enzyme, the displayed gamma-lactamase exhibited optimum temperature of 30 degrees C other than 90 degrees C, with a substantial decrease of 60 degrees C. Under the preparation system, the engineered E. coli with autodisplayed gamma-lactamase converted 100 g racemic vince lactam to produce 49.2 g (-) vince lactam at 30 degrees C within 4 h. By using chiral HPLC, the ee value of the produced (-) vince lactam was determined to be 99.5 %. The whole cell biocatalyst exhibited excellent stability under the operational conditions. Our results indicate that the E. coli with surface displayed gamma-lactamase is an efficient and economical whole cell biocatalyst for preparing the antiviral drug intermediate (-) vince lactam at mild temperature, eliminating expensive energy cost performed at high temperature. PMID- 24756322 TI - Affinity purification of recombinant proteins using a novel silica-binding peptide as a fusion tag. AB - We recently reported that silica is deposited on the coat of Bacillus cereus spores as a layer of nanometer-sized particles (Hirota et al. 2010 J Bacteriol 192: 111-116). Gene disruption analysis revealed that the spore coat protein CotB1 mediates the accumulation of silica (our unpublished results). Here, we report that B. cereus CotB1 (171 amino acids [aa]) and its C-terminal 14-aa region (corresponding to residues 158-171, designated CotB1p) show strong affinity for silica particles, with dissociation constants at pH 8.0 of 2.09 and 1.24 nM, respectively. Using CotB1 and CotB1p as silica-binding tags, we developed a silica-based affinity purification method in which silica particles are used as an adsorbent for CotB1/CotB1p fusion proteins. Small ubiquitin-like modifier (SUMO) technology was employed to release the target proteins from the adsorbed fusion proteins. SUMO-protease-mediated site-specific cleavage at the C terminus of the fused SUMO sequence released the tagless target proteins into the liquid phase while leaving the tag region still bound to the solid phase. Using the fluorescent protein mCherry as a model, our purification method achieved 85 % recovery, with a purity of 95 % and yields of 0.60 +/- 0.06 and 1.13 +/- 0.13 mg per 10-mL bacterial culture for the CotB1-SUMO-mCherry and CotB1p-SUMO-mCherry fusions, respectively. CotB1p, a short 14-aa peptide, which demonstrates high affinity for silica, could be a promising fusion tag for both affinity purification and enzyme immobilization on silica supports. PMID- 24756323 TI - Correlation of Parkinson disease severity and 18F-DTBZ positron emission tomography. AB - IMPORTANCE: Currently, diagnosis of Parkinson disease is mainly based on clinical criteria characterized by motor symptoms including bradykinesia, rigidity, resting tremor, and postural instability. Reliable in vivo biomarkers to monitor disease severity and reflect the underlying dopaminergic degeneration are important for future disease-modifying therapy in Parkinson disease. OBJECTIVES: To use [18F]9-fluoropropyl-(+)-dihydrotetrabenazine (18F-DTBZ; [18F]AV-133) positron emission tomography (PET) to explore the characteristics of vesicular monoamine transporter type 2 imaging in patients with Parkinson disease (PD) with different severity levels as well as to investigate its capability in monitoring clinical severity. DESIGN, SETTING, AND PARTICIPANTS: Regional uptakes for 18F DTBZ PET of different disease stages were measured. Seventeen healthy control participants and 53 patients in 3 groups of mild, moderate, and advanced stages of PD were recruited for 18F-DTBZ PET scans from the Movement Disorders Clinic in the Chang Gung Memorial Hospital, Taiwan. MAIN OUTCOMES AND MEASURES: The severity of disease in patients with PD was quantified by modified Hoehn-Yahr Scale, Unified Parkinson Disease Rating Scale total scores and subscores of posture instability and gait disturbance, tremor, akinesia, and rigidity while not taking medication. Both voxelwise- and volume of interest-based image analyses were performed. The specific uptake ratio (SUR) of each volume of interest and voxel was calculated as (target uptake - reference uptake) / reference uptake using the occipital reference region from magnetic resonance imaging-based spatially normalized 18F-DTBZ images for each participant. Average SUR images were displayed as 2-dimensional and 3-dimensional to illustrate the image patterns in each group. The nonparametric Kruskal-Wallis test on regional SUR was used for group comparison between healthy control participants and patients with PD at different stages. Quantitative parameters were correlated with severity of disease and disease duration by Spearman correlation. Voxelwise analysis for evaluating dopaminergic neuron decline of different PD stages was performed by SPM5. RESULTS: The 2-dimensional and 3-dimensional 18F-DTBZ PET images demonstrated that the reduction of vesicular monoamine transporter type 2 availability was obviously correlated with the severity of disease in patients with PD. The mean reductions of vesicular monoamine transporter type 2 density for the caudate, putamen,and substantia nigra were 21.50%, 58.20%, and 21.10% for mild PD[Parkinson disease];60.75%, 79.49%,and 39.87%formoderate PD; and63.94%,83.20%, and 44.00% for advanced PD, respectively [corrected]. The SURs of bilateral striatal regions exhibited significantly exponential correlations to stage; disease duration; Unified Parkinson Disease Rating Scale motor score; posture instability and gait disturbance; and akinesia, rigidity, and tremor scores. CONCLUSIONS AND RELEVANCE: In PD, 18F-DTBZ PET is a potential imaging biomarker for measuring dopaminergic degeneration in vivo and monitoring the severity of disease. PMID- 24756324 TI - Effects of diode laser on direct pulp capping treatment : a pilot study. AB - At the present time, evidence-based, best practices have yet to be established for maintaining the vitality of teeth by managing caries-associated pulp exposure in permanent teeth. In terms of biomechanical and esthetic considerations, pulp capping has proven to be more effective than root-canal therapy. Given the low success rate of conventional methods, new techniques, such as laser-assisted repairs, should be developed. The purpose of this study was to compare the effectiveness of conventional and diode laser-assisted methods in direct pulp capping of carious teeth. Ten patients ranging in age from 12 to 40 were assigned randomly to experimental and control groups in this clinical trial in which the participants' teeth were treated with different techniques, i.e., conventional treatment and diode 808-nm, laser-assisted treatment. For each of these groups, five cases were chosen for treatment with the same method under rubber dam isolation. The data were analyzed by the runs test using SPSS software. The success rate was significantly different between conventional (60 %) and diode 808-nm, laser-assisted (100 %) groups after one year (P > 0.05). The laser assisted procedure proved to be more effective than the conventional technique in enhancing the outcomes of pulp-capping therapy in carious exposures. PMID- 24756325 TI - Thermal effects and morphological aspects of varying Er:YAG laser energy on demineralized dentin removal: an in vitro study. AB - The aim of this study was to evaluate thermal changes, dentin ablation removal capacity, and morphological aspects of sound and demineralized human dentin surface irradiated with different output energies of an erbium: yttrium-aluminium garnet (Er:YAG) laser. Eighty sound human tooth specimens were assigned into two groups: demineralized dentin and sound dentin (control group). The dentin groups were subdivided into four subgroups (n = 10) according to the irradiation energy used (120, 160, 200, or 250 mJ) at a constant frequency level of 6 Hz, in focused mode, and under refrigeration. Quantitative analysis of the sound and carious dentin ablation was performed using light microscopy (LM) by measuring (mm) the remaining demineralized tissue with the Axion VisionTM software. Qualitative analysis was performed using the images obtained with a scanning electron microscope (SEM), and the temperature increase was recorded with an infrared digital thermometer. The Er:YAG laser promoted a gradual increase in temperature for all groups, and no difference was observed between the sound and demineralized dentin. The groups of 200 and 250 mJ showed the highest values, yet a variation in temperature did not exceed 5 degrees C. The energy output of 120 mJ selectively removed demineralized tissue when compared to 250 mJ, while also providing more regular surfaces in the cavity preparation. It was concluded that the temperature increase during sound and demineralized dentin removal had a strong positive correlation with the Er:YAG laser energy level output. However, the higher energies used did not present selectivity to the demineralized tissue, and the parameters used did not cause an increase in temperature over 5 degrees C. PMID- 24756326 TI - New LLLT protocol to speed up the bone healing process-histometric and immunohistochemical analysis in rat calvarial bone defect. AB - A new low-level laser therapy (LLLT) protocol is proposed and compared to another previously studied, in animal models, aiming to establish a more practical LLLT protocol. Protocol 1, the same used in other works and based on the clinical LLLT protocol for bone regeneration, consists of punctual transcutaneous applications in the defect region with fluence of 16 J/cm(2) every 48 h for 15 days. Protocol 2, proposed in this work, consists of three sessions: the first application directly on the defect site with fluency of 3.7 J/cm(2), during the surgical procedure, followed by two transcutaneous applications, 48 and 120 h postoperatively. The Thera Lase(r) (lambda = 830 nm) was used, and the dosimetry of the first application of protocol 2 was calculated based on in vitro studies. Forty-five male rats were used, in which critical-size bone defects with 8 mm of diameter were surgically created in calvaria. The animals were randomly divided into three groups of 15 animals, named group 1 (protocol 1), group 2 (protocol 2), and control, which was not submitted to laser treatment. After 7, 15, and 45 days, five animals of each group were euthanized, and the pieces of calvarial bone were collected for microscopic and immunohistochemistry for vascular endothelial growth factor (VEGF), osteocalcin (OC), and osteopontin (OP) analysis. Histomorphometry showed that newly formed bone of 15-day samples from group 2 is higher than the control group (p < 0.05, ANOVA, Tukey). At 7 days, in the central part of the defect, VEGF expression was the same for all groups, OC was higher for protocol 2, and OP for protocol 1. The results suggest LLLT using the protocol 2 hastened the bone healing process in the early periods after surgery. PMID- 24756327 TI - Radiation safety knowledge and practices among Irish orthopaedic trainees. AB - INTRODUCTION: Fluoroscopy is frequently used in orthopaedic surgery, particularly in a trauma setting. Exposure of patients and staff to ionising radiation has been studied extensively; however, little work has been done to evaluate current knowledge and practices among orthopaedic trainees. AIMS: This study aimed to investigate the knowledge and practices of Irish orthopaedic trainees regarding use of ionising radiation. METHODS: A confidential internet-based survey on workplace radiation safety practices was distributed via email to 40 higher specialist trainees. Questions included related to radiation safety training and regular work practices. RESULTS: A total of 26 trainees completed the questionnaire (65% response rate). All reported regular exposure to ionising radiation. Compliance with body shields was high (25, 96%), however, other protective measures such as thyroid shields were less frequently employed. The 'as low as reasonably achievable principle' was practised regularly by 14 (54%). Radiation safety training was variable-while just over half (14) respondents felt adequately trained in radiation safety, 17 (65%) had attended a radiation protection course. Use of dosimeters was particularly poor, with only 4 (15%) using them regularly and most citing lack of availability as the main barrier. CONCLUSION: Although most Irish orthopaedic trainees have some knowledge regarding radiation safety, many do not regularly use all available measures to reduce exposure to ionising radiation. Barriers to use of protective mechanisms include lack of availability and perceived impracticality. PMID- 24756328 TI - Seasonal succession of phytoplankton community and its relationship with environmental factors of North Temperate Zone water of the Zhalong Wetland, in China. AB - A data set of phytoplankton community and environmental parameters in a hydrological integrity period, i.e. a poor water term, a medium term and a rich water term of North Temperate Zone climate, was analyzed in order to describe seasonal variation of phytoplankton community and its relationship with environmental variables in the Zhalong Wetland of China. The algal population of the Zhalong Wetland was not abundant, with a mean density of 5.08 * 10(7) cell/L (ranged from 4.54 * 10(7) cell/L in a poor term to 5.56 * 10(7) cell/L a medium term). However, its diversity was essentially limited to Cryptophyta, Bacillariophyta, Chlorophyta, Euglenophyta being the group with highest densities. There were considerable seasonal variations in phytoplankton composition. In general, the dominance of Bacillariophyceae was found in a medium term, which was higher than the other period (p < 0.05). The rich water period also showed Bacillariophyceae and Chlorophyta dominance while the phytoplankton was dominated by Cryptophyta erosa in a poor water term. 10 environmental variables, which were significant (p < 0.05) during the studied periods in one way analysis of covariance, were selected to explore the relationship between phytoplankton structure and environmental factors by canonical correspondence analysis (CCA). The results of the CCA applied to the environmental factors indicated that water temperature (WT) and ammonia (NH3-N) significantly influenced the phytoplankton community (p < 0.05; Monte Carlo test of first constrained axis). Besides WT and NH3-N, the most discriminate physic-chemical variables were nitrite (NO2-N), suspend solid, nitrate (NO3-N), silicon dioxide (SiO2) and all the 10 physical-chemical parameters had a higher marginal effect and lambdaA in the series of constrained CCAs though they were not significant. PMID- 24756330 TI - Ensuring correct interpretation of diagnostic test results. PMID- 24756329 TI - Ingestion and sublethal effects of physically and chemically dispersed crude oil on marine planktonic copepods. AB - Planktonic copepods play a key function in marine ecosystems, however, little is known about the effects of dispersants and chemically dispersed crude oil on these important planktonic organisms. We examined the potential for the copepods Acartia tonsa, Temora turbinata and Parvocalanus crassirostris to ingest crude oil droplets and determined the acute toxicity of the dispersant Corexit((r)) 9500A, and physically and chemically dispersed crude oil to these copepods. We detected ingestion of crude oil droplets by adults and nauplii of the three copepod species. Exposure to crude oil alone (1 uL L(-1), 48 h) caused a reduction of egg production rates (EPRs) by 26-39 %, fecal pellet production rates (PPRs) by 11-27 %, and egg hatching (EH) by 1-38 % compared to the controls, depending on the species. Dispersant alone (0.05 uL L(-1), 48 h) produced a reduction in EPR, PPR and EH by 20-35, 12-23 and 2-11 %, respectively. Dispersant-treated crude oil was the most toxic treatment, ~1.6 times more toxic than crude oil alone, causing a reduction in EPR, PPR and EH by 45-54, 28-41 and 11-31 %, respectively. Our results indicate that low concentrations of dispersant Corexit 9500A and chemically dispersed crude oil are toxic to marine zooplankton, and that the ingestion of crude oil droplets by copepods may be an important route by which crude oil pollution can enter marine food webs. PMID- 24756331 TI - Apoptotic effects of dipyrido [3,2-a:2',3'-c] phenazine (dppz) Au(III) complex against diethylnitrosamine/phenobarbital induced experimental hepatocarcinogenesis in rats. AB - We evaluated the effects of dipyrido [3,2-a:2',3'-c] phenazine (dppz) Au(III) complex ([Au(dppz)Cl2]Cl) on apoptosis during chemically induced hepatocellular carcinoma. 48 male Spraque-Dawley rats were divided into six groups; group I (control), group II [Dimethyl sulfoxide (DMSO)], group III ([Au(dppz)Cl2]Cl), group IV [diethylnitrosamine + Phenobabital (DEN + PB)], group V (DEN + PB + [Au(dppz)Cl2]Cl (2nd week)), and group VI (DEN + PB + [Au(dppz)Cl2]Cl (7th week). The rats in groups IV through VI were administrated with DEN in a single dose of intraperitoneal 175 mg/kg. After 2 weeks of DEN administration, these groups of rats were given daily PB in a dose of 500 ppm. In group V, after two weeks of DEN administration, [Au(dppz)Cl2]Cl complex (2 mg/kg) was given once a week by intraperitoneal injection. In the group VI, the rats were given a dose of 2 mg/kg [Au(dppz)Cl2]Cl complex once a week, 7 weeks after DEN administration. At the end of the study, blood and tissue samples were collected from the rats to determine levels of serum AST, ALT, and LDH, and caspase 3, p53, Bax, Bcl-2 and DNA fragmentation in liver. AST, ALT, LDH, and Bcl-2 levels were higher in group IV, compared to group I, but caspase 3 and p53 levels were lower. In group V, caspase 3, p53, Bax, and DNA fragmentation levels were higher than those of group IV. Caspase 3 and p53 levels increased in group VI compared with group IV. In conclusion, [Au(dppz)Cl2]Cl complex induced apoptosis by elevating levels of caspase 3, p53, Bax, and DNA fragmentation. PMID- 24756332 TI - Physicochemical characterization of ambient air particulate matter in Tabriz, Iran. AB - Atmospheric particulate matter (PM) was measured concurrently from September, 2012, to June, 2013, at two sites, urban and industrial suburban, in Tabriz, Iran. The annual average concentration of total suspended particulates (TSP), PM10, PM2.5, and PM1 at the urban site were 142.2 +/- 76.3, 85.3 +/- 43.9, 39 +/- 19.1, and 28.4 +/- 14.9 ug/m(3) (mean +/- SD), respectively. A total of 11 inorganic water-soluble ions in the TSP and PM10 were identified by ion chromatography. In the urban site, concentrations of total water-soluble ions in TSP and PM10 were 20.3 +/- 20.8 and 16.0 +/- 14.1 ug/m(3), respectively. In this sampling site, secondary inorganic aerosols (i.e., Sigma [Formula: see text], [Formula: see text], and [Formula: see text] concentrations) were the main measured water-soluble ions, which collectively accounted for 13.9 % of TSP mass and 17.7 % of PM10 mass. Correlations between [Formula: see text] with [Formula: see text] and [Formula: see text] indicated that the main source of these ions in PM was the combustion processes. Results of elemental analysis in the industrial suburban site showed that natural sources were the dominant source of PM in this area. PMID- 24756333 TI - Effect of fly ash deposition on photosynthesis, growth and yield of rice. AB - An experiment was conducted to assess the effect of fly ash deposition without and with (0.25, 0.50, 1.0 and 1.5 g m(-2 )day(-1)) foliar dusting on the photosynthesis, stomatal conductance, transpiration, leaf temperature, albedo and productivity of rice. Dusting of 0.5 g m(-2 )day(-1) fly ash and above significantly reduced the photosynthesis, stomatal conductance, transpiration and albedo. Panicle initiation and flowering stages were more influenced by the fly ash deposition as compared to active tillering stage. At higher rates of fly ash deposition, all growth and yield parameters were significantly influenced due to increased heat load and reduced intercellular CO2 concentration. A significant reduction of 12.3, 15.7 and 20.2 % in grain yield was recorded over control when fly ash was dusted at 0.5, 1.0 and 1.5 g m(-2 )day(-1), respectively. PMID- 24756334 TI - [Approaching Physically Inactive Elderly for Physical Activity]. AB - The majority of elderly persons are still not sufficiently physically active. Therefore the aim of this study was to investigate different approaches (physical activity courses, poster, online-survey) for activating elderly to participate in physical activity. The most effective approach was target group physical activity courses with which higher course participation rates in men as well as in people with lower levels of education were achieved. Referring to the transtheoretical model (TTM) it is necessary for future analyses of target group approaches to consider more intensely the initial motivational position of physically inactive elderly. PMID- 24756335 TI - A highly crystalline single Au wire network as a high temperature transparent heater. AB - A transparent conductor which can generate high temperatures finds important applications in optoelectronics. In this article, a wire network made of Au on quartz is shown to serve as an effective high temperature transparent heater. The heater has been fabricated by depositing Au onto a cracked sacrificial template. The highly interconnected Au wire network thus formed exhibited a transmittance of ~87% in a wide spectral range with a sheet resistance of 5.4 Omega ?(-1). By passing current through the network, it could be joule heated to ~600 degrees C within a few seconds. The extraordinary thermal performance and stability owe much to the seamless junctions present in the wire network. Furthermore, the wire network gets self-annealed through joule heating as seen from its increased crystallinity. Interestingly, both transmittance and sheet resistance improved following annealing to 92% and 3.2 Omega ?(-1), respectively. PMID- 24756336 TI - Early prediction of complex midgut volvulus in neonates and infants. AB - INTRODUCTION: Prognosis of midgut volvulus in neonates and infants younger than 1 year remains poor, as diagnostic findings may not be apparent until gut infarction had occurred. To characterize factors that help to predict complex midgut volvulus early was aim of this study. METHODS: Institutionally approved retrospective analysis of all children younger than 1 year treated for midgut volvulus at the author's center from January 2002 to December 2011. Medical history, symptoms, laboratory and radiologic findings as well as sequelae of midgut volvulus were evaluated. RESULTS: In 10 years, 37 children fulfilled the inclusion criteria. Of these, 43% developed complications, and mortality rate was 16%. In 30% of the patients, the only clinical sign was a sudden worsening of the general condition and abdominal distension (complex 19% vs. simple 38%). In one child with simple midgut volvulus, all clinical, laboratory and radiologic signs were negative. CART analysis identified a base excess below -1.70 and preterm birth (<36 weeks) as the best discriminators of complex and simple midgut volvulus. A score >1pt (comprised of these two factors) was found in all children with complex and in 14% of simple midgut volvulus (p < 0.001). A positive score (>1pt) offers a sensitivity of 100% (81.7-100%), specificity of 85.7% (71.8 85.7%), a PPV of 84.2% (68.8-84.2%) and NPV 100% (83.8-100%). DISCUSSION: The study shows that midgut volvulus has a substantial morbidity and mortality. Unfortunately, not all affected children get picked up by history, laboratory and imaging. However, the proposed score helps to identify subject with increased risk of complications. It has the potential to facilitate and accelerate diagnosis of complex midgut volvulus; ultimately, it might help to reduce morbidity and mortality. PMID- 24756338 TI - A simple BODIPY-aniline-based fluorescent chemosensor as multiple logic operations for the detection of pH and CO2 gas. AB - A simple 4-aniline boron-dipyrromethene (BODIPY) dye (1) was developed as a highly sensitive acidic pH fluorescent probe excitable with visible light based on a photoinduced electron transfer (PeT) mechanism. The pH titration indicates that the fluorescence intensity increases more than 500-fold within the pH range of 4.12-1.42 with a pKa value of 3.24 in methanol-water (1 : 1, v/v) solution, which is valuable for studying strongly acidic conditions. Density functional theory (DFT) calculations reproduce the fluorescence off-on behavior. 1 has also been used as a fluorescent chemosensor for the visual detection of dissolved carbon dioxide (CO2) gas. The underlying mechanism of the sensing process is rationalized. This probe can be recovered by bubbling nitrogen (N2) gas into CO2 treated solutions for over 10 cycles. In addition, two logic gates (OR and INH) have been achieved at the molecular level by changing the initial states of system 1 and chemical inputs. PMID- 24756337 TI - The gymnasts' hip and groin: a magnetic resonance imaging study in asymptomatic elite athletes. AB - OBJECTIVE: Specific patterns of developmental adaptation of the proximal femur have been recognized in some sports. Gymnastics are characterized by repetitive axial loading and hip rotations in combination with extreme hip positions. It is unknown how and if these forces can affect an immature skeleton in the long term. We sought to evaluate this, by means of magnetic resonance imaging of the hip and groin of such elite asymptomatic athletes. MATERIALS AND METHODS: We performed a case-control comparative MR imaging study of both hips and groin of 12 (7 male, 5 female) skeletally mature young (mean age 18.6 years) asymptomatic international level gymnasts with a minimum of 10 years' training with age-matched non athletes. At the time of recruitment, none of the athletes had a recorded musculoskeletal complaint or injury in the anatomical area around the hip. RESULTS: The study showed that elite gymnasts share four common morphological characteristics on MRI that deviate from normal and are considered to be the result of adaptational changes to the specific sport: high centre-column diaphysis angle (coxa valga140 degrees on average), ligamentum teres hypertrophy, friction of the iliotibial band with oedema surrounding the greater trochanter, and a high incidence (62.5 %) of radiological appearances of ischiofemoral impingement. CONCLUSION: Our study showed that elite gymnasts share four common morphological characteristics on MRI that deviate from normal. These findings were in asymptomatic subjects; hence, radiologists and sports physicians should be aware of them in order to avoid unnecessary treatment. PMID- 24756339 TI - Morphology control and multicolor up-conversion luminescence of GdOF:Yb3+/Er3+, Tm3+, Ho3+ nano/submicrocrystals. AB - In this paper, well defined GdOF:Yb(3+)/Er(3+), Tm(3+), Ho(3+) nano/submicrocrystals with multiform morphologies were prepared via the urea based precipitation method without using any surfactants. The morphologies of the GdOF products, including spindles and spheres with different sizes (30-550 nm), could be easily modulated by changing the fluorine sources, and the possible formation mechanism has been presented. XRD, FT-IR, SEM, TEM, as well as up conversion (UC) photoluminescence spectra were used to characterize the prepared samples. Under 980 nm NIR excitation, the relative emission intensities and emission colors of Yb(3+)/Er(3+), Yb(3+)/Tm(3+) and Yb(3+)/Ho(3+) doped GdOF could be precisely adjusted over a wide range by tuning the Yb(3+) doping concentration. The strategies for color tuning of UC emission proposed in the current system may be helpful to achieve efficient multicolor luminescence under 980 nm laser excitation. In addition, the corresponding UC mechanisms in the co doping GdOF systems were analyzed in detail based on the emission spectra and the plot of luminescence intensity to pump power. PMID- 24756340 TI - Unexplained abuses of human IgG subclass denomination in antibody patents. PMID- 24756341 TI - Matching asymmetry of tremor with asymmetry of postmortem cerebellar hemispheric changes in essential tremor. AB - Although the number of postmortem studies in essential tremor (ET) has grown in recent years, clinical-pathological correlations remain limited. We are unaware of a study that has assessed whether the pathological changes in ET, if asymmetric, lateralize to the cerebellar hemisphere that is ipsilateral to the arm with more severe action tremor, as one would predict if the lesions were tremor producing. We compared postmortem changes in the right vs. left cerebellar hemispheres in ET and examined how these correlated with asymmetry of tremor on neurological examination. Action tremor in each arm was quantified using a reliable and valid clinical rating scale. Cases were divided into three clinical groups: tremor more severe on right, tremor more severe on left, and tremor symmetric. Calbindin D28k immunohistochemistry was performed on 100 MUm vibrotome sections from a standard tissue block of both right and left neocerebellums to quantify Purkinje cell linear density, torpedo counts, and a group of previously described changes in Purkinje cell axonal shape (thickened axonal profiles) and connectivity (axon recurrent collaterals, axonal branching, terminal axonal sprouting, arciform axons, extent of recurrent collateral plexus). ET cases were divided into three postmortem groups: findings greatest on right, findings greatest on left, and findings symmetric. In 18 (72.0 %) of 25 ET cases, clinical and pathological features were concordant (i.e., both clinically and pathologically right-predominant (one case), both clinically and pathologically left-predominant (five cases), or both clinically and pathologically symmetric (12 cases), p = 0.007). In the remaining seven (28.0 %) ET cases, clinical and pathological data were not concordant, and in none were they completely discordant (i.e., tremor was more severe on the right, and postmortem cerebellar changes were paradoxically more severe on the left or vice versa). Among the seven ET cases with >20 % side-to-side difference in tremor severity, six cases (85.7 %) had the expected pathological asymmetry, with quantified postmortem cerebellar changes more marked ipsilateral to the more clinically affected side. We also created continuous measures of asymmetry. For the entire sample, there was a positive correlation between the clinical asymmetry index and the pathological asymmetry index = 0.52, p = 0.01 (i.e., the right-left difference in clinical asymmetry was correlated with the right-left difference in postmortem changes). For the seven ET cases with clear clinical asymmetry, the correlation was even more robust (r = 0.78, p = 0.039). Clinical-pathological correlations are important in terms of understanding the significance of observed pathological changes. The correlation between clinical laterality or symmetry of tremor and pathological changes in the majority of ET cases provides additional evidence that the pathological changes in the cerebellum in ET are of patho-mechanistic importance. PMID- 24756342 TI - Role of FKBP5 in emotion processing: results on amygdala activity, connectivity and volume. AB - Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders. PMID- 24756344 TI - In vitro and in vivo protection against enterovirus 71 by an antisense phosphorothioate oligonucleotide. AB - Enterovirus 71 (EV71) is a highly infectious virus that is a major cause of hand, foot, and mouth disease (HFMD), which can lead to severe neurological complications. Currently, there is no effective therapy against EV71. Five antisense oligodeoxynucleotides targeting the 5'-terminal conserved domain of the viral genome were designed using a method based on multiple predicted target mRNA structures. They were then screened for anti-EV71 activity in vitro based on their ability to inhibit an EV71-induced cytopathic effect (CPE). A novel antisense oligonucleotide (EV5) was tested both in rhabdomyosarcoma (RD) cells and in vivo using a mouse model, with a random oligonucleotide (EV5R) of EV5 as a control. EV5 was identified as having significant anti-EV71 activity in vitro and in vivo without significant cytotoxicity. Treatment of RD and Vero cells with antisense oligodeoxynucleotide EV5 significantly and specifically alleviated the cytopathic effect of EV71 in vitro. The inhibitory effect was dose dependent and specific, with a corresponding decrease in viral RNA and viral protein levels. In vivo, EV5 was specifically effective against EV71 virus in preventing death, decreasing weight reduction and reducing the viral RNA copy number and the level of viral proteins in the lungs, intestines and muscles. These results demonstrate the potential and feasibility of using antisense oligodeoxynucleotides specific for the 5'-terminal conserved domain of the viral genome as an antiviral therapy for EV71 disease. PMID- 24756345 TI - Identification and genetic characterization of porcine hemagglutinating encephalomyelitis virus from domestic piglets in China. AB - In this study, we investigated an acute outbreak of porcine hemagglutinating encephalomyelitis on a farm of 127 pigs in Jilin province, China. Porcine hemagglutinating encephalomyelitis virus (PHEV) was detected in suckling and weaning pigs by RT-PCR assays. Coronavirus-like particles were observed by electron microscopy. The virus isolate was designated PHEV-JT06. The clinical signs, nervous symptoms and positive labeling of neurons in the cerebral cortex with an immunohistochemical stain in PHEV-JT06-infected BALB/c mice supported the diagnosis of PHEV infection. The five full-length PHEV-JT06 structural genes were cloned, sequenced and analyzed. Phylogenetic studies based on the nucleotide and amino acid sequences of the five genes in the outbreak showed that PHEV remained genetically stable. PHEV shares 95.3-99.3% amino acid sequence identity with American strains (AY078417), suggesting that the Chinese isolate is most likely derived from the North American strain. Additionally, PHEV, HCoV-OC43 and BCoV were genetically close. These results may provide some insights into the genotype of the etiological agent responsible for the porcine hemagglutinating encephalomyelitis outbreak and could also provide a comparative view of the genomics of the five structural proteins of PHEV. PMID- 24756343 TI - Environmental endocrine disruption of energy metabolism and cardiovascular risk. AB - Rates of metabolic diseases have increased at an astounding rate in recent decades. Even though poor diet and physical inactivity are central drivers, these lifestyle changes alone fail to fully account for the magnitude and rapidity of the epidemic. Thus, attention has turned to identifying novel risk factors, including the contribution of environmental endocrine disrupting chemicals. Epidemiologic and preclinical data support a role for various contaminants in the pathogenesis of diabetes. In addition to the vascular risk associated with dysglycemia, emerging evidence implicates multiple pollutants in the pathogenesis of atherosclerosis and cardiovascular disease. Reviewed herein are studies linking endocrine disruptors to these key diseases that drive significant individual and societal morbidity and mortality. Identifying chemicals associated with metabolic and cardiovascular disease as well as their mechanisms of action is critical for developing novel treatment strategies and public policy to mitigate the impact of these diseases on human health. PMID- 24756346 TI - Complete genome sequence of a novel calicivirus from a goose. AB - A novel goose calicivirus (GoCV) was sequenced. The 8013-nt-long genome was organized into two open reading frames that were in the same frame and separated by 3 nucleotides. This feature is similar to what has been observed in turkey calicivirus (TuCV). Comparison of GoCV with other caliciviruses showed that it shared the highest amino acid sequence identities of 62, 38, and 52% in the nonstructural protein, VP1, and VP2, respectively, with TuCV. Phylogenetic analysis based on the amino acid sequences of nonstructural protein and VP1 demonstrated that GoCV was most closely related to but distinct from TuCV. Thus, GoCV was identified as a novel member in the proposed genus Nacovirus. PMID- 24756347 TI - Complete genome sequence of a natural mutant of grapevine virus A (GVA). AB - A new genetic variant of grapevine virus A (GVA) of phylogenetic group I was identified during comparative analysis of the viruses infecting two sibling grapevines cv. Shiraz. The grapevines were propagated from a single mother plant. One of them become infected with Shiraz disease (SD), which is highly destructive on noble grapevine cultivars Shiraz and Merlot in South Africa. The new variant was not associated with SD, as it was present in both SD-affected and SD-free plants. However, unlike in an earlier study of grapevines affected by this disease, this GVA variant of group I strongly dominated over a coinfecting variant of group II associated with SD and a variant of group III. The variant, named I327-5, was mechanically transmitted from SD-affected grapevine to Nicotiana benthamiana, and its genome was fully sequenced. The sequence data revealed that the most distinctive genomic feature of variant I327-5 is the deletion of three nucleotides in the region where the ORF2 and ORF3 genes overlap. These genes of GVA encode a 19.8-kDa protein, the function of which remains unknown, and a 31-kDa protein that is indispensable for the movement of the virus in plants. An alignment of the amino acid sequences of these proteins encoded by variant I327-5 with the corresponding proteins encoded by other members of group I suggested that, as the result of mutations, a neutral threonine or alanine and a negatively charged glutamic acid, respectively, were removed from the proteins of GVA variant I327-5. PMID- 24756348 TI - The role of cytoreductive surgery in the management of progressive glioblastoma : a systematic review and evidence-based clinical practice guideline. AB - QUESTION: Should patients with previously diagnosed malignant glioma who are suspected of experiencing progression of the neoplasm process undergo repeat open surgical resection? TARGET POPULATION: These recommendations apply to adults with previously diagnosed malignant glioma who are suspected of experiencing progression of the neoplastic process and are amenable to surgical resection. RECOMMENDATIONS LEVEL II: Repeat cytoreductive surgery is recommended in symptomatic patients with locally recurrent or progressive malignant glioma. The median survival in these patient diagnosed with glioblastoma is expected to range from 6 to 17 months following a second procedure. It is recommended that the following preoperative factors be considered when evaluating a patient for repeat operation: location of recurrence in eloquent/critical brain regions, Karnofsky Performance Status and tumor volume. PMID- 24756349 TI - Exogenous endothelin-1 induces cell migration and matrix metalloproteinase expression in U251 human glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor characterized by its rapid infiltration to surrounding tissues during the early stages. The fast spreading of GBM obscures the initiation of the tumor mass making the treatment outcome undesirable. Endothelin-1 is known as a secretory protein presented in various types of brain cells, which has been indicated as a factor for cancer pathology. The aim of the present study was to investigate the molecular mechanism of cell migration in GBM. We found that various malignant glioma cells expressed higher amounts of endothelin-1, ETA, and ETB receptors than nonmalignant human astrocytes. The application of endothelin-1 enhanced the migratory activity in human U251 glioma cells corresponding to increased expression of matrix metalloproteinase (MMP)-9 and MMP-13. The endothelin-1 induced cell migration was attenuated by MMP-9 and MMP-13 inhibitors and inhibitors of mitogen-activated protein (MAP) kinase and PI3 kinase/Akt. Furthermore, the elevated levels of phosphate c-Jun accumulation in the nucleus and activator protein-1 (AP-1)-DNA binding activity were also found in endothelin 1 treated glioma cells. In migration-prone sublines, cells with greater migration ability showed higher endothelin-1, ETB receptor, and MMP expressions. These results indicate that endothelin-1 activates MAP kinase and AP-1 signaling, resulting in enhanced MMP-9 and MMP-13 expressions and cell migration in GBM. PMID- 24756350 TI - Prognostic utility of gene therapy with herpes simplex virus thymidine kinase for patients with high-grade malignant gliomas: a systematic review and meta analysis. AB - The aim of this study was to assess the effectiveness of adding viral vector mediated gene therapy with herpes simplex virus thymidine kinase (HSV-tk) to standard treatment, in comparison with standard treatment alone to treat patients with high-grade gliomas (HGGs). A literature search of the databases PubMed, Embase, the Cochrane Library, Web of Science, and Chinese biomedicine was performed to identify eligible studies. Three randomized controlled trials (involving a total of 532 patients) were included in this systematic review. A meta-analysis of included studies demonstrated a significant increase in median survival time (MST) in patients who were treated with HSV-tk gene therapy (mean deviation 0.59, 95% CI: 0.41-0.76, p < 0.0001). The results of pooled analysis for different patient groups show that overall survival (OS) for all HGG patients was improved by adding gene therapy [hazard ratio (HR) = 0.91, 95% CI: 0.74-1.13, p = 0.42], while a different result was seen for glioblastoma multiforme (GBM) patients (HR = 1.06, 95% CI: 0.80-1.41, p = 0.70). Furthermore, the combined results for tumor progression implied that standard therapy was superior to gene therapy [odds ratio (OR) = 1.31, p = 0.09]; yet differences in HR and OR between experimental groups and control groups had no statistical significance (p > 0.05). Based on the best available evidence, it appears that adding gene therapy with HSV-tk has some effect in treating HGG patients, especially with respect to MST. However, neither the pooled analysis of OS, nor the combined analysis of tumor progress indicates any significant advantage to adding gene therapy compared with standard treatment alone. More prospective studies are needed to draw solid conclusions about whether gene therapy has significant prognostic advantage. PMID- 24756351 TI - Identification of microRNAs involved in growth arrest and cell death in hydrogen peroxide-treated human dermal papilla cells. AB - microRNAs (miRNAs) are small non-coding RNAs that regulate various biological processes by interfering with the translation of target genes. Several studies have suggested that miRNAs are involved in cellular responses to hydrogen peroxide (H2O2). Reactive oxygen species (ROS) are involved in hair malignancies, however, the H2O2-induced, miRNA-dependent regulatory mechanisms of human dermal papilla (HDP) cells are not fully understood. Our previous study demonstrated that changes in miRNA expression function to regulate growth arrest and apoptosis in UVB-irradiated HDPs. In the present study, miRNA expression was profiled in HDPs treated with H2O2. The transcriptome analysis of H2O2-treated HDPs enabled the identification of 68 differentially expressed miRNAs (62 were upregulated and 6 were downregulated) and 14,316 putative target genes of the miRNAs. Gene ontology (GO) analysis was utilized to verify that the putative target genes of the altered miRNAs were associated with H2O2-induced cell growth arrest and apoptosis. This bioinformatics analysis indicated that H2O2-response pathways involved in growth arrest and apoptosis were significantly affected. The identification of miRNAs and their putative targets may offer new therapeutic strategies for H2O2-induced hair follicle disorders. PMID- 24756353 TI - Smart aid: a catalytic converter. PMID- 24756352 TI - Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. AB - IMPORTANCE: Information on age-specific risk for Parkinson disease (PD) in patients with Gaucher disease (GD) and glucocerebrosidase (GBA) heterozygotes is important for understanding the pathophysiology of the genetic association and for counseling these populations. OBJECTIVE: To estimate the age-specific risk for PD in Ashkenazi Jewish patients with type 1 GD and in GBA heterozygotes. DESIGN, SETTING, AND PARTICIPANTS: The study included patients with GD from 2 tertiary centers, Shaare Zedek Medical Center, Jerusalem, Israel (n = 332) and Mount Sinai School of Medicine, New York, New York (n = 95). GBA noncarrier non PD spouse control participants were recruited at the Center for Parkinson's Disease at Columbia University, New York (n = 77). All participants were Ashekanzi Jewish and most patients (98.1%) with GD carried at least 1 N370S mutation. MAIN OUTCOMES AND MEASURES: The main outcome measure was a diagnosis of PD. Diagnosis was established in patients with GD on examination. We used a validated family history interview that identifies PD with a sensitivity of 95.5% and specificity of 96.2% to identify PD in family members. Kaplan-Meier survival curves were used to estimate age-specific PD risk among patients with GD (n = 427), among their parents who are obligate GBA mutation carriers (heterozygotes, n = 694), and among noncarriers (parents of non-PD, non-GD control participants, n = 154). The age-specific risk was compared among groups using the log-rank test. RESULTS: Among those who developed PD, patients with GD had a younger age at onset than GBA heterozygotes (mean, 54.2 vs 65.2 years, respectively; P = .003). Estimated age-specific risk for PD at 60 and 80 years of age was 4.7% and 9.1% among patients with GD, 1.5% and 7.7% among heterozygotes, and 0.7% and 2.1% among noncarriers, respectively. The risk for PD was higher in patients with GD than noncarriers (P = .008, log-rank test) and in heterozygotes than noncarriers (P = .03, log-rank test), but it did not reach statistical significance between patients with GD and GBA heterozygotes (P = .07, log-rank test). CONCLUSIONS AND RELEVANCE: Patients with GD and GBA heterozygotes have an increased age-specific risk for PD compared with control individuals, with a similar magnitude of PD risk by 80 years of age; however, the number of mutant alleles may play an important role in age at PD onset. PMID- 24756355 TI - Men's Health Innovation. PMID- 24756354 TI - [Importance of osteotomy around to the knee for medial gonarthritis. Indications, technique and results]. AB - BACKGROUND: Frontal plane deformities result in significant overload of the (ipsilateral) affected compartment of the knee and in rapid progression of osteoarthritis. The indication for osteotomy around the knee is related mainly to the constitutional metaphyseal deformity in the frontal plane. METHODS: Exact analysis and planning based on a long-leg standing radiograph is mandatory. Valgus high tibial osteotomy can be performed safely and atraumatically by biplanar open-wedge osteotomy from medial using a specific plate-fixator. A new technique of closed wedge biplanar distal femur osteotomy with fixation by a new plate fixator is also presented. RESULTS: Our multicenter follow-up study with 533 patients revealed good functional outcome scores with a small complication rate. The subjective ratings were better than in comparable groups with unicondylar knee replacement and with total knee arthroplasty. Metaanalysis from the literature have proven good long-term results of osteotomy around the knee. CONCLUSION: Osteotomy around the knee results in good middle-term and long-term results if the indication criteria are respected and a specific surgical technique is used. PMID- 24756356 TI - An examination of stroke-related knowledge in male stroke survivors living in the South Carolina Stroke Belt. AB - Racial differences have been observed in stroke-related knowledge and knowledge of specific stroke risk factors and stroke prevention practices. Using data from 134 male stroke survivors, racial differences in overall knowledge, risk factor knowledge, and stroke prevention practices were examined using the Stroke Knowledge Test. Knowledge that diabetes doubles ones risk of stroke was present in 48% of the participants, while knowledge of aspirin in the prevention of stroke by stopping blood clot formation was reported in 83% of the participants. Findings indicate participants were knowledgeable that obesity increased risk of stroke (71%) and high blood pressure was the most important stroke risk factor (70%). Participants indicated knowledge that diet, exercise, and controlling blood pressure and cholesterol reduces risk of stroke (86%). In regression models, there were no significant race differences in overall stroke knowledge or the odds of knowledge of information related to stroke risk factors and stroke prevention practices after adjusting for age, education, and marital status. Although stroke-related knowledge did not differ by race, stroke survivors exhibited gaps in stroke knowledge particularly of knowledge of common risk factors. These factors should be considered in approaches to improve stroke related knowledge in all stroke survivors. PMID- 24756358 TI - (68)Ga-PSMA PET/CT imaging of metastatic clear cell renal cell carcinoma. PMID- 24756359 TI - Forming a ruthenium isomerisation catalyst from Grubbs II: a DFT study. AB - A DFT investigation into the mechanism for the decomposition of Grubbs 2nd generation pre-catalyst (2) in the presence of methanol, is presented. Gibbs free energy profiles for decomposition of the pre-catalyst (2) via two possible mechanisms were computed. We predict that decomposition following tricyclohexylphosphane dissociation is most favoured compared to direct decomposition of the pre-catalyst (2). However, depending on the reaction conditions, an on-pathway mechanism may be competitive with ruthenium hydride formation. PMID- 24756360 TI - A highly sensitive and reductant-resistant fluorescent probe for nitroxyl in aqueous solution and serum. AB - A novel coumarin-based fluorescent probe, P-CM, for quantitative detection of nitroxyl (HNO) was developed. P-CM exhibits a selective response to HNO over other biological reductants and was also applied for quantitative detection of HNO in bovine serum with satisfactory results. PMID- 24756361 TI - Abuse potential of intravenous oxycodone/naloxone solution in nondependent recreational drug users. AB - BACKGROUND AND OBJECTIVE: Abuse of opioid analgesics has become a public health issue. Some opioid abusers use intravenous administration to increase the magnitude of positive reinforcing effects. Intravenous co-administration of oxycodone with naloxone, an opioid antagonist, may reduce these rewarding effects and discourage abuse. A 2:1 oxycodone:naloxone (OXN) tablet formulation has been studied in the USA for the management of moderate-to-severe chronic pain. Intravenous administration of a 2:1 oxycodone:naloxone solution (sOXN) reflects the oxycodone:naloxone ratio found in laboratory studies of OXN following tampering for intravenous administration. The objective of this study was to characterize abuse-deterrent properties of sOXN. METHODS: This single-center, double-blind, randomized, placebo-controlled, active-controlled, crossover study enrolled nondependent recreational opioid users with experience using multiple (two or more) routes of administration. Following demonstration that subjects could discern between placebo and oxycodone, 24 eligible male and female subjects were randomized to receive intravenous injections of 0.07 mg/kg oxycodone (OXY), 0.07 mg/kg oxycodone and 0.035 mg/kg naloxone solution (sOXN), or matching placebo over three visits. Pharmacokinetics, pharmacodynamics, safety, and tolerability were assessed at scheduled times up to 8 h post-dose. Parameters were computed and statistically compared among treatments. RESULTS: Pharmacokinetics were similar between OXY and sOXN. Subjects reported significantly fewer rewarding effects with sOXN compared with OXY; differences between sOXN and placebo were generally not significant. sOXN was well tolerated. CONCLUSIONS: Significant reductions in drug liking and other subjective effects following administration of sOXN compared with OXY indicate that naloxone concentrations were sufficient to antagonize the effects of oxycodone when abused by the intravenous route of administration in opioid-experienced drug users. PMID- 24756362 TI - Pharmacokinetic and exposure-response analyses of leuprolide following administration of leuprolide acetate 3-month depot formulations to children with central precocious puberty. AB - BACKGROUND AND OBJECTIVE: A pharmacokinetic substudy was conducted within a phase 3 clinical trial that evaluated the efficacy and safety of two leuprolide acetate 3-month depot formulations in children with central precocious puberty (CPP), where the pharmacokinetics of leuprolide and the exposure-response relationship between leuprolide concentration and the probability of luteinizing hormone (LH) suppression were assessed. METHODS: Children diagnosed with CPP (N = 42 in each dosing cohort), who were treatment naive or previously treated, received a total of two intramuscular injections of either leuprolide acetate depot 11.25 or 30 mg formulations administered 3 months apart. Serial blood samples were collected for leuprolide concentration determination in a subset of subjects (N = 24 in each cohort). One-way analysis of covariance was used to assess dose proportionality. The probability of LH suppression (peak-stimulated LH concentrations <4 mIU/mL) exposure-response relationship was modelled using repeated measures logistic regression. The predicted probability of LH suppression and the corresponding 95 % confidence interval at the mean leuprolide concentration of each dose group and at each time of measurement were computed. RESULTS: Mean leuprolide concentrations between weeks 4 and 12 for 11.25 and 30 mg doses were relatively constant and dose proportional, with no accumulation of leuprolide upon repeated administration. Body weight and age were not found to be significant covariates on leuprolide pharmacokinetics. Higher leuprolide concentrations were associated with higher probability of LH suppression and both doses provided LH suppression levels <4 mIU/mL. CONCLUSION: Leuprolide pharmacokinetics were characterized for 11.25 and 30 mg 3-month depot injections. An exposure-response model was developed to link leuprolide concentrations and probability of peak-stimulated LH suppression. PMID- 24756363 TI - Characterisation of the electronic structure of some stable nitroxyl radicals using variable energy photoelectron spectroscopy. AB - The photoionization of three stable nitroxyl radicals has been studied in the valence and core regions using synchrotron radiation. We observed different variations of the relative band intensities with the photon energy for two pyrrolidine nitroxyls (nitroxyl8 and nitroxyl9) in the valence ionization region. This is due to strong intramolecular interactions between the amide substituent and the ring pi-orbital when present. In the core ionization region we observed chemical shifts which were consistent with the relative electron affinities of different atoms. We also observed the multiplet splitting of core level binding energies in the final ionic states. The core electron binding energies calculated via the restricted open shell Hartree-Fock based DeltaSCF method exhibit good agreement with the experimental core ionization bands and with the assignment of the spectra by empirical analysis. PMID- 24756364 TI - Arsenic trioxide: marked suppression of tumor metastasis potential by inhibiting the transcription factor Twist in vivo and in vitro. AB - PURPOSE: Arsenic trioxide (ATO) has been found effective in several types of cancer cells, including acute promyelocytic leukemia, and recently in hepatocellular carcinoma (HCC). In this study, we investigated the role of ATO in regulating the invasive activity of HCC after transarterial embolization (TAE). METHODS: Cell migration and invasion were observed using Transwell and wound healing assay. The molecular changes in E-cadherin, N-cadherin, and Vimentin of surviving tumor cells were determined by Western blotting. The effects of ATO on Twist activity of the tumor cells were further analyzed. In animal study, 40 male buffalo rats implanted with McA-RH7777 tumor in the liver were randomly divided into four groups: control, TAE, ATO, and TAE + ATO. TAE procedures were performed on the 14th day after implantation. Lung metastases were observed using fluorescence imaging, and the molecular changes in residual tumor cells were evaluated by Western blotting or immunohistochemistry. Tumor growth and survival analysis were also evaluated. RESULTS: Arsenic trioxide markedly reduced cell migration and invasiveness, which were enhanced by hypoxia after TAE. Western blot analysis revealed ATO inhibited the expression of epithelial-mesenchymal transition (EMT) markers by suppressing Twist. The marked suppression effect of ATO on invasiveness and metastatic potential related to EMT was also shown in tissue. CONCLUSION: The results of this study demonstrated that ATO is an effective anticancer agent in combination with TAE in the treatment of HCC, by suppressing tumor progression and metastasis via selectively inducing tumor cell apoptosis and arresting EMT by inhibiting the Twist activation. PMID- 24756365 TI - Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies. AB - PURPOSE: Aurora kinases are key regulators of mitotic events. Dysfunction of these kinases can cause polyploidy and chromosomal instability, a contributor to tumorigenesis. MK-5108 is a potent inhibitor of Aurora A kinase that has shown preclinical potent activity in malignancies of breast, cervical, colon, ovarian, and pancreatic origin. We sought to assess the preclinical efficacy of MK-5108 in a panel of non-small-cell lung cancer cell lines as a single agent and in combination with cisplatin and docetaxel. METHODS: Eleven lung cancer cell lines were studied. Growth inhibition by MK-5108 was assessed with short- and long-term MTT assays. Cell cycling was measured by flow cytometry. Immunoblotting was used to determine targeted activity of MK-5108 on Aurora A and downstream effects (TACC3 and Plk1). Efficacy of combination studies performed with cisplatin and docetaxel was evaluated by median effect analysis. RESULTS: All cell lines demonstrated sustained growth inhibition following MK-5108 at varying nanomolar concentrations. MK-5108 induced G2/M accumulation, polyploidy, and apoptosis (increased sub-G1/PARP cleavage). Levels of Aurora A, TACC3, and Plk1 diminished. Concurrent treatment of MK-5108 with cisplatin or docetaxel synergistically inhibited cell growth with the docetaxel combination performing better. When administered sequentially, treatment with docetaxel first followed by MK-5108 exhibited greater growth inhibition than the inverse; yet concurrent treatment remained superior. CONCLUSIONS: MK-5108 has potent anti-proliferative activity in lung cancer cell lines alone and in combination with chemotherapies. Determining how best to integrate Aurora inhibitors into current lung cancer treatment regimens would be beneficial. PMID- 24756366 TI - Perioperative landiolol administration reduces atrial fibrillation after cardiac surgery: A meta-analysis of randomized controlled trials. AB - INTRODUCTION: Postoperative atrial fibrillation (POAF) is one of the most common complications after cardiac surgery. Patients who develop POAF have a prolonged stay in the intensive care unit and hospital and an increased risk of postoperative stroke. Many guidelines for the management of cardiac surgery patients, therefore, recommend perioperative administration of beta-blockers to prevent and treat POAF. Landiolol is an ultra-short acting beta-blocker, and some randomized controlled trials of landiolol administration for the prevention of POAF have been conducted in Japan. This meta-analysis evaluated the effectiveness of landiolol administration for the prevention of POAF after cardiac surgery. METHODS: The Medline/PubMed and BioMed Central databases were searched for randomized controlled trials comparing cardiac surgery patients who received perioperative landiolol with a control group (saline administration, no drug administration, or other treatment). Two independent reviewers selected the studies for inclusion. Data regarding POAF and safety outcomes were extracted. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method (fixed effects model). RESULTS: Six trials with a total of 560 patients were included in the meta-analysis. Landiolol administration significantly reduced the incidence of POAF after cardiac surgery (OR 0.26, 95% CI 0.17-0.40). The effectiveness of landiolol administration was similar in three groups: all patients who underwent coronary artery bypass grafting (CABG) (OR 0.27, 95% CI 0.17-0.43), patients who underwent CABG compared with a control group who received saline or nothing (OR 0.28, 95% CI 0.17-0.45), and all patients who underwent cardiac surgery compared with a control group who received saline or nothing (OR 0.27, 95% CI 0.17-0.42). Only two adverse events associated with landiolol administration were observed (2/302, 0.7%): hypotension in one patient and asthma in one patient. CONCLUSION: Landiolol administration reduces the incidence of POAF after cardiac surgery and is well tolerated. PMID- 24756367 TI - Trabectedin: novel insights in the treatment of advanced sarcoma. AB - Soft tissue sarcomas are a heterogenous group of malignancies with relatively high mortality rates. The outlook for these patients has been poor, with only a few drugs showing measurable activity. Trabectedin is a new alkylating agent with significant activity in sarcomas, but particularly in liposarcomas and leiomyosarcomas, both as a single agent or in combination with other drugs. Phase I and II studies of trabectedin have shown measurable benefit. Currently there are several Phase III trials which have completed accrual to better study its use as a single agent or in combination therapy, although outcomes have not yet been reported. Trabectedin (Yondelis) is approved for the treatment of sarcomas by the EMEA, but is not yet approved by the FDA, pending the results of the currently maturing phase III trials. PMID- 24756368 TI - Aquaporins in the honeybee crop--a new function for an old organ. AB - Nectar used by bees as a food source is collected and stored in the crop, where it is transported and converted into honey. The production of honey involves water uptake from nectar. However, the crop is a portion of the insect foregut that has been characterized solely as a food storage organ. Aquaporins are integral membrane proteins that function as specific canal for water transport and are abundant in tissues with high water permeability. In this study, we detected five predicted genes for aquaporins in the gut of the honeybee Apis mellifera. We evaluated the aquaporins' localization in the crop by using an anti aquaporin antibody produced against the peptide sequence from one of the expressed genes, which was detected in the crop epithelium, particularly in the apical portions of the cells. Furthermore, we also showed an increase in sugar concentration in a sucrose solution collected from the crop lumen a few minutes after feeding, indicating that water uptake occurs during storage of nectar in the crop, suggesting a previously unidentified function for the honeybee crop. PMID- 24756370 TI - Molecular biomarkers of residual disease after surgical debulking of high-grade serous ovarian cancer. AB - PURPOSE: Residual disease following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of residual disease has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease. METHODS: We interrogated two publicly available datasets from chemonaive primary high-grade serous ovarian tumors for genes overexpressed in patients with residual disease and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using quantitative RT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for residual disease. Predictive success was evaluated using a one-sided Fisher exact test. RESULTS: Forty-seven probe sets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold and had high expression levels associated with increased incidence of residual disease. In the validation cohort (n = 139), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a prespecified threshold, we found 30 of 35 cases of residual disease in the predicted high-risk group (positive predictive value = 86%) and 54 of 104 among the remaining patients (P = 0.0002; OR, 5.5). CONCLUSION: High FABP4 and ADH1B expression is associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy. PMID- 24756371 TI - New strategies in ewing sarcoma: lost in translation? AB - Ewing sarcoma is the second most common pediatric malignant bone tumor. Aggressive multimodality therapy has led to an improvement in outcomes, particularly in patients with localized disease. However, therapy-related toxicities are not trivial, and the prognosis for patients with relapsed and/or metastatic disease continues to be poor. In this article, we outline some of the promising therapies that have the potential to change the Ewing sarcoma therapeutic paradigm in the not-too-distant future: insulin-like growth factor receptor inhibitors, targeting of the fusion protein, epigenetic manipulation, PARP inhibitors, and immunotherapy. PMID- 24756369 TI - Functional ultrastructure of the plant nucleolus. AB - Nucleoli are nuclear domains present in almost all eukaryotic cells. They not only specialize in the production of ribosomal subunits but also play roles in many fundamental cellular activities. Concerning ribosome biosynthesis, particular stages of this process, i.e., ribosomal DNA transcription, primary RNA transcript processing, and ribosome assembly proceed in precisely defined nucleolar subdomains. Although eukaryotic nucleoli are conservative in respect of their main function, clear morphological differences between these structures can be noticed between individual kingdoms. In most cases, a plant nucleolus shows well-ordered structure in which four main ultrastructural components can be distinguished: fibrillar centers, dense fibrillar component, granular component, and nucleolar vacuoles. Nucleolar chromatin is an additional crucial structural component of this organelle. Nucleolonema, although it is not always an unequivocally distinguished nucleolar domain, has often been described as a well grounded morphological element, especially of plant nucleoli. The ratios and morphology of particular subcompartments of a nucleolus can change depending on its metabolic activity which in turn is correlated with the physiological state of a cell, cell type, cell cycle phase, as well as with environmental influence. Precise attribution of functions to particular nucleolar subregions in the process of ribosome biosynthesis is now possible using various approaches. The presented description of plant nucleolar morphology summarizes previous knowledge regarding the function of nucleoli as well as of their particular subdomains not only in the course of ribosome biosynthesis. PMID- 24756372 TI - Molecular pathways: niches in metastatic dormancy. AB - Despite the best available treatments for primary tumors, cancer can return, even after a long disease-free interval. During this period, cancer cells are believed to lie dormant in either primary sites, metastatic sites, or independent sites like bone marrow, effectively escaping adjuvant cytotoxic treatments. To date, little is known about how these cells transition to dormancy, or how they are reactivated if cancer recurs. Recent studies have revealed the effects of tumor microenvironment or niche on the regulation of tumor dormancy via the signaling pathways of growth arrest-specific 6, bone morphogenetic protein 7, and TGFbeta1, and that the balance between activation of p38 MAPK and ERK MAPK plays a pivotal role in tumor dormancy. In this review, we discuss tumor dormancy from the perspective of the niche and consider potential therapeutic targets. Greater understanding of the mechanisms involved will help guide innovation in the care of patients with advanced cancer. PMID- 24756373 TI - Molecular pathways: turning proteasomal protein degradation into a unique treatment approach. AB - Cancer treatment regimens have evolved from single cytotoxic substances affecting all proliferative tissues toward antibodies and kinase inhibitors targeting tumor specific pathways. Treatment efficacy and cancer survival have improved overall, and side effects have become less frequent. The ubiquitin-proteasome system mediated proteasomal protein degradation is the most critical pathway to regulate the quantity of signal proteins involved in carcinogenesis and tumor progression. These processes are, as well as protein recycling, highly regulated and offer targets for biomarker and drug development. Unspecific proteasome inhibitors such as bortezomib and carfilzomib have shown clinical efficacy and are approved for clinical use. Inhibitors of more substrate-specific enzymes of degradation processes are being developed and are now in early clinical trials. The novel compounds focus on the degradation of key regulatory proteins such as p53, p27(Kip1), and beta-catenin, and inhibitors specific for growth factor receptor kinase turnover are in preclinical testing. PMID- 24756374 TI - The Maastricht Study: an extensive phenotyping study on determinants of type 2 diabetes, its complications and its comorbidities. AB - The Maastricht Study is an extensive phenotyping study that focuses on the etiology of type 2 diabetes (T2DM), its classic complications, and its emerging comorbidities. The study uses state-of-the-art imaging techniques and extensive biobanking to determine health status in a population-based cohort of 10,000 individuals that is enriched with T2DM individuals. Enrollment started in November 2010 and is anticipated to last 5-7 years. The Maastricht Study is expected to become one of the most extensive phenotyping studies in both the general population and T2DM participants world-wide. The Maastricht study will specifically focus on possible mechanisms that may explain why T2DM accelerates the development and progression of classic complications, such as cardiovascular disease, retinopathy, neuropathy and nephropathy and of emerging comorbidities, such as cognitive decline, depression, and gastrointestinal, musculoskeletal and respiratory diseases. In addition, it will also examine the association of these variables with quality of life and use of health care resources. This paper describes the rationale, overall study design, recruitment strategy and methods of basic measurements, and gives an overview of all measurements that are performed within The Maastricht Study. PMID- 24756375 TI - A systematic approach to CT evaluation of orbital trauma. AB - Computed tomography (CT) is widely used in the initial evaluation of patients with craniofacial trauma. Due to anatomical proximity, craniofacial trauma often involves concomitant injury to the eye and orbit. These injuries may have devastating consequences to vision, ocular motility, and cosmesis. CT imaging provides a rapid and detailed evaluation of bony structures and soft tissues of the orbit, is sensitive in detection of orbital foreign bodies, and often guides clinical and surgical management decisions in orbital trauma. For this reason, radiologists should be prepared to rapidly recognize common orbital fracture patterns, accurately describe soft tissue injuries of the orbit, detect and localize retained foreign bodies within the globe and orbit, and recognize abnormalities of the contents and integrity of the globe. In this review, we present a systematic approach to assist radiologists in the rapid evaluation of orbital trauma using the "BALPINE" mnemonic-bones, anterior chamber, lens, posterior globe structures, intraconal orbit, neurovascular structures, and extraocular muscles/extraconal orbit. Using this approach, we describe common traumatic findings within each of these spaces, and present common postsurgical appearances that can mimic findings of acute trauma. PMID- 24756376 TI - Minocycline increases the activity of superoxide dismutase and reduces the concentration of nitric oxide, hydrogen peroxide and mitochondrial malondialdehyde in manganese treated Drosophila melanogaster. AB - The toxicity caused by high concentrations of manganese (Mn) could be due to a production of free radicals. Minocycline is an effective antioxidant with a high potential to capture free radicals. We investigated the effect of minocycline in the activities of superoxide dismutase (SOD) and catalase, and in the concentrations of nitric oxide (NO), hydrogen peroxide (H2O2) and mitochondrial malondialdehyde (MDA) in manganese-treated Drosophila melanogaster. Five groups of flies were used: (1) control: not treated; (2) continuously treated with minocycline (0.05 mM); (3) treated with 30 mM Mn for 6 days and then no additional treatment; (4) continuously treated with Mn; (5) treated only with Mn for 6 days and then treated with minocycline; (6) simultaneously treated with Mn and minocycline. On the 6th day, Mn treatment caused 50% mortality; in the surviving flies increased levels of MDA (67.93%), NO (11.04%), H2O2 (14.62%) and SOD and catalase activity (165.34 and 71.43%, respectively) were detected. All the flies continuously treated with Mn died by the 21st day. On day 40, MDA levels were decreased in groups two, three and five (43.04, 29.67, and 34.72% respectively), as well as NO in group two (29.21%) and H2O2 in groups two and five (53.94% and 78.69%, respectively), while in group three the concentration of H2O2 was increased (408.25%). In conclusion, Mn exerted a pro-oxidant effect on the 6th day as shown by the increased levels of oxidative markers. Minocycline extended the lifespan, increased the activity of SOD and reduced the levels of NO, H2O2 and mitochondrial MDA. PMID- 24756377 TI - Asiaticoside, a component of Centella asiatica, inhibits melanogenesis in B16F10 mouse melanoma. AB - Melanogenesis is the process of generating pigmentation via melanin synthesis and delivery. Three key enzymes, tyrosinase, tyrosinase-related protein 1 (TRP1) and TRP2, metabolize melanin from L-tyrosine. Melanin synthesizing enzymes are regulated by microphthalmia-associated transcription factor (MITF). The titrated extract of Centella asiatica (TECA) contains the major components asiatic acid, asiaticoside and madecassic acid. The present study revealed that TECA reduces the melanin content in melanocytes. Moreover, the asiaticoside contained in TECA modulated melanogenesis by inhibiting tyrosinase mRNA expression. The decrease in tyrosinase mRNA levels was mediated through MITF. Uniquely, asiaticoside inhibited MITF by decreasing its DNA binding affinity. In conclusion, the results of the present study indicate that asiaticoside treatment may have beneficial effects in hyperpigmentation diseases or for skin whitening. PMID- 24756378 TI - Are the harms of false-positive screening test results minimal or meaningful? PMID- 24756379 TI - Silyl alkynylphosphine-boranes: key precursors of triazolylphosphines via tandem desilylation-click chemistry. AB - A versatile synthesis of 1,2,3-triazolyl-4-phosphines from the borane complexes of phosphino-alkynes is reported. The efficiency of the procedure relies on the use of readily available silyl-protected alkynylphosphine-boranes, which were subjected to desilylation with TBAF followed by copper-catalyzed azide-alkyne cycloaddition in one pot. Subsequent treatment with DABCO afforded the targeted triazolylphosphines in high yields. The reported method was applied to the synthesis of the first example of an enantioenriched P-stereogenic triazolylphosphine (98.8% ee). PMID- 24756380 TI - Cost analysis of miniaturized ECMO in H1N1-related ARDS managed by a single caregiver. PMID- 24756382 TI - Di- and tri-oxalkyl derivatives of a boron dipyrromethene (BODIPY) rotor dye in lipid bilayers. AB - The environment-sensitive fluorescent probes provide excellent tools for studying membranes in their native state. We have modified the BODIPY-based fluorescent molecular rotor by increasing the number of alkyl moieties from one to two or three to achieve a more defined and deeper positioning of the probe in membranes. Detailed characterisation of fluorescence properties and localisation/orientation of probes was performed using a variety of fluorescence techniques and model membranes composed of different lipids. As expected, additional alkyls attached to the fluorophore moiety led to a deeper and more defined localisation of the probe in the lipid bilayer. The results strongly indicate that fluorescence properties of such probes are influenced not only by lipid packing but also by the orientation of the probe in membranes. The orientation of rotors studied herein was significantly altered by changes in the lipid composition of membranes. Our observations demonstrate the limits of BODIPY-based molecular rotors as environmental sensors in cellular membranes with complex lipid composition. The results presented herein also underline the importance of the detailed characterisation of fluorescent membrane dyes and provide a guide for future testing. PMID- 24756381 TI - Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span. AB - IMPORTANCE: Age-related cognitive decline among older individuals with normal cognition is a complex trait that potentially derives from processes of aging, inherited vulnerabilities, environmental factors, and common latent diseases that can progress to cause dementia, such as Alzheimer disease and vascular brain injury. OBJECTIVE: To use cerebrospinal fluid (CSF) biomarkers to gain insight into this complex trait. DESIGN, SETTING, AND PARTICIPANTS: Secondary analyses of an academic multicenter cross-sectional (n = 315) and longitudinal (n = 158) study of 5 neuropsychological tests (Immediate Recall, Delayed Recall, Trail Making Test Parts A and B, and Category Fluency) in cognitively normal individuals aged 21 to 100 years. MAIN OUTCOMES AND MEASURES: To investigate the association of these cognitive function test results with age, sex, educational level, inheritance of the epsilon4 allele of the apolipoprotein E gene, and CSF concentrations of beta-amyloid 42 (Abeta42) and tau (biomarkers of Alzheimer disease) as well as F2-isoprostanes (measures of free radical injury). RESULTS: Age and educational level were broadly predictive of cross-sectional cognitive performance; of the genetic and CSF measures, only greater CSF F2-isoprostane concentration was significantly associated with poorer executive function (adjusted R2 <=0.31). Longitudinal measures of cognitive abilities, except Category Fluency, also were associated broadly with age; of the genetic and CSF measures, only lower baseline CSF Abeta42 concentration was associated with longitudinal measures of immediate and delayed recall (marginal R2 <=0.31). CONCLUSIONS AND RELEVANCE: Our results suggest that age and educational level accounted for a substantial minority of variance in cross-sectional or longitudinal cognitive test performance in this large group of cognitively normal adults. Latent Alzheimer disease and other diseases that produce free radical injury, such as vascular brain injury, accounted for a small amount of variation in cognitive test performance across the adult human life span. Additional genetic and environmental factors likely contribute substantially to age-related cognitive decline. PMID- 24756383 TI - Recurrent loss of consciousness despite DDD pacing: psychogenic pseudosyncope in a 19-year-old man. PMID- 24756385 TI - [Hypothalamic hamartomas]]. PMID- 24756386 TI - Updated Recommendations for MRI of the Breast. AB - The managing board of the Breast Imaging Working Group of the German Radiological Society revised the recommendations regarding technique, methods, indications, evaluation, and documentation of MR mammography from the year 2005 1 and adapted them to the improved technical options and the latest scientific knowledge. In relation to technical imaging parameters, these recommendations describe the minimum requirements for acquiring high-quality MRI images of the breast. The recommendations are a general guide to be adjusted by the examiner as needed to suit the individual situation. PMID- 24756387 TI - Evaluation of correlations between underlying disease and port complications. AB - PURPOSE: Evaluation of correlations between underlying disease and port complications. MATERIALS AND METHODS: Retrospective analysis of a data set of 3160 port systems, which had been interventionally implanted over a period of 10 years. Of these, 1393 were included in the final evaluation. The 7 most common underlying diseases and port-induced complications were considered. Port-related thrombotic events, port pocket infections as well as the port-induced sepsis were evaluated and classified as either early or late complications. RESULTS: In 1393 ports, 131 experienced complications. Of these, 22.1 % (n = 29) were early and 79.6 % (n = 102) late complications. The overall incidence rate of late complications was 0.253/1000 observed days. It differed significantly between the underlying diseases (p < 0.001) and was significantly lower in colon carcinoma when compared with pancreatic (p = 0.049), gastric (p = 0.012) and bronchial carcinoma (p = 0.042). The incidence rate of the port sepsis between the underlying diseases also differed significantly (p = 0.006) and had the highest rate in gastric and bronchial carcinoma. The occurrence of a thrombotic event also showed a significant difference in the incidence rates between the underlying diseases (p = 0.045) and was highest in pancreatic and gastric carcinoma. CONCLUSION: There are significant differences in the incidences of complications between the underlying diseases. Knowledge about this can help to improve the port-care and to take specific preventive measures. PMID- 24756388 TI - [Main focus: the conventional roentgen image - an immense diagnostic treasure]. PMID- 24756389 TI - [Successful research support thanks to junior academies]. PMID- 24756390 TI - [Press release on the organizational and disciplinary subordinate status of the MTRA under nursing direction]. PMID- 24756391 TI - [FOLRAD -Forum for leading MTRA]. PMID- 24756392 TI - [Academy for Graduate and Continuing Education in Radiology informs]. PMID- 24756394 TI - [Recognition as so-called "developing practice" and the demands of a below average in claims practice regarding the reimbursement settlement law]. PMID- 24756395 TI - Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVES: A fixed-dose combination of the bronchodilators umeclidinium and vilanterol is in development for the long-term, once-daily treatment of chronic obstructive pulmonary disease (COPD). We characterized the pharmacokinetics of umeclidinium and vilanterol in ~1,635 patients with COPD, evaluating the impact of patient demographics and baseline characteristics on umeclidinium and vilanterol exposure. METHODS: Plasma concentrations of umeclidinium and vilanterol were evaluated in patients enrolled in two phase III, randomized, double-blind, parallel-group, placebo-controlled trials using inhaled umeclidinium/vilanterol combination therapy and inhaled umeclidinium and vilanterol monotherapies as treatments. Population-pharmacokinetic models were developed using non-linear mixed-effects analyses, performed using NONMEM((r)) software. A likelihood-based approach was used to characterize the data below limit of quantification. Umeclidinium and vilanterol exposures at clinical doses were simulated based on the population model. RESULTS: For the umeclidinium and vilanterol population-pharmacokinetic analyses, 1,635 and 1,637 patients provided 8,498 and 8,405 observations, respectively. Umeclidinium and vilanterol pharmacokinetics were best described by a two-compartment model with first-order absorption. For umeclidinium, bodyweight, age, and creatinine clearance (CLCR) were statistically significant covariates for apparent inhaled clearance (CL/F); bodyweight was a statistically significant covariate for volume of distribution of central compartment (V 2/F).The population parameter estimates namely CL/F and V 2/F for umeclidinium were 218 L/h and 1,160 L and 40.9 L/h and 268 L for vilanterol. For vilanterol, bodyweight and age were statistically significant covariates for CL/F. The effect of covariates on umeclidinium and vilanterol systemic exposure was marginal. The population model indicates that a 10 % increase in bodyweight will result in a 2 % increase in CL/F for umeclidinium and vilanterol and 6 % increase in umeclidinium V 2/F. A 10 % increase in age will provide a 7 and 4 % decrease in umeclidinium and vilanterol CL/F, respectively. A 10 % decrease in CLCR will result in a 3 % decrease in umeclidinium CL/F. Umeclidinium and vilanterol population-pharmacokinetic model-based systemic exposure predictions showed no pharmacokinetic interactions between umeclidinium and vilanterol when administered in combination. CONCLUSIONS: There were no apparent pharmacokinetic interactions when umeclidinium and vilanterol were co administered in patients with COPD. The effects of patient demographics, including age, bodyweight, and CLCR, on umeclidinium or vilanterol systemic exposure were minimal, and therefore no dose adjustments are necessary. PMID- 24756396 TI - Boosting the salt recognition abilities of L-ornithine based multitopic molecular receptors by harnessing a double cooperative effect. AB - A family of L-ornithine based salt receptors 1a-f was synthesized, bearing a cation binding site and multiple anion binding sites (nitrophenylurea and amide groups) that may simultaneously associate with a single anion. The variation in H bond donor abilities of one of these anion binding sites has relatively little influence on NO2(-) anion binding when the anion is accompanied by a noncoordinating TBA cation. However, in the presence of a sodium cation, which strongly coordinates with the cation binding domain of 1a-f, the increased H-bond donor abilities of the anion binding group result in a significant enhancement of NO2(-) anion binding. A direct correlation between the anion binding site H-bond donor tendencies and the binding cooperation of sodium cations and nitrite anions was also observed. Cation complexation fixes the nitrophenylurea moiety orientation and exposes that domain to bind anions. This cation and anion cooperation induces a second cooperative effect, namely the simultaneous association of a single anion with both urea and amide binding groups. Receptor 1d was found to be highly selective for NaNO2 over sodium bromide and nitrate. A transport experiment using a bulky liquid membrane showed that this receptor can effectively transport NaNO2 from the aqueous phase through the organic phase. PMID- 24756397 TI - Novel oral anticoagulants: the translation of 'de Leidraad' into daily clinical practice. PMID- 24756398 TI - Cost analysis favours SPECT over PET and CTA for evaluation of coronary artery disease: the SPARC study. PMID- 24756410 TI - Accountable care organizations 2.0: linking beneficiaries. PMID- 24756406 TI - Characterization of complex, co-adapted skeletal biomechanics phenotypes: a needed paradigm shift in the genetics of bone structure and function. AB - The genetic architecture of skeletal biomechanical performance has tremendous potential to advance our knowledge of the biological mechanisms that drive variation in skeletal fragility and osteoporosis risk. Research using traditional approaches that focus on specific gene pathways is increasing our understanding of how and to what degree those pathways may affect population-level variation in fracture susceptibility, and shows that known pathways may affect bone fragility through unsuspected mechanisms. Non-traditional approaches that incorporate a new appreciation for the degree to which bone traits co-adapt to functional loading environments, using a wide variety of redundant compensatory mechanisms to meet both physiological and mechanical demands, represent a radical departure from the dominant reductionist paradigm and have the potential to rapidly advance our understanding of bone fragility and identification of new targets for therapeutic intervention. PMID- 24756411 TI - Substituted 3-acyl-2-phenylamino-1,4-naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death. AB - Naphthoquinones interact with biological systems by generating reactive oxygen species (ROS) that can damage cancer cells. The cytotoxicity and the antitumor activity of 3-acyl-2-phenylamino-1,4-naphthoquinones (DPB1-DPB9) were evaluated in the MCF7 human breast cancer cell line and in male Ehrlich tumor-bearing Balb/c mice. DPB4 was the most cytotoxic derivative against MCF7 cells (EC50 15 uM) and DPB6 was the least cytotoxic one (EC50 56 uM). The 1,4-naphthoquinone derivatives were able to cause DNA damage and promote DNA fragmentation as shown by the plasmid DNA cleavage assay (FII form). In addition, 1,4-naphthoquinone derivatives possibly interacted with DNA as intercalating agents, which was demonstrated by the changes caused in the fluorescence of the DNA-ethidium bromide complexes. Cell death of MCF7 cells induced by 3-acyl-2-phenylamino-1,4 naphthoquinones was mostly due to apoptosis. The DNA fragmentation and subsequent apoptosis may be correlated to the redox potential of the 1,4-naphthoquinone derivatives that, once present in the cell nucleus, led to the increased generation of ROS. Finally, certain 1,4-naphthoquinone derivatives and particularly DPB4 significantly inhibited the growth of Ehrlich ascites tumors in mice (73%). PMID- 24756412 TI - Distribution and assessment of Pb in the supergene environment of the Huainan Coal Mining Area, Anhui, China. AB - Coal mining area is highly subject to lead (Pb) pollution from coal mining activities. Several decades of coal mining and processing practices in dozens of coal mines in the Huainan Coal Mining Area (HCMA) have led to the accumulation of massive amounts of coal gangue, which piled in dumps. In order to investigate the impacts of coal gangue dumps on Pb level in the supergene media of the HCMA, a systematic sampling campaign comprising coal gangue, soil, wheat, and earthworm samples was conducted. The average Pb content in the coal mining area soil is 24 mg/kg, which is slightly higher than the associated coal gangues (23 mg/kg) and markedly higher than reference region soil (12.6 mg/kg). Soil in the HCMA present a slight to moderate Pb contamination, which might be related to the weathering and leaching of coal gangue dumps. Lateral distribution of Pb in HCMA soil differed among individual coal mines. The soil profile distribution of Pb depends on both natural and anthropogenic contributions. Average Pb content is higher in roots than in stems, leaves, and wheat husks, while the Pb level in seeds exceeded the maximum Pb allowance for foods (Maximum Levels of Contaminants in Foods of China, GB 2762-2012). Earthworms in the selected area are significantly enriched in Pb, suggesting higher bio-available Pb level in soil in the HCMA. PMID- 24756413 TI - Evaluation of dispersal volcanic products of recent events in lichens in environmental gradient, Nahuel Huapi National Park, Argentina. AB - The atmospheric transport of volcanic products are subject to several variables, mainly the height of the eruption column and wind direction, thus elements associated with the ashes are deposited in major or lesser degree depending on variables as latitude, wind and humidity. The lichens are able to reflect the atmospheric fallout. The present work evaluated the correlation between meteorological parameters, geographic locations, sulphur and other element concentrations in lichens genus Usnea affected by Puyehue-Cordon Caulle complex (North Patagonia Andean Range) eruption of June 4, 2011. Semiquantitative analyses of biological elements by scanning electron microscope methods, sulphur (S) by LECO and other elements by instrumental neutron activation were evaluated by principal component analysis. Elements as antimony, arsenic, barium, bromine, calcium, caesium, potassium, rubidium, selenium, and uranium correlated with distance to volcano, also calcium and potassium with longitude while bromine, rubidium, and potassium with humidity. Those results indicate that Usnea sp. is a good bioindicator of the atmospheric volcanic emissions in relation to environmental gradient. PMID- 24756414 TI - Natural attenuation of coal combustion waste in river sediments. AB - The weathering of coal combustion products (CCPs) in a lotic environment was assessed following the Tennessee Valley Authority (Kingston, TN) fly ash release of 2008 into surrounding rivers. Sampled materials included stockpiled ash and sediment collected from 180 to 880 days following the release. Total recoverable concentrations of heavy metals and metalloids in sediment were measured, and percent ash was estimated visually or quantified by particle counts. Arsenic and selenium in sediment were positively correlated with percent ash. For samples collected 180 days after the release, total concentrations of trace elements downstream of the release were greater than reference levels but less than concentrations measured in stockpiled ash. Total concentrations of trace elements remained elevated in ash-laden sediment after almost 2.5 years. A sequential extraction procedure (SEP) was used to speciate selected fractions of arsenic, copper, lead, nickel, and selenium in decreasing order of bioavailability. Concentrations of trace elements in sequentially extracted fractions were one to two orders of magnitude lower than total recoverable trace elements. The bulk of sequentially extractable trace elements was associated with iron-manganese oxides, the least bioavailable fraction of those measured. By 780 days, trace element concentrations in the SEP fractions approached reference concentrations in the more bioavailable water soluble, ion exchangeable, and carbonate-bound fractions. For each trace element, the percentage composition of the bioavailable fractions relative to the total concentration was calculated. These SEP indices were summed and shown to significantly decrease over time. These results document the natural attenuation of leachable trace elements in CCPs in river sediment as a result of the loss of bioavailable trace elements over time. PMID- 24756415 TI - Fluorescein-guided surgery for malignant gliomas: a review. AB - Fluorescein is widely used as a fluorescent tracer for many applications. Its capacity to accumulate in cerebral areas where there has been blood-brain barrier damage makes it particularly suitable as a dye for the intraoperative visualization of malignant gliomas (MGs). In this report, we describe the results of a comprehensive review on the use of fluorescein in the surgical treatment of MGs. A comprehensive literature search and review for English-written articles concerning the use of fluorescein in the resection of MGs has been conducted. The search was executed through a PubMed literature search using the following keywords: malignant gliomas, glioblastomas, high-grade gliomas, YELLOW 560, total removal, dedicated filter, neurosurgery, brain tumors, intracranial tumors, and confocal microscopy. The literature search resulted in the retrieval of 412 evidence-based articles. Of these, 17 were found to be strictly related to the resection of MG with the aid of fluorescein. In addition to these 17, we have included 2 articles derived from a personal database of the corresponding author (FA). The analysis of the articles reviewed revealed three major applications of fluorescein during surgery for MGs that was documented: Fluorescein-guided resection of MGs with white-light illumination, fluorescein-guided resection of MGs with a surgical microscope equipped with a dedicated filter for fluorescein, and confocal microscopy for intraoperative histopathological analysis on MGs. The systemic review conducted on the use of fluorescein in MGs explored the applications and the different modalities in which fluorescein has been used. The data we have gathered indicates that fluorescein-guided surgery is a safe, effective, and convenient technique to achieve a high rate of total removal in MGs. Further prospective comparative trials, however, are still necessary to prove the impact of fluorescein-guided surgery on both progression-free survival and overall survival. PMID- 24756416 TI - Patient- and family-centered medical education: the next revolution in medical education? PMID- 24756418 TI - The effectiveness of the Stop Now and Plan (SNAP) program for boys at risk for violence and delinquency. AB - Among the available treatments for disruptive behavior problems, a need remains for additional service options to reduce antisocial behavior and prevent further development along delinquent and violent pathways. The Stop Now and Plan (SNAP) Program is an intervention for antisocial behavior among boys between 6 and 11. This paper describes a randomized controlled treatment effectiveness study of SNAP versus standard behavioral health services. The treatment program was delivered to youth with aggressive, rule-breaking, or antisocial behavior in excess of clinical criterion levels. Outcomes were measured at 3, 9, and 15 months from baseline. Youth in the SNAP condition showed significantly greater reduction in aggression, conduct problems, and overall externalizing behavior, as well as counts of oppositional defiant disorder and attention deficit hyperactivity disorder symptoms. Additional benefits for SNAP were observed on measures of depression and anxiety. Further analyses indicated that the SNAP program was more effective among those with a higher severity of initial behavioral problems. At 1 year follow-up, treatment benefits for SNAP were maintained on some outcome measures (aggression, ADHD and ODD, depression and anxiety) but not others. Although overall juvenile justice system contact was not significantly different, youth in SNAP had significantly fewer charges against them relative to those standard services. The SNAP Program, when contrasted with standard services alone, was associated with greater, clinically meaningful, reductions in targeted behaviors. It may be particularly effective for youth with more severe behavioral problems and may result in improvements in internalizing problems as well. PMID- 24756420 TI - Extracellular adenosine metabolism in immune cells in melanoma. AB - Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, which leads to a strong immunosuppression associated with a rapid tumor progression. Adenosine is considered as one of the main immunosuppressive factors in the tumor environment. It is produced via enzymatic hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 localized on cell surface. Using the ret transgenic mouse melanoma model that closely mimics human melanoma, we demonstrated an increased frequency of ectonucleotidase positive myeloid-derived suppressor cells (MDSCs) in melanoma lesions and lymphoid organs. Furthermore, we observed that conventional CD4(+)FoxP3(-) and CD8(+) T cells infiltrating melanoma lesions of ret transgenic mice were distinctly enriched in the CD39(+)CD73(+) subpopulation that co-expressed also PD 1. Ectonucleotidase expression was also up-regulated in CD4(+) and CD8(+) T cells upon activation. In addition, these ectoenzymes were largely found to be expressed on memory T cell compartment (in particular, on effector memory cells). Our data suggest that extracellular adenosine produced by regulatory T cells (Tregs) and MDSCs can suppress T cell effector functions through paracrine signaling. Another mechanism involves its production also by effector T cells and an inhibition of their anti-tumor reactivity via autocrine signaling as a part of the negative feedback loop. This mode of adenosine signaling could be also used by Tregs and MDSCs to enhance their immunosuppressive activity. PMID- 24756419 TI - Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine. AB - Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4(+) T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide mediated augmentation of specific CD8(+) T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund's adjuvant. The 6MHP vaccine is comprised of 6 peptides representing melanocytic differentiation proteins gp100, tyrosinase, Melan-A/MART-1, and cancer testis antigens from the MAGE family. CD4(+) and CD8(+) T cell responses were assessed in peripheral blood and in sentinel immunized nodes (SIN) by thymidine uptake after exposure to helper peptides and by direct interferon-gamma ELIspot assay against 14 MHC class I-restricted peptides. Vaccine-induced CD4(+) T cell responses to individual epitopes were detected in the SIN of 63 % (22/35) and in the peripheral blood of 38 % (14/37) of participants for an overall response rate of 65 % (24/37). The most frequently immunogenic peptides were MAGE A3281-295 (49 %) and tyrosinase386-406 (32 %). Responses were not limited to HLA restrictions originally described. Vaccine-associated CD8(+) T cell responses against class I-restricted peptides were observed in 45 % (5/11) of evaluable participants. The 6MHP vaccine induces both CD4(+) and CD8(+) T cell responses against melanoma antigens. CD4(+) T cell responses were detected beyond reported HLA-DR restrictions. Induction of CD8(+) T cell responses suggests epitope spreading and systemic activity mediated at the tumor site. PMID- 24756421 TI - [Not Available]. AB - An 85-year-old patient suffered from progressive deterioration (NYHA III) for several months. Cardiac disease was suspected. Echocardiography as well as a CT scan of the heart revealed a heart tumor to be the cause. Tumor staging was negative. After transvenous biopsy, the diagnosis of a Burkitt lymphoma could be established. Due to the advanced age of the patient, the intented surgical therapy was turned down and the patient was treated with 6 courses of a potentially therapeutic chemotherapy (CHOP scheme), which was well tolerated by the patient. The following CT scan showed a complete remission of the tumor. Six months after chemotherapy the patient is in NYHA stage I. PMID- 24756422 TI - Central venous pressure catheter for large-volume paracentesis in refractory ascites. AB - BACKGROUND AND AIMS: About 10 % of cirrhotic patients are unresponsive to sodium restriction and diuretics and develop refractory ascites. Such patients usually require recurrent large-volume paracentesis and lots of hospital admissions. Hereby, we introduce a method applying a central vein (CV) catheter for large volume paracentesis in patients with refractory ascites in up to 4 days associated with sodium restriction and high dose of diuretics. METHODS: Non tunneled triple lumen CV catheter was used to drain the ascites fluid of 30 cirrhotic patients. After precise percussion, the point of highest fluid accumulation was marked for puncture. Then, the skin and subcutaneous tissue were anesthetized. CV catheter set guide wire was entered into the peritoneal cavity and the dilator of the CV catheter set was passed through the guide wire and extracted after some rotations around its insertion site on the skin. The catheter was passed over the guide wire and the guide wire was extracted gradually from one of the lumens and fixed to the skin. RESULTS: Nineteen males and 11 females with mean (+/-SD) age of 59.4 +/- 11.7 years old underwent the procedure. A minimum of 9 and maximum of 29 L (12 +/- 6.6 L) ascites fluid drained during a minimum of 2 and maximum of 5 days of hospital stay. All catheters were patent during the drainage. None of the patients developed hemodynamic instability. Number of re-hospitalizations for paracentesis was 1.9 times during the following year. No complication occurred. CONCLUSIONS: This technique is a simple noninvasive method that can be performed in the endoscopy unit or even at the patient's bedside and may reduce the need for repeated admissions. PMID- 24756423 TI - ADAMTS13 deficiency, despite well-compensated liver functions in patients with noncirrhotic portal hypertension. AB - BACKGROUND: We have reported A disintegrin and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency in noncirrhotic intrahepatic portal hypertension (NCIPH) patients of European origin with preserved liver function. We aimed to study ADAMTS13-von Willebrand factor (vWF) imbalance in Indian patients with NCIPH. METHODS: Twenty-nine cases with NCIPH [22 males; 29 years (13-58); Child's A, 23; B, 6], 22 disease controls with cryptogenic chronic liver disease [15 males; 46 years (18-74); Child's A, 9; B, 9; C, 4] and 17 healthy controls [14 males; 32 years (27-45)] were enrolled in the study. We measured ADAMTS13 antigen and activity (by collagen binding assay (CBA) and by fluorescence resonance energy transfer [FRET] assay), and vWF antigen levels in plasma of study patients. RESULTS: ADAMTS13 activity by CBA in NCIPH patients (32 %, 5 % to 100 %; median, range; p-value <0.001) and disease controls (36 %, 5 % to 144 %; p = 0.001) was significantly lower than in healthy controls (87 %; 60 % to 148 %). ADAMTS13 antigen and activity by FRET assay were also lower in cases and disease controls. ADAMTS13 activity (by CBA) to antigen ratio was lower in NCIPH and disease controls than in healthy controls. Of 29 NCIPH patients, 3 (all in Child's A) had severe ADAMTS13 deficiency (<10 % ADAMTS13 activity), and 8 (Child's A, 7; B, 1) had moderate ADAMTS13 deficiency (10 % to 25 % activity). Conversely, vWF antigen and vWF:ADAMTS13 ratio were higher in patients with NCIPH and in disease controls than in healthy controls. CONCLUSIONS: This study validates the finding of ADAMTS13 deficiency in NCIPH despite preserved liver functions in an Indian population suggesting its involvement in pathogenesis of NCIPH. PMID- 24756424 TI - Readmission after living donor liver transplantation: predictors, causes, and outcomes. AB - BACKGROUND: Complications following liver transplantation requiring readmission may be serious and potentially life threatening. Most reports on readmission have been about after deceased donor liver transplantation (DDLT). We hypothesized that readmission after living donor liver transplantation (LDLT) is due to different reasons and analyzed our experience. METHODS: We retrospectively analyzed the records of 172 consecutive patients who underwent liver transplantation at our institute between January 2010 and June 2012. The primary outcome measure was readmission. We classified readmission into early (<3 months after discharge) and late (>3 months). RESULTS: The study population was 140 after excluding pediatric patients (12), DDLT recipients (2), and those who died during the index admission (18). Their median age was 42 years, and there were 117 males and 23 females. Thirty-eight patients were readmitted (56 episodes) after LDLT. There were 35 early and 21 late readmission episodes. The most common cause for early readmissions was infection (46 %) and that for late readmissions was biliary stricture (62 %). On univariate analysis, pretransplant portal vein thrombosis, more than one bile duct in the liver graft, revised arterial anastomosis or two arteries in the graft, and higher serum alkaline phosphatase levels at discharge were significantly associated with readmission. Readmission was also significantly associated with a higher overall mortality than non readmission in which there was no mortality. CONCLUSION: Pretransplant portal vein thrombosis, more than one bile duct in the liver graft, revision of the arterial anastomosis or two arteries in the graft, and higher serum alkaline phosphatase levels at discharge were significantly associated with readmission. Infective and biliary complications were the commonest causes of early and late readmission after LDLT. PMID- 24756425 TI - Semiconducting composite oxide Y2CuO4-5CuO thin films for investigation of photoelectrochemical properties. AB - An octa-nuclear heterobimetallic complex [Y2Cu6Cl0.7(dmae)6(OAc)7.3(OH)4(H2O)2].3H2O.0.3CH3C6H5 (dmae = dimethylaminoethanoate; OAc = acetato) was synthesized, characterized by melting point analysis, elemental analysis, FT-IR, and single crystal X-ray diffraction analysis and implemented at 600 degrees C under an oxygen atmosphere for the deposition of Y2CuO4-5CuO composite thin films by aerosol assisted chemical vapor deposition (AACVD). The chemical composition and surface morphology of the deposited thin film have been determined by X-ray diffraction, scanning electron microscopy and energy dispersive X-ray analysis that suggest the formation of impurity-free crystallite mixtures of the Y2CuO4-5CuO composite, with well defined evenly distributed particles in the size range of 19-24 nm. An optical band gap energy of 1.82 eV was estimated by UV-visible spectrophotometry. PEC studies show that under illumination with a 150 W halogen lamp and at a potential of 0.8 V, a photocurrent density of 9.85 MUA cm(-2) was obtained. PMID- 24756427 TI - Spinal cord motion: influence of respiration and cardiac cycle. AB - PURPOSE: To assess physiological spinal cord motion during the cardiac cycle compared with the influence of respiration based on magnetic resonance imaging (MRI) measurements. MATERIALS AND METHODS: Anterior-posterior spinal cord motion within the spinal canal was assessed in 16 healthy volunteers (median age, 25 years) by cardiac-triggered and cardiac-gated gradient echo pulse sequence MRI. Image acquisition was performed during breath-holding, normal breathing, and forced breathing. Normal spinal cord motion values were computed using descriptive statistics. Breathing-dependent differences were assessed using the Wilcoxon signed-rank test and compared with the cardiac-based cord motion. RESULTS: A normal value table was set up for the spinal cord motion of each vertebral cervico-thoracic-lumbar segment. Significant differences in cord motion were found between cardiac-based motion while breath-holding and the two breathing modalities (P < 0.01 each). Spinal cord motion was found to be highest during forced breathing, with a maximum in the lower cervical spinal segments (C5; mean, 2.1 mm +/- 1.17). Image acquisition during breath-holding revealed the lowest motion. CONCLUSION: MRI permits the demonstration and evaluation of cardiac and respiration-dependent spinal cord motion within the spinal canal from the cervical to lumbar segments. Breathing conditions have a considerably greater impact than cardiac activity on spinal cord motion. KEY POINTS: * Cardiac triggered and ECG-gated MRI allows for demonstration of the smallest spinal cord motions.* Respiratory influences seem to have the highest impact on spine motion.* In contrast, the influence of the cardiac cycle seems to be small.* The smallest spinal cord motions were measured during breath-hold. PMID- 24756426 TI - Assessment of the hepatic veins in poor contrast conditions using dual energy CT: evaluation of a novel monoenergetic extrapolation software algorithm. AB - PURPOSE: To evaluate a novel monoenergetic post-processing algorithm (MEI+) in patients with poor intrahepatic contrast enhancement. MATERIALS AND METHODS: 25 patients were retrospectively included in this study. Late-phase imaging of the upper abdomen, which was acquired in dual-energy mode (100/140 kV), was used as a model for poor intrahepatic contrast enhancement. Traditional monoenergetic images (MEI), linearly weighted mixed images with different mixing ratios (MI), sole 100 and 140 kV and MEI+ images were calculated. MEI+ is a novel technique which applies frequency-based mixing of the low keV images and an image of optimal keV from a noise perspective to combine the benefits of both image stacks. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the intrahepatic vasculature (IHV) and liver parenchyma (LP) were objectively measured and depiction of IHV was subjectively rated and correlated with portal venous imaging by two readers in consensus. RESULTS: MEI+ was able to increase the SNR of the IHV (5.7 +/- 0.4 at 40keV) and LP (4.9 +/- 1.0 at 90keV) and CNR (2.1 +/- 0.6 at 40keV) greatly compared to MEI (5.1 +/- 1.1 at 80keV, 4.7 +/- 1.0 at 80keV, 1.0 +/- 0.4 at 70keV), MI (5.2 +/- 1.1 M5:5, 4.8 +/- 1.0 M5:5, 1.0 +/- 3.5 M9:1), sole 100 kV images (4.4 +/- 1.0, 3.7 +/- 0.8, 1.0 +/- 0.3) and 140 kV images (2.8 +/- 0.5, 3.1 +/- 0.6, 0.1 +/- 0.2). Subjective assessment rated MEI+ of virtual 40 keV superior to all other images. CONCLUSION: MEI+ is a very promising algorithm for monoenergetic extrapolation which is able to overcome noise limitations associated with traditional monoenergetic techniques at low virtual keV levels and consequently does not suffer from a decline of SNR and CNR at low keV values. This algorithm allows an improvement of IHV depiction in the presence of poor contrast. KEY POINTS: * The evaluated new image-based algorithm for virtual monoenergetic imaging allows calculating low virtual keV images from dual energy datasets with significantly improved contrast-to-noise ratios. * The image based novel monoenergetic extrapolation algorithm applies frequency-based mixing of the low keV images and an image of optimal keV from a noise perspective to combine the benefits of both image stacks.* When compared to traditional monoenergetic images, the novel monoenergetic algorithm has improved contrast-to noise ratios for both low and high virtual keV images.* Contrast-enhanced dual energy images with poor contrast conditions can be significantly improved, e.g. late phase imaging of the liver. PMID- 24756428 TI - High-pitch computed tomography of the lung in pediatric patients: an intraindividual comparison of image quality and radiation dose to conventional 64 MDCT. AB - PURPOSE: The aim of this study was to investigate frequencies of typical artifacts in low-dose pediatric lung examinations using high-pitch computed tomography (HPCT) compared to MDCT, and to estimate the effective radiation dose (Eeff). MATERIALS AND METHODS: Institutional review board approval for this retrospective study was obtained. 35 patients (17 boys, 18 girls; mean age 112 +/ 69 months) were included and underwent MDCT and follow-up scan by HPCT or vice versa (mean follow-up time 87 days), using the same tube voltage and current. The total artifact score (0 - 8) was defined as the sum of artifacts arising from movement, breathing or pulsation of the heart or pulmonary vessels (0 - no; 1 - moderate; 2 - severe artifacts). Eeff was estimated according to the European Guidelines on Quality Criteria for Multislice Computed Tomography. The Mann Whitney U test was used to analyze differences between the patient groups. The Spearman's rank correlation coefficient was used for correlation of ordinal variables. RESULTS: The scan time was significantly lower for HPCT compared to MDCT (0.72 +/- 0.13 s vs. 3.65 +/- 0.81s; p < 0.0001). In 28 of 35 (80 %) HPCT examinations no artifacts were visible, whereas in MDCT artifacts occurred in all examinations. The frequency of pulsation artifacts and breathing artifacts was higher in MDCT compared to HPCT (100 % vs. 17 % and 31 % vs. 6 %). The total artifact score significantly correlated with the patient's age in MDCT (r = - 0.42; p = 0.01), but not in HPCT (r = - 0.32; p = 0.07). The estimated Eeff was significantly lower in HPCT than in MDCT (1.29 +/- 0.31 vs. 1.47 +/- 0.37 mSv; p < 0.0001). CONCLUSION: Our study indicates that the use of HPCT has advantages for pediatric lung imaging with a reduction of breathing and pulsation artifacts. Moreover, the estimated Eeff was lower. In addition, examinations can be performed without sedation or breath-hold without losing image quality. KEY POINTS: * Fewer artifacts in pediatric lung imaging with HPCT* Reduced Eeff in HPCT* HPCT without sedation or breath-hold without loss of image quality. PMID- 24756429 TI - Chronic thromboembolic pulmonary hypertension (CTEPH) - potential role of multidetector-row CT (MD-CT) and MR imaging in the diagnosis and differential diagnosis of the disease. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) can be defined as pulmonary hypertension (resting mean pulmonary arterial pressure of 25 mm Hg or more determined at right heart catheterization) with persistent pulmonary perfusion defects. It is a rare, but underdiagnosed disease with estimated incidences ranging from 0.5% to 3.8% of patients after an acute pulmonary embolism (PE), and in up to 10% of those with a history of recurrent PE. CTEPH is the only form of pulmonary hypertension that can be surgically treated leading to normalization of pulmonary hemodynamics and exercise capacity in the vast majority of patients. The challenges for imaging in patients with suspected CTEPH are fourfold: the imaging modality should have a high diagnostic accuracy with regard to the presence of CTEPH and allow for differential diagnosis. It should enable detection of patients suitable for PEA with great certainty, and allow for quantification of PH by measuring pulmonary hemodynamics (mPAP and PVR), and finally, it can be used for therapy monitoring. This overview tries to elucidate the potential role of ECG-gated multidetector CT pulmonary angiography (MD-CTPA) and MR imaging, and summarizes the most important results that have been achieved so far. Generally speaking, ECG-gated MD-CTPA is superior to MR in the assessment of parenchymal and vascular pathologies of the lung, and allows for the assessment of cardiac structures. The implementation of iodine maps as a surrogate for lung perfusion enables functional assessment of lung perfusion by CT. MR imaging is the reference standard for the assessment of right heart function and lung perfusion, the latter delineating typical wedge-shaped perfusion defects in patients with CTEPH. New developments show that with MR techniques, an estimation of hemodynamic parameters like mean pulmonary arterial pressure and pulmonary vascular resistance will be possible. CT and MR imaging should be considered as complementary investigations providing comprehensive information in patients with CTEPH. PMID- 24756430 TI - Critical appraisal of classification criteria for vasculitides. AB - The vasculitides are a group of protean diseases, some of which are caused by conditions including infections, other autoimmune diseases, or neoplasias. They are a challenge to the clinician, in terms of both diagnosis and therapy. No diagnostic criteria exist, although a multinational effort to develop them is in progress. However, many classification criteria have been proposed, and these have served as diagnostic surrogates and have made it possible to discriminate between many, although not all, of the vasculitides, mainly for epidemiological and therapeutic trial design purposes. In this review we recognise the difficulties of defining such criteria, but at the same time attempt to provide a critical overview of efforts to do so. The increasing knowledge regarding many of these diseases makes us confident that the time will come when their aetiology, or at least their main pathogenic features, is known, rendering proposed classification criteria obsolete. PMID- 24756432 TI - Degarelix: a review of its use in patients with prostate cancer. AB - Degarelix (Firmagon((r)); Gonax((r))) is a gonadotropin-releasing hormone receptor antagonist that is approved for the treatment of advanced (hormone dependent) prostate cancer in the US and EU and the treatment of prostate cancer in Japan. In a pivotal randomized, controlled, 12-month phase III study, degarelix (initial subcutaneous dose of 240 mg followed by monthly dosages of 80 mg) was noninferior to leuprolide (monthly intramuscular dosages of 7.5 mg) in patients with prostate cancer of any stage for which endocrine treatment was indicated (except neoadjuvant hormonal therapy) with regard to suppression of testosterone to castration levels (i.e. <=0.5 ng/mL). Suppression of testosterone and prostate-specific antigen (PSA) levels was faster with degarelix than with leuprolide, and no testosterone surges or microsurges were seen in degarelix recipients. Suppression of testosterone and PSA levels was maintained for the 12 month study duration and continued for up to 5 years in an extension to the main trial (including in patients switching from leuprolide to degarelix in the extension). The drug was generally well tolerated, with most adverse events being mild to moderate in severity. Injection-site reactions and events reflecting the expected effects of testosterone suppression (e.g. hot flushes, weight increase) were the most common treatment-emergent adverse events. Thus, degarelix is a useful option for the treatment of prostate cancer in patients for whom endocrine treatment is indicated. PMID- 24756434 TI - Distal-less homeobox 2 promotes the osteogenic differentiation potential of stem cells from apical papilla. AB - Dental tissue-derived mesenchymal stem cells (MSCs) are a reliable cell source for dental tissue regeneration. However, the molecular mechanisms underlying the directed differentiation of MSCs remain unclear; thus, their use is limited. The histone demethylase, lysine (K)-specific demethylase 4B (KDM4B), plays critical roles in the osteogenic commitment of MSCs by up-regulating distal-less homeobox 2 (DLX2) expression. The DLX2 gene is highly expressed in dental tissue-derived MSCs but the roles of DLX2 in osteogenesis are unclear. Here, we investigate DLX2 function in stem cells from apical papilla (SCAPs). We found that, in vitro, DLX2 expression was up-regulated in SCAPs by adding BMP4 and by inducing osteogenesis. The knock-down of DLX2 in SCAPs decreased alkaline phosphatase (ALP) activity and mineralization. DLX2 depletion affected the mRNA expression of ALP, bone sialoprotein (BSP) and osteocalcin (OCN) and inhibited SCAP osteogenic differentiation in vitro. Over-expression of DLX2 enhanced ALP activity, mineralization and the expression of ALP, BSP and OCN in vitro. In addition, transplant experiments in nude mice confirmed that SCAP osteogenesis was triggered when DLX2 was activated. Furthermore, DLX2 expression led to the expression of the key transcription factor, osterix (OSX) but not to the expression of runt-related transcription factor 2 (RUNX2). Taken together, these results indicate that DLX2 is stimulated by BMP signaling and enhances SCAP osteogenic differentiation by up-regulating OSX. Thus, the activation of DLX2 signaling might improve tissue regeneration mediated by MSCs of dental origin. These results provide insight into the mechanism underlying the directed differentiation of MSCs of dental origin. PMID- 24756431 TI - Early versus delayed initiation of pharmacotherapy in Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and pathologically is characterised by a progressive loss of dopaminergic cells of the nigrostriatal pathway. Clinically, PD is mainly defined by the presence of the motor symptoms of bradykinesia, rigidity, rest tremor and postural instability, but non-motor symptoms such as depression, dementia and autonomic disturbances are recognised as integral parts of the disease. Although pharmacotherapy for PD was introduced almost 50 years ago, and has improved significantly over the intervening period, the timing of initiation of treatment in newly diagnosed PD remains controversial. While some physicians favour an early start of pharmacotherapy at or soon after diagnosis, others prefer to delay pharmacological treatment until a certain degree of disability has developed. This article aims to discuss the advantages and disadvantages of both strategies by exploring their effects on symptoms, disease progression and quality of life. Although the data on putative disease-modifying effects of early pharmacological intervention in PD are still inconclusive, we believe that the most important indication for an early initiation of anti-parkinsonian treatment should be to maintain the quality of life of PD patients and to secure their socioeconomic status as long as possible. PMID- 24756435 TI - Inhibition of invasion and epithelial-mesenchymal transition of human breast cancer cells by hydrogen sulfide through decreased phospho-p38 expression. AB - Sodium hydrosulfide (NaHS) is an exogenous hydrogen sulfide (H2S)-releasing molecule and has antitumor potential against a wide variety of human cancer types. The effect of exogenous H2S on the invasion of breast cancer and the possible underlying mechanisms remain unknown. The present study aimed to investigate the in vitro effects of H2S on transforming growth factor-beta1 (TGF beta1)-induced human breast cancer cells and the associated mechanisms. MCF-7 cells were incubated with TGF-beta1 to induce epithelial-mesenchymal transition (EMT) and an MTT assay was performed to detect cell viability. Flow cytometry, using propidium iodide (PI) staining, was used to determine the stages of the cell cycle. Apoptosis was detected with Annexin V-fluorescein isothiocyanate and PI double staining. Western blotting was performed to detect the protein expression of cystathionine gamma-lyase (CSE, an endogenous H2S producer), phospho-p38 (a signaling protein associated with apoptosis), and SNAI1 (Snail, associated with the induction of EMT). A Boyden chamber invasion assay was performed to detect tumor invasion. The results demonstrated that when NaHS was administered to TGF-beta1-treated MCF-7 cells, the cells exhibited decreased proliferation, G0/G1 phase cell cycle arrest and increased apoptosis. NaHS treatment following TGF-beta1 administration also resulted in decreased cell invasion and decreased EMT, which was indicated by decreased Snail protein expression. In addition, incubation with NaHS increased endogenous CSE protein expression and decreased p38 mitogen-activated protein kinase phosphorylation in MCF-7 cells stimulated by TGF-beta1. Furthermore, the inhibition of endogenous CSE by DL-propargylglycine increased EMT in the MCF-7 cells treated with NaHS and TGF-beta1. In conclusion, the present study provides insights into a novel anticancer effect of H2S on breast cancer cells through activation of the CSE/H2S pathway and decreased expression of phospho-p38. PMID- 24756437 TI - Effect of nonmyeloablative unrelated fetal and neonatal murine peripheral blood mononuclear cell infusion on MRL/lpr mice. AB - For patients with refractory systemic lupus erythematosus (SLE), current medications are insufficient to control their condition, and new treatments are necessary. We investigated the effect of fetal and neonatal murine peripheral blood (FNPB) mononuclear cells on MRL/lpr lupus-prone mice. Female MRL/lpr mice were randomized to three groups (control, radiation and infusion groups). The infusion group had significantly better results for survival rate, body weight increase, reduction of spleen index, serum anti-ds-DNA antibody, antinuclear antibodies (ANA) and creatinine (Cr), 24 h urine protein and pathological renal tissue lesions than either the control or radiation group. Graft versus host disease (GVHD) was not observed in MRL/lpr mice in the infusion group. The infusion group also had better hematogenesis reconstruction than the radiation group. Flow cytometry analysis revealed a significant increase in Th1, CD8+ T and T reg cells and a reduction in Th2, CD4+ T and Th17 cells in the peripheral blood of the radiation and infusion groups compared with the control group. Immunocytochemical assay revealed a significant increase in serum transforming growth factor (TGF)-beta and a significant reduction in interleukin (IL)-17 in the radiation and infusion groups compared with the control group. Therefore, our study showed that FNPB mononuclear cell infusion has a significant role in regulating CD4+ T cells, Th1/Th2, Th17/T reg balance and their corresponding cytokines in MRL/lpr mice. The FNPB mononuclear cell infusion provided evidence in animals and suggested a potential clinical application for umbilical cord blood transplantation to treat SLE patients. PMID- 24756436 TI - The mediating role of self-stigma and unmet needs on the recovery of people with schizophrenia living in the community. AB - PURPOSE: For people with schizophrenia living in the community and receiving outpatient care, the issues of stigma and discrimination and dearth of recovery oriented services remain barriers to recovery and community integration. The experience of self-stigma and unmet recovery needs can occur regardless of symptom status or disease process, reducing life satisfaction and disrupting overall well-being. The present study examined the mediating role of self-stigma and unmet needs in the relationship between psychiatric symptom severity and subjective quality of life. METHODS: Structural equation modeling and mediation analyses were conducted based on a community sample of 400 mental health consumers with schizophrenia spectrum disorders in Hong Kong. RESULTS: The model of self-stigma and unmet needs as mediators between symptom severity and subjective quality of life had good fit to the data (GFI = .93, CFI = .93, NNFI = .92, RMSEA = .06, chi(2)/df ratio = 2.62). A higher level of symptom severity was significantly associated with increased self-stigma (R (2) = .24) and a greater number of unmet needs (R (2) = .53). Self-stigma and unmet needs were in turn negatively related to subjective quality of life (R (2) = .45). CONCLUSIONS: It is essential that service providers and administrators make greater efforts to eliminate or reduce self-stigma and unmet recovery needs, which are associated with the betterment of the overall quality of life and long-term recovery. Both incorporating empowerment and advocacy-based interventions into recovery-oriented services and providing community-based, person-centered services to people based on personally defined needs are important directions for future recovery-oriented efforts. PMID- 24756439 TI - Attitudes about mandated coverage of birth control medication and other health benefits in a US national sample. PMID- 24756451 TI - Contemporary gender-specific outcomes in Germany after radical cystectomy for bladder cancer. AB - In 2008, urothelial carcinoma of the bladder (UCB) was the 8th most common cause of death in Germany. An increasing body of evidence suggests differences in the presentation and prognosis of UCB between genders. Large population-based and multi-institutional studies have found a higher incidence of UCB in men, while women treated with radical cystectomy (RC) have shown unfavorable outcomes compared to their male counterparts. Indeed, it is important to note that UCB incidence and outcomes have regional and country-specific variability. These distinct country and gender-specific differences must be considered in patient counseling, treatment decisions, and UCB management. This review summarizes the contemporary literature regarding the impact of gender on UCB outcomes, focusing on patients treated with RC in Germany. We evaluated the most current literature regarding gender-specific differences in UCB incidence, treatment patterns, and oncological outcomes, including pathological stage distribution and survival. PMID- 24756452 TI - The evolution of the inflatable penile prosthetic device and surgical innovations with anatomical considerations. AB - Historically, early surgical treatment for erectile dysfunction involved the placement of rigid devices outside of the corpora cavernosa. This practice resulted in high rates of erosion and infection. Today, most urologists in the United States place an inflatable penile prosthesis (IPP) with an infection retardant coating inside the corpora cavernosa. In addition to changes in the type of implant used, surgical techniques have evolved greatly in recent years, resulting in reduced operating times, lower infection rates, and improved outcomes. However, anatomical considerations have directed the prosthetic surgeon to improve patient outcomes and satisfaction rates by employing both new surgical techniques and postoperative maneuvers. PMID- 24756453 TI - Early experience of robotic-assisted inguinal lymphadenectomy: review of surgical outcomes relative to alternative approaches. AB - Inguinal lymph node dissection is a diagnostic and potentially curative treatment for penile carcinoma, which has historically been associated with high morbidity rates. This review summarizes the initial outcomes of robotic-assisted inguinal lymphadenectomy (RAIL) compared with the outcomes of the standard open and endoscopic approaches. The early experience suggests that RAIL may yield comparable oncologic outcomes, although future prospective studies of RAIL with greater numbers of participants and long-term follow-up are needed to evaluate the incidence and severity of perioperative and postoperative complications. PMID- 24756454 TI - Enhancement of PM2.5 exposure estimation using PM10 observations. AB - The adverse consequences of particulate matter (PM) inhalation on human health are well documented. Most of the epidemiological work assessing the health impacts of PM exposure concentrates on PM2.5, however, many of the PM monitoring records available for retrospective studies are of coarser PM10 data. This study explores the possibility to simulate PM2.5 data using PM10 records and assesses the trade-off between introduction of the unavoidable simulation errors and the improved spatial coverage enabled by the simulated series. Several modelling approaches are studied, bearing in mind the range of exposure time scales typical to environmental epidemiology studies. The modelling capability is evaluated by cross-testing between three stations observing both the PM2.5 and PM10 fractions. The trade-off between improved spatial coverage and simulation errors is assessed using leave-one-out cross-validation interpolations. Interpolations including both original and simulated data resulted in richer spatial patterns. Their cross validated performance was comparable to or slightly better than that obtained using the original PM2.5 data only. The study provides methodologies and guidelines for scientists and practitioners on how to properly exploit their PM10 data to enhance their PM2.5 spatial coverage and minimise investment in new PM2.5 monitoring. PMID- 24756457 TI - Use of chemotherapy within the last 14 days of life in patients treated at a comprehensive cancer center. PMID- 24756455 TI - Role of interleukin-6 in regulation of immune responses to remodeling after myocardial infarction. AB - Myocardial remodeling following myocardial infarction (MI) is emerging as key causes of chronic infarct mortality. Interleukin-6 is a classic pro-inflammatory cytokine needed to mount an effective immune response. It seems that interleukin 6 acts as an important role in the dynamic and superbly orchestrated process of innate immunity after MI. Interleukin-6 timely suppresses of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function, and thus tunes myocardial remodeling. A comprehensive understanding of biological processes of interleukin-6 in innate immunity leading to inflammatory response and disease-related ventricular remodeling is helpful to find the solution of chronic heart failure. To accomplish this, we reviewed the articles of interleukin-6 regard to inflammation, innate immunity, and cardiac remodeling. This review focuses on the role of interleukin-6 that dominates cell-mediated immunity, especially on neutrophils, monocytes, macrophages, and fibroblasts. In addition, we will also briefly discuss other inflammatory cytokines involved in this process within the paper. PMID- 24756458 TI - Surgical procedures in femoral neck fractures in Finland: a nationwide study between 1998 and 2011. AB - PURPOSE: For femoral neck fractures, recent scientific evidence supports cemented hemiarthroplasty (HA) over uncemented HA and suggests that total hip arthroplasty (THA) should be performed more frequently. We report the current surgical trends in treating femoral neck fractures in Finland. METHODS: The study was conducted using the Finnish National Hospital Discharge Register and included all Finns at least 50 years of age who underwent surgery for femoral neck fractures from 1998 through 2011. Age- and sex-specific incidence rates and annual proportion of each treatment method were calculated. RESULTS: During 1998-2011, a total of 49,514 operations for femoral neck fracture were performed in Finland. The proportion of uncemented HA increased from 8.1% in 2005 to 22.2% in 2011. During the same time, the proportion of cemented HA decreased from 63.9 to 52.5%, internal fixation decreased from 23.2 to 16.1% and THA increased from 4.9 to 9.2%. CONCLUSIONS: Between 2005 and 2011, the proportion of uncemented HA for femoral neck fractures increased markedly in Finland, while cemented HA and internal fixation declined. During this time, the use of THA nearly doubled. The current evidence-based guidelines for treatment of femoral neck fractures were mainly followed, but the increase in uncemented HA procedures contradicts recent scientific evidence. PMID- 24756459 TI - A case of delayed occlusive dissection of the right coronary artery during coronary intervention of the left anterior descending artery. AB - Catheter-induced coronary artery dissection occurs rarely during selective coronary angiography but generally progresses to complete coronary occlusion. We present a case of delayed occlusive dissection of the right coronary artery during coronary intervention of the left anterior descending artery. Bailout stenting was employed to treat the giant hematoma quickly using a unique technique. The use of two guidewires created a high probability that the true lumen was selected, and aspiration of the hematoma with the microcatheter and indeflator effectively repaired a catheter-induced coronary artery dissection. PMID- 24756460 TI - Trifluoroacetic acid-promoted Michael addition-cyclization reactions of vinylogous carbamates. AB - A simple and efficient methodology has been developed for the synthesis of pyrrolobenzoxazine and 3-arylamino coumarin derivatives promoted by trifluoroacetic acid. The initial step in the current protocol involves a Michael addition of the 1,4-benzoxazinone derivatives, a novel class of vinylogous carbamates to the Michael acceptors and subsequent cyclization. PMID- 24756461 TI - Small interfering RNA targeting ILK inhibits EMT in human peritoneal mesothelial cells through phosphorylation of GSK-3beta. AB - Emerging evidence has suggested that human peritoneal mesothelial cells (HPMCs) undergo epithelial-mesenchymal transition (EMT) in peritoneal fibrosis. The molecular mechanisms underlying peritoneal fibrosis and the key molecules involved are not yet fully elucidated. In order to enhance the understanding of peritoneal fibrosis, the present study investigated the roles of integrin-linked kinase (ILK) and glycogen synthase kinase 3beta (GSK-3beta) in high glucose induced phenotypic alterations of HPMCs. It was observed that HPMCs exhibited a cobblestone morphology under normal glucose conditions, whereas under high glucose conditions they had a spindle morphology. Additionally, under high glucose conditions it was found that E-cadherin expression was decreased and vimentin expression was increased in HPMCs, suggesting HPMCs underwent EMT. ILK expression in high glucose conditions was also increased in a dose- and time dependent manner. The role of ILK in the induction of EMT in HPMCs was further investigated using small interfering RNA (siRNA). Following knockdown of ILK gene expression by siRNA, low vimentin expression as well as high E-cadherin expression were observed, suggesting that EMT was inhibited. ILK-knockdown also inhibited phosphorylation of GSK-3beta. These results indicate that ILK-knockdown inhibits EMT of HPMCs through inhibition of GSK-3beta phosphorylation. These findings suggest that ILK may be used as a novel diagnostic and therapeutic target for HPMC fibrosis in the future. PMID- 24756462 TI - Bioequivalence study of two formulations of ibandronic acid 150-mg film-coated tablets in healthy volunteers under fasting conditions: a randomized, open-label, three-way, reference-replicated crossover study. AB - AIMS: This bioequivalence study aimed to compare rate and extent of absorption of a generic medicinal product of ibandronic acid 150-mg film-coated tablet versus Bonviva((r)). METHODS: This was a single-centre, open-label, randomized, three way, three-sequence, reference-replicated, crossover bioequivalence study, under fasting conditions. A single oral dose of ibandronic acid as one 150-mg film coated tablet was administered in each study period. Each washout period lasted 14 days. Blood samples were collected according to a predefined sampling schedule and up to 48.0 hours after administraton in each period. Plasma concentrations of ibandronic acid were measured using a liquid chromatograph-mass spectrometry/mass spectrometry method. Bioequivalence between generic and reference medicinal products is acceptable if the 90 % confidence intervals (CI) of ratio of least squares means between the test and the reference product of ln-transformed area under the serum concentration-time curve from time zero to time of last measurable concentration (AUC0-t ) is within the 80.00-125.00 % interval. Prospectively, a scaled average bioequivalence approach for maximum serum concentration (C max) was established. RESULTS: 153 healthy volunteers were enrolled and randomized. After the test formulation (T) and first and second Bonviva((r)) (R) dosing, the C max was 96.71 +/- 90.19 ng/mL, 92.67 +/- 91.48 ng/mL and 87.94 +/- 60.20 ng/mL and the AUC0-t was 390.83 +/- 287.27 ng.h/mL, 388.54 +/- 356.76 ng.h/mL and 383.53 +/- 246.72, respectively. Ratios of T/R and 90 % CI were 100.92 % (94.35-107.94) for AUC0-t , 100.90 % (94.37-107.88) for AUC0-inf and 102.56 % (95.05-110.67) for C max. CONCLUSIONS: Test formulation of ibandronic acid is bioequivalent in rate and extent of absorption to Bonviva((r)) following a 150-mg dose, under fasting conditions. PMID- 24756463 TI - Performance of Mashona doelings supplemented with different levels of velvet bean (Mucuna pruriens L. DC. var. utilis) seed meal. AB - The objective of the current study was to evaluate the effects of feeding increasing levels of velvet bean seed meal (VBM; 0, 12, 24, and 36 %) on the performance of Mashona doelings. Dry matter intake was lower (P < 0.05) for the control diet compared to VBM diets, but linearly declined (P < 0.05) with increasing levels of VBM. Average daily weight gain was significantly different between experimental groups. Doelings' final live weights and average daily gains were slightly higher in control group than other three supplemented groups where they linearly declined (P < 0.05) with increasing levels of VBM. The cost per kilogram of feed, however, decreased with high inclusion level of VBM. Result suggested that high inclusion level of VBM negatively influenced the growth of young goats probably due to the presence of some anti-nutritional factors which needs further investigation. PMID- 24756464 TI - Association of a novel SNP in exon 10 of the IGF2 gene with growth traits in Egyptian water buffalo (Bubalus bubalis). AB - Insulin-like growth factor 2 (IGF2) plays an important role in muscle growth and it might be used as a marker for the growth traits selection strategies in farm animals. The objectives of this study were to detect polymorphisms in exon 10 of IGF2 and to determine associations between these polymorphisms and growth traits in Egyptian water buffalo. PCR-single-strand conformation polymorphism (SSCP) and DNA sequencing methods were used to detect any prospective polymorphism. A novel single nucleotide polymorphism (SNP), C287A, was detected. It was a non synonymous mutation and led to replacement of glutamine (Q) amino acid (aa) by histidine (H) aa. Three different SSCP patterns were observed: AA, AC, and CC, with frequencies of 0.540, 0.325, and 0.135, respectively. Association analyses revealed that the AA individuals had a higher average daily gain (ADG) than other individuals (CC and AC) from birth to 9 months of age. We conclude that the AA genotype in C287A SNP in the exon 10 of the IGF2 gene is associated with the ADG during the age from birth to 9 months and could be used as a potential genetic marker for selection of growth traits in Egyptian buffalo. PMID- 24756465 TI - First evidence of avian metapneumovirus subtype A infection in turkeys in Egypt. AB - Although avian metapneumovirus (aMPV) infection has been reported in most regions of the world, to date, only subtype B has been detected in Egypt. At the end of November 2013, dry oropharyngeal swabs were collected during an outbreak of respiratory diseases in a free-range, multi-age turkey dealer farm in Northern Upper Egypt. The clinical signs that appeared when turkeys were 3 weeks-old were characterized by ocular and nasal discharge and swelling of sinuses. aMPV of subtype A was detected by real-time reverse transcription-polymerase chain reaction. In order to confirm the results and obtain more information on the molecular characteristics of the virus, F and G protein genes were partially sequenced and compared with previously published sequences deposited in GenBank by using BLAST. Subtype of the strain was confirmed by sequencing of partial F and G protein genes. The highest percentages of identity were observed when G sequence of the Egyptian strain was compared with the sequence of an aMPV-A isolated in Nigeria (96.4 %) and when the F sequence was compared with strains isolated respectively in Italy and in UK (97.1 %). Moreover, the alignment of the sequences with commercial subtype A vaccine or vaccine-derived strains showed differences in the Egyptian strain that indicate its probable field origin. The detection of aMPV in the investigated turkey flock highlights some relevant epidemiological issues regarding the role that multi-age farms and dealers may play in perpetuating aMPV infection within and among farms. To our knowledge, this is the first report of aMPV subtype A in Egypt. PMID- 24756466 TI - Higher feeding diets effects on age and liveweight gain at puberty in crossbred Nelore * Hereford heifers. AB - This study was conducted to determine the age and liveweight at puberty of 120 crossbred beef heifers submitted to four diets to achieve predetermined weight gains (kg/day): 0.5 (G500; n = 32), 0.75 (G750; n = 32), 1.0 (G1000; n = 29), and 1.25 (G1250; n = 27). Animals were classified depending on their level of crossing between Nelore (N) and Hereford (H): 25%N-75%H, 37.5%N-63.5%H, 43.7%N 56.7%H, 50%N-50%H, and 75%N-25%H. Reproductive evaluation was performed at the beginning and at the end of the experimental period by ultrasonography and hormone analysis. The average age and liveweight at puberty were 388.0 +/- 1.9 days and 331.4 +/- 1.3 kg, respectively. Animals from the 25%N-75%H group reached puberty earlier than heifers from other genetic groups supplemented with G1250 diet (P < 0.05). Heifers with higher degree of Nelore (75%N-25%H) fed with G1000 diet showed estrus 42 days prior to mating, but only 57% reached puberty at mating (P < 0.05). Heifers with follicles of higher diameter reached puberty (P < 0.05) earlier. Higher average daily weight gain showed a positive effect on follicular diameter and IGF-I level at puberty (P < 0.01). Concentrations of GH were lower in heifers fed G1250 compared to G1000 diet (P < 0.05). There was a significant interaction between nutritional level and insulin levels at puberty (P < 0.01). We demonstrated the relationship between IGF-I and average daily gain on the onset of puberty in heifers. In conclusion, heifers submitted to the higher feeding level showed a higher follicular diameter and were younger at puberty. PMID- 24756467 TI - Biometric system for measuring gait and fall characteristics captured on video. AB - This paper presents a methodology that quantifies gait and fall characteristics from video of real-life fall events. The method consists in selecting on-screen the points on the ground where the feet are in contact with the ground. The essence of the method lies in establishing a transformation from the video frames to the "real world." In projected images, geometric properties such as lengths, angles, and parallelism are not preserved; thus, concepts of projective geometry are applied, namely homography. Because the ground is an invariant plane, using this plane for homography results in a constant transformation. The homographic transformation relies on the accuracy in the selection of on-screen points. An optimization algorithm that minimizes the errors caused by inaccurate on-screen point selection improves the results of the homographic transformation. Experimental trials are conducted at three walking velocities (slow, preferred, and fast) using two video cameras and a GAITRite walkway system. Spatial parameters of two independent video analyses are compared with the GAITRite system, yielding a limit of agreement of step length from -2.12 cm to 2.03 cm. Temporal parameters are less confident due to the existence of dropped frames in the video footage. This method is then used to analyze two real fall events as demonstrative cases. First, the gait characteristics are analyzed before imbalance, and subsequently, the characteristics of stepping are analyzed during the fall. In particular, we propose the stepping/impact angle as the metric that quantifies how much stepping affected the direction of the fall. PMID- 24756471 TI - Radiation-induced heart disease: an under-recognized entity? AB - OPINION STATEMENT: Radiation-induced heart disease (RIHD) represents a spectrum of cardiovascular disease in patients who have undergone mediastinal, thoracic, or breast radiotherapy (RT). RIHD may involve any cardiac structure and is a major cause of morbidity and mortality in cancer survivors. While large cohort studies have demonstrated that symptomatic RIHD is a common late finding in this population, the incidence of asymptomatic disease is likely to be even higher. Long-term follow-up with regular screening for RIHD plays an important role in the management of cancer survivors who have undergone RT. Aggressive modification of traditional cardiovascular risk factors such as hypertension, dyslipidemia, and cigarette smoking is essential in patients at risk for RIHD, as these have been shown to potentiate the risks of radiation. In patients with symptomatic RIHD, medical and/or percutaneous therapies are often preferable to surgical interventions in view of the increased surgical risk associated with radiation damage to surrounding tissues. Percutaneous revascularization should generally be favored over surgical revascularization. Transcatheter valve replacements have not been widely used in this population but may offer an alternative to high-risk surgical valve procedures. Pericardiectomy is usually associated with extremely poor short-term and long-term outcomes in patients with RIHD and should be avoided in most cases. Heart transplantation is also higher risk in patients with RIHD than in patients with other etiologies of heart failure, but may be considered in young patients without other comorbidities. PMID- 24756472 TI - Hypolipidemic effect of dietary water-soluble protein extract from chicken: impact on genes regulating hepatic lipid and bile acid metabolism. AB - BACKGROUND: Amount and type of dietary protein have been shown to influence blood lipids. The present study aimed to evaluate the effects of a water-soluble fraction of chicken protein (CP) on plasma and hepatic lipid metabolism in normolipidemic rats. METHODS: Male Wistar rats were fed either a control diet with 20 % w/w casein as the protein source, or an experimental diet where casein was replaced with CP at 6, 14, or 20 % w/w for 4 weeks. RESULTS: Rats fed CP had markedly reduced levels of triacylglycerols (TAG) and cholesterol in both plasma and liver, accompanied by stimulated hepatic mitochondrial fatty acid oxidation and carnitine palmitoyltransferase 2 activity in the 20 % CP group compared to the control group. In addition, reduced activities and gene expression of hepatic enzymes involved in lipogenesis were observed. The gene expression of sterol regulatory element-binding transcription factor 1 was reduced in the 20 % CP-fed rats, whereas gene expression of peroxisome proliferator-activated receptor alpha was increased. Moreover, 6, 14, and 20 % CP-fed rats had significantly increased free carnitine and acylcarnitine plasma levels compared to control rats. The plasma methionine/glycine and lysine/arginine ratios were reduced in 20 % CP treated rats. The mRNA level of ATP-binding cassette 4 was increased in the 20 % CP group, accompanied by the increased level of plasma bile acids. CONCLUSIONS: The present data suggest that the hypotriglyceridemic property of a water-soluble fraction of CP is primarily due to effects on TAG synthesis and mitochondrial fatty acid oxidation. The cholesterol-lowering effect by CP may be linked to increased bile acid formation. PMID- 24756473 TI - GSH protects against oxidative stress and toxicity in VL-17A cells exposed to high glucose. AB - PURPOSE: The deficiency of glutathione (GSH) has been linked to several diseases. The study investigated the role of GSH as a protective factor against hyperglycemia-mediated injury in VL-17A cells treated with 50 mM glucose. METHODS: The cell viability and different oxidative stress parameters including glyoxalase I activity were measured. RESULTS: GSH supplementation with 2 mM N acetyl cysteine (NAC) or 0.1 mM ursodeoxycholic acid (UDCA) increased the viability, GSH level and the GSH-dependent glyoxalase I activity in 50 mM glucose treated VL-17A cells. Further, pretreatment of 50 mM glucose-treated VL-17A cells with NAC or UDCA decreased oxidative stress (levels of reactive oxygen species and protein carbonylation), apoptosis (caspase 3 activity and annexin V-propidium iodide positive cells) and glutathionylated protein formation, a measure of oxidative stress. GSH depletion with 0.4 mM buthionine sulfoximine (BSO) or 1 mM diethyl maleate (DEM) potentiated the decrease in viability, glyoxalase I activity and increase in oxidative stress and apoptosis, with decreased GSH levels in 50 mM glucose-treated VL-17A cells. CONCLUSION: Thus, changes in GSH levels with exogenous agents such as NAC, UDCA, BSO or DEM modulate hyperglycemia mediated injury in a cell model of VL-17A liver cells. PMID- 24756475 TI - Dielectrophoresis-based purification of antibiotic-treated bacterial subpopulations. AB - Persistence of bacteria during antibiotic therapy is a widespread phenomenon, of particular importance in refractory mycobacterial infections such as leprosy and tuberculosis. Persistence is characterized by the phenotypic tolerance of a subpopulation of bacterial cells to antibiotics. Characterization of these "persister" cells is often difficult due to the transient, non-heritable nature of the phenotype and due to the presence of contaminating material from non persisting cells, which usually comprise the larger fraction. In this study, we use 3D carbon-electrode arrays for dielectrophoresis-based separation of intact cells from damaged cells, revealed by differential staining with propidium iodide, and we use this procedure to purify intact cells from cultures of Mycobacterium smegmatis treated with isoniazid, a frontline anti-tuberculosis drug. The method presented in this study could be used for rapid label-free enrichment of intact persister cells from antibiotic-treated cultures while preserving the metastable persister phenotype. This approach would facilitate the downstream analysis of low-frequency subpopulations of cells using conventional omics techniques, such as transcriptomic and proteomic analysis. PMID- 24756474 TI - Body mass index and cancer screening: findings from the English Longitudinal Study of Ageing. AB - OBJECTIVES: Obesity is associated with an increased cancer incidence and mortality and therefore cancer screening is particularly important for obese individuals. However, some US studies find lower screening uptake in this group. This study explored whether rates of breast and colorectal screening in England are lower for obese than healthy weight individuals. SETTING: Data were from the English Longitudinal Study of Ageing (ELSA). METHODS: We analysed data from adults who were eligible to have been invited to the UK national screening programmes for breast or colorectal cancer (CRC) in the last five years, and had been given the screening module in Wave 5 of ELSA (N = 1804 for CRC screening, N = 2401 for breast cancer screening). Weight and height were measured by a nurse at Wave 4 (two years earlier). Logistic regression was used to calculate the odds of breast and CRC screening (ever) for participants in higher weight categories (Body Mass Index [BMI] >= 25) compared with healthy weight individuals (BMI <25), controlling for socio-demographic variables. RESULTS: Of ELSA participants, 63% reported CRC screening, and 92% of the women reported breast cancer screening. Obesity was associated with lower CRC screening, but effects were strongest for class III obesity (BMI >=40) (45% screened; OR = 0.48, 95% CI = 0.32-0.93, P = .029). There was no association between weight status and breast cancer screening. CONCLUSION: Severe obesity appears to be a deterrent to CRC screening but not breast cancer screening. Targeted interventions may be required to promote CRC screening uptake in this group, which already has a heightened risk as a consequence of weight. PMID- 24756477 TI - Generation of umbilics by Poiseuille flows. AB - The Fredericks transition in homeotropic nematic layers submitted to an electric field can be described in terms of a 2D vectorial order parameter [Formula: see text]. We have shown previously that umbilics which are point defects of the field [Formula: see text] can be generated in a controlled manner by magnetic fields. Here we report on a serendipitous discovery of generation of umbilics during cleaning of a sample and on a series of experiments which were performed with the aim to unveil conditions necessary for a controlled reproduction of this phenomenon. From the analysis of all circumstances in which umbilics were generated we conclude that umbilics are generated by Poiseuille flows and appear in pi-walls in points where these walls are orthogonal to the flow direction. We discuss theoretical aspects of the action of Poiseuille flows on the field [Formula: see text] and unveil the relationship [Formula: see text]-> system pi walls. Finally we explain why and where umbilics are generated in pi-walls. PMID- 24756476 TI - Blue light-filtering intraocular lenses and post-operative mood: a pilot clinical study. AB - The purpose of the study was to determine if implantation of blue-filtering intraocular lenses (IOLs) affects post-operative mood, inducing more depression, compared to patients undergoing implantation with conventional IOLs. The study was conducted at the Angers University Hospital, France. This was a prospective with a lowercase pilot study, including consecutive patients planned to undergo cataract surgery in both eyes within 1 week. The same type of IOL was used in both eyes of each patient. The choice of IOL was not randomized but driven by the habits and experience of each participating surgeon. Cognitively healthy patients (an MMSE score higher than 25) were assessed before and after surgery, using the 30-item geriatric depression scale (GDS) to seek symptoms of depression. Univariate and multiple logistic regressions were used to examine the association between the type of IOL and the 30-item GDS score improvement during the 3 months after lens implantation, while adjusting for participants' characteristics (age, visual acuity). Blue-filtering IOLs were used in 16 patients (mean +/- standard deviation, 75.6 +/- 7.5 years; 75 % female), and untinted IOLs in 18 patients (77.3 +/- 6.9 years; 77.8 %female). Pre-operatively visual acuity and GDS scores were comparable in the two groups. The post-operative GDS score was improved by 1.91 +/- 3.10 points in the whole sample (P = 0.002), as well as in each subgroup of patients. Three months after surgery, the mean change in GDS score did not differ between groups (P = 0.365), nor did the mean visual acuity (P = 0.198). PMID- 24756478 TI - Surfactant micelles: model systems for flow instabilities of complex fluids. AB - Complex fluids such as emulsions, colloidal gels, polymer or surfactant solutions are all characterized by the existence of a "microstructure" which may couple to an external flow on time scales that are easily probed in experiments. Such a coupling between flow and microstructure usually leads to instabilities under relatively weak shear flows that correspond to vanishingly small Reynolds numbers. Wormlike micellar surfactant solutions appear as model systems to study two examples of such instabilities, namely shear banding and elastic instabilities. Focusing on a semidilute sample we show that two-dimensional ultrafast ultrasonic imaging allows for a thorough investigation of unstable shear-banded micellar flows. In steady state, radial and azimuthal velocity components are recovered and unveil the original structure of the vortical flow within an elastically unstable high shear rate band. Furthermore thanks to an unprecedented frame rate of up to 20,000 fps, transients and fast dynamics can be resolved, which paves the way for a better understanding of elastic turbulence. PMID- 24756479 TI - Irreversible dynamics: a topical issue dedicated to Paul Manneville. PMID- 24756480 TI - Self-assembly of peptides to nanostructures. AB - The formation of well-ordered nanostructures through self-assembly of diverse organic and inorganic building blocks has drawn much attention owing to their potential applications in biology and chemistry. Among all organic building blocks, peptides are one of the most promising platforms due to their biocompatibility, chemical diversity, and resemblance to proteins. Inspired by the protein assembly in biological systems, various self-assembled peptide structures have been constructed using several amino acids and sequences. This review focuses on this emerging area, the recent advances in peptide self assembly, and formation of different nanostructures, such as tubular structures, fibers, vesicles, and spherical and rod-coil structures. While different peptide nanostructures have been discovered, potential applications are explored in drug delivery, tissue engineering, wound healing, and surfactants. PMID- 24756481 TI - Massive naproxen overdose with serial serum levels. AB - CONTEXT: Massive naproxen overdose is not commonly reported. Severe metabolic acidosis and seizure have been described, but the use of renal replacement therapy has not been studied in the context of overdose. CASE DETAILS: A 28-year old man ingested 70 g of naproxen along with an unknown amount of alcohol in a suicidal attempt. On examination in the emergency department 90 min later, he was drowsy but had normal vital signs apart from sinus tachycardia. Serum naproxen level 90 min after ingestion was 1,580 mg/L (therapeutic range 25-75 mg/L). He developed metabolic acidosis requiring renal replacement therapy using sustained low efficiency dialysis (SLED) and continuous venovenous hemofiltration (CVVH) and had recurrent seizure activity requiring intubation within 4 h from ingestion. He recovered after 48 h. DISCUSSION: Massive naproxen overdose can present with serious toxicity including seizures, altered mental status, and metabolic acidosis. CONCLUSION: Hemodialysis and renal replacement therapy may correct the acid base disturbance and provide support in cases of renal impairment in context of naproxen overdose, but further studies are needed to determine the extraction of naproxen. PMID- 24756482 TI - Does diabetes have an impact on health-state utility? a study of Asians in Singapore. AB - OBJECTIVE: Our objective was to compare the time trade-off (TTO) values of EQ-5D 3L health states elicited from Singaporeans with and without type 2 diabetes mellitus (T2DM) and T2DM patients with and without complications. METHODS: The TTO values of ten EQ-5D-3L health states were elicited from a consecutive sample of T2DM patients and a general Singaporean population sample using similar valuation protocols. In face-to-face interviews, T2DM patients and members of the general population were asked to value five and ten health states, respectively. The difference in TTO values between the two samples and between T2DM patients with and without complications was examined using multiple linear regression models. RESULTS: A total of 109 T2DM patients and 46 individuals without T2DM provided data. All ten health states considered, the mean TTO value was -0.02 for the general population sample and -0.04 for T2DM patients, with the unadjusted and adjusted difference being -0.06 (95 % confidence interval [CI] -0.16, 0.03) and 0.02 (95 % CI -0.12, 0.15). The general population sample had systematically lower TTO values for mild health states, with the adjusted difference being -0.13 (95 % CI -0.25, -0.02); while the two samples had similar TTO values for severe health states, with the adjusted difference being 0.02 (95 % CI -0.16, 0.19). T2DM patients without complications had systematically lower TTO values than those with complications, with the adjusted difference being -0.10 (95 % CI 0.23, 0.03). CONCLUSIONS: It appears that diabetes and its complications affect patients' valuation of health states. Hence, the EQ-5D-3L health-state values based on the general population may underestimate the utility of health interventions for T2DM. PMID- 24756483 TI - Omega-3 polyunsaturated Fatty acids reduce the incidence of postoperative atrial fibrillation in patients with history of prior myocardial infarction undergoing isolated coronary artery bypass grafting. AB - INTRODUCTION: The impact of omega-3 polyunsaturated fatty acids (PUFAs) for prevention of atrial fibrillation (AF) is still part of a lively debate. The present study evaluates the impact of orally administered omega-3 ethyl ester concentrate (omega-3 PUFA) on postoperative onset of AF in patients with recent myocardial infarction (<= 3 months) undergoing isolated coronary artery bypass grafting (CABG). Patients and METHODS: The study included a total of 198 patients with recent (<= 3 months) myocardial infarction. The treatment group consisted of 99 prospectively and randomly assigned patients. A matched control group was generated out of the entirety of patients undergoing isolated CABG during the same time period, being not treated with omega-3 PUFA. Primary endpoint was onset of postoperative AF. Patients of the treatment group received a daily dose of 2 g omega-3 PUFA, initiated 5 days before surgery. Effective serum levels were confirmed by laboratory testing. RESULTS: Patients of the treatment group had less frequently postoperative AF (treatment: 31.3% vs. control: 48.0%; p = 0.017). The reduction in relative risk was 34.8% in the treatment group, which conforms a number needed to treat (NNT) of 6.0 patients. A more pronounced effect with a NNT of 4.1 was observed in patients <= 70 years (p = 0.007). Besides, patients of the treatment group had a shorter intensive care unit stay (p = 0.001) and suffered less frequently from impaired wound healing by trend (p = 0.063). One patient out of treatment group and two out of control group died during hospital stay (p = 1.000). CONCLUSION: Preoperative administration of 2 g omega-3 PUFA reduces incidence of postoperative AF in patients with recent (<= 3 months) myocardial infarction undergoing isolated CABG. PMID- 24756485 TI - Covalently linked perylenetetracarboxylic diimide dimers and trimers with rigid "J-type" aggregation structure. AB - Covalently linked perylenetetracarboxylic diimide (PDI) dimers (D1 and D2) and trimers (T1 and T2) with slipped "face-to-face" stacked structure are prepared and their molecular structures are characterized by 1H NMR, MALDI-TOF mass spectroscopy and elemental analysis. The rigid molecular structures of these compounds make it easier to establish a direct correlation between the aggregate structure and the photophysical properties. The minimized molecular structures of these compounds reveal that they are all "face-to-face" stacked aggregates with large longitudinal displacement. Their absorption spectra show red-shifted bands, suggesting the presence of "J" type excitonic coupling between the PDI subunits in these compounds. However, their steady state and time resolved fluorescence spectra revealed that the emission from the "excimer-like" states dominates the fluorescence of these compounds, this is similar to that of "H-type" aggregates and may be ascribed to the "face-to-face" stacked structure. In the fluorescence spectra of these compounds, a minor "J-type" emission can be identified for the compounds with a relatively large longitudinal displacement. An increase in the number of subunits in one aggregate from 2 to 3 also brings about distinctive changes in their photophysical properties, which can be ascribed to the changes in the stacking structure caused by the steric hindrance. PMID- 24756486 TI - Medicine's uncomfortable relationship with math: calculating positive predictive value. PMID- 24756487 TI - Warmed, humidified carbon dioxide insufflation versus standard carbon dioxide in laparoscopic cholecystectomy: a double-blinded randomized controlled trial. AB - BACKGROUND: During laparoscopic cholecystectomy (LCHE), the insufflation with warmed and humidified carbon dioxide (CO2) may reduce postoperative pain. The aim of the study was to evaluate the positive effects of heated and humidified carbon dioxide gas on patients with regard to postoperative pain after LCHE. PATIENTS AND METHODS: This is a prospective, randomized, double-blinded, controlled clinical trial. 148 patients (female = 98, male = 50) scheduled for elective LCHE were randomized into two groups: receiving either heated humidified carbon dioxide, or standard gas. Intraoperative core temperature was measured. The perioperative management was identical for both groups. Postoperative pain intensity was assessed using a visual analog pain scale, and the amount of analgesic consumption was recorded. The postoperative pain management was also standardized and equal for both groups. RESULTS: 67 out of 148 received standard gas (group A), and 81 received warmed, humidified gas (group B). The groups were comparable demographically. The amount of analgesic consumption was recorded. Intraoperative core temperature was significant higher in group B than in group A. Pain was significantly less in group B (p = 0.025) 6 h postoperatively. On the first postoperative day, no significant difference in pain between the two groups was detectable (p = 0.437). CONCLUSION: The use of warmed and humidified carbon dioxide during LCHE reduces postoperative pain at the day of operation. PMID- 24756490 TI - Cabeza (Back of Head): Salomon Huerta. PMID- 24756491 TI - European-led project strives to simulate the human brain. PMID- 24756492 TI - Easy-to-use overdose antidote earns fast-track approval. PMID- 24756505 TI - How neurologists can choose (even more) wisely: prioritizing waste reduction targets and identifying gaps in knowledge. PMID- 24756506 TI - Global opportunities and challenges for clinical neuroscience. PMID- 24756507 TI - Neurology at a crossroads: opportunities and challenges. PMID- 24756508 TI - A piece of my mind. Decisions. PMID- 24756509 TI - tPA for stroke: important progress in achieving faster treatment. PMID- 24756510 TI - Acetazolamide for pseudotumor cerebri: evidence from the NORDIC trial. PMID- 24756511 TI - Advancing neurotherapeutics in the 21st century. PMID- 24756512 TI - Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial. AB - IMPORTANCE: Time to thrombolysis is crucial for outcome in acute ischemic stroke. OBJECTIVE: To determine if starting thrombolysis in a specialized ambulance reduces delays. DESIGN, SETTING, AND PARTICIPANTS: In the Prehospital Acute Neurological Treatment and Optimization of Medical care in Stroke Study (PHANTOM S), conducted in Berlin, Germany, we randomly assigned weeks with and without availability of the Stroke Emergency Mobile (STEMO) from May 1, 2011, to January 31, 2013. Berlin has an established stroke care infrastructure with 14 stroke units. We included 6182 adult patients (STEMO weeks: 44.3% male, mean [SD] age, 73.9 [15.0] y; control weeks: 45.2% male, mean [SD] age, 74.3 [14.9] y) for whom a stroke dispatch was activated. INTERVENTIONS: The intervention comprised an ambulance (STEMO) equipped with a CT scanner, point-of-care laboratory, and telemedicine connection; a stroke identification algorithm at dispatcher level; and a prehospital stroke team. Thrombolysis was started before transport to hospital if ischemic stroke was confirmed and contraindications excluded. MAIN OUTCOMES AND MEASURES: Primary outcome was alarm-to-thrombolysis time. Secondary outcomes included thrombolysis rate, secondary intracerebral hemorrhage after thrombolysis, and 7-day mortality. RESULTS: Time reduction was assessed in all patients with a stroke dispatch from the entire catchment area in STEMO weeks (3213 patients) vs control weeks (2969 patients) and in patients in whom STEMO was available and deployed (1804 patients) vs control weeks (2969 patients). Compared with thrombolysis during control weeks, there was a reduction of 15 minutes (95% CI, 11-19) in alarm-to-treatment times in the catchment area during STEMO weeks (76.3 min; 95% CI, 73.2-79.3 vs 61.4 min; 95% CI, 58.7-64.0; P < .001). Among patients for whom STEMO was deployed, mean alarm-to-treatment time (51.8 min; 95% CI, 49.0-54.6) was shorter by 25 minutes (95% CI, 20-29; P < .001) than during control weeks. Thrombolysis rates in ischemic stroke were 29% (310/1070) during STEMO weeks and 33% (200/614) after STEMO deployment vs 21% (220/1041) during control weeks (differences, 8%; 95% CI, 4%-12%; P < .001, and 12%, 95% CI, 7%-16%; P < .001, respectively). STEMO deployment incurred no increased risk for intracerebral hemorrhage (STEMO deployment: 7/200; conventional care: 22/323; adjusted odds ratio [OR], 0.42, 95% CI, 0.18-1.03; P = .06) or 7-day mortality (9/199 vs 15/323; adjusted OR, 0.76; 95% CI, 0.31-1.82; P = .53). CONCLUSIONS AND RELEVANCE: Compared with usual care, the use of ambulance based thrombolysis resulted in decreased time to treatment without an increase in adverse events. Further studies are needed to assess the effects on clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01382862. PMID- 24756513 TI - Door-to-needle times for tissue plasminogen activator administration and clinical outcomes in acute ischemic stroke before and after a quality improvement initiative. AB - IMPORTANCE: The benefits of intravenous tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) are time dependent and guidelines recommend a door-to-needle (DTN) time of 60 minutes or less. However, studies have found that less than 30% of US patients are treated within this time window. TARGET: Stroke was designed as a national quality improvement initiative to improve DTN times for tPA administration in patients with AIS. OBJECTIVES: To evaluate DTN times for tPA administration and the proportion of patients with times of 60 minutes or less before and after initiation of a quality improvement initiative and to determine whether potential improvements in DTN times were associated with improvements in clinical outcomes. DESIGN, SETTING, AND PATIENTS: The TARGET: Stroke initiative disseminated 10 care strategies to achieve faster DTN times for tPA administration, provided clinical decision support tools, facilitated hospital participation, and encouraged sharing of best practices. This study included 71,169 patients with AIS treated with tPA (27,319 during the preintervention period from April 2003-December 2009 and 43,850 during the postintervention period from January 2010-September 2013) from 1030 Get With The Guidelines-Stroke participating hospitals (52.8% of total). MAIN OUTCOMES AND MEASURES: The DTN times for tPA administration of 60 minutes or less and in hospital risk-adjusted mortality, symptomatic intracranial hemorrhage, ambulatory status at discharge, and discharge destination. RESULTS: Median DTN time for tPA administration declined from 77 minutes (interquartile range [IQR], 60-98 minutes) during the preintervention period to 67 minutes (IQR, 51-87 minutes) during the postintervention period (P < .001). The DTN times for tPA administration of 60 minutes or less increased from 26.5% (95% CI, 26.0%-27.1%) of patients during the preintervention period to 41.3% (95% CI, 40.8%-41.7%) during the postintervention period (P < .001). The DTN times of 60 minutes or less increased from 29.6% (95% CI, 27.8%-31.5%) of patients in the quarter immediately before the intervention (fourth quarter of 2009) to 53.3% (95% CI, 51.5%-55.2%) in the final postintervention quarter (third quarter of 2013) (P < .001). The annual rate of improvement in DTN times of 60 minutes or less increased from 1.36% (95% CI, 1.04%-1.67%) per year preintervention to 6.20% (95% CI, 5.58%-6.78%) per year postintervention (P < .001). In-hospital all-cause mortality improved significantly from the preintervention to the postintervention period (9.93% vs 8.25%, respectively; adjusted odds ratio [OR], 0.89 [95% CI, 0.83-0.94], P < .001), symptomatic intracranial hemorrhage within 36 hours was less likely to occur (5.68% vs 4.68%; adjusted OR, 0.83 [95% CI, 0.76-0.91], P < .001), and discharge to home was more frequent (37.6% vs 42.7%; adjusted OR, 1.14 [95% CI, 1.09-1.19], P < .001). CONCLUSIONS AND RELEVANCE: Implementation of a national quality improvement initiative was associated with improved timeliness of tPA administration following AIS on a national scale, and this improvement was associated with lower in-hospital mortality and intracranial hemorrhage, along with an increase in the percentage of patients discharged home. PMID- 24756517 TI - Pharmacological treatment of Parkinson disease: a review. AB - IMPORTANCE: Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. OBJECTIVE: To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. EVIDENCE REVIEW: References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. RESULTS: Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, beta-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies. CONCLUSIONS AND RELEVANCE: Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established. PMID- 24756515 TI - Lorazepam vs diazepam for pediatric status epilepticus: a randomized clinical trial. AB - IMPORTANCE: Benzodiazepines are considered first-line therapy for pediatric status epilepticus. Some studies suggest that lorazepam may be more effective or safer than diazepam, but lorazepam is not Food and Drug Administration approved for this indication. OBJECTIVE: To test the hypothesis that lorazepam has better efficacy and safety than diazepam for treating pediatric status epilepticus. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, randomized clinical trial was conducted from March 1, 2008, to March 14, 2012. Patients aged 3 months to younger than 18 years with convulsive status epilepticus presenting to 1 of 11 US academic pediatric emergency departments were eligible. There were 273 patients; 140 randomized to diazepam and 133 to lorazepam. INTERVENTIONS: Patients received either 0.2 mg/kg of diazepam or 0.1 mg/kg of lorazepam intravenously, with half this dose repeated at 5 minutes if necessary. If status epilepticus continued at 12 minutes, fosphenytoin was administered. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was cessation of status epilepticus by 10 minutes without recurrence within 30 minutes. The primary safety outcome was the performance of assisted ventilation. Secondary outcomes included rates of seizure recurrence and sedation and times to cessation of status epilepticus and return to baseline mental status. Outcomes were measured 4 hours after study medication administration. RESULTS: Cessation of status epilepticus for 10 minutes without recurrence within 30 minutes occurred in 101 of 140 (72.1%) in the diazepam group and 97 of 133 (72.9%) in the lorazepam group, with an absolute efficacy difference of 0.8% (95% CI, -11.4% to 9.8%). Twenty-six patients in each group required assisted ventilation (16.0% given diazepam and 17.6% given lorazepam; absolute risk difference, 1.6%; 95% CI, -9.9% to 6.8%). There were no statistically significant differences in secondary outcomes except that lorazepam patients were more likely to be sedated (66.9% vs 50%, respectively; absolute risk difference, 16.9%; 95% CI, 6.1% to 27.7%). CONCLUSIONS AND RELEVANCE: Among pediatric patients with convulsive status epilepticus, treatment with lorazepam did not result in improved efficacy or safety compared with diazepam. These findings do not support the preferential use of lorazepam for this condition. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00621478. PMID- 24756518 TI - Serum brain-derived neurotrophic factor and the risk for dementia. PMID- 24756519 TI - Deep brain stimulation for Parkinson's disease with early motor complications. PMID- 24756514 TI - Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. AB - IMPORTANCE: Acetazolamide is commonly used to treat idiopathic intracranial hypertension (IIH), but there is insufficient information to establish an evidence base for its use. OBJECTIVE: To determine whether acetazolamide is beneficial in improving vision when added to a low-sodium weight reduction diet in patients with IIH and mild visual loss. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-masked, placebo-controlled study of acetazolamide in 165 participants with IIH and mild visual loss who received a low-sodium weight-reduction diet. Participants were enrolled at 38 academic and private practice sites in North America from March 2010 to November 2012 and followed up for 6 months (last visit in June 2013). All participants met the modified Dandy criteria for IIH and had a perimetric mean deviation (PMD) between -2 dB and -7 dB. The mean age was 29 years and all but 4 participants were women. INTERVENTIONS: Low-sodium weight-reduction diet plus the maximally tolerated dosage of acetazolamide (up to 4 g/d) or matching placebo for 6 months. MAIN OUTCOMES AND MEASURES: The planned primary outcome variable was the change in PMD from baseline to month 6 in the most affected eye, as measured by Humphrey Field Analyzer. Perimetric mean deviation is a measure of global visual field loss (mean deviation from age-corrected normal values), with a range of 2 to -32 dB; larger negative values indicate greater vision loss. Secondary outcome variables included changes in papilledema grade, quality of life (Visual Function Questionnaire 25 [VFQ-25] and 36-Item Short Form Health Survey), headache disability, and weight at month 6. RESULTS: The mean improvement in PMD was greater with acetazolamide (1.43 dB, from -3.53 dB at baseline to -2.10 dB at month 6; n = 86) than with placebo (0.71 dB, from -3.53 dB to -2.82 dB; n = 79); the difference was 0.71 dB (95% CI, 0 to 1.43 dB; P = .050). Mean improvements in papilledema grade (acetazolamide: -1.31, from 2.76 to 1.45; placebo: -0.61, from 2.76 to 2.15; treatment effect, -0.70; 95% CI, -0.99 to -0.41; P < .001) and vision-related quality of life as measured by the National Eye Institute VFQ-25 (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98, from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47; P = .003) and its 10-item neuro ophthalmic supplement (acetazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45 to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001) were also observed with acetazolamide. Participants assigned to acetazolamide also experienced a reduction in weight (acetazolamide: -7.50 kg, from 107.72 kg to 100.22 kg; placebo: -3.45 kg, from 107.72 kg to 104.27 kg; treatment effect, 4.05 kg, 95% CI, -6.27 to -1.83 kg; P < .001). CONCLUSIONS AND RELEVANCE: In patients with IIH and mild visual loss, the use of acetazolamide with a low sodium weight-reduction diet compared with diet alone resulted in modest improvement in visual field function. The clinical importance of this improvement remains to be determined. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01003639. PMID- 24756520 TI - Testing the presumption of consent to emergency treatment for acute ischemic stroke. PMID- 24756521 TI - Financial relationships between medical communication companies and industry. PMID- 24756522 TI - Financial relationships between medical communication companies and industry. PMID- 24756523 TI - Financial relationships between medical communication companies and industry- reply. PMID- 24756524 TI - Strategies to overcome medication nonadherence. PMID- 24756516 TI - Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. AB - IMPORTANCE: Whether conservative management is superior to interventional treatment for unruptured brain arteriovenous malformations (bAVMs) is uncertain because of the shortage of long-term comparative data. OBJECTIVE: To compare the long-term outcomes of conservative management vs intervention for unruptured bAVM. DESIGN, SETTING, AND POPULATION: Population-based inception cohort study of 204 residents of Scotland aged 16 years or older who were first diagnosed as having an unruptured bAVM during 1999-2003 or 2006-2010 and followed up prospectively for 12 years. EXPOSURES: Conservative management (no intervention) vs intervention (any endovascular embolization, neurosurgical excision, or stereotactic radiosurgery alone or in combination). MAIN OUTCOMES AND MEASURES: Cox regression analyses, with multivariable adjustment for prognostic factors and baseline imbalances if hazards were proportional, to compare rates of the primary outcome (death or sustained morbidity of any cause by Oxford Handicap Scale [OHS] score >=2 for >=2 successive years [0 = no symptoms and 6 = death]) and the secondary outcome (nonfatal symptomatic stroke or death due to bAVM, associated arterial aneurysm, or intervention). RESULTS: Of 204 patients, 103 underwent intervention. Those who underwent intervention were younger, more likely to have presented with seizure, and less likely to have large bAVMs than patients managed conservatively. During a median follow-up of 6.9 years (94% completeness), the rate of progression to the primary outcome was lower with conservative management during the first 4 years of follow-up (36 vs 39 events; 9.5 vs 9.8 per 100 person years; adjusted hazard ratio, 0.59; 95% CI, 0.35-0.99), but rates were similar thereafter. The rate of the secondary outcome was lower with conservative management during 12 years of follow-up (14 vs 38 events; 1.6 vs 3.3 per 100 person-years; adjusted hazard ratio, 0.37; 95% CI, 0.19-0.72). CONCLUSIONS AND RELEVANCE: Among patients aged 16 years or older diagnosed as having unruptured bAVM, use of conservative management compared with intervention was associated with better clinical outcomes for up to 12 years. Longer follow-up is required to understand whether this association persists. PMID- 24756525 TI - Strategies to overcome medication nonadherence--reply. PMID- 24756529 TI - The postencephalitic Parkinson syndrome. PMID- 24756530 TI - JAMA patient page. Warning signs of a stroke. PMID- 24756531 TI - An ignored cause of inflammation in patients undergoing continuous ambulatory peritoneal dialysis: periodontal problems. AB - AIM: We aimed to assess whether there is a significant relation between periodontal health status and inflammation in uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and also to reveal the efficiency of periodontal treatment in patients with various degrees of periodontal problems. PATIENTS AND METHODS: Overall, 68 patients undergoing CAPD were included in the study. Clinical indices and measurements were obtained at baseline and panoramic radiographies were used for the diagnosis. According to the baseline values, patients were stratified into four groups according to the severity of periodontal problems as follows: healthy/gingivitis, slight-to moderate, and severe periodontitis. A control examination was performed 3 months after the periodontal treatment for only 43 patients. Clinical and laboratory parameters before and after treatment were compared. RESULTS: The frequency of periodontal disease was found to be high in uremic patients on CAPD. The frequency and severity of periodontitis was also found to be significantly (p < 0.01) higher in patients with high sensitive C-reactive protein levels and longer duration of peritoneal dialysis (p < 0.01). In addition, the periodontitis rate was found to be higher in patients with cardiovascular disease (p < 0.05) and diabetes mellitus (p < 0.01). CONCLUSION: A meticulous periodontal examination should be a routine part of management of the uremic patients on CAPD because periodontal disease could be one of the hidden sources of unexplained inflammatory status. PMID- 24756532 TI - Clinical outcomes of ANCA-associated vasculitis in elderly patients. AB - BACKGROUND: Older age is independently associated with mortality in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). We hypothesized that a reduced-dose immunosuppressive treatment would result in similar effectiveness and comparable treatment-related morbidity in elderly patients as the regular dose in younger patients. We also postulated that the higher baseline comorbidities may contribute to the higher mortality of the elderly subjects. METHODS: Ninety-three consecutive patients with AAV between 1998 and 2012 were retrospectively analyzed. Forty-one individuals were defined as "elderly" (age >65 years) and 52 as "younger" (age <65 years). All cause and cardiovascular mortality, death due to vasculitis and infections, and effectiveness of "reduced dose" immunosuppressive treatment in the elderly group were compared to the effects of "full-dose" treatment in younger individuals. RESULTS: Mortality in the elderly group was higher (p = 0.007). Cardiovascular death was significantly increased (p = 0.002) in the elderly, but mortality due to vasculitis or infections was comparable. Treatment effectiveness was also similar in elderly and younger patients. At the end of the first follow-up year, 37 % of the elderly and 27 % of the younger patients died (p = 0.22). In univariate Cox regression analyses, being older than 65 year, having cardiovascular disease at baseline, need for dialysis at diagnosis, and lower serum albumin were associated with an increased hazard of mortality. CONCLUSIONS: Delivering reduced dose of immunosuppression for elderly patients was associated with satisfactory outcome and favorable treatment-related complication profile. The higher mortality in the elderly could be attributed mainly to baseline cardiovascular morbidity. PMID- 24756533 TI - Reliability and validity of carpal alignment measurements in evaluating deformities of scaphoid fractures. AB - PURPOSE: Several radiographic carpal alignment indices are used to evaluate the deformities of scaphoid fractures. The purpose of this study was to determine the reliabilities and validities of radiographic carpal alignment indices commonly used to evaluate deformities of scaphoid fractures. METHODS: Thirty-six patients with a scaphoid fracture were evaluated. Five carpal alignment indices were assessed on lateral plain radiographs, namely, scapholunate angle, radioscaphoid angle, radiolunate angle, radiocapitate angle, and capitolunate angle. Three examiners measured these radiographic indices at two sessions, and intraobserver and interobserver reliabilities were determined and expressed as intraclass correlation coefficients. Discriminant validities of radiographic carpal alignment indicies between injured and uninjured wrists were evaluated. For convergent validity testing, the correlation between the radiographic carpal alignment indices and intrascaphoid angles (ISAs) or height-to-length (HL) ratios on CT longitudinal scans was assessed. Further, carpal alignment indices after surgical reconstruction were compared to the Mayo wrist score. RESULTS: Scapholunate and radiolunate angles had the highest reliabilities, and radiocapitate angle had the lowest. Radiolunate angle had the highest discriminant validity followed by scapholunate, and capitolunate angles. In convergent validity testing, scapholunate angles and radiolunate angles correlated with ISA angles, and radiolunate and capitolunate angles correlated with HL ratios. Only the radiolunate angles correlated with the Mayo wrist scores. CONCLUSIONS: Among radiographic carpal alignment measures, radiolunate angle is the most reliable and valid carpal alignment index for evaluating deformities of scaphoid fractures. Scapholunate and capitolunate angles could be used as an alternative, but have less validity. PMID- 24756534 TI - ACL reconstruction using bone-patella tendon-bone autograft: press-fit technique vs. interference screw fixation. AB - PURPOSE: The gold standard in ACL reconstructions has been the bone-patellar tendon-bone autograft fixed with interference screws. This prospective, randomized clinical trial aimed to compare two methods of fixation for BPTB grafts: press-fit fixation vs. interference screw, over a 12-month follow-up interval. METHODS: 158 patients with an average age of 29.8 years, between 2011 and 2012, were treated for torn ACL. 82 patients underwent reconstruction with BPTB autograft with a press fit fixation technique, and in 76 cases an interference screw was used. At the time of final follow-up, 71 patients in press fit group and 65 patients in interference screw group were evaluated in terms of return to pre-injury activity level, pain, knee stability, range of motion, IKDC score and complications. RESULTS: At 12-month follow-up, 59 (83 %) and 55 (85 %) in press-fit and screw group, respectively had good-to-excellent IKDC score (p > 0.05). The mean laxity assessed using a KT-1000 arthrometer improved to 2.7 and 2.5 mm in press-fit and screw group, respectively. Regarding Lachman and pivot shift test, there was a statistically significant improvement in the integrity of the ACL in both the groups, but no significant differences was noted between groups. There were no significant differences in terms of femur circumference difference, effusion, knee range of motion, pain and complications. CONCLUSIONS: The press-fit technique is an efficient procedure. Its outcome was comparable with the interference screw group. Furthermore it has unlimited bone-to-bone healing, no need for removal of hardware, ease for revision and cost effectiveness. PMID- 24756535 TI - Neurological manifestations of thoracic myelopathy. AB - INTRODUCTION: Investigation of preoperative manifestations of thoracic myelopathy in a large population has not been reported. The aim of this study was to identify symptoms specific to anatomical pathology or compressed segments in thoracic myelopathy through investigation of preoperative manifestations. MATERIALS AND METHODS: Subjects were 205 patients [143 men, 62 women; mean age, 62.2 (range 21-87 years)] with thoracic myelopathy who underwent surgery at our affiliate institutions from 2000 to 2011. The disease distribution included ossification of the ligamentum flavum (OLF) in 106 patients, ossification of the posterior longitudinal ligament (OPLL) in 17, OLF with OPLL in 17, intervertebral disc herniation (IDH) in 23, OLF with IDH in 3, and spondylosis in 39. We assessed (1) initial and preoperative complaints, (2) neurological findings, (3) Japanese Orthopaedic Association scores (JOA, full score, 11 points), (4) the compressed segments, and (5) preoperative duration. Multivariate analyses were performed to examine potential relationships between preoperative manifestations and anatomical pathology or compressed segments. RESULTS: The multivariate analyses revealed relationships between lower limb muscle weakness and T10/11 anterior compression; lower limb pain and T11/12 anterior compression; low back pain and T11/12 compression; and hyporeflexia in the patellar tendon reflex/foot drop and T12/L1 anterior compression. CONCLUSION: This study elucidated symptoms specific to anatomical pathology or compressed segments in thoracic myelopathy. These relationships can be helpful in the initial investigation of thoracic diseases, although additional measures such as MRI or CT are necessary for definitive diagnosis. PMID- 24756536 TI - Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells. AB - In the present study, we designed and conducted a series of assays to determine the expression of voltage-gated sodium channel (VGSC) neonatal isoform Nav1.5 (nNav1.5) in human brain astrocytoma and its effect on the proliferation, migration, invasion and apoptosis of astrocytoma U251 cells. The results showed that nNav1.5 mRNA and protein were expressed in both human brain astrocytoma and normal brain tissues, but their expression levels in astrocytoma were significantly higher (P<0.05). In astrocytomas, nNav1.5 mRNA and protein levels were also different (P<0.05) and were correlated with pathological grades. The immunofluorescence confocal microscopy observations demonstrated that nNav1.5 protein was expressed in the nucleus, cytoplasm and membrane of the astrocytoma cells. After transfection, the small interfering RNA (siRNA) targeted to nNav1.5 significantly reduced the expression levels of SCN5A/nNav1.5 mRNA and protein by 57.2% (P<0.05) and 66.6% (P<0.05), respectively. The MTT, wound healing, Matrigel invasion and flow cytometric assays confirmed that following siRNA downregulation of the expression of the SCN5A/nNav1.5 gene, the in vitro proliferation and in vitro invasiveness of the U251 cells were significantly reduced (P<0.05 for both comparisons), and the apoptosis rate was significantly increased (P<0.05). These results revealed that nNav1.5 expression in human brain astrocytoma was upregulated, and its expression was positively correlated with the degree of malignancy. Additionally, reduced nNav1.5 expression significantly suppressed the proliferation and invasiveness of astrocytoma cells, indicating a new target in the molecular diagnosis and therapy of astrocytoma. PMID- 24756537 TI - Novel single-loop and double-loop knot stitch in comparison with the modified Mason-Allen stitch for rotator cuff repair. AB - PURPOSE: In rotator cuff repair, strong and long-lasting suturing techniques that do not require additional implants are needed. This study examines the ultimate load to failure and the Young's modulus at the suture-tendon interface for a novel single-loop knot stitch and double-loop knot stitch. These values are compared to those of the modified Mason-Allen stitch. METHODS: Twenty-four infraspinatus muscles with tendons were dissected from porcine shoulders (twelve Goettingen minipigs). The preparations were randomly allocated to three groups of eight samples. Load-to-failure testing of the single-loop knot stitch, the double loop knot stitch and the mMAS were performed using a Zwick 1446 universal testing machine (Zwick-Roell AG, Ulm, Germany). RESULTS: The highest ultimate load to failure for the three techniques occurred with the double-loop knot stitch with a median value of 382.2 N (range 291.8-454.2 N). These values were significantly higher than those of the single-loop knot stitch, which had a median value of 259.5 N (range 139.6-366.3 N) and the modified Mason-Allen stitch, which had a median value of 309.3 N (range 84.55-382.9 N). The values of the single-loop knot stitch and the modified Mason-Allen stitch did not differ significantly. Regarding the Young's modulus, no significant differences were found between the double-loop knot stitch with a median value of 496.02 N/mm2 (range 400.4-572.6 N/mm2) and the modified Mason-Allen stitch with 498.5 N/mm2 (range 375.5-749.2 N/mm2) with respect to the stiffness of the suture-tendon complex. The median value for the Young's modulus of the single-loop knot stitch of 392.1 N/mm2 (range 285.7-510.6 N/mm2) was significantly lower than those of the double-loop knot stitch and modified Mason-Allen stitch. CONCLUSION: This in vitro animal study demonstrated that both the single-loop knot stitch and the double-loop knot stitch have excellent ultimate load-to-failure properties when used for rotator cuff repair. The introduced single-loop knot stitch and double-loop knot stitch offer an alternative to other common used stitch techniques in rotator cuff repair. PMID- 24756538 TI - Associations of isokinetic knee steadiness with hop performance in patients with ACL deficiency. AB - PURPOSE: Contrary to the ample data available regarding the functional significance of isokinetic knee strength in patients with anterior cruciate ligament deficiency (ACLD), much less is known about the functional significance of isokinetic knee steadiness. This cross-sectional study aimed to evaluate, in patients with ACLD, the independent impact of isokinetic quadriceps and hamstrings torque steadiness on single-leg hop performance. METHODS: Eighty-seven patients with unilateral ACLD participated. Patients performed isokinetic quadriceps and hamstrings steadiness and strength testing at 60 degrees /s on an isokinetic dynamometer. Muscle steadiness and strength were represented by the wavelet-derived mean instantaneous frequency and peak value of the torque-time curves, respectively. To measure hop performance, patients performed a single-leg hop for distance and a 6-m single-leg hop for velocity. RESULTS: One of two patients [n = 45 (51 %)] had a 10 % or greater difference in knee torque frequency levels between the ACLD and contralateral knees. In multivariable models adjusted for age, sex, knee pain, and knee strength, hamstrings steadiness was significantly related with hop velocity whilst quadriceps steadiness was significantly related with both hop distance and velocity. Variance decomposition analyses suggested that quadriceps steadiness was similar in importance to hamstrings strength on hop distance and velocity. CONCLUSIONS: In patients with ACLD, isokinetic knee steadiness deficits were common and were independently associated with single-leg hop performance. Knee torque steadiness-a heretofore understudied variable-may prove a useful adjunct to conventional peak torque measurements by offering additional information to researchers and rehabilitation professionals about muscle performance and neuromuscular knee control. LEVEL OF EVIDENCE: Prognostic studies, Level III. PMID- 24756539 TI - Selection of antiepileptic drugs in older people. AB - OPINION STATEMENT: Elderly people are one of the fastest-growing populations in the United States, and the incidence of epilepsy in older people is much higher than in other population subgroups. This age group is the most vulnerable because of the increased incidence of multiple medical comorbidities, including stroke. The diagnosis of epilepsy is extremely challenging and often delayed in this age group because of an atypical presentation. Seizures are manifest through extremely vague complaints, such as episodes of altered mental status or memory lapses. Once the diagnosis is established by careful history taking and diagnostic testing, anticonvulsants are the mainstay of treatment. The choice of anticonvulsants in elderly patients requires careful evaluation of medical comorbidities, which vary on an individual basis. This subgroup also is more susceptible to adverse effects because of the physiologic changes in the body due to older age, which affect the pharmacokinetics of most anticonvulsants. The ideal drug in this age group should have linear pharmacokinetics, fewer adverse effects, minimal or no drug-drug interactions, no enzyme induction/inhibition, a long half-life, and minimal protein binding, and should be cost-effective. As such, there is no ideal drug for this patient population, although both older- and newer-generation anticonvulsants are used for long-term treatment. Most newer anticonvulsants have the advantage of a favorable pharmacokinetic profile, minimal or no drug-drug interactions, and fewer adverse events, as well as being well tolerated. The older anticonvulsants still are widely used, because the newer anticonvulsants are much more expensive. PMID- 24756540 TI - Asymmetric dinuclear bis(dipyrrinato)zinc(II) complexes: broad absorption and unidirectional quantitative exciton transmission. AB - Asymmetric, heteroleptic dinuclear bis(dipyrrinato)zinc(II) complexes were synthesized and demonstrated to collect a wide range of light across the UV and visible regions (340-655 nm). The complexes also conveyed excitons across their structure from one end to the other, with spectroscopic studies demonstrating quantitative and fast energy transfer. PMID- 24756541 TI - Practically convenient and industrially-aligned methods for iridium-catalysed hydrogen isotope exchange processes. AB - The use of alternative solvents in the iridium-catalysed hydrogen isotope exchange reaction with developing phosphine/NHC Ir(I) complexes has identified reaction media which are more widely applicable and industrially acceptable than the commonly employed chlorinated solvent, dichloromethane. Deuterium incorporation into a variety of substrates has proceeded to deliver high levels of labelling (and regioselectivity) in the presence of low catalyst loadings and over short reaction times. The preparative outputs have been complemented by DFT studies to explore ligand orientation, as well as solvent and substrate binding energies within the catalyst system. PMID- 24756542 TI - The Mandarin Childhood Autism Spectrum Test (CAST): sex differences. AB - Sex differences in social and communication behaviours related to autism spectrum conditions (ASC) have been investigated mainly in Western populations. Little research has been done in Chinese populations. This study explored sex differences related to ASC characteristics by examining differences in item responses and score distributions in relation to a screening instrument, the Childhood Autism Spectrum Test (CAST), used with Chinese children. A Mandarin Chinese version of the CAST (M-CAST) was distributed to 737 children aged 6-11 years in mainstream schools in Beijing. Questionnaires from 682 (93%) children were available for analysis. The median score for boys was higher than for girls [boys, median = 8 (IQR 6, 11); girls, median = 7 (IQR 4, 9); p < 0.001]. There were differences in the proportions of boys and girls across all three score groups (<=11, 12-14, >=15) with more boys being found in the higher score groups (p = 0.035). This finding provides evidence that boys and girls have different social and communication development profiles, consistent with previous findings in Western cultures. These results suggest that sex differences related to ASC are consistent across cultures. PMID- 24756543 TI - Implementation of pseudoreceptor-based pharmacophore queries in the prediction of probable protein targets: explorations in the protein structural profile of Zea mays. AB - Molecular docking plays an important role in the protein target identification by prioritizing probable druggable proteins using docking energies. Due to the limitations of docking scoring schemes, there arises a need for structure-based approaches to acquire confidence in theoretical binding affinities. In this direction, we present here a receptor (protein)-based approach to predict probable protein targets using a small molecule of interest. We adopted a reverse approach wherein the ligand pharmacophore features were used to decipher interaction complementary amino acids of protein cavities (a pseudoreceptor) and expressed as queries to match the cavities or binding sites of the protein dataset. These pseudoreceptor-based pharmacophore queries were used to estimate total probabilities of each protein cavity thereby representing the ligand binding efficiency of the protein. We applied this approach to predict 3 experimental protein targets among 28 Zea mays structural data using 3 co crystallized ligands as inputs and compared its effectiveness using conventional docking results. We suggest that the combination of total probabilities and docking energies increases the confidence in prioritizing probable protein targets using docking methods. These prediction hypotheses were further supported by DrugScoreX (DSX) pair potential calculations and molecular dynamic simulations. PMID- 24756544 TI - Designing and operationalizing a customized internal evaluation model for cancer treatment support programs. AB - Be The Match(r) Patient and Health Professional Services (PHPS) supports patients undergoing hematopoietic cell transplant (HCT) and caregivers by providing educational programs and resources. HCT is a potentially curative therapy for blood cancers such as leukemia and lymphoma. To help meet the increasing demand for support services, PHPS implemented a multipronged plan to build and sustain the organization's capacity to conduct evaluation of its programs and resources. To do so, PHPS created and operationalized an internal evaluation model, developed customized resources to help stakeholders incorporate evaluation in program planning, and implemented utilization-focused evaluation for quality improvement. Formal mentorship was also critical in the development of an evidence-based, customized model and navigating inherent challenges throughout the process. Our model can serve as a guide for evaluators on establishing and operationalizing an internal evaluation program. Ultimately, we seek to improve support and education services from the time of diagnosis through survivorship. PMID- 24756545 TI - Barriers and facilitators to colorectal cancer screening in Vietnamese Americans: a qualitative analysis. AB - Vietnamese Americans are the fourth largest Asian ethnic group in the USA. Colorectal cancer (CRC) ranks as one of the most common cancers in Vietnamese Americans. However, CRC screening rates remain low among Vietnamese Americans, with 40 % of women and 60 % of men reporting never having a sigmoidoscopy, colonoscopy, or fecal occult blood test (FOBT). We partnered with a Federally Qualified Health Center (FQHC) in Seattle, WA, to conduct focus groups as part of a process evaluation. Using interpreters, we recruited and conducted three focus groups comprised of six women screened for CRC, six women not screened for CRC, and seven men screened for CRC, which made up a total of 19 FQHC patients of Vietnamese descent between 50 and 79 years old. Three team members analyzed transcripts using open coding and axial coding. Major themes were categorized into barriers and facilitators to CRC screening. Barriers include lack of health problems, having comorbidities, challenges with medical terminology, and concerns with the colonoscopy. Participants singled out the risk of perforation as a fear they have toward colonoscopy procedures. Facilitators include knowledge about CRC and CRC screening, access to sources of information and social networks, and physician recommendation. Our focus groups elicited information that adds to the literature and has not been previously captured through published surveys. Findings from this study can be used to develop more culturally appropriate CRC screening interventions and improve upon existing CRC screening programs for the Vietnamese American population. PMID- 24756546 TI - Patient educational needs of patients undergoing surgery for lung cancer. AB - There often exists a discrepancy between the information health care professionals (HCPs) provide to patients in preoperative teaching sessions and the information patients perceive as important. This study's purpose was to determine what information patients undergoing a lung cancer surgical resection wanted to learn before and after their surgery and also to uncover the information HCPs currently provide to these patients. Ten patients were interviewed preoperatively and postoperatively, and eleven HCPs involved in both their preoperative and postoperative care were interviewed. Emerging themes were noted. Patients reported that the most helpful aspects of the preoperative education included surgical details and the importance of physiotherapy, including exercises. Postoperatively, patients wished they had known more about postoperative pain. HCPs provided information that they felt prepared, informed and empowered their patients. Overall, patients expressed satisfaction with the information they received; they felt prepared for their surgery but not for postoperative pain control. PMID- 24756547 TI - The ALPPS approach: should we sacrifice basic therapeutic rules in the name of innovation? PMID- 24756548 TI - Long-term quality of life after Ivor Lewis esophagectomy for esophageal cancer. AB - BACKGROUND: Esophagectomy has a potentially high impact on physical, emotional, and social functions. The aim of this study was to assess long-term health related quality of life (QOL) after esophageal cancer surgery. METHODS: We analyzed all patients who underwent an Ivor Lewis esophagectomy for resectable esophageal cancer in our hospital from 1999 to 2010. QOL was assessed using the European Organization for Research and Treatment of Cancer general questionnaire QLQ-C30 and esophagus-specific questionnaire QLQ-OES18. RESULTS: A total of 150 patients were operated in the surveyed 12-year period. At the time of analysis, 46 patients (31 %) were eligible for assessment, 97 patients (65 %) had died or experienced tumor recurrence, and seven patients (5 %) were lost to follow-up. Of the 46 eligible patients, 43 (94 %) returned the questionnaires. The median observation interval between the operation and QOL assessment was 40 (range 21 135) months. The QLQ-C30 mean score of global health status and general QOL was similar to that of a healthy reference population. Most of the QLQ-C30 mean scores of functional and symptom scales and QLQ-OES18 symptom scales showed a worse result than for a healthy reference population. The highest mean scores were reflux and eating problems. CONCLUSIONS: In the long term, Ivor Lewis esophagectomy provides a generally good QOL for patients with esophageal cancer, which is comparable to a healthy reference population. However, some patients suffer from significant symptoms. Reflux and eating problems were the most relevant complaints. Dietary counseling is therefore important in the postoperative course. PMID- 24756551 TI - Computational investigations on the electronic and structural properties of the unsaturated silylenoid HP=SiLiF. AB - The structures of unsaturated silylenoid HP=SiLiF were studied by density functional theory at the B3LYP/6-311+G(d,P) level. Four equilibrium structures, the three-membered ring (1), the four-membered ring (2), the "classical" silane (3), and the linear (4) structures, were located. Their energies are in the order of 4 > 3 > 1 > 2. To exploit the stability of HP=SiLiF, the insertions reaction of 2 and HP=Si into C-Cl have been investigated, respectively. The results show that the insertion of HP=Si is more favorable. To compare with the saturated silylenoid, the insertion reaction of H2SiLiF was also investigated. The calculations indicate that the insertion of HP=SiLiF (2) is more favorable. The unsaturated siylenoid HP=SiLiF has similar reaction characters to saturated silylenoid H2SiLiF and silylene HP=Si. PMID- 24756550 TI - Combined structure- and ligand-based pharmacophore modeling and molecular dynamics simulation studies to identify selective inhibitors of MMP-8. AB - Matrix metalloproteinase-8 (MMP-8) is the key mediator in initiating type I collagen degradation and is associated with rheumatoid arthritis. In the present study, a pharmacophore hypothesis was developed based on selective non zinc binding inhibitors of MMP-8. The pharmacophore hypothesis was refined manually and validated by observing structures and the interactions of MMP-8 inhibitors. The refined pharmacophore model was able to discriminate the non-zinc binding inhibitors of MMP-8 with respect to other inhibitors. Hence this study proposes a combined structure- and ligand-based pharmacophore model that is suitable for retrieving the novel inhibitors of MMP-8. The pharmacophore hypothesis AADRH was used as query for retrieving potential compounds from the Zinc database and hits were selected based on the catalytic selective amino acid residues of Arg 222, and Tyr 227. We identified six compounds as potent inhibitors and their selectivity profile were checked against different subtypes of MMPs using the cross-docking method. Molecular dynamics results indicated that ZINC 00673680 forms a stable interaction with the key amino acid residues and avoids the zinc atom with a distance of 5.49 A. Our computational study might be useful for further development of selective MMP-8 inhibitors. PMID- 24756552 TI - Discovery of in silico hits targeting the nsP3 macro domain of chikungunya virus. AB - The recent emergence and re-emergence of alphaviruses, in particular the chikungunya virus (CHIKV), in numerous countries has invoked a worldwide threat to human health, while simultaneously generating an economic burden on affected countries. There are currently no vaccines or effective drugs available for the treatment of the CHIKV, and with few lead compounds reported, the vital medicinal chemistry is significantly more challenging. This study reports on the discovery of potential inhibitors for the nsP3 macro domain of CHIKV using molecular docking, virtual screening, and molecular dynamics simulations, as well as work done to evaluate and confirm the active site of nsP3. Virtual screening was carried out based on blind docking as well as focused docking, using the database of 1541 compounds from NCI Diversity Set II, to identify hit compounds for nsP3. The top hit compounds were further subjected to molecular dynamic simulations, yielding a greater understanding of the dynamic behavior of nsP3 and its complexes with various ligands, concurrently confirming the outcomes of docking, and establishing in silico lead compounds which target the CHIKV nsP3 enzyme. PMID- 24756553 TI - Impact sensitivity and crystal lattice compressibility/free space. AB - There is considerable evidence, which we discuss, indicating that compressibility and available free space in the crystal lattice are among the factors that govern the sensitivity of an explosive compound. Expanding and extending earlier work, we demonstrate, for 25 explosives, that there is an overall general tendency for greater impact sensitivity as the estimated free space per molecule increases. More specific relationships can be discerned by looking at subgroups of the compounds. The nitramine sensitivities, most of which are quite high, increase nearly linearly but only very gradually with free space. The nitroaromatics cover a wide range of sensitivities but all have an approximately similar intermediate level of free space. The remaining types of compounds show a reasonable sensitivity-free space relationship with one outlier: FOX-7 (1,1-diamino-2,2 dinitroethylene). PMID- 24756555 TI - Adsorption and splitting of H2S on 2D-ZnO(1-x)N(y): first-principles analysis. AB - We present a thorough analysis of molecular adsorption of a toxic gas, H2S, on pristine, defective and N-substituted 2D-ZnO using first-principles simulations within density functional theory and the parameterized form of van der Waals (vdW) interaction. We find that the binding of H2S with pristine 2D-ZnO is relatively weak (adsorption energy EA = -29 to -36 kJ mol(-1)) as it is mainly through the vdW interaction. However, substitutional nitrogen doping in 2D-ZnO leads to a drastic increase in the adsorption energy (EA = -152 kJ mol(-1)) resulting in dissociation of H2S molecules. This originates fundamentally from a strong covalent bonding interaction between an unpaired electron in the p-orbital of nitrogen and an electron in the s-orbital of H. While O-vacancy in 2D-ZnO has little effect on its interaction with H2S at lower coverages, a strong interaction at higher coverages leads to splitting of H2S and formation of H2 molecules. Our work shows that 2D-ZnO is a promising material to facilitate capturing of toxic H2S from the environment and at the same time converting it to a green source of energy. PMID- 24756554 TI - "I know it when I see it." The complexities of measuring resilience among parents of children with cancer. AB - PURPOSE: Promoting parent resilience may provide an opportunity to improve family level survivorship after pediatric cancer; however, measuring resilience is challenging. METHODS: The "Understanding Resilience in Parents of Children with Cancer" was a cross-sectional, mixed-methods study of bereaved and non-bereaved parents. Surveys included the Connor-Davidson Resilience scale, the Kessler-6 psychological distress scale, the Post-Traumatic Growth Inventory, and an open ended question regarding the ongoing impact of cancer. We conducted content analyses of open-ended responses and categorized our impressions as "resilient," "not resilient," or "unable to determine." "Resilience" was determined based on evidence of psychological growth, lack of distress, and parent-reported meaning/purpose. We compared consensus impressions with instrument scores to examine alignment. Analyses were stratified by bereavement status. RESULTS: Eighty-four (88 %) non-bereaved and 21 (88 %) bereaved parents provided written responses. Among non-bereaved, 53 (63 %) were considered resilient and 15 (18 %) were not. Among bereaved, 11 (52 %) were deemed resilient and 5 (24 %) were not. All others suggested a mixed or incomplete picture. Rater-determined "resilient" parents tended to have higher personal resources and lower psychological distress (p = <0.001-0.01). Non-bereaved "resilient" parents also had higher post traumatic growth (p = 0.02). Person-level analyses demonstrated that only 50-62 % of parents had all three instrument scores aligned with our impressions of resilience. CONCLUSIONS: Despite multiple theories, measuring resilience is challenging. Our clinical impressions of resilience were aligned in 100 % of cases; however, instruments measuring potential markers of resilience were aligned in approximately half. Promoting resilience therefore requires understanding of multiple factors, including person-level perspectives, individual resources, processes of adaptation, and emotional well-being. PMID- 24756556 TI - Unique RNA 2 sequences of two Brazilian isolates of Pepper ringspot virus, a tobravirus. AB - Pepper ringspot virus (PepRSV) is a tobravirus reported only in Brazil. Here, the sequences of the complete RNA 2 segments and the 3' end of the RNA 1 genomic regions of two new isolates from tomato plants were analyzed. The main ORF encodes the CP gene as other tobraviruses and termed ORF 1 of RNA 2. The second ORF was found only in one of the new isolates, although this gene was absent in the type isolate, CAM (collected in the 1960's). Interestingly, this ORF 2 gene did not show any nucleotide and amino acid sequence similarities with known 2b genes of tobraviruses, an essential gene of tobraviruses for nematodes transmission. The 5'UTR sequence of RNA 2 segment of CAM isolate was previously reported showing two impaired direct repeats; however, the direct-repeats were absent in these new isolates. An additional ORF was predicted upstream of the CP gene. This putative protein possessed a transmembrane domain similar to the ORFN1 of RNA 2 of Tobacco rattle virus SYM isolate, although there was no sequence similarity. This is the first report on the diversity of the RNA 2 sequences of PepRSV. PMID- 24756557 TI - The relationship of health aid to population health improvements. AB - IMPORTANCE: International aid to the health sector is an important component of all health spending in many developing countries. The relationship between health aid and changes in population health among aid recipients remains unknown. OBJECTIVE: To quantify the relationship between health aid and changes in life expectancy and mortality in children younger than 5 years (under-5 mortality) among aid recipient nations. DESIGN: Cross-country panel data analysis of the relationship between measures of health aid, life expectancy, and under-5 mortality. Using difference models for longitudinal data with fixed effects for countries and years, we estimated the unique relationship between health aid and changes in life expectancy and under-5 mortality, controlling for gross domestic product per capita, urbanization, and total fertility rate. SETTING AND PARTICIPANTS: A total of 140 aid-recipient countries between 1974 and 2010. EXPOSURE: Annual amount of development assistance directed to the health sector in constant 2010 US dollars. MAIN OUTCOMES AND MEASURES: Improvements in under-5 mortality and life expectancy in the period following aid receipt. RESULTS: Between 1974 and 2010, each 1% increase in health aid was associated with 0.24 months greater increase in life expectancy (95% CI, 0.02-0.46) (P = .03) and a 0.14 per 1000 live births faster decline in the probability of under-5 deaths per 1000 live births (95% CI, 0.02-0.26) (P = .02). The association between health aid and health improvements has strengthened over time, with the closest association occurring between 2000 and 2010. Health improvements associated with health aid are measurable for 3 to 5 years after aid disbursement. These findings imply that an increase of $1 billion in health aid could be associated with 364,800 fewer under-5 deaths (95% CI, 98,400-630,000). CONCLUSIONS AND RELEVANCE: International aid to the health sector is related to increasing life expectancy and declining under-5 mortality. The benefits from aid appear to last for several years and have been greatest between 2000 and 2010, possibly because of improving health technologies or effective targeting of aid. PMID- 24756560 TI - Bone marrow aspirate concentrate and platelet-rich plasma enhanced bone healing in distraction osteogenesis of the tibia. PMID- 24756559 TI - The role of prepregnancy pelvic floor dysfunction in postnatal pelvic morbidity in primiparous women. AB - INTRODUCTION AND HYPOTHESIS: Little is known about the natural history of pelvic floor dysfunction (PFD). We investigated the association between prepregnancy and postnatal PFD in premenopausal primiparous women and the associated effect of mode of delivery. METHODS: A prospective cohort study, nested within the parent Screening for Pregnancy Endpoints (SCOPE) study, was performed in a tertiary referral teaching hospital with approximately 9,000 deliveries per annum. The validated Australian pelvic floor questionnaire was completed by 872 nulliparous women at 15 weeks' gestation, at the time of recruitment to the SCOPE study and 1 year postnatally. The questionnaire contained four sections with questions about urinary, faecal, prolapse and sexual dysfunction. RESULTS: One year postnatally urinary dysfunction was present in 73%, faecal in 49%, prolapse in 14% and sexual in 58% of participants. Prepregnancy PFD persistent postnatally constituted more than half of total PFD. The majority of affected (71%) had multicompartment involvement. Participants with persistent PFD had higher prevalence of severe symptoms and bothersome symptoms within the group. Severity of prepregnancy PFD worsened in <15% cases postnatally. CONCLUSIONS: The main damage to the pelvic floor seems to occur in the majority of patients before first pregnancy, where first childbearing does not worsen prepregnancy PFD in the majority of cases. Pregnancy appears to affect more pre-existing symptoms of urgency and urge incontinence comparing to stress incontinence. Caesarean section seems to be more protective against postnatal worsening of prepregnancy PFD comparing to de novo onset pathology. However, larger studies are needed to confirm these findings. PMID- 24756562 TI - Prenatal renal vein thrombosis in dichorionic twin pregnancy. AB - BACKGROUND: Prenatal renal vein thrombosis is a rarely described diagnostic finding. The etiology is unclear in the majority of cases, although thrombophilia was found in some affected fetuses. Precise ultrasound scan can improve detection rate of neonatal thrombosis due to characteristic findings. CASE REPORT: We present the unusual case of a dichorionic twin pregnancy in 31 weeks of gestation with one affected fetus, showing already intrauterine a bilaterally enlarged kidney and absence of renal venous flow. Additionally, the fetus showed signs of circulatory compromise and fetal distress, while dichorionic male co-twin was healthy. The postnatal thrombophilia investigations revealed a heterozygous factor V Leiden mutation. CONCLUSION: Fetal renal vein thrombosis may occur bilateral and may also involve the inferior vena cava. Rapid deterioration of fetal condition, abnormal fetal Doppler, appearance of hydrops fetalis, may accompany fetal venous thrombosis. By color Doppler flow mapping abnormal arterial and absent venous perfusion of the affected kidney may be demonstrated in addition. PMID- 24756563 TI - Patient satisfaction and willingness to return to the provider among women undergoing gynecological surgery. AB - PURPOSE: To identify factors associated with 'patient satisfaction' and 'willingness to return to the provider' in gynecology and to assess similarities as well as differences between the two concepts. METHODS: Study data were obtained from 968 randomly selected gynecology patients discharged from 22 hospitals who responded to a mailed survey. The validated instrument consisted of 37 items and assessed medical and service aspects of care, patient and visit characteristics. The dependent variables consisted of ratings of willingness to return to the provider and overall satisfaction. Bivariate and multivariate techniques were used to reveal relationships between indicators and both dependent variables. RESULTS: The multivariate analyses identified individualized medical care, kindness of medical practitioners, treatment outcome and organization of discharge as the most consistent predictors of the patients' likelihood to return and overall satisfaction. Differences between both concepts pertained to the significance of service variables (cleanliness and quality of food) for patient satisfaction and visit-related characteristics (length of stay and occurrence of complications) for willingness to return. CONCLUSIONS: Study findings suggest that patient satisfaction and willingness to return to the provider do not reflect the same concepts. Although service aspects such as quality of food influence satisfaction ratings, they do not increase the likelihood that patients choose the same hospital in case of another treatment. Communication between patients and medical practitioners is highly important. Revealed predictors of both concepts are alterable by healthcare professionals and should be focused on to enhance patient satisfaction and to increase the probability patients return to their provider. PMID- 24756564 TI - Impaired tumor angiogenesis and VEGF-induced pathway in endothelial CD146 knockout mice. AB - CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angiogenic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout (CD146(EC-KO)) mice using the Tg(Tek-cre) system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146(EC KO) mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells (ECs) of CD146(EC-KO) mice. Mechanistic studies further confirmed that VEGF-induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/NF kappaB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146(EC KO) mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis. PMID- 24756566 TI - Mechanomics: an emerging field between biology and biomechanics. AB - Cells sense various in vivo mechanical stimuli, which initiate downstream signaling to mechanical forces. While a body of evidences is presented on the impact of limited mechanical regulators in past decades, the mechanisms how biomechanical responses globally affect cell function need to be addressed. Complexity and diversity of in vivo mechanical clues present distinct patterns of shear flow, tensile stretch, or mechanical compression with various parametric combination of its magnitude, duration, or frequency. Thus, it is required to understand, from the viewpoint of mechanobiology, what mechanical features of cells are, why mechanical properties are different among distinct cell types, and how forces are transduced to downstream biochemical signals. Meanwhile, those in vitro isolated mechanical stimuli are usually coupled together in vivo, suggesting that the different factors that are in effect individually could be canceled out or orchestrated with each other. Evidently, omics analysis, a powerful tool in the field of system biology, is advantageous to combine with mechanobiology and then to map the full-set of mechanically sensitive proteins and transcripts encoded by its genome. This new emerging field, namely mechanomics, makes it possible to elucidate the global responses under systematically-varied mechanical stimuli. This review discusses the current advances in the related fields of mechanomics and elaborates how cells sense external forces and activate the biological responses. PMID- 24756568 TI - Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis. AB - BACKGROUND: auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS). OBJECTIVES: to confirm these findings. METHODS: we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls. RESULTS: anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining. CONCLUSIONS: we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported. PMID- 24756565 TI - Intercellular protein-protein interactions at synapses. AB - Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer's disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders. PMID- 24756569 TI - Adherence in multiple sclerosis (ADAMS): classification, relevance, and research needs. A meeting report. AB - BACKGROUND: Adherence to medical interventions is a global problem. With an increasing amount of partially effective but expensive drug treatments adherence is increasingly relevant in multiple sclerosis (MS). Perceived lack of efficacy and side effects as well as neuropsychiatric factors such as forgetfulness, fatigue and depression are major determinants. However, research on adherence to behavioural interventions as part of rehabilitative interventions has only rarely been studied. METHODS: In a one-day meeting health researchers as well as patient representatives and other stakeholders discussed adherence issues in MS and developed a general draft research agenda within a focus group session. RESULTS: The focus group addressed four major areas: (1) focussing patients and their informal team; (2) studying health care professionals; (3) comparing practice across cultures; and (4) studying new adherence interventions. CONCLUSIONS: A focus on patient preferences as well as a non-judgmental discussion on adherence issues with patients should be at the core of adherence work. PMID- 24756567 TI - The regulation of TGF-beta/SMAD signaling by protein deubiquitination. AB - Transforming growth factor-beta (TGF-beta) members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-beta type II (TbetaR II) and type I (TbetaRI) and serine/threonine kinases receptors. Aberrant activation of TGF-beta signaling leads to diseases, including cancer. In advanced cancer, the TGF-beta/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-beta/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-beta signaling components by deubiquitinating enzymes (DUBs). In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-beta signaling pathway. The regulatory roles of these DUBs as a driving force for cancer progression as well as their underlying working mechanisms are also discussed. PMID- 24756571 TI - Discovery of protein-RNA networks. AB - Coding and non-coding RNAs associate with proteins to perform important functions in the cell. Protein-RNA complexes are essential components of the ribosomal and spliceosomal machinery; they are involved in epigenetic regulation and form non membrane-bound aggregates known as granules. Despite the functional importance of ribonucleoprotein interactions, the precise mechanisms of macromolecular recognition are still poorly understood. Here, we present the latest developments in experimental and computational investigation of protein-RNA interactions. We compare performances of different algorithms and discuss how predictive models allow the large-scale investigation of ribonucleoprotein associations. Specifically, we focus on approaches to decipher mechanisms regulating the activity of transcripts in protein networks. Finally, the catRAPID omics express method is introduced for the analysis of protein-RNA expression networks. PMID- 24756570 TI - Protein phospholipase C Zeta1 expression in patients with failed ICSI but with normal sperm parameters. AB - PURPOSE: This study was conducted to determine if expression of the testis specific phospholipase C Zeta1 (PLCZ1) correlated with low success or fertilization failure after ICSI in patients with normal parameters after standard semen analysis (SA). METHODS: Couples <43 years with one or two failed or low fertilization ICSI cycles. Standard Semen Analysis (SA) was performed to determine sperm parameters in male partners, whereas females were evaluated for antral follicle counts (AFC), day 3 FSH levels and peak Estradiol (E2) levels. The presence of PLCZ1 in sperm was ascertained using Western blotting and Immunofluorescence (IF) analysis. The ability of sperm to initiate changes in the intracellular concentrations of free calcium ([Ca(2+)]i), which is characteristic of mammalian sperm, was performed after injection of human sperm into mouse eggs loaded with the Ca(2+) sensitive dye fura-2 AM. RESULTS: Male partners of couples with failed or low success ICSI fertilization but with normal SA parameters showed low expression levels of PLCZ1 as determined by western blotting and reduced fluorescent signal during IF studies. In addition, fewer of these males' sperm showed PLCZ1 expression and were able to initiate robust [Ca(2+)]i oscillations upon injection into eggs. CONCLUSION: Our data suggest that in patients with normal SA parameters but with repeated low fertilization or outright failed fertilization results after ICSI, abnormal PLCZ1 function should be considered as the underlying mechanism responsible for the failure of fertilization. PMID- 24756572 TI - Bis-chlorination of a hexapeptide-PCP conjugate by the halogenase involved in vancomycin biosynthesis. AB - Vancomycin is an important nosocomial antibiotic containing a glycosylated, cross linked and doubly chlorinated heptapeptide backbone. During the biosynthesis of the vancomycin aglycone, two beta-hydroxytyrosine (Bht) residues are inserted at positions-2 and -6 into the heptapeptide backbone by a non-ribosomal peptide synthetase. A single flavin-dependent chlorinase (VhaA) is responsible for chlorinating both Bht residues at some ill-defined point in the assembly process. We show here using in vitro assays that VhaA is able to introduce a chlorine atom into each aromatic ring of both Bht residues at positions-2 and -6 of a peptide carrier protein-bound hexapeptide. The results suggest that VhaA can recognize and chlorinate two quite different sites within a linear hexapeptide intermediate during vancomycin biosynthesis. PMID- 24756575 TI - NF-kappaB signaling modulates radiation-induced microglial activation. AB - Microglial activation has been suggested to be associated with the incidence of radiation-induced brain injury. The present study investigated the molecular mechanism(s) involved in radiation-induced activation of the microglia. Mouse microglial BV-2 cells were exposed to different doses of radiation. The release of inflammatory factors was evaluated by enzyme-linked immunosorbent assay and real-time reverse transcriptase polymerase chain reaction. Protein expression was determined by immunocytochemistry and immunoblotting. Microglial activation was induced by radiation [>16 Gray (Gy)]. Activated cells exhibited a stouter spherical morphology and the levels of ionized calcium-binding adapter molecule-1 and CD68 were considerably upregulated. The generation of inflammatory factors, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, toll-like receptor 8 (TLR-8) and cyclooxygenase 2 (COX-2), was increased and peaked at either 3 or 6 h after radiation treatment. Phosphorylated gamma histone 2A, member X (gamma-H2AX), which facilitates DNA double-strand breaks (DSBs), was upregulated at 3 h post-radiation treatment. This was accompanied by the nuclear translocation of the nuclear factor-kappaB (NF-kappaB) p65 subunit. Moreover, 3 h following radiation treatment, the NF-kappaB essential modulator (NEMO) was markedly elevated, whereas the NF-kappaB regulatory inhibitor-alpha (IkappaB-alpha) was considerably decreased. Our results demonstrate that the NF kappaB signaling pathway may trigger microglial activation and release of inflammatory factors following irradiation. These findings may provide valuable insight into understanding the molecular mechanism(s) involved in brain injury induced by radiation therapy. PMID- 24756576 TI - Enhancing photo-induced ultrafast charge transfer across heterojunctions of CdS and laser-sintered TiO2 nanocrystals. AB - Enhancing the charge transfer process in nanocrystal sensitized solar cells is vital for the improvement of their performance. In this work we show a means of increasing photo-induced ultrafast charge transfer in successive ionic layer adsorption and reaction (SILAR) CdS-TiO2 nanocrystal heterojunctions using pulsed laser sintering of TiO2 nanocrystals. The enhanced charge transfer was attributed to both morphological and phase transformations. At sufficiently high laser fluences, volumetrically larger porous networks of the metal oxide were obtained, thus increasing the density of electron accepting states. Laser sintering also resulted in varying degrees of anatase to rutile phase transformation of the TiO2, producing thermodynamically more favorable conditions for charge transfer by increasing the change in free energy between the CdS donor and TiO2 acceptor states. Finally, we report aspects of apparent hot electron transfer as a result of the SILAR process which allows CdS to be directly adsorbed to the TiO2 surface. PMID- 24756577 TI - Expanding endoscopic interventions for pancreatic pseudocyst and walled-off necrosis. AB - BACKGROUND: Recently, several endoscopists have described the usefulness of the endoscopic ultrasonography (EUS)-guided, single transluminal gateway technique (SGT) using transmural placement of single or multiple plastic stents or metal stents for a pancreatic pseudocyst (PC) and walled-off necrosis (WON). Moreover, the uses of the multiple transluminal gateway technique (MTGT) and single transluminal gateway transcystic multiple drainages (SGTMD) for complicated pancreatic walled-off necrosis have recently been reported. The aim of this study is to evaluate retrospectively the feasibility and efficacy of endotherapy for the treatment of complicated PC and WON cases. METHODS: Eighty-nine patients with a PC (n = 14) and WON (n = 75) were treated under EUS guidance. RESULTS: In a total of 89 cases using SGT in combination with MTGT or SGTMD, the present study showed a technical success rate of 100 %, a final clinical success rate of 97.8 %, an adverse event during procedure rate of 0 %, an early adverse event rate of 12.4 %, and a mortality rate of 2.2 %. CONCLUSIONS: Even complicated WON cases can be treated using combination endotherapies, although a surgical approach as well as a percutaneous approach should be considered in the cases refractory to endoscopic therapies. PMID- 24756578 TI - A reciprocal interplay between psychosocial job stressors and worker well-being? A systematic review of the "reversed" effect. AB - OBJECTIVES: Work represents an important role in society, and the nature and consequences of job stress have garnered significant research interest. In recent years, considerable effort has been made to elucidate the occupational stressor strain relationship, or the interplay between unfavorable working conditions (stressor) and worker well-being (strain). In line with Bandura's notion of "reciprocal determinism", a reciprocal occupational stressor-strain relationship is now increasingly postulated, where variables exert mutual influences on each other over time. The objective of this study was to determine the extent of empirical support for three specific "reversed" (strain-to-stressor) effects, guided by the Demand-Control-Support model. METHODS: A systematic literature review was conducted (1996-2012 inclusive) through a search of databases. After relevant studies were identified, a methodological quality appraisal was performed based on four key criteria: sample size, measurement, non-spuriousness, and non-response bias. Subsequently, a quantitative synthesis of evidence from high-quality studies was performed by calculating a standardized index of convergence for each reversed effect. RESULTS: Twenty-three qualifying studies were found and evidence from ten high-quality studies ultimately contributed to the synthesis. Moderately strong evidence in support of a positive strain-to-job demands effect was found, but there was no evidence in support of either a strain to-job control or a strain-to-workplace social support effect CONCLUSIONS: In conjunction with available evidence on the corresponding "normal" (stressor-to strain) effect, this review gives credence to the possibility of a reciprocal stressor-strain relationship involving job demands and worker well-being. PMID- 24756580 TI - Production and molecular characterization of somatic hybrids between Pleurotus florida and Lentinula edodes. AB - Nine inter-generic somatic hybrids named as pfle were produced through PEG mediated protoplast fusion between Pleurotus florida and Lentinula edodes using double selection method. Hybridity of the newly developed strains was established on the basis of colony morphology, mycelial growth, hyphal traits, fruit-body productivity and inter single sequence repeat (ISSR) marker profiling. Hybrid population was assessed with different phenotypic variables by one-way analysis of variance. Principal component matrices were analyzed for the six phenotypic variables in scatter plot showing maximum positive correlation between each variable for all strains examined. Six ISSR primers generated 66 reproducible fragments with 98.48 % polymorphism. The dendrogram thus created based on unweighted pair-group method with mathematic averages method of clustering and Euclidean distance which exhibited three major groups between the parents and pfle hybrids. Though P. florida parent remained in one group but it showed different degrees of genetic distance with all the hybrid lines belonging to the other two groups while L. edodes was most distantly related to all the hybrid lines. L. edodes specific sequence-rich ISSR amplicon was recorded in all the hybrid lines and in L. edodes but not in P. florida. All the fruit body generating pfle hybrid lines could produce basidiocarp on paddy straw in sub tropical climate and showed phenotypic resemblance to the P. florida parent. PMID- 24756581 TI - "Early years of biological agents therapy in Crohn's disease and risk of the human polyomavirus JC reactivation" by Anna Bellizzi, Valentina Barucca, Daniela Fioriti, Maria T. Colosimo, Monica Mischitelli, Elena Anzivino, Fernanda Chiarini and Valeria Pietropaolo. PMID- 24756586 TI - HIV/AIDS. PMID- 24756587 TI - Turning the tide toward an AIDS free generation: is it within our reach? PMID- 24756588 TI - Evidence on delay in sexual initiation, multiple partnerships and condom use among young people: review of Caribbean HIV behavioural studies. AB - OBJECTIVE: To develop a Caribbean regional profile of youth sexual behaviour associated with risk of HIV. DESIGN AND METHODS: A review of sexual behaviour surveys with youth aged 15-24 years was conducted as part of the Pan American Health Organization (PAHO) HIV Caribbean Office's Review and Gender Analysis of Caribbean HIV Behavioural and Seroprevalence Studies. Studies with internationally recommended indicators were prioritized. Studies were sought via database searches and contact with researchers and National AIDS Programmes. RESULTS: Inter-country comparisons and longitudinal analyses were limited by lack of uniformity in study age groups and indicators. Data were sufficient to identify the following among 15-24-year olds: .More males than females report sexual intercourse before the age of 15 years. .More than half of sexually active youth report sex before age 16 years. .First sexual encounter is usually with someone older, with age differences larger for females. .More males than females report multiple partnerships, with 20%-76% of males reporting this in the past year. .Condom use varies widely, with no clear pattern by gender. CONCLUSION: There are substantial levels of early sexual initiation, intergenerational sex among females and multiple partnerships among males, while condom use is inconsistent. Efforts to promote delay in sexual initiation, partner reduction and consistent condom use should be supplemented with initiatives against harmful gender norms, child abuse and transactional sex and skills to negotiate safe sex. Standardization of survey methods to facilitate cross-study comparisons should continue and encompass additional risk factors such as transactional sex, gender based violence, drug use and HIV treatment adherence. PMID- 24756589 TI - Optimizing chronic HIV care in the Dutch Caribbean: a questionnaire based study on experience and perception of healthcare workers. AB - OBJECTIVE: Human immunodeficiency virus (HIV) infection has become a chronic disorder for which adaptation of current healthcare practices is needed. In Curacao, a new organization of chronic HIV care is being set up based on task shifting in which healthcare workers (HCWs) will deliver HIV care more prominently within the primary healthcare system. In preparation for implementation of the proposed task-shifting model, we investigated the perception of HCWs regarding existing HIV care in Curacao and the need for training in HIV/AIDS among HCWs. SUBJECTS AND METHODS: An in-depth questionnaire based study was used. Nineteen HCWs of seven different cadres were interviewed. The questionnaire constituted four sections: quality of existing HIV care, respondents own knowledge and willingness to be trained, need for training in HIV/AIDS and preferred educational approaches. RESULTS: Quality of existing HIV services in Curacao is considered acceptable but needs improvement mainly to facilitate integration of chronic HIV care. All respondents indicated that training in HIV/AIDS is needed among HCWs in Curacao, especially for nurses and general practitioners. All were willing to participate in training with varying amounts of time to be spent. Training should be tailored to the level of expertise of HCWs and to the role a HCW is expected to have in the new healthcare delivery framework. CONCLUSION: There is need for training to ensure the effective integration of chronic HIV care into the existing healthcare delivery system in Curacao.There is a willingness and need in all cadres for training with e-learning as a preferred educational tool. PMID- 24756590 TI - Ophthalmic manifestations of HIV in the highly active anti-retroviral therapy era. AB - HIV-related eye disease can be classified as retinal HIV microangiopathy, opportunistic infections, neuro-ophthalmic manifestations and unusual malignancies. There is a 52-100% lifetime accumulative risk of HIV patients developing eye problems. Seventy-seven per cent of patients with ocular manifestations of HIV had CD4 counts < 200 cells/MUL. Cytomegalovirus (CMV) is the most prevalent opportunistic infection, however, Africa has a low incidence of this, and more commonly squamous cell carcinoma, compared to the western hemisphere. Due to highly active antiretroviral therapy (HAART), the anti-CMV therapy may be discontinued if the CD4+ T cell count is > 100 cells/MUL for a minimum of three months. Despite HAART, patients with a CD4 count < 50 cells/MUL have a similar risk of developing CMV retinitis as compared to the pre-HAART era. Opportunistic infections include CMV, herpetic retinopathy (progressive outer retinal necrosis - PORN), less commonly toxoplasmosis, pneumocystis and cryptococcus. Malignancies associated with HIV include Kaposi's sarcoma and conjunctival squamous cell carcinoma. Cranial nerve palsies, optic disc swelling and atrophy are characteristic neuro-ophthalmic features. They usually occur secondary to meningitis/encephalitis (from cryptococcus and tuberculosis). With the advent of HAART, new complications have developed in CMV retinitis: immune recovery uveitis (IRU) and cystoid macula oedema (CMO). Immune recovery uveitis occurs in 71% of patients if HAART is started before the induction of the anti CMV treatment. However, this is reduced to 31% if HAART is started after the induction treatment. Molluscum contagiosum and Kaposi's sarcoma can spontaneously resolve on HAART. Highly active anti-retroviral therapy has reduced the frequencies of opportunistic infections and improved the remission duration in HIV patients. PMID- 24756591 TI - Cervical intraepithelial neoplasia in a cohort of HIV-positive women at the University Hospital of the West Indies: management and outcome. AB - OBJECTIVE: To determine the rate of recurrence of cervical intraepithelial neoplasia (CIN) in HIV-positive women evaluated at the University Hospital of the West Indies (UHWI). METHOD: A chart review of all non-pregnant HIV-positive women who attended the gynaecologic and colposcopic clinics between January 1994 and December 2004 identified 21 such women. Fifteen of these patients who had CIN and had at least one follow-up Pap smear were the main subjects of this study. These patients were compared to 21 HIV-negative controls who were seen during the same period and who also had at least one follow-up Pap smear. Treatment modalities for the groups included cold coagulation and large loop excision of the transformation zone (LLETZ). Cox proportional hazards analysis was used to determine the effect of HIV status on the time to first recurrence of CIN. RESULTS: The mean ages of the subjects were 32.7 +/- 8.0 and 33.2 +/- 8.1 years, respectively. With a mean follow-up period of 1.7 years, the rate of recurrence of CIN in patients with and without HIV was 66.24 (95% CI 27.6, 159.1) and 3.0 (95% CI 1.3, 7.3) per 100 person years. The hazards rate ratio for recurrence in subjects with HIV after adjusting for age and CIN stage was 19.1 (95% CI 4.4, 82.1). CONCLUSION: HIV increases the risk of recurrence of CIN. PMID- 24756592 TI - HIV/AIDS knowledge and sexual behaviour among junior high school students in New Providence, Bahamas. AB - OBJECTIVE: To determine accuracy of knowledge and sexual behaviour patterns of junior high school students in New Providence towards HIV/AIDS and identify gender variations. METHODS: A cross-sectional study with cluster sampling of classrooms was undertaken at two schools utilizing a questionnaire. SPSS was used for statistical analysis. RESULTS: Three hundred and fifty-four students participated in the study; the mean age was 12.25 years, 55.1% males and 44.9% females. Most (88%) students identified sexual intercourse as a mode of HIV transmission, 62.5% were accurate regarding anal sex and 32.9% were accurate about sexual intercourse in the water, as modes of HIV transmission. Abstinence was identified as a method of HIV prevention by 54.1% of students although 85.2% of students knew that condoms were a method of prevention. On beliefs regarding transmission, 21.2% believed mosquito bites and 13.1% believed toilet seats were routes for disease spread. Only 16.9% of participants reported a history of sexual intercourse; of those, 57.6% indicated that they were age <= 10 years when they first had intercourse. Concerning use of birth control, 64.5% of sexually experienced respondents reported never using any method. CONCLUSION: Junior high school students have fairly accurate knowledge of HIV/AIDS but misconceptions regarding transmission are still prevalent; patterns in gender variation are few. PMID- 24756593 TI - The burden of HIV infection among women attending antenatal clinic in a semi urban Nigerian town. AB - BACKGROUND: Stable heterosexual relationships are a major determinant of the HIV epidemic and seroprevalence rate of HIV amongst antenatal women is a reflection of what is happening in the larger society. OBJECTIVES: This study aims to determine the HIV seroprevalence rate and to identify factors responsible for this rate among pregnant women. METHOD: The study was a three-year (July 2008 June 2011) cross-sectional evaluation of cases of HIV in pregnancy. Data were collected with the aid of a closed structured self-administered questionnaire for all the positive women and randomly selected negative cases. The study was carried out at Niger Delta University Teaching Hospital in Bayelsa State, Nigeria. RESULTS: The seroprevalence rate during the study period was 4.9%. Parity, age at first coitus, educational status, marital status and occupation do not seem to increase the risk. However, partner being unemployed, hospital/clinic delivery, the route of last delivery, previous induced abortion and the number of lifetime partners were identified as risk for HIV seropositivity (all p-values < 0.005). CONCLUSION: Sex education on the dangers of sexual promiscuity, availability of barrier methods of contraception, delivery with strict adherence to the principles of universal precaution and routine screening of all pregnant women during the antenatal period will help to decrease the prevalence of HIV in our environment. PMID- 24756594 TI - Knowledge, attitudes and behaviours related to HIV/AIDS among female migrant workers in the restaurant industry in Guangzhou, China. AB - OBJECTIVE: The goal of the present study was to assess knowledge and attitudes related to HIV/AIDS among the migrant female workers in the restaurant industry in Guangzhou City, China. METHODS: We performed a questionnaire survey using a judgmental sampling method in the health examination clinic of Yuexiu District of Guangzhou during March 2011. A total of 428 participants completed and returned the questionnaires and data were analysed by descriptive statistics, t-test, one way ANOVA, and Wilcoxon test. RESULTS: Of 428 respondents, the average score of HIV/AIDS-related knowledge was 19.6 (full marks, 26). Knowledge on HIV/AIDS among respondents was classified as poor for 8.2%, fair for 42.5%, and good for 49.3%. The average score of AIDS-related attitudes of respondents was 7.2 (full marks, 10). Most of the respondents (88.8%) had relatively positive attitudes toward AIDS. Unmarried status, ages less than 30 years old and higher levels of education had higher scores of knowledge. Among the respondents who had sex experiences, 57.7% (130/225) reported that they never or only some of the time used condom. The young, unmarried women had significantly higher proportion of condom use than those above 30 years old, and/or married ones. CONCLUSION: Overall, a half of respondents had only moderate and low levels of awareness about HIV/AIDS knowledge, although most of them had tolerant and positive attitudes toward HIV/AIDS. In addition, a relatively lower rate of condom use was reported. The findings indicate that there exists broad space for improvement of knowledge and behaviours toward HIV/AIDS for migrant women in China. PMID- 24756595 TI - A review of the HIV-infected homeless sub-population at the Centre for HIV/AIDS Research, Education and Services, Department of Medicine, University Hospital of the West Indies. AB - OBJECTIVE: The twin epidemics of HIV and homelessness present several challenging aspects to the development of programmes for the provision of treatment and care. This paper describes the characteristics of this population being managed by a collaborative effort between the Centre for HIV/AIDS Research, Education and Services, Department of Medicine, University Hospital of the West Indies and the National Council on Drug Abuse. SUBJECTS AND METHODS: A retrospective descriptive study was conducted via review of patients'medical files. Demographic and clinical data of the HIV-infected homeless population were summarized, highlighting issues related to the provision of care, rates of antiretroviral therapy (ART) uptake and subsequent adherence to treatment and known factors associated with HIV transmission. RESULTS: A total of 12 cases were included in the analysis. There was an average age of 38.0 years (IQR 32.5-49.25) with the majority being female, nine (75.0%). Late stage diagnosis was a common feature. The majority of cases were eligible for ART on first contact, with CD4 counts on average being 284.4 (95% CI 10.9.0, 459.8). Significant risk factors for HIV transmission were also identified as all cases reported being sexual active with limited condom use reported and high reported numbers of lifetime partners, 30 (IQR 25.0-100.0). Other factors identified include eight (66.6%) cases reporting sexually transmitted infection (STI) symptoms, 10 (83.3%) reporting substance abuse and nine (75.0%) reporting sex work. CONCLUSION: The implementation of combination interventions providing a comprehensive package of services that address the multitude of issues facing the HIV-infected homeless population is required in order to appropriately manage this population. PMID- 24756596 TI - Psychological distress and substance abuse in Jamaican youths living with HIV/AIDS. AB - OBJECTIVE: Current epidemiological research indicates that HIV/AIDS endures and continues to be a significant vulnerability among adolescents and youths despite the increased access to antiretroviral drugs and the reduction in the global progression of the disease. This study examined the association between substance use and psychological distress within the Jamaican population of youths coping with the illness. METHOD: This is a cross-sectional survey that utilized a correlational design. The sample population consisted of 62 youths, age range 15 25 years, living with HIV/AIDS. Sociodemographic information was gathered through interviews and self-report scales were used to measure depression, anxiety, stress and substance use. Chi-square was used to assess the relationship between the variables under study: psychological distress and substance use. RESULTS: More than half the sample were heterosexuals who contracted the virus through consensual intercourse. The average age of respondents was 21.29 years and slightly more than half were female (56.5%). The majority of respondents were single (54.8%), unemployed (73%), heterosexual (69.4%) youths with a secondary level education (63%). There was a statistically significant relationship between psychological distress and substance use (chi2 = 7.3959, df = 3, p = 0.047). CONCLUSION: The emotional needs of youths living with HIV/AIDS are just as important as their medical needs. PMID- 24756597 TI - The role of the University of the West Indies Mona libraries in HIV/AIDS information access and dissemination. AB - The recommendations for controlling HIV/AIDS, whether prescriptive or descriptive, underscore the value of information: its translation into knowledge, and knowledge into behaviour. Thus, accessing, evaluating, disseminating and applying authoritative, credible and scholarly information on HIV/AIDS are critical elements in the control of this pandemic in the Web 2.0 era. The University of the West Indies (UWI) Mona libraries have embraced this information role. This article provides insights into three of the information initiatives implemented by the UWI Mona libraries in this important capacity. In this regard, it also provides ideas for other West Indian information units and enhances communication on access to information products and services, albeit incrementally, in an important area of health services for the West Indies. PMID- 24756598 TI - Calculating the affordability of antiretrovirals in St Lucia. AB - The cost of antiretrovirals is borne by donors in many low- and middle-income countries, including St Lucia. Although donor involvement has facilitated access to antiretrovirals, donor engagement in HIV/AIDS has changed over the years. This paper assesses the affordability of antiretrovirals at the individual level if donors were no longer available to fund the cost of first and second-line antiretrovirals and a prospective third-line regimen. Various conceptions of affordability are reviewed using different assumptions of what is required to maintain a standard of living that would avoid individuals descending into poverty as a result of antiretroviral purchases. These concepts of affordability are operationalized using data from the Household Budgeting Survey conducted in St Lucia in 2005/2006. While there is a range of results for the affordability of first and second-line antiretrovirals depending on which standard of affordability is used, third-line antiretrovirals are unaffordable to more than 80% of the population across the four standards of affordability used - the national poverty line, 50% of median annual consumption, 10% of annual consumption and a proposed reasonable minimum standard. PMID- 24756599 TI - What are the benefits and barriers of communicating parental HIV status to seronegative children and the implications for Jamaica? A narrative review of the literature in low/middle income countries. AB - OBJECTIVE: To examine the benefits/barriers for HIV positive parents of communicating their status to seronegative children in low/middle income countries in order to inform policy and practice in Jamaica. METHODS: The authors carried out a systematic search of published literature on parental disclosure in low/middle income countries written in the English language between January 1991 and September 2012, identified from databases: Academic Search Complete, CINAHL, EBSCOhostEJS, Gender Studies Database, Health Policy Reference Centre, MEDLINE (includes the West Indian Medical Journal), PsycARTICLES , PsycINFO , SocINDEX, AMED, Global Health, Embase, Social Policy and Practice, Maternity and Infant Care. The authors also refer to articles on parental disclosure in high income countries which appeared in peer-reviewed journals and conducted a local search in Jamaica for articles on HIV disclosure in the Caribbean region. RESULTS: Global estimates of parental disclosure rates were 20-97% in high income countries and 11-44% in resource constrained countries. Mean age of children at disclosure was age 10-18 years. Mothers were more likely to disclose to older children, female children, and when they had strong support networks. Barriers included fear of stigma/discrimination, not knowing how to tell the child, fear of the child disclosing to others and believing a child was too young to cope. Of the 16 articles identified which met the search criteria, 10 studies and three reviews noted positive benefits of disclosure on parental health and the parent child relationship. CONCLUSION: Significant differences in attitudes and rates of maternal disclosure in low/middle income countries compared to high income countries reflect the impact of cultural, structural, economic and social factors and highlight the need for culturally-specific research. Implications for policy and practice in Jamaica are discussed. PMID- 24756600 TI - A case of systemic cryptococcal disease in HIV infection. AB - Globally, Cryptococcosis is the most common invasive mycosis in HIV disease. Incidence rates vary widely by geographical region and resource availability and reportedly range from 0.04 to 12% per year (1). Sub-Saharan Africa accounts for the greatest burden with a median incidence of 3.2% per year (1). Since the advent of widespread use of antiretroviral therapy (ART), incidence rates of opportunistic infections have been significantly declining (2). PMID- 24756601 TI - Sustained increase of serum creatine phosphokinase levels and progressive muscle abnormalities associated with raltegravir use during 32-week follow-up in an HIV 1 experienced patient on simplified HAART regimen, intolerant to protease inhibitors and abacavir: a case report. AB - Sustained increase of serum creatine phosphokinase (CPK) concentrations and muscle abnormalities have been reported in patients taking raltegravir (RAL). In this report, we describe a case of sustained and asymptomatic increase of serum CPK concentrations associated with raltegravir, zidovudine, and lamivudine in an HIV-1 experienced patient with intolerance to protease inhibitor, abacavir and penicillin during 32 weeks of continuous drug monitoring. PMID- 24756602 TI - High HIV prevalence among men who have sex with men in Jamaica is associated with social vulnerability and other sexually transmitted infections. AB - BACKGROUND: Human immunodeficiency virus (HIV) prevalence among men who have sex with men (MSM) is thought to be high in Jamaica. The objective of this study was to estimate HIV prevalence and identify risk factors in order to improve prevention approaches. METHODS: With the help of influential MSM, an experienced research nurse approached MSM in four parishes to participate in a cross sectional survey in 2007. Men who have sex with men were interviewed and blood taken for HIV and syphilis tests, and urine taken for gonorrhoea, chlamydia and trichomonas testing using transcription-mediated amplification assays. A structured questionnaire was administered by the nurse. RESULTS: One third (65 of 201; 32%, 95% Confidence Interval (CI) 25.2, 47.9) of MSM were HIV positive. Prevalence of other sexually transmitted infections (STI) was: chlamydia 11%, syphilis 6%, gonorrhoea 3.5% and trichomonas 0%. One third (34%) of MSM identified themselves as being homosexual, 64% as bisexual and 1.5% as heterosexual. HIV positive MSM were significantly more likely to have ever been told by a doctor that they had an STI (48% vs 27%, OR 2.48 CI 1.21, 5.04, p = 0.01) and to be the receptive sexual partner at last sex (41% vs 23%, OR 2.41 CI 1.21, 4.71, p = 0.008). Men who have sex with men who were of low socio-economic status, ever homeless and victims of physical violence were twice as likely to be HIV positive. The majority (60%) of HIV positive MSM had not disclosed their status to their partner and over 50% were not comfortable disclosing their status to anyone. CONCLUSIONS: The high HIV prevalence among MSM is an important factor driving the HIV epidemic in Jamaica. More effective ways need to be found to reduce the high prevalence of HIV among MSM including measures to reduce their social vulnerability, combat stigma and discrimination and empower them to practice safe sex. PMID- 24756606 TI - Specific detection of Vibrio parahaemolyticus by fluorescence quenching immunoassay based on quantum dots. AB - In this study, anti-Vibrio parahaemolyticus polyclonal and monoclonal antibodies were prepared through intradermal injection immune and lymphocyte hybridoma technique respectively. CdTe quantum dots (QDs) were synthesized at pH 9.3, 98 degrees C for 1 h with stabilizer of 2.7:1. The fluorescence intensity was 586.499, and the yield was 62.43%. QD probes were successfully prepared under the optimized conditions of pH 7.4, 37 degrees C for 1 h, 250 MUL of 50 mg/mL EDC . HCl, 150 MUL of 4 mg/mL NHS, buffer system of Na2HPO4-citric acid, and 8 MUL of 2.48 mg/mL polyclonal antibodies. As gold nanoparticles could quench fluorescence of quantum dots, the concentration of V. parahaemolyticus could be detected through measuring the reduction of fluorescence intensity in immune sandwich reaction composed of quantum dot probe, gold-labeled antibody, and the sample. For pure culture, fluorescence intensity of the system was proportional with logarithm concentration of antigen, and the correlation coefficient was 99.764%. The fluorescence quenching immunoassay based on quantum dots is established for the first time to detect Vibrio parahaemolyticus. This method may be used as rapid testing procedure due to its high simplicity and sensitivity. PMID- 24756607 TI - Modeling the kinetics of complex systems: enzymatic hydrolysis of lignocellulosic substrates. AB - Lignocellulosic biomass is mainly composed of cellulose, hemicellulose, and lignin. Fuzzy logic, in turn, is a branch of many-valued logic based on the paradigm of inference under vagueness. This paper presents a methodology, based on computational intelligence, for modeling the kinetics of a complex reactional system. The design of a fuzzy interpolator to model cellulose hydrolysis is reported, within the perspective of applying kinetic models in bioreactor engineering. Experimental data for various types of lignocellulosic materials were used to develop the interpolator. New experimental data from the enzymatic hydrolysis of a synthetic substrate, on the other hand, were used to validate the methodology. The accuracy of the results indicates that this is a promising approach to extend the application of models fitted for specific situations to different cases, thus enhancing their generality. PMID- 24756609 TI - Fluorescent push-pull pH-responsive probes for ratiometric detection of intracellular pH. AB - A family of fluorescent push-pull pH-responsive probes based on 2 dicyanomethylidene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran as a strong electron acceptor group is described. Small structural variations allow obtaining pK(a) ranging from 4.8 to 8.6, underlining the role of the substituent in modulating the acidic properties. Remarkable changes in the optical properties (in particular the fluorescence intensity ratios) were observed as a function of pH. The most interesting probes with pK(a) close to neutrality were used for ratiometric imaging of intracellular pH. PMID- 24756610 TI - Consequences of false-positive screening mammograms. AB - IMPORTANCE: False-positive mammograms, a common occurrence in breast cancer screening programs, represent a potential screening harm that is currently being evaluated by the US Preventive Services Task Force. OBJECTIVE: To measure the effect of false-positive mammograms on quality of life by measuring personal anxiety, health utility, and attitudes toward future screening. DESIGN, SETTING, AND PARTICIPANTS: The Digital Mammographic Imaging Screening Trial (DMIST) quality-of-life substudy telephone survey was performed shortly after screening and 1 year later at 22 DMIST sites and included randomly selected DMIST participants with positive and negative mammograms. EXPOSURE: Mammogram requiring follow-up testing or referral without a cancer diagnosis. MAIN OUTCOMES AND MEASURES: The 6-question short form of the Spielberger State-Trait Anxiety Inventory state scale (STAI-6) and the EuroQol EQ-5D instrument with US scoring. Attitudes toward future screening as measured by women's self-report of future intention to undergo mammographic screening and willingness to travel and stay overnight to undergo a hypothetical new type of mammography that would identify as many cancers with half the false-positive results. RESULTS: Among 1450 eligible women invited to participate, 1226 (84.6%) were enrolled, with follow-up interviews obtained in 1028 (83.8%). Anxiety was significantly higher for women with false-positive mammograms (STAI-6, 35.2 vs 32.7), but health utility scores did not differ and there were no significant differences between groups at 1 year. Future screening intentions differed by group (25.7% vs 14.2% more likely in false-positive vs negative groups); willingness to travel and stay overnight did not (9.9% vs 10.5% in false-positive vs negative groups). Future screening intention was significantly increased among women with false-positive mammograms (odds ratio, 2.12; 95% CI, 1.54-2.93), younger age (2.78; 1.5-5.0), and poorer health (1.63; 1.09-2.43). Women's anticipated high-level anxiety regarding future false-positive mammograms was associated with willingness to travel overnight (odds ratio, 1.94; 95% CI, 1.28-2.95). CONCLUSIONS AND RELEVANCE: False-positive mammograms were associated with increased short-term anxiety but not long-term anxiety, and there was no measurable health utility decrement. False-positive mammograms increased women's intention to undergo future breast cancer screening and did not increase their stated willingness to travel to avoid a false-positive result. Our finding of time-limited harm after false-positive screening mammograms is relevant for clinicians who counsel women on mammographic screening and for screening guideline development groups. PMID- 24756611 TI - Facile synthesis of yolk-shell structured Si-C nanocomposites as anodes for lithium-ion batteries. AB - Yolk-shell structured Si-C nanocomposites are easily synthesized by using a new method based on alkaline etching technology, and exhibit high specific capacity, good cycling stability and rate performance as anodes for lithium-ion batteries. PMID- 24756612 TI - Inflammatory myofibroblastic tumors of the nasal cavity and paranasal sinus: a clinicopathologic study of 25 cases and review of the literature. AB - Inflammatory myofibroblastic tumor (IMT) is rare in nasal cavity and paranasal sinus. The aim of this study was to describe the clinicopathological features of sinonasal IMT and analyze the relationship between the clinicopathological features and the prognosis. A retrospective study of 25 IMT patients between 2001 and 2012 was performed. Data on clinical features, treatment, and follow-up were recorded. The histological characters were observed. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan-Meier method. Clinically, the most common symptoms were nasal obstruction, facial pain, and toothache. Twenty patients received follow-ups 6-120 months after initial diagnosis. Fifteen (75 %) developed recurrence 1 or more times. One patient had left cervical lymph node metastasis (5 %). Five patients died of the tumor (25 %). Histologically, the IMTs composed of bland spindle cells admixed with a prominent infiltrate of plasma cells and lymphocytes and showed obvious atypia in recurrent cases. Histology with necrosis, mitosis (>=1/10 HPF), ganglion-like cells, histological pattern I or II and relapse (>=4 times) was significantly associated with poor OS and EFS. IMT of the nasal cavity and paranasal sinuses exhibits relatively bland histologic appearances, but can shows strongly aggressive behavior and relatively poor outcomes. Multiple relapse, necrosis, frequent mitosis, the presence of ganglion-like cells, and histological pattern might be associated with poor clinical outcomes. PMID- 24756613 TI - The median forehead flap reviewed: a histologic study on vascular anatomy. AB - Local skin flaps can be divided into two types: random flaps and axial flaps. An axial flap is defined as a flap containing a named artery in its pedicle. For the paramedian forehead flap (PMFF) a lot of surgeons insist on the point that the pedicle must contain the supratrochlear artery. To demonstrate that median forehead flaps (MFF) need not contain a named artery, we selected first 8 patients with a PMFF and further 12 patients who had undergone reconstructive surgery using a MFF. After division, we analysed the pedicle of the flap histologically and measured the diameter of the arteries or arterioles and compared them to anatomical descriptions of the frontal arteries. In none of the 12 cases could we find a functional artery of approximately 1 mm in diameter that could correspond to the supratrochlear artery. The MFF is an axial flap but not in accordance with the current definition of this term. In contrast to published literature, we show that only in a part of cases a named artery was present in the pedicle. Despite this fact, the MFF is a secure flap for full thickness defect repair on the nose. PMID- 24756614 TI - Is the grading system of the severity of the OSAHS used presently rational or not?: from the view of incidence of hypertension in different severity groups. AB - The grading system of the severity of obstructive sleep apnea hypopnea syndrome (OSAHS) used presently showed that the severe OSAHS had an extensive range of apnea hypopnea index (AHI) (>= 30, even over 100). So this grading system is not rational. From Jan 1999 to June 2011, there were 2,618 patients complaining of snoring took the polysomnography. The patients were divided into 11 groups according to their AHI. Frequencies of OSAHS with hypertension in each group were tested using crosstabs. The incidence of hypertension was increased as the increasing of AHI. Crosstab analysis showed that there were four cutoff points of AHI (5, 30, 50, 100). There was a significant difference in the incidence of hypertension between the groups of AHI more than the cutoff point and AHI less than the cutoff point. So from the view of hypertension in each group, we recommend that the AHI <5 should be considered as normal or simple snorer, AHI = 5-30 as mild degree of OSAHS, AHI = 30-50 as moderate degree of OSAHS, AHI = 50 100 as severe degree of OSAHS, and AHI >= 100 as profound degree of OSAHS. PMID- 24756615 TI - Salvage surgery for head and neck squamous cell carcinoma. PMID- 24756617 TI - The effect of endoscopic sheaths on visualization in distal chip and fiberoptic laryngoscopy. AB - Endoscopic sheaths covering the laryngoscope are advised to prevent cross contamination, but might hamper visualization as the most important tool in the diagnostic approach of laryngeal disease. We evaluated whether endoscopic sheaths change image quality and diagnostic accuracy of flexible distal chip laryngoscopy (DCL) and flexible fiberoptic laryngoscopy (FOL). Twelve healthy volunteers underwent a flexible laryngoscopy using a distal chip and a fiberoptic laryngoscope with and without endoscopic sheaths, and in this way 48 images were collected. To determine diagnostic accuracy, the 48 images were mixed with images of 40 patients. All images were randomly shown to four experts in the field of laryngology and head and neck oncology. Observers were asked to validate image quality, choose a diagnosis, and express their confidence level of that diagnosis. Image quality was validated better in DCL as compared to FOL (p < 0.05) both with or without endoscopic sheaths. Endoscopic sheaths worsened image quality in DCL (p < 0.05) but not in FOL. No differences were observed between DCL and FOL with or without endoscopic sheaths in diagnostic accuracy (79-89%). Confidence levels (7.7-8.1) were comparable in DCL and FOL and not influenced by endoscopic sheaths. Image quality in DCL is superior to FOL, but significantly hampered by the use of endoscopic sheaths. In FOL the image quality is already low and not further diminished by endoscopic sheaths. PMID- 24756616 TI - Use of cidofovir in HPV patients with recurrent respiratory papillomatosis. AB - Recurrent respiratory papillomatosis is a viral-induced disease, associated with exophytic epithelial lesions affecting the upper airways. Problem of treatment is the high recurrence of papilloma growth after surgical removal; therefore, adjuvant therapy schemes have been established. We used cidofovir, 7.5 mg/ml, in adjuvant therapy in the past years. Out of 31 adult patients treated with the drug, 26 (83.9 %) are at the moment in complete response. 19 (73 % of pts with CR) of those 26 patients were cured with a number of injections between 1 and 4 (mean 2.5). We did not see any clinical manifestation of renal toxicity or neutropenia (superinfection) necessitating a blood test. Six patients presented dysplasia during the treatment with the drug, while six patients had dysplasia prior to cidofovir injection. Due to recurrent nature of the disease and the high number of mechanical and laser surgeries required we treated one tracheal stenosis, two scarred larynx, and two glottic synechiaes. There is still an ongoing discussion within the European Laryngological Society about the effectiveness and possible side effects of this drug. Results show promising long term effects of adjuvant use of cidofovir, without any relevant side effects. PMID- 24756618 TI - Outcome of cochlear implantation in children with cochlear malformation [corrected]. PMID- 24756619 TI - Applying support vector regression analysis on grip force level-related corticomuscular coherence. AB - Voluntary motor performance is the result of cortical commands driving muscle actions. Corticomuscular coherence can be used to examine the functional coupling or communication between human brain and muscles. To investigate the effects of grip force level on corticomuscular coherence in an accessory muscle, this study proposed an expanded support vector regression (ESVR) algorithm to quantify the coherence between electroencephalogram (EEG) from sensorimotor cortex and surface electromyogram (EMG) from brachioradialis in upper limb. A measure called coherence proportion was introduced to compare the corticomuscular coherence in the alpha (7-15Hz), beta (15-30Hz) and gamma (30-45Hz) band at 25 % maximum grip force (MGF) and 75 % MGF. Results show that ESVR could reduce the influence of deflected signals and summarize the overall behavior of multiple coherence curves. Coherence proportion is more sensitive to grip force level than coherence area. The significantly higher corticomuscular coherence occurred in the alpha (p < 0.01) and beta band (p < 0.01) during 75 % MGF, but in the gamma band (p < 0.01) during 25 % MGF. The results suggest that sensorimotor cortex might control the activity of an accessory muscle for hand grip with increased grip intensity by changing functional corticomuscular coupling at certain frequency bands (alpha, beta and gamma bands). PMID- 24756620 TI - Health workers murdered as Pakistan vaccinates 8.4 million children. PMID- 24756621 TI - New legitimacy to concerns about fracking and health. PMID- 24756622 TI - Using military resources to fight disease. PMID- 24756624 TI - Alcohol inhalation. PMID- 24756625 TI - Child abuse and mental disorders in Canada. AB - BACKGROUND: Nationally representative Canadian data on the prevalence of child abuse and its relation with mental disorders are lacking. We used contemporary, nationally representative data to examine the prevalence of 3 types of child abuse (physical abuse, sexual abuse and exposure to intimate partner violence) and their association with 14 mental conditions, including suicidal ideation and suicide attempts. METHODS: We obtained data from the 2012 Canadian Community Health Survey: Mental Health, collected from the 10 provinces. Respondents aged 18 years and older were asked about child abuse and were selected for the study sample (n = 23,395). The survey had a multistage stratified cluster design (household response rate 79.8%). RESULTS: The prevalence of any child abuse was 32% (individual types ranged from 8% to 26%). All types of child abuse were associated with all mental conditions, including suicidal ideation and suicide attempts, after adjustment for sociodemographic variables (adjusted odds ratios ranged from 1.4 to 7.9). We found a dose-response relation, with increasing number of abuse types experienced corresponding with greater odds of mental conditions. Associations between child abuse and attention deficit disorder, suicidal ideation and suicide attempts showed stronger effects for women than men. INTERPRETATION: We found robust associations between child abuse and mental conditions. Health care providers, especially those assessing patients with mental health problems, need to be aware of the relation between specific types of child abuse and certain mental conditions. Success in preventing child abuse could lead to reductions in the prevalence of mental disorders, suicidal ideation and suicide attempts. PMID- 24756626 TI - Progressive thrombocytopenia after cardiac surgery in a 67-year-old man. PMID- 24756628 TI - Federal Wi-Fi safety report is deeply flawed, say experts. PMID- 24756629 TI - Drug therapy for multiple sclerosis. PMID- 24756630 TI - Evaluation of liquid and solid culture media for the recovery and enrichment of Burkholderia cenocepacia from distilled water. AB - Burkholderia cepacia complex (BCC) presence has been the cause of recalls of both sterile and non-sterile pharmaceutical products since these opportunistic pathogens have been implicated to cause infections to susceptible individuals. BCC are ubiquitous in nature, but in pharmaceutical settings the most common source is contaminated water systems. Some strains of BCC, previously described as Pseudomonas cepacia, were not readily detected by standard culture methods. We have explored different strategies to recover and enrich Burkholderia cenocepacia previously cultured in distilled water for 40 days. Enrichment media of varied nutrient concentrations and composition were used, including modified Tryptic Soy Agar or Broth (TSA or TSB), Reasoner's 2nd Agar or Broth (R2A or R2AB), Brain Heart Infusion Broth (BHIB), Mueller-Hinton Broth (MHB), and Ashdown's (ASH) medium. Of the various broth media tested, cell growth was significantly greater in TSB and R2AB than in BHIB, MHB, or ASH broth. TSB and R2AB were also compared for their recovery efficiency. Generally, there was no significant difference between the numbers of B. cenocepacia grown on 15 differently modified TSA and five modified R2A solid media. Overall, however, diluted TSA and TSB media, and R2A and R2AB showed better recovery efficiency than TSA and TSB for inocula containing small numbers of cells. All strains persisted in distilled water for 40 days. Broth media were more effective than solid media for recovery of B. cenocepacia from distilled water. These results may assist in improving detection assays with recovery and enrichment strategies to maximize recovery of these fastidious organisms. PMID- 24756631 TI - Tuber aestivum association with non-host roots. AB - Mycorrhizal fungi provide direct and functional interconnection of soil environment with their host plant roots. Colonization of non-host plants have occasionally been described, but its intensity and functional significance in complex plant communities remain generally unknown. Here, the abundance of ectomycorrhizal fungus Tuber aestivum was measured in the roots of host and non host (non-ectomycorrhizal) plants in a naturally occurring T. aestivum colony using a quantitative PCR approach. The roots of non-host plant species found inside the brule area were extensively colonized by T. aestivum mycelium, although the levels were significantly lower than those found in host Carpinus betulus roots. However, fungal biomass concentration in the non-host roots was one to two orders of magnitude higher than that in the surrounding soil. This indicates existence of an important biotic interaction between T. aestivum mycelium and the non-host, mostly herbaceous plants. Roots, either host or non host, thus probably constitute hot spots of T. aestivum activity in the soil ecosystem with as yet uncovered functional significance. PMID- 24756632 TI - Carbon and nitrogen fluxes between beech and their ectomycorrhizal assemblage. AB - To determine the exchange of nitrogen and carbon between ectomycorrhiza and host plant, young beech (Fagus sylvatica) trees from natural regeneration in intact soil cores were labelled for one growing season in a greenhouse with (13)CO2 and (15)NO3 (15)NH4. The specific enrichments of (15)N and (13)C were higher in ectomycorrhizas (EMs) than in any other tissue. The enrichments of (13)C and (15)N were also higher in the fine-root segments directly connected with the EM (mainly second-order roots) than that in bulk fine or coarse roots. A strict, positive correlation was found between the specific (15)N enrichment in EM and the attached second-order roots. This finding indicates that strong N accumulators provide more N to their host than low N accumulators. A significant correlation was also found for the specific (13)C enrichment in EM and the attached second-order roots. However, the specific enrichments for (15)N and (13)C in EM were unrelated showing that under long-term conditions, C and N exchange between host and EMs are uncoupled. These findings suggest that EM mediated N flux to the plant is not the main control on carbon flux to the fungus, probably because EMs provide many different services to their hosts in addition to N provision in their natural assemblages. PMID- 24756633 TI - Deoxydehydration of polyols. AB - The development of sustainable chemical processes for the conversion of highly oxygenated biomass feedstocks to chemical products requires efficient and selective processes for partial oxygen removal and refunctionalization. Here we review the development of the deoxydehydration (DODH) reaction, which converts vicinal diols (glycols) to olefins. Uncatalyzed deoxygenative eliminations were first established. The catalyzed DODH reactions have largely employed oxo-rhenium catalysts and a variety of reductants, including PR3, dihydrogen, sulfite, and alcohols. A variety of glycol and biomass-derived polyol substrates undergo the DODH reaction in moderate to good efficiency, regioselectively, and stereoselectively. Observations regarding selectivity, mechanistic probes, and computational studies support the general operation of a catalytic process involving three basic stages: glycol condensation to an M-glycolate, reduction of the oxo-metal, glycol condensation to produce a metal-glycolate, and alkene extrusion from the reduced metal-glycolate. Recent practical developments include the discovery of non-precious V- and Mo-oxo DODH catalysis. PMID- 24756634 TI - Transition metal-catalyzed C-C bond activation of four-membered cyclic ketones. AB - With the advent of new synthetic methodologies, carbon-carbon bond (C-C) activation strategies have uncovered not only new fundamental reactivity but also the potential for use as a highly efficient synthetic protocol. This chapter specifically discusses the use of four-membered ketone-based starting materials for C-C activation initiated transformations using a variety of transition metals. The two major modes of activation, oxidative addition and beta-C elimination, are presented as each pathway shows different mechanistic details and the ability to effect several types of reactions. Applications to the synthesis of complex molecules are presented and perspectives on future applications are considered. PMID- 24756635 TI - Cortical HCN channels: function, trafficking and plasticity. AB - The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated potassium ion channels. They are, however, activated by hyperpolarizing potentials and are permeable to cations. Four HCN subunits have been cloned, of which HCN1 and HCN2 subunits are predominantly expressed in the cortex. These subunits are principally located in pyramidal cell dendrites, although they are also found at lower concentrations in the somata of pyramidal neurons as well as other neuron subtypes. HCN channels are actively trafficked to dendrites by binding to the chaperone protein TRIP8b. Somato dendritic HCN channels in pyramidal neurons modulate spike firing and synaptic potential integration by influencing the membrane resistance and resting membrane potential. Intriguingly, HCN channels are present in certain cortical axons and synaptic terminals too. Here, they regulate synaptic transmission but the underlying mechanisms appear to vary considerably amongst different synaptic terminals. In conclusion, HCN channels are expressed in multiple neuronal subcellular compartments in the cortex, where they have a diverse and complex effect on neuronal excitability. PMID- 24756636 TI - Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology. AB - Neuronal nitric oxide synthase (nNOS or NOS1) is the major endogenous source of myocardial nitric oxide (NO), which facilitates cardiac relaxation and modulates contraction. In the healthy heart it regulates intracellular Ca(2+), signalling pathways and oxidative homeostasis and is upregulated from early phases upon pathogenic insult. nNOS plays pivotal roles in protecting the myocardium from increased oxidative stress, systolic/diastolic dysfunction, adverse structural remodelling and arrhythmias in the failing heart. Here, we show that the downstream target proteins of nNOS and underlying post-transcriptional modifications are shifted during disease progression from Ca(2+)-handling proteins [e.g. PKA-dependent phospholamban phosphorylation (PLN-Ser(16))] in the healthy heart to cGMP/PKG-dependent PLN-Ser(16) with acute angiotensin II (Ang II) treatment. In early hypertension, nNOS-derived NO is involved in increases of cGMP/PKG-dependent troponin I (TnI-Ser(23/24)) and cardiac myosin binding protein C (cMBP-C-Ser(273)). However, nNOS-derived NO is shown to increase S nitrosylation of various Ca(2+)-handling proteins in failing myocardium. The spatial compartmentation of nNOS and its translocation for diverse binding partners in the diseased heart or various nNOS splicing variants and regulation in response to pathological stress may be responsible for varied underlying mechanisms and functions. In this review, we endeavour to outline recent advances in knowledge of the molecular mechanisms mediating the functions of nNOS in the myocardium in both normal and diseased hearts. Insights into nNOS gene regulation in various tissues are discussed. Overall, nNOS is an important cardiac protector in the diseased heart. The dynamic localization and various mediating mechanisms of nNOS ensure that it is able to regulate functions effectively in the heart under stress. PMID- 24756637 TI - Autonomic neural control of heart rate during dynamic exercise: revisited. AB - The accepted model of autonomic control of heart rate (HR) during dynamic exercise indicates that the initial increase is entirely attributable to the withdrawal of parasympathetic nervous system (PSNS) activity and that subsequent increases in HR are entirely attributable to increases in cardiac sympathetic activity. In the present review, we sought to re-evaluate the model of autonomic neural control of HR in humans during progressive increases in dynamic exercise workload. We analysed data from both new and previously published studies involving baroreflex stimulation and pharmacological blockade of the autonomic nervous system. Results indicate that the PSNS remains functionally active throughout exercise and that increases in HR from rest to maximal exercise result from an increasing workload-related transition from a 4 : 1 vagal-sympathetic balance to a 4 : 1 sympatho-vagal balance. Furthermore, the beat-to-beat autonomic reflex control of HR was found to be dependent on the ability of the PSNS to modulate the HR as it was progressively restrained by increasing workload related sympathetic nerve activity. IN CONCLUSION: (i) increases in exercise workload-related HR are not caused by a total withdrawal of the PSNS followed by an increase in sympathetic tone; (ii) reciprocal antagonism is key to the transition from vagal to sympathetic dominance, and (iii) resetting of the arterial baroreflex causes immediate exercise-onset reflexive increases in HR, which are parasympathetically mediated, followed by slower increases in sympathetic tone as workloads are increased. PMID- 24756638 TI - Wave reflections in the pulmonary arteries analysed with the reservoir-wave model. AB - Conventional haemodynamic analysis of pressure and flow in the pulmonary circulation yields incident and reflected waves throughout the cardiac cycle, even during diastole. The reservoir-wave model provides an alternative haemodynamic analysis consistent with minimal wave activity during diastole. Pressure and flow in the main pulmonary artery were measured in anaesthetized dogs and the effects of hypoxia and nitric oxide, volume loading and positive end expiratory pressure were observed. The reservoir-wave model was used to determine the reservoir contribution to pressure and flow and once subtracted, resulted in 'excess' quantities, which were treated as wave-related. Wave intensity analysis quantified the contributions of waves originating upstream (forward-going waves) and downstream (backward-going waves). In the pulmonary artery, negative reflections of incident waves created by the right ventricle were observed. Overall, the distance from the pulmonary artery valve to this reflection site was calculated to be 5.7 +/- 0.2 cm. During 100% O2 ventilation, the strength of these reflections increased 10% with volume loading and decreased 4% with 10 cmH2O positive end-expiratory pressure. In the pulmonary arterial circulation, negative reflections arise from the junction of lobar arteries from the left and right pulmonary arteries. This mechanism serves to reduce peak systolic pressure, while increasing blood flow. PMID- 24756639 TI - The role of hydrogen sulphide in the control of breathing in hypoxic zebrafish (Danio rerio). AB - The current study investigated the role of hydrogen sulphide (H2S) in oxygen sensing, intracellular signalling and promotion of ventilatory responses to hypoxia in adult and larval zebrafish (Danio rerio). Both larval and adult zebrafish exhibited a dose-dependent increase in ventilation to sodium sulphide (Na2S), an H2S donor. In vertebrates, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE) are enzymes that catalyse the endogenous production of H2S. In adult zebrafish, inhibition of both CBS and CSE with aminooxyacetate (AOA) and propargyl glycine (PPG) blunted or abolished the hypoxic hyperventilation, and the addition of Na2S to the water partially rescued the effects of inhibiting endogenous H2S production. In zebrafish larvae (4 days post-fertilization), gene knockdown of either CBS or CSE using morpholinos attenuated the hypoxic ventilatory response. Furthermore, the intracellular calcium concentration of isolated neuroepithelial cells (NECs), which are putative oxygen chemoreceptors, increased significantly when these cells were exposed to 50 MUm Na2S, supporting a role for H2S in Ca(2+)-evoked neurotransmitter release in these cells. Finally, immunohistochemical labelling showed that NECs dissociated from adult gill contained CBS and CSE, whereas cutaneous NECs in larval zebrafish expressed only CSE. Taken together, these data show that H2S can be produced in the putative oxygen-sensing cells of zebrafish, the NECs, in which it appears to play a pivotal role in promoting the hypoxic ventilatory response. PMID- 24756640 TI - A novel short-term plasticity of intrinsic excitability in the hippocampal CA1 pyramidal cells. AB - Changes in neuronal activity often trigger compensatory mechanisms aimed at regulating network activity homeostatically. Here we have identified and characterized a novel form of compensatory short-term plasticity of membrane excitability, which develops early after the eye-opening period in rats (P16-19 days) but not before that developmental stage (P9-12 days old). Holding the membrane potential of CA1 neurons right below the firing threshold from 15 s to several minutes induced a potentiation of the repolarizing phase of the action potentials that contributed to a decrease in the firing rate of CA1 pyramidal neurons in vitro. Furthermore, the mechanism for inducing this plasticity required the action of intracellular Ca(2+) entering through T-type Ca(2+) channels. This increase in Ca(2+) subsequently activated the Ca(2+) sensor K(+) channel interacting protein 3, which led to the increase of an A-type K(+) current. These results suggest that Ca(2+) modulation of somatic A-current represents a new form of homeostatic regulation that provides CA1 pyramidal neurons with the ability to preserve their firing abilities in response to membrane potential variations on a scale from tens of seconds to several minutes. PMID- 24756642 TI - Balance between the proximal dendritic compartment and the soma determines spontaneous firing rate in midbrain dopamine neurons. AB - Midbrain dopamine (DA) neurons are slow intrinsic pacemakers that require the elaborate composition of many ion channels in the somatodendritic compartments. Understanding the major determinants of the spontaneous firing rate (SFR) of midbrain DA neurons is important because they determine the basal DA levels in target areas, including the striatum. As spontaneous firing occurs synchronously at the soma and dendrites, the electrical coupling between the soma and dendritic compartments has been regarded as a key determinant for the SFR. However, it is not known whether this somatodendritic coupling is served by the whole dendritic compartments or only parts of them. In the rat substantia nigra pars compacta (SNc) DA neurons, we demonstrate that the balance between the proximal dendritic compartment and the soma determines the SFR. Isolated SNc DA neurons showed a wide range of soma size and a variable number of primary dendrites but preserved a quite consistent SFR. The SFR was not correlated with soma size or with the number of primary dendrites, but it was strongly correlated with the area ratios of the proximal dendritic compartments to the somatic compartment. Tetrodotoxin puff and local Ca(2+) perturbation experiments, computer simulation, and local glutamate uncaging experiments suggest the importance of the proximal dendritic compartments in pacemaker activity. These data indicate that the proximal dendritic compartments, not the whole dendritic compartments, play a key role in the somatodendritic balance that determines the SFR in DA neurons. PMID- 24756641 TI - The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? AB - The gut-brain axis is the bidirectional communication between the gut and the brain, which occurs through multiple pathways that include hormonal, neural and immune mediators. The signals along this axis can originate in the gut, the brain or both, with the objective of maintaining normal gut function and appropriate behaviour. In recent years, the study of gut microbiota has become one of the most important areas in biomedical research. Attention has focused on the role of gut microbiota in determining normal gut physiology and immunity and, more recently, on its role as modulator of host behaviour ('microbiota-gut-brain axis'). We therefore review the literature on the role of gut microbiota in gut homeostasis and link it with mechanisms that could influence behaviour. We discuss the association of dysbiosis with disease, with particular focus on functional bowel disorders and their relationship to psychological stress. This is of particular interest because exposure to stressors has long been known to increase susceptibility to and severity of gastrointestinal diseases. PMID- 24756644 TI - UHRF1 depletion suppresses growth of gallbladder cancer cells through induction of apoptosis and cell cycle arrest. AB - Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1), overexpressed in various human malignancies, functions as an important regulator in cell proliferation and epigenetic regulation. Depletion of UHRF1 has shown potential antitumor activities in several types of cancer. However, the role of UHRF1 in gallbladder cancer (GBC) has not been investigated. RT-PCR, western blotting and immunohistochemistry were performed to examine UHRF1 expression at mRNA and protein levels in GBC tissues and cell lines. UHRF1 siRNA and UHRF1 shRNA were used to deplete the expression of UHRF1. The results showed that UHRF1 was overexpressed in GBC and its expression correlated with advanced TNM stage and presence of lymph node metastasis. UHRF1 depletion in GBC-SD and NOZ cells markedly inhibited proliferation, migration in vitro and the ability of these cells to form tumors in vivo. UHRF1 depletion upregulated the expression of PML and triggered extrinsic and intrinsic apoptotic pathways by promoting the expression of FasL/FADD, bax, cytosolic cytochrome c, cleaved caspase-8, -9 and 3 and cleaved PRAP and by suppressing bcl-2 expression in GBC-SD and NOZ cells. In addition, UHRF1 depletion induced cell cycle arrest at G1/S transition by inducing p21 in a p53-independent manner in GBC-SD and NOZ cells. Our findings suggest that UHRF1 is involved in the proliferation and migration of GBC cells and may serve as a biomarker or even a therapeutic target for GBC. PMID- 24756643 TI - Maternal alcohol consumption in pregnancy enhances arterial stiffness and alters vasodilator function that varies between vascular beds in fetal sheep. AB - While the impact of alcohol consumption by pregnant women on fetal neurodevelopment has received much attention, the effects on the cardiovascular system are not well understood. We hypothesised that repeated exposure to alcohol (ethanol) in utero would alter fetal arterial reactivity and wall stiffness, key mechanisms leading to cardiovascular disease in adulthood. Ethanol (0.75 g (kg body weight)(-1)) was infused intravenously into ewes over 1 h daily for 39 days in late pregnancy (days 95-133 of pregnancy, term ~147 days). Maternal and fetal plasma ethanol concentrations at the end of the hour were ~115 mg dl(-1), and then declined to apparent zero over 8 h. At necropsy (day 134), fetal body weight and fetal brain-body weight ratio were not affected by alcohol infusion. Small arteries (250-300 MUm outside diameter) from coronary, renal, mesenteric, femoral (psoas) and cerebral beds were isolated. Endothelium-dependent vasodilatation sensitivity was reduced 10-fold in coronary resistance arteries, associated with a reduction in endothelial nitric oxide synthase mRNA (P = 0.008). Conversely, vasodilatation sensitivity was enhanced 10-fold in mesenteric and renal resistance arteries. Arterial stiffness was markedly increased (P = 0.0001) in all five vascular beds associated with an increase in elastic modulus and, in cerebral vessels, with an increase in collagen Ialpha mRNA. Thus, we show for the first time that fetal arteries undergo marked and regionally variable adaptations as a consequence of repeated alcohol exposure. These alcohol-induced vascular effects occurred in the apparent absence of fetal physical abnormalities or fetal growth restriction. PMID- 24756645 TI - Iron deficiency without anemia is associated with anger and fatigue in young Japanese women. AB - Iron deficiency without anemia (IDNA), the most prevalent nutritional deficiency worldwide, affects young women of reproductive age. This study aimed to elucidate the relationship between IDNA and mental and somatic symptoms including anger and fatigue using the Japanese version of the Cornell Medical Index Health Questionnaire (CMI-J). Data regarding demographic characteristics, anthropometry, hematological, and biochemical indices of the iron status, frequencies of selected food intakes assessed by self-administered food frequency questionnaires (FFQs), frequencies of nonspecific symptoms, and grades of neurotic tendencies assessed by CMI-J were collected from 76 young women aged 18-22 years living in the metropolitan area of Tokyo, Japan. The subjects were classified as having IDNA (hemoglobin (Hb)>=12 g/dL and serum ferritin<20 ng/mL; n=29), having iron deficiency anemia (IDA) (Hb<12 g/dL and serum ferritin<20 ng/mL; n=10), or having a normal iron status (Hb>=12 g/dL and serum ferritin>=20 ng/mL; n=36). One subject was excluded from the analyses because of Hb<12 g/dL and serum ferritin>=20 ng/mL. Fisher's protected least significant difference and the Dwass Steel-Chritchlow-Fligner multiple comparison tests were used to compare the data of the three groups. P values<0.05 were considered significant. Sections M-R (mental complaints) were significantly higher in the IDNA subjects than in the normal subjects. No significant difference in CMI scores was found between the normal and IDA subjects. Sections I (fatigability), Q (anger), and R (tension) were significantly higher in the IDNA subjects than in the normal subjects, regardless of no significant differences between the normal and IDA subjects in those sections. Young women with IDNA demonstrated a significantly higher proportion of neurotic tendencies (grades II-IV). The intake frequency score of canned or bottled green tea fortified with vitamin C was significantly higher in the IDNA subjects than the IDA subjects. The findings suggest that IDNA may be a risk factor for anger, fatigue, and tension in women of childbearing age. PMID- 24756646 TI - Effects of supplemental copper on the serum lipid profile, meat quality, and carcass composition of goat kids. AB - To evaluate the effects of copper (Cu) supplementation on the serum lipid profile, meat quality, and carcass composition of goat kids, thirty-five 3-4 month-old Jian Yang big-eared goat kids (BW 20.3+/-0.6 kg) were randomly assigned to one of seven dietary Cu treatments (n=5/treatment). The dietary Cu concentrations were: (1) control (no supplemental Cu), (2) 20 mg, (3) 40 mg, (4) 80 mg, (5) 160 mg, (6) 320 mg, and (7) 640 mg of supplemental Cu/kg dry matter (DM). Copper was supplemented as CuSO4.5H2O (25.2 % Cu). The goats were fed a high-concentrate basal diet with the different concentrations of supplemental Cu/kg DM for 96 days. The serum lipid profile was determined on day 51 and day 96. Meat quality and carcass composition of longissimus dorsi muscle were measured after the goats were slaughtered at 96 days. Serum total cholesterol, triglycerides, high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) were not affected by treatment (P>0.18). No differences were observed in drip loss, cooking loss, a* (redness/greenness) and b* (yellowness/blueness) values (P>0.17); however, the 24-h pH value (linear; P=0.0009) and L* (brightness) value (linear; P=0.0128) decreased, and shear force increased (linear; P=0.0005) as Cu supplementation increased. The intramuscular fat (%) increased (linear; P=0.001) as supplemental Cu increased. No differences (P>0.21) in the moisture, crude protein, and ash (%) were observed. Results of this study indicate that supplemental Cu does not modify the serum lipid profile; however, it can impact intramuscular fat content and the meat quality of goat kids. PMID- 24756647 TI - Personality disorders. PMID- 24756648 TI - A view of personality disorder from the colonial periphery. AB - OBJECTIVE: To examine the history of personality disorder in the context of contemporary post-colonial Jamaican society. METHODS: The literature outlining the development and classification of personality disorder is reviewed. The social, psychiatric and epidemiological studies of personality disorder in Jamaica are presented. RESULTS: A categorical classification system of personality disorder has been in use by the International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual of Mental Disorders (DSM) from the mid 20th century. Challenging that approach is the Minnesota Multiphasic Personality Inventory (MMPI), which represents the dimensional method, which views pathology as a continuum from normal personality traits. Both systems suffer from an absence of cultural flexibility, an absence of a a system of severity, and a lack of treatment specificity, which foster misdiagnosis while making treatment planning difficult and unreliable. The proposed DSM-5 attempts to integrate a prototypematching system and identification of personality traits promises disappointing outcomes. The University of the West Indies, Section of Psychiatry, proposes a phenomenological nosological approach, advocating an alternate DSM Axis I category called Shakatani derived from Swahili shaka (problem), tani (power), and developing a 38-item Jamaica Personality Disorder Inventory (JPDI) screening questionnaire for diagnosing this condition. The epidemiological results using this instrument are reviewed, and the Jamaican print, broadcast and social media responses to this research in Jamaica are described. CONCLUSIONS: The heritage of slavery and colonial oppression in Jamaica has resulted in maladaptive personality disorders that have led to extremely high rates of homicide, violence and transgressive behaviour. PMID- 24756649 TI - The creation and validation of the Jamaica Personality Disorder Inventory. AB - OBJECTIVE: To describe the creation and validation of the Jamaica Personality Disorder Inventory (JPDI) screening questionnaire. METHOD: Using the phenomenological triad of power management, dependency and psychosexual issues, drafts of the JPDI were piloted on patients from psychiatric and medical wards. The JPDI consisted of 38 close-ended, yes/no questions. Validation was conducted in a sample of 200 patients, using the International Personality Disorder Examination-Screening Instrument (IPDE-S), the Brief Screen for Depression and consultant psychiatrists' Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) personality disorder interview. Construct validity was assessed through principal component factor analysis; Spearman correlation was used to assess criterion-related and discriminant validity; Cronbach's alpha was used to assess reliability of the entire scale as well as the resulting factors. The Multitrait Multimethod Matrix (MTMM) was used to assess discriminant and construct validity. RESULTS: Factor analysis revealed eight clusters consisting of 30 of the 38 questions, which had close congruence with the clinical triad. Cronbach's alpha for the entire scale was alpha = 0.79, ranging from a high 0.70 to 0.82 to low 0.63 to 0.45. The JPDI exhibited a sensitivity of 95.06% and a specificity of 67.71%. Significant correlation of scores for the JPDI and IPDE-S (r = 0.432, p = 0.000) and the JPDI and the DSM IV-TR diagnosis (r = 0.598, p = 0.000) established concurrent validity for the JPDI. Correlations (r = 0.293, p = 0.000) suggested that the JPDI possessed predictive validity. The complete sample matrix of the MTMM provided evidence of both convergent and discriminant validity, and thereby, construct validity. CONCLUSION: The JPDI demonstrated reliability, and criterion-related and discriminant validity. PMID- 24756650 TI - Shakatani: the phenomenology of personality disorder in Jamaican patients. AB - OBJECTIVE: To examine the distribution and clinically significant patterns of the phenomenology of a cohort of Jamaican patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM) Axis II diagnosis of personality disorder and to clarify the conventional diagnostic deficiencies of DSM-based personality disorder categories. METHODS: In a case-control study from the naturalistic clinical setting of a private psychiatric practice in Kingston, Jamaica, between 1974 and 2007, the phenomenology of a cohort of 351 patients with an Axis II DSM diagnosis of personality disorder is qualitatively described and quantitatively compared with that of a control group of patients with an Axis I DSM clinical diagnosis, matched for age, gender and socio-economic class. RESULTS: There were 166 males (47.3%); 238 (67.8%) of the patients were between age 18 and 39 years. Ethnically, 325 (92.6%) were Black, 10 (2.8%) White and 16 (4.6%) Other. The majority of patients (20.7%) had a DSM-IV diagnosis of dependent personality disorder. Patients with an Axis II diagnosis were significantly more likely to display symptoms of a 'clinical triad' of power management, dependency and psychosexual issues. Qualitative analysis of the phenomenological symptoms of personality disorder diagnosed patients suggests aetiological interconnections based on early childhood experiences as explained by object relations and attachment theories. CONCLUSIONS: The phenomenological approach to personality disorder may be a viable replacement for the four-cluster classification of DSM IV in a Jamaican population with the clinical triad called Shakatani, derived from the Swahili words shaka (problem) and tani (power). This phenomenological approach may provide more clinical utility to practitioners. PMID- 24756651 TI - Correlates of conflict, power and authority management, aggression and impulse control in the Jamaican population. AB - OBJECTIVE: The object of this study is to establish the correlates of the phenomenology of conflict and power management in the Jamaican population. METHODS: A total of 1506 adult individuals were sampled from 2150 households using a stratified sampling method and assessed using the 12 questions of the Jamaica Personality Disorder Inventory (JPDI) on the phenomenology of conflict and power management that are grouped into the psychological features of aggressive social behaviour, unlawful behaviour, socially unacceptable behaviour and financial transgressive behaviour. The database of responses to the demographic and JPDI questionnaires was created and analysed using the Statistical Package for the Social Sciences (SPSS) version 17. RESULTS: Of the national population sampled, 69.1% denied having any phenomenological symptoms of abnormal power management relations while 30.9% of the population admitted to having some degree of conflict and power management, ranging from mild (10.3%), to moderate (17.1), or severe (3.5%). There were 46.55% of the population which had problems with aggressive social behaviour, 9.33% had problems with unlawful behaviour, 9.58% had problems with unacceptable social behaviour and 37.74% had problems with financial transgressive behaviour. Significant gender and socio economic class patterns for conflict and power management were revealed. This pattern of conflict and power management behaviour is critical in understanding the distinction between normal and abnormal expression of these emotions and actions. CONCLUSION: Nearly one-third of the sample population ' studied reported problems with conflict, abnormal power and authority management, impulse control and serious aggressive and transgressive behaviour. PMID- 24756652 TI - The psychological correlates of dependency in the Jamaican population. AB - OBJECTIVE: To establish the prevalence of psychological dependency in the Jamaican society in order to examine the relationship between the psychological correlates of dependency and socio-political dependency in this post-colonial country. METHODS: A total of 1506 adult individuals were sampled from 2150 households using a stratified sampling method and assessed using the 17 questions of the Jamaica Personality Disorder Inventory (JPDI) on the phenomenology of dependency that are grouped into the psychological features of physiological dependency, financial dependency, and psychological dependency. The database of responses to the demographic and JPDI questionnaires was created and analysed using the Statistical Package for the Social Sciences (SPSS) version 17. RESULTS: Of the national population sampled, 77.1% denied having any of these phenomenological symptoms of dependence while 22.63% of the population admitted to having some phenomenology of dependency, ranging from mild (5.6%), to moderate (12.1), or severe (4.9%). Substance use (physiological dependency) responders accounted for 21.23%, financial dependency responders for 43.45%, and psychological dependency responders for 15.96%. Significant gender and socio economic class patterns of dependency were revealed. This substantial swathe of the Jamaican population acknowledged their own dependency and behavioural withdrawal response to physical or emotional loss in their life, and reported having dependency problems in managing their financial and monetary affairs. CONCLUSIONS: Three-quarters of the Jamaican responders of this survey ostensibly are free of the phenomenology of dependency while a more vulnerable one-quarter has insight that they are still locked in a struggle for psychological independence. The political and economic relations between psychological dependency and socio-political dependency are discussed. PMID- 24756653 TI - Correlates of psychosexual issues in the Jamaican population. AB - OBJECTIVE: To examine the relationship between the psychopathological correlates of psychosexual phenomena in post-colonial Jamaica. METHODS: A total of 1506 adult individuals were sampled from 2150 households using a stratified sampling method and assessed with the Jamaica Personality Disorder Inventory (JPDI). Responses to the seven questions on the psychological features of homosexual practices, sexual practices and dysfunction were tabulated and analysed using the Statistical Package for the Social Sciences (SPSS) version 17. RESULTS: Of the sample, 79.38% denied having phenomenological symptoms of psychosexual phenomena while 20.33% of the population admitted to having some degree of heterosexual and homosexual phenomena, ranging from mild (5.13%), to moderate (11.40), or severe (3.80%). Sixteen (1.06%) responders described homosexual practices in their lives, and 53 (3.52%) described thinking frequently about homosexual experiences in their subjective psychic lives. Significantly more (p > 0.001) male responders (348, 23.11%) had difficulty being sexually faithful to one person at a time than females (122, 8.10%). The lower class cohort members (348, 23.11%) were more likely to have had multiple sexual relationships over the previous 12 months than socio-economic class (SEC) 1-3 responders (54, 3.58%) and were more likely (681, 45.21%) to fantasize about sexual relationships with persons other than their partners (p < 0.001) than SEC 1-3 responders (94, 6.24%). CONCLUSION: Significant levels of multiple sexual partnerships and feelings of infidelity in a swathe of Jamaican people reveal underlying psychosexual anxiety and guilt, poor impulse control and difficulties with partner intimacy. This psychopathology is correlated to concomitant high-risk public health sexual behaviour such as teenage pregnancy, sexually transmitted diseases (STDs) and HIV/AIDS existing in the Jamaican society. PMID- 24756654 TI - Interpersonal competence and sex risk behaviours among Jamaican adolescents. AB - OBJECTIVE: Of particular public health concern to the Jamaican authorities is the consistently high numbers of new HIV infections among adolescents and young adults. The thrust in HIV/AIDS prevention campaigns has largely been toward an increase in knowledge and attitudes as opposed to personality variables. However, it is widely believed that persons with high interpersonal skills may be less likely to engage in sex risk behaviours. This study investigated interpersonal competence as a personality characteristic associated with sexual risk-taking among Jamaican adolescents. METHODS: A cross-sectional survey of 500 adolescents, ages 13-18 years (250 males and 250 females) from nine randomly selected secondary government schools within Kingston and St Andrew was used. The sample ensured maximum variation in age groups. The BarOn EQ-i:YV(S) was utilized to provide a measure of interpersonal competence and the Sex Risk Scale from the Adolescent Risk Inventory acted as a measure of sex risk behaviours. The Spearman's rho correlational statistic was used to investigate the hypothesis. RESULTS: Of the students surveyed, 58.6% reported that they were sexually active; 31.8% reported having multiple sexual partners and 28.2% reporting inconsistent condom use. A significant, inverse relationship was observed between interpersonal competence and sex risk behaviours (p < 0.05). CONCLUSION: This research provided evidence that adolescents with high interpersonal skills are less likely to participate in risky sexual behaviours. Therefore, interventions aimed at reducing risky adolescent sexual practices might benefit from the inclusion of strategies to build interpersonal skills. PMID- 24756655 TI - Studying personality and personality disorders among people in the Caribbean: advocating for an emic-etic approach. AB - This article discusses issues relevant to the examination of personality and personality disorder in contexts, such as the Caribbean, which are under represented in this scholarship. The article argues that because normal personality is the standard against which definitions of non-normality (and at the extreme, disorder) are derived, a crucial first step in identifying personality disorder is clear and culturally relevant definitions of normal personality. Two key conceptual perspectives on personality development and manifestation are presented, followed by a brief exploration, using the etic traits approach, of the problematic nature of any one perspective on normal personality. The article argues for the need for combined emic-etic approaches to understanding normal and non-normal personality, particularly in under represented contexts such as the Caribbean. It ends by offering concrete suggestions on developing, in the Caribbean, programmes of research committed to these tasks. PMID- 24756656 TI - The treatment of personality disorder in Jamaica with psychohistoriographic brief psychotherapy. AB - OBJECTIVE: To assess the clinical outcome of patients with personality disorder, receiving treatment with psychohistoriographic brief psychotherapy (PBP). METHOD: Patients seen in the author's private practice from 1974-2010 with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV TR) personality disorder diagnosis were treated with PBP. Demographic, clinical responses and one-year clinical outcome measures were disaggregated and analysed, using SPSS, version 17. RESULTS: One hundred patients completed treatment with PBP, male:female 34:64; mean age of 35.86 +/- 10.28 (range 16 - 66) years. Forty five per cent were married, 73% were of predominantly African racial origin, with 59% from socio-economic class (SEC) I and 39% from SEC II and III. The presenting complaints were interpersonal conflict (35%), anxiety (21%) and depressed mood (20%). Major depression (30%), substance abuse disorder (18%) and generalized anxiety disorder (13%) were the most common Axis I diagnoses. Histrionic personality disorder (39%) and avoidant personality disorder (35%) were the main Axis II diagnoses. Psychohistoriography was completed with all patients, and charted by 96%. Transference variants were experienced by all patients and worked through with 87%. The quadranting process was completed by 42% with goal setting instituted by 96% and actualization scoring fully completed by 34%. A continuous exercise programme was instituted by all patients, and was maintained by 56% at one-year follow-up. Ninety-four per cent reported fair (10%), good (68%) to very good/excellent (16%) improvement on completion of PBP, with 72% assessed as maintaining fair to good clinical improvement by the therapist at one-year follow up. CONCLUSION: Patients with personality disorders showed clinical improvement one year after being treated with psychohistoriographic brief psychotherapy. PMID- 24756657 TI - Are Jamaicans really that stigmatizing? A comparison of mental health help seeking attitudes. AB - Research suggests that there is a high level of stigma surrounding mental illness in the English-speaking Caribbean, limited knowledge about aetiology and scepticism about the effectiveness of treatment. Further, in spite of experiencing symptoms of distress, a growing body of literature has suggested that Caribbean nationals hold negative attitudes toward seeking professional psychological help. It has been suggested that these attitudes may be even more negative than for other populations. This paper presents the results of two studies which sought to examine this assumption. It was hypothesized that Jamaicans would hold more negative attitudes toward seeking professional mental health services than samples from other populations. Data regarding attitudes toward seeking professional psychological help were collected from 339 Jamaican adolescents. In study 1, a review of the literature was conducted. Three published studies that utilized the same measure of help-seeking attitudes, had a sample similar in age, and published their sample size, means and standard deviations, which were compared to the Jamaican sample. In study 2, data from the Jamaican sample were compared to a sample of African-American adolescents (n = 81). Results did not support the hypothesis. Jamaicans were generally found to be either similar or more positive in their attitudes toward seeking professional psychological help. These encouraging results are discussed. Suggestions for improving education and reducing mental health stigma are presented. PMID- 24756658 TI - Prevalence and correlates of personality disorder in the Jamaican population. AB - OBJECTIVE: To identify the prevalence and correlates of personality disorder in a representative sample of the Jamaican population using the Jamaica Personality Disorder Inventory (JPDI). METHOD: A four-stage stratified random sampling method was used to obtain a representative population sample consisting of 1506 Jamaicans, M:F = 727 (48.3%):779 (51.7%), ages 18-64 years. A demographic questionnaire and the JPDI were administered to all participants. RESULTS: Two fifths of the population (41.4%) scored above the scale's cut-point indicating a diagnosis of personality disorder with the level of severity ranging from mild to severe. Persons with personality disorder were significantly more likely to be single (63%), male (60%), between the ages 18 and 44 years (77%) and of a lower socio-economic status (65%) (p < 0.50 to p < 0.001). CONCLUSION: This is the only population study of personality disorder recorded in the English-speaking Caribbean. This suggests a high risk of behavioural dysfunction in the Jamaican population, having significant implications in light of the country's high rate of crime and violence. The findings highlight the need to develop effective and targeted prevention and intervention measures. PMID- 24756659 TI - Media representation of personality disorder in Jamaica - public scholarship as a catalyst of health promotion. AB - OBJECTIVE: To ascertain whether the public scholarship of the epidemiology of personality disorder (PD) in Jamaica prompted a health promotion outcome. METHODS: A January 2011 to December 2012 trawl of news media articles linking 'PD' to published public scholarship articles on the epidemiology of PD recorded titles and contents of the reports that were culled to capture the emotional responses and psychological defence mechanisms expressed. These were analysed with concomitant social, psychological or behavioural activities occurring in Jamaica, using SPSS version 17 software. RESULTS: Two public scholarship interventions to two major broadsheet newspapers triggered 25 contributed articles, which in turn prompted 160 responses from the public, five commentaries on leading radio stations and four Internet blogs. One hundred and sixty-six (84.2%) of the titles targeted PD in the Jamaican nation; 31 (13.7) articles targeted PD in leaders, athletes, inmates, individuals, families and productivity in Jamaica. One hundred and fifty-five (79.1%) expressed agreement with the scientific epidemiological observations, while 20.9% (n = 41) expressed disagreement. Eighty-two (41.8%) of the responses expressed rationalizations, 47 (24%) were expressions of reaction formation, 27 (13.8%) were in frank denial, while 25 (12.8%) were expressing open acting out responses or blunt projection (15, 7.7%) to the published epidemiology. The difference between 139 (70.9%) popular media responses to contemporary social problems and 57 (29.1%) reports that made no reference to social problems was statistically significant (p < 0.03). CONCLUSIONS: The hypothesis that public scholarship reports prompted a popular media response, generating a health promotion outcome linking contemporary social events to this medical research is confirmed. PMID- 24756660 TI - Personality disorder in convicted Jamaican murderers. AB - OBJECTIVE: To establish the aetiology and historical prevalence of personality disorder in violent homicidal men in Jamaica. METHODS: Examination and analysis of primary data from the psychosocial case study interviews of 36 convicted murderers from the Jamaican Government Barnett Commission of Enquiry in 1976. The disaggregated social and clinical data were analysed using a Chi-square statistical analysis. RESULTS: The mean age at time of arrest for the male convicted murderers was 24.26 +/- 8.48 years. Twenty-three (66%) of the subjects had loving relationships with mothers, particularly in those men reared in the rural areas. Twenty-one (59%) cases showed marked paternal rejection and absence of integrated family life. Twenty-four (69%) of the cases experienced severe parental disciplinary methods, and two-thirds were illiterate or barely literate. Twenty-nine (83%) were from very poor socio-economic conditions. Thirty (86%) of all the murder victims were adult males. There were significant differences between the urban reared murderers (URM) and rural reared murderers (RRM). Sixteen (94%) of the victims of the URM ensued from robbery and police confrontation, while 13 (72%) of the victims of the RRM resulted from domestic disputes (p < 0.00). Seventeen (49%) of the men had normal personalities; 18 (51%) were diagnosed as having antisocial and inadequate personalities. Diagnosis of primary data using Diagnostic and Statistical Manual of Mental Disorders fourth edition, text revision (DSM-IV-TR) criteria revealed 23 (66%) men with Antisocial Personality Disorder (APD). There were significantly more APD in the URM than the RRM (p < 0.01). CONCLUSIONS: Antisocial personality disorder as an aetiological precursor of homicidal violence represents a major public health problem in contemporary Jamaica. PMID- 24756661 TI - The prevalence of personality disorder in a psychiatric and substance abuse population in Jamaica. AB - OBJECTIVE: To determine the prevalence of personality disorders in patients admitted to the psychiatric wards of the University Hospital of the West Indies (UHWI). METHOD: Patients (n = 100) sequentially admitted to the psychiatric wards of the UHWI were assessed for personality disorder using the gold standard of a consultant assessment using the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM IV-TR) diagnostic criteria for personality disorder, the International Personality Disorder Examination Screening questionnaire (IPDE-S), and the Jamaica Personality Disorder Inventory (JPDI). RESULTS: The three assessment instruments identified a prevalence of personality disorder in the cohort of patients of 51% consultant DSM-IV-TR assessment, 57% JPDI and 86% IPDE-S. The prevalence rate identified by the IPDE-S was significantly higher that the local instruments used (p < 0.000). CONCLUSIONS: The prevalence of personality disorder assessed by the JPDI and the consultant DSM IV-TR instruments in Jamaica is comparable to the prevalence rate of studies in other countries in a similar population. PMID- 24756662 TI - The prevalence of personality disorder in a general medical hospital population in Jamaica. AB - OBJECTIVE: To determine the prevalence of personality disorders in patients admitted to the general medical wards of the University Hospital of the West Indies (UHWI). METHOD: Patients (n = 100) sequentially admitted to the general medical wards of the UHWI were assessed for the diagnosis of personality disorder using the gold standard of a consultant assessment based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM IV-TR) diagnostic criteria for personality disorder, the International Personality Disorder Examination Screening questionnaire (IPDE-S) and the Jamaica Personality Disorder Inventory (JPDI). RESULTS: The three assessment instruments identified a prevalence of personality disorder in the cohort of patients of 21% consultant DSM IV-TR assessment, 28% JPDI and 70% IPDE-S. The prevalence rate identified by the IPDE-S was significantly higher than the local instruments used (p < 0.000). CONCLUSIONS: The prevalence of personality disorder assessed by the JPDI and the IPDE-S and the consultant DSM IV-TR instruments in Jamaica is significantly higher than the prevalence rate of studies in other countries. PMID- 24756663 TI - The prevalence of Type D personality in a Trinidadian cardiac population. AB - OBJECTIVE: The current study investigated the prevalence of Type D personality in persons with self-reported cardiovascular disease and the interactions of Type D personality, reported cardiovascular disease and gender in a Trinidadian cardiac population. METHODS: Between June 2009 and August 2009, 425 participants were recruited from the Eric Williams Medical Sciences Complex (EWMSC) Heart Clinic and all the participants completed the Type D Scale. Clinical and demographic variables were obtained from the sociodemographic questionnaire. RESULTS: Forty two per cent of participants with self-reported cardiovascular disease were identified as Type D as compared to 26% of participants who did not report having a cardiovascular illness. The odds ratio indicated individuals identified with Type D personality are 2.0 times more likely to report having cardiovascular disease and females with cardiac disease are 1.6 times more likely to be identified with Type D personality as compared to males. CONCLUSIONS: Previous studies suggest Type D personality is a risk factor for adverse prognosis in the cardiac population, therefore future research examining the link between Type D personality and cardiovascular disease is warranted. PMID- 24756664 TI - Historiographic analysis of the Jamaican 'Shakatani' scotoma from the short stories of Erna Brodber. AB - OBJECTIVE: To use historiography in the analysis of the fictional writings of a Jamaican novelist to identify aspects of psychopathology of Jamaican people. METHOD: Each of 12 stories of "The World is a High Hill" by novelist Erna Brodber was assigned an explanatory title and a 'psychic centrality'. A narrative qualitative analysis of the fourteen main themes of each story was created using a Lickert scale, calculating the psychopathological penetrance or weighted significance of each theme. RESULTS: The four main psychic centrality containments that emerged from this analysis were the black/white racial paradox (n = 4, 33%) and the partisan/political paradox (n = 1, 8%), the sexual/duplicity paradox (n = 5, 43%) and the social/spiritual paradox (n = 2, 17%). Five of fourteen themes reached maximal penetrance: family (92%), representation of generations with families (92%), issues of intimacy (92%), sex (75%) and issues of dependency (67%). Seven themes - personal and social conflicts (64%), issues of child development (53%), sexual identity (50%), pregnancy (48%), and political (42%), racial (36%), and religious (33%) conflicts reached moderate penetrance. The two themes of migration (30%) and homosexuality (14%) reached minimal penetrance. CONCLUSIONS: The analysis reveals a profound and practical historiographic representation of the contemporary scotoma that currently paralyses many Jamaicans as a product of the enslavement of Africans in the New World, and mirrors the clinical syndrome of personality disorder revealed from contemporary Jamaican medical research. PMID- 24756665 TI - Psychopathology and psychiatric co-morbidities in patients seeking rhinoplasty for cosmetic reasons. AB - AIM: The purpose of the study was to examine psychopathological traits and psychiatric co-morbidities in seekers of cosmetic rhinoplasty. SUBJECTS AND METHODS: Fifty persons seeking cosmetic rhinoplasty and 50 control subjects were admitted to the study. Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI) and Symptom Checklist-90 [Revised] (SCL-90-R) were administered to people who requested cosmetic rhinoplasty and control subjects. All participants were also screened by the Structured Clinical Interview for DSM-IV-(SCIDI/CV, SCID II). RESULTS: Thirteen cosmetic rhinoplasty seekers [CRS] (26%) and three control subjects (6%) had at least one psychiatric diagnosis. There was a significant difference between the two groups (p = 0.006). Beck depression inventory (p = 0.002) and BAI (p = 0.046) levels above the cut-off point were significantly higher in the CRS group than in the normal control. Somatoform disorders were statistically higher in the CRS than control group (p = 0.007). Nine CRS (18%) and two control subjects (4%) had at least one personality disorder. There were differences between the two groups (p = 0.025). The average of SCL-90-R was significantly higher in the CRS than in the control subjects (p < 0.001). The most prevalent somatoform disorders of the CRS were six with body dysmorphic disorder [BDD] (12%). The most prevalent personality disorders of the CRS were three with avoidant (6%) and three with narcissistic (6%) personality. CONCLUSION: Assessment of detailed psychopathological aspects and psychiatric co morbidities could help to define the clinical profile of people requesting cosmetic rhinoplasty in cosmetic surgery settings. Research into these factors may be important as it is essential to detect crucial problems such as personality disorders and BDD before surgery. PMID- 24756666 TI - Metabolic signatures associated with environmental pollution by metals in Donana National Park using P. clarkii as bioindicator. AB - Bioindicators can reflect the effects of pollutants on their metabolism, being widely used to assess environmental stress. In this sense, the crab Procambarus clarkii has been previously proposed to monitor the contamination in Donana National Park (southwest Spain) using conventional biomarkers. In this work, a metabolomic approach based on direct infusion mass spectrometry, which allows an easy and quick study of a large number of metabolites in a single run, was used for pollution assessment of this area, considering the biological response of this organism to contamination. In addition, metal accumulation in crab tissues was determined. Thus, the integrated analysis of metabolomic and metallomic data enabled the study of metabolic response of the organism against pollution. Several metabolites were discovered as potential biomarkers of pollution, such as decreased levels of carnosine, alanine, niacinamide, acetoacetate, pantothenic acid, ascorbate, glucose-6-phosphate, arginine, glucose, lactate, phospholipids, and tryglicerides, as well as elevated levels of acetyl carnitine, phosphocholine, choline, and uric acid. In this way, metal-induced toxicity could be related to metabolic impairments, principally oxidative stress, metabolic dysfunction, and dyslipidemia. PMID- 24756667 TI - Degradation of anti-inflammatory drug ketoprofen by electro-oxidation: comparison of electro-Fenton and anodic oxidation processes. AB - The electrochemical degradation of the nonsteroidal anti-inflammatory drug ketoprofen in tap water has been studied using electro-Fenton (EF) and anodic oxidation (AO) processes with platinium (Pt) and boron-doped diamond (BDD) anodes and carbon felt cathode. Fast degradation of the parent drug molecule and its degradation intermediates leading to complete mineralization was achieved by BDD/carbon felt, Pt/carbon felt, and AO with BDD anode. The obtained results showed that oxidative degradation rate of ketoprofen and mineralization of its aqueous solution increased by increasing applied current. Degradation kinetics fitted well to a pseudo-first-order reaction. Absolute rate constant of the oxidation of ketoprofen by electrochemically generated hydroxyl radicals was determined to be (2.8 +/- 0.1) * 10(9) M(-1) s(-1) by using competition kinetic method. Several reaction intermediates such as 3-hydroxybenzoic acid, pyrogallol, catechol, benzophenone, benzoic acid, and hydroquinone were identified by high performance liquid chromatography (HPLC) analyses. The formation, identification, and evolution of short-chain aliphatic carboxylic acids like formic, acetic, oxalic, glycolic, and glyoxylic acids were monitored with ion exclusion chromatography. Based on the identified aromatic/cyclic intermediates and carboxylic acids as end products before mineralization, a plausible mineralization pathway was proposed. The evolution of the toxicity during treatments was also monitored using Microtox method, showing a faster detoxification with higher applied current values. PMID- 24756668 TI - Insecticide residues in bats along a land use-gradient dominated by cotton cultivation in northern Benin, West Africa. AB - Many regions in Africa are currently being converted from subsistence to cash crop farming such as cotton. Agricultural intensification is usually accompanied by increased use of pesticides, which can have an impact on non-target organisms. Bats are particularly sensitive to insecticide loads while providing substantial ecosystem services as predators of herbivorous insects. In this study, pesticide residues in bats in a landscape in northern Benin were investigated, which spanned a land use gradient from an agricultural zone dominated by cotton farms, through a buffer zone, and into a national park. Insecticides used in cotton cultivation, such as endosulfan, chlorpyrifos, flubendiamide, and spirotetramat, as well as persistent insecticides such as bis(4-chlorophenyl)-1,1,1 trichloroethane (DDT), lindane, and aldrine, were analysed. Insecticide residues detected in bats comprised DDT, endosulfan, and their corresponding transformation products. Maximum concentrations in the sampled bats were 11.2 mg/kg lipid of p,p'-DDE (median: 0.0136 mg/kg lipid) and 0.797 mg/kg lipid of beta-endosulfan (median: below detection limit [DL]). While insecticide concentrations were below lethal concentrations our data suggest that DDT had probably been recently used in the study region, and larger scale use would pose an increased risk for bat populations due to the high biomagnification of DDT. PMID- 24756669 TI - Evaluation of spatial distribution and accumulation of novel brominated flame retardants, HBCD and PBDEs in an Italian subalpine lake using zebra mussel (Dreissena polymorpha). AB - Because of the reduction in the use of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD), novel brominated flame retardants (NBFRs), including 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), decabromodiphenyl ethane (DBDPE), hexabromobenzene (HBB), and pentabromoethylbenzene (PBEB), started to be marketed as alternatives to the banned formulations. In this study, the spatial distribution and accumulation of NBFRs, PBDEs, and HBCD in the biota have been investigated in the littoral compartment of a large and deep subalpine lake (Lake Maggiore, Northern Italy), using zebra mussel Dreissena polymorpha and roach (Rutilus rutilus) as bioindicators. To our knowledge, this is the first study reporting the contamination of NBFRs in the freshwater invertebrate D. polymorpha. Contamination of zebra mussel due to PBEB, HBB, and BTBPE was low, ranging from 0.9 to 2.9 ng/g lipid weight, from 1.1 to 2.9 ng/g l.w., and from 3.5 to 9.5 ng/g l.w., respectively. PBEB and BTBPE in roach were always below the detection limit, while the contamination of HBB ranged from < limits of detection (LOD) to 1.74 ng/g l.w., indicating a weak contamination. DBDPE was < LOD in all the considered biological samples. Finally, HBCD was detected in all organic tissues with mean concentrations up to 74.4 ng/g l.w. PBDE results, supported by principal component analysis elaboration, suggested a possible contamination due to the congeners composing the penta- and deca-BDE technical formulations, which are present in the Lake Maggiore basin. The biomagnification factor values showed that tetra- and penta-BDE biomagnified, while octa-, nona-, and deca-BDE were still bioavailable and detectable in the fish muscles, but they do not biomagnified. Considering the other BFRs, only HBCD showed a moderate biomagnification potential. PMID- 24756670 TI - Occurrence of perfluorinated alkyl substances in sediment from estuarine and coastal areas of the East China Sea. AB - Perfluorinated alkyl substances (PFAS) have drawn much attention due to their environmental persistence, ubiquitous existence, and bioaccumulation potential. The occurrence and spatial variation of PFAS were investigated through collection of riverine and marine sediments from estuarine and coastal areas of the East China Sea. Among them, perfluorooctanesulfonic acid (PFOS), perfluoroheptanoic acid (PFHpA), and perfluorooctanoic acid (PFOA) were the three predominant PFAS with the highest detection frequencies in the sediment. PFOS up to 32.4 ng g(-1) dw and ?PFAS up to 34.8 ng g(-1) dw were detected. Compared to other studies, high levels of PFOS were found in sediments from the East China Sea. PFHpA was also detected at higher frequency and concentration than those of other studies, which suggests point sources in this area. Concentrations of PFAS in riverine sediments were much higher than in marine sediments. Analysis of spatial variations presented overall decreasing trends of PFAS from inshore to offshore areas. PMID- 24756671 TI - New approaches for low-invasive contaminated site characterization, monitoring and modelling. PMID- 24756672 TI - Contribution of harbour activities and ship traffic to PM2.5, particle number concentrations and PAHs in a port city of the Mediterranean Sea (Italy). AB - In this work, an assessment of the impact of ship traffic and related harbour activities (loading/unloading of ships and hotelling in harbour) on PM 2.5 and particle number concentrations (PNC) separating the contribution associated to ship traffic from that of harbour-related activities is reported. Further, an assessment of the impact and environmental risks associated to polycyclic aromatic hydrocarbon (PAH) concentrations was performed. Results refer to the city of Brindisi (88,500 inhabitants) in the south-eastern part of Italy and its harbour (with yearly 9.5 Mt of goods, over 520,000 passengers and over 175,000 vehicles). PM2.5 and PNC concentrations show a clear daily pattern correlated with daily ship traffic pattern in the harbour. High temporal resolution measurements and correlations with wind direction were used to estimate the average direct contribution to measured concentrations of this source. The average relative contribution of ship traffic was 7.4% (+/-0.5%) for PM2.5 and 26% (+/-1%) for PNC. When the contribution associated to harbour-related activities is added, the percentages become 9.3% (+/-0.5%) for PM2.5 and 39% (+/ 1%) for PNC. In the site analysed, air coming from the harbour/industrial sector was richer in PAHs (5.34 ng/m3) than air sampled from all directions (3.89 ng/m3). The major compounds were phenanthrene, fluoranthene and pyrene, but the congener profiles were different in the two direction sectors: air from the harbour/industrial sector was richer in phenanthrene and fluorene, which are the most abundant PAHs in ship emissions. Results showed that lighter PAHs are associated to the gas phase, while high molecular weight congeners are mostly present in the particulate phase. The impact on the site studied of the harbour/industrial source to PAHs was 56%(range, 29-87%). PMID- 24756673 TI - Coagulation of highly turbid suspensions using magnesium hydroxide: effects of slow mixing conditions. AB - Laboratory experiments were carried out to study the effects of slow mixing conditions on magnesium hydroxide floc size and strength and to determine the turbidity and total suspended solid (TSS) removal efficiencies during coagulation of highly turbid suspensions. A highly turbid kaolin clay suspension (1,213 +/- 36 nephelometric turbidity units (NTU)) was alkalized to pH 10.5 using a 5 M NaOH solution; liquid bittern (LB) equivalent to 536 mg/L of Mg(2+) was added as a coagulant, and the suspension was then subjected to previously optimized fast mixing conditions of 100 rpm and 60 s. Slow mixing speed (20, 30, 40, and 50 rpm) and time (10, 20, and 30 min) were then varied, while the temperature was maintained at 20.7 +/- 1 degrees C. The standard practice for coagulation flocculation jar test ASTM D2035-13 (2013) was followed in all experiments. Relative floc size was monitored using an optical measuring device, photometric dispersion analyzer (PDA 2000). Larger and more shear resistant flocs were obtained at 20 rpm for both 20- and 30-min slow mixing times; however, given the shorter duration for the former, the 20-min slow mixing time was considered to be more energy efficient. For slow mixing camp number (Gt) values in the range of 8,400-90,000, it was found that the mixing speed affected floc size and strength more than the time. Higher-turbidity removal efficiencies were achieved at 20 and 30 rpm, while TSS removal efficiency was higher for the 50-rpm slow mixing speed. Extended slow mixing time of 30 min yielded better turbidity and TSS removal efficiencies at the slower speeds. PMID- 24756674 TI - Fluoride removal from aqueous solution by direct contact membrane distillation: theoretical and experimental studies. AB - Direct contact membrane distillation (DCMD) process using polyvinylidene fluoride (PVDF) membrane was used for fluoride removal from aqueous solution. This study has been carried out on heat and mass transfer analyses in DCMD. The dusty-gas model was used to analyze the mass transfer mechanism and to calculate the permeate flux. The heat transfer is analyzed based on energy balance, and the different layers are considered as a series of thermal resistances. Mass transfer analysis showed that the transition Knudsen-molecular diffusion is the dominant mechanism to describe the transport of water vapor through the pores of the PVDF membrane. The most significant operating parameter is the feed temperature. The permeate increases sensitively with feed temperature and velocity, and it shows insignificant change with feed salts concentration. Heat transfer analysis showed the conduction through the matrix of the membrane presents the major part of available energy. The increasing feed temperature leads to increase thermal efficiency (TE) and decrease temperature polarization coefficient (TPC). The experimental results are in good agreement with theoretical values. Therefore, it is suggested to work at high feed temperature, which will benefit both the thermal efficiency and permeate flux. The experimental results proved that DCMD process is able to produce almost fluoride-free water suitable for many beneficial uses. PMID- 24756675 TI - An experimental approach to measure particle deposition in large circular ventilation ducts. AB - The topic of this study is related to airborne particle dynamics in indoor environments. Lab-scale experiments have been performed to investigate particle deposition velocity to six different surfaces orientations (with respect to gravity) for fully developed turbulent flow in horizontal large circular ventilation ducts. Monodispersed aerosol particles (1-6 MUm) were used in the deposition experiments. A very low particle mass (40 ng) was measured reliably above background level on duct surfaces by a means of a nondestructive stencil technique associated with fluorescence analysis. For 2-6 MUm particles (diffusion and impaction regime), deposition rates to floors were much greater than rates to the ceiling and greater than rates to the wall. For 1-MUm particles, the effect of surface orientation to particle deposition was not significant. Results were compared to the very few similar and published studies. This work was conducted in the frame of the CleanAirNet project which aimed at producing new knowledge, models, and techniques to help controlling the safety food stuffs, through a better control of aerosol particle (bioaerosols) transport and deposition in the ventilation networks of the food industry. PMID- 24756676 TI - Novel chitosan/PVA/zerovalent iron biopolymeric nanofibers with enhanced arsenic removal applications. AB - Enhanced removal application of both forms of inorganic arsenic from arsenic contaminated aquifers at near-neutral pH was studied using a novel electrospun chitosan/PVA/zerovalent iron (CPZ) nanofibrous mat. CPZ was carefully examined using scanning electron microscopy (SEM) equipped with energy-dispersive X-ray analysis (EDX), transmission electron microscopy (TEM), atomic fluorescence spectroscopy (AFM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and thermal gravimetric analysis (TGA). Application of the adsorbent towards the removal of total inorganic arsenic in batch mode has also been studied. A suitable mechanism for the adsorption has also been discussed. CPZ nanofibers mat was found capable to remove 200.0+/-10.0 mg g(-1) of As(V) and 142.9+/-7.2 mg g(-1) of As(III) from aqueous solution of pH 7.0 at ambient condition. Addition of ethylenediaminetetraacetic acid (EDTA) enabled the stability of iron in zerovalent state (ZVI). Enhanced capacity of the fibrous mat could be attributed to the high surface area of the fibers, presence of ZVI, and presence of functional groups such as amino, carboxyl, and hydroxyl groups of the chitosan and EDTA. Both Langmuir and Freundlich adsorption isotherms were applicable to describe the removal process. The possible mechanism of adsorption has been explained in terms of electrostatic attraction between the protonated amino groups of chitosan/arsenate ions and oxidation of arsenite to arsenate by Fentons generated from ZVI and subsequent complexation of the arsenate with the oxidized iron. These CPZ nanofibrous mats has been prepared with environmentally benign naturally occurring biodegradable biopolymer chitosan, which offers unique advantage in the removal of arsenic from contaminated groundwater. PMID- 24756677 TI - Phytotoxicity of nanoparticles--problems with bioassay choosing and sample preparation. AB - For a full estimation of the risk related with the presence of engineered nanoparticles (ENPs) in the environment, the use of the current ecotoxicological methods may prove insufficient. In the study presented herein, various methods of assessment of ecotoxicity were applied to compare the phytotoxicity of three ENPs: nano-ZnO, nano-TiO2 and nano-Ni. The toxicity was assayed both for aqueous solutions of the ENPs (the germination/elongation test and Phytotestkit F(TM)) and for ENPs added to soil (Phytotoxkit F(TM) and modified Phytotoxkit F(TM)). Lepidium sativum was used as a test plant. The scope of the study also included the assessment of the effect of the method of ENP application to the soil (as powder and aqueous suspension) on their phytotoxicity. In the course of the study, no effect of the studied ENPs and their bulk counterparts on the germination of seeds was observed. The root growth inhibition of L. sativum depended on the kind of test applied. The trend between concentration of ENPs and effect depended on the method used and kind of ENPs. For most nanoparticles (despite of the method used), the differences in phytotoxicity between nano and bulk particles were observed. Depending on the kind of ENPs, their phytotoxicity differs between water and soil. ZnO (nano and bulk) and nano-Ni were more toxic in soil than in water. For TiO2 and bulk-Ni, reverse trend was observed. A different method of ENP application to soil differently affects the phytotoxicity. PMID- 24756678 TI - A contemporary landscape of air pollution and greenhouse gas emissions leads to inevitable phenomena of low birthweight. AB - The objective of the study is to empirically examine the air pollution, greenhouse gas (GHG) emissions and low birth weight in Pakistan through the cointegration and error correction model over a 36-year time period, i.e., between 1975 and 2012. The study employed the Johansen cointegration technique to estimate the long-run relationship between the variables, while an error correction model was used to determine the short-run dynamics of the system. The study was limited to the following variables, including carbon dioxide emissions, methane emissions, nitrous oxide emissions, GHG emissions, and low birth weight in order to manage robust data analysis. The results reveal that air pollution and GHG emissions significantly affects the low birth weight in Pakistan. In the long run, carbon dioxide emissions act as a strong contributor for low birth weight, as the coefficient value indicates there is a more elastic relationship (i.e., -1.214, p<0.000) between them, whereas in the short run, this results has been evaporated. Subsequently, in the short run, GHG emissions have a one-to-one corresponding relationship with the low birth weight in Pakistan. Nitrous oxide emissions, both in the short and long run, have a significant and less elastic relationship (i.e., -0.517 with p<0.001 and -0.335 with p<0.090). Methane emissions have no significant relationship with the low birth weight in Pakistan. PMID- 24756679 TI - Degradation of a textile dye, Rhodamine 6G (Rh6G), by heterogeneous sonophotoFenton process in the presence of Fe-containing TiO2 catalysts. AB - In this study, degradation of Rhodamine 6G (Rh6G) was investigated with ultrasound-assisted heterogeneous photoFenton process by iron-containing TiO2 catalysts. The catalysts were prepared by incipient wetness impregnation method and characterized by XRD, SEM, FT-IR, nitrogen adsorption, and ICP-AES measurements. Almost complete color removal (99.9 %) was achieved after a reaction time of 90 min while chemical oxygen demand (COD) could be removed by 24 % only with the 1 wt% iron-containing TiO2 catalyst. Initial color removal after 15 min of reaction and total COD abatement after 90 min of reaction decreased with increasing calcination temperature of the catalyst from 573 to 973 K. This indicated that the catalytic activity of the catalyst depend on the percentage of anatase phase in the TiO2, which was decreased with increasing calcination temperature. PMID- 24756680 TI - Application of solar photo-Fenton at circumneutral pH to nanofiltration concentrates for removal of pharmaceuticals in MWTP effluents. AB - In view of the inefficient elimination of micro-pollutants by today's conventional biological treatments and new legislation requiring elimination of at least 80 % of their concentration, the application of an advanced tertiary treatment must be studied. A good option would be advanced oxidation processes (AOPs), which have very often been combined with physicochemical pre-treatSments to increase efficiency or reduce operating costs. This study focused on the combination of membrane nanofiltration and solar photo-Fenton for the main purpose of removing five pharmaceuticals (sulfamethoxazole, ibuprofen, ofloxacin, carbamazepine and flumequine) from real MWTP effluents under realistic conditions (MUg L(-1)). This research also included tests performed with modified photo Fenton using a low iron concentration at circumneutral pH and a low hydrogen peroxide dose, in an attempt to reduce major treatment costs. Over 80 % of dissolved organic carbon, chemical oxygen demand and turbidity were also retained during nanofiltration, making pharmaceutical removal less efficient in terms of concentrate treatment time than direct treatment, i.e. the concentrate illumination time was around 150 min while direct treatment was around 40 min. Nevertheless, it should be highlighted that, although no savings in installation costs was observed for the combined system (nanofiltration/solar photo-Fenton), the reaction rate improved and so, there was a savings in reagent costs (mainly hydrogen peroxide and sulfuric acid). PMID- 24756681 TI - Local deposition of mercury in topsoils around coal-fired power plants: is it always true? AB - Mercury (Hg) is a toxic element that is emitted to the atmosphere through human activities, mainly fossil fuel combustion. Hg accumulations in soil are associated with atmospheric deposition, while coal-burning power plants remain the most important source of anthropogenic mercury emissions. In this study, we analyzed the Hg concentration in the topsoil of the Kozani-Ptolemais basin where four coal-fired power plants (4,065 MW) run to provide 50 % of electricity in Greece. The study aimed to investigate the extent of soil contamination by Hg using geostatistical techniques to evaluate the presumed Hg enrichment around the four power plants. Hg variability in agricultural soils was evaluated using 276 soil samples from 92 locations covering an area of 1,000 km(2). We were surprised to find a low Hg content in soil (range 1-59 MUg kg(-1)) and 50 % of samples with a concentration lower than 6 MUg kg(-1). The influence of mercury emissions from the four coal-fired power plants on soil was poor or virtually nil. We associate this effect with low Hg contents in the coal (1.5-24.5 MUg kg(-1)) used in the combustion of these power plants (one of the most Hg-poor in the world). Despite anthropic activity in the area, we conclude that Hg content in the agricultural soils of the Kozani-Ptolemais basin is present in low concentrations. PMID- 24756682 TI - Survey of the occurrence of pharmaceuticals in Spanish finished drinking waters. AB - Fifty samples of finished drinking waters (FDWs) from Spain covering 12 million inhabitants were tested for 53 pharmaceuticals pertaining to 12 different Anatomical Therapeutic Chemical (ATC) classification system codes. The studied compounds are a combination of most commonly consumed pharmaceuticals with other barely reported in the literature. Five compounds, azithromycin, clarithromycin, erythromycin, sulfamethoxazole, and ibuprofen were tentatively identified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in some samples (2 to 15 %), but only ibuprofen and azithromycin could be confirmed when analyzed by liquid chromatography-high-resolution mass spectrometry (LC-HRMS) with a quadrupole-Orbitrap instrument. Concentration levels of ibuprofen in the positive samples ranged from 12 to 17 ng/L (n = 6) while for azithromycin values from 5 to 9.5 ng/L (n = 3) were found. Ibuprofen fragmentation behaviour in different mass spectrometry instrument configurations (triple quadrupole, quadrupole-ion trap, and quadrupole-Orbitrap) was evaluated. PMID- 24756683 TI - Characterization of top phase oil obtained from co-pyrolysis of sewage sludge and poplar sawdust. AB - To research the impact of adding sawdust on top phase oil, a sewage sludge and poplar sawdust co-pyrolysis experiment was performed in a fixed bed. Gas chromatography (GC)/mass spectrometry (MS) was used to analyze the component distribution of top phase oil. Higher heating value, viscosity, water content, and pH of the top phase oil product were determined. The highest top phase oil yield (5.13 wt%) was obtained from the mixture containing 15% poplar sawdust, while the highest oil yield (16.51 wt%) was obtained from 20% poplar sawdust. Top phase oil collected from the 15% mixture also has the largest amount of aliphatics and the highest higher heating value (28.6 MJ/kg). Possible reaction pathways were proposed to explain the increase in the types of phenols present in the top phase oil as the proportion of poplar sawdust used in the mixture increased. It can be concluded that synergetic reactions occurred during co pyrolysis of sewage sludge and poplar sawdust. The results indicate that the high ash content of the sewage sludge may be responsible for the characteristic change in the top phase oil obtained from the mixtures containing different proportions of sewage sludge and poplar sawdust. Consequently, co-pyrolysis of the mixture containing 15 % poplar sawdust can increase the yield and the higher heating value of top phase oil. PMID- 24756684 TI - Silver-modified clinoptilolite for the removal of Escherichia coli and heavy metals from aqueous solutions. AB - This paper investigates the potential of using the silver antibacterial properties combined with the metal ion exchange characteristics of silver modified clinoptilolite to produce a treatment system capable of removing both contaminants from aqueous streams. The results have shown that silver-modified clinoptilolite is capable of completely eliminating Escherichia coli after 30-min contact time demonstrating its effectiveness as a disinfectant. Systems containing both E. coli and metals exhibited 100 % E. coli reduction after 15-min contact time and maximum metal adsorption removal efficiencies of 97, 98, and 99 % for Pb(2+), Cd(2+), and Zn(2+) respectively after 60 min; 0.182-0.266 mg/g of metal ions were adsorbed by the zeolites in the single- and mixed-metal containing solutions. Nonmodified clinoptilolite showed no antibacterial properties. This study demonstrated that silver-modified clinoptilolite exhibited high disinfection and heavy metal removal efficiencies and consequently could provide an effective combined treatment system for the removal of E. coli and metals from contaminated water streams. PMID- 24756685 TI - Assessment of cadmium accumulation, toxicity, and tolerance in Brassicaceae and Fabaceae plants--implications for phytoremediation. AB - This study, based on a greenhouse pot culture experiment conducted with 15-day old rapeseed (Brassica campestris L. cv. Pusa Gold; family Brassicaceae) and moong bean (Vigna radiata L. Wilczek cv. Pusa Ratna; family Fabaceae) plants treated with cadmium (Cd) concentrations (0, 50, and 100 mg kg(-1) soil), investigates their potential for Cd accumulation and tolerance, and dissects the underlying basic physiological/biochemical mechanisms. In both species, plant dry mass decreased, while Cd concentration of both root and shoot increased with increase in soil Cd. Roots harbored a higher amount of Cd (vs. shoot) in B. campestris, while the reverse applied to V. radiata. By comparison, root Cd concentration was higher in B. campestris than in V. radiata. The high Cd concentrations in B. campestris roots and V. radiata shoots led to significant elevation in oxidative indices, as measured in terms of electrolyte leakage, H2O2 content, and lipid peroxidation. Both plants displayed differential adaptation strategies to counteract the Cd burden-caused anomalies in their roots and shoots. In B. campestris, increasing Cd burden led to a significantly decreased reduced glutathione (GSH) content but a significant increase in activities of GSH reductase (GR), GSH peroxidase (GPX), and GSH sulfotransferase (GST). However, in V. radiata, increasing Cd burden caused significant increase in GSH content and GR activity, but a significant decline in activities of GPX and GST. Cross talks on Cd burden of tissues and the adapted Cd tolerance strategies against Cd burden accrued toxicity indicated that B. campestris and V. radiata are good Cd stabilizer and Cd extractor, respectively, wherein a fine tuning among the major components (GR, GPX, GST, GSH) of the GSH redox system helped the plants to counteract differentially the Cd load-induced anomalies in tissues. On the whole, the physiological/biochemical characterization of the B. campestris and V. radiata responses to varying Cd concentrations can be of great help in elaborating the innovative plant-based remediation technologies for metal/metalloid-contaminated sites. PMID- 24756686 TI - Occurrence of PCDD/Fs and dioxin-like PCBs in superficial sediment of Portuguese estuaries. AB - Superficial sediments collected from seven estuarine systems located along the Portuguese coast were analyzed for 7 polychlorinated dibenzo-p-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), and 12 dioxin-like polychlorinated biphenyls (dl-PCBs). Total PCDD/F concentration ranged from 4.6 to 464 pg g(-1) dry weight (dw), while that of dl-PCBs varied from 26.6 to 8,693 pg g(-1) dw. In general, the highest PCDD/F and dl-PCB concentrations were associated with densely populated and industrially impacted areas. Additionally, PCDD/F revealed a predominance of octachlorodibenzodioxin (OCDD) to total PCDD/Fs, while PCB 118 was the major contributor to total dl-PCBs. This study provided a global perspective of the contamination status of Portuguese estuaries by dioxin-like compounds and allowed a comparison between the investigated systems and other systems worldwide. PCDD/F and dl-PCB levels found in the collected sediments were lower than those of highly impacted areas from different parts of the globe. Nevertheless, comparison with guidelines and quality standards from other countries indicated that some Portuguese estuarine areas with a high industrialization level present PCDD/F and dl-PCB concentrations in superficial sediment that may constitute a risk to aquatic organisms. PMID- 24756687 TI - Distribution and ecological risk assessment of organochlorine pesticides in surface sediments from the East Lake, China. AB - Organochlorine pesticides (OCPs) are ubiquitous pollutants, and their presence in urban lakes is a concern for human and ecological health. Surface sediments in the East Lake, China, were collected in winter 2012 and summer 2013 to investigate concentrations, distribution patterns, possible sources, and potential ecological risks of OCPs in this area. The total concentrations of 14 OCPs ranged from 6.3 to 400 ng g(-1) dry weight (dw) with an average concentration of 79 ng g(-1) dw. The mean values of hexachlorocyclohexanes (HCHs) (alpha-, beta-, gamma-, and delta-HCH) and dichlorodiphenyltrichloroethanes (DDTs) (p,p'-DDE, p,p'-DDD, and p,p'-DDT) were 36 and 7.6 ng g(-1) dw, accounting for 45 and 10 % of the total OCPs, respectively. The concentrations of OCPs in sediment samples collected in winter were significantly higher than those in summer, especially the HCHs, of which in winter were two times greater than summer. Composition analyses indicated that DDTs and endosulfan were mainly from historical contribution. Historical use of technical HCH and new input of lindane were probably the source of HCHs in the East Lake. Most sampling sites of HCHs and DDTs were found to have the potential ecological risk based on levels specified in the sediment quality standards. PMID- 24756688 TI - Transcriptional responses and embryotoxic effects induced by pyrene and methylpyrene in Japanese medaka (Oryzias latipes) early life stages exposed to spiked sediments. AB - Japanese medaka (Oryzias latipes) embryos were exposed to sediments spiked with environmental concentrations (300 and 3,000 ng/g dry weight) of pyrene (Pyr) and methylpyrene (MePyr) throughout their development. Embryotoxicity, teratogenicity, and transcriptional responses (qRT-PCR) were analyzed in embryos and newly hatched larvae. The genotoxicity of the two polycyclic aromatic hydrocarbons (PAHs) was also tested in prolarvae using the comet assay. Exposure to each compound had a clear impact on embryonic development and resulted in several teratogenic effects, including cardiovascular injuries, reduced absorption of yolk sac reserves, and jaw and spinal deformities. Interestingly, the overall toxic effects of Pyr and MePyr considerably overlapped those induced following dioxin exposure. qRT-PCR analysis revealed the transcriptional induction of genes involved in mitochondrial energetic metabolism (coxI), xenobiotic biotransformation (cyp1a), and cell cycle regulation (wnt1) by the two PAHs. MePyr also activated cell cycle arrest (p53), oxidative DNA damage repair (ogg1), and retinoid-mediated (raldh2 and raralpha1) gene transcription. DNA damage was not found to be significantly increased following Pyr and MePyr exposure. The lack of significant genotoxic effect in comparison to the control might be the consequence of the efficient onset of DNA damage repair mechanisms as suggested by ogg1 gene transcription upregulation. Results reported in the present study have brought new insights into the modes of action of Pyr, and the effects of MePyr exposure have been investigated in fish ELS for the first time. PMID- 24756689 TI - Assessment of natural and calcined starfish for the amelioration of acidic soil. AB - Quality improvement of acidic soil (with an initial pH of approximately 4.5) with respect to soil pH, exchangeable cations, organic matter content, and maize growth was attempted using natural (NSF) and calcined starfish (CSF). Acidic soil was amended with NSF and CSF in the range of 1 to 10 wt.% to improve soil pH, organic matter content, and exchangeable cations. Following the treatment, the soil pH was monitored for periods up to 3 months. The exchangeable cations were measured after 1 month of curing. After a curing period of 1 month, the maize growth experiment was performed with selected treated samples to evaluate the effectiveness of the treatment. The results show that 1 wt.% of NSF and CSF (700 and 900 degrees C) were required to increase the soil pH to a value higher than 7. In the case of CSF (900 degrees C), 1 wt.% was sufficient to increase the soil pH value to 9 due to the strong alkalinity in the treatment. No significant changes in soil pHs were observed after 7 days of curing and up to 3 months of curing. Upon treatment, the cation exchange capacity values significantly increased as compared to the untreated samples. The organic content of the samples increased upon NSF treatment, but it remains virtually unchanged upon CSF treatment. Maize growth was greater in the treated samples rather than the untreated samples, except for the samples treated with 1 and 3 wt.% CSF (900 degrees C), where maize growth was limited due to strong alkalinity. This indicates that the amelioration of acidic soil using natural and calcined starfish is beneficial for plant growth as long as the application rate does not produce alkaline conditions outside the optimal pH range for maize growth. PMID- 24756690 TI - Outpatient care patterns and organizational accountability in Medicare. AB - IMPORTANCE: Fostering accountability in the Medicare Accountable Care Organization (ACO) programs may be challenging because traditional Medicare beneficiaries have unrestricted choice of health care providers, are attributed to ACOs based on utilization, and often receive fragmented care. OBJECTIVE: To measure 3 related constructs relevant to ACO incentives and their capacity to manage care: stability of patient assignment, leakage of outpatient care, and contract penetration. DESIGN, SETTING, AND PARTICIPANTS: Using 2010-2011 Medicare claims and rosters of physicians in organizations participating in ACO programs, we examined these constructs among 524,246 beneficiaries hypothetically assigned to 145 ACOs prior to the start of the Medicare ACO programs. We compared estimates by patient complexity, ACO size, and the primary care orientation of ACO specialty mix. MAIN OUTCOMES AND MEASURES: Three related construct measurements: stability of assignment, defined as the proportion of patients whose assignment to an ACO in 2010 was unchanged in 2011; leakage of outpatient care, defined as the proportion of office visits for an assigned population that occurred outside of the contracting organization; and contract penetration, defined as the proportion of Medicare outpatient spending billed by an ACO that was devoted to assigned patients. RESULTS: Of beneficiaries assigned to an ACO in 2010, 80.4% were assigned to the same ACO in 2011. Of those assigned to an ACO in 2010 or 2011, 66.0% were consistently assigned in both years. Unstable assignment was more common among beneficiaries with fewer conditions and office visits but also among those in several high-cost categories, including the highest decile of per-beneficiary spending. Among ACO-assigned beneficiaries, 8.7% of office visits with primary care physicians were provided outside of the assigned ACO, and 66.7% of office visits with specialists were provided outside of the assigned ACO. Leakage of outpatient specialty care was greater for higher-cost beneficiaries and substantial even among specialty-oriented ACOs (54.6% for lowest quartile of primary care orientation). Of Medicare spending on outpatient care billed by ACO physicians, 37.9% was devoted to assigned beneficiaries. This proportion was higher for ACOs with greater primary care orientation (60.0% for highest quartile vs 33.6% for lowest). CONCLUSIONS AND RELEVANCE: Care patterns among beneficiaries served by ACOs suggest distinct challenges in achieving organizational accountability in Medicare. Continued monitoring of these patterns may be important to determine the regulatory need for enhancing ACOs' incentives and their ability to improve care efficiency. PMID- 24756691 TI - Genetic distance and age affect the cuticular chemical profiles of the clonal ant Cerapachys biroi. AB - Although cuticular hydrocarbons (CHCs) have received much attention from biologists because of their important role in insect communication, few studies have addressed the chemical ecology of clonal species of eusocial insects. In this study we investigated whether and how differences in CHCs relate to the genetics and reproductive dynamics of the parthenogenetic ant Cerapachys biroi. We collected individuals of different ages and subcastes from several colonies belonging to four clonal lineages, and analyzed their cuticular chemical signature. CHCs varied according to colonies and clonal lineages in two independent data sets, and correlations were found between genetic and chemical distances between colonies. This supports the results of previous research showing that C. biroi workers discriminate between nestmates and non-nestmates, especially when they belong to different clonal lineages. In C. biroi, the production of individuals of a morphological subcaste specialized in reproduction is inversely proportional to colony-level fertility. As chemical signatures usually correlate with fertility and reproductive activity in social Hymenoptera, we asked whether CHCs could function as fertility-signaling primer pheromones determining larval subcaste fate in C. biroi. Interestingly, and contrary to findings for several other ant species, fertility and reproductive activity showed no correlation with chemical signatures, suggesting the absence of fertility related CHCs. This implies that other cues are responsible for subcaste differentiation in this species. PMID- 24756692 TI - Neurology's stake in foundational neuroscience research. PMID- 24756693 TI - A novel device based on smart textile to control heart's activity during exercise. AB - In recent years, several systems have been developed to control cardiac function during exercise, and some are also capable of recording RR data to provide heart rate variability (HRV) analyses. In this study we compare time between heart beats and HRV parameters obtained with a smart textile system (GOW; Weartech sl., Spain) and an electrocardiogram machine commonly used in hospitals during continuous cycling tests. Twelve cardiology patients performed a 30-min cycling test at stable submaximal intensity. RR interval data were recorded during the test by both systems. 3-min RR segments were taken to compare the time intervals between beats and HRV variables using Bland-Altman analyses and intraclass correlation coefficients. Limits of agreement (LoAs) on RR intervals were stable at around 3 ms (widest LoAs -5.754 to 6.094 ms, tightest LoAs -2.557 to 3.105 ms, medium LoAs -3.638 +/- 0.812 to 3.145 +/- 0.539 ms). HRV parameters related to short-term change presented wide LoAs (RMSSD -0.17 to 18.41 %, HF -17.64 to 33.21 %, SD1 -0.50 to 17.54 %) as an effect of the error measurement of the GOW system. The GOW system is a valid tool for controlling HR during physical activity, although its use as a clinical tool for HRV cannot be supported. PMID- 24756695 TI - NKT cell-infiltrating aseptic meningitis on the central nervous system in Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib. PMID- 24756696 TI - Concurrent administration of darbepoetin alfa, cyclosporine A, and prednisolone is useful for T cell large granular lymphocyte leukemia associated with myelodysplastic syndrome complicated by Coombs-negative hemolytic anemia. PMID- 24756697 TI - Polyserase-1/TMPRSS9 induces pro-tumor effects in pancreatic cancer cells by activation of pro-uPA. AB - Polyserase-1/TMPRSS9 is a type II transmembrane serine protease showing a complex molecular architecture characterized by the presence of three tandem serine protease domains in its amino acid sequence. This protease is widely expressed in mouse and human tissues, however, its functional significance is unknown in both normal and pathological conditions. In the present study, we evaluated the possible role of polyserase-1 in cancer progression. First, we showed that polyserase-1 increased the invasive capacities of PANC-1 and SK-PC-3 pancreatic cancer cells. Moreover, the presence of polyserase-1 enhanced anchorage independent growth and diminished the adhesion capability of PANC-1 cells to different extracellular matrix components. These effects were mediated by the efficient conversion of pro-uPA to active uPA and high phosphorylation levels of ERK detected in the PANC-1 cells expressing exogenous polyserase-1. Collectively, our data suggest that polyserase-1 may be involved in cancer progression and, similarly to what has been proposed for the closely related serine proteases matriptase and TMPRSS4, inhibition of TMPRSS9 activity may contribute to the inhibition of tumor growth. PMID- 24756699 TI - Ecohealth as a field: looking forward. AB - This forum paper proposes a reflection on the "field of ecohealth" and on how best to sustain a supportive environment that enables the evolution of diverse partnerships and forms of collaboration in the field. It is based on the results of a preconference workshop held in October 2012, in Kunming, China at the fourth biennial conference of the International Association for Ecology and Health. Attended by 105 persons from 38 countries, this workshop aimed to have a large group and encompassing discussion about ecohealth as an emerging field, touching on subjects such as actors, processes, structures, standards, and resources. Notes taken were used to conduct a qualitative thematic analysis combined with a semantic network analysis. Commonalities highlighted by these discussions draw a portrait of a field in which human health, complex systems thinking, action, and ecosystem health are considered central issues. The need to reach outside of academia to government and the general public was identified as a shared goal. A disconnect between participants' main concerns and what they perceived as the main concerns of funding agencies emerged as a primary roadblock for the future. PMID- 24756698 TI - Geldanamycin attenuates 3-nitropropionic acid-induced apoptosis and JNK activation through the expression of HSP 70 in striatal cells. AB - Although selective striatal cell death is a characteristic hallmark in the pathogenesis of Huntington's disease (HD), the underlying mechanism of striatal susceptibility remains to be clarified. Heat shock proteins (HSPs) have been reported to suppress the aggregate formation of mutant huntingtin and concurrent striatal cell death. In a previous study, we observed that heat shock transcription factor 1 (HSF1), a major transcription factor of HSPs, significantly attenuated 3-nitropropionic acid (3NP)-induced reactive oxygen species (ROS) production and apoptosis through the expression of HSP 70 in striatal cells. To investigate the differential roles of HSPs in 3NP-induced striatal cell death, the effect of geldanamycin (GA), an HSP 90 inhibitor, was examined in 3NP-stimulated striatal cells. GA significantly attenuated 3NP induced striatal apoptosis and ROS production with an increased expression of HSP 70. Triptolide (TL), an HSP 70 inhibitor, abolished GA-mediated protective effects in 3NP-stimulated striatal cells. To understand the underlying mechanism by which GA-mediated HSP 70 protects striatal cells against 3NP stimulation, the involvement of various signaling pathways was examined. GA significantly attenuated 3NP-induced c-Jun N-terminal kinase (JNK) phosphorylation and subsequent c-Jun phosphorylation in striatal cells. Taken together, the present study demonstrated that GA exhibits protective properties against 3NP-induced apoptosis and JNK activation via the induction of HSP 70 in striatal cells, suggesting that expression of HSP 70 may be a valuable therapeutic target in the treatment of HD. PMID- 24756700 TI - TRPs: truly remarkable proteins. AB - The family of transient receptor potential cation channels has received in the last 10 years a tremendous interest because members of this family are involved in a plethora of cell functions and have been identified as causal for many hereditary and acquired diseases. We shortly introduce these channels, summarize nomenclature and chromosomal location of the 28 mammalian Trp genes, and list the available Trp-deficient mouse lines. PMID- 24756701 TI - TRPC1. AB - The TRPC1 ion channel was the first mammalian TRP channel to be cloned. In humans, it is encoded by the TRPC1 gene located in chromosome 3. The protein is predicted to consist of six transmembrane segments with the N- and C-termini located in the cytoplasm. The extracellular loop connecting transmembrane segments 5 and 6 participates in the formation of the ionic pore region. Inside the cell, TRPC1 is present in the endoplasmic reticulum, plasma membrane, intracellular vesicles, and primary cilium, an antenna-like sensory organelle functioning as a signaling platform. In human and rodent tissues, it shows an almost ubiquitous expression. TRPC1 interacts with a diverse group of proteins including ion channel subunits, receptors, and cytosolic proteins to mediate its effect on Ca(2+) signaling. It primarily functions as a cation nonselective channel within pathways controlling Ca(2+) entry in response to cell surface receptor activation. Through these pathways, it affects basic cell functions, such as proliferation and survival, differentiation, secretion, and cell migration, as well as cell type-specific functions such as chemotropic turning of neuronal growth cones and myoblast fusion. The biological role of TRPC1 has been studied in genetically engineered mice where the Trpc1 gene has been experimentally ablated. Although these mice live to adulthood, they show defects in several organs and tissues, such as the cardiovascular, central nervous, skeletal and muscular, and immune systems. Genetic and functional studies have implicated TRPC1 in diabetic nephropathy, Parkinson's disease, Huntington's disease, Duchenne muscular dystrophy, cancer, seizures, and Darier-White skin disease. PMID- 24756702 TI - TRPC2. AB - Trp2 was the second ortholog of the Drosophila trp gene to be identified. Whereas full-length TRPC2 transcripts have been cloned in a number of species including mice, rats, and New World monkeys, TRPC2 is a pseudogene in humans, apes, Old World monkeys, and in a number of other vertebrates. TRPC2 is highly expressed in the rodent VNO. It is also detectable at the protein level in murine erythroblasts, sperm, and brain and has been detected in other tissues by RT-PCR. Its activation by DAG and by erythropoietin has been described in greatest detail, and inhibition by Ca(2+)-calmodulin has been reported. The major demonstrated functions of TRPC2 are regulation of pheromone-evoked signaling in the rodent VNO, regulation of erythropoietin-stimulated calcium influx in murine erythroid cells, and ZP3-evoked calcium influx into sperm. Depletion of TRPC2 in knockout mice resulted in changes in behavior including altered sex discrimination and lack of male-male aggression. The red cells of TRPC2 knockout mice showed increased mean corpuscular volume, mean corpuscular hemoglobin, and hematocrit and reduced mean corpuscular hemoglobin concentration. TRPC2-depleted red cells were resistant to oxidative stress-induced hemolysis. PMID- 24756703 TI - TRPC3: a multifunctional signaling molecule. AB - TRPC3 represents one of the first identified mammalian relative of the Drosophila trp gene product. Despite extensive biochemical and biophysical characterization as well as ambitious attempts to uncover its physiological role in native cell systems, the channel protein still represents a rather enigmatic member of the TRP superfamily. TRPC3 is significantly expressed in the brain and heart and appears of (patho)physiological importance in both non-excitable and excitable cells, being potentially involved in a wide spectrum of Ca(2+) signaling mechanisms. TRPC3 cation channels display unique gating and regulatory properties that allow for recognition and integration of multiple input stimuli including lipid mediators, cellular Ca(2+) gradients, as well as redox signals. Physiological/pathophysiological functions of this highly versatile cation channel protein are as yet incompletely understood. Its ability to associate in a dynamic manner with a variety of partner proteins enables TRPC3 to serve coordination of multiple downstream signaling pathways and control of divergent cellular functions. Here, we summarize current knowledge on ion channel features as well as possible signaling functions of TRPC3 and discuss the potential biological relevance of this signaling molecule. PMID- 24756704 TI - TRPC4- and TRPC4-containing channels. AB - TRPC4 proteins comprise six transmembrane domains, a putative pore-forming region, and an intracellularly located amino- and carboxy-terminus. Among eleven splice variants identified so far, TRPC4alpha and TRPC4beta are the most abundantly expressed and functionally characterized. TRPC4 is expressed in various organs and cell types including the soma and dendrites of numerous types of neurons; the cardiovascular system including endothelial, smooth muscle, and cardiac cells; myometrial and skeletal muscle cells; kidney; and immune cells such as mast cells. Both recombinant and native TRPC4-containing channels differ tremendously in their permeability and other biophysical properties, pharmacological modulation, and mode of activation depending on the cellular environment. They vary from inwardly rectifying store-operated channels with a high Ca(2+) selectivity to non-store-operated channels predominantly carrying Na(+) and activated by Galphaq- and/or Galphai-coupled receptors with a complex U shaped current-voltage relationship. Thus, individual TRPC4-containing channels contribute to agonist-induced Ca(2+) entry directly or indirectly via depolarization and activation of voltage-gated Ca(2+) channels. The differences in channel properties may arise from variations in the composition of the channel complexes, in the specific regulatory pathways in the corresponding cell system, and/or in the expression pattern of interaction partners which comprise other TRPC proteins to form heteromultimeric channels. Additional interaction partners of TRPC4 that can mediate the activity of TRPC4-containing channels include (1) scaffolding proteins (e.g., NHERF) that may mediate interactions with signaling molecules in or in close vicinity to the plasma membrane such as Galpha proteins or phospholipase C and with the cytoskeleton, (2) proteins in specific membrane microdomains (e.g., caveolin-1), or (3) proteins on cellular organelles (e.g., Stim1). The diversity of TRPC4-containing channels hampers the development of specific agonists or antagonists, but recently, ML204 was identified as a blocker of both recombinant and endogenous TRPC4-containing channels with an IC50 in the lower micromolar range that lacks activity on most voltage-gated channels and other TRPs except TRPC5 and TRPC3. Lanthanides are specific activators of heterologously expressed TRPC4- and TRPC5-containing channels but can block individual native TRPC4-containing channels. The biological relevance of TRPC4 containing channels was demonstrated by knockdown of TRPC4 expression in numerous native systems including gene expression, cell differentiation and proliferation, formation of myotubes, and axonal regeneration. Studies of TRPC4 single and TRPC compound knockout mice uncovered their role for the regulation of vascular tone, endothelial permeability, gastrointestinal contractility and motility, neurotransmitter release, and social exploratory behavior as well as for excitotoxicity and epileptogenesis. Recently, a single-nucleotide polymorphism (SNP) in the Trpc4 gene was associated with a reduced risk for experience of myocardial infarction. PMID- 24756705 TI - TRPC5. AB - Human canonical transient receptor potential channel 5 (TRPC5) has been cloned from the Xq23 region on chromosome X as a suspect in nonsyndromic mental retardation. TRPC5 is a Ca(2+)-permeable cation channel predominantly expressed in the CNS, including the hippocampus, cerebellum, amygdala, sensory neurons, and retina. It also shows more restricted expression in the periphery, notably in the kidney and cardiovascular system. Homotetrameric TRPC5 channels are primarily activated by receptors coupled to Gq and phospholipase C and/or Gi proteins, but TRPC5 channels may also gate in a store-dependent manner, which requires other partner proteins such TRPC1, STIM1, and Orai1. There is an impressive array of other activators of TRPC5 channels, such as nitric oxide, lysophospholipids, sphingosine-1-phosphate, reduced thioredoxin, protons, lanthanides, and calcium, and many can cause its direct activation. Moreover, TRPC5 shows constitutive activity, and it is responsive to membrane stretch and cold. Thus, TRPC5 channels have significant potential for synergistic activation and may serve as an important focal point in Ca(2+) signalling and electrogenesis. Moreover, TRPC5 functions in partnership with about 60 proteins, including TRPC1, TRPC4, calmodulin, IP3 receptors, NHERF, NCS-1, junctate, stathmin 2, Ca(2+)-binding protein 1, caveolin, and SESTD1, while its desensitisation is mediated by both protein kinases A and C. TRPC5 has a distinct voltage dependence shared only with its closest relative, TRPC4. Its unique N-shaped activation curve underlined by intracellular Mg(2+) block seems to be perfectly "shaped" to trigger action potential discharge, but not to grossly interfere with the action potential shape. The range of biological functions of TRPC5 channels is also impressive, from neurotransmission to control of axon guidance and vascular smooth muscle cell migration and contractility. Recent studies of Trpc5 gene knockouts begin to uncover its roles in fear, anxiety, seizures, and cold sensing. PMID- 24756706 TI - TRPC6: physiological function and pathophysiological relevance. AB - TRPC6 is a non-selective cation channel 6 times more permeable to Ca(2+) than to Na(+). Channel homotetramers heterologously expressed have a characteristic doubly rectifying current-voltage relationship and are directly activated by the second messenger diacylglycerol (DAG). TRPC6 proteins are also regulated by specific tyrosine or serine phosphorylation and phosphoinositides. Given its specific expression pattern, TRPC6 is likely to play a number of physiological roles which are confirmed by the analysis of a Trpc6 (-/-) mouse model. In smooth muscle Na(+) influx through TRPC6 channels and activation of voltage-gated Ca(2+) channels by membrane depolarisation is the driving force for contraction. Permeability of pulmonary endothelial cells depends on TRPC6 and induces ischaemia-reperfusion oedema formation in the lungs. TRPC6 was also identified as an essential component of the slit diaphragm architecture of kidney podocytes and plays an important role in the protection of neurons after cerebral ischaemia. Other functions especially in immune and blood cells remain elusive. Recently identified TRPC6 blockers may be helpful for therapeutic approaches in diseases with highly activated TRPC6 channel activity. PMID- 24756707 TI - Transient receptor potential canonical 7: a diacylglycerol-activated non selective cation channel. AB - Transient receptor potential canonical 7 (TRPC7) channel is the seventh member of the mammalian TRPC channel family. TRPC7 mRNA, protein, and channel activity have been detected in many tissues and organs from the mouse, rat, and human. TRPC7 has high sequence homology with TRPC3 and TRPC6, and all three channels are activated by membrane receptors that couple to isoforms of phospholipase C (PLC) and mediate non-selective cation currents. TRPC7, along with TRPC3 and TRPC6, can be activated by direct exogenous application of diacylglycerol (DAG) analogues and by pharmacological maneuvers that increase endogenous DAG in cells. TRPC7 shows distinct properties of activation, such as constitutive activity and susceptibility to negative regulation by extracellular Ca(2+) and by protein kinase C. TRPC7 can form heteromultimers with TRPC3 and TRPC6. Although TRPC7 remains one of the least studied TRPC channel, its role in various cell types and physiological and pathophysiological conditions is beginning to emerge. PMID- 24756708 TI - TRPV1. AB - TRPV1 is a well-characterised channel expressed by a subset of peripheral sensory neurons involved in pain sensation and also at a number of other neuronal and non neuronal sites in the mammalian body. Functionally, TRPV1 acts as a sensor for noxious heat (greater than ~42 degrees C). It can also be activated by some endogenous lipid-derived molecules, acidic solutions (pH < 6.5) and some pungent chemicals and food ingredients such as capsaicin, as well as by toxins such as resiniferatoxin and vanillotoxins. Structurally, TRPV1 subunits have six transmembrane (TM) domains with intracellular N- (containing 6 ankyrin-like repeats) and C-termini and a pore region between TM5 and TM6 containing sites that are important for channel activation and ion selectivity. The N- and C- termini have residues and regions that are sites for phosphorylation/dephosphorylation and PI(4,5)P2 binding, which regulate TRPV1 sensitivity and membrane insertion. The channel has several interacting proteins, some of which (e.g. AKAP79/150) are important for TRPV1 phosphorylation. Four TRPV1 subunits form a non-selective, outwardly rectifying ion channel permeable to monovalent and divalent cations with a single-channel conductance of 50-100 pS. TRPV1 channel kinetics reveal multiple open and closed states, and several models for channel activation by voltage, ligand binding and temperature have been proposed. Studies with TRPV1 agonists and antagonists and Trpv1 (-/-) mice have suggested a role for TRPV1 in pain, thermoregulation and osmoregulation, as well as in cough and overactive bladder. TRPV1 antagonists have advanced to clinical trials where findings of drug-induced hyperthermia and loss of heat sensitivity have raised questions about the viability of this therapeutic approach. PMID- 24756709 TI - TRPV2. AB - Transient receptor potential vanilloid type 2, TRPV2, is a calcium-permeable cation channel belonging to the TRPV channel family. This channel is activated by heat (>52 degrees C), various ligands, and mechanical stresses. In most of the cells, a large portion of TRPV2 is located in the endoplasmic reticulum under unstimulated conditions. Upon stimulation of the cells with phosphatidylinositol 3-kinase-activating ligands, TRPV2 is translocated to the plasma membrane and functions as a cation channel. Mechanical stress may also induce translocation of TRPV2 to the plasma membrane. The expression of TRPV2 is high in some types of cells including neurons, neuroendocrine cells, immune cells involved in innate immunity, and certain types of cancer cells. TRPV2 may modulate various cellular functions in these cells. PMID- 24756711 TI - The TRPV4 channel. AB - The widely distributed TRPV4 cationic channel participates in the transduction of both physical (osmotic, mechanical, and heat) and chemical (endogenous, plant derived, and synthetic ligands) stimuli. In this chapter we will review TRPV4 expression, biophysics, structure, regulation, and interacting partners as well as physiological and pathological insights obtained in TRPV4 animal models and human genetic studies. PMID- 24756710 TI - TRPV3. AB - Transient receptor potential vanilloid-3 (TRPV3) is a Ca(2+)-permeable nonselective cation channel widely expressed in skin keratinocytes, as well as oral and nasal epithelia. TRPV3 is activated by innocuous warm as well as noxious hot temperatures. Activation of TRPV3 in skin keratinocytes causes release of multiple substances, which in turn regulate diverse functions including skin barrier formation, hair growth, wound healing, temperature sensing, and itch and pain perceptions. While several natural and synthetic ligands have been described for TRPV3, only one of them, farnesyl pyrophosphate, is naturally produced in animal cells. Together with the use of genetic mouse models, applications of these compounds have revealed not only the physiological functions but also regulatory mechanisms of TRPV3 channel by extracellular Ca(2+), Mg(2+), and protons as well as intracellular Ca(2+)-calmodulin, ATP, phosphatidylinositol 4,5 bisphosphate, polyunsaturated fatty acids, protons, and Mg(2+). Gain-of-function genetic mutations of TRPV3 in rodents and humans have been instrumental in unveiling the critical role of this channel in skin health and disease. PMID- 24756712 TI - TRPV5: a Ca(2+) channel for the fine-tuning of Ca(2+) reabsorption. AB - TRPV5 is one of the two channels in the TRPV family that exhibit high selectivity to Ca(2+) ions. TRPV5 mediates Ca(2+) influx into cells as the first step to transport Ca(2+) across epithelia. The specialized distribution in the distal tubule of the kidney positions TRPV5 as a key player in Ca(2+) reabsorption. The responsiveness in expression and/or activity of TRPV5 to hormones such as 1,25 dihydroxyvitamin D3, parathyroid hormone, estrogen, and testosterone makes TRPV5 suitable for its role in the fine-tuning of Ca(2+) reabsorption. This role is further optimized by the modulation of TRPV5 trafficking and activity via its binding partners; co-expressed proteins; tubular factors such as calbindin-D28k, calmodulin, klotho, uromodulin, and plasmin; extracellular and intracellular factors such as proton, Mg(2+), Ca(2+), and phosphatidylinositol-4,5 bisphosphate; and fluid flow. These regulations allow TRPV5 to adjust its overall activity in response to the body's demand for Ca(2+) and to prevent kidney stone formation. A point mutation in mouse Trpv5 gene leads to hypercalciuria similar to Trpv5 knockout mice, suggesting a possible role of TRPV5 in hypercalciuric disorders in humans. In addition, the single nucleotide polymorphisms in Trpv5 gene prevalently present in African descents may contribute to the efficient renal Ca(2+) reabsorption among African descendants. TRPV5 represents a potential therapeutic target for disorders with altered Ca(2+) homeostasis. PMID- 24756713 TI - TRPV6 channels. AB - TRPV6 (former synonyms ECAC2, CaT1, CaT-like) displays several specific features which makes it unique among the members of the mammalian Trp gene family (1) TRPV6 (and its closest relative, TRPV5) are the only highly Ca(2+)-selective channels of the entire TRP superfamily (Peng et al. 1999; Wissenbach et al. 2001; Voets et al. 2004). (2) Translation of Trpv6 initiates at a non-AUG codon, at ACG, located upstream of the annotated AUG, which is not used for initiation (Fecher-Trost et al. 2013). The ACG codon is nevertheless decoded by methionine. Not only a very rare event in eukaryotic biology, the full-length TRPV6 protein existing in vivo comprises an amino terminus extended by 40 amino acid residues compared to the annotated truncated TRPV6 protein which has been used in most studies on TRPV6 channel activity so far. (In the following numbering occurs according to this full-length protein, with the numbers of the so far annotated truncated protein in brackets). (3) Only in humans a coupled polymorphism of Trpv6 exists causing three amino acid exchanges and resulting in an ancestral Trpv6 haplotype and a so-called derived Trpv6 haplotype (Wissenbach et al. 2001). The ancestral allele encodes the amino acid residues C197(157), M418(378) and M721(681) and the derived alleles R197(157), V418(378) and T721(681). The ancestral haplotype is found in all species, the derived Trpv6 haplotype has only been identified in humans, and its frequency increases with the distance to the African continent. Apparently the Trpv6 gene has been a strong target for selection in humans, and its derived variant is one of the few examples showing consistently differences to the orthologues genes of other primates (Akey et al. 2004, 2006; Stajich and Hahn 2005; Hughes et al. 2008). (4) The Trpv6 gene expression is significantly upregulated in several human malignancies including the most common cancers, prostate and breast cancer (Wissenbach et al. 2001; Zhuang et al. 2002; Fixemer et al. 2003; Bolanz et al. 2008). (5) Male mice lacking functional TRPV6 channels are hypo-/infertile making TRPV6 one of the very few channels essential for male fertility (Weissgerber et al. 2011, 2012). PMID- 24756714 TI - TRPM1. AB - The transient receptor potential (TRP) channels play a wide variety of essential roles in the sensory systems of various species, both invertebrates and vertebrates. The TRP channel was first identified as a molecule required for proper light response in Drosophila melanogaster. We and another group recently revealed that TRPM1, the founding member of the melanoma-related transient receptor potential (TRPM) subfamily, is required for the photoresponse in mouse retinal ON-bipolar cells. We further demonstrated that Trpm1 is a component of the transduction cation channel negatively regulated by the metabotropic glutamate receptor 6 (mGulR6) cascade in ON-bipolar cells through a reconstitution experiment using CHO cells expressing Trpm1, mGluR6, and Goalpha. Furthermore, human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function and suffer from night blindness starting in early childhood. In addition to the function of transduction cation channel, TRPM1 is one of the retinal autoantigens in some paraneoplastic retinopathy (PR) associated with retinal ON-bipolar cell dysfunction. In this chapter, we describe physiological functions of the TRPM1 channel and its underlying biochemical mechanisms in retinal ON-bipolar cells in association with CSNB and PR. PMID- 24756715 TI - TRPM2. AB - TRPM2 is the second member of the transient receptor potential melastatin-related (TRPM) family of cation channels. The protein is widely expressed including in the brain, immune system, endocrine cells, and endothelia. It embodies both ion channel functionality and enzymatic ADP-ribose (ADPr) hydrolase activity. TRPM2 is a Ca(2+)-permeable nonselective cation channel embedded in the plasma membrane and/or lysosomal compartments that is primarily activated in a synergistic fashion by intracellular ADP-ribose (ADPr) and Ca(2+). It is also activated by reactive oxygen and nitrogen species (ROS/NOS) and enhanced by additional factors, such as cyclic ADPr and NAADP, while inhibited by permeating protons (acidic pH) and adenosine monophosphate (AMP). Activation of TRPM2 leads to increases in intracellular Ca(2+) levels, which can serve signaling roles in inflammatory and secretory cells through release of vesicular mediators (e.g., cytokines, neurotransmitters, insulin) and in extreme cases can induce apoptotic and necrotic cell death under oxidative stress. PMID- 24756716 TI - TRPM3. AB - Like most other members of the TRP family, the Trpm3 gene encodes proteins that form cation-permeable ion channels on the plasma membrane. However, TRPM3 proteins have several unique features that set them apart from the other members of this diverse family. The Trpm3 gene encodes for a surprisingly large number of isoforms generated mainly by alternative splicing. Only for two of the (at least) eight sites at which sequence diversity is generated the functional consequences have been elucidated, one leading to nonfunctional channels, the other one profoundly affecting the ionic selectivity. In the Trpm3 gene an intronic microRNA (miR-204) is co-transcribed with Trpm3. By regulating the expression of a multitude of genes, miR-204 increases the functional complexity of the Trpm3 locus. Over the past years, important progress has been made in discovering pharmacological tools to manipulate TRPM3 channel activity. These substances have facilitated the identification of endogenously expressed functional TRPM3 channels in nociceptive neurons, pancreatic beta cells, and vascular smooth muscle cells, among others. TRPM3 channels, which themselves are temperature sensitive, thus have been implicated in sensing noxious heat, in modulating insulin release, and in secretion of inflammatory cytokines. However, in many tissues where TRPM3 proteins are known to be expressed, no functional role has been identified for these channels so far. Because of the availability of adequate pharmacological and genetic tools, it is expected that future investigations on TRPM3 channels will unravel important new aspects and functions of these channels. PMID- 24756717 TI - TRPM4. AB - TRPM4 is a Ca(2+)-activated nonselective cation channel. The channel is activated by an increase of intracellular Ca(2+) and is regulated by several factors including temperature and Pi(4,5)P2. TRPM4 allows Na(+) entry into the cell upon activation, but is completely impermeable to Ca(2+). Unlike TRPM5, its closest relative in the transient receptor potential family, TRPM4 proteins are widely expressed in the body. Currents with properties that are reminiscent of TRPM4 have been described in a variety of tissues since the advent of the patch clamp technology, but their physiological role is only beginning to be clarified with the increasing characterization of knockout mouse models for TRPM4. Furthermore, mutations in the TRPM4 gene have been associated with cardiac conduction disorders in human patients. This review aims to overview the currently available data on the functional properties of TRPM4 and the current understanding of its physiological role in healthy and diseased tissue. PMID- 24756718 TI - TRPM5. AB - TRPM5 is a Ca(2+)-activated cation channel that mediates signaling in taste and other chemosensory cells. Within taste cells, TRPM5 is the final element in a signaling cascade that starts with the activation of G protein-coupled receptors by bitter, sweet, or umami taste molecules and that requires the enzyme PLCbeta2. PLCbeta2 breaks down PIP2 into DAG and IP3, and the ensuing release of Ca(2+) from intracellular stores activates TRPM5. Since its initial discovery in the taste system, TRPM5 has been found to be distributed in sparse chemosensory cells located throughout the digestive track, in the respiratory system, and in the olfactory system. It is also found in pancreatic islets, where it contributes to insulin secretion. This review highlights recent work on the mechanisms of the activation of the TRPM5 channel and its regulation by voltage, phosphoinositides, temperature, and pH. The distribution of the channel in the body and its functional contribution to various sensory and nonsensory processes are discussed. PMID- 24756719 TI - TRPM6. AB - TRPM6 is a bifunctional protein comprising a TRP cation channel segment covalently linked to an alpha-type serine/threonine protein kinase. TRPM6 is expressed in the intestinal and renal epithelial cells. Loss-of-function mutations in the human TRPM6 gene give rise to hypomagnesemia with secondary hypocalcemia (HSH), suggesting that the TRPM6 channel kinase plays a central role in systemic Mg(2+) homeostasis. In contrast, Trpm6 null mice show a delay in prenatal development, neural tube defects, and prenatal death. Possible functions of TRPM6 in prenatal and adult organisms will be discussed in this chapter. PMID- 24756721 TI - TRPM8. AB - Transient receptor potential melastatin 8 (TRPM8) was originally cloned from prostate tissue. Shortly thereafter, the protein was identified as a cold- and menthol-activated ion channel in peripheral sensory neurons, where it plays a critical role in cold temperature detection. In this chapter, we review our current understanding of the molecular and biophysical properties, the pharmacology, and the modulation by signaling molecules of this TRP channel. Finally, we examine the physiological role of TRPM8 and its emerging link to various human diseases, including pain, prostate cancer, dry eye disease, and metabolic disorders. PMID- 24756722 TI - TRPA1. AB - The transient receptor potential ankyrin subtype 1 protein (TRPA1) is a nonselective cation channel permeable to Ca(2+), Na(+), and K(+). TRPA1 is a promiscuous chemical nocisensor that is also involved in noxious cold and mechanical sensation. It is present in a subpopulation of Adelta- and C-fiber nociceptive sensory neurons as well as in other sensory cells including epithelial cells. In primary sensory neurons, Ca(2+) and Na(+) flowing through TRPA1 into the cell cause membrane depolarization, action potential discharge, and neurotransmitter release both at peripheral and central neural projections. In addition to being activated by cysteine and lysine reactive electrophiles and oxidants, TRPA1 is indirectly activated by pro-inflammatory agents via the phospholipase C signaling pathway, in which cytosolic Ca(2+) is an important regulator of channel gating. The finding that non-electrophilic compounds, including menthol and cannabinoids, activate TRPA1 may provide templates for the design of non-tissue damaging activators to fine-tune the activity of TRPA1 and raises the possibility that endogenous ligands sharing binding sites with such non-electrophiles exist and regulate TRPA1 channel activity. TRPA1 is promising as a drug target for novel treatments of pain, itch, and sensory hyperreactivity in visceral organs including the airways, bladder, and gastrointestinal tract. PMID- 24756720 TI - TRPM7. AB - The channel kinases TRPM6 and TRPM7 are fusion proteins with an ion transport domain and an enzymatically active kinase domain. TRPM7 has been found in every mammalian tissue investigated to date. The two-in-one protein structure, the ubiquitous expression profile, and the protein's unique biophysical characteristics that enable divalent ion transport involve TRPM7 in a plethora of (patho)physiological processes. With its prominent role in cellular and systemic magnesium homeostasis, TRPM7 emerges as a key player in embryonic development, global ischemia, cardiovascular disease, and cancer. PMID- 24756723 TI - TRPML1: an ion channel in the lysosome. AB - The first member of the mammalian mucolipin TRP channel subfamily (TRPML1) is a cation-permeable channel that is predominantly localized on the membranes of late endosomes and lysosomes (LELs) in all mammalian cell types. In response to the regulatory changes of LEL-specific phosphoinositides or other cellular cues, TRPML1 may mediate the release of Ca(2+) and heavy metal Fe(2+)/Zn(2+)ions into the cytosol from the LEL lumen, which in turn may regulate membrane trafficking events (fission and fusion), signal transduction, and ionic homeostasis in LELs. Human mutations in TRPML1 result in type IV mucolipidosis (ML-IV), a childhood neurodegenerative lysosome storage disease. At the cellular level, loss-of function mutations of mammalian TRPML1 or its C. elegans or Drosophila homolog gene results in lysosomal trafficking defects and lysosome storage. In this chapter, we summarize recent advances in our understandings of the cell biological and channel functions of TRPML1. Studies on TRPML1's channel properties and its regulation by cellular activities may provide clues for developing new therapeutic strategies to delay neurodegeneration in ML-IV and other lysosome-related pediatric diseases. PMID- 24756724 TI - TRPML2 and mucolipin evolution. AB - The TRPML2 protein, encoded by the Mcoln2 gene, is one of the three mucolipins (TRPML1-3), a subset of the TRP superfamily of ion channels. Although there are no thorough studies on the cellular distribution of TRPML2, its mRNA appears to be largely restricted to lymphocytes and other immune cells. This contrasts with the ubiquitous expression of TRPML1 and the limited but diverse expression of TRPML3 and clearly suggests a specialized role for TRPML2 in immunity. Localization studies indicate that TRPML2 is present in lysosomes (including the specialized lysosome-related organelle that B-lymphocytes use for processing of the antigen-bound B-cell receptor), late endosomes, recycling endosomes, and, at a much lower level, the plasma membrane. Heterologously expressed TRPML2, like TRPML1 and/or TRPML3, forms ion channels that can be activated by a gain-of function mutation (alanine to proline in the fifth transmembrane domain, close to the pore) that favors the open state, by a transient reduction of extracellular sodium followed by sodium replenishment, by small chemicals related to sulfonamides, and by PI(3,5)P2, a rare phosphoinositide that naturally accumulates in the membranes of endosomes and lysosomes and thus could act as a physiologically relevant agonist. TRPML2 channels are inwardly rectifying and permeable to Ca(2+), Na(+), and Fe(2+). When heterologously co-expressed, TRPML2 can form heteromultimers with TRPML1 and TRPML3. In B-lymphocytes, TRPML2 and TRPML1 may play redundant roles in the function of their specialized lysosome. Although the specific subcellular function of TRPML2 is unknown, distribution and channel properties suggest roles in calcium release from endolysosomes, perhaps to regulate vesicle fusion and/or subsequent scission or to release calcium from intracellular acidic stores for signaling in the cytosol. Alternatively, TRPML2 could function in the plasma membrane, and its abundance in vesicles of the endocytic pathway could simply be due to regulation by endocytosis and exocytosis. The Mcoln2 gene is closely downstream from and in the same orientation as Mcoln3 in the genomes of most jawed vertebrates (from humans to sharks) with the exception of pigs, Xenopus tropicalis, and ray-finned fishes. The close homology of TRPML2 and 3 (closer to each other than to TRPML1) suggests that Mcoln2 and Mcoln3 arose from unequal crossing over that duplicated a common ancestor and placed both gene copies in tandem. These genes would have come apart subsequently in pigs, Xenopus, and the ancestor to ray-finned fishes. All jawed vertebrates for which we have thorough genomic knowledge have distinct Mcoln1, 2, and 3 genes (except ray-finned fishes which, probably due to the whole-genome duplication in their common ancestor, have two Mcoln1-like genes and two Mcoln3 like genes, although only one Mcoln2 gene). However, the available genomes of invertebrate deuterostomes (a sea urchin, lancelet, and two tunicates) contain a single mucolipin gene that is equally distant from the three vertebrate mucolipins. Hence, vertebrate mucolipins arose through two rounds of gene duplication (the first one likely producing Mcoln1 and the ancestor to Mcoln2 and 3) at some time between the onset of craniates and that of jawed vertebrates. This is also the evolutionary period during which adaptive immunity appeared. Given the restricted expression of TRPML2 in immune cells, this evolutionary history suggests a functional role in the adaptive immunity characteristic of vertebrates. PMID- 24756725 TI - TRPML3. AB - TRPML3 belongs to the MCOLN (TRPML) subfamily of transient receptor potential (TRP) channels comprising three genes in mammals. Since the discovery of the pain sensing, capsaicin- and heat-activated vanilloid receptor (TRPV1), TRP channels have been found to be involved in regulating almost all kinds of our sensory modalities. Thus, TRP channel members are sensitive to heat or cold; they are involved in pain or osmosensation, vision, hearing, or taste sensation. Loss or mutation of TRPML1 can cause retina degeneration and eventually blindness in mice and men (mucolipidosis type IV). Gain-of-function mutations in TRPML3 cause deafness and circling behavior in mice. A special feature of TRPML channels is their intracellular expression. They mostly reside in membranes of organelles of the endolysosomal system such as early and late endosomes, recycling endosomes, lysosomes, or lysosome-related organelles. Although the physiological roles of TRPML channels within the endolysosomal system are far from being fully understood, it is speculated that they are involved in the regulation of endolysosomal pH, fusion/fission processes, trafficking, autophagy, and/or (hormone) secretion and exocytosis. PMID- 24756726 TI - The TRPP subfamily and polycystin-1 proteins. AB - It has been exciting times since the identification of polycystic kidney disease 1 (PKD1) and PKD2 as the genes mutated in autosomal dominant polycystic kidney disease (ADPKD). Biological roles of the encoded proteins polycystin-1 and TRPP2 have been deduced from phenotypes in ADPKD patients, but recent insights from vertebrate and invertebrate model organisms have significantly expanded our understanding of the physiological functions of these proteins. The identification of additional TRPP (TRPP3 and TRPP5) and polycystin-1-like proteins (PKD1L1, PKD1L2, PKD1L3, and PKDREJ) has added yet another layer of complexity to these fascinating cellular signalling units. TRPP proteins assemble with polycystin-1 family members to form receptor-channel complexes. These protein modules have important biological roles ranging from tubular morphogenesis to determination of left-right asymmetry. The founding members of the polycystin family, TRPP2 and polycystin-1, are a prime example of how studying human disease genes can provide insights into fundamental biological mechanisms using a so-called "reverse translational" approach (from bedside to bench). Here, we discuss the current literature on TRPP ion channels and polycystin-1 family proteins including expression, structure, physical interactions, physiology, and lessons from animal model systems and human disease. PMID- 24756728 TI - Influence of Alpha-2-Macroglobulin 5 bp I/D and Ile1000Val polymorphisms on the susceptibility of Alzheimer's disease: a systematic review and meta-analysis of 52 studies. AB - Accumulating studies have evaluated the association of Alpha-2-Macroglobulin gene (A2M) 5 bp insertion/deletion (5 bp I/D, rs3832852) and Ile1000Val (rs669) polymorphisms with Alzheimer's disease (AD) risk, but the results remain inconclusive. To investigate whether these two polymorphisms facilitate the susceptibility to AD, we conducted a comprehensive systematic review and meta analysis. Databases of PubMed, Embase, Web of Science, Medline, CNKI, and Google Scholar were searched to get the genetic association studies. All statistical analyses were conducted with Review Manager 5.2 and STATA11.0. Fifty-two articles were included in the final meta-analysis. We performed meta-analysis of 39 studies involving 8,267 cases and 7,932 controls for the 5 bp I/D polymorphism and 27 studies involving 6,585 cases and 6,637 controls for the Ile/Val polymorphism. Overall results did not show significant association between these two polymorphisms and AD risk in dominant, recessive, and multiplicative genetic models. On the stratification analyses by ethnicity and APOE epsilon4 status with genotypes of polymorphism sites, similar negative associations were found. The meta-analysis suggests that there is no enough evidence for associations of A2M gene polymorphisms (5 bp I/D, Ile1000Val) with AD risk at present, even after stratification by ethnicity and APOE epsilon4 with genotypes of polymorphism sites. However, due to the heterogeneity in the meta-analysis, the results should be interpreted with caution. PMID- 24756727 TI - Potential for cell therapy in Parkinson's disease using genetically programmed human embryonic stem cell-derived neural progenitor cells. AB - Neural transplantation is a promising strategy for restoring dopaminergic dysfunction and modifying disease progression in Parkinson's disease (PD). Human embryonic stem cells (hESCs) are a potential resource in this regard because of their ability to provide a virtually limitless supply of homogenous dopaminergic progenitors and neurons of appropriate lineage. The recent advances in developing robust cell culture protocols for directed differentiation of hESCs to near pure populations of ventral mesencephalic (A9-type) dopaminergic neurons has heightened the prospects for PD cell therapy. Here, we focus our review on current state-of-the-art techniques for harnessing hESC-based strategies toward development of a stem cell therapeutic for PD. Importantly, we also briefly describe a novel genetic-programming approach that may address many of the key challenges that remain in the field and that may hasten clinical translation. PMID- 24756729 TI - Identification of the microRNA expression profile in the regenerative neonatal mouse heart by deep sequencing. AB - MicroRNAs (miRNAs) are small noncoding RNAs that are involved in key biological processes, including development, differentiation, and regeneration. The global miRNA expression profile that regulates the regenerative potential of the neonatal mouse heart has not been reported. We performed deep sequencing to determine the genome-wide miRNA expression profile of the neonatal mouse heart at three key ages (1, 6, and 7 days). The miRNAs at least 1.4-fold differentially expressed between the three time points were selected for further analysis. Two miRNAs (mmu-miR-22-5p and mmu-miR-338-3p) were significantly upregulated, and nine miRNAs (mmu-miR-324-5p, mmu-miR-337-5p, mmu-miR-339-5p, mmu-miR-365-1-5p, mmu-miR-500-3p, mmu-miR-505-5p, mmu-miR-542-5p, mmu-miR-668-3p, and mmu-miR-92a-1 5p) were significantly downregulated in cardiac tissue of 7-day-old mice compared to 1- and 6-day-old mice. The expression patterns of five significantly different miRNAs were verified by quantitative real-time PCR. Furthermore, the potential targets of these putative miRNAs were suggested using miRNA target prediction tools. The candidate target genes are involved in the myocardial regenerative process, with a prominent role for the Notch signaling pathway. Our study provides a valuable resource for future investigation of the biological function of miRNAs in heart regeneration. PMID- 24756730 TI - Mitochondrial P-glycoprotein ATPase contributes to insecticide resistance in the cotton bollworm, Helicoverpa armigera (Noctuidae: Lepidoptera). AB - Cotton bollworm, Helicoverpa armigera, is one of the most damaging polyphagous pests worldwide, which has developed high levels of resistance to commonly applied insecticides. Mitochondrial P-glycoprotein (Pgp) was detected in the insecticide-resistant strain of H. armigera using C219 antibodies, and its possible role was demonstrated in the efflux of xenobiotic compounds using spectrofluorometer. The TMR accumulated in mitochondria in the absence of ATP, and effluxed out in presence of ATP; the process of efflux was inhibited in the presence of ortho-vandate, an inhibitor of Pgp, in insecticide-resistant larvae of H. armigera. The mitochondria isolated from insecticide-resistant larvae were resistant to insecticide-induced inhibition of oxygen consumption and cytochrome c release. Membrane potential decreased in a dose-dependent manner in the presence of higher concentration of insecticides (>50 uM) in mitochondria of insecticide-resistant larvae. In conclusion, mitochondrial Pgp ATPase detected in the insecticide-resistant larvae influenced the efflux of xenobiotic compounds. Pgp might be involved in protecting the mitochondrial DNA and the components of the electron transport chain from damage due to insecticides, and contributing to the resistance to the deleterious effects of insecticides on the growth of insecticide-resistant H. armigera larvae. PMID- 24756731 TI - Overcoming barriers to discussing out-of-pocket costs with patients. PMID- 24756732 TI - Cadmium, nicotine and cigarettes: any hypertension paradox? PMID- 24756733 TI - Pandemic influenza A (H1N1) 2009 in the English- and Dutch-speaking Caribbean: an epidemiological overview. AB - OBJECTIVE: To describe epidemiological trends of pandemic influenza A (H1N1) in the English and Dutch-speaking Caribbean during the pandemic period. DESIGN AND METHODS: Data on laboratory-confirmed cases and deaths associated with pandemic influenza A (H1N1) contained in two regional databases at the Caribbean Epidemiology Centre (CAREC) were analysed. The data sources were epidemiological and laboratory reports from English and Dutch-speaking countries and the CAREC laboratory information system (LABIS). RESULTS: In the English- and Dutch speaking Caribbean, pandemic influenza A (H1N1) was the predominant circulating influenza virus type during the pandemic period. There were three distinct phases: a first pandemic wave during mid-April to end of August 2009 (734 cases), a second pandemic wave during September-December 2009 (570 cases) and a phase of low transmission during January to mid-August 2010 (55 cases). The majority of cases (76%) were aged less than 30 years, with children of school age being most affected. Most cases (89%) presented with symptoms of the respiratory tract and smaller proportions (20-40%) presented with gastrointestinal and other symptoms. No cases tested were resistant to oseltamivir. A quarter of cases required hospitalization and the case fatality rate was 1.8%. CONCLUSIONS: The epidemiological characteristics of the pandemic in the English- and Dutch speaking Caribbean were consistent with that in other parts of the world. It is important that post pandemic surveillance (epidemiological and virological) for respiratory illnesses continues to be enhanced in order to give a better understanding of seasonality and changing trends in respiratory illnesses and their aetiologic agents. PMID- 24756734 TI - The brainstem localization of gastric preganglionic parasympathetic neurons in the agouti (Dasyprocta leporina). AB - This study was designed to determine qualitatively, the source of gastric vagal nerve fibres in the Agouti. A total of 18 male and female adult agoutis were used for the present investigation. Following anaesthesia, laparotomy was performed and the stomach exteriorized. Multiple intramuscular injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) were then made into different areas of the stomach in the experimental animals. The control animals were divided into four groups of two animals each. The first group had intraperitoneal injection of the tracer, the second had intramuscular injection of normal saline, the third group had injection of tracer into the hepatic portal vein and the last group had injection of the tracer into the gastric walls followed immediately by bilateral vagotomy. Following a survival period of five to seven days, the animals were sacrificed by transcardial perfusion, first with normal saline followed by fixative and finally with 20% buffered sucrose. Following perfusion, the brainstem was extracted from the brain, immersed in 20% buffered sucrose and kept refrigerated overnight for cryoprotection. The brainstems were subsequently sectioned serially, processed for WGA-HRP neurohistochemistry and then analysed under light and dark-field illuminations. The analysis of the sections taken from the experimental animals revealed bilateral presence of WGA-HRP labelled neurons in the dorsal motor nucleus of the vagus nerve (DMNV) and the nucleus ambiguus (nA) of the medulla oblongata. No labelled neurons were seen in any of the sections taken from the control animals. The implications of the findings are discussed. PMID- 24756735 TI - An evaluation of treatment strategies for head and neck cancer in an African American population. AB - OBJECTIVE: This study evaluated treatment strategies for head and neck cancers in a predominantly African American population. METHODS: Data were collected utilizing medical records and the tumour registry at the Howard University Hospital. Kaplan-Meier method was used for survival analysis and Cox proportional hazards regression analysis predicted the hazard of death. RESULTS: Analysis revealed that the main treatment strategy was radiation combined with platinum for all stages except stage I. Cetuximab was employed in only 1% of cases. Kaplan Meier analysis revealed stage II patients had poorer outcome than stage IV while Cox proportional hazard regression analysis (p = 0.4662) showed that stage I had a significantly lower hazard of death than stage IV (HR = 0.314; p = 0.0272). Contributory factors included tobacco and alcohol but body mass index (BMI) was inversely related to hazard of death. CONCLUSIONS: There was no difference in survival using any treatment modality for African Americans. PMID- 24756736 TI - Myasthenia gravis in South Trinidad. AB - OBJECTIVE: There is no previous research on Myasthenia Gravis (MG) in Trinidad and Tobago. This study sought to determine the prevalence and to characterize MG in South Trinidad. METHODS: A cross-sectional study was performed over 30 months in South Trinidad to identify, interview and statistically analyse data on MG cases. RESULTS: Among 36 prevalent patients, female:male ratio was 1.6:1. Estimated MG point prevalence in South Trinidad on March 31, 2010 was 78 per million. Mean age of prevalent patients was 50.5 years. Mean age of onset was 35 years. A higher prevalence was detected in Africans than East Indians (178 vs 68 per million; p = 0.003). Ocular and extremity muscle weakness were the most common initial symptoms. Autoimmune conditions (mainly thyroid disease) co existed in 25.7%. Treatment involved pyridostigmine and/or immunosuppressants for all except two that went into remission with just steroids. Generalized MG occurred in 60%; 42.9% expressed social and/or professional handicap. One case with suggestive clinical features tested positive for muscle specific tyrosine kinase antibody. CONCLUSIONS: While many features of MG in South Trinidad were similar to international data, the unique, statistically significant higher prevalence in Africans than East Indians warrants further research, given the paucity of reports from Africa and India. Patients with MG suffered a diminished quality of life, necessitating improved health planning. PMID- 24756737 TI - Mean platelet volume in nasal polyps. AB - BACKGROUND: Many studies in literature point out that inflammation related to nasal polyp is mostly dependent on eosinophils and their inflammatory products. Beside eosinophils, platelets may have a role in nasal polyp development. Platelets are involved in haemostasis, tissue repairing and inflammation. However, to our knowledge, there are no reports in the literature that study the association between platelet parameters and nasal polyps. SUBJECTS AND METHODS: Forty-three patients with nasal polyps and forty-nine healthy controls were enrolled in the study, retrospectively. Laboratory data of patients with nasal polyp were obtained at the time of diagnosis. RESULTS: There were no statistically significant differences between the two groups in terms of white blood count, haemoglobin, haematocrit and platelet count. The mean platelet volume (MPV) value of the nasal polyp group was significantly lower than the control group (p = 0.025). Mean eosinophil count was significantly elevated in the nasal polyp group compared to the control group (p < 0.001). CONCLUSIONS: Reduction in MPV may be an indicator for nasal polyp formation. Further studies with a larger study population are needed to detect the possible correlation between eosinophil count and MPV values in patients with nasal polyps. PMID- 24756738 TI - Mean platelet volume is associated with glycaemic control and retinopathy in patients with type 2 diabetes mellitus. AB - OBJECTIVES: To investigate the relationship between mean platelet volume (MPV) and glycometabolic indices, to compare MPV according to HbA1c levels, and to analyse the difference in MPV between patients with and without microvascular complications. METHODS: This retrospective study was conducted on 60 Type 2 diabetic patients and 50 age- and sex-matched non-diabetic controls. We obtained demographic, clinical and laboratory data including MPV, platelet count, fasting and postprandial blood glucose (FBG and PBG), haemoglobin A1c (HbA1c), lipid profile, creatinine, systolic and diastolic blood pressure (BP) in patient and control groups, and diabetic microvascular complications including nephropathy, neuropathy, and retinopathy in the patient group. All analyses were performed using SPSS version 15.0 for Windows. RESULTS: Mean platelet volume in the diabetic group was higher than in the control group (p = 0.001). Mean platelet volume was positively correlated with FBG and HbA1c levels (p = 0.03 and p < 0.001, respectively). It was also negatively related to platelet count (p < 0.001). Mean platelet volume in patients with HbA1c > 7% was significantly higher than those with HbA1c <= 7% (p < 0.001). Mean platelet volume was significantly increased in patients with retinopathy compared to those without retinopathy (p = 0.04). CONCLUSION: This study has shown that an increased MPV is closely associated with poor glycaemic control, which may be a risk factor for diabetic retinopathy. Nonetheless, further prospective studies are needed to assess the relationship between MPV, glycaemic indices and microvascular complications. PMID- 24756739 TI - Effects of a mat Pilates programme on body composition in elderly women. AB - BACKGROUND: With ageing, the ability to mobilize fat is reduced and this, coupled with gradual decrease in lean body mass (LBM) from lessened exercise, allows for an increased body fat percentage (%BF). Exercising is considered a key to maintaining an appropriate body mass (BM), as it improves fat oxidation, while maintaining LBM. Although the effects of endurance and/or resistance training on fat mass (FM) and LBM in the elderly have well been established, limited data are forthcoming regarding the effects of Pilates as a training modality on these variables in the elderly. OBJECTIVE: The present study was therefore conducted to determine the effects of a mat Pilates programme on body fat in elderly women. METHODS: Fifty sedentary, apparently healthy females aged 60 years and older were randomly assigned a control (CG, n = 25) or an intervention (IG, n = 25) group. The IG took part in an eight-week progressive mat Pilates exercise programme, three times weekly while the CG were instructed to maintain their normal daily activities throughout the eight-week experimental period. All subjects underwent pre- and post-test in which FM and LBM were assessed. RESULTS: Eight weeks of mat Pilates demonstrated a significant (p <= 0.05) decrease in % BF (p = 0.016) and FM (p = 0.038), with a significant increase in LBM (p = 0.006), while not showing any significant changes (p >= 0.05) in BM (p = 0.979) and BMI (p = 0.992). The CG, however, did not produce any significant (p >= 0.05) changes in any of the tested anthropometric variables (BM: p = 0.266; BMI: p = 0.123; % BF: p = 0.516; FM: p = 0.937 and LBM: p = 0.522) after completion of the eight-week Pilates programme. CONCLUSION: An eight-week mat Pilates exercise programme may contradict or even reverse some of the most serious consequences of ageing associated with an increased fat mass and reduced lean body mass in elderly females. PMID- 24756740 TI - Surgical management of exertional anterior compartment syndrome of the leg. AB - OBJECTIVE: To describe the characteristic presentation of exertional leg pain in athletes and to discuss the diagnostic options and surgical management of exertional anterior compartment syndrome of the leg in this group of patients. METHODS: Data from a series of athletes presenting with exertional leg pain were analysed and categorized according to aetiology. RESULTS: Sixty-six athletes presenting with exertional leg pain in 102 limbs were analysed. Sixteen patients in a first group of 20 patients with a provisional diagnosis of exertional anterior compartment syndrome of the leg underwent a closed fasciotomy with complete resolution of symptoms. A second group of 42 patients were diagnosed as medial tibial stress syndrome and a third group of four patients had confirmed stress fracture of the tibia. CONCLUSION: Exertional leg pain is a common presenting complaint of athletes to sports physicians and physiotherapists. Careful analysis can lead to an accurate diagnosis and commencement of effective treatment. Exertional anterior compartment syndrome can be successfully treated utilizing a closed fasciotomy with a rapid return to sport. PMID- 24756742 TI - Results from a preliminary study to develop the quality adjustments for quality adjusted life year values for Trinidad and Tobago. AB - OBJECTIVE: No country can afford to provide all necessary healthcare for its citizens, so prioritization among interventions must feature in all health systems. Resources in health should be allocated among interventions/facilities/patients in such a way as to be in line with the objectives of the health system. To achieve this, resource allocation decisions must be informed by the relative contributions that prospective interventions will make to societal health and to costs. Internationally, the EQ-5D based quality adjusted life year (QALY) now dominates this kind of analysis. This paper reports on a pilot study to develop an EQ-5D-3L value set for Trinidad and Tobago based on a protocol that avoids some of the issues that are associated with other approaches to developing such value sets such as the complex elicitation tasks that respondents must carry out, and the large respondent samples required for collecting multiple valuation subset values using blocked designs. METHODS: An orthogonal discrete choice experiment design was used to elicit a set of choices from a sample of respondents. RESULTS: The choice data were analysed using mixed multinomial logistic regression to produce an internally valid model that predicts well. CONCLUSION: This paper marks an important milestone in the development of health resource allocation in the Caribbean. It sets out the importance of incorporating the impact of health interventions to inform health resource allocation decisions, describes the elicitation and analysis methods used in the pilot and provides an illustration of the use of the EQ-5D value set. PMID- 24756741 TI - Correlates of symptoms of depression and anxiety among clinic patients in western Jamaica. AB - OBJECTIVES: There is a paucity of studies on psychosocial disorders in clinic populations in Jamaica. Therefore, we sought to determine the prevalence and correlates of symptoms of depression and anxiety in a clinic population in western Jamaica. METHODS: A total of 338 participants from four outpatient clinics of : A total of 338 participants from four outpatient clinics of the Western Regional Health Authority (WRHA) were screened for symptoms of depression and anxiety using questions from the Beck Depression Inventory-II and the Beck Anxiety Inventory. The Chi-square test was used to examine differences in symptoms of anxiety and depression by gender. Multivariate linear and logistic regression were used to examine the associations between symptoms and sociodemographic variables with significance set at p<0.05. RESULTS: Approximately 30% of participants had moderate or severe depression symptoms while 18.6% had moderate or severe anxiety symptoms. Participants aged 30-39 years were more likely than older participants to have moderate or severe anxiety symptoms (odds ratio [OR]: 2.0, 95% confidence interval [CI]: 1.39, 5.56). Women reported a statistically significant higher prevalence of anxiety symptoms (10.0% vs 7.1%, p = 0.003). There was also a statistically significant difference between anxiety means by gender. Furthermore, income was found to be a significant predictor of anxiety for women only (p = 0.0113). Married persons were more likely than those who had never married to have moderate or severe anxiety symptoms (OR: 2.57, 95% CI: 1.14, 5.76). CONCLUSIONS: Our findings suggest that the prevalence of depression may be higher than global estimates in similar outpatient settings. Screening and intervention efforts may need to focus on younger persons, women, and married persons. PMID- 24756743 TI - Bilateral wrist drop complicating axillary crutches mobilization in a young adult. AB - OBJECTIVE: Axillary crutches are simple rehabilitative devices that are globally used temporarily or permanently to assist in ambulation of patients and rarely present with complication. This report is about bilateral wrist drop incidentally noticed in a young adult patient mobilized on axillary crutches after internal fixation of a simple right tibia fracture. METHODS: The fracture was fixed by intramedullary nailing and the patient was mobilized on axillary crutches. At six weeks, patient fearfully refused to be commenced on partial weight bearing and at 12 weeks after surgery he was noticed to be totally weightbearing on the bars of the appropriately long axillary crutches and had developed bilateral wrist drop. There was radiological evidence of healing at the fracture sites. Treatment included mobilization on one elbow crutch on the left, physical therapy and nerve stimulation. RESULTS: At six weeks of physiotherapy, the power of the dorsiflexors of the wrists had recovered completely. CONCLUSION: Bilateral posterior cord palsy of brachial plexus could occur even in young healthy patients but total recovery could occur if the diagnosis and treatment are prompt. Patients should be told in unequivocal terms not to weight bear directly on axillary bars. PMID- 24756744 TI - Simultaneous bilateral femoral neck stress fractures in a 24-year old male recruit: a case report. PMID- 24756745 TI - Intrathoracic hibernoma: an uncommon tumour. AB - Hibernomas are uncommon benign tumours that arise from the remnants of fetal brown adipose tissue. They are usually asymptomatic and have a slow growth pattern. Intrathoracic and pleural locations are exceptional for localization of hibernoma. A review of the English language medical literature revealed more than 110 cases, 20 of which were intrathoracic. In the article below, we discuss a 40 year old male patient who had pleural involvement and was treated by surgical resection. Following resection, the patient has remained problem-free for nine years. PMID- 24756746 TI - Orchiectomy performed in two patients with Brucella orchitis mimicking testicular tumour. AB - Brucellosis is a zoonosis caused by gram negative coccobacilli and it is an endemic infectious disease in Turkey. Infection is usually acquired as a result of direct contact with infected animals or by consuming milk or cheese freshly made from them. There exists a wide spectrum of clinical signs and symptoms in brucellosis. Many systems including musculoskeletal, gastrointestinal, cardiovascular and genitourinary may be involved in brucellosis. The genitourinary system is affected in 2% to 20% of the cases with brucellosis. The most common forms of brucellosis are epididymo-orchitis, testicular abscess and atrophy. The serum agglutination test to detect the presence of antibodies is a reliable test in patients with urogenital symptoms. Long-term and combined antibacterial therapy have been found to be effective in brucellosis. We present two cases undergoing orchiectomy because of testicular mass before the diagnosis of brucellosis was made. PMID- 24756747 TI - A case of pseudotumour in a haemophiliac. PMID- 24756748 TI - A rare adnexal mass in a teenager. PMID- 24756749 TI - Re-implantation of a degloving amputation of distal index finger caused by fireworks: a case report and literature review. AB - Amputations associated with fireworks are customarily treated by stump revision resulting in permanent disability. In this case report, we present an eight-year old boy who suffered an amputation of his right distal index finger at the level of the epiphyseal disk with degloving injury of the amputated finger caused by fireworks. Successful re-implantation was achieved. Two-year follow-up revealed fair cosmesis and acceptable functional and aesthetic recovery though the free distal phalanx had been absorbed completely. Re-implantation of a degloving amputation finger caused by fireworks is possible and can provide good distal soft tissue coverage and recovery of sensory and motor functions. PMID- 24756750 TI - Attitudes and awareness toward organ donation among clinic attendees in Trinidad and Tobago. PMID- 24756751 TI - A study on the effectiveness of recent traffic accident prevention measures based on trends in the number of traffic accidents in Japan: specific measures for the future based on recent conditions. PMID- 24756752 TI - Penile incarceration caused by an axe ring: an unusual case of sexual perversion. PMID- 24756753 TI - Novel target genes of RUNX2 transcription factor and 1,25-dihydroxyvitamin D3. AB - The RUNX2 transcription factor is indispensable for skeletal development and controls bone formation by acting as a signaling hub and transcriptional regulator to coordinate target gene expression. A signaling partner of RUNX2 is the nuclear vitamin D receptor (VDR) that becomes active when bound by its ligand 1,25-dihydroxyvitamin D3 (VD3). RUNX2 and VDR unite to cooperatively regulate the expression of numerous genes. In this study, we overexpressed RUNX2 in NIH3T3 fibroblasts concomitantly treated with VD3 and show that RUNX2 alone, or in combination with VD3, failed to promote an osteoblastic phenotype in NIH3T3 cells. However, the expression of numerous osteoblast-related genes was up regulated by RUNX2 and large-scale gene expression profiling using microarrays identified over 800 transcripts that displayed a twofold of greater change in expression in response to RUNX2 overexpression or VD3 treatment. Functional analysis using gene ontology (GO) revealed GO terms for ossification, cellular motility, biological adhesion, and chromosome organization were enriched in the pool of genes regulated by RUNX2. For the set of genes whose expression was modulated by VD3, the GO terms response to hormone stimulus, chemotaxis, and metalloendopeptidase activity where overrepresented. Our study provides a functional insight into the consequences of RUNX2 overexpression and VD3 treatment in NIH3T3 cells in addition to identifying candidate genes whose expression is controlled by either factor individually or through their functional cooperation. PMID- 24756756 TI - Low expression of let-7 predicts poor prognosis in patients with multiple cancers: a meta-analysis. AB - The connection between microRNA expression and cancers has been identified, and microRNAs may be considered as important prognostic biomarkers. However, it is still inconsistent whether expression of let-7 can predict prognosis in patients with multiple cancers. A meta-analysis was performed by searching PubMed, EMBASE, and ISI Web of Science databases. All data were extracted from articles comparing prognosis in patients with multiple cancers having low expression of let-7 with those having high expression. Pooled hazard ratios (HRs) and corresponding 95 % confidence intervals (CIs) were calculated. Subgroup analyses were conducted for cancer type and ethnicity. A total of 1,757 cases of multiple cancers were involved for this meta-analysis. The HR of low let-7 expression in multiple cancers was 1.80 (95 % CI 1.18-2.76), and that in lung cancer was 1.99 (95 % CI 1.17-3.40). A subgroup analysis was performed on ethnicity; combined HR was 1.61 (95 % CI 0.84-3.11) for Asians and 1.94 (95 % CI 1.11-3.39) for non-Asians. Low expression of let-7 might predict poor prognosis in patients with multiple cancers, especially in lung cancer. Furthermore, let-7 might be a biomarker in non-Asian patients with favorable prognosis. PMID- 24756757 TI - Relationships of FOXE1 and ATM genetic polymorphisms with papillary thyroid carcinoma risk: a meta-analysis. AB - We conducted the meta-analysis of all relevant case-control studies aiming to evaluate the relationships of common polymorphisms in forkhead box E1 (FOXE1) and ataxia telangiectasia mutated (ATM) genes to the risk of papillary thyroid carcinoma (PTC). A range of electronic databases were searched without language restrictions: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). This meta-analysis was conducted using the STATA 12.0 software. Crude odds ratio (OR) with their 95 % confidence interval (CI) were calculated. Eight case-control studies with 2,085 PTC patients and 10,341 healthy controls were included. Fourteen common polymorphisms were evaluated, including rs3758249 A > G, rs907577 G > A, rs1867277 G > A, rs3021526 C > T, rs1443434 G > T, rs907580 G > A, rs965513 A > G, rs944289 C > T, and rs189037 G > A polymorphisms in the FOXE1 gene and rs373759 G > A, rs4988099 A > G, rs1801516 G > A, rs664677 T > C, and rs609429 G > C polymorphisms in the ATM gene. Our results demonstrated that the FOXE genetic polymorphisms might be closely related to an increased risk of developing PTC under five genetic models (all P < 0.005), especially for rs3758249, rs907577, rs1867277, rs3021526, rs1443434, rs907580, rs704839, rs894673, and rs10119760 polymorphisms. Nevertheless, no positive associations were found between the ATM genetic polymorphisms and the development of PTC (all P > 0.05). The current meta analysis provided evidence that FOXE1 genetic polymorphisms may contribute to increased PTC risk, especially for rs3758249, rs907577, rs1867277, rs3021526, rs1443434, rs907580, rs704839, rs894673, and rs10119760 polymorphisms. However, the ATM genetic polymorphisms may not be important dominants of susceptibility to PTC. PMID- 24756758 TI - Association of endothelia nitric oxide synthase gene rs1799983 polymorphism with susceptibility to prostate cancer: a meta-analysis. AB - Genetic polymorphism of endothelial nitric oxide synthase (NOS3) rs1799983 (Glu298Asp) has been implicated to alter the risk of prostate cancer, but the results are controversial. Two investigators independently searched the PubMed, Cochrane Library, and Embase electronic databases up to September 30, 2013. Summary odds ratios (OR) and 95 % confidence interval (CI) for rs1799983 polymorphism and prostate cancer were calculated. Statistical analysis was performed with the software program Review Manage, version 5.0 and Stata 11.0. A total of 7 independent studies, including 1,792 cases and 2,411 controls, were identified. Our analysis suggested that rs1799983 was associated with prostate cancer risk in overall population under dominant model (OR = 1.15, 95%CI = 1.01 1.30, P = 0.03) and allelic model (OR = 1.11, 95%CI = 1.00-1.22, P = 0.04). In the subgroup analysis, we detected no association between rs1799983 polymorphism and prostate risk in Caucasian population under all the genetic models. This meta analysis showed the evidence that NOS3 rs1799983 polymorphism was associated with a risk of prostate cancer development in overall populations. PMID- 24756759 TI - Association of periodontal disease with oral cancer: a meta-analysis. AB - The objective is to evaluate the association of periodontal disease with the risk of oral cancer. Literature retrieval, selection and assessment, data extraction, and meta-analyses were performed according to the RevMan 5.0 guidelines. In the meta-analysis, we utilized random-effect model to pool the odds ratio (OR) according to the test of heterogeneity. A total of five eligible studies included 1,191 oral cancer patients and 1,992 healthy control subjects were analyzed. By meta-analysis, we found a significant association of periodontal disease with oral cancer [OR = 3.53, 95 % CI (1.52-8.23); P = 0.003]. Patients with periodontal disease have increased susceptibility to oral cancer. PMID- 24756760 TI - Aberrant DNA methylation of integrin alpha4 in human breast cancer. AB - Integrins are cell surface receptors that mediate cell-cell/extracellular interactions and have shown an association with metastasis or transformation in several cancers. However, the correlation between the clinicopathological status of breast cancer and the altered integrin alpha4 status is not clear. In this study, we investigated DNA methylation of integrin alpha4 in breast cancer. We retrieved 351 cases of surgically resected breast cancer (290 invasive carcinoma and 61 intraductal carcinoma). Methylation-specific polymerase chain reaction was performed to determine integrin alpha4 methylation status. Integrin alpha4 methylation was frequently observed in breast cancer specimens (145/351 cases, 41.3 %). In addition, DNA methylation of integrin alpha4 showed statistical correlation with HER2 positivity and higher histologic grade (p = 0.001, 0.008 in ductal carcinoma in situ and 0.003 in invasive ductal carcinoma). However, other clinicopathological data such as estrogen receptor, progesterone receptor, metastasis, and TNM status showed no statistical correlation. Moreover, we found that the downregulated expression of integrin alpha4 in a heavily methylated breast cancer cell line (ZR-75) was restored by treatment with 5-aza 2'deoxycytidine, a DNA methyltransferase inhibitor, implying transcriptional silencing by DNA methylation. We observed that integrin alpha4 methylation is associated with the histologic grade of tumors and lymph node metastasis. Also, this data supports a previous study that suggested integrin alpha4 and HER2 are involved in the same signaling pathway. DNA methylation of integrin alpha4 may be a poor prognostic factor which affects undifferentiated histologic change of breast cancer. PMID- 24756761 TI - Nicotine upregulates microRNA-21 and promotes TGF-beta-dependent epithelial mesenchymal transition of esophageal cancer cells. AB - A consistent positive association between cigarette smoking and the human esophageal cancer has been confirmed all over the world. However, details in the association need to be more focused on and be identified. Recently, aberrantly expressed microRNAs (miRNAs) have been shown to be promising biomarkers for understanding the tumorigenesis of a wide array of human cancers, including the esophageal cancer, and the deregulation on the epithelial to mesenchymal transition (EMT) by miRNAs is involved in the tumorigenesis. In present study, we were going to identify the role of nicotine-induced miR-21 in the EMT of esophageal cells. We found that there was an overexpression of miR-21 in esophageal specimens, having an association with cigarette smoking, and the upregulation of miR-21 was also induced by nicotine in esophageal carcinoma cell line, EC9706. Moreover, the upregulated miR-21 by nicotine promoted EMT transforming growth factor beta (TGF-beta) dependently. Thus, the present study reveals a novel oncogenic role of nicotine in human esophageal cancer. PMID- 24756762 TI - 11-trifluoromethyl-phenyldiazirinyl neurosteroid analogues: potent general anesthetics and photolabeling reagents for GABAA receptors. AB - RATIONALE: While neurosteroids are well-described positive allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors, the binding sites that mediate these actions have not been definitively identified. OBJECTIVES: This study was conducted to synthesize neurosteroid analogue photolabeling reagents that closely mimic the biological effects of endogenous neurosteroids and have photochemical properties that will facilitate their use as tools for identifying the binding sites for neurosteroids on GABAA receptors. RESULTS: Two neurosteroid analogues containing a trifluromethyl-phenyldiazirine group linked to the steroid C11 position were synthesized. These reagents, CW12 and CW14, are analogues of allopregnanolone (5alpha-reduced steroid) and pregnanolone (5beta-reduced steroid), respectively. Both reagents were shown to have favorable photochemical properties with efficient insertion into the C-H bonds of cyclohexane. They also effectively replicated the actions of allopregnanolone and pregnanolone on GABAA receptor functions: they potentiated GABA-induced currents in Xenopus laevis oocytes transfected with alpha1beta2gamma2L subunits, modulated [(35)S]t butylbicyclophosphorothionate binding in rat brain membranes, and were effective anesthetics in Xenopus tadpoles. Studies using [(3)H]CW12 and [(3)H]CW14 showed that these reagents covalently label GABAA receptors in both rat brain membranes and in a transformed human embryonal kidney (TSA) cells expressing either alpha1 and beta2 subunits or beta3 subunits of the GABAA receptor. Photolabeling of rat brain GABAA receptors was shown to be both concentration-dependent and stereospecific. CONCLUSIONS: CW12 and CW14 have the appropriate photochemical and pharmacological properties for use as photolabeling reagents to identify specific neurosteroid-binding sites on GABAA receptors. PMID- 24756764 TI - Predisposing effects of neonatal visceral pain on abuse-related effects of morphine in adult male Sprague Dawley rats. AB - RATIONALE: Adverse early life experiences are risk factors for drug abuse and addiction. Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but the impact of these changes on abuse-related effects of morphine are unknown. The NVP procedure used models chronic visceral hyperalgesia persisting across development. OBJECTIVES: Intravenous self administration, drug discrimination, and locomotor activity were used to compare the abuse-related effects of morphine in NVP and control rats. METHODS: Rats self administered 0.3 mg/kg/inj morphine under an FR1 schedule, and dose-effect functions for morphine were then established. Separate rats were trained to discriminate 3.2 mg/kg morphine from saline under an FR20 schedule, and morphine dose-effect functions were then determined in the absence and presence of 0.1 mg/kg naltrexone. A third group of rats was tested with a range of morphine doses in an assay of locomotor activity, then injected daily with 10 mg/kg morphine to assess locomotor sensitization. RESULTS: NVP rats self-administered more morphine than controls at reinforcing doses. Discriminative stimulus effects of morphine were similar between groups, but in the presence of naltrexone, the ED50 for morphine was more than 12* greater in control rats than in NVP animals. Morphine did not stimulate locomotor activity at any tested dose in NVP rats, although significant effects were observed in controls. Finally, significant locomotor sensitization was observed only in NVP rats. CONCLUSIONS: NVP-induced changes in brain opioid systems have persistent pharmacological consequences into adulthood and may increase sensitivity to abuse-related effects of opioids across development. PMID- 24756763 TI - Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans? AB - RATIONALE: A robust epidemiological literature suggests an association between chronic stress and the development of affective disorders. However, the precise biological underpinnings of this relationship remain elusive. Central to the human response and adaptation to stress, activation and inhibition of the hypothalamic pituitary adrenal (HPA) axis involves a multi-level, multi-system, neurobiological stress response which is as comprehensive in its complexity as it is precarious. Dysregulation in this complex system has implications for human stress related illness. OBJECTIVES: The pioneering research of Robert Purdy and colleagues has laid the groundwork for advancing our understanding of HPA axis regulation by stress-derived steroid hormones and their neuroactive metabolites (termed neurosteroids), which are potent allosteric modulators of GABAA receptor function in the central nervous system. This review will describe what is known about neurosteroid modulation of the HPA axis in response to both acute and chronic stress, particularly with respect to the current state of our knowledge of this process in humans. RESULTS: Implications of this research to the development of human stress-related illness are discussed in the context of two human stress-related psychiatric disorders - major depressive disorder and premenstrual dysphoric disorder. CONCLUSIONS: Neurosteroid-mediated HPA axis dysregulation is a potential pathophysiologic mechanism which may cross traditional psychiatric diagnostic classifications. Future research directions are identified. PMID- 24756765 TI - Cholesterol metabolism changes under long-term dietary restrictions while the cholesterol homeostasis remains unaffected in the cortex and hippocampus of aging rats. AB - Maintaining cholesterol homeostasis in the brain is vital for its proper functioning. While it is well documented that dietary restriction modulates the metabolism of cholesterol peripherally, little is known as to how it can affect cholesterol metabolism in the brain. The present study was designed to elucidate the impact of long-term dietary restriction on brain cholesterol metabolism. Three-month-old male Wistar rats were exposed to long-term dietary restriction until 12 and 24 months of age. The concentrations of cholesterol, its precursors and metabolites, and food-derived phytosterols were measured in the serum, cortex, and hippocampus by gas chromatography/mass spectrometry. Relative changes in the levels of proteins involved in cholesterol synthesis, transport, and degradation were determined by Western blot analysis. Reduced food intake influenced the expression patterns of proteins implicated in cholesterol metabolism in the brain in a region-specific manner. Dietary restriction decreased the concentrations of cholesterol precursors, lanosterol in the cortex, and lanosterol and lathosterol in the hippocampus at 12 months, while the level of desmosterol was elevated in the hippocampus at 24 months. The concentrations of cholesterol and 24(S)-hydroxycholesterol remained unaffected. Food-derived phytosterols were significantly lower after dietary restriction in both the cortex and hippocampus at 12 and 24 months. These findings provide new insight into the effects of dietary restriction on cholesterol metabolism in the brain, lending further support to its neuroprotective effect. PMID- 24756766 TI - Methylphenidate blocks effort-induced depletion of regulatory control in healthy volunteers. AB - A recent wave of studies--more than 100 conducted over the last decade--has shown that exerting effort at controlling impulses or behavioral tendencies leaves a person depleted and less able to engage in subsequent rounds of regulation. Regulatory depletion is thought to play an important role in everyday problems (e.g., excessive spending, overeating) as well as psychiatric conditions, but its neurophysiological basis is poorly understood. Using a placebo-controlled, double blind design, we demonstrated that the psychostimulant methylphenidate (commonly known as Ritalin), a catecholamine reuptake blocker that increases dopamine and norepinephrine at the synaptic cleft, fully blocks effort-induced depletion of regulatory control. Spectral analysis of trial-by-trial reaction times revealed specificity of methylphenidate effects on regulatory depletion in the slow-4 frequency band. This band is associated with the operation of resting-state brain networks that produce mind wandering, which raises potential connections between our results and recent brain-network-based models of control over attention. PMID- 24756767 TI - Living among the affluent: boon or bane? AB - This study examined whether national income can have effects on happiness, or subjective well-being (SWB), over and above those of personal income. To assess the incremental effects of national income on SWB, we conducted cross-sectional multilevel analysis on data from 838,151 individuals in 158 nations. Although greater personal income was consistently related to higher SWB, we found that national income was a boon to life satisfaction but a bane to daily feelings of well-being; individuals in richer nations experienced more worry and anger on average. We also found moderating effects: The income-SWB relationship was stronger at higher levels of national income. This result might be explained by cultural norms, as money is valued more in richer nations. The SWB of more residentially mobile individuals was less affected by national income. Overall, our results suggest that the wealth of the nation one resides in has consequences for one's happiness. PMID- 24756768 TI - The evolution of cancer risk assessment in the era of next generation sequencing. AB - Cancer genetics professionals face a new opportunity and challenge in adapting to the availability of cancer genetic testing panels, now available as a result of Next Generation Sequencing (NGS) technology. While cancer panels have been available for over a year, we believe that there is not yet enough data to create practice guidelines. Despite this, a year of experience allows us to provide our opinion on points to consider as cancer genetic counselors incorporate this testing technology into genetic counseling practice models. NGS technology offers the ability to potentially diagnose hereditary cancer syndromes more efficiently by testing many genes at once for a fraction of what it would cost to test each gene individually. However, there are limitations and additional risks to consider with these tests. Obtaining informed consent for concurrent testing of multiple genes requires that genetics professionals modify their discussions with patients regarding the potential cancer risks and the associated implications to medical management. We propose dividing the genes on each panel into categories that vary by degree of cancer risk (e.g. penetrance of the syndrome) and availability of management guidelines, with the aim to improve patient understanding of the range of information that can come from this testing. The increased risk for identifying variants of uncertain significance (VUS) when testing many genes at once must be discussed with patients. Pretest genetic counseling must also include the possibility to receive unexpected results as well as the potential to receive a result in the absence of related medical management guidelines. It is also important to consider whether a single gene test remains the best testing option for some patients. As panels expand, it is important that documentation reflects exactly which genes have been analyzed for each patient. While this technology holds the promise of more efficient diagnosis for many of our patients, it also comes with new challenges that we must recognize and address. PMID- 24756769 TI - Berberine combined with atorvastatin downregulates LOX-1 expression through the ET-1 receptor in monocyte/macrophages. AB - Studies have shown that the oxidative modification of low-density lipoprotein (oxLDL) plays a major role in atherogenesis. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediated the transport of oxLDL into macrophages, which promoted foam cell formation. Targeting LOX-1 may therefore be a promising approach to inhibit atherosclerosis. In the present study, we aimed to investigate the effect of berberine combined with atorvastatin on LOX-1 and explore the underlying molecular mechanism involved. Expression of LOX-1 in monocyte-derived macrophages (MDMs) exposed to berberine (0, 0.1, 1, 10 and 100 nM) and atorvastatin (100 nM) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis. Results showed that the expression of LOX-1 was decreased in a dose-dependent manner. Additionally, knockdown of the endothelin-1 (ET-1) receptor significantly blocked the inhibitory effect of berberine on LOX-1 expression. Body weight (BW), liver weight (LW) and kidney weight (KW) in the model rats were markedly increased at concentrations of berberine >=1 umol/kg, while heart weight (HW) and spleen weight (SW) remained constant among all groups. Berberine combined with atorvastatin also decreased serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels in the rat model as well as inflammation and oxidative stress. Furthermore, plasma ET-1 levels and LOX-1 expression were decreased by berberine combined with atorvastatin treatment, and the inhibitory effect on LOX-1 was impeded by an ET-1 receptor antagonist. The results demonstrated that berberine combined with atorvastatin downregulates LOX 1 expression through ET-1 receptors in monocyte/macrophages in vitro and in vivo. PMID- 24756770 TI - Deconvoluting effects of vine and soil properties on grape berry composition. AB - BACKGROUND: Grape berry composition is influenced by several factors including grapevine and soil properties and their interactions. Understanding how these factors interact to determine berry composition is integral to producing berries with desired composition. Here we used extensive spatio-temporal data to identify significant vine and soil features that influence Shiraz berry composition. RESULTS: The concentrations of berry flavonoids (anthocyanins, tannin and total phenolics), total soluble solids and pH were typically negatively associated with canopy, crop and berry size factors whereas titratable acidity was positively associated. The strengths of the associations, however, were generally greater with the crop and berry size factors than with the canopy size factor. The analyses also resolved separate influences of berry and crop size on berry composition. Soil properties had significant influences on berry composition; however, when influences of soil factors on vine-attributes were accounted for, the apparent effects of soil factors on berry composition were largely non existent. CONCLUSION: At each site, variations in berry composition were more strongly associated with crop and berry size than with canopy size factors. Apparent influences of soil properties on berry composition are indirect, being mediated via their effects on vine attributes (canopy, crop and berry sizes). PMID- 24756772 TI - Role of celiac disease screening for children with functional gastrointestinal disorders. PMID- 24756773 TI - Multivalent recognition of concanavalin A by {Mo132 } glyconanocapsules--toward biomimetic hybrid multilayers. AB - Herein, we consider Muller's spherical, porous, anionic, molybdenum oxide based capsule, (NH4)42[{(Mo(VI))Mo(VI)5O21(H2O)6}12{Mo(V)2O4(CH3COO)}30]?10 CH3COONH4?300 H2O=(NH4)42?1 a?crystal ingredients=1, {Mo132}, as an effective sugar-decorated nanoplatform for multivalent lectin recognition. The ion-exchange of NH4(+) ions of 1 with cationic-sugars, D-mannose-ammonium chloride (2) or D glucose-ammonium chloride (3) results in the formation of glyconanocapsules (NH4)(42-n)2n?1 a and (NH4)(42-m)3m?1 a. The Mannose (NH4)(42-n)2n?1 a capsules bind selectively Concanavalin A (Con A) in aqueous solution, giving an association avidity constant of K(a)(multi)=4.6*10(4) M(-1) and an enhancement factor of beta=K(a)(multi)/K(ass)(mono)=21.9, reminiscent of the formation of "glycoside clusters" on the external surface of glyconanocapsule. The glyconanocapsules (NH4)(42-n)2n?1 a and (NH4)(42-m)3m?1 a self-assemble in "hybrid multilayers" by successive layer-by-layer deposition of (NH4)(42-n)2n?1 a or (NH4)(42-m)3m?1 a and Con A. These architectures, reminiscent of versatile mimics of artificial tissues, can be easily prepared and quantified by using quartz crystal microgravimetry (QCM). The "biomimetic hybrid multilayers" described here are stable under a continual water flow and they may serve as artificial networks for a greater depth of understanding of various biological mechanisms, which can directly benefit the fields of chemical separations, sensors or storage-delivery devices. PMID- 24756775 TI - A motor learning-based intervention to ameliorate freezing of gait in subjects with Parkinson's disease. AB - Freezing of gait (FOG) is an episodic gait disturbance that is commonly seen in Parkinson's disease (PD). To date, treatment efficacy is limited. We tested the hypothesis that an intervention that utilizes motor learning provided through intensive cueing can alleviate this symptom. Fifteen subjects with PD suffering from FOG participated in a 6 week progressive motor learning program (three training sessions per week--open trial). A training session included FOG provoking situations (e.g., turns). Prior to each presumed FOG provocation (e.g., just before a turn), rhythmic auditory stimulation (RAS) was elicited and the subject was trained to walk rhythmically, coordinate left-right stepping and to increase step size, utilizing the RAS cueing. Net training duration increased from week to week and secondary cognitive tasks while walking were added to increase FOG propensity. FOG symptom burden was assessed before, immediately, and 4 weeks after the training period. The mean number of FOG episodes (+/-SEM) per 10 m of walking in a standardized gait assessment decreased from 0.52 +/- 0.29 in the pre-testing to 0.15 +/- 0.04 in the post-testing (p < 0.05). The duration of FOG episodes decreased from 4.3 +/- 2.1 to 2.6 +/- 0.6 s (p < 0.05). Additional measures (e.g., FOG questionnaire, gait speed) varied in their responsiveness to the treatment. These effects were retained 4 weeks after the training. The results of this open label study support the possibility that a motor learning based intervention is apparently effective in reducing FOG burden, suggesting that RAS can deliver 'anti-FOG' training. PMID- 24756776 TI - Cisplatin-induced senescence in ovarian cancer cells is mediated by GRP78. AB - Glucose-regulated protein 78 (GRP78), the most abundant and well-characterized glucose-regulated protein, is a major stress-inducible chaperone localized to the endoplasmic reticulum (ER). The purpose of the present study was to investigate the mechanisms of GRP78 involved in the senescence sensitivity of ovarian cancer cells to cisplatin. In the present study, we found that the chemotherapy sensitive ovarian tumor sections showed strong staining for heterochromatin protein 1-gamma (HP1-gamma), but weak staining for GRP78. Cisplatin-sensitive A2780 cells with low expression of GRP78 tended to undergo senescence easily when compared with the cisplatin-resistant C13K cells following a dose-gradient cisplatin exposure. Forced overexpression of GRP78 protected the cisplatin sensitive A2780 cells from cisplatin-induced senescence through P53 and CDC2. Knockdown of GRP78 rescued the senescence sensitivity of cisplatin-resistant C13K cells to cisplatin through P21 and CDC2. Twisting of Ca2+ release from ER stores by GRP78 was established to be associated with the sensitivity of cisplatin induced senescence in ovarian cancer cell lines. In conclusion, GRP78 may have anti-senescence effects on ovarian cancer cells involving multiple mechanisms. Intervention against GRP78 may reduce cisplatin resistance in ovarian cancer. PMID- 24756777 TI - C and APUD cells and endocrine tumours. Pearse's laboratory in the years 1965 1969: a personal recollection. AB - This paper is a personal recollection of the studies, conducted in Prof. Pearse's laboratory in London in the years 1965-1969, which led to the discovery of production of calcitonin by parafollicular C cells and medullary carcinomas of the thyroid. The author's intention is to underline the combination of technical excellence, brilliant intuition, dedication and serendipity which led to a series of major discoveries and, historically, established the pivotal role to be played by immunohistochemistry in endocrine research and diagnosis. The formulation of Pearse's APUD cell theory gave a formal credence to the existence of common endocrine mechanisms, molecular markers and structural features in dispersed cells, all belonging to a diffuse endocrine system. This represented a major breakthrough which primed, in the following years, the studies on polypeptide hormone-producing cells and tumours, thus paving the way to the endocrine histology and pathology as we know, and practice them today. PMID- 24756779 TI - Compliance properties of collagen-coated polyethylene terephthalate vascular prostheses. AB - BACKGROUND: Compliance mismatch between native artery and a prosthetic graft used for infrainguinal bypass is said to be a factor for graft failure. The aim of this study was to develop a technique for measuring the compliance of collagen coated polyethylene terephthalate (PET) vascular prostheses and to analyze the influence of several key properties on the elastic behavior of the grafts. METHODS: Compliance testing was performed on 3 prostheses with and without internal compliant membrane (ICM). The principle of this test was to study the dimensional changes of prostheses submitted to internal pressure from 30 to 240 mm Hg at intervals of predetermined values. RESULTS: We demonstrated that the ICM created links with the inner surface of the crimps and considerably modified the graft behavior when submitted to internal pressure. The results showed that compliance properties were dependent on the wall thickness and the crimping geometry of textile vascular prostheses. Mechanical analysis predicts the circumferential tensile behavior of these arterial grafts and validates tests for measuring compliance. PMID- 24756774 TI - Prospects for engineering neurons from local neocortical cell populations as cell mediated therapy for neurological disorders. AB - There is little cell replacement following neurological injury, limiting the regenerative response of the CNS. Progress in understanding the biology of neural stem cells has raised interest in using stem cells for replacing neurons lost to injury or to disease. Stem cell therapy may also have a role in rebuilding deficient neural circuitry underlying mood disorders, epilepsy, and pain modulation among other roles. In vitro expansion of stem cells with directed differentiation prior to transplantation is one approach to stem cell therapy. Emerging evidence suggests that it may be possible to convert in vivo endogenous neural cells to a neuronal fate directly, providing an alternative strategy for stem cell therapy to the CNS. This review assesses the evidence for engineering a subtype-specific neuronal fate of endogenous neural cells in the cerebral cortex as a function of initial cell lineage, reactive response to injury, conversion factors, and environmental context. We conclude with a discussion of some of the challenges that must be overcome to move this alternative in vivo engineered conversion process toward becoming a viable therapeutic option. PMID- 24756780 TI - Mechanical characterization of human gastrocolic ligament until failure. AB - Road accidents can lead to abdominal injuries ranging from severe to lethal, that include hemorrhage of organs and their attachment system. A good understanding and prediction of abdominal injuries therefore requires investigation of the mechanical properties of the attachment systems of abdominal organs. In particular, the gastrocolic ligament (GCL) is one major link between the stomach and the transverse colon. This study aims to investigate the mechanical properties of the GCL under very low and high strain rate uniaxial tensile tests until failure. Thirty-five GCL samples were dissected from 7 embalmed cadavers and tested at a rate of 1 mm/s and 1 m/s. Incidence of freezing was also evaluated. The mechanical response of GCL samples showed an approximately bilinear curve. Within the first linear region (less than 5% of ligament strain), the apparent elastic modulus was estimated at 247+/-144 kPa, while in the second region, it was estimated at 690+/-282 kPa. The average failure stress (sigmafail) and failure strain (epsilonfail) were 131.6+/-50 kPa and 29%+/-8%, respectively. High strain rate loading also showed high sensitivity to strain rate. The estimated GCL mechanical properties in this study can be implemented in finite element models of the abdomen to further investigate the mechanical contribution of the organ attachment system under traumatic loading conditions. PMID- 24756781 TI - Short-term effects of microstructured surfaces: role in cell differentiation toward a contractile phenotype. AB - Cell adhesion plays a key role in cell behavior, in terms of migration, proliferation, differentiation and apoptosis. All of these events concur with tissue regeneration and remodeling mechanisms, integrating a complex network of intracellular signaling modules. Morphogenetic responses, which involve changes in cell shape, proliferation and differentiation, are thought to be controlled by both biochemical and biophysical cues. Indeed, the extracellular matrix not only displays adhesive ligands necessary for cell adhesion but also plays an essential biomechanical role - responsible, for instance, for the acquisition of the contractile phenotype. The substrate topography around the forming tissues and the associated mechanical stresses that are generated regulate cellular morphology, proliferation and differentiation. Thus, the ability to tailor topographical features around cells can be a crucial design parameter in tissue engineering applications, inducing cells to exhibit the required performances.In this work, we designed micropillared substrates using highly spaced arrays (interspacing equal to 25 um) to evaluate the effects of topography on C2C12 myoblasts' adhesion and differentiation. Optical and fluorescence microscopy images were used to observe cell adhesion, together with Western blot analysis on vinculin and focal adhesion kinase (FAK) expression, a protein highly involved in adhesive processes. Differentiation marker (Myf5, myogenin and myosin heavy chain [MHC]) expression was also studied, in relation to the effect of different substrate topographies on the enhancement of a contractile phenotype. Our results demonstrated that microstructured surfaces may play a key role in the regeneration of functional tissues. PMID- 24756782 TI - Thermal isotherms in PMMA and cell necrosis during total hip arthroplasty. AB - BACKGROUND: Polymethylmethacrylate (PMMA), also known as bone cement, is a commonly used adhesive material to fix implants in Total Hip Arthroplasty (THA). During implantation, bone cement undergoes a polymerization reaction which is an exothermic reaction and results in the release of heat to the surrounding bone tissue, which ultimately leads to thermal necrosis. Necrosis in the bony tissue results in early loosening of the implant, which causes pain and reduces the life of the implant. PURPOSE: The main objective of the present study was to understand the thermal isotherms in PMMA and to determine the optimal cement mantle thickness to prevent cell necrosis during THA. METHODS: In this study, the environment in the bony tissue during implantation was simulated by constructing 3D solid models to observe the temperature distribution in the bony tissue at different cement mantle thicknesses (1 mm, 3 mm and 5 mm), by applying the temperature conditions that exist during the surgery. Stems made with Co-Cr-Mo, 316L stainless steel and Ti6Al4V were used, which acted as heat sinks, and a thermal damage equation was used to measure the bone damage. FEA was conducted based on temperature conditions and thermal isotherms at different cement mantle thicknesses were obtained. RESULTS: Thermal isotherms derived with respect to distance in the bony tissue from the center of the cement mantle, and cell necrosis was determined at different mantle thicknesses. Based on the deduced results, cement mantle thickness of 1-5 mm does not cause thermal damage in the bony tissue. CONCLUSION: Considering the long term stability of the implant, cement mantle thickness range from 3 mm-5 mm was found to be optimal in THA to prevent cell necrosis. PMID- 24756783 TI - Imatinib mesylate. AB - Imatinib mesylate (Gleevec, Glivec [Novartis, Basel, Switzerland], formerly referred to as STI571 or CGP57148B) represents the paradigm of a new class of anticancer agents, so-called small molecules. They have a high selectivity against a specific molecular target known to be the cause for the establishment and maintenance of the malignant phenotype. Imatinib is a rationally designed oral signal transduction inhibitor that specifically targets several protein tyrosine kinases, Abl, Arg (Abl-related gene), the stem cell factor receptor (c KIT), platelet-derived growth factor receptor (PDGF-R), and their oncogenic forms, most notably BCR-ABL. Imatinib has been shown to have remarkable clinical activity in patients with chronic myeloid leukemia (CML) and malignant gastrointestinal stroma tumors (GIST) leading to its approval for treatment of these diseases. Treatment with imatinib is generally well tolerated with a low incidence of severe side effects. The most common adverse events include mild to moderate edema, muscle cramps, diarrhea, nausea, skin rashes, and myelosuppression. Several mechanisms of resistance have been identified. Clonal evolution, amplification, or overexpression of BCR-ABL as well as mutations in the catalytic domain, P-loop, and other mutations have been demonstrated to play a role in primary and secondary resistance to imatinib, respectively. Understanding of the underlying mechanisms of resistance has led to the development of new second- and third-generation tyrosine kinase inhibitors (see chapters on dasatinib, nilotinib, bosutinib, and ponatinib). PMID- 24756784 TI - Dasatinib. AB - Dasatinib is an orally available short-acting dual ABL/SRC tyrosine kinase inhibitor (TKI). It potently inhibits BCR-ABL and SRC family kinases (SRC, LCK, YES, FYN), but also c-KIT, PDGFR-alpha and PDGFR-beta, and ephrin receptor kinase. Dasatinib is an effective treatment for chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Both diseases are characterized by a constitutively active tyrosine kinase; BCR-ABL. Dasatinib inhibits BCR-ABL with greater potency compared with other BCR-ABL inhibitors and is active in CML resistant or intolerant to imatinib. Dasatinib is approved for the treatment of CML (all phases) and for the treatment of Ph+ ALL, resistant or intolerant to prior imatinib treatment. Randomized trial data in CML show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses, correlated with improved longer-term outcomes. A once-daily dose of 100 mg in chronic phase CML results in high hematologic and molecular remission rates and prolongation of survival. In accelerated and blastic phase of CML, as well as in Ph+ ALL, complete hematologic and cytogenetic remissions frequently occur. Remissions however are very short. In these patients, once-daily 140 mg is the recommended dose. The effect of dasatinib in other malignancies including solid tumors is subject of clinical studies. Regardless of many clinical trials in different tumor types and in different combinations of dasatinib with other agents, the role of dasatinib in the treatment of solid tumors has not yet been defined. Side effects of dasatinib are frequent but mostly moderate and manageable and include cytopenias and pleural effusions. The review presents the preclinical and clinical activity of dasatinib with a focus on clinical studies in CML. PMID- 24756785 TI - Nilotinib. AB - Targeted therapy of Philadelphia chromosome-positive chronic myeloid leukemia (CML) using the tyrosine kinase inhibitor imatinib mesylate has been one of the most striking achievements in modern cancer medicine. However, while imatinib can establish long-term remission in many cases, resistance to or intolerance of imatinib is eventually experienced by a substantial number of patients. Subsequent advances have led to the development of novel tyrosine kinase inhibitors (TKIs). One such inhibitor, nilotinib, was rationally designed to increase its affinity and specificity for the oncogenic tyrosine kinase Bcr-Abl compared with imatinib and has been shown to be effective after imatinib failure. Recently, nilotinib has been shown to be more effective when used as first-line therapy of chronic phase CML. PMID- 24756786 TI - Bosutinib: a novel second-generation tyrosine kinase inhibitor. AB - Bosutinib (SKI-606) is a 4-anilino-3-quinoline carbonitrile, which acts as a dual inhibitor of Src and ABL kinases. In addition, the BCR-ABL fusion gene product, a constitutively activated tyrosine kinase which is crucial for the development of chronic myeloid leukemia (CML), is highly sensitive to bosutinib. Interestingly, distinctly lower concentrations of bosutinib are required to ablate BCR-ABL phosphorylation when compared to the first-generation tyrosine kinase inhibitor imatinib (IM). Bosutinib is a potent inhibitor of CML cell proliferation in vitro and has demonstrated promising activity in CML patients resistant or intolerant to IM as well as in newly diagnosed patients with chronic phase CML (CML-CP). Remarkably, bosutinib has been found to be capable of overcoming the majority of IM-resistant BCR-ABL mutations. Bosutinib has the potency to induce deep and fast responses in second- and third-/fourth-line treatment, and as a consequence, the drug has recently been licensed for patients previously treated with one or more tyrosine kinase inhibitor(s) and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Due to its potency and differing toxicity profile, it promises to be a good therapeutic option for a defined cohort of patients. The most common side effects are gastrointestinal with most of the patients suffering from nausea, vomiting, or diarrhea. For the most part, these gastrointestinal symptoms occur early after treatment initiation, are manageable, and often self-limiting. Continuous monitoring of liver enzymes upon treatment initiation is necessary during bosutinib treatment. In addition to CML treatment, bosutinib has shown some efficacy in selected patients suffering from advanced-stage solid tumors. In conclusion, bosutinib is a promising novel small molecule inhibitor approved now for targeted therapy of CML and in clinical development for other malignancies. PMID- 24756787 TI - Ponatinib: a third-generation inhibitor for the treatment of CML. AB - The establishment of imatinib as the standard therapy for CML marked the beginning of a new era of treatment. Due to occurring intolerance and resistance against the drug, developing newer inhibitors was promoted. This led to the second-generation inhibitors dasatinib, nilotinib and bosutinib. Despite all achieved improvement, all first- and second-generation inhibitors are ineffective against the BCR-ABL T315I "gatekeeper" mutation. In order to overcome this issue and to further improve the inhibitory effect, the third-generation inhibitor ponatinib was developed. Various clinical trials have been launched to study the effect of ponatinib in the clinical setting. Based on positive phase 1 and phase 2 trials, ponatinib was approved for the second-line treatment of CML and Ph+ ALL in December 2012 in the United States and in July 2013 in the European Union. Further trials investigate the potential effect of ponatinib in kinase-dependent subgroups of other malignancies. In conclusion, ponatinib has proved to be a powerful BCR-ABL inhibitor, which exhibits clinical activity both in BCR-ABL wild type and mutant CML, including activity against the T315I mutation. Despite previous TKI failure, chronic-phase CML patients can achieve sustained remissions using the novel drug, offering a new therapeutic option in the treatment for CML. PMID- 24756788 TI - Erlotinib. AB - The epidermal growth factor receptor (EGFR) has been implicated in a multiplicity of cancer-related signal transduction pathways such as cellular proliferation, adhesion, migration, neoangiogenesis and apoptosis inhibition, all of them are important features of cancerogenesis and tumour progression. Its tyrosine kinase activity plays a central role in mediating these processes and has been intensely studied to exploit it as a therapeutic target. Inhibitors of this pathway have been developed and assessed in trials with significant efficacy in clinical applications. The current review focuses in particular on the clinical data of EGFR tyrosine kinase inhibition in different tumour entities, preferably non small cell lung cancer and pancreatic cancer with emphasis to the approved small molecule erlotinib. Its clinical applications, evidence-based efficacy and toxicity as well as predictive markers of response are discussed. PMID- 24756789 TI - Lapatinib. AB - The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases plays an important role in the biology of many cancers. In breast and gastric cancer, and maybe also additional tumor types, HER2 and its homo- or heterodimerization with HER1 or HER3 are essential for cancer cell growth and survival. Breast cancer patients overexpressing HER2 have a poor prognosis, which can be substantially improved upon HER2-targeted therapy using the monoclonal antibody trastuzumab. Lapatinib is a dual tyrosine kinase inhibitor (TKI), blocking HER1 and HER2 tyrosine kinase activity by binding to the ATP-binding site of the receptor's intracellular domain. This results in the inhibition of tumor cell growth. In patients, the drug is relatively well tolerated with mostly low-grade adverse effects. In particular and unlike to trastuzumab, it has very little, if any, adverse effects on cardiac function. In 2007, lapatinib has been approved in combination with capecitabine in patients with advanced HER2-positive breast cancer upon progressive disease following standard therapy with anthracyclines, taxanes, and trastuzumab. In 2010, the approval was extended to the treatment of postmenopausal women with advanced, hormone receptor- and HER2 positive breast cancer, for whom hormonal therapy is indicated. Ongoing and future studies will explore its role in the (neo)adjuvant therapy setting, in further drug combinations as well as in the treatment of HER2-positive tumors other than breast cancer. PMID- 24756790 TI - Sorafenib: targeting multiple tyrosine kinases in cancer. AB - Sorafenib (BAY 43-9006, Nexavar(r)) is an oral multiple tyrosine kinase inhibitor. Main targets are receptor tyrosine kinase pathways frequently deregulated in cancer such as the Raf-Ras pathway, vascular endothelial growth factor (VEGF) pathway, and FMS-like tyrosine kinase 3 (FLT3). Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer. Multiple clinical trials are undertaken to further investigate the role of sorafenib alone or in combination for the treatment of various tumor entities. PMID- 24756791 TI - Sunitinib in the treatment of advanced solid tumors. AB - Sunitinib is an oral multikinase inhibitor that blocks the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) alpha and beta, c-kit, and other receptors. These attributes have proven to be efficacious in the treatment of metastatic renal cell carcinoma (RCC), unresectable gastrointestinal stromal tumors (GIST), and well-differentiated advanced pancreatic neuroendocrine tumors (PNET). Though activity has been reported in other tumor types, phase III trials have not yet demonstrated improved survival outcomes in these cancers. Most side effects including hypertension, hand-foot syndrome, and diarrhea are generally well manageable. This review will detail the preclinical data leading up to the results of the pivotal phase III clinical trials that have led to the widespread use of sunitinib in advanced RCC, GIST, and PNET. PMID- 24756792 TI - Regorafenib. AB - Regorafenib (BAY 73-4506, Stivarga(r)) is an oral diphenylurea multikinase inhibitor that targets angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-beta, FGFR), and oncogenic receptor tyrosine kinases (KIT, RET, and RAF). Regorafenib is the first small-molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Consequently, regorafenib was FDA approved for this indication. In addition, regorafenib treatment resulted in a significant improvement in progression-free survival (PFS) compared with placebo in patients with metastatic gastrointestinal stromal tumors (GIST) after progression on standard treatments and is also an FDA approved indication. Currently, regorafenib is examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and soft tissue sarcoma (STS). PMID- 24756793 TI - Crizotinib. AB - Crizotinib is an ATP-competitive small-molecule inhibitor of the receptor tyrosine kinases (RTK) c-Met, anaplastic lymphoma kinase (ALK), and ROS1. There is convincing clinical evidence for the effectiveness in non-small-cell lung cancer (NSCLC) harboring EML4-ALK rearrangements resulting in constitutional activation of the ALK-RTK. The drug is approved for this entity, which represents no more than 3-5% of all NSCLC. However, in this population, impressive response rates are generated. The same seems to be true for ROS-1 rearrangements; however, these only occur in approximately 1% of all NSCLC. The role in c-Met altered cancers needs to be determined. Toxicities include visual impairment, nausea, peripheral edema, QT-prolongation, and liver enzyme elevation. Also, the occurrence of renal cysts is reported. Fluorescence in situ hybridization (FISH) detecting the ALK rearrangement has to be performed on tumor tissue to predict crizotinib efficacy. The role of immunohistochemistry in this setting needs to be determined. It has high concordance with FISH results when strongly positive or completely negative. The high efficacy of crizotinib in ALK- and ROS-positive lung cancer as new molecular targets beside the epidermal growth factor receptor (EGFR) underscores the importance of molecular typing in NSCLC. PMID- 24756794 TI - Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. AB - Cabozantinib is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, FLT3, c-KIT, and RET. Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies. Of note, cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET. Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer (MTC), NSCLC, breast, ovarian, pancreatic, and prostate cancer. In MTC, gain of function mutations of RET are central for tumorigenesis. Hereditary forms of MTC (MEN II) are caused by germline mutations of RET, in sporadic MTC in up to 50% of cases RET mutations occur. Additionally, activating molecular changes in VEGFR and MET pathways have also been implicated in MTC progression. Clinical responses with cabozantinib in MTC could be observed in early clinical trials, and following confirmation of clinical benefit in a randomized phase III trial, cabozantinib gained FDA approval for first-line treatment of advanced MTC in 2012. In prostate cancer models, MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis. A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer. Therefore, randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients. PMID- 24756795 TI - Vemurafenib. AB - The activating BRAF mutation V600E and related mutations in this codon are most important for the activation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signalling pathway in melanoma. BRAF V600E mutations have been detected in ~40% of melanoma patients and BRAF V600K mutations in ~5% of melanoma patients. Activation of the MAPK pathway results in continuous stimulation of cell proliferation and inhibits programmed cell death. Vemurafenib (PLX4032) was developed as a low molecular weight molecule for the inhibition of the mutated serine threonine kinase BRAF, and it selectively binds to the ATP-binding site of BRAF-V600E kinase and inhibits its activity. The biochemical affinity of vemurafenib for mutated BRAF translates to potent inhibition of ERK phosphorylation and of cell proliferation exclusively in BRAF-mutant cell lines. In animal model experiments, it was demonstrated that vemurafenib achieved tumour regressions in cells harbouring the BRAF V600E mutation. The clinical trials with vemurafenib in unresectable metastatic melanoma in phase I, II, and III for patients harbouring BRAF V600E mutations demonstrated all unexpected high objective response rates ranging between 50 and 80%. Median progression-free survival was prolonged from two months with dacarbazine to seven months with vemurafenib, and median overall survival was respectively prolonged from 9 to 14 months. A major problem that remains is the development of resistance to vemurafenib treatment after several months in the majority of patients, and multiple resistance mechanisms have already been described. Under vemurafenib treatment, about 25% of patients developed cutaneous squamous cell carcinomas of the keratoacanthoma type with low invasive potential and without occurrence of metastasis. The overall tolerability of the drug was quite good, and a number of patients remained on treatment for long times. As other solid tumours like papillary thyroid cancer, colorectal cancer, non-small-cell lung cancer, and ovarian cancer likewise harbour BRAF mutation, vemurafenib is also tested in these entities. In future, combinations of vemurafenib with other kinase inhibitors and with immunotherapies will improve its therapeutic potential. PMID- 24756796 TI - Dabrafenib. AB - Dabrafenib was developed as a highly specific reversible inhibitor of V600-mutant BRAF kinase, an oncogenic mutation driving proliferation in many different types of aggressive tumors. Metastatic melanoma has a high prevalence of V600-mutant BRAF, and clinical trials showed that dabrafenib improved response rates and median progression-free survival in patients with V600E BRAF mutations, including those with brain metastasis. Preliminary results suggest that dabrafenib may also have some role in non-melanoma V600-mutant solid tumors; however, more studies are needed. With a well-tolerated toxicity profile and few drug interactions, dabrafenib is effective as a monotherapy; however, resistance eventually develops in most patients after persistent exposure to the drug. Current research focuses on combination strategies with dabrafenib to not only improve response rates but also overcome resistance. PMID- 24756797 TI - Trametinib. AB - The mitogen-activated protein kinase (MEK MAPK/ERK kinase) signaling pathways play a critical role in regulation of diverse cellular activities, including survival, differentiation, proliferation, motility, and angiogenesis. Therefore, MEK inhibition was recognized as a promising target for antineoplastic therapy. While multiple MEK inhibitors have been tested clinically only trametinib (GSK1120212), an oral MEK inhibitor which is selective for MEK1 and MEK2 has shown promising activity in several clinical trials on melanoma and colorectal cancer and it is being evaluated by the FDA for the treatment of metastatic melanoma. Mechanistically it was shown that trametinib induces cell cycle arrest in vitro. In this overview, important preclinical and clinical data for trametinib are presented including mechanism-based in vitro studies as well as findings from different clinical studies. Future clinical trial in different solid tumor entities will define the therapeutic role of this targeted therapy approach, possibly as a combination with other targeted therapies such as BRAF inhibitors. PMID- 24756798 TI - Ruxolitinib. AB - Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of JAK1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis, which is characterized, biologically, by the activation of the JAK-STAT pathway and, clinically, by bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of myelofibrosis patients, and it may also have a favorable effect on survival. Treatment response apparently does not depend on the presence of a JAK2 V617F mutation. The predominant toxicities are thrombocytopenia and anemia. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently studied in myelofibrosis or other immuno inflammatory diseases. PMID- 24756799 TI - Ibrutinib. AB - Abnormal B-cell receptor (BCR) signaling is a key mechanism of disease progression in B-cell malignancy. Bruton's tyrosine kinase (BTK) has a pivotal role in BCR signaling. Ibrutinib (PCI-32765) is a novel agent which serves as a covalent irreversible inhibitor of BTK. It is characterized by high selectivity for BTK and high potency. Preliminary data from phase I and ongoing phase II trials have proven very promising so far. It suggests the substance has high efficacy in B-cell malignancies such as chronic lymphocytic leukemia (CLL); diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantel cell lymphoma (MCL), and multiple myeloma (MM) and is very well tolerable. Most notably, the substance does not cause myelosuppression. This chapter discusses structure, mechanism of action, and toxicities of ibrutinib and also presents important preclinical and clinical data. Phase III trials will have to determine the definite role of ibrutinib in clinical practice but the data available so far suggests it may be a powerful new weapon in the battle against B-cell malignancies. PMID- 24756800 TI - Decitabine. AB - Besides 5-azacytidine (azacitidine, Vidaza(r)), 5-aza-2'-deoxycytidine (decitabine, Dacogen(r)) is the most widely used inhibitor of DNA methylation, which triggers demethylation leading to consecutive reactivation of epigenetically silenced tumor suppressor genes in vitro and in vivo. Although antileukemic activity of decitabine is known for almost 40 years, its therapeutic potential in hematologic malignancies has only recently led to its approval in higher-risk MDS patients and as first-line treatment in AML patients>65 years who are not candidates for intensive chemotherapy. Several clinical trials showed promising activity of low-dose decitabine also in CML and hemoglobinopathies, whereas its efficacy in solid tumors is very limited. Clinical responses appear to be exerted both by epigenetic alterations and by induction of cell-cycle arrest and/or apoptosis. Recent and ongoing clinical trials investigate new dosing schedules, routes of administration, and combination of decitabine with other agents, including histone deacetylase inhibitors. PMID- 24756801 TI - 5-Azacytidine/5-Azacitidine. AB - The hypomethylating agent 5-Azacytidine epigenetically modulates various genes, including tumor suppressor genes. For many years, the "new agent", which was first discovered in the 1960s, remained fairly unobtrusive in the rank of salvage treatment options for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). When the significance of epigenetics in tumorigenesis became clear, 5 Azacytidine attracted new attention. Finally, it was the first drug approved for the treatment of all categories of MDS, and its survival benefit over best conventional care was confirmed. Today, in many clinical situations, when aggressive therapies including allogeneic hematopoietic cell transplantation are not an option, 5-Azacytidine is the first treatment of choice. Preliminary data on combinations of the hypomethylating agent with other new drugs are promising, and innovative strategies involving immune modulation and regenerative tissue repair hold a broad potential for future developments. PMID- 24756802 TI - Bortezomib. AB - The ubiquitin-mediated degradation of proteins in numerous cellular processes, such as turnover and quality control of proteins, cell cycle and apoptosis, transcription and cell signaling, immune response and antigen presentation, and inflammation and development makes the ubiquitin-proteosome systems a very interesting target for various therapeutic interventions. Proteosome inhibitors were first synthesized as tools to probe the function and specificity of this particle's proteolytic activities. Most synthetic inhibitors rely on a peptide base, which mimics a protein substrate, attached at a COOH terminal "warhead." Notable warheads include boronic acids, such as bortezomib and epoxy ketones, such as carfilzomib. A variety of natural products also inhibit the proteosome that are not peptide-based, most notably lactacystin, that is related to NPI 0052, or salinosporamide A, another inhibitor in clinical trials. The possibility that proteosome inhibitors could be drug candidates was considered after studies showed that they induced apoptosis in leukemic cell lines. The first proteasome inhibitor in clinical application, bortezomib showed activity in non-small-cell lung and androgen-independent prostate carcinoma, as well as MM and mantle cell and follicular non-Hodgkin's lymphoma. It is now licensed for the treatment of newly diagnosed as well as relapsed/progressive MM and has had a major impact on the improvement in the treatment of MM in the last few years. PMID- 24756803 TI - Lenalidomide. AB - Lenalidomide is an immunomodulatory drug (IMiD), which is well established and approved in the treatment of multiple myeloma (MM) and 5q-myelodysplastic syndrome (MDS). The mode of action includes immune modulation, anti-angiogenetic, anti-inflammatory, and anti-proliferative effects. Development of lenalidomide initiated a profound shift in therapeutic approaches especially toward MM. This chapter will discuss the mode of action of lenalidomide as well as its clinical applications. Important clinical phase II and III data of lenalidomide are presented. Currently, lenalidomide is not only investigated in MM and MDS, but also in malignant lymphomas and other entities. PMID- 24756804 TI - Pomalidomide. AB - Pomalidomide (originally CC-4047 or 3-amino-thalidomide) is a derivative of thalidomide that is antiangiogenic and also acts as an immunomodulator. Pomalidomide, as the newest immunomodulatory agent (IMiD), has shown substantial in vitro antiproliferative and proapoptotic effects. In vivo studies have suggested limited cross-resistance between lenalidomide and pomalidomide, and the response of pomalidomide in relapsed and refractory (RR) multiple myeloma (MM) patients, including those who are refractory to both lenalidomide and bortezomib, has induced notable enthusiasm. Several studies have evaluated continuous (2 mg/day) or alternate (5 mg/2 day) dose schedules of pomalidomide, as well as 2 versus 4 mg schedules, and pomalidomide alone versus in combination with dexamethasone or other antimyeloma agents. Since pomalidomide plus low-dose dexamethasone has shown better responses, progression-free and overall survival than high-dose dexamethasone or pomalidomide alone, subsequent trials investigating pomalidomide combination therapy have been initiated. Among these trials combinations with alkylating agents (cyclophosphamide, bendamustin), anthracyclins (pegylated liposomal doxorubicin), proteasome inhibitors (bortezomib, carfilzomib), and various others can be found. Pomalidomide has also been assessed in AL amyloidosis, MPNs (myelofibrosis [MF]), Waldenstrom's macroglobulinemia, solid tumors (sarcoma, lung cancer), or HIV and--for AL amyloidosis and MF--has already proven remarkable activity. Due to its potency, pomalidomide was approved by the US Food and Drug Administration (FDA) for RRMM in 2/2013 and has also been approved by the European Medicines Agency (EMA). PMID- 24756805 TI - Everolimus. AB - Everolimus (RAD001, Afinitor(r)) is an oral protein kinase inhibitor of the mammalian target of rapamycin (mTOR) serine/threonine kinase signal transduction pathway. The mTOR pathway regulates cell growth, proliferation, and survival and is frequently deregulated in cancer. Everolimus has been approved by the FDA and the EMA for the treatment of advanced renal cell carcinoma (RCC), subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TSC), pancreatic neuroendocrine tumors (PNET), in combination with exemestane in advanced hormone-receptor (HR)-positive, HER2-negative breast cancer. Everolimus shows promising clinical activity in additional indications. Multiple phase 2 and phase 3 trials of everolimus alone or in combination are ongoing and will help to further elucidate the role of mTOR in oncology. For a review on everolimus as immunosuppressant, please consult other sources. PMID- 24756806 TI - Temsirolimus. AB - Temsirolimus, an ester of sirolimus (rapamycin), selectively inhibits the kinase mammalian target of rapamycin (mTOR) and consequently blocks the translation of cell cycle regulatory proteins and prevents overexpression of angiogenic growth factors. It has been found to have antitumour activity in patients with relapsed or refractory mantle cell lymphoma (MCL). In addition, patients with advanced renal cell carcinoma (RCC) and a poor prognosis who received a once-weekly intravenous (IV) infusion of temsirolimus 25 mg experienced significant survival benefits compared with patients receiving standard interferon-alpha (IFN-alpha) therapy in a large phase III clinical study. In this study, median overall survival was 10.9 versus 7.3 months and objective response rates were 8.6% in temsirolimus recipients versus 4.8% IFN-alpha recipient group. Temsirolimus monotherapy recipients experienced significantly fewer grade 3 or 4 adverse events and had fewer withdrawals for adverse events than patients receiving IFN alpha. The role of temsirolimus in sequential and combination therapy is yet to be found. PMID- 24756807 TI - Vismodegib. AB - Vismodegib (GDC-0449, Erivedge(r)) is a novel small molecule antagonist of the hedgehog (Hh) pathway that binds to smoothened (SMO) and leads to inhibition of an aberrant activation of the Hh pathway. Dysregulated Hh signaling results in uncontrolled proliferation in basal cell carcinoma (BCC) and has also been found present in medulloblastoma, and many other cancers such as those of gastrointestinal tract, brain, lung, breast, and prostate. In January 2012, vismodegib became the first agent to target the Hh pathway to receive approval by the United States Food and Drug Administration (FDA) and in July 2013 approval by the European Medicines Agency (EMA) followed for the treatment of adult patients with symptomatic metastatic BCC, or locally advanced BCC inappropriate for surgery or radiotherapy. At the moment, many trials are ongoing to further investigate the role of vismodegib in other malignancies than BCC. PMID- 24756809 TI - Three angels are dancing on the head of the esophageal cancer pin, but shouldn't we not topple one or two? PMID- 24756808 TI - Bacillus alkalicola sp. nov., an alkaliphilic, gram-positive bacterium isolated from Zhabuye Lake in Tibet, China. AB - A Gram-positive, alkaliphilic bacterium, designated strain Zby6(T), was isolated from Zhabuye Lake in Tibet, China. The strain was able to grow at pH 8.0-11.0 (optimum at pH 10.0), in 0-8 % (w/v) NaCl (optimum at 3 %, w/v) and at 10-45 degrees C (optimum at 37 degrees C). Cells of the isolate were facultatively anaerobic and spore-forming rods with polar flagellum. The predominant isoprenoid quinone was MK-7, and its cell wall peptidoglycan contained meso-diaminopimelic acid. The major cellular fatty acids were iso-C(15:0), C(16:0) and anteiso C(15:0). The major polar lipids consisted of phosphatidylglycerol, diphosphatidylglycerol, and phosphatidylethanolamine. The genomic DNA G+C content of the isolate was 38.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain Zby6(T) was a member of the genus Bacillus and most closely related to Bacillus cellulosilyticus DSM 2522(T) (97.7 % similarity). The DNA-DNA relatedness value between strain Zby6(T) and B. cellulosilyticus DSM 2522(T) was 59.2 +/- 1.8 %. Comparative analysis of genotypic and phenotypic features indicated that strain Zby6(T) represents a novel species of the genus Bacillus, for which the name Bacillus alkalicola sp. nov. is proposed; the type strain is Zby6(T) (=CGMCC 1.10368(T) = JCM 17098(T) = NBRC 107743(T)). PMID- 24756810 TI - Can breast surgeons provide breast cancer genetic testing? An American Society of Breast Surgeons survey. AB - BACKGROUND: Whether breast cancer surgeons are adequately trained, skilled, and experienced to provide breast cancer genetic assessment, testing, and counseling came under debate in September 2013 when a major third-party payer excluded nongenetics specialists from ordering such testing. A literature search having failed to uncover any study on breast surgeons' skill and practice in this area, the American Society of Breast Surgeons (ASBrS) surveyed its members on their experience with the recognized crucial components of such testing. METHODS: In late 2013, ASBrS e-mailed a link to an online questionnaire to its U.S. members (n = 2,603) requesting a self-assessment of skills and experience in genetic assessment, testing, interpretation, and counseling. After approximately 6 weeks, the results were collated and evaluated. RESULTS: By January 2, 2014, 907 responses (34.84 %) had arrived from breast surgeons nationwide working in academic settings (20 %), solo or small group private practice (39 %), large multispecialty groups (18 %), and other settings. More than half said they performed 3-generation pedigrees, ordered genetic testing, and provided pre- and posttest counseling. Most noted that they would welcome continuing educational support in genetics. CONCLUSIONS: Currently the majority of breast surgeons provide genetic counseling and testing services to their patients. They report practices that meet or exceed recognized guidelines, including the necessary elements and processes for best practices in breast cancer genetics test counseling. Because breast cancer genetic testing is grossly underutilized relative to the size of the U.S. BRCA mutation carrier population, these appropriate services should not be restricted but rather supported and expanded. PMID- 24756811 TI - Impact of breast reconstruction on the decision to undergo contralateral prophylactic mastectomy. AB - BACKGROUND: In the last decade, there has been increasing use of contralateral prophylactic mastectomy (CPM) in patients with unilateral breast cancer and ductal carcinoma-in-situ (DCIS) undergoing mastectomy. Although many factors have been proposed to explain this trend, the impact of breast reconstruction on CPM has not been studied. METHODS: A retrospective review of patients with unilateral invasive breast cancer or DCIS from Surveillance, Epidemiology, and End Results registry data (2004-2008) was conducted. Characteristics of patients undergoing CPM and reconstruction were evaluated. RESULTS: A total of 102,674 patients diagnosed with DCIS or stage I to III infiltrating breast cancer underwent mastectomy for their primary lesion. Of these, 16,197 patients (16 %) underwent a CPM. A significantly higher proportion of women undergoing CPM had reconstruction performed (46 %) than those patients not undergoing CPM (15 %) (p < 0.001). Of the 20,760 patients (20 %) who underwent reconstruction, 7410 (36 %) had implant reconstruction, 7705 (37 %) tissue reconstruction, and 1941 (9 %) combined tissue/implant reconstruction; there were no data for 3,702 (18 %). There was an increasing trend of patients undergoing reconstruction from 2004 (n = 3390, 16.3 %) to 2008 (n = 5406, 26 %) (p < 0.001). On multivariable analysis, significant variables predicting CPM included age <45 years, stage I disease (odds ratio [OR] 1.44, 95 % confidence interval [CI] 1.35-1.54), lobular histology (OR 1.15, 95 % CI 1.11-1.20), and undergoing breast reconstruction (OR 3.58, 95 % CI 3.41-3.75). CONCLUSIONS: Besides age, undergoing reconstructive surgery is the factor most strongly associated with CPM. This suggests that apart from risk reduction, the availability of and/or patient willingness to undergo breast reconstruction may influence the decision to undergo CPM. PMID- 24756812 TI - Neoadjuvant chemotherapy with bevacizumab may improve outcome after cytoreduction and hyperthermic intraperitoneal chemoperfusion (HIPEC) for colorectal carcinomatosis. AB - BACKGROUND: In selected patients with colorectal peritoneal carcinomatosis (PC), cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) may improve survival. We aimed to assess whether neoadjuvant chemotherapy with or without bevacizumab is indicated in this patient population. METHODS: Colorectal PC patients were treated with CRS and HIPEC using oxaliplatin (200-460 mg/m(2)) or mitomycin C (35 mg/m(2)). Postoperative outcome and long-term survival were prospectively recorded. The impact of clinical variables on overall survival (OS) was assessed using univariate and Cox multivariate analysis. RESULTS: Between October 2002 and May 2012, 166 patients were treated with CRS and HIPEC. Neoadjuvant chemotherapy alone was administered to 21 % and neoadjuvant chemotherapy with bevacizumab to 16 % of patients. Postoperative mortality and major morbidity were 2.4 and 35 %, respectively. Half of the patients received adjuvant chemotherapy. After a median follow-up of 18 months, OS was 27 months (95 % confidence interval 20.8-33.2). On univariate analysis, OS was associated with extent of disease (P < 0.001), neoadjuvant chemotherapy with bevacizumab (P = 0.021), completeness of cytoreduction (CC) (P < 0.001), and adjuvant chemotherapy (P = 0.04), but not with primary disease site, synchronous presentation, or chemoperfusion drug. In multivariate Cox regression, independent predictors of OS were CC (hazard ratio 0.29, P < 0.001) and neoadjuvant therapy containing bevacizumab (hazard ratio 0.31, P = 0.019). CONCLUSIONS: Long-term OS after CRS and HIPEC for colorectal cancer is associated with CC and neoadjuvant therapy containing bevacizumab. This regimen merits prospective study in patients with resectable PC of colorectal origin. PMID- 24756813 TI - Sentinel lymph node biopsy in pregnant women with breast cancer. AB - BACKGROUND: Sentinel lymph node biopsy (SNB) in pregnant women with breast cancer is uncommonly pursued given concern for fetal harm. This study evaluated efficacy and safety outcomes in pregnant breast cancer patients undergoing SNB. METHODS: Patients who underwent SNB while pregnant were identified from a retrospective parent cohort of women diagnosed with breast cancer during pregnancy. Chart review was performed to tabulate patient/tumor characteristics, method/outcome of SNB, and short-term maternal/fetal outcomes. RESULTS: Within a cohort of 81, 47 clinically node-negative patients had surgery while pregnant: 25 (53.2 %) SNB, 20 (42.6 %) upfront axillary lymph node dissection, and 2 (4.3 %) no lymph node surgery. Of SNB patients, 8, 9, and 8 had SNB in the first, second, and third trimesters, respectively. 99 m-Technetium (99-Tc) alone was used in 16 patients, methylene blue dye alone in 7 patients, and 2 patients had unknown mapping method. Mapping was successful in all patients. There were no SNB-associated complications. At a median of 2.5 years from diagnosis, there was one locoregional recurrence, one new primary contralateral tumor, three distant recurrences, and one breast cancer death. Among patients who underwent SNB, there were 25 liveborn infants, of whom 24 were healthy, and 1 had cleft palate (in the setting of other maternal risk factors). CONCLUSIONS: SNB in pregnant breast cancer patients appears to be safe and accurate using either methylene blue or 99 Tc. This is one of the largest reported experiences of SNB during pregnancy; however, numbers remain limited. SNB rates in this cohort were lower than in non pregnant breast cancer patients. PMID- 24756814 TI - Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial. AB - BACKGROUND: This update of a randomized, prospective study presents the effect of external beam radiation therapy (EBRT) on long-term overall survival, local control, and limb function following limb-sparing surgery (LSS) for the treatment extremity soft tissue sarcoma (STS). METHODS: Following LSS, patients with extremity STS were randomized to receive EBRT or surgery alone. All patients with high-grade STS received adjuvant chemotherapy. Long-term follow-up was obtained through telephone interviews using a questionnaire based on validated methods. Overall survival (OS) was determined by Kaplan-Meier method. RESULTS: A total of 141 patients with extremity STS were randomized to receive adjuvant EBRT (n = 70) or LSS alone (n = 71). Median follow-up was 17.9 years. The 10- and 20-year survival was 77 % (95 % CI 66-85 %) and 64 % (95 % CI 52-75 %) for patients receiving LSS alone and 82 % (95 % CI 72-90 %) and 71 % (95 % CI 59-81 %) for patients receiving EBRT (p = 0.22). Of the 54 patients who completed telephone interviews, the incidence of local recurrence during the follow-up period was 4 % (1 of 24) in the LSS alone cohort compared with 0 % (0 of 30) in those who received EBRT (p = 0.44). Patients treated with EBRT tended to have more wound complications (17 vs. 12.5 %, p = 0.72), clinically significant edema (25 vs. 12 %, p = 0.31), and functional limb deficits (15 vs. 12 %, p = 0.84). CONCLUSIONS: Adjuvant EBRT following surgery for STS of the extremity provides excellent local control with acceptable treatment-related morbidity and no statistically significant improvement in overall survival. PMID- 24756815 TI - Phenolic constituents from stem bark of Erythrina poeppigiana and their inhibitory activity on human glyoxalase I. AB - A novel isoflavone, erythgianin A (1), along with nine known compounds 2-10, was isolated from the stem bark of Erythrina poeppigiana (Leguminosae). The unusual isoflavone structure of 1, possessing a highly oxidized 3",4"-dihydroxy-2" hydroxymethyl-2"-methyl-2",3"-dihydropyrano substituent, was determined on the basis of spectroscopic analyses. All of the isolated compounds were evaluated for their in vitro inhibitory activity toward human glyoxalase I. Among the isolates, isolupalbigenin (10) with two prenyl groups showed the highest inhibitory activity. PMID- 24756818 TI - Determination of Meserine, a new candidate for Alzheimer's disease in mice brain by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic and tissue distribution study. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Meserine ((-)-meptazinol phenylcarbamate), a novel potent inhibitor of acetylcholinesterase (AChE), was developed, validated, and applied to a pharmacokinetic study in mice brain. The lower limit of quantification (LLOQ) was 1 ng mL(-1) and the linear range was 1-1,000 ng mL(-1). The analyte was eluted on a Zorbax SB-Aq column (2.1 * 100 mm, 3.5 MUm) with the mobile phase composed of methanol and water (70:30, v/v, aqueous phase contained 10 mM ammonium formate and 0.3% formic acid) using isocratic elution, and monitored by positive electrospray ionization in multiple reaction monitoring (MRM) mode. The flow rate was 0.25 mL min(-1). The injection volume was 5 MUL and total run time was 4 min. The relative standard deviation (RSD) of intraday and interday variation was 2.49-7.81 and 3.01-7.67%, respectively. All analytes were stable after 4 h at room temperature and 6 h in autosampler. The extraction recoveries of Meserine in brain homogenate were over 90%. The main brain pharmacokinetic parameters obtained after intranasal administration were T max = 0.05 h, C max = 462.0 +/- 39.7 ng g(-1), T 1/2 = 0.4 h, and AUC(0-infinity) = 283.1 +/- 9.1 ng h g(-1). Moreover, Meserine was distributed rapidly and widely into brain, heart, liver, spleen, lung, and kidney tissue. The method is validated and could be applied to the pharmacokinetic and tissue distribution study of Meserine in mice. PMID- 24756819 TI - Biosynthesis of the structurally unique polycyclopropanated polyketide-nucleoside hybrid jawsamycin (FR-900848). AB - The biosynthetic gene cluster of antifungal agent jawsamycin (FR-900848) has been identified by heterologous expression. A series of gene inactivations and in vitro and in vivo analysis of key enzymes in the biosynthetic pathway established their functions. A novel mechanism involving a radical S-adenosyl methionine (SAM) cyclopropanase collaborating with an iterative polyketide synthase is proposed for the construction of the unique polycyclopropanated backbone. Our reconstitution system sets the stage for studying the catalytic mechanism of this intriguing contiguous cyclopropanation. PMID- 24756820 TI - Targeting ribonucleotide reductase M2 subunit by small interfering RNA exerts anti-oncogenic effects in gastric adenocarcinoma. AB - Ribonucleotide reductase M2 subunit (RRM2) is one of the two subunits of human ribonucleotide reductase which plays a critical role in tumor progression. The aim of the present study was to analyze its expression, clinical significance and biological functions in gastric adenocarcinoma. We observed the upregulation of RRM2 mRNA and protein in all nine gastric cancer cell lines examined. In paired primary gastric cancers, both mRNA and protein levels of RRM2 were significantly upregulated in tumors compared with the corresponding non-tumorous gastric tissues. RRM2 protein expression correlated with higher tumor grade, advanced T stage and poor disease-specific survival. RRM2 knockdown in gastric cancer cell lines AGS, MKN1 and MKN28 significantly suppressed cell proliferation, inhibited monolayer colony formation, reduced cell invasion and induced apoptosis. Downregulation of RRM2 suppressed xenograft formation in vivo. Collectively, these findings suggest that RRM2 plays a crucial role in gastric tumorigenesis and may serve as a potential prognostic marker and therapeutic target in gastric cancer. PMID- 24756821 TI - Intra-laboratory validation of microplate methods for total phenolic content and antioxidant activity on polyphenolic extracts, and comparison with conventional spectrophotometric methods. AB - BACKGROUND: Total phenolic content (TPC) and antioxidant activity (AA) assays in microplates save resources and time, therefore they can be useful to overcome the fact that the conventional methods are time-consuming, labour intensive and use large amounts of reagents. An intra-laboratory validation of the Folin-Ciocalteu microplate method to measure TPC and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) microplate method to measure AA was performed and compared with conventional spectrophotometric methods. RESULTS: To compare the TPC methods, the confidence intervals of a linear regression were used. In the range of 10-70 mg L(-1) of gallic acid equivalents (GAE), both methods were equivalent. To compare the AA methodologies, the F-test and t-test were used in a range from 220 to 320 umol L( 1) of Trolox equivalents. Both methods had homogeneous variances, and the means were not significantively different. The limits of detection and quantification for the TPC microplate method were 0.74 and 2.24 mg L(-1) GAE and for the DPPH 12.07 and 36.58 umol L(-1) of Trolox equivalents. The relative standard deviation of the repeatability and reproducibility for both microplate methods were <= 6.1%. The accuracy ranged from 88% to 100%. CONCLUSION: The microplate and the conventional methods are equals in a 95% confidence level. PMID- 24756822 TI - Discovering gold mines in HRM. AB - Two of my favorite tasks as a risk management professional are to mentor new risk managers and to educate the public about our profession. This profession requires an incredible depth of knowledge and the capacity to keep an open mind. Most days are challenging, but they are rarely boring or repetitive. It's wonderful to mentor a new person, whom you've just persuaded to take a job in risk management, and help him or her to develop over time into a true risk management professional. PMID- 24756823 TI - The evolution of HRM-growing pains lead to positive outcomes. PMID- 24756824 TI - The Active Risk Control (ARC) toolkit: a new approach to designing risk control interventions. AB - Current practice in healthcare risk management is supported by many tools for risk assessment (understanding problems), but none for risk control (solving problems). THE RESULTS: a failure to improve safety, and a waste of the investment made in risk assessment. The Active Risk Control (ARC) Toolkit, available for free, fills this void with a systematic, structured approach to risk control. PMID- 24756825 TI - Mandatory presuit mediation: 5-year results of a medical malpractice resolution program. AB - The Florida Patient Safety and Presuit Mediation Program (FLPSMP) is a mandatory mediation program designed to provide deserving patients with fast, fair compensation while limiting the healthcare provider expenses incurred during traditional litigation. Mediation occurs before litigation begins; therefore, patients with meritorious claims receive compensation often years earlier than they would with extended litigation. This early mediation fosters confidential and candid communication between doctors and patients, which promotes early fact finding and candid discussion. The program went into effect across the University of Florida (UF) Health system on January 1, 2008. In an article previously published in this journal, we discussed the positive trend observed 2 years after the implementation of the FLPSMP. This article incorporates 5 years of data, which includes new benchmarks with state and national data, to demonstrate that the program can be used successfully as a medical malpractice solution. PMID- 24756826 TI - Vacuum-assisted vaginal delivery (VAVD)-basics for the risk manager. AB - The neonatal intensive care unit (NICU) manager calls you about a baby delivered last night now with brain trauma. She understands that it was a difficult delivery with a vacuum. There were "multiple pop-offs" and, after the baby was delivered, the NICU resuscitation team was called. The Apgar scores were 3 and 5. They are requesting risk management to lead a debriefing today. What to ask? How many pop-offs are allowed? What was the interaction between the nurses and physician? Why wasn't the resuscitation team in attendance before the delivery? Was the vacuum placed properly? How many pulls? How long was the vacuum in place? What should be documented, and was the documentation adequate? All of these are appropriate questions for an adequate analysis of an adverse outcome resulting from a vacuum-assisted vaginal delivery (VAVD). This article focuses on the risk management issues of VAVD in order to give the risk manager a better understanding of appropriate use, data-gathering tools, educational opportunities, and assistance in establishing a culture of safety for the entire perinatal team regarding the use of the vacuum device. PMID- 24756827 TI - Surgical malpractice claims in the United States. AB - Despite ongoing reform, there is still significant physician concern regarding the impact of medical claims on their practices. It is important that physicians and healthcare risk management professionals have a good understanding of the outcomes of medical malpractice to participate in its restructuring as needed and to prevent potentially harmful practices. In our study, we reviewed National Practitioner Data Bank (NPDB) paid malpractice claim reports from September 1, 1990, through July 30, 2011, and identified the 10 most common surgery-related allegations against physicians, excluding those listed as unspecified. Data were collected on the number of claims, the cost of the claims, and physician and patient characteristics. PMID- 24756828 TI - Barriers to the implementation of checklists in the office-based procedural setting. AB - BACKGROUND: Patient safety is critical for the patients, providers, and risk managers in the office-based procedural setting, and the same standard of care should be maintained regardless of the healthcare environment. Checklists may improve patient safety and potentially decrease risk. This study explored utilization of checklists in the office-based setting and the potential barriers to their implementation. METHODS: A cross-sectional prospective study was performed by using a 19-question anonymous survey designed with REDCap(r). Medical providers including physicians and nurses from 25 different offices that performed procedures participated, and 38 individual responses were included in the study. RESULTS: Only 50% of offices surveyed use safety checklists in their practice. Only 34% had checklists or equivalent protocol for emergencies such as anaphylaxis or failed airway. As many as 23.7% of respondents indicated that they encountered barriers to implementing checklists. The top barriers identified in the study were no incentive to use a checklist (77.8%), no mandate from a local or federal regulatory agency (44.4%), being too time consuming (33.3%), and lack of training (33.3%). Reasons identified that would encourage providers to use checklists included a clear mandate (36.8%) and evidence-based research (26.3%). CONCLUSIONS: Checklists are not being universally utilized in the office-based setting. There are barriers preventing their successful implementation. Risk managers may be able to improve patient safety and decrease risk by encouraging practitioners, possibly through incentives, to use customizable safety checklists. PMID- 24756829 TI - Case law update. O'Brien v Synott , No. 2012-164 (Vt May 17, 2013). PMID- 24756830 TI - Patterns of surveillance following curative intent therapy for gastroesophageal cancer. AB - PURPOSE: Our aims were to examine surveillance strategies after curative treatment of early gastroesophageal (GE) cancer and to evaluate the impact of different approaches on outcomes. METHODS: A total of 292 patients with non metastatic GE cancer who were referred to the BC Cancer Agency from 2001 to 2010 for curative intent treatment were analyzed. Surveillance practices were classified into the following: cohort 1 (discharge to general practitioner), cohort 2 (follow-up by oncologist with clinical assessments), cohort 3 (specialist follow-up with laboratory investigations), and cohort 4 (specialist follow-up with imaging or endoscopy). Outcomes were compared across cohorts using Kaplan-Meier methods and Cox regression. RESULTS: In total, median age was 63 years and 76 % were men. Eighty-nine (30%), 18 (6%), 32 (11%), and 152 (53%) patients were classified into cohorts 1 to 4, respectively. Patients with primary lesions involving the distal esophagus were more likely to undergo intensive surveillance which involved imaging studies and endoscopic procedures (p = 0.001). Individuals affected by specific histological subtypes, such as squamous cell carcinoma and the signet cell variant, and those whose disease were managed with definitive chemoradiotherapy without surgery were also more inclined to receive intensive follow-up (p = 0.008 and p = 0.001, respectively) There were no significant differences in overall (p = 0.34) or relapse-free survival (p = 0.59) among the different surveillance strategies, even after adjusting for measured prognostic factors. CONCLUSION: In this population-based analysis, outcomes of GE cancer were comparable irrespective of surveillance strategy. Intensive follow-up with routine imaging and endoscopy may not be justified given the financial implications of these costly investigations. PMID- 24756831 TI - Familial pancreatic cancer: challenging diagnostic approach and therapeutic management. AB - BACKGROUND: Familial predisposition characterizes up to 10% of the patients with pancreatic cancer (PC). Although many syndromes have been associated with an increased risk for PC, familial pancreatic cancer (FPC) accounts for the majority of hereditary cases. FPC is defined by families with at least a pair of first degree relatives (FDRs) who have been diagnosed with PC and do not fulfill the criteria of other inherited tumor syndromes. METHODS AND RESULTS: Genetic counseling is of great importance to estimate the prevalence and recommend further molecular testing. Regarding the screening program for individuals with increased risk for PC, a consortium summit stated that candidates for screening are FDRs of patients with PC from a familial kindred with at least two affected FDRs, patients with Peutz-Jeghers syndrome and p16, BRCA2, and hereditary nonpolyposis colorectal cancer (HNPCC) mutation carriers. It was also agreed that initial screening should include endoscopic ultrasonography (EUS) and/or magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) instead of computed tomography (CT) or endoscopic retrograde cholangiopancreatography (ERCP). CONCLUSIONS: However, the optimal age of initial screening remains undefined. Furthermore, a multidisciplinary assessment is required to determine whether surgical interventions should be performed at high volume specialty centers. The aim of this study is to collect all the recent information considering the genetic basis, screening protocols, and treatment of FPC in order to provide an update on the current contemporary concepts of therapeutic management of the disease. PMID- 24756832 TI - The impact of capsaicin intake on risk of developing gastric cancers: a meta analysis. AB - BACKGROUND: Reported associations of capsaicin with gastric cancer development have been conflicting. Here, we examine 10 published articles that explore these associations using 2,452 cases and 3,996 controls. METHODS: We used multiple search strategies in MEDLINE through PubMed to seek for suitable articles that had case-control design with gastric cancer as outcome. RESULTS: The outcomes of our study shows protection (odds ratio [OR] 0.55, P = 0.003) and susceptibility (OR 1.94, P = 0.0004), both significant with low and medium-high intake of capsaicin, respectively, although under relatively heterogeneous conditions (P(heterogeneity) = <0.0001). Outlier analysis resulted in loss of overall heterogeneity (P = 0.14) without affecting the pooled ORs. Among the subgroups, low intake elicited protection in both Korean (OR 0.37) and Mexican (OR 0.63) populations while high intake rendered these subgroups susceptible (OR 2.96 and OR 1.57, respectively). These subgroup values were highly significant (P = 0.0001 0.01) obtained in heterogeneous conditions (P(heterogeneity) < 0.0001-0.04). The homogeneous (P(heterogeneity) = 0.27-0.37) H. pylori (OR 0.60 and 1.69) effects were highly significant (P < 0.001) in the low and medium-high intake analyses, respectively. Given outcomes from the tests of interaction, high capsaicin intake is significantly different from the protection that low consumption offers. CONCLUSIONS: This meta-analysis implies moderation in capsaicin consumption in order to derive its protective benefits. PMID- 24756833 TI - A case report--treatment of metastatic colorectal cancer in a patient on hemodialysis. PMID- 24756834 TI - miR-219 inhibits the proliferation, migration and invasion of medulloblastoma cells by targeting CD164. AB - It is known that microRNA-219 (miR-219) expression is downregulated in medulloblastoma. In the present study, we investigated the expression, targets and functional effects of miR-219 in D283-MED medulloblastoma cells. We first demonstrated that miR-219 not only inhibits proliferation, but also suppresses the invasion and migration of D283-MED cells. Moreover, the knockdown of miR-219 promoted the proliferation, migration and invasion of the D283-MED cells. Secondly, we predicted that miR-219 targets the 3' untranslated region (3'UTR) of CD164 and orthodenticle homeobox 2 (OTX2) and then confirmed that it significantly downregulated the protein expression of CD164 and OTX2 in D283-MED cells. Finally, we demonstrated that the proliferation, invasion and migration of D283-MED cells were promoted by theectopic expression of CD164. These results indicate that miR-219 suppresses the proliferation, migration and invasion of medulloblastoma cells by targeting CD164. The results also suggest that miR-219 may serve as a potential therapeutic agent for medulloblastoma. PMID- 24756835 TI - Next-generation sequencing: a change of paradigm in molecular diagnostic validation. AB - Next-generation sequencing (NGS) is beginning to show its full potential for diagnostic and therapeutic applications. In particular, it is enunciating its capacity to contribute to a molecular taxonomy of cancer, to be used as a standard approach for diagnostic mutation detection, and to open new treatment options that are not exclusively organ-specific. If this is the case, how much validation is necessary and what should be the validation strategy, when bringing NGS into the diagnostic/clinical practice? This validation strategy should address key issues such as: what is the overall extent of the validation? Should essential indicators of test performance such as sensitivity of specificity be calculated for every target or sample type? Should bioinformatic interpretation approaches be validated with the same rigour? What is a competitive clinical turnaround time for a NGS-based test, and when does it become a cost-effective testing proposition? While we address these and other related topics in this commentary, we also suggest that a single set of international guidelines for the validation and use of NGS technology in routine diagnostics may allow us all to make a much more effective use of resources. PMID- 24756836 TI - The relationship between diabetes attitudes and treatment among free clinic patients and volunteers. AB - Free clinics provide free primary care to the under or uninsured and have been playing an important role in serving the socio-economically disadvantaged. Free clinic patients represent a group of people who experience significant barriers to receiving diabetes prevention and intervention. This study examined diabetes attitudes among free clinic patients and volunteers. English or Spanish speaking patients and volunteers (N = 384), aged 18 years or older completed a self administered survey. Diabetic patients and volunteers shared similar levels of diabetes attitudes compared to non-diabetic patients. Among patients, ethnicity, education level, diabetes education, and family history affected diabetes attitudes. Among volunteers, diabetes education was an important factor associated with positive diabetes attitudes. Whether the volunteer is a healthcare professional or student was related only to one aspect of diabetes attitudes, seriousness of type 2 diabetes. The results, indicating free clinic diabetic patients and volunteers shared similar levels of diabetes attitudes, were positive for maintaining and developing diabetes education programs at a free clinic. Unfortunately, the average length of volunteering at this free clinic was short and student volunteers likely leave the clinic upon graduation. Future research should examine issues of volunteer retention in free clinics. Diabetes education for patients may need to be diversified according to ethnicity, family history of diabetes, and educational level. Finally, non healthcare professional volunteers could potentially be involved in diabetes education at a free clinic. PMID- 24756837 TI - Palivizumab compliance by infants in Puerto Rico during the 2009-2010 respiratory syncytial virus season. AB - Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants. We assessed palivizumab prophylaxis compliance for infants in Puerto Rico. We retrospectively studied data from 868 infants (409 females, 459 males) during the 2009-2010 RSV season. The infants had a mean gestational age of 33 weeks (range 23-41) and a mean birth weight of 1,767 g (range 509-4,120). Only 74 % of the infants with indications received prophylaxis. The main reasons for noncompliance were non-approval by the medical insurance (53 %), parents' unavailability (31 %), and infant sickness (11 %). Infants with the government medical insurance were more likely to be denied prophylaxis and to receive fewer doses. Parents need to be educated on the importance of RSV prophylaxis. Physicians should be aware that many infants are not being dosed appropriately and that strategies need to be established to improve compliance. PMID- 24756838 TI - Activation of elemental sulfur by aluminum dihydride: isolation of mono- and bis(hydrogensulfide) complexes of aluminum. AB - The conversions of the dimeric imidazolin-2-iminato aluminum dihydride {MU L(Dipp)AlH2}2 (1) with 1/4 or 1/2 equivalents of S8 gave the elusive hydrogensulfide {MU-L(Dipp)Al(H)SH}2 (2) and the bisthiol {MU-L(Dipp)Al(SH)2}2 (3), respectively (L(Dipp)=NC(N(Dipp)CH)2, Dipp=2,6-diisopropylphenyl). Notably, these transformations proceeded in the absence of a promoter. The reaction of {MU L(Mes)AlH2}2 (4), a less bulky congener of 1, with phenyl disulfide produces the phenyl sulfide {MU-L(Mes)Al(H)SPh}2 (5; L(Mes)=NC(N(Mes)CH)2, Mes=2,4,6 trimethylphenyl). The hitherto unknown compounds 2-5 were characterized by using spectroscopic methods and single-crystal X-ray diffraction analysis. PMID- 24756839 TI - Advances in Perfusion Techniques: Minimally Invasive Procedures. AB - There is a growing demand from patients and referring physicians for minimally invasive cardiac surgery. Minimally invasive cardiac procedures are technically unique from conventional cardiac procedures and require a thorough understanding of the surgical, anesthetic, and perfusion strategies. Strategies include routine use of augmented venous drainage, alternative arterial and venous cannulation sites, and special cannulas designed for minimally invasive procedures. The following review describes the strategies and safety systems that should be considered when performing minimally invasive cardiac surgery. PMID- 24756840 TI - eComment. Healing process of a novel zero-porosity vascular graft. PMID- 24756841 TI - eComment. Heparin-induced thrombocytopenia or non-heparin-induced thrombocytopenia in patients who undergo cardiac surgery? PMID- 24756842 TI - eComment. Health education and quality of life in patients undergoing coronary artery bypass grafting. PMID- 24756843 TI - Regression of left ventricular hypertrophy in children following the Ross procedure. AB - OBJECTIVES: Left ventricular hypertrophy (LVH) frequently accompanies the progression of aortic valve disease in children. The extent of LVH regression following surgical relief of aortic valve disease in children has not been clearly elucidated. We hypothesized that significant regression of LVH will occur in children following the Ross procedure. METHODS: We examined LVH over time in children <18 years of age who underwent the Ross procedure. Left ventricular mass index (LVMI) and corresponding z scores were calculated based on height, age and gender. Left ventricular hypertrophy was defined as an LVMI of > 39 g/m(2.7) and a z score of >1.6. RESULTS: Twenty-five children underwent the Ross procedure. The left ventricular mass increased proportionally with the growth of the child from baseline to the latest follow-up at 7.3 +/- 2.9 years (121.1 +/- 81.5 vs 133.1 +/- 79.8 g, P = 0.4). However, 96% (24/25) of children demonstrated LVMI regression from baseline. Mean LVMI decreased from 70.8 +/- 31.2 to 41.8 +/- 16.6 g/m(2.7) (P < 0.001). Similarly, LVMI z scores decreased from 2.2 +/- 1.2 to 0.2 +/- 1.9 (P < 0.001). Freedom from LVH was 83% at 10 years. Examination of LVMI and z scores over time demonstrated that the largest decrease occurred after the first year, with continued gradual decline over 10 years of follow-up. CONCLUSIONS: The Ross procedure is effective in reversing LVH in children with aortic valve disease. PMID- 24756844 TI - eComment. Thoracoscopic approach to bilateral pulmonary metastasis: is it justified? PMID- 24756845 TI - eComment. Epidural analgesia versus paravertebral analgesia technique. PMID- 24756846 TI - eResponse. Re: Epidural analgesia versus paravertebral analgesia technique. PMID- 24756847 TI - eComment. Re: Intraoperative management of failed single lung ventilation using a Fogarty balloon catheter through the open bronchus during off-pump left lung transplantation. PMID- 24756848 TI - eResponse. Re: Intraoperative management of failed single lung ventilation using a Fogarty balloon catheter through the open bronchus during off-pump left lung transplantation. PMID- 24756849 TI - eComment. Improving long-term prognosis after complete revascularization. PMID- 24756850 TI - Catastrophic presentation of anomalous origin of right pulmonary artery in a neonate--an interesting differential! AB - A 36-hour-old term neonate presented with refractory cardiogenic shock and multi organ dysfunction. On suspecting coarctation of aorta, intravenous prostaglandin was started but without any benefit. Echocardiography revealed isolated anomalous origin of right pulmonary artery from ascending aorta causing massive aortic steal, supra-systemic pulmonary arterial hypertension (PAH), multi-organ dysfunction and right ventricular failure. The main pulmonary artery was solely continued as left pulmonary artery. Emergency surgery at 48 h was life-saving and mid-term follow-up is excellent. The authors present this case as an important alternative diagnosis to duct dependent systemic lesions. The English literature in the last two decades was reviewed to discuss the characteristics, the diagnosis and treatment of neonatal presentation of this rare anomaly. Incidentally, the reported case is the youngest successful survivor of this surgery. PMID- 24756851 TI - Frontonasal dysplasia with severe occipital lobe hypoplasia. PMID- 24756852 TI - High-resolution modeling of antibody structures by a combination of bioinformatics, expert knowledge, and molecular simulations. AB - In the second antibody modeling assessment, we used a semiautomated template based structure modeling approach for 11 blinded antibody variable region (Fv) targets. The structural modeling method involved several steps, including template selection for framework and canonical structures of complementary determining regions (CDRs), homology modeling, energy minimization, and expert inspection. The submitted models for Fv modeling in Stage 1 had the lowest average backbone root mean square deviation (RMSD) (1.06 A). Comparison to crystal structures showed the most accurate Fv models were generated for 4 out of 11 targets. We found that the successful modeling in Stage 1 mainly was due to expert-guided template selection for CDRs, especially for CDR-H3, based on our previously proposed empirical method (H3-rules) and the use of position specific scoring matrix-based scoring. Loop refinement using fragment assembly and multicanonical molecular dynamics (McMD) was applied to CDR-H3 loop modeling in Stage 2. Fragment assembly and McMD produced putative structural ensembles with low free energy values that were scored based on the OSCAR all-atom force field and conformation density in principal component analysis space, respectively, as well as the degree of consensus between the two sampling methods. The quality of 8 out of 10 targets improved as compared with Stage 1. For 4 out of 10 Stage-2 targets, our method generated top-scoring models with RMSD values of less than 1 A. In this article, we discuss the strengths and weaknesses of our approach as well as possible directions for improvement to generate better predictions in the future. PMID- 24756853 TI - Life-threatening bleeding after tooth extraction due to vascular malformation: a case report and literature review. AB - Severe hemorrhages of the oral cavity may be caused by arteriovenous malformations. This case report concerns a 52-year-old healthy female who presented with a painful lower third molar and an extensive arteriovenous high flow malformation of the floor of the right side of the mouth. During the extraction of the right lower wisdom tooth, an episode of massive life threatening bleeding occurred. Since the therapy for intraoral arteriovenous malformations of the soft tissue is complex and often difficult to perform, the modus operandi of the present case is presented, and a review of the literature is included. PMID- 24756854 TI - Retroperitoneal fibrosis: a clinical and outcome analysis of 58 cases and review of literature. AB - The purpose of the study was to investigate the clinical features and outcomes of retroperitoneal fibrosis (RPF). Fifty-eight RPF treatment cases in the First Affiliated Hospital of China Medical University were retrospectively analyzed, including clinical characteristics and laboratory data. RPF was found predominantly in elderly men with atypical clinical manifestations of back pain, abdominal pain, and lower limb edemas. In laboratory examinations, the acute phase reactants such as erythrocyte sedimentation rate and C-reactive protein levels increased significantly. Renal function failure was frequently found in patients with urethral obstruction. All patients had retroperitoneal soft tissue shadows or urethral obstructions on computed tomography (CT) or magnetic resonance imaging (MRI), seven of which had histological diagnosis of idiopathic RPF. Forty-two patients received surgical interventions; 29 patients received medication treatment alone including corticosteroids, immunosuppressants, and tamoxifen; 17 patients received corticosteroids after surgical intervention. Surgery followed by medication was most effective for RPF. CT and MRI help to exclude secondary causes, but biopsy remains the gold standard for diagnosis. Long-term low-dose corticosteroids and immunosuppressants may prevent relapse of RPF. PMID- 24756855 TI - Prognostic value of cytoplasmic expression of S100A4 protein in endometrial carcinoma. AB - The S100A4 protein, a member of the S100 family of calcium-binding proteins, has been considered as a candidate prognostic marker in patients with cancer. The present study was conducted to evaluate the prognostic value of S100A4 and to examine its correlation with the clinicopathological parameters and the overall survival and progression-free survival in patients with endometrial carcinoma (EC). To do this, we performed immunohistochemistry of formalin-fixed tissue sections obtained from 135 cases of EC. In addition, we quantified the level of S100A4 mRNA using the quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). The cytoplasmic expression of S100A4 protein was observed in 35 cases (25.9%). There was a significant association between the expression of S100A4 and clinicopathological parameters such as histologic grade, FIGO stage, lymph node metastasis and loss of progesterone receptor (PR). qRT-PCR demonstrated that the level of S100A4 mRNA was significantly higher in ECs as compared with normal endometrium. The cytoplasmic expression of S100A4 had a significant correlation with shorter overall survival and progression-free survival on the Kaplan-Meyer survival analysis. In multivariate analysis, there was a significant correlation between S100A4 expression and a poorer OS. In conclusion, our results indicate that S100A4 may be a biological marker indicating the recurrence and poor prognosis in patients with EC. PMID- 24756856 TI - Analytic calculation of finite-population reproductive numbers for direct- and vector-transmitted diseases with homogeneous mixing. AB - The basic reproductive number, R0, provides a foundation for evaluating how various factors affect the incidence of infectious diseases. Recently, it has been suggested that, particularly for vector-transmitted diseases, R0 should be modified to account for the effects of finite host population within a single disease transmission generation. Here, we use a transmission factor approach to calculate such "finite-population reproductive numbers," under the assumption of homogeneous mixing, for both vector-borne and directly transmitted diseases. In the case of vector-borne diseases, we estimate finite-population reproductive numbers for both host-to-host and vector-to-vector generations, assuming that the vector population is effectively infinite. We find simple, interpretable formulas for all three of these quantities. In the direct case, we find that finite population reproductive numbers diverge from R0 before R0 reaches half of the population size. In the vector-transmitted case, we find that the host-to-host number diverges at even lower values of R0, while the vector-to-vector number diverges very little over realistic parameter ranges. PMID- 24756857 TI - Cyclic negative feedback systems: what is the chance of oscillation? AB - Many biological oscillators have a cyclic structure consisting of negative feedback loops. In this paper, we analyze the impact that the addition of a positive or a negative self-feedback loop has on the oscillatory behavior of the three negative feedback oscillators proposed by Tsai et al. (Science 231:126-129, 2008) where, in contrast with numerous oscillator models, the interactions between elements occur via the modulation of the degradation rates. Through analytical and computational studies we show that an additional self-feedback affects the oscillatory behavior. In the high-cooperativity limit, i.e., for large Hill coefficients, we derive exact analytical conditions for oscillations and show that the relative location between the dissociation constants of the Hill functions and the ratio of kinetic parameters determines the possibility of oscillatory activities. We compute analytically the probability of oscillations for the three models and show that the smallest domain of periodic behavior is obtained for the negative-plus-negative feedback system whereas the additional positive self-feedback loop does not modify significantly the chance to oscillate. We numerically investigate to what extent the properties obtained in the sharp situation applied in the smooth case. Results suggest that a switch like coupling behavior, a time-scale separation, and a repressilator-type architecture with an even number of elements facilitate the emergence of sustained oscillations in biological systems. An additional positive self feedback loop produces robustness and adaptability whereas an additional negative self-feedback loop reduces the chance to oscillate. PMID- 24756858 TI - Significant structural differences between transient amyloid-beta oligomers and less-toxic fibrils in regions known to harbor familial Alzheimer's mutations. AB - Small oligomers of the amyloid beta (Abeta) peptide, rather than the monomers or the fibrils, are suspected to initiate Alzheimer's disease (AD). However, their low concentration and transient nature under physiological conditions have made structural investigations difficult. A method for addressing such problems has been developed by combining rapid fluorescence techniques with slower two dimensional solid-state NMR methods. The smallest Abeta40 oligomers that demonstrate a potential sign of toxicity, namely, an enhanced affinity for cell membranes, were thus probed. The two hydrophobic regions (residues 10-21 and 30 40) have already attained the conformation that is observed in the fibrils. However, the turn region (residues 22-29) and the N-terminal tail (residues 1-9) are strikingly different. Notably, ten of eleven known Abeta mutants that are linked to familial AD map to these two regions. Our results provide potential structural cues for AD therapeutics and also suggest a general method for determining transient protein structures. PMID- 24756859 TI - Changes in trends and pattern of strong opioid prescribing in primary care. AB - BACKGROUND: This study evaluated the prescribing trends of four commonly prescribed strong opioids in primary care and explored utilization in non-cancer and cancer users. METHODS: This cross-sectional study was conducted from 2000 to 2010 using the UK Clinical Practice Research Datalink. Prescriptions of buprenorphine, fentanyl, morphine and oxycodone issued to adult patients were included in this study. Opioid prescriptions issued after patients had cancer medical codes were defined as cancer-related use; otherwise, they were considered non-cancer use. Annual number of prescriptions and patients, defined daily dose (DDD/1000 inhabitants/day) and oral morphine equivalent (OMEQ) dose were measured in repeat cross-sectional estimates. RESULTS: In total, there were 2,672,022 prescriptions (87.8% for non-cancer) of strong opioids for 178,692 users (59.9% female, 83.9% non-cancer, mean age 67.1 +/- 17.0 years) during the study period. The mean annual (DDD/1000 inhabitants/day) was higher in the non-cancer group than in the cancer group for all four opioids; morphine (0.73 +/- 0.28 vs. 0.12 +/- 0.04), fentanyl (0.46 +/- 0.29 vs. 0.06 +/- 0.24), oxycodone (0.24 +/- 0.19 vs. 0.038 +/- 0.028) and buprenorphine (0.23 +/- 0.15 vs. 0.008 +/- 0.006). The highest proportion of patients were prescribed low opioid doses (OMEQ <= 50 mg/day) in both non-cancer (50.3%) and cancer (39.9%) groups, followed by the dose ranks of 51-100 mg/day (26.2% vs. 28.7%), 101-200 mg/day (15.1% vs. 19.2%) and >200 mg/day (8.25% vs. 12.1%). CONCLUSIONS: There has been a huge increase in strong opioid prescribing in the United Kingdom, with the majority of prescriptions for non-cancer pain. Morphine was the most frequently prescribed, but the utilization of oxycodone, buprenorphine and fentanyl increased markedly over time. PMID- 24756860 TI - Emotional effects on time-to-contact judgments: arousal, threat, and fear of spiders modulate the effect of pictorial content. AB - Recently, responses to looming visual stimuli have been shown to depend on the emotional content of the stimulus. A threatening stimulus is judged to arrive sooner compared to a neutral stimulus, possibly buying the organism time to prepare defensive actions. Here, we explored the underlying mechanism. We found that time-to-contact judgments of threatening pictures did not differ from those of highly arousing pleasant pictures (Experiment 1), suggesting that arousal, not fear, modulates the perception of looming. Specific fear modulated the effects of arousal (Experiment 2): Spider-fearful participants' judgments showed a threat advantage effect, while non-fearful participants' judgments were less affected by emotional content. In Experiment 3, arrival times were less overestimated when pictures induced arousal. However, this effect interacted with the valence of the stimulus: For unpleasant stimuli, arousal induced shorter time-to-contact judgments, whereas for pleasant stimuli, an inverted U-shaped relation was found. We propose a general content effect to explain the overestimation with neutral pictures: Pictorial content may draw visual attention to inner contours instead of to the outer edges of the picture. This could delay time-to-contact judgments according to the known size-arrival effect. Our results add to the growing literature examining affective influences on visual perception. PMID- 24756861 TI - The role of sleep in processing emotional and contextual information: from mechanism to impact on everyday life and emotional health. PMID- 24756862 TI - Aberrant self-renewal and quiescence contribute to the aggressiveness of glioblastoma. AB - Cancer cells with enhanced self-renewal capacity influence tumour growth in glioblastoma. So far, a variety of surrogate markers have been proposed to enrich these cells, emphasizing the need to devise new characterization methods. Here, we screen a large panel of glioblastoma cultures (n = 21) cultivated under stem cell-permissive conditions and identify several cell lines with enhanced self renewal capacity. These cell lines are capable of matrix-independent growth and form fast-growing, orthotopic tumours in mice. Employing isolation, re-plating, and label-retention techniques, we show that self-renewal potential of individual cells is partitioned asymmetrically between daughter cells in a robust and cell line-specific fashion. This yields populations of fast- and slow-cycling cells, which differ in the expression of cell cycle-associated transcripts. Intriguingly, fast-growing cells keep their slow-cycling counterparts in a reversible state of quiescence associated with high chemoresistance. Our results suggest that two different subpopulations of tumour cells contribute to aberrant growth and tumour recurrence after therapy in glioblastoma. PMID- 24756863 TI - Molecular docking to understand the metabolic behavior of GNF-351 by CYP3A4 and its potential drug-drug interaction with ketoconazole. AB - GNF-351 is a candidate drug used to treat some diseases through antagonizing aryl hydrocarbon receptor. In the present study, molecular docking method was employed to understand the interaction between ketoconazole and GNF-351. The structure of cytochrome P450 (CYP) 3A4 was obtained from protein data bank, and 2-dimensional structure of GNF-351 with standard bond lengths and angles was drawn using chemdraw software. 30 possible binding orientations was generated and docked into the X-ray crystallographic structure of human CYP3A4. The predicted binding mode of GNF-351 into CYP3A4 appeared to adopt an orientation with interactions between their flat aromatic rings and Phe 302 and Phe 304. The comparison for the binding of GNF-351 and ketoconazole into the activity cavity indicated that they exhibited similar distance towards heme, indicating the potential interaction between GNF-351 and ketoconazole. These data remind us the necessary monitoring when future utilization between GNF-351 and ketoconazole. PMID- 24756867 TI - The WRAIR projectile concussive impact model of mild traumatic brain injury: re design, testing and preclinical validation. AB - The WRAIR projectile concussive impact (PCI) model was developed for preclinical study of concussion. It represents a truly non-invasive closed-head injury caused by a blunt impact. The original design, however, has several drawbacks that limit the manipulation of injury parameters. The present study describes engineering advancements made to the PCI injury model including helmet material testing, projectile impact energy/head kinematics and impact location. Material testing indicated that among the tested materials, 'fiber-glass/carbon' had the lowest elastic modulus and yield stress for providing an relative high percentage of load transfer from the projectile impact, resulting in significant hippocampal astrocyte activation. Impact energy testing of small projectiles, ranging in shape and size, showed the steel sphere produced the highest impact energy and the most consistent impact characteristics. Additional tests confirmed the steel sphere produced linear and rotational motions on the rat's head while remaining within a range that meets the criteria for mTBI. Finally, impact location testing results showed that PCI targeted at the temporoparietal surface of the rat head produced the most prominent gait abnormalities. Using the parameters defined above, pilot studies were conducted to provide initial validation of the PCI model demonstrating quantifiable and significant increases in righting reflex recovery time, axonal damage and astrocyte activation following single and multiple concussions. PMID- 24756868 TI - Are urinary porphyrins a valid diagnostic biomarker of autism spectrum disorder? AB - A fundamental challenge to the timely diagnosis of Autism Spectrum Disorder (ASD) is the reliance on the observation of a set of aberrant behavior. Consequently, the diagnostic process requires that the child reach an age where the behaviors would typically be exhibited. The identification of a reliable biological marker (biomarker) could be of considerable benefit to the diagnostic process. As a diagnostic biomarker, porphyrins present an attractive prospect as previous studies have reported consistent findings of children with ASD showing significant elevations in porphyrin levels in contrast to controls. Furthermore, there is some evidence that ASD severity may be associated with porphyrins, which would be a valuable characteristic of any ASD biomarker. Importantly, for practical use, porphyrins can be tested non-invasively via a sample of urine. The present study sought to investigate whether porphyrin profiles can reliably be used to (a) differentiate ASD cases from healthy controls; and (b) predict ASD severity. The study compared the porphyrin levels of three groups of children aged 2-6 years: Group 1-children diagnosed with ASD (n = 70); Group 2-healthy, normally developing siblings of children diagnosed with ASD (n = 36); and Group 3 healthy, normally developing children with no known blood relative diagnosed with ASD (n = 54). The results of logistic regression analyses failed to find support for the hypotheses that porphyrin levels could be used as a valid tool to detect ASD cases or predict severity. PMID- 24756869 TI - A novel dual-flow bioreactor simulates increased fluorescein permeability in epithelial tissue barriers. AB - Permeability studies across epithelial barriers are of primary importance in drug delivery as well as in toxicology. However, traditional in vitro models do not adequately mimic the dynamic environment of physiological barriers. Here, we describe a novel two-chamber modular bioreactor for dynamic in vitro studies of epithelial cells. The fluid dynamic environment of the bioreactor was characterized using computational fluid dynamic models and measurements of pressure gradients for different combinations of flow rates in the apical and basal chambers. Cell culture experiments were then performed with fully differentiated Caco-2 cells as a model of the intestinal epithelium, comparing the effect of media flow applied in the bioreactor with traditional static transwells. The flow increases barrier integrity and tight junction expression of Caco-2 cells with respect to the static controls. Fluorescein permeability increased threefold in the dynamic system, indicating that the stimulus induced by flow increases transport across the barrier, closely mimicking the in vivo situation. The results are of interest for studying the influence of mechanical stimuli on cells, and underline the importance of developing more physiologically relevant in vitro tissue models. The bioreactor can be used to study drug delivery, chemical, or nanomaterial toxicity and to engineer barrier tissues. PMID- 24756870 TI - Physical rehabilitation approaches for the recovery of function and mobility following stroke. AB - BACKGROUND: Various approaches to physical rehabilitation may be used after stroke, and considerable controversy and debate surround the effectiveness of relative approaches. Some physiotherapists base their treatments on a single approach; others use a mixture of components from several different approaches. OBJECTIVES: To determine whether physical rehabilitation approaches are effective in recovery of function and mobility in people with stroke, and to assess if any one physical rehabilitation approach is more effective than any other approach.For the previous versions of this review, the objective was to explore the effect of 'physiotherapy treatment approaches' based on historical classifications of orthopaedic, neurophysiological or motor learning principles, or on a mixture of these treatment principles. For this update of the review, the objective was to explore the effects of approaches that incorporate individual treatment components, categorised as functional task training, musculoskeletal intervention (active), musculoskeletal intervention (passive), neurophysiological intervention, cardiopulmonary intervention, assistive device or modality.In addition, we sought to explore the impact of time after stroke, geographical location of the study, dose of the intervention, provider of the intervention and treatment components included within an intervention. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched December 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 12, 2012), MEDLINE (1966 to December 2012), EMBASE (1980 to December 2012), AMED (1985 to December 2012) and CINAHL (1982 to December 2012). We searched reference lists and contacted experts and researchers who have an interest in stroke rehabilitation. SELECTION CRITERIA: Randomised controlled trials (RCTs) of physical rehabilitation approaches aimed at promoting the recovery of function or mobility in adult participants with a clinical diagnosis of stroke. Outcomes included measures of independence in activities of daily living (ADL), motor function, balance, gait velocity and length of stay. We included trials comparing physical rehabilitation approaches versus no treatment, usual care or attention control and those comparing different physical rehabilitation approaches. DATA COLLECTION AND ANALYSIS: Two review authors independently categorised identified trials according to the selection criteria, documented their methodological quality and extracted the data. MAIN RESULTS: We included a total of 96 studies (10,401 participants) in this review. More than half of the studies (50/96) were carried out in China. Generally the studies were heterogeneous, and many were poorly reported.Physical rehabilitation was found to have a beneficial effect, as compared with no treatment, on functional recovery after stroke (27 studies, 3423 participants; standardised mean difference (SMD) 0.78, 95% confidence interval (CI) 0.58 to 0.97, for Independence in ADL scales), and this effect was noted to persist beyond the length of the intervention period (nine studies, 540 participants; SMD 0.58, 95% CI 0.11 to 1.04). Subgroup analysis revealed a significant difference based on dose of intervention (P value < 0.0001, for independence in ADL), indicating that a dose of 30 to 60 minutes per day delivered five to seven days per week is effective. This evidence principally arises from studies carried out in China. Subgroup analyses also suggest significant benefit associated with a shorter time since stroke (P value 0.003, for independence in ADL).We found physical rehabilitation to be more effective than usual care or attention control in improving motor function (12 studies, 887 participants; SMD 0.37, 95% CI 0.20 to 0.55), balance (five studies, 246 participants; SMD 0.31, 95% CI 0.05 to 0.56) and gait velocity (14 studies, 1126 participants; SMD 0.46, 95% CI 0.32 to 0.60). Subgroup analysis demonstrated a significant difference based on dose of intervention (P value 0.02 for motor function), indicating that a dose of 30 to 60 minutes delivered five to seven days a week provides significant benefit. Subgroup analyses also suggest significant benefit associated with a shorter time since stroke (P value 0.05, for independence in ADL).No one physical rehabilitation approach was more (or less) effective than any other approach in improving independence in ADL (eight studies, 491 participants; test for subgroup differences: P value 0.71) or motor function (nine studies, 546 participants; test for subgroup differences: P value 0.41). These findings are supported by subgroup analyses carried out for comparisons of intervention versus no treatment or usual care, which identified no significant effects of different treatment components or categories of interventions. AUTHORS' CONCLUSIONS: Physical rehabilitation, comprising a selection of components from different approaches, is effective for recovery of function and mobility after stroke. Evidence related to dose of physical therapy is limited by substantial heterogeneity and does not support robust conclusions. No one approach to physical rehabilitation is any more (or less) effective in promoting recovery of function and mobility after stroke. Therefore, evidence indicates that physical rehabilitation should not be limited to compartmentalised, named approaches, but rather should comprise clearly defined, well-described, evidenced-based physical treatments, regardless of historical or philosophical origin. PMID- 24756871 TI - A secure RFID authentication protocol for healthcare environments using elliptic curve cryptosystem. AB - With the fast advancement of the wireless communication technology and the widespread use of medical systems, the radio frequency identification (RFID) technology has been widely used in healthcare environments. As the first important protocol for ensuring secure communication in healthcare environment, the RFID authentication protocols derive more and more attentions. Most of RFID authentication protocols are based on hash function or symmetric cryptography. To get more security properties, elliptic curve cryptosystem (ECC) has been used in the design of RFID authentication protocol. Recently, Liao and Hsiao proposed a new RFID authentication protocol using ECC and claimed their protocol could withstand various attacks. In this paper, we will show that their protocol suffers from the key compromise problem, i.e. an adversary could get the private key stored in the tag. To enhance the security, we propose a new RFID authentication protocol using ECC. Detailed analysis shows the proposed protocol not only could overcome weaknesses in Liao and Hsiao's protocol but also has the same performance. Therefore, it is more suitable for healthcare environments. PMID- 24756872 TI - C-H oxygenation and N-trifluoroacylation of arylamines under metal-free conditions: a convenient approach to 2-aminophenols and N-trifluoroacyl-ortho aminophenols. AB - Direct ortho-hydroxylation through C-H oxygenation and N-trifluoroacylation of anilines was achieved in a single step under metal-free conditions by using a combination of TFA and oxone. The method allowed the formation of functionalised amino phenolic compounds such as ortho-hydroxy-N-trifluoroacetanilides in good yields with broad substrate scope. PMID- 24756873 TI - Ratio of peripheral blood absolute lymphocyte count to absolute monocyte count at diagnosis is associated with progression-free survival in follicular lymphoma. AB - The prognosis of follicular lymphoma (FL) is significantly associated with host immunity and tumor microenvironment. Lymphopenia has been identified as a negative prognostic factor for FL. The association between monocytosis and progression-free survival (PFS) in FL remains controversial. It is unknown whether the ratio of peripheral blood absolute lymphocyte count to absolute monocyte count (ALC/AMC) at diagnosis is associated with FL prognosis. We studied 99 consecutive patients with FL who were treated with rituximab-containing chemotherapy at Kitano Hospital or Kyoto University Hospital between 2000 and 2012. We analyzed individual variables associated with the ALC/AMC ratio before treatment, as well as known prognostic factors of FL, and found that an ALC/AMC ratio of 4.7 was the best cut-off value for PFS. Kaplan-Meier analysis showed that a decreased ALC/AMC ratio was associated with inferior PFS (P = 0.022). Multivariate analysis showed that a decreased ALC/AMC ratio was a significant poor prognostic factor independent of other variables (hazard ratio, 2.714; 95 % confidence interval, 1.060-6.948; P = 0.037). The ALC/AMC ratio before treatment may be a significant prognostic factor predicting PFS of FL. PMID- 24756874 TI - Influences of vascular niches on hematopoietic stem cell fate. AB - The fate decision of hematopoietic stem cells (HSCs), quiescence, proliferation or differentiation, is uniquely determined by functionally specialized microenvironments defined as the HSC niches. However, whether quiescence and proliferation of HSCs are regulated by spatially distinct niches is unclear. Although various candidate stromal cells have been identified as potential niche cells, the spatial localization of quiescent HSCs in the bone marrow remains controversial. In our recent study, we have established whole-mount confocal immunofluorescence techniques, which allow us to precisely assess the localization of HSCs and their relationships with stromal structures. Furthermore, we have assessed the significance of these associations using a computational simulation. These novel analyses have revealed that quiescent HSCs are specifically associated with small caliber arterioles, which are predominantly distributed in the endosteal bone marrow while the associations with sinusoidal vessels or osteoblasts are not significant. Physical ablation of the arteriolar niche causes the shift of HSC localization to sinusoidal niches, where HSCs are switched into non-quiescent status. This new imaging analyses together with previous studies suggest the presence of spatially distinct vascular niches for quiescent and non-quiescent (proliferating) HSCs in the bone marrow. PMID- 24756875 TI - Effect of acute normobaric hypoxia on the ventilatory threshold. AB - PURPOSE: This study investigated the response of the ventilatory threshold (VT) to acute normobaric hypoxia and compared the agreement between software-based algorithms which use automatic detection to identify the VT. Results were used to examine whether the VT can be used as a physiological parameter to prescribe and monitor exercise intensity in hypoxic exercise training programs. METHODS: Fourteen untrained individuals (7 women, 7 men; age 22 +/- 2 years, [Formula: see text]O2peak 46 +/- 7 mL kg(-1) min(-1)) completed five identical graded exercise tests (randomized order) on a cycle ergometer to measure VT at sea-level (SL) and in response to four normobaric hypoxic conditions (FIO2: 0.185, 0.165, 0.142, 0.125) equivalent to 1,000, 2,000, 3,000 and 4,000 m. Data were analyzed using a one-way analysis of variance (ANOVA) with repeated measures. RESULTS: The VT was similar across all conditions (SL = 1.98 +/- 0.46, 1,000 m = 2.03 +/- 0.61, 2,000 m = 2.27 +/- 0.62, 3,000 m = 1.84 +/- 0.50, 4,000 m = 2.29 +/- 0.58 L min(-1)) for all algorithms used despite a reduction in arterial oxygen saturation at 3,000 (P <= 0.01) and 4,000 m (P <= 0.01) compared with SL values. CONCLUSION: The VT appears to be a suitable physiological parameter for exercise prescription in normobaric hypoxia up to an altitude of 4,000 m. PMID- 24756876 TI - Solitary organizing pneumonia mimicking lung adenocarcinoma in systemic sclerosis. PMID- 24756877 TI - Municipal interventions against inequalities in health: The view of their managers. AB - BACKGROUND: European city councils are increasingly developing interventions against health inequalities. There is little knowledge about how they are perceived. This study describes and analyses good practices and challenges for local interventions on inequalities in health through the narratives of European city managers. METHODS: A qualitative study was conducted. Each participating city (Amsterdam, Barcelona, Cluj-Napoca, Helsinki, Lisbon, London, Madrid, Rotterdam) selected interventions following these criteria: at least 6 months of implementation; an evaluation performed or foreseen; the reduction of health inequalities among their objectives, and only one of the interventions selected could be based on health care. Managers of these local interventions were interviewed following an outline. Eleven individual in-depth interviews describing nine local interventions were obtained. A thematic content analysis was performed. RESULTS: One or more local interventions against health inequalities were identified in each city. Most relied on quantitative data and were linked to national strategies. Few interventions addressed socio-economic determinants. Health care, employment and education were the main determinants addressed. With variable depth, evidence-base, participation and intersectorality were regular components of the interventions. Half of them targeted the city and half some deprived neighbourhoods. Few interventions had been evaluated. Scarcity of funding and sustainability of the projects were the main perceived barriers by the managers. CONCLUSIONS: City intervention managers were familiar with health inequalities and concepts as intersectorality, participation and evidence-based action, but others such as socioeconomic aims, gradient approach, evaluation and sustainability were not so widely applied. Managers' capacities and political leadership in governance for health should be reinforced. PMID- 24756878 TI - Exchangeability in the case-crossover design. AB - In cohort and case-control studies, confounding that arises as a result of differences in the distribution of determinants of the outcome between exposure groups leading to non-exchangeability are addressed by restriction, matching or with statistical models. In case-only studies, this issue is addressed by comparing each individual with his/herself. Although case-only designs use self matching and only include individuals who develop the outcome of interest, issues of non-exchangeability are identical to those that arise in traditional case control and cohort studies. In this review, we describe one type of case-only design, the case-crossover design, and discuss how the concept of exchangeability can be used to understand issues of confounding, carryover effects, period effects and selection bias in case-crossover studies. PMID- 24756879 TI - A simple contact mapping algorithm for identifying potential peptide mimetics in protein-protein interaction partners. AB - A simple, static contact mapping algorithm has been developed as a first step at identifying potential peptide biomimetics from protein interaction partner structure files. This rapid and simple mapping algorithm, "OpenContact" provides screened or parsed protein interaction files based on specified criteria for interatomic separation distances and interatomic potential interactions. The algorithm, which uses all-atom Amber03 force field models, was blindly tested on several unrelated cases from the literature where potential peptide mimetics have been experimentally developed to varying degrees of success. In all cases, the screening algorithm efficiently predicted proposed or potential peptide biomimetics, or close variations thereof, and provided complete atom-atom interaction data necessary for further detailed analysis and drug development. In addition, we used the static parsing/mapping method to develop a peptide mimetic to the cancer protein target, epidermal growth factor receptor. In this case, secondary, loop structure for the peptide was indicated from the intra-protein mapping, and the peptide was subsequently synthesized and shown to exhibit successful binding to the target protein. The case studies, which all involved experimental peptide drug advancement, illustrate many of the challenges associated with the development of peptide biomimetics, in general. PMID- 24756880 TI - Practices and opinions regarding HPV vaccination among French general practitioners: evaluation through two cross-sectional studies in 2007 and 2010. AB - OBJECTIVES: To use both quantitative and qualitative methods to investigate the evolution of practices and opinions regarding human papillomavirus (HPV) vaccination among French general practitioners. METHODS: A cross-sectional study (self-questionnaires) was performed in 2007 and repeated in 2010 among 271 general practitioners. Semi-structured interviews were conducted on 27 voluntary participants by a sociologist and analyzed according to content analysis. RESULTS: Acceptability of HPV vaccination had increased from 2007 to 2010 (79.9 vs. 87.1%, respectively), just as the practice of HPV vaccination among 14-year old girls (19.0 vs. 49.1%, respectively). Though about 60% reported complications associated with HPV vaccination, irrespective of year, the types of difficulties have varied: difficulties related to "questions asked by patients" had decreased, though concerns about side effects had remained stable. During interviews, difficulties related to "the reason for medical consultation" and "the target age" were often associated with addressing the issue of sexuality, especially when the parents were present. CONCLUSIONS: Although the high level of acceptability of HPV vaccination among general practitioners, which increased from 2007 to 2010, there remain difficulties in addressing this practice. PMID- 24756882 TI - Coordination adducts of niobium(V) and tantalum(V) azide M(N3)5 (M=Nb, Ta) with nitrogen donor ligands and their self-ionization. AB - Several new donor-acceptor adducts of niobium and tantalum pentaazide with N donor ligands have been prepared from the pentafluorides by fluoride-azide exchange with Me3SiN3 in the presence of the corresponding donor ligand. With 2,2'-bipyridine and 1,10-phenanthroline, the self-ionization products [MF4(2,2' bipy)2](+)[M(N3)6](-), [M(N3)4(2,2'-bipy)2](+)[M(N3)6](-) and [M(N3)4(1,10 phen)2](+)[M(N3)6](-) were obtained. With the donor ligands 3,3'-bipyridine and 4,4'-bipyridine the neutral pentaazide adducts (M(N3)5)2?L (M=Nb, Ta; L=3,3' bipy, 4,4'-bipy) were formed. PMID- 24756881 TI - Cloning and expression analysis of an MYB gene associated with calyx persistence in Korla fragrant pear. AB - KEY MESSAGE: We isolated an MYB-like gene from Korla fragrant pear using differential display RT-PCR. Expression of this gene in flowers appears to be correlated with calyx persistence. Korla fragrant pear (Pyrus brestschneideri Rehd) is an economically important pear cultivar in China. A persistent calyx results in the deformation of the fruit. We used differential display RT-PCR to obtain 42 cDNA fragments from Korla fragrant pear flowers. Alignments of nucleotide and amino acid sequences suggested that two fragments (kfp1and kfp4) were related to calyx persistence. The fragments were 78% homologous with Malus * domestica SPL transcription factor (SPL3) and 83% homologous with Malus * domestica MYB transcription factor (MYB12). The complete cDNA sequence of kfpMYB was determined to clarify the role of MYB in calyx persistence. kfpMYB contained a 116 bp 5'-UTR, a 1122 bp open reading frame encoding 374 amino acids, and a 319 bp 3'-UTR. The nucleotide and amino acid sequences of the cDNA in Korla fragrant pear were highly homologous with those of MYB transcription factors in other plant species, suggesting that the sequence is a MYB transcription factor gene. The abundance of kfpMYB mRNA varied significantly between the second and fourth flowers on the branch. Furthermore, kfpMYB expression changed significantly during anthesis and was significantly higher in Jinfeng pear (persistent calyx) and Korla fragrant pear than in Yali pear (deciduous calyx). Expression of kfpMYB was significantly reduced by naphthalene (NAA), abscisic acid (ABA), PBO, and paclobutrazol (PP333). Uniconazole, ethylene (ETH), and gibberellic acid (GA3) had no signicant effect on kfpMYB expression. In conclusion, the expression of kfpMYB appears to be correlated with calyx persistence in Korla fragrant pear. PMID- 24756883 TI - Discordant patterns of tissue-specific genetic characteristics in the HIV-1 env gene from HIV-associated neurocognitive disorder (HAND) and non-HAND patients. AB - The genetic evolution of HIV-1 in the central nervous system (CNS) is different from that in peripheral tissues. We analyzed 121 clonal sequences of the V3-V5 regions of the env gene generated from paired cerebrospinal fluid (CSF) and plasma samples from nine chronically infected patients (four with HIV-associated neurocognitive disorder (HAND) and five without HAND). The sequence analysis indicated the significant differences between CSF and plasma was only observed in the C4 region (P = 0.043) in HAND patients. Significant increases in synonymous substitutions (dS) within the V4 region (P = 0.020) and in nonsynonymous substitutions (dN) within the C4 region (P = 0.029) were observed in the CSF derived sequences. By contrast, CSF-derived sequences from non-HAND patients showed similar levels of diversity; dS and dN as the plasma-derived sequences. Signature differences between the CSF- and plasma-derived sequences were found at 12 amino acid positions for HAND patients and nine positions for non-HAND patients. Interestingly, five sites (positions 388, 396, 397, 404, and 406) that all belong to signature patterns exhibited positive selection pressure in CSF samples, but only site 406 was positively selected in the plasma samples from the HAND patients. Conversely, in the non-HAND patients, there were four sites (positions 397, 404, 432, and 446) showed positive selection pressure in the plasma samples, but only site 446 in the CSF samples. These results suggest that discordant patterns of genetic evolution occur between the tissue-specific HIV-1 quasispecies in the HAND and non-HAND patients. Viral molecular heterogeneity between specific tissues is greater in patients with HAND compared to non-HAND patients. PMID- 24756884 TI - A new method based on the regression of step response data for monitoring a freeze-drying cycle. AB - This paper deals with the problem of monitoring the freeze-drying process of thermo-labile products and particularly tracking the temperature and the position of the interface of sublimation. A novel and affordable way is proposed to estimate the vapor flow rate and, thus, retrieve the parameters of interest. This method is referred to as pressure decrease test (PDT) and is based on the shutoff of the controlled leakage valve and on the subsequent model-based analysis of the response of the process. In this paper, a detailed description of the PDT algorithm is given; furthermore, the method was tested upon two placebo formulations, that is, sucrose- and mannitol-based solutions, showing that the tool can give an accurate, complete, and noninvasive estimation of all the parameters of interest. These results also show that the method is a valid solution to various technical problems that arise when attempting to apply other techniques proposed in the literature, for example, the pressure rise test and the tunable diode laser absorption spectroscopy technology. PMID- 24756885 TI - Ameliorating slice gaps in multislice magnetic resonance images: an interpolation scheme. AB - PURPOSE: Standard two-dimension (2D) magnetic resonance imaging (MRI) clinical acquisition protocols utilize orthogonal plane images which contain slice gaps (SG). The purpose of this work is to introduce a novel interpolation method for these orthogonal plane MRI 2D datasets. Three goals can be achieved: (1) increasing the resolution based on a priori knowledge of scanning protocol, (2) ameliorating the loss of data as a result of SG and (3) reconstructing a three dimension (3D) dataset from 2D images. METHODS: MRI data was collected using a 3T GE scanner and simulated using Matlab. The procedure for validating the MRI data combination algorithm was performed using a Shepp-Logan and a Gaussian phantom in both 2D and 3D of varying matrix sizes (64-512), as well as on one MRI dataset of a human brain and on an American College of Radiology magnetic resonance accreditation phantom. RESULTS: The squared error and mean squared error were computed in comparing this scheme to common interpolating functions employed in MR consoles and workstations. The mean structure similarity matrix was computed in 2D as a means of qualitative image assessment. Additionally, MRI scans were used for qualitative assessment of the method. This new scheme was consistently more accurate than upsampling each orientation separately and averaging the upsampled data. CONCLUSION: An efficient new interpolation approach to resolve SG was developed. This scheme effectively fills in the missing data points by using orthogonal plane images. To date, there have been few attempts to combine the information of three MRI plane orientations using brain images. This has specific applications for clinical MRI, functional MRI, diffusion-weighted imaging/diffusion tensor imaging and MR angiography where 2D slice acquisition are used. In these cases, the 2D data can be combined using our method in order to obtain 3D volume. PMID- 24756887 TI - Indigenizing CBPR: evaluation of a community-based and participatory research process implementation of the Elluam Tungiinun (towards wellness) program in Alaska. AB - The process that community based participatory research (CBPR) implementation takes in indigenous community contexts has serious implications for health intervention outcomes and sustainability. An evaluation of the Elluam Tungiinun (Towards Wellness) Project aimed to explore the experience of a Yup'ik Alaska Native community engaged within a CBPR process and describe the effects of CBPR process implementation from an indigenous community member perspective. CBPR is acknowledged as an effective strategy for engaging American Indian and Alaska Native communities in research process, but we still know very little about the experience from a local, community member perspective. What are the perceived outcomes of participation in CBPR from a local, community member perspective? Qualitative methods were used to elicit community member perspectives of participation in a CBPR process engaged with one Yup'ik community in southwest Alaska. Results focus on community member perceptions of CBPR implementation, involvement in the process and partnership, ownership of the project with outcomes observed and perceived at the community, family and individual levels, and challenges. A discussion of findings demonstrates how ownership of the intervention arose from a translational and indigenizing process initiated by the community that was supported and enhanced through the implementation of CBPR. Community member perspectives of their participation in the research reveal important process points that stand to contribute meaningfully to implementation science for interventions developed by and for indigenous and other minority and culturally diverse peoples. PMID- 24756888 TI - Purple lip. PMID- 24756886 TI - Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. AB - BACKGROUND: Evidence has accumulated indicating that microglia within the spinal cord play a critical role in morphine tolerance. The present study investigated the effects and possible mechanisms of 5' adenosine monophosphate-activated protein kinase (AMPK) activator resveratrol and AICAR to inhibit microglial activation and to limit the decrease in antinociceptive effects of morphine. METHODS: The microglial cell line BV-2 was used. Cytokine expression was measured using quantitative polymerase chain reaction. Cell signalling was assayed by Western blot and immunohistochemistry. The antinociception and morphine tolerance were assessed in CD-1 mice using the hot plate and tail-flick tests. RESULTS: (1) Morphine induces robust BV-2 cell activation, as evidenced by increased p38 mitogen-activated protein kinase phosphorylation, nuclear factor-kappaB translocation and mRNA expression of pro-inflammatory cytokines [including interleukin-1beta (IL-1beta), IL-6 and tumour necrosis factor-alpha], inducible nitric oxide synthase and Toll-like receptor-4, and these changes are inhibited by resveratrol. (2) Resveratrol activates AMPK to suppress morphine-induced BV-2 cell activation. AICAR, another AMPK activator, can mimic the effects of resveratrol, whereas compound C, an AMPK inhibitor, reverses the inhibitory effects of resveratrol treatment. (3) Systemic or spinal administration of resveratrol with morphine significantly blocks microglial activation in the spinal cord and then attenuates the development of acute and chronic morphine tolerance in both male and female mice. CONCLUSION: Resveratrol directly suppresses morphine-induced microglial activation through activating AMPK, resulting in significant attenuation of morphine antinociceptive tolerance. PMID- 24756890 TI - Sacral doming progression in developmental spondylolisthesis: a demonstrative case report with two different evolutions. AB - STUDY DESIGN: Demonstrative case report of two different evolutions in developmental spondylolisthesis. To our knowledge spontaneous sacral doming reconstruction and healing has never been previously reported. METHODS: Presentation of two cases with developmental spondylolisthesis and no sacral dome that had at the beginning a similar presentation and finally evolved in different ways. RESULTS: Initially, both cases were without sacral dome. In the first case, sacral dome appeared and completely healed in presence of a stable elongata pars and stable spondylolisthesis. In the second case, apparition, progression of sacral dome, rolling up of L5 and spondylolisthesis occurred in the presence of lytic defect in the pars. CONCLUSION: Sacral doming is secondary to L5 abnormal position regarding to S1. The mechanism of sacral doming looks like as an osteochondritis phenomena. Loss of support of the sacral plateau by sacral rounding may induce high grade spondylolisthesis. PMID- 24756892 TI - Prospective comparative study between straight and curved probe for pedicle screw insertion. AB - PURPOSE: To evaluate difference in accuracy of pedicle screw insertion in thoracic and lumbosacral spine using a straight pedicle probe vis-a-vis a curved one. METHODS: Prospective, comparative, non-randomized, single-blind study. Straight and curved pedicle probes used on opposite sides of same vertebra in patients undergoing thoracolumbar pedicle screw fixation for various indications. Postoperative blinded evaluation for pedicle breaches done with a CT scan. Pedicle breaches graded as grade 0: no breach, grade 1: <2 mm, grade 2: 2-4 mm and grade 3: >4 mm breach. RESULTS: After appropriate statistical power analysis, 300 screws inserted in 59 patients from T4-L5 levels. No significant differences noted between the two probes in terms of screw length [two-tailed p = 0.16]; grade 0 screws [two-tailed p = 0.49] or screws with grade 2/3 breaches [two tailed p = 0.68]. With the right-hand-dominant operating-surgeon standing to left of patient during surgery, no difference noted between the two probes for either the right or left-side pedicle screw insertion [two-tailed p = 1]. Repeating these tests in the subset of thoracic pedicle screws too, revealed no significant difference. CONCLUSIONS: No significant difference in outcome of pedicle screw insertion with either a straight or a curved pedicle probe. PMID- 24756893 TI - Is it feasible to treat unstable hangman's fracture via the primary standard anterior retropharyngeal approach? AB - PURPOSE: The goal of this study was to evaluate the results and feasibility of primary anterior cervical discectomy and fusion (ACDF) with plating for unstable traumatic spondylolisthesis of the axis, the so-called hangman's fracture, via the standard anterior retropharyngeal approach. METHODS: The clinical and radiological records of 17 patients (14 males and 3 females, mean age: 51 years, range 17-73 years) with unstable hangman's fracture who were treated between January 1996 and June 2012 were reviewed retrospectively. ACDF with plating at C2 3 level was performed in all patients (type II fracture: 12 patients, type IIA fracture: 3 patients and type III fracture: 2 patients, based on the Levine and Edwards classification). Combined morbidity, complications, neurological improvement and fusion rate were assessed. RESULTS: Seventeen patients underwent fusion surgery via the standard anterior retropharyngeal approach. Four patients required an additional posterior arthrodesis to augment the anterior procedure. Patients wore a Philadelphia collar for 4-6 weeks and fusion at C2-3 was achieved in all patients. Two cases of complications were observed during treatment, comprising of one case of non-union and one case of transient dysphagia that resolved after 3 months. However, none of the patients experienced worsening of the neurological function post-operatively. There were no cases of permanent nerve injury or infection. CONCLUSIONS: Treatment of the hangman's fracture is dependent on the stability of the injury. Although the treatment for unstable hangman's fracture is still controversial, we carefully suggest that primary ACDF with plating via the standard anterior retropharyngeal approach may be a feasible treatment option. It provides immediate stability and allows for early ambulation while promoting a stable bone union with minimal morbidity. PMID- 24756894 TI - Curcumin inhibits the AKT/NF-kappaB signaling via CpG demethylation of the promoter and restoration of NEP in the N2a cell line. AB - Curcumin (CUR), a non-toxic polyphenol from Curcuma longa, has been investigated as a potential therapy with anti-inflammatory and anti-oxidative effects for Alzheimer's disease (AD), which depicts features of chronic inflammatory environment resulting in cellular death. However, it remains largely unknown whether the anti-inflammatory effect of CUR in AD is associated with its property of CpG demethylation, which is another function of CUR with the most research interest during recent years. Neprilysin (NEP, EP24.11), a zinc-dependent metallopeptidase expressed relatively low in the brain, is emerging as a potent inhibitor of AKT/Protein Kinase B. In addition, hypermethylated promoter of NEP has been reported to be associated with decreases in NEP expression. In the present study, using bisulfite-sequencing PCR (BSP) assay, we showed that the CpG sites in NEP gene were hypermethylated both in wild-type mouse neuroblastoma N2a cells (N2a/wt) and N2a cells stably expressing human Swedish mutant amyloid precursor protein (APP) (N2a/APPswe) associated with familial early onset AD. CUR treatment induced restoration of NEP gene via CpG demethylation. This CUR mediated upregulation of NEP expression was also concomitant with the inhibition of AKT, subsequent suppression of nuclear transcription factor-kappaB (NF-kappaB) and its downstream pro-inflammatory targets including COX-2, iNOS in N2a/APPswe cells. This study represents the first evidence on a link between CpG demethylation effect on NEP and anti-inflammation ability of CUR that may provide a novel mechanistic insight into the anti-inflammatory actions of CUR as well as new basis for using CUR as a therapeutic intervention for AD. PMID- 24756895 TI - Exercise for osteoarthritis of the hip. AB - BACKGROUND: Current international treatment guidelines recommending therapeutic exercise for people with symptomatic hip osteoarthritis (OA) report are based on limited evidence. OBJECTIVES: To determine whether land-based therapeutic exercise is beneficial for people with hip OA in terms of reduced joint pain and improved physical function and quality of life. SEARCH METHODS: We searched five databases from inception up to February 2013. SELECTION CRITERIA: All randomised controlled trials (RCTs) recruiting people with hip OA and comparing some form of land-based therapeutic exercise (as opposed to exercises conducted in water) with a non-exercise group. DATA COLLECTION AND ANALYSIS: Four review authors independently selected studies for inclusion. We resolved disagreements through consensus. Two review authors independently extracted data, assessed risk of bias and the quality of the body of evidence for each outcome using the GRADE approach. We conducted analyses on continuous outcomes (pain, physical function and quality of life) and dichotomous outcomes (proportion of study withdrawals). MAIN RESULTS: We considered that seven of the 10 included RCTs had a low risk of bias. However, the results may be vulnerable to performance and detection bias as none of the RCTs were able to blind participants to treatment allocation and, while most RCTs reported blinded outcome assessment, pain, physical function and quality of life were participant self reported. One of the 10 RCTs was only reported as a conference abstract and did not provide sufficient data for the evaluation of bias risk.High-quality evidence from nine trials (549 participants) indicated that exercise reduced pain (standardised mean difference (SMD) -0.38, 95% confidence interval (CI) -0.55 to -0.20) and improved physical function (SMD 0.38, 95% CI -0.54 to -0.05) immediately after treatment. Pain and physical function were estimated to be 29 points on a 0- to 100-point scale (0 was no pain or loss of physical function) in the control group; exercise reduced pain by an equivalent of 8 points (95% CI 4 to 11 points; number needed to treat for an additional beneficial outcome (NNTB) 6) and improved physical function by an equivalent of 7 points (95% CI 1 to 12 points; NNTB 6). Only three small studies (183 participants) evaluated quality of life, with overall low quality evidence, with no benefit of exercise demonstrated (SMD -0.07, 95% CI -0.23 to 0.36). Quality of life was estimated to be 50 points on a norm-based mean (standard deviation (SD)) score of 50 (10) in the general population in the control group; exercise improved quality of life by 0 points. Moderate-quality evidence from seven trials (715 participants) indicated an increased likelihood of withdrawal from the exercise allocation (event rate 6%) compared with the control group (event rate 3%), but this difference was not significant (risk difference 1%; 95% CI -1% to 4%). Of the five studies reporting adverse events, each study reported only one or two events and all were related to increased pain attributed to the exercise programme.The reduction in pain was sustained at least three to six months after ceasing monitored treatment (five RCTs, 391 participants): pain (SMD -0.38, 95% CI -0.58 to -0.18). Pain was estimated to be 29 points on a 0- to 100 point scale (0 was no pain) in the control group, the improvement in pain translated to a sustained reduction in pain intensity of 8 points (95% CI 4 to 12 points) compared with the control group (0 to 100 scale). The improvement in physical function was also sustained (five RCTs, 367 participants): physical function (SMD -0.37, 95% CI -0.57 to -0.16). Physical function was estimated to be 24 points on a 0- to 100-point scale (0 was no loss of physical function) in the control group, the improvement translated to a mean of 7 points (95% CI 4 to 13) compared with the control group.Only five of the 10 RCTs exclusively recruited people with symptomatic hip OA (419 participants). There was no significant difference in pain or physical function outcomes compared with five studies recruiting participants with hip or knee OA (130 participants). AUTHORS' CONCLUSIONS: Pooling the results of these 10 RCTs demonstrated that land-based therapeutic exercise programmes can reduce pain and improve physical function among people with symptomatic hip OA. PMID- 24756896 TI - Engineering the productivity of recombinant Escherichia coli for limonene formation from glycerol in minimal media. AB - The efficiency and productivity of cellular biocatalysts play a key role in the industrial synthesis of fine and bulk chemicals. This study focuses on optimizing the synthesis of (S)-limonene from glycerol and glucose as carbon sources using recombinant Escherichia coli. The cyclic monoterpene limonene is extensively used in the fragrance, food, and cosmetic industries. Recently, limonene also gained interest as alternative jet fuel of biological origin. Key parameters that limit the (S)-limonene yield, related to genetics, physiology, and reaction engineering, were identified. The growth-dependent production of (S)-limonene was shown for the first time in minimal media. E. coli BL21 (DE3) was chosen as the preferred host strain, as it showed low acetate formation, fast growth, and high productivity. A two-liquid phase fed-batch fermentation with glucose as the sole carbon and energy source resulted in the formation of 700 mg L(org) (-1) (S) limonene. Specific activities of 75 mU g(cdw) (-1) were reached, but decreased relatively quickly. The use of glycerol as a carbon source resulted in a prolonged growth and production phase (specific activities of >=50 mU g(cdw) (-1) ) leading to a final (S)-limonene concentration of 2,700 mg L(org) (-1) . Although geranyl diphosphate (GPP) synthase had a low solubility, its availability appeared not to limit (S)-limonene formation in vivo under the conditions investigated. GPP rerouting towards endogenous farnesyl diphosphate (FPP) formation also did not limit (S)-limonene production. The two-liquid phase fed-batch setup led to the highest monoterpene concentration obtained with a recombinant microbial biocatalyst to date. PMID- 24756897 TI - Nucleophilic difluoromethylation of epoxides with PhSO(NTBS)CF2H by a preorganization strategy. AB - Unlike the facile synthesis of beta-monofluoromethyl alcohols by nucleophilic monofluoromethylation of epoxides, the synthesis of beta-difluoromethyl alcohols by nucleophilic difluoromethylation of epoxides still remains a challenge. Herein, studies on tackling this problem with PhSO(NTBS)CF2H (2; TBS=tert butyldimethylsilyl) are reported. The preorganization of 2 and epoxides with BF3?Et2O was found to be crucial for the reaction. The reaction shows excellent regioselectivity and has a broad substrate scope. The facile transformation of the ring-opened products to beta-difluoromethyl, gamma-difluoromethyl, and beta difluoromethylenyl alcohols demonstrates the synthetic utility of the reaction. PMID- 24756899 TI - Effects of ball-milling and cryomilling on sulfamerazine polymorphs: a quantitative study. AB - The effects of ball-milling and cryomilling on sulfamerazine forms I and II (SMZ FI, FII) were investigated using X-ray powder diffraction, infrared and near infrared (NIR) spectroscopy. Cryomilling resulted in a complete amorphization of both polymorphs. Milling at room temperature gave mixtures of amorphous SMZ (FA) and FII. Calibration models were developed for the quantitative analysis of binary (FI/FII, FI/FA, and FII/FA) and ternary (FI/FII/FA) mixtures using NIR spectroscopy combined with partial least-squares (PLS) regression. The PLS models for binary (0%-100%), ternary (0%-100%), and low-level (0%-10%) binary mixtures had root-mean-square errors of prediction of <=1.8%, <=5.1%, and <=0.80%, respectively. The calibration models were used to obtain a detailed quantitative picture of solid-state transformations during milling and any subsequent recrystallizations. FA prepared by cryomilling FI for less than 60 min recrystallized to mixtures of FI and FII, whereas samples milled for more than 60 min crystallized to pure FII. The effect of comilling SMZ with stoichiometric amounts of additives was investigated. SMZ formed amorphous materials with oxalic, dl-tartaric, and citric acids that were more stable toward recrystallization than FA. Amorphous SMZ/oxalic acid was found to recrystallize to a 2:1 cocrystal during storage. PMID- 24756900 TI - CSF otorhinorrhea in a child with inner ear dysplasia: diagnosis with T2-weighted and intrathecal contrast-enhanced MR cisternography. AB - During the follow-up of recurrent pneumonia in a 9-month-old girl, rhinorrhea with discharge of a positional and intermittent nature was discovered. Radiological assessment was requested to detect any skull base openings and cerebrospinal fluid (CSF) leakage. T2-weighted MR cisternography showed bilateral inner ear dysplasia, communication of the internal auditory canal with the vestibule, and effusion in the right middle ear. Intrathecal contrast-enhanced MR cisternography revealed a CSF fistula from the right internal auditory canal to the Eustachian tube. The patient was operated upon on the right side, and the presence of a CSF leak near the oval window was confirmed. No adverse effects were seen during the short-term and long-term follow-up. Diagnosing this case required special attention, careful examination, and relevant investigations to find the site of CSF leakage in this patient with bilateral inner ear dysplasia. PMID- 24756901 TI - Modified interventional obliteration for variceal hemorrhage from elevated jejunum after pylorus-preserving pancreatoduodenectomy. AB - Ectopic variceal hemorrhage caused by sinistral portal hypertension after splenic vein ligation during a pyloric-preserving pancreatoduodenectomy is a rare entity. We report the case of a 58-year-old man with symptoms of refractory melena. The varices could not be treated endoscopically and surgery was considered unsuitable due to severe adhesions and altered anatomy. Following clinical failure of partial splenic embolization, an alternative obliteration method by a retrograde trans-portal-venous approach was successfully performed and resolved the problem. It seems to be an effective method for ectopic variceal bleeding, especially when other interventions are unavailable or highly risky. PMID- 24756902 TI - Highly diastereo- and enantioselective silver-catalyzed double [3+2] cyclization of alpha-imino esters with isocyanoacetate. AB - Presented herein is a new complexity-generating method in which both functionalities of alpha-imino esters undergo stereoselective cyclization with isocyanoacetates to produce directly linked oxazole-imidazolines, which can be transformed into highly functionalized alpha,beta-diamino esters and imidazolinium salts in high diastereo- and enantiopurity. PMID- 24756903 TI - Use of whole-blood transcriptomic profiling to highlight several pathophysiologic pathways associated with response to rituximab in patients with rheumatoid arthritis: data from a randomized, controlled, open-label trial. AB - OBJECTIVE: To identify a molecular signature that could be predictive of the clinical response to rituximab (RTX) and elucidate the transcriptomic changes after RTX therapy in patients with rheumatoid arthritis (RA), with the use of whole-blood transcriptomic profiling. METHODS: A microarray assay of the whole human genome was performed using RNA from peripheral blood samples obtained before the first cycle of RTX from 68 patients with RA in the SMART study. The transcriptomic profile was also assessed 24 weeks after the first administration of RTX (among 24 nonresponders and 44 responders, according to the European League Against Rheumatism response criteria at week 24). Ingenuity Interactive Pathways Analysis was used to identify molecular pathways that were modified by RTX therapy according to the clinical response. Quantitative polymerase chain reaction was performed to confirm the microarray results. RESULTS: In total, 198 genes showed significant baseline differential expression between patient groups according to their subsequent response to RTX (good or moderate responder versus nonresponder). This molecular signature could be reduced to 143 genes, which allowed for correctly classifying 89% of the patients by their EULAR response status at week 24, with 93% identification of responders and 100% identification of nonresponders. The signature for response featured up-regulation of inflammatory genes centered on NF-kappaB, including IL33 and STAT5A, and down regulation of the interferon pathway. As expected, at week 24 post-RTX therapy, genes involved in the development and functions of B cells were the genes most strongly down-regulated, without any difference between the 2 groups. CONCLUSION: Whole-blood transcriptomic analyses may accurately identify patients with RA who will not respond to RTX therapy. These findings could open new perspectives on the clinical management of RA. PMID- 24756905 TI - The initial experience of introducing the Onstep technique for inguinal hernia repair in a general surgical department. AB - BACKGROUND AND AIMS: A new technique for the repair of inguinal hernia, called Onstep, has been described. This technique places the mesh in the preperitoneal space medially and between the internal and external oblique muscles laterally. The Onstep technique has not yet been described outside the inventors' departments. This study was based on the first 80 patients operated by the Onstep technique in a general surgical department. The objective of the study was to investigate postoperative pain and complications following the Onstep repair of inguinal hernia. MATERIAL AND METHODS: A total of 80 patients, operated in our department, were followed up in the medical files and contacted by letter. Patients were asked to fill out the Inguinal Pain Questionnaire, Carolinas Comfort Scale, and the Activity Assessment Scale, in order to assess postoperative pain. RESULTS: No perioperative complications occurred. The response rate was 85% on the mailed questionnaires. No patients had any activities they were not able to perform. Activity Assessment Scale results: 80.3% did not have substantial pain-related impairment of daily function. Carolinas Comfort Scale results: 94.8% did not have a symptomatic repair. Inguinal Pain Questionnaire results: 95.5% reported no pain or pain that was easily ignored. CONCLUSIONS: It seems from this study that the Onstep technique is a safe method for inguinal hernia repair regarding perioperative and postoperative complications. The postoperative pain seems to be equal to or lower than after the Lichtenstein technique. PMID- 24756904 TI - Intrathecal administration of botulinum toxin type A improves urinary bladder function and reduces pain in rats with cystitis. AB - BACKGROUND: Botulinum toxin A (Onabot/A) has been shown to have an antinociceptive effect. This might be due to an impairment of sensory nerves not only in the peripheral but also in the central nervous system. In this work, we analysed both systems by studying the effect of intrathecal (i.t.) administration of botulinum toxin A in an animal model of bladder pain and hyperactivity induced by cyclophosphamide (CYP). METHODS: Rats were implanted with an i.t. catheter at the L6 segment. Bladder pain was induced by intraperitoneal (i.p.) injection of CYP. Five experimental groups were created: (1) Saline i.p. + i.t.; (2) Onabot/A i.t.; (3) CYP i.p. + saline i.t.; (4) CYP i.p. + Onabot/A i.t. 48 h after CYP; and (5) Onabot/A i.t. 30 days. Mechanical sensitivity was assessed in the abdomen and hindpaws. Motor activity was observed in an open-field arena. Bladder reflex activity was evaluated by cystometry. At the end, bladders and spinal cord were immunoreacted (IR) against cleaved SNAP-25 (cSNAP-25), c-Fos, p-ERK, calcitonin gene-related peptide (CGRP) and GAP43. RESULTS: The toxin reduced pain symptoms, bladder hyperactivity, expression of neuronal activation markers and CGRP, typically up-regulated in this inflammatory model. The presence of cSNAP-25 was detected in the spinal cord and bladder fibres from animals treated with Onabot/A. No somatic or visceral motor impairments were observed. CONCLUSIONS: Our findings suggest that i.t. Onabot/A has a strong analgesic effect in a model of severe bladder pain. This route of administration can be further explored to treat intractable forms of pain. PMID- 24756906 TI - Measurement of GABA using J-difference edited 1H-MRS following modulation of synaptic GABA concentration with tiagabine. AB - Though GABA is the major inhibitory neurotransmitter in the brain, involved in a wide variety of brain functions and many neuropsychiatric disorders, its intracellular and metabolic presence provides uncertainty in the interpretation of the GABA signal measured by (1)H-MRS. Previous studies demonstrating the sensitivity of this technique to pharmacological manipulations of GABA have used nonspecific challenges that make it difficult to infer the exact source of the changes. In this study, the synaptic GABA reuptake inhibitor tiagabine, which selectively blocks GAT1, was used to test the sensitivity of J-difference edited (1)H-MRS to changes in extracellular GABA concentrations. MEGA-PRESS was used to obtain GABA-edited spectra in 10 male individuals, before and after a 15-mg oral dose of tiagabine. In the three voxels measured, no significant changes were found in GABA+ concentration after the challenge compared to baseline. This dose of tiagabine is known to modulate synaptic GABA and neurotransmission through studies using other imaging modalities, and significant increases in self reported sleepiness scales were observed. Therefore, it is concluded that recompartmentalization of GABA through transport block does not have a significant impact on total GABA concentration. Furthermore, it is likely that the majority of the magnetic resonance spectroscopy (MRS)-derived GABA signal is intracellular. It should be considered, in individual interpretation of GABA MRS studies, whether it is appropriate to attribute observed effects to changes in neurotransmission. PMID- 24756907 TI - The origins of cellular life. AB - All life on earth can be naturally classified into cellular life forms and virus like selfish elements, the latter being fully dependent on the former for their reproduction. Cells are reproducers that not only replicate their genome but also reproduce the cellular organization that depends on semipermeable, energy transforming membranes and cannot be recovered from the genome alone, under the famous dictum of Rudolf Virchow, Omnis cellula e cellula. In contrast, simple selfish elements are replicators that can complete their life cycles within the host cell starting from genomic RNA or DNA alone. The origin of the cellular organization is the central and perhaps the hardest problem of evolutionary biology. I argue that the origin of cells can be understood only in conjunction with the origin and evolution of selfish genetic elements. A scenario of precellular evolution is presented that involves cohesion of the genomes of the emerging cellular life forms from primordial pools of small genetic elements that eventually segregated into hosts and parasites. I further present a model of the coevolution of primordial membranes and membrane proteins, discuss protocellular and non-cellular models of early evolution, and examine the habitats on the primordial earth that could have been conducive to precellular evolution and the origin of cells. PMID- 24756908 TI - Cytisus villosus from Northeastern Algeria is nodulated by genetically diverse Bradyrhizobium strains. AB - Fifty-one rhizobial strains isolated from root nodules of Cytisus villosus growing in Northeastern Algeria were characterized by genomic and phenotypic analyses. Isolates were grouped into sixteen different patterns by PCR-RAPD. The phylogenetic status of one representative isolate from each pattern was examined by multilocus sequence analyses of four housekeeping genes (16S rRNA, glnII, recA, and atpD) and one symbiotic gene (nodC). Analysis of 16S rRNA gene sequences showed that all the isolates belonged to the genus Bradyrhizobium. Phylogenetic analyses based on individual or concatenated genes glnII, recA, and atpD indicated that strains cluster in three distinct groups. Ten out of the sixteen strains grouped together with Bradyrhizobium japonicum, while a second group of four clustered with Bradyrhizobium canariense. The third group, represented by isolates CTS8 and CTS57, differed significantly from all other bradyrhizobia known to nodulate members of the Genisteae tribe. In contrast with core genes, sequences of the nodC symbiotic gene from all the examined strains form a homogeneous group within the genistearum symbiovar of Bradyrhizobium. All strains tested nodulated Lupinus angustifolius, Lupinus luteus, and Spartium junceum but not Glycine max. From these results, it is concluded that C. villosus CTS8 and CTS57 strains represent a new lineage within the Bradyrhizobium genus. PMID- 24756909 TI - Divergence in age patterns of mortality change drives international divergence in lifespan inequality. AB - In the past six decades, lifespan inequality has varied greatly within and among countries even while life expectancy has continued to increase. How and why does mortality change generate this diversity? We derive a precise link between changes in age-specific mortality and lifespan inequality, measured as the variance of age at death. Key to this relationship is a young-old threshold age, below and above which mortality decline respectively decreases and increases lifespan inequality. First, we show for Sweden that shifts in the threshold's location have modified the correlation between changes in life expectancy and lifespan inequality over the last two centuries. Second, we analyze the post World War II (WWII) trajectories of lifespan inequality in a set of developed countries-Japan, Canada, and the United States-where thresholds centered on retirement age. Our method reveals how divergence in the age pattern of mortality change drives international divergence in lifespan inequality. Most strikingly, early in the 1980s, mortality increases in young U.S. males led to a continuation of high lifespan inequality in the United States; in Canada, however, the decline of inequality continued. In general, our wider international comparisons show that mortality change varied most at young working ages after WWII, particularly for males. We conclude that if mortality continues to stagnate at young ages yet declines steadily at old ages, increases in lifespan inequality will become a common feature of future demographic change. PMID- 24756910 TI - An investigation into the effect of fine lactose particles on the fluidization behaviour and aerosolization performance of carrier-based dry powder inhaler formulations. AB - The effect of milled and micronized lactose fines on the fluidization and in vitro aerosolization properties of dry powder inhaler (DPI) formulations was investigated, and the suitability of static and dynamic methods for characterizing general powder flow properties of these blends was assessed. Lactose carrier pre-blends were prepared by adding different lactose fines (Lactohale(r) (LH) 300, 230 and 210) with coarse carrier lactose (Lactohale100) at 2.5, 5, 10 and 20 wt% concentrations. Powder flow properties of lactose pre blends were characterized using the Freeman Technology FT4 and Schulze RST-XS ring shear tester. A strong correlation was found between the basic flow energy (BFENorm) measured using the Freeman FT4 Rheometer and the flowability number (ffc) measured on Schulze RST-XS. These data indicate that both static and dynamic methods are suitable for characterizing general powder flow properties of lactose carriers. Increasing concentration of fines corresponded with an increase in the normalized fluidization energy (FENorm). The inclusion of fine particles of lactose resulted in a significant (p < 0.05) increase in fine particle delivery of budesonide and correlated with FENorm. This trend was strongest for lactose containing up to 10 wt% LH300. A similar trend was found for the milled lactose grades LH230 and LH210. However, the increase in FENorm upon addition of milled fines only corresponded to a very slight improvement in the performance. These data suggest that whilst the fluidization energy correlated with fine particle delivery, this relationship is specific to lactose grades of similar particle size. PMID- 24756911 TI - Dedicated training in adult education among otolaryngology faculty. AB - OBJECTIVES/HYPOTHESIS: Most faculty members undergo ad hoc training in education. This survey was developed to assess the prevalence and type of dedicated training in education received by academic otolaryngology-head and neck surgery (OTO-HNS) faculty in the United States. STUDY DESIGN: Survey. METHODS: An 11-item survey was developed to assess the prevalence of dedicated instruction in education theory and practice, the types of instruction received, and the barriers to receiving instruction. The survey was sent to all OTO-HNS program directors for distribution among their respective faculty. RESULTS: A total of 216 responses were received. Seventy respondents (32.7%) serve as program director, associate program director, or assistant program director in their respective programs. Forty-six respondents (21.8%) had received dedicated training in education. Of the respondents who described the type of education training received, 48.7% participated in didactics/seminar, 35.9% in degree/certificate programs, 10.3% in multimodality training, and 5.1% online training. Among the barriers encountered to participation in instruction in education, time/productivity pressures was the most commonly cited reason (60.2%), followed by not knowing about the opportunity to receive training (36.4%), lack of departmental support (26.2%), lack of available training (22.3%), and the perception that such training would not be useful (7.8%). CONCLUSION: Presently, only a minority of surveyed academic otolaryngologists in the United States have received any dedicated instruction in the theory and practice of education. Personal, departmental, and institutional barriers exist in many practice environments that hinder otolaryngology faculty from participating in education training. LEVEL OF EVIDENCE: N/A. PMID- 24756912 TI - Clinical characteristics and treatment outcomes of autoimmune-associated hemophagocytic syndrome in adults. AB - OBJECTIVE: To better define the clinical characteristics and treatment outcomes of autoimmune-associated hemophagocytic syndrome (AAHS) in adults. METHODS: Adults with AAHS (defined as pathologic evidence of hemophagocytosis without any obvious cause other than an autoimmune disease) were identified through a review of the literature. RESULTS: Among 116 patients identified, underlying diseases included systemic lupus erythematosus (SLE) in 52.3%, adult-onset Still's disease (AOSD) in 26.7%, and dermatomyositis in 6.9%. Fever, lymphadenopathy, hepatomegaly, and splenomegaly were found in 86.8%, 41.0%, 41.8%, and 45.5% of patients, respectively. Cytopenia, liver dysfunction, and hyperferritinemia developed frequently, and coagulopathy was seen in 50.6% of patients. Normal or low C-reactive protein levels were characteristic of patients with underlying SLE. The most commonly used therapy was corticosteroids, which were initially administered in 95.7% of patients, with 57.7% responding. Patients with corticosteroid-refractory disease were usually treated with cyclosporine, intravenous cyclophosphamide (IV CYC), or intravenous immunoglobulin (IVIG), with IV CYC being highly effective. Treatment with biologic agents resulted in favorable effects in the majority of patients. The mortality rate was 12.9%. Male sex (odds ratio [OR] 6.47, 95% confidence interval [95% CI] 2.06-30.39, P < 0.01), dermatomyositis (OR 5.57, 95% CI 1.08-28.65, P < 0.05), and anemia (hemoglobin <8 gm/dl; OR 3.74, 95% CI 1.02-13.8, P < 0.05) were identified as factors associated with mortality. CONCLUSION: AAHS is potentially fatal. Corticosteroids are a mainstay of initial treatment. For corticosteroid refractory disease, IV CYC may be beneficial as compared with cyclosporine or IVIG. Treatment that proceeds directly from corticosteroids to biologic agents is promising. PMID- 24756913 TI - Randomized clinical trial of selective versus routine preoperative duplex ultrasound imaging before arteriovenous fistula surgery. AB - BACKGROUND: Anatomical suitability for arteriovenous fistula (AVF) formation was formerly determined by clinical examination alone. There are potential benefits from imaging to assess anatomical suitability. Existing studies examined the role of routine preoperative ultrasonography versus clinical examination alone. The role of a selective duplex ultrasound imaging policy is unknown. This study aimed to compare a policy of selective versus routine ultrasound assessment before AVF formation. METHODS: All patients referred for fistula formation were assessed for inclusion. Suitable patients were randomized to either routine or selective preoperative ultrasound imaging; selective imaging was performed only when clinical criteria were not met. The primary outcome measures were site of AVF formation and 30-day primary failure rate, and secondary outcome measures included the rate of complications. RESULTS: A total of 106 patients were assessed, and 94 were randomized: 47 to selective and 47 to routine duplex ultrasonography. The groups were well matched for age, co-morbidities and medications. The primary failure rate (29 per cent overall) was not significantly different between the selective and routine imaging groups: 36 per cent (14 of 39) and 21 per cent (8 of 38) respectively (P = 0.144). There were no significant differences in the sites of AVF formation or complication rates. CONCLUSION: Routine preoperative ultrasound vessel imaging did not significantly reduce early failure rates, influence the site of AVF formation or reduce complications. If clinical evaluation detects anatomy suitable for AVF formation, duplex imaging may not be needed. REGISTRATION NUMBER: NCT01004627 (http://www.clinicaltrials.gov). PMID- 24756914 TI - Discrepancies between medical oncologists and surgeons in assessment of resectability and indication for chemotherapy in patients with colorectal liver metastases. AB - BACKGROUND: Multidisciplinary discussion of the treatment of patients with colorectal liver metastases (CRLM) is advocated currently. The aim of this study was to investigate medical oncologists' and surgeons' assessment of resectability and indication for chemotherapy, and the effect of an educational intervention on such assessment. METHODS: Medical histories of 30 patients with CRLM were presented to ten experienced medical oncologists and 11 surgeons at an initial virtual tumour board meeting (TB1). Treatment recommendations were obtained from each participant by voting for standardized answers. Following lectures on the potential of chemotherapy and surgery, assessment was repeated at a second virtual tumour board meeting (TB2), using the same patients and participants. RESULTS: Overall, 630 answers (21 * 30) were obtained per tumour board meeting. At TB1, resectability was expected more frequently by surgeons. Participants changed 56.8 per cent of their individual answers at TB2. Assessment shifted from potentially resectable to resectable CRLM in 81 of 161 and from unresectable to (potentially) resectable CRLM in 29 of 36 answers. Preoperative chemotherapy was indicated more often by medical oncologists, and overall was included in 260 answers (41.3 per cent) at TB1, compared with only 171 answers (27.1 per cent) at TB2. Medical oncologists more often changed their decision to primary resection in resectable patients (P = 0.006). Postoperative chemotherapy was included in 51.9 and 52.4 per cent of all answers at TB1 and TB2 respectively, with no difference in changes between medical oncologists and surgeons (P = 0.980). CONCLUSION: Resectability and indication for preoperative chemotherapy were assessed differently by medical oncologists and surgeons. The educational intervention resulted in more patients deemed resectable by both oncologists and surgeons, and less frequent indication for chemotherapy. PMID- 24756915 TI - Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy. AB - Although protracted cognitive impairment has been reported to occur after radiotherapy even when such therapy is not directed to brain areas, the mechanism remains unclear. This study investigated whether breast cancer patients exposed to local radiotherapy showed lower cognitive function mediated by higher plasma interleukin (IL)-6 levels than those unexposed. We performed the Wechsler Memory Scale-Revised (WMS-R) and measured plasma IL-6 levels for 105 breast cancer surgical patients within 1 year after the initial therapy. The group differences in each of the indices of WMS-R were investigated between cancer patients exposed to adjuvant regional radiotherapy (n = 51) and those unexposed (n = 54) using analysis of covariance. We further investigated a mediation effect by plasma IL-6 levels on the relationship between radiotherapy and the indices of WMS-R using the bootstrapping method. The radiotherapy group showed significantly lower Immediate Verbal Memory Index and Delayed Recall Index (P = 0.001, P = 0.008, respectively). Radiotherapy exerted an indirect effect on the lower Delayed Recall Index of WMS-R through elevation of plasma IL-6 levels (bootstrap 95% confidence interval = -2.6626 to -0.0402). This study showed that breast cancer patients exposed to adjuvant regional radiotherapy in conservation therapy might have cognitive impairment even several months after their treatment. The relationship between the therapy and the cognitive impairment could be partially mediated by elevation of plasma IL-6 levels. PMID- 24756916 TI - Laparoscopic hernia complexity predicts operative time and length of stay. AB - PURPOSE: Laparoscopic ventral hernia repair (LVHR) is associated with shorter hospitalization and lower complication rates compared to open ventral hernia repair. We sought to determine if hernia-related factors, such as defect size and re-operative status correlate with postoperative complications, operative times and length of stay (LOS). METHODS: The study is a retrospective review of 30-day perioperative outcomes following LVHR in 91 patients who underwent surgery at a single institution from August 2009 through June 2012. A single surgeon performed all procedures. RESULTS: Indications for surgery were recurrent incisional hernia in 33 % of patients and primary incisional or ventral abdominal hernias in the rest. Coated polyester mesh with an average size of 348 cm(2) (+/-214; range 113 1,036) was used. Mean operative time was 132 min (+/-66.1; range 53-412). The mean LOS was 4.0 days (+/-3.5; range 1-22). Complications occurred in 13 patients for overall morbidity of 16.5 % and no mortality. There was one recurrence in 30 days (1.1 %). Patients who had a surgery >120 min or a LOS >1 day were statistically more likely to have multiple hernias, larger defect sizes (>40 cm(2)), larger mesh sizes (>300 cm(2)) or a history of recurrent hernia (P < 0.05). No other clinical or demographic variable evaluated in this study correlated with operative time or LOS. CONCLUSIONS: LVHR is safe with a low incidence of perioperative complications. Patients with multiple, larger and recurrent hernias have longer operative times and LOS. This information can be used to guide preoperative planning for the patient, surgeon and treating institution. PMID- 24756917 TI - Comparative study of open abdomen treatment: ABTheraTM vs. abdominal dressingTM. AB - INTRODUCTION: Negative pressure therapy (NPT) is a widely recognised procedure for the temporary closure of open abdominal wounds. In this study, we compare two NPT products, the V.A.C.(r) abdominal dressing (AD) system and the new ABTheraTM (ABT) system, in terms of the primary closure rates achieved, types of closure, and the associated morbidity. METHODS: We employed a retrospective comparative study of open-abdomen patients treated with NPT using either AD or ABT. The indications for treatment were damage control surgery, abdominal compartment syndrome, or severe abdominal sepsis. RESULTS: The group of patients treated with ABT showed a higher percentage of primary closures (41 vs. 11%) and required fewer days of NPT (17 vs. 26 days) than the AD group. Differences were statistically significant. In addition, only 4% of patients in the ABT group exhibited enteroatmospheric fistulae, compared to 17% in the AD group. CONCLUSIONS: Compared to the AD system, ABT can achieve faster primary closure after open abdomen treatment with only minor complications. PMID- 24756919 TI - Evidence of Pragmatic Impairments in Speech and Proverb Interpretation in Schizophrenia. AB - Schizophrenia has been suggested to involve linguistic pragmatic deficits. In this study, two aspects of pragmatic ability were assessed; comprehension and production. Drawing on relevance theory and Gricean implicatures to assess shared attention and interpretation in a linguistic context, discourse samples and proverb interpretation were transcribed from recorded interviews with patients with schizophrenia and control subjects. The productive aspect of implicatures was assessed by quantifying the use of 'connectors' in discourse. Receptive aspects were assessed by scoring interpretations of four common proverbs. Statistically significant effects were found: patients with schizophrenia used connectors less than controls as well as performing worse in proverb comprehension. Positive correlations between connectors and proverb interpretation in all subjects suggested an underlying pragmatic root for both productive and receptive aspects. The relative number of connectors (as a percentage of words used) provided a better index of pragmatic ability than total number because total output appeared to be influenced by additional factors such as IQ. Deficits were found in the use of connectors and in proverb interpretation even when controlling for verbal IQ, suggesting that pragmatic aspects of language are particularly vulnerable in schizophrenia compared with other verbal abilities. PMID- 24756920 TI - Tetravinylethylene. AB - The first four-fold cross coupling reaction involving alkenic partners leads to the title hydrocarbon on multi-gram scale in one step from commercially available precursors. In stark contrast to its close structural relatives, tetravinylethylene is a remarkably robust, bench-stable compound. The pi-bond rich hydrocarbon is shown to undergo one-pot sequences of pericyclic reactions leading to the formation of complex systems with four new rings, seven C-C bonds and ten stereocenters with a very high level of stereoselectivity. Insights into the reactivity of this and related systems is provided using the accurate composite ab initio MO G4(MP2) method. PMID- 24756918 TI - Challenging a surgical dictum: results from a 10-year experience on the safety of open inguinal herniorrhaphy in patients on chronic warfarin therapy. AB - BACKGROUND: Previous reports document the safety of open inguinal herniorrhaphy in patients on chronic warfarin therapy; however, the practice remains controversial. This study is a 10-year update of our experience. METHODS: A retrospective review of 1,839 consecutive patients undergoing open inguinal hernia repair was conducted from 2000 to 2010. All patients on chronic warfarin therapy were included. Three groups: continuation (CW), discontinuation (DW) and case-matched control (C) not on warfarin therapy were compared for operative details and postoperative complications. RESULTS: One hundred and fifty-eight patients were on chronic warfarin therapy. Of these, 40 patients (25%) continued on warfarin during the perioperative period (CW). Average preoperative international normalized ratio (INR) was 2.15 +/- 0.76 for CW and 1.38 +/- 0.42 for DW, p < 0.001. Mean operative times were equivalent between all three groups (88 min CW vs. 85 min DW vs. 79 min C, p = 0.518). Although CW patients experienced higher incidences of both hematoma and urinary retention overall, no statistically significant differences in complication rates were seen between the three groups (hematoma = 10 vs. 8% DW vs. 5% C, p = 0.703; urinary retention = 15 vs. 10% DW vs. 8% C, p = 0.541). Comparing patients by INR, there were no statistically different postoperative complication rates, particularly for hematoma (8% INR <2 vs. 9.5% INR = 2-3 vs. 20% INR >3, p = 0.65). CONCLUSION: Maintenance of warfarin therapy during the perioperative period for open inguinal herniorrhaphy results in equivalent operative times and postoperative complications as discontinuation. PMID- 24756922 TI - An unusual case of pancytopenia in a nonagenarian: visceral leishmaniasis. AB - Older patients referred for further investigation of pancytopenia is common in internal medicine and geriatric clinics and it is important to consider a wide range of underlying diagnoses. We present an unusual case of febrile pancytopenia in a nonagenarian who was diagnosed with visceral leishmaniasis. This is a rare and unusual diagnosis in nonagenarians, although the leishmaniasis is endemic on the Mediterranean coast of Spain. It is important to identify it because it is treatable and curable. PMID- 24756921 TI - Insight into the recognition, binding, and reactivity of catalytic metallodrugs targeting stem loop IIb of hepatitis C IRES RNA. AB - The complex Cu-GGHYrFK-amide (1-Cu) was previously reported as a novel metallotherapeutic that catalytically inactivates stem loop IIb (SLIIb) of the hepatitis C virus (HCV) internal ribosomal entry site (IRES) RNA and demonstrates significant antiviral activity in a cellular HCV replicon assay. Herein we describe additional studies focused on understanding the cleavage mechanism as well as the relationship of catalyst configuration to structural recognition and site-selective cleavage of the structured RNA motif. These are advanced by use of a combination of MALDI-TOF mass spectrometry, melting temperature determinations, and computational analysis to develop a structural model for binding and reactivity toward SLIIb of the IRES RNA. In addition, the binding, reactivity, and structural chemistry of the all-D-amino acid form of this metallopeptide, complex 2-Cu, are reported and compared with those of complex 1-Cu. In vitro RNA binding and cleavage assays for complex 2-Cu show a KD value of 76 +/- 3 nM, and Michaelis-Menten parameters of kcat =0.14 +/- 0.01 min(-1) and KM =7.9 +/- 1.2 MUM, with a turnover number exceeding 40. In a luciferase-based cellular replicon assay Cu-GGhyrfk-amide shows activity similar to that of the 1-Cu parent peptide, with an IC50 value of 1.9 +/- 0.4 MUM and cytotoxicity exceeding 100 MUM. RT-PCR experiments confirm a significant decrease in HCV RNA levels in replicon assays for up to nine days when treated with complex 1-Cu in three-day dosing increments. This study shows the influence that the alpha-carbon stereocenter has for this new class of compounds, while detailed mass spectrometry and computational analyses provide new insight into the mechanisms of recognition, binding, and reactivity. PMID- 24756923 TI - Copper-free click-chemistry platform to functionalize cisplatin prodrugs. AB - The ability to rationally design and construct a platform technology to develop new platinum(IV) [Pt(IV)] prodrugs with functionalities for installation of targeting moieties, delivery systems, fluorescent reporters from a single precursor with the ability to release biologically active cisplatin by using well defined chemistry is critical for discovering new platinum-based therapeutics. With limited numbers of possibilities considering the sensitivity of Pt(IV) centers, we used a strain-promoted azide-alkyne cycloaddition approach to provide a platform, in which new functionalities can easily be installed on cisplatin prodrugs from a single Pt(IV) precursor. The ability of this platform to be incorporated in nanodelivery vehicle and conjugation to fluorescent reporters were also investigated. PMID- 24756924 TI - Editorial. Gordon L. Amidon Dedicated Issue. PMID- 24756925 TI - The subspecialization of surgery: a paradigm shift. AB - General surgery has become increasingly fragmented into subspecialties and diseases previously treated by general surgeons are now managed by "specialists". The Resident Education Committee of the Society for Surgery of the Alimentary Tract (SSAT) has reviewed the history of surgical training and factors that have contributed to this evolution to subsepcialization. As it is unlikely that this paradigm shift is reversible, a clear understanding of the contributing factors is essential. Herein, we present a timeline and taxonomy of forces in this evolution to subspecialization. PMID- 24756926 TI - Gender-related differences in pathological and clinical tumor response based on immunohistochemical proteins expression in rectal cancer patients treated with short course of preoperative radiotherapy. AB - BACKGROUND: Prognostic value of pretreatment expression of proteins in rectal cancer for early pathological tumor response (pTR), clinical tumor response (CTR) to preoperative radiotherapy (RT), and the potential difference between these parameters depending on patient gender is not established. MATERIAL AND METHODS: One hundred eleven patients were treated with short preoperative course of RT (SCRT) with 5 Gy dose per fraction during 5 days, followed by surgery 3 to 53 days (mean, 21 days) later. Expression of CD34, Ki-67, GLUT-1, Ku70, BCL-2, and P53 proteins was assessed immunohistochemically. RESULTS: There were 76 men and 35 women. There were 27, 69, and 15 clinical tumor-node-metastasis (cTNM) tumor stages I, II, and III, respectively. Significant differences in Ki-67, GLUT-1, Ku 70, and BCL-2 expressions between male and female tumors were observed for pathological TNM (pTNM) stage and grade. Association between proteins expression and pTNM, pTR, and CTR was analyzed separately for short (<=15 days) and long (>15 days) break between RT and surgery and males and female patients. For SCRT with short break, no protein was significantly related to pTNM; for pTR, higher Ki-67 and lower BCL-2 expression were correlated with pTR. In the male subgroup, BCL-2 overexpression was predictive. For SCRT with long break, none of the proteins was predictive for pTR, but Ki-67, Ku70 (in female subgroup), and BCL-2 expressions were positively correlated with pTNM. BCL-2 overexpression was associated with CTR in the females only. CONCLUSION: In SCRT, long break in the treatment should be avoided because correlation between Ki-67, KU70, and BCL-2 expressions and pTNM after RT might indicate tumor progression. PMID- 24756927 TI - Small bowel obstruction caused by an unusual variant of paraduodenal hernia. The "middle congenital mesocolic hernia": case report. AB - Internal hernias account for 0.2-0.9 % of all small bowel obstructions and are associated with a mortality rate of 50 % when strangulation is present. Congenital mesocolic hernias, traditionally called paraduodenal hernias, caused by an abnormal rotation of the primitive midgut, are the most common type of internal hernia. They can be divided into three types: the right and the left congenital mesocolic hernias, accounting for the 25 and 75 % of all cases, respectively, and the extremely rare transverse congenital mesocolic hernia. A high preoperative misdiagnosis rate has been reported and a surgical exploration is recommended to identify strangulation. The present case report describes a case of small bowel obstruction due to an unusual variant of congenital mesocolic hernia never previously reported in the literature. We discuss the clinical appearance, pathogenesis, diagnosis, and treatment of the case, with a brief review of the literature focused on the pathogenesis and management of mesocolic congenital hernias. PMID- 24756928 TI - Interpreting in vitro micronucleus positive results: simple biomarker matrix discriminates clastogens, aneugens, and misleading positive agents. AB - The specificity of in vitro mammalian cell genotoxicity assays is low, as they yield a high incidence of positive results that are not observed in animal genotoxicity and carcinogenicity tests, that is, "misleading" or "irrelevant" positives. We set out to develop a rapid and effective follow-up testing strategy that would predict whether apparent in vitro micronucleus-inducing effects are due to a clastogenic, aneugenic, or secondary irrelevant mode(s) of action. Priority was given to biomarkers that could be multiplexed onto flow cytometric acquisition of micronucleus frequencies, or that could be accomplished in parallel using a homogeneous-type assay. A training set of 30 chemicals comprised of clastogens, aneugens, and misleading positive chemicals was studied. These experiments were conducted with human TK6 cells over a range of closely spaced concentrations in a continuous exposure design. In addition to micronucleus frequency, the following endpoints were investigated, most often at time of harvest: cleaved Parp-positive chromatin, cleaved caspase 3-positive chromatin, ethidium monoazide bromide-positive chromatin, polyploid nuclei, phospho-histone H3-positive (metaphase) cells, tetramethylrhodamine ethyl ester-negative cells, cellular ATP levels, cell cycle perturbation, and shift in gamma-H2AX fluorescence relative to solvent control. Logistic regression was used to identify endpoints that effectively predict chemicals' a priori classification. Cross validation using a leave-one-out approach indicated that a promising base model includes gamma-H2AX shift and change in phospho-histone H3-positive events (25/30 correct calls). Improvements were realized when one or two additional endpoints were included (26-30/30 correct calls). These models were further evaluated with a test set of 10 chemicals, and also by evaluating 3 chemicals at a collaborating laboratory. The resulting data support the hypothesis that a matrix of high throughput-compatible biomarkers can effectively delineate two important modes of genotoxic action as well as identify cytotoxicity that can lead to irrelevant positive results. PMID- 24756929 TI - The dynamics of psychiatric bed use in general hospitals. AB - This study examines general hospitals' adjustments in psychiatric bed utilization practices in response to increases in psychiatric inpatient admissions. Using panel data from 439 hospitals, monthly observations (N = 7,831) between 2007 and 2010 on psychiatric admissions, psychiatric bed occupancy rates, and average length-of-stay were created for psychiatric inpatients. In fixed-effects regressions, an increase in psychiatric admissions was associated with an increase in the probability of psychiatric bed use exceeding 100 % occupancy and with a reduction of mean length-of-stay. These results were confirmed in instrumental variables models. General hospitals may dynamically adjust bed utilization practices in response to changing psychiatric bed needs. An implication of this dynamic adjustment model is that bed shortages are likely to be local, transitory events. PMID- 24756930 TI - The efficacy of metacognitive therapy for anxiety and depression: a meta-analytic review. AB - BACKGROUND: Metacognitive therapy (MCT) is a relatively new approach to treating mental disorders. The aim of the current meta-analysis was to examine the efficacy of MCT in patients with mental disorders. METHOD: A comprehensive literature search revealed 16 published as well as unpublished studies on the efficacy of MCT, of which nine were controlled trials. These studies report on 384 participants suffering from anxiety or depression. Treatment efficacy was examined using a random effects model. RESULTS: On primary outcome measures the aggregate within-group pre- to posttreatment and pretreatment to follow-up effect sizes for MCT were large (Hedges' g = 2.00 and 1.65, respectively). Within-group pre- to posttreatment changes in metacognitions were also large (Hedges' g = 1.18) and maintained at follow-up (Hedges' g = 1.31). Across the controlled trials, MCT was significantly more effective than both waitlist control groups (between-group Hedges' g = 1.81) as well as cognitive behavior therapy (CBT; between-group Hedges' g = 0.97). CONCLUSIONS: Results suggest that MCT is effective in treating disorders of anxiety and depression and is superior compared to waitlist control groups and CBT, although the latter finding should be interpreted with caution. The implications of these findings are limited by small sample sizes and few active control conditions. Future studies should include larger sample sizes and also include comparisons of MCT with other empirically supported therapies. PMID- 24756932 TI - Recent improvement in coronary computed tomography angiography diagnostic accuracy. AB - Although invasive coronary angiography has been the gold standard for evaluating coronary artery disease (CAD), it should not be routinely performed as an initial test to assess CAD in subjects with suspected CAD by the recent guidelines, due to cost, invasiveness, and measurable risk. Coronary computed tomography angiography (CCTA) is a rapidly growing, noninvasive imaging modality that developed quickly over the last decade, and its role for evaluation of CAD becomes of great promise with high diagnostic accuracy. Although artifact issues have created some challenges for CCTA, recent advances-including the introduction of more detectors, leading to broader coverage, and faster and higher-definition scanners-allow improved precision and fewer uninterpretable studies. This review article summarizes the current key literature regarding the diagnostic accuracy of CCTA in native coronary arteries, stents, coronary artery bypass grafts, lesions with high calcification, and the functional assessment of CAD. PMID- 24756933 TI - Cost-effectiveness of early laparoscopic cholecystectomy for mild acute gallstone pancreatitis. AB - BACKGROUND: A recent Cochrane review suggested that laparoscopic cholecystectomy carried out early following mild gallstone pancreatitis was safe. This study compared the cost-effectiveness of laparoscopic cholecystectomy performed within 3 days of admission, during the same admission but after more than 3 days, or electively in a subsequent admission. METHODS: A model-based cost-utility analysis was performed estimating mean costs and quality-adjusted life-years (QALYs) per patient in the UK National Health Service with a 1-year time horizon. A decision tree model was constructed and populated with probabilities, outcomes and cost data from published sources for mild gallstone pancreatitis, including one-way and probabilistic sensitivity analyses. RESULTS: The costs of laparoscopic cholecystectomy performed within 3 days of admission, beyond 3 days but in the same admission, and electively in a subsequent admission were ? 2748, ? 3543 and ? 3752 respectively; the QALYs were 0.888, 0.888 and 0.884 respectively. Early laparoscopic cholecystectomy had a 91 per cent probability of being cost-effective at the maximum willingness to pay for a QALY commonly used in the UK. It is acknowledged that many hospitals do not have access to magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography, especially at weekends, and that implementing a 3-day target is unrealistic without allocating new resources that could erode the cost effectiveness. CONCLUSION: Performing laparoscopic cholecystectomy for mild gallstone pancreatitis within 3 days of admission is cost-effective, but may not be feasible without significant resource allocation. After 3 days there is little financial advantage to same-admission operation. PMID- 24756934 TI - To the Editor; A Commentary on "Switching From Originator to Biosimilar Human Growth Hormone Using a Dialogue Teamwork: Single-Center Experience From Sweden". PMID- 24756935 TI - A new risk-adjusted Bernoulli cumulative sum chart for monitoring binary health data. AB - To monitor a health event in patients with a specific risk of developing the event, a risk-adjusted cumulative sum chart is needed. The risk-adjusted cumulative sum chart proposed in the literature has some limitations. Setting appropriate control limits is not straightforward, there is no simple formula for constructing them, and they remain sensitive to changes in the underlying risk distribution and the baseline incidence rate. To overcome these limits, we propose a new risk-adjusted Bernoulli cumulative sum chart as a simple and efficient solution. Analyses of simulated and real data sets illustrate the performance and usefulness of the proposed procedure. PMID- 24756937 TI - Enamel-Renal-Gingival syndrome, hypodontia, and a novel FAM20A mutation. PMID- 24756936 TI - A CD8 T cell/indoleamine 2,3-dioxygenase axis is required for mesenchymal stem cell suppression of human systemic lupus erythematosus. AB - OBJECTIVE: Allogeneic mesenchymal stem cells (MSCs) exhibit therapeutic effects in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain largely unknown. The aim of this study was to investigate how allogeneic MSCs mediate immunosuppression in lupus patients. METHODS: The effects of allogeneic umbilical cord-derived MSCs (UC-MSCs) on inhibition of T cell proliferation were determined. MSC functional molecules were stimulated with peripheral blood mononuclear cells from healthy controls and SLE patients and examined by real-time polymerase chain reaction. CD4+ and CD8+ T cells were purified using microbeads to stimulate MSCs in order to determine cytokine expression by MSCs and to further determine which cell subset(s) or which molecule(s) is involved in inhibition of MSC-mediated T cell proliferation. The related signaling pathways were assessed. We determined levels of serum cytokines in lupus patients before and after UC-MSC transplantation. RESULTS: Allogeneic UC-MSCs suppressed T cell proliferation in lupus patients by secreting large amounts of indoleamine 2,3-dioxygenase (IDO). We further found that interferon-gamma (IFNgamma), which is produced predominantly by lupus CD8+ T cells, is the key factor that enhances IDO activity in allogeneic MSCs and that it is associated with IFNGR1/JAK-2/STAT signaling pathways. Intriguingly, bone marrow-derived MSCs from patients with active lupus demonstrated defective IDO production in response to IFNgamma and allogeneic CD8+ T cell stimulation. After allogeneic UC-MSC transplantation, serum IDO activity increased in lupus patients. CONCLUSION: We found a previously unrecognized CD8+ T cell/IFNgamma/IDO axis that mediates the therapeutic effects of allogeneic MSCs in lupus patients. PMID- 24756939 TI - The RNA code: nature's Rosetta Stone. PMID- 24756940 TI - The genetic code. PMID- 24756942 TI - Clinical examiners, simulated patients, and student self-assessed empathy in medical students during a psychiatry objective structured clinical examination. AB - OBJECTIVES: This study aims to assess and compare objective and subjective scores of empathy in final-year medical students by using firstly a validated student self-assessment just prior to the psychiatry objective structured clinical examination (OSCE), and then comparing this to clinical examiner's and simulated patient's (SP's) assessments of empathy of students using a Global Rating of Empathy scale (GRE) during a psychiatry OSCE. METHODS: In 2011, all final-year medical students in the University College Dublin were invited to complete a subjective, self-assessed empathy questionnaire (The Jefferson scale of physician empathy-student version (JSPE-S)). They were also assessed for empathy in four OSCEs by the clinical examiner and the SP acting in that OSCE scenario. RESULTS: Included in the analysis were 163 of 184 final-year students JSPE-S (88.6%) questionnaires. The female students scores on the JSPE-S were significantly higher than those of their male peers (t=3.34, p=0.001). Concurrent validity was greater between the SPs' assessments of empathy in the OSCE and the JSPE-S score than between the clinical examiners assessments of empathy and the JSPE-S score (r=0.23, p<0.005; r=0.14, p<0.08). Inter-rater reliability of SP's and clinical examiner's using the GRE was found to be high (F=0.868 (df=171, 171), p value<0.001). CONCLUSIONS: SPs may be valid assessors of empathy in medical students during an OSCE. PMID- 24756943 TI - Gold-catalyzed 1,2-oxoarylations of nitriles with pyridine-derived oxides. AB - We report the first success in the gold-catalyzed oxoarylations of nitriles with pyridine-derived N-oxides using gold carbenes as initiators. These oxoarylations were also achieved satisfactorily in intermolecular three-component oxidations, including diverse alkenyldiazo esters, nitriles, and pyridine-based oxides. PMID- 24756944 TI - SMART designs in observational studies. PMID- 24756945 TI - Directly observed care: can unannounced standardized patients address a gap in performance measurement? AB - There are three potential sources of information for evaluating a clinician's performance: documentation, patient report, and directly observed care. Current measures draw on just two of these: data recorded in the medical record and surveys of patients. Neither captures an array of performance characteristics, including clinician attention to symptoms and signs while taking a history or conducting a physical exam, accurate recording in the medical record of information obtained during the encounter, evidence based communication strategies for preventive care counseling, and effective communication behavior. Unannounced Standardized Patients (USPs) have been widely deployed as a research strategy for systematically uncovering significant performance deficits in each of these areas, but have not been adopted for quality improvement. Likely obstacles include concerns about the ethics of sending health professionals sham patients, the technical challenges of the subterfuge, and concerns about the relatively small sample sizes and substantial costs involved. However, the high frequency of significant and remediable performance deficits unmasked by USPs, and the potential to adapt registration and record keeping systems to accommodate their visits, suggest that their selective and purposeful deployment could be a cost effective and powerful strategy for addressing a gap in performance measurement. PMID- 24756946 TI - Capsule commentary on Thomas et al., A comparison of the willingness of resident and attending physicians to comply with the requests of patients at the end of life. PMID- 24756947 TI - Hypertension among the young invincibles. PMID- 24756948 TI - Through-vial impedance spectroscopy of the mechanisms of annealing in the freeze drying of maltodextrin: the impact of annealing hold time and temperature on the primary drying rate. AB - The study aims to investigate the impact of annealing hold time and temperature on the primary drying rate/duration of a 10% (w/v) solution of maltodextrin with an emphasis on how the mechanisms of annealing might be understood from the in vial measurements of the ice crystal growth and the glass transition. The electrical impedance of the solution within a modified glass vial was recorded between 10 and 10(6) Hz during freeze-drying cycles with varying annealing hold times (1-5 h) and temperatures. Primary drying times decreased by 7%, 27% and 34% (1.1, 4.3 and 5.5 h) with the inclusion of an annealing step at temperatures of 15 degrees C, -10 degrees C and -5 degrees C, respectively. The glass transition was recorded at approximately -16 degrees C during the re-heating and re-cooling steps, which is close to the glass transition (Tg ') reported for 10% (w/v) maltodextrin and therefore indicates that a maximum freeze concentration (~86%, w/w, from the Gordon-Taylor equation) was achieved during first freezing, with no further ice being formed on annealing. This observation, coupled to the decrease in electrical resistance that was observed during the annealing hold time, suggests that the reduction in the drying time was because of improved connectivity of ice crystals because of Ostwald ripening rather than devitrification. PMID- 24756949 TI - Glial scar and immune cell involvement in tissue remodeling and repair following acute CNS injuries. AB - Inadequate axonal regeneration is a common phenomenon occurring following acute injury to the central nervous system (CNS), and is often associated with permanent neurological deficits. The injured axons attempting to regenerate face the inhospitable environment of the CNS scar, which can hinder axonal growth and sprouting. In addition, in response to the insult, intense activation and infiltration of immune cells take place. Both the scar tissue and immune response, which have received a bad reputation in the context of CNS repair are essential for the overall recovery from CNS injuries, but are not optimally controlled. The glial scar contributes to protection of the spared neural tissues by establishing a boundary between damaged and salvageable tissue, and by educating the immune cells to promote the healing of the CNS tissue. In turn, the immune cells, and in particular the infiltrating macrophages, exert several functions at the lesion site, including resolution of the microglial response, control of scar tissue degradation, and production of growth factors; thereby, promoting neuronal survival, axonal regeneration, and tissue remodeling. As axonal regeneration and tissue remodeling are viewed as critical steps for the overall functional recovery following CNS injury, a detailed understanding of the mechanisms underlying the timely formation and degradation of the CNS scar, and its crosstalk with the inflammatory response, are of great importance, both biologically and clinically. PMID- 24756950 TI - Photodelivery of CO by designed PhotoCORMs: correlation between absorption in the visible region and metal-CO bond labilization in carbonyl complexes. AB - The therapeutic potential of photoactive CO-releasing molecules (photoCORMs) have called for close examination of the roles of the ligand(s) and the central metal atoms on the overall photochemical labilization of the metal-CO bonds. Along this line, we have synthesized four metal complexes, namely, [MnBr(azpy)(CO)3 ] (1), [Mn(azpy)(CO)3 (PPh3 )]ClO4 (2), [ReBr(azpy)(CO)3 ] (3), and [Re(azpy)(CO)3 (PPh3 )]ClO4 (4), derived from 2-phenylazopyridine. These complexes were characterized by spectroscopic and crystallographic studies. Although both 1 and 3 exhibit strong metal-to-ligand charge-transfer bands in the 500-600 nm region, only 1 photoreleases CO upon illumination with visible light. Results of theoretical studies were used to gain insight into this surprising difference. Strong spin orbit coupling (prominent in heavy metals) appears to promote intersystem crossing to a triplet state in 3, a step that discourages CO release upon illumination with visible light. Slow release of CO from 2 and 4 also indicates that strong sigma-donating ligands, such as Br(-) , accelerate the rate of CO photorelease relative to pi-acid ligands, such as PPh3 . PMID- 24756952 TI - Lessons Learned in Andrology: Back to the future: making children in bed (at the right time). PMID- 24756953 TI - Advances in understanding the genetics underlying male infertility and evolving diagnostic and treatment options. PMID- 24756954 TI - Transport properties of puerarin and effect of extract of Radix Angelicae dahuricae on puerarin intestinal absorption using in situ and in vitro models. AB - The root of Angelica dahurica (Radix Angelicae Dahuricae, RAD), which contains coumarins and volatile oil as its main classes of active components, is often given in conjunction with Pueraria root (Radix Puerariae, RP), which contains the phytoestrogen puerarin. The two herbs are considered to be compatible 'herb pairs' in traditional Chinese medicine. The present investigation investigates the absorption of puerarin from RP and the effect of the total coumarins and volatile oil from RAD on its absorption. The everted gut sac and single-pass intestinal perfusion methods were used, respectively. The results showed that the absorption of puerarin in the jejunum was significantly increased in the presence of the coumarins and/or volatile oil. The absorption rate constant (K(a)) of puerarin increased gradually until the concentration reached 160 ug . mL(-1), after which its absorption became saturated and the apparent permeability (P(app)) values significantly decreased. The results showed that the intestinal absorption mechanisms of puerarin involved active transportation processes and that puerarin is likely to be a substrate of P-gp because verapamil significantly affected its P(app) and K(a). The absorption of puerarin significantly increased (p < 0.01) when combined with RAD extracts, as shown by the increase in concentration of puerarin in blood from the hepatic portal vein, supporting the concept of RAD and RP as a compatible herb-pair. PMID- 24756956 TI - Aldrin epoxidation in flathead mullet (Mugil cephalus): possible involvement of CYP1A and CYP3A. AB - The primary objective of this study was to determine specific cytochrome P450 isozyme(s) involved in the metabolism of aldrin to its toxic metabolite dieldrin in flathead mullet (Mugil cephalus) liver microsomes. To identify the cytochrome P450 isozyme responsible for the aldrin metabolism in mullet liver, the effects of mammalian-specific cytochrome P450 inhibitors and substrates were determined in the epoxidation reaction of aldrin. CYP3A-related inhibitors, ketoconazole, SKF-525A, and cimetidine, inhibited the metabolism of aldrin. The contribution of CYP1A to the aldrin metabolism was shown by the inhibition of 7-ethoxyresorufin-O deethylase activity in the presence of aldrin. The results indicate that CY1A and CYP3A are the cytochrome P450s involved in aldrin epoxidase activity in mullet. In addition, the suitability of aldrin epoxidase activity for monitoring of environmental pollution was also assessed in the fish samples caught from four different locations of the West Black Sea coast of Turkey. PMID- 24756955 TI - Small molecule compounds targeting the p53 pathway: are we finally making progress? AB - Loss of function of p53, either through mutations in the gene or through mutations to other members of the pathway that inactivate wild-type p53, remains a critically important aspect of human cancer development. As such, p53 remains the most commonly mutated gene in human cancer. For these reasons, pharmacologic activation of the p53 pathway has been a highly sought after, yet unachieved goal in developmental therapeutics. Recently progress has been made not only in the discovery of small molecules that target wild-type and mutant p53, but also in the initiation and completion of the first in-human clinical trials for several of these drugs. Here, we review the current literature of drugs that target wild type and mutant p53 with a focus on small-molecule type compounds. We discuss common means of drug discovery and group them according to their common mechanisms of action. Lastly, we review the current status of the various drugs in the development process and identify newer areas of p53 tumor biology that may prove therapeutically useful. PMID- 24756957 TI - Longitudinal effects of intravenous immunoglobulin on Alzheimer's cerebrospinal fluid proteome. AB - Intravenous immunoglobulin (IVIg) therapy has shown promise in the treatment of Alzheimer's disease (AD). In this study, serial cerebrospinal fluid (CSF) samples from a group of subjects with AD undergoing IVIg immunotherapy are analyzed to identify IVIg-related changes. CSF samples from eight subjects were collected before therapy, after 6 months of therapy, and after a 3-month drug washout period. Samples were analyzed using a gel-based proteomics strategy and IVIg related changes were determined by gel spot percent volumes. An initial assessment of the data revealed consistent and considerable change in 69 spots. A statistical analysis revealed 79 protein spots with a significant change after 6 months; furthermore, in a subset of these (25), the percent volume change was either maintained or reversed in the washout samples. The proteins that showed a significant change during IVIg therapy, including Ig molecules, gelsolin, transferrin, and transthyretin, have been previously implicated in AD. This study provides preliminary findings regarding a group of CSF proteins that may be associated with the treatment of AD, as well as the potential use of IVIg as an AD immunotherapy. PMID- 24756958 TI - Community oncology practices cope with sequestration: cuts impacting staffing, patient care. PMID- 24756959 TI - Diabetes associated with increased risk of liver cancer. PMID- 24756960 TI - Cancer mutation tied to scleroderma. PMID- 24756961 TI - Possible reason for breast cancer treatment resistance. PMID- 24756962 TI - Prenatal anti-Ro antibody exposure, congenital complete atrioventricular heart block, and high-dose steroid therapy: impact on neurocognitive outcome in school age children. AB - OBJECTIVE: To determine the impact of prenatal exposure to maternal anti-Ro antibodies, slow fetal heart rate, and/or prolonged dexamethasone therapy for immune-mediated congenital atrioventricular heart block (CAVB) on the cognitive and academic performance of these children at school age. METHODS: We performed a prospective, blinded assessment of the cognitive functioning of 3 cohorts of children ages 6-16 years with in utero exposure to maternal anti-Ro antibodies in the following groups: no CAVB and no prenatal dexamethasone treatment (n = 14), CAVB without prenatal treatment (n = 10), and CAVB with prenatal dexamethasone treatment (n = 16). Domains assessed included intelligence, visual perceptual and visual motor skills, auditory and visual attention, verbal learning and memory, visual memory, executive function, and behavior. RESULTS: All cohorts scored within the normal range and were not significantly different in terms of intelligence scores, verbal comprehension, perceptional reasoning, working memory, and processing speed. For children with CAVB who were treated prenatally, there were no significant associations between the neurocognitive function scores, the minimal fetal heart rate (range 47-80 beats per minute), and either the duration (range 2-15 weeks) or dosage (range 56-824 mg) of dexamethasone therapy. CONCLUSION: CAVB and transplacental treatment with dexamethasone was not associated with neurocognitive impairment in school-age children. Larger numbers of children are needed to validate our observation, and assessment of other cognitive abilities is warranted. PMID- 24756963 TI - Darwin's statements on reversion or atavism. PMID- 24756964 TI - Remote enantioselective Friedel-Crafts alkylations of furans through HOMO activation. AB - Catalytic asymmetric Friedel-Crafts alkylation is a powerful protocol for constructing a chiral C(sp(2))-C(sp(3)) bond. Most previous examples rely on LUMO activation of the electrophiles using chiral catalysts with subsequent attack by electron-rich arenes. Presented herein is an alternative strategy in which the HOMO of the aromatic pi system of 2-furfuryl ketones is raised through the formation of a formal trienamine species using a chiral primary amine. Exclusive regioselective alkylation at the 5-position occurred with alkylidenemalononitriles, and high reactivity and excellent enantioselectivity (up to 95% ee) was obtained by this remote activation. PMID- 24756965 TI - Margins in breast conservation: a clinician's perspective and what the literature tells us. AB - The optimal margin in breast-conserving surgery is controversial, and re-excision is common. Pathologic margin assessment is not standardized, and tumor biology and the use of systemic therapy have a major impact on local control. A study level meta-analysis found no difference in local recurrence for margin widths of 1, 2, and 5 mm, leading a multidisciplinary panel to recommend adoption of no ink on tumor as the standard definition of a negative margin. PMID- 24756966 TI - Short- and long-term functional plasticity of white matter induced by oligodendrocyte depolarization in the hippocampus. AB - Plastic changes in white matter have received considerable attention in relation to normal cognitive function and learning. Oligodendrocytes and myelin, which constitute the white matter in the central nervous system, can respond to neuronal activity with prolonged depolarization of membrane potential and/or an increase in the intracellular Ca(2+) concentration. Depolarization of oligodendrocytes increases the conduction velocity of an action potential along axons myelinated by the depolarized oligodendrocytes, indicating that white matter shows functional plasticity, as well as structural plasticity. However, the properties and mechanism of oligodendrocyte depolarization-induced functional plastic changes in white matter are largely unknown. Here, we investigated the functional plasticity of white matter in the hippocampus using mice with oligodendrocytes expressing channelrhodopsin-2. Using extracellular recordings of compound action potentials at the alveus of the hippocampus, we demonstrated that light-evoked depolarization of oligodendrocytes induced early- and late-onset facilitation of axonal conduction that was dependent on the magnitude of oligodendrocyte depolarization; the former lasted for approximately 10 min, whereas the latter continued for up to 3 h. Using whole-cell recordings from CA1 pyramidal cells and recordings of antidromic action potentials, we found that the early-onset short-lasting component included the synchronization of action potentials. Moreover, pharmacological analysis demonstrated that the activation of Ba(2+) -sensitive K(+) channels was involved in early- and late-onset facilitation, whereas 4-aminopyridine-sensitive K(+) channels were only involved in the early-onset component. These results demonstrate that oligodendrocyte depolarization induces short- and long-term functional plastic changes in the white matter of the hippocampus and plays active roles in brain functions. PMID- 24756967 TI - PdO/TiO2 and Pd/TiO2 heterostructured nanobelts with enhanced photocatalytic activity. AB - Heterostructures play an important role not only in the manufacture of semiconductor devices, but also in the field of catalysis. Herein, we report the synthesis of PdO/TiO2 and Pd/TiO2 heterostructured nanobelts by means of a simple co-precipitation method, followed by a reduction process using surface-modified TiO2 nanobelts as templates. The as-obtained heterostructures were characterized by transmission electron microscopy, X-ray photoelectron spectroscopy, and UV/Vis diffuse reflectance spectroscopy. PdO and Pd nanoparticles with a size of about 1.3 and 1.6 nm were assembled uniformly on the surface of TiO2 nanobelts, respectively. Compared with TiO2 nanobelts, PdO/TiO2 and Pd/TiO2 hybrid nanobelts exhibit enhanced photocatalytic activity upon UV and visible-light irradiation. Photoelectrochemical technology was used to study the heterostructure effect on enhanced photocatalytic activity. Our mechanistic investigation revealed that energy-band matching is the major factor in the observed enhancement of photocatalytic activity. PMID- 24756968 TI - Can tonsillectomy modify the innate and adaptive immunity pathways involved in IgA nephropathy? AB - The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p <= 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/beta1, p = 0.039; LPM7/beta5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin-proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT. PMID- 24756969 TI - Nationwide biopsy survey of renal diseases in the Czech Republic during the years 1994-2011. AB - BACKGROUND: We describe data on 10,472 renal biopsies gathered by the Czech Registry of Renal Biopsies over a period of 18 years. METHODS: We assessed the main demographic, clinical and histological data of individuals who underwent renal biopsies of native kidneys in 31 centers in the Czech Republic (population 10.3 million) during the period 1994-2011. RESULTS: We evaluated 10,472 renal biopsies: males 57.8%, children (<=15 years) 13.6%, elderly (>60 years) 19.1%. The most frequent biopsy-proven diseases were primary (55.7%) and secondary (29.1%) glomerulonephritides (GN). Tubulointerstitial nephritis (TIN) was observed in 3.4 % and vascular diseases in 4.1%. The samples were non-diagnostic in 4.2%. Among primary GN the most frequent diagnoses were IgA nephropathy (IgAN) (37.4%), membranous GN (MGN) (13%) and focal segmental glomerulosclerosis (FSGS) (12.6%). Among secondary GN, systemic lupus erythematosus (SLE) represented 23.2%, hereditary diseases 19.8% and necrotizing vasculitis (NV) 19.4%. Among adults, mild renal insufficiency [serum creatinine (SCr) 111-200 MUmol/l] was present in 24.7%, advanced renal insufficiency (SCr 201-400 MUmol/l) in 15.3, and 12.3% of patients had SCr > 400 MUmol/l. The most common diseases in patients with nephrotic proteinuria were minimal change disease (MCD) (39.7%) among children, IgAN (26.2%) in adults aged 16-60 years and amyloidosis (42.7%) among the elderly. The mean annual incidence (per million population) was: primary GN 30.9, secondary GN 18.1, IgAN 11.6, MGN 4.0, SLE 4.0, FSGS 3.9, MCD 3.4, NV 3.2, diabetic nephropathy 2.3, thin basement membrane glomerulopathy 2.0, mesangioproliferative GN 1.9, and TIN 1.9. Ultrasound needle guidance was used in 66.8%. The frequency of serious complications (symptomatic hematoma, gross hematuria, blood transfusion) was approximately 3.2%. CONCLUSIONS: This report provides representative population-based data on native biopsy-proven renal diseases in the Czech Republic. Over the 18 years of nationwide biopsy survey, we noted an increase of the mean age of renal biopsy cases, an increasing proportion of elderly, and a cardinal change in biopsy technique towards ultrasonography needle guidance. PMID- 24756970 TI - Chronotropic incompetence, echocardiographic abnormalities and exercise intolerance in renal transplant recipients. AB - BACKGROUND: Chronotropic incompetence (CI) is an independent predictor of cardiovascular events and overall mortality. The prevalence and significance of CI in renal transplant patient has not been examined. METHODS: 38 non-heart failure renal transplant recipients were recruited for a transthoracic echocardiogram and treadmill stress test using the modified Bruce protocol. RESULTS: 15 patients (39.5%) had CI (defined as failure to reach 85% of the maximum age-predicted heart rate, or <8 0% of predicted heart rate reserve). CI patients had higher left ventricular (LV) mass (216.5 +/- 56.1 vs. 183.1 +/- 40.0 g, p = 0.04), increased septal wall thickness (11.7 +/- 1.4 vs. 10.7 +/- 1.1 mm, p = 0.03) and posterior wall thickness (10.9 +/- 1.9 vs. 9.5 +/- 1.7 mm, p = 0.02). At multivariate analysis, CI was associated with elevated serum creatinine [odds ratio (OR) 1.04, p = 0.03] and increased LV mass (OR 1.03, p = 0.03). CI was associated with shorter exercise duration (3.53 +/- 2.20 vs. 8.08 +/- 2.34 min, p < 0.01) and lower metabolic equivalents (5.40 +/- 2.05 vs. 9.82 +/- 2.39, p < 0.01). At multivariate analysis, exercise duration was negatively associated with CI (beta = -0.54, p < 0.01). CONCLUSIONS: CI is present in approximately 40% of asymptomatic renal transplant recipients and is associated with reduced exercise tolerance, left ventricular hypertrophy, and worse allograft function . PMID- 24756972 TI - Growth in children with chronic kidney disease: 13 years follow up study. AB - BACKGROUND: Growth retardation is one of the most visible comorbid conditions of chronic kidney disease (CKD) in children. To our knowledge, published data on longitudinal follow-up of growth in pediatric patients with CKD is lacking from the region of South-East Europe. Herein we report the results from the Serbian Pediatric Registry of Chronic Kidney Disease. METHODS: The data reported in the present prospective analysis were collected between 2000 and 2012. A total of 324 children with CKD were enrolled in the registry. RESULTS: Prevalence of growth failure at registry entry was 29.3 %. Mean height standard deviation scores (HtSDS) in children with stunting and those with normal stature were -3.00 [95 % confidence interval (CI) -3.21 to -2.79] and -0.08 (95 % CI -0.22 to 0.05) (p < 0.001), respectively. Children with hereditary nephropathy had worse growth at registration (-1.51; 95 % CI -1.97 to -1.04, p = 0.008). Those with CKD stages 4 and 5 before registration had more chance to have short stature at registration than those with CKD stages 2 and 3 [odds ratio (OR) = 0.458, CI 0.268-0.782, p = 0.004]. Dialysis was an independent negative predictor for maintaining optimal stature during the follow-up period (OR = 0.324, CI = 0.199-0.529, p < 0.001), while transplantation was an independent positive predictor for improvement of small stature during follow-up (OR = 3.706, CI = 1.785-7.696, p < 0.001). CONCLUSION: Growth failure remains a significant problem in children with CKD, being worst in patients with hereditary renal disease. Growth is not improved by standard dialysis, but transplantation has a positive impact on growth in children. PMID- 24756971 TI - Osteoprotegerin and kidney disease. AB - Vascular calcification in chronic kidney disease (CKD) patients is associated to increased mortality. Osteoprotegerin (OPG) is a soluble tumor necrosis factor (TNF) superfamily receptor that inhibits the actions of the cytokines receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis inducing ligand (TRAIL) by preventing their binding to signaling receptors in the cell membrane. OPG-deficient mice display vascular calcification while OPG prevented calcification of cultured vascular smooth muscle cells and protected kidney cells from TRAIL-induced death. OPG may be a biomarker in patients with kidney disease. Circulating OPG is increased in predialysis, dialysis and transplant CKD patients and may predict vascular calcification progression and patient survival. By contrast, circulating OPG is decreased in nephrotic syndrome. In addition, free and exosome-bound urinary OPG is increased in human kidney disease. Increased urinary OPG has been associated with lupus nephritis activity. Despite the association of high OPG levels with disease, experimental functional information available suggests that OPG might be protective in kidney disease and in vascular injury in the context of uremia. Thus, tissue injury results in increased OPG, while OPG may protect from tissue injury. Recombinant OPG was safe in phase I randomized controlled trials. Further research is needed to fully define the therapeutic and biomarker potential of OPG in patients with kidney disease. PMID- 24756973 TI - Sex specific association between carnosinase gene CNDP1 and cardiovascular mortality in patients with type 2 diabetes (ZODIAC-22). AB - INTRODUCTION: Homozygosity for a 5-leucine repeat (5L-5L) in the carnosinase gene (CNDP1) has been associated with a reduced prevalence of diabetic nephropathy in cross-sectional studies in patients with type 2 diabetes, particularly in women. Prospective studies on mortality are not available. This study investigated whether 5L-5L was associated with mortality and progression of renal function loss and to what extent this effect is modified by sex. METHODS: In a prospective cohort of patients with type 2 diabetes, a Cox proportional hazard model was used to compare 5L-5L with other genotypes regarding (cardiovascular) mortality. Renal function slopes were obtained by within-individual linear regression of the estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) equation, and were compared between 5L-5L and other genotypes. RESULTS: 871 patients were included (38% with 5L-5L). After 9.5 years of follow-up, hazards ratios (HR) for all-cause and cardiovascular mortality in 5L-5L versus other genotypes were 1.09 [95% confidence interval (CI) 0.88-1.36] and 1.12 (95% CI 0.79-1.58), respectively. There was a significant interaction between CNDP1 and sex for the association with cardiovascular mortality (p = 0.01), not for all-cause mortality (p = 0.32). Adjusted HR in 5L-5L for cardiovascular mortality was 0.69 (95% CI 0.39-1.23) in men and 1.77 (95% CI 1.12 2.81) in women. The slopes of eGFR-MDRD did not significantly differ between 5L 5L and other genotypes. CONCLUSIONS: The association between CNDP1 and cardiovascular mortality was sex-specific, with a higher risk in women with 5L-5L genotype. CNDP1 was not associated with all-cause mortality or change in eGFR. PMID- 24756974 TI - Increased urine semaphorin-3A is associated with renal damage in hypertensive patients with chronic kidney disease: a nested case-control study. AB - BACKGROUND: Semaphorins are guidance proteins implicated in several processes such as angiogenesis, organogenesis, cell migration, and cytokine release. Experimental studies showed that semaphorin-3a (SEMA3A) administration induces transient massive proteinuria, podocyte foot process effacement and endothelial cell damage in healthy animals. While SEMA3A signaling has been demonstrated to be mechanistically involved in experimental diabetic glomerulopathy and in acute kidney injury, to date its role in human chronic kidney disease (CKD) has not been investigated. METHODS: To test the hypothesis that SEMA3A may play a role in human CKD, we performed a cross-sectional, nested, case-control study on 151 matched hypertensive patients with and without CKD. SEMA3A was quantified in the urine (USEMA) by ELISA. Glomerular filtration rate was estimated (eGFR) by the CKD-EPI formula and albuminuria was measured as albumin-to-creatinine ratio (ACR). RESULTS: USEMA levels were positively correlated with urine ACR (p = 0.001) and serum creatinine (p < 0.001). USEMA was higher in patients with both components of renal damage as compared to those with only one and those with normal renal function (p < 0.007 and <0.001, respectively). The presence of increased USEMA levels (i.e. top quartile) entailed a fourfold higher risk of combined renal damage (p < 0.001) and an almost twofold higher risk of macroalbuminuria (p = 0.005) or of reduced eGFR, even adjusting for confounding factors (p = 0.002). CONCLUSIONS: USEMA is independently associated with CKD in both diabetic and non diabetic hypertensive patients. Further studies may help clarify the mechanisms underlying this association and possibly the pathogenic changes leading to the development of CKD. PMID- 24756975 TI - Packaged baby and toddler foods: questions of sugar and sodium. AB - BACKGROUND: Sugar and sodium levels in packaged foods is a critical consideration when it comes to the public health of Americans, yet little is known about the sugar and salt contained in packaged foods targeted at our youngest consumers. OBJECTIVES: To examine the sugar and sodium content of packaged baby and toddler foods sold in the American marketplace and to evaluate them in light of current intake recommendations and the current policy context. METHODS: Content analysis of baby and toddler foods (n = 240) found in nine US retail stores. Summary statistics were created for sugar and sodium; the products' per-serving sodium levels were assessed in light of the US Institute of Medicine's dietary reference intakes while the products' sugar levels were evaluated in light of American Heart Association recommendations. RESULTS: Fifty-eight percent of the products assessed either have a high level of sodium or >20% of calories from sugar. Sodium levels in toddler foods were of concern in certain product categories (i.e., toddler entrees) and 15% of toddler foods exceeded the 'moderate level' recommended for sodium. Sugar levels were high in 45% of the products coded, and over half of those products - 56% - were designed for babies. More than one in six products had sugar as the first or second ingredient. CONCLUSIONS: Baby and toddler foods are not, by definition, 'healthy' foods and some exceed normal expectations for sugar and sodium. A policy opportunity exists to consider placing limits on the allowable levels of sugar and sodium in these packaged food products. PMID- 24756976 TI - Transoral incisionless fundoplication effective in eliminating GERD symptoms in partial responders to proton pump inhibitor therapy at 6 months: the TEMPO Randomized Clinical Trial. AB - BACKGROUND: Incomplete control of troublesome regurgitation and extraesophageal manifestations of chronic gastroesophageal reflux disease (GERD) is a known limitation of proton pump inhibitor (PPI) therapy. This multicenter randomized study compared the efficacy of transoral incisionless fundoplication (TIF) against PPIs in controlling these symptoms in patients with small hiatal hernias. METHODS: Between June and August 2012, 63 patients were randomized at 7 US community hospitals. Patients in the PPI group were placed on maximum standard dose (MSD). Patients in the TIF group underwent esophagogastric fundoplication using the EsophyX2 device. Primary outcome was elimination of daily troublesome regurgitation or extraesophageal symptoms. Secondary outcomes were normalization of esophageal acid exposure (EAE), PPI usage and healing of esophagitis. RESULTS: Of 63 randomized patients (40 TIF and 23 PPI), 3 were lost to follow-up leaving 39 TIF and 21 PPI patients for analysis. At 6-month follow-up, troublesome regurgitation was eliminated in 97% of TIF patients versus 50% of PPI patients, relative risk (RR) = 1.9, 95% confidence interval (CI) = 1.2-3.11 (P = .006). Globally, 62% of TIF patients experienced elimination of regurgitation and extraesophageal symptoms versus 5% of PPI patients, RR = 12.9, 95% CI = 1.9-88.9 (P = .009). EAE was normalized in 54% of TIF patients (off PPIs) versus 52% of PPI patients (on MSD), RR = 1.0, 95% CI = 0.6-1.7 (P = .914). Ninety percent of TIF patients were off PPIs. CONCLUSION: At 6-month follow-up, TIF was more effective than MSD PPI therapy in eliminating troublesome regurgitation and extraesophageal symptoms of GERD. PMID- 24756977 TI - Laparoscopically implanted system for stimulation of the hypogastric plexus induces colonic motility, defecation, and micturition: experimental study. AB - BACKGROUND: Modulation of the enteric nervous system seems to be promising in several functional colorectal disorders for which targeted, causal treatment methods do not exist. However, sacral nerve stimulation can induce undesirable muscle contraction or paresthesia. Therefore, we have developed a laparoscopic technique for implanting a neural electrode, placed directly over the pelvic autonomic nerve plexus. The aim of this experimental study was to evaluate the effect of stimulating the hypogastric plexus and pelvic nerves on inducing distal colon contraction, defecation, and micturition. METHOD: A total of 10 white, male healthy pigs (25-30 kg) were subjected to the laparoscopic implantation of the electrode and the stimulator. In the third and fourth weeks postimplantation, the efficacy of the acute and chronic stimulation to induce defecation was evaluated. RESULTS: The average operative time was 105 minutes (85-150 minutes). In all pigs, acute stimulation activated induced defecation, every second day, every time on demand, with an average delay of 139.7 s. Micturition was induced incidentally. Acute or chronic stimulation did not cause any harm, pain, or suffering to the animals. No adverse effects of the stimulation were observed, and no septic complications or macroscopic fibrosis around the electrodes were found on autopsy. CONCLUSION: Hypogastric plexus stimulation can be a useful and safe option of distal colon contraction, defecation, and micturition. However, the efficacy of the stimulation was observed for a relatively short period of time, and it is not known if it will be sustained for a longer duration. PMID- 24756978 TI - Analysis of the draft genome of Pseudomonas fluorescens ATCC17400 indicates a capacity to take up iron from a wide range of sources, including different exogenous pyoverdines. AB - All fluorescent pseudomonads (Pseudomonas aeruginosa, P. putida, P. fluorescens, P. syringae and others) are known to produce the high-affinity peptidic yellow green fluorescent siderophore pyoverdine. These siderophores have peptide chains that are quite diverse and more than 50 pyoverdine structures have been elucidated. In the majority of the cases, a Pseudomonas species is also able to produce a second siderophore of lower affinity for iron. Pseudomonas fluorescens ATCC 17400 has been shown to produce a unique second siderophore, (thio)quinolobactin, which has an antimicrobial activity against the phytopathogenic Oomycete Pythium debaryanum. We show that this strain has the capacity to utilize 16 different pyoverdines, suggesting the presence of several ferripyoverdine receptors. Analysis of the draft genome of P. fluorescens ATCC 17400 confirmed the presence of 55 TonB-dependent receptors, the largest so far for Pseudomonas, among which 15 are predicted to be ferripyoverdine receptors (Fpv). Phylogenetic analysis revealed the presence of two different clades containing ferripyoverdine receptors, with sequences similar to the P. aeruginosa type II FpvA forming a separate cluster. Among the other receptors we confirmed the presence of the QbsI (thio)quinolobactin receptor, an ferri-achromobactin and an ornicorrugatin receptor, several catecholate and four putative heme receptors. Twenty five of the receptors genes were found to be associated with genes encoding extracytoplasmic sigma factors (ECF sigma) and transmembrane anti-sigma sensors. PMID- 24756979 TI - Antidiabetic effect of nepodin, a component of Rumex roots, and its modes of action in vitro and in vivo. AB - Many active components derived from edible natural resources such as plant extracts have recently attracted attention for their potential use as functional foods or drugs for preventing and treating metabolic diseases such as diabetes. To obtain a novel modulator of glucose metabolism, we conducted screening of a small compound library in cultured L6 myotubes. We identified nepodin that stimulated glucose uptake dose-dependently in differentiated L6 myotubes. The stimulatory effect of nepodin on glucose uptake was abrogated by a 5'-adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, nepodin stimulated the phosphorylation of AMPK. Nepodin also stimulated the translocation of GLUT4 to the plasma membrane in L6 myoblasts transfected with a Glut4 cDNA coding vector and in differentiated L6 myotubes. In in vivo study, nepodin suppressed the increases in fasting blood glucose levels and improved the glucose intolerance of C57BL/KsJ-db/db mice, a type 2 diabetic animal model. Nepodin rescued the impaired phosphorylation of AMPK in the skeletal muscle of db/db mice. These results suggest that nepodin has an antidiabetic effect, which is at least partly mediated by stimulation of GLUT4 translocation via AMPK activation by nepodin. PMID- 24756980 TI - Treeline advances along the Urals mountain range - driven by improved winter conditions? AB - High-altitude treelines are temperature-limited vegetation boundaries, but little quantitative evidence exists about the impact of climate change on treelines in untouched areas of Russia. Here, we estimated how forest-tundra ecotones have changed during the last century along the Ural mountains. In the South, North, Sub-Polar, and Polar Urals, we compared 450 historical and recent photographs and determined the ages of 11,100 trees along 16 altitudinal gradients. In these four regions, boundaries of open and closed forests (crown covers above 20% and 40%) expanded upwards by 4 to 8 m in altitude per decade. Results strongly suggest that snow was an important driver for these forest advances: (i) Winter precipitation has increased substantially throughout the Urals (~7 mm decade(-1) ), which corresponds to almost a doubling in the Polar Urals, while summer temperatures have only changed slightly (~0.05 degrees C decade(-1) ). (ii) There was a positive correlation between canopy cover, snow height and soil temperatures, suggesting that an increasing canopy cover promotes snow accumulation and, hence, a more favorable microclimate. (iii) Tree age analysis showed that forest expansion mainly began around the year 1900 on concave wind sheltered slopes with thick snow covers, while it started in the 1950s and 1970s on slopes with shallower snow covers. (iv) During the 20th century, dominant growth forms of trees have changed from multistemmed trees, resulting from harsh winter conditions, to single-stemmed trees. While 87%, 31%, and 93% of stems appearing before 1950 were from multistemmed trees in the South, North and Polar Urals, more than 95% of the younger trees had a single stem. Currently, there is a high density of seedlings and saplings in the forest-tundra ecotone, indicating that forest expansion is ongoing and that alpine tundra vegetation will disappear from most mountains of the South and North Urals where treeline is already close to the highest peaks. PMID- 24756981 TI - Prevalence and heritability of obsessive-compulsive spectrum and anxiety disorder symptoms: A survey of the Australian Twin Registry. AB - While past twin studies indicate moderate levels of heritability of "obsessive compulsive related" and anxiety disorder symptoms, no single study has reported such estimates in the same twin population nor examined potential genetic sex differences. We assessed symptoms of obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, hypochondriasis, panic disorder, social phobia and generalized anxiety disorder in 2,495 adult twins (1,468 female). Prevalence estimates for the corresponding symptom measures were determined using empirically derived cut-off scores. Twin resemblance was assessed by Pearson correlations and biometrical model-fitting analyses, incorporating sex-specific effects, using OpenMx. Prevalence estimates ranged from 1.6% in the symptoms of generalized anxiety to 16.9% for social phobia. Female twins demonstrated significantly higher prevalence rates across all domains with the exception of obsessive-compulsive symptoms. Additive genetic factors accounted for a moderate proportion of the total liability to each symptom domain. Evidence suggesting qualitative genetic sex differences (i.e., distinct genetic influences between genders) was observed for body dysmorphic concern and panic symptoms, while quantitative differences were observed for hoarding and social phobia symptoms, indicating stronger heritability in females. Novel findings in this study include the observation of probable genetic sex differences in liability towards hoarding symptoms and dysmorphic concern, as well as the lack of such differences in hypochondriasis. The trend towards qualitative sex differences in panic symptoms has some intuitive appeal with regard to biological-experimental models of panic. PMID- 24756982 TI - Pattern-based detection of toxic metals in surface water with DNA polyfluorophores. AB - Heavy metal contamination of water can be toxic to humans and wildlife; thus the development of methods to detect this contamination is of high importance. Here we describe the design and application of DNA-based fluorescent chemosensors on microbeads to differentiate eight toxic metal ions in water. We developed and synthesized four fluorescent 2'-deoxyribosides of metal-binding ligands. A tetramer-length oligodeoxy-fluoroside (ODF) library of 6561 members was constructed and screened for sequences responsive to metal ions, of which seven sequences were selected. Statistical analysis of the response patterns showed successful differentiation of the analytes at concentrations as low as 100 nM. Sensors were able to classify water samples from 13 varied sites and quantify metal contamination in unknown specimens. The results demonstrate the practical potential of bead-based ODF chemosensors to analyze heavy metal contamination in water samples by a simple and inexpensive optical method. PMID- 24756983 TI - Correlation of CXCL10, tumor necrosis factor receptor type II, and galectin 9 with disease activity in juvenile dermatomyositis. AB - OBJECTIVE: Juvenile dermatomyositis (DM) is a systemic autoimmune disorder of unknown immunopathogenesis in which the immune system targets the microvasculature of skeletal muscles, skin, and other organs. The current mainstay of therapy is a steroid regimen in combination with other immunosuppressive treatments. To date, no validated markers for monitoring disease activity have been identified, which hampers personalized treatment. This study was undertaken to identify a panel of proteins specifically related to active disease in juvenile DM. METHODS: We performed a multiplex immunoassay for plasma levels of 45 proteins related to inflammation in 25 patients with juvenile DM in 4 clinically well-defined groups, as determined by clinical activity and treatment. We compared them to 14 age-matched healthy children and 8 age-matched children with nonautoimmune muscle disease. RESULTS: Cluster analysis of circulating proteins showed distinct profiles for juvenile DM patients and controls based on a group of 10 proteins. In addition to CXCL10, tumor necrosis factor receptor type II (TNFRII) and galectin 9 were significantly increased in active juvenile DM. The levels of these 3 proteins were tightly linked to active disease and correlated with clinical scores (as measured by the Childhood Myositis Assessment Scale and physician's global assessment of disease activity on a visual analog scale). CONCLUSION: Our findings indicate that CXCL10, TNFRII, and galectin 9 correspond to disease status in juvenile DM and thus could be helpful in monitoring disease activity and guiding treatment. Furthermore, they might provide new knowledge about the pathogenesis of this autoimmune disease. PMID- 24756984 TI - Genetic polymorphisms in the microRNA binding-sites of the thymidylate synthase gene predict risk and survival in gastric cancer. AB - Thymidylate synthase (TYMS) plays a crucial role in folate metabolism as well as DNA synthesis and repair. We hypothesized that functional polymorphisms in the 3' UTR of TYMS are associated with gastric cancer risk and survival. In the present study, we tested our hypothesis by genotyping three potentially functional (at miRNA binding sites) TYMS SNPs (rs16430 6bp del/ins, rs2790 A>G and rs1059394 C>T) in 379 gastric cancer patients and 431 cancer-free controls. Compared with the rs16430 6bp/6bp + 6bp/0bp genotypes, the 0bp/0bp genotype was associated with significantly increased gastric cancer risk (adjusted OR = 1.72, 95% CI = 1.15 2.58). Similarly, rs2790 GG and rs1059394 TT genotypes were also associated with significantly increased risk (adjusted OR = 2.52, 95% CI = 1.25-5.10 and adjusted OR = 1.57, 95% CI = 1.04-2.35, respectively), compared with AA + AG and CC + CT genotypes, respectively. In the haplotype analysis, the T-G-0bp haplotype was associated with significantly increased gastric cancer risk, compared with the C A-6bp haplotype (adjusted OR = 1.34, 95% CI = 1.05-1.72). Survival analysis revealed that rs16430 0bp/0bp and rs1059394 TT genotypes were also associated with poor survival in gastric cancer patients who received chemotherapy treatment (adjusted HR = 1.61, 95% CI = 1.05-2.48 and adjusted HR = 1.59, 95% CI = 1.02 2.48, respectively). These results suggest that these three variants in the miRNA binding sites of TYMS may be associated with cancer risk and survival of gastric cancer patients. Larger population studies are warranted to verify these findings. PMID- 24756985 TI - Encapsulation enhanced dimerization of a series of 4-aryl-N-methylpyridinium derivatives in water: new building blocks for self-assembly in aqueous media. AB - The construction of supramolecular systems in aqueous media is still a great challenge owing to the limited sources of building blocks. In this study, a series of 4-aryl-N-methylpyridinium derivatives have been synthesized. They formed very stable host-guest (1:2) complexes with CB[8] in water (binding constants up to 10(14) M(-2)) with the two guest molecules arranged in a head-to tail manner and the complexes showed high thermostability, which was revealed by (1) H NMR and UV/Vis spectroscopic studies, ITC, and crystallographic analysis. PMID- 24756986 TI - Coherent magnetic resonance of nanocrystal quantum-dot luminescence as a window to blinking mechanisms. AB - Blinking of colloidal nanocrystal quantum dots, random intermittency in the stream of photons emitted by single particles, has long commanded the curiosity of researchers. Why does the particle suddenly shut off, and what are the pathways to quench emission? Single-particle microscopy is not the only way to approach these fundamental questions on the interaction of light and matter: time domain sub-ensemble spectroscopies can also yield relevant information on microscopic electronic processes. We illustrate recent advances in pulsed optically detected magnetic resonance and highlight the conceptual relevance to unravelling mechanisms controlling intermittency on the single-particle level. Magnetic resonance reveals two distinct luminescence quenching channels, which appear to be related to those previously surmised from single-particle studies: a trapped charge-separated state in which the exciton is quenched by dissociation and the particle remains neutral; and a charged state of the particle in which spin-dependent Auger recombination quenches luminescence. PMID- 24756987 TI - Is there any difference in pelvic floor muscles performance between continent and incontinent women? AB - AIMS: To compare pelvic floor muscles (PFMs) performance in women with and without stress urinary incontinence (SUI) during endurance test. METHODS: It is a prospective case-control clinical trial. After determining PFM maximal voluntary contraction (MVC) by electromyography (EMG), women underwent endurance test, which consisted of consecutively PFM 1-sec fast contractions reaching MVC amplitude followed by 1-sec rest. Training time guided by Borg perceived exertion scale was noted. Heart rate (HR) behavior and EMG variables were assessed before and after training making a physiological analysis in both groups. RESULTS: A total of 56 women, mean age 52.19 years old, were evaluated (26 continent and 30 incontinent women). The time that SUI and continent women took to reach fatigue (Borg 10) was 9.1 +/- 4.7 and 14.19 +/- 8.32 min, respectively (P = 0.006). Confirming that all women performed similar effort during the test, analysis of variance with repeated measures showed that during the endurance test both groups presented similar increase in HR, showing detectable and significant increase from resting time to Borg 10 (P < 0.001). Besides, there was similar behavior in EMG for continent and SUI women, with a decrease from the baseline resting amplitude (P = 0.003 for SUI women and P = 0.006 for continent women). CONCLUSIONS: Women with SUI showed worse performance during an endurance test than continent women. It suggests that women have different capacity to perform PFM training. An initial evaluation based on PFM performance would help to define the best individualized PFM training. PMID- 24756988 TI - Reply: To PMID 24449582. PMID- 24756989 TI - OMIP-020: phenotypic characterization of human gammadelta T-cells by multicolor flow cytometry. PMID- 24756990 TI - Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. AB - Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bethigh IFN-gamma- "T-helper (Th)1 suppressing" phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-gamma; T-bet+IFN-gamma+), thus becoming "Th1-like" cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-gamma, ultimately leading to complete, full Th1-like Treg differentiation. CONCLUSION: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ. PMID- 24756991 TI - Ebullitive methane emissions from oxygenated wetland streams. AB - Stream and river carbon dioxide emissions are an important component of the global carbon cycle. Methane emissions from streams could also contribute to regional or global greenhouse gas cycling, but there are relatively few data regarding stream and river methane emissions. Furthermore, the available data do not typically include the ebullitive (bubble-mediated) pathway, instead focusing on emission of dissolved methane by diffusion or convection. Here, we show the importance of ebullitive methane emissions from small streams in the regional greenhouse gas balance of a lake and wetland-dominated landscape in temperate North America and identify the origin of the methane emitted from these well oxygenated streams. Stream methane flux densities from this landscape tended to exceed those of nearby wetland diffusive fluxes as well as average global wetland ebullitive fluxes. Total stream ebullitive methane flux at the regional scale (103 Mg C yr(-1) ; over 6400 km(2) ) was of the same magnitude as diffusive methane flux previously documented at the same scale. Organic-rich stream sediments had the highest rates of bubble release and higher enrichment of methane in bubbles, but glacial sand sediments also exhibited high bubble emissions relative to other studied environments. Our results from a database of groundwater chemistry support the hypothesis that methane in bubbles is produced in anoxic near-stream sediment porewaters, and not in deeper, oxygenated groundwaters. Methane interacts with other key elemental cycles such as nitrogen, oxygen, and sulfur, which has implications for ecosystem changes such as drought and increased nutrient loading. Our results support the contention that streams, particularly those draining wetland landscapes of the northern hemisphere, are an important component of the global methane cycle. PMID- 24756992 TI - Perfluorobutyric acid and its monohydrate: a chirped pulse and cavity based fourier transform microwave spectroscopic study. AB - Rotational spectra of perfluorobutyric acid (PFBA) and its monohydrate were studied with a broadband chirped pulse and a narrow-band cavity based Fourier transform microwave spectrometer, and high-level ab initio calculations. Extensive conformational searches were performed for both the acid and its monohydrate at the MP2/6-311++G(2d,p) level of theory. Two and three conformers were predicted to exist for PFBA and its monohydrate, respectively. One set of rotational transitions was observed and assigned for each, PFBA and its monohydrate. Based on the measured broadband spectra, we confidently conclude that only one dominant conformer exists in each case. The orientation of the hydroxyl group in PFBA was determined by using isotopic analysis. Comparison of the observed transition intensities and the calculated electric dipole moment components allowed us to identify the most stable monohydrate conformation, which takes on an insertion hydrogen-bonding topology. Comparisons to the shorter chain analogues, that is, trifluoroacetic acid, perfluoropropionic acid, and their monohydrates, are made to elucidate the general trend in their conformational preference and binding topologies. PMID- 24756993 TI - Oral versus intravenous steroids in multiple sclerosis relapses - a perennial question? PMID- 24756995 TI - ST6GalNAcII mediates the invasive properties of breast carcinoma through PI3K/Akt/NF-kappaB signaling pathway. AB - Metastasis of tumor cells is the most deadly attribute of breast cancer patients. Aberrant sialylation is closely associated with malignant phenotype of tumor cells, including invasiveness and metastasis. The objective of this study is to clarify the possible role and mechanism of ST6GalNAcII in the metastasis process of breast carcinoma. Real-time PCR, Western blot, and immunohistochemical were used to analyze differential expression of ST6GalNAc II in breast carcinoma cell lines and tissue specimens. PI3K/AKt signaling pathway was also analyzed. The high expression level of ST6GalNAcII was corresponding to invasive phenotype of breast cancer cells both in vitro and in vivo. Further data indicated that manipulation of ST6GalNAcII gene expression led to alter the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway. Blocking the PI3K/Akt pathway resulted in reduced capacity in invasion of MDA-MB-231 cells. ST6GalNAcII elucidated the unusual properties of invasion in breast cancer cell via modulating the PI3K/AKt signaling pathway. PMID- 24756996 TI - New conjugated molecules with two and three dithienyldiketopyrrolopyrrole (DPP) moieties substituted at meta positions of benzene toward p- and n-type organic photovoltaic materials. AB - Two conjugated molecules, TADPP3 and TADPP2-TT, are reported, in which three and two dithienyldiketopyrrolopyrrole (DPP) moieties, respectively, are substituted at the meta positions of benzene. Based on cyclic voltammetry and absorption data, TADPP3 and TADPP2-TT possess similar HOMO and LUMO energies of about -5.2 and -3.4 eV, respectively. Thin films of TADPP3 and TADPP2-TT exhibit p-type semiconducting behavior with hole mobilities of 2.36*10(-3) and 3.76*10(-4) cm(2) V(-1) s(-1) after thermal annealing. Molecules TADPP3 and TADPP2-TT were utilized as p-type photovoltaic materials to fabricate organic solar cells after blending with phenyl C71 butyric acid methyl ester (PC71BM) and phenyl C61 butyric acid methyl ester (PC61BM). The relatively low JSC and fill factor values can be attributed to poor film morphologies based on AFM and XRD studies. A solar cell with a thin film of TADPP3 with PC71BM in a weight ratio of 1:2 exhibits a high open-circuit voltage (VOC) of 0.99 V and a power conversion efficiency (PCE) of 2.47 %. Interestingly, TADPP3 can also be employed as an n-type photovoltaic material. The blended thin film of TADPP3 with P3HT in a weight ratio of 1:2 gave a high VOC of 1.11 V and a PCE of 1.08 % after thermal annealing. PMID- 24756997 TI - The case of Anders Behring Breivik - language of a lone terrorist. AB - Anders Behring Breivik carried out a massacre in Norway on July 22, 2011, killing a total 77 persons and leaving 42 others severely wounded. He detonated a bomb in Oslo and then drove to the island of Utoya, where he shot and killed youngsters gathered at a youth camp. The authors performed an analysis of Breivik's writing style in his extensive manifesto which he published hours before the attacks, and also referred to the two psychiatrists' reports. The first report concluded that he suffered from paranoid schizophrenia. The authors concurred with the second report. Breivik seemed to be a person with narcissistic personality disorder, whose grandiosity might have caused him to be regarded initially as mentally deranged; however, closer examination revealed his deliberate attempt to methodically indoctrinate and deceive potential readers, to alarm potential targets and to terrorize a nation. PMID- 24756998 TI - Choosing Wisely: the American College of Rheumatology's Top 5 for pediatric rheumatology. AB - OBJECTIVE: To create a pediatric rheumatology Top 5 list as part of the American Board of Internal Medicine Foundation's Choosing Wisely campaign. METHODS: Delphi surveys of a core group of representative pediatric rheumatology providers from across North America generated candidate Top 5 items. Items with high content agreement and perceived to be of prevalent use and of high impact were included in a survey of all American College of Rheumatology (ACR) members who identified themselves as providing care to pediatric patients. Items with the highest ratings were subjected to literature review and further evaluation. RESULTS: A total of 121 candidate items were proposed in the initial Delphi survey and were reduced to 28 items in subsequent surveys. These 28 items were sent to 1,198 rheumatology providers who care for pediatric patients, and 397 (33%) responded. Based upon survey data and literature review, the Top 5 items were identified. These items focused on testing for antinuclear antibodies, autoantibody panels, Lyme disease, methotrexate toxicity monitoring, and use of routine radiographs. CONCLUSION: The ACR pediatric rheumatology Top 5 is one of the first pediatric subspecialty-specific Choosing Wisely Top 5 lists and provides an opportunity for patients and providers to discuss appropriate use of health care in pediatric rheumatology. PMID- 24757000 TI - Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect. AB - Currently, six inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature are known. The "Primary 3-methylglutaconic aciduria," 3 methylglutaconyl-CoA hydratase deficiency or AUH defect, is a disorder of leucine catabolism. For all other subtypes, also denoted "Secondary 3-methylglutaconic acidurias" (TAZ defect or Barth syndrome, SERAC1 defect or MEGDEL syndrome, OPA3 defect or Costeff syndrome, DNAJC19 defect or DCMA syndrome, TMEM70 defect, "not otherwise specified (NOS) 3-MGA-uria"), the origin of 3-methylglutaconic aciduria remains enigmatic but is hypothesized to be independent from leucine catabolism. Here we show the results of leucine loading test in 21 patients with different inborn errors of metabolism who present with 3-methylglutaconic aciduria. After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect. This strongly supports the hypothesis that 3 methylglutaconic aciduria is independent from leucine breakdown in other inborn errors of metabolism with 3-methylglutaconic aciduria and also provides a simple test to discriminate between primary and secondary 3-methylglutaconic aciduria in regular patient care. PMID- 24757001 TI - Actomyosin networks and tissue morphogenesis. AB - Tissue morphogenesis is driven by coordinated cellular deformations. Recent studies have shown that these changes in cell shape are powered by intracellular contractile networks comprising actin filaments, actin cross-linkers and myosin motors. The subcellular forces generated by such actomyosin networks are precisely regulated and are transmitted to the cell cortex of adjacent cells and to the extracellular environment by adhesive clusters comprising cadherins or integrins. Here, and in the accompanying poster, we provide an overview of the mechanics, principles and regulation of actomyosin-driven cellular tension driving tissue morphogenesis. PMID- 24757002 TI - Bioengineering approaches to guide stem cell-based organogenesis. AB - During organogenesis, various molecular and physical signals are orchestrated in space and time to sculpt multiple cell types into functional tissues and organs. The complex and dynamic nature of the process has hindered studies aimed at delineating morphogenetic mechanisms in vivo, particularly in mammals. Recent demonstrations of stem cell-driven tissue assembly in culture offer a powerful new tool for modeling and dissecting organogenesis. However, despite the highly organotypic nature of stem cell-derived tissues, substantial differences set them apart from their in vivo counterparts, probably owing to the altered microenvironment in which they reside and the lack of mesenchymal influences. Advances in the biomaterials and microtechnology fields have, for example, afforded a high degree of spatiotemporal control over the cellular microenvironment, making it possible to interrogate the effects of individual microenvironmental components in a modular fashion and rapidly identify organ specific synthetic culture models. Hence, bioengineering approaches promise to bridge the gap between stem cell-driven tissue formation in culture and morphogenesis in vivo, offering mechanistic insight into organogenesis and unveiling powerful new models for drug discovery, as well as strategies for tissue regeneration in the clinic. We draw on several examples of stem cell derived organoids to illustrate how bioengineering can contribute to tissue formation ex vivo. We also discuss the challenges that lie ahead and potential ways to overcome them. PMID- 24757004 TI - Hemogenic endothelium generates mesoangioblasts that contribute to several mesodermal lineages in vivo. AB - The embryonic endothelium is a known source of hematopoietic stem cells. Moreover, vessel-associated progenitors/stem cells with multilineage mesodermal differentiation potential, such as the 'embryonic mesoangioblasts', originate in vitro from the endothelium. Using a genetic lineage tracing approach, we show that early extra-embryonic endothelium generates, in a narrow time-window and prior to the hemogenic endothelium in the major embryonic arteries, hematopoietic cells that migrate to the embryo proper, and are subsequently found within the mesenchyme. A subpopulation of these cells, distinct from embryonic macrophages, co-expresses mesenchymal and hematopoietic markers. In addition, hemogenic endothelium-derived cells contribute to skeletal and smooth muscle, and to other mesodermal cells in vivo, and display features of embryonic mesoangioblasts in vitro. Therefore, we provide new insights on the distinctive characteristics of the extra-embryonic and embryonic hemogenic endothelium, and we identify the putative in vivo counterpart of embryonic mesoangioblasts, suggesting their identity and developmental ontogeny. PMID- 24757005 TI - Growth control by a moving morphogen gradient during Drosophila eye development. AB - During morphogenesis, organs grow to stereotyped sizes, but growth control mechanisms are poorly understood. Here, we measured the signaling dynamics of the morphogen Dpp, one of several Drosophila factors controlling morphogenetic growth, in the developing eye. In this tissue, the Dpp expression domain advances from the posterior to the anterior tissue edge. In front of this moving morphogen source, signaling inputs including Dpp activate the target gene hairy in a gradient that scales with tissue size. Proliferation, in turn, occurs in a mitotic wave in front of the source, whereas behind it, cells arrest and differentiate. We found that cells divide when their signaling levels have increased by around 60%. This simple mechanism quantitatively explains the proliferation and differentiation waves in wild type and mutants. Furthermore, this mechanism may be a common feature of different growth factors, because a Dpp independent growth input also follows this growth rule. PMID- 24757003 TI - Genomic imprinting in development, growth, behavior and stem cells. AB - Genes that are subject to genomic imprinting in mammals are preferentially expressed from a single parental allele. This imprinted expression of a small number of genes is crucial for normal development, as these genes often directly regulate fetal growth. Recent work has also demonstrated intricate roles for imprinted genes in the brain, with important consequences on behavior and neuronal function. Finally, new studies have revealed the importance of proper expression of specific imprinted genes in induced pluripotent stem cells and in adult stem cells. As we review here, these findings highlight the complex nature and developmental importance of imprinted genes. PMID- 24757006 TI - Arabidopsis UNHINGED encodes a VPS51 homolog and reveals a role for the GARP complex in leaf shape and vein patterning. AB - Asymmetric localization of PIN proteins controls directionality of auxin transport and many aspects of plant development. Directionality of PIN1 within the marginal epidermis and the presumptive veins of developing leaf primordia is crucial for establishing leaf vein pattern. One mechanism that controls PIN protein distribution within the cell membranes is endocytosis and subsequent transport to the vacuole for degradation. The Arabidopsis mutant unhinged-1 (unh 1) has simpler leaf venation with distal non-meeting of the secondary veins and fewer higher order veins, a narrower leaf with prominent serrations, and reduced root and shoot growth. We identify UNH as the Arabidopsis vacuolar protein sorting 51 (VPS51) homolog, a member of the Arabidopsis Golgi-associated retrograde protein (GARP) complex, and show that UNH interacts with VPS52, another member of the complex and colocalizes with trans Golgi network and pre vacuolar complex markers. The GARP complex in yeast and metazoans retrieves vacuolar sorting receptors to the trans-Golgi network and is important in sorting proteins for lysosomal degradation. We show that vacuolar targeting is reduced in unh-1. In the epidermal cells of unh-1 leaf margins, PIN1 expression is expanded. The unh-1 leaf phenotype is partially suppressed by pin1 and cuc2-3 mutations, supporting the idea that the phenotype results from expanded PIN1 expression in the marginal epidermis. Our results suggest that UNH is important for reducing expression of PIN1 within margin cells, possibly by targeting PIN1 to the lytic vacuole. PMID- 24757007 TI - High-resolution analysis of gene activity during the Xenopus mid-blastula transition. AB - The Xenopus mid-blastula transition (MBT) marks the onset of large-scale zygotic transcription, as well as an increase in cell cycle length and a loss of synchronous cell divisions. Little is known about what triggers the activation of transcription or how newly expressed genes interact with each other. Here, we use high-resolution expression profiling to identify three waves of gene activity: a post-fertilisation wave involving polyadenylation of maternal transcripts; a broad wave of zygotic transcription detectable as early as the seventh cleavage and extending beyond the MBT at the twelfth cleavage; and a shorter post-MBT wave of transcription that becomes apparent as development proceeds. Our studies have also allowed us to define a set of maternal mRNAs that are deadenylated shortly after fertilisation, and are likely to be degraded thereafter. Experimental analysis indicates that the polyadenylation of maternal transcripts is necessary for the establishment of proper levels of zygotic transcription at the MBT, and that genes activated in the second wave of expression, including Brachyury and Mixer, contribute to the regulation of genes expressed in the third. Together, our high-resolution time series and experimental studies have yielded a deeper understanding of the temporal organisation of gene regulatory networks in the early Xenopus embryo. PMID- 24757009 TI - MRI assessment of cerebral oxygen metabolism in cocaine-addicted individuals: hypoactivity and dose dependence. AB - Long-term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural-activity specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine-addicted subjects and 13 age- and gender-matched control subjects, and examined the impact of long-term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine-addicted subjects (152 +/- 16 umol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 +/- 20 umol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long-term effects of cocaine use on the brain. PMID- 24757010 TI - Requirements for "Fire and ICE" differ between animal models of autoimmunity: comment on the article by Kahlenberg et al. PMID- 24757011 TI - OMIP-021: Simultaneous quantification of human conventional and innate-like T cell subsets. PMID- 24757012 TI - Changing forest water yields in response to climate warming: results from long term experimental watershed sites across North America. AB - Climate warming is projected to affect forest water yields but the effects are expected to vary. We investigated how forest type and age affect water yield resilience to climate warming. To answer this question, we examined the variability in historical water yields at long-term experimental catchments across Canada and the United States over 5-year cool and warm periods. Using the theoretical framework of the Budyko curve, we calculated the effects of climate warming on the annual partitioning of precipitation (P) into evapotranspiration (ET) and water yield. Deviation (d) was defined as a catchment's change in actual ET divided by P [AET/P; evaporative index (EI)] coincident with a shift from a cool to a warm period - a positive d indicates an upward shift in EI and smaller than expected water yields, and a negative d indicates a downward shift in EI and larger than expected water yields. Elasticity was defined as the ratio of interannual variation in potential ET divided by P (PET/P; dryness index) to interannual variation in the EI - high elasticity indicates low d despite large range in drying index (i.e., resilient water yields), low elasticity indicates high d despite small range in drying index (i.e., nonresilient water yields). Although the data needed to fully evaluate ecosystems based on these metrics are limited, we were able to identify some characteristics of response among forest types. Alpine sites showed the greatest sensitivity to climate warming with any warming leading to increased water yields. Conifer forests included catchments with lowest elasticity and stable to larger water yields. Deciduous forests included catchments with intermediate elasticity and stable to smaller water yields. Mixed coniferous/deciduous forests included catchments with highest elasticity and stable water yields. Forest type appeared to influence the resilience of catchment water yields to climate warming, with conifer and deciduous catchments more susceptible to climate warming than the more diverse mixed forest catchments. PMID- 24757013 TI - Breivik--the Norwegian terrorist case. AB - On July 22, 2011, there were two murderous attacks in Norway. Both assaults - the bombing of governmental buildings in Oslo City center and the lethal shooting down of young members of the Labour Party on an island - were planned and accomplished by a lone perpetrator. These episodes give rise to several interesting questions. What happened really, and how could it happen? Was the perpetrator sane or insane? What was the ideological background for the attacks? It is unnecessary to discuss in any detail whether or not these acts should be categorized as terrorism. However, there is good reason to consider what these terror attacks imply for Norwegian society at large. What significance did the attacks have for Norwegian democracy, and did they have any impact on the 2013 parliamentary elections? What will be the future for the offender, both in the short term and in years to come? What will happen to the Norwegian insanity defense? These questions are addressed in this article. PMID- 24757014 TI - Fast pirouetting motion in a pyridine bisamine-containing copper-complexed rotaxane. AB - The present work reports the introduction of pyridine bisamine terdentate ligands in the structure of a pirouetting copper rotaxane. Rotaxane 2[PF6] constitutes the first example of the incorporation of imine-based dynamic covalent chemistry in the synthesis of switchable copper-complexed interlocked systems. In this rotaxane, the substitution of the classical terpyridine terdentate unit by a pyridine bisamine moiety has led to a significant stabilization of the pentacoordinated site. That fact has been evidenced by EPR spectroscopy and cyclic voltammetry. Regarding the tetracoordinated site, the congestion around the coordination sphere has been reduced to accelerate the typically slow reorganization of the Cu(II). Ethynyl-3,8-substitution on the axis phenanthroline along with the 2,9-diphenyl-1,10-phenanthroline (dpp) present in the macrocycle afforded a very stable coordination environment for Cu(I), which is at the same time labile upon oxidation. In summary, the incorporation of a pyridine bisamine unit as a terdentate ligand and the optimization of the bidentate ligand of the axle not only has led to a simplification of the synthetic procedures, but it has also given rise to a bistable systems with an enhanced energetic separation between states and an acceleration of the reorganization processes. Thus far, rotaxane 2[PF6] presents the fastest switching cycle reported to date in copper interlocked dynamic systems. PMID- 24757015 TI - Linking interdecadal changes in British river ecosystems to water quality and climate dynamics. AB - Macroinvertebrate communities in Western European rivers have changed substantially in recent decades. Understanding the causes is challenging because improvements in water quality have coincided with climatic variations over this period. Using data covering >2300 rivers and 21 years (1991-2011) across England and Wales, we analysed family-level distributions and nationwide trends in prevalence (proportion of sampling locations where an organism was present) to diagnose the causes of ecological change. Our aims were to: (i) reveal the taxa driving assemblage-level trends; (ii) identify the main changes in family-level prevalence and distribution patterns; and (iii) test whether changes were accounted for by improving water quality, increasing temperatures or variations in discharge. While previous analyses revealed increasing richness among British river invertebrates, a partial turnover of taxa is now evident. Two distinct components of temporal trend have comprised: (i) overall increases or decreases in taxon prevalence over 21 years, which correlated with pollution sensitivity and discharge; and (ii) short-term variations in prevalence that correlated primarily with temperature and nutrient concentrations. The longer-term changes in prevalence were reflected in expansions or contractions in families' distributions linked to water quality, with little evidence of shifts consistent with increasing temperatures. Although these monitoring data had limitations (e.g., family-level data, few headwaters), they provide no clear evidence of long term climate effects on invertebrates; the one feature consistent with climate warming - a small northward expansion of the range of many taxa - was accounted for by large improvements in water quality in northern England. Nevertheless, changes linked to discharge and temperature over the shorter-term (<2 years) point to the climatic sensitivity of invertebrate communities. It is therefore likely that any long-term climatic changes since 1990 have been outweighed by the strength and geographical extent of the recovery from poor water quality. PMID- 24757016 TI - Mistaken identity: purified basophils likely contaminated with dendritic cells. PMID- 24757018 TI - Abdominal pain, flank pain, blurry vision, and lower extremity weakness in a 16 year-old female. PMID- 24757019 TI - Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB * NZW)F1 and NZM2410 mice. AB - OBJECTIVE: To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission, and relapse of nephritis in murine lupus models using transcriptome analysis. METHODS: Kidneys from (NZB * NZW)F1 (NZB/NZW) and NZM2410 mice were harvested at intervals during the disease course or after remission induction. Genome-wide expression profiles were obtained from microarray analysis of perfused kidneys. Real-time polymerase chain reaction (PCR) analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire data set using singular value decomposition and self-organizing maps were performed. RESULTS: Few changes in the renal molecular profile were detected in prenephritic kidneys, but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation, occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Endothelial cell activation, tissue remodeling, and tubular damage were the major pathways associated with loss of renal function. Remission induction reversed most, but not all, of the inflammatory changes, and progression toward relapse was associated with recurrence of inflammation, mitochondrial dysfunction, and metabolic stress signatures. CONCLUSION: Immune cell infiltration and activation is associated with proteinuria onset and is reversed by immunosuppressive therapy, but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy for lupus nephritis may therefore need to target both immune and nonimmune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in the kidneys of lupus patients suggests potential new biomarkers and therapeutic targets. PMID- 24757020 TI - Highly efficient orange and warm white phosphorescent OLEDs based on a host material with a carbazole-fluorenyl hybrid. AB - A new carbazole-fluorenyl hybrid compound, 3,3'(2,7-di(naphthaline-2-yl)-9H fluorene-9,9-diyl)bis(9-phenyl-9H-carbazole) (NFBC) was synthesized and characterized. The compound exhibits blue-violet emission both in solution and in film, with peaks centered at 404 and 420 nm. In addition to the application as a blue emitter, NFBC is demonstrated to be a good host for phosphorescent dopants. By doping Ir(2-phq)3 in NFBC, a highly efficient orange organic light-emitting diode (OLED) with a maximum efficiency of 32 cd A(-1) (26.5 Lm W(-1)) was obtained. Unlike most phosphorescent OLEDs, the device prepared in our study shows little efficiency roll-off at high brightness and maintains current efficiencies of 31.9 and 26.8 cd A(-1) at a luminance of 1000 and 10,000 cd m( 2), respectively. By using NFBC simultaneously as a blue fluorescence emitter and as a host for a phosphorescent dopant, a warm white OLED with a maximum efficiency of 22.9 Lm W(-1) (21.9 cd A(-1)) was also obtained. PMID- 24757022 TI - Human identification using dental techniques: A case report. AB - Dental identification of skeletal remains frequently relies on data comparison. Comparative dental identification is used to establish with a high degree of certainty that the remains of a corpse and a person represented by ante-mortem dental records are the same individual. There is no minimum number of concordant points necessary to perform a positive identification; rather, each case is unique and should be treated as such. In this paper, we present a report of a case in which positive identification was made by a paramolar tubercle in both upper first deciduous molars. PMID- 24757021 TI - Development and validation of the Lupus Impact Tracker: a patient-completed tool for clinical practice to assess and monitor the impact of systemic lupus erythematosus. AB - OBJECTIVE: To derive and validate a brief patient-completed instrument, the Lupus Impact Tracker (LIT), to assess and monitor the impact of systemic lupus erythematosus (SLE). METHODS: Items for the LIT were selected from the LupusPRO, a validated patient-reported outcomes measure, using 3 approaches: confirmatory factor analysis (CFA), stepwise regression, and patient focus groups. CFA was conducted to find items from the LupusPRO that fit a unidimensional structure to allow scoring as a single index. Stepwise regression methods identified items with the strongest relationship (convergent validity) with disease activity measures and patient health rating. Focus groups (n = 26 patients) identified the most important items describing SLE impact. Selected items were evaluated for reliability and validity. RESULTS: CFA found 21 items that fit a unidimensional structure. Stepwise regressions identified 15 of 21 items having good convergent validity with clinical measures. Patient focus groups identified 9 of 15 items as best capturing the impact of SLE. Overall, 7 items were selected across all 3 approaches (CFA, stepwise regression, and focus groups). Another 15 items were selected across 2 approaches. Through consensus with rheumatology clinician experts, a final set of 10 items was selected for the LIT. The LIT items showed good internal consistency (0.89) and test-retest reliabilities (0.87). Mean LIT scores differed significantly (P < 0.05) across criterion groups in the hypothesized direction, providing evidence of discriminant validity and responsiveness. CONCLUSION: The LIT is reliable and valid in SLE patients and offers a practical way for physicians and patients to assess and monitor the impact of SLE. PMID- 24757023 TI - Vesicle structures from bolaamphiphilic biosurfactants: experimental and molecular dynamics simulation studies on the effect of unsaturation on sophorolipid self-assemblies. AB - The formation of giant-vesicle-like structures by self-assembling linolenic acid sophorolipid (LNSL) molecules is revealed. Sophorolipids belong to the class of bolaamphiphilic glycolipid biosurfactants. Interestingly, the number of double bonds present in the hydrophobic core of sophorolipids is seen to have a great influence on the type of self-assembled structures formed. Dye encapsulation results establish the presence of an aqueous compartment inside the LNSL vesicles. Molecular dynamics simulation (MD) studies suggest the existence of two possible conformations of LNSLs inside the self-assembled structures and that LNSL molecules arrange in layered structures. PMID- 24757024 TI - The proximal lateral lower leg perforator flap revisited: anatomical study and clinical applications. AB - BACKGROUND: The proximal lateral lower leg flap is a flap suited for the reconstruction of small and thin defects. The purpose of this study was to map the position and consistency of the perforator vessels and to review its reliability and technical considerations clinically. METHODS: The location, number, and size of perforator vessels in the proximal third of the lateral lower leg were investigated in 20 fresh frozen cadaveric lower limbs. This was analyzed together with 22 clinical cases. RESULTS: Cadaveric dissection showed that there were 1-2 perforators in the proximal third of the lateral lower leg and these perforator vessels were found to be 63% septocutaneous and 37% musculocutaneous. The source vessel of the perforators was variable. Clinically the recipient site consisted of the head and neck in 8 cases, the foot and ankle region in 13 cases, and 1 case in the hand. The mean thickness of this flap was 5.8 +/- 0.8 mm. Vascular pedicle length ranged from 5 to 8.5 cm. The mean diameter of flap artery was 1.3 +/- 0.3 mm. One flap failure was seen due to arterial thrombosis. The overall flap survival rate was 95%. CONCLUSIONS: The proximal lateral lower leg flap has the advantages of being thin and pliable, quick to harvest with no major arteries sacrificed. There is minimal donor site morbidity and primary closure of the donor site is possible in the majority of cases. PMID- 24757025 TI - Flow cytometric phenotyping of lymphocytes in patients with systemic lupus erythematosus. PMID- 24757026 TI - Sites for methane activation on lithium-doped magnesium oxide surfaces. AB - Density functional calculations yield energy barriers for H abstraction by oxygen radical sites in Li-doped MgO that are much smaller (12+/-6 kJ mol(-1)) than the barriers inferred from different experimental studies (80-160 kJ mol(-1)). This raises further doubts that the Li(+)O(-) site is the active site as postulated by Lunsford. From temperature-programmed oxidative coupling reactions of methane (OCM), we conclude that the same sites are responsible for the activation of CH4 on both Li-doped MgO and pure MgO catalysts. For a MgO catalyst prepared by sol gel synthesis, the activity proved to be very different in the initial phase of the OCM reaction and in the steady state. This was accompanied by substantial morphological changes and restructuring of the terminations as transmission electron microscopy revealed. Further calculations on cluster models showed that CH4 binds heterolytically on Mg(2+)O(2-) sites at steps and corners, and that the homolytic release of methyl radicals into the gas phase will happen only in the presence of O2. PMID- 24757027 TI - Advancements in identifying biomechanical determinants for abdominal aortic aneurysm rupture. AB - Abdominal aortic aneurysms are a common health problem and currently the need for surgical intervention is determined based on maximum diameter and growth rate criteria. Since these universal variables often fail to predict accurately every abdominal aortic aneurysms evolution, there is a considerable effort in the literature for other markers to be identified towards individualized rupture risk estimations and growth rate predictions. To this effort, biomechanical tools have been extensively used since abdominal aortic aneurysm rupture is in fact a material failure of the diseased arterial wall to compensate the stress acting on it. The peak wall stress, the role of the unique geometry of every individual abdominal aortic aneurysm as well as the mechanical properties and the local strength of the degenerated aneurysmal wall, all confer to rupture risk. In this review article, the assessment of these variables through mechanical testing, advanced imaging and computational modeling is reviewed and the clinical perspective is discussed. PMID- 24757028 TI - In memoriam: James A DeWeese, MD. PMID- 24757029 TI - A reversible dual mode chemodosimeter for the detection of cyanide ions in natural sources. AB - Herein, we report the synthesis of two indolium probes 1 and 2 based on anthracene and pyrene derivatives and their interactions with various anions. Of these probes, the pyrene conjugate 2 acts as a dual colorimetric and fluorescent chemodosimeter for the selective and sensitive detection of cyanide ions. The detection limit of probe 2 for CN(-) ions was found to be 10 ppb (30 nM). The nature of interaction has been thoroughly studied through various techniques such as (1)H NMR and IR spectroscopy, HRMS, and isothermal calorimetric (ITC) studies. These studies confirm that probe 2 forms a 1,2-adduct in the presence of CN(-) ions. Kinetic studies using probe 2 showed the completion of the reaction within 15 s with a rate constant of k' = 0.522+/-0.063 s(-1). This probe can be coated on a solid surface (dipstick) and a polymer matrix for the on-site analysis and quantification of endogenous cyanide ions in natural sources such as Indian almonds. PMID- 24757030 TI - Establishment of gene copy number-specific normal ranges for serum C4 and its utility for interpretation in patients with chronically low serum C4 concentrations. AB - OBJECTIVE: To establish gene copy number (GCN)-specific normal ranges for serum C4 genes and to determine their utility with respect to the interpretation of chronically low serum C4 concentrations in patients with clinically quiescent systemic lupus erythematosus (SLE). METHODS: C4 serum concentrations were estimated by automated turbidimetry, and C4 GCNs were determined using the TaqMan real-time polymerase chain reaction (PCR) analysis in 184 unselected individuals and in 10 patients with type 1 diabetes mellitus (DM) who were selected for the presence of only 2 copies of the C4 gene. C4 GCNs were also determined in 11 patients with clinically quiescent SLE who had chronically low serum C4 concentrations. RESULTS: A total of 33% of the variation in serum C4 concentrations could be accounted for by both C4A and C4B GCNs (R(2) = 0.30, P <= 0.0001). There was a median of 2 gene copies at the C4A locus (53.8%) and 2 at the C4B locus (58.7%). The median total number of C4 genes was 4 (55.4%). C4 GCN specific normal ranges were established. A chronically low serum C4 concentration was explained by a low C4 GCN in 3 of 11 patients tested. CONCLUSION: This study establishes the feasibility of establishing C4 GCN-specific normal ranges using the TaqMan real-time PCR assay. Chronically low serum C4 concentrations in SLE patients are sometimes explained by low C4 GCNs. PMID- 24757031 TI - Variation in mortality among populations is higher for pymetrozine than for imidacloprid and spiromesifen in Trialeurodes vaporariorum in greenhouses in Finland. AB - BACKGROUND: Insecticide resistance in Trialeurodes vaporariorum W. is unknown in the species' northern distribution range where it inhabits mainly commercial greenhouses. Resistance development in whiteflies feeding on year-round crops in greenhouses is possible owing to the use of chemical treatments to back up biocontrol. The authors tested the response levels to spiromesifen, pymetrozine and imidacloprid in whiteflies collected from seven greenhouses within a 35 km radius in western Finland. RESULTS: All except one (PR) population had LC50 values below the recommended concentrations for the tested compounds. However, some populations showed reduced susceptibility to pymetrozine in comparison with the reference susceptible population. Resistance ratios to pymetrozine were highly variable (resistance ratio 0.5-39.7), even among closely located greenhouses, and higher than those for imidacloprid (resistance ratio 1.05-10.5) and spiromesifen (resistance ratio 0.8-11.5). LC50 values and application frequencies of pymetrozine correlated positively among the sampled populations. CONCLUSION: High variation in resistance levels to pymetrozine among populations within natural whitefly dispersal limits reflects variation in the usage of this compound among individual greenhouse crop producers. Thus, resistance management is recommended at the individual greenhouse crop producer level, even in a dense production cluster. (c) 2014 Society of Chemical Industry. PMID- 24757032 TI - Effects of two physiotherapy booster sessions on outcomes with home exercise in people with knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: Enhancing exercise adherence over the longer term is an important goal in self-management of knee osteoarthritis (OA). Following an initial period of more intensive exercise supervision, this study investigated whether 2 additional physiotherapy visits improved outcomes with continued home exercise over a subsequent 24-week period. METHODS: A total of 78 people with medial knee OA (mean +/- SD age 62.1 +/- 6.9 years, mean +/- SD body mass index 29.4 +/- 4.0 kg/m(2) , and radiographic disease severity 19% mild, 49% moderate, and 32% severe) who completed a 12-week physiotherapist-supervised exercise trial were randomly allocated to 2 30-minute physiotherapy booster sessions (delivered by 8 physiotherapists in private clinics) or no booster sessions for the subsequent 24 weeks. All participants were asked to continue home exercises 4 times weekly. Primary outcomes were change in pain, using a 100-mm visual analog scale, and self-reported physical function, measured using the Western Ontario McMaster Universities Osteoarthritis Index. Participants and physiotherapists were unblinded to group allocation, although participants were blinded to the study hypothesis. RESULTS: A total of 74 participants (95%) completed the trial. There was no significant difference between groups for change in pain (mean difference [95% confidence interval (95% CI)] 0.7 mm [-9.4, 8.0]; P = 0.88) or physical function (-0.3 units [95% CI -4.0, 3.5]; P = 0.88). The mean +/- SD percentage of home exercise sessions completed was 56% +/- 34% in the booster group and 51% +/- 37% in the control group (P > 0.05). CONCLUSION: Two booster sessions with a physiotherapist did not influence pain or physical function outcomes, or measures of home exercise adherence. These findings suggest other more effective strategies are needed to maximize longer-term adherence with the aim to achieve greater improvements in clinical outcomes from exercise in this patient population. PMID- 24757033 TI - Glycogen synthase kinase 3 inhibition stimulates human cartilage destruction and exacerbates murine osteoarthritis. AB - OBJECTIVE: To assess the role of glycogen synthase kinase 3 (GSK-3) as a regulator of cartilage destruction in human tissue and a murine model of osteoarthritis (OA). METHODS: Surgical destabilization of the medial meniscus (DMM) was performed to induce experimental murine OA, and joint damage was assessed histologically. Bovine nasal and human OA cartilage samples were incubated with interleukin-1 (IL-1) plus oncostatin M (OSM) and GSK-3 inhibitor. Collagen and proteoglycan release was assessed by hydroxyproline measurement and dye binding assay, collagenase activity was assessed by bioassay, and gene expression was analyzed by real-time polymerase chain reaction. Human articular chondrocytes were isolated by enzymatic digestion and cultured prior to gene silencing and immunoblotting of cell lysates and nuclear fractions. RESULTS: Mice treated with GSK-3 inhibitor exhibited significantly greater cartilage damage compared with sham-operated control mice. GSK-3 inhibition in bovine cartilage dramatically accelerated IL-1 plus OSM-stimulated degradation, concomitant with a profound increase in collagenase activity. GSK-3 inhibitor induced collagen release from human OA cartilage in the presence of IL-1 plus OSM and increased proteoglycan loss. Gene expression profiling of resorbing OA cartilage revealed a marked procatabolic switch in gene expression upon GSK-3 inhibition. This was mirrored in human articular chondrocytes following GSK3 silencing, particularly with the GSK-3beta isoform. GSK-3 inhibition or silencing led to enhanced IL-1 plus OSM-stimulated abundance and activity of Jun, and silencing of c-jun ameliorated GSK-3 inhibitor-mediated procatabolic gene expression. CONCLUSION: GSK-3 is an important regulator of matrix metalloproteinase (MMP)-mediated joint destruction, the inhibition of which by proinflammatory stimuli de-represses catabolic gene expression. Therapeutic strategies that maintain cartilage GSK-3 activity may therefore help curtail aberrant MMP activity during pathologic joint destruction. PMID- 24757034 TI - Socioeconomic disparities in the health of african americans with rheumatoid arthritis from the southeastern United States. AB - OBJECTIVE: To examine cross-sectional baseline data from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis registry for the association between socioeconomic status (SES) with clinical and self-report health outcomes. METHODS: We analyzed data on 937 African Americans who provided comprehensive sociodemographic data in addition to self-reported health outcomes. SES measures included educational attainment, homeownership, household income, and occupation. Outcomes included measures of disease activity, joint damage, autoantibody status, and self-reported measures. Multivariable linear, logistic, and zero-inflated Poisson regression models were used to estimate associations of each SES measure with rheumatoid arthritis (RA) outcomes, controlling for sex, age, disease duration, comorbid conditions, body mass index, smoking, methotrexate/leflunomide use, and biologic agent use. RESULTS: The mean age was 54 years, 86% were women, and the mean RA disease duration was 7.8 years. Approximately 24% had less than a high school degree, 56% had a nonprofessional occupation, 75% had a household income <=$30,000, and 55% were nonhomeowners. In multivariable regression models, significantly increased associations of disease activity measures and self-reported health outcomes were observed with low household income (<=$30,000/year) and nonhomeownership. Education less than high school was primarily associated with self-reported health outcomes. Among participants with disease duration <2 years, associations of SES were confined to self-reported measures. CONCLUSION: Our results indicate significant socioeconomic disparities in self-reported physical and mental health, clinical disease activity measures, and autoantibody status among African Americans with RA not explained by differences in demographics, medication use, and health behaviors. PMID- 24757036 TI - The effects of storage time and temperature on recovery of salivary secretory immunoglobulin A. AB - OBJECTIVES: This study aimed to determine the optimal storage temperature to minimise degradation of salivary s-IgA for field-based surveillance applications in resource-limited settings. METHODS: Saliva samples from 40 Zambian adults were stored at +25 degrees C, +4 degrees C, -20 degrees C, and -80 degrees C and each tested by ELISA for salivary s-IgA concentration at 0, 1, 2, 7, and 15 days. Differences were determined among concentrations over time and temperature compared with baseline values. Kruskal-Wallis tests were applied to analyse variance. Single and multivariate regression analyses estimated the influence of storage time and temperature on recoverable s-IgA. RESULTS: Results revealed a statistically significant decrease in salivary s-IgA concentration as storage time increased and as temperature decreased. Degradation during storage time was most pronounced at lower temperatures. CONCLUSIONS: s-IgA is stable at ambient temperatures in Zambia for at least 15 days, suggesting no need for cold chain handling before analysis in field-based surveillance applications. PMID- 24757038 TI - Iatrogenic cushing syndrome secondary to a probable interaction between voriconazole and budesonide. AB - Oral budesonide is commonly used for the management of Crohn's disease given its high affinity for glucocorticoid receptors and low systemic activity due to extensive first-pass metabolism through hepatic cytochrome P450 (CYP) 3A4. Voriconazole, a second-generation triazole antifungal agent, is both a substrate and potent inhibitor of CYP isoenzymes, specifically CYP2C19, CYP2C9, and CYP3A4; thus, the potential for drug-drug interactions with voriconazole is high. To our knowledge, drug-drug interactions between voriconazole and corticosteroids have not been specifically reported in the literature. We describe a 48-year-old woman who was receiving oral budesonide 9 mg/day for the management of Crohn's disease and was diagnosed with fluconazole-resistant Candida albicans esophagitis; oral voriconazole 200 mg every 12 hours for 3 weeks was prescribed for treatment. Because the patient experienced recurrent symptoms of dysphagia, a second 3-week course of voriconazole therapy was taken. Seven weeks after originally being prescribed voriconazole, she came to her primary care clinic with elevated blood pressure, lower extremity edema, and weight gain; she was prescribed a diuretic and evaluated for renal dysfunction. At a follow-up visit 6 weeks later with her specialty clinic, the patient's blood pressure was elevated, and her physical examination was notable for moon facies, posterior cervical fat pad prominence, and lower extremity pitting edema. Iatrogenic Cushing syndrome due to a drug-drug interaction between voriconazole and budesonide was suspected, and voriconazole was discontinued. Budesonide was continued as previously prescribed for her Crohn's disease. On reevaluation 2 months later, the patient's Cushingoid features had markedly regressed. To our knowledge, this is the first published case report of iatrogenic Cushing syndrome due to a probable interaction between voriconazole and oral budesonide. In patients presenting with Cushingoid features who have received these drugs concomitantly, clinicians should consider the potential drug interaction between these agents, and the risks and benefits of continued therapy must be considered. PMID- 24757035 TI - Correlation analysis of genetic admixture and social identification with body mass index in a Native American community. AB - OBJECTIVES: Body mass index (BMI) is a well-known measure of obesity with a multitude of genetic and non-genetic determinants. Identifying the underlying factors associated with BMI is difficult because of its multifactorial etiology that varies as a function of geoethnic background and socioeconomic setting. Thus, we pursued a study exploring the influence of the degree of Native American admixture on BMI (as well as weight and height individually) in a community sample of Native Americans (n = 846) while accommodating a variety of socioeconomic and cultural factors. METHODS: Participants' degree of Native American (NA) ancestry was estimated using a genome-wide panel of markers. The participants also completed an extensive survey of cultural and social identity measures: the Indian Culture Scale (ICS) and the Orthogonal Cultural Identification Scale (OCIS). Multiple linear regression was used to examine the relation between these measures and BMI. RESULTS: Our results suggest that BMI is correlated positively with the proportion of NA ancestry. Age was also significantly associated with BMI, while gender and socioeconomic measures (education and income) were not. For the two cultural identity measures, the ICS showed a positive correlation with BMI, while OCIS was not associated with BMI. CONCLUSIONS: Taken together, these results suggest that genetic and cultural environmental factors, rather than socioeconomic factors, account for a substantial proportion of variation in BMI in this population. Further, significant correlations between degree of NA ancestry and BMI suggest that admixture mapping may be appropriate to identify loci associated with BMI in this population. PMID- 24757039 TI - A bifunctional perovskite catalyst for oxygen reduction and evolution. AB - La0.3(Ba0.5Sr0.5)0.7Co0.8Fe0.2O3d is a promising bifunctional perovskite catalyst for the oxygen reduction reaction and the oxygen evolution reaction. This catalyst has circa 10 nm-scale rhombohedral LaCoO3 cobaltite particles distributed on the surface. The dynamic microstructure phenomena are attributed to the charge imbalance from the replacement of A-site cations with La3+ and local stress on Cosite sub-lattice with the cubic perovskite structure. PMID- 24757040 TI - Fabrication of macroporous films with closed honeycomb-like pores from exponentially growing layer-by-layer assembled polyelectrolyte multilayers. AB - We report an innovative method for the fabrication of macroporous films with closed honeycomb-like pores of several micrometers by post-treatment of micrometer-thick poly(acrylic acid) (PAA)/poly(allylamine hydrochloride) (PAH) films. The precursor PAA/PAH films are fabricated by exponential layer-by-layer assembly of PAA and PAH, which produces PAA/PAH films with highly interpenetrated structures. We disclose that the high mobility of PAA and PAH, which originates from the highly interpenetrated film structures, allows a large-scale phase separation to take place upon post-treatment to produce micrometer-sized honeycomb pores. These macroporous PAA/PAH films can be conveniently released from substrates to produce free-standing films with satisfactory mechanical stability. PMID- 24757041 TI - Effect of fiber orientation of collagen-based electrospun meshes on human fibroblasts for ligament tissue engineering applications. AB - Within the past two decades polylactic-co-glycolic acid (PLGA) has gained considerable attention as a biocompatible and biodegradable polymer that is suitable for tissue engineering and regenerative medicine. In this present study, we have investigated the potential of PLGA, collagen I (ColI), and polyurethane (PU) scaffolds for ligament tissue regeneration. Two different ratios of PLGA (50:50 and 85:15) were used to determine the effects on mechanical tensile properties and cell adhesion. The Young's modulus, tensile stress at yield, and ultimate tensile strain of PLGA(50:50)-ColI-PU scaffolds demonstrated similar tensile properties to that of ligaments found in the knee. Whereas, scaffolds composed of PLGA(85:15)-ColI-PU had lower tensile properties than that of ligaments. Furthermore, we investigated the effect of fiber orientation on mechanical properties and our results indicate that aligned fiber scaffolds demonstrate higher tensile properties than scaffolds with random fiber orientation. Also, human fibroblasts attached and proliferated with no need for additional surface modifications to the presented electrospun scaffolds in both categories. Collectively, our investigation demonstrates the effectiveness of electrospun PLGA scaffolds as a suitable candidate for regenerative medicine, capable of being manipulated and combined with other polymers to create three dimensional microenvironments with adjustable tensile properties to mimic native tissues. PMID- 24757042 TI - Combinatorial approach to chiral tris-ligated carbophilic platinum complexes: application to asymmetric catalysis. AB - A straightforward methodology for the synthesis of libraries of chiral tris ligated cationic platinum complexes and their in situ evaluation as asymmetric carbophilic catalysts in a model domino hydroarylation/cyclization reaction of a 1,6-enyne was developed. A catalyst-generation process based on a combination of a monodentate and a bidentate phosphorus ligand allowed the formation of 108 chiral complexes. One-pot screening of the stereoinduction obtained with this library in a test domino addition/cyclization reaction validated this approach and stressed the key role played by the monodentate ligand partner in obtaining high enantioselectivities. In the case of two challenging substrate/nucleophile combinations, the combinatorial approach resulted in a significant gain in enantioselectivity. PMID- 24757043 TI - Overweight and obesity in patients with cystic fibrosis: a center-based analysis. AB - OBJECTIVE: Cystic fibrosis (CF) has long been associated with malnutrition. However, due to early diagnosis, nutritional supplements, and increased prevalence of obesity in the general population, overweight, and obesity in the CF patient population is becoming a concern. The aim of this study was to determine the prevalence of obesity and overweight in patients with CF seen at our center, to analyze factors associated with nutritional status, to evaluate the relation between nutritional status and lung function, and to document any adverse health outcomes. METHODS: The CF Patient Registry was queried for patients aged 2-18 who were seen at our center between June 2011 and June 2012. Nutritional statuses of patients were classified in accordance with the CF Foundation guidelines. Analysis of variance was utilized to analyze the differences in lung function between the five weight status groups. RESULTS: Of the 226 patients with CF aged 2-18 years, 129 (57%) had a BMI percentile consistent with a healthy weight status, 16 (7%) were in nutritional failure, 28 (12%) were at risk of nutritional failure, 35 (15%) were overweight, and 18 (8%) were obese. Based on fecal elastase levels, 50% of the overweight patients and 20% of the obese patients were pancreatic insufficient. FEV1 % predicted was lowest in patients with nutritional failure (P = 0.005). No significant differences were noted between the other four weight groups. In our obese and overweight population, three patients have impaired glucose tolerance, one has CF related diabetes (CFRD) with fasting hyperglycemia, three have hypertension, and one has obstructive sleep apnea (OSA). CONCLUSIONS: The prevalence of overweight and obesity in our CF center is noteworthy, and a significant number of the patients were pancreatic insufficient. In our patient population, overweight, and obesity were not associated with further improvement of lung function. Nutritional approaches need to address the adverse outcomes of overweight and obesity. PMID- 24757044 TI - Dual echo vessel-encoded ASL for simultaneous BOLD and CBF reactivity assessment in patients with ischemic cerebrovascular disease. AB - PURPOSE: Blood oxygenation level-dependent (BOLD)-weighted and vessel-encoded arterial spin labeling (VE-ASL) MRI provide complementary information and can be used in sequence to gauge hemodynamic contributions to cerebrovascular reactivity. Here, cerebrovascular reactivity is assessed using dual echo VE-ASL MRI to understand how VE labeling preparations influence BOLD and ASL contrast in flow-limited and healthy perfusion territories. METHODS: Patients (n = 12; age = 55 +/- 14 years; 6F/6M) presenting with ischemic steno-occlusive cerebrovascular disease underwent 3.0T angiographic imaging, T1 -weighted structural, and planning-free dual echo hypercarbic hyperoxic (i.e., carbogen) VE-ASL MRI. Vasculopathy extent, timecourses, and cerebrovascular reactivity (signal change and Z-statistic) for different VE-ASL images were contrasted across flow territories and Bonferroni-corrected P-values reported. RESULTS: BOLD cerebrovascular reactivity (i.e., long-TE VE-ASL) Z-statistics were similarly sensitive to asymmetric disease (P <= 0.002) regardless of labeling scenario. Cerebral blood flow reactivity correlated significantly with BOLD reactivity (Z statistic). However, BOLD signal changes did not differ significantly between labeling scenarios (P > 0.003) or across territories (P > 0.002), indicating BOLD signal changes in response to carbogen offer low sensitivity to lateralizing disease. CONCLUSION: Dual echo VE-ASL can provide simultaneous cerebral blood flow and qualitative BOLD contrast consistent with lateralizing disease severity in patients with asymmetric steno-occlusive disease. The methodological strengths and limitations of composite BOLD and VE-ASL measurements in the clinic are discussed. PMID- 24757045 TI - Parental influence on systemic sclerosis. AB - OBJECTIVE: To examine parental influence on the development of systemic sclerosis (SSc; scleroderma). We designed 3 studies: mitochondrial inheritance, birth order (a possible surrogate marker for microchimerism), and paternal age at conception (a possible surrogate for telomere erosion) to examine their association with development of SSc. METHODS: SSc was defined by International Classification of Diseases, Ninth and Tenth Revision codes (ICD-9 710.1 and ICD 10 M34.0, M34.1, and M34.9) and identified from statewide discharge data, University of Utah Health Science Center Enterprise Data Warehouse (UUHSC), and death certificates that were linked to the Utah Population Database (UPDB) for analysis. Mitochondrial inheritance was evaluated by conditional logistic regression and population attributable risk using familial standardized incidence ratio as the covariate. Chi-square test and logistic regression were used to evaluate birth order and maternal/paternal age at conception of the SSc proband. RESULTS: We found 1,947 unique SSc patients from UUHSC and UPDB. We selected 5 controls per case (n = 9,115), matched by birth year and sex. Mitochondrial inheritance analysis indicated no evidence to suggest SSc was associated with mitochondrial inheritance. Birth order and maternal/paternal age at conception analysis results show that they also do not significantly affect SSc development. CONCLUSION: Results suggest that although heritable risk of SSc is observed, mitochondrial inheritance, birth order, and parental age are not likely responsible for pathogenesis. PMID- 24757046 TI - Can genome array screening replace FISH as a front-line test in multiple myeloma? AB - Multiple myeloma (MM) is a malignant disorder characterized by neoplastic transformation of mature B cells in the bone marrow (BM), accompanied by complex genetic changes. The disease is heterogeneous at both the clinical and genomic levels. Molecular genetics and genomic investigations have demonstrated that disease evolution is associated with an accumulation of specific aberrations, mostly genome imbalances, which not only shed light on the disease pathogenesis but also allow risk assessment and treatment monitoring. We used a catalogue version of the Agilent 8x60K oligo-array with immuno-magnetically isolated CD138(+) cells from BM samples of 50 patients with myeloma to evaluate the merit of array comparative genomic hybridization (aCGH) as a diagnostic tool. We demonstrate the ability of aCGH to detect clonal imbalances to a level well below established clinically significant thresholds. aCGH, combined with target enrichment and complemented with tests for IGH rearrangements offers a cost neutral alternative to multiprobe fluorescence in situ hybridization screening. While we recognize the limitations of the standard version of the 8x60k array we demonstrate the value of aCGH as a first tier test in the diagnostic workup of MM. The array technology enables high-risk disease stratification with the added benefit of providing whole genome data to assist in establishing clinically relevant predicative markers. PMID- 24757047 TI - Effective Nurse Communication With Type 2 Diabetes Patients: A Review. AB - Many type 2 diabetes mellitus patients have difficulties reaching optimal blood glucose control. With patients treated in primary care by nurses, nurse communication plays a pivotal role in supporting patient health. The twofold aim of the present review is to categorize common barriers to nurse-patient communication and to review potentially effective communication methods. Important communication barriers are lack of skills and self-efficacy, possibly because nurses work in a context where they have to perform biomedical examinations and then perform patient-centered counseling from a biopsychosocial approach. Training in patient-centered counseling does not seem helpful in overcoming this paradox. Rather, patient-centeredness should be regarded as a basic condition for counseling, whereby nurses and patients seek to cooperate and share responsibility based on trust. Nurses may be more successful when incorporating behavior change counseling based on psychological principles of self-regulation, for example, goal setting, incremental performance accomplishments, and action planning. PMID- 24757048 TI - Community leader perceptions of the health needs of older adults. AB - The purpose of this needs assessment was to determine community leader perceptions of health-related needs and resources available to rural-dwelling older adults as part of a community-academic partnership in the rural Midwest. A community advisory board, in accordance with community-based participatory research principles, was influential in study design and implementation. Key informant interviews (N = 30) were conducted with community leaders including professionals from schools, businesses, churches, and health care as well as government officials. Thematic analysis revealed "Family Is Central," "Heritage," "Strength," and "Longevity" as important themes related to older adults and their health care needs within the community. "Close-knit" and "Church Is Central" were also identified as important aspects of elder care. Community leaders perceived the "Rural Economy," "Distance to Resources," and "Seasonal Resources" as significant barriers for older adults. This work contributes important insights into community leaders' perceptions of health needs and challenges faced by older adults in rural settings. PMID- 24757049 TI - A modest proposal for dropping poor arms in clinical trials. AB - This paper presents a simple procedure for clinical trials comparing several arms with control. Demand for streamlining the evaluation of new treatments has led to phase III clinical trials with more arms than would have been used in the past. In such a setting, it is reasonable that some arms may not perform as well as an active control. We introduce a simple procedure that takes advantage of negative results in some comparisons to lessen the required strength of evidence for other comparisons. We evaluate properties analytically and use them to support claims made about multi-arm multi-stage designs. PMID- 24757050 TI - Diketopyrrolopyrrole j-aggregates formed by self-organization with DNA. AB - Bis(2-thienyl)diketopyrrolopyrrole with two Zn(II)-cyclens (ZnCyc-DPP) was designed and synthesized to evaluate the selective binding of Zn(II)-cyclen with thymine base in single-strand DNA as a tool for the construction of a highly ordered multichromophore system on DNAs. Through UV/Vis titrations, gel filtration chromatography, and circular dichroism spectroscopy, ZnCyc-DPP formed J-type DPP aggregates with oligo-dTn DNAs. The DPP aggregates absorbed on a gold electrode exhibited good photocurrent responses. The present results show that binding Zn(II)-cyclen-chromophore conjugates and thymine bases together is a powerful tool for preparing DNA-templated multichromophoric systems with specific functions. PMID- 24757051 TI - Palladium-catalyzed Heck-type cross-couplings of unactivated alkyl iodides. AB - A palladium-catalyzed, intermolecular Heck-type coupling of alkyl iodides and alkenes is described. This process is successful with a variety of primary and secondary unactivated alkyl iodides as reaction partners, including those with hydrogen atoms in the beta position. The mild catalytic conditions enable intermolecular C-C bond formations with a diverse set of alkyl iodides and alkenes, including substrates containing base- or nucleophile-sensitive functionality. PMID- 24757052 TI - Myosin directionality results from coupling between ATP hydrolysis, lever motion, and actin binding. PMID- 24757053 TI - Two-photon imaging of Zn2+ dynamics in mossy fiber boutons of adult hippocampal slices. AB - Mossy fiber termini in the hippocampus accumulate Zn(2+), which is released with glutamate from synaptic vesicles upon neural excitation. Understanding the spatiotemporal regulation of mobile Zn(2+) at the synaptic level is challenging owing to the difficulty of visualizing Zn(2+) at individual synapses. Here we describe the use of zinc-responsive fluorescent probes together with two-photon microscopy to image Zn(2+) dynamics mediated by NMDA receptor-dependent long-term potentiation induction at single mossy fiber termini of dentate gyrus neurons in adult mouse hippocampal slices. The membrane-impermeant fluorescent Zn(2+) probe, 6-CO2H-ZAP4, was loaded into presynaptic vesicles in hippocampal mossy fiber termini upon KCl-induced depolarization, which triggers subsequent endocytosis and vesicular restoration. Local tetanic stimulation decreased the Zn(2+) signal observed at individual presynaptic sites, indicating release of the Zn(2+) from vesicles in synaptic potentiation. This synapse-level two-photon Zn(2+) imaging method enables monitoring of presynaptic Zn(2+) dynamics for improving the understanding of physiological roles of mobile Zn(2+) in regular and aberrant neurologic function. PMID- 24757054 TI - Current perspectives and the future of domestication studies. AB - It is difficult to overstate the cultural and biological impacts that the domestication of plants and animals has had on our species. Fundamental questions regarding where, when, and how many times domestication took place have been of primary interest within a wide range of academic disciplines. Within the last two decades, the advent of new archaeological and genetic techniques has revolutionized our understanding of the pattern and process of domestication and agricultural origins that led to our modern way of life. In the spring of 2011, 25 scholars with a central interest in domestication representing the fields of genetics, archaeobotany, zooarchaeology, geoarchaeology, and archaeology met at the National Evolutionary Synthesis Center to discuss recent domestication research progress and identify challenges for the future. In this introduction to the resulting Special Feature, we present the state of the art in the field by discussing what is known about the spatial and temporal patterns of domestication, and controversies surrounding the speed, intentionality, and evolutionary aspects of the domestication process. We then highlight three key challenges for future research. We conclude by arguing that although recent progress has been impressive, the next decade will yield even more substantial insights not only into how domestication took place, but also when and where it did, and where and why it did not. PMID- 24757055 TI - Exploration of sequence space as the basis of viral RNA genome segmentation. AB - The mechanisms of viral RNA genome segmentation are unknown. On extensive passage of foot-and-mouth disease virus in baby hamster kidney-21 cells, the virus accumulated multiple point mutations and underwent a transition akin to genome segmentation. The standard single RNA genome molecule was replaced by genomes harboring internal in-frame deletions affecting the L- or capsid-coding region. These genomes were infectious and killed cells by complementation. Here we show that the point mutations in the nonstructural protein-coding region (P2, P3) that accumulated in the standard genome before segmentation increased the relative fitness of the segmented version relative to the standard genome. Fitness increase was documented by intracellular expression of virus-coded proteins and infectious progeny production by RNAs with the internal deletions placed in the sequence context of the parental and evolved genome. The complementation activity involved several viral proteins, one of them being the leader proteinase L. Thus, a history of genetic drift with accumulation of point mutations was needed to allow a major variation in the structure of a viral genome. Thus, exploration of sequence space by a viral genome (in this case an unsegmented RNA) can reach a point of the space in which a totally different genome structure (in this case, a segmented RNA) is favored over the form that performed the exploration. PMID- 24757056 TI - Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1. AB - During mammalian development, DNA methylation patterns need to be reset in primordial germ cells (PGCs) and preimplantation embryos. However, many LTR retrotransposons and imprinted genes are impervious to such global epigenetic reprogramming via hitherto undefined mechanisms. Here, we report that a subset of such genomic regions are resistant to widespread erasure of DNA methylation in mouse embryonic stem cells (mESCs) lacking the de novo DNA methyltransferases (Dnmts) Dnmt3a and Dnmt3b. Intriguingly, these loci are enriched for H3K9me3 in mESCs, implicating this mark in DNA methylation homeostasis. Indeed, deletion of the H3K9 methyltransferase SET domain bifurcated 1 (Setdb1) results in reduced H3K9me3 and DNA methylation levels at specific loci, concomitant with increased 5 hydroxymethylation (5hmC) and ten-eleven translocation 1 binding. Taken together, these data reveal that Setdb1 promotes the persistence of DNA methylation in mESCs, likely reflecting one mechanism by which DNA methylation is maintained at LTR retrotransposons and imprinted genes during developmental stages when DNA methylation is reprogrammed. PMID- 24757057 TI - Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis. AB - The capacity to repair different types of DNA damage varies among individuals, making them more or less susceptible to the detrimental health consequences of damage exposures. Current methods for measuring DNA repair capacity (DRC) are relatively labor intensive, often indirect, and usually limited to a single repair pathway. Here, we describe a fluorescence-based multiplex flow-cytometric host cell reactivation assay (FM-HCR) that measures the ability of human cells to repair plasmid reporters, each bearing a different type of DNA damage or different doses of the same type of DNA damage. FM-HCR simultaneously measures repair capacity in any four of the following pathways: nucleotide excision repair, mismatch repair, base excision repair, nonhomologous end joining, homologous recombination, and methylguanine methyltransferase. We show that FM HCR can measure interindividual DRC differences in a panel of 24 cell lines derived from genetically diverse, apparently healthy individuals, and we show that FM-HCR may be used to identify inhibitors or enhancers of DRC. We further develop a next-generation sequencing-based HCR assay (HCR-Seq) that detects rare transcriptional mutagenesis events due to lesion bypass by RNA polymerase, providing an added dimension to DRC measurements. FM-HCR and HCR-Seq provide powerful tools for exploring relationships among global DRC, disease susceptibility, and optimal treatment. PMID- 24757059 TI - The trouble with (group II) introns. PMID- 24757058 TI - Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. AB - 5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation have not been fully elucidated. Moreover, although the ten-eleven translocation (Tet) family of enzymes is known to be essential for converting methylated DNA to 5-hmC, the role of individual Tet proteins in the adult cortex remains unclear. Using 5-hmC capture together with high-throughput DNA sequencing on individual mice, we show that fear extinction, an important form of reversal learning, leads to a dramatic genome-wide redistribution of 5-hmC within the infralimbic prefrontal cortex. Moreover, extinction learning-induced Tet3-mediated accumulation of 5-hmC is associated with the establishment of epigenetic states that promote gene expression and rapid behavioral adaptation. PMID- 24757060 TI - Poly(epsilon-caprolactone)/keratin-based composite nanofibers for biomedical applications. AB - Keratin-based composite nanofibers have been fabricated by an electrospinning technique. Aqueous soluble keratin extracted from human hair was successfully blended with poly(epsilon-caprolactone) (PCL) in different ratios and transformed into nanofibrous membranes. Toward the potential use of this nanofibrous membrane in tissue engineering, its physicochemical properties, such as morphology, mechanical strength, crystallinity, chemical structure, and integrity in aqueous medium were studied and its cellular compatibility was determined. Nanofibrous membranes with PCL/keratin ratios from 100/00 to 70/30 showed good uniformity in fiber morphology and suitable mechanical properties, and retained the integrity of their fibrous structure in buffered solutions. Experimental results, using cell viability assays and scanning electron microscopy imaging, showed that the nanofibrous membranes supported 3T3 cell viability. The ability to produce blended nanofibers from protein and synthetic polymers represents a significant advancement in development of composite materials with structural and material properties that will support biomedical applications. This provides new nanofibrous materials for applications in tissue engineering and regenerative medicine. PMID- 24757061 TI - A call to action: the development of enteral access safety teams. AB - Safety concerns regarding the verification of nasogastric feeding tube placement prompted the American Society for Parenteral and Enteral Nutrition to call for an interdisciplinary, interorganizational group to work on best practices and new technologies to address this issue in pediatric patients. This commentary calls for the development of specialized teams within hospitals to improve the quality of care provided to children and infants who require nasogastric feeding tubes. It is expands on the information presented in an article in the issue by Irving et al regarding the current status of nasogastric tube placement and verification methods. PMID- 24757062 TI - Lessons Learned From Implementing a Novel Feeding Protocol: Results of a Multicenter Evaluation of Educational Strategies. AB - Background: This study describes the results of an evaluation of educational strategies used to implement a novel enteral feeding protocol in 9 North American intensive care units (ICUs). Materials and Methods: Members of the protocol implementation teams at each ICU distributed a questionnaire to ICU nurses after the implementation of the Enhanced Protein-Energy Provision via the Enteral Route Feeding Protocol in Critically Ill Patients (PEP uP) protocol. Eight different educational strategies were evaluated. Questionnaires were distributed in both paper and electronic format to all nursing staff and used both a visual analog Likert-type scale and open-ended questions. Results: The response rate to the questionnaire was 166 of 434 or 38.2%. More than 70% of respondents rated 5 of the educational strategies as very useful or somewhat useful, including the long PowerPoint presentation at in-services and critical care rounds, the short PowerPoint presentation for 1-on-1 and group bedside teaching, and a self learning module. The percentage of nurses who found the bedside protocol tools of the enteral feeding order set, gastric feeding flowchart, and volume-based feeding schedule either "very easy" or "somewhat easy" to use were 64.0%, 60.5%, and 59.1%, respectively. Conclusion: The use of multiple teaching formats, including the long and short PowerPoint presentations and self-teaching module, appeared to meet the learning needs of most of the group. The majority of the bedside tools developed to facilitate the implementation of the PEP uP protocol were considered easy to use. PMID- 24757063 TI - Integrating the "conversation ready" initiative into nutrition practice. PMID- 24757064 TI - Redox-controlled hydrogen bonding: turning a superbase into a strong hydrogen bond donor. AB - Herein the synthesis, structures and properties of hydrogen-bonded aggregates involving redox-active guanidine superbases are reported. Reversible hydrogen bonding is switched on by oxidation of the hydrogen-donor unit, and leads to formation of aggregates in which the hydrogen-bond donor unit is sandwiched by two hydrogen-bond acceptor units. Further oxidation (of the acceptor units) leads again to deaggregation. Aggregate formation is associated with a distinct color change, and the electronic situation could be described as a frozen stage on the way to hydrogen transfer. A further increase in the basicity of the hydrogen-bond acceptor leads to deprotonation reactions. PMID- 24757065 TI - 1H NMR based metabolic profiling in Crohn's disease by random forest methodology. AB - The present study was designed to search for metabolic biomarkers and their correlation with serum zinc in Crohn's disease patients. Crohn's disease (CD) is a form of inflammatory bowel disease that may affect any part of the gastrointestinal tract and can be difficult to diagnose using the clinical tests. Thus, introduction of a novel diagnostic method would be a major step towards CD treatment. Proton nuclear magnetic resonance spectroscopy ((1)H NMR) was employed for metabolic profiling to find out which metabolites in the serum have meaningful significance in the diagnosis of CD. CD and healthy subjects were correctly classified using random forest methodology. The classification model for the external test set showed a 94% correct classification of CD and healthy subjects. The present study suggests Valine and Isoleucine as differentiating metabolites for CD diagnosis. These metabolites can be used for screening of risky samples at the early stages of CD diagnoses. Moreover, a robust random forest regression model with good prediction outcomes was developed for correlating serum zinc level and metabolite concentrations. The regression model showed the correlation (R(2)) and root mean square error values of 0.83 and 6.44, respectively. This model suggests valuable clues for understanding the mechanism of zinc deficiency in CD patients. PMID- 24757066 TI - Editor's note. PMID- 24757067 TI - Using intravoxel incoherent motion MR imaging to evaluate cortical defects in the first episode of upper urinary tract infections: preliminary results. AB - PURPOSE: To compare intravoxel incoherent motion diffusion weight imaging IVIM DWI MRI with DMSA for the evaluation of cortical defect in pediatric upper urinary tract infection (UTI) patients. MATERIALS AND METHODS: Forty-three kidneys of 22 pediatric patients with the first episode of febrile upper UTI were evaluated. DWI using IVIM model was performed with eight b factors. The presence of cortical defect was evaluated on apparent diffusion coefficient (ADC) map. DMSA was used as the standard of reference. ADC, true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (F) in both defect and nondefect area were calculated and compared. RESULTS: Cortical defects were detected in 14 kidneys by IVIM-DWI. The sensitivity, specificity, positive predictive value, and negative predictive value of IVIM-DWI MRI for the detection of defects was 93.3%, 100%, 100%, and 96.5%, respectively. Mean values of ADC, D, D*, and F were 1.12 +/- 0.15, 1.05 +/- 0.10, 33 +/- 17 (* 10(-3) mm(2) /s), and 0.14 +/- 0.09 in the defect foci. In normal foci, ADC, D, D*, and F were 1.37 +/- 0.09, 1.31 +/- 0.10, 43 +/- 19 (* 10(-3) mm(2) /s), and 0.12 +/- 0.04, respectively. ADC and D were significantly lower in defect group than nondefect group (P < 0.01). CONCLUSION: IVIM-DWI can allow both direct visualization and quantitative measurement of cortical defects. PMID- 24757068 TI - Impact of the model-building strategy on inference about nonlinear and time dependent covariate effects in survival analysis. AB - Cox's proportional hazards (PH) model assumes constant-over-time covariate effects. Furthermore, most applications assume linear effects of continuous covariates on the logarithm of the hazard. Yet, many prognostic factors have time dependent (TD) and/or nonlinear (NL) effects, that is, violate these conventional assumptions. Detection of such complex effects could affect prognosis and clinical decisions. However, assessing the effects of each of the multiple, often correlated, covariates in flexible multivariable analyses is challenging. In simulations, we investigated the impact of the approach used to build the flexible multivariable model on inference about the TD and NL covariate effects. Results demonstrate that the conclusions regarding the statistical significance of the TD/NL effects depend heavily on the strategy used to decide which effects of the other covariates should be adjusted for. Both a failure to adjust for true TD and NL effects of relevant covariates and inclusion of spurious effects of covariates that conform to the PH and linearity assumptions increase the risk of incorrect conclusions regarding other covariates. In this context, iterative backward elimination of nonsignificant NL and TD effects from the multivariable model, which initially includes all these effects, may help discriminate between true and spurious effects. The practical importance of these issues was illustrated in an example that reassessed the predictive ability of selected biomarkers for survival in advanced non-small-cell lung cancer. In conclusion, a careful model-building strategy and flexible modeling of multivariable survival data can yield new insights about predictors' roles and improve the validity of analyses. PMID- 24757069 TI - Generation of basic centers in high-silica zeolites and their application in gas phase upgrading of bio-oil. AB - High-silica zeolites have been reported recently as efficient catalysts for liquid- and gas-phase condensation reactions because of the presence of a complementary source of basicity compared to Al-rich basic zeolites. Herein, we describe the controlled generation of these active sites on silica-rich FAU, BEA, and MFI zeolites. Through the application of a mild base treatment in aqueous Na2CO3, alkali-metal-coordinating defects are generated within the zeolite whereas the porous properties are fully preserved. The resulting catalysts were applied in the gas-phase condensation of propanal at 673 K as a model reaction for the catalytic upgrading of pyrolysis oil, for which an up to 20-fold increased activity compared to the unmodified zeolites was attained. The moderate basicity of these new sites leads to a coke resistance superior to traditional base catalysts such as CsX and MgO, and comparable activity and excellent selectivity is achieved for the condensation pathways. Through strategic acid and base treatments and the use of magic-angle spinning NMR spectroscopy, the nature of the active sites was investigated, which supports the theory of siloxy sites as basic centers. This contribution represents a key step in the understanding and design of high-silica base catalysts for the intermediate deoxygenation of crude bio-oil prior to the hydrotreating step for the production of second generation biofuels. PMID- 24757070 TI - Transition-metal-free BF3-mediated oxidative and non-oxidative cross-coupling of pyridines. AB - We report a BF3-mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross-coupling). Moreover, we have developed a novel transition-metal-free cross-coupling method between alkylmagnesium reagents and 4-substituted pyridines, such as isonicotinonitrile and 4-chloropyridine, by employing BF3?OEt2 as a promoter. The combination of these methods enabled us to efficiently prepare a range of di-, tri-, and tetrasubstituted pyridines. PMID- 24757071 TI - Partially degradable friction-welded pure iron-stainless steel 316L bone pin. AB - This article describes the development of a partially degradable metal bone pin, proposed to minimize the occurrence of bone refracture by avoiding the creation of holes in the bone after pin removal procedure. The pin was made by friction welding and composed of two parts: the degradable part that remains in the bone and the nondegradable part that will be removed as usual. Rods of stainless steel 316L (nondegradable) and pure iron (degradable) were friction welded at the optimum parameters: forging pressure = 33.2 kPa, friction time = 25 s, burn-off length = 15 mm, and heat input = 4.58 J/s. The optimum tensile strength and elongation was registered at 666 MPa and 13%, respectively. A spiral defect formation was identified as the cause for the ductile fracture of the weld joint. A 40-um wide intermetallic zone was identified along the fusion line having a distinct composition of Cr, Ni, and Mo. The corrosion rate of the pin gradually decreased from the undeformed zone of pure iron to the undeformed zone of stainless steel 316L. All metallurgical zones of the pin showed no toxic effect toward normal human osteoblast cells, confirming the ppb level of released Cr and Ni detected in the cell media were tolerable. PMID- 24757072 TI - Synthesis and properties of semiconducting bispyrrolothiophenes for organic field effect transistors. AB - A series of new highly soluble bispyrrolothiophenes were synthesized from vinyl azides by using transition-metal-catalyzed C-H-bond functionalization. In addition to modifying the substituents present on the end-pyrrolothiophene moieties, the arene linker in between the two units was also varied. The solution state properties and field-effect-transistor (FET) electrical behavior of these bispyrrolothiophenes was compared. Our investigations identified that the optical properties and oxidation potential of our compounds were dominated by the pyrrolothiophene unit with a lambdamax value of approximately 400 nm and oxidation at approximately 1 V. FET devices constructed with thin films of these bispyrrolothiophenes were also fabricated by means of thin-film solution processing. One of these compounds, a bispyrrolothiophene linked with benzothiodiazole, exhibits a mobility of approximately 0.3 cm(2) V(-1) s(-1) and the Ion/Ioff value is greater than 10(6). PMID- 24757073 TI - Electron spin resonance (ESR/EPR) of free radicals observed in human red hair: a new, simple empirical method of determination of pheomelanin/eumelanin ratio in hair. AB - The definition of the concentration of pheomelanin in the skin is an issue of great interest because in the case of being influenced by UV radiation, it manifests itself as a prooxidant, causing various skin disorders including melanoma that might help to explain the relatively high incidence of skin cancer among individuals with red hair. The ESR spectra of red hair samples were investigated. It was found that at low microwave power, they are characterized by two types of spectra. Red hair ESR signals result from a superposition of two spectral shapes, a singlet spectrum as a result of the existence of eumelanin and a triplet spectrum as a result of the existence of pheomelanin. At high microwave power, only triplet spectra shape was detected, caused by saturation of the eumelanin singlet. Using different concentration ratios of black to red hair, we measured ESR spectra and plotted the ratio values in each sample against a measured 'g-factor' (experimental). We found that there is a linear relationship between these two parameters. So, it is evident that using these results, the concentration ratio of pheomelanin to eumelanin in a sample of hair can be easily determined by an almost noninvasive method. This can be considered a potential advantage for many practical activities compared with other invasive methods. The concentration dependence curve of pheomelanin (ug/mg) on gexp-factor in an ESR spectrum of hair has been designed, which allows the determination of the amount of pheomelanin in hair of any color. PMID- 24757074 TI - Reply: To PMID 22504829. PMID- 24757075 TI - Risk of retinal tear or detachment with oral fluoroquinolone use: a cohort study. AB - PURPOSE: The aim of this study is to determine if oral fluoroquinolone exposure is associated with an increased hazard for having a retinal tear or detachment. METHODS: A retrospective cohort study was performed using individuals who met inclusion criteria from The Health Improvement Network database. Cohorts were created for individuals who had a prescription written for either an oral fluoroquinolone or an oral beta-lactam antibiotic (comparison group). Subjects were excluded if they had a previous diagnosis of a retinal tear or detachment (hereafter retinal break (RB)), or a procedure code to treat an RB, where in the practice for less than 365 days, had a previous prescription for either antibiotic within 365 days of the index date or had intraocular surgery or a diagnosis of endophthalmitis within 90 days prior to the antibiotic prescription. Covariates of interest were age, gender, diabetes, and year of index. The primary outcome measure of interest was the hazard ratio (HR) of undergoing a procedure to treat an RB within 7, 30, 90, or 365 days after exposure to an oral fluoroquinolone prescription versus an oral beta-lactam prescription. RESULTS: After exclusions, 6,604,423 prescriptions (290,393 fluoroquinolone; 6,314,030 beta-lactam) from 3,413,498 patients (247,073 fluoroquinolone; 3,303,641 beta lactam) and 2685 RB procedures were eligible for analysis (661 retinal tears and 2024 retinal detachments). For fluoroquinolones, 0, 1, 5, and 23 RBs occurred at the 7-, 30-, 90-, and 365-day time points, respectively. For beta-lactam prescriptions, 7, 28, 87, and 373 RBs occurred at the 7-, 30-, 90-, and 365-day time points, respectively. Because of zero events occurring in the fluoroquinolone cohort during the 7-day observation period, an unadjusted or an adjusted HR (and subsequent p-value or confidence intervals) was unable to be calculated. Univariate and multivariate analyses demonstrated that fluoroquinolones were not significantly associated with RB in the 30-, 90-, or 365-day observation periods (30-day HR = 0.78, p = 0.80, 95%CI: 0.11, 5.71; 90 day HR = 1.25, p = 0.63, 95%CI: 0.51, 3.08; and 365-day HR = 1.35, p = 0.16, 95%CI: 0.89, 2.06). CONCLUSIONS: Our results do not support an association between oral fluoroquinolone use and subsequent procedures to treat an RB. PMID- 24757076 TI - Age of Bioterrorism: Are You Prepared? Review of Bioweapons and Their Clinical Presentation for Otolaryngologists. AB - OBJECTIVES: This review on Category A bioweapons is intended to help otolaryngologists (1) understand the concepts of bioterrorism, (2) identify a bioterrorism attack, and (3) recognize specific otolaryngologic symptoms and signs of Category A bioweapons. DATA SOURCES: PubMed and Medline databases. REVIEW METHODS: Review of current literature regarding Category A agents of biological warfare and their relationships to otolaryngology was performed using PubMed, Medline, and articles written by experts in the field of bioterrorism. Each Category A agent was paired with the term otolaryngology and then paired with epistaxis, sinusitis, airway obstruction, pharyngitis, tonsillitis, hearing loss, otitis media, and lymphadenopathy individually. For the latest accepted treatment and diagnostic strategies, bioterrorism was searched with filters for human studies, English language, and the past 5 years. Titles, abstracts, and papers were read for relevancy. CONCLUSION: While the use of bioweapons initially leads to nonspecific symptoms, a high index of suspicion and clustering of abnormal pathology will often lead the astute physician to the correct diagnosis of bioweapons. Some disease presentations of Category A agents (anthrax, smallpox, tularemia, botulism, plague, hemorrhagic fever) will involve the realm of otolaryngology. IMPLICATIONS FOR PRACTICE: The head and neck manifestations of a Category A bioweapon attack will require knowledgeable otolaryngologists for prompt diagnosis, treatment, and notification of public authorities. This will help decrease the morbidity and mortality of any potential bioterrorism attack. PMID- 24757077 TI - Step-up testing procedure for multiple comparisons with a control for a latent variable model with ordered categorical responses. AB - In clinical studies, multiple comparisons of several treatments to a control with ordered categorical responses are often encountered. A popular statistical approach to analyzing the data is to use the logistic regression model with the proportional odds assumption. As discussed in several recent research papers, if the proportional odds assumption fails to hold, the undesirable consequence of an inflated familywise type I error rate may affect the validity of the clinical findings. To remedy the problem, a more flexible approach that uses the latent normal model with single-step and stepwise testing procedures has been recently proposed. In this paper, we introduce a step-up procedure that uses the correlation structure of test statistics under the latent normal model. A simulation study demonstrates the superiority of the proposed procedure to all existing testing procedures. Based on the proposed step-up procedure, we derive an algorithm that enables the determination of the total sample size and the sample size allocation scheme with a pre-determined level of test power before the onset of a clinical trial. A clinical example is presented to illustrate our proposed method. PMID- 24757078 TI - Palladium and gold nanotubes as oxygen reduction reaction and alcohol oxidation reaction catalysts in base. AB - Palladium (PdNTs) and gold nanotubes (AuNTs) were synthesized by the galvanic displacement of silver nanowires. PdNTs and AuNTs have wall thicknesses of 6 nm, outer diameters of 60 nm, and lengths of 5-10 and 5-20 MUm, respectively. Rotating disk electrode experiments showed that the PdNTs and AuNTs have higher area normalized activities for the oxygen reduction reaction (ORR) than conventional nanoparticle catalysts. The PdNTs produced an ORR area activity that was 3.4, 2.2, and 3.7 times greater than that on carbon-supported palladium nanoparticles (Pd/C), bulk polycrystalline palladium, and carbon-supported platinum nanoparticles (Pt/C), respectively. The AuNTs produced an ORR area activity that was 2.3, 9.0, and 2.0 times greater than that on carbon-supported gold nanoparticles (Au/C), bulk polycrystalline gold, and Pt/C, respectively. The PdNTs also had lower onset potentials than Pd/C and Pt/C for the oxidation of methanol (0.236 V), ethanol (0.215 V), and ethylene glycol (0.251 V). In comparison to Pt/C, the PdNTs and AuNTs further demonstrated improved alcohol tolerance during the ORR. PMID- 24757079 TI - Stereocontrolled synthesis of adjacent acyclic quaternary-tertiary motifs: application to a concise total synthesis of (-)-filiformin. AB - Lithiation/borylation methodology has been developed for the synthesis of acyclic quaternary-tertiary motifs with full control of relative and absolute stereochemistry, thus leading to all four possible isomers of a stereodiad. A novel intramolecular Zweifel-type olefination enabled acyclic stereocontrol to be transformed into cyclic stereocontrol. These key steps have been applied to the shortest enantioselective synthesis of (-)-filiformin to date (9 steps) with full stereocontrol. PMID- 24757080 TI - Intermolecular and regioselective access to polysubstituted benzo- and dihydrobenzo[c]azepine derivatives: modulating the reactivity of group 6 non heteroatom-stabilized alkynyl carbene complexes. AB - We highlight the versatility of non-heteroatom-stabilized tungsten-carbene complexes 3 synthesized in situ, which have been used in a modular approach to access 2-benzazepinium isolable intermediates 5. By employing very mild conditions, benzazepinium derivatives 5 have been obtained in high yield from simple compounds, such as acetylides 2, Fischer-type alkoxycarbenes 1, and phenylimines 4. The process, involving a formal [4+3] heterocycloaddition, occurs in a totally regioselective manner, which differs from the approach previously observed in similar procedures for other carbene analogues. This work, which involves three components, reveals a control of the reactivity of non-heteroatom stabilized carbene complexes 3 ([4+3] vs. [2+2]-heterocycloaddition reactions) depending on the acetylide substitution pattern. The influence of the substitution pattern in the behavior of the complexes has been computationally analyzed and rationalized. Finally, elaboration of the 2-benzazepinium intermediates allows access to 3H-benzo[c]azepines 6 and 3H-1,2 dihydrobenzo[c]azepines 7-9 with high control of the substitution of the nine positions of the heterocycle. PMID- 24757081 TI - On-line determination of 4-nitrophenol by combining molecularly imprinted solid phase extraction and fiber-optic spectrophotometry. AB - In the present paper, we describe a new on-line SPE system where molecular imprinting, fiber-optic detection and flow injection analysis were combined for the first time. This new system has been applied for the on line detection of 4 nitrophenol (4-NP). Initially, molecularly imprinted polymers (MIP) have been prepared for the selective extraction of 4-NP using 4-vinylpyridine and ethylene glycol dimethacrylate as functional and cross-linking monomers, respectively. Selective extraction was achieved using the designed MIP with 97% of recovery on imprinted polymer and 10% on control polymer. The system provided a high degree of accuracy, with RSDs varying between 0.7 and 1.39%. In respect of accuracy, reproducibility, and rapidity, this system is comparable with HPLC. In short, the system allows simple, fast, and accurate analyte determination with the possibility of future automation. PMID- 24757082 TI - Acetone-induced polymerisation of 3-aminopropyltrimethoxysilane (APTMS) as revealed by NMR spectroscopy. AB - We followed the reactivity of acetone with 3-aminopropyltrimethoxysilane, a potential organosilane coupling agent, by (1)H, (13)C and (29)Si NMR spectroscopy. Selective 1D and 2D-edited NMR experiments significantly contributed to simplify the spectral complexity of reaction solution and elucidated molecular structures within progressive reaction phases. The course of the 3-aminopropyltrimethoxysilane reaction with acetone was shown by a progressive decrease of both reactants, and a concomitant appearance of water and methanol, due to formation of imine and hydrolysis of alkoxysilane groups, respectively. The occurrence of multiple siloxane linkages in a progressively larger cross-linked macromolecular structure was revealed by DOSY-NMR experiments and new signals in (29)Si-NMR spectra at different reaction times. The NMR approach described here may be applied to investigate the reactivity of other gamma-aminopropylalkoxysilanes and contribute to define procedures for the preparation of silica-based materials. PMID- 24757083 TI - Systemic lupus erythematosus prevalence in Sweden in 2010: what do national registers say? AB - OBJECTIVE: Worldwide prevalence estimates of systemic lupus erythematosus (SLE) range from 3 to 207 per 100,000, depending on region and population, SLE definition, case sources, and other methodologic considerations. We aimed to determine the prevalence of SLE in Sweden on January 1, 2010, using population based registers. METHODS: Linking multiple national registers, we identified all possible inpatient and outpatient visits with SLE-specific discharge diagnoses and relevant prescription dispensations among living individuals registered in Sweden on January 1, 2010. SLE was defined from a lenient classification (requiring only a single visit) to stricter definitions that required multiple visits with a history of relevant specialist care and a dispensation for common SLE medications. Prevalence was calculated overall and by sex, age (0-14 years, 15-49 years, and >=50 years, as well as in 5-year age groups), and county of residence. RESULTS: Overall prevalence ranged from 46 per 100,000 for the strictest definition to 85 per 100,000 for the least strict definition. As expected, SLE was more common among females (range 79-144 per 100,000) than males (range 12-25 per 100,000) and varied by age. The up to 4-fold variation by county was unexpected. Prevalence generally increased with age (2, 52, and 95 per 100,000 by increasing age group, 0-14 years, 15-49 years, and >=50 years, respectively, using a moderately strict definition) and also varied by county. CONCLUSION: Variations of prevalence by age and sex were consistent with previous studies and overall ranged from 46 to 85 per 100,000. We observed a surprising geographic variation in the prevalence of SLE in Sweden on January 1, 2010, according to multiple definitions. PMID- 24757084 TI - The efficacy and safety of ivabradine hydrochloride versus atenolol in Chinese patients with chronic stable angina pectoris. AB - PURPOSE: The aim of this study was to assess the efficacy and safety of ivabradine (Iva) noninferiority to atenolol (Aten) in Chinese patients with chronic stable angina pectoris. METHODS: In this double-blind, double-dummy trial, patients with symptomatic angina pectoris and positive exercise tolerance test were randomized into the Iva [5 or 7.5 mg bis in die (BID)] or Aten group (12.5 or 25 mg BID) according to computer-generated random numbers for 12 weeks. RESULTS: One hundred and sixty-eight patients were randomized to the Iva group and 166 to the Aten group. In a full analysis set, increases in the total exercise duration (TED) were 54.3 +/- 120.1 seconds with Iva 5 mg and 58.8 +/- 114.7 seconds with Aten 12.5 mg at the fourth week, and at the 12th week, TED improved by 84.1 +/- 130.5 seconds with Iva and 77.8 +/- 126.6 seconds with Aten (95%CI: -21.4-34.1 seconds, p = 0.0011 for noninferiority). The analysis of per protocol set yielded similar results (95%CI: -31.4-33.0 seconds, p = 0.0131 for noninferiority). Heart rate was reduced in both groups at rest and during peak exercise. There were small, nonsignificant differences in the number of adverse events between the two groups (66 in Iva and 73 in Aten, p > 0.05). Nine patients (5.42%) were reported to develop phosphenes/luminous phenomena and blurred vision in the Iva group (p = 0.0035). CONCLUSIONS: Iva is effective in reducing heart rates and improving exercise capacity and noninferior to Aten in Chinese patients with chronic stable angina pectoris. Iva is well tolerated and safe. PMID- 24757085 TI - Clinical features, outcome, and prognostic factors for survival and evolution to multiple myeloma of solitary plasmacytomas: a report of the Greek myeloma study group in 97 patients. AB - Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary plasma cell tumors. The treatment of choice is local radiotherapy (R/T) +/- surgical excision. The role of adjuvant chemotherapy (C/T) or novel agents (NA) is uncertain. Data related to prognostic factors are inconclusive. Herein, we describe the clinical features, survival and prognosis of 97 consecutive patients, 65 with bone SP (SBP), and 32 with extramedullary SP (SEP), diagnosed and treated in 12 Greek Myeloma Centers. Objective response rate (>=PR) and complete response (CR) was 91.8% and 61.9%, respectively, and did not differ between the 2 groups. Overall, 38 patients relapsed or progressed to multiple myeloma (MM). After a median follow-up of 60 months, 5 and 10-year overall survival (OS) probability was 92% and 89% in SEP and 86% and 69% in SBP, respectively (P = 0.2). The 5- and 10-year MM-free survival (MMFS) probability was 90% and 70% for patients with SEP vs. 59% and 50% for patients with SBP, respectively (P = 0.054). Overall, the 5- and 10-year OS probability, plasmacytoma relapse-free survival (PRFS), progression-free survival and MMFS was 84% and 78%, 72% and 58%, 58% and 43%, and 70% and 59%, respectively. In the multivariate analysis, prolonged PRFS and young age were positive predictors of OS. Achievement of CR was the only positive predictor of PRFS. Immunoparesis was the only negative predictor of progression to MM. The addition of C/T or NA-based treatment increased toxicity without offering any survival advantage over R/T. PMID- 24757086 TI - Molybdenum carbide as a highly selective deoxygenation catalyst for converting furfural to 2-methylfuran. AB - Selectively cleaving the C=O bond outside the furan ring of furfural is crucial for converting this important biomass-derived molecule to value-added fuels such as 2-methylfuran. In this work, a combination of density functional theory (DFT) calculations, surface science studies, and reactor evaluation identified molybdenum carbide (Mo2 C) as a highly selective deoxygenation catalyst for converting furfural to 2-methylfuran. These results indicate the potential application of Mo2 C as an efficient catalyst for the selective deoxygenation of biomass-derived oxygenates including furanics and aromatics. PMID- 24757087 TI - Heterolytic cleavage of hydrogen by an iron hydrogenase model: an Fe-H???H-N dihydrogen bond characterized by neutron diffraction. AB - Hydrogenase enzymes in nature use hydrogen as a fuel, but the heterolytic cleavage of H-H bonds cannot be readily observed in enzymes. Here we show that an iron complex with pendant amines in the diphosphine ligand cleaves hydrogen heterolytically. The product has a strong Fe-H???H-N dihydrogen bond. The structure was determined by single-crystal neutron diffraction, and has a remarkably short H???H distance of 1.489(10) A between the protic N-H(delta+) and hydridic Fe-H(delta-) part. The structural data for [Cp(C5F4N)FeH(P(tBu)2N(tBu)2H)](+) provide a glimpse of how the H-H bond is oxidized or generated in hydrogenase enzymes. These results now provide a full picture for the first time, illustrating structures and reactivity of the dihydrogen complex and the product of the heterolytic cleavage of H2 in a functional model of the active site of the [FeFe] hydrogenase enzyme. PMID- 24757088 TI - Social interactions and malaria preventive behaviors in sub-saharan Africa. AB - This paper examines the existence of social interactions in malaria preventive behaviors in Sub-Saharan Africa, that is, whether an individual's social environment has an influence on the individual's preventive behaviors. We focus on the two population groups which are the most vulnerable to malaria (children under 5 years and pregnant women) and on two preventive behaviors (sleeping under a bednet and taking intermittent preventive treatment during pregnancy). We define the social environment of the individual as people living in the same region. To detect social interactions, we calculate the size of the social multiplier by comparing the effects of an exogenous variable at individual and regional levels. Our data come from 92 surveys for 29 Sub-Saharan countries between 1999 and 2012, and they cover approximately 660,000 children and 95,000 women. Our results indicate that there are social interactions in malaria preventive behaviors in the form of social multipliers effects of women's education and household wealth. The long-run effects of these characteristics on preventive behaviors at the regional level are larger than those apparent at the individual level. PMID- 24757089 TI - Regulating Schwann cells growth by chitosan micropatterning for peripheral nerve regeneration in vitro. AB - To address the effect of chitosan micropatterning on nerve regeneration, two sizes of parallel microstripes of chitosan are fabricated on the surface of coverslips using a micromodeling method. The morphology of the prepared polydimethylsiloxane stamps and chitosan micropatterning is observed by scanning electron microscopy and the wettability of the prepared micropatterning is evaluated using water contact-angle measurements. Schwann cell (SC) culture is used to evaluate the effect of chitosan micropatterning on cell behavior. The results show that the stripe-like chitosan micropatterning can be successfully fabricated on coverslip surfaces. SCs on 30/30 MUm chitosan micropatterning shows the most obvious cell orientation. Moreover, the secretion of nerve growth factor by SCs indicate that the chitosan micropatterning has no negative influence on the normal physiological function of the cells. Thus, the study suggests that chitosan micropatterning can induce and regulate the growth of SCs well, which may have potential application in peripheral nerve regeneration. PMID- 24757090 TI - Sustainable heterogeneous platinum catalyst for direct methylation of secondary amines by carbon dioxide and hydrogen. AB - Pt and MoO(x) co-loaded TiO2 is found to be highly effective for direct methylation of aliphatic and aromatic secondary amines by CO2 and H2 under solvent-free conditions. This is the first additive-free and reusable heterogeneous catalytic system with acceptable turnover number. PMID- 24757091 TI - Who decides if research will be published, authors or sponsors? Comment on the article by Curtis et al. PMID- 24757092 TI - Lenalidomide-based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients. AB - A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro inflammatory cytokine present at high levels within patients, can induce TNF receptor-2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune-surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL-2 and IFNgamma production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome. PMID- 24757094 TI - Recurrent sepsis post-cardiac device removal. PMID- 24757095 TI - Paget's disease of bone. AB - Paget's disease of bone is a common disorder characterized by increased but disorganized bone remodelling. Some patients are asymptomatic but others present with bone pain or other complications such as fracture and deformity. Major advances have been made in understanding the pathophysiology of Paget's disease in recent years and highly effective agents are now available with which to suppress the abnormal bone turnover that causes the disease. Here we review recent advances in the epidemiology, pathogenesis, clinical features and management of Paget's disease. We also reflect upon the future challenges that remain to be overcome to explain the unusual distribution of the disease and to favourably alter the natural history and prevent the development of complications. PMID- 24757096 TI - Nocardia brain abscess. PMID- 24757097 TI - Vascular manifestations and post-treatment changes of epidermal nevus syndrome. PMID- 24757098 TI - Combination of carbon nitride and carbon nanotubes: synergistic catalysts for energy conversion. AB - Due to their versatile features and environmental friendliness, functionalized carbon materials show great potential in practical applications, especially in energy conversion. Developing carbon composites with properties that can be modulated by simply changing the ratio of the original materials is an intriguing synthetic strategy. Here, we took cyanamide and multiwalled carbon nanotubes as precursors and introduced a facile method to fabricate a series of graphitic carbon nitride/carbon nanotubes (g-C3 N4 /CNTs) composites. These composites demonstrated different practical applications with different weight ratios of the components, that is, they showed synergistic effects in optoelectronic conversion when g-C3 N4 was the main ingredient and in oxygen reduction reaction (ORR) when CNTs dominated the composites. Our experiments indicated that the high electrical conductivity of carbon nanotubes promoted the transmission of the charges in both cases. PMID- 24757099 TI - Inverse peptide synthesis via activated alpha-aminoesters. AB - A mild, practical, and simple procedure for peptide-bond formation is reported. Instead of activation of the carboxylic acid functionality, the reaction involves an unprecedented use of activated alpha-aminoesters. The method provides a straightforward entry to dipeptides and was effective when a sensitive cysteine residue was used, as no epimerization was detected in this case. The applicability of this method to iterative peptide synthesis was illustrated by the synthesis of a model tetrapeptide in the challenging reverse N->C direction. PMID- 24757100 TI - Identification and localization of two sensory neuron membrane proteins from Spodoptera litura (Lepidoptera: Noctuidae). AB - Sensory neuron membrane proteins (SNMPs), which are located on the dendritic membrane of olfactory sensory neurons (OSNs), are proposed to be associated with odor reception in insects. Recent studies have demonstrated that SNMP1 is essential for electrophysiological responses of OSNs to the sex pheromone, cis vaccenyl acetate (cVA) in Drosophila melanogaster. To investigate the function of Lepidoptera SNMPs, we cloned two SNMP genes, SlituSNMP1 and SltiuSNMP2, from Spodoptera litura (Lepidoptera: Noctuidae). Sequence alignment and phylogenetic analysis showed that both genes bear the general characteristics of SNMPs, including six conserved cysteine residues and two transmembrane domains. Further expression profile experiments showed that SlituSNMP1 is mainly expressed in the antenna, while SlituSNMP2 is broadly expressed in various tissues. By in situ hybridization experiments, it was found that SlituSNMP1 expressing cells are surrounded by the SlituSNMP2 expressing cells in the pheromone sensitive sensilla, suggesting different functions of the two SNMPs in insect olfaction. PMID- 24757101 TI - Thermal ethane activation by bare [V2O5]+ and [Nb2O5]+ cluster cations: on the origin of their different reactivities. AB - The gas-phase reactivity of [V2O5](+) and [Nb2O5](+) towards ethane has been investigated by means of mass spectrometry and density functional theory (DFT) calculations. The two metal oxides give rise to the formation of quite different reaction products; for example, the direct room-temperature conversions C2H6 >C2H5OH or C2H6->CH3CHO are brought about solely by [V2O5](+). In distinct contrast, for the couple [Nb2O5](+)/C2H6, one observes only single and double hydrogen-atom abstraction from the hydrocarbon. DFT calculations reveal that different modes of attack in the initial phase of C-H bond activation together with quite different bond-dissociation energies of the M-O bonds cause the rather varying reactivities of [V2O5](+) and [Nb2O5](+) towards ethane. The gas-phase generation of acetaldehyde from ethane by bare [V2O5](+) may provide mechanistic insight in the related vanadium-catalyzed large-scale process. PMID- 24757102 TI - Geomagnetic storms can trigger stroke: evidence from 6 large population-based studies in Europe and Australasia. AB - BACKGROUND AND PURPOSE: Although the research linking cardiovascular disorders to geomagnetic activity is accumulating, robust evidence for the impact of geomagnetic activity on stroke occurrence is limited and controversial. METHODS: We used a time-stratified case-crossover study design to analyze individual participant and daily geomagnetic activity (as measured by Ap Index) data from several large population-based stroke incidence studies (with information on 11 453 patients with stroke collected during 16 031 764 person-years of observation) in New Zealand, Australia, United Kingdom, France, and Sweden conducted between 1981 and 2004. Hazard ratios and corresponding 95% confidence intervals (CIs) were calculated. RESULTS: Overall, geomagnetic storms (Ap Index 60+) were associated with 19% increase in the risk of stroke occurrence (95% CI, 11%-27%). The triggering effect of geomagnetic storms was most evident across the combined group of all strokes in those aged <65 years, increasing stroke risk by >50%: moderate geomagnetic storms (60-99 Ap Index) were associated with a 27% (95% CI, 8%-48%) increased risk of stroke occurrence, strong geomagnetic storms (100-149 Ap Index) with a 52% (95% CI, 19%-92%) increased risk, and severe/extreme geomagnetic storms (Ap Index 150+) with a 52% (95% CI, 19%-94%) increased risk (test for trend, P<2*10(-16)). CONCLUSIONS: Geomagnetic storms are associated with increased risk of stroke and should be considered along with other established risk factors. Our findings provide a framework to advance stroke prevention through future investigation of the contribution of geomagnetic factors to the risk of stroke occurrence and pathogenesis. PMID- 24757103 TI - N-terminal pro-B-type natriuretic peptide and stroke risk: the reasons for geographic and racial differences in stroke cohort. AB - BACKGROUND AND PURPOSE: Improved identification of those at risk of stroke might improve prevention. We evaluated the association of the cardiac function biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) with stroke risk in the 30 239 black and white participants of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. METHODS: During 5.4 years of follow-up after enrollment in 2003 to 2007, NT-proBNP was measured in baseline blood samples of 546 subjects with incident ischemic stroke and 956 without stroke. RESULTS: NT-proBNP was higher with older age and in those with heart disease, kidney disease, atrial fibrillation, and lower low-density lipoprotein cholesterol. Adjusting for age, race, sex, income, education, and traditional stroke risk factors, there was an increased risk of stroke across quartiles of NT proBNP; participants with NT-proBNP in the top versus the bottom quartile had a hazard ratio of 2.9 (95% confidence interval, 1.9-4.5). There was no impact of added adjustment for kidney function and heart failure. Among pathogenetic stroke subtypes, the association was largest for cardioembolic stroke, with a hazard ratio of 9.1 (95% confidence interval, 2.9-29.2). Associations did not differ by age, sex, or race, or after excluding those with baseline heart failure or atrial fibrillation. Predicted stroke risk was more accurate in 27% of participants if NT-proBNP was considered after traditional stroke risk factors (P<0.001). CONCLUSIONS: NT-proBNP was a major independent risk marker for stroke. Considering this and other data for stroke, coronary disease, and atrial fibrillation, the clinical use of NT-proBNP measurement in primary prevention settings should be considered. PMID- 24757104 TI - Delayed hyperbaric oxygen therapy promotes neurogenesis through reactive oxygen species/hypoxia-inducible factor-1alpha/beta-catenin pathway in middle cerebral artery occlusion rats. AB - BACKGROUND AND PURPOSE: Hyperbaric oxygen (HBO) has been reported to be neuroprotective and to improve neurofunctional outcomes in acute stroke. However, it is not clear whether delayed HBO enhances endogenous neurogenesis and promotes neurofunctional recovery. The aim of this study is to evaluate the effects of delayed HBO therapy on neurogenesis and its potential mechanisms. METHODS: One hundred eleven male Sprague-Dawley rats that survived for 7 days from 2 hours of middle cerebral artery occlusion and reperfusion were used. Delayed and multiple HBO were administrated beginning at 7 days after middle cerebral artery occlusion and lasting for 42 days with 3 HBO-free intervals (5 days each). Motor sensory deficits were measured by foot-fault test, and learning and memory abilities were evaluated by Morris water maze. Neurogenesis was examined by double immunostaining of bromodeoxyuridine and doublecortin, bromodeoxyuridine and neuronal nuclei at day 42. For mechanism studies, inhibitors for reactive oxygen species (ROS), hypoxia-inducible factor (HIF)-1alpha, and beta-catenin were administrated, and the levels of ROS, HIF-1alpha, beta-catenin, lymphoid enhancer binding factor-1, T-cell factor-1, neurogenin-1, doublecortin, and synapsin-1 were assessed by ELISA or Western blot at day 14. RESULTS: Delayed HBO treatment promoted neurogenesis and improved neurofunctional recovery at day 42, and the improvements were reversed by inhibition of ROS and HIF-1alpha. Delayed HBO significantly increased ROS and HIF-1alpha, and upregulated the expression of neurogenin-1, doublecortin, and synapsin-1. Inhibition of ROS and HIF-1alpha removed the effects of delayed HBO. CONCLUSIONS: Delayed HBO enhanced endogenous neurogenesis and improved neurofunctional recovery in the late-chronic phase of stroke possibly mediated by ROS/HIF-1alpha/beta-catenin pathway. Delayed HBO may serve as an alternative treatment to improve long-term recovery of stroke survivors. PMID- 24757105 TI - Serial montreal cognitive assessments demonstrate reversible cognitive impairment in patients with acute transient ischemic attack and minor stroke. AB - BACKGROUND AND PURPOSE: Cognitive changes after ischemic stroke are often overlooked, particularly acutely and in patients with mild or transient deficits. We assessed patients with transient ischemic attack (TIA)/minor stroke with serial cognitive screening tests. We tested the hypothesis that mild acute deficits are transient and improve after TIA/minor stroke. METHODS: Patients with acute TIA/minor ischemic stroke, without a history of cognitive impairment, presenting with a National Institute of Health Stroke Scale score <=3 were assessed <72 hours of onset. Patients were administered the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) at days 1, 7, 30, and 90. Cognitive impairment was defined as MoCA <26 and MMSE <=26. RESULTS: One hundred patients with a median (interquartile range) National Institute of Health Stroke Scale score of 1 (2) and median age of 68 (20) years were included. Baseline median MoCA score (26 [4]) was lower than the MMSE (29 [2]; P<0.0001). Cognitive impairment was detected in 54 of 100 patients (54%) with MoCA and 16 of 100 (16%; P=0.001) with MMSE. MoCA scores improved at day 7 (27 [5]), day 30 (28 [2]), and day 90 (28 [2]; P<0.0001). Resolution of cognitive deficits was because of resolution of recall deficits. CONCLUSIONS: Acute temporary cognitive impairment after TIA/minor stroke is common. The MoCA is sensitive to these changes, but the MMSE is not. Routine cognitive assessment after TIA/minor stroke may be warranted and relevant to return to activities even when other neurological deficits are not evident. PMID- 24757106 TI - Linking physical function outcomes in rheumatology: performance of a crosswalk for converting Health Assessment Questionnaire scores to Short Form 36 physical functioning scale scores. AB - OBJECTIVE: To evaluate the reliability of a crosswalk, developed in The Netherlands, between the Health Assessment Questionnaire (HAQ) disability index (DI) and the Short Form 36 physical functioning scale (PF-10) in a sample of patients with various rheumatic diseases in the US. METHODS: Baseline data from patients with rheumatoid arthritis (RA; n = 29,020), fibromyalgia (FM; n = 3,776), and systemic lupus erythematosus (SLE; n = 1,609) participating in the National Data Bank for Rheumatic Diseases were analyzed. Reliability of the crosswalk was evaluated by calculating intraclass correlation coefficients (ICCs), and agreement between observed and predicted scores was evaluated using the Bland-Altman approach. RESULTS. The crosswalk produced reliable conversions for both the HAQ DI (ICC range 0.70-0.77) and PF-10 (ICC range 0.73-0.78) in all 3 disease groups. The mean difference between observed and expected scores was close to zero in US patients with RA. For all 3 disease groups, the limits of agreement were fairly wide and conversion at the level of individual patients is not recommended. CONCLUSION: The crosswalk produced reliable conversions at the group level in a crosscultural setting and can be used to convert HAQ DI to PF-10 scores and vice versa in US patients with RA, FM, or SLE. PMID- 24757107 TI - Introduction: the importance of cognition in movement disorders. PMID- 24757108 TI - The tools of the trade: a state of the art "How to Assess Cognition" in the patient with Parkinson's disease. AB - Cognitive impairment in Parkinson's disease is heterogeneous both in severity and pattern and subject to influences both integral to and external to the disease. Diagnostic Criteria have been developed by the Movement Disorders Society that help to guide clinicians and researchers to an accurate diagnosis of Parkinson's disease - mild cognitive impairment or Parkinson's disease dementia. To operationalize these criteria, and to assess the pattern and severity of cognitive dysfunction we need: (1) Valid measures of cognitive abilities covering the major domains of cognition, (2) amethod to determine whether or not the performance represents a decline from a person's previous level of functioning, and (3) an assessment of how the individual's cognitive abilities enable (or disable) function in day to day activities. This paper will discuss the methods of assessment and the measures that can be used to make a comprehensive assessment of cognition in Parkinson's disease. PMID- 24757109 TI - Cognitive deficits in Parkinson's disease: a cognitive neuroscience perspective. AB - Progress in characterization of the nature, neural basis, and treatment of cognitive deficits in Parkinson's disease is reviewed from the perspective of cognitive neuroscience. An initial emphasis on fronto-striatal executive deficits is surveyed along with the discoveries of disruption as well as remediation of certain impairments by dopaminergic mediation and their association with theories of reinforcement learning. Subsequent focus on large cohorts has revealed considerable heterogeneity in the cognitive impairments as well as a suggestion of at least two distinct syndromes, with the dopamine-dependent fronto-striatal deficits being somewhat independent of other signs commonly associated with Parkinson's disease dementia. The utility is proposed of a new, integrated cognitive neuroscience approach based on combining genetic and neuroimaging methodologies with neuropsychological and, ultimately, psychopharmacological approaches. PMID- 24757110 TI - The spectrum of cognitive impairment in Lewy body diseases. AB - Cognitive impairment represents an important and often defining component of the clinical syndromes of Lewy body disorders: Parkinson's disease and dementia with Lewy bodies. The spectrum of cognitive deficits in these Lewy body diseases encompasses a broad range of clinical features, severity of impairment, and timing of presentation. It is now recognized that cognitive dysfunction occurs not only in more advanced Parkinson's disease but also in early, untreated patients and even in those patients with pre-motor syndromes, such as rapid eye movement behavior disorder and hyposmia. In recent years, the concept of mild cognitive impairment as a transitional or pre-dementia state in Parkinson's disease has emerged. This has led to much research regarding the diagnosis, prognosis, and underlying neurobiology of mild cognitive impairment in Parkinson's disease, but has also raised questions regarding the usefulness of this concept and its application in clinical and research settings. In addition, the conundrum of whether Parkinson's disease dementia and dementia with Lewy bodies represent the same or different entities remains unresolved. Although these disorders overlap in many aspects of their presentations and pathophysiology, they differ in other elements, such as timing of cognitive, behavioral, and motor symptoms; medication responses; and neuropathological contributions. This article examines the spectrum and evolution of cognitive impairment in Lewy body disorders and debates these controversial issues in the field using point-counterpoint approaches. PMID- 24757111 TI - What can biomarkers tell us about cognition in Parkinson's disease? AB - Cognitive decline is common in Parkinson's disease (PD), even in the early motor stage, and this non-motor feature impacts quality of life and prognosis tremendously. In this article, we discuss marker candidates for cognitive decline in PD from different angles, including functional and structural imaging techniques, biological fluid markers in cerebrospinal fluid, and blood genetic predictors, as well as gait as a surrogate marker of cognitive decline. Specifically, imaging-based markers of cognitive impairment in PD include cortical atrophy, reduced cortical metabolism, loss of cortical cholinergic and frontal dopaminergic function, as well as an increased cortical amyloid load. Reduced beta-amyloid(1-42) in cerebrospinal fluid and lower plasma levels of epidermal growth factor are predictors for cognitive decline in PD. In addition, genetic variation in the apolipoprotein E (APOE), catechol-O-methyltransferase (COMT), microtubule-associated protein tau (MAPT), and glucocerebrosidase (GBA) genes may confer risk for cognitive impairment in PD; and gait disturbance may also indicate an increased risk for dementia. Other marker candidates have been proposed and are discussed. All of the current studies are hampered by gaps in our knowledge about the molecular causes of cognitive decline, which will have to be considered in future biomarker studies. PMID- 24757114 TI - Cognitive impairment and dementia in Parkinson's disease: practical issues and management. AB - Cognitive impairment and dementia pose particular challenges in the management of patients with Parkinson's disease (PD). Decision-making capacity can render patients vulnerable in a way that requires careful ethical considerations by clinicians with respect to medical decision making, research participation, and public safety. Clinicians should discuss how future decisions will be made as early in the disease course as possible. Because of cognitive, visual, and motor impairments, PD may be associated with unsafe driving, leading to early driving cessation in many. DBS of the STN and, to a lesser degree, globus pallidus interna (GPi) has consistently been associated with decreased verbal fluency, but significant global cognitive decline is usually not observed in patients who undergo rigorous selection. There are some observations suggesting lesser cognitive decline in GPi DBS than STN DBS, but further research is required. Management of PD dementia (PDD) patients involves both pharmacological and nonpharmacological measures. Patients with PDD should be offered treatment with a cholinesterase inhibitor taking into account expected benefits and potential risks. Treatment with neuroleptics may be necessary to treat psychosis; classical neuroleptics, as well as risperidone and olanzapine, should be avoided. Quetiapine might be considered first-line treatment because it does not need special monitoring, although the strongest evidence for efficacy exists for clozapine. Evidence from randomized, controlled studies in the PDD population is lacking; selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors may be used to treat depressive features. Clonazepam or melatonin may be useful in the treatment of rapid eye movement behavior disorder. PMID- 24757112 TI - The neurobiological basis of cognitive impairment in Parkinson's disease. AB - The recent formalization of clinical criteria for Parkinson's disease with dementia (PDD) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PDD occurs on the background of severe dopamine deficits with, the main pathological drivers of cognitive decline being a synergistic effect between alpha-synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin, and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the alpha-synuclein gene, lead to a clear increased risk of PDD, whereas others, such as parkin mutations, are associated with a reduced risk of PDD. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low-dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. Whereas dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies, and genetic factors in PD-MCI remains to be fully elucidated. PMID- 24757115 TI - The cognitive burden in Huntington's disease: pathology, phenotype, and mechanisms of compensation. AB - Huntington's disease (HD) is an inherited autosomal dominant neurodegenerative disorder. The most prominent sign of HD is the presence of involuntary motor movements. However, HD is also characterized by marked cognitive decline, which often precedes the onset of motor symptoms and is generally considered to be more debilitating to the patients and their families, compared to motor symptoms. Cognitive decline is widespread across most faculties of cognition in later stages of the disease, but seems to be selective in preclinical and early stages of the disease, with deficits in the HD patients' ability to multitask, their speed of processing, and executive function. It is now well established that preceding clinical diagnosis there is a preclinical stage, during which HD gene mutation carriers are relatively symptom free, despite disease pathological onset and the presence of neurodegeneration. Evidence from functional brain imaging studies suggests the presence of neural compensation in preclinical stages of HD, whereby the brain undergoes functional reorganization in response to neurodegeneration to preserve motor and cognitive performance. In this review, we will describe the underlying HD pathology with a focus on how it links to the cognitive phenotype. We will also present evidence regarding the presence of neural compensation in HD and the possible mechanisms supporting it. Finally, we will discuss current research in the field of cognitive interventions that aim to support and enhance neural compensation in HD. These research efforts could, one day, prolong the preclinical stage and assist with symptom management of those affected with HD. PMID- 24757113 TI - Psychiatric issues in cognitive impairment. AB - Neuropsychiatric symptoms (NPS) such as depression, hallucinations and apathy commonly occur in Parkinson's disease (PD) and have major clinical consequences including a negative impact on quality of life. This review discusses the epidemiology, clinical features, diagnostic procedures and treatment issues of NPS in PD and related disorders in the perspective of cognitive impairment, focusing on depression, anxiety, visual hallucinations, apathy, sleep disturbances, impulse control disorder and non-motor fluctuations. The majority of NPS are more common in PD patients with dementia, possibly related to shared underlying pathologies. Recent studies also suggest that NPS are associated with mild cognitive impairment in PD, in particular with the amnestic type. Accurate diagnosis of NPS is important but can be difficult, due to overlapping symptoms and similar appearance of symptoms of motor symptoms of parkinsonism, cognitive impairment, mood disorders and apathy. There are few systematic studies focusing on the management of NPS in PD with cognitive impairment. PMID- 24757116 TI - Cognition in corticobasal syndrome and progressive supranuclear palsy: a review. AB - Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) represent challenging neurodegenerative disorders for clinicians and nonclinical scientists alike. Although initially lumped together as "Parkinson's-Plus" syndromes, CBS and PSP are clinically and pathologically distinct from Parkinson's disease. It is now clear that behavioral and cognitive changes are common in both syndromes and affect impact quality of life and carer burden considerably. We briefly review the clinical, pathological, and neuroradiological features of each syndrome, followed by more detailed descriptions of the behavioral and cognitive deficits encountered in CBS and PSP. Clinically and pathologically heterogeneous, CBS is characterized by a wide range of cognitive and behavioral disturbances. impairments in executive function and memory are common, but nonspecific. In contrast, deficits in language and visuospatial abilities appear to be more distinctive features of CBS; the relevance of specific patterns of impairment to the underlying histopathology, or prognosis, remains to be fully elucidated. As in CBS, behavioral and cognitive changes are almost universal in PSP, with a wide range of reported deficits. Apathy is very common, often paradoxically accompanied by impulsivity. Executive dysfunction is prominent, but memory and visuospatial deficits also occur. An emerging field is the study of social cognition, which appears impaired in both syndromes. As therapeutic strategies for neurodegenerative pathologies emerge, more specific diagnostic tools in CBS and PSP will be required. Careful clinicopathological correlation, and the development of biomarkers for specific histopathologies, will be important milestones on the road to effective treatments. PMID- 24757117 TI - Cognitive impairment in "Other" movement disorders: hidden defects and valuable clues. AB - There is a group of less-common movement disorders in which a clear cognitive phenotype coexists alongside the motor abnormality, and the recognition of this co-occurrence is essential to diagnose these disorders in an early phase. Examples include chorea-acanthocytosis, Niemann-Pick type C, some dominant ataxias, and pantothotenate kinase-associated neurodegeneration. However, also, in some more-common movement disorders, such as primary dystonia and essential tremor, of which the perception is that these have a more or less pure motor phenotype, cognitive deficits are commonly present, although it is not clear whether these deficits-which may be mild in the more "pure" motor disorders-have a functionally relevant impact. In both scenarios, disruption of relevant frontal subcortical loops appears to be key, with the striatum and cerebellum as important (but not exclusive) nodes. PMID- 24757119 TI - Plant trichomes have mixed impacts on predatory insects. PMID- 24757118 TI - Cognition in movement disorders: where can we hope to be in ten years? AB - Cognitive impairment and dementia associated with movement disorders represent a major management challenge and area of unmet need. This article has focused upon Parkinson's disease as an exemplar condition, but many of the roadblocks and efforts to overcome these are applicable, in a general sense, to other disorders. Short of a "penicillin moment"-a chance discovery or piece of unintended good fortune-progress is likely to be incremental. Cognitive therapies may end up being multiple and possibly multimodal, parallel with the cancer therapy field. Ultimately, benefit for one condition may extend to others as commonality in protein aggregation, synergistic pathological effects between proteins, and pathological spread emerges. (c) 2014 International Parkinson and Movement Disorder Society. PMID- 24757120 TI - An enantiospecific synthesis of jiadifenolide. AB - A Robinson annulation, van Leusen homologation, and a desymmetrizing C-H oxidation enabled an enantiospecific synthesis of the neurotrophic natural product jiadifenolide. From a pulegone-derived building block, a key propellane intermediate was constructed through the use of simple reagents in a highly diastereoselective fashion. A short series of oxidations of this tricylic framework allowed progression to the natural product. PMID- 24757123 TI - Bright coppertunities: multinuclear Cu(I) complexes with N-P ligands and their applications. AB - Easy come, easy go: the great structural diversity of Cu(I) complexes is an ambivalent trait. Apart from the well-known catalytic properties of Cu(I), a great number of potent luminescent complexes have been found in the last ten years featuring a plethora of structural motifs. The downside of this variety is the undesired formation of other species upon processing. In here, strategies to avoid this behavior are presented: Only one favorable structural unit often exists for multinuclear Cu(I) complexes with bridging ligands. In addition, these complexes exhibit favorable photophysical properties due to cooperative effects of the metal halide core. Furthermore, we demonstrate the broad range of applications of emitting Cu(I) compounds. PMID- 24757124 TI - Risk factors for juvenile dermatomyositis: exposure to tobacco and air pollutants during pregnancy. AB - OBJECTIVE: To evaluate the influence of exposure to inhaled environmental factors during pregnancy on the diagnosis of juvenile dermatomyositis (DM). METHODS: We performed a case-control study comprising 20 juvenile DM patients and 56 healthy controls matched by age and sex who were residents in the metropolitan region of a large city. A questionnaire assessed demographic data and environmental inhalation exposure during pregnancy (occupational exposure to demolition, chalk, construction and/or quarry dust, paints, varnish, gasoline vapor, and/or battery fluids; stationary sources of inhaled pollution near the mother's home; and maternal tobacco exposure). Daily concentrations of inhaled particulate matter, SO2, NO2, O3, and carbon monoxide (CO) were evaluated throughout the gestational period. RESULTS: Maternal occupational exposure to school chalk dust/gasoline vapor in the juvenile DM group was significantly higher compared with controls (50% versus 4.6%; P = 0.001). Smoking mothers and secondhand smoke exposure at home during pregnancy were significantly higher in the juvenile DM group versus controls (smoking mothers: 20% versus 1.7%; P = 0.01, and secondhand smoke: 35% versus 19%; P = 0.07). In univariate logistic regression models, maternal smoking, occupational exposure to inhaled agents, and the highest tertile of tropospheric CO (3.2-5.4 parts per million) in the third trimester were significantly associated with juvenile DM (P <= 0.05). In the multivariate analysis, smoking mother (odds ratio [OR] 13.26 [95% confidence interval (95% CI) 1.21-144.29], P = 0.03), occupational exposure (OR 35.39 [95% CI 1.97-632.80], P = 0.01), and CO (third tertile) exposure in the third trimester of gestation (OR 12.21 [95% CI 1.28-115.96], P = 0.03) remained risk factors for juvenile DM. CONCLUSION: Inhaled pollutants and tobacco smoking during fetal development may contribute to juvenile DM. PMID- 24757125 TI - Polymeric Schiff bases as low-voltage redox centers for sodium-ion batteries. AB - The redox entity comprising two Schiff base groups attached to a phenyl ring ( N=CH-Ar-HC=N-) is reported to be active for sodium-ion storage (Ar=aromatic group). Electroactive polymeric Schiff bases were produced by reaction between non-conjugated aliphatic or conjugated aromatic diamine block with terephthalaldehyde unit. Crystalline polymeric Schiff bases are able to electrochemically store more than one sodium atom per azomethine group at potentials between 0 and 1.5 V versus Na(+)/Na. The redox potential can be tuned through conjugation of the polymeric chain and by electron injection from donor substituents in the aromatic rings. Reversible capacities of up to 350 mA h g(-1) are achieved when the carbon mixture is optimized with Ketjen Black. Interestingly, the "reverse" configuration (-CH=N-Ar-N=HC-) is not electrochemically active, though isoelectronic. PMID- 24757126 TI - Macrographia in essential tremor: a study of patients with and without rest tremor. PMID- 24757127 TI - Cortisol administration increases hippocampal activation to infant crying in males depending on childhood neglect. AB - Animal studies show that exposure to parental neglect alters stress regulation and can lead to neural hyposensitivity or hypersensitivity in response to cortisol, most pronounced in the hippocampus. Cortisol, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, has also been related to parenting more directly, for example, in both sexes, cortisol levels increase when listening to infants crying, possibly to activate and facilitate effective care behavior. Severe trauma is known to negatively affect the HPA-axis in humans; however, it is unknown whether normal variation in parental care in the healthy population can alter sensitivity of the hippocampus to cortisol. Here, we investigate whether variation in experienced neglect changes neural sensitivity to cortisol when humans listen to infant crying, which is an unequivocal signal relevant for care behavior. In a placebo-controlled, within-subject neuroimaging study, we administered 40 mg cortisol to 21 healthy young males without children and used a validated task for measuring neural responses to infant crying. The Dutch version of the Childhood Trauma Questionnaire was used to index participants' early exposure to abuse and neglect. The data show that cortisol markedly increased hippocampal activation toward crying infants, and this effect varied significantly with parental neglect, even in our nonclinical subject sample. Without exposure to severe trauma or neglect, reduced self-experienced quality of parental care in the normal range already substantially increased hippocampal responsivity to cortisol. Altered hippocampal sensitivity to cortisol might be a cross-species marker for the risk of developing later life psychopathology. PMID- 24757128 TI - Copper-catalyzed dehydrogenative cross-coupling reaction between allylic C-H bonds and alpha-C-H bonds of ketones or aldehydes. AB - A dehydrogenative cross-coupling reaction between allylic C-H bonds and the alpha C-H bond of ketones or aldehydes was developed using Cu(OTf)2 as a catalyst and DDQ as an oxidant. This synthetic approach to gamma,delta-unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)2 as a Lewis acid catalyst was also proposed (DDQ=2,3 dichloro-5,6-dicyano-1,4-benzoquinone; Tf=trifluoromethanesulfonate). PMID- 24757129 TI - Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis? PMID- 24757130 TI - Editorial: HLA-B27, Cytokines, and spondyloarthritis: noncanonical functions of a curious class I major histocompatibility complex gene. PMID- 24757131 TI - The epidemiology of rheumatoid arthritis in Ontario, Canada. AB - OBJECTIVE: Epidemiologic assessments of sufficiently large populations are required in order to obtain robust estimates of disease prevalence and incidence, particularly when exploring the influence of various factors (age, sex, calendar time). We undertook this study to describe the epidemiology of rheumatoid arthritis (RA) over the past 15 years. METHODS: We used the Ontario Rheumatoid Arthritis administrative Database (ORAD), a validated population-based research database of all Ontarians with RA. The ORAD records were linked with census data to calculate crude and age and sex-standardized prevalence and incidence rates from 1996 to 2010. Vital statistics were used to estimate annual all-cause mortality during the study period. RESULTS: As of 2010, there were 97,499 Ontarians with RA, corresponding to a cumulative prevalence of 0.9%. Age and sex standardized RA prevalence increased steadily over time from 473 (95% confidence interval [95% CI] 469-478) per 100,000 population (0.49%) in 1996 to 784 (95% CI 779-789) per 100,000 population (0.9%) in 2010. Age and sex-standardized incidence per 100,000 population ranged from 62 (95% CI 60-63) in 1996 to 54 (95% CI 52-55) in 2010. All-cause mortality decreased by a relative 21.4% since 1996. CONCLUSION: Over a 15-year period, we observed an increase in RA prevalence over time. This rise may be attributed to the increasing time to ascertain cases (which may have been latent in the population during earlier years of the study), increasing survival, and/or an increase in the aging background population. Incidence appears to be stable. PMID- 24757132 TI - Development and validation of modified disease activity scores in rheumatoid arthritis: superior correlation with magnetic resonance imaging-detected synovitis and radiographic progression. AB - OBJECTIVE: To develop and validate composite disease activity scores, based on widely available clinical measures, that would demonstrate improved correlation with detection of synovitis on magnetic resonance imaging (MRI) and radiographic progression, in comparison with conventional measures, in patients with rheumatoid arthritis (RA). METHODS: This study was conducted as a secondary study of 2 RA clinical trials, GO-BEFORE (development cohort) and GO-FORWARD (validation cohort). Generalized estimating equations were used to evaluate independent cross-sectional associations of component variables (from all time points) with concurrent MRI measures of synovitis and bone edema in the development cohort. Based on regression coefficients, modified versions of the Disease Activity Score in 28 joints (M-DAS28), Simplified Disease Activity Index (M-SDAI), and Clinical Disease Activity Index (M-CDAI) were generated for each subject in the validation cohort. The M-DAS28, M-SDAI, and M-CDAI scores were compared to conventional scores of disease activity with regard to associations with MRI measures of synovitis and radiographic progression, assessed using Pearson's and Spearman's correlations, linear/logistic regression, and receiver operating characteristic analysis. RESULTS: Four variables were independently associated with MRI-detected synovitis and bone edema in the development cohort: C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), swollen joint count in 28 joints (SJC28), and evaluator's global assessment of disease activity using a visual analog scale (EvGA score). Modified disease activity scores were generated using the regression coefficients obtained in the synovitis models for all subjects in the validation cohort; modified scores were calculated as M-DAS28 = 0.49 * ln(CRP) + 0.15 * SJC28 + 0.22 * EvGA + 1 and M-SDAI = CRP + SJC28 + EvGA. Both modified and conventional disease activity scores correlated significantly with MRI measures of synovitis. Modified scores showed superior correlation with synovitis, as compared to conventional scores, at all time points (P < 0.05). Furthermore, the M-DAS28 and M-SDAI had superior test characteristics for prediction of radiographic progression at 52 weeks (both P < 0.05). CONCLUSION: Modified disease activity scores demonstrated superior correlation with MRI detection of synovitis at all time points, and more accurately predicted radiographic progression in patients with RA in a clinical trial setting. PMID- 24757133 TI - Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: Methotrexate has shown efficacy for the treatment of several diseases, especially rheumatoid arthritis (RA). Methotrexate has also been implicated as a causative agent in interstitial lung disease. Patients with RA may develop pulmonary manifestations of their disease and are at increased risk of respiratory infection. The aim of this study was to evaluate the relative risk (RR) of pulmonary disease among patients with RA treated with methotrexate. METHODS: We searched the PubMed and Cochrane databases (publication dates January 1, 1990 to February 1, 2013) for double-blind, randomized, controlled trials of methotrexate versus placebo or active comparator agents in adults with RA. Studies with <100 subjects or with a duration of <24 weeks were excluded. Two investigators independently searched both databases, and all of the investigators reviewed the selected studies. We compared differences in the RR using the Mantel Haenszel random-effects method. RESULTS: A total of 22 studies with 8,584 participants met the inclusion criteria. Heterogeneity across studies was not significant (I(2) = 3%), allowing combination of the trial results. Methotrexate was associated with an increased risk of all adverse respiratory events (RR 1.10, 95% confidence interval [95% CI] 1.02-1.19) and respiratory infection (RR 1.11, 95% CI 1.02-1.21). Patients treated with methotrexate were not at increased risk of death due to lung disease (RR 1.53, 95% CI 0.46-5.01) or noninfectious respiratory events (RR 1.02, 95% CI 0.65-1.60). A subgroup analysis of studies in which pneumonitis was described revealed an increased risk associated with methotrexate (RR 7.81, 95% CI 1.76-34.72). CONCLUSION: Our study demonstrated a small but significant increase in the risk of lung disease in patients with RA treated with methotrexate compared with other disease-modifying antirheumatic drugs and biologic agents. PMID- 24757134 TI - Rheumatoid factor as a potentiator of anti-citrullinated protein antibody mediated inflammation in rheumatoid arthritis. AB - OBJECTIVE: The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. METHODS: In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor alpha production measured as a readout of macrophage activation. RESULTS: Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor alpha production (P = 0.003 versus ACPA ICs alone). CONCLUSION: The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA. PMID- 24757135 TI - Contribution of functional LILRA3, but not nonfunctional LILRA3, to sex bias in susceptibility and severity of anti-citrullinated protein antibody-positive rheumatoid arthritis. AB - OBJECTIVE: Leukocyte immunoglobulin-like receptor A3 belongs to a family of receptors with inhibitory or activating functions. Since Caucasian individuals lacking LILRA3 have been found to be susceptible to multiple sclerosis and Sjogren's syndrome, we undertook this study to examine whether LILRA3 deletion is a novel genetic risk factor for rheumatoid arthritis (RA) (another autoimmune disease), whether there are sex-specific effects, and whether LILRA3 influences the subtype and severity of RA. METHODS: The LILRA3 deletion and its tagging single-nucleotide polymorphism rs103294 were genotyped in a Northern Han Chinese cohort (N-Han) (1,618 cases and 1,658 controls) and a Southern Han Chinese cohort (S-Han) (575 cases and 549 controls). Association analyses were performed on the complete data set and subsets. The effect of the nondeleted (functional) LILRA3 allele on radiographic severity and LILRA3 expression was evaluated. RESULTS: In the N-Han discovery cohort, we unexpectedly observed a higher frequency of the functional LILRA3 in RA patients compared with healthy individuals (10.1% versus 6.3%; P = 4.01 * 10(-5) , odds ratio [OR] 1.92). The association was replicated in the S-Han cohort and confirmed by meta-analysis (P = 5.63 * 10(-6) , OR 1.83). Functional LILRA3 conferred greater risk for RA in males (P = 1.09 * 10(-6) , OR 4.47), and was specifically associated with anti-citrullinated protein antibody (ACPA)-positive RA (P = 3.05 * 10(-4) , OR 1.75). Furthermore, functional LILRA3 was associated with higher radiographic scores in ACPA-positive patients with early RA (P = 9.70 * 10(-3) ) and higher LILRA3 messenger RNA levels (P = 3.31 * 10(-8) ). CONCLUSION: Our study provides the first evidence that functional LILRA3 is a novel genetic risk factor for RA, especially in males. It appears to highly predispose to ACPA-positive RA and confers an increased risk of disease severity in patients with early RA. PMID- 24757136 TI - Inactivation of patched1 in murine chondrocytes causes spinal fusion without inflammation. AB - OBJECTIVE: During development of the vertebrate skeleton, chondrocytes form a cartilage template that is gradually replaced by bone. Hormones of the Hedgehog (HH) family have been implicated in the ossification process, but their exact relationship to normal or pathogenic bone formation is unclear. This study was undertaken to establish a genetic tool that allows the discrete inactivation of genes in spinal chondrocytes, and to investigate in vivo how chondrocyte-specific ablation of the inhibitory HH receptor Patched 1 (Ptch1) affects skeleton integrity. METHODS: A Cre-deleter mouse strain, mb1-Cre, for selective gene recombination in spinal chondrocytes was identified by in situ hybridization and histologic analysis. The mb1-Cre(+/-) animals were crossed with mice that harbor a loxP-flanked Ptch1 gene (Ptch1(flox/flox) ) to abrogate the inhibition of the HH signaling pathway in chondrocytes. The skeletal integrity of F1 mice was characterized by high-resolution flat-panel-based volume computed tomography and histologic staining procedures. RESULTS: During the first weeks after birth, all mb1-Cre(+/-) /Ptch1(flox/flox) mice developed progressive spinal fusion with malformation of the vertebrae. This phenotype was caused by aberrant chondrocyte proliferation in the intervertebral discs that blocked endochondral ossification. Importantly, the disease pattern occurred in an inflammation-independent manner. CONCLUSION: Our findings indicate that chronic activation of the HH signal pathway in spinal chondrocytes can trigger an ankylosing spine morphology without immune cell contributions. Hence, the destruction of cartilage and loss of axial joint integrity can result from chondrocyte-intrinsic defects of monogenic origin. PMID- 24757137 TI - Reverse interferon signature is characteristic of antigen-presenting cells in human and rat spondyloarthritis. AB - OBJECTIVE: In HLA-B27-transgenic rats, the development of a disorder that mimics spondyloarthritis (SpA) is highly correlated with dendritic cell (DC) dysfunction. The present study was undertaken to analyze the underlying mechanisms of this via transcriptome analysis. METHODS: Transcriptome analysis of ex vivo-purified splenic CD103+CD4+ DCs from B27-transgenic rats and control rats was performed. Transcriptional changes in selected genes were confirmed by quantitative reverse transcriptase-polymerase chain reaction. A meta-analysis of our rat data and published data on gene expression in macrophages from ankylosing spondylitis (AS) patients was further performed. RESULTS: Interferon (IFN) signaling was the most significantly affected pathway in DCs from B27-transgenic rats; the majority of genes connected to IFN were underexpressed in B27 transgenic rats as compared to controls. This pattern was already present at disease onset, persisted over time, and was conserved in 2 disease-prone B27 transgenic rat lines. In DCs from B27-transgenic rats, we further found an up regulation of suppressor of cytokine signaling 3 (which may account for reverse IFN signaling) and a down-regulation of interleukin-27 (a cytokine that opposes Th17 differentiation and promotes Treg cells). The meta-analysis of data on conventional DCs from rats and data on monocyte-derived macrophages from humans revealed 7 IFN-regulated genes that were negatively regulated in both human and rat SpA (i.e., IRF1, STAT1, CXCL9, CXCL10, IFIT3, DDX60, and EPSTI1). CONCLUSION: Our results suggest that expression of HLA-B27 leads to a defect in IFNgamma signaling in antigen-presenting cells in both B27-transgenic rats and SpA patients, which may result in Th17 expansion and Treg cell alteration (as shown in B27-transgenic rats) and contribute to disease pathogenesis. PMID- 24757138 TI - Fcgamma receptor III and Fcgamma receptor IV on macrophages drive autoimmune valvular carditis in mice. AB - OBJECTIVE: Arthritis and valvular carditis coexist in several human rheumatic diseases, including systemic lupus erythematosus, rheumatic fever, and rheumatoid arthritis. T cell receptor-transgenic K/BxN mice develop spontaneous autoantibody associated arthritis and valvular carditis. The common Fc receptor gamma (FcRgamma) signaling chain is required for carditis to develop in K/BxN mice. FcRgamma pairs with numerous receptors in a variety of cells. The aim of this study was to identify the FcRgamma-associated receptors and Fcgamma receptor (FcgammaR)-expressing cells that mediate valvular carditis in this model. METHODS: We bred K/BxN mice lacking the genes that encode activating Fcgamma receptors (FcgammaRI, FcgammaRIII, and FcgammaRIV), and we assessed these mice for valvular carditis. We similarly evaluated complement component C3-deficient K/BxN mice. Immunohistochemistry, bone marrow transplantation, and macrophage depletion were used to define the key FcRgamma-expressing cell type. RESULTS: Genetic deficiency of only one of the activating Fcgamma receptors did not prevent carditis, whereas deficiency of all 3 activating Fcgamma receptors did. Further analysis demonstrated that FcgammaRIII and FcgammaRIV were the key drivers of valve inflammation; FcgammaRI was dispensable. C3 was not required. FcRgamma expression by radioresistant cells was critical for valvular carditis to develop, and further analysis indicated that macrophages were the key candidate FcgammaR-expressing effectors of carditis. CONCLUSION: FcgammaRIII and FcgammaRIV act redundantly to promote valvular carditis in K/BxN mice with systemic autoantibody-associated arthritis. Macrophage depletion reduced the severity of valve inflammation. These findings suggest that pathogenic autoantibodies engage Fcgamma receptors on macrophages to drive valvular carditis. Our study provides new insight into the pathogenesis of cardiovascular inflammation in the setting of autoantibody-associated chronic inflammatory diseases. PMID- 24757139 TI - Regulation of apoptosis and inflammatory responses by insulin-like growth factor binding protein 3 in fibroblast-like synoviocytes and experimental animal models of rheumatoid arthritis. AB - OBJECTIVE: Insulin-like growth factor binding protein 3 (IGFBP-3) is known to interfere with the NF-kappaB signaling pathway, and it effectively promotes apoptosis in tumor cells by a variety of mechanisms. NF-kappaB activation and apoptosis resistance of fibroblast-like synoviocytes (FLS) play pivotal roles in rheumatoid arthritis (RA). This study was undertaken to evaluate whether IGFBP-3 has antiarthritic effects. METHODS: To deliver IGFBP-3, we used an adenovirus containing IGFBP-3 complementary DNA (AdIGFBP-3) or IGFBP-3 mutant that is devoid of IGF binding affinity but retains IGFBP-3 receptor binding ability (AdmtIGFBP 3). The regulatory roles of IGFBP-3 in inflammation and bone destruction were investigated in mice with collagen-induced arthritis (CIA). RESULTS: IGFBP-3 levels were significantly higher in patients with RA than in those with osteoarthritis (OA) and were notably higher in patients with active RA. AdIGFBP-3 suppressed NF-kappaB activation, chemokine production, and matrix metalloproteinase secretion induced by tumor necrosis factor alpha (TNFalpha) in RA FLS. AdIGFBP-3 sensitized RA FLS to TNFalpha-induced apoptosis in vitro and also significantly increased apoptosis in an in vivo model of Matrigel implants engrafted into immunodeficient mice. AdIGFBP-3-injected mice with CIA had attenuated arthritis severity and reduced radiologic and pathologic abnormalities. Moreover, AdIGFBP-3 down-regulated local and systemic levels of NF kappaB-targeted proinflammatory cytokines. Of note, RA FLS and mice with CIA treated with AdmtIGFBP-3 exhibited similar effects as those treated with AdIGFBP 3. CONCLUSION: Our results suggest that both the inflammatory response and bone destruction are reduced with blockage of NF-kappaB activation and induction of apoptosis in RA FLS by IGFBP-3. Therefore, IGFBP-3 may have therapeutic potential in RA. PMID- 24757140 TI - Rebamipide suppresses collagen-induced arthritis through reciprocal regulation of th17/treg cell differentiation and heme oxygenase 1 induction. AB - OBJECTIVE: Rebamipide, a gastroprotective agent, has the ability to scavenge reactive oxygen radicals. Increased oxidative stress is implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to investigate the impact of rebamipide on the development of arthritis and the pathophysiologic mechanisms by which rebamipide attenuates arthritis severity in a murine model of RA. METHODS: Collagen-induced arthritis (CIA) was induced in DBA/1J mice. Anti type II collagen antibody titers and interleukin-17 (IL-17) levels were determined using enzyme-linked immunosorbent assay. The expression of transcription factors was analyzed by immunostaining and Western blotting. Frequencies of IL-17-producing CD4+ T cells (Th17 cells) and CD4+CD25+FoxP3+ Treg cells were analyzed by flow cytometry. RESULTS: Rebamipide reduced the clinical arthritis score and severity of histologic inflammation and cartilage destruction in a dose-dependent manner. The joints isolated from rebamipide-treated mice with CIA showed decreased expression of nitrotyrosine, an oxidative stress marker. Rebamipide-treated mice showed lower circulating levels of type II collagen specific IgG, IgG1, and IgG2a. Whereas the number of Th17 cells in spleens was decreased in rebamipide-treated mice with CIA, a significant increase in the number of Treg cells in spleens was observed. In vitro, rebamipide inhibited Th17 cell differentiation through STAT-3/retinoic acid receptor-related orphan nuclear receptor gammat and reciprocally induced Treg cell differentiation through FoxP3. Rebamipide increased Nrf2 nuclear activities in murine CD4+ T cells and LBRM-33 murine T lymphoma cells. Heme oxygenase 1 (HO-1) expression in the spleens was markedly increased in rebamipide-treated mice. CONCLUSION: The inhibitory effects of rebamipide on joint inflammation are associated with recovery from an imbalance between Th17 cells and Treg cells and with activation of an Nrf2/HO-1 antioxidant pathway. PMID- 24757141 TI - Interleukin-21 receptor deficiency increases the initial toll-like receptor 2 response but protects against joint pathology by reducing Th1 and Th17 cells during streptococcal cell wall arthritis. AB - OBJECTIVE: The cytokine interleukin-21 (IL-21) can have both proinflammatory and immunosuppressive effects. The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17 cells. METHODS: Antigen-induced arthritis (AIA) and chronic streptococcal cell wall (SCW) arthritis were induced in IL-21 receptor-deficient (IL-21R(-/-) ) and wild type mice. Knee joints, synovial tissue, and serum were analyzed for arthritis pathology and inflammatory markers. RESULTS: During AIA and chronic SCW arthritis, IL-21R deficiency protected against severe inflammation and joint destruction. This was accompanied by suppressed serum IgG1 levels and antigen specific T cell responses. Levels of IL-17 were reduced during AIA, and synovial lymphocytes isolated during SCW arthritis for flow cytometry demonstrated that mainly IL-17+ interferon-gamma (IFNgamma)-positive T cells were reduced in IL 21R(-/-) mice. However, during the acute phases of SCW arthritis, significantly higher joint swelling scores were observed, consistent with enhanced tumor necrosis factor and IL-6 expression. Interestingly, IL-21R(-/-) mice were significantly less capable of up-regulating suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 messenger RNA. IL-21 stimulation also affected the Toll-like receptor 2 (TLR-2)/caspase recruitment domain 15 response to SCW fragments in vitro, indicating that impaired SOCS regulation in the absence of IL-21 signaling might contribute to the increased local activation during SCW arthritis. CONCLUSION: In contrast to the proinflammatory role of IL-21 in adaptive immunity, which drives IL-17+IFN+ cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS-1 and SOCS-3. If this dual role of IL-21 in various immune processes is present in human disease, it could make IL-21 a difficult therapeutic target in rheumatoid arthritis. PMID- 24757142 TI - Activation of spinal NF-kappaB/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis. AB - OBJECTIVE: It is known that noxious stimuli from inflamed tissue may increase the excitability of spinal dorsal horn neurons (a process known as central sensitization), which can signal back and contribute to peripheral inflammation. However, the underlying mechanisms have yet to be fully defined. A number of recent studies have indicated that spinal NF-kappaB/p65 is involved in central sensitization, as well as pain-related behavior. Thus, the aim of this study was to determine whether NF-kappaB/p65 can facilitate a peripheral inflammatory response in rat adjuvant-induced arthritis (AIA). METHODS: Lentiviral vectors encoding short hairpin RNAs that target NF-kappaB/p65 (LV-shNF-kappaB/p65) were constructed for gene silencing. The spines of rats with AIA were injected with LV shNF-kappaB/p65 on day 3 or day 10 after treatment with Freund's complete adjuvant (CFA). During an observation period of 20 days, pain-related behavior, paw swelling, and joint histopathologic changes were evaluated. Moreover, the expression levels of spinal tumor necrosis factor alpha (TNFalpha), interleukin 1beta (IL-1beta), and cyclooxygenase 2 (COX-2) were assessed on day 14 after CFA treatment. RESULTS: The presence of peripheral inflammation in rats with AIA induced an increase in NF-kappaB/p65 expression in the spinal cord, mainly in the dorsal horn neurons and astrocytes. Delivery of LV-shNF-kappaB/p65 to the spinal cord knocked down the expression of NF-kappaB/p65 and significantly attenuated hyperalgesia, paw edema, and joint destruction. In addition, spinal delivery of LV-shNF-kappaB/p65 reduced the overexpression of spinal TNFalpha, IL-1beta, and COX-2. CONCLUSION: These findings indicate that spinal NF-kappaB/p65 plays an important role in the initiation and development of both peripheral inflammation and hyperalgesia. Thus, inhibition of spinal NF-kappaB/p65 expression may provide a potential treatment to manage painful inflammatory disorders. PMID- 24757143 TI - Endogenous myeloperoxidase is a mediator of joint inflammation and damage in experimental arthritis. AB - OBJECTIVE: Myeloperoxidase (MPO) is implicated as a local mediator of tissue damage when released extracellularly in many chronic inflammatory diseases. The purpose of this study was to explore the role of endogenous MPO in experimental rheumatoid arthritis (RA). METHODS: K/BxN serum-transfer arthritis was induced in C57BL/6 wild-type (WT) and MPO knockout (MPO(-/-) ) mice, and disease development was assessed. MPO activity was measured in joint tissues from mice with or without K/BxN arthritis. Collagen-induced arthritis (CIA) was induced in WT and MPO(-/-) mice, and disease development and immune responses were examined. MPO expression was assessed in synovial biopsy samples from patients with active RA, and the effect of MPO on synovial fibroblasts was tested in vitro. RESULTS: MPO was up-regulated in the joints of mice with K/BxN arthritis, and MPO deficiency attenuated the severity of the disease without affecting circulating cytokine levels. In CIA, MPO(-/-) mice had enhanced CD4+ T cell responses and reduced frequency of regulatory T cells in the lymph nodes and spleen, as well as augmented interleukin-17A and diminished interferon-gamma secretion by collagen stimulated splenocytes, without an effect on circulating anticollagen antibody levels. Despite enhanced adaptive immunity in secondary lymphoid organs, CIA development was attenuated in MPO(-/-) mice. Intracellular and extracellular MPO was detected in the synovium of patients with active RA, and human MPO enhanced the proliferation and decreased the apoptosis of synovial fibroblasts in vitro. CONCLUSION: MPO contributes to the development of arthritis despite suppressing adaptive immunity in secondary lymphoid organs. This suggests distinct effects of local MPO on arthritogenic effector responses. PMID- 24757144 TI - STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. AB - OBJECTIVE: To investigate the impact of STA-21, a promising STAT-3 inhibitor, on the development and progression of inflammatory arthritis and to determine the possible mechanisms by which STA-21 has antiarthritic effects in interleukin-1 receptor antagonist-knockout (IL-1Ra-KO) mice, an animal model of rheumatoid arthritis (RA). METHODS: IL-1Ra-KO mice were treated with intraperitoneal injections of STA-21 (0.5 mg/kg) or vehicle 3 times per week for 3 weeks. The mouse joints were assessed for clinical and histologic features of inflammatory arthritis. CD4+CD25+FoxP3+ Treg cells and CD4+IL-17+ cells were defined. Human peripheral blood mononuclear cell-derived monocytes or mouse bone marrow-derived monocyte/macrophage (BMM) cells were cultured in the presence of macrophage colony-stimulating factor alone or together with RANKL and various concentrations of STA-21, followed by staining of the cells for tartrate-resistant acid phosphatase activity to determine osteoclast formation. RESULTS: STA-21 suppressed inflammatory arthritis in IL-1Ra-KO mice. The proportion of Th17 cells was decreased and the proportion of Treg cells expressing FoxP3 was markedly increased in the spleens of STA-21-treated mice. Adoptive transfer of CD4+CD25+ T cells obtained from STA-21-treated IL-1Ra-KO mice markedly suppressed inflammatory arthritis. In vitro treatment with STA-21 induced the expression of FoxP3 and repressed IL-17 expression in both mouse and human CD4+ T cells. Moreover, STA-21 prevented both mouse BMM cells and human monocytes from differentiating into osteoclasts in vitro. CONCLUSION: STA-21 improved the clinical course of arthritis in IL-1Ra-KO mice. It increased not only the number of Treg cells but also the function of the Treg cells. It also suppressed Th17 cells and osteoclast formation. These data suggest that STA-21 might be an effective treatment for patients with RA. PMID- 24757146 TI - Neuromuscular versus quadriceps strengthening exercise in patients with medial knee osteoarthritis and varus malalignment: a randomized controlled trial. AB - OBJECTIVE: To compare the effects of neuromuscular exercise (NEXA) and quadriceps strengthening (QS) on the knee adduction moment (an indicator of mediolateral distribution of knee load), pain, and physical function in patients with medial knee joint osteoarthritis (OA) and varus malalignment. METHODS: One hundred patients with medial knee pain, mostly moderate-to-severe radiographic medial knee OA, and varus malalignment were randomly allocated to one of two 12-week exercise programs. Each program involved 14 individually supervised exercise sessions with a physiotherapist plus a home exercise component. Primary outcomes were peak external knee adduction moment (3-dimensional gait analysis), pain (visual analog scale), and self-reported physical function (Western Ontario and McMaster Universities Osteoarthritis Index). RESULTS: Eighty-two patients (38 [76%] of 50 in the NEXA group and 44 [88%] of 50 in the QS group) completed the trial. There was no significant between-group difference in the change in the peak knee adduction moment (mean difference 0.13 Nm/[body weight * height]% [95% confidence interval (95% CI) -0.08, 0.33]), pain (mean difference 2.4 mm [95% CI 6.0, 10.8]), or physical function (mean difference -0.8 units [95% CI -4.0, 2.4]). Neither group showed a change in knee moments following exercise, whereas both groups showed similar significant reductions in pain and improvement in physical function. CONCLUSION: Although comparable improvements in clinical outcomes were observed with both neuromuscular and quadriceps strengthening exercise in patients with moderate varus malalignment and mostly moderate-to severe medial knee OA, these forms of exercise did not affect the knee adduction moment, a key predictor of structural disease progression. PMID- 24757145 TI - Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome wide association studies. AB - OBJECTIVE: To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA. METHODS: A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 * 10(-5) were considered significant. RESULTS: SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 * 10(-5) , odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06-1.17) and rs1241164 (P = 1.47 * 10(-5) , OR 0.82, 95% CI 0.74-0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 * 10(-5) , OR 0.87, 95% CI 0.82-0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 * 10(-5) , OR 0.85, 95% CI 0.79 0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened. CONCLUSION: Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated. PMID- 24757147 TI - Gene expression pattern of cells from inflamed and normal areas of osteoarthritis synovial membrane. AB - OBJECTIVE: To compare the gene expression patterns of synovial cells from inflamed or normal/reactive areas of synovial membrane obtained from the same patient with osteoarthritis (OA). METHODS: At the time of total knee replacement, synovial tissues were obtained from 12 patients with knee OA. The inflammation status of the synovial membrane was characterized according to macroscopic criteria and classified as normal/reactive or inflamed. Biopsy samples were cultured separately for 7 days. Microarray gene expression profiling was performed on normal/reactive and inflamed areas. Western blot and immunohistochemistry were used to confirm the identified genes that were differentially expressed. RESULTS: We identified 896 genes that were differentially expressed between normal/reactive and inflamed areas. The key pathways were related to inflammation, cartilage metabolism, Wnt signaling, and angiogenesis. In the inflammation network, the genes TREM1 and S100A9 were strongly up-regulated. The genes MMP3, MMP9, CTSH (cathepsin H), and CTSS (cathepsin S) were significantly up-regulated in the cartilage catabolism pathway, while the most up-regulated anabolism enzyme gene was HAS1. In the Wnt signaling pathway, the genes for Wnt-5a and low-density lipoprotein receptor related protein 5 were up-regulated, while the gene FZD2 and the gene for Dkk-3 were down-regulated. Finally, STC1, which codes for a protein involved in angiogenesis, was identified as the most up-regulated gene in inflamed compared with normal/reactive areas. CONCLUSION: This study is the first to identify different expression patterns between 2 areas of the synovial membrane from the same patient. These differences concern several key pathways involved in OA pathogenesis. This analysis also provides information regarding new genes and proteins as potential targets of treatment. PMID- 24757148 TI - Long noncoding RNA related to cartilage injury promotes chondrocyte extracellular matrix degradation in osteoarthritis. AB - OBJECTIVE: Long noncoding RNAs (lncRNAs) play crucial regulatory roles in diverse biologic processes, but knowledge of lncRNAs in osteoarthritis (OA) is limited. The aim of this study was to identify lncRNA expression in articular cartilage and to explore the function of cartilage injury-related lncRNAs (lncRNA-CIR) in OA. METHODS: To identify lncRNAs specifically expressed in OA cartilage, we compared the expression of lncRNAs in OA cartilage with that in normal cartilage using microarray and quantitative polymerase chain reaction (qPCR) analyses. In OA cartilage, lncRNA-CIR was specifically, differentially, and highly expressed. The function of lncRNA-CIR was determined by silencing and overexpression in vitro. Extracellular matrix (ECM)-related molecules were detected by qPCR, Western blot, and immunofluorescence analyses. RESULTS: Up to 152 lncRNAs were found to be differentially expressed (>8-fold) in OA and normal cartilage (82 lncRNAs more highly expressed and 70 less highly expressed in OA cartilage than in normal cartilage). A specific differentially expressed lncRNA-CIR was selected according to the results of the higher expression in OA cartilage and OA chondrocytes. The expression of lncRNA-CIR increased in chondrocytes with in vitro treatment with interleukin-1beta and tumor necrosis factor alpha. Silencing of lncRNA-CIR by small interfering RNA promoted the formation of collagen and aggrecan and reduced the expression of matrix-degrading enzymes, such as MMP13 and ADAMTS5. The expression of collagen and aggrecan was reduced, whereas the expression of matrix-degrading enzymes was increased, after overexpression of lncRNA-CIR. CONCLUSION: The results indicate that lncRNA-CIR contributes to ECM degradation and plays a key role in the pathogenesis of OA. We propose that lncRNA-CIR could be used as a potential target in OA therapy. PMID- 24757149 TI - A computer simulation approach to assessing therapeutic intervention points for the prevention of cytokine-induced cartilage breakdown. AB - OBJECTIVE: To use a novel computational approach to examine the molecular pathways involved in cartilage breakdown and to use computer simulation to test possible interventions for reducing collagen release. METHODS: We constructed a computational model of the relevant molecular pathways using the Systems Biology Markup Language, a computer-readable format of a biochemical network. The model was constructed using our experimental data showing that interleukin-1 (IL-1) and oncostatin M (OSM) act synergistically to up-regulate collagenase protein levels and activity and initiate cartilage collagen breakdown. Simulations were performed using the COPASI software package. RESULTS: The model predicted that simulated inhibition of JNK or p38 MAPK, and overexpression of tissue inhibitor of metalloproteinases 3 (TIMP-3) led to a reduction in collagen release. Overexpression of TIMP-1 was much less effective than that of TIMP-3 and led to a delay, rather than a reduction, in collagen release. Simulated interventions of receptor antagonists and inhibition of JAK-1, the first kinase in the OSM pathway, were ineffective. So, importantly, the model predicts that it is more effective to intervene at targets that are downstream, such as the JNK pathway, rather than those that are close to the cytokine signal. In vitro experiments confirmed the effectiveness of JNK inhibition. CONCLUSION: Our study shows the value of computer modeling as a tool for examining possible interventions by which to reduce cartilage collagen breakdown. The model predicts that interventions that either prevent transcription or inhibit the activity of collagenases are promising strategies and should be investigated further in an experimental setting. PMID- 24757151 TI - Peripheral neuropathies in systemic lupus erythematosus: clinical features, disease associations, and immunologic characteristics evaluated over a twenty five-year study period. AB - OBJECTIVE: To characterize peripheral neuropathy subtypes, ancillary studies, and immunologic profiles associated with peripheral neuropathies in patients with systemic lupus erythematosus (SLE). METHODS: In this 25-year study of 2,097 SLE patients, we characterized peripheral neuropathies due to SLE and compared clinical and SLE-related features in patients with versus those without neuropathy. RESULTS: The prevalence of peripheral neuropathies was 5.9% (123 of 2,097 patients), and 66.7% of these patients (82 of 123) had peripheral neuropathies attributable to SLE. We noted that 17.1% of the patients with peripheral neuropathies due to SLE (14 of 82 patients) had small-fiber neuropathy, which is a painful neuropathy not included in the American College of Rheumatology (ACR) neuropsychiatric SLE (NPSLE) case definitions. SLE patients with small-fiber neuropathies could present with unorthodox neuropathic pain patterns not consistent with a stocking-glove distribution and had associated skin biopsy results suggestive of dorsal root ganglion neuronal cell loss. Compared to SLE patients without peripheral neuropathies, those with peripheral neuropathies had lower mean disease activity (P = 0.01) and higher disease damage (P < 0.01) and were more likely to have a history of herpes zoster virus infection (P < 0.01), osteoporotic fractures (P < 0.01), and opportunistic infections (P < 0.01). CONCLUSION: Our findings indicate that small-fiber neuropathy is a frequently occurring peripheral neuropathy. The skin biopsy findings in small-fiber neuropathy patients support the notion that distinct mechanisms target the dorsal root ganglia as well as distal axons. SLE patients with peripheral neuropathy have lower mean disease activity scores and higher disease damage. Our findings suggest that revision of the ACR NPSLE case definitions, which currently do not include small-fiber neuropathies, is warranted. PMID- 24757150 TI - CTLA-4Ig-induced T cell anergy promotes Wnt-10b production and bone formation in a mouse model. AB - OBJECTIVE: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease characterized by severe joint erosion and systemic osteoporosis. Chronic T cell activation is a hallmark of RA, and agents that target the CD28 receptor on T cells, which is required for T cell activation, are being increasingly used as therapies for RA and other inflammatory diseases. Lymphocytes play complex roles in the regulation of the skeleton, and although activated T cells and B cells secrete cytokines that promote skeletal decline, under physiologic conditions lymphocytes also have key protective roles in the stabilization of skeletal mass. Consequently, disruption of T cell costimulation may have unforeseen consequences for physiologic bone turnover. This study was undertaken to investigate the impact of pharmacologic CD28 T cell costimulation blockade on physiologic bone turnover and structure. METHODS: C57BL6 mice were treated with CTLA-4Ig, a pharmacologic CD28 antagonist or with irrelevant control antibody (Ig), and serum biochemical markers of bone turnover were quantified by enzyme-linked immunosorbent assay. Bone mineral density and indices of bone structure were further measured by dual x-ray absorptiometry and micro-computed tomography, respectively, and static and dynamic indices of bone formation were quantified using bone histomorphometry. RESULTS: Pharmacologic disruption of CD28 T cell costimulation in mice significantly increased bone mass and enhanced indices of bone structure, a consequence of enhanced bone formation, concurrent with enhanced secretion of the bone anabolic factor Wnt-10b by T cells. CONCLUSION: Inhibition of CD28 costimulation by CTLA-4Ig promotes T cell Wnt-10b production and bone formation and may represent a novel anabolic strategy for increasing bone mass in osteoporotic conditions. PMID- 24757152 TI - Identification of cadherin 11 as a mediator of dermal fibrosis and possible role in systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is a chronic autoimmune disease clinically manifesting as progressive fibrosis of the skin and internal organs. Recent microarray studies demonstrated that cadherin 11 (Cad-11) expression is increased in the affected skin of patients with SSc. The purpose of this study was to examine our hypothesis that Cad-11 is a mediator of dermal fibrosis. METHODS: Biopsy samples of skin from SSc patients and healthy control subjects were used for real-time quantitative polymerase chain reaction analysis to assess Cad-11 expression and for immunohistochemistry to determine the expression pattern of Cad-11. To determine whether Cad-11 is a mediator of dermal fibrosis, Cad-11 deficient mice and anti-Cad-11 monoclonal antibodies (mAb) were used in the bleomycin-induced dermal fibrosis model. In vitro studies with dermal fibroblasts and bone marrow-derived macrophages were used to determine the mechanisms by which Cad-11 contributes to the development of tissue fibrosis. RESULTS: Levels of messenger RNA for Cad-11 were increased in skin biopsy samples from patients with SSc and correlated with the modified Rodnan skin thickness scores. Cad-11 expression was localized to dermal fibroblasts and macrophages in SSc skin. Cad 11-knockout mice injected with bleomycin had markedly attenuated dermal fibrosis, as quantified by measurements of skin thickness, collagen levels, myofibroblast accumulation, and profibrotic gene expression, in lesional skin as compared to the skin of wild-type mice. In addition, anti-Cad-11 mAb decreased fibrosis at various time points in the bleomycin-induced dermal fibrosis model. In vitro studies demonstrated that Cad-11 regulated the production of transforming growth factor beta (TGFbeta) by macrophages and the migration of fibroblasts. CONCLUSION: These data demonstrate that Cad-11 is a mediator of dermal fibrosis and TGFbeta production and suggest that Cad-11 may be a therapeutic target in SSc. PMID- 24757153 TI - Inhibition of myogenic microRNAs 1, 133, and 206 by inflammatory cytokines links inflammation and muscle degeneration in adult inflammatory myopathies. AB - OBJECTIVE: The molecular basis of inflammatory myopathies such as dermatomyositis (DM), polymyositis, and inclusion body myositis, which share the characteristics of chronic muscle inflammation and skeletal muscle wasting, are poorly understood. As such, effective targeted treatments for these diseases are lacking, resulting in critical unmet medical needs for these devastating diseases. The purpose of this study was to identify possible new targets for drug development by exploring the mechanism by which inflammation may play a role in the pathology of the inflammatory myopathies. METHODS: We compared expression levels of inflammatory cytokines and microRNAs (miRNAs) between muscle biopsy samples from patients with inflammatory myopathies and those from donors without myositis. In vitro human and mouse model systems were then used to characterize the role of these cytokines and microRNAs on myoblast-to-myocyte differentiation. RESULTS: We observed increased expression of inflammatory cytokines, including tumor necrosis factor alpha (TNFalpha), interferon-alpha (IFNalpha), IFNbeta, and interleukin-1beta, in different subtypes of inflammatory myopathies. We observed decreased expression of microRNA-1 (miR-1), miR-133a, and miR-133b in all of the inflammatory myopathy subtypes we evaluated, as well as decreased expression of miR-206 in DM; these miRNAs are essential for adult skeletal muscle differentiation and maintenance. TNFalpha was significantly inversely correlated with decreased myogenic miRNA expression in the inflammatory myopathy subtypes. In mechanistic studies, TNFalpha inhibited the expression of myogenic miRNAs and suppressed the differentiation of C2C12 myoblasts to myocytes/myotubes in an NF kappaB-dependent manner. This block in differentiation by TNFalpha was relieved by overexpression of miR-1, miR-206, or miR-133a/b. CONCLUSION: Taken together, these results provide a new mechanistic link between the action of proinflammatory cytokines and the degenerative pathology of inflammatory myopathies, and suggest therapeutic approaches for these diseases. PMID- 24757154 TI - Effectiveness of first-line treatment with recombinant interleukin-1 receptor antagonist in steroid-naive patients with new-onset systemic juvenile idiopathic arthritis: results of a prospective cohort study. AB - OBJECTIVE: To conduct a prospective cohort study using anakinra, a recombinant IL 1 receptor antagonist (IL-1Ra), as first-line therapy in patients with new-onset systemic juvenile idiopathic arthritis (JIA). METHODS: Therapy with recombinant IL-1Ra (2 mg/kg) was initiated in 20 patients who fulfilled the International League of Associations for Rheumatology criteria for systemic JIA, before systemic steroid treatment was administered. Patients were monitored clinically and immunologically. The protocol contained a stop strategy for patients who met at least the adapted American College of Rheumatology 90% criteria for improvement in JIA (ACR Pediatric 90 [ACR Pedi 90]) after 3 months. RESULTS: We included consecutive patients with new-onset systemic JIA. The mean followup period was 32 months (range 12-54 months). At the 3-month time point, 85% of the patients showed an adapted ACR Pedi 90 response or had inactive disease; 75% of the patients achieved this response while receiving recombinant IL-1Ra alone. After 1 year, 17 of the 20 patients met the criteria for clinically inactive disease, and 13 of these patients met these criteria while receiving monotherapy with recombinant IL-1Ra. However, because of persistent disease activity, 7 of the 20 patients required additional therapy besides recombinant IL-1Ra. According to our stop strategy, 73% of patients with at least an adapted ACR Pedi 90 response at 3 months could stop recombinant IL-1Ra treatment within 1 year. After 2 years, 12 (86%) of 14 patients met the criteria for disease remission, either while receiving (n = 4) or not receiving (n = 8) medication. After 3 years, 10 (91%) of 11 patients met the criteria for disease remission, either while receiving (n = 2) or not receiving (n = 8) medication. CONCLUSION: This is the first prospective study in which recombinant IL-1Ra was used as first-line therapy in patients with systemic JIA. We observed excellent responses in nearly all patients within 3 months. In the majority of responding patients, treatment with recombinant IL-1Ra could be stopped within 1 year, with remission being preserved during followup. In approximately one-third of patients, concomitant therapy was required for maintenance of clinical response. PMID- 24757156 TI - Direct and indirect rituximab-induced T cell depletion: comment on the article by Melet et Al. PMID- 24757155 TI - Assessment of joint and fascia manifestations in chronic graft-versus-host disease. AB - OBJECTIVE: To investigate the usefulness of various scales for evaluating joint and fascia manifestations in patients with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation, and to compare the scales in terms of simplicity of use and ability to yield reliable and clinically meaningful results. METHODS: In a prospective, multicenter, longitudinal, observational cohort of patients with chronic GVHD (n = 567), we evaluated 3 scales proposed for assessing joint status: the National Institutes of Health (NIH) joint/fascia scale, the Hopkins fascia scale, and the Photographic Range of Motion (P-ROM) scale. Ten other scales were also tested for assessment of symptoms, quality of life, and physical functions. RESULTS: Joint and fascia manifestations were present at study enrollment in 164 (29%) of the patients. Limited range of motion was most frequent at the wrists or fingers. Among the 3 joint assessment scales, changes in the NIH scale correlated with both clinician- and patient-perceived improvement of joint and fascia manifestations, with higher sensitivity than the Hopkins fascia scale. Changes in all 3 scales correlated with clinician- and patient-perceived worsening, but the P-ROM scale was the most sensitive in this regard. Onset of joint and fascia manifestations was not associated with subsequent mortality. CONCLUSION: Joint and fascia manifestations are common in patients with chronic GVHD and should be assessed carefully in these patients. Our results support the use of the NIH joint/fascia scale and P ROM scale to assess joint and fascia manifestations. The NIH scale better captures improvement, while the P-ROM scale better captures worsening. The utility of these scales could also be tested in the rheumatic diseases. PMID- 24757157 TI - Reply: To PMID 23918413. PMID- 24757158 TI - Is the glass half full or half empty? Comment on the article by Gartner et Al. PMID- 24757159 TI - Reply: To PMID 23686535. PMID- 24757160 TI - Lupus headache may not exist: comment on the article by Hanly et Al. PMID- 24757161 TI - Reply: To PMID 24166793. PMID- 24757162 TI - Synovial bursa protruding through the triceps brachii muscle. PMID- 24757163 TI - The anatomy and ontogeny of the head, neck, pectoral, and upper limb muscles of Lemur catta and Propithecus coquereli (primates): discussion on the parallelism between ontogeny and phylogeny and implications for evolutionary and developmental biology. AB - Most anatomical studies of primates focus on skeletal tissues, but muscular anatomy can provide valuable information about phylogeny, functional specializations, and evolution. Herein, we present the first detailed description of the head, neck, pectoral, and upper limb muscles of the fetal lemuriforms Lemur catta (Lemuridae) and Propithecus coquereli (Indriidae). These two species belong to the suborder Strepsirrhini, which is often presumed to possess some plesiomorphic anatomical features within primates. We compare the muscular anatomy of the fetuses with that of infants and adults and discuss the evolutionary and developmental implications. The fetal anatomy reflects a phylogenetically more plesiomorphic condition in nine of the muscles we studied and a more derived condition in only two, supporting a parallel between ontogeny and phylogeny. The derived exceptions concern muscles with additional insertions in the fetus which are lost in adults of the same species, that is, flexor carpi radialis inserts on metacarpal III and levator claviculae inserts on the clavicle. Interestingly, these two muscles are involved in movements of the pectoral girdle and upper limb, which are mainly important for activities in later stages of life, such as locomotion and prey capture, rather than activities in fetal life. Accordingly, our findings suggest that some exceptions to the "ontogeny parallels phylogeny" rule are probably driven more by ontogenetic constraints than by adaptive plasticity. PMID- 24757164 TI - Is multifocality a prognostic factor in childhood hepatoblastoma? AB - BACKGROUND: The aim of this study was to assess the prognostic value of multifocality and the effectiveness of two different therapeutic strategies in patients with newly diagnosed hepatoblastoma. PROCEDURES: Between 1998 and 2011, 31 patients diagnosed with hepatoblastoma were referred to Ospedale Papa Giovanni XXIII, Bergamo, Italy. Patients were stratified according to SIOPEL protocols into high-risk (HR if AFP <100 ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease and/or metastases) and standard-risk (SR, all others). The patient data we evaluated were: multifocality; patient age; gender; platelet count; AFP level at diagnosis, during treatment and follow-up; histotype; gestational age; birth weight; surgery (either resection or transplantation) and chemotherapy regimen adopted before and after surgery. The outcome measures were event free survival (EFS) and overall survival (OS); survival curves were estimated according to Kaplan-Meier. RESULTS: EFS and OS were associated significantly with multifocality (3-year EFS 40% vs. 95%, P = 0.006; 3-year OS 42% vs. 95%, P = 0.004). Multivariate analysis demonstrated that multifocality predicts lower EFS (hazard ratio 10.01, P = 0.007). Other factors at diagnosis did not reach statistical significance. A marked treatment dependent improvement was associated with intensive chemotherapy given both before and after liver transplantation (P = 0.06). CONCLUSIONS: Patients diagnosed with multifocal tumors had lower EFS levels. Multifocality should be taken into account for future stratification and further studied to assess genetic profile, immunochemistry and prognostic role. PMID- 24757165 TI - Organocatalytic atroposelective aldol condensation: synthesis of axially chiral biaryls by arene formation. AB - Axially chiral compounds are of significant importance in modern synthetic chemistry and particularly valuable in drug discovery and development. Nonetheless, current approaches for the preparation of pure atropisomers often prove tedious. We demonstrate here a synthetic method that efficiently transfers the stereochemical information of a secondary amine organocatalyst into the axial chirality of tri-ortho-substituted biaryls. An aromatic ring is formed during the dehydration step of the described aldol condensation cascade, leading to highly enantioenriched binaphthyl derivatives. The fundamental course of the reaction is related to the biosynthesis of aromatic polyketides. PMID- 24757166 TI - The MID-PIWI module of Piwi proteins specifies nucleotide- and strand-biases of piRNAs. AB - Piwi-interacting RNAs (piRNAs) guide Piwi Argonautes to suppress transposon activity in animal gonads. Known piRNA populations are extremely complex, with millions of individual sequences present in a single organism. Despite this complexity, specific Piwi proteins incorporate piRNAs with distinct nucleotide- and transposon strand-biases (antisense or sense) of unknown origin. Here, we examined the contribution of structural domains in Piwi proteins toward defining these biases. We report the first crystal structure of the MID domain from a Piwi Argonaute and use docking experiments to show its ability to specify recognition of 5' uridine (1U-bias) of piRNAs. Mutational analyses reveal the importance of 5' end-recognition within the MID domain for piRNA biogenesis in vivo. Finally, domain-swapping experiments uncover an unexpected role for the MID-PIWI module of a Piwi protein in dictating the transposon strand-orientation of its bound piRNAs. Our work identifies structural features that allow distinguishing individual Piwi members during piRNA biogenesis. PMID- 24757167 TI - Derivation and characterization of Dicer- and microRNA-deficient human cells. AB - We have used genome editing to generate inactivating deletion mutations in all three copies of the dicer (hdcr) gene present in the human cell line 293T. As previously shown in murine ES cells lacking Dicer function, hDcr-deficient 293T cells are severely impaired for the production of mature microRNAs (miRNAs). Nevertheless, RNA-induced silencing complexes (RISCs) present in these hDcr deficient cells are readily programmed by transfected, synthetic miRNA duplexes to repress mRNAs bearing either fully or partially complementary targets, including targets bearing incomplete seed homology to the introduced miRNA. Using these hDcr-deficient 293T cells, we demonstrate that human pre-miRNA processing can be effectively rescued by ectopic expression of the Drosophila Dicer 1 protein, but only in the presence of the PB isoform of Loquacious (Loqs-PB), the fly homolog of the hDcr cofactor TRBP. In contrast, Drosophila Dicer 2, even in the presence of its cofactors Loqs-PD and R2D2, was unable to support human pre miRNA processing. Interestingly, although ectopic Drosophila Dicer 1/Loqs-PB or hDcr both rescued pre-miRNA processing effectively in these hDcr-deficient cells, there were significant differences in the ratio of the miRNA isoforms that were produced, especially in the case of miR-30 family members, and we also noted differences in the relative expression level of miRNAs vs. passenger strands for a subset of human miRNAs. These data demonstrate that the mechanisms underlying the accurate processing of pre-miRNAs are largely, but not entirely, conserved between mammalian and insect cells. PMID- 24757168 TI - An adaptable pentaloop defines a robust neomycin-B RNA aptamer with conditional ligand-bound structures. AB - Aptamers can be highly specific for their targets, which implies precise molecular recognition between aptamer and target. However, as small polymers, their structures are more subject to environmental conditions than the more constrained longer RNAs such as those that constitute the ribosome. To understand the balance between structural and environmental factors in establishing ligand specificity of aptamers, we examined the RNA aptamer (NEO1A) previously reported as specific for neomycin-B. We show that NEO1A can recognize other aminoglycosides with similar affinities as for neomycin-B and its aminoglycoside specificity is strongly influenced by ionic strength and buffer composition. NMR and 2-aminopurine (2AP) fluorescence studies of the aptamer identified a flexible pentaloop and a stable binding pocket. Consistent with a well-structured binding pocket, docking analysis results correlated with experimental measures of the binding energy for most ligands. Steady state fluorescence studies of 2AP substituted aptamers confirmed that A16 moves to a more solvent accessible position upon ligand binding while A14 moves to a less solvent accessible position, which is most likely a base stack. Analysis of binding affinities of NEO1A sequence variants showed that the base in position 16 interacts differently with each ligand and the interaction is a function of the buffer constituents. Our results show that the pentaloop provides NEO1A with the ability to adapt to external influences on its structure, with the critical base at position 16 adjusting to incorporate each ligand into a stable pocket by hydrophobic interactions and/or hydrogen bonds depending on the ligand and the ionic environment. PMID- 24757169 TI - Chemical synthesis of the 5-taurinomethyl(-2-thio)uridine modified anticodon arm of the human mitochondrial tRNA(Leu(UUR)) and tRNA(Lys). AB - 5-Taurinomethyluridine (taum(5)U) and 5-taurinomethyl-2-thiouridine (taum(5)s(2)U) are located at the wobble position of human mitochondrial (hmt) tRNA(Leu(UUR)) and tRNA(Lys), respectively. Both hypermodified units restrict decoding of the third codon letter to A and G. Pathogenic mutations in the genes encoding hmt-tRNA(Leu(UUR)) and hmt-tRNA(Lys) are responsible for the loss of the discussed modifications and, as a consequence, for the occurrence of severe mitochondrial dysfunctions (MELAS, MERRF). Synthetic oligoribonucleotides bearing modified nucleosides are a versatile tool for studying mechanisms of genetic message translation and accompanying pathologies at nucleoside resolution. In this paper, we present site-specific chemical incorporation of taum(5)U and taum(5)s(2)U into 17-mers related to the sequence of the anticodon arms hmt tRNA(Leu(UUR)) and hmt-tRNA(Lys), respectively employing phosphoramidite chemistry on CPG support. Selected protecting groups for the sulfonic acid (4 (tert-butyldiphenylsilanyloxy)-2,2-dimethylbutyl) and the exoamine function ( C(O)CF3) are compatible with the blockage of the canonical monomeric units. The synthesis of taum(5)s(2)U-modified RNA fragment was performed under conditions eliminating the formation of side products of 2-thiocarbonyl group oxidation and/or oxidative desulphurization. The structure of the final oligomers was confirmed by mass spectroscopy and enzymatic cleavage data. PMID- 24757171 TI - Student perceptions and effectiveness of an innovative learning tool: Anatomy Glove Learning System. AB - A trend in anatomical education is the development of alternative pedagogical approaches to replace or complement experiences in a cadaver laboratory; however, empirical evidence on their effectiveness is often not reported. This study aimed to evaluate the effectiveness of Anatomy Glove Learning System (AGLS), which enables students to learn the relationship between hand structure and function by drawing the structures onto a worn glove with imprinted bones. Massage therapy students (n = 73) were allocated into two groups and drew muscles onto either: (1) the glove using AGLS instructional videos (3D group); or (2) paper with palmar/dorsal views of hand bones during an instructor-guided activity (2D group). A self-confidence measure and knowledge test were completed before, immediately after, and one-week following the learning conditions. Self confidence of hand anatomy in the 3D group gradually increased (3.2/10, 4.7/10, and 4.8/10), whereas self-confidence in the 2D group began to decline one-week later (3.2/10, 4.4/10, and 3.9/10). Knowledge of hand anatomy improved in both groups immediately after learning, (P < 0.001). Students' perceptions of AGLS were also assessed using a 10-pt Likert scale evaluation questionnaire (10 = high). Students perceived the AGLS videos (mean = 8.3 +/- 2.0) and glove (mean = 8.1 +/- 1.8) to be helpful in improving their understanding of hand anatomy and the majority of students preferred AGLS as a learning tool (mean = 8.6 +/- 2.2). This study provides evidence demonstrating that AGLS and the traditional 2D learning approach are equally effective in promoting students' self-confidence and knowledge of hand anatomy. PMID- 24757172 TI - Intact facial adaptation in autistic adults. AB - Adaptation paradigms seek to bias subsequently viewed stimuli through prolonged exposure to an adapting stimulus, thereby giving rise to an aftereffect. Recent experiments have found that children with autism spectrum disorders (ASD) show reduced facial aftereffects, prompting some researchers to speculate that all individuals with ASD exhibit deficient facial adaptation. However, caution is required when generalizing findings from samples of children with ASD to the wider ASD population. The reduced facial aftereffects seen in child samples may instead reflect delayed or atypical developmental trajectories, whereby individuals with ASD are slower to develop adaptive mechanisms. In the present study, two experiments were conducted to determine whether high-functioning adults with ASD also show diminished aftereffects for facial identity and expression. In Experiment 1, using a procedure that minimized the contribution of low-level retinotopic adaptation, we observed substantial aftereffects comparable to those seen in matched controls, for both facial identity and expression. A similar pattern of results was seen in Experiment 2 using a revised procedure that increased the contribution of retinotopic adaptation to the facial aftereffects observed. That adults with autism can show robust facial aftereffects raises the possibility that group differences are seen only at particular points during development, and may not be a lifelong feature of the condition. PMID- 24757173 TI - EPR imaging of dose distributions aiming at applications in radiation therapy. AB - A one-dimensional electron paramagnetic resonance (EPR) imaging method for visualisation of dose distributions in photon fields has been developed. Pressed pellets of potassium dithionate were homogeneously irradiated in a (60)Co radiation field to 600 Gy. The EPR analysis was performed with an X-Band (9.6 GHz) Bruker E540 EPR and EPR imaging spectrometer equipped with an E540 GC2X two axis X-band gradient coil set with gradients along the y axis (along the sample tube) and z axis (along B0) and an ER 4108TMHS resonator. Image reconstruction, including deconvolution, baseline corrections and corrections for the resonator sensitivity, was performed using an in-house-developed Matlab code for the purpose to have a transparent and complete algorithm for image reconstruction. With this method, it is possible to visualise a dose distribution with an accuracy of ~5 % within +/-5 mm from the centre of the resonator. PMID- 24757174 TI - Further biodosimetry investigations using murine partial-body irradiation model. AB - This study evaluates both the effects of physical restraint and use of candidate biomarkers in a CD2F1 male mouse partial-body irradiation model for biological dosimetry diagnostic assays. Mice were irradiated (6-Gy, 250-kVp X ray) to 3/3rd (total body), 2/3rd (gut and torso), 1/3rd (gut only) and 0/3rd (sham) of total body. Blood was sampled for haematology and blood plasma proteomic biomarkers at 1 and 2 d after exposure. Increases in the body fraction exposed showed progressive decreases in lymphocyte counts and increases in the neutrophil-to lymphocyte ratios with no significant differences in the neutrophil and platelet counts. The radioresponse for plasma biomarker Flt3L showed proportional increases; however, G-CSF and SAA levels exhibited dramatic and non-proportional increases in levels. Physical restraint at 1 d post-exposure increased lymphocyte counts and SAA, decreased neutrophil-to-lymphocyte ratio and Flt3L and showed no effects on neutrophil and platelet counts or G-CSF. PMID- 24757175 TI - Simulation and measurement of the radiation field of the 1.4-GeV electron beam dump of the FERMI free-electron laser. AB - The authors examine the radiation field produced in the vicinity of the main beam dump of the FERMI free-electron laser under the impact of a 1.4-GeV electron beam. Electromagnetic and neutron dose rates are calculated with the Fluka Monte Carlo code and compared with ionisation chamber and superheated drop detector measurements in various positions around the dump. Experimental data and simulation results are in good agreement with a maximum deviation of 25 % in a single location. PMID- 24757176 TI - Automating dicentric chromosome detection from cytogenetic biodosimetry data. AB - We present a prototype software system with sufficient capacity and speed to estimate radiation exposures in a mass casualty event by counting dicentric chromosomes (DCs) in metaphase cells from many individuals. Top-ranked metaphase cell images are segmented by classifying and defining chromosomes with an active contour gradient vector field (GVF) and by determining centromere locations along the centreline. The centreline is extracted by discrete curve evolution (DCE) skeleton branch pruning and curve interpolation. Centromere detection minimises the global width and DAPI-staining intensity profiles along the centreline. A second centromere is identified by reapplying this procedure after masking the first. Dicentrics can be identified from features that capture width and intensity profile characteristics as well as local shape features of the object contour at candidate pixel locations. The correct location of the centromere is also refined in chromosomes with sister chromatid separation. The overall algorithm has both high sensitivity (85 %) and specificity (94 %). Results are independent of the shape and structure of chromosomes in different cells, or the laboratory preparation protocol followed. The prototype software was recoded in C++/OpenCV; image processing was accelerated by data and task parallelisation with Message Passaging Interface and Intel Threading Building Blocks and an asynchronous non-blocking I/O strategy. Relative to a serial process, metaphase ranking, GVF and DCE are, respectively, 100 and 300-fold faster on an 8-core desktop and 64-core cluster computers. The software was then ported to a 1024 core supercomputer, which processed 200 metaphase images each from 1025 specimens in 1.4 h. PMID- 24757178 TI - Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer. AB - The Met receptor tyrosine kinase is activated or genetically amplified in some gastric cancers, but resistance to small-molecule inhibitors of Met often emerges in patients. We found that Met abundance correlated with a proliferation marker in patient gastric tumor sections, and gastric cancer cell lines that have MET amplifications depended on Met for proliferation and anchorage-independent growth in culture. Inhibition of Met induced temporal changes in gene expression in the cell lines, initiated by a rapid decrease in the expression of genes encoding transcription factors, followed by those encoding proteins involved in epithelial mesenchymal transition, and finally those encoding cell cycle-related proteins. In the gastric cancer cell lines, microarray and chromatin immunoprecipitation analysis revealed considerable overlap between genes regulated in response to Met stimulation and those regulated by signal transducer and activator of transcription 3 (STAT3). The activity of STAT3, extracellular signal-regulated kinase (ERK), and the kinase Akt was decreased by Met inhibition, but only inhibitors of STAT3 were as effective as the Met inhibitor in decreasing tumor cell proliferation in culture and in xenografts, suggesting that STAT3 mediates the pro-proliferative program induced by Met. However, the phosphorylation of ERK increased after prolonged Met inhibition in culture, correlating with decreased abundance of the phosphatases DUSP4 and DUSP6, which inhibit ERK. Combined inhibition of Met and the mitogen-activated protein kinase kinase (MEK)-ERK pathway induced greater cell death in cultured gastric cancer cells than did either inhibitor alone. These findings indicate combination therapies that may counteract resistance to Met inhibitors. PMID- 24757179 TI - Esophageal duplication cyst. AB - Esophageal duplication cyst is a rare congenital mediastinal cyst. Most of these cysts become symptomatic in childhood and only rare cases remain asymptomatic until adolescence. They may produce symptoms due to esophageal and respiratory system compression, rupture, and infection. A 25-year-old man presented with pulmonary infection and bronchiectasis that did not improve with medical treatment. A diagnosis of esophageal duplication cyst was made intraoperatively. PMID- 24757177 TI - Nuclear envelope lamin-A couples actin dynamics with immunological synapse architecture and T cell activation. AB - In many cell types, nuclear A-type lamins regulate multiple cellular functions, including higher-order genome organization, DNA replication and repair, gene transcription, and signal transduction; however, their role in specialized immune cells remains largely unexplored. We showed that the abundance of A-type lamins was almost negligible in resting naive T lymphocytes, but was increased upon activation of the T cell receptor (TCR). The increase in lamin-A was an early event that accelerated formation of the immunological synapse between T cells and antigen-presenting cells. Polymerization of F-actin in T cells is a critical step for immunological synapse formation, and lamin-A interacted with the linker of nucleoskeleton and cytoskeleton (LINC) complex to promote F-actin polymerization. We also showed that lamin-A expression accelerated TCR clustering and led to enhanced downstream signaling, including extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, as well as increased target gene expression. Pharmacological inhibition of the ERK pathway reduced lamin-A-dependent T cell activation. Moreover, mice lacking lamin-A in immune cells exhibited impaired T cell responses in vivo. These findings underscore the importance of A-type lamins for TCR activation and identify lamin-A as a previously unappreciated regulator of the immune response. PMID- 24757180 TI - Bronchial injuries in children: single-center experience. AB - OBJECTIVE: To present our experience of the management of bronchial injuries in children. METHODS: Between 2001 and 2012, we diagnosed 11 cases of bronchial injuries in children and reviewed their records. RESULTS: The age range was 3-12 years. Etiologies were passenger traffic accidents in 55%, pedestrian traffic accidents in 27%, and a fall from a height in 18%. Clinical manifestations were pneumothorax with continuous air leak in 81%, subcutaneous emphysema in 55%, and failure of lung expansion in 64%. Three (27%) cases were diagnosed late. All patients were operated on through a posterolateral thoracotomy. Main stem bronchial rupture was identified in the right side in 72% and in the left side in 28%. Bronchial repair was feasible in 7 (64%) cases, but resection was inevitable in 4 cases (3 pneumonectomies and one lobectomy). Two of the patients who required resection died; they had associated intraabdominal injuries. All survivors were discharged in stable condition without complications. CONCLUSION: Bronchial injuries in children are rare and challenging. Clinical, radiological, and bronchoscopic examinations facilitate the diagnosis. Early diagnosis and bronchial repair offers favorable results. Delayed diagnosis, lung resection, and associated injuries adversely affect the outcome. PMID- 24757181 TI - Calculation of limits for significant unidirectional changes in two or more serial results of a biomarker based on a computer simulation model. AB - BACKGROUND: Reference change values (RCVs) were introduced more than 30 years ago and provide objective tools for assessment of the significance of differences in two consecutive results from an individual. However, in practice, more results are usually available for monitoring, and using the RCV concept on more than two results will increase the number of false-positive results. Therefore, a simple method is needed to interpret the significance of a difference when all available serial biomarker results are considered. METHODS: A computer simulation model using Excel was developed. Based on 10,000 simulated data from healthy individuals, a series of up to 20 results from an individual was generated using different values for the within-subject biological variation plus the analytical variation. Each new result in this series was compared to the initial measurement result. These successive serial relative differences were computed to give limits for significant unidirectional differences with a constant cumulated maximum probability of both 95% (P < 0.05) and 99% (P < 0.01). RESULTS: Factors used to multiply the first result from an individual were calculated to create the limits for constant cumulated significant differences. The factors were shown to become a simple function of the number of results and the total coefficient of variation. CONCLUSIONS: To interpret unidirectional differences in two or more serial results of a biomarker, the limits for significances are easily calculated using the presented factors. The first result is multiplied by the appropriate factor for increase or decrease, which gives the limits for a significant difference. PMID- 24757182 TI - Comparison of cardiac TnI outliers using a contemporary and a high-sensitivity assay on the Abbott Architect platform. AB - BACKGROUND: Assays for cardiac troponin (cTn) have undergone improvements in sensitivity and precision in recent years. Increased rates of outliers, however, have been reported on various cTn platforms, typically giving irreproducible, falsely higher results. We aimed to evaluate the outlier rate occurring in patients with elevated cTnI using a contemporary and high-sensitivity assay. METHODS: All patients with elevated cTnI (up to 300 ng/L) performed over a 21 month period were assayed in duplicate. A contemporary assay (Abbott STAT Troponin-I) was used for the first part of the study and subsequently a high sensitivity assay (Abbott STAT High-Sensitive Troponin-I) was used. Outliers exceeded a calculated critical difference (CD) (CD = z * ?2 * SDAnalytical) where z = 3.5 (for probability of 0.0005) and critical outliers also were on a different side of the decision level. RESULTS: The respective outlier and critical outlier rates were 0.22% and 0.10% for the contemporary assay (n = 4009) and 0.18% and 0.13% for the high-sensitivity assay (n = 3878). There was no significant reduction in outlier rate between the two assays (chi(2) = 0.034, P = 0.854). Fifty-six percent of outliers occurred in samples where cTn was an 'add on' test (and was stored and refrigerated prior to assay). CONCLUSION: Despite recent improvements in cTn methods, outliers (including critical outliers) still occur at a low rate in both a contemporary and high-sensitivity cTnI assay. Laboratory and clinical staff should be aware of this potential analytical error, particularly in samples with suboptimal sample handling such as add-on tests. PMID- 24757183 TI - Pulmonary cryptococcosis: comparison of CT findings in immunocompetent and immunocompromised patients. AB - BACKGROUND: Computed tomography (CT) findings in patients with pulmonary cryptococcosis have been reported, however, many reports were limited by the small number of patients, and not taken into account the distinction between immunocompetent and immunocompromised patients. PURPOSE: To retrospectively evaluate thoracic CT findings in patients with pulmonary cryptococcosis whose immune status ranged from normal to severely compromised, and determine characteristic imaging features of pulmonary cryptococcosis between patients with different immune status. MATERIAL AND METHODS: CT scan findings of 29 immunocompetent and 43 immunocompromised patients with clinically proven pulmonary cryptococcosis were reviewed retrospectively. Different patterns of CT scan abnormalities between immunocompromised and immunocompetent patients, AIDS and non-AIDS immunocompromised patients were compared by Fisher's exact test. RESULTS: Pulmonary nodules/masses, either solitary or multiple, were the most common CT finding, present in 65 (90.3%) of the 72 patients; associated findings included CT halo sign (n = 24), cavitation (n = 23), and air bronchogram (n = 17). Areas of consolidation (n = 14), areas of GGO (n = 13), linear opacities (n = 11), lymphadenopathy (n = 5), and pleural effusion (n = 8) were uncommon. The parenchymal abnormalities were peripherally located in 47 (65.2%) of the cases. Cavitations within nodules/masses were more frequently present in immunocompromised patients than in immunocompetent patients (P = 0.009), and in AIDS patients than in non-AIDS immunocompromised patients (P = 0.002). Air bronchograms within nodules/masses were more frequent present in immunocompetent patients than in immunocompromised patients (P = 0.005). Nodules/masses with halo sign were less frequent in AIDS patients than those in non-AIDS immunocompromised patients (P = 0.027). CONCLUSION: Pulmonary cryptococcosis should be considered in the differential diagnosis of solitary or multiple pulmonary nodules. Cavitations within nodules/masses were more commonly seen in immunocompromised patients, especially AIDS patients, while air bronchograms were more commonly seen in immunocompetent patients. PMID- 24757184 TI - The annoying pulmonary nodule on CT. PMID- 24757185 TI - Value of 3T 1H-magnetic resonance spectroscopy in the differentiation of benign and malignant breast tumors. PMID- 24757186 TI - Response to "Application value of 3T 1H-magnetic resonance spectroscopy in diagnosing breast tumors". PMID- 24757187 TI - Reliability of on-call radiology residents' interpretation of 64-slice CT pulmonary angiography for the detection of pulmonary embolism: methodological error. PMID- 24757188 TI - Response to Sabour and Ghassemi. PMID- 24757193 TI - Cell replacement strategies aimed at reconstitution of the beta-cell compartment in type 1 diabetes. AB - Emerging technologies in regenerative medicine have the potential to restore the beta-cell compartment in diabetic patients, thereby overcoming the inadequacies of current treatment strategies and organ supply. Novel approaches include: 1) Encapsulation technology that protects islet transplants from host immune surveillance; 2) stem cell therapies and cellular reprogramming, which seek to regenerate the depleted beta-cell compartment; and 3) whole-organ bioengineering, which capitalizes on the innate properties of the pancreas extracellular matrix to drive cellular repopulation. Collaborative efforts across these subfields of regenerative medicine seek to ultimately produce a bioengineered pancreas capable of restoring endocrine function in patients with insulin-dependent diabetes. PMID- 24757194 TI - The importance of the liver in insulin replacement therapy in insulin-deficient diabetes. PMID- 24757195 TI - Amyloid and the macrophage: it's all about local production of IL-1beta. PMID- 24757196 TI - MicroRNAs emerge as modulators of NAD+-dependent energy metabolism in skeletal muscle. PMID- 24757197 TI - Diabetes improvement following Roux-en-Y gastric bypass: understanding dynamic changes in insulin secretion and action. PMID- 24757198 TI - Even silent hypoglycemia induces cardiac arrhythmias. PMID- 24757199 TI - The DCCT/EDIC study: epigenetic clues after three decades. PMID- 24757200 TI - Zinc-rs13266634 and the arrival of diabetes pharmacogenetics: the "zinc mystique". PMID- 24757201 TI - MicroRNA-149 inhibits PARP-2 and promotes mitochondrial biogenesis via SIRT-1/PGC 1alpha network in skeletal muscle. AB - High-fat diet (HFD) plays a central role in the initiation of mitochondrial dysfunction that significantly contributes to skeletal muscle metabolic disorders in obesity. However, the mechanism by which HFD weakens skeletal muscle metabolism by altering mitochondrial function and biogenesis is unknown. Given the emerging roles of microRNAs (miRNAs) in the regulation of skeletal muscle metabolism, we sought to determine whether activation of a specific miRNA pathway would rescue the HFD-induced mitochondrial dysfunction via the sirtuin-1 (SIRT 1)/ peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC 1alpha) pathway, a pathway that governs genes necessary for mitochondrial function. We here report that miR-149 strongly controls SIRT-1 expression and activity. Interestingly, miR-149 inhibits poly(ADP-ribose) polymerase-2 (PARP-2) and so increased cellular NAD(+) levels and SIRT-1 activity that subsequently increases mitochondrial function and biogenesis via PGC-1alpha activation. In addition, skeletal muscles from HFD-fed obese mice exhibit low levels of miR-149 and high levels of PARP-2, and they show reduced mitochondrial function and biogenesis due to a decreased activation of the SIRT-1/PGC-1alpha pathway, suggesting that mitochondrial dysfunction in the skeletal muscle of obese mice may be because of, at least in part, miR-149 dysregulation. Overall, miR-149 may be therapeutically useful for treating HFD-induced skeletal muscle metabolic disorders in such pathophysiological conditions as obesity and type 2 diabetes. PMID- 24757203 TI - Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes 2008;57:1002-1017. DOI: 10.2337/db07-0339. PMID- 24757204 TI - Intranasal insulin ameliorates experimental diabetic neuropathy. Diabetes 2009;58:934-945. DOI: 10.2337/db08-1287. PMID- 24757202 TI - Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. AB - Recent trials of intensive glycemic control suggest a possible link between hypoglycemia and excess cardiovascular mortality in patients with type 2 diabetes. Hypoglycemia might cause arrhythmias through effects on cardiac repolarization and changes in cardiac autonomic activity. Our aim was to study the risk of arrhythmias during spontaneous hypoglycemia in type 2 diabetic patients with cardiovascular risk. Twenty-five insulin-treated patients with type 2 diabetes and a history of cardiovascular disease or two or more risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring. Frequency of arrhythmias, heart rate variability, and markers of cardiac repolarization were compared between hypoglycemia and euglycemia and between hyperglycemia and euglycemia matched for time of day. There were 134 h of recording at hypoglycemia, 65 h at hyperglycemia, and 1,258 h at euglycemia. Bradycardia and atrial and ventricular ectopic counts were significantly higher during nocturnal hypoglycemia compared with euglycemia. Arrhythmias were more frequent during nocturnal versus daytime hypoglycemia. Excessive compensatory vagal activation after the counterregulatory phase may account for bradycardia and associated arrhythmias. QT intervals, corrected for heart rate, >500 ms and abnormal T-wave morphology were observed during hypoglycemia in some participants. Hypoglycemia, frequently asymptomatic and prolonged, may increase the risk of arrhythmias in patients with type 2 diabetes and high cardiovascular risk. This is a plausible mechanism that could contribute to increased cardiovascular mortality during intensive glycemic therapy. PMID- 24757205 TI - Update of retraction--Blockade of receptor for advanced glycation end products in a model of type 1 diabetic leukoencephalopathy. Diabetes. 19 November 2012 [Epub ahead of print]. DOI: 10.2337/db12-0317. PMID- 24757207 TI - Comment on Laker et al. Exercise prevents maternal high-fat diet-induced hypermethylation of the pgc-1alpha gene and age-dependent metabolic dysfunction in the offspring. Diabetes 2014;63:1605-1611. PMID- 24757208 TI - Response to comment on Laker et al. Exercise prevents maternal high-fat diet induced hypermethylation of the pgc-1alpha gene and age-dependent metabolic dysfunction in the offspring. Diabetes 2014;63:1605-1611. PMID- 24757209 TI - Comment on Sprouse et al. SLC30A8 nonsynonymous variant is associated with recovery following exercise and skeletal muscle size and strength. Diabetes 2014;63:363-368. PMID- 24757210 TI - Response to Comment on Sprouse et al. SLC30A8 nonsynonymous variant is associated with recovery following exercise and skeletal muscle size and strength. Diabetes 2014;63:363-368. PMID- 24757211 TI - Triosephosphate isomerase is dispensable in vitro yet essential for Mycobacterium tuberculosis to establish infection. AB - ABSTRACT Triosephosphate isomerase (TPI) catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P). This reaction is required for glycolysis and gluconeogenesis, and tpi has been predicted to be essential for growth of Mycobacterium tuberculosis. However, when studying a conditionally regulated tpi knockdown mutant, we noticed that depletion of TPI reduced growth of M. tuberculosis in media containing a single carbon source but not in media that contained both a glycolytic and a gluconeogenic carbon source. We used such two-carbon-source media to isolate a tpi deletion (Deltatpi) mutant. The Deltatpi mutant did not survive with single carbon substrates but grew like wild-type (WT) M. tuberculosis in the presence of both a glycolytic and a gluconeogenic carbon source. (13)C metabolite tracing revealed the accumulation of TPI substrates in Deltatpi and the absence of alternative triosephosphate isomerases and metabolic bypass reactions, which confirmed the requirement of TPI for glycolysis and gluconeogenesis in M. tuberculosis. The Deltatpi strain was furthermore severely attenuated in the mouse model of tuberculosis, suggesting that M. tuberculosis cannot simultaneously access sufficient quantities of glycolytic and gluconeogenic carbon substrates to establish infection in mice. IMPORTANCE The importance of central carbon metabolism for the pathogenesis of M. tuberculosis has recently been recognized, but the consequences of depleting specific metabolic enzymes remain to be identified for many enzymes. We investigated triosephosphate isomerase (TPI) because it is central to both glycolysis and gluconeogenesis and had been predicted to be essential for growth of M. tuberculosis. This work identified metabolic conditions that make TPI dispensable for M. tuberculosis growth in culture and proved that M. tuberculosis relies on a single TPI enzyme and has no metabolic bypass for the TPI-dependent interconversion of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate in glycolysis and gluconeogenesis. Finally, we demonstrate that TPI is essential for growth of the pathogen in mouse lungs. PMID- 24757212 TI - Revealing the bacterial butyrate synthesis pathways by analyzing (meta)genomic data. AB - Butyrate-producing bacteria have recently gained attention, since they are important for a healthy colon and when altered contribute to emerging diseases, such as ulcerative colitis and type II diabetes. This guild is polyphyletic and cannot be accurately detected by 16S rRNA gene sequencing. Consequently, approaches targeting the terminal genes of the main butyrate-producing pathway have been developed. However, since additional pathways exist and alternative, newly recognized enzymes catalyzing the terminal reaction have been described, previous investigations are often incomplete. We undertook a broad analysis of butyrate-producing pathways and individual genes by screening 3,184 sequenced bacterial genomes from the Integrated Microbial Genome database. Genomes of 225 bacteria with a potential to produce butyrate were identified, including many previously unknown candidates. The majority of candidates belong to distinct families within the Firmicutes, but members of nine other phyla, especially from Actinobacteria, Bacteroidetes, Fusobacteria, Proteobacteria, Spirochaetes, and Thermotogae, were also identified as potential butyrate producers. The established gene catalogue (3,055 entries) was used to screen for butyrate synthesis pathways in 15 metagenomes derived from stool samples of healthy individuals provided by the HMP (Human Microbiome Project) consortium. A high percentage of total genomes exhibited a butyrate-producing pathway (mean, 19.1%; range, 3.2% to 39.4%), where the acetyl-coenzyme A (CoA) pathway was the most prevalent (mean, 79.7% of all pathways), followed by the lysine pathway (mean, 11.2%). Diversity analysis for the acetyl-CoA pathway showed that the same few firmicute groups associated with several Lachnospiraceae and Ruminococcaceae were dominating in most individuals, whereas the other pathways were associated primarily with Bacteroidetes. IMPORTANCE Microbiome research has revealed new, important roles of our gut microbiota for maintaining health, but an understanding of effects of specific microbial functions on the host is in its infancy, partly because in-depth functional microbial analyses are rare and publicly available databases are often incomplete/misannotated. In this study, we focused on production of butyrate, the main energy source for colonocytes, which plays a critical role in health and disease. We have provided a complete database of genes from major known butyrate-producing pathways, using in-depth genomic analysis of publicly available genomes, filling an important gap to accurately assess the butyrate-producing potential of complex microbial communities from " omics"-derived data. Furthermore, a reference data set containing the abundance and diversity of butyrate synthesis pathways from the healthy gut microbiota was established through a metagenomics-based assessment. This study will help in understanding the role of butyrate producers in health and disease and may assist the development of treatments for functional dysbiosis. PMID- 24757213 TI - Amplification of aminoglycoside resistance gene aphA1 in Acinetobacter baumannii results in tobramycin therapy failure. AB - Gene amplification is believed to play an important role in antibiotic resistance but has been rarely documented in clinical settings because of its unstable nature. We report a rise in MICs from 0.5 to 16 MUg/ml in successive Acinetobacter baumannii isolated over 4 days from a patient being treated with tobramycin for an infection by multidrug-resistant A. baumannii, resulting in therapeutic failure. Isolates were characterized by whole-genome sequencing, real time and reverse transcriptase PCR, and growth assays to determine the mechanism of tobramycin resistance and its fitness cost. Tobramycin resistance was associated with two amplification events of different chromosomal fragments containing the aphA1 aminoglycoside resistance gene part of transposon Tn6020. The first amplification event involved low amplification (6 to 10 copies) of a large DNA fragment that was unstable and conferred tobramycin MICs of <= 8 MUg/ml. The second event involved moderate (10 to 30 copies) or high (40 to 110 copies) amplification of Tn6020. High copy numbers were associated with tobramycin MICs of 16 MUg/ml, impaired fitness, and genetic instability, whereas lower copy numbers resulted in tobramycin MICs of <=8 MUg/ml and no fitness cost and were stably maintained in vitro. Exposure in vitro to tobramycin of the initial susceptible isolate and of the A. baumannii AB0057 reference strain led to similar aphA1 amplifications and elevated tobramycin MICs. To the best of our knowledge, this is the first report of in vivo development of antibiotic resistance secondary to gene amplifications resulting in therapy failure. IMPORTANCE A combination of whole-genome sequencing and mapping were used to detect an antibiotic resistance mechanism, gene amplification, which has been presumed for a long time to be of major importance but has rarely been reported in clinical settings because of its unstable nature. Two gene amplification events in a patient with an Acinetobacter baumannii infection treated with tobramycin were identified. One gene amplification event led to high levels of resistance and was rapidly reversible, while the second event led to low and more stable resistance since it incurred low fitness cost on the host. Gene amplification, with an associated rise in tobramycin MICs, could be readily reproduced in vitro from initially susceptible strains exposed to increasing concentrations of tobramycin, suggesting that gene amplification in A. baumannii may be a more common mechanism than currently believed. This report underscores the importance of rapid molecular techniques for surveillance of drug resistance. PMID- 24757214 TI - Diverse antibiotic resistance genes in dairy cow manure. AB - Application of manure from antibiotic-treated animals to crops facilitates the dissemination of antibiotic resistance determinants into the environment. However, our knowledge of the identity, diversity, and patterns of distribution of these antibiotic resistance determinants remains limited. We used a new combination of methods to examine the resistome of dairy cow manure, a common soil amendment. Metagenomic libraries constructed with DNA extracted from manure were screened for resistance to beta-lactams, phenicols, aminoglycosides, and tetracyclines. Functional screening of fosmid and small-insert libraries identified 80 different antibiotic resistance genes whose deduced protein sequences were on average 50 to 60% identical to sequences deposited in GenBank. The resistance genes were frequently found in clusters and originated from a taxonomically diverse set of species, suggesting that some microorganisms in manure harbor multiple resistance genes. Furthermore, amid the great genetic diversity in manure, we discovered a novel clade of chloramphenicol acetyltransferases. Our study combined functional metagenomics with third generation PacBio sequencing to significantly extend the roster of functional antibiotic resistance genes found in animal gut bacteria, providing a particularly broad resource for understanding the origins and dispersal of antibiotic resistance genes in agriculture and clinical settings. IMPORTANCE The increasing prevalence of antibiotic resistance among bacteria is one of the most intractable challenges in 21st-century public health. The origins of resistance are complex, and a better understanding of the impacts of antibiotics used on farms would produce a more robust platform for public policy. Microbiomes of farm animals are reservoirs of antibiotic resistance genes, which may affect distribution of antibiotic resistance genes in human pathogens. Previous studies have focused on antibiotic resistance genes in manures of animals subjected to intensive antibiotic use, such as pigs and chickens. Cow manure has received less attention, although it is commonly used in crop production. Here, we report the discovery of novel and diverse antibiotic resistance genes in the cow microbiome, demonstrating that it is a significant reservoir of antibiotic resistance genes. The genomic resource presented here lays the groundwork for understanding the dispersal of antibiotic resistance from the agroecosystem to other settings. PMID- 24757215 TI - MexY-promoted aminoglycoside resistance in Pseudomonas aeruginosa: involvement of a putative proximal binding pocket in aminoglycoside recognition. AB - The resistance-nodulation-division (RND) family multidrug efflux system MexXY OprM is a major determinant of aminoglycoside resistance in Pseudomonas aeruginosa, although the details of aminoglycoside recognition and export by MexY, the substrate-binding RND component of this efflux system, have not been elucidated. To identify regions/residues of MexY important for aminoglycoside resistance, plasmid-borne mexY was mutagenized and mutations that impaired MexY promoted aminoglycoside (streptomycin) resistance were identified in a DeltamexY strain of P. aeruginosa. Sixty-one streptomycin-sensitive mexY mutants were recovered; among these, 7 unique mutations that yielded wild-type levels of MexY expression were identified. These mutations compromised resistance to additional aminoglycosides and to other antimicrobials and occurred in both the transmembrane and periplasmic regions of the protein. Mapping of the mutated residues onto a 3-dimensional structure of MexY modeled on Escherichia coli AcrB revealed that these tended to occur in regions implicated in general pump operation (transmembrane domain) and MexY trimer assembly (docking domain) and, thus, did not provide insights into aminoglycoside recognition. A region corresponding to a proximal binding pocket connected to a periplasm-linked cleft, part of a drug export pathway of AcrB, was identified in MexY and proposed to play a role in aminoglycoside recognition. To test this, selected residues (K79, D133, and Y613) within this pocket were mutagenized and the impact on aminoglycoside resistance was assessed. Mutations of D133 and Y613 compromised aminoglycoside resistance, while, surprisingly, the K79 mutation enhanced aminoglycoside resistance, confirming a role for this putative proximal binding pocket in aminoglycoside recognition and export. IMPORTANCE Bacterial RND pumps do not typically accommodate highly hydrophilic agents such as aminoglycosides, and it is unclear how those, such as MexY, which accommodate these unique substrates, do so. The results presented here indicate that aminoglycosides are likely not captured and exported by this RND pump component in a unique manner but rather utilize a previously defined export pathway that involves a proximal drug-binding pocket that is also implicated in the export of nonaminoglycosides. The observation, too, that a mutation in this pocket enhances MexY-mediated aminoglycoside resistance (K79A), an indication that it is not optimally designed to accommodate these agents, lends further support to earlier proposals that antimicrobials are not the intended pump substrates. PMID- 24757217 TI - Cryptococcus at work: gene expression during human infection. AB - Meningitis is a frequent manifestation of infection due to Cryptococcus neoformans and a major cause of increased morbidity in patients with AIDS. Numerous in vitro gene expression and genetic studies of the fungus have predicted a myriad of genes, pathways, and biological processes that may be critical for pathogenesis, and many studies using animal models have supported the role of these processes during infection. However, the relevance of these hypotheses based on in vitro and animal models has often been questioned. A recent study by Chen et al. [Y. Chen, D. L. Toffaletti, J. L. Tenor, A. P. Litvintseva, C. Fang, T. G. Mitchell, T. R. McDonald, K. Nielsen, D. R. Boulware, T. Bicanic, and J. R. Perfect, mBio 5(1):e01087-13, 2014] represents an important step in understanding the cryptococcal response during human infection. PMID- 24757216 TI - Global population structure and evolution of Bordetella pertussis and their relationship with vaccination. AB - Bordetella pertussis causes pertussis, a respiratory disease that is most severe for infants. Vaccination was introduced in the 1950s, and in recent years, a resurgence of disease was observed worldwide, with significant mortality in infants. Possible causes for this include the switch from whole-cell vaccines (WCVs) to less effective acellular vaccines (ACVs), waning immunity, and pathogen adaptation. Pathogen adaptation is suggested by antigenic divergence between vaccine strains and circulating strains and by the emergence of strains with increased pertussis toxin production. We applied comparative genomics to a worldwide collection of 343 B. pertussis strains isolated between 1920 and 2010. The global phylogeny showed two deep branches; the largest of these contained 98% of all strains, and its expansion correlated temporally with the first descriptions of pertussis outbreaks in Europe in the 16th century. We found little evidence of recent geographical clustering of the strains within this lineage, suggesting rapid strain flow between countries. We observed that changes in genes encoding proteins implicated in protective immunity that are included in ACVs occurred after the introduction of WCVs but before the switch to ACVs. Furthermore, our analyses consistently suggested that virulence-associated genes and genes coding for surface-exposed proteins were involved in adaptation. However, many of the putative adaptive loci identified have a physiological role, and further studies of these loci may reveal less obvious ways in which B. pertussis and the host interact. This work provides insight into ways in which pathogens may adapt to vaccination and suggests ways to improve pertussis vaccines. IMPORTANCE Whooping cough is mainly caused by Bordetella pertussis, and current vaccines are targeted against this organism. Recently, there have been increasing outbreaks of whooping cough, even where vaccine coverage is high. Analysis of the genomes of 343 B. pertussis isolates from around the world over the last 100 years suggests that the organism has emerged within the last 500 years, consistent with historical records. We show that global transmission of new strains is very rapid and that the worldwide population of B. pertussis is evolving in response to vaccine introduction, potentially enabling vaccine escape. PMID- 24757218 TI - Resistotype of Helicobacter pylori isolates: the impact on eradication outcome. AB - Antibiotic resistance is increasing worldwide, and it has been regarded as the main factor reducing the efficacy of Helicobacter pylori therapy. The aim of this study was to determine the phenotype and genotype of antibiotic-resistant strains of H. pylori in the Malaysian population and to evaluate the impact of antibiotic resistance to eradication outcome. One hundred and sixty-one H. pylori isolates were analysed in this study. Metronidazole, clarithromycin, fluoroquinolone, amoxicillin and tetracycline susceptibilities were determined by Etest. PCR followed by DNA sequencing was carried out to determine mutations. The medical records of the patients infected with resistant strains were reviewed to determine the eradication outcome. Metronidazole resistance was encountered in 36.6 % of H. pylori isolates, whereas clarithromycin and fluoroquinolone resistance was observed in 1.2 and 1.9 % of isolates, respectively. All strains tested were susceptible to amoxicillin and tetracycline. Frameshift and nonsense mutations in rdxA and frxA genes resulting in stop codons contributed to metronidazole resistance, which leads to reduced eradication efficacy. A2142G and A2143G mutations of 23S rRNA were identified as causing failure of the eradication therapy. Mutation at either codon 87 or 91 of the gyrA gene was identified in fluoroquinolone-resistant strains. However, the effect of resistance could not be assessed. This study showed that frameshift and nonsense mutations in rdxA or frxA genes and point mutations in the 23S rRNA affected the efficacy of H. pylori eradication therapy. PMID- 24757219 TI - Hepatitis B and hepatitis C virus infections among antiretroviral-naive and experienced HIV co-infected adults. AB - Most HIV positive people have not been tested for viral hepatitis and their treatments have not been optimized for possible co-infections. The aim of this study was to investigate the serological pattern of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among antiretroviral (ARV)-naive and experienced HIV co-infected adults in Addis Ababa, Ethiopia. A total of 500 frozen HIV positive serum and plasma samples collected from ARV-naive (n = 250) and -experienced (n = 250) adults were randomly selected and screened for HBsAg, anti-HBs, HBeAg and anti-HCV using rapid two-site sandwich immunochromatographic assay. The test was performed at Aklilu Lemma Institute of Pathobiology, Addis Ababa University. Positive specimens for HBsAg and anti-HCV markers were further confirmed using third generation ELISA. Of the 500 specimens tested, 15 (3 %), 58 (11.6 %), 3 (0.6 %), 18 (3.6 %), 3 (0.6 %) and 1 (0.2 %) were positive for HBsAg, anti-HBs, HBeAg, anti-HCV, HBsAg and HBeAg, and HBsAg and anti-HBs markers, respectively. No specimen tested positive for both HBeAg and anti-HBs, and 442 (88.4 %) individuals were non-immune to HBV. Of the 250 ARV-naive individuals, 8 (3.2 %), 33 (13.2 %), 2 (0.8 %), 10 (4 %), 2 (0.8 %), and 1 (0.4 %) were positive for HBsAg, anti-HBs, HBeAg, anti-HCV, HBsAg and HBeAg, and HBsAg and anti-HBs markers, respectively. Of the 250 ARV-experienced individuals, 7 (2.8 %), 25 (10 %), 1 (0.4 %), 8 (3.2 %), 1 (0.4 %), and 0 (0 %) were positive for HBsAg, Anti HBs, HBeAg, anti-HCV, HBsAg and HBeAg, and HBsAg and anti-HBs markers, respectively. In summary, seroprevalence of HIV/HBV and HIV/HCV co-infections was lower in Addis Ababa, Ethiopia, than in Sub-Saharan Africa and globally. HBV and HCV infections were not significantly different between HIV positive subjects who were or who were not on ARV. This suggests that the two groups have equal chance of being infected with these two viruses; despite this, disease progression could be different. PMID- 24757221 TI - Struggles with clinical translation of immune intervention trials. PMID- 24757222 TI - microRNAs: what the clinician should know about this new frontier. PMID- 24757223 TI - Gerald M. Reaven, MD: Demonstration of the central role of insulin resistance in type 2 diabetes and cardiovascular disease. PMID- 24757224 TI - The artificial pancreas: are we there yet? PMID- 24757225 TI - Closed-loop artificial pancreas systems: physiological input to enhance next generation devices. AB - To provide an understanding of both the preclinical and clinical aspects of closed-loop artificial pancreas systems, we provide a discussion of this topic as part of this two-part Bench to Clinic narrative. Here, the Bench narrative provides an in-depth understanding of insulin-glucose-glucagon physiology in conditions that mimic the free-living situation to the extent possible in type 1 diabetes that will help refine and improve future closed-loop system algorithms. In the Clinic narrative, Doyle and colleagues compare and evaluate technology used in current closed-loop studies to gain further momentum toward outpatient trials and eventual approval for widespread use. PMID- 24757226 TI - Closed-loop artificial pancreas systems: engineering the algorithms. AB - In this two-part Bench to Clinic narrative, recent advances in both the preclinical and clinical aspects of artificial pancreas (AP) development are described. In the preceding Bench narrative, Kudva and colleagues provide an in depth understanding of the modified glucoregulatory physiology of type 1 diabetes that will help refine future AP algorithms. In the Clinic narrative presented here, we compare and evaluate AP technology to gain further momentum toward outpatient trials and eventual approval for widespread use. We enumerate the design objectives, variables, and challenges involved in AP development, concluding with a discussion of recent clinical advancements. Thanks to the effective integration of engineering and medicine, the dream of automated glucose regulation is nearing reality. Consistent and methodical presentation of results will accelerate this success, allowing head-to-head comparisons that will facilitate adoption of the AP as a standard therapy for type 1 diabetes. PMID- 24757227 TI - Overnight closed-loop insulin delivery in young people with type 1 diabetes: a free-living, randomized clinical trial. AB - OBJECTIVE: To evaluate feasibility, safety, and efficacy of overnight closed-loop insulin delivery in free-living youth with type 1 diabetes. RESEARCH DESIGN AND METHODS: Overnight closed loop was evaluated at home by 16 pump-treated adolescents with type 1 diabetes aged 12-18 years. Over a 3-week period, overnight insulin delivery was directed by a closed-loop system, and on another 3 week period sensor-augmented therapy was applied. The order of interventions was random. The primary end point was time when adjusted sensor glucose was between 3.9 and 8.0 mmol/L from 2300 to 0700 h. RESULTS: Closed loop was constantly applied over at least 4 h on 269 nights (80%); sensor data were collected over at least 4 h on 282 control nights (84%). Closed loop increased time spent with glucose in target by a median 15% (interquartile range -9 to 43; P < 0.001). Mean overnight glucose was reduced by a mean 14 (SD 58) mg/dL (P < 0.001). Time when glucose was <70 mg/dL was low in both groups, but nights with glucose <63 mg/dL for at least 20 min were less frequent during closed loop (10 vs. 17%; P = 0.01). Despite lower total daily insulin doses by a median 2.3 (interquartile range -4.7 to 9.3) units (P = 0.009), overall 24-h glucose was reduced by a mean 9 (SD 41) mg/dL (P = 0.006) during closed loop. CONCLUSIONS: Unsupervised home use of overnight closed loop in adolescents with type 1 diabetes is safe and feasible. Glucose control was improved during the day and night with fewer episodes of nocturnal hypoglycemia. PMID- 24757228 TI - First use of model predictive control in outpatient wearable artificial pancreas. AB - OBJECTIVE: Inpatient studies suggest that model predictive control (MPC) is one of the most promising algorithms for artificial pancreas (AP). So far, outpatient trials have used hypo/hyperglycemia-mitigation or medical-expert systems. In this study, we report the first wearable AP outpatient study based on MPC and investigate specifically its ability to control postprandial glucose, one of the major challenges in glucose control. RESEARCH DESIGN AND METHODS: A new modular MPC algorithm has been designed focusing on meal control. Six type 1 diabetes mellitus patients underwent 42-h experiments: sensor-augmented pump therapy in the first 14 h (open-loop) and closed-loop in the remaining 28 h. RESULTS: MPC showed satisfactory dinner control versus open-loop: time-in-target (70-180 mg/dL) 94.83 vs. 68.2% and time-in-hypo 1.25 vs. 11.9%. Overnight control was also satisfactory: time-in-target 89.4 vs. 85.0% and time-in-hypo: 0.00 vs. 8.19%. CONCLUSIONS: This outpatient study confirms inpatient evidence of suitability of MPC-based strategies for AP. These encouraging results pave the way to randomized crossover outpatient studies. PMID- 24757230 TI - Treatment of recent-onset type 1 diabetic patients with DiaPep277: results of a double-blind, placebo-controlled, randomized phase 3 trial. AB - OBJECTIVE: To evaluate safety and efficacy of DiaPep277 in preserving beta-cell function in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: DIA-AID 1 is a multinational, phase 3, balanced-randomized, double-blind, placebo-controlled, parallel-group clinical study. Newly diagnosed patients (N = 457, aged 16-45 years) were randomized to subcutaneous injections of DiaPep277 or placebo quarterly for 2 years. The primary efficacy end point was the change from baseline in the area under the glucagon-stimulated C-peptide curve. Secondary end points were the change from baseline in mixed-meal stimulated C-peptide secretion and in fasting C-peptide and achieving target HbA1c <=7% (<=53 mmol/mol). Partial remission (target HbA1c on insulin <=0.5 units/kg/day) and hypoglycemic event rate were exploratory end points. RESULTS: DiaPep277 was safe and well tolerated. Significant preservation of C-peptide secretion was observed in the DiaPep277 treated group compared with the placebo (relative treatment effects of 23.4%, P = 0.037, and 29.2%, P = 0.011, in the modified intent-to-treat [mITT] and per protocol [PP] populations, respectively). The mixed-meal stimulation failed to distinguish between the groups. There was a trend toward efficacy in fasting C peptide levels, though not statistically significant. Significantly more DiaPep277-treated than placebo-treated patients maintained target HbA1c (mITT 56% versus 44%, P = 0.03; PP 60% versus 45%, P = 0.0082) and entered partial remission (mITT 38% versus 29%, P = 0.08; PP 42% versus 30%, P = 0.035). DiaPep277 treatment reduced the relative hypoglycemic event risk (mITT by 20%; PP by 28%). CONCLUSIONS: DiaPep277 safely contributes to preservation of beta-cell function and to improved glycemic control in patients with type 1 diabetes. PMID- 24757229 TI - Frequency of morning ketosis after overnight insulin suspension using an automated nocturnal predictive low glucose suspend system. AB - OBJECTIVE: To assess the effect of overnight insulin pump suspension in an automated predictive low glucose suspend system on morning blood glucose and ketone levels in an attempt to determine whether routine measurement of ketone levels is useful when a closed-loop system that suspends insulin delivery overnight is being used. RESEARCH DESIGN AND METHODS: Data from an in-home randomized trial of 45 individuals with type 1 diabetes (age range 15-45 years) were analyzed, evaluating an automated predictive low glucose pump suspension system in which blood glucose, blood ketone, and urine ketone levels were measured on 1,954 mornings. RESULTS: One or more pump suspensions occurred during 744 of the 977 intervention nights (76%). The morning blood ketone level was >=0.6 mmol/L after 11 of the 744 nights (1.5%) during which a pump suspension occurred and 2 of the 233 nights (0.9%) during which there was no suspension compared with 11 of 977 control nights (1.1%). The morning blood ketone level was >=0.6 mmol/L after only 2 of 159 nights (1.3%) with a pump suspension exceeding 2 h. Morning fasting blood glucose level was not a good predictor of the presence of blood ketones. CONCLUSIONS: Routine measurement of blood or urine ketones during use of an automated pump suspension system using continuous glucose monitoring, whether threshold based or predictive, is not necessary. Recommendations for checking ketone levels should be no different when a patient is using a system with automated insulin suspension than it is for conventional diabetes self-management. PMID- 24757231 TI - Normalizing metabolism in diabetic pregnancy: is it time to target lipids? AB - Outcomes in pregnancies complicated by preexisting diabetes (type 1 and type 2) and gestational diabetes mellitus have improved, but there is still excess morbidity compared with normal pregnancy. Management strategies appropriately focus on maternal glycemia, which demonstrably improves pregnancy outcomes for mother and infant. However, we may be reaching the boundaries of obtainable glycemic control for many women. It has been acknowledged that maternal lipids are important in pregnancies complicated by diabetes. Elevated maternal lipids are associated with preeclampsia, preterm delivery, and large-for-gestational-age infants. Despite this understanding, assessment of management strategies targeting maternal lipids has been neglected to date. Consideration needs to be given to whether normalizing maternal lipids would further improve pregnancy outcomes. This review examines the dyslipidemia associated with pregnancy complicated by diabetes, reviews possible therapies, and considers whether it is time to start actively managing this aspect of maternal metabolism. PMID- 24757233 TI - Comment on Evert et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes care 2013;36:3821-3842. PMID- 24757234 TI - Comment on Evert et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes care 2013;36:3821-3842. PMID- 24757235 TI - Response to comments on Evert et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes care 2013;36:3821-3842. PMID- 24757236 TI - Comment on Hinnouho et al. Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter? Diabetes care 2013;36:2294-2300. PMID- 24757237 TI - Response to comment on Hinnouho et al. Metabolically healthy obesity and risk of mortality: does the definition of metabolic health matter? Diabetes care 2013;36:2294-2300. PMID- 24757238 TI - Comment on Goldfine et al. Targeting inflammation using salsalate in patients with type 2 diabetes: effects on flow-mediated dilation (TINSAL-FMD). Diabetes care 2013;36:4132-4139. PMID- 24757239 TI - Response to comment on Goldfine et al. Targeting inflammation using salsalate in patients with type 2 diabetes: effects on flow-mediated dilation (TINSAL-FMD). Diabetes care 2013;36:4132-4139. PMID- 24757240 TI - Comment on Khunti et al. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes care 2013;36:3411 3417. PMID- 24757241 TI - Response to comment on Khunti et al. Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes care 2013;36:3411-3417. PMID- 24757242 TI - Comment on Lazaro-Martinez et al. Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: a randomized comparative trial. Diabetes care 2014;37:789-795. PMID- 24757243 TI - Response to comment on Lazaro-Martinez et al. Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: a randomized comparative trial. Diabetes care 2014;37:789-795. PMID- 24757244 TI - Comment on Dalmas et al. Intima-media thickness in severe obesity: links with BMI and metabolic status but not with systemic or adipose tissue inflammation. Diabetes care 2013;36:3793-3802. PMID- 24757245 TI - Response to comment on Dalmas et al. Intima-media thickness in severe obesity: links with BMI and metabolic status but not with systemic or adipose tissue inflammation. Diabetes care 2013;36:3793-3802. PMID- 24757246 TI - Comment on Tesfaye et al. Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes care 2013;36:2456-2465. PMID- 24757247 TI - Artifactual hypoglycemia: an old term for a new classification. PMID- 24757249 TI - FGF23 in type 2 diabetic patients: relationship with bone metabolism and vascular disease. PMID- 24757248 TI - Tyrosine kinase inhibitor sunitinib allows insulin independence in long-standing type 1 diabetes. PMID- 24757250 TI - Diabetic charcot neuroarthropathy of the hand: clinical course, diagnosis, and treatment options. PMID- 24757251 TI - Interference of intravenous vitamin C with blood glucose testing. PMID- 24757252 TI - Exercise-induced improvement in insulin sensitivity is not mediated by change in cardiorespiratory fitness. PMID- 24757253 TI - Effect of the holiday season in patients with diabetes: glycemia and lipids increase postholiday, but the effect is small and transient. PMID- 24757259 TI - Hibernia. PMID- 24757258 TI - PI3K and Bcl-2 inhibition primes glioblastoma cells to apoptosis through downregulation of Mcl-1 and Phospho-BAD. AB - Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT 263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell-like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases. Mechanistically, GDC-0941 depleted pAKT (Serine 473) levels and suppressed Mcl-1 protein levels, lowering the threshold for the cytotoxic actions of ABT-263. GDC 0941 decreased Mcl-1 in a posttranslational manner and significantly decreased the half-life of Mcl-1 protein. Ectopic expression of human Mcl-1 mitigated apoptotic cell death induced by the drug combination. Furthermore, GDC-0941 modulated the phosphorylation status of BAD, thereby further enhancing ABT-263 mediated cell death. IMPLICATIONS: Combination therapy with ABT-263 and GDC-0941 has novel therapeutic potential by specifically targeting aberrantly active, deregulated pathways in GBM, overcoming endogenous resistance to apoptosis. PMID- 24757261 TI - Acute headache. PMID- 24757262 TI - Recurrent pilonidal sepsis. PMID- 24757263 TI - Faxing ECGs from peripheral hospitals to tertiary paediatric cardiology units--is it safe and sustainable? AB - INTRODUCTION: [corrected] Recent local involvement with the United Kingdom"Safe and Sustainable review of paediatric cardiology services" has highlighted the need for development of clinical networks and improvement of the communication infrastructure within and between teams. One common communication between peripheral and tertiary hospitals is facsimile transfer of electrocardiograms. The quality of fax transmission can be variable, raising concerns regarding the quality of the received image, accuracy of the diagnosis and appropriateness of the resultant advice. METHODS: We performed a systematic quality evaluation of faxed ECGs to determine whether they should be replaced on the basis of patient safety and information governance. A sample of 50 ECGs was selected from over 300 which had been faxed to our tertiary department. These were scored according to a structured system leading to a 10 point Likert scale, assessing technical quality and the ability to make a clinically relevant assessment of the information. RESULTS: Only 1 from 50 faxed ECGs fulfilled all 9 objective criteria set. Heart rate and quadrant of the QRS axis were only identifiable in 10%. Comparing the faxed ECGs with the rating given to an original ECG confirmed a significant difference in the interpretability of faxed and original ECGs (p<0.05). CONCLUSION: Our study suggests that faxed ECGs do not provide consistent, accurate diagnostic information. It suggests that this currently widespread practice should be considered as a potential patient safety issue within developing paediatric cardiology networks. We would recommend that faxing of ECGs be replaced with scanning of ECGs, transmitted via secure email. PMID- 24757264 TI - Recurrent pelvic organ prolapse (POP) following traditional vaginal hysterectomy with or without colporrhaphy in an Irish population. PMID- 24757265 TI - A guide to childhood motor stereotypies, tic disorders and the tourette spectrum for the primary care practitioner. AB - Movement disorders presenting in childhood are often complex and a heterogenous group of difficulties which can be a minefield for the primary care doctor. The recent activities of the European Society for the Study of Tourette Syndrome (ESSTS) have included publication of European clinical guidelines for Tourette syndrome and other Tic disorders aimed at guiding paediatricians and psychiatrists in managing these children. This paper aims to summarise the key points for primary care teams and impart important facts and general information on related childhood movement disorders in early development. PMID- 24757266 TI - Dimitrios Oreopoulos, the plane tree of Kos and the Belfast City Hospital. PMID- 24757267 TI - A sextet of contrasting styles. PMID- 24757268 TI - The challenges of cancer pain assessment. PMID- 24757269 TI - "The analgesic stepladder--missing rungs.". PMID- 24757270 TI - Antiphospholipid antibody syndrome: diffuse alveolar hemorrhage and Libman-Sacks endocarditis in the absence of prior thrombotic events. PMID- 24757271 TI - What becomes of the broken nose? PMID- 24757272 TI - General paediatric surgery: a survey of Northern Ireland general surgery specialist registrars. PMID- 24757273 TI - Lactic acid bacterial infection, probiotics and gut microbiomes. PMID- 24757274 TI - A potential diagnostic role of dual-phase 18F-FDG PET/CT scanning. PMID- 24757275 TI - Doctor-patient ratios and acute medical admissions: a simple solution for an important problem! PMID- 24757276 TI - The burden of motorcycle trauma and seasonal change at a regional trauma centre. PMID- 24757277 TI - Awareness of adverse effects of azathioprine in patients with inflammatory bowel disease--more to be done? PMID- 24757281 TI - So you want to be a cardiologist. PMID- 24757282 TI - TNF blocking therapies and immunomonitoring in patients with inflammatory bowel disease. AB - Since their appearance in the armamentarium for inflammatory bowel disease (IBD) more than a decade ago, antitumor necrosis factor (TNF) inhibitors have demonstrated beneficial activity in induction and maintenance of clinical remission, mucosal healing, improvement in quality of life, and reduction in surgeries and hospitalizations. However, more than one-third of patients present primary resistance, and another one-third become resistant over time. One of the main factors associated with loss of response is the immunogenicity of anti-TNF biologics leading to the production of antidrug antibodies (ADAbs) accelerating their clearance. In this review we present the current state of the literature on the place of TNF and its blockage in the treatment of patients with IBD and discuss the usefulness of serum trough levels and ADAb monitoring in the optimization of anti-TNF therapies. PMID- 24757283 TI - 5-azacytidine promotes an inhibitory T-cell phenotype and impairs immune mediated antileukemic activity. AB - Demethylating agent, 5-Azacytidine (5-Aza), has been shown to be active in treatment of myeloid malignancies. 5-Aza enhances anticancer immunity, by increasing expression of tumor-associated antigens. However, the impact of 5-Aza immune responses remains poorly understood. Here, T-cell mediated tumor immunity effects of 5-Aza, are investigated in vitro and in vivo. T-cells from healthy donors were treated with 5-Aza and analyzed by qRT-PCR and flow cytometry for changes in gene expression and phenotype. Functionality was assessed by a tumor lysis assay. Peripheral blood from patients treated with 5-Aza after alloSCT was monitored for changes in T-cell subpopulations. 5-Aza treatment resulted in a decrease in CD8+ T-cells, whereas CD4+ T-cells increased. Furthermore, numbers of IFN-gamma + T-helper 1 cells (Th1) were reduced, while Treg-cells showed substantial increase. Additionally, CD8+ T-cells exhibited limited killing capacity against leukemic target cells. In vivo data confirm the increase of Treg compartment, while CD8+ T-effector cell numbers were reduced. 5-Aza treatment results in a shift from cytotoxic to regulatory T-cells with a functional phenotype and a major reduction in proinflammatory Th1-cells, indicating a strong inhibition of tumor-specific T-cell immunity by 5-Aza. PMID- 24757284 TI - IL-21 receptor expression in human tendinopathy. AB - The pathogenetic mechanisms underlying tendinopathy remain unclear, with much debate as to whether inflammation or degradation has the prominent role. Increasing evidence points toward an early inflammatory infiltrate and associated inflammatory cytokine production in human and animal models of tendon disease. The IL-21/IL-21R axis is a proinflammatory cytokine complex that has been associated with chronic inflammatory diseases including rheumatoid arthritis and inflammatory bowel disease. This project aimed to investigate the role and expression of the cytokine/receptor pair IL-21/IL-21R in human tendinopathy. We found significantly elevated expression of IL-21 receptor message and protein in human tendon samples but found no convincing evidence of the presence of IL-21 at message or protein level. The level of expression of IL-21R message/protein in human tenocytes was significantly upregulated by proinflammatory cytokines (TNFalpha/IL-1beta) in vitro. These findings demonstrate that IL-21R is present in early human tendinopathy mainly expressed by tenocytes and macrophages. Despite a lack of IL-21 expression, these data again suggest that early tendinopathy has an inflammatory/cytokine phenotype, which may provide novel translational targets in the treatment of tendinopathy. PMID- 24757285 TI - Local and systemic pathogenesis and consequences of regimen-induced inflammatory responses in patients with head and neck cancer receiving chemoradiation. AB - Treatment-related toxicities are common among patients with head and neck cancer, leading to poor clinical outcomes, reduced quality of life, and increased use of healthcare resources. Over the last decade, much has been learned about the pathogenesis of cancer regimen-related toxicities. Historically, toxicities were separated into those associated with tissue injury and those with behavioural or systemic changes. However, it is now clear that tissue-specific damage such as mucositis, dermatitis, or fibrosis is no longer the sole consequence of direct clonogenic cell death, and a relationship between toxicities that results in their presentation as symptom clusters has been documented and attributed to a common underlying pathobiology. In addition, the finding that patients commonly develop toxicities representing tissue injury outside radiation fields and side effects such as fatigue or cognitive dysfunction suggests the generation of systemic as well as local mediators. As a consequence, it might be appropriate to consider toxicity syndromes, rather than the traditional approach, in which each side effect was considered as an autonomous entity. In this paper, we propose a biologically based explanation which forms the basis for the diverse constellation of toxicities seen in response to current regimens used to treat cancers of the head and neck. PMID- 24757287 TI - TLR2 elicits IL-17-mediated RANKL expression, IL-17, and OPG production in neutrophils from arthritic mice. AB - We investigated the ability of neutrophils to express receptor activator of nuclear factor kappa-B ligand (RANKL), to secrete osteoprotegerin (OPG), and to produce IL-17. Arthritis was induced by intra-articular injection of zymosan, a ligand for Toll-like receptor 2 (TLR2). Frequencies of neutrophils in bone marrow (BM), blood and synovial fluid (SF), receptor expression, and cytokine production were evaluated by flow cytometry. 1A8 antibody (1A8 Ab) was used to deplete neutrophils in zymosan-injected SCID mice. IL-17, RANKL, and OPG amounts in SF, serum, or cell cultures were determined by ELISA. The development of arthritis was associated with increased secretion of IL-17, RANKL, and OPG in serum and SF, elevated frequencies of Ly6G(+)CD11b(+) cells in BM, blood, and SF and upregulated RANKL expression. Both IL-17 and OPG were absent in serum and SF after neutrophil depletion; therefore we assume that they were released by neutrophils. In vitro blood Ly6G(+)CD11b(+) cells from arthritic mice produced spontaneously IL-17, IFN-gamma, and OPG and expressed RANKL. This phenotype was sustained by IL-17. TLR2 engagement increased IL-17 and IFN-gamma production, potentiated IL-17-mediated RANKL expression, and inhibited OPG secretion. We conclude that TLR2 regulates the destructive potential of neutrophils and its targeting might limit joint alterations in arthritis. PMID- 24757286 TI - Inflammatory lung disease in Rett syndrome. AB - Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n = 228) and to examine lung histology in a Mecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228) of patients versus ~18% of healthy controls, with "high" (39.8%) and "low" (34.8%) patterns dominating over "mixed" (19.6%) and "simple mismatch" (5.9%) types. Increased plasma levels of non-protein-bound iron (NPBI), F2-isoprostanes (F2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examined Mecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease. PMID- 24757288 TI - Monocyte subsets in schistosomiasis patients with periportal fibrosis. AB - A major issue with Schistosoma mansoni infection is the development of periportal fibrosis, which is predominantly caused by the host immune response to egg antigens. Experimental studies have pointed to the participation of monocytes in the pathogenesis of liver fibrosis. The aim of this study was to characterize the subsets of monocytes in individuals with different degrees of periportal fibrosis secondary to schistosomiasis. Monocytes were classified into classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), and nonclassical (CD14(+)CD16(++)). The expressions of monocyte markers and cytokines were assessed using flow cytometry. The frequency of classical monocytes was higher than the other subsets. The expression of HLA-DR, IL-6, TNF-alpha, and TGF-beta was higher in monocytes from individuals with moderate to severe fibrosis as compared to other groups. Although no differences were observed in receptors expression (IL-4R and IL-10R) between groups of patients, the expression of IL-12 was lower in monocytes from individuals with moderate to severe fibrosis, suggesting a protective role of this cytokine in the development of fibrosis. Our data support the hypothesis that the three different monocyte populations participate in the immunopathogenesis of periportal fibrosis, since they express high levels of proinflammatory and profibrotic cytokines and low levels of regulatory markers. PMID- 24757289 TI - Peptidases from latex of Carica candamarcensis upregulate COX-2 and IL-1 mRNA transcripts against Salmonella enterica ser. Typhimurium-mediated inflammation. AB - The immunomodulatory properties of a mixture of cysteine peptidases (P1G10) obtained from the fruit lattice of Carica candamarcensis were investigated. P1G10 was obtained from fresh latex samples by chromatography in a Sephadex column and initially administered to Swiss mice (n = 5; 1 or 10 mg/kg) via i.p. After 30 min, the mice were injected with carrageenan (0.5 mg/mouse) or heat-killed S. Typhimurium (10(7) CFU/mL; 100 degrees C/30 min) into the peritoneal cavity. Afterwards, two animal groups were i.p. administered with P1G10 (n = 6; 1, 5, or 10 mg/Kg) or PBS 24 hours prior to challenge with live S. Typhimurium (10(7) CFU/mL). P1G10 stimulated the proliferation of circulating neutrophils and lymphocytes, 6 h after injection of carrageenan or heat-killed bacteria, respectively. Furthermore, survival after infection was dose-dependent and reached 60% of the animal group. On the other hand, control mice died 1-3 days after infection. The examination of mRNA transcripts in liver cells 24 h after infection confirmed fold variation increases of 5.8 and 4.8 times on average for IL-1 and COX-2, respectively, in P1G10 pretreated mice but not for TNF-alpha, IL 10, gamma-IFN and iNOS, for which the results were comparable to untreated animals. These data are discussed in light of previous reports. PMID- 24757290 TI - Lead exposure exacerbates cardiovascular risk. PMID- 24757291 TI - A review on the role of nutraceuticals as simple as se(2+) to complex organic molecules such as glycyrrhizin that prevent as well as cure diseases. AB - Nutraceuticals are nutritional medicines which are present in edible food items. Most of them are antioxidants with various other biological properties viz, anti inflammatory, anti atherogenic, anticancer, anti viral, anti aging properties etc. They are as simple as minerals like Se(2+) to complex organic molecules such as glycyrrhizin (Ca(2+), K(+) salts of glycyrrhizic acid). They can prevent as well as cure various diseases. Most of the medical people are not aware of the importance of the nutraceuticals as such matters are not part of their text books. Many still think that vitamins are the major nutritional medicines. Actually other dietary principles like terpenes, carotenes, phytosterols, polyphenols, flavanoids, di and poly sulphides, their sulfoxides and their precursor amino acids are necessary to scavenge free radicals in the body which are reactive oxygen species to protect and maintain the vitamin levels in the body. They down regulate the activities of those enzymes which are increased in diseases and they increase those that remove oxidants and detoxify carcinogens. They are immune boosters too. Recently glucosinolates, non toxic alkaloids, certain proteins and even fiber are included in the list of nutraceuticals. PMID- 24757292 TI - Hypoxic Stress Induced TREM-1 and Inflammatory Chemokines in Human Peripheral Blood Mononuclear Cells. AB - Hypoxia is a condition of low pO2, which creates a unique microenvironment affecting cell phenotype and subsequent immune response generation. Little is known about the impact of hypoxia on the phenotypic expression of NK cell, TREM 1, TLR-4 and inflammatory chemokines. In the present study we have determined the frequency of peripheral blood populations of CD16/CD56 (NK Cells) expressing cells, presence of activation marker CD354 (TREM-1), Toll like receptor (CD 284) on the cell surface and chemokines IL-8 and RANTES in the cellular supernatant of normoxia and hypoxia exposed cells by flow cytometry. GRP-78 expression was determined by reverse transcriptase polymerase chain reaction. The blood was collected from healthy individuals and exposed to normoxic and hypoxic (0.5 %) environment for 24 h. The percentage of NK cells (CD 16/56) was marginally up regulated while TLR-4 expression was diminished in hypoxia exposed cells as compare to the normoxic cells. TREM-1 expression was significantly up-regulated (p < 0.05) in hypoxia as compared to the normoxic control. In addition when monocytic cell line THP-1 was exposed to 0.5 % hypoxia for 24 h, TLR4 expression was significantly decreased in hypoxic cells as compared to normoxic cells. Furthermore, GRP-78 mRNA expression was also upregulated by hypoxia or LPS exposure. These events are paralleled by strengthening up-regulation of the chemokines IL-8 and RANTES an otherwise necessary event for the chemotaxis of the neutrophils and macrophages to the inflammatory site. In conclusion, this study provides a novel insight into the mechanism linking low oxygen tension to the regulation of immune and inflammatory responses, leading to new perspectives of the role of hypoxia in programming immune cell functions. PMID- 24757293 TI - Association of inflammatory cytokines, lipid peroxidation end products and nitric oxide with the clinical severity and fetal outcome in preeclampsia in Indian women. AB - Preeclampsia is a multisystem disorder associated with maternal hypertension, placental abnormalities and adverse fetal outcomes. The various pathways involved in its etiology include endothelial dysfunction, inflammatory milieu, lipid peroxidation and immunological imbalance. The present study was conducted to evaluate the causative and predictive role of nitric oxide, lipid peroxidation end products (MDA) and inflammatory cytokines (IL-6, TNF-alpha) in clinical presentation, severity and fetal outcome in preeclampsia. The study population was divided into 3 groups- Non- pregnant females comprising the control population; G1 and G2 groups included normal pregnant and pregnant females with preeclampsia with 50 patients in each group. Nitric Oxide and MDA levels were found to be highest in the preeclamptic patients as compared to other two groups. ROC curve analysis shows the superiority of the inflammatory markers as determinants of severity of preeclampsia which suggests the emerging role of pro inflammatory markers in the various pathological changes in preeclampsia. TNF alpha emerged as the best marker in multivariate analysis and thus, has the potential for being used as a marker for PIH. Our study illustrates the multifactorial etiology of preeclampsia involving oxidative stress, proinflammatory milieu and endothelial dysfunction. PMID- 24757294 TI - Inflammatory cytokines, apoptotic, tissue injury and remodeling biomarkers in children with congenital heart disease. AB - The present study aims to evaluate specific biomarkers involved in congenital heart disease (CHD), and whether there is a significant differences between the levels of these biomarkers in the cyanotic CHD (CCHD) and acyanotic CHD (ACHD). We prospectively measured tumor necrosis factor (TNF-alpha), interleukin-6 (IL 6), C-reactive protein (CRP), vasoendothelial growth factor (VEGF), troponin T, creatin kinase MB (CKMB), and Caspase 3 levels in 120 consecutive children with CHD (60 cyanotic and 60 a cyanotic with age 1:4 years), and 30 healthy control children. Significant elevated levels of inflammatory markers; TNF-alpha, IL-6 and CRP was detected in CHD, with percentage increase in cyanotic than a cyanotic subjects as compared to the normal one. Apoptotic biomarker; caspase 3 showed also significant increases in CCHD than ACHD. In addition, tissue injury mechanisms included troponin T and CKMB, exhibited significant increase in cyanotic than a cyanotic CHD. The present results demonstrate also, significant enhancement in remodeling process (VEGF), in cyanotic than a cyanotic patients. Thus, it could be concluded that, the children with CCHD were shown to have elevated levels of inflammatory cytokines, caspase 3, troponin T, and CKMB as these biomarkers may implicated in cardiac functional status. PMID- 24757295 TI - Archaeosome: as new drug carrier for delivery of Paclitaxel to breast cancer. AB - In the present study, paclitaxel was archaeosomed to reduce side effects and improve its therapeutic index. Carriers have made a big evolution in treatment of many diseases in recent years. Lipid carriers are of special importance among carriers. Archaeosome is one of the lipid carriers. Paclitaxel is one of the drugs used to treat breast cancer which has some unwanted side effects despite its therapeutic effects. Archaeosomes were extracted from methanogenic archi bacteria and synthesized with a certain ratio of paclitaxel in PBS. The mean diameter of archaeosomal paclitaxel was measured by Zeta sizer instrument, Drug releasing of archaeosomal paclitaxel was examined within 26 h which results showed that the most drug releasing occurs during first 3 h. The cytotoxicity effect of archaeosomal paclitaxel on breast cancer's cell line was evaluated by MTT assay which results showed that the cytotoxicity effect of archaeosomal paclitaxel on breast cancer's cell line is more than that of the standard paclitaxel formulation. The results indicated that new drug delivery of paclitaxel using archaeosome, increases the therapeutic index of the drug. PMID- 24757296 TI - Synthesis of Gold Nanoparticles Coated with Aspartic Acid and Their Conjugation with FVIII Protein and FVIII Antibody. AB - Carboxylate-modified gold nanoparticles (GNPs) were synthesized in a simple one step process based on the reduction of tetrachloroauric acid by aspartic acid in water. GNPs were identified by UV-Vis spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy. Conjugation of protein molecules with functionalized nanoparticles was performed through electrostatic interaction. The GNP-protein conjugates were characterized by gel electrophoresis. The interaction between functionalized GNPs and protein molecules lead to conformational transition of protein structure after conjugation of protein with GNPs. This process was investigated by fluorescence spectroscopy and circular dichroism spectroscopy. PMID- 24757297 TI - Comparison of Mass Versus Activity of Creatine Kinase MB and Its Utility in the Early Diagnosis of Re-infarction. AB - Currently employed markers for the detection of acute coronary syndrome are Troponin T, CK (Creatine Kinase) and CKMB activity. CKMB activity measured by immunoinhibition method can give falsely elevated results due to the presence of atypical CK and CKBB and at times lead to the mis-diagnosis of acute coronary syndrome. Hence, CKMB mass (CKMB) measured by electrochemiluminence sandwich principle was employed. In this cross-sectional study 183 samples of 61 patients were analyzed within 6 h of diagnosis of acute coronary syndrome and followed up to 72 h. The correlation coefficient between CKMB activity and CKMBM at 4-6 h was 0.744, while at 12-24 h it was 0.909 and at 48-72 h it was 0.337. Thus there was good association between the two methods at 12-24 h but, statistically for method comparison studies and for replacing one method by another, the two methods need to be in agreement with one another. In this study the two methods are not in agreement with one another and thus analytically not replaceable. Another finding was obtained that CKMBM reached cut off levels prior to CKMB enzyme activity and hence, CKMBM is clinically better than CKMB activity to detect reinfarction. PMID- 24757298 TI - Establishment of Trimester-Specific Reference Intervals of Serum TSH & fT4 in a Pregnant Indian Population at North Kolkata. AB - Reference intervals (RIs) of serum thyroid stimulating hormone (TSH) and free thyroxine (fT4) were determined in 402 healthy pregnant women by enzyme-linked immunosorbent assay (ELISA) technique after partitioning them into three trimesters. The reference population was chosen from a study population of 610 pregnant females by applying strict inclusion and exclusion criteria. The assays were done using proper quality control measures. RIs were calculated from the central 95 % of the distribution of TSH and fT4 values located between the lower reference limit of 2.5 percentile and upper reference limit of 97.5 percentile value 0.90 confidence intervals for the upper and lower reference limits were also determined. The reference intervals for TSH were 0.25-3.35 MUIU/ml for the first trimester; 0.78-4.96 MUIU/ml for the second trimester and 0.89-4.6 MUIU/ml for the third trimester. Similarly, the reference intervals for fT4 for first, second and third trimesters were 0.64-2.0, 0.53-2.12 and 0.64-1.98 ng/dl respectively. The values thus obtained varied from those provided by the kit literature. In comparison to our derived reference intervals, the reference data from kit manufacturer under-diagnosed both subclinical hypo- and hyper-thyroidism within our pregnant reference population. PMID- 24757299 TI - Serum Level of Some Minerals during Three Trimesters of Pregnancy in Iranian Women and Their Newborns: A Longitudinal Study. AB - Concentrations of various trace elements are altered during pregnancy with changes in the mother's physiology and the requirements of growing fetus. The aim of the present longitudinal study was to learn the changes of micronutrients Iron (Fe), Calcium (Ca), zinc (Zn) Magnesium (Mg) and copper (Cu) of pregnant woman and their relations with newborns levels. Serum levels of iron, calcium, zinc, magnesium and copper of 162 pregnant women and their newborns were determined by an inductively couple plasma mass spectrometer (ICP/MS). The results showed that majority (41 %) of pregnant women were in age group 26-36 years 55 % had high school and diploma levels of education and the total income ranged between 3 and 5 Rials million per month There was significant difference in iron levels during first, second and third trimesters, 76.0 +/- 17.8, 63.5 +/- 15.2 and 70.1 +/- 14.4 MUg/dl respectively. Significant difference was shown in zinc levels 79.5 +/ 15, 74.5 +/- 16.1, and 65.3 +/- 14.9 MUg/dl during three trimesters. Copper levels during pregnancy were significantly different (130.9 +/- 43.5, 172.0 +/- 38.94, 193.2 +/- 28.5 MUg/dl. The serum levels of calcium and magnesium during pregnancy were constant (Ca: 8.96 +/- 0.48, 8.86 +/- 0.47, 8.91 +/- 0.42 mg/dl and Mg: 2.10 +/- 0.21, 2.08 +/- 0.28, 2.09 +/- 0.29 mg/dl). Results showed that 13 % of pregnant women had hypocalcaemia and hypomagnesaemia. Thirty eight percent and 42 % of pregnant women had iron and zinc deficiency respectively. In this study, unlike zinc, no pregnant women were found deficient in serum copper levels. Calcium, iron, zinc, copper and magnesium levels in the newborn's cord blood were 8.93 +/- 0.43, 106.0 +/- 26.1, 85.35 +/- 16.6, 57.04 +/- 13.8 and 1.99 +/- 0.27 mg/dl respectively. In the present study the levels of iron and zinc in cord blood were higher than the levels of iron and zinc in maternal serum. The mean level of copper in cord blood serum in the current study was lower than maternal values. The mean serum calcium and magnesium in the serum cord blood and in the serum of the pregnant women were similar. PMID- 24757300 TI - Study of the concentration of trace elements fe, zn, cu, se and their correlation in maternal serum, cord serum and colostrums. AB - A study of iron, zinc, copper and selenium concentration levels was carried out in three compartments namely, maternal serum (MS), colostrums and cord blood serum (CS) of healthy Indian mothers (n = 42) who delivered healthy normal neonates without any congenital anomalies at Bhabha Atomic Research Centre hospital, Mumbai. Fe, Zn, Cu in maternal serum, cord blood and colostrums were estimated by flame atomic absorption spectrometry while Se was determined by graphite furnace absorption spectrometry. It was seen that there was a significant difference in the level of trace elements in the three compartments. The average levels of Fe in the three compartments were 1,132 +/- 519, 2,312 +/- 789 and 1,183 +/- 602 MUg/L while Zn was 514 +/- 149, 819 +/- 224 and 7,148 +/- 2,316 MUg/L respectively. Mean Cu values were 1,614 +/- 295, 301 +/- 77 and 392 +/- 174 MUg/L respectively while Se values were 70 +/- 15, 36 +/- 10 and 23 +/- 8 MUg/L respectively. The results indicated a positive correlation of Fe and Zn concentrations in MS versus CS which were (r = 0.386), (r = 0.572) respectively and Fe levels in MS and colostrums (r = 0.235). A few inter element correlations were found within compartments. Zn and Se showed a negative correlation in both MS (r = -0.489) and colostrums (r = -0.258) while a positive inter correlation of Fe and Zn was seen in MS (r = 0.44) and in CS (r = 0.54). This study gave us an overview of the serum and colostrum values of mother and neonates in Indian population, data of which are scarce. PMID- 24757301 TI - TSH Comparison Between Chemiluminescence (Architect) and Electrochemiluminescence (Cobas) Immunoassays: An Indian Population Perspective. AB - Although 3rd generation TSH assays are the most widely used immunoassays, credible comparison studies, specially involving Indian sub-populations are practically non-existent. To compare the TSH measurements between chemiluminescence (Architect) and electrochemiluminescence (Cobas) inmmunoassays in an urban ambulatory Indian population. 1,615 subjects were selected randomly from the usual laboratory workflow, their TSH measured in Architect and Cobas and the paired data thus generated were statistically analysed. TSH values of Cobas were observed to be higher than the Architect values by 28.7 %, with a significant proportional difference between the two, but majority of the Cobas values (above 90 %) were within the limits of agreement with Architect values. In situations where both the instruments are in use simultaneously, a standardization of the methods is imperative, in larger interest of the patient populace. PMID- 24757302 TI - Metabolic issues in schizophrenic patients receiving antipsychotic treatment. AB - Schizophrenia is a psychotic disorder with a complex pathophysiology and requires treatment that includes long term administration of antipsychotics that is said to be associated with metabolic syndrome. This study was designed to evaluate the impact of seven different antipsychotics prescribed to schizophrenic patients, on development of metabolic syndrome in the patients. A total of 210 patients with schizophrenia (30 patients in each drug therapy group) were recruited according to ICD-10 criteria and were assigned to receive the drug for 16 weeks. Measurement of anthropometric (body weight, waist circumference, blood pressure) and biochemical parameters (glucose, insulin, HOMA-IR, triglycerides, LDL, HDL) was done and the patients were subjected to ATP-III defined criteria for metabolic syndrome. Patients undergoing treatment with olanzapine were more prone to metabolic syndrome as the drug induces weight gain after 16 weeks of treatment. It also induces dyslipidemia (P < 0.001) and hyperglycemia (P < 0.01). Clozapine was found to be second most potent drug in inducing metabolic syndrome as the weight in clozapine treated patients increased after 16 weeks, along with a significant increase in glycemic (P < 0.001) and lipid parameters (P < 0.01). Aripriazole and amisulphride are comparatively safer drugs as their role in inducing metabolic abnormalities in schizophrenic patients was insignificant, although the impact of long term administration of these drugs needs to be explored. It is clear from the study that antipsychotic treatment induces metabolic syndrome so, it becomes important that the metabolic and cardiovascular risk factors should be surveillance regularly in schizophrenic patients undergoing antipsychotic treatment. PMID- 24757303 TI - Potential Chemoprevention of 7,12-Dimethylbenz[a]anthracene Induced Renal Carcinogenesis by Moringa oleifera Pods and Its Isolated Saponin. AB - Present investigation shows that hydroethanolic extract of Moringa oleifera (MOHE) and its isolated saponin (SM) attenuates DMBA induced renal carcinogenesis in mice. Isolation of SM was achieved by TLC and HPLC and characterization was done using IR and (1)H NMR. Animals were pre-treated with MOHE (200 and 400 mg/kg body weight; p.o), BHA as a standard (0.5 and 1 %) and SM (50 mg/kg body weight) for 21 days prior to the administration of single dose of DMBA (15 mg/kg body weight). Administration of DMBA significantly (p < 0.001) enhanced level of xenobiotic enzymes. It enhanced renal malondialdehyde, with reduction in renal glutathione content, antioxidant enzymes and glutathione-S-transferase. The status of renal aspartate transaminase, alanine transaminase, alkaline phosphatase and total protein content were also found to be decreased along with increase in total cholesterol in DMBA administered mice. Pretreatment with MOHE and SM significantly reversed the DMBA induced alterations in the tissue and effectively suppressed renal oxidative stress and toxicity. PMID- 24757304 TI - Suitability of stem latex of jatropha gossypifolia as a protein precipitant for biochemical analysis. AB - The extract of Jatropha Gossypifolia stem was obtained by cutting the stem with a sharp knife and the fluid expressed out. The suitability of the stem latex extract as a precipitant for biochemical analysis was determined. The precipitating efficacy of the extract for creatinine and protein estimation was found to be optimum at 1/4 and 1/5 dilutions respectively aqueous solution. Plasma protein was precipitated with stem extract of J. Gossypifolia at the stated dilution. The mean plasma creatinine values obtained from 0.5 % sodium tungstate as a protein precipitant were compared with the values of plasma creatinine obtained when 1/4 dilution of stem extract of J. Gossypifolia was used as protein precipitant. Similarly mean cerebrospinal fluid (CSF) and urinary protein values obtained from 3 % Tricholoro-acetic acid as protein precipitant were compared with values obtained from 1/5 dilution of stem extract of J. Gossypifolia as protein precipitant. The values obtained from the stem latex extract at the stated dilutions were comparable with values obtained from the conventional protein precipitants (p < 0.05). The stem latex extract of J. Gossypifolia is suitable as a protein precipitant for creatinine, CSF and urinary protein estimations. However further work need to be done to purify the extract and determine the exact concentration at the stated dilutions as well as the active ingredient in stem latex. PMID- 24757305 TI - Anticancer Effect of dl-Glyceraldehyde and 2-Deoxyglucose in Ehrlich Ascites Carcinoma Bearing Mice and Their Effect on Liver, Kidney and Haematological Parameters. AB - Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect). Compounds that inhibit glycolysis have potential applications in cancer treatment. dl-glyceraldehyde (DLG) and 2-Deoxyglucose (2-DG) have been proven effective in the inhibition of glucose metabolism. Ehrlich ascites carcinoma (EAC) cells were injected intraperitoneally (i.p) in 10-12 weeks old Swiss albino mice, weighing between 20 and 30 g. The anticancer activity of DLG and 2-DG were determined by tumor volume, tumor weight, viable and nonviable tumor cell count, average survival time, percentage increase in life span and tumor inhibition ratio. The blood samples were obtained for biochemical analysis after 9 days of treatment to study the effect on liver, kidney and haematological parameters. Histopathological examination of liver and kidney was also performed. One-way ANOVA test and Dunnett's test were used for comparisons of parameters in study groups. Both DLG and 2-DG individually decreased the tumor weight, tumor volume, viable tumor cell count and significantly increased the life span of treated mice, however the combination was found to be better. The biochemical parameters of liver and kidney functions and haematological parameters were restored close to control group as compared with the EAC bearing mice. Histopathological examination of liver and kidney in EAC control group showed large areas of necrosis, congestion and mononuclear cell infiltration but such changes were not observed in liver and kidney sections observed after i.p injection of DLG and 2-DG for 9 days. Improvement was much better in the group where combination of these two drugs were used. PMID- 24757307 TI - Identification of Pre-examination Errors in the Chemical Pathology Laboratory at the University Hospital of the West Indies. AB - This study evaluated the types and frequencies of pre-examination errors recorded in the chemical pathology laboratory at the University Hospital of the West Indies, Jamaica. This was a retrospective analysis of errors recorded over a three year period. Data analysis was done on an average of 519,084 samples collected and tested per year. Samples included blood, urine, stool and other fluids. Pre-examination errors were identified and recorded following visual inspection of the samples and corresponding request forms by laboratory staff, then subsequently by the Senior Medical Technologist. Errors were generally classified as inappropriate sample (58 %), inappropriate form (23.4 %), inappropriate sample volume (9.3 %) and inappropriate sample tube (9.3 %). Over 90 % of recorded pre-examination errors were related to blood samples while urine samples accounted for 6.8 % error. Pre-examination errors were lower at this study location than elsewhere. Measures aimed at reducing instances of these errors are recommended for improved laboratory quality output. PMID- 24757306 TI - Evaluation of antioxidants in the kidney of streptozotocin induced diabetic rats. AB - Diabetes mellitus is one of the most common endocrine metabolic disorders. Dual endocrine deficits of impaired insulin action (insulin resistance) and inadequate insulin secretion create an environment of chronic hyperglycemia and general metabolic disarray. Oxidative stress plays an important role in diabetic pathogenesis. Oxidative stress induced by streptozotocin (STZ) has been shown to damage pancreatic beta cell and produce hyperglycemia in rats. The present study was made to evaluate the antioxidant activity of ethanolic extract of the Evolvulus alsinoides in STZ induced rats. The antioxidant activities were done by using standard protocols. For histopathological analysis, the pancreatic tissues of all experimental groups were fixed with 10 % formalin for 24 h then the samples were stained with hematoxylin-eosin for the microscopic observation. Our results showed the significant decrease in lipid peroxidation and increases in the antioxidant (both enzymatic and nonenzymatic) levels after treatment with standard as well as the E. alsinoides. There is no significant difference between control and plant alone group rats. The histopathology reports also revealed non toxic effect and protective effect of E. alsinoides in the kidney of STZ induced diabetic rats. Our result indicated that the E. alsinoides extract effectively increased the antioxidant level thereby it prevents oxidative stress during diabetes mellitus and also it showed the protective effect on kidney of STZ induced rats. Hence it can be used to maintain the antioxidant level during diabetes mellitus. PMID- 24757308 TI - Alteration of micronutrient status in compensated and decompensated liver cirrhosis. AB - Decompensation followed by death is the most serious outcome in patients suffering from cirrhosis of the liver. Alteration of trace elements may play a vital role in the process of decompensation. To examine the change in status of trace elements during the decompensation process, we analysed the zinc, copper, iron, magnesium, bilirubin and albumin levels in the serum of compensated (n = 34) and decompensated (n = 31) liver cirrhosis patients and compared them with healthy control group (n = 36) by post hoc ANOVA. We observed significant alteration in the selected micronutrients in the diseased group relative to healthy controls (P < 0.05). Moreover, mean serum zinc and iron levels were significantly lower with a higher level of serum copper in decompensated cirrhosis group than in compensated group (P < 0.05). However, no significant decrease of serum magnesium was found between the two diseased groups. Our findings imply that the trace elements like zinc, copper and iron might exert important contributory roles in decompensation process in liver cirrhosis and hence, may be utilized as important biomarkers for these patients. Furthermore, we propose that replacements of those micronutrients at an early stage can delay or prevent the severe outcomes like hepatic encephalopathy, gastrointestinal bleeding, severe jaundice or ascites in these patients. PMID- 24757309 TI - Protein thiols and butryrylcholinestrase in saliva of oral cancer patients. AB - Oral squamous cell carcinoma is one of the most common malignancies recognized. Biomarkers which can predict presence of cancer and its progression can help in better management of these disorders. Over production of lipid peroxidation byproducts and disturbances in antioxidant defense system have been implicated in the pathogenesis of several diseases including oral cancer. Studies have shown a correlation of butyrylcholinesterase (BChE), with tumourigenesis, cell proliferation and cell differentiation. Earlier we have observed a significant elevation in plasma BChE and protein thiols in oral cancer patients which correlated well with stages of cancer. As it was not clear whether the above markers will be altered in saliva of oral cancer patients this study was undertaken. Institutional Ethics Committee gave permission to carry out this study. Total of 55 subjects comprising healthy controls (n = 30) and biopsy proven oral cancer patients (n = 25) consented to participate in this study. Salivary samples from cases were taken before any definitive treatment. Protein thiols and BChE were estimated in salivary samples using validated assay methods. Oral cancer patients had a significant increase in pre-treatment salivary BChE levels (p <= 0.001) and a significant decrease (p <= 0.001) in salivary thiols as compared to respective values in controls. Salivary protein thiols and BChE may have a role in pathophysiology of oral cancer. Saliva can be used as a potential non-invasive screening tool in oral cancer patients. PMID- 24757310 TI - Effect of sodium chloride on efficiency of cisplatinum dissolved in dimethyl sulfoxide: an in vitro study. AB - Cisplatinum (Cispt) is an anti-cancer drug with a low level of solubility. One of Cispt's solvents is dimethyl sulfoxide (DMSO) which can be substituted with chlorine of drug as Cispt's solvent. Applying such a solvent in biological studies is impossible due to intense reduction in activity. On the other hand, it is specified that Cispt's stability is increased in aqueous media by increasing sodium chloride (NaCl) concentration up to 0.9 %. Consequently, we intended to study the effect of DMSO on cytotoxicity of Cispt in presence of sodium. MTT assay was employed to study cytotoxicity effect of Cispt + NaCl + DMSO and Cispt + DMSO on G-292 cell line. Cytotoxicity in dilutions of 300 and 9 (p < 0.01) of Cispt in Cispt + NaCl + DMSO formulation was equal to 78 and 7 %. These values were estimated 79 and 18 % for Cispt + DMSO formulation and 79 and 24 % for free drug. IC50 values demonstrated reduction of 45 % in cytotoxicity of Cispt in Cispt + DMSO formulation. Studying chemical structure of Cispt and Cispt dissolved in DMSO showed that NaCl cannot inhibit inactivating effect of DMSO on Cispt and effect of this solvent on Cispt is independent from presence of NaCl. Results represented that using NaCl does not result in stability and keeping cytotoxicity properties of Cispt in DMSO. Findings suggest more studies for using DMSO as a solvent of Cispt. PMID- 24757311 TI - Comparison of the Carcinogenic Potential of Smokeless Tobacco and Smoked Tobacco by Quantifying the Excretion of Nicotine Metabolite NNAL in Patients with Oral Leukoplakia. AB - The case control study was conducted to quantify the amount of the carcinogenic tobacco specific nitrosamine in smokeless tobacco users and smokers in patients with oral leukoplakia and also to emphasize the role of tobacco-specific nitrosamine in the incidence of oral leukoplakia. The study was conducted on 30 patients. The urine samples were obtained from smokeless tobacco users with oral leukoplakia, smokers with oral leukoplakia and non-tobacco users (i.e. people who do not use tobacco in any form). The collected samples were processed by gas chromatography-mass spectrometry. A highly significant difference of NNAL[4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol] in smokeless tobacco users than tobacco smokers P = 0.0002 (Table 1) was obtained. This significant difference shows smokeless tobacco is more carcinogenic than smoked tobacco. This study confirmed that NNAL is a potent biomarker for calculating the risk of occurrence of carcinoma in smokeless tobacco users and smokers, and that smokeless tobacco is more harmful than smoked tobacco. PMID- 24757312 TI - Spurious hyperphosphatemia in a case of multiple myeloma. AB - A 50 year old male was admitted in our hospital with anemia and impaired renal function. He was subsequently found to have extremely elevated serum phosphate level (24 mg/dL, reference interval: 2.5-4.5 mg/dL) with normal serum calcium when assayed on a Beckman Coulter AU 480((r)) analyser. Clinico-biochemical discrepancy led to the suspicion of spurious hyperphosphatemia. Serum total protein was grossly elevated with gross reversal of albumin to globulin ratio. Serum electrophoresis revealed a large M band and was confirmed as Ig G-Kappa type on immunofixation. Subsequently a bone marrow aspiration biopsy confirmed the diagnosis of multiple myeloma. The patient serum was then reassayed for phosphate on a Vitros((r)) 250 Dry Chemistry platform and the result was within normal reference interval. Paraproteinemias are a common cause of analytical interference in clinical biochemistry laboratories and as multilayered film technology platforms like Vitros((r)) assay most routine analytes on a protein free filtrate they are unaffected by paraprotein interference. Clinically discordant patient results should always be interpreted keeping such interferences in mind. PMID- 24757313 TI - Partial empty sella syndrome: a case report and review. AB - Empty sella syndrome is a damaged pituitary gland. Either the gland has shrunk or has been crushed and flattened making it look like an empty sella on MRI scan. The reported prevalence of primary empty sella in general population is 8-35 %. The incidence is more in females, the ratio being 5:1. It is generally found in middle aged women who are obese and hypertensive. PMID- 24757314 TI - Congenital lead poisoning: an unusual presentation. AB - Lead poisoning presents a common acquired as well as congenital environmental threat to children's health today. An unusual case of severe lead poisoning in breast fed male infant is presented here. The objective of the study is to describe a patient who developed clinical lead intoxication with an uncommon source of poisoning. A 6 months old male baby presented with gradual loss of weight, not feeding well and persistent vomiting. Laboratory investigation revealed that he was having anemia (Hb level 5.4 gm/dl), abnormal liver enzymes (including elevated transaminase activity) and high blood lead value (83 MUg/dl). RBC morphology showed basophilic stippling with cabot ring, suggestive of a case of lead poisoning. A course of chelation treatment using calcium versenate (EDTACaNa2) was prescribed following which a radical solution for mobilization of lead from his systems was observed. PMID- 24757315 TI - Urinary retention as a cause of hyponatremia in an elderly man. AB - Hyponatremia is a common disorder in elderly and can result in changes in cognition, seizures, coma or even respiratory arrest if not recognised and treated. Syndrome of inappropriate anti diuretic hormone secretion (SIADH) is the most common cause of hyponatremia in elderly hospitalised patients and in most cases the etiology cannot be determined on routine investigations. We present a 76 year old male with symptomatic hyponatremia who had chronic urinary retention due to a urethral stricture. His sodium levels improved with catheterisation and worsened again after the catheter was removed. This supports the hypothesis that urinary retention and bladder distension can stimulate ADH release from the posterior pituitary, producing a picture similar to SIADH. PMID- 24757317 TI - Retraction Note: Frequency of TP53 Mutations and its Impact on Drug Sensitivity in Acute Myeloid Leukemia? PMID- 24757316 TI - Inhibition of Glycolysis for Glucose Estimation in Plasma: Recent Guidelines and their Implications. PMID- 24757318 TI - Increased resistance to fungal wilts in transgenic eggplant expressing alfalfa glucanase gene. AB - The wilt diseases caused by Verticillium dahliae and Fusarium oxysporum are the major diseases of eggplant (Solanum melongena L.). In order to generate transgenic resistance against the wilt diseases, Agrobacterium-mediated gene transfer was performed to introduce alfalfa glucanase gene encoding an acidic glucanase into eggplant using neomycin phosphotransferase (npt-II) gene as a plant selection marker. The transgene integration into eggplant genome was confirmed by Polymerase chain reaction (PCR) and Southern blot analysis and transgene expression by the glucanase activity and western blot analysis. The selected transgenic lines were challenged with V. dahliae and F. oxysporum under in vitro and in vivo growth conditions, and transgenic lines showed enhanced resistance against the wilt-causing fungi with a delay of 5-7 days in the disease development as compared to wild-type plants. PMID- 24757319 TI - Arabidopsis mutant plants with diverse defects in polyamine metabolism show unequal sensitivity to exogenous cadaverine probably based on their spermine content. AB - Arabidopsis plants do not synthesize the polyamine cadaverine, a five carbon chain diamine and structural analog of putrescine. Mutants defective in polyamine metabolic genes were exposed to exogenous cadaverine. Spermine-deficient spms mutant grew well while a T-DNA insertion mutant (pao4-1) of polyamine oxidase (PAO) 4 was severely inhibited in root growth compared to wild type (WT) or other pao loss-of-function mutants. To understand the molecular basis of this phenomenon, polyamine contents of WT, spms and pao4-1 plants treated with cadaverine were analyzed. Putrescine contents increased in all the three plants, and spermidine contents decreased in WT and pao4-1 but not in spms. Spermine contents increased in WT and pao4-1. As there were good correlations between putrescine (or spermine) contents and the degree of root growth inhibition, effects of exogenously added putrescine and spermine were examined. Spermine mimicked the original phenomenon, whereas high levels of putrescine evenly inhibited root growth, suggesting that cadaverine-induced spermine accumulation may explain the phenomenon. We also tested growth response of cadaverine-treated WT and pao4-1 plants to NaCl and found that spermine-accumulated pao4-1 plant was not NaCl tolerant. Based on the results, the effect of cadaverine on Arabidopsis growth and the role of PAO during NaCl stress are discussed. PMID- 24757320 TI - The physiological response of Artemisia annua L. to salt stress and salicylic acid treatment. AB - Salinity has a great influence on plant growth and distribution. A few existing reports on Artemisia annua L. response to salinity are concentrated on plant growth and artemisinin content; the physiological response and salt damage mitigation are yet to be understood. In this study, the physiological response of varying salt stresses (50, 100, 200, 300, or 400 mM NaCl) on A. annua L. and the effect of exogenous salicylic acid (0.05 or 0.1 mM) at 300-mM salt stress were investigated. Plant growth, antioxidant enzyme activity, proline, and mineral element level were determined. In general, increasing salt concentration significantly reduced plant growth. Superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were stimulated by salt treatment to a higher enzyme activity in treated plants than those in untreated plants. Content of proline had a visible range of increment in the salt-treated plants. Distribution of mineral elements was in inconformity: Na(+) and Ca(2+) were mainly accumulated in the roots; K(+) and Mg(2+) were concentrated in leaves and stems, respectively. Alleviation of growth arrest was observed with exogenous applications of salicylic acid (SA) under salt stress conditions. The activity of SOD and POD was notably enhanced by SA, but the CAT action was suppressed. While exogenous SA had no discernible effect on proline content, it effectively inhibited excessive Na(+) absorption and promoted Mg(2+) absorption. Ca(2+) and K(+) contents showed a slight reduction when supplemented with SA. Overall, the positive effect of SA towards resistance to the salinity of A. annua will provide some practical basis for A. annua cultivation. PMID- 24757321 TI - Chloroplast pigments, proteins, lipid peroxidation and activities of antioxidative enzymes during maturation and senescence of leaves and reproductive organs of Cajanus cajan L. AB - A comparative investigation was undertaken with pigeon pea leaves and attached flower buds/flowers/pods during their developmental stages including senescence in a natural system in experimental plots. Alterations in chloroplast pigments, total soluble proteins, lipid peroxidation, malondialdehyde (MDA) content and activities of guaiacol peroxidase (POD, EC 1.11.1.7) and superoxide dismutase (SOD, EC 1.15.1.1) were studied at 5-day interval from initial to 40-day stage. Chloroplast pigments and proteins of leaves increased upto 15 and 20-day stages respectively followed by a steady decline. Reproductive parts, however, exhibited rise in chloroplast pigments upto 25-day and protein till last stage as developing pods gain the amount from the senescing leaves which are nearest to them. Senescing leaves show very high POD activity than the developing and senescing pods and POD appears to be associated with chlorophyll degradation. Considerably higher activity and amount of LOX and MDA respectively have been noticed in senescing leaves than in flowers and pods. Increase in SOD activity during early stage of leaf growth and maturation indicates protective role that declined at senescent stages. Pods are unique in having very high SOD activity, only last stage of senescence does show a decline. PMID- 24757322 TI - Differential expression analysis of transcripts related to oil metabolism in maturing seeds of Jatropha curcas L. AB - Jatropha curcas has been widely studied at the molecular level due to its potential as an alternative source of fuel. Many of the reports till date on this plant have focussed mainly on genes contributing to the accumulation of oil in its seeds. A suppression subtractive hybridization strategy was employed to identify genes which are differentially expressed in the mid maturation stage of J. curcas seeds. Random expressed sequence tag sequencing of the cDNA subtraction library resulted in 385 contigs and 1,428 singletons, with 591 expressed sequence tags mapping for enzymes having catalytic roles in various metabolic pathways. Differences in transcript levels in early and mid-to-late maturation stages of seeds were also investigated using sequence information obtained from the cDNA subtraction library. Seven out of 12 transcripts having putative roles in central carbon metabolism were up regulated in early seed maturation stage while lipid metabolism related transcripts were detected at higher levels in the later stage of seed maturation. Interestingly, 4 of the transcripts revealed putative alternative splice variants that were specifically present or up regulated in the early or late maturation stage of the seeds. Transcript expression patterns from the current study using maturing seeds of J. curcas reveal a subtle balancing of oil accumulation and utilization, which may be influenced by their energy requirements. PMID- 24757323 TI - Delayed expression of SAGs correlates with longevity in CMS wheat plants compared to its fertile plants. AB - Reproductive sinks regulate monocarpic senescence in crop plants. Monocarpic senescence was studied in wheat fertile (cv. HW 2041) and its isonuclear cytoplasmic male sterile (CMS) line. CMS plants exhibited slower rate of senescence accompanied by longer green leaf area duration and slower deceleration in chlorophyll, protein content, PN and rubisco content coupled with lower protease activities than fertile (F) plants. CMS plants also exhibited lower ROS levels and less membrane damage than F plants. CMS plants maintained better antioxidant defense, less oxidative damage in chloroplast and higher transcript levels of both rbcL and rbcS genes during senescence than F plants. F plants exhibited early induction and higher expression of SAGs like serine and cysteine proteases, glutamine synthetases GS1 and GS2, WRKY53 transcription factor and decline in transcript levels of CAT1 and CAT2 genes than CMS plants. Hence, using genetically fertile and its CMS line of wheat it is confirmed that delayed senescence in the absence of reproductive sinks is linked with slower protein oxidation, rubisco degradation and delayed activation of SAGs. Better antioxidant defense in chloroplasts at later stages of senescence was able to mitigate the deleterious effects of ROS in CMS plants. We propose that delayed increase in ROS in cytoplasmic male sterile wheat plants resulted in delayed activation of WRKY53, SAGs and the associated biochemical changes than fertile plants. PMID- 24757324 TI - PGPR regulate caspase-like activity, programmed cell death, and antioxidant enzyme activity in paddy under salinity. AB - The response of two root associated bacteria Pseudomonas pseudoalcaligenes and Bacillus pumilus were studied in the (salt-sensitive) rice GJ17 cultivar to salinity under controlled environmental growth conditions for protection of plant from adverse effect of salinity. Salinity affects the growth of salt-sensitive cultivar, but inoculation of plant growth promoting rhizobacteria (PGPR) reduces the harmful effect of salinity. The present study states that PGPR helps to reduce lipid peroxidation and superoxide dismutase activity in salt-sensitive GJ17 cultivar under salinity and play an important role in the growth regulation for positive adaptation of plants to salt stress. This study shows that inoculation of paddy (Oryza sativa) with such bacteria could provide salt tolerant ability by reducing the toxicity of reactive oxygen species by reducing plant cell membrane index, cell caspase-like protease activity, and programmed cell death and hence resulted in increase cell viability. As these isolates remain associated with the roots, the effects of tolerance against salinity are observed here. Results also indicate that isolated PGPR strain help in alleviating up to 1.5 % salinity stress as well as improve tolerance. PMID- 24757325 TI - Assessment of genetic diversity in rice [Oryza sativa L.] germplasm based on agro morphology traits and zinc-iron content for crop improvement. AB - Genetic resources of landraces (84 cultivars) were collected from various agro ecological regions of West Bengal and adjoining areas and characterized based on qualitative and quantitative agro-morphological descriptors along with zinc (Zn) and iron (Fe) content. The DUS protocol was employed to study 16 agro morphological passport data such as: vegetative data (anthocyanin pigmentation, plant habit), reproductive data (flag leaf attitude, stigma colour, panicle attitude), including eight grain quality traits: grain length, grain width, 1000 grains weight, kernel length, kernel breadth etc. Highest seed weight was found in cultivar Khechri (32.04 g/1000 seeds), collected from Sundarban and least seed weight was 9.6 g/1000seeds in Katharibhog. Maturity duration was found very short (<100 days) in Jumla Marshi (97 days) collected from world's coldest rice growing area, Jumla, Nepal. Penultimate leaves breadth was observed broad (>2 cm) in one cultivar Jungli (2.3 cm). Seeds per panicle were 180 in Chinisakkar (medium range), 177 in Dudheswar, and 151 in Ladua. Flag leaf was found in erect condition in late observation in Dudheswar, Enda and Ghiosh. Seventeen cultivars were grouped in the aromatic rice category out of total 84 local landraces. Twenty-one cultivars were with awn, whose length ranges from 1.6 mm (Anandi) to 22.5 mm (Tulaipanji). Kernel colour varies from red, yellowish, brownish, creamy white to white. Kernel length varies from 4 mm to 8 mm and breadth 1.90 mm to 3 mm. Kernel length/breadth ration varied from 1.6 to 3.9. Highest ratio of L/B was found in Pusa Basmati 1(3.9) and lowest in Dudhey (1.6). Elongation ration was highest in Kalokure (2.07) and lowest in Phoolpakri (0.62). Nutritional values of mineral contents of iron (Fe) and zinc (Zn) were estimated in all cultivars by Atomic Absorption Spectrophotometic method. Iron concentration varies from 0.25 MUg/g to 34.8 MUg/g and zinc from 0.85 MUg/g to 195.3 MUg/g in the landraces. Highest iron containing rice was Swetonunia with 34.8 MUg/g and highest amount of Zn was found in Nepali Kalam which was 195.3 MUg/g. Anaerobic germination (AG) was observed in 18 cultivars among 84 land races (viz. Jungli, Kumrogore, Dudheshwar, Rambhog and Tulsi etc.), the trait is highly desired by the rice breeder for the introgression of this gene (QTL) to the HYV for direct seeding in the field for saving labour cost and reduced maturity time. Dendrogram showed genetic diversity among 84 landraces by grouping them into five major clusters. All the descriptors evaluated in this study have showed that there is enough genetic diversity among landraces and this information can be helpful to the breeders to choose the right parent for crop improvement. PMID- 24757326 TI - Genetic diversity and geographical differentiation of Iranian landrace, cultivars, and exotic chickpea lines as revealed by morphological and microsatellite markers. AB - Assessment of the extent of genetic variability within chickpea is fundamental for chickpea breeding and conservation of genetic resources and is particularly useful as a general guide in the choice of parents for breeding hybrids. To establish genetic diversity among 60 accessions of chickpea comprising landraces, internationally developed improved lines, and cultivars, genetic distances were evaluated using 14 simple sequence repeat markers. These markers showed a high level of polymorphism; a total of 59 different alleles were detected, with a mean of 4.2 alleles per locus. The polymorphic information content (PIC) value ranged from 0.31 to 0.89. All the markers, with the exception of TAA170, TA110, GA34, and Ts35, were considered to be informative (PIC > 0.5), indicating their potential usefulness for cultivar identification. Based on the UNJ clustering method, all accessions were clustered in five groups, which indicated the probable origin and region similarity of Iranian landraces over the other cultivars. It also represents a wide diversity among available germplasm. The result has firmly established that introduction of genetic materials from exotic sources has broadened the genetic base of the national chickpea breeding program. As further implications of the findings, this study can be useful for selective breeding for specific traits and in enhancing the genetic base of breeding programs. PMID- 24757327 TI - Plant regeneration from leaf explants of Aloe barbadensis Mill. and genetic fidelity assessment through DNA markers. AB - An efficient plant regeneration protocol was developed from leaf explants of Aloe barbadensis Mill on Murashige and Skoog's (MS) medium supplemented with 2.0 mg/l 6-benzyladenine (BA) or Kinetin (Kn), 0.25-0.5 mg/l NAA (1-napthalene acetic acid) and 3 % (w/v) sucrose within 4 weeks of culture. The maximum number of shoot buds were obtained on MS medium supplemented with 2.0 mg/l BA, 0.5 mg/l NAA, 40 mg/l Ads (adenine sulphate) within 4-6 weeks of subculture. Inclusion of 0.25-0.50 mg/l gibberellic acid into the medium, the shoot buds became elongated. Repeated subculture on regeneration medium induces higher rate of shoot regeneration. The root induction from excised microshoots was achieved on half strength MS medium supplemented with 0.25-1.0 mg/l NAA or indole-3-butyric acid (IBA) and 2 % (w/v) sucrose. Maximum percentage of rooting was achieved on medium having 0.5 mg/l NAA with 3 % (w/v) sucrose. About 80 % of in vitro raised plantlets were hardened in the greenhouse and successfully established in the soil. Both Random Amplified Polymorphic DNA (RAPD) and Inter Simple Sequence Repeat (ISSR) markers were used to detect the variability among the regenerated plants developed in vitro. The results showed that there was no polymorphism among the regenerated plantlets. This study will help for propagation of quality planting material of Aloe barbadensis for commercialization. PMID- 24757328 TI - Synergistic effect of BAP and GA3 on in vitro flowering of Guizotia abyssinica Cass.-A multipurpose oil crop. AB - Apical and axillary buds of Guizotia abyssinica Cass., isolated from seedlings raised in vitro, were cultured. High frequency of shoot regeneration was achieved on MS medium with BAP (1 mgl(-1)). Effect of BAP, Kn and GA3 applied successively in culture on shoot regeneration and flower bud formation has been studied. The shoots differentiated in cultures elongated on this medium. These rooted subsequently on half strength MS medium. The shoots flowered in vitro on MS medium with a combination of BAP (0.1mgl(-1)) + GA3 (0.1 mgl(-1)). The plantlets thus formed were successfully hardened with 90 % survival. PMID- 24757329 TI - In vitro morphogenic response of different explants of Gentiana kurroo Royle from Western Himalayas-an endangered medicinal plant. AB - Micropropagation offers a great potential to produce millions of clonal individuals through tissue culture via induction of morphogenesis. The aim of this work was to obtain an efficient protocol for callus regeneration for Gentiana kurroo Royle. The morphogenic response of different explants (leaves, petioles, roots) varied and responded differently for regeneration according to combinations of growth regulators. The petiole explants were best responding for callus induction and subsequently for indirect and direct regeneration. The callus induction was achieved on MS basal + 1.0 mg/l benzyladenine (BA) and 3.00 mg/l naphthalene acetic acid (NAA). MS medium supplemented with 0.10 mg/l NAA and 1.0 mg/l thidiazuron (TDZ) was recorded as the best medium for indirect regeneration. However, for direct regeneration the maximum number of shoot emergence was observed on MS basal fortified with 0.10 mg/l NAA + 0.75 mg/l TDZ. Half strength MS basal supplemented with indole-3-butyric acid (IBA) 1.00 mg/l gave best response for root induction. Subsequently, the plantlets were transferred and 100 % survival rate was recorded only on autoclaved cocopeat. No morphological variations were recorded in the callus regenerated plantlets. PMID- 24757330 TI - Hairy root induction and plant regeneration of medicinal plant Dracocephalum kotschyi. AB - An efficient hairy root induction system for an important endangered medicinal plant, Dracocephalum kotschyi, was developed through Agrobacterium rhizogenes mediated transformation by modifying the co-cultivation medium using five bacterial strains, A4, ATCC15834, LBA9402, MSU440, and A13 (MAFF-02-10266). A drastic increase in transformation frequency was observed when a Murashige and Skoog medium lacking NH4NO3 KH2PO4, KNO3 and CaCl2 was used, resulting in hairy root induction frequencies of 52.3 %, 69.6 %, 48.6 %, 89.0 %, and 80.0 % by A4, A13, LBA9402, MSU440, and ATCC15834 strains, respectively. For shoot induction, hairy roots and unorganized tumors induced by strain ATCC15834 were placed on an MS media supplemented with 0.1, 0.25, 0.5, and 1 mg/l BA plus 0.1 mg/l NAA. The high frequency of shoot regeneration and number of shoot were obtained in the medium containing 0.25 mg/l BA and 0.1 mg/l NAA. Root induction occurred from the base of regenerated shoots on the MS medium supplemented with 0.5 mg/l IBA after 10 days. PMID- 24757331 TI - A simple and efficient protocol for isolation of high quality functional RNA from different tissues of turmeric (Curcuma longa L.). AB - Many experiments in plant molecular biology require processing of a large number of RNA samples and in some cases large quantities are required for a single application. In turmeric, a major spice and medicinal plant, a protocol for RNA isolation is not available. The major difficulty encountered while using other popular protocols is the low yield and quality of RNA which hampers the downstream applications like qRT-PCR, cDNA synthesis and micro RNA isolation. Commercial kits though available are costly and were found to be unsuccessful in case of rhizomes and root tissues that are rich in polyphenols, polysaccharides and alkaloids. It was thus felt that a quick, handy and cheap protocol of total RNA isolation from different tissues of turmeric was required for day to day working in our lab. The new protocol utilizes SDS based extraction buffer including beta-mercaptoethanol and PVP with sequential acid phenol:chloroform extraction to remove polyphenols and proteins, followed by the purification with sodium acetate to eliminate polysaccharides. The protocol is simple and can be completed in less than 3 h. The RNA yield from rhizome was higher by more than fivefold with both A260/280 and A260/230 ratio in the range of 1.8-2.0. The protocol worked well with leaf, rhizome, pseudostem and root tissues with RIN >7.0 and the isolated RNA could be successfully used for cDNA synthesis, RT-PCR, qRT-PCR and small RNA isolation including microRNA. PMID- 24757332 TI - Influence of mevinolin on chloroplast terpenoids in Cannabis sativa. AB - Plants synthesize a myriad of isoprenoid products that are required both for essential constitutive processes and for adaptive responses to the environment. Two independent pathways for the biosynthesis of isoprenoid precursors coexist within the plant cell: the cytosolic mevalonic acid (MVA) pathway and the plastidial methylerythritol phosphate (MEP) pathway. In this study, we investigated the inhibitory effect of the MVA pathway on isoprenoid biosynthesized by the MEP pathway in Cannabis sativa by treatment with mevinolin. The amount of chlorophyll a, b, and total showed to be significantly enhanced in treated plants in comparison with control plants. Also, mevinolin induced the accumulation of carotenoids and alpha-tocopherol in treated plants. Mevinolin caused a significant decrease in tetrahydrocannabinol (THC) content. This result show that the inhibition of the MVA pathway stimulates MEP pathway but none for all metabolites. PMID- 24757333 TI - Give until it hurts. PMID- 24757334 TI - Gestational diabetes mellitus: insulinic management. AB - Diabetic pregnancies have attendant risks. Adverse fetal, neonatal, and maternal outcomes in a diabetic pregnancy can be avoided by optimum glycemic control. Most pregnancies with GDM can be managed with non-insulinic management, which includes medical nutrition therapy. However, many necessitate concomitant insulinic management. The new insulin analogs present undoubted advantages in reducing the risk of hypoglycemia, mainly during the night, and in promoting a more physiologic glycemic profile in pregnant women with diabetes. Rapid-acting insulin analogs seem to be safe and efficient in reducing postprandial glucose levels more proficiently than regular human insulin, with less hypoglycemia. The long-acting insulin analogs do not have a pronounced peak effect as NPH insulin, and cause less hypoglycemia, mainly during the night. The review focuses on glycemic goals in pregnancy, insulinic management of GDM, and posology of insulin and its analogs. Clear understanding of the insulinic management of GDM is essential for women's health care providers to provide comprehensive care to women whose pregnancies are complicated with diabetes and rechristen the ''diabetic capital of the world'' to the ''diabetic care capital of the world.'' PMID- 24757335 TI - Childhood ovarian malignancy. AB - Objective of this article is to appraise diagnostic aspects and treatment modalities in childhood ovarian tumor in background of available evidence. Literature search on Pubmed revealed various aspects of epidemiology, histopathological diagnosis, and treatment of pediatric ovarian tumor. 85 % of childhood tumors are germ cell tumors. The varied histopathological picture in germ cell tumors poses a diagnostic and therapeutic challenge. Immunohistochemistry and newer genetic markers like SALL4 and karyopherin-2 (KPNA2) have been helpful in differentiating ovarian yolk sac tumor from dysgerminoma, teratomas, and other pictures of hepatoid, endometrioid, clear cell carcinomatous, and adenocarcinomatous tissues with varied malignant potential. Before platinum therapy, these tumors were almost fatal in children. Fertility conserving surgery with bleomycin, etoposide, and cisplatin has dramatically changed the survival rates in these patients. This modality gives cancer cure with healthy offspring to female patients with childhood ovarian tumor. Evidence also supports this protocol resulting in successful pregnancy rates and safety of cytotoxic drugs in children born to these patients. PMID- 24757336 TI - Pre-induction with Mifepristone for Second Trimester Termination of Pregnancy. AB - OBJECTIVE: To study the efficacy and safety of combining mifepristone before misoprostol use in second trimester to considerably reduce the induction-abortion interval with the lowest possible dose and adverse reaction. MATERIAL AND METHODS: A prospective study was conducted which included 60 patients visiting the antenatal OPD for elective abortions between 13 and 20 weeks of gestation as per the MTP act. They were randomly divided into two groups of 30 each-the study group received mifepristone 200 mg orally before misoprostol, whereas the control group was induced with misoprostol alone. The results were analyzed. OBSERVATION: Statistical analysis of the study was done using chi(2) test. The induction abortion interval was significantly shorter in the study group, thereby decreasing the side-effects of the drug as well as duration of hospital stay. CONCLUSION: This study, like many others, offers a reliable, safe, and cost effective option by combining mifepristone before misoprostol to decrease the induction-abortion interval. PMID- 24757337 TI - Prevalence of overt and subclinical thyroid dysfunction among pregnant women and its effect on maternal and fetal outcome. AB - AIM: To determine the current prevalence of thyroid dysfunction in normal pregnant women and to study the impact of thyroid dysfunction on maternal and fetal outcome. METHODS: 400 pregnant women between 13 and 26 weeks of gestation were registered for the study. Apart from routine obstetrical investigations, TSH tests were done. Free T4 and anti-TPO antibody tests were done in patients with deranged TSH. Patients were followed up till delivery. Their obstetrical and perinatal outcomes were noted. RESULTS: The prevalence of hypothyroidism and hyperthyroidism was 12 and 1.25 %, respectively. Adverse maternal effects in overt hypothyroidism included preeclampsia (16.6 vs. 7.8 %) and placental abruption (16.6 vs. 0.8 %). Subclinical hypothyroidism was associated with preeclampsia (22.3 vs. 7.8 %) as compared to the euthyroid patients. Adverse fetal outcomes in overt hypothyroidism included spontaneous abortion (16.6 vs. 2.39 %), preterm birth (33.3 vs. 5.8 %), low birth weight (50 vs. 12.11 %), intrauterine growth retardation (25 vs. 4.9 %), and fetal death (16.6 vs. 1.7 %) as compared to the euthyroid women. Adverse fetal outcomes in subclinical hypothyroidism included spontaneous abortion (5.5 vs. 2.39 %), preterm delivery (11.2 vs. 5.8 %), low birth weight (25 vs. 12.11 %), and intrauterine growth retardation (8.4 vs. 4.9 %) as compared to the euthyroid women. CONCLUSIONS: The prevalence of thyroid disorders was high in our study with associated adverse maternal and fetal outcomes. Routine screening of thyroid dysfunction is recommended to prevent adverse fetal and maternal outcome. PMID- 24757338 TI - The risk factors for failure of labor induction: a cohort study. AB - PURPOSE: To assess how some factors may influence the failure of labor induction. METHODS: We conducted a prospective observational study from January 2009 to December 2011 with 248 patients who were admitted to the Obstetrics Unit of Ferrara University for labor induction. We selected only patients with unfavorable characteristics such as nulliparity, maternal and gestational age, and Bishop score and specific obstetric conditions such as mild preeclampsia, isolated oligohydramnios, premature rupture membrane, gestational diabetes, and hypertension for the success of labor induction. RESULTS: The induction was carried out by rapid-release gel dinoprostone. 200 patients (80.6 %) delivered vaginally (Group A), while 48 (19.4 %) underwent a cesarean section (Group B). Maternal age was one independent significant variable (p = 0.01, OR 1.08) determining the risk of cesarean delivery. Patients affected by mild preeclampsia had a three times higher risk for cesarean section. Despite the several unfavorable characteristics of the patients, the cesarean section rate was comparable to that of the normal population. CONCLUSIONS: Several factors and clinical conditions historically considered as negative predictors of induction result should be reassessed. The success of labor induction is determined by many maternal and fetal variables, which must all be taken into account to avoid unnecessary cesarean sections. PMID- 24757339 TI - Variation of papp-a level in the first trimester of pregnancy and its clinical outcome. AB - INTRODUCTION: Abnormalities in maternal serum marker levels and fetal measurements obtained during the first trimester screening can be a marker not only for certain chromosomal disorders and anomalies in the fetus but also for specific pregnancy complications. In particular, low maternal serum pregnancy associated plasma protein-A (PAPP-A), at 11-13 weeks of gestation, is associated with stillbirth, infant death, intrauterine growth restriction, preterm birth, and pre-eclampsia in chromosomally normal fetuses, while a raised nuchal translucency is associated with specific structural abnormalities and genetic syndromes. We have studied the serum Papp-A level in 560 pregnant patients (11-13 weeks gestation) registered at Bharati Hospital and Research Centre, Pune. All patients undergoing testing were followed till the delivery and their neonatal outcome was also taken into consideration. AIMS AND OBJECTIVES: Our aim is to study the pregnancy outcome in relation to the variations of Papp-A level in the first trimester of pregnancy. MATERIALS AND METHODS: Every patient visiting the antenatal OPD was counseled for testing of First Trimester Screening to assess fetal well-being. Patients who were registered for delivery at our hospital were taken into the trial. Blood samples were taken at 11-13 weeks of pregnancy and sent to the PerkinElmer lab for analysis. Results were expressed in Multiple of Median and patients having MOM value less than 0.5 were carefully observed till the delivery, and a thorough neonatal examination was done by a pediatrician. OBSERVATIONS: 524 patients were included in the trial out of which 452 patients were found to have a normal Papp-A level of >0.5 MOM. All these patients were followed further during the antenatal period where 18 patients developed preterm labor and few patients developed pregnancy-induced hypertension. The obstetric outcome of patients with a normal Papp-A level was fairly uneventful as compared to others with a low Papp-A level. CONCLUSIONS: Though Papp-A level in the first trimester of pregnancy (11-13 weeks) is an important predictor of future obstetric outcome, it has poor positive predictive value. Patients having a Papp A level less than 0.5 MOM have a high risk for preterm delivery, fetal growth restriction, and stillbirths along with increased incidence of hypertensive disorders of pregnancy. A low Papp-A level is a useful indicator of risk of preterm delivery and future chance of development of pregnancy-induced hypertension. PMID- 24757340 TI - Low amniotic fluid index at term as a predictor of adverse perinatal outcome. AB - AIM: To determine whether an antepartum low amniotic fluid index (AFI) is a predictor of adverse perinatal outcome in normal pregnancy and to determine a threshold level of AFI that could predict an adverse outcome. METHODS: This was a prospective study conducted among 180 pregnant women at 37-40 weeks of gestation with no known obstetric or medical complications with an AFI <= 5th percentile. The results were statistically analyzed and compared. RESULTS: In the control group, the mean AFI was 10.14 cm and in the study group, it was 4.14 cm. 65 % patients in the study group and 24 % in the control group had a non-reactive non stress Test. In the control group, 53 % of patients were induced for reasons other than oligohydramnios, while in the study group, 86 % of patients were induced for oligohydramnios. Among the control group, 33 % had a LSCS, while 67 % delivered vaginally; and in the study group, 34 % delivered vaginally and 66 % had a LSCS. In our study, a 5-min APGAR < 7 was seen in 34 % in the study group and 11 % in the control group. 33 % neonates in the control group and 64 % in the study group had birth weights <2.5 kg. CONCLUSIONS: In the presence of oligohydramnios, perinatal morbidity and mortality are high. Determination of AFI is a valuable screening test for predicting fetal distress. PMID- 24757341 TI - Serum estradiol as a predictor of success of in vitro fertilization. AB - AIM: The aim of this study was to assess the role of total serum estradiol on the day of injection HCG, estradiol per mature follicle, and estradiol per oocytes retrieved (OR) on clinical pregnancy rate (CPR) and oocyte/embryo quality in assisted reproduction. MATERIALS AND METHODS: A retrospective review of 342 in vitro fertilization cycles with normal ovarian reserve in women who underwent long GnRH agonist protocol was included. The outcomes assessed are number of OR, number of mature oocytes (MO), number of oocytes fertilized (FO), fertilization rate, number of embryos cleaved (EC), cleavage rate (CR), number of Grade I embryos (E), number of cryopreserved embryos (CPE), and CPR. The Estradiol/follicle ratio (E2/fol) was defined as estradiol level per mature follicle >14 mm in diameter. Estradiol/oocyte (E2/O) ratio was defined as estradiol level per OR. These two ratios were categorized by the 25th percentile into four groups. RESULTS: A positive correlation was seen between E2/fol and OR (r = .334, p value = .0001), MO (r = .335, p value = .0001), FO (r = .222, p value = .002), and CPE (r = .289, p value = .0001). Increased CPR was seen in Group C (E2/fol = 200-299.99) compared to Group A, B, and D (p value = .033). With E2/O ratio, negative correlation was seen between E2/O and OR (r = -.281, p value = .002), MO (r = -.296, p value = .008), FO (r = -.220, p value = .003), EC (r = -.211, p value = .004), Grade 1 embryo (r = -.216, p value = .001), and CPE (r = -.206, p value = .005). No difference in FR, CR, or CPR was seen. No difference was seen in CPR with total serum estradiol. CONCLUSIONS: In conclusion, serum estradiol is an important determinant of IVF success. While total serum estradiol does not exert any positive or negative influence on IVF outcome, estradiol per mature follicle and retrieved oocytes do have an impact. Pregnancy rate is better when E2/fol is between 200 and 299.99 pg/ml. Also, increasing serum E2/fol positively correlates with better oocytes and embryo quality. In contrast, E2/O negatively correlates with oocytes and embryo quality parameters. PMID- 24757342 TI - Anti-mullerian hormone: a new marker of ovarian function. AB - OBJECTIVES: The aim of this study was to determine day 3 Serum AMH, FSH, LH, Estradiol (E2), Inhibin B levels, ovarian volume, and antral follicular count to assess ovarian function. METHODS: This study was conducted on 130 infertile women between age 18 and 43 years. Day 3 Serum AMH level was estimated by sandwich enzyme immunoassay; Serum FSH, S. LH, S. E2, by solid-phase two-site chemiluminescent immunometric assay; Inhibin B by ELISA; and Ovarian volume and AFC, by transvaginal ultrasonography. RESULTS: With advancing age, Serum AMH level (p < 0.0001), AFC (p < 0.05), ovarian volume (>0.05), and Inhibin B (>0.05) were decreased, and Serum FSH (p < 0.05), LH (p > 0.05), and E2 (p < 0.05) were increased. Serum AMH level was 4-6.8 ng/ml with optimal fertility in 26.15 % cases and 2.2-4.0 ng/ml with satisfactory fertility in 53.85 % cases. Serum AMH levels were more strongly correlated with AFC (p < 0.0001) and ovarian volume (p < 0.0001). CONCLUSION: Serum AMH levels were more robustly correlated with AFC than FSH, LH, E2, and Inhibin B on day 3 of the cycle. This suggested that serum AMH might be taken as single test to reflect ovarian reserve. PMID- 24757343 TI - Success in pregnancy through intrauterine insemination at first cycle in 300 infertile couples: an analysis. AB - OBJECTIVE: The aim of this article was to determine digital levels of the association of factors of pregnancy success after the first cycle of intrauterine insemination (IUI) with 300 infertile couples. METHODS: The IUI procedure was followed at 36 h after triggering the ovulation, if at least one follicle measured >15 mm. Endometrium thickness (ET) and serum luteinizing hormone (LH) levels were measured at day 10 for each patient. The post-wash total motile fraction (TMF) of semen of the partner of each patient was also evaluated. The principal component analysis (PCA) was done with the data to quantify the associations of related factors. RESULTS: The clinical pregnancy rate of first cycle IUI attempts was 17.3 %, observed in females, aged 20-39 years and men with TMF >5 million spermatozoa. The ovarian stimulation enabled the development of follicles measuring >16 mm, with LH levels <10 mIU/L and ET >5 mm for success. The PCA revealed that with the female-age parameter, three factors, NF, ET, and LH were related in the component 1; similarly, NF, LH, and RFS were related in component 2; age, NF, ET, LH, LFS, and TMF were related in component 3; and NF, ET, LH, RFS, and LFS in component 4 were related, i.e., the best correlation. CONCLUSIONS: Associated principal determinative factors, LH, female-age, NF and LFS values were highly significant, but the factors, ET, RFS and TMF were statistically insignificant for success through IUI in pregnancy. PMID- 24757344 TI - Aggressive angiomyxoma of rectovaginal septum, mimicking a huge recto-enterocele: a rare case report. PMID- 24757345 TI - Cotyledonoid leiomyoma of uterus. PMID- 24757346 TI - Malignant brenner tumor of ovary. PMID- 24757347 TI - A Three-Dimensional Way to Prevent Pregnancy: The IUB Intra Uterine Ball-A Newly Introduced IUD in Clinical Trials. PMID- 24757348 TI - Beware of the evidence!: a cautionary note. PMID- 24757350 TI - Analysis of fracture resistance of endodontically treated teeth restored with different post and core system of variable diameters: an in vitro study. AB - The restoration of endodontically treated teeth requires the fabrication of a post and core; to provide retention and support for the final crowns. The purpose of this study was to evaluate fracture resistance of endodontically treated teeth restored with prefabricated zirconia post (CP), milled zirconia post (MZ), pressable ceramic post (PC) and cast metal post (Ni-Cr) of 1.4 and 1.7 mm diameter. 48 freshly extracted human maxillary central incisors were used for this study. The teeth were distributed in four groups of 12 teeth each. From each group, 6 teeth were selected for 1.4 mm diameter post and rest of the 6 teeth, is selected for 1.7 mm diameter post. All teeth were restored with metal crowns. Each specimen from the group was subjected to "load to fracture" in universal testing machine at 130 degrees angle and the maximum load at failure was recorded. Statistically significant difference was found between the failure load of the groups studied. In group I (Ni-Cr)-1.4 mm diameter post and core recorded a maximum fracture load of 534.83 +/- 1.28 N and 1.7 mm diameter post and core showed 294.33 +/- 1.02 N. In group II (PC)-1.4 mm diameter post and core recorded a maximum fracture load of 205.33 +/- 1.61 N and 1.7 mm post and core showed 375.00 +/- 1.57 N. In group III (CP)-1.4 mm diameter post and cores recorded a maximum fracture load of 313.00 +/- 0.73 N and 1.7 mm post and core showed 638.67 +/- 0.81 N. In group IV (MZ)-1.4 mm diameter post and cores recorded a maximum fracture load of 312.00 +/- 0.86 N and 1.7 mm post and core showed 415.00 +/- 0.89 N. Prefabricated zirconia post (1.7 mm) with pressable ceramic core (Cosmo post)-exhibited higher fracture resistance. Milled zirconia and prefabricated zirconia post-showed same value with 1.4 mm diameter post. Pressable ceramic post and core showed satisfactory result with 1.7 mm post, but showed lesser values with 1.4 mm diameter post. PMID- 24757349 TI - Heat generated by dental implant drills during osteotomy-a review: heat generated by dental implant drills. AB - STATEMENT OF PROBLEM: Osseointegration is the more stable situation and results in a high success rate of dental implants. Heat generation during rotary cutting is one of the important factors influencing the development of osseointegration. PURPOSE: To assess the various factors related to implant drills responsible for heat generation during osteotomy. MATERIALS AND METHODS: To identify suitable literature, an electronic search was performed using Medline and Pubmed database. Articles published in between 1960 to February 2013 were searched. The search is focused on heat generated by dental implant drills during osteotomy. Various factors related to implant drill such effect of number of blades; drill design, drill fatigue, drill speed and force applied during osteotomies which were responsible for heat generation were reviewed. Titles and abstracts were screened, and literature that fulfilled the inclusion criteria was selected for a full-text reading. RESULTS: The initial literature search resulted in 299 articles out of which only 70 articles fulfils the inclusion criteria and were included in this systematic review. Many factors related to implant drill responsible for heat generation were found. Successful preparation of an implant cavity with minimal damage to the surrounding bone depends on the avoidance of excessive temperature generation during surgical drilling. CONCLUSION: The relationship between heat generated and implant drilling osteotomy is multifactorial in nature and its complexity has not been fully studied. Lack of scientific knowledge regarding this issue still exists. Further studies should be conducted to determine the various factors which generate less heat while osteotomy such as ideal ratio of force and speed in vivo, exact time to replace a drill, ideal drill design, irrigation system, drill-bone contact area. PMID- 24757351 TI - The effect of surface treatments on the bond strength of a nonprecious alloy ceramic interface: an invitro study. AB - The purpose of this study was to compare the effect of seven different alloy surface treatments on the bond strength of the porcelain-metal interface. Three layers of opaque porcelain and a measured thickness of dentin porcelain were applied to nickel-chromium alloy, A tensile bond strength test was used. The alloy surface treatment that exhibited the highest bond strength was sandblast + surface grinding + sandblast + de-gas, whereas the alloy surface treatment that exhibited the lowest bond strength was sandblast + surface grinding + sandblast + steam cleaning + de-gas. There was a significant difference between the two methods (P < 0.05). It was concluded that de-gassing the alloy prior to porcelain application increased the bond strength and excess surface grinding of the alloy reduced bond strength; steam cleaning the alloy surface prior to de-gassing and porcelain application also significantly reduced the bond strength. PMID- 24757352 TI - Influence of smear layer treatment on resistance to root fracture in tooth restored with epoxy fiber post. AB - To evaluate the influence of complete smear layer removal by EDTA on the resistance of root fracture of tooth restored with fiber post. Twenty single rooted premolars with average root length 16 +/- 1 mm were randomly divided into two groups of ten each. All teeth were obturated with guttapercha after root canal preparation, sectioned 4 mm above the cement-enamel junction. In group I, teeth root canals were etched with 37 % phosphoric acid, fiber post cemented with self adhesive resin cement. In group II, teeth radicular dentin was treated with 17 % EDTA, followed by fiber post cementation with dual cure resin cement. Coronal part of the teeth reestablished with posterior composite and NiCr full veneer coping along with 2 mm circumferential ferrule. Restored teeth were loaded with incremental force at 30 degrees to the long axis of the root until fracture occurred. The data obtained was evaluated with paired sample T test to compare the fracture resistance between the test groups. Group I had the mean failure load of 1,883.70 N while group II had 1,622.80 N mean failure load. Paired sample T test showed statistically significant (p value = 0.033) failure load difference between the groups tested. Within the limits of this study, it may be concluded that: the complete removal of smear layer by EDTA found to have reduced the fracture strength of tooth roots restored with an epoxy fiber post. PMID- 24757353 TI - Patient satisfaction with complete dentures fabricated using two neutral zone techniques: a within-subject cross-over pilot study. AB - Several studies have compared complete dentures fabricated using conventional and neutral zone (NZ) techniques. However, studies comparing patient satisfaction with complete dentures fabricated using swallowing and phonetic NZ techniques are lacking in literature. To compare patient satisfaction with the complete dentures fabricated using the two NZ techniques. To compare the bucco-lingual dimensions of the NZ records obtained with these techniques. Ten completely edentulous subjects dissatisfied with their existing mandibular complete dentures participated in the study. Five subjects first received the swallowing neutral zone (SNZ) dentures and five the phonetic neutral zone (PNZ) dentures. Tissue conditioner was used as the recording material in both the techniques. After having worn the prosthesis for a minimum of 2 months, subjects responded to a questionnaire that measured their perceptions of various factors associated with the prosthesis. The prostheses were then changed and the procedures repeated. Student t test and non-parametric Mann-Whitney tests were used for statistical analysis. Level of statistical significance was set p < 0.05. There was no statistical significant difference in patient satisfaction with the SNZ and PNZ complete dentures for all the variables assessed. Statistical significant difference was observed for majority of the variables when the two NZ dentures were compared with patients' old dentures. The difference in the mean dimensions of the two NZ records was also found to be statistically insignificant except in the maxillary left premolar region. The study indicated that patient satisfaction with the complete dentures fabricated using SNZ technique did not significantly differ from that of the PNZ technique. Data gathered at the final appointment showed that SNZ dentures were preferred by the patients with regards to esthetics, stability, comfort and ability to chew. For ability to speak, mixed preferences were found. PMID- 24757354 TI - A mathematical derivation to prove reduced denture retention in v shaped palate. AB - The impact of oral health on the quality of life of older individuals have significantly increased over the last few decades. Edentulism substantially affect oral and general health and overall quality of life. Complete denture retention is the resistance to displacement of the denture base away from the ridge which is the main source of psychological comfort for the patient. Special retention problems are seen in patients exhibiting highly tapered steep palatal vault. In these cases a metal base or subsequent bench cure reline procedure would be incorporated into the initial treatment plan. In this article, we have derived a mathematical proof for the clinical experience that reduction in the palatal angle, results in lesser denture retention. PMID- 24757355 TI - Evaluation of Bone Density Around the Implants Placed Using Drilling Technique and Bone Expansion Technique: An In vivo Study. AB - Bone density is a key parameter in determining the surgical procedure of implant placement and for the predictability of successful implant treatment. Several clinical studies have shown lower survival rates of implants in maxilla which was attributed to poor bone quality. The present study compared the variations in the pre-operative and post-operative bone density values in Hounsfield units using CT between drilling technique and bone expansion technique at 0.25 and 1.0 mm sections at two sites which were selected in maxillary arch between the second premolar regions of either quadrants and results have shown bone expansion technique is superior to drilling technique in division III bone. PMID- 24757356 TI - Effect of 5.25 % sodium hypochlorite on color stability of acrylic and silicone based soft liners and a denture base acrylic resin. AB - The purpose of the current study was to investigate the effect of a chemical disinfectant (sodium hypochlorite 5.25 %) on color stability of a denture base acrylic resin and two processed soft denture lining materials of two different types (acrylic-based and silicone-based). Ten specimens from each type of materials tested were made (2 * 20 * 20 mm). All specimens were immersed in sodium hypochlorite (5.25 %). Colorimetric measurements for each specimen were taken before immersion, and after 24 h and 7 days of immersion. Color changes were evaluated using the CIE L*a*b* colorimetric system. Data were statistically analyzed with one-way analysis of variance (ANOVA) (alpha = 0.05). ANOVA was followed by Bonferroni test to determine which groups differed from each other. DeltaE and DeltaL* of the silicone-based liner at the 1st and 7th days of immersion were significantly more than of denture base acrylic resin and acrylic based liner. Change in DeltaL* values of denture base acrylic resin and acrylic based liner was small and statistically insignificant after 24 h of its immersion. However, the increase in DeltaL* values of the acrylic-based liner after 7 days of immersion was considerably more than of denture base acrylic resin. Color changes in denture base acrylic resin and soft denture liners tended to increase with longer immersion times, and the color stability of the soft denture liners was influenced by its chemical type. PMID- 24757357 TI - Implant retained auricular prosthesis with a modified hader bar: a case report. AB - Auricular prostheses for defects of external ear are retained either by mechanical means or implants. All implant retained prostheses are retained by various means such as bar and clip, magnetic attachments or a combination of bar, clip and magnets. The commonest problem encountered with the bar and clip system is loosening of the clip after 3-4 months. When magnets are used as retaining component they tend to corrode over a period of time. So various alternative retention methods which possess good retentive qualities, ease of reparability and patient friendly were tried. In the present case a newly modified Hader bar design which can act as an additional retentive feature apart from the clip is employed to increase retention. The major advantages in the modified Hader bar system were that only two implants were employed, the additional loops in the Hader bar prevented micro movements and the retentive acrylic locks were easy to repair if broken. The modified Hader bar has anti-rotational slots which prevents the sliding or rotation of the prosthesis which gave new confidence to the patient who was otherwise worried of inadvertent displacement of the ear prosthesis while playing. PMID- 24757358 TI - Restoration of large cranial defect for cranioplasty with alloplastic cranial implant material: a case report. AB - Cranial defects result either from trauma or after intentional osteocraniotomies or external decompression craniectomies. These defects occur most frequently during wartime, but their incidence during peacetime, as a result of accident or disease, makes knowledge of cranioplasty useful to the interested practitioner. Most cranial defects will have some variable proportion of cosmetic and mechanical aspects, and the decision regarding cranioplasty must be influenced by the patient's age, prognosis, activity level and the specific conditions of the scalp and calvarium. This case report is oriented towards post-traumatic restoration of large cranial defect with alloplastic heat-cure poly methyl methacrylate resin material. PMID- 24757360 TI - Federal Investigative Report Questions 340B Contract Pharmacy Programs: Office of Pharmacy Affairs Promises Regulatory Response. AB - Investigators question 340B contract pharmacy programs. PMID- 24757359 TI - Affirmative warnings (do this) may be better understood than negative warnings (do not do that). AB - For warnings, "do this" may be better than "don't do that." PMID- 24757362 TI - Pharmaceutical approval update. AB - Ibrutinib (Imbruvica) for chronic lymphocytic leukemia, tasimelteon (Hetlioz) for non-24-hour sleep-wake disorder, and anti-inhibitor coagulant complex (Feiba) to prevent or reduce bleeding in hemophilia A or B. PMID- 24757363 TI - Suvorexant, a dual orexin receptor antagonist for the management of insomnia. AB - Suvorexant, a dual orexin receptor antagonist for the management of insomnia. PMID- 24757364 TI - Evaluation of discharge medication orders following automatic therapeutic substitution of commonly exchanged drug classes. AB - OBJECTIVE: Automatic therapeutic substitution (ATS) is a mechanism that, upon patient hospitalization, prompts the pharmacist to exchange an equivalent formulary drug for a nonformulary medication, typically without prescriber contact. In facilities utilizing ATS, there is the possibility that physicians and patients may be unaware of the substitution, potentially leading to drug-drug interactions, therapeutic duplication, and/or increased patient expense following discharge should the original regimen not be resumed. The purpose of this study was to determine the frequency with which hospitalized patients subjected to an ATS protocol were not returned to outpatient drug therapy. METHODS: A retrospective chart review of adult patients admitted to an academic medical center between January 1 and June 30, 2011, was conducted. Patients were included if they were admitted on angiotensin-converting enzyme (ACE) inhibitors, antidepressants, nonsedating antihistamines, histamine (H2) receptor antagonists, or proton pump inhibitors (PPIs), and were then prescribed a different agent via ATS. Admission and discharge medication reconciliation documents, dictated discharge summaries, and patient education documentation reports were reviewed for drug therapies and doses, as well as medication counseling evidence. The primary endpoint was the percentage of patients not returned to original outpatient therapy following ATS. Secondary endpoints included prescribing events in patients not returned to original therapy, the rate and source of drug therapy counseling at discharge, and the number of patients discharged on a potentially cost-prohibitive drug, defined as any drug available only as a branded product during the study period. RESULTS: A total of 317 interventions were identified through review of pharmacy records. Of these, 47 patients (15%) were not returned to original outpatient therapy. Within this subsection, 15 patients (32%) were discharged on the substituted drug, eight patients (17%) resumed initial therapy but received a dosage adjustment from previous outpatient therapy, and three patients (6%) were discharged on a drug that was neither the substituted product nor the previous outpatient therapy. The remaining 21 patients had therapy discontinued (n = 12/47, 26%) or lacked documentation of discharge therapy (9/47, 19%). Nursing staff provided medication counseling to 288 of the 317 patients (91%). Overall, 51 patients (16%) were identified as receiving a cost-prohibitive drug. CONCLUSION: Patients subject to ATS of commonly substituted drug classes were returned to their original outpatient drug therapy more than 85% of the time following inpatient hospitalizations, with similar rates of medication counseling at discharge. The prescribing of cost-prohibitive drugs has been identified as a potential area for pharmacist intervention at discharge. PMID- 24757365 TI - The pharmaceutical industry tussles over biosimilars: federal and state decisions will have a big impact on pharmacists. AB - Unlike a generic drug, a "generic" biologic won't be identical to the branded product. Manufacturers are divided over whether pharmacists should have to tell doctors when they prescribe one of the "biosimilars" that will soon appear on the market. PMID- 24757367 TI - CMS Shelves Proposal To Eliminate Classes of 'Protected' Part D Drugs. PMID- 24757366 TI - Carlos Fernandez-del Castillo Confronts The Challenge of Pancreatic Cancer: Although Progress Has Been Slow, a Renowned Expert On the Disease Sees Reasons for Hope. AB - The prognosis for patients with pancreatic cancer remains poor, but a widely recognized expert on pancreatic and biliary surgery at Massachusetts General Hospital and Harvard Medical School expresses optimism about improvements in the next decade. PMID- 24757368 TI - Hypertension: is it time to replace drugs with nutrition and nutraceuticals? AB - Many hypertension patients want to learn about ways to reduce reliance on pharmaceuticals, says functional medicine practitioner Mark Houston, who believes it is often possible to reduce or eliminate reliance on drugs using nutrition and nutraceuticals. PMID- 24757369 TI - DA-6034 Induces [Ca(2+)]i Increase in Epithelial Cells. AB - DA-6034, a eupatilin derivative of flavonoid, has shown potent effects on the protection of gastric mucosa and induced the increases in fluid and glycoprotein secretion in human and rat corneal and conjunctival cells, suggesting that it might be considered as a drug for the treatment of dry eye. However, whether DA 6034 induces Ca(2+) signaling and its underlying mechanism in epithelial cells are not known. In the present study, we investigated the mechanism for actions of DA-6034 in Ca(2+) signaling pathways of the epithelial cells (conjunctival and corneal cells) from human donor eyes and mouse salivary gland epithelial cells. DA-6034 activated Ca(2+)-activated Cl(-) channels (CaCCs) and increased intracellular calcium concentrations ([Ca(2+)]i) in primary cultured human conjunctival cells. DA-6034 also increased [Ca(2+)]i in mouse salivary gland cells and human corneal epithelial cells. [Ca(2+)]i increase of DA-6034 was dependent on the Ca(2+) entry from extracellular and Ca(2+) release from internal Ca(2+) stores. Interestingly, these effects of DA-6034 were related to ryanodine receptors (RyRs) but not phospholipase C/inositol 1,4,5-triphosphate (IP3) pathway and lysosomal Ca(2+) stores. These results suggest that DA-6034 induces Ca(2+) signaling via extracellular Ca(2+) entry and RyRs-sensitive Ca(2+) release from internal Ca(2+) stores in epithelial cells. PMID- 24757370 TI - Korean red ginseng water extract restores impaired endothelial function by inhibiting arginase activity in aged mice. AB - Cardiovascular disease is the prime cause of morbidity and mortality and the population ages that may contribute to increase in the occurrence of cardiovascular disease. Arginase upregulation is associated with impaired endothelial function in aged vascular system and thus may contribute to cardiovascular disease. According to recent research, Korean Red Ginseng water extract (KRGE) may reduce cardiovascular disease risk by improving vascular system health. The purpose of this study was to examine mechanisms contributing to age-related vascular endothelial dysfunction and to determine whether KRGE improves these functions in aged mice. Young (10+/-3 weeks) and aged (55+/-5 weeks) male mice (C57BL/6J) were orally administered 0, 10, or 20 mg/mouse/day of KRGE for 4 weeks. Animals were sacrificed and the aortas were removed. Endothelial arginase activity, nitric oxide (NO) generation and reactive oxygen species (ROS) production, endothelial nitric oxide synthase (eNOS) coupling, vascular tension, and plasma peroxynitrite production were measured. KRGE attenuated arginase activity, restored nitric oxide (NO) generation, reduced ROS production, and enhanced eNOS coupling in aged mice. KRGE also improved vascular tension in aged vessels, as indicated by increased acetylcholine-induced vasorelaxation and improved phenylephrine-stimulated vasoconstriction. Furthermore, KRGE prevented plasma peroxynitrite formation in aged mice, indicating reduced lipid peroxidation. These results suggest KRGE exerts vasoprotective effects by inhibiting arginase activity and augmenting NO signaling and may be a useful treatment for age-dependent vascular diseases. PMID- 24757371 TI - Push-in Head Restraining Apparatus for Intracranial Self Stimulation Tasks in Rats. AB - Head restraining is an experimental technique that firmly secures the animal's head to a fixation apparatus for the precise control and sensing of behaviors. However, procedural and surgical difficulties and limitations have been obstructing the use of the technique in neurophysiological and behavioral experiments. Here, we propose a novel design of the head-restraining apparatus which is easy to develop and convenient for practical use. Head restraining procedure can be completed by sliding the head mounter, which is molded by dental cement during implantation surgery, into the port, which serves as matching guide rails for the mounter, of the fixation bar. So neither skull-attached plates nor screws for fixation are needed. We performed intracranial self stimulation experiment in rats using the newly designed device. Rats were habituated to acclimatize the head-restraint environment and trained to discriminate two spatially distinguished cues using a customized push-pull lever as an operandum. Direct electrical stimulation into the medial forebrain bundle served as reward. We confirmed that head restraining was stable throughout experiments and rats were able to learn to manipulate the lever after successful habituation. Our experimental framework might help precise control or sensing of behavior under head fixed rats using direct electrical brain stimulation as a reward. PMID- 24757372 TI - Multiple Effects of a Novel Epothilone Analog on Cellular Processes and Signaling Pathways Regulated by Rac1 GTPase in the Human Breast Cancer Cells. AB - The epothilones are a class of microtubule inhibitors that exhibit a strong antitumor activity. UTD2 is a novel epothilone analog generated by genetic manipulation of the polyketide biosynthetic gene cluster. This study investigated the effects of UTD2 on the actin cytoskeleton and its critical regulators, and the signaling pathways which are essential for cell motility, growth and survival in MCF-7 breast cancer cells. Results showed that UTD2 inhibited the cellular functions of actin cytoskeleton, such as wound-closure, migration and invasion, as well as adhesion. Our study further demonstrated that UTD2 suppressed Rac1 GTPase activation and reduced the activity of PAK1, which is a downstream effector of Rac1, while the activity of Cdc42 was not affected. Additionally, the phosphorylation of p38 and ERK were significantly inhibited, but the phosphorylation of JNK remained the same after UTD2 treatment. Moreover, UTD2 inhibited the activity and mRNA expression of MMP-2, which plays a key role in cell motility. UTD2 also reduced the phosphorylation of Akt, which is an important signaling kinase regulating the cell survival through Rac1. Furthermore, UTD2 interrupted the synergy between Rac1 and Raf in focus formation assays. Taken together, these results indicated that UTD2 exerted multiple effects on the actin cytoskeleton and signaling pathways associated with Rac1. This study provided novel insights into the molecular mechanism of the antineoplastic and antimetastatic activities of epothilones. Our findings also suggest that the signaling pathways regulated by Rac1 may be evaluated as biomarkers for the response to therapy in clinical trials of epothilones. PMID- 24757373 TI - Effects of acupuncture stimulation at different acupoints on formalin-induced pain in rats. AB - Acupuncture is the process of stimulating skin regions called meridians or acupoints and has been used to treat pain-related symptoms. However, the pain relieving effects of acupuncture may be different depending on acupoints. In the present study, the effects of acupuncture on behavioral responses and c-Fos expression were evaluated using a formalin test in male Sprague-Dawley rats in order to clarify the analgesic effects of three different acupoints. Each rat received manual acupuncture at the ST36 (Zusanli), SP9 (Yinlingquan) or BL60 (Kunlun) acupoint before formalin injection. Flinching and licking behaviors were counted by two blinded investigators. Fos-like immunoreactivity was examined by immunohistochemistry in the rat spinal cord. Manual acupuncture treatment at BL60 acupoint showed significant inhibition in flinching behavior but not in licking. Manual acupuncture at ST36 or SP9 tended to inhibit flinching and licking behaviors but the effects were not statistically significant. The acupuncture at ST36, SP9, or BL60 reduced c-Fos expression as compared with the control group. These results suggest that acupuncture especially at the BL60 acupoint is more effective in relieving inflammatory pain than other acupoints. PMID- 24757374 TI - Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease. AB - It has been suggested that transition metal ions such as iron can produce an oxidative injuries to nigrostriatal dopaminergic neurons, like Parkinson's disease (PD) and subsequent compensative increase of tetrahydrobiopterin (BH4) during the disease progression induces the aggravation of dopaminergic neurodegeneration in striatum. It had been established that the direct administration of BH4 into neuron would induce the neuronal toxicity in vitro. To elucidate a role of BH4 in pathogenesis in the PD in vivo, we assessed the changes of dopamine (DA) and BH4 at striatum in unilateral intranigral iron infused PD rat model. The ipsistriatal DA and BH4 levels were significantly increased at 0.5 to 1 d and were continually depleting during 2 to 7 d after intranigral iron infusion. The turnover rate of BH4 was higher than that of DA in early phase. However, the expression level of GTP-cyclohydrolase I mRNA in striatum was steadily increased after iron administration. These results suggest that the accumulation of intranigral iron leads to generation of oxidative stress which damage to dopaminergic neurons and causes increased release of BH4 in the dopaminergic neuron. The degenerating dopaminergic neurons decrease the synthesis and release of both BH4 and DA in vivo that are relevance to the progression of PD. Based on these data, we propose that the increase of BH4 can deteriorate the disease progression in early phase of PD, and the inhibition of BH4 increase could be a strategy for PD treatment. PMID- 24757375 TI - The Downregulation of Somatic A-Type K(+) Channels Requires the Activation of Synaptic NMDA Receptors in Young Hippocampal Neurons of Rats. AB - The downregulation of A-type K(+) channels (IA channels) accompanying enhanced somatic excitability can mediate epileptogenic conditions in mammalian central nervous system. As IA channels are dominantly targeted by dendritic and postsynaptic processings during synaptic plasticity, it is presumable that they may act as cellular linkers between synaptic responses and somatic processings under various excitable conditions. In the present study, we electrophysiologically tested if the downregulation of somatic IA channels was sensitive to synaptic activities in young hippocampal neurons. In primarily cultured hippocampal neurons (DIV 6~9), the peak of IA recorded by a whole-cell patch was significantly reduced by high KCl or exogenous glutamate treatment to enhance synaptic activities. However, the pretreatment of MK801 to block synaptic NMDA receptors abolished the glutamate-induced reduction of the IA peak, indicating the necessity of synaptic activation for the reduction of somatic IA. This was again confirmed by glycine treatment, showing a significant reduction of the somatic IA peak. Additionally, the gating property of IA channels was also sensitive to the activation of synaptic NMDA receptors, showing the hyperpolarizing shift in inactivation kinetics. These results suggest that synaptic LTP possibly potentiates somatic excitability via downregulating IA channels in expression and gating kinetics. The consequential changes of somatic excitability following the activity-dependent modulation of synaptic responses may be a series of processings for neuronal functions to determine outputs in memory mechanisms or pathogenic conditions. PMID- 24757376 TI - The hepatotoxicity and testicular toxicity induced by arecoline in mice and protective effects of vitamins C and e. AB - Arecoline is a major alkaloid of areca nuts which are widely chewed by southeast Asian and it manifests various toxic effects in different organs of human and animals. In this work, mature mice were treated by vitamins C plus E, arecoline, or both daily for four weeks. The results showed that arecoline significantly increased the levels of serum alkaline phosphatase (ALP), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT) and significantly decreased the levels of reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) in the liver tissues. Additionally, the body weight, testis weight, sperm counts, motility and normal sperms also were significantly decreased. The supplement of vitamins C and E can bring the activities of ALP and GPT to normal levels and partially restore the sperm counts compared to the arecoline-treated group but have no other positive effects. In conclusion, the vitamins C and E partially attenuated the arecoline induced hepatotoxiciy but basically had on protective effects against the arecoline-induced testicular toxicity. PMID- 24757377 TI - Ginger and its pungent constituents non-competitively inhibit serotonin currents on visceral afferent neurons. AB - Nausea and emesis are a major side effect and obstacle for chemotherapy in cancer patients. Employ of antiemetic drugs help to suppress chemotherapy-induced emesis in some patients but not all patients. Ginger, an herbal medicine, has been traditionally used to treat various kinds of diseases including gastrointestinal symptoms. Ginger is effective in alleviating nausea and emesis, particularly, for cytotoxic chemotherapy drug-induced emesis. Ginger-mediated antiemetic effect has been attributed to its pungent constituents-mediated inhibition of serotonin (5 HT) receptor activity but its cellular mechanism of action is still unclear. Emetogenic chemotherapy drugs increase 5-HT concentration and activate visceral vagal afferent nerve activity. Thus, 5-HT mediated vagal afferent activation is essential to provoke emesis during chemotherapy. In this experiment, water extract of ginger and its three major pungent constituent's effect on 5-HT-evoked responses were tested on acutely dispersed visceral afferent neurons with patch clamp methods. The ginger extract has similar effects to antiemetic drug ondansetron by blocking 5-HT-evoked responses. Pungent constituents of the ginger, [6]-shogaol, [6]-gingerol, and zingerone inhibited 5-HT responses in a dose dependent manner. The order of inhibitory potency for these compounds were [6]-shogaol>[6]-gingerol>zingerone. Unlike well-known competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonist. Our results imply that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons. PMID- 24757378 TI - Regulatory B Subunits of Protein Phosphatase 2A Are Involved in Site-specific Regulation of Tau Protein Phosphorylation. AB - Overexpression of amyloid precursor protein with the Swedish mutation causes abnormal hyperphosphorylation of the microtubule-associated protein tau. Hyperphosphorylated isoforms of tau are major components of neurofibrillary tangles, which are histopathological hallmarks of Alzheimer's disease. Protein phosphatase 2A (PP2A), a major tau protein phosphatase, consists of a structural A subunit, catalytic C subunit, and a variety of regulatory B subunits. The B subunits have been reported to modulate function of the PP2A holoenzyme by regulating substrate binding, enzyme activity, and subcellular localization. In the current study, we characterized regulatory B subunit-specific regulation of tau protein phosphorylation. We showed that the PP2A B subunit PPP2R2A mediated dephosphorylation of tau protein at Ser-199, Ser-202/Thr-205, Thr-231, Ser-262, and Ser-422. Down-regulation of PPP2R5D expression decreased tau phosphorylation at Ser-202/Thr-205, Thr-231, and Ser-422, which indicates activation of the tau kinase glycogen synthase kinase 3 beta (GSK3beta) by PP2A with PPP2R5D subunit. The level of activating phosphorylation of the GSK3beta kinase Akt at Thr-308 and Ser-473 were both increased by PPP2R5D knockdown. We also characterized B subunit specific phosphorylation sites in tau using mass spectrometric analysis. Liquid chromatography-mass spectrometry revealed that the phosphorylation status of the tau protein may be affected by PP2A, depending on the specific B subunits. These studies further our understanding of the function of various B subunits in mediating site-specific regulation of tau protein phosphorylation. PMID- 24757379 TI - Regular exercise training increases the number of endothelial progenitor cells and decreases homocysteine levels in healthy peripheral blood. AB - Endothelial progenitor cells (EPCs) are known to play an important role in the repair of damaged blood vessels. We used an endothelial progenitor cell colony forming assay (EPC-CFA) to determine whether EPC numbers could be increased in healthy individuals through regular exercise training. The number of functional EPCs obtained from human peripheral blood-derived AC133 stem cells was measured after a 28-day regular exercise training program. The number of total endothelial progenitor cell colony-forming units (EPC-CFU) was significantly increased compared to that in the control group (p=0.02, n=5). In addition, we observed a significant decrease in homocysteine levels followed by an increase in the number of EPC-CFUs (p=0.04, n=5), indicating that the 28-day regular exercise training could increase the number of EPC colonies and decrease homocysteine levels. Moreover, an inverse correlation was observed between small-endothelial progenitor cell colony-forming units (small-EPC-CFUs) and plasma homocysteine levels in healthy men (r=-0.8125, p=0.047). We found that regular exercise training could increase the number of EPC-CFUs and decrease homocysteine levels, thus decreasing the cardiovascular disease risk in men. PMID- 24757380 TI - Identification and Functional Characterization of Novel Genetic Variations in the OCTN1 Promoter. AB - Human organic cation/carnitine transporter 1 (OCTN1) plays an important role in the transport of drugs and endogenous substances. It is known that a missense variant of OCTN1 is significantly associated with Crohn's disease susceptibility. This study was performed to identify genetic variants of the OCTN1 promoter in Korean individuals and to determine their functional effects. First, the promoter region of OCTN1 was directly sequenced using genomic DNA samples from 48 healthy Koreans. OCTN1 promoter activity was then measured using a luciferase reporter assay in HCT-116 cells. Seven variants of the OCTN1 promoter were identified, two of which were novel. There were also four major OCTN1 promoter haplotypes. Three haplotypes (H1, H3, and H4) showed decreased transcriptional activity, which was reduced by 22.9%, 23.0%, and 44.6%, respectively (p<0.001), compared with the reference haplotype (H2). Transcription factor binding site analyses and gel shift assays revealed that NF-Y could bind to the region containing g.-1875T>A, a variant present in H3, and that the binding affinity of NF-Y was higher for the g.-1875T allele than for the g.-1875A allele. NF-Y could also repress OCTN1 transcription. These data suggest that three OCTN1 promoter haplotypes could regulate OCTN1 transcription. To our knowledge, this is the first study to identify functional variants of the OCTN1 promoter. PMID- 24757381 TI - Expression profile of neuro-endocrine-immune network in rats with vascular endothelial dysfunction. AB - This study was to determine the correlation between endothelial function and neuro-endocrine-immune (NEI) network through observing the changes of NEI network under the different endothelial dysfunction models. Three endothelial dysfunction models were established in male Wistar rats after exposure to homocysteine (Hcy), high fat diet (HFD) and Hcy+HFD. The results showed that there was endothelial dysfunction in all three models with varying degrees. However, the expression of NEI network was totally different. Interestingly, treatment with simvastatin was able to improve vascular endothelial function and restored the imbalance of the NEI network, observed in the Hcy+HFD group. The results indicated that NEI network may have a strong association with endothelial function, and this relationship can be used to distinguish different risk factors and evaluate drug effects. PMID- 24757382 TI - Preventive Effect of Polysaccharide of Larimichthys crocea Swim Bladder on Reserpine Induced Gastric Ulcer in ICR Mice. AB - This project's aim was to determine the reserpine-induced gastric ulcer preventive effect of polysaccharide of Larimichthys crocea swim bladder (PLCSB) in ICR mice. The anti-gastric ulcer effects of polysaccharide of Larimichthys crocea swim bladder was evaluated in mice model using morphological test, serum levels assay, cytokine levels assay, tissue contents analysis, reverse transcription-polymerase chain reaction (RT-PCR) analysis and western bolt assay. High concentration (50 mg/kg dose) of PLCSB reduced IFN-gamma as compared to low concentration (25 mg/kg dose) and control mice. SS and VIP serum levels of PLCSB treated mice were higher than those of control mice, and MOT and SP serum levels were lower than control mice. Gastric ulcer inhibitory index of PLCSB treatment groups mice were much lower than control mice, and the high concentration treated mice were similar to the ranitidine treated mice. The SOD and GSH-Px activities of PLCSB treated mice were higher than control mice, close to normal mice and ranitidine treated mice. PLCSB treated mice also showed the similar contents of NO and MDA to normal group. By RT-PCR and western blot assay, PLCSB significantly induced inflammation in tissues of mice by downregulating NF-kappaB, iNOS, and COX-2, and upregulating IkappaB-alpha. These results suggest that PLCSB showed a good gastric ulcer preventive effect as the gastric ulcer drug of ranitidine. Polysaccharide of Larimichthys crocea swim bladder may be used as a drug material from marine products. PMID- 24757383 TI - Association mapping of yield-related traits and SSR markers in wild soybean (Glycine soja Sieb. and Zucc.). AB - Wild soybean, the progenitor of cultivated soybean, is an important gene pool for ongoing soybean breeding efforts. To identify yield-enhancing quantitative trait locus (QTL) or gene from wild soybean, 113 wild soybeans accessions were phenotyped for five yield-related traits and genotyped with 85 simple sequence repeat (SSR) markers to conduct association mapping. A total of 892 alleles were detected for the 85 SSR markers, with an average 10.49 alleles; the corresponding PIC values ranged from 0.07 to 0.92, with an average 0.73. The genetic diversity of each SSR marker ranged from 0.07 to 0.93, with an average 0.75. A total of 18 SSR markers were identified for the five traits. Two SSR markers, sct_010 and satt316, which are associated with the yield per plant were stably expressed over two years at two experimental locations. Our results suggested that association mapping can be an effective approach for identifying QTL from wild soybean. PMID- 24757384 TI - Impact of wheat-Leymus racemosus added chromosomes on wheat adaptation and tolerance to heat stress. AB - Adaptation of wheat (Triticum aestivum L.) to high temperatures could be improved by introducing alien genes from wild relatives. We evaluated the responses of wheat-Leymus racemosus chromosome introgression lines to high temperature to determine their potentiality for developing improved wheat cultivars. Introgression lines and their parent Chinese Spring were evaluated in a growth chamber at the seedling stage and in the field at the reproductive stage in two heat-stressed environments in Sudan. Optimum and late planting were used to ensure exposure of the plants to heat stress at the reproductive stage. The results revealed the impact of several Leymus chromosomes in improving wheat adaptation and tolerance to heat. Three lines possessed enhanced adaptation, whereas two showed high heat tolerance. Two addition lines showed a large number of kernels per spike, while one possessed high yield potential. Grain yield was correlated negatively with the heat susceptibility index, days to heading and maturity and positively with kernel number per spike and triphenyl tetrazolium chloride assay under late planting. The findings suggest that these genetic stocks could be used as a bridge to introduce the valuable Leymus traits into a superior wheat genetic background, thus helping maximize wheat yield in heat stressed environments. PMID- 24757385 TI - Development of a new selection method and quality improvement of sugary-1 rice mutants. AB - Brown rice of sugary-1 mutants has a wrinkled character because of the presence of phytoglycogen instead of starch in the inner part of the endosperm. Because the wrinkled phenotype was used as a sole selection marker for progeny of the sugary-1 strain, identification of mutant seeds with improved appearance is very difficult. We found that sugary-1 varieties contained not only phytoglycogen but also free glucose in the endosperm, and these were positively correlated. In the segregated F2 seeds that resulted from crossing Hokurikutou237 (sugary-1) and Koshihikari strains, glucose and phytoglycogen were also significantly correlated. Thus, we identified new sugary types with improved appearance from these progeny using glucose measurements. The F4 seeds of the improved strain had moderate phytoglycogen contents and seed germination characteristics. Native-PAGE showed that pullulanase activity in the improved strain increased in developing seeds compared with Hokurikutou237, although isoamylase activity was extremely low and similar to that in sugary-1 types. The new selection method in this study efficiently aids the development of improved sugary rice types that lack the wrinkled phenotype. PMID- 24757386 TI - Development and evaluation of chromosome segment substitution lines (CSSLs) carrying chromosome segments derived from Oryza rufipogon in the genetic background of Oryza sativa L. AB - The wild relatives of rice (Oryza sativa L.) are useful sources of alleles that have evolved to adapt in diverse environments around the world. Oryza rufipogon, the known progenitor of the cultivated rice, harbors genes that have been lost in cultivated varieties through domestication or evolution. This makes O. rufipogon an ideal source of value-added traits that can be utilized to improve the existing rice cultivars. To explore the potential of the rice progenitor as a genetic resource for improving O. sativa, 33 chromosome segment substitution lines (CSSLs) of O. rufipogon (W0106) in the background of the elite japonica cultivar Koshihikari were developed and evaluated for several agronomic traits. Over 90% of the entire genome was introgressed from the donor parent into the CSSLs. A total of 99 putative QTLs were detected, of which 15 were identified as major effective QTLs that have significantly large effects on the traits examined. Among the 15 major effective QTLs, a QTL on chromosome 10 showed a remarkable positive effect on the number of grains per panicle. Comparison of the putative QTLs identified in this study and previous studies indicated a wide genetic diversity between O. rufipogon accessions. PMID- 24757387 TI - Mapping three new interspecific hybrid sterile loci between Oryza sativa and O. glaberrima. AB - Hybrid sterility hinders the transfer of useful traits between Oryza sativa and O. glaberrima. In order to further understand the nature of interspecific hybrid sterility between these two species, a strategy of multi-donors was used to elucidate the range of interspecific hybrid sterility in this study. Fifty-nine accessions of O. glaberrima were used as female parents for hybridization with japonica cultivar Dianjingyou 1, after several backcrossings using Dianjingyou 1 as the recurrent parent and 135 BC6F1 sterile plants were selected for genotyping and deducing hybrid sterility QTLs. BC6F1 plants containing heterozygous target markers were selected and used to raise BC7F1 mapping populations for QTL confirmation and as a result, one locus for gamete elimination on chromosome 1 and two loci for pollen sterility on chromosome 4 and 12, which were distinguished from previous reports, were confirmed and designated as S37(t), S38(t) and S39(t), respectively. These results will be valuable for understanding the range of interspecific hybrid sterility, cloning these genes and improving rice breeding through gene introgression. PMID- 24757388 TI - QTL pyramiding for improving of cold tolerance at fertilization stage in rice. AB - Vigorous cold tolerance at the fertilization stage (CTF) is a very important characteristic for stable rice production in cold temperature conditions. Because CTF is a quantitatively inherited trait, pyramiding quantitative trait loci (QTLs) using marker-assisted selection (MAS) is effective for improving CTF levels in rice breeding programs. We previously identified three QTLs controlling CTF, qCTF7, qCTF8 and qCTF12, using backcrossed inbred lines derived from a cross between rice cultivar Eikei88223 (vigorous CTF) and Suisei (very weak CTF). However, pyramiding of these QTLs for the application of MAS in practical rice breeding programs have not yet been elucidated. In this study, we examined the effect of pyramiding QTLs for improvement of CTF level using eight possible genotype classes from the 152 F3 population derived from a cross between Eikei88223 and Suisei. Increasing of CTF levels in combinations between qCTF7 and qCTF12 and between qCTF8 and qCTF12 were detected. Furthermore, we compared the haplotype pattern around the QTLs for CTF among the rice cultivars from Hokkaido. These results are useful for improvement of new cultivars with high CTF levels using MAS and identification of genetic resources with the novel QTL(s) for CTF. PMID- 24757389 TI - Objective evaluation of whiteness of cooked rice and rice cakes using a portable spectrophotometer. AB - The whiteness of cooked rice and rice cakes was evaluated using a portable spectrophotometer with a whiteness index (WI). Also, by using boiled rice for measurement of Mido values by Mido Meter, it was possible to infer the whiteness of cooked rice without rice cooking. In the analysis of varietal differences of cooked rice, 'Tsuyahime', 'Koshihikari' and 'Koshinokaori' showed high whiteness, while 'Satonoyuki' had inferior whiteness. The whiteness of rice cakes made from 'Koyukimochi' and 'Dewanomochi' was higher than the whiteness of those made from 'Himenomochi' and 'Koganemochi'. While there was a significant correlation (r = 0.84) between WI values and whiteness scores of cooked rice by the sensory test, no correlation was detected between the whiteness scores and Mido values, indicating that the values obtained by a spectrophotometer differ from those obtained by a Mido Meter. Thus, a spectrophotometer may be a novel device for measurement of rice eating quality. PMID- 24757390 TI - Production of high yield short duration Brassica napus by interspecific hybridization between B. oleracea and B. rapa. AB - Brassica napus is a leading oilseed crop throughout many parts of the world. It is well adapted to long day photoperiods, however, it does not adapt well to short day subtropical regions. Short duration B. napus plants were resynthesized through ovary culture from interspecific crosses in which B. rapa cultivars were reciprocally crossed with B. oleracea. From five different combinations, 17 hybrid plants were obtained in both directions. By self-pollinating the F1 hybrids or introgressing them with cultivated B. napus, resynthesized (RS) F3 and semi-resynthesized (SRS) F2 generations were produced, respectively. In field trial in Bangladesh, the RS B. napus plants demonstrated variation in days to first flowering ranging from 29 to 73 days; some of which were similar to cultivated short duration B. napus, but not cultivated short duration B. rapa. The RS and SRS B. napus lines produced 2-4.6 and 1.6-3.7 times higher yields, respectively, as compared to cultivated short duration B. napus. Our developed RS lines may be useful for rapeseed breeding not only for subtropical regions, but also for areas such as Canada and Europe where spring rapeseed production can suffer from late spring frosts. Yield and earliness in RS lines are discussed. PMID- 24757392 TI - Relationship of nosocomial infections with the development of necrotizing enterocolitis in preterm infants. AB - OBJECTIVE: The aim of this study was to determine the association between the number of nosocomial infections prior to necrotizing enterocolitis (NEC) diagnosis as well as to evaluated how it contributed to development of NEC in premature infants. MATERIAL AND METHODS: The study included 51 preterm infants diagnosed with NEC and 71 preterm infants without NEC hospitalized in the neonatal intensive care unit (NICU) of Clinical Center University of Sarajevo. We evaluated the correlation of the number of nosocomial infections prior to NEC diagnosis with the development of NEC. RESULTS: There was a statistically significant association of the number of nosocomial infections prior NEC diagnosis with the development of NEC (odds ratio, 3.32; 95% confidence interval, 1.09-10.01). CONCLUSION: Increased number of nosocomial infections prior to NEC diagnosis is associated with increased risk of necrotizing enterocolitis. PMID- 24757391 TI - Brain metastasis in bone and soft tissue cancers: a review of incidence, interventions, and outcomes. AB - Bone and soft tissue malignancies account for a small portion of brain metastases. In this review, we characterize their incidence, treatments, and prognosis. Most of the data in the literature is based on case reports and small case series. Less than 5% of brain metastases are from bone and soft tissue sarcomas, occurring most commonly in Ewing's sarcoma, malignant fibrous tumors, and osteosarcoma. Mean interval from initial cancer diagnosis to brain metastasis is in the range of 20-30 months, with most being detected before 24 months (osteosarcoma, Ewing sarcoma, chordoma, angiosarcoma, and rhabdomyosarcoma), some at 24-36 months (malignant fibrous tumors, malignant peripheral nerve sheath tumors, and alveolar soft part sarcoma), and a few after 36 months (chondrosarcoma and liposarcoma). Overall mean survival ranges between 7 and 16 months, with the majority surviving < 12 months (Ewing's sarcoma, liposarcoma, malignant fibrous tumors, malignant peripheral nerve sheath tumors, angiosarcoma and chordomas). Management is heterogeneous involving surgery, radiosurgery, radiotherapy, and chemotherapy. While a survival advantage may exist for those given aggressive treatment involving surgical resection, such patients tended to have a favorable preoperative performance status and minimal systemic disease. PMID- 24757393 TI - Epidemiological surveillance of bacterial nosocomial infections in the surgical intensive care unit. AB - INTRODUCTION: Intensive care units (ICUs) are associated with a greater risk of developing nosocomial infections (NIs) than other departments. AIM: The aim of this study was to determine the rate, the site and causative organisms of NIs in the surgical ICU at University Clinical Center Tuzla. METHODS: All patients admitted to the surgical ICU were followed prospectively, for the development of NIs (January-December 2010). Determination of NIs was performed using standardized the Centers for Disease Control and Prevention (CDC) criteria. RESULTS: 94 out of 834 patients (11.27%) developed NIs. Respiratory tract infections were seen in 56 (60%), urinary tract infections in 15 (16%) and gastrointestinal tract infections in 8 (9%) patients. Other infections identified were surgical site, bloodstream and skin infections. Gram-negative organisms were reported in approximately 75% of cases (78.7% extended-spectrum beta-lactamase (ESBL)-producers). Klebsiella pneumoniae was the commonest (51.0%), followed by Proteus mirabilis (21.3%) and Pseudomonas aeruginosa (10.6%). Methicillin resistant Staphylococcus aureus (MRSA) (16%), and Clostridium difficile (9.6%) were the commonest among gram-positive bacteria. CONCLUSION: Respiratory and urinary tract infections made up the great majority of NIs. ICU patients are more susceptible to NIs, emphasizing the importance of continuous surveillance and enforcement of specific infection control measures. PMID- 24757394 TI - Clinical presentation of hypertensive crises in emergency medical services. AB - OBJECTIVES: The objective of this study is to evaluate the incidence and clinical presentation of hypertensive crises in the Emergency medical services of the Community Health Centre "Dr. Mustafa Sehovic" Tuzla in relation to age, sex, duration and severity of hypertension, as well as the prevalence of accompanying symptoms and clinical manifestations. METHODS: The study was conducted between November 2009 and April 2010 and included 180 subjects of both sexes, aged 30-80 with a diagnosis of arterial hypertension. All subjects were divided into two groups: a control group, which consisted of subjects without hypertensive crisis (95 subjects) and an experimental group that consisted of subjects with hypertensive crisis (85 subjects). RESULTS: The study results indicate that female subjects were significantly over- represented compared to men (60% vs. 40 %, p=0.007). The average age of the male subjects was 55.83+/-11.06 years, while the female subjects' average age was 59.41+/-11.97 years. The incidence of hypertensive crisis was 47.22%, with hypertensive urgency significantly more represented than emergency (16.47% vs. 83.53%, p<0.0001). The majority of subjects in the experimental group (28.23%) belonged to the age group of 60-69 years of age: 26.76% urgency and 35.71% emergency. The most common accompanying symptoms in hypertensive subjects were headache (75%), chest pain (48.33%), vertigo (44.44%), shortness of breath (38.88%) and nausea (33.89%). The most common symptoms in subjects with hypertensive crisis were headache (74.11%), chest pain and shortness of breath (62.35%), vertigo (49.41%), and nausea and vomiting (41.17%). CONCLUSIONS: Chest pain, shortness of breath, nausea and vomiting were significantly over-represented in subjects with hypertensive crisis (p<0.005). Clinical manifestations of hypertensive emergencies in almost all subjects included acute coronary syndrome, and only one subject had acute pulmonary edema. PMID- 24757395 TI - Hyperlipidemia as a risk factor for persons in specific professions. AB - INTRODUCTION: The increase in lipid levels associated with other risk factors for the occurrence of ischemic heart disease and stroke is one of the most important health problems in the world. Risk for development of changes is greater for people of specific occupations such as police officers. MATERIAL AND METHODS: This prospective study included 300 police officers, 150 as experimental and 150 respondents as a control group. To both groups same methods have been applied: A detailed history, physical examination, complete laboratory evaluation, lipid electrophoresis targeted to hypercholesterolemia, ultrasound of the abdomen and Color Doppler of the neck vascular structures. The results obtained by statistical analysis of the data showed that there was a significant increase in levels of cholesterol and triglyceride levels in experimental compared to the control group. Ultrasound of the abdomen showed fatty infiltrated liver in 16% of respondents from the experimental and 2% of the respondents in the control group 2%. Color Doppler of the neck blood vessels in 14% of respondents from experimental group showed changes in blood vessels, which ranged from mild thickening of the intima of the vessel to a 50% decrease in circulation. For the control group, this percentage was 0.66%. Considering that this study involved young, active working population, hyperlipidemia becomes a bigger problem. PMID- 24757396 TI - Clinical analysis of midfacial fractures. AB - PURPOSE: To analyze the features of midfacial fractures. METHODS: Data of 320 patients treated for midfacial fractures during the past 10 years were retrospectively analyzed. RESULTS: Patients were 192 male and 128 female. Their age ranged from 1 to 96 years old with the average of 42.1. Injury most frequently occurred by traffic accidents in 168 patients, followed by falls in 78, assaults in 31 and sports in 25. Pattern of the fractures was classified into zygoma in 159 patients, alveolus in 60, multiple sites in 54, maxilla in 45 and nasal bone in 2. Facial injury severity scale ranged from 1 to 12 with the average of 1.52. Injuries to other sites of the body were found in 90 patients. Fractures of multiple sites showed higher facial injury severity scale and were associated with injuries to other sites of the body at a higher rate. Observation was most frequently chosen in 153 patients, followed by open reduction and internal fixation in 72, intramaxillary fixation in 43 and transcutaneous reduction in 26. CONCLUSIONS: Midfacial fractures showed a variety of features in terms of the site and severity and associated injuries. Understanding these features is important to manage these patients properly. PMID- 24757397 TI - An epidemiological study on ankylosing spondylitis in southern Albania. AB - OBJECTIVES: To evaluate the incidence and prevalence of ankylosing spondylitis (AS) in southern Albania and to assess the association of various demographic risk factors with the severity of disease. MATERIAL AND METHODS: This is an observational study with cross-sectional analyses, conducted in the region of Gjirokaster, between 1995 until 2011. The diagnosis of AS was based on the modified New York criteria. Data on population are obtained from the reports of the National Institute of Statistics. RESULTS: Between 1995 and 2011, there were 54 patients diagnosed with AS. Of them, 48 subjects were males (88.9%) and 6 subjects females (11.1%). The AS prevalence in adult population (>=14 years of age), in December 2010, was 0.061%. The 5-year incidence (2006-2010) in adult population was 0.006 %. The mean age at the onset of disease was 29.7+/-8.4 years. The mean age in 2011 (n=50 subjects) was 51.6+/-12.7 years. The duration of the disease was 22.7+/-11.2 years. More than two thirds of the patients (70.3%) were in the advanced radiological stages of the disease. A younger age at the onset of the disease, longer delay in diagnosis, lower educational level and smoking were significant independent factors associated with the advanced forms of the disease. CONCLUSION: In southern Albania, the AS prevalence in 2010 was 0.061% and the 5-year incidence (2006-2010) was 6 new cases per 105 adults. The incidence and prevalence of AS in Southern Albania are close to the respective regional epidemiological data. PMID- 24757398 TI - Nurses' perceptions of usefulness of nursing information system: module of electronic medical record for patient care in two university hospitals of iran. AB - INTRODUCTION: For almost fifteen years, the application of computer in hospitals increasingly has become popular. Nurses' beliefs and attitudes towards computer is one of the most important indicators of the application of nursing information system. The purpose of this study was to investigate the perceptions of nurses on the usefulness of nursing information system for patient care. METHODS: Here, a descriptive study was carried out. Sample was consisted of 316 nurses working in teaching hospitals in an urban area of Iran. This study was conducted during 2011 to 2012. A reliable and valid questionnaire was developed as a data collection tool. The collected data was analyzed using descriptive and inferential statistics. RESULTS: It was not believed that nursing information system was useful for patient care. However, it was mentioned that nursing information system is useful in some aspects of patient care such as expediting care, making early diagnosis and formulating diet plan. A significant association was found between the demographic background of sample and their perceptions of the usefulness of nursing information system (P<0.05). CONCLUSION: Totally, it can be concluded that nursing information system has a potential for improving patient care in hospital settings. Therefore, policy makers should consider implementing nursing information system in teaching hospitals. PMID- 24757399 TI - Human relationships in palliative care of cancer patient: lived experiences of Iranian nurses. AB - BACKGROUND: cancer patients require palliative care. AIM: the purpose of this study was to explore the experiences of nurses, who provide palliative care for cancer patients, within the context of Iranian culture. METHODS: we conducted a hermeneutic phenomenological study. Semi structured in-depth interviews with 10 nurses were audio taped and transcribed. The transcriptions were then analyzed by Van Manen's method. RESULTS: one of the most important themes that emerged was "human relationships", which also contained the subthemes of "comprehensive acceptance" and "psychological support". CONCLUSIONS: the results provide deep understanding of human relationships in palliative care of cancer patients in Iran. PMID- 24757400 TI - Treatment of children with protein - losing enteropathy after fontan and other complex congenital heart disease procedures in condition with limited human and technical resources. AB - BACKGROUND: Protein-losing enteropathy (PLE) is a disorder characterized by abnormal and often profound enteric protein loss. It's relatively uncommon complication of Fontan and other complex congenital heart disease (CCHD) procedures. Because of the complexity and rarity of this disease process, the pathogenesis and pathophysiology of protein-losing enteropathy remain poorly understood, and attempts at treatment seldom yield long-term success. AIM OF PRESENTATION: is to describe single centre experience in diagnosis, evaluation, management and treatment of children with protein-losing enteropathy after Fontan and other CCHD procedures in the current era and in centre with limited human and technical resources, follows with a comprehensive review of protein-losing enteropathy publications, and concludes with suggestions for prevention and treatment. MATERIAL AND METHODOLOGY: Retrospectively we analyzed patients with CCHD and protein-losing enteropathy in our institution, starting from January 2000 to December 2012. The including criteria were age between two and 17 years, to have a complex congenital heart disease and available complete documentation of cardiac surgery under cardiopulmonary bypass. RESULTS: Of all patients we evaluated 18 cases with protein-losing enteropathy, aged 6 to 19 years (mean 14+/ 9); there were three children who had undergone screening procedure for D transposition, one Tetralogy of Fallot, and remaining 14 patients had undergone Fontan procedures; (anatomic diagnosis are: six with tricuspid atresia, seven with d-transposition, double outlet right ventricle and pulmonary atresia and two with hypoplastic left heart syndrome). The diagnosis of protein-losing enteropathy was made at median age of 5.6 years, ranging from 13 months to 15 years. Diagnosis was made using alpha 1-antitrypsin as a gold marker in stool. By physical examination in 14 patients edema was found, in three ascites, and six patients had pleural effusion. Laboratory findings at the time of diagnosis are: abnormal enteric protein loss was documented at the time of diagnosis in all 18 patients. At the time of diagnosis all patients receiving some form of anticoagulation, 17 patients receiving other medication: 17 - diuretics and ACE inhibitors, 12 digoxin, 9 antiarrhytmics. Cross-sectional echocardiography was performed for all patients and different abnormalities were registered. In 14 patients also magnetic resonance was performed. Therapeutic approach was based on the non-specific medication (diet, diuretics, digoxin, ACE inhibitors, and anticoagulants), heparin and corticosteroids therapy. Long-term response to this type of therapy was registered in three patients. Nine patients underwent treatment with heparin and corticosteroids and no one experienced long term benefit. Despite of needs for catheter therapy or surgical intervention in our study, in the absent of technical and human resources now any one had underwent those procedures. Six patients has been transferred abroad and in five of them surgical intervention was perform. CONCLUSION: Protein-losing enteropathy remains a devastating complication of Fontan procedure and despite in advantages in surgical and medical therapy there is no evidence that protein-losing enteropathy is less common in the current area. PMID- 24757401 TI - Demographic factors and determinants of physical activity and breast feeding practices during puerperium in saudi women. AB - AIM: This cross-sectional study describes the practice of different myths regarding newborns and maternal physical activity among Saudi women during puerperium. MATERIAL AND METHODS: The study was conducted at Mother and Child Hospital, Buraidah from January to December 2011. RESULTS: The multinomial logistic regression (MRA) on age, education, occupation, parity and mode of delivery was statistically significant (chi(2) (60) = 487.656, p < .001). Individuals who were between 25 and 30, had education level primary or below, para2 -4 were more likely to limit household activities. Women in the age group of 25-30 were 41 times more likely to have no exercise. Women with parity 2-4 were 24 times more likely to abstain from sex during puerperium as compared to Para 5 and above. Individuals who had a normal vaginal birth were approximately 9 times less likely to be in the kofalaya's group. Individuals below college level education were more likely to believe that breast feeding in front of others may steal mother's milk. Women below 25 years of age and women with vaginal delivery were more likely to avoid colostrums feeding. CONCLUSION: Health Education programs are needed to encourage women to increase physical activity during puerperium and encourage breast feeding. Focus groups for improving physical activity should include age group 25-30 and women with primary and below level education. Women with cesarean delivery should be counseled against kofalayas and women with vaginal delivery should be encouraged for colostrums feeding. PMID- 24757402 TI - Receptive functions at childbearing age, perimenopause and postmenopause. AB - INTRODUCTION: Receptive functions represents higher mental processes by which people carry out normal daily living tasks. The specificity of these functions is that they stimulate specific physiological functions in the body. They are reflected in the ability to select, classify and integrate the information received. MATERIAL AND METHODS: We performed an assessment of visual-perceptual abilities by Purdue nonverbal test (PNT-TV) in 135 patients. Patients are classified into three age groups of 45 patients. The first group consisted of patients of childbearing age (25-39 years), second group of patients in perimenopausal age (40-54 years) and a third group of postmenopausal patients (>=55 years). RESULTS: The distribution of the results are statistically different between groups, suggesting that at the onset of menopause there is a decrease of visual-perceptual abilities in patients (Friedman test was significant with p<0.001). CONCLUSION: By the distribution of the results of our study, and the statistical significance of Friedman's, it can be concluded that patients who enter menopause have tendency to decrease of receptive functions. PMID- 24757403 TI - Estrogen and progesterone receptors in endometrium in women with unexplained infertility. AB - AIM: The purpose of the present study is to evaluate the relationship between endometrial concentrations of estrogen and progesterone receptors throughout the menstrual cycle in women with unexplained infertility. MATERIAL AND METHODS: In forty four infertile women with unexplained infertility, biopsy of the endometrium was performed during simultaneous laparoscopy and hysteroscopy. Material was prepared for immunohistochemical staining. Forty four endometrial samples obtained from women with normal menstrual cycles were divided into four categories: early proliferative, late proliferative, early secretory and late secretory. Immunohistochemical localization of estrogen receptors (ER) and progesterone receptors (PR) was scored according to intensity of staining and proportion of cells specifically stained in glandular epithelium and stroma and results were analyzed. CONCLUSION: The early secretory phase appeared to be period of transition from the strong and ubiquitous staining for receptor characteristic of proliferative phase of endometrium to the weak, focal pattern of estrogen receptors. Progesterone receptors in early secretory phase were of strong staining and sufficient number of stained cells. PMID- 24757404 TI - Incidence of cesarean section at the department of gynecology and obstetrics of hospital in travnik during 2012. AB - INTRODUCTION: Caesarean section is obstetrical surgery by which through incision of the abdominal wall and the lower uterine segment performs extraction of the fetus in the advanced stages of pregnancy and childbirth ends by abdominal myomectomy. Because of its significance it is one of the most important surgical procedures performed in gynecology and obstetrics. MATERIAL AND METHODS: The goal of this study is to show the incidence of cesarean section in the Public Hospital in Travnik during 2012, and the most frequent indications for surgical completion of delivery. During 2012 at the Department of Gynecology and Obstetrics of Cantonal Hospital Travnik there was 927 deliveries. RESULTS: Of the total number of births, in 115 (12.41%) of cases a caesarean section was performed, while in 812 (87.59%) delivery was completed vaginally. Descriptive analysis reveals that 55 (5.93%) women had repeated cesarean section after a previous cesarean section, while in 60 (6.47%) cases in 2012 for the first time underwent cesarean section. As the most common indications in 7.33% of the women was reported cefalopelvinea disproportion and breech presentation. At 6.67% of the women caesarean section was performed due to asphyxia and 4% due to preeclampsia. The incidence of other indications such as abruption, placenta previa, multiple pregnancy and other was less than 3%. CONCLUSION: On the basis of the data we conclude that in the maternity hospital Travnik vaginal birth is most common. However, although the percentage of cesarean sections was much lower than in the regional maternity hospitals, we cannot ignore that the rate of caesarean sections is slowly increasing and requires that obstetricians in their practice make professional triage when setting indications for cesarean section so that a trend of surgically completed births should not reach epidemic proportions. PMID- 24757405 TI - Tuberculosis Incidence and Case Notification Rates in Kosovo and the Balkans in 2012: Cross-country Comparison. AB - AIM: Tuberculosis (TB) continues to be a considerable burden especially for millions of young adults and disadvantaged people worldwide. The TB incidence and notification rates are good indicators of TB situation in a country. Our aim was to compare TB incidence and notification rates in Kosovo and in seven other Balkan countries. METHODS: Retrospective epidemiologic analysis of published data on TB incidence and notification rates in eight Balkan countries in 2012. Notification rates were expressed per 100,000 inhabitants and were calculated based on the number of TB cases reported divided by the population of each country under analysis. RESULTS: The TB incidence in Kosovo (47/100,000) was considerably higher compared to its four neighboring countries: Albania (16/100,000), Macedonia, Montenegro (18/100,000) and Serbia (23/100,000). The TB notification rates in Kosovo and other countries closely mimicked the incidence rates in these countries. CONCLUSION: The exceptionally high TB incidence rate in Kosovo could be due to many factors including low health and medical-seeking behaviors of the local population, poverty and low education levels. Effective interventions should be adapted to the local context in order to increase the chances of success. PMID- 24757406 TI - Qualitative approach and treatment of patients with prostate cancer in cantonal hospital bihac during two years period. AB - INTRODUCTION: Prostate cancer is an important cause of morbidity and mortality in human pathology. In recent years there has been an increase in the number of new cases. MATERIAL AND METHODS: In this article, we want to show the number of patients diagnosed and treated due to prostate cancer in the Cantonal Hospital Bihac, Bosnia and Herzegovina, over a two year period. After examining the medical records, we selected 70 patients diagnosed with prostate cancer. Average age was 70.9 years (51-91 years). The total PSA ranged from 1.6 to 3332 ng/ml. For each patient is determined the PSA ratio f/t PSA, with an average value of 0.13 (0.02 to 0.627). RESULTS: From the data analysis, we concluded that nearly half of the patients (30 patients), came to the urology clinic with advanced disease. The stage of the disease is well correlated with PSA value. CONCLUSION: The PSA can be considered as a reliable marker in the diagnosis and treatment of prostate cancer. Regardless of the current controversy on the issue of screening on prostate cancer using the PSA analysis, we believe that the use of this simple test in selected populations is justified for the purpose of early disease detection. PMID- 24757407 TI - Developing framework for agent- based diabetes disease management system: user perspective. AB - BACKGROUND: One of the characteristics of agents is mobility which makes them very suitable for remote electronic health and tele medicine. The aim of this study is developing a framework for agent based diabetes information management at national level through identifying required agents. METHODS: The main tool is a questioner that is designed in three sections based on studying library resources, performance of major organizations in the field of diabetes in and out of the country and interviews with experts in the medical, health information management and software fields. Questionnaires based on Delphi methods were distributed among 20 experts. In order to design and identify agents required in health information management for the prevention and appropriate and rapid treatment of diabetes, the results were analyzed using SPSS 17 and Results were plotted with FREEPLANE mind map software. RESULTS: ACCESS TO DATA TECHNOLOGY IN PROPOSED FRAMEWORK IN ORDER OF PRIORITY IS: mobile (mean 1/80), SMS, EMAIL (mean 2/80), internet, web (mean 3/30), phone (mean 3/60), WIFI (mean 4/60). CONCLUSIONS: In delivering health care to diabetic patients, considering social and human aspects is essential. Having a systematic view for implementation of agent systems and paying attention to all aspects such as feedbacks, user acceptance, budget, motivation, hierarchy, useful standards, affordability of individuals, identifying barriers and opportunities and so on, are necessary. PMID- 24757408 TI - Communication in nursing practice. AB - Good communication between nurses and patients is essential for the successful outcome of individualized nursing care of each patient. To achieve this, however, nurses must understand and help their patients, demonstrating courtesy, kindness and sincerity. Also they should devote time to the patient to communicate with the necessary confidentiality, and must not forget that this communication includes persons who surround the sick person, which is why the language of communication should be understood by all those involved in it. Good communication also is not only based on the physical abilities of nurses, but also on education and experience. PMID- 24757409 TI - Vitamin D - Dependent Rickets, Type II Case Report. AB - AIM: The aim of this work the report of one case with vitamin D-dependent rickets, type II. METHODS: Diagnosis has been established based on anamnesis, physical examination, laboratory findings and radiological examination. RESULTS: A female child (age 25 months) has been hospitalized due to bone deformity, bone pain, alopecia and walking difficulties. The laboratory findings have revealed that the calcium values was low (1.20 mmol/L), phosphates in the reference value (1.30 mmol/L) the alkaline phosphatase value was quite high (852 IU/L), high value of parathyroid hormone (9.21 pmol/L), normal value of 25- hydroxyvitamin D, whereas the values of 1,25-dihydroxyvitamin D was high (185 MUmol/L). Radiographic changes were evident and typical in the distal metaphysis of radius and ulna as well as in the bones of lower limbs (distal metaphysis of femur and proximal metaphysis of tibia and fibula). After treatment with calcium and calcitriol, the above mentioned clinical manifestations, laboratory test values and the radiographic changes in bones withdrew. CONCLUSIONS: Vitamin D-dependent rickets, type II is a rare genetic recessive disease, and its treatment includes a constant use of calcium and calcitriol. PMID- 24757410 TI - Genetic algorithm and graph theory based matrix factorization method for online friend recommendation. AB - Online friend recommendation is a fast developing topic in web mining. In this paper, we used SVD matrix factorization to model user and item feature vector and used stochastic gradient descent to amend parameter and improve accuracy. To tackle cold start problem and data sparsity, we used KNN model to influence user feature vector. At the same time, we used graph theory to partition communities with fairly low time and space complexity. What is more, matrix factorization can combine online and offline recommendation. Experiments showed that the hybrid recommendation algorithm is able to recommend online friends with good accuracy. PMID- 24757411 TI - Fragile histidine triad (FHIT) suppresses proliferation and promotes apoptosis in cholangiocarcinoma cells by blocking PI3K-Akt pathway. AB - Fragile histidine triad (FHIT) is a tumor suppressor protein that regulates cancer cell proliferation and apoptosis. However, its exact mechanism of action is poorly understood. Phosphatidylinositol 3-OH kinase (PI3K)-Akt-survivin is an important signaling pathway that was regulated by FHIT in lung cancer cells. To determine whether FHIT can regulate this pathway in cholangiocarcinoma QBC939 cells, we constructed an FHIT expression plasmid and used it to transfect QBC939 cells. Protein and mRNA expression were measured by western blotting and qRT-PCR, respectively. The viability and apoptosis of QBC939 cells were then assessed using MTT assays and flow cytometry. Our results revealed that the expression of survivin and Bcl-2 was downregulated, and caspase 3 was upregulated, in cells overexpressing FHIT. In addition, FHIT suppressed the phosphorylation of Akt. The changes in cell proliferation and apoptosis were obvious in cells overexpressing FHIT which parallels that of treatment with LY294002, a potent inhibitor of phosphoinositide 3-kinases. Treatment with LY294002 further decreased the expression of survivin and Bcl-2 and increased caspase-3 levels. These results suggest that FHIT can block the PI3K-Akt-survivin pathway by suppressing the phosphorylation of Akt and the expression of survivin and Bcl-2 and upregulating caspase 3. PMID- 24757412 TI - A directed continuous time random walk model with jump length depending on waiting time. AB - In continuum one-dimensional space, a coupled directed continuous time random walk model is proposed, where the random walker jumps toward one direction and the waiting time between jumps affects the subsequent jump. In the proposed model, the Laplace-Laplace transform of the probability density function P(x, t) of finding the walker at position x at time t is completely determined by the Laplace transform of the probability density function phi(t) of the waiting time. In terms of the probability density function of the waiting time in the Laplace domain, the limit distribution of the random process and the corresponding evolving equations are derived. PMID- 24757413 TI - Dynamic cooperative clustering based power assignment: network capacity and lifetime efficient topology control in cooperative ad hoc networks. AB - Cooperative communication (CC) is used in topology control as it can reduce the transmission power and expand the transmission range. However, all previous research on topology control under the CC model focused on maintaining network connectivity and minimizing the total energy consumption, which would lead to low network capacity, transmission interruption, or even network paralysis. Meanwhile, without considering the balance of energy consumption in the network, it would reduce the network lifetime and greatly affect the network performance. This paper tries to solve the above problems existing in the research on topology control under the CC model by proposing a power assignment (DCCPA) algorithm based on dynamic cooperative clustering in cooperative ad hoc networks. The new algorithm clusters the network to maximize network capacity and makes the clusters communicate with each other by CC. To reduce the number of redundant links between clusters, we design a static clustering method by using Kruskal algorithm. To maximize the network lifetime, we also propose a cluster head rotating method which can reach a good tradeoff between residual energy and distance for the cluster head reselection. Experimental results show that DCCPA can improve 80% network capacity with Cooperative Bridges algorithm; meanwhile, it can improve 20% network lifetime. PMID- 24757414 TI - Influence of pore structure on compressive strength of cement mortar. AB - This paper describes an experimental investigation into the pore structure of cement mortar using mercury porosimeter. Ordinary Portland cement, manufactured sand, and natural sand were used. The porosity of the manufactured sand mortar is higher than that of natural sand at the same mix proportion; on the contrary, the probable pore size and threshold radius of manufactured sand mortar are finer. Besides, the probable pore size and threshold radius increased with increasing water to cement ratio and sand to cement ratio. In addition, the existing models of pore size distribution of cement-based materials have been reviewed and compared with test results in this paper. Finally, the extended Bhattacharjee model was built to examine the relationship between compressive strength and pore structure. PMID- 24757415 TI - Renoprotective effect of Egyptian cape gooseberry fruit (Physalis peruviana L.) against acute renal injury in rats. AB - This study aimed to evaluate the renoprotective effect of Physalis peruviana L. extract (PPE) on acute renal injury in rats. Adult male rats (n = 36) were divided into six groups that were fed with basal diet throughout the experiment (33 days). The first group was normal group, the second and the third groups were administered orally with 100 and 150 mg PPE/kg body weight (BW) respectively, the fourth group was injected intraperitoneally with 5 mg/kg BW cisplatin once on the 28th day to induced ARI, and the fifth and sixth groups were treated like the second and the third groups and were injected with cisplatin on the 28th day. Many bioactive compounds were found in PPE. PPE did not cause any changes in the second and third groups compared to normal control group. Administration of PPE prior to cisplatin injection caused significant reduction in relative kidney weight, serum creatinine, urea, blood urea nitrogen, and significant increments in body weight, feed intake, total protein, albumin, and total globulin compared to cisplatin group. Pretreatment with PPE improved kidney histology and diminished the level of thiobarbituric acid reactive substances and enhanced other antioxidant enzymes in kidney homogenate compared to cisplatin group. PMID- 24757416 TI - Determination of suitable microspore stage and callus induction from anthers of kenaf (Hibiscus cannabinus L.). AB - Kenaf (Hibiscus cannabinus L.) is one of the important species of Hibiscus cultivated for fiber. Availability of homozygous parent lines is prerequisite to the use of the heterosis effect reproducible in hybrid breeding. The production of haploid plants by anther culture followed by chromosome doubling can be achieved in short period compared with inbred lines by conventional method that requires self pollination of parent material. In this research, the effects of the microspore developmental stage, time of flower collection, various pretreatments, different combinations of hormones, and culture condition on anther culture of KB6 variety of Kenaf were studied. Young flower buds with immature anthers at the appropriate stage of microspore development were sterilized and the anthers were carefully dissected from the flower buds and subjected to various pretreatments and different combinations of hormones like NAA, 2,4-D, Kinetin, BAP, and TDZ to induce callus. The best microspore development stage of the flower buds was about 6-8 mm long collected 1-2 weeks after flower initiation. At that stage, the microspores were at the uninucleate stage which was suitable for culture. The best callus induction frequency was 90% in the optimized semisolid MS medium fortified with 3.0 mg/L BAP + 3.0 mg/L NAA. PMID- 24757417 TI - Critical state of sand matrix soils. AB - The Critical State Soil Mechanic (CSSM) is a globally recognised framework while the critical states for sand and clay are both well established. Nevertheless, the development of the critical state of sand matrix soils is lacking. This paper discusses the development of critical state lines and corresponding critical state parameters for the investigated material, sand matrix soils using sand kaolin mixtures. The output of this paper can be used as an interpretation framework for the research on liquefaction susceptibility of sand matrix soils in the future. The strain controlled triaxial test apparatus was used to provide the monotonic loading onto the reconstituted soil specimens. All tested soils were subjected to isotropic consolidation and sheared under undrained condition until critical state was ascertain. Based on the results of 32 test specimens, the critical state lines for eight different sand matrix soils were developed together with the corresponding values of critical state parameters, M, lambda, and Gamma. The range of the value of M, lambda, and Gamma is 0.803-0.998, 0.144 0.248, and 1.727-2.279, respectively. These values are comparable to the critical state parameters of river sand and kaolin clay. However, the relationship between fines percentages and these critical state parameters is too scattered to be correlated. PMID- 24757418 TI - Anisotropic hardy spaces of Musielak-Orlicz type with applications to boundedness of sublinear operators. AB - Let phi : R(n) * [0, infinity)->[0, infinity) be a Musielak-Orlicz function and A an expansive dilation. In this paper, the authors introduce the anisotropic Hardy space of Musielak-Orlicz type, H(A)(phi)(R(n)), via the grand maximal function. The authors then obtain some real-variable characterizations of H(A)(phi)(R(n)) in terms of the radial, the nontangential, and the tangential maximal functions, which generalize the known results on the anisotropic Hardy space H(A)(p) (R(n)) with p ? (0,1] and are new even for its weighted variant. Finally, the authors characterize these spaces by anisotropic atomic decompositions. The authors also obtain the finite atomic decomposition characterization of H(A)(phi)(R(n)), and, as an application, the authors prove that, for a given admissible triplet (phi, q, s), if T is a sublinear operator and maps all (phi, q, s)-atoms with q < infinity (or all continuous (phi, q, s)-atoms with q = infinity) into uniformly bounded elements of some quasi-Banach spaces B, then T uniquely extends to a bounded sublinear operator from H(A)(phi)(R(n)) to B. These results are new even for anisotropic Orlicz-Hardy spaces on R(n). PMID- 24757419 TI - Exposing image forgery by detecting consistency of shadow. AB - We propose two tampered image detection methods based on consistency of shadow. The first method is based on texture consistency of shadow for the first kind of splicing image, in which the shadow as well as main body is copied and pasted from another image. The suspicious region including shadow and nonshadow is first selected. Then texture features of the shadow region and the nonshadow region are extracted. Last, correlation function is used to measure the similarity of the two texture features. By comparing the similarity, we can judge whether the image is tampered. Due to the failure in detecting the second kind of splicing image, in which main body, its shadow, and surrounding regions are copied and pasted from another image, another method based on strength of light source of shadows is proposed. The two suspicious shadow regions are first selected. Then an efficient method is used to estimate the strength of light source of shadow. Last, the similarity of strength of light source of two shadows is measured by correlation function. By combining the two methods, we can detect forged image with shadows. Experimental results demonstrate that the proposed methods are effective despite using simplified model compared with the existing methods. PMID- 24757421 TI - Local convexity-preserving C2 rational cubic spline for convex data. AB - We present the smooth and visually pleasant display of 2D data when it is convex, which is contribution towards the improvements over existing methods. This improvement can be used to get the more accurate results. An attempt has been made in order to develop the local convexity-preserving interpolant for convex data using C(2) rational cubic spline. It involves three families of shape parameters in its representation. Data dependent sufficient constraints are imposed on single shape parameter to conserve the inherited shape feature of data. Remaining two of these shape parameters are used for the modification of convex curve to get a visually pleasing curve according to industrial demand. The scheme is tested through several numerical examples, showing that the scheme is local, computationally economical, and visually pleasing. PMID- 24757420 TI - Modulating the p66shc signaling pathway with protocatechuic acid protects the intestine from ischemia-reperfusion injury and alleviates secondary liver damage. AB - Intestinal ischemia-reperfusion (I/R) injury is a serious clinical pathophysiological process that may result in acute local intestine and remote liver injury. Protocatechuic acid (PCA), which has been widely studied as a polyphenolic compound, induces expression of antioxidative genes that combat oxidative stress and cell apoptosis. In this study, we investigated the effect of PCA pretreatment for protecting intestinal I/R-induced local intestine and remote liver injury in mice. Intestinal I/R was established by superior mesenteric artery occlusion for 45 min followed by reperfusion for 90 min. After the reperfusion period, PCA pretreatment markedly alleviated intestine and liver injury induced by intestinal I/R as indicated by histological alterations, decreases in serological damage parameters and nuclear factor-kappa B and phospho foxo3a protein expression levels, and increases in glutathione, glutathione peroxidase, manganese superoxide dismutase protein expression, and Bcl-xL protein expression in the intestine and liver. These parameters were accompanied by PCA induced adaptor protein p66shc suppression. These results suggest that PCA has a significant protective effect in the intestine and liver following injury induced by intestinal I/R. The protective effect of PCA may be attributed to the suppression of p66shc and the regulation of p66shc-related antioxidative and antiapoptotic factors. PMID- 24757423 TI - Strong convergence theorems for a common fixed point of a finite family of Bregman weak relativity nonexpansive mappings in reflexive Banach spaces. AB - We introduce an iterative process for finding an element of a common fixed point of a finite family of Bregman weak relatively nonexpansive mappings. Our theorems improve and unify most of the results that have been proved for this important class of nonlinear operators. PMID- 24757422 TI - Solvent extraction of tellurium from chloride solutions using tri-n-butyl phosphate: conditions and thermodynamic data. AB - The extractive separation of tellurium (IV) from hydrochloric acid media with tri n-butyl phosphate (TBP) in kerosene was investigated. The dependence on the extraction of tellurium species, concentrations of tellurium and TBP, extraction time and stage, organic/aqueous ratio, and interferences from coexist metallic ions were examined and are discussed. Besides, the stripping agent and stripping time were also studied. It was found that the extraction reaction corresponds to the neutral complex formation mechanism and the extracted species is TeCl4 . 3TBP and that the extraction process is exothermic. The thermodynamic parameters of enthalpy (DeltaH), entropy (DeltaS), and free energy (DeltaG) of the extraction process were evaluated at -26.2 kJ . mol(-1), -65.6 J . mol(-1) . K(-1), and -7.0 kJ . mol(-1), respectively at 293 K. PMID- 24757424 TI - Multicompare tests of the performance of different metaheuristics in EEG dipole source localization. AB - We study the use of nonparametric multicompare statistical tests on the performance of simulated annealing (SA), genetic algorithm (GA), particle swarm optimization (PSO), and differential evolution (DE), when used for electroencephalographic (EEG) source localization. Such task can be posed as an optimization problem for which the referred metaheuristic methods are well suited. Hence, we evaluate the localization's performance in terms of metaheuristics' operational parameters and for a fixed number of evaluations of the objective function. In this way, we are able to link the efficiency of the metaheuristics with a common measure of computational cost. Our results did not show significant differences in the metaheuristics' performance for the case of single source localization. In case of localizing two correlated sources, we found that PSO (ring and tree topologies) and DE performed the worst, then they should not be considered in large-scale EEG source localization problems. Overall, the multicompare tests allowed to demonstrate the little effect that the selection of a particular metaheuristic and the variations in their operational parameters have in this optimization problem. PMID- 24757425 TI - Personality, category, and cross-linguistic speech sound processing: a connectivistic view. AB - Category formation of human perception is a vital part of cognitive ability. The disciplines of neuroscience and linguistics, however, seldom mention it in the marrying of the two. The present study reviews the neurological view of language acquisition as normalization of incoming speech signal, and attempts to suggest how speech sound category formation may connect personality with second language speech perception. Through a questionnaire, (being thick or thin) ego boundary, a correlate found to be related to category formation, was proven a positive indicator of personality types. Following the qualitative study, thick boundary and thin boundary English learners native in Cantonese were given a speech-signal perception test using an ABX discrimination task protocol. Results showed that thick-boundary learners performed significantly lower in accuracy rate than thin boundary learners. It was implied that differences in personality do have an impact on language learning. PMID- 24757427 TI - A novel iterative scheme and its application to differential equations. AB - The purpose of this paper is to employ an alternative approach to reconstruct the standard variational iteration algorithm II proposed by He, including Lagrange multiplier, and to give a simpler formulation of Adomian decomposition and modified Adomian decomposition method in terms of newly proposed variational iteration method-II (VIM). Through careful investigation of the earlier variational iteration algorithm and Adomian decomposition method, we find unnecessary calculations for Lagrange multiplier and also repeated calculations involved in each iteration, respectively. Several examples are given to verify the reliability and efficiency of the method. PMID- 24757428 TI - Setting and reaching targets with computer-assisted cochlear implant fitting. AB - OBJECTIVE: The paper aims to demonstrate the feasibility of defining a substantial set of psychoacoustic outcome measures with preset targets and to adopt a systematic methodology for reaching these targets in a large group of subjects, by more than one clinical centre. DESIGN: Retrospective data analysis. SETTING: Multicentre with 14 participating centres. PATIENTS: 255 adults and children using the Advanced Bionics HiRes90k cochlear implant. INTERVENTION: Target driven fitting with the fitting to outcomes expert (FOX) system. MAIN OUTCOME MEASURES: For each patient, 66 measurable psychoacoustical outcomes were recorded several times after cochlear implantation: free field audiometry (6 measures) and speech audiometry (4), spectral discrimination (20), and loudness growth (36), defined from the ASE test battery. These outcomes were reduced to 22 summary variables. The initial results were compared with the latest results. RESULTS: The state of the fitting process could be well monitored by means of the measured variables. The use of the FOX computer assisted CI-programming significantly improved the proportion of the 22 variables on target. When recipients used the automated MAPs provided at switch-on, more than half (57%) of the 22 targets were already achieved before any further optimisation took place. Once the FOX system was applied there was a significant 24% (P < 0.001) increase in the number of targets achieved. CONCLUSIONS: This study demonstrates that it is feasible to set targets and to report on the effectiveness of a fitting strategy in terms of these targets. FOX provides an effective tool for achieving a systematic approach to programming, allowing for better optimisation of recipients' MAPs. The setting of well-defined outcome targets allowed a range of different centres to successfully apply a systematic methodology to monitoring the quality of the programming provided. PMID- 24757429 TI - Biomechanical analysis of the efficacy of locking plates during cyclic loading in metacarpal fractures. AB - PURPOSE: To analyse the biomechanical characteristics of locking plates under cyclic loading compared to a nonlocking plate in a diaphyseal metacarpal fracture. METHODS: Oblique diaphyseal shaft fractures in porcine metacarpal bones were created in a biomechanical fracture model. An anatomical reduction and stabilization with a nonlocking and a comparable locking plate in mono- or bicortical screw fixation followed. Under cyclic loading, the displacement, and in subsequent load-to-failure tests, the maximum load and stiffness were measured. RESULTS: For the monocortical screw fixation of the locking plate, a similar displacement, maximum load, and stiffness could be demonstrated compared to the bicortical screw fixation of the nonlocking plate. CONCLUSIONS: Locking plates in monocortical configuration may function as a useful alternative to the currently common treatment with bicortical fixations. Thereby, irritation of the flexor tendons would be avoided without compromising the stability, thus enabling the necessary early functional rehabilitation. PMID- 24757430 TI - Human-manipulator interface using particle filter. AB - This paper utilizes a human-robot interface system which incorporates particle filter (PF) and adaptive multispace transformation (AMT) to track the pose of the human hand for controlling the robot manipulator. This system employs a 3D camera (Kinect) to determine the orientation and the translation of the human hand. We use Camshift algorithm to track the hand. PF is used to estimate the translation of the human hand. Although a PF is used for estimating the translation, the translation error increases in a short period of time when the sensors fail to detect the hand motion. Therefore, a methodology to correct the translation error is required. What is more, to be subject to the perceptive limitations and the motor limitations, human operator is hard to carry out the high precision operation. This paper proposes an adaptive multispace transformation (AMT) method to assist the operator to improve the accuracy and reliability in determining the pose of the robot. The human-robot interface system was experimentally tested in a lab environment, and the results indicate that such a system can successfully control a robot manipulator. PMID- 24757426 TI - Targeting mitochondria as therapeutic strategy for metabolic disorders. AB - Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting. PMID- 24757431 TI - A novel key-frame extraction approach for both video summary and video index. AB - Existing key-frame extraction methods are basically video summary oriented; yet the index task of key-frames is ignored. This paper presents a novel key-frame extraction approach which can be available for both video summary and video index. First a dynamic distance separability algorithm is advanced to divide a shot into subshots based on semantic structure, and then appropriate key-frames are extracted in each subshot by SVD decomposition. Finally, three evaluation indicators are proposed to evaluate the performance of the new approach. Experimental results show that the proposed approach achieves good semantic structure for semantics-based video index and meanwhile produces video summary consistent with human perception. PMID- 24757432 TI - Efficient parallel video processing techniques on GPU: from framework to implementation. AB - Through reorganizing the execution order and optimizing the data structure, we proposed an efficient parallel framework for H.264/AVC encoder based on massively parallel architecture. We implemented the proposed framework by CUDA on NVIDIA's GPU. Not only the compute intensive components of the H.264 encoder are parallelized but also the control intensive components are realized effectively, such as CAVLC and deblocking filter. In addition, we proposed serial optimization methods, including the multiresolution multiwindow for motion estimation, multilevel parallel strategy to enhance the parallelism of intracoding as much as possible, component-based parallel CAVLC, and direction-priority deblocking filter. More than 96% of workload of H.264 encoder is offloaded to GPU. Experimental results show that the parallel implementation outperforms the serial program by 20 times of speedup ratio and satisfies the requirement of the real time HD encoding of 30 fps. The loss of PSNR is from 0.14 dB to 0.77 dB, when keeping the same bitrate. Through the analysis to the kernels, we found that speedup ratios of the compute intensive algorithms are proportional with the computation power of the GPU. However, the performance of the control intensive parts (CAVLC) is much related to the memory bandwidth, which gives an insight for new architecture design. PMID- 24757433 TI - An approximation solution to refinery crude oil scheduling problem with demand uncertainty using joint constrained programming. AB - This paper is devoted to develop an approximation method for scheduling refinery crude oil operations by taking into consideration the demand uncertainty. In the stochastic model the demand uncertainty is modeled as random variables which follow a joint multivariate distribution with a specific correlation structure. Compared to deterministic models in existing works, the stochastic model can be more practical for optimizing crude oil operations. Using joint chance constraints, the demand uncertainty is treated by specifying proximity level on the satisfaction of product demands. However, the joint chance constraints usually hold strong nonlinearity and consequently, it is still hard to handle it directly. In this paper, an approximation method combines a relax-and-tight technique to approximately transform the joint chance constraints to a serial of parameterized linear constraints so that the complicated problem can be attacked iteratively. The basic idea behind this approach is to approximate, as much as possible, nonlinear constraints by a lot of easily handled linear constraints which will lead to a well balance between the problem complexity and tractability. Case studies are conducted to demonstrate the proposed methods. Results show that the operation cost can be reduced effectively compared with the case without considering the demand correlation. PMID- 24757434 TI - A fast overlapping community detection algorithm with self-correcting ability. AB - Due to the defects of all kinds of modularity, this paper defines a weighted modularity based on the density and cohesion as the new evaluation measurement. Since the proportion of the overlapping nodes in network is very low, the number of the nodes' repeat visits can be reduced by signing the vertices with the overlapping attributes. In this paper, we propose three test conditions for overlapping nodes and present a fast overlapping community detection algorithm with self-correcting ability, which is decomposed into two processes. Under the control of overlapping properties, the complexity of the algorithm tends to be approximate linear. And we also give a new understanding on membership vector. Moreover, we improve the bridgeness function which evaluates the extent of overlapping nodes. Finally, we conduct the experiments on three networks with well known community structures and the results verify the feasibility and effectiveness of our algorithm. PMID- 24757435 TI - Gene technology for papaya ringspot virus disease management. AB - Papaya (Carica papaya) is severely damaged by the papaya ringspot virus (PRSV). This review focuses on the development of PRSV resistant transgenic papaya through gene technology. The genetic diversity of PRSV depends upon geographical distribution and the influence of PRSV disease management on a sequence of PRSV isolates. The concept of pathogen-derived resistance has been employed for the development of transgenic papaya, using a coat protein-mediated, RNA-silencing mechanism and replicase gene-mediated transformation for effective PRSV disease management. The development of PRSV-resistant papaya via post-transcriptional gene silencing is a promising technology for PRSV disease management. PRSV resistant transgenic papaya is environmentally safe and has no harmful effects on human health. Recent studies have revealed that the success of adoption of transgenic papaya depends upon the application, it being a commercially viable product, bio-safety regulatory issues, trade regulations, and the wider social acceptance of the technology. This review discusses the genome and the genetic diversity of PRSV, host range determinants, molecular diagnosis, disease management strategies, the development of transgenic papaya, environmental issues, issues in the adoption of transgenic papaya, and future directions for research. PMID- 24757436 TI - Nonoscillatory solutions for system of neutral dynamic equations on time scales. AB - We will discuss nonoscillatory solutions to the n-dimensional functional system of neutral type dynamic equations on time scales. We will establish some sufficient conditions for nonoscillatory solutions with the property lim(t -> infinity) x(i) (t) = 0, i = 1, 2,..., n. PMID- 24757437 TI - On the iterative methods of linearization, decrease of order and dimension of the Karman-type PDEs. AB - Iterative methods to achieve a suitable linearization as well as a decrease of the order and dimension of nonlinear partial differential equations of the eighth order into the biharmonic and Poisson-type differential equations with their simultaneous linearization are proposed in this work. Validity and reliability of the obtained results are discussed using computer programs developed by the authors. PMID- 24757438 TI - Simulation and prediction of ion transport in the reclamation of sodic soils with gypsum based on the support vector machine. AB - The effect of gypsum on the physical and chemical characteristics of sodic soils is nonlinear and controlled by multiple factors. The support vector machine (SVM) is able to solve practical problems such as small samples, nonlinearity, high dimensions, and local minima points. This paper reports the use of the SVM regression method to predict changes in the chemical properties of sodic soils under different gypsum application rates in a soil column experiment and to evaluate the effect of gypsum reclamation on sodic soils. The research results show that (1) the SVM soil solute transport model using the Matlab toolbox represents the change in Ca(2+) and Na(+) in the soil solution and leachate well, with a high prediction accuracy. (2) Using the SVM model to predict the spatial and temporal variations in the soil solute content is feasible and does not require a specific mathematical model. The SVM model can take full advantage of the distribution characteristics of the training sample. (3) The workload of the soil solute transport prediction model based on the SVM is greatly reduced by not having to determine the hydrodynamic dispersion coefficient and retardation coefficient, and the model is thus highly practical. PMID- 24757439 TI - Channel estimation in DCT-based OFDM. AB - This paper derives the channel estimation of a discrete cosine transform-(DCT-) based orthogonal frequency-division multiplexing (OFDM) system over a frequency selective multipath fading channel. Channel estimation has been proved to improve system throughput and performance by allowing for coherent demodulation. Pilot aided methods are traditionally used to learn the channel response. Least square (LS) and mean square error estimators (MMSE) are investigated. We also study a compressed sensing (CS) based channel estimation, which takes the sparse property of wireless channel into account. Simulation results have shown that the CS based channel estimation is expected to have better performance than LS. However MMSE can achieve optimal performance because of prior knowledge of the channel statistic. PMID- 24757440 TI - Fertilization and colors of plastic mulch affect biomass and essential oil of sweet-scented geranium. AB - Sweet-scented geranium (Pelargonium graveolens L'Her), a plant belonging to the Geraniaceae family, has medicinal and aromatic properties and is widely used in the cosmetic, soap, perfume, aromatherapy, and food industries. The aim of this study was to evaluate the influence of fertilization and the use of different colors of plastic mulch on sweet-scented geranium biomass and essential oil. Three colors of plastic mulch (black, white, and silver-colored) and a control without plastic mulch were assessed along with three fertilizers (20,000 L . ha( 1) of cattle manure; 1,000 kg . ha(-1) of NPK 3-12-6; and 20,000 L . ha(-1) of cattle manure + 1,000 kg . ha(-1) of NPK 3-12-6 fertilizer) and a control without fertilizer. The absence of a soil cover negatively influenced the agronomical variables, while coverage with plastic mulch was associated with increased biomass. The use of fertilizer had no effect on the evaluated agronomic variables. When cattle manure and NPK 3-12-6 were used together, combined with white or black plastic mulch, the highest yields of essential oil were obtained. For the silver-colored plastic mulch, higher amounts of essential oil (6,9 guaiadien) were obtained with mineral fertilizer. PMID- 24757441 TI - Interlayer simplified depth coding for quality scalability on 3D high efficiency video coding. AB - A quality scalable extension design is proposed for the upcoming 3D video on the emerging standard for High Efficiency Video Coding (HEVC). A novel interlayer simplified depth coding (SDC) prediction tool is added to reduce the amount of bits for depth maps representation by exploiting the correlation between coding layers. To further improve the coding performance, the coded prediction quadtree and texture data from corresponding SDC-coded blocks in the base layer can be used in interlayer simplified depth coding. In the proposed design, the multiloop decoder solution is also extended into the proposed scalable scenario for texture views and depth maps, and will be achieved by the interlayer texture prediction method. The experimental results indicate that the average Bjontegaard Delta bitrate decrease of 54.4% can be gained in interlayer simplified depth coding prediction tool on multiloop decoder solution compared with simulcast. Consequently, significant rate savings confirm that the proposed method achieves better performance. PMID- 24757442 TI - Inhibitory effect of veterinary antibiotics on denitrification in groundwater: a microcosm approach. AB - Veterinary antibiotics in groundwater may affect natural microbial denitrification process. A microcosm study was conducted to evaluate the influence of sulfamethazine and chlortetracycline at different concentrations (0, 0.01, 0.1, and 1.0 mg/L) on nitrate reduction in groundwater under denitrifying condition. Decrease in nitrate removal and nitrite production was observed with the antibiotics. Maximum inhibition of nitrate removal was observed after seven days of incubation with 0.01 mg/L sulfamethazine (17.0%) and 1.0 mg/L chlortetracycline (15.4%). The nitrite production was inhibited with 1.0 mg/L sulfamethazine to 82.0% and chlortetracycline to 31.1%. The initial/final nitrate concentrations indicated that 0.01 mg/L sulfamethazine and 1.0 mg/L chlortetracycline were most effective in inhibiting activity of denitrifying bacteria in groundwater. After 12 days of incubation, the sulfamethazine biodegradation was observed whereas chlortetracycline was persistent. Sulfamethazine and chlortetracycline in groundwater could inhibit the growth and capability of naturally occurring denitrifying bacteria, thereby threatening nitrate pollution in groundwater. PMID- 24757443 TI - Multidimensional optimization of signal space distance parameters in WLAN positioning. AB - Accurate indoor localization of mobile users is one of the challenging problems of the last decade. Besides delivering high speed Internet, Wireless Local Area Network (WLAN) can be used as an effective indoor positioning system, being competitive both in terms of accuracy and cost. Among the localization algorithms, nearest neighbor fingerprinting algorithms based on Received Signal Strength (RSS) parameter have been extensively studied as an inexpensive solution for delivering indoor Location Based Services (LBS). In this paper, we propose the optimization of the signal space distance parameters in order to improve precision of WLAN indoor positioning, based on nearest neighbor fingerprinting algorithms. Experiments in a real WLAN environment indicate that proposed optimization leads to substantial improvements of the localization accuracy. Our approach is conceptually simple, is easy to implement, and does not require any additional hardware. PMID- 24757445 TI - Allergic sensitization to perennial allergens in adults and children sensitized to Japanese cedar or Japanese cypress pollen in Japan. AB - In Japan, seasonal allergic rhinitis in the spring due to exposure to Japanese cedar or Japanese cypress pollen is common. However, the allergic profile for perennial allergens in spring pollinosis remains unclear. Therefore, in this study, we investigated the allergic profiles of 652 patients with rhinitis. Total serum IgE, serum-specific IgE, and blood eosinophil counts were measured. Allergic sensitization, determined by the serum allergen-specific IgE level, did not always correspond with the patient's symptoms. Only 27% of patients with allergic symptoms in response to spring pollens were sensitized to these allergens alone; 31% of patients were also sensitized to perennial allergens, even without symptoms due to perennial allergens. Total serum IgE and eosinophil cell counts were significantly elevated in patients sensitized to perennial allergens and spring pollens, as compared to patients sensitized only to spring pollens. Most children sensitized to spring pollen (84%) were sensitized to perennial allergens, at a higher rate than adults (49%). Patients sensitized to spring pollens are likely to be latently sensitized to perennial allergens. This is especially true for children and should be monitored closely. Improvement in seasonal allergic conditions, including latent perennial allergy, is important to prevent symptoms that could advance to asthma. PMID- 24757444 TI - Identification of Sphingomyelinase on the Surface of Chlamydia pneumoniae: Possible Role in the Entry into Its Host Cells. AB - We have recently suggested a novel mechanism, autoendocytosis, for the entry of certain microbes into their hosts, with a key role played by the sphingomyelinase catalyzed topical conversion of sphingomyelin to ceramide, the differences in the biophysical properties of these two lipids providing the driving force. The only requirement for such microbes to utilize this mechanism is that they should have a catalytically active SMase on their outer surface while the target cells should expose sphingomyelin in the external leaflet of their plasma membrane. In pursuit of possible microbial candidates, which could utilize this putative mechanism, we conducted a sequence similarity search for SMase. Because of the intriguing cellular and biochemical characteristics of the poorly understood entry of Chlamydia into its host cells these microbes were of particular interest. SMase activity was measured in vitro from isolated C. pneumoniae elementary bodies (EB) and in the lysate from E. coli cells transfected with a plasmid expressing CPn0300 protein having sequence similarity to SMase. Finally, pretreatment of host cells with exogenous SMase resulting in loss plasma membrane sphingomyelin attenuated attachment of EB. PMID- 24757446 TI - Chlamydia trachomatis Antibody Testing in Vaginal Mucosal Material versus Blood Samples of Women Attending a Fertility Clinic and an STI Clinic. AB - Background. Chlamydia infections often follow an asymptomatic course but may damage the reproductive tract. Chlamydia antibodies in serum are used as markers for past infections and can relate to tubal pathology and infertility. This "proof of principle" study aimed to assess whether Chlamydia antibodies are detectable in easier to obtain, noninvasive, vaginal mucosa samples and relate to current or past infection. Methods. We compared outcomes of Chlamydia IgG and IgA antibody tests in serum and vaginal mucosal swabs in (a) 77 women attending a fertility clinic, of whom 25 tested positive for serum-IgG and (b) 107 women visiting an STI centre, including 30 Chlamydia PCR-positive subjects. Results. In the STI clinic, active Chlamydia infections were linked to serum-IgG and serum IgA (P < 0.001) and mucosa-IgA (P < 0.001), but not mucosa-IgG. In the fertility clinic, mucosa-IgG had stronger correlations with serum-IgG (P = 0.02) than mucosa-IgA (P = 0.06). Women with tubal pathology or Chlamydia history more commonly had serum-IgG and mucosa-IgA (both P < 0.001), whereas this link was weaker for mucosa-IgG (P = 0.03). Conclusion. Chlamydia IgG and IgA are detectable in vaginal mucosal material. Serum-IgG had stronger associations with current or past infections. Mucosa-IgA also showed associations with (past) infection and complications. IgA presence in vaginal mucosa warrants further epidemiological studies. PMID- 24757447 TI - Placenta-specific protein 1: a potential key to many oncofetal-placental OB/GYN research questions. AB - Placenta-specific protein 1 (PLAC1) is a secreted protein found in trophoblasts. Several reports implicate a central role for PLAC1 in establishment and maintenance of the placenta. In addition to placentae PLAC1 is expressed in a variety of solids including breast, endometrial, and ovarian cancers. In order to show that PLAC1 is potentially relevant to a number of research questions in OB/GYN, we report on PLAC1 expression in a selected panel that includes two choriocarcinoma cell lines, normal placental tissues, and endometrial and ovarian tumors. We report for the first time that PLAC1 is also expressed in human fetal tissues. PLAC1 is transcriptionally heterogeneous with one promoter (P1) generating two transcripts with alternately spliced 5' UTRs and the other promoter (P2) generating a third transcript. Placental tissues favor P2 transcripts, while P1 is favored in most of the other cells. Mechanisms determining multiple PLAC1 transcripts and promoter preferences are as yet unknown, but it is clear that this protein is likely to be important in a variety of phenomena relevant to both gynecologic oncology and maternal-fetal medicine. PMID- 24757448 TI - Migration, proliferation, and differentiation of cord blood mesenchymal stromal cells treated with histone deacetylase inhibitor valproic Acid. AB - Mesenchymal stromal cells (MSC) have great potential for cellular therapies as they can be directed to differentiate into certain lineages or to exert paracrine effects at sites of injury. The interactions between stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 play pivotal roles in the migration of MSC to injured tissues. We evaluated whether a histone deacetylase inhibitor valproic acid (VPA) modulates the migration of cord blood (CB-) derived MSC towards SDF-1 and their proliferation and differentiation. We found that in MSC, VPA increased (i) the gene and total protein expression of CXCR4 and CXCR7 and primed migration towards a low gradient of SDF-1, (ii) the gene expression of MMP 2 and secretion and activation of proMMP-2, (iii) the proliferation and gene expression of pluripotency markers SOX2 and Oct-4, and exposure to lower concentrations of VPA (<=5 mM) had no effect on their differentiation to osteocytes and chondrocytes. Thus, our study indicates that VPA enhances the migration of CB MSC towards SDF-1 by increasing the expression of CXCR4, CXCR7, and MMP-2. VPA at low concentrations may be used for ex vivo treatment of MSC to increase their recruitment to sites of injury without compromising their ability to proliferate or differentiate. PMID- 24757449 TI - Review of stereotactic radiosurgery for intramedullary spinal lesions. AB - Stereotactic radiosurgery (SR) represents an increasingly utilized modality in the treatment of intracranial and extracranial pathologies. Stereotactic spine radiosurgery (SSR) uses an alternative strategy to increase the probability of local control by delivering large cumulative doses of radiation therapy (RT) in only a few fractions. SSR in the treatment of intramedullary lesions remains in its infancy-this review summarizes the current literature regarding the use of SSR for treating intramedullary spinal lesions. Several studies have suggested that SSR should be guided by the principles of intracranial radiosurgery with radiation doses placed no further than 1-2mm apart, thereby minimizing exposure to the surrounding spinal cord and allowing for delivery of higher radiation doses to target areas. Maximum dose-volume relationships and single-point doses with SSR for the spinal cord are currently under debate. Prior reports of SR for intramedullary metastases, arteriovenous malformations, ependymomas, and hemangioblastomas demonstrated favorable outcomes. In the management of intrame dullary spinal lesions, SSR appears to provide an effective and safe treatment compared to conventional RT. SSR should likely be utilized for select patient scenarios given the potential for radiation-induced myelopathy, though high quality literature on SSR for intramedullary lesions remains limited. PMID- 24757450 TI - Technical Report of Free Hand Pedicle Screw Placement using the Entry Points with Junction of Proximal Edge of Transverse Process and Lamina in Lumbar Spine: Analysis of 2601 Consecutive Screws. AB - OBJECTIVE: A variety of different pedicle screws entry point techniques are used for the lumbar pedicle screws placement. This study reported Kim's entry point of lumbar pedicle screws with free hand technique and the accuracy of this technique. METHODS: We retrospectively reviewed the 584 cases with free hand placed lumbar pedicle screw placement. The diagnosis included 491 cases with degenerative spine, 59 cases with trauma, 29 cases with metastatic disease, and 5 cases with scoliosis. A total of 2601 lumbar pedicle screws were placed, and the entry points of lumbar pedicle screws were the junction of proximal edge of transverse process and lamina. Incidence and extent of cortical breach by misplaced pedicle screw was determined by review of intra-operative and post operative radiographs and/or computed tomography. RESULTS: Among the total 2601 lumbar free hand placed pedicle screws, 114 screws (4.4%) in 79 patients (13.5%) were repositioned screws with suspected screw malposition during operation, and 37 screws (1.4%) in 31 patients (5.3%) were identified as moderate to severe breaching the pedicle after post-operative imaging studies. Among the patient with malpositioned screws, 3 patients showed nerve irritation sign of the lesion, and 2 cases were symptom improved after nerve block and conservative management, and 1 case was removed the screw after the failure of the treatment. CONCLUSION: Free hand pedicle screw placement based on external landmark with the junction of proximal edge of transverse process and lamina showed acceptable safety and accuracy and avoidance of radiation exposure. PMID- 24757451 TI - Comparative analysis between thoracic spinal cord and sacral neuromodulation in a rat spinal cord injury model: a preliminary report of a rat spinal cord stimulation model. AB - OBJECTIVE: The purpose of this study is to compare a neuroprotective effect of thoracic cord neuromodulation to that of sacral nerve neuromodulation in rat thoracic spinal cord injury (SCI) model. METHODS: Twenty female Sprague Dawley rats were randomly divided into 4 groups: the normal control group (n=5), SCI with sham stimulation group (SCI, n=5), SCI with electrical stimulation at thoracic spinal cord (SCI + TES, n=5), and SCI with electrical stimulation at sacral nerve (SCI + SES, n=5). Spinal cord was injured by an impactor which dropped from 25mm height. Electrical stimulation was performed by the following protocol: pulse duration, 0.1ms; frequency, 20 Hz; stimulation time, 30 minutes; and stimulation duration at thoracic epidural space and S2 or 3 neural foramina for 4 weeks. Locomotor function, urodynamic study, muscle weights, and fiber cross sectional area (CSA) were investigated. RESULTS: All rats of the SCI + TES group expired within 3 days after the injury. The locomotor function of all survived rats improved over time but there was no significant difference between the SCI and the SCI + SES group. All rats experienced urinary retention after the injury and recovered self-voiding after 3-9 days. Voiding contraction interval was 25.5+/-7.5 minutes in the SCI group, 16.5+/-5.3 minutes in the SCI+SES group, and 12.5+/-4.2 minutes in the control group. The recovery of voiding contraction interval was significant in the SCI + SES group comparing to the SCI group (p<0.05). Muscle weight and CSA were slightly greater in the SCI + SES than in the SCI group, but the difference was not significant. CONCLUSION: We failed to establish a rat spinal cord stimulation model. However, sacral neuromodulation have a therapeutic potential to improve neurogenic bladder and muscle atrophy. PMID- 24757452 TI - Heterotopic Ossification after Cervical Arthroplasty with ProDisc-C: Time Course Radiographic Follow-up over 3 years. AB - OBJECTIVE: Heterotopic ossification (HO) is a well-known complication after total hip replacement. But the occurrence rate by the time-course, clinical effect and risk factors of HO after total cervical disc replacement (TCDR) are not well described. The purpose of this study is to evaluate the occurrence rate by the time-course and risk factors for HO after TCDR with a ProDisc-C. METHODS: Thirty two patients whom followed up more than one year after the TCDR are enrolled. Radiographic study was done at 12, 24 and 36 months after the TCDR and classified HO with McAfee classification. Segmental range of motion, preoperative existence of spondylosis, type of operation, disc space occupying ratio by artificial disc, surgical level are analyzed to identify the risk factors of HO. The visual analog scale and the neck disability index were evaluated preoperatively and at last follow-up time for clinical parameters. RESULTS: Eighteen patients (56%) showed HO at 12 months, 18 patients (86%) showed HO at 24 months and 6 patients (89%) showed HO at 36 months after the TCDR. Clinical significant HO(Grade 3 and 4) was shown in one patient (3%) at 12 months, 3 patients (14%) at 24 months and 5 patients (56%) at 36 months. Only post-operative follow-up period increases the risk of development clinical significant HO. All patients showed improvement of clinical parameters (p<0.005). CONCLUSION: Incidence of HO is getting higher as time course progress. However, there are no relation between clinical outcome and radiologic change of ROM and the grade of HO. PMID- 24757453 TI - Repeated migration of a fusion cage after posterior lumbar interbody fusion. AB - Although posterior lumbar interbody fusion (PLIF) is a widely accepted procedure, perioperative and postoperative complications are still encountered. In particular, cage migration can result in severe sequelae, and revision surgery is technically demanded. Here, we report a rare case of repeated migration of a fusion cage after PLIF. To the best of our knowledge, no report has been previously issued on repeated migration of a fusion cage after PLIF. The authors discuss the radiological and clinical findings of this unusual complication with a review of the literature. PMID- 24757454 TI - Large thoracolumbar extradural arachnoid cyst excised by minimal skipped hemilaminectomy: a case report. AB - The standard treatment for symptomatic spinal extradural arachnoid cyst (SEAC) is complete surgical removal of cyst and closure of the dural defect. In most cases, total laminectomy has been performed at affected vertebra for complete removal of the SEAC. However, this invasive surgery may result in postoperative kyphosis and back pain. We report a case of large SEAC involving T10-L1 which was excised through the minimal skipped hemilaminectomy, to minimize the risk of postoperative kyphotic deformity. Simultaneously, we closed the dural defect after preoperative precise identification of the site through several radiological studies. PMID- 24757455 TI - Spinal extradural arachnoid cyst: a case report. AB - Spinal arachnoid cyst is a rare cause of myelopathy secondary to spinal cord compression. We report a case presenting extradural arachnoid cyst of probable traumatic origin leading to irreversible neurological deficits including paraparesis and neurogenic bladder. The patient presented progressive paraparesis and voiding difficulty. Magnetic resonance imaging (MRI) of the spine revealed long segmental cystic lesion of cerebrospinal fluid (CSF) signal intensity at dorsal extramedullary space of T11 to L3 level suggesting arachnoid cyst with diffuse cord compression. On the operation, an ovoid shaped dural defect was identified at right sided dorsolateral aspect of the dura mater between nerve root sleeves at T11 and T12 level. The patient was treated by microsurgical repair of the dural defect and intraoperative findings revealed no further leakage of CSF. The neurological status of the patient was stationary on follow up examination postoperatively. We postulate that delayed-onset post-traumatic extradural arachnoid cyst should be taken into consideration on the differential diagnosis of intrapinal cysts. PMID- 24757456 TI - Asymptomatic cervical isthmic spondylolisthesis and associated occult spinal bifida: a case report. AB - We report a case of rare cervical isthmic spondylolisthesis of C6-7 combined occult spinal bifida at C6, and review the radiologic finding, different diagnosis and treatment. A 23-year old female presented nuchal, back pain after traffic accident. Radiologic finding showed the 6(th) cervical isthmic defect, spondylolisthesis and dysplasia. The patient was conservatively treated about 8 weeks, and 10 months after injury, she was symptom free with full range of motion of cervical spine and she was followed up. Cervical spondylolysis is a very rare condition. This clinical importance is vulnerable to trauma. For whatever reasons, symptomatic patients need to be treated by conservative or surgical option. PMID- 24757457 TI - Arnold Chiari I malformation with tip-toe gait: a case report. AB - The Arnold-Chiari type I malformation has many symptoms such as headache, neck pain, gait impairment, abnormal movements or postures. But a few cases reported association of specific symptom including headache, neck pain, vertigo or ataxia. We report a case of 12 year-old boy presenting with tip-toe gait. Magnetic resonance imaging (MRI) study of brain and spine revealed underlying Arnold Chiari type I malformation. This case shows that it is need for central nervous system evaluation in patients with changes of lower extremities tone. PMID- 24757458 TI - Redundant nerve roots of cauda equina mimicking intradural disc herniation: a case report. AB - Redundant Nerve Roots (RNRs) is an uncommon clinical condition characterized by a tortuous, serpentine, large and elongated nerve root of the cauda equina. To our knowledge, most cases of RNRs are associated with lumbar stenosis, and RNRs associated with lumbar disc herniation has not been reported until now. Here we present a rare case of unusual RNRs associated with lumbar disc herniation mimicking intradural disc herniation. PMID- 24757459 TI - Postoperative Cervical Cord Compression Induced by Hydrogel Dural Sealant (DuraSeal(r)). AB - Cerebrospinal fluid (CSF) leakage is a potential complication of cranial and spinal surgery. Postoperative CSF leakage can induce delayed healing, wound infection and meningitis. DuraSeal(r) (Covidien, Waltham, MA, USA) is a synthetic product which has been increasingly used to facilitate watertight repair of dural defects after cranial and spinal surgery. Despite some advantages of Duraseal(r), the authors report a patient who developed cord compression following the use of DuraSeal(r) in cervical spine surgery in which the expansion of the DuraSeal(r) was believed to be the causative factor. PMID- 24757460 TI - Clinical analysis of microscopic removal of discal cyst. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical presentation and surgical outcome in patients with symptomatic discal cyst. METHODS: The authors reviewed consequent 9 patients in whom microscopic excision of the discal cyst with or without additional discectomy for discal cyst from 2005 to 2012. Diagnostic imagings including simple radiographs, computed tomography with discogram and magnetic resonance images were performed in each case. The patients were reviewed to evaluate the clinical presentation, surgical outcome and related complications. RESULTS: In all patients, discal cyst was located in the lumbar region and they presented with back pain and unilateral radiating pain. The preoperative magnetic resonance images (MRI) and computed tomography (CT) scan with discogram showed a connection between the cyst and the involved intervertebral disc. All patients obtained immediate relief of symptoms after microscopic excision of discal cyst. There were no recurrent lesions during follow-up period. The mean preoperative visual analogue scale (VAS) was 7.8 when compared with 2.6 in preoperative assessment. All patients obtained excellent or good outcome according to modified MacNab's criteria. CONCLUSION: Discal cysts are rare lesions that can lead to back pain and refractory sciatica. Microscopic excision of the cyst can achieve remarkable improvement of symptoms. PMID- 24757461 TI - Radiographic Results of Minimally Invasive (MIS) Lumbar Interbody Fusion (LIF) Compared with Conventional Lumbar Interbody Fusion. AB - OBJECTIVE: To evaluate the radiographic results of minimally invasive (MIS) anterior lumbar interbody fusion (ALIF) and transforaminal lumbar interbody fusion (TLIF). METHODS: Twelve and nineteen patients who underwent MIS-ALIF, MIS TLIF, respectively, from 2006 to 2008 were analyzed with a minimum 24-months' follow-up. Additionally, 18 patients treated with single level open TLIF surgery in 2007 were evaluated as a comparative group. X-rays and CT images were evaluated preoperatively, postoperatively, and at the final follow-up. Fusion and subsidence rates were determined, and radiographic parameters, including lumbar lordosis angle (LLA), fused segment angle (FSA), sacral slope angle (SSA), disc height (DH), and foraminal height (FH), were analyzed. These parameters were also compared between the open and MIS-TLIF groups. RESULTS: In the MIS interbody fusion group, statistically significant increases were observed in LLA, FSA, and DH and FH between preoperative and final values. The changes in LLA, FSA, and DH were significantly increased in the MIS-ALIF group compared with the MIS-TLIF group, but SSA and FH were not significantly different. No significant differences were seen between open and MIS-TLIF except for DH. The interbody subsidence and fusion rates of the MIS groups were 12.0+/-4% and 96%, respectively. CONCLUSION: Radiographic results of MIS interbody fusion surgery are as favorable as those with conventional surgery regarding fusion, restoration of disc height, foraminal height, and lumbar lordosis. MIS-ALIF is more effective than MIS-TLIF for intervertebral disc height restoration and lumbar lordosis. PMID- 24757462 TI - ACDF Using the Solis Cage with Iliac Bone Graft in Single Level: Clinical and Radiological Outcomes in Average 36 months Follow-up. AB - OBJECTIVE: To evaluate the utility of anterior cervical discectomy and fusion (ACDF) with polyetheretherketone (PEEK) cage and autograft through long term(average 36 months) follow-up. METHODS: Thirty selected patients (male:20/female:10) who suffered from cervical radiculopathy, myelopathy or radiculomyelopathy underwent a single level ACDF with PEEK cage and autograft from iliac crest from March 2006 to July 2008 in single institute. We followed patients for an average 36.4+/-8.1 months (ranged from 23 to 49 months). The Japanese Orthopedic Association (JOA) score for evaluation of myelopathy and visual analogue scale (VAS) for radiating pain was used to estimate postoperative clinical outcome. Plain x-ray on true lateral standing flexion, extension and neutral position view and 3D CT scan were used every 6 months after surgery during follow-up period. RESULTS: The mean VAS and JOA scoring improved significantly after the surgery and radiological fusion rate was accomplished by 100% 36 months after the surgery. We had no complication related with the surgery except one case of osteomyelitis. There was one case of Grade I fusion, four cases of grade II, and 25 cases of grade III by radiologic evaluation. CONCLUSION: This long term follow-up study for ACDF with PEEK cage shows that this surgical method is comparable with other anterior cervical fusion methods in terms of clinical outcomes and radiologic fusion rate. PMID- 24757463 TI - Spontaneous regression of extruded lumbar disc herniation: three cases report. AB - Herniated nucleus pulposus (HNP) is a common disease that induces back pain and radicular pain. Some cases require surgical treatment due to persistent severe pain. However, in some cases, pain can be relieved with conservative treatment or at times relived spontaneously. Therefore, the most effective treatment method for HNP is undefinable. Spontaneous regression of HNP has been recognized with the advancement of radiological diagnostic tools and can explain the reason of spontaneous relief of symptoms without treatment. PMID- 24757464 TI - Desmoid tumor of the facet joint: a case report. AB - Desmoid tumors represent a particular type of fibromatosis. The common sites for extra-abdominal desmoid tumors, known as aggressive fibromatosis, are the shoulder, chest wall, and thigh. Desmiod tumors are rare at facet joints of the spine. We describe a patient with a desmoid tumor of a lumbar facet joint. PMID- 24757465 TI - Hemorrhagic synovial cyst associated with rheumatoid atlantoaxial subluxation. AB - Synovial cyst on prevertebral space of C1-2 joint is rare but may be associated hemorrhagic event. We describe a case of a 72-year-old woman who presented with sudden severe headache in her left occipital area with dyspnea. She had rheumatoid arthritis for 14-years. Large hemorrhagic cystic mass was seen around prevertebral space of the atlantoaxial joint on the left side on cervical MRI (magnetic resonance image) and it obstructed the nasopharyngeal cavity. Aspiration of the cystic lesion was performed via transoral approach, followed by posterior occipito-cervical fusion. The specimen was xanthochromic, suggesting old hemorrhage. The patient was tolerable on her postoperative course and showed good respiration and relieved headache. We suggest that repeated microtrauma due to atalantoaxial subluxation associated with rheumatoid arthritis as a main cause of hemorrhagic event on the cyst. PMID- 24757466 TI - Steroid-induced Spinal Epidural Lipomatosis after Suprasella Tumor Resection. AB - Spinal epidural lipomatosis (SEL) is an abnormal localized accumulation of fat tissues in the epidural space. It is strongly related with steroid administration. The symptoms of SEL are various and range from back pain to paraplegia. In severe cases, decompressive laminectomy is the choice of treatment. A 32-year-old woman who had been under long-term steroid administration after suprasellar tumor resection was admitted for both leg radiating pain and weakness. She was diagnosed with SEL and had a decompressive laminectomy. During the operation, we found the nerve roots were compressed by epidural fat tissues and engorged vessels. After the operation, her radiating pain was relieved and motor weakness was improved. PMID- 24757467 TI - Triple primary origin tumor: a case report. AB - Generally, among the extradural spinal tumors, metastatic spinal tumor is much more common than primary spinal tumors. Thus, in the case of a spinal tumor patient with cancer history (such as lung cancer, breast cancer, etc.), we used to infer that the spinal lesion is the metastasis from, primary malignancy. We introduce an experience of a case of triple primary origin tumor in a 57-year-old man. When the spinal lesion was found on the abdominal computed tomography scan, he already had a history of colon cancer and liver cancer. Initially, it was thought that the lesion would probably be a metastatic tumor from the liver or colon cancers, and the operation was performed accordingly. In the pathologic final report, however, the mass was proven to plasmacytoma - the third primary lesion. The patient underwent chemotherapy after surgery. Globally, the triple primary origin tumor has been reported very rarely. With this report, we wish to emphasize the necessity of pathologic confirmation and adequate treatment even in a patient with known malignancies. PMID- 24757468 TI - Gelfoam-induced Swallowing Difficulty after Anterior Cervical Spine Surgery. AB - Symptomatic diffuse idiopathic skeletal hyperostosis (DISH) is not common. Gelfoam is one of the most commonly used topical hemostatic agents. But, in the partially moistened state, air retained in its pores may result in excessive expansion on contact with liquid. The onset of swallowing difficulty after anterior cervical spine surgery due to appling gelfoam is a rare complication. A 77-year-old man with swallowing difficulty was admitted to our hospital and we diagnosed him as DISH confirmed by radiological study. After removing the DISH, patient's symptom was relieved gradually. However, on postoperative day (POD) 7, the symptom recurred but lesser than the preoperative state. We confirmed no hematoma and esophageal perforation on the operation site. We observed him closely and controlled the diet. Three months later, he had no symptom of swallowing difficulty, and was able to be back on a regular diet, including solid foods. We present a complication case of swallowing difficulty occurring by gelfoam application. PMID- 24757469 TI - Tuberculous spondylitis after percutaneous vertebroplasty: misdiagnosis or complication? AB - So far, there have been few previous reports of tuberculous spondylitis occurring after percutaneous vertebroplasty. We report an unusual case of tuberculous spondylitis diagnosed after percutaneous vertebroplasty in a patient who had a history of pulmonary tuberculosis for the first time. A 58-year-old woman, who had a history of complete recovery from pulmonary tuberculosis six years previously, was hospitalized due to severe back pain after a fall. Radiological studies revealed a fresh compression fracture at the T12 thoracic vertebra. The back pain improved dramatically, and the patient was discharged two days after the vertebroplasty. However, cold sweats and a low grade fever with severe back pain developed four weeks after the procedure. Magnetic resonance imaging revealed a severe kyphosis and the T11-T12 disc space had collapsed with heterogeneous signal intensity. The results of the culture of the biopsy specimens were negative, and did not lead to identification of the causative micro-organism. However, the polymerase chain reaction for Mycobacterium tuberculosis was positive. Treatment for tuberculous spondylitis was started and she underwent posterior fusion and instrumentation from T9-L2 after the markers for infection returned to normal. After surgical intervention, the pain improved and the kyphotic deformity was corrected. PMID- 24757470 TI - Anterior Screw Fixation of Anteriorly Displaced Type III Odontoid Fracture Corrected by Transoral Digital Manipulation. AB - Type III odontoid fractures have been treated by several methods. In case of anteriorly displaced type III odontoid fracture which is not corrected by closed reduction, anterior screw fixation cannot be used. We report the first case of anterior screw fixation of anteriorly displaced type III odontoid fracture corrected by transoral digital manipulation. PMID- 24757471 TI - Extraforaminal lumbar interbody fusion for cage migration after screw removal: a case report. AB - The use of titanium cages for posterior lumbar interbody fusion (PLIF) has gained popularity because it offers the advantages of anterior column support and stabilization. However, cage migration into the spinal canal may have severe or disastrous consequences. Here, the authors report an unexpected case of posterior migration of fusion cages after screw removal in a patient that underwent PLIF 12 months previously. Removal of the offending cages through revision extraforaminal lumbar interbody fusion (ELIF) with percutaneous screw fixation successfully managed this complication. As far as the authors' knowledge, this is the first case report to describe this sort of complication, and cautions that care must be taken to prevent cage migration. PMID- 24757472 TI - Prophylactic intrawound application of vancomycin powder in instrumented spinal fusion surgery. AB - OBJECTIVE: We evaluated the effect of intrawound application of vancomycin powder for infection prophylaxis in wounds caused by instrumented spinal surgery. METHODS: From July 2012 to December 2012, 74 instrumented spinal fusion procedures were performed by 1 neurosurgeon at a single institute. We divided the patients into 2 groups, depending on the use of local application of vancomycin powder: Group A (intrawound application of vancomycin powder with perioperative intravenous cefazolin) and Group B (perioperative intravenous cefazolin alone). A retrospective cohort comparative study was conducted between the 2 groups. The age, sex, comorbidities, smoking, surgical procedure, and surgical site infection (SSI) of consecutive patients were analyzed. RESULTS: Among the 74 patients, 34 patients were assigned to group A and 40 patients to group B. No wound infections were found in group A. However, in group B, 5 cases of SSI (12.5%) were found. A statistically significant reduction in SSI incidence was observed in group A (p<0.033). The 5 cases of SSI in group B consisted of 3 cases of deep wound infection and 2 cases of superficial wound infection. All SSIs were found in cases of posterior approach surgery and tended to be more frequent in older patients. CONCLUSION: Adjunctive intrawound local application of vancomycin powder is a simple uncomplicated procedure and can result in a significant reduction of SSI in instrumented spinal fusions. Furthermore, culture of the drainage tip is very important for confirmation of deep wound infection. PMID- 24757473 TI - Mid-term Clinical Outcomes of Stand-alone Posterior Interbody Fusion with Rectangular Cages: A 4-year-minimum Follow-up. AB - OBJECTIVE: We sought to determine minimum 4 years of clinical outcomes including fusion rate, revision rate and complications of patients who underwent placement of rectangular stand-alone cages. METHODS: Thirty-three cases of degenerative spine that had been followed for at least 4-years were reviewed retrospectively. Cages were inserted at L4-L5 level or L5-S1 in 27 or in 6 cases respectively. Visual analogue scale (VAS), Odom's criteria, fusion rate, intervertebral disc height and lumbar lordosis were determined pre- and post-operatively on standing x-rays. Amount of intra- and postoperative blood loss, total volume transfused, duration of surgery and perioperative complications were also evaluated. RESULTS: The mean VAS score of back pain and sciatica were improved from 8.0 and 7.0 points to 3.4 and 2.4 during 1 years follow-up visit and the scores was raised gradually. Also, during the follow-up, 94% of patients showed excellent or good outcomes by the Odom's criteria. Intervertebral disc height was increased from 8.2+/-1.4mm to 9.2+/-1.9mm at the first year of follow-up, however, found to be decreased and stabilized to 8.3+/-1.8mm after 2 years. The fusion rate was approximately 91% after 4 year postoperative. The segmental angle of lordosis was increased significantly by two years but it was not maintained after four years. A statistically insignificant change in total lumbar lordosis was also observed. Three patients (9%) had experienced perioperative complications. CONCLUSION: The use of rectangular stand-alone cages for posterior lumbar interbody fusion (PLIF) resulted in a various degree of subsidence and demonstrate very low complication rate, high functional stability and improved clinical outcomes in patients with degenerative lumbar disc disease. PMID- 24757474 TI - Neurologic Outcome of Laminoplasty for Acute Traumatic Spinal Cord Injury without Instability. AB - OBJECTIVE: The purpose of this study is to evaluate the efficacy of laminoplasty in the treatment of spinal cord injury (SCI) without instability. METHODS: 79 patients with SCI without instability who underwent surgical treatment in our institute between January 2005 and September 2012 were retrospectively reviewed. Twenty nine patients fulfilled the inclusion criteria as follows: SCI without instability, spinal cord contusion in MRI, cervical stenosis more than 20%, follow up at least 6 months. Preoperative neurological state, clinical outcome and neurological function was measured using the American Spinal Injury Association (ASIA) impairment scale, modified Japanese Orthopedic Association (mJOA) grading scale and Hirabayashi recovering rate. RESULTS: Seventeen patients showed improvement in ASIA grade and twenty six patients showed improvement in mJOA scale at 6 month follow up. However, all patients with ASIA grade B and C have shown improvement of one or more ASIA grade. Mean Hirabayashi recovery rate was 47.4+/-23.7%. There was better neurologic recovery in those who had cervical spondylosis without ossification of posterior longitudinal ligament (OPLL) (p<0.05, chi(2) test). CONCLUSIONS: It is different in B, C, D with ASIA A that there are debates going on about the application of surgical treatment in ASIA A, and surgical treatment is helpful in B, C, D since it contributes to neurologic improvement. We concluded that laminoplasty provided good neurologic recovery in SCI without instability that cervical canal stenosis, especially spondylosis without OPLL and neurologic deterioration in ASIA B, C and D. PMID- 24757475 TI - Clinical features and surgical results of cervical myelopathy caused by soft disc herniation. AB - OBJECTIVE: There are many causes of cervical myelopathy including trauma, degenerative conditions, tumors and demyelinating disorders. However, myelopathy caused by soft disc herniation might be seen rarely than the spondylosis caused by hard disc. Here, authors retrospectively analyzed the clinical features and results of cervical myelopathy caused by soft disc herniation. METHODS: From March 2010 to December 2010, 134 patients with degenerative cervical spinal disease were treated with anterior cervical discectomy and interbody fusion. Among them, 21 patients with cervical myelopathy secondary to cervical soft disc herniation were analyzed. Their clinical features, preoperative and, postoperative clinical results were evaluated by Nurick Grade and Japanese Orthopaedic Association scale (JOA) retrospectively. Preoperative clinical features including duration of myelopathy, pain intensity and postoperative clinical results including improvement rate of myelopathy and radiculopathy were retrospectively analyzed by Nurick Grade and JOA scale. We also evaluated correlation between the duration of symptom, type of the disc herniation, pain intensity and clinical outcome. RESULTS: Mean age was 49.7 and male was predominant. Gait disturbance with mild to moderate pain was most common symptom in clinical features. Severe pain was shown in only 9 cases, and the other 12 cases experienced mild to moderate pain. Mean duration of myelopathy was 1.18 month. The mean JOA scores were 11.22 before surgery and 14.2 after surgery. The mean Nurick grades were 2.78 before treatment and 1.67 after treatment. Neurologic status of mild or moderate pain group on preoperative state is worse than that of severe pain group. The patients with duration of myelopathy symptom (<1 month) showed lower clinical improvement rate than the patients with myelopathy over 1 month. Patients with median type of disc herniation showed poorer neurological status than those with paramedian type of herniation in preoperative state. CONCLUSION: Authors reviewed the clinical features and surgical outcome of the cervical myelopathy secondary to cervical soft disc herniation. We presumed that patients of more than one month of symptom duration, mild to moderate initial symptom would be related with better postoperative improvement rate. PMID- 24757477 TI - Analysis of factors contributing to postoperative spinal instability after lumbar decompression for spinal stenosis. AB - OBJECTIVE: Decompressive laminectomy is one of the most commonly used surgical methods for the treatment of spinal stenosis. We retrospectively examined the risk factors that induce spinal instability, including slippage (spondylolisthesis) and/or segmental angulation after decompressive laminectomy on the lumbar spine. METHODS: From January 1, 2006 to June 30, 2010, 94 consecutive patients underwent first-time single level decompressive laminectomy without fusion and discectomy. Of these 94 patients, 42 with a follow-up period of at least 2 years were selected. We measured the segmental angulation and slippage in flexion and extension dynamic lumbar radiographs. We analyzed the following contributing factors to spinal instability: age/sex, smoking history, disc space narrowing, body mass index (kg/m(2)), facet joint tropism, effect of the lordotic angle on lumbar spine, asymmetrical paraspinal muscle volume, and surgical method and level. RESULTS: Female patients, normal lordotic angle, and asymmetrical paraspinal muscle volume were factors more significantly associated with spondylolisthesis (p-value=0.026, 0.015, <0.01). Statistical results indicated that patients with facet tropism were more likely to have segmental angulation (p-value=0.046). Facet tropism and asymmetry of paraspinal muscle volume were predisposing factors to spinal instability (p-value=0.012, <0.01). CONCLUSION: Facet joint tropism and asymmetry of paraspinal muscle volume are the most important factors associated with spinal instability; therefore, careful follow-up after decompressive laminectomy in affected patients is necessary. PMID- 24757476 TI - Comparative study on the period of absolute bed rest of vertebral compression fracture. AB - OBJECTIVE: As a conservative treatment of compression fractures, absolute bed rest (ABR) for a certain period has been recommended, but no guideline on the period has yet been established. Considering that a long ABR period may adversely affect patients, the difference in prognosis according to the ABR period was investigated in this study. METHODS: A prospective study was conducted who were diagnosed with compression fracture. Groups A and B were put on ABR (one week for group A and two weeks for group B). X-ray images at baseline, 1, 2, 4, and 8 weeks were obtained from both groups, for assessment purposes. RESULTS: The compression rates of both groups were no significant difference at baseline, 1, 2, 4, and 8 weeks. The conditions of 25.9% and 21.2% of the subjects deteriorated in groups A and B, showing no significant difference. Between the groups of age and bone mineral densities (BMD), no significant difference was observed in the incidence of deterioration. In terms of complications development including constipation and other Gastrointestinal problems, voiding difficulty, etc., group A reported 57.4%, and group B, 84.8%, showing a significant difference (p value=0.001). CONCLUSION: No significant difference in the conservative period was observed between the groups. Group B, however, reported a higher complications development rate than group A. Therefore, a short ABR period may be helpful in the early stage of conservative treatment. PMID- 24757478 TI - The Comparisons of Surgical Outcomes and Clinical Characteristics between the Far Lateral Lumbar Disc Herniations and the Paramedian Lumbar Disc Herniations. AB - OBJECTIVE: The purpose of this study is to analyze clinical characteristics and surgical outcomes of the far lateral and the paramedian disc herniations. METHODS: The 88 patients who underwent an operation for lumbar disc herniations were reviewed. Visual analogue scale of leg and back pain, occurrence of sensory dysesthesia and motor deficit before and after operations were used to compare the far lateral with the paramedian disc herniations. RESULTS: Statistically, the far lateral herniations had more severe radicular leg pain and showed more frequent occurrence of sensory dysesthesia than paramedian herniations before operation (p<0.05). In the far lateral herniation group, preoperatively, 15 patients (75%) had sensory dysesthesia and among them, 4 patients (27%) showed improvement. In the paramedian herniation group, preoperatively, 25 patients (37%) had sensory dysesthesia and among them, 21 patients (84%) showed improvement. The degree of improvement in sensory dysesthesia was statistically higher in paramedian herniation group (p<0.05). In the far lateral herniation group, preoperatively, 11 patients (55%) had motor deficit and among them, 10 patients (91%) showed improvement. In the paramedian herniations, preoperatively, 29 patients (43%) had motor deficit and among them, 25 patients (86%) showed improvement. The degree of improvement in motor deficit was not statistically significant between groups (p>0.05). CONCLUSION: Preoperatively, the far lateral herniations had more severe radicular leg pain and frequent occurrence of sensory dysesthesia. Postoperatively, the sensory dysesthesia was less improved and back pain was more severe in the far lateral herniations. PMID- 24757479 TI - Radiologic changes of anterior cervical discectomy and fusion using allograft and plate augmentation: comparison of using fixed and variable type screw. AB - OBJECTIVE: To evaluate radiologic result of anterior cervical discectomy and fusion with allobone graft and plate augmentation, and the change of radiologic outcome between screw type and insertion angle. METHODS: Retrospective review of clinical and radiological data of 29 patients. Segmental angle, height and screw angles were measured and followed. The fusion rate was assessed by plain radiography and CT scans. We divided the patients into two groups according to screw type and angles. Group A: fixed screw, Group B: variable screw. Interscrew angle was measured between most upper and lower screws with Cobb's methods. RESULTS: Overall fusion rate was 86.2% on plain radiography. Fusion was also assessed by CT scan and Bridwell's grading system. There was no difference in fusion and subsidence rates between two groups. Subsidence was found in 5 patients (17.2%). Segmental lordotic angle was increased from preoperative status and maximized at the immediate postoperative period and then reduced at 1 year follow up. Segmental height showed similar increase and decrease values. CONCLUSION: ACDF with allograft and plate showed favorable fusion rates, and the screw type and angle did not affect results of surgery. PMID- 24757480 TI - Posterior C2-C3 Fixation for Unstable Hangman's Fracture. AB - OBJECTIVE: This is a retrospective review of 13 unstable Hangman's fractures who underwent posterior C2-3 fixation to describe clinical outcomes with a literature review. METHODS: Thirteen patients for unstable Hangman's fracture were enrolled between July 2007 and June 2010 were included in this study. The medical records of all patients were reviewed. Concurrently, clinical outcomes were evaluated using Neck Disability Index (NDI) scores and Visual Analogue Scale (VAS) scores during preoperative and postoperative follow up period. Plain radiographs were obtained on postoperative 1day, 1week, and then at 1, 2, 6, and 12 months. CT was done at postoperative 12 months in all patients for evaluation of bone fusion. The mean period of clinical follow-up was 17 months. RESULTS: Mean age were 43 years old. Bone fusion was recognized in all cases at the final follow-up. The average preoperative VAS score for neck pain was 8.3+/-1.1, while the final follow-up VAS score was 2.07+/-0.8 (p<0.001). The average immediate postoperative NDI was 84% points and final NDI was 22% points (p<0.001). There were one case of infection and 1 case of screw loosening. CONCLUSION: In the treatment of the patients with unstable Hangman's fracture, posterior C2-C3 fusions is effective and curative treatments to achieve cervical spinal stability. PMID- 24757481 TI - Acute spontaneous cervical epidural hematoma mimicking cerebral stroke: a case report and literature review. AB - Spontaneous cervical epidural hematoma (SCEDH) is a rare disease, but can cause severe neurologic impairment. We report a case of a 68-year-old female who presented with sudden onset, posterior neck pain, right shoulder pain, and progressive right hemiparesis mimicking stroke with no trauma history. Initial brain CT and diffusion MRI performed to rule out brain lesion did not show any positive findings. Laboratory examination presented only severe thrombocytopenia (45,000/mm(3)). Subsequent cervical MRI revealed a cervical epidural mass lesion. We confirmed that it was pure hematoma through C5 unilateral total laminectomy and C6 partial hemilaminectomy. She achieved complete neurologic recovery with active rehabilitation. Early surgical decompression for SCEDH with neurologic impairment should be recommended for better outcome. PMID- 24757482 TI - Delayed esophageal perforation after cervical spine plating. AB - Although anterior approaches to the cervical spine are popular and safe, they cause some of complications. Esophageal perforation after anterior spinal fusion is a rare but potentially life-threatening complication. We present a rare case of delayed esophageal perforation caused by a cervical screw placed via the anterior approach. A 43-year-old man, who had undergone surgery for complete cord injury at another orthopedic department 8 years previously, was admitted to our institute due to painful neck swelling and dysphagia. Radiological studies revealed a protruding screw and esophageal perforation. The perforation was found during surgery and was successfully repaired. This case emphasizes the need for careful long-term follow-up to check for delayed esophageal perforation in patients that have undergone anterior cervical spine plating. PMID- 24757484 TI - Traumatic Intradural Lumbar Disc Herniation without Bone Injury. AB - Intradural lumbar disc herniation is a rare disease. According to the reports of intradural lumbar disc herniations, most cases have developed as a chronic degenerative disc diseases. Traumatic intradural lumbar disc herniations are even rarer. A 52-year-old man visited our emergency center with numbness in his left calf and ankle after falling accident. Initial impression by radiologic findings was a spinal subdural hematoma at the L1 level. A follow up image two weeks later, however, did not demonstrate any interval change. The patient was decided to have an operation. In operative findings, a ruptured disc particle penetrating the ventral and dorsal dura was indentified after laminectomy. It was assumed to be a traumatic outcome not a degenerative change. PMID- 24757483 TI - Extra and intramedullary anaplastic ependymoma in thoracic spinal cord. AB - Spinal ependymoma occupies 40-60% of primary spinal cord tumors and has a feature of intramedullary tumor. The tumor most commonly arises from the central canal of the spinal cord, the conus medullaris or the filum terminale and its pathological features are usually benign. Unlike above characteristics, intra and extramedullary ependymomas are reported very rarely and have wide variety of histological features. We present a rare case of spinal anaplastic ependymoma with an accompanied exophytic lesions extramedullary as well. The tumor was poorly delineated between a spinal cord and the extramedullary components in operative view. After we had confirmed the frozen biopsy as anaplastic ependymoma, the remnant mass embedded in the spinal cord was remained because of its unclear resection margin and the risk of neurological deterioration. She underwent radiotherapy with 50.4 Gy, and there were newly developed mass lesions at the lumbosacral region on the MRI, 14 months postoperatively. PMID- 24757485 TI - Tophaceous gout of the spine causing neural compression. AB - Gout is a common metabolic disease in which monosodium urate crystals called tophi develop. Spinal involvement in gout resulting in neural compression is unusual. We describe a case of a 64-year-old man with a history of gouty arthritis of the knee. The patient presented with thoracic myelopathy and radiculopathy. Imaging of the spine revealed an extradural mass lesion with bony erosion of the thoracic spine. A decompressive operation was performed, and a chalky white material was found. Histopathological examination confirmed a gouty tophus. The symptoms of spinal gout vary and its radiological features are not sufficiently specific to provide a definite diagnosis. Therefore, in patients with a history of gouty arthritis who present with neural compressive symptoms of the spine, spinal gout should be strongly suspected. PMID- 24757486 TI - Cervical Myelopathy Secondary to Atlanto-occipital Assimilation: The Usefulness of the Simple Decompressive Surgery. AB - Atlanto-occipital assimilation is one of the most common osseous anomalies observed at the craniocervical junction. Most patients with atlas assimilation show no symptom, but some have neurological problems such as myelopathy that may require surgical treatment. Occipitocervical fusion may be required if atlato occipital assimilation is accompanied by occipito-axial instability. However, in cases of symptomatic atlas assimilation with minor cord compression without instability, simple decompressive surgery may be the treatment modality. This report describes a case of successful treatment of a patient with myelopathy secondary to atlanto-occipital assimilation without instability, using posterior simple decompressive surgery. PMID- 24757487 TI - Combined Chronic Occipito-atlantal and Atlanto-axial Rotator Fixation with Cerebral Palsy. AB - Occipito-atlantalrotatory subluxation that occurs in conjunction with atlanto axial rotator fixation is extremely rare. The common clinical characteristics are painful torticollis and cock robin position presented with the head tilted to one side and rotated to the other side. The object of this report is to emphasize that AARF combined with OARF may be caused by a variety of conditions, to be must need algorithm for proper management, apparently. A torticollis patient who had cerebral palsy presented with severe nuchal pain and wryneck for a long period. The patient had a history of fallen down 16 years ago which caused severe nuchal pain. The conservative management had failed to correct the deformity and instability. we decided to operate using occiput-C1-C2 arthrodesis and C3-4-5 bilateral screw fixation for reinforcement. Now he doesn't have neurologic deficit and shows good outcome enough to sustain his head, not using his hands, in his daily life. PMID- 24757488 TI - Surgical treatment of lumbar hyperextension injury in ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic systemic and inflammatory rheumatic disease with a variable course of the axial skeleton. Spinal involvement may accompany ossification of the ligaments, intervertebral disc, end-plates and apophyseal structures, and seems to be "bamboo spine". Because of these natures of the spine in AS, a spinal fracture can be occurred with minor trauma or spontaneously. The fracture of the AS can cause neurological complications extremely high, so special attention to prevent neurological deterioration. Operative management of the injured spine with AS is difficult, and associated with a high complication rate. Extreme care must be taken for surgery to prevent secondary neurological deterioration. PMID- 24757489 TI - Giant anterior cervical osteophyte leading to Dysphagia. AB - Large anterior cervical osteophytes can occur in degeneration of the cervical spine or in diffuse idiopathic skeletal hyperostosis(DISH). Large osteophytes can produce otolaryngological symptoms such as dysphagia, dysphonia, and foreign body sensation. We describe a DISH patient with giant anterior cervical osteophyte causing chronic dysphagia and dysphonia. A 56-year-old man presented with increasing dysphagia, dysphonia, neck pain and neck stiffness. Physical examination of the neck showed a non-tender and hard mass on the left side at the level of C4-5. Radiography showed extensive ossification of anterior longitudinal ligament along the left anterolateral aspect of vertebral bodies from C2 to T1. The ossification was espe cially prominent at the level of C4-5 and linear breakage was noted at same level. Esophagogram revealed a filling defect along the pharynx and lateral displacement of the esophagus. Giant anterior cervical osteophyte was removed through the leftsided anterolateral cervical approach to the spine. Anterior cervical interbody fusion at C4-5 was followed by posterior cervical fixation using lateral mass screws from C3 to C6. After surgery, dysphagia and dysphonia improved immediately. One year later, cervical CT showed bone fusion at C4-5 bodies and no recurrence of osteophyte. DISH is a common cause of anterior cervical osteophyte leading to progressive dysphagia. Keeping this clinical entity in the differential diagnosis is important in patients with progressive neck stiffness, dysphagia or dysphonia. And surgical treatment of symptomatic anterior cervical osteophyte due to DISH should be considered with a solid fusion procedure preventing postoperative instability or osteophyte progress. PMID- 24757490 TI - Spinal epidural hematoma related to intracranial hypotension. AB - A 45-year-old female patient visited the hospital complaining of severe sudden headache and posterior neck pain. The patient did not have any traumatic history or abnormal neurologic finding. The patient had sudden quadriplegia and sensory loss. Cervical spine MRI scan was taken, and the compatible findings to acute epidural hematoma were shown. The emergency operation was performed. After the operation, the patient recovered all motor and senses. As there was CSF leakage in the postoperative wound, this was confirmed by cervical spinal computed tomography (CT). Then lumbar drainage was thus performed. The opening pressure upon lumbar puncture was not measured as it was very low. As a result of continous CSF leakage, dural repair was performed. After the operation, the patient had been discharged without neurologic deficits. In this case, it is sensible to suspect intracranial hypotension as a possible cause of spinal EDH. PMID- 24757491 TI - Corals and their potential applications to integrative medicine. AB - Over the last few years, we have pursued the use and exploitation of invertebrate immune systems, most notably their humoral products, to determine what effects their complex molecules might exert on humans, specifically their potential for therapeutic applications. This endeavor, called "bioprospecting," is an emerging necessity for biomedical research. In order to treat the currently "untreatable," or to discover more efficient treatment modalities, all options and potential sources must be exhausted so that we can provide the best care to patients, that is, proceed from forest and ocean ecosystems through the laboratory to the bedside. Here, we review current research findings that have yielded therapeutic benefits, particularly as derived from soft and hard corals. Several applications have already been demonstrated, including anti-inflammatory properties, anticancer properties, bone repair, and neurological benefits. PMID- 24757492 TI - Danggui-Shaoyao-San Improves Learning and Memory in Female SAMP8 via Modulation of Estradiol. AB - Previous studies showed that Danggui-Shaoyao-San (DSS), a traditional Chinese medicinal prescription, could alleviate cognitive dysfunction of Alzheimer's disease (AD) patients. However, the mechanisms remain unclear; we have now examined the effect of DSS on SAMP8 and elucidated the possible mechanism. Animals were treated with DSS for 2 months, and step-down test and Morris water maze (MWM) test were used to evaluated cognitive abilities. The estradiol (E2), NO, and glycine in blood plasma or in hippocampus were detected to explore the possible mechanisms. The latency of SAMP8 in step-down test was shorter than that of age-matched SAMR1, and DSS increased the latency especially in female animals. In MWM test, we got similar results; SAMP8 spent more time to find the platform, and DSS decreased the time before finding the platform, with little effect on swim velocity, during the training sessions. During test session, DSS increased the time spent in target quadrant especially in female SAMP8. In female SAMP8, plasma E2, NO, and glycine were elevated in plasma or hippocampus tissue. In conclusion, DSS could ameliorate deterioration of cognition in SAMP8, especially in female animals. Increasing E2, NO, and glycine might contribute to the cognitive improvement effect of DSS in female SAMP8. PMID- 24757494 TI - Alpha-Asarone Protects Endothelial Cells from Injury by Angiotensin II. AB - alpha -Asarone is the major therapeutical constituent of Acorus tatarinowii Schott. In this study, the potential protective effects of alpha -asarone against endothelial cell injury induced by angiotensin II were investigated in vitro. The EA.hy926 cell line derived from human umbilical vein endothelial cells was pretreated with alpha -asarone (10, 50, 100 umol/L) for 1 h, followed by coincubation with Ang II (0.1 umol/L) for 24 h. Intracellular nitric oxide (NO) and reactive oxygen species (ROS) were detected by fluorescent dyes, and phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser(1177) was determined by Western blotting. alpha -Asarone dose-dependently mitigated the Ang II-induced intracellular NO reduction (P < 0.01 versus model) and ROS production (P < 0.01 versus model). Furthermore, eNOS phosphorylation (Ser(1177)) by acetylcholine was significantly inhibited by Ang II, while pretreatment for 1 h with alpha -asarone partially prevented this effect (P < 0.05 versus model). Additionally, cell viability determined by the MTT [3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay (105~114.5% versus control, P > 0.05) was not affected after 24 h of incubation with alpha -asarone at 1-100 umol/L. Therefore, alpha -asarone protects against Ang II-mediated damage of endothelial cells and may be developed to prevent injury to cardiovascular tissues. PMID- 24757495 TI - Amoebicidal Activity of Essential Oil of Dysphania ambrosioides (L.) Mosyakin & Clemants in an Amoebic Liver Abscess Hamster Model. AB - Amebiasis is a parasitic disease that extends worldwide and is a public health problem in developing countries. Metronidazole is the drug recommended in the treatment of amebiasis, but its contralateral effects and lack of continuity of treatment induce low efficiency, coupled with the appearance of resistant amoebic strains. Therefore, the search of new compounds with amoebicidal activity is urgent and important. In this study, we evaluated the in vitro and in vivo antiamoebic activity of the essential oil Dysphania ambrosioides (L.) Mosyakin & Clemants. It exhibited an IC50 = 0.7 mg/mL against trophozoites. The oral administration of essential oil (8 mg/kg and 80 mg/kg) to hamster infected with Entamoeba histolytica reverted the infection. Ascaridole was identified as the main component of essential oil of D. ambrosioides. The identification of amoebicidal activity of Ascaridole gives support to the traditional use. Further studies with Ascaridole will be carried out to understand the mechanism involved. PMID- 24757496 TI - L-arginine/NO pathway is altered in children with haemolytic-uraemic syndrome (HUS). AB - The haemolytic uraemic syndrome (HUS) is the most frequent cause of acute renal failure in childhood. We investigated L-arginine/NO pathway in 12 children with typical HUS and 12 age-matched healthy control subjects. Nitrite and nitrate, the major NO metabolites in plasma and urine, asymmetric dimethylarginine (ADMA) in plasma and urine, and dimethylamine (DMA) in urine were determined by GC-MS and GC-MS/MS techniques. Urinary measurements were corrected for creatinine excretion. Plasma nitrate was significantly higher in HUS patients compared to healthy controls (P = 0.021), whereas urine nitrate was borderline lower in HUS patients compared to healthy controls (P = 0.24). ADMA plasma concentrations were insignificantly lower, but urine ADMA levels were significantly lower in the HUS patients (P = 0.019). Urinary DMA was not significantly elevated. In HUS patients, nitrate (R = 0.91) but not nitrite, L-arginine, or ADMA concentrations in plasma correlated with free haemoglobin concentration. Our results suggest that both NO production and ADMA synthesis are decreased in children with typical HUS. We hypothesize that in the circulation of children with HUS a vicious circle between the L-arginine/NO pathway and free haemoglobin-mediated oxidative stress exists. Disruption of this vicious circle by drugs that release NO and/or sulphydryl groups-containing drugs may offer new therapeutic options in HUS. PMID- 24757497 TI - Omega-3 fatty acids and depression: scientific evidence and biological mechanisms. AB - The changing of omega-6/omega-3 polyunsaturated fatty acids (PUFA) in the food supply of Western societies occurred over the last 150 years is thought to promote the pathogenesis of many inflammatory-related diseases, including depressive disorders. Several epidemiological studies reported a significant inverse correlation between intake of oily fish and depression or bipolar disorders. Studies conducted specifically on the association between omega-3 intake and depression reported contrasting results, suggesting that the preventive role of omega-3 PUFA may depend also on other factors, such as overall diet quality and the social environment. Accordingly, tertiary prevention with omega-3 PUFA supplement in depressed patients has reached greater effectiveness during the last recent years, although definitive statements on their use in depression therapy cannot be yet freely asserted. Among the biological properties of omega-3 PUFA, their anti-inflammatory effects and their important role on the structural changing of the brain should be taken into account to better understand the possible pathway through which they can be effective both in preventing or treating depression. However, the problem of how to correct the inadequate supply of omega-3 PUFA in the Westernized countries' diet is a priority in order to set food and health policies and also dietary recommendations for individuals and population groups. PMID- 24757498 TI - Modulation of cytokine production by drugs with antiepileptic or mood stabilizer properties in anti-CD3- and anti-Cd40-stimulated blood in vitro. AB - Increased cytokine production possibly due to oxidative stress has repeatedly been shown to play a pivotal role in the pathophysiology of epilepsy and bipolar disorder. Recent in vitro and animal studies of valproic acid (VPA) report antioxidative and anti-inflammatory properties, and suppression of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha. We tested the effect of drugs with antiepileptic or mood stabilizer properties, namely, primidone (PRM), carbamazepine (CBZ), levetiracetam (LEV), lamotrigine (LTG), VPA, oxcarbazepine (OXC), topiramate (TPM), phenobarbital (PB), and lithium on the production of the following cytokines in vitro: interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-17, IL 22, and TNF-alpha. We performed a whole blood assay with stimulated blood of 14 healthy female subjects. Anti-human CD3 monoclonal antibody OKT3, combined with 5C3 antibody against CD40, was used as stimulant. We found a significant reduction of IL-1 and IL-2 levels with all tested drugs other than lithium in the CD3/5C3-stimulated blood; VPA led to a decrease in IL-1beta, IL-2, IL-4, IL-6, IL 17, and TNF-alpha production, which substantiates and adds knowledge to current hypotheses on VPA's anti-inflammatory properties. PMID- 24757500 TI - Synthesis, LSD1 Inhibitory Activity, and LSD1 Binding Model of Optically Pure Lysine-PCPA Conjugates. AB - Compounds that inhibit the catalytic function of lysine-specific demethylase 1 (LSD1) are interesting as therapeutic agents. Recently, we identified three lysine-phenylcyclopropylamine conjugates, NCD18, NCD25, and NCD41, which are potent LSD1 inactivators. However, in our previous study, because we tested those compounds as mixtures of (1S,2R)- and (1R,2S)-disubstituted cyclopropane rings, the relationship between the stereochemistry of the cyclopropane ring and their biological activity remained unknown. In this work, we synthesized optically active compounds of NCD18, NCD25, and NCD41 and evaluated their LSD1 inhibitory activities. In enzyme assays, the LSD1 inhibitory activities of (1R,2S)-NCD18 and (1R,2S)-NCD25 were approximately eleven and four times more potent than those of the corresponding (1S,2R)-isomers, respectively. On the other hand, (1S,2R)-NCD41 was four times more potent than (1R,2S)-NCD41. Binding simulation with LSD1 indicated that the aromatic rings of the compounds and the amino group of the cyclopropylamine were important for the interaction with LSD1, and that the stereochemistry of the 1,2-disubstituted cyclopropane ring affected the position of the aromatic rings and the hydrogen bond formation of the amino group in the LSD1 catalytic site. These findings are expected to contribute to the further development of LSD1 inactivators. PMID- 24757499 TI - Site-specific functionalization of proteins and their applications to therapeutic antibodies. AB - Protein modifications are often required to study structure and function relationships. Instead of the random labeling of lysine residues, methods have been developed to (sequence) specific label proteins. Next to chemical modifications, tools to integrate new chemical groups for bioorthogonal reactions have been applied. Alternatively, proteins can also be selectively modified by enzymes. Herein we review the methods available for site-specific modification of proteins and their applications for therapeutic antibodies. PMID- 24757501 TI - NMR Characterization of Self-Association Domains Promoted by Interactions with LC8 Hub Protein. AB - Most proteins in interaction networks have a small number of partners, while a few, called hubs, participate in a large number of interactions and play a central role in cell homeostasis. One highly conserved hub is a protein called LC8 that was originally identified as an essential component of the multi-subunit complex dynein but later shown to be also critical in multiple protein complexes in diverse systems. What is intriguing about this hub protein is that it does not passively bind its various partners but emerging evidence suggests that LC8 acts as a dimerization engine that promotes self-association and/or higher order organization of its primarily disordered monomeric partners. This structural organization process does not require ATP but is triggered by long-range allosteric regulation initiated by LC8 binding a pair of disordered chains forming a bivalent or polybivalent scaffold. This review focuses on the role of LC8 in promoting self-association of two of its binding partners, a dynein intermediate chain and a non dynein protein called Swallow. PMID- 24757503 TI - Cofactor Specificity Engineering of Streptococcus mutans NADH Oxidase 2 for NAD(P)(+) Regeneration in Biocatalytic Oxidations. AB - Soluble water-forming NAD(P)H oxidases constitute a promising NAD(P)(+) regeneration method as they only need oxygen as cosubstrate and produce water as sole byproduct. Moreover, the thermodynamic equilibrium of O2 reduction is a valuable driving force for mostly energetically unfavorable biocatalytic oxidations. Here, we present the generation of an NAD(P)H oxidase with high activity for both cofactors, NADH and NADPH. Starting from the strictly NADH specific water-forming Streptococcus mutans NADH oxidase 2 several rationally designed cofactor binding site mutants were created and kinetic values for NADH and NADPH conversion were determined. Double mutant 193R194H showed comparable high rates and low K m values for NADPH (k cat 20 s(-1), K m 6 uM) and NADH (k cat 25 s(-1), K m 9 uM) with retention of 70% of wild type activity towards NADH. Moreover, by screening of a SeSaM library S. mutans NADH oxidase 2 variants showing predominantly NADPH activity were found, giving further insight into cofactor binding site architecture. Applicability for cofactor regeneration is shown for coupling with alcohol dehydrogenase from Sphyngobium yanoikuyae for 2 heptanone production. PMID- 24757502 TI - Open questions in origin of life: experimental studies on the origin of nucleic acids and proteins with specific and functional sequences by a chemical synthetic biology approach. AB - In this mini-review we present some experimental approaches to the important issue in the origin of life, namely the origin of nucleic acids and proteins with specific and functional sequences. The formation of macromolecules on prebiotic Earth faces practical and conceptual difficulties. From the chemical viewpoint, macromolecules are formed by chemical pathways leading to the condensation of building blocks (amino acids, or nucleotides) in long-chain copolymers (proteins and nucleic acids, respectively). The second difficulty deals with a conceptual problem, namely with the emergence of specific sequences among a vast array of possible ones, the huge "sequence space", leading to the question "why these macromolecules, and not the others?" We have recently addressed these questions by using a chemical synthetic biology approach. In particular, we have tested the catalytic activity of small peptides, like Ser-His, with respect to peptide- and nucleotides-condensation, as a realistic model of primitive organocatalysis. We have also set up a strategy for exploring the sequence space of random proteins and RNAs (the so-called "never born biopolymer" project) with respect to the production of folded structures. Being still far from solved, the main aspects of these "open questions" are discussed here, by commenting on recent results obtained in our groups and by providing a unifying view on the problem and possible solutions. In particular, we propose a general scenario for macromolecule formation via fragment-condensation, as a scheme for the emergence of specific sequences based on molecular growth and selection. PMID- 24757504 TI - Site-specific Labeling of a Protein Lysine Residue By Novel Kinetic Labeling Combinatorial Libraries. AB - The first example of a kinetic labeling library designed to enable the discovery of affinity labels is presented. Each library component (1) consists of a variable peptidyl component linked to a biotinyl moiety by a 4-mercaptobenzoyl linker in thioester format. We demonstrate that an affinity label can be uncovered by measuring reaction rates between library pools and the protein target, human serum albumin (HSA) and identifying significant outliers. By choosing peptide functionality compatible with a potentially reactive thioester labeling entity, libraries can be screened in pools. It is noteworthy that a limited subset of amino acids (R, S, E, F, Y, l, M, W, and Q) that compose the affinity moiety is sufficient to produce rate variances that guide the discovery process. After two rounds of deconvolution, J-FLYEE-NH2 (7-E) emerges as a bona fide affinity label of HSA. Unlike known affinity labels, the affinity moiety is not retained in the protein product, but is extruded upon acylation of the protein. This feature affords a method of introducing various payloads, without extraneous elements, onto protein frameworks. PMID- 24757505 TI - Aluminium in biological environments: a computational approach. AB - The increased availability of aluminium in biological environments, due to human intervention in the last century, raises concerns on the effects that this so far "excluded from biology" metal might have on living organisms. Consequently, the bioinorganic chemistry of aluminium has emerged as a very active field of research. This review will focus on our contributions to this field, based on computational studies that can yield an understanding of the aluminum biochemistry at a molecular level. Aluminium can interact and be stabilized in biological environments by complexing with both low molecular mass chelants and high molecular mass peptides. The speciation of the metal is, nonetheless, dictated by the hydrolytic species dominant in each case and which vary according to the pH condition of the medium. In blood, citrate and serum transferrin are identified as the main low molecular mass and high molecular mass molecules interacting with aluminium. The complexation of aluminium to citrate and the subsequent changes exerted on the deprotonation pathways of its tritable groups will be discussed along with the mechanisms for the intake and release of aluminium in serum transferrin at two pH conditions, physiological neutral and endosomatic acidic. Aluminium can substitute other metals, in particular magnesium, in protein buried sites and trigger conformational disorder and alteration of the protonation states of the protein's sidechains. A detailed account of the interaction of aluminium with proteic sidechains will be given. Finally, it will be described how alumnium can exert oxidative stress by stabilizing superoxide radicals either as mononuclear aluminium or clustered in boehmite. The possibility of promotion of Fenton reaction, and production of hydroxyl radicals will also be discussed. PMID- 24757507 TI - Malarial Infection among Antenatal and Maternity Clinics Attendees at the Federal Medical Centre, Makurdi, Benue State, Nigeria. AB - This study assessed the level of malarial infection in relation to some epidemiological factors, gravidity and pregnancy period of antenatal clinic attendees of the Federal Medical Centre, Makurdi, Benue State, Nigeria. We also assessed malarial infection in placental blood in relation to gravidity of pregnant women at delivery in the maternity clinic of the same hospital. Thin and thick blood films were prepared for microscopic examination. A questionnaire was administered to each pregnant woman at the antenatal clinic to collect data on educational level, occupation, gravidity, pregnancy period, malaria preventive measures and malaria symptoms. Of the 163 pregnant women examined at the antenatal clinic, 68.3% (111/163) were infected with malaria. Pregnant women that are illiterates (chi(2) =15.44, P=0.100) and those that are farmers (chi(2) =9.20, P=0.270) had the highest infection rate with no significant difference respectively. Malarial infection was significantly higher in the multigravidae, 57.6% (34/59) (chi(2) =5.16, P=0.007) and non-significant in the pregnant women at their third trimester of pregnancy, 60.9% (53/89) (chi(2) =4.45, P=0.108). Placental malaria was significantly higher in the primigravidae among pregnant women at delivery (chi(2) =9.33, P=0.000). A significant difference (chi(2) =33.52, P=0.000) was observed between pregnant women that did not use any malaria preventive methods, 91.2% (31/34) and those that used single, 64.3% (65/101) and combined, 46.4% (13/28) methods of prevention. Malaria remains highly prevalent among antenatal clinics attendees in Makurdi, Nigeria. Combined method of prevention (insecticides treated nets and insecticide spray) yielded good results and its use is advocated in preventing malaria among the pregnant women. PMID- 24757508 TI - Myositis in a child with murine typhus. AB - A 12-year-old boy presented with fever, lower extremity pain and weakness. Examination revealed paraparesis, thigh and calf tenderness. Labs showed high creatinine phosphokinase and Rickettsia typhi titers. This case illustrates endemic typhus should be considered in the differential diagnosis of myositis especially in areas with high prevalence of the disease. To our knowledge, this is the first reported case of myositis and paraparesis associated with a case of murine typhus. PMID- 24757506 TI - Maturation and migration of murine CD4 single positive thymocytes and thymic emigrants. AB - T lymphopoiesis in the thymus was thought to be completed once they reach the single positive (SP) stage, when they are "fully mature" and wait to be exported at random or follow a "first in-first out" manner. Recently, accumulating evidence has revealed that newly generated SP thymocytes undergo further maturation in the thymic medulla before they follow a tightly regulated emigrating process to become recent thymic emigrants (RTEs). RTEs in the periphery then experience a post-thymic maturation and peripheral tolerance and eventually become licensed as mature naive T cells. This review summarizes the recent progress in the late stage T cell development in and outside of the thymus. The regulation of this developmental process is also discussed. PMID- 24757509 TI - Renal hemorrhagic actinomycotic abscess in pregnancy. AB - Actinomyces israelii is a gram-positive, filamentous anaerobic bacteria colonizing the oral and gastrointestinal tracts. Retroperitoneal actinomycotic abscess is uncommon and its rare presentation as a hemorrhagic mass may be confused with malignancy. We present a case of this unusual infection complicating pregnancy. Increased awareness of actinomycotic abscess in the differential diagnosis of renal mass concerning for malignancy is critical to early recognition and treatment of this rare infection and most importantly, avoidance of unnecessary surgical intervention. PMID- 24757511 TI - Editorial. PMID- 24757510 TI - A complicated case of an immunocompetent patient with disseminated nocardiosis. AB - Nocardia species are aerobic, gram positive filamentous branching bacteria that have the potential to cause localized or disseminated infection. Nocardiosis is a rare disease that usually affects immunocompromised patients and presents as either pulmonary, cutaneous or disseminated nocardiosis. Forty-two year-old hispanic male presented to our care with bilateral lower extremity weakness, frontal headache, subjective fever, nausea, and vomiting. Brain computed tomography (CT) revealed multiple hyperdense lesions with vasogenic edema in the frontal, parietal and left temporal lobes. Chest CT demonstrated bilateral cavitary nodules in the lung and right hilar lymphadenopathy. Brain magnetic resonance imaging revealed multiple bilateral supratentorial and infratentorial rim enhancing lesions involving the subcortical gray-white matter interface with vasogenic edema. Patient was started on empiric therapy for unknown infectious etiology with no response. He eventually expired and autopsy findings revealed a right hilar lung abscess and multiple brain abscesses. Microscopic and culture findings from tissue sample during autopsy revealed nocardia wallacei species with multidrug resistance. The cause of death was stated as systemic nocadiosis (nocardia pneumonitis and encephalitis). The presence of simultaneous lung and brain abscesses is a reliable indication of an underlying Nocardia infection. An increased awareness of the various presentations of nocardiosis and a high index of clinical suspicion can help in a rapid diagnosis and improve survival in an otherwise fatal disease. This case highlights the importance of obtaining a tissue biopsy for definitive diagnosis on the initial presentation when an infectious process is considered in the differential diagnosis and early treatment can be initiated. PMID- 24757512 TI - Working together: interactions between vaccine antigens and adjuvants. AB - The development of vaccines containing adjuvants has the potential to enhance antibody and cellular immune responses, broaden protective immunity against heterogeneous pathogen strains, enable antigen dose sparing, and facilitate efficacy in immunocompromised populations. Nevertheless, the structural interplay between antigen and adjuvant components is often not taken into account in the published literature. Interactions between antigen and adjuvant formulations should be well characterized to enable optimum vaccine stability and efficacy. This review focuses on the importance of characterizing antigen-adjuvant interactions by summarizing findings involving widely used adjuvant formulation platforms, such as aluminum salts, emulsions, lipid vesicles, and polymer-based particles. Emphasis is placed on the physicochemical basis of antigen-adjuvant associations and the appropriate analytical tools for their characterization, as well as discussing the effects of these interactions on vaccine potency. PMID- 24757513 TI - Influenza vaccination in children at high risk of respiratory disease. AB - Chronic respiratory diseases (CRDs) are a heterogeneous group of diseases that can affect the pediatric population and health authorities throughout the world recommend influenza vaccination because of the significant risk of influenza related complications. However, despite this recommendation, vaccine coverage is generally unsatisfactory. The aim of this review is to analyze the impact of influenza on children at high risk of respiratory disease, and the immunogenicity, safety and efficacy of influenza vaccination in such children. The results show that there is a significant risk of influenza-related complications in preterm neonates and infants, in whom influenza vaccines are immunogenic and safe (although their efficacy has not been specifically studied). There are conflicting data concerning the effect of influenza infection on asthma morbidity in children, and whether or not influenza vaccination helps to prevent asthma exacerbations. Recent data provide no evidence that influenza is more frequent in patients with cystic fibrosis than in healthy subjects, or that it is responsible for increased lower respiratory tract morbidity. The lack of any clear correlate of protection suggests that future studies should also consider the efficacy of the different influenza vaccines and not only evaluate them in terms of immunogenicity. Furthermore, there is a need for clinical studies to assess the effectiveness of the available vaccines in patients with other rare CRDs and other chronic underlying diseases with possibly severe respiratory involvement. It is also important to determine whether children with recurrent respiratory tract infections should be included in the list of those for whom influenza vaccination is recommended. In the meantime, given the increasing evidence of the burden of influenza on the population as a whole and the benefits associated with vaccination, annual influenza vaccinations should be recommended for all children at high risk of respiratory disease and the members of their households. PMID- 24757514 TI - The rationale of vectored gene-fusion vaccines against cancer: evolving strategies and latest evidence. AB - The development of vaccines that target tumor antigens in cancer has proven difficult. A major reason for this is that T cells specific for tumor self antigens and neoantigens are eliminated or inactivated through mechanisms of tolerance. Antigen fusion strategies which increase the ability of vaccines to stimulate T cells that have escaped tolerance mechanisms, may have a particular potential as immunotherapies. This review highlights antigen fusion strategies that have been successful in stimulating the induction of T-cell immunity against cancer and counteracting tumor-associated tolerance. In preclinical studies, these strategies have shown to improve the potency of vectored vaccines through fusion of tumor antigen to proteins or protein domains that increase CD4+ T-cell help, CD8+ T-cell responses or both the CD4+ and CD8+ T-cell responses. However, in clinical trials such strategies seem to be less efficient when provided as a DNA vaccine. The first clinical trial using a viral vectored fusion-gene vaccine is expected to be tested as a partner in a heterologous prime-boost regimen directed against cervical cancer. PMID- 24757515 TI - How to fight pertussis? AB - Universal pertussis vaccination has successfully decreased pertussis mortality and morbidity in childhood. However, despite intensive vaccination of young children, pertussis remains a major public health problem in both developing and industrialized regions. Recent epidemics in California and Australia demonstrated that the agent of the disease is still circulating. They also revealed several aspects that must not be neglected concerning vaccine-preventable diseases. Indeed, pertussis is one of the oldest vaccine-preventable bacterial diseases, so can provide a good illustration of all of the aspects associated with the need for surveillance after the introduction of vaccination. (i) The type of vaccine: two types of pertussis vaccine, whole cell and acellular, inducing different types of immunity are now used around the world. (ii) The vaccine strategy, the vaccine coverage and the duration of vaccine immunity: pertussis epidemics provide evidence that 90% of the infants must be vaccinated, vaccination must be sufficiently early and both vaccine-induced immunity and natural infection induced immunity to pertussis wane with time indicating that pertussis is not only a pediatric disease. (iii) The agents of the disease, Bordetella pertussis and Bordetella parapertussis: the intensive vaccination of young infants modified the herd immunity, controlled bacteria similar to the vaccine strains but not all, revealing polymorphism of the agents of the disease evidencing the importance of continuing their isolation and their surveillance as well as monitoring their antibiotic resistance. (iv) The diagnosis of the disease: the epidemics showed the importance of specific diagnostic techniques that are easy to use by medical laboratories and the availability of the reagents required. (v) Communication with the public, the health authorities and the health providers: any changes of vaccine type, vaccine strategy, characteristics of the disease, and biological diagnosis must be associated with appropriate communication with the public and training of healthcare workers. Currently, herd immunity needs to be increased by introducing vaccine boosters for adolescents and adults to protect the most vulnerable group: unvaccinated newborns. PMID- 24757516 TI - Preventive and therapeutic applications of neutralizing antibodies to Human Immunodeficiency Virus Type 1 (HIV-1). AB - The development of a preventive vaccine to neutralize the highly variable and antigenically diverse human immunodeficiency virus type 1 (HIV-1) has been an indomitable goal. The recent discovery of a number of cross-neutralizing and potent monoclonal antibodies from elite neutralizers has provided important insights in this field. Neutralizing antibodies (NAbs) are useful in identifying neutralizing epitopes of vaccine utility and for understanding the mechanism of potent and broad cross-neutralization thus providing a modality of preventive and therapeutic value. In this article we review the current understanding on the potential use of broadly neutralizing antibodies (bNAbs) in their full-length IgG structure, engineered domain antibody or bispecific versions towards preventive and therapeutic applications. The potential implications of NAbs are discussed in the light of the recent developments as key components in vaccination against HIV 1. The development of a vaccine immunogen which elicits bNAbs and confers protective immunity remains a real challenge. PMID- 24757517 TI - The role of Human Papilloma Virus (HPV) vaccination in the prevention of anal cancer in individuals with Human Immunodeficiency Virus-1 (HIV-1) infection. AB - The incidence of anal cancer is increasing in the general population and especially in high-risk groups. A total of 90% of anal cancers are caused by human papilloma virus (HPV) infection of the anal canal. Similar to cervical cancer, anal cancer progresses through a predictable series of premalignant stages before resulting in invasive cancer; this process begins with persistent HPV infection. The HPV vaccine represents a promising strategy to combat the increasing incidence of anal cancer. Human Immunodeficiency Virus (HIV) predisposes people to persistent HPV infection, dysplasia, and subsequent anal cancer. Patients infected with HIV should be targeted for vaccination against HPV. There are difficulties in targeting this population, the most notable being that the optimal age for vaccination is prior to identification with any high risk groups. Universal vaccination against HPV represents the best strategy to achieve maximum protection against anal cancer in high-risk groups. PMID- 24757518 TI - Novel HIV vaccine strategies: overview and perspective. AB - A human immunodeficiency virus (HIV) vaccine remains a central component in the quest to control the worldwide epidemic. To examine the status of the development of HIV vaccines, we review the results of the efficacy trials carried out to date and the immunologic principles that guided them. Four vaccine concepts have been evaluated in HIV-1 vaccine efficacy trials, and the results of these trials have provided significant information for future vaccine development. While one of these trials demonstrated that a safe and effective HIV vaccine is possible, many questions remain regarding the basis for the observed protection and the most efficient way to stimulate it. Novel HIV vaccine strategies including induction of highly potent broadly neutralizing antibodies, use of novel homologous and heterologous vector systems, and vectored immunoprophylaxis seek to expand and build upon the knowledge gained from these trials. PMID- 24757519 TI - An update on vaccines against Shigella. AB - Despite intensive research efforts for more than 60 years, utilizing diverse vaccine strategies, a safe and efficacious vaccine against shigellosis is not available yet. We are currently witnessing innovative approaches based on elucidation of the virulence mechanisms of Shigella, understanding the immune response to the pathogen and progress in molecular technology for developing Shigella vaccines. It is hoped that these will lead to a licensed effective Shigella vaccine to protect humans against the significant worldwide morbidity and mortality caused by this microorganism. PMID- 24757521 TI - Advances and controversies in yellow fever vaccination. AB - Ever since its development in 1937, the live-attenuated 17D yellow fever (YF) vaccine has been one of the most effective vaccines available to man. In this review we highlight the major steps in the development of 17D YF vaccine. We discuss the use of neutralizing antibodies as a surrogate marker for protection, and explore the strengths and weaknesses of the current plaque reduction neutralization test (PRNT), a technique developed in the 1960s that continues to be superior to every modern test in both sensitivity and specificity. The neutralizing antibodies demonstrated by the PRNT can be detected for several decades after vaccination, possibly even for the remainder of the recipient's natural life. We review the available evidence on the duration of protection after primary vaccination, a topic that has been the subject of controversy over the last few months. For persons who are immunocompromised due to disease, medication or advancing age, the duration of protection may be shorter: they should always have their vaccine response checked by PRNT. Due to the higher risk of severe adverse events after vaccination with 17D YF in this group, the development of a new, inactivated vaccine will have substantial benefits in this population. PMID- 24757520 TI - Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants. AB - A principal barrier to the development of effective vaccines is the availability of adjuvants and formulations that can elicit both effector and long-lived memory CD4 and CD8 T cells. Cellular immunity is the presumptive immune correlate of protection against intracellular pathogens: a group composed of bacteria, viruses and protozoans that is responsible for a staggering level of morbidity and mortality on a global scale. T-cell immunity is also correlated with clinical benefit in cancer, and the development of therapeutic strategies to harness the immune system to treat diverse malignancies is currently undergoing a renaissance. Cyclic dinucleotides (CDNs) are ubiquitous small molecule second messengers synthesized by bacteria that regulate diverse processes and are a relatively new class of adjuvants that have been shown to increase vaccine potency. CDNs activate innate immunity by directly binding the endoplasmic reticulum-resident receptor STING (stimulator of interferon genes), activating a signaling pathway that induces the expression of interferon-beta (IFN-beta) and also nuclear factor-kappaB (NF-kappaB) dependent inflammatory cytokines. The STING signaling pathway has emerged as a central Toll-like receptor (TLR) independent mediator of host innate defense in response to sensing cytosolic nucleic acids, either through direct binding of CDNs secreted by bacteria, or, as shown recently, through binding of a structurally distinct CDN produced by a host cell receptor in response to binding cytosolic double-stranded (ds)DNA. Although this relatively new class of adjuvants has to date only been evaluated in mice, newly available CDN-STING cocrystal structures will likely intensify efforts in this field towards further development and evaluation in human trials both in preventive vaccine and immunotherapy settings. PMID- 24757522 TI - Latest developments and future directions in dengue vaccines. AB - Dengue is a mosquito-borne disease which is currently an expanding global health problem. The disease is caused by four closely related viruses, the dengue virus. There are no specific dengue therapeutics and prevention is currently limited to vector control measures. Development of an effective tetravalent dengue vaccine would therefore represent a major advance in the control of the disease and is considered a high public health priority. While a licensed dengue vaccine is not yet available, the scope and intensity of dengue vaccine development has increased dramatically in the last decade. The uniqueness of the dengue viruses and the spectrum of disease resulting from infection have made dengue vaccine development difficult. Several vaccine candidates are currently being evaluated in clinical studies. The candidate currently at the most advanced clinical development stage, a live-attenuated tetravalent vaccine based on chimeric yellow fever dengue virus, has progressed to phase III efficacy studies. Several other live-attenuated vaccines, as well as subunit, DNA and purified inactivated vaccine candidates, are at earlier stages of clinical development. Additional technological approaches, such as virus-vectored and virus-like particle-based vaccines, are under evaluation in preclinical studies. PMID- 24757523 TI - A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs. AB - Recent advances strongly suggest that mRNA rather than DNA will be the nucleotide basis for a new class of vaccines and drugs. Therapeutic cancer vaccines against a variety of targets have been developed on this basis and initial clinical experience suggests that preclinical activity can be successfully translated to human application. Likewise, prophylactic vaccines against viral pathogens and allergens have demonstrated their activity in animal models. These successes could be extended preclinically to mRNA protein and gene replacement therapy as well as the induction of pluripotent stem cells by mRNA encoded transcription factors. The production of mRNA-based vaccines and drugs is highly flexible, scalable and cost competitive, and eliminates the requirement of a cold chain. mRNA-based drugs and vaccines offer all the advantages of a nucleotide-based approach at reduced costs and represent a truly disruptive technology that may start a revolution in medicine. PMID- 24757524 TI - Successes and challenges in varicella vaccine. AB - Varicella is a highly contagious disease caused by primary infection with varicella zoster virus (VZV). VZV infection, as well as varicella vaccination, induces VZV-specific antibody and T-cell-mediated immunity, essential for recovery. The immune responses developed contribute to protection following re exposure to VZV. When cell-mediated immunity declines, as occurs with aging or immunosuppression, reactivation of VZV leads to herpes zoster (HZ). It has been almost 20 years since universal varicella vaccination has been implemented in many areas around the globe and this has resulted in a significant reduction of varicella-associated disease burden. Successes are reviewed here, whilst emphasis is put on the challenges ahead. Most countries that have not implemented routine childhood varicella vaccination have chosen to vaccinate high-risk groups alone. The main reasons for not introducing universal vaccination are discussed, including fear of age shift of peak incidence age and of HZ incidence increase. Possible reasons for not observing the predicted increase in HZ incidence are explored. The advantages and disadvantages of universal vs targeted vaccination as well as different vaccination schedules are discussed. PMID- 24757525 TI - Advances in immune-modulating therapies to treat atherosclerotic cardiovascular diseases. AB - In addition to hypercholesterolemia, innate and adaptive immune mechanisms play a critical role in atherogenesis, thus making immune-modulation therapy a potentially attractive way of managing atherosclerotic cardiovascular disease. These immune-modulation strategies include both active and passive immunization and confer beneficial reduction in atherosclerosis. Preclinical studies have demonstrated promising results and we review current knowledge on the complex role of the immune system and the potential for immunization as an immune modulation therapy for atherosclerosis. PMID- 24757529 TI - The genetic patterns of bladder cancer. Where do we stand now? PMID- 24757528 TI - MMP7 and MMP8 genetic polymorphisms in bladder cancer patients. AB - INTRODUCTION: Breakdown of the extracellular matrix by matrix metalloproteinases (MMPs), as we know, is one of mechanisms involved and required in tumor invasion. MMP7 is a negative prognostic factor of various malignances, while MMP8 exhibits an inhibitory effect on tumorigenesis and metastasis. We evaluated the potential association of functional polymorphisms in the promoter of the MMP7 (rs11568818) and MMP8 (rs11225395) genes and bladder cancer (BCa) risk. MATERIALS AND METHODS: The study included 241 BCa cases and 199 healthy population controls that were collected at the First Department of Urology, Medical University (Lodz, Poland) and at the Nofer Institute of Occupational Medicine (Lodz, Poland). Genomic DNA samples were isolated from venous blood and genetic polymorphisms were analyzed by real-time polymerase chain reaction using TaqMan fluorescent probes. Associations between genotype and allele status were estimated by logistic regression models adjusted for classic risk factors (e.g. age, gender and cigarette smoking). RESULTS: MMP7 and MMP8 genotypes were distributed similarly in BCa patients and in controls and at least one variant allele was not associated with BCa cancer risk (OR, 0.91; 95% CI, 0.60-1.39; p = 0.662 for MMP7 and OR, 0.96; 95% CI, 0.63-1.46; p = 0.836 for MMP8). We observed higher prevalence of MMP7 GG genotypes among BCa patients than in controls (OR, 1.54; 95% CI, 0.93-2.55; p = 0.093). Additionally, genetic polymorphisms in the MMP7 and MMP8 were not associated with the tumor grade or stage. CONCLUSIONS: Our results suggest that genetic variations in two genes encoding members of the MMP7 and MMP8 are not associated with a risk of BCa in the Caucasian population. PMID- 24757527 TI - Renal cell carcinoma: how to hit the targets? AB - INTRODUCTION: Renal cell carcinoma (RCC) is a widespread oncourological disease with a tendency towards a slow increase of incidence. In the recent decade, there has been development of numerous effective drugs targeted at different molecules that play a dominant role in RCC carcinogenesis. Understanding of RCC carcinogenesis confirms the key role of angiogenesis in maintaining the viability of renal tumours and their metastases. MATERIAL AND METHODS: We aimed to systemize numerous medicines, used to inhibit the angiogenesis in patients with advanced RCC according to their targets, and to analyze their efficacy. RESULTS: There are roughly four main mechanisms of action of the targeted drugs:Blockade of circulating extracellular VEGF molecules.The selective blockade of tyrosine kinase receptors' domains.The simultaneous blockage of the tyrosine kinase receptors' domains and intracellular tyrosine kinases.The blockade of mammalian target of rapamycin (mTOR) which is responsible for support of vital functions of cancer cells. In addition to FDA officially approved drugs, numerous experimental agents have been synthesized, which are currently on initial stages of clinical studies in RCC treatment. CONCLUSIONS: The results of the currently used targeted drugs demonstrate perspectives of metastatic RCC conservative treatment, that are able to prolong cancer-specific survival in previously doomed patients for up to 29 months. The development of schedules for sequential treatment or combination targeted therapy remains a current challenge. The quality of life is an important factor that influences remedy choice. The advantages and disadvantages of neoadjuvant and adjuvant targeted therapy are currently being intensively discussed. PMID- 24757530 TI - Cajal-like interstitial cells as a novel target in detrusor overactivity treatment: true or myth? AB - INTRODUCTION: The Cajal-like intestitial cells (ICCs) act as a pacemaker and are responsible for generating smooth muscle activity in the gastrointestinal tract (GI). Interstitial cells that resemble ICCs in the GI have been identified in the urinary bladder. MATERIALS AND METHODS: This review is based on a systemic literature research. The medline/pubmed, scopus, embase, and Web of Science databases were browsed in order to identify original and review articles, as well as editorials relating to cajal-like cells, urinary bladder, detrusor overactivity, overactive bladder, glivec, etc. The controlled vocabulary of the Medical Subject Headings (MeSH) database was used to ensure the sensitivity of the searches. 40 papers met the criteria and were used for this review. RESULTS: Cajal cells lie in close proximity to the muscle cells, autonomic nerve endings, and urothelial cells. There is increasing evidence that ICCs play role in urinary tract dysfunction development (e.g. detrusor overactivity, primary obstructive megaureter, congenital ureteropelvic junction obstruction, etc.). ICCs may be responsible for generating electrical potentials and induction of detrusor muscle contractions. Novel pathomechanisms of detrusor overactivity development have been postulated, as follows: 1) the disturbance of spontaneous contractility caused by altered signal transduction of ICCs between nerves and detrusor muscle cells, and 2). the alteration in signal transduction between urothelium and afferent nerve endings via suburothelial ICCs. The c-kit receptor is not only a detection marker of these cells, but may also play a crucial role in the control of bladder function. CONCLUSIONS: Cajal cells in urinary bladder suggest that the c-kit receptor may provide a novel target for treating detrusor overactivity. The review presents the current knowledge of ICCs, its role in urinary bladder function, and potential novel therapeutic strategy. PMID- 24757531 TI - The value of EORTC risk tables in evaluating recurrent non-muscle-invasive bladder cancer in everyday practice. AB - INTRODUCTION: Due to the risk of recurrence and progression, patients with non muscle-invasive bladder cancer have to be under observation. The aim of this study is the evaluation of early recurrence at the first control cystoscopy, as a prognostic factor for recurrence and progression based on EORTC risk tables. MATERIAL AND METHODS: This study analyzed 243 patients with non-muscle-invasive bladder cancer, with an average observation time of 46 months. Recurrence was observed in case of 99 patients. Among these patients, we selected 79 who had the first cystoscopy 3 months after the transurethral electroresection of the bladder tumor. Subsequently, 45 patients with early recurrence at the first control cystoscopy were compared with 34 patients whose cancer recurred at later control cystoscopies. The patients were compared with respect to the number of points assigned by EORTC tables. RESULTS: Those patients who had an early recurrence had a significantly higher score in the EORTC table in the progression scale (p = 0.017) but not in the recurrence scale (p = 0.11), as compared with patients who had a late recurrence. CONCLUSIONS: Early recurrence that occurs within 3 months after TURBT indicates a higher risk of progression, as compared with a late recurrence. Patients who had an early recurrence had a significantly higher EORTC risk score for progression. Their EORTC risk score for recurrence was also higher, but the difference was not statistically significant. Every patient with an early recurrence has a worse prognosis and a higher risk of progression. PMID- 24757526 TI - Adult Stem Cells and Diseases of Aging. AB - Preservation of adult stem cells pools is critical for maintaining tissue homeostasis into old age. Exhaustion of adult stem cell pools as a result of deranged metabolic signaling, premature senescence as a response to oncogenic insults to the somatic genome, and other causes contribute to tissue degeneration with age. Both progeria, an extreme example of early-onset aging, and heritable longevity have provided avenues to study regulation of the aging program and its impact on adult stem cell compartments. In this review, we discuss recent findings concerning the effects of aging on stem cells, contributions of stem cells to age-related pathologies, examples of signaling pathways at work in these processes, and lessons about cellular aging gleaned from the development and refinement of cellular reprogramming technologies. We highlight emerging therapeutic approaches to manipulation of key signaling pathways corrupting or exhausting adult stem cells, as well as other approaches targeted at maintaining robust stem cell pools to extend not only lifespan but healthspan. PMID- 24757533 TI - Obesity and prostate cancer research. PMID- 24757532 TI - Obesity, diabetes and aggressive prostate cancer hormone-naive at initial diagnosis. AB - INTRODUCTION: Epidemiologic studies have implicated obesity in prostate cancer (PCa) development and aggressiveness; nevertheless, no clear consensus has been reached. The aim of the research was to investigate the association of obesity with PCa, hormone-naive at initial diagnosis. METHODS: A retrospective analysis of 266 patients undergoing prostate biopsy at our institution, between 2006 and 2009, was conducted. We examined obesity and PCa association in 133 patients with PCa, hormone-naive at initial diagnosis, versus 133 age-matched controls. Men with incomplete data available, a history of hormone therapy or chemotherapy, prostate or bladder surgery were excluded. RESULTS: Obesity was significantly associated (OR 2.25) with aggressive PCa (Gleason score >=7) and inversely related (OR 0.35) to non-aggressive PCa (Gleason score <=6). Particularly, obesity in diabetic patients was significantly linked with aggressive PCa (OR 4.17). No association was noted between obesity and PCa development. CONCLUSIONS: In our study, obese patients, particularly in combination with diabetes mellitus (DM), were more likely to present with more aggressive PCa. Further research with larger samples should be done to confirm these associations and to stabilize future prevention strategies. PMID- 24757534 TI - Author'S reply. PMID- 24757535 TI - Tumor growth in intestinal neobladder. AB - The case of a 73 years old man with tumor in intestinal neobladder was presented. Tumor was resected using standard TUR technique. Tumor proved to be benign, follow-up revealed no recurrences. The schedule of lifelong follow-up was proposed. PMID- 24757536 TI - Kidney angiomyolipoma in pregnancy. AB - Neoplasms are rare in pregnant women, however they are always a challenging diagnostic and curative problem. We present a case of a benign kidney tumor (angiomyolipoma) imitating nephroblastoma on magnetic resonance diagnosed in pregnancy. Cesarean section was performed in 29. gestotic week followed immediately by right radical nephrectomy. PMID- 24757537 TI - A spontaneous paraganglioma-pheochromocytoma syndrome. AB - We present a case of a 40-year old woman diagnosed with a four-place spontaneous paraganglioma-pheochromocytoma syndrome, which was treated surgically. The presence of the succinate dehydrogenase complex subunit D (SDHD) mutation that causes the pheochromocytoma was confirmed but no mutations in the family members were found. After the excision of the paragangliomas located in the areas of the division of carotid arteries, and mediastinum, as well as a tumor on the left site of the celiac trunk, the patient remains asymptomatic and is regularly followed-up. PMID- 24757538 TI - Approach to kidney stones associated with ureteropelvic junction obstruction during laparoscopic pyeloplasty. AB - INTRODUCTION: We have performed laparoscopic pyeloplasty (LP) in our department since 2004. Our goal is to describe, step by step, the approach of kidney stones during transperitoneal laparoscopic pyeloplasty and the outcomes after the procedure. MATERIAL AND METHODS: Twelve patients with kidney stones treated by transperitoneal laparoscopic pyeloplasty were found. The hospital records with clinical features, supplementary tests, and imaging studies were reviewed for demographic, procedural, and efficacy data. RESULTS: Kidney stones were found in 12 of 62 patients (19%) who had undergone transperitoneal laparoscopic pyeloplasty. Eight cases were treated using a flexible cystoscope and a nitinol N Circle basket; in the remaining four cases the stones were extracted using laparoscopic grasping instruments. We want to emphasize a case of horseshoe kidney associated with ureteropelvic junction (UPJ) obstruction and a kidney stone in which the procedure was performed successfully. CONCLUSIONS: Laparoscopic pyeloplasty has now emerged as a standard approach to UPJ obstruction. Associated renal abnormalities or kidney stones add complexity to the procedure, however, as shown in our results, centers with experience in the laparoscopic approach of reconstructive urology make this technique feasible. PMID- 24757539 TI - Laparoscopic pyeloplasty with concomitant pyelolithotomy - too much of a good thing? PMID- 24757540 TI - The evolution of the treatment of urinary stone disease. PMID- 24757541 TI - Choice of surgical access for retroperitoneoscopic ureterolithotomy according to the results of 3D reconstruction of operational zone agreed with the patient: initial experience. AB - INTRODUCTION: For the procedure retroperitoneoscopic ureterolithotomy, the problems of access choice and thus visualization with utilizing minimally invasive surgical access (either with gasless single port method or gas insufflation) are solved. The decisions are based on the method of presurgery planning, grounded on matching the patient with a 3D model of the zone of surgical interest reconstructed according to the results of tomographic examination. MATERIAL AND METHODS: We used a hardware-software complex (HSC) for virtual modeling of the surgery zone and choosing the optimum points for minimally invasive surgical access. The HSC was recruited to choose optimum surgical access, realize presurgery planning, and estimation of the safety of the way of access chosen. The original method of matching the system of coordinates of a virtual model with the patient was offered. RESULTS: 12 patients with the calculus in the upper part of ureter averaging 11.5 (9-14) mm in size underwent gasless retroperitoneoscopic ureterolithotomy with use of the HSC. Mean age of the patients was 36.4 (25-49) years old. The surgeries lasted an average of 35.5 (25-40) minutes. Blood loss was averaged at 55.0 (30-90) ml. Healing by first intention was registered with all the patients. The mean hospitalization time was 6.0 (4-7) days. There were neither any complications nor difficulties, nor conversions from incorrectly chosen surgical access. CONCLUSIONS: The choice of the optimum surgical access according to the results of a virtual 3D model of the operation zone, matching the system of coordinates of the model with patient concurrence, and presurgery planning, was effective in cases of gasless single port and with gas insufflation retroperitoneoscopic ureterolithotomy. PMID- 24757542 TI - Virtual guidance of urologic surgery. PMID- 24757543 TI - Do we really always need gimmicks? PMID- 24757545 TI - URS versus ESWL: another contribution to the never-ending debate. PMID- 24757544 TI - Management of lower ureteric stones: a prospective study. AB - OBJECTIVE: To discuss the current concepts in lower ureteric stone management. MATERIAL AND METHODS: Between October 2008 and November 2010, 190 patients of both sexes and of different age groups with lower ureteric stones, underwent in situ extracorporeal shock wave lithotripsy (ESWL) (48 cases), ureterorenoscopy (URS) (120 cases) and open stone surgery (OSS) (22 cases). The patients' clinical and radiological findings, as well as stone characteristics, were reviewed and correlated with the stone-free status. RESULTS: In the ESWL group, the operative time was 43.13 +22.5 min; the average number of sessions/patients was 1.5 sessions; the average number of SW/patients was 4500 SW/patients; the average energy was 16.5 kV; the average stone burden was 7.8/mm; the overall stone-free rate was 75% (36/48); and the average radiation exposure time was 3.5 min. In the URS group, the operative time was 49.21 +16.09 min; the average stone burden was 10.81mm; the overall stone-free rate was 97.5% (117/120); the average hospital stay was 3.99 days; and the average radiation exposure time was 0.75 min. In the OSS group, the operative time was 112.38 +37.1 min; the overall stone-free rate was 100% (22/22); and the average hospital stay was 9.74 days. CONCLUSION: In the management of patients with lower ureteral stones, URS, SWL and OSS were considered acceptable treatment options. This recommendation was based on the stone-free results, morbidity and retreatment rates for each therapy. PMID- 24757546 TI - Large impacted distal ureteric stones are treated better by URS: putting priorities. PMID- 24757547 TI - Psychotropics and sexual dysfunction. AB - INTRODUCTION: Sexual dysfunction (SD) is common in patients taking antipsychotics, and is the most bothersome symptom and adverse drug effect compromising treatment compliance. Mechanisms involved in psychotropics-induced SD are either largely unknown or poorly understood. The aim of this review is to present an updated analysis of SD associated with the use of psychotropic drugs in psychiatric patients. RESULTS: Contemporary evidence from available studies demonstrates that SD rates are drug-related rather than drug-class specific, and that these rates vary widely. Mechanisms involved in psychotropics-induced SD are either largely unknown or poorly understood. Our understanding of psychotropics induced SD is limited by the inability to differentiate whether these effects are really drug-induced or due to different inclusion criteria. CONCLUSIONS: Rigorous research, basic and clinical, is needed to understand the exact incidence, severity and mechanisms involved in the development of SD induced by various psychotropic treatment regimens. PMID- 24757548 TI - Disturbances of trace element metabolism in ESRD patients receiving hemodialysis and hemodiafiltration. AB - INTRODUCTION: Accumulation of trace elements occurs in conditions of decreased kidney function. In some conditions, increased trace elements can have toxic features. On the other hand, studies are showing that concentration of some trace elements could be decreased in ERSD patients as well. The most important factor affecting trace element concentration in ERSD patients is the degree of renal failure and the usage of replacement therapy. MATERIALS AND METHODS: We analyzed the trace elements' (boron, aluminum, vanadium, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, rubidium, strontium, cadmium, cesium, barium and lead) concentration in the whole blood of 41 ESRD patients who were treated with hemodialysis and hemodiafiltration and also of 61 healthy blood donors. In addition, comparison of trace element blood levels of patients receiving hemodialysis and hemofiltration was carried out. Whole blood trace element concentration was determined using inductive coupled plasma mass spectrometry (ICPMS). RESULTS: Levels of boron, aluminum, vanadium, chromium, manganese, zinc, strontium, cadmium, barium and lead were significantly increased in ESRD patients. Significantly decreased levels were observed for nickel, arsenic, selenium and rubidium. Blood levels of cobalt, copper, cadmium and lead in hemodialysis patients were significantly higher compared to patients receiving hemodiafiltration. CONCLUSIONS: ESRD is accompanied with serious and multidirectional changes of trace element blood levels. The highest degree of blood level increases were observed for nonessential and toxic trace elements. Disorders of essential trace elements were manifested in a minor degree. Besides this, there were observed differences of trace element concentrations between ESRD patients receiving hemodialysis and hemo-diafiltration. PMID- 24757549 TI - Experiences with the management of paraurethral cysts in adult women. AB - INTRODUCTION: Paraurethral cysts may be acquired or congenital pathology, and are rarely encountered in urogynecologic practice. Therefore, no consensus on management of paraurethral cyst could be reached. We aimed to report our experience on the management of paraurethral cysts in adult women. MATERIAL AND METHODS: A retrospective chart review was conducted on adult women diagnosed with paraurethral cysts between 2011 and 2012. Patients' complaints, parity, physical signs, diagnostic tests and the obtained findings, surgical intervention, duration of follow-up period, complications, recurrence and histologic examination of the cysts wall were evaluated in the patients included. RESULTS: Ten adult women, aged 23-48 years (mean: 41 years) with paraurethral cysts between 2011 and 2012 were identified. All patients were multiparous. The patients' complaints included palpable mass, dyspareunia, and dysuria. All patients underwent preoperative urethrocystoscopy. All the cysts were solitary and in dimension of 1 to 3.5 cm and localized in the distal urethra. All patients underwent surgical excision. The mean follow-up period was 8 months (range: 6-12 months). Neither complications nor recurrences were observed. Histopathological examination showed that 5 cysts were lined with squamous epithelium, 2 were lined with transitional epithelium, and 3 were lined with both types of epithelium. CONCLUSIONS: Paraurethral cysts may be symptomatic and routine urological examinations are sufficient for diagnosis without using advanced imaging technique. In such symptomatic adult patients, partial surgical resection combined with fulguration can be performed effectively without complications. This treatment modality seems exceptional according to the literature. PMID- 24757551 TI - Salvage procedures in reconstructive urology. PMID- 24757550 TI - Continent ileovesicostomy after bladder neck closure as salvage procedure for intractable incontinence. AB - INTRODUCTION: We evaluated the success rate of continent vesicostomy using an ileal segment with seroserosally embedded, tapered ileum for bladder augmentation with continent stoma following bladder neck closure (BNC) for severely damaged bladders or persistent urinary incontinence. MATERIAL AND METHODS: A total of 15 patients were treated for persistent urinary incontinence or non-reconstructible bladder outlet between 2003 and 2012. Underlying diagnosis included post prostatectomy incontinence (n = 5), recurrent bladder neck stenosis (n = 5), neurogenic bladder (n = 3), urethral tumor recurrence following orthotopic neobladder (n = 1) and post-TVT and colposuspension incontinence (n = 1). All patients underwent open BNC, omental interposition and continent vesicoileostomy. The continent outlet was placed in the lower abdomen using a circumferential subcutaneous and skin plasty to avoid retraction. Data collected included age, underlying diagnosis, stoma site, time to complications and need for subsequent surgical revisions. All patients received a standardized questionnaire at the time of data acquisition and were personally interviewed. RESULTS: Median follow up was 24 months (range: 2-111). Primary BNC was successful in all patients and primary continence rate was 86.7%. Two patients (13.3%) suffered from failure of the continence mechanism, caused by stoma stenosis at skin level and insufficiency of the bladder augmentation and stoma due to local infection. One additional patient developed a mild stomal incontinence without need for further reconstruction. Regardless of the number of revisions, at the last follow-up 93.3% of patients had a functional channel. All complications occurred within the first postoperative year. CONCLUSIONS: This technique is an effective last resort treatment for patients with non-reconstructible bladder outlet. PMID- 24757552 TI - Bougie urethral dilators: revival or survival? AB - OBJECTIVES: To present our center's experience in managing bladder outlet obstruction (BOO) conditions using bougie dilators. We described the dilation technique methodically for teaching purpose. PATIENTS AND METHOD: Retrospectively, a total of 196 medical records over the last four years denoting BOO conditions in men, women, and children were retrieved for analysis. Data reviewed for common complications was namely: perforation, recurrence, urinary tract obstruction (UTI) and inability to overcome the obstruction. RESULTS: Among the 196 analyzed cases, 24 (12.2%) cases were cured, whereas 172 (87.8%) cases reported complications. Within the complicated cases analyzed, 134 (68.4%) cases had recurrent obstructions, 13 (6.6%) cases had perforations, 6 (3.0%) cases developed UTI, while in 19 (9.7%) cases, we failed to pass the obstruction. CONCLUSIONS: In our center where urethral dilation technique has revived four years ago, it turned back to be the standard choice in managing BOO cases. We propose the technique to Urology training program directors, all over the world, to teach it as a compulsory skill for junior urologists to master. PMID- 24757553 TI - The initial treatment of urethral strictures: simple dilatation or urethrotomy?: "Bougie urethral dilators: revival or survival?" - pros. PMID- 24757554 TI - "Bougie urethral dilators: revival or survival?" - cons. PMID- 24757555 TI - Foreign body in the kidney: an unusual case and its management. AB - Encountering a foreign body (FB) in the kidney is uncommon. Most of the time a FB is introduced externally (violence or accident) or through endourological interventions. An ingested FB reaching the kidneys is extremely rare. This article includes an interesting case of FB, which apparently reached the kidney through the gastrointestinal tract as well as a brief review of the relevant literature. The case was successfully managed laparoscopically. PMID- 24757556 TI - Significance of urinary proteome pattern in renal allograft recipients. AB - Urinary proteomics is developing as a platform of urinary biomarkers of immense potential in recent years. The definition of urinary proteome in the context of renal allograft and characterization of different proteome patterns in various graft dysfunctions have led to the development of a distinct science of this noninvasive tool. Substantial numbers of studies have shown that different renal allograft disease states, both acute and chronic, could portray unique urinary proteome pattern enabling early diagnosis of graft dysfunction and proper manipulation of immunosuppressive strategy that could impact graft prognosis. The methodology of the urinary proteome is nonetheless not more complex than that of other sophisticated assays of conventional urinary protein analysis. Moreover, the need for a centralized database is also felt by the researchers as more and more studies have been presenting their results from different corners and as systems of organizing these newly emerging data being developed at international and national levels. In this context concept of urinary proteomics in renal allograft recipients would be of significant importance in clinical transplantation. PMID- 24757557 TI - Linguatula serrata (Porocephalida: Linguatulidae) Infection among Client-Owned Dogs in Jalingo, North Eastern Nigeria: Prevalence and Public Health Implications. AB - Pentastomiasis is a parasitic zoonosis endemic to western and central Africa. This study was undertaken to determine the prevalence and public health implications of Linguatulosis in client-owned dogs in Jalingo, North Eastern Nigeria. Seven hundred and seventy seven (777) dogs brought for treatment at the hospital were subjected to buccal (sublingual) examination for pentastomiasis. Parameters such as age, sex, and breeds were determined. Also, the months of the year were taken into consideration. An overall prevalence of 37.45% was recorded. Of the 477 dogs examined in 2010, 184 were positive representing prevalence of 38.57% and in 2011 107 were positive representing prevalence of 35.67%. The infection was higher in the male than in the female which does not differ significantly (P > 0.05). There was no significant difference between sexes (P > 0.05). However, significant difference (P < 0.05) was observed between breeds and age of dogs examined. Season did not have much influence on the prevalence of Linguatulosis. The high prevalence of Linguatulosis in dogs and other animals found in this study highlights the need of improving preventative measures to reduce the rate of infection, which may pose a hazard to human health. PMID- 24757558 TI - Partial Purification of Integral Membrane Antigenic Proteins from Trypanosoma evansi That Display Immunological Cross-Reactivity with Trypanosoma vivax. AB - Trypanosoma evansi and Trypanosoma vivax, which are the major causative agents of animal trypanosomosis in Venezuela, have shown a very high immunological cross reactivity. Since the production of T. vivax antigens is a limiting factor as this parasite is difficult to propagate in experimental animal models, our goal has been to identify and isolate antigens from T. evansi that cross-react with T. vivax. Here, we used the Venezuelan T. evansi TEVA1 isolate to prepare the total parasite lysate and its corresponding cytosolic and membranous fractions. In order to extract the T. evansi integral membrane proteins, the particulate portion was further extracted first with Triton X-100, and then with sodium dodecyl sulfate. After discarding the cytosolic and Triton X-100 solubilized proteins, we employed sedimentation by centrifugation on linear sucrose gradients to partially purify the sodium dodecyl sulfate-solubilized proteins from the Triton X-100 resistant particulate fraction of T. evansi. We obtained enriched pools containing polypeptide bands with apparent molecular masses of 27 kDa, 31 kDa, and 53 kDa, which were recognized by anti-T. vivax antibodies from experimentally and naturally infected bovines. PMID- 24757559 TI - Gender and ocular manifestations of connective tissue diseases and systemic vasculitides. AB - Ocular manifestations are present in many connective tissue diseases which are characterized by an immune system that is directed against self. In this paper, we review the ocular findings in various connective tissue diseases and systemic vasculitides and highlight gender differences in each disease. In rheumatoid arthritis, we find that dry eyes affect women nine times more than men. The other extra-articular manifestations of rheumatoid arthritis affect women three times more commonly than men. Systemic lupus erythematosus can involve all ocular structures and women are nine times more affected than men. Systemic sclerosis is a rare disease but, again, it is more common in women with a female to male ratio of 8 : 1. Polymyositis and dermatomyositis also affect women more commonly than men but no gender differences have been found in the incidence or disease course in the systemic vasculitides associated with antineutrophil cytoplasmic antibody such as granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis). Finally, Behcet's disease is more common in males, and male gender is a risk factor for Behcet's disease. There is a slight female preponderance in sarcoidosis with female gender carrying a worse prognosis in the outcome of ocular disease. PMID- 24757560 TI - Chronic Electromagnetic Exposure at Occupational Safety Level Does Not Affect the Metabolic Profile nor Cornea Healing after LASIK Surgery. AB - LASIK eye surgery has become a very common practice for myopic people, especially those in the military. Sometimes undertaken by people who need to keep a specific medical aptitude, this surgery could be performed in secret from the hierarchy and from the institute medical staff. However, even though the eyes have been previously described as one of the most sensitive organs to electromagnetic fields in the human body, no data exist on the potential deleterious effects of electromagnetic fields on the healing eye. The consequences of chronic long lasting radar exposures at power density, in accordance with the occupational safety standards (9.71 GHz, 50 W/m(2)), were investigated on cornea healing. The metabolic and clinical statuses after experimental LASIK keratotomy were assessed on the different eye segments in a New Zealand rabbit model. The analysis methods were performed after 5 months of exposure (1 hour/day, 3 times/week). Neither clinical or histological examinations, nor experimental data, such as light scattering, (1)H-NMR HRMAS metabolomics, (13)C-NMR spectra of lipidic extracts, and antioxidant status, evidenced significant modifications. It was concluded that withdrawing the medical aptitude of people working in electromagnetic field environments (i.e., radar operators in the navy) after eye surgery was not justified. PMID- 24757561 TI - Prevalence and trends of obesity and association with socioeconomic status in Thai adults: National Health Examination Surveys, 1991-2009. AB - We determined the prevalence of obesity in Thai adults aged 20 and over in 2009 and examined trends of body mass index (BMI) between 1991 and 2009. Data from Thai National Health Examination Survey for 19,181 adults in 2009 and 64,480 adults between 1991 and 2004 were used to calculate age-adjusted mean and prevalence. Logistic regression was used to examine the association of obesity with education level. In 2009, age-adjusted prevalence of obesity classes I (BMI 25-29.9 kg/m(2)) and II (BMI >=30 kg/m(2)) in Thai adults aged >=20 years were 26.0% and 9.0%, respectively. Compared with primary education, the odds of obesity class I were highest in men with university education. For women, the odds of obesity classes I and II were highest in those with primary education. BMI significantly increased from 21.6 kg/m(2) in men and 22.8 kg/m(2) in women in 1991 to 23.3 kg/m(2) and 24.4 kg/m(2) in 2009, respectively. The average BMI increases per decade were highest in men with secondary education (1.0 kg/m(2), P < 0.001) and in women with primary education with the same rate. There were increasing trends in BMI with slight variation by SES groups in Thai men and women during 1991-2009. PMID- 24757563 TI - A review of advance care planning programs in long-term care homes: are they dementia friendly? AB - Background. Persons living with dementia in the long-term care home (LTCH) setting have a number of unique needs, including those related to planning for their futures. It is therefore important to understand the advance care planning (ACP) programs that have been developed and their impact in order for LTCH settings to select a program that best suits residents' needs. Methods. Four electronic databases were searched from 1990 to 2013, for studies that evaluated the impact of advance care planning programs implemented in the LTCH setting. Studies were critically reviewed according to rigour, impact, and the consideration of the values of residents with dementia and their family members according to the Dementia Policy Lens Toolkit. Results and Conclusion. Six ACP programs were included in the review, five of which could be considered more "dementia friendly." The programs indicated a variety of positive impacts in the planning and provision of end-of-life care for residents and their family members, most notably, increased ACP discussion and documentation. In moving forward, it will be important to evaluate the incorporation of residents with dementia's values when designing or implementing ACP interventions in the LTCH settings. PMID- 24757562 TI - The aetiology of delay to commencement of adjuvant chemotherapy following colorectal resection. AB - PURPOSE: Timely administration of adjuvant chemotherapy following colorectal resection is associated with improved outcome. We aim to assess the factors which are associated with delay to adjuvant chemotherapy in patients who underwent colorectal resection as part of an enhanced recovery protocol. METHOD: A univariate and multivariate analysis of patient data collected as part of a prospectively maintained database of colorectal cancer patients between 2007 and 2012. RESULTS: 166 patients underwent colorectal resection followed by adjuvant chemotherapy. Median postoperative hospital stay was 6 days, and time to commencement of adjuvant chemotherapy was 50 days. Longer inpatient stay correlated with increased time to adjuvant chemotherapy (P = 0.05). Factors found to be independently associated with duration of hospital stay and time to commencement of adjuvant chemotherapy included stoma formation (P = 0.032), anastaomotic leak (P = 0.027), and preoperative albumin (P = 0.027). The use of laparoscopic surgery was associated with shorter time to adjuvant chemotherapy but did not reach significance (P = 0.143). CONCLUSION: A number of independent variables associated with delay to adjuvant therapy previously not described have been identified. Further work may be required to elucidate the effect that these variables have on long-term outcome. PMID- 24757564 TI - Early trends in cystatin C and outcomes in patients with cirrhosis and acute kidney injury. AB - Background. Acute kidney injury (AKI) is a common and severe complication in patients with cirrhosis. Progression of AKI to a higher stage associates with increased mortality. Intervening early in AKI when renal dysfunction is worsening may improve outcomes. However, serum creatinine correlates poorly with glomerular filtration in patients with cirrhosis and fluctuations may mask progression early in the course of AKI. Cystatin C, a low-molecular-weight cysteine proteinase inhibitor, is a potentially more accurate marker of glomerular filtration. Methods. We conducted a prospective multicenter study in patients with cirrhosis comparing changes in cystatin and creatinine immediately following onset of AKI as predictors of a composite endpoint of dialysis or mortality. Results. Of 106 patients, 37 (35%) met the endpoint. Cystatin demonstrated less variability between samples than creatinine. Patients were stratified into four groups reflecting changes in creatinine and cystatin: both unchanged or decreased 38 (36%) (Scr-/CysC-); only cystatin increased 25 (24%) (Scr-/CysC+); only creatinine increased 15 (14%) (Scr+/CysC-); and both increased 28 (26%) (Scr+/CysC+). With Scr-/CysC- as the reference, in both instances where cystatin rose, Scr-/CysC+ and Scr+/CysC+, the primary outcome was significantly more frequent in multivariate analysis, P = 0.02 and 0.03, respectively. However, when only creatinine rose, outcomes were similar to the reference group. Conclusions. Changes in cystatin levels early in AKI are more closely associated with eventual dialysis or mortality than creatinine and may allow more rapid identification of patients at risk for adverse outcomes. PMID- 24757566 TI - Reliability of the Function in Sitting Test (FIST). AB - The function in sitting test (FIST) is a newly developed, performance-based measure examining deficits in seated postural control. The FIST has been shown to be internally consistent and valid in persons with neurological dysfunction but intra- and interrater reliability and test-retest reliability have not been previously described. Seven patients with chronic neurologic dysfunction were tested and videotaped performing the FIST on two consecutive days. Seventeen acute care and inpatient rehabilitation physical therapist raters scored six of the videotaped performance of the FIST on two occasions at least 2 weeks apart. Intraclass correlation coefficients were used to calculate the test-retest and intra- and interrater reliability of the FIST. ICC of 0.97 (95% CI 0.847-0.995) indicated excellent test-retest reliability of the FIST. Intra- and interrater reliability was also excellent with ICCs of 0.99 (95% CI 0.994-0.997) and 0.99 (95% CI 0.988-0.994), respectively. Physical therapists and other rehabilitation professionals can confidently use the FIST in a variety of clinical practice and research settings due to its favorable reliability characteristics. More studies are needed to describe the responsiveness and minimal clinically important level of change in FIST scores to further enhance clinical usefulness of this measure. PMID- 24757567 TI - Burden of Illness in Prostate Cancer Patients with a Low-to-Moderate Risk of Progression: A One-Year, Pan-European Observational Study. AB - Objective. To assess the impact of low-to-moderate risk prostate cancer on patients' quality of life (QoL) at diagnosis and within the first year of treatment. Subjects and Methods. Men (n = 672) aged 50-75 years with prostate cancer (Gleason score <=7, PSA <=20 ng/mL and clinical staging T1c-T2b) were enrolled in five European countries. Patients completed five questionnaires, including EORTC Quality of Life Questionnaire-Prostate Cancer 25 (QLQ-PR25) and EORTC Quality of Life Questionnaire-Cancer 30 (QLQ-C30). Questionnaires were completed at baseline, at 3 months and 12 months after starting treatment. The primary endpoint was the change in QLQ-PR25 urinary symptoms subscale score from baseline to the assessment at 3 months. Results. Mean (SD) age was 65.0 (5.7) years and 400 (66%) men had Gleason score <=6 prostate cancer. The most frequently used initial treatment was radical prostatectomy (71% of patients). QLQ-PR25 urinary symptoms subscale score was significantly increased at 3 months (P < 0.001), indicating that urinary symptoms worsened after treatment. The score was lower at 12 months than at 3 months, but it was still significantly higher than at baseline (P < 0.001). Hormonal treatment-related symptoms, sexual functioning, and sexual activity scores significantly worsened at 3 and 12 months (all P < 0.001). For the QLQ-C30 questionnaire, global health status/QoL score significantly decreased at month 3 but was not different from baseline by month 12. Scales for physical, role, and social functioning, and fatigue, showed significant deterioration at 3 and 12 months. Conclusions. Low-to-moderate risk prostate cancer may have a substantial effect on patients' QoL within one year following treatment. PMID- 24757568 TI - Fluoxetine dose and administration method differentially affect hippocampal plasticity in adult female rats. AB - Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat. PMID- 24757570 TI - Downregulated GABA and BDNF-TrkB pathway in chronic cyclothiazide seizure model. AB - Cyclothiazide (CTZ) has been reported to simultaneously enhance glutamate receptor excitation and inhibit GABAA receptor inhibition, and in turn it evokes epileptiform activities in hippocampal neurons. It has also been shown to acutely induce epileptic seizure behavior in freely moving rats. However, whether CTZ induced seizure rats could develop to have recurrent seizure still remains unknown. In the current study, we demonstrated that 46% of the CTZ induced seizure rats developed to have recurrent seizure behavior as well as epileptic EEG with a starting latency between 2 weeks and several months. In those chronic seizure rats 6 months after the seizure induction by the CTZ, our immunohistochemistry results showed that both GAD and GAT-1 were significantly decreased across CA1, CA3, and dentate gyrus area of the hippocampus studied. In addition, both BDNF and its receptor TrkB were also decreased in hippocampus of the chronic CTZ seizure rats. Our results indicate that CTZ induced seizure is capable of developing to have recurrent seizure, and the decreased GABA synthesis and transport as well as the impaired BDNF-TrkB signaling pathway may contribute to the development of the recurrent seizure. Thus, CTZ seizure rats may provide a novel animal model for epilepsy study and anticonvulsant drug testing in the future. PMID- 24757571 TI - Paraplegia after gastrectomy in a patient with cervical disc herniation: a case report and review of literature. AB - Paraplegia is a rare postoperative complication. We present a case of acute paraplegia after elective gastrectomy surgery because of cervical disc herniation. The 73-year-old man has the medical history of cervical spondylitis with only symptom of temporary pain in neck and shoulder. Although the patient's neck was cautiously preserved by using the Discopo, an acute paraplegia emerged at about 10 hours after the operation. Severe compression of the spinal cord by herniation of the C4-C5 cervical disc was diagnosed and emergency surgical decompression was performed immediately. Unfortunately the patient showed limited improvement in neurologic deficits even after 11 months. PMID- 24757565 TI - The role of suppressors of cytokine signalling in human neoplasms. AB - Suppressors of cytokine signalling 1-7 (SOCS1-7) and cytokine-inducible SH2 containing protein (CIS) are a group of intracellular proteins that are well known as JAK-STAT and several other signalling pathways negative feedback regulators. More recently several members have been identified as tumour suppressors and dysregulation of their biological roles in controlling cytokine and growth factor signalling may contribute to the development of many solid organ and haematological malignancies. This review explores their biological functions and their possible tumour suppressing role in human neoplasms. PMID- 24757572 TI - A case of carcinoid likely causing jejunal intussusception. AB - A 34-year-old female was admitted to Emergency Department with an abrupt onset of diffuse abdominal pain. A CT scan done prior to her transfer revealed significant dilated loops of bowel as well as multiple target signs with likely torsed bowel. The patient consented to an exploratory laparotomy. During surgery, the proximal jejunum was found to be intussuscepted, a rare finding in an adult. There was evidence of mesenteric foreshortening throughout the small bowel and multiple whitish lesions within the mesentery, both consistent with the desmoplastic response that is characteristic of carcinoid. The interest for this case report comes from the patient's surgical findings of jejunal intussusception as well as her extensive history, which includes a bowel resection with an ileocolic anastomosis for presumed ischemia and a carcinoid tumor in the stomach which had been removed endoscopically. PMID- 24757573 TI - Assessment of risk factors associated with malaria transmission in tubu village, northern botswana. AB - This study investigated potential risk factors associated with malaria transmission in Tubu village, Okavango subdistrict, a malaria endemic area in northern Botswana. Data was derived from a census questionnaire survey, participatory rural appraisal workshop, field observations, and mosquito surveys. History of malaria episodes was associated with several factors: household income (P < 0.05), late outdoor activities (OR = 7.016; CI = 1.786-27.559), time spent outdoors (P = 0.051), travel outside study area (OR = 2.70; CI = 1.004-7.260), nonpossession of insecticide treated nets (OR = 0.892; CI = 0.797-0.998), hut/house structure (OR = 11.781; CI = 3.868-35.885), and homestead location from water bodies (P < 0.05). No associations were established between history of malaria episodes and the following factors: being a farmer (P > 0.05) and number of nets possessed (P > 0.05). Eave size was not associated with mosquito bites (P > 0.05), frequency of mosquito bites (P > 0.05), and time of mosquito bites (P > 0.05). Possession of nets was very high (94.7%). Close proximity of a health facility and low vegetation cover were added advantages. Some of the identified risk factors are important for developing effective control and elimination strategies involving the community, with limited resources. PMID- 24757574 TI - A cytological study of palpable superficial nodules of parasitic origin: a study of 41 cases. AB - Background. Few parasitic infestations present as only superficial palpable subcutaneous or intramuscular nodule. The current study highlights the role of FNAC in the diagnosis of superficial palpable parasitic lesions. Methods. This was a retrospective study in which we reviewed the FNAC record of all patients over a period of two years from September 2011 to August 2013. During this period, FNA was performed on 5954 cases which presented as superficial palpable lump at various sites of body. There were 41 cases diagnosed as parasitic lesion or suspicious of parasitic lesion on cytology which were included in the study. Results. In the present study, most of the patients were children and young adults. The lesions were located over trunk in 18 (43.9%) cases, extremities in 12 (29.3%) cases, and head and neck region in 11 (26.8%) cases. Out of 41 cases, 27 (65.8%) cases were confirmed on cytology and/or histopathology as parasitic lesions, including 21 (51.2%) cases of cysticercosis, 5 (12.2%) cases of filariasis, and one (2.4%) case of hydatid cyst. Cytological findings of remaining cases were suggestive of parasitic lesion. Conclusion. Careful assessment of cytological material is helpful to detect parasite or inflammatory response to parasite even in asymptomatic patients. PMID- 24757575 TI - Functional Balance and Motor Impairment Correlations with Gait Parameters during Timed Up and Go Test across Three Attentional Loading Conditions in Stroke Survivors. AB - The aim of this study was to determine whether stroke survivor's gait performance during dual-task Timed Up and Go (TUG) test is correlated with the level of functional balance and motor impairment. Thirty stroke survivors (22 men, 8 women) were recruited for this study. The level of functional balance (Berg Balance Scale) and motor impairment (Fugl-Meyer assessment lower extremity) were assessed prior to the TUG test. TUG test was conducted under three attentional loading conditions (single, dual motor, and dual-cognitive). The time and number of steps were used to quantify gait parameters. The Spearmen's rank correlation coefficient was used to evaluate the relationship between these variables. There was moderate to strong negative correlation between functional balance and gait parameters (range -0.53 to -0.73, P < 0.05). There was a weak negative correlation observed between the time taken to complete the single task and motor impairment (r s = -0.43; P = 0.02) dual motor task and motor impairment (r s = 0.41; P = 0.02). However, there were no significant correlations between lower limb motor impairment and the number of steps in all conditions. These findings suggest that functional balance may be an influential domain of successful dual task TUG in stroke. PMID- 24757576 TI - Sit-to-Stand in People with Stroke: Effect of Lower Limb Constraint-Induced Movement Strategies. AB - Background. Weight-bearing asymmetry and impaired balance may contribute to the increased fall risk in people with stroke when rising to stand from sitting. Objective. This study investigated the effect of constraint-induced movement (CIM) strategies on weight-bearing symmetry and balance during sit-to-stand in people with stroke. Methods. A nonrandom convenience sample of fifteen people with stroke performed the sit-to-stand task using three CIM strategies including a solid or compliant (foam) block strategy, with the unaffected limb placed on the block, and an asymmetrical foot position strategy, with the unaffected limb placed ahead of the affected limb. Duration of the task, affected limb weight bearing, and centre of pressure and centre of mass displacement were measured in the frontal and sagittal plane. Results. Affected limb weight-bearing was increased and frontal plane centre of pressure and centre of mass moved toward the affected limb compared to baseline with all CIM strategies. Centre of mass displacement in the sagittal plane was greater with the compliant block and asymmetrical foot strategies. Conclusions. The CIM strategies demonstrated greater loading of the affected limb and movement of the centre of pressure and centre of mass toward the affected limb. The compliant block and asymmetrical foot conditions may challenge sagittal plane balance during sit-to-stand in people with stroke. PMID- 24757577 TI - Signalment and blood types in cats being evaluated as blood donors at two italian university blood banks. AB - Data from potential feline blood donors presented at two university blood banks in Italy were recorded. Blood typing was performed using an immunochromatographic method. Over the three years of the study 357 cats representing 15 breeds, 45.3% female and 54.7% male, with a mean age of 3.8 years were evaluated. Of these 90.5% were blood type A, 5.6% type B, and 3.9% type AB. The majority of the cats (54.6%) were European DSH (92.3% were type A, 5.1% type B, and 2.6% type AB), and 21% were Maine Coon (MCO) cats (100% blood type A). The estimated frequencies of transfusion reactions following an unmatched transfusion between DSH (donors and recipients), MCO (donor and recipients), DSH donors and MCO recipients, and MCO donors and DSH recipients were 4.8%, 0%, 0%, and 5.1% for major reactions and 7.2%, 0%, 7.7%, and 0% for minor transfusions reactions, respectively. In a population of blood donors that includes DSH and MCO the risk of transfusion reaction is between 5% and 8% if typing is not performed on donor and recipient blood. Blood typing should therefore be performed before transfusion to remove the risk of transfusion reactions due to blood type incompatibilities. PMID- 24757578 TI - Urinary Metabolomics on the Biochemical Profiles in Diet-Induced Hyperlipidemia Rat Using Ultraperformance Liquid Chromatography Coupled with Quadrupole Time-of Flight SYNAPT High-Definition Mass Spectrometry. AB - Ultraperformance liquid chromatography coupled with quadrupole time-of-flight synapt high-definition mass spectrometry metabolomics was used to characterize the urinary metabolic profiling of diet-induced hyperlipidaemia in a rat model. Analysis was done by orthogonal partial least squares discriminant analysis, correlation analysis, heat map analysis, and KEGG pathways analysis. Potential biomarkers were chosen by S-plot and were identified by accurate mass, isotopic pattern, and MS/MS fragments information. Significant differences in fatty acid, amino acid, nucleoside, and bile acid were observed, indicating the perturbations of fatty acid, amino acid, nucleoside, and bile acid metabolisms in diet-induced hyperlipidaemia rats. This study provides further insight into the metabolic profiling across a wide range of biochemical pathways in response to diet-induced hyperlipidaemia. PMID- 24757579 TI - Simultaneous Quantitative and Qualitative Analysis of Flavonoids from Ultraviolet B Radiation in Leaves and Roots of Scutellaria baicalensis Georgi Using LC-UV-ESI Q/TOF/MS. AB - Scutellaria baicalensis Georgi is one of the most widely used traditional Chinese herbal medicines. It has been used for anti-inflammatory, anticancer, antibacterial activities, and so forth. Long-term enhanced ultraviolet-B (UV-B) radiation caused more effect on leaves than on roots of the plant. Liquid chromatography-ultraviolet detection coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (LC-UV-ESI-Q/TOF/MS) method was applied for simultaneous quantitative and qualitative analysis of flavonoids in leaves and roots of S. baicalensis by enhanced UV-B radiation. Both low-intensity radiation and high-intensity radiation were not significantly increaseing the contents of baicalin, wogonoside, and wogonin in roots. However different intensity of radiation has different effects on several flavonoids in leaves. Both low-intensity radiation and high-intensity radiation had no significant effect on contents of baicalin and tectoridin in leaves; the content of scutellarin was significantly decreased by low-intensity radiation; chrysin was detected in low-intensity radiation and high-intensity radiation, and chrysin content is the highest in low-intensity radiation, but chrysin was not detected in control group. Different changes of different flavonoids under enhanced UV-B radiation indicate that induction on flavonoids is selective by enhanced UV-B radiation. PMID- 24757580 TI - Knowledge of, Perception of, and Attitude towards Uterine Fibroids among Women with Fibroids in Lagos, Nigeria. AB - Objectives. The study was to assess the level of knowledge of, perception of, and attitude towards uterine fibroids among women diagnosed with the condition. Methods. It is a cross-sectional descriptive study carried out among women diagnosed as having uterine fibroids in two gynaecological clinics in Lagos, Nigeria. Eligible women were recruited and a structured interviewer-administered questionnaire was used to collect the required information. Statistical analysis of data was done using EPI Info 2008. Results. Knowledge of fibroids was reported in 98.6% of the respondents and the information on uterine fibroids was obtained from radio, parents/relatives, health workers, and television in 29%, 27.3%, 18.7%, and 18.3%, respectively, by the respondents. Most of the women believed that being black, being nulliparous, or having positive family history predisposes women to having uterine fibroids. Up to 69.0% of the respondents believed that fibroid is a spiritual problem and many thought it requires spiritual healing. Fear of complications of surgery keeps most sufferers away from the hospital until fibroids become advanced or associated with complications. Conclusion. Awareness of uterine fibroids is high, but correct knowledge on aetiology and proper treatment is low. Intensive enlightenment of the populace using the mass media by trained personnel is recommended. PMID- 24757581 TI - Mechanistic Studies of Gold and Palladium Cooperative Dual-Catalytic Cross Coupling Systems. AB - Double-label crossover, modified-substrate, and catalyst comparison experiments in the gold and palladium dual-catalytic rearrangement/cross-coupling of allenoates were performed in order to probe the mechanism of this reaction. The results are consistent with a cooperative catalysis mechanism whereby 1) gold activates the substrate prior to oxidative addition by palladium, 2) gold acts as a carbophilic rather than oxophilic Lewis acid, 3) competing olefin isomerization is avoided, 4) gold participates beyond the first turnover and therefore does not serve simply to generate the active palladium catalyst, and 5) single-electron transfer is not involved. These experiments further demonstrate that the cooperativity of both gold and palladium in the reaction is essential because significantly lower to zero conversion is achieved with either metal alone in comparison studies that examined multiple potential gold, palladium, and silver catalysts and precatalysts. Notably, employment of the optimized cocatalysts, PPh3AuOTf and Pd2dba3, separately (i.e., only Au or only Pd) results in zero conversion to product at all monitored time points compared to quantitative conversion to product when both are present in cocatalytic reactions. PMID- 24757582 TI - Hemimasticatory spasm: report of a case and review of the literature?. AB - BACKGROUND: Hemimasticatory spasm is a very rare movement disorder characterized by unilateral, involuntary, paroxysmal contractions of the jaw-closing muscles, causing clinically brief twitches and/or spasms. CASE REPORT: A 62-year-old female consulted us with a 30-year history of unusual involuntary twitches in the preauricular region and spasms that hampered jaw opening. During these spasms, she could not open her mouth. On physical examination, we also observed hypertrophy of the masseter and temporalis muscles, which can be features of hemimasticatory spasm. She was treated with botulinum toxin type A, with excellent response. Here, we present her case and review the literature. DISCUSSION: Hemimasticatory spasm is a rare movement disorder. Given the excellent response to botulinum toxin type A treatment, it should be considered within the spectrum of facial spasms. PMID- 24757583 TI - Change in Non-motor Symptoms in Parkinson's Disease and Essential Tremor Patients: A One-year Follow-up Study. AB - BACKGROUND: Non-motor symptoms (NMS) in Parkinson's disease (PD) differ from those in essential tremor (ET), even before a definitive diagnosis is made. It is not clear whether patient's knowledge of the diagnosis and treatment influence their subsequent reporting of NMS. METHODS: 1 year after a clinical and instrumental diagnosis, we compared the motor impairment (Movement Disorders Society (MDS)-Unified Parkinson's Disease Rating Scale-III) and non-motor symptoms (NMSQuest) in PD (n = 31) and ET (n = 21) patients. RESULTS: PD patients reported more NMS than did the ET patients (p = 0.002). When compared to their baseline report, at follow-up, PD patients reported less nocturia (p = 0.02), sadness (p = 0.01), insomnia (p = 0.02), and restless legs (p = 0.04) and more nausea (p = 0.024), unexplained pain (p = 0.03), weight change (p = 0.009), and daytime sleepiness (p = 0.03). When compared to their baseline report, ET patients reported less loss of interest (p = 0.03), anxiety (p = 0.006), and insomnia (p = 0.02). Differences in reported weight change (p<0.0001) and anxiety (p = 0.001) between PD and ET patients were related to pharmacological side effects or to a reduction in the ET individuals. DISCUSSION: The reporting of NMS is influenced by subjective factors, and might vary with the patient's knowledge of the diagnosis or the effectiveness of treatment. PMID- 24757584 TI - Elucidating the nature and mechanism of tic improvement in tourette syndrome: a pilot study. AB - BACKGROUND: For unclear reasons, many Tourette syndrome (TS) children report near complete tic remission by young adulthood. Immature maturation of brain networks, observed with resting-state functional MRI (rs-fc-MRI) in adolescents and adults with TS, might evolve to a mature pattern in adults who experience tic improvement or remission. We explored the feasibility of testing this hypothesis in our population of young adult TS males, each with prior clinical assessments completed during childhood as part of a separate TS Association Genetics Consortium study. METHODS: A total of 10 TS males (off tic suppressing drugs for at least 6 months) aged 19-32 years, mean follow-up interval 7.5 (2 to 13) years, and 11 neurologically normal controls were enrolled and underwent 3-Tesla structural and rs-fc-MRI sequences. RESULTS: The mean change in Yale Global Tic Severity Scale (YGTSS) was -31.5% (total) and -26.6% (YGTSS motor+vocal). Two subjects reported resolution of tic-related disability, with drops from mean 45 to 16.5 (YGTSS-total) and 25 to 11.5 (YGTSS motor+vocal.). Rs-fc-MRI revealed significantly increased connectivity between the ipsilateral anterior and mid cingulate cortex and striatum, increased connectivity between local connections, and decreased connectivity between more distant connections; representing an immature connectivity pattern. DISCUSSION: Similar to previous reports, we found immature patterns of functional connectivity in adult TS subjects. Despite a lack of complete tic remission, two subjects exhibited dramatic drops in tic severity that correlated with tic-related disability improvement. More work is needed to elucidate the mechanism of such dramatic improvement in TS. PMID- 24757585 TI - Identifying Motor, Emotional-Behavioral, and Cognitive Deficits that Comprise the Triad of HD Symptoms from Patient, Caregiver, and Provider Perspectives. AB - BACKGROUND: The objective of this study was to identify important attributes associated with the triad of symptoms (cognition, emotional-behavioral, and motor) of Huntington's disease (HD) from patient, caregiver, and medical provider perspectives to facilitate development of a new disease-specific, health-related quality of life (HRQOL) instrument. METHODS: We conducted a targeted literature review of HD and HRQOL instruments, expert surveys, and patient and caregiver phone-based interviews to extract information on the symptoms and issues most relevant to the HD symptom triad (HD triad). The data collected from these sources were used to generate themes and subdomains and to develop an integrated schema that highlights the key dimensions of the triad. RESULTS: THE SEARCH IDENTIFIED THE FOLLOWING AREAS: emotional functioning/behavioral changes (e.g., positive emotions, sadness/depression); cognitive functioning (e.g., memory/learning, attention/comprehension); physical functioning (e.g., motor functioning, medication); social functioning (e.g., leisure, interpersonal relationships); end-of-life concerns/planning; and gene testing. Fifteen individuals diagnosed with HD and 16 HD caregivers, recruited from several Huntington's Disease Society of America support group networks, completed phone interviews. Nineteen US medical providers who specialize in HD completed the online survey. Twenty-six subdomains of the HD symptom triad (seven cognition, 12 emotional-behavioral, and seven motor) emerged relatively consistently across patient, caregiver, and provider samples. These included movements/chorea, memory impairment, depression, and anxiety. DISCUSSION: Based on an integrated, mixed methods approach, important HD triad symptom were identified and organized into a guiding schema. These patient-, caregiver-, and provider-triangulated data served as the basis for development of a HD-specific HRQOL instrument, the HD-PRO TRIADTM. PMID- 24757586 TI - DYT6 in Brazil: Genetic Assessment and Clinical Characteristics of Patients. AB - BACKGROUND: Several genes associated with dystonia have been identified. A mutation in one of these, THAP1 (DYT6), is linked to isolated dystonia. The aim of this study was to assess the prevalence of THAP1 gene mutations and the clinical characteristics of patients with these mutations in a clinical population in Brazil. METHODS: Seventy-four patients presenting with dystonia involving the cervical muscles and without mutations in the TOR1A (DYT1) gene or any other movement disorders were recruited at a movement disorders clinic between June 2008 and June 2009. All the patients underwent clinical examination and were screened for mutations of the THAP1 gene. RESULTS: Three patients had the novel p.Gln97Ter THAP1 nonsense mutation in heterozygosis. One of them had no family history of dystonia. Symptoms in this patient first appeared in his right arm, and the condition progressed to the generalized form. The other two patients belonged to the same family (cousins). Symptoms in the first patient started in her right arm at the age of 18 years and the condition progressed to the segmental form. The second patient, who carried the p.Arg169Gln missense mutation, developed dystonia in her left arm at the age of 6 years. The condition progressed to generalized dystonia. DISCUSSION: We conclude that THAP1 mutations are also a cause, albeit uncommon, of segmental and generalized dystonia in the Brazilian population. PMID- 24757587 TI - Focal Task-specific Dystonia-From Early Descriptions to a New, Modern Formulation. AB - BACKGROUND: Vivid descriptions of the phenomenology of focal task-specific dystonia (FTSD) date back to the late nineteenth century. METHODS: In this review, I summarize the natural history, phenomenology, and treatment of FTSD, focusing on nineteenth-century neurologists' descriptions of the phenomenology, etiology, treatment, and mechanism. RESULTS: Examining these texts through a twenty-first-century lens, the "modern" ideas of a dystonic endophenotype, disordered physiology, and dystonic metabolic networks actually appeared in these texts more than a century ago. DISCUSSION: By incorporating these ideas with recent investigations, I present a new conceptual model for understanding this mysterious malady. PMID- 24757588 TI - Regenerative Wound Healing: The Role of Interleukin-10. AB - Significance: Postnatal wounds heal with characteristic scar formation. In contrast, the mid-gestational fetus is capable of regenerative healing, which results in wound repair that is indistinguishable from uninjured skin. However, the underlying mechanisms of fetal regenerative phenotype are unknown. Recent Advances: The potent anti-inflammatory cytokine, interleukin-10 (IL-10), plays an essential role in the ability of the fetus to heal regeneratively and has been shown to recapitulate scarless healing in postnatal tissue. IL-10's ability to facilitate regenerative healing is likely a result of pleiotropic effects, through regulation of the inflammatory response, as well as novel roles as a regulator of the extracellular matrix, fibroblast cellular function, and endothelial progenitor cells. Overexpression of IL-10 using a variety of methods has been demonstrated to recapitulate the fetal regenerative phenotype in post natal tissue, in conjunction with promising results of Phase II clinical trials using recombinant IL-10. Critical Issues: Successful wound healing is a complex process that requires coordination of multiple growth factors, cell types, and extracellular cellular matrix components. IL-10 has been demonstrated to be critical in the fetus' intrinsic ability to heal without scars, and, further, can induce scarless healing in postnatal tissue. The mechanisms through which IL-10 facilitates this regeneration are likely the result of IL-10's pleiotropic effects. Efforts to develop IL-10 as an anti-scarring agent have demonstrated promising results. Future Directions: Further studies on the delivery, including dose, route, and timing, are required in order to successfully translate these promising findings from in vitro studies and animal models into clinical practice. IL-10 holds significant potential as an anti-scarring therapeutic. PMID- 24757589 TI - Targeting Inflammatory Cytokines and Extracellular Matrix Composition to Promote Wound Regeneration. AB - Significance: Delayed wound healing is one of the most challenging complications of several diseases, including diabetes. There is a vast interest in finding efficient treatments that promote scarless wound healing. The ability of the fetus to regenerate skin wounds after injury has generated much interest in the fetus as a model of regeneration. In this review, we evaluate the role and differential regulation of inflammation, extracellular matrix (ECM) composition, and mechanical stress in determining wound phenotype after injury. Recent Advances: Comparisons between postnatal and fetal wounds have revealed many differences in the healing process. Fetal skin wound healing is characterized by a reduced inflammatory response, an ECM rich in type III collagen and high molecular-weight hyaluronic acid (HMW-HA), and minimal mechanical stress. In contrast, adult wounds have a sustained inflammatory response, an ECM with increased type I collagen, and low-molecular-weight (LMW-HA) and are subject to significant mechanical load. Critical Issues: The differential regulation of these processes in the fetus compared with the adult plays a critical role in promoting regeneration in the fetus while resulting in scar formation in the adult. Future Directions: Understanding the significance of inflammation and biomechanical forces in wound healing may help in designing therapeutic strategies for the management of chronic nonhealing wounds. PMID- 24757591 TI - The Elusive Nature of Truth in Scientific Studies and the Importance of Peer Review. PMID- 24757590 TI - The Importance of Mast Cells in Dermal Scarring. AB - Significance: Mast cells are resident inflammatory cells present in high numbers in the skin. They are one of the first cell types to respond to damage and they do so by quickly releasing a variety of preformed mediators that are stored within mast cell granules. Mast cells are not only active early on, where they help induce inflammation, but they also stimulate the proliferation of several important cell types and influence the production and remodeling of collagen. Recent Advances: Recent studies have highlighted the importance of mast cells in determining the amount of scar tissue that forms as a result of the repair process. Mast cells are found in low numbers and in a less activated state in scarless wounds, whereas high numbers of activated mast cells are associated with scarring and fibrosis. Furthermore, animals that lack mast cells or have been treated with degranulation inhibitors or drugs that block the activity of mast cell proteases have been shown to heal with reduced scar tissue. Critical Issues: Despite evidence suggesting that mast cells regulate scar tissue development, the entire range of mast cell activities during wound repair and scar formation has not been completely characterized. In addition, the potential therapeutic benefits of targeting mast cells clinically have yet to be fully explored. Future Directions: More studies are needed to determine whether inhibiting mast cell activation and blocking the function of mast cell mediators are viable options to prevent or reduce the appearance of scars. PMID- 24757592 TI - Nonthermal Dielectric Barrier Discharge (DBD) Plasma Suppresses Herpes Simplex Virus Type 1 (HSV-1) Replication in Corneal Epithelium. AB - PURPOSE: Herpes keratitis (HK) is the leading cause of cornea-derived and infection-associated blindness in the developed world. Despite the availability of effective antivirals, some patients develop refractory disease, drug-resistant infection, and topical toxicity. A nonpharmaceutical treatment modality may offer a unique advantage in the management of such cases. This study investigated the antiviral effect of nonthermal dielectric barrier discharge (DBD) plasma, a partially ionized gas that can be applied to organic substances to produce various biological effects. METHODS: Human corneal epithelial cells and explanted corneas were infected with herpes simplex virus type 1 (HSV-1) and exposed to culture medium treated with nonthermal DBD plasma. The extent of infection was measured by plaque assay, quantitative PCR, and Western blot. Corneal toxicity assessment was performed with fluorescein staining, histologic examination, and 8 OHdG detection. RESULTS: Application of DBD plasma-treated medium to human corneal epithelial cells and explanted corneas produced a dose-dependent reduction of the cytopathic effect, viral genome replication, and the overall production of infectious viral progeny. Toxicity studies showed lack of detrimental effects in explanted human corneas. CONCLUSIONS: Nonthermal DBD plasma substantially suppresses corneal HSV-1 infection in vitro and ex vivo without causing pronounced toxicity. TRANSLATIONAL RELEVANCE: Nonthermal plasma is a versatile tool that holds great biomedical potential for ophthalmology, where it is being investigated for wound healing and sterilization and is already in use for ocular microsurgery. The anti-HSV-1 activity of DBD plasma demonstrated here could be directly translated to the clinic for use against drug resistant herpes keratitis. PMID- 24757594 TI - Erratum. AB - [This corrects the article on p. 2 in vol. 2.]. PMID- 24757593 TI - Intravitreal Injection of Normal Saline Induces Retinal Degeneration in the C57BL/6J Mouse. AB - PURPOSE: To investigate the adverse effect of intravitreal injection of normal saline (NS) and phosphate buffered saline (PBS) in mouse eyes. METHODS: NS or PBS was injected intravitreally into C57BL/6J mouse eyes. Retinal lesions were monitored by fundus imaging, spectral-domain optical coherence tomography (SD OCT), and histological investigations. Retinal immune gene expression was determined by real-time polymerase chain reaction (PCR). The toxic effect of NS and PBS or retinal protein from NS- or PBS-injected eyes on retinal pigment epithelium (RPE) was tested in B6-RPE-07 mouse RPE cell cultures. RESULTS: Intravitreal injection of NS dose-dependently induced localized retinal lesion in mice. Histological investigations revealed multiple vacuoles in photoreceptor outer segments and RPE cells. The lesions recovered over time and by 3 weeks post injection the majority of lesions vanished in eyes receiving 1 MUl NS. Inflammatory genes, including TNF-alpha, IL-1beta, IL-6, iNOS, and VEGF were upregulated in NS injected eyes. Intravitreal injection of PBS did not cause any pathology. The treatment of B6-RPE07 cells with 30% PBS or 30% NS did not affect RPE viability. However, incubation of 1-MUg/ml retinal protein from NS-injected eyes, but not PBS-injected eyes induced RPE cell death. CONCLUSION: NS is toxic to the C57BL/6J mouse retina and should not be used as a vehicle for intraocular injection. PBS is not toxic to the retina and is a preferred vehicle. TRANSLATIONAL RELEVANCE: NS is not a physiological solution for intraocular injection in the C57BL/6J mice and questions its suitability for intraocular injection in other species, including human. PMID- 24757595 TI - A comparative study of cardioprotective effect of three anesthetic agents by measuring serum level of troponin-T after coronary artery bypass grafting. AB - BACKGROUND: Cardiac surgery is associated with some degree of myocardial injury. Preconditioning first described in 1986 was pharmacologic and non- pharmacologic. Among the long list of anesthetic drugs, isoflurane as an inhaling agent along with midazolam and propofol as injectable substances have been documented to confer some preconditioning effects on myocardium. OBJECTIVES: In this study cardiac Troponin T (cTnT) ,as a reliable marker, was used for evaluating myocardial injury. METHODS: This prospective double blind study was comprised of 60 patients scheduled for CABG and were randomly assigned into three groups who received infusion of propofol or midazolam or isoflorane. Surgical procedures and anesthetics were similar for 3 groups. cTnT measured preoperatively and at 12, 24 and 36hr after arrival in ICU. RESULTS: There were no statistically significant differences in mean cTnT levels between three groups in the preoperative period and 12-24 hours after arrival in ICU. However, mean cTnT in 3 groups at 36 hours after arrival in ICU were different (P< 0.013) and cTnT level was significantly higher in midazolam group (P<0.001) and lowest in isoflurane group (P=0.002). CONCLUSION: There were significant differences on cTnT levels between anesthetic groups of isofluran, midazolam and propofol at 36 hr after surgery. Preconditioning effect of isoflurane was higher than the other two groups. PMID- 24757596 TI - Plausible impact of dietary habits on reduced blood sugar in diabetic opium addicts with coronary artery disease. AB - BACKGROUND: The effect of opium on glycemic control in diabetics is a controversial issue, as some studies have shown glucose lowering effect of opium in diabetes while the results of other studies do not support this idea. The possible role of opioid peptides in the regulation of food intake has been previously investigated. However, there is no data available about relationship between opium using and dietary pattern. OBJECTIVES: The aim of the present study was to determine the daily intake of different nutrients in opium addict with diabetes diagnosed with coronary artery disease (CAD). METHODS: This study comprised 232 consecutive diabetic patients with CAD, and candidates for isolated coronary artery bypass surgery in Tehran Heart Center. Of these, 26 patients were opium addicts. Nutritional assessment was obtained by a validated semi quantitative food frequency questionnaire (FFQ). RESULTS: In opium addicts compared to non-addicts, consumption of carbohydrates (360.0+/-120.9 versus 447.8+/-249.8 Gr/day, P=0.016) and vitamin A (1170.4+/-570.2 versus 1496.3+/ 889.6 MUg/d as Retinol Activity Equivalent (RAE), P=0.040) was lower than non addicts and intake of other nutrients were similar across two group of patients. CONCLUSIONS: Opium addiction in diabetic patients may lead to decrease of vitamin A and carbohydrate intake. This study showed that carbohydrate intake in addicted diabetic patients is lower than their non-addict counterpart. Thus, the so called lowering effect of opium on blood sugar may be due to nutritional habit of addicted patients. PMID- 24757598 TI - Relationship between Renal Artery Stenosis and Severity of Coronary Artery Disease in Patients with Coronary Atherosclerotic Disease. AB - OBJECTIVE: The aim of the present investigation was to explore probable association of renal artery stenosis (RAS) with coronary artery disease (CAD) and the prevalence of renal artery stenosis (RAS) in patients with CAD. PATIENTS AND METHODS: This study comprised 165 consecutive patients with CAD, including 52.7% males and 47.2% females with respective mean ages of 60.3 +/-8.9 and 59.5+/-10.1. The patients underwent simultaneous coronary and renal angiographies, and the lumen reduction of 50% or more was considered as significant stenosis. Indeed, stenosis of more than 70% of the arterial lumen was regarded as severe. RESULTS: According to our findings, the prevalence of renal artery stenosis in our hypertensive and normotensive patients were 46.2% and 19.5% respectively (p=0.002). Renal artery angiography revealed that 64 (38.8%) of the patients had simultaneous renal artery stenosis. RAS is more common in females than males (p=0.031). Multivariate analysis revealed that among all examined factors, hypertension and serum creatinine were associated with RAS. There was no correlations found between gensini score and RAS (p=0.63). CONCLUSION: We found a relatively high prevalence of RAS including 46.2% in hypertensive and 19.5% in normotensive patients in our patients with CAD. PMID- 24757597 TI - A Comparative Study of the Management of Stage 2 hypertension by Combined therapy with Losartan, Amlodipine and Hydrochlorothiazide. AB - BACKGROUND: The most effective and accurate treatment of hypertensive patients reduces cardiovascular events and improves the quality of life. OBJECTIVE: This study compared the efficacy and safety of combined (combination therapy) with an angiotensin-receptor blocker (ARB) a calcium-channel blocker (CCB) (Losartan / Amloidipine 50/10mg) vs maximal combination doses of ARB with hydrochlorothiazide (Losartan /HCTZ 100/25 mg) and maximal combination doses of CCB with HCTZ (Amlodipine /HCTZ 10/25 mg) in the management of stage 2 hypertension. METHODS: This randomized clinical trial (RTC) comprised 478 hypertensive patients with mean age 50.5+/-5.21 years, and took place between January 2010 and December 2011 in Vasei Hospital clinic in Sabzevar. Antihypertensive drugs were washed out after 5 days of discontinuation of drugs and the patients with mean blood pressure in sitting position >= 160 and <200 mmHg in systole and >= 100 and <110 mmHg in diastole were randomized into three groups: Losartan / Amlodipine 50/10 mg (n =164) , Losartan / HCTZ 100/25 mg (n =155) and Amlodipine / HCTZ 10/25 mg (n =159). The end point was reaching the blood pressure below 140/90 within 56 days of treatment in each group. RESULTS: There was a significant difference in systolic blood pressure reductions between treatment groups (P<0.001) and also there was a significant difference between groups in reducing diastolic blood pressure (P<0.01). The highest systolic and diastolic blood pressure reduction respectively was found in Amlodipine/losartane and losartane/HTCZ group. The ANCOVA analysis revealed that only treatment regimen had a significant effect (P=0.01) and other factor including Age, Gender, Diabetes Mellitus, Smoking and High serum cholesterol didn't have significant effect on blood pressure reduction. CONCLUSION: ARB/CCB combination therapy reduced blood pressure more effectively than the maximal doses of ARB or CCB with HCTZ in stage 2 hypertensive patients within this period of study. PMID- 24757599 TI - Suppression of Myocardial Injury Markers following Percutaneous Coronary Interventions by Pre-treatment with Carvedilol. AB - BACKGROUND: Retrospective studies and clinical trials have indicated that beta receptor blockers have an influential role in improving survival and reducing risk of recurrent infarction in patients with myocardial infarction. However, there is still controversy regarding the effects of beta-receptor blockers on the markers of myocardial infarction following percutaneous coronary interventions (PCI). OBJECTIVE: The aim of this study was to evaluate the pre-treatment effect of Carvedilol on markers of myocardial injury in patients undergoing elective PCI. METHOD AND MATERIALS: In this clinical trial patients undergoing elective PCI were categorized randomly in the Carvedilol group including 100 patients who received two doses of 12.5 mg, 6 and 12 hours prior to PCI, and the control group (105 patients). Blood samples were obtained to analyse cardiac biomarker, 12 and 24 hours after PCI. RESULTS: The clinical features were not significantly different between the two groups. A increase in the level of Troponin I was observed in the control group 24 hours following PCI (P=0.042), whereas this rise in troponin I was slight and insignificant in the Carvedilol group (P>0.05). some difference was observed between the two groups in regard to the level of CPK-MB after PCI (P=0.041). CONCLUSION: The findings of our study indicate that pre treatment with Carvedilol confers cardio-protection by limiting the rise of markers of myocardial injury following PCI. PMID- 24757600 TI - The prevalence of hypomagnesaemia in pediatric patients with mitral valve prolapse syndrome and the effect of mg therapy. AB - BACKGROUND: A paucity of data exists regarding the prevalence and relationship of hypomagnesaemia with clinical symptoms of mitral valve prolapse (MVP) in pediatric patients. OBJECTIVE: In this study we evaluated the prevalence of magnesium (Mg) deficiency in pediatric patients with MVP syndrome and attempted to clarify the effect of Mg therapy on alleviating their symptoms. METHODS: The present study was conducted from April 2010 to January 2012, and included 230 patients (90 males and 140 females) with symptoms of mitral valve prolapse and mean age of 11.6+/-3.66. Serum magnesium (Mg) level less than 1.5 mg/dl was defined as hypomagnesaemia. Patients with 2 mm leaflet displacement and maximum leaflet thickness of 5 mm in echocardiography were considered to have classic MVP, while those with leaflet thickness less than 5 mm were considered as non classic MVP. Patients with hypomagnesaemia were orally treated with 4.5 mg/kg/day Mg chloride for 5 weeks followed by re-evaluation of symptoms of chest pain, palpitation, fatigue and dyspnea. RESULTS: Hypomagnesaemia was found in 19 (8.2 %) of 230 patients with mitral valve prolapse. The re-evaluation of patients with Hypomagnesaemia after 5 weeks of Mg therapy, showed statistically significant relief of chest pain (P=0.01). However, no significant changes was detected in regard to palpitation (P=0.06), fatigue (P= 0.5) and dyspnea (P=0.99). CONCLUSION: This study revealed that the prevalence of hypomagnesaemia in pediatric patients with mitral valve prolapse is relatively low compared to adults, but treatment with oral Mg in patient with hypomagnesaemia decreases chest pain. PMID- 24757601 TI - Opium addiction as a novel predictor of atrial fibrillation after cardiac surgery. PMID- 24757602 TI - Live/Real Time Three-Dimensional Trans Esophageal Echocardiographic Findings in Amplatzer ASD Closure Devices in Adults. AB - Six female patients aged from 19 to 73 years, with ostium secundum atrial septal defect underwent closure procedure with Amplatzer septal occluder device. Three dimensional Echocardiography (3D-TEE) was done during the procedure or one day after the procedure. 3D-TEE provides incremental value over Two- dimensional trans-esophageal echocardiography in measuring Amplatzer septal occluder disc sizes and correlates well with manufacture device size. 3D-TEE will surely prove to increase the technical efficiency and it will become an important tool for the interventionists for periprocedural evaluation of device closures. PMID- 24757603 TI - A Study on the Relationship between Serum Beta 2-Microglobulin Levels, Underlying Chronic Kidney Disease, and Peripheral Arterial Disease in High-Vascular-Risk Patients. AB - BACKGROUND: Serum beta 2-microglobulin (B2M) levels have been found to be increased in patients with peripheral arterial disease (PAD), yet it is still unknown whether B2M correlates with PAD intensity. OBJECTIVES: We aim to evaluate the correlation between B2M and the ankle-brachial index (ABI) values in high vascular-risk patients. METHODS: This is a cross-sectional study of 63 high vascular-risk patients admitted to the Cardiology Department or evaluated as outpatients in the Internal Medicine Department of our institution. Patients were classified into two groups according to their ABI: patients without PAD (n = 44, ABI values between 0.9 and 1.4) and patients with PAD (n = 19, ABI values lower than 0.9 or higher than 1.4). We performed univariate and multivariate analysis based on a multiple linear regression model. RESULTS: Serum B2M levels were higher in patients with pathological ABI values than in those without PAD (2.36 +/- 1.13 vs. 1.80 +/- 0.65 mg/L; P<0.05). We found no correlation between B2M and ABI in our total population (r = -0.12) or in patients with PAD (r = -0.09; NS for both comparisons). Age, gender, arterial hypertension, estimated glomerular filtration rate (eGFR), uric acid, total cholesterol, and LDL-cholesterol correlated with B2M in the univariate analysis. In the final linear regression model, eGFR, uric acid and total cholesterol correlated independently with B2M (P<0.01). CONCLUSION: We found no correlation between B2M levels and ABI values in high-vascular-risk patients that could usefully help in the subsequent diagnosis of PAD. However, we observed a significant correlation between B2M and eGFR, even when renal function was only slightly impaired. PMID- 24757604 TI - Interventional Revascularization of Coronary Artery Lesions in Diabetic Patients; In-hospital and One Year Follow up. AB - BACKGROUND: Diabetes mellitus is a life threatening disease accompanied by several micro- and macro vascular complications. Several modalities are available for interventional revascularization of coronary artery lesions, but their efficacy in diabetic patients is studied only in few patients. MATERIALS AND METHOD: This study evaluated major in- hospital complications and clinical outcome after one year in 200 consecutive patients who underwent percutaneous Coronary Intervention from 2007 to 2009. RESULTS: Our findings showed comparable single and 2 vessel stenting, regarding major adverse cardiovascular event in diabetic and nondiabetic patients. In connection with long term and in hospital outcome, no statistically significant difference was found between one and two vessel stenting when drug eluting stent was used in diabetic patients. CONCLUSION: The use of drug eluting stent in single or two vessel disease of diabetic patients is technically satisfactory and clinically safe and can substitute for coronary artery bypass grafting. PMID- 24757605 TI - The viable mitral annular dynamics and left ventricular function after mitral valve repair by biological rings. AB - OBJECTIVE: Considering the importance of annular dynamics in the valvular and ventricular function, we sought to evaluate the effects of treated pericardial annuloplasty rings on mitral annular dynamics and left-ventricular (LV) function after mitral valve repair. The results were compared with the mitral annular dynamics and LV function in patients with rigid and flexible rings and also in those without any heart problems. MATERIALS AND METHODS: One hundred and thirty six consecutive patients with a myxomatous mitral valve and severe regurgitation were prospectively enrolled in this observational cohort study. The patients underwent comparable surgical mitral valve reconstruction; of these 100 received autologous pericardium rings (Group I), 20 were given flexible prosthetic rings (Group II), and 16 received rigid rings (Group III). Other repair modalities were also performed, depending on the involved segments. The patients were compared with 100 normal subjects in whom an evaluation of the coronary artery was not indicative of valvular or myocardial abnormalities (Group IV). At follow-up, LV systolic indices were assessed via two-dimensional echocardiography at rest and during dobutamine stress echocardiography. Mitral annular motion was examined through mitral annulus systolic excursion (MASE). Peak transmitral flow velocities (TMFV) and mitral valve area (MVA) were also evaluated by means of continuous-wave Doppler. RESULTS: A postoperative echocardiographic study showed significant mitral regurgitation (>=2+) in one patient in Group I, one patient in Group II, and none in Group III. None of the patients died. There was a noteworthy increase in TMFV with stress in all the groups, the increase being more considerable in the prosthetic ring groups (Group I from 1.10 +/- 0.08 to 1.36 +/- 0.13 m/s, Group II from 1.30 +/- 0.11 to 1.59 +/- 0.19 m/s, Group III from 1.33 +/- 0.09 to 1.69 +/- 0.21 m/s, and Group IV from 1.08 +/- 0.08 to 1.21 +/- 0.12 m/s). Recruitment of LVEF reserve during stress was observed in the pericardial ring and normal groups (Group I from 54.6+/-6.2 to 64.6+/-7.3%, P<0.005; and Group IV from 55.3 +/- 5.7 to 66 +/- 6.2%, P<0.05), but no significant changes were detected in the prosthetic ring groups (Group II from 50.4 +/- 5 to 55.0 +/- 5.1, and Group III from 51.1 +/- 6.6 to 53.8 +/- 4.7). There was a significant MASE increase in both of the studied longitudinal segments at rest and during stress in Groups I and IV compared with the prosthetic ring groups. There was no calcification of the pericardial rings. CONCLUSIONS: The use of treated autologous pericardium rings for mitral valve annuloplasty yields excellent mitral annular dynamics, preserves LV function during stress conditions, and leaves no echocardiographic signs of degeneration. PMID- 24757606 TI - The increasing rate of secondary amputation in popliteal arterial injury associated with multi-organ injuries and hypotension. AB - OBEJECTIVES: To study the role of hypotension and associated injuries in increasing the chances of secondary amputation in lower limb with vascular injuries. METHODS: This study was conducted in the Department of cardiovascular and thoracic surgery( CVTS ), Sher-i- Kashmir Institute of Medical Sciences, ( SKIMS ) Srinagar Kashmir India and comprised all patients sustaining vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height during the last five years. Following admission to our Department, the patients were divided into two groups. The first group with associated injuries was hemodynamically unstable during vascular repair or in post-operative period and the second group had no associated injuries and was hemodynamically stable during vascular repair and in post-operative period. RESULTS: During the past five years, 95 patients were operated for lower limb vascular injury in our department. Of these 25 patients had associated multi organ injuries and were hemodynamically unstable and needed intensive care monitoring after surgical intervention. Additionally, 10 patients died due to associated multiple organ injuries, 10 needed amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved. Seventy patients who had isolated limb vascular injuries with no associated injuries or hypotension were hemodynamically stable and were kept in low dependency unit after vascular repair. Only Four patients from this group needed amputation for thrombosis of the anastomosis. CONCLUSION: [corrected] Patients with shock and related injuries face significant rate of amputation. These patients whether with multi-organ injuries or isolated vascular injuries need judicious treatment for hypovolumic shock during surgical intervention and in post-operative period. PMID- 24757607 TI - Evaluation of asymptomatic peripheral arterial disease by ankle- brachial index in patients with concomitant coronary arterial disease. AB - BACKGROUND: Peripheral arterial disease is associated with adverse cardiovascular outcomes. As such, it is found that screening for peripheral arterial disease (PAD) improves risk assessment. Thus, intensive risk factor modification and medical treatment in these patients are necessary. OBJECTIVES: The purpose of this study was to determine the prevalence of asymptomatic peripheral arterial disease in patients with concomitant coronary arterial disease. METHODS: Asymptomatic peripheral arterial disease was investigated in 400 patients (60% males, 40% females, aged 59.7+/- 11.3) with a documented coronary arterial disease. RESULTS: Among patients with documented CAD, 12% had asymptomatic PAD with the ABI ratio of less than 0.9. CONCLUSIONS: It is advisable to screen for PAD not only as a disease but also as a risk assessment method for atherosclerosis. PMID- 24757608 TI - Right ventricular thrombus: a rare complication of ovarian hyperstimulation syndrome. AB - A 22 years old lady was admitted because of progressive dyspnea, severe abdominal protrusion and lower extremity edema. She had undergone ovarian hyperstimulation for primary infertility by Clomiphen and Human chorionic gonadotropin for 3 months. Abdominopelvic ultrasonography revealed bilateral enlarged multi cystic ovaries and massive ascites. Transesophageal echocardiography revealed a large thrombus in right ventrice apex. Spiral chest CT scan showed normal pulmonary vasculature with no evidence of pulmonary thromboembolism. Heparin was started and repeat echocardiographic study showed gradual disappearance of right ventricular thrombus. Human chorionic gonadotropin is the most important substance which leads to capillary leakage and fluid accumulation in third space. Fluid shift and hypovolemia may cause hypotension, hemoconcentration and formation of vascular thrombus. PMID- 24757609 TI - Neovascularization in left atrial myxoma. AB - ABSTRACT: We report a case with a left atrial mass who underwent coronary angiography to rule out coronary artery disease. Coronary angiography revealed an anomalous tortuous vascular structure originating from the left circumflex coronary artery to the left atrial tumor suggestive of neovascularization. Preoperative coronary angiography is useful for coronary artery evaluation and also provides additional information regarding the feeding vessel supplying the mass. PMID- 24757610 TI - A comparative study on the effect of amiodarone and metaprolol for prevention of arrythmias after open heart surgery. AB - OBJECTIVES: The aim of this study was to compare the effect of amiodarone and metaprolol in prevention of atrial fibrillation in patients, following open heart surgery. METHODS: This prospective study was carried out between May 2008 to Nov. 2010, and comprised a total of 50 patients with normal preoperative sinus rhythm undergoing open heart surgery using cardio pulmonary bypass. RESULTS: Mean age of patients was 47+2.7 years, of which 60% who developed atrial fibrillation aged from 51 to 60 years. Most patients (62%) were in NYHA Class III. Patients who received amiodarone showed significant improvement in LVEF compared to those treated with Metaprolol. Amiodarone treated group exhibited lesser incidence and short-lasting atrial fibrillation, lower ventricular rate, shorter hospitalization, and lesser cost of care than those in metaprolol group. CONCLUSIONS: The present study showed that amiodarone was more efficient in controlling post-operative atrial fibrillation as compared to metaprolol. However, a larger randomized controlled trial is needed to corroborate the result of this study. PMID- 24757611 TI - Short-term Changes in Aortic Regurgitation after Percutaneous Mitral Valvuloplasty. AB - OBJECTIVES: The aim of this study was to evaluate the short- term effects of percutaneous mitral valvuloplasty (PMV) on coexisting AR. METHODS: Clinical, echocardiographic and catheterization data from hospital records of a total of 327 patients with rheumatic mitral stenosis who underwent PMV at a tertiary centre were retrospectively reviewed and aortic regurgitation changes 48 hours post PMV was recorded. RESULTS: The study population consisted of 282 females and 45 males. Mean age at the time of intervention was 47.13+/-11 years. Before PMV, 142 (43.3%) patients had no AR, 124 (37.9%) had mild AR and 61 (18.7%) had moderate AR. There was no change in AR severity in post- PMV follow-up. AR progression after PMV and during the follow-up was not significant and there was no increase in the need for aortic valve replacement (AVR) procedures. CONCLUSIONS: Our findings indicated that a considerable number of patients with rheumatic mitral stenosis had concurrent AR. At the time of PMV concomitant AR does affect procedural success and is not associated with inferior outcomes. Patients with moderate degrees of AR remain good candidates for PMV. PMID- 24757612 TI - Effects of omega-3 polyunsaturated Fatty acids on heart function and oxidative stress biomarkers in pediatric patients with dilated cardiomyopathy. AB - OBJECTIVES: Dilated cardiomyopathy is the most prevalent type of cardiomyopathy in children, which results in congestive heart failure and causes significant morbidity and mortality. This study, aims to investigate the effect of supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFA) on heart function and oxidative stress biomarkers in these patients. METHODS: The present research was a case-control study on pediatric patients with dilated cardiomyopathy, who received n-3 PUFA and anti-failure therapy for 6 months (group 1, n = 6), or anti-failure therapy alone for 6 months (group 2, n = 6), as well as age matched normal individuals (group 3, n = 6), and evaluated the cardiac function and biomarkers of oxidative stress. RESULTS: Echocardiographic parameters, such as left ventricular ejection fraction, shortening fraction, tissue Doppler Ea and Aa waves of lateral annulus of tricuspid valve, and Ea and S wave of septum, were significantly improved in group 1 after n-3 PUFA compared to pre- treatment status, while they were not changed after treatment in group 2. Antioxidant enzymes, including catalase and glutathione peroxidase activities in erythrocytes were slightly decreased, while plasma 8-iso-prostaglandin F2alpha concentrations were somewhat increased in group 1 compared to groups 2 and 3, however these changes were not statistically significant. Total antioxidant capacity of plasma was similar in all 3 groups. CONCLUSIONS: The results indicate that some echocardiographic parameters were significantly improved in patients receiving omega-3 fish oil. However, omega-3 had no significant effect on oxidative stress biomarkers. PMID- 24757613 TI - Comparison of right anterolateral thorocotomy with standard median steronotomy for mitral valve replacement. AB - OBEJECTIVES: The objectives of this study were to compare and analyze the results of right anterolateral thoracotomy and median sternotomy approach for primary mitral valve replacement with reference to the exposure during Valve Replacement , length of surgical incision, mean cross clamp time, mean bypass time, intensive care unit (ICU) stay, hospitalization, overall comorbidity with sternotomy; sepsis, dehiscence, healing cosmetic issues and cost effectiveness. METHODS: The present study comprised 68 patients with rheumatic mitral valve disease who underwent mitral valve replacement in the Department ofCardiovascular and Thoracic Surgery at Sher-i-Kashmir Institute of Medical Sciences from September 2009 to August 2011. RESULTS: This study comprised 64 patients with 23 (35.9%) males and 41 (64.1%) females. Sternotomy group had 10 males (31.3%) and 22 females (68.7%). Thoracotomy group had 13 males (40.6%) and 19(59.4%) females. The length of incision between the two groups was statistically significant (P<0.0001). Mean incision length were 24.6+/-2.1 cm and 14.8+/-2.3 cm in sternotomy and thoracotomy respectively. Statistically significant difference regarding duration of ICU stay was found between the two groups (P<0.0001). Scar visibility was 100% in sternotomy and around 25% in thoracotomy( P<0.0001). CONCLUSIONS: Thoracotomy through a right anterolateral aspect was easy to perform while maintaining maximum security for the patients. Besides its satisfactory cosmetic result especially in female patients, this approach proved to have several advantages. It offers a better exposure to the mitral apparatus even in patients with small left, allowing easy mitral valve replacement which is apparent from the lower cross-clamp time in the test group. The invaluable advantage of the above- mentioned thoracotomy is total eradication of the risk of deep sternal infection. The shorter hospital stay and cost effectiveness of thoracotomy approach are additional relief to the family. PMID- 24757614 TI - The prognosis of primary percutaneous coronary intervention after one year clinical follow up. AB - OBJECTIVES: The aim of this study was to evaluate the clinical outcomes, one year after primary percutaneous coronary intervention(PCI). PATIENTS AND METHODS: From September 2009 to March 2012, primary PCI was performed on 70 cases, and the data relating to their catheterization were recorded. Peri-interventional treatment data included PCI with drug-eluting or bare-metal stent or balloon angioplasty alone. RESULTS: The mean age of the patients was 61.34+11.31 years, and 72.9% of them were males. The ratios of patients with diabetes, hypertension and, hyperlipidemia were 61.4%, 71.4%, and 52.9% respectively. In clinical follow-up, total incidence of death was 4.3%, with no death occurring during 30 days. However, 3 patients died after one-year, of which one patient (1.4%) had cardiac problem and the other 2 (2.9%) died because of non-cardiac reasons. Target vessel revascularization, reinfarction within 30 days, and mechanical complication or stroke were not found in any of the patients. Patients with hypertension (6%) and those with LAD ST-elevation myocardial infarction (5%) died after one year (P= 0.263 and P= 0.319 respectively). However, no mortality was reported in patients with RCA and LCX ST-elevation myocardial infarction. Of subjects with multivessel disease, 7% died after one-year (P= 0.161), but there was no reported mortality in those with single vessel disease. CONCLUSIONS: The prognosis was satisfactory in patients undergoing PCI after one year clinical follow up. PMID- 24757615 TI - Predictors of blood transfusion in patients undergoing coronary artery bypass grafting surgery. AB - OBJECTIVES: The aim of this retrospective study is to identify intraoperative patient's characteristics predicting the need for blood transfusion during CABG in our local cardiac surgical service. METHODS: This study included 1835 consecutive patients, 1311 males and 524 females with mean age 58.8+/-9.9 years, undergoing coronary artery bypass grafting. Risk factors detected by univariate study were entered in a multivariate logistic regression model of the relationship between preoperative variables and blood transfusion. RESULTS: Blood transfusion was used in 435 patients (29.9%). Univariate analysis identified hemoglobin, smoking, hypertension, sex, diabetes, BMI and use of cardiopulmonary bypass (CPB) as significant predictors. Multivariate analysis revealed hemoglobin (OR: 0.8; CI: 0.74-0.86; P<0.001), CPB use (OR: 12.2; CI: 8.2-18.1; P<0.001) and female gender (OR: 2.29; CI:1.72-3.04; P<0.001) as independent risk factors for blood transfusion. CONCLUSIONS: The predictors of RBC transfusion after isolated CABG were performing CPB, preoperative hemoglobin and female gender. These factors can be used as a clinical tool to preserve blood bank resources without increasing patient's risk. PMID- 24757616 TI - Cardiomyopathy due to nonsustained ventricular tachycardia originating from the aortic sinus cusp. AB - We report a case of idiopathic nonsustained ventricular tachycardia (VT) originating from the aortic sinus cusp referred for presyncope and LV dysfunction and frequent premature ventricular complex with no response to 3 months anti arrhythmic medication for heart failure and arrhythmia. She was then referred to us for frequent PVC's and runs of nonsustained VT. ECG recorded during the nonsustained VT showed a left bundle branch block pattern in the precordial leads and an inferior axis and early transition in precordial leads in V3-V4. QS morphology in lead V1 was noticed with notching on the downward deflection. Electrophysiologic study was conducted to map ventricular outflow tract as a classic method, although pace map failed to find any matched QRS with the spontaneous PVCs. The mapping of aortic cusps was also performed. The best potential was recorded in a region located at the commissure of left-right aortic cusps. A single radiofrequency energy was delivered which resulted in immediate elimination of PVCs. The patient was discharged the day after ablation without any PVC recorded on monitor. Left ventricular ejection fraction(LVEF) improved to normal level two months later. There was no PVC detected at serial holter monitoring. It seems logical not to overlook even an isolated or nonsustained ventricular arrhythmia considering the available and effective treatments such as ablation rather than congestive heart failure(CHF) therapy especially in a young patient. PMID- 24757617 TI - The treatment of heart failure-related symptoms with ivabradine in a case with peripartum cardiomyopathy. AB - ABSTRACT: Peripartum cardiomyopathy is a form of dilated cardiomyopathy that is defined as deterioration in cardiac function presenting typically between the last month of pregnancy and up to five months postpartum. As with other forms of dilated cardiomyopathy, PPCM involves systolic dysfunction of the heart with a decrease of the left ventricular ejection fraction with associated congestive heart failure. In heart failure sinus tachycardia is a poor prognostic factor and the common symptom. In this paper, we presented a case treated with ivabradine which provided additional benefit in patient with acute heart failure. PMID- 24757618 TI - LBBB: State-of-the-Art Criteria. PMID- 24757619 TI - The effect of diabetes mellitus on short term mortality and morbidity after isolated coronary artery bypass grafting surgery. AB - BACKGROUND: This study was conducted to determine whether Diabetes Mellitus (DM) is a predictor of short term mortality ; morbidity, or early readmission to hospital after Coronary Artery Bypass Graft (CABG). METHODS: We analyzed a large cohort of 952 patients who had undergone isolated CABG. The preoperative, intera operative and postoperative risk factors as well as the complications and 30-day mortality rates were compared between the diabetics and non-diabetics. Among the 952 patients; 734 ones (77.1%) were in non-diabetic group and 218 (22.9%) were diabetics. RESULTS: Having DM did not increase the risk of 30-day mortality. In addition, DM did not affect the major complications; arrhythmia, Myocardial Infarction(MI), infective complications, neurological complications, Pulmonary Embolism (PE) except renal complications that was higher in the diabetics (5.5% vs 1.4%; P<0.001, OR=4.2) However reoperation for bleeding was higher in non diabetic patients (7.9% vs 4.6%; P=0.009, OR=1.7). Nevertheless ,no significant difference was observed between the two groups regarding mechanical ventilation time (hour), reintubation, length of ICU stay (day), length of hospital stay (day), and readmitting as postoperative variables. CONCLUSIONS: Except for renal complications, DM was not associated with adverse outcomes in the patients undergoing isolated CABG. PMID- 24757620 TI - Premature coronary heart disease and traditional risk factors-can we do better? AB - BACKGROUND: Traditional cardiovascular risk factors are strong predictors of an increased likelihood for premature CHD. Considering the benefits of risk factors? management, it is imperative to find and treat them before looking for more unknown and weak risk factors. OBJECTIVES: Limited information is available about the demographic and historical characteristics of the patients with premature Coronary Heart Disease (CHD) in IR Iran. The main objective of this study was to determine the prevalence of the traditional risk factors in these patients. Also, the researchers hypothesized that there are insufficient risk assessment and preventive intervention methods for the asymptomatic adult population. METHODS: This study was conducted on 125 patients with premature CHD (age<50 years) who were admitted in two academic hospitals with acute coronary syndromes. The patients were accepted since they had a definite CHD on the basis of acute myocardial infarction (elevated cardiac enzymes) or documented CAD in coronary angiography. RESULTS: The mean age of the study population was 42.50+/-5.65 (26 to 49 years). Among the patients,92 (73.6%) were male, 113 (90.4%) were married, 58 (46.4%) were smokers,19 (15.2%) were opium users, 97 (77.6%) had dyslipidemia, 44 (35.2%) had hypertension, and 33 (26.4%) had diabetes mellitus. In addition, family history was presented in 54 patients (43.2%). Among the study population, 120 patients (96%) had at least one of the traditional risk factors, including dyslipidemia, hypertension, diabetes mellitus, cigarette smoking, and family history of CHD. However, none of the dyslipidemic patients had controlled total cholesterol, LDL, HDL, and triglyceride. Also, none of the diabetic patients had hemoglobin A1C<7%. Among the 44 hypertensive patients, blood pressure of 15 ones (34%) was within the normal range. Besides, only 3 patients (2.4%) had regular physical activity (at least 30 minutes, three times a week). CONCLUSIONS: Premature Coronary Heart Disease is a public health problem. However, there is lack of effective and intensive treatments of well-defined traditional risk factors and prevention methods for the majority of the patients experiencing premature CHD. In sum, there is still plenty of room for improvement of risk management in IR Iran. PMID- 24757621 TI - The Correlation between Troponin and Ferritin Serum Levels in the Patients with Major Beta-Thalassemia. AB - BACKGROUND: Thalassemia is a hereditary hemoglobinopathy whose most common complication is cardiac involvement which ends up in these patients' death. Since troponin is a sensitive and specific marker for the detection of microinfarct, we studied the relationship between troponin and ferritin serum levels for early diagnosis of cardiac involvement in these patients. MATERIALS AND METHODS: This case-control study was performed on 80 patients, including 40 patients with major thalassemia and normal echocardiography and 40 healthy volunteers ranging from 6 months to 16 years old. All the children were examined and the eligible children who were not infected with known heart disease, iron deficiency anemia, kidney disease, diabetes, fever, and systemic diseases were enrolled into the study after obtaining written informed consents from their parents. At 8:00 A.M. before breakfast, 5cc blood was drawn from these children. After collecting the samples, ferritin and troponin serum levels were evaluated using ELISA and electro- kymonolonsense methods, respectively. The gathered data were analyzed through the SPSS statistical software (v. 20) and T-test. Besides, P value<0.05 was considered as statistically significant. RESULTS: The study results revealed a significant difference between the two groups regarding the mean of the serum levels of troponin (P=0.045) and ferritin (P=0.001). In this study, no significant correlation was observed between serum troponin and ferritin levels and age and BMI in the two groups. Also, no significant relationship was found between serum troponin level and sex (P=0.264). CONCLUSIONS: In microinfarct, troponin increases independent of ferritin; therefore, it can be used for early detection of cardiac involvement in thalassemia patients to determine the sub clinical effects. PMID- 24757622 TI - Differences in the Prevalence of Obesity among Fars-Native, Turkman, and Sisstanish Ethnic Groups in Iranian Northern Adults in 2010. AB - OBJECTIVES: The aim of this study was to evaluate the differences of obesity rate among three ethnic groups in northern adults in IR Iran in 2010. METHODS: The present cross-sectional, analytical study was conducted on 2994 cases of the same age and sex in three ethnic proportions (Fars-native=1625, Turkman=977, and Sisstani=392). The subjects aged between 15 and 65 years old and were selected by multistage cluster sampling techniques including 150 clusters each containing 20 subjects in urban and rural areas in 11 districts in Golestan province (northern IR Iran). Obesity was defined after WHO classification by BMI (Body Mass Index) equal or over 30 kg/m(2). SPSS 16.0 software was used for statistical analysis and P value<0.05 was considered as statistically significant. RESULTS: Mean+/-SD of BMI in Fars-native, Turkman, and Sisstanish ethnic groups was 26.72+/-5.56, 26.18+/-5.34, and 24.59+/-6.72 kg/m(2), respectively. Averagely, obesity was common in 22.8% of the subjects and was significantly higher among the females compared to males (32.3% vs13.3%) (P=0.001). Also, its prevalence was estimated as 25%, 22.6%, and 14% in Fars-native, Turkman, and Sisstanish ethnic groups, respectively. Statistical differences were significant among the three ethnic groups (P=0.001). The risk of obesity was 2.041 [95% CI, 1.502-2.722] in Fars native and 1.781 [95% CI, 1.298-2.472] in Turkman groups compared to Sisstanish ethnic group. CONCLUSIONS: Over one out of five adults in northern IR Iran suffer from obesity and an alarming rate was shown among the women. Among the three ethnic groups, the highest and the lowest rates were seen in Fars-native and Sisstanish ethnic groups, respectively. PMID- 24757623 TI - Urine beta 2-Microglobolin in the Patients with Congenital Heart Disease. AB - BACKGROUND: This study aimed to evaluate the renal tubular function in the patients with congenital heart disease using beta2-microglobulin. METHODS: In this case-control study, based on oxymetry, the patients with congenital heart disease were divided into two groups of cyanotic (n=20) and acyanotic (n=20). Congenital heart disease was diagnosed by echocardiography. Healthy individuals within the same age and sex groups were used as controls. Na(+), beta2-micro globulin, creatinine (Cr), and beta2-microglobulin/Cr ratio were measured in random urine samples and the results were compared to the same parameters in the control group using Tukey, One-Way ANOVA, and X(2) tests. RESULTS: Based on the study results, urine sodium in the patients with cyanotic heart disease was significantly different from that of the controls (P=0.023). The results also revealed a significant difference between the two groups with congenital heart disease regarding urine beta2-microglobulin (P=0.045). In addition, the patients with cyanotic heart disease were significantly different from those with acyanotic heart disease and the controls regarding urine beta2-micro globulin/Cr ratio (P=0.012 and P=0.026, respectively). CONCLUSIONS: The results of this study demonstrated that renal tubular dysfunction began in the patients with congenital heart disease, especially in those with cyanotic congenital heart disease. Besides, early diagnosis before cardiac surgery leads to better control of renal tubular disease. PMID- 24757624 TI - Native arterio-venous fistula is the vascular access of choice for hemodialysis in end stage renal disease. AB - OBJECTIVES: THE AIM OF THE STUDY WAS: Is primary Arterio-venous fistula the vascular access of choice for adequate dialysis and better patient outcome in end stage renal disease. MATERIALS AND METHODS: The present study was done in the department of cardiovascular and thoracic surgery at Sher-i-Kashmir institute of medical sciences, Soura, Srinagar Kashmir. Native Arterio-Venous (AV) fistulas were made in the patients with end stage renal disease for performing hemodialysis. They were followed for patency and adequacy of blood flow during hemodialysis. All the patients were operated under local anesthesia. RESULTS: The results showed that 77% of the AV fistulas based on radial artery with side-to side anastomosis and 80% of those with end-to-side anastomosis were functionally patent after one year. After two years, the patency rate in side-to-side and end to-side anastomosis was 50% and 55%, respectively. In addition, the patency rate was 90% in brachial artery based AV fistula with end-to-side anastomosis, whether done primarily or secondarily, at the end of one year. However, a rapid decline was observed in the patency rate during the third year in both radial artery based and brachial artery based AV fistulas. CONCLUSIONS: We concluded that Arterialised arm superficial veins after primary AV fistula was the optimal and rational vascular access for hemodialysis providing adequate blood flow during this process. Besides, failure of primary AV fistula should be replaced by secondary AV fistula preferably based on brachial artery. PMID- 24757625 TI - Tricuspid Valve Replacement, Mechnical vs. Biological Valve, Which Is Better? AB - BACKGROUND: The initial trial in tricuspid surgery is repair; however, replacement is done whenever the valve is badly diseased. Tricuspid valve replacement comprises 1.7% of all tricuspid valve surgeries. MATERIALS AND METHODS: The present retrospective study was performed using the medical records of 21 cases who underwent tricuspid valve replacement from January 2002 until the end of December 2010. The mean age of the participants was 52.3+/-8.8 years and 66.7% were females. In addition, tricuspid valve replacement was associated with mitral valve surgery, aortic valve surgery, and both in 14.3%, 4.8%, and 33.3% of the cases, respectively. Yet, isolated tricuspid valve replacement and redo surgery were performed in 10 cases (47.6%) and 8 cases (38.1%), respectively. Besides, trial of repair was done in 14 cases (66.7%). Moreover, biological and mechanical valves were used in 76.2% and 23.8% of the patients, respectively. RESULTS: According to the results, early mortality was 23.8% and one year survival was 66.7%. Moreover, early mortality was caused by right ventricular failure, multiorgan failure, medistinitis, and intracerbral bleeding in 42%, 28.6%, 14.3%, and 14.3% of the cases, respectively. In addition, 57.1% of the deaths had occurred in the cases where the biological valve was used, while 42.9% of the deaths had taken place where the mechanical one was utilized. CONCLUSIONS: The patients who require tricuspid valve replacement are usually high risk surgical candidates with early and long term mortality. The findings of the current study showed no significant hemodynamic difference between mechanical and biological valves. PMID- 24757626 TI - Percutaneus mitral balloon valvulotomy using left femoral vein; an unusual case. AB - Balloon valvulotomy is the procedure of choice for relief of mitral stenosis. Inoue technique is the most widely accepted technique which uses the right femoral vein to access the interatial septum. Due to technical issues, left femoral vein approach is less recommended. We report an unusual case in which the right femoral vein was not accessible and mitral balloon valvulotomy was done via left femoral approach. Left femoral vein may be used in special cases where the right femoral vein is not accessible. PMID- 24757627 TI - The impact of education on weight loss in overweight and obese adults. AB - BACKGROUND: Prevalence of obesity is rapidly rising. To reverse the obesity epidemic, efforts should be made to incorporate intensive weight loss programs into medical practice. The primary aim of this study was to change the behavior for achieving a mean weight loss of 5-10% of initial body weight over 6 months in overweight and obese adults. METHODS: In this quasi-experimental study, 266 out of 533 subjects screened for coronary heart disease risk factors in Shiraz Healthy Heart House were overweight or obese. 140 individuals with BMI>=25 completed this study's 6 month program. The subjects were visited on day 1 and at 2 week intervals and taught intensive lifestyle modification. The subjects who did not lose 5% of their initial body weight after 3 months were assigned to receive 120 mg orlistat three times daily for 3 months in addition to counseling sessions. The main outcome measures were body weight and BMI. RESULTS: The mean weight and BMI of participants were 78.6+/-10.7 kg and 30+/-0.2 kg/m2, respectively. Women included 58% of the sample. 110 subjects (78.5%) lost >=5% of their initial body weight during 3 months. The Mean weight and BMI loss in these subjects were 7.6+/-0.8 kg and 2.4+/-0.3 kg/m2, respectively. CONCLUSIONS: Teaching of how to modify lifestyle and to gain more self-control with eating have the major role in reducing weight and BMI. So, training accompanied by continual follow up for performing the instructions could lead to favourable results. PMID- 24757628 TI - Evaluation of cardiac and valvular function after arterial switch operation: a midterm follow-up. AB - OBJECTIVES: Transposition of Great Arteries (TGA) is a serious congenital heart disease and anatomic correction in the first few weeks of life has revealed good outcomes nowadays. In this study, we aimed to evaluate the myocardial and valvular function at midterm postoperative follow-up. PATIENTS AND METHODS: In this study, thirty-three patients with TGA and Arterial Switch Operation (ASO) were evaluated by 2-dimensional, M-mode, Doppler, and pulsed Tissue Doppler. These patients were compared with 33 healthy children of the same age and gender as the normal control group. Student's t-test and Pearson correlation were used to analyze the data. Besides, P<0.05 was considered as statistically significant. RESULTS: The mean follow up time was 40.9+/-5.6 months. Among the 33 patients with ASO, 6% had mild pulmonary stenosis, while 3% had mild pulmonary insufficiency. Aortic stenosis and aortic insufficiency of trivial to mild degree was seen in 12% and 12% of the patients, respectively. The patients' systolic velocity of tricuspid (S), early diastolic velocity of tricuspid (Ea), and late velocity of tricuspid valve (Aa) were significantly different from those of the controls (P<0.001). Also, pulmonary annulus diameter was significantly dilated in the patients compared to the controls (1.67+/-0.41 vs. 1.29+/-0.28, P<=0.001). Besides, aortic annulus diameter (1.56+/-0.42 vs. 1.24+/-0.21, P=0.001) and also aortic sinus diameter (2.06+/-0.41 vs. 1.44+/-0.34, P=0.002) were significantly dilated, while sinutuboar junction diameter (1.65+/-0.5 vs. 1.28+/-0.29, P=0.094) was not dilated. Left ventricular function was in the normal range. CONCLUSIONS: This study showed good left ventricular function, but some abnormalities in lateral tricuspid tissue Doppler velocities. Neoaortic and pulmonary diameters were significantly dilated, while aortic and pulmonary insufficiencies were clinically insignificant in most of the patients. Long-term follow-up is necessary in these patients. PMID- 24757629 TI - Comparing Aortic Valve Replacement through Right Anterolateral Thoracotomy with Median Sternotomy. AB - BACKGROUND: Aortic Valve Replacement (AVR) is usually done through median sternotomy. The present study aimed to compare the right anterolateral thoracotomy and median sternotomy approaches for AVR. MATERIALS AND METHODS: The present prospective study was conducted on 60 patients who had aortic valve disease and were subjected to AVR. Thirty patients underwent aortic valve replacement via right anterolateral thoracotomy (study group) and thirty patients via median sternotomy (control group). Statistical analysis was done using Mann Whitney U test and Fischer's Exact test. Statistical Package SPSS -17 was used for data analysis. RESULTS: The mean length of the incision was 18.7+/-1.8 cm in the patients who had undergone AVR through median sternotomy, while 7.8+/-0.9 cm in the study group patients. Besides, the mean bypass time was 121.8+/-18.6 minutes for the patients who had undergone AVR through median sternotomy, while 122.1+/-20.8 minutes for the study group. In addition, the mean aortic cross clamp time was 67.7+/-13.4 minutes for the patients who had undergone AVR through median sternotomy, while 68.0+/-8.9 minutes for the study group. The mean operating time was 181.6+/-31.5 minutes for the patients who had undergone AVR through median sternotomy, while 190.8+/-29.8 minutes for the study group. Patient satisfaction with respect to cosmesis was higher in the study group. Only 50% of the patients who had undergone AVR through median sternotomy in comparison to 73.3% of those in the study group were satisfied with the cosmesis. CONCLUSIONS: The right anterolateral thoracotomy approach for aortic valve replacement proved to be easy to perform whilst maintaining the maximum security for the patients. Besides its better cosmetic result especially in female patients, this approach proved to have several advantages. PMID- 24757630 TI - Association between Serum Iron and the Severity of Coronary Artery Disease. AB - BACKGROUND: Coronary Artery Disease (CAD) is the most important cause of mortality in the world. About half of cardiovascular risk factors have not been completely understood. Oxidation of LDL by oxidants such as iron plays a central role in atherogenesis. As a result, evaluation of the iron stores is important in the risk evaluation of the atherosclerotic disease. MATERIALS AND METHODS: This cross sectional study was performed on 337 patients with chronic stable angina hospitalized in Sari heart center, Mazandaran University of Medical Sciences from February 2010 to July 2012. Coronary angiography was performed and the angiograms were evaluated by two cardiologists. Moreover, blood samples were collected after a 14-hour fast immediately before the coronary angiography in order to measure the total cholesterol, HDL- cholesterol, and glucose. The patients were divided into four groups to evaluate the severity of Coronary Artery Disease (CAD) according to Syntax scoring system. RESULTS: The study results revealed a significant difference among the four study groups regarding the iron serum level. It was significantly higher in the sever atherosclerosis group compared to the normal (P=0.0122), mild (P=0.023), and moderate CAD groups (P<0.001). CONCLUSIONS: The findings indicated that the serum level of iron was higher in the atherosclerotic patients and increased with the severity of CAD. Therefore, a basic relationship probably exists between the serum iron level and CAD. Further prospective and experimental studies are needed to confirm the association between the iron status and atherosclerosis. PMID- 24757631 TI - QT Dispersion and T Wave Peak-to-end Interval Dispersion in Children with Kawasaki Disease. AB - BACKGROUND: The main complication of Kawasaki disease is the Coronary Artery (CA) involvement and long term follow up of patients depends on the severity of coronary arterial aneurysms, ischemia, and thrombosis. Early diagnosis of these complications can lead to a more desirable outcome for patients. Myocardial ischemia can prolong QT dispersion and increase the risk of cardiac arrhythmias as well as sudden cardiac arrests. Also, T wave peak-to-end (Tp-Te) interval dispersion, which provides a valuable index of transmural dispersion of repolarization, can trigger the arrhythmia. MATERIALS AND METHODS: We evaluated the non-corrected QT interval dispersion (QTD) and the corrected QT (QTc) dispersion and measured Tp-Te interval dispersion in 49 Iranian children (28 males and 21 females) with the diagnosis of Kawasaki disease (KD) in the acute phase and 49 age-matched controls in a prospective study from 2009 to 2012. Student's t-test and Pearson correlation were used to analyze the data. All the statistical analyses were performed through the SPSS 16. Besides, P<0.05 was considered as statistically significant. RESULTS: Patients with KD had significantly longer QTc dispersion (0.099+/-0.055 s versus. 0.040+/-0.018 s; P<0.001), non-corrected QT dispersion (0.075+/-0.046 versus 0.042+/-0.019; P<0.001), and Tp-Te dispersion (0.047+/-0.054 versus 0.022+/-0.011; P=0.015). The patients with elevation in white blood cell count (above 15000) had a statistically significant increased in QTD (P=0.011). No significant correlation was found between coronary involvement and repolarization indexes. CONCLUSIONS: In conclusion, the QT interval (corrected or non-corrected) and the Tp-Te dispersion significantly increased in the patients with KD which shows repolarization changes during the acute phase of KD. However, there is no correlation between the QT interval and the coronary involvement. PMID- 24757632 TI - Mitral Stenosis, LV Aneurysm, Myocardial Bridge, and Myocardial Infarction: The Mystery Demystified. AB - Coronary embolisation, spontaneous coronary artery dissection, and myocardial bridges are rare causes of Myocardial Infarction (MI) in the youth. Here, we report a young male who developed myocardial infarction at the age of 19. Investigations revealed that he had mitral stenosis, myocardial bridge, and angiographic features of healed coronary dissection. PMID- 24757633 TI - Lucky guy knife assault. AB - We reported a young male with knife assault to his chest. He was transferred to the hospital without manipulating the knife. He was completely conscious and had sinus tachycardia and regular breathing. Emergency thoracotomy was performed and the knife was removed. No organ was damaged. This case presentation showed that in this kind of trauma, it is mandatory not to manipulate the penetrating foreign body during the transfer to the hospital. PMID- 24757634 TI - Exercise Training and Grape Seed Extract Co-Administration Improves Lipid Profile, Weight Loss, Bradycardia, and Hypotension of STZ-Induced Diabetic Rats. AB - BACKGROUND: Exercise Training (ET) and Grape Seed Extract (GSE) as an antioxidant have many positive effects on controlling diabetes mellitus and its complications. OBJECTIVES: This study aimed to determine the effects of GSE alone or combined with ET on body weight, plasma lipid profile, blood pressure, and heart rate in STZ-induced diabetic rats. METHODS: IN THIS STUDY, MALE WISTAR RATS WERE RANDOMLY ASSIGNED TO FIVE GROUPS: sedentary control, sedentary diabetic, trained diabetic, GSE treated sedentary diabetic, and GSE treated trained diabetic. ET was conducted on the treadmill daily for 8 weeks. One way ANOVA followed by LSD test was used for statistical analysis. RESULTS: Reduction of body weight, high density lipoproteins, heart rate, and systolic blood pressure and increment of total cholesterol, triglyceride, low density lipoprotein, and very low density lipoproteins were observed after STZ injection. Co administration of GSE and ET had more positive effects on lipid profile compared to each method alone. In addition, GSE and ET modified heart rate partially, while their combination was more effective in improvement of heart rat in conscious rats. On the other hand, administration of ET or GSE alone did not affect systolic blood pressure and body weight, while their combination restored systolic blood pressure completely and improved body weight partially. CONCLUSIONS: The study findings indicated that ET combined with GSE had more beneficial effects compared to each one alone on the complications of STZ induced diabetes. This may constitute a convenient and inexpensive therapeutic approach to diabetic complications. PMID- 24757635 TI - Comorbidity influences multiple aspects of well-being of patients with ischemic heart disease. AB - BACKGROUND: Comorbidity is prevalent among patients with Ischemic Heart Disease (IHD) and may influence patients' subjective and objective domains of well-being. OBJECTIVES: We aimed to investigate the associations between comorbidity and different measures of well-being (i.e. health related quality of life, psychological distress, sleep quality, and dyadic adjustment) among patients with IHD. METHODS: In this cross-sectional study, 796 outpatients with documented IHD were enrolled from an outpatient cardiology clinic in 2006. Comorbidity (Ifudu index), quality of life (SF36), psychological distress (Hospital Anxiety Depression Scale; HADS), sleep quality (Pittsburg Sleep Quality Index; PSQI), and dyadic adjustment quality (Revised Dyadic Adjustment Scale; RDAS) were measured. Associations between comorbidity and different measures of well-being were determined. RESULTS: Significant correlations were found between comorbidity score and all measures of well-being. Comorbidity score was correlated with physical quality of life (r = -0.471, P < 0.001), mental quality of life (r = 0.447, P < 0.001), psychological distress (r = 0.344, P < 0.001), sleep quality (r = 0.358, P < 0.001), and dyadic adjustment (r = -0.201, P < 0.001). CONCLUSIONS: This study showed a consistent pattern of associations between somatic comorbidities and multiple aspects of well-being among patients with IHD. Findings may increase cardiologists' interest to identify and treat somatic conditions among IHD patients. PMID- 24757636 TI - Gender differences in coronary artery disease: correlational study on dietary pattern and known cardiovascular risk factors. AB - BACKGROUND: The relationship between diet and cardiovascular risk factors in men and women with Coronary Artery Disease (CAD) has been the subject of recent studies. We studied a group of Iranian CAD patients to analyze any relationship between diet and CAD risk factors based on gender. METHODS: In this study, 461 consecutive patients were assessed before their planned isolated coronary artery bypass graft surgery. They were interviewed to obtain the quantity and components of nutrients and micronutrients based on a validated food frequency questionnaire. Diet scores were calculated in each dietary group and the total score was reported as the Mediterranean Diet Quality Index (Med-DQI). Physical activity was assessed using International Physical Activity Questionnaire (IPAQ). Functional class, EuroSCORE and the frequency of the known risk factors in the men and women were recorded as well. RESULTS: The women were more likely than the men to present with obesity, diabetes mellitus, hypercholesterolemia, and hypertension (all Ps < 0.001). Also, the women had higher functional class and mean of EuroSCORE (P < 0.001 and P = 0.03). Only six women (5.7%) reported to have regular physical activity. In addition, Women's energy intake was more likely to be supplied through fat. Cereals, fruit, and vegetable consumption in both genders was within the safe recommended range, while olive and fish consumption was low in both sexes. MedDQI score was different between men and women with hypertension (P = 0.018) and obesity (P = 0.048). CONCLUSIONS: Modifiable classical risk factors for CAD, except for smoking, were more prevalent in women and were associated with their diet. Therefore, women probably need to maintain low calorie intake while improving physical activity and dietary patterns to decrease the frequency and severity of modifiable cardiac risk factors. PMID- 24757637 TI - Serum Lactate Is not Correlated with Mixed or Central Venous Oxygen Saturation for Detecting Tissue Hypo Perfusion During Coronary Artery Bypass Graft Surgery: A Prospective Observational Study. AB - OBJECTIVES: Effective assessment of tissue perfusion is highly important during Coronary Artery Bypass Graft (CABG). Mixed venous O2 saturation (Svo2) is one of the best and routinely used markers of tissue perfusion. However, this method is costly and leads to considerable complications. Thus, the present study aimed to determine whether the Svo2 can be substituted with central venous saturation (Scvo2) and if there is any correlation between lactate level and Svo2. METHODS: This prospective observational study was conducted on 62 patients scheduled for CABG. After induction and maintenance of anesthesia, blood samples drawn from central venous, pulmonary artery, and radial artery were used to measure Scvo2, Svo2 and serum lactate level respectively before and after Cardio Pulmonary Bypass (CPB). Pearson's correlation test was used to determine the correlation between Svo2 and Scvo2 as well as between Svo2 and serum lactate level. Besides, P < 0.05 was considered as statistically significant. RESULTS: Overall, 62 Patients, 33 males (53.2%) and 29 females (46.8%) were enrolled into the present study. The most common coexisting illness was hypertension detected in 33 patients (53.2%) followed by hypercholesterolemia in 28 ones (44.4%). In this study, Svo2 was positively correlated with Scvo2 (r = 0.63, P < 0.001). However, no correlation was found between Svo2 and lactate (r = 0.124, P = 0.348). CONCLUSIONS: In summary, Scvo2 is considered as the best substitute of Svo2 for detecting tissue hypo perfusion during CPB. Although the lactate level had been considered as an appropriate marker of tissue perfusion and ischemia, it was not correlated to Svo2 during CABG. PMID- 24757638 TI - The Relationship between QT Interval Dispersion and End-Stage Liver Disease Score in the Patients Undergoing Orthotopic Liver Transplantation. AB - BACKGROUND: This study was performed to determine the changes in corrected QT (QTc) and QT dispersion and their relationship with end-stage liver disease score in the children undergoing orthotopic liver transplantation. METHODS: This case control study was performed in a 2-year period from February 2009 to March 2011 in Department of Organ Transplantation of Nemazee Hospital. We consecutively included all the 22 pediatric patients undergoing orthotopic liver transplantation and 22 healthy age- and sex-matched controls. Electrocardiogram (ECG) was performed for all the patients and controls before and 6 months after the transplantation and the QTc was calculated according to Bazett's formula in lead I, aVF, andV1. Besides, QT dispersion was calculated by the difference between maximum and minimum QTc in the three leads. The data were statistically analyzed using independent sample t-test, chi-square test, paired t-test, and Pearson correlation analysis. In addition, P value < 0.05 was considered as statistically significant. RESULTS: The patients with end-stage liver disease had significantly longer QTc dispersion (P = 0.002) compared to the controls. The post-transplantation QTc dispersion (P = 0.003) was also significantly longer compared to the healthy controls. Moreover, pretransplant QTc dispersion was negatively correlated with weight (r = -0.589, P = 0.004) and Child-Pugh score (r = -0.549, P = 0.008). CONCLUSIONS: The patients with ESLD awaiting liver transplantation suffer from prolonged QTc interval predisposing them to ventricular tachycardia. The QTc prolongation in these patients does not response to liver transplantation. This study revealed a fine negative correlation between the Child- Pugh score and QTc. PMID- 24757640 TI - Longitudinal deformation of pulmonary artery: a case series study. AB - OBJECTIVES: In this study, pulmonary artery longitudinal deformation was evaluated and attempted to clarify pulmonary artery deformation. METHODS: Eight healthy men and seven healthy women with structurally normal hearts were enrolled. In the parasternal short axis view at the aortic valve level, longitudinal axis of pulmonary artery was obtained and color coded Doppler myocardial imaging applied. RESULTS: The systolic strain was positive in most the pulmonary segments, velocity and strain rate waves had three defined peaks, one positive in systole and two negative in diastole. CONCLUSIONS: This study revealed for first time, deformation pattern of pulmonary artery by color coded Doppler myocardial imaging and can be basis for future researches in cardiopulmonary diseases. PMID- 24757639 TI - Gender modifies the effects of education and income on sleep quality of the patients with coronary artery disease. AB - BACKGROUND: This study aimed to investigate the interaction between gender and other socio-economic characteristics on sleep quality of the patients with Coronary Artery Disease (CAD). METHODS: This cross sectional study was conducted on 717 patients with CAD. The socio- economic status (education level, income, marital status, and place of residence) was considered as the independent variable. Besides, the study outcome was the quality of sleep which was measured using Pittsburgh Sleep Quality Index (PSQI). Gender was considered as a possible effect modifier. Two-way ANOVA was used to evaluate the interaction between gender and socio-economic factors on sleep quality. As defined by Baron and Kenny, moderator was defined as a variable that affected the direction or magnitude of the association of interest. RESULTS: Female gender, low education level, and low income were predictive of poor sleep quality. Among female (10.0 +/- 4.3 vs. 7.6 +/- 5.0, P < 0.05), but not male patients (6.7 +/- 4.2 vs. 7.0 +/ 4.2, P > 0.05), low education was associated with poor sleep quality. Also, among female (10.0 +/- 4.3 vs. 5.7 +/- 2.5, P < 0.05), but not male patients (7.0 +/- 4.2 vs. 6.0 +/- 3.8, P > 0.05), low income was predictive of poor sleep quality. Gender did not modify the effect of other socio-economic factors on sleep quality. CONCLUSIONS: Among female but not male patients with CAD, low education and income were associated with poor sleep quality. This information helps us better understand the mechanisms behind the poor sleep quality of the female patients with CAD. This is important because poor sleep is a prognostic factor among the CAD patients. PMID- 24757641 TI - Cardiac hydatid cyst: an unusual cause of chest pain. AB - Hydatid disease is a parasitic infection caused by larvae of Echinococcus granulosus. Cardiac involvement in hydatid disease is uncommon, constituting only 0.5 - 2% of all cases of hydatidosis. Most patients with cardiac echinococcosis are asymptomatic, and the disease is often latent because a hydatid cyst in the heart grows very slowly. Only approximately 10 % of patients, especially those with large hydatid cysts, have clinical manifestations. Precordial pain is the one of the common symptoms and is most often vague and does not resemble angina pectoris. PMID- 24757642 TI - Implantation of transvenous permanent pacemaker in a patient with persistent left superior vena cava and absent right superior vena cava. AB - Vascular access has remained a major challenge for implantation of permanent pacemaker leads. A persistent Left Superior Vena Cava (LSVC), especially with an absent Right Superior Vena Cava (RSVC), is a rare finding during pacemaker implantation and is accompanied by technical difficulties. Herein, we describe a case of sinoatrial node arrest, in which finding a suitable vein for passing the lead was challenging. The patient had a persistent LSVC with an absent RSVC. PMID- 24757643 TI - The Correlation between Serum ApoA1 and B and Coronary Artery Disease as Well as Its Severity. AB - BACKGROUND: Some patients with Coronary Artery Disease (CAD) have no well-known risk factors of this disease, but are diagnosed with cardiovascular events. The present study aimed to assess the association between Apo A1 and ApoB and the severity of CAD and determine whether these parameters are better predictors of Ischemic Heart Disease (IHD). METHODS: In this case control study, 271 individuals who were suspicious of having CAD and had been referred to Arak Amir al-Momenin hospital underwent coronary angiography. Based on the results of angiography, the participants with presence or absence of coronary artery stenosis were allocated into the case and the control group, respectively. The severity of CAD involvement was determined by Gensini score. The data were entered into the SPSS statistical software and analyzed through parametric and non-parametric tests, sensitivity analysis, and logistic regression. RESULTS: The results revealed no significant correlation between apoA-1 and severity of CAD involvement (GS) (r = 0.017, P = 0.797). However, a significant correlation was found between apoB and GS (r = 0.127, P = 0.047). Logistic regression model showed ApoB, sex, DM and, FH as the only proper predictors of IHD (P < 0.048, P < 0.002, P < 0.040, and P < 0.001, respectively). In comparison to angiography for diagnosis of CAD, ROC analysis represented ApoB as a more useful predictor (P = 0.023). CONCLUSIONS: In addition to measurement of conventional parameters for assessing CAD high risk groups, according to the results of this study using ApoB would be resonable as well. Further investigations are recommended to clear the problem. PMID- 24757644 TI - The Correlation between High-Sensitivity C-Reactive Protein (hsCRP) Serum Levels and Severity of Coronary Atherosclerosis. AB - BACKGROUND: Considering the increasing incidence of coronary artery stenosis as well as its related complications, the importance of its etiology, and inconsistent reports, we aimed to determine the relationship between High sensitivity C-reactive protein (hsCRP) serum levels and severity of coronary atherosclerosis. METHODS: This cross-sectional study was conducted on the patients who referred to Taleghani Hospital, Tehran, Iran and met the inclusion criteria in 2011. Regarding the severity of the disease, the angiographic findings were categorized to mild (< 10), moderate (10 - 50), and severe (> 50) using the Gensini score classification. 1 mL blood sample was taken from each patient and transferred to the laboratory after clotting. After centrifugation, the serum hsCRP level was measured and classified in 3 levels of 1, 1 to 3, and more than 3 mg / L. The relationship between hsCRP serum levels and the severity of coronary atherosclerosis was analyzed using Chi-square test (N = 85, P value < 0.010). RESULTS: This study was performed on 85 patients with the mean age of 55.7 +/- 7.06 years. Besides, 64.7% of the participants were male. According to the results, 34.1%, 37.7%, and 28.2% of the patients experienced mild, moderate, and severe disease intensity, respectively. Moreover, the serum hsCRP levels were < 1, between1 and 3, and > 3 mg / L in 28.2%, 27.1%, and 44.7% of the patients, respectively. The hsCRP serum levels were significantly higher in the patients with moderate and severe artery stenosis compared to those with mild stenosis (P < 0.010). CONCLUSIONS: The hsCRP serum levels were significantly related to the severity of coronary atherosclerosis. PMID- 24757645 TI - Gender Differences in the Association between Lipid Profile and Sexual Function among Patients with Coronary Artery Disease. AB - BACKGROUND: Although several studies have been conducted on the association between lipid profile and sexual function among men with coronary artery disease, there is a paucity of knowledge about this association among women with coronary artery disease. OBJECTIVES: Our study aimed to evaluate the link between lipid profile and sexual function in men and women with coronary artery disease. METHODS: One hundred and twenty patients with documented coronary artery disease were consecutively sampled from an outpatient cardiovascular clinic. The patients were assessed for lipid profile and sexual relationship using the Relation and Sexuality Scale (RSS). In addition, the Hospital Anxiety and Depression Scale (HADS) was used to measure the symptoms of anxiety and depression. The characteristics of chest pain were also measured using the Rose Angina Questionnaire. The data were analyzed through linear regression analysis. RESULTS: This study was conducted on 91 males (75.8%) and 29 females (24.2%). Multivariate analysis showed that low-density lipoprotein cholesterol was correlated with sexual function (B = 0.01, P = 0.010) and total sexual relationship (B = 0.01, P = 0.050). A correlation was also observed between the level of high-density lipoprotein and sexual frequency score (B = -0.02, P = 0.040). Gender moderated these correlations. Among males, serum cholesterol (r = 0.193, P = 0.047) and low-density lipoprotein (r = 0.224, P = 0.037) were correlated to sexual function. In females, however, low-density lipoprotein was correlated to the total sexual relationship (r = 0.426, P = 0.021) and high density lipoprotein was correlated to sexual frequency (r = -0.334, P = 0.046). CONCLUSIONS: The findings of this study showed a relationship between lipid profile and sexual relationship among both male and female patients with coronary artery disease. The link between lipid profile and sexual function of the patients with coronary artery disease is thus beyond just the effect of lipid profile on erectile dysfunction. PMID- 24757646 TI - Evaluating peripheral vascular injuries: is color Doppler enough for diagnosis? AB - BACKGROUND: Vascular injury poses a serious threat to limb and life. Thus, diagnosis should be made immediately with minimally invasive methods. Doppler is a good aid in diagnosis of vascular injury. METHODS: The present prospective study was conducted on 150 patients who presented with soft signs (the signs which are suggestive but not confirmatory) of vascular injury. They were subjected to color Doppler examination before exploration. The patients with the features of vascular injury on color Doppler were subjected to exploration. On the other hand, those who had normal Doppler were subjected to CT- angiography. Then, the findings of the exploration were matched with those of color Doppler. The data were analyzed using the SPSS statistical software. RESULTS: Out of the 150 Doppler examinations, 110 (73.33%) were reported as positive, while 40 were reported as negative for vascular injury. These were subjected to CT-angiography and seven of them had the features of vascular injury on CT-angiography. All the patients with positive Doppler or CT angiography findings were subjected to exploration. Doppler had a sensitivity of 94% and specificity of 82.5% in diagnosis of vascular injury using Binary classification test. CONCLUSIONS: Color Doppler is an easily available, reliable, and handy method of diagnosing a vascular injury. It has a very high sensitivity and specificity in diagnosis of vascular injuries. PMID- 24757647 TI - The Relationship between Left Atrial Volume and Ventricular Arrhythmias in the Patients with Dilated Cardiomyopathy. AB - BACKGROUND: The present study aimed to investigate the relationship between Left Atrial Volume (LAV), a marker of diastolic dysfunction, and the frequency of malignant ventricular arrhythmia in the patients with left ventricular dysfunction and a previously implanted Implantable Cardioverter Defibrillator (ICD) device. METHODS: This cross-sectional study was conducted on 32 patients with ischemic or idiopathic dilated cardiomyopathy, each having had an ICD device implanted at least 1 year beforehand. The ventricular arrhythmia episodes which were detected and stored by the device were retrieved and evaluated. In addition to routine echocardiographic measurements, all the patients had their LAV and LAV indexes calculated. After all, student's t-test, Mann-Whitney U test, and Pearson correlation were used to analyze the data. Besides, P value < 0.05 was considered as statistically significant. RESULTS: This study was conducted on 4 female and 28 male patients with the mean age of 58.41 +/- 9.97 years. Among the study patients, 21 had at least one previous myocardial infarction. In addition, 17 patients had experienced sustained VT or VF within the last year. No significant difference was found between the patients with and without malignant ventricular arrhythmias (sustained VT or VF) regarding LAV (17 patients with arrhythmia (68 + 23.39 mL) vs. 15 patients without arrhythmia (55.13 +/- 20.41 mL); P = 0.100). However, the LAV index was significantly higher in the patients with arrhythmia compared to those without arrhythmia (39.27 +/- 12.19 mL / m2 vs. 25.18 +/- 7.45 mL / m2; P = 0.004). Both LAV (73.33 +/- 17.64 mL and 57.52 +/- 23.15 mL, respectively; P = 0.040) and LAV index (40.86 +/- 8.47 mL / m2 and 28.20 +/- 11.77 mL / m2, respectively; P = 0.010) were significantly greater in the patients with ICD shock therapy within the last year compared to the others. However, both groups were similar regarding Left Ventricular Volume (LVV), LVV index, and ejection fraction. CONCLUSIONS: The study findings demonstrated that LAV and LAV index could be used in detecting the patients who are at high risk of malignant ventricular arrhythmias. PMID- 24757648 TI - QT Dispersion in Young, Ideal, and Old Aged Pregnancies. AB - BACKGROUND: Obstetricians regard maternal age of 20 to 35 years as the optimal age for pregnancy. Adolescent pregnancy and pregnancy at the ages of 35 years and above are associated with higher risks. Pregnancy is pro-arrhythmic and rarely precipitates ventricular arrhythmias. OBJECTIVES: QT dispersion is an index of heterogeneity of ventricular repolarization and a predictor of propensity of ventricular arrhythmias. In this study, this index was used to find any relationship between maternal age and ventricular arrhythmia risk. METHODS: This study was performed among a group of healthy pregnant ladies between 36 and 40 weeks of gestation. An ECG was taken from each patient. QT dispersions were calculated on a computer screen with high magnitude. The results were then divided into three groups based on the age of the participants. The first, second, and third groups included the women below 20, between 20 and 35, and over 35 years, respectively. The three groups were compared using Kruskal-Wallis test. RESULTS: The mean QTd was 61.77 ms (+/- 16.61) in the first group, 64.15 ms (+/- 18.65) in the second group, and 55.95 ms (+/- 23.04) in the third group. Although QTd was prolonged in all, no significant difference was observed among the three groups regarding QTd. CONCLUSIONS: Our results showed QT prolongation in pregnancy, but showed that maternal age did not affect the heterogeneity of ventricular repolarization and propensity of ventricular arrhythmias in pregnancy. PMID- 24757649 TI - Implanting CRT via Endo-Cardiac Route When Tricuspid Valve is Metallic. AB - Prosthetic tricuspid valve is an obstacle to implant cardiac devise. Cardiac Resynchronization therapy is one of the most popular therapies for heart failure patients these days. We present this case of prosthetic tricuspid valve and left ventricular dysfunction which we overcome the problem by implanting two leads to coronary sinus branches. Patient improved in few months of follow up. PMID- 24757650 TI - Entrapped Catheter across the Fossa Ovalis in an Adult with Pulmonary Stenosis - A Case Report of Surgical Relief. AB - Percutaneous pulmonary balloon valvuloplasty as a procedure of choice in adults has been established since the last three decades. Even though the complications are rare, they are scarcely reported in the literature. We report such a case in an adult female patient of severe pulmonary valular stenosis in whom, entrapped catheter across the fossa ovalis was noted in chest x-ray and echocardiogram following unsuccessful percutaneous pulmonary balloon valvuloplasty. Our case emphasizes this rare complication and its successful surgical outcome. PMID- 24757651 TI - False positive dobutamine stress echocardiography induced by esmolol. PMID- 24757652 TI - Management of portal hypertensive gastropathy and other bleeding. AB - A major cause of cirrhosis related morbidity and mortality is the development of variceal bleeding, a direct consequence of portal hypertension. Less common causes of gastrointestinal bleeding are peptic ulcers, malignancy, angiodysplasia, etc. Upper gastrointestinal bleeding has been classified according to the presence of a variceal or non-variceal bleeding. Although non variceal gastrointestinal bleeding is not common in cirrhotic patients, gastroduodenal ulcers may develop as often as non-cirrhotic patients. Ulcers in cirrhotic patients may be more severe and less frequently associated with chronic intake of non-steroidal anti-inflammatory drugs, and may require more frequently endoscopic treatment. Portal hypertensive gastropathy (PHG) refers to changes in the mucosa of the stomach in patients with portal hypertension. Patients with portal hypertension may experience bleeding from the stomach, and pharmacologic or radiologic interventional procedure may be useful in preventing re-bleeding from PHG. Gastric antral vascular ectasia (GAVE) seems to be different disease entity from PHG, and endoscopic ablation can be the first-line treatment. PMID- 24757653 TI - Hepatic venous pressure gradient: clinical use in chronic liver disease. AB - Portal hypertension is a severe consequence of chronic liver diseases and is responsible for the main clinical complications of liver cirrhosis. Hepatic venous pressure gradient (HVPG) measurement is the best available method to evaluate the presence and severity of portal hypertension. Clinically significant portal hypertension is defined as an increase in HVPG to >10 mmHg. In this condition, the complications of portal hypertension might begin to appear. HVPG measurement is increasingly used in the clinical fields, and the HVPG is a robust surrogate marker in many clinical applications such as diagnosis, risk stratification, identification of patients with hepatocellular carcinoma who are candidates for liver resection, monitoring of the efficacy of medical treatment, and assessment of progression of portal hypertension. Patients who had a reduction in HVPG of >= 20% or to <= 12 mmHg in response to drug therapy are defined as responders. Responders have a markedly decreased risk of bleeding/rebleeding, ascites, and spontaneous bacterial peritonitis, which results in improved survival. This review provides clinical use of HVPG measurement in the field of liver disease. PMID- 24757654 TI - Do cirrhotic patients with a high MELD score benefit from TIPS? PMID- 24757656 TI - Role of 15-hydroxyprostaglandin dehydrogenase down-regulation on the prognosis of hepatocellular carcinoma. AB - BACKGROUND/AIMS: The role of prostaglandin E2 (PGE2) in the modulation of cell growth is well established in colorectal cancer. The aim of this study was to elucidate the significance of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) down-regulation on the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: The expression of 15-PGDH in HCC cell lines and resected HCC tissues was investigated, and the correlation between 15-PGDH expression and HCC cell-line proliferation and patient survival was explored. RESULTS: The interleukin-1-beta induced suppression of 15-PGDH did not change the proliferation of PLC and Huh-7 cells in the MTS [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The induction of 15-PGDH by transfection in HepG2 cells without baseline 15-PGDH expression was suppressed at day 2 of proliferation compared with empty vector transfection, but there was no difference at day 3. Among the 153 patients who received curative HCC resection between 2003 and 2004 at our institution, 15 PGDH expression was observed in resected HCC tissues in 56 (36.6%), but the 5 year survival rate did not differ from that of the remaining 97 non-15-PGDH expressing patients (57.1% vs 59.8%; P=0.93). Among 50 patients who exhibited baseline 15-PGDH expression in adjacent nontumor liver tissues, 28 (56%) exhibited a reduction in 15-PGDH expression score in HCC tissues, and there was a trend toward fewer long-term survivors compared with the remaining 22 with the same or increment in their 15-PGDH expression score in HCC tissues. CONCLUSIONS: The prognostic significance of 15-PGDH down-regulation in HCC was not established in this study. However, maintenance of 15-PGDH expression could be a potential therapeutic target for a subgroup of HCC patients with baseline 15-PGDH expression in adjacent nontumor liver tissue. PMID- 24757655 TI - Clinical outcomes of transjugular intrahepatic portosystemic shunt for portal hypertension: Korean multicenter real-practice data. AB - BACKGROUND/AIMS: This retrospective study assessed the clinical outcome of a transjugular intrahepatic portosystemic shunt (TIPS) procedure for managing portal hypertension in Koreans with liver cirrhosis. METHODS: Between January 2003 and July 2013, 230 patients received a TIPS in 13 university-based hospitals. RESULTS: Of the 229 (99.6%) patients who successfully underwent TIPS placement, 142 received a TIPS for variceal bleeding, 84 for refractory ascites, and 3 for other indications. The follow-up period was 24.9 +/- 30.2 months (mean +/- SD), 74.7% of the stents were covered, and the primary patency rate at the 1 year follow-up was 78.7%. Hemorrhage occurred in 30 (21.1%) patients during follow-up; of these, 28 (93.3%) cases of rebleeding were associated with stent dysfunction. Fifty-four (23.6%) patients developed new hepatic encephalopathy, and most of these patients were successfully managed conservatively. The cumulative survival rates at 1, 6, 12, and 24 months were 87.5%, 75.0%, 66.8%, and 57.5%, respectively. A high Model for End-Stage Liver Disease (MELD) score was significantly associated with the risk of death within the first month after receiving a TIPS (P=0.018). Old age (P<0.001), indication for a TIPS (ascites vs. bleeding, P=0.005), low serum albumin (P<0.001), and high MELD score (P=0.006) were associated with overall mortality. CONCLUSIONS: A high MELD score was found to be significantly associated with early and overall mortality rate in TIPS patients. Determining the appropriate indication is warranted to improve survival in these patients. PMID- 24757657 TI - The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients. AB - BACKGROUND/AIMS: Lipid profile and insulin resistance (IR) are associated with hepatitis C virus (HCV) and may predict the chronic hepatitis C (CHC) treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment. METHODS: In total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA) of IR (HOMA-IR), and HOMA of beta cells (HOMA-beta) were evaluated before interferon plus ribavirin therapy (BTx), at the end of treatment (DTx), and 24 weeks after the end of treatment (ATx). RESULTS: A sustained virologic response (SVR) was achieved by 81% of all patients (49/60), 60% (n=36) of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24). Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0 +/- 11.2 years, mean +/- SD; non-SVR, 56.6 +/- 9.9 years; P<0.01), there were no significant differences in the baseline characteristics between the SVR and non-SVR groups. In the SVR group, low density lipoprotein-cholesterol (LDL-C) had significantly changed at DTx and ATx compared to BTx. In addition, HOMA-IR and HOMA-beta were significantly changed at DTx in the SVR group. Among those with a high baseline insulin resistance (HOMA-IR >2.5), HOMA-IR was significantly changed at DTx in the SVR group. CONCLUSIONS: LDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5). PMID- 24757658 TI - The Refit model for end-stage liver disease-Na is not a better predictor of mortality than the Refit model for end-stage liver disease in patients with cirrhosis and ascites. AB - BACKGROUND/AIMS: The modification of the Model for End-Stage Liver Disease (MELD) scoring system (Refit MELD) and the modification of MELD-Na (Refit MELDNa), which optimized the MELD coefficients, were published in 2011. We aimed to validate the superiority of the Refit MELDNa over the Refit MELD for the prediction of 3-month mortality in Korean patients with cirrhosis and ascites. METHODS: We reviewed the medical records of patients admitted with hepatic cirrhosis and ascites to the Konkuk University Hospital between January 2006 and December 2011. The Refit MELD and Refit MELDNa were compared using the predictive value of the 3-month mortality, as assessed by the Child-Pugh score. RESULTS: In total, 530 patients were enrolled, 87 of whom died within 3 months. Alcohol was the most common etiology of their cirrhosis (n=271, 51.1%), and the most common cause of death was variceal bleeding (n=20, 23%). The areas under the receiver operating curve (AUROCs) for the Child-Pugh, Refit MELD, and Refit MELDNa scores were 0.754, 0.791, and 0.764 respectively; the corresponding values when the analysis was performed only in patients with persistent ascites (n=115) were 0.725, 0.804, and 0.796, respectively. The significant difference found among the Child-Pugh, Refit MELD, and Refit MELDNa scores was between the Child-Pugh score and Refit MELD in patients with persistent ascites (P=0.039). CONCLUSIONS: Refit MELD and Refit MELDNa exhibited good predictability for 3-month mortality in patients with cirrhosis and ascites. However, Refit MELDNa was not found to be a better predictor than Refit MELD, despite the known relationship between hyponatremia and mortality in cirrhotic patients with ascites. PMID- 24757659 TI - Inactive hepatitis B surface antigen carriers and intrafamilial tramsmission: results of a 10-year study. AB - BACKGROUND/AIMS: The aims of the present study were to determine the outcomes of inactive hepatitis B virus (HBV) surface antigen (HBsAg) carriers over a 10-year study period and to elucidate the HBV serological profile of their family members. METHODS: We retrospectively analyzed the medical files of inactive HBsAg carriers followed up at the Department of Infectious Diseases of Kocatepe University Medical Faculty Hospital between March 2001 and January 2011. RESULTS: In total, 438 inactive HBsAg carriers were enrolled in this trial. The follow-up period was 33.7 +/- 22.5 months (mean +/- SD). Anti-hepatitis-B surface antibody seroconversion occurred in 0.7% of cases, while chronic hepatitis B was found in 0.5%. The anti-hepatitis-D virus (HDV) status was evaluated in 400 patients and anti-hepatitis C virus (HCV) in 430. It was found that 1% and 0.2% were positive for anti-HDV and anti-HCV, respectively. HBV serology was investigated in at least 1 family member of 334/438 (76.3%) patients. The HBsAg positivity rate was 34.6% in 625 family members of 334 patients. A comparison of the HBsAg positivity rates in terms of HBV DNA levels in index cases revealed that HBsAg seropositivity rates were higher in family members of HBV DNA-negative patients than in family members of HBV DNA-positive cases (P=0.0001). CONCLUSIONS: The HBsAg positivity rate was higher in family members of inactive HBsAg carriers than in the general population; these family members therefore have a higher risk of HBV transmission. Furthermore, despite negative HBV DNA levels, transmission risk was not reduced in these patients, and horizontal transmission seems to be independent of the HBV DNA value. PMID- 24757660 TI - Radiofrequency ablation of very-early-stage hepatocellular carcinoma inconspicuous on fusion imaging with B-mode US: value of fusion imaging with contrast-enhanced US. AB - BACKGROUND/AIMS: To determine the value of fusion imaging with contrast-enhanced ultrasonography (CEUS) and computed tomography (CT)/magnetic resonance (MR) images for percutaneous radiofrequency ablation (RFA) of very-early-stage hepatocellular carcinomas (HCCs) that are inconspicuous on fusion imaging with B mode ultrasound (US) and CT/MR images. METHODS: This retrospective study was approved by our institutional review board and the requirement for informed consent was waived. Fusion imaging with CEUS using Sonazoid contrast agent and CT/MR imaging was performed on HCCs (<2 cm) that were inconspicuous on fusion imaging with B-mode US. We evaluated the number of cases that became conspicuous on fusion imaging with CEUS. Percutaneous RFA was performed under the guidance of fusion imaging with CEUS. Technical success and major complication rates were assessed. RESULTS: In total, 30 patients with 30 HCCs (mean, 1.2 cm; range, 0.6 1.7 cm) were included, among which 25 (83.3%) became conspicuous on fusion imaging with CEUS at the time of the planning US and/or RFA procedure. Of those 25 HCCs, RFA was considered feasible for 23 (92.0%), which were thus treated. The technical success and major complication rates were 91.3% (21/23) and 4.3% (1/23), respectively. CONCLUSIONS: Fusion imaging with CEUS and CT/MR imaging is highly effective for percutaneous RFA of very-early-stage HCCs inconspicuous on fusion imaging with B-mode US and CT/MR imaging. PMID- 24757661 TI - Allopurinol-induced DRESS syndrome mimicking biliary obstruction. AB - An 84-year-old man was admitted to our hospital with fever, jaundice, and itching. He had been diagnosed previously with chronic renal failure and diabetes, and had been taking allopurinol medication for 2 months. A physical examination revealed that he had a fever (38.8C), jaundice, and a generalized maculopapular rash. Azotemia, eosinophilia, atypical lymphocytosis, elevation of liver enzymes, and hyperbilirubinemia were detected by blood analysis. Magnetic resonance cholangiography revealed multiple cysts similar to choledochal cysts in the liver along the biliary tree. Obstructive jaundice was suspected clinically, and so an endoscopic ultrasound examination was performed, which ruled out a diagnosis of obstructive jaundice. The patient was diagnosed with DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome due to allopurinol. Allopurinol treatment was stopped and steroid treatment was started. The patient died from cardiac arrest on day 15 following admission. PMID- 24757662 TI - Improved severe hepatopulmonary syndrome after liver transplantation in an adolescent with end-stage liver disease secondary to biliary atresia. AB - Hepatopulmonary syndrome (HPS) is a serious complication of end-stage liver disease, which is characterized by hypoxia, intrapulmonary vascular dilatation, and liver cirrhosis. Liver transplantation (LT) is the only curative treatment modality for patients with HPS. However, morbidity and mortality after LT, especially in cases of severe HPS, remain high. This case report describes a patient with typical findings of an extracardiac pulmonary arteriovenous shunt on contrast-enhanced transesophageal echocardiography (TEE), and clubbing fingers, who had complete correction of HPS by deceased donor LT. The patient was a 16 year-old female who was born with biliary atresia and underwent porto-enterostomy on the 55th day after birth. She had been suffered from progressive liver failure with dyspnea, clubbing fingers, and cyanosis. Preoperative arterial blood gas analysis revealed severe hypoxia (arterial O2 tension of 54.5 mmHg and O2 saturation of 84.2%). Contrast-enhanced TEE revealed an extracardiac right-to left shunt, which suggested an intrapulmonary arteriovenous shunt. The patient recovered successfully after LT, not only with respect to physical parameters but also for pychosocial activity, including school performance, during the 30-month follow-up period. PMID- 24757663 TI - Sinusoidal obstruction syndrome after oxaliplatin-based chemotherapy. PMID- 24757664 TI - Sonography of hepatic hemangioma accompanied by arterioportal shunt. PMID- 24757665 TI - Essential functional modules for pathogenic and defensive mechanisms in Candida albicans infections. AB - The clinical and biological significance of the study of fungal pathogen Candida albicans (C. albicans) has markedly increased. However, the explicit pathogenic and invasive mechanisms of such host-pathogen interactions have not yet been fully elucidated. Therefore, the essential functional modules involved in C. albicans-zebrafish interactions were investigated in this study. Adopting a systems biology approach, the early-stage and late-stage protein-protein interaction (PPI) networks for both C. albicans and zebrafish were constructed. By comparing PPI networks at the early and late stages of the infection process, several critical functional modules were identified in both pathogenic and defensive mechanisms. Functional modules in C. albicans, like those involved in hyphal morphogenesis, ion and small molecule transport, protein secretion, and shifts in carbon utilization, were seen to play important roles in pathogen invasion and damage caused to host cells. Moreover, the functional modules in zebrafish, such as those involved in immune response, apoptosis mechanisms, ion transport, protein secretion, and hemostasis-related processes, were found to be significant as defensive mechanisms during C. albicans infection. The essential functional modules thus determined could provide insights into the molecular mechanisms of host-pathogen interactions during the infection process and thereby devise potential therapeutic strategies to treat C. albicans infection. PMID- 24757667 TI - Development and evaluation of an open-source software package "CGITA" for quantifying tumor heterogeneity with molecular images. AB - BACKGROUND: The quantification of tumor heterogeneity with molecular images, by analyzing the local or global variation in the spatial arrangements of pixel intensity with texture analysis, possesses a great clinical potential for treatment planning and prognosis. To address the lack of available software for computing the tumor heterogeneity on the public domain, we develop a software package, namely, Chang-Gung Image Texture Analysis (CGITA) toolbox, and provide it to the research community as a free, open-source project. METHODS: With a user friendly graphical interface, CGITA provides users with an easy way to compute more than seventy heterogeneity indices. To test and demonstrate the usefulness of CGITA, we used a small cohort of eighteen locally advanced oral cavity (ORC) cancer patients treated with definitive radiotherapies. RESULTS: In our case study of ORC data, we found that more than ten of the current implemented heterogeneity indices outperformed SUVmean for outcome prediction in the ROC analysis with a higher area under curve (AUC). Heterogeneity indices provide a better area under the curve up to 0.9 than the SUVmean and TLG (0.6 and 0.52, resp.). CONCLUSIONS: CGITA is a free and open-source software package to quantify tumor heterogeneity from molecular images. CGITA is available for free for academic use at http://code.google.com/p/cgita. PMID- 24757666 TI - New Enlightenment of Skin Cancer Chemoprevention through Phytochemicals: In Vitro and In Vivo Studies and the Underlying Mechanisms. AB - Skin cancer is still a major cause of morbidity and mortality worldwide. Skin overexposure to ultraviolet irradiations, chemicals, and several viruses has a capability to cause severe skin-related disorders including immunosuppression and skin cancer. These factors act in sequence at various steps of skin carcinogenesis via initiation, promotion, and/or progression. These days cancer chemoprevention is recognized as the most hopeful and novel approach to prevent, inhibit, or reverse the processes of carcinogenesis by intervention with natural products. Phytochemicals have antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification capabilities thereby considered as efficient chemopreventive agents. Considerable efforts have been done to identify the phytochemicals which may possibly act on one or several molecular targets that modulate cellular processes such as inflammation, immunity, cell cycle progression, and apoptosis. Till date several phytochemicals in the light of chemoprevention have been studied by using suitable skin carcinogenic in vitro and in vivo models and proven as beneficial for prevention of skin cancer. This revision presents a comprehensive knowledge and the main molecular mechanisms of actions of various phytochemicals in the chemoprevention of skin cancer. PMID- 24757668 TI - Does rTMS alter neurocognitive functioning in patients with panic disorder/agoraphobia? An fNIRS-based investigation of prefrontal activation during a cognitive task and its modulation via sham-controlled rTMS. AB - OBJECTIVES: Neurobiologically, panic disorder (PD) is supposed to be characterised by cerebral hypofrontality. Via functional near-infrared spectroscopy (fNIRS), we investigated whether prefrontal hypoactivity during cognitive tasks in PD-patients compared to healthy controls (HC) could be replicated. As intermittent theta burst stimulation (iTBS) modulates cortical activity, we furthermore investigated its ability to normalise prefrontal activation. METHODS: Forty-four PD-patients, randomised to sham or verum group, received 15 iTBS-sessions above the left dorsolateral prefrontal cortex (DLPFC) in addition to psychoeducation. Before first and after last iTBS-treatment, cortical activity during a verbal fluency task was assessed via fNIRS and compared to the results of 23 HC. RESULTS: At baseline, PD-patients showed hypofrontality including the DLPFC, which differed significantly from activation patterns of HC. However, verum iTBS did not augment prefrontal fNIRS activation. Solely after sham iTBS, a significant increase of measured fNIRS activation in the left inferior frontal gyrus (IFG) during the phonological task was found. CONCLUSION: Our results support findings that PD is characterised by prefrontal hypoactivation during cognitive performance. However, verum iTBS as an "add-on" to psychoeducation did not augment prefrontal activity. Instead we only found increased fNIRS activation in the left IFG after sham iTBS application. Possible reasons including task-related psychophysiological arousal are discussed. PMID- 24757669 TI - Effect of chronic exposure to prometryne on oxidative stress and antioxidant response in red swamp crayfish (Procambarus clarkii). AB - The aim of the study was to investigate effects of the triazine herbicide prometryne on red swamp crayfish on the basis of oxidative stress, antioxidant indices in hepatopancreas and muscle, and histopathology of hepatopancreas. Crayfish were exposed to prometryne concentrations of 0.51 MU g L(-1), 0.144 mg L(-1), and 1.144 mg L(-1) for 11 and 25 days. Indices of oxidative stress (thiobarbituric acid reactive substances (TBARS)), and antioxidant parameters (superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR)) in crayfish muscle and hepatopancreas were measured. Chronic exposure to prometryne did not showed the impact of oxidative damage to cells. Changes activity of the antioxidant enzymes SOD, CAT, and GR were observed in all tested concentrations to prometryne for 11 and 25 days (P < 0.01) as compared with the control group. We did not see any differences in histopatological examination to hepatopancreas. Prolonged exposure of prometryne did not result in oxidative damage to cell lipids and proteins, but it led to changes in antioxidant activity in crayfish tissues. Changes in antioxidant systems were also observed in the environmental prometryne concentration of 0.51 MU g L(-1). The results suggest that antioxidant responses may have potential as biomarkers for monitoring residual triazine herbicides in aquatic environments. PMID- 24757670 TI - Potent anti-inflammatory activity of carbohydrate polymer with oxide of zinc. AB - Pebisut is a biological adhesive composed of naturally occurring carbohydrates combined with zinc oxide (ZnO) initially used as a coadjutant for healing of anastomoses. Likewise some works demonstrated that carbohydrate complexes exerts anti-inflammatory activity and it is widely known that ZnO modulate inflammation. However, the direct effects of Pebisut on isolated cells and acute inflammatory responses remained to be investigated. The present study evaluated anti inflammatory effect of Pebisut using lipopolysaccharide (LPS) stimulated human mononuclear cells, chemotaxis, and cell infiltration in vivo in a murine model of peritonitis. Our data show that human cells treated with different dilutions of Pebisut release less IL-6, IL-1 beta , and IL-8 after LPS stimuli compared with the control treated cells. In addition, Pebisut lacked chemotactic activity in human mononuclear cells but was able to reduce chemotaxis towards CCL2, CCL5, and CXCL12 that are representative mononuclear cells chemoattractants. Finally, in a murine model of peritonitis, we found less number of macrophages (F4/80(+)) and T lymphocytes (CD3(+)) in peritoneal lavages from animals treated with Pebisut. Our results suggest that Pebisut has anti-inflammatory activity, which might have a beneficial effect during anastomoses healing or wounds associated with excessive inflammation. PMID- 24757671 TI - Current and future lymphatic imaging modalities for tumor staging. AB - Tumor progression is supported by the lymphatic system which should be scanned efficiently for tumor staging as well as the enhanced therapeutic outcomes. Poor resolution and low sensitivity is a limitation of traditional lymphatic imaging modalities; thus new noninvasive approaches like nanocarriers, magnetic resonance imaging, positron-emission tomography, and quantum dots are advantageous. Some newer modalities, which are under development, and their potential uses will also be discussed in this review. PMID- 24757672 TI - Perinatal hypoxia-ischemia reduces alpha 7 nicotinic receptor expression and selective alpha 7 nicotinic receptor stimulation suppresses inflammation and promotes microglial Mox phenotype. AB - Inflammation plays a central role in neonatal brain injury. During brain inflammation the resident macrophages of the brain, the microglia cells, are rapidly activated. In the periphery, alpha 7 nicotinic acetylcholine receptors ( alpha 7R) present on macrophages can regulate inflammation by suppressing cytokine release. In the current study we investigated alpha 7R expression in neonatal mice after hypoxia-ischemia (HI). We further examined possible anti inflammatory role of alpha 7R stimulation in vitro and microglia polarization after alpha 7R agonist treatment. Real-time PCR analysis showed a 33% reduction in alpha 7R expression 72 h after HI. Stimulation of primary microglial cells with LPS in combination with increasing doses of the selective alpha 7R agonist AR-R 17779 significantly attenuated TNF alpha release and increased alpha 7R transcript in microglial cells. Gene expression of M1 markers CD86 and iNOS, as well as M2 marker CD206 was not influenced by LPS and/or alpha 7R agonist treatment. Further, Mox markers heme oxygenase (Hmox1) and sulforedoxin-1 (Srx1) were significantly increased, suggesting a polarization towards the Mox phenotype after alpha 7R stimulation. Thus, our data suggest a role for the alpha 7R also in the neonatal brain and support the anti-inflammatory role of alpha 7R in microglia, suggesting that alpha 7R stimulation could enhance the polarization towards a reparative Mox phenotype. PMID- 24757673 TI - Analysis of differentially expressed genes and signaling pathways related to intramuscular fat deposition in skeletal muscle of sex-linked dwarf chickens. AB - Intramuscular fat (IMF) plays an important role in meat quality. However, the molecular mechanisms underlying IMF deposition in skeletal muscle have not been addressed for the sex-linked dwarf (SLD) chicken. In this study, potential candidate genes and signaling pathways related to IMF deposition in chicken leg muscle tissue were characterized using gene expression profiling of both 7-week old SLD and normal chickens. A total of 173 differentially expressed genes (DEGs) were identified between the two breeds. Subsequently, 6 DEGs related to lipid metabolism or muscle development were verified in each breed based on gene ontology (GO) analysis. In addition, KEGG pathway analysis of DEGs indicated that some of them (GHR, SOCS3, and IGF2BP3) participate in adipocytokine and insulin signaling pathways. To investigate the role of the above signaling pathways in IMF deposition, the gene expression of pathway factors and other downstream genes were measured by using qRT-PCR and Western blot analyses. Collectively, the results identified potential candidate genes related to IMF deposition and suggested that IMF deposition in skeletal muscle of SLD chicken is regulated partially by pathways of adipocytokine and insulin and other downstream signaling pathways (TGF- beta /SMAD3 and Wnt/catenin- beta pathway). PMID- 24757674 TI - Physical performance is associated with working memory in older people with mild to severe cognitive impairment. AB - BACKGROUND: Physical performances and cognition are positively related in cognitively healthy people. The aim of this study was to examine whether physical performances are related to specific cognitive functioning in older people with mild to severe cognitive impairment. METHODS: This cross-sectional study included 134 people with a mild to severe cognitive impairment (mean age 82 years). Multiple linear regression was performed, after controlling for covariates and the level of global cognition, with the performances on mobility, strength, aerobic fitness, and balance as predictors and working memory and episodic memory as dependent variables. RESULTS: The full models explain 49-57% of the variance in working memory and 40-43% of episodic memory. Strength, aerobic fitness, and balance are significantly associated with working memory, explaining 3-7% of its variance, irrespective of the severity of the cognitive impairment. Physical performance is not related to episodic memory in older people with mild to severe cognitive impairment. CONCLUSIONS: Physical performance is associated with working memory in older people with cognitive impairment. Future studies should investigate whether physical exercise for increased physical performance can improve cognitive functioning. This trial is registered with ClinicalTrials.gov NTR1482. PMID- 24757675 TI - Long noncoding RNA plays a key role in metastasis and prognosis of hepatocellular carcinoma. AB - Long noncoding RNAs (lncRNAs) have been attracting immense research interests. However, only a handful of lncRNAs had been thoroughly characterized. They were involved in fundamental cellular processes including regulation of gene expression at epigenetics as well as tumorogenesis. In this paper, we give a systematic and comprehensive review of existing literature about lncRNA involvement in hepatocellular carcinoma. This review exhibited that lncRNAs played important roles in tumorigenesis and subsequent prognosis and metastasis of hepatocellular carcinoma and elucidated the role of some specific lncRNAs such as MALAT1 and HOTAIR in the pathophysiology of hepatocellular carcinoma and their potential of being therapeutic targets. PMID- 24757676 TI - Rosiglitazone regulates anti-inflammation and growth inhibition via PTEN. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) agonist has anti inflammatory and anticancer properties. However, the mechanisms by which PPARgamma agonist rosiglitazone interferes with inflammation and cancer via phosphatase and tensin homolog-(PTEN)-dependent pathway remain unclear. We found that lower doses (<25 MU M) of rosiglitazone significantly inhibited lipopolysaccharide-(LPS)-induced nitric oxide (NO) release (via inducible nitric oxide synthase, iNOS), prostaglandin E2 (PGE2) production (via cyclooxygenase-2, COX-2), and activation of Akt in RAW 264.7 murine macrophages. However, rosiglitazone did not inhibit the production of reactive oxygen species (ROS). In PTEN knockdown (shPTEN) cells exposed to LPS, rosiglitazone did not inhibit NO release, PGE2 production, and activation of Akt. These cells had elevated basal levels of iNOS, COX-2, and ROS. However, higher doses (25-100 MU M) of rosiglitazone, without LPS stimulation, did not block NO release and PGE2 productions, but they inhibited p38 MAPK phosphorylation and blocked ROS generation in shPTEN cells. In addition, rosiglitazone caused G1 arrest and reduced the number of cells in S + G2/M phase, leading to growth inhibition. These results indicate that the anti-inflammatory property of rosiglitazone is related to regulation of PTEN independent of inhibition on ROS production. However, rosiglitazone affected the dependence of PTEN-deficient cell growth on ROS. PMID- 24757677 TI - A proteomic view to characterize the effect of chitosan nanoparticle to hepatic cells: is chitosan nanoparticle an enhancer of PI3K/AKT1/mTOR pathway? AB - Chitosan nanoparticle, a biocompatible material, was used as a potential drug delivery system widely. Our current investigation studies were the bioeffects of the chitosan nanoparticle uptake by liver cells. In this experiment, the characterizations of chitosan nanoparticles were measured by transmission electron microscopy and particle size analyzer. The average size of the chitosan nanoparticle was 224.6 +/- 11.2 nm, and the average zeta potential was +14.08 +/- 0.7 mV. Moreover, using proteomic approaches to analyze the differential protein expression patterns resulted from the chitosan nanoparticle uptaken by HepG2 and CCL-13 cells identified several proteins involved in the PI3K/AKT1/mTOR pathway. Our experimental results have demonstrated that the chitosan nanoparticle may involve in the liver cancer cell metastasis and proliferation. PMID- 24757678 TI - Alcohol consumption during adolescence and risk of diabetes in young adulthood. AB - BACKGROUND: There is very limited data available on the association between underage drinking and risk of diabetes. The aim of this study is to investigate the association between alcohol use during adolescence and the risk of diabetes while controlling for a wide range of confounders, including parental alcohol use. METHODS: This population-based study used data collected from the National Longitudinal Study of Adolescent Health (Add Health). Participants were initially recruited in 1994-1995 (Wave I), then followed up in 1996 (Wave II) and in 2001 2002 (Wave III), and in 2008-2009 (Wave IV). Analysis included 2,850 participants (46% male) who were successfully followed up at Waves I, III, and IV without a known diagnosis of diabetes at Waves I and III and who provided all necessary information for the analysis. RESULTS: During adolescence, frequent alcohol consumption at levels reaching 5 or more drinks, 3-7 days/week, substantially increased the risk of diabetes in young adulthood, with an odds ratio of 12.57 (95% CI 4.10-38.61) compared to current abstainers. CONCLUSIONS: Heavy alcohol use during adolescence may increase the risk of diabetes in young adulthood. The Significant finding of the Study. PMID- 24757679 TI - Advanced imaging for the early diagnosis of local recurrence prostate cancer after radical prostatectomy. AB - Currently the diagnosis of local recurrence of prostate cancer (PCa) after radical prostatectomy (RT) is based on the onset of biochemical failure which is defined by two consecutive values of prostate-specific antigen (PSA) higher than 0.2 ng/mL. The aim of this paper was to review the current roles of advanced imaging in the detection of locoregional recurrence. A nonsystematic literature search using the Medline and Cochrane Library databases was performed up to November 2013. Bibliographies of retrieved and review articles were also examined. Only those articles reporting complete data with clinical relevance for the present review were selected. This review article is divided into two major parts: the first one considers the role of PET/CT in the restaging of PCa after RP; the second part is intended to provide the impact of multiparametric-MRI (mp MRI) in the depiction of locoregional recurrence. Published data indicate an emerging role for mp-MRI in the depiction of locoregional recurrence, while the performance of PET/CT still remains unclear. Moreover Mp-MRI, thanks to functional techniques, allows to distinguish between residual glandular healthy tissue, scar/fibrotic tissue, granulation tissue, and tumour recurrence and it may also be able to assess the aggressiveness of nodule recurrence. PMID- 24757682 TI - Chronic wounds with emphasis in diabetic foot ulcers. PMID- 24757680 TI - Adipokines, biomarkers of endothelial activation, and metabolic syndrome in patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. AS patients also display a high prevalence of features clustered under the name of metabolic syndrome (MeS). Anti-TNF- alpha therapy was found to be effective to treat AS patients by suppressing inflammation and also improving endothelial function. Previously, it was demonstrated that a short infusion of anti-TNF- alpha monoclonal antibodyinfliximab induced a rapid and dramatic reduction in serum insulin levels and insulin resistance along with a rapid improvement of insulin sensitivity in nondiabetic AS patients. The role of adipokines, MeS-related biomarkers and biomarkers of endothelial cell activation and inflammation seem to be relevant in different chronic inflammatory diseases. However, its implication in AS has not been fully established. Therefore, in this review we summarize the recent advances in the study of the involvement of these molecules in CV disease or MeS in AS. The assessment of adipokines and biomarkers of endothelial cell activation and MeS may be of potential relevance in the stratification of the CV risk of patients with AS. PMID- 24757681 TI - Neuropeptide Y in the adult and fetal human pineal gland. AB - Neuropeptide Y was isolated from the porcine brain in 1982 and shown to be colocalized with noradrenaline in sympathetic nerve terminals. The peptide has been demonstrated to be present in sympathetic nerve fibers innervating the pineal gland in many mammalian species. In this investigation, we show by use of immunohistochemistry that neuropeptide Y is present in nerve fibers of the adult human pineal gland. The fibers are classical neuropeptidergic fibers endowed with large boutons en passage and primarily located in a perifollicular position with some fibers entering the pineal parenchyma inside the follicle. The distance from the immunoreactive terminals to the pinealocytes indicates a modulatory function of neuropeptide Y for pineal physiology. Some of the immunoreactive fibers might originate from neurons located in the brain and be a part of the central innervation of the pineal gland. In a series of human fetuses, neuropeptide Y containing nerve fibers was present and could be detected as early as in the pineal of four- to five-month-old fetuses. This early innervation of the human pineal is different from most rodents, where the innervation starts postnatally. PMID- 24757684 TI - Adipose-derived mesenchymal stem cells from ventral hernia repair patients demonstrate decreased vasculogenesis. AB - INTRODUCTION: In adipose tissue healing, angiogenesis is stimulated by adipose derived stromal stem cells (ASCs). Ventral hernia repair (VHR) patients are at high risk for wound infections. We hypothesize that ASCs from VHR patients are less vasculogenic than ASCs from healthy controls. METHODS: ASCs were harvested from the subcutaneous fat of patients undergoing VHR by the component separation technique and from matched abdominoplasty patients. RNA and protein were harvested on culture days 0 and 3. Both groups of ASCs were subjected to hypoxic conditions for 12 and 24 hours. RNA was analyzed using qRT-PCR, and protein was used for western blotting. ASCs were also grown in Matrigel under hypoxic conditions and assayed for tubule formation after 24 hours. RESULTS: Hernia patient ASCs demonstrated decreased levels of VEGF-A protein and vasculogenic RNA at 3 days of growth in differentiation media. There were also decreases in VEGF-A protein and vasculogenic RNA after growth in hypoxic conditions compared to control ASCs. After 24 hours in hypoxia, VHR ASCs formed fewer tubules in Matrigel than in control patient ASCs. CONCLUSION: ASCs derived from VHR patients appear to express fewer vasculogenic markers and form fewer tubules in Matrigel than ASCs from abdominoplasty patients, suggesting decreased vasculogenic activity. PMID- 24757683 TI - Study of effect of salvianolic acid B on motor function recovery in rats with spinal cord injury. AB - In this study effect of salvianolic acid B was observed on motor function recovery of rats with spinal cord injury. 50 rats were selected and after inducing SCI their recovery under controlled conditions was studied using Sal B and PBS (as control). Both compounds were introduced intraperitoneally in respective groups of traumatic rats at the same time intervals for 28 days. It was observed that Sal B introduced at 5 mg/kg/day resulted in better motor function recovery. BBB score was recorded which increased significantly along with the reduction in cavity area observed by bright field microscopy of tissues, that is, from 1 to 10 and from 0.20 +/- 0.05 mm(2) to 0.10 +/- 0.03 mm(2), in Sal B treated group, respectively, compared to PBS group. Statistical analysis was carried out using SPSS software (SPSS, Chicago, IL, USA), values were expressed as mean +/- SEM, and P value <0.01 was considered significant. Effect of Sal B on expression of NF-kB p65 and IkB alpha was studied and OD values of densitometry of western blots were taken. MPO activity was also studied. It was observed that treatment of Sal B significantly reduced the expression of both compounds in Sal B treated group as compared to control group after 28 days of treatment. PMID- 24757685 TI - The politics and analytics of health policy. PMID- 24757686 TI - The curse of wealth - Middle Eastern countries need to address the rapidly rising burden of diabetes. AB - The energy boom of the last decade has led to rapidly increasing wealth in the Middle East, particularly in the oil and gas-rich Gulf Cooperation Council (GCC) countries. This exceptional growth in prosperity has brought with it rapid changes in lifestyles that have resulted in a significant rise in chronic disease. In particular the number of people diagnosed with diabetes has increased dramatically and health system capacity has not kept pace. In this article, we summarize the current literature to illustrate the magnitude of the problem, its causes and its impact on health and point to options how to address it. PMID- 24757687 TI - Enabling compassionate healthcare: perils, prospects and perspectives. AB - There is an emerging consensus that caring and compassion are under threat in the frenetic environment of modern healthcare. Enabling and sustaining compassionate care requires not only a focus on the needs of the patient, but also on those of the care giver. As such, threats and exhortations to health professionals are likely to have limited and perverse effects and it is to the organisational and system arrangements which support staff that attention should shift. Any approach to supporting compassionate care may work for some services, for some patients and staff, some of the time. No single approach is likely to be a panacea. Unravelling the contexts within which different approaches are effectual will allow for more selective development of support systems and interventions. PMID- 24757688 TI - Determining the frequency of defensive medicine among general practitioners in Southeast Iran. AB - BACKGROUND: Defensive medicine prompts physicians not to admit high-risk patients who need intensive care. This phenomenon not only decreases the quality of healthcare services, but also wastes scarce health resources. Defensive medicine occurs in negative and positive forms. Hence, the present study aimed to determine frequency of positive and negative defensive medicine behaviors and their underlying factors among general practitioners in Southeast Iran. METHODS: The present cross-sectional study was performed among general practitioners in Southeast Iran. 423 subjects participated in the study on a census basis and a questionnaire was used for data collection. Data analysis was carried out using descriptive and analytical statistics through SPSS 20. RESULTS: The majority of participants were male (58.2%). The mean age of physicians was 40 +/- 8.5. The frequency of positive and negative defensive medicine among general practitioners in Southeast Iran was 99.8% and 79.2% respectively. A significant relationship was observed between working experience, being informed of law suits against their colleagues, and committing defensive medicine behavior (P< 0.001). CONCLUSION: The present study indicated high frequency of defensive medicine behavior in the Southeast Iran. So, it calls policy-makers special attention to improve the status quo. PMID- 24757689 TI - Health sector reforms and changes in prevalence of untreated morbidity, choice of healthcare providers among the poor and rural population in India. AB - BACKGROUND: India's health sector witnessed some major policy changes in 1990s that aimed at making health services more accessible to the population. METHODS: In this paper, I tried to present some preliminary results of the significant changes that occurred between 1995/6 and 2004, especially in relation to the question of access to healthcare for the poor and rural population using data from 52nd (1995-6) and 60th round (2004) of National Sample Survey Organization on 'morbidity and healthcare'. RESULTS: The analysis suggests that overall utilization of healthcare services have declined and the odds of not seeking care due to financial inability has further increased among the poor and rural population during the period of reforms. RESULTS of the multivariate logit regression model indicate that the non-poor, middle and above educated people were having greater likelihood of using services from private health care provider. CONCLUSION: Interestingly, poor and rural residents were more likely to have used healthcare from public facilities in 2004 than in 1995-6, suggesting that the shift from private to public sector is encouraging, provided they receive good quality health care services at public facilities and do not face catastrophic health expenditures. PMID- 24757690 TI - The profile of patients' complaints in a regional hospital. AB - BACKGROUND: A hospital should be an institution of understanding and respecting patients' rights, their families, physicians and other caregivers. Hospitals and all other healthcare centers must be cautious toward respecting ethical aspects of care and treatment. On the other hand, patients' satisfaction reflects capabilities of physicians and medical staff as well as the extent patients' rights and treatment quality are observed. Nowadays, complaints handling is considered as an essential component of healthcare system in line with promoting health standards. In the present study, researchers attempt to identify the resources, individuals, complained issues, and measures which are considered to handle these issues in a regional hospital. METHODS: We employed a descriptive, cross-sectional study to conduct this research. The research population included cases registered at the complaints unit of one of the hospitals in Isfahan in selected months of 2012 to 2013. The data were collected through observation of available documents. Excel software program was used for data analysis. RESULTS: Findings indicate that despite a decrease in the total number of complaints, there was an increase in the number of complaints about medical staff. Nursing staff were considered as the second highly complained unit during the study period. CONCLUSION: RESULTS obtained from the present study can be taken as experiences to modify and amend the hospital's future performance. In general, the existence of complaints in a system is an indication of gaps when providing healthcare services. Creating an organized system to collect complaints and reviewing them helps hospitals to be cognizant of their defects and plan to prevent their reoccurrence. PMID- 24757691 TI - The quality assessment of family physician service in rural regions, Northeast of Iran in 2012. AB - BACKGROUND: Following the implementation of family physician plan in rural areas, the quantity of provided services has been increased, but what leads on the next topic is the improvement in expected quality of service, as well. The present study aims at determining the gap between patients' expectation and perception from the quality of services provided by family physicians during the spring and summer of 2012. METHODS: This was a cross-sectional study in which 480 patients who referred to family physician centers were selected with clustering and simple randomized method. Data were collected through SERVQUAL standard questionnaire and were analyzed with descriptive statistics, using statistical T-test, Kruskal Wallis, and Wilcoxon signed-rank tests by SPSS 16 at a significance level of 0.05. RESULTS: The difference between the mean scores of expectation and perception was about -0.93, which is considered as statistically significant difference (P<= 0.05). Also, the differences in five dimensions of quality were as follows: tangible -1.10, reliability -0.87, responsiveness -1.06, assurance 0.83, and empathy -0.82. Findings showed that there was a significant difference between expectation and perception in five concepts of the provided services (P<= 0.05). CONCLUSION: There was a gap between the ideal situation and the current situation of family physician quality of services. Our suggestion is maintaining a strong focus on patients, creating a medical practice that would exceed patients' expectations, providing high-quality healthcare services, and realizing the continuous improvement of all processes. In both tangible and responsive, the gap was greater than the other dimensions. It is recommended that more attention should be paid to the physical appearance of the health center environment and the availability of staff and employees. PMID- 24757692 TI - A new synthesis in search of synthesizing agents Comment on "A new synthesis". AB - In a recent editorial in this journal Pierre-Gerlier Forest foretells a coming revolution in health policy based on the synthesis of four conceptual innovations and one technological breakthrough. As much as I agree with the intellectual story told in this editorial I present a more skeptical view of the effect of paradigm shifts on healthcare systems on the ground. I argue that ideas triumph when times are ripe and times are ripe in health policy when payers and providers can find a compromise between the need to value what providers do and their professional autonomy. I also argue that autonomy is a product of the market: patients value autonomy and prefer doctors to insurers. PMID- 24757693 TI - Breaking gridlock in health policy?; Comment on "A new synthesis". AB - Pierre-Gerlier Forest has put forward the case that we are on the brink of a revolution in health policy that will be the result of the interplay of five factors. I would not challenge any of them but would emphasize the need to address socio-economic health inequalities, which have the potential to become a major cost driver in a time of growing economic inequality. To Dr. Forest's list, I would add two important shifts that are taking shape. The first is the development of an outcome focus in healthcare that seeks to measure improvements in individual and population health status. The second is a Copernican revolution in which healthcare providers revolve around the patient. These developments will enable us to answer many questions about resource allocation and return on investment in healthcare, although I still think there will be an outstanding question of how many resources society is willing and able to allocate to healthcare. PMID- 24757694 TI - Clinical governance: costs and benefits. PMID- 24757695 TI - International Journal of Esthetic Dentistry. PMID- 24757696 TI - Direct composite restorations in anterior teeth. Managing symmetry in central incisors. AB - In direct restorations of anterior teeth, particularly central incisors, symmetry plays an important role. The clinician can take advantage of silicone indexes based on a wax-up to build palatal and incisal walls; however, when he has to reproduce free-hand chair-side symmetrical items like interproximal emergence profiles, macro- and microsurface textures, and chromatic characteristics, the result can often be unpredictable. A step-by-step class IV restoration treatment will be described, as well as a simple procedure to help reproduce, check and correct symmetrically interproximal wall contours and chromatic characteristics. PMID- 24757697 TI - Patient and team communication in the iPad era - a practical appraisal. AB - Communication with the patient and within the team is a critical factor that can influence the treatment outcome, especially in complex and multidisciplinary dental treatments. Indeed, effective communication, not focused on marketing but on proper information of the patient's intraoral situation, can encourage greater acceptance of treatment and also greater treatment satisfaction. Better communication within the dental team is also a very important factor to improve the final result and reduce the time needed to reach it. Thanks to new technological devices widely available, such as tablets, we can use visual communication and interaction with the clinical images of the patient in order to improve communication with the patient, and especially within the dental team. The use of this method allows us to obtain a facial, dentolabial and dental esthetic analysis of the patient that can be used in various clinical steps, improving the predictability of the esthetic outcome and at the same time reducing the number of clinical sessions usually required. PMID- 24757698 TI - Mucogingival therapy to treat implant fenestration in the esthetic zone: a case report after 2 year follow up. AB - Soft tissue fenestration in implants is considered not only as a situation that could negatively influence the long-term stability of the implant, but also creates an esthetic problem when it occurs in the visible area of the mouth. This article describes the resolution of a case that presented a vestibular fenestration of an osseointegrated implant placed to substitute the upper right incisor, which does not respect the recommendations of ideal three-dimensional position in a young patient with a high smile line. The case was treated using two mucogingival surgical techniques to avoid a more invasive approach. A prosthetic immediate final abutment was inserted in the day of the second surgery. The fenestration was successfully covered and 2 years later it remains stable. In this article, the details about the treatment are described. PMID- 24757699 TI - Micromorphology of ceramic etching pattern for two CAD-CAM and one conventional feldspathic porcelain and need for post-etching cleaning. AB - The aim of this in vitro study was to observe the effect of hydrofluoric acid (HF) on the surface of two glass ceramics for Cerec and to compare it with the effect on a conventional glass ceramic. Discs were cut from a feldspathic ceramic block (VitaMKII) and from a leucite reinforced glass ceramic (IPS EMPRESS CAD) for Cerec. 5% and 9% HF concentrations were used during 1 min and 2 min each. Afterwards samples were thoroughly water rinsed for 30 s. Half of the 9% HF 1 min samples were subsequently submitted to a complex post-etching cleaning. All samples were observed under a scanning electron microscope (SEM). The conventional feldspathic ceramic samples were built up on a refractory die and a platinum foil. They were treated with 9% HF for 2 min and water rinsed for 30 s. Half of the samples were submitted to the same post-etching cleaning protocol. All samples were examined under SEM and EDX. The Cerec ceramic samples and the platinum foil ones were clean and free of any precipitate after 30 s of water rinsing. Acid concentration, times of application and the postetching cleaning treatment did not influence the cleanliness of the samples. A thick layer of deposit was observed only on the refractory die samples. This was only diminished after the post-etching treatment. The EDX analysis detected the presence of fluoride (F) only on the refractory die samples. PMID- 24757700 TI - Superficial roughness on composite surface, composite enamel and composite dentin junctions after different finishing and polishing procedures. Part I: roughness after treatments with tungsten carbide vs diamond burs. AB - The aim of this study is to investigate different instruments for finishing composite restorations, as well as examining different surfaces and interfaces of the same restoration. The null hypothesis is represented by the fact that there are no significant differences on roughness of composite restorations finishing between tungsten carbide and diamond burs, furthermore the null hypothesis is that there are no significant differences on roughness between finishing on composite surfaces (C), compositeenamel (CE) and composite-dentin (CD) interfaces. The study was performed on 28 teeth, and class V cavities were prepared on the extracted teeth. Restorations were done in Filtek XTE nanofilled composite (3M Espe) in a standardized method, to then be finished. A comparison was made in the phase 1 between tungsten carbide burs (16 blades), diamond burs (46 MUm), with a similar shape by the same manufacturer (Komet). Each surface received 5 bur applications. Consequently, an analysis with a profilometer was performed. Phase 2 involved further confrontation of ulterior finishing with ultrafine tungsten carbide burs (30 blades) and with extra and ultrafine diamond burs (25 and 8 MUm) (the same shape as previously mentioned). A second analysis was then performed with a profilometer. All measurements were taken on C surfaces, CE and CD interfaces. Statistical analyses were carried out with c2 test (a = 0.05). CONCLUSIONS: The finishing procedures with fine grit or toothing burs gave a better smoothness with tungsten carbide burs compared to diamond burs. While with the ultrafine grit no significant differences were noted between tungsten carbide and diamond burs on the CE and CD interfaces, the diamond bur left less superficial roughness on the C surfaces. With regards to the superficial roughness of the different areas of restoration, it can be concluded that: minor roughness was detected on C surfaces, while the CD interface had the most superficial roughness, regardless of whether the diamond burs or tungsten carbide burs were used. This study shows some statistical differences that could not be clinically perceivable. The clinical relevance could be resumed as follows: the fine tungsten carbide burs provided less roughness compared to a fine diamond bur. There were no differences between the ultrafine tungsten carbide and diamond burs. The less favourable interface to be finished is CD, compared to the CE interface and C surfaces. PMID- 24757701 TI - Influence of ceramic color and translucency on shade match of CAD/CAM porcelain veneers. AB - OBJECTIVE: To investigate the influence of translucency of CAD/CAM ceramic milling blocks on the final color of porcelain veneer cemented using resin cement with two different opacities. MATERIALS AND METHODS: A standardized incisal lap preparation was made on a maxillary right central incisor that was duplicated using composite resin material (Z250, A4, 3M ESPE). The resin dies were individually laser scanned (Bluecam, Sirona) in order to build a 3D model of the porcelain veneer on the CAD software (Cerec 3D). Three types of milling blocks were used to fabricate the required restorations: multichromatic, high translucency, and low translucency milling blocks (IPS Empress CAD, A1 Vita shade tab). The milled veneers were polished, glazed, and bonded on the resin dies using high opacity and low opacity resin cements (Panavia F2.0). A digital shade guide device (Easyshade Advance, Vita) was used to measure color parameters (CIE Lab values) at the incisal, middle, and cervical third of each cemented restoration. DeltaE values of the cemented veneers were calculated against the target color (A1). RESULTS: Cementation of porcelain veneers resulted in significant color change of the resin die (A4) as DeltaE values ranged between 8.9 and 13.7. However, the type of milling block did not have an observable effect on final color as the measured DeltaE values, against original die color, were very close for the multichromatic block (DeltaE = 10.7 +/- 0.1), high translucency (DeltaE = 9.7 +/- 0.09), and low translucency blocks (DeltaE = 13.4 +/- 0.11). The opacity of the used resin cement did not affect the final shade match, as the observed DeltaE values using either high opacity and low opacity resin cement were less than 2 for the three used ceramic blocks. The greatest color difference was observed between the incisal third of multichromatic veneers (DeltaE = 8.9) and the cervical third of low translucency veneers (DeltaE = 13.7), while for the rest of the test groups this shift was not clinically observable (DeltaE < 2.5). CONCLUSION: Within the limitations of this study, the shade match of CAD/CAM porcelain veneers was not influenced by the translucency of used milling block or the opacity of the resin cement. PMID- 24757702 TI - Comparison of fracture resistance and fracture characterization of bilayered zirconia/fluorapatite and monolithic lithium disilicate all ceramic crowns. AB - PURPOSE: To compare the fracture resistance between bilayered zirconia/ fluorapatite and monolithic lithium disilicate heat-pressed crowns and characterize the mode of fracture failure. MATERIALS AND METHODS: Thirty crown samples were sequentially fitted on a mandibular right first molar metal replica of an ivory prepared molar tooth. The crown specimens were divided in three groups (A, B, and C; n = 10 for each group). Group A consisted of bilayered zirconia/fluorhapatite pressed-over crowns with standard design crown copings (0.7 mm uniform thickness), Group B of bilayered zirconia/fluorhapatite with anatomical design crown copings, and Group C of lithium disilicate monolithic crowns. The samples were then dynamically loaded under water for 100,000 cycles with a profile of 250 N maximum load at 1,000 N/s rate and 2.0 Hz frequency. Loading was performed with a steel ball (5 mm in diameter) coming into contact with the test crown, loading to maximum, holding for 0.2 s, unloading and lifting off 0.5 mm. The samples were then fractured under static loading, in order to determine the ultimate crown strength. Analysis of the recorded fracture load values was carried out with one-way analysis of variance (ANOVA) followed by Tukey tests. Fractured specimens were examined by stereomicroscopy and scanning electron microscopy. RESULTS: The fracture loads measured were (N, means and standard deviations): Group A: 561.87 (72.63), Group B: 1,014.16 (70.18) and Group C: 1,360.63 (77.95). All mean differences were statistically significant (P < 0.001). Catastrophic fractures occurred in Group C, whereas mainly veneer fractures were observed in Groups A and B. CONCLUSION: In the present study, the heat-pressed monolithic lithium-disilicate crowns showed more fracture resistance than zirconia/fluorapatite pressed-over crowns. Within the bilayered groups, the anatomical zirconia coping design presented increased ceramic fracture resistance. PMID- 24757704 TI - Publish or perish, publish and perish. PMID- 24757706 TI - Universal or Multi-mode Adhesives: Why and How? PMID- 24757707 TI - Characterization of biofluids prepared by sessile drop formation. AB - Sessile drop formation, also called drop deposition, has been studied as a potential medical diagnostic, but the effects of complex biofluid rheology on the final deposition pattern are not well understood. We studied two model biofluids, blood plasma and synovial fluid, when deposited onto slightly hydrophilic substrates forming a contact angle of 50-90 degrees . Drops were imaged during the evaporation process and geometric properties of the drop, such as contact angle and drop height, were calculated from the images. The resulting dried biofluid drops were then examined using light microscopy and Raman spectroscopy to assess morphological and chemical composition of the dried drop. The effect of substrate contact angle (surface wetting) and fluid concentration was examined. We found that when biofluids are deposited onto slightly hydrophilic surfaces, with a contact angle of 50-90 degrees , a ring-shaped deposit was formed. Analysis of the drying drop's geometric properties indicates that biofluid dynamics follow the piling model of drop formation, as proposed by Deegan et al. The final deposition pattern varied with substrate surface and concentration, as shown by light microscopy photos of dried drops. The chemical composition of the outer ring was minimally affected by substrate surface, but the spatial heterogeneity of protein distribution within the ring varied with concentration. These results indicate that biofluid drop deposition produces ring-shaped deposits which can be examined by multiple analytical techniques. PMID- 24757708 TI - Selective electrochemical detection of dopamine in a microfluidic channel on carbon nanoparticulate electrodes. AB - There is a continuous need for the construction of detection systems in microfluidic devices. In particular, electrochemical detection allows the separation of signals from the analyte and interfering substances in the potential domain. Here, a simple microfluidic device for the sensitive and selective determination of dopamine in the presence of interfering substances was constructed and tested. It employs a carbon nanoparticulate electrode allowing the separation of voltammetric signals of dopamine and common interfering substances (ascorbic acid and acetaminophen) both in quiescent conditions and in flow due to the electrocatalytic effect. These voltammograms were also successfully simulated. The limit of detection of dopamine detected by square wave voltammetry in 1 mM solutions of interfering substances in phosphate buffered saline is about 100 nM. In human serum a clear voltammetric signal could be seen for a 200 nM solution, sufficient to detect dopamine in the cerebral fluid. Flow injection analysis allows a decrease in the limit of detection down to 3.5 nM. PMID- 24757709 TI - Opioid mortality: flawed analysis? PMID- 24757710 TI - [Burning mouth syndrome (glossalgia)]. AB - Burning mouth syndrome (glossalgia) is manifested by oral pin and tingling sensations, numbness and even burning and severe pains, more frequently in the tongue. Unpleasant sensations may involve the anterior two thirds of the tongue or be extended to the front part of the hard palate and the mucous membrane of the lower lip. This condition is characterized by "mirror" and "food dominant" symptoms, disordered salivation, dysgeusia, or psychological disorders. The disease shows a chronic course. Its etiology may be multifactorial. There are no universally accepted diagnostic criteria; the diagnosis of glossalgia is made to rule out all other causes. A thorough examination should be conducted to establish a differential diagnosis. Glossalgia occurs primarily in middle-aged and elderly people. Women get sick much more frequently than men of the same age. Glossalgia remains difficult to treat. Continuous symptomatic treatment and follow-up help relieve its symptoms. PMID- 24757711 TI - Viroid-like RNAs from cherry trees affected by leaf scorch disease: further data supporting their association with mycoviral double-stranded RNAs. AB - Cherry trees from Spain affected by cherry leaf scorch (CLS), a fungal disease proposed to be caused by Apiognomonia erythrostoma, show symptoms (translucent chlorotic leaf spots evolving into rusty areas) very similar to those of cherry chlorotic rusty spot disease (CCRS) and Amasya cherry disease, reported in Italy and Turkey, respectively. The three maladies are closely associated with 10-12 double-stranded viral RNAs, and CCRS is additionally associated with two cherry small circular RNAs (cscRNA1 and cscRNA2). Here, we report that a small viroid like RNA similar to the CCRS-associated cscRNA1 is also present in CLS-affected trees, thus extending the link between the two diseases. Both CLS and CCRS cscRNA1 elements have common features, including sequence identity (88 %), a predicted quasi rod-like conformation with short bifurcations at both termini, and the presence of hammerhead ribozymes in the strands of both polarities. However, cscRNA2, apparently derived from cscRNA1 by deletion of a short hairpin, was not detected in CLS-affected material. Although the biological nature of cscRNAs is unknown, the identification of at least cscRNA1 in different cherry cultivars and in two distinct geographic areas (Spain and Italy), always in close association with the same mycoviral dsRNAs, supports that these viroid-like RNAs could be satellite RNAs. PMID- 24757712 TI - Genomic sequence analysis of Helicoverpa armigera nucleopolyhedrovirus isolated from Australia. AB - The complete genomic sequence of Helicoverpa armigera nucleopolyhedrovirus from Australia, HearNPV-Au, was determined and analyzed. The HearNPV-Au genome was 130,992 bp in size with a G + C content of 39 mol% and contained 134 predicted open reading frames (ORFs) consisting of more than 150 nucleotides. HearNPV-Au shared 94 ORFs with AcMNPV, HearSNPV-G4 and SeMNPV, and was most closely related to HearSNPV-G4. The nucleotide sequence identity between HearNPV-Au and HearSNPV G4 genome was 99 %. The major differences were found in homologous regions (hrs) and baculovirus repeat ORFs (bro) genes. Five hrs and two bro genes were identified in the HearNPV-Au genome. All of the 134 ORFs identified in HearNPV-Au were also found in HearSNPV-G4, except the homologue of ORF59 (bro) in HearSNPV G4. The sequence data strongly suggested that HearNPV-Au and HearSNPV-G4 belong to the same virus species. PMID- 24757713 TI - Reply to Bar-Oz et al.: Commensalism and mutualism as early incentives for cat domestication. PMID- 24757714 TI - Reply to Bos and De Jonge: Between-subject data do provide first empirical support for critical slowing down in depression. PMID- 24757715 TI - Viral mimicking ternary polyplexes: a reduction-controlled hierarchical unpacking vector for gene delivery. AB - Reduction-controlled hierarchical unpacking is proposed for the development of virus-mimicking gene carriers. Disulfide-bond-modified hyaluronic acid (HA) is deposited onto the surface of diselenide-conjugated oligoethylenimine/DNA polyplexes to form DNA/OEI-SeSex/HA-SS-COOH (DOS) polyplexes. The cleavage of the disulfide and diselenide bonds is triggered by the gradient GSH level at the tumor site and inside the cells. The transfection efficiency of DOS show significant enhancement over DNA/poly(ethylene imine) (DP) in vitro and in vivo. PMID- 24757716 TI - High charge carrier mobilities and lifetimes in organolead trihalide perovskites. AB - Organolead trihalide perovskites are shown to exhibit the best of both worlds: charge-carrier mobilities around 10 cm2 V-1 s-1 and low bi-molecular charge recombination constants. The ratio of the two is found to defy the Langevin limit of kinetic charge capture by over four orders of magnitude. This mechanism causes long (micrometer) charge-pair diffusion lengths crucial for flat-heterojunction photovoltaics. PMID- 24757717 TI - Obituary: Janet Davison Rowley 1925-2013. PMID- 24757719 TI - Vemurafenib oral bioavailability: an insoluble problem. PMID- 24757720 TI - Indications and outcomes of pancreatic surgery after liver transplantation. AB - BACKGROUND: Prior liver transplantation and immunosuppression potentially translate into significant morbidity and poor outcomes after any type of pancreatic surgery. Little is known about the outcomes of pancreatic surgery after liver transplantation. This study was designed to review our experience regarding the indications and outcomes of pancreatic surgery following liver transplantation. METHODS: A retrospective review of all liver transplant recipients who underwent pancreatic surgery between 1991 and 2009 was performed. RESULTS: A total of 3196 patients underwent liver transplantation, of whom 18 (0.6%) subsequently required pancreatic surgery. The most common indications were necrotizing pancreatitis and lesions of the head and tail of the pancreas. Procedures performed included pancreaticoduodenectomy, distal pancreatectomy, and pancreatic necrosectomy. The estimated blood loss was 500 mL and operative time was 430 +/- 224 min. Pathology results revealed malignant lesions in six (33%) patients, pre-malignant lesions in 2 (11%) patients, and benign lesions in 10 (56%) patients. The median time from transplantation to pancreatic surgery was 61 months. The 30-d postoperative complication rate was 77.8%, with median hospital stay of 15 d. The three-, 12-, and 24-month survival rates were 78%, 48%, and 24%, respectively. CONCLUSIONS: Pancreatic surgery after liver transplantation results in significant 30-d complications. Prior liver transplantation, however, should not be a contraindication for subsequent pancreatic surgery, due to its decent survival outcome. PMID- 24757718 TI - Downregulation of the Werner syndrome protein induces a metabolic shift that compromises redox homeostasis and limits proliferation of cancer cells. AB - The Werner syndrome protein (WRN) is a nuclear protein required for cell growth and proliferation. Loss-of-function mutations in the Werner syndrome gene are associated with the premature onset of age-related diseases. How loss of WRN limits cell proliferation and induces replicative senescence is poorly understood. Here, we show that WRN depletion leads to a striking metabolic shift that coordinately weakens the pathways that generate reducing equivalents for detoxification of reactive oxygen species and increases mitochondrial respiration. In cancer cells, this metabolic shift counteracts the Warburg effect, a defining characteristic of many malignant cells, resulting in altered redox balance and accumulation of oxidative DNA damage that inhibits cell proliferation and induces a senescence-like phenotype. Consistent with these findings, supplementation with antioxidant rescues at least in part cell proliferation and decreases senescence in WRN-knockdown cancer cells. These results demonstrate that WRN plays a critical role in cancer cell proliferation by contributing to the Warburg effect and preventing metabolic stress. PMID- 24757721 TI - The impact of recurrence of primary glomerulonephritis on renal allograft outcome. AB - Twenty-yr patient and death-censored graft survival of 348 kidney transplant recipients with primary glomerulonephritis (GN) and of 696 matched controls were 82.2% in GN patients and 75% in controls (p = 0.037) and 49.5% and 54%, respectively (p = 0.013). GN patients had a higher incidence of graft failure than controls even considering death as a competing risk (p = 0.004). In the GN group, graft survival of deceased and of living donor recipients was similar. At multivariate analysis, GN as primary disease (RR: 1.47), delayed graft function recovery (RR: 2.34), acute rejection (RR: 2.36), and any PRA positivity (RR: 1.01) were predictive of graft loss. GN recurred in 85 of 348 grafts (24.4%), and 43 were lost for recurrence. In non-recurrent patients, graft survival at 20 yr was significantly better than in recurrent patients (59.4% vs. 24.4%, p = 0.000), but not different from that of controls (59.4 vs. 54%, p = 0.9). At multivariate analysis, young age at transplantation (RR: 0.97), shorter duration of dialysis (RR: 1.05 per each dialysis year), and graft from living donors (RR: 1.668) were independent predictors of recurrence. Patients with primary GN have reduced graft survival in comparison with controls, and this is mainly due to recurrence of original disease. However, the most frequent recurrence in living recipients does not compromise graft survival. PMID- 24757722 TI - Usefulness of p16/Ki67 immunostaining in the triage of women referred to colposcopy. AB - BACKGROUND: This study compared the performance of p16/Ki67 dual-staining and human papillomavirus (HPV) testing in women referred to colposcopy and sought to determine the usefulness of a morphological evaluation of the double-stained cells. METHODS: This prospective study included 1123 women (mean age, 35.8 +/- 10.9 years) referred to colposcopy from October 2009 to November 2012 due to positive HPV testing or abnormal cytology results (atypical squamous cells of unknown significance, or worse abnormalities). Liquid-based cytology specimens (PreservCyt, Hologic) were used for HPV detection (Hybrid Capture 2 [HC2]; Qiagen) and p16/Ki67 dual-staining (CINtec Plus; Roche-mtm Laboratories). All women underwent histological study. After completion of the study, 18 patients were classified as having cervical cancer (CC), 378 had a high-grade squamous intraepithelial lesion (HSIL), 304 had a low-grade squamous intraepithelial lesion, and 423 were negative. RESULTS: The sensitivity and specificity of p16/Ki67 dual-staining for HSIL/CC were 90.9% (95% confidence interval [CI] = 87.9-93.9) and 72.1 (95% CI = 68.7-75.4), respectively. For HC2, the figures were, respectively, 96.0% (95% CI = 93.9-98.0) and 41.4 (95% CI = 37.7-45.0). The values were high both in women < 30 and >= 30 years old (86.9% and 63.3% versus 92.3% and 77.8%, respectively). The addition of a morphological evaluation of the dual-stain-positive cells with establishment of HSIL features as the threshold for a positive reaction increased the specificity (93.5%) but decreased the sensitivity (84.1%). CONCLUSIONS: Use of the molecular markers p16 and Ki67 has higher specificity than HC2 tests for HSIL or CC, which may support p16/Ki67 dual staining use in the triage of patients referred for abnormal screening results. Morphological evaluation of p16/Ki67-positive cells may have some benefits in women younger than 30 years or with low-grade squamous intraepithelial lesion. PMID- 24757723 TI - Biochemical perspectives of xylitol extracted from indigenous agricultural by product mung bean (Vigna radiata) hulls in a rat model. AB - BACKGROUND: The production of xylitol from lignocellulosic material is of great interest around the world. It can be used as bulk sweetener and its possible lower energy value has increased acceptance for discerning consumers. Xylitol was produced from indigenous agricultural by-product (mung bean hulls) through Candida tropicalis fermentation. Further, xylitol incorporation at different concentrations (0, 100 and 200 g kg-1) was carried out with the purpose of appraising the suitability and claimed health benefits of this dietetic ingredient in food products. Asserted biochemical perspectives of the xylitol intake were evaluated through biological studies for normal and streptozotocin induced diabetic rats. RESULTS: The addition of xylitol significantly affected feed intake, weight gain, liver and cecum weight in both normal and diabetic rats. The biochemical profile of serum was improved with xylitol incorporation in the diet. Serum glucose, cholesterol and triglycerides levels were decreased depending on xylitol intake level. CONCLUSION: The results of the present study demonstrated that mung bean hulls have high potential as a new feedstock for xylitol production. In addressing the current concerns of obesity and diabetes, xylitol extracted from such agricultural waste should be considered in diet-based therapies for weight loss programmes. PMID- 24757725 TI - ["Simply stay loose!"]. PMID- 24757724 TI - [Epigenetics: between genes and environment]. PMID- 24757726 TI - Response to implementation of rapid cortisol during adrenal vein sampling. PMID- 24757727 TI - Systematic review and meta-analysis of respiratory syncytial virus infection epidemiology in Latin America. AB - Respiratory syncytial virus (RSV) is a frequent cause of acute respiratory infection and the most common cause of bronchiolitis in infants. The aim of this systematic review and meta-analysis was to obtain a comprehensive epidemiological picture of the data available on disease burden, surveillance, and use of resources in Latin America. Pooled estimates are useful for cross-country comparisons. Data from published studies reporting patients with probable or confirmed RSV infection in medical databases and gray literature were included from 74 studies selected from the 291 initially identified. When considering all countries, the largest pooled percentage RSV in low respiratory tract infection patients was found in the group between 0 and 11 months old, 41.5% (95% CI 32.0 51.4). In all countries, percentages were increasingly lower as older children were included in the analyses. The pooled percentage of RSV in LRTIs in the elderly people was 12.6 (95% CI 4.2-24.6). The percentage of RSV infection in hospitalized newborns was 40.9% (95% CI 28.28-54.34). The pooled case fatality ratio for RSV infection was 1.74% (95% CI 1.2-2.4) in the first 2 years of life. The average length of stay excluding intensive care unit admissions among children with risk factors for severe disease was 12.8 (95% CI 8.9-16.7) days, whereas it averaged 7.3 (95% CI 6.1/8.5) days in otherwise healthy children.We could conclude that infants in their first year of age were the most vulnerable population. To our knowledge, this is the first systematic review on RSV disease burden and use of health resources in Latin America. PMID- 24757728 TI - Inhibitory receptor molecules in chronic hepatitis B and C infections: novel targets for immunotherapy? AB - Chronic HBV and HCV infections are the leading cause of liver-related morbidity and mortality. For effective antiviral immunity, virus-specific T cells are required, but these cells have been shown to be weak or absent in chronic HBV and HCV patients. One of the mechanisms that underlies the impaired T-cell response is the result of the continuously high viral load that causes HBV-specific and HCV-specific T cells to become exhausted, which is characterized by impaired proliferation, cytokine production and cytotoxic activity of T cells as well as high susceptibility to apoptosis. In vitro studies from chronic HBV and HCV patients as well as in vivo studies in animal models demonstrated a reversible state of T-cell exhaustion, which can be manipulated to reinvigorate the specific antiviral immune responses. In chronic HCV infection, this concept has been explored in clinical trials by administration of specific antibody to block the inhibitory pathways. The manipulation of inhibitory receptors is a promising and potential strategy for immunotherapeutic interventions in chronic HBV and HCV patients to facilitate complete elimination of the viruses or sustained viral control. PMID- 24757729 TI - Response to hypertension guidelines: political correctness trumping expertise? PMID- 24757730 TI - Response to should more significance be granted to medication response to antihypertensives in patients with resistant hypertension? PMID- 24757731 TI - Response to more research is needed to investigate the effect of denervation on blood pressure. PMID- 24757732 TI - [Reply]. PMID- 24757733 TI - Detection of Toxoplasma gondii in two southern Wooly spider monkeys (Brachyteles arachnoides-Geoffroy, 1806) from the Rio de Janeiro primate center, Brazil. AB - BACKGROUND: Toxoplasmosis led to the death of two Brachyteles arachnoides, an endangered atelid. METHODS: The diagnosis was established by necropsy, histopathological, immunohistochemical and ultrastructural changes. RESULTS: The analysis confirms the presence of Toxoplasma gondii. CONCLUSIONS: This report contributes to the development of protocols for health surveillance on maintenance and conservation of southern muriquis. PMID- 24757734 TI - European funding allows further research into fingerprint drug screening. PMID- 24757735 TI - Rapid detector developed for Chlamydia trachomatis. PMID- 24757736 TI - Study identifies novel biomarker of prostate cancer reoccurrence. PMID- 24757737 TI - Collaboration for precision medicine. PMID- 24757738 TI - Saliva-based test for Parkinson's disease. PMID- 24757739 TI - Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. AB - PURPOSE: To determine the overall survival for patients with metastatic pancreatic cancer treated with lapatinib and gemcitabine. MATERIALS AND METHODS: Patients with metastatic pancreatic cancer received lapatinib, 1,500 mg/d, and Gemcitabine, 1 g/m(2)/wk for 3 weeks followed by 1 week off, until disease progression. This multicenter phase II study was planned to enter 125 patients to evaluate whether the treatment regimen could achieve a 1-year survival of 30% and a median survival of 7 months. An additional subset of 20 patients were to receive 2 months of single agent lapatinib followed by lapatinib and gemcitabine. RESULTS: At a planned 6 month analysis, the Brown University Oncology Group Data Safety Monitoring Board terminated accrual after 29 patients because of futility analysis. The median survival was 4 months (95% confidence interval, 3.0-5.0 months). Three of the 29 (10%) patients had a partial response. The 4 patients who received single agent lapatinib all progressed at 1 month. CONCLUSION: Lapatinib is not effective in pancreatic cancer. Evaluation of HER2 inhibitors in pancreatic cancer is not warranted. PMID- 24757740 TI - Retraction: 'The malignant obesity hypoventilation syndrome (MOHS)' by P. E. Marik. PMID- 24757742 TI - [The opportunities for extracorporeal treatment of hepatic failure]. PMID- 24757743 TI - [The history of fundoplication (the era before laparoscopy)]. PMID- 24757744 TI - [The doctors who treated P.I. Bagration after his wound]. PMID- 24757745 TI - [Professor M.S. Subbotin and the development of the aseptic technique in Russia]. PMID- 24757749 TI - Reply from the author. PMID- 24757750 TI - Emergency managers as community change agents: an expanded vision of the profession. AB - Reflecting the historical evolution of attack preparedness, technological failures, and so-called natural disaster events, the profession of emergency management confronts new challenges today. In part, these reflect important cultural differences among stakeholder groups, especially local emergency managers. homeland security personnel, and those focused on public health threats and business continuity. An expanded and more strategic vision of the profession is required wherein fundamental assumption sets are placed into broader contexts. Contrary to the drift experienced in the US during the past decade, a major paradigm shift is required reflecting new orientations and program priorities. PMID- 24757751 TI - The efficacy of pralidoxime in organophosphorus poisoning: a commentary. PMID- 24757752 TI - Commentary on projects not initiated by investigators: a retrospective analysis of the queries raised by the institutional ethics committees of a teaching hospital. PMID- 24757753 TI - Authors' reply. PMID- 24757754 TI - Authors' reply. PMID- 24757755 TI - The figure one problem. PMID- 24757756 TI - Life as a serial entrepreneur. PMID- 24757757 TI - Biomedical and health informatics: future prospects for the field and for our students. PMID- 24757758 TI - The super aged society: Japan's The KAITEKI Institute studies how to keep the elderly healthy and active. PMID- 24757759 TI - The fallacy of genetic selection. PMID- 24757760 TI - An early telegraph idea: physicians often feel attracted to engineering: an illustration of how old, wide, and intermingled science and technology are. PMID- 24757761 TI - Authors' reply. PMID- 24757763 TI - [Overview on the control of MAC disease]. PMID- 24757762 TI - Folate receptor-targeted single-photon emission computed tomography/computed tomography to detect activated macrophages in atherosclerosis: can it distinguish vulnerable from stable atherosclerotic plaques? AB - The need for noninvasive imaging to distinguish stable from vulnerable atherosclerotic plaques is evident. Activated macrophages play a role in atherosclerosis and express folate receptor folate receptor beta (FR-beta). The feasibility of folate targeting to detect atherosclerosis was demonstrated in human and mouse plaques, and it was suggested that molecular imaging of FR-beta through folate conjugates might be a specific marker for plaque vulnerability. However, these studies did not allow differentiation between stable and vulnerable atherosclerotic plaques. We investigated the feasibility of a folate based radiopharmaceutical (111)In-EC0800) with high-resolution animal single photon emission computed tomography/computed tomography (SPECT/CT) to differentiate between stable and vulnerable atherosclerotic plaques in apolipoprotein E(-/-) mice in which we can induce plaques with the characteristics of stable and vulnerable plaques by placing a flow-modifying cast around the common carotid artery. Both plaques showed (111)In-EC0800 uptake, with higher uptake in the vulnerable plaque. However, the vulnerable plaque was larger than the stable plaque. Therefore, we determined tracer uptake per plaque volume and demonstrated higher accumulation of (111)In-EC0800 in the stable plaque normalized to plaque volume. Our data show that (111)In-EC0800 is not a clear-cut marker for the detection of vulnerable plaques but detects both stable and vulnerable atherosclerotic plaques in a mouse model of atherosclerosis. PMID- 24757764 TI - [Recent findings on MRI testing--clinical application of 3T ultra-high magnetic apparatus]. PMID- 24757765 TI - [Basic techniques for cervical dissection]. PMID- 24757766 TI - [New development in rehabilitation in facial nerve paralysis]. PMID- 24757767 TI - [Diagnosis and treatment of eosinophilic paranasal sinusitis]. PMID- 24757768 TI - Transformed insect cells as high throughput screening tools for the discovery of new bioactive compounds. PMID- 24757769 TI - The use of relative quantitative RT-PCR for expression analysis in azalea flower color sports. AB - The fastest way to create new azalea (Rhododendron simsii hybrids) cultivars is by making use of flower colour sports, which appear spontaneously on azalea plants. Unfortunately, there is still very little known on how bud sport induction occurs. Therefore, genes coding for two key enzymes of the azalea flavonoid biosynthesis pathway, chalcon synthase (chs) and dihydroflavonol 4 reductase (dfr) that were reported before to be apt for modification by the action of bud sporting, were isolated and characterized. The expression of these two flower colour genes in the petals of azalea flowers will be compared between all 'Hellmut Vogel' flower colour sports. To measure the expression levels of both genes, relative quantitative RT-PCR analysis will be worked out on a real time PCR machine. The expression of housekeeping genes, which is expected to be the same for all sports, will be used to calculate the relative expression level of the two genes of interest. The optimisation of this technique will be discussed. PMID- 24757770 TI - Screening of remote Rhododendron species and hybrids for interspecific hybridization with R. simsii hybrids. AB - To introduce yellow, blue or orange pigmentation in the Rhododendron subgenus Tsutsusi (including R. simsii hybrids) by classical breeding, intersubgeneric pollination experiments involving Hymenanthes, Pentanthera and Rhododendron (including Vireya) species and hybrids were started. Prefertilization research by pollen tube staining revealed a different behaviour between bilateral crosses. Ovule culture was applied as a means to save a substantially larger amount of hybrid embryos from abortion. Though flower/seed capsule abortion eliminated many crosses in an early developmental stage, ovules of many crosses could be initiated in vitro on various time intervals after pollination. Germination was achieved on basal Rhododendron medium + 50 mg/l GA3. Green seedlings were obtained after Tsutsusi x Hymenanthes, Hymenanthes x Tsutsusi, Tsutsusi x Rhododendron, Rhododendron x Tsutsusi and Vireya x Tsutsusi pollination. Many seedlings have little growth vigour and next to green seedlings albino seedlings occur frequently, depending on the pollination type. The first true leaves of many assumed hybrids obviously lack chlorophyll. The ploidy level of Vireya x Tsutsusi and Tsutsusi x Pentanthera seedlings is intermediate, which strongly suggests their hybrid origin. Molecular analysis through SSR confirmed the interspecific charachter of seedlings in half of the crosses tested. PMID- 24757771 TI - Exceptionally high heterologous protein levels in transgenic dicotyledonous seeds using Phaseolus vulgaris regulatory sequences. AB - Seeds are concentrated sources of protein and thus may be ideal 'bioreactors' for the production of heterologous proteins. For this application, strong seed specific expression signals are required. A set of expression cassettes were designed using 5' and 3' regulatory sequences of the seed storage protein gene arcelin 5-I (arc5-I) from Phaseolus vulgaris, and evaluated for the production of heterologous proteins in dicotyledonous plant species. A murine single-chain variable fragment (scFv) was chosen as model protein because of the current industrial interest to produce antibodies and derived fragments in crops. Because the highest scFv accumulation in seed had previously been achieved in the endoplasmic reticulum (ER), the scFv-encoding sequence was provided with signal sequences for accumulation in the ER. Transgenic Arabidopsis seed stocks, expressing the scFv under control of the 35S promoter, contained scFv accumulation levels in the range of 1% of total soluble protein (TSP). However, the seed storage promoter constructs boosted the scFv to exceptionally high levels. Maximum scFv levels were obtained in homozygous seed stocks, being 12.5% of TSP under control of the arc5-I regulatory sequences and even up to 36.5% of TSP upon replacing the arc5-I promoter by the beta-phaseolin promoter of Phaseolus vulgaris. Even at such very high levels, the scFv proteins retain their full antigen-binding activity. Moreover, the presence of very high scFv levels has only minory effects on seed germination and no effect on seed production. These results demonstrate that the expression levels of arcelin 5-I and beta phaseolin seed storage protein genes can be transferred to heterologous proteins, giving exceptionally high levels of heterologous proteins, which can be of great value for the molecular farming industry by raising production yield and lowering bio-mass production and purification costs. Finally, the feasibility of heterologous protein production using the arcelin 5-I construct was demonstrated in the legume Phaseolus acutifolius, an interesting and promising crop for large scale production. PMID- 24757772 TI - Molecular markers for cold tolerance and early vigour in maize (Zea mays L.). AB - Planting maize earlier than the current guidelines recommend, would give great contributions to ecological and sustainable agriculture. In order to plant maize earlier, maize varieties with good cold tolerance and strong early vigour are required. Therefore cold tolerance and early vigour should be important goals in modern maize breeding programmes. Both traits however have a complex, quantitative genetic background and are therefore not easily introduced into modern maize varieties. Marker assisted selection (MAS) can improve the efficiency of breeding activities. In this research project we aim to identify the molecular markers for cold tolerance and early vigour in one of our breeding populations through a QTL analysis. So far nine QTLs for cold tolerance and six QTLs for early vigour could be identified and there is even one QTL in common for the two traits under investigation. The analysis of more populations should reveal whether or not these QTLs might be useful in maize breeding programmes over the world. PMID- 24757773 TI - Genetic analysis of resistance to blast in the Vietnamese rice cultivar 'Chiembac'. AB - The resistance to rice blast disease in the Vietnamese traditional rice cultivar 'Chiembac' was studied. The blast resistance spectrum in 'Chiembac' and 15 rice differentials carrying different known resistance genes was identified using 25 Pyricularia grisea isolates derived from 15 AFLP lineages from the North, Center and South of Vietnam. None of the differential lines carrying a single resistance gene could effectively control all tested Vietnamese blast isolates. 'Chiembac' showed a different resistance pattern compared to that of the differential lines. A cross between 'Chiembac' and 'CR203', an improved rice cultivar, was made and the F2 population was used for characterization and mapping of the resistance genes in 'Chiembac'. Genetic analysis showed that the resistance against two representative isolates from two predominant lineages, VT7 and 12, in 'Chiembac' was controlled by the single dominant genes Pi-VT7 and Pi-I2. The resistance gene Pi-VT7 was closely linked to Pi-I2 and was mapped to chromosome 12 using the framework mapping population 'IR64' x 'Azucena' of 124 double haploid progenies. The resistance to the Vietnamese blast isolate VT7 in 'IR64' was also studied. The latter was controlled by one locus with major effect located on chromosome 12 and mapped closely to the AFLP marker NIN080, which was also tightly linked to the resistance gene Pi-VT7 in 'Chiembac'. Thus, the resistance locus Pi-VT7 and the resistance locus in 'IR64' probably belong to a cluster of resistance genes. PMID- 24757774 TI - Melaphen-- the new harmless regulator of plants growth. PMID- 24757775 TI - Cross-pollination between genetically modified and conventional oilseed rape fields. AB - Since the introduction of genetically modified crops in Europe, gene flow from those crops to conventional crops and wild relatives has been a key element in the safety assessment. In this experiment cross-pollination frequencies from a genetically modified herbicide tolerant oilseed rape crop to a conventional one were measured at six defined distances from the GM crop by taking seed samples in the conventional crop and analysing the progeny for presence of the herbicide tolerance gene. Levels of cross-pollination tend to decrease with increasing distance from the pollen source. Transgenic volunteers emerging in the subsequent crop can however be readily controlled with normal agricultural practices. PMID- 24757776 TI - Evening primrose (Oenothera paradoxa) cake as an unconventional protein source. AB - An efficient procedure of a protein isolate production from the evening primrose cake was developed. The cake is a by-product of oil extraction from seeds by using the cold pressing method. The evening primrose cake contains 22.7% of protein. Its content in the protein isolate derived from the cake is 74%. Proteins present in evening primrose seeds are rich in Trp (7%) and Met (3%), but Lys-deficient (1.3%) as compared to the FAO protein standard. Apart from the proteins, the protein isolate contains 8.5% (w/w per s.s.) dietary fiber, that negatively affects its digestibility. To enhance the bio-availability of the protein isolate, it was partially hydrolyzed with commercial preparations of trypsin and other proteases (Alcalase and Flavourzyme, Novozymes. Denmark). The most advanced proteolysis (52%) was achieved by 6 h digestion of 2% protein suspension with a mixture of Flavourzyme and Alcalase (350 and 600 U per g of protein, respectively) at 50 degrees C and pH 9.0. PMID- 24757777 TI - Fingerprinting and quantification of GMOs in the agro-food sector. AB - Most strategies for analyzing GMOs in plants and derived food and feed products, are based on the polymerase chain reaction (PCR) technique. In conventional PCR methods, a 'known' sequence between two specific primers is amplified. To the contrary, with the 'anchor PCR' technique, unknown sequences adjacent to a known sequence, can be amplified. Because T-DNA/plant border sequences are being amplified, anchor PCR is the perfect tool for unique identification of transgenes, including non-authorized GMOs. In this work, anchor PCR was applied to characterize the 'transgene locus' and to clarify the complete molecular structure of at least six different commercial transgenic plants. Based on sequences of T-DNA/plant border junctions, obtained by anchor PCR, event specific primers were developed. The junction fragments, together with endogeneous reference gene targets, were cloned in plasmids. The latter were then used as event specific calibrators in real-time PCR, a new technique for the accurate relative quantification of GMOs. We demonstrate here the importance of anchor PCR for identification and the usefulness of plasmid DNA calibrators in quantification strategies for GMOs, throughout the agro-food sector. PMID- 24757778 TI - Bio-imaging used for understanding cell-matrix interactions in foods. PMID- 24757779 TI - Laser scanning cytometry to detect viable but non-culturable C. jejuni in drinking water. AB - Laser scanning cytometry has been investigated as a tool to detect viable but non culturable C. jejuni in drinking water. After suspending the cells in sterile drinking water, a sample was taken every seven days, the (see text) were retained on a polyester membrane filter and labelled using a fluorescein derivative as a substrate for intracellular esterases. The number of green fluorescent bacteria was automatically counted by an Ar laser scanning device in three minutes. In parallel, the number of culturable cells was determined on a non-selective medium. The number of culturable cells decreased to below the detection limit for cultivation in less then 50 days. At the contrary, fluorescent bacteria remained at the initial level during the 71 days of incubation. The discrepancy between the two results can be assigned to the presence of VBNC C. jejuni cells. Therefore laser scanning cytometry can be used as a fast and sensitive tool to detect viable but non-culturable C. jejuni in drinking water. PMID- 24757780 TI - Effects of gelatin concentration on the growth parameters of Listeria innocua in a model gel system. AB - In this work, the growth of Listeria innocua was studied responding to the addition of different concentrations of gelatin (see text) model gel system in a modi_ed Brain Heart Infusion medium at 12 C and an initial pH of 6.2. The global number of viable cells as a function of incubation time and the corresponding pH, lactic acid concentration and glucose concentration were measured. Each set of data was fitted with the growth model of Baranyi and Roberts (1994) to estimate the maximum specific growth rate and the maximum cell concentration. Gelatin had a significant e_ect on the growth rate of Listeria innocua, which reduced as the gelatin concentration increased. A tail was observed after a certain concentration of gelatin indicating that there exists a maximum concentration beyond which no further reduction could be observed. There was, however, within the gelatin concentration range studied, no appreciable effect on the maximum cell concentration. A distinct morphological change of colonies was also observed with increasing gelatin concentration. PMID- 24757781 TI - Quality assurance in the egg production chain to reduce the bacterial contamination of the eggshell. AB - Washing eggs in sterile plastic bags with diluent is an efficient sample preparation method for the determination of the bacterial contamination on eggshells. The total count of aerobic bacteria and the total count of Gramnegative bacteria on the eggshell can be used to detect critical contamination points in the egg production chain. The number of eggs to be sampled in a point of the production chain was determined on a statistical basis and fixed on 40 for non-graded eggs and on 20 for graded eggs. In two production chains, one cage production and one organic production system, critical contamination points were identified. The influence of the housing system on the bacterial contamination of the eggshell at the stable was studied. A positive correlation was found between the initial bacterial eggshell contamination and the concentration of bacteria in the air of the poultry houses. With the exception of heavily soiled shells, like shells from ground eggs, there is a poor correlation between the level of bacterial contamination and the visual eggshell contamination. PMID- 24757782 TI - CFD approach for modelling microbial inactivation during thermal processing of intact eggs. AB - Combined conductive and convective heat transfer during thermal pasteurisation of intact eggs was studied using a commercial Computational Fluid Dynamics (CFD) package. A kinetic inactivation model for Salmonella enteritidis was combined with the CFD model, enabling evaluation and assessment of egg pasteurisation processes. Simulated temperature profiles were found to be in good agreement with experimentally observed data. The obtained results offer a useful tool for assessment and optimisation of egg pasteurisation processes. PMID- 24757783 TI - Antimicrobial activity of lactic acid bacteria strains isolated from GI tract of infants againts gram positive and gram negative bacteria. PMID- 24757784 TI - Evaluation of the potential of meat born lactic acid bacteria for use as protective cultures in the biopreservation of cooked meat products. AB - In this study, 97 lactic acid bacteria were subjected to a step-by-step screening and characterisation to search for potential protective cultures to be used in the cooked cured meat industry. Strains were first tested on their homofermentative and psychrotrophic character and salt tolerance. Secondly, the antibacterial capacities towards Listeria monocytogenes, Leuconostoc mesenteroides, Leuconostoc carnosum and Brochotrix thermosphacta were determined in an agar spot test. Finally, 12 selected strains were evaluated on their competitive nature by comparing their growth rate, acidifying character and lactic acid production at 7 degrees C under anaerobic conditions. PMID- 24757785 TI - Predicting inhibition and inactivation of Yersinia enterocolitica through lactic acid production by Lactobacillus sakei. AB - In food technology, there is a need for models taking into account the interactions between microorganisms, in order to correctly predict the safety and shelf life of food products. When leaving these interactions out of consideration, a discrepancy between the model prediction and the actual microbial evolution may occur for certain types of food products. In this study, a model describing the inhibition of the pathogenic Yersinia enterocolitica in mono- and coculture with Lactobacillus sakei was extended to describe also the subsequent inactivation of Y. enterocolitica. During the development of a suitable model structure to describe the inactivation process, biological knowledge about this process was incorporated. The extended model was able to predict evolution of Y. enterocolitica in coculture as well as in monoculture. PMID- 24757786 TI - Industrial scale pilot plant operation by Kefir yeast cells immobilized on delignified cellulosic material for whey treatment. AB - Kefir yeast cells immobilized on Delignified Cellulosic Materials (DCM) is proposed as a suitable form of biocatalyst for whey treatment. A bioreactor of 11.000L was used in all experiments. 5 repeated batch fermentations were taken place with whey volumes of 3000L and 5000L. Fermentation times achieved were below 15 h and final ethanol concentration was of the level of 2%v/v. Residual sugar was low while conversion rate reached 95%. In a second frame of experiments the immobilized cells bioreactor was operated on a feed-batch process, beginning from 2000L of whey and adding 2000L in every feed. In a third frame of experiments, whey fermentation was performed on a continuous operation for a period of 13 days. The system retained its operational stability, exhibiting relatively high ethanol yield and ethanol productivity. All experiments indicated that the biocatalyst of kefir yeast cells immobilized on delignified cellulosic materials has a carry through property on whey fermentation on industrial scale. PMID- 24757787 TI - The effect of some parameters of milk protein coagulation on the transfer of a commercial enzymatic preparation to cheese grain. AB - The effect of coagulation conditions of raw, skimmed and pasteurized milk on the transfer of commercial enzymatic preparations (Chymogen, Fromase and Hala) to cheese grain, was studied. It was found that the transfer degree of the above preparations was dependent on some coagulation parameters such as milk acidity and temperature. The duration of cheese grain retention did not have a significant effect on the transfer of the analyzed preparations. PMID- 24757788 TI - The effect of some conditions on the secretion of extracellular beta galactosidase synthesised by Kluyveromyces fragilis 28. AB - To induce extracellular secretion of beta-galactosidase synthesised by Kluyveromyces fragilis 28, it was used glycine, L-asparagine, L-leucine, dimethyl fluoride, dimethyl sulfoxide, cetyldimethylethylammonium bromide, penicillin G and glycolipids from Candida antarctica. The highest increase in the secretion of beta-galactosidase was obtained in the yeast culture cultivated in the medium with polypeptone when glycine was used as the secretion inductor. The extracellular activity of beta-galactosidase reached 0.416 A.U./ml, and was 10 fold higher than the beta-galactosidase activity reported in the control group. PMID- 24757789 TI - Detection of soy DNA in margarines. AB - The method in which to discriminate between genetically modified (GM) versus non modified foodstuffs is based on the presence of newly introduced genes at the protein or DNA level. Current available methods are almost exclusively based on the polymerase chain reaction (PCR). This procedure consists of three steps: DNA isolation, the amplification of the desired DNA fragment and visualisation of the obtained amplification products. The first and crucial step is the DNA isolation. Due to several processing steps, the quality of the extracted DNA may be damaged, rendering PCR analysis, and therefore GMO detection, impossible. In this study, the DNA quality of soy lecithin in margarines has been evaluated by PCR. For this purpose, DNA was isolated from margarines with different levels of lecithin with two different extraction methods, including the CTAB method proposed by the European Committe for Standardization (CEN). The amplification of soy DNA by PCR resulted to be difficult, which could be explained by the difficult DNA extraction from margarine and the low lecithin content. PMID- 24757790 TI - Applaying of high pressure to yoghurt preservation. AB - Effects of the high pressure treatment in the range of 200 - 1000 MPa/15 min., at the room temperature, on survivability of Streptococcus thermophilus and Lactobacillus delbrueckii ssp. bulgaricus was investigated. Sensorial characteristics of yoghurt was conducted by a panel of experts. Influence of yoghurt acidity on the effect of pressurization was also determined. In the experiment, we also attempted to extend shelf-life of yoghurt, subjecting it to the pressure of 550 MPa/15 min. Pressure treated yoghurt was stored for 4-weeks at room and refrigerated temperature; every seven days microbial number, acidity and sensory attributes of the beverage was determined. Addition of fruit jam on the effect of pressurization was also checked. Survivability of microorganisms depends on the value of pressure used in the experiment. The research displayed that yoghurt acidity did not influence the effect of pressurization. During 4 weeks of storage, yoghurt processed at 550 MPa maintained its beneficial characteristics longer compared to the non-pressurized one. Addition of fruit jam beneficially affected consistency of the pressure treated yoghurt. The conducted studies showed that there was possibility of preserving yoghurt by the method of high pressures. Thus, to preserve yoghurt, the complete inactivation of microflora is not necessary. PMID- 24757791 TI - A comparative study on galactoologosaccharide synthesis by selected beta galactosidase preparations. AB - The transgalactosilating ability of beta-galactosidase preparations obtained from Kluyveromyces fragilis, Penicillium canescens, and Escherichia coli was investigated. In samples of hydrolysates of 20% lactose solutions without or with a 2% addition of glucose, the galactose or fructose obtained with the use of the investigated preparations and the content of saccharides was determined with the HPLC method. Under experimental conditions, the highest quantity (56.0-64.1%) of galactooligosaccharides was synthesised by beta-galactosidase obtained from E. coli, while the lowest number (11.25-25.2%) was obtained by beta-galactosidase obtained from P. canescens. Beta-galactosidase from E. coli also synthesised considerable amounts of lactulose. PMID- 24757792 TI - Fractal analysis of structure of beta-lactoglobulin preparations. AB - Beta-lactoglobulin (beta-Lg) preparations obtained from whey retentate through (a) salting out at high NaCl concentration in a strongly acid medium (30% NaCl, pH 2.0), (b) alfa-lactalbumin (alfa-La) removal at mild conditions (55 degrees C/30 min, pH 3.9) and (c) alfa-La removal with 6% TCA solutions (20 degrees C/40 min) were characterized by high values (1.31 to 1.33) for fractal dimension (D(L)), indicating their developed surface. At the same time, a small differentiation between these values allows assuming that the methods of the protein isolation from whey retentate did not influence the surface development. High values for correlation coefficients indicated a great accuracy of the method used for the measurements of the protein particles. PMID- 24757793 TI - Effect of temperature and high pressure on the foaming properties of beta lactoglobulin salted out at pH 2. AB - Heat treatment and pressurization affected the foaming capacity and stability of beta-lactoglobulin--stabilized foams. The foaming capacity of heated beta lactoglobulin (beta-Lg) was lower than of the non-heated protein by 9-30%, depending on the medium acidity. At pH 5.0 and 7.0, the stability of beta-Lg stabilized foams was 3-fold lower and at pH 6.0 it was 3-fold higher than the stability of foams stabilized by the non-heated protein. Pressurization at 300 MPa/10 min increased the protein foaming capacity by about 25% and the foam stability almost 3-fold, comparing with the non-pressurized protein. Longer (20 30 min) pressurization at 300 MPa did not affect the foaming capacity of beta-Lg, slightly increasing the foam stability. Pressurization at 600 and 900 MPa did not change the foaming capacity, but decreased drastically the foam stability. Beta Lg pressurized at 300 MPa/10 min had the foaming capacity and foam stability better at pH 6.0 and 7.0, whereas beta-Lg pressurized at 600 MPa/10 min had those properties better at pH 5.0, as compared with the non-pressurized protein. PMID- 24757794 TI - Improvement of beta-galactosidase immobilization and its application to ethanol fermentation of lactose. AB - To intensify ethanol fermentation of lactose, a co-immobilized biocatalyzer was used. It consisted of yeast cells of Saccharomyces cerevisiae co-immobilized with beta-galactosidase preparation from A. oryzae. The experiment was focused on the improvement of biocatalyzer operational stability. An increase in the concentration of a carrier (2% calcium alginate) did not improve the effectiveness of binding beta-galactosidase. However, its initial cross-linking with glutaraldehyde and its co-immobilization with distillery industrial yeast produced a stable biocatalyzer able to ferment mash from permeate (12% lactose) with an average efficiency of 6.5% v/v of alcohol during 10 experimental series (30 days). PMID- 24757795 TI - The characteristics of fermentation abilities of K. fragilis immobilized on Siran. AB - The aim of this paper was to evaluate the suitability of Siran, a highly porous mineral carrier, to immobilization of Kluyveromyces fragilis--directly lactose fermenting yeast. The ethanol concentration in the post-fermentation mash was 4.7 5.8% v/v and was less advantageous than in previous experiments with calcium alginate (on average 6.04% v/v in 9 sequential fermentations). The introduction of another yeast strain to the experiment--S. cerevisiae--enhanced the efficiency of the lactose mash fermentation. The ethanol concentration in the mash in sequential series of the process increased on average to 6.14% v/v. PMID- 24757796 TI - Application of synbiotics in fermented sausage production. AB - The aim of the study was to produce of no-maturating fermented sausage with addition of inulin and probiotic strains. The study included production of sausages with addition of probiotics strains, growth promoting and texture inulin, determination of growth of probiotic bacteria in a final product during its storage period, determination of influence of synbiotic on undesired microflora and organoleptic quality of product. Microbial quality of sausages has been satisfactory. The number of undesired rods didn't exceed admissible standards. Amount of probiotic bacteria, which had been added to 3 types of products, achieved the level up to 1.010(6) cfu/g in all samples of sausages stored at different temperature. No significant differences in number of probiotic bacteria have been noted as a result of prebiotic addition. In organoleptic evaluation a beneficial effect of synbiotics on sensory properties, especially their structure and consistency has been observed. PMID- 24757797 TI - Fermented vegetable juices obtained from celery, parsley and tomato. AB - Application of starter cultures in fermented food industry results in obtaining high quality products, standardized sensory properties and allows to shorten a time of production. Employment of appropriate starter cultures indices the possibility of develop a new assortment of fermented products which can not be obtain in traditional way. The aim of study was to produce fermented vegetable juices using starter cultures with different quantitative and qualitative composition. Parsley, celery and tomato juices have been fermented using 0.25 5.0% addition of starter culture. The most acceptable sensory properties exhibited juices produced with 0.25-3.0% addition of starter culture composed of Lactobacillus brevis 6, Lactococcus lactis ssp. lactis 5K and Lactobacillus plantarum 5, Lactococcus lactis ssp. lactis 4K. The value of pH of fermented juices varied from 3.8 to 3.6. Concentration of lactic acid was at a level from 0.8 to 1.2%. Stability of fermented juices at a temperature of 6 degrees C was 4 weeks. PMID- 24757798 TI - Evaluation of antibacterial and fungistatic activity of yogurts with addition of Propionibacterium jensenii and Propionibacterium acidipropionici strains. AB - The aim of the studies was to determine the antibacterial and fungistatic effects of experimental yogurts containing: 5% and 10% of P. jensenii and P. acidipropionic, cultures, centrifuged cells from P. acidipropionici culture and supernatant. Test strains were 14 strains of rods from the family Enterobacteriaceae, five strains of mold and three strains of yeast. The control yogurt contained no additives. It was found that adding 5% of cultures of both strains to the experimental yogurts had no influence on their antibacterial and antifungal activity. The growth of the majority of test rods was inhibited by the yogurt containing 10% of P. acidipropionici culture. This yogurt inhibited also the growth of most fungal strains for seven to ten days, and its sensory properties were acceptable. The yogurt with biomass of P. acidipropionici cells was characterized by the strongest antibacterial and antifungal effects--it inhibited the growth of all rods and the majority of fungal strains for eight to ten days. However, its taste was rather unpleasant, strong and sour. The yogurt containing supernatant showed antifungal activity, delaying the growth of most fungi, but had no influence on the development of test rods. PMID- 24757799 TI - Estimation of nitrate and nitrogen forms of vegetables by UV-spectrophotometry after photo-oxydation. AB - An alternative method for the estimation of nitrate and nitrogen forms in vegetables is proposed. Nitrate can be directly estimated by UV-spectrophotometry after an extraction step with water. The other nitrogen compounds are photo oxidized into nitrate, and then estimated by UV-spectrophotometry. An oxidative solution of sodium persulfate and a Hg-UV lamp is used. Preliminary assays were realized with vegetables like salade, spinachs, artichokes, small peas, broccolis, carrots, watercress; acceptable correlations between expected and experimental values of nitrate amounts were obtained, while the detection limit needs to be lowered. The optimization of the method is underway. PMID- 24757800 TI - A new indirect impedancemeter to detect microbial contaminations in agro-food industry. AB - The impedancemetry method can be used in Microbiology to perform the detection, quantification and even identification of some bacteria. Basic knowledge about this subject can be stated from Ur and Brown (1975), Firstenberg-Eden and Eden (1984), the reviews of Silley and Forsythe (1996), and Wawerla et al. (1999). With Escherichia coli, Bacillus subtilis and Saccharomyces cerevisiae cultures, the conductimetric responses were highly replicable, and repeatable for inocula concentrations from 1 to 10(8) CFU mL(-1). The main use of such devices could be the detection of contaminations of foodstuff. Several of these foodstuffs incubated at 37 degrees C spontaneously release quite large amounts of CO2. Our impedancemeter, however, was able to detect an Escherichia coli presence in canned French beans down to 2.35 10(-2) colony forming units (CFU) mL(-1), and a Saccharomyces cerevisae contamination of apple puree in glass jars down to 6.1 10(-3) CFU mL(-1). PMID- 24757801 TI - Individual-based modelling: a mechanistic complement underpinning macroscopic models in predictive microbiology. AB - In the field of predictive microbiology, mathematical models are developed to describe and predict the behaviour and possible outgrowth of spoilage and pathogenic microorganisms in food products. Research has mainly focused on the development of macroscopic models, describing the evolution of macroscopical quantities like the total cell number N. This macroscopic approach has a number of inherent disadvantages. This paper proposes the individual-based modelling methodology as a complement to macroscopic models to overcome some of these issues. As a case study, the paper proposes a new bacterial growth model to describe the stationary phase of bacterial growth. The new model is implemented in an individual-based framework and exploratory results are presented. PMID- 24757802 TI - The influence of temperature shifts on the lag phase of Escherichia coli. PMID- 24757803 TI - Production of Gouda cheese and Camembert with probiotic cultures: the suitability of some commercial probiotic cultures to be implemented in cheese. AB - The behaviour of 10 probiotic cultures (L. acidophilus, Bifidobacterium sp., L. rhamnosus and L. paracasei) was examined during the production and ripening of Gouda cheese and Camembert. The overall objective of this research project was to obtain a product (cheese) containing at least 10(7) probiotic cfu/g. In general 10(6) cfu of a probiotic culture must be implemented per ml cheese milk, together with the cheesestarter, to reach this objective. L. paracasei sp. have the ability to grow more than 2 log units during cheese ripening. A lower inoculation value can be considered for these cultures. PMID- 24757804 TI - The changes in protein fraction of milk subjected to vibration. AB - This paper presents a model study into the effect of vibration on the changes in the nitrogen compound system of whole milk. It was found that milk protein destabilization increases with an increase in vibration frequency. Moreover, it was observed that in skimmed milk obtained from whole milk subjected to vibration, the total and dissolved nitrogen contents and the casein dehydration degree tended to decrease while the NPN+PPN level increased. PMID- 24757805 TI - The effect of vibration frequency on changes in the salt system of milk. AB - This paper presents a model study into the effect of varied frequencies (10-60 Hz) of vertical and horizontal vibrations at a constant acceleration of 1g for 60 min. exposures on the changes in the salt system of milk. It was found that the tendencies of changes in the salt system of milk under vertical and horizontal vibrations are similar and are determined by the applied frequency. Their intensity increased with an increase in vibration frequency. PMID- 24757806 TI - Mucosal immune responses following oral immunisation of pigs with fimbrial antigens of enterotoxigenic E. coli. AB - The intestinal mucosal immune system can discriminate actively between harmful pathogens and harmless food antigens resulting in different immune responses namely IgA production and oral tolerance, respectively. Whereas particulate antigen (microorganisms) can induce an IgA response, soluble antigen often leads to tolerance. Recently, it has been demonstrated that F4 fimbrial antigens of enterotoxigenic E. coli (F4 ETEC) can be used to immunise piglets. Oral administration of soluble F4 to F4R+ piglets (pigs with a receptor for these fimbriae (F4R+) on their small intestinal villous enterocytes) results in an intestinal mucosal immune response that completely protects the piglets against a challenge infection. In F4R- pigs, such an intestinal mucosal immune response does not occur. However, a priming of the systemic immune system can be seen similar to the priming in pigs fed with the same dose of a food antigen, suggesting that F4 in F4R- pigs behaves as a food antigen. These results indicate that a receptor-mediated mechanism is involved in the induction of a protective intestinal mucosal immune response using soluble antigen. However, oral administration of soluble F18 fimbriae of verotoxigenic E. coli to F18R+ piglets could not induce a similar protective immune response. So the type of the receptor and/or the nature of the antigen seem to be important to obtain an intestinal IgA response. PMID- 24757807 TI - Refolded recombinant FaeG adhesin induces a systemic and mucosal F4-specific immune response following oral immunization of weaned piglets. AB - The importance of adhesins in the pathogenicity of several bacteria resulted in studies on their usefulness in vaccines. In this study, the gene of the F4 fimbrial adhesin FaeG of the pathogenic enterotoxigenic Escherichia coli (ETEC) strain GIS26 was cloned into the pET30Ek-LIC vector and expressed with an N terminal His- and S-tag in the cytoplasm of BL21(DE3). Recombinant FaeG (rFaeG) subunits were isolated from insoluble cytoplasmic aggregates and refolded into a native-like F4R-binding conformation. Indeed, ELISA showed the presence of conformational epitopes and the ability to bind to the F4 receptor (F4R) was observed by inhibiting the adhesion of F4+ ETEC to F4R+ villi with increasing concentrations of native-like refolded rFaeG subunits. The rFaeG subunits appear as monomers, whereas purified F4 fimbriae are multimers. Oral immunization of newly weaned piglets with native-like rFaeG induced a mucosal and systemic F4 specific immune response, significantly reducing F4+ E. coli excretion from 2 till 5 days following challenge infection. However, improvement of stability and immunogenicity of rFaeG must be considered since a higher F4-specific response was obtained following immunization with purified F4 fimbriae. Furthermore, the N terminal fusion of a His- and S-tag was not detrimental for F4R binding, supporting the use of FaeG as mucosal carrier. In conclusion, this is the first report of an oral immunization with a recombinant fimbrial adhesin subunit of Escherichia coli inducing a mucosal and systemic fimbriae-specific immune response in pigs. PMID- 24757808 TI - Predominance of the PapGII allele among avian pathogenic Escherichia coli (APEC) with high sequence homology to human isolates. AB - Avian pathogenic Escherichia coli (APEC) is often found in poultry and is responsible for a set of diseases, commonly referred to as avian colibacillosis. One of the important virulence factors is adhesion to different epithelial surfaces, which is mediated by pili. P pili are thought to play a role by means of their PapG adhesin, which occurs in three molecular variants: PapGI, PapGII and PapGIII. This study is the first to determine and analyze the distribution of the different papG alleles in avian E. coli strains. Our results show a significant predominance of allele papGII above all other alleles or allele combinations. No statistically significant associations could be found between papG allele distribution and the animal breed, organ of isolation and serotype. The papGII and papGIII sequences showed a high homology with mammalian (including human) papG sequences, implicating a possible zoonosis. Finally, due to its predominant character, papGII is a promising potential vaccine candidate for APEC. PMID- 24757809 TI - Chlamydophila psittaci DNA vaccination in turkeys in the presence of maternal antibodies. AB - Plasmid DNA (pcDNA1::MOMP D) expressing the major outer membrane protein of an avian Chlamydophila psittaci serovar D strain was tested for its ability to induce protective immunity against Chlamydophila psittaci challenge in the presence of maternal antibodies. A combined parenteral (intramuscular injection) and mucosal route (DNA drops administered to the nares) of DNA inoculation was used. Only placebo-vaccinated turkeys showed a primary response following challenge, although DNA vaccination didn't generate high antibody titres. Following pcDNA::MOMP vaccination, both T-helper and B-cell memory were primed. However, high maternal antibodies titres affected the induction of vaccine specific antibody responses as assessed by MOMP-specific antibody levels in ELISA. Cell-mediated immunity was unaltered as demonstrated by the significantly heightened proliferative responses of peripheral blood lymphocytes following vaccination. DNA vaccination could significantly reduce clinical symptoms, pharyngeal and cloacal excretion as well as chlamydophila replication, even in the presence of maternal antibodies. PMID- 24757810 TI - Evidence for a type III secretion system in Chlamydophila psittaci. AB - In order to examine the presence of a type III secretion system in Chlamydophila psittaci, we focused on the SctW (CopN) coding region in a locus containing four genes encoding putative products with similarity to chaperones (Sccl), secretion pore components (Cds1 and Cds2) and secreted proteins (CopN) formerly identified in the type III secretion system of other gram-negative bacteria. SctW regulates type III secretion in gram-negative bacteria. SctW expression was examined in C. psittaci infected HeLa cells using SctW-specific polyclonal antibodies in an indirect immunofluorescence staining. SctW expression was detected 29 hours post inoculation and was absent in uninfected control cells. Immunoblotting of whole HeLa cell lysate 72 hours post inoculation with the SctW-specific polyclonal antibody also revealed the presence of SctW. Results demonstrated SctW of C. psittaci to be expressed in at least one stage of the intracellular bacterial life cycle. The present finding may contribute to the future identification of a functional type III secretion apparatus in C. psittaci. PMID- 24757811 TI - Genetically modified organisms (GMOs) and aquaculture. AB - This paper reviews the nature of genetically modified organisms (GMOs), the range of aquatic species in which GMOs have been produced, the methods and target genes employed, the benefits to aquaculture, the problems attached to use of GMOs in aquatic species and the regulatory and other social frameworks surrounding them. A set of recommendations aimed at best practice is appended. This states the potential value of GMOs in aquaculture but also calls for improved knowledge particularly of sites of integration, risk analysis, progress in achieving sterility in fish for production and better dissemination of relevant information. PMID- 24757812 TI - Genetic resistance towards Salmonella infection in pigs. AB - A PCR-RFLP of intron 1 and intron 2 of the Nramp1 gene described as a potential candidate gene in controlling pig resistance to Salmonella infections was optimised and an association between the Salmonella status and the polymorphisms was investigated. For intron 1 new primers were designed and the amplicon of 622 bp was restricted with Hinf I to give fragments of 280 bp, 220 bp and 100 bp for allele A and 76 bp, 100 bp, 144 bp, and 280 bp for allele B. For intron 2 a new polymorphism was detected (a deletion) with fragments of 210 bp and 199 bp after amplification respectively for allele A and B. The frequency of allele B and A was 0.93 and 0.90 on a total of 180 and 205 pigs for the polymorphism in intron 1 and intron 2 respectively in a mixed population of hybrid and purebred pigs. Similar allele frequencies of allele B and A of 0.90 and 0.91 respectively in intron 1 and intron 2 were found in a sample of 392 and 391 slaughter pigs. In the latter population, no association between the Nramp1 genotypes and the colon Salmonella status or the ELISA status could be demonstrated. PMID- 24757813 TI - Polymorphisms of candidate genes for meat and carcass quality in Belgian pig populations. AB - Polymorphisms described in literature for several candidate genes affecting meat and carcass quality traits were analysed in pigs of pure breeds and hybrid lines used in Belgium. Associations with phenotypic traits were also examined when possible. A total of 92 pigs were screened for a HincII polymorphism in the calpain, large polypeptide L3 (CAPN3) gene, but all tested animals revealed homogenous. A HinfI heart fatty acid-binding protein (H-FABP) gene polymorphism was tested in 74 pigs, of which 51 had known intramuscular fat content. The frequency of the H allele, characterised by an additional HinfI restriction site compared to the h allele, varied between 0.5 and 1 for the different breeds or lines. No animals of the hh genotype were present and no association with the intramuscular fat content was apparent. An AluI polymorphism in the adrenocorticotrope hormone receptor (MC2R) gene and a SacII polymorphism in the uncoupling protein (UCP2) gene were examined in 368 and 392 pigs respectively, with 330 pigs shared. For both genes, one allele was clearly predominant with an overall frequency of 0.90 and 0.94 respectively. A few lines or breeds differed from the overall pattern. There was no association between the frequencies of the MC2R and UCP2 gene polymorphisms. Due to the low frequency of one of the homozygous genotypes for both genes, a possible association with carcass fat thickness could not be properly examined, but the large differences between both homozygous genotypes nevertheless deserve further attention. The MC2R gene polymorphism was also tested on 246 piglets that have died from colibacillosis. Remarkably, the frequencies of the subordinate allele and the corresponding homozygous genotype were much higher in this population compared to the healthy pig population examined. PMID- 24757814 TI - Serological and molecular characterization of Chlamydophila psittaci strains using serovar-specific monoclonal antibodies and ompA sequence analysis. AB - In the present study, 21 avian Chlamydophila psittaci field isolates from 4 different European countries (Belgium, Germany, Italy and The Netherlands) were characterized using serovar-specific monoclonal antibodies as well as ompA sequence analysis, enabling the comparison between the two characterization methods for future epidemiological studies. The 21 European isolates included 6 isolates from the order Psittaciformes, 6 isolates from the Anseriformes, 5 isolates from the order Columbiformes and 4 Galliformes respectively. Only 19 on 21 isolates could be serotyped while all isolates were successfully genotyped. In addition, genotyping revealed the presence of mixed infections in 5 on 21 isolates while serotyping could only detect one of these 5 mixed infections. Interestingly, genotyping indicated the existence of a new genotype designated E/B. The E/B genotype is closely related to the genotypes A, B and E but the ompA gene of E/B strains shows a guanosine on position 1006 and 1021 in combination with a cytidine on position 1022 to be unique. Genotype E/B isolates reacted with both the serovar E- and B-specific monoclonal antibody leading to the conclusion of a mixed infection while only one specific ompA sequence was present in the sample. For epidemiological studies genotyping by use of ompA sequence analysis is to be preferred as it is more sensitive than serotyping and can distinguish genotype B, E and E/B strains. PMID- 24757815 TI - The effect of a MspI polymorphism at the porcine pituitary specific transcription factor (PIT-1) gene on backfat thickness. AB - In the present study the association between a MspI polymorphism in the porcine PIT-1 gene and backfat thickness in Belgian slaughter pigs was investigated. The polymorphism was analysed with an improved PCR-RFLP test, using primers chosen on the sequence of intron 3 of the PIT-1 gene. The polymorphism was confirmed in a number of dam breeds (Landrace, Large White, Synthetic Lines) and in the main Belgian terminal sire breed Pietrain. In crossbred progeny (n = 185), a mixed animal model analysis indicated that the MspI D allele could possibly be associated with a higher backfat thickness, but the effect only approached significance (P = 0.06). In addition, this effect has to be interpreted carefully in view of the reverse allelic effects between studies and the low number of CC homozygous animals in this study. PMID- 24757816 TI - The selectivity of some fungal lipases. AB - Selectivity is one of the most important lipase properties which depends on a wide range of factors. In order to choose the right enzyme for a special purpose, it is necessary to check its selectivity. Fatty acid selectivity of lipases determined for natural substrales was different from that determined for p nitrophenyl esters and those determined for each substrate. Enantoiselectivity of lipase from Mucor circinelloides (MCL) determined for 2 was over 100 (E > > 100). In this case, inversion of enantiopreferences was observed; the conversion was 10% and (R)-alcohol was preferentially produced PMID- 24757817 TI - Characteristic of fungal lipases and their application in synthesis of structered lipids. AB - The experiments showed the possibility of the MLM type structured triacylglycerol synthesis. Such sTAGs should have polyene acids positioned in sn-2 (in this case evening primrose oil was the source of polyene acids) and caprylic acid in the sn 1 and sn-3 positions. The sTAG synthesis was carried out in two-stages: 1. alcoholysis and synthesis of 2-MAG; 2. 2-MAG esterification with caprylic acid. For further experiments 4 lipase preparations were selected: MCL, RDL, Lipozyme RM and TL. The lipase preparations synthesized 2-MAG with the yields of 85.7%,. 87.5%,. 54.3%,. 65.2%, respectively. The 2-MAGs separated by crystallization contained over 70% of C18:1 acid and over 7% of C18:3, n-6 acid. The two-staged sTAG synthesis was shown to be more efficient by analyzing the products composition. The two- stage process gave over 70% of MLM type triacylglycerols and about 3% of side-products, whereas the acidolysis or interesterification produced only about 30% MLM or MLL type triacylglycerols. PMID- 24757818 TI - The application of immobilized biocatalyzers to intensify the ethanol fermentation of lactose. AB - Ethanol fermentation of lactose mash by biocatalyzers immobilized in sodium alginate was studied in order to improve the process productivity and economy. The fermentation effectiveness of S.cerevisiae co-immobilized with a p galactosidase and the directly lactose- fermenting immobilized yeast: K. fragilis and C. pseudotropicalis were compared The application of the immobilized K. fragilis produced desirable results and even after its 9th (18 days) fermentation, the immobilized yeast provided the stable high fermentation level (on average about 6 ralvol of ethano/) while maintaining its activity. Such lactose-mash fermentation was greater than in conventional method (by free cells). In addition, the application of s. cerevisiae co-immobilized with p galactosidase produced somewhat greater ferm levels than the conventional method, however, the system stability deteriorated after 6 days of fermentation. PMID- 24757819 TI - [Microbial model of Halobacterium salinarum for screening inhibitors of sterol biosynthesis]. AB - A highly effective and simple microbial test system for screening inhibitors of sterol biosynthesis (ISB) is described. The system is based on cultivation of the bacterial strain Halobacterium salinarum (former Halobacterium halobium), that possesses mevalonate pathway of sterol biosynthesis and is much similar in the biosynthesis to cholesterol formation in humans. In the H. salinarum test system the ISB were found as compounds that inhibited the test culture growth. Mevalonate which is one of the crucial intermediates of sterol biosynthesis dismissed the inhibitory effect of many microbial metabolites thus being evident of their action at the early stages of the sterol biosynthesis, including the HMG CoA reductase stage. The H. salinarum test system was developed as a micromethod and could be easily mechanized by miniaturization of the microbiological procedures, cultivation in sterile 96-well plates and using automatic micropipettes and dispensers. The H. salinarum test system was effective in testing crude extracts of the culture broths and advantageous at early stage of screening. The use of the H. salinarum test system was shown possible for screening antitumor antibiotics. PMID- 24757820 TI - [Pattern dynamics of bacteriemia and sepsis pathogens in ICU patients of emergency service]. AB - The results of microbiological tests of 2382 blood specimens from 698 patients of three ICUs of the N. V. Sklifosovsky Research Institute of Emergency Service were analysed for a period of 2009 to 2012. No microbial growth was detected in 1160 specimens (48.7%). In the subsequent tests 816 isolates were used. The quota of grampositive isolates in the pathogen pattern decreased from 51.68 to 35.9% and that of gramnegative isolates increased from 38.26 to 48.1%. The number of the Candida isolates increased from 7.38 to 15.2%. The frequency of the S. aureus and Enterococcus spp. isolates lowered from 26.2 to 13.3% and from 15.4 to 11.5% respectively. The quota of K. pneumoniae isolates and Acinetobacter spp. increased from 8.1 to 18.9% and from 14.1 to 17.4% respectively. Most of the S. aureus isolates were methicillin resistant. All the staphylococcal isolates were susceptible to vancomycin and linezolid. All the strains of K. pneumoniae isolated in 2009-2012 produced extended spectrum beta-lactamases. In 2012 7.8% the K. pneumoniae isolates were resistant to carbapenems. In 2012 25.5% of the Acinetobacter spp. isolates were susceptible to carbapenems and 70.2% were susceptible to cefoperazon/sulbactam. PMID- 24757821 TI - [Immunotropic properties of anaferon and anaferon pediatric]. AB - Anaferon and pediatric anaferon based on release-active antibodies to interferon gamma (R-A antibodies to INF-gamma) proved to be efficient in the treatment of many viral infections. Immunomodulating (immunotropic) properties of the drugs were revealed in the preclinical studies at many Russian and foreign research medical institutions and are reviewed herein. Anaferon and pediatric anaferon stimulated the humoral and cellular immune responses and increased the neutrophil and macrophage activity. The crucial mechanism of the immunotropic action of R-A antibodies to INF-gamma was the effect on the system of interferons and in particular on INF-gamma and functionally conjugated cytokines, resulting in normalization of the functional activity of the innate factors of the immune defense and increasing of the antiviral action. The broad spectrum of the immunotropic activity provided the success of anaferon and anaferon pediatric for more than 10 years in the treatment and prophylaxis of the diseases associated with disorders in the immune system functional state. PMID- 24757822 TI - [Cycloferon in complex therapy management of chronic laryngitis]. AB - The clinical course of various forms of chronic laryngitis, including contact granulomas not only persistant and relapsing, but also inclined to oncologic pathology due to hyperplastic changes in the larynx resulting in malignization was described. Inhibition of the leukocyte interferon-synthesizing activity was observed in more than 88.1% of the subjects. Pathogenic viruses were isolated from 48.2% of the patients, EBV and mycoplasma prevailing. High direct correlation between chronic laryngitis and Herpes viruses was shown. The presence of three-component virus associations in the larynx mucosa was likely indicative of the bening process malignancy. The use of the interferon inductor cycloferon in the complex surgical and medicamentous management of chronic laryngitis was shown valid. The rate of the relapses lowered to 1.7 episodes a year. PMID- 24757823 TI - [Rational antimicrobial therapy of chronic bacterial prostatitis]. PMID- 24757824 TI - [Microbial antibiotic resistance: resistome, its volume, diversity and development]. AB - The known conceptions of resistome as a complex of all the antibiotic resistance genes in the genomes of all the microorganisms, pathogenic and nonpathogenic ones, in nature are considered. The data on the origin, evolution and distribution of antibiotic resistance genes and possible approaches to the resistance distribution control are presented. PMID- 24757825 TI - [Virus infections and interferon inducers in the complex therapy]. AB - Interferon inductors of various chemical groups, belonging to antivirals, and induction of several types of endogenous interferon in blood serum are described. Cycloferon was shown efficient in the complex treatment of chronic hepatitis C, tuberculosis in HIV-infected subjects, arbovirus diseases, influenza and acute respiratory virus infections. PMID- 24757826 TI - [Imipenem: 30-year experience in therapy]. PMID- 24757827 TI - [Microbial models in screening of inhibitors of sterol biosynthesis]. AB - On the base of previously developed microbial models high effective scheme for screening of inhibitors of sterol biosynthesis (ISB) is proposed. It is based on cultivation of halophilic bacteria Halobacterium salinarum (former Halobacterium halobium), possessing mevalonate pathway of sterol biosynthesis, and cultivation of fungus Acremonium fusidioides (former Fusidium coccineum), that is producer of steroid antibiotic fusidin (fusidic acid), which biosynthesis has great similarity (with coincidence of its initial steps till squalene formation) to cholesterol biosynthesis in human organism. In H. salinarum model ISB are revealed as compounds that inhibit test-culture growth, whereas in A. fusidioides test-system they are revealed as compounds that strongly reduce fusidin production without any visible influence on producer's growth. Mevalonate that is one of the crucial intermediates of sterol biosynthesis remove inhibition induced by many microbial metabolites that is the evidence of their action at early stages of sterol biosynthetic pathway, including HMG-CoA reductase step. Both test-systems are developed as micromethod and could be easily mechanized due to miniaturization of microbiological procedures, cultivation in sterile 96-well plates and usage of automatic micropipettes and dispensers. Effectiveness of both test-systems, as well as their sensitiveness, laboriousness and ability to give false-positive or false-negative results in ISB screening work is compared. The proposed scheme of screening of ISB includes microbial models at early steps of screening procedures and Hep G2 test-system at the late step. The preliminary screening of microbial metabolites possessing antifungal activity at initial step is compulsory. Miniaturization and mechanization of microbial processes and purification of producers' culture broth with micro- and ultrafiltration are under consideration as well. PMID- 24757828 TI - [Characteristics of antibiotic therapy in neonates with polyorgan insufficiency]. AB - Polyorgan insufficiency (POI) is the main cause of death in ISU patients. The highest rates of morbidity and mortality due to POI are recorded among newborns. Antibbacterial therapy of probable infections processes is widely used in neonatology, however long-term antibacterial therapy is not favouable for newborn infants. The aim of the present study was to investigate the peculiarities of antibacterial therapy in newborn with POI. The trial enrolled 453 infants antibacterial therapy was used in all of them (100%). The most frequent drugs used in the treatment were the III and IV generation cephalosporines and aminoglycosides. The POI antibacterial therapy in severe cases was more intensive and prolonged. The most long-term therapy was applied to newborns weighting 1500 g. Recovery of the organ function served as a criterion for discontinuation of the antibacterial therapy. Antibacterial of neonate infants with POI requires optimization. PMID- 24757829 TI - [Cycloferon as an agent for the anti-relapse therapy in patients with chronic hyperplastic sinusitis]. AB - The data on the efficacy of cycloferon as an agents of antirelapsing therapy in management of 123 patients with chronic hyperplastic sinusitis are presented. The drug induction of endogenous interferons was validated by the properties of the local mucosal immunity, virus invasion and virus persistence in the nasal an d accessory nasal sinuses mucosa, as well as by different levels ofthe interferon production deficiency. The clinical efficacy was stated in 53% of the cases. The relapses were recorded in 13.1% of the patients treated with cycloferon vs. 33.3% of the patients under the local corticosteroid therapy. PMID- 24757830 TI - [Invasive mucormycosis in patients with hemoblastosis in St.-Petersburg]. AB - Thirty four patients with mucormycosis in 10 hospitals of St. Petersburg were observed in 2004-2013. The most frequent underlying diseases of mucormycosis were acute leukoses (64%). In 100% of the patients mucormycosis developed as a nosocomial infection. The risk factors, etiology, basic clinical signs and strategy in the treatment of mucormycosis were analyzed. PMID- 24757831 TI - [Role of intraosteal administration of antibiotics in treatment of local oral mucinous carcinoma]. AB - The problems of prophylaxis of infectious complications in the treatment of oral local mucinous carcinoma are considered relevant to 204 respective cases. More favourable results of the combined and complex treatment of the patients were shown when a multidisciplinary approach was used with obligatory participation of stomatologists. Special stomatologic prophylactic and therapeutic procedures with using reamberin orally and intravenously in the chemo- and radiotherapy and adequate antibiotic therapy during the surgical operation resulted in less frequent infectious complications, that was in favour of the patients life quality. Intraosteal administration of antibiotics was shown preferable. PMID- 24757832 TI - [Preclinical investigation of pharmaceuticals impact against cytochrome P450 activity and prognosis of substrate affinity as means for providing substrate therapy safety]. AB - Tricyclic antidepressants, not influencing the P450 3A4 activity, are safe in combination with drugs of other groups used in the treatment of comorbid patients. Azaphen is is one of the agents most widely used in the clinical practice. The in vitro electrochemical analysis showed that pipofezin (azaphen) was not a substrate, inductor, and/or inhibitor of cytochrome P450 CYP3A4 isoenzymes. The Guzar programme computer modelling and the literature data demonstrated the substrate affinity of pipifezin to CYP1A2. PMID- 24757833 TI - [Discordance of estrogen receptor status between primary and metastatic breast cancer--possible reasons and prognostic value]. AB - The aim of the review was systematization of the data on discordance in expression of estrogen receptors between primary and metastatic breast cancer, different metastases and repeated analyses of the same tissue. The possible reasons for the phenomenon are discussed. The authors emphasize the need to analyze estrogen receptors in breast cancer metastases, regardless of the receptor status of the primary tumor, for predicting the course of the metastatic disease and providing an adequate treatment of the metastatic tumor in strict accordance with its receptor status during drug therapy. The works cited in the search engine Pub Med to May 2013 were analyzed. PMID- 24757834 TI - [Biological properties of some sepsis-associated low molecular aromatic microbial metabolites]. AB - Physico-chemical and biological properties of sepsis-associated low molecular aromatic compounds are summarized and analysed in the review. Phenylcarbonic acids (PCAs), such as para-hydroxyphenyllactic acid (p-HPLA), phenyllactic acid (PLA), para-hydroxyphenylacetic (p-HPAA), phenylacetic acid (PAA), benzoic acid (BA), and phenylpropionic acid (PPA) are shown to have biorequlatory activity and be able to affect both bacteria and eukaryotic cells. In the review there are presented data on the diagnostic and pathogenetic value of PCAs, their bacteriostatic and bacteriocidal properties and biosynthesis by clinically significant bacterial species, as well as description of the mechanisms of microbial resistance to PCAs, the pathways of PCAs metabolism by prokaryotes, PCAs membrane transport and excretion pathways in humans, the data on the use of PCAs in clinical practice. The authors are of the opinion that PCAs of microbial origin share the metabolic and signal pathways in integration of the microbiome and man. On the basis of the literature data and personal studies the authors validated the hypothesis of possible development of new therapeutic strategies, grounded on regulation of the local and systemic balance of aromatic microbial metabolites in the human body. PMID- 24757835 TI - [Analysis of mutations in patients with suspected autosomal dominant form of the Parkinson disease]. AB - The Parkinson disease (PD) is a severe neurological disorder. Diverse genetic systems and environmental factors are involved in the pathogenesis of this disease. However, despite extensive research into the disease, its causes are not fully elucidated, and the exact spectrum of genes and mutations involved in the development of hereditary forms of PD has not been fully clarified yet. The present work is devoted to the analysis of mutations that lead to the development of monogenic forms of PD in patients with suspected autosomal dominant form of PD using Multiplex Ligation-dependent Probe Amplification (MLPA). We have identified several mutations (G2019S in LRRK2, heterozygous deletions of 2-3, 3-4 exons and heterozygous duplication of 2-4 exons in PARK2, deletion of 3 exon in PARK7) that lead to the development of PD in only 7 people out of 70 (18.4%), which suggests the need for further search of new mutations, for example, using exome sequencing. In the future it will help to develop the molecular genetic tests for early preclinical diagnosis and risk evaluation of the development of PD, and to understand better the causes and mechanisms of this disease. PMID- 24757836 TI - [A study of the single nucleotide polymorphism fragments of the AUR gene metalloprotease strains of Staphylococcus aureus isolated from the skin of patients with atopic dermatitis]. AB - OBJECTIVE: to study the heterogeneity of internal fragments of the aur gene coding a proteolytic enzyme aureolysin in strains of Staphylococcus aureus with different enzymatic activity, which were allocated with the affected skin of patients with atopic dermatitis. MATERIALS AND METHODS: the study included 125 patients aged 1 to 35 years old with the diagnosis of atopic dermatitis. 100 clinical strains of Staphylococcus aureus were studied in monoculture. Identification of the strains of Staphylococcus aureus in skin was performed using standard classical methods. Specific biochemical microtests using a set of APIs Staph 20 (bioMerieux SA, France) were conducted to confirm the obtained results. Reference strains of S. aureus ATCC 29213, NCTC at 8.325 were used. Specific aur gene loci were detected by the method of multiplex polymerase chain reaction. Proteolytic activity was determined by the ability to split the substrate (human IgG, Sigma) into fragments using as inhibitors of matrix 0.01 0.1M solutions of sodium EDTA. The sequencing of the amplified areas of aur gene, including the preliminary stages of separation and purification of DNA, was performed by Syntol, Moscow. RESULTS: different strains of the conservative plot amplicon fragment of aur contains up to 9 polymorphic nucleotides. The index of the nucleotide diversity for proteolytic active strains was less (Pi = 0.04) than for proteolytically inactive (Pi = 0.07), p < 0.05. It should be noted that all proteolytically active strains were isolated from the skin of patients with high and moderate severity of atopic dermatitis (67.8 +/- 5.4 points on SCORAD scale) with erythematous form of the disease. The inactive strains were allocated in patients of older age with reduced severity of atopic dermatitis (with the dry form of skin lesions). PMID- 24757837 TI - [Francisella tularensis strains molecular typing using the multiple-locus variable-number tandem repeat analysis]. AB - Variable-number tandem repeat analysis (VNTR) of 25 loci was used for molecular typing of the Francisella tularensis strains isolated from different regions of Russia and the former Soviet Union. This approach allowed us to subdivide F. tularensis subspecies and determine genotype diversity with regard to the geographical prevalence. All 25 loci were examined for their ability to discriminate subspecies and local geographical group. 42 genotypes among the 58 investigated F. tularensis subsp. holarctica isolates were found using cluster VNTR analysis. PMID- 24757838 TI - [The manganese-induced infidelity of the DNA synthesis as a possible cause of manganism]. AB - The impact of the 8 most common bivalent metal cations (Mg2+, Mn2+, Co2+, Cd2+, Zn2+, Ni2+, Ca2+, Cu2+) on the operation of the whole complex of DNA polymerases in mice brain cell extracts was tested. A decrease in the fidelity of the DNA synthesis was observed in the presence of several metals; among them, Mn2+ caused the most significant effect. It was also demonstrated that this effect was mainly due to the DNA polymerase iota (Pol iota) activity. It is well known that occupational or environmental exposure to excessive Mn could lead to development of neurodegenerative diseases (e.g., manganism). However, the molecular mechanism underlying these pathologies is still unknown. Our results suggest that the neurotoxic effect of Mn2+ may be associated with local activation of highly error prone Pol iota that increases incorrect DNA synthesis at elevated concentrations of this metal. PMID- 24757839 TI - [Genovariants of the cholera agent biovar El Tor: construction, molecular genetic, and proteomic analysis]. AB - Experimental modeling of origination of the virulent Vibrio cholerae El Tor genovariants is presented. It was demonstrated that the genovariants obtained did not differ from the natural genetically modified strains emerged in a natural population of the agent, either in phenotypical or genotypic properties. Using the PCR assay and sequencing techniques it was proved that the constructed genovariants carried a CTX(Class phi) prophage genome region with ctxBl gene of the V. cholerae classical biovar in the chromosome. It is shown that the prophage structure alterations lead to the increase in the toxigenicity and virulence in the genovariants compared to the typical strain-recipient. Moreover, as regards proteomics, changes in the expression of 26 proteins that perform various functions in the cell, such as metabolism, energy exchange, transportation, etc., were demonstrated. The data are indicative of the impact that a new DNA region in the genome of the genovariants has on the expression level of different house keeping genes. The results obtained testify to the fact that one of the mechanisms of the genovariant emergence in the natural populations of the agent can be horizontal gene transfer. PMID- 24757840 TI - [Molecular evolution of the West Nile virus]. AB - Sixty eight nucleotide sequences encoding protein E of the West Nile virus (WNV) were used for the phylogenetic analysis and estimation of the evolution rate of the WNV. Nucleotide substitution accumulation rate was evaluated as 2.5 x 10(-4) substitutions per site per year. Phylogenetic analysis and divergence time estimation carried out using the molecular clocks methodology showed that genotypes 1, 2, and 4 of the WNV circulated in the area of the European Russia with estimated divergence times from a common ancestor of approximately 2360, 2800, and 5950 years ago, respectively. The non-synonymous (dN) to the synonymous (dS) substitution values were found between 0.022-0.275 for the different WNV strains that were grouped by geographical and/or filogenetic characteristics. The highest dN/dS values were found in the group of WNV isolates coming from Russia and North America that have disseminated in these new regions over the past 14 years. Estimation of dN/dS for WNV shows that the dN/ dS value can be used as an indicator of the intraspecies variability and for evaluation of evolution rate for new isolates of WNV. This confirms the hypothesis about of the favorable conditions for the wide dissemination and rapid evolution of different' genotypes of WNV occurring from 2 up to 6 thousand years ago in modern geographical and climatic conditions. PMID- 24757841 TI - Potassium hydroxide-ethylene diamine tetraacetic acid method for the rapid preparation of small-scale PCR template DNA from actinobacteria. AB - Genomic DNA extraction from Gram-positive bacteria is a laborious and time consuming process. A rapid and convenient method was established to extract genomic DNA from a single colony as a PCR template. KOH-EDTA is used as a lysis buffer to disrupt the cell envelope, releasing genomic DNA, and Tris-HCl (pH = 4) is then added to neutralize the lysate. The lysate can be used directly as a template for PCR amplification. 16S rDNA was successfully amplified from Gram positive bacteria from the genera of Bacillus, Streptomyces, Micromonospora, Nonomuraea, Microbispora, and Staphylococcus. Amplification of the trpB gene indicated that this method could also be applied to the amplification of functional genes. Compared to colony PCR methods without KOH-EDTA, this method is extremely fast and efficient, and it is applicable to high-throughput PCR amplifications. PMID- 24757842 TI - [Analysis of publication activity in the field of biomedical engineering in 2003 2012]. PMID- 24757843 TI - [Portable neutron generators in medicine]. PMID- 24757844 TI - [Optoelectronic data-measuring system for monitoring polyhexamethylene guanidine based decontaminants]. PMID- 24757845 TI - [A system for monitoring a nd correction of parameters of human body functioning in sleep]. PMID- 24757846 TI - [A system for locomotion therapy]. PMID- 24757847 TI - [Tomography of brain and stereotactic guidance]. PMID- 24757848 TI - [PET in stereotactic neurosurgery]. PMID- 24757849 TI - [Femoral muscle dynamometer]. PMID- 24757850 TI - [Hydroxyapatite biocomposites for medical use]. PMID- 24757851 TI - [Principal component analysis of cardiac rhythm variability]. PMID- 24757852 TI - [Biomechanical simulation of behavior of sine-shaped helical wire stent in artery]. PMID- 24757853 TI - [Software package for evaluation of medical image complexity]. PMID- 24757854 TI - [Unipolar and bipolar measurement schemes for the reconstruction of spatial distribution of radiation sources using hexagonal coded apertures]. PMID- 24757855 TI - [Simulation of local blood flow gain]. PMID- 24757856 TI - [The prognostic value of biochemical indicators under neonatal hepatitis of different etiology]. AB - Recently, the share of children with verified neonatal hepatitis induced by genetic predisposition, malformations of biliary tracts, inborn infections with affection of hepatobiliary system increased. The comprehensive biochemical examination of 62 children aged from 1.5 months to 2 years old with diagnosis of neonatal hepatitis. The changes of standard indicators of cytolysis, cholestasis and protein metabolism were on average moderate in group with reliable increase of protein concentration of acute phase of inflammation. The peak changes of biochemical indicators during primary examination are revealed in group of children with malformations of hepatobiliary system conditioned by viruses of herpetic group and in the process of development of expressed fibrosis of liver up to first year of life. The detection of proteins of acute phase makes it possible to objectively evaluate the presence of prolonged inflammatory process in liver and to promote prognosis of course of neonatal hepatitis in children of early age and timely correction of therapy and improvement of outcomes of disease. The detection of C-reactive protein, alpha2-macroglobulin and alpha1 antitripsin is recommended to be included into algorithm of examination of children with neonatal hepatitis. PMID- 24757857 TI - [The early diagnostic of chorionic -amnionitic and intrauterine infection on content of nitrite and non-tiolate nitrosocompounds in plasma under premature discharge of amniotic fluid]. AB - The article deals with the results of examination of 33 pregnant women with premature discharge of amniotic fluid with purpose to choose an optimal criterion of diagnostic of intrauterine infection. In blood plasma of all female patients the increased, from 0.5 to 2.5 mkmol/l, total content of nitrite and non-tiolate nitrosocompounds non-containing iron (NO2+RNO). In case of pregnant women without intrauterine infection the content of nitrite and netiolate nitrosocompounds did not exceed 0.1 mkmol/l as in all other subjects without inflammatory diseases. The antibacterial and anti-inflammatory therapy applied to female patients with premature discharge of amniotic fluid resulted in lowering of concentration of NO2+RNO up to 0.1 mmol/l and even lower. The study results permit to suppose that concentration of NO2+RNO in plasma is one of sensitive indicators of presence of inflammatory processes concomitant to premature discharge of amniotic fluid which by its sensitivity and specificity is superior to such indicators as number of leucocytes, ESR and concentration of C-reactive protein. PMID- 24757858 TI - [The criterion prognostic significance of examinations of chemiluminescence of oral fluid under impact of chemical pollutants of manufacture of rubber and rubber technical production]. AB - The article presents the results of studies concerning the effect of unfavorable factors of chemical nature on fluid of oral cavity among workers of the Ufa plant of elastomer materials, articles and structures. It is established that in persons contacting with chemical pollutants of manufacture of rubber and rubber technical production the indicators of chemiluminescence of saliva fluid are significantly expressed and depend on professional standing. PMID- 24757859 TI - [The evaluation of parameters of erythropoiesis and ferrokinetics in children born with extreme low body mass]. AB - The article deals with the results of examination of 51 neonatal infants born with extreme low body mass in terms of gestation 22-31 week at first day of life and in 38-40 weeks of post conception age. The study established lowering of both values of indicators of erythrocyte sprout and level of iron-binding proteins in premature infants with extreme low body mass at birth and at achievement of age of mature infant. PMID- 24757860 TI - [The new indicators of total blood test in clinical practice]. AB - The article deals with the analysis of diagnostic value of new reticulocyte, erythrocyte, thrombocyte and leucocyte parameters of total blood test derivable using flow cytofluometry. The ranges of normal values of analyzed parameters in control sampling are calculated. The number of immature thrombocytes has the most diagnostic value during monitoring of gestosis. The stroke is characterized by adequate leukaemicus reaction and increased number of fragmented erythrocytes. The stroke complicated by sepsis is characterized by negative values of delta hemoglobin and absence of contingency between number of leukocytes and immature granulocytes. PMID- 24757861 TI - [The comparative evaluation of information value of traditionally analyzed indicators of total blood test and leucocytes index of intoxication in women with physiological and complicated course of pregnancy]. AB - The article demonstrates that on the basis of retrospective analysis of 34 cases of physiological and 218 cases of complicated course of pregnancy the evaluation of leucocytes index of intoxication is more informative than the standard analysis of leukogram. The increase of leucocytes index of intoxication and tendency of increase of percentage of concentration of leucocytes at early stage of pregnancy are detected mainly in women with complicated course of pregnancy. PMID- 24757862 TI - [The detection of Leiden mutation using technique of enzymatic extension of allele-specific primer with double bioluminescent detection (PED-Biolum)]. AB - The article deals with comparing technique of detection of Leiden mutation on the basis of PEXT-reaction with subsequent bioluminescent microanalysis of products with technique based on RT-PCR. The sampling for testing comprised 83 specimen of genome DNA including 35 specimens with known Leiden heterozygote mutation. The commercial kit "SNP-express-PB" (Litex) was used as a comparison test. It is demonstrated that proposed approach is a simple in its application, effective and relatively inexpensive technique of detection of Leiden one-nucleotide polymorphism in gene V of blood coagulation factor. The technique "PED-Biolum" has no differences in comparison with commercial technique RT-PCR concerning ability to detect mutant allele and matches it in parameters of economic effectiveness. PMID- 24757863 TI - [The non-etherifying and free fatty acids of blood plasma. Pathogenesis of arterial hypertension and symptoms of syndrome of overeating-metabolic syndrome: a lecture]. AB - From point of view of physiology, the metabolic syndrome is a syndrome of overeating when an optimal by the content of fatty acids in food is too much a physologically. This condition forms an omental variant of increase of body mass. The oleic triglycerides cumulate in fatty cells of omentum and after activation of lypolisis at the level of paracrinically regulating associations of cells and organs release into blood many non-etherifying fatty acids. The albumin has no possibilities to bind them all. The polar fatty acids-free fatty acids which are not bind by albumin form in blood direct heterogeneous micelles which spontaneously incorporate into plasmatic membrane of monolayer of endothelium. At that, the hydrophilic lipid pores are formed through which Ca2+, Na+ and water get into cytosol and K+ gets out. The hydration of cytosol and hypercalcinemia increase dimensions, thickness of monolayer of epithelium, narrow lumen of arterioles of muscular type and increase resistance to blood flow in distal section of arterial channel. The hydrodynamic pressure increases compensatory in proximal section of arterial channel along with the development of arterial hypertension. The late in phylogenesis insulin has no possibilities to block lipolysis in fatty cells of omentum hence these cells have no receptors to this insulin. While in blood plasma the concentration of non-etherifying acids is increased the cell will not absorb and oxidize glucose. The non-etherifying form the resistance too late in phylogenesis insulin, hyperglycemia and hyperinsulinemia. The concentration of oleic triglycerides increases in blood. The increase in omentum of number of fatty cells of loose connective tissue forms biological reaction of inflammation right up to destruction of overloaded oleic triglycerides cells on the type of apoptosis. This occurrence increases the concentration of C-reactive protein in blood plasma. All symptoms of syndrome of overeating (metabolic syndrome) are formed in the framework of integrated pathogenesis. PMID- 24757864 TI - [The diagnostic value of enzyme-linked immunosorbent assay technique in detection of anti-tuberculosis antibodies in groups of patients with HIV-positive and HIV negative reaction]. AB - The article analyzes the results of evaluation of diagnostic value of enzyme linked immunosorbent assay for detection of antituberculosis antibodies with purpose to diagnose tuberculosis of lungs separately in groups of both HIV positive and HIV-negative persons. A moderate diagnostic value of enzyme-linked immunosorbent assay is established under screening for tuberculosis of lungs in HIV-negative patients. The evidence of reliability of results depended mainly of actual form of tuberculosis of lungs. In view of many positive results in detection of anti-tuberculosis antibodies in control group of patients with HIV infection the data testified the low diagnostic significance of enzyme-linked immunosorbent assay in group of patients with HIV-infection. The drawbacks of enzyme-linked immunosorbent assay technique of diagnostic of tuberculosis of lungs in common group of HIV-infected patients partially compensated by possibility of its application at late stages of development of HIV-infection. PMID- 24757865 TI - [The effectiveness of BACTEC MGIT 960 system hit analysis of surgery material of patients with tubercular spondylitis]. AB - The article considers the comparison of effectiveness of cultivation of 290 surgery samples from focus of destruction in patients with tubercular spondylitis in liquid medium Middlebrook 7119 with fluorescent detection of growth and two dense egg medium -Levenschtein-Yensen and Finn-II. The sensitivity of methods of inoculation in liquid medium Middlebrook 7H9 and in dense egg mediums has no difference (38.2% and 43.1%, p = 0.271). The duration of growth consisted 2 +/- 2.3 days for liquid mediums and 40.6 +/- 3.2 days for dense mediums. The method of pre-inoculation processing of surgery material. In case of inoculation of 440 samples in liquid mediums contamination consisted 3.9%. In case of inoculation of bone fragments of focus of destruction in liquid medium Middlebrook 7119 the culture was isolated in 43.5% of samples of patients with tubercular spondylitis. PMID- 24757866 TI - [The evaluation of effectiveness of application of automated system of polymerase chain reaction to detect meticillin-resistant and meticillin-sensitive Staphylococcus aureus in clinical material from trauma orthopedic patients]. AB - The article considers the evaluation of effectiveness of application of automated polymerase chain reaction system GeneXpert DX ("Cepheid USA) as compared with bacteriologic method in detection of S. aureus (SA) and meticillin-resistant S. aureus (MRSA) under infection of skin and soft tissues in orthopedic patients. The results of analysis of material from patients got in 2009-2011 using analyzer Vitek-2 to identify microorganisms demonstrated that separation and identification of agent was successful in 70.04% of 2153 examined samples. The representatives of genus of Staphylococcus made up 56% of strains. The percentage of MSRA consisted 29.8% of SA isolates. In 2012, the GeneXpert DX system was used to analyze 50 samples of clinical material. The analysis established full matching of results of detection of SA/MRSA in case of using this method and bacteriological analysis to detect agent. The DNA of SA was detected in 61.5% of patients in whom the application of bacteriological method was unsuccessful in separation and identification of agent. In 25% of patients DNA of MRSA was detected. This occurrence made it possible to begin corresponding therapy and to get clinical effect. The diagnostic using GeneXpert DX system took less than 1.5 hours from moment of availability of sample in laboratory. The application of polymerase chain reaction system GeneXpert DX is an effective additional method to identify SA/MRSA which does not exclude application of bacteriological analysis. PMID- 24757867 TI - [The new possibilities in serologic diagnostic of Ixodes mite-borne borreliosis using ImmunoChip]. AB - The new kit of reagents in format of the immunochip "ImmunoChip Borreliosis" for multiplex serologic analysis of mite-borne borreliosis demonstrated high diagnostic sensitivity and specificity. The percentage of detection of specific immunoglobulins was higher in "ImmunoChip Borreliosis" as compared with screening results in immune enzyme analysis. The high correlation between results of testing in immunochip and data of immune blotting is demonstrated to. PMID- 24757868 TI - [The algorithms of evaluation of economic effectiveness of laboratory technologies]. AB - The article considers several practical situations requiring estimation of economic effectiveness. The protocols of estimation, costs and effectiveness accounting requirements of practical public health are proposed. The necessity of development of correct epidemiological model is demonstrated to estimate profit of innovations of diagnostic stage. The estimation "costs-effectiveness" is made for troponins at diagnostic of cardiac infarction and prostate-specific antigen under screening of prostate cancer. PMID- 24757869 TI - Spotlight on SNFs. PMID- 24757870 TI - 5 ways to create more value in the ED. PMID- 24757871 TI - Buyer's brief: cognitive computing in the age of big data. PMID- 24757872 TI - Protecting corporate value in affiliation transactions. AB - Understanding the risks and rewards of affiliations is critical to determining whether the partnership will address specific challenges without compromising organizational goals. An analysis of the tension points and potential risks associated with an affiliation also should identify possible strategies for resolution. Hospitals can mitigate potential affiliation downsides through a well run process that follows several key steps. PMID- 24757873 TI - Distributing shared savings for population health management. AB - Lessons from outcomes-based fee-for-service payment models that can be applied to population health management models include the following: Focus on outcomes, not processes. Limit the number of outcomes measures used. Ensure that the amount distributed is substantial enough to motivate behavior change. Communicate results clearly and transparently. Ensure that the financial consequence of poor performance is proportional to the cost increase it generates. Focus on reducing the rate of excess preventable outcomes. PMID- 24757874 TI - Setting the right path and pace for integration. AB - Far from being a monolithic trend, integration in health care today is progressing in various forms, and at different rates in different markets within and across the range of healthcare organizations. Each organization should develop a tailored strategy that delineates the level and type of integration it will pursue and at what pace to pursue it. This effort will require evaluation of external market conditions with respect to integration and competition and a candid assessment of intraorganizational integration. The compared results of the two analyses will provide the basis for formulating strategy. PMID- 24757875 TI - Combining forces to manage the continuum of care. AB - Many healthcare organizations are pursuing affiliation strategies to effectively manage population health. Healthcare organizations should take the following key steps in setting such a strategy: Ensuring the strategy aligns with the organization's mission Identifying potential partners. Outlining expectations for the affiliation. Assessing affiliation structure options. PMID- 24757876 TI - A 3-pillar approach to integrated population health management. AB - Successful integrated population health management models include: A leadership team that includes financial managers, physicians, and advisers. A plan that clearly connects tactics to measurable goals. Infrastructure that includes care coordinators and robust IT to avoid duplicative care and ensure care protocols are followed. PMID- 24757877 TI - A strategic approach to healthcare transformation. AB - Transforming the care model is a necessary first step to succeeding under value based payment models where payment is linked to outcomes. To maintain acceptable margins while improving quality of care and reducing costs, healthcare executives should develop strategies for: Managing care across the continuum. Reducing readmissions for all diagnoses. Building and supporting the patient-centered medical home model. Achieving clinical integration. PMID- 24757878 TI - Evaluating the fair market value of pay for performance. AB - When assessing a pay-for-performance arrangement, the following factors should be considered: Existence and/or size of minimum savings threshold before savings are allocated. Savings allocation percentage available to physicians. Benchmarks used to measure quality against past performance and/or medical evidence. Ways in which quality outcomes are measured and paid for. Per member per month payments for patient management. Physician investment (participation fee, time, or capital). Existence of downside risk to physicians. Employed compensation structure (if applicable). PMID- 24757879 TI - Developing an enterprisewide data strategy. AB - When considering information governance, CFOs should ask two primary questions: How accurate are our data, and is there a process in place to ensure that data are reliable, timely, up-to-date, and consistent? CFOs also should have at least a general sense of how and where data are flowing and whether the data accurately reflect services rendered. The goal of a formal enterprisewide information governance process is to enable employees to identify data-quality issues up front, thereby avoiding the need to devote valuable time and resources to resolving problems after an error occurs. PMID- 24757880 TI - Hospital-owned medical practices gaining the benefits without the losses. AB - Hospitals can correct most of the causes of reduced performance in hospital-owned medical practices by setting appropriate performance expectations and implementing correct operating principles. Engaging employed physicians and executives as partners who provide principle-based direction and support to practice managers encourages performance improvement. A critical determinant of a hospital's ability to successfully own medical practices is understanding and implementing the principles for success in this unique ambulatory business. PMID- 24757881 TI - Viewing U.S. health care as a growth industry. PMID- 24757882 TI - Now is not the time to cut your quality resources. PMID- 24757883 TI - Why the SGR is still the elephant in the room of deficit reduction. PMID- 24757884 TI - Alternative financing: risks require effective disclosure. PMID- 24757885 TI - Evidence based medicine. PMID- 24757886 TI - CT analysis of renal stone composition: a novel and non invasive method to analyse stones. PMID- 24757887 TI - Use of lean principals to improve flow of patients with fractured neck of femur- the HOPE study. AB - We describe the implementation of a care pathway for patients with fractured neck of femur (NOF) using Lean and Six Sigma principles. After introduction of the Lean pathway, 32 patients out a total of 86 (37%) with fractured NOF were admitted to the Trauma Ward within 4 hours of presentation to the hospital; prior to implementation this was 16 patients out of a total of 59 (27%). Post-Lean an earlier mean theatre start time of 8.40am was achieved, resulting in a 38 minute increase in daily theatre time. An additional 52 patients (12%) received surgery within 24 hours of admission, resulting in 1 night length of stay reduction. Lean methodology proved an effective method to guide change resulting in an improved journey for the patient and significant workflow gains. PMID- 24757888 TI - Comparison of comorbidities in patients with pre-diabetes to those with diabetes mellitus type 2. AB - A cross sectional study performed on 309 pre-diabetes and 309 type 2 diabetes patients, selected from General Practices in Cork. The prevalence of complications was calculated and the data analysed to determine is there a statistically significant difference in prevalence of complications. The prevalence of co-morbidities in the type 2 diabetic group are Ischaemic Heart Disease 55 (17.8%), Chronic Kidney Disease 17 (5.5%), cerebrovascular disease 16 (5.2%), peripheral vascular disease 40 (12.9%), eye disease 20 (6.5%), peripheral neuropathy 27 (8.7%) and autonomic neuropathy 11 (3.6%). The prevalence of co morbidities in the pre-diabetic group are Ischaemic Heart Disease 64 (20.6%), Chronic Kidney Disease 12 (3.9%), cerebrovascular disease 11 (3.5%), PVD 24 (7.7%), eye disease 1 (0.3%), peripheral neuropathy 8 (2.6%) and autonomic neuropathy 17 (5.5%). The prevalence of many of the co-morbidities assessed is statistically the same in pre-diabetes patients with only peripheral vascular disease, eye disease and cerebrovascular disease having a statistically significant higher prevalence in type 2 diabetes. PMID- 24757889 TI - Seasonal influenza vaccine uptake in HSE-funded hospitals and nursing homes during the 2011/2012 influenza season. AB - Annual seasonal influenza vaccine is recommended for all health care workers (HCWs) in Ireland. For the 2011/2012 influenza season, information was collected on influenza vaccination uptake among HCWs employed in Health Service Executive (HSE)-funded hospitals (primarily acute) and of nursing homes (NHs) and also among NH long-term and short-term respite care residents. Forty-five hospitals (80%) and 120 NHs (75%) provided uptake data. Nationally, influenza vaccine uptake among hospital employed HCWs was estimated to be 18% and 14% among HCWs in NHs; in NHs vaccine uptake among long-term care residents was estimated to 88%. These findings highlight the continued low uptake among HCWs of all categories and demonstrate the need for sustained measures to improve uptake rates. PMID- 24757890 TI - Analysis of the last decade of weekend out-of-hours CT imaging: how have things changed? AB - CT has become an invaluable diagnostic tool. The clinical applications and technological capacity of CT has continued to increase. There is an increasing demand for radiology services including during weekend on-call hours. The objective of this study was to assess the trend in weekend CT imaging requests over a ten-year period form 2001-2010. Electronic data was retrieved from the hospital Radiology Inpatient System. In total 8530 CT scans were performed during weekend on-call hours. Over the decade weekend imaging grew from 466 to 1448 (210.7%) CT examinations. CT brain imaging accounted for 3944 of the total 8530(46%) and this was a 126% increase. A ten-fold, eight-fold and three-fold increase occurred in adult CT thorax, CT pelvis and CT abdominal imaging respectively. These results demonstrate rising demand on radiology services and need to plan for continued future growth. Radiology and emergency departments need to prepare and develop pathways to deal with this projected growth. PMID- 24757891 TI - Staff support for the Health Service Executive (HSE) global health programme. AB - The Global Health programme (GHP) within the Health Service Executive (HSE) aims to improve health in developing countries by creating partnerships between Irish and developing world healthcare institutions. To ascertain the level of interest among HSE staff for the GHP a web-based survey was conducted. 1,028 responses were received. Medical professionals, 202 (27.7%) composed the largest category of respondents. The majority, 503 (69.3%) of respondents wished to actively participate in the GHP. 237 (23.1%) staff had previous experience of working in the developing world. This survey highlighted a number of themes respondents considered important for successful partnerships including: reciprocal staff exchange, joint scientific research, the avoidance of "brain drain" and utilising the Internet to link institutions. Less than 1% (2/203) of comments expressed a negative view of the GHP. PMID- 24757892 TI - The ictal bradycardia syndrome: persistence of seizures despite cardiac pacemaker implantation. AB - Ictal bradycardic syndrome (IBS), a rare manifestation of temporal lobe epilepsy is both difficult to diagnose and treat. Our case study of a 24 year old with persistent and unexplained syncope highlights the typical presentation, investigation and treatment of IBS. PMID- 24757893 TI - A grossly abnormal trachea- severe tracheal diverticulosis and Mounier-Kuhn syndrome. AB - A 53-year-old smoker presented with a history of recurrent lower respiratory tract infections. A diagnosis of Tracheal Diverticulosis due to Tracheobronchomegaly (Mounier-Kuhn Syndrome) was made. The clinical history, diagnosis and treatment options are discussed. PMID- 24757894 TI - The national incidence and outcomes of gastroschisis repairs. AB - The birth prevalence of gastroschisis worldwide has increased over the past decades. We aim to determine the Irish national incidence of gastroschisis repairs (NIGR) over a 5 year period (2007- 2011) and clinical outcomes by a retrospective cohort review of cases admitted to all Irish paediatric surgical units. Seventy patients were identified. The NIGR per 10,000 live births was 1.96 (SD 0.51) per year. Fifty eight (82%) were antenatally detected. Twenty eight (40%) had primary repair day 1 with the remaining repaired in a median of 3(2 5.75) days. Thirty three (47%) experienced a central catheter related infection. Duration of stay was significantly correlated with decreasing gestational age (p = 0.016), decreasing birthweight (p = 0.005), increasing numbers of blood transfusions (p < 0.001) and co-morbidity or complication (p < 0.001). This study provides individual centres with patient outcomes and national data that can be provided to parents and clinical staff regarding the clinical course of gastroschisis. PMID- 24757895 TI - Unscheduled undergraduate teaching in surgery: a multi-institutional analysis. AB - A significant amount of valuable undergraduate medical teaching may be informal, unscheduled and delivered by non-consultant hospital doctors (NCHDs). 800 Questionnaires were distributed to consultants, NCHDs and medical students in Irish teaching hospitals. The aim was to quantify the level of unscheduled teaching carried out in these hospitals and the manner in which it was performed. The response rate was 46% (364/800). 71% of doctors who replied are independently teaching undergraduate medical students (77/109), including 71% of interns and senior house officers (48/68). Students tend to prefer small group teaching. Fifty-six percent of students suggest they would benefit from more surgical teaching time (144/255). No interns surveyed were scheduled to teach as part of a formal curriculum. A significant amount of unscheduled teaching by interns and senior house officers takes place in Irish hospitals. It may prove beneficial to incorporate interns into scheduled surgical teaching curricula. PMID- 24757896 TI - Paediatric diabetes: information-seeking behaviours of families. AB - The Internet provides patients and their families with ready access to on-line health related information. However, this information is not always accurate, understandable or provided by health professionals or advocacy groups. One hundred children with Type 1 diabetes mellitus, or their parents, attending a paediatric diabetes clinic during September to November 2011 were invited sequentially to participate in this questionnaire-based survey of Internet use in searching for diabetes-related information. Sixty-seven (67%) returned completed anonymised questionnaires: 36/67 (53%) were categorised as socio-economic groups C1/C2. Of the 67 families who returned completed questionnaires, 64 (96%) had a home computer and 62 (93%) had home Internet access; 27 (40%) rarely, and 40 (60%) frequently, searched on-line for diabetes-related information. Key search terms were not provided by respondents. There appears to be considerable internet use in seeking health related information for children with Type 1 diabetes mellitus. Clinicians should make efforts to direct patients and their families to websites that present accurate and current information. PMID- 24757897 TI - Electronic discharge summaries--are they being done and do they have the required information? AB - A retrospective audit was conducted to evaluate the completeness of the available electronic discharge summaries. Forty-five randomly selected patients had their respective electronic discharge summaries reviewed including criteria such as length of stay; discharge summary availability; documentation of discharge medications; medication changes; medical co-morbidities and follow-up arrangements. There were electronic discharge summaries available for thirty-six (80%) of the included patients of which; thirty-three (91.7%) had the medication list available; twenty-six (72.2%) had clear documentation of medication changes; thirty-five (97.2%) had clear documentation of the patients' co-morbidities; and thirty (83.3%) had clear follow-up plans documented. The readmission rate was found to be high when compared to published numbers with a quarter of the discharged patients being readmitted within 28 days. The recommendations resulting from this audit include the need for improved education on the requirements of the electronic dischange summary, appropriate documentation and possible implementation of out-of-hour discharge summary availability. PMID- 24757898 TI - The value of health libraries and librarians to the Irish health system. AB - Librarians working in the Irish health sector are under threat. This is a relatively young profession in comparison with international counterparts, with a low staffing base even at its peak. The public sector moratorium has led to professionally qualified librarians and library assistants not being replaced right across the health system. Librarians are employed in the HSE, voluntary sector, and university sectors. The value that this profession brings to healthcare has been documented in systematic reviews and literature in other countries. In Ireland this group is represented by the Health Science Libraries Group (HSLG), a section of the Library Association of Ireland. The HSLG commissioned research into the status of the profession as well as Irish health libraries. This resulted in the publication of the "SHeLLI Report" in 2011. Results of the report are outlined here and selected examples of value of librarians to healthcare are described. PMID- 24757899 TI - Down in the wards: point prevalence of antidepressant and benzodiazepine use. PMID- 24757900 TI - Regulations and poignancy. PMID- 24757901 TI - Pricing radiology bundled CPT codes accurately: 2014. PMID- 24757902 TI - Using iPads to improve patient care. PMID- 24757903 TI - Radiologist assistant: best fit for medical imaging. AB - The radiologist assistant (RA) is an emerging mid-level provider who can benefit radiologists, technologists, radiology departments, patients, and the healthcare system in the United States. A review of the peer-reviewed literature published from 2005-2013 revealed a moderate amount of research about these benefits, which was supplemented with research on collaborative relationships and advanced practice registered nurses (APRN). As an advanced practice radiologic technologist, the RA has a strong technically based, patient-centered background and is the ideal mid-level provider in an imaging-centered clinical environment. PMID- 24757904 TI - The value we provide our organizations. PMID- 24757905 TI - Digital radiography and accountable care. AB - Patient perception of the radiology experience will impact a hospital's HCAHPS results, and radiologic technology has a critical role to play in making those experiences as positive as they can be. Recent advances in DR acquisition and workstation technology make the modality an ideal fit for healthcare organizations focused on improving patient safety and satisfaction. This article will look at how DR and workstation technology can improve technologist responsiveness to patients, radiology report generation, recognition of patient acuity, cleanliness and quietness of facilities, patient transport and positioning, and dose management. PMID- 24757906 TI - Physician supervision of radiology services. PMID- 24757907 TI - ICD-10 peripheral vascular disease. PMID- 24757908 TI - Lessons in disaster: the Boston Marathon bombing. AB - The events of a disaster and its aftermath often focus on what the doctors and nurses did to treat the victims. The ancillary departments, such as radiology, also play a very important role. Staff participate in drills routinely to prepare for such events, and had just recently participated in one with mass casualties, but the sheer volume was beyond the scope of comprehension. Everyone worked as quickly as possible in getting quality images for the physician staff. For future disasters, counselors need to be available to the staff quicker, and a debriefing session specific to radiology is necessary right away. Any disaster has a beginning and an end for the event itself, but the reverberations continue long after and staff need to be prepared for that. PMID- 24757909 TI - A nod to the past. PMID- 24757910 TI - The medical device excise tax. PMID- 24757912 TI - Personal tech one key to better health. PMID- 24757911 TI - Life and death. PMID- 24757913 TI - 50 years of progress, but still a way to go. PMID- 24757914 TI - Self-efficacy: a mediator of smoking behavior and depression among college students. AB - Cigarette smoking is a growing problem among adolescents. This correlational study tested theoretical relationships between the dependent variable (smoking behavior) and the independent variables (depression and smoking resistance self efficacy) in a convenience sample of 364 college students ages 18 to 21 years recruited from a large urban public college. An a priori mediational model tested the role of smoking resistance self-efficacy as a mediator in the relationship between smoking behavior and depression. Findings showed there was a statistically significant positive relationship between depression and smoking behavior (r = 0.122, p = 0.01). There was a statistically significant negative relationship between smoking resistance self-efficacy and smoking behavior (r = 0.744, p = 0.01). Additionally, smoking resistance self-efficacy was a mediator of the relationship between depression and smoking behavior (beta = -0.757, p = 0.001). This study identifies a need for further theory-driven study of the relation of adolescent depression and smoking behavior. The findings of this study have implications for nursing interventions targeted to both current smokers and smoking initiation prevention programs. PMID- 24757915 TI - Influenza and oseltamivir phosphate (Tamiflu) in infants: what you need to know. AB - Influenza is a highly contagious virus that causes an average of 20,000 hospitalizations a year in children under five years of age. As of March 30, 2013, the 2012-2013 flu season had seen 111 pediatric deaths, with 21 deaths in the 0- to 23-month-old range. Rates of influenza-associated hospitalization are substantially higher among infants and young children than among older children, and those under six months old are at the highest risk. Research shows that influenza vaccine is not as effective in children two years of age relative to adults, and the vaccine is not approved in infants younger than six months. Thus, preventing influenza and proper treatment are important for keeping this high risk group safe from complications. With infants being highest at risk for complications and the extrapolation of efficacy and safety from the older population, the U.S. Food and Drug Administration (FDA) recently approved the use of the antiviral oseltamivir phosphate (Tamiflu) for treatment of uncomplicated influenza in patients two weeks and older. This young population is susceptible to the benefits as well as the risks of the drug. Health care providers must be aware of dosing, adverse reactions, and monitoring parameters to better treat and educate their patients. PMID- 24757917 TI - Recycled data. PMID- 24757916 TI - Chronological progression of body dissatisfaction and drive for thinness in females 12 to 17 years of age. AB - The purpose of this secondary study of cross-sectional data was to examine patterns of scores on the Eating Disorders Inventory in a healthy sample of female adolescents thought to have a high potential for risk. Data were obtained as part of a consultation to identify risk of developing eating disorders. The screening and subsequent group level analysis was carried out with 44 female dancers 12 to 17 years of age enrolled in grades 7 to 12 in a Magnet school. This secondary analysis examined three components of the Eating Disorder Inventory (EDI-3): body dissatisfaction, drive for thinness, and bulimia for the purpose of comparing group findings across ages and grades. Some level of body dissatisfaction was widespread in the population, body dissatisfaction increased beginning notably at age 14 and increased sharply at age 15, with further increases until age 16. The correlation between body dissatisfaction and drive for thinness was shown to be statistically significant (r = 0.83, p < 0.001). Awareness that body dissatisfaction and drive for thinness increase at ages 15 and 16 means disordered eating may begin at this time. If body dissatisfaction and drive for thinness begins early in life and markedly increases at ages 14 and 15, eating disorder prevention must begin in childhood and continue into adolescence. PMID- 24757918 TI - Effectiveness of high-fidelity simulation for pediatric staff nurse education. AB - A pre-test post-test control group design was used to compare the effectiveness of high-fidelity simulation (HFS) with traditional static mannequins as a teaching strategy for pediatric staff nurse education. Thirty-three nurses from a metropolitan pediatric Magnet hospital completed the study that evaluated knowledge retention, skill performance, and team confidence during the American Heart Association's (AHA) Pediatric Emergency Assessment, Recognition and Stabilization (PEARS) course. Written exams, competency and skill performance measures, and the Mayo High Performance Teamwork Scale (MHPTS) were used to compare the outcomes between the two groups. Results indicated that knowledge retention was maintained, skill performance improved, and teamwork performance scores increased in the experimental group. This study provides a foundation supporting the use of HFS as an effective teaching modality when educating pediatric staff nurses in the identification and intervention of the deteriorating pediatric patient. PMID- 24757919 TI - Screening for autism spectrum disorders in infants before 18 months of age. AB - Autism spectrum disorders (ASDs) are a group of developmental disabilities that can cause significant social, communication, and behavioral challenges for children and families. An estimated one in 88 children in the United States are affected by an ASD. Early identification and intervention have been shown to improve outcomes for these children, and the routine well-child visit is a critical opportunity for pediatric health care providers to obtain developmental information relating to ASD identification. Although current recommendations suggest ASD screening at 18 and 24 months of age, research suggests that ASD specific behaviors and delays emerge earlier in infancy. The purpose of this article is to identify key developmental tasks that can be assessed by pediatric primary care providers to determine increased risk for ASD in infants at nine, 12, and 15 months prior to formal screening for ASD at 18 and 24 months. PMID- 24757921 TI - Creating a legacy for and with hospitalized children. PMID- 24757920 TI - Encouraging positive behavior in 'challenging' children: the Nurtured Heart Approach. AB - Conventional parenting approaches often fall short of the mark for children who exhibit difficult behavior, sometimes inadvertently leading to increased oppositionality and poor self-esteem. As a result, parents of children with intense personalities and challenging behaviors need strategies that work very differently. The Nurtured Heart Approach is a philosophy/technique developed to help parents rewrite the often negative parenting scripts used with these children by limiting the amount of attention given to negative or undesirable behaviors while noticing and acknowledging even small positive behaviors, naming them, "energizing" attention given to them, and valuing their occurrence. Although there has been very limited empirical study of the Nurtured Heart Approach to date, it has been used, with anecdotal reports of success, in a variety of settings, including Head Start programs, schools, foster care agencies, a treatment center, and a pre-adolescent diversion program (Glasser, 2000). PMID- 24757922 TI - Pediatric nursing knowledge and attitude survey regarding pain. PMID- 24757923 TI - For a friend. PMID- 24757924 TI - Sponsor article. PMID- 24757925 TI - Sponsor article. PMID- 24757926 TI - Why I am a tripartite member. PMID- 24757927 TI - A sense of belonging. PMID- 24757928 TI - Members making a difference. PMID- 24757929 TI - "How can costly student scheme be justified?". PMID- 24757930 TI - Student HCA pilot costs over pound 2.3m. PMID- 24757931 TI - Hike in car parking charges could force nursing students to quit. PMID- 24757932 TI - Hospital nurses left to look after children who have self-harmed. PMID- 24757933 TI - "Hunt has been deliberately provocative with NHS pay plan". PMID- 24757934 TI - "There can be no excellence in practice without senior nurses". PMID- 24757935 TI - Hands-free communication to free up nursing time. AB - The design of a hospital, including how the beds are spaced and where clinical areas and supplies are located, affects the amount of time staff spend walking around wards instead of spending time with patients providing direct clinical care. A number of technological solutions are emerging that have the potential to reduce unnecessary walking and give nurses more time to spend with patients. One is the Vocera, a hands-free mobile voice communication system. This article discusses whether this device reduces the average distance staff walk during a shift and their experiences of using it. The study was undertaken on a 32-bed ward with all single-room en-suite accommodation. The distance staff walked reduced by an average of 19.8% when the device was used. However, semi-structured interviews showed that signal reception and voice recognition need further development. This study adds to a growing body of evidence that hands-free communication devices free up nursing time by increasing the effectiveness and efficiency of communication on inpatient wards. PMID- 24757936 TI - Implications of a new form of online education. AB - This article discusses the development of massive open online courses. It examines the benefits and potential problems associated with this method of education delivery and describes how these courses are influencing nurse education. It also explains how changing delivery methods and access to higher education may alter how nurses engage with higher education in the future. PMID- 24757937 TI - Using texts to increase access to school nurses. AB - Although young people find school nurses approachable and caring, too few access their services. A text messaging service was set up in two secondary schools to raise awareness of the school nurse and encourage teenagers to make contact for health advice and support. Pupils were involved in developing promotional materials. The majority of text contact was for sexual health and relationship issues, with 44 out of the 202 text messages leading to face-to-face contact with the nurse. PMID- 24757938 TI - How to recruit caring and compassionate HCAs. AB - Heathcare organisations are faced with the challenge of recruiting staff who have caring and compassionate values so need to ensure these can be identified at interview. We piloted multiple mini-interviews as a possible solution to recruiting healthcare assistants. This article outlines how these were implemented and highlights some of the pitfalls of using this approach. Although the work has not been evaluated formally we decided to share our early experiences of using this approach so others can learn from our practice. PMID- 24757939 TI - Complication of chickenpox infection without skin rashes. PMID- 24757940 TI - 60 seconds with Grainne Wokes. PMID- 24757941 TI - Inspiring cancer patients. PMID- 24757942 TI - Applications of graphene in mass spectrometry. AB - This paper reviews the up-to-date research about the applications of graphene and its related materials in the field of mass spectrometry (MS). Due to its large surface area, delocalized pi-electrons, thermal conductivity, stability and rich interaction chemistry, graphene has been widely used in MS-based analytical chemistry. Graphene-based materials were applied as very effective matrixes or surfaces for many kinds of organic molecules in laser desorption/ionization (LDI) MS analysis. Many advantages of this novel matrix have been proved, which included: low interference ions from matrix itself, good reproducibility, high salt tolerance and so on. The unique properties of graphene also make it a superior sorbent used in solid-phase extraction (SPE). Further development of online SPE methods based on graphene coupling directly with LDI-MS, GC-MS and LC MS greatly simplifies the MS-based analytical procedure for complex samples and makes the corresponding high-throughput and automatic analysis performable. Their applications as a platform in proteolysis for the rapid identification of proteins have been also developed. In addition, graphene was found to be a unique precursor for the generation of large-sized carbon cluster anions in the gas phase. Finally, the possible challenges and future perspectives in their applications in MS are discussed too. PMID- 24757943 TI - Recent progress in voltage-sensitive dye imaging for neuroscience. AB - Voltage-sensitive dye imaging (VSDi) enables visualization of information processing in different areas of the brain with reasonable spatial and temporal resolution. VSDi employs different chemical compounds to transduce neural activity directly into the changes in intrinsic optical signal. Physically, voltage-sensitive dyes (VSDs) are chemical probes that reside in the neural membrane and change their fluorescence or absorbance in response to membrane potential changes. Based on these features, VSDs can be divided into two groups absorbance and fluorescence. The spatial and temporal resolution of the VSDi is limited mainly by the technical characteristics of the optical imaging setup (e.g., computer and light-sensitive device-charge-coupled device (CCD) camera or photodiode array). In this article, we briefly review the development of the VSD, technique of VSDi and applications in functional brain imaging. PMID- 24757944 TI - The role of nanotechnology in combating multi-drug resistant bacteria. AB - The development of antibiotics has played a significant role in combating the dreaded infectious disease such as tuberculosis, pneumonia, typhoid fever and meningitis in 20th century. However, the improper use of antibiotics led to the development of multidrug resistance (MDR) in microbial flora raising a global public health concern of 21st century. This unforeseen threat demands the development of new drugs and strategies for combating antibiotic resistance shown by many microbial species. Recent developments in nanotechnology to engineer nanoparticles with desired physicochemical properties have been projected as a new line of defense against MDR micro-organism. In this review, we summarized and discussed the recent development demonstrating the potential of nanomaterials to evade the MDR. Nanoparticles have shown effective antimicrobial activity against MDR bacteria, such as Acinetobacter baumanii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Mycobacterium tuberculosis, vancomycin resistant enterococci, methicillin-resistant Staphylococcus aureus and others. Furthermore, new strategies like combination of radiation and drugs with nanoparticle that are being explored to potentiate the effectiveness against MDR bacteria have also been summarized. PMID- 24757945 TI - Recent advances in gold and silver nanoparticles: synthesis and applications. AB - In the last decade, gold and silver nanomaterials have received considerable attention due to their attractive electronic and chemical properties and their potential applications in the development of new technologies. Recent advances in the study of various gold and silver nanomaterials have led to their utilization in a number of very important applications including biosensing, diagnostic imaging, and cancer diagnosis and therapy. This review surveys the various synthetic methods of gold and silver nanomaterials. Recent experimental studies focusing on the use of gold and silver nanomaterials in catalysis, food industry, and environmental conservation are also reviewed. This review also highlights the advantages of gold and silver nanomaterials in the development of fluorescence biosensors, glucose biosensors, nucleic acids-based biosensors, and protein-based biosensors. Moreover, the potent in vitro and in vivo anti-microbial and cyto genotoxic effects of various gold and silver nanomaterials are underlined. Finally, recent advances in the employment of gold and silver nanomaterials as effective drug delivery vehicles and promising cancer therapeutic agents are summarized. Despite their use in remediating numerous medical and health-related conditions, the efficacy and safety of many gold and silver nanomaterials is still under some scrutiny. Needless to say, researchers are facing many challenges and obstacles in their ample attempts to synthesize nanomaterials that are relatively easy to design, inexpensive to fabricate, and effective in treating various diseases, but at the same time display a very low, if any, toxicity to the body. Future investigations should aim at overcoming such challenges in an attempt to design nanomaterials that will prove to be useful in diagnosing and treating life-threatening diseases while ensuring a high degree of efficacy and safety. PMID- 24757946 TI - Bio-inspired electrospun micro/nanofibers with special wettability. AB - Inspired by the extreme wetting states displayed by the natural materials, various techniques have been widely investigated to fabricate superhydrophobic and superhydrophilic surfaces. Electrospinning has gained huge amount of interest as fibers with suitable combination of surface chemistry and surface roughness can be easily obtained. This study provides a comprehensive overview of the progress that has been made on electrospun fibers that display superhydrophobicity, superhydrophilicity or a combination of both. The article discusses various modification techniques that can be implemented to obtain fibers with surface heterogeneity for improving its hydrophobicity or hydrophilicity. Both nanometer size of the fibers and secondary nanoscale structures ensure that the fibers have suitable surface topography to exhibit extreme wetting states. Additionally, for the first time, we critically review and identify the role of intrinsic structures such as crystallinity and chain orientation on the wettability of the fibers. We highlight some new emerging application areas that are being explored using superhydrophobic and superhydrophilic fibers. Further, methods for fabricating smart materials with special wettability are also discussed. Such fibers with special wettability show tremendous promise for water harvesting, unidirectional water collection and oil water filtration applications. PMID- 24757947 TI - Threshold voltage instability mechanisms of nitride based charge trap flash memory--a review. AB - Technological scaling of charge trap device has become significantly more challenging due to two major physical limits revealed by International Technology Roadmap for Semiconductors (ITRS) 2011, i.e., (1) neighboring bit interference due to consistent shrinking in design floor space; (2) balancing act of ensuring sufficient number of electrons in shrinking storage layer to maintain stable threshold voltage (V(t)) against various V(t) instability mechanisms. Nitride based charge trap flash (CTF) is one of the better candidates to replace floating gate (FG) flash as the mainstream flash memory technology due to its inherent immunity to point defects and better device scalability. However, post cycled V(t) instability in the form of V(t) distribution shift and broadening of programmed/erased cells is still genuine reliability concerns for nitride based CTF devices. This is because the shift and broadening of V(t) distribution could degrade the operating window and thus caused premature failures of the devices. V(t) instability of nitride based CTF memory inevitably introduces statistical fluctuations in V(t) distribution of nitride based CTF which is detrimental to its long-term data retention performance. The scope of this review paper focuses on critical reliability challenges of future development of nitride based CTF development with emphasis on cell level V(t) instability mechanisms. Our review on recent findings of V(t) instability mechanisms are useful references for future development of nitride based CTF devices. PMID- 24757948 TI - Cancer nanotechnology: enhanced therapeutic response using peptide-modified gold nanoparticles. AB - The applications of nanoparticles (NPs) for improved therapeutics are at the forefront of cancer nanotechnology. Gold nanoparticles (GNPs) have been extensively used due to their ability to act as both an anticancer drug carrier in chemotherapy and as a dose enhancer in radiotherapy. GNPs used in the studies were predominantly localized in the cell cytoplasm. However, the therapeutic response can be further enhanced if NPs can be effectively targeted into the nucleus. Here, we present an effective strategy for designing a GNP-peptide complex for nuclear targeting. Two peptides were conjugated onto a NP: One peptide enhanced the uptake while the other peptide enhanced the nuclear delivery. The nuclear targeted cells displayed a four-fold increase in the therapeutic response when treated with radiation as compared to untargeted ones. There was a modest increase in the DNA damage for radiated cells with nuclear targeted GNPs. This research will establish a more successful NP-based platform for combining more than one treatment modality, such as chemotherapy and radiotherapy, and creates a more aggressive approach in eradicating cancer. PMID- 24757949 TI - Formulation and optimization of raloxifene-loaded solid lipid nanoparticles to enhance oral bioavailability. AB - The main aim of this study was to improve the oral bioavailability of raloxifene (RXF), a selective estrogen receptor modulator, by incorporation into solid lipid nanoparticles (SLN). RXF-loaded SLN was prepared by homogenization-sonication technique and characterized through physicochemical, pharmacokinetic, and cytotoxicity studies. The optimized SLN formulation exhibited a spherical shape with average size around 140 nm, easing its transport across the lymphatic system. Augmentation in the profiles of C(max) (308%) and AUC (270%) indicated a significant enhancement in the rate and extent of bioavailability by SLN formulations compared to free drug. In vitro cytotoxicity study performed in NIH 3T3 cells revealed that RXF-SLN was cytocompatible, and SLN remained unchanged during the freeze-drying process. Furthermore, the optimized formulation was quite stable at room temperature for more than two months, exemplifying its superior performance. In conclusion, SLN provides a promising platform for the pronounced enhancement of RXF bioavailability. PMID- 24757951 TI - Photo-controllable molecular hydrogels for drug delivery. AB - A photocleavable nitrobenzyl ester group was introduced in the backbone of self assembling peptides using standard Fmoc-peptide systhesis. The nitrobenzyl ester group could be used as a cleavable linker to connect a gelator and a hydrophilic group. Photo-irradiation would lead to the generation of the molecular gelator and the formation of a molecular hydrogel. The nitrobenzyl ester group could also be used as one part of hydrophobic capping group for short peptides to produce molecular hydrogelators. In this case, photo-irradiation would lead to the release of hydrophobic anti-imflammatory drug of Naproxen and the gel-sol phase transition. The application of photocleavable group in molecular self-assembly would lead to photo-controllable self-assembly materials for controlled drug release, tissue engineering, and regenerative medicine. PMID- 24757950 TI - Anisotropic multi-spot DBR porous silicon chip for the detection of human immunoglobin G. AB - Asymmetric porous silicon multilayer (APSM)-based optical biosensor was developed to specify human Immunoglobin G (Ig G). APSM chip was generated by an electrochemical etching of silicon wafer using an asymmetric electrode configuration in aqueous ethanolic HF solution and constituted with nine arrayed porous silicon multilayer. APSM prepared from anisotropic etching conditions displayed a sharp reflection resonance in the reflectivity spectrum. Each spot displayed single reflection resonance at different wavelengths as a function of the lateral distance from the Pt counter electrode. The sensor system was consisted of the 3 x 3 spot array of APSM modified with protein A. The system was probed with an aqueous human Ig G. Molecular binding and specificity was monitored as a shift in wavelength of reflection resonance. PMID- 24757952 TI - Pluronic-poly[alpha-(4-aminobutyl)-1-glycolic acid] polymeric micelle-like nanoparticles as carrier for drug delivery. AB - Pluronic-poly[alpha-(4-aminobutyl)-1-glycolic acid] (Pluronic-PAGA) with different types of Pluronic, the different molecule weight of PAGA, and the different molar ratios of Pluronic to PAGA were synthesized. These materials were bio-degradable, amphiphilic, could be degraded into non-toxic small molecules and could be used to carry drugs. 5-Fluorouracil (5-Fu) loaded Pluronic-PAGA micelle like nanoparticles (5-Fu loaded P-PAGA NPs) were prepared by a simple self assembly method, and characterized by dynamic light scattering, transmission electron microscope. The degradation and release characteristics have also been studied in this paper. With the time passing, the 5-Fu loaded P-PAGA NPs degraded into smaller ones with the similar characteristics of the original NPs. Both the types of Pluronic and the molecule weight of the PAGA affected the releasing progresses. It was found that 5-Fu loaded P-PAGA NPs exhibited high growth inhibitory effect on human gastric cancer cells by MTT assay. The cellular uptake of Rhodamine B loaded P-PAGA NPs was higher than free Rhodamine B. This study suggested that the Pluronic-PAGA with acceptable drug entrapment efficiencies, drug loading efficiencies and tunable release profiles could offer an alternative carrier for 5-Fu delivery and have the potential for the delivery of other anti tumour drug. PMID- 24757954 TI - The C(RgdyK)-conjugated Fe3O4 nanoparticles with high drug load for dual targeting integrin alpha(v)beta3-expressing cancer cells. AB - A novel drug delivery system c(RGDyK)-modified Fe3O4 nanoparticles with high DOX load (R-DMP), which combines magnetic targeting, integrin alpha(v)beta3 targeting and high drug loading properties, was developed by chemical coupling both doxorubicin and peptide c(RGDyK) on the synthetic dual function magnetic nanoparticles (DMP) using a multi-hand cross-linker poly-L-glutamic acid. R-DMP has high drug loading ratio and trapping efficiency for magnetic targeting, and the drug loading ratio can be controlled by adjusting the reactant ratio. Moreover, R-DMP presents narrow size distribution and is sensitive to pH for drug releasing. Compare with those of doxorubicin coupled DMP without peptide c(RGDyK) modification, D-DMP shows enhanced uptake by integrin alpha(v)beta3 targeting expressing tumor cells and displays stronger cancer cell cytotoxicity. This investigate provides a new approach for the dual-targeted delivery of therapeutic agents to tumors with controlled low carrier toxicity and high efficiency. PMID- 24757953 TI - The effect of gold nanoparticles on the proliferation and differentiation of murine osteoblast: a study of MC3T3-E1 cells in vitro. AB - The current study involves in identification and molecular levels characterization of optimal size and concentration of gold nanoparticles (AuNPs). Stable, gold nanoparticles were synthesized and characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). The concentration and size dependent effects of the gold nanoparticles on proliferation of pre osteoblast cells MC3T3-E1 was evaluated employing MTT cell proliferation assay. The results revealed that 30 nm diameter gold nanoparticles at a concentration of 10(-11) ppm were the most effective in promoting cell proliferation. Assay for alkaline phosphatase (ALP) activity and ALP staining were also used to confirm the effect of gold nanoparticles on osteoblast proliferation and differentiation. Moreover, reverse transcriptase polymerase chain reaction (RT-PCR) was used to measure the expression of the osteogenic genes Runx2, ALP, OCN and OPN as response gold nanoparticles. The data demonstrated that 30 nm gold nanoparticles at a concentration of 10(-11) ppm was the best combination of size and concentration to promote the proliferation and differentiation of osteoblasts, as indicated by an increase in the ALP activity and expression of the osteogenic genes Runx2, ALP, OCN and OPN. Collectively the results of this study suggest that gold nanoparticles can promote the proliferation and differentiation of osteoblasts and could be used effectively in treatments promoting bone regeneration. PMID- 24757955 TI - Bis-demethoxy curcumin analog nanoparticles: synthesis, characterization, and anticancer activity in vitro. AB - We have optimized a protocol for the preparation of bisdemethoxy curcumin analog nanoparticles (BDMCA-NP) by the solvent assisted process. The structural similarities between bulk and nano BDMCA were determined by Co-TLC, NMR and F TIR. This shows that our synthesis protocol enhanced the dispersibility and reduce the size of BDMCA without altering the integrity of functional moieties and structure, which is crucial for anticancer and antioxidant activities. The morphology and size of BDMCA-NP as determined by SEM, HRTEM and DLS was found to be around 80 nm. BDMCA-NP treated breast cancer cell lines (MCF 7) showed cell death as characterized by MTT assay. Flow cytometric analysis of BDMCA-NP treated MCF 7 cell lines showed an increase of cell count in G2/M phase indicates the cell cycle arrest. Western blot analysis revealed the presence of caspase 3, caspase 9, cleaved fragments of PARP and Bax proteins in the BDMCA-NP treated MCF 7 cell lines, but not in untreated cell lines. To recap, we have prepared BDMCA NP by solvent assisted process, which exerted anticancer activity against breast cancer cells, which may be due to (i) enhanced dispersibility and surface: volume ratio, (ii) apoptosis (iii) mitochondrial pathway induced cell death, (iv) G2/M phase cell cycle arrest and (v) disassembly of mitotic spindle of the cancer cells. Thus, nano BDMCA can be used as a potent anticancer agent. PMID- 24757956 TI - A lucid build-up of nanostructured curcumin, quercetin and their interaction with DNA. AB - Nanostructured phyto-drugs such as curcumin and quercetin were prepared by simple sonochemical method and studied for their bio-activities. FT-IR spectra indicate that the chemical structures of these nanostructured drugs are identical with their commercially available microcrystalline counterparts. Scanning Electron Microscopic (SEM) analysis reveals that the curcumin and quercetin, form as nanocube and nanoneedle like structures respectively. These nanocrystalline drugs have enhanced solubility in neutral aqueous medium at room temperature and thus exhibit better bioavailability than their commercially available microcrystalline form. Their DNA interactions and the observed binding constants were investigated through UV-vis spectral technique. Nanocurcumin, due to its small size, exhibits significantly high DNA binding constant (1.2 x 10(6) M(-1)). The voltammetric and CD spectral changes observed for the nanocurcumin reveal its deep penetration into the core of the DNA through the minor grooves, where it forms H-bonds with the floor nitrogen/oxygen atoms of the DNA bases. PMID- 24757957 TI - Microarray analysis reveals moderate gene expression changes in cortical neural stem cells cultured on nanowire arrays. AB - Although nanowires are widely used in biological applications, especially as cell manipulation tools, the effect of nanowires on living cells has not been fully investigated. Here, we examined the full gene expression of mouse cortical stem cells cultured on vertical nanowire substrates using RNA microarrays. Genes involved in cell adhesion, cell morphology regulation and cell metabolism were up regulated on the nanowire substrates as compared to flat controls. Scanning electron microscopy images of the samples corroborated our findings, revealing significant differences in cell morphology and adhesion between the nanowire and the flat substrates. Cells on nanowires exhibited a round morphology with a mature appearance characterized by numerous and long processes adhering to the nanowires, while cells on flat substrates had a flat, spread-out morphology and very little neurite outgrowth. PMID- 24757958 TI - Detection of Pseudomonas aeruginosa based on magnetic enrichment and nested PCR. AB - Pseudomonas aeruginosa is a common opportunistic pathogen in clinics. The species specific ecfX gene of Pseudomonas aeruginosa has high specificity. In this experiment, we are intended to develop a new method for the detection of Pseudomonas aeruginosa based on magnetic enrichment and nested PCR, and the specific ecfX gene of Pseudomonas aeruginosa was used as the detection object. The genomic DNA of Pseudomonas aeruginosa was extracted using amino-modified magnetic nanoparticles (MNPs). The ecfX gene was amplified by nested PCR and the product of PCR was detected by agarose gel electrophoresis. The results showed that the optimal annealing temperature was 64 degrees C and 62 degrees C respectively in the first and the second rounds of PCR. The lowest concentration of Pseudomonas aeruginosa that could be detected was 10 cfu/mL. The method provides a reliable, timely and accurate technology for early detection of Pseudomonas aeruginosa. Furthermore, the method can shorten the procedure and time from DNA extraction to detection, which made automation more convenient. PMID- 24757959 TI - Bacterial filtration efficiency of green soy protein based nanofiber air filter. AB - High bacterial filtration efficiency (BFE) filters, based on nanofibers derived from blends of grain proteins and poly-ethylene-oxide (PEO), were produced by an electrospinning process. Specifically, polymer blends consisting of purified soy flour/PEO with a ratio of 7/3 were spun into nanofibers and characterized. A new laboratory based experimental apparatus for testing BFE was designed and used to test BFE of bacterial aerosols consisting of Escherichia coli (E. coli). Performances of soy protein based nanofiber filters with nanofiber mass varying from 1 to 5 g/m2 as well as a nanofiber filters prepared from pure PEO were compared. The results showed that BFE values for filters containing 5 g/m2 protein based nanofibers and PEO nanofiber filter were 100 and 81.5%, respectively. The results also indicated that the BFE increased as the protein content in the nanofiber filter increased. These novel protein based nanofiber filters have demonstrated a clear potential for effective removal and retention of E. coli bacteria during air-filtration. These filters can be effectively deployed in environments such as hospitals and senior residential areas to reduce bacterial infections. PMID- 24757960 TI - Spectroscopic studies of interaction between biologically synthesized silver nanoparticles and bovine serum albumin. AB - Binding interaction of biologically synthesized silver nanoparticles with bovine serum albumin (BSA) has been investigated by UV-Vis and fluorescence spectroscopic techniques. UV-Vis analysis implies the formation of the ground state complex between BSA and silver nanoparticles. The analysis of fluorescence spectrum and fluorescence intensity indicates that silver nanoparticles (SNP) have a strong ability to quench the intrinsic fluorescence of BSA by dynamic quenching mechanisms. The number of binding sites 'n' and binding constants 'K' were determined at different temperatures based on fluorescence quenching. The thermodynamic parameters namely deltaH, deltaG, and deltaS were calculated at different temperatures (20, 30, and 40 degrees C) and the results indicate that both hydrophobic and electrostatic interactions were predominantly present in the SNP-BSA complex. Negative deltaG values imply that the binding process is spontaneous. PMID- 24757961 TI - Fluorescence quenching of uranine on confeito-like Au nanoparticles. AB - Effect of structure and size of Au nanoparticles (AuNPs) on fluorescence behavior of uranine was examined. Confeito-like AuNPs with different sizes (30 nm, 60 nm and 100 nm, respectively) had plasmon absorption bands at 555, 600 and 660 nm, while the band of spherical AuNP (20 nm in size) was at 525 nm. Fluorescence of uranine was significantly quenched by the small and medium confeito-like AuNPs, and the quenching effect by the large particle was less. In comparison, the spherical AuNP quenched more remarkable than the confeito-like AuNPs. A mechanism of resonance energy transfer from uranine to AuNPs via the surface plasmon was suggested, and the strong quenching effect of the small AuNPs could be explained by the energy transfer from adsorbed uranine molecules to AuNPs. These behaviors indicate that the large confeito-like AuNPs can be a preferable nano-probe and useful for plasmonic devices, which can tune or maintain the fluorescence properties of other markers. PMID- 24757962 TI - Ecotoxicological evaluation of poly(epsilon-caprolactone) nanocapsules containing triazine herbicides. AB - The triazine class of herbicides includes the compounds ametryn, atrazine, and simazine, which are used to control weeds in plantations of crops such as maize, sorghum, and sugar cane. Despite their acceptance in agriculture, these herbicides can be dangerous to the environment, depending on their toxicity, the degree of contamination, and the duration of exposure. Controlled release systems are increasingly used to mitigate problems of toxicity and minimize environmental impacts, and can also increase herbicide efficiency. The objective of this work was to prepare poly(epsilon-caprolactone) nanocapsules containing ametryn and atrazine, and evaluate their toxicity to aquatic organisms as well as in cytogenetic tests employing human lymphocyte cultures. The PCL nanocapsules were prepared according to the interfacial deposition of pre-formed polymer method. Ecotoxicological assays were performed with the alga Pseudokirchneriella subcapitata and the microcrustacean Daphnia similis. The cytogenetic tests consisted of observing mitotic index alterations after exposing lymphocyte cell cultures to different formulations. Encapsulation of the herbicides in the nanocapsules resulted in lower toxicity to the alga and higher toxicity to the microcrustacean, compared to the herbicides alone. The cytogenetic tests showed that formulations of nanocapsules containing the herbicides were less toxic than the herbicides alone. The findings indicate the potential of the nanocapsule formulations in agricultural applications, where they could help to reduce the quantities of herbicides used as well as impacts on the environment and human health. PMID- 24757963 TI - Tribological properties of polypropylene composites with carbon nanotubes and sepiolite. AB - Carbon nanotubes (CNTs) and sepiolite (SEP) were modified in order to improve their compatibility with the polypropylene (PP) matrix. Carboxylic groups were introduced into the CNTs through an oxidative treatment and aliphatic chains were incorporated on SEP by ion exchange of a cationic surfactant. Maleic anhydride grafted polypropylene (PPgMA) was mixed with neat PP to introduce polar groups into the polymer matrix. Composites including modified and non-modified fillers were prepared by melt extrusion. Dispersion and interaction of the CNTs with the PP and PPgMA matrices were evaluated by Raman spectroscopy while a focused ion beam/scanning electron microscopy (FIB/SEM) was used for SEP containing composites. Scratch resistance, microhardness, dynamic friction and wear were determined. Raman spectroscopy shows that the introduction of polar groups into PP matrices has a positive effect on the dispersion of modified CNTs. FIB/SEM results show that the modification of SEP improves its dispersion in the polypropylene matrix; filler clusters found in the PPgMA matrix are much times smaller than those in the neat PP. Despite of SEP agglomerates in the composites, a good interaction between both phases is seen; SEP particles are fully coated and embedded inside the PP matrix. The 'lack of cooperation' between unmodified PP and its fillers results in nanocomposites with larger residual depths; by contrast, PPgMA does 'cooperate' with its fillers so that the nanocomposites in scratch resistance testing have smaller residual depths R(h) than the neat PPgMA. Addition of the fillers to PPgMA also increases the hardness. As for wear rates, some our fillers provide higher and some lower wear rates than PP. PMID- 24757964 TI - Synthesis and characterization of ZnS-TiO2 photocatalyst and its excellent sun light driven catalytic activity. AB - The different wt% of ZnS loaded TiO2 (ZnS-TiO2) catalysts were successfully synthesized by precipitation cum sol-gel method and used for degradation of phenol dye, Phenol red sodium salt (PRSS) under natural sun light. Highly efficient 10.7 wt% of ZnS-TiO2 was characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), Transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive spectrum (EDS), diffuse reflectance spectra (DRS), photoluminescence spectra (PL) and BET surface area measurements. ZnS-TiO2 is found to be more efficient than bare TiO2, TiO2 P25 and ZnS at pH 6.5 for the mineralization of PRSS dye. The effects of operational parameters such as the amount of photocatalyst and dye concentration have been analyzed. The mineralization of PRSS dye has been confirmed by chemical oxygen demand (COD) measurements. A dual mechanism has been proposed for the degradation of PRSS under solar light. This catalyst is found to be reusable. PMID- 24757965 TI - Synthesis of high-quality water-soluble near-infrared-emitting CdTe quantum dots capped with 3-mercaptobutyric acid. AB - Highly fluorescent CdTe quantum dots (QDs) with emission in red to near-infrared (NIR) wavelength were successfully prepared by using 3-mercaptobutyric acid (3MBA) as capping agent. The maximum of quantum yield (QY) could reach up to 82% for QDs with emission peak at 686 nm and FWHM of 66 nm at optimal conditions. The QY of these QDs could maintain above 65% in the 650-750 nm region and QDs with emission over 800 nm were still strong fluorescent (28-41%). These optical properties of CdTe quantum dots are among the best results prepared by the state of-the-art methods, suggesting their promising applications in bio-imaging. The success of 3MBA as excellent capping agent in this method was attributed to the balanced chain length and methyl side chain in comparison to a series of linear and branched mercapto acids, namely thioglycolic acid, thiolactic acid, 3 mercaptopropionic acid, 4-mercaptobutyric acid, 5-mercaptovaleric acid, 4 mercaptovaleric acid and 3-mercapto-2-methylbutyric acid. PMID- 24757966 TI - Magnetic activated carbon-Fe3O4 nanocomposites--synthesis and applications in the removal of acid yellow dye 17 from water. AB - In this work, synthesis of activated carbon-Fe3O4 composites using activated carbon and iron benzoate/oxalate precursors by simple pyrolytic method and its utility for the removal of acid yellow dye from water are presented. Iron carboxylates held up into the pores of carbon dissociate at their decomposition temperatures form dispersed Fe3O4 nanoparticles in carbon matrix. The composites were characterized by FTIR, PXRD, SEM, TEM, EDX and magnetization measurements. The size of the nano iron oxides are in the range of 21-33 nm formed from iron benzoate precursor and 6-11 nm from iron oxalate precursor. The oxides are magnetic and their saturation magnetization in the range of 0.08-0.16 emu/g and Coercivity (H(c)) 474-600, being lower and higher than that of bare bulk Fe3O4 are due to the nano size of oxides. Composites find application in the removal of acid yellow dye 17 from the synthetic aqueous solution at pH 5. The adsorption data are found to fit well for Langmuir adsorption isotherm. Kinetics data of adsorption of dyes indicate that the adsorption follows pseudo-second order kinetic model. PMID- 24757967 TI - Oil lubricant tribological behaviour improvement through dispersion of few layer graphene oxide. AB - Few layer graphene oxide (GO) nanosheets were prepared by a very fast modified Hummers method and widely characterized. Avoiding further chemical reactions, trying to take advantage of the easy exfoliation of GO favoring the formation of a tribofilm, and using a methodology well known to the lubricant industry, they were added to a mineral oil by the help of a dispersant. The tribological behaviour of GO in mineral oil was investigated under a wide spectrum of conditions, from boundary and mixed lubrication to elastohydrodynamic regimes. A ball on disc setup tribometer has been used to verify the friction reduction due to nanosheets dispersed in mineral oil. Their good friction and anti-wear properties may possibly be attributed to the small and extremely thin laminated structure, which offer lower shear stress and prevent interaction between metal interfaces. Furthermore, the results clearly prove that graphene platelets in oil easily form a protective film to prevent the direct contact between steel surfaces and, thereby, improving the frictional behaviour of the base oil. This evidence is also related to the frictional coefficient trend in boundary regime. PMID- 24757968 TI - Investigating the nature of graphene-based films prepared by vacuum filtration of graphene dispersions. AB - Though the graphene-based films prepared by vacuum filtration of graphene dispersions can be well and easily prepared so far and show great prospects in conductive, transparent, and flexible devices and coatings, the nature of these films has been rarely investigated. In order to reveal how graphene flakes constitute these films, herein we prepared a thin graphene-based film by vacuum filtering graphene dispersions and characterized the film by diverse techniques. Microscopic analyses evidenced the layer structure nature of the film. Raman spectra, transmission electron microscopy, and X-ray diffraction results indicate that the film is neither graphene nor graphite, but intrinsically a graphene block constituted by numerous graphene flakes which are randomly stacked. Though aggregation of graphene flakes happens in the filtration process, the aggregation is not a process to drive graphene flakes stacked in Bernal AB style to form bulk graphite. The adjoining graphene flakes are poorly coupled, likely due to the interlayer adventitious impurities introduced from liquid-phase processing. PMID- 24757969 TI - Hydrothermal synthesis of graphene/nickel oxide nanocomposites used as the electrode for supercapacitors. AB - Graphene (GR)-based nanocomposites with different mass ratios of NiO and GR are prepared via hydrothermal method using Ni(NO3)2 as the origin of nickel and urea as the hydrolysis-controlling agent. The morphology and electrochemical performance of the GR/NiO nanocomposites are closely associated with the mass ratios of GR to NiO. The chemical composition and morphology of the composites together with the pure GR and NiO are characterized by thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscope (SEM), and transmission electron microscope (TEM). It is found that the GR sheets and NiO particles form uniform nanocomposites with the NiO particles absorbed on the GR surface. A specific capacitance of 384 F g(-1) at a current density of 0.1 A g( 1) is achieved when the coating amount of NiO is up to 74 wt%. In addition, the attenuation of the specific capacitance is less than 6% after 500 cycles, indicating such nanocomposite has excellent cycling performance. PMID- 24757970 TI - Study on the origin of amorphous carbon peaks on graphene films synthesized on nickel catalysts. AB - We present our investigation results on the origin of the morphological defects on graphene films synthesized by chemical vapor deposition method on nickel catalytic substrates. These defects are small-base-area (SBA) peaks with tens of nanometer heights, and they diminish the applicability of graphene films. From atomic force microscopy observations on the graphene films prepared in various ways, we found that significant portion of the SBA peaks is formed in the crevices on the nickel substrates. Our results may be useful for developing an efficient synthesis method to produce high-quality graphene films without the SBA peaks. PMID- 24757971 TI - A hydrothermal synthesis of Pr3+ doped mesoporous TiO2 for UV light photocatalysis. AB - Pr3+ doped mesoporous TiO2 photocatalysts with a different molar ratio of Pr to Ti were prepared by a hydrothermal method using triblock copolymer as the template. The as-prepared samples were systematically characterized by X-ray diffraction, N2 adsorption-desorption, X-ray photoelectron spectra, transmission electron microscopy and UV-visible diffuse reflectance spectroscopy. The characterizations indicated all the samples had mesoporous structure and narrow pore size distribution. Pr3+ doping enlarged the surface area and decreased the crystallite size. The surface area of the samples varied from 136 to 170 m2/g, and the average crystallite size ranged between 5.04 and 7.60 nm. The effect of Pr3+ doping amount on the photocatalytic activity of mesoporous TiO2 was evaluated by the degradation of methyl orange under UV light irradiation. The results showed that the suitable amount of Pr3+ doped samples exhibited the higher photocatalytic activity than mesoporous TiO2. Among the samples, 1 at.% Pr3+ doped mesoporous TiO2 showed the highest photocatalytic activity. PMID- 24757972 TI - Band gap engineered P3HT/CdPbS composites for utilization of low energy photons. AB - In the present study, CdPbS composite has been synthesized in the P3HT matrix in a single step. The synthesis has been carried out at a temperature of 120 degrees C by the decomposition of xanthate compound in the polymer matrix. This synthesis method helps in proper distribution of nanoparticles in the polymer matrix. The synthesized materials were characterized using UV-Vis spectroscopy, X-ray diffraction, transmission electron microcopy, photoluminescence (PL) and time resolved florescence spectroscopy. The P3HT/CdPbS nanoparticle composite can absorb photon in the range of 0.7 eV to 2.7 eV and a charge transfer between CdPbS and P3HT has been observed. It has been proposed that this composite may increase both the Voc as well as Jsc by better utilization of solar spectrum and increased charge transfer. PMID- 24757973 TI - Optical and structural properties of nanostructured CuIn0.7Ga0.3(Se(1-x)Te(x))2 chalcopyrite thin films--effect of stoichiometry and annealing. AB - The aim of this work was to study the dependence of the optical, structural and morphological properties of CuIn0.7Ga0.3(Se(1-x)Te(x))2 (briefly CIGSeTe) thin films for two different stoichiometries (for x = 0.2 and 0.8). The films have been deposited onto soda lime glass (SLG) substrates by the e-beam evaporation technique. The films showed high absorption and revealed optical band gaps ranging from 1.17 eV to 1.06 eV for x = 0 with highest annealing temperatute at 525 degrees C and 1.12 eV to 1.02 eV for x = 0.8 and with highest annealed temperature at 600 degrees C. These results were correlated with the microstructural analysis by Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM) and X-ray diffractometry (XRD). The linear dependence of the lattice parameters as a function of Se and Te contents was examined. X-ray diffraction analyses showed that the films had the single phase chalcopyrite structure. The lattice parameters (a and c) varied linearly with the increase in Te content x from x = 0.2 to x = 0.8. The peak correspondng to the (1 1 2) plane orientation of the films increased with annealing process. Also, SEM images showed that both the grains size and the RMS (root mean square) values increased with annealing and higher Te amount that caused grains aggregation. The relative 600 degrees C elemental composition present in the deposited CIGS films have been measured by using energy dispersive X-ray analysis (EDX). PMID- 24757974 TI - In-situ preparation and characterization of acid functionalized single walled carbon nanotubes with polyimide nanofibers. AB - Nanofiber composites (Polyimide/f-SWCNT) of Pyromellitic dianhydride, 4,4' Oxydianiline, and 4,4'-(4,4'-isopropylidene diphenyl-1,1'-diyl dioxy) dianiline (PMDA-ODA/IDDA) and surface-functionalized single walled carbon nanotubes (f SWCNT) were made by electrospinning a solution of poly(amic acid) (PAA) containing 0-2 wt% f-SWCNT followed by thermal imidization. X-ray photoelectron spectroscopy spectra verified the oxidation of SWCNT surface after acid treatment, and indicated possible hydrogen bonding interactions between the f SWCNTs and polyamic acid. High-resolution scanning electron microscopy images showed the average diameter of nanofibers to be below 150 nm, and transmission electron microscopy images showed that SWCNTs were aligned inside the polymer nanofiber. In thermogravimetric analysis, all composites showed increased thermal stability with increasing f-SWCNT content compared to neat PI. Storage modulus also increased from 124 MPa to 229 MPa from neat PI to 2% f-SWCNT composite. PMID- 24757975 TI - Organic thin-film-transistor Au/poly(3-hexylthiophene)/ (bilayer dielectrics)/Si having carbon nanotubes chemically bonded to poly(3-hexylthiophene) in the active layer. AB - Using poly(3-hexylthiophene) (P3HT) covalently bonded with carbon nanotubes (CNT) as an active layer in a bottom-gate/top contact, Au/(P3HT)/(bilayer dielectric)/Si OTFT device has resulted in an enhanced charge transport. The CNTs were firstly functionalized via ligand exchange with ferrocene, next lithiated by sec-butyllithium (s-BuLi) and then linked anionically with P3HT which has been synthesized via the modified Grignard metathesis method. Compared to the pristine P3HT, the CNTs-containing P3HT composite material has a higher energy level of HOMO and a smaller electrochemical bandgap E(g)(chem). The smaller bandgap enhances the charge carrier transport and the higher HOMO energy level indicates a reduced barrier and an increased injection rate for charge carriers at the source contact. Furthermore, the threshold voltage V(T) of CNTs-containing P3HT samples is lower and its saturation current I(D) and the the field-effect mobility are higher. An OTFT device fabricated with such a composite sample containing 1.16% CNTs has a carrier mobility and saturation current three to five times higher than pristine P3HT. PMID- 24757976 TI - Electrochemical performances of surface modified CePO4-coated LiMn2O4 cathode materials for rechargeable lithium ion batteries. AB - Improved electrochemical performances of Spinel LiMn2O4 cathode was prepared by a sol-gel coating of CePO4 to the surface of the LiMn2O4 powder and subsequent heat treatment at 600 degrees C for 8 h in air. The surface modified LiMn2O4 cathode materials were characterized by using TG/DTA, X-ray diffraction, Scanning electron microscope, X-ray photoelectron spectroscope, cyclic voltammetry techniques and charge/discharge studies. XRD and SEM results show that no significant bulk structural differences are observed between the coated and pristine LiMn2O4. 2 wt.% CePO4 coated LiMn2O4 cathode materials was enhance the particle size compared to pristine due to small layer of CePO4 particle covered on the over the surface. XPS data illustrated that, the CePO4 was completely coated over the surface of the LiMn2O4 core materials. Galvanostatic charge/discharge studies of the uncoated and CePO4-coated LiMn2O4 cathode materials were carried out in the voltage range between 3.0 and 4.5 V at elevated temperature (50 degrees C). The composition of CePO4 coating was increased from 0.0 to 3.0 Wt.%, the initial capacity of the samples decreased slightly. But the cycling stability was increased remarkably between 3-4.5 V. 2.0 Wt.% CePO4-coated LiMn2O4 cathode has satisfied the structural stability, high reversible capacity and excellent electrochemical performances. This result indicates that, the surface treatment should be an effective way to improve the comprehensive properties of the cathode materials for lithium ion batteries. PMID- 24757977 TI - Effect of aspect ratio and temperature on magnetic properties of permalloy nanowires. AB - Arrays of permalloy nanowires (NWs) were fabricated into the pores of self engineered Anodic Aluminium Oxide (AAO) templates by a simple electrodeposition technique (EDT) with a diameter -200 nm. By varying the length of the nanowires from 1.5 to 7.5 microm, got corresponding changes in aspect ratio from 7.5 to 37.5. We studied the growth and structural properties of permalloy nanowires using scanning electron microscopy, X-ray diffraction spectra and transmission electron microscopy. We performed the magnetic measurements of permalloy nanowires using vibrating sample magnetometer. The coercivity (H(c)) and anisotropy field (H(an)) observed considerably higher when the applied magnetic field was perpendicular to the nanowires axial direction (In-Plane) compare to the applied magnetic field was parallel to the nanowire axial direction (Out-of plane). Reverse trend was observed for the maximum remanent ratio (M(r)/M(s)). So we concluded that the magnetic easy axis of the permalloy nanowires are along the axial direction of the nanowires and magnetic hardness of the nanowires higher in transverse direction compare to the axial direction of nanowires. For the first time temperature (80 K < or = T < or = 300 K) and aspect ratio dependence magnetic properties of the permalloy nanowires have been studied in detail. PMID- 24757978 TI - Morphology analysis of sodium chloride crystallization on the mica substrate using atomic force microscope. AB - The morphology of the specific face growth of sodium chloride (NaCI) crystal on the mica surface was analyzed using atomic force microscope (AFM). The supersaturation of the NaCI was induced to lead to the crystal nucleation and growth by the addition of methylalcohol. The effects of methylalcohol concentration and mica surface functionality on the NaCI crystal growth morphology were investigated. The crystalline nucleus was formed scaterringly on the mica surface at 10% methylalcohol. It was grown laterally at 20% methylalcohol and agglomerated at 30% methylalcohol before lateral growth. The difference in the crystallization efficiency originated from the surface conditions is discussed by comparison of the crystallizations on surfaces of the bare mica and mica treated with Mg2+, 3-aminopropyltriethoxysilane, and ethyltriethoxysilane. The lateral growth of sodium chloride crystal was restricted by the different treatment of the mica surface. From these results, it was known that sodium chloride crystal growth morphology could be controlled by using additional solvent and substrate surface treatment. These results imply that the morphology analysis as well as reaction kinetics should be conducted in the crystallization analysis. PMID- 24757979 TI - Fabrication of fluorescent magnetic Fe3O4@ZnS nanocomposites. AB - A novel Fe3O4@ZnS nanomaterial with fluorescent and superparamagnetic properties has been successfully fabricated via TOPO-TOP synthesis with an additional coordinating component (OAm). The adsorption of OAm on the preformed magnetite nanoparticles, which were prepared in phenyl ether with oleic acid and oleyl amine, played an essential role in directing the structure of the Fe3O4@ZnS composites. The obtained materials were characterized by FTIR, TEM, XRD, X-ray photoelectron spectroscopy (XPS), UV-vis, fluorescence spectrophotometer and VSM. The results indicated that the Fe3O4 nanoparticles were successfully combined with ZnS and the coating of ZnS can be controlled by adjusting the molar ratio of Fe3O4 to ZnS. The saturation magnetization values of Fe3O4, Fe3O4@ZnS (1:2) and Fe3O4@ZnS (1:5) nanoparticles are 57.0 emu g(-1), 44.4 emu g(-1) and 34.2 emu g( 1), respectively at 300 K and the nanocomposites exhibit better fluorescence without evident quenching. The combined magnetic and fluorescent properties endow the nanocomposites with great potential applications in "nano-conveyer-belt" platform technology for drug targeting, bioseparation, diagnostic analysis and so on. PMID- 24757980 TI - Formation and structure of ordered pentachlorobenzenethiol self-assembled monolayers on Au(111) studied by scanning tunneling microscopy. AB - Molecular-scale surface structures of self-assembled monolayers (SAMs) prepared by the adsorption of pentafluorobenzenethiols (PFBT) and pentachlorobenzenethiols (PCBT) on Au(111) were investigated by scanning tunneling microscopy (STM). High resolution STM imaging revealed that PFBT SAMs on Au(111) have long-range ordered domains with a row structure at room temperature, whereas PCBT SAMs have small ordered domains, with disordered domains as the main phase. This may reflect the larger diffusion barriers of PCBT molecules on Au(111) surfaces compared to PFBT molecules during SAM formation. The structural transitions of PCBT SAMs from the mixed phase containing disordered and ordered domains to the uniform ordered domains were observed at 50 degrees C depending on immersion time. The ordered packing structure of PCBT SAMs is an incommensurate (square root of 3 x square root of 10)R45 degrees structure, which differs from that of PFBT SAMs with a (2 x 5 square root of 13)R30 degrees structure. We found that a small modification in the chemical structures of aromatic rings using a halo-substituent strongly affects the self-assembly mechanism and packing structure of aromatic thiol SAMs on Au(111). Moreover, we demonstrated that highly ordered PCBT SAMs can be obtained at a solution temperature of 50 degrees C after immersion for 60 min. PMID- 24757981 TI - Optimization of oleylamine-Fe3O4/MWCNTs nanocomposite modified GC electrode for electrochemical determination of ofloxacin. AB - Iron oxide (Fe3O4) nanoparticles are prepared by nucleation method using oleylamine (OLA) as the capping agent. The OLA capped Fe3O4 nanoparticles (OLA Fe3O4) are characterized by Fourier Transform Infrared (FT-IR) spectroscopy, X ray Diffraction (XRD) and High Resolution Transmission Electron Microscopic (HRTEM) analysis. The morphology of the OLA-Fe3O4 nanoparticles is found to be spherical with an average size of 7.5 +/- 0.5 nm. OLA-Fe3O4 nanoparticles are incorporated into the carboxyl functionalized Multi-walled carbon nanotubes (MWCNTs) at different 10, 20, 30, 40 and 50 wt% by ultrasonication. The optimum loading of OLA-Fe3O4 nanoparticles on the MWCNTs was characterized by FTIR, Raman spectroscopy, Field Emission Scanning Electron Microscopy (FESEM) and Linear Sweep Voltammetry (LSV). Finally, the 40wt% of OLA-Fe3O4 nanoparticles on MWCNTs was chosen as the optimum loading and this composition was used for the electrochemical oxidation of ofloxacin (OFX). For determination of OFX in OLA Fe3O4/MWCNTs modified glassy carbon (GC) electrode show high sensitivity and fast response. The sensitivity of the modified electrode was calculated to be 0.578 microAmicroM(-1) with a detection limit of 0.060 microM. The high sensitivity, wider linear range, good reproducibility and the minimal surface fouling make this OLA-Fe3O4/MWCNTs/GC modified electrode acts as a promising platform for electrochemical determination of OFX. PMID- 24757982 TI - Effect of an organic buffer layer on the stability of zinc oxide thin-film transistors. AB - Compared with other materials, zinc oxide (ZnO) exhibits stability in air, high electron mobility, transparency and low light sensitivity. We investigated these properties in ZnO thin-film transistors (TFTs) containing a cross-linked poly(vinyl alcohol) (C-PVA) (1:3) buffer layer stacked between the semiconductor and gate dielectric. We measured the impact of this C-PVA layer on gate bias stress. We measured the transfer characteristics of the saturation region to determine the threshold voltage and the field-effect mobility of the transistors. We recorded a threshold voltage of 11.53 V in the ZnO TFTs with the C-PVA buffer layer, the field-effect mobility was 0.2 cm2/Vs. There was a positive shift in the threshold voltage of deltaV(TH) approximately 10 V in response to the application of a gate bias stress of 20 V. The positive shift in the threshold voltage was lower than that in pristine ZnO TFTs. This finding suggests that the shift in threshold voltage was due to reduced charge trapping at the semiconductor-gate dielectric interface. Our report indicates that the organic buffer layer enhanced the stability of ZnO TFTs. PMID- 24757983 TI - Surface engineered dendrimers as antiangiogenic agent and carrier for anticancer drug: dual attack on cancer. AB - The present research work describes the formulation of arginine conjugated 3.0G Poly(propylene) imine (PPI) dendrimers, mimicking the surface structure of an endogenous angiogenesis-inhibitor endostatin; for tumor specific delivery of a model anticancer drug, doxorubicin hydrochloride (Dox). Synthesis of PPI dendrimers and conjugation of arginine to surface groups was confirmed by FTIR, NMR, TEM and mass spectrometry. Drug was loaded by equilibrium dialysis method and developed formulation was evaluated for entrapment efficiency, hemolytic toxicity, in vitro drug release, stability, anti-angiogenic activity via in vivo chick embryo chorioallantoic membrane (CAM) assay, and anticancer activity and cell uptake using MCF-7 cancer cell lines. The system exhibited the initial rapid release followed by sustained release of Dox with significant antiangiogenic activity in the CAM assay. Further, the arginine conjugated dendrimers was found to inhibit growth of cancer cells in ex vivo studies with MCF-7 cell lines. Cell uptake studies suggested that in comparison to free drug the formulation was preferably taken up by the tumor cells. Thus the two pronged attack on cancerous tissue i.e., inhibition of angiogenesis and killing of cancer cells by anticancer drug, might prove to be a promising approach in the treatment of fatal disease, cancer. PMID- 24757984 TI - ZnO nanowires-C microfiber hybrid nanosensor for liquefied petroleum gas detection. AB - Zinc oxide nanowires are integrated onto carbon microfibers using a two-step approach which includes electrochemical deposition of zinc and its thermal oxidation. Such nano-on-micro hybrid architecture is then used as resistive gas sensor. Some properties like mechanical flexibility, low cost and large-area fabrication make this design appealing for different applications. The huge surface-to-volume ratio of such structure comes from being structured at both microscale and nanoscale (ZnO nanowires and C microfiber) and leads to a strong and rapid response/recovery times when it is used as a gas sensor. The fabrication process of the ZnO-microC device is very simple and doesn't involve any expensive lithographic step. The sensors show excellent liquefied petroleum gas sensing properties, with very fast response on gas exposure (about 3 s) and very good reversibility (less than 2%). In addition, the carbon microfiber substrate allows the use of the ZnO-microC sensor also in applications where flexibility is required (for example integrated in fabric). PMID- 24757985 TI - Nanostructured Er2O3 thin films grown by metalorganic chemical vapour deposition. AB - Metalorganic chemical vapor deposition (MOCVD) of nanostructured Er2O3 thin films was performed using the Er-tris-guanidinate precursor [Er(DPDMG)3] (DPDMG = diisopropyl-2-dimethylamidoguanidinato) as the Er source and oxygen. Film deposition was carried out on Si(100) and quartz glass substrates and the process parameters namely temperature, pressure and oxygen flow rate were varied. The resulting thin films were characterised by X-ray diffraction (XRD), scanning electron microscopy (SEM) for investigating the crystallinity and morphology, respectively. The chemical composition of the film was investigated by X-ray photoelectron spectroscopy (XPS) measurements. Transmittance and absorption spectra of the 600 degrees C film grown on glass substrates were performed by UV vis measurements revealing more than 80% transmittance. The potential of Er2O3 thin films as gate dielectrics was verified by carrying out capacitance-voltage (C-V) and current-voltage (I-V) measurements. Dielectric constants estimated from the accumulation capacitance were found to be in the range of 10-12 in AC frequencies of 1 MHz down to 10 kHz and the leakage current of the order of 2 x 10(-8) A/cm2 at the applied field of 1 MV cm(-1) was measured for films deposited under optimised process conditions. The low leakage current and high dielectric constant implies good quality of the Er2O3 layers relevant for high-k applications. These layers were found to be paramagnetic with a slightly reduced magnetic moment of the Er3+ ions. PMID- 24757986 TI - Monte Carlo simulation studies on the effect of entropic attraction on the electric conductivity in polymer nano-composites. AB - The effect of non-conductive nano-particles on the electrical percolating network formation and the electrical conductivity of conductive nano-particles in polymer matrices is investigated using Monte Carlo simulations and a percolation theory. Both conductive and non-conductive nano-particles are modeled as spheres but with different diameters. Non-conductive nano-particles are up to four times bigger than conductive nano-particles. Equilibrated configurations for mixtures of nano particles are obtained via Monte Carlo simulations and are used to estimate the probability (P) of forming an electrical percolating network and the percolation threshold conductive nano-particle volume fraction (phi(c)). As the volume fraction (phi(nc)) of non-conductive nano-particles increases, phi(c) decreases significantly, thus increasing the electrical conductivity. When non-conductive nano-particles mix with conductive nano-particles, they make the effective interaction energy W(r) between conductive nano-particles attractive, which should facilitate the formation of the electrical percolating network. For a given phi(nc), phi(c) increases slightly with an increase in the non-conductive nano-particle diameter (sigma(nc)). We also carry out simulations with non conductive nano-particles of different structures and find that phi(c) is relatively insensitive to the non-conductive nano-particle structure. PMID- 24757987 TI - Effects of co-doping on the red fluorescent OLEDS. AB - The device performance of red organic light-emitting diodes (OLEDs) was dramatically improved by co-doping of the red fluorescent material of (2Z,2'Z) 3,3'-[4,4"-bis(dimethylamino)-1,1':4',1"-terphenyl-2',5'-diyl]-bis(2 phenylacrylonitrile) (ABCV-P) with the hole transport material of N'-bis-(1 naphyl)-N,N'-diphenyl-1,1 '-biphenyl-4,4'-diamine (NPB) and the electron transport material of bis(2-methyl-8-quninolinato)-4-phenylphenolate aluminum (BAlq). The device structures were ITO/NPB/emitting layers/BAlq/Liq/Al in which the emitting layers were MADN:ABCV-P (40%) (device A), MADN:ABCV-P (40%):NPB (10%) (device B), MADN:ABCV-P (40%):BAlq (10%) (device C) and MADN:ABCV-P (40%):NPB (10%):BAlq (10%) (device D), respectively. The device D co-doped with NPB and BAlq exhibited maximum luminance of 9784 cd/m2, maximum luminous efficiency of 2.82 cd/A and maximum quantum efficiency of 3.19%, respectively, whereas those of the device A doped with only ABCV-P were 7563 cd/m2, 1.98 cd/A and 1.99%. PMID- 24757988 TI - A gold nanoparticle ink suitable for the fabrication of electrochemical electrode by inkjet printing. AB - Inkjet printing is a non-contact and low-cost method for high resolution deposition of nanomaterials and mass production of electro-devices. In this study, an environmentally friendly gold nanoparticles (AuNPs) ink was prepared and electrochemical electrodes were fabricated through inkjet printing technology. Electrochemical behaviors of the printed electrodes with different printing layers and laser sintering intensities were studied by cyclic voltammetry. Electrode sintered at 0.6 A with double layers showed a good reproducibility and well linear relation in voltammetric measurement of potassium ferricyanide. Moreover, the prepared electrode was found to be effective for formaldehyde electro-oxidation in alkaline medium. The above results indicated that this AuNPs ink, which can be facilely prepared, may have great potential applications for the preparation of flexible and low-cost electrochemical sensing devices and biosensors by inkjet printing. PMID- 24757989 TI - Catalytic conversion of cellulose over mesoporous Y zeolite. AB - Mesoporous Y zeolite (Meso-Y) was applied, for the first time, to the catalytic pyrolysis of cellulose which is a major constituent of lignocellulosic biomass, to produce high-quality bio-oil. A representative mesoporous catalyst Al-MCM-41 was also used to compare its catalytic activity with that of Meso-Y. Pyrolysis gas chromatography/mass spectrometry was used for the experiments. Meso-Y, with higher acidity, led to larger yields of aromatics and furans with high value added than Al-MCM-41, resulting in the production of bio-oil with higher quality. The effect of temperature on the catalytic pyrolysis was not significant within the range of 400-500 degrees C. When the Meso-Y to cellulose ratio was increased from 1/1 via 2/1 to 3/1, the deoxygenation efficiency increased, leading to increased yield of aromatics. PMID- 24757990 TI - Synthesis and electrochemical properties of spinel LiMn1.95M(x)O(4-y)F(y) for lithium ion batteries. AB - Spinel phase LiMn1.95M(x)O(4-y)F(y) (M = Co and Y) were prepared by a rheological phase reaction method. The samples were characterized by X-ray diffraction, scanning electron microscopy, AC impedance, and galvanostatic charge/discharge profile measurement. These results showed that the LiMn1.95M(x)O(4-y)F(y) had better cycling performance than pure LiMn2O4. Among all the doped samples, the LiMn1.95Co0.03Y0.02O3.96F0.04 sample showed the best cycling performance, the initial discharge capacitiy is 129 mAh/g, and the discharge capacity of 124 mAh/g at a rate of 0.5 C after 50 cycles. The loss of its capacity was only 3.4%. The possible reasons for the outstanding electrochemical properties of LiMn1.95Co0.03Y0.02O3.96F0.04 are also discussed. PMID- 24757991 TI - Homeotropic alignment of dendritic columnar liquid crystal induced by hydrogen bonded triphenylene core bearing fluoroalkyl chains. AB - A 1:3 molar complex of the fluoroalkyl side chain-substituted 2,6,10-tris carboxymethoxy-3,7,11-tris(4,4,5,5,6,6,7,7,7-nonafluoroheptyloxy)triphenylene (TPF4) with the second generation dendron 3,5-bis(3,4-bis-dodecyloxybenzyloxy)-N pyridin-4-yl-benzamide (DN) assembled through complementary hydrogen bonding to form a supramolecular columnar liquid crystal, which exhibited homeotropic alignment when sandwiched between octadecyltrichlorosilane (OTS)-coated or indium tin oxide (ITO)-coated glass plates due to specific interactions between the fluoroalkyl side chains and the substrates. PMID- 24757992 TI - The estimation of possibility of using order-disorder transition phenomena in Ni, Cu and Au nanoclusters for advancing the efficiency of information recording processes. AB - The opportunity of transition metals nanoclusters' usage as a data bits in memory devices for the recording transition "order-disorder" has been analyzed. Therefore, with the help of the molecular dynamics method on the basis of TB-SMA potential the simulation of metal nanoparticles (D = 1.6-5.0 nm) crystallization processes have been studied. Influence of various conditions of crystallization on formation of internal structure in metal nanoclusters is investigated. The stability boundaries of various crystalline isomers are analyzed. The obtained dependences are compared with the corresponding data obtained for gold, copper and nickel nanoparticles having similar sizes. Nickel and copper clusters are shown to exhibit common features in the formation of their structural properties, whereas gold clusters demonstrate much more complex behavior. The limiting size of nanoparticles is determined, for which a structural "order-disorder" transition necessary for the data recording is still possible. PMID- 24757993 TI - Benzoxazine resin/carbon nanotube nanostructured composite's degradation kinetic. AB - In the last decades a new class of thermoset phenolic resin is emerging as a substitute of the traditional epoxy and phenolic resins in the aircraft industry. This new class is called polybenzoxazines and its associates the epoxy resin's mechanical properties and phenolic resin's thermal and flame retardant properties, resulting in a resin with superior properties when analyzed with the others singly. The introduction of carbon nanotubes in low concentration into polymeric matrices can produce nanostructured materials with good properties. Thus, in this study, nanostructured composites of benzoxazine resin were processed with different concentration of carbon nanotubes (0.1%, 0.5% and 1.0% w/w). In order to evaluate the thermostability of the benzoxazine resin and its nanostructured composites, it was performed a degradation kinetic study using the thermogravimetric technique. For that, the analysis have been done with the temperature ranging from 25 degrees C to 1000 degrees C at nitrogen atmosphere (100 mL x min(-1)) and in different heating rates (2, 4, 6, 8, 10 and 20 degrees C x min(-1)), in order to obtain the kinetic parameters (activation energy, E(a), and pre-exponential factor, A), based on Ozawa-Wall-Flynn model. The results showed excellent agreement between the thermogravimetric curves obtained and the Ozawa-Wall-Flynn method. The degradation kinetic study showed that the introduction of carbon nanotubes in the benzoxazine matrix does not change the thermostability of the resin, so that it does not have a significant influence in the shelf life of the material. PMID- 24757994 TI - A colloidal gold nanoparticle-based immunochromatographic test strip for rapid and convenient detection of Staphylococcus aureus. AB - An immunochromatographic test strip using gold nanoparticles-staphylococcus aureus monoclonal antibody conjugates was developed for the rapid and convenient detection of staphylococcus aureus based on a double-antibody sandwich format. The detection limit and the detection rate of this test strip is 10(3) CFU /mL and 98.7%, respectively. It could be used for the rapid detection of staphylococcus aureus in food and the results can be visually identified by the naked eye within 10 min. Compared with conventional bacterial detection methods, this developed immunochromatographic assay based test strip has several advantages including simple, fast, low-cost, favorable sensitivity and specificity, exhibiting a great potential for application in food safety control systems and clinical diagnosis. PMID- 24757995 TI - Supercapacitors based on ordered mesoporous carbon derived from furfuryl alcohol: effect of the carbonized temperature. AB - Supercapacitors are successfully prepared from ordered mesoporous carbon (OMC) synthesized by employing the mesoporous silica, SBA-15 as template and furfuryl alcohol as carbon source. It is found that the carbonized temperature greatly influences the physical properties of the synthesized mesoporous carbon materials. The optimal carbonized temperature is measured to be 600 degrees C under which OMC with the specific surface area of 1219 m2/g and pore volume of 1.31 cm3/g and average pore diameter of - 3 nm are synthesized. The OMC materials synthesized under different carbonized temperature are used as electrode material of supercapacitors and the electrochemical properties of the OMC materials are compared by using cyclic voltammetry, electrochemical impedance spectroscopy, galvanostatic charge-discharge and self-discharge tests. The results show that the electrochemical properties of the OMC materials are directly related to the specific surface area and pore volume of the mesoporous carbon and the electrode prepared from the OMC synthesized under the carbonized temperature of 600 degrees C (OMC-600) exhibits the most excellent electrochemical performance with the specific capacitance of 207.08 F/g obtained from cyclic voltammetry at the scan rate of 1 mV/s, small resistance and low self-discharge rate. Moreover, the supercapacitor based on the OMC-600 material exhibits good capacitance properties and stable cycle behavior with the specific capacitance of 105 F/g at the current density of 700 mA/g, and keeps a specific capacitance of 98 F/g after 20000 consecutive charge/discharge cycles. PMID- 24757996 TI - Schottky-barrier resistive memory with highly uniform switching. AB - Using stacked GeO/SrTiO resistive memory with high-work-function Ni electrode, forming-free switching, low sub-microW power and highly uniform current distributions (on-off ratio > 1000x) are realized. The Schottky barrier at Ni/GeO(x) interface and current compliance function can effectively stabilize electron hopping between oxygen vacancies to reach uniform voltage and current distributions under a sub-microW operating power. PMID- 24757997 TI - Optical and structural properties of plasma-treated ZnO nanostructures. AB - We studied the effect of plasma treatment on the structural and optical properties of ZnO nanostructures prepared by chemical bath deposition in an aqueous solution of Zn(NO3)2 and hexamethylenetetramine. The room-temperature photoluminescence (PL) spectrum of the as-grown ZnO nanostructures exhibited two emission bands due to exciton emission and defect emission. After treating with hydrogen plasma, the treated ZnO nanostructures exhibited stronger exciton emission than the as-grown, untreated ZnO nanostructures in their respective cathodoluminescence and PL spectra. The low-temperature PL spectrum of the hydrogen plasma-treated ZnO nanostructures showed a strong exciton emission at 3.34 eV, attributing to the bound exciton and its longitudinal optical-phonon sidebands. The strong exciton emission is thought to be due to the combined effect of exciton emission enhancement by defect passivation and optical confinement resulting from nanostructure geometry. PMID- 24757998 TI - Electron and phonon coupling dynamics in low-gap semiconductor: quantum versus classical scale. AB - We have studied the characteristics of longitudinal-optical-phonon-plasmon coupled (LOPC) mode by using the ultrashort pulsed laser with 45 THz bandwidth as a function of thickness in InAs epilayers, ranging from 10 to 900 nm. We have observed the LOPC modes split into the upper (L(+) mode) and the lower (L(-) mode) branches only in the classical scale, but the longitudinal-optical (LO) phonon peak was persistently observed. The shorter decay time of the plasmon-like L(+) modes rather than the phonon-like L(-) modes should be associated with carrier-carrier scattering which is further considered with diffusion properties in the low-gap semiconductors. This result leads to that the absence of the LOPC modes in a scale less than exciton Bohr radius manifests the role of electron diffusion rather than the carrier screening via drift motion in surface depletion region. PMID- 24757999 TI - Enhanced near-band edge emission from ZnO nanorods by V2Os coating and subsequent thermal annealing. AB - V2O5-coated ZnO 1D nanostructures were prepared by using a two step process: thermal evaporation of a mixture of ZnO and graphite powders (ZnO:C = 1:1) in an oxidative atmosphere and sputter-deposition of V2O5. Scanning electron microscopy revealed that the nanostructures had a rod-like morphology with the thickness diminishing gradually from an end to the other. The thicknesses and lengths of the nanorods range from a few tens to a few hundreds of nanometers and from a few to a few tens of micrometers, respectively. Transmission electron microscopy and X-ray diffraction analyses revealed that the ZnO cores and V2O5 shells of the core-shell nanorods were wurtzite-type hexagonal close-packed structured single crystal and amorphous, respectively. The intensity ratio of the near-band edge (NBE) emission to the deep-level emission was increased about three times by coating the ZnO nanorods with a V2o5 thin film about 10 nm thick. The NBE emission enhancement may be mainly attributed to two sources: the effects of suppression of capturing of carriers by surface states and suppression of visible emission and nonradiative recombination by depletion regions formed in the ZnO cores. In addition, it was found that postannealing of V2O5-coated ZnO nanorods is not desirable, whereas post annealing makes a positive effect on the NBE emission enhancement in uncoated ZnO nanorods. PMID- 24758000 TI - Synthesis and properties of new low band gap semiconducting polymers. AB - Low band gap organic semiconducting polymers were prepared as p-type donors for organic photovoltaic devices. A novel dibrominated monomer composed of phenothiazine, thiophene, and benzothiadiazole (DPDTBT) was synthesized as a low band gap core block. DPDTBT was copolymerized with three different boronic esters of dithiophene, fluorene, and phenothiazine by the Suzuki coupling polycondensation reaction. The band gap energies of the synthesized polymers ranged between 2.05 and 2.11 eV, depending on the polymer structure. Bulk heterojunction solar cells fabricated using the polymers and [6,6]-phenyl C71 butyric acid methyl ester (PC70BM) as an acceptor were characterized. The best power conversion efficiency obtained from the fabricated devices under simulated AM 1.5 G solar irradiation of 100 mW/cm2 was 0.46%. PMID- 24758001 TI - Dependence of interface charge trapping on channel engineering in pentacene field effect transistors. AB - We investigate the dependence of charge carrier mobility by trap states at various interface regions through channel engineering. Prior to evaluation of interface trap density, the electrical performance in pentaene field effect transistors (FET) with high-k gate oxide are also investigated depending on four channel engineering. As a channel engineering, gas treatment, coatings of thin polymer layer, and chemical surface modification using small molecules were carried out. After channel engineering, the performance of device as well as interface trap density calculated by conductance method are remarkably improved. It is found that the reduced interface trap density is closely related to decreasing the sub-threshold swing and improving the mobility. Particularly, we also found that performance of device such as mobility, subthreshold swing, and interface trap density after gas same is comparable to those of OTS. PMID- 24758002 TI - Effect of nitrogen flow rate on the properties of copper nitride thin films. AB - Copper nitride (Cu3N) thin films were deposited at 300 degrees C on glass substrates by reactive magnetron sputtering method with changing various nitrogen flow rates. The results showed that the nitrogen flow rate has a significant effect on the properties of the Cu3N thin films. XRD data exhibited that two phases of Cu3N and Cu coexisted for the thin films deposited at 300 degrees C, irrespective of nitrogen flow rate. The preferential orientation of the film grown at 400 degrees C was transformed from Cu3N to Cu phase. The optical band gap was gradually increased with increasing the nitrogen flow rate. The grain size showed the minimum of 22 nm for the Cu3N thin film deposited at 30%, where the highest value of the carrier concentration was obtained. The results suggest that the properties of the Cu3N thin films can be controlled by the nitrogen flow rate. PMID- 24758003 TI - DCM-based organic dyes with electron donating groups for dye-sensitized solar cells. AB - Herein, 4-(dicyanomethylene)-2-methyl-6-[p-(dimethylamino)styryl]-4H-pyran (DCM) based dyes with electron donating groups were designed and their electronic and optical properties were investigated theoretically for dye-sensitized solar cells (DSSCs). Among the dyes, the D1 and D2 dyes were composed of single electron donating group and the D3 and D4 dyes composed of dual donating group. We performed DFT/TDDFT calculations to get insight into the factors responsible for photovoltaic properties as dye sensitizers. It showed that all the dyes in this work are available as dye sensitizers from the energy consideration compared to TiO2 electrode and iodide electrolyte. It also showed that the D3 and D4 dyes produced additional absorption bands by the introduction of dual donor in absorption spectra and the absorption band of the D4 dye is more red-shifted than that of the D3 dye. It is attributed to the fact that the M2 (a coumarin derivative) moiety with stronger electron withdrawing ability stabilized its LUMO level. In terms of molar extinction coefficient and panchromatic feature, we suggest that the D4 dye would show better performance than other dyes in the present study as a dye sensitizer for DSSCs. PMID- 24758004 TI - Synthesis of functional ZnO nanowall networks using simple solution etching. AB - We report the synthesis of high quality single crystalline ZnO nanowall networks (NNs) using ammonia solution etching of a ZnO nanowire-nanowall heterojunction (NNH) structure. Synchrotron X-ray diffraction revealed that the full-width-at half-maximum of the ZnO (0002) peak in the ZnO NN sample was much narrower than that of the ZnO NNH sample. Temperature-dependent photoluminescence (PL) measurements revealed more intense and narrower bound exciton peak emission in the NN sample compared to that in the NNH sample. Moreover, the clear observation of free exciton emission in the PL spectrum of the NN sample, even at temperatures as low as 30 K, suggested incorporation of a small number of impurities into the NN sample. In addition, I-V characteristics confirm the higher conductivity of the ZnO NNs as compared to those of the NNH structures, indicating that the NN sample had a superior crystalline property than NNH sample. PMID- 24758005 TI - Gate-controlled spin-orbit coupling in InAs/InGaAs quantum well structures. AB - We have investigated gate electric field controlled Rashba spin-orbit coupling (SOC) constant (alpha) in In0.53Ga0.47As and InAs-inserted quantum well (QW) structures. More than three times larger gate controllability of a in the InAs inserted QW has been observed compared to the In0.53Ga0.47As QW. The enhanced gate controllability of alpha directly results from the larger zero-field SOC in narrow band gap InAs QW. Furthermore, the lower contact resistance and higher electron mobility imply that the InAs QW is a more promising channel for spintronic device applications. PMID- 24758006 TI - Effect of growth pressure on the synthesis of vertically aligned carbon nanotubes and their growth termination. AB - When vertically aligned carbon nanotubes (VACNTs) are synthesized by thermal chemical vapor deposition (TCVD), their structural features such as height and density can be determined by TCVD growth conditions. In this study we investigated the effect of growth pressure on the structural features of VACNTs. Changes in growth pressure significantly affected the height, density, and crystalinity of synthesized VACNTs. In addition, we suggest that the growth termination of VACNTs could be due to the lack of carbon feedstock supply to the center of the VACNT film induced by the pressure-dependent adsorption of amorphous carbon at the edge of the VACNT film. In addition, the field emission characteristics of the VACNT film were carried out. The turn-on voltage of the VACNT film was 1.62 V/microm and the field enhancement factor (beta) was 2478. These results provide useful information for practical applications of VACNTs, such as field emission display and X-ray source. PMID- 24758007 TI - Fabrication of 3-D nanodimensioned electric double layer capacitor structures using block copolymer templates. AB - The need for materials for high energy storage has led to very significant research in supercapacitor systems. These can exhibit electrical double layer phenomena and capacitances up to hundreds of F/g. Here, we demonstrate a new supercapacitor fabrication methodology based around the microphase separation of PS-b-PMMA which has been used to prepare copper nanoelectrodes of dimension -13 nm. These structures provide excellent capacitive performance with a maximum specific capacitance of -836 F/g for a current density of 8.06 A/g at a discharge current as high as 75 mA. The excellent performance is due to a high surface area: volume ratio. We suggest that this highly novel, easily fabricated structure might have a number of important applications. PMID- 24758008 TI - Propagation effects of THz waves in InAs-based heterostructures. AB - We have investigated THz radiation characteristics along different directions, either reflective or along lateral by using InAs-based heterostructures. Firstly, we demonstrate the phase shift with InAs layer thickness, revealing the change of dominant THz wave generation mechanism along both directions. Along the lateral direction, the time-domain signals in thin InAs epilayers showed an abrupt phase and amplitude change at certain time delays which suggest the interference between two rays at the photoconductive switch. This behavior was further substantiated by the multiple cavity modes in Fourier-transformed spectra and by the amplitude variation with excitation spot displacement. PMID- 24758009 TI - Synthesis of fluorescent and magnetic bi-functional NaLuF4-based upconversion nanocrystals. AB - Fluorescent and magnetic bi-functional NaLuF4-based upconversion nanocrystals have been developed by a facile thermal decomposition method. The influences of Mn2+ and Gd3+ doping on the upconversion luminescent and magnetic properties of the nanocrystals were investigated. The results show that Mn2+ doping can promote the transition of green to red and increase the red emission significantly. When the Mn2+ and Gd3+ are co-doped in the nanocrystals, it has a synergistic effect which can further improve the transition and red emission. Moreover, the nanocrystals co-doped with Mn2+ and Gd3+ exhibit excellent superparamagnetic properties. These results suggest that the developed nanocrystals, which have strong pure red upconversion emission and superparamagnetic properties, can serve as a potential upconversion luminescence and magnetic resonance probe for dual modality bioimaging. This work presents a facile and effective method for modulating the transition of short-wavelength emission to red emission of upconversion nanocrystals, leading the naocrystals exhibiting excellent upconversion luminescence and magnetic properties. PMID- 24758010 TI - Aqueous synthesis of MPA-capped CdTe nanocrystals emitted in near infrared with high quantum yield. AB - The high luminescent near infrared (NIR)--emitting CdTe nanocrystals (NCs) with 3 mercaptopropionic acid (MPA) as the stabilized molecules had been sucessfully fabricated by a facile and simple water-reflux method. By virtue of the characterizations for the as-prepared MPA-capped CdTe NCs, such as UV-Vis absorption, steady-state photoluminescence (PL), time-resolved PL spectra and PL image, the optical properties, diameters and morphologies of the CdTe NCs were investigated detailedly. With the increase of reflux time, the PL peak wavelength of NCs gradually shifted from red light to NIR spectra range within 7 h, and the PL quantum yield (QY) was increased firstly and then decreased slightly. It was worth noted that the NCs still showed a relative high PL QY of 47% as well as a narrow full width at half maximum (FWHM) of PL spectra even when the NCs emitted at the NIR wavelength of 754 nm. In addition, the average PL lifetime also exhibited an obvious increase as the growth of CdTe NCs due to the formation of thin CdS shell on the surface of CdTe. The PL stabilities for these NIR-emitting NCs (754 nm) in phosphate-buffered saline (PBS) buffer solution with various concentrations ranged from 0.005 to 0.1 M were also checked accordingly, and the results indicated that the as-prepared NIR-emitting CdTe NCs had a satisfied PL stability, implying a potential application in the biological field. Hopefully, all the superiority of these NIR-emitting CdTe NCs, such as high PL QY and PL lifetime, narrow FWHM of PL spectra, high PL stability in PBS solution, would make them to be a good candidate for biological applications in future. PMID- 24758011 TI - Nonionic surfactant-assisted, seed-mediated growth of gold nanotoroids. AB - Gold (Au) nanotoroids with ring-like structures and vacancies at their center are successfully synthesized through a seed-mediated method using nonionic Brij35 surfactant, which acted as a reducing, surface-stabilizing, and shape-directing agent. The relative amount of Au seed nanoparticles significantly affects the formation yield of Au nanotoroids and the morphologies of the resulting Au nanostructures. The possible formation mechanisms are discussed by analyzing time resolved microscopy images and UV-Vis spectra. PMID- 24758012 TI - Removal of heavy metals and dyes by supported nano zero-valent iron on barium ferrite microfibers. AB - The binary nano zero-valent iron/barium ferrite (NZVI/BFO) microfibers with uniform diameters and high porosity were prepared by the organic gel-thermal selective reduction process. The composite microfibers are fabricated from nano zero-valent iron and nano BaFe12O19 grains. The effects of pH, adsorbent dosage, and contact time on the adsorption of heavy metals and dyes have been investigated. The adsorption isotherms of heavy metals and dyes on the microfibers are well described by the Langmuir model, in which the estimated adsorption capacities are 14.5, 29.9, 68.3 and 110.4 mg/g for Pb(II), As(V), Congo red and methylene blue, respectively. After five cycles, these microfibers still exhibit a high removal efficiency for As(V), Pb(II), Congo red and methylene blue. The enhanced adsorption characteristics can be attributed to the porous structure, strong surface activity and electronic hopping. Therefore, the magnetic NZVI/BFO microfibers can be used as an efficient, fast and high capacity adsorbent for heavy metals and dyes removal. PMID- 24758013 TI - Preparation and transdermal diffusion evaluation of the prazosin hydrochloride loaded electrospun poly(vinyl alcohol) fiber mats. AB - This study reports on the use of electrospun polyvinyl alcohol (PVA) nanofiber mats loaded with prazosin hydrochloride (PRH) as a transdermal drug delivery system, investigating the morphology of electrospun PVA nanofibers, the in vitro release characteristics of the drug from the as-spun fibers, and the influence of permeation enhancer (water-resoluble azone, WSA) on transdermal diffusion of PRH through a rat skin. The same was also conducted on the PRH -loaded as-cast PVA films for comparison. Results indicated that the morphology of PRH-loaded PVA fibers observed by scanning electron microscopy (SEM) relied on the electrospinning processing parameters, and the addition of WSA had obvious effects on the diameter and morphology of electrospun PVA fibers. The PRH-loaded electrospun PVA fiber mats exhibited much higher accumulated release dose and release rate of PRH than as-cast PVA films. And WAS can improve the release amount and rate of PRH from drug-loaded samples. The content of PRH in receiver was more than that in the stratum corneum and in the dermis. It was concluded that the PRH-loaded electropun PVA fiber mats as a transdermal patches can be a promising candidate for the conventional preparation. PMID- 24758014 TI - Impact of annealing on surface morphology and photoluminescence of self-assembled Ge and Si quantum dots. AB - Controlled growth and characterization of germanium (Ge) and silicon (Si) nanostructure are the key issues for optoelectronic device fabrication. The role of post-annealing on the structural and optical properties of radio frequency (rf) magnetron sputtering grown of Ge and Si quantum dots (QDs) deposited on Si(100) substrate is studied. Atomic force microscopy confirmed the formation of Si and Ge QDs with estimated sizes lower than -17 nm and -14 nm respectively. The X-ray diffraction analysis revealed the formation of Si and Ge QDs accompanied by SiO2 with estimated sizes of -5 and -7 nm for post-annealed Si and pre-annealed Ge QDs respectively. The room temperature photoluminescence spectra for Ge and Si demonstrated an emission peak at 3.20 and 2.72 eV respectively, which are attributed to the electron and hole recombination within QDs. A shift in the PL peak is observed through annealing which is ascribable to the changes in size of QDs and quantum confinement effect. The thermal annealing at 600 degrees C is found to play an important role in controlling the shape, number density, root mean square (rms) roughness and the energy shift of the luminescence band for both Si and Ge QDs. The influence of annealing on growth morphology for Ge QDs is appeared to be stronger than Si. PMID- 24758015 TI - Synthesis and magnetic properties of hard-soft SRFe10Al2O19/NiZnFe2O4 ferrite nanocomposites. AB - Pure phase exchange-coupled nanocomposites of hard-soft magnetic oxides, (hard) SrFe10Al2O19(-) (soft) Ni0.75Zn0.25Fe2O4 were prepared via autocombution method. Magnetic properties of the nanocomposites were assessed as a function of soft phase content in the nanocomposite. A 40% increase in M(s) value was observed for nanocomposite with 30 Wt.% of the soft phase. A linear increase in M(r)/M(s) with soft-phase content indicates the presence of enhanced exchange-coupling between hard and soft phases of the nanocomposite. The highest M(r)/M(s) ratio of 0.68 was obtained for nanocomposite containing 30 Wt.% of the soft-phase. The observed reduction in coercieve field values of the nanocomposite with increase in soft phase content is explained on the basis of competition between exchange and dipolar interaction between hard-soft and soft-soft phases of the nanocomposite. PMID- 24758016 TI - Electrochemical performance of yttrium substituted LiY(x)Ni(1-x)O2 (0.00 < or = X < or = 0.20) cathode materials for rechargeable lithium-ion batteries. AB - Pristine LiNiO2 and yttrium substituted LiY(x)Ni(1-x)O2 (0.00 < or = X < or = 0.20) cathode materials were synthesized by sol-gel technique using aqueous solutions of metal nitrates and tartaric acid as a chelating agent. Physical properties of synthesized materials were characterized by using X-ray diffraction analysis (XRD), Scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). X-ray powder diffraction analysis showed an increase in lattice parameters with increasing yttrium content yttrium occupies within the layer. SEM and TEM analyses were used to visualize the nature and surface morphological aspects of the oxides. Electrochemical studies were made for the assembled cells using galvanostatic charge/discharge studies discharge rate 0.5 C in the potential range between 3 and 4.5 V. Among them, LiY0.15Ni0.85O2 behaved much better, losing about 5% of its initial capacity (195 mA h g(-1)) after 60 cycles at 185 mA h g(-1). While the pristine LiNiO2 lost about 10% of its initial capacity (164 mA h g(-1)). The substitution of Ni with yttrium, in LiY0.15Ni0.85O2 enhanced the high discharge capacity, good reversibility and best electrochemical performance of rechargeable lithium-ion batteries. PMID- 24758017 TI - Effect of gold nanoparticles on the efficiency of poly(3-hexylthiophene): phenyl C61-butyric-acid-methylester solar cells. AB - Different surface densities of gold nanoparticles (AuNPs) were deposited on (3 aminopropyl)-trimethoxysilane (APTMS)-modified indium tin oxide (ITO) electrode. The electrodes were then used in poly(3-hexylthiophene): phenyl-C61-butyric-acid methylester (P3HT:PCBM) solar cells. Enhanced photo-conversion efficiency was observed from solar cells containing adsorbed AuNPs with surface density equals to 10 +/- 3 NPs/microm2. For higher surface densities (215 +/- 10 NPs/microm2), the presence of the plasmonic material significantly reduced the efficiency of the solar cell. Impedance spectroscopy (IS) indicates changes of the electrical characteristics, evident by a drastic reduction of the impedance relative to the reference cells, from electrodes modified with high densities of AuNPs. PMID- 24758018 TI - Structural, optical and sensing properties of pure and Cu-doped SnO2 nanowires. AB - In present work, pure and copper (Cu) doped SnO2 nanowires have been synthesized by thermal evaporation process at ambient pressure. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) indicated the growth of wire like pure and Cu-doped SnO2 nanostructures with their length of about 50 microm and 80 microm whereas transverse dimension of about 50-80 nm and 20-50 nm, respectively. The HRTEM and SAED pattern reveals the growth of single crystalline Cu-doped SnO2 nanowire. The EDX confirms that Cu has been doped in the SnO2 nanowires and atomic fraction of Cu in nanowires is about 2.5 at% when concentration of CuO in starting source powder is 50 wt%. X-ray diffraction showed that Cu gets incorporated into the SnO2 lattice and also confirms their tetragonal rutile structure. For comparative study of gas sensing properties of pure and Cu-doped SnO2 nanowire, isolated single nanowire based sensors have been fabricated for detection of ethanol gas. The doping of Cu was found to enhance the ethanol sensitivity of SnO2 nanowire based sensors and the sensor response improves with increase in ethanol concentration. This sensing behaviour offers a suitable application of the Cu-doped SnO2 nanowire sensor for detection of ethanol gas. PMID- 24758019 TI - Stimulated emission features of bound excitons in ZnO nanotubes. AB - We have investigated the detailed features of photoluminescence (PL) in vertically aligned ZnO nanotube (NT) arrays as a function of temperature, pumping power, and experimental geometries. In samples with different wall thickness (15 or 60 nm), the temperature-dependent PL energy followed the Varshni's formula whose fitting parameters were found to be rather close to zero-dimensional case in the 15 nm-thick NTs with much larger intensity. In reflective geometry with circular excitation beam shape, the emission gradually evolved from spontaneous to stimulated regime, inferred from amplitude and line-width variation. On the other hand, in the edge-emission geometry with needle-like excitation shape, the interaction length dependence was directly traced by using an adjustable slit. PMID- 24758020 TI - Electrochemical characteristics of zinc oxide-polyethyleneglycol complex films using EQCM. AB - ZnO-PEG-ZnO complex film was fabricated by forming ZnO thin film on the Polyethyleneglycol (PEG) thin film. ZnO thin films were formed by an electrostatic method and ZnO-PEG complex films were fabricated by adsorbing PEG on the ZnO thin films surface with hydrogen bond. The electrochemical characteristic of the ZnO-PEG-ZnO film was analyzed by EQCM techniques. The resonance frequency, resistance and current changes were measured simultaneously with scan rate 100 mV/s, sweep range -1.4-1.2 V in 5 mM ZnCl2 aqueous solution. The electrochemical characteristic of the ZnO-PEG-ZnO complex film was compared with that of the ZnO thin film, and the possible electrode applications of ZnO PEG-ZnO complex films were examined. PMID- 24758021 TI - Effects of insertion of hole injection layers on pentacene rectifying diodes. AB - The main issue of the organic rectifier, the key element in radio frequency identification tags, is to improve forward-bias current density of an organic diode in the rectifier, which increases the frequency response of the rectifier. One approach to achieve high current density is inserting a hole injection layer (HIL) between the anode and the active layer to enhance the charge injection efficiency. Here we study the effect of HILs in pentacene rectifying diodes. Three different hole injection layers are applied to the pentacene diode: molybdenum trioxide (MoO3), 1,4,5,8,9,11-hexaazatriphenylene hexacarbonitrile (HAT-CN), and poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT:PSS). A rectifier consists of the diode with a capacitor. The results show that current density of diodes with HILs is increased by more than three orders of magnitude compared with the diode without a HIL. The diode with MoO3 and that with HAT-CN shows similar forward bias current density, while that of the diode with PEDOT:PSS is slightly lower than those. Finally, the output voltage of the rectifier with a HIL is 4.6 V at 100 MHz when input voltage of 10 V is applied. PMID- 24758022 TI - Luminescence color tuning of the iridium complexes by interligand energy transfer (ILET) with ancillary ligands for organic light emitting diode. AB - The series of new iridium complexes, Ir(C--N)2(LX), (main ligand, C--N = the anion of 2-phenylpyridine (ppy), 4-difluoro-2-phenylpyridine (F2-ppy) and 4 methyl-2,3-diphenylquinoline (4-Me-2,3-dpq); ancillary ligand, LX = 2-(2 hydroxyphenyl)benzoxazolate (BOX) and 2-(2-hydroxyphenyl)benzothiazolate (BTZ)) were prepared and their luminescence properties were investigated. We expected that the relative energy levels of the main ligands and ancillary ligands in the complexes could determine the possibility of interligand energy transfer (ILET) in the complexes and thereby luminescence properties. As the main ligands, F2 ppy, ppy and 4-Me-2,3-dpq, which have drastically different energy gap between the HOMO and LUMO energy levels, were chosen and their complexes were synthesized. BOX and BTZ were chosen as the ancillary ligands which can form a stable 6-membered metallacycle with the iridium center. The iridium complexes showed various emission ranges from 510 to 643 nm, depending upon the relative energy levels of their main and ancillary ligands. The studies of photoabsorption, electrochemistry, photoluminescence and electroluminescence revealed that ILET might contribute to absorption and luminescence process of the iridium complexes containing the ppy-based ligands and BOX. PMID- 24758023 TI - A facile and rapid process to fabricate platinum counter electrode in dye sensitized solar cell using nanosecond pulsed laser sintering at room temperature. AB - To fabricate the platinum (Pt) counter electrode in dye-sensitized solar cells (DSSCs), rapid and low sintering process was carried out using nanosecond pulsed laser sintering (LS) method based on third harmonic (355 nm) of an Nd:YAG laser at room temperature. The surface morphology of LS-Pt on fluorine-doped tin oxide (FTO) electrode showed thin and compact structure, consisting of particles size of - 10-30 nm and thickness of below 30 nm. The DSSCs with the LS-Pt/FTO counter electrodes displayed the power conversion efficiency of 4.4% with short-circuit current = 9.07 mA/cm2, open-circuit voltage = 0.79 V and fill factor = 61.3. PMID- 24758024 TI - Theoretical study of new blue iridium complexes comprising a bipyridine derivative and various ancillary ligands. AB - New blue emitting ligand Iridium(III) complexes with two phosphines trans to each other and two ancillary ligands, such as Ir(dfpypy)(PPh3)2(H)(CI) and Ir(dfpypy)(PPh3)2(H)(CN), [dfpypy = 2,6-difluoro-3-(pyridin-2-yl)pyridine] were designed and studied to tune the phosphorescence wavelength to the deep blue region and to enhance the luminescence efficiencies. To gain insight into the factors responsible for the emission color change and the different luminescence efficiency, we performed the DFT and TD-DFT calculations on the ground and excited states of these phosphors. (1) The fluorine-substituted dfpypy ligand lower the HOMO energy levels because a N of the pyridyl ligand is more electronegative than a C of the nonsubstituted phenyl ligand and also (2) mono cyclometalated Iridium(III) complexes using two phosphines trans to each other increased HOMO-LUMO gap by strong field effects of ancillary ligands. From these results, we discuss how the dfpypy ligand and the ancillary ligand influences the emission peak as well as the metal to ligand charge transfer (MLCT) transition efficiency. As the maximum emission spectra of FIrpic known as blue phosphorescence material is about 475 nm. The resulting Iridium(III) complexes, Ir(dfpypy)(PPh3)2(H)(CN), would appear pure blue region about 415 nm with more intensified efficiency. PMID- 24758025 TI - Effect of gallium concentrations on the morphologies, structural and optical properties of Ga-doped ZnO nanostructures. AB - The effect of gallium ion concentrations (0.5 and 2%) on the morphologies, structural and optical properties of Ga-doped ZnO nanostructures are presented. Ga-doped ZnO nanostructures were synthesized on silicon substrates by simple thermal evaporation process using metallic zinc and Ga powders in the presence of oxygen. Interestingly, it was observed that Ga-ions incorporation in ZnO nanomaterials play an important role on the growth kinetics and hence on the morphologies of as-grown Ga-doped ZnO nanostructures. It was seen that at low Ga concentration, needle-shaped Ga-doped ZnO nanostructures are formed, presumably by subsequent stacking of hexagonal plates. However, when increasing the Ga concentration, multipods of Ga-doped ZnO were grown. In addition to the morphologies, incorporating Ga-ions into ZnO also affect the room-temperature photoluminescence properties. Therefore, at lower Ga-ion concentration, an intense UV emission was observed while at high Ga-concentration a deep level emission was seen in the room-temperature photoluminescence spectra. This research demonstrates that by controlling the Ga-ion concentration the morphologies and optical properties of ZnO nanomaterials can be tailored. PMID- 24758026 TI - Band gap engineering from Vis to NIR range in CdPbS nanoparticles synthesized by one-step low-temperature decomposition of xanthate compound. AB - In the present study, a generic method for the modification of optical band gap of CdS nanostructures material over a wide spectral range due to Pb doping and formation of Cd(1-x)Pb(x)S nanoparticles and its size confinement is reported. The composite investigated in this study was grown by thermal decomposition of metal xanthates and lead concentration was varied to obtain different lead doping. This is a direct decomposition one pot synthesis route that avoids use of toxic phosphine and injection of chemicals during the reaction. The prepared nanoparticles were characterized by XRD, SEM, EDX, and HRTEM. The optical absorption properties of the Cd(1-x)Pb(x)S nanostructures were investigated by UV visible spectroscopy. Cd(1-x)Pb(x)S nanoparticles showed tuning of the band gap from 2.7 eV to 0.7 eV. PMID- 24758027 TI - Enhancement of organic solar cells efficiency with acetic acid modulated poly(3,4 ethylenedioxythiophene) poly(styrenesulfonate) buffer layers. AB - Bulk-heterojunction organic solar cells (OSCs) based on poly(3-hexylthiophene) as a donor material and (6.6) phenyl-C61-butyric acid methyl ester as an acceptor material were investigated using a poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS) buffer layer that was modulated with acetic acid. The 1.71 x 10(-1) omega x cm resistivity of the pristine PEDOT:PSS film decreased to 2.29 x 10(-2) omega x cm when acetic acid was applied. This modified PEDOT:PSS buffer layer improved the power conversion efficiency (PCE) of OSCs by reducing their already low series resistance and contact resistance. The PCE of OSCs in which the PEDOT:PSS buffer layers had been treated with acetic acid was 2.91%, an improvement over the 1.82% PCE for cells with pristine PEDOT:PSS layers. We optimized the ratio of acetic acid and PEDOT:PSS solution for high PCE of OSCs in this manuscript. The value of this modification method for hole transporting layer is clearly demonstrated and be applicable to other organic devices. PMID- 24758028 TI - Optical studies of pulsed laser deposited nanostructured Pb(Zr0.52Ti0.48)O3 thin film by spectroscopic ellipsometry. AB - Pulsed laser deposition method was employed to grow nanostructured Pb(Zr0.52Ti0.48)O3 (PZT) thin film on Si(100) substrate. The structural and morphological properties of the thin film were investigated by X-ray diffraction (XRD) and scanning electron microscope (SEM) respectively. Optical properties of PZT thin film were studied using spectroscopic ellipsometry (SE) and a four layer model was applied. Spectra of ellipsometric parameters such as psi and delta were measured as a function of energy at room temperature. The refractive index (n), extinction coefficient (k), absorption coefficient (alpha) and the dielectric constants (epsilon(r) and epsilon(i)) of the thin film were obtained as a function of wavelength (200 to 900 nm range). The energy gap (E(g)) of the PZT thin film was estimated to be 3.65 eV. The thickness of the thin films was determined by the ellipsometric data (524 nm) and grain size is found to be in the range of 50-100 nm. PMID- 24758029 TI - Facile growth of barium oxide nanorods: structural and optical properties. AB - This paper reports a large-scale synthesis of barium oxide nanorods (BaO-NRs) by simple solution method at a very low-temperature of - 60 degrees C. The as-grown BaO-NRs were characterized in terms of their morphological, structural, compositional, optical and thermal properties. The morphological characterizations of as-synthesized nanorods were done by scanning electron microscopy (SEM) which confirmed that the synthesized products are rod shaped and grown in high density. The nanorods exhibits smooth and clean surfaces throughout their lengths. The crystalline property of the material was analyzed with X-ray diffraction pattern (XRD). The compositional and thermal properties of synthesized nanorods were observed via Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis which confirmed that the synthesized nanorods are pure BaO and showed good thermal stability. The nanorods exhibited good optical properties as was confirmed from the room-temperature UV-vis spectroscopy. Finally, a plausible mechanism for the formation of BaO-NRs is also discussed in this paper. PMID- 24758030 TI - Photothermolysis of lymphatic endothelial cells by gold nanoshell-mediated hyperthermia. AB - Tumor-associated lymphatics and lymphangiogenesis have been shown to play important roles in promoting tumor growth and metastasis. However, the lymphatic system has received much less attention as a target of intervention in cancer treatment compared to the blood vascular system. In this study, we explored the feasibility of photothermal therapy targeting the lymphatic system as a strategy for inhibiting lymphatics-mediated tumor metastasis. Specifically, photothermolysis of lymphatic endothelial cells (LECs) via gold nanoshell mediated hyperthermia was investigated. Near-Infrared-absorbing Au nanoshells (AuNSs) were synthesized and used as the photothermal coupling agent. After 24-hr incubation, significant amount of the AuNSs were taken up by murine simian virus lymphatic endothelial cells with minimal cytotoxicity. Thermally-induced injury to LECs was found to occur above a threshold temperature of 46 degrees C. Preliminary data also suggested apoptosis as the mechanism of thermally-induced cell death in this temperature range. In a proof-of-concept experiment, AuNS mediated photothermal heating was found to induce cell death in statistically higher percent of LECs incubated with AuNSs after 15-min laser irradiation compared to the controls. We believed that the findings in this study represent the first step in developing AuNS-mediated photothermal therapy as a potential strategy to disrupt tumor-associated lymphatics. PMID- 24758031 TI - In vivo imaging of brain cancer using epidermal growth factor single domain antibody bioconjugated to near-infrared quantum dots. AB - Diagnosis of glioblastoma multiform (GBM) with MRI lacks molecular information and requires a biopsy for pathologic confirmation. The EGFRvIII, is a constitutively active mutant of the EGF receptor, identified in a high percentage of brain cancers and associated with increased invasiveness and resistance, making it a good target to improve imaging and diagnosis. The present study shows that conjugation of near-infrared quantum dot (Qd800) to an anti-EGFRvIII single domain antibody, made of the variable region with an extra cysteine for site specific conjugation (EG2-Cys), increased its internalization in U87MG-EGFRvIII cells in vitro compared to Qd800 conjugated with the Fc region of the antibody (EG2-hFc) or unconjugated. EG2-Cys also improved the contrast in Near-Infrared Imaging of mice bearing orthotopic glioblastoma. The increased accumulation was confirmed by fluorescence microscopy of brain sections. The specificity of EG2 Cys in brain tumor expressing the EGFRvIII mutant receptor may provide an accurate less invasive diagnosis and determine the level of tumor aggressiveness and resistance. PMID- 24758032 TI - Analysis on controlling factors for the synthesis of carbon nanotubes and nano onions in counterflow diffusion flames. AB - It is important to identify the dominant factors for governing the growth of carbon nanotubes (CNTs) and nano-onions (CNOs). A diffusion flame of a gas mixture of methane-ethylene was used as the carbon and heat sources and Ni as the catalyst for the synthesis of CNTs and CNOs. The effects of CH4/C2H4 ratio in the fuel side and oxygen concentration in the oxidizer side for counterflow diffusion flames were investigated. It was found that oxygen concentration can greatly affect the morphologies of synthesized products with a threshold of 30% distinguishing the formation of CNO or CNT. CNOs were fabricated at higher oxygen concentrations (30%, 40%, 50%), and CNTs were synthesized only at lower oxygen concentrations (21%, 30%). The fuel composition has minor effects on the morphologies except for the threshold value of oxygen concentration (30%). More carbon sources are required for the synthesis of CNOs than for CNTs, but the temperature requirements are similar (1140-1160 K for CNTs, 1070-1160 K for CNOs). The nanostructures were synthesized as long as the fuel concentration is sufficiently high regardless of the oxygen concentration. Higher fabrication tendency was found for ethylene as fuel to form nanostructures than for methane. PMID- 24758033 TI - Synthesis and characterization of C70-corrole--a new electron transfer dyad. AB - A new electron transfer dyad, covalently linked C70-corrole, was prepared via C70 and 10-(4-Formylaryl)-5,15-bis(pentafluorophenyl). The structures and the properties of the new material were investigated by HPLC, MALDI-TOF-MS, UV-Vis NIR spectroscopy, NMR, fluorescence analysis and CV/DPV. The free-energy of C70 corrole calculated by employing the redox potentials and singlet excited-state energy suggested the possibility of electron transfer from the excited singlet state of corrole to the fullerene entity, which agreed with the results of the theoretical calculation. PMID- 24758035 TI - P-si nanowires/n-ZnO thin film based core-shell heterojunction diodes with improved effective Richardson constant. AB - This paper reports the temperature dependent electrical parameters of p-Silicon nanowires (SiNWs)/n-ZnO thin film based core-shell heterojunction diodes fabricated by conformally deposited zinc oxide (ZnO) by atomic layer deposition (ALD) technique on metal-assisted chemically etched SiNWs. The temperature dependent current-voltage characteristics of the device have been estimated using the modified thermionic emission model in which a Gaussian distributed barrier height function is assumed to include the effects of barrier inhomogeneity phenomenon at the p-SiNW /n-ZnO heterojunction interface. Various parameters such as the turn-on voltage, ideality factor (eta), barrier height (phi(b)) and reverse saturation current are estimated over the operating temperature range of 303 K to 423 K of the diode. The value of the Richardson constant is observed to be largely changed from an impractical value of 1.989 x 10(-6) A cm(-2) K-2 to a realistic value of 36.6 A cm(-2) K-2 once the barrier inhogeneity phenomenon is taken into consideration in the analysis. The estimated value of the Richardson constant is believed to be the best among the reported results. The study is also believed to be the first in case of p-SiNWs/n-ZnO core-shell heterojunction diodes. PMID- 24758034 TI - Substituent effect on the self-assembled structures of two carboxyl functionalised phthalocyanine derivatives on highly oriented pyrolytic graphite. AB - The self-assembling behaviour of two kinds of 4-carboxyphenoxy phthalocyanines (Pc1 and Pc2) has been investigated by scanning tunneling microscope (STM). Pc1 and Pc2 are isomers with the same substituent at alpha- andbeta-position of the phthalocyanine core, respectively. Our STM results have shown that the Pc1 molecule fabricates into stable networks with nanoscale cavities, while Pc2 forms an unstable linear-like structure at the 1-heptanoic acid/graphite interface. The different supramolecular assembling structures may result from the different substituent position of the carboxyl groups which influence the formation of intermolecular hydrogen bonds. PMID- 24758036 TI - IrO2 nanodot formation by plasma enhanced atomic layer deposition as a charge storage layer. AB - IrO2 nanodot (ND) growth by plasma enhanced atomic layer deposition as a charge storage layer has been investigated. As-deposited IrO2 NDs showed a high density of 2.38 x 10(12)/cm2 and a small mean diameter of 3.22 nm, and turned into a spherical shape with a large dot-to-dot separation after annealing. The metal oxide-semiconductor capacitor with Al2O3 blocking and IrO2 ND charge storing layers showed a memory window of 7.2 V. Compared with the sample without Ir2O3 NDs, the sample with NDs showed superior memory characteristics. PMID- 24758037 TI - TiO2 embedded Si nanowire network based Schottky detector for enlarged light detection. AB - The Si nanowire (NW) network was fabricated on the Si substrate with the help of glancing angle synthesized Ag NPs assisted etching technique. The horizontal Si NWs network was characterized by field emission gun-scanning electron microscopy which shows the formation of long Si NWs of diameter within the range of 110-180 nm. The TiO2 thin film (TF) was deposited on the Si NWs, which shows -2.5 times enlarged optical absorption than that of bare Si substrate. Ag-TiO2 contacts exhibit Schottky behaviour and higher photoconduction was observed for TiO2-Si NW detector than that of TiO2 TF under illumination. The dark currents of TiO2 TF and TiO2-Si NW devices were exerted to be 0.1 mA/cm2 and 0.2 mA/cm2 at +1 V, which increased to 0.2 mA/cm2 and 1.23 mA/cm2, respectively, under the illumination of 100 W filament bulb. A threefold enhanced photodetection for the Si NW device was observed compared to the TiO2 TF device. The nonlinear rise of photocurrent of 2 x 10(-2) mA/cm2, after 5 min light illumination was observed due to carrier diffusion effect. PMID- 24758039 TI - Formation process of metallic copper fine particles from cupric oxide microparticles at room temperature. AB - Copper (Cu) fine particles were prepared by room-temperature hydrazine reduction of Cu oxide microparticles. In this study, to reveal the formation process of metallic Cu homogeneous fine particles from cupric oxide (CuO) microparticles, hydrazine was added to a CuO slurry at room temperature. The morphological changes in the product during the reduction with and without ammonia were observed by using scanning electron microscopy (SEM). The SEM images indicated that not only did the Cu2+ dissolve in water by complex formation with ammonia or hydrazine, but also that Cu2+ ions on the surface of CuO microparticles were reduced by hydrazine to form metallic Cu fine particles. Tuning the sizes of Cu particles by the stabilizing reagent is also discussed. PMID- 24758038 TI - Flow cytometric assessment of reactive oxygen species generations that are directly related to cellular ZnO nanoparticle uptake. AB - In this study, a simple flow cytometry protocol to evaluate nanoparticle associated biological response was proposed. Particularly, we have evaluated the effect of surface charge on the cellular nanoparticle associations and nanoparticle-induced apoptosis. Significant enhancement in side scattering intensity was observed for the HeLa cells treated with positively charged (PLL)ZnO nanoparticles, suggesting that the (PLL)ZnO nanoparticles may induce cell death via adsorption and endocytosis of the nanoparticles. On the other hand, the negatively charged (PAA)ZnO nanoparticle seems to cause cell death process indirectly via the released Zn ions, with less contribution from cellular association of nanoparticles. Time- and dose-dependent studies on cellular association of ZnO nanoparticles, and ZnO associated reactive oxygen species generation were also performed for the HeLa cells exposed to the (PLL)ZnO nanoparticle. For those cells associated with (PLL)ZnO nanoparticle, a significant enhancement in reactive oxygen species generation was observed even at a lower concentration (10 ppm), which was not observable for the results with the whole cell population. By using this approach, we are able to distinguish biological responses (e.g., reactive oxygen species (ROS) generation) directly related to the cellular associations of NPs from those indirectly related to the cellular associations of NPs, such as the cytotoxicity caused by the NP released metal ions. PMID- 24758040 TI - PbS nanostructured thin films by in situ Cu-doping. AB - PbS:Cu nanocrystalline films were prepared by chemical bath at temperature of 80 degrees C and deposited on glass substrates. Different Cu-doping levels were obtained changing the volume of the Cu-reagent-solution into the PbS growing solution. X-ray diffraction (XRD) and optical absorption (OA) measurements were carried out to characterize the semiconductor. The morphological changes of the layers were analyzed using an atomic force microscopy. Diffraction X-ray spectra displayed peaks at 2 theta = (26.00, 30.07, 43.10, 51.00 and 53.48), indicating growth on the zinc blende face. The grain size determined by X-rays diffraction of the undoped samples, was found -37 nm, whereas with the doped sample was - 32 25 nm. Raman spectra reports strong band in - 133-140 cm(-1) attributed to a combination of longitudinal and transversal acoustic modes. Optical absorption, forbidden band gap energy (E(g)) shift disclose a shift in the range 1.4-2.4 eV. Gibbs free energy calculation for the Cu doping PbS is also included heading. PMID- 24758041 TI - Shape-controlled synthesis of ZnO microstructures: the effects of inorganic shape directing and pH altering agents. AB - In this work, shape-controlled synthesis of zinc oxide (ZnO) microstructures were demonstrated using liquid-phase route utilizing zinc acetate hydrate as zinc ion precursor and ammonia as pH buffering agent and source for zinc-ammonia complexes. Glass substrate coated with indium tin oxide layer was used as the growth substrate. Zinc-ammonia complex was thought of as the component of growth for ZnO crystals. Inorganic shape-directing agents, instead of organic ones were used in this study e.g., trisodium citrate or aluminum nitrate hexahydrate. The effect of pH altering agent e.g., sodium hydroxide towards the crystal structure was also probed. Without shape-directing agents, the resultant ZnO crystals exhibited multilayer petals flower shape with uniform size (e.g., diameter of 2.5 microm). Adding trisodium citrate, led to the formation of burger crystals with uniform size (e.g., height of -200 nm and diameter of -800 nm). Adding aluminum nitrate hexahydrate resulted in the formation of hexagonal disk with wide variation in size (diameter varied between -0.8 to 4 microm). The addition of sodium hydroxide, strong base, altered the pH into high value very rapidly in the beginning of the synthesis and caused faster nucleation rate in a NaOH containing solution with respect to that in a NH3 solution. In this case, crystals with different morphology are obtained, e.g., dot like, monopetal-flower like and octahedron like. The detailed processes pertaining for each case were explained in this work. PMID- 24758042 TI - Manufacturing a durable superhydrophobic polypropylene coating on aluminum alloy substrate by adding nano-titania nanoparticles. AB - A superhydrophobic polypropylene (PP) coating on the surface of aluminum alloy coupons is unstable because of the existence of metastable state in curing process. Nano-titania particles were added into PP solution to form hierarchical micro- and nano-structures of PP coatings on the surface of aluminum alloy coupons. The morphology of the coatings was observed with Scanning Electron Microscopy (SEM), and the corresponding structure and components were investigated with Energy Dispersive Spectrometer (EDS) and X-ray diffractometer (XRD), respectively. The results indicated that nano-TiO2 particles are the main nucleation cores in the curing of the coatings; PP in solution is enclosed in these cores and crystallizes gradually. The coatings can preserve the stable micro- and nano-structure on six months due to the nucleation action of nano-TiO2 particles, and its durable water contact angle (WCA) is about 164 +/- 1.5 degrees. PMID- 24758043 TI - Diethanolamine-modified magnetic fluorescent Fe3O4@ZnS nanoparticles for ultrasensitive detection and removal of Cu2+. AB - Currently, growing attention has been paid to the sensitive determination and removal of Cu2+ because excessive levels of Cu2+ could do harm to organisms. Herein, a novel diethanolamine-modified magnetic fluorescent Fe3O4@ZnS nanoparticle (MFNP) for simultaneous detection and removal of Cu2+ was designed and synthesized through dithiocarbamate linkage strategy. The characterization of MFNP was confirmed by transmission electron microscope (TEM), infrared (IR) and emission spectra. The results showed that MFNP could quantificationally detect Cu2+ with high sensitivity and selectivity under a broad pH range (pH 4.5-9). The removal of Cu2+ was achieved by the aggregation-induced sedimentation (AIS) strategy and by external magnetic field. PMID- 24758044 TI - Dielectric properties of polymer composites with carbon nanotubes of different diameters. AB - The dielectric properties of Polymethylmetacrylate (PMMA) composites filled with CVD made multiwalled carbon nanotubes (MWCNT) of different mean outer diameters (d - 9 nm and 12-14 nm) were investigated at temperatures from 300 K to 390 K and in a wide frequency range (20 Hz-1 MHz). The percolation threshold is lower in composites with thick nanotubes. Below percolation threshold the dielectric permittivity was found also to be higher for composites with thicker carbon nanotubes. The temperature dependence of the complex dielectric permittivity of the investigated composites below percolation is mainly caused by beta relaxation in pure PMMA polymer matrix. The potential barrier for PMMA molecules rotation is higher in composites with thicker MWCNT and demonstrates non-monotonous concentration dependence. PMID- 24758045 TI - Bio-based hyperbranched thermosetting polyurethane/triethanolamine functionalized multi-walled carbon nanotube nanocomposites as shape memory materials. AB - Here, bio-based shape memory polymers have generated immense interest in recent times. Here, Bio-based hyperbranched polyurethane/triethanolamine functionalized multi-walled carbon nanotube (TEA-f-MWCNT) nanocomposites were prepared by in situ pre-polymerization technique. The Fourier transform infrared spectroscopy and the transmission electron microscopic studies showed the strong interfacial adhesion and the homogeneous distribution of TEA-f-MWCNT in the polyurethane matrix. The prepared epoxy cured thermosetting nanocomposites exhibited enhanced tensile strength (6.5-34.5 MPa), scratch hardness (3.0-7.5 kg) and thermal stability (241-288 degrees C). The nanocomposites showed excellent shape fixity and shape recovery. The shape recovery time decreases (24-10 s) with the increase of TEA-f-MWCNT content in the nanocomposites. Thus the studied nanocomposites have potential to be used as advanced shape memory materials. PMID- 24758046 TI - Effect of the temperature on structural and optical properties of zinc oxide nanoparticles. AB - Zinc nitrate hexahydrate, Zn(NO3)2 x 6H2O was used as a precursor with urea NH2CONH2 to prepare hydrozincite Zn5(CO3)2(OH)6 powder using hydrothermal method for 8 h at 90 degrees C. Zinc oxide (ZnO) nanoparticles (NPs) were prepared by thermal annealing of hydrozincite powder at different annealing temperatures, i.e., 350, 550 750 and 950 degrees C in air for 2 h. The resulting materials were characterized by X-ray diffraction, scanning electron microscopy (SEM) and thermal gravimetric analysis (TGA). The optical properties of the products were characterized by Fourier transform infrared spectroscopy (FT-IR), UV-Vis spectroscopy and photoluminescence (PL) spectra. It was found that the particle size increased from - 33 to 250 nm with increasing in the annealing temperatures. FTIR results showed that the standard peaks of zinc oxide were presented at 428.17 and 532.32 cm(-1). Thermal analysis study showed that the primary weight loss starts at - 93 degrees C is due to solvent evaporation. The secondary weight loss, observed at - 378 degrees C, is due to phase transition from hydrated zinc oxide to zinc oxide. The band gaps of the products were in the range - 3.26-3.30 eV. The PL spectrum showed that the as-synthesized ZnO nanoparticles had UV (381 nm) and green (537 nm) emissions. PMID- 24758047 TI - Characterization of single crystalline CdS nanowires synthesized by solvothermal method. AB - Cadmium sulfide (CdS) nanowires with uniform diameter were prepared by the solvothermal method using ethylenediamine (en) as solvent. The products were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scan electron microscopy (SEM), energy dispersive spectroscopy (EDS) and transmission electron microscopy (TEM). It was found that the products are hexagonal crystals of CdS nanowires with diameter of 28 nm and length up to several micrometres. Selected area electron diffraction (SAED) and high resolution TEM (HRTEM) studies indicate the single-crystalline nature of CdS nanowires with an oriented growth along the c-axis direction. The absorption spectrum of the as-prepared CdS nanowires shows an absorption peak of around 485 nm. These CdS nanowires exhibit bright photoluminescence (PL) with two distinct emission bands at 502 nm and 696 nm. PMID- 24758048 TI - Electromagnetic properties of composite materials for the electrical power device. AB - The current-voltage characteristics and the mechanism of memorized magnetic effect of a BiSrCaCuO superconductor were studied to develop a superconductor device. An external magnetic field produced an out-put voltage across the superconducting sample which increased with increasing the applied magnetic flux. The out-put voltage was not completely disappeared after removal of the magnetic field at a temperature. The appearance of the voltage was ascribed to the trapping of magnetic flux. The magnetic effect arose from the interaction between a trapped magnetic flux and a weak link of the superconducting bulk. The type and distribution of second phases are important factors to control magnetic pinning effect for a precisely controlled device. PMID- 24758049 TI - Two-dimensional ordered silicon dioxide cavities array as matrix for the immobilization of horseradish peroxidase and its direct electrochemistry. AB - A silicon dioxide (SiO2) cavities array was fabricated on indium-tin oxide (ITO) electrode with polystyrene (PS) particles array as template by using sol-gel technique. The electrochemical properties of SiO2 cavities array indicated that it acted as microelectrode array. Horseradish peroxidase (HRP) was immobilized on the surface of SiO2 cavities by adsorption method. Direct electrochemistry of HRP modified SiO2 cavities array was studied. The results showed that the microenvironment of SiO2 cavities can accelerate electron transfer of HRP efficiently and the electron transfer rate was calculated to be 1.98 s(-1). PMID- 24758050 TI - Synthesis of multi-walled carbon nanotube-Ag-nanoparticles composite nanomaterials using proton beam irradiation. AB - A new synthetic route for decorating carbon nanotubes (MWCNTs) with silver nanoparticles by proton beam irradiation at room temperature is presented. Pristine- and surface-modified MWCNTs were comparatively utilized for the preparation of MWCNT-Ag-nanoparticles nanohybrid. Silver nanoparticles on the surfaces of MWCNTs were produced in situ without any additional reducing reagents, and more importantly, all the solutions were aqueous phase-based. The surfaces of MWCNTs were functionalized with thiol groups using several steps, which included an oxidation step. The silver nanocrystals on the surface-modified MWCNTs were spherical and -4 nm in diameter. Thiolated MWCNTs were well decorated with Ag nanoparticles, whereas pristine MWCNTs were not. PMID- 24758051 TI - Fabrication and characterization for the nanoconjugates of pyridyldithio functionalized multiwalled carbon nanotubes and cytochrome c in Langmuir-Blodgett films. AB - Monolayers and Langmuir-Blodgett (LB) films of pyridyldithio-functionalized multiwalled carbon nanotubes (pythio-MWNTs) conjugated with cytochrome c were investigated. Quartz crystal microbalance measurements revealed that monolayers of pythio-MWNTs could be deposited on the substrate surface with a surface density of about 270 ng/cm2. The as-prepared LB films of pythio-MWNTs could act as a support to immobilize cytochrome c with the surface density of about 5.2 microg/cm2. Composition, structure and morphology of the films were characterized by using absorption and X-ray photoelectron spectra as well as atomic force microscope. A reversible redox process for the immobilized cytochrome c was revealed with the cathodic and anionic potentials at about -0.55 and -0.3 V versus Ag/AgCl, respectively. PMID- 24758052 TI - Formation mechanism and red light emission photoluminescence of single-phase crystalline Eu2O2CO3 nanoplates compared with Y2O3:Eu phosphor. AB - The photoluminescence properties and formation mechanism of a novel stoichiometric phosphor are presented. Nanoplates of pure single-phase crystalline Eu2O2CO3 oxycarbonate (hexagonal type-II) were synthesized by dry autoclaving under autogenic pressure (under 3 MPa) using an efficient, high yield solid state green-chemistry route that can be extended to other rare-earth oxycarbonate and oxide systems, resulting in the full conversion of a simple commercial precursor in single-crystalline nanoplates with strong visible luminescence. Phosphors made of an oxide host and an active luminescent dopant ion are the commercial standard (i.e., Y2O3:Eu). It is generally considered that the activity of luminescent species, such as Eu3+, is quenched and disappears above a certain concentration of them in the lattice (concentration quenching). The truly stoichoimetric oxycarbonate phosphor without active dopant ions exhibits very strong red emission when excited by different excitations, in the UV and visible range, without any concentration quenching effect. The bright red light emission spectra of the of the photo-excited phosphor nanoplates under UV and visible light excitation is compared with that of a standard Y2O3:Eu commercial red phosphor powder, and the thermal conversion mechanism is proposed to obtain the single-phase stable stoichiometric oxycarbonate nanoplates. PMID- 24758053 TI - Uncatalyzed synthesis and characterization of a water-soluble polyacetylene: poly[2-ethynyl-N-(propylsulfonate)pyridinium betaine]. AB - A new ionic conjugated polymer was prepared by the activated polymerization of 2 ethynylpyridine with the ring-opening of 1,3-propanesultone without any additional initiator or catalyst. This polymer was characterized by various instrumental methods to have conjugated polymer backbone system with pendant N propylsulfonate functional groups. The photoluminescence spectrum of polymer showed that the PL peak is located at 552 nm corresponding to the photon energy of 2.25 eV. The cyclovoltammograms of polymer exhibited the irreversible electrochemical behaviors between the oxidation and reduction peaks. The oxidation current density of polymer versus the scan rates is approximately linear relationship in the range of 30-120 mV/sec. It was found that the kinetics of the redox process is almost controlled by the reactant diffusion process from the oxidation current density of polymer versus the scan rates. PMID- 24758054 TI - Self catalytic growth of indium oxide (In2O3) nanowires by resistive thermal evaporation. AB - Self catalytic growth of Indium Oxide (In2O3) nanowires (NWs) have been grown by resistive thermal evaporation of Indium (In) in the presence of oxygen without use of any additional metal catalyst. Nanowires growth took place at low substrate temperature of 370-420 degrees C at an applied current of 180-200 A to the evaporation boat. Morphology, microstructures, and compositional studies of the grown nanowires were performed by employing field emission scanning electron microscopy (FESEM), X-Ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS) and X-ray photoelectron spectroscopy (XPS) respectively. Nanowires were uniformly grown over the entire Si substrate and each of the nanowire is capped with a catalyst particle at their end. X-ray diffraction study reveals the crystalline nature of the grown nanowires. Transmission electron microscopy study on the nanowires further confirmed the single crystalline nature of the nanowires. Energy dispersive X-ray analysis on the nanowires and capped nanoparticle confirmed that Indium act as catalyst for In2O3 nanowires growth. A self catalytic Vapor-Liquid-Solid (VLS) growth mechanism was responsible for the growth of In2O3 nanowires. Effect of oxygen partial pressure variation and variation of applied currents to the evaporation boat on the nanowires growth was systematically studied. These studies concluded that at oxygen partial pressure in the range of 4 x 10(-4), 6 x 10(-4) mbar at applied currents to the evaporation boat of 180-200 A were the best conditions for good nanowires growth. Finally, we observed another mode of VLS growth along with the standard VLS growth mode for In2O3 nanowires similar to the growth mechanism reported for GaAs nanowires. PMID- 24758055 TI - A new approach way for white organic light-emitting diodes based on single emitting layer and large stokes shift. AB - New red dopant, DPPZ based on porphyrin moiety was synthesized. DPPZ showed UV Vis and PL maximum values of 412 and 638 nm, indicating the large stokes shift. New blue host compound, TATa was also synthesized and used for co-mixed white emission. TATa exhibited UV-Vis. and PL maximum values of 403 nm and 463 nm in film state. Thus, when two compounds are used as co-mixed emitter in OLED device, there is no energy transfer from blue emission of TATa to DPPZ due to large stokes shift of DPPZ. Based on the PL result, it is available to realize two colored white in PL and EL spectra. As a result of this, two-mixed compounds showed vivid their own PL emission peaks of 466 and 638 nm in film state. Also, white OLED device using two-mixed compounds system was fabricated. EL spectrum shows 481 and 646 nm peaks and two separate EL peaks. As the operation voltage is increased from 8 to 11 V, EL spectrum does not change the peak shape and maximum wavelength values. EL performance of white device showed 0.041 cd/A, 0.018 Im/W, and CIE (0.457, 0.331) at 8 V. PMID- 24758056 TI - Synthesis and characterization of phenylpyridine-based iridium(III) complex for solution-processed phosphorescent organic light-emitting diode. AB - A novel main ligand 2-(2,4-dimethoxyphenyl)-5-trifluoromethylpyridine (MeO2CF3ppy) and its complex bis[2-(2,4-dimethoxy-phenyl)-5-trifluoromethyl pyridinato-N,C2]iridium acetylacetonate (MeO2CF3ppy)2Ir(acac) was synthesized. 2,4-Dimethoxy and 5-trifluoromethyl group were incorporated into main ligand to tune luminescence color. The phosphorescence organic light-emitting diodes (PhOLEDs) based on this complex with the configuration of ITO/PEDOT:PSS (40 nm)/PVK:CBP:Ir(III) complex (50 nm)/BCP (20 nm)/LiF (0.7 nm)/Al (100 nm) were fabricated. The solution-processed PhOLEDs based on (MeO2CF3ppy)2Ir(acac) exhibited a maximum quantum efficiency of 4.18% and luminance efficiency 9.04 cd/A with CIE coordinate of (0.32, 0.64). PMID- 24758057 TI - Fabrication of transition metal oxide-carbon nanofibers with novel hierarchical architectures. AB - We report a facile two-step methodology; electrospinning followed by high temperature treatment, to produce manganese oxide-based nanofibers with well controlled nanoscale architectures. Electrospinning of manganese acetate-based solution (MnOx precursor) has been utilized to fabricate meso-porous manganese oxide nanofibers. These fibers have diameters of about 200-300 nm and fiber mats have been shown to have specific surface area of over 12 m2/g. Scanning and transmission electron microscopy results show that electrospinning has been successfully utilized to create nanofibers with deep inter-connected internal meso-pores for high surface area. In addition, fibers have been spun in a co axial arrangement to fabricate hollow meso-porous nanofibers, or to develop core shell nanofibers with nanoparticles of manganese oxides decorated over current conducting carbon core. X-ray diffraction analysis of the oxide fibers confirms the presence of manganese oxides (MnO2, Mn3O4) after calcination at 700 degrees C. These architectures, we believe, are potentially favorable for use in Li-ion batteries, Li-air batteries and supercapacitors. PMID- 24758058 TI - Effect of calcination temperature on catalytic activity of Pd/C particle prepared by ionic liquid for hexafluoropropylene hydrogenation. AB - Palladium particles were simply synthesized using 1-hexyl-3-methylimidazolium hexafluorophosphate ([Hmim][PF6]). The morphology of the particles was significantly affected by the ionic liquid. Palladium was impregnated on a carbon powder for hexafluoropropylene hydrogenation catalysts. Catalytic activity was varied by the calcination temperature. Under the identical conditions, the catalyst prepared using the ionic liquid after calcined at 500 degrees C was the most active in this reaction. PMID- 24758059 TI - Evaluation of antimicrobial activity of silver nanoparticles for carboxymethylcellulose film applications in food packaging. AB - In this study, silver nanoparticles were prepared and incorporated into carboxymethylcellulose films to evaluate the antimicrobial activity for food packaging applications. The techniques carried out for material characterization were: infrared spectroscopy and thermal analysis for the silver nanoparticles and films, as well as particle size distribution for the nanoparticles and water vapor permeability for the films. The antimicrobial activity of silver nanoparticles prepared by casting method was investigated. The minimum inhibitory concentration (MIC) value of the silver nanoparticles to test Gram-positive (Enterococcus faecalis) and Gram-negative (Escherichia coli) microorganisms was carried out by the serial dilution technique, tested in triplicate to confirm the concentration used. The results were developed using the Mcfarland scale which indicates that the presence or absence of turbidity tube demonstrates the inhibition of bacteria in relation to the substance inoculated. It was found that the silver nanoparticles inhibited the growth of the tested microorganisms. The carboxymethylcellulose film embedded with silver nanoparticles showed the best antimicrobial effect against Gram-positive (E. faecalis) and Gram-negative (E. coli) bacteria (0.1 microg cm(-3)). PMID- 24758060 TI - Effects of different chain lengths and chiral branched amino acids on the synthesis of mesoporous silica. AB - Ordered mesoporous silica was successfully synthesized by using different chain length chiral anionic surfactants, N-acylalanine and N-acylvaline as templates, and N-trimethoxy silylpropyl-N, N, N-trimethyl ammonium (TMAPS) as a co-structure directing agent (CSDA) under weakly acidic conditions. The synthesized products were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and nitrogen sorption analysis. In the TMAPS/N acylalanine system, the mesophase changed from a 3D disordered stucture into a 3D hexagonally structure for the first, and finally into a 3D cubic structure with increased hydrophobic chain lengths of the anionic surfactants. But in the TMAPS/N-acylvaline system, the mesophase changed into a 2D hexagonally structure for the first, and finally into a 3D hexagonally structured mesoporous silica with the helical pore channels. The changes of the pore diameter, the surface area and the pore volume with the chain lengths were also discussed. PMID- 24758061 TI - Synthesis of luminescent SnO2:Eu3+ nanorods via a salt-assisted solution combustion process. AB - SnO2:Eu3+ nanorods have been successfully synthesized by annealing products from microwave-induced KCl-assisted solution combustion reaction, which uses tin (IV) chloride pentahydrate and europium nitrate as cationic source, ethyl glycol as fuel and ammonium nitrate as combustion-supporting agent. The structural and photoluminescent properties of SnO2:Eu3+ nanorods were investigated by high resolution transmission electron microscopy (HRTEM), scanning electron microscopy (SEM), selected area electron diffractometry (SAED), X-ray diffractometry (XRD) and photoluminescence spectroscopy. The phase transformation in the synthetic process was observed by X-ray diffraction pattern. Accordingly, the growth mechanism of SnO2:Eu3+ nanorods was discussed. The results showed that the SnO2:Eu3+ nanorods were rutile-structured single crystals with 10-15 nm in diameter and 200-250 nm in length. Proper addition of KCl into redox mixture solution is critical to the formation of SnO2:Eu3+ nanorods. The doped Eu3+ concentration has obvious effect on the photoluminescence of SnO2:Eu3+ nanorods. The approach is convenient, inexpensive and efficient for the high yield preparation of SnO2:Eu3+ nanorods. PMID- 24758062 TI - Magnetic and noble metallic nanoparticles deposited on silica spheres via silanization. AB - A sol-gel technique has been developed to deposit various nanoparticles (NPs) on silica spheres. The silanization of the silica spheres using 3 mercaptopropyltrimethoxysilane (MPS) with mercapto groups (-SH) plays an important role for the deposition. After being functionalized by MPS, the deposition of magnetic and noble metallic NPs was performed by the reduction of Au3+ and Ag+ ions in-situ using sodium borohydride (NaBH4) or the co precipitation reaction of Fe2+/Fe3+ ions and ammonia (NH3 H2O) at low reactant concentrations at room temperature. The transmission electron microscope (TEM) observation of samples exhibited the homogeneous deposition of Ag, Au, and Fe3O4 NPs on the silica spheres, in which the average size of Au and Ag NPs is 5 nm in diameter while the ones of Fe3O4 NPs is about 10 nm. In the case of without the silanization of silica spheres, the nucleation and growth of the NPs in solutions occur instead of the homogenous deposition. The results demonstrates that MPS containing the -SH metal-chelating functionality, can grow a layer in an ethanol solution on the silica spheres, thus improving the performance of the silica surface by grafting -SH groups. These hybrids offer a high absorption capacity for metal ions, all kinds of NPs can be deposited on the surface by co precipitation channel on the basis of such property. The results presented hear may open up a novel and simple approach for the preparation of composite NPs. PMID- 24758063 TI - One-step solid state reaction to synthesis of hexagonal BN crystals with rod-like morphology. AB - Hexagonal BN crystals have been synthesized from a facile one-step solid state reaction route by sodium tetraphenylborate, hydrazine, zinc powder and sulphur powder as the reactants. The SEM and TEM results showed the BN crystals had the morphology of one-dimensional rod-like shape and with diameters in the range of 100-200 nm and lengths up to several micrometers. Compared with the other reported methods, this route has greatly reduced the reaction temperature. In addition, the growth mechanism of the BN nanorods was discussed in detail. Meanwhile, thermal gravimetric analysis results indicated that the as-prepared BN nanorods have the excellent thermal stability and anti-oxidation properties. PMID- 24758064 TI - Carbon nanotubes altering specificity of repeated PCR and DNA integrity properties. AB - We have investigated the impact of aqueous suspension of single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) on performance of repeated PCR, and discussed their thermal impact on DNA characteristics. Both SWCNTs and MWCNTs are found significantly enhancing the specificity of the repeated PCR and capable of inhibition of long DNA thermal degradation. SWCNTs performed a better specificity in repeated PCR than MWCNTs did. MWCNT-DNA binding was more favorable for protecting long DNA from thermal degradation than SWCNT DNA binding. The results suggested that CNTs are very useful in repeated PCR working on limited amount of DNA resources. PMID- 24758065 TI - Hydrothermal synthesis of nanocrystalline NaX zeolite at room temperature. AB - NaX zeolites were prepared by hydrothermal synthesis under room-temperature conditions. Some influence parameters such as crystallization time, Al2O3/SiO2, Na2O/SiO2 and H2O/SiO2 molar ratios on the crystalline end products were studied, the products were characterized by XRD, SEM, TEM, particle size analysis and N2 adsorption-desorption techniques. The results indicated that although 28 days product was fully crystalline according to the XRD investigation, the crystals were able to continue to grow. The TEM revealed that the samples were composed of highly crystalline NaX zeolite nanocrystals with the average size of around 30 nm. Long crystallization time favored the aggregation of individual nanocrystals, which led to the formation of large congregated agglomerates. Furthermore, mild alkalinity circumstance was favorable for the crystallization of FAU zeolite. However, higher water quantity resulted in the formation of larger steady congregated agglomerates. The samples obtained with H2O/SiO2 molar ratios of 100, 150, 250, 300 and 400 showed the mean particle sizes of 42, 108, 359, 551 and 962 nm, with the particle size distribution ranges of 30-63, 62-140, 215-602, 345-746 and 498-1395 nm, respectively. PMID- 24758066 TI - Impedance and structural studies on plasticized PCL-LiSO3CF3-SiO2 polymer electrolytes. AB - Plasticized polymer electrolytes in this study are consist of biodegradable polycaprolactone (PCL) as a host, ethylene carbonate (EC) as a plasticizer, lithium triflate (LiSO3CF3) as salt and nanocomposite silicon dioxide (SiO2) as filler. Solution cast technique is used in the preparation of the plasticized polymer electrolytes. The electrical properties of the plasticized polymer electrolytes with different composition of lithium salt, plasticizer and nano sized filler are reported in this paper. Conductivity as high as 4.30 x 10(-3) S cm(-1) is obtained in ambient temperature. Ionic conductivity of the plasticized polymer electrolytes are measured using electrochemistry impedance spectroscopy (EIS). The structural and complex formations are studied by X-ray diffraction (XRD) and Fourier Transform Infrared (FTIR) spectroscopy. The ionic conductivity result can be further verified and supported by XRD and FTIR reading in which the ionic conductivity is directly proportional to the amorphous phase behaviour of the sample. PMID- 24758067 TI - Self-assembling of peptides is tuned via an extended amphipathic helix. AB - Four peptides, C1 (spanning the helical segment of human neuropeptide Y from residue 15 to residue 29), C2 (spanning the helical segment of 21 to 31), C3 (the C-terminal fragment of neuropeptide Y involving residues 20 to 36) and P34-C3 (replacement of the glutamine with proline in position 34 of C3) were synthesized to study interaction between species. The information about the intermolecular interactions was extracted from their self-assembly behaviors. The results from CD and NMR showed that the addition of 2,2,2-trifluoroethanol (TFE) induces a stable amphipathic helix in each peptides and an extended helix was formed at the N-terminal of C1 and the C-terminal of C3. Pulsed field gradient NMR data revealed that C3 may undergo an enhanced interaction with TFE and a more favorable self-assembly as temperature was increased. In contrast, other three peptides were found to form larger size of oligomers at lower temperature and continuously dissociate into the monomeric form with increased temperature. Our results demonstrate that the self-assembly behavior may be tuned by the entropy and the energetics contributed by an extended helical conformation at terminus. PMID- 24758068 TI - Annealing effect on structural and optical properties of hydrothermally synthesized TiO2 nanowires. AB - TiO2 nanowires (TiO2 NWs) were successfully synthesized in large amounts through the one step hydrothermal process in 10 M NaOH aqueous solution at 150 degrees C for 15 h followed by annealing at 300-800 degrees C for 2 h. The products were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scan electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM) and high resolution TEM (HRTEM). The optical properties of TiO2 nanowires were characterized using UV-VIS-NIR Spectrophotometers. It was found that the TiO2 nanowires persist in the anatase phase even after annealing at 500 degrees C and that the morphology of the nanowires was maintained. At 800 degrees C, the nanowires transformed into a rod like shapes with a rutile structure. The optical band gap of TiO2 nanowires was found to decrease when the annealing temperature increases. PMID- 24758069 TI - Non-Fourier two-temperature heat conduction model used to analyze ultrashort pulse laser processing of nanoscale metal film. AB - This paper utilizes non-Fourier two-temperature heat conduction model to investigate the temperature field in nanometer-sized thin films irradiated by an ultrashort-pulse laser. Ultrashort-pulse laser processing for nanometer-sized devices is usually applied in MEMS and nanotechnology. For ultrashort-pulse laser interaction with metals, the two-temperature model was proposed to describe the heat transport in metals due to a substantial nonequilibrium between the electron and lattice temperature. For heat conduction in nanoscale devices, Fourier law is inadequate for describing the heat conduction in nanoscale due to the boundary scattering and the finite relaxation time of heat carriers. Therefore, in this work, the Non-Fourier two-temperature heat conduction model used to analyze ultrashort-pulse laser processing of nanoscale metal film. The result obtained from non-Fourier heat conduction equations is compared with the available experimental data. The parametric effects are also discussed. PMID- 24758070 TI - Tunable synthesis of hexagram-shaped hematite iron oxide microcrystals with shape dependent magnetic properties. AB - Uniform hexagram-shaped alpha-Fe2O3 microcrystals with tunable morphologies were fabricated by a facile hydrothermal method followed by annealing in air. The highly anisotropic hexagram-shaped alpha-Fe2O3 particles with the higher coercivity forces and remannent magnetizations showed weak ferromagnetic behaviors at room temperature and displayed the typical shape-dependent magnetic behaviors. PMID- 24758071 TI - Laser induced structural phase transformation of cobalt oxides nanostructures. AB - Face-centered-cubic (fcc) and hexagonal-close-packed (hcp) phases of cobalt monoxide (CoO) nanostructures are prepared using thermolysis route at the same reaction temperature 296 degrees C with synthetic approach conditions. These nanostructures show mixture of nearly spherical and nanoflake morphologies. The structural phases of these nanostructures transform to spinel-Co3O4 by application of heat or Raman excitation laser beam power. The absorbance spectra of fcc and hcp-CoO and Co3O4 nanostructures yield significantly higher values of band gap which can be explained by electron confinement. Such results provide new opportunities for optimizing and enhancing the properties and performance of cobalt oxide nanomaterial. PMID- 24758072 TI - [The significance of introducing registry study in the post-marketing safety research for Chinese medicine and pharmacy]. AB - There is a new research model named 'registry study/patient registry' in Western medicine, which could be referred to by Chinese medicine researchers, such as active safety surveillance. This article will introduce registry study from different aspects as the developing history, features, and application in order to inform Chinese medicine researchers of future studies. PMID- 24758073 TI - [Etanercept combined with Tripterygium wilfordii polyglycoside for treatment of rheumatoid arthritis in the elderly: a clinical study]. AB - OBJECTIVE: To evaluate the efficacy and safety of etanercept plus Tripterygium wilfordii polyglycoside (TWP) in elderly patients with active rheumatoid arthritis (RA). METHODS: Totally 46 elderly patients with active RA were randomly assigned to the treatment group (22 cases) and the control group (24 cases). All patients received subcutaneous injection of etanercept, 25 mg each time, twice per week. The dosage was reduced to once per week 3 months later. Patients in the treatment group took TWP Tablet (10 mg each time, three times per day), while those in the control group took methotrexate (MTX), 10 mg each time, once per week. The whole course lasted for 24 weeks. Patients' rest pain, tender joint number, swollen joint number, health assessment questionnaire (HAQ), patients' global assessment, physicians' global assessment, erythrocyte sediment rate (ESR), C reactive protein (CRP), rheumatic factor were assessed at week 0, 4, 8, 12, and 24. The curative effect was statistically evaluated by the United States Institute of Rheumatology ACR20, ACR50, and ACR70 improvement criteria. Meanwhile, any adverse event was recorded and evaluated. RESULTS: Totally 41 completed the trial, and 5 dropped off (3 in the treatment group and 2 in the control group). Compared with the control group, there was no statistical difference in ACR20, ACR50, or ACR70 in the treatment group (P > 0.05). Compared with before treatment in the same group, there was some improvement in tender joint number, swollen joint number, visual analogue scale (VAS) for patients' global assessment, VAS for physicians' global assessment, ESR, CRP, and HAQ between the two groups, showing statistical difference (P < 0.05). Compared with the control group in the same phase, there was no statistical difference in the treatment group (P > 0.05). There was no statistical difference in the occurrence of adverse events between the two groups. CONCLUSIONS: Etanercept plus TWP could achieve equivalent therapeutic effect to that of Etanercept plus MTX. The two regimens could improve clinical signs, symptoms, and QOL related to RA. They were well tolerated in the treatment of elderly patients with active RA. PMID- 24758074 TI - [Correlation study between interleukin-17 and ESR and CRP in serum and the synovial fluid of rheumatoid arthritis patients of accumulated dampness-heat obstruction in joints syndrome]. AB - OBJECTIVE: To probe the function of interleukin-17 (IL-17) in rheumatoid arthritis (RA) patients of accumulated dampness-heat obstruction in joints syndrome (ADOJS) by detecting levels of IL-17 in serum and the synovial fluid and analyzing its correlation with erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). METHODS: From January 2011 to January 2013, recruited were 90 RA inpatients of ADOJS at Department of Integrative Medical Rheumatism, General Hospital of Chengdu Military Region, of which 28 patients had knee joint effusion. Besides, 30 healthy volunteers who received physical examination at our hospital were recruited as the normal control group, and 30 patients with osteoarthritis (OA) who had knee joint effusion were recruited as the synovial fluid control group. The expression levels of IL-17 in serum and the synovial fluid were detected by enzyme linked immunosorbent assay (ELISA), and contents of ESR and CRP were detected in RA patients. Then correlation analyses were performed between levels of IL-17 and contents of ESR and CRP. RESULTS: Compared with the normal serum control group, the expression levels of IL-17 in serum of RA patients significantly increased (P < 0.05). Compared with the serum of RA patients and the synovial fluid of OA patients, the expression levels of IL-17 in the synovial fluid of RA patients significantly increased (P < 0.05). The expression levels of IL-17 in serum of RA patients were not correlated with ESR or CRP (r = 0.092, -0.082; P > 0.05), and the expressional levels of IL-17 in the synovial fluid of RA patients were not correlated with ESR or CRP (r = 0.113, 0.034; P > 0.05). CONCLUSIONS: IL-17 was the main effector cytokine of Th17 cells. The expressional levels of IL-17 significantly increased in serum and the synovial fluid of RA patients of ADOJS, but with no correlation to ESR or CRP. It indicated that IL-17 participated in the occurrence and development of RA. Concrete mechanisms needed to be further proved in larger samples. PMID- 24758075 TI - [Treatment of rheumatoid arthritis by Yangxue Tongluo Recipe combined with immunosuppressive agents: a clinical observation]. AB - OBJECTIVE: To observe the therapeutic effect of Yangxue Tongluo Recipe (YTR) combined with immunosuppressive agents in the treatment of rheumatoid arthritis (RA). METHODS: Totally 88 RA patients were randomly assigned to the treatment group [47 cases, YTR combined Methotrexate (MTX) + Leflunomide (LEF) treatment] and the control group (41 cases, MTX + LEF therapy). All patients received 12 week treatment. Clinical symptoms and signs, laboratory tests [erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and C reactive protein (CRP)], and adverse reactions were observed before and after treatment. RESULTS: The total effective rate was 91.5% (43/47 cases) in the treatment group, and the total effective rate was 75.6% (31/41 cases) in the control group. There was statistical difference between the two groups (P < 0.05). The morning stiffness, the rest pain, the number of tender joints, the number of swollen joints, tender joint index, swollen joint index, ESR, RF, and CRP were significantly improved in the two groups after treatment (P < 0.01). Besides, clinical symptoms and signs, ESR, RF, and CRP were more improved in the treatment group after treatment, when compared with those in the control group (P < 0.05). Gastrointestinal discomfort was the main adverse reaction in the two groups, but the occurrence was lower in the treatment group than in the control group (P > 0.05). CONCLUSIONS: The clinical efficacy of YTR combined MTX + LEF in the treatment of RA was better than using Western medicine alone. It was more safe with less adverse reactions. PMID- 24758076 TI - [Chinese medical syndromes of rheumatoid arthritis: a clinical literature study]. AB - OBJECTIVE: To explore the distribution features of Chinese medical syndromes of rheumatoid arthritis (RA) by literature retrieval. METHODS: Pertinent articles on treating RA by syndrome differentiation were retrieved from China National Knowledge Infrastructure Databases (CNKI), VIP Chinese Biomedical Journal Database, Guizhou Digital Library, and Duxiu Chinese Academic Periodicals full papers database from January 2000 to December 2011. RESULTS: A total of 33 documents were recruited covering 4 233 cases. Damp-heat blocking collaterals syndrome occupied the top in the occurrence frequency (20 times, 60.61%), followed by deficiency of Gan and Shen syndrome (18 times, 54.55%), intermingled phlegm and blood-stasis syndrome (17 times, 51.52%), wind-cold-damp impediment syndrome (15 times, 45.45%), cold-damp blocking collaterals syndrome (14 times, 42.42%), wind-damp-heat impediment and deficiency of qi and blood syndrome (10 times, 30.30%), and intermingled cold and heat syndrome (9 times, 27.27%). According to the case number of patients, it was sequenced as damp-heat blocking collaterals syndrome syndrome (768 cases, 18.14%), wind-damp-heat impediment syndrome(666 cases, 15.73%), wind-cold-damp impediment syndrome(584 cases, 13.80%), cold-damp blocking collaterals syndrome syndrome (517 cases, 12.21%), intermingled cold and heat syndrome (415 cases, 9.80%), intermingled phlegm and blood-stasis syndrome (364 cases, 8.60%), deficiency of Gan and Shen syndrome (235 cases, 5.55%),asthenia of healthy energy due to lingering arthralgia syndrome (223 cases, 5.27%). The case numbers of remaining syndromes did not exceed 5%. CONCLUSION: Damp-heat blocking collaterals syndrome was the main syndrome in RA patients, followed by wind-cold-damp impediment syndrome,wind-damp heat impediment syndrome,cold-damp blocking collaterals syndrome,intermingled phlegm and blood-stasis syndrome, and deficiency of Gan and Shen syndrome. PMID- 24758077 TI - [Effect of catgut implantation at acupoint on the content of tumor necrosis factor alpha of patients with ankylosing spondylitis]. AB - OBJECTIVE: To observe the effect of catgut implantation at acupoint on the content of tumor necrosis factor alpha (TNF-alpha), and to explore its mechanism for treatment of ankylosing spondylitis (AS). METHODS: Seventy-four AS patients were randomly assigned to the observation group and the control group by digit random table, 37 in each group. Patients in the control group took Sulfasalazine Enteric-coated Tablet (SECT), 0.5 g each time, three times daily for 3 months. Those in the observation group additionally received catgut implantation at acupoint for 3 months. Changes of visual analogue scale (VAS), Schober test, pillow wall distance, thoracic activity, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and TNF-alpha were compared after 3 months of treatment. RESULTS: There was obvious change in VAS, Schober test, pillow wall distance, thoracic activity, ESR, CRP, and TNF-alpha after treatment in the both groups, showing statistical difference when compared with before treatment (P < 0.05, P < 0.01). The aforesaid indices were obviously improved after treatment in the observation group (P < 0.05, P < 0.01). CONCLUSION: Catgut implantation at acupoint, as an assistant therapy, could significantly improve clinical symptoms and signs, decrease the level of TNF-alpha, and its effect was superior to that of oral SECT administration alone. PMID- 24758078 TI - [Ginkgo leaves tablet improved the memory quotient of patients with mild cognitive impairment: a clinical observation]. AB - OBJECTIVE: To observe the effect of Ginkgo Leaves Tablet (GLT) on memory quotient (MQ) of mild cognitive impairment (MCI) patients. METHODS: One hundred and thirteen patients were randomly assigned to the control group (55 cases) and the treatment group (58 cases). Patients in the control group received dietetic therapy and physical exercises, while those in the treatment group additionally took GLT, 19.2 mg each time, three times daily. The treatment course was 12 months for all. The MQ of all the patients was assessed by WMS-RC before treatment,at 6-month of treatment, and 12-month of treatment. RESULTS: Compared with the control group, the improvement of MQ increased in the treatment group 0.5 and 1 year after treatment (P < 0.05). The clinical efficiency of MQ obviously increased in the treatment group (48.28% and 50.00%), showing statistical difference when compared with the control group (30.91% and 27.27%, P < 0.05, P < 0.01). There was statistical difference in added scores of recognition, regeneration, understanding, and recitation test at 6-month of treatment and 12-month of treatment between the treatment group and the control group (P < 0.05, P < 0.01). CONCLUSION: GLT was effective in improving MQ of MCI patients, especially in improving recognition, regeneration, understanding, and recitation test. PMID- 24758079 TI - [Effect of Busheng Huoxue Capsule on the quality of life of primary osteoporosis senile males]. AB - OBJECTIVE: To investigate the effect of Busheng Huoxue Capsule (BHC) on the quality of life (QOL) in senile male osteoporosis (OP) patients, and to explore its mechanisms. METHODS: Totally 200 senile primary OP patients were randomly assigned to two groups according to random digit table method, 100 in each group. Patients in the treatment group took BHC plus caltrate-D (600 mg CaCO3), while those in the control group took alendronate (70 mg per week) plus caltrate-D. The therapeutic course was 12 months for all. Chinese medical symptom score and quality of life (QUALEFFO-41) score, bone mineral density (BMD) of lumbar vertebra (L2 -L4) and left femoral neck were compared between the two groups before and after treatment. Serum free testosterone (FT) and estradiol (E2) were also measured. RESULTS: Chinese medical symptom scores and QUALEFFO-41 scores, serum FT and E2 levels increased in the two groups after treatment (P < 0.05, P < 0.01). The therapeutic effect was superior in the treatment group (P < 0.05, P < 0.01). After treatment the BMD of lumbar vertebra (L2 -L4) and the left femoral neck were somewhat improved (P < 0.05), but with no statistical difference between the two groups (P > 0.05). CONCLUSION: BHC could effectively improve the QOL of senile male OP patients, which might be correlated with elevating the BMD levels and regulating the levels of sex hormones. PMID- 24758080 TI - [C825T polymorphism of G protein beta3 subunit gene and Uygur Hilit type of essential hypertension: a correlation study]. AB - OBJECTIVE: To explore the association between C825T polymorphism of G protein beta3 subunit (GNB3) gene and different Hilit types of essential hypertension (EH) in the Uygur nationality of Xinjiang. METHODS: According to Uygur medical theories, EH patients (as the EH group) and non-EH patients (as the control group) were assigned to four Hilit groups. The C825T polymorphism of GNB3 was detected in 161 EH patients and 379 non-EH subjects of different Hilit types by using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) to explore the difference of the genotypes and allelic frequencies and hypertension. RESULTS: (1) In Xinjiang Uygur population, the distribution frequencies of GNB3 C825T polymorphism were in accordance with Hardy-Weinberg (chi2 = 0.871, P = 0.647). (2) There was no statistical difference in the distribution frequencies of three genotypes and two alleles of GNB3 between the EH group and the control group (P > 0.05). (3) There was statistical difference in distribution frequencies of three genotypes between the abnormal Sapra and non abnormal Sapra group (the sum of abnormal Sewda, abnormal Kan, and abnormal Balhem) (chi2 = 6.905, P = 0.032), especially between the abnormal Sapra and abnormal Balhem groups (chi2 = 10.404, P = 0.006), but there was no statistical difference in distribution frequencies of alleles between the two groups (P > 0.05). (4) In 161 EH patients, there was statistical difference in the distribution frequencies of three genotypes and two alleles between the abnormal Sapra and non-abnormal Sapra group (chi2 = 9.034, P = 0.011; chi2 = 4.701, P = 0.03). CONCLUSIONS: Both TT genotype and T allele of GNB3 C825T polymorphism might not be associated with EH patients in Xinjiang Uygur populations. However, they were correlated with hypertension patients of non-abnormal Sapra, indicating the pathogeneses of EH with different Hilit types might be different. PMID- 24758081 TI - [Effect of Chinese drugs for activating blood circulation and removing blood stasis on carotid atherosclerosis and ischemic cerebrovascular events]. AB - OBJECTIVE: To explore the effect of Chinese drugs for activating blood circulation and removing blood stasis (CDABCRBS) on carotid atherosclerotic plaque and long-term ischemic cerebrovascular events. METHODS: By using open and control method, effect of 4 groups of platelet antagonists, platelet antagonists + CDABCRBS, platelet antagonists +atorvastatin, platelet antagonists +atorvastatin +CDABCRBS on carotid atherosclerotic plaque and long-term ischemic cerebrovascular events of 90 cerebral infarction patients were analyzed. RESULTS: Through survival analysis, there was no statistical difference in the effect of the 4 interventions on the variation of carotid stenosis rates or ischemic cerebrovascular events (P > 0.05). The occurrence of ischemic cerebrovascular events could be postponed by about 4 months in those treated with platelet antagonists + CDABCRBS and platelet antagonists + atorvastatin +CDABCRBS. By multivariate Logistic analysis, age, hypertension, and clopidogrel were associated with stenosis of extracranial carotid arteries (P <0.05). Age, diabetes, aspirin, clopidogrel, CDABCRBS were correlated with cerebrovascular accidents (P < 0.05). CONCLUSIONS: Whether or not accompanied with hypertension is an influential factor for carotid stenosis, but it does not affect the occurrence of ischemic cerebrovascular events. CDABCRBS could effectively prolong the occurrence time of ischemic cerebrovascular events. PMID- 24758083 TI - [Effect of Yangjing Zhongyu Decoction on mRNA and protein expression of PCNA, StAR, and FSHR in ovarian granulosa cells cultured by excess androgen]. AB - OBJECTIVE: To observe the effect of Yangjing Zhongyu Decoction (YZD) on mRNA and protein expression of PCNA, StAR, and FSHR in ovarian granulose cells (GCs) cultured by excess androgen. METHODS: Ovarian GCs from porcine follicles were isolated and cultured in vitro. Follicular stimulating hormone (FSH) or YZD was added in the GCs treated by excess testosterone propionate. Totally 48 h later mRNA and protein expression of PCNA, StAR, and FSHR were detected by RT-PCR and Western blot. RESULTS: Excess androgen inhibited mRNA and protein expression of PCNA, StAR, and FSHR of GCs. FSH and YZD could antagonize inhibition of excess androgens, and promote mRNA and protein expression of PCNA, StAR, and FSHR in GCs. CONCLUSION: YZD could antagonize the inhibition of excess androgen on mRNA and protein expression of PCNA, StAR and FSHR in GCs. Thus, we inferred that YZD could improve the follicle dysplasia by promoting mRNA and protein expression of PCNA, StAR and FSHR in GCs. PMID- 24758082 TI - [Research on syndrome distribution features, etiologies, and pathogeneses of Japanese encephalitis]. AB - OBJECTIVE: To explore Chinese medical syndrome distribution features of Japanese encephalitis (JE), and to analyze its correlation between syndromes and features of etiologies and pathogeneses. METHODS: Recruited were 277 patients with confirmative diagnosis of JE from Wuhan Medical Treatment Center, Children's Hospital Affiliated to Chongqing Medical University, Fifth People's Hospital of Guiyang City, Hangzhou Sixth People's Hospital, and Chengdu Hospital of Infectious Diseases between July to September 2012. Chinese medical syndrome distribution features were summarized from their general materials and detailed records of clinical data, including medical history, symptoms and signs, tongue fur, and pulse figures.The frequency of symptoms and signs was calculated according to mild, ordinary, severe, extreme severe degrees. The distribution of Chinese medical syndromes was summarized. And its correlation between syndromes and features of etiologies and pathogeneses were analyzed. RESULTS: After clustering analysis, Chinese medical syndromes of JE could be categorized as four groups: toxicity accumulation in Fei and Wei syndrome (TAFWS), brain collateral impaired by poison syndrome (BCIPS), depression of toxicity in the pericardium syndrome (DTPS), exhaustion of yin and yang syndrome (EYYS). BCIPS and DTPS were dominated, accounting for 74.0% (205 cases). The main causes covered evil of summer heat [accounting for 92.42% (256/277 cases)], heat [accounting for 87.73% (243/277 cases)], and toxin [accounting for 99.64% (276/277 cases)]. CONCLUSIONS: The four Chinese medical syndrome types of JE met Chinese medical clinical features of encephalitis. It is induced by infestation of dampness-heat, resulting in toxicity accumulation in Fei and Wei, brain collateral impaired by poison, depression of toxicity in the pericardium. Yin fluid and blood is exhausted as time goes by. Qi and yin are impaired to form intermingled deficiency and excess, and finally causing exhaustion of yin and yang. PMID- 24758084 TI - [Effect of Bushen Tiaojing Recipe containing serum on FSH/cAMP-PKA pathway in in vitro cultured human ovarian granular cells]. AB - OBJECTIVE: To explore the potential molecular mechanisms for Bushen Tiaojing Recipe (BTR) improving the endocrine function of ovarian granular cells by observing the effect of BTR containing serum on follicle stimulating hormone/cyclic adenosine monophosphate-protein kinase A (FSH/ cAMP-PKA) pathway in in vitro cultured human ovarian granular cells. METHODS: The primary ovarian granular cells collected from in vitro fertilization-embryo transfer patients were cultured for 24 h. The human and rat serum containing different concentrations of BTR (low, medium, high dose), and their normal serums were co incubated with ovarian granular cells for 48 h respectively, and then they were divided into the low, medium, high dose BTR groups and the control group. The levels of estradiol (E2), progesterone (P), and cyclic adenosine monophosphate (cAMP) in the culture medium were measured by radioimmunoassay. The protein expression of FSHR in ovarian granular cells was detected by Western Blot. The mRNA expression of follicle stimulating hormone receptor (FSHR) and P450 aromatase (P450arom) in ovarian granular cells were detected by Real-time PCR. RESULTS: In human BTR containing serum groups: Compared with control group, the levels of E2 and cAMP in the culture medium were higher (both P < 0.05) in the medium and high dose BTR groups; the levels of P in the culture medium decreased in the medium dose BTR group (P < 0.01). The protein and mRNA expression of FSHR in ovarian granular cells increased (all P < 0.01), the mRNA expressions of P450arom in ovarian granular cells were higher (P < 0.05, P< 0.01) in the medium and high dose BTR groups. In rat BTR containing serum groups: Compared with the control group, the levels of E2 in the culture medium were higher (all P < 0.01), cAMP in the culture medium were higher (P < 0.05, P < 0.01) in the medium and high dose BTR group; the levels of P in the culture medium decreased in the medium dose BTR group (P < 0.01). The protein and mRNA expression of FSHR in ovarian granular cells were higher (all P < 0.01), the mRNA expression of P450arom in ovarian granular cells increased in the medium and high dose BTR groups (P < 0.05, P < 0.01). CONCLUSION: BTR could possibly improve the endocrine function of ovarian granular cells by regulating main effector molecules FSHR, cAMP, P450arom, and E2 in FSH/cAMP-PKA pathway of ovarian granular cells. PMID- 24758085 TI - [Mechanisms of yanshu injection for overcoming multidrug resistance in breast carcinoma MCF-7 cells: an experimental research]. AB - OBJECTIVE: To investigate the mechanism of Yanshu Injection (YI) for overcoming multidrug resistance in breast carcinoma MCF-7 cells. METHODS: Human breast carcinoma MCF-7 cells and doxorubicin-resistant MCF-7/DOX cells were treated with YI. Its inhibition on the cell proliferation was detected by MTT assay. The fluorescence intensity of doxorubicin was detected by flow cytometry. The expression of apoptosis related protein and P-glycoprotein were examined by immunoblotting after treated by YI. RESULTS: The inhibitory action of YI on MCF 7/DOX cells was similar to that of MCF-7 cells, indicating no cross resistance (P > 0.05). 1/16 YI could obviously induce the apoptosis of MCF-7 cells and DOX cells. 1/256 YI +5 nmol/L doxorubicin and 1/128 YI +5 nmol/L doxorubicin could reduce the survival rate of MCF-7/ DOX resistant cells from 86.8% to 74.6% (P < 0.05) and 71.6% (P < 0.01) respectively, showing obvious synergistic effect. Besides, the accumulation of doxorubicin was increased after treated by YI in the MCF-7/ DOX cells. Results of immunoblotting indicated that reduction of P glycoprotein expression was detected in MCF-7/DOX cells after exposure to YI. CONCLUSION: YI could overcome the multidrug resistance in breast carcinoma MCF-7 cells possibly through reducing the expression of P-glycoprotein. PMID- 24758086 TI - [Effect of Actinidia chinensis planch polysaccharide on the growth and apoptosis, and p-p38 expression in human gastric cancer SGC-7901 cells]. AB - OBJECTIVE: To investigate the effect of Actinidia chinensis Planch polysaccharide (ACPS) on the growth and apoptosis of human gastric cancer SGC-7901 cells, and to explore the effect of SGC-7901 cells on p-p38 expression. METHODS: The inhibition rates at different concentrations of ACPS on SGC-7901 cells at 24, 48, and 72 h were detected using CCK-8 method. Apoptosis ratios in SGC-7901 were determined by flow cytometry after 48-h treatment of different concentrations of ACPS. The expression of pro-caspase-9, PARP, and p-p38 in SGC-7901 cells after treated by different concentrations of ACPS was detected using Western blot. The expression of pro-caspase-9, PARP, and p-p38 was detected after SGC-7901 cells were pre treated by p38 specific inhibitor. RESULTS: Compared with the control group, the optical density of SGC-7901 cells decreased after treated by 1, 2.5, 5, and 10 mg/mL ACPS (P < 0.05). Meanwhile, the longer the acting time, the lower the optic density (P < 0.01). IC50 was 7.43 mg/mL at 24 h; 3.88 mg/mL at 48 h, and 1.32 mg/mL at 72 h respectively. ACPS suppressed the protein expression of pro-caspase 9 (P < 0.01) and up-regulated the expression of PARP (89KD) (both P < 0.01). Further study showed that the protein expression of p-p38 was up-regulated in SGC 7901 cells treated by ACPS of different concentrations at 24 h (P < 0.05). The expression of phosphorylation p38 and the ACPS induced apoptosis of SGC-7901 cells could be inhibited after treated by specific inhibitor for 2 h. CONCLUSIONS: ACPS could inhibit the growth of SGC-7901 cells and induce apoptosis. The underlying mechanism of inducing apoptosis was partially due to activating the p38MAPK path and further activating Caspase9 and PARP, finally leading to cell death. PMID- 24758087 TI - [Effect of electric acupuncture on the expression of NgR in the cerebral cortex, the medulla oblongata, and the spinal cord of hypertensive rats after cerebral infarction]. AB - OBJECTIVE: To observe the effect of electric acupuncture (EA) on the Nogo receptors (NgR) protein expression in the cerebral cortex, the medulla oblongata, and the spinal cord of cerebral ischemia-reperfusion (I/R) stroke-prone renovascular hypertensive rats (RHRSP) with middle cerebral artery occlusion (MCAO) at different time points, and to investigate its possible mechanisms for remote-organ injury of acute cerebral infarction (ACI). METHODS: The RHRSP model was duplicated in male SPF grade SD rats. Then the MCAO model was prepared by a thread stringing method. Rats were divided into the hypertension group,the sham operation group, the MCAO group, the EA group, and the sham-acupoint group by random number table method, 60 in each group. Rats in the MCAO group only received MCAO reperfusion treatment. Those in the sham-operation group only received surgical trauma. Baihui (DU20) and Dazhui (DU14) were needled in the EA group, once daily for a total of 28 days.The needles were acupunctured at the skin one cun distant from Baihui (DU20) and Dazhui (DU14) and then the same EA treatment was performed in the sham-acupoint group. At day 1, 7, 14, 28 after treatment, six rats were executed from each group, and their right cortex and medulla oblongata, and the left spinal cord were isolated. The infarct volume was detected by Nissl's staining method. The NgR expression was detect by Western blot. RESULTS: (1) In the cortex area: compared with the hypertension group,the NgR expression increased in the MCAO group at day 1,7,14,and 28 after MCAO (P < 0.05). Compared with the MCAO group, the NgR expression of the EA group and the sham-acupoint group were equivalent at 1 day af ter MCAO (P > 0.05). At day 7, 14,and 28 after MCAO, the NgR expression decreased in the EA group (P < 0.05), it was quite similar to that in the sham-acupoint group (P > 0.05). (2) In the medulla oblongata area: compared with the hypertension group, the NgR expression was equivalent in the sham-operation group. the MCAO group,the EA group, and the sham-acupoint group at 1 day after MCAO (P > 0.05). At day 7.14, and 28 after MCAO, the NgR expression increased in the MCAO group (P < 0.05). Compared with the MCAO group,the NgR expression decreased in the EA group at day 7, 14, and 28 after MCAO (P < 0.05), whereas it was similar in the sham-acupoint group (P > 0.05). (3) In the spinal cord area: compared with the hypertension group, the NgR expression was equivalent in the sham-operation group, the MCAO group,the EA group, and the sham-acupoint group at day 1 and 7 after MCAO (P > 0.05). At day 14 and 28 after MCAO, the NgR expression increased in the MCAO group (P < 0.05). Compared with the MCAO group, the NgR expression decreased in the EA group at day 14 and 28 after MCAO (P < 0.05), whereas it was equivalent in the sham-acupoint group (P > 0.05). CONCLUSIONS: Increased NgR expression in the cerebral cortex, the medulla oblongata, and the spinal cord of cerebral infarct rats was an important reason for involving remote-organ injury of ACI. The protective effect of EA on hypertensive I/R cerebral injury rats might be closely related to down regulating central nervous system myelin growth inhibition mediated factors Nogo A receptor NgR protein expression. PMID- 24758088 TI - [Effect of Buyang Huanwu Decoction and its disassembled recipes on rats' neurogenesis after focal cerebral ischemia]. AB - OBJECTIVE: To explore the effect of Buyang Huanwu Decoction (BYHWD) and its disassembled recipes on rats' neurogenesis after focal cerebral ischemia and to investigate its underlying molecular mechanisms. METHODS: Focal cerebral ischemia model was induced by occlusion of the right middle cerebral artery for 90 min using the intraluminal filament model. Rats were divided into the sham-operation group, the model group, the BYHWD group, the qi supplementing group, and the blood activating group. Medication was performed by gastrogavage 24 h after ischemia for 14 successive days. 5-bromodeoxyuridine (BrdU) (at 50 mg/kg) was intraperitoneally injected, once per day for 14 successive days. The neurological function was assessed using modified neurological severity score (mNSS) and the corner test at day 1, 7, and 14 after ischemia. BrdU/Nestin, BrdU/NeuN, and BrdU/GFAP positive cells were examined by double immunofluorescence at day 14 after ischemia. The protein expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were detected by Western blot at day 14 after ischemia. RESULTS: Compared with the model group, the score of mNSS and the frequency of turning right significantly decreased in the BYHWD group and the qi supplementing group (P < 0.01), the number of BrdU/Nestin in the subventricular zone of the lateral ventricle, and BrdU/ NeuN and BrdU/GFAP positive cells in the peripheral ischemic cortex increased (P < 0.05, P < 0.01), protein expression of BDNF and VEGF increased (P < 0.05, P < 0.01). In the qi supplementing group, there was no statistical difference in BrdU/GFAP. But there was no statistical difference in each index of the blood activating group (P > 0.05). Compared with BYHWD group, the number of BrdU/Nestin, BrdU/ NeuN, and BrdU/GFAP positive cells significantly decreased (P < 0.01), and the protein expression of BDNF and VEGF were significantly reduced in the qi supplementing group and the blood activating group (P < 0.01). CONCLUSIONS: BYHWD could significantly improve neurogenesis and neurological function recovery after focal cerebral ischemia in rats. Its mechanisms might be related to up-regulating protein expression of BDNF and VEGF. Drugs for qi supplementing and drugs for blood activating had synergistic effects. PMID- 24758089 TI - [Effect of Yiguan Decoction on differentiation of bone marrow mesenchymal stem cells into hepatocyte-like cells: an experimental research]. AB - OBJECTIVE: To observe the effect of Yiguan Decoction (YGD) on differentiation of bone marrow mesenchymal stem cells (BMSCs) into hepatocyte-like cells in vitro. METHODS: Rat BMSCs were isolated using whole bone marrow adherent method. The properties of BMSCs were identified by analyzing the expression of surface cytokines by flow cytometry. The third passage cells were differentiated into fat cells to identify their features. BMSCs were incubated with hepatocyte growth factor (HGF) plus fibroblast growth factor 4 (FGF4) or YGD containing serum YGD for 21 days. The mRNA expression of alpha-fetoprotein (alphaAFP), albumin (Alb), and hepatocyte nuclear factor 4alpha (HNF4alpha) were detected by real time PCR. Expression of AFP and cytokeratin 18 (CK18) protein was detected by cell immunofluorescence. Glycogen synthesis was observed using periodic acid-Schiff stain (PAS). CK18, Wnt 3alpha, and alphacatenin protein expressions were detected by Western blot. RESULTS: High expression of CD90, CD29, and CD44, and low expression of CD34 and CD11b were observed in BMSCs isolated by whole bone mar- row adherent method, and numerous lipid droplets were observed in BMSCs using oil red O staining. Both YGD containing serum and growth factor stimulated the expression levels of Alb, AFP, HNF4alpha mRNA and CK18 protein. The down regulated expression of Wnt 3alpha and beta-catenin could be detected at 21 days after induction. The synthesized glycogen granule could be seen. Down-regulated Wnt 3alpha and beta-catenin expression could also be observed. CONCLUSION: YGD could induce the differentiation of rat BMSCs into hepatocyte-like cells, which was related to down-regulating Wnt/beta-catenin signal pathway. PMID- 24758090 TI - [Effect of aerospace weightlessness on cognitive functions and the relative dialectical analysis of Chinese medicine]. AB - Aerospace medicine has paid more and more attention to abnormal changes of physiological functions induced by weightlessness and studies on their prevention during space flight. In this paper, the effect of space weightlessness on cognitive functions was introduced. We tried to analyze the correlation between the cognitive function changes and relevant Chinese medical syndromes, thus providing a potential available way to prevent and treat weightlessness induced cognitive deficit during space flight. PMID- 24758091 TI - [Progress of experimental research on treating Alzheimer's disease by acupuncture]. AB - To discuss the pathogenesis of Alzheimer's disease (AD), we summarized the mechanisms of treating AD animal models by acupuncture from literatures in recent years as follows. Senile dementia rats' cognitive capabilities and memory could be improved by reduction of beta-amyloid protein, attenuation of excessive phosphorylation of tau protein, regulation of center neurotransmitter dysmetabolism, oxidation of anti-free radicals, reduction of neuron apoptosis in the cortex and the hippocampus, inhibition of glial cells' differentiation, adjustment of G protein signaling transduction, and improvement of the mitochondrial dysfunction, thus providing experimental evidence for treating AD by acupuncture. PMID- 24758092 TI - [The particularity of female coronary heart disease and the thinking way of its diagnosis and treatment by integrative medicine]. AB - Coronary heart disease (CHD) is a major disease greatly harmful to the health of human beings. The incidence and case fatality rate of female CHD show an increasing tendency due to lack of enough attention. Through analyzing the epidemiology, risk factors, and clinical characteristics of female CHD, we emphasized that it is necessary to pay enough attention to the particularity of female CHD, and put forward the thinking way of diagnosis and treatment of integrative medicine as "integrating Chinese medicine and Western medicine by mutual complement of advantages; combining syndrome typing and disease identification by grasping laws; treating physically and mentally by a wholism concept; spreading health education, preventing and treating comprehensively". PMID- 24758093 TI - [Progress of Chinese materia medica research model on inflammation of the central nervous system]. PMID- 24758094 TI - [Chinese materia medica monomers and components research progress on treating Alzheimer's disease by targeting gamma-secretase]. PMID- 24758095 TI - [Antibiotics induced renal injury and research progress of treatment by integrative medicine]. PMID- 24758096 TI - [Increasing difficulties for scientific publication in Venezuela]. AB - A very important increase in the costs of the edition of scientific journals has taken place in Venezuela, due to difficulties in obtaining imported free acid paper and other materials used for handling documents. Like other journals, Investigaci6n Clinica has been considering switching completely to a digital publication format; however there are several reasons that prevent us to doing it at this time: the journal is distributed in printed form to many national institutions, which do not have immediate access to digital information. In addition, there exists a commitment of shipment of printed issues for some international indices and in exchange with other national and foreign journals, whose printed format we receive. Another important aspect is that our University maintains a weak technological platform that makes difficult the immediacy required for the interchange with authors and consulted referees of received papers; and there is a latent danger of limitations in the use of digital technologies, due to current national politic problems. Consequently, we need to continue with the printed format, but must reduce the amount of printed issues, so as not to limit the number of papers published in each edition. Nevertheless, there is an ever increasing number of contributions from foreign researches and Investigaci6n Clinica has been recently included in two new international indices, the SEIIC from Argentina and the Infobase Index from India, reasons that obligate us to maintain our levels of excellence and commitment to our authors and readers. PMID- 24758097 TI - [Hepatic steatosis, visceral fat and metabolic alterations in apparently healthy overweight/obese individuals]. AB - Clinical observation indicates that many obese individuals do not display important metabolic alterations. Consequently, the objective of this study was to establish whether simple obesity, non concurrent with other important risk factors, was associated with metabolic alterations; or if the phenomenon known as "obesity paradox" was present. A clinical history, measurements of anthropometric and metabolic parameters and estimation of hepatic steatosis and visceral fat, were determined in 30, apparently healthy, individuals from Maracaibo, Venezuela, between 20 and 59 years of age and a body mass index (BMI) above 25 kg/m2, and compared to a lean control group of 11 individuals with BMI less than 25 kg/m2. The study demonstrated that only one third of overweight/obese individuals (OW/OB), with high body mass index (BMI) and waist circumference (WC), presented elevated values of insulin, HOMA-IR and triglycerides. Nevertheless, the presence of hepatic steatosis was elevated in the OW/OB group (91%) vs. 9% in the control group. The visceral fat in the lean control group was associated with both, WC and glycemia; however, it was not related to the BMI or insulin, HOMA-IR and HDLc. The visceral fat in the OW/OB group, although elevated in relation to the lean group, revealed a loss of these associations. In the OW/OB it was the BMI that was associated with insulin and HOMA-IR. The results emphasize the importance of investigating for the presence of hepatic steatosis, rather than visceral fat, in individuals with OW/OB, to identify subjects with high cardiometabolic risk. PMID- 24758098 TI - [Methotrexate as inducer of proinflammatory cytokines by epithelial cells]. AB - Methotrexate (MTX), a drug commonly used in childhood cancer, has also been indicated as a cytotoxic agent of the oral mucosa, which can trigger the inflammatory process and increase the vascularity of epithelial tissues during the early stages of oral mucositis. The aim of this study was to determine the production of proinflammatory cytokines IL-1beta, IL-6 y TNF-alpha in epithelial cell cultures treated with MTX. Epithelial cells of human larynx, obtained from the cell line Hep-2, were cultured with different doses of MTX during different incubation times. The drug cytotoxicity was analyzed by means of the colorimetric test, which is based on the metabolic reduction of the bromide of 3-(4, 5 dimetiltiazol-2-ilo)-2,5-difeniltetrazol (MTT); and the proinflammatory cytokines production by the test enzyme-linked immunosorbent assay (ELISA). Cultures of HEp 2 cells showed increased production of proinflammatory cytokines at 72 hours with 0.32 microM of MTX. These results suggest that depending on the dose and exposure time, MTX alters the physiology of human epithelial cells, which may play an important role during the phases of initiation and development of oral mucositis. PMID- 24758099 TI - Genetic variations of beta-MYH7 in Venezuelan patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a cardiac disease, characterized by marked hypertrophy and genetic variability. HCM has been associated with sarcomere protein mutations, being cardiac beta-myosin (coded by the MYH7 gene) and myosin binding protein C (coded by the MYBPC3 gene) the most frequently affected proteins. As in Venezuela only the clinical analysis are performed in HCM patients, we decided to search for genetic variations in the MYH7 gene. Coding regions, including the junction exon-intron of the MYH7 gene, were studied in 58 HCM patients, whose samples were collected at the ASCARDIO Hospital (Barquisimeto, Lara state, Venezuela) and 106 control subjects from the ASCARDIO Hospital and the IVIC (Barquisimeto Lara state and Miranda, Venezuela, respectively). The blood samples were analyzed by genomic DNA isolation, followed by polymerase chain reaction and sequence analysis. The screening of the MYH7 gene revealed eight already reported polymorphic variants, as well as two intronic variations in these HCM patients. Neither any missense mutations nor other pathological mutations in the MYH7 gene were found in the HCM patients. PMID- 24758100 TI - [Prevalence of beta-lactamase CTX-M-15 in phylogenetic groups of uropathogenic Escherichia coli isolated from patients in the community of Merida, Venezuela]. AB - In this study we determined the prevalence of extended-spectrum beta-lactamases (ESBLs) in phylogenetic groups of uropathogenic E. coli (UPEC) isolated from patients in the community. Twenty one UPEC strains with reduced susceptibility to broad-spectrum cephalosporins were collected between January 2009 and July 2010, from patients with urinary tract infection who attended the Public Health Laboratory in Merida, Venezuela. Genotypic characterization determined that all UPEC strains harbored blaBLEEs genes: 76.2% of the strains showed the presence of a single ESBL-producer gene, represented by blaCTX-M-15, whereas 23.8% of UPEC showed various combinations of bla genes (blacCTX-M-15 + blaTEM-1, blaCTX-M-15 + blaSHV and blaSHV + blaTEM-1). In this study, 61.9% of the isolates were placed in phylogroup A and the remaining strains were assigned to group B2 (38.1%). There was no evidence of spread of a particular UPEC clone; only seven strains belonged to a clonal group with an index of similarity greater than 85%. To our knowledge, this is the first description of blxCTX-M-15 in UPEC from patients with community-acquired urinary tract infections, which shows that Venezuela is also part of the so-called CTX-M-15 pandemic. The findings in this study, as well as its clinical and epidemiological implications, lead to the need for monitoring and controlling the spread of CTX-M-15 producing UPECs, not only regionally, but also nationwide. PMID- 24758101 TI - Frequency of common CFTR gene mutations in Venezuelan patients with cystic fibrosis. AB - Mutations in the CFTR gene in Cystic Fibrosis (CF) patients have geographic differences and there is scant data on their prevalence in Venezuelan patients. This study determined the frequency of common CFTR gene mutations in these patients. We amplified and sequenced exons 7, 10, 11, 19, 20 and 21, which contain the most common CFTR mutations, from 105 Venezuelan patients in the National CF Program. Eleven different mutations were identified, four with frequencies greater than 1%: p.Phe508del (26,17%), p.Gly542X (3,33%), p.Arg334Trp (1,43%) and p.Arg1162X (1.43%). No mutations were found in 63.3% of patients. This report represents the largest group of Venezuelan CF patients ever examined and includes a wider mutation panel than has been previously studied in this population. Southern European CFTR mutations predominate in the Venezuelan population, but a high percentage of the causative alleles remain unidentified. PMID- 24758102 TI - [Exudative onycholysis and acute bacterial paronychia related to BIBF-1120 and paclitaxel: response to topical therapy]. AB - A case of a 50 years-old breast cancer patient treated with weekly paclitaxel and BIBF 1120 is reported herein. At the end of the twelfth cycle of chemotherapy, the patient developed distal onycholysis with intense hyponychium serous exudates, pain and malodor in all her fingernails. It was treated with topical fusidic acid and 1% methylprednisolone aceponate two times daily, with an excellent clinical response from the first three days of treatment. Bacterial paronychia with nail plate loss of the fifth left fingernail was observed a week after the topical therapy was started, with positive cultures for Methicillin susceptible Staphylococcus aureus. There are few reported cases of exudative onycholysis associated with chemotherapy. However, these are especially related to paclitaxel. No recurrences of nail disturbances were observed weeks after the end of chemotherapy. Topical corticosteroids and fusidic acid could be considered as a therapeutic option when exudative onycholysis related to paclitaxel is established PMID- 24758103 TI - [Role of toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) in viral infections]. AB - The immune system (IS) cells are capable of recognizing a wide variety of microorganisms, through receptors that are expressed and distributed throughout the cell architecture. The interaction between the pathogen-associated molecular patterns or damage-associated molecular patterns (PAMPs or DAMPs) and pattern recognition receptors (PRR), present in host cells, is a critical event that involves intracellular signaling processes that end up in the expression of both, proinflammatory and antiviral mediators. Accordingly, the proper functioning of the different mechanisms of signal transduction from the cell membrane to the cytoplasm will depend on the integrity of these receptors (PRR); and therefore, the IS response triggered against pathogens including viral agents. Hence, in this review we discuss the role of toll-like receptors (TLRs) and nucleotide binding oligomerization domain receptors (NLRs) in viral infections, using as evidence the studies in humans and mice known to date. PMID- 24758104 TI - [Natural history of the infection for human papillomavirus: an actualization]. AB - In recent years, there have been major advances in our understanding of the biology and natural history of Human Papilloma Virus (HPV). Most papillomavirus infections are transmitted by close contact of either skin to skin or mucosa to mucosa. Sexual intercourse is not a requirement for genital HPV infection. Digital-oral infections occur and there is evidence that digital-genital and oral genital contacts can result in the transmission of HPV, although in a relatively low percentage. Vertical transmission from mother to fetus is a common route of infection; in fact, it is recognized that more than 80% of infants born from mothers infected with genital HPV will be positive for HPV DNA determination in the nasal-pharyngeal region and oral mucosa. Women with transient infections often develop cytological abnormalities that take place while there is active HPV replication. This occurs because productive HPV infections result in cytological abnormalities in infected epithelial cells. The strong association between the risk of HPV infection and increased immune suppression, supports a direct biological effect of Human Immunodeficiency Virus (HIV) infection on the natural history of HPV. PMID- 24758105 TI - [The intestinal parasitic diseases as a global health problem]. PMID- 24758106 TI - Characterization of a low pathogenic avian influenza H5N2 virus isolated from a turkey breeder flock in Manitoba, Canada. AB - In November 2010, an outbreak of avian influenza (AI) due to the H5N2 subtype virus occurred in a turkey breeder farm in northern Manitoba, Canada. The only clinical signs observed were depression, decrease in food consumption, and loss of egg production. The hemagglutinin (HA) cleavage (HA(0)) site of the isolated H5N2 virus was PQRETR/GLF, consistent with low pathogenic AI viruses. The intravenous pathogenicity index of this virus was zero. Whole-genome sequencing of two isolates that originated from two different barns was performed, and both isolates had 100% identical protein sequence in PB2, HA, NP, M1, M2, NS1, and NS2. The remaining gene segments (PB1, PA, and NA) had a single amino-acid difference when compared with each other. The nucleotide and protein sequences of eight gene segments from both isolates showed 99 or greater identity with other AI viruses that have been circulating in free-living aquatic birds in Canada and the United States within the last 10 yr. Phylogenetic analysis of the HA and neuraminidase (NA) gene segments showed that these viruses are closely related to other H5 strains that have been isolated from Manitoba and other parts of Canada. Serologic testing of archived serum samples collected from these turkeys a week before the outbreak showed no evidence of AI infection. In addition, other farms that were located within 3 km radius from the infected farm and farms that had epidemiologic connection with the farm also tested negative for the presence of H5N2 AI virus or antibody. This indicates that the virus might have been introduced to the farm from wild aquatic birds only a short time before detection. Results of this study highlight the importance of early detection and the significance of ongoing Canada-wide surveillance of AI in domestic poultry as well as in wild aquatic birds/ducks. PMID- 24758107 TI - Safety of fenbendazole in Chinese ring-necked pheasants (Phasianus colchicus). AB - Ring-necked pheasants raised on propagation farms can be severely parasitized with Syngamus trachea (gapeworm) and other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic that is not currently approved for game bird species in the United States. The objective of this work was to provide target animal safety data to support a label claim for fenbendazole in pheasants at 100 parts per million (ppm) in the feed for 7 consecutive days. Demonstration of safety in young pheasants and a separate demonstration of reproductive safety in adult birds were required. In the young bird study, 160 Chinese ring-necked pheasants (Phasianus colchicus, 80 males and 80 females) were fed a commercial game bird starter ration containing no antibiotics, growth promoters, or coccidiostats until day 0 of the study (approximately 21 days of age). On day 0 the birds were placed on their respective study diets containing fenbendazole at 0, 100, 300, and 500 ppm for 21 days (three times the normal treatment duration). Clinical observations were recorded twice daily. Feed consumption, feed conversion rate, and body weights were determined for each pen. Three birds from each pen were randomly selected for necropsy, histopathology, and clinical pathology. Birds were carefully examined for feathering abnormalities immediately following euthanasia. The remaining birds in each pen were submitted for drug concentration analysis so that concentrations (for low vs. high treatment levels) could be correlated with clinical observations, clinical pathology, and histologic findings. There no morbidities or mortalities after study day--1. There were no statistically significant treatment-related differences in feed consumption, feed conversion rates, body weights, serum biochemistry profiles, hematologic profiles, gross necropsy findings, histopathologic examination, and feathering. Allowable liver and muscle concentrations of fenbendazole sulfone in turkeys are 6 and 2 ppm, respectively, with a 6-hr feed withdrawal. Analysis of fenbendazole concentrations in kidney, liver, leg/thigh, and breast muscle and skin with associated fat revealed that, even at the highest dose level used and with no feed withdrawal, fenbendazole concentrations were relatively low in these tissues. These findings indicate that fenbendazole has a relatively wide margin of safety in young pheasants and that the proposed dose of 100 ppm in the feed for 7 consecutive days is well within the margin of safety. In the reproductive safety study, two large game bird farms fed fendbendazole at 100 ppm for 7 days and collected data on hatching percentage of pheasant eggs before and after treatment. Reproductive performance in hen pheasants was not adversely affected. PMID- 24758108 TI - Isolation and identification of Aspergillus spp. from brown kiwi (Apteryx mantelli) nocturnal houses in New Zealand. AB - Aspergillosis, a disease caused by infection with Aspergillus spp., is a common cause of death in birds globally and is an irregular cause of mortality of captive kiwi (Apteryx spp.). Aspergillus spp. are often present in rotting plant material, including the litter and nesting material used for kiwi in captivity. The aim of this study was to survey nocturnal kiwi houses in New Zealand to assess the levels of Aspergillus currently present in leaf litter. Samples were received from 11 nocturnal kiwi houses from throughout New Zealand, with one site supplying multiple samples over time. Aspergillus was isolated and quantified by colony counts from litter samples using selective media and incubation temperatures. Isolates were identified to the species level by amplification and sequencing of ITS regions of the ribosomal. Aspergillus spp. were recovered from almost every sample; however, the levels in most kiwi houses were below 1000 colony-forming units (CFU)/g of wet material. The predominant species was Aspergillus fumigatus, with rare occurrences of Aspergillus niger, Aspergillus nidulans, and Aspergillus parasiticus. Only one site had no detectable Aspergillus. The limit of detection was around 50 CFU/g wet material. One site was repeatedly sampled as it had a high loading of A. fumigatus at the start of the survey and had two recent clinical cases of aspergillosis diagnosed in resident kiwi. Environmental loading at this site with Aspergillus spp. reduced but was not eliminated despite changes of the litter. The key finding of our study is that the background levels of Aspergillus spores in kiwi nocturnal houses in New Zealand are low, but occasional exceptions occur and are associated with the onset of aspergillosis in otherwise healthy birds. The predominant Aspergillus species present in the leaf litter was A. fumigatus, but other species were also present. Further research is needed to confirm the optimal management of leaf litter to minimize Aspergillus spore counts. However, in the interim, our recommendations are that leaf litter should be freshly collected from areas of undisturbed forest areas and spread immediately after collection, without interim storage. PMID- 24758109 TI - An experimental infection model for Escherichia coli egg peritonitis in layer chickens. AB - The present study describes an experimental infection model for avian pathogenic Escherichia coli (APEC)-induced egg peritonitis in layer chickens. First, a pilot study which consisted of two separate experiments was carried out to compare two routes of inoculations of APEC to induce peritonitis and to examine if the presence of egg yolk in the peritoneum would facilitate APEC-induced peritonitis. This study showed that the presence of egg yolk in the peritoneum facilitated the development of egg peritonitis when the APEC was inoculated via the intra-uterine (IU) route. Based on the results of the pilot study, 56-wk-old white leghorn hens were divided into two groups of five chickens, Group G (inoculated with E. coli APECO78 strain) and Group H (control). Both groups were inoculated with 2-3 ml of egg yolk via the intraperitoneal route (IP). Subsequently, hens in Group H were inoculated with only egg yolk whereas the hens in Group G were inoculated with 1 x 10(9) colony-forming units of APECO78 bacteria via the IU route. Parameters such as mortality, clinical signs (anorexia, depression, and egg production efficiency), gross lesion scores, bacterial loads in internal organs, and histopathology of ovary and oviduct were assessed to evaluate the success of the infection model. Group G showed 40% acute mortality, severe depression, and anorexia with markedly reduced egg production and developed peritonitis associated lesions such as accumulation of yellowish caseous fluid in the peritoneum, salpingitis, and oophoritis. Histopathologically, ovarian and oviduct tissues from group G exhibited severe inflammatory changes such as infiltration of mononuclear cells and edema. Group G also showed significant bacterial loads in the peritoneum, ovary, and oviduct. Interestingly, deceased birds from group G had also developed mild perihepatitis and pericarditis with heavy bacterial loads in the internal organs. On the other hand, group H birds did not exhibit any of the clinical signs and remained healthy until the end of the experiment. To summarize, our results demonstrate that IP administration of egg yolk followed by IU inoculation of APECO78 induced peritonitis in laying hens. Experimental infection models are often required to understand the mechanisms of disease pathogenesis. Therefore, the present infection model will aid in the studies of pathogenesis of layer peritonitis caused by APEC and in evaluating vaccine candidates to control the disease. PMID- 24758110 TI - A rapid profiling assay for avian leukosis virus subgroup E proviruses in chickens. AB - Endogenous retroviral elements (ERVs) are prolific components of the genomes of complex species, typically occupying more sequence space than do essential, protein-encoding genes. Much of what we know today about the structure and function, as well as the evolution and pathogenic potential, of ERVs was fleshed out over several decades during the last century using the avian leukosis virus subgroup E-related (ALVE) family of endogenous retroviruses of chickens as a model system. A critical enabling factor in the elucidation of ALVE structure and function is the ability to detect and unambiguously identify specific ALVE proviral elements and to develop accurate element profiles for individual chickens under study. Currently, the most common approach for ALVE locus detection involves element-specific PCR assays carried out using primers that target host DNA near the insertion site of the provirus (i.e., the upstream and downstream flanks of the unoccupied site). Here we describe a new approach for proviral detection that exploits restriction enzyme sites in flanking DNA to develop ALVE element profiles more rapidly than with assays currently in use. Moreover, unlike element-specific PCR tests, the "profiling" assay detects novel ALVEs for which insertion sites have not yet been identified as well as previously characterized elements. PMID- 24758111 TI - Virulence repertoire, characterization, and antibiotic resistance pattern analysis of Escherichia coli isolated from backyard layers and their environment in India. AB - This study was undertaken to observe the prevalence, serogroup, avian pathogenic Escherichia coli (APEC)-associated virulence gene, randomly amplified polymorphic DNA (RAPD) pattern, and antibiotic resistance genes of E. coli in backyard layers and their environment in India. From the 360 samples of healthy layers and their environment, 272 (75.5%) E. coli were isolated. The majority (28.67%) of them were untypeable. Among the studied virulence genes (papC, tsh, iucC, astA), 52 (14.32%) isolates were found to possess astA, including the isolates from the drinking water of the birds (4/272, 1.47%). These strains belonged to 18 different serogroups. Most of the isolates were typeable by RAPD and they produced different patterns. Phenotypic resistance of the isolates was most frequently observed to erythromycin (95.83%), chloramphenicol (87.52%), and cotrimoxazole (78.26%). None of the isolates was found to possess extended spectrum beta-lactamases (bla(TEM), bla(SHV), bla(CTX-M) or quinolone resistance (qnrA) genes by PCR. The present study was the first attempt in India to assess APEC distribution in backyard poultry production. PMID- 24758112 TI - Adjuvant effects of chitosan and calcium phosphate particles in an inactivated Newcastle disease vaccine. AB - The adjuvant activity of chitosan (CS) and calcium phosphate (CAP) particles was studied following intranasal (mucosal) administration to commercial chickens with inactivated Newcastle disease virus (NDV) vaccine. After three vaccinations with inactivated NDV in combination with CS or CAP an increase in antibody titers in blood and mucosal samples in chickens was observed when compared with the administration of NDV antigen only. A lower level of humoral immunity was observed in broiler chickens compared to layer-type birds. The CS-based vaccine demonstrated higher antigenic and protective activity following lethal challenge than the vaccine containing CAP. Because CS particles efficiently changed mucosal and humoral immunity and protective activity, CS may in the future be considered for use as a potential adjuvant for production of vaccines for poultry. PMID- 24758113 TI - Evaluation of avian influenza serologic and virologic diagnostic methods in wild Anseriformes and Charadriiformes. AB - Evaluation of avian influenza virus (AIV) diagnostic methods, including a nucleoprotein (NP) competitive enzyme-linked immunosorbent assay (c-ELISA), hemagglutination inhibition (HI) test, type A real-time reverse transcription polymerase chain reaction (RRT-PCR), and embryonating chicken egg (ECE) virus isolation (VI), suggested validity of these tests in wild birds comparable to that reported in poultry. This was determined by analyzing the results from experimental inoculation of three species of wild birds with a low-pathogenicity AIV and from field surveillance data. The NP c-ELISA in a high-AIV prevalence setting had 100% diagnostic sensitivity (Se; 95% confidence interval [CI]: 81.5% 100%) and 91% diagnostic specificity (Sp; 95% CI: 70.8%-98.9%) in negative controls compared with the RRT-PCR. In low-AIV prevalence flocks using a > 60% inhibition positivity threshold, relative to the HI test, c-ELISA performed with 90.5% Se (95% CI: 86.2%-93.8%) and 41.2% Sp (95% CI: 38.1%-44.5%). Assessment of HI suggests a titer > or = 8 is a positive test result in wild-bird sera, and using this titer had 83.3% Se (95% CI: 58.6%-96.4%) in experimentally infected birds. The RRT-PCR diagnostic performance compared with VI in cloacal swabs varied over 2-6 days postinoculation, having high Se (83.3%-100%) and Sp (94.1% 100%) with substantial agreement (kappa = 0.8). The cycle thresholds (C(t)) for the RRT-PCR of C(t) < 37 for positivity and C(t) = 37-40 as indeterminate were found to be valid for the species included in this study. In view of the interpretative diagnostic difficulties in heterogeneous populations of wild birds, this evaluation in three species of wild birds and in surveillance data should provide greater confidence in the application of these methods routinely used in poultry. PMID- 24758114 TI - Blackhead disease: reduced sensitivity of Histomonas meleagridis to nitarsone in vitro and in vivo. AB - Histomonas meleagridis, a flagellated protozoan parasite, is the causative agent of blackhead disease or histomoniasis in gallinaceous birds. Currently nitarsone (4-nitrophenylarsonic acid) is the only approved preventative drug available in the United States against blackhead disease. Initially we tested the sensitivity of three different isolates of H. meleagridis collected from outbreaks in North Carolina (strain MNC), Michigan (strain ZM), and Georgia (strain BG) to nitarsone using in vitro culture conditions. Strain ZM and strain BG at 100 and 400 ppm showed reduced growth in comparison to their respective control groups. However, there was no inhibition of growth in strain MNC treated with nitarsone at 100 ppm, while reduced growth was seen at 400 ppm. To test the resistance of strain MNC to nitarsone in vivo, turkey poults fed a nitarsone or a control diet were inoculated cloacally with H. meleagridis. The nitarsone-treated group of birds did not show any significant difference compared to that of infected control group when measuring weight gain and liver and cecal lesions scores. Histomonas meleagridis were reisolated from the nitarsone-fed turkeys and subjected to the in vitro assay. Regenerated H. meleagridis maintain their resistance to nitarsone at 100 ppm. This study demonstrates that strain MNC has acquired partial resistance to nitarsone. PMID- 24758115 TI - Serotype and antimicrobial resistance patterns of Salmonella isolates from commercial birds and poultry environment in Mississippi. AB - To obtain information about Salmonella from commercial birds and poultry environments within Mississippi, 50 Salmonella enterica isolates were collected and characterized by intergenic sequence ribotyping (ISR) serotyping and by determining antimicrobial resistance. ISR assigned serotype to all 50 Salmonella enterica isolates whereas the Kauffman-White-LeMinor antibody-based scheme assigned serotype to 48. Agreement between both methods was K = 89.58. Within the set, 12 serotypes were detected. The antimicrobial resistance patterns (ARP) of 12 serotypes, namely Enteritidis, Typhimurium, Kentucky, Bredeney, Mbandaka, Saintpaul, Montevideo, Cubana, Lille, Senftenberg, Johannesburg, and one serotype UN0094, were determined using minimum inhibitory concentration values. The antibiograms demonstrated differences between Salmonella serotypes and among isolates of the same serotype. All isolates were 100% susceptible to enrofloxacin and trimethoprim/sulfamethoxazole. The number of antimicrobials to which the isolates were resistant ranged from two to nine. Twenty-two different ARPs were identified and ARP1, with resistance to spectinomycin and sulfadimethoxine, was most frequently observed. Forty isolates (80%) were resistant to three or more antimicrobials and were thus designated multidrug resistant. Detection of a unique serotype, and variation in antibiograms within the set, demonstrates that it is important to survey isolates periodically from a region to follow epidemiologic trends. PMID- 24758117 TI - Experimental comparison of hemolytic and nonhemolytic Ornithobacterium rhinotracheale field isolates in vivo. AB - Ornithobacterium rhinotracheale (ORT) is a nonhemolytic, gram-negative, pleomorphic, rod-shaped bacterium that causes upper and lower respiratory tract disease in poultry. Recently, hemolytic strains of ORT have been isolated with increasing frequency from field outbreaks. A study was conducted to determine whether the hemolytic phenotype is associated with any change in virulence. Briefly, 225 turkey poults, vaccinated against hemorrhagic enteritis at 4 wk of age, were randomly divided into nine replicates housed in separate rooms: three sham treatment controls (25 poults/replicate), three challenged with a nonhemolytic (NH) field isolate (24 poults/replicate), and three challenged with a hemolytic (H) field isolate (24 poults/replicate). Nine days postvaccination, poults were inoculated intratracheally with either 0.2 ml sterile phosphate buffered saline (PBS), 2 x 10(8) colony-forming units (CFU) of the NH isolate in 0.2 ml PBS, or 2 x 10(8) CFU of the H isolate in 0.2 ml PBS. Serum and body weights were obtained at 0, 7, 14, and 21 days postinoculation (dpi). Tissues were taken for culture and histopathology from five randomly selected poults/replicates at 7, 14, and 21 dpi. When compared with poults inoculated with the H isolate or controls, those inoculated with the NH isolate showed a highly significant depression in weight gain at 7 dpi. NH poults also had significantly higher levels of antibody against ORT at 14 and 21 dpi. Reisolations decreased over time and, by 21 dpi, only the NH phenotype could be found. Based on a Likert type scale, poults inoculated with the NH isolate had significantly higher histopathologic lesion scores in lung tissue at 7, 14, and 21 dpi. Results suggest that nonhemolytic field isolates are more virulent then hemolytic ones. These findings are unusual because hemolytic phenotypes are often more virulent in other bacterial species. PMID- 24758116 TI - Flock prevalence of exposure to avian adeno-associated virus, chicken anemia virus, fowl adenovirus, and infectious bursal disease virus among Ontario broiler chicken flocks. AB - Samples from 231 randomly selected commercial broiler chicken flocks in Ontario were tested at slaughter for exposure to chicken anemia virus (CAV), fowl adenovirus (FAdV), and infectious bursal disease virus (IBDV). Fifteen blood samples per flock were collected and analyzed for the presence of antibodies against CAV, FAdV, and IBDV by ELISA or agar gel immunodiffusion test. Fifteen cecal tonsils and cloacal swabs per flock were analyzed for the presence of CAV, FAdV, and IBDV by PCR. The prevalence of exposure to avian adeno-associated virus (AAAV) was estimated by a PCR test on a subset of FAdV-PCR-positive samples from 178 flocks. Genotypes of FAdV and IBDV were identified on a subset of isolates (n = 353 and 45, respectively). The flock-level period prevalence of exposure to AAAV, CAV, FAdV, and IBDV during grow-out were 88.76% (95% CI: 84.08-93.45%), 77.06% (95% CI: 71.59-82.52%), 96.54% (95% CI: 94.16-98.91%), and 48.92% (95% CI: 42.42-55.41%), respectively. Results of a multivariable logistic regression model showed a significant association of exposure to FAdV with exposure to AAAV (OR = 18.57, 95% CI: 3.67-93.86, P = 0.004) but not with exposure to CAV (P = 0.7752) or exposure to IBDV (P = 0.2274). Pathogenic FAdV genotypes (FAdV-02, FAdV-08, and FAdV-11) constituted 39.38% of the isolates. The most-common IBDV genotypes identified were IBDV NC171 (60%) and IBDV 05SA8 (28.89%). This is the first large scale study to estimate the baseline flock prevalence of exposure to AAAV, CAV, FAdV, and IBDV in commercial broiler flocks in Canada. Potentially pathogenic genotypes of FAdV and IBDV that can guide vaccine development and disease control efforts in Ontario were identified. PMID- 24758118 TI - Infectious bronchitis virus S2 expressed from recombinant virus confers broad protection against challenge. AB - We developed a recombinant Newcastle disease virus (NDV) LaSota (rLS) expressing the infectious bronchitis virus (IBV) S2 gene (rLS/IBV.S2). The recombinant virus showed somewhat-reduced pathogenicity compared to the parental lentogenic LaSota strain but effectively elicited hemagglutination inhibition antibodies against NDV and protected chickens against lethal challenge with virulent NDV/CA02. IBV heterotypic protection was assessed using a prime-boost approach with a commercially available attenuated IBV Massachusetts (Mass)-type vaccine. Specific pathogen-free chickens primed ocularly with rLS/IBV.S2 at 4 days of age and boosted with Mass at 18 days of age were completely protected against challenge at 41 days of age with a virulent Ark-type strain. In a second experiment, we compared protection conferred by priming with rLS/IBV.S2 and boosting with Mass (rLS/IBV.S2+Mass) versus priming and boosting with Mass (Mass+Mass). We also modified the timing of vaccination to prime at 1 day of age and boost at 12 days of age. Challenge with virulent Ark was performed at 21 days of age. Based on clinical signs, both vaccinated groups appeared equally protected against challenge compared to unvaccinated challenged chickens. Viral loads in lachrymal fluids of birds receiving rLS/IBV.S2+Mass showed a clear tendency of improved protection compared to Mass+Mass; however, the difference did not achieve statistical significance. A significant difference (P < 0.05) was determined between these groups regarding incidence of detection of challenge IBV RNA in the trachea; viral RNA was detected in 50% of rLS/IBV.S2+Mass-vaccinated chickens while chickens vaccinated with Mass+Mass and unvaccinated challenged controls showed 84 and 90% incidence of IBV RNA detection in the trachea, respectively. These results demonstrate that overexposing the IBV S2 to the chicken immune system by means of a vectored vaccine, followed by boost with whole virus, protects chickens against IBV showing dissimilar S1. PMID- 24758119 TI - Avian gyrovirus 2 and avirulent Newcastle disease virus coinfection in a chicken flock with neurologic symptoms and high mortalities. AB - A disease with severe neurologic symptoms caused 100% mortality in a small broiler operation in the Gauteng Province, South Africa in late March 2013. Routine diagnostic PCR testing failed to identify a possible cause of the outbreak; thus, samples were submitted for virus isolation, serology, and bacteriology. An avirulent Newcastle disease virus (NDV) strain isolated was identified as a V4-like genotype 1 strain, by DNA sequencing, with a cleavage site of 112GKQGR decrease L117. Real-time reverse transcription PCR identified NDV in the brain but not in cecal tonsils or pooled tracheas, spleens, lungs, and livers. A random amplification deep sequencing of a transcriptome library generated from pooled tissues produced 927,966 paired-end reads. A contig of 2,309 nucleotides was identified as a near-complete avian gyrovirus 2 (AGV2) genome. This is the first report on the African continent of AGV2, which has been reported in southern Brazil, The Netherlands, and Hong Kong thus far. A real-time PCR for AGV2 only detected the virus in the brain but not in cecal tonsils or pooled tracheas, spleens, lungs, and livers. Sequence reads also mapped to the genomes of mycoplasma, Escherichia coli, avian leukosis virus subtype J, and Marek's disease virus but excluded influenza A virus, Ornithobacterium rhinotracheale, avian rhinotracheitis virus, avian encephalomyelitis virus, and West Nile virus. Air sac swabs were positive on bacterial culture for E. coli. The possibility of a synergistic pathogenic effect between avirulent NDV and AGV2 requires further investigation. PMID- 24758120 TI - Epithelial cell tumors of the hen reproductive tract. AB - There is a paucity of preclinical models that simulate the development of ovarian tumors in humans. At present, the egg-laying hen appears to be the most promising model to study the spontaneous occurrence of ovarian tumors in the clinical setting. Although gross classification and histologic grade of tumors have been used prognostically in women with ovarian tumors, there is currently no single system that is universally used to classify reproductive tumors in the hen. Four hundred and one 192-wk-old egg-laying hens were necropsied to determine the incidence of reproductive tumors using both gross pathology and histologic classification. Gross pathologic classifications were designated as follows: birds presenting with ovarian tumors only (class 1), those presenting with oviductal and ovarian tumors (class 2), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract (class 3), those with ovarian and oviductal tumors that metastasized to the gastrointestinal tract and other distant organs (class 4), those with oviductal tumors only (class 5), those with oviductal tumors that metastasized to other organs with no ovarian involvement (class 6), and those with ovarian tumors that metastasized to other organs with no oviductal involvement (class 7), including birds with gastrointestinal tumors and no reproductive involvement (GI only) and those with no tumors (normal). Histopathologic classifications range from grades 1 to 3 and are based on mitotic developments and cellular differentiation. An updated gross pathology and histologic classification systems for the hen reproductive malignancies provides a method to report the range of reproductive tumors revealed in a flock of aged laying hens. PMID- 24758121 TI - Comparison of vaccine subpopulation selection, viral loads, vaccine virus persistence in trachea and cloaca, and mucosal antibody responses after vaccination with two different Arkansas Delmarva Poultry Industry -derived infectious bronchitis virus vaccines. AB - Factors responsible for the persistence of Arkansas Delmarva Poultry Industry (ArkDPI)-derived infectious bronchitis vaccines in commercial flocks and the high frequency of isolation of ArkDPI-type infectious bronchitis viruses in respiratory cases are still unclear. We compared dynamics of vaccine viral subpopulations, viral loads, persistence in trachea and cloaca, and the magnitude of infectious bronchitis virus (1BV)-specific antibody induction after vaccination with two commercial ArkDPI-derived Arkansas (Ark) serotype vaccines. One of the vaccines (coded vaccine B) produced significantly higher vaccine virus heterogeneity in vaccinated chickens than the other vaccine (coded A). Chickens vaccinated with vaccine B had significantly higher viral loads in tears at 5 days postvaccination (DPV) than those vaccinated with vaccine A. Vaccine B also induced a significantly higher lachrymal immunoglobulin M response at 11 DPV, an earlier peak of IBV-specific lachrymal immunoglobulin A, and higher serum antibodies than vaccine A. In addition, a significantly higher proportion of birds vaccinated with vaccine B had vaccine virus detected in the trachea at 20 DPV than those vaccinated with vaccine A. Furthermore, the virus detected at 20 DPV in most of the chickens vaccinated with vaccine B was a single specific subpopulation (subpopulation 4) selected from multiple vaccine subpopulations detected earlier at 5 and 7 DPV in the same chickens. On the other hand, a higher proportion of chickens vaccinated with vaccine A had virus detected in cloacal swabs at 20 DPV. Thus we found differences in mucosal antibody induction and selection and persistence of vaccine viruses between two ArkDPI-derived vaccines from different manufacturers. The higher vaccine virus heterogeneity observed in chickens vaccinated with vaccine B compared with those vaccinated with vaccine A may be responsible for these differences. Thus the high frequency of Ark IBV viruses in the field may be due to the inherent ability of some ArkDPI-derived vaccine viruses to be selected and persist in vaccinated chickens. Vaccine virus persistence may offer genetic material for recombination or may undergo mutations with the potential to result in increased virulence. PMID- 24758122 TI - Disease screening of three breeding populations of adult exhibition budgerigars (Melopsittacus undulatus) in New Zealand reveals a high prevalence of a novel polyomavirus and avian malaria infection. AB - Disease surveillance is vital to the management of New Zealand's endemic and threatened avian species. Three infectious agents that are potential threats to New Zealand's endemic birds include avian polyomavirus (APV), beak and feather disease virus (BFDV), and avian malaria. All three agents have been reported in New Zealand; however, possible reservoir populations have not been identified. In this communication, we report the first study of APV, BFDV, and avian malaria in introduced adult exhibition budgerigars (Melopsittacus undulatus) in New Zealand. Blood samples were collected from 90 living adult budgerigars from three breeding locations in the North Island of New Zealand. An overall APV prevalence of 22% was determined using a broad-spectrum nested PCR that amplified the major capsid protein VP1 gene of polyomavirus. Phylogenetic analysis of the VP1 gene revealed a unique isolate of APV, which had a sequence divergence of 32% to previously reported budgerigar fledgling disease strains and 33% to the recently reported New Zealand finch isolate. All of the budgerigars sampled were found to be PCR negative for BFDV, and an overall prevalence of 30% was detected by PCR for avian malaria. Sequencing revealed the presence of ubiquitous malarial strains and also the potentially destructive Plasmodium relictum strain. The results of this study suggest that both APV and avian malaria are present in New Zealand adult budgerigars, and our study highlights the need for further studies to determine whether these pathogens in captive bird populations may be a threat or spill over into New Zealand's endemic and threatened avifauna and whether prevention and control methods need to be implemented. PMID- 24758123 TI - Detection and characterization of Newcastle disease virus in formalin-fixed, paraffin-embedded tissues from commercial broilers in Egypt. AB - Newcastle disease (ND) is highly contagious and causes severe economic losses to the poultry industry due to high morbidity and mortality. In this report, we describe the detection of Newcastle disease virus (NDV) in formalin-fixed tissues from an outbreak of ND on broiler farms in Egypt. The affected birds experienced respiratory and/or nervous signs and a 75% mortality rate. Tissue samples were collected and placed in 10% neutral buffered formalin followed by embedding in paraffin. RNA was extracted from 80-microm formalin-fixed paraffin-embedded tissue blocks and recovered in 60 microl of elution buffer. All samples were negative for influenza virus by real-time reverse-transcription (RT)-PCR but positive for NDV. These flocks were known to have been vaccinated with a live NDV vaccine (LaSota strain). The nucleic acid sequences of the virus detected in this study were similar to those of a velogenic virus at its cleavage site 111GRRQKR*F117 and clustered with class II genogroup VII lineage of NDV, with a nucleotide sequence identity of 94%-99%. Although extraction and amplification of NDV from paraffin-embedded tissues from experimentally infected birds has been reported previously, this study reports on the use of RT-PCR on formalin-fixed tissues from actual field samples. PMID- 24758124 TI - Epidemiology of fowl cholera in free range broilers. AB - Fowl cholera, caused by Pasteurella multocida, remains a major problem of poultry worldwide. In the current report, we describe an outbreak in free range organic broilers. In addition to culturing samples from dead broilers, we attempted to isolate P. multocida from feral cats trapped on the farm. The isolates were identified by PCR as P. multocida and then serotyped using the Heddleston scheme and genotyped using both a multilocus sequence typing (MLST) method and an enterobacterial repetitive intergenic consensus (ERIC)-PCR method. A total of 123 isolates of P. multocida were recovered from 12 broilers. All 123 isolates were examined by ERIC-PCR, and only one pattern was identified. A subset of seven broiler isolates were examined by MLST and all were typed as sequence type (ST) 20. A total of 28 isolates of P. multocida were recovered from 17 cats, and five ERIC-PCR genotypes were identified, with one genotype (E-1, shared by 19 isolates) being the same as the ERIC-PCR pattern associated with the broilers. One representative cat strain for each ERIC-PCR pattern was subjected to MLST. The cat isolate with the same ERIC-PCR genotype as the broiler isolates was confirmed as having the same MLST result, ST 20. The other five cat ERIC-PCR patterns were allocated to four STs: E-2 and E-5 to ST 265, E-3 to ST 30, E-4 to ST 20, and E-6 to ST 264. Both genotyping methods confirmed that isolates of P. multocida were common between the feral cats and the chickens. It was not clear whether the strain was transmitted from the cats to the chicken or whether the cats obtained the strain preying on chicken. The study has shown that cats can harbor P. multocida strains with the same genotype found in chickens affected with fowl cholera. PMID- 24758125 TI - Avian paramyxovirus serotype 1 (Newcastle disease virus), avian influenza virus, and Salmonella spp. in mute swans (Cygnus olor) in the Great Lakes region and Atlantic Coast of the United States. AB - Since their introduction to the United States in the late 19th century, mute swans (Cygnus olor) have become a nuisance species by causing damage to aquatic habitats, acting aggressively toward humans, competing with native waterfowl, and potentially transmitting or serving as a reservoir of infectious diseases to humans and poultry. In an effort to investigate their potential role as a disease reservoir and to establish avian health baselines for pathogens that threaten agricultural species or human health, we collected samples from 858 mute swans and tested them for avian paramyxovirus serotype 1 (APMV-1), avian influenza virus (AIV), and Salmonella spp. when possible. Our results indicate that exposure to APMV-1 and AIV is common (60%, n = 771, and 45%, n = 344, antibody prevalence, respectively) in mute swans, but detection of active viral shedding is less common (8.7%, n = 414, and 0.8%, n = 390, respectively). Salmonella was isolated from three mute swans (0.6%, n = 459), and although the serovars identified have been implicated in previous human outbreaks, it does not appear that Salmonella is commonly carried by mute swans. PMID- 24758126 TI - Molecular and phylogenetic analysis of a novel turkey-origin picobirnavirus. AB - A previous metagenomic analysis of the turkey gut RNA virus community identified novel enteric viruses that may play roles in poultry enteric diseases or in performance problems noted in the field. As part of the molecular characterization of these novel enteric viruses, a reverse transcriptase-PCR diagnostic assay was developed, targeting a novel turkey-origin picobirnavirus (PBV) initially identified in a pooled intestinal sample from turkey poults in North Carolina. Little detailed molecular information exists regarding the family Picobirnaviridae, particularly for the PBVs that have been described in avian species. This diagnostic assay targets the turkey PBV RNA-dependent RNA polymerase gene and produces an 1135-bp amplicon. This assay was validated using in vitro transcribed RNA and was tested using archived enteric samples collected from turkey flocks in the southeastern United States. Further, a phylogenetic analysis suggests the turkey PBV is unique because it does not group closely with the recognized PBV genogroups circulating in mammalian hosts. PMID- 24758127 TI - Phylogenetic relationship of serovar C-1 isolates of Avibacterium paragallinarum. AB - The bacterium Avibacterium paragallinarum is the etiologic agent of infectious coryza of chickens. Serovar C-1 has emerged in infectious coryza outbreaks in layer hens of Ecuador and Mexico. In the current study, genotyping and phylogenetic analyses of five Ecuadorian and 10 Mexican isolates of Av. paragallinarum serovar C-1 were performed. All 15 isolates share a unique enterobacterial repetitive intergenic consensus-based-PCR fingerprint and have identical 16S ribosomal RNA and hemagglutinin antigen gene sequences. Results indicate that Ecuadorian and Mexican isolates of serovar C-1 of Av. paragallinarum have a clonal relationship. PMID- 24758128 TI - Cross-protective immune responses between genotypically distinct lineages of infectious laryngotracheitis viruses. AB - Recent phylogenetic studies have identified different genotypic lineages of infectious laryngotracheitis virus (ILTV), and these lineages can recombine in the field. The emergence of virulent recombinant field strains of ILTV by natural recombination between commercial vaccines belonging to different genotypic lineages has been reported recently. Despite the use of attenuated ILTV vaccines, these recombinant viruses were able to spread and cause disease in commercial poultry flocks, raising the question of whether the different lineages of ILTV can induce cross-protective immune responses. This study examined the capacity of the Australian-origin A20 ILTV vaccine to protect against challenge with the class 8 ILTV recombinant virus, the genome of which is predominantly derived from a heterologous genotypic lineage. Following challenge, birds vaccinated via eyedrop were protected from clinical signs of disease and pathological changes in the tracheal mucosa, although they were not completely protected from viral infection or replication. In contrast, the challenge virus induced severe clinical signs and tracheal pathology in unvaccinated birds. This is the first study to examine the ability of a vaccine from the Australian lineage to protect against challenge with a virus from a heterologous lineage. These results suggest that the two distinct genotypic lineages of ILTV can both induce cross protection, indicating that current commercial vaccines are still likely to assist in control of ILTV in the poultry industry, in spite of the emergence of novel recombinants derived from different genotypic lineages. PMID- 24758129 TI - Occurrence and characterization of rotavirus A in broilers, layers, and broiler breeders from Brazilian poultry farms. AB - Rotaviruses are a major cause of diarrhea in humans and animals, including several mammalian and avian species. Using different PCR protocols, we report the occurrence of rotavirus A in 21 (53.84%; 21/39) from 39 fecal pool samples of broilers, layers, and broiler breeders from Brazilian avian farms. We typed the G5, G8, G11, G19, and P[31] genotypes. PMID- 24758130 TI - Astroviruses in Polish commercial turkey farms in 2009-2012. AB - Avian astrovirus infections are widespread in many countries, and infections have been connected with enteritis and increased mortality in young birds. In the present study, fecal samples were collected during 2009-2012 from a total of 156 meat turkey flocks. Astrovirus presence and type differentiation was performed with the use of two molecular diagnostic approaches. Out of 156 flocks, 48.7% were found to be TAstV positive. Depending on the method used for type differentiation, TAstV-2 and TAstV-1 prevalence was between 31.4%-41% and 9.6% 15.4%, respectively. No avian nephritis virus was detected. About 30% of astrovirus-positive flocks were infected with both types of TAstV. Phylogenetic analysis based on the partial polymerase gene sequence revealed the genetic variability of isolated TAstV, and most of the detected TAstV-2 belonged to the European lineage of astroviruses. Statistical analysis suggested the positive but weak correlation between the presence of astrovirus and health status (slightly more frequent detection of TAstV in sick, diarrheic birds) and also negative medium correlation between age and astrovirus occurrence. PMID- 24758131 TI - Presence of Salmonella enteritidis and Salmonella gallinarum in commercial laying hens diagnosed with fowl typhoid disease in Colombia. AB - A severe outbreak of salmonellosis in commercial brown table egg layers first occurred in Colombia in 2006. From 2008 to 2012, 35 samples collected from commercial layers farms in the states of Cundinamarca, Santander, Bolivar, and San Andres, were positive for Salmonella enterica. Salmonella was isolated from liver and spleen (71.42%), pools of organs (liver, spleen, and ovarian follicles; 25.71%), and drag swabs (2.85%). Serotype was assigned using single nucleotide polymorphisms or DNA microarray hybridization. Sixteen strains of Salmonella Enteritidis, and 13 of Salmonella Gallinarum were identified. Seven strains yielded three unique sequences, and they were designated as UN0038, UN0052, and UN0054 by intergenic sequence ribotyping. These strains were later identified as Salmonella serotypes Isangi, Braenderup, and Yoruba, respectively, by DNA microarray hybridization. The discovery that a common human pathogen (Salmonella Enteritidis) was coisolated from farms with an avian pathogen (Salmonella Gallinarum) in similar commercial brown layer hens and in different regions indicates that it is important to investigate the dynamics of Salmonella infection and determine the serotypes circulating within the same ecologic niche. PMID- 24758132 TI - Four cases of fatal toxoplasmosis in three species of endemic New Zealand birds. AB - Four cases of fatal toxoplasmosis in three endemic New Zealand avian species are reported. Between 2009 and 2012, two kereru (Hemiphaga novaeseelandiae), one North Island brown kiwi (Apteryx mantelli), and one North Island kaka (Nestor meridionalis) were submitted for necropsy examination. On gross postmortem, the kiwi had marked hepatosplenomegaly while the kaka and two kereru had swollen, slightly firm, deep-red lungs. Histologically there was extensive hepatocellular necrosis in the liver of the kiwi while the kaka and kereru showed severe fibrinous bronchointerstitial pneumonia. In the kiwi, protozoal organisms were present within both hepatocytes and Kupffer cells of the liver and within the epithelial cells and macrophages of the interstitium of the lungs in the kaka and two kereru. The diagnosis of toxoplasmosis was confirmed with immunohistochemistry and PCR of paraffin-embedded formalin-fixed tissue of the liver, lungs, or both. Genotyping of up to seven markers revealed that an atypical Type II isolate of Toxoplasma gondii was present in at least three of the cases. This study provides evidence that T. gondii can cause mortality in these endemic species and suggests further research is needed to determine the full extent of morbidity and mortality caused by this parasite in New Zealand's unique avifauna. PMID- 24758133 TI - Cluster of atherosclerosis in a captive population of black kites (Milvus migrans subsp.) in France and effect of nutrition on the plasma lipid profile. AB - From January 2010 to March 2013, a captive colony of 83 black kites (Milvus migrans subsp.) in France experienced increased mortality related to atherosclerosis with an incidence of 4.4% per year. On histopathology, all kites had advanced atherosclerotic lesions, with several birds presenting abdominal hemorrhage and aortic rupture. In January 2012, a dietary change was instituted and consisted of introducing fish into the kites' diet. During the following 15 mo, the plasma lipid profile was monitored as well as body weight, food offered, and flight activity. Total and low-density lipoprotein cholesterol initially increased, but in December 2012 and March 2013, an overall decrease from initial values was observed. High-density lipoprotein cholesterol also increased during this period. Despite positive plasma lipid changes induced by dietary modifications, there was no decrease in mortality from atherosclerosis, which was probably associated with the severity of the atherosclerotic lesions at time of dietary management. However, owing to the long and progressive development of atherosclerotic lesions, long-term beneficial effects are probable. This report suggests that black kites are particularly susceptible to atherosclerosis and aortic dissection in captivity. To prevent degenerative diseases associated with captivity in birds of prey, species-specific lifestyle and dietary requirements and susceptibility to these diseases should be considered. PMID- 24758134 TI - Diagnosis of Leucocytozoon caulleryi infection in commercial broiler breeders in South Korea. AB - This report confirms a recent outbreak of a Leucocytozoon caulleryi infection in a commercial broiler breeder flock in South Korea. Seven, 18-day-old broiler breeders (Gallus gallus) were necropsied following a history of depression, sudden death, and subcutaneous hemorrhages. On necropsy, subcutaneous hemorrhages were identified in the wings and legs, pectoral and thigh muscles, thymus, epicardium, pancreas, and kidneys. On histopathology, there were numerous schizonts and merozoits of a Leucocytozoon sp. noted in the heart, spleen, liver, kidneys, thymus, and bursa of Fabricius. Molecular analysis of the mitochondrial cytochrome oxidase b confirmed that the causative agent was Leucocytozoon caulleryi. Although L. caulleryi was diagnosed previously in South Korea, there had been no reports of L. caulleryi over the past several decades. PMID- 24758135 TI - Fatal proventricular dilatation disease in captive native psittacines in Brazil. AB - An outbreak of proventricular dilatation disease (PDD), a fatal inflammatory disease of psittacines (Aves: Psittaciformes), is described in native Brazilian psittacines. Twenty captive psittacines that died of suspected PDD were necropsied and 10 were submitted to histopathology, reverse transcriptase PCR (RT PCR), and immunohistochemistry (IHC) for avian bornavirus (ABV). Examined species were one pileated parrot (Pionopsitta pileata), three vinaceous-breasted parrots (Amazona vinacea), two blue-winged macaws (Primolius maracana), one scarlet macaw (Ara macao), one chestnut-fronted macaw (Ara severa), one scaly-headed parrot (Pionus maximiliani), and one red-browed Amazon parrot (Amazona rhodocorytha). Gross examination and histopathology revealed typical PDD lesions in all birds. The presence of ABV was confirmed in four psittacines including one red-browed Amazon parrot, one blue-winged macaw, one scarlet macaw, and one chestnut-fronted macaw. In the red-browed Amazon parrot and in one blue-winged macaw, IHC demonstrated ABV antigens in the nucleus and cytoplasm of cells in various organs. This is the first description of PDD by ABV in Brazilian psittacines and indicates the necessity for adopting a strategic control plan for reducing its impact in native birds. PMID- 24758137 TI - Nickel-catalyzed cross-coupling of aryl fluorides and organozinc reagents. AB - Ni(PCy3)2Cl2 was demonstrated to effectively catalyze cross-coupling of aryl fluorides and organozinc reagents. Both electron-poor and -rich aryl fluorides can react effectively with nucleophiles including aryl-, methyl-, and benzylzinc chlorides. A wide range of substituents and functional groups are tolerated. In the presence of a directing group, PhC(O), the reaction is selective for cleavage of the C-F bond ortho to the carbonyl substituent in a difluoroarene. PMID- 24758136 TI - Hypoxia and reoxygenation induce endothelial nitric oxide synthase uncoupling in endothelial cells through tetrahydrobiopterin depletion and S-glutathionylation. AB - Ischemia-reperfusion injury is accompanied by endothelial hypoxia and reoxygenation that trigger oxidative stress with enhanced superoxide generation and diminished nitric oxide (NO) production leading to endothelial dysfunction. Oxidative depletion of the endothelial NO synthase (eNOS) cofactor tetrahydrobiopterin can trigger eNOS uncoupling, in which the enzyme generates superoxide rather than NO. Recently, it has also been shown that oxidative stress can induce eNOS S-glutathionylation at critical cysteine residues of the reductase site that serves as a redox switch to control eNOS coupling. While superoxide can deplete tetrahydrobiopterin and induce eNOS S-glutathionylation, the extent of and interaction between these processes in the pathogenesis of eNOS dysfunction in endothelial cells following hypoxia and reoxygenation remain unknown. Therefore, studies were performed on endothelial cells subjected to hypoxia and reoxygenation to determine the severity of eNOS uncoupling and the role of cofactor depletion and S-glutathionylation in this process. Hypoxia and reoxygenation of aortic endothelial cells triggered xanthine oxidase-mediated superoxide generation, causing both tetrahydrobiopterin depletion and S glutathionylation with resultant eNOS uncoupling. Replenishing cells with tetrahydrobiopterin along with increasing intracellular levels of glutathione greatly preserved eNOS activity after hypoxia and reoxygenation, while targeting either mechanism alone only partially ameliorated the decrease in NO. Endothelial oxidative stress, secondary to hypoxia and reoxygenation, uncoupled eNOS with an altered ratio of oxidized to reduced glutathione inducing eNOS S glutathionylation. These mechanisms triggered by oxidative stress combine to cause eNOS dysfunction with shift of the enzyme from NO to superoxide production. Thus, in endothelial reoxygenation injury, normalization of both tetrahydrobiopterin levels and the glutathione pool are needed for maximal restoration of eNOS function and NO generation. PMID- 24758138 TI - In vitro maturation and surrogacy in patients with vascular-type Ehlers-Danlos syndrome--a safe assisted reproductive technology approach. AB - Ehlers-Danlos syndrome (EDS) is an autosomal dominant connective tissue disorder with one of the highest maternal mortality rates of any condition. Patients with the vascular type of EDS are prone to spontaneous arterial and visceral ruptures. The occurrence of these severe and life-threatening complications is increased in pregnancy. Moreover, these patients carry a 50% risk of having an affected child. However, little is known about the risks of assisted conception treatments on these patients. We present the case of a 33-year-old woman suffering from EDS with a history of repeated ruptures of arterial aneurysms and a recently ruptured aneurysm of the splenic artery during her first intracytoplasmic sperm injection (ICSI) cycle who was then advised to undergo only unstimulated cycles. After a few natural ICSI cycles, the patient safely underwent two in vitro maturation cycles with pre-implantation genetic diagnosis in our unit. An unaffected blastocyst was transferred into a surrogate host. To our knowledge, this is the first case of EDS in assisted reproduction technologies including pre implantation genetic diagnosis to be reported in the medical literature. This case has shown that unstimulated in vitro maturation and pre-implantation genetic diagnosis can safely be offered for vascular-type Ehlers-Danlos patients. PMID- 24758139 TI - Implantable microchip: the futuristic controlled drug delivery system. AB - There is no doubt that controlled and pulsatile drug delivery system is an important challenge in medicine over the conventional drug delivery system in case of therapeutic efficacy. However, the conventional drug delivery systems often offer a limited by their inability to drug delivery which consists of systemic toxicity, narrow therapeutic window, complex dosing schedule for long term treatment etc. Therefore, there has been a search for the drug delivery system that exhibit broad enhancing activity for more drugs with less complication. More recently, some elegant study has noted that, a new type of micro-electrochemical system or MEMS-based drug delivery systems called microchip has been improved to overcome the problems related to conventional drug delivery. Moreover, micro-fabrication technology has enabled to develop the implantable controlled released microchip devices with improved drug administration and patient compliance. In this article, we have presented an overview of the investigations on the feasibility and application of microchip as an advanced drug delivery system. Commercial manufacturing materials and methods, related other research works and current advancement of the microchips for controlled drug delivery have also been summarized. PMID- 24758140 TI - Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system. AB - The main aim of this work was to develop rectal suppositories for better delivery of metoprolol tartrate (MT). The various bases used were fatty, water soluble and emulsion bases. The physical properties of the prepared suppositories were characterized such as weight variation, hardness, disintegration time, melting range and the drug content uniformity. The in vitro release of MT from the prepared suppositories was carried out. The evaluation of the pharmacological effects of MT on the blood pressure and heart rate of the healthy rabbits after the rectal administration compared to the oral tablets was studied. Moreover, the formulation with the highest in vitro release and the highest pharmacological effects would be selected for a further pharmacokinetics study compared to the oral tablets. The results revealed that the emulsion bases gave the highest rate of the drug release than the other bases used. The reduction effect of the emulsion MT suppository base on the blood pressure and heart rate was found to be faster and greater than that administered orally. The selected emulsion suppository base (F11) showed a significant increase in the AUC (1.88-fold) in rabbits as compared to the oral tablets. From the above results we can conclude that rectal route can serve as an efficient alternative route to the oral one for systemic delivery of MT which may be due to the avoidance of first-pass effect in the liver. PMID- 24758141 TI - pH triggered delivery of curcumin from Eudragit-coated chitosan microspheres for inflammatory bowel disease: characterization and pharmacodynamic evaluation. AB - OBJECTIVE: This investigation deals with the development and evaluation (in vitro and in vivo) of pH triggered Eudragit-coated chitosan microspheres of curcumin (CUR) for treating ulcerative colitis. METHODS: CUR-loaded chitosan microspheres were initially prepared by emulsion cross linking method followed by coating with Eudragit S-100. The pharmacodynamics of the developed formulation was analyzed in mice by acetic acid induced colitis model. RESULTS: The developed microspheres were of uniform spherical shape with high entrapment efficiency. CUR-chitosan microspheres showed less intense peaks compared to free CUR confirming inclusion of drug within microspheres as revealed by X-ray diffractogram. Uncoated CUR chitosan microspheres exhibited burst release within initial 4 h while microspheres coated with Eudragit S-100 prevented premature release of CUR and showed controlled release up to 12 h following Higuchi model. In vivo organ biodistribution study showed negligible amount of CUR in stomach and small intestine confirming integrity of microsphere in upper gastrointestinal tract (GIT). In vivo study revealed significant reduction in severity and extent of colonic damage with CUR-loaded microspheres as compared to pure CUR which was further confirmed by histopathological study. CONCLUSION: In vitro and in vivo studies proved the developed formulations as a promising system for pH-dependent delivery of drug to colon in ulcerative colitis. PMID- 24758142 TI - Conformational fluctuation dynamics of domain I of human serum albumin in the course of chemically and thermally induced unfolding using fluorescence correlation spectroscopy. AB - The present study elucidates the involvement of conformational fluctuation dynamics during chemically and thermally induced unfolding of human serum albumin (HSA) by fluorescence correlation spectroscopic (FCS) study, time-resolved fluorescence measurements, and circular dichroism (CD) spectroscopic methods. Two fluorescent probes, tetramethylrhodamine-5-maleimide (TMR) and N-(7-dimethylamino 4-methylcoumarin-3-yl) iodoacetamide (DACIA) were used to selectively label the domain I of HSA through the reaction with cys-34 for these studies. The guanidine hydrochloride (GnHCl) induced global structural change of HSA is monitored through its hydrodynamic radius (r(H)) and CD response, which is found to be two step in nature. In FCS experiment, along with the diffusion time component we have observed an exponential relaxation time component (tau(R)) that has been ascribed to the concerted chain dynamics of HSA. Unlike in the global structural change, we found that the tau(R) value changes in a different manner in the course of the unfolding. The dependence of tau(R) on the concentration of GnHCl was best fitted with a four state model, indicating the involvement of two intermediate states during the unfolding process, which were not observed through the CD response and r(H) data. The fluorescence lifetime measurement also supports our observation of intermediate states during the unfolding of HSA. However, no such intermediate states were observed during thermally induced unfolding of HSA. PMID- 24758144 TI - Construction of ZnO/ZnS/CdS/CuInS2 core-shell nanowire arrays via ion exchange: p n junction photoanode with enhanced photoelectrochemical activity under visible light. AB - ZnO/ZnS/CdS/CuInS2 core-shell nanowire arrays with enhanced photoelectrochemical activity under visible light were successfully prepared via ion exchange and hydrothermal methods. The samples were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, UV-vis absorption, X-ray photoemission spectroscopy, and photoelectrochemical response. As a p-n junction photoanode, ZnO/ZnS/CdS/CuInS2 heterostructure shows much higher visible light photoelectrocatalytic activity toward water splitting than ZnO/ZnS/CdS and ZnO/ZnS films. The ZnO/ZnS/CdS/CuInS2 film with optimal constitution exhibits the highest photocurrent of 10.5 mA/cm(2) and the highest IPCE of approximately 57.7% at 480 nm and a bias potential of 0 V versus Ag/AgCl. The critical roles of CdS and ZnS in ZnO/ZnS/CdS/CuInS2 heterostructure were investigated. ZnS, as a passivation layer, suppresses the recombination of the photogenerated charge carriers at the interface of the oxide and CuInS2. CdS enhances the absorption of visible light and forms p-n junctions with CuInS2, which promotes the transport of charge carriers and retards the recombination of electrons and holes in CuInS2 to improve the photoelectrochemical performance of ZnO/ZnS/CdS/CuInS2 heterostructure. PMID- 24758143 TI - Cross-sectional associations between the screen-time of parents and young children: differences by parent and child gender and day of the week. AB - BACKGROUND: Greater time spent screen-viewing (SV) has been linked to adverse health outcomes. The aim of this study was to examine whether parental SV time is associated with child SV time on week and weekend days. METHODS: Cross-sectional survey of 1078 children aged 5-6 and at least 1 parent. Child and parent SV was reported for weekday and weekend days. Logistic regression examined whether parental SV time was associated with child SV time, with separate analyses for mothers and fathers and interaction terms for child gender. RESULTS: 12% of boys, 8% of girls and 30% of mothers and fathers watched >= 2 hours of TV each weekday. On a weekend day, 45% of boys, 43% of girls, 53% of mothers and 57% of fathers spent >= 2 hours watching TV. Where parents exceeded 2 hours TV-watching per weekday, children were 3.4 times more likely to spend >= 2 hours TV-watching if their father exceeded the threshold with odds of 3.7 for mothers. At weekends, daughters of fathers who exceeded 2 hours watching TV were over twice as likely as sons to exceed this level. Evidence that parent time spent using computers was associated with child computer use was also strongest between fathers and daughters (vs. sons) (OR 3.5 vs. 1.0, p interaction=0.027). CONCLUSIONS: Strong associations were observed between parent and child SV and patterns were different for weekdays versus weekend days. Results show that time spent SV for both parents is strongly associated with child SV, highlighting the need for interventions targeting both parents and children. PMID- 24758145 TI - Black carbon emissions in gasoline exhaust and a reduction alternative with a gasoline particulate filter. AB - Black carbon (BC) mass and solid particle number emissions were obtained from two pairs of gasoline direct injection (GDI) vehicles and port fuel injection (PFI) vehicles over the U.S. Federal Test Procedure 75 (FTP-75) and US06 Supplemental Federal Test Procedure (US06) drive cycles on gasoline and 10% by volume blended ethanol (E10). BC solid particles were emitted mostly during cold-start from all GDI and PFI vehicles. The reduction in ambient temperature had significant impacts on BC mass and solid particle number emissions, but larger impacts were observed on the PFI vehicles than the GDI vehicles. Over the FTP-75 phase 1 (cold start) drive cycle, the BC mass emissions from the two GDI vehicles at 0 degrees F (-18 degrees C) varied from 57 to 143 mg/mi, which was higher than the emissions at 72 degrees F (22 degrees C; 12-29 mg/mi) by a factor of 5. For the two PFI vehicles, the BC mass emissions over the FTP-75 phase 1 drive cycle at 0 degrees F varied from 111 to 162 mg/mi, higher by a factor of 44-72 when compared to the BC emissions of 2-4 mg/mi at 72 degrees F. The use of a gasoline particulate filter (GPF) reduced BC emissions from the selected GDI vehicle by 73 88% at various ambient temperatures over the FTP-75 phase 1 drive cycle. The ambient temperature had less of an impact on particle emissions for a warmed-up engine. Over the US06 drive cycle, the GPF reduced BC mass emissions from the GDI vehicle by 59-80% at various temperatures. E10 had limited impact on BC emissions from the selected GDI and PFI vehicles during hot-starts. E10 was found to reduce BC emissions from the GDI vehicle by 15% at standard temperature and by 75% at 19 degrees F (-7 degrees C). PMID- 24758146 TI - Chemerin suppresses murine allergic asthma by inhibiting CCL2 production and subsequent airway recruitment of inflammatory dendritic cells. AB - BACKGROUND: Chemerin has been implicated to play opposing roles, either pro inflammatory or anti-inflammatory, in various tissue inflammation processes primarily through the regulation of tissue recruitment of immune cells. However, the effect of chemerin in allergic asthma has not yet been explored. We sought to investigate the role of chemerin in the murine model of allergic asthma and explore the underlying mechanism. METHODS: We examined the effect of intranasal (i.n.) administration of chemerin during antigen challenge in murine models of asthma. Moreover, we examined whether administration of CCL2 or bone marrow derived dendritic cells (BMDCs) transfer reversed the effects of chemerin on ovalbumin-induced asthma. We finally examined the effect of chemerin on CCL2 expression in activated lung epithelial cells in vitro. RESULTS: The administration of chemerin attenuated allergic airway inflammation and airway hyperreactivity during antigen challenge. Chemerin treatment caused significant decreases in BALF CD4(+) T-cell accumulation and mRNA expression of Th2 attracting chemokines, CCL17 and CCL22, which was accompanied by significantly decreased BALF CD11c(+) CD11b(+) inflammatory DC accumulation and CCL2 production. Furthermore, airway administration of exogenous CCL2 or adoptive transfer of CD11c(+) CD11b(+) BMDCs abrogated the suppressive effects of chemerin on allergic asthma. Finally, in vitro study showed that chemerin inhibited CCL2 secretion by low-dose LPS-stimulated lung epithelial cells, which led to decreased chemotaxis of BMDCs. CONCLUSIONS: Our study demonstrates that chemerin plays a protective role in allergic asthma by suppressing airway recruitment of inflammatory CD11c(+) CD11b(+) DCs through the inhibition of CCL2 secretion by active lung epithelial cells. PMID- 24758147 TI - Nitric oxide synthase inhibitors that interact with both heme propionate and tetrahydrobiopterin show high isoform selectivity. AB - Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of alpha-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors. PMID- 24758148 TI - Antenatal interventions to reduce preterm birth: an overview of Cochrane Systematic Reviews. AB - BACKGROUND: Several factors are associated with an increased risk of preterm birth (PTB); therefore, various interventions might have the potential to influence it. Due to the large number of interventions that address PTB, the objective of this overview is to summarise evidence from Cochrane reviews regarding the effects and safety of these different interventions. METHODS: We conducted a systematic literature search in the Cochrane Database of Systematic Reviews. Included reviews should be based on randomised controlled trials comparing antenatal non-pharmacological and pharmacological interventions that directly or indirectly address PTB with placebo/no treatment or routine care in pregnant women at less than 37 completed weeks of gestation without signs of threatened preterm labour. We considered PTB at less than 37 completed weeks of gestation as the primary outcome. RESULTS: We included 56 Cochrane systematic reviews. Three interventions increased PTB risk significantly. Twelve interventions led to a statistically significant lower incidence of PTBs. However, this reduction was mostly observed in defined at-risk subgroups of pregnant women. The remaining antenatal interventions failed to prove a significant effect on PTB < 37 weeks, but some of them at least showed a positive effect in secondary outcomes (e.g., reduction in early PTBs). As an unintended result of this review, we identified 28 additional Cochrane reviews which intended to report on PTB < 37 weeks, but were not able to find any RCTs reporting appropriate data. CONCLUSIONS: The possible effects of a diverse range of interventions on PTB have been evaluated in Cochrane systematic reviews. Few interventions have been demonstrated to be effective and a small number have been found to be harmful. For around half of the interventions evaluated, the Cochrane review concluded that there was insufficient evidence to provide sound recommendations for clinical practice. No RCT evidence is available for a number of potentially relevant interventions. PMID- 24758149 TI - Secondary structure-stretched forms of long intron RNA products from the view point of initiation of chromosome homologs somatic pairing. AB - In different types of chromosome pairing (meiotic, somatic, and sister chromatids pairing) initiation stages are less elucidated. In somatic homolog pairing initiation, the long intron RNA products interference may play the essential role. The strongest somatic pairing in Drosophila melanogaster 28B1-B2 locus and its enrichment by long bi-directional transcripts prone us to analyze the pre mRNA secondary structures. The comparison of sense (pre-mRNA) and antisense (lncRNA) portions corresponding to the lengthy introns for some others' genes loci reveals the significant correlation of stretched folding form lengths with the homologue pairing percentage. Also for 28B1-B2 locus, the most significant homologue pairing is justified by the plurality of sense and antisense RNA variants for lengthy introns. The stretched forms of long intron products with multiple stem-loop clusters widely presented for sense and antisense strands may interact by multiple loops during transcription being connected to different chromosomes and hypothetically may serve for the pairing initiation. Stretched rod-like or V-shape-like are dominating forms for the whole intron RNA products or their central portions while predominantly star-like for others intron fragments. PMID- 24758150 TI - Iranian mothers' perceptions of the impact of the environment on psychological birth trauma: A qualitative study. AB - Childbirth is a unique experience in women's life. Various factors including human and non-human environment are involved in shaping the experience of childbirth.This study investigated the role of the environment on the psychological birth trauma from the perceptions of Iranian mothers. A qualitative descriptive study was conducted from September 2011 to February 2012, using audiotaped interviews with 23 Iranian women recruited from Tehran and Isfahan. The interviews were transcribed verbatim and analysed using the content analysis. Two themes were extracted from the data: human and non-human environment; and several categories also emerged from the data, which are communication with mother, awareness of mother's needs, support for mother, medical clinical competence, professional responsibility, hospital's physical structure, hospital's equipment, routine care in hospital and rules governing the hospital's environment, respectively. Considering the significant role of environment in psychological birth trauma of the mother, an appropriate intervention must be developed to enhance both human and non-human environment in order to reduce the psychological birth trauma. PMID- 24758152 TI - Scaling up the evaluation of psychotherapy: evaluating motivational interviewing fidelity via statistical text classification. AB - BACKGROUND: Behavioral interventions such as psychotherapy are leading, evidence based practices for a variety of problems (e.g., substance abuse), but the evaluation of provider fidelity to behavioral interventions is limited by the need for human judgment. The current study evaluated the accuracy of statistical text classification in replicating human-based judgments of provider fidelity in one specific psychotherapy--motivational interviewing (MI). METHOD: Participants (n = 148) came from five previously conducted randomized trials and were either primary care patients at a safety-net hospital or university students. To be eligible for the original studies, participants met criteria for either problematic drug or alcohol use. All participants received a type of brief motivational interview, an evidence-based intervention for alcohol and substance use disorders. The Motivational Interviewing Skills Code is a standard measure of MI provider fidelity based on human ratings that was used to evaluate all therapy sessions. A text classification approach called a labeled topic model was used to learn associations between human-based fidelity ratings and MI session transcripts. It was then used to generate codes for new sessions. The primary comparison was the accuracy of model-based codes with human-based codes. RESULTS: Receiver operating characteristic (ROC) analyses of model-based codes showed reasonably strong sensitivity and specificity with those from human raters (range of area under ROC curve (AUC) scores: 0.62 - 0.81; average AUC: 0.72). Agreement with human raters was evaluated based on talk turns as well as code tallies for an entire session. Generated codes had higher reliability with human codes for session tallies and also varied strongly by individual code. CONCLUSION: To scale up the evaluation of behavioral interventions, technological solutions will be required. The current study demonstrated preliminary, encouraging findings regarding the utility of statistical text classification in bridging this methodological gap. PMID- 24758153 TI - Leaves and fruits of Bauhinia (Leguminosae, Caesalpinioideae, Cercideae) from the Oligocene Ningming Formation of Guangxi, South China and their biogeographic implications. AB - BACKGROUND: The pantropical genus Bauhinia, along with the northern temperate Cercis and several tropical genera, bear bilobate, bifoliolate, or sometimes unifoliolate leaves, which constitute the tribe Cercideae as sister to the rest of the family Leguminosae based on molecular phylogenetics. Hence, the fossil record of Cercideae is pivotal to understand the early evolution and biogeographic history of legumes. RESULTS: Three fossil species of Bauhinia were described from the Oligocene Ningming Formation of Guangxi, South China. Bauhinia ningmingensis sp. nov. is characterized by its bifoliolate, pulvinate leaves bearing basal acrodromous primary veins and brochidodromous secondary veins. B. cheniae sp. nov. bears moderately or deeply bilobate, pulvinate leaves, with basal actinodromous primary veins and eucamptodromous secondary veins. B. larsenii D.X. Zhang et Y.F. Chen emend. possesses shallowly or moderately bilobate, pulvinate leaves bearing basal actinodromous primary veins and brochidodromous secondary veins, as well as elliptic, stipitate, non-winged, and oligo-seeded fruits. Meanwhile, previously reported Bauhinia fossils were reviewed, and those pre-Oligocene foliage across the world are either questionable or have been rejected due to lacking of reliable evidence for their pulvini or/and basal actinodromous or acrodromous venations. Besides Oligocene leaves and fruits presented here, foliage and/or wood of Bauhinia have been documented from the Miocene-Pliocene of Thailand, India, Nepal, Uganda, and Ecuador. CONCLUSIONS: Bauhinia has exhibited a certain diversity with bifoliolate and bilobate-leafed species in a low-latitude locality-Ningming since at least the Oligocene, implying that the tropical zone of South China may represent one of the centres for early diversification of the genus. The reliable macrofossils of Bauhinia and Cercis have made their debut in the Eocene-Oligocene floras from mid-low latitudes and appeared to lack in the coeval floras at high latitudes, implying a possible Tethys Seaway origin and spread of legumes. However, detailed scenarios for the historical biogeography of Bauhinia and its relatives still need more robust dataset from palaeobotany and molecular phylogeny in future research. PMID- 24758154 TI - One-electron activation of water oxidation catalysis. AB - Rapid water oxidation catalysis is observed following electrochemical oxidation of [Ru(II)(tpy)(bpz)(OH)](+) to [Ru(V)(tpy)(bpz)(O)](3+) in basic solutions with added buffers. Under these conditions, water oxidation is dominated by base assisted Atom Proton Transfer (APT) and direct reaction with OH(-). More importantly, we report here that the Ru(IV)?O(2+) form of the catalyst, produced by 1e(-) oxidation of [Ru(II)(tpy)(bpz)(OH2)](2+) to Ru(III) followed by disproportionation to [Ru(IV)(tpy)(bpz)(O)](2+) and [Ru(II)(tpy)(bpz)(OH2)](2+), is also a competent water oxidation catalyst. The rate of water oxidation by [Ru(IV)(tpy)(bpz)(O)](2+) is greatly accelerated with added PO4(3-) with a turnover frequency of 5.4 s(-1) reached at pH 11.6 with 1 M PO4(3-) at an overpotential of only 180 mV. PMID- 24758151 TI - The cardiac ryanodine receptor luminal Ca2+ sensor governs Ca2+ waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice. AB - CASQ2 (cardiac calsequestrin) is commonly believed to serve as the SR (sarcoplasmic reticulum) luminal Ca2+ sensor. Ablation of CASQ2 promotes SCWs (spontaneous Ca2+ waves) and CPVT (catecholaminergic polymorphic ventricular tachycardia) upon stress but not at rest. How SCWs and CPVT are triggered by stress in the absence of the CASQ2-based luminal Ca2+ sensor is an important unresolved question. In the present study, we assessed the role of the newly identified RyR2 (ryanodine receptor 2)-resident luminal Ca2+ sensor in determining SCW propensity, CPVT susceptibility and cardiac hypertrophy in Casq2 KO (knockout) mice. We crossbred Casq2-KO mice with RyR2 mutant (E4872Q+/-) mice, which lack RyR2-resident SR luminal Ca2+ sensing, to generate animals with both deficiencies. Casq2+/- and Casq2-/- mice showed stress-induced VTs (ventricular tachyarrhythmias), whereas Casq2+/-/E4872Q+/- and Casq2-/-/E4872Q+/- mice displayed little or no stress-induced VTs. Confocal Ca2+ imaging revealed that Casq2-/- hearts frequently exhibited SCWs after extracellular Ca2+ elevation or adrenergic stimulation, whereas Casq2-/-/E4872Q+/- hearts had few or no SCWs under the same conditions. Cardiac hypertrophy developed and CPVT susceptibility increased with age in Casq2-/- mice, but not in Casq2-/-/E4872Q+/- mice. However, the amplitudes and dynamics of voltage-induced Ca2+ transients in Casq2-/- and Casq2-/-/E4872Q+/- hearts were not significantly different. Our results indicate that SCWs, CPVT and hypertrophy in Casq2-null cardiac muscle are governed by the RyR2-resident luminal Ca2+ sensor. This implies that defects in CASQ2-based lumi nal Ca2+ sensing can be overridden by the RyR2-resident luminal Ca2+ sensor. This makes this RyR2-resident sensor a promising molecular target for the treatment of Ca2+-mediated arrhythmias. PMID- 24758155 TI - Subnormothermic machine perfusion for ex vivo preservation and recovery of the human liver for transplantation. AB - To reduce widespread shortages, attempts are made to use more marginal livers for transplantation. Many of these grafts are discarded for fear of inferior survival rates or biliary complications. Recent advances in organ preservation have shown that ex vivo subnormothermic machine perfusion has the potential to improve preservation and recover marginal livers pretransplantation. To determine the feasibility in human livers, we assessed the effect of 3 h of oxygenated subnormothermic machine perfusion (21 degrees C) on seven livers discarded for transplantation. Biochemical and microscopic assessment revealed minimal injury sustained during perfusion. Improved oxygen uptake (1.30 [1.11-1.94] to 6.74 [4.15-8.16] mL O2 /min kg liver), lactate levels (4.04 [3.70-5.99] to 2.29 [1.20 3.43] mmol/L) and adenosine triphosphate content (45.0 [70.6-87.5] pmol/mg preperfusion to 167.5 [151.5-237.2] pmol/mg after perfusion) were observed. Liver function, reflected by urea, albumin and bile production, was seen during perfusion. Bile production increased and the composition of bile (bile salts/phospholipid ratio, pH and bicarbonate concentration) became more favorable. In conclusion, ex vivo subnormothermic machine perfusion effectively maintains liver function with minimal injury and sustains or improves various hepatobiliary parameters postischemia. PMID- 24758156 TI - Female Genital Cutting (FGC) and the ethics of care: community engagement and cultural sensitivity at the interface of migration experiences. AB - BACKGROUND: Female Genital Cutting (FGC) anchored in a complex socio-cultural context becomes significant at the interface of access of health and social services in host countries. The practice of FGC at times, understood as a form of gender-based violence, may result in unjustifiable consequences among girls and women; yet, these practices are culturally engrained traditions with complex meanings calling for ethically and culturally sensitive health and social service provision. Intents and meanings of FGC practice need to be well understood before before any policies that criminalize and condemn are derived and implemented. FGC is addressed as a global public health issue with complex legal and ethical dimensions which impacts ability to access services, far beyond gender sensitivity. The ethics of terminology are addressed, building on the sustained controversial debate in regards to the delicate issue of conceptualization. An overview of international policies is provided, identifying the current trend of condemnation of FGC practices. Socio-cultural and ethical challenges are discussed in light of selected findings from a community-based research project. The illustrative examples provided focus on Western countries, with a specific emphasis on Canada. DISCUSSION: The examples provided converge with the literature confirming the utmost necessity to engage with the FGC practicing communities allowing for ethically sensitive strategies, reduction of harm in relation to systems of care, and prevention of the risk of systematic gendered stigmatization. A culturally competent, gender and ethically sensitive approach is argued for to ensure the provision of quality ethical care for migrant families in host countries. We argue that socio-cultural determinants such as ethnicity, migration, sex and gender need to be accounted for as integral to the social construction of FGC. SUMMARY: Working partnerships between the public health sector and community based organisations with a true involvement of women and men from practicing communities will allow for more sensitive and congruent clinical guidelines. In order to honour the fundamental principles and values of medical ethics, such as compassion, beneficence, non-malfeasance, respect, and justice and accountability, socio-cultural interactions at the interface of health and migration will continue to require proper attention. It entails a commitment to recognise the intrinsic value and dignity of girls' and women's context. PMID- 24758157 TI - HCV core antigen and HCV-RNA in HIV/HCV co-infected patients with different HCV genotypes. AB - BACKGROUND: A good correlation between HCV core antigen (HCVAg) and different HCV RNA assays has been described, but little data are available in HCV/HIV co infection. We aimed to evaluate HCVAg in comparison with HCV-RNA and to determine their kinetics during antiviral treatment in selected HCV/HIV co-infected patients. METHODS: 355 samples from 286 HCV/HIV co-infected subjects for whom HCV RNA (Abbott RealTime) was requested were analysed also for HCVAg (Abbott ARCHITECT) in order to evaluate the correlation between the two parameters both in patients treated or untreated for chronic hepatitis C and according to different HCV genotypes. The differences between percentages were evaluated by chi square or Fisher's exact test, while mean and median values were compared by Student's t test or the Mann-Whitney test, respectively. All differences were considered significant for a p value <0.05. RESULTS: HCVAg was detectable on 288/315 sera (91.4%) positive for HCV-RNA and in 5 out of40 (12.5%) sera with undetectable HCV-RNA for a total concordance of 90.1%. The correlation was fair both in untreated (r = 0.742) and in treated (r = 0.881) patients and stronger for genotypes 1 and 4 than for genotype 3. Both HCV-RNA and HCVAg levels were significantly higher (p = 0.028 and p = 0.0098, respectively) in patients infected by genotype 1 than by genotype 3. The mean ratio of Log values between HCV-RNA (IU/mL) and HCVAg (fmol/liter) was 2.27 +/- 1.09 in untreated and 2.20 +/ 0.82 in treated patients (p = n.s.),consistent with a sensitivity of HCVAg corresponding to about 1,000 IU/mL of HCV-RNA, and ranged from 2.21 to 2.32 among HCV genotypes with no significant differences; five samples (1.4%; 2 genotype 1a or 1c, 3 genotype 3a) showed highly divergent values. The analysis of 18 monitoring profiles from patients treated with PEG-IFN and Ribavirin showed similar trends, except in one case in which relapse could be predicted by HCVAg and not by HCV-RNA. CONCLUSION: These results suggest that HCVAg represents an adequate tool for determining an ongoing HCV infection also in HIV co-infected patients, with lower costs and faster turnaround time than HCV-RNA. PMID- 24758158 TI - Opening Minds Stigma Scale for Health Care Providers (OMS-HC): examination of psychometric properties and responsiveness. AB - BACKGROUND: Diminishing stigmatization for those with mental illnesses by health care providers (HCPs) is becoming a priority for programming and policy, as well as research. In order to be successful, we must accurately measure stigmatizing attitudes and behaviours among HCPs. The Opening Minds Stigma Scale for Health Care Providers (OMS-HC) was developed to measure stigma in HCP populations. In this study we revisit the factor structure and the responsiveness of the OMS-HC in a larger, more representative sample of HCPs that are more likely to be targets for anti-stigma interventions. METHODS: Baseline data were collected from HCPs (n = 1,523) during 12 different anti-stigma interventions across Canada. The majority of HCPs were women (77.4%) and were either physicians (MDs) (41.5%), nurses (17.0%), medical students (13.4%), or students in allied health programs (14.0%). Exploratory factor analysis (EFA) was conducted using complete pre-test (n = 1,305) survey data and responsiveness to change analyses was examined with pre and post matched data (n = 803). The internal consistency of the OMS-HC scale and subscales was evaluated using the Cronbach's alpha coefficient. The scale's sensitivity to change was examined using paired t-tests, effect sizes (Cohen's d), and standardized response means (SRM). RESULTS: The EFA favored a 3-factor structure which accounted for 45.3% of the variance using 15 of 20 items. The overall internal consistency for the 15-item scale (alpha = 0.79) and three subscales (alpha = 0.67 to 0.68) was acceptable. Subgroup analysis showed the internal consistency was satisfactory across HCP groups including physicians and nurses (alpha = 0.66 to 0.78). Evidence for the scale's responsiveness to change occurred across multiple samples, including student-targeted interventions and workshops for practicing HCPs. The Social Distance subscale had the weakest level of responsiveness (SRM <= 0.50) whereas the more attitudinal-based items comprising the Attitude (SRM <= 0.91) and Disclosure and Help-seeking (SRM <= 0.68) subscales had stronger responsiveness. CONCLUSIONS: The OMS-HC has shown to have acceptable internal consistency and has been successful in detecting positive changes in various anti-stigma interventions. Our results support the use of a 15-item scale, with the calculation of three sub scores for Attitude, Disclosure and Help-seeking, and Social Distance. PMID- 24758159 TI - Neuromyelitis optica pathology in rats following intraperitoneal injection of NMO IgG and intracerebral needle injury. AB - INTRODUCTION: Animal models of neuromyelitis optica (NMO) are needed for drug testing and evaluation of NMO disease pathogenesis mechanisms. RESULTS: We describe a novel passive-transfer model of NMO in which rats made seropositive for human anti-aquaporin-4 (AQP4) immunoglobulin G antibody (NMO-IgG) by intraperitoneal (IP) injections were subject to intracerebral needle injury. Following a single IP injection, NMO-IgG distributed rapidly to peripheral AQP4 expressing cells (kidney collecting duct, gastric glands, airways, skeletal muscle) and area postrema in brain, but not elsewhere in the central nervous system; however, no pathology was seen in brain, spinal cord, optic nerve or peripheral tissues. After testing various maneuvers to produce NMO-IgG-dependent pathology in brain, we found that transient puncture of brain parenchyma with a 28-gauge needle in NMO-IgG seropositive rats produced robust NMO pathology around the needle track, with loss of AQP4 and glial fibrillary acidic protein, granulocyte and macrophage infiltration, centrovascular deposition of activated complement, and blood-brain barrier disruption, with demyelination by 5 days. Pathology was not seen in rats receiving control (non-NMO) human IgG or in NMO IgG-seropositive rats made complement-deficient by cobra venom factor. Interestingly, at 1 day a reversible, multifocal astrocytopathy was seen with loss of AQP4 and GFAP (but not myelin) in areas away from the needle track. CONCLUSIONS: NMO-IgG-seropositivity alone is not sufficient to cause NMO pathology in rats, but a single intracerebral needle insertion, without pre existing inflammation or infusion of pro-inflammatory factors, was sufficient to produce robust NMO pathology in seropositive rats. PMID- 24758160 TI - Respondents' recall of injury events: an investigation of recall bias in cross sectional injury data from the Sudan Household Health Survey 2010. AB - Recall bias is a well-documented limitation of population-based cross-sectional injury surveys. To fill some gaps in this area, we investigated the extent and nature of recall bias in Sudan Household Health Survey (SHHS 2010) injury data. The extent of incomplete recall was measured by comparing the total reported injuries over 12 months with the annualised number of injuries in the four weeks preceding the survey. Multivariable logistic regression was used to investigate the association of socio-demographic variables, injury attributes and interviewee characteristics with differential recall. Relevant interactions were tested. Overall, reported injuries were 33% of the expected. Injuries among children 1-4 years had lower odds of being reported to have occurred earlier than the four weeks preceding the survey than people aged 65 years and over (OR = 0.24, 95% CI 0.12-0.47). Injuries that received inpatient care in the first week were more likely to be recalled than those that did not receive care (OR = 2.07, 95% CI 1.14-3.75). Respondent's age was associated with differential recall. Differential injury recall should be considered when using SHHS 2010 to compare injury occurrence between children under five and older groups or at the level of health care received. PMID- 24758161 TI - Long term effects of cocaine on the heart assessed by cardiovascular magnetic resonance at 3T. AB - BACKGROUND: Cocaine is an addictive, sympathomimetic drug with potentially lethal effects. The prevalence and features of cocaine cardiotoxicity are not well known. We aimed to assess these effects using a comprehensive cardiovascular magnetic resonance (CMR) protocol in a large group of asymptomatic cocaine users. METHODS: Consecutive (n = 94, 81 males, 36.6 +/-7 years), non-selected, cocaine abusers were recruited and had a medical history, examination, ECG, blood test and CMR. The CMR study included measurement of left and right ventricular (LV, RV) dimensions and ejection fraction (EF), sequences for detection of myocardial oedema and late gadolinium enhancement (LGE). Images were compared to a cohort of healthy controls. RESULTS: Years of regular cocaine use were 13.9 +/- 9. When compared to the age-matched healthy cohort, the cocaine abusers had increased LV end-systolic volume, LV mass index and RV end-systolic volume, with decreased LVEF and RVEF. No subject had myocardial oedema, but 30% had myocardial LGE indicating myocardial damage. CONCLUSIONS: CMR detected cardiovascular disease in 71% of this cohort of consecutive asymptomatic cocaine abusers and mean duration of abuse was related to probability of LV systolic dysfunction. PMID- 24758162 TI - High rates of early treatment discontinuation in hepatitis C-infected US veterans. AB - BACKGROUND: Patients with chronic hepatitis C (HCV) frequently discontinued dual therapy with pegylated interferon alfa (Peg-IFN) plus ribavirin (RBV) before reaching the recommended duration of 48 or 24 weeks for genotypes (G) 1/4 or 2/3, respectively. We quantified rates of discontinuation despite efficacy (non-LOE) versus lack of efficacy (LOE) versus discontinuation for unknown reasons in a national database of United States veterans. METHODS: We identified a population based cohort of U.S. veterans with encounters from 2004 through 2009 who had lab confirmed HCV infection and initiated therapy with Peg-IFN plus RBV in Veterans Health Administration medical centers. Pharmacy data were used to determine therapy duration, defined as the sum of Peg-IFN days supplied. Patients "discontinued" if they failed to receive at least 44 (G1/4) or 20 weeks (G2/3) of therapy. We classified discontinuations as due to non-LOE, LOE, or unknown reasons using a classification rule based on treatment duration and laboratory confirmed response. RESULTS: Of 321,238 diagnosed HCV patients during the evaluation period, 9.7% initiated therapy and 6.4% met all other inclusion criteria. 54.9% of patients discontinued early; of these, 41.2% discontinued due to non-LOE reasons, 12.5% discontinued for LOE reasons, and 46.3% discontinued for unknown reasons. Among non-LOE discontinuers, most (60.1%) discontinued in the first 4 weeks of therapy, which constitutes 13.6% of all treated patients. CONCLUSIONS: We observed a high proportion of early discontinuations with dual therapy regimens in a national cohort of HCV-infected veterans. If this trend persists in the triple-therapy era, then efforts must be undertaken to improve adherence. PMID- 24758163 TI - Visual gene-network analysis reveals the cancer gene co-expression in human endometrial cancer. AB - BACKGROUND: Endometrial cancers (ECs) are the most common form of gynecologic malignancy. Recent studies have reported that ECs reveal distinct markers for molecular pathogenesis, which in turn is linked to the various histological types of ECs. To understand further the molecular events contributing to ECs and endometrial tumorigenesis in general, a more precise identification of cancer associated molecules and signaling networks would be useful for the detection and monitoring of malignancy, improving clinical cancer therapy, and personalization of treatments. RESULTS: ECs-specific gene co-expression networks were constructed by differential expression analysis and weighted gene co-expression network analysis (WGCNA). Important pathways and putative cancer hub genes contribution to tumorigenesis of ECs were identified. An elastic-net regularized classification model was built using the cancer hub gene signatures to predict the phenotypic characteristics of ECs. The 19 cancer hub gene signatures had high predictive power to distinguish among three key principal features of ECs: grade, type, and stage. Intriguingly, these hub gene networks seem to contribute to ECs progression and malignancy via cell-cycle regulation, antigen processing and the citric acid (TCA) cycle. CONCLUSIONS: The results of this study provide a powerful biomarker discovery platform to better understand the progression of ECs and to uncover potential therapeutic targets in the treatment of ECs. This information might lead to improved monitoring of ECs and resulting improvement of treatment of ECs, the 4th most common of cancer in women. PMID- 24758164 TI - Evaluating an audit and feedback intervention for reducing antibiotic prescribing behaviour in general dental practice (the RAPiD trial): a partial factorial cluster randomised trial protocol. AB - BACKGROUND: Antibiotic prescribing in dentistry accounts for 9% of total antibiotic prescriptions in Scottish primary care. The Scottish Dental Clinical Effectiveness Programme (SDCEP) published guidance in April 2008 (2nd edition, August 2011) for Drug Prescribing in Dentistry, which aims to assist dentists to make evidence-based antibiotic prescribing decisions. However, wide variation in prescribing persists and the overall use of antibiotics is increasing. METHODS: RAPiD is a 12-month partial factorial cluster randomised trial conducted in NHS General Dental Practices across Scotland. Its aim is to compare the effectiveness of individualised audit and feedback (A&F) strategies for the translation into practice of SDCEP recommendations on antibiotic prescribing. The trial uses routinely collected electronic healthcare data in five aspects of its design in order to: identify the study population; apply eligibility criteria; carry out stratified randomisation; generate the trial intervention; analyse trial outcomes. Eligibility was determined on contract status and a minimum level of recent NHS treatment provision. All eligible dental practices in Scotland were simultaneously randomised at baseline either to current audit practice or to an intervention group. Randomisation was stratified by single-handed/multi-handed practices. General dental practitioners (GDPs) working at intervention practices will receive individualised graphical representations of their antibiotic prescribing rate from the previous 14 months at baseline and an update at six months. GDPs could not be blinded to their practice allocation. Intervention practices were further randomised using a factorial design to receive feedback with or without: a health board comparator; a supplementary text-based intervention; additional feedback at nine months. The primary outcome is the total antibiotic prescribing rate per 100 courses of treatment over the year following delivery of the baseline intervention. A concurrent qualitative process evaluation will apply theory-based approaches using the Consolidated Framework for Implementation Research to explore the acceptability of the interventions and the Theoretical Domains Framework to identify barriers and enablers to evidence based antibiotic prescribing behaviour by GDPs. DISCUSSION: RAPiD will provide a robust evaluation of A&F in dentistry in Scotland. It also demonstrates that linked administrative datasets have the potential to be used efficiently and effectively across all stages of an randomised controlled trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49204710. PMID- 24758165 TI - Perceptions and recommendations by scientists for a potential release of genetically modified mosquitoes in Nigeria. AB - BACKGROUND: The use of genetically modified mosquitoes (GMMs) for the control of malaria and other mosquito-borne diseases has been proposed in malaria-endemic countries, such as Nigeria, which has the largest burden in Africa. Scientists are major stakeholders whose opinions and perceptions can adversely affect the success of the trials of GMMs if they are not involved early. Unfortunately, information on the awareness of Nigerians scientists and their overall perception of the GMMs is practically non-existent in the literature. Therefore, this study aimed at understanding how receptive Nigerian scientists are to a potential release of GMMs for the control of malaria. METHODS: The sample consisted of 164 scientists selected from academic and research institutions in Nigeria. Data were collected from participants using a semi-structured, self-administered questionnaire. Questions were asked about the cause and prevention of malaria, genetic modification and biotechnology. Specific questions on perception and acceptable conditions for the potential release of GM mosquitoes in Nigeria were also covered. RESULTS: All participants cited mosquitoes as one of several causes of malaria and used various methods for household control of mosquitoes. The main concerns expressed by the scientists were that GMMs can spread in an uncontrolled way beyond their release sites (89%) and will mate with other mosquito species to produce hybrids with unknown consequences (94.5%). Most participants (92.7%) agreed that it was important that before approving the release of GMMs in Nigeria, there had to be evidence of contingency measures available to remove the GMMs should a hazard become evident during the course of the release. In general, a majority (83.5%) of scientists who participated in this study were sceptical about a potential release in Nigeria, while 16.5% of the participants were in support. CONCLUSIONS: Although a majority of the participants are sceptical about GMMs generally, most encourage the use of genetic modification techniques to make mosquitoes incapable of spreading diseases provided that there are contingency measures to remove GMMs if a hazard becomes evident during the course of the release. PMID- 24758166 TI - Inactivation of mammalian Ero1alpha is catalysed by specific protein disulfide isomerases. AB - Disulfide formation within the endoplasmic reticulum is a complex process requiring a disulfide exchange protein such as PDI (protein disulfide-isomerase) and a mechanism to form disulfides de novo. In mammalian cells, the major pathway for de novo disulfide formation involves the enzyme Ero1alpha (endoplasmic reticulum oxidase 1alpha) which couples oxidation of thiols to the reduction of molecular oxygen to form hydrogen peroxide (H2O2). Ero1alpha activity is tightly regulated by a mechanism that requires the formation of regulatory disulfides. These regulatory disulfides are reduced to activate and reform to inactivate the enzyme. To investigate the mechanism of inactivation we analysed regulatory disulfide formation in the presence of various oxidants under controlled oxygen concentration. Neither molecular oxygen nor H2O2 was able to oxidize Ero1alpha efficiently to form the correct regulatory disulfides. However, specific members of the PDI family, such as PDI or ERp46 (endoplasmic reticulum-resident protein 46), were able to catalyse this process. Further studies showed that both active sites of PDI contribute to the formation of regulatory disulfides in Ero1alpha and that the PDI substrate-binding domain is crucial to allow electron transfer between the two enzymes. The results of the present study demonstrate a simple feedback mechanism of re-gulation of mammalian Ero1alpha involving its primary substrate. PMID- 24758167 TI - Be smart against cancer! A school-based program covering cancer-related risk behavior. AB - BACKGROUND: Several studies suggest that most school-age children are poorly informed about cancer risk factors. This study examines the effectiveness of the 'Be smart against cancer' (BSAC) program in promoting cancer awareness and intentions to engage in health-promoting behavior. METHODS: 235 seventh-grade students were randomized to either the intervention (N = 152) or the wait-control group (N = 83). The intervention included the modules: "What is cancer?," "Sun protection," "Non smoking," and "Physical activity, Healthy nutrition, and Limited alcohol consumption." Outcomes measured at baseline and at the end of the one week BSAC program included knowledge of cancer and its behavioral risk factors, health-promoting intentions, and reported risk behavior. RESULTS: BSAC was effective in increasing knowledge about cancer and risk factors for cancer (p < .001), as well as in increasing intentions to engage in health-promoting behavior (p < .001), independent of a student's risk profile. Knowledge did not serve as a mediator for intention building. CONCLUSIONS: The BSAC is an effective school-based program for raising awareness of cancer, associated risk factors and intentions to engage in cancer-preventive behavior. The results indicate that the effectiveness of BSAC is independent of a student's risk profile. Therefore, it holds considerable promise as a broadly applicable program to raise cancer awareness and promote healthy behavior intentions. PMID- 24758168 TI - Robust volume-targeted balanced steady-state free-precession coronary magnetic resonance angiography in a breathhold at 3.0 Tesla: a reproducibility study. AB - BACKGROUND: Transient balanced steady-state free-precession (bSSFP) has shown substantial promise for noninvasive assessment of coronary arteries but its utilization at 3.0 T and above has been hampered by susceptibility to field inhomogeneities that degrade image quality. The purpose of this work was to refine, implement, and test a robust, practical single-breathhold bSSFP coronary MRA sequence at 3.0 T and to test the reproducibility of the technique. METHODS: A 3D, volume-targeted, high-resolution bSSFP sequence was implemented. Localized image-based shimming was performed to minimize inhomogeneities of both the static magnetic field and the radio frequency excitation field. Fifteen healthy volunteers and three patients with coronary artery disease underwent examination with the bSSFP sequence (scan time = 20.5 +/- 2.0 seconds), and acquisitions were repeated in nine subjects. The images were quantitatively analyzed using a semi automated software tool, and the repeatability and reproducibility of measurements were determined using regression analysis and intra-class correlation coefficient (ICC), in a blinded manner. RESULTS: The 3D bSSFP sequence provided uniform, high-quality depiction of coronary arteries (n = 20). The average visible vessel length of 100.5 +/- 6.3 mm and sharpness of 55 +/- 2% compared favorably with earlier reported navigator-gated bSSFP and gradient echo sequences at 3.0 T. Length measurements demonstrated a highly statistically significant degree of inter-observer (r = 0.994, ICC = 0.993), intra-observer (r = 0.894, ICC = 0.896), and inter-scan concordance (r = 0.980, ICC = 0.974). Furthermore, ICC values demonstrated excellent intra-observer, inter-observer, and inter-scan agreement for vessel diameter measurements (ICC = 0.987, 0.976, and 0.961, respectively), and vessel sharpness values (ICC = 0.989, 0.938, and 0.904, respectively). CONCLUSIONS: The 3D bSSFP acquisition, using a state-of-the art MR scanner equipped with recently available technologies such as multi transmit, 32-channel cardiac coil, and localized B0 and B1+ shimming, allows accelerated and reproducible multi-segment assessment of the major coronary arteries at 3.0 T in a single breathhold. This rapid sequence may be especially useful for functional imaging of the coronaries where the acquisition time is limited by the stress duration and in cases where low navigator-gating efficiency prohibits acquisition of a free breathing scan in a reasonable time period. PMID- 24758169 TI - Rationale and design of REACT: a randomised controlled trial assessing the effectiveness of home-collection to increase chlamydia retesting and detect repeat positive tests. AB - BACKGROUND: Repeat infection with Chlamydia trachomatis is common and increases the risk of sequelae in women and HIV seroconversion in men who have sex with men (MSM). Despite guidelines recommending chlamydia retesting three months after treatment, retesting rates are low. We are conducting the first randomised controlled trial to assess the effectiveness of home collection combined with short message service (SMS) reminders on chlamydia retesting and reinfection rates in three risk groups. METHODS/DESIGN: The REACT (retest after Chlamydia trachomatis) trial involves 600 patients diagnosed with chlamydia: 200 MSM, 200 women and 200 heterosexual men recruited from two Australian sexual health clinics where SMS reminders for retesting are routine practice. Participants will be randomised to the home group (3-month SMS reminder and home-collection) or the clinic group (3-month SMS reminder to return to the clinic). Participants in the home group will be given the choice of attending the clinic if they prefer. The mailed home-collection kit includes a self-collected vaginal swab (women), UriSWAB (Copan) for urine collection (heterosexual men), and UriSWAB plus rectal swab (MSM). The primary outcome is the retest rate at 1-4 months after a chlamydia diagnosis, and the secondary outcomes are: the repeat positive test rate; the reinfection rate; the acceptability of home testing with SMS reminders; and the cost effectiveness of home testing. Sexual behaviour data collected via an online survey at 4-5 months, and genotyping of repeat infections, will be used to discriminate reinfections from treatment failures. The trial will be conducted over two years. An intention to treat analysis will be conducted. DISCUSSION: This study will provide evidence about the effectiveness of home-collection combined with SMS reminders on chlamydia retesting, repeat infection and reinfection rates in three risk groups. The trial will determine client acceptability and cost effectiveness of this strategy. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12611000968976. PMID- 24758170 TI - Fear extinction requires Arc/Arg3.1 expression in the basolateral amygdala. AB - BACKGROUND: Prolonged re-exposure to a fear-eliciting cue in the absence of an aversive event extinguishes the fear response to the cue, and has been clinically used as an exposure therapy. Arc (also known as Arg3.1) is implicated in synaptic and experience-dependent plasticity. Arc is regulated by the transcription factor cAMP response element binding protein, which is upregulated with and necessary for fear extinction. Because Arc expression is also activated with fear extinction, we hypothesized that Arc expression is required for fear extinction. FINDINGS: Extinction training increased the proportion of Arc-labeled cells in the basolateral amygdala (BLA). Arc was transcribed during latter part of extinction training, which is possibly associated with fear extinction, as well as former part of extinction training. Intra-BLA infusions of Arc antisense oligodeoxynucleotide (ODN) before extinction training impaired long-term but not short-term extinction memory. Intra-BLA infusions of Arc antisense ODN 3 h after extinction training had no effect on fear extinction. CONCLUSION: Our findings demonstrate that Arc is required for long-term extinction of conditioned fear and contribute to the understanding of extinction as a therapeutic manner. PMID- 24758171 TI - MKL1/2 and ELK4 co-regulate distinct serum response factor (SRF) transcription programs in macrophages. AB - BACKGROUND: Serum response factor (SRF) is a widely expressed transcription factor involved in multiple regulatory programs. It is believed that SRF can toggle between disparate programs of gene expression through association with different cofactors. However, the direct evidence as to how these factors function on a genome-wide level is still lacking. RESULTS: In the present study, I explored the functions of SRF and its representative cofactors, megakaryoblastic leukemia 1/2 (MKL1/2) and ETS-domain protein 4 (ELK4), during fungal infection challenge in macrophages. The knockdown study, combined with gene expression array analysis, revealed that MKL1/2 regulated SRF-dependent genes were related to actin cytoskeleton organization, while ELK4 regulated SRF dependent genes were related to external stimulus responses. Subsequent chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-seq) suggested that many of these regulations were mediated directly in cis. CONCLUSIONS: I conclude that SRF utilizes MKL1/2 to fulfill steady state cellular functions, including cytoskeletal organization, and utilizes ELK4 to facilitate acute responses to external infection. Together, these findings indicate that SRF, along with its two cofactors, are important players in both cellular homeostasis and stress responses in macrophages. PMID- 24758172 TI - Evidence for significant influence of host immunity on changes in differential blood count during malaria. AB - BACKGROUND: Malaria has been shown to change blood counts. Recently, a few studies have investigated the alteration of the peripheral blood monocyte-to lymphocyte count ratio (MLCR) and the neutrophil-to-lymphocyte count ratio (NLCR) during infection with Plasmodium falciparum. Based on these findings this study investigates the predictive values of blood count alterations during malaria across different sub-populations. METHODS: Cases and controls admitted to the Department of Infectious Diseases and Tropical Medicine from January 2000 through December 2010 were included in this comparative analysis. Blood count values and other variables at admission controlled for age, gender and immune status were statistically investigated. RESULTS: The study population comprised 210 malaria patients, infected with P. falciparum (68%), Plasmodium vivax (21%), Plasmodium ovale (7%) and Plasmodium malariae (4%), and 210 controls. A positive correlation of parasite density with NLCR and neutrophil counts, and a negative correlation of parasite density with thrombocyte, leucocyte and lymphocyte counts were found. An interaction with semi-immunity was observed; ratios were significantly different in semi-immune compared to non-immune patients (P <0.001).The MLCR discriminated best between malaria cases and controls (AUC = 0.691; AUC = 0.741 in non-immune travellers), whereas the NLCR better predicted severe malaria, especially in semi-immune patients (AUC = 0.788). CONCLUSION: Malaria causes typical but non-specific alterations of the differential blood count. The predictive value of the ratios was fair but limited. However, these changes were less pronounced in patients with semi-immunity. The ratios might constitute easily applicable surrogate biomarkers for immunity. PMID- 24758173 TI - Measurement of a drowning incidence rate combining direct observation of an exposed population with mortality statistics. AB - Drowning risk factors may be identified by comparing drowning incidence rates for comparable at-risk populations but precise methods are lacking. To address this knowledge gap, an ecological study extrapolated crude time-duration exposure to water for a specified at-risk sample of surf bathers to estimate the bather population for all wave-dominated beaches in Victoria, Australia, over a four year summer season period. An incidence rate was calculated using surf bather drowning deaths frequencies matched for time and location. For the sample, 47,341 hours of surf bathing were estimated from 177,528 bathing episodes. Generalising these results to Victoria, the crude drowning deaths incidence rate in the summer season was 0.41 per 1,000,000 person-hours of surf bathing (95% CI 0.37-0.45). Further application of the method, particularly in open water settings, may be used to identify candidate drowning risk factors to advance drowning prevention strategies. PMID- 24758174 TI - Traditional healers and the potential for collaboration with the national tuberculosis programme in Vanuatu: results from a mixed methods study. AB - BACKGROUND: This study was conducted in the Pacific island nation of Vanuatu. Our objective was to assess knowledge, attitudes and practice of traditional healers who treat lung diseases and tuberculosis (TB), including their willingness to collaborate with the national TB programme. METHODS: This was a descriptive study using both qualitative and quantitative methods. Quantitative analysis was based on the responses provided to closed-ended questions, and we used descriptive analysis (frequencies) to describe the knowledge, attitudes and practice of the traditional healers towards TB. Qualitative analysis was based on open-ended questions permitting fuller explanations. We used thematic analysis and developed a posteriori inductive categories to draw original and unbiased conclusions. RESULTS: Nineteen traditional healers were interviewed; 18 were male. Fifteen of the healers reported treating short wind (a local term to describe lung, chest or breathing illnesses) which they attributed to food, alcohol, smoking or pollution from contact with menstrual blood, and a range of other physical and spiritual causes. Ten said that they would treat TB with leaf medicine. Four traditional healers said that they would not treat TB. Twelve of the healers had referred someone to a hospital for a strong wet-cough and just over half of the healers (9) reported a previous collaboration with the Government health care system. Eighteen of the traditional healers would be willing to collaborate with the national TB programme, with or without compensation. CONCLUSIONS: Traditional healers in Vanuatu treat lung diseases including TB. Many have previously collaborated with the Government funded health care system, and almost all of them indicated a willingness to collaborate with the national TB programme. The engagement of traditional healers in TB management should be considered, using an evidence based and culturally sensitive approach. PMID- 24758175 TI - Conserved residues that modulate protein trans-splicing of Npu DnaE split intein. AB - The first crystal trans-structure of a naturally occurring split intein has been determined for the Npu (Nostoc punctiforme PCC73102) DnaE split intein. Guided by this structure, the residues NArg50 and CSer35, well conserved in DnaE split inteins, are identified to be critical in the trans-splicing of Npu DnaE split intein. An in vitro splicing assay demonstrates that NArg50 and CSer35 play synergistic roles in modulating its intein activity. The C-terminal CAsn36 exhibits two orientations of its side chain and interacts with both NArg50 and CSer35 through hydrogen bonding. These interactions likely facilitate the cyclization of asparagine in the course of protein splicing. The mutation of either residue reduces intein activity, and correlates with the low activity of the Ssp (Cyanobacterium synechocystis sp. strain PCC6803) DnaE split intein. On the other hand, NArg50 also forms a hydrogen bond with the highly conserved F block CAsp17, thus influencing the N-S acyl shift during N-terminal cleavage. Sequence alignments show that residues NArg50 and CSer35 are rather conserved in those split inteins that lack a penultimate histidine residue. The conserved non catalytic residues of split inteins modulate the efficiency of protein trans splicing by hydrogen-bond interactions with the catalytic residues at the splice junction. PMID- 24758176 TI - Legibility difference between e-books and paper books by using an eye tracker. AB - The aim of the study was to evaluate the difference in legibility between e-books and paper books by using an eye tracker. Eight male and eight female subjects free of eye disease participated in the experiment. The experiment was conducted using a 2 * 3 within-subject design. The book type (e-book, paper book) and font size (8 pt, 10 pt, 12 pt) were independent variables, and fixation duration time, saccade length, blink rate and subjective discomfort were dependent variables. In the results, all dependent variables showed that reading paper books provided a better experience than reading e-books did. These results indicate that the legibility of e-books needs further improvement, considering fixation duration time, saccade movement, eye fatigue, device and so on. PRACTITIONER SUMMARY: This study evaluated the legibility difference between e-books and paper books from the viewpoint of readability, eye fatigue and subjective discomfort by using an eye tracker. The results showed that paper books provided a better experience than e-books. This indicates that the readability of e-books needs further improvement in relation to paper books. PMID- 24758178 TI - Disorders of sex development (DSDs): an update. AB - CONTEXT: Disorders of sex development (DSDs) may arise from genetic defects in testis or ovary determination. Current analytical technologies and improved understanding of major regulatory pathways have cast new insight into the genetic basis for these disorders. EVIDENCE ACQUISITION: A PubMed search was performed for the years 2011-13 using the terms "disorder of sex development," "gonadal dysgenesis," "ovarian dysgenesis," "array CGH," and "whole exome sequencing." Only articles from peer-reviewed journals were included. EVIDENCE SYNTHESIS: Key themes that emerged included aberrant regulation of SOX9 via the hTES promoter in 46,XY gonadal DSDs, the role of the MAPK pathway in normal and aberrant gonadal development, and the role of new technologies in identification of gonadal DSDs. CONCLUSIONS: With the advent of the robust new technologies of array comparative genomic hybridization and genomic sequencing in recent years, many new sex determining genes have been identified. These genes have been organized into ovarian- and testicular-determining pathways that can block each other's activities. Identification of a mutation in a sex-determining gene in an individual affected with a DSD may warrant more extensive investigation for other phenotypic effects as well as genetic testing of other family members. PMID- 24758177 TI - Nuclear factor kappaB-dependent regulation of angiogenesis, and metastasis in an in vivo model of thyroid cancer is associated with secreted interleukin-8. AB - CONTEXT: Development of novel strategies in the treatment of advanced thyroid cancer are needed. Our laboratory has previously identified a role for nuclear factor kappaB (NF-kappaB) signaling in human thyroid cancer cell growth, survival, and invasion. OBJECTIVE: Our goal was to establish the role of NF kappaB signaling on thyroid cancer growth and metastases in vivo and to begin to dissect mechanisms regulating this effect. SETTING AND DESIGN: We examined tumor formation of five thyroid cancer cell lines in an in vivo model of thyroid cancer and observed tumor establishment in two of the cell lines (8505C and BCPAP). RESULTS: Inhibition of NF-kappaB signaling by overexpression of a dominant negative IkappaBalpha (mIkappaBalpha) significantly inhibited thyroid tumor growth in tumors derived from both cell lines. Further studies in an experimental metastasis model demonstrated that NF-kappaB inhibition impaired growth of tumor metastasis and prolonged mouse survival. Proliferation (mitotic index) was decreased in 8505C tumors, but not in BCPAP tumors, while in vitro angiogenesis and in vivo tumor vascularity were significantly inhibited by mIkBalpha only in the BCPAP cells. Cytokine antibody array analysis demonstrated that IL-8 secretion was blocked by mIkappaBalpha expression. Interestingly, basal NF-kappaB activity and IL-8 levels were significantly higher in the two tumorigenic cell lines compared with the nontumorigenic lines. Furthermore, IL-8 transcript levels were elevated in high-risk human tumors, suggesting that NF-kappaB and IL-8 are associated with more aggressive tumor behavior. CONCLUSIONS: These studies suggest that NF-kappaB signaling is a key regulator of angiogenesis and growth of primary and metastatic thyroid cancer, and that IL-8 may be an important downstream mediator of NF-kappaB signaling in advanced thyroid cancer growth and progression. PMID- 24758179 TI - The clinical phenotype of SDHC-associated hereditary paraganglioma syndrome (PGL3). AB - CONTEXT: Mutations in the genes encoding subunits of the succinate dehydrogenase complex cause hereditary paraganglioma syndromes. Although the phenotypes associated with the more commonly mutated genes, SDHB and SDHD, are well described, less is known about SDHC-associated paragangliomas. OBJECTIVE: To describe functionality, penetrance, number of primary tumors, biological behavior, and location of paragangliomas associated with SDHC mutations. DESIGN: Families with an SDHC mutation were identified through a large cancer genetics registry. A retrospective chart review was conducted with a focus on patient and tumor characteristics. In addition, clinical reports on SDHC-related paragangliomas were identified in the medical literature to further define the phenotype and compare findings. SETTING: A cancer genetics clinic and registry at a tertiary referral center. PATIENTS: Eight index patients with SDHC-related paraganglioma were identified. RESULTS: Three of the eight index patients had mediastinal paraganglioma and four of the eight patients had more than one paraganglioma. Interestingly, the index patients were the only affected individuals in all families. When combining these index cases with reported cases in the medical literature, the mediastinum is the second most common location for SDHC-related paraganglioma (10% of all tumors), occurring in up to 13% of patients. CONCLUSIONS: Our findings suggest that thoracic paragangliomas are common in patients with SDHC mutations, and imaging of this area should be included in surveillance of mutation carriers. In addition, the absence of paragangliomas among at-risk relatives of SDHC mutation carriers suggests a less penetrant phenotype as compared to SDHB and SDHD mutations. PMID- 24758180 TI - Three-year growth response to growth hormone treatment in very young children born small for gestational age-data from KIGS. AB - CONTEXT: Children born small for gestational age (SGA) with poor growth during the first years of life may remain short in stature during childhood and as adults. OBJECTIVE: To evaluate the 3-year growth response to GH treatment in very young short children born SGA, and to test the existing predictions models for growth response developed for older SGA children. SETTING: KIGS (The Pfizer International Growth Database). PATIENTS: A total of 620 SGA children (birth length and/or weight below -2 SD score [SDS]) on GH treatment, 156 in the 2- to 4 year-old group (100 boys; median age, 3.3 y), and 464 in the 4- to 6-year-old group (284 boys; median age, 4.9 y). RESULTS: Median values and 10th-90th percentiles are presented. Both groups presented a significant increase in height velocity during GH treatment. Median height SDS increased from -3.9 (-5.4 to 2.9) at the start to -2.2 (-3.8 to -1.0) at 3 years in the 2- to 4-year-old group (P < .01) and from -3.4 (-4.5 to -2.6) to -2.0 (-3.3 to -0.9) in the 4- to 6-year old group (P < .01). Median weight SDS increased from -3.8 (-5.9 to -2.4) to -2.1 (-4.1 to -0.5) in the 2- to 4-year-old group (P < .01). Respective values for the 4- to 6-year-old group were -3.1 (-4.8 to -1.8) to -1.6 (-3.1 to -0.1) SDS (P < .01). First- and second-year growth response could be estimated by the SGA model. CONCLUSION: Very young children born SGA without spontaneous catch-up growth presented a significant improvement in height and weight during the 3 years of GH treatment. Growth response could be estimated by the SGA model. PMID- 24758181 TI - The risk of osteonecrosis of the jaws in Taiwanese osteoporotic patients treated with oral alendronate or raloxifene. AB - BACKGROUND: This study aimed to explore the possible association between osteonecrosis of the jaws (ONJ) and oral alendronate or raloxifene used for osteoporosis and to estimate its absolute and attributable risks in the Taiwanese population. METHODS: Using an electronic medical records system and manual confirmation of ONJ, we identified patients who began taking alendronate or raloxifene for osteoporosis and developed ONJ between January 2000 and April 2012. RESULTS: The incidence of ONJ associated with oral alendronate for the management of osteoporosis began after 1 year of drug exposure and progressively increased with longer durations of therapy, specifically from 0.23% to 0.92% as the duration of treatment went from 2 years to 10 years. The overall frequency of ONJ related to oral alendronate over a 12-year period was 0.55%. The incidence rate of ONJ attributed to alendronate exposure was 283 per 100 000 persons per year. On multivariate Cox proportional analysis, adjusting for the potential confounders, alendronate remains an independent predictor for ONJ occurrence [hazard ratio 7.42 (1.02-54.09)] compared with raloxifene. Advanced age, drug duration, and coexisting diabetes and rheumatoid arthritis are contributing factors to the development of oral alendronate-related ONJ. CONCLUSION: We provided the evidence to support the association of ONJ with oral alendronate used in the treatment or prevention of osteoporosis. PMID- 24758182 TI - Possible targets for nonimmunosuppressive therapy of Graves' orbitopathy. AB - CONTEXT: Graves' orbitopathy (GO) is caused by expansion of the orbital contents by excess adipogenesis and overproduction of hyaluronan (HA). Immunosuppressive and antiinflammatory treatments of GO are not always effective and can have side effects, whereas targeting GO-associated tissue remodeling might be a more logical therapeutic strategy. Previously we reported that signaling cascades through IGF1 receptor and thyrotropin receptor within orbital preadipocytes/fibroblasts drove adipogenesis and HA production. Our current study combined the stimulation of IGF1 receptor and thyrotropin receptor increase of HA accumulation, which we hypothesize is by activation of phosphatidylinositol 3 kinase (PI3K)-1A/PI3K1B, respectively. The central aim of this study was to investigate whether PI3K/mammalian target of rapamycin complex 1 (mTORC1) inhibitors affected adipogenesis and/or HA production within orbital preadipocyte/fibroblasts. METHODS: Human orbital preadipocytes were treated with/without inhibitors, LY294002 (PI3K1A/mTORC1), AS-605240 (PI3K1B), or PI103 (PI3K1A/mTORC1) in serum-free medium for 24 hours or cultured in adipogenic medium for 15 days. Quantitative PCR was used to measure hyaluronan synthases (HAS2) transcripts and the terminal adipogenesis differentiation marker lipoprotein lipase. HA accumulation in the medium was measured by an ELISA. RESULTS: Unlike AS-605240, both LY294002 (10 MUM) and PI-103 (5 MUM) significantly decreased HAS2 transcripts/HA accumulation and adipogenesis. Because PI-103 and LY294002 are dual PI3K/mTOR inhibitors, we investigated the inhibition of mTORC1 (rapamycin 100 nM), which significantly decreased adipogenesis but had no effect on HAS2 transcripts/HA, implicating PI3K-1A in the latter. CONCLUSIONS: The combined inhibition of PI3K1A and mTORC1 signaling in vitro decreased both HA accumulation and adipogenesis. Because PI3K and mTOR inhibitors are clinically used to treat other conditions, they have the potential to be repositioned to be used as an alternative nonimmunosuppressive therapy of GO. PMID- 24758183 TI - Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit? AB - CONTEXT: Somatic mutations in genes that influence cell entry of calcium have been identified in aldosterone-producing adenomas (APAs) of adrenal cortex in primary aldosteronism (PA). Many adrenal glands removed for suspicion of APA do not contain a single adenoma but nodular hyperplasia. OBJECTIVE: The objective of the study was to assess multinodularity and phenotypic and genotypic characteristics of adrenals removed because of the suspicion of APAs. DESIGN AND METHODS: We assessed the adrenals of 53 PA patients for histopathological characteristics and immunohistochemistry for aldosterone (P450C18) and cortisol (P450C11) synthesis and for KCNJ5, ATP1A1, ATP2B3, and CACNA1D mutations in microdissected nodi. RESULTS: Glands contained a solitary adenoma in 43% and nodular hyperplasia in 53% of cases. Most adrenal glands contained only one nodule positive for P450C18 expression, with all other nodules negative. KCNJ5 mutations were present in 22 of 53 adrenals (13 adenoma and nine multinodular adrenals). An ATP1A1 and a CACNA1D mutation were found in one multinodular gland each and an ATP2B3 mutation in five APA-containing glands. Mutations were always located in the P450C18-positive nodule. In one gland two nodules containing two different KCNJ5 mutations were present. Zona fasciculata-like cells were more typical for KCNJ5 mutation-containing nodules and zona glomerulosa-like cells for the other three genes. CONCLUSIONS: Somatic mutations in KCNJ5, ATP1A1, or CACNA1D genes are not limited to APAs but are also found in the more frequent multinodular adrenals. In multinodular glands, only one nodule harbors a mutation. This suggests that the occurrence of a mutation and nodule formation are independent processes. The implications for clinical management remain to be determined. PMID- 24758184 TI - Cell-specific dysregulation of microRNA expression in obese white adipose tissue. AB - CONTEXT: Obesity is characterized by the excessive accumulation of dysfunctional white adipose tissue (WAT), leading to a strong perturbation of metabolic regulations. However, the molecular events underlying this process are not fully understood. OBJECTIVE: MicroRNAs (miRNAs) are small noncoding RNAs acting as posttranscriptional regulators of gene expression in multiple tissues and organs. However, their expression and roles in WAT cell subtypes, which include not only adipocytes but also immune, endothelial, and mesenchymal stem cells as well as preadipocytes, have not been characterized. Design/Results: By applying differential miRNome analysis, we demonstrate that the expression of several miRNAs is dysregulated in epididymal WAT from ob/ob and high-fat diet-fed mice. Adipose tissue-specific down-regulation of miR-200a and miR-200b and the up regulation of miR-342-3p, miR-335-5p, and miR-335-3p were observed. Importantly, a similarly altered expression of miR-200a and miR-200b was observed in obese diabetic patients. Furthermore, cell fractionation of mouse adipose tissue revealed that miRNAs are differentially expressed in adipocytes and in subpopulations from the stromal vascular fraction. Finally, integration of transcriptomic data showed that bioinformatically predicted miRNA target genes rarely showed anticorrelated expression with that of targeting miRNA, in contrast to experimentally validated target genes. CONCLUSION: Taken together, our data indicate that the dysregulated expression of miRNAs occurs in distinct cell types and is likely to affect cell-specific function(s) of obese WAT. PMID- 24758185 TI - Pitfalls in genetic analysis of pheochromocytomas/paragangliomas-case report. AB - CONTEXT: About 35% of patients with pheochromocytoma/paraganglioma carry a germline mutation in one of the 10 main susceptibility genes. The recent introduction of next-generation sequencing will allow the analysis of all these genes in one run. When positive, the analysis is generally unequivocal due to the association between a germline mutation and a concordant clinical presentation or positive family history. When genetic analysis reveals a novel mutation with no clinical correlates, particularly in the presence of a missense variant, the question arises whether the mutation is pathogenic or a rare polymorphism. OBJECTIVE: We report the case of a 35-year-old patient operated for a pheochromocytoma who turned out to be a carrier of a novel SDHD (succinate dehydrogenase subunit D) missense mutation. With no positive family history or clinical correlates, we decided to perform additional analyses to test the clinical significance of the mutation. METHODS: We performed in silico analysis, tissue loss of heterozygosity analysis, immunohistochemistry, Western blot analysis, SDH enzymatic assay, and measurement of the succinate/fumarate concentration ratio in the tumor tissue by tandem mass spectrometry. RESULTS: Although the in silico analysis gave contradictory results according to the different methods, all the other tests demonstrated that the SDH complex was conserved and normally active. We therefore came to the conclusion that the variant was a nonpathogenic polymorphism. CONCLUSIONS: Advancements in technology facilitate genetic analysis of patients with pheochromocytoma but also offer new challenges to the clinician who, in some cases, needs clinical correlates and/or functional tests to give significance to the results of the genetic assay. PMID- 24758187 TI - Renal impairment as a surgical indication in primary hyperparathyroidism: do the data support this recommendation? AB - CONTENT: Management of primary hyperparathyroidism has evolved over the past two decades, yet impaired renal function has consistently been a surgical indication. This recommendation has been based upon the historical association between primary hyperparathyroidism and renal impairment, and a review of the literature is needed to determine whether such a recommendation is warranted. EVIDENCE ACQUISITION AND SYNTHESIS: PubMed was utilized to identify English-language articles published between January 1990 and February 2014 using keywords related to hyperparathyroidism and renal function. The keywords were "primary hyperparathyroidism," "surgery," "parathyroidectomy," "kidney," "renal," "glomerular filtration rate," and "creatinine." Of the 1926 articles obtained with this search, all articles germane to the topic that quantified the relationship between primary hyperparathyroidism and renal function were included. All references within these articles were investigated for inclusion. When helpful, data tables were constructed to summarize the results succinctly. CONCLUSIONS: A secondary elevation of PTH levels has not been consistently shown to occur at the threshold currently indicated for surgical intervention. While renal impairment is seen with more significant disease, mild asymptomatic primary hyperparathyroidism has not been conclusively associated with renal impairment. Furthermore, there is no evidence to suggest that surgically curing primary hyperparathyroidism via a parathyroidectomy has any impact upon renal function. PMID- 24758188 TI - Enhanced delivery of gentamicin to infection foci due to Staphylococcus aureus using gold nanorods. AB - Bacterial infections continue to be one of the major causes of morbidity and mortality. Although many methods for diagnosing and treating of infectious diseases currently exist, there is an urgent need for new and improved approaches for bacterial destruction. The present study focuses on the conjugation of gold nanorods (GNRs) with gentamicin via the Nanothink acid linker and its application in delivery of gentamicin to infection foci due to Staphylococcus aureus. The interaction between gentamicin and gold nanorods was confirmed by FT-IR spectroscopy. The high performance liquid chromatography (HPLC) and atomic absorption spectroscopy analyses showed that 2050 gentamicin molecules were attached to each gold nanorod. The minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of gentamicin-GNRs conjugate showed the enhancement of antibacterial effect of gentamicin. The biodistribution study demonstrated localization of the complex at the site of Staphylococcal infection with high sensitivity in mouse model. PMID- 24758186 TI - Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma. AB - CONTEXT: Telomere maintenance via telomerase activation and the alternative lengthening of telomeres (ALT) mechanism was assessed in medullary thyroid carcinoma. SETTING AND DESIGN: In total, 42 medullary thyroid carcinomas (MTC) were studied including 24 rearranged during transfection (RET)- mutated cases. Relative telomerase reverse transcriptase (TERT) expression, splice forms, and telomere length were determined by PCR-based methods, and telomerase activity by ELISA. The ALT mechanism was detected by Southern blot analysis and immunofluorescence. RESULTS: TERT expression and telomerase activity were detected in 21/42 tumors (50%), and was independent of the common somatic M918T RET mutation. Mean telomere length was shorter in MTCs compared with thyroids. Telomerase activation was associated with large tumor size (P = .027), advanced clinical stage (P = .0001), and short survival (P = .0001). Full-length TERT and the alpha(-) and beta(-)-deletion forms were revealed, and the full-length form was associated with short survival (P = .04). A subset of cases without telomerase activation showed involvement of the ALT mechanism, which was associated with a low MIB-1 proliferation index (P = .024). CONCLUSIONS: Stabilization of telomeres by telomerase activation occurs in half of the MTCs and by the ALT mechanism in a subset of cases. Telomerase activation may be used as an additional prognostic marker in medullary thyroid carcinoma. PMID- 24758189 TI - Thermosensitive PEG-PCL-PEG (PECE) hydrogel as an in situ gelling system for ocular drug delivery of diclofenac sodium. AB - Development of efficient ocular drug delivery systems was still a challenging task. The objective of this article was to develop a thermosensitive PEG-PCL-PEG (PECE) hydrogel and investigate its potential application for ocular drug delivery of diclofenac sodium (DIC). PECE block polymers were synthesized by coupling MPEG-PCL co-polymer using IPDI reagent, and then its sol-gel transition as a function with temperature was investigated by a rheometer. The results showed that 30% (w/v) PECE aqueous solution exhibited sol-gel transition at approximately 35 degrees C. In vitro release profiles showed the entrapped DIC was sustained release from PECE hydrogels up to 7 days and the initial drug loading greatly effect on release behavior of DIC from PECE hydrogels. MTT assay results indicated that no matter PECE or 0.1% (w/v) DIC-loaded PECE hydrogels were nontoxic to HCEC and L929 cells after 24 h culturing. In vivo eye irritation test showed that the instillation of either 30% (w/v) PECE hydrogels or 0.1% (w/v) DIC-loaded PECE hydrogels to rabbit eye did not result in eye irritation within 72 h. In vivo results showed that the AUC0-48 h of 0.1% (w/v) DIC-loaded PECE hydrogels exhibited 1.6-fold increment as compared with that of commercial 0.1% (w/v) DIC eye drops, suggesting the better ophthalmic bioavailability could be obtained by the instillation of 0.1% (w/v) DIC-loaded PECE hydrogels. PMID- 24758191 TI - Comprehensive behavioral study of mGluR3 knockout mice: implication in schizophrenia related endophenotypes. AB - BACKGROUND: We previously performed systematic association studies of glutamate receptor gene family members with schizophrenia, and found positive associations of polymorphisms in the GRM3 (a gene of metabotropic glutamate receptor 3: mGluR3) with the disorder. Physiological roles of GRM3 in brain functions and its functional roles in the pathogenesis of schizophrenia remain to be resolved. RESULTS: We generated mGluR3 knockout (KO) mice and conducted comprehensive behavioral analyses. KO mice showed hyperactivity in the open field, light/dark transition, and 24-hour home cage monitoring tests, impaired reference memory for stressful events in the Porsolt forced swim test, impaired contextual memory in cued and contextual fear conditioning test, and impaired working memory in the T Maze forced alternation task test. Hyperactivity and impaired working memory are known as endophenotypes of schizophrenia. We examined long-term synaptic plasticity by assessing long-term potentiation (LTP) in the CA1 region in the hippocampi of KO and wild-type (WT) mice. We observed no differences in the amplitude of LTP between the two genotypes, suggesting that mGluR3 is not essential for LTP in the CA1 region of the mouse hippocampus. As hyperactivity is typically associated with increased dopaminergic transmission, we performed in vivo microdialysis measurements of extracellular dopamine in the nucleus accumbens of KO and WT mice. We observed enhancements in the methamphetamine (MAP)-induced release of dopamine in KO mice. CONCLUSIONS: These results demonstrate that a disturbance in the glutamate-dopamine interaction may be involved in the pathophysiology of schizophrenia-like behavior, such as hyperactivity in mGluR3 KO mice. PMID- 24758192 TI - A comparison of long-term survivors and short-term survivors with glioblastoma, subventricular zone involvement: a predictive factor for survival? AB - OBJECTIVE: Long-term survival is rare in patients with glioblastoma (GBM). We set out to determine prognostic factors for patients with favorable and poor prognosis in regard of tumor localization to the subventricular zone (SZV). METHODS: We reviewed the clinical records, pre-operative and post-operative MRI imaging of 50 LTS long-term survivors (LTS) (> 3 years) and 50 short-term survivors (STS) (< 1 year) with glioblastoma. These groups were matched for clinical characteristics being consistently associated with prolonged or shortened survival. All patients had undergone initial surgery or biopsy to confirm GBM diagnosis followed by radio- or chemoradiotherapy. RESULTS: LTS had a median progression-free survival PFS of 25, 4 months (2, 3-97, 8 months) and overall-survival (OS) of 55, 9 months (38, 2-98, 6 months) compared to STS who had a significantly lower PFS of 4, 2 months (1, 4-10, 2 months) and OS of 6, 6 months (2, 2-11, 6 months) (each p < 0,001).Survival analysis showed that age under 60 years (p < 0,001), total resection status (p < 0,001) and tumor localization without SVZ contact (p = 0,05) were significant factors for prolonged survival. CONCLUSION: Our findings underline that survival in GBM patients is heterogeneous and influenced by multiple factors. This study confirms that tumor location with regard to the SVZ is significantly associated with survival. PMID- 24758190 TI - Impact of impaired glomerular filtration rate and revascularization strategy on one-year cardiovascular events in acute coronary syndrome: data from Taiwan acute coronary syndrome full spectrum registry. AB - BACKGROUND: The optimal revascularization strategy for patients with impaired glomerular filtration rate (IGFR) has not been established in acute coronary syndrome (ACS). We investigated the prognosis and impact of IGFR and invasive strategy on the cardiovascular outcomes in the ACS population. METHODS: In a Taiwan national-wide registry, 3093 ACS patients were enrolled. The invasive strategy was defined as patients with ST-elevation ACS (STE-ACS) undergoing primary angioplasty or fibrinolysis or coronary angiography with intent to revascularization performed within 72 hours of symptom onset in non-ST-elevation ACS (NSTE-ACS). IGFR was defined as an estimated GFR of less than 60 ml/min per 1.73 m2. Primary endpoint was a composite of death, non-fatal myocardial infarction or stroke at one year. RESULTS: Patients with IGFR (n = 1226) had more comorbidities but received less evidence-based medications during admission than those without IGFR (n = 1867). The primary endpoint-free survival rate is lower in the IGFR patients, in the whole, STE-ACS and NSTE-ACS population (all log-rank tests p < 0.01). Cox regression analysis revealed IGFR subjects had higher primary endpoint after adjusting by age, sex, medication at discharge and traditional risk factors (all p < 0.01). Kaplan-Meier curves showed IGFR patients without invasive strategy had the worst outcome in the STE-ACS and NSTE-ACS population (both p < 0.01). The invasive strategies, either with early angiography only or angioplasty, were associated with reduced primary endpoints among IGFR patients in the NSTE-ACS population (both p ? 0.024). CONCLUSIONS: IGFR patients suffering from ACS had poor prognosis and an invasive strategy could improve cardiovascular outcome in the NSTE-ACS population. PMID- 24758193 TI - Oligohydramnios in a pregnant Pakistani woman with Plasmodium vivax malaria. AB - In the Western world, the diagnosis and management of Plasmodium vivax malaria in pregnant women can be challenging, and the pathogenesis of adverse outcomes for both the mother and the foetus is still poorly known. The authors describe the case of a 29-year-old Pakistani woman at the 29th week of her second pregnancy, who was admitted to the Hospital following the abrupt onset of fever. At the time of admission, she had been living in Italy without travelling to any malaria endemic areas for eight months. She was diagnosed with vivax malaria after a thin blood smear revealed the presence of plasmodial trophozoites and gametocytes and treated accordingly. Due to the onset of oligohydramnios, she underwent caesarian section at the 31st week of pregnancy with no further complications. Histological examination of the placenta showed no evidence of plasmodial infection, but was inconclusive. It is unclear whether oligohydramnios is a complication of pregnancy-related Plasmodium vivax malaria. Given the long latency of hypnozoites, every febrile pregnant patient with a previous stay in an endemic area should be screened for malaria with a thick and a thin blood smear. PMID- 24758194 TI - Transcriptome assembly and microarray construction for Enchytraeus crypticus, a model oligochaete to assess stress response mechanisms derived from soil conditions. AB - BACKGROUND: The soil worm Enchytraeus crypticus (Oligochaeta) is an ecotoxicology model species that, until now, was without genome or transcriptome sequence information. The present research aims at studying the transcriptome of Enchytraeus crypticus, sampled from multiple test conditions, and the construction of a high-density microarray for functional genomic studies. RESULTS: Over 1.5 million cDNA sequence reads were obtained representing 645 million nucleotides. After assembly, 27,296 contigs and 87,686 singletons were obtained, from which 44% and 25% are annotated as protein-coding genes, respectively, sharing homology with other animal proteomes. Concerning assembly quality, 84% of the contig sequences contain an open reading frame with a start codon while E. crypticus homologs were identified for 92% of the core eukaryotic genes. Moreover, 65% and 77% of the singletons and contigs without known homologs, respectively, were shown to be transcribed in an independent microarray experiment. An Agilent 180 K microarray platform was designed and validated by hybridizing cDNA from 4 day zinc- exposed E. crypticus to the concentration corresponding to 50% reduction in reproduction after three weeks (EC50). Overall, 70% of all probes signaled expression above background levels (mean signal + 1x standard deviation). More specifically, the probes derived from contigs showed a wider range of average intensities when compared to probes derived from singletons. In total, 522 significantly differentially regulated transcripts were identified upon zinc exposure. Several significantly regulated genes exerted predicted functions (e.g. zinc efflux, zinc transport) associated with zinc stress. Unexpectedly, the microarray data suggest that zinc exposure alters retro transposon activity in the E. crypticus genome. CONCLUSION: An initial investigation of the E. crypticus transcriptome including an associated microarray platform for future studies proves to be a valuable resource to investigate functional genomics mechanisms of toxicity in soil environments and to annotate a potentially large number of lineage specific genes that are responsive to environmental stress conditions. PMID- 24758195 TI - Phosphoric acid loaded azo (-N?N-) based covalent organic framework for proton conduction. AB - Two new chemically stable functional crystalline covalent organic frameworkds (COFs) (Tp-Azo and Tp-Stb) were synthesized using the Schiff base reaction between triformylphloroglucinol (Tp) and 4,4'-azodianiline (Azo) or 4,4' diaminostilbene (Stb), respectively. Both COFs show the expected keto-enamine form, and high stability toward boiling water, strong acidic, and basic media. H3PO4 doping in Tp-Azo leads to immobilization of the acid within the porous framework, which facilitates proton conduction in both the hydrous (sigma = 9.9 * 10(-4) S cm(-1)) and anhydrous state (sigma = 6.7 * 10(-5) S cm(-1)). This report constitutes the first emergence of COFs as proton conducting materials. PMID- 24758197 TI - Application of the triage assessment system for psychological assessment for pregnant women with a deadly fetal abnormality. AB - To explore suitable scales to assess psychological status of pregnant women whose fetuses have grave deformities, a face-to-face interview guided by the Triage Assessment System (TAS) was conducted. Also, a questionnaire of the Impact of Event Scale-Revised (IES-R) was obtained in 44 pregnant women diagnosed with a fetal deformity. Percentages and non-parametric Spearman correlations were used to analyse the scores of the two scales. The total score of TAS ranged from 3 to 26, with a mean of 9.93; and the total score of IES-R ranged from 5 to 63, with a mean of 40.36. The total score and the two subscales of each scale were significantly correlated (P < 0.05). The TAS subscale of emotion and IES-R subscale of intrusion were not significantly correlated, with r = 0.24 (P = 0.11). Combined use of TAS and IES-R can make up for each other's deficiencies and guide the clinician to make individual interventions during screening and treatment. PMID- 24758196 TI - Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus. AB - In addition to disturbed apoptosis and insufficient clearance of apoptotic cells, there is recent evidence for a role of neutrophils in the aetiopathogenesis of systemic lupus erythematosus (SLE). In response to various stimuli, neutrophils can rapidly release DNA fibres decorated with citrullinated histones and anti microbial peptides. These structures are referred to as neutrophil extracellular traps (NETs). In addition to apoptotic cell-derived microparticles, these NETs may comprise a further source of autoantigens, able to drive the autoimmune response in SLE. Our group recently identified specific histone modifications occurring during apoptosis that play an important role in the autoimmune response in SLE. In the current study, we evaluated the presence and immunostimulatory potential of these previously identified histone modifications in NETs. Compared to NETs from healthy donors, the histones present in NETs formed by SLE-derived neutrophils contain increased amounts of acetylated and methylated residues, which we previously observed to be associated with apoptosis and SLE. Treatment of neutrophils with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), prior to induction of NETosis, induced NETs containing hyperacetylated histones, endowed with an increased capacity to activate macrophages. This implies that specific histone modifications, in particular acetylation, might enhance the immunostimulatory potential of NETs in SLE. PMID- 24758198 TI - Effects of added silica nanoparticles on the nematic liquid crystal phase formation in beidellite suspensions. AB - In this article, we present a study of the liquid crystal phase behavior of mixed suspensions of the natural smectite clay mineral beidellite and nonadsorbing colloidal silica particles. While virtually all smectite clays dispersed in water form gels at very low concentrations, beidellite displays a first order isotropic nematic phase transition before gel formation (J. Phys. Chem. B, 2009, 113, 15858 15869). The addition of silica nanospheres shifts the concentrations of the coexisting isotropic and nematic phases to slightly higher values while at the same time markedly accelerating the phase separation process. Furthermore, beidellite suspensions at volume fractions above the isotropic-nematic phase separation, trapped in a kinetically arrested gel state, liquefy on the addition of silica nanospheres and proceed to isotropic-nematic phase separation. Using small-angle X-ray scattering (SAXS), we probe the structural changes caused by the addition of the silica nanospheres, and we relate the modification of the phase transition kinetics to the change of the rheological properties. PMID- 24758199 TI - Disseminated tuberculosis presenting with finger swelling and skin ulcer: a case report. PMID- 24758200 TI - Modeling the impacts of multiple environmental stress factors on estuarine copepod populations. AB - Many studies have focused on natural stress factors that shape the spatial and temporal distribution of calanoid copepods, but bioassays have shown that copepods are also sensitive to a broad range of contaminants. Although both anthropogenic and natural stress factors are obviously at play in natural copepod communities, most studies consider only one or the other. In the present investigation, we modeled the combined impact of both anthropogenic and natural stress factors on copepod populations. The model was applied to estimate Eurytemora affinis densities in the contaminated Scheldt estuary and the relatively uncontaminated Darbeta-Zingst estuary in relation to temperature, salinity, chlorophyll a, and sediment concentrations of cadmium, copper, and zinc. The results indicated that temperature was largely responsible for seasonal fluctuations of E. affinis densities. Our model results further suggested that exposure to zinc and copper was largely responsible for the reduced population densities in the contaminated estuary. The model provides a consistent framework for integrating and quantifying the impacts of multiple anthropogenic and natural stress factors on copepod populations. It facilitates the extrapolation of laboratory experiments to ecologically relevant end points pertaining to population viability. PMID- 24758201 TI - Clamping instability and van der Waals forces in carbon nanotube mechanical resonators. AB - We investigate the role of weak clamping forces, typically assumed to be infinite, in carbon nanotube mechanical resonators. Due to these forces, we observe a hysteretic clamping and unclamping of the nanotube device that results in a discrete drop in the mechanical resonance frequency on the order of 5-20 MHz, when the temperature is cycled between 340 and 375 K. This instability in the resonant frequency results from the nanotube unpinning from the electrode/trench sidewall where it is bound weakly by van der Waals forces. Interestingly, this unpinning does not affect the Q-factor of the resonance, since the clamping is still governed by van der Waals forces above and below the unpinning. For a 1 MUm device, the drop observed in resonance frequency corresponds to a change in nanotube length of approximately 50-65 nm. On the basis of these findings, we introduce a new model, which includes a finite tension around zero gate voltage due to van der Waals forces and shows better agreement with the experimental data than the perfect clamping model. From the gate dependence of the mechanical resonance frequency, we extract the van der Waals clamping force to be 1.8 pN. The mechanical resonance frequency exhibits a striking temperature dependence below 200 K attributed to a temperature-dependent slack arising from the competition between the van der Waals force and the thermal fluctuations in the suspended nanotube. PMID- 24758202 TI - Mycobacterium abscessus hand-and-foot disease in children: rare or emerging disease? AB - Mycobacterium abscessus is emerging as an important cause of cutaneous infections in sporadic cases and outbreak settings. Although immunosuppressed or elderly patients are most commonly affected, in 2006 an outbreak of clinically distinct cutaneous lesions on the hands and feet caused by M. abscessus in a population of healthy children using a public swimming pool was reported. This article describes an outbreak of skin infection in a population of healthy Italian children attending the same school and using the same swimming pool. In January 2010 we identified three children with multiple, painful nodules on the palms and soles. M. abscessus was isolated from one child's lesions. A public health investigation was conducted and a team of dermatologists and public health officers visited all of the children; 514 children were screened and 29 cases were identified overall. All of the affected children had used the school's swimming pool. These children were treated with oral clarithromycin for 4 to 8 weeks. Because of the long period of time between the presentation and diagnosis of the first cases, the possibility that the number of cases may have been underestimated cannot be excluded. To our knowledge, this is the second largest reported cluster of M. abscessus skin infection suspected to be related to swimming pool exposure in a population of otherwise healthy children. It is unclear whether this disease is rare or should be considered as an emerging clinical entity. PMID- 24758203 TI - Lipofibromatosis: an institutional and literature review of an uncommon entity. AB - We report six new cases of lipofibromatosis, an uncommon pediatric soft tissue neoplasm. This is the only series of patients to be described since the initial case series of 45 patients that characterized this entity in 2000. The purpose of this study was to characterize the presentation of lipofibromatosis to further define the clinical phenotype of this rare entity. Six patients were diagnosed with lipofibromatosis at our institution from 2000 to 2012. Patient age, sex, and ethnicity were recorded, along with tumor site and size, management, and recurrence data. Half of our patients were younger than 2 years old at presentation and the other half were school age. Boys and girls were affected with equal frequency. In five of six patients, lipofibromatosis presented in its "classic" form as a mass on the distal extremities. These tumors typically measured 1 to 2 cm in diameter, in contrast to case reports in the medical literature highlighting the occurrence of lipofibromatosis of greater size and at varied anatomic sites. The tumors in our series were managed using excision, with recurrence noted in 33%. Lipofibromatosis is an uncommon tumor typically found on the distal extremities of infants, although it can appear in various sizes and locations. It should be considered in the differential diagnosis of pediatric soft tissue neoplasms. PMID- 24758204 TI - A novel elastin gene mutation in a Vietnamese patient with cutis laxa. AB - We report a 3-year-old girl from Vietnam with severe congenital cutis laxa; no cardiovascular, pulmonary, neurologic, or visceral involvement; and no family history of cutis laxa. Mutational analysis of the elastin gene identified heterozygosity for a previously unreported de novo c.2184delT mutation in exon 30 not present in either parent. PMID- 24758205 TI - Asymptomatic skin-colored papules and nodules in a young boy. PMID- 24758206 TI - Persistent pruritic plaque on the right forearm of a child. PMID- 24758207 TI - Sclerodermatous skin changes in an infant. PMID- 24758208 TI - HLA-G 3' untranslated region polymorphisms influence the susceptibility for human papillomavirus infection. AB - Human leukocyte antigen (HLA)-G molecule acts as a potential factor for the regulation of immune responses and its expression in virus-infected cells may enable them to escape immunosurveillance. Besides its polymorphic promoter region, the 3' untranslated region (UTR) seems to play an important role in regulating HLA-G expression. In this study, we investigated the influence of HLA G 14 bp (rs66554220) and +3142 (rs1063320) polymorphisms in 179 women with active human papillomavirus (HPV) infection and 143 age-matched, unrelated, HPV negative, normal Chinese Han population. Our findings showed that frequency of the allele +3142 C [31.3% vs 44.4%, odds ratio (OR) = 0.57, Pc < 0.01] and the genotype +3142 CC (10.6% vs 21.7%, OR = 0.43, Pc = 0.012) was significantly decreased in HPV infected patients compared with normal controls. Furthermore, the haplotype -14 bp/C was associated with a reduced risk for HPV infection (OR = 0.57, Pc = 0.001). Our findings also showed that HLA-G homozygous +14 bp/+14 bp genotype was significantly associated with an increased risk for HPV18 infection (OR = 12.95, P < 0.01), whereas HLA-G heterozygous +14 bp/-14 bp genotype increased risk for HPV58 (OR = 5.55, P < 0.05). Furthermore, frequency of the haplotype +14 bp/G was significantly increased in HPV18 infected patients (60.0% vs 27.3%, OR = 4.00, Pc < 0.05). Taken together, our results supported a role of the HLA-G 3' UTR polymorphisms as a susceptible factor for the active HPV infection, and suggested a possible interference of the HLA-G molecule in the response to virus infection. PMID- 24758209 TI - Self-rated mental health and socio-economic background: a study of adolescents in Sweden. AB - BACKGROUND: Adolescents' mental health is a major public health issue. Previous research has shown that socio-economic factors contribute to the health status of adolescents. The present study explores the association between socio-economic status and self-rated mental health among adolescents. METHODS: Cross sectional data from the Halmstad Youth Quality of Life cohort was collected in a town in Sweden. In all, 948 adolescents (11-13 younger age group and 14-16 older age group) participated. Information on self-rated mental health was collected from the subscale Psychological functioning in the Minneapolis Manchester Quality of Life instrument. The items were summarized into a total score and dichotomized by the mean. Indicators measuring socio-economic status (SES) were collected in a questionnaire using the Family Affluence Scale (FAS) and additional factors regarding parents' marital status and migration were added. Logistic models were used to analyze the data. RESULTS: Girls were more likely to rate their mental health below the mean compared to boys. With regard to FAS (high, medium, low), there was a significantly increased risk of self-rated mental health below the mean among younger boys in the medium FAS score OR; 2.68 (95% CI 1.35;5.33) and among older boys in the low FAS score OR; 2.37 (1.02;5.52) compared to boys in the high FAS score. No such trend was seen among girls. For younger girls there was a significant protective association between having parents born abroad and self-rated mental health below mean OR: 0.47 (0.24;0.91). CONCLUSIONS: A complex pattern of associations between SES and self-rated mental health, divergent between age and gender groups, was shown. The total FAS score was only associated with boys' self-rated mental health in both age groups, whereas parents' migratory status influenced only the girls' self-rated mental health. Because of the different association for girls' and boys' self-rated mental health and SES, other factors than SES should also be considered when investigating and exploring the mental health of adolescents in affluent communities. PMID- 24758210 TI - Radical intermediates in the addition of OH to propene: photolytic precursors and angular momentum effects. AB - We investigate the photolytic production of two radical intermediates in the reaction of OH with propene, one from addition of the hydroxyl radical to the terminal carbon and the other from addition to the center carbon. In a collision free environment, we photodissociate a mixture of 1-bromo-2-propanol and 2-bromo 1-propanol at 193 nm to produce these radical intermediates. The data show two primary photolytic processes occur: C-Br photofission and HBr photoelimination. Using a velocity map imaging apparatus, we measured the speed distribution of the recoiling bromine atoms, yielding the distribution of kinetic energies of the nascent C3H6OH radicals + Br. Resolving the velocity distributions of Br((2)P(1/2)) and Br((2)P(3/2)) separately with 2 + 1 REMPI allows us to determine the total (vibrational + rotational) internal energy distribution in the nascent radicals. Using an impulsive model to estimate the rotational energy imparted to the nascent C3H6OH radicals, we predict the percentage of radicals having vibrational energy above and below the lowest dissociation barrier, that to OH + propene; it accurately predicts the measured velocity distribution of the stable C3H6OH radicals. In addition, we use photofragment translational spectroscopy to detect several dissociation products of the unstable C3H6OH radicals: OH + propene, methyl + acetaldehyde, and ethyl + formaldehyde. We also use the angular momenta of the unstable radicals and the tensor of inertia of each to predict the recoil kinetic energy and angular distributions when they dissociate to OH + propene; the prediction gives an excellent fit to the data. PMID- 24758211 TI - The paths leading from attachment to ageism: a structural equation model approach. AB - The study introduces a model in which attachment patterns serve as predictors, empathy and fear of death as mediators, and ageism as the predicted variable. Data were collected from young adults (N = 440). Anxious attachment was directly and positively correlated with ageism, and also indirectly and positively by the mediator "fear of death." Avoidant attachment was indirectly and negatively correlated with ageism by the mediator "empathy". It is suggested that interventions for reducing ageist attitudes among younger adults would focus on existential fears, as well as on empathic ability, according to the attachment tendencies of these individuals. PMID- 24758212 TI - Two perspectives on the needs of individuals bereaved by suicide. AB - To qualitatively explore the needs of suicidally bereaved individuals, researchers interviewed 11 suicide bereaved individuals and 4 mental health workers. Common themes of bereaved persons included the suicide grief experience, coping, interpersonal domain, struggle with meaning, self-reflection, and moving forward. Mental health workers emphasized the nature of the helping relationship, the need to emotionally process the grief, the centrality of meaning making, importance of support groups, and the role of individual counseling. These 2 perspectives informed "best practices" for postvention (e.g., understanding the need for meaning-making while recognizing when to move on). PMID- 24758213 TI - Switching suicide methods in order to achieve lethality: a study of Greek suicide victims. AB - This article focused on the relation between the method of last attempted suicide and the method used during the subsequent completed suicide. Using the method of psychological autopsy, the authors studied all suicide cases from the Athens Greater Area during a 2-year period. Twenty-four percent of the victims had history of previous suicide attempts. The majority of the suicide attempters switched to a different method (p < 0.001) for their final act. This difference is primarily due to the individuals who had chosen self-poisoning or wrist cutting in their last attempted suicide. Both of these groups switched to hanging or jumping from a height for their final attempt. Individuals who attempted suicide by hanging or jumping became completers using mainly the same methods. PMID- 24758214 TI - Grieving online: newcomers' constructions of grief in an online support group. AB - Research into peer conversations in online grief support groups remains scarce. The authors used discourse analysis to examine 107 initial posts to one such group to examine how newcomers constructed their initial posts to display their eligibility for membership. The authors identified three discursive features: formulating unusual stories of loss, describing uncontrollable emotional and physical states, and engaging in "troubles telling." These discursive patterns illustrate how grief is constructed in ways that may simultaneously conform to and resist norms around grief that exist offline. Implications for practitioners include the need to support individuals through validation of their "nonnormal" grief. PMID- 24758215 TI - Developing the yearning in situations of loss scale: convergent and discriminant validity for bereavement, romantic breakup, and homesickness. AB - Yearning is common in situations involving loss, and a hallmark of complicated grief. To study yearning empirically, the present study develops the Yearning in Situations of Loss scale (YSL), which measures yearning bereavement, romantic breakup, or homesickness. In Study 1, we identified shared characteristics across situations of loss, tested an initial version and removed items with the lowest item-scale reliability. In Study 2, the 21-item YSL was compared to scales of anxiety, depression, and loneliness, and existing scales, relevant to each loss situation. The YSL showed discriminant and convergent validity that applies to bereavement, romantic breakup, and homesickness. PMID- 24758216 TI - Perceptions of organ donors and willingness to donate organs upon death: a test of the prototype/willingness model. AB - Understanding people's organ donation decisions may narrow the gap between organ supply and demand. In two studies, participants who had not recorded their posthumous organ donation decision (Study 1, N = 210; Study 2, N = 307) completed items assessing prototype/willingness model (PWM; attitude, subjective norm, donor prototype favorability and similarity, willingness) constructs. Attitude, subjective norm, and prototype similarity predicted willingness to donate. Prototype favorability and a Prototype Favorability * Similarity interaction predicted willingness (Study 2). These findings provide support for the PWM in altruistic health contexts, highlighting the importance of people's perceptions about organ donors in their donation decisions. PMID- 24758217 TI - Let me hear of your mercy in the mourning: forgiveness, grief, and continuing bonds. AB - Clarity about the utility of continuing bonds (CB) continues to be evasive in the research. In 2 different correlational studies, the authors explored the relationship between CB and 2 other variables: 1 representing mental health (forgiveness of the deceased) and the other representing psychological distress (prolonged grief). Although researchers have addressed the latter relationship in the literature, assessing the relationship between CB and forgiveness has not been undertaken. Results suggest that forgiveness in general, and affective aspects of forgiveness in particular, predict psychological forms of CB. Results related to grief depended on how CB was assessed. These findings provide evidence of the relative health of certain types of relationship with deceased persons and also suggest that forgiveness interventions may be a way of promoting such healthy bonds. PMID- 24758218 TI - Prolonged grief disorder and depression in a German community sample. AB - The aims of this study were to examine rates and risk factors for prolonged grief and to investigate the association between prolonged grief and depression. The authors interviewed a heterogeneous bereaved sample of 61 Germans, 6 of whom had prolonged grief and depression, respectively. The 2 syndromes were strongly linked to one another. Risk factors for prolonged grief were being a woman and having high levels of religious beliefs and low levels of satisfaction with one's religious beliefs, emotional closeness to the deceased, and unanticipated loss. Symptoms of prolonged grief may endure years post-loss and often overlap with depression. PMID- 24758220 TI - Use of the extended therapy outcome measure for children with dysarthria. AB - Increasing demand on healthcare resources has led to a greater emphasis on the examination of the impact of service delivery on outcomes. Clinical assessments frequently do not cover all aspects of change associated with interventions for those with complex conditions. This paper reviews the need for more comprehensive outcome measurement suitable for clinical practice and benchmarking. It describes an extension of the Therapy Outcome Measure for specific use in reflecting the impact of the broad range of interventions commonly required when managing children with dysarthria. Three case histories are used to illustrate the approach, and data from four speech-language pathology services are used to illustrate the value of benchmarking. PMID- 24758221 TI - Composite manganese oxide percolating networks as a suspension electrode for an asymmetric flow capacitor. AB - In this study, we examine the use of a percolating network of metal oxide (MnO2) as the active material in a suspension electrode as a way to increase the capacitance and energy density of an electrochemical flow capacitor. Amorphous manganese oxide was synthesized via a low-temperature hydrothermal approach and combined with carbon black to form composite flowable electrodes of different compositions. All suspension electrodes were tested in static configurations and consisted of an active solid material (MnO2 or activated carbon) immersed in aqueous neutral electrolyte (1 M Na2SO4). Increasing concentrations of carbon black led to better rate performance but at the cost of capacitance and viscosity. Furthermore, it was shown that an expanded voltage window of 1.6 V could be achieved when combining a composite MnO2-carbon black (cathode) and an activated carbon suspension (anode) in a charge balanced asymmetric device. The expansion of the voltage window led to a significant increase in the energy density to ~11 Wh kg(-1) at a power density of ~50 W kg(-1). These values are ~3.5 times and ~2 times better than a symmetric suspension electrode based on activated carbon. PMID- 24758222 TI - Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents. AB - BACKGROUND: Chronic stress is generally known to exacerbate the development of numerous neuropsychiatric diseases such as fear and anxiety disorders, which is at least partially due to the disinhibition of amygdala subsequent to the prolonged stress exposure. GABA receptor A (GABAAR) mediates the primary component of inhibition in brain and its activation produces two forms of inhibition: the phasic and tonic inhibition. While both of them are critically engaged in limiting the activity of amygdala, their roles in the amygdala disinhibition subsequent to chronic stress exposure are largely unknown. RESULTS: We investigated the possible alterations of phasic and tonic GABAAR currents and their roles in the amygdala disinhibition subsequent to chronic stress. We found that both chronic immobilization and unpredictable stress led to long lasting loss of tonic GABAAR currents in the projection neurons of lateral amygdala. By contrast, the phasic GABAAR currents, as measured by the spontaneous inhibitory postsynaptic currents, were virtually unaltered. The loss of tonic inhibition varied with the duration of daily stress and the total days of stress exposure. It was prevented by pretreatment with metyrapone to block corticosterone synthesis or RU 38486, a glucocorticoid receptor antagonist, suggesting the critical involvement of glucocorticoid receptor activation. Moreover, chronic treatment with corticosterone mimicked the effect of chronic stress and reduced the tonic inhibition in lateral amygdala of control mice. The loss of tonic inhibition resulted in the impaired GABAergic gating on neuronal excitability in amygdala, which was prevented by metyrapone pretreatment. CONCLUSIONS: Our study suggests that enduring loss of tonic but not phasic GABAAR currents critically contributes to the prolonged amygdala disinhibition subsequent to chronic stress. We propose that the preferential loss of tonic inhibition may account for the development of stress-related neuropsychiatric diseases. PMID- 24758223 TI - Brainstem infarcts predict REM sleep behavior disorder in acute ischemic stroke. AB - BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance in which patients enact their dreams while in REM sleep. The behavior is typically violent in association with violent dream content, so serious harm can be done to the patient or the bed partner. The prevalence of RBD is well known in Parkinson's disease, Lewy body dementia, and multiple systems atrophy. However, its prevalence and causes in stroke remained unclear. The aim of this study was to determine factors influencing the appearance of RBD in a prospective cohort of patients with acute ischemic stroke. METHODS: A total of 2,024 patients with first-ever or recurrent acute ischemic stroke were admitted to the Acute Stroke Unit at the Prince of Wales Hospital between January 2010 and November 2011; 775 of them received an MRI scan. Within 2 days of admission, a research nurse collected demographic and clinical data and assessed the severity of each stroke using the National Institute of Health Stroke Scale (NIHSS). One hundred and nineteen of the 775 patients meeting study entry criteria formed the study sample. All eligible participants were invited to attend a research clinic 3 months after the onset of the index stroke. In the attendance, a research assistant administered the MMSE and the 13-item RBD questionnaire (RBDQ). RESULTS: Among 119 stroke patients, 10.9% were exhibited RBD, defined as an REM sleep behavior disorder questionnaire score of 19 or above. The proportion of patients with acute brainstem infarct was significantly higher in RBD patients than those without RBD. Compared with patients without RBD, RBD patients were more likely to have brainstem infarcts and had smaller infarct volumes. In a multivariate analysis, in which stroke location and infarct volume were inserted, brainstem infarcts were an independent predictor of RBD (odds ratio = 3.686; P = 0.032). CONCLUSIONS: The results support the notion of a predominant role of brainstem injury in the development of RBD and suggest that patients with brainstem infarcts RBD should be evaluated by a clinical neurologist. PMID- 24758224 TI - Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial. AB - BACKGROUND: Radiation therapy is one of the recommended treatment options for localized prostate cancer. In randomized trials, dose escalation was correlated with better biochemical control but also with higher rectal toxicity. A prospective multicenter phase II study was carried out to evaluate the safety, clinical and dosimetric effects of the hydrogel prostate-rectum spacer. Here we present the 12 months toxicity results of this trial. METHODS: Fifty two patients with localized prostate cancer received a transperineal PEG hydrogel injection between the prostate and rectum, and then received IMRT to a dose of 78 Gy. Gastrointestinal and genitourinary toxicity were recorded during treatment and at 3, 6 and 12 months following irradiation by using the RTOG/EORTC criteria. Additionally, proctoscopy was performed 12 months after treatment and the results were scored using the Vienna Rectoscopy Scale (VRS). RESULTS: Of the patients treated 39.6% and 12.5% experienced acute Grade 1 and Grade 2 GI toxicity, respectively. There was no Grade 3 or Grade 4 acute GI toxicity experienced in the study. Only 4.3% showed late Grade 1 GI toxicity, and there was no late Grade 2 or greater GI toxicity experienced in the study. A total of 41.7%, 35.4% and 2.1% of the men experienced acute Grade 1, Grade 2 and Grade 3 GU toxicity, respectively. There was no Grade 4 acute GU toxicity experienced in the study. Late Grade 1 and Grade 2 GU toxicity was experienced in 17.0% and 2.1% of the patients, respectively. There was no late Grade 3 or greater GU toxicity experienced in the study. Seventy one percent of the patients had a VRS score of 0, and one patient (2%) had Grade 3 teleangiectasia. There was no evidence of ulceration, stricture or necrosis at 12 months. CONCLUSION: The use of PEG spacer gel is a safe and effective method to spare the rectum from higher dose and toxicity. PMID- 24758225 TI - Advances in the approach to novel drug clinical development for breast cancer. AB - INTRODUCTION: In the post-genomic era clinical development of new agents to treat breast cancer (BC) can be a real challenge. Different from chemotherapy agents, with a broad but not specific spectrum of activity, novel drugs are being developed as 'targeted' agents, potentially benefiting a subgroup of patients. In BC, different clinically identifiable subtypes are now separately addressed in specific clinical trials. AREAS COVERED: In this review, the authors discuss the clinical development of targeted drugs that have become part of the current treatment of BC. They also highlight the challenges that in other cases determined the failure of promising compounds. Furthermore, the article reports on how combinations of targeted agents have emerged as valid strategies to overcome acquired resistance. It also provides discussion of how 'old' therapies can be retargeted to certain patient populations or 'reinvented' as safer and more effective with the creation of drug conjugates. They also discuss how novel clinical trial designs are emerging to accelerate the successful matching of targeted drugs to the right patient population. EXPERT OPINION: It is important not to forget that the development of BC therapeutics is a 'moving target', as its biology evolves in time under the pressure of ongoing treatments. There are currently a finite number of resources available for the development of new therapeutics, which means that resources need to be carefully allocated. There is also a need to prioritize clinical trials that can reduce the number of patients who are candidates for expensive treatments. PMID- 24758228 TI - Administration costs of intravenous chemotherapy in treating peripheral T-cell lymphoma. AB - OBJECTIVE: This retrospective cohort analysis was conducted to examine the cost components of administering IV chemotherapy to peripheral T-cell lymphoma (PTCL) patients in the US to inform decision makers. METHODS: Patients diagnosed with PTCL (ICD-9 code 202.7X) between 1 October 2007 and 30 September 2012 were identified from a US administrative claims database. Costs for patients receiving at least one NCCN recommended IV chemotherapy were assessed using the allowed payment from claim line items, categorized into cost components (study drug costs, IV administration costs and other visit-related services). RESULTS: The mean costs to the payer for IV cancer therapy administration in a PTCL patient population averaged about $5735 per visit and $9356 per member per month (PMPM). Across all therapies, mean IV administration costs accounted for $127-$794 per visit and $594-$1808 PMPM, contributing an additional 2-32% to the total costs of the drug alone. Mean other visit-related services costs for treating PTCL accounted for $70-$2487 per visit and $444-$3094 PMPM, contributing an additional 2-74% to the total costs. Combined, these additional costs represent an additional mean cost of $220-$3150 per visit and $1193-$4609 PMPM to the base price of the drug alone. LIMITATIONS: This study used a convenience sample to identify PTCL patients and only included visits where at least one NCCN recommended IV chemotherapy was administered. CONCLUSIONS: The costs of IV administration and other visit-related services add measurable costs to the total cost of IV therapy for treating PTCL. When considering the cost of the drug, these additional costs can represent a substantial proportion of the overall costs and must be considered when evaluating the costs of IV treatment options for PTCL. PMID- 24758227 TI - Severe hypoxia exerts parallel and cell-specific regulation of gene expression and alternative splicing in human mesenchymal stem cells. AB - BACKGROUND: The endosteum of the bone marrow provides a specialized hypoxic niche that may serve to preserve the integrity, pluripotency, longevity and stemness of resident mesenchymal stem cells (MSCs). To explore the molecular genetic consequences of such a niche we subjected human (h) MSCs to a pO2 of 4 mmHg and analyzed global gene expression and alternative splicing (AS) by genome-exon microarray and RT-qPCR, and phenotype by western blot and immunostaining. RESULTS: Out of 446 genes differentially regulated by >2.5-fold, down-regulated genes outnumbered up-regulated genes by 243:203. Exon analyses revealed 60 hypoxia-regulated AS events with splice indices (SI) >1.0 from 53 genes and a correlation between high SI and degree of transcript regulation. Parallel analyses of a publicly available AS study on human umbilical vein endothelial cells (HUVECs) showed that there was a strong cell-specific component with only 11 genes commonly regulated in hMSCs and HUVECs and 17 common differentially spliced genes. Only 3 genes were differentially responsive to hypoxia at the gene (>2.0) and AS levels in both cell types. Functional assignments revealed unique profiles of gene expression with complex regulation of differentiation, extracellular matrix, intermediate filament and metabolic marker genes. Antioxidant genes, striated muscle genes and insulin/IGF-1 signaling intermediates were down-regulated. There was a coordinate induction of 9 out of 12 acidic keratins that along with other epithelial and cell adhesion markers implies a partial mesenchymal to epithelial transition. CONCLUSIONS: We conclude that severe hypoxia confers a quiescent phenotype in hMSCs that is reflected by both the transcriptome profile and gene-specific changes of splicosome actions. The results reveal that severe hypoxia imposes markedly different patterns of gene regulation of MSCs compared with more moderate hypoxia. This is the first study to report hypoxia-regulation of AS in stem/progenitor cells and the first molecular genetic characterization of MSC in a hypoxia-induced quiescent immobile state. PMID- 24758229 TI - Optical quality and visual performance with customised soft contact lenses for keratoconus. AB - PURPOSE: This study investigated how aberration-controlling, customised soft contact lenses corrected higher-order ocular aberrations and visual performance in keratoconic patients compared to other forms of refractive correction (spectacles and rigid gas-permeable lenses). METHODS: Twenty-two patients (16 rigid gas-permeable contact lens wearers and six spectacle wearers) were fitted with standard toric soft lenses and customised lenses (designed to correct 3rd order coma aberrations). In the rigid gas-permeable lens-wearing patients, ocular aberrations were measured without lenses, with the patient's habitual lenses and with the study lenses (Hartmann-Shack aberrometry). In the spectacle-wearing patients, ocular aberrations were measured both with and without the study lenses. LogMAR visual acuity (high-contrast and low-contrast) was evaluated with the patient wearing their habitual correction (of either spectacles or rigid gas permeable contact lenses) and with the study lenses. RESULTS: In the contact lens wearers, the habitual rigid gas-permeable lenses and customised lenses provided significant reductions in 3rd-order coma root-mean-square (RMS) error, 3rd-order RMS and higher-order RMS error (p <= 0.004). In the spectacle wearers, the standard toric lenses and customised lenses significantly reduced 3rd-order RMS and higher-order RMS errors (p <= 0.005). The spectacle wearers showed no significant differences in visual performance measured between their habitual spectacles and the study lenses. However, in the contact lens wearers, the habitual rigid gas-permeable lenses and standard toric lenses provided significantly better high-contrast acuities compared to the customised lenses (p <= 0.006). CONCLUSIONS: The customised lenses provided substantial reductions in ocular aberrations in these keratoconic patients; however, the poor visual performances achieved with these lenses are most likely to be due to small, on eye lens decentrations. PMID- 24758230 TI - Socioeconomic factors, attitudes and practices associated with malaria prevention in the coastal plain of Chiapas, Mexico. AB - BACKGROUND: Mexico is in the malaria pre-elimination phase; therefore, continuous assessment and understanding of the social and behavioural risk factors related to exposure to malaria are necessary to achieve the overall goal. The aim of this research was to investigate socio-economic backgrounds, attitudes and practices related with malaria in rural locations from the coastal plain of Chiapas. METHODS: In January 2012, 542 interviews were conducted to householders from 20 villages across the coastal plain of Chiapas. Questions were about housing conditions, protection from mosquito bites and general information of householders. Chi2 analyses were performed to see whether there was a dependence of those reported having malaria with their house conditions and their malaria preventive practices. Results were discussed and also compared statistically against those obtained 17 years ago from the same area. RESULTS: Most households had 2-5 people (73.6%), 91.6% of houses had 1-3 bedrooms. The physical structure of the houses consisted of walls mainly made of block or brick 72.3%, the floor made of cement 90.0%, while the roof made of zinc sheet 43.9%, and straw or palm 42.2%. A 23.1% of the interviewed completed elementary school and 16.6% was illiterate. A 9.9% of the residents reported at least one family member having had malaria. A 98.1% of families used some method to prevent mosquito bites; those using bed nets were 94.3%. Almost 72% of families bought products for mosquito protection. A total of 537 out of 542 families agreed with the indoor residual spraying (IRS) of insecticide and a frequency of application as often as every two months was preferred. CONCLUSION: Housing conditions and malaria preventive practices have improved in these rural areas in 17 years, which could be in favor of malaria elimination in this area. Information generated by this study could help in the decision making about whether to use insecticide as indoor residual spraying or to implement massive distribution of long-lasting impregnated bed nets, considering the number of bedrooms and the structure of houses in the region, which may lead to a more efficient vector control for the coastal plain of Chiapas. PMID- 24758231 TI - A cross-sectional study on dermatological diseases among male prisoners in southern Lazio, Italy. AB - BACKGROUND: Prisoners have heightened health needs, and only recently has the importance of skin diseases in this group been recognized. The aim of this study was to estimate the prevalences of dermatological diseases among prisoners in the jails of southern Lazio and to investigate the determinants of these. METHODS: A cross-sectional study was carried out in three jails in southern Lazio. Retrospective data collection for sociodemographic characteristics, lifestyle habits, and health status was realized using patients' charts. RESULTS: The study sample consisted of 2653 male prisoners detained during 1995-2000. A total of 7.9% of the sample were found to have dermatological disease. The most common diseases were nonspecific dermatitis (3.1%), acne (1.5%), mycosis (1.4%), and scabies (0.7%). Multiple regression analyses were conducted to establish the associations of skin diseases with substance addiction status and age. In addition, a highly significant association emerged between length of detention and rate of dermatological disease. CONCLUSIONS: This study shows that habitual offenders, foreign inmates, prisoners serving long sentences, and prisoners who are illiterate are the most affected by dermatological disease. The conditions of detention may be the main reason; preventative strategies such as limiting overcrowding and the provision of electronic case sheets and a centralized database to collect and maintain patient clinical data might be effective in improving public health in jails. PMID- 24758232 TI - Prevalences of skin diseases among primary schoolchildren in Damietta, Egypt. AB - OBJECTIVES: Information on prevalences of pediatric dermatoses in Egypt is scanty. This study aimed to supplement existing data. METHODS: A cross-sectional study was conducted in Damietta, Egypt between October 2011 and March 2012. It involved 6162 pupils randomly selected from 30 primary schools. The sample was equally divided (3081 pupils/15 schools) between urban and rural areas. Each participant was interviewed for age, gender, residence and complaint. Hygiene status was evaluated and a clinical examination was carried out for skin diseases. Data were coded and analyzed. RESULTS: Although most children revealed more than one dermatosis, the majority (76.2%) had not complained of disease. The most common disease group included benign neoplasms (87.0%), followed by pigmentary disorders (68.3%), infections (50.9%), adnexal disorders (14.1%), hypersensitivity diseases (14.0%), genodermatoses (0.3%) and papulosquamous diseases (0.2%). The most common subgroup of diseases comprised parasitic infections (47.5%), among which pediculosis prevailed (47.5%), followed by dermatitis (10.0%) in which pityriasis alba dominated (6.0%), followed by hair disorders (9.3%), bacterial infections (5.9%), urticaria (4.4%), sebaceous gland disorders (2.7%), sweat gland disorders (2.3%), viral infections (1.6%) and fungal infections (0.7%). The most commonly found diseases included, in descending order, acquired melanocytic nevus, post-inflammatory hyperpigmentation, pediculosis, leukoderma, cafe au lait spots, atrophic scar, cicatricial alopecia, hypertrophic scar, pityriasis alba, papular urticaria, xerosis and impetigo. CONCLUSIONS: The high prevalence of skin diseases, especially of trauma-related disorders and infections, may be mainly attributable to a lack of appropriate health awareness and care, which has created a tendency within the population to adapt without complaining or seeking medical help. Such circumstances, unfortunately, have resulted in a growing community of silent patients. PMID- 24758233 TI - Changes in quality of life associated with surgical risk in elderly patients undergoing cardiac surgery. AB - The study aims to verify quality of life of elderly patients submitted to cardiac surgery, and correlating surgical risk to health-related quality of life instrument domains. Prospective cohort study, performed at a cardiology hospital. It included elderly patients who had undergone elective cardiac surgery. Pre- and postoperative quality of life was evaluated by applying the World Health Organization Quality of Life-Old (WHOQOL-OLD) scale and the Short-Form Health Survey (SF-36) questionnaire. Surgical risk was stratified using the European System for Cardiac Operative Risk Evaluation (EuroSCORE). Fifty-four patients, mostly men (64.8%), were included, with a mean age of 69.3 +/- 5.7 years. The eight domains of the SF-36 questionnaire, and the four facets presented for the WHOQOL-OLD scale showed improved quality of life 6 months after surgery (P < 0.001). No difference was found in the association of EuroSCORE with the domains of the health-related quality of life instruments. The data showed improved quality of life of elderly people submitted to cardiac surgery, unrelated to surgical risk. PMID- 24758234 TI - Entanglement model of antibody viscosity. AB - Antibody solutions are typically much more viscous than solutions of globular proteins at equivalent volume fraction. Here we propose that this is due to molecular entanglements that are caused by the elongated shape and intrinsic flexibility of antibody molecules. We present a simple theory in which the antibodies are modeled as linear polymers that can grow via reversible bonds between the antigen binding domains. This mechanism explains the observation that relatively subtle changes to the interparticle interaction can lead to large changes in the viscosity. The theory explains the presence of distinct power law regimes in the concentration dependence of the viscosity as well as the correlation between the viscosity and the charge on the variable domain in our antistreptavidin IgG1 model system. PMID- 24758235 TI - Interplay between local anisotropies in binuclear complexes. AB - A systematic study has been undertaken to determine how local distortions affect the overall (molecular) magnetic anisotropies in binuclear complexes. For this purpose we have applied a series of distortions to two binuclear Ni(II) model complexes and extracted the magnetic anisotropy parameters of multispin and giant spin model Hamiltonians. Furthermore, local and molecular magnetic axes frames have been determined. It is shown that certain combinations of local distortions can lead to constructive interference of the local anisotropies and that the largest contribution to the anisotropic exchange does not arise from the second rank tensor normally included in the multispin Hamiltonian, but rather from a fourth-rank tensor. From the comparison of the extracted parameters, simple rules are obtained to maximize the molecular anisotropy by controlling the local magnetic anisotropy, which opens the way to tune the anisotropy in binuclear or polynuclear complexes. PMID- 24758236 TI - Washing-free heterogeneous immunosensor using proximity-dependent electron mediation between an enzyme label and an electrode. AB - Washing processes, essential in most heterogeneous labeled assays, have been a big hurdle in simplifying the detection procedure and reducing assay time. Nevertheless, less attention has been paid to washing-free heterogeneous labeled assays. We report a purely washing-free immunosensor that allows fast, sensitive, and single-step detection of prostate-specific antigen in serum with low interference. Proximity-dependent electron mediation of ferrocenemethanol (Fc) between an indium-tin oxide (ITO) electrode and a glucose-oxidase (GOx) label allows us to discriminate between a bound and an unbound label: a bound label offers faster electron mediation than an unbound one. The electrooxidation of Fc at a low applied potential (0.13 V vs Ag/AgCl) and a low electrocatalytic ITO electrode and the oxidation of l-ascorbic acid by l-ascorbate oxidase minimize the effect of the interfering species. With a high concentration of glucose (200 mM), the signal and background levels are hardly dependent on the glucose concentration variation in the sample. The washing-free immunosensor can detect a concentration of ca. 1 pg/mL for mouse IgG in phosphate-buffered saline and a concentration of ca. 10 pg/mL for prostate-specific antigen spiked in female serum after an incubation period of 10 min. The concentrations measured with actual clinical serum samples are in good agreement with the concentrations measured with a commercial instrument, which renders the washing-free heterogeneous immunosensor appealing for practical use. PMID- 24758237 TI - Hydrated manganese(II) phosphate (Mn3(PO4)2.3H2O) as a water oxidation catalyst. AB - The development of a water oxidation catalyst has been a demanding challenge in realizing water splitting systems. The asymmetric geometry and flexible ligation of the biological Mn4CaO5 cluster are important properties for the function of photosystem II, and these properties can be applied to the design of new inorganic water oxidation catalysts. We identified a new crystal structure, Mn3(PO4)2.3H2O, that precipitates spontaneously in aqueous solution at room temperature and demonstrated its high catalytic performance under neutral conditions. The bulky phosphate polyhedron induces a less-ordered Mn geometry in Mn3(PO4)2.3H2O. Computational analysis indicated that the structural flexibility in Mn3(PO4)2.3H2O could stabilize the Jahn-Teller-distorted Mn(III) and thus facilitate Mn(II) oxidation. This study provides valuable insights into the interplay between atomic structure and catalytic activity. PMID- 24758238 TI - Simple, creative devices in the management of plantar foot injury. PMID- 24758239 TI - Themes for our journal: 2014-2016. PMID- 24758240 TI - Guidelines for the diagnosis and treatment of Helicobacter pylori infection in Korea, 2013 revised edition. AB - The Korean College of Helicobacter and Upper Gastrointestinal Research first developed guidelines for the diagnosis and treatment of Helicobacter pylori (H. pylori) infection in 1998, and revised guidelines were proposed in 2009 by the same group. Although the revised guidelines were based on a comprehensive review of published articles and the consensus of expert opinions, the revised guidelines were not developed using an evidence-based process. The new guidelines presented in this study include specific changes regarding indication and treatment of H. pylori infection in Korea, and were developed through the adaptation process using an evidence-based approach. After systematic review of the literature, six guidelines were selected using the Appraisal of Guidelines for Research and Evaluation (AGREE) II process. A total of 21 statements were proposed with the grading system and revised using the modified Delphi method. After the guideline revisions, 11 statements about indication of test and treatment, four statements about diagnosis, and four statements about treatment of H. pylori infection were developed. The revised guidelines were reviewed by external experts before receiving official endorsement from the Korean College of Helicobacter and Upper Gastrointestinal Research, and disseminated to physicians and other medical professionals for use in clinical practice in Korea. The guidelines will continue to be updated and revised periodically. PMID- 24758241 TI - Association of IGF1R polymorphisms with the development of HBV-related hepatocellular carcinoma. AB - Although the involvement of insulin-like signaling in cancer has been well documented in various types of cancers, the association between the genetic variants in the insulin-like signaling and the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. In this study, a total of 498 individuals including 173 HBV related cirrhosis patients, 171 HBV related HCC patients, and 154 healthy controls were enrolled. Sixteen single nucleotide polymorphisms (SNPs) in IGF1, IGF2, IGF1R and IGF2R have been genotyped by employing SNaPshot assays. We found A/A genotype at rs3743251 of IGF1R was negatively associated with HBV related HCC [odds ratio (OR) = 0.38, 95% confidence interval (CI) = 0.20-0.72, P = 0.037]; A/G genotype decreased the risk of portal vein thrombosis (OR = 0.38, 95%CI = 0.18-0.82, P = 0.01). These results indicate that rs3743251 polymorphism in IGF1R is associated with the susceptibility of HBV-related HCC. PMID- 24758242 TI - Minor diterpene glycosides from the leaves of Stevia rebaudiana. AB - Two new diterpene glycosides in addition to five known glycosides have been isolated from a commercial extract of the leaves of Stevia rebaudiana. Compound 1 (rebaudioside KA) was shown to be 13-[(O-beta-d-glucopyranosyl)oxy]ent-kaur-16-en 19-oic acid 2-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl ester and compound 2, 12-alpha-[(2-O-beta-d-glucopyranosyl-beta-d-glucopyranosyl)oxy]ent-kaur-16-en-19 oic acid beta-d-glucopyranosyl ester. Five additional known compounds were identified, rebaudioside E, rebaudioside M, rebaudioside N, rebaudioside O, and stevioside, respectively. Enzymatic hydrolysis of stevioside afforded the known ent-kaurane aglycone 13-hydroxy-ent-kaur-16-en-19-oic acid (steviol) (3). The isolated metabolite 1 possesses the ent-kaurane aglycone steviol (3), while compound 2 represents the first example of the isomeric diterpene 12-alpha hydroxy-ent-kaur-16-en-19-oic acid existing as a glycoside in S. rebaudiana. The structures of the isolated metabolites 1 and 2 were determined based on comprehensive 1D- and 2D-NMR (COSY, HSQC, and HMBC) studies. A high-quality crystal of compound 3 has formed, which allowed the acquisition of X-ray diffraction data that confirmed its structure. The structural similarities between the new metabolites and the commercially available stevioside sweeteners suggest the newly isolated metabolites should be examined for their organoleptic properties. Accordingly rebaudiosides E, M, N, O, and KA have been isolated in greater than gram quantities. PMID- 24758243 TI - Risk factors of diarrhoeal disease in under-five children among health extension model and non-model families in Sheko district rural community, Southwest Ethiopia: comparative cross-sectional study. AB - BACKGROUND: Worldwide diarrheal disease is the second leading cause of death in under-five year's children. In Ethiopia diarrhoea kills half million under-five children every year second to pneumonia. Poor sanitation, unsafe water supply and inadequate personal hygiene are responsible for 90% of diarrhoea occurrence; these can be easily improved by health promotion and education. The Ethiopian government introduced a new initiative health extension programme in 2002/03 as a means of providing a comprehensive, universal, equitable and affordable health service. As a strategy of the programme; households have been graduated as model families after training and implementing the intervention packages. Therefore the aim of the study was to assess risk factor of diarrheal disease in under-five children among health extension model and non-model families. METHOD: A community based comparative cross-sectional study design was employed in 2012 at Sheko district. Multi-stage sampling technique was employed to select 275 model and 550 non-model households that had at least one under-five children. Data was collected using structured questioner and/or checklist by trained data collectors. A summery descriptive, binary and multivariate logistic regression was computed to describe the functional independent predictors of childhood diarrhoea. RESULT: The two weeks diarrhoea prevalence in under-five children among health extension model and non-model households were 6.4% and 25.5%, respectively. The independent predictors of childhood diarrhoea revealed in the study were being mothers can't read and write [OR: 1.74, 95% CI: (1.03, 2.91)], monthly family income earn less than 650 Birr [OR: 1.75, 95% CI: (1.06, 2.88)], mothers hand washing not practice at critical time [OR: 2.21, 95% CI: (1.41, 3.46)], not soap use for hand washing [OR: 7.40, 95% CI: (2.61, 20.96)], improper refuse disposal [OR: 3.19, 95% CI: (1.89, 5.38)] and being non-model families for the health extension programme [OR: 4.50, 95% CI: (2.52, 8.03]. CONCLUSION: The level of diarrheal disease variation was well explained by maternal education, income, personal hygiene, waste disposal system and the effect of health extension programme. Thus encouraging families to being model families for the programme and enhancing community based behavioural change communication that emphasize on personal hygiene and sanitation should be strengthening to reduce childhood diarrhoea. PMID- 24758244 TI - Antimicrobial peptides. AB - With increasing antibiotics resistance, there is an urgent need for novel infection therapeutics. Since antimicrobial peptides provide opportunities for this, identification and optimization of such peptides have attracted much interest during recent years. Here, a brief overview of antimicrobial peptides is provided, with focus placed on how selected hydrophobic modifications of antimicrobial peptides can be employed to combat also more demanding pathogens, including multi-resistant strains, without conferring unacceptable toxicity. PMID- 24758245 TI - A ventilation strategy during general anaesthesia to reduce postoperative atelectasis. AB - BACKGROUND: Atelectasis is common during and after general anaesthesia. We hypothesized that a ventilation strategy, without recruitment manoeuvres, using a combination of continuous positive airway pressure (CPAP) or positive end expiratory pressure (PEEP) and a reduced end-expiratory oxygen fraction (FETO2) before ending mask ventilation with CPAP after extubation would reduce the area of postoperative atelectasis. METHODS: Thirty patients were randomized into three groups. During induction and emergence, inspiratory oxygen fractions (FIO2) were 1.0 in the control group and 1.0 or 0.8 in the intervention groups. No CPAP/PEEP was used in the control group, whereas CPAP/PEEP of 6 cmH2O was used in the intervention groups. After extubation, FIO2 was set to 0.30 in the intervention groups and CPAP was applied, aiming at FETO2 < 0.30. Atelectasis was studied by computed tomography 25 min postoperatively. RESULTS: The median area of atelectasis was 5.2 cm(2) (range 1.6-12.2 cm(2)) and 8.5 cm(2) (3-23.1 cm(2)) in the groups given FIO2 1.0 with or without CPAP/PEEP, respectively. After correction for body mass index the difference between medians (2.9 cm(2)) was statistically significant (confidence interval 0.2-7.6 cm(2), p = 0.04). In the group given FIO2 0.8, in which seven patients were ex- or current smokers, the median area of atelectasis was 8.2 cm(2) (1.8-14.7 cm(2)). CONCLUSION: Compared with conventional ventilation, after correction for obesity, this ventilation strategy reduced the area of postoperative atelectasis in one of the intervention groups but not in the other group, which included a higher proportion of smokers. PMID- 24758247 TI - Furfural-induced hydrothermal synthesis of ZnO@C gemel hexagonal microrods with enhanced photocatalytic activity and stability. AB - Here we report the synthesis of ZnO@C coaxial gemel hexagonal microrods with a thin hydrothermal carbon (HTC) layer on their surface by a facile one-step hydrothermal method with furfural as the carbon precursor. The furfural has a unique dual role, which not only induces the nucleation of ZnO in the initial stage of hydrothermal process, but also forms a thin HTC layer deposited on the ZnO surface. The thickness of the surface HTC layer increases with the hydrothermal time until 16 h under the conditions adopted in the present study. It has been found that the HTC layer has resulted in a significant improvement in the photocatalytic activities and photostabilities of the ZnO@C microrods for the UV-irradiated photodegradation of methylene blue solution. The mechanism involved in the process is proposed and discussed in terms of the photodegradation scheme and the properties of the ZnO@C microrods. PMID- 24758246 TI - Epidemiologic comparison of injured high school basketball athletes reporting to emergency departments and the athletic training setting. AB - CONTEXT: Basketball is a popular US high school sport with more than 1 million participants annually. OBJECTIVE: To compare patterns of athletes with basketball related injuries presenting to US emergency departments from 2005 through 2010 and the high school athletic training setting from the 2005-2011 seasons. DESIGN: Descriptive epidemiology study. SETTING: Data from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission and the High School Reporting Information Online database. MAIN OUTCOME MEASURE(S): Complex sample weights were used to calculate national estimates of basketball-related injuries for comparison. PATIENTS OR OTHER PARTICIPANTS: Adolescents from 13 to 19 years of age treated in US emergency departments for basketball-related injuries and athletes from 13 to 19 years of age from schools participating in High School Reporting Information Online who were injured while playing basketball. RESULTS: Nationally, an estimated 1,514,957 (95% confidence interval = 1,337,441, 1,692,474) athletes with basketball-related injuries reported to the emergency department and 1,064,551 (95% confidence interval = 1,055,482, 1,073,620) presented to the athletic training setting. Overall, the most frequent injuries seen in the emergency department were lacerations and fractures (injury proportion ratios [IPRs] = 3.45 and 1.72, respectively), whereas those seen in the athletic training setting were more commonly concussions and strains/sprains (IPRs = 2.23 and 1.19, respectively; all P values < .0001). Comparisons of body site and diagnosis combinations revealed additional differences. For example, athletes with lower leg fractures more often presented to the emergency department (IPR = 6.53), whereas those with hand fractures more frequently presented to the athletic training setting (IPR = 1.18; all P values < .0001). CONCLUSIONS: Patterns of injury differed among high school basketball players presenting for treatment in the emergency department and the athletic training setting. Understanding differences specific to clinical settings is crucial to grasping the full epidemiologic and clinical picture of sport-related injuries. Certified athletic trainers play an important role in identifying, assessing, and treating athletes with sport-related injuries who might otherwise present to clinical settings with higher costs, such as the emergency department. PMID- 24758248 TI - A gross anatomic study of distal tibia and fibula for single-incision approach. AB - OBJECTIVE: This study aimed to investigate the feasibility of single incision for plating for the treatment of distal tibia and fibula fractures by a gross anatomic study. METHODS: The anatomical structures of the anterolateral lower legs were identified. The lower leg length was measured from the top of fibular head to the tip of lateral malleolus. The distances between the extensor digitorum longus and anterior border of distal thirds of the tibia as well as the fibula were also measured. Additionally, their mutual relationships to the surrounding anatomical structures were described. RESULTS: The distances from the proximal, middle, and distal thirds of the tibia to the extensor digitorum longus were 2.96 +/- 0.46, 1.85 +/- 0.25, and 2.15 +/- 0.30 cm, respectively; the distances from the proximal, middle, and distal thirds of the fibula to the extensor digitorum longus were 1.82 +/- 0.28, 2.09 +/- 0.31, and 2.30 +/- 0.27 cm, respectively. The results indicated that the safe gap from the distal tibia to extensor digitorum longus (EDL) was 1.6-3.4 cm and from the EDL to fibula was 1.5-2.6 cm. In addition, the average number of vascular pedicle in tibialis anterior, extensor hallucis longus, extensor digitorum longus, peroneus longus, and peroneus brevis was 2-3. Injuries generated by retracting medially and laterally in vascular pedicle could hardly affect the distal muscles. CONCLUSIONS: Therefore, we suggest that it is feasible to plate fractures of both the distal tibia and fibula through one anterolateral incision. PMID- 24758249 TI - Seasonal ambient air pollution correlates strongly with spontaneous abortion in Mongolia. AB - BACKGROUND: Air pollution is a major health challenge worldwide and has previously been strongly associated with adverse reproductive health. This study aimed to examine the association between spontaneous abortion and seasonal variation of air pollutants in Ulaanbaatar, Mongolia. METHODS: Monthly average O3, SO2, NO2, CO, PM10 and PM2.5 levels were measured at Mongolian Government Air Quality Monitoring stations. The medical records of 1219 women admitted to the hospital due to spontaneous abortion between 2009-2011 were examined retrospectively. Fetal deaths per calendar month from January-December, 2011 were counted and correlated with mean monthly levels of various air pollutants by means of regression analysis. RESULTS: Regression of ambient pollutants against fetal death as a dose-response toxicity curve revealed very strong dose-response correlations for SO2 r > 0.9 (p < 0.001) while similarly strongly significant correlation coefficients were found for NO2 (r > 0.8), CO (r > 0.9), PM10 (r > 0.9) and PM2.5 (r > 0.8), (p < 0.001), indicating a strong correlation between air pollution and decreased fetal wellbeing. CONCLUSION: The present study identified alarmingly strong statistical correlations between ambient air pollutants and spontaneous abortion. Further studies need to be done to examine possible correlations between personal exposure to air pollutants and pregnancy loss. PMID- 24758250 TI - Polymer-drug conjugates: recent progress on administration routes. AB - INTRODUCTION: Polymer-drug conjugates are an important part of polymer therapeutics. Recently, they have been used as an appealing platform for drug delivery. As a delivery vector, the route of administration performs a serious impact on the accessibility of drug molecules to their respective target site and therapeutic index. Furthermore, the physicochemical and biological properties of conjugates also correlate distinctly with the route of administration. AREAS COVERED: This article reviews the recent advances of polymer-drug conjugates as drug delivery systems through parenteral, enteral and topical routes. In particular, it mainly focuses on the classical and emerging routes such as injection, oral, transdermal, pulmonary and ocular routes using polymer-drug conjugates as delivery systems. EXPERT OPINION: Although polymer-conjugated drug delivery systems reported so far face severe shortcoming of being incomplete methodology and limited routes for administration (mostly concentrated in injection), some polymer carriers like poly(amidoamine) and hyaluronic acid still offer an appealing platform to deliver drug. Acquiring the particular characteristics of each polymer carrier, exploiting novel biodegradable polymer, expanding classical drug administration ways by emerging routes and developing a rational and systematic methodology to design administration routes will be the promising directions. PMID- 24758251 TI - Differences in respiratory-induced pancreatic tumor motion between 4D treatment planning CT and daily cone beam CT, measured using intratumoral fiducials. AB - BACKGROUND: In radiotherapy, the magnitude of respiratory-induced tumor motion is often measured using a single four-dimensional computed tomography (4DCT). This magnitude is required to determine the internal target volume. The aim of this study was to compare the magnitude of respiratory-induced motion of pancreatic tumors on a single 4DCT with the motion on daily cone beam CT (CBCT) scans during a 3-5-week fractionated radiotherapy scheme. In addition, we investigated changes in the respiratory motion during the treatment course. MATERIAL AND METHODS: The mean peak-to-peak motion (i.e. magnitude of motion) of pancreatic tumors was measured for 18 patients using intratumoral gold fiducials visible on CBCT scans made prior to each treatment fraction (10-27 CBCTs per patient; 401 CBCTs in total). For each patient, these magnitudes were compared to the magnitude measured on 4DCT. Possible time trends were investigated by applying linear fits to the tumor motion determined from daily CBCTs as a function of treatment day. RESULTS: We found a significant (p <= 0.01) difference between motion magnitude on 4DCT and on CBCT in superior-inferior, anterior-posterior and left-right direction, in 13, 9 and 12 of 18 patients, respectively. In the anterior- posterior and left-right direction no fractions had a difference >= 5 mm. In the superior-inferior direction the difference was >= 5 mm for 17% of the 401 fractions. In this direction, a significant (p <= 0.05) time trend in tumor motion was observed in 4 of 18 patients, but all trends were small (- 0.17-0.10 mm/day) and did not explain the large differences in motion magnitude between 4DCT and CBCT. CONCLUSION: A single measurement of the respiratory-induced motion magnitude of pancreatic tumors using 4DCT is often not representative for the magnitude during daily treatment over a 3-5-week radiotherapy scheme. For this patient group it may be beneficial to introduce breath-hold to eliminate respiratory-induced tumor motion. PMID- 24758253 TI - A case of protothecosis in a patient with multiple myeloma. PMID- 24758252 TI - PTRcombiner: mining combinatorial regulation of gene expression from post transcriptional interaction maps. AB - BACKGROUND: The progress in mapping RNA-protein and RNA-RNA interactions at the transcriptome-wide level paves the way to decipher possible combinatorial patterns embedded in post-transcriptional regulation of gene expression. RESULTS: Here we propose an innovative computational tool to extract clusters of mRNA trans-acting co-regulators (RNA binding proteins and non-coding RNAs) from pairwise interaction annotations. In addition the tool allows to analyze the binding site similarity of co-regulators belonging to the same cluster, given their positional binding information. The tool has been tested on experimental collections of human and yeast interactions, identifying modules that coordinate functionally related messages. CONCLUSIONS: This tool is an original attempt to uncover combinatorial patterns using all the post-transcriptional interaction data available so far. PTRcombiner is available at http://disi.unitn.it/~passerini/software/PTRcombiner/. PMID- 24758254 TI - Vessels making loud sounds. PMID- 24758255 TI - Clusterin/Apolipoprotein J immunolocalization on carotid artery is affected by TNF-alpha, cigarette smoking and anti-platelet treatment. AB - BACKGROUND: Clusterin (CLU) /Apolipoprotein J is a protein biosensor of oxidative stress and inflammation, which is upregulated in many pathological processes including atherosclerosis. Previous studies have shown that in aortic tissue, CLU expression increases with atherosclerotic lesion progression and it has been coupled with vascular damage and coronary artery disease. A few studies enter into CLU and carotid atherosclerosis while the apolipoprotein's expression on human carotid tissue and its association with parameters related to the disease development has not been examined. The present study was designed to reveal the relationships between the degree of CLU immunolocalization on carotid artery and demographic characteristics, blood parameters and pharmacological treatment of patients underwent internal carotid artery endarterectomy. METHODS: CLU expression was detected by immunohistochemistry in 42 carotid endarterectomy specimens. Patients' serum levels of tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), high sensitive C-reactive protein (hsCRP) and classical parameters related to atherosclerosis such as lipid profile, as well as thrombosis related parameters such as fibrinogen, antithrombin III, protein C and protein S were determined. Demographic characteristics, smoking habits and the use of medications were recorded. Comparisons between groups were performed by students't-test and analysis of variance. Independent associations with CLU expression on carotid tissue were denoted by linear regression analysis. RESULTS: CLU imuunolocalization was denser in smokers than in non-smokers (p = 0.041) while it was rarefied in specimens of patients on cropidogrel treatment (p = 0.045) compared to the rest not taking this medication. Clopidogrel intake was independent predictor of lower CLU expression on carotid artery (p =0.045). CLU was positively correlated with serum TNF-a concentration (r = 0.33, p = 0.040) that was independent predictor of higher expression of the apolipoprotein (p = 0.001). IL-6, hsCRP and classical parameters related to atherosclerosis and thrombosis were not associated with CLU immunolocalization. CONCLUSION: Our study suggests that CLU expression on carotid artery is affected by TNF-alpha, cigarette smoking confirming its association with oxidative and cellular stress and anti-platelet medication reflecting the protective effects of such pharmacological treatment on vascular wall. PMID- 24758257 TI - Constipation and defecation pattern the first 30 days after hip fracture. AB - Constipation is often an overlooked aspect of patient care and increases the risk of postoperative complications, can prolong hospital stay, increase financial cost and add to staff nursing care time. A prospective descriptive design was used. One hundred six patients with hip fracture participated. On admission, day of discharge and 30 days after surgery, patients' normal and actual defecation pattern, stool consistency and if they had experienced problems with defecation were assessed using Bristol Stool Scale and a scale composed by Rasmussen. There were 69.1% of the patients who developed constipation during the first postoperative days and 62.3% reported the same problems 30 days after surgery. Normal defecation pattern was re-established 9.5 days after surgery, though 22.7% of the patients did not re-establish normal defecation pattern within the first 30 days after surgery. The results imply that further studies are needed to prevent constipation and help patients to cope with this side-effect of surgery after discharge. PMID- 24758256 TI - Estimating the duration of speciation from phylogenies. AB - Speciation is not instantaneous but takes time. The protracted birth-death diversification model incorporates this fact and predicts the often observed slowdown of lineage accumulation toward the present. The mathematical complexity of the protracted speciation model has barred estimation of its parameters until recently a method to compute the likelihood of phylogenetic branching times under this model was outlined (Lambert et al. ). Here, we implement this method and study using simulated phylogenies of extant species how well we can estimate the model parameters (rate of initiation of speciation, rate of extinction of incipient and good species, and rate of completion of speciation) as well as the duration of speciation, which is a combination of the aforementioned parameters. We illustrate our approach by applying it to a primate phylogeny. The simulations show that phylogenies often do not contain enough information to provide unbiased estimates of the speciation-initiation rate and the extinction rate, but the duration of speciation can be estimated without much bias. The estimate of the duration of speciation for the primate clade is consistent with literature estimates. We conclude that phylogenies combined with the protracted speciation model provide a promising way to estimate the duration of speciation. PMID- 24758258 TI - Modulating the sensor response to halide using NBD-based azamacrocycles. AB - Ligand L (2,6-bis{[7-(7-nitrobenzo[1,2,5]oxadiazole-4-yl)-3,10-dimethyl-1,4,7,10 tetraazacyclododeca-1-yl]methyl}phenol) is a fluorescent sensor that is useful for detecting Cu(II), Zn(II), and Cd(II). Some of the complexes formed are able to sense the presence of halides in solution. L passes through the cellular membrane, becoming fluorescent inside cells. The H(-1)L- species is able to form dinuclear complexes with [M(2)H(-1)L]3+ stoichiometry with Cu(II), Zn(II), and Cd(II) ions, experiencing a CHEF effect upon metal coordination in an acetonitrile/water 95:5 (v/v) solution. In all three of the complexes investigated, the metal cations are coordinatively unsaturated and can therefore bind secondary ligands as anionic species. The crystal structure of [Cd(2)(H( 1)L)Cl(2)](ClO(4)).4H(2)O is discussed. The Zn(II) complex behaves as an OFF-ON sensor for fluoride and chloride anions. PMID- 24758259 TI - Molecular dynamics investigations of the alpha-helix to beta-barrel conformational transformation in the RfaH transcription factor. AB - The C-terminal domain (CTD) of the transcription antiterminator RfaH folds to an alpha-helix bundle when it interacts with its N-terminal domain (NTD) but it undergoes an all-alpha to all-beta conformational transformation when it does not interact with the NTD. The RfaH-CTD in the all-alpha topology is involved in regulating transcription whereas in the all-beta topology it is involved in stimulating translation by recruiting a ribosome to an mRNA. Because the conformational transformation in RfaH-CTD gives it a different function, it is labeled as a transformer protein, a class that may eventually include many other functional proteins. The structure and function of RfaH is of interest for its own sake, as well as for the value it may serve as a model system for investigating structural transformations in general. We used replica exchange molecular dynamics simulations with implicit solvent to investigate the alpha helix to beta-structure transformation of RfaH-CTD, followed by structural relaxation with detailed all atom simulations for the best replica. The importance of interfacial interactions between the two domains of RfaH is highlighted by the compromised structural integrity of the helical form of the CTD in the absence NTD. Calculations of free-energy landscape and transfer entropy elucidate the details of the RfaH-CTD transformation process. PMID- 24758260 TI - Highly regio- and enantioselective synthesis of polysubstituted 2H-pyrroles via Pd-catalyzed intermolecular asymmetric allylic dearomatization of pyrroles. AB - A highly efficient synthesis of chiral polysubstituted 2H-pyrrole derivatives via a Pd-catalyzed intermolecular asymmetric allylic dearomatization reaction of pyrroles is presented. With the commercially available palladium precursor and chiral ligand, the polysubstituted 2H-pyrrole products containing a chiral quaternary carbon center were obtained with up to 97% ee and >95/5 regioselectivity. PMID- 24758261 TI - The importance of tobacco research focusing on marginalized groups. PMID- 24758262 TI - HLA-B*55:46, a novel allele, identified in a Chinese platelet donor. PMID- 24758263 TI - Microbiology of the infected recurrent sacrococcygeal pilonidal sinus. AB - The aim of the present retrospective single centre study was to define the changes in the microbiological flora of the recurring sacrococcygeal pilonidal sinus (PS). Microbiological findings of swab samples of abscess-forming PS from 2000 to 2010 were evaluated. Within this time span, 73 swab samples were taken from primary sacrococcygeal pilonidal sinus (pPS) and 23 swab samples of patients with recurring sacrococcygeal pilonidal sinus (rPS). Our results show a statistically significant shift of the bacterial flora towards the gram-positive range (P = 0.029) and a shift with tendency towards the aerobic range (P = 0.090). Pathogens of pPS are not always solely anaerobic or gram-negative, and those of rPS not always aerobic or gram-positive. Therefore, antibiosis preceding microbiological examination should cover both the aerobic and anaerobic bacteria as well as the gram-positive and the gram-negative spectrum. PMID- 24758265 TI - Common clinical quandaries encountered by nephrologists: more questions answered. PMID- 24758264 TI - Online Pestkoppenstoppen: systematic and theory-based development of a web-based tailored intervention for adolescent cyberbully victims to combat and prevent cyberbullying. AB - BACKGROUND: The purpose of this article is to give an integrative insight into the theoretical and empirical-based development of the Online Pestkoppenstoppen (Stop Bullies Online/Stop Online Bullies). This intervention aims to reduce the number of cyberbully victims and their symptoms of depression and anxiety (program goal), by teaching cyberbully victims how to cope in an adequate and effective manner with cyberbully incidents (program's outcomes). METHOD/DESIGN: In developing the program the different steps of the Intervention Mapping protocol are systematically used. In this article we describe each step of Intervention Mapping. Sources used for the development were a literature review, a Delphi study among experts, focus group interviews with the target group, and elements from a proven effective anti-bullying program. The result is a fully automated web-based tailored intervention for cyberbully victims (12-15 years) consisting of three web-based advice sessions delivered over three months. The first advice aims to teach participants how behavior is influenced by the thoughts they have, how to recognize and dispute irrational thoughts and how to form rational thoughts. In the second advice, participants will learn about the way bullying emerges, how their behavior influences bullying and how they can use effective coping strategies in order to stop (online) bullying. In the third advice, participants receive feedback and will learn how to use the Internet and mobile phones in a safe manner. Each advice is tailored to the participant's personal characteristics (e.g., personality, self-efficacy, coping strategies used and (ir)rational thoughts). To ensure implementation of the program after testing it for effectiveness, the intervention was pretested in the target population and an implementation plan was designed. Finally, we will elaborate on the planned randomized controlled trial in which the intervention will be compared to a general information group and waiting list control group. This evaluation will provide insight into the intervention's efficacy to reduce cyberbullying and its negative effects. DISCUSSION: Intervention Mapping is a time consuming but profound way to ensure that each step of developing an intervention is taken, and resulted in three web-based tailored pieces of advices that teach adolescents how to cope more effectively with cyberbullying experiences. TRIAL REGISTRATION: NTR3613, 14-09-2012. PMID- 24758268 TI - Aplysinellamides A-C, bromotyrosine-derived metabolites from an Australian Aplysinella sp. marine sponge. AB - Mass-directed fractionation of an extract from the Australian marine sponge Aplysinella sp., from the Great Barrier Reef, resulted in the isolation of four new bromotyrosine derivatives, aplysinellamides A-C (1-3) and aplysamine-1-N oxide (4), along with six known compounds (5-10). The structure elucidation of compounds 1-4 was based on their 1D and 2D NMR and MS spectroscopic data. Aplysamine-1 (6) increased the apolipoprotein E secretion from human CCF-STTG1 astrocytoma cells by 2-fold at the concentration of 30 MUM. PMID- 24758269 TI - Hedgehog/Gli promotes epithelial-mesenchymal transition in lung squamous cell carcinomas. AB - BACKGROUND: Squamous cell carcinomas (SCC) account for approximately 30% of non small cell lung cancer. Investigation of the mechanism of invasion and metastasis of lung SCC will be of great help for the development of meaningful targeted therapeutics. This study is intended to understand whether the activation of Hedgehog (Hh) pathway is involved in lung SCC, and whether activated Hh signaling regulates metastasis through epithelial-mesenchymal transition (EMT) in lung SCC. METHODS: Two cohorts of patients with lung SCC were studied. Protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. Protein expression levels in tissue specimens were scored and correlations were analyzed. Vismodegib and a Gli inhibitor were used to inhibit Shh/Gli activity, and recombinant Shh proteins were used to stimulate the Hh pathway in lung SCC cell lines. Cell migration assay was performed in vitro. RESULTS: Shh/Gli pathway components were aberrantly expressed in lung SCC tissue samples. Gli1 expression was reversely associated with the expression of EMT markers E-Cadherin and beta Catenin in lung SCC specimens. Inhibition of the Shh/Gli pathway suppressed migration and up-regulated E-Cadherin expression in lung SCC cells. Stimulation of the pathway increased migration and down-regulated E-Cadherin expression in lung SCC cells. CONCLUSIONS: Our results suggested that the Shh/Gli pathway may be critical for lung SCC recurrence, metastasis and resistance to chemotherapy. Inhibition of the Shh/Gli pathway activity/function is a potential therapeutic strategy for the treatment of lung SCC patients. PMID- 24758270 TI - Effects of continuous renal replacement therapy on intestinal mucosal barrier function during extracorporeal membrane oxygenation in a porcine model. AB - BACKGROUNDS: Extracorporeal membrane oxygenation (ECMO) has been recommended for treatment of acute, potentially reversible, life-threatening respiratory failure unresponsive to conventional therapy. Intestinal mucosal barrier dysfunction is one of the most critical pathophysiological disorders during ECMO. This study aimed to determine whether combination with CRRT could alleviate damage of intestinal mucosal barrier function during VV ECMO in a porcine model. METHODS: Twenty-four piglets were randomly divided into control(C), sham(S), ECMO(E) and ECMO + CRRT(EC) group. The animals were treated with ECMO or ECMO + CRRT for 24 hours. After the experiments, piglets were sacrificed. Jejunum, ileum and colon were harvested for morphologic examination of mucosal injury and ultrastructural distortion. Histological scoring was assessed according to Chiu's scoring standard. Blood samples were taken from the animals at -1, 2, 6, 12 and 24 h during experiment. Blood, liver, spleen, kidney and mesenteric lymphnode were collected for bacterial culture. Serum concentrations of diamine oxidase (DAO) and intestinal fatty acid binding protein (I-FABP) were tested as markers to assess intestinal epithelial function and permeability. DAO levels were determined by spectrophotometry and I-FABP levels by enzyme linked immunosorbent assay. RESULTS: Microscopy findings showed that ECMO-induced intestinal microvillus shedding and edema, morphological distortion of tight junction between intestinal mucous epithelium and loose cell-cell junctions were significantly improved with combination of CRRT. No significance was detected on positive rate of serum bacterial culture. The elevated colonies of bacterial culture in liver and mesenteric lymphnode in E group reduced significantly in EC group (p < 0.05). Compared with E group, EC group showed significantly decreased level of serum DAO and I-FABP (p < 0.05). CONCLUSIONS: CRRT can alleviate the intestinal mucosal dysfunction and bacterial translocation during VV ECMO, which may extenuate the ECMO-associated SIRS and raise the clinical effect and safety. PMID- 24758271 TI - Effect of an Empowerment Intervention on Antiretroviral Drug Adherence in Thai Youth. AB - A pilot study was conducted to determine effects of an empowerment intervention on antiretroviral therapy (ART) adherence among Thai youth living with HIV/AIDS. It compared two groups of 23 young persons (15-24 years) who receive ART from AIDS clinics at two community hospitals. One hospital's patients served as the experimental group, and the other as a control group. The experimental groups attended five sessions that empowered them to take control of their own health. The control group received the standard of care. The data were analyzed using descriptive statistics and Chi-square statistics. Before the empowerment, no one from the experimental group or the control group had ART adherence >= 95%. After the intervention, the 82.6% of the experimental group had >= 95% adherence compared to the control group, which had 21.7% adherence (p < .0001). The empowerment intervention resulted in a significant increase in ART adherence among Thai youth. PMID- 24758273 TI - Enzyme kinetics modeling as a tool to optimize food industry: a pragmatic approach based on amylolytic enzymes. AB - Modeling is an important tool in the food industry since it is able to simplify explanation of phenomena and optimize processes that cover a broad field from manufacture to byproducts treatment. The goal of the current article is to explore the development of enzyme kinetic models and their evolution over the last decades. For this reason, corresponding simulations were classified in deterministic, empirical, and stochastic models, prior investigating limitations, corrections, and industrial applications in each case. The ultimate goal is to provide an answer to a major problem: how can we develop an intermediate complexity model that achieves satisfactorily representation of the main phenomena with a limited number of parameters? PMID- 24758272 TI - A house finch (Haemorhous mexicanus) spleen transcriptome reveals intra- and interspecific patterns of gene expression, alternative splicing and genetic diversity in passerines. AB - BACKGROUND: With its plumage color dimorphism and unique history in North America, including a recent population expansion and an epizootic of Mycoplasma gallisepticum (MG), the house finch (Haemorhous mexicanus) is a model species for studying sexual selection, plumage coloration and host-parasite interactions. As part of our ongoing efforts to make available genomic resources for this species, here we report a transcriptome assembly derived from genes expressed in spleen. RESULTS: We characterize transcriptomes from two populations with different histories of demography and disease exposure: a recently founded population in the eastern US that has been exposed to MG for over a decade and a native population from the western range that has never been exposed to MG. We utilize this resource to quantify conservation in gene expression in passerine birds over approximately 50 MY by comparing splenic expression profiles for 9,646 house finch transcripts and those from zebra finch and find that less than half of all genes expressed in spleen in either species are expressed in both species. Comparative gene annotations from several vertebrate species suggest that the house finch transcriptomes contain ~15 genes not yet found in previously sequenced vertebrate genomes. The house finch transcriptomes harbour ~85,000 SNPs, ~20,000 of which are non-synonymous. Although not yet validated by biological or technical replication, we identify a set of genes exhibiting differences between populations in gene expression (n = 182; 2% of all transcripts), allele frequencies (76 FST ouliers) and alternative splicing as well as genes with several fixed non-synonymous substitutions; this set includes genes with functions related to double-strand break repair and immune response. CONCLUSIONS: The two house finch spleen transcriptome profiles will add to the increasing data on genome and transcriptome sequence information from natural populations. Differences in splenic expression between house finch and zebra finch imply either significant evolutionary turnover of splenic expression patterns or different physiological states of the individuals examined. The transcriptome resource will enhance the potential to annotate an eventual house finch genome, and the set of gene-based high-quality SNPs will help clarify the genetic underpinnings of host-pathogen interactions and sexual selection. PMID- 24758275 TI - Highly stretchable and transparent ionogels as nonvolatile conductors for dielectric elastomer transducers. AB - Large deformation of soft materials is harnessed to provide functions in the nascent field of soft machines. This paper describes a new class of systems enabled by highly stretchable, transparent, stable ionogels. We synthesize an ionogel by polymerizing acrylic acid in ionic liquid 1-ethyl-3-methylimidazolium ethylsulfate ([C2mim][EtSO4]). The ionogel exhibits desired attributes of adequate conductivity (0.22 S m(-1)), low elastic modulus (~3 kPa), large rupturing stretch (~4.6), and negligible hysteresis and degradation after cyclic stretches of large amplitude. Using the ionogel and a dielectric elastomer, we fabricate electromechanical transducers that achieve a voltage-induced areal strain of 140%. The ionogel is somewhat hygroscopic, but the transducers remain stable after a million cycles of excitation in a dry oven and in air. The transparency of the ionogels enable the transducers with conductors placed in the path of light, and the nonvolatility of the ionogels enable the transducers to be used in open air. PMID- 24758274 TI - A comprehensive representation of the birth-experience: identification and prioritization of birth-specific domains based on a mixed-method design. AB - BACKGROUND: In obstetrics, effectiveness and cost-effectiveness studies often present several specific outcomes with likely contradicting results and may not reflect what is important for women. A birth-specific outcome measure that combines the core domains into one utility score would solve this problem. The aim of this study was to investigate which domains are most relevant for women's overall experience of labor and birth and should be included in such a measure. METHODS: A sequential mixed-method design with three steps was applied. First, the domains were identified by literature review and online focus groups consisting of pregnant women, women who recently gave birth, and their partners. Second, in a prioritizing task, women who recently gave birth and professionals (midwives, gynecologists, and researchers) selected and ranked their top seven domains. Third, the domains that were most frequently selected and had the highest ranking scores determined the basis for a consensus discussion with experts, whereby the definitive list of domains was formed. RESULTS: In the first step, 34 birth-specific domains were identified, which cover domains regarding the caregivers, intrapersonal aspects of the mother, partner support, and contextual and medical aspects of birth. Based on the prioritizing task results (step 2) of 96 women and 89 professionals, this list was reduced to 14 most relevant domains. In a consensus discussion, the final seven domains were selected by combining several of the 14 remaining domains and giving priority to the domains indicated to be relevant by mothers. The seven definite domains were: 1) availability of competent health professionals; 2) health professionals' support; 3) provision of information; 4) health professionals' response to needs and requests; 5) feelings of safety; 6) worries about the child's health; and 7) experienced duration until the first contact with the child. CONCLUSIONS: The experienced availability and quality of received care, concerns about safety and the baby's health, and first contact with the baby are regarded as key aspects for a mother's overall birth experience. Therefore, these domains are considered to be the most crucial for inclusion in a birth-specific outcome measure. PMID- 24758276 TI - Investigational drugs for treating psoriatic arthritis. AB - INTRODUCTION: Psoriatic arthritis (PsA) is an inflammatory arthritis occurring in up to 30% of patients with psoriasis and can lead to progressive joint damage and disability. The emergence of 'biological' treatments, typified by the TNF inhibitors, has significantly advanced treatment of psoriatic disease over the last two decades and has led to an expanding field of drugs designed to target specific pathways identified in the pathogenesis of the disease. AREAS COVERED: This review article describes current knowledge pertaining to genetic susceptibility and that gleaned from animal models. It discusses putative drug targets and drugs in development, up to Phase II, while acknowledging that many of these drugs are being investigated in rheumatoid arthritis and psoriasis rather than PsA alone. EXPERT OPINION: Ongoing trials of some of these drugs, such as the JAK inhibitors, appear particularly promising, while the evolution of dual-targeting therapies affords the aspiration of enhanced efficacy, safety and remission. Paramount to the future of drug discovery and development is the affordability of these agents to the healthcare purchaser as well as their accessibility to the patient. PMID- 24758277 TI - Joined at the hip: linked characters and the problem of missing data in studies of disparity. AB - Paleontological investigations into morphological diversity, or disparity, are often confronted with large amounts of missing data. We illustrate how missing discrete data affect disparity using a novel simulation for removing data based on parameters from published datasets that contain both extinct and extant taxa. We develop an algorithm that assesses the distribution of missing characters in extinct taxa, and simulates data loss by applying that distribution to extant taxa. We term this technique "linkage." We compare differences in disparity metrics and ordination spaces produced by linkage and random character removal. When we incorporated linkage among characters, disparity metrics declined and ordination spaces shrank at a slower rate with increasing missing data, indicating that correlations among characters govern the sensitivity of disparity analysis. We also present and test a new disparity method that uses the linkage algorithm to correct for the bias caused by missing data. We equalized proportions of missing data among time bins before calculating disparity, and found that estimates of disparity changed when missing data were taken into account. By removing the bias of missing data, we can gain new insights into the morphological evolution of organisms and highlight the detrimental effects of missing data on disparity analysis. PMID- 24758279 TI - Accuracy of self-reported and measured anthropometric data in the inpatient population. AB - Self-reported body mass index (BMI) is commonly used to assess nutritional status. The aim of the study was to assess the accuracy of self-reported and measured data obtained from the inpatient population. A total of 296 individuals admitted to five hospital wards were included in the study. Patients provided details of their height and weight, and measurements of height and weight were subsequently taken. BMI measurements were calculated from both the self-reported and the measured data. In general, the study participants overestimated their height and underestimated their weight. Older people and women were significantly more likely to overestimate their height, whereas better educated people were more likely to underestimate their weight. Inaccurate height and weight reporting led to BMI values being underestimated. The findings of this study support previously published research questioning the accuracy of self-reported height and weight measurements. PMID- 24758278 TI - Fat body, fat pad and adipose tissues in invertebrates and vertebrates: the nexus. AB - The fat body in invertebrates was shown to participate in energy storage and homeostasis, apart from its other roles in immune mediation and protein synthesis to mention a few. Thus, sharing similar characteristics with the liver and adipose tissues in vertebrates. However, vertebrate adipose tissue or fat has been incriminated in the pathophysiology of metabolic disorders due to its role in production of pro-inflammatory cytokines. This has not been reported in the insect fat body. The link between the fat body and adipose tissue was examined in this review with the aim of determining the principal factors responsible for resistance to inflammation in the insect fat body. This could be the missing link in the prevention of metabolic disorders in vertebrates, occasioned by obesity. PMID- 24758280 TI - Prevalence and correlates of diabetic retinopathy in a population-based survey of older people in Nakuru, Kenya. AB - PURPOSE: To estimate the prevalence of and factors associated with diabetic retinopathy (DR) among people aged >= 50 years in Nakuru, Kenya. METHODS: Probability-proportional-to-size sampling was used to select 100 clusters of 50 people aged >= 50 years during 2007-2008. Households within clusters were selected through compact segment sampling. Participants underwent dilated slit lamp biomicroscopy (SLB) by an ophthalmologist and digital retinal photography. Images were graded for DR at the Moorfields Eye Hospital Reading Centre, UK. Diagnosis of DR was based on retinal images where available, otherwise on SLB. Anthropometric measures, including random glucose, and lifestyle factors were measured. RESULTS: We examined 4414 adults (response rate 88.1%), of whom 287 had diabetes. A total of 277 of these were screened for DR by SLB, and 195 also underwent retinal photography. The prevalence of any DR diagnosed by retinal images among diabetics was 35.9% (95% confidence interval, CI, 29.7-42.6%). The most common grade of DR was mild/moderate non-proliferative DR (NPDR; 22.1%, 95% CI 16.1-29.4%), while severe NPDR and proliferative DR were less frequent (13.9%, 95% CI 10.0-18.8%). SLB significantly underdiagnosed DR compared to retinal photography, particularly for milder grades. Of 87 individuals with DR, 23 had visual impairment (visual acuity <6/12). DR was associated with younger age, male sex, duration and control of diabetes, and treatment compliance. Coverage of photocoagulation in those needing immediate laser was low (25%). CONCLUSION: DR remains a threat to sight in people with diabetes in this elderly Kenyan population. Screening diabetics may enable those requiring treatment to be identified in time to preserve their sight. PMID- 24758281 TI - Painful nodule on the leg. PMID- 24758282 TI - Identification of the vibrational modes in the far-infrared spectra of ruthenium carbonyl clusters and the effect of gold substitution. AB - High-quality far-IR absorption spectra for a series of ligated atomically precise clusters containing Ru3, Ru4, and AuRu3 metal cores have been observed using synchrotron radiation, the latter two for the first time. The experimental spectra are compared with predicted IR spectra obtained following complete geometric optimization of the full cluster, including all ligands, using DFT. We find strong correlations between the experimental and predicted transitions for the low-frequency, low-intensity metal core vibrations as well as the higher frequency and intensity metal-ligand vibrations. The metal core vibrational bands appear at 150 cm(-1) for Ru3(CO)12, and 153 and 170 cm(-1) for H4Ru4(CO)12, while for the bimetallic Ru3(MU-AuPPh3)(MU-Cl)(CO)10 cluster these are shifted to 177 and 299 cm(-1) as a result of significant restructuring of the metal core and changes in chemical composition. The computationally predicted IR spectra also reveal the expected atomic motions giving rise to the intense peaks of metal ligand vibrations at ca. 590 cm(-1) for Ru3, 580 cm(-1) for Ru4, and 560 cm(-1) for AuRu3. The obtained correlations allow an unambiguous identification of the key vibrational modes in the experimental far-IR spectra of these clusters for the first time. PMID- 24758283 TI - Abstracts 2014. [corrected]. PMID- 24758284 TI - Somatic mutation in acute myelogenous leukemia cells imitate novel germline HLA-A allele: a case report. AB - A somatic mutation of the human leukocyte antigen (HLA)-A gene revealed in tumour cells of acute myelogenous leukemia (AML) is described. A patient with AML and her siblings were routinely typed for HLA in order to find a suitable donor for haematopoietic stem cell transplantation. Sequencing-based typing of the initial patient's sample characterized by high proportion of blasts revealed unknown G/A exchange at position 781 of the HLA-A gene (exon 4) associated with HLA-A*02:01 allele. Importantly, this G781A variant was completely absent in the patient's remission sample obtained after the clearance of blasts. Our results are a reminder that HLA mutations in tumour cells may interfere with routine HLA typing and should always be considered, namely, in patients with haematological malignancies. PMID- 24758285 TI - Hepatic emphysema associated with ultrasound-guided liver biopsy in a dog. AB - An eleven-year-old Chinese Crested Powder Puff dog presented with polydipsia/polyuria, inappetence, diarrhea and vomiting underwent an ultrasound guided percutaneous liver biopsy. Two days post-biopsy the clinical condition of the dog acutely deteriorated with fever, dyspnea, ataxia and subcutaneous emphysema. Radiographs and ultrasound showed focal severe hepatic emphysema in the region of the previous liver biopsy. Post-mortem examination revealed chronic hepatitis with dissecting fibrosis, acute hepatitis with hemorrhage and in the hindlimb musculature extensive hemorrhage and necrosis. Pure cultures of the gas producing bacteria Clostridium perfringens were isolated in samples from the hind limb musculature. We propose that the hepatic emphysema in the region of the biopsy site was a result of a clostridial infection. PMID- 24758286 TI - A mixed ecologic-cohort comparison of physical activity & weight among young adults from five populations of African origin. AB - BACKGROUND: Examination of patterns and intensity of physical activity (PA) across cultures where obesity prevalence varies widely provides insight into one aspect of the ongoing epidemiologic transition. The primary hypothesis being addressed is whether low levels of PA are associated with excess weight and adiposity. METHODS: We recruited young adults from five countries (500 per country, 2500 total, ages 25-45 years), spanning the range of obesity prevalence. Men and women were recruited from a suburb of Chicago, Illinois, USA; urban Jamaica; rural Ghana; peri-urban South Africa; and the Seychelles. PA was measured using accelerometry and expressed as minutes per day of moderate-to vigorous activity or sedentary behavior. RESULTS: Obesity (BMI >= 30) prevalence ranged from 1.4% (Ghanaian men) to 63.8% (US women). South African men were the most active, followed by Ghanaian men. Relatively small differences were observed across sites among women; however, women in Ghana accumulated the most activity. Within site-gender sub-groups, the correlation of activity with BMI and other measures of adiposity was inconsistent; the combined correlation across sites was -0.17 for men and -0.11 for women. In the ecological analysis time spent in moderate-to-vigorous activity was inversely associated with BMI (r = -0.71). CONCLUSION: These analyses suggest that persons with greater adiposity tend to engage in less PA, although the associations are weak and the direction of causality cannot be inferred because measurements are cross-sectional. Longitudinal data will be required to elucidate direction of association. PMID- 24758287 TI - Chronic kidney disease and implantable cardioverter defibrillator related complications: 16 years of experience. AB - INTRODUCTION: Implantable cardioverter defibrillator (ICD) implantation has become an accepted therapy for the prevention of sudden cardiac death. However, serious comorbidities such as chronic kidney disease (CKD) are influencing the beneficial effects of ICD therapy. In this study, the association between kidney function and the occurrence of ICD related complications was assessed. METHODS: All patients receiving an ICD or cardiac resynchronization therapy-defibrillator between 1996 and 2012 were included. Renal function was categorized as: glomerular filtration rate (GFR) >90, GFR 30-90 or GFR <30 mL/min/1.73 m(2) . Registered complications were pocket hematoma, pneumothorax, lead complications, and device infection. RESULTS: In 3,147 device recipients, 236 patients (7.5%) suffered from at least 1 complication. Patients with a GFR <30 (n = 110) had a higher event rate for hematoma, pneumothorax, and infection. These patients were older, had a higher incidence of hypertension, diabetes, and a lower body mass index (BMI; P < 0.05). After correcting for these risk factors, hematoma remained independently associated with a GFR <30 mL/min (OR 2.7, CI: 1.05-6.9, P = 0.04). Device infection, pneumothorax, and lead complications were not independently associated with a GFR <30 mL/min/1.73 m(2) . CONCLUSIONS: Patients with CKD suffered from more ICD related complications than patients without kidney disease. This was partially associated with kidney dysfunction itself as was the case with the occurrence of hematoma. However, the high burden of risk factors associated with device complications in patients with renal disease played an important role as well. PMID- 24758289 TI - Irrigation of chronic wounds with tap water as a prerequisite for improved healing. PMID- 24758290 TI - RTA-treated carbon fiber/copper core/shell hybrid for thermally conductive composites. AB - In this paper, we demonstrate a facile route to produce epoxy/carbon fiber composites providing continuous heat conduction pathway of Cu with a high degree of crystal perfection via electroplating, followed by rapid thermal annealing (RTA) treatment and compression molding. Copper shells on carbon fibers were coated through electroplating method and post-treated via RTA technique to reduce the degree of imperfection in the Cu crystal. The epoxy/Cu-plated carbon fiber composites with Cu shell of 12.0 vol % prepared via simple compression molding, revealed 18 times larger thermal conductivity (47.2 W m(-1) K(-1)) in parallel direction and 6 times larger thermal conductivity (3.9 W m(-1) K(-1)) in perpendicular direction than epoxy/carbon fiber composite. Our novel composites with RTA-treated carbon fiber/Cu core/shell hybrid showed heat conduction behavior of an excellent polymeric composite thermal conductor with continuous heat conduction pathway, comparable to theoretical values obtained from Hatta and Taya model. PMID- 24758288 TI - Role of gut microbiota in a zebrafish model with chemically induced enterocolitis involving toll-like receptor signaling pathways. AB - BACKGROUND/AIMS: It is believed that inflammatory bowel disease (IBD) involves a breakdown in interactions between the resident commensal microbiota and the host immune response. Recent studies have revealed that gut physiology and pathology relevant to human IBD can be rapidly modeled in zebrafish larvae with a number of advantages compared with murine models. The objective of this study was to evaluate the role of gut microbiota in zebrafish models with IBD-like enterocolitis. METHODS: IBD-like enterocolitis was induced by exposing larval zebrafish to 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Assays were performed using larval zebrafish collected at 8 and 10 days postfertilization (dpf ). RESULTS: In the absence of gut microbiota, the TNBS-induced enterocolitis was less extensive. The expression of toll-like receptor 3 (TLR3) and the TLRs signaling pathway molecules MyD88 and TRIF, the activation of NF-kappaB, and the production of inflammatory cytokine tumor necrosis factor-alpha were stimulated in TNBS-treated zebrafish but there was no corresponding alteration in germ-free fish. With microbial colonization, all results reverted to a pattern similar to that observed in conventionally reared zebrafish. CONCLUSION: We described the key role of gut microbiota in the etiology of a chemically induced larval zebrafish IBD-like model, showing an involvement of TLR signaling pathways. PMID- 24758291 TI - E2F3a gene expression has prognostic significance in childhood acute lymphoblastic leukemia. AB - OBJECTIVES: To study E2F3a expression and its clinical significance in children with acute lymphoblastic leukemia (ALL). METHODS: We quantified E2F3a expression at diagnosis in 148 children with ALL by real-time PCR. In the test cohort (n = 48), receiver operating characteristic (ROC) curve was used to find the best cut off point to divide the patients into E2F3a low- and high-expression groups. The prognostic significance of E2F3a expression was investigated in the test cohort and confirmed in the validation cohort (n = 100). The correlations of E2F3a expression with the clinical features and treatment outcome of these patients were analyzed. RESULTS: ROC curve analysis indicated that the best cut-off point of E2F3a expression was 0.3780. In the test cohort, leukemia-free survival (LFS) and event-free survival (EFS) of the low-expression group were lower than those of the high-expression group (log rank: P = 0.026 for both). This finding was verified in the validation cohort. LFS, EFS, and overall survival were also lower in the low-expression group than in the high-expression group (log rank, P = 0.015, 0.008, and 0.002 respectively). E2F3a low expression was correlated with the existence of BCR-ABL fusion. An algorithm composed of E2F3a expression and minimal residual disease (MRD) could predict relapse or induction failure more precisely than current risk stratification. These results were still significant in the ALL patients without BCR-ABL fusion. CONCLUSIONS: Low expression of E2F3a was associated with inferior prognosis in childhood ALL. An algorithm composed of E2F3a expression and MRD could predict relapse or induction failure more precisely than that of the current risk stratification. PMID- 24758292 TI - Phenyl- vs cyclohexyl-substitution in methanol: implications for the OH conformation and for dispersion-affected aggregation from vibrational spectra in supersonic jets. AB - The monomers and hydrogen-bonded dimers of benzyl alcohol, cyclohexylmethanol, and 2-methyl-1-propanol are investigated by jet-FTIR spectroscopy, complemented by Raman spectra and quantum chemical calulations, including CCSD(T) corrections. A large variety of London dispersion effects from the interacting carbon cycles is revealed, sometimes adding to and sometimes competing with the alcoholic hydrogen bonds. Conformational (in-)flexibility provides the key for understanding these effects, and this requires accurate predictions of monomer conformational preferences, which are shown to be subtly at variance with experiment even for some triple-zeta MP2 calculations. In some observed dimers, cooperative OH...OH...pi patterns are sacrificed to optimize sigma-pi dispersion interactions. In other competitive dimers, dispersion interactions are far from maximized, because that would imply a substantial weakening of the hydrogen bond. In the series from methanol dimer to 1-indanol dimer, which this contribution bridges, B3LYP-D3 appears to switch from an overestimation to a slight underestimation of cohesion, but overall it provides a very useful modeling tool for vibrational spectra of systems affected by both hydrogen bonds and London dispersion. PMID- 24758293 TI - Comparison of methods for fecal microbiome biospecimen collection. AB - BACKGROUND: Effective means are needed to efficiently collect fecal samples for microbiome analysis in large-scale epidemiological studies. Using twenty-four fecal aliquots prepared from three healthy individuals, we compared the following four fecal sample collection methods for assessment of human gut microbiome: 1) fecal occult blood test cards, held at room temperature for three days, 2) Eppendorf tubes, at room temperature for three days, 3) Eppendorf tubes with RNAlater, at room temperature, and 4) as controls, samples immediately frozen at 80 degrees C. The 24 samples were assayed by 16S rRNA gene sequencing to compare overall microbiome structure and taxon distributions according to collection method. RESULTS: Storing fecal occult blood test card samples at room temperature for three days did not affect total DNA purity and relative 16S rRNA bacterial gene contents, compared with fresh frozen collection. Overall microbiome structure, based on phylogenetic UniFrac index, differed significantly by subject (p = 0.001), but microbiome structure (p = 0.497) and relative abundance of major microbial taxa (phyla) (p > 0.05) did not differ significantly by collection method. CONCLUSIONS: Our findings suggest that low-cost fecal occult blood test card collection may be a feasible means of sample collection for fecal microbiome assessment in large-scale population-based studies. PMID- 24758295 TI - An integrated literature review on sexuality of elderly nursing home residents with dementia. AB - This study presents an integrative literature review on sexuality among elderly people with dementia living in nursing homes. Original research studies published from 1980 to 2012 were included in the review. Sexual expressions ranged from holding hands to sexual intercourse. These behaviours were sometimes directed towards caregivers while the latter were providing daily care. Sexual expressions were sometimes assessed and reported subjectively without context. Responses to sexual expressions varied from positive to negative. Some sexual expressions were dealt with inconsistently, and some were considered to be problematic due to a lack of policy or privacy. It is important to assess and report sexual expressions objectively, preferably with a standardized form, and to consider context in doing so. Effort is required to provide privacy for residents' sexual expressions and a safe environment for all residents and caregivers. It is important that a policy and guidelines for care be established regarding issues related to sexuality among elderly people with dementia. PMID- 24758294 TI - Classification and characteristics of Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study. AB - INTRODUCTION: We investigated the clinical and serological features of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan using data from a nationwide, prospective, inception cohort study. METHODS: In total, 156 Japanese patients with newly diagnosed AAV were classified according to the European Medicines Agency (EMEA) algorithm with exploratory surrogate markers for AAV-related non-granulomatous pulmonary lesions, predefined as alveolar haemorrhage and interstitial lung disease (ILD), and their clinical and serological features were evaluated. RESULTS: Using the EMEA algorithm, we identified 14 patients (9.0%) with eosinophilic granulomatosis with polyangiitis (EGPA), 33 (21.2%) with granulomatosis with polyangiitis (GPA), 78 (50.0%) with microscopic polyangiitis and renal-limited vasculitis (MPA/RLV), and 31 (19.9%) with unclassifiable vasculitis. The average ages of patients with EGPA (male/female, 5/9), GPA (12/21), and MPA/RLV (35/43) and unclassifiable (9/22) were 58.0, 63.6, 71.1, and 70.6 years, respectively. Myeloperoxidase (MPO)-ANCA and proteinase-3 ANCA positivity was 50.0% and 0% for EGPA, 54.6% and 45.5% for GPA, 97.4% and 2.6% for MPA/RLV, and 93.5% and 3.2% for unclassifiable, respectively. According to the Birmingham Vasculitis Activity Score (BVAS), cutaneous (71.4%) and nervous system (92.9%) manifestations were prominent in EGPA and ear, nose, and throat manifestations (84.9%) and chest manifestations (66.7%) in GPA. Renal manifestations developed frequently in MPA/RLV (91.0%) and GPA (63.6%). The average serum creatinine levels were 0.71 mg/dL for EGPA, 1.51 mg/dL for GPA, 2.46 mg/dL for MPA/RLV, and 0.69 mg/dL for unclassifiable. The percentages of patients with ILD were 14.3% for EGPA, 9.0% for GPA, 47.4% for MPA/RLV, and 61.3% for unclassifiable. Patients with ILD (n = 61) had significantly lower BVAS (P = 0.019) with fewer ear, nose, and throat and cardiovascular manifestations than patients without ILD (n = 95). CONCLUSIONS: MPO-ANCA-positive MPA/RLV is the most common form of AAV in Japanese patients, and one-half of patients with GPA were positive for MPO-ANCA. ILD is an important clinical manifestation in Japanese patients with AAV. Unclassifiable vasculitis with MPO-ANCA positivity and ILD may represent a novel variant of MPA. TRIAL REGISTRATION: The University Hospital Medical Information Network Clinical Trials Registry: UMIN000001648. Registered 28 February 2009. PMID- 24758296 TI - Cost-effectiveness of aripiprazole once-monthly compared with paliperidone palmitate once-monthly injectable for the treatment of schizophrenia in the United States. AB - OBJECTIVE: To develop a decision-analytic model to estimate the cost effectiveness of initiating maintenance treatment with aripiprazole once-monthly (AOM) vs paliperidone long-acting injectable (PLAI) once-monthly among patients with schizophrenia in the US. METHODS: A decision-analytic model was developed to evaluate a hypothetical cohort of patients initiating maintenance treatment with AOM or PLAI. Rates of relapse, adverse events (AEs), and direct medical costs were estimated for 1 year. Patients either remained on initial treatment or discontinued treatment due to lack of efficacy, AEs, or other reasons, including non-adherence. Data from placebo-controlled pivotal trials and product prescribing information (PI) were used to estimate treatment efficacy and AEs. Analyses were performed assuming dosing of clinical trials, real-world practice, PIs, and highest therapeutic dose available, because of variation in practice settings. The main outcome of interest was incremental cost per schizophrenia hospitalization averted with AOM vs PLAI. RESULTS: Based on placebo-controlled pivotal trials' dosing, AOM improved clinical outcomes by reducing schizophrenia relapses vs PLAI (0.181 vs 0.277 per person per year [pppy]) at an additional cost of US$1276 pppy, resulting in an incremental cost-effectiveness ratio (ICER) of US$13,280/relapse averted. When PI dosing was assumed, this ICER increased to US$19,968/relapse averted. When real-world dosing and highest available dosing were assumed, AOM was associated with fewer relapses and lower overall treatment costs vs PLAI. CONCLUSIONS: AOM consistently provided favorable clinical benefits. Under various dosing scenarios, AOM results indicated fewer relapses at lower overall costs or a reasonable cost-effectiveness threshold (i.e., less than the cost of a hospitalization relapse) vs PLAI. Given the heterogeneous nature of schizophrenia and variability in treatment response, health plans may consider open access for treatments like AOM. Since model inputs were based on data from separate placebo-controlled trials, generalization of results to the real-world setting is limited. PMID- 24758297 TI - Breast tumor specific mutation in GATA3 affects physiological mechanisms regulating transcription factor turnover. AB - BACKGROUND: The transcription factor GATA3 is a favorable prognostic indicator in estrogen receptor-alpha (ERalpha)-positive breast tumors in which it participates with ERalpha and FOXA1 in a complex transcriptional regulatory program driving tumor growth. GATA3 mutations are frequent in breast cancer and have been classified as driver mutations. To elucidate the contribution(s) of GATA3 alterations to cancer, we studied two breast cancer cell lines, MCF7, which carries a heterozygous frameshift mutation in the second zinc finger of GATA3, and T47D, wild-type at this locus. METHODS: Immunofluorescence staining and subcellular fractionation were employed to verify cellular localization of GATA3 in T47D and MCF7 cells. To test protein stability, cells were treated with translation inhibitor, cycloheximide or proteasome inhibitor, MG132, and GATA3 abundance was measured over time using immunoblot. GATA3 turn-over in response to hormone was determined by treating the cells with estradiol or ERalpha agonist, ICI 182,780. DNA binding ability of recombinant GATA3 was evaluated using electrophoretic mobility shift assay and heparin chromatography. Genomic location of GATA3 in MCF7 and T47D cells was assessed by chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq). RESULTS: GATA3 localized in the nucleus in T47D and MCF7 cells, regardless of the mutation status. The truncated protein in MCF7 had impaired interaction with chromatin and was easily released from the nucleus. Recombinant mutant GATA3 was able to bind DNA to a lesser degree than the wild-type protein. Heterozygosity for the truncating mutation conferred protection from regulated turnover of GATA3, ERalpha and FOXA1 following estrogen stimulation in MCF7 cells. Thus, mutant GATA3 uncoupled protein-level regulation of master regulatory transcription factors from hormone action. Consistent with increased protein stability, ChIP-seq profiling identified greater genome-wide accumulation of GATA3 in MCF7 cells bearing the mutation, albeit with a similar distribution across the genome, comparing to T47D cells. CONCLUSIONS: We propose that this specific, cancer-derived mutation in GATA3 deregulates physiologic protein turnover, stabilizes GATA3 binding across the genome and modulates the response of breast cancer cells to estrogen signaling. PMID- 24758298 TI - Synthesis and characterization of injectable, biodegradable, phosphate containing, chemically cross-linkable, thermoresponsive macromers for bone tissue engineering. AB - Novel, injectable, biodegradable macromer solutions that form hydrogels when elevated to physiologic temperature via a dual chemical and thermo-gelation were fabricated and characterized. A thermogelling, poly(N-isopropylacrylamide)-based macromer with pendant phosphate groups was synthesized and subsequently functionalized with chemically cross-linkable methacrylate groups via degradable phosphate ester bonds, yielding a dual-gelling macromer. These dual-gelling macromers were tuned to have transition temperatures between room temperature and physiologic temperature, allowing them to undergo instantaneous thermogelation as well as chemical gelation when elevated to physiologic temperature. Additionally, the chemical cross-linking of the hydrogels was shown to mitigate hydrogel syneresis, which commonly occurs when thermogelling materials are raised above their transition temperature. Finally, degradation of the phosphate ester bonds of the cross-linked hydrogels yielded macromers that were soluble at physiologic temperature. Further characterization of the hydrogels demonstrated minimal cytotoxicity of hydrogel leachables as well as in vitro calcification, making these novel, injectable macromers promising materials for use in bone tissue engineering. PMID- 24758299 TI - Combination of running-buffer-mediated extraction and polyamidoamine-dendrimer assisted capillary electrophoresis for rapid and sensitive determination of free fatty acids in edible oils. AB - A method was developed for determining free fatty acids in edible plant oils by incorporation of running-buffer-mediated liquid-liquid extraction and polyamidoamine-dendrimer-assisted capillary electrophoresis-capacitively coupled contactless conductivity detection. The recoveries for the extraction were in the range of 90.1% and 110.3%. Addition of dendrimer to the running buffer improved the separation of fatty acids. Under the optimized buffer conditions, i.e., 3 mM pelargonic acid, 39 mM tris(hydroxymethyl)aminomethane, 30 mM polyoxyethylene 23 lauryl ether, 35% acetonitrile, 15% 2-propanol, 2.5% 1-octanol, and 300 MUM polyamidoamine generation 2 at apparent pH 8.53, the 10 model fatty acids were separated in 18 min with detection limits ranging from 0.46 to 3.28 MUM. The successful determination of fatty acids in real samples suggests that the method is simple, cost-effective, and easy to operate and is suitable for scanning free fatty acid in edible plant oils. PMID- 24758301 TI - Advanced glycation end product 3 (AGE3) suppresses the mineralization of mouse stromal ST2 cells and human mesenchymal stem cells by increasing TGF-beta expression and secretion. AB - In diabetic patients, advanced glycation end products (AGEs) cause bone fragility because of deterioration of bone quality. We previously showed that AGEs suppressed the mineralization of mouse stromal ST2 cells. TGF-beta is abundant in bone, and enhancement of its signal causes bone quality deterioration. However, whether TGF-beta signaling is involved in the AGE-induced suppression of mineralization during the osteoblast lineage remains unknown. We therefore examined the roles of TGF-beta in the AGE-induced suppression of mineralization of ST2 cells and human mesenchymal stem cells. AGE3 significantly (P < .001) inhibited mineralization in both cell types, whereas transfection with small interfering RNA for the receptor for AGEs (RAGEs) significantly (P < .05) recovered this process in ST2 cells. AGE3 increased (P < .001) the expression of TGF-beta mRNA and protein, which was partially antagonized by transfection with RAGE small interfering RNA. Treatment with a TGF-beta type I receptor kinase inhibitor, SD208, recovered AGE3-induced decreases in osterix (P < .001) and osteocalcin (P < .05) and antagonized the AGE3-induced increase in Runx2 mRNA expression in ST2 cells (P < .001). Moreover, SD208 completely and dose dependently rescued AGE3-induced suppression of mineralization in both cell types. In contrast, SD208 intensified AGE3-induced suppression of cell proliferation as well as AGE3-induced apoptosis in proliferating ST2 cells. These findings indicate that, after cells become confluent, AGE3 partially inhibits the differentiation and mineralization of osteoblastic cells by binding to RAGE and increasing TGF-beta expression and secretion. They also suggest that TGF-beta adversely affects bone quality not only in primary osteoporosis but also in diabetes-related bone disorder. PMID- 24758303 TI - Discovery and characterization of the first genuine avian leptin gene in the rock dove (Columba livia). AB - Leptin, the key regulator of mammalian energy balance, has been at the center of a great controversy in avian biology for the last 15 years since initial reports of a putative leptin gene (LEP) in chickens. Here, we characterize a novel LEP in rock dove (Columba livia) with low similarity of the predicted protein sequence (30% identity, 47% similarity) to the human ortholog. Searching the Sequence-Read Archive database revealed leptin transcripts, in the dove's liver, with 2 noncoding exons preceding 2 coding exons. This unusual 4-exon structure was validated by sequencing of a GC-rich product (76% GC, 721 bp) amplified from liver RNA by RT-PCR. Sequence alignment of the dove leptin with orthologous leptins indicated that it consists of a leader peptide (21 amino acids; aa) followed by the mature protein (160 aa), which has a putative structure typical of 4-helical-bundle cytokines except that it is 12 aa longer than human leptin. Extra residues (10 aa) were located within the loop between 2 5'-helices, interrupting the amino acid motif that is conserved in tetrapods and considered essential for activation of leptin receptor (LEPR) but not for receptor binding per se. Quantitative RT-PCR of 11 tissues showed highest (P < .05) expression of LEP in the dove's liver, whereas the dove LEPR peaked (P < .01) in the pituitary. Both genes were prominently expressed in the gonads and at lower levels in tissues involved in mammalian leptin signaling (adipose; hypothalamus). A bioassay based on activation of the chicken LEPR in vitro showed leptin activity in the dove's circulation, suggesting that dove LEP encodes an active protein, despite the interrupted loop motif. Providing tools to study energy-balance control at an evolutionary perspective, our original demonstration of leptin signaling in dove predicts a more ancient role of leptin in growth and reproduction in birds, rather than appetite control. PMID- 24758304 TI - Asymmetric mismatch in strain-specific genital morphology causes increased harm to Drosophila females. AB - Although several evolutionary forces have been proposed to contribute to genital morphological diversification, it is unclear which might act early during the evolution of novel structural traits. We test the hypothesis that mismatch between interacting male and female secondary sexual structures gives rise to increased harm to females, consistent with the outcome predicted from a history of sexual conflict. We mate Drosophila sechellia females to males from a collection of D. mauritiana-D. sechellia interspecific genetic introgression lines that possess quantitative morphological variation in the posterior lobe of the genital arch, an external genital structure that can cause wounds to the female abdomen during mating. We find that males with smaller posterior lobes, and those that possess lobes with similarities in shape to D. mauritiana, cause more severe wounding compared to either D. sechellia males with strain-specific morphologies or introgression males that possess larger lobes or lobes with more pronounced D. sechellia features. These results suggest a possible history of sexual conflict during the evolution of the posterior lobe in D. sechellia, but also suggest a potential contribution of divergence in sensory recognition mechanisms to posterior lobe evolution. PMID- 24758302 TI - Emerging multifunctional roles of Claudin tight junction proteins in bone. AB - The imbalance between bone formation and resorption during bone remodeling has been documented to be a major factor in the pathogenesis of osteoporosis. Recent evidence suggests a significant role for the tight junction proteins, Claudins (Cldns), in the regulation of bone remodeling processes. In terms of function, whereas Cldns act "canonically" as key determinants of paracellular permeability, there is considerable recent evidence to suggest that Cldns also participate in cell signaling, ie, a "noncanonical function". To this end, Cldns have been shown to regulate cell proliferation, differentiation, and gene expression in a variety of cell types. The present review will discuss Cldns' structure, their expression profile, regulation of expression, and their canonical and non- canonical functions in general with special emphasis on bone cells. In order to shed light on the noncanonical functions of Cldns in bone, we will highlight the role of Cldn-18 in regulating bone resorption and osteoclast differentiation. Collectively, we hope to provide a framework for guiding future research on understanding how Cldns modulate osteoblast and osteoclast function and overall bone homeostasis. Such studies should provide valuable insights into the pathogenesis of osteoporosis, and may highlight Cldns as novel targets for the diagnosis and therapeutic management of osteoporosis. PMID- 24758305 TI - The frequency of body dysmorphic disorder in dermatology and cosmetic dermatology clinics: a study from Turkey. AB - BACKGROUND: Body dysmorphic disorder (BDD) is a distressing and impairing preoccupation with a slight or imagined defect in appearance. There are few reports on the prevalence of BDD in the Turkish population. AIM: To investigate the frequency of BDD in dermatology settings, and to compare the results from cosmetic dermatology with those from general dermatology settings. METHODS: This cross-sectional study recruited 400 patients from cosmetic dermatology (CD) (n = 200) and general dermatology (GD) clinics (n = 200). A mini-survey was used to collect demographic and clinical characteristics, and the dermatology version of a brief self-report BDD screening questionnaire was administered. A five-point Likert scale was used for objective scoring of the stated concern, which was performed by dermatologists, and patients who scored >= 3 were excluded from the study. RESULTS: In total, 318 patients (151 in the CD group and 167 in the GD group) completed the study, and of these, 20 were diagnosed with BDD. The CD group had a higher rate of BDD (8.6%) than the GD group (4.2%) but this was not significant (P = 0.082). The major concern focused on body and weight (40.0%), followed by acne (25.0%). CONCLUSIONS: The number of cosmetic procedures in dermatology practices is increasing Therefore, it is becoming more important to recognize patients with BDD. Although the rates of BDD found in the present study are in agreement with the literature data, population-based differences still exist between this study and previous studies. PMID- 24758306 TI - Creating air-stable supported lipid bilayers by physical confinement induced by phospholipase A2. AB - Supported lipid bilayer platforms have been used for various biological applications. However, the lipid bilayers easily delaminate and lose their natural structure after being exposed to an air-water interface. In this study, for the first time, we demonstrated that physical confinement can be used instead of chemical modifications to create air-stable membranes. Physical confinement was generated by the obstacle network induced by a peripheral enzyme, phospholipase A2. The enzyme and reacted lipids could be washed away from the obstacle network, which was detergent-resistant and strongly bonded to the solid support. On the basis of these properties, the obstacle framework on the solid support was reusable and lipid bilayers with the desired composition could be refilled and formed in the region confined by the obstacle framework. The results of fluorescence recovery after photobleaching (FRAP) indicate that the diffusivities of the lipid bilayers before drying and after rehydration were comparable, indicating the air stability of the physically confined membrane. In addition, we observed that the obstacles could trap a thin layer of water after the air-water interface passed through the lipid bilayer. Because the obstacles were demonstrated to be several times higher than a typical lipid membrane on a support, the obstacles may act as container walls, which can trap water above the lipid membrane. The water layer may have prevented the air-water interface from directly contacting the lipid membrane and, therefore, buffered the interfacial force, which could cause membrane delamination. The results suggest the possibility of using physical confinement to create air-stable membranes without changing local membrane rigidity or covering the membrane with protecting molecules. PMID- 24758307 TI - Trap-free transport in ordered and disordered TiO2 nanostructures. AB - Understanding the influence of different film structures on electron diffusion in nanoporous metal oxide films has been challenging. Because of the rate-limiting role that traps play in controlling the transport properties, the structural effects of different film architectures are largely obscured or reduced. We describe a general approach to probe the impact of structural order and disorder on the charge-carrier dynamics without the interference of transport-limiting traps. As an illustration of this approach, we explore the consequences of trap free diffusion in vertically aligned nanotube structures and random nanoparticle networks in sensitized titanium dioxide solar cells. Values of the electron diffusion coefficients in the nanotubes approached those observed for the single crystal and were up to 2 orders of magnitude greater than those measured for nanoparticle films with various average crystallites sizes. Transport measurements together with modeling show that electron scattering at grain boundaries in particle networks limits trap-free diffusion. In presence of traps, transport was 10(3)-10(5) times slower in nanoparticle films than in the single crystal. Understanding the link between structure and carrier dynamics is important for systematically altering and eventually controlling the electronic properties of nanoscaled materials. PMID- 24758308 TI - Isolation of iron(II) aqua and hydroxyl complexes featuring a tripodal H-bond donor and acceptor ligand. AB - A tripodal ligand platform, tris(5-cycloiminopyrrol-2-ylmethyl)amine (H3[N(pi(Cy))3]), that features a hydrogen bond-accepting secondary coordination sphere when bound anionically to an iron center is reported. Neutral coordination to iron affords ligand tautomerization, resulting in a hydrogen bond-donating secondary coordination sphere, and formation of the tris(5-cyclohexyl amineazafulvene-2-methyl)amine, H3[N(afa(Cy))3], scaffold. Both binding motifs result in formation of stable, high-spin iron(II) complexes featuring ancillary water, triflate, or hydroxo ligands. Structural analysis reveals that these complexes exhibit distorted trigonal-bipyramidal geometries with coordination of the apical nitrogen to iron as well as three equatorial amine or imine nitrogens, depending on the axial ancillary ligand. Formation of the aqua complex K[(N(pi(Cy))3)Fe(OH2)] (3) illustrated the propensity of the ligand to be hydrogen bond-accepting, whereas the iron triflate species [N(afa(Cy))3Fe](OTf)2 (4) features a hydrogen bond-donating secondary coordination sphere. The ability of each of the three arms of the ligand to tautomerize independently was observed during the formation of the iron-hydroxyl species [N(afa(Cy))2(pi(Cy))]FeOH (5) and characterized by X-ray crystallography and IR spectroscopy. The combined data for the iron complexes established that each arm of the tripodal ligand can tautomerize independently and is likely dependent on the electronic needs of the iron center when binding various substrates. PMID- 24758309 TI - Averaging improves strain images of the biceps brachii using quasi-static ultrasound elastography. AB - OBJECTIVE: Quasi-static ultrasound elastography is a technique for measuring tissue deformation (strain) under externally applied loading and can be used to identify the presence of abnormalities. The objective of this study was to demonstrate the efficacy of averaging strain images from repeated compression cycles in mitigating user-induced error using quasi-static ultrasound elastography. METHODS: Freehand compressions were performed with an ultrasound transducer on the biceps brachii of nine participants (five males and four females), as well as with a custom automated compression system. Sets of strain images from the freehand techniques were averaged to create single representative images and compared against strain images from the automated compressions using both qualitative and quantitative metrics. RESULTS: Significant improvements in intra-operator repeatability and interoperator reproducibility can be achieved by averaging strain images from four to eight repeated compressions. The resulting strain images did not lose significant image data compared with strain images from single automated compressions. CONCLUSION: Averaging is introduced as a feasible and appropriate technique to improve strain image quality without sacrificing important image data. ADVANCES IN KNOWLEDGE: Simple averaging of multiple freehand elastography measures can achieve a similar degree of accuracy, repeatability and reproducibility as that of more awkward and expensive automated methods. The resulting elastograms can be used to obtain a more accurate and complete diagnosis without additional cost to the doctor or the patient. PMID- 24758310 TI - The CTLA4 +49 A/G (rs231775) polymorphism influences susceptibility to SLE in South Indian Tamils. AB - Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with complex etiology. Loss of immune tolerance and synthesis of autoantibodies against nuclear antigens contributes to the disease. Genetic aberrations disrupting the functions of immune regulatory receptors may facilitate the development of autoimmune diseases. Cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor for T cells and this study was carried out to analyze the influence of CTLA4 +49A/G (rs231775) polymorphism on susceptibility to SLE in ethnic Tamils. Three hundred SLE patients and 460 age and sex similar, ethnicity-matched controls were screened for the +49 A/G polymorphism by real time polymerase chain reaction (PCR). The wild allele (A) frequency in controls and cases was 63% and 47%, respectively. The presence of heterozygous (AG) and homozygous mutant (GG) genotype was associated with a significant risk to develop SLE (P = 0.0001, OR 2.29, 95% confidence interval (CI), 1.6-3.3) and (P = 0.0001, OR-4.3, 95% CI, 2.8 6.99). The frequency of mutant allele (G) in patients was also significantly associated with SLE (P = 0.0001, OR-1.9, 95% CI, 1.5-2.4). However, this polymorphism did not influence the clinical or serological phenotypes in our study. Therefore the CTLA4 +49 A/G polymorphism is a potential genetic risk factor for lupus susceptibility in South Indian Tamils, but does not appear to influence either the clinical or serological phenotype. PMID- 24758311 TI - Historical contingency and the gradual evolution of metabolic properties in central carbon and genome-scale metabolisms. AB - BACKGROUND: A metabolism can evolve through changes in its biochemical reactions that are caused by processes such as horizontal gene transfer and gene deletion. While such changes need to preserve an organism's viability in its environment, they can modify other important properties, such as a metabolism's maximal biomass synthesis rate and its robustness to genetic and environmental change. Whether such properties can be modulated in evolution depends on whether all or most viable metabolisms - those that can synthesize all essential biomass precursors - are connected in a space of all possible metabolisms. Connectedness means that any two viable metabolisms can be converted into one another through a sequence of single reaction changes that leave viability intact. If the set of viable metabolisms is disconnected and highly fragmented, then historical contingency becomes important and restricts the alteration of metabolic properties, as well as the number of novel metabolic phenotypes accessible in evolution. RESULTS: We here computationally explore two vast spaces of possible metabolisms to ask whether viable metabolisms are connected. We find that for all but the simplest metabolisms, most viable metabolisms can be transformed into one another by single viability-preserving reaction changes. Where this is not the case, alternative essential metabolic pathways consisting of multiple reactions are responsible, but such pathways are not common. CONCLUSIONS: Metabolism is thus highly evolvable, in the sense that its properties could be fine-tuned by successively altering individual reactions. Historical contingency does not strongly restrict the origin of novel metabolic phenotypes. PMID- 24758313 TI - Concerned significant others of people with gambling problems in Finland: a cross sectional population study. AB - BACKGROUND: Problem gambling not only impacts those directly involved, but also the concerned significant others (CSOs) of problem gamblers. The aims of this study were to investigate the proportion of male and female CSOs at the population level; to investigate who the CSOs were concerned about; and to investigate sociodemographic factors, gender differences, gambling behaviour, and health and well-being among CSOs and non-CSOs. METHODS: The data (n = 4484) were based on a cross-sectional population study. Structured telephone interviews were conducted in 2011-2012. The data were weighted based on age, gender and residency. The respondents were defined as CSOs if they reported that at least one of their significant others (father, mother, sister/brother, grandparent, spouse, own child/children, close friend) had had gambling problems. Statistical significance was determined by chi-squared and Fisher's exact tests, and logistic regression analysis. RESULTS: Altogether, 19.3% of the respondents were identified as CSOs. Most commonly, the problem gambler was a close friend (12.4%) of the CSO. The percentage of close friends having a gambling problem was larger among male CSOs (14.4%) compared with female CSOs (10.3%; p <= 0.001), while the percentage of partners with gambling problem was larger among females (2.6%) than among males (0.8%; p <= 0.001). In the best fitting model, the odds ratio (95% CI) of being a male CSO was 2.03 (1.24-3.31) for past-year gambling problems, 1.46 (1.08-1.97) for loneliness and 1.78 (1.38-2.29) for risky alcohol consumption. The odds ratio (95% CI) of being a female CSO was 1.51 (1.09-2.08) for past-year gambling involvement, 3.05 (1.18-7.90) for past-year gambling problems, 2.21 (1.24-3.93) for mental health problems, 1.39 (1.03-1.89) for loneliness and 1.97 (1.43-2.71) for daily smoking. CONCLUSIONS: CSOs of problem gamblers often experience cumulating problems such as their own risky gambling behaviour, health problems and other addictive disorders. The clearest gender difference was seen in smoking by CSO. In order to develop efficient and targeted support and services for CSOs, it is necessary to understand the correlates related to different subgroups of CSOs. PMID- 24758312 TI - Predictive score for mortality in patients with COPD exacerbations attending hospital emergency departments. AB - BACKGROUND: Limited information is available about predictors of short-term outcomes in patients with exacerbation of chronic obstructive pulmonary disease (eCOPD) attending an emergency department (ED). Such information could help stratify these patients and guide medical decision-making. The aim of this study was to develop a clinical prediction rule for short-term mortality during hospital admission or within a week after the index ED visit. METHODS: This was a prospective cohort study of patients with eCOPD attending the EDs of 16 participating hospitals. Recruitment started in June 2008 and ended in September 2010. Information on possible predictor variables was recorded during the time the patient was evaluated in the ED, at the time a decision was made to admit the patient to the hospital or discharge home, and during follow-up. Main short-term outcomes were death during hospital admission or within 1 week of discharge to home from the ED, as well as at death within 1 month of the index ED visit. Multivariate logistic regression models were developed in a derivation sample and validated in a validation sample. The score was compared with other published prediction rules for patients with stable COPD. RESULTS: In total, 2,487 patients were included in the study. Predictors of death during hospital admission, or within 1 week of discharge to home from the ED were patient age, baseline dyspnea, previous need for long-term home oxygen therapy or non-invasive mechanical ventilation, altered mental status, and use of inspiratory accessory muscles or paradoxical breathing upon ED arrival (area under the curve (AUC) = 0.85). Addition of arterial blood gas parameters (oxygen and carbon dioxide partial pressures (PO2 and PCO2)) and pH) did not improve the model. The same variables were predictors of death at 1 month (AUC = 0.85). Compared with other commonly used tools for predicting the severity of COPD in stable patients, our rule was significantly better. CONCLUSIONS: Five clinical predictors easily available in the ED, and also in the primary care setting, can be used to create a simple and easily obtained score that allows clinicians to stratify patients with eCOPD upon ED arrival and guide the medical decision-making process. PMID- 24758314 TI - Expression of Epstein-Barr virus in children with sacrococcygeal pilonidal sinus determined by immunohistochemical methods. AB - In this study, we probed whether chronic infections of skin such as pilonidal sinus could be a potential site of Epstein-Barr virus (EBV) replication. Pilonidal sinus is associated with a high recurrence rate. Therefore, we decided to determine the role of EBV's presence to explain whether it is correlated with the recurrence of pilonidal sinuses. This study was conducted on 36 patient samples with sacrococcygeal pilonidal sinus. Samples were immunohistochemically stained for EBV, CD3 and CD20 expression. Thirty-six adolescents with pilonidal disease were evaluated. EBV-positive cells were located in dermis with high inflammatory activity. EBV-positive cells stained positive for the B-cell antigen CD20 and were detected in 10 of 36 (27%) pilonidal sinus specimens. Among those who had experienced a relapse, three were positive for EBV expression. In addition, EBV expression was detected in eight cases with severe inflammation, and in two with minimal or moderate inflammation. Our study advances the field by demonstrating that similar to gastrointestinal mucosa, skin could be a reservoir for EBV. EBV was found to be restricted to B cells in skin lesions, and it was found that skin lesions with severe inflammation showed higher frequency of EBV expression in comparison to minimal or moderately inflammed skin lesions. Additionally, recurrence was more frequently observed among EBV-positive cases. These findings point out for a role of EBV infection in the recurrence of pilonidal sinuses. PMID- 24758315 TI - Repeated radiofrequency ablation of atrial tachycardia in restrictive cardiomyopathy secondary to myofibrillar myopathy. AB - Myofibrillar myopathy is characterized by nonhyaline and hyaline lesions due to mutations in nuclear genes encoding for extra-myofibrillar or myofibrillar proteins. Cardiac involvement in myofibrillar myopathy may be phenotypically expressed as dilated, hypertrophic, or restrictive cardiomyopathy. Radiofrequency ablation of atrial fibrillation and flutter has so far not been reported in myofibrillar myopathy. We report the case of a young female with myofibrillar myopathy and deteriorating heart failure due to restrictive cardiomyopathy and recurrent atrial fibrillation and atrial tachycardias intolerant to pharmacotherapy. Cardiac arrhythmias were successfully treated with repeat radiofrequency ablations and resulted in regression of heart failure, thus postponing the necessity for cardiac transplantation. PMID- 24758316 TI - Next-generation polymer-electrolyte-membrane fuel cells using titanium foam as gas diffusion layer. AB - In spite of their high conversion efficiency and no emission of greenhouse gases, polymer electrolyte membrane fuel cells (PEMFCs) suffer from prohibitively high cost and insufficient life-span of their core component system, the membrane electrode assembly (MEA). In this paper, we are proposing Ti foam as a promising alternative electrode material in the MEA. Indeed, it showed a current density of 462 mA cm(-2), being ca. 166% higher than that with the baseline Toray 060 gas diffusion layer (GDL) (278 mA cm(-2)) with 200 ccm oxygen supply at 0.7 V, when used as the anode GDL, because of its unique three-dimensional strut structure promoting highly efficient catalytic reactions. Furthermore, it exhibits superior corrosion resistance with almost no thickness and weight changes in the accelerated corrosion test, as opposed to considerable reductions in the weight and thickness of the conventional GDL. We believe that this paper suggests profound implications in the commercialization of PEMFCs, because the metallic Ti foam provides a longer-term reliability and chemical stability, which can reduce the loss of Pt catalyst and, hence, the cost of PEMFCs. PMID- 24758317 TI - Paroxysmal nocturnal hemoglobinuria: a single Spanish center's experience over the last 40 yr. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease. To date, many reviews and series have been described. We report the experience of our center by presenting a review of 56 PNH patient cases with an average age at diagnosis of 38 yr and follow-ups beginning at approximately 40 yr; the median survival rate was 11 yr. The average clonal size upon diagnosis was 48%, presenting a variable evolution. Thrombotic episodes and cancer were five each, and the main causes of death among our patients were equal at 8.9%. Radiological study by magnetic resonance imaging is presented as a fundamental technique for estimating the deposit of iron levels in the liver and kidney, as well as in some decisive cases at the start of eculizumab therapy. Sixteen patients have been treated with eculizumab so far in our series, and being a safe drug, it provides improvement in the patients' quality of life, and the disappearance of clinical symptoms, and avoids the emergence of new thrombosis. PMID- 24758318 TI - International study on inter-reader variability for circulating tumor cells in breast cancer. AB - INTRODUCTION: Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch(r) system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement. METHODS: CellSearch(r) images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (kappa) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test. RESULTS: For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median kappa of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and >=3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median kappa of 0.74 (range 0.25 to 0.90). CONCLUSIONS: The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are required. PMID- 24758319 TI - Discovery of a novel rumen methanogen in the anaerobic fungal culture and its distribution in the rumen as revealed by real-time PCR. AB - BACKGROUND: The novel archaea belonging to Rumen Cluster C (RCC), which may play an important role in methane production in the rumen have received increased attention. However, the present information on RCC in the rumen is limited by the unsuccessful isolation of axenic pure RCC from the rumen. In the present study, RCC grown in anaerobic fungal subcultures was identified by the molecular and culture methods. RESULTS: A novel RCC species existing in the fungal subcultures was identified and demonstrated by the 16S rRNA gene clone library. Interestingly, the novel RCC species survived in the fungal cultures over all the subculture transferring, even in the 62nd subculture, in contrast to the other methanogens, which disappeared during subcultures. Further work showed that subculture transfer frequency significantly affected the relative abundance of the novel RCC species in the fungal subcultures. The five-day and seven-day transfer frequencies increased the relative abundance of the RCC species (P<0.05). In addition, quantitative real-time PCR revealed that high concentrate diets did not affect the abundance of archaea, but numerically reduced the abundance of the novel RCC species in the rumen. In addition, the relative abundance of the RCC species was numerically higher in the rumen liquid fraction than in the rumen epithelium and solid fractions. Finally, a purified fungal culture containing the RCC species was successfully obtained. PCR and sequencing analysis showed that the novel RCC species contained a mcrA gene, which is known to play a crucial role in methanogenesis, and thus could be identified as a methanogen. CONCLUSION: In this study, a novel RCC species was identified as a methanogen and closely associated with anaerobic fungi. This novel approach by using co-culture with anaerobic fungi may provide a feasible way to culture and investigate not yet identified methanogens. PMID- 24758320 TI - How precise is the PRECICE compared to the ISKD in intramedullary limb lengthening? Reliability and safety in 26 procedures. AB - BACKGROUND AND PURPOSE: The PRECICE intramedullary limb lengthening system uses a new technique with a magnetic rod and a motorized external remote controller (ERC) with rotational magnetic field. We evaluated the reliability and safety of the PRECICE system. METHODS: We compared our preliminary results with PRECICE in 24 patients (26 nails) with the known difficulties in the use of mechanical lengthening devices such as the ISKD. We used the Paley classification for evaluation of problems, obstacles, and complications. RESULTS: 2 nails were primarily without function, and 24/26 nails lengthened over the desired distance. Lengthening desired was 38 mm and lengthening obtained was 37 mm. There were 2 nail breakages, 1 in the welding seam and 1 because of a fall that occurred during consolidation. ERC usage was problematic mostly in patients with femoral lengthening. Adjustment of the ERC was necessary in 10 of 24 cases. 15 cases had implant-associated problems, obstacles were seen in 5 cases, and complications were seen in each of 4 cases. INTERPRETAION: The reliability of the PRECICE system is comparable to that of other intramedullary lengthening devices such as the ISKD. The motorized external remote controller and its application by the patients is a weak point of the system and needs strict supervision. PMID- 24758321 TI - Changes in blood ion levels after removal of metal-on-metal hip replacements: 16 patients followed for 0-12 months. AB - BACKGROUND AND PURPOSE: In patients with metal-on-metal (MoM) hip prostheses, pain and joint effusions may be associated with elevated blood levels of cobalt and chromium ions. Since little is known about the kinetics of metal ion clearance from the body and the rate of resolution of elevated blood ion levels, we examined the time course of cobalt and chromium ion levels after revision of MoM hip replacements. PATIENTS AND METHODS: We included 16 patients (13 female) who underwent revision of a painful MoM hip (large diameter, modern bearing) without fracture or infection, and who had a minimum of 4 blood metal ion measurements over an average period of 6.1 (0-12) months after revision. RESULTS: Average blood ion concentrations at the time of revision were 22 ppb for chromium and 43 ppb for cobalt. The change in ion levels after revision surgery varied extensively between patients. In many cases, over the second and third months after revision surgery ion levels decreased to 50% of the values measured at revision. Decay of chromium levels occurred more slowly than decay of cobalt levels, with a 9% lag in return to normal levels. The rate of decay of both metals followed second-order (exponential) kinetics more closely than first-order (linear) kinetics. INTERPRETATION: The elimination of cobalt and chromium from the blood of patients who have undergone revision of painful MoM hip arthroplasties follows an exponential decay curve with a half-life of approximately 50 days. Elevated blood levels of cobalt and chromium ions can persist for at least 1 year after revision, especially in patients with high levels of exposure. PMID- 24758322 TI - In vivo and ex vivo measurement of polyethylene wear in total hip arthroplasty: comparison of measurements using a CT algorithm, a coordinate-measuring machine, and a micrometer. AB - BACKGROUND: Determination of the amount of wear in a polyethylene liner following total hip arthroplasty (THA) is important for both the clinical care of individual patients and the development of new types of liners. PATIENTS AND METHODS: We measured in vivo wear of the polyethylene liner using computed tomography (CT) (obtained in the course of regular clinical care) and compared it to coordinate-measuring machine (CMM) readings. Also, changes in liner thickness of the same retrieved polyethylene liner were measured using a micrometer, and were compared to CT and CMM measurements. The distance between the centers of the acetabular cup and femoral head component was measured in 3D CT, using a semi automatic analysis method. CMM readings were performed on each acetabular liner and data were analyzed using 3D computer-aided design software. Micrometer readings compared the thickest and thinnest regions of the liner. We analyzed 10 THA CTs and retrievals that met minimal requirements for CT slice thickness and explanted cup condition. RESULTS - For the 10 cups, the mean difference between the CT readings and the CMM readings was -0.09 (-0.38 to 0.20) mm. This difference was not statistically significant (p = 0.6). Between CT and micrometer, the mean difference was 0.11 (-0.33 to 0.55) mm. This difference was not statistically significant (p = 0.6). INTERPRETATION - Our results show that CT imaging is ready to be used as a tool in clinical wear measurement of polyethylene liners used in THA. PMID- 24758324 TI - Prosthetic joint infections: a need for health economy studies. PMID- 24758323 TI - Projections of total hip replacement in Sweden from 2013 to 2030. AB - BACKGROUND AND PURPOSE: The continuously increasing demand for joint replacement surgery in the past decades imposes higher constraints on the budgets of hospitals and healthcare providers. We undertook an analysis of historical trends in total hip replacement performed in Sweden between 1968 and 2012 in order to provide projections of future demand. DATA AND METHODS: We obtained data on total hip replacements registered every year and on the evolution of the Swedish population between 1968 and 2012. We assumed the existence of a maximum incidence. So we adopted a regression framework that assumes the existence of an upper limit of total hip replacement incidence. RESULTS: We found that the incidence of total hip replacement will continue to increase until a projected upper incidence level of about 400 total hip replacements per 10(5) Swedish residents aged 40 years and older will be reached around the year 2107. In 2020, the estimated incidence of total hip replacement will be 341 (95% prediction interval (PI): 302-375) and in 2030 it will be 358 (PI: 317-396). Using official forecasted population growth data, about 18,000 operations would be expected to be performed in 2020 and 20,000 would be expected to be performed in 2030. INTERPRETATION: Growing incidence, population growth, and increasing life expectancy will probably result in increased demand for hip replacement surgery. Our findings could serve as a basis for decision making. PMID- 24758326 TI - Remembering Yoshifumi Ninomiya. PMID- 24758325 TI - Distal tibia fractures: locked or non-locked plating? A systematic review of outcomes. AB - BACKGROUND AND PURPOSE: Although plating is considered to be the treatment of choice in distal tibia fractures, controversies abound regarding the type of plating for optimal fixation. We conducted a systematic review to evaluate and compare the outcomes of locked plating and non-locked plating in treatment of distal tibia fractures. PATIENTS AND METHODS: A systematic review was conducted using PubMed to identify articles on the outcomes of plating in distal tibia fractures that were published up to June 2012. We included English language articles involving a minimum of 10 adult cases with acute fractures treated using single-plate, minimally invasive techniques. Study-level binomial regression on the pooled data was conducted to determine the effect of locking status on different outcomes, adjusted for age, sex, and other independent variables. RESULTS: 27 studies met the inclusion criteria and were included in the final analysis of 764 cases (499 locking, 265 non-locking). Based on descriptive analysis only, delayed union was reported in 6% of cases with locked plating and in 4% of cases with non-locked plating. Non-union was reported in 2% of cases with locked plating and 3% of cases with non-locked plating. Comparing locked and non-locked plating, the odds ratio (OR) for reoperation was 0.13 (95% CI: 0.03 0.57) and for malalignment it was 0.10 (95% CI: 0.02-0.42). Both values were statistically significant. INTERPRETATION: This study showed that locked plating reduces the odds of reoperation and malalignment after treatment for acute distal tibia fracture. Future studies should accurately assess causality and the clinical and economic impact of these findings. PMID- 24758327 TI - Holokinetic drive: centromere drive in chromosomes without centromeres. AB - Similar to how the model of centromere drive explains the size and complexity of centromeres in monocentrics (organisms with localized centromeres), our model of holokinetic drive is consistent with the divergent evolution of chromosomal size and number in holocentrics (organisms with nonlocalized centromeres) exhibiting holokinetic meiosis (holokinetics). Holokinetic drive is proposed to facilitate chromosomal fission and/or repetitive DNA removal (or any segmental deletion) when smaller homologous chromosomes are preferentially inherited or chromosomal fusion and/or repetitive DNA proliferation (or any segmental duplication) when larger homologs are preferred. The hypothesis of holokinetic drive is supported primarily by the negative correlation between chromosome number and genome size that is documented in holokinetic lineages. The supporting value of two older cross-experiments on holokinetic structural heterozygotes (the rush Luzula elegans and butterflies of the genus Antheraea) that indicate the presence of size-preferential homolog transmission via female meiosis for holokinetic drive is discussed, along with the further potential consequences of holokinetic drive in comparison with centromere drive. PMID- 24758328 TI - Ion sponge: a 3-dimentional array of quadrupole ion traps for trapping and mass selectively processing ions in gas phase. AB - In this study, the concept of ion sponge has been explored for developing 3D arrays of large numbers of ion traps but with simple configurations. An ion sponge device with 484 trapping units in a volume of 10 * 10 * 3.2 cm has been constructed by simply stacking 9 meshes together. A single rf was used for trapping ions and mass-selective ion processing. The ion sponge provides a large trapping capacity and is highly transparent for transfer of ions, neutrals, and photons for gas phase ion processing. Multiple layers of quadrupole ion traps, with 121 trapping units in each layer, can operate as a single device for MS or MS/MS analysis, or as a series of mass-selective trapping devices with interlayer ion transfers facilitated by AC and DC voltages. Automatic sorting of ions to different trapping layers based on their mass-to-charge (m/z) ratios was achieved with traps of different sizes. Tandem-in-space MS/MS has also been demonstrated with precursor ions and fragment ions trapped in separate locations. PMID- 24758329 TI - Prognostic value of secreted phosphoprotein-1 in pleural effusion associated with non-small cell lung cancer. AB - BACKGROUND: Malignant pleural effusion (MPE) is a common complication of advanced lung cancer. Research has shown that secreted phosphoprotein-1 (SPP1) is essential in MPE associated with lung cancer. This retrospective study was performed to evaluate the prognostic significance of SPP1 in the MPE of patients with non-small cell lung cancer (NSCLC). METHODS: MPE specimens were obtained from 85 NSCLC patients (study group), and pleural effusion specimens were obtained from 24 patients with benign lung disease (control group). Specimens were tested for SPP1 using enzyme-linked immunosorbent assay (ELISA). Based on the cutoff value of receiver operating characteristic (ROC) curve analysis, the study patients were divided into a high-SPP1-expression subgroup and a low expression subgroup. The primary and secondary endpoints of this study were progression-free survival (PFS) and overall survival (OS). RESULTS: The SPP1 levels of the study group were significantly higher compared to those of the controls (Mann-Whitney U test, P = 0.017). The number of extrapulmonary metastases was significantly higher in the high-SPP1-expressing patients than in the low-expressing patients (P = 0.03). Kaplan-Meier survival analysis showed that SPP1 levels were negatively associated with OS and PFS in both subgroups of study patients (P = 0.026; P = 0.039, respectively). Cox regression analysis showed that SPP1 was an independent prognostic factor in patients with NSCLC (HR = 1.832, 95% confidence interval: 1.003-3.345; P = 0.049). CONCLUSION: SPP1 in pleural effusion can be used for the auxiliary diagnosis of MPE and used to determine the prognosis of patients with NSCLC. PMID- 24758330 TI - Cu-catalyzed C(sp3)-H bond activation reaction for direct preparation of cycloallyl esters from cycloalkanes and aromatic aldehydes. AB - Cu-catalyzed dehydrogenation-olefination and esterification of C(sp(3))-H bonds of cycloalkanes with TBHP as an oxidant has been developed. The reaction involves four C-H bond activations and gives cycloallyl ester products directly from cycloalkanes and aromatic aldehydes. PMID- 24758332 TI - Extensive unilateral hyperkeratotic plaques in a blaschkoid distribution. PMID- 24758331 TI - Targeting the Achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance. PMID- 24758333 TI - Impact of amino acid substitutions in the V2 and C2 regions of human immunodeficiency virus type 1 CRF01_AE envelope glycoprotein gp120 on viral neutralization susceptibility to broadly neutralizing antibodies specific for the CD4 binding site. AB - BACKGROUND: The CD4 binding site (CD4bs) of envelope glycoprotein (Env) gp120 is a functionally conserved, important target of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies. Two neutralizing human monoclonal antibodies, IgG1 b12 (b12) and VRC01, are broadly reactive neutralizing antibodies which recognize conformational epitopes that overlap the CD4bs of Env gp120; however, many CRF01_AE viruses are resistant to neutralization mediated by these antibodies. We examined the mechanism underlying the b12 resistance of the viruses using CRF01_AE Env (AE-Env)-recombinant viruses in this study. RESULTS: Our results showed that an amino acid substitution at position 185 in the V2 region of gp120 played a crucial role in regulating the b12 susceptibility of AE Env-recombinant viruses by cooperating with 2 previously reported potential N linked glycosylation (PNLG) sites at positions 186 (N186) and 197 (N197) in the V2 and C2 regions of Env gp120. The amino acid residue at position 185 and 2 PNLG sites were responsible for the b12 resistance of 21 of 23 (>91%) AE-Env clones tested. Namely, the introduction of aspartic acid at position 185 (D185) conferred b12 susceptibility of 12 resistant AE-Env clones in the absence of N186 and/or N197, while the introduction of glycine at position 185 (G185) reduced the b12 susceptibility of 9 susceptible AE-Env clones in the absence of N186 and/or N197. In addition, these amino acid mutations altered the VRC01 susceptibility of many AE-Env clones. CONCLUSIONS: We propose that the V2 and C2 regions of AE-Env gp120 contain the major determinants of viral resistance to CD4bs antibodies. CRF01_AE is a major circulating recombinant form of HIV-1 prevalent in Southeast Asia. Our data may provide important information to understand the molecular mechanism regulating the neutralization susceptibility of CRF01_AE viruses to CD4bs antibodies. PMID- 24758334 TI - The association of HLA-DRB1 and HLA-DQB1 alleles with the development of factor VIII inhibitors in severe haemophilia A patients in India. PMID- 24758335 TI - EndoNet: an information resource about the intercellular signaling network. AB - BACKGROUND: In multicellular organisms, an intercellular signaling network communicates information from the environment or distant tissues to defined target cells. Intercellular signaling (mostly mediated by hormones) can affect the metabolic state and the gene expression program of target cells, thereby coordinating development, homeostasis of the organism and its reactions to external stimuli. Knowledge of the components of the intercellular signaling (specifically: the endocrine) network and their relations is an important, though so far a largely neglected part of systems biology. DESCRIPTION: EndoNet is an information resource about the endocrine system in human. The content of this database comprises information about the biological components of the endocrine system, like hormones, receptors and cells, as well as their relations like the secretion or the binding of a hormone to its receptor. All data within EndoNet have been manually annotated from the scientific literature. The web interface of EndoNet provides the content by a detailed page for each component. These pages list information about the component, links to external resources including literature as well as to related entities of EndoNet. The anatomical ontology Cytomer is used, in conjunction with the Ontology Based Answers service (OBA), to query and list related anatomical structures ranging from the level of individual cells to complete organs. While querying the web interface the user can add components to an individual network. This network, or the complete network stored in the database, can be further analyzed in a configurable pipeline or can be exported in various formats. CONCLUSION: EndoNet is an important and unique information resource about the intercellular signaling network. Since the intercellular network is an integral part of systems biology, EndoNet provides essential information for analyzing interaction between different cellular networks. PMID- 24758336 TI - Paying tribute. PMID- 24758338 TI - ISSWSH position statement. PMID- 24758339 TI - Monopicolinate cross-bridged cyclam combining very fast complexation with very high stability and inertness of its copper(II) complex. AB - The synthesis of a new cross-bridged 1,4,8,11-tetraazacyclotetradecane (cb cyclam) derivative bearing a picolinate arm (Hcb-te1pa) was achieved by taking advantage of the proton sponge properties of the starting constrained macrocycle. The structure of the reinforced ligand as well as its acid-base properties and coordination properties with Cu(2+) and Zn(2+) was investigated. The X-ray structure of the free ligand showed a completely preorganized conformation that lead to very fast copper(II) complexation under mild conditions (instantaneous at pH 7.4) or even in acidic pH (3 min at pH 5) at room temperature and that demonstrated high thermodynamic stability, which was measured by potentiometry (at 25 degrees C and 0.10 M in KNO3). The results also revealed that the complex exists as a monopositive copper(II) species in the intermediate pH range. A comparative study highlighted the important selectivity for Cu(2+) over Zn(2+). The copper(II) complex was synthesized and investigated in solution using different spectroscopic techniques and DFT calculations. The kinetic inertness of the copper(II) complex in acidic medium was evaluated by spectrophotometry, revealing the very slow dissociation of the complex. The half-life of 96 days, in 5 M HClO4, and 465 min, in 5 M HCl at 25 degrees C, show the high kinetic stability of the copper(II) chelate compared to that of the corresponding complexes of other macrocyclic ligands. Additionally, cyclic voltammetry experiments underlined the perfect electrochemical inertness of the complex as well as the quasi-reversible Cu(2+)/Cu(+) redox system. The coordination geometry of the copper center in the complex was established in aqueous solution from UV vis and EPR spectroscopies. PMID- 24758340 TI - Compatibility of electroanatomical mapping systems with a concurrent percutaneous axial flow ventricular assist device. AB - BACKGROUND: Hemodynamic instability hinders activation and entrainment mapping during ventricular tachycardia ablation. The Impella 2.5 microaxial flow device (MFD; Abiomed Inc., Danvers, MA, USA) is used to prevent hemodynamic instability during electrophysiologic study. However, electromagnetic interference (EMI) generated by this device can preclude accurate electroanatomic mapping. METHODS: Impella was placed in the left ventricle of 7 canines for circulatory support. Electroanatomic mapping during sinus rhythm, ventricular pacing, and ventricular fibrillation (VF) was performed using magnet- (CARTO3, Biosense Webster Inc., Diamond Bar, CA, USA) and impedance- (EnSite Velocity System/EnSite NavX, St. Jude Medical Inc., St. Paul, MN, USA) based systems. Distance from device to points with severe EMI precluding acquisition was compared to points with mild/no EMI. Two methods were used to reduce EMI: (1) titration of MFD performance, and (2) impedance-only mapping combined with manual annotation of activation. RESULTS: Severe EMI did not occur during impedance-based mapping. Severe EMI was observed using CARTO3 at 9.4% of all points attempted at maximum performance level (P8) of device. Severe EMI occurred at points closer to device (40.1 +/- 16.8 mm) versus (55.5 +/- 20.0 mm) for mild/no EMI, P < 0.0001. Severe EMI using CARTO3 was resolved by either (1) reduction of performance from P8 to P6 or (2) impedance-only mapping with manual annotation. CONCLUSION: Concurrent use of MFD caused EMI to prevent acquisition of points with magnet-based mapping. Predictors for EMI were distance from device and performance level. Temporary reductions to P6 or impedance-only mapping are 2 methods to resolve EMI. PMID- 24758341 TI - MC1R and NR4A receptors in cellular stress and DNA repair: implications for UVR protection. AB - Ultraviolet radiation (UVR) is the most common mutagen that melanocytes are exposed to. UVR causes a diverse range of DNA photolesions contributing to genome instability and promotes melanoma and non-melanoma development. Melanocytes are pigment-producing cells that synthesise the photoprotective melanins when the melanocortin-1 receptor (MC1R) is activated. MC1R is a G-protein-coupled receptor expressed predominantly in melanocytes. Its signalling pathway has been directly linked to melanogenesis, enhanced cytoprotection against UV damage and augmented DNA repair response. Interestingly, previous studies have revealed that MC1R signalling induces the transcription of the NR4A subfamily of orphan nuclear receptors in response to UV. In line with this, studies have also observed that NR4A receptors are recruited to distinct nuclear foci in response to cellular stress, independent of their transcriptional roles. Here, we review the regulated expression of NR4A2 and its potential roles upon cellular stress conditions. Current work in developing synthetic NR4A2 agonists further provides exciting avenues for exploring the potential role of NR4A2 as an antiskin cancer drug target. PMID- 24758342 TI - Soluble receptor for advanced glycation end-products and progression of airway disease. AB - BACKGROUND: The receptor for advanced glycation end-products (RAGE) is highly expressed in the lung, where it is believed to have a homeostatic role. Reduced plasma levels of soluble RAGE (sRAGE) have been reported in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the association of plasma sRAGE levels with a longitudinal decline of lung function. We have also measured plasma levels of high mobility group box 1 (HMGB1), a RAGE ligand which has been associated with chronic inflammatory diseases including COPD. METHODS: Baseline plasma concentrations of sRAGE and HMGB1 were measured in non-smokers (n = 32), smokers without COPD (n = 212), and smokers with COPD (n = 51), and the associations of the plasma sRAGE and HMGB1 levels with longitudinal declines of lung function during a 4-year follow-up period were analysed. RESULTS: The plasma levels of sRAGE were significantly lower in smokers without COPD and in smokers with COPD, as compared to those of non-smokers. Plasma sRAGE levels positively correlated with FVC and FEV1 and inversely correlated with BMI and pack-years. Lower sRAGE levels were associated with greater declines of FEV1/FVC over 4 years in all participants. Moreover, multivariate regression analysis indicated that the baseline plasma sRAGE concentration was an independent predictor of FEV1/FVC decline in all groups. A subgroup analysis showed that decreased sRAGE levels are significantly associated with a more rapid decline of FEV1/FVC in smokers with COPD. There was no significant correlation between plasma HMGB1 levels and longitudinal decline of lung function. CONCLUSIONS: Lower plasma concentrations of sRAGE were associated with greater progression of airflow limitations over time, especially in smokers with COPD, suggesting that RAGE might have a protective role in the lung. PMID- 24758343 TI - Comparison of outcomes from sepsis between patients with and without pre-existing left ventricular dysfunction: a case-control analysis. AB - INTRODUCTION: The aim of this study was to determine if there are differences between patients with pre-existing left ventricular dysfunction and those with normal antecedent left ventricular function during a sepsis episode in terms of in-hospital mortality and mortality risk factors when treated in accordance with a sepsis treatment algorithm. METHODS: We performed a retrospective case-control analysis of patients selected from a quality improvement database of 1,717 patients hospitalized with sepsis between 1 January 2005 and 30 June 2010. In this study, 197 patients with pre-existing left ventricular systolic dysfunction and sepsis were compared to 197 case-matched patients with normal prior cardiac function and sepsis. RESULTS: In-hospital mortality rates (P = 0.117) and intubation rates at 24 hours (P = 0.687) were not significantly different between cases and controls. There was no correlation between the amount of intravenous fluid administered over the first 24 hours and the PaO2/FiO2 ratio at 24 hours in either cases or controls (r2 = 0.019 and r2 = 0.001, respectively). Mortality risk factors for cases included intubation status (P = 0.016, OR = 0.356 for no intubation), compliance with a sepsis bundle (P = 0.008, OR = 3.516 for failed compliance), a source of infection other than the lung (P = 0.019, OR = 2.782), and the initial mixed venous oxygen saturation (P = 0.004, OR = 0.997). Risk factors for controls were the initial platelet count (P = 0.028, OR = 0.997) and the serum lactate level (P = 0.048, OR = 1.104). Patients with pre-existing left ventricular dysfunction who died had a lower initial mean mixed venous oxygen saturation than those who survived (61 +/- 18% versus 70 +/- 16%, P = 0.002). CONCLUSIONS: Clinical outcomes were not different between septic patients with pre-existing left ventricular dysfunction and those with no cardiac disease. There was no correlation between fluid administration and oxygenation at 24 hours in either cohort. The mortality risk factor profile of patients with pre-existing left ventricular dysfunction was different when compared with control patients, and may be related to oxygen delivery determinants. PMID- 24758344 TI - Induction of labor in grand multiparous women with previous cesarean delivery: how safe is this? AB - OBJECTIVE: To compare the outcome of induced and spontaneous labor in grand multiparous women with one previous lower segment cesarean section (CS), so that the safety of labor induction could be assessed. METHODS: In 102 women (study group), labor was induced and the outcome was compared with 280 women (control group) who went into spontaneous labor. All 382 women were grand multiparous and had one previous CS. RESULTS: There were no significant difference in oxytocin augmentation, CS, scar dehiscence, fetal birth weight or apgar scores between groups. There was one neonatal death, two still births, one early neonatal death and one congenital malformation in the study group and this was not significant. There was no significant difference in vaginal birth in the study (80.9%) and the control group (83.8%). CONCLUSION: In this moderate-sized study, induction of labor may be a safe option in grand multiparous women, if there is no absolute induction for repeating CS. PMID- 24758346 TI - Measurement invariance across chronic conditions: a systematic review and an empirical investigation of the Health Education Impact Questionnaire (heiQTM). AB - BACKGROUND: To examine whether lack of measurement invariance (MI) influences mean comparisons among different disease groups, this paper provides (1) a systematic review of MI in generic constructs across chronic conditions and (2) an empirical analysis of MI in the Health Education Impact Questionnaire (heiQTM). METHODS: (1) We searched for studies of MI among different chronic conditions in online databases. (2) Multigroup confirmatory factor analyses were used to study MI among five chronic conditions (orthopedic condition, rheumatism, asthma, COPD, cancer) in the heiQTM with N = 1404 rehabilitation inpatients. Impact on latent and composite mean differences was examined. RESULTS: (1) A total of 30 relevant studies suggested that about one in three items lacked MI. However, only four studies examined impact on latent mean differences. Scale means were only affected in one of these three studies. (2) Across the eight heiQTM scales, seven scales had items with lack of MI in at least one disease group. However, in only two heiQTM scales were some latent or composite mean differences affected. CONCLUSIONS: Lack of MI among disease groups is common and may have a relevant influence on mean comparisons when using generic instruments. Therefore, when comparing disease groups, tests of MI should be implemented. More studies of MI and according impact on mean differences in generic questionnaires are needed. PMID- 24758347 TI - Starch biosynthetic genes and enzymes are expressed and active in the absence of starch accumulation in sugar beet tap-root. AB - BACKGROUND: Starch is the predominant storage compound in underground plant tissues like roots and tubers. An exception is sugar beet tap-root (Beta vulgaris ssp altissima) which exclusively stores sucrose. The underlying mechanism behind this divergent storage accumulation in sugar beet is currently not fully known. From the general presence of starch in roots and tubers it could be speculated that the lack in sugar beet tap-roots would originate from deficiency in pathways leading to starch. Therefore with emphasis on starch accumulation, we studied tap roots of sugar beet using parsnip (Pastinaca sativa) as a comparator. RESULTS: Metabolic and structural analyses of sugar beet tap-root confirmed sucrose as the exclusive storage component. No starch granules could be detected in tap-roots of sugar beet or the wild ancestor sea beet (Beta vulgaris ssp. maritima). Analyses of parsnip showed that the main storage component was starch but tap-root tissue was also found to contain significant levels of sugars. Surprisingly, activities of four main starch biosynthetic enzymes, phosphoglucomutase, ADP-glucose pyrophosphorylase, starch synthase and starch branching enzyme, were similar in sugar beet and parsnip tap-roots. Transcriptional analysis confirmed expression of corresponding genes. Additionally, expression of genes involved in starch accumulation such as for plastidial hexose transportation and starch tuning functions could be determined in tap-roots of both plant species. CONCLUSION: Considering underground storage organs, sugar beet tap-root upholds a unique property in exclusively storing sucrose. Lack of starch also in the ancestor sea beet indicates an evolved trait of biological importance.Our findings in this study show that gene expression and enzymatic activity of main starch biosynthetic functions are present in sugar beet tap-root during storage accumulation. In view of this, the complete lack of starch in sugar beet tap roots is enigmatic. PMID- 24758349 TI - Synthesis and characterization of complexes of a novel proton transfer salt and their inhibition studies on carbonic anhydrase isoenzymes. AB - A novel proton transfer compound (HClABT)(+)(HDPC.H2DPC)(-) (1) and its Fe(III), Co(II), Ni(II) and two different Cu(II) complexes (2-6) have been prepared and characterized by spectroscopic techniques. Additionally, single crystal X-ray diffraction techniques were applied to all complexes. All compounds, including acetazolamide (AAZ) as the control compound, were also evaluated for their in vitro inhibition effects on human hCA I and hCA II for their hydratase and esterase activities. Although there is no inhibition for hydratase activities, all compounds have inhibited the esterase activities of hCA I and II. The comparison of the inhibition studies of 1-6 to parent compounds, ClABT and H2DPC, indicates that 1-6 have superior inhibitory effects. The inhibition effects of 2 6 are also compared to the inhibitory properties of the simple metal complexes of ClABT and H2DPC, revealing an improved transfection profile. Data have been analysed by using a one-way analysis of variance for multiple comparisons. PMID- 24758348 TI - Intrinsic thermodynamics of sulfonamide inhibitor binding to human carbonic anhydrases I and II. AB - Human carbonic anhydrase (CA) I and II are cytosolic proteins, where their expression disorders can cause diseases such as glaucoma, edema, epilepsy or cancer. There are numerous inhibitors that target these isozymes, but it is difficult to design compounds that could bind to one of these proteins specifically. The binding of sulfonamide inhibitor to a CA is linked to several protonation reactions, namely, deprotonation of the sulfonamide group, protonation of the active site zinc hydroxide and the compensating protonation deprotonation of buffer. By performing binding experiments at various pHs and buffers, all those contributions were dissected and the "intrinsic" binding parameters were calculated. Intrinsic thermodynamic binding parameters to CA I and II were determined for such widely studied drugs as acetazolamide, ethoxzolamide, methazolamide, trifluoromethanesulfonamide and dichlorophenamide. The assignment of all contributions should enhance our understanding of the underlying energetics and increase our capability to design more potent and specific CA inhibitors. PMID- 24758351 TI - Pathways to social evolution: reciprocity, relatedness, and synergy. AB - Many organisms live in populations structured by space and by class, exhibit plastic responses to their social partners, and are subject to nonadditive ecological and fitness effects. Social evolution theory has long recognized that all of these factors can lead to different selection pressures but has only recently attempted to synthesize how these factors interact. Using models for both discrete and continuous phenotypes, we show that analyzing these factors in a consistent framework reveals that they interact with one another in ways previously overlooked. Specifically, behavioral responses (reciprocity), genetic relatedness, and synergy interact in nontrivial ways that cannot be easily captured by simple summary indices of assortment. We demonstrate the importance of these interactions by showing how they have been neglected in previous synthetic models of social behavior both within and between species. These interactions also affect the level of behavioral responses that can evolve in the long run; proximate biological mechanisms are evolutionarily stable when they generate enough responsiveness relative to the level of responsiveness that exactly balances the ecological costs and benefits. Given the richness of social behavior across taxa, these interactions should be a boon for empirical research as they are likely crucial for describing the complex relationship linking ecology, demography, and social behavior. PMID- 24758353 TI - Enantioselective allylic amination of trifluoromethyl group substituted racemic and unsymmetrical 1,3-disubstituted allylic esters by palladium catalysts. AB - The palladium-catalyzed regio- and enantioselective allylic amination of trifluoromethyl group substituted racemic and unsymmetrical 1,3-disubstituted allylic esters has been accomplished. The enantioselective formation of the alpha type allylic amines was attained by the dynamic kinetic asymmetric transformation (DYKAT). PMID- 24758352 TI - Assessment of lower urinary tract function in children with Down syndrome. AB - BACKGROUND: Despite the fact that functional lower urinary tract symptoms are common among people with Down syndrome (DS), their voiding function has not been studied precisely. Our goal was to assess the lower urinary tract functions in DS. METHODS: Fifty-five DS children aged 5-15 years old and 35 age-matched control children were evaluated by ultrasonography and uroflowmetry. RESULTS: Eleven (20%) DS children had no uresiesthesia, 21 (38%) were urinated under guidance, nine (16%) urinated fewer than three times a day, two (4%) urinated more than 10 times a day, three (5%) used diapers, and 26 (47%) had urinary incontinence. Seven (13%), 15 (27%), and 10 (18%) DS children had weak, prolonged and intermittent urination, respectively, and seven (13%) had urination with straining. In contrast, none of the control subjects had urinary problems. In the uroflowmetrical analysis, 10 (18%), 20 (37%), 11 (20%) and five (9%) DS children showed "bell-shaped," "plateau," "staccato" and "interrupted" patterns, respectively; the remaining nine (16%) could not be analyzed. In contrast, 21 (60%), one (3%), four (11%), three (9%) and two (6%) control subjects showed bell shaped, tower-shaped, plateau, staccato and interrupted patterns, respectively; the remaining four (11%) could not be analyzed. Residual urine was demonstrated in four (7%) DS children and one (3%) control child. CONCLUSIONS: Lower urinary tract symptoms and abnormal uroflowmetry findings, which can lead to further progressive renal and urinary disorders, are common in DS children. Therefore, lower urinary tract functions should be assessed at the life-long regular medical check-ups for subjects with DS. PMID- 24758354 TI - Lived experiences of women who developed uterine rupture following severe obstructed labor in Mulago hospital, Uganda. AB - BACKGROUND: Maternal mortality is a major public health challenge in Uganda. Whereas uterine rupture remains a major cause of maternal morbidity and mortality, there is limited research into what happens to women who survive such severe obstetric complications. Understanding their experiences might delineate strategies to support survivors. METHODS: This qualitative study used a phenomenological approach to explore lived experiences of women who developed uterine rupture following obstructed labor. In-depth interviews initially conducted during their hospitalization were repeated 3-6 months after the childbirth event to explore their health and meanings they attached to the traumatic events and their outcomes. Data were analyzed using thematic analysis. RESULTS: The resultant themes included barriers to access healthcare, multiple "losses" and enduring physical, psychosocial and economic consequences. Many women who develop uterine rupture fail to access critical care needed due to failure to recognise danger signs of obstructed labor, late decision making for accessing care, geographical barriers to health facilities, late or failure to diagnose obstructed labor at health facilities, and failure to promptly perform caesarean section. Secondly, the sequel of uterine rupture includes several losses (loss of lives, loss of fertility, loss of body image, poor quality of life and disrupted marital relationships). Thirdly, uterine rupture has grim economic consequences for the survivors (with financial loss and loss of income during and after the calamitous events). CONCLUSION: Uterine rupture is associated with poor quality of care due to factors that operate at personal, household, family, community and society levels, and results in dire physical, psychosocial and financial consequences for survivors. There is need to improve access to and provision of emergency obstetric care in order to prevent uterine rupture consequent to obstructed labor. There is also critical need to provide counselling and support to survivors to enable them cope with physical, social, psychological and economic consequences. PMID- 24758355 TI - Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis. AB - BACKGROUND: Zalypsis((r)) is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing's sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy. METHODS: Using in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified these results in culture and in vivo xenograft studies. RESULTS: Zalypsis resistance was dependent on the expression levels of PDGFRalpha or constitutive phosphorylation of c-Kit, indicating that the activation of tyrosine kinase receptors (TKRs) may determine resistance to Zalypsis. To validate our observation, we measured the levels of total and active (phosphorylated) forms of the RTKs PDGFRalpha/beta, c-Kit, and EGFR in a new panel of diverse solid tumor cell lines and found that the IC50 to the drug correlated with RTK activation in this new panel. We further tested our predictions about Zalypsis determinants for response in vivo in xenograft models. All cells lines expressing low levels of RTK signaling were sensitive to Zalypsis in vivo, whereas all cell lines except two with high levels of RTK signaling were resistant to the drug. CONCLUSIONS: RTK activation might provide important signals to overcome the cytotoxicity of Zalypsis and should be taken into consideration in current and future clinical trials. PMID- 24758356 TI - The Italian version of the Physical Therapy Patient Satisfaction Questionnaire - [PTPSQ-I(15)]: psychometric properties in a sample of inpatients. AB - BACKGROUND: In a previous study we described the translation, cultural adaptation, and validation of the Italian version of the PTPSQ [PTPSQ-I(15)] in outpatients. To the authors' knowledge, the PTPSQ was never studied in a hospital setting.The aims of this study were: (1) to establish the psychometric properties of the Physical Therapy Patient Satisfaction Questionnaire [PTPSQ- I(15)] in a sample of Italian inpatients, and (2) to investigate the relationships between the characteristics of patients and physical therapists and the indicators of satisfaction. METHODS: The PTPSQ-I(15) was administered to inpatients in a Physical Medicine and Rehabilitation Unit. Reliability of the PTPSQ-I(15) was measured by internal consistency (Cronbach's alpha) and test-retest stability (ICC 3,1). The internal structure was investigated by factor analysis. Divergent validity was measured by comparing the PTPSQ-I(15) with a Visual Analogue Scale (VAS) for pain and with a 5-point Likert-type scale evaluating the Global Perceived Effect (GPE) of the physical therapy treatment. RESULTS: The PTPSQ I(15) was administered to 148 inpatients, and 73 completed a second administration. The PTPSQ-I(15) showed high internal consistency (alpha = 0.949) and test-retest stability (ICC = 0.996). Divergent validity was moderate for the GPE (r = - 0.502, P < 0.001) and strong for the VAS (r = -0.17, P = 0.07). Factor analysis showed a one-factor structure. CONCLUSIONS: The administration of PTPSQ I(15) to inpatients demonstrated strong psychometric properties and its use can be recommended with Italian-speaking population. Further studies are suggested on the concurrent validity and on the psychometric properties of the PTPSQ-I(15) in different hospital settings or with other pathological conditions. PMID- 24758357 TI - Symptoms and signs in interpreting gamma-hydroxybutyrate (GHB) intoxication - an explorative study. AB - BACKGROUND: Acute poisoning with gamma-hydroxybutyrate (GHB) has been a serious medical and social problem in different parts of the world including Sweden. GHB is a drug of abuse which acts primarily as central nervous system (CNS) depressants. GHB has serious toxicity, although many young users do not recognise GHB as a dangerous drug. The aim of this pilot study was to explore how symptoms with risk of failure in vital functions would be valued among professionals that encounter GHB intoxication in the emergency phase. METHODS: A web-based survey focusing on the assessment of vital clinical signs for possible GHB intoxication using a numeric scale was carried out during April and May 2011. The participants, n 105, are all professionals who encounter GHB intoxicated in the emergency phase, but have different levels of training in GHB intoxication, mainly Registered Nurses (RNs) in southwest Sweden, employed in pre-hospital or emergency departments at somatic and most psychiatric health care facilities, as well as police officers who in their work come into contact with drug users. Responses in the survey were scored according to risk of GHB intoxication with serious failure of vital functions. The score value was then referred to a so called evidence based priority (EBP) scale and analysed using descriptive statistics and Fisher's exact test. RESULTS: Cardiac arrest, coma, hypoxia, general convulsions, slow respiratory and heart rate and pale skin are symptoms with the highest risk of serious failure in vital physical functions and were predominantly recognised as such. CONCLUSION: Despite the professionals' different levels of training in GHB intoxication, all of them were relatively well aware of and in accordance regarding the most risky symptoms. The interpretation score for the less risky symptoms and signs of GHB intoxication varied depending on their degree of training. The results should be viewed cautiously, as the size of the professional groups and their general knowledge of critical symptoms of GHB poisoning varied. PMID- 24758358 TI - Ultrasound B-mode and elastographic findings of angiomatoid fibrous histiocytoma. PMID- 24758360 TI - Cross-coupling reactions using samarium(II) iodide. PMID- 24758359 TI - RNAi-assisted genome evolution in Saccharomyces cerevisiae for complex phenotype engineering. AB - A fundamental challenge in basic and applied biology is to reprogram cells with improved or novel traits on a genomic scale. However, the current ability to reprogram a cell on the genome scale is limited to bacterial cells. Here, we report RNA interference (RNAi)-assisted genome evolution (RAGE) as a generally applicable method for genome-scale engineering in the yeast Saccharomyces cerevisiae. Through iterative cycles of creating a library of RNAi induced reduction-of-function mutants coupled with high throughput screening or selection, RAGE can continuously improve target trait(s) by accumulating multiplex beneficial genetic modifications in an evolving yeast genome. To validate the RNAi library constructed with yeast genomic DNA and convergent promoter expression cassette, we demonstrated RNAi screening in Saccharomyces cerevisiae for the first time by identifying two known and three novel suppressors of a telomerase-deficient mutation yku70Delta. We then showed the application of RAGE for improved acetic acid tolerance, a key trait for microbial production of chemicals and fuels. Three rounds of iterative RNAi screening led to the identification of three gene knockdown targets that acted synergistically to confer an engineered yeast strain with substantially improved acetic acid tolerance. RAGE should greatly accelerate the design and evolution of organisms with desired traits and provide new insights on genome structure, function, and evolution. PMID- 24758362 TI - B-cell activating factor detected on both naive and memory B cells in bullous pemphigoid. AB - B-cell activating factor (BAFF), an important immune regulatory cytokine, is involved in development of autoimmune diseases. Although BAFF is expressed in various cells, including dendritic cells (DCs) and monocytes, BAFF expression on B cells has not been well documented. In the present study, BAFF molecules on DCs and naive and memory B cells in autoimmune bullous diseases, including pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid (BP), were analysed by flow cytometry. Compared with healthy controls (HC), BAFF expression on naive and memory B cells increased significantly in BP. No difference in BAFF receptor expression in naive and memory B cells was shown among all study groups. Furthermore, BAFF expression in both naive and memory B cells of BP, but not HC, was detected by confocal microscopic analysis. These results implied that BAFF expressed by B cells may play a pathogenic role in autoimmune bullous diseases, particularly BP. PMID- 24758361 TI - Bone morphogenetic proteins and their antagonists: current and emerging clinical uses. AB - Bone morphogenetic proteins (BMPs) are members of the TGFbeta superfamily of secreted cysteine knot proteins that includes TGFbeta1, nodal, activins and inhibins. BMPs were first discovered by Urist in the 1960s when he showed that implantation of demineralized bone into intramuscular tissue of rabbits induced bone and cartilage formation. Since this seminal discovery, BMPs have also been shown to play key roles in several other biological processes, including limb, kidney, skin, hair and neuronal development, as well as maintaining vascular homeostasis. The multifunctional effects of BMPs make them attractive targets for the treatment of several pathologies, including bone disorders, kidney and lung fibrosis, and cancer. This review will summarize current knowledge on the BMP signalling pathway and critically evaluate the potential of recombinant BMPs as pharmacological agents for the treatment of bone repair and tissue fibrosis in patients. PMID- 24758363 TI - Velamentous cord insertion: is it associated with adverse perinatal outcomes? AB - INTRODUCTION: Velamentous cord insertion (VCI) can be identified on prenatal ultrasound with an incidence of around 1%. We set out to examine the association between VCI and perinatal outcomes. METHODS: This was a retrospective cohort study of 482,812 pregnancies using the California vital statistics birth cohort dataset linked with patient discharge dataset from 2006 during which 2327 (0.48%) were complicated by VCI. Outcomes examined included intrauterine fetal demise (IUFD), small for gestational age (SGA), preterm delivery, manual removal of the placenta and cesarean delivery. Statistical analysis was performed using Chi squared tests and multivariable logistic regression analyses. RESULTS: Pregnancies with VCI, compared to those without, were associated with an increased risk of IUFD (2.6% versus 0.28%, p = 0.001), SGA (16.93% versus 10.17%, p = 0.001), preterm delivery <37 weeks (12.5% versus 9.10%, p = 0.001), manual removal of placenta (14.47% versus 0.76%, p = 0.01) and postpartum hemorrhage (6.66% versus 2.88%, p = 0.001). Adjusting for confounders, the adjusted odds of IUFD were more than nine times in pregnancies with VCI (aOR 9.56; 95% CI 6.76 13.5) than those without. DISCUSSION: VCI is associated with an increased risk of adverse perinatal outcomes such as IUFD, SGA, preterm delivery <37 weeks, need for manual removal of placenta and post-partum hemorrhage. Routine identification of the placental cord insertion site should be considered. Close surveillance of these pregnancies should be undertaken. Future research should focus on the optimal management including the gestational age for delivery of these pregnancies. PMID- 24758364 TI - Health-related quality of life in chronic obstructive pulmonary disease patients in Korea. AB - BACKGROUND: There are few publications on quality measurement of COPD health state according to the severity level using EQ-5D in Korea. The present study aimed to evaluate the health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD) in terms of disease severity in Korea. METHODS: Totally two hundred patients with COPD were consecutively recruited in one tertiary hospital of Korea. Each respondent was asked to fill out the questionnaire through a face-to-face interview after providing informed consent. The questionnaire included general and clinical characteristics as well as the EQ-5D and Clinical COPD Questionnaire (CCQ). HRQoL was evaluated according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and severity of breathlessness. RESULTS: The adjusted mean EQ-5D index scores were 0.83, 0.88, 0.81 and 0.60 in stage I, II, III and IV, respectively. The EQ-5D index tended to decrease with GOLD criteria. The adjusted mean EQ-Visual Analog Scale (VAS) scores ranged from 65.1 in stage IV to 73.9 in stage I. The CCQ total scores deteriorated with an increasing GOLD stage and severity of breathlessness (all P < 0.001). The correlation between CCQ total score and EQ-5D index was 0.69. CONCLUSIONS: Our study shows that HRQoL in COPD measured by EQ-5D and CCQ worsens with the GOLD stage and severity of breathlessness. EQ-5D and CCQ could be useful instruments for an evaluation of HRQoL in COPD patients in Korea. PMID- 24758367 TI - A case-control review of placentas from patients with intrahepatic cholestasis of pregnancy. AB - OBJECTIVE: To compare the incidence of histopathological features in placentas from women with cholestasis of pregnancy to healthy individuals without ICP. METHODS: Placentas from mothers with and without cholestasis of pregnancy were reviewed by a pathologist masked to the study group. Subjects were excluded if they had medical problems already associated with placental histopathology. RESULTS: Twenty-four cases and 30 controls placentas were reviewed. Seventeen placental histopathological features were found. There was no statistically significant difference between the groups. Amongst patients with cholestasis, there was a decrease in villitis of unknown etiology in those treated with ursodeoxycholic acid. CONCLUSION: There is no difference in the placental histopathology in cholestasis of pregnancy compared to normal pregnancies, but treatment of patients with cholestasis of pregnancy with ursodeoxycholic acid may decrease findings of villitis of unknown etiology. PMID- 24758366 TI - Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens. AB - BACKGROUND: Increasing evidence supports a role for altered gene expression in mediating the lasting effects of cocaine on the brain, and recent work has demonstrated the involvement of chromatin modifications in these alterations. However, all such studies to date have been restricted by their reliance on microarray technologies that have intrinsic limitations. RESULTS: We use next generation sequencing methods, RNA-seq and ChIP-seq for RNA polymerase II and several histone methylation marks, to obtain a more complete view of cocaine induced changes in gene expression and associated adaptations in numerous modes of chromatin regulation in the mouse nucleus accumbens, a key brain reward region. We demonstrate an unexpectedly large number of pre-mRNA splicing alterations in response to repeated cocaine treatment. In addition, we identify combinations of chromatin changes, or signatures, that correlate with cocaine dependent regulation of gene expression, including those involving pre-mRNA alternative splicing. Through bioinformatic prediction and biological validation, we identify one particular splicing factor, A2BP1(Rbfox1/Fox-1), which is enriched at genes that display certain chromatin signatures and contributes to drug-induced behavioral abnormalities. Together, this delineation of the cocaine induced epigenome in the nucleus accumbens reveals several novel modes of regulation by which cocaine alters the brain. CONCLUSIONS: We establish combinatorial chromatin and transcriptional profiles in mouse nucleus accumbens after repeated cocaine treatment. These results serve as an important resource for the field and provide a template for the analysis of other systems to reveal new transcriptional and epigenetic mechanisms of neuronal regulation. PMID- 24758365 TI - An update on male hypogonadism therapy. AB - INTRODUCTION: Men who have symptoms associated with persistently low serum total testosterone level should be assessed for testosterone replacement therapy. AREAS COVERED: Acute and chronic illnesses are associated with low serum testosterone and these should be recognized and treated. Once the diagnosis of male hypogonadism is made, the benefits of testosterone treatment usually outweigh the risks. Without contraindications, the patient should be offered testosterone replacement therapy. The options of testosterone delivery systems (injections, transdermal patches/gels, buccal tablets, capsules and implants) have increased in the last decade. Testosterone improves symptoms and signs of hypogonadism such as sexual function and energy, increases bone density and lean mass and decreases visceral adiposity. In men who desire fertility and who have secondary hypogonadism, testosterone can be withdrawn and the patients can be placed on gonadotropins. New modified designer androgens and selective androgen receptor modulators have been in preclinical and clinical trials for some time. None of these have been assessed for the treatment of male hypogonadism. EXPERT OPINION: Despite the lack of prospective long-term data from randomized, controlled clinical trials of testosterone treatment on prostate health and cardiovascular disease risk, the available evidence suggests that testosterone therapy should be offered to symptomatic hypogonadal men. PMID- 24758368 TI - Disparities in pre-eclampsia and eclampsia among immigrant women giving birth in six industrialised countries. AB - OBJECTIVE: To assess disparities in pre-eclampsia and eclampsia among immigrant women from various world regions giving birth in six industrialised countries. DESIGN: Cross-country comparative study of linked population-based databases. SETTING: Provincial or regional obstetric delivery data from Australia, Canada, Spain and the USA and national data from Denmark and Sweden. POPULATION: All immigrant and non-immigrant women delivering in the six industrialised countries within the most recent 10-year period available to each participating centre (1995-2010). METHODS: Data was collected using standardised definitions of the outcomes and maternal regions of birth. Pooled data were analysed with multilevel models. Within-country analyses used stratified logistic regression to obtain odds ratios (OR) with 95% confidence intervals (95% CI). MAIN OUTCOME MEASURES: Pre-eclampsia, eclampsia and pre-eclampsia with prolonged hospitalisation (cases per 1000 deliveries). RESULTS: There were 9,028,802 deliveries (3,031,399 to immigrant women). Compared with immigrants from Western Europe, immigrants from Sub-Saharan Africa and Latin America & the Caribbean were at higher risk of pre eclampsia (OR: 1.72; 95% CI: 1.63, 1.80 and 1.63; 95% CI: 1.57, 1.69) and eclampsia (OR: 2.12; 95% CI: 1.61, 2.79 and 1.55; 95% CI: 1.26, 1. 91), respectively, after adjustment for parity, maternal age and destination country. Compared with native-born women, European and East Asian immigrants were at lower risk in most industrialised countries. Spain exhibited the largest disparities and Australia the smallest. CONCLUSION: Immigrant women from Sub-Saharan Africa and Latin America & the Caribbean require increased surveillance due to a consistently high risk of pre-eclampsia and eclampsia. PMID- 24758369 TI - A novel pathogenic peptide of thyroglobulin (2208-2227) induces autoreactive T cell and B-cell responses in both high and low responder mouse strains. AB - Experimental autoimmune thyroiditis (EAT) is commonly induced by thyroglobulin (Tg) or Tg peptides in mice genetically susceptible to thyroiditis. In the present study, we investigated the immunogenic and pathogenic potential of a novel 20mer human Tg peptide, p2208 (amino acids 2208-2227), in mouse strains classified as low (LR) or high (HR) responders in EAT. The peptide was selected for its content in overlapping binding motifs for MHC class II products, associated with either resistance (A(b)), or susceptibility (A(s), E(k)) to EAT. We therefore immunized LR BALB/c (H-2(d)) and C57BL/6 (H-2(b)) strains, as well as HR CBA/J (H-2(k)) and SJL/J (H-2(s)) mice with 100 nmol of p2208 in adjuvant and collected their sera, lymph nodes and thyroid glands for further analysis. The p2208 peptide was found to contain B-cell and cryptic T-cell epitope(s) in two of the four strains examined, one LR and one HR. Specifically, it elicited direct EAT in C57BL/6 mice (two of seven mice, infiltration index 1-3), as well as in SJL/J mice (two of six mice, infiltration index 1-2). Such an EAT model could provide insights into the immunoregulatory cascades taking place in resistant hosts. PMID- 24758370 TI - A novel high-resolution anorectal manometry parameter based on a three dimensional integrated pressurized volume of a spatiotemporal plot, for predicting balloon expulsion in asymptomatic normal individuals. AB - BACKGROUND: Anorectal manometry with simulated evacuation (SE) has limited applicability in predicting balloon expulsion (BE) test results. The newly developed high-resolution anorectal manometry (HRAM) technique can yield spatiotemporal plots with three-dimensional pressurization. We aimed to define new parameters based on three-dimensional integrated pressurized volume (IPV) for predicting the BE test results in asymptomatic normal individuals. METHODS: Fifty four asymptomatic healthy individuals were prospectively enrolled. BE tests were performed using 50 mL of water, and a requirement of more than 1 min was considered as delayed BE. HRAM profiles were converted into ASCII files and analyzed using a MATLAB program. A three-dimensional IPV was plotted after transforming the data to a cubic spline interpolation followed by resampling the manometry position at 0.1-cm intervals. KEY RESULTS: Eight of the 54 (15%) individuals demonstrated delayed BE. Conventional manometric profiles did not differ significantly between cases of early and delayed BE. Receiver-operator characteristic curve analysis revealed that the ratio of the IPVs of the upper 1 cm to the lower 4 cm of the anorectal canal with balloon distension was more predictable of the BE results (area under curve, 0.73: 95% confidence interval, 0.53-0.92; p = 0.04) than the other IPVs or their ratios. CONCLUSIONS & INFERENCES: The newly developed IPV methods could predict delayed BE tests during SE better than the conventional parameters defined on the basis of linear waves. Well-designed prospective trials on a large number of subjects are warranted to validate the clinical application of this novel parameter. PMID- 24758371 TI - In silico design and enzymatic synthesis of functional RNA nanoparticles. AB - CONSPECTUS: The use of RNAs as scaffolds for biomedical applications has several advantages compared with other existing nanomaterials. These include (i) programmability, (ii) precise control over folding and self-assembly, (iii) natural functionalities as exemplified by ribozymes, riboswitches, RNAi, editing, splicing, and inherent translation and transcription control mechanisms, (iv) biocompatibility, (v) relatively low immune response, and (vi) relatively low cost and ease of production. We have tapped into several of these properties and functionalities to construct RNA-based functional nanoparticles (RNA NPs). In several cases, the structural core and the functional components of the NPs are inherent in the same construct. This permits control over the spatial disposition of the components, intracellular availability, and precise stoichiometry. To enable the generation of RNA NPs, a pipeline is being developed. On one end, it encompasses the rational design and various computational schemes that promote design of the RNA-based nanoconstructs, ultimately producing a set of sequences consisting of RNA or RNA-DNA hybrids, which can assemble into the designed construct. On the other end of the pipeline is an experimental component, which takes the produced sequences and uses them to initialize and characterize their proper assembly and then test the resulting RNA NPs for their function and delivery in cell culture and animal models. An important aspect of this pipeline is the feedback that constantly occurs between the computational and the experimental parts, which synergizes the refinement of both the algorithmic methodologies and the experimental protocols. The utility of this approach is depicted by the several examples described in this Account (nanocubes, nanorings, and RNA-DNA hybrids). Of particular interest, from the computational viewpoint, is that in most cases, first a three-dimensional representation of the assembly is produced, and only then are algorithms applied to generate the sequences that will assemble into the designated three-dimensional construct. This is opposite to the usual practice of predicting RNA structures from a given sequence, that is, the RNA folding problem. To be considered is the generation of sequences that upon assembly have the proper intra- or interstrand interactions (or both). Of particular interest from the experimental point of view is the determination and characterization of the proper thermodynamic, kinetic, functionality, and delivery protocols. Assembly of RNA NPs from individual single-stranded RNAs can be accomplished by one-pot techniques under the proper thermal and buffer conditions or, potentially more interestingly, by the use of various RNA polymerases that can promote the formation of RNA NPs cotransciptionally from specifically designed DNA templates. Also of importance is the delivery of the RNA NPs to the cells of interest in vitro or in vivo. Nonmodified RNAs rapidly degrade in blood serum and have difficulties crossing biological membranes due to their negative charge. These problems can be overcome by using, for example, polycationic lipid-based carriers. Our work involves the use of bolaamphiphiles, which are amphipathic compounds with positively charged hydrophilic head groups at each end connected by a hydrophobic chain. We have correlated results from molecular dynamics computations with various experiments to understand the characteristics of such delivery agents. PMID- 24758372 TI - Effect of Cinnamomum cassia methanol extract and sildenafil on arginase and sexual function of young male Wistar rats. AB - INTRODUCTION: Herbs have been used as an aphrodisiac since ages. Cinnamomum cassia is an important ingredient of many Ayurvedic formulations to treat male sexual disorder including erectile dysfunction (ED). AIM: The objective of the present study was to evaluate erectogenic and aphrodisiac activity of methanol extract of C. cassia bark in young male rats. METHODS: Methanol extract of C. cassia was screened in vitro for arginase inhibition potential and IC50 was determined. Effect of the extract was observed in vitro on phenylephrine pre contracted isolated rat corpus cavernosum smooth muscle (CCSM) at 0.1, 1, 10, and 100 MUg/mL. Young male Wistar rats were dosed with extract at 100 mg/kg body weight for 28 days and its effects on sexual behavior and penile smooth muscle : collagen level were observed. MAIN OUTCOME MEASURE: Effect of C. cassia was studied on arginase activity in vitro and sexual behavior of young male rats. RESULTS: C. cassia inhibited arginase activity in vitro with an IC50 of 61.72 +/- 2.20 MUg/mL. The extract relaxed phenylephrine pre-contracted isolated rat CCSM up to 43% and significantly increased (P < 0.05) sexual function of young male rats. Treatment with the extract also increased smooth muscle level and decreased collagen level in rat penile tissue. CONCLUSION: The study proves usefulness of methanol extract of C. cassia bark for increasing sexual function. PMID- 24758374 TI - Early procedure-related adverse events by gender in MADIT-CRT. AB - BACKGROUND: Whether gender differences exist in procedure-related adverse events following cardiac resynchronization therapy (CRT-D) implantation is unknown. We investigated the type and frequency of procedure-related adverse events among those enrolled in MADIT-CRT and identified clinical predictors for gender specific events. METHODS: We compared differences in the rate of procedure related adverse events by gender (444 females and 1,346 males) that occurred <=30 days after the index procedure in the implantable cardioverter defibrillator (ICD) and CRT-D groups. Eight types of major adverse events were identified, defined as procedure-related complications deemed potentially life-threatening. Best subset regression analysis (P < 0.10) was performed to identify baseline clinical factors associated with procedure-related adverse events that differed by gender. RESULTS: Women randomized to CRT-D received a greater reduction in the risk of heart failure or death versus men (P < 0.001). Women were twice as likely as men to experience a major procedure-related adverse event (6.3% vs. 2.7%; P < 0.001), including pneumothorax/hemothorax (3% vs. 1%; P < 0.001). Women were more likely to experience a major adverse event related to CRT-D than ICD implantation (7.7% vs. 2.9%; P = 0.018). Clinical predictors of major adverse events in females were smaller body mass index (BMI), elevated blood urea nitrogen, and elevated creatinine. The main predictor for pneumothorax/hemothorax was reduced BMI for women and men. CONCLUSION: Women demonstrate greater clinical benefit from CRT than men but are more likely to experience adverse procedure-related events within the first 30 days after device implantation. A smaller BMI seems to be a major factor associated with pneumothorax/hemothorax in both females and males. PMID- 24758373 TI - Histone acetylation associated up-regulation of the cell wall related genes is involved in salt stress induced maize root swelling. AB - BACKGROUND: Salt stress usually causes crop growth inhibition and yield decrease. Epigenetic regulation is involved in plant responses to environmental stimuli. The epigenetic regulation of the cell wall related genes associated with the salt induced cellular response is still little known. This study aimed to analyze cell morphological alterations in maize roots as a consequence of excess salinity in relation to the transcriptional and epigenetic regulation of the cell wall related protein genes. RESULTS: In this study, maize seedling roots got shorter and displayed swelling after exposure to 200 mM NaCl for 48 h and 96 h. Cytological observation showed that the growth inhibition of maize roots was due to the reduction in meristematic zone cell division activity and elongation zone cell production. The enlargement of the stele tissue and cortex cells contributed to root swelling in the elongation zone. The cell wall is thought to be the major control point for cell enlargement. Cell wall related proteins include xyloglucan endotransglucosylase (XET), expansins (EXP), and the plasma membrane proton pump (MHA). RT-PCR results displayed an up-regulation of cell wall related ZmEXPA1, ZmEXPA3, ZmEXPA5, ZmEXPB1, ZmEXPB2 and ZmXET1 genes and the down-regulation of cell wall related ZmEXPB4 and ZmMHA genes as the duration of exposure was increased. Histone acetylation is regulated by HATs, which are often correlated with gene activation. The expression of histone acetyltransferase genes ZmHATB and ZmGCN5 was increased after 200 mM NaCl treatment, accompanied by an increase in the global acetylation levels of histones H3K9 and H4K5. ChIP experiment showed that the up-regulation of the ZmEXPB2 and ZmXET1 genes was associated with the elevated H3K9 acetylation levels on the promoter regions and coding regions of these two genes. CONCLUSIONS: These data suggested that the up-regulation of some cell wall related genes mediated cell enlargement to possibly mitigate the salinity-induced ionic toxicity, and different genes had specific function in response to salt stress. Histone modification as a mediator may contribute to rapid regulation of cell wall related gene expression, which reduces the damage of excess salinity to plants. PMID- 24758375 TI - Visuomotor behaviours when using a myoelectric prosthesis. AB - BACKGROUND: A recent study showed that the gaze patterns of amputee users of myoelectric prostheses differ markedly from those seen in anatomically intact subjects. Gaze behaviour is a promising outcome measures for prosthesis designers, as it appears to reflect the strategies adopted by amputees to compensate for the absence of proprioceptive feedback and uncertainty/delays in the control system, factors believed to be central to the difficulty in using prostheses. The primary aim of our study was to characterise visuomotor behaviours over learning to use a trans-radial myoelectric prosthesis. Secondly, as there are logistical advantages to using anatomically intact subjects in prosthesis evaluation studies, we investigated similarities in visuomotor behaviours between anatomically intact users of a trans-radial prosthesis simulator and experienced trans-radial myoelectric prosthesis users. METHODS: In part 1 of the study, we investigated visuomotor behaviours during performance of a functional task (reaching, grasping and manipulating a carton) in a group of seven anatomically intact subjects over learning to use a trans-radial myoelectric prosthesis simulator (Dataset 1). Secondly, we compared their patterns of visuomotor behaviour with those of four experienced trans-radial myoelectric prosthesis users (Dataset 2). We recorded task movement time, performance on the SHAP test of hand function and gaze behaviour. RESULTS: Dataset 1 showed that while reaching and grasping the object, anatomically intact subjects using the prosthesis simulator devoted around 90% of their visual attention to either the hand or the area of the object to be grasped. This pattern of behaviour did not change with training, and similar patterns were seen in Dataset 2. Anatomically intact subjects exhibited significant increases in task duration at their first attempts to use the prosthesis simulator. At the end of training, the values had decreased and were similar to those seen in Dataset 2. CONCLUSIONS: The study provides the first functional description of the gaze behaviours seen during use of a myoelectric prosthesis. Gaze behaviours were found to be relatively insensitive to practice. In addition, encouraging similarities were seen between the amputee group and the prosthesis simulator group. PMID- 24758377 TI - Macromolecular engineering by atom transfer radical polymerization. AB - This Perspective presents recent advances in macromolecular engineering enabled by ATRP. They include the fundamental mechanistic and synthetic features of ATRP with emphasis on various catalytic/initiation systems that use parts-per-million concentrations of Cu catalysts and can be run in environmentally friendly media, e.g., water. The roles of the major components of ATRP--monomers, initiators, catalysts, and various additives--are explained, and their reactivity and structure are correlated. The effects of media and external stimuli on polymerization rates and control are presented. Some examples of precisely controlled elements of macromolecular architecture, such as chain uniformity, composition, topology, and functionality, are discussed. Syntheses of polymers with complex architecture, various hybrids, and bioconjugates are illustrated. Examples of current and forthcoming applications of ATRP are covered. Future challenges and perspectives for macromolecular engineering by ATRP are discussed. PMID- 24758376 TI - Hepatitis B spliced protein (HBSP) promotes the carcinogenic effects of benzo [alpha] pyrene by interacting with microsomal epoxide hydrolase and enhancing its hydrolysis activity. AB - BACKGROUND: The risk of hepatocellular carcinoma (HCC) increases in chronic hepatitis B surface antigen (HBsAg) carriers who often have concomitant increase in the levels of benzo[alpha]pyrene-7,8-diol-9,10-epoxide(+/-) (BPDE)-DNA adduct in liver tissues, suggesting a possible co-carcinogenesis of Hepatitis B virus (HBV) and benzo[alpha]pyrene in HCC; however the exact mechanisms involved are unclear. METHODS: The interaction between hepatitis B spliced protein (HBSP) and microsomal epoxide hydrolase (mEH) was confirmed using GST pull-down, co immunoprecipitation and mammalian two-hybrid assay; the effects of HBSP on mEH mediated B[alpha]P metabolism was examined by high performance liquid chromatography (HPLC); and the influences of HBSP on B[alpha]P carcinogenicity were evaluated by bromodeoxyuridine cell proliferation, anchorage-independent growth and tumor xenograft. RESULTS: HBSP could interact with mEH in vitro and in vivo, and this interaction was mediated by the N terminal 47 amino acid residues of HBSP. HBSP could greatly enhance the hydrolysis activity of mEH in cell-free mouse liver microsomes, thus accelerating the metabolism of benzo[alpha]pyrene to produce more ultimate carcinnogen, BPDE, and this effect of HBSP requires the intact HBSP molecule. Expression of HBSP significantly increased the formation of BPDE-DNA adduct in benzo[alpha]pyrene-treated Huh-7 hepatoma cells, and this enhancement was blocked by knockdown of mEH. HBSP could enhance the cell proliferation, accelerate the G1/S transition, and promote cell transformation and tumorigenesis of B[alpha]P-treated Huh-7 hepatoma cells. CONCLUSIONS: Our results demonstrated that HBSP could promote carcinogenic effects of B[alpha]P by interacting with mEH and enhancing its hydrolysis activity. PMID- 24758378 TI - Introduction: Bioinorganic enzymology II. PMID- 24758380 TI - A strain induced change of mechanism from a [2 + 2 + 2] to a [2 + 1 + 2 + 1] cycloaddition reaction. AB - While investigating the [2 + 2 + 2] cycloaddition as a tool to build up strained oligophenyl systems with a diyne-ethylene glycol macrocyle, a surprising change of mechanism was observed. Instead of the expected [2 + 2 + 2] para-terphenyl, the ortho-terphenyl product explained by a formal [2 + 1 + 2 + 1] cycloaddition was formed. An eta(4)-coordinated metal-cyclobutadiene is proposed as the key structure in the catalytic cycle, which is formed to release the induced strain. The optical properties of the ortho-terphenyl products have been measured as well as the coordination ability of Na(+) and K(+). PMID- 24758381 TI - Down-regulation of A-type potassium channel in gastric-specific DRG neurons in a rat model of functional dyspepsia. AB - BACKGROUND: Although without evidence of organic structural abnormalities, pain or discomfort is a prominent symptom of functional dyspepsia and considered to reflect visceral hypersensitivity whose underlying mechanism is poorly understood. Here, we studied electrophysiological properties and expression of voltage-gated potassium channels in dorsal root ganglion (DRG) neurons in a rat model of functional dyspepsia induced by neonatal gastric irritation. METHODS: Male Sprague-Dawley rat pups at 10-day old received 0.1% iodoacetamide (IA) or vehicle by oral gavage for 6 days and studied at adulthood. Retrograde tracer labeled gastric-specific T8 -T12 DRG neurons were harvested for the patch-clamp study in voltage and current-clamp modes and protein expression of K(+) channel in T8 -T12 DRGs was examined by western blotting. KEY RESULTS: (1) Gastric specific but not non-gastric DRG neurons showed an enhanced excitability in neonatal IA-treated rats compared to the control: depolarized resting membrane potentials, a lower current threshold for action potential (AP) activation, and an increase in the number of APs in response to current stimulation. (2) The current density of tetraethylammonium insensitive (transiently inactivating A type current), but not the tetraethylammonium sensitive (slow-inactivating delayed rectifier K(+) currents), was significantly smaller in IA-treated rats (65.4 +/- 6.9 pA/pF), compared to that of control (93.1 +/- 8.3 pA/pF). (3) Protein expression of KV 4.3 was down-regulated in IA-treated rats. CONCLUSIONS & INFERENCES: A-type potassium channels are significantly down-regulated in the gastric-specific DRG neurons in adult rats with mild neonatal gastric irritation, which in part contribute to the enhanced DRG neuron excitabilities that leads to the development of gastric hypersensitivity. PMID- 24758382 TI - Analytical validation of whole exome and whole genome sequencing for clinical applications. AB - BACKGROUND: Whole exome and genome sequencing (WES/WGS) is now routinely offered as a clinical test by a growing number of laboratories. As part of the test design process each laboratory must determine the performance characteristics of the platform, test and informatics pipeline. This report documents one such characterization of WES/WGS. METHODS: Whole exome and whole genome sequencing was performed on multiple technical replicates of five reference samples using the Illumina HiSeq 2000/2500. The sequencing data was processed with a GATK-based genome analysis pipeline to evaluate: intra-run, inter-run, inter-mode, inter machine and inter-library consistency, concordance with orthogonal technologies (microarray, Sanger) and sensitivity and accuracy relative to known variant sets. RESULTS: Concordance to high-density microarrays consistently exceeds 97% (and typically exceeds 99%) and concordance between sequencing replicates also exceeds 97%, with no observable differences between different flow cells, runs, machines or modes. Sensitivity relative to high-density microarray variants exceeds 95%. In a detailed study of a 129 kb region, sensitivity was lower with some validated single-base insertions and deletions "not called". Different variants are "not called" in each replicate: of all variants identified in WES data from the NA12878 reference sample 74% of indels and 89% of SNVs were called in all seven replicates, in NA12878 WGS 52% of indels and 88% of SNVs were called in all six replicates. Key sources of non-uniformity are variance in depth of coverage, artifactual variants resulting from repetitive regions and larger structural variants. CONCLUSION: We report a comprehensive performance characterization of WES/WGS that will be relevant to offering laboratories, consumers of genome sequencing and others interested in the analytical validity of this technology. PMID- 24758383 TI - Comparison of novel granulated pellet-containing tablets and traditional pellet containing tablets by artificial neural networks. AB - Novel granulated pellets technique was adopted to prepare granulated pellet containing tablets (GPCT). GPCT and traditional pellet-containing tablets (PCT) were prepared according to 29 formulations devised by the Design Expert 7.0, with doxycycline hydrochloride as model drug, blends of Eudragit FS 30D and Eudragit L 30D-55 as coating materials, for the comparison study to confirm the superiority of GPCT during compaction. Eudragit FS 30D content, coating weight gain, tablet hardness and pellet size were chosen as influential factors to investigate the properties and drug release behavior of tablets. The correlation coefficients between the experimental values and the predicted values by artificial neural networks (ANNs) for PCT and GPCT were 0.9474 and 0.9843, respectively, indicating the excellent prediction of ANNs. The similarity factors (f2) for release profiles of GPCT and the corresponding original pellets were higher than those of PCT, suggesting that the excipient layer of granulated pellets absorbed the compressing force and protected the integrity of coating films during compaction. PMID- 24758384 TI - Matrix tablets based on a carrageenan with the modified-release of sodium riboflavin 5'-phosphate. AB - The focus of this work was to produce modified-release monolithic matrix tablets containing sodium riboflavin 5'-phosphate (vitamin B2) as active pharmaceutical ingredient (API). Riboflavin 5'-phosphate is absorbed from the upper gastrointestinal tract by a specific transport mechanism. The aim of this work was the development of modified-release tablets from which most or the entire API can dissolve within 5 h. The dissolution was started in medium pH 1.2 (gastric juice) and finished in medium pH 4.5. The matrix former was iota-carrageenan combined with microcrystalline cellulose (MCC) and lactose in different ratios. Factorial design was used in this work so as to study the effects of the MCC/lactose ratio on the parameters of the tablets, and especially on the dissolution process. The dissolution data were subjected to statistical analysis, and the release profiles were fitted with different models. It was found that the MCC/lactose ratio influenced the quality of the tablets to a high degree. The Korsmeyer-Peppas model proved to characterize the total dissolution profile best, but fitting of the separate sections was also possible with a linear model. PMID- 24758385 TI - Immunohistochemical expression of p63, Ki67 and beta-catenin in canine transitional cell carcinoma and polypoid cystitis of the urinary bladder. AB - Transitional cell carcinoma (TCC) is a urinary bladder tumour associated with high mortality in dogs. In this study, we investigated the feasibility of using p63, Ki67 or beta-catenin as a clinical marker for predicting biological behaviour and prognosis in canine TCC. Expression levels of these proteins in TCC (n = 25), polypoid cystitis (n = 5) and normal urinary bladder (n = 5) were scored after immunohistochemical staining. The staining scores for p63 (P < 0.01) and beta-catenin (P < 0.05) in TCC were significantly lower than those in normal urinary bladder and polypoid cystitis. In contrast, Ki67 (P < 0.01) staining scores in TCC were significantly higher than those in normal urinary bladder and polypoid cystitis. In TCC, low p63 expression was significantly related to the presence of vessel invasion (P < 0.05) and metastasis (P < 0.01) as well as short survival time (P < 0.05). These findings show that p63 could be a reliable marker for predicting prognosis in canine TCC. PMID- 24758386 TI - Development of a folate receptor (FR)-targeted indenoisoquinoline using a pH sensitive N-ethoxybenzylimidazole (NEBI) bifunctional cross-linker. AB - This Communication describes the synthesis and evaluation of a folate-conjugated drug delivery system (DDS) that incorporates an acid-sensitive N ethoxybenzylimidazole (NEBI) bifunctional linker and a novel imidazole-containing indenoisoquinoline. Indenoisoquinolines are a class of TOP1 inhibitors that exhibit broad anticancer activity. Here, we examined whether a DDS that comprised an indenoisoquinoline attached to a folate moiety could help target activity to cancer cells that naturally overexpress the folate receptor (FR), thereby increasing the specificity of these compounds. Evaluation of the DDS revealed an 11-fold increased toxicity in folate receptor (FR)-overexpressing cells compared to in FR-knockdown cancer cells. Microscopy studies demonstrate enhanced internalization and localization of the DDS in acidic lysosomal compartments of FR-overexpressing cells, supporting a receptor-mediated mechanism for uptake and activation. Together with control experiments, the results support that the cytotoxic activity of this DDS is dependent on both the presence of the folate group as well as the presence of the acid-sensitive hydrolyzable group. This work represents the first example of a cell receptor-targeted indenoisoquinoline, which could help pave the way for the use of this class of compounds in anticancer therapy. PMID- 24758387 TI - The role of interferon in the new era of hepatitis C treatments. AB - Interferon has been the backbone of HCV treatment since this agent was first introduced nearly two decades ago. Interferon acts to eradicate HCV via two mechanisms: by directly inhibiting HCV replication via an indirect anti-viral mechanism and by modulating an immune response against hepatocytes infected with HCV. The current treatment of chronic HCV genotype 1 is the combination of peginterferon, ribavirin and a single direct acting anti-viral agent (DAA). Within the next 1-2 years multiple DAA combinations will eradicate and cure HCV at high rates without interferon. The role interferon will play in the next era of HCV treatment will depend upon balancing cost, efficacy and the development of an interferon with a more favorable adverse event profile. PMID- 24758389 TI - Olmsted syndrome in an Iranian boy with a new de novo mutation in TRPV3. AB - Olmsted syndrome (OS) is a rare congenital skin disorder characterized by palmoplantar keratoderma, periorificial hyperkeratotic lesions and alopecia. Constriction of digits, onychodystrophy and pruritus may also occur. Recently, pathogenic heterozygous mutations in TRPV3 were identified, with most cases showing de novo dominant inheritance. We present the clinical and molecular features of OS in a 10-year-old Iranian boy. He had mutilating palmoplantar keratoderma, periorificial keratotic plaques, diffuse alopecia and constriction bands (pseudoainhum), which led to autoamputation of two digits. TRPV3 was sequenced and a new de novo heterozygous missense mutation, c.2076G>C (p.Trp692Cys), was identified. This case illustrates the characteristic clinical features and complications that can present in OS, and further expands the molecular basis of this genodermatosis. PMID- 24758388 TI - Rutin protects against cognitive deficits and brain damage in rats with chronic cerebral hypoperfusion. AB - BACKGROUND AND PURPOSE: Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion. EXPERIMENTAL APPROACH: We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses. KEY RESULTS: BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin. CONCLUSION AND IMPLICATIONS: Our results provide new insights into the pharmacological actions of rutin and suggest that rutin has multi-targeted therapeutical potential on cognitive deficits associated with conditions with chronic cerebral hypoperfusion such as vascular dementia and Alzheimer's disease. PMID- 24758390 TI - Increased serum HMGB1 levels in patients with Henoch-Schonlein purpura. AB - High-mobility group box-1 (HMGB1) has been implicated as a pro-inflammatory cytokine in the pathogenesis of various inflammatory and autoimmune diseases. However, information about HMGB1 in Henoch-Schonlein purpura (HSP) is still unclear. Herein, we investigated the role of HMGB1 in patients with HSP and the pro-inflammatory effects of HMGB1 on human dermal microvascular endothelial cell line (HMEC-1). Serum HMGB1 levels in patients with HSP together with patients with allergic vasculitis (AV) and urticarial vasculitis (UV) were detected by enzyme-linked immunosorbent assay (ELISA). HMEC-1 cells were treated with HMGB1 at concentrations ranging from 4 ng/ml to 100 ng/ml. Serum HMGB1 levels were significantly increased in patients with HSP, AV and UV, when compared with those in control group. Moreover, abundant cytoplasmic expression of HMGB1 was observed in endothelial cells in lesional skin of HSP patients. Using membrane cytokine antibody array, we indicate that HMGB1 markedly induced TNF-alpha and IL-6 release in cultured supernatant. Furthermore, by real-time quantitative PCR and ELISA, the effects of HMGB1 on these cytokines production in HMEC-1 cells were established. Finally, Western blot data revealed that HMGB1 can induce phosphorylation of inhibitor of kappaB-alpha (IkappaBalpha) and the nuclear translocation of nuclear factor-kappaB (NF-kappaB) p65 in HMEC-1 cells. In conclusion, this study provides first observations on the association of HMGB1 with HSP. We suggest that HMGB1 may be an important mediator of endothelial inflammation through the induction of TNF-alpha and IL-6 production and may play a crucial role in the pathogenesis of HSP. PMID- 24758391 TI - Use of dynamic time warping for accurate ECG signal timing characterization. AB - Dynamic time warping techniques have been used to characterize the timing variation of the constituent components of the human electrocardiogram (ECG). Lead II ECG recordings were obtained in 21 subjects, 10 male and 11 female aged between 13-65 years. The fiducial points in each cardiac cycle were identified in the recordings across the range of heart rate from 46-184 beats/min. A set of second order equations in the square root of the cardiac cycle time was obtained to describe the duration each of the constituent components in the ECG signal. The accuracy of the dynamic time warping technique was verified against professionally annotated clinical recordings in the on-line PhysioNetTM database. The equations obtained allow a Lead II ECG signal to be synthesized in which the variation with heart rate of the profile of each in the signal mirrors the true in-vivo behaviour. PMID- 24758393 TI - MRI-PET image fusion based on NSCT transform using local energy and local variance fusion rules. AB - Image fusion means to integrate information from one image to another image. Medical images according to the nature of the images are divided into structural (such as CT and MRI) and functional (such as SPECT, PET). This article fused MRI and PET images and the purpose is adding structural information from MRI to functional information of PET images. The images decomposed with Nonsubsampled Contourlet Transform and then two images were fused with applying fusion rules. The coefficients of the low frequency band are combined by a maximal energy rule and coefficients of the high frequency bands are combined by a maximal variance rule. Finally, visual and quantitative criteria were used to evaluate the fusion result. In visual evaluation the opinion of two radiologists was used and in quantitative evaluation the proposed fusion method was compared with six existing methods and used criteria were entropy, mutual information, discrepancy and overall performance. PMID- 24758392 TI - Development and tests of a paediatric and neonatal immobilizer for ambulance transfers. AB - There are many stretcher models able to adequately achieve the spinal immobilization of adult patients during emergency transports but do not work well with children. A paediatric and neonatal immobilizer has been designed, constructed and tested. It is simple, radio-transparent, able to be adequately fastened to an ambulance, adaptable to a wide range of paediatric patient's size, providing a correct spinal immobilization without an excessive immobilization of the rest of the body, without impairing the aperture of an aerial way or the cardiopulmonary resuscitation (CPR) and without reducing the accessibility of the medical personnel to the paediatric patient. It is able to be adapted to the size and injuries of the patient instead of adapting the position of the patient to the characteristics of the immobilizer. It can also be effectively fastened to the bed of an emergency helicopter, allowing the aerial transport of the paediatric patients. PMID- 24758394 TI - Pre-transplant visualization of combined images for predictive medical analysis. AB - It is sometimes required to shift and/or merge the sampled images for complex perception development in medical and engineering applications. In most cases, for such requirements images are merged at the intensity level. This paper presents a study which shows that intensity level merge is not sufficient enough to analyse certain cases where sharp precision is needed to take a crucial decision. A method has been presented which could be used in precision implant engineering and biological applications like stent placement, where more accurate prediction is required of a combined phenomenon. Accurate merging of intended pixels can be achieved using frequency domain techniques for geometrical and geographical suitability assessment and visualization of post-stenting situation. This paper introduces a technique to merge various images and demonstrates how a surgeon can determine critical midpoint alignment of the stent and visualize the effect of a transplant before actually doing that. PMID- 24758395 TI - Inter-electrode tissue resistance is not affected by tissue oedema when electrically stimulating the lower limb of sepsis patients. AB - ICU patients typically are given large amounts of fluid and often develop oedema. The purpose of this study was to evaluate whether the oedema would change inter electrode resistance and, thus, require a different approach to using non invasive electrical stimulation of nerves to assess muscle force. Inter-electrode tissue resistance in the lower leg was measured by applying a 300 us constant current pulse and measuring the current through and voltage across the stimulating electrodes. The protocol was administered to nine ICU patients with oedema, eight surgical patients without oedema and eight healthy controls. No significant difference in inter-electrode resistance was found between the three groups. For all groups, resistance decreased as stimulation current increased. In conclusion, inter-electrode resistance in ICU patients with severe oedema is the same as the resistance in regular surgical patients and healthy controls. This means that non-invasive nerve stimulation devices do not need to be designed to accommodate different resistances when used with oedema patients; however, surface stimulation does require higher current levels with oedema patients because of the increased distance between the skin surface and the targeted nerve or muscle. PMID- 24758396 TI - Pentoxifylline in heart failure: a meta-analysis of clinical trials. AB - BACKGROUND: Pentoxifylline possess antiinflammatory and rheological properties and has been tested in heart failure (HF). METHODS: A comprehensive search was performed from 1980 until July 2013 in PubMed, to identify randomized controlled trials evaluating pentoxifylline versus placebo in HF, to determine impact on mortality. Search strategy is as follows: "Pentoxifylline" AND "heart" AND "trial". Study selection of six randomized controlled trials evaluating mortality as outcome. Then, we conducted a meta-analysis of randomized controlled trials versus placebo in HF. Determination of Mantel-Haenszel fixed effect and random effect pooled odds ratios for all-cause mortality and corresponding 95% confidence intervals. RESULTS: Data from a total of 221 patients with LVEF <=40% from six randomized controlled trials were included in this analysis. Pentoxifylline 1200 mg per day was administered during 6 months, except in one study (administered during 1 month for severe acute HF). The use of pentoxifylline was not significantly associated with a reduction in mortality in HF in individual studies. The pooled data including 221 patients showed a nearly fourfold reduction in mortality (5.4% vs. 18.3%; OR 0.29; CI 0.12-0.74; P < 0.01) with homogenous results (I2 0%). CONCLUSION: A meta-analysis evaluating pentoxifylline versus placebo in HF suggested a significant nearly fourfold decrease in all-cause mortality in the pentoxifylline group. PMID- 24758397 TI - Chemical control of channel interference in two-photon absorption processes. AB - The two-photon absorption (TPA) process is the simplest and hence the most studied nonlinear optical phenomenon, and various aspects of this process have been explored in the past few decades, experimentally as well as theoretically. Previous investigations have shown that the two-photon (TP) activity of a molecular system can be tuned, and at present, performance-tailored TP active materials are easy to develop by monitoring factors such as length of conjugation, dimensionality of charge-transfer network, strength of donor acceptor groups, polarity of solvents, self-aggregation, H-bonding, and micellar encapsulation to mention but a few. One of the most intriguing phenomena affecting the TP activity of a molecule is channel interference. The phrase "channel interference" implies that if the TP transition from one electronic state to another involves more than one optical pathway or channel, characterized by the corresponding transition dipole moment (TDM) vectors, the channels may interfere with each other depending upon the angles between the TDM vectors and hence can either increase (constructive interference) or decrease (destructive interference) the overall TP activity of a system to a significant extent. This phenomenon was first pointed out by Cronstrand, Luo, and Agren [Chem. Phys. Lett. 2002, 352, 262-269] in two-dimensional systems (i.e., only involving two components of the transition moment vectors). For three-dimensional molecules, an extended version of this idea was required. In order to fill this gap, we developed a generalized model for describing and exploring channel interference, valid for systems of any dimensionality. We have in particular applied it to through-bond (TB) and through-space (TS) charge-transfer systems both in gas phase and in solvents with different polarities. In this Account, we will, in addition to briefly describing the concept of channel interference, discuss two key findings of our recent work: (1) how to control the channel interference by chemical means, and (2) the role of channel interference in the anomalous solvent dependence of certain TP chromophores. For example, we will show that simple structurally induced changes in certain dihedral angles of the well-known betaine dye (TB type) will help fine-tune the constructive channel interference and hence increase the overall TP activity of molecules with this general TP channel structure. Another intriguing result we will discuss is observed for a tweezer trinitrofluorinone complex (TS type) where, on moving from polar to essentially nonpolar solvents, the nature of the channel interference switches from destructive to constructive, leading to a net abnormal solvent dependence of the TP activity of the system. The present Account highlights the usefulness of the channel interference effect and establishes it as a new and unique way of controlling the TP transition probability in different types of three-dimensional molecules. PMID- 24758398 TI - High cardiac background activity limits 99mTc-MIBI radioguided surgery in aortopulmonary window parathyroid adenomas. AB - BACKGROUND: Radioguided surgery using 99m-Technetium-methoxyisobutylisonitrile (99mTc-MIBI) has been recommended for the surgical treatment of mediastinal parathyroid adenomas. However, high myocardial 99mTc-MIBI uptake may limit the feasibility of radioguided surgery in aortopulmonary window parathyroid adenoma. CASE PRESENTATION: Two female patients aged 72 (#1) and 79 years (#2) with primary hyperparathyroidism caused by parathyroid adenomas in the aortopulmonary window were operated by transsternal radioguided surgery. After intravenous injection of 370 MBq 99mTc-MIBI at start of surgery, the maximum radioactive intensity (as counts per second) was measured over several body regions using a gamma probe before and after removal of the parathyroid adenoma. Relative radioactivity was calculated in relation to the measured ex vivo radioactivity of the adenoma, which was set to 1.0. Both patients were cured by uneventful removal of aortopulmonary window parathyroid adenomas of 4400 (#1) and 985 mg (#2). Biochemical cure was documented by intraoperative measurement of parathyroid hormone as well as follow-up examination. Ex vivo radioactivity over the parathyroid adenomas was 196 (#1) and 855 counts per second (#2). Before parathyroidectomy, relative radioactivity over the aortopulmonary window versus the heart was found at 1.3 versus 2.6 (#1) and 1.8 versus 4.8 (#2). After removal of the adenomas, radioactivity within the aortopulmonary window was only slightly reduced. CONCLUSION: High myocardial uptake of 99mTc-MIBI limits the feasibility of radioguided surgery in aortopulmonary parathyroid adenoma. PMID- 24758400 TI - Fear begets function in the 'brown' world of detrital food webs. AB - Theory suggests that predators in detritus-based food webs should negatively influence plants, through direct effects on plant-facilitating detritivores. In a three-level food web of predaceous beetles, earthworms and plants, Zhao et al. (2013) report evidence to the contrary. They found that predators drove positive indirect effects on both plant-facilitating soil properties and above-ground plant biomass and that these positive effects were driven by predator-mediated vertical shifts in detritivore habitat use. Their study reinforces the importance of trait-mediated indirect interactions across both 'green' and 'brown' trophic cascades and emphasizes that understanding the spatial dimension of trophic cascade mechanisms remains a critical research priority. PMID- 24758399 TI - Usefulness of artificial vascular graft for venous reconstruction in liver surgery. AB - BACKGROUND: The purpose of this study was to evaluate the results of hepatectomy with inferior vena cava or hepatic vein resection, followed by vessel reconstruction with an artificial vascular graft. METHODS: From 2000 to 2011, 1,434 patients underwent several types of hepatectomy at our institution. Of these, we reviewed the cases of eight patients (0.56%) who underwent hepatectomy with inferior vena cava or hepatic vein resection and subsequent reconstruction using an expanded polytetrafluoroethylene (PTFE) graft. RESULTS: We resected the inferior vena cava in six patients and the hepatic vein in two patients. All eight patients underwent subsequent reconstruction using an expanded PTFE graft. The median operative time was 443 minutes and the median blood loss was 2,017 mL. The median postoperative hospital stay period was 18.5 days and the in-hospital mortality rate was 0%. Complications occurred in four patients: two patients experienced bile leakage, one experienced a wound infection, and one experienced pleural effusion. The two patients who experienced bile leakage had undergone reoperation on postoperative day 1. No complication with the artificial vascular graft occurred in these eight cases. Histological invasion to the replaced inferior vena cava or hepatic vein was confirmed in four cases. All artificial vascular grafts remained patent during the observation period. CONCLUSIONS: Hepatectomy combined with inferior vena cava or hepatic vein resection, followed by reconstruction with an expanded PTFE graft can be performed safely in selected patients. PMID- 24758401 TI - Decreased L-type calcium current in antral smooth muscle cells of STZ-induced diabetic rats. AB - BACKGROUND: Diabetic gastroparesis (delayed gastric emptying) is associated with antral hypomotility. L-type Ca(2+) channels play an important role in generation of action potentials and activation of contractions. This study was designed to investigate if the function of the L-type Ca(2+) channels of antral circular smooth muscle cells (SMCs) is impaired in streptozotocin (STZ)-induced diabetic rats. METHODS: Eight weeks after the injection of STZ or vehicle, whole-cell patch clamp was used to record Ca(2+) currents, and isometric tension recording was used to measure Ca(2+) influx-induced contractions in circular muscle strips. Solid gastric emptying was measured in diabetic and control rats. Protein expression of Ca(2+) alphalC-subunit in antral smooth muscles was compared between diabetic and control rats. KEY RESULTS: (1) Solid gastric emptying, independent of age or bodyweight, was slower in the diabetic rats, even after acute correction of hyperglycemia. (2) Verapamil, a potent calcium channel blocker, dose dependently reduced solid gastric emptying in normal rats. (3) Current density of L-type Ca(2+) channel at 10 mV in antral circular SMCs was significantly decreased in the diabetic rats (-9.8 +/- 0.7 pA/pF vs -15.9 +/- 1.0 pA/pF in control, p < 0.001). However, protein expression of the Ca(2+) channel in antral muscles did not differ between diabetic and control rats. (4) Contractile responses to 1 and 3 mM [Ca(2+) ] were significantly reduced in the diabetic antral circular muscle strips, indicative of reduced Ca(2+) influx. CONCLUSIONS & INFERENCES: These data suggested that the decreased L-type Ca(2+) current in antral SMCs may contribute to antral hypomotility in STZ-induced diabetic rats. PMID- 24758402 TI - Catheter ablation related mitral valve injury: the importance of early recognition and rescue mitral valve repair. AB - INTRODUCTION: An increasing number of catheter ablations involve the mitral annular region and valve apparatus, increasing the risk of catheter interaction with the mitral valve (MV) complex. We review our experience with catheter ablation-related MV injury resulting in severe mitral regurgitation (MR) to delineate mechanisms of injury and outcomes. METHODS: We searched the Mayo Clinic MV surgical database over a 19-year period (1993-2012) and the electrophysiologic procedures database over a 23-year period (1990-2013) and identified 9 patients with catheter ablation related MV injury requiring clinical intervention. RESULTS: Indications for ablation included atrial fibrillation (AF) [n = 4], ventricular tachycardia (VT) [n = 3], and left-sided accessory pathways [n = 2]. In all 4 AF patients, a circular mapping catheter entrapped in the MV apparatus was responsible for severe MR. In all 3 VT patients, radiofrequency energy delivery led to direct injury to the MV apparatus. In the 2 patients with accessory pathways, both mechanisms were involved (1 per patient). Six patients required surgical intervention (5 MV repair, 1 catheter removal). One patient developed severe functional MR upon successful endovascular catheter disentanglement that improved spontaneously. Two VT patients with persistent severe postablation MR were managed nonsurgically, 1 of whom died 3 months postprocedure. CONCLUSION: Circular mapping catheter entrapment and ablation at the mitral annulus are the most common etiologies of MV injury during catheter ablation. Close surveillance of the MV is needed during such procedures and early surgical repair is important for successful salvage if significant injury occurs. PMID- 24758404 TI - Inhibitory effects of thought substitution in the think/no-think task: evidence from independent cues. AB - When people try not to think about a certain item, they can accomplish this goal by using a thought substitution strategy and think about something else. Research conducted with the think/no-think (TNT) paradigm indicates that such strategy leads subsequently to forgetting the information participants tried not to think about. The present study pursued two goals. First, it investigated the mechanism of forgetting due to thought substitution, contrasting the hypothesis by which forgetting is due to blocking caused by substitutes with the hypothesis that forgetting is due to inhibition (using an independent cue methodology). Second, a boundary condition for forgetting due to thought substitution was examined by creating conditions under which the generation of appropriate substitutes would be impaired. In two experiments, participants completed a TNT task under thought substitution instructions in which either words or pseudo-words were used as original cues and memory was assessed with original and independent cues. The results revealed forgetting in both original and independent cue tests, supporting the inhibitory account of thought substitution, but only when cues were words, and not when they were non-words, pointing to the ineffectiveness of a thought substitution strategy when original cues lack semantic content. PMID- 24758403 TI - Phylogeny and oscillating expression of period and cryptochrome in short and long photoperiods suggest a conserved function in Nasonia vitripennis. AB - Photoperiodism, the ability to respond to seasonal varying day length with suitable life history changes, is a common trait in organisms that live in temperate regions. In most studied organisms, the circadian system appears to be the basis for photoperiodic time measurement. In insects this is still controversial: while some data indicate that the circadian system is causally involved in photoperiodism, others suggest that it may have a marginal or indirect role. Resonance experiments in the parasitic wasp Nasonia vitripennis have revealed a circadian component in photoperiodic time measurement compatible with a mechanism of internal coincidence where a two components oscillator system obtains information from dawn and dusk, respectively. The identity of this oscillator (or oscillators) is still unclear but possible candidates are the oscillating molecules of the auto-regulatory feedback loops in the heart of the circadian system. Here, we show for the first time the circadian oscillation of period and cryptochrome mRNAs in the heads of Nasonia females kept under short and long photoperiods. Period and cryptochrome mRNA levels display a synchronous oscillation in all conditions tested and persist, albeit with reduced amplitude, during the first day in constant light as well as constant darkness. More importantly, the signal for the period and cryptochrome oscillations is set by the light-on signal. These results, together with phylogenetic analyses, indicate that Nasonia's period and cryptochrome display characteristics of homologous genes in other hymenopteran species. PMID- 24758405 TI - Biomechanical and functional variation in rat sciatic nerve following cuff electrode implantation. AB - BACKGROUND: Nerve cuff electrodes are commonly and successfully used for stimulating peripheral nerves. On the other hand, they occasionally induce functional and morphological changes following chronic implantation, for reasons not always clear. We hypothesize that restriction of nerve mobility due to cuff implantation may alter nerve conduction. METHODS: We quantified acute changes in nerve-muscle electrophysiology, using electromyography, and nerve kinematics in anesthetized Sprague Dawley rat sciatic nerves during controlled hindlimb joint movement. We compared electrophysiological and biomechanical response in uncuffed nerves and those secured within a cuff electrode using analysis of variance (ANOVA) and regression analysis. RESULTS: Tethering resulting from cuff implantation resulted in altered nerve strain and a complex biomechanical environment during joint movement. Coincident with biomechanical changes, electromyography revealed significantly increased variability in the response of conduction latency and amplitude in cuffed, but not free, nerves following joint movement. CONCLUSION: Our findings emphasize the importance of the mechanical interface between peripheral nerves and their devices on neurophysiological performance. This work has implications for nerve device design, implantation, and prediction of long-term efficacy. PMID- 24758407 TI - Cocoon-in-web-like superhydrophobic aerogels from hydrophilic polyurea and use in environmental remediation. AB - Polyurea (PUA) develops H-bonding with water and is inherently hydrophilic. The water contact angle on smooth dense PUA derived from an aliphatic triisocyanate and water was measured at theta=69.1+/-0.2 degrees . Nevertheless, texture related superhydrophobic PUA aerogels (theta'=150.2 degrees ) were prepared from the same monomer in one step with no additives, templates, or surfactants via sol gel polymerization carried out in polar, weakly H-bonding acetonitrile. Those materials display a unique nanostructure consisting of micrometer-size spheres distributed randomly and trapped in a nanofiber web of the same polymer. Morphostructurally, as well as in terms of their hydrophobic properties, those PUA aerogels are analogous to well-studied electrospun fiber mats incorporating particle-like defects. PUA aerogels have the advantage of easily scalable synthesis and low cost of the raw materials. Despite large contact angles and small contact areas, water droplets (5 MUL) stick to the aerogels surface when the substrate is turned upside-down. That so-called Petal effect is traced to H bonding at the points of contact between the water droplet and the apexes of the roughness of the aerogel surface. Monoliths are flexible and display oleophilicity in inverse order to their hydrophobicity; oil fills all the available open porosity (94% v/v) of cocoon-in-web like aerogels with bulk density rhob=0.073 g cm(-3); that capacity for oil absorption is >10:1 w/w and translates into ~6:1 w/v relative to state-of-the-art materials (e.g., graphene derived aerogels). Oil soaked monoliths float on water and can be harvested off. PMID- 24758406 TI - The Theobroma cacao B3 domain transcription factor TcLEC2 plays a duel role in control of embryo development and maturation. AB - BACKGROUND: The Arabidopsis thaliana LEC2 gene encodes a B3 domain transcription factor, which plays critical roles during both zygotic and somatic embryogenesis. LEC2 exerts significant impacts on determining embryogenic potential and various metabolic processes through a complicated genetic regulatory network. RESULTS: An ortholog of the Arabidopsis Leafy Cotyledon 2 gene (AtLEC2) was characterized in Theobroma cacao (TcLEC2). TcLEC2 encodes a B3 domain transcription factor preferentially expressed during early and late zygotic embryo development. The expression of TcLEC2 was higher in dedifferentiated cells competent for somatic embryogenesis (embryogenic calli), compared to non-embryogenic calli. Transient overexpression of TcLEC2 in immature zygotic embryos resulted in changes in gene expression profiles and fatty acid composition. Ectopic expression of TcLEC2 in cacao leaves changed the expression levels of several seed related genes. The overexpression of TcLEC2 in cacao explants greatly increased the frequency of regeneration of stably transformed somatic embryos. TcLEC2 overexpressing cotyledon explants exhibited a very high level of embryogenic competency and when cultured on hormone free medium, exhibited an iterative embryogenic chain reaction. CONCLUSIONS: Our study revealed essential roles of TcLEC2 during both zygotic and somatic embryo development. Collectively, our evidence supports the conclusion that TcLEC2 is a functional ortholog of AtLEC2 and that it is involved in similar genetic regulatory networks during cacao somatic embryogenesis. To our knowledge, this is the first detailed report of the functional analysis of a LEC2 ortholog in a species other then Arabidopsis. TcLEC2 could potentially be used as a biomarker for the improvement of the SE process and screen for elite varieties in cacao germplasm. PMID- 24758408 TI - Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. AB - BACKGROUND: Tamoxifen resistance is a major problem in the treatment of estrogen receptor (ER) alpha -positive breast cancer patients. Although the mechanisms behind tamoxifen resistance are still not completely understood, clinical data suggests that increased expression of receptor tyrosine kinases is involved. Here, we studied the estrogen and anti-estrogen sensitivity of human breast cancer MCF7 cells that have a moderate, retroviral-mediated, ectopic expression of epidermal growth factor receptor (MCF7-EGFR). METHODS: Proliferation of MCF7 EGFR and parental cells was induced by 17beta-estradiol (E2), epidermal growth factor (EGF) or a combination of these. Inhibition of proliferation under these conditions was investigated with 4-hydroxy-tamoxifen (TAM) or fulvestrant at 10( 12) to 10(-6) M. Cells were lysed at different time points to determine the phosphorylation status of EGFR, MAPK1/3, AKT and the expression of ERalpha. Knockdown of target genes was established using smartpool siRNAs. Transcriptomics analysis was done 6 hr after stimulation with growth factors using Affymetrix HG U133 PM array plates. RESULTS: While proliferation of parental MCF7 cells could only be induced by E2, proliferation of MCF7-EGFR cells could be induced by either E2 or EGF. Treatment with TAM or fulvestrant did significantly inhibit proliferation of MCF7-EGFR cells stimulated with E2 alone. EGF treatment of E2/TAM treated cells led to a marked cell proliferation thereby overruling the anti-estrogen-mediated inhibition of cell proliferation. Under these conditions, TAM however did still inhibit ERalpha- mediated transcription. While siRNA mediated knock-down of EGFR inhibited the EGF- driven proliferation under TAM/E2/EGF condition, knock down of ERalpha did not. The TAM resistant cell proliferation mediated by the conditional EGFR-signaling may be dependent on the PI3K/Akt pathway but not the MEK/MAPK pathway, since a MEK inhibitor (U0126), did not block the proliferation. Transcriptomic analysis under the various E2/TAM/EGF conditions revealed that E2 and EGF dependent transcription have little overlap and rather operate in a parallel fashion. CONCLUSIONS: Our data indicate that enhanced EGFR-driven signalling is sufficient to overrule the TAM- mediated inhibition of E2-driven cell proliferation. This may have profound implications for the anti-estrogen treatment of ER-positive breast cancers that have increased levels of EGFR. PMID- 24758409 TI - Structure assignment, electronic properties, and magnetism quenching of endohedrally doped neutral silicon clusters, Si(n)Co (n = 10-12). AB - The structures of neutral cobalt-doped silicon clusters have been assigned by a combined experimental and theoretical study. Size-selective infrared spectra of neutral Si(n)Co (n = 10-12) clusters are measured using a tunable IR-UV two-color ionization scheme. The experimental infrared spectra are compared with calculated spectra of low-energy structures predicted at the B3P86 level of theory. It is shown that the Si(n)Co (n = 10-12) clusters have endohedral caged structures, where the silicon frameworks prefer double-layered structures encapsulating the Co atom. Electronic structure analysis indicates that the clusters are stabilized by an ionic interaction between the Co dopant atom and the silicon cage due to the charge transfer from the silicon valence sp orbitals to the cobalt 3d orbitals. Strong hybridization between the Co dopant atom and the silicon host quenches the local magnetic moment on the encapsulated Co atom. PMID- 24758410 TI - Understanding the interface of six-shell cuboctahedral and icosahedral palladium clusters on reduced graphene oxide: experimental and theoretical study. AB - Studies on noble-metal-decorated carbon nanostructures are reported almost on a daily basis, but detailed studies on the nanoscale interactions for well-defined systems are very rare. Here we report a study of reduced graphene oxide (rGOx) homogeneously decorated with palladium (Pd) nanoclusters with well-defined shape and size (2.3 +/- 0.3 nm). The rGOx was modified with benzyl mercaptan (BnSH) to improve the interaction with Pd clusters, and N,N-dimethylformamide was used as solvent and capping agent during the decoration process. The resulting Pd nanoparticles anchored to the rGOx-surface exhibit high crystallinity and are fully consistent with six-shell cuboctahedral and icosahedral clusters containing ~600 Pd atoms, where 45% of these are located at the surface. According to X-ray photoelectron spectroscopy analysis, the Pd clusters exhibit an oxidized surface forming a PdO(x) shell. Given the well-defined experimental system, as verified by electron microscopy data and theoretical simulations, we performed ab initio simulations using 10 functionalized graphenes (with vacancies or pyridine, amine, hydroxyl, carboxyl, or epoxy groups) to understand the adsorption process of BnSH, their further role in the Pd cluster formation, and the electronic properties of the graphene-nanoparticle hybrid system. Both the experimental and theoretical results suggest that Pd clusters interact with functionalized graphene by a sulfur bridge while the remaining Pd surface is oxidized. Our study is of significant importance for all work related to anchoring of nanoparticles on nanocarbon-based supports, which are used in a variety of applications. PMID- 24758412 TI - EGF receptor-targeting peptide conjugate incorporating a near-IR fluorescent dye and a novel 1,4,7-triazacyclononane-based (64)Cu(II) chelator assembled via click chemistry. AB - A new Boc-protected 1,4,7-triazacyclononane (TACN)-based pro-chelator compound featuring a "clickable" azidomethylpyridine pendant has been developed as a building block for the construction of multimodal imaging agents. Conjugation to a model alkyne (propargyl alcohol), followed by deprotection, generates a pentadentate ligand, as confirmed by X-ray crystallographic analysis of the corresponding distorted square-pyramidal Cu(II) complex. The ligand exhibits rapid (64)Cu(II)-binding kinetics (>95% radiochemical yield in <5 min) and a high resistance to demetalation. It may thus prove suitable for use in (64)Cu(II) based in vivo positron emission tomography (PET). The new chelating building block has been applied to the construction of a bimodal (PET/fluorescence) peptide-based imaging probe targeting the epidermal growth factor (EGF) receptor, which is highly overexpressed on the surface of several types of cancer cells. The probe consists of a hexapeptide sequence, Leu-Ala-Arg-Leu-Leu-Thr (designated "D4"), followed by a Cys-beta-Ala-beta-Ala spacer, then a beta homopropargylglycine residue with the TACN-based chelator "clicked" to its side chain. A sulfonated near-infrared (NIR) fluorescent cyanine dye (sulfo-Cy5) was introduced at the N-terminus to study the EGF receptor-binding ability of the probe by laser-fluorescence spectroscopy. Binding was also confirmed by coimmunoprecipitation methods, and an apparent dissociation constant (Kd) of ca. 10 nM was determined from radioactivity-based measurements of probe binding to two EGF receptor-expressing cell lines (FaDu and A431). The probe is shown to be a biased or partial allosteric agonist of the EGF receptor, inducing phosphorylation of Thr669 and Tyr992, but not the Tyr845, Tyr998, Tyr1045, Tyr1068, or Tyr1148 residues of the receptor, in the absence of the orthosteric EGF ligand. Additionally, the probe was found to suppress the EGF-stimulated autophosphorylation of these latter residues, indicating that it is also a noncompetitive antagonist. PMID- 24758379 TI - Metalloproteins containing cytochrome, iron-sulfur, or copper redox centers. PMID- 24758411 TI - Pulmonary arteriovenous malformations after the superior cavopulmonary shunt: mechanisms and clinical implications. AB - Children with functional single ventricle heart disease are commonly palliated down a staged clinical pathway toward a Fontan completion procedure (total cavopulmonary connection). The Fontan physiology is fraught with long-term complications associated with lower body systemic venous hypertension, eventually resulting in significant morbidity and mortality. The bidirectional Glenn shunt or superior cavopulmonary connection (SCPC) is commonly the transitional stage in single ventricle surgical management and provides excellent palliation. Some studies have demonstrated lower morbidity and mortality with the SCPC when compared with the Fontan. Unfortunately the durability of the SCPC is significantly limited by the development of pulmonary arteriovenous malformations (PAVMs) which have been commonly attributed to the absence of hepatic venous blood flow and the lack of pulsatile flow to the affected lungs. Abnormal angiogenesis has been suggested as a final common pathway to PAVM development. Understanding these fundamental mechanisms through the investigation of angiogenic pathways associated with the pathogenesis of PAVMs would help to develop medical therapies that could prevent or reverse this complication following SCPC. Such therapies could improve the longevity of the SCPC, potentially eliminate or significantly postpone the Fontan completion with its associated complications, and improve long-term survival in children with single ventricle disease. PMID- 24758413 TI - Intermittent auscultation of the fetal heart rate during labor: an opportunity for shared decision making. AB - Electronic fetal heart rate monitoring is the most common form of intrapartal fetal assessment in the United States. Intermittent auscultation of the fetal heart rate is an acceptable option for low-risk laboring women, yet it is underutilized in the hospital setting. Several expert organizations have proposed the use of intermittent auscultation as a means of promoting physiologic childbirth. Within a shared decision-making model, the low-risk pregnant woman should be presented with current evidence about options for fetal heart rate assessment during labor. PMID- 24758414 TI - Acquired hypopigmented suprapubic macules. PMID- 24758415 TI - Comparison of structure and organization of cutaneous lipids in a reconstructed skin model and human skin: spectroscopic imaging and chromatographic profiling. AB - The use of animals for scientific research is increasingly restricted by legislation, increasing the demand for human skin models. These constructs present comparable bulk lipid content to human skin. However, their permeability is significantly higher, limiting their applicability as models of barrier function, although the molecular origins of this reduced barrier function remain unclear. This study analyses the stratum corneum (SC) of one such commercially available reconstructed skin model (RSM) compared with human SC by spectroscopic imaging and chromatographic profiling. Total lipid composition was compared by chromatographic analysis (HPLC). Raman spectroscopy was used to evaluate the conformational order, lateral packing and distribution of lipids in the surface and skin/RSM sections. Although HPLC indicates that all SC lipid classes are present, significant differences are observed in ceramide profiles. Raman imaging demonstrated that the RSM lipids are distributed in a non-continuous matrix, providing a better understanding of the limited barrier function. PMID- 24758417 TI - Modulation of endothelial function by Korean red ginseng (Panax ginseng C.A. Meyer) and its components in healthy individuals: a randomized controlled trial. AB - AIMS: Ginseng root and its derivatives remain atop the most widely used medicinal herbs in cardiovascular disease, despite inadequate substantiation of efficacy. We previously reported the potential of Korean red ginseng (KRG) to affect vascular tone by decreasing arterial wave reflection via an unknown mechanism. Given the preclinical link between ginseng intake and vasoactivity related to nitric oxide (NO) production, we sought to directly evaluate the effects of KRG root and its major root components, on an established noninvasive measure of endothelial function. METHODS: In an acute, randomized, placebo-controlled, double-blind, crossover design, 16 healthy participants (9M:7F, age:30 +/- 9y, BMI: 24 kg +/-3 kg/m(2) , systolicBP/diastolicBP: 109 +/- 11/66 +/- 8 mmHg) on four occasions were administered: KRG root (3 g), KRG ginsenosides extract, KRG polysaccharides extract, and cornstarch control. Extracted fractions were delivered at doses bioequivalent to those found in 3 g of KRG. Flow-mediated vasodilatation (FMD) assessment, preceding a brachial blood pressure measurement, was performed at baseline and at 90 and 180 min posttreatment to assess endothelial function. RESULTS: KRG significantly improved FMD posttreatment. Maximal vasodilatation of Delta2.57 +/- 2.8% occurred at 180 min compared with control (Delta-0.83 +/- 2.7%, P = 0.003 for all comparisons). The ginsenoside extract produced a comparable response (Delta1.75 +/- 2.6%), but not the polysaccharide fraction (Delta0.10 +/- 2.7%). Brachial blood pressure remained unchanged for all treatments (P = 0.45). CONCLUSIONS: KRG acutely improved endothelial function in healthy individuals, which appears to be attributable to its ginsenoside containing fraction. Our data confirm preclinical data and support the potential for these compounds as targets for therapeutic strategies in disorders involving endothelial dysfunction. PMID- 24758416 TI - Revisiting CFTR inhibition: a comparative study of CFTRinh -172 and GlyH-101 inhibitors. AB - BACKGROUND AND PURPOSE: For decades, inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have been used as tools to investigate the role and function of CFTR conductance in cystic fibrosis research. In the early 2000s, two new and potent inhibitors of CFTR, CFTRinh -172 and GlyH-101, were described and are now widely used to inhibit specifically CFTR. However, despite some evidence, the effects of both drugs on other types of Cl(-) -conductance have been overlooked. In this context, we explore the specificity and the cellular toxicity of both inhibitors in CFTR-expressing and non-CFTR-expressing cells. EXPERIMENTAL APPROACH: Using patch-clamp technique, we tested the effects of CFTRinh -172 and GlyH-101 inhibitors on three distinct types of Cl(-) currents: the CFTR-like conductance, the volume-sensitive outwardly rectifying Cl(-) conductance (VSORC) and finally the Ca(2+) -dependent Cl(-) conductance (CaCC). We also explored the effect of both inhibitors on cell viability using live/dead and cell proliferation assays in two different cell lines. KEY RESULTS: We confirmed that these two compounds were potent inhibitors of the CFTR-mediated Cl(-) conductance. However,GlyH-101 also inhibited the VSORC conductance and the CaCC at concentrations used to inhibit CFTR. The CFTRinh -172 did not affect the CaCC but did inhibit the VSORC, at concentrations higher than 5 uM. Neither inhibitor (20 uM; 24 h exposure) affected cell viability, but both were cytotoxic at higher concentrations. CONCLUSIONS AND IMPLICATIONS: Both inhibitors affected Cl(-) conductances apart from CFTR. Our results provided insights into their use in mouse models. PMID- 24758418 TI - Recurrent facial keratoacanthoma in a patient with diabetes: a case report. AB - BACKGROUND: Keratoacanthoma is a relatively common low-grade malignancy that originates in the pilosebaceous glands. Pathologically, it closely resembles squamous cell carcinoma. Keratoacanthoma is believed to have a good prognosis; however, it has been reclassified as squamous cell carcinoma, keratoacanthoma type, to reflect the difficulty in histologic differentiation of this lesion as well as its uncommon but potentially aggressive nature. Keratoacanthoma infrequently presents as multiple tumors and may enlarge (5-15 cm), become locally aggressive, and rarely metastasize. CASE PRESENTATION: A 66-year-old Arab male patient with diabetes was referred to the Maxillofacial Surgery Department with a chief complaint of a dome-shaped nodule with a smooth, shiny surface and central crateriform ulceration with a keratin plug in the form of a horn-like projection. Skin papules were present in the right lateral canthal area and extended to the lateral border of the lower eyelid, measuring 1.3 cm. On palpation, the lesion was firm, movable, and tender. The patient had a history of a similar lesion in another area of his face that had spontaneously regressed. CONCLUSION: Histological differentiation between keratoacanthoma and well differentiated squamous cell carcinoma is difficult, particularly when a secondary infection is present. Careful establishment of the correlation among the history, clinical findings, and histopathology is highly indicated to avoid unnecessary surgical intervention. PMID- 24758419 TI - Two cases of thymoma with pulmonary metastasis: a case report. AB - BACKGROUND: Pulmonary metastases of thymomas are relatively rare. We report on two patients who underwent surgery for resection of pulmonary metastases. METHODS AND RESULTS: One patient was a 74-year-old man. A chest CT scan showed a mediastinal mass and a hilar nodule in the left lung. The patient underwent surgical resection of both of these lesions. The histological diagnosis was type A thymoma with intrapulmonary metastasis, classified as stage IVb. He did not receive any adjuvant therapy following the operation because the resection was complete. There has been no evidence of recurrence in four years.The other patient was a 68-year-old man with myasthenia gravis. At the age of 61 years, he underwent extended thymectomy with combined resection of the surrounding involved structures. The histological diagnosis was type B3 thymoma, stage III. Adjuvant radiation (40 Gy) was administered postoperatively; however, a pulmonary nodule occurred seven years following the initial operation (patient age, 68 years). He subsequently underwent right lower lobectomy and a diagnosis of intrapulmonary metastasis of thymoma was made. There has been no evidence of recurrence in two years. CONCLUSIONS: Long-term follow-up is important to detect recurrence in any cases of thymoma. Lung metastases should be operated upon if they appear to be completely resectable and this can achieve long-term survival. PMID- 24758420 TI - Determination of lutein from green tea and green tea by-products using accelerated solvent extraction and UPLC. AB - We aimed to identify the optimum conditions for the extraction of lutein from green tea using accelerated solvent extraction, and achieve improved analytical resolution and sensitivity between lutein and zeaxanthin using an ultra performance liquid chromatography (UPLC) system. The optimized method employed 80% ethanol as the extraction solvent, 160 degrees C as the temperature, 2 static cycles, and 5 min of static time. In the validation of the UPLC method, recovery was found to be in the range approximately 93.73 to 108.79%, with a correlation coefficient of 0.9974 and a relative standard deviation of <9.29% in inter- and intraday precision analyses. Finally, the lutein contents of green tea and green tea by-products were measured as 32.67 +/- 0.70 and 18.18 +/- 0.68 mg/100g dw, respectively. Furthermore, we verified that green tea by-products, which are discarded after producing green tea beverages, might be used as a great resource for massive lutein production. PRACTICAL APPLICATION: We have demonstrated that the common problem of inadequate resolution between lutein and zeaxanthin during carotenoid analyses can be overcome by optimizing the combined techniques of accelerated solvent extraction and ultra performance liquid chromatography (UPLC). UPLC was highly effective for saving time, solvent, and labor, as well as providing better resolution. The results in this study demonstrated that green tea by-products could be used as new sources for industrial lutein production owing to their massive production during the extraction of green tea beverages. PMID- 24758422 TI - Surface roughening of PET films through blend phase coarsening. AB - In this study, a novel method to increase the surface roughness of polyethylene terephthalate (PET) films is proposed. The mechanism of phase coarsening at the surface in extruded thin films of PET blended with low concentrations of polystyrene (PS) was investigated. A small amount of poly(hyroxyl ether) of bisphenol A (phenoxy resin, PKHH) was found to significantly increase the surface roughness due to its effect on the PS-PET interfacial tension. X-ray photoelectron spectroscopy (XPS) results indicated that in the presence of PKHH, PS droplets migrated spontaneously towards the surface of the polymer film. An increased local concentration of PS near the surface took the form of encapsulated droplets. Above the flow temperature of the blend, the local concentration of PS eventually reached a level where a co-continuous morphology occurred, resulting in the instabilities on the surface of the film. The adhesion properties of films with various roughnesses were determined using a pull-off test and found to be significantly increased, which suggested that co-continuous morphology and the coarsening process increased the adhesive properties of the film. PMID- 24758421 TI - Physiological effects of over-expressing compartment-specific components of the protein folding machinery in xylose-fermenting Saccharomyces cerevisiae. AB - BACKGROUND: Efficient utilization of both glucose and xylose is necessary for a competitive ethanol production from lignocellulosic materials. Although many advances have been made in the development of xylose-fermenting strains of Saccharomyces cerevisiae, the productivity remains much lower compared to glucose. Previous transcriptional analyses of recombinant xylose-fermenting strains have mainly focused on central carbon metabolism. Very little attention has been given to other fundamental cellular processes such as the folding of proteins. Analysis of previously measured transcript levels in a recombinant XR/XDH-strain showed a wide down-regulation of genes targeted by the unfolded protein response during xylose fermentation. Under anaerobic conditions the folding of proteins is directly connected with fumarate metabolism and requires two essential enzymes: FADH2-dependent fumarate reductase (FR) and Ero1p. In this study we tested whether these enzymes impair the protein folding process causing the very slow growth of recombinant yeast strains on xylose under anaerobic conditions. RESULTS: Four strains over-expressing the cytosolic (FRD1) or mitochondrial (OSM1) FR genes and ERO1 in different combinations were constructed. The growth and fermentation performance was evaluated in defined medium as well as in a complex medium containing glucose and xylose. Over expression of FRD1, alone or in combination with ERO1, did not have any significant effect on xylose fermentation in any medium used. Over-expression of OSM1, on the other hand, led to a diversion of carbon from glycerol to acetate and a decrease in growth rate by 39% in defined medium and by 25% in complex medium. Combined over-expression of OSM1 and ERO1 led to the same diversion of carbon from glycerol to acetate and had a stronger detrimental effect on the growth in complex medium. CONCLUSIONS: Increasing the activities of the FR enzymes and Ero1p is not sufficient to increase the anaerobic growth on xylose. So additional components of the protein folding mechanism that were identified in transcription analysis of UPR related genes may also be limiting. This includes i) the transcription factor encoded by HAC1 ii) the activity of Pdi1p and iii) the requirement of free FAD during anaerobic growth. PMID- 24758424 TI - Evaluation of a rapid von Willebrand factor activity latex immuno assay for monitoring of patients with von Willebrand disease (VWD) receiving DDAVP or VWF replacement therapy. AB - Haemostatic management of surgery in patients with von Willebrand disease (VWD) includes DDAVP or von Willebrand factor (VWF)-containing concentrates. Although the recommendations are for monitoring by VWF activity assays, it is quite common for clinicians to use factor VIII due usually to longer turnaround times required for VWF ristocetin cofactor assay (VWF:RCo) measurements. The aim of this study was to evaluate use of the rapid HaemosIL VWF activity (VWF:Act) latex immuno assay (LIA) on an automated coagulometer (ACL TOP(TM) 700; Instrumentation Laboratory, Bedford, MA, USA) compared to platelet-based VWF:RCo assays in this setting. One hundred and sixty-seven plasma samples from 42 patients [Type 1 (n = 22), Type 2A (n = 2), Type 2B (n = 3), Type 2M (n = 10), Type 3 (n = 3)] and acquired von Willebrand syndrome (n = 2) with VWD treated with DDAVP or VWF containing concentrates were included in the study. Method comparison and method bias were evaluated by Bland-Altman analysis (BA) and Passing and Bablok regression modelling respectively. BA of baseline samples (n = 39) showed a mean difference of -3.0 (+/-1.96 SD -25.2 to +19.4). Post (treatment) samples (n = 120) were separated into two groups. Group 1 contained samples with VWF:RCo levels 10 to <=175 IU dL(-1) (n = 97) and group 2, samples with VWF:RCo levels >175 IU dL(-1) (n = 23). BA of group 1 postsamples showed a mean difference of +3.4 (+/-1.96 SD -44.6 to +51.5), and the BA of Group 2 samples was -23.9 (+/ 1.96 SD -136.1 to +88.3). In conclusion, use of HaemosIL VWF:Act LIA test on an automated coagulometer is a reproducible and rapid assay that can be used as an alternative test for monitoring VWF replacement therapy, facilitating dose adjustments on a real-time basis. PMID- 24758426 TI - Base free catalyzed enantioselective Michael reaction of bis(phenylsulfonyl)methane to alpha,beta -unsaturated aldehydes under iminium activation. AB - The Michael reaction of bis(phenylsulfonyl)methane with alpha,beta-unsaturated aldehydes in the presence of catalytic amounts of a chiral secondary amine is presented. This transformation proceeds in good to excellent yields furnishing the corresponding Michael adducts in excellent enantioselectivities. Furthermore, other chiral building blocks are accessible from the obtained adducts by carrying out selective manipulation of the functional groups present at their structure, being possible to obtain a wide variety of sulfones with good results. PMID- 24758427 TI - Stereoselective synthesis of polysubstituted piperazines and oxopiperazines. Useful building blocks in medicinal chemistry. AB - Many pharmaceutical agents include piperazines or oxopiperazines as part of their core structures. The presence of substituents on these heterocycles has a significant influence on the biological activity, thus the search for efficient routes to control the substitution at different ring positions might have a crucial impact, especially to promote the use of such scaffolds in SAR studies. Many research groups have been engaged in the stereoselective synthesis of polysubstituted piperazines and oxopiperazines and in the majority of cases the stereochemistry of the final compounds is dependent on the starting material configuration. In the present minireview we have summarized some of the most significant approaches towards the stereoselective synthesis and functionalization of substituted piperazines and oxopiperazines, with a particular focus on our own contributions mainly based on readily available natural amino-acids as "chiral pool" starting materials. An efficient and scalable route to orthogonally protected 2-oxopiperazines has been developed using the corresponding diamines as key intermediates: diastereoselective elaboration of the resulting heterocycles was possible by metalation and reaction with electrophiles, leading to anti 3,5-disubstituted-oxopiperazines, in agreement with the model for a conventional 1,3-asymmetric induction. Both piperazines and tetrahydropyrazines could be prepared via LiAlH4-mediated reduction of 2-oxopiperazines, depending on reaction conditions. Finally, the diastereoselective synthesis of cyclopropane- containing analogs 2,5-diaza bicyclo[4.1.0]heptanes was demonstrated by application of the classic Simmons Smith reaction on enantiomerically enriched dihydro-2H-pyrazines. PMID- 24758425 TI - Electroanatomic mapping and late gadolinium enhancement MRI in a genetic model of arrhythmogenic atrial cardiomyopathy. AB - INTRODUCTION: Although atrial arrhythmias may have genetic causes, very few data are available on evaluation of the arrhythmic substrate in genetic atrial diseases in humans. In this study, we evaluate the nature and evolution of the atrial arrhythmic substrate in a genetic atrial cardiomyopathy. METHODS AND RESULTS: Repeated electroanatomic mapping and tomographic evaluations were used to investigate the evolving arrhythmic substrate in 5 patients with isolated arrhythmogenic atrial cardiomyopathy, caused by Natriuretic Peptide Precursor A (NPPA) gene mutation. Atrial fibrosis was assessed using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). The substrate of atrial tachycardia (AT) and atrial fibrillation (AF) was biatrial dilatation with patchy areas of low voltage and atrial wall scarring (in the right atrium: 68.5% +/- 6.0% and 22.2% +/- 10.2%, respectively). The evolution of the arrhythmic patterns to sinus node disease with atrial standstill (AS) was associated with giant atria with extensive low voltage and atrial scarring areas (in the right atrium: 99.5% +/- 0.7% and 57.5% +/- 33.2%, respectively). LGE-MRI-proven biatrial fibrosis (Utah stage IV) was associated with AS. Atrial conduction was slow and heterogeneous, with lines of conduction blocks. The progressive extension and spatial distribution of the scarring/fibrosis were strictly associated with the different types of arrhythmias. CONCLUSION: The evolution of the amount and distribution of atrial scarring/fibrosis constitutes the structural substrate for the different types of atrial arrhythmias in a pure genetic model of arrhythmogenic atrial cardiomyopathy. PMID- 24758428 TI - Recent syntheses and biological activity of lentiginosine and its analogues. AB - (+)-Lentiginosine, a natural trans-1,2-dihydroxyindolizidine belonging to the class of iminosugars, is a potent inhibitor of amyloglucosidase, and a good inhibitor of Hsp90. The non-natural enantiomer, (-)-lentiginosine, induces apoptosis on tumor cells of different origin and is poorly cytotoxic towards non transformed cells. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review is an update of a previous survey and summarizes the most recent achievements on biological studies as well as total syntheses of lentiginosine and trans-1,2-dihydroxyindolizidine analogues. PMID- 24758429 TI - Enantioselective synthesis of PPAR (peroxisome proliferator-activated receptors) agonists and antagonists. AB - This review deals with stereoselective issues in PPAR ligands some of which are in clinical use for treating certain metabolic disorders. After a short introduction of these nuclear receptor and their agonists, some cases of enantioselective separations are reported. The main part concerns stereoselective synthesis first starting with asymmetric synthesis from chiral precursors followed by what we refer to as "true" enantioselective methods. Some examples are discussed in detail for each particular heading. PMID- 24758430 TI - Asymmetric 1,3-dipolar cycloadditons of stabilized azomethine ylides with nitroalkenes. AB - This review highlights the biological importance of many polysubstituted nitro prolines and -pyrrolidines. Their preparation using asymmetric 1,3-dipolar cycloadditions of azomethine ylides with nitroalkenes using diastereoselective and enantioselective strategies is described remarking the scope and main features of each one. PMID- 24758431 TI - Enantiopure 1,2,3-triazolyl-beta-amino acids via click cycloaddition reaction on racemic alkynyl precursors followed by separation of stereoisomers. AB - In recent years, peptidomimetics have gained enormous importance in drug design aiming to achieve increased drug metabolic stability and higher selectivity. In the field of peptidomimetics, beta-peptides incorporating beta2- and beta3-amino acids (the higher homologs of natural alpha-amino acids) provide a powerful method for the synthesis of peptidomimetics with particular secondary structures. In this regard, 1,2,3-triazole-modified peptidomimetics can act as effective peptide surrogates, and therefore have gained considerable attention. In the present report, 1,4-disubstituted 1,2,3-triazoles attached to beta-amino acids were prepared selectively from the corresponding alkynyl-beta2-amino acids according to Huisgen's copper-catalyzed 1,3-dipolar cycloaddition (CuAAC), under mild conditions and with very high efficiency. Different azide derivatives, including some incorporating alpha-amino acids, were employed in this cycloaddition reaction. The enantiopure compounds were obtained via diastereomeric salt formation with chiral adjuvants, and subsequent separation. PMID- 24758432 TI - Chiral thiazoline and thiazole building blocks for the synthesis of peptide derived natural products. AB - Thiazoline and thiazole heterocycles are privileged motifs found in numerous peptide-derived natural products of biological interest. During the last decades, the synthesis of optically pure building blocks has been addressed by numerous groups, which have developed a plethora of strategies to that end. Efficient and reliable methodologies that are compatible with the intricate and capricious architectures of natural products are a must to further develop their science. Structure confirmation, structure-activity relationship studies and industrial production are fields of paramount importance that require these robust methodologies in order to successfully bring natural products into the clinic. Today's chemist toolbox is assorted with many powerful methods for chiral thiazoline and thiazole synthesis. Ranging from biomimetic approaches to stereoselective alkylations, one is likely to find a suitable method for their needs. PMID- 24758434 TI - Conformational preferences of chiral acyclic homooligomeric beta(2,2)-peptides. AB - alpha-Methylisoserine, a chiral acyclic quaternary beta-amino acid, has been used to mimic secondary structures, when it is incorporated in a homogeneous beta(2,2) dipeptide. In particular, the observed folded conformations in aqueous solution can be regarded as mimics of beta-turn. PMID- 24758433 TI - Enantioselective synthesis in carbohydrate-based drug discovery: imino sugars, alkaloids and macrolide antibiotics. AB - This review is dedicated to enantioselective methods for the generation of carbohydrate-based lead compounds for drug research. Selected examples encompassing imino sugars, bicyclic imino sugar-type alkaloids such as castanospermine, swainsonine, or alexine, as well as macrolide glycosides are covered and discussed. PMID- 24758435 TI - Recent advances on the enantioselective synthesis of C-nucleosides inhibitors of inosine monophosphate dehydrogenase (IMPDH). AB - This review will describe the recent advances in the synthesis of C-nucleosides with inhibitory activity of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the biosynthesis of guanine nucleotides. The review will cover synthetic approaches of structural analogues showing modifications in the furanose ring as well as in the heterocyclic base. Heterocyclic sugar nucleoside analogues in which the furanose ring has been replaced by a different heterocyclic ring including aza analogues, thioanalogues as well as dioxolanyl and isoxazolidinyl analogues are also considered. PMID- 24758436 TI - Enantioselective synthesis in organic and medicinal chemistry. PMID- 24758437 TI - Michael Jackson, Bin Laden and I: functions of positive and negative, public and private flashbulb memories. AB - This study examined the perceived psychosocial functions of flashbulb memories: It compared positive and negative public flashbulb memories (positive: Bin Laden's death, negative: Michael Jackson's death) with private ones (positive: pregnancy, negative: death of a loved one). A sample of n = 389 young and n = 176 middle-aged adults answered canonical category questions used to identify flashbulb memories and rated the personal significance, the psychological temporal distance, and the functions of each memory (i.e., self-continuity, social-boding, directive functions). Hierarchical regressions showed that, in general, private memories were rated more functional than public memories. Positive and negative private memories were comparable in self-continuity and directionality, but the positive private memory more strongly served social functions. In line with the positivity bias in autobiographical memory, positive flashbulb memories felt psychologically closer than negative ones. Finally, middle-aged adults rated their memories as less functional regarding self continuity and social-bonding than young adults. Results are discussed regarding the tripartite model of autobiographical memory functions. PMID- 24758438 TI - Theoretical study of the oxidation mechanisms of naphthalene initiated by hydroxyl radicals: the H abstraction pathway. AB - Reaction mechanisms for the initial stages of naphthalene oxidation at high temperatures (T >= 600 K) have been studied theoretically using density functional theory along with various exchange-correlation functionals, as well as the benchmark CBS-QB3 quantum chemical approach. These stages correspond to the removal of hydrogen atoms by hydroxyl radical and the formation thereby of 1- and 2-naphthyl radicals. Bimolecular kinetic rate constants were estimated by means of transition state theory. The excellent agreement with the available experimental kinetic rate constants demonstrates that a two-step reaction scheme prevails. Comparison with results obtained with density functional theory in conjunction with various exchange-correlation functionals also shows that DFT remains unsuited for quantitative insights into kinetic rate constants. Analysis of the computed structures, bond orders, and free energy profiles demonstrates that the reaction steps involved in the removal of hydrogen atoms by OH radicals satisfy Hammond's principle. Computations of branching ratios also show that these reactions do not exhibit a particularly pronounced site-selectivity. PMID- 24758439 TI - Public health, evidence-based policy-making and the role of epidemiology. PMID- 24758440 TI - Selective oestrogen receptor modulators (SERMs) for prevention of breast cancer. PMID- 24758441 TI - Risk factors associated with tobacco habits among adolescents: a cross-sectional school-based study. AB - BACKGROUND: The increase in tobacco use among adolescents in India is fraught with serious public health implications. The knowledge of factors which influence this habit could assist in tackling this problem. Hence, we aimed to determine factors associated with tobacco use among school students. METHODS: The increase in tobacco use among adolescents in India is fraught with serious public health implications. The knowledge of factors which influence this habit could assist in tackling this problem. Hence, we aimed to determine factors associated with tobacco use among school students. RESULTS: Of the 4786 students, 'current tobacco use' was reported by 197 (4.1%) students; 107 (2.2%) were exclusive smokers, 49 (1%) were exclusive tobacco chewers and 41 (0.9%) used both forms of tobacco. Tobacco use was less frequent among children of white collar than blue collar fathers (p<0.05) and also among children of more educated than less educated mothers (p<0.05). Tobacco use of father, mother, siblings and friends had a significant association with the student's tobacco use. The habits were 10.6-, 6.4-, 3.1- fold higher among students if they bought tobacco for teachers, brothers, father/relatives, respectively. Among tobacco users, 31.5% adopted these habits to refresh themselves, 45.9% preferred smoking outside home and 61% were influenced by actors smoking in films. CONCLUSION: Socioeconomic status, family and peer influence play an important role in students using tobacco. PMID- 24758443 TI - Emotional intelligence, perceived stress and burnout among resident doctors: an assessment of the relationship. AB - BACKGROUND: Burnout is an increasing problem among the medical fraternity, especially resident doctors. We assessed the relationship between burnout, emotional intelligence and perceived stress in an attempt to explore a probable solution. METHODS: Residents in the departments of medicine (n=29) and surgery (n=27) were assessed with a specially designed proforma consisting of participant's profile sheet, Shirom-Melamed Burnout Measure (SMBM), Trait Emotional Intelligence Questionnaire and Perceived Stress Scale (PSS). Correlation and mediational analysis were used to analyse the data. RESULTS: The findings showed a positive correlation of burnout with perceived stress and a negative correlation with trait emotional intelligence (EI). Perceived stress also showed a negative correlation with trait EI. Mediation analysis showed that perceived stress mediates the effect of trait EI on burnout. CONCLUSION: Enhancing EI through training may be an important intervention for targeting burnout. PMID- 24758444 TI - Disseminated histoplasmosis: a comparative study of the clinical features and outcome among immunocompromised and immunocompetent patients. AB - BACKGROUND: Disseminated histoplasmosis is a chronic granulomatous disease caused by the dimorphic fungus, Histoplasma capsulatum. Clinical presentation can vary from the acute pulmonary to the chronic disseminated form. In India, disseminated histoplasmosis often presents with pyrexia of unknown origin with a presentation similar to 'disseminated tuberculosis' involving the adrenal glands and bone marrow. Due to rarity of the disease, data are lacking regarding its clinical presentation and outcome among immunocompromised and immunocompetent patients. METHODS: During January 2000 to December 2010, we identified 37 patients of disseminated histoplasmosis and attempted to characterize the differences between immuno- compromised and immunocompetent patients. Demographic characteristics, clinical presentation, risk factors, laboratory findings, diagnostic yield, treatment received and prognosis were noted and compared between the two groups. RESULTS: Eleven of 37 patients with disseminated histo- plasmosis were immunocompromised and 26 were immuno- competent. Comparison of their clinical features showed a higher frequency of skin lesions in the immunocompromised compared to the immunocompetent group (54.5% v. 11.5%). Pancytopenia and anaemia were more common among the immunocompromised (81.8%) compared to the immunocompetent (46.2%) group. In the immuno- compromised patients, the diagnosis was made most often by bone marrow aspirate and culture (72.7%) compared to the immunocompromised group where the diagnosis was most often obtained by adrenal gland biopsy and fungal cultures (57.7%). The cure rate was significantly higher in the immunocompetent group (73% v. 45%). CONCLUSION: The clinical presentation and outcome of patients with disseminated histoplasmosis differs among immunocompromised and immunocompetent patients. PMID- 24758442 TI - Nature, prevalence and risk factors of alcohol use in an urban slum of Southern India. AB - BACKGROUND: There is a paucity of data on the use of alcohol in urban slums of southern India. METHODS: We screened 2811 men for alcohol use via a household level census in an urban slum in Vellore, Tamil Nadu, and interviewed 220 age- and area-matched pairs of men drinkers and non-drinkers to examine factors associated with alcohol use. Alcohol Use Disorder Identification Test (AUDIT), a standard instrument, was used to assess risk levels of drinking of 354 drinkers. Prevalence rates were calculated using age- adjusted direct standardization. Odds ratios (ORs) of drinking status and higher-risk drinking were calculated using conditional logistic regression and ordinal logistic regression, respectively. RESULTS: Among all men, we estimated that 46.1% consumed alcohol and 31.4% were hazardous drinkers (19% increased-risk, 7.7% high-risk and 4.7% dependent drinkers). Factors associated with alcohol use were: manual labour occupations (OR 2.08); presence of a common mental disorder (OR 1.50) and smoking (OR 2.08); while Muslim religion was protective (OR 0.43). Factors associated with higher risk alcohol use were: being reported as a non-drinker during the census (OR 3.96); presence of a common mental disorder (OR 3.83); smoking (OR 1.78); drinking before legal age of 21 years (OR 2.71); spending more than '100 per day on alcohol (OR 6.17); and mainly drinking Indian-made foreign liquor (OR 5.45). CONCLUSION: High prevalence of hazardous drinking and the factors associated with it suggest the need for population- wide interventions and further investigations to effectively reduce hazardous alcohol use and its harmful effects. PMID- 24758445 TI - Cryptococcoma of the brain in an immunocompetent man. AB - Cryptococcosis is a common opportunistic systemic disease in immunocompromised patients. Pulmonary or brain cryptococcosis is the most common clinical presentation. Immunocompetent patients can also be affected, especially in tropical and subtropical zones where the life cycle of the causal agent, Cryptococcus gattii, is completed. We present a previously healthy man with progressive intracranial hypertension and a right paraventricular mass on CT scan and MRI. Cryptococcus gattii yeasts were isolated from the cerebrospinal fluid. A ventriculoperitoneal shunt was placed and the patient was treated with amphotericin B, fluconazole and dexamethasone. The patient died due to severe intracranial hypertension. PMID- 24758446 TI - Screening for colorectal cancer: do we have a definitive answer? PMID- 24758447 TI - Tumour size and lymph node metastases as prognostic markers of pancreatic cancer: old lessons revisited. PMID- 24758448 TI - Which oral anticoagulant to use: factor Xa inhibitor or thrombin inhibitor? PMID- 24758449 TI - Student performance during the medical course: role of pre-admission eligibility and selection criteria. AB - BACKGROUND: Marks scored in class XII determine the eligibility to apply to a medical course in India; selection is through an entrance test. Some students do poorly in the medical course. We assessed the eligibility and selection criteria as predictors of in-course performance. METHOD: This cross-sectional study included marks in class XII and in each professional examination, and the Delhi University Medical-Dental Entrance Test (DUMET) rank for five batches of medical students. Students were grouped as those who passed professionals in the first attempt and those who did not. Unpaired t-test and Mann-Whitney U test compared class XII marks and mean DUMET scores between the two groups; ROC analysis determined class XII cut-off marks above which no student failed a professional. RESULTS: Students who passed a professional in the first attempt had higher marks in class XII (p?0.001). DUMET rank, however, was comparable for the two groups (p>0.05 each). Above a cut-off of 77.8% (in physics, chemistry and biology) students were significantly likely to never fail any professional. CONCLUSION: Prior academic achievement is a useful measure of in-course performance; however, the current eligibility cut-off results in poor in-course performance by some students. The DUMET is a poor predictor of performance. There is need to reform eligibility and selection criteria to admit students who will do well in the medical course. PMID- 24758450 TI - Awareness to action through multi-channel advocacy for effective tobacco control in India: a case study from Bihar. AB - Developing a synergistic relationship between the government machinery and civil society is crucial for advancing the tobacco control movement in India. With diverse patterns of tobacco use and far reach of the tobacco industry, stringent enforcement mechanisms along with innovative and culturally appropriate advocacy efforts are imperative. In this paper, we evaluate multi- level tobacco control interventions undertaken in the Indian state of Bihar and the subsequent success achieved in strengthening government-non-government partnerships and commitment towards tobacco control in the state. Our experience shows that sustained advocacy at the policy and grassroots levels, along with willingness of the administrative machinery, can present result- oriented tobacco control initiatives at the state and grassroots levels. PMID- 24758451 TI - Factors that influenced the development of health services in India. PMID- 24758452 TI - Addressing language barriers to healthcare in India. AB - In spite of a growing recognition of the importance of doctor-patient communication, the issue of language barriers to healthcare has received very little attention in India. The Indian population speaks over 22 major languages with English used as the lingua franca for biomedicine. Large-scale internal migration has meant that health workers are encountering increasing instances of language discordance within clinical settings. Research done predominantly in the West has shown language discordance to significantly affect access to care, cause problems of comprehension and adherence, and decrease the satisfaction and quality of care. Addressing language barriers to healthcare in India requires a stronger political commitment to providing non-discriminatory health services, especially to vulnerable groups such as illiterate migrant workers. Research will have to address three broad areas: the ways in which language barriers affect health and healthcare, the efficacy of interventions to overcome language barriers, and the costs of language barriers and efforts to overcome them. There is a need to address such barriers in health worker education and clinical practice. Proven strategies such as hiring multilingual healthcare workers, providing language training to health providers, employing in situ translators or using telephone interpretation services will have to be evaluated for their appropriateness to the Indian context. Internet-based initiatives, the proliferation of mobile phones and recent advances in machine translation promise to contribute to the solution. PMID- 24758453 TI - John Angus Black. PMID- 24758454 TI - Natesan Rangabashyam. PMID- 24758455 TI - Letter from Chennai. PMID- 24758456 TI - Letter from Iran. PMID- 24758463 TI - P2Y12 inhibitor in acute coronary syndromes. PMID- 24758464 TI - Entomological investigation of chikungunya outbreaks in a few sites in Tamil Nadu during 2010. PMID- 24758466 TI - Biomedical research: a career option after MBBS. PMID- 24758465 TI - Saying no to NEET is certainly not neat. PMID- 24758467 TI - Serious threat posed by new bird flu. PMID- 24758468 TI - Kidney sales continue in Tamil Nadu. PMID- 24758469 TI - National cancer grid in India established at same time as cervical and breast cancer in the news. PMID- 24758471 TI - Oxidative degradation of quercetin with hydrogen peroxide using continuous-flow kinetic electrospray-ion trap-time-of-flight mass spectrometry. AB - The time-dependent hydrogen peroxide-induced oxidative degradation of aqueous quercetin at pH 7.4 was measured using an in-house-built online continuous-flow device made of concentric capillary tubes, modified to fit a photodiode array (PDA) detector and the inlet of an electrospray ionization-ion trap-time-of flight mass spectrometer (ESI-IT-TOF-MS). As the reaction time was increased, the deprotonated quercetin ion signal, [Q - H](-), decreased, and the formation of degradation product ions was observed. Structures for degradation product ions were proposed using higher order tandem mass spectrometry (up to MS(3)) and high mass accuracy. The determined degradation pathways included oxidation, hydroxylation, cyclic peroxylation, ring cleavage, and small molecule loss. The most intense degradation product observed was 2,4,6-trihydroxybenzoate, which was proposed to be the end point of the peroxylation pathway and the favored degradation pathway under these conditions. This pathway is believed to be the result of nucleophilic attack by hydrogen peroxide at the C2 position of quercetin. This was followed by a cross ring cyclic peroxylation event at C2-C4, which resulted in an intermediate depside that was defined by C-ring-opening due to loss of C3-OH and cleavage of the peroxy bond. Further cleavage of the depside resulted in the 2,4,6-trihydroxybenzoate. A sodiated pseudo adduct of the dimerized trihydroxybenzoate was believed to be induced under electrospray conditions. A computational study was performed to justify the position within the C-ring for both the attack by nucleophilic oxidants and the cyclic peroxylated intermediate structure. PMID- 24758472 TI - Waterbirth fundamentals for clinicians. PMID- 24758474 TI - Transcriptional profiling of human gingival fibroblasts in response to multi species in vitro subgingival biofilms. AB - Periodontitis is an infectious inflammatory disease that destroys the tooth supporting tissues. It is initiated by complex subgingival biofilms, triggering an inflammatory response by the juxtaposed gingival tissue. The range of transcriptional events initiated in the gingiva following biofilm challenge is not fully elucidated. By employing gene microarray technology, this study aimed to characterize the overall transcriptional changes (more than two-fold regulation) of cultured human gingival fibroblasts in response to a 10-species in vitro subgingival biofilm model (BF), over a challenge period of 6 h. The relative involvement of the three 'red complex' species in these transcriptional events was evaluated by omitting these species from the biofilm composition (BF RC). When compared with the unchallenged control, challenge with BF and BF-RC differentially regulated 386 and 428 genes, respectively, with an overlap of 52 75%. Interestingly, the expression of only three genes was significantly different between the BF and BF-RC challenged groups. There was also a strong overlap of the affected signalling pathways and gene ontology processes. These signalling pathways involved primarily the immune response, and included toll like receptors, interleukin-1, interleukin-17 and heat-shock proteins 60 and 70. In conclusion, subgingival biofilms elicited a large number of transcriptional changes in gingival fibroblasts, while the presence of the 'red complex' in the biofilm did not yield any substantial differences. These findings show a uniform 'non-specific' transcriptional response of host cells to subgingival biofilms, and denote that redundancies may exist in the virulence properties of individual bacterial species within a polymicrobial biofilm community. PMID- 24758476 TI - Understanding. PMID- 24758475 TI - Pharmacological characterization of tachykinin tetrabranched derivatives. AB - BACKGROUND AND PURPOSE: Peptide welding technology (PWT) is a novel chemical strategy that allows the synthesis of multibranched peptides with high yield, purity and reproducibility. Using this technique, we have synthesized and pharmacologically characterized the tetrabranched derivatives of the tachykinins, substance P (SP), neurokinin A (NKA) and B (NKB). EXPERIMENTAL APPROACH: The following in vitro assays were used: calcium mobilization in cells expressing human recombinant NK receptors, BRET studies of G-protein - NK1 receptor interaction, guinea pig ileum and rat urinary bladder bioassays. Nociceptive behavioural response experiments were performed in mice following intrathecal injection of PWT2-SP. KEY RESULTS: In calcium mobilization studies, PWT tachykinin derivatives behaved as full agonists at NK receptors with a selectivity profile similar to that of the natural peptides. NK receptor antagonists display similar potency values when tested against PWT2 derivatives and natural peptides. In BRET and bioassay experiments PWT2-SP mimicked the effects of SP with similar potency, maximal effects and sensitivity to aprepitant. After intrathecal administration in mice, PWT2-SP mimicked the nociceptive effects of SP, but with higher potency and a longer-lasting action. Aprepitant counteracted the effects of PWT2-SP in vivo. CONCLUSIONS AND IMPLICATIONS: The present study has shown that the PWT technology can be successfully applied to the peptide sequence of tachykinins to generate tetrabranched derivatives characterized with a pharmacological profile similar to the native peptides. In vivo, PWT2-SP displayed higher potency and a marked prolongation of action, compared with SP. PMID- 24758477 TI - Assessing urology and nephrology research activity in Arab countries using ISI web of science bibliometric database. AB - BACKGROUND: Bibliometric analysis is increasingly being used for research assessment. The main objective of this study was to assess research output in Urology and Nephrology subject from the Arab countries. Original scientific articles or reviews published from the 21 Arab countries in "Urology and Nephrology" subject were screened using the ISI Web of Science database. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analyzing the annual productivity, names of journals, citations; top 10 active institution and authors as well as country contribution to Urology and Nephrology research. RESULTS: Three thousand and seventy six documents in "urology and nephrology" subject category were retrieved from 104 journals. This represents 1.4% of the global research output in "urology and nephrology". Four hundred and two documents (12.66%) were published in Annales D Urologie Journal. The h-index of the retrieved documents was 57. The total number of citations, at the time of data analysis, was 30401 with an average citation of 9.57 per document. Egypt, with a total publication of 1284 (40.43%) ranked first among the Arab countries in "urology and nephrology" subject category. Mansoura University in Egypt was the most productive institution with a total of 561 (15.33%) documents. Arab researchers collaborated most with researchers from the United States of America (226; 7.12%) in urology and nephrology research. CONCLUSION: The present data reveals a good contribution of some Arab countries to the field of "urology and nephrology". More efforts are needed by some other Arab countries to bridge the gap in urology and nephrology research. Overall, the quality of urology/nephrology research is considered relatively high as measured by h-index. Cooperation in urology/nephrology research should be encouraged in the Arab world to bridge the gap with that from developed countries. PMID- 24758478 TI - Coffee rings as low-resource diagnostics: detection of the malaria biomarker Plasmodium falciparum histidine-rich protein-II using a surface-coupled ring of Ni(II)NTA gold-plated polystyrene particles. AB - We report a novel, low-resource malaria diagnostic platform inspired by the coffee ring phenomenon, selective for Plasmodium falciparum histidine-rich protein-II (PfHRP-II), a biomarker indicative of the P. falciparum parasite strain. In this diagnostic design, a recombinant HRP-II (rcHRP-II) biomarker is sandwiched between 1 MUm Ni(II)nitrilotriacetic acid (NTA) gold-plated polystyrene microspheres (AuPS) and Ni(II)NTA-functionalized glass. After rcHRP II malaria biomarkers had reacted with Ni(II)NTA-functionalized particles, a 1 MUL volume of the particle-protein conjugate solution is deposited onto a functionalized glass slide. Drop evaporation produces the radial flow characteristic of coffee ring formation, and particle-protein conjugates are transported toward the drop edge, where, in the presence of rcHRP-II, particles bind to the Ni(II)NTA-functionalized glass surface. After evaporation, a wash with deionized water removes nonspecifically bound materials while maintaining the integrity of the surface-coupled ring produced by the presence of the protein biomarker. The dynamic range of this design was found to span 3 orders of magnitude, and rings are visible with the naked eye at protein concentrations as low as 10 pM, 1 order of magnitude below the 100 pM PfHRP-II threshold recommended by the World Health Organization. Key enabling features of this design are the inert and robust gold nanoshell to reduce nonspecific interactions on the particle surface, inclusion of a water wash step after drop evaporation to reduce nonspecific binding to the glass, a large diameter particle to project a large two-dimensional viewable area after ring formation, and a low particle density to favor radial flow toward the drop edge and reduce vertical settling to the glass surface in the center of the drop. This robust, antibody-free assay offers a simple user interface and clinically relevant limits of biomarker detection, two critical features required for low-resource malaria detection. PMID- 24758479 TI - Solid fermentation of wheat bran for hydrolytic enzymes production and saccharification content by a local isolate Bacillus megatherium. AB - BACK GROUND: For enzyme production, the costs of solid state fermentation (SSF) techniques were lower and the production higher than submerged cultures. A large number of fungal species was known to grow well on moist substrates, whereas many bacteria were unable to grow under this condition. Therefore, the aim of this study was to isolate a highly efficient strain of Bacillus sp utilizing wheat bran in SSF and optimizing the enzyme production and soluble carbohydrates. RESULTS: A local strain Bacillus megatherium was isolated from dung sheep. The maximum production of pectinase, xylanase and alpha-amylase, and saccharification content (total soluble carbohydrates and reducing sugars) were obtained by application of the B. megatherium in SSF using wheat bran as compared to grasses, palm leaves and date seeds. All enzymes and saccharification content exhibited their maximum production during 12-24 h, at the range of 40-80% moisture content of wheat bran, temperature 37-45 degrees C and pH 5-8. An ascending repression of pectinase production was observed by carbon supplements of lactose, glucose, maltose, sucrose and starch, respectively. All carbon supplements improved the production of xylanase and alpha-amylase, except of lactose decreased alpha amylase production. A little increase in the yield of total reducing sugars was detected for all carbon supplements. Among the nitrogen sources, yeast extract induced a significant repression to all enzyme productivity. Sodium nitrate, urea and ammonium chloride enhanced the production of xylanase, alpha-amylase and pectinase, respectively. Yeast extract, urea, ammonium sulphate and ammonium chloride enhanced the productivity of reducing sugars. CONCLUSIONS: The optimization of enzyme production and sccharification content by B. megatherium in SSF required only adjustment of incubation period and temperature, moisture content and initial pH. Wheat bran supplied enough nutrients without any need for addition of supplements of carbon and nitrogen sources. PMID- 24758480 TI - A model system to analyse the ability of human keratinocytes to form hair follicles. AB - Earlier studies showed that dermal cells lose trichogenic capacity with passage, but studies on the effect of keratinocyte passage on human hair follicle neogenesis and graft quality have been hampered by the lack of a suitable model system. We recently documented human hair follicle neogenesis in grafted dermal epidermal composites, and in the present study, we determined the effects of keratinocyte passage on hair follicle neogenesis. Dermal equivalents were made with cultured human dermal papilla cells and were overlaid with either primary or passaged human keratinocytes to form dermal-epidermal composites; these were then grafted onto immunodeficient mice. Superior hair follicle neogenesis was observed using early keratinocyte cultures. Characteristics such as formation of hair shafts and sebaceous glands, presence of hair follicles with features of anagen or telogen follicles, and reproducible hair and skin function parameters make this model a tool to study human hair follicle neogenesis and development. PMID- 24758481 TI - Improvement in quality of life impairment followed by relapse with 6-monthly periodic administration of omalizumab for severe treatment-refractory chronic urticaria and urticarial vasculitis. PMID- 24758482 TI - Development of a scale to assess cancer stigma in the non-patient population. AB - BACKGROUND: Illness-related stigma has attracted considerable research interest, but few studies have specifically examined stigmatisation of cancer in the non patient population. The present study developed and validated a Cancer Stigma Scale (CASS) for use in the general population. METHODS: An item pool was developed on the basis of previous research into illness-related stigma in the general population and patients with cancer. Two studies were carried out. The first study used Exploratory factor analysis to explore the structure of items in a sample of 462 postgraduate students recruited through a London university. The second study used Confirmatory factor analysis to confirm the structure among 238 adults recruited through an online market research panel. Internal reliability, test-retest reliability and construct validity were also assessed. RESULTS: Exploratory factor analysis suggested six subscales, representing: Awkwardness, Severity, Avoidance, Policy Opposition, Personal Responsibility and Financial Discrimination. Confirmatory factor analysis confirmed this structure with a 25 item scale. All subscales showed adequate to good internal and test-retest reliability in both samples. Construct validity was also good, with mean scores for each subscale varying in the expected directions by age, gender, experience of cancer, awareness of lifestyle risk factors for cancer, and social desirability. Means for the subscales were consistent across the two samples. CONCLUSIONS: These findings highlight the complexity of cancer stigma and provide the Cancer Stigma Scale (CASS) which can be used to compare populations, types of cancer and evaluate the effects of interventions designed to reduce cancer stigma in non-patient populations. PMID- 24758483 TI - Discrepancy in von Willebrand factor activity determined by ristocetin cofactor and immunotubidometric assays. PMID- 24758485 TI - The possible role of antimicrobial proteins in obesity-associated immunologic alterations. AB - Currently, obesity-associated metabolic disturbances are envisioned as chronic inflammatory processes, characterized by activation of both innate and adaptive immunity. Although the features of chronic inflammation in obese subjects are clearly defined, the signals and mechanisms that trigger chronic inflammation are not well understood. Recent studies suggest an imbalance in circulating antimicrobial proteins as a possible cause of obesity-associated metabolic disturbances and insulin resistance. This imbalance promotes a relative failure in the capacity of buffering external insults and might cause the onset of chronic inflammation and immunologic alterations in obesity. Here, we review the current literature on the possible role of circulating antimicrobial proteins in obesity-associated immunologic alterations. PMID- 24758484 TI - Clinical evaluation of cetuximab combined with an S-1 and oxaliplatin regimen for Chinese patients with advanced gastric cancer. AB - BACKGROUND: The prognosis of patients with advanced gastric cancer is poor. The goal of this study was to evaluate the efficacy and safety of combination therapy of cetuximab and S-1 combined with oxaliplatin (SOX) in Chinese patients with advanced gastric cancer. METHODS: For patients in the experimental group (cetuximab in combination with SOX (Ce-SOX), 30 patients), once-weekly cetuximab (400 mg/m2 at the first infusion then 250 mg/m2 every week) was administered. For patients in both the control (SOX alone, 26 patients) and experimental groups, oxaliplatin (100 mg/m2) was administered intravenously on day 1, while S-1 (80 mg/m2/day) was given orally twice daily for 14 days. The endpoints of this study included progression-free survival, response rate, and disease-control rate. RESULTS: There was no statistically significant difference in response rate between the Ce-SOX and SOX groups (54.8% versus 44%, P=0.225). The difference in disease-control rate was also statistically insignificant between the two groups (87.1% versus 76%, P=0.162). Median progression-free survival in the Ce-SOX group was significantly higher than that in the SOX group (12.8 versus 10.1 months, P=0.007). The median overall survival of the Ce-SOX group and SOX group was 14.0 and 12.2 months, respectively (P=0.043). The one-year survival rate for the Ce SOX group was 57% compared to 40% in the SOX group. There was no statistical difference in the grade 3 or 4 adverse effects between the two groups. CONCLUSIONS: These findings suggest that the cetuximab combined with SOX regimen is feasible and shows promising efficacy with tolerable adverse effects in Chinese patients with advanced gastric cancer. PMID- 24758486 TI - Lozenges as delivery system for upper respiratory catarrh medication. AB - Lozenges, the small medicated candies that dissolve slowly in the mouth have always been a favoured delivery system, particularly for drugs meant for relieving sore throats and cold symptoms. This predilection can be attributed mainly to their ability to keep the naso-pharyngeal mucosa moist, enhance the swallowing reflex and provide longer contact time of the drug with the naso pharyngeal mucosa. A number of innovative technologies have been developed to improve the conventional forms of lozenges i.e. hard candies and compressed tablets. These include the use of novel ingredients/ techniques to enhance taste, reduce calorie content, facilitate quick manufacture and modify the drug release characteristics. Though used extensively for delivery of all kinds of medications for upper respiratory tract disorders, lozenges remain one of the least researched delivery systems. This article reviews various aspects of lozenges as a delivery system. The rationale behind the use of lozenges as the most favoured dosage form for delivery of anti-tussive substances is presented. Delving deeper, various anti-tussive substances that have been delivered as the lozenges including the patents thereof, are also discussed briefly along with the innovative approaches that have been utilised for their formulation improvements. PMID- 24758487 TI - An overview of recent patents on nanosuspension. AB - Pharmaceutical scientists involved in drug discovery and drug development are facing serious problems with newer poorly water soluble drugs with respect to their dissolution and bioavailability. Reducing the particle size of active pharmaceutical ingredient has been an efficient and reliable method for improving the bioavailability of insoluble drugs. Nanosuspension has emerged as an efficient and promising strategy for delivery of insoluble drugs due to its unique advantages such as ease of modification, process flexibility, targeting capabilities, altered pharmacokinetic profile leading to safety and efficacy. These unique features of nanosuspension have enabled its use in various dosage forms, including specialized delivery systems such as oral, parenteral, peroral, ocular and pulmonary routes. Currently, efforts are being directed to extend their applications in site-specific drug delivery. Large numbers of products based on nanosuspension are in the market and few are under clinical trials. The commercialization potential of nanosuspension based formulation for oral route is well established and products for other routes will enter the market within short span. Among the various techniques available, only wet milling technique has been successfully used for commercial production of nanosuspension. Nanosuspension based patents have extensive potential of reaching faster in the market as compared to other nanotechnology based formulations. This review covers various aspects of techniques of preparation, route of administration and commercialization of nanosuspension with main focus on the recent patents granted in the field. PMID- 24758488 TI - Degradation of endogenous and exogenous genes of genetically modified rice with Cry1Ab during food processing. AB - In order to assess the degradation of endogenous and exogenous genes during food processing, genetically modified rice with Cry1Ab was used as raw material to produce 4 processed foods: steamed rice, rice noodles, rice crackers, and sweet rice wine. The results showed various processing procedures caused different degrees of degradation of both endogenous and exogenous genes. During the processing of steamed rice and rice noodles, the procedures were so mild that only genes larger than 1500 bp were degraded, and no degradation of NOS terminator and Hpt gene was detected. For rice crackers, frying was the most severe procedure, followed by microwaving, baking, boiling, 1st drying, and 2nd drying. For sweet rice wine, fermentation had more impact on degradation of genes than the other processing procedures. All procedures in this study did not lead to degradation of genes to below 200 bp, except for NOS terminator. In the case of stability of the genes studied during processing of rice crackers and sweet rice wine, SPS gene was the most, followed by the Cry1Ab gene, Hpt gene, Pubi promoter, and NOS terminator. PRACTICAL APPLICATION: In our study, we gained some information about the degradation of endogenous and exogenous genes during 4 foods processing, compared the different stabilities between endogenous and exogenous genes, and analyzed different effects of procedure on degradation of genes. In addition, the fragments of endogenous and exogenous genes about 200 bp could be detected in final products, except NOS terminator. As a result, we provided some base information about risk assessment of genetically modified (GM) food and appropriate length of fragment to detect GM component in processed foods. PMID- 24758490 TI - Effect of particle size on salt-induced diffusiophoresis compared to Brownian mobility. AB - For ternary polymer-salt-water systems at low polymer concentration (0.5%, w/w), we have experimentally investigated the effect of polymer size on polymer diffusiophoresis (i.e., polymer migration induced by a salt concentration gradient) and salt osmotic diffusion (i.e., salt migration induced by a polymer concentration gradient). Specifically, Rayleigh interferometry was employed to measure ternary diffusion coefficients for aqueous solutions of poly(ethylene glycol) (PEG) and KCl at 25 degrees C. Our investigation focused on four polymer molecular masses (from 10 to 100 kg mol(-1)) and two salt concentrations (0.25 and 0.50 M). To describe and examine our experimental results, we introduced a normalized diffusiophoresis coefficient as the ratio of polymer diffusiophoresis to polymer Brownian mobility. This coefficient was found to increase with polymer molecular mass, thereby demonstrating that the relative importance of polymer diffusiophoresis compared to its intrinsic Brownian mobility increases with particle size. The observed behavior was linked to preferential hydration (water thermodynamic excess) and hydration (bound water) of the macromolecule. The ratio of salt osmotic diffusion to binary salt-water diffusion approximately describes the nonuniform spatial distribution of salt along a static polymer concentration gradient at equilibrium. The significance of polymer diffusiophoresis, especially at high PEG molecular mass, was examined by considering a steady-state diffusion problem showing that salt concentration gradients can produce large enhancements and depletions of polymer concentration. This work is valuable for understanding and modeling the effect of salt concentration gradients on diffusion-based transport of polymers with applications to interfacial processes. PMID- 24758491 TI - Enhancement predicting accuracy for elastin-like polypeptides temperature transition by back propagation neural network. AB - Elastin-like polypeptides (ELPs) have been widely used to promote the development of a variety of smart biomaterials. Transition temperature is a key attribute of ELPs central to ELPs researches. Therefore, it is essential to establish predictive models of transition temperature that are both computationally efficient and reliable by employing simple parameters. Back propagation neural network (BPNN), a powerful feed-forward algorithm designed to solve problems with overwhelming complexity, has been successfully used in non-linear predictor model. In this study, two pH-sensitive ELPs were expressed, purified and determined for temperature transition across a range of pH. The pH, concentration and molecular weight (MW) as well as isoelectric point (PI) and pseudo amino acid (PseAA) of these two ELPs were adopted as input parameters. Support vector machine (SVM) and back propagation neural network (BPNN) were performed respectively. We selected Lamda (lambda) value by training set and evaluated predictor model by jackknife test that combined with Uniform Design (UD). According to the results of BPNN and SVM, whose mean absolute error (MAE) of BPNN model jackknife test were 4.80 and 4.95 respectively, the predictive ability of BPNN is a minor improvement over SVM. Applying Mackay's data, MAE of BPNN jackknife test was 2.02, while the MAE between experimental and predicted transition temperature was 2.30 in Mackay's predictor model. Compared with Mackay predictor model, the enhancement in the accuracy indicates that the proposed BPNN method could play a complementary role to predict ELPs transition temperature. PMID- 24758492 TI - Effectiveness of an educational intervention of physiotherapy in parents of children with haemophilia. AB - Haemophilia is a haematological disorder with an orthopaedic outcome. It requires not only medical but rather comprehensive care from infancy. The aim of this study was to assess the effectiveness of an educational intervention of Physiotherapy in parents of children with haemophilia under 4 years old. This is a non-randomized clinical trial, in which 22 parents participated children's with haemophilia under 4 years old. Half of them received an educational intervention of Physiotherapy. At the beginning and end of the study, a psychologist blinded to the assignment of subjects to each of the study groups, assessed the perceived quality of life, anxiety, perceived stress and family functioning of parents. A significant improvement was observed in the variables of perceived stress and family functioning of parents in the experimental group. The realization of an educational intervention in parents of children with haemophilia under 4 years old is effective. It reduces the stressors perceived by the parents and improves family cohesion and adaptability, as a consequence of the disease. It is necessary to carry out studies with follow-up periods to assess the effectiveness of educational programs of Physiotherapy for long term. PMID- 24758489 TI - Biokinetics of nanoparticles and susceptibility to particulate exposure in a murine model of cystic fibrosis. AB - BACKGROUND: Persons with cystic fibrosis (CF) are at-risk for health effects from ambient air pollution but little is known about the interaction of nanoparticles (NP) with CF lungs. Here we study the distribution of inhaled NP in a murine CF model and aim to reveal mechanisms contributing to adverse effects of inhaled particles in susceptible populations. METHODS: Chloride channel defective CftrTgH (neoim) Hgu mice were used to analyze lung function, lung distribution and whole body biokinetics of inhaled NP, and inflammatory responses after intratracheal administration of NP. Distribution of 20-nm titanium dioxide NP in lungs was assessed on ultrathin sections immediately and 24 h after a one-hour NP inhalation. NP biokinetics was deduced from total and regional lung deposition and from whole body translocation of inhaled 30-nm iridium NP within 24 h after aerosol inhalation. Inflammatory responses were assessed within 7 days after carbon NP instillation. RESULTS: Cftr mutant females had moderately reduced lung compliance and slightly increased airway resistance compared to wild type mice. We found no genotype dependent differences in total, regional and head deposition or in secondary-organ translocation of inhaled iridium NP. Titanium dioxide inhalation resulted in higher NP uptake by alveolar epithelial cells in Cftr mutants. Instillation of carbon NP induced a comparable acute and transient inflammatory response in both genotypes. The twofold increase of bronchoalveolar lavage (BAL) neutrophils in Cftr mutant compared to wild type mice at day 3 but not at days 1 and 7, indicated an impaired capacity in inflammation resolution in Cftr mutants. Concomitant to the delayed decline of neutrophils, BAL granulocyte colony stimulating factor was augmented in Cftr mutant mice. Anti-inflammatory 15 hydroxyeicosatetraenoic acid was generally significantly lower in BAL of Cftr mutant than in wild type mice. CONCLUSIONS: Despite lacking alterations in lung deposition and biokinetics of inhaled NP, and absence of significant differences in lung function, higher uptake of NP by alveolar epithelial cells and prolonged, acute inflammatory responses to NP exposure indicate a moderately increased susceptibility of lungs to adverse effects of inhaled NP in Cftr mutant mice and provides potential mechanisms for the increased susceptibility of CF patients to air pollution. PMID- 24758493 TI - Epstein-Barr virus-positive diffuse large B-cell lymphoma in an elderly patient. AB - Epstein-Barr virus-positive (EBV) diffuse large B-cell lymphoma (DLCBL) of the elderly is a newly described lymphoproliferative disorder that arises in elderly patients without a predisposing immunodeficiency. Clinical features at presentation may include lymphadenopathy, B-symptoms and extranodal involvement. The main sites of extranodal involvement are the skin, lung, tonsil and stomach. Histopathological findings include atypical large lymphoid cells with variable amounts of reactive cells, such as small lymphocytes, plasma cells and histiocytes. The neoplastic cells are positive for CD20, and in situ hybridization for EBV-encoded RNA is positive in the majority of neoplastic cells. We present a new case of EBV-positive DLBCL in an 85-year-old man, who presented to our clinic with a 2-month history of asymptomatic cutaneous lesions involving his face and scalp. PMID- 24758494 TI - Observational evidence and strength of evidence domains: case examples. AB - BACKGROUND: Systematic reviews of healthcare interventions most often focus on randomized controlled trials (RCTs). However, certain circumstances warrant consideration of observational evidence, and such studies are increasingly being included as evidence in systematic reviews. METHODS: To illustrate the use of observational evidence, we present case examples of systematic reviews in which observational evidence was considered as well as case examples of individual observational studies, and how they demonstrate various strength of evidence domains in accordance with current Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) methods guidance. RESULTS: In the presented examples, observational evidence is used when RCTs are infeasible or raise ethical concerns, lack generalizability, or provide insufficient data. Individual study case examples highlight how observational evidence may fulfill required strength of evidence domains, such as study limitations (reduced risk of selection, detection, performance, and attrition); directness; consistency; precision; and reporting bias (publication, selective outcome reporting, and selective analysis reporting), as well as additional domains of dose-response association, plausible confounding that would decrease the observed effect, and strength of association (magnitude of effect). CONCLUSIONS: The cases highlighted in this paper demonstrate how observational studies may provide moderate to (rarely) high strength evidence in systematic reviews. PMID- 24758495 TI - Protein coronas on gold nanorods passivated with amphiphilic ligands affect cytotoxicity and cellular response to penicillin/streptomycin. AB - We probe how amphiphilic ligands (ALs) of four different types affect the formation of protein coronas on gold nanorods (NRs) and their impact on cellular response. NRs coated with cetyltrimethylammonium bromide were ligand exchanged with polyoxyethylene[10]cetyl ether, oligofectamine, and phosphatidylserine (PS). Protein coronas from equine serum (ES) were formed on these NR-ALs, and their colloidal stability, as well as cell uptake, proliferation, oxidative stress, and gene expression, were examined. We find that the protein corona that forms and its colloidal stability are affected by AL type and that the cellular response to these NR-AL-coronas (NR-AL-ES) is both ligand and corona dependent. We also find that the presence of common cell culture supplement penicillin/streptomycin can impact the colloidal stability and cellular response of NR-AL and NR-AL-ES, showing that the cell response is not necessarily inert to pen/strep when in the presence of nanoparticles. Although the protein corona is what the cells see, the underlying surface ligands evidently play an important role in shaping and defining the physical characteristics of the corona, which ultimately impacts the cellular response. Further, the results of this study suggest that the cellular behavior toward NR-AL is mediated by not only the type of AL and the protein corona it forms but also its resulting colloidal stability and interaction with cell culture supplements. PMID- 24758496 TI - Organocatalytic stereoselective synthesis of acyclic gamma-nitrothioesters with all-carbon quaternary stereogenic centers. AB - A method for the stereoselective synthesis of acyclic thioesters bearing adjacent quaternary and tertiary stereogenic centers under mild organocatalytic conditions was developed. alpha-Substituted monothiomalonates (MTMs) were used as thioester enolate equivalents. They reacted cleanly with nitroolefins in the presence of 1 6 mol % of cinchona alkaloid urea derivatives, and provided access to gamma nitrothioesters with quaternary stereocenters in high yields and diastereo- and enantioselectivities. Mechanistic investigations provided insight into the parameters that determine the stereoselectivity and showed that the diastereoselectivity can be controlled by the nature of the MTM substrate. The different reactivities of the three functional groups (oxoester, thioester, nitro moieties) within the conjugate addition products allowed for straightforward access to other compounds with quaternary stereogenic centers, such as gamma nitroaldehydes and gamma-butyrolactams. PMID- 24758497 TI - Applicability of the NANDA-I and Nursing Interventions Classification taxonomies to mental health nursing practice. AB - PURPOSE: To assess the applicability of the systematization of nursing care (NCS) to outpatient nursing appointments using the NANDA-I and Nursing Interventions Classification (NIC) taxonomies. METHODS: Data were collected from 40 patients who had appointments with a nurse who specialized in mental health. Nursing diagnoses (NDs) and interventions were classified using the NANDA-I and NIC taxonomies, respectively. FINDINGS: A total of 14 different NDs were detected (minimum of one and maximum of three per appointment). The most frequently made diagnoses were impaired social interaction (00052), anxiety (00146), and ineffective self-health management (00078). A total of 23 nursing interventions were prescribed (approximately two per appointment), of which the most frequent were socialization enhancement (5100), self-care assistance (1800), and exercise promotion (0200). Significant associations were found between the most frequently detected NDs and the most commonly prescribed interventions (p > .05). CONCLUSIONS: The NCS through the use of classification systems allows mental health nurses to better identify and assist poorly adjusted patients. IMPLICATIONS FOR NURSING PRACTICE: The assessment of the applicability of the NCS to different areas of health care and types of medical assistance contributes significantly to the quality of nursing care. PMID- 24758498 TI - Current nursing practice for patients on oral chemotherapy: a multicenter survey in Japan. AB - BACKGROUND: With a paradigm shift toward a chronic care model in cancer, the issue of adherence is becoming increasingly important in oncology. METHODS: We mailed two self-reported surveys on current nursing practices for patients on oral chemotherapy to all 309 designated cancer centers and 141 large general hospitals in Japan. The first survey was based on a nurse-based questionnaire containing 40 items concerning nurse's characteristics, nurse staffing at workplace, general nursing care for new patients on oral chemotherapy and those with refilled prescriptions, follow-up, and system-based approach. The second survey was based on a patient-based questionnaire containing 10 items about patient characteristics and adherence-related nursing practice for 249 patients taking oral chemotherapy of 903 systematically sampled. We used multivariate logistic regression to identify factors that were associated with adherence related nursing practices. RESULTS: A total of 62 nurses (mean age: 41.5 years) from 62 hospitals who consented participated in the both nurse-based survey and patient-based survey about 249 patients. The results of nurse-based survey indicated that practices varied, but nurses were less likely to ask adherence related questions of patients with refilled prescriptions than of new patients. The results of patient-based survey found that questions on side effects, discussions about barriers to achieving balance between treatment and daily life activities, and medication management were all significantly related to the question about unused medicines. Logistic regression revealed that adherence related nursing practices were associated with the nurse's background, type of treatment, and healthcare system-related factors. Patient orientation on oral chemotherapy, interdisciplinary learning, and having a system-based approach for detecting prescription errors were identified as healthcare system-related factors. CONCLUSIONS: A more systematic approach must be developed to ensure patients receive safe and effective oral chemotherapy, while nurses should play significant roles in patient education and monitoring. PMID- 24758499 TI - In memoriam: Krystyna Golinska (1933-2013). PMID- 24758500 TI - [WHO classification of tumours of soft tissue and bone 2013: the main changes compared to the 3rd edition]. AB - In early 2013, the new classification of tumours of soft tissue and bones was released. This edition belongs to the fourth series of so-called Blue Books published under the auspices of the World Health Organisation (WHO). The current classification follows the previous third edition, from which it differs in several aspects. The vast majority of changes are related to the soft tissue tumour section, which was enriched with three new chapters, some entities or terms were removed, new diagnoses were introduced, and several tumours were reallocated to other categories. Albeit to a lesser extent, similar changes have occurred also in the classification of bone tumours. Compared to the previous edition, more detailed molecular and cytogenetic data were incorporated in the current issue. The rapidly increasing knowledge of the genetics of mesenchymal tumours allows us to make more accurate diagnoses as well as to better understand of the pathogenesis of these lesions. However, abundant molecular and cytogenetic data highlight an increasing problem of growing numbers of genetic overlaps even among quite different tumours. The coexistence of several grading systems of soft tissue tumours is another controversial issue mentioned in the recent WHO classification. The main advantages and limitations of the two most widely used grading systems are also discussed. PMID- 24758501 TI - [Molecular pathology of pulmonary carcinomas]. AB - The group of non-small cell lung carcinomas includes tumors that are variable at the clinical, histopathological and molecular levels. Advances in the understanding of molecular pathology of lung adenocarcinomas in particular has led to changes in their histopathological classification and treatment. Patients diagnosed with lung adenocarcinoma harboring specific mutations benefit from the administration of specific targeted therapy. Therefore, pathologists closely involved in the diagnostics of lung tumors significantly contribute to the diagnostic-therapeutical algorithm. Analysis of EGFR gene mutations in lung adenocarcinomas is already routinely performed and the presence of activating mutations in EGFR is the main indication for the administration of tyrosinkinase inhibitors. Besides EGFR mutations, EML4-ALK rearrangement is also being analysed and there is potential in analysing BRAF mutations as well. The aim of this review is to summarize the role of the most relevant molecules that also serve as the therapeutic target for practicing pathologists. PMID- 24758502 TI - [Gastrointestinal stromal tumor (GIST): advances in 2013]. AB - Gastrointestinal stromal tumors (GIST) are currently regarded as a heterogenous group of tumors sharing common histological appearance, KIT immunopositivity and supposed origin from tissue progenitor cells capable of differentiation into the phenotype of Cajal interstitial cells. GISTs can be divided according to immunoexpression of the beta subunit of mitochondrial enzyme succinate dehydrogenase (SDHB) to SDHB-positive (encompassing KIT, PDGFRA and NF1 mutated GISTs), and SDHB-deficient GISTs (including Carney-Stratakis syndrome, Carney triad, sporadic pediatric GISTs, and a small subset of sporadic adult GISTs). The individual molecular subtypes differ in biological behavior and in their response to systemic targeted therapy, which is indicated in metastatic GISTs or in tumors with high risk of recurrence. Although several risk-stratification classifications have been developed, strictly defined criteria to identify patients at risk are still lacking. Pharmacogenomics have been successful in designing drugs to overcome not only the primary resistance of GISTs to the action of imatinib (e.g. GISTs with a substitution of Asp842Val in exon 18 PDGFRA or SDHB-deficient GISTs), but also the secondary resistance caused by secondary mutation of a gene encoding either the receptor tyrosine kinase or other molecules involved in the respective signalling cascade. Future directions concentrate on rational molecular targeting for systemic therapy based on complex genetic investigation of the tumor. Peripheral blood is planned to be used as a source of information for genetic events responsible for the secondary resistance of metastatic tumors. PMID- 24758503 TI - [Hereditary thyroid carcinoma and its molecular diagnostics]. AB - Thyroid carcinoma is the most common malignancy of the endocrine system and its incidence is still growing. The majority of thyroid tumors occur in sporadic form, however, some are inherited in families. The carcinomas can be divided into two groups according to the types of thyroid cells. Medullary thyroid carcinoma is derived from parafollicular C-cells. 20 - 25% of medullary thyroid carcinomas are inherited in multiple endocrine neoplasia type 2 syndromes. Genetic causes are activated by germ-line mutations in the RET proto-oncogene, which are transmitted autosomal, dominantly. At present the routine genetic screening and presymptomatic treatment (i.e. prophylactic total thyreoidectomy) on the basis of genotype-phenotype correlation has already been developed. The second group consists of carcinomas derived from follicular cells of thyroid that can be divided into differentiated (papillary and follicular) and nondifferentiated (anaplastic and poorly differentiated) ones. Also in this group 5-15% of carcinomas are cases of different familial syndromes (Gardner, Cowden, Werner syndromes and Carney complex) or only simple familial papillary thyroid carcinoma. Although the genetic basis of inherited cancer syndromes are mostly known (APC, PTEN, PRKAR1alpha and WRN genes), the cause of nonsyndromic familial papillary thyroid carcinoma is still under investigation, several predisposition genetic loci are recognized. PMID- 24758504 TI - [Where does Ewing sarcoma end and begin - two cases of unusual bone tumors with t(20;22)(EWSR1-NFATc2) alteration]. AB - The authors present two cases of Ewing-like sarcoma of the humerus and femur of a 12-year-old boy and a 28-year-old male, respectively. Identical morphology in both tumors consisted of multiple solid nests with a mosaic collection of small, round, uniform cells with clear cytoplasm and no apparent nuclear atypia. A monotonous structural arrangement, including both rich vascularity of bordering septae and significant admixtures of eosinophil leucocytes, resulted in a final organoid "neuroendocrine-like" pattern. Immunohistochemistry revealed diffuse strong CD10, CD99 and CD138 positivity. Detailed molecular analysis in both tumors confirmed translocation t(20;22) resulting in an EWSR1-NFATc2 fusion gene. Additionally, this translocation was accompanied by amplification of the proximal part of the genes and surrounding areas. Clinically, both neoplasms behaved aggressively and they were primarily chemoresistant. Four years later, the patient with the lesion in the humerus developed a massive local recurrence with a disruption of osteosynthesis. The last follow-up disclosed suspicious metastatic deposits in the lung. The boy with the femoral tumor underwent a total femoral prosthesis and there are no signs of local or systemic recurrence after 11 months of follow-up. The authors discuss the taxonomic placement of these rare examples of Ewing-like sarcoma family in the light of new molecular discoveries. PMID- 24758505 TI - Epidermolytic hyperkeratosis of the vulva associated with basal cell carcinoma in a patient with vaginal condyloma acuminatum and vaginal intraepithelial neoplasia harboring HPV, type 42. AB - The occurrence of basal cell carcinoma (BCC) of the vulva is rare. We report the case of a 79-year-old woman with a medical history of intravaginal condyloma acuminatum and vaginal intraepithelial neoplasia 3 (VaIN 3) who presented with a solitary whitish lesion sized 8x5 mm with a central desquamation located on the right labium majus. Histopathologic examination revealed a typical superficial and nodular BCC. Additionally, there were multiple remarkable foci of epidermolytic hyperkeratosis (EH). These foci both merged with superficial BCC or were sharply demarcated from the tumor. Retrospective molecular-biological examination of all the available material revealed HPV type 42 in both condyloma acuminatum and VaIN 3 specimen but not in the BCC associated with EH. To our best knowledge, involvement of the lower female genitalia by EH is a rare finding with six cases published to date. Awareness of EH in this location and its distinction is important because it may be potentially misinterpreted as a viral condyloma. PMID- 24758506 TI - [Use of archival formalin-fixed, paraffin-embedded (FFPE) tissue samples for molecular genetic analysis in diffuse large B-cell lymphoma (DLBCL)]. AB - The currently valid molecular genetic subclassification of patients with diffuse large B-cell lymphoma (DLBCL) into three prognostic subgroups based on expression profiling has been the objective of numerous genetic studies. In routine clinical practice, however, expression profiling technology remains unavailable for the most of centers. Apart from the technology, in some cases molecular genetic laboratories have problems obtaining high-quality material, i.e. fresh tissues, for RNA isolation to determine gene expression. One possibility is to determine the gene expression from RNA obtained by isolation from formalin-fixed, paraffin embedded (FFPE) tissue. This pilot study aimed at isolating RNA from FFPE in patients diagnosed with DLBCL and verifying the potential use of such RNA for the expression analysis of 7 selected genes. Although the study showed that it is possible to isolate RNA and determine the expression of the selected genes from archival material, the values of relative expression of some genes in the set were too variable to be used for unambiguous prognostic classification. It was confirmed that retrospective analyses of selected genes may be performed with sufficient material obtained, and that properly archived blocks may be used for molecular biology analyses even after 8 years. PMID- 24758507 TI - [The current staging for uterine body malignancies and its importance for clinical practice]. AB - Reliable staging system should facilitate prognosis assessment, decision on treatments, and evaluation of their outcomes. A good staging system must meet three basic characteristics: validity, reliability, and practicality. The purpose of such system is to offer classification of the extent and progress of gynaecological cancer that will allow the comparison of different treatment methods and the choice of optimal treatment for individual patients. The previously developed staging of gynaecological cancers has become outdated because it has not considered results of current medical research that allow refinement of prognostic subgroupings. Changes based on new findings were proposed for staging of uterine malignancies by the FIGO (The International Federation of Gynecology and Obstetrics) Committee on Gynecologic Oncology and approved by the FIGO Executive Board in 2008, and were published in 2009. Stage 0 was deleted, since it did not represent any stage of invasive tumor. Four fundamental changes were made in the staging system of endometrium carcinoma. The revised staging system for endometrium carcinoma divides patients to groups with similar prognosis; carcinosarcoma is staged identically. The novel system will facilitate exchange of relevant information between diverse oncological centers and thereby promote knowledge dissemination and stimulate research around the globe. A different staging system was proposed for adenosarcomas, leiomyosarcomas and endometrial stromal sarcomas. It is based on features used for the sarcomas of other soft tissues. The purpose of the text is to review current knowledge in this area. PMID- 24758508 TI - Anything but basic: Nursing's challenge in meeting patients' fundamental care needs. AB - PURPOSE: Nursing has not explored the fundamental aspects of patient care in a systematic, conceptually coherent, scientific way, and this has created a number of ongoing challenges. ORGANIZING CONSTRUCT: Each challenge is identified and addressed in the form of a proposition, with evidence provided to support the arguments put forward and defend the proposed actions. FINDINGS: The challenges include: the need for an integrated way of thinking about the fundamentals of care from a conceptual, methodological, and practical perspective; the ongoing and unresolved tension in nursing practice between a depersonalized and mechanistic approach (termed a "task and time" driven culture) and the need for consistency around understanding and managing the dynamics of the nurse-patient relationship or encounter (termed a "thinking and linking" approach); and the need for a systematic approach to the fundamentals or basics of care that combines the physical, psychosocial, and relational dimensions of the care encounter within the wider context of the care environment. Pragmatic and practical frameworks are needed to ensure that the basic physical and psychosocial needs of patients are embedded not only in the practice but also in the thinking, reflection, and assessment processes of the nurse. CONCLUSIONS: Nursing's challenge to meet patients' basic or fundamental needs is complex. Developing a knowledge base will include identifying researchable questions, using rigorous methodologies, ensuring the relational dimensions are not lost, and ensuring the new knowledge is applied in practice. This requires collaboration on an international scale to achieve improvements in care. CLINICAL RELEVANCE: To work collaboratively to generate, test, and implement meaningful ways of capturing nursing practice around basic or fundamental care in order to ensure more integrated, holistic patient care nursing practices. PMID- 24758509 TI - Attributable risk from distributed lag models. AB - BACKGROUND: Measures of attributable risk are an integral part of epidemiological analyses, particularly when aimed at the planning and evaluation of public health interventions. However, the current definition of such measures does not consider any temporal relationships between exposure and risk. In this contribution, we propose extended definitions of attributable risk within the framework of distributed lag non-linear models, an approach recently proposed for modelling delayed associations in either linear or non-linear exposure-response associations. METHODS: We classify versions of attributable number and fraction expressed using either a forward or backward perspective. The former specifies the future burden due to a given exposure event, while the latter summarizes the current burden due to the set of exposure events experienced in the past. In addition, we illustrate how the components related to sub-ranges of the exposure can be separated. RESULTS: We apply these methods for estimating the mortality risk attributable to outdoor temperature in two cities, London and Rome, using time series data for the periods 1993-2006 and 1992-2010, respectively. The analysis provides estimates of the overall mortality burden attributable to temperature, and then computes the components attributable to cold and heat and then mild and extreme temperatures. CONCLUSIONS: These extended definitions of attributable risk account for the additional temporal dimension which characterizes exposure-response associations, providing more appropriate attributable measures in the presence of dependencies characterized by potentially complex temporal patterns. PMID- 24758511 TI - Antibacterial activity of essential oils of edible spices, Ocimum canum and Xylopia aethiopica. AB - The essential oils of 2 Cameroonian spices, namely, Xylopia aethiopica and Ocimum canum, were chemically investigated and screened for their antibacterial activity. The essential oils were analyzed by means of GC, GC/MS, and NMR. X. aethiopica oil contained myrtenol (12%), a monoterpenoid in highest concentration. The essential oil of O. canum belonged to the known linalool (44%) rich chemotype. The results of the antibacterial screening against the food spoiling bacteria revealed a significant and broad spectrum of activity for these essential oils. The present material of X. aethiopica, which is having myrtenol in relatively higher concentration, has shown moderate antibacterial activity. The bioassay-guided fractionation of Ocimum canum oil through flash chromatography showed that minor compounds, namely, alpha-terpineol, chavicol, chavibetol, and trans-p-mentha-2,8-dien-ol, significantly contributed for the overall activity observed. Hence, these results evidenced the possible potential of the essential oil of O. canum as a suitable antibacterial for controlling food borne pathogens whereas the X. aethiopica oil has moderate possibility. PRACTICAL APPLICATION: There is a strong global demand for the microbe-free, safe, and healthy foods. In this study, we showed that the essential oil of O. canum (wild basil) can be used as antibacterial for food items. Also, we showed that a value addition in the antibacterial potential of O. canum oil can be done by processing the essential oil through flash chromatographic separations. PMID- 24758510 TI - Fractional flow reserve or optical coherence tomography guidance to revascularize intermediate coronary stenosis using angioplasty (FORZA) trial: study protocol for a randomized controlled trial. AB - BACKGROUND: The management of patients with angiographically intermediate coronary lesions is a major clinical issue. Fractional flow reserve provides validated functional insights while optical coherence tomography provides high resolution anatomic imaging. Both techniques may be applied to guide management in case of angiographically intermediate coronary lesions. Moreover, these techniques may be used to optimize the result of percutaneous coronary intervention. We aim to compare the clinical and economic impact of fractional flow reserve versus optical coherence tomography guidance in patients with angiographically intermediate coronary lesions. METHODS/DESIGN: Patients with at least one angiographically intermediate coronary lesion will be randomized (ratio 1:1) to fractional flow reserve or optical coherence tomography guidance. In the fractional flow reserve arm, percutaneous coronary intervention will be performed if fractional flow reserve value is <=0.80, and will be conducted with the aim of achieving a post-percutaneous coronary intervention fractional flow reserve target value of >=0.90. In the optical coherence tomography arm, percutaneous coronary intervention will be performed if percentage of area stenosis (AS%) is >=75% or 50 to 75% with minimal lumen area <2.5 mm2, or if a major plaque ulceration is detected. In case of percutaneous coronary intervention, optical coherence tomography will guide the procedure in order to minimize under expansion, malapposition, and edge dissections.Cost load and clinical outcome will be prospectively assessed at one and thirteen months. The assessed clinical outcome measures will be: major cardiovascular events and occurrence of significant angina defined as a Seattle Angina Questionnaire score <90 in the angina frequency scale. DISCUSSION: The FORZA trial will provide useful guidance for the management of patients with coronary artery disease by prospectively assessing the use of two techniques representing the gold standard for functional and anatomical definition of coronary plaques. TRIAL REGISTRATION: Clinicaltrials.gov NCT01824030. PMID- 24758512 TI - DFT-D study of 14N nuclear quadrupolar interactions in tetra-n-alkyl ammonium halide crystals. AB - The density functional theory-based method with periodic boundary conditions and addition of a pair-wised empirical correction for the London dispersion energy (DFT-D) was used to study the NMR quadrupolar interaction (coupling constant CQ and asymmetry parameter etaQ) of (14)N nuclei in a homologous series of tetra-n alkylammonium halides (C(x)H(2x+1))4N(+)X(-) (x = 1-4), (X = Br, I). These (14)N quadrupolar properties are particularly challenging for the DFT-D computations because of their very high sensitivity to tiny geometrical changes, being negligible for other spectral property calculations as, for example, NMR (14)N chemical shift. In addition, the polarization effect of the halide anions in the considered crystal mesophases combines with interactions of van der Waals type between cations and anions. Comparing experimental and theoretical results, the performance of PBE-D functional is preferred over that of B3LYP-D. The results demonstrated a good transferability of the empirical parameters in the London dispersion formula for crystals with two or more carbons per alkyl group in the cations, whereas the empirical corrections in the tetramethylammonium halides appeared to be inappropriate for the quadrupolar interaction calculation. This is attributed to the enhanced cation-anion attraction, which causes a strong polarization at the nitrogen site. Our results demonstrated that the (14)N CQ and etaQ are predominantly affected by the molecular structures of the cations, adapted to the symmetry of the anion arrangements. The long-range polarization effect of the surrounding anions at the target nitrogen site becomes more important for cells with lower spatial symmetry. PMID- 24758513 TI - Microcalcifications in breast cancer: an active phenomenon mediated by epithelial cells with mesenchymal characteristics. AB - BACKGROUND: Mammary microcalcifications have a crucial role in breast cancer detection, but the processes that induce their formation are unknown. Moreover, recent studies have described the occurrence of the epithelial-mesenchymal transition (EMT) in breast cancer, but its role is not defined. In this study, we hypothesized that epithelial cells acquire mesenchymal characteristics and become capable of producing breast microcalcifications. METHODS: Breast sample biopsies with microcalcifications underwent energy dispersive X-ray microanalysis to better define the elemental composition of the microcalcifications. Breast sample biopsies without microcalcifications were used as controls. The ultrastructural phenotype of breast cells near to calcium deposits was also investigated to verify EMT in relation to breast microcalcifications. The mesenchymal phenotype and tissue mineralization were studied by immunostaining for vimentin, BMP-2, beta2-microglobulin, beta-catenin and osteopontin (OPN). RESULTS: The complex formation of calcium hydroxyapatite was strictly associated with malignant lesions whereas calcium-oxalate is mainly reported in benign lesions. Notably, for the first time, we observed the presence of magnesium-substituted hydroxyapatite, which was frequently noted in breast cancer but never found in benign lesions. Morphological studies demonstrated that epithelial cells with mesenchymal characteristics were significantly increased in infiltrating carcinomas with microcalcifications and in cells with ultrastructural features typical of osteoblasts close to microcalcifications. These data were strengthened by the rate of cells expressing molecules typically involved during physiological mineralization (i.e. BMP-2, OPN) that discriminated infiltrating carcinomas with microcalcifications from those without microcalcifications. CONCLUSIONS: We found significant differences in the elemental composition of calcifications between benign and malignant lesions. Observations of cell phenotype led us to hypothesize that under specific stimuli, mammary cells, which despite retaining a minimal epithelial phenotype (confirmed by cytokeratin expression), may acquire some mesenchymal characteristics transforming themselves into cells with an osteoblast-like phenotype, and are able to contribute to the production of breast microcalcifications. PMID- 24758514 TI - Surgical treatment for late-appearing adrenal metastasis from gastric cancer: report of two cases. AB - Adrenal metastasis following gastrectomy for gastric cancer is often encountered as part of advanced systemic dissemination, which is usually unresectable. Thus, there are very few published case reports describing metastasectomy for adrenal metastasis from gastric cancer. Herein we present our experience in treating two patients diagnosed and treated for adrenal metastasis 6 years following initial surgery for advanced gastric cancer (pT2bN1M0 and pT2bN0M0, respectively, according to the classification system set forth in the sixth edition of The TNM Classification of Malignant Tumours by the International Union against Cancer). They underwent successful en bloc R0 resections, followed by systemic chemotherapy with close postoperative follow-up for another recurrence, and have remained alive without recurrence for 1 year. These results suggest that active surgical treatment for resectable metastatic gastric cancer in the adrenal glands has an important role in prolonging survival in selected patients. PMID- 24758515 TI - Modulation of imidazoline I2 binding sites by CR4056 relieves postoperative hyperalgesia in male and female rats. AB - BACKGROUND AND PURPOSE: CR4056 is a novel imidazoline-2 (I2 ) ligand exhibiting potent analgesic activity in animal models of pain. In this study, we investigated the effects of CR4056 in a well-established model of postoperative pain where rats develop hyperalgesia in the injured hind paw. EXPERIMENTAL APPROACH: By measuring paw withdrawal threshold to mechanical pressure, we studied the pharmacology of CR4056, potential sex differences in pain perception and response to treatment, and the pharmacodynamic interaction of CR4056 with morphine. KEY RESULTS: Oral CR4056 and subcutaneous morphine dose-dependently reversed the hyperalgesic response. Analgesic effects of CR4056 were completely suppressed by the non-selective imidazoline I2 /alpha2 -adrenoceptor antagonist idazoxan, were partially reduced (~30%; P < 0.05) by the selective alpha2 adrenoceptor antagonist yohimbine, but were not influenced by the non-selective I1 /alpha2 -adrenoceptor antagonist efaroxan or by the MU opioid receptor antagonist naloxone. We found no differences in responses to CR4056 or morphine between male and female rats. However, females had a lower pain threshold than males, and needed lower doses of drugs to reach a significant analgesia. When CR4056 and morphine were combined, their median effective doses were lower than expected for additive effects, both in males and in females. Isobolographic analysis confirmed a synergism between CR4056 and morphine. CONCLUSIONS AND IMPLICATIONS: CR4056 is a novel pharmacological agent under development for postoperative pain both as stand-alone treatment and in association with morphine. CR4056 has successfully completed Phase I studies for tolerability and pharmacokinetics in healthy volunteers, and is currently entering the first proof of-concept study in patients. PMID- 24758516 TI - High resolution structure of cleaved Serpin 42 Da from Drosophila melanogaster. AB - BACKGROUND: The Drosophila melanogaster Serpin 42 Da gene (previously Serpin 4) encodes a serine protease inhibitor that is capable of remarkable functional diversity through the alternative splicing of four different reactive centre loop exons. Eight protein isoforms of Serpin 42 Da have been identified to date, targeting the protease inhibitor to both different proteases and cellular locations. Biochemical and genetic studies suggest that Serpin 42 Da inhibits target proteases through the classical serpin 'suicide' inhibition mechanism, however the crystal structure of a representative Serpin 42 Da isoform remains to be determined. RESULTS: We report two high-resolution crystal structures of Serpin 42 Da representing the A/B isoforms in the cleaved conformation, belonging to two different space-groups and diffracting to 1.7 A and 1.8 A. Structural analysis reveals the archetypal serpin fold, with the major elements of secondary structure displaying significant homology to the vertebrate serpin, neuroserpin. Key residues known to have central roles in the serpin inhibitory mechanism are conserved in both the hinge and shutter regions of Serpin 42 Da. Furthermore, these structures identify important conserved interactions that appear to be of crucial importance in allowing the Serpin 42 Da fold to act as a versatile template for multiple reactive centre loops that have different sequences and protease specificities. CONCLUSIONS: In combination with previous biochemical and genetic studies, these structures confirm for the first time that the Serpin 42 Da isoforms are typical inhibitory serpin family members with the conserved serpin fold and inhibitory mechanism. Additionally, these data reveal the remarkable structural plasticity of serpins, whereby the basic fold is harnessed as a template for inhibition of a large spectrum of proteases by reactive centre loop exon 'switching'. This is the first structure of a Drosophila serpin reported to date, and will provide a platform for future mutational studies in Drosophila to ascertain the functional role of each of the Serpin 42 Da isoforms. PMID- 24758517 TI - Self-emulsification of alkaline-dissolved clove bud oil by whey protein, gum arabic, lecithin, and their combinations. AB - Low-cost emulsification technologies using food ingredients are critical to various applications. In the present study, a novel self-emulsification technique was studied to prepare clove bud oil (CBO) emulsions, without specialized equipment or organic solvents. CBO was first dissolved in hot alkaline solutions, added at 1% v/v into neutral solutions with 1% w/v emulsifier composed of whey protein concentrate (WPC), gum arabic, lecithin, or their equal mass mixtures, and adjusted to pH 7.0. The self-emulsification process did not affect UV-vis absorption spectrum, reversed-phase HPLC chromatogram, or antimicrobial activity of CBO against Escherichia coli O157:H7, Listeria monocytogenes Scott A, and Salmonella Enteritidis. The entrapment efficiency after extraction by petroleum ether was determined to be about 80%. Most emulsions were stable during 7 days of storage. Emulsions prepared with WPC had smaller particles, whereas emulsions prepared with emulsifier mixtures had more stable particle dimensions. The studied self-emulsification technique may find numerous applications in the preparation of low-cost food emulsions. PMID- 24758519 TI - Crosstalk between dendritic cell subsets and implications for dendritic cell based anticancer immunotherapy. AB - Dendritic cells (DCs) are a family of professional antigen-presenting cells that have an indispensable role in the initiation of innate and adaptive immune responses against pathogens and tumor cells. The DC family is very heterogeneous. Two main types of naturally occurring DCs circulate in peripheral blood, each with its unique phenotypic and functional characteristics: myeloid DCs and plasmacytoid. There is an ample number of studies that have focused on the bi directional crosstalk between DCs and natural killer cells or T cells. However, the crosstalk among the different DC subsets, in the context of infectious diseases and cancer, has until now not received much attention. Here, we review all available literature that has dealt with the crosstalk between plasmacytoid and myeloid DCs and the potential mode of action. Emphasis will be given to the therapeutic potential of the combination of DC subsets for DC-based immunotherapy. PMID- 24758518 TI - Similar appearance, different mechanisms: xerosis in HIV, atopic dermatitis and ageing. AB - Xerosis is one of the most common dermatologic disorders occurring in the elderly and in patients with atopic dermatitis (AD) and human immunodeficiency virus (HIV) infection. Xerosis has been linked to an impaired skin barrier function of the stratum corneum. Using Raman microspectroscopy, we concentrated on deeper skin layers, viable epidermis and dermis of 47 volunteers and associated molecular alterations to the evolution of xerosis and the skin barrier, for example, lipid, water and antioxidant content. A decrease in lipids within the viable epidermis is found for elderly and HIV-patients. Lipid and water values of AD patients and their healthy reference group are similar. Decreases in lipids and simultaneous increases in water are found in the dermis for HIV and AD patients in comparison to their healthy reference groups. Excessive levels of epidermal carotenoids, mainly lycopene, in HIV-patients were found potentially leading to adverse effects such as premature skin ageing. PMID- 24758520 TI - Epigallocatechin-3-gallate (EGCG)-stabilized selenium nanoparticles coated with Tet-1 peptide to reduce amyloid-beta aggregation and cytotoxicity. AB - Alzheimer's disease (AD), the most common neurodegenerative disease, is caused by an accumulation of amyloid-beta (Abeta) plaque deposits in the brains. Evidence is increasingly showing that epigallocatechin-3-gallate (EGCG) can partly protect cells from Abeta-mediated neurotoxicity by inhibiting Abeta aggregation. In order to better understand the process of Abeta aggregation and amyloid fibril disaggregation and reduce the cytotoxicity of EGCG at high doses, we attached EGCG onto the surface of selenium nanoparticles (EGCG@Se). Given the low delivery efficiency of EGCG@Se to the targeted cells and the involvement of selenoprotein in antioxidation and neuroprotection, which are the key factors for preventing the onset and progression of AD, we synthesized EGCG-stabilized selenium nanoparticles coated with Tet-1 peptide (Tet-1-EGCG@Se, a synthetic selenoprotein analogue), considering the affinity of Tet-1 peptide to neurons. We revealed that Tet-1-EGCG@Se can effectively inhibit Abeta fibrillation and disaggregate preformed Abeta fibrils into nontoxic aggregates. In addition, we found that both EGCG@Se and Tet-1-EGCG@Se can label Abeta fibrils with a high affinity, and Tet-1 peptides can significantly enhance the cellular uptake of Tet-1-EGCG@Se in PC12 cells rather than in NIH/3T3 cells. PMID- 24758521 TI - Improvement in quality of life in patients with nasopharyngeal carcinoma treated with non-invasive extracorporeal radiofrequency in combination with chemoradiotherapy. AB - PURPOSE: To improve the quality of life (QOL) of patients with nasopharyngeal carcinoma (NPC) after chemoradiotherapy (CRT), it is necessary to find an effective method to reduce the toxic side-effects of CRT. MATERIALS AND METHODS: Between June 2007 and June 2010, 83 previously untreated patients with NPC were randomized to receive CRT either with or without non-invasive extracorporeal radiofrequency (ERF). All the patients underwent radiation, and weekly chemotherapy of paclitaxel 135-175 mg/m(2) and cisplatin 60-90 mg/m(2). In addition, the patients in the treatment group also underwent non-invasive ERF on a radiofrequency machine at 13.56 MHz for 1 hour at 41-43 degrees C. After the completion of treatment, evaluation was carried out to determine the survival rate, disease-free survival time, and QOL. QOL was analyzed by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Cancer Module (EORTC QLQ H&N35) every 6 months during the three-year period. RESULTS: After completion of the treatments, the 36-month survival rate was 0.730 in the treatment group and 0.535 in the reference group (p = 0.041); the average disease-free survival time was 48 months in the treatment group and only 37.5 months in the reference group (p = 0.048). In the post- treatment questionnaires, several NPC-specific (pain, swallowing, speech, social eating, opening mouth, dry mouth, sticky saliva) QOL domains were better preserved with CRT + ERF compared to CRT at different time points. CONCLUSIONS: The combination treatment of ERF with CRT can prolong the survival rate and disease-free survival time and improve the QOL for patients with NPC. PMID- 24758524 TI - Scientific misconduct: also an issue in nursing science? AB - PURPOSE: Scientific misconduct (SMC) is an increasing concern in nursing science. This article discusses the prevalence of SMC, risk factors and correlates of scientific misconduct in nursing science, and highlights interventional approaches to foster good scientific conduct. METHODS: Using the "Fostering Research Integrity in Europe" report of the European Science Foundation as a framework, we reviewed the literature in research integrity promotion. FINDINGS: Although little empirical data exist regarding prevalence of scientific misconduct in the field of nursing science, available evidence suggests a similar prevalence as elsewhere. In studies of prospective graduate nurses, 4% to 17% admit data falsification or fabrication, while 8.8% to 26.4% report plagiarizing material. Risk factors for SMC exist at the macro, meso, and micro levels of the research system. Intervention research on preventing scientific misconduct in nursing is limited, yet findings from the wider field of medicine and allied health professions suggest that honor codes, training programs, and clearly communicated misconduct control mechanisms and misconduct consequences improve ethical behavior. CONCLUSIONS: Scientific misconduct is a multilevel phenomenon. Interventions to decrease scientific misconduct must therefore target every level of the nursing research systems. CLINICAL RELEVANCE: Scientific misconduct not only compromises scientific integrity by distorting empirical evidence, but it might endanger patients. Because nurses are involved in clinical research, raising their awareness of scientifically inappropriate behavior is essential. PMID- 24758522 TI - Genetic markers of treatment response to tumour necrosis factor-alpha inhibitors in the treatment of psoriasis. AB - BACKGROUND: Anti-tumour necrosis factor (TNF)-alpha therapies have revolutionized the treatment of psoriasis; however, up to 50% of patients do not respond satisfactorily. Identification of pharmacogenetic markers of treatment response is an important stop in the development of individually tailored treatment. The objective of this study was to assess the association of human leucocyte antigen (HLA)-C, killer immunoglobulin receptor (KIR) and vitamin D receptor (VDR) genotypes with response to treatment by etanercept and adalimumab. METHODS: This was a study of 138 patients with severe chronic plaque psoriasis who were treated with etanercept and/or adalimumab. Patients were classified as responders if they achieved a 75% reduction in PASI (PASI75) or were almost clear of psoriasis after 24 weeks of therapy. The frequencies of HLA-C and KIR haplotypes and VDR polymorphisms were compared in responders and nonresponders. The frequency of all HLA-C and KIR genotypes were compared between the 138 patients with psoriasis and 247 healthy donors. RESULTS: The number of patients classified as responders was 46 of 94 (49%) in the etanercept group and 50 of 76 (66%) in the adalimumab group. None of the HLA-C, KIR or VDR genotypes examined was predictive of treatment response. Compared with healthy controls, patients with psoriasis were more likely to have the HLA-C*06 genotype (P < 0.001) and less likely to have the HLA-C*07 genotype (P < 0.001), whereas there was no significant difference in frequencies of any KIR subtype. CONCLUSIONS: Using the candidate gene approach to identify biomarkers of treatment response in psoriasis may have limited utility. This was a small study with limited power. Future larger studies are needed to further examine these findings and to explore alternative approaches to identify predictors of treatment response to biological agents. PMID- 24758525 TI - Cost-effectiveness of protease inhibitor based regimens for chronic hepatitis C: a systematic review of published literature. AB - The treatment of chronic hepatitis C has experienced a substantial progress with the arrival of Boceprevir and Telaprevir due to the significant increase in sustained viral response. Given the high cost, their approval has been followed by great deal of pharmacoeconomic literature analysing their efficiency. A systematic review of this literature was carried out, evaluating both its results and the methodology employed. 54 references were revised including 11 studies, 6 on naive populations, 3 on pre-treated patients and 2 in both of them. As the clinical heterogeneity of patients influenced sustained viral response, therapy regimens were assessed conditioned to the interleukin 28B polymorphism, the early response to treatment and the level of fibrosis, among other variables. Most of the options evaluated on a naive population presented ICERs below the acceptability threshold. The same occurred in the pre-treated population, where the subgroups analysis is perceived as a methodological limitation. PMID- 24758526 TI - Eye tracking research to answer questions about augmentative and alternative communication assessment and intervention. AB - Recently, eye tracking technologies (i.e., technologies that automatically track the point of an individual's gaze while that person views or interacts with a visual image) have become available for research purposes. Based on the sampling of the orientation of the individual's eyes, researchers can quantify which locations within the visual image were fixated (viewed), for how long, and how many times. These automated eye tracking research technologies open up a wealth of avenues for investigating how individuals with developmental or acquired communication disabilities may respond to aided augmentative and alternative communication (AAC) systems. In this paper, we introduce basic terminology and explore some of the special challenges of conducting eye tracking research with populations with disabilities who might use AAC, including challenges of inferring attention from the presence of fixation and challenges related to calibration that may result from participant characteristics, behavioral idiosyncracies, and/or the number of calibration points. We also examine how the technology can be applied to ask well-structured experimental questions that have direct clinical relevance, with a focus on the unique contributions that eye tracking research can provide by (a) allowing evaluation of skills in individuals who are difficult to assess via traditional methods, and (b) facilitating access to information on underlying visual cognitive processes that is not accessible via traditional behavioral measures. PMID- 24758528 TI - Evaluation of hexane and ethyl acetate extracts of the sponge Jaspis diastra collected from Mauritius Waters on HeLa cells. AB - OBJECTIVES: Based on previous screening results, the cytotoxic effect of the hexane (JDH) and ethyl acetate extracts (JDE) of the marine sponge Jaspis diastra were evaluated on HeLa cells and the present study aimed at determining their possible mechanism of cell death. METHODS: Nuclear staining, membrane potential change, flow cytometry analysis of cell cycle distribution and annexin V staining were undertaken to investigate the effects of JDE and JDH. Electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance were used to characterize an isolated bioactive molecule. KEY FINDINGS: JDE displayed an IC50 25 times more significant than the JDH. Flow cytometry analysis revealed JDE induced apoptosis in HeLa cells accompanied by the collapse of mitochondrial membrane potential. Fractionation of JDE resulted in the isolation of the known cytotoxic cyclodepsipeptide, Jaspamide. CONCLUSIONS: Taking our results together suggest that JDE can be valuable for the development of anticancer drugs, especially for cervical cancer. Further investigations are currently in progress with the aim to determine and isolate other bioactive compounds from this extract. PMID- 24758527 TI - FOLFIRI(r) and bevacizumab in first-line treatment for colorectal cancer patients: safety, efficacy and genetic polymorphisms. AB - BACKGROUND: Over 50% of colorectal cancer (CRC) patients develop metastases. The aim of this study was to evaluate efficacy and tolerance of first-line FOLFIRI(r) + bevacizumab (B) treatment for metastatic CRC, and to assess genetic polymorphisms as potential markers. METHODS: Adult patients with histologically proven, non-resectable metastatic CRC and ECOG <= 2 were included. 14-day cycles consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m2), bolus FU (400 mg/m2) and leucovorin (400 mg/m2), followed by 46-hour FU infusions (2400 mg/m2). Primary endpoint was response rate according to RECIST criteria. Secondary endpoints were overall (OS) and progression-free (PFS) survivals, response duration, and toxicity. Associations between clinical data, UGT1A1, thymidylate synthase, VEGFA polymorphisms and PFS, OS and toxicity were analyzed. RESULTS: Sixty-two patients were enrolled (median age 68y). 59/62 patients were eligible and evaluable for response at 6 months: 28 showed partial response (47.5%; 95% CI; 34.3-60.9), 20 stable disease (33.9%) and 11 progression (18.6%). Grade 3/4 toxicities were as follows: neutropenia 16.1%; diarrhea 11.3%; nausea-vomiting 1.6%. Median response duration was 9.5 months (range 2.7-20); median PFS 10.3 months (range 8.8-11.7); and median OS 25.7 months (range 20.2-29.7). 11/59 initially unresectable patients were resectable after treatment. VEGFA polymorphism (rs25648) was associated with better OS (HR: 3.61; 95% CI: 1.57 8.30). CONCLUSIONS: FOLFIRI(r) + bevacizumab is active with good response rate, long median OS, and a good safety profile. A VEGFA polymorphism might have a prognostic value in this malignancy. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00467142 (registration date: April 25, 2007). PMID- 24758529 TI - Postsynthetic metalation of bipyridyl-containing metal-organic frameworks for highly efficient catalytic organic transformations. AB - We have designed highly stable and recyclable single-site solid catalysts via postsynthetic metalation of the 2,2'-bipyridyl-derived metal-organic framework (MOF) of the UiO structure (bpy-UiO). The Ir-functionalized MOF (bpy-UiO-Ir) is a highly active catalyst for both borylation of aromatic C-H bonds using B2(pin)2 (pin = pinacolate) and ortho-silylation of benzylicsilyl ethers; the ortho silylation activity of the bpy-UiO-Ir is at least 3 orders of magnitude higher than that of the homogeneous control. The Pd-functionalized MOF (bpy-UiO-Pd) catalyzes the dehydrogenation of substituted cyclohexenones to afford phenol derivatives with oxygen as the oxidant. Most impressively, the bpy-UiO-Ir was recycled and reused 20 times for the borylation reaction without loss of catalytic activity or MOF crystallinity. This work highlights the opportunity in designing highly stable and active catalysts based on MOFs containing nitrogen donor ligands for important organic transformations. PMID- 24758531 TI - Dopant-assisted atmospheric pressure photoionization of patulin in apple juice and apple-based food with liquid chromatography-tandem mass spectrometry. AB - A dopant-assisted atmospheric pressure photoionization (APPI) with liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine patulin in apple juice and apple-based food. Different dopants, dopant flow rates, and LC separation conditions were evaluated. Using toluene as the dopant, the LC-APPI-MS/MS method achieved a linear calibration from 12.5 to 2000 MUg/L (r(2) > 0.99). Matrix-dependent limits of quantitation (LOQs) were from 8 MUg/L (solvent) to 12 MUg/L (apple juice). [(13)C]-Patulin-fortified apple juice samples were directly analyzed by the LC-APPI-MS/MS method. Other apple-based food was fortified with [(13)C]-patulin, diluted using water (1% formic acid), centrifuged, and filtered, followed by LC-APPI-MS/MS analysis. In clear apple juice, unfiltered apple cider, applesauce, and apple-based baby food, average recoveries were 101 +/- 6% (50 MUg/kg), 103 +/- 5% (250 MUg/kg), and 102 +/- 5% (1000 MUg/kg) (av +/- SD, n = 16). Using the suggested method, patulin was detected in 3 of 30 collected market samples with concentrations ranging from 74 years, with good cognitive function, living independently in one UK city were recruited through general practices and other sources, then randomised to: (1) 6 weeks of short one-to-one telephone calls, followed by 12 weeks of group telephone calls with up to six participants, led by a trained volunteer facilitator; or (2) a control group. The main trial required the recruitment of 248 participants in a 1-year accrual window, of whom 124 were to receive telephone befriending. The pilot specified three success criteria which had to be met in order to progress the main trial to completion: recruitment of 68 participants in 95 days; retention of 80% participants at 6 months; successful delivery of telephone befriending by local franchise of national charity. The primary clinical outcome was the Short Form (36) Health Instrument (SF-36) Mental Health (MH) dimension score collected by telephone 6 months following randomisation. RESULTS: We informed 9,579 older people about the study. Seventy consenting participants were randomised to the pilot in 95 days, with 56 (80%) providing valid primary outcome data (26 intervention, 30 control). Twenty-four participants randomly allocated to the research arm actually received telephone befriending due to poor recruitment and retention of volunteer facilitators. The trial was closed early as a result. The mean 6-month SF-36 MH scores were 78 (SD 18) and 71 (SD 21) for the intervention and control groups, respectively (mean difference, 7; 95% CI, -3 to 16). CONCLUSIONS: Recruitment and retention of participants to a definitive trial with a recruitment window of 1 year is feasible. For the voluntary sector to recruit sufficient volunteers to match demand for telephone befriending created by trial recruitment would require the study to be run in more than one major population centre, and/or involve dedicated management of volunteers. TRIAL REGISTRATION: ISRCTN28645428. PMID- 24758532 TI - Quiescent melanocytes form primary cilia. AB - We show, for the first time, that melanocytes can form a primary cilium in vitro, corresponding to an immotile or sensory cilium. Such cilia are observed when melanocytes reach confluence or when medium nutrient levels are insufficient. This observation should greatly improve our understanding of the signal transduction processes potentially occurring in these cells during embryonic development, homeostasis in adulthood and melanomagenesis. PMID- 24758533 TI - Antimicrobial resistance and characteristics of eradication therapy of Helicobacter pylori in Japan: a multi-generational comparison. AB - BACKGROUND: Eradication of Helicobacter pylori (H. pylori) at a younger age is considered to be effective in preventing gastric cancer. This study assessed the characteristics of eradication therapy in young patients. MATERIALS AND METHODS: We enrolled 1073 patients with H. pylori infection between 2000 and 2013. The subjects were divided into three groups according to age into the young (<=30 years), middle-aged (31-50 years), and elder (>=51 years) groups. We also examined 472 cases to investigate clinical eradication characteristics. RESULTS: The rate of clarithromycin (CAM) resistance was 57.9%, 34.5%, and 35.2% in the young, middle-aged, and elder group, respectively, in 2012-2013 and was significantly higher in the young group than in the elder group (p = .01). Metronidazole (MNZ) resistance was similar among the three groups at each time point. While CAM resistance rose over the study period, MNZ resistance was noted to have decreased of late. The overall initial eradication success rate was 91.9% (95% CI, 89.1-94.1) in our cohort. Eradication efficiency was comparable in the young, middle-aged, and elder group at 94.3% (95% CI, 87.4-97.5), 90.2% (95% CI, 82.9-94.6), and 91.8% (95% CI, 88.1-94.5) respectively. Side effects such as skin rash were observed in 14.8%, 3.9%, and 3.5% of the respective groups. There were significant differences in the incidence of side effects between the young group and other groups (p < .05, respectively). CONCLUSION: Since CAM resistance and the incidence of side effects are higher in young individuals, it is especially important to select eradication regimens based on testing for antimicrobial susceptibility. PMID- 24758534 TI - Meta-analysis and meta-modelling for diagnostic problems. AB - BACKGROUND: A proportional hazards measure is suggested in the context of analyzing SROC curves that arise in the meta-analysis of diagnostic studies. The measure can be motivated as a special model: the Lehmann model for ROC curves. The Lehmann model involves study-specific sensitivities and specificities and a diagnostic accuracy parameter which connects the two. METHODS: A study-specific model is estimated for each study, and the resulting study-specific estimate of diagnostic accuracy is taken as an outcome measure for a mixed model with a random study effect and other study-level covariates as fixed effects. The variance component model becomes estimable by deriving within-study variances, depending on the outcome measure of choice. In contrast to existing approaches - usually of bivariate nature for the outcome measures - the suggested approach is univariate and, hence, allows easily the application of conventional mixed modelling. RESULTS: Some simple modifications in the SAS procedure proc mixed allow the fitting of mixed models for meta-analytic data from diagnostic studies. The methodology is illustrated with several meta-analytic diagnostic data sets, including a meta-analysis of the Mini-Mental State Examination as a diagnostic device for dementia and mild cognitive impairment. CONCLUSIONS: The proposed methodology allows us to embed the meta-analysis of diagnostic studies into the well-developed area of mixed modelling. Different outcome measures, specifically from the perspective of whether a local or a global measure of diagnostic accuracy should be applied, are discussed as well. In particular, variation in cut-off value is discussed together with recommendations on choosing the best cut off value. We also show how this problem can be addressed with the proposed methodology. PMID- 24758536 TI - Current Issues in the Management of Pediatric Functional Abdominal Pain. AB - Chronic abdominal pain (CAP) is a prevalent disorder related to functional gastrointestinal disorders (FGIDs). In pediatric setting, CAP is a common presenting problem among children and adolescents ages 2 to 18 years with a median prevalence rate of 12%. It was proposed that CAP is the result of the altered pain sensation due to a dysfunction of the brain-gut axis after a complex interaction among biological, psychological and social factors. Children with CAP experience decrease in quality of life compared to children with identifiable organic disease such as inflammatory bowel disease. Despite treatment, 30% of children with CAP have long-lasting complaints with evidence that CAP is a risk factor for the occurrence of irritable bowel syndrome in adults. Efforts have subsequently been made to standardize the diagnostic criteria and adequate follow up. CAP is associated with significative impairment with considerable impact on self-reported quality of life. The direct and indirect costs are not known in pediatric population and the access to investigations it's frequent. A more appropriate use of Rome III criteria would allow for a clinical diagnosis. The focus of this article will be to report the updated criteria for the diagnosis, follow-up and treatment of this condition. PMID- 24758537 TI - Irradiation Toxicity and Inflammatory Bowel Diseases (IBD): Review. AB - BACKGROUND/AIM: The evaluation of radiotherapy toxicity in oncologic IBD patients. Defining the optimal patient and treatment factors that would be able to reduce the risk to organs. MATERIALS AND METHODS: A review of all published radiotherapy trials was performed to identify the clinical and treatment factors of inflammatory bowel disease's patients treated for different solid tumors. RESULTS: Overall, acute (Grade >= 3) gastrointestinal complications attributable to RT ranged between 20-21% of the treated patients. A late Grade >= 3 gastrointestinal toxicity was developed in a range between 8-29%. CONCLUSION: A special attention should be given to the description of IBD location, activity status, concurrent chemotherapy, irradiation dose and technique, in order to minimize post-irradiation morbidity. It is not easy to distinguish late morbidity attributable to radiotherapy due to the IBD itself. PMID- 24758535 TI - Assessment of the quality of measures of child oral health-related quality of life. AB - BACKGROUND: Several measures of oral health-related quality of life have been developed for children. The most frequently used are the Child Perceptions Questionnaire (CPQ), the Child Oral Impacts on Daily Performances (C-OIDP) and the Child Oral Health Impact Profile (COHIP). The aim of this study was to assess the methodological quality of the development and testing of these three measures. METHODS: A systematic search strategy was used to identify eligible studies published up to December 2012, using both MEDLINE and Web of Science. Titles and abstracts were read independently by two investigators and full papers retrieved where the inclusion criteria were met. Data were extracted by two teams of two investigators using a piloted protocol. The data were used to describe the development of the measures and their use against existing criteria. The methodological quality and measurement properties of the measures were assessed using standards proposed by the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) group. RESULTS: The search strategy yielded 653 papers, of which 417 were duplicates. Following analysis of the abstracts, 119 papers met the inclusion criteria. The majority of papers reported cross-sectional studies (n = 117) with three of longitudinal design. Fifteen studies which had used the original version of the measures in their original language were included in the COSMIN analysis. The most frequently used measure was the CPQ. Reliability and construct validity appear to be adequate for all three measures. Children were not fully involved in item generation which may compromise their content validity. Internal consistency was measured using classic test theory with no evidence of modern psychometric techniques being used to test unidimensionality of the measures included in the COSMIN analysis. CONCLUSION: The three measures evaluated appear to be able to discriminate between groups. CPQ has been most widely tested and several versions are available. COHIP employed a rigorous development strategy but has been tested in fewer populations. C-OIDP is shorter and has been used successfully in epidemiological studies. Further testing using modern psychometric techniques such as item response theory is recommended. Future developments should also focus on the development of measures which can evaluate longitudinal change. PMID- 24758538 TI - The Emerging Role of NRAS Mutations in Colorectal Cancer Patients Selected for Anti-EGFR Therapies. AB - Colorectal cancer (CRC) is one of the most common cancers worldwide. Despite the improvement in overall survival (OS) due to new treatments and targeted therapies alone or in combination with chemotherapy up-to-date, little is known about cellular mechanisms, both of primary and acquired resistance of CRC to anti Epidermal Growth Factor Receptor (EGFR) antibodies. EGFR is characterized by tyrosine kinase activity and occupies a key-role in the control of cellular transduction pathways. Its activation triggers both the RAS-RAF and PIK3CA pathways and is required to promote cell growth, differentiation, proliferation, and invasion. Cetuximab and panitumumab are both monoclonal antibodies (MoAbs) directed against the extracellular domain of EGFR, thus leading to inhibition of the downstream signaling pathways. Mutations in oncogene Kirsten-RAS (KRAS) are frequently associated with resistance to anti-EGFR therapy. However, a significant number of KRAS wild-type (WT) tumors fail to obtain disease control with anti-EGFR agents. Therefore, additional biomarkers of response/resistance to these drugs such as BRAF, NRAS, PIK3CA and PTEN have been investigated. This review will point attention on Neuroblastoma-RAS (NRAS) status in metastatic CRC (mCRC) patients (pts) selected for anti-EGFR therapy. PMID- 24758539 TI - Recent Clinical Evidence in Bisphosphonate-related Osteomyelitis of the Jaw: Focus on Risk, Prevention and Treatment. AB - Bisphosphonates (BPs) are widely used for the treatment of a range of conditions involving bone, such as osteoporosis and bone metastases of cancer, and their efficacy has been confirmed. Nevertheless, a first case of bisphosphonate- related osteonecrosis of the jaw (BRONJ) as an adverse effect of BP treatment was reported in 2003, and several clinical studies since then have elaborated the risk, prevention and treatment of BRONJ or bisphosphonate-related osteomyelitis of the jaw (BROMJ). However, effective decision making on BP risk is hampered by a lack of accurate information for patients, physicians or dentists. Furthermore, the narrow definition of BRONJ used to date has precluded the wider development of clinical research on risk. In this review, we discuss current issues in BROMJ, with a focus on risk, prevention and treatment. In particular, we reconsider the definition of BRONJ from the standpoint of clinical evidence. Finally, we propose a new strategy for the treatment of BROMJ. PMID- 24758540 TI - Defining professionalism: Simplex sigillum veri! PMID- 24758541 TI - Solvated states of poly-L-alanine alpha-helix explored by Raman optical activity. AB - Raman optical activity (ROA) reveals surprising details of the secondary structure of polypeptides and proteins in solution phase. Yet specific spectral features, such as in the extended amide III region of hydrated alpha-helix, did not seem explicable by the generally accepted sensitivity of ROA to the local conformation. This is reconciled in the present study by simulations of ROA spectra for model alpha-helical structures. Two positive ROA peaks often observed at around 1340 and 1300 cm(-1) for polypeptides and proteins have been assigned to two types of solvated alpha-helices; one is stable in hydrophilic environment where amide groups make hydrogen bonds to solvent molecules or polar side chains (~1340 cm(-1)), and the other is supported by a hydrophobic environment without the possibility of external hydrogen bonds (~1300 cm(-1)). For poly-L-alanine (PLA), regarded as a good model of alpha-helical structure, the experimentally observed relative intensity ratio of the two ROA bands has been explained by a conformational equilibrium depending on the solvent polarity. The intensities of the bands reflect solvated and unsolvated alpha-helical geometries, with peptide backbone torsional angles (phii+1, psii) of (-66 degrees , -41 degrees ) and (-59 degrees , -44 degrees ), respectively. Quantum-mechanical simulations of the ROA spectra utilizing the normal mode optimization and Cartesian tensor transfer methods indicate, however, that the change in dielectric constant of the solvent is the main factor for the spectral intensity change, whereas the influence of the conformational change is minor. PMID- 24758543 TI - Influence of molecular structure and adsorbent properties on sorption of organic compounds to a temperature series of wood chars. AB - Chars from wildfires and soil amendments (biochars) are strong adsorbents that can impact the fate of organic compounds in soil, yet the effects of solute and adsorbent properties on sorption are poorly understood. We studied sorption of benzene, naphthalene, and 1,4-dinitrobenzene from water to a series of wood chars made anaerobically at different heat treatment temperatures (HTT) from 300 to 700 degrees C, and to graphite as a nonporous, unfunctionalized reference adsorbent. Peak suppression in the NMR spectrum by sorption of the paramagnetic relaxation probe TEMPO indicated that only a small fraction of char C atoms lie near sorption sites. Sorption intensity for all solutes maximized with the 500 degrees C char, but failed to trend regularly with N2 or CO2 surface area, micropore volume, mesopore volume, H/C ratio, O/C ratio, aromatic fused ring size, or HTT. A model relating sorption intensity to a weighted sum of microporosity and mesoporosity was more successful. Sorption isotherm linearity declined progressively with carbonization of the char. Application of a thermodynamic model incorporating solvent-water and char-graphite partition coefficients permitted for the first time quantification of steric (size exclusion in pores) and pi-pi electron donor-acceptor (EDA) free energy contributions, relative to benzene. Steric hindrance for naphthalene increases exponentially from 9 to 16 kJ/mol (~ 1.6-2.9 log units of sorption coefficient) with the fraction of porosity in small micropores. pi-pi EDA interactions of dinitrobenzene contribute -17 to -19 kJ/mol (3-3.4 log units of sorption coefficient) to sorption on graphite, but less on chars. pi-pi EDA interaction of naphthalene on graphite is small (-2 to 2 kJ/mol). The results show that sorption is a complex function of char properties and solute molecular structure, and not very predictable on the basis of readily determined char properties. PMID- 24758542 TI - N-nitroso-N-ethylurea activates DNA damage surveillance pathways and induces transformation in mammalian cells. AB - BACKGROUND: The DNA damage checkpoint signalling cascade sense damaged DNA and coordinates cell cycle arrest, DNA repair, and/or apoptosis. However, it is still not well understood how the signalling system differentiates between different kinds of DNA damage. N-nitroso-N-ethylurea (NEU), a DNA ethylating agent induces both transversions and transition mutations. METHODS: Immunoblot and comet assays were performed to detect DNA breaks and activation of the canonical checkpoint signalling kinases following NEU damage upto 2 hours. To investigate whether mismatch repair played a role in checkpoint activation, knock-down studies were performed while flow cytometry analysis was done to understand whether the activation of the checkpoint kinases was cell cycle phase specific. Finally, breast epithelial cells were grown as 3-dimensional spheroid cultures to study whether NEU can induce upregulation of vimentin as well as disrupt cell polarity of the breast acini, thus causing transformation of epithelial cells in culture. RESULTS: We report a novel finding that NEU causes activation of major checkpoint signalling kinases, Chk1 and Chk2. This activation is temporally controlled with Chk2 activation preceding Chk1 phosphorylation, and absence of cross talk between the two parallel signalling pathways, ATM and ATR. Damage caused by NEU leads to the temporal formation of both double strand and single strand breaks. Activation of checkpoints following NEU damage is cell cycle phase dependent wherein Chk2 is primarily activated during G2-M phase whilst in S phase, there is immediate Chk1 phosphorylation and delayed Chk2 response. Surprisingly, the mismatch repair system does not play a role in checkpoint activation, at doses and duration of NEU used in the experiments. Interestingly, NEU caused disruption of the well formed polarised spheroid archithecture and upregulation of vimentin in three dimensional breast acini cultures of non-malignant breast epithelial cells upon NEU treatment indicating NEU to have the potential to cause early transformation in the cells. CONCLUSION: NEU causes damage in mammalian cells in the form of double strand and single strand breaks that temporally activate the major checkpoint signalling kinases without the occurrence of cross-talk between the pathways. NEU also appear to cause transformation in three-dimensional spheroid cultures. PMID- 24758545 TI - Multiple bullae in a newborn. PMID- 24758544 TI - Giant cell angiofibroma misdiagnosed as a vascular malformation and treated with absolute alcohol for one year: a case report and review of the literature. AB - PURPOSE: To present the clinical, imaging, pathological and immunohistochemical features of giant cell angiofibroma (GCA). CASE PRESENTATION: In this paper we report an atypical case of a GCA extending from the parotid to the parapharyngeal space. The lesion was being treated as a vascular malformation for one year prior to surgical removal. We summarize the clinical manifestations, imaging, pathological and molecular features of this rare disease.After complete surgical removal of the tumor, immunohistochemical analysis revealed strong positivity for the mesenchymal markers vimentin, CD34, CD31 and CD99 in neoplastic cells. Tumor proliferation antigen marker Ki67 was partly positive (<5% of cells). Tumor cells were negative for muscle-specific actin, epithelial membrane antigen, smooth muscle actin, cytokeratin pan, S100, desmin, glial fibrillary acidic protein, myogenin, MyoD1 and F8. The morphological and immunohistochemical profile was consistent with the diagnosis of GCA. CONCLUSION: GCA is a rare soft tissue tumor that can easily be misdiagnosed in the clinical preoperative setting. In view of the clinical, pathological and molecular features of the tumor, complete surgical removal is the current optimal treatment option, providing accurate diagnosis and low to minimal recurrence rate. PMID- 24758546 TI - High osteoprotegerin levels predict MACCE in STEMI patients, but are not associated with myocardial salvage. AB - OBJECTIVES: High circulating levels of osteoprotegerin (OPG) carry prognostic impact in cohorts with various cardiovascular diagnoses. With the present study, we aim to investigate the role of OPG within the scale of myocardial damage. DESIGN: This study includes 219 consecutive patients with acute ST-elevation myocardial infarction randomized to primary percutaneous coronary intervention (pPCI) or pPCI and remote ischemic per-conditioning. Salvage index via myocardial single-photon emission CT assessment (data available in 61% of the patients) was performed, and derived from Day 1 (myocardial area at risk) and Day 30 (final infarct size). Plasma OPG levels were measured using an in-house immunoassay. A combined end-point of all-mortality, myocardial infarction, stroke, readmission for heart failure and ischemic stroke/transient ischemic attack (Major Adverse Cardiac and Cerebrovascular Events [MACCE]) was used for follow-up; 45 (38-48 months). RESULTS: High OPG levels were associated with the severity of cardiovascular disease. During follow-up, OPG was a predictor of MACCE (unadjusted, HR: 2.1, 95% CI: 1.14-3.85, P = 0.017). Adjustments for age, gender, and body mass index preserved the independent predictive power of OPG. However, OPG levels were neither associated with salvage index nor with the final infarct size. Remote ischemic per-conditioning had no effect on OPG levels. CONCLUSION: Despite absent association between OPG levels and the scale of myocardial damage, high OPG levels predict a significantly increased risk of MACCE. PMID- 24758547 TI - Intracellular pH-sensitive metallo-supramolecular nanogels for anticancer drug delivery. AB - For drug delivery systems, the most important factors are biocompatibility and stability. To achieve excellent biocompatibility, learning from naturally occurring systems may be the best choice. Herein, a series of pH-sensitive metallo-supramolecular nanogels (MSNs) were prepared by the metallo supramolecular coordinated interaction between histidine and iron-meso tetraphenylporphin, which mimicks the way that hemoglobin carries oxygen. With the excellent biocompatibility and special supramolecular pH sensitivity, MSNs had been exploited to load and release anticancer drug doxorubicin (DOX). In vitro drug release profiles showed that only a small amount of the loaded DOX was released in PBS solution at pH 7.4, while up to about 80% of the loaded DOX could be quickly released at pH 5.3 due to the pH-dependent disassembly of MSNs. Confocal laser scanning microscopy (CLSM) and flow cytometry were used to verify the cellular uptake and intracellular drug release behaviors of DOX-loaded MSNs toward MCF-7. Efficient cellular proliferation inhibition against MCF-7 and HeLa cells was also observed by a 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. These features suggested that MSNs could be of great potential as intelligent drug delivery systems. PMID- 24758551 TI - Quantitative challenges facing patient-centered outcomes research. AB - Patient-centered outcomes research collects and analyzes data from patients and other stakeholders to improve health care delivery and outcomes and guide health care decisions. However, there are a number of challenges in conducting quantitative analyses of patient-centered data. This article provides an overview of the analytical challenges and describes approaches to consider to overcome the challenges, as well as directions for future development. PMID- 24758549 TI - Multi-ethnic minority nurses' knowledge and practice of genetics and genomics. AB - PURPOSE: Exploratory studies establishing how well nurses have integrated genomics into practice have demonstrated there remains opportunity for education. However, little is known about educational gaps in multi-ethnic minority nurse populations. The purpose of this study was to determine minority nurses' beliefs, practices, and competency in integrating genetics-genomics information into practice using an online survey tool. DESIGN: A cross-sectional survey with registered nurses (RNs) from the participating National Coalition of Ethnic Minority Organizations (NCEMNA). Two phases were used: Phase one had a sample of 27 nurses who determined the feasibility of an online approach to survey completion and need for tool revision. Phase two was a main survey with 389 participants who completed the revised survey. The survey ascertained the genomic knowledge, beliefs, and practice of a sample of multi-ethnic minority nurses who were members of associations comprising the NCEMNA. METHODS: The survey was administered online. Descriptive survey responses were analyzed using frequencies and percentages. Categorical responses in which comparisons were analyzed used chi square tests. FINDINGS: About 40% of the respondents held a master's degree (39%) and 42% worked in direct patient care. The majority of respondents (79%) reported that education in genomics was important. Ninety-five percent agreed or strongly agreed that family health history could identify at-risk families, 85% reported knowing how to complete a second- and third-generation family history, and 63% felt family history was important to nursing. Conversely, 50% of the respondents felt that their understanding of the genetics of common disease was fair or poor, supported by 54% incorrectly reporting they thought heart disease and diabetes are caused by a single gene variant. Only 30% reported taking a genetics course since licensure, and 94% reported interest in learning more about genomics. Eighty-four percent believed that their ethnic minority nurses' organizations should have a visible role in genetics and genomics in their communities. CONCLUSIONS: Most respondents felt genomics is important to integrate into practice but demonstrated knowledge deficits. There was strong interest in the need for continuing education and the role of the ethnic minority organizations in facilitating the continuing education efforts. This study provides evidence of the need for targeted genomic education to prepare ethnic minority nurses to better translate genetics and genomics into practice. CLINICAL RELEVANCE: Genomics is critical to the practice of all nurses, most especially family health history assessment and the genomics of common complex diseases. There is a great opportunity and interest to address the genetic-genomic knowledge deficits in the nursing workforce as a strategy to impact patient outcomes. PMID- 24758548 TI - Carbon monoxide and the CNS: challenges and achievements. AB - Haem oxygenase (HO) and its product carbon monoxide (CO) are associated with cytoprotection and maintenance of homeostasis in several different organs and tissues. This review focuses upon the role of exogenous and endogenous CO (via HO activity and expression) in various CNS pathologies, based upon data from experimental models, as well as from some clinical data on human patients. The pathophysiological conditions reviewed are cerebral ischaemia, chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases), multiple sclerosis and pain. Among these pathophysiological conditions, a variety of cellular mechanisms and processes are considered, namely cytoprotection, cell death, inflammation, cell metabolism, cellular redox responses and vasomodulation, as well as the different targeted neural cells. Finally, novel potential methods and strategies for delivering exogenous CO as a drug are discussed, particularly approaches based upon CO-releasing molecules, their limitations and challenges. The diagnostic and prognostic value of HO expression in clinical use for brain pathologies is also addressed. PMID- 24758552 TI - Impact of maternal breast cancer on school-aged children in Saudi Arabia. AB - BACKGROUND: We examine whether mothers with breast cancer told their children about the diagnosis, explore mothers' perceptions of the impact of doing so on the mother-child relationship, and assess perceptions of how this affected the children. METHODS: A convenience sample of 28 women with breast cancer ages 35 to 60 was interviewed using a 39-item close-ended questionnaire at the Al-Amoudi Breast Cancer Center of Excellence, King Abdulaziz University, Jeddah, Saudi Arabia. Inclusion criteria were having a diagnosis of breast cancer and having school-aged children (ages 5 to 16 years). Questions were asked concerning each child (n = 99). RESULTS: The majority of women (75%) told their children about the diagnosis, and explained the treatment (61%). In most cases, telling the children had a positive effect on how the children treated their mothers (84%), on the maternal-child relationship (80%), and on the personality and behavior of the child (90%). The most common negative reaction by children was increased clinging behavior to the mother (15%). Despite the perceived positive impact on the mother-child relationship and on the child's overall behavior towards the mother, school performance suffered as a result (77%). CONCLUSIONS: These preliminary results suggest that when a mother with breast cancer tells a child about the diagnosis and discusses it with them, this often results in an improvement in the maternal-child relationship. However, the knowing the mother's diagnosis may adversely affect the child's school performance, which will need to be anticipated and addressed with formal counseling if it persists. PMID- 24758553 TI - High exposure, spontaneous clearance, and low incidence of active Helicobacter pylori infection: the Sorbo San Basile study. AB - BACKGROUND: A decreased incidence of Helicobacter pylori infection has been prospected to occur nowadays. AIM: To evaluate the exposure to H. pylori, prevalence and incidence of active infection, and related risk factors in the general population. METHODS: In a small town of Southern Italy (932 inhabitants), 595 (3-97 years) and 157 (12-82 years) subjects among those with no evidence of active H. pylori infection participated at baseline and 10 years later, respectively. A questionnaire was administered. Active H. pylori infection was assessed by (13) C-urea breath test (UBT). Serum VacA and CagA antibodies were determined. RESULTS: Of 518 subjects who were evaluated by both UBT and serology, 310 (59.8%) were UBT positive, 479 (92.4%) VacA positive, and 369 (71.2%) CagA positive. Subjects UBT negative and serology positive were 169 (32%), ranging 1 (14.2%) to 29 (82.8%) from last to first decades of life. Age, female gender, and people per room were independent risk factors for subjects UBT positive compared to those UBT negative and serology positive. Ten years later, subjects who became UBT positive were four of 157 (0.25% per year) while those who became seropositive for VacA and/or CagA were 17 of 26 (6.5% per year). CONCLUSIONS: H. pylori infection is highly dynamic with wide range of spontaneous clearance. It is easily cleared in the first decades of life, more recent years, less crowded homes, and males. It disappears and recurs more often than it was previously thought, implying that the current decline in its prevalence is due to real clearance instead of a fall in infection rate. PMID- 24758554 TI - Traumatic optic neuropathy prediction after blunt facial trauma: derivation of a risk score based on facial CT findings at admission. AB - PURPOSE: To determine the specific facial computed tomographic (CT) findings that can be used to predict traumatic optic neuropathy (TON) in patients with blunt craniofacial trauma and propose a scoring system to identify patients at highest risk of TON. MATERIALS AND METHODS: This study was compliant with HIPAA, and permission was obtained from the institutional review board. Facial CT examination findings in 637 consecutive patients with a history of blunt facial trauma were evaluated retrospectively. The following CT variables were evaluated: midfacial fractures, extraconal hematoma, intraconal hematoma, hematoma along the optic nerve, hematoma along the posterior globe, optic canal fracture, nerve impingement by optic canal fracture fragment, extraconal emphysema, and intraconal emphysema. A prediction model was derived by using regression analysis, followed by receiver operating characteristic analysis to assess the diagnostic performance. To examine the degree of overfitting of the prediction model, a k-fold cross-validation procedure (k = 5) was performed. The ability of the cross-validated model to allow prediction of TON was examined by comparing the mean area under the receiver operating characteristic curve (AUC) from cross validations with that obtained from the observations used to create the model. RESULTS: The five CT variables with significance as predictors were intraconal hematoma (odds ratio, 12.73; 95% confidence interval [CI]: 5.16, 31.42; P < .001), intraconal emphysema (odds ratio, 5.21; 95% CI: 2.03, 13.36; P = .001), optic canal fracture (odds ratio, 4.45; 95% CI: 1.91, 10.35; P = .001), hematoma along the posterior globe (odds ratio, 0.326; 95% CI: 0.111, 0.958; P = .041), and extraconal hematoma (odds ratio, 2.36; 95% CI: 1.03, 5.41; P = .042). The AUC was 0.818 (95% CI: 0.734, 0.902) for the proposed model based on the observations used to create the model and 0.812 (95% CI: 0.723, 0.9) after cross-validation, excluding substantial overfitting of the model. CONCLUSION: The risk model developed may help radiologists suggest the possibility of TON and prioritize ophthalmology consults. However, future external validation of this prediction model is necessary. PMID- 24758555 TI - Intrastriatal transplantation of retinal pigment epithelial cells for the treatment of Parkinson disease: in vivo longitudinal molecular imaging with 18F P3BZA PET/CT. AB - PURPOSE: To evaluate the performance of N-[2-(diethylamino)ethyl]-(18)F-5 fluoropicolinamide ((18)F-P3BZA) for visualizing porcine retinal pigment epithelium (pRPE) cells transplanted in the striatum for the treatment of Parkinson disease and to monitor the long-term activity of implanted pRPE cells by means of (18)F-P3BZA positron emission tomography (PET)/computed tomography (CT) in vivo. MATERIALS AND METHODS: Animal work was conducted in accordance with the administrative panel on laboratory animal care. In vitro cell uptake of (18)F P3BZA was determined with incubation of melanotic pRPE or amelanotic ARPE-19 cells with (18)F-P3BZA. To visualize the implanted pRPE cells in vivo, normal rats (four per group) were injected with pRPE or ARPE-19 cells attached to gelatin microcarriers in the left striatum and with control gelatin microcarriers in the right striatum and followed up with small animal PET/CT. Longitudinal PET/CT scans were acquired in 12 rats up to 16 days after surgery. Postmortem analysis, which included autoradiography and hematoxylin-eosin, Fontana-Masson, and immunofluorescence staining, was performed. Data were compared with the Student t test, analysis of variance, and regression analysis. RESULTS: (18)F P3BZA accumulated in pRPE cells effectively (3.48% of the injected dose [ID] per gram of brain tissue +/- 0.58 at 1 hour after injection of the probe at 2 days after surgery in vivo) but not in control ARPE-19 cells (P < .05). Longitudinal PET/CT scans revealed that the activity of implanted pRPE cells decreased over time, as evidenced by a reduction in (18)F-P3BZA uptake (3.39% ID/g +/- 0.18, 2.49% ID/g +/- 0.41, and 1.20% ID/g +/- 0.13 at days 2, 9, and 16, respectively; P < .05). Postmortem analysis helped confirm the results of in vivo imaging. CONCLUSION: (18)F-P3BZA PET/CT is a feasible technique for visualizing and detecting the activity of implanted RPE cells in vivo. PMID- 24758556 TI - Unenhanced MR angiography of the foot: initial experience of using flow-sensitive dephasing-prepared steady-state free precession in patients with diabetes. AB - PURPOSE: To assess image quality and diagnostic performance of unenhanced magnetic resonance (MR) angiography with use of flow-sensitive dephasing (FSD) prepared steady-state free precession (SSFP) of the foot arteries in patients with diabetes. MATERIALS AND METHODS: This prospective study was approved by institutional review board. Informed consent was obtained from all subjects. Thirty-two healthy volunteers and 38 diabetic patients who had been scheduled for lower-extremity contrast material-enhanced MR angiography were recruited to undergo unenhanced MR angiography with a 1.5-T MR unit. Image quality and diagnostic accuracy of unenhanced MR angiography in the detection of significant arterial stenosis (>=50%) were assessed by two independent reviewers. Contrast enhanced MR angiography was used as the reference standard. The difference in the percentage of diagnostic arterial segments at unenhanced MR angiography between healthy volunteers and diabetic patients was evaluated with the McNemar test and generalized estimating equation for correlated data. Signal-to-noise ratio (SNR) and artery-to-muscle contrast-to-noise ratio (CNR) of pedal arteries were measured and compared between the two MR angiography techniques by using the paired t test. RESULTS: All subjects successfully underwent unenhanced MR angiography of the foot. Unenhanced MR angiography yielded a high percentage of diagnostic arterial segments in both healthy volunteers (303 of 320 segments, 95%) and patients (341 of 370 segments, 92%), and there was no difference in the percentage between the two populations (P = .195). In patients, the average SNR and CNR at unenhanced MR angiography were higher than those at contrast-enhanced MR angiography (SNR: 90.7 +/- 38.1 vs 81.7 +/- 34.7, respectively, P = .023; CNR: 85.2 +/- 33.2 vs 76.6 +/- 33.5, respectively, P = .013). The average sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of unenhanced MR angiography were 88% (35 of 40 segments), 93% (107 of 115 segments), 81% (35 of 43 segments), 96% (107 of 112 segments), and 92% (142 of 155 segments), respectively. Interobserver agreement between the two readers for diagnostic accuracy was good (kappa = 0.83). CONCLUSION: Unenhanced MR angiography with use of FSD-prepared SSFP allows clear depiction of the foot arterial tree and accurate detection of significant arterial stenosis. The technique has the potential to be a safe and reliable screening tool for the assessment of foot arteries in diabetic patients without the use of gadolinium based contrast material. PMID- 24758557 TI - Addition of shear-wave elastography during second-look MR imaging-directed breast US: effect on lesion detection and biopsy targeting. AB - PURPOSE: To determine if adding shear-wave elastography (SWE) to second-look ultrasonography (US) after breast dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging helps find or target lesions seen on DCE MR images for US-guided biopsy. MATERIALS AND METHODS: This HIPAA-compliant prospective study was approved by the institutional review board, and written informed consent was obtained from patients. From May 2011 to July 2012, 73 women with 96 Breast Imaging Reporting and Data System (BI-RADS) category 4 or 5 lesions after DCE MR imaging prospectively consented to undergo SWE during second look US. If a lesion was not confidently seen with B-mode US, SWE during real time scanning was performed to determine if SWE helped find or target lesions for US biopsy. A qualitative SWE six-point color scale was used to record the maximum elasticity in and around lesions. All lesions underwent US or DCE MR imaging guided core biopsy. RESULTS: Median participant age was 52 years (range, 21-81 years). In 72 patients who underwent DCE MR imaging, 96 BI-RADS category 4 or 5 lesions were detected in 81 breasts. There were 29 (30%) malignancies (one malignancy was of nonbreast origin), 14 (15%) high-risk lesions, and 53 (55%) benign lesions. US revealed 22 cancers, and seven cancers were detected only with MR imaging. Real-time SWE helped find one lesion and target four lesions that were incompletely assessed with gray-scale US. These five lesions that were localized or targeted for biopsy were invasive cancers, representing 23% of the 22 malignancies detected with US. CONCLUSION: Real-time SWE added to second-look US after DCE MR imaging increased the detection rate of cancers and helped target cancers for US-guided biopsy. PMID- 24758558 TI - Protective effects of different antioxidants against cadmium induced oxidative damage in rat testis and prostate tissues. AB - The present study was performed to determine the effects of different antioxidants on testicular histopathology and oxidative damage induced by cadmium (Cd) in rat testis and prostate. Twenty five rats were equally divided into five groups (n = 5/group). The control group was injected subcutaneously with saline while the Cd alone treated group received a subcutaneous injection of 0.2 mg/kg CdCl(2). Other groups were treated with sulphoraphane (25 ug/rat), vitamin E (75 mg/kg), and Ficus Religiosa plant extract (100 mg/kg) orally along with subcutaneous injections of 0.2 mg/kg CdCl(2) for fifteen days. Oxidative damage in the testicular and prostate tissues were assessed by the estimation of catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and glutathione reductase (GSR) activity. Lipid peroxidation (TBARS), protein estimation, and histomorphology were also assessed. Cadmium exposure caused a significant decrease in antioxidant enzymes like CAT, POD, SOD, GSR, protein concentrations, and a marked increase in TBARS activity in rat testis and prostate. Histological examination of adult male rat testes showed a disruption in the arrangement of seminiferous tubules along with a reduction in the number of germ cells, Leydig cells, tunica albuginea thickness, diameter of seminiferous tubules, and height of germinal epithelium. Co-treatment with vitamin E, sulphoraphane, and Ficus religiosa were found to be effective in reversing Cd induced toxicity, representing potential therapeutic options to protect the reproductive tissues from the detrimental effects of Cd toxicity. PMID- 24758559 TI - Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice. AB - NAFLD (non-alcoholic fatty liver disease) involves significant changes in liver metabolism characterized by oxidative stress, lipid accumulation and fibrogenesis. Mitochondrial dysfunction and bioenergetic defects also contribute to NAFLD. In the present study, we examined whether differences in mtDNA influence NAFLD. To determine the role of mitochondrial and nuclear genomes in NAFLD, MNX (mitochondrial-nuclear exchange) mice were fed an atherogenic diet. MNX mice have mtDNA from C57BL/6J mice on a C3H/HeN nuclear background and vice versa. Results from MNX mice were compared with wild-type C57BL/6J and C3H/HeN mice fed a control or atherogenic diet. Mice with the C57BL/6J nuclear genome developed more macrosteatosis, inflammation and fibrosis compared with mice containing the C3H/HeN nuclear genome when fed the atherogenic diet. These changes were associated with parallel alterations in inflammation and fibrosis gene expression in wild-type mice, with intermediate responses in MNX mice. Mice with the C57BL/6J nuclear genome had increased State 4 respiration, whereas MNX mice had decreased State 3 respiration and RCR (respiratory control ratio) when fed the atherogenic diet. Complex IV activity and most mitochondrial biogenesis genes were increased in mice with the C57BL/6J nuclear or mitochondrial genome, or both fed the atherogenic diet. These results reveal new interactions between mitochondrial and nuclear genomes and support the concept that mtDNA influences mitochondrial function and metabolic pathways implicated in NAFLD. PMID- 24758560 TI - Evaluation of multiple-turnover capability of locked nucleic acid antisense oligonucleotides in cell-free RNase H-mediated antisense reaction and in mice. AB - The multiple-turnover ability of a series of locked nucleic acid (LNA)-based antisense oligonucleotides (AONs) in the RNase H-mediated scission reaction was estimated using a newly developed cell-free reaction system. We determined the initial reaction rates of AONs under multiple-turnover conditions and found that among 24 AONs tested, AONs with melting temperatures (Tm) of 40 degrees C-60 degrees C efficiently elicit multiple rounds of RNA scission. On the other hand, by measuring Tm with two 10-mer RNAs partially complementary to AONs as models of cleaved 5' and 3' fragments of mRNA, we found that AONs require adequate binding affinity for efficient turnover activities. We further demonstrated that the efficacy of a set of 13-mer AONs in mice correlated with their turnover efficiency, indicating that the intracellular situation where AONs function is similar to multiple-turnover conditions. Our methodology and findings may provide an opportunity to shed light on a previously unknown antisense mechanism, leading to further improvement of the activity and safety profiles of AONs. PMID- 24758561 TI - Involvement of two-component signalling systems in the regulation of stomatal aperture by light in Arabidopsis thaliana. AB - Two-component signalling (TCS) systems play important roles in cytokinin and ethylene signalling in Arabidopsis thaliana. Although the involvement of histidine kinases (AHKs) in drought stress responses has been described, their role and that of histidine phosphotransferases (AHPs) in guard cell signalling remain to be fully elucidated. Here, we investigated the roles of TCS genes, the histidine phosphotransferase AHP2 and the histidine kinases AHK2 and AHK3, previously reported to play roles in cytokinin and abscisic acid (ABA) signalling. We show that AHP2 is present in the nucleus and the cytoplasm, and is involved in light-induced opening. We also present evidence that there is some redistribution of AHP2 from the nucleus to the cytoplasm on addition of ABA. In addition, we provide data to support a role for the cytokinin receptors AHK2 and AHK3 in light-induced stomatal opening and, by inference, in controlling the stomatal sensitivity to ABA. Our results provide new insights into the operation of TCS in plants, cross-talk in stomatal signalling and, in particular, the process of light-induced stomatal opening. PMID- 24758562 TI - Photohardening of polymorphic light eruption patients decreases baseline epidermal Langerhans cell density while increasing mast cell numbers in the papillary dermis. AB - The pathogenesis of polymorphic light eruption (PLE) has been linked to a lack of UV-induced immune suppression. To determine the role of Langerhans cells (LC), mast cells and regulatory T cells, biopsies from PLE patients were taken from exposed sites in spring before and after photohardening with 311 nm or PUVA as well as again in summer. Skin sections were assessed for the presence of Langerin/CD1a+ LC and CD3+, CD4+, CD25+ or FoxP3+ T cells and mast cells. Photohardening transiently decreased the density of epidermal LC and significantly increased a low baseline mast cell density in the papillary dermis of PLE patients. Baseline T cell numbers in the skin were low, and there was no difference in PLE patients among any time point. This suggests that LC suppression together with recruitment of mast cells into photohardened skin may be a key cellular event underlying the mechanism by which phototherapy protects from PLE. PMID- 24758563 TI - Agenda-setting for Canadian caregivers: using media analysis of the maternity leave benefit to inform the compassionate care benefit. AB - The Compassionate Care Benefit was implemented in Canada in 2004 to support employed informal caregivers, the majority of which we know are women given the gendered nature of caregiving. In order to examine how this policy might evolve over time, we examine the evolution of a similar employment insurance program, Canada's Maternity Leave Benefit. National media articles were reviewed (n = 2,698) and, based on explicit criteria, were analyzed using content analysis. Through the application of Kingdon's policy agenda-setting framework, the results define key recommendations for the Compassionate Care Benefit, as informed by the developmental trajectory of the Maternity Leave Benefit. Recommendations for revising the Compassionate Care Benefit are made. PMID- 24758564 TI - Clinicopathological significance of cancer stem cells marked by CD133 and KAI1/CD82 expression in laryngeal squamous cell carcinoma. AB - BACKGROUND: Presently, CD133 is one of the hottest markers to characterize cancer stem cells and KAI1/CD82 is reported as an important marker for the metastasis and prognosis of many cancers. The purpose of our study is to explore the relationship between cancer stem cells (CSCs) marked by CD133 and KAI1/CD82 expression and the clinicopathological characteristics of patients with laryngeal squamous cell carcinoma (LSCC). METHODS: Immunohistochemical analysis was used to detect the expression of CD133 and KAI1/CD82 in 83 archival surgical specimens of human LSCC and 83 cases of normal laryngeal tissues. RESULTS: In LSCC, positive rates of 49.4% and 41.0% were obtained for CD133 and KAI1/CD82, respectively. The expression of CD133 in LSCC tissues was significantly higher than that in normal tissues (P<0.001), and the expression of CD133 was positively associated with pTNM stage (P=0.005), pathological grade (P=0.001), and lymph node metastasis (P<0.001). The reduced expression of KAI1/CD82 was present in LSCC tissues. The positive rate of KAI1/CD82 expression was negatively correlated with pTNM stage (P=0.014), pathological grade (P<0.001), and lymph node metastasis (P=0.007). A correlation analysis showed that there was a negative relationship between the expression of CD133 and KAI1/CD82 protein in LSCC tissues (P<0.001). By Kaplan Meier analysis, the expression of CD133 was negatively correlated with overall survival (OS) (log-rank=40.949, P<0.001) and disease-free survival (DFS) (log rank=39.307, P<0.001) time of LSCC. The expression of KAI1/CD82 was positively correlated with OS (log-rank=40.279, P<0.001) and DFS (log-rank=39.271, P<0.001) time of LSCC. Cox regression analysis: the expression of CD133 and KAI1/CD82, and pTNM stages were independent prognostic factors of LSCC (P<0.05). CONCLUSIONS: Thus the detection of CD133 and KAI1/CD82 proteins may be used as a potential indicator of LSCC prognosis. PMID- 24758566 TI - Interventions to support children's engagement in health-related decisions: a systematic review. AB - BACKGROUND: Children often need support in health decision-making. The objective of this study was to review characteristics and effectiveness of interventions that support health decision-making of children. METHODS: A systematic review. Electronic databases (PubMed, the Cochrane Library, Web of Science, Scopus, ProQuest Dissertations and Theses, CINAHL, PsycINFO, MEDLINE, and EMBASE) were searched from inception until March 2012. Two independent reviewers screened eligibility: a) intervention studies; b) involved supporting children (<=18 years) considering health-related decision(s); and c) measured decision quality or decision-making process outcomes. Data extraction and quality appraisal were conducted by one author and verified by another using a standardized data extraction form. Quality appraisal was based on the Cochrane Risk of Bias tool. RESULTS: Of 4313 citations, 5 studies were eligible. Interventions focused on supporting decisions about risk behaviors (n = 3), psycho-educational services (n = 1), and end of life (n = 1). Two of 5 studies had statistically significant findings: i) compared to attention placebo, decision coaching alone increased values congruence between child and parent, and child satisfaction with decision making process (lower risk of bias); ii) compared to no intervention, a workshop with weekly assignments increased overall decision-making quality (higher risk of bias). CONCLUSIONS: Few studies have focused on interventions to support children's participation in decisions about their health. More research is needed to determine effective methods for supporting children's health decision-making. PMID- 24758568 TI - Aroma active volatiles in four southern highbush blueberry cultivars determined by gas chromatography-olfactometry (GC-O) and gas chromatography-mass spectrometry (GC-MS). AB - Aroma active volatiles in four southern highbush blueberry cultivars ('Prima Dona', 'Jewel', 'Snow Chaser', and 'Kestrel') were determined using solid phase microextraction (SPME) in combination with gas chromatography-olfactometry (GC-O) and identified via GC-PFPD and GC-MS using retention indices of reference compounds and mass spectral data. The aromas of total, unseparated SPME extracts evaluated using GC-O were rated 8.2-9.0/10 for the four cultivars in terms of similarity to the original blueberry homogenates. In terms of GC-O aroma similarity, those aroma active volatile groups characterized as green, fruity, and floral were most intense. Of the 43 volatiles found to have aroma activity, 38 were identified and 13 had not been previously reported in blueberries. Although linalool and (E)-2-hexenal were common major aroma impact volatiles, dominant aroma-active volatiles were different for each cultivar. Principal component analysis confirmed that each cultivar possessed a unique aroma active profile as each cultivar was clustered into a separate score plot quadrant. PMID- 24758565 TI - Biomarkers can predict potential clinical responders to DIMS0150 a toll-like receptor 9 agonist in ulcerative colitis patients. AB - BACKGROUND: Glucocorticoids (GCS) remain one of the mainstay treatments in the management of ulcerative colitis (UC) but up to a third of patients will ultimately fail to respond and progress to a more severe and difficult to manage disease state. Previous clinical studies suggest that the Toll-Like Receptor 9 (TLR9) agonist DIMS0150 not only induces production of key anti-inflammatory cytokines as IL-10 but interestingly also enhances steroid sensitivity in steroid refractory UC patients. We investigated, in the context of a clinical study, whether a pre-selection of steroid response genes could identify steroid refractory UC subjects most likely to respond to DIMS0150 treatment. METHODS: In a non-interventional pilot study, blood from steroid refractory UC patients and healthy volunteers was taken and thirty-four previously described steroid response genes were analysed by real time PCR analysis. To establish clinical utility of the identified biomarkers, a placebo controlled, randomized, double blinded study in active steroid dependent and steroid resistant UC patients on concomitant steroid therapies was used (EudraCT number: 2006-001846-15). RESULTS: We identified three potential biomarkers CD163, TSP-1 and IL-1RII whose response to steroids was significantly enhanced when DIMS0150 was applied. Thirty-four subjects were randomized to receive a single rectal administration of placebo or 30 mg of DIMS0150. Blood derived PBMCs were obtained prior to dosing and assayed for evidence of a steroid enhancing effect following steroid incubation in the presence of DIMS0150. Comparison to established steroid sensitivity marker IL-6 confirmed that clinical responders are steroid refractory UC patients. Upon study completion and un-blinding, the biomarker assay correctly predicted a clinical response in over 90% of the patients. CONCLUSION: Using specific steroid response biomarkers, GCS refractory UC patients most likely to benefit from DIMS0150 treatment could be identified and illustrates the usefulness of a personalized treatment approach. PMID- 24758567 TI - Hypoxia augments the calcium-activated chloride current carried by anoctamin-1 in cardiac vascular endothelial cells of neonatal mice. AB - BACKGROUND AND PURPOSE: The molecular identity of calcium-activated chloride channels (CaCCs) in vascular endothelial cells remains unknown. This study sought to identify whether anoctamin-1 (Ano1, also known as TMEM16A) functions as a CaCC and whether hypoxia alters the biophysical properties of Ano1 in mouse cardiac vascular endothelial cells (CVECs). EXPERIMENTAL APPROACH: Western blot, quantitative real-time PCR, confocal imaging analysis and patch-clamp analysis combined with pharmacological approaches were used to determine whether Ano1 was expressed and functioned as CaCC in CVECs. KEY RESULTS: Ano1 was expressed in CVECs. The biophysical properties of the current generated in the CVECs, including the Ca(2+) and voltage dependence, outward rectification, anion selectivity and the pharmacological profile, are similar to those described for CaCCs. The density of ICl ( C a) detected in CVECs was significantly inhibited by T16Ainh -A01, an Ano1 inhibitor, and a pore-targeting, specific anti-Ano1 antibody, and was markedly decreased in Ano1 gene knockdown CVECs. The density of ICl ( C a) was significantly potentiated in CVECs exposed to hypoxia, and this hypoxia-induced increase in the density of ICl ( C a) was inhibited by T16Ainh A01 or anti-Ano1 antibody. Hypoxia also increased the current density of ICl ( C a) in Ano1 gene knockdown CVECs. CONCLUSIONS AND IMPLICATIONS: Ano1 formed CaCC in CVECs of neonatal mice. Hypoxia enhances Ano1-mediated ICl ( C a) density via increasing its expression, altering the ratio of its splicing variants, sensitivity to membrane voltage and to Ca(2+) . Ano1 may play a role in the pathophysiological processes during ischaemia in heart, and therefore, Ano1 might be a potential therapeutic target to prevent ischaemic damage. PMID- 24758569 TI - Analysis of Spanish generic medicines retail market: recommendations to enhance long-term sustainability. AB - The use of generic medicines in Spain is traditionally low compared to other European countries, despite efforts of the Spanish government in the past. This paper provides a perspective on the Spanish generic medicines retail market and how the current policy environment may affect the long-term sustainability. The Spanish government's focus on prices of generic medicines (e.g., mandatory price cuts, reference price set at the lowest level) have made them amongst the lowest in Europe. In our opinion, this combination of continuous pressure on prices and limited diffusion of generic medicines may undermine the long-term sustainability of the Spanish generic medicines retail market. The unique experience in Spain shows the impact of demand-side policies on the use of generic medicines. Because a sustainable generic medicines retail market is important to maintain future competition in the off-patent medicines market, this perspective paper rounds off with recommendations to increase its sustainability. PMID- 24758570 TI - A novel carboxyethyltin functionalized sandwich-type germanotungstate: synthesis, crystal structure, photosensitivity, and application in dye-sensitized solar cells. AB - A novel sandwich-type germanotungstate [C(NH2)3]10[Mn2{Sn(CH2)2COOH}2(B-alpha GeW9O34)2].8H2O (1) represents the first single crystalline polyoxometalate (POM) functionalized by open chain carboxyethyltin, which was designed and synthesized in aqueous solution and applied to a dye-sensitized solar cell (DSSC) for the first time. Its photosensitivity was explored through a fluorescence spectrum (FL), surface photovoltage spectrum (SPV), electrochemical method, and solid diffuse spectrum. 1 displays the primary features of sensitizers in DSSCs, and the efficiency of the solar cell is 0.22%. Delightedly, when 1 was employed to assemble a cosensitized solar cell configuration by preparing a 1-doped TiO2 electrode and additionally adsorbing N719 dyes, a considerably improved efficiency was achieved through increasing spectral absorption and accelerating electron transport, which is 19.4% higher than that of single N719 sensitization. This result opens up a new way to position different dyes on a single TiO2 film for cosensitization. PMID- 24758571 TI - Impact of a smoking cessation educational program on nurses' interventions. AB - PURPOSE: To evaluate a brief educational program about smoking cessation on the frequency of nurses' interventions with smokers, and impact of nurses' smoking status on outcomes. DESIGN: Prospective, single group design with prestudy and 3 months post-study data. METHODS: Nurses in the Czech Republic attended hospital based 1-hr educational programs about helping smokers quit. They completed surveys about the frequency (i.e., always, usually, sometimes, rarely, never) of their smoking cessation interventions with patients using the five A's framework (i.e., ask, advise, assess, assist, arrange), and their attitudes prior to and 3 months after the course. Demographic data included smoking status. FINDINGS: Among the 98 nurses with prestudy and post-study data, all were female, mean age was 43 years, 33% were current smokers, and 64% worked in a medical or surgical or oncology settings. At 3 months, compared to baseline, significantly (p < .05) more nurses assessed patients' interest in quitting, assisted with quit attempts, and recommended the use of the quitline for cessation. At 3 months after the program, nurses who smoked were less likely to ask about smoking status (odds ratio [OR] = 4.24, 95% confidence interval [CI; 1.71, 10.53]), advise smokers to quit (OR = 3.03, 95% CI [1.24,7.45]), and refer patients to a quitline (OR = 2.92, 95% CI [0.99, 8.63]) compared to nonsmokers, despite no differences in delivery of interventions at baseline. CONCLUSIONS: Three months after attendance at an educational program focused on the nurses' role in supporting smoking cessation efforts, more nurses engaged in interventions to help smokers quit. However, the program was less effective for nurses who smoked. CLINICAL RELEVANCE: This program demonstrated promise in building capacity among Czech nurses to assist with smoking cessation, but nurses' smoking poses a challenge. PMID- 24758573 TI - Shear-induced membrane fusion in viscous solutions. AB - Large unilamellar lipid vesicles do not normally fuse under fluid shear stress. They might deform and open pores to relax the tension to which they are exposed, but membrane fusion occurring solely due to shear stress has not yet been reported. We present evidence that shear forces in a viscous solution can induce lipid bilayer fusion. The fusion of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposomes is observed in Couette flow with shear rates above 3000 s(-1) provided that the medium is viscous enough. Liposome samples, prepared at different viscosities using a 0-50 wt % range of sucrose concentration, were studied by dynamic light scattering, lipid fusion assays using Forster resonance energy transfer (FRET), and linear dichroism (LD) spectroscopy. Liposomes in solutions with 40 wt % (or more) sucrose showed lipid fusion under shear forces. These results support the hypothesis that under suitable conditions lipid membranes may fuse in response to mechanical-force-induced stress. PMID- 24758572 TI - New insight into the SSC8 genetic determination of fatty acid composition in pigs. AB - BACKGROUND: Fat content and fatty acid composition in swine are becoming increasingly studied because of their effect on sensory and nutritional quality of meat. A QTL (quantitative trait locus) for fatty acid composition in backfat was previously detected on porcine chromosome 8 (SSC8) in an Iberian x Landrace F2 intercross. More recently, a genome-wide association study detected the same genomic region for muscle fatty acid composition in an Iberian x Landrace backcross population. ELOVL6, a strong positional candidate gene for this QTL, contains a polymorphism in its promoter region (ELOVL6:c.-533C < T), which is associated with percentage of palmitic and palmitoleic acids in muscle and adipose tissues. Here, a combination of single-marker association and the haplotype-based approach was used to analyze backfat fatty acid composition in 470 animals of an Iberian x Landrace F2 intercross genotyped with 144 SNPs (single nucleotide polymorphisms) distributed along SSC8. RESULTS: Two trait associated SNP regions were identified at 93 Mb and 119 Mb on SSC8. The strongest statistical signals of both regions were observed for palmitoleic acid (C16:1(n 7)) content and C18:0/C16:0 and C18:1(n-7)/C16:1(n-7) elongation ratios. MAML3 and SETD7 are positional candidate genes in the 93 Mb region and two novel microsatellites in MAML3 and nine SNPs in SETD7 were identified. No significant association for the MAML3 microsatellite genotypes was detected. The SETD7:c.700G > T SNP, although statistically significant, was not the strongest signal in this region. In addition, the expression of MAML3 and SETD7 in liver and adipose tissue varied among animals, but no association was detected with the polymorphisms in these genes. In the 119 Mb region, the ELOVL6:c.-533C > T polymorphism showed a strong association with percentage of palmitic and palmitoleic fatty acids and elongation ratios in backfat. CONCLUSIONS: Our results suggest that the polymorphisms studied in MAML3 and SETD7 are not the causal mutations for the QTL in the 93 Mb region. However, the results for ELOVL6 support the hypothesis that the ELOVL6:c.-533C > T polymorphism has a pleiotropic effect on backfat and intramuscular fatty acid composition and that it has a role in the determination of the QTL in the 119 Mb region. PMID- 24758574 TI - Assessing the quality of life of children with sickle cell anaemia using self-, parent-proxy, and health care professional-proxy reports. AB - OBJECTIVES: The quality of life (QoL) of children with sickle cell anaemia (SCA) in the United Kingdom has not been examined, and a discrepancy measure based on Gap theory has rarely been used. This study investigated whether (1) child self reports of QoL using a discrepancy measure (the Generic Children's QoL Measure; GCQ) are lower than those from healthy children, (2) proxy reports from parents and health care professionals are lower than child self-reports, and (3) demographic and disease severity indicators are related to QoL. DESIGN AND METHODS: An interdependent groups, cross-sectional design was implemented. Seventy-four children with SCA, their parent, and members of their health care team completed the GCQ. Demographic and disease severity indicators were recorded. GCQ data from healthy children were obtained from the UK Data Archive. RESULTS: Contrary to past research, when examining generic discrepancy QoL, children with SCA did not report a lower QoL than healthy children, and parent- and health care professional-proxy reports were not lower than child self reports. Few of the demographic and disease severity indicators were related to QoL. CONCLUSIONS: Proxy reports may be used to gain a more complete picture of QoL, but should not be a substitute for self-reports. The explanation for the relatively high levels of QoL reported is not clear, but children with SCA may have realistic expectations about their ideal-self, place greater emphasis on aspects other than health in shaping their QoL, and define achievements within the limits of their illness. Future research should focus on psychological factors in explaining QoL. Statement of contribution What is already known on this subject? Children with sickle cell disease (SCD) generally have a reduced QoL compared with healthy children, but there appears to be no research measuring QoL in paediatric SCD in the United Kingdom. Proxy QoL reports from parents are often lower than child self-reports, but there is less research examining proxy reports from health care professionals. Previous research has measured paediatric QoL using measures of current health-related QoL, but this is not in line with the WHO's definition of QoL as the discrepancy between current state and expectations. What does this study add? Children with Sickle cell anaemia do not have an impaired discrepancy QoL; they may have realistic expectations about their ideal-self and define achievements within the limits of their illness. Health care professionals are able to gauge a SCA child's discrepancy QoL better than parents. The GCQ (a generic discrepancy measure of QoL) takes into account expectations about ideal QoL and does not emphasize health; it may be of use to Psychologists working with SCA children. PMID- 24758575 TI - IgG4-related skin lesions: case report and review of the literature. AB - IgG4-related disease (IgG4-RD) is a systemic disease, mostly affecting the pancreas. It presents as accumulation of IgG4-producing plasma cells in various tissues. Other possible affected organs include the lacrimal glands, salivary glands, lungs, kidneys, liver, bile duct, retroperitoneum, breast, aorta, pituitary gland and prostate. A cutaneous presentation has also been described in the literature, and might be the initial presenting feature of IgG4-RD. We describe a 73-year-old white man who presented with two infiltrated, erythematous nodules on his abdomen. The histopathological characteristics were highly suggestive of IgG4-related cutaneous disease. Immunohistochemical stains were positive for IgG4. In the past, the patient's other organs had also been affected by IgG4-RD. Cutaneous presentation of IgG4-RD has been described previously in the literature but only in Asian patients (both East and South Asian). We also provide an overview of previously reported cutaneous manifestations of IgG4-RD. PMID- 24758576 TI - Drp1 stabilizes p53 on the mitochondria to trigger necrosis under oxidative stress conditions in vitro and in vivo. AB - Oxidative-stress-induced necrosis is considered to be one of the main pathological mediators in various neurological disorders, such as brain ischaemia. However, little is known about the mechanism by which cells modulate necrosis in response to oxidative stress. In the present study, we showed that Drp1 (dynamin-related protein 1), a primary mitochondrial fission protein, stabilizes the well-known stress gene p53 and is required for p53 translocation to the mitochondria under conditions of oxidative stress. We found that Drp1 binding to p53 induced mitochondria-related necrosis. In contrast, inhibition of Drp1 hyperactivation by Drp1 siRNA reduced necrotic cell death in cell cultures exposed to oxidative stress. Most significantly, we demonstrated that inhibition of Drp1 by the Drp1 peptide inhibitor P110, which was developed recently by our group, abolished p53 association with the mitochondria and reduced brain infarction in rats subjected to brain ischaemia/reperfusion injury. Taken together, these findings reveal a novel mechanism of Drp1 hyperactivation in the induction of mitochondrial damage and subsequent cell death. We propose that a Drp1 inhibitor such as P110 is a possible therapeutic agent for diseases in which hyperactivated Drp1 contributes to the pathology. PMID- 24758577 TI - Autosomal mutants of proton-exposed kidney cells display frequent loss of heterozygosity on nonselected chromosomes. AB - High-energy protons found in the space environment can induce mutations and cancer, which are inextricably linked. We hypothesized that some mutants isolated from proton-exposed kidneys arose through a genome-wide incident that causes loss of heterozygosity (LOH)-generating mutations on multiple chromosomes (termed here genomic LOH). To test this hypothesis, we examined 11 pairs of nonselected chromosomes for LOH events in mutant cells isolated from the kidneys of mice exposed to 4 or 5 Gy of 1 GeV protons. The mutant kidney cells were selected for loss of expression of the chromosome 8-encoded Aprt gene. Genomic LOH events were also assessed in Aprt mutants isolated from isogenic cultured kidney epithelial cells exposed to 5 Gy of protons in vitro. Control groups were spontaneous Aprt mutants and clones isolated without selection from the proton-exposed kidneys or cultures. The in vivo results showed significant increases in genomic LOH events in the Aprt mutants from proton-exposed kidneys when compared with spontaneous Aprt mutants and when compared with nonmutant (i.e., nonselected) clones from the proton-exposed kidneys. A bias for LOH events affecting chromosome 14 was observed in the proton-induced Aprt mutants, though LOH for this chromosome did not confer increased radiation resistance. Genomic LOH events were observed in Aprt mutants isolated from proton-exposed cultured kidney cells; however the incidence was fivefold lower than in Aprt mutants isolated from exposed intact kidneys, suggesting a more permissive environment in the intact organ and/or the evolution of kidney clones prior to their isolation from the tissue. We conclude that proton exposure creates a subset of viable cells with LOH events on multiple chromosomes, that these cells form and persist in vivo, and that they can be isolated from an intact tissue by selection for a mutation on a single chromosome. PMID- 24758578 TI - Military participants at U.S. Atmospheric nuclear weapons testing--methodology for estimating dose and uncertainty. AB - Methods were developed to calculate individual estimates of exposure and dose with associated uncertainties for a sub-cohort (1,857) of 115,329 military veterans who participated in at least one of seven series of atmospheric nuclear weapons tests or the TRINITY shot carried out by the United States. The tests were conducted at the Pacific Proving Grounds and the Nevada Test Site. Dose estimates to specific organs will be used in an epidemiological study to investigate leukemia and male breast cancer. Previous doses had been estimated for the purpose of compensation and were generally high-sided to favor the veteran's claim for compensation in accordance with public law. Recent efforts by the U.S. Department of Defense (DOD) to digitize the historical records supporting the veterans' compensation assessments make it possible to calculate doses and associated uncertainties. Our approach builds upon available film badge dosimetry and other measurement data recorded at the time of the tests and incorporates detailed scenarios of exposure for each veteran based on personal, unit, and other available historical records. Film badge results were available for approximately 25% of the individuals, and these results assisted greatly in reconstructing doses to unbadged persons and in developing distributions of dose among military units. This article presents the methodology developed to estimate doses for selected cancer cases and a 1% random sample of the total cohort of veterans under study. PMID- 24758579 TI - The correlation between the expression of differentiated embryo-chondrocyte expressed gene l and oral squamous cell carcinoma. AB - BACKGROUND: This study aims to explore the correlation between expression of differentiated embryo-chondrocyte expressed gene l (DEC1) and oral squamous cell carcinoma (OSCC), which could provide the reference for treatment and prognosis assessment of OSCC. METHODS: The expression of DEC1 in tissues from 56 primary OSCC patients and 20 normal oral mucosa samples were detected using real-time polymerase chain reaction and immunohistochemical methods, respectively. RESULTS: The results showed that the positive expression rate of DEC1 in the OSCC group was significantly higher than that in the normal group (P <0.05); further, the expression of DEC1 in different OSCC groups was statistically significant (P <0.05). The expression of DEC1 in the 1-year recurrence OSCC group was significantly higher than other groups. The expression of DEC1 in the 3-years no recurrence OSCC group was the lowest. CONCLUSIONS: The expression of DEC1 was associated with the incidence of OSCC and there was a negative correlation between the expression of DEC1 and the prognosis of OSCC. PMID- 24758580 TI - The public health foundation of health services for American Indians & Alaska Natives. AB - The integration of public health practices with federal health care for American Indians and Alaska Natives (AI/ANs) largely derives from three major factors: the sovereign nature of AI/AN tribes, the sociocultural characteristics exhibited by the tribes, and that AI/ANs are distinct populations residing in defined geographic areas. The earliest services consisted of smallpox vaccination to a few AI/AN groups, a purely public health endeavor. Later, emphasis on public health was codified in the Snyder Act of 1921, which provided for, among other things, conservation of the health of AI/AN persons. Attention to the community was greatly expanded with the 1955 transfer of the Indian Health Service from the US Department of the Interior to the Public Health Service and has continued with the assumption of program operations by many tribes themselves. We trace developments in integration of community and public health practices in the provision of federal health care services for AI/AN persons and discuss recent trends. PMID- 24758581 TI - Constitutive salicylic acid accumulation in pi4kIIIbeta1beta2 Arabidopsis plants stunts rosette but not root growth. AB - Phospholipids have recently been found to be integral elements of hormone signalling pathways. An Arabidopsis thaliana double mutant in two type III phosphatidylinositol-4-kinases (PI4Ks), pi4kIIIbeta1beta2, displays a stunted rosette growth. The causal link between PI4K activity and growth is unknown. Using microarray analysis, quantitative reverse transcription polymerase chain reaction (RT-qPCR) and multiple phytohormone analysis by LC-MS we investigated the mechanism responsible for the pi4kIIIbeta1beta2 phenotype. The pi4kIIIbeta1beta2 mutant accumulated a high concentration of salicylic acid (SA), constitutively expressed SA marker genes including PR-1, and was more resistant to Pseudomonas syringae. pi4kIIIbeta1beta2 was crossed with SA signalling mutants eds1 and npr1 and SA biosynthesis mutant sid2 and NahG. The dwarf phenotype of pi4kIIIbeta1beta2 rosettes was suppressed in all four triple mutants. Whereas eds1 pi4kIIIbeta1beta2, sid2 pi4kIIIbeta1beta2 and NahG pi4kIIIbeta1beta2 had similar amounts of SA as the wild-type (WT), npr1pi4kIIIbeta1beta2 had more SA than pi4kIIIbeta1beta2 despite being less dwarfed. This indicates that PI4KIIIbeta1 and PI4KIIIbeta2 are genetically upstream of EDS1 and need functional SA biosynthesis and perception through NPR1 to express the dwarf phenotype. The slow root growth phenotype of pi4kIIIbeta1beta2 was not suppressed in any of the triple mutants. The pi4kIIIbeta1beta2 mutations together cause constitutive activation of SA signalling that is responsible for the dwarf rosette phenotype but not for the short root phenotype. PMID- 24758582 TI - Geographic variations and temporal trends in prostate cancer in Martinique over a 25-year period. AB - BACKGROUND: In Martinique, prostate cancer incidence rates have been increasing since the 1980s and are actually among the highest worldwide. Exposure to lifestyle (changes in dietary habits), environmental factors (exposure to organochlorine pesticides) and modifications in diagnostic and screening procedures, are favored etiological hypotheses. The aim of the present study is to describe and interpret prostate cancer incidence trends over the past 25 years (1981-2005) in Martinique. METHODS: Data on incident prostate cancer cases from 1981 to 2005 were obtained from the population-based Martinique Cancer Registry. World age-standardised incidence rates were calculated and an age-period-cohort model was used to determine average annual variations for prostate cancer during the study period. Age and period effects were assessed, employing the method proposed by Clayton and Schifflers. Relative changes in prostate cancer incidence, at five-year intervals between 1981 and 2005, were also studied with an organochlorine pesticide exposure index, built as a proxy of the relative intensity of chlordecone use on the island between 1973 and 1993. RESULTS: Prostate cancer incidence was found to increase by 5.07% annually between 1981 and 2005. Compared to 1981-1985, prostate cancer relative risk, in men aged 50-74 years and 75 years and above was respectively 5.98% and 3.07% from 2001 to 2005. An inverse association between population pesticide exposure levels and prostate cancer risk was also highlighted, with highest prostate cancer incidences observed in urban zones showing the lowest soil contamination levels by the chlordecone pesticide (zone 1). CONCLUSION: No conclusive association was found between the intensity of pesticide use and the subsequent rise in prostate cancer incidence. However, it remains necessary to develop and reinforce continuous monitoring of prostate cancer incidence and mortality trends on the island. Further studies are also needed in order to consider other risk factors such as modifications in diagnostic and screening procedures over the last 25 years. PMID- 24758583 TI - Human genetic research, race, ethnicity and the labeling of populations: recommendations based on an interdisciplinary workshop in Japan. AB - BACKGROUND: A challenge in human genome research is how to describe the populations being studied. The use of improper and/or imprecise terms has the potential to both generate and reinforce prejudices and to diminish the clinical value of the research. The issue of population descriptors has not attracted enough academic attention outside North America and Europe. In January 2012, we held a two-day workshop, the first of its kind in Japan, to engage in interdisciplinary dialogue between scholars in the humanities, social sciences, medical sciences, and genetics to begin an ongoing discussion of the social and ethical issues associated with population descriptors. DISCUSSION: Through the interdisciplinary dialogue, we confirmed that the issue of race, ethnicity and genetic research has not been extensively discussed in certain Asian communities and other regions. We have found, for example, the continued use of the problematic term, "Mongoloid" or continental terms such as "European," "African," and "Asian," as population descriptors in genetic studies. We, therefore, introduce guidelines for reporting human genetic studies aimed at scientists and researchers in these regions. CONCLUSION: We need to anticipate the various potential social and ethical problems entailed in population descriptors. Scientists have a social responsibility to convey their research findings outside of their communities as accurately as possible, and to consider how the public may perceive and respond to the descriptors that appear in research papers and media articles. PMID- 24758584 TI - Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus. AB - Irradiation with ultraviolet (UV) light is an important exacerbating factor in cutaneous lupus erythematosus (CLE) and induces various effects in the skin of patients with the disease, such as cell death and inflammation. Recently, we demonstrated the ability of a broad-spectrum sunscreen to prevent UV-induced damage both in patients with CLE and healthy controls (HCs). The aim of this study was to evaluate whether the UV-dependent activation of interferon (IFN) driven inflammation in CLE can also be prevented by application of the sunscreen. In 20 patients with different subtypes of CLE and 10 HCs, defined areas on the upper back were treated with a broad-spectrum liposomal sunscreen 20 min prior to a combined standardized UVA/UVB irradiation. Immunohistological analyses using antibodies directed against MxA, CD11c, CD123 and CD68 were performed from skin biopsies taken from areas before UV irradiation as well as from sunscreen-treated and sunscreen-untreated areas 24 and 72 h after UV irradiation. The expression of MxA was completely prevented by the sunscreen applied prior to UV irradiation in CLE patients and HCs. Additionally, sunscreen protection significantly diminished the number of the CD11c- and CD123-positive dendritic cells, which are suggested to be a major source of type I/III IFNs, in UV-irradiated skin of patients with CLE. Moreover, the application of the sunscreen prevented the increase in CD68 positive macrophages in both groups 72 h after UV irradiation. The data of this study demonstrate that UV protection reduces lesional tissue damage and inhibits the typical IFN-driven inflammatory response in CLE. PMID- 24758586 TI - Surface immobilization of a tetra-ruthenium substituted polyoxometalate water oxidation catalyst through the employment of conducting polypyrrole and the layer by-layer (LBL) technique. AB - A tetra Ru-substituted polyoxometalate Na10[{Ru4O4(OH)2(H2O)4}(gamma-SiW10O36)2] (Ru4POM) has been successfully immobilised onto glassy carbon electrodes and indium tin oxide (ITO) coated glass slides through the employment of a conducting polypyrrole matrix and the layer-by-layer (LBL) technique. The resulting Ru4POM doped polypyrrole films showed stable redox behavior associated with the Ru centres within the Ru4POM, whereas, the POM's tungsten-oxo redox centres were not accessible. The films showed pH dependent redox behavior within the pH range 2-5 whilst exhibiting excellent stability towards redox cycling. The layer-by-layer assembly was constructed onto poly(diallyldimethylammonium chloride) (PDDA) modified carbon electrodes by alternate depositions of Ru4POM and a Ru(II) metallodendrimer. The resulting Ru4POM assemblies showed stable redox behavior for the redox processes associated with Ru4POM in the pH range 2-5. The charge transfer resistance of the LBL films was calculated through AC-Impedance. Surface characterization of both the polymer and LBL Ru4POM films was carried out using atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM). Initial investigations into the ability of the Ru4POM LBL films to electrocatalytically oxidise water at pH 7 have also been conducted. PMID- 24758585 TI - The International Network for Evaluating Outcomes of very low birth weight, very preterm neonates (iNeo): a protocol for collaborative comparisons of international health services for quality improvement in neonatal care. AB - BACKGROUND: The International Network for Evaluating Outcomes in Neonates (iNeo) is a collaboration of population-based national neonatal networks including Australia and New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the UK. The aim of iNeo is to provide a platform for comparative evaluation of outcomes of very preterm and very low birth weight neonates at the national, site, and individual level to generate evidence for improvement of outcomes in these infants. METHODS/DESIGN: Individual-level data from each iNeo network will be used for comparative analysis of neonatal outcomes between networks. Variations in outcomes will be identified and disseminated to generate hypotheses regarding factors impacting outcome variation. Detailed information on physical and environmental factors, human and resource factors, and processes of care will be collected from network sites, and tested for association with neonatal outcomes. Subsequently, changes in identified practices that may influence the variations in outcomes will be implemented and evaluated using quality improvement methods. DISCUSSION: The evidence obtained using the iNeo platform will enable clinical teams from member networks to identify, implement, and evaluate practice and service provision changes aimed at improving the care and outcomes of very low birth weight and very preterm infants within their respective countries. The knowledge generated will be available worldwide with a likely global impact. PMID- 24758587 TI - Parotid gland metastasis of lung cancer: a case report. AB - BACKGROUND: Parotid gland metastasis in lung cancer is extremely rare, very few cases have been reported. CASE PRESENTATION: We report on the case of a 61-year old Chinese male patient who presented with parotid swelling metastasizing from advanced lung cancer. We therefore performed an operation of partial parotidectomy with preservation of the facial nerve and advised the patient receive chemotherapy, however, the patient died four months later. CONCLUSION: Although it is extremely rare, a potential metastasis of lung cancer should not be ignored in the diagnosis of parotid tumor. Preoperative routine examination, such as a chest X-ray and lung computational tomography scan, may play an important role in differential diagnosis. The management of the metastatic tumor to the parotid gland was controversial however, despite combined treatment modalities, long-term survival was not attained. PMID- 24758588 TI - Long-term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience. AB - BACKGROUND: The long-term efficacy of infliximab (IFX) for patients with refractory ulcerative colitis (UC) is unclear. The aim of this study was to assess the long-term outcomes of IFX treatment in patients with refractory UC. METHODS: Thirty-three patients with refractory UC who received IFX treatment at Kyoto University Hospital between 2003 and 2013 were retrospectively evaluated. IFX intensification was defined as a dose escalation (up to 10 mg/kg) and/or shorter intervals between infusions (every 4-6 weeks). RESULTS: Of the 33 patients who received scheduled infusions of IFX, 24 (72.7%) achieved clinical remission within 8 weeks after initiating IFX treatment. Of these 24 responders, 17 (70.8%) experienced a relapse of UC and required IFX intensification, and 16 (66.7%) eventually maintained clinical remission with IFX treatment, including IFX intensification. Of the 33 patients, 6 (18.2%) underwent colectomy during IFX treatment. Multivariate regression analysis showed that a serum C-reactive protein (CRP) concentration <5 mg/L two weeks after starting IFX was a predictor of a positive clinical response to IFX induction therapy. No severe adverse events occurred in UC patients treated with IFX. CONCLUSION: IFX intensification was necessary for long-term maintenance of remission and to prevent colectomy in patients with refractory UC. PMID- 24758590 TI - Near- and far-field properties of plasmonic oligomers under radially and azimuthally polarized light excitation. AB - We present a comprehensive experimental and theoretical study on the near- and far-field properties of plasmonic oligomers using radially and azimuthally polarized excitation. These unconventional polarization states are perfectly matched to the high spatial symmetry of the oligomers and thus allow for the excitation of some of the highly symmetric eigenmodes of the structures, which cannot be excited by linearly polarized light. In particular, we study hexamer and heptamer structures and strikingly find very similar optical responses, as well as the absence of a Fano resonance. Furthermore, we investigate the near field distributions of the oligomers using near-field scanning optical microscopy (NSOM). We observe significantly enhanced near-fields, which arise from efficient excitation of the highly symmetric eigenmodes by the radially and azimuthally polarized light fields. Our study opens up possibilities for tailored light matter interaction, combining the design freedom of complex plasmonic structures with the remarkable properties of radially and azimuthally polarized light fields. PMID- 24758589 TI - Renal telocytes contribute to the repair of ischemically injured renal tubules. AB - Telocytes (TCs), a distinct type of interstitial cells, have been identified in many organs via electron microscopy. However, their precise function in organ regeneration remains unknown. This study investigated the paracrine effect of renal TCs on renal tubular epithelial cells (TECs) in vitro, the regenerative function of renal TCs in renal tubules after ischaemia-reperfusion injury (IRI) in vivo and the possible mechanisms involved. In a renal IRI model, transplantation of renal TCs was found to decrease serum creatinine and blood urea nitrogen (BUN) levels, while renal fibroblasts exerted no such effect. The results of histological injury assessments and the expression levels of cleaved caspase-3 were consistent with a change in kidney function. Our data suggest that the protective effect of TCs against IRI occurs via inflammation-independent mechanisms in vivo. Furthermore, we found that renal TCs could not directly promote the proliferation and anti-apoptosis properties of TECs in vitro. TCs did not display any advantage in paracrine growth factor secretion in vitro compared with renal fibroblasts. These data indicate that renal TCs protect against renal IRI via an inflammation-independent pathway and that growth factors play a significant role in this mechanism. Renal TCs may protect TECs in certain microenvironments while interacting with other cells. PMID- 24758591 TI - delta-Opioid receptors in the accumbens shell mediate the influence of both excitatory and inhibitory predictions on choice. AB - BACKGROUND AND PURPOSE: Stimuli that predict rewarding events can control choice between future actions, and this control could be mediated by delta-opioid receptors in the nucleus accumbens shell (NAc-S). Stimuli predicting the absence of important events can also guide choice, although it remains unknown whether they do so via changes in an accumbal delta-opioid receptor-related process. EXPERIMENTAL APPROACH: delta-opioid receptor-eGFP mice were trained to perform two instrumental actions that delivered different food outcomes. Choice between the two actions was then tested in the presence of stimuli paired with either the delivery or the non-delivery of each of the two outcomes. Bilateral infusions of the delta-opioid receptor antagonist naltrindole into the NAc-S were used to determine the role of these receptors at the time of choice and delta-opioid receptor expression in the NAc-S used to assess functional activity. KEY RESULTS: A stimulus predicting a specific outcome biased choice performance towards the action previously earning that same outcome. In contrast, a stimulus signalling the absence of that outcome biased performance away from the action that delivered that outcome towards actions associated with the absence of that outcome. Both effects were associated with increased delta-opioid receptor expression on the membrane of cholinergic interneurons within the NAc-S. Furthermore, both effects were blocked by naltrindole infused into the NAc-S. CONCLUSIONS AND IMPLICATIONS: These findings suggest that delta-opioid receptors in the NAc-S were involved in the effects of predictive learning on choice between actions, whether those predictions involve the presence or absence of specific rewarding events. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. PMID- 24758592 TI - Evidence of Rift Valley fever seroprevalence in the Sahrawi semi-nomadic pastoralist system, Western Sahara. AB - BACKGROUND: The increasing global importance of Rift Valley fever (RVF) is clearly demonstrated by its geographical expansion. The presence of a wide range of host and vector species, and the epidemiological characteristics of RVF, have led to concerns that epidemics will continue to occur in previously unaffected regions of Africa. The proximity of the Sahrawi territories of Western Sahara to endemic countries, such as Mauritania, Senegal, and Mali with periodic isolation of virus and serological evidence of RVF, and the intensive livestock trade in the region results in a serious risk of RVF spread in the Sahrawi territories, and potentially from there to the Maghreb and beyond. A sero-epidemiological survey was conducted in the Saharawi territories between March and April 2008 to investigate the possible presence of the RVF virus (RVFV) and associated risk factors. A two-stage cluster sampling design was used, incorporating 23 sampling sites. RESULTS: A total of 982 serum samples was collected from 461 sheep, 463 goats and 58 camels. Eleven samples (0.97%) tested positive for IgG against the RVFV. There were clusters of high seroprevalence located mostly in the Tifariti (7.69%) and Mehaires (7.14%) regions, with the Tifariti event having been found in one single flock (4/26 positive animals). Goats and older animals were at a significantly increased risk being seropositive (p = 0.007 and p = 0.007, respectively). CONCLUSION: The results suggest potential RVF activity in the study area, where intense livestock movement and trade with neighbouring countries might be considered as a primary determinant in the spread of the disease. The importance of a continuous field investigation is reinforced, in light of the risk of RVF expansion to historically unaffected regions of Africa. PMID- 24758593 TI - Discovering up-regulated VEGF-C expression in swine umbilical vein endothelial cells by classical swine fever virus Shimen. AB - Infection of domestic swine with the highly virulent Shimen strain of classical swine fever virus causes hemorrhagic lymphadenitis and diffuse hemorrhaging in infected swine. We analyzed patterns of gene expression for CSFV Shimen in swine umbilical vein endothelial cells (SUVECs). Transcription of the vascular endothelial growth factor (VEGF) C gene (VEGF-C) and translation of the corresponding protein were significantly up-regulated in SUVECs. Our findings suggest that VEGF-C is involved in mechanisms of acute infection caused by virulent strains of CSFV. PMID- 24758595 TI - Medication-assisted therapies--tackling the opioid-overdose epidemic. PMID- 24758594 TI - Detergent-free purification of ABC (ATP-binding-cassette) transporters. AB - ABC (ATP-binding-cassette) transporters carry out many vital functions and are involved in numerous diseases, but study of the structure and function of these proteins is often hampered by their large size and membrane location. Membrane protein purification usually utilizes detergents to solubilize the protein from the membrane, effectively removing it from its native lipid environment. Subsequently, lipids have to be added back and detergent removed to reconstitute the protein into a lipid bilayer. In the present study, we present the application of a new methodology for the extraction and purification of ABC transporters without the use of detergent, instead, using a copolymer, SMA (polystyrene-co-maleic acid). SMA inserts into a bilayer and assembles into discrete particles, essentially solubilizing the membrane into small discs of bilayer encircled by a polymer, termed SMALPs (SMA lipid particles). We show that this polymer can extract several eukaryotic ABC transporters, P-glycoprotein (ABCB1), MRP1 (multidrug-resistance protein 1; ABCC1), MRP4 (ABCC4), ABCG2 and CFTR (cystic fibrosis transmembrane conductance regulator; ABCC7), from a range of different expression systems. The SMALP-encapsulated ABC transporters can be purified by affinity chromatography, and are able to bind ligands comparably with those in native membranes or detergent micelles. A greater degree of purity and enhanced stability is seen compared with detergent solubilization. The present study demonstrates that eukaryotic ABC transporters can be extracted and purified without ever being removed from their lipid bilayer environment, opening up a wide range of possibilities for the future study of their structure and function. PMID- 24758596 TI - Chronic pain, addiction, and Zohydro. PMID- 24758597 TI - Various ways to improve whole cancer cell vaccines. AB - Immunotherapy based on whole cancer cell vaccines is regarded as a promising avenue for cancer treatment. However, limited efficacy in the first human clinical trials calls for more optimized whole cancer cell vaccines and better patient selection. It is suggested that whole cancer cell vaccines consist preferably of immunogenically killed autologous cancer stem cells associated with dendritic cells. Adjuvants should stimulate both immune effector cells and memory cells, which could be achieved through their correct dosage and timing of administration. There are indications that whole cancer cell vaccination is less effective in patients who are immunocompromised, who have specific genetic defects in their immune or cancer cells, as well as in patients in an advanced cancer stage. However, such patients form the bulk of enrolled patients in clinical trials, prohibiting an objective evaluation of the true potential of whole cancer cell immunotherapy. Each key point will be discussed. PMID- 24758598 TI - Variation in amylose fine structure of starches from different botanical sources. AB - The molecular structures of amylose and amylopectin have an impact on functional properties of starch-containing food. This is the first study comparing amylose size distributions from various plant sources. Chain-length distributions (CLDs) of amylose and amylopectin branches ("fine structure") are characterized using size-exclusion chromatography [sometimes termed gel permeation chromatography (GPC)] and parametrized by both biosynthesis-based and empirical fits, to understand the starch biosynthesis mechanism and identify associations with starch digestibility. All starches show bimodal amylose weight CLDs, varying with plant sources, with potato tuber and sweet potato root starch having relatively longer branches than the others. The digestograms of all starches fit first-order kinetics. Unlike what has been seen in cooked grains/flours, amylose and amylopectin fine structures have no association with the digestibility of freshly gelatinized starch. This suggests that the observed effect in cooked grains/flours arises from a secondary interaction between amylose fine structure and higher order structural features. PMID- 24758600 TI - Patch testing for vulval symptoms: our experience with 282 patients. AB - BACKGROUND: Vulval allergic contact dermatitis (ACD) may be a primary disorder or may be associated with an underlying vulval dermatosis. Few studies have looked at the incidence of ACD and the allergens responsible for it. AIMS: We report the incidence of vulval ACD and the responsible allergens in 282 patients investigated over a 6-year period in a large teaching hospital. METHODS: We performed a retrospective case notes review of all patients investigated for vulval symptoms in our tertiary referral contact dermatitis investigation unit. A total of 282 patients underwent patch testing. RESULTS: The overall incidence of ACD was 54%. The age range of patients was 14-89 years. Pruritus was the most common presenting symptom. Nickel was the most commonly found allergen, but was usually not relevant. Fragrances and topical antibiotics/anaesthetics were less commonly detected, but were almost always relevant to the presentation. Positive reactions were more commonly found in patients who had long-standing symptoms and/or had used many products in the vulval area. CONCLUSIONS: Vulval ACD affects women of a wide age range, and presents with nonspecific symptoms such as pruritus and/or vulval irritation. Patients may have experienced symptoms for many years before presenting to a dermatologist. The diagnosis of vulval ACD is more common in those who have been exposed to many potential sensitizers. PMID- 24758599 TI - The validity and reliability of a novel indoor player tracking system for use within wheelchair court sports. AB - The aim of the current study was to investigate the validity and reliability of a radio frequency-based system for accurately tracking athlete movement within wheelchair court sports. Four wheelchair-specific tests were devised to assess the system during (i) static measurements; (ii) incremental fixed speeds; (iii) peak speeds; and (iv) multidirectional movements. During each test, three sampling frequencies (4, 8 and 16 Hz) were compared to a criterion method for distance, mean and peak speeds. Absolute static error remained between 0.19 and 0.32 m across the session. Distance values (test (ii)) showed greatest relative error in 4 Hz tags (1.3%), with significantly lower errors seen in higher frequency tags (<1.0%). Relative peak speed errors of <2.0% (test (iii)) were revealed across all sampling frequencies in relation to the criterion (4.00 +/- 0.09 m . s-(1)). Results showed 8 and 16 Hz sampling frequencies displayed the closest-to-criterion values, whilst intra-tag reliability never exceeded 2.0% coefficient of variation (% CV) during peak speed detection. Minimal relative distance errors (<0.2%) were also seen across sampling frequencies (test (iv)). To conclude, the indoor tracking system is deemed an acceptable tool for tracking wheelchair court match play using a tag frequency of 8 or 16 Hz. PMID- 24758601 TI - Impact of source data on the interpretation of contrast-enhanced magnetic resonance angiography of the lower limbs. AB - BACKGROUND: The primary purpose of this study is to examine whether use of source data is effective in increasing the number of arterial segments that can be interpreted from maximum intensity projections of lower limb MR angiograms. Correlation between sites of arterial disease and venous contamination was also measured. Interpretation of source data is performed routinely by radiologists, but the value of this has not been well studied with randomized studies. RESULTS: The proportion of segments visible above the knee was 87% using maximal intensity projection alone (MIP) and 88% when the MIP was combined with source data. The proportions were 67% for MIP and 72% for MIP plus source data below the knee. There was substantial agreement between presence of arterial disease and venous contamination in the calf and thigh. CONCLUSION: The use of source data increases the number of assessable segments, but not individuals, by a statistically significant but small amount (1.2%, p <0.05). This study supports the association between arterial disease and venous contamination. PMID- 24758602 TI - Effects of changes in health insurance reimbursement level on outpatient service utilization of rural diabetics: evidence from Jiangsu Province, China. AB - BACKGROUND: Outpatient reimbursement levels of the New Rural Cooperative Medical Scheme have changed in recent years in China, and those changes may have a greater impact on patients with chronic diseases due to their higher outpatient expenses. This study represents the first attempt to identify the effects of reimbursement level on outpatient service utilization for chronic patients in rural China and it also gives strong estimation results by conducting a tracer illness study in order to control for possible biases associated with studying several diseases together. METHODS: This study used difference-in-differences models to examine how changes in yearly maximum reimbursement amount and outpatient reimbursement rates affected rural residents with type 2 diabetes in three counties in Jiangsu Province, China. Other factors, such as sex, age and severity of illness, were also included in the model estimations. To make sure the treated group and control group are comparable, Propensity Score Match (PSM) was used to analysis the gender, age and severity of illness of the two groups. RESULTS: The results indicate that an increase in yearly maximum reimbursement amount for outpatient visits could cause an increase in yearly total outpatient expenses for patients with type 2 diabetes mellitus. However, changes in outpatient reimbursement rates between 2010 and 2011 did not significantly affect the utilization of different types of health institution. CONCLUSIONS: The reimbursement rates of village clinics should be substantially increased from the existing basis and the gap of reimbursement rates among different institutions should be further widened. It is also important for village clinics to improve their services. Moreover, measures to improve the quality of care and scope of services at lower-level healthcare institutions, and promote the health service utilization of rural women should be considered. PMID- 24758603 TI - Metal-free TEMPO-promoted C(sp3)-H amination to afford multisubstituted benzimidazoles. AB - An efficient TEMPO-air/cat. TEMPO-O2 oxidative protocol was developed to synthesize multisubstituted or fused tetracyclic benzimidazoles via a metal-free oxidative C-N coupling between the sp(3) C-H and free N-H of readily available N(1)-benzyl/alkyl-1,2-phenylenediamines. PMID- 24758604 TI - NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease. AB - BACKGROUND: Chronic oxidative stress is one of the key mechanisms responsible for disease progression in non-alcoholic fatty liver disease. However, so far, few studies reported increased circulating levels of oxidative stress markers in patients with non-alcoholic fatty liver and no study has been performed with newer markers of systemic oxidative stress. The aim was to assess the relationship between urinary 8-iso-prostaglandin F2alpha and serum soluble NOX2 derived peptide and the severity of liver steatosis in subjects with non alcoholic fatty liver. METHODS: The study was performed in 264 consecutive patients referred for suspected metabolic disease. Steatosis was defined according to Hamaguchi ultrasonographic criteria. Oxidative stress was assessed by urinary 8-iso- prostaglandin F2alpha and serum soluble NOX2-derived peptide levels. RESULTS: Patients with non-alcoholic fatty liver had higher (p < 0.001) mean values of urinary 8-iso-PGF2alpha and of serum soluble NOX2-derived peptide, alanine aminotransferase, Cytokeratin-18 and homeostasis model of insulin resistance and lower values of serum adiponectin as compared to those without. Prevalence of metabolic syndrome and of its clinical features was significantly higher in patients with non-alcoholic fatty liver. Same findings were also observed after the exclusion of obese subjects, or subjects with diabetes or with metabolic syndrome and in those not taking statin medication. In addition, the levels of urinary 8-iso-PGF2alpha were independent predictors of non-alcoholic fatty liver and a strong association of urinary 8-iso-PGF2alpha and of serum soluble NOX2-derived peptide with the severity of steatosis at ultrasound was also observed. CONCLUSIONS: We demonstrated increased markers of oxidative stress in subjects with non-alcoholic fatty liver. Urinary 8-iso-PGF2alpha and serum soluble NOX2-derived peptide levels were independent from obesity, diabetes and metabolic syndrome and increased with the severity of liver steatosis at ultrasound. PMID- 24758607 TI - Prevalence and risk factors for heterotopic gastric mucosa of the upper esophagus among men undergoing routine screening colonoscopy. AB - The prevalence of heterotopic gastric mucosa of the upper esophagus (inlet patch) has a wide range depending on the method and detail of examination. The inlet patch is believed to be a congenital malformation that rarely leads to symptoms. We aimed to quantify the prevalence of the inlet patch in a non-referred population and determine if there are any risk factors or associated symptoms. Men between ages 50 and 79 presenting for routine colonoscopy at two clinical sites were recruited to undergo an upper endoscopy. Endoscopists were prompted to examine for the presence of the inlet patch. Of the 822 enrolled patients, 795 had data regarding the presence of an inlet patch. Of these, 55 (6.9%) had an inlet patch identified. Education was inversely associated (odds ratio [OR] advanced degree vs. high school or less = 0.310; 95% confidence interval [CI] = 0.111, 0.869), and tobacco use was positively associated with the presence of an inlet patch (current vs. never smokers OR = 2.87; 95% CI = 1.23, 6.69; former vs. never smokers OR = 1.93; 95% CI = 0.922, 4.02). No association between the inlet patch and symptoms of heartburn, globus, or dysphagia was found. In a cross sectional study of colon cancer screenees, inlet patches were common and were not associated with symptoms. Tobacco use appears to be associated with the presence of an inlet patch. PMID- 24758608 TI - Fully deuterated magnetically oriented system based on fatty acid direct hexagonal phases. AB - There is strong demand in the field of NMR for simple oriented lipid supramolecular assemblies, the constituents of which can be fully deuterated, for specifically studying the structure of host protonated molecules (e.g., peptides, proteins...) in a lipid environment. Also, small-angle neutron scattering (SANS) in fully deuterated oriented systems is powerful for gaining information on protonated host molecules in a lipid environment by using the contrast proton/deuterium method. Here we report on a very simple system made of fatty acids (dodecanoic and tetradecanoic) and ethanolamine in water. All components of this system can be obtained commercially as perdeuterated. Depending on the molar ratio and the concentration, the system self-assembles at room temperature into a direct hexagonal phase that is oriented by moderate magnetic fields of a few tesla. The orientation occurs within the magnetic field upon cooling the system from its higher-temperature isotropic phase: the lipid cylinders of the hexagonal phase become oriented parallel to the field. This is shown by solid-state NMR using either perdeuterated fatty acids or ethanolamine. This system bears strong interest for studying host protonated molecules but also in materials chemistry for building oriented solid materials. PMID- 24758605 TI - Neurobehaviour between birth and 40 weeks' gestation in infants born <30 weeks' gestation and parental psychological wellbeing: predictors of brain development and child outcomes. AB - BACKGROUND: Infants born <30 weeks' gestation are at increased risk of long term neurodevelopmental problems compared with term born peers. The predictive value of neurobehavioural examinations at term equivalent age in very preterm infants has been reported for subsequent impairment. Yet there is little knowledge surrounding earlier neurobehavioural development in preterm infants prior to term equivalent age, and how it relates to perinatal factors, cerebral structure, and later developmental outcomes. In addition, maternal psychological wellbeing has been associated with child development. Given the high rate of psychological distress reported by parents of preterm children, it is vital we understand maternal and paternal wellbeing in the early weeks and months after preterm birth and how this influences the parent-child relationship and children's outcomes. Therefore this study aims to examine how 1) early neurobehaviour and 2) parental mental health relate to developmental outcomes for infants born preterm compared with infants born at term. METHODS/DESIGN: This prospective cohort study will describe the neurobehaviour of 150 infants born at <30 weeks' gestational age from birth to term equivalent age, and explore how early neurobehavioural deficits relate to brain growth or injury determined by magnetic resonance imaging, perinatal factors, parental mental health and later developmental outcomes measured using standardised assessment tools at term, one and two years' corrected age. A control group of 150 healthy term-born infants will also be recruited for comparison of outcomes. To examine the effects of parental mental health on developmental outcomes, both parents of preterm and term-born infants will complete standardised questionnaires related to symptoms of anxiety, depression and post-traumatic stress at regular intervals from the first week of their child's birth until their child's second birthday. The parent-child relationship will be assessed at one and two years' corrected age. DISCUSSION: Detailing the trajectory of infant neurobehaviour and parental psychological distress following very preterm birth is important not only to identify infants most at risk, further understand the parental experience and highlight potential times for intervention for the infant and/or parent, but also to gain insight into the effect this has on parent-child interaction and child development. PMID- 24758609 TI - Over 40 cd/A efficient green quantum dot electroluminescent device comprising uniquely large-sized quantum dots. AB - Green CdSe@ZnS quantum dots (QDs) of 9.5 nm size with a composition gradient shell are first prepared by a single-step synthetic approach, and then 12.7 nm CdSe@ZnS/ZnS QDs, the largest among ZnS-shelled visible-emitting QDs available to date, are obtained through the overcoating of an additional 1.6 nm thick ZnS shell. Two QDs of CdSe@ZnS and CdSe@ZnS/ZnS are incorporated into the solution processed hybrid QD-based light-emitting diode (QLED) structure, where the QD emissive layer (EML) is sandwiched by poly(9-vinlycarbazole) and ZnO nanoparticles as hole and electron-transport layers, respectively. We find that the presence of an additional ZnS shell makes a profound impact on device performances such as luminance and efficiencies. Compared to CdSe@ZnS QD-based devices the efficiencies of CdSe@ZnS/ZnS QD-based devices are overwhelmingly higher, specifically showing unprecedented values of peak current efficiency of 46.4 cd/A and external quantum efficiency of 12.6%. Such excellent results are likely attributable to a unique structure in CdSe@ZnS/ZnS QDs with a relatively thick ZnS outer shell as well as a well-positioned intermediate alloyed shell, enabling the effective suppression of nonradiative energy transfer between closely packed EML QDs and Auger recombination at charged QDs. PMID- 24758610 TI - Leisure-time physical activity and the risk of metabolic syndrome: meta-analysis. AB - BACKGROUND: The purpose of this study was to assess the association between leisure-time physical activity (LPA) and the risk of metabolic syndrome (MS). METHODS: Prospective cohort studies of the association between LPA and the risk of MS were retrieved from the PubMed and Embase databases up to 12 August 2013. The statistical analysis in this study was performed using Stata 11.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the effect of LPA on the risk of MS. RESULTS: A total of five articles were included in this meta-analysis. The overall effect sizes indicated that people with moderate level LPA (OR = 0.89, 95% CI: 0.82 to 0.96, P = 0.003) or high level LPA (OR = 0.58, 95% CI: 0.38 to 0.89, P = 0.012) had lower risk of MS than people with low level LPA. The subgroup analysis by gender showed that high level LPA could reduce the risk of MS in populations of different genders (female, OR = 0.20, 95% CI: 0.08 to 0.49, P <0.001; male, OR = 0.59, 95% CI: 0.43 to 0.82, P = 0.002). However, compared with low level LPA, Americans with high level LPA did not significantly reduce the risk of MS (OR = 0.59, 95% CI: 0.43 to 0.82, P = 0.002), while a significant decrease of the risk of MS was found in Europeans with high level LPA (OR = 0.49, 95% CI 0.32 to 0.77, P = 0.002) in the subgroup analysis by region. CONCLUSIONS: The meta-analysis confirmed that a moderate and high level of LPA could reduce the risk of MS. PMID- 24758611 TI - Is rivaroxaban associated with lower inpatient costs compared to warfarin among patients with non-valvular atrial fibrillation? AB - BACKGROUND: Warfarin has been the mainstay treatment used by patients with a moderate-to-high risk of stroke due to non-valvular atrial fibrillation (NVAF). Unlike rivaroxaban, laboratory monitoring to allow the attainment of the prothrombin time international normalized ratio goal is required with warfarin, thereby potentially increasing a patient's hospitalization costs. OBJECTIVE: To compare hospitalization costs between hospitalized NVAF patients using rivaroxaban versus warfarin in a real-world setting. METHODS: A retrospective claims analysis was conducted using the Premier Perspective Comparative Hospital Database from November 2010 to September 2012. The study included adult patients hospitalized for NVAF after November 2011. Patients using rivaroxaban during hospitalization were matched with up to four warfarin users by propensity score analyses. Hospitalization costs were compared between the matched cohorts using generalized estimating equations. A sub-analysis was performed for patients who were first administered their treatment on day three or later of their hospital stay. Sensitivity analyses were conducted on matched cohorts with a primary diagnosis of AF. RESULTS: The matched cohorts' (2809 rivaroxaban and 11,085 warfarin users) characteristics were well balanced. The mean age of cohorts was 71 years and 49% of patients were female. The average hospitalization cost of rivaroxaban users was $11,993 compared to $13,255 for warfarin users. The cost difference was significantly lower by $1284 (P < 0.001). Patients who were administered rivaroxaban treatment on day three or after incurred significantly lower hospitalization costs (cost difference: $4350; P < 0.001) compared to warfarin users. Rivaroxaban users with a primary diagnosis of AF also had significantly lower costs compared to warfarin users. LIMITATIONS: These included possible inaccuracies or omissions in diagnoses, completeness of baseline characteristics, and a study population that included patients newly initiated on and patients who continued anticoagulant therapy. CONCLUSION: Hospitalization costs for rivaroxaban were significantly lower than those for warfarin in NVAF patients treated with rivaroxaban. PMID- 24758613 TI - Porous spherical carbon/sulfur nanocomposites by aerosol-assisted synthesis: the effect of pore structure and morphology on their electrochemical performance as lithium/sulfur battery cathodes. AB - Porous spherical carbons (PSCs) with tunable pore structure (pore volume, pore size, and surface area) were prepared by an aerosol-assisted process. PSC/sulfur composites (PSC/S, S: ca.59 wt %) were then made and characterized as cathodes in lithium/sulfur batteries. The relationships between the electrochemical performance of PSC/S composites and their pore structure and particle morphology were systematically investigated. PSC/S composite cathodes with large pore volume (>2.81 cm(3)/g) and pore size (>5.10 nm) were found to exhibit superior electrochemical performance, likely due to better mass transport in the cathode. In addition, compared with irregularly shaped carbon/sulfur composite, the spherical shaped PSC/S composite showed better performance due to better electrical contact among the particles. PMID- 24758612 TI - Lung ultrasound for the diagnosis of pneumonia in adults: a systematic review and meta-analysis. AB - BACKGROUND: Guidelines do not currently recommend the use of lung ultrasound (LUS) as an alternative to chest X-ray (CXR) or chest computerized tomography (CT) scan for the diagnosis of pneumonia. We conducted a meta-analysis to summarize existing evidence of the diagnostic accuracy of LUS for pneumonia in adults. METHODS: We conducted a systematic search of published studies comparing the diagnostic accuracy of LUS against a referent CXR or chest CT scan and/or clinical criteria for pneumonia in adults aged >=18 years. Eligible studies were required to have a CXR and/or chest CT scan at the time of evaluation. We manually extracted descriptive and quantitative information from eligible studies, and calculated pooled sensitivity and specificity using the Mantel Haenszel method and pooled positive and negative likelihood ratios (LR) using the DerSimonian-Laird method. We assessed for heterogeneity using the Q and I2 statistics. RESULTS: Our initial search strategy yielded 2726 articles, of which 45 (1.7%) were manually selected for review and 10 (0.4%) were eligible for analyses. These 10 studies provided a combined sample size of 1172 participants. Six studies enrolled adult patients who were either hospitalized or admitted to Emergency Departments with suspicion of pneumonia and 4 studies enrolled critically-ill adult patients. LUS was performed by highly-skilled sonographers in seven studies, by trained physicians in two, and one did not mention level of training. All studies were conducted in high-income settings. LUS took a maximum of 13 minutes to conduct. Nine studies used a 3.5-5 MHz micro-convex transducer and one used a 5-9 MHz convex probe. Pooled sensitivity and specificity for the diagnosis of pneumonia using LUS were 94% (95% CI, 92%-96%) and 96% (94%-97%), respectively; pooled positive and negative LRs were 16.8 (7.7-37.0) and 0.07 (0.05-0.10), respectively; and, the area-under-the-ROC curve was 0.99 (0.98 0.99). CONCLUSIONS: Our meta-analysis supports that LUS, when conducted by highly skilled sonographers, performs well for the diagnosis of pneumonia. General practitioners and Emergency Medicine physicians should be encouraged to learn LUS since it appears to be an established diagnostic tool in the hands of experienced physicians. PMID- 24758614 TI - Talk-in-interaction and neuropsychological processes. AB - Talk-in-interaction is characterized by a pattern of turn-taking between conversational partners and rapid shifts from turn to turn without pauses between turns. During talk-in-interaction speakers constantly adjust to one another's terminology, repeat expressions from turn to turn and imitate each other's verbal as well as nonverbal behavior, a phenomenon characterized by automatic processing referred to as interactive alignment. Recent studies have shown how interactive alignment is subserved by neural coupling of brain activity of speakers and listeners, integrating comprehension and language production across many brain areas. Verbal behavior during talk-in-interaction is also dependent on the ability to draw inferences from verbally ambiguous expressions, to a large extent subserved by right hemisphere (RH) functioning, but the nature of the RH contribution to the activation and selection of inferences is under discussion in the research literature. There is emerging evidence of synchrony in neural activity and psychophysiological processing reflecting the interactive alignment observed on the behavioral level during talk-in-interaction. An understanding of neuropsychological aspects of talk-in-interaction may have potential implications for our understanding of doctor-patient dialogue. PMID- 24758615 TI - Grape seed pro-anthocyanidins ameliorates radiation-induced lung injury. AB - Radiation-induced lung injury (RILI) is a potentially fatal and dose-limiting complication of thoracic radiotherapy. This study was to investigate the protective effects of grape seed pro-anthocyanidins (GSPs), an efficient antioxidant and anti-carcinogenic agent, on RILI. In our study, it was demonstrated that acute and late RILI was ameliorated after GSPs treatment possibly through suppressing TGF-beta1/Smad3/Snail signalling pathway and modulating the levels of cytokines (interferon-gamma, IL-4 and IL-13) derived from Th1/Th2 cells. In addition, a sustained high level of PGE2 was also maintained by GSPs treatment to limited fibroblast functions. As shown by electron spin resonance spectrometry, GSPs could scavenge hydroxyl radical (*OH) in a dose-dependent manner, which might account for the mitigation of lipid peroxidation and consequent apoptosis of lung cells. In vitro, GSPs radiosensitized lung cancer cell A549 while mitigating radiation injury on normal alveolar epithelial cell RLE-6TN. In conclusion, the results showed that GSPs protects mice from RILI through scavenging free radicals and modulating RILI associated cytokines, suggesting GSPs as a novel protective agent in RILI. PMID- 24758616 TI - It's five o'clock somewhere: An examination of the association between happy hour drinking and negative consequences. AB - BACKGROUND: This study aims to understand which young adults' drinking behaviors change in the presence of happy hour specials, the ways in which they change, and whether a link exists between happy hour drinking behavior and negative outcomes. METHODS: Using data collected from bar-going respondents (n = 1,423) within a print survey administered to a general college sample (n = 2,349), we identify significant differences in changes in happy hour behavior between demographic groups using chi(2) tests and determine whether this behavior is related to six negative alcohol-related outcomes using logistical and ordinary least squares regression models with a variety of controls, including age of onset and frequency of use. RESULTS: Women, students under 21, non-athletes, members of Greek-affiliated organizations, more affluent and unemployed students, and students living on campus were more likely to change their drinking behavior in the presence of happy hour specials. In general, the most robust predictors of negative events are gender, alcohol use frequency, age of alcohol use onset, and increasing drinking due to happy hours/bar specials. While it was linked to various negative and illegal behaviors, altered happy hour drinking was not associated with an increased likelihood of an alcohol-related arrest. CONCLUSIONS: This study lends support to the idea that alcohol price specials should be regulated in an effort to reduce high consumption and alcohol-related negative consequences. Future research into the relationship between happy hour drinking and negative outcomes is necessary and should examine the impact of happy hour advertisements, different types of specials, and the timing of happy hours. PMID- 24758617 TI - Treating our "situations" with science, not shame. PMID- 24758618 TI - ICU-acquired weakness and recovery from critical illness. PMID- 24758619 TI - Images in clinical medicine. Giant papillae in vernal keratoconjunctivitis. PMID- 24758620 TI - Case records of the Massachusetts General Hospital. Case 13-2014. A 41-year-old man with fever and abdominal pain after stem-cell transplantation. PMID- 24758622 TI - Clinical decisions. The guidelines battle on starting statins. PMID- 24758623 TI - Incidence of childhood obesity in the United States. PMID- 24758624 TI - Incidence of childhood obesity in the United States. PMID- 24758625 TI - Incidence of childhood obesity in the United States. PMID- 24758626 TI - A trial of mass isoniazid preventive therapy for tuberculosis control. PMID- 24758627 TI - A trial of mass isoniazid preventive therapy for tuberculosis control. PMID- 24758628 TI - A trial of mass isoniazid preventive therapy for tuberculosis control. PMID- 24758629 TI - Helicase-primase inhibitor pritelivir for HSV-2 infection. PMID- 24758630 TI - Romosozumab in postmenopausal women with osteopenia. PMID- 24758631 TI - Romosozumab in postmenopausal women with osteopenia. PMID- 24758632 TI - PTX3 deficiency and aspergillosis. PMID- 24758633 TI - PTX3 deficiency and aspergillosis. PMID- 24758634 TI - PTX3 deficiency and aspergillosis. PMID- 24758635 TI - Hepatitis B virus rtI233V mutation and resistance to adefovir. PMID- 24758639 TI - Images in clinical medicine. Sunitinib-associated hair depigmentation. PMID- 24758642 TI - Surgical damage to the sural nerve. PMID- 24758641 TI - Delaying the oocyte maturation trigger by one day leads to a higher metaphase II oocyte yield in IVF/ICSI: a randomised controlled trial. AB - BACKGROUND: The negative impact of rising progesterone levels on pregnancy rates is well known, but data on mature oocyte yield are conflicting. We examined whether delaying the oocyte maturation trigger in IVF/ICSI affected the number of mature oocytes and investigated the potential influence of serum progesterone levels in this process. METHODS: Between January 31, 2011, and December 31, 2011, 262 consecutive patients were monitored using ultrasound plus hormonal evaluation. Those with > =3 follicles with a mean diameter of > =18 mm were divided into 2 groups depending on their serum progesterone levels. In cases with a progesterone level < = 1 ng/ml, which was observed in 59 patients, 30-50% of their total number of follicles (only counting those larger than 10 mm) were at least 18 mm in diameter. These patients were randomised into 2 groups: in one group, final oocyte maturation was triggered the same day; for the other, maturation was triggered 24 hours later. Seventy-two patients with progesterone levels > 1 ng/ml were randomised in the same manner, irrespective of the percentage of larger follicles (> = 18 mm). The number of metaphase II oocytes was our primary outcome variable. Because some patients were included more than once, correction for duplicate patients was performed. RESULTS: In the study arm with low progesterone (<= 1 ng/ml), the mean number of metaphase II oocytes (+/ SD) was 10.29 (+/-6.35) in the group with delayed administration of the oocyte maturation trigger versus 7.64 (+/-3.26) in the control group. After adjusting for age, the mean difference was 2.41 (95% CI: 0.22-4.61; p = 0.031). In the study arm with elevated progesterone (>1 ng/ml), the mean numbers of metaphase II oocytes (+/-SD) were 11.81 (+/-9.91) and 12.03 (+/-7.09) for the delayed and control groups, respectively. After adjusting for PCOS (polycystic ovary syndrome) and female pathology, the mean difference was -0.44 (95% CI: -3.65 2.78; p = 0.79). CONCLUSIONS: Delaying oocyte maturation in patients with low progesterone levels yields greater numbers of mature oocytes. PMID- 24758643 TI - The therapeutic potential of targeting the epithelial-mesenchymal transition in cancer. AB - INTRODUCTION: The process of epithelial-to-mesenchymal transition (EMT) has long been advocated as a process during tumor progression and the acquisition of metastatic potential of human cancers. EMT has also been linked with resistance to cancer therapies. AREAS COVERED: Basic research has provided evidence connecting EMT to increased invasion, angiogenesis and metastasis of cancer cells. A number of signaling pathways such as notch, wnt, hedgehog and PI3K-AKT, and various other individual factors therein, have been intricately connected to the onset of EMT. Here, we provide latest updates on the evidences that further highlight an association between various signaling pathways and EMT, with a focus on therapeutic targets that may have the potential to reverse EMT. EXPERT OPINION: Our understanding of EMT and its underlying causes is rapidly evolving and a number of putative targets have been identified. It is crucial, now than ever before, to design novel translational and clinical studies for the benefit of advanced stage cancer patients with metastatic disease. PMID- 24758640 TI - Reconceptualizing sex, brain and psychopathology: interaction, interaction, interaction. AB - In recent years there has been a growing recognition of the influence of sex on brain structure and function, and in relation, on the susceptibility, prevalence and response to treatment of psychiatric disorders. Most theories and descriptions of the effects of sex on the brain are dominated by an analogy to the current interpretation of the effects of sex on the reproductive system, according to which sex is a divergence system that exerts a unitary, overriding and serial effect on the form of other systems. We shortly summarize different lines of evidence that contradict aspects of this analogy. The new view that emerges from these data is of sex as a complex system whose different components interact with one another and with other systems to affect body and brain. The paradigm shift that this understanding calls for is from thinking of sex in terms of sexual dimorphism and sex differences, to thinking of sex in terms of its interactions with other factors and processes. Our review of data obtained from animal models of psychopathology clearly reveals the need for such a paradigmatic shift, because in the field of animal behaviour whether a sex difference exists and its direction depend on the interaction of many factors including, species, strain, age, specific test employed and a multitude of environmental factors. We conclude by explaining how the new conceptualization can account for sex differences in psychopathology. PMID- 24758645 TI - Journal club: The pediatric appendix: defining normal. AB - OBJECTIVE: The purpose of this study was to characterize the normal pediatric appendix and the variables that affect its diameter. MATERIALS AND METHODS: Imaging and medical records, including CT studies, from 420 unique patients with normal appendixes were reviewed by two pediatric radiologists. Appendiceal diameter was measured on the axial images, and appendiceal content and the presence of enlarged lymph nodes were recorded. RESULTS: The mean appendiceal diameter was 5.6 +/- 1.4 and 5.7 +/- 1.5 mm for reviewer 1 and reviewer 2, respectively, with 34% and 39% of appendixes measuring larger than 6 mm. Appendiceal diameter was normally distributed across the population and was significantly associated with patient age (p < 0.0001). Diameter increased by 0.4 mm/y until 6-7 years of age, after which, it remained stable. The quantity of pericecal fat (p = 0.03 and p < 0.0001) and type of appendiceal content (p = 0.0002 and p < 0.0001), respectively, were multivariate predictors of diameter. Lymphoid stimulation was a multivariate predictor of diameter for only one reviewer (p = 0.0008). Patient sex and the month or season of imaging were not predictors of diameter. CONCLUSION: Uniform diameter cutoffs for appendiceal diameter should not be applied across the pediatric population because the appendix grows during childhood. Additionally, this study calls into question a 6 mm diameter cutoff for appendicitis. Normal pediatric appendixes measure up to 8.7 mm, with up to 39% measuring more than 6 mm in diameter. Nonpathologic factors, including pericecal fat, appendiceal content, and presence of lymphoid stimulation, influence appendiceal diameter in healthy children. PMID- 24758646 TI - Common and uncommon applications of bowel ultrasound with pathologic correlation in children. AB - OBJECTIVE: The purpose of this article is to describe the indications and techniques for bowel ultrasound for inflammatory bowel disease and other common and uncommon entities and describe and illustrate their imaging appearances, including endoscopic or surgical correlation. CONCLUSION: Ultrasound is a useful tool for the evaluation of inflammatory bowel disease and many other bowel diseases. Radiologists must become familiar with the full potential of ultrasound in the evaluation of the bowel in children because the need for alternative radiation-free imaging techniques continues to grow. PMID- 24758647 TI - Clinical and imaging features of focal nodular hyperplasia in children. AB - OBJECTIVE: The purpose of this article is to review the clinical and imaging features of focal nodular hyperplasia (FNH) developed in children. MATERIALS AND METHODS: At a single institution, pediatric patients who underwent imaging studies and who had pathologically proven FNH were studied. Clinical characteristics, including presenting symptoms and signs and the presence of underlying disease, were reviewed from the medical records. Imaging features of FNHs, including the number, size, ultrasound echogenicity and vascularity, CT attenuation, MRI signal intensity and enhancement pattern, and the presence of a central scar, were evaluated. RESULTS: Twenty-five patients (11 boys and 14 girls; median age, 8.6 years) were found to have a solitary (n = 23) or multiple (n = 2) FNH lesions with a mean size of 4.9 cm (range, 1-10 cm). Multiple lesions were associated with small size of the lesions and history of malignancy treated by chemotherapy. Most patients were asymptomatic (n = 22). Biliary atresia was the most common underlying disease (n = 5). On ultrasound, FNHs most commonly appeared to be isoechoic and hypervascular. On dynamic CT and MRI, strong enhancement on the arterial phase and becoming isoattenuated or of isointense signal intensity on the portal or delayed phase was common. A central scar was usually noted in large lesions in about half the cases. CONCLUSION: Pediatric FNH is uncommon and usually is found incidentally in otherwise healthy children. However, it may occur in children who have underlying diseases, including biliary atresia. In addition, it can be encountered during surveillance of childhood cancer survivors with less common imaging features, including lack of a central scar and multiplicity. PMID- 24758649 TI - MRI of pediatric cardiac masses. AB - OBJECTIVE: The purpose of this article is to describe the characteristic cardiac MRI features of primary and secondary cardiac tumors, including differentiation from masslike lesions, such as thrombus or focal myocardial hypertrophy. CONCLUSION: The frequency and type of cardiac tumors in children differ from those in adults. Although transthoracic echocardiography is the initial imaging technique of choice for evaluation of cardiac tumors, cardiac MRI is an important complementary modality for characterization of the mass and effect on cardiac function. PMID- 24758648 TI - Safety of ultrasound contrast agents in the pediatric oncologic population: a single-institution experience. AB - OBJECTIVE: Little information is available regarding the safety of ultrasound contrast agents in children. The purpose of this article was to assess the safety profile of the i.v. administration of ultrasound contrast agents in the pediatric oncology population. MATERIALS AND METHODS: Patients with pediatric solid malignancies who were enrolled on institutional clinical trials conducted between June 2003 and January 2013 and who met our institutional screening criteria for contrast-enhanced ultrasound (CEUS) were eligible. After providing informed consent or assent for CEUS, subjects received i.v. bolus injections of one of two contrast agents for imaging of the primary tumor or a metastatic target lesion. Hemodynamic parameters, including heart rate, cardiac rhythm, and oxygen saturation, were monitored immediately before and for 30 minutes after the administration of the contrast agent. Interviews with the subject or a guardian were conducted by the principal investigator or a radiologist coinvestigator before and after the examination to assess for any adverse effects. RESULTS: Thirty-four subjects (21 male and 13 female) ranging in age from 8 months to 20.7 years (median, 8.7 years) underwent 134 CEUS. No detrimental change in hemodynamic status occurred in any subject. Three subjects (3/134, 2.2%) reported mild transient side effects on one occasion each, two (2/134, 1.5%) had taste alteration, and one (1/134, 0.8%) reported mild transient tinnitus and lightheadedness. These reactions did not recur in these subjects on subsequent CEUS examinations. CONCLUSION: The i.v. administration of ultrasound contrast agents is safe and well tolerated in the pediatric oncology population. Further studies in children are needed to confirm our findings. PMID- 24758650 TI - Differentiation between mucus secretion and endoluminal tumors in the airway: analysis and comparison of CT findings. AB - OBJECTIVE: The objective of our study was to suggest CT features that help differentiate transient mucus secretion from airway tumors in the evaluation of soft-tissue nodular lesions confined within the airway lumen. MATERIALS AND METHODS: Forty-two patients with airway tumors (mean age, 57.6 +/- 14.9 [SD] years) and 48 patients with secretion (mean age, 67.8 +/- 13.4 years) were included. Two observers analyzed the following features on contrast-enhanced CT in consensus readings: shape (round, ovoid, lobulating, or complex); margin (circumscribed or uncircumscribed); size (including change in size between mediastinal and lung window images); location (anterior, posterior, or unclear); angle between the lesion and contacting airway wall (acute, obtuse, or unclear); attenuation (quantitative and qualitative analyses); and presence of air, fat, or calcification within the lesion. The positive predictive value (PPV) of each CT finding was calculated for secretion and tumor, respectively. RESULTS: Round (90.0%) or lobulating (92.9%) shape, uncircumscribed margin (100.0%), unclear location (87.5%), unclear angle (87.5%), a CT number of 21.7 HU or more (91.7%), and internal features such as fat (100.0%) or calcification (100.0%) showed high PPVs for tumors. Complex shape (100.0%), change in size of more than 15.9% (96.8%), a CT number of less than 21.7 HU (83.3%), and internal air density (100.0%) showed high PPVs for secretion. CONCLUSION: On contrast-enhanced CT, the evaluation of shape, change in size between mediastinal and lung window images, the measurement of CT number, and internal features such as air, fat, or calcification might help differentiate secretion from tumors. PMID- 24758651 TI - CT angiography (CTA) and diagnostic performance of noninvasive fractional flow reserve: results from the Determination of Fractional Flow Reserve by Anatomic CTA (DeFACTO) study. AB - OBJECTIVE: Fractional flow reserve (FFR) computed from standard coronary CT scans (FFRCT) is a novel noninvasive method for determining the functional significance of coronary artery lesions. Compared with CT alone, FFRCT significantly improves diagnostic accuracy and discrimination for patients with and without hemodynamically significant coronary artery stenoses. To date, the impact of CT image quality on diagnostic performance of FFRCT is unknown. We evaluated the impact of patient preparation, CT scan protocol, and factors related to image quality on the diagnostic accuracy of FFRCT. SUBJECTS AND METHODS: We studied stable patients with suspected coronary artery disease (CAD), enrolled from 17 centers, who underwent CT, invasive coronary angiography, FFR, and FFRCT. The accuracy of CT and FFRCT for diagnosis of ischemia was compared against an invasive FFR reference standard. Anatomically obstructive CAD was defined by a stenosis value of at least 50 by CT or invasive coronary angiography, whereas ischemia was defined by an FFR or FFRCT of up to 0.80. Ischemia was assessed at the per-patient and per-vessel levels. Diagnostic performance of FFRCT was then evaluated in relation to patient preparation, including administration before CT of a beta-blocker or nitroglycerin, as well as in relation to imaging characteristics, including misalignment, noise, motion, and coronary artery calcium. RESULTS: Among 252 study participants, 137 (54.0%) had an abnormal FFR. Administration of a beta-blocker increased FFRCT specificity (51.0% vs 66.0%; p = 0.03) with lower bias (-0.084 vs -0.048; p = 0.008), whereas nitroglycerin pretreatment within 30 minutes of CT was associated with improved specificity (54.0% vs 75.0%; p = 0.013). Misalignment artifacts resulted in impaired sensitivity (43.0% vs 86.0%; p = 0.001) with resultant reductions in overall accuracy (56.0% vs 71.0%; p = 0.03). No differences in diagnostic performance of FFRCT were noted in the presence of coronary motion or increasing coronary artery calcium score. CONCLUSION: Use of beta-blockade and nitroglycerin administration before CT improve diagnostic performance of FFRCT. Diagnostic accuracy of FFRCT is significantly reduced in the setting of misalignment artifacts. PMID- 24758653 TI - Recent advances in the diagnosis and management of autoimmune pancreatitis. AB - OBJECTIVE: Autoimmune pancreatitis (AIP) is a rare chronic relapsing steroid responsive fibroinflammatory disorder of the pancreas that is likely caused by immune dysregulation. It is now thought that AIP consists of two distinct clinicopathologic syndromes currently designated as types 1 and 2. CONCLUSION: A current update on etiopathogenesis, pathology, and clinical and imaging findings of AIP is provided with an emphasis on diagnosis and management. PMID- 24758652 TI - Added value of diffusion-weighted acquisitions in MRI of the abdomen and pelvis. AB - OBJECTIVE: The purpose of this article is to review abdominopelvic applications of diffusion-weighted imaging (DWI), discuss advantages and limitations of DWI, and illustrate these with examples. CONCLUSION: High-quality abdominopelvic DWI can be performed routinely on current MRI systems and may offer added value in image interpretation. Particularly in unenhanced MRI examinations, DWI may provide an alternative source of image contrast and improved conspicuity to identify and potentially characterize pathology. DWI is a powerful technique that warrants implementation in routine abdominal and pelvic imaging protocols. PMID- 24758654 TI - Age-related change of the secretory flow of pancreatic juice in the main pancreatic duct: evaluation with cine-dynamic MRCP using spatially selective inversion recovery pulse. AB - OBJECTIVE: The purpose of this study is to evaluate age-related changes in the secretory flow of pancreatic juice in the main pancreatic duct noninvasively by means of nonpharmacologic cine-dynamic MRCP using spatially selective inversion recovery (IR) pulse. MATERIALS AND METHODS: Fifty-three subjects without a history of pancreatic disease were included. Four-second breath-hold MRCP using spatially selective IR pulse was performed every 15 seconds during 5 minutes (acquiring a total of 20 images) in cine-dynamic fashion. The secretion grade was classified into five grades by the distance of pancreatic juice inflow within the tagged area. The mean secretion grade and the frequency of secretion in cine dynamic MRCP were compared among three age-range groups (group 1, < 40 years; group 2, 40-70 years; and group 3, > 70 years). Statistical analysis was performed using Spearman rank correlation coefficient and Kruskal-Wallis and Mann Whitney U tests. RESULTS: The secretion grade and the frequency of secretion were significantly reduced with aging (r = -0.77, p < 0.001; and r = -0.74, p < 0.001, respectively). The mean secretion grade and the frequency of secretion were significantly lower in group 3 than in group 2 (mean grade, 0.36 vs 1.48, p = 0.001; and 4.8 vs 11.9 times, p = 0.001) and were lower in group 2 than in group 1 (mean grade, 1.48 vs 2.48, p < 0.001; and 11.9 vs 16.2 times, p = 0.011). CONCLUSION: Cine-dynamic MRCP using spatially selective IR pulse was able to show the age-related decrease of the secretory flow of pancreatic juice in the main pancreatic duct visually and noninvasively. PMID- 24758655 TI - Direct visualization of pancreatic juice flow using unenhanced MRI with spin labeling can be aid in diagnosing chronic pancreatitis. AB - OBJECTIVE: The purpose of this study is to prospectively assess whether direct visualization of pancreatic juice flow using an unenhanced MRI technique with spin labeling can aid in the diagnosis of chronic pancreatitis. SUBJECTS AND METHODS: Ten healthy volunteers and 50 patients who were categorized as having no chronic pancreatitis (n = 11), early chronic pancreatitis (n = 7), or established chronic pancreatitis (n = 32) underwent MRI, including direct pancreatic juice visualization using a flow-out technique with a time-spatial labeling inversion pulse, comprising a nonselective inversion recovery pulse immediately followed by a spatially selective inversion labeling pulse. The mean velocities and volumes of pancreatic juice excretion were also obtained. Variance tests were used to evaluate the clinical groups with respect to the appearance rate and mean velocity; the Kruskal-Wallis test was used for volume. RESULTS: There were no significant differences between healthy volunteers and patients with no chronic pancreatitis. The appearance rate, mean velocity, and volume of pancreatic juice excretion tended to decrease with the degree of chronic pancreatitis. Although the difference in these values was statistically significant between the healthy group and the established chronic pancreatitis group, the values of the early group and other groups were not statistically significant. There was a significant correlation between the appearance rate of pancreatic juice and the clinical groups (tau = -0.4376, p = 0.0015). CONCLUSION: The measurement of directly visualized pancreatic juice flow may aid in establishing the diagnosis of chronic pancreatitis. PMID- 24758656 TI - MRI with spin labeling for diagnosis of early chronic pancreatitis. AB - OBJECTIVE: The purpose of this article is to discuss MRI with spin labeling for diagnosis of chronic pancreatitis. CONCLUSION: Because of the unique functional information it can provide, MRI with spin labeling appears to be a useful adjunctive technique that can be added to routine anatomic imaging of the pancreas and pancreatic duct. PMID- 24758657 TI - Abdominopelvic MRI for lesion characterization after prior imaging: factors associated with likelihood of added value. AB - OBJECTIVE: The purpose of this article is to evaluate factors associated with the likelihood that abdominopelvic MRI examinations performed for characterization of lesions identified on other imaging modalities will provide information that adds value to patient management. MATERIALS AND METHODS: One thousand one hundred thirty-two lesions in 863 patients undergoing MRI for further characterization after detection by an alternative imaging modality were identified. Reports of the MRI examinations and of previous studies were reviewed to classify cases in terms of patient-, examination-, and lesion-related factors. MRI reports were also classified in terms of measures reflecting inclusion of content with the potential to add value to patient management. Data were analyzed using logistic regression for correlated data. RESULTS: MRI provided a definitive diagnosis in 79.2% (897/1132), upgraded the severity of the favored diagnosis in 5.3% (60/1132), downgraded the severity of the favored diagnosis in 34.5% (390/1132), and showed an absence of the suspected lesion in 12.1% (137/1132) of cases. Provision of a definitive diagnosis (most common in liver, kidney, gallbladder, bowel, myometrium, and adrenal gland) was significantly associated with the organ containing the lesion (p < 0.001). A change in severity of the favored diagnosis (most common after CT or PET/CT) and the absence of the suspected lesion (most common after PET/CT) were significantly associated with the prior imaging modality (p <= 0.001). Among the lesions that were upgraded in severity, 76.7% subsequently underwent intervention or change in medical management. CONCLUSION: Abdominopelvic MRI examinations performed for further lesion characterization may affect clinical management in a high fraction of cases, the likelihood of which is influenced by factors related to the given examination. PMID- 24758658 TI - Characterization of lipid-poor adrenal adenoma: chemical-shift MRI and washout CT. AB - OBJECTIVE: The purpose of this article is to retrospectively compare the accuracy of MRI and CT in characterizing lipid-poor adrenal adenomas with respect to lesion-attenuation values measured on unenhanced CT. MATERIALS AND METHODS: Fifty two lipid-poor adrenal masses measuring greater than 10 HU on unenhanced CT were identified in 52 patients who underwent both chemical-shift MRI and washout CT. Accuracies using the adrenal-to-spleen ratio (< 0.71) or signal intensity index (> 16.5%) for MRI and using absolute (>= 60%) or relative (>= 40%) percentage washout for CT were calculated to determine which modality was more accurate for lipid-poor adenoma characterization. Sensitivities of MRI and CT were also compared according to the lesion-attenuation values measured on unenhanced CT. Follow-up imaging or histologic diagnosis was used as the standard reference. The McNemar test was used to compare the accuracies of CT and MRI. RESULTS: Lipid poor adrenal masses consisted of 37 adenomas and 15 nonadenomas. The sensitivities and specificities for adenoma on MRI versus CT were 75.7% (28/37) versus 100% (37/37) and 60.0% (9/15) versus 80.0% (12/15), respectively. CT achieved a higher accuracy than did MRI (p = 0.008). The sensitivities for adenomas measuring 20 HU or less on unenhanced CT were 100% (12/12) in both MRI and CT, whereas those measuring more than 20 HU were 64.0% (16/25) and 100% (25/25) in MRI and CT, respectively. CONCLUSION: MRI is equivalent to CT for characterizing adenomas measuring 20 HU or less on unenhanced CT. However, MRI is inferior to CT for adenomas measuring more than 20 HU because of decreased MR sensitivity. PMID- 24758659 TI - Triage of low-risk prostate cancer patients with PSA levels 10 ng/ml or less: comparison of apparent diffusion coefficient value and transrectal ultrasound guided target biopsy. AB - OBJECTIVE: The purpose of our study was to identify low-risk prostate cancer on the basis of the D'Amico clinical risk score in patients with prostate-specific antigen (PSA) levels 10 ng/mL or less who had undergone radical prostatectomy by comparing apparent diffusion coefficient (ADC) with transrectal ultrasound (TRUS) guided target biopsy. MATERIALS AND METHODS: In the preliminary study, we used receiver operating characteristic (ROC) analysis and determined the cutoff ADC to identify prostate cancer with a Gleason score of 6 or less for 117 patients. In the primary study, we assessed the combination of routine MRI (T2-weighted and diffusion-weighted imaging) plus the cutoff ADC value ("method A") to identify low-risk prostate cancer for another 89 patients. Their diagnostic value was compared with that of routine MRI combined with the Gleason score obtained from TRUS-guided target biopsies ("method B"). RESULTS: The preliminary study showed that a mean ADC of 1.04 * 10(-3) mm(2)/s was the best cutoff. In the primary study, accuracy was statistically higher with method A for each reader (p = 0.041). CONCLUSION: In patients with PSA levels 10 ng/mL or less, the combination of MRI findings plus the cutoff ADC is significantly more accurate for the identification of low-risk prostate cancer than is the combination of MRI followed by TRUS-guided target biopsy. PMID- 24758660 TI - Cost accounting for the radiologist. AB - OBJECTIVE: Cost accounting is the branch of managerial accounting that deals with the analysis of the costs of a product or service. This article reviews methods of classifying and allocating costs and relationships among costs, volume, and revenues. CONCLUSION: Radiology practices need to know the cost of a procedure or service to determine the selling price of a product, bid on contracts, analyze profitability, and facilitate cost control and cost reduction. PMID- 24758662 TI - Financial impact of Medicare code bundling of CT of the abdomen and pelvis. AB - OBJECTIVE: On January 1, 2011, the Current Procedural Terminology version 4 codes for CT of the abdomen and CT of the pelvis were bundled together. The relative value units attached to the new single codes were lower than the sum of the relative value units accruing to the two separate codes. The purpose of this study was to assess the effect of this new policy on Medicare part B reimbursements for these studies. MATERIALS AND METHODS: The nationwide 2001-2011 Medicare part B data files were used to select the codes for CT of the abdomen and pelvis before and after bundling occurred in 2011. Procedure volumes were ascertained, and utilization rates per 1000 Medicare beneficiaries were calculated. Aggregate Medicare reimbursements were determined, and Medicare specialty codes were used to determine the reimbursements to radiologists. RESULTS: In 2011, use of CT of the two body regions remained approximately the same as in 2010 (before bundling), but because the two codes were bundled into one in 2011, the actual rate per 1000 decreased from 277.1 to 148.1. Medicare reimbursements for CT of the abdomen and pelvis had risen steadily from 2001 to 2005 but remained relatively stable thereafter through 2010. However, in 2011 reimbursements decreased from $971.5 million the previous year to $687.0 million- a drop of $284.5 million (29%) in a single year. Radiologists experienced $218.6 million of this decrease. CONCLUSION: Code bundling of CT of the abdomen and CT of the pelvis resulted in a large reduction in reimbursements for imaging. PMID- 24758661 TI - Prioritizing examination-centered over patient-centered dose reduction: a hazard of institutional "benchmarking". AB - OBJECTIVE: The purpose of this article is to evaluate whether examination specific radiation dose metrics reliably measure an institution's success in reducing cancer risks. MATERIALS AND METHODS: We projected health benefits from dose-reduction programs in a hypothetical institution that sought to decrease exposures from abdominopelvic CT. Using modeling techniques to project radiation induced cancer risks and tertiary center data to inform the institution's abdominopelvic CT age distribution, we compared a program in which effective doses were reduced equally (from 10 to 7 mSv) across all scans with programs in which dose reduction was age dependent. For each program, we projected lethal cancers averted, life expectancy gained, and average institutional dose achieved. Markov Chain Monte Carlo methods were used to estimate uncertainty in projections. RESULTS: The analysis's age distribution drew from 20,979 CT scans; 39% were from patients 65 years old and older. To illustrate trends yielded, if all patients in the hypothetical institution underwent 7-mSv (instead of 10-mSv) scans, we projected the maximum number of lethal cancers averted to be seven per 100,000 patients, and maximum life expectancy gained to be 0.26 days per patient, when averaged over the institution's population. When restricting dose reduction (from 10 to 7 mSv) to patients younger than 65 years, benefits were slightly lower (five lethal cancers averted per 100,000 patients and 0.22 days per patient gained); however, the average institutional dose was substantially higher (8.2 mSv). Although dose reduction in patients 65 years old and older accounted for only 16% of possible institutional life expectancy gains, this patient group contributed disproportionately (39%) to the institution's average dose. CONCLUSION: Institutional examination-specific dose metrics can be misleading, because the least-benefited patients may contribute disproportionately toward "improved" averages. PMID- 24758663 TI - Evaluation of patient effective dose of neurovascular imaging protocols for C-arm cone-beam CT. AB - OBJECTIVE: The purpose of this study was threefold: to estimate the organ doses and effective doses (EDs) for seven neurovascular imaging protocols, to study the effect of beam collimation on ED, and to derive protocol-specific dose-area product (DAP)-to-ED conversion factors. MATERIALS AND METHODS: A cone-beam CT system was used to measure the organ doses for seven neurovascular imaging protocols. Two datasets were obtained: seven protocols without beam collimation (FOV, entire head) and four with beam collimation (FOV, from the base to the top of the skull). Measurements were performed on an adult male anthropomorphic phantom with 20 metal oxide semiconductor field-effect transistor (MOSFET) detectors placed in selected organs. The DAP values were recorded from the console. The EDs of five protocols were also estimated using Monte Carlo simulations software. The ED values were computed by multiplying measured organ doses to corresponding International Commission on Radiological Protection tissue weighting factors. RESULTS: Without collimation, the EDs ranged from 0.16 to 1.6 mSv, and the DAP-to-ED conversion factors ranged from 0.035 to 0.076 mSv/Gy.cm(2). For the four protocols investigated with beam collimation, the ED was reduced by a factor of approximately 2, and the DAP-to-ED conversion factors were reduced by approximately 30%. For the five protocols also estimated with the Monte Carlo method, the estimated EDs were in agreement (< 20% deviation) with those determined by the MOSFET method. CONCLUSION: We have estimated ED for standard adult neuroimaging protocols in a 3D rotational angiography system. Our results provide a simple means of ED estimation using DAP console readings. PMID- 24758664 TI - High prevalence of abnormal MR findings of the distal semimembranosus tendon: contributing factors based on demographic, radiographic, and MR features. AB - OBJECTIVE: The objective of our study was to determine the prevalence of thickening and signal alteration of the distal semimembranosus (SM) tendon on knee MRI and analyze the patient factors associated with abnormal MR findings of the distal SM tendon. MATERIALS AND METHODS: Knee MRI scans of 116 subjects (58 men, 58 women; mean age, 48.5 years; range, 18-79 years) who underwent knee surgery were evaluated to assess the distal SM tendons in terms of signal alteration and thickness. To determine the factors associated with MR findings of the distal SM tendon, we assessed demographic characteristics; Kellgren-Lawrence radiographic osteoarthritis grading; history of trauma; the condition of the cruciate ligaments, collateral ligaments, and menisci; and whether there were cystic lesions around the SM tendon. In addition, 55 control subjects with normal knee MRI findings based on the electronic MRI patient database who had anterior knee pain and did not undergo surgery were enrolled. RESULTS: Abnormal thickening of the distal SM tendon was found in 52.6% of knees and signal alteration in 44.8%. Univariate analysis revealed significant associations between abnormal thickening and age, body mass index, history of trauma, osteoarthritis, medial collateral ligament (MCL) thickening, and anterior cruciate ligament (ACL) tear. As for signal alteration, univariate analysis showed that age, body mass index, osteoarthritis, and MCL thickening were statistically significant factors. Multivariate binary logistic regression analyses showed that osteoarthritis and MCL thickening were the strong independent predictors in thickening and signal alteration of the distal SM tendon. CONCLUSION: Signal alteration and abnormal thickening of the distal SM tendon on MRI are frequently seen in daily practice. These MR findings are strongly associated with osteoarthritis and MCL thickening. PMID- 24758665 TI - Ultrasound elastography of lateral epicondylosis: clinical feasibility of quantitative elastographic measurements. AB - OBJECTIVE: The objective of our study was to investigate the clinical feasibility of ultrasound elastography for assessing patients with lateral epicondylosis and to establish an objective and quantitative method of elastographic measurement in the affected tendon. SUBJECTS AND METHODS: A total of 97 symptomatic and 89 asymptomatic common extensor tendons from both elbows of 79 consecutive patients with lateral epicondylosis and 14 healthy participants were prospectively examined by gray-scale sonography, color Doppler sonography, and compression based elastography. Real-time color-coded elastography was performed and quantified with two regions of interest: the adjacent subcutis (S1) for a reference area and the common extensor tendon (S2) for the target area. The mean strain ratio (S1/S2) was used for quantitative comparisons. The difference in the mean strain ratio between symptomatic and asymptomatic tendons was assessed with conditional regression analysis. RESULTS: In symptomatic elbows, 87 of 97 tendons (89.7%) showed intratendinous hypoechogenicity, 86 of 97 (88.7%) showed swelling, and 70 of 97 tendons (72.2%) showed intratendinous hyperemia. Color-coded elastography revealed a soft area on 73 of 97 tendons (75.3%). The mean strain ratio was 1.45 (SD, 0.45) for symptomatic tendons and 2.07 (SD, 0.70) for asymptomatic tendons. The mean strain ratio of the symptomatic tendons was significantly lower than that of asymptomatic tendons (p < 0.001), indicating that the symptomatic tendons were softer. CONCLUSION: Our results revealed that patients with lateral epicondylosis had significantly lower strain ratios in their common extensor tendon origins. Ultrasound elastography using quantitative strain ratio measurements could be a promising supplementary method to evaluate tendon abnormalities in lateral epicondylosis. PMID- 24758666 TI - CT of globe rupture: analysis and frequency of findings. AB - OBJECTIVE: The objective of our study was to evaluate the CT characteristics of globe rupture. MATERIALS AND METHODS: The medical records of patients seen in the emergency department with blunt, penetrating, or explosive orbit injury were retrospectively reviewed. A total of 75 patients (76 injured globes) were included (56 males and 19 females; average age, 45.1 years; age range, 5-95 years). CT examinations were reviewed by two experienced radiologists without knowledge of ophthalmologic findings, original orbital CT images, or surgical outcomes. RESULTS: Of the 76 globe injuries, 33 (43%) were ruptured and 43 (57%) were nonruptured. There were significant differences between the ruptured and nonruptured globes with respect to intraocular hemorrhage, lens dislocation and destruction, an intraocular foreign body, intraocular gas, anterior chamber depth (ACD), and globe deformity and wall irregularity (p < 0.05). There was good interrater agreement between the two radiologists (kappa value range, 0.63-0.96). The average sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of CT for the detection of globe rupture based on readings by two radiologists were 76%, 85%, 80%, 82%, and 81%, respectively. CONCLUSION: Although CT is extremely useful in the evaluation of ocular trauma, it should not be solely relied on for the diagnosis of globe rupture because of the potentially catastrophic consequences of an undiagnosed injury. A difference in ACD can be diagnostic of globe rupture. PMID- 24758667 TI - Redefining normal facial nerve enhancement: healthy subject comparison of typical enhancement patterns--unenhanced and contrast-enhanced spin-echo versus 3D inversion recovery-prepared fast spoiled gradient-echo imaging. AB - OBJECTIVE: Normal facial nerve enhancement patterns derived from spin-echo (SE) sequences have not been systematically compared on contrast-enhanced 3D inversion recovery-prepared fast spoiled gradient-echo (IR-FSPGR) sequences, now in widespread use. We hypothesize that features unique to IR-FSPGR may engender differences in the appearance of the normal facial nerve, which may confound analysis of pathologic enhancement. We compared unenhanced and contrast-enhanced SE and IR-FSPGR sequences in a cohort of patients without facial nerve pathology. MATERIALS AND METHODS: Twenty-three patients without facial nerve pathology were examined. Unenhanced and contrast-enhanced signal intensity (SI) of seven facial nerve segments was assessed on SE and IR-FSPGR by two neuroradiologists. SI was assigned a value of 0-3 (0, absent; 1, faint; 2, equivalent to brain; 3, equivalent to enhancing dural sinus). Statistically significant differences were assessed for each segment. RESULTS: Significantly higher unenhanced and contrast enhanced SI was present in most facial nerve segments on IR-FSPGR compared with SE, including cisternal, canalicular, labyrinthine, and geniculate segments (p <= 0.01). Enhancement patterns were generally similar; however, significant enhancement of the labyrinthine segment was detected only on SE (p = 0.011). For unenhanced images, mean kappa statistic was 0.32, and for the contrast-enhanced images, mean kappa statistic was 0.04, implying fair and slight agreement between readers, respectively. CONCLUSION: Significantly greater SI is observed in most facial nerve segments on both unenhanced and contrast-enhanced IR-FSPGR among healthy subjects and may be misinterpreted as pathologic when evaluated in the context of existing enhancement paradigms. Examiners should remain cognizant of normal deviations from expected enhancement patterns in IR-FSPGR imaging to avoid misdiagnosis and other interpretive pitfalls. PMID- 24758668 TI - FDG PET metabolic tumor volume segmentation and pathologic volume of primary human solid tumors. AB - OBJECTIVE: The purpose of this study was to establish the correlation and reliability among the pathologic tumor volume and gradient and fixed threshold segmentations of (18)F-FDG PET metabolic tumor volume of human solid tumors. MATERIALS AND METHODS: There were 52 patients included in the study who had undergone baseline PET/CT with subsequent resection of head and neck, lung, and colorectal tumors. The pathologic volume was calculated from three dimensions of the gross tumor specimen as a reference standard. The primary tumor metabolic tumor volume was segmented using gradient and 30%, 40%, and 50% maximum standardized uptake value (SUVmax) threshold methods. Pearson correlation coefficient, intraclass correlation coefficient, and Bland-Altman analyses were performed to establish the correlation and reliability among the pathologic volume and segmented metabolic tumor volume. RESULTS: The mean pathologic volume; gradient-based metabolic tumor volume; and 30%, 40%, and 50% SUVmax threshold metabolic tumor volumes were 13.46, 13.75, 15.47, 10.63, and 7.57 mL, respectively. The intraclass correlation coefficients among the pathologic volume and the gradient-based and 30%, 40%, and 50% SUVmax threshold metabolic tumor volumes were 0.95, 0.85, 0.80, and 0.76, respectively. The Bland-Altman biases were -0.3, -2.0, 2.82, and 5.9 mL, respectively. Of the small tumors (< 10 mL), 23 of the 35 patients had PET segmented volume outside 50% of the pathologic volume, and among the large tumors (>= 10 mL) three of the 17 patients had PET segmented volumes that were outside 50% of pathologic volume. CONCLUSION: FDG PET metabolic tumor volume estimated using gradient segmentation had superior correlation and reliability with the estimated ellipsoid pathologic volume of the tumors compared with threshold method segmentation. PMID- 24758669 TI - CT angiographic evaluation of genetic vascular disease: role in detection, staging, and management of complex vascular pathologic conditions. AB - OBJECTIVE: Arterial dissection and aneurysm rupture are significant sources of morbidity and mortality in patients with connective tissue diseases. This article provides a detailed analysis of cardiovascular involvement in Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome. CONCLUSION: Although these syndromes share some overlapping features, they have discriminating clinical and imaging features, and knowledge of these features enables the radiologist to aid the referring clinician in making the correct diagnosis. PMID- 24758671 TI - CT-guided percutaneous cryoablation for osteoid osteoma: initial experience in adults. AB - OBJECTIVE: The purpose of this study was to investigate the safety and efficacy of CT-guided percutaneous cryoablation for the treatment of osteoid osteoma in adults. MATERIALS AND METHODS: A retrospective case series over a 30-month period involved 10 consecutive adult patients (nine male and one female patients; mean age, 27.9 years; age range, 16-49 years) who underwent CT-guided percutaneous cryoablation for management of osteoid osteoma. Clinical and technical success was evaluated with postprocedure MRI at 4-5 weeks and with digital numeric pain scores taken before and immediately after the procedure, as well as at primary follow-up (4-10 weeks; average, 5 weeks) and secondary follow-up (23-29 weeks; average, 24 weeks). RESULTS: Clinical and technical success rates were 100%. Average digital numeric pain scores were 7.4 before the procedure, 1.5 after procedure, 0.5 at the primary follow-up, and 0.3 at secondary follow-up. No minor or major complications were noted during the procedure, recovery period, primary follow-up, or secondary follow-up. CONCLUSION: CT-guided percutaneous cryoablation is safe and effective in the treatment of osteoid osteoma in adults. PMID- 24758670 TI - Yttrium-90 radioembolization of malignant tumors of the liver: gallbladder effects. AB - OBJECTIVE: After (90)Y-microsphere radioembolization for unresectable hepatic neoplasms, the nearby gallbladder is susceptible to radiation-induced cholecystitis, an uncommon complication. The purpose of this study was to characterize the imaging findings after (90)Y radioembolization of the gallbladder and to assess the incidence of clinically significant radiation induced cholecystitis. MATERIALS AND METHODS: Medical records were retrospectively reviewed for cholecystectomy after (90)Y treatment of 133 consecutively registered patients (76 men, 57 women; average age, 65 years). Thirty-four of the patients had primary and 99 had secondary liver neoplasms. The pretreatment and posttreatment cross-sectional images of 85 of the patients were available for review. RESULTS: Clinically significant radiation-induced cholecystitis occurred in 1 of the 133 patients (0.8%). After radioembolization, gallbladder imaging abnormalities were found in 84 of 85 patients (99%), but none was associated with clinically significant radiation-induced cholecystitis. CONCLUSION: The incidence of clinically significant radiation-induced cholecystitis was only 0.8% despite a high prevalence of gallbladder imaging abnormalities after (90)Y radioembolization. Therefore, in the postinterventional care of patients with abdominal pain after (90)Y radioembolization, even if imaging abnormalities of the gallbladder are identified, cholecystectomy should be reserved for patients in whom other causes of pain have been excluded. PMID- 24758672 TI - Distant metastatic disease manifestations in infiltrating lobular carcinoma of the breast. AB - OBJECTIVE: This article reviews unusual distant metastatic patterns of infiltrating lobular carcinoma (ILC) of the breast. CONCLUSION: ILC of the breast tends to spread to the gastrointestinal tract, genitourinary tract, peritoneum, retroperitoneum, and leptomeninges in addition to common visceral sites such as the liver, bone, and lung. Knowledge of these unusual metastatic manifestations and disease patterns may aid in differentiating distant metastatic disease from secondary primary cancers and help plan appropriate therapy. PMID- 24758673 TI - Breast imaging in the transgender patient. AB - OBJECTIVE: Limited information exists regarding breast health in the transgender population. In this article, we review transgender terminology, barriers faced by transgender patients, current breast care screening recommendations, and normal and abnormal imaging findings in this population. CONCLUSION: Health disparities in the transgender population continue. Educating physicians on the breast health care needs of transgender patients is important for improving their care. PMID- 24758674 TI - The ABCs of accessory breast tissue: basic information every radiologist should know. AB - OBJECTIVE: Accessory breast tissue, residual breast tissue persisting from embryologic development, is found in up to 6% of the population, most commonly in the axilla along the "milk line." CONCLUSION: Radiologists should be able to recognize the imaging appearance of this normal variant on multiple modalities, while at the same time understanding that the same spectrum of pathologic processes that occur in normal breast tissue can occur in accessory breast tissue as well. PMID- 24758676 TI - Acquired abnormalities of the pulmonary arteries. PMID- 24758677 TI - Malignant skin and subcutaneous neoplasms in adults: multimodality imaging with CT, MRI, and 18F-FDG PET/CT. AB - OBJECTIVE: The purpose of this article is to enlighten radiologists with the clinical presentation, multimodality imaging features, local recurrence, distant spread, differential diagnosis, and prognosis of skin and subcutaneous malignancies. CONCLUSION: Cutaneous and subcutaneous malignancies represent the most common type of cancer and frequently present with overlapping imaging appearances. CT, MRI, and (18)F-FDG PET/CT are commonly used for staging, preoperative planning, and posttreatment assessment. Knowledge of the multimodality imaging features can narrow down the differential diagnosis and elucidate their metastatic pattern. PMID- 24758678 TI - Distribution pattern of MRI abnormalities within the knee and wrist of juvenile idiopathic arthritis patients: signature of disease activity. AB - OBJECTIVE: The aim of this study in clinically active juvenile idiopathic arthritis (JIA) was to assess the frequency and distribution pattern of synovitis as hallmark of disease and additional soft-tissue and bony abnormalities on MRI in the knee and wrist as two target joints. MATERIALS AND METHODS: MRI datasets of 153 clinically active JIA patients (110 with knee and 43 with wrist involvement) were evaluated independently by two readers for the presence of literature-based imaging features: "synovial hypertrophy," "bone marrow changes," "bone erosions," "tenosynovitis" (only in the wrist), and "cartilage lesions" (only in the knee) in accordance with validated definitions and scoring locations. RESULTS: Synovial hypertrophy was most frequently observed--both in the knee and in the wrist (61.8-65.1% of cases). For the knee, the most frequently involved locations were the cruciate ligaments (46/183 locations [25.1%] affected with synovial hypertrophy) and medial patella (18/62 locations [29.0%] with bone marrow changes). Cartilage lesions and bone erosions were rare (5.5-7.3% of cases). For the wrist, most frequently involved were the radiocarpal joint (21/64 locations [32.8%] with synovial hypertrophy), lunate (7/46 locations [15.2%] with bone marrow changes), and capitate or triquetrum (6/28 locations [21.4%] with bone erosions). Tenosynovitis was a common wrist-specific feature (46.5% of cases). MRI showed no abnormalities in a subgroup of patients with clinically active knee (23.6%) and wrist (16.3%) involvement. CONCLUSION: The distribution pattern of MRI abnormalities in the knee and wrist of active JIA patients provides a practical tool to detect a signature of JIA disease activity in target joints. PMID- 24758679 TI - Dose reduction of the female breast in chest CT. AB - OBJECTIVE: Organ-based tube current modulation has been shown to significantly reduce the radiation dose to the female breast in phantom studies. We sought to assess the proportions of female breast and glandular tissues that are within the range of organ-based tube current modulation in different age groups and whether these proportions could be optimized by clothing. The secondary objective of our study was to determine whether metal parts of brassieres cause artifacts that impair the diagnostic value. SUBJECTS AND METHODS: Five hundred seventy-eight female patients undergoing chest CT were included in this study. Two hundred nine patients were prospectively examined wearing a brassiere (group A), and the control patients (group B; n = 369) were scanned according to our previous standard without wearing a brassiere during CT. The two groups were subdivided according to cup size (A-E). For CT data acquisition, an angle-dependent tube current modulation, which reduces the tube current for anterior tube position to minimize direct exposure to anteriorly located organs, was used. The proportion of breast tissue and glandular tissue located within and outside the region of tube current reduction was assessed. RESULTS: The results showed that 60.4% of total breast tissue and 67.1% of glandular tissue was inside the region of tube current reduction in group B; the proportions were significantly improved, to an average of 91.3% and 96%, respectively, in group A. Diagnostically relevant artifacts were introduced in none of the patients. Patients' age correlated with this effect, with higher rates of improvement in the older patient group. Angle dependent tube current modulation was most effective in patients with cup size A while wearing a brassiere. In this group, 97.5% of breast tissue and 98.1% of glandular tissue was inside the region of tube current reduction. Women with a cup size of E had the largest effect of wearing a brassiere, increasing the rate of breast tissue that was affected by angle-dependent tube current modulation from 30.0% to 83.3% and that of glandular tissue from 31.8% to 90.0%. CONCLUSION: We show that wearing a brassiere increases the percentage of breast tissue within the region of reduced tube current and, therefore, improves the performance of angle-dependent tube current modulation technique. PMID- 24758680 TI - Emphysema quantification by combining percentage and size distribution of low attenuation lung regions. AB - OBJECTIVE: The purpose of this study was to investigate efficacy of two types of emphysema quantification: percentage of low-attenuation lung regions (%LA); and size distribution of these regions. On a log-log plot, cumulative frequency-size distribution of low-attenuation lung regions can be fitted by a straight line whose slope (D) has been reported to reflect diffusing capacity. In this study, %LA and D were compared with pulmonary function test (PFT) parameters, especially with ratio of diffusing capacity of carbon monoxide to effective alveolar ventilation (i.e., DLCO/VA). MATERIALS AND METHODS: Thin-section unenhanced CT images were acquired from 30 patients (25 men, five women; mean [SD] age, 70.1 +/ 12.1 years), of whom 25 had received diagnosis of COPD, and %LA and D were calculated at 20 thresholds, ranging from -995 to -900 HU. To determine utility of %LA and D, we used Pearson's correlation for emphysema quantification and PFT. Significance of the coefficients was determined with Bonferroni correction (p < 0.0025). Finally, the relationships between emphysema quantification and DLCO/VA were examined by linear models and Akaike information criterion (AIC). RESULTS: The correlation coefficients for %LA and DLCO/VA were statistically significant at all the thresholds (optimal coefficient, -0.761). The correlation coefficients for D and DLCO/VA were statistically significant at the thresholds from -945 to 900 HU (optimal coefficient, -0.646). AIC values showed that the most accurate prediction of DLCO/VA was obtained by the model incorporating both %LA and D. CONCLUSION: Both %LA and D showed significant correlation with DLCO/VA. Combining %LA and D resulted in more accurate evaluation of DLCO/VA than did using %LA or D alone. PMID- 24758681 TI - Prostate cancer: role of pretreatment multiparametric 3-T MRI in predicting biochemical recurrence after radical prostatectomy. AB - OBJECTIVE: The purpose of this study is to retrospectively investigate whether pretreatment multiparametric MRI findings can predict biochemical recurrence in patients who underwent radical prostatectomy (RP) for localized prostate cancer. MATERIALS AND METHODS: In this study, 282 patients with biopsy-proven prostate cancer who received RP underwent pretreatment MRI using a phased-array coil at 3 T, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced MRI (DCE-MRI). MRI variables included apparent tumor presence on combined imaging sequences, extracapsular extension, and tumor size on DWI or DCE-MRI. Clinical variables included baseline prostate-specific antigen (PSA) level, clinical stage, and Gleason score at biopsy. The relationship between clinical and imaging variables and biochemical recurrence was evaluated using Cox regression analysis. RESULTS: After a median follow-up of 26 months, biochemical recurrence developed in 61 patients (22%). Univariate analysis revealed that all the imaging and clinical variables were significantly associated with biochemical recurrence (p < 0.01). On multivariate analysis, however, baseline PSA level (p = 0.002), Gleason score at biopsy (p = 0.024), and apparent tumor presence on combined T2WI, DWI, and DCE-MRI (p = 0.047) were the only significant independent predictors of biochemical recurrence. Of the independent predictors, apparent tumor presence on combined T2WI, DWI, and DCE MRI showed the highest hazard ratio (2.38) compared with baseline PSA level (hazard ratio, 1.05) and Gleason score at biopsy (hazard ratio, 1.34). CONCLUSION: The apparent tumor presence on combined T2WI, DWI, and DCE-MRI of pretreatment MRI is an independent predictor of biochemical recurrence after RP. This finding may be used to construct a predictive model for biochemical recurrence after surgery. PMID- 24758682 TI - Accuracy of contrast-enhanced dual-energy MDCT for the assessment of iodine uptake in renal lesions. AB - OBJECTIVE: The objective of our study was to assess the accuracy of iodine related attenuation and iodine quantification as imaging biomarkers of iodine uptake in renal lesions on a single-phase nephrographic image with dual-energy MDCT. MATERIALS AND METHODS: Fifty-nine patients (41 men, 18 women; age range, 28 84 years) with 80 renal lesions underwent contrast-enhanced dual-energy CT during the nephrographic phase of enhancement. Renal lesions were characterized as enhancing or nonenhancing on color-coded iodine overlay maps using iodine-related attenuation (in Hounsfield units) and iodine quantification (in milligrams per milliliter). For iodine-related attenuation the iodine uptake thresholds of 15 and 20 HU were tested; a threshold of 0.5 mg/mL was used for iodine quantification. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of iodine-related attenuation and iodine quantification were calculated from chi-square tests of contingency with histopathology or imaging follow-up as the reference standard. The 95% CIs were calculated from binomial expression. Differences in sensitivity and specificity were assessed by means of McNemar analysis. RESULTS: A significant difference in sensitivity and specificity was found between iodine-related attenuation with the thresholds of 15 HU (sensitivity, 91.4%; specificity, 93.3%; PPV, 91.4%; NPV, 93.3%) and 20 HU (sensitivity, 77.1%; specificity, 100%; PPV, 100%; NPV, 84.9%) (p = 0.008) and between iodine quantification (sensitivity, 100%; specificity, 97.7%; PPV, 97.2%; NPV, 100%) and iodine-related attenuation with a threshold of 20 HU (p = 0.004). No significant difference in sensitivity and specificity was found between iodine quantification and iodine-related attenuation with a threshold of 15 HU. CONCLUSION: Contrast-enhanced dual-energy MDCT with iodine related attenuation and iodine quantification allows accurate evaluation of iodine uptake in renal lesions on a single-phase nephrographic image. PMID- 24758683 TI - Use of transoral sonography with an endocavitary transducer in diagnosis, fine needle aspiration biopsy, and intraoperative localization of retropharyngeal masses. AB - OBJECTIVE: The purpose of this article is to describe the use of transoral sonography in the diagnosis, fine-needle aspiration (FNA) biopsy, and intraoperative localization of retropharyngeal masses. MATERIALS AND METHODS: We reviewed images and data for eight patients with a retropharyngeal mass identified on CT, MRI, or PET/CT as being suspicious for a metastatic Rouviere node. Transoral ultrasound was performed using a commercially available endorectal or endovaginal transducer. Transoral ultrasound-guided FNA biopsy was performed using a needle guide attached to the transducer shaft. Color and power Doppler imaging were used to identify the internal carotid artery and jugular vein and to plan the safest path to the targeted mass. The mass was intraoperatively localized by marking the mucosa with a permanent marker or by injecting methylene blue. RESULTS: There were six patients with a history of thyroid cancer (five papillary cancers and one medullary cancer), one patient with a history of esthesioneuroblastoma, and one patient with no history of cancer. Transoral ultrasound imaging was successful in all eight patients. Transoral ultrasound-guided FNA biopsy was performed in four patients, and a satisfactory cytologic diagnosis was obtained in all cases, although in one of those four cases, an additional core biopsy with an 18-gauge needle was performed to completely rule out lymphoma. Six patients underwent a transoral resection of the lesion. In three of them, the lesion was localized intraoperatively by making a mark on the mucosa and in one case by adding transoral ultrasound-guided injection of methylene blue. CONCLUSION: Transoral ultrasound can be used to visualize, sample, and localize abnormal masses in the retropharyngeal space, such as metastatic Rouviere nodes in patients with a history of head and neck cancer. PMID- 24758684 TI - Three-dimensional registration of images obtained before and after radiofrequency ablation of hepatocellular carcinoma to assess treatment adequacy. AB - OBJECTIVE: The aim of our study was to evaluate the value of 3D registration images reconstructed by fusion of pre- and posttreatment CT or MRI for the assessment of ablative margins after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From January 2007 to May 2011, we performed RFA in 84 patients to treat 139 HCC nodules, the margins of which had been assessed by comparing pre- and postablation images side by side. The same nodules were retrospectively assessed again with 3D registration images after classification into four margin grades. We analyzed the cumulative local recurrence rate for each grade and reviewed the origin of recurrence. RESULTS: Three-dimensional registration images predicted local recurrences more accurately than did the conventional side-by-side method (area under the curve, 0.678 and 0.536, respectively; p = 0.0144). The cumulative rates of local recurrence were significantly different among the margin grades assessed with 3D registration images (p = 0.0088). Three-dimensional registration images detected that the major origins of recurrence (n = 22) were residuals (n = 13) and sites of no margin (n = 6), especially proximate to blood vessels more than 3 mm in diameter. CONCLUSION: Three-dimensional registration of pre- and postablation CT or MRI more accurately assesses the ablative margin than the conventional method. It can predict a proclivity for local recurrence after RFA according to margin grade. It also indicated that residuals and sites of no margin proximate to blood vessels that are more than 3 mm in diameter are high-risk locations for local recurrence after ablation. PMID- 24758685 TI - Diffusion-weighted MRI: association between patient characteristics and apparent diffusion coefficients of normal breast fibroglandular tissue at 3 T. AB - OBJECTIVE: The purpose of this study is to assess associations between patient characteristics and apparent diffusion coefficient (ADC) values of normal breast fibroglandular tissue on diffusion-weighted imaging (DWI) at 3 T. MATERIALS AND METHODS: The retrospective study included 103 women with negative bilateral findings on 3-T breast MRI examinations (BI-RADS category 1). DWI was acquired during clinical breast MRI scans using b = 0 and b = 800 s/mm(2). Mean ADC of normal breast fibroglandular tissue was calculated for each breast using a semiautomated software tool in which parenchyma pixels were selected by interactive thresholding of the b = 0 s/mm(2) image to exclude fat. Intrasubject right- and left-breast ADC values were compared and averaged together to evaluate the association of mean breast ADC with age, mammographic breast density, and background parenchymal enhancement. RESULTS: Overall mean +/- SD breast ADC was 1.62 +/- 0.30 * 10(-3) mm(2)/s. Intrasubject right- and left-breast ADC measurements were highly correlated (R(2) = 0.89; p < 0.0001). Increased breast density was strongly associated with increased ADC (p <= 0.0001). Age and background parenchymal enhancement were not associated with ADC. CONCLUSION: Normal breast parenchymal ADC values increase with mammographic density but are independent of age and background parenchymal enhancement. Because breast malignancies have been shown to have low ADC values, DWI may be particularly valuable in women with dense breasts owing to greater contrast between lesion and normal tissue. PMID- 24758686 TI - Medicolegal-malpractice and ethical issues in radiology. Will saying "I'm sorry" prevent a malpractice lawsuit? PMID- 24758687 TI - The Canadian National Breast Screening Study: caveat emptor. PMID- 24758688 TI - Novel strategy to create hypoallergenic peanut protein-polyphenol edible matrices for oral immunotherapy. AB - Peanut allergy is an IgE-mediated hypersensitivity. Upon peanut consumption by an allergic individual, epitopes on peanut proteins bind and cross-link peanut specific IgE on mast cell and basophil surfaces triggering the cells to release inflammatory mediators responsible for allergic reactions. Polyphenolic phytochemicals have high affinity to bind proteins and form soluble and insoluble complexes with unique functionality. This study investigated the allergenicity of polyphenol-fortified peanut matrices prepared by complexing various polyphenol rich plant juices and extracts with peanut flour. Polyphenol-fortified peanut matrices reduced IgE binding to one or more peanut allergens (Ara h 1, Ara h 2, Ara h 3, and Ara h 6). Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) suggested changes in secondary protein structure. Peanut protein-cranberry polyphenol fortified matrices triggered significantly less basophil degranulation than unmodified flour in an ex vivo assay using human blood and less mast cell degranulation when used to orally challenge peanut allergic mice. Polyphenol fortification of peanut flour resulted in a hypoallergenic matrix with reduced IgE binding and degranulation capacity, likely due to changes in protein secondary structure or masking of epitopes, suggesting potential applications for oral immunotherapy. PMID- 24758689 TI - The clinical case report: a review of its merits and limitations. AB - BACKGROUND: The clinical case report has a long-standing tradition in the medical literature. While its scientific significance has become smaller as more advanced research methods have gained ground, case reports are still presented in many medical journals. Some scholars point to its limited value for medical progress, while others assert that the genre is undervalued. We aimed to present the various points of view regarding the merits and limitations of the case report genre. We searched Google Scholar, PubMed and select textbooks on epidemiology and medical research for articles and book-chapters discussing the merits and limitations of clinical case reports and case series. RESULTS: The major merits of case reporting were these: Detecting novelties, generating hypotheses, pharmacovigilance, high applicability when other research designs are not possible to carry out, allowing emphasis on the narrative aspect (in-depth understanding), and educational value. The major limitations were: Lack of ability to generalize, no possibility to establish cause-effect relationship, danger of over-interpretation, publication bias, retrospective design, and distraction of reader when focusing on the unusual. CONCLUSIONS: Despite having lost its central role in medical literature in the 20th century, the genre still appears popular. It is a valuable part of the various research methods, especially since it complements other approaches. Furthermore, it also contributes in areas of medicine that are not specifically research-related, e.g. as an educational tool. Revision of the case report genre has been attempted in order to integrate the biomedical model with the narrative approach, but without significant success. The future prospects of the case report could possibly be in new applications of the genre, i.e. exclusive case report databases available online, and open access for clinicians and researchers. PMID- 24758690 TI - Tautomeric properties and gas-phase structure of acetylacetone. AB - The tautomeric and structural properties of acetylacetone, CH3C(O)CH2C(O)CH3, have been studied by gas-phase electron diffraction (GED) and quantum chemical calculations (B3LYP and MP2 approximation with different basis sets up to aug-cc pVTZ). The analysis of GED intensities resulted in the presence of 100(3)% of the enol tautomer at 300(5) K and 64(5)% of the enol at 671(7) K. The enol tautomer possesses Cs symmetry with a planar ring and strongly asymmetric hydrogen bond. The diketo form possesses C2 symmetry. The experimental geometric parameters of both tautomeric forms are reproduced very closely by B3LYP/aug-cc-pVTZ and MP2/cc pVTZ methods. PMID- 24758691 TI - Effective access to health care in Mexico. AB - BACKGROUND: Effective access measures are intended to reflect progress toward universal health coverage. This study proposes an operative approach to measuring effective access: in addition to the lack of financial protection, the willingness to make out-of-pocket payments for health care signifies a lack of effective access to pre-paid services. METHODS: Using data from a nationally representative health survey in Mexico, effective access at the individual level was determined by combining financial protection and effective utilization of pre paid health services as required. The measure of effective access was estimated overall, by sex, by socioeconomic level, and by federal state for 2006 and 2012. RESULTS: In 2012, 48.49% of the Mexican population had no effective access to health services. Though this represents an improvement since 2006, when 65.9% lacked effective access, it still constitutes a major challenge for the health system. Effective access in Mexico presents significant heterogeneity in terms of federal state and socioeconomic level. CONCLUSIONS: Measuring effective access will contribute to better target strategies toward universal health coverage. The analysis presented here highlights a need to improve quality, availability, and opportuneness (location and time) of health services provision in Mexico. PMID- 24758692 TI - Distinct carbon isotope fractionation during anaerobic degradation of dichlorobenzene isomers. AB - Chlorinated benzenes are ubiquitous organic contaminants found in groundwater and soils. Compound specific isotope analysis (CSIA) has been increasingly used to assess natural attenuation of chlorinated contaminants, in which anaerobic reductive dechlorination plays an essential role. In this work, carbon isotope fractionation of the three dichlorobenzene (DCB) isomers was investigated during anaerobic reductive dehalogenation in methanogenic laboratory microcosms. Large isotope fractionation of 1,3-DCB and 1,4-DCB was observed while only a small isotope effect occurred for 1,2-DCB. Bulk enrichment factors (epsilonbulk) were determined from a Rayleigh model: -0.8 +/- 0.1 0/00 for 1,2-DCB, -5.4 +/- 0.4 0/00 for 1,3-DCB, and -6.3 +/- 0.2 0/00 for 1,4-DCB. epsilonbulk values were converted to apparent kinetic isotope effects for carbon (AKIE) in order to characterize the carbon isotope effect at the reactive positions for the DCB isomers. AKIE values are 1.005 +/- 0.001, 1.034 +/- 0.003, and 1.039 +/- 0.001 for 1,2-DCB, 1,3-DCB, and 1,4-DCB, respectively. The large difference in AKIE values between 1,2-DCB and 1,3-DCB (or 1,4-DCB) suggests distinct reaction pathways may be involved for different DCB isomers during microbial reductive dechlorination by the methanogenic cultures. PMID- 24758694 TI - Going home? An ethnographic study of assessment of capacity and best interests in people with dementia being discharged from hospital. AB - BACKGROUND: A significant proportion of patients in an acute hospital is made up of older people, many of whom have cognitive impairment or dementia. Rightly or wrongly, if a degree of confusion is apparent, it is often questioned whether the person is able to return to the previous place of residence. We wished to understand how, on medical wards, judgements about capacity and best interests with respect to going home are made for people with dementia and how decision making around hospital discharge for people with dementia and their families might be improved. Our research reflects the jurisdiction in which we work, but the importance of residence capacity rests on its implications for basic human rights. METHODS: The research employed a ward-based ethnography. Observational data were captured through detailed fieldnotes, in-depth interviews, medical record review and focus groups. Themes and key issues were identified using constant comparative analysis of 29 cases. Theoretical sampling of key stakeholders was undertaken, including patients with dementia (with and without residence capacity), their relatives and a range of practitioners. The research was carried out in three hospital wards (acute and rehabilitation) in two hospitals within two National Health Service (NHS) healthcare trusts in the North of England over a period of nine months between 2008 and 2009. RESULTS: Our analysis highlights the complexity of judgements about capacity and best interests in relation to decisions about place of residence for people with dementia facing discharge from hospital. Five key themes emerged from data: the complexity of borderline decisions; the requirement for better understanding of assessment approaches in relation to residence capacity; the need for better documentation; the importance of narrative; and the crucial relevance of time and timing in making these decisions. CONCLUSIONS: We need: more support and training for practitioners, as well as support for patients and families; clarity about the information to be imparted to the person with dementia; more advocacy for people with dementia; appropriate assessments embedded in routine clinical practice; the patient with dementia to be centre-stage; and properly resourced step-down or rehabilitation units to facilitate timely and good decision-making about place of residence. PMID- 24758695 TI - Rapid crystallization of faujasitic zeolites: mechanism and application to zeolite membrane growth on polymer supports. AB - Zeolites are microporous, crystalline aluminosilicates with the framework made up of T-O-T (T = Si, Al) bonds and enclosed cages and channels of molecular dimensions. Influencing and manipulating the nucleation and growth characteristics of zeolites can lead to novel frameworks and morphologies, as well as decreased crystallization time. In this study, we show that manipulating the supersaturation during synthesis of zeolite X/Y (FAU) via dehydration led to extensive nucleation. Controlled addition of water to this nucleated state promotes the transport of nutrients, with a 4-fold increase in the rate of crystal growth, as compared to conventional hydrothermal process. Structural signature of the nucleated state was obtained by electron microscopy, NMR, and Raman spectroscopy. This extensively intermediate nucleated state was isolated and used as the starting material for zeolite membrane synthesis on porous polymer supports, with membrane formation occurring within an hour. With this time frame for growth, it becomes practical to fabricate zeolite/polymer membranes using roll-to-roll technology, thus making possible new commercial applications. PMID- 24758693 TI - Meta-analysis of the effects of endoscopy with narrow band imaging in detecting dysplasia in Barrett's esophagus. AB - Narrow band imaging (NBI) is a real-time imaging technique. The aim of this meta analysis was to estimate the sensitivity, specificity, and diagnostic accuracy on the role of NBI in the detection and characterization of specialized intestinal metaplasia (SIM), high-grade dysplasia (HGD) in the Barrett's esophagus. We identified studies by performing a literature search of Medline, EMBASE, and the Cochrane Library databases up to May 2013. We performed data analysis using Meta DiSc (version 1.4) software. To assess study quality and potential for bias, we used the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2). Overall, seven eligible studies including over 3988 lesions of 502 patients were retrieved. The results showed that endoscopic diagnosis of dysplasia performed using NBI has a high diagnostic performance, with an area under the summary receiver operating characteristic (SROC) curve near 0.90 both in HGD lesions and SIM lesions. We also found that NBI has a sensitive and specificity of 0.91 (95% confidence interval [CI] = 0.86-0.94) and 0.85 (95% CI = 0.76-0.92) on a per patient element, and 0.97 (95% CI = 0.95-0.98) and 0.64 (95% CI = 0.59-0.68) on a per-lesion element for SIM diagnosis, respectively. The pooled per-patient sensitivity and specificity for identifying HGD are 0.91 (95% CI = 0.75-0.98) and 0.95 (95% CI = 0.91-0.97). The pooled per-lesion sensitivity and specificity for identifying HGD are 0.69 (95% CI = 0.63-0.74) and 0.90 (95% CI = 0.88-0.91). In conclusion, we found that endoscopic diagnosis with NBI is an accurate test to diagnosis dysplasia of Barrett's esophagus. PMID- 24758696 TI - let-7e replacement yields potent anti-arrhythmic efficacy via targeting beta 1 adrenergic receptor in rat heart. AB - Beta-adrenoceptor (beta-AR) exerts critical regulation of cardiac function. MicroRNAs (miRNAs) are potentially involved in a variety of biological and pathological processes. This study aimed to investigate the role of miRNA let-7e in the up-regulation of beta(1) -AR and arrhythmogenesis in acute myocardial infarction (AMI) in rats. beta(1) -AR expression was significantly up-regulated and let-7a, c, d, e and i were markedly down-regulated in the infarcted heart after 6 and 24 hrs myocardial infarction. Forced expression of let-7e suppressed beta(1) -AR expression at the protein level, without affecting beta(1) -AR mRNA level, in neonatal rat ventricular cells (NRVCs). Silencing of let-7e by let-7e antisense inhibitor (AMO-let-7e) enhanced beta(1) -AR expression at the protein level in NRVCs. Administration of the lentivirus vector containing precursor let 7e (len-pre-let-7e) significantly inhibited beta(1) -AR expression in rats, whereas len-AMO-let-7e up-regulated beta(1) -AR relative to the baseline control level, presumably as a result of depression of tonic inhibition of beta(1) -AR by endogenous let-7e. Len-negative control (len-NC) did not produce significant influence on beta(1) -AR expression. Len-pre-let-7e also profoundly reduced the up-regulation of beta(1) -AR induced by AMI and this effect was abolished by len AMO-let-7e. Importantly, len-pre-let-7e application significantly reduced arrhythmia incidence after AMI in rats and its anti-arrhythmic effect was cancelled by len-AMO-let-7e. Notably, anti-arrhythmic efficacy of len-pre-let-7e was similar to propranolol, a non-selective beta-AR blocker and metoprolol, a selective beta(1) -AR blocker. Down-regulation of let-7e contributes to the adverse increase in beta(1) -AR expression in AMI and let-7e supplement may be a new therapeutic approach for preventing adverse beta(1) -AR up-regulation and treating AMI-induced arrhythmia. PMID- 24758698 TI - Nanoparticle metamorphosis: an in situ high-temperature transmission electron microscopy study of the structural evolution of heterogeneous Au:Fe2O3 nanoparticles. AB - High-temperature in situ electron microscopy and X-ray diffraction have revealed that Au and Fe2O3 particles fuse in a fluid fashion at temperatures far below their size-reduced melting points. With increasing temperature, the fused particles undergo a sequence of complex structural transformations from surface alloy to phase segregated and ultimately core-shell structures. The combination of in situ electron microscopy and spectroscopy provides insights into fundamental thermodynamic and kinetic aspects governing the formation of heterogeneous nanostructures. The observed structural transformations present an interesting analogy to thin film growth on the curved surface of a nanoparticle. Using single-particle observations, we constructed a phase diagram illustrating the complex relationships among composition, morphology, temperature, and particle size. PMID- 24758697 TI - Role of cyclooxygenase isoforms in the altered excitatory motor pathways of human colon with diverticular disease. AB - BACKGROUND AND PURPOSE: The COX isoforms (COX-1, COX-2) regulate human gut motility, although their role under pathological conditions remains unclear. This study examines the effects of COX inhibitors on excitatory motility in colonic tissue from patients with diverticular disease (DD). EXPERIMENTAL APPROACH: Longitudinal muscle preparations, from patients with DD or uncomplicated cancer (controls), were set up in organ baths and connected to isotonic transducers. Indomethacin (COX-1/COX-2 inhibitor), SC-560 (COX-1 inhibitor) or DFU (COX-2 inhibitor) were assayed on electrically evoked, neurogenic, cholinergic and tachykininergic contractions, or carbachol- and substance P (SP)-induced myogenic contractions. Distribution and expression of COX isoforms in the neuromuscular compartment were assessed by RT-PCR, Western blot and immunohistochemical analysis. KEY RESULTS: In control preparations, neurogenic cholinergic contractions were enhanced by COX inhibitors, whereas tachykininergic responses were blunted. Carbachol-evoked contractions were increased by indomethacin or SC 560, but not DFU, whereas all inhibitors reduced SP-induced motor responses. In preparations from DD patients, COX inhibitors did not affect electrically evoked cholinergic contractions. Both indomethacin and DFU, but not SC-560, decreased tachykininergic responses. COX inhibitors did not modify carbachol-evoked motor responses, whereas they counteracted SP-induced contractions. COX-1 expression was decreased in myenteric neurons, whereas COX-2 was enhanced in glial cells and smooth muscle. CONCLUSIONS AND IMPLICATIONS: In control colon, COX-1 and COX-2 down-regulate cholinergic motility, whereas both isoforms enhance tachykininergic motor activity. In the presence of DD, there is a loss of modulation by both COX isoforms on the cholinergic system, whereas COX-2 displays an enhanced facilitatory control on tachykininergic contractile activity. PMID- 24758700 TI - Swainsonine-containing plants and their relationship to endophytic fungi. AB - Swainsonine, an indolizidine alkaloid with significant physiological activity, is an alpha-mannosidase and mannosidase II inhibitor that alters glycoprotein processing and causes lysosomal storage disease. Swainsonine is present in a number of plant species worldwide and causes severe toxicosis in livestock grazing these plants. Consumption of these plants by grazing animals leads to a chronic wasting disease characterized by weight loss, depression, altered behavior, decreased libido, infertility, and death. This review focuses on the three plant families and the associated taxa that contain swainsonine; the fungi that produce swainsonine, specifically the fungal endophytes associated with swainsonine-containing taxa; studies investigating the plant, endophyte, and swainsonine relationship; the influence of environmental factors on swainsonine concentrations in planta; and areas of future research. PMID- 24758699 TI - Identifying pathogenic processes by integrating microarray data with prior knowledge. AB - BACKGROUND: It is of great importance to identify molecular processes and pathways that are involved in disease etiology. Although there has been an extensive use of various high-throughput methods for this task, pathogenic pathways are still not completely understood. Often the set of genes or proteins identified as altered in genome-wide screens show a poor overlap with canonical disease pathways. These findings are difficult to interpret, yet crucial in order to improve the understanding of the molecular processes underlying the disease progression. We present a novel method for identifying groups of connected molecules from a set of differentially expressed genes. These groups represent functional modules sharing common cellular function and involve signaling and regulatory events. Specifically, our method makes use of Bayesian statistics to identify groups of co-regulated genes based on the microarray data, where external information about molecular interactions and connections are used as priors in the group assignments. Markov chain Monte Carlo sampling is used to search for the most reliable grouping. RESULTS: Simulation results showed that the method improved the ability of identifying correct groups compared to traditional clustering, especially for small sample sizes. Applied to a microarray heart failure dataset the method found one large cluster with several genes important for the structure of the extracellular matrix and a smaller group with many genes involved in carbohydrate metabolism. The method was also applied to a microarray dataset on melanoma cancer patients with or without metastasis, where the main cluster was dominated by genes related to keratinocyte differentiation. CONCLUSION: Our method found clusters overlapping with known pathogenic processes, but also pointed to new connections extending beyond the classical pathways. PMID- 24758702 TI - The effects of age on the neural correlates of feedback processing in a naturalistic gambling game. AB - We examined age-related differences in the spatiotemporal distribution of event related brain potentials (ERPs) related to feedback processing in a virtual blackjack game. The behavioral data revealed that older adults were less risk seeking than younger adults both within and across trials. Age-related differences were observed in the amplitude of several ERP components (P2-FN-P3a, P3a, slow wave activity) related to feedback processing. These components were localized to the anterior and posterior cingulate, the occipital cortex, and the inferior and medial frontal cortices. The effects of aging on the ERPs ranged from 200-2,000 ms after feedback onset. Our findings indicate that aging affects the activity of a distributed neural network that underpins processing the valence and motivational significance of feedback related to risky decisions. PMID- 24758701 TI - Incidence and risk factors of preterm birth in a rural Bangladeshi cohort. AB - BACKGROUND: Globally, about 15 million neonates are born preterm and about 85% of global preterm birth occurs in Asia and Africa regions. We aimed to estimate the incidence and risk factors for preterm birth in a rural Bangladeshi cohort. METHODS: Between June 2007 and September 2009, community health workers prospectively collected data from 32,126 mother-live-born baby pairs on household socio-demographic status, pregnancy history, antenatal care seeking and newborn gestational age determined by recall of date of last menstrual period. RESULTS: Among all live births, 22.3% were delivered prior to 37 weeks of gestation (i.e. preterm); of which 12.3% were born at 35-36 weeks of gestation (late preterm), 7.1% were born at 32-34 weeks (moderate preterm), and 2.9% were born at 28-31 weeks of gestation (very preterm). Overall, the majority of preterm births (55.1%) were late preterm. Risk of preterm birth was lower among women with primary or higher level of education (RR: 0.92; 95% CI: 0.88, 0.97), women who sought antenatal care at least once during the index pregnancy (RR: 0.86; 95% CI: 0.83, 0.90), and women who had completed all birth preparedness steps (RR: 0.32; 95% CI: 0.30, 0.34). In contrast, risk of preterm birth was higher among women with a history of child death (RR: 1.05; 95% CI: 1.01, 1.10), who had mid-upper arm circumference (MUAC) <=250 mm, indicative of under nutrition (for women having MUAC <214 mm the risk was higher; RR: 1.26; 95% CI: 1.17, 1.35), who reported an antenatal complication (RR: 1.32; 95% CI: 1.14, 1.53), and who received iron-folic acid supplementation for 2-6 months during the index pregnancy (RR: 1.33; 95% CI: 1.24, 1.44). CONCLUSIONS: In resource poor settings with high burden of preterm birth, alike Bangladesh, preterm birth risk could be reduced by close monitoring and/or frequent follow-up of women with history of child death and antenatal complications, by encouraging women to seek antenatal care from qualified providers, to adopt birth preparedness planning and to maintain good nutritional status. Additional research is needed to further explore the associations of antenatal iron supplementation and maternal nutritional status on preterm birth. PMID- 24758703 TI - The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test. AB - BACKGROUND: The BTB-KELCH protein Gigaxonin plays key roles in sustaining neuron survival and cytoskeleton architecture. Indeed, recessive mutations in the Gigaxonin-encoding gene cause Giant Axonal Neuropathy (GAN), a severe neurodegenerative disorder characterized by a wide disorganization of the Intermediate Filament network. Growing evidences suggest that GAN is a continuum with the peripheral neuropathy Charcot-Marie-Tooth diseases type 2 (CMT2). Sharing similar sensory-motor alterations and aggregation of Neurofilaments, few reports have revealed that GAN and some CMT2 forms can be misdiagnosed on clinical and histopathological examination. The goal of this study is to propose a new differential diagnostic test for GAN/CMT2. Moreover, we aim at identifying the mechanisms causing the loss-of-function of Gigaxonin, which has been proposed to bind CUL3 and substrates as part of an E3 ligase complex. RESULTS: We establish that determining Gigaxonin level constitutes a very valuable diagnostic test in discriminating new GAN cases from clinically related inherited neuropathies. Indeed, in a set of seven new families presenting a neuropathy resembling GAN/CMT2, only five exhibiting a reduced Gigaxonin abundance have been subsequently genetically linked to GAN. Generating the homology modeling of Gigaxonin, we suggest that disease mutations would lead to a range of defects in Gigaxonin stability, impairing its homodimerization, BTB or KELCH domain folding, or CUL3 and substrate binding. We further demonstrate that regardless of the mutations or the severity of the disease, Gigaxonin abundance is severely reduced in all GAN patients due to both mRNA and protein instability mechanisms. CONCLUSIONS: In this study, we developed a new penetrant and specific test to diagnose GAN among a set of individuals exhibiting CMT2 of unknown etiology to suggest that the prevalence of GAN is probably under-evaluated among peripheral neuropathies. We propose to use this new test in concert with the clinical examination and prior to the systematic screening of GAN mutations that has shown strong limitations for large deletions. Combining the generation of the structural modeling of Gigaxonin to an analysis of Gigaxonin transcripts and proteins in patients, we provide the first evidences of the instability of this E3 ligase adaptor in disease. PMID- 24758704 TI - Psoriasis: 'the badge of shame'. A case report of a psychological intervention to reduce and potentially clear chronic skin disease. AB - The psychological effects of skin disorders have long been established. Most research on psychological interventions for people with skin disorders has focused predominantly on cognitive behavioural therapy (CBT); however, CBT is not appropriate for everyone. We assessed the benefits of a psychological intervention, using the principles of systemic family therapy (SFT). The key to SFT is the understanding of problems in the context of family and social relationships, and how reciprocal dynamics influence problems. Problems thus have a dual construction; they do not exist only within individuals but rather are a product of the interactions between people and wider systems, such as communities and cultures. This report focuses on the importance of practice-based evidence and the need for more research. A 46-year-old female with a 40-year history of psoriasis was referred for psychological therapy for feelings of shame and low self-esteem. Many medications, including biologics, had been tried previously with no success. Initially, the patient attended therapy alone; later, her husband and other family members joined her. Issues around her past, relationships, and personal beliefs/assumptions were explored. Over ten 50-min sessions, she was able to view her dynamics and relationships in a more helpful way. Her psoriasis cleared, reinforcing that it may have been caused by underlying psychological difficulties. Dermatologists need to work in a more holistic way to provide quality care to patients, meeting their psychological and dermatological needs. There is also a need to develop a broader evidence base and interventions for people with skin disorders. PMID- 24758705 TI - Should I stay or should I go? The impact of working time and wages on retention in the health workforce. AB - BACKGROUND: Turnover in the health workforce is a concern as it is costly and detrimental to organizational performance and quality of care. Most studies have focused on the influence of individual and organizational factors on an employee's intention to quit. Inspired by the observation that providing care is based on the duration of practices, tasks and processes (issues of time) rather than exchange values (wages), this paper focuses on the influence of working-time characteristics and wages on an employee's intention to stay. METHODS: Using data from the WageIndicator web survey (N = 5,323), three logistic regression models were used to estimate health care employee's intention to stay for Belgium, Germany and the Netherlands. The first model includes working-time characteristics controlling for a set of sociodemographic variables, job categories, promotion and organization-related characteristics. The second model tests the impact of wage-related characteristics. The third model includes both working-time- and wage-related aspects. RESULTS: Model 1 reveals that working time-related factors significantly affect intention to stay across all countries. In particular, working part-time hours, overtime and a long commuting time decrease the intention to stay with the same employer. The analysis also shows that job dissatisfaction is a strong predictor for the intention to leave, next to being a woman, being moderately or well educated, and being promoted in the current organization. In Model 2, wage-related characteristics demonstrate that employees with a low wage or low wage satisfaction are less likely to express an intention to stay. The effect of wage satisfaction is not surprising; it confirms that besides a high wage, wage satisfaction is essential. When considering all factors in Model 3, all effects remain significant, indicating that attention to working and commuting times can complement attention to wages and wage satisfaction to increase employees' intention to stay. These findings hold for all three countries, for a variety of health occupations. CONCLUSIONS: When following a policy of wage increases, attention to the issues of working time including overtime hours, working part-time, and commuting time-and wage satisfaction are suitable strategies in managing health workforce retention. PMID- 24758706 TI - Improving understanding of the quitting process: psychological predictors of quit attempts versus smoking cessation maintenance among college students. AB - This study examined motivation, positive and negative outcome expectations of quitting, and self-efficacy as predictors of quit attempts and cessation maintenance in a smoking cessation intervention for college students (N = 303). Psychological measures assessed at baseline were used to predict smoking behavior outcomes. Analysis of variance (ANOVA) and logistic regression analysis revealed that motivation and self-efficacy were strong, differential predictors of quit attempts and cessation maintenance, respectively. This study extends the previous findings regarding psychological predictors of quitting processes to college students, and suggests the need for interventions tailored according to phases of quitting processes. PMID- 24758707 TI - Near-visible light generation of a quinone methide from 3-hydroxymethyl-2 anthrol. AB - Excitation of 2-hydroxy-3-(diphenylhydroxymethyl)anthracene (7) to S1 initiates photodehydration, giving the corresponding quinone methide (QM) that was detected by laser flash photolysis (LFP) in 2,2,2-trifluoroethanol (lambda = 580 nm, tau = 690 +/- 10 ns). The QM decays by protonation, giving a cation (lambda = 520 nm, tau = 84 +/- 3 MUs), which subsequently reacts with nucleophiles. The rate constants in the reactions with nucleophiles were determined by LFP, whereas the adducts were isolated via preparative photolyses. The photogeneration of QMs in the anthrol series is important for potential use in biological systems since the chromophore absorbs at wavelengths > 400 nm. Antiproliferative investigations conducted with 2-anthrol derivative 7 on three human cancer cell lines showed higher activity for irradiated cells. PMID- 24758708 TI - Lifelong exposure to n-3 PUFA affects pubertal mammary gland development. AB - There is growing evidence that early developmental periods may importantly influence future breast cancer risk. Also, there is great interest in the role of dietary fat in breast cancer risk, but the role of dietary fat during pubertal mammary gland development remains poorly understood. This study investigated the effect of n-3 polyunsaturated fatty acids (PUFA) using complementary dietary and genetic approaches to examine the effect of lifelong exposure of n-3 PUFA or n-6 PUFA (control) on mammary gland development and fatty acid composition. n-3 PUFA from both diet and genetics were enriched in mammary glands as early as 3 weeks of age. Parameters related to mammary gland development, including number of terminal end buds (TEB), percent coverage of ductal tree, and infiltration of TEB, were influenced by n-3 PUFA at 3 and 4 weeks of age. Overall, findings suggest that n-3 PUFA incorporation into the mammary gland early in life plays a role in the morphological development of the mammary gland during puberty. PMID- 24758709 TI - The functional barometer -a self-report questionnaire in accordance with the International Classification of Functioning, Disability and Health for pain related problems; validity and patient-observer comparisons. AB - BACKGROUND: The International Classification of Functioning, Disability and Health, (ICF) provides a unified, international standardized framework for describing and classifying health and health-related functioning and disability. Based on an ICF core sets the Functional Barometer, (FB), was developed for assessments of perceived pain-related problems with functions, activity and quality-of-life by patients suffering from long-term pain. The aim was to evaluate the construct validity, and to compare the assessments of a patient's problems from the perspectives of the patient and of the examining professional when using the validated FB and corresponding ICF-classification form, respectively. METHODS: Patients with long-term pain for more than 3 months that visited one of four pain clinics during specified time periods of data collections were eligible. The self-report Balanced Inventory for Spinal disorders was used for validation of the FB. Correspondingly to the validated FB an ICF-classification form for professional's assessment was developed. The data sets for these inter-scale and the patient-professional comparisons were collected adjacent to the clinical examination. By the statistical method used for evaluation of the pairs of ordinal data presence of systematic disagreement was identified and measured separately from additional individual variations. RESULTS: The validation process resulted in a revised FB(2.0) that meets the requirements of good construct and content validity. The professionals' ICF classifications of the patients' problems disagreed with the patients' assessments on the FB(2.0); the percentage agreements ranged from 18% to 51%. The main reason was that the practitioners systematically underestimated the patients' levels of problems but the different professionals contributed also to a large individual variability (noise) in assessment. CONCLUSIONS: This study presents an ICF-based validated self-report questionnaire, The FB, to be used for identifying and describing pain-related problems with current functioning, activities and quality-of-life as perceived by patients suffering from long-term pain. The strong evidences of underestimation of the patients' problems and the variability in the professionals' ICF-classifications demonstrated the importance of describing the patient's problems both from the patient's and the professional's perspective beneficial for the patient's rehabilitation. PMID- 24758710 TI - Internal nanosecond dynamics in the intrinsically disordered myelin basic protein. AB - Intrinsically disordered proteins lack a well-defined folded structure and contain a high degree of structural freedom and conformational flexibility, which is expected to enhance binding to their physiological targets. In solution and in the lipid-free state, myelin basic protein belongs to that class of proteins. Using small-angle scattering, the protein was found to be structurally disordered similar to Gaussian chains. The combination of structural and hydrodynamic information revealed an intermediary compactness of the protein between globular proteins and random coil polymers. Modeling by a coarse-grained structural ensemble gave indications for a compact core with flexible ends. Neutron spin echo spectroscopy measurements revealed a large contribution of internal dynamics to the overall diffusion. The experimental results showed a high flexibility of the structural ensemble. Displacement patterns along the first two normal modes demonstrated that collective stretching and bending motions dominate the internal modes. The observed dynamics represent nanosecond conformational fluctuations within the reconstructed coarse-grained structural ensemble, allowing the exploration of a large configurational space. In an alternative approach, we investigated if models from polymer theory, recently used for the interpretation of fluorescence spectroscopy experiments on disordered proteins, are suitable for the interpretation of the observed motions. Within the framework of the Zimm model with internal friction (ZIF), a large offset of 81.6 ns is needed as an addition to all relaxation times due to intrachain friction sources. The ZIF model, however, shows small but systematic deviations from the measured data. The large value of the internal friction leads to the breakdown of the Zimm model. PMID- 24758711 TI - Effectiveness and predictors of outcome in routine out-patient mental health care for older adults. AB - ABSTRACT Background: Meta-analyses show efficacy of several psychological and pharmacological interventions for late-life psychiatric disorders, but generalization of effects to routine mental health care for older people remains unknown. Aim of this study is to investigate the improvement of functioning within one year of referral to an outpatient mental health clinic for older adults. Methods: Pre-post measurement of the Health of Nations Outcome Scale 65+ (HoNOS 65+) in 704 older people referred for psychiatric problems (no dementia) to any of the seven participating mental health care organizations. Results: The pre-post-test Cohen's d effect size was 1.08 in the total group and 1.23 in depressed patients, the largest subgroup. Linear regression identified better functioning at baseline, comorbid personality disorder, somatic comorbidity and life events during treatment as determinants of a worse outcome. Conclusions: Functioning of older persons with psychiatric problems largely improves after treatment in routine mental health care. PMID- 24758712 TI - Crystallization of progesterone polymorphs using polymer-induced heteronucleation (PIHn) method. AB - Progesterone is a natural hormone steroid used in humans for several treatments and in livestock for artificial insemination, which exhibits two polymorphic forms at ambient conditions: form 1 and form 2. Form 2 is metastable and more soluble than form 1; however, it is not suitable to use as powder raw material because it transforms into form 1 by the effects of grinding. A polymorphic screening of progesterone based on polymer-induced heteronucleation method was performed as an alternative to prepare the metastable form. Polyvinyl alcohol, hydroxypropyl methylcellulose (HPMC), dextran, gelatin, polyisoprene (PI) and acrylonitrile-butadiene (NBR) copolymer were used. Crystals were prepared from 0.5, 10 and 40 mg/mL solutions in acetone at room temperature by solvent evaporation. The samples were characterized by X-ray powder diffraction, differential scanning calorimetry (DSC), scanning electron microcopy and attenuated total reflectance infrared Fourier transform spectroscopy. Form 1 was nucleated from 40 mg/mL solutions on the six polymers and from 10 mg/mL solutions on PI and NBR. The mixture of form 1 and form 2 was obtained from 10 mg/mL solution on HPMC, dextran and gelatin and from 0.5 mg/mL solution crystallizations. Therefore, the polymeric devices, which crystallized the metastable and more soluble polymorph (2) of progesterone, would be a promissory alternative for the pharmaceutical applications. PMID- 24758713 TI - Cameron lesions in patients with hiatal hernias: prevalence, presentation, and treatment outcome. AB - Cameron lesions, as defined by erosions and ulcerations at the diaphragmatic hiatus, are found in the setting of gastrointestinal (GI) bleeding in patients with a hiatus hernia (HH). The study aim was to determine the epidemiology and clinical manifestations of Cameron lesions. We performed a retrospective cohort study evaluating consecutive patients undergoing upper endoscopy over a 2-year period. Endoscopy reports were systematically reviewed to determine the presence or absence of Cameron lesions and HH. Inpatient and outpatient records were reviewed to determine prevalence, risk factors, and outcome of medical treatment of Cameron lesions. Of 8260 upper endoscopic examinations, 1306 (20.2%) reported an HH. When categorized by size, 65.6% of HH were small (<3 cm), 23.0% moderate (3-4.9 cm), and 11.4% were large (>=5 cm). Of these, 43 patients (mean age 65.2 years, 49% female) had Cameron lesions, with a prevalence of 3.3% in the presence of HH. Prevalence was highest with large HH (12.8%). On univariate analysis, large HH, frequent non-steroidal anti-inflammatory drug (NSAID) use, GI bleeding (both occult and overt), and nadir hemoglobin level were significantly greater with Cameron lesions compared with HH without Cameron lesions (P <= 0.03). Large HH size and NSAID use were identified as independent risk factors for Cameron lesions on multivariate logistic regression analysis. Cameron lesions are more prevalent in the setting of large HH and NSAID use, can be associated with GI bleeding, and can respond to medical management. PMID- 24758714 TI - Poly(ethylene glycol) lipid-shelled microbubbles: abundance, stability, and mechanical properties. AB - Poly(ethylene glycol) (PEG) is widely used on the outside of biomedical delivery vehicles to impart stealth properties. Encapsulated gas microbubbles (MBs) are being increasingly considered as effective carriers for therapeutic intervention to deliver drug payloads or genetic vectors. MBs have the advantage that they can be imaged and manipulated by ultrasound fields with great potential for targeted therapy and diagnostic purposes. Lipid-shelled MBs are biocompatible and can be functionalized on the outer surface for tissue targeting and new therapeutic methods. As MBs become a key route for drug delivery, exploring the effect of PEG ylation on the MB properties is important. Here, we systematically investigate the effect of PEG-lipid solution concentration ranging between 0 and 35 mol % on the formation of MBs in a microfluidic flow-focusing device. The abundance of the MBs is correlated with the MB lifetime and the whole MB mechanical response, as measured by AFM compression using a tipless cantilever. The maximal MB concentration and stability (lifetime) occurs at a low concentration of PEG-lipid (~5 mol %). For higher PEG-lipid concentrations, the lifetime and MB concentration decrease, and are accompanied by a correlation between the predicted surface PEG configuration and the whole MB stiffness, as measured at higher compression loads. These results inform the rationale design and fabrication of lipid-based MBs for therapeutic applications and suggest that only relatively small amounts of PEG incorporation are required for optimizing MB abundance and stability while retaining similar mechanical response at low loads. PMID- 24758715 TI - Decreasing household contribution to TB transmission with age: a retrospective geographic analysis of young people in a South African township. AB - BACKGROUND: Tuberculosis (TB) transmission rates are exceptionally high in endemic TB settings. Adolescence represents a period of increasing TB infection and disease but little is known as to where adolescents acquire TB infection. We explored the relationship between residential exposure to adult TB cases and infection in children and adolescents in a South African community with high burdens of TB and HIV. METHODS: TB infection data were obtained from community, school-based tuberculin skin test (TST) surveys performed in 2006, 2007 and 2009. A subset of 2007 participants received a repeat TST in 2009, among which incident TB infections were identified. Using residential address, all adult TB cases notified by the community clinic between 1996 and 2009 were cross-referenced with childhood and adolescent TST results. Demographic and clinic data including HIV status were abstracted for TB cases. Multivariate logistic regression models examined the association of adult TB exposure with childhood and adolescent prevalent and incident TB infection. RESULTS: Of 1,100 children and adolescents included in the prevalent TB infection analysis, 480 (44%) were TST positive and 651 (59%) were exposed to an adult TB case on their residential plot. Prevalent TB infection in children aged 5-9 and 10-14 years was positively associated with residential exposure to an adult TB case (odds ratio [OR]:2.0; 95% confidence interval [CI]: 1.1-3.6 and OR:1.5; 95% CI: 1.0-2.3 respectively), but no association was found in adolescents >=15 years (OR:1.4; 95% CI: 0.9-2.0). HIV status of adult TB cases was not associated with TB infection (p = 0.62). Of 67 previously TST negative children, 16 (24%) converted to a positive TST in 2009. These incident infections were not associated with residential exposure to an adult TB case (OR: 1.9; 95% CI: 0.5-7.3). CONCLUSIONS: TB infection among young children was strongly associated with residential exposure to an adult TB case, but prevalent and incident TB infection in adolescents was not associated with residential exposure. The HIV-status of adult TB cases was not a risk factor for transmission. The high rates of TB infection and disease among adolescents underscore the importance of identifying where infection occurs in this age group. PMID- 24758717 TI - Viscosity of ionic liquids: an extensive database and a new group contribution model based on a feed-forward artificial neural network. AB - A knowledge of various thermophysical (in particular transport) properties of ionic liquids (ILs) is crucial from the point of view of potential applications of these fluids in chemical and related industries. In this work, over 13 000 data points of temperature- and pressure-dependent viscosity of 1484 ILs were retrieved from more than 450 research papers published in the open literature in the last three decades. The data were critically revised and then used to develop and test a new model allowing in silico predictions of the viscosities of ILs on the basis of the chemical structures of their cations and anions. The model employs a two-layer feed-forward artificial neural network (FFANN) strategy to represent the relationship between the viscosity and the input variables: temperature, pressure, and group contributions (GCs). In total, the resulting GC FFANN model employs 242 GC-type molecular descriptors that are capable of accurately representing the viscosity behavior of ILs composed of 901 distinct ions. The neural network training, validation, and testing processes, involving 90, 5, and 5% of the whole data pool, respectively, gave mean square errors of 0.0334, 0.0595, and 0.0603 log units, corresponding to squared correlation coefficients of 0.986, 0.973, and 0.972 and overall relative deviations at the level of 11.1, 13.8, and 14.7%, respectively. The results calculated in this work were shown be more accurate than those obtained with the best current GC model for viscosity of ILs described in the literature. PMID- 24758716 TI - Identification of glutathione (GSH)-independent glyoxalase III from Schizosaccharomyces pombe. AB - BACKGROUND: Reactive carbonyl species (RCS), such as methylglyoxal (MG) and glyoxal (GO), are synthesized as toxic metabolites in living systems. Mechanisms of RCS detoxification include the glutathione (GSH)-dependent system consisting of glyoxalase I (GLO1) and glyoxalase II (GLO2), and GSH-independent system involving glyoxalase III (GLO3). Hsp31 and DJ-1 proteins are weakly homologous to each other and belong to two different subfamilies of the DJ-1/Hsp31/PfpI superfamily. Recently, the Escherichia coli Hsp31 protein and the DJ-1 proteins from Arabidopsis thaliana and metazoans have been demonstrated to have GLO3 activity. RESULTS: We performed a systematic survey of homologs of DJ-1 and Hsp31 in fungi. We found that DJ-1 proteins have a very limited distribution in fungi, whereas Hsp31 proteins are widely distributed among different fungal groups. Phylogenetic analysis revealed that fungal and metazoan DJ-1 proteins and bacterial YajL proteins are most closely related and together form a sister clade to bacterial and fungal Hsp31 proteins. We showed that two Schizosaccharomyces pombe Hsp31 proteins (Hsp3101 and Hsp3102) and one Saccharomyces cerevisiae Hsp31 protein (ScHsp31) displayed significantly higher in vitro GLO3 activity than S. pombe DJ-1 (SpDJ-1). Overexpression of hsp3101, hsp3102 and ScHSP31 could confer MG and GO resistance on either wild-type S. pombe cells or GLO1 deletion of S. pombe. S. pombe DJ-1 and Hsp31 proteins exhibit different patterns of subcellular localization. CONCLUSIONS: Our results suggest that fungal Hsp31 proteins are the major GLO3 that may have some role in protecting cells from RCS toxicity in fungi. Our results also support the view that the GLO3 activity of Hsp31 proteins may have evolved independently from that of DJ-1 proteins. PMID- 24758718 TI - Effects of the endogenous cannabinoid anandamide on voltage-dependent sodium and calcium channels in rat ventricular myocytes. AB - BACKGROUND AND PURPOSE: The endocannabinoid anandamide (N-arachidonoyl ethanolamide; AEA) exerts negative inotropic and antiarrhythmic effects in ventricular myocytes. EXPERIMENTAL APPROACH: Whole-cell patch-clamp technique and radioligand-binding methods were used to analyse the effects of anandamide in rat ventricular myocytes. KEY RESULTS: In the presence of 1-10 MUM AEA, suppression of both Na(+) and L-type Ca(2+) channels was observed. Inhibition of Na(+) channels was voltage and Pertussis toxin (PTX) - independent. Radioligand-binding studies indicated that specific binding of [(3) H] batrachotoxin (BTX) to ventricular muscle membranes was also inhibited significantly by 10 MUM metAEA, a non-metabolized AEA analogue, with a marked decrease in Bmax values but no change in Kd . Further studies on L-type Ca(2+) channels indicated that AEA potently inhibited these channels (IC50 0.1 MUM) in a voltage- and PTX-independent manner. AEA inhibited maximal amplitudes without affecting the kinetics of Ba(2+) currents. MetAEA also inhibited Na(+) and L-type Ca(2+) currents. Radioligand studies indicated that specific binding of [(3) H]isradipine, was inhibited significantly by metAEA. (10 MUM), changing Bmax but not Kd . CONCLUSION AND IMPLICATIONS: Results indicate that AEA inhibited the function of voltage dependent Na(+) and L-type Ca(2+) channels in rat ventricular myocytes, independent of CB1 and CB2 receptor activation. PMID- 24758721 TI - Honeycombs in honeycombs: complex liquid crystal alumina composite mesostructures. AB - Small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM) were used to study orientation patterns of two polyphilic liquid crystals (LC) confined to cylindrical pores of anodic aluminum oxide (AAO). The hierarchical hybrid systems had the LC honeycomb (lattice parameter 3.5-4 nm) inside the pores of the AAO honeycomb (diameters 60 and 400 nm). By conducting complete reciprocal space mapping using SAXS, we conclude that the columns of both compounds align in planes normal to the AAO pore axis, with a specific crystallographic direction of the LC lattice aligning strictly parallel to the pore axis. AFM of LC-containing AAO fracture surfaces further revealed that the columns of the planar anchoring LC (compound 1) formed concentric circles in the plane normal to the pore axis near the AAO wall. Toward the pore center, the circles become anisometric "racetrack" loops consisting of two straight segments and two semicircles. This mode compensates for slight ellipticity of the pore cross section. Indications are, however, that for perfectly circular pores, circular shape is maintained right to the center of the pore, the radius coming down to the size of a molecule. For the homeotropically anchoring compound 2, the columns are to the most part straight and parallel to each other, arranged in layers normal to the AAO pore axis, like logs in an ordered pile. Only near the pore wall the columns splay somewhat. In both cases, columns are confined to layers strictly perpendicular to the AAO pore axis, and there is no sign of escape to the third dimension or of axial orientation, the latter having been reported previously for some discotic LCs. The main cause of the two new LC configurations, the "racetrack" and the "logpile", and of their difference from those of confined nematic LC, is the very high splay energy and low bend energy of columnar phases. PMID- 24758719 TI - A novel TLR2-triggered signalling crosstalk synergistically intensifies TNF mediated IL-6 induction. AB - Toll-like receptors (TLR) recognize pathogens and trigger the production of vigorous pro-inflammatory cytokines [such as tumour necrosis factor (TNF)] that induce systemic damages associated with sepsis and chronic inflammation. Cooperation between signals of TLR and TNF receptor has been demonstrated through the participation of TNF receptor 1 (TNFR) adaptors in endotoxin tolerance. Here, we identify a TLR2-mediated synergy, through a MyD88-independent crosstalk, which enhances subsequent TNF-mediated nuclear factor-kappa B activation and interleukin-6 induction. Membrane-associated adaptor MAL conduces the link between TNF receptor-associated factor 6 (TRAF6) and TNFR-associated death domain, leading to a distinctive K63-ubiquitinylated TRAF6 recruitment into TNFR complex. In summary, our results reveal a novel route of TLR signal that synergistically amplifies TNF-mediated responses, indicating an innovative target for inflammation manipulation. PMID- 24758720 TI - Automated structure refinement for a protein heterodimer complex using limited EPR spectroscopic data and a rigid-body docking algorithm: a three-dimensional model for an ankyrin-CDB3 complex. AB - We report here specialized functions incorporated recently in the rigid-body docking software toolkit TagDock to utilize electron paramagnetic resonance derived (EPR-derived) interresidue distance measurements and spin-label accessibility data. The TagDock package extensions include a custom methanethiosulfonate spin label rotamer library to enable explicit, all-atom spin label side-chain modeling and scripts to evaluate spin-label surface accessibility. These software enhancements enable us to better utilize the biophysical data routinely available from various spin-labeling experiments. To illustrate the power and utility of these tools, we report the refinement of an ankyrin:CDB3 complex model that exhibits much improved agreement with the EPR distance measurements, compared to model structures published previously. PMID- 24758722 TI - Step-down versus outpatient psychotherapeutic treatment for personality disorders: 6-year follow-up of the Ulleval personality project. AB - BACKGROUND: Although psychotherapy is considered the treatment of choice for patients with personality disorders (PDs), there is no consensus about the optimal level of care for this group of patients. This study reports the results from the 6-year follow-up of the Ulleval Personality Project (UPP), a randomized clinical trial comparing outpatient individual psychotherapy with a long-term step-down treatment program that included a short-term day hospital treatment followed by combined group and individual psychotherapy. METHODS: The UPP included 113 patients with PDs. Outcome was evaluated after 8 months, 18 months, 3 years and 6 years and was based on a wide range of clinical measures, such as psychosocial functioning, interpersonal problems, symptom severity, and axis I and II diagnoses. RESULTS: At the 6-year follow-up, there were no statistically significant differences in outcome between the treatment groups. Effect sizes ranged from medium to large for all outcome variables in both treatment arms. However, patients in the outpatient group had a marked decline in psychosocial functioning during the period between the 3- and 6-year follow-ups; while psychosocial functioning continued to improve in the step-down group during the same period. This difference between groups was statistically significant. CONCLUSIONS: The findings suggest that both hospital-based long-term step-down treatment and long-term outpatient individual psychotherapy may improve symptoms and psychosocial functioning in poorly functioning PD patients. Social and interpersonal functioning continued to improve in the step-down group during the post-treatment phase, indicating that longer-term changes were stimulated during treatment. TRIAL REGISTRATION: NCT00378248. PMID- 24758725 TI - Palau'chlor: a practical and reactive chlorinating reagent. AB - Unlike its other halogen atom siblings, the utility of chlorinated arenes and (hetero)arenes are twofold: they are useful in tuning electronic structure as well as acting as points for diversification via cross-coupling. Herein we report the invention of a new guanidine-based chlorinating reagent, CBMG or "Palau'chlor", inspired by a key chlorospirocyclization en route to pyrrole imidazole alkaloids. This direct, mild, operationally simple, and safe chlorinating method is compatible with a range of nitrogen-containing heterocycles as well as select classes of arenes, conjugated pi-systems, sulfonamides, and silyl enol ethers. Comparisons with other known chlorinating reagents revealed CBMG to be the premier reagent. PMID- 24758724 TI - Side-chain oxysterols modulate cholesterol accessibility through membrane remodeling. AB - Side-chain oxysterols, such as 25-hydroxycholesterol (25-HC), are key regulators of cholesterol homeostasis. New evidence suggests that the alteration of membrane structure by 25-HC contributes to its regulatory effects. We have examined the role of oxysterol membrane effects on cholesterol accessibility within the membrane using perfringolysin O (PFO), a cholesterol-dependent cytolysin that selectively binds accessible cholesterol, as a sensor of membrane cholesterol accessibility. We show that 25-HC increases cholesterol accessibility in a manner dependent on the membrane lipid composition. Structural analysis of molecular dynamics simulations reveals that increased cholesterol accessibility is associated with membrane thinning, and that the effects of 25-HC on cholesterol accessibility are driven by these changes in membrane thickness. Further, we find that the 25-HC antagonist LY295427 (agisterol) abrogates the membrane effects of 25-HC in a nonenantioselective manner, suggesting that agisterol antagonizes the cholesterol-homeostatic effects of 25-HC indirectly through its membrane interactions. These studies demonstrate that oxysterols regulate cholesterol accessibility, and thus the availability of cholesterol to be sensed and transported throughout the cell, by modulating the membrane environment. This work provides new insights into how alterations in membrane structure can be used to relay cholesterol regulatory signals. PMID- 24758726 TI - Eruptive cutaneous squamous cell carcinoma and psoriasis: response to cetuximab. AB - Cutaneous squamous cell carcinomas (CSCCs) comprise 20-30% of nonmelanoma skin cancers (NMSCs), and continue to increase in incidence. We report a case of a patient with severe psoriasis who had recurrent and eruptive CSCCs on her leg, which were successfully treated with cetuximab and radiotherapy. The patient had successful long-term clearance of her skin tumours, with the additional finding of resolution of psoriasis while on cetuximab therapy. PMID- 24758723 TI - Two-stage model in perceptual learning: toward a unified theory. AB - Training or exposure to a visual feature leads to a long-term improvement in performance on visual tasks that employ this feature. Such performance improvements and the processes that govern them are called visual perceptual learning (VPL). As an ever greater volume of research accumulates in the field, we have reached a point where a unifying model of VPL should be sought. A new wave of research findings has exposed diverging results along three major directions in VPL: specificity versus generalization of VPL, lower versus higher brain locus of VPL, and task-relevant versus task-irrelevant VPL. In this review, we propose a new theoretical model that suggests the involvement of two different stages in VPL: a low-level, stimulus-driven stage, and a higher-level stage dominated by task demands. If experimentally verified, this model would not only constructively unify the current divergent results in the VPL field, but would also lead to a significantly better understanding of visual plasticity, which may, in turn, lead to interventions to ameliorate diseases affecting vision and other pathological or age-related visual and nonvisual declines. PMID- 24758727 TI - Etiologic exploration of magnetic resonance tomographic angiography negative trigeminal neuralgia. AB - Our objective was to explore the etiologic factors involved in trigeminal neuralgia with negative magnetic resonance tomographic angiography (MRTA) results. Clinical data from 341 patients with idiopathic trigeminal neuralgia who were treated with neurovascular decompression between March 2003 and December 2011 were retrospectively analyzed. The etiologic causes of preoperative MRTA negative trigeminal neuralgia were categorized based on comparisons between preoperative MRTA and intraoperative endoscopic images. MRTA was highly sensitive (92.4%, 291/315) to neurovascular compression, whereas its specificity was 65.4% (17/26). Among the 24 false-negative cases, there were nine patients with petrosal vein compression, 12 with superior cerebellar artery compression, two with superior cerebellar arterial branch compression, and one patient with anterior inferior cerebellar artery compression. Among the 17 true-negative cases, three patients had arachnoid adhesions, one had a protruding temporal eminence, five had micro-cholesteatomas, and eight patients exhibited no compression. The factors responsible for the MRTA-negative results included small diameter arterial vessels, veins with slow blood flow, arachnoid adhesions, protruding temporal eminences, micro-cholesteatomas, and other pathologies such as multiple sclerosis. Preoperative diagnoses of MRTA-negative patients need to integrate the MRI results from multiple sequences to discriminate between arteriolar compression, venous compression, and small compressive lesions. When narrow cerebellopontine angles are shown in MRTA, arachnoid adhesion and temporal eminence compression should be considered. PMID- 24758728 TI - Medium effects on the 1,3-dipolar cycloaddition of pyridazinium dicyanomethanide with ethyl vinyl ketone in pure and mixed solvents from QM/MM simulations. AB - The 1,3-dipolar cycloaddition reaction between pyridazinium dicyanomethanide 1 and ethyl vinyl ketone (EVK) has been reported to be a concerted mechanism based on gas-phase ab initio calculations. Our current investigation of this 1,3 dipolar cycloaddition reaction in water, methanol, acetonitrile, H2O-CH3CN, and CH3OH-CH3CN mixtures using novel two-dimensional potentials of mean force (2-D PMF) calculations coupled to QM/MM simulations predicts an alternative free energy surface that supports a stepwise mechanism. The results for the kinetic effect are uniformly in close accord with experimental data and reflect a trigger point for the exponential rate rise in water-acetonitrile mixture. When methanol replaced water, the rate enhancements are more gradual, and there is no trigger point. Calculations in pure solvents and their mixtures at 25 degrees C and with pure water and acetonitrile at 37 degrees C indicate that the secondary bridging H-bonding from the first water molecules is necessary for the exponential rate enhancements, which is strong supported by the experimental results. This work provides new insight into solvent effects on 1,3-dipolar cycloaddition reaction. PMID- 24758729 TI - Accuracy and acceptability of the 6-day Enlite continuous subcutaneous glucose sensor. AB - OBJECTIVE: This study evaluated the performance and acceptability of the Enlite((r)) glucose sensor (Medtronic MiniMed, Inc., Northridge, CA). SUBJECTS AND METHODS: Ninety adults with type 1 or type 2 diabetes wore two Enlite sensors on the abdomen and/or buttock for 6 days and calibrated them at different frequencies. On Days 1, 3, and 6, accuracy was evaluated by comparison of sensor glucose values with frequently sampled plasma glucose values collected over a 12 h period. Accuracy was assessed at different reference glucose concentrations and during times when absolute glucose concentration rates of change were <1, 1-2, and >2 mg/dL/min. The sensor's ability to detect hypoglycemia or hyperglycemia was evaluated with simulated alerts. Subject satisfaction was evaluated with a 7 point Likert-type questionnaire, with a score of 7 indicating strong agreement. RESULTS: With abdomen sensors under actual-use calibration (mean, 2.8 +/- 0.9 times/day), the overall mean (median) absolute relative difference (ARD) values between sensor and reference values were 13.6% (10.1%); the corresponding buttock sensor ARD values were 15.5% (10.5%). With abdomen sensors under minimal calibration (mean, 1.2 +/- 0.9 times/day), the mean (median) ARD values were 14.7% (10.8%). Mean ARD values of abdomen sensors at rates of change of <1, 1-2, and >2 mg/dL/min were 13.6%, 12.9%, and 16.3%, respectively. With abdomen sensors, 79.5% and 94.1% of hypoglycemic and hyperglycemic events, respectively, were correctly detected; 81.9% and 94.9% of hypoglycemic and hyperglycemic alerts, respectively, were confirmed. The failure rates for abdomen and buttock sensors were 19.7% and 13.9%, respectively. Mean responses to survey questions for all subjects related to comfort and ease of use were favorable. CONCLUSIONS: The Enlite sensor provided accurate data at different glucose concentrations and rates of change. Subjects found the sensor comfortable and easy to use. PMID- 24758730 TI - Is the masked continuous glucose monitoring system clinically useful for predicting hemoglobin A1C in type 1 diabetes? AB - BACKGROUND: The masked continuous glucose monitoring system (Masked-CGMS) differs from standard CGMSs in three ways: (1) there is no feedback to the user so that no immediate regimen changes can be made; (2) it can only be worn for up to 5 days; and (3) there are no alarms to warn of hyperglycemia or hypoglycemia. Since 2008 masked-CGMS has become popular for identifying reasons that a patient's hemoglobin A1C does not correlate closely with his or her capillary blood glucose measurements. To date only one study addressing the clinical utility of Masked CGMS for improving A1C in diabetes has been published. No studies are available specifically examining the variability and correlation of Masked-CGMS and A1C. SUBJECTS AND METHODS: We performed 156 Masked-CGMS studies (40 patients studied sequentially a maximum of four times each) in type 1 diabetes patients. We then analyzed the resulting interstitial glucose levels obtained from the Masked-CGMS compared with an A1C measurement performed within 1 week of the Masked-CGMS study. RESULTS: There was a very low correlation between the A1C and the Masked CGMS-derived mean interstitial glucose level. This statistic did not provide sufficiently predictive information to be clinically useful for changing an individual patient's intensive insulin therapy regimen. CONCLUSIONS: Our data demonstrate that a very weak correlation exists between 5 days of masked CGMS and a concurrently measured A1C level. For the individual type 1 diabetes patient, this relationship would unlikely to be clinically useful in altering the individual's treatment regimen. PMID- 24758732 TI - Local expression of interleukin-17a is correlated with nasal eosinophilia and clinical severity in allergic rhinitis. AB - Interleukin (IL)-17A is a major cytokine produced by Th17 cells, which are associated with chronic inflammations. The local expression of IL-17A in allergic rhinitis (AR) remains to be characterized. We sought to determine the role of IL 17A expression in human inferior turbinate mucosa in the pathophysiology of AR. Inferior turbinate mucosa was sampled from medical treatment-resistant, surgery required patients with perennial AR (PAR, n = 21), nonallergic rhinitis with eosinophilia syndrome (NARES, n = 7), and nonallergic hypertrophic rhinitis (HR, n = 13). IL-17A expression was determined with immunohistochemical staining. The mean number of IL-17A(+) cells and eosinophils per field were counted. Total serum immunoglobulin E (IgE) levels, blood eosinophil count, and forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio were also examined in each patient. IL-17A was primarily expressed in infiltrating inflammatory cells. The number of IL-17A(+) cells in nasal mucosa was significantly higher in the PAR group compared with HR (p = 0.002) and NARES (p = 0.021) groups. There was a significant and positive correlation between the number of IL-17A(+) cells and total nasal symptom score (rho = 0.403; p = 0.011), especially sneezing score (rho = 0.471; p = 0.003). The number of IL-17A(+) cells was significantly and positively correlated with the degree of eosinophil infiltration (rho = 0.623; p < 0.001), but not with total serum IgE levels (rho = 0.284; p = 0.098), blood eosinophil counts (rho = 0.302; p = 0.056), or FEV1/FVC ratio (rho = 0.092; p = 0.569). The present study provides evidence that IL-17A expression in the nasal mucosa is associated with the pathophysiology of AR, including disease severity and nasal eosinophilia. PMID- 24758733 TI - A cost-effective interdisciplinary approach to microbiologic send-out test use. AB - CONTEXT: Use of reference laboratories for selected laboratory testing (send-out tests) represents a significant source of laboratory costs. As the use of more complex molecular analyses becomes common in the United States, strategies to reduce costs in the clinical laboratory must evolve in order to provide high value, cost-effective medicine. OBJECTIVE: To report a strategy that employs clinical pathology house staff and key hospital clinicians in the effective use of microbiologic send-out testing. DESIGN: The George Washington University Hospital is a 370-bed academic hospital in Washington, DC. In 2012 all requisitions for microbiologic send-out tests were screened by the clinical pathology house staff prior to final dispensation. Tests with questionable utility were brought to the attention of ordering clinicians through the use of interdisciplinary rounds and direct face-to-face consultation. RESULTS: Screening resulted in a cancellation rate of 38% of send-out tests, with proportional cost savings. Nucleic acid tests represented most of the tests screened and the largest percentage of cost saved through screening. Following consultation, requested send-out tests were most often canceled because of a lack of clinical indication. CONCLUSIONS: Direct face-to-face consultation with ordering physicians is an effective, interdisciplinary approach to managing the use of send-out testing in the microbiology laboratory. PMID- 24758734 TI - Importance of toxicokinetics for interspecies variation in sensitivity to chemicals. AB - Interspecies variation in sensitivity to synthetic chemicals can be orders of magnitude large. Species traits causing the variation can be related to toxicokinetics (uptake, distribution, biotransformation, elimination) or toxicodynamics (interaction with biological target sites). We present an approach to systematically measure and model the contribution of uptake, biotransformation, internal distribution, and elimination kinetics toward species sensitivity differences. The aim is to express sensitivity as target tissue specific, internal lethal concentrations. A case study with the pesticides diazinon, imidacloprid, and propiconazole and the aquatic invertebrates Gammarus pulex, Gammarus fossarum, and Lymnaea stagnalis illustrates the approach. L. stagnalis accumulates more pesticides than Gammaridae when measured in whole organisms but less in target tissues such as the nervous system. Toxicokinetics, i.e. biotransformation and distribution, explain the higher tolerance of L. stagnalis to the insecticide diazinon when compared to Gammaridae. L. stagnalis was again more tolerant to the other neurotoxicant imidacloprid; however, the difference in sensitivity could not be explained by toxicokinetics alone, indicating the importance of toxicodynamic differences. Sensitivity to propiconazole was comparable among all species and, when expressed as internal lethal concentrations, falls in the range of baseline toxicity. PMID- 24758735 TI - Depressive symptoms are independently associated with recurrent falls in community-dwelling older adults. AB - ABSTRACT Background: Falls and depression are two major public health problems that affect millions of older people each year. Several factors associated with falls are also related to depressive symptoms such as medical conditions, sleep quality, use of medications, cognitive functioning, and physical capacities. To date, studies that investigated the association between falls and depressive symptoms did not control for all these shared factors. The current study addresses this issue by examining the relationship between falls and depression symptoms after controlling for several confounders. Methods: Eighty-two community dwelling older adults were enrolled in this study. The Geriatric Depression Scale (GDS-30) was used to evaluate the presence of depressive symptoms, and the following question was used to assess falls: "Did you fall in the last 12 months, and if so, how many times?" Results: Univariate analyses indicated that the number of falls was significantly correlated with gender (women), fractures, asthma, physical inactivity, presence of depressive symptoms, complaints about quality of sleep, use of antidepressant drugs, and low functional capacities. Multivariate analyses revealed that depressive symptoms were significantly and independently linked to recurrent falls after controlling for confounders. Conclusions: Results of the present study highlight the importance of assessing depressive symptoms during a fall risk assessment. PMID- 24758736 TI - Effect of baclofen on the acid pocket at the gastroesophageal junction. AB - Previous studies established that a pocket of highly acidic gastric juice is present postprandially at the gastroesophageal junction in man. The GABA-B agonist baclofen inhibits postprandial reflux events through its effects on the lower esophageal sphincter (LES). The aim of the current study was to investigate whether baclofen would affect the location and the extent of the postprandial acid pocket in healthy volunteers. Twelve healthy volunteers underwent acid pocket studies on two different occasions, at least 1 week apart. LES position was determined preprandially with pull-through manometry. Dual pH electrode and manometry probe stepwise pull-through (1 cm/minute, LES-10 to +5 cm) was performed at 30-minute intervals for 150 minutes, with administration of placebo or baclofen 40 mg after the first and ingestion of a liquid meal after the second pull-through. After placebo, a significant drop in intragastric gastric pH was present at the gastroesophageal junction after the meal, reflecting the acid pocket, and this was associated with a drop in LES pressure. Baclofen did not affect the presence of the acid pocket, but prevented the postprandial drop in LES pressure, and the extent of the acid pocket above the upper margin of the manometrically located LES was significantly decreased by baclofen (1.6 +/- 0.7 vs. 0.3 +/- 0.4 cm at 60 minutes, 2.2 +/- 0.6 vs. 0.2 +/- 0.6 at 90 minutes, and 1.5 +/- 0.5 vs. 0.7 +/- 0.7 cm at 120 minutes, all P < 0.05). Baclofen does not alter the intragastric acid pocket, but limits its extension into the distal esophagus, probably through an increase in postprandial LES pressure. PMID- 24758738 TI - From bipolar to quadrupolar electrode structures: an application of bond-detach lithography for dielectrophoretic particle assembly. AB - We describe a new, simple process for fabricating transparent quadrupolar electrode arrays enabling large-scale particle assembly by means of dielectrophoresis. In the first step, interdigitated electrode arrays are made by chemical wet etching of indium tin oxide (ITO). Then, the transition from a bipolar to a quadrupolar electrode arrangement is obtained by covering the electrode surface with a thin poly(dimethylsiloxane) (PDMS) film acting as an electrical insulation layer in which selective openings are formed using bond detach lithography. The PDMS insulating layer thickness was optimized and controlled by adjusting experimental parameters such as the PDMS viscosity (modulated by the addition of heptane) and the PDMS spin-coating velocity. The insulating character of the PDMS membrane was successfully demonstrated by performing a dielectrophoretic assembly of polystyrene particles using interdigitated electrodes with and without a PDMS layer. The results show that the patterned PDMS film functions properly as an electrical insulation layer and allows the reconfiguration of the electric field cartography. Electric field simulations were performed in both configurations to predict the dielectrophoretic behavior of the particles. The simulation results are in perfect agreement with experiments, in which we demonstrated the formation of concentrated clusters of polystyrene particles and living cells of regular size and shape. PMID- 24758737 TI - The impact of RNA structure on coding sequence evolution in both bacteria and eukaryotes. AB - BACKGROUND: Many studies have found functional RNA secondary structures are selectively conserved among species. But, the effect of RNA structure selection on coding sequence evolution remains unknown. To address this problem, we systematically investigated the relationship between nucleotide conservation level and its structural sensitivity in four model organisms, Escherichia coli, yeast, fly, and mouse. RESULTS: We define structurally sensitive sites as those with putative local structure-disruptive mutations. Using both the Mantel Haenszel procedure and association test, we found structurally sensitive nucleotide sites evolved more slowly than non-sensitive sites in all four organisms. Furthermore, we observed that this association is more obvious in highly expressed genes and region near the start codon. CONCLUSION: We conclude that structurally sensitive sites in mRNA sequences normally have less nucleotide divergence in all species we analyzed. This study extends our understanding of the impact of RNA structure on coding sequence evolution, and is helpful to the development of a codon model with RNA structure information. PMID- 24758739 TI - Interpreting the conductance blockades of DNA translocations through solid-state nanopores. AB - Solid-state nanopore electrical signatures can be convoluted and are thus challenging to interpret. In order to better understand the origin of these conductance changes, we investigate the translocation of DNA through small, thin pores over a range of voltage. We observe multiple, discrete populations of conductance blockades that vary with applied voltage. To describe our observations, we develop a simple model that is applicable to solid-state nanopores generally. These results represent an important step toward understanding the dynamics of the electrokinetic translocation process. PMID- 24758740 TI - Abnormal origins of the coronary arteries from the aortic root. AB - Anomalous origin of a coronary artery from the aorta is a potentially serious anomaly that occurs in about 0.1-0.2% of the population. This percentage is small; however, it translates into about 4000 annual births with these anomalies. The clinical presentation of these anomalies is rare, and hence most are and will remain asymptomatic. The various anatomic anomalies are described, with anomalous origin of the left coronary artery that then passes between the aorta and pulmonary artery being the most serious of these anomalies. The pathophysiology resulting from these anomalies is described, as are methods for identifying those who require treatment; however, we still do not know the best methods of determining which patients need treatment. PMID- 24758743 TI - Insoluble Fe-humic acid complex as a solid-phase electron mediator for microbial reductive dechlorination. AB - We report that the insoluble Fe-HA complex, which was synthesized with both commercial Aldrich humic acid (HA) and natural HA, functions as a solid-phase electron mediator (EM) for the anaerobic microbial dechlorination of pentachlorophenol. Spectroscopic characterizations and sequential Fe extraction demonstrated that the Fe-HA complex was predominated with Na4P2O7-labile Fe (represented as the organically bound Fe fraction) and poorly ordered Fe fraction (the fraction left in the residue after the sequential extraction), which were associated with different possible binding processes with carboxylate and phenolic groups. The change in the electron-mediating activity caused by Fe extraction indicated that the electron-mediating function of the Fe-HA complex is attributable to the Na4P2O7-labile Fe fraction. The Fe-HA complex also accelerated the microbial reduction of Fe(III) oxide, which suggested the presence of multiple electron-mediating functions in the complex. The electron shuttle assay showed that the Fe-HA complex had an electron-accepting capacity of 0.82 mequiv g(-1) dry Fe-HA complex. The presence of redox-active moieties in the Fe-HA complex was verified by cyclic voltammetry analysis of the sample after electrical reduction, with a redox potential estimated at 0.02 V (vs a standard hydrogen electrode). PMID- 24758741 TI - Oestrogen-induced angiogenesis promotes adenomyosis by activating the Slug-VEGF axis in endometrial epithelial cells. AB - Adenomyosis is an oestrogen-dependent disease characterized by the invasion of endometrial epithelial cells into the myometrium of uterus, and angiogenesis is thought to be required for the implantation of endometrial glandular tissues during the adenomyotic pathogenesis. In this study, we demonstrate that compared with eutopic endometria, adenomyotic lesions exhibited increased vascularity as detected by sonography. Microscopically, the lesions also exhibited an oestrogen associated elevation of microvascular density and VEGF expression in endometrial epithelial cells. We previously reported that oestrogen-induced Slug expression was critical for endometrial epithelial-mesenchymal transition and development of adenomyosis. Our present studies demonstrated that estradiol (E2) elicited a Slug VEGF axis in endometrial epithelial cells, and also induced pro-angiogenic activity in vascular endothelial cells. The antagonizing agents against E2 or VEGF suppressed endothelial cells migration and tubal formation. Animal experiments furthermore confirmed that blockage of E2 or VEGF was efficient to attenuate the implantation of adenomyotic lesions. These results highlight the importance of oestrogen-induced angiogenesis in adenomyosis development and provide a potential strategy for treating adenomyosis through intercepting the E2 Slug-VEGF pathway. PMID- 24758742 TI - UV photodegradation of murine growth hormone: chemical analysis and immunogenicity consequences. AB - During manufacturing, therapeutic proteins may be exposed to ultraviolet (UV) radiation. Such exposure is of concern because UV radiation may cause photooxidative damage to proteins, which in turn could lead to physical changes such as aggregation and enhanced immunogenicity. We exposed murine growth hormone (mGH) to controlled doses of UV radiation, and examined the resulting chemical, physical and immunogenic changes in the protein. mGH chemical structure was analyzed by mass spectrometry after UV irradiation. Photooxidation products detected by mass spectrometry included methionine sulfoxide formed at Met[127] and Met[149] residues, and, tentatively assigned by MS/MS analysis, ether cross links between original Ser[78] and Cys[188], and Cys[206] and Ser[213], and a thioether cross-link between Cys[17] and Cys[78] residues, transformation of Cys[189] into Ala, and various hydrolytic fragments. Physical damage to UV irradiated mGH was monitored by infrared spectrometry, chromatographic analyses, and particle counting by micro-flow imaging. UV radiation caused mGH to aggregate, forming insoluble microparticles containing mGH with non-native secondary structure. When administered subcutaneously to Balb/c or Nude Balb/c mice, UV-irradiated mGH provoked antibodies that cross-reacted with unmodified mGH in a fashion consistent with a T-cell dependent immune response. In wildtype Balb/c mice, titers for anti-mGH IgG1 antibodies increased with increasing UV radiation doses. PMID- 24758744 TI - New canine models of copper toxicosis: diagnosis, treatment, and genetics. AB - The One Health principle recognizes that human health, animal health, and environmental health are inextricably linked. An excellent example is the study of naturally occurring copper toxicosis in dogs to help understand human disorders of copper metabolism. Besides the Bedlington terrier, where copper toxicosis is caused by a mutation in the COMMD1 gene, more complex hereditary forms of copper-associated hepatitis were recognized recently in other dog breeds. The Labrador retriever is one such breed, where an interplay between genetic susceptibility and exposure to copper lead to clinical copper toxicosis. Purebred dog populations are ideal for gene mapping studies, and because genes involved in copper metabolism are highly conserved across species, newly identified gene mutations in the dog may help unravel the genetic complexity of different human forms of copper toxicosis. Furthermore, increasing knowledge with respect to diagnosis and treatment strategies will benefit both species. PMID- 24758745 TI - Homochiral columns constructed by chiral self-sorting during supramolecular helical organization of hat-shaped molecules. AB - A library of dendronized cyclotriveratrylene (CTV) crowns substituted with chiral, racemic, or achiral peripheral alkyl chains, including enantiopure R and S branched alkyls, "racemic by mixture", "racemic by synthesis", n-octyl, and n dodecyl groups was synthesized. In solvophobic solvents and in bulk they self assemble in helical columns. Their solution and bulk shape-persistent supramolecular structures were determined by a complementary combination of circular dichroism (CD) and UV in solution and thin film, microspot CD in thin film, differential scanning calorimetry combined with fiber X-ray diffraction, computer simulation, and molecular models. In solution, self-assembly via a cooperative mechanism generates single-handed columns from enantiopure CTVs and mixtures of right- and left-handed columns from racemic by mixture, racemic by synthesis, other combinations of R and S, and even from achiral compounds. In bulk state all supramolecular columns form a 3D hexagonal crystalline phase, Phi(h)(k) (P63 symmetry), that can be obtained only from single-handed columns and a columnar hexagonal 2D liquid crystal, Phi(h). The highest order Phi(h)(k) consists of enantiopure single-handed columns that are slightly distorted 12-fold triple helices. The "hat-shaped" dendronized CTV assembles in bent-branch pine tree columns that allow interdigitation of alkyl groups in adjacent columns regardless of their direction. Enantiomerically rich, racemic, and achiral compositions undergo deracemization in the crystal state by transfer of the transient disc-like conformer of dendronized CTV from column to column during crown inversion. Solid state NMR experiments identified motional processes that allow such transfer. This unprecedented supramolecular chiral self-sorting will impact the creation of functions in complex systems. PMID- 24758746 TI - Discovery of a potent, selective, and orally active phosphodiesterase 10A inhibitor for the potential treatment of schizophrenia. AB - We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats. PMID- 24758747 TI - Shorter myotomy on the gastric site (<=2.5 cm) provides adequate relief of dysphagia in achalasia patients. AB - The right length of the myotomy on the gastric side for esophageal achalasia is still a debated issue. We aimed to investigate the final outcome after classic myotomy (CM) as compared with a longer myotomy on the gastric side (LM) in two cohorts of achalasia patients. Forty-four achalasia patients who underwent laparoscopic Heller-Dor were considered; patients with a sigmoid-shaped esophagus were excluded. Symptoms were scored using a detailed questionnaire for dysphagia, regurgitation, and chest pain. Barium swallow, endoscopy, and esophageal manometry were performed before and 6 months after the surgical treatment; 24 hour pH-monitoring was also performed 6 months after the procedure. CM was defined as a gastric myotomy length in the range of 1.5-2.0 cm, while LM was 2.5 3 cm in length. The surgical treatment (CM or LM) was adopted in two consecutive cohorts. Treatment failure was defined as a postoperative symptom score >10th percentile of the preoperative score (i.e. >8). Of the 44 patients representing the study population, 20 had CM and 24 had LM. The patients' demographic and clinical parameters (age, sex, symptom score, duration of symptoms, esophageal diameter, and manometric pattern) were similar in the two groups. The median follow up was 24 months (interquartile range 12-39). One patient in each group was classified as a treatment failure. After the treatment, there was a significant decrease in both groups' symptom score, and resting and residual pressure (P < 0.01), with no statistically significant differences between the two groups in terms of postoperative symptom score, resting and residual pressure, or total and abdominal lower esophageal sphincter length and esophageal diameter. Extending the length of the myotomy on the gastric side does not seem to change the final outcome of the laparoscopic Heller-Dor procedure. PMID- 24758748 TI - Lithium chloride-mediated stereoselective synthesis of cyclopropanecarboxamides from gamma,delta-epoxy malonates through a domino cyclopropanation/lactonization/aminolysis process. AB - The stereoselective synthesis of novel multifunctionalized cyclopropanes from gamma,delta-epoxy malonates and amines mediated by LiCl under mild conditions was carried out. This domino reaction involves the initial cyclopropanation via intramolecular ring-opening of gamma,delta-epoxy malonates through the cooperative catalysis of LiCl (acting as a Lewis acid) and a Bronsted base (a primary or, in selected cases, a secondary amine). The sequential events consisted of lactonization and aminolysis of the lactone ring, which ultimately furnished cyclopropanecarboxamides with different substitution patterns in good isolated yields. In all cases, a quaternary stereogenic center could be perfectly assembled, with a single diastereoisomer being obtained. This method proceeds with high atom economy, is remarkably modular and operationally simple, and tolerates a variety of functional groups. The involvement of readily available starting materials, the broad scope, and the use of a sustainable solvent (methanol or ethanol) at ambient temperature make this domino process highly effective. A reaction mechanism is proposed on the basis of the experimental observations involving the preparation and reactivity of cyclopropylidene lactones as possible intermediates of the domino process. PMID- 24758749 TI - Comparative study of the measurement of enamel demineralization and remineralization using transverse microradiography and electron probe microanalysis. AB - Transverse microradiography (TMR) and electron probe microanalysis (EPMA) are commonly used for characterizing dental tissues. TMR utilizes an approximately monochromatic X-ray beam to determine the mass attenuation of the sample, which is converted to volume percent mineral (vol%min). An EPMA stimulates the emission of characteristic X-rays from a variable volume of sample (dependent on density) to provide compositional information. The aim of this study was to compare the assessment of sound, demineralized, and remineralized enamel using both techniques. Human enamel samples were demineralized and a part of each was subsequently remineralized. The same line profile through each demineralized lesion was analyzed using TMR and EPMA to determine vol%min and wt% elemental composition and atomic concentration ratio information, respectively. The vol%min and wt% values determined by each technique were significantly correlated but the absolute values were not similar. This was attributable to the complex ultrastructural composition, the variable density of the samples analyzed, and the nonlinear interaction of the EPMA-generated X-rays. EPMA remains an important technique for obtaining atomic ratio information, but its limitations in determining absolute mineral content indicate that it should not be used in place of TMR for determining the mineral density of dental hard tissues. PMID- 24758750 TI - Involving patients in detecting quality gaps in a fragmented healthcare system: development of a questionnaire for Patients' Experiences Across Health Care Sectors (PEACS). AB - OBJECTIVE: The purpose of this study was to develop and validate a generic questionnaire to evaluate experiences and reported outcomes in patients who receive treatment across a range of healthcare sectors. DESIGN: Mixed-methods design including focus groups, pretests and field test. SETTING: The patient questionnaire was developed in the context of a nationwide program in Germany aimed at quality improvements across the healthcare sectors. PARTICIPANTS: For the field test, 589 questionnaires were distributed to patients via 47 general practices. MAIN MEASUREMENTS: Descriptive item analyzes non-responder analysis and factor analysis (PCA). Retest coefficients (r) calculated by correlation of sum scores of PCA factors. Quality gaps were assessed by the proportion of responders choosing a response category defined as indicating shortcomings in quality of care. RESULTS: The conceptual phase showed good content validity. Four hundred and seventy-four patients who received a range of treatment across a range of sectors were included (response rate: 80.5%). Data analysis confirmed the construct, oriented to the patient care journey with a focus on transitions between healthcare sectors. Quality gaps were assessed for the topics 'Indication', including shared-decision-making (6 items, 24.5-62.9%) and 'Discharge and Transition' (10 items; 20.7-48.2%). Retest coefficients ranged from r = 0.671 until r = 0.855 and indicated good reliability. Low ratios of item non-response (0.8-9.3%) confirmed a high acceptance by patients. CONCLUSIONS: The number of patients with complex healthcare needs is increasing. Initiatives to expand quality assurance across organizational borders and healthcare sectors are therefore urgently needed. A validated questionnaire (called PEACS 1.0) is available to measure patients' experiences across healthcare sectors with a focus on quality improvement. PMID- 24758751 TI - Molecular characterization of full-length genome of Japanese encephalitis virus genotype V isolated from Tibet, China. AB - OBJECTIVE: To determine the molecular characterization of full-length genome of Japanese encephalitis virus (JEV) genotype V. METHODS: The full-length nucleotide sequences of JEV strains isolated from different locations and sources were used in sequence and phylogenetic analysis. RESULTS: The full-length genome of genotypes V JEV, XZ0934, and Muar strain were composed of 10 983 and 10 988 nucleotides respectively and shared a lower level of identity with JEV genotypes I-IV, ranging from 78.4% (G I, KV1899) to 79.7% (G III, JaGAr01), for the nucleotide sequences, and from 90.0% (G I, KV1899) to 91.8% (G III, JaGAr01) for the amino acid sequences. The open reading frame (ORF) of JEV genotype V spanned nucleotides 96 to 10 397 and encoded 3 433 amino acids. Interestingly, a comparison with JEV genotype I-IV revealed that 3 nucleotides (encoded with a serine residue) were inserted in the NS4A gene of JEV genotype V, and the insertion of nucleotides was also found in downstream of the ORF stop codon in 3' untranslated region. Moreover, numerous amino acid mutations were observed in 3 functional domains of the E gene of JEV genotype V. CONCLUSION: The molecular characterization of JEV genotype V is significantly different from that of the known genotypes I-IV. The mutations located in the coding region and the non coding region may be molecular markers of JEV genotype V and warrant further studies to determine their effects on biology and immunogenicity of genotype V strains. PMID- 24758752 TI - A novel reassortant H2N3 influenza virus isolated from China. AB - OBJECTIVE: To analyze the genetic composition of a novel H2N3 virus isolate identified from a duck cage swab in a live poultry market (LPM) in 2009 in Guangdong province of China. METHODS: PCR-positive specimens were inoculated into embryonated chicken eggs and subtyped by conventional RT-PCR. All segments of the virus A/environment/Guangdong/2/2009 were sequenced, and phylogenetic trees were constructed and analyzed. RESULTS: The genes of this virus belong to Eurasian lineage avian viruses. The virus is a reassortant with the HA gene from an H2N2 virus and the NA gene from an H5N3 virus. The PB1, PB2, and NP genes were from an H4N6 virus, the PA was from an H3N8 virus, the M gene was from an H1N3 virus, and the NS gene was from an H10N6 virus. CONCLUSION: A novel avian-origin reassortant H2N3 influenza virus was detected in a live poultry market. Its potential impacts and evolution should be closely monitored. PMID- 24758753 TI - Rapid and high-throughput identification of recombinant bacteria with mass spectrometry assay. AB - OBJECTIVE: To construct a rapid and high-throughput assay for identifying recombinant bacteria based on mass spectrometry. METHODS: Matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) techniques were used to identify 12 recombinant proteins (10 of Yersinia pestis, 1 of Campylobacter jejuni and 1 of Helicobacter pylori). A classification model for the various phase of recombinant bacteria was established, optimized and validated, using MALDI-TOF MS-ClinProTools system. The differences in the peptide mass spectra were analyzed by using Biotyper and FlexAnalysis softwares. RESULTS: Models of GA, SNN, and QC were established. After optimizing the parameters, the GA recognition model showed good classification capabilities: RC=100%, mean CVA=98.7% (the CVA was 96.4% in phase 1, 100% in phase 2, 98.4% in phase 3, and 100% in phase 4, respectively) and PPV=95%. This model can be used to classify the bacteria and their recombinant, which only requires 3.7*103 cells for analysis. The total time needed is only 10 min from protein extraction to reporting the result for one sample. Furthermore, this assay can automatically detect and test 96 samples concurrently. A total of 48 specific peaks (9, 16, 9, and 14 for the four stages, respectively) was found in the various phase of recombinant bacteria. CONCLUSION: MALDI-TOF MS can be used as a fast, accurate, and high-throughput method to identify recombinant bacteria, which provide a new ideas not only for recombinant bacteria but also for the identification of mutant strains and bioterrorism pathogens. PMID- 24758754 TI - Indoor 222Rn levels and effective dose estimation of academic staff in Izmir, Turkey. AB - OBJECTIVE: To investigate the annual effective doses from indoor radon received by academic staff in the Faculty building. METHODS: Measurements of indoor radon concentrations were performed in the Arts and Sciences Faculty of Dokuz Eylul University for two surveys of about 1 month duration respectively using the SSNTD (Solid State Nuclear Track Detectors) method with LR115 detectors. Time integrated measurements comprised different locations inside the faculty building: classrooms, toilets, canteen and offices. Homes of academic staff were also tested for radon. RESULTS: The arithmetic mean radon concentration is 161 Bq m-3 with a range between 40 and 335 Bq m-3 in the Faculty. Six offices and three classrooms have a radon concentration above 200 Bq m-3. The results show that the radon concentration in classrooms is generally higher than in offices. Based on the measured indoor radon data, the annual effective doses received by staff in the Faculty were estimated to range from 0.79 to 4.27 mSv, according to UNSCEAR methodology. The annual effective doses received by staff ranged from 0.78 to 4.20 mSv in homes. On average, the Faculty contributed 56% to the annual effective dose. CONCLUSION: Reported values for radon concentrations and corresponding doses are within the ICRP recommended limits for workplaces. PMID- 24758755 TI - Di-(n-butyl)-phthalate-induced oxidative stress and depression-like behavior in mice with or without ovalbumin immunization. AB - OBJECTIVE: To investigate the relationship between atopic allergy and depression and the role of DBP in the development of depression. METHODS: BALB/c mice were randomly divided into eight groups: saline; ovalbumin (OVA)-immunized; saline+DBP (0.45 mg/kg*d); saline+DBP (45 mg/kg*d); DBP (0.45 mg/kg*d) OVA-immunized; DBP (45 mg/kg*d) OVA-immunized; saline+hydrocortisone (30 mg/kg*d); and hydrocortisone (30 mg/kg*d)-exposed OVA-immunized. Behavior (e.g. open-field, tail suspension, and forced swimming tests), viscera coefficients (brain and spleen), oxidative damage [e.g. reactive oxygen species (ROS), malondialdehyde (MDA), and glutathione (GSH)], as well as levels of IgE and IL-4, were then analyzed. RESULTS: In the saline and OVA groups, the degree of depression symptoms in mice increased with increasing DBP concentration. Additionally, the OVA-immunity groups were associated with more serious depressive behavior compared with the same exposure concentration in the saline group. Oxidative damage was associated with a dose-dependent increase in DBP in the different groups. IL-4 and IgE levels were associated with low-dose DBP stimulation, which changed to high-dose inhibition with increasing DBP exposure, possibly due to spleen injury seen at high DBP concentrations. CONCLUSION: Development of an atopic allergy has the potential to increase the risk of depression in mice, and it seems that DBP helps OVA to exert its effect in our present model. Moreover, the results of our study implicate a certain connection between brain oxidative stress and depression, which deserves a further exploration. PMID- 24758756 TI - Toxic effects of atrazine on reproductive system of male rats. AB - OBJECTIVE: This study was designed to evaluate the toxic effects of Atrazine (ATZ) on the reproductive system of male rats. METHODS: Male Sprague-Dawley rats were exposed to ATZ by gavage at dosages of 0, 38.5, 77, and 154 mg/kg bw/day for 30 d. The toxic effects of ATZ to rats were assessed through histopathologcal observation, spermatozoa quality evaluation, testicular marker enzyme indicators, antioxidant capacity and reproductive hormone levels. RESULTS: Significant adverse effects on reproductive system were observed in rats exposed to ATZ at different dosages compared with 0 mg/kg group, including an irregular and disordered arrangement of the seminiferous epithelium in 154 mg/kg group; a decreased spermatozoa number and an increased spermatozoa abnormality rate in 77 and 154 mg/kg groups; decreased levels of acid phosphatase (ACP), alkaline phosphatase (AKP), lactic dehydrogenase (LDH), and succinate dehydrogenase (SDH) with the increasing of ATZ concentration; a decreased level of total antioxidant capacity (TAC) in a dose-dependent manner, and a decreased reduced glutathione (GSH) level and an increased malondialdehyde (MDA) content in 154 mg/kg group; and decreased serum levels of testosterone (T) and inhibin-B (INH-B) and an increased serum level of follicle stimulating hormone (FSH) in 77 and 154 mg/kg groups, and an increased serum level of luteinizing hormone (LH) in 154 mg/kg group. CONCLUSION: These results suggested that relatively high doses of ATZ could exert reproductive toxicity of male rats. PMID- 24758757 TI - A novel high nitrogen nickel-free coronary stents system: evaluation in a porcine model. AB - OBJECTIVE: To study the safety of the novel high nitrogen nickel-free austenitic stainless steel bare metal stents (BMS) in a recognized porcine coronary model and to select a better grid structure of it. METHODS: Three types of stents were randomly implanted in different coronary arteries of the same pig: 316 L stainless steel BMS (316 L-BMS) (n=12), novel high nitrogen nickel-free stents Grid A (NF-A-BMS) (n=12) and novel high nitrogen nickel-free stents Grid B (NF-B BMS) (n=12). In total, eighteen animals underwent successful random placement of 36 oversized stents in the coronary arteries. Coronary angiography was performed after 36 d of stents implantation. Nine animals were respectively sacrificed after 14 d and 36 d for histomorphologic analysis. RESULTS: Quantitative coronary angiography (QCA) showed similar luminal loss (LL) in the three groups: (0.21 +/- 0.17) mm for 316 L-BMS, (0.16 +/- 0.12) mm for NF-A-BMS, (0.24 +/- 0.15) mm for NF-B-BMS (P>0.05). Histomorphomeric analysis after 15 d and 36 d revealed that there was also no significant difference among the three groups in neointimal area (NA) with similar injury scores respectively. High magnification histomorphologic examination showed similar inflammation scores in the three groups, but NF-A-BMS group had poorer endothelialization scores compared with NF B-BMS group, 2.00 +/- 0.63 vs. 2.83 +/- 0.41 (P=0.015) at 15 d, which also could be proved by the scanning electron microscope. However, the difference could not been observed at 36 d. CONCLUSION: The novel NF-BMS showed similar safety as 316 L-BMS during the short-term study. NF-B-BMS had better endothelialization than NF A-BMS and this may owe to the specific strut units. PMID- 24758758 TI - Anti-nociceptive effect in mice of thillai flavonoid rutin. AB - We investigated the anti-nociceptive effect of Excoecaria agallocha (E.agallocha) against chemically and thermally induced nociception, Albino mice received a dose of 10, 15, 20, or 25 mg/kg of alkaline chloroform fraction (Alk-CF) of E.agallocha by oral administration. Compared with controls, Alk-CF decreased the writhing numbers (P<0.01) in a dose dependent manner. Further we determined that, Alk-CF contained, a potent compared to control, also potent anti-nociceptive agent that acted via opioid receptors and using HPLC, identified this compound as Rutin. Docking simulation demonstrated that Rutin interacted strongly with cyclooxygenase, forming a number of specific hydrogen bonds. In conclusion we have identified peripheral and central anti-nociceptive activities of E.agallocha that involve opioid receptor, and in which the active compound is Rutin. PMID- 24758759 TI - Protective effects of ginsenoside Rb1 on septic rats and its mechanism. AB - This study aims to observe the protective effects of ginsenoside Rb1 on liver and lung in rats with septic shock and reveal its mechanism. Rats were randomly divided into three groups: sham, cecal ligation and puncture (CLP), and CLP with ginsenoside Rb1. Then, the survival rate, arterial blood pressure, TLR4 mRNA, and TNF-alpha levels were determined. The liver and lung tissues were stained with hematoxylin-eosin (HE). The overall survival rate of the Rb1 group was significantly higher than that of the CLP group. Mean arterial blood pressure went down in both the CLP and Rb1 groups after CLP, and there was a significant difference both in the sham and Rb1 groups when compared with the CLP group. The Rb1 treatment group had markedly lower TLR4 mRNA expression and TNF-alpha levels than the CLP group. In the CLP group, pathology showed swelling, degeneration, necrosis, and neutrophil infiltration in the liver and alveolar epithelial cells. However, in the Rb1 group, there was mild degeneration and slight neutrophil infiltration, but no obvious necrosis. Rb1 may improve the survival rate, ameliorate arterial blood pressure, and protect the liver and lung in septic shock rats by downregulating the expression of TLR4 mRNA and inhibiting the production of TNF-alpha. PMID- 24758760 TI - The nationwide impact of injury-related deaths on average life expectancy in China. AB - To expand the evidence base to inform future public policy aimed at accident prevention, we investigated the impact of different categories of injury on average life expectancy in China. We used data from the National Death Cause Registration Information System and National Maternity and Children Health Surveillance databases, as well as 2010 population data from the National Bureau of Statistics. We then calculated the average life expectancy of the Chinese population, in addition to life expectancy after eliminating injury-related mortality. The average life expectancy of the Chinese population in 2010 was 74.93 years. After eliminating deaths due to injuries, the fourth leading cause of mortality in China, average life expectancy increased by 1.36 years. When this was broken down by population sub-groups, these gains were 1.76 and 0.79 years in men and women, 0.94 and 1.56 years in urban and rural residents, and 1.11, 1.30, and 1.67 years for residents in the Eastern, Central and Western regions respectively. After eliminating all categories of injury, the average life expectancy of the Chinese population was found to increase by 1.36 years. This figure was higher for males and residents of rural areas and Western China. PMID- 24758761 TI - Association between macroscopic-factors and identified HIV/AIDS cases among injecting drug users: an analysis using geographically weighted regression model. AB - Drug use (DU), particularly injecting drug use (IDU) has been the main route of transmission and spread of Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS) among injecting drug users (IDUs). Previous studies have proven that needles or cottons sharing during drug injection were major risk factors for HIV/AIDS transmission at the personal level. Being a social behavioral issue, HIV/AIDS related risk factors should be far beyond the personal level. Therefore, studies on HIV/AIDS related risk factors should focus not only on the individual factors, but also on the association between HIV/AIDS cases and macroscopic-factors, such as economic status, transportation, health care services, etc. The impact of the macroscopic-factors on HIV/AIDS status might be either positive or negative, which are potentially reflected in promoting, delaying or detecting HIV/AIDS epidemics. PMID- 24758762 TI - C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2. AB - Core 1 beta1,3-galactosyltransferase (C1GALT1) transfers galactose (Gal) to N acetylgalactosamine (GalNAc) to form Galbeta1,3GalNAc (T antigen). Aberrant O glycans, such as T antigen, are commonly found in colorectal cancer. However, the role of C1GALT1 in colorectal cancer remains unclear. Here we showed that C1GALT1 was frequently overexpressed in colorectal tumors and is associated with poor survival. C1GALT1 overexpression promoted cell survival, migration, invasion, and sphere formation as well as tumor growth and metastasis of colon cancer cells. Conversely, knockdown of C1GALT1 with small interference (si) RNA was sufficient to suppress these malignant phenotypes in vitro and in vivo. Moreover, we are the first to show that fibroblast growth factor receptor (FGFR) 2 carried O-glycans in colon cancer cells. Mechanistic investigations showed that C1GALT1 modified the O-glycans on FGFR2 and enhanced bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. In addition, BGJ398, a selective inhibitor of FGFR, blocked the effects of C1GALT1. These findings suggest that C1GALT1 overexpression modifies O-glycans on FGFR2 and enhances its phosphorylation to promote the invasive behavior and cancer stem-like property in colon cancer cells, indicating a critical role of O-glycosylation in the pathogenesis of colorectal cancer. PMID- 24758763 TI - Spatially explicit methane emissions from petroleum production and the natural gas system in California. AB - We present a new, spatially resolved inventory of methane (CH4) emissions based on US-EPA emission factors and publically available activity data for 2010 California petroleum production and natural gas production, processing, transmission, and distribution. Compared to official California bottom-up inventories, our initial estimates are 3 to 7 times higher for the petroleum and natural gas production sectors but similar for the natural gas transmission and distribution sectors. Evidence from published "top-down" atmospheric measurement campaigns within Southern California supports our initial emission estimates from production and processing but indicates emission estimates from transmission and distribution are low by a factor of approximately 2. To provide emission maps with more accurate total emissions we scale the spatially resolved inventory by sector-specific results from a Southern California aircraft measurement campaign to all of California. Assuming uncertainties are determined by the uncertainties estimated in the top-down study, our estimated state total CH4 emissions are 541 +/- 144 Gg yr(-1) (as compared with 210.7 Gg yr(-1) in California's current official inventory), where the majority of our reported uncertainty is derived from transmission and distribution. We note uncertainties relative to the mean for a given region are likely larger than that for the State total, emphasizing the need for additional measurements in undersampled regions. PMID- 24758764 TI - Subclinical hypothyroidism as a new therapeutic target for patients with heart failure with preserved ejection fraction. PMID- 24758765 TI - Current trends in use of implantable cardioverter defibrillators and cardiac resynchronization therapy with a pacemaker or defibrillator in Japanese pediatric patients: results from a nationwide questionnaire survey. AB - BACKGROUND: In Japan, the use of implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy with a biventricular pacemaker (CRTP) and CRT with a defibrillator (CRTD) in children has not been studied statistically, and dual-chamber (DDD) pacemakers are still used for pediatric CRT because of current government regulations. METHODS AND RESULTS: Data were obtained from 15 children's and 74 general hospitals through a questionnaire survey regarding the aforementioned therapies performed before 2012 in Japanese children (<16 years old). ICD, CRT with DDD, CRTP and CRTD were used in 64 (42%), 47 (31%), 34 (22%) and 7 (5%), respectively, of all cases reported (n=152). Among all CRTP and CRT DDD cases (n=81), the use of DDD accounted for 41% in general hospitals vs. 89% in children's hospitals, and CRT-DDD and CRTP were effective in 67 cases (83%). Of 64 ICD cases, appropriate shocks were experienced in 28 cases (44%), and inappropriate shocks in 19 cases (29%). Additionally, data from the Japan Arrhythmia Device Industry Association obtained for overall device usage analysis revealed that CRTP was more commonly used in children than in adults. CONCLUSIONS: There is an increasing need for pediatric device therapy, especially CRTP. However, many children's hospitals were still using DDD pacemakers in 2012. Although the demand for device therapy in children may be small, it is indispensable in pediatric cardiology. PMID- 24758766 TI - Adipose-derived stem cells stimulate reendothelialization in stented rat abdominal aorta. AB - BACKGROUND: Although drug-eluting stents (DES) have been widely used for the treatment of coronary artery disease, they potentially increase the risk of late thrombosis. It is, therefore, desirable to establish a strategy to stimulate reendothelialization. Endothelial injury models have been widely used to analyze the mechanisms of coronary restenosis. However, animal models deployed with coronary stents in the blood vessels are necessary to accurately analyze the mechanisms of coronary restenosis and late thrombosis because persistent inflammation occurs around the coronary stents. METHODS AND RESULTS: Coronary stents were implanted into rat abdominal aorta and adipose tissue-derived stem cells (ASC) were administered from the adventitial side. Reendothelialization was then visualized by Evans blue staining, and neointimal formation was analyzed histologically. ASC significantly stimulated reendothelialization and inhibited neointimal formation in bare metal stents (BMS)-implanted aorta. In addition, ASC promoted reendothelialization in DES-implanted aorta; however, the effects were weaker than in BMS-implanted aorta. Among the cytokines that ASC produce, adrenomedullin (AM) significantly stimulated reendothelialization and inhibited neointimal formation in BMS-implanted aorta, when an adenovirus expressing AM was administered from the adventitial side. CONCLUSIONS: These results suggest that ASC produce several cytokines that stimulate reendothelialization and inhibit neointimal formation in stent-deployed vessels, and that AM could mediate these effects. PMID- 24758770 TI - Abstracts of the 14th Asian Pacific Congress of Nephrology, 14-17 May 2014, Tokyo, Japan. PMID- 24758771 TI - The near edge structure of hexagonal boron nitride. AB - Hexagonal boron nitride (hBN) is a promising material for a range of applications including deep-ultraviolet light emission. Despite extensive experimental studies, some fundamental aspects of hBN remain unknown, such as the type of stacking faults likely to be present and their influence on electronic properties. In this paper, different stacking configurations of hBN are investigated using CASTEP, a pseudopotential density functional theory code. AB-b stacking faults, in which B atoms are positioned directly on top of one another while N atoms are located above the center of BN hexagons, are shown to be likely in conventional AB stacked hBN. Bandstructure calculations predict a single direct bandgap structure that may be responsible for the discrepancies in bandgap type observed experimentally. Calculations of the near edge structure showed that different stackings of hBN are distinguishable using measurements of core-loss edges in X-ray absorption and electron energy loss spectroscopy. AB stacking was found to best reproduce features in the experimental B and N K-edges. The calculations also show that splitting of the 1s to pi* peak in the B K-edge, recently observed experimentally, may be accounted for by the presence of AB-b stacking faults. PMID- 24758773 TI - Isoflurane impairs learning and hippocampal long-term potentiation via the saturation of synaptic plasticity. AB - BACKGROUND: General anesthesia induces long-lasting cognitive and learning deficits. However, the underlying mechanism remains unknown. The GluA1 subunit of AMPAR is a key molecule for learning and synaptic plasticity, which requires trafficking of GluA1-containing AMPARs into the synapse. METHODS: Adult male rats were exposed to 1.8% isoflurane for 2 h and subjected to an inhibitory avoidance task, which is a hippocampus-dependent contextual fear learning paradigm (n = 16 to 39). The in vitro extracellular field potential of hippocampal synapses between the Schaffer collateral and the CA1 was evaluated using a multielectrode recorder (n = 6 per group). GluA1 expression in the synaptoneurosome was assessed using Western blotting (n = 5 to 8). The ubiquitination level of GluA1 was evaluated using immunoprecipitation and Western blotting (n = 7 per group). RESULTS: Seven days after exposure to 1.8% isoflurane for 2 h (Iso1.8), the inhibitory avoidance learning (control vs. Iso1.8; 294 +/- 34 vs. 138 +/- 28, the mean +/- SEM [%]; P = 0.002) and long-term potentiation (125.7 +/- 6.1 vs. 105.7 +/- 3.3; P < 0.001) were impaired. Iso1.8 also temporarily increased GluA1 in the synaptoneurosomes (100 +/- 9.7 vs. 138.9 +/- 8.9; P = 0.012) and reduced the GluA1 ubiquitination, a main degradation pathway of GluA1 (100 +/- 8.7 vs. 71.1 +/- 6.1; P = 0.014). CONCLUSIONS: Isoflurane impairs hippocampal learning and modulates synaptic plasticity in the postanesthetic period. Increased GluA1 may reduce synaptic capacity for additional GluA1-containing AMPARs trafficking. PMID- 24758774 TI - Phosphodiesterase 2A localized in the spinal cord contributes to inflammatory pain processing. AB - BACKGROUND: Phosphodiesterase 2A (PDE2A) is an evolutionarily conserved enzyme that catalyzes the degradation of the cyclic nucleotides, cyclic adenosine monophosphate, and/or cyclic guanosine monophosphate. Recent studies reported the expression of PDE2A in the dorsal horn of the spinal cord, pointing to a potential contribution to the processing of pain. However, the functions of PDE2A in spinal pain processing in vivo remained elusive. METHODS: Immunohistochemistry, laser microdissection, and quantitative real-time reverse transcription polymerase chain reaction experiments were performed to characterize the localization and regulation of PDE2A protein and messenger RNA in the mouse spinal cord. Effects of the selective PDE2A inhibitor, BAY 60-7550 (Cayman Chemical, Ann Arbor, MI), in animal models of inflammatory pain (n = 6 to 10), neuropathic pain (n = 5 to 6), and after intrathecal injection of cyclic nucleotides (n = 6 to 8) were examined. Also, cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in spinal cord tissues were measured by liquid chromatography tandem mass spectrometry. RESULTS: The authors here demonstrate that PDE2A is distinctly expressed in neurons of the superficial dorsal horn of the spinal cord, and that its spinal expression is upregulated in response to hind paw inflammation. Administration of the selective PDE2A inhibitor, BAY 60-7550, increased the nociceptive behavior of mice in animal models of inflammatory pain. Moreover, BAY 60-7550 increased the pain hypersensitivity induced by intrathecal delivery of cyclic adenosine monophosphate, but not of cyclic guanosine monophosphate, and it increased the cyclic adenosine monophosphate levels in spinal cord tissues. CONCLUSION: Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord. PMID- 24758775 TI - Comparison of three techniques for ultrasound-guided femoral nerve catheter insertion: a randomized, blinded trial. AB - BACKGROUND: Ultrasound guidance for continuous femoral perineural catheters may be supplemented by electrical stimulation through a needle or through a stimulating catheter. The authors tested the primary hypothesis that ultrasound guidance alone is noninferior on both postoperative pain scores and opioid requirement and superior on at least one of the two. Second, the authors compared all interventions on insertion time and incremental cost. METHODS: Patients having knee arthroplasty with femoral nerve catheters were randomly assigned to catheter insertion guided by: (1) ultrasound alone (n = 147); (2) ultrasound and electrical stimulation through the needle (n = 152); or (3) ultrasound and electrical stimulation through both the needle and catheter (n = 138). Noninferiority between any two interventions was defined for pain as not more than 0.5 points worse on a 0 to 10 verbal response scale and for opioid consumption as not more than 25% greater than the mean. RESULTS: The stimulating needle group was significantly noninferior to the stimulating catheter group (difference [95% CI] in mean verbal response scale pain score [stimulating needle vs. stimulating catheter] of -0.16 [-0.61 to 0.29], P < 0.001; percentage difference in mean IV morphine equivalent dose of -5% [-25 to 21%], P = 0.002) and to ultrasound-only group (difference in mean verbal response scale pain score of -0.28 [-0.72 to 0.16], P < 0.001; percentage difference in mean IV morphine equivalent dose of -2% [-22 to 25%], P = 0.006). In addition, the use of ultrasound alone for femoral nerve catheter insertion was faster and cheaper than the other two methods. CONCLUSION: Ultrasound guidance alone without adding either stimulating needle or needle/catheter combination thus seems to be the best approach to femoral perineural catheters. PMID- 24758776 TI - Intraperitoneal local anesthetics have predominant local analgesic effect: a randomized, double-blind study. AB - BACKGROUND: It remains unclear whether analgesia from intraperitoneal local anesthetics is via local or central mechanisms. This double-blind clinical trial tests the hypothesis that intraperitoneal local anesthetic is superior to continuous IV infusion for pain management. Primary outcome was morphine consumption during 0 to 24 h. METHODS: Informed consent was obtained from 60 patients, age 30 to 75 yr, American Society of Anesthesiologists physical status I to II, undergoing abdominal hysterectomy. A computer-generated program randomized patients in parallel arms to group IV: continuous infusion of lidocaine 50 mg/h (10 ml) IV and saline 10 ml/h intermittently intraperitoneal; group IP: injection of lidocaine 50 mg/h (10 ml) once every hour intraperitoneally and continuous infusion of saline 10 ml/h intravenously; and group P (placebo): saline 10 ml/h both intravenously and intermittent intraperitoneal injection. Postoperative morphine consumption, pain intensity, recovery, home discharge, and lidocaine concentrations were measured. RESULTS: Morphine consumption during 0 to 24 h was lower in group IP versus group IV, mean difference -22.6 mg (95% CI, 11.4 to 33.8; P < 0.01). No difference was seen between group IV and group P. The total mean plasma concentration of lidocaine in group IP was significantly lower than group IV, 0 to 4.5 h postoperatively (P = 0.03) with no evidence of systemic toxicity. Pain intensity and other recovery parameters were similar between the groups. CONCLUSION: The lower supplemental morphine consumption and plasma lidocaine concentration in group IP would confirm that the effects of local anesthetics are likely to be predominant via local intraperitoneal receptors or anti-inflammatory effects and not via central mechanisms alone. PMID- 24758778 TI - Frequent expansions of the bitter taste receptor gene repertoire during evolution of mammals in the Euarchontoglires clade. AB - Genome studies of mammals in the superorder Euarchontoglires (a clade that comprises the orders Primates, Dermoptera, Scandentia, Rodentia, and Lagomorpha) are important for understanding the biological features of humans, particularly studies of medical model animals such as macaques and mice. Furthermore, the dynamic ecoevolutionary signatures of Euarchontoglires genomes may be discovered because many species in this clade are characterized by their successful adaptive radiation to various ecological niches. In this study, we investigated the evolutionary trajectory of bitter taste receptor genes (TAS2Rs) in 28 Euarchontoglires species based on homology searches of 39 whole-genome assemblies. The Euarchontoglires species possessed variable numbers of intact TAS2Rs, which ranged from 16 to 40, and their last common ancestor had at least 26 intact TAS2Rs. The gene tree showed that there have been at least seven lineage-specific events involving massive gene duplications. Gene duplications were particularly evident in the ancestral branches of anthropoids (the anthropoid cluster), which may have promoted the adaptive evolution of anthropoid characteristics, such as a trade-off between olfaction and other senses and the development of herbivorous characteristics. Subsequent whole-gene deletions of anthropoid cluster TAS2Rs in hominoid species suggest ongoing ectopic homologous recombination in the anthropoid cluster. These findings provide insights into the roles of adaptive sensory evolution in various ecological niches and important clues related to the molecular mechanisms that underlie taste diversity in Euarchontoglires mammalian species, including humans. PMID- 24758777 TI - Paralogous radiations of PIN proteins with multiple origins of noncanonical PIN structure. AB - The plant hormone auxin is a conserved regulator of development which has been implicated in the generation of morphological novelty. PIN-FORMED1 (PIN) auxin efflux carriers are central to auxin function by regulating its distribution. PIN family members have divergent structures and cellular localizations, but the origin and evolutionary significance of this variation is unresolved. To characterize PIN family evolution, we have undertaken phylogenetic and structural analyses with a massive increase in taxon sampling over previous studies. Our phylogeny shows that following the divergence of the bryophyte and lycophyte lineages, two deep duplication events gave rise to three distinct lineages of PIN proteins in euphyllophytes. Subsequent independent radiations within each of these lineages were taxonomically asymmetric, giving rise to at least 21 clades of PIN proteins, of which 15 are revealed here for the first time. Although most PIN protein clades share a conserved canonical structure with a modular central loop domain, a small number of noncanonical clades dispersed across the phylogeny have highly divergent protein structure. We propose that PIN proteins underwent sub- and neofunctionalization with substantial modification to protein structure throughout plant evolution. Our results have important implications for plant evolution as they suggest that structurally divergent PIN proteins that arose in paralogous radiations contributed to the convergent evolution of organ systems in different land plant lineages. PMID- 24758779 TI - Transamidation of carboxamides catalyzed by Fe(III) and water. AB - The highly efficient transamidation of several primary, secondary, and tertiary amides with aliphatic and aromatic amines (primary and secondary) is described. The reaction is performed in the presence of a 5 mol % concentration of different hydrated salts of Fe(III), and the results show that the presence of water is crucial. The methodology was also applied to urea and phthalimide to demonstrate its versatility and wide substrate scope. An example of its use is an intramolecular application in the synthesis of 2,3-dihydro-5H-benzo[b]-1,4 thiazepin-4-one, which is the bicyclic core of diltiazem and structurally related drugs (Budriesi, R.; Cosimelli, B.; Ioan, P.; Carosati, E.; Ugenti, M. P.; Spisani, R. Curr. Med. Chem. 2007, 14, 279-287). A plausible mechanism that explains the role of water is proposed on the basis of experimental observations and previous mechanistic suggestions for transamidation reactions catalyzed by transition metals such as copper and aluminum. This methodology represents a significant improvement over other existing methods; it can be performed in air and with wet or technical grade solvents. PMID- 24758780 TI - Reconstruction of the Medial Patellofemoral Ligament: Clinical Outcomes and Return to Sports. AB - BACKGROUND: Recent studies have shown that medial patellofemoral ligament (MPFL) reconstruction using a standardized technique provides significant improvements in all outcome scoring systems, with low complication rates and good patient satisfaction. Although numerous studies have assessed clinical results, there is little published literature investigating return to sporting activities after reconstruction of the MPFL. PURPOSE: To demonstrate postoperative outcomes and the return-to-sports rate a minimum of 2 years after isolated MPFL reconstruction in a young patient cohort. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 2007 and 2010, a total of 72 isolated MPFL reconstructions (in 68 patients) were performed for recurrent patellar dislocation. Pre- and postoperative knee assessment included a thorough history of symptoms and a clinical examination consisting of crepitus, range of motion, patellofemoral pain, and patellar apprehension. Knee function was assessed using the Kujala score, International Knee Documentation Committee score, Tegner activity score, visual analog scale (VAS), and Activity Rating Scale (ARS). RESULTS: Of patients who participated in sports preoperatively (62/68 patients), 100% returned to sports after MPFL reconstruction; 53% returned at equal or higher levels, whereas 47% returned at lower levels. Fifty-four of 68 patients (79.4%) rated themselves as very satisfied or satisfied with the results. The median Kujala score improved significantly from 66 to 87.5 and the median International Knee Documentation Committee score from 60 to 79.8. The median VAS for pain score illustrated significant preoperative to postoperative improvement, from 4 to 2. Conversely, patients' activity levels according to the Tegner activity score dropped from 4.5 to 4, and the median Activity Rating Scale score dropped from 6 to 3. There was also a persistent instability rate of 10% as well as a slight loss of knee flexion in 24 of 72 knees. CONCLUSION: Reconstruction of the MPFL is a safe and effective treatment for patellofemoral instability without severe trochlear dysplasia and allows most patients to engage in regular sports activities 2 years postoperatively, at least at a recreational level. However, potential complications, such as persistent instability, pain, and loss of flexion, must be considered. PMID- 24758781 TI - Levels of Evidence in the Clinical Sports Medicine Literature: Are We Getting Better Over Time? AB - BACKGROUND: There has been an increased emphasis on improving the level of evidence used as the basis for clinical treatment decisions. Several journals now require a statement of the level of evidence as a basic gauge of the study's strength. PURPOSE: To review the levels of evidence in published articles in the clinical sports medicine literature and to determine if there has been an improvement in the levels of evidence published over the past 15 years. STUDY DESIGN: Systematic review. METHODS: All articles from the years 1995, 2000, 2005, and 2010 in The American Journal of Sports Medicine (AJSM), Arthroscopy, and sports medicine-related articles from The Journal of Bone and Joint Surgery American (JBJS-A) were analyzed. Articles were categorized by type and ranked for level of evidence according to guidelines from the Centre for Evidence-Based Medicine. Excluded were animal, cadaveric, and basic science articles; editorials; surveys; special topics; letters to the editor; and correspondence. Statistical analysis was performed with chi-square. RESULTS: A total of 1580 articles over the 4 periods met the inclusion criteria. The percentage of level 1 and 2 studies increased from 6.8% to 12.6%, 22.9%, and 23.5%, respectively (P < .0001), while level 4 and 5 studies decreased from 78.9% to 72.4%, 63.9%, and 53.0% (P < .0001). JBJS-A had a significant increase in level 1 and 2 studies (4.1%, 5.1%, 28.2%, 27.8%; P < .0001), as did AJSM (9.4%, 17.1%, 36.1%, 30.1%; P < .0001). Arthroscopy showed no significant change over time. Diagnostic, therapeutic, and prognostic studies all showed significant increases in level 1 and 2 studies over time (P < .05). CONCLUSION: There has been a statistically significant increase in the percentage of level 1 and 2 studies published in the sports medicine literature over the past 15 years, particularly in JBJS-A and AJSM. The largest increase was seen in diagnostic studies, while therapeutic and prognostic studies demonstrated modest improvement. The emphasis on increasing levels of evidence to guide treatment decisions for sports medicine patients may be taking effect. PMID- 24758782 TI - The Fascial Elevation and Tendon Origin Resection Technique for the Treatment of Chronic Recalcitrant Medial Epicondylitis. AB - BACKGROUND: Medial epicondylitis is a tendinopathy of the common flexor-pronator origin, and surgical treatment is required when this condition fails to respond to nonoperative methods. This study details the development of a new technique, termed fascial elevation and tendon origin resection (FETOR), which facilitates the complete visualization and resection of the CFPO with limited soft tissue dissection. PURPOSE: To evaluate the outcomes of FETOR for the treatment of chronic recalcitrant medial epicondylitis. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The electronic medical records of patients who underwent FETOR from January 2008 to July 2011 were retrospectively reviewed. Outcome assessments included the visual analog scale (VAS) for average pain, pain at rest, and pain experienced during hard work or heavy lifting; the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire; and pain-free grip strength. Preoperative and postoperative data were compared. RESULTS: A total of 22 elbows in 20 patients with a mean age of 48.8 years (range, 29-58 years) were included. At a mean follow-up of 35.6 months (range, 16-77 months), the VAS score decreased by 93% for average pain, 94% for pain at rest, and 83% for pain during hard work or heavy lifting (P < .001). The patients' perception of arm function as assessed using the DASH recovered to the level of the healthy population (from a mean of 51.6 +/- 18.0 to 8.0 +/- 11.1; P < .001). The mean pain-free grip strength improved significantly from 53.7% +/- 30.3% to 97.3% +/- 19.8% of the uninvolved arm (P < .001). Eighteen (90%) patients were satisfied with the surgical outcomes, while 2 patients changed their jobs because of decreased elbow function. No major complications occurred. CONCLUSION: The FETOR technique is an effective and safe method for the treatment of chronic recalcitrant medial epicondylitis. PMID- 24758783 TI - Long-term Subjective, Clinical, and Radiographic Outcome Evaluation of Meniscal Allograft Transplantation in the Knee. AB - BACKGROUND: Although meniscal allograft transplantation (MAT) has been performed for nearly 30 years, there are few long-term published studies of the technique. HYPOTHESIS/PURPOSE: The goal of this study was to report the long-term results of a patient cohort whose medium-term results have been reported and to evaluate whether the results are maintained in the long term or deteriorate after a certain period. The hypothesis was that the subjective, clinical, and radiographic results are consistent in the long term without significant deterioration. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty patients from the original cohort of 49 patients (50 MATs) who underwent MAT at least 9 years before this study were evaluated with the Knee injury and Osteoarthritis Outcome Score (KOOS); Lysholm, Tegner, and Short Form-36 scores; and a visual analog score for pain. A standardized clinical examination was performed to objectively evaluate knee-related symptoms. Standard weightbearing radiographs, including a full-leg standing radiograph, were performed to evaluate joint space narrowing and any progression of osteoarthritis and malalignment. These results, at a mean follow-up time of 12 years and 8 months (152 months; range, 112-216 months), were compared with the preoperative data and the outcome results at medium-term follow-up (mean, 8 years and 9 months). RESULTS: Of the original 49 patients, 6 (12.2%) required conversion to a total knee arthroplasty during the study period and were considered failures, and 17 (34.7%) required a second surgical procedure during the study period. Excluding the 6 total knee arthroplasty cases, 90% of patients reported being very satisfied or satisfied and would undergo the procedure again. Only 1 patient reported not wanting to undergo the procedure again. Results of the visual analog score, KOOS and all KOOS subscales, Lysholm, and Short Form-36 all showed a statistically significant improvement at estimated follow-up periods of 7.5 and 12.5 years compared with preoperative scores. There was no statistically significant difference for these scores between 7.5 and 12.5 years postoperatively. Despite the improvement in outcome scores, the Tegner activity level score remained unchanged during the entire follow-up period. Regarding radiographic outcomes, there was a progressive increase in the Kellgren-Lawrence rating over the study period. There was a statistically significant (P = .0208) progressive joint space narrowing between estimates at the 7.5-year (5.45 mm) and 12.5-year (4.95 mm) follow-up. However, there was no statistically significant (P = .6724) difference in absolute value of alignment deviation from the 0 degrees mechanical axis between 7.5 years (2.32 degrees ) and 12.5 years (2.51 degrees ) postoperatively. There was no difference between medial and lateral transplants. CONCLUSION: Despite an increase in joint space narrowing, MAT resulted in significant improvements in pain and functional outcomes over the study period. There was no change in these improvements between the medium- and long-term follow-up period. This study confirms the good and consistent results found in the literature concerning satisfaction, pain resolution, and functional scores at long-term follow-up. PMID- 24758786 TI - Worldwide research productivity of paracetamol (acetaminophen) poisoning: a bibliometric analysis (2003-2012). AB - PURPOSE: There is a lack of data concerning the evaluation of scientific research productivity in paracetamol poisoning from the world. The purposes of this study were to analyse the worldwide research output related to paracetamol poisoning and to examine the authorship pattern and the citations retrieved from the Scopus database for over a decade. METHODS: Data were searched for documents with specific words regarding paracetamol poisoning as 'keywords' in the title or/and abstract. Scientific output was evaluated based on a methodology developed and used in other bibliometric studies. Research productivity was adjusted to the national population and nominal gross domestic product (GDP) per capita. RESULTS: There were 1721 publications that met the criteria during study period from the world. All retrieved documents were published from 72 countries. The largest number of articles related to paracetamol poisoning was from the United States (US; 30.39%), followed by India (10.75%) and the United Kingdom (UK; 9.36%). The total number of citations at the time of data analysis was 21,109, with an average of 12.3 citations per each documents and median (interquartile range) of 4 (1-14). The h-index of the retrieved documents was 57. After adjusting for economy and population power, India (124.2), Nigeria (18.6) and the US (10.5) had the highest research productivity. Countries with large economies, such as the UK, Australia, Japan, China and France, tended to rank relatively low after adjustment for GDP over the entire study period. CONCLUSION: Our study demonstrates evidence that research productivity related to paracetamol poisoning has increased rapidly during the recent years. The US obviously dominated in research productivity. However, certain smaller country such as Nigeria has high scientific output relative to their population size and GDP. A highly noticeable increase in the contributions of Asia-Pacific and Middle East regions to scientific literature related to paracetamol poisoning was also observed. PMID- 24758787 TI - Three new quill mite species of the genus Neoaulonastus Skoracki (Acari: Syringophilidae) parasitizing passerines in Tanzania. AB - Three new species of the genus Neoaulonastus Skoracki, 2004 found inside the quills of the body feathers are described: N. tanzanicus sp. nov. from Euplectes axillaris (Smith) (Passeriformes: Ploceidae), N. quelea sp. nov. from Quelea quelea Linnaeus (Ploceidae) and N. granatina sp. nov. from Granatina ianthinogaster Reichenow (Estrildidae). All avian hosts were captured in Tanzania. Key to Neoaulonastus species is proposed. PMID- 24758785 TI - Can anisodamine be a potential substitute for high-dose atropine in cases of organophosphate poisoning? AB - A case of organophosphate (OP) poisoning was admitted to the emergency room. The patient accepted treatment with pralidoxime (PAM), atropine, and supporting therapy. It was observed that even after 22 h after treatment, 960 mg of atropine was not enough for the patient to be atropinized. However, a 160-mg follow-up treatment of anisodamine was quite enough for atropinization after 4 h. As a case report, more studies are required before any definite conclusion can be reached regarding the use of anisodamine as a potential substitute for high-dose atropine in cases of OP poisoning. PMID- 24758788 TI - Review of Madagascaran Agalliini (Hemiptera: Cicadellidae: Megophthalminae) with descriptions of a new genus and six new species. AB - Studies on the Agalliini leafhoppers collected from the Terrestrial Arthropods of Madagascar inventory project of the California Academy of Sciences, resulted in the discovery of one new genus Agallidwipa gen. nov. (type-species: A. biramosa sp. nov.) with three new species, A. biramosa sp. nov., A. bispinosa sp. nov. and A. webbi sp. nov. and three new species of the genus Igerna Kirkaldy, I. delta sp. nov., I. flavocosta sp. nov. and I. malagasica sp. nov. Two new combinations proposed are Agallidwipa pauliana (Evans) comb. nov. (from genus Agalliana Oman) and Igerna neosa (Webb) comb. nov. (from genus Stonasla White), a species previously recorded from Aldabra Islands. A previous record of Igerna bimaculicollis (Stal) from Madagascar is shown most likely to be a case of misidentification. All the taxa are described and illustrated. Keys to species of Agalliini from Madagascar are included along with notes on the distinction between Agalliana and Agallidwipa. PMID- 24758789 TI - Preimaginal stages of Triplectides misionensis Holzenthal and Triplectides gracilis (Burmeister) (Trichoptera: Leptoceridae: Triplectidinae), with notes on the cases occupied by these species. AB - The larvae, pupae and cases of Triplectides misionensis Holzenthal and T. gracilis (Burmeister) are described from specimens collected in protected areas from northeastern Argentina. The larvae are easily differentiated by the coloration of the cephalic capsule, shape of the ventral apotome and submentum, anterior border of the pronotum, and coloration of the legs, among other characters, while the pupae can be recognized by the chaetotaxy of the head. The larvae occupy empty cases of Grumicha grumicha Valot and Nectopsyche gemma (Muller), as well as hollow twigs. Triplectides misionensis is found almost exclusively in cases of G. grumicha while T. gracilis prefers twigs of different sizes. PMID- 24758790 TI - Contribution to the knowledge on the Oriental genus Perittopus Fieber, 1861 (Hemiptera: Heteroptera: Veliidae) with descriptions of four new species from China and Thailand. AB - Five species of the genus Perittopus Fieber, 1861 from China and Thailand are treated in this paper including four new species: P. crinalis sp. nov., P. falciformis sp. nov., and P. yunnanensis sp. nov. are from Yunnan Province, China; and P. zhengi sp. nov. from Chiang Mai, Thailand. The morphological descriptions are given for all the treated species. The photographs and the drawings of female habitus and male and female diagnostics are provided. A key to these five species is provided. The discussion on the identity of P. asiaticus Zettel, 2001 is given. PMID- 24758791 TI - Notes on southern Africa Jerusalem crickets (Orthoptera: Stenopelmatidae: Sia). AB - The Old World Jerusalem cricket (JC) subfamily Siinae contains one genus, Sia, with two subgenera: Sia (Sia) with two fully winged species from southeast Asia, and Sia (Maxentius) with four wingless species from southern Africa. Because there is a dearth of published data about the behavior and biology of these insects, we present new field and laboratory research on southern African Sia (Maxentius), gather museum and literature information, and present guidelines for collecting and rearing specimens. While we make no taxonomic decisions, this review should be useful for future studies, including a needed taxonomic revision. We also compare results from these southern African JCs with recent investigations on related New World taxa, where fascinating biological traits and extensive cryptic biodiversity have been uncovered. DNA analysis reveals that these Old and New World JCs are polyphyletic. PMID- 24758792 TI - A new species of the genus Gracixalus (Amphibia: Anura: Rhacophoridae) from Southern Guangxi, China. AB - A new species of the genus Gracixalus is described from Nonggang National Nature Reserve, based on eleven specimens from evergreen karst forests in Sino Vietnamese border region of southern China. The new species, Gracixalus nonggan gensis sp. nov., is medium sized species of Gracixalus that can be distinguished from its congeners by a combination of the following characters: SVL ranging from 29.9-35.3 mm in males and 33.6-38.0 mm in females; vomerine teeth absent; distinct tympanum as wide as the disc of finger III; the lower part of the tympanum with many small tubercles; tibiotarsal articulation reaching the tip of the snout; dorsum smooth yellowish-olive in life with a wide, dark-green irregular mark; throat, chest and belly white with light grey-blue tint and brown marbling; broad, dark olive, transverse stripes on limbs; finger webbing absent, toes one-third webbed; male with internal subgular vocal sac. Based on a 16S ribosomal RNA mitochondrial gene fragment, G. nonggangensis sp. nov. forms a monophyletic group embedded within the genus Gracixalus. PMID- 24758793 TI - Phenotypic variation of Leptodactylus cupreus Caramaschi, Sao-Pedro and Feio, 2008 (Anura, Leptodactylidae). AB - This study describes for the first time the female of Leptodactylus cupreus and provides new information concerning its geographical distribution, male's morphology and bioacustics. Leptodactylus cupreus, a poorly known species from the Brazilian Atlantic Forest, was originally allocated in the L. mystaceus complex of the L. fuscus species group. Based on morphological observations, we infer that L. cupreus should be in fact related to L. mystacinus, a species that, although assigned to the L. fuscus species group, is not assigned to the L. mystaceus complex. Therefore, we comment the phylogenetic relationships concerning L. cupreus, L. mystaceus and L. mystacinus. PMID- 24758794 TI - Molecular characterization of Haemoproteus sacharovi (Haemosporida, Haemoproteidae), a common parasite of columbiform birds, with remarks on classification of haemoproteids of doves and pigeons. AB - Haemoproteus (Haemosporida, Haemoproteidae) is the largest genus of avian haemosporidian parasites, some species of which cause lethal diseases in birds. Subgenera Parahaemoproteus and Haemoproteus are usually accepted in this genus; these parasites are transmitted by biting midges (Ceratopogonidae) and hippoboscid flies (Hippoboscidae), respectively. As of yet, species of Parahaemoproteus have not been reported to infect doves and pigeons (Columbiformes), parasites of these birds have not been reported to be transmitted by biting midges (Ceratopogonidae). Applying microscopy and PCR based methods, we identified mitochondrial cytochrome b (cyt b) sequences of Haemoproteus sacharovi, a wide-spread parasite of doves and pigeons. Phylogenetic relationships of dove haemoproteids, which traditionally have been classified in the subgenus Haemoproteus, showed that H. sacharovi and H. turtur, common parasites of doves, branch in the clade with Parahaemoproteus species, indicating that these haemoproteids may belong to this subgenus and are likely transmitted by biting midges. This study provides barcodes for H. sacharovi, clarifies the taxonomic positions of H. sacharovi and H. turtur, and indicates directions for development of classification of avian haemoproteid species. Our analysis shows that the current subgeneric classification of avian haemoproteids is generally effective, but the position of some species may need to be revised. PMID- 24758795 TI - Cercyon hungaricus, a new junior subjective synonym of C. bononiensis (Coleoptera: Hydrophilidae). AB - Cercyon bononiensis Chiesa, 1964 was described from two specimens collected in northern Italy in 1924-1925. For some time, these specimens were identified as C. inquinatus Wollaston, 1854. Only 40 years later, having examined the type of the latter species, Chiesa (1964) realized that the two specimens belonged to an undescribed species that he then described as Cercyon bononiensis. Based on the chagrined elytra mentioned in the original description, C. bononiensis has been placed in the Cercyon tristis group by subsequent authors. Recently, we examined a small number of Cercyon specimens from northern Italy and surprisingly found two specimens of C. hungaricus Endrody-Younga, 1967, an easily recognizable member of the C. tristis group which was previously considered a Pannonian endemic by Fikacek et al. (2009) but was recently also found in northern Germany (Base 2010). The presence of this unusual species led us to question whether C. hungaricus might be conspecific with C. bononiensis. This was subsequently confirmed by the study of the types of both species. Here, we provide a summary of our studies and synonymize C. hungaricus with C. bononiensis. Examined specimens are deposited in the following collections: Hungarian Natural History Museum, Budapest, Hungary (HNHM), Museo Civico di Storia Naturale Milano, Italy (MSNM), collection of S. Rocchi at the Museo di Storia Naturale dell'Universita di Firenze, Sezione di Zoologia "La Specola" (CRO). PMID- 24758796 TI - Miyakella nom. nov., a replacement name for Miyakea Manning, 1995, (Crustacea: Stomatopoda: Squillidae), preoccupied by Miyakea Marumo, 1933 (Insecta: Lepidoptera: Crambidae). PMID- 24758797 TI - The mesothoracic wings of Afrotropical Scutelleridae (Hemiptera: Heteroptera): morphology and taxonomic significance. AB - Mesothoracic wings have been examined and compared in 32 species representing 20 genera of Afrotropical Scutelleridae. Morphological characters of the corium are described. Three main types of mesothoracic wing venation patterns can be recognized. The taxonomic significance of forewing characters in Scutelleridae is briefly discussed. PMID- 24758798 TI - A new acaremyid rodent (Hystricognathi: Octodontoidea) from the middle Miocene of Patagonia (South America) and considerations on the early evolution of Octodontoidea. AB - Octodontoidea is the most speciose and ecologically diverse superfamily of caviomorph rodents. The systematic relationships of modern octodontoids is moderately accepted, however, the relationships of fossils (from the Eocene? middle Miocene) are not clear. In recent years the hypothesis of a complex early evolution of the superfamily has emerged, with "basal octodontoids" representing different evolutionary lineages. The extinct family Acaremyidae may represent one such lineage, consisting of the genera Acaremys, Sciamys, Galileomys, and variably Platypittamys. In this work we describe a new octodontoid rodent recorded in post-Colloncuran? levels exposed at the locality of El Petiso, Northwest of Chubut Province, Argentina. Based on a systematic analysis of dental characters, we conclude that the new specimens correspond to a new species of Sciamys. Additionally, if the post-Colloncuran age for El Petiso is verified, the new species will extend the temporal range of the family Acaremyidae until, at least, the late middle Miocene, as well as the temporal range for the genus Sciamys from the Santacrucian SALMA. Our phylogenetic analyses corroborate the position of the new species as a member of Sciamys, and confirm that Acaremyidae represents an extinct family from Patagonian South America that lived until the middle Miocene. Massoiamys obliquus qualifies as morphological ancestor that pre announces the octodontiform tooth pattern of octodontids. Thus, the octodontiform tooth pattern appears at least twice within the superfamily Octodontoidea. PMID- 24758799 TI - A new species of the blind cave gudgeon Milyeringa (Pisces: Gobioidei, Eleotridae) from Barrow Island, Western Australia, with a redescription of M. veritas Whitley. AB - A new species of the eyeless eleotrid genus Milyeringa is described from wells sunk on Barrow Island, Western Australia. Milyeringa justitia n. sp. is the third species of the genus to be named. Morphological data and cytochrome c oxidase subunit I (COI) DNA sequence data from a wide sample of localities at which the genus occurs was used to evaluate relationships and species limits. Milyeringa veritas is redescribed, and M. brooksi is synonymised with M. veritas. The unique form and ecology of these fishes, plus the threats to their survival, warrants immediate and continuing attention in management. PMID- 24758800 TI - Cyrtodactylus dati, a new forest dwelling Bent-toed Gecko (Squamata: Gekkonidae) from southern Vietnam. AB - A new species of Bent-toed Gecko, Cyrtodactylus dati sp. nov. is described from the secondary evergreen forests of Bu Dop District, Binh Phuoc Province, Vietnam. It differs from all other species of Indochinese and Thai-Malay Cyrtodactylus by having a maximum SVL of 70.1 mm (n=6); no distinct dark blotches on the head in adults; no continuous nuchal loop; a blotched dorsal pattern; 17-19 interorbital scales across the frontal bone; 23-26 scales in a straight line between eye and nostril; 42-48 rows of ventral scales between ventrolateral folds; 20-22 irregular, longitudinal rows of keeled tubercles at midbody between the ventrolateral folds; a series of five or six precloacal pores medially interrupted by one poreless scale in males; three or four femoral pores on each thigh in males; 4-7 enlarged scales beneath thighs; 12-13 subdigital lamellae on first toe; 18-19 subdigital lamellae on fourth toe; and small subcaudal scales. PMID- 24758801 TI - Identity of Eumenodora encrypta Meyrick, a cryptic Australian moth (Lepidoptera:Gelechioidea). AB - A hitherto neglected gelechioid moth genus Eumenodora Meyrick (Gelechioidea: Elachistidae; Cosmopterigidae; Xyloryctidae) is redescribed. The genus, originally assigned to the Elachistidae and later transferred to the Cosmopterigidae, is monotypic. The single constituent species, E. encrypta Meyrick, 1906, has long been known only from the holotype, collected in Brisbane, Queensland (Australia). The specimen lacks its abdomen. The genus is characterized and the single recognized species redescribed based on recently collected adult males and a female. Evidence from morphology, supported by DNA sequences, is provided to support the placement of the taxon in the Hierodoris group of the Xyloryctidae, in spite of its atypical external appearance. PMID- 24758802 TI - A new species of Bachia Gray, 1845 (Squamata: Gymnophthalmidae) from the Eastern Brazilian Cerrado, and data on its ecology, physiology and behavior. AB - A new species of Bachia of the bresslaui group, Bachia geralista sp. nov., is described from Planalto dos Gerais, an old and partially dissected plateau extending along the Cerrados of Bahia, Minas Gerais and Tocantins states, Brazil. The new species is morphologically similar to B. bresslaui, with which it has been confused; however head scalation resembles other species from sandy spots within the Cerrado (B. psamophila and B. oxyrhina). Like in B. psamophila and B. oxyrhina, the shovel-shaped snout of the new species is highly prominent, a typical trait of psammophilous habits in other gymnophthalmids. The examination of specimens of B. bresslaui from several populations within the Cerrado revealed great variation among localities, leading to the reidentification of a specimen from Utiariti, Mato Grosso, previously referred to in the literature as the second record of B. bresslaui, as the recently described B. didactyla, suggesting that cryptic diversity might remain still undiscovered within this genus in the Cerrado. Despite occurring in a relatively open Cerrado, thermal physiology of Bachia geralista sp. nov. restricts its occurrence to shaded microhabitats within this habitat. PMID- 24758803 TI - Remarks on the sexual dimorphism and taxonomy of Fabia Dana, 1851 (Crustacea, Brachyura, Pinnotheridae). AB - A study of the holotype of Pinnotheres hemphilli Rathbun, 1918, revealed it is an early post-hard female, not a male, of Fabia Dana, 1851. The morphology of Pinnotheres emiliai Melo, 1971 (based on a male specimen) and Fabia insularis Melo, 1971 (based on a female specimen) confirm earlier hypothesis that they belong to a sexually dimorphic species that should be known as F. emiliai (Melo, 1971). The redescription of the holotype of Fabia felderi Gore, 1986, supports its generic assignment and its relationship with F. emiliai. The implication of sexual dimorphism and intersexes in the taxonomy of Fabia is discussed. PMID- 24758804 TI - Checklist of lizards and amphisbaenians of Argentina: an update. AB - We update the list of lizards of Argentina, reporting a total of 261 species from the country, arranged in 27 genera and 10 families. Introduced species and dubious or erroneous records are discussed. Taxonomic, nomenclatural and distributional comments are provided when required. Considering species of probable occurrence in the country (known to occur in Bolivia, Brazil, Chile and Paraguay at localities very close to the Argentinean border) and still undescribed taxa, we estimate that the total number of species in Argentina could exceed 300 in the next few years. PMID- 24758806 TI - A review of the Japanese Cybocephalidae (Coleoptera: Cucujoidea). AB - The Cybocephalidae of Japan is taxonomically treated. The following four species are recognized: Cybocephalus (Cybocephalus) nipponicus Endrody-Younga, 1971, C. (C.) politissimus Reitter, 1898, C. (C.) chlorocapitis sp. nov., and Pastillus eminentithorax sp. nov. Also, species of the genus Pastillus are first recorded from the Palaearctic Region, and C. (C.) politissimus is first recorded from Japan. Cybocephalus (C.) flavocapitis Smith 2007 is newly designated as a junior synonym of C. (C.) politissimus Reitter, syn. nov. All species are described or redescribed. Dorsal habitus images, illustrations of male and female genitalia, and other important diagnostic characters are provided for all species. A key for identification of all Japanese taxa is also given. PMID- 24758805 TI - Phylogenetic relationships and description of a new upland species of Bent-toed Gecko (Cyrtodactylus Gray, 1827) of the C. sworderi complex from northeastern Peninsular Malaysia. AB - Molecular and morphological analyses indicate that a new upland species of the Cyrtodactylus sworderi complex, C. tebuensis sp. nov. from Gunung Tebu, Terengganu, Malaysia is most closely related to C. sworderi and together they form the sister lineage to C. quadrivirgatus. Cyrtodactylus tebuensis sp. nov. is differentiated from all other species of Sundaland Cyrtodactylus on the basis of having the unique combination of large, conical, keeled body tubercles; tubercles present on top of head, occiput, nape, and limbs, and extending posteriorly beyond base of tail; 43-51 ventral scales; no transversely enlarged, median subcaudal scales; proximal, subdigital lamellae transversely expanded; 17-21 subdigital lamellae on fourth toe; an abrupt transition between posterior and ventral femoral scales; enlarged femoral scales; no femoral or precloacal pores; no precloacal groove; body bearing four wide, bold, dark brown stripes (lateral stripe on each flank and a pair of paravertebral stripes); and a pairwise sequence divergence of 13.0% from its closest relative C. sworderi based on the mitochondrial gene ND2. Cyrtodactylus tebuensis sp. nov. is the first endemic upland species of gekkonid from northeastern Peninsular Malaysia and underscores the necessity for additional field work in all upland systems. PMID- 24758807 TI - On the enigmatic Heterostomus curvipalpis Bigot, 1857, with a description of the pupa (Diptera, Brachycera). AB - The previously unknown pupa of Heterostomus curvipalpis Bigot is described. The morphology of the pupa of Heterostomus is compared with the pupae of Xylophagomorpha, Tabanomorpha and Stratiomyomorpha families, based on five characters, and its phylogenetic position is discussed. Currently placed in Xylophagidae, we conclude that the pupa of Heterostomus shares most characters with the pupae of Pelecorhynchidae. PMID- 24758808 TI - A new species and new records of Tachygerris Drake, 1957 (Hemiptera: Heteroptera: Gerridae) from Colombia. AB - A new species of the genus Tachygerris Drake, 1957 (Gerrinae: Tachygerrini) is described from the Amazon region of Colombia. Tachygerris tucanensis sp. nov. is differentiated from other species of the genus by features of the male genitalia and of last abdominal sternite of female. New records of T. adamsoni, T. celocis, and T. opacus are also presented. PMID- 24758809 TI - The advertisement call of the poorly known Leptodactylus tapiti (Anura, Leptodactylidae). PMID- 24758810 TI - Two new species of the genus Pseudostenophylax Martynov (Trichoptera: Limnephilidae) from the Indian Himalaya. AB - Two new species of the genus Pseudostenophylax Martynov 1909 from the Indian Himalaya are described and illustrated. These include P. himachalica sp. n. from Sathrundi (Himachal Pradesh) and P. gulmargensis sp. n. from Gulmarg (Jammu & Kashmir), both belonging to the P. aniketos Group. With these two additions, Pseudostenophylax is now represented in India by 25 species. PMID- 24758811 TI - Ambohitantelya yuripopovi gen. nov. et sp. nov., a new apterous Mezirinae from Madagascar (Hemiptera: Heteroptera: Aradidae) with unique metathoracic evaporatoria. AB - In addition to the ten genera of apterous Mezirinae recorded to date from Madagascar, a new genus Ambohitanlelya gen. nov. with uniquely formed metathoracic evaporatoria is erected for the A. yuripopovi sp. nov., which is described and illustrated. PMID- 24758812 TI - The authorship and type locality of Melanocorypha leucoptera (Aves: Alaudidae). PMID- 24758813 TI - New species of Central American Rhopalothrix Mayr, 1870 (Hymenoptera, Formicidae). AB - The ant genus Rhopalothrix is a rare inhabitant of wet forest leaf litter and soil. We propose a monophyletic R. isthmica clade that is restricted to the Neotropics, contains most of the species in the genus, and has its center of abundance and diversity in Central America. Thirteen species are recognized in the R. isthmica clade, of which eight are described as new and three are redescribed. A key to species in the R. isthmica clade is provided, and the following eight new species are described: R. andersoni Longino & Boudinot, sp. nov., R. apertor Longino & Boudinot, sp. nov., R. atitlanica Longino & Boudinot, sp. nov., R. megisthmica Longino & Boudinot, sp. nov., R. nubilosa Longino & Boudinot, sp. nov., R. subspatulata Longino & Boudinot, sp. nov., R. therion Longino & Boudinot, sp. nov., and R. triumphalis Longino & Boudinot, sp. nov.. Queens are newly associated with workers for three Central American species. New synonymy is proposed for Rhopalothrix plaumanni Brown & Kempf, 1960 = R. acutipilis Kempf, 1962, syn. nov. PMID- 24758814 TI - Family-group names in the scale insects (Hemiptera: Sternorrhyncha: Coccoidea)--a supplement. AB - Williams (1969) published a list of the family-group names in the Coccoidea (scale insects) recognised at that time. The present paper supplements this earlier list and includes all nominal genera that have had family-group names based on them, including those in the earlier paper, in case it is not readily available to some workers. Nominal genera and their family-group names are listed alphabetically in catalogue form. There are now 49 families generally recognised in the scale insects, of which 16 are only known as fossils. Furthermore, 180 nominal genera have now had family-group names based on them. As stated in the 1969 list, all categories in the family group are deemed to be of coordinate status in nomenclature. PMID- 24758815 TI - A new species of the Pristimantis orestes group (Amphibia: Strabomantidae) from the high Andes of Ecuador, Reserva Mazar. AB - We describe a new Pristimantis from La Libertad and Rumiloma, Reserva Mazar, Andes of Southeastern Ecuador, at elevations between 2895-3415 m. This species is assigned to the P. orestes group, from whose members it differs by its small body size (adult males <= 18.1 mm; adult females <= 23.7 mm), usually reticulated ventral pattern, and visible tympanum. The vocalization of the new species consists of a series of calls; each call is composed by a pulsed, non-modulated note in frequency, and with a dominant frequency of 3122-3171 Hz. A molecular phylogeny based on a fragment of the mitochondrial gene 12S shows that the new species is sister to Pristimantis simonbolivari. PMID- 24758816 TI - A new species of the spider genus Eridantes Crosby & Bishop from the southwestern United States and mainland Mexico with a revised diagnosis of the genus (Araneae, Linyphiidae, Erigoninae). AB - A new Eridantes Crosby & Bishop (1933) species, E. diodontos n. sp., discovered in the United States in the state of Arizona and in Mexico in the state and city of San Luis Potosi, is described and illustrated. Both males and females are very similar to the respective sexes of the type species, E. erigonoides (Emerton 1882), but can be distinguished by the higher cephalic lobe, position of the prosomal pit, and the form of the palpal tibia in the male and by the convolution of the m-shaped carinae of the epigynum in the female. Comparative illustrations of the male bulb of E. erigonoides and a distribution map of the three known species are also provided. Pending formal taxonomic revision of Eridantes, a revised diagnosis and a brief description of the genus are presented based on examination of specimens of the type species and of the new species described here. The mesal rather than ectal position of the paracymbium and the broadly divided dorsal and ventral sclerites of the largely membranous radix are proposed synapomorphies that distinguish Eridantes from all similar genera. PMID- 24758817 TI - On the genus Tenagogonus Stal (Hemiptera: Heteroptera: Gerridae) from India with a description of a new species. AB - Tenagogonus venkataramani sp. nov. from Great Nicobar Biosphere Reserve (GNBR), Andaman and Nicobar Islands, India, is described and compared with allied species. Morphological notes on T. ceylonensis Hungerford and Matsuda, 1962, and T. nicobarensis Andersen, 1964, known from India, are presented along with distribution maps of these three Indian species. PMID- 24758818 TI - Two new species of the ladybird beetle Hong Slipinski from Chile (Coleoptera: Coccinellidae: Microweiseinae). AB - The ladybird beetle genus Hong Slipinski was previously known from a single female specimen from a subtropical forest in South East Queensland, Australia. Hong guerreroi sp. nov. and H. slipinskii sp. nov. from a temperate forests of Central and Southern Chile are described and illustrated. A key for the species of the genus and complementary characters, including the first description of males, are provided. PMID- 24758819 TI - Biodiversity discovery program Bush Blitz yields a new species of goblin spider, Cavisternum attenboroughi (Araneae: Oonopidae), from the Northern Territory. PMID- 24758820 TI - New species of Australian Pseudopallene (Pycnogonida: Callipallenidae) based on live colouration, morphology and DNA. AB - Callipallenid sea spiders are commonly found in southern Australian waters. The genera Pseudopallene and Stylopallene are frequent epibionts of arborescent bryozoan colonies of Orthoscuticella spp. and Amathia spp. Based on external morphology, colouration patterns, and sequence divergence of nuclear and mitochondrial markers, we differentiate species of Pseudopallene and Stylopallene from southeast Tasmania, New South Wales and Victoria. In this paper we describe five species new to science: P. tasmania, P. gracilis, P. constricta, P. flava and P. harrisi, and propose the 'variabilis'- complex, which is yet to be resolved based on additional material. Also, two species previously known from Southern Australia are reported as new records for Tasmania. The use of molecular data in resolving species identities of Australian Pycnogonida appears crucial, particularly in the understanding of the amazing, yet undiscovered diversity of brightly colourful callipallenid species. The genus Pseudopallene previously known from 20 species distributed in both southern and northern hemispheres now includes 14 Australian endemic species and at least one species complex yet to be resolved. PMID- 24758821 TI - Annotated checklist of the grasshoppers and crickets (Orthoptera) of the Czech Republic. AB - A checklist is presented of the Orthoptera of the Czech Republic. Based on the critical revision of published data and previous lists of species, which often contained only general or questionable data and which often inaccurately cited each other, we found 96 species of Orthoptera belonging to the fauna of the Czech Republic. We emphasize those changes that are based on comparison with previous checklists. We provide information on missing, unclear, and extinct species and on newly detected species, and we confirm the status of species that have been missing for a long time (Leptophyes boscii, Polysarcus denticauda, Ruspolia nitidula, Eumodicogryllus bordigalensis, Tetrix bolivari, Mecostethus parapleurus). We also note those species for which only several individuals have been detected (Pteronemobius heydenii) or those survived only at a single locality (Platycleis montana, Aiolopus thalassinus, Dociostaurus brevicollis, Omocestus petraeus) or at two localities (Poecilimon intermedius, Platycleis veyseli, Pseudopodisma nagyi). Phaneroptera nana is recorded as new for Bohemia. PMID- 24758822 TI - A review of the rudderfish genus Tubbia (Stromateoidei: Centrolophidae) with the description of a new species from the Southern Hemisphere. AB - A combination of morphological and molecular techniques was used to confirm the existence of a second species of the monotypic centrolophid genus Tubbia. Adults of the seamount rudderfish, T. stewarti sp. nov., which reaches about 56 cm SL, is mesopelagic at depths of 525-1438 m in the temperate waters of the Southern Hemisphere. It has a confirmed distribution off Australia and New Zealand where it occurs sympatrically with the wider ranging T. tasmanica Whitley. Like most other members of the group, juveniles live in the epipelagic zone where they have been taken at 30-50 m depth. The new species has a more robust head, more slender body, more flattened interorbit, longer jaws, denser head pores, relatively larger eyes and nostrils, narrower caudal peduncle and more vertebral centra than T. tasmanica, and also differs subtly in some morphometric ratios. A rediagnosis of T. tasmanica is also provided. PMID- 24758823 TI - On the ornithological collection of Friedrich Sellow in Brazil (1814-1831), with some considerations about the provenance of his specimens. AB - The Prussian naturalist Friedrich Sellow (1789-1831) traveled through Brazil, Uruguay and Argentina between 1814 and 1831 gathering numerous zoological and botanical specimens. Despite the effort spent in those countries, the ornithological collection assembled by Sellow did not receive adequate care after it had been deposited in the Zoologische Museum in Berlin, thus compromising its integrity. In the present article we discuss the treatment given by Lichtenstein and by Sellow to this bird material, with special focus on some cases in which incorrect label information on Sellow's specimens led to faulty conclusions on the zoogeography of South American birds. PMID- 24758824 TI - Ascidia subterranea sp. nov. (Phlebobranchia: Ascidiidae), a new tunicate belonging to the A. sydneiensis Stimpson, 1855 group, found as burrow associate of Axiopsis serratifrons A. Milne-Edwards, 1873 (Decapoda: Axiidae) on Derawan Island, Indonesia. AB - A new tunicate, Ascidia subterranea sp. nov., was found in burrows of the axiid crustacean Axiopsis serratifrons on Derawan Island, Indonesia. It differs from other ascidians in its habitat as well as numerous morphological peculiarities which are described in detail. The shrimp Rostronia stylirostris Holthuis, 1952 was found inside A. subterranea sp. nov., and 4 species of bivalves, 3 species of polychaetes, 1 gastropod, 1 polyplacophoran and 1 sponge species were found as burrow associates besides the ascidian. PMID- 24758825 TI - A new species of false spider crab of the genus Elamena H. Milne Edwards, 1837 (Crustacea: Decapoda: Brachyura: Hymenosomatidae), from Davao Gulf, Philippines. AB - A new species of hymenosomatid crab of the genus Elamena H. Milne Edwards, 1837, is described from the island of Samal, in the Davao Gulf, Mindanao, southern Philippines. Elamena samalensis sp. nov. belongs to the Elamena truncata species group and is most similar to E. simplidenta Ng & Chuang, 1996, in the general form of the carapace and in the presence of only one subdistal tooth on the ambulatory dactyli. It can be distinguished from this species, however, by its more projecting rostrum, relatively longer and more slender ambulatory legs, and by the pointed apex of the female pleotelson. PMID- 24758826 TI - Microgastrinae (Hymenoptera: Braconidae) of Reunion Island: a catalogue of the local species, including 18 new taxa and a key to species. AB - Microgastrine wasps (Hymenoptera: Braconidae) are primary parasitoids of Lepidoptera. Some of them parasitise major economic pests and have been largely used for biocontrol programs. We revise here the fauna of Reunion Island: 34 species were recorded, belonging to 13 genera. One genus and 18 species are newly described: Dodogaster gen. nov, Apanteles minatchy sp. nov., A. pashmina sp. nov., A. romei sp. nov., Cotesia xavieri sp. nov., Dolichogenidea ashoka sp. nov., D. broadi sp. nov., D. lumba sp. nov., D. uru sp. nov., D. villemantae sp. nov., Distatrix yunae sp. nov., Dodogaster grangeri sp. nov., Exoryza safranum sp. nov., Glyptapanteles chidra sp. nov., Nyereria ganges sp. nov., N. mayurus sp. nov., Parapanteles covino sp. nov., P. darignac sp. nov. and Wilkinsonellus narangahus sp. nov.. On the remaining 16 species, 12 are new distribution records. Finally, Glyptapanteles antsirabensis (Granger) comb. nov., G. ficus (Granger) comb. nov., G. subandinus (Blanchard) comb. nov., and Venanides curticornis (Granger) comb. nov. are reassigned from the traditionally defined Apanteles genus to these respective genera. A key to all genera and species is provided. PMID- 24758827 TI - Dialeurolonga re-defined (Hemiptera: Aleyrodidae): with a new genus and species from India, two new genera from Australia, and discussion of host-correlated puparial variation. AB - Aleuropositus Dubey gen. n., Australeurodes Dubey gen. n. and Septemaleurodes Dubey gen. n. are proposed with their respective type species as A. sinus Dubey sp. n. from India, D. operculobata Martin & Carver from Australia, and D. swainei Martin from Australia. A. sinus sp. n. is described from Kerala, India, illustrated with line drawings, microphotographs and SEM images. The puparia are asymmetric in taxonomic characters and shape, and variation in puparia associated with a single host is discussed. A generic diagnosis of Dialeurolonga is provided based on SEM study of the type species, D. elongata. Australian species placed in this genus have puparial characteristics that distinguish them from Afrotropical assemblages, and are here referred to two new genera. PMID- 24758828 TI - The feather mites (Acari, Astigmata) of the Violet-capped Woodnymph, Thalurania glaucopis (Gmelin) (Aves, Trochilidae), with descriptions of three new species. AB - Six feather mites of the Violet-capped Woodnymph, Thalurania glaucopis are herein reported: Allodectes sejugaspis sp. n., A. thaluraniae sp. n., Trochilodectes brevipenis sp. n., Toxerodectes biscutatus Park & Atyeo (Proctophyllodidae), and two unidentified species from the families Analgidae (Protalginae, genus Protalges) and Ptyssalgidae (genus Ptyssalges). These are the first feather mites to be reported from this host. PMID- 24758829 TI - New species of Mesenopsis Godman & Salvin, 1886 (Lepidoptera: Riodinidae: Symmachiini) from southeastern Brazil, with an illustrated key to the genus. AB - A new species, Mesenopsis jordana sp. nov., from southeastern Brazilian states of Minas Gerais, Rio de Janeiro, and Sao Paulo is described and a taxonomic dichotomous key for species of the genus Mesenopsis is provided. Additionally, mimetic models for species of Mesenopsis are suggested and a new distribution record for M. albivitta is provided. PMID- 24758830 TI - Redescription and taxonomic status of Paguristes weddellii (H. Milne Edwards) (Crustacea: Anomura: Paguroidea: Diogenidae) from the eastern Pacific. AB - The type and additional material of Paguristes weddellii (H. Milne Edwards, 1848) were examined. The species is redescribed and illustrated in details. Comparison of P. weddellii with the monotypic genus Tetralobistes Ayon-Parente & Hendrickx, 2010b, shows many similarities, principally in the armature of the distal margin of the male first pleopod and the shape of the telson, which in both cases feature a tetralobular posterior margin, a character considered unique among the Diogenidae. Consequently, Pagurus weddellii is transfered to the genus Tetralobistes. Paguristes hirtus Dana, 1851, a subjective junior synonym of Pagurus weddellii is removed from the synonymy based on lack of direct evidences. PMID- 24758831 TI - A new Frenguelliidae (Insecta: Odonata) from the early Eocene of Laguna del Hunco, Patagonia, Argentina. AB - The discovery of a new specimen of Frenguelliidae, attributed to the new species Frenguellia Argentina, is noteworthy for the knowledge of the diversity within this little-known family. PMID- 24758832 TI - A comparative study on collagen type I and hyaluronic acid dependent cell behavior for osteochondral tissue bioprinting. AB - Bioprinting is a promising technique for engineering composite tissues, such as osteochondral tissues. In this study, as a first step toward bioprinting-based osteochondral tissue regeneration, we systematically examined the behavior of chondrocytes and osteoblasts to hyaluronic acid (HA) and type I collagen (Col-1) hydrogels. First, we demonstrated that cells on hydrogels that were comprised of major native tissue extracellular matrix (ECM) components (i.e. chondrocytes on HA hydrogels and osteoblasts on Col-1 hydrogels) exhibited better proliferation and cell function than cells on non-native ECM hydrogels (i.e., chondrocytes on Col-1 hydrogels and osteoblasts on HA hydrogels). In addition, cells located near their native ECM hydrogels migrated towards them. Finally, we bioprinted three dimensional (3D) osteochondral tissue-mimetic structures composed of two compartments, osteoblast-encapsulated Col-1 hydrogels and chondrocyte encapsulated HA hydrogels, and found viability and functions of each cell type were well maintained within the 3D structures up to 14 days in vitro. These results suggest that with proper choice of hydrogel materials, bioprinting-based approaches can be successfully applied for osteochondral tissue regeneration. PMID- 24758834 TI - Oxygen octahedral distortions in LaMO3/SrTiO3 superlattices. AB - In this work we study the interfaces between the Mott insulator LaMnO3 (LMO) and the band insulator SrTiO3 (STO) in epitaxially grown superlattices with different thickness ratios and different transport and magnetic behaviors. Using atomic resolution electron energy-loss spectral imaging, we analyze simultaneously the structural and chemical properties of these interfaces. We find changes in the oxygen octahedral tilts within the LaMnO3 layers when the thickness ratio between the manganite and the titanate layers is varied. Superlattices with thick LMO and ultrathin STO layers present unexpected octahedral tilts in the STO, along with a small amount of oxygen vacancies. On the other hand, thick STO layers exhibit undistorted octahedra while the LMO layers present reduced O octahedral distortions near the interfaces. These findings are discussed in view of the transport and magnetic differences found in previous studies. PMID- 24758835 TI - Rolling Nagoya mouse strain (PROD-rol/rol) with classic piebald mutation. AB - Ataxic rolling Nagoya (PROD-rol/rol) mice, which carry a mutation in the alpha1 subunit of the Cav2.1 channel (Cacna1a) gene, were discovered in 1969. They show white spots on agouti coat and have a mutation in the piebald spotting (s) locus. However, mutation analysis of the s locus encoding the endothelin receptor type B (Ednrb) gene in PROD-rol/rol mice had not been performed. Here, we examined the genomic and mRNA sequences of the Ednrb gene in PROD-rol/rol and wild-type rolling Nagoya (PROD-s/s) and studied the expression patterns of Ednrb and Cacna1a genes in these mice in comparison with C57BL/6J mice. Polymerase chain reaction analyses revealed two silent nucleotide substitutions in the coding region and insertion of a retroposon-like element in intron 1 of the Ednrb gene. Expression analyses demonstrated similar localizations and levels of Ednrb and Cacna1a expression in the colon between PROD-rol/rol and PROD-s/s mice, but the expression levels of both genes were diminished compared with C57BL/6J mice. Microsatellite genotyping showed that at least particular regions of chromosome 14 proximal to the Ednrb locus of the PROD strain were derived from Japanese fancy piebald mice. These results indicated that PROD-rol/rol mice have two mutant genes, Ednrb and Cacna1a. As no PROD strain had an intact Ednrb gene, using congenic rolling mice would better serve to examine rolling Nagoya-type Cav2.1 channel dysfunctions. PMID- 24758836 TI - Decreased level of albumin in peripheral blood mononuclear cells of streptozotocin-induced diabetic rats. AB - We investigated the phenotypic level of albumin in peripheral blood mononuclear cells (PBMC) of streptozotocin (STZ)-induced diabetic rats. A specific reduction of albumin was identified by 2-dimensional electrophoresis and mass spectrometry. Decreased albumin content was also confirmed by immunoblotting and quantitative real-time PCR. Since albumin is a major and predominant antioxidant in plasma, the PBMC albumin may also contribute to their antioxidant activity. By measuring the amount of H2O2, lipid peroxidation and the redox form of glutathione, it was found that the production of the oxidative stress was elevated in STZ-diabetic rats compared to that of normal control. We suggest, therefore, that decreased albumin content may lead to the decreased antioxidant activity in the PBMC of type 1 diabetic rats. PMID- 24758839 TI - Universal bursty behaviour in human violent conflicts. AB - Understanding the mechanisms and processes underlying the dynamics of collective violence is of considerable current interest. Recent studies indicated the presence of robust patterns characterizing the size and timing of violent events in human conflicts. Since the size and timing of violent events arises as the result of a dynamical process, we explore the possibility of unifying these observations. By analyzing available catalogs on violent events in Iraq (2003 2005), Afghanistan (2008-2010) and Northern Ireland (1969-2001), we show that the inter-event time distributions (calculated for a range of minimum sizes) obeys approximately a simple scaling law which holds for more than three orders of magnitude. This robust pattern suggests a hierarchical organization in size and time providing a unified picture of the dynamics of violent conflicts. PMID- 24758837 TI - Non-viral adeno-associated virus-based platform for stable expression of antibody combination therapeutics. AB - Antibody combination therapeutics (ACTs) are polyvalent biopharmaceuticals that are uniquely suited for the control of complex diseases, including antibiotic resistant infectious diseases, autoimmune disorders and cancers. However, ACTs also represent a distinct manufacturing challenge because the independent manufacture and subsequent mixing of monoclonal antibodies quickly becomes cost prohibitive as more complex mixtures are envisioned. We have developed a virus free recombinant protein expression platform based on adeno-associated viral (AAV) elements that is capable of rapid and consistent production of complex antibody mixtures in a single batch format. Using both multiplexed immunoassays and cation exchange (CIEX) chromatography, cell culture supernatants generated using our system were assessed for stability of expression and ratios of the component antibodies over time. Cultures expressing combinations of three to ten antibodies maintained consistent expression levels and stable ratios of component antibodies for at least 60 days. Cultures showed remarkable reproducibility following cell banking, and AAV-based cultures showed higher stability and productivity than non-AAV based cultures. Therefore, this non-viral AAV-based expression platform represents a predictable, reproducible, quick and cost effective method to manufacture or quickly produce for preclinical testing recombinant antibody combination therapies and other recombinant protein mixtures. PMID- 24758842 TI - [Strengths and future of the Revista Medica del Instituto Mexicano del Seguro Social]. AB - The journals of medicine arose as a communication tool more than 200 years ago. At the beginning, their nature was local; later, their aim was to spread medical information along the nation; and, finally, they sought to reach the world distribution. The Revista Medica del Instituto Mexicano del Seguro Social was published for the first time 52 years ago, and it has walked its way from local to international distribution. This journal has 23 000 subscribers, it is included in Medline and it reached a 0.112 SCImago Journal Rank in 2012. Its website receives around 200 000 visits monthly and 45 % are foreign visits. In the future, the peer review system is going to be strengthened, and the journal is going to offer audio, video, and applications to reinforce interactive participation between authors, readers in order to reach modernity and draw young new attention. PMID- 24758841 TI - Prolactin receptor in regulation of neuronal excitability and channels. AB - Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by regulating receptor potential thresholds, neuronal excitability and/or neurotransmission efficiency. PRL also influences neuronal functions via activation of certain neurons, resulting in Ca(2+) influx and/or electrical firing with subsequent release of neurotransmitters. Although PRL was identified almost a century ago, very little specific information is known about how PRL regulates neuronal functions. Nevertheless, important initial steps have recently been made including the identification of PRL-induced transient signaling pathways in neurons and the modulation of neuronal transient receptor potential (TRP) and Ca(2+) -dependent K(+) channels by PRL. In this review, we summarize current knowledge and recent progress in understanding the regulation of neuronal excitability and channels by PRL. PMID- 24758843 TI - [The golden age of rheumatoid arthritis treatment]. AB - Today, we enjoy the golden age of rheumatology. In the 1970s, the paradigm for treating rheumatoid arthritis consisted in a pyramid. In the decade of the 1980s, and shortly after began a revolution in the understanding and treatment of rheumatic diseases. Methotrexate and tumor necrosis factor-blockers came on the scene. PMID- 24758844 TI - [In regards to the letter "Excessive use of foreign references"]. PMID- 24758840 TI - Mechanisms of activation of receptor tyrosine kinases: monomers or dimers. AB - Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR) family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights. PMID- 24758845 TI - [Comments to the paper "Historical notes about the scientific research in the Instituto Mexicano del Seguro Social"]. PMID- 24758846 TI - [Comments concerning "Chi squared test, from the expected to the observed"]. PMID- 24758847 TI - [Comments in regards to "Risk factors associated to the epidemic outbreak of dengue virus infection"]. PMID- 24758848 TI - [What is a fellow?]. PMID- 24758849 TI - [Complications of endoscopic nasal and sinus surgery: experience in 150 patients]. AB - BACKGROUND: Endoscopic nasal and sinus surgery has been used greatly for the treatment of inflammatory and neoplasm pathology, as well as for the approach of the extrasinus structures. Although it has proven to be a very successful method, it is not exempt of complications. Our objective was to identify the frequency of complications in patients with sinus and nasal pathology that underwent an endoscopic surgery of the nose and sinuses. METHODS: A total of 150 patients who underwent endoscopic sinus surgery, 75 women and 75 men, in a specialties hospital of the Instituto Mexicano del Seguro Social (IMSS). The type of pathology, surgical technique done, major and minor adverse event presented were recorded. RESULTS: We observed an overall complication rate of 18 %: 2.7 % corresponded to major, and 15.3 % to minor. The main pathologies were chronic rhinosinusitis without polyps (24.7 %) and sinus nasal tumors (22 %). CONCLUSIONS: The overall complications and the major rates were similar to those reported in the literature. On the other hand, the minor adverse events were slightly higher. Still, endoscopic surgery has become a safe surgical treatment option. PMID- 24758850 TI - [Anthropometric and biochemical indices in the nutritional assessment of the newborn with extremely low weight]. AB - OBJECTIVE: To evaluate anthropometric and biochemical indices of the nutritional status of newborn with extremely low weight. METHODS: It was carried out a cohort study with 10 patients included, of both sexes, and weight at birth between 700 1200 g, who were under treatment with parenteral nutrition (PN), and/or minimal enteric stimulus (MES). RESULTS: Nine patients (90 %) received PN plus MES. One patient received only oral or enteric nutrition. Daily increase in weight was 7 23.8 g with an average of 15.6 g. In size, weekly increase was 0.30-1.5 cm with an average of 0.78 cm. In cephalic perimeter, the weekly increase was between 0.1 1.1 cm weekly with an average of 0.57 cm. Once the PN treatment was stopped and the patients were managed only with oral feeding, the weigh increases ranged between 12.5-35 g per day with an average of 22.7 g/day; height increased weekly from 0.45 to 1.1 cm, with an average of 0.89 cm/week; cephalic perimeter increased weekly from 0.45 to 1.3 cm, with an average of 0.80 cm. All the patients (100 %) had a positive nitrogen balance. CONCLUSIONS: The treatment of PN and MES is a useful strategy in order to keep a positive nitrogen balance and promote the increase in weight, size and cephalic perimeter so that the newborn could get the rate of growth in utero. PMID- 24758851 TI - [Menopause and ultrasonographic measurements of calcaneus]. AB - BACKGROUND: In Mexico, calcaneal ultrasound measurements -bone mineral density (BMD), broadband ultrasound attenuation (BUA), speed of sound (SOS), ultrasonic quantitative index (QUI)- and their differences in regards to menopause have not been documented. METHODS: It was carried out a cross-sectional study in 862 women from 20 to 90 years old, incorporated through consecutive sample, who were users of the Sistema para el Desarrollo Integral de la Familia (DIF) in Morelos. Sociodemographic, reproductive and life style factors were identified. BMD, BUA, SOS and QUI were measured with quantitative ultrasound (QUS), using a Sunlight Omnisense 7000 S device. Adjusted differences in the mean of these measurements were estimated between pre and postmenopausal women through multiple linear regression. RESULTS: The medians were: BMD, 0.455 g/cm2 (IQR, interquartile range = 0.378, 0.538); BUA, 66.0 dB/mHz (IQR = 54.3, 78.1); SOS, 1530.7 m/s (IQR = 1509.8, 1551.7); QUI = 83.7 units (IQR = 71.1, 96.6). In postmenopausal women, adjusted mean for BUA was -4.34 dB/mHz (CI 95 % = -8.23,-0.43); for SOS, -4.26 m/s (CI 95 % = -13.82, 5.30) ; for QUI, -4.42 units (CI 95 % = -8.64,-0.19). CONCLUSIONS: This report increases information about the clinical applicability of QUS. SOS in calcaneus does not reflect changes related with menopause. PMID- 24758852 TI - [Acute otitis media: could it be a sentinel indicator of health care?]. AB - BACKGROUND: Acute otitis media is the most common bacterial disease in children under five years; therefore, is one of the most common causes of pediatric consultation. Our objective was to determine the feasibility to consider this disease as a sentinel factor of medical attention. METHODS: All the new cases of acute otitis media registered between 2008 and 2011 were collected and analyzed. Proportions, ratios, and incidence rates were determined. Also, the limits for proportions were calculated using mid P exact test. RESULTS: In children under five years, we observed 20 % of the cases of non-suppurative otitis media, and suppurative otitis media in 17 %. The reason for acute respiratory infection in relation to cases of otitis media in children of this age increased from 87:1 in 2008 to 53:1 in 2011. CONCLUSIONS: The reason of suppurative otitis media decreased in children under five years, even in 2009, when it was registered the highest number of new cases of acute respiratory infection. It was not feasible to determine if acute otitis media is a sentinel indicator; however, we could monitor medical attention indirectly. PMID- 24758854 TI - [Management of bilateral vocal cord paralysis with laser cordectomy]. AB - BACKGROUND: Bilateral vocal fold paralysis (BVFP) is characterized by fold immobility in complete adduction or abduction, secondary to a vagus nerve lesion, through the recurrent laryngeal nerve. The manifestation is variable dyspnea and stridor, fatal if the airway is not secured. There are endolaryngeal and extralaryngeal techniques to increase the glottic opening, improving ventilation and deglutition, and the possibility of decannulation and phonation. METHODS: Case series consisting of BVFP patients, treated with posterior cordectomy, from January 2004 to January 2010. Clinical charts were reviewed to obtain data and registries of presurgical and postsurgical control endolaryngoscopies. RESULTS: Nineteen patients were identified. Twelve (63.2 %) had a tracheotomy cannula in place, and seven (36.8 %) didn't. Total thyroidectomy was the principal cause of the BVFP in 17 patients (89.5 %). A right cordectomy was performed on 10 patients (52.6 %). At 12 months, endolaryngoscopy detected a 40.26 % average increase in the glottic opening (p < 0.05), allowing for decannulation in 10 (83.3 %) of the tracheotomy patients. CONCLUSIONS: Laser cordectomy is a simple procedure for the treatment of BVFP, with few complications, permitting oronasal ventilation, decannulation and phonation. PMID- 24758853 TI - [Kidney function in marginalized population: a pilot study]. AB - BACKGROUND: Chronic kidney disease (CKD) is a public health problem; more than 6 % of worldwide population suffers from it. Low education and socioeconomic status, as well as limited access to medical care increase the probability of kidney damage. The objective was to evaluate and classify renal function in Yucatan's marginalized population. METHODS: A transversal descriptive survey was carried out among non-hospitalized adults of a general hospital. The study population included marginalized subjects (confirmed by socioeconomic survey), without oedema, pregnancy or diabetes mellitus. Renal function was evaluated by glomerular filtration rate. Patients were staged according to KDOQI guidelines. Likewise, weight, height, body mass index (BMI), fat percentage and blood pressure were measured. The results were compared between gender groups as well as rural and urban population. RESULTS: 165 subjects were included (83 % female). High risk of kidney damage was observed in 44.2 % of patients; 1.8 %, 49.1 %, and 4.8 % were in stages 1 to 3, respectively. There was no difference when comparing data between different groups. CONCLUSIONS: This study found high prevalence of CKD in Yucatan's marginalized population. PMID- 24758855 TI - [Sexual profile of women with cervical cytology in a first level unit]. AB - BACKGROUND: The sexual profile of women shapes a set of components that interact and play a fundamental role in the onset of human papillomavirus (HPV) or cervical cancer. The objective was to establish the sexual profile of women who underwent cervical cytology in a first level unit of the Instituto Mexicano del Seguro Social from Estado de Mexico, Mexico. METHODS: We studied women attending for cytological detection of malignant tumor in cervix. We interviewed them in order to obtain sociodemographic, gynecologic and obstetrical histories. Statistical analysis was made using Fisher's exact test, Mantel-Haenszel chi squared test, and Spearman correlation. RESULTS: There were 299 women; 67.56 % reported having only one sexual partner. The tendency of infection by HPV fell discretely as the age increased. Women with more than one sexual partner were at greater risk for developing some type of cervical neoplasia (OR = 1.016, CI 95 % = 0.6069-1.7, p = 0.953). CONCLUSIONS: It was a diverse group, a source of richness and plurality, but also of challenges. Therefore, it requires more work regarding sex education. Young women frequently present determining factors related to HPV and the development of cervical neoplasia. PMID- 24758856 TI - [Clinical features of acute leukemia and its relationship to the season of the year]. AB - BACKGROUND: In 2009, 17.9 % of hospital morbidity by malignant tumors in Mexico corresponded to hematological malignancies, mainly acute leukemia. Some studies suggest a seasonal pattern, since most of the cases are registered during summer. Our objective was to estimate the relationship between the different subtypes of acute leukemia with the age when the disease arose, and the season of the year. METHODS: Retrospective and observational study, based on records of a hematology department from January 2006 to April 2012. Only the patients diagnosed with de novo acute leukemia, stratified according to the French-American-British classification, were included. Seasonal analysis was performed using Edward's periodic model. RESULTS: The study included 833 acute leukemia cases: 48 % of women (400), and 52 % of men (433). Median age was 36.2 +/- 19.8 years. Acute lymphoblastic leukemia predominated over acute myeloblastic leukemia subtype M4 (p < 0.05), and we found differences (p < 0.01) between lymphoblastic and myeloblastic leukemias: 32.3 and 41.8. Despite the existence of pronounced peaks in the time series, they did not repeat periodically. CONCLUSIONS: The most common variety of acute leukemia was lymphoblastic type L2, followed by myeloblastic type M4. People over 40 years of age were the most affected. A seasonal pattern of acute leukemias was not observed. PMID- 24758857 TI - [Fraudulent publication in medical journals]. AB - Fraud can be present in some scientific medical publications; however, the magnitude of this situation is unknown. One of the associated factors for this transgression of the good practice of investigation is the need to publish and obtain recognition and benefits, regardless of the means. The deliberate fabrication and falsification of data, plagiarism and duplication of publications are some of the scientific misconducts. Many cases of fraud in publications are known, and they have reached public opinion and have been a matter of legal sanctions (the names of Woo Suk Hwang, Jon Sudbo, Joachim Blodt, Robert Slutsky, and William Summerlin reminds us a few known cases). In the last decades, national and international regulatory organisms have been created in order to intervene against this scientific misconduct. Currently, we can rely on several effective software programs, whose function is to detect plagiarism and falsification of data. The prevention of scientific misconduct through information and education of the investigators could lead to the decrease of the presence of this problem, which damages scientific credibility and put at risk the patient's safety. PMID- 24758858 TI - [Heart failure. Importance and utility of the echocardiographic evaluation]. AB - Millions of people die every year due to cardiovascular diseases. The objective against these diseases is primary prevention, but secondary prevention is the major goal in those individuals who already suffered an event. The order of the cardiovascular complication is the next one: arrhythmia, heart failure, myocardial infarction or stroke, and death. Approximately between 1 and 2 % of adults present heart failure, but this percentage rises to more than 10 % in adults over 70 years. Therefore, it is necessary to diagnose and to treat this complication. Left ventricular ejection fraction is the most important prognosis factor in these patients, because it decreases in 50 % of them. Almost 50 % of patients with heart failure have a conserved systolic function, but a decreased diastolic function. Treatment must improve the structural and functional heart abnormalities. Echocardiography is a useful tool in these patients due to its exactitude, accessibility, safety, and low cost. It provides information about the characteristics of the cardiac chambers and its volumes, the diameter in the walls, and about the diastolic, systolic and valvular function. Recently, echocardiography evolved to third dimension techniques, which seem to be more exact. In the next years, we will have more evidence about this diagnostic modality. PMID- 24758859 TI - [Clinical research XX. From clinical judgment to multiple logistic regression model]. AB - The complexity of the causality phenomenon in clinical practice implies that the result of a maneuver is not solely caused by the maneuver, but by the interaction among the maneuver and other baseline factors or variables occurring during the maneuver. This requires methodological designs that allow the evaluation of these variables. When the outcome is a binary variable, we use the multiple logistic regression model (MLRM). This multivariate model is useful when we want to predict or explain, adjusting due to the effect of several risk factors, the effect of a maneuver or exposition over the outcome. In order to perform an MLRM, the outcome or dependent variable must be a binary variable and both categories must mutually exclude each other (i.e. live/death, healthy/ill); on the other hand, independent variables or risk factors may be either qualitative or quantitative. The effect measure obtained from this model is the odds ratio (OR) with 95 % confidence intervals (CI), from which we can estimate the proportion of the outcome's variability explained through the risk factors. For these reasons, the MLRM is used in clinical research, since one of the main objectives in clinical practice comprises the ability to predict or explain an event where different risk or prognostic factors are taken into account. PMID- 24758860 TI - [Prevalence of chronic pruritus in patients of a tertiary care hospital]. AB - BACKGROUND: Chronic pruritus is occasionally intractable; it has different etiologies and affects life quality. Our objective was to describe the prevalence of pruritus in newly-arrived patients at the Instituto Nacional de Ciencias Medicas y Nutricion "Salvador Zubiran". METHODS: A cross-sectional study was developed in newly-arrived patients. We conducted previous surveys in order to identify those patients with pruritus. With a second survey we inquired their sociodemographic traits, comorbidities, drugs being administered, the characteristics of pruritus, and the impact on the patient's quality of life. RESULTS: Of 554 previous surveys, we identified 70 cases of chronic pruritus. Most of the cases were women in their middle ages (42 years). According to the classification of pruritus, 67.2 % was associated to the underlying disease, 14.8 % was related to dermatologic condition, 3.3 % to pharmacological effects, 4.9 % to other conditions, and 9.8 % was idiopathic. Life quality was not affected in 7 %, was minimally affected in 28 %, and was mild to severe in 26 %. CONCLUSIONS: Chronic pruritus was highly prevalent in the Institute. It was mainly associated with the underlying disease, and affected significantly the quality of life. More studies are needed for better understanding its pathophisiology. Furthermore, new treatments will be available to control pruritus, bringing a better quality to those affected patients. PMID- 24758861 TI - [Complications due to malnutrition and intrauterine growth restriction in preterm newborns]. AB - BACKGROUND: To analyze neonatal complications in preterm infants with or without previous diagnosis of intrauterine growth restriction (IUGR) and malnutrition at birth. METHODS: We integrated four preterm cohorts: IUGR and malnourished at birth (n = 24), IUGR without malnutrition (n = 22), without IUGR and malnourished (n = 43), and with proper weight without IUGR (n = 224). Nutritional status was determined by weighted index adjusted for weeks of gestation and fetal ultrasound IUGR. Apgar, type of resuscitation, neonatal morbidities, and hospital days of stay were analyzed at birth. RESULTS: Malnutrition was observed more frequently in infants with preeclamptic or eclamptic mothers, or in multiple pregnancies. There were no differences in birth conditions between groups. There were more complications in cohorts of infants with IUGR, but even more if they had malnutrition as well. Infants with IUGR adjusted for gestational age had more days of hospital stay, without differences regarding their nutritional status. CONCLUSIONS: In preterm infants, important growth impairments at birth (malnutrition) after being diagnosed with IUGR increase the likelihood of neonatal complications. PMID- 24758862 TI - [Clinical and epidemiological characterization of patients evaluated at a pediatric ophthalmology department]. AB - BACKGROUND: The appropriate treatment for a disease requires a deep knowledge in regards to the epidemiology of the most common pathological entities. Therefore, it is important to make studies of clinical and epidemiological characterization in order to establish the evolution of the diseases in the outpatient services. The objective of this study was to perform a clinical and epidemiological characterization of patients evaluated at a pediatric ophthalmology department during the course of twelve months, in Medellin, Colombia. METHODS: Descriptive and retrospective study, in which the clinical records of all patients below the age of 18 were reviewed, regardless of their referral diagnosis. RESULTS: The most frequently diseases identified were pathological refractive errors, physiological refractive errors, and strabismus, with a prevalence of 55.1 %, 40.5 % and 32.9 %, respectively. Among strabismus, the most common were primary, residual, and accommodative. CONCLUSIONS: Among pediatric patients referred to a pediatric ophthalmology department, both refractive errors (mainly mild astigmatism) and strabismus were the most prevalent diseases. Therefore, the general physician and the general ophthalmologist should be prepared to recognize, diagnose and refer the cases that require attention. PMID- 24758863 TI - [Rosai-Dorfman disease with spinal and cranial tumors. A clinical case reported]. AB - Rosai-Dorfman disease, known as well as sinus histiocytosis with massive lymphadenopathy, is a histiocytic proliferative disorder which may affect, with an extranodal presentation, the central nervous system, in 5 % of cases with exceptional reports of simultaneous development of spinal and cranial tumors. When it affects the central nervous system it appears more in men and it is shown as a mass in the cranial dura mater or in the spinal cord. The clinical symptoms of Rosai-Dorfman disease are fever, general malayse, weight loss, and nocturnal diaphoresis. Also, when Rosai-Dorfman disease affects the spinal cord, it has an impact on the thoracic spine, which causes paraparesis, quadriparesis, and sensory disorder. Histopathologically, the lymph nodes show emperipolesis. The diagnosis of Rosai-Dorfman disease is usually good, since 40 % of the patients present a spontaneous remission if they are treated with oral corticosteroids, even though the lesion can be managed with fractionated radiotherapy or with radical surgery. We report the case of a 34-year-old male who started with spinal injuries, and a year later showed intracranial lesions. PMID- 24758864 TI - [Rosai-Dorfman disease presented with involvement of the adrenal gland. A clinical case reported]. AB - BACKGROUND: Adrenal gland involvement is a very rare extranodal presentation of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Its pathogenesis still remains unknown with many theories about its probable cause. Symptoms and signs of adrenal involvement presentation are uncertain. Although, it is a disease with a good prognosis and a favorable clinical course in most cases, the low index of suspicion and difficulty in radiological differential diagnosis lead to radical treatment. CLINICAL CASE: We present a case of Rosai Dorfman disease with right adrenal plus left infrahiliar nodal involvement. It was treated with adrenalectomy and node exeresis. The infrahilial involvement evolution was appropriate. CONCLUSIONS: Rosai-Dorfman disease is a rare disease and the extra-nodal presentation is even more rare. The incidence and evolution of this disease in the adrenal gland is unknown. The presence of this pathology should be considered if the patient shows adrenal gland affected and lymph node growth, in order to consider the individualized treatment, which may vary (treatment with corticosteroids, chemotherapy and/or radiotherapy). PMID- 24758865 TI - [Seventy years of medicine in the Instituto Mexicano del Seguro Social]. AB - The purpose of these lines is to remember and refer some of the historical landmarks in the evolution of the medical services of the Instituto Mexicano del Seguro Social (IMSS, according to its initials in Spanish) since it was founded, in 1943. We also want to bring to the reader's attention that the dimensions and impacts on health that IMSS has achieved, throughout its history, have strengthened the citizenship, as well as social sustainability. Also, those impacts have determined the creation and the reinforcement of human capital in Mexico. Throughout this concise balance, all the controversy surrounding the foundation of the Institute is being recalled (the protest in the Mexico City Zocalo, or the attack to an hospital in San Angel -a neighborhood located in the Southwest of Mexico City-), as well as the way the IMSS incorporated several words into the vocabulary of Mexicans. We also remember the previous antecedent of the Revista Medica del Instituto Mexicano del Seguro Social, as well as the Revista de Enfermeria, and the emblematic Archives of Medical Research. The IMSS has 70 years of achievements, seven decades covered. PMID- 24758866 TI - [The anatomical pathology, an indispensable discipline, and its only Latin American journal]. AB - As a medical discipline, pathological anatomy was born between the 16th and 17th centuries, when the bases for scientific and technological development, as we know them today, were established. Giovanni Battista Morgagni (1682-1771), one of the greatest clinicians of the 18th century, introduced the concept of correlation between clinical manifestations and pathological anatomic structures. Just like that the pathology has contributed to the characterization of many diseases. Correlation of anatomopathological changes with signs and symptoms of disease is still common practice to date, which constitutes the basis for one of the most relevant pedagogical activities in medicine: the clinical pathological conference. The American Society of Investigative Pathology describes pathology as "the medical specialty that provides the scientific foundation of medical practice". Advances in this discipline have been transmitted mainly in periodical publications as early as the 19th century, and many scientific journals dedicated to communication of relevant findings from all over the world have been created since. The uninterrupted publication of a scientific journal for 51 years, the journal Patologia. Revista Latinoamericana, dedicated to one of the most important medical disciplines is, undoubtedly, an achievement worthy of celebration, for being the only one in Spanish in Latin America. PMID- 24758867 TI - Valsartan improves the electrophysiological characteristics of left ventricular hypertrophic myocardium in spontaneously hypertensive rats. AB - The objective was to investigate the effects of valsartan on the electrophysiological characteristics of left ventricular hypertrophic myocardium in spontaneously hypertensive rats (SHR). A total of 24 10-week-old male SHR were divided into two groups: valsartan and non-valsartan groups (n=12 in each). Twelve 10-week-old Wistar-Kyoto rats were served as the control group. Kv4.2 expression was measured in left ventricular myocardium using western blots. In addition, the systolic blood pressure, left ventricular mass index (LVMI), ventricular effective refractory period and ventricular fibrillation threshold (VFT) were also measured after eight weeks. INa, ICaL, Ito and membrane capacitance were measured in left ventricular myocytes after 8 weeks by whole cell patch clamp. Valsartan decreased LVMI compared with the non-Valsartan group (Valsartan vs. non-Valsartan: 3.2+/-0.03 mg g(-1) vs. 3.7+/-0.02 mg g(-1), P<0.01). Valsartan also enhanced the VFT compared with the non-Valsartan group (Valsartan vs. non-Valsartan: 18.6+/-0.3 mA vs. 15.4+/-0.4 mA, P<0.01). The expression of Kv4.2 was significantly lower in the non-Valsartan and Valsartan groups compared with the control group (P<0.01). The expression of Kv4.2 was significantly higher in the Valsartan group compared with the non-Valsartan group (P<0.01). Valsartan decreased the density of ICaL compared with non-Valsartan group (Valsartan vs. non-Valsartan: -5.5+/-0.6 pA/pF vs. -7.2+/-0.9 pA/pF, P<0.05). Valsartan improved the density of Ito compared with non-Valsartan group(Valsartan vs. non-Valsartan: 13.93+/-0.8 pA/pF vs. 11.22+/-1.0 pA/pF, P<0.05). Valsartan improves the electrophysiological characteristics of left ventricular hypertrophic myocardium in spontaneously hypertensive rat. PMID- 24758868 TI - Experimental plug and play quantum coin flipping. AB - Performing complex cryptographic tasks will be an essential element in future quantum communication networks. These tasks are based on a handful of fundamental primitives, such as coin flipping, where two distrustful parties wish to agree on a randomly generated bit. Although it is known that quantum versions of these primitives can offer information-theoretic security advantages with respect to classical protocols, a demonstration of such an advantage in a practical communication scenario has remained elusive. Here we experimentally implement a quantum coin flipping protocol that performs strictly better than classically possible over a distance suitable for communication over metropolitan area optical networks. The implementation is based on a practical plug and play system, developed by significantly enhancing a commercial quantum key distribution device. Moreover, we provide combined quantum coin flipping protocols that are almost perfectly secure against bounded adversaries. Our results offer a useful toolbox for future secure quantum communications. PMID- 24758869 TI - Insufficient colostrum ingestion is a risk factor for polyarthritis and/or phlegmon in hand-reared reticulated giraffes (Giraffa camelopardalis reticulata): 7 cases (2003-2012). AB - Seven reticulated giraffes were hand-reared at Nogeyama Zoological Gardens, because the dam had agalactia. Six of the 7 calves exhibited polyarthritis and/or phlegmon in the lower legs. However, the cause of the disorder was unclear. The present study reviewed the clinical records of the 7 giraffes, including the type and amount of colostrum ingested during the first 72 hr. The disorder involved the fetlocks and carpal and tarsal joints in 6 of the 7 calves within an average of 8 days of birth. The average amount of fed bovine or powdered colostrum was 0 2.4 l in the first 24 hr and 2.0-6.2 l during the first 72 hr. Insufficient colostrum quantity might be a factor in polyarthritis and/or phlegmon. PMID- 24758870 TI - Quantitative strain and compositional studies of InxGa1-xAs Epilayer in a GaAs based pHEMT device structure by TEM techniques. AB - In GaAs-based pseudomorphic high-electron mobility transistor device structures, strain and composition of the In x Ga1-x As channel layer are very important as they influence the electronic properties of these devices. In this context, transmission electron microscopy techniques such as (002) dark-field imaging, high-resolution transmission electron microscopy (HRTEM) imaging, scanning transmission electron microscopy-high angle annular dark field (STEM-HAADF) imaging and selected area diffraction, are useful. A quantitative comparative study using these techniques is relevant for assessing the merits and limitations of the respective techniques. In this article, we have investigated strain and composition of the In x Ga1-x As layer with the mentioned techniques and compared the results. The HRTEM images were investigated with strain state analysis. The indium content in this layer was quantified by HAADF imaging and correlated with STEM simulations. The studies showed that the In x Ga1-x As channel layer was pseudomorphically grown leading to tetragonal strain along the [001] growth direction and that the average indium content (x) in the epilayer is ~0.12. We found consistency in the results obtained using various methods of analysis. PMID- 24758872 TI - Electrospun fiber scaffolds of poly (glycerol-dodecanedioate) and its gelatin blended polymers for soft tissue engineering. AB - For tissue engineering applications, biodegradable scaffolds play a vital role in supporting and guiding the seeded cells to form functional tissues by mimicking the structure and function of native extracellular matrices. Previously, we have developed a biodegradable elastomer poly (glycerol-dodecanedioate) (PGD) with mechanical properties suitable for soft tissue engineering. In the study, we found that the PGD and PGD blended with gelatin (PGD/gelatin) were able to be electrospun into fibrous scaffolds, and the diameters of the fibers could be adjusted by controlling the PGD concentration. When using our newly designed electrospinning collector, fibers could be easily harvested and the size of the fiber mat could be flexibly adjusted. The data of Raman spectra also confirmed the esterfication reaction in PGD polymerization and showed no significant structure change after electrospinning. Biocompatibility testing of the PGD and PGD/gelatin, by using human foreskin fibroblasts, indicated that gelatin could enhance cell adhesion and proliferation. Overall, electrospun fibers made from PGD and PGD/gelatin exhibited several advantages including easy synthesis from renewable raw materials, flexible fabrication by using less toxic solvents like ethanol, and good biocompatibility. PMID- 24758871 TI - Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1. AB - A naphthoquinone inhibitor of human arylamine N-acetyltransferase 1 (hNAT1), a potential cancer biomarker and therapeutic target, has been reported which undergoes a distinctive concomitant color change from red to blue upon binding to the enzyme. Here we describe the use of in silico modeling alongside structure activity relationship studies to advance the hit compound towards a potential probe to quantify hNAT1 levels in tissues. Derivatives with both a fifty-fold higher potency against hNAT1 and a two-fold greater absorption coefficient compared to the initial hit have been synthesized; these compounds retain specificity for hNAT1 and its murine homologue mNat2 over the isoenzyme hNAT2. A relationship between pKa, inhibitor potency and colorimetric properties has also been uncovered. The high potency of representative examples against hNAT1 in ZR 75-1 cell extracts also paves the way for the development of inhibitors with improved intrinsic sensitivity which could enable detection of hNAT1 in tissue samples and potentially act as tools for elucidating the unknown role hNAT1 plays in ER+ breast cancer; this could in turn lead to a therapeutic use for such inhibitors. PMID- 24758873 TI - Association between interleukin 10 gene polymorphisms and risk of type 2 diabetes mellitus in a Chinese population. AB - OBJECTIVE: To investigate the relationship between the interleukin 10 (IL10) gene single nucleotide polymorphisms (SNP) -1082 G/A (rs1800896), -819 T/C (rs1800871) and -592 A/C (rs1800872) and risk of type 2 diabetes mellitus in a Chinese population. METHODS: This case-control study recruited patients with type 2 diabetes mellitus and healthy control subjects. Genotyping of the -1082 G/A (rs1800896), -819 T/C (rs1800871) and -592 A/C (rs1800872) SNPs was conducted and genotype frequencies were compared between the two groups. RESULTS: The study recruited 364 patients with type 2 diabetes mellitus and 677 healthy controls. Patients carrying the -1082 GG genotype had a significantly increased risk of type 2 diabetes mellitus (adjusted odds ratio [OR] 1.57, 95% confidence interval [CI] 1.03, 2.68), as did those patients carrying the -592 AA genotype (adjusted OR 1.63, 95% CI 1.06, 2.53). Subjects carrying both the -1082 GA + GG and -592 AC + AA genotypes had a significantly increased risk of type 2 diabetes mellitus (adjusted OR 2.03, 95% CI 1.24, 3.15). CONCLUSIONS: The SNPs -1082G/A and -592 A/C increased the risk for type 2 diabetes mellitus, and could be potential targets for screening for the early detection of the risk of type 2 diabetes mellitus. PMID- 24758875 TI - Open access publication, journal policy, and scientific community. PMID- 24758874 TI - First in man: adipose-derived stromal vascular fraction cells may promote restorative cardiac function. PMID- 24758876 TI - The reply. PMID- 24758877 TI - Electrocardiography in pericarditis and ST-elevation myocardial infarction: timing of observation is critical. PMID- 24758878 TI - The reply. PMID- 24758879 TI - An evaluation of a clinical decision support tool. PMID- 24758880 TI - The reply. PMID- 24758881 TI - Lowering blood glucose without increasing mortality. PMID- 24758882 TI - Associated factors of acute myocardial infarction in patients with systemic sclerosis. PMID- 24758883 TI - 'Check the box' medicine not practiced by choice. PMID- 24758884 TI - Check the box medicine. PMID- 24758885 TI - Left main coronary artery stent thrombosis: a challenging case. PMID- 24758886 TI - Prophylaxis for acute gout flares after initiation of urate-lowering therapy. AB - This review summarizes evidence relating to prophylaxis for gout flares after the initiation of urate-lowering therapy (ULT). We searched MEDLINE via PubMed for articles published in English from 1963 to 2013 using MEsH terms covering all aspects of prophylaxis for flares. Dispersion of monosodium urate crystals during the initial phase of deposit dissolution with ULT exposes the patient to an increased rate of acute flares that could contribute to poor treatment adherence. Slow titration of ULT might decrease the risk of flares. According to the most recent international recommendation, the two first-line options for prophylaxis are low-dose colchicine (0.5 mg once or twice a day) or low-dose NSAIDs such as naproxen 250 mg orally twice a day. They can be given for up to 6 months. If these drugs are contraindicated, not tolerated or ineffective, low-dose corticosteroids (prednisone or prednisolone) might be used. Recently, reports for four trials described the efficacy of canakinumab and rilonacept, two IL-1 inhibitors, for preventing flares during the initiation of allopurinol therapy. Prophylaxis for flares induced by ULT is an important consideration in gout management. Low-dose colchicine and low-dose NSAIDs are the recommended first line therapies. Although no IL-1 blockers are approved as prophylactic treatment, this class of drug could become an interesting option for patients with gout with intolerance or contraindication to colchicine, NSAIDs or corticosteroids. PMID- 24758887 TI - Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics--a large multicentre UK study. AB - OBJECTIVES: The prevalence of interstitial lung disease (ILD) in RA is ~5%. Previous work identified increasing age, active articular disease and articular damage as risk factors for RA-associated ILD (RA-ILD). The roles of high resolution CT (HRCT) and lung function testing in defining the nature and extent of pulmonary involvement have recently been explored. This study is the first to examine predictive and prognostic factors for the development of RA-ILD and to report on the physiological and radiological characteristics of the condition from a large multicentre UK network. METHODS: We collected data from centres across the UK on patients with both RA and ILD (proved on HRCT) diagnosed over a 25-year period from 1987 to 2012 using a standard pro forma. Potential predictors of RA-ILD were analysed. Baseline lung function data were recorded and related to HRCT findings. We analysed HRCT for subtype and extent of lung involved and examined the relationship between these and both all-cause and pulmonary mortality. We compared our results with case controls matched for age and gender using computer-generated selection from the RA population from one contributing centre. RESULTS: A total of 230 patients were identified from across the UK with proven RA-ILD diagnosed over 25 years. Median age at diagnosis was 64 years and the male:female ratio was 1:1.09. Univariate analysis showed anti-CCP antibody titres to be the single most strongly associated predictor of RA-ILD. Male gender, age at onset, smoking and RF were all independently associated with RA ILD on multivariate analysis. Vital capacity (VC) was preserved in limited disease but reduced in extensive disease, while gas transfer was reduced in both. Usual interstitial pneumonia (UIP) was the most common subtype on HRCT and both this and extensive disease were associated with increased all-cause mortality. CONCLUSION: This is the largest study of RA-ILD in the UK. Anti-CCP antibodies were strongly associated with RA-ILD in both sexes. Smoking was strongly associated with ILD in males, which may explain the higher frequency of RA-ILD in men. The predominant HRCT pattern was UIP and most patients had limited disease at presentation. The presence of UIP and extensive disease are associated with increased mortality. Baseline gas transfer is a useful screening tool for ILD, while the preservation of VC at baseline might predict limited disease on HRCT. PMID- 24758888 TI - Treat to target in gout by combining two modes of action. PMID- 24758889 TI - Varicella vaccination in the immunocompromised. PMID- 24758890 TI - Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep*. AB - OBJECTIVES: Regional tidal lung strain may trigger local inflammation during mechanical ventilation, particularly when additional inflammatory stimuli are present. However, it is unclear whether inflammation develops proportionally to tidal strain or only above a threshold. We aimed to 1) assess the relationship between regional tidal strain and local inflammation in vivo during the early stages of lung injury in lungs with regional aeration heterogeneity comparable to that of humans and 2) determine how this strain-inflammation relationship is affected by endotoxemia. DESIGN: Interventional animal study. SETTING: Experimental laboratory and PET facility. SUBJECTS: Eighteen 2- to 4-month-old sheep. INTERVENTIONS: Three groups of sheep (n = 6) were mechanically ventilated to the same plateau pressure (30-32 cm H2O) with high-strain (VT = 18.2 +/- 6.5 mL/kg, positive end-expiratory pressure = 0), high-strain plus IV lipopolysaccharide (VT = 18.4 +/- 4.2 mL/kg, positive end-expiratory pressure = 0), or low-strain plus lipopolysaccharide (VT = 8.1 +/- 0.2 mL/kg, positive end expiratory pressure = 17 +/- 3 cm H2O). At baseline, we acquired respiratory gated PET scans of inhaled NN to measure tidal strain from end-expiratory and end inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [F]fluoro-2-deoxy-D-glucose scans were acquired to quantify metabolic activation, indicating local neutrophilic inflammation, in the same regions of interest. MEASUREMENTS AND MAIN RESULTS: Baseline regional tidal strain had a significant effect on [F]fluoro-2-deoxy-D-glucose net uptake rate Ki in high-strain lipopolysaccharide (p = 0.036) and on phosphorylation rate k3 in high-strain (p = 0.027) and high-strain lipopolysaccharide (p = 0.004). Lipopolysaccharide exposure increased the k3-tidal strain slope three-fold (p = 0.009), without significant lung edema. The low-strain lipopolysaccharide group showed lower baseline regional tidal strain (0.33 +/- 0.17) than high-strain (1.21 +/- 0.62; p < 0.001) or high-strain lipopolysaccharide (1.26 +/- 0.44; p < 0.001) and lower k3 (p < 0.001) and Ki (p < 0.05) than high-strain lipopolysaccharide. CONCLUSIONS: Local inflammation develops proportionally to regional tidal strain during early lung injury. The regional inflammatory effect of strain is greatly amplified by IV lipopolysaccharide. Tidal strain enhances local [F]fluoro-2-deoxy-D-glucose uptake primarily by increasing the rate of intracellular [F]fluoro-2-deoxy-D-glucose phosphorylation. PMID- 24758891 TI - Characteristics, perceived side effects and benefits of electronic cigarette use: a worldwide survey of more than 19,000 consumers. AB - BACKGROUND: Electronic cigarette (EC) use has grown exponentially over the past few years. The purpose of this survey was to assess the characteristics and experiences of a large sample of EC users and examine the differences between those who partially and completely substituted smoking with EC use. METHODS: A questionnaire was prepared, translated into 10 different languages and uploaded in an online survey tool. EC users were asked to participate irrespective of their current smoking status. Participants were divided according to their smoking status at the time of participation in two subgroups: former smokers and current smokers. RESULTS: In total, 19,414 participants were included in the analysis, with 88 of them (0.5%) reported not being smokers at the time of EC use initiation. Complete substitution of smoking was reported by 81.0% of participants (former smokers) while current smokers had reduced smoking consumption from 20 to 4 cigarettes per day. They were using ECs for a median of 10 months. They initiated EC use with a median of 18 mg/mL nicotine-concentration liquids; 21.5% used higher than 20 mg/mL. Only 3.5% of participants were using 0 nicotine liquids at the time of the survey. Former smokers were highly dependent (Fagerstrom Test for Cigarette Dependence = 7) and were heavier smokers (21 cigarettes per day when smoking) compared to current smokers. The most important reasons for initiating EC use for both subgroups was to reduce the harm associated with smoking and to reduce exposure of family members to second-hand smoking. Most considered ECs as less harmful than tobacco cigarettes, while 11.0% considered them absolutely harmless. Side effects were reported by more than half of the participants (59.8%), with the most common being sore/dry mouth and throat; side effects were mild and in most cases were subsequently resolved (partially or completely). Participants experienced significant benefits in physical status and improvements in pre-existing disease conditions (including respiratory disease such as asthma and chronic obstructive lung disease). Being former smoker was independently associated with positive effects in health and improvements in disease conditions. CONCLUSIONS: The results of this worldwide survey of dedicated users indicate that ECs are mostly used to avoid the harm associated with smoking. They can be effective even in highly-dependent smokers and are used as long-term substitutes for smoking. High levels of nicotine are used at initiation; subsequently, users try to reduce nicotine consumption, with only a small minority using non-nicotine liquids. Side effects are minor and health benefits are substantial, especially for those who completely substitute smoking with EC use. Further population and interventional studies are warranted. PMID- 24758892 TI - Mortality from cancers of the digestive system among grand multiparous women in Taiwan. AB - The aim of this study is to evaluate the significance of grand multiparous (GM) status in the mortality from cancers of the digestive system among a cohort of GM women in Taiwan during the period 1978-2008. The study cohort consisted of 144,922 women with at least five children (GM women) in the Taiwan Birth Register between 1 January 1978 and 31 December 2003. Standardized mortality ratios (SMRs) for cancers of the digestive system including esophagus, stomach, colon, rectum, liver, and pancreas were calculated by dividing the numbers of observed cancer deaths to the expected numbers of deaths based on the rates of national female population. Among the 144,922 GM women, a total of 23, 220, 213, 92, 397, and 65 deaths were caused by cancers of the esophagus, stomach, colon, rectum, liver, and pancreas, respectively. The SMRs among GM women were 1.61 (95% confidence intervals (CI): 0.95-2.27) for esophageal cancer, 1.15 (95% CI: 1.00-1.31) for stomach cancer, 1.07 (95% CI: 0.93-1.22) for colon cancer, 0.94 (95% CI: 0.75 1.14) for rectal cancer, 1.18 (95% CI: 1.06-1.30) for liver cancer, and 0.79 (95% CI: 0.60-0.98) for pancreatic cancer. This study provides evidence that grand multiparity may confer a protective effect on the risk of death from pancreatic cancer. However, the results suggest that GM women may increase the risk of death from cancers of the liver and stomach. PMID- 24758893 TI - Joint exposure to chemical and nonchemical neurodevelopmental stressors in U.S. women of reproductive age in NHANES. AB - Lead (Pb) and methyl mercury (MeHg) are well established neurodevelopmental toxicants (NDTs), but joint exposure to chemical and nonchemical (e.g., maternal stress) stressors has rarely been considered. We characterized exposure to Pb, MeHg and a measure of physiological dysregulation associated with chronic stress and examined race/ethnicity as a predictor of joint NDT exposure. Using data from the 2003-2004 NHANES, potential chronic stress exposure was estimated using allostatic load (AL), a quantitative measure of physiological dysregulation. A Hazard Index was calculated for joint exposure to Pb and MeHg (HI(NDT)). Logistic regression was used to assess the relationship between an indicator of elevated joint NDT exposures (HI(NDT) > 1) and race/ethnicity. The multivariate model was stratified by AL groups to examine effect measure modification. African American (adjusted odds ratio [OR] [95% confidence interval] = 2.2 [1.4, 3.3]) and Mexican American (1.4 [0.7, 2.6]) women were more likely to have an HI(NDT) > 1 compared to Caucasian women. Chronic stress was identified as an effect measure modifier with the largest ORs among women with high AL scores (African Americans = 4.3 [2.0, 9.5]; Mexican Americans = 4.2 [1.3, 14.1]). Chronic stress was found to modify the association between elevated joint NDT exposure and race/ethnicity, highlighting the importance of evaluating chemical and nonchemical stressor exposures leading to a common endpoint. PMID- 24758894 TI - Epidemiological risk analysis of home injuries in Italy (1999-2006). AB - Home injuries are an important public health issue in both developed and developing countries. This study focused on the Italian epidemiological framework between 1999 and 2006, using a nation-representative sample provided by the National Institute of Statistics. Every year, about 3,000,000 Italian residents reported at least one home injury, with an overall annual rate of 5.2/100 (95% CI 5.1-5.4); 3.2/100 (3.0-3.4) for males and 7.2/100 (6.9-7.4) for females. Poisson regression models were used for different age-specific populations (children, young/adults and older people), to evaluate the effects of socio-demographic, health/income satisfaction and housing variables. For children, non-applicable variables (including smoking and health satisfaction) were taken as those of the head of family, while housework time was taken the family mean time. Evidence of decreasing time trend in risk of home injury was found only among young/adults (p < 0.01). The following were risk factors: female gender (adjusted relative risk- RR 2.0 for older people and RR 1.9 for young/adults, p < 0.01); one additional hour of work at home (RR 1.009, p < 0.01 for young/adults and RR 1.016, p = 0.01 for children); smoking (RR 1.3, p < 0.01 for young/adults and p = 0.02 for children); health dissatisfaction (RR 1.3, p = 0.05 for children, RR 1.6 for young/adults and RR 1.7 for older people, p < 0.01); income dissatisfaction (RR 1.2, p < 0.01 for young/adults ); living alone (RR 1.5, p < 0.01 for young/adults and RR 1.2, p < 0.02 for the older people); having a garden (RR 1.1, p < 0.01 for young/adults ). Awareness of the need for safety at home could be boosted by information campaigns on the risk, and its social cost could be reduced by specific prevention schemes. Developing tools for assessing the risk at home and for removing the main hazards would be useful for both informative and prevention interventions. PMID- 24758895 TI - Association of overweight and elevation with chronic knee and low back pain: a cross-sectional study. AB - It is known that overweight is associated with chronic knee pain (CKP) and chronic low back pain (CLBP). Several risk factors for these conditions have been postulated, including age, sex, overweight, occupation, and socioeconomic factors. In addition, physical environment has been studied as a potential risk factor in recent years. However, the associations of overweight and physical environment with CKP and CLBP remains unclear. The aim of this study conducted in a rural mountainous region was to examine whether overweight individuals living at higher elevations have an increased probability of experiencing CKP and CLBP. In 2009, we conducted a mail survey with a random sample aged between 40 to 79 years. Questionnaires were sent to 6,000 individuals and a total of 4,559 individuals responded to this survey. After excluding the respondents with missing data, we conducted a logistic regression analysis of the data for 3,109 individuals. There was statistically significantly higher adjusted odds ratio (aOR) of CKP for those who were overweight living at low elevation (aOR = 1.90, 95% CI = 1.21-2.98), moderate elevation (aOR = 1.73, 95% CI = 1.05-2.87), and high elevation (aOR = 2.13, 95% CI = 1.31-3.46) than those who were not overweight living at low elevation. However, similar patterns were not observed for CLBP. Our results show that specific overweight-elevation associations were observed for CKP in a rural mountainous region. PMID- 24758896 TI - Effects of nitrogen fertilizers on the growth and nitrate content of lettuce (Lactuca sativa L.). AB - Nitrogen is an essential element for plant growth and development; however, due to environmental pollution, high nitrate concentrations accumulate in the edible parts of these leafy vegetables, particularly if excessive nitrogen fertilizer has been applied. Consuming these crops can harm human health; thus, developing a suitable strategy for the agricultural application of nitrogen fertilizer is important. Organic, inorganic, and liquid fertilizers were utilized in this study to investigate their effect on nitrate concentrations and lettuce growth. The results of this pot experiment show that the total nitrogen concentration in soil and the nitrate concentration in lettuce increased as the amount of nitrogen fertilizer increased. If the recommended amount of inorganic fertilizer (200 kg.N.ha-1) is used as a standard of comparison, lettuce augmented with organic fertilizers (200 kg.N.ha-1) have significantly longer and wider leaves, higher shoot, and lower concentrations of nitrate. PMID- 24758897 TI - Adaptive response in animals exposed to non-ionizing radiofrequency fields: some underlying mechanisms. AB - During the last few years, our research group has been investigating the phenomenon of adaptive response in animals exposed to non-ionizing radiofrequency fields. The results from several separate studies indicated a significant increase in survival, decreases in genetic damage as well as oxidative damage and, alterations in several cellular processes in mice pre-exposed to radiofrequency fields and subsequently subjected to sub-lethal or lethal doses of gamma-radiation or injected with bleomycin, a radiomimetic chemical mutagen. These observations indicated the induction of adaptive response providing the animals the ability to resist subsequent damage. Similar studies conducted by independent researchers in mice and rats have supported our observation on increased survival. In this paper, we have presented a brief review of all of our own and other independent investigations on radiofrequency fields-induced adaptive response and some underlying mechanisms discussed. PMID- 24758898 TI - Effects of intrahippocampal GABAB receptor antagonist treatment on the behavioral long-term potentiation and Y-maze learning performance. AB - GABAB receptor is present at pre- and post-synaptic sites and participates in many brain functions including cognition, reward and anxiety. Although a lot of research has shown that activation or blockade of GABAB receptor may produce different even opposing effects on long-term potentiation (LTP) and cognitive function, there is little information available concerning the effect of GABAB receptor on behavioral LTP, a learning-induced LTP model. Herein, we firstly examined the effects of 2-OH saclofen, a GABAB receptor antagonist, on the induction of behavioral LTP and Y-maze learning performance. In addition, GABAB receptor has been reported to be present on cholinergic terminals and to regulate the ACh release. Therefore, we also investigated the effect of 2-OH saclofen on the impairments in behavioral LTP and cognitive function induced by scopolamine, an acetylcholine receptor antagonist. We found that intrahippocampal application of 2-OH saclofen could significantly enhance the population spike (PS) amplitude with a dose-response relationship, and 20 MUM 2-OH saclofen evidently facilitated the formation of behavioral LTP in the perforant pathway to the dentate gyrus (PP DG) and led to an obvious improvement in maze learning performance. Furthermore, intrahippocampal 20 MUM 2-OH saclofen administration could markedly reverse the scopolamine-induced impairments in behavioral LTP and maze performance. Our data demonstrate that blockade of GABAB receptor displays a facilitatory role in the induction of behavioral LTP and maze learning task, and the antagonist of GABAB receptor seems to exert the potentially therapeutic value in the cognitive defect induced by cholinergic dysfunction. PMID- 24758899 TI - Frontal midline theta connectivity is related to efficiency of WM maintenance and is affected by aging. AB - Representations in working memory (WM) are temporary, but can be refreshed for longer periods of time through maintenance mechanisms, thereby establishing their availability for subsequent memory tests. Frontal brain regions supporting WM maintenance operations undergo anatomical and functional changes with advancing age, leading to age related decline of memory functions. The present study focused on age-related functional connectivity changes of the frontal midline (FM) cortex in the theta band (4-8 Hz), related to WM maintenance. In the visual delayed-match-to-sample WM task young (18-26 years, N=20) and elderly (60-71 years N=16) adults had to memorize sample stimuli consisting of 3 or 5 items while 33 channel EEG recording was performed. The phase lag index was used to quantify connectivity strength between cortical regions. The low and high memory demanding WM maintenance periods were classified based on whether they were successfully maintained (remembered) or unsuccessfully maintained (unrecognized later). In the elderly reduced connectivity strength of FM brain region and decreased performance were observed. The connectivity strength between FM and posterior sensory cortices was shown to be sensitive to both increased memory demands and memory performance regardless of age. The coupling of frontal regions (midline and lateral) and FM-temporal cortices characterized successfully maintained trials and declined with advancing age. The findings provide evidence that a FM neural circuit of theta oscillations that serves a possible basis of active maintenance process is especially vulnerable to aging. PMID- 24758900 TI - Lentivirus-mediated RNA interference targeting the long noncoding RNA HOTAIR inhibits proliferation and invasion of endometrial carcinoma cells in vitro and in vivo. AB - OBJECTIVE: The overexpression of long noncoding RNA HOTAIR is associated with various aggressive solid carcinomas. However, its relationship with endometrial carcinoma has not been reported. The present study aimed to investigate the expression of the long noncoding RNA HOTAIR in endometrial carcinoma, its relationship with the carcinoma's clinicopathologic features, and the biological function of HOTAIR in regulating endometrial cancer cell proliferation and invasion in vitro and in vivo. METHODS: The expression of HOTAIR was detected in different tissues and cell lines by real-time PCR. Lentivirus-mediated HOTAIR specific shRNAvectors were transfected into endometrial cancer HEC-1A cells. Cell proliferation and colony formation were examined by CCK-8 assays and colony formation assays, respectively. Invasion and migration were examined by Transwell assays. Flow cytometry assay was used to examine the cell cycle. In addition, xenograft model assays were performed to analyze the growth of endometrial cancer cells in vivo. RESULTS: Our data showed that HOTAIR expression was higher in endometrial cancer cells and tissues than in normal endometrial tissues. HOTAIR expression was closely related to the tumor stage (P = 0.045), myometrial invasion (P = 0.014), and lymph node metastasis (P = 0.033). The down-regulation of HOTAIR resulted in a significant inhibition of cell proliferation, migration, and invasion and in cell cycle arrest at the G0/G1 phase. Furthermore, HOTAIR depletion significantly suppressed the endometrial cancer tumorigenesis in vivo. CONCLUSIONS: This study is the first to suggest that HOTAIR plays an important role in the carcinogenesis of endometrial cancer. Targeting HOTAIR may be a novel therapeutic strategy for endometrial cancer. PMID- 24758902 TI - [The question and analysis about maintenance therapy in advanced non-small cell lung cancer]. AB - Recently, several studies have been carried about maintenance therapy in non small cell lung cancer, and some chemotherapy agents have been approved for clinical practice. But there are still a lot of questions about maintenance therapy that we have to consider. For example, the defects of design in maintenance therapy trials; how to choose gold standard of maintenance therapy for evaluation; who benefit from the maintenance therapy and how to estimate pharmaceutical economics. In this paper, we will make deep analysis about these issues. PMID- 24758901 TI - Hydrogen sulfide attenuates the recruitment of CD11b+Gr-1+ myeloid cells and regulates Bax/Bcl-2 signaling in myocardial ischemia injury. AB - Hydrogen sulfide, an endogenous signaling molecule, plays an important role in the physiology and pathophysiology of the cardiovascular system. Using a mouse model of myocardial infarction, we investigated the anti-inflammatory and anti apoptotic effects of the H2S donor sodium hydrosulfide (NaHS). The results demonstrated that the administration of NaHS improved survival, preserved left ventricular function, limited infarct size, and improved H2S levels in cardiac tissue to attenuate the recruitment of CD11b(+)Gr-1(+) myeloid cells and to regulate the Bax/Bcl-2 pathway. Furthermore, the cardioprotective effects of NaHS were enhanced by inhibiting the migration of CD11b(+)Gr-1(+) myeloid cells from the spleen into the blood and by attenuating post-infarction inflammation. These observations suggest that the novel mechanism underlying the cardioprotective function of H2S is secondary to a combination of attenuation the recruitment of CD11b(+)Gr-1(+) myeloid cells and regulation of the Bax/Bcl-2 apoptotic signaling. PMID- 24758903 TI - [Expert consensus for thermal ablation of primary and metastatic lung tumors]. PMID- 24758905 TI - [Accumulation-associated protein gene and TGF-beta 1 affects the formation of lung cancer-related biological material Staphylococcus epidermidis biofilm]. AB - BACKGROUND AND OBJECTIVE: This study was conducted to evaluate the effects of the accumulation-associated protein (Aap) gene and transform growth factor-beta 1 (TGF-beta1) on the biofilm formation of lung cancer-related Staphylococcus epidermidis (SE). METHODS: Species identification was performed to isolate SE strains from clinically implanted materials in lung cancer patients. Stable genetic aggregated proteins, which are associated with negative and positive isolates, were obtained. The biofilm-formation ability of the SE Aap gene was determined by PCR. Density gradient method was used to extract peripheral blood mononuclear cells from patients with non-small cell lung cancer. After 30 h, these cells were co-cultured with A549 at different TGF-beta1 concentrations. The supernatant was then combined with SE Aap+ and SE Aap- strains and co-cultured with a medical silicone rubber. A semi-quantitative adhesion test was performed for each bacterial biofilm formation. Scanning electron microscopy was also conducted to observe the microcosmic condition of this material on the bacterial biofilm surface. RESULTS: The Aap gene was closely related to SE biofilm formation. At 10 ng/mL, 20 ng/mL, and 40 ng/mL, SE Aap+ biofilm on the medical silicone rubber surface was thicker in the TGF-beta1 group than in the control group. No significant differences were found between TGF-beta1 groups. For the SE Aap- strains, no evident biofilm was formed in TGF-beta1 and control groups. CONCLUSIONS: In plant material-related infection of lung cancer patients, SE Aap+ strain easily forms biofilm. Furthermore, TGF-beta1 was conducive for the biofilm formation of SE Aap+ strains. PMID- 24758904 TI - [Effects of tumor suppressor gene TCF21 on the proliferation, migration and apoptosis of A549 cells]. AB - BACKGROUND AND OBJECTIVE: TCF21, a newly discovered gene, exhibits tumor suppressor function in a variety of tumors. This study aims to observe the effects of TCF21 on the proliferation, apoptosis and migration of A549 human lung adenocarcinoma epithelial cells. METHODS: TCF21 was overexpressed in A549 cells via lentiviral transfection. Fluorescence-based quantitative polymerase chain reaction and Western blot analysis were used to analyze the expression of the target gene. Transwell, proliferation assay, and flow cytometry were applied to detect the effect of TCF21 overexpression on the migration, proliferation, and apoptosis of A549 cells after transfection. RESULTS: The proliferation and migration of A549 cells were inhibited, and the apoptotic rate was increased by overexpressing TCF21. CONCLUSIONS: The tumor suppressor gene, TCF21, significantly inhibits the proliferation and migration, as well as facilitates early apoptosis of A549 cells. PMID- 24758906 TI - [Significance of epithelial-mesenchaymal transition phenotype in invasive tumor front cells of lung squamous cell carcinoma]. AB - BACKGROUND AND OBJECTIVE: The invasive tumor front (ITF) refers to cells or invasive nests in the junctional region of a tumor and its host. The ITF contains the most invasive cells of a tumor, and has a high prognostic value in carcinoma. The aim of this study is to investigate the epithelial-mesenchymal transformation phenotype in ITF cells of lung squamous cell carcinoma (SCC), and analyze the relationship between clinicopathological features and clinical outcomes of patients. METHODS: Semiquantitative immunohistochemistry was used to examine the expression of epithelial markers (E-cadherin and beta-catenin) and mesenchymal marker (vimentin) in 104 lung SCC tumor tissues. RESULTS: A decrease in E cadherin expression in ITF cells was observed in 56 of 104 (53.8%) tumors from patients. This result was markedly lower than that of non-ITF cells, which eventually developed metastatic tumors and were also associated with death (P=0.04). Vimentin expression was observed in 44 of 104 (42.3%) ITF cells, which was much higher than that of non-ITF cells. The downregulation of E-cadherin and overexpression of vimentin were associated with tumor invasive pattern, lymphatic metastasis, and poor prognosis (P<0.01). The expression of beta-catenin was 67.3% (70/104) in ITF cells. Moreover, ITF cells showed more nuclear and plasma positive cells, which were closely associated with metastasis (P<0.01). CONCLUSIONS: The loss in expression of E-cadherin/beta-catenin and overexpression of vimentin in ITF cells may be associated with poor prognosis of lung SCC patients. PMID- 24758907 TI - [Association between GNAS1 T393C polymorphism and therapeutic efficacy of tyrosine kinase inhibitor in pretreated advanced non-small cell lung cancer with unknown EGFR mutation status]. AB - BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR)-activating mutation predicts excellent response to EGFR tyrosine kinase inhibitors (TKIs). However, lung cancer patients are often with unknown EGFR mutation status because there are little tumor specimen to determine. TKIs induce tumor cell apoptosis which associates with several apoptosis-related genes. To explore the association between GNAS1 T393C polymorphism and therapeutic efficacy of TKI in pretreated advanced non-small cell lung cancer (NCSLC) with unknown EGFR mutation status. METHODS: A total of 116 patients were recruited for the study from Zhejiang Cancer Hospital, all of whom were treated with gefitinib or erlotinib after failure to prior chemotherapy. We detected the genotype of peripheral blood lymphocytes of patients with GNAS1 T393C polymorphism through polymerase chain reaction (PCR). Statistical analysis was performed by SPSS version 18.0. RESULTS: The overall response rate was 29.3%. No significant associations were found among GNAS1 T393C polymorphism and the objective response rate. The disease control rate of patients with GNAS1 T393C CC genotype was lower than that of patients with variant genotype (TT or CT) (46.2% vs 73.8%, P=0.039). Univariate analysis identified gender, smoking history, histology and GNAS1 T393C polymorphism as predictive marker of PFS (P=0.04, P<0.001, P<0.001 and P=0.005). Multivariate analysis of factors, including smoking history, performance status score, histology, GNAS1 T393C polymorphism demonstrated that GNAS1 T393C polymorphism was correlated independently with PFS (P=0.007). CONCLUSIONS: Our data suggest the role of GNAS1 T393C CC genotype as a poor predictive marker both of DCR and PFS in advanced NSCLC patients treated with tyrosine kinase inhibitor. PMID- 24758908 TI - [A meta-analysis of platinum plus docetaxel or vinorelbine in the first-line treatment of advanced non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Platinum plus a third-generation agent doublet chemotherapy is the standard regimen and first-line chemotherapy for the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy and safety of docetaxel plus platinum (DP) compared with vinorelbine plus platinum (VP) regimens in patients with advanced NSCLC. METHODS: We searched the PubMed, EMBASE, Cochrane Library, CNKI, CBM, VIP, and WanFang databases for randomized controlled trials (RCTs), in which DP regimen was compared with VP regimen. A quality assessment of qualified RCTs was performed according to Cochrane Handbook 5.1.0, and Stata 12.0 was used to perform meta-analysis. RESULTS: Seven RCTs involving 2,318 patients were included. Meta-analysis results indicated that the DP regimen increased the two year survival rate (HR=0.887, 95%CI: 0.810-0.972, P=0.010), response rate (RR=1.276, 95%CI: 1.107 -1.450, P=0.001), and diarrhea rate (RR=3.134, 95%CI: 1.918-5.121, P<0.001) compared with the VP regimen. Anemia rate was also reduced (RR=0.386, 95%CI: 0.311-0.478, P<0.001). No statistical differences were observed between DP and VP regimens in terms of one-year survival rate, leukopenia, neutropenia, thrombocytopenia, anorexia, nausea, and vomiting. CONCLUSIONS: DP regimen reduced the rate of anemia and increased the rate of diarrhea, two-year survival rate, and response rate. Therefore, DP regimen may be a more effective option as a first-line treatment for advanced NSCLC compared with VP regimen. PMID- 24758909 TI - [The intra-observer variability of volumetric measurement of pulmonary nodules: comparison of two-dimensional and three-dimensional method]. AB - BACKGROUND AND OBJECTIVE: Software oriented three-dimensional (3D) volumetric measurement of pulmonary nodules has been feasible in the follow-up of indeterminate pulmonary nodules, however, its value need a further validation. The purpose of this study is to retrospectively analyze the chest CT data of patients with pulmonary nodules to compare the intra-observer variability of 3D and two-dimensional (2D) volumetric measurement. METHODS: Eighty-six pulmonary nodules in chest CT scans of 79 subjects were retrospectively analyzed. One radiologist measured the nodules twice with a 7 days interval using 2D and 3D methods respectively. The maximal diameter (X), the perpendicular diameter (Y) on maximal cross sectional area of the nodule and the caudo-cranial diameter (Z) were measured and the volume was calculated by two models: spherical and elliptical model. The 3D measurements were acquired with semi-automated software with manual adjustment on unsatisfied nodule segmentation. Logistic regression analysis was performed to evaluate the effect of nodule location and morphology on 3D nodule segmentation. ANOVA and correlation test were used to evaluate the difference among three methods. Bland-Altman method was applied to quantify the intra-observer variability. RESULTS: Software achieved satisfied segmentation for 86.4% nodules. The irregular and juxtavacular nodules have significantly high odds rations (OR) of unsatisfied segmentation as 4.0, 4.5, respectively. The volume measured by three method was significantly different (F=6.5, P=0.012), while the repeated measurements did not led to significant difference (F=1.813, P=0.182). The Spearman correlation efficient between 3D volume and 2D volume with sphere and ellipsoid model was 0.97, 0.88. The 95% limits of agreement of RD between two repeated measurements were -14%-11.6%, -37.7%-39.9% and -39.8%-45.8% for 3D, 2D with elliptical model and spherical model, respectively. CONCLUSIONS: The 3D volume measurement of pulmonary nodules is more repeatable than 2D volume measurement. Unsatisfied segmentation can occurred on a small number of nodules, especially for irregular and juxtavascular nodules. For these nodules, the measurement of 3D diameters is recommended. PMID- 24758910 TI - [Adverse events of afatinib as first-line treatment for five cases of advanced lung adenocarcinoma and review of literature]. AB - BACKGROUND AND OBJECTIVE: Afatinib is an irreversible ErbB-family blocker with a clinical activity in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations. The aim of this study is to assess the safety of afatinib in patients with advanced lung adenocarcinoma. METHODS: Patients with lung adenocarcinoma (stage IIIb or IV) with EGFR mutations were first-line treated with an oral administration of afatinib (40 mg/d) until disease progression. Adverse events, effects, and survival condition were observed. RESULTS: The most common adverse events were diarrhea (n=5, 100%), skin rash (n=4, 80%), and mucositis/stomatitis (n=4, 80%). Moderate toxicities not exceeding grade 3 were observed. Relatively, the most serious adverse reaction was mucositis/stomatitis. Mild diarrhea occurred in all patients. Three patients experienced temporary drug withdrawal and dose reduction because of adverse reaction. Among the four patients who were evaluated, partial response was observed in two patients (50%), one with stable disease (25%) and one with progressive disease (25%). Median progression-free survival was 9.7 months, whereas median overall survival was 18.4 months. CONCLUSIONS: Afatinib was approved as first-line treatment for patients with advanced lung adenocarcinoma. The most common adverse events were diarrhea and skin rash. However, mucositis/stomatitis related to afatinib should also be considered. Considering the small number of cases, the conclusion requires more trials for confirmation. PMID- 24758911 TI - [Advances of the relationship between leptin system and non-small cell lung cancer]. AB - Leptin system plays an important role in lung inflammation and tumorigenesis, but the precise function in the tumormicrovironment and the prognosis value of the leptin system in lung cancer have not been fully elucidated. This review will focus on the relationship between leptin system and non-small cell lung cancer (NSCLC), in which special attentions will be paid on the expression of leption and its receptor (LepR) in peripheral blood and tumor tissues, leptin-related signal transduction pathways, the interaction between leption and regulatory T cells (Treg) and the gene polymorphisms of leptin and leptin receptor, and possibly provide new strategies for diagnosis and treatment of NSCLC. PMID- 24758912 TI - [Radiation pneumonitis after stereotactic body radiation therapy for early stage non-small cell lung cancer]. AB - With the development of radiation technology, stereotactic body radiation therapy (SBRT) has been widely used in early stage non-small cell lung cancer (NSCLC). It is not only the standard therapy for medically inoperable early-stage NSCLC, but also one of the therapies for operable early-stage NSCLC. Radiation pneumonitis (RP) is one of the most common adverse effects after SBRT, it may reduce the patients' quality of life, even cause treatment failure. Therefore, in order to improve the patients' quality of life and enhance local control rate of tumor, it is important to reduce the risk of RP. The unique fractionation schemes and the dose distribution of SBRT make it not only different from conventional fraction radiation therapy in treatment outcomes, but also in the incidence of radiation pneumonitis. This article reviews the applying of SBRT for early stage NSCLC, the incidence of radiation pneumonitis, radiological appearance after SBRT and predictive factors. PMID- 24758913 TI - [Clinical developments for the EGFR-TKI combined with radiotherapy in advanced non-small cell lung cancer]. AB - Lung cancer is one of the most common malignant tumor in the world, severely threatening human life. Recently, targeted therapy such as the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) made huge progress in treatment of lung cancer. EGFR-TKIs, with its high selectivity and low toxicity, is the first choice for EGFR-mutated patients in stage IV non-small cell lung cancer (NSCLC). However, secondary drug resistance becomes a clinical problem to be urgently resolved. In recent years, a series of preclinical studies showed that EGFR-TKI can enhance the antitumor activity of ionizing radiation. Therefore, EGFR-TKI combined with radiation is extremely promising therapy pattern for advanced NSCLC. This review will discuss the research status in EGFR TKI and radiotherapy for advanced NSCLC. PMID- 24758914 TI - The screening of the 3'UTR sequence of LRRK2 identified an association between the rs66737902 polymorphism and Parkinson's disease. AB - Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinants of familial and sporadic Parkinson's disease (PD). Most of the mutational screenings analyzed the exon-coding sequence. Our aim was to determine whether LRRK2 3' untranslated region (UTR) variants were associated with the risk of developing PD in a large cohort of patients (n=743) and controls (n=523) from Spain. We identified a total of 12 3'UTR variants (two new). Single nucleotide polymorphism (SNP) rs66737902 C allele was overrepresented in patients (P=0.005; odds ratio=1.47). This SNP was in linkage disequilibrium with the p.R1441G mutation, but the association remained significant among mutation negative cases. We found a significant lower level of the LRRK2 transcript in the Substantia nigra (SN) of PD postmortem donors (n=9) who were rs66737902 C carriers (P=0.01). This SNP was predicted to affect a binding site for miR-138-2 3p. We showed that this microRNA was expressed in all the SN samples. In conclusion, we found a significant association between SNP rs66737902 and the risk of developing PD. This effect on PD risk could be explained by differences in LRRK2 transcript levels between the two alleles. PMID- 24758916 TI - High-coherence electron and ion bunches from laser-cooled atoms. AB - Cold atom electron and ion sources produce electron bunches and ion beams by photoionization of laser-cooled atoms. They offer high coherence and the potential for high brightness, with applications including ultra-fast electron diffractive imaging of dynamic processes at the nanoscale. The effective brightness of electron sources has been limited by nonlinear divergence caused by repulsive interactions between the electrons, known as the Coulomb explosion. It has been shown that electron bunches with ellipsoidal shape and uniform density distribution have linear internal Coulomb fields, such that the Coulomb explosion can be reversed using conventional optics. Our source can create bunches shaped in three dimensions and hence in principle achieve the transverse spatial coherence and brightness needed for picosecond-diffractive imaging with nanometer resolution. Here we present results showing how the shaping capability can be used to measure the spatial coherence properties of the cold electron source. We also investigate space-charge effects with ions and generate electron bunches with durations of a few hundred picoseconds. Future development of the cold atom electron and ion source will increase the bunch charge and charge density, demonstrate reversal of Coulomb explosion, and ultimately, ultra-fast coherent electron-diffractive imaging. PMID- 24758915 TI - Ceramide inhibits connective tissue growth factor expression by human retinal pigment epithelial cells. AB - Connective tissue growth factor (CTGF) is known to be involved in retinal fibrotic disorders. We used human retinal pigment epithelial cells (HRPE), which play critical roles in retinal fibrosis, to examine the expression of CTGF and its regulation by ceramide and TGF-beta. Real-time PCR analysis showed downregulation of CTGF mRNA by C2 ceramide and upregulation by TGF-beta. C2 ceramide also inhibited constitutive and TGF-beta-enhanced CTGF secretion by HRPE cells. Predominant secretion (>80% of total) of CTGF from the apical side was observed in highly polarized HRPE cells. Fumonosin, an inhibitor of ceramide synthesis, stimulated CTGF secretion while 4HPR, an activator of ceramide synthesis, downregulated CTGF secretion. Based on these results demonstrating ceramide regulation of CTGF secretion by HRPE, we suggest that ceramide may have therapeutic potential for the treatment of retinal fibrotic diseases by inhibiting CTGF production. PMID- 24758917 TI - Changes in pattern of practice: a personal challenge for accreditation. PMID- 24758918 TI - Peer review in British Columbia: a general radiologist's perspective. PMID- 24758919 TI - The Lung Reporting and Data System (LU-RADS): a proposal for computed tomography screening. AB - Despite the positive outcome of the recent randomized trial of computed tomography (CT) screening for lung cancer, substantial implementation challenges remain, including the clear reporting of relative risk and suggested workup of screen-detected nodules. Based on current literature, we propose a 6-level Lung Reporting and Data System (LU-RADS) that classifies screening CTs by the nodule with the highest malignancy risk. As the LU-RADS level increases, the risk of malignancy increases. The LU-RADS level is linked directly to suggested follow-up pathways. Compared with current narrative reporting, this structure should improve communication with patients and clinicians, and provide a data collection framework to facilitate screening program evaluation and radiologist training. In overview, category 1 includes CTs with no nodules and returns the subject to routine screening. Category 2 scans harbor minimal risk, including <5 mm, perifissural, or long-term stable nodules that require no further workup before the next routine screening CT. Category 3 scans contain indeterminate nodules and require CT follow up with the interval dependent on nodule size (small [5-9 mm] or large [>= 10 mm] and possibly transient). Category 4 scans are suspicious and are subdivided into 4A, low risk of malignancy; 4B, likely low-grade adenocarcinoma; and 4C, likely malignant. The 4B and 4C nodules have a high likelihood of neoplasm simply based on screening CT features, even if positron emission tomography, needle biopsy, and/or bronchoscopy are negative. Category 5 nodules demonstrate frankly malignant behavior on screening CT, and category 6 scans contain tissue-proven malignancies. PMID- 24758920 TI - The Resazurin Reduction Assay Can Distinguish Cytotoxic from Cytostatic Compounds in Spheroid Screening Assays. AB - Spheroid-based cellular screening approaches represent a highly physiologic experimental setup to identify novel anticancer drugs and an innovative preclinical model to reduce the high failure rate of anticancer compounds in clinical trials. The resazurin reduction (RR) assay, known as the alamarBlue or CellTiter-Blue assay, is frequently used to determine cell viability/proliferation capacity in eukaryotic cells. Whether this assay is applicable to assess viability in multicellular spheroids has not been evaluated. We analyzed the RR assay to measure cytotoxic and/or cytostatic responses in tumor cell spheroids compared with conventional 2D cultures. We found that tight cell-cell interactions in compact spheroids hamper resazurin uptake and its subsequent reduction to resorufin, leading to lowered reduction activity in relation to the actual cellular health/cell number. Treatment with staurosporine disrupted close cell-cell contacts, which increased resazurin reduction compared with untreated controls. Loss of tight junctions by trypsinization or addition of EGTA or EDTA restored high resazurin reduction rates in untreated spheroids. In conclusion, the RR assay is unsuited to quantitatively measure cellular health/cell number in compact spheroids. However, it can be used to distinguish between cytotoxic versus cytostatic compounds in spheroids. Restoration of the correlation of cell viability/number to resazurin reduction capacity can be achieved by disruption of tight junctions. PMID- 24758921 TI - Involvement of the long-chain fatty acid receptor GPR40 in depression-related behavior. AB - The functional role of brain G protein-coupled receptor 40 (GPR40) remains unclear. We investigated GPR40 signaling in depression-related behavior in mice via the forced swim test. A repeated but not a single intracerebroventricular administration of the GPR40 agonist, GW9508, reduced the duration of immobility behavior. Moreover, the levels of hippocampal non-esterified docosahexaenoic acid and arachidonic acid were decreased immediately after the forced swimming. These results suggested that brain GPR40 signaling may regulate depression-related behavior. PMID- 24758922 TI - Cyclovirobuxine D induces autophagy-associated cell death via the Akt/mTOR pathway in MCF-7 human breast cancer cells. AB - Autophagy is a highly regulated and multi-step biological process that serves to remove damaged cytoplasmic components and organelles. It has been suggested that the activation of autophagy may be a promising therapeutic strategy for cancer treatment by triggering cell death. In this study, we reported that cyclovirobuxine D (CVB-D), an alkaloid component in a traditional Chinese herb, could induce autophagy in the MCF-7 human breast cancer cell line. CVB-D inhibited the viability of MCF-7 cells in a concentration- and time-dependent manner. Activation of autophagy was characterized by transmission electron microscopy, monodansylcadaverine staining, and expression of autophagy marker microtubule-associated protein 1 light chain 3 (LC3). After CVB-D treatment, a clear accumulation of autophagosomes was observed accompanied with elevated LC3 fluorescent puncta. Western blot analysis revealed that CVB-D significantly promoted the conversion from LC3-I to LC3-II and the expression of autophagy related protein 5 (ATG5), which are both essential for autophagosome formation. On the other hand, CVB-D-induced autophagy and decrease in cell viability could be blocked by 3-methyladenine, a well-established autophagy inhibitor. Moreover, CVB-D attenuated the phosphorylation of Akt and mTOR, two pivotal suppressors in autophagy pathways. These findings shed new light on the pharmacological actions and mechanism of CVB-D and may support the potential utility of autophagy inducers in cancer treatment. PMID- 24758923 TI - Gentamicin blocks the ACh-induced BK current in guinea pig type II vestibular hair cells by competing with Ca2+ at the L-type calcium channel. AB - Type II vestibular hair cells (VHCs II) contain big-conductance Ca2+-dependent K+ channels (BK) and L-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh) evoked the BK current by triggering the influx of Ca2+ ions through L-type Ca2+ channels, which was mediated by M2 muscarinic ACh receptor (mAChRs). Aminoglycoside antibiotics, such as gentamicin (GM), are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage independent, and dose-dependent with an IC50 value of 36.3 +/- 7.8 uM. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca2+ concentration ([Ca2+]0) could antagonize it. Moreover, 50 uM GM potently blocked Ca2+ currents activated by (-)-Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca2+ at the L-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II. PMID- 24758924 TI - Effects of RNAi-mediated knockdown of histone methyltransferases on the sex specific mRNA expression of Imp in the silkworm Bombyx mori. AB - Sexual differentiation in Bombyx mori is controlled by sex-specific splicing of Bmdsx, which results in the omission of exons 3 and 4 in a male-specific manner. In B. mori, insulin-like growth factor II mRNA-binding protein (Imp) is a male specific factor involved in male-specific splicing of Bmdsx. Male-specific Imp mRNA results from the male-specific inclusion of exon 8. To verify the link between histone methylation and alternative RNA processing in Imp, we examined the effects of RNAi-mediated knockdown of several histone methyltransferases on the sex-specific mRNA expression of Imp. As a result, male-specific expression of Imp mRNA was completely abolished when expression of the H3K79 methyltransferase DOT1L was repressed to <10% of that in control males. Chromatin immunoprecipitation-quantitative PCR analysis revealed a higher distribution of H3K79me2 in normal males than in normal females across Imp. RNA polymerase II (RNAP II) processivity assays indicated that RNAi knockdown of DOT1L in males caused a twofold decrease in RNAP II processivity compared to that in control males, with almost equivalent levels to those observed in normal females. Inhibition of RNAP II-mediated elongation in male cells repressed the male specific splicing of Imp. Our data suggest the possibility that H3K79me2 accumulation along Imp is associated with the male-specific alternative processing of Imp mRNA that results from increased RNAP II processivity. PMID- 24758925 TI - Modeling and docking studies on novel mutants (K71L and T204V) of the ATPase domain of human heat shock 70 kDa protein 1. AB - The purpose of exploring protein interactions between human adenovirus and heat shock protein 70 is to exploit a potentially synergistic interaction to enhance anti-tumoral efficacy and decrease toxicity in cancer treatment. However, the protein interaction of Hsp70 with E1A32 kDa of human adenovirus serotype 5 remains to be elucidated. In this study, two residues of ATPase domain of human heat shock 70 kDa protein 1 (PDB: 1 HJO) were mutated. 3D mutant models (K71L and T204V) using PyMol software were then constructed. The structures were evaluated by PROCHECK, ProQ, ERRAT, Verify 3D and ProSA modules. All evidence suggests that all protein models are acceptable and of good quality. The E1A32 kDa motif was retrieved from UniProt (P03255), as well as subjected to docking interaction with NBD, K71L and T204V, using the Autodock 4.2 program. The best lowest binding energy value of -9.09 kcal/mol was selected for novel T204V. Moreover, the protein-ligand complex structures were validated by RMSD, RMSF, hydrogen bonds and salt bridge analysis. This revealed that the T204V-E1A32 kDa motif complex was the most stable among all three complex structures. This study provides information about the interaction between Hsp70 and the E1A32 kDa motif, which emphasizes future perspectives to design rational drugs and vaccines in cancer therapy. PMID- 24758926 TI - The effect of size on Ag nanosphere toxicity in macrophage cell models and lung epithelial cell lines is dependent on particle dissolution. AB - Silver (Ag) nanomaterials are increasingly used in a variety of commercial applications. This study examined the effect of size (20 and 110 nm) and surface stabilization (citrate and PVP coatings) on toxicity, particle uptake and NLRP3 inflammasome activation in a variety of macrophage and epithelial cell lines. The results indicated that smaller Ag (20 nm), regardless of coating, were more toxic in both cell types and most active in the THP-1 macrophages. TEM imaging demonstrated that 20 nm Ag nanospheres dissolved more rapidly than 110 nm Ag nanospheres in acidic phagolysosomes consistent with Ag ion mediated toxicity. In addition, there were some significant differences in epithelial cell line in vitro exposure models. The order of the epithelial cell lines' sensitivity to Ag was LA4 > MLE12 > C10. The macrophage sensitivity to Ag toxicity was C57BL/6 AM > MARCO null AM, which indicated that the MARCO receptor was involved in uptake of the negatively charged Ag particles. These results support the idea that Ag nanosphere toxicity and NLRP3 inflammasome activation are determined by the rate of surface dissolution, which is based on relative surface area. This study highlights the importance of utilizing multiple models for in vitro studies to evaluate nanomaterials. PMID- 24758927 TI - A new type I peritrophic membrane protein from larval Holotrichia oblita (Coleoptera: Melolonthidae) binds to chitin. AB - Peritrophic membranes (PMs) are composed of chitin and protein. Chitin and protein play important roles in the structural formation and function of the PM. A new type I PM protein, HoCBP76, was identified from the Holotrichia oblita. HoCBP76 was shown as a 62.3 kDa protein by SDS-PAGE analysis and appeard to be associated with the PM throughout its entire length. In H. oblita larvae, the midgut is the only tissue where HoCBP76 could be detected during the feeding period of the larvae. The predicted amino acid sequence indicates that it contains seven tandem chitin binding domains belonging to the peritrophin-A family. HoCBP76 has chitin binding activity and is strongly associated with the PM. The HoCBP76 was not a mucin-like glycoprotein, and the consensus of conserved cysteines appeared to be CX13-17CX5CX9CX12CX7C. Western blot analysis showed that the abundance of HoCBP76 in the anterior, middle and posterior regions of the midgut was similar, indicating that HoCBP76 was secreted by the whole midgut epithelium, and confirmed the H. oblita PM belonged to the Type I PM. Immunolocalization analysis showed that HoCBP76 was mainly localized in the PM. The HoCBP76 is the first PM protein found in the H. oblita; however, its biochemical and physiological functions require further investigation. PMID- 24758929 TI - Preparation and characterization of gelatin nanofibers containing silver nanoparticles. AB - Ag nanoparticles (NPs) were synthesized in formic acid aqueous solutions through chemical reduction. Formic acid was used for a reducing agent of Ag precursor and solvent of gelatin. Silver acetate, silver tetrafluoroborate, silver nitrate, and silver phosphate were used as Ag precursors. Ag+ ions were reduced into Ag NPs by formic acid. The formation of Ag NPs was characterized by a UV-Vis spectrophotometer. Ag NPs were quickly generated within a few minutes in silver nitrate (AgNO3)/formic acid solution. As the water content of formic acid aqueous solution increased, more Ag NPs were generated, at a higher rate and with greater size. When gelatin was added to the AgNO3/formic acid solution, the Ag NPs were stabilized, resulting in smaller particles. Moreover, gelatin limits further aggregation of Ag NPs, which were effectively dispersed in solution. The amount of Ag NPs formed increased with increasing concentration of AgNO3 and aging time. Gelatin nanofibers containing Ag NPs were fabricated by electrospinning. The average diameters of gelatin nanofibers were 166.52 +/- 32.72 nm, but these decreased with the addition of AgNO3. The average diameters of the Ag NPs in gelatin nanofibers ranged between 13 and 25 nm, which was confirmed by transmission electron microscopy (TEM). PMID- 24758928 TI - Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds. AB - Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines' release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD. PMID- 24758930 TI - The lethal giant larvae gene in Tribolium castaneum: molecular properties and roles in larval and pupal development as revealed by RNA interference. AB - We identified and characterized the TcLgl gene putatively encoding lethal giant larvae (Lgl) protein from the red flour beetle (Tribolium castaneum). Analyses of developmental stage and tissue-specific expression patterns revealed that TcLgl was constitutively expressed. To examine the role of TcLgl in insect development, RNA interference was performed in early (1-day) larvae, late (20-day) larvae, and early (1-day) pupae. The early larvae injected with double-stranded RNA of TcLgl (dsTcLgl) at 100, 200, and 400 ng/larva failed to pupate, and 100% mortality was achieved within 20 days after the injection or before the pupation. The late larvae injected with dsTcLgl at these doses reduced the pupation rates to only 50.3%, 36.0%, and 18.2%, respectively. The un-pupated larvae gradually died after one week, and visually unaffected pupae failed to emerge into adults and died during the pupal stage. Similarly, when early pupae were injected with dsTcLgl at these doses, the normal eclosion rates were reduced to only 22.5%, 18.0%, and 11.2%, respectively, on day 7 after the injection, and all the adults with abnormal eclosion died in two days after the eclosion. These results indicate that TcLgl plays an essential role in insect development, especially during their metamorphosis. PMID- 24758932 TI - Treatment of single or multiple brain metastases by hypofractionated stereotactic radiotherapy using helical tomotherapy. AB - This study investigated the clinical outcomes of a 4-fraction stereotactic radiotherapy (SRT) study using helical tomotherapy for brain metastases. Between August 2009 and June 2013, 54 patients with a total of 128 brain metastases underwent SRT using tomotherapy. A total dose of 28 or 28.8 Gy at 80% isodose was administered in 4 fractions for all tumors. The mean gross tumor volume (GTV) was 1.9 cc. Local control (LC) rates at 6, 12, and 18 months were 96%, 91%, and 88%, respectively. The 12-month LC rates for tumors with GTV <=0.25, >0.25 and <=1, and >1 cc were 98%, 82%, and 93%, respectively; the rates were 92% for tumors >3 cc and 100% for >10 cc. The 6-month rates for freedom from distant brain failure were 57%, 71%, and 55% for patients with 1, 2, and >3 brain metastases, respectively. No differences were significant. No major complications were observed. The 4-fraction SRT protocol provided excellent tumor control with minimal toxicity. Distant brain failure was not so frequent, even in patients with multiple tumors. The results of the current study warrant a prospective randomized study comparing single-fraction stereotactic radiosurgery (SRS) with SRT in this patient population. PMID- 24758931 TI - An environmentally benign protocol for aqueous synthesis of tetrahydrobenzo[b]pyrans catalyzed by cost-effective ionic liquid. AB - A mild, efficient, and environmentally benign protocol for the synthesis of tetrahydrobenzo[b]pyran derivatives in the presence of readily accessible, biodegradable, and choline hydroxide based ionic liquid as catalyst has been established. The key features of the reported methodology include good to excellent yields of desired products, simple work-up procedure and good recyclability of catalysts, which may be a practical alternative to the existing conventional processes for the preparation of 4-H pyrans to cater to the requirements of academia as well as industry. PMID- 24758933 TI - Protective effect of resveratrol against IL-1beta-induced inflammatory response on human osteoarthritic chondrocytes partly via the TLR4/MyD88/NF-kappaB signaling pathway: an "in vitro study". AB - Resveratrol is a natural polyphenolic compound that prevents inflammation in chondrocytes and animal models of osteoarthritis (OA) via yet to be defined mechanisms. The purpose of this study was to determine whether the protective effect of resveratrol on IL-1beta-induced human articular chondrocytes was associated with the TLR4/MyD88/NF-kB signaling pathway by incubating human articular chondrocytes (harvested from osteoarthritis patients) with IL-1beta before treatment with resveratrol. Cell viability was evaluated using the MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and TNFalpha levels in culture supernatants were measured by ELISA(Enzymelinked immunosorbent assay). The levels of TLR4 and its downstream signaling targets (MyD88 and TRAF6) and IL-1beta were assessed by measuring the levels of mRNA and protein expression by real-time RT-PCR and western blot analysis, respectively, in addition to assessing NF-kB activation. In addition, TLR4 siRNA was used to block TLR4 expression in chondrocytes further demonstrating that resveratrol prevented IL 1beta-mediated inflammation by TLR4 inhibition. We found that resveratrol prevented IL-1beta-induced reduction in cell viability. Stimulation of chondrocytes with IL-1beta caused a significant up-regulation of TLR4 and its downstream targets MyD88 and TRAF6 resulting in NF-kB activation associated with the synthesis of IL-1beta and TNFalpha. These IL-1beta-induced inflammatory responses were all effectively reversed by resveratrol. Furthermore, activation of NF-kB in chondrocytes treated with TLR4 siRNA was significantly attenuated, but not abolished, and exposure to resveratrol further reduced NF-kB translocation. These data suggested that resveratrol prevented IL-1beta-induced inflammation in human articular chondrocytes at least in part by inhibiting the TLR4/MyD88/NF-kB signaling pathway suggesting that resveratrol has the potential to be used as a nutritional supplement to counteract OA symptoms. PMID- 24758934 TI - Doublecortin may play a role in defining chondrocyte phenotype. AB - Embryonic development of articular cartilage has not been well understood and the role of doublecortin (DCX) in determination of chondrocyte phenotype is unknown. Here, we use a DCX promoter-driven eGFP reporter mouse model to study the dynamic gene expression profiles in mouse embryonic handplates at E12.5 to E13.5 when the condensed mesenchymal cells differentiate into either endochondral chondrocytes or joint interzone cells. Illumina microarray analysis identified a variety of genes that were expressed differentially in the different regions of mouse handplate. The unique expression patterns of many genes were revealed. Cytl1 and 3110032G18RIK were highly expressed in the proximal region of E12.5 handplate and the carpal region of E13.5 handplate, whereas Olfr538, Kctd15, and Cited1 were highly expressed in the distal region of E12.5 and the metacarpal region of E13.5 handplates. There was an increasing gradient of Hrc expression in the proximal to distal direction in E13.5 handplate. Furthermore, when human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. These findings suggest that DCX may play a role in defining chondrocyte phenotype. PMID- 24758935 TI - Systemic immune effects of titanium dioxide nanoparticles after repeated intratracheal instillation in rat. AB - The potential immune effects of titanium dioxide nanoparticles (nano-TiO2) are raising concern. Our previous study verified that nano-TiO2 induce local immune response in lung tissue followed by intratracheal instillation administration. In this study, we aim to evaluate the systemic immune effects of nano-TiO2. Sprague Dawley rats were treated by intratracheal instillation with nano-TiO2 at doses of 0.5, 4, and 32 mg/kg body weight, micro-TiO2 with 32 mg/kg body weight and 0.9% NaCl, respectively. The exposure was conducted twice a week, for four consecutive weeks. Histopathological immune organs from exposed animals showed slight congestion in spleen, generally brown particulate deposition in cervical and axillary lymph node. Furthermore, immune function response was characterized by increased proliferation of T cells and B cells following mitogen stimulation and enhanced natural killer (NK) cell killing activity in spleen, accompanying by increased number of B cells in blood. No significant changes of Th1-type cytokines (IL-2 and INF-gamma) and Th2-type cytokines (TNF-alpha and IL-6) were observed. Intratracheal exposure to nano-TiO2 may be one of triggers to be responsible for the systemic immune response. Further study is needed to confirm long-lasting lymphocyte responses and the potential mechanisms. PMID- 24758936 TI - Synthesis of environmentally friendly highly dispersed magnetite nanoparticles based on rosin cationic surfactants as thin film coatings of steel. AB - This work presents a new method to prepare monodisperse magnetite nanoparticles capping with new cationic surfactants based on rosin. Core/shell type magnetite nanoparticles were synthesized using bis-N-(3-levopimaric maleic acid adduct-2 hydroxy) propyl-triethyl ammonium chloride (LPMQA) as capping agent. Fourier transform infrared spectroscopy (FTIR) was employed to characterize the nanoparticles chemical structure. Transmittance electron microscopies (TEM) and X ray powder diffraction (XRD) were used to examine the morphology of the modified magnetite nanoparticles. The magnetite dispersed aqueous acid solution was evaluated as an effective anticorrosion behavior of a hydrophobic surface on steel. The inhibition effect of magnetite nanoparticles on steel corrosion in 1 M HCl solution was investigated using potentiodynamic polarization curves and electrochemical impedance spectroscopy (EIS). Results obtained from both potentiodynamic polarisation and EIS measurements reveal that the magnetite nanoparticle is an effective inhibitor for the corrosion of steel in 1.0 M HCl solution. Polarization data show that magnetite nanoparticles behave as a mixed type inhibitor. The inhibition efficiencies obtained from potentiodynamic polarization and EIS methods are in good agreement. PMID- 24758939 TI - Single nucleotide polymorphisms in growth hormone gene and their association with growth traits in Siniperca chuatsi (Basilewsky). AB - Growth hormone (GH) has been considered as a candidate gene for growth traits in fish. In this study, polymorphisms of the GH gene were evaluated for associations with growth traits in 282 Siniperca chuatsi individuals. Using directly sequencing, four single nucleotide polymorphisms (SNPs) were identified in GH gene, with two mutations in intron 4 (g.4940A>C, g.4948A>T), one mutation in exon 5 (g.5045T>C) and one in intron 5 (g.5234T>G). Notably, three of them were significantly associated with growth performance, particularly for g.4940A>C which was highly correlated with all the four growth traits. In conclusion, our results demonstrated that these SNPs in GH gene could influence growth performance of S.chuatsi and could be used for marker-assisted selection (MAS) in this species. PMID- 24758938 TI - Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury. AB - Mesenchymal stem cells from human bone marrow (hMSC) have the potential to differentiate into hepatocyte-like cells in vitro and continue to maintain important hepatocyte functions in vivo after transplantation into host mouse livers. Here, hMSC were differentiated into hepatocyte-like cells in vitro (hMSC HC) and transplanted into livers of immunodeficient Pfp/Rag2-/- mice treated with a sublethal dose of acetaminophen (APAP) to induce acute liver injury. APAP induced a time- and dose-dependent damage of perivenous areas of the liver lobule. Serum levels of aspartate aminotransferase (AST) increased to similar levels irrespective of hMSC-HC transplantation. Yet, hMSC-HC resided in the damaged perivenous areas of the liver lobules short-term preventing apoptosis and thus progress of organ destruction. Disturbance of metabolic protein expression was lower in the livers receiving hMSC-HC. Seven weeks after APAP treatment, hepatic injury had completely recovered in groups both with and without hMSC-HC. Clusters of transplanted cells appeared predominantly in the periportal portion of the liver lobule and secreted human albumin featuring a prominent quality of differentiated hepatocytes. Thus, hMSC-HC attenuated the inflammatory response and supported liver regeneration after acute injury induced by acetaminophen. They hence may serve as a novel source of hepatocyte-like cells suitable for cell therapy of acute liver diseases. PMID- 24758937 TI - Drug-induced hepatotoxicity: metabolic, genetic and immunological basis. AB - Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around "trigger point" papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention. PMID- 24758940 TI - Protein conformational dynamics dictate the binding affinity for a ligand. AB - Interactions between a protein and a ligand are essential to all biological processes. Binding and dissociation are the two fundamental steps of ligand protein interactions, and determine the binding affinity. Intrinsic conformational dynamics of proteins have been suggested to play crucial roles in ligand binding and dissociation. Here, we demonstrate how protein dynamics dictate the binding and dissociation of a ligand through a single-molecule kinetic analysis for a series of maltose-binding protein mutants that have different intrinsic conformational dynamics and dissociation constants for maltose. Our results provide direct evidence that the ligand dissociation is determined by the intrinsic opening rate of the protein. PMID- 24758942 TI - Energetics of gating MscS by membrane tension in azolectin liposomes and giant spheroplasts. AB - Mechanosensitive (MS) ion channels are molecular sensors that detect and transduce signals across prokaryotic and eukaryotic cell membranes arising from external mechanical stimuli or osmotic gradients. They play an integral role in mechanosensory responses including touch, hearing, and proprioception by opening or closing in order to facilitate or prevent the flow of ions and organic osmolytes. In this study we use a linear force model of MS channel gating to determine the gating membrane tension (gamma) and the gating area change (DeltaA) associated with the energetics of MscS channel gating in giant spheroplasts and azolectin liposomes. Analysis of Boltzmann distribution functions describing the dependence of MscS channel gating on membrane tension indicated that the gating area change (DeltaA) was the same for MscS channels recorded in both preparations. The comparison of the membrane tension (gamma) gating the channel, however, showed a significant difference between the MscS channel activities in these two preparations. PMID- 24758941 TI - Dual inhibitory pathways of metallofullerenol Gd@C82(OH)22 on matrix metalloproteinase-2: molecular insight into drug-like nanomedicine. AB - Cancer metastasis is an important criterion to evaluate tumor malignancy. Matrix metalloproteinases (MMPs) play a crucial role in cancer proliferation and migration by virtue of their proteolytic functions in angiogenesis and extracelluar matrix (ECM) degradation, making them potential targets of anti metastaic therapeutics. Recently we showed with both in vivo and in vitro experiments that metallofullerenol Gd@C82(OH)22 can effectively inhibit MMP-2 and MMP-9 with high antitumoral efficacy. Furthermore, our in silico study revealed that Gd@C82(OH)22 could indirectly inhibit the proteolysis of MMP-9 via allosteric modulation exclusively at the ligand specificity S1' loop. Here, we expand our study toward another gelatinase, MMP-2, using molecular dynamics simulations. Despite the high structural similarity with 64.3% sequence identity, their responses to Gd@C82(OH)22 were quite different. Toward MMP-2, Gd@C82(OH)22 could block either the Zn(2+)-catalylitic site directly or the S1' loop indirectly. Surface electrostatics uniquely determines the initial adsorption of Gd@C82(OH)22 on MMP-2, and then its further location of the most favorable binding site(s). These findings not only illustrated how the inhibitory mechanism of Gd@C82(OH)22 is distinguished between the two gelatinase MMPs with atomic details, but also shed light on the de novo design of anti-metastatic nanotherapeutics with enhanced target specificity. PMID- 24758945 TI - Managing ADHD and disruptive behaviour disorders with combination psychostimulant and antipsychotic treatment. PMID- 24758944 TI - Have we met before? Neural correlates of emotional learning in women with social phobia. AB - BACKGROUND: Altered memory processes are thought to be a key mechanism in the etiology of anxiety disorders, but little is known about the neural correlates of fear learning and memory biases in patients with social phobia. The present study therefore examined whether patients with social phobia exhibit different patterns of neural activation when confronted with recently acquired emotional stimuli. METHODS: Patients with social phobia and a group of healthy controls learned to associate pseudonames with pictures of persons displaying either a fearful or a neutral expression. The next day, participants read the pseudonames in the magnetic resonance imaging scanner. Afterwards, 2 memory tests were carried out. RESULTS: We enrolled 21 patients and 21 controls in our study. There were no group differences for learning performance, and results of the memory tests were mixed. On a neural level, patients showed weaker amygdala activation than controls for the contrast of names previously associated with fearful versus neutral faces. Social phobia severity was negatively related to amygdala activation. Moreover, a detailed psychophysiological interaction analysis revealed an inverse correlation between disorder severity and frontolimbic connectivity for the emotional > neutral pseudonames contrast. LIMITATIONS: Our sample included only women. CONCLUSION: Our results support the theory of a disturbed cortico limbic interplay, even for recently learned emotional stimuli. We discuss the findings with regard to the vigilance-avoidance theory and contrast them to results indicating an oversensitive limbic system in patients with social phobia. PMID- 24758946 TI - A 16-year experience in minimally invasive aortic valve replacement: context for the changing management of aortic valve disease. AB - OBJECTIVE: The aim of this study was to evaluate short- and long-term morbidity and mortality in patients with aortic valve disease who had minimally invasive aortic valve replacement (AVR) through upper hemisternotomy. METHODS: From July 1996 to June 2012, a total of 1639 patients underwent minimally invasive aortic valve surgery (AVR). Patient data were extracted from hospital electronic records after institutional review board approval. Outcomes of interest included postoperative complication rates, perioperative mortality, and long-term survival. RESULTS: The mean age was 67 years (SD, 14 years; range, 22-95 years). Of the total cohort, 211 (13%) underwent reoperative AVR. Postoperatively, 2.3% (37/1639) had reoperations to correct bleeding, 2.7% (44/1639) had strokes, 20.4% (334/1639) had new-onset atrial fibrillation, and 1.5% (24/1639) required permanent pacemakers. Only 34% (571/1639) of the patients received packed red blood cells. The median discharge was on day 6 (5-8), and 72.2% of the patients (1184/1639) were discharged home. Operative mortality was 2.9% (48/1639), and long-term survival at 1, 5, 10, and 15 years was 96%, 93%, 92%, and 92%, respectively. Operative mortality was 5.7% (12/208) for the reoperative patients. CONCLUSIONS: The upper hemisternotomy approach for AVR is safe and reliable, especially for patients undergoing reoperations and those older than 80 years. PMID- 24758947 TI - Minimally invasive approach to the supradiaphragmatic inferior vena cava: total thoracoscopic caval isolation. AB - Minimally invasive techniques for cardiac operations have evolved in safety and popularity. To our knowledge, a thoracoscopic technique for control of the inferior vena cava (IVC) has not been previously described. We report a case of a right renal cell cancer with tumor extension into the IVC. Total thoracoscopic isolation and occlusion of the IVC were performed. Intraoperative real-time transesophageal echocardiography confirmed complete cessation of caval flow upon cinching the Rummel tourniquet. As extensive intra-abdominal operations are more often being attempted laparoscopically or robotically, video-assisted thoracoscopic IVC occlusion for proximal control for tumors extending into the cava can be achieved to offer a minimally invasive thoracic approach. PMID- 24758948 TI - The HeartShield device reduces the risk for right ventricular damage in patients with deep sternal wound infection. AB - OBJECTIVE: Right ventricular rupture, resulting in serious bleeding, is a life threatening complication associated with negative-pressure wound therapy (NPWT) in cardiac surgery. The use of a rigid barrier between the heart and the sharp sternal edges has been successfully tested on pigs. In the present article, we demonstrate increased safety in NPWT through the use of the HeartShield device. METHODS: Six patients were treated with a specially designed device in combination with NPWT. The device consists of a horizontally placed disk covered in foam. The back of the T-shaped device sticks up between the sternal edges and up above skin level. This part of the device is also covered in foam. Drainage is performed through two holes at the top of the device. The device and foam are changed every second to third day, and -120 mm Hg of continuous therapy is used. Six patients were treated with traditional NPWT, serving as control group. RESULTS: No signs of calluslike formation were seen on the right ventricle in the group treated with the HeartShield device. In the conventional NPWT control group, all six patients had calluslike formation (>1 * 2 cm2) on the anterior part of the right ventricle. All patients in the HeartShield group had grade 1 epicardial petechial bleeding (<0.5 cm2) on the right ventricle. In the control group, one patient had grade 1 (<0.5 cm2), three patients had grade 2 (0.5-2.0 cm2), and two patients had grade 3 (>2.0 cm2) epicardial petechial bleeding on the right ventricle. No major bleeding or mortality was observed in either group during the course of the study. CONCLUSIONS: The use of the HeartShield device significantly minimizes the contact between the right ventricle and the sternal edges, thereby decreasing the risk for life-threatening complications due to bleeding. PMID- 24758949 TI - Six-month healing of the nonocclusive coronary anastomotic connector in an off pump porcine bypass model. AB - OBJECTIVE: This pilot study evaluates the anastomotic healing of the Excimer Laser Assisted Nonocclusive Anastomosis coronary connector at 6 months in a porcine off-pump coronary artery bypass (OPCAB) model. METHODS: Left internal thoracic artery to left anterior descending coronary artery bypass in two animals and left internal thoracic artery to left anterior descending coronary artery and right internal thoracic artery to right coronary artery bypasses in one animal were evaluated intraoperatively and at 6 months. The anastomoses (n = 4) were examined by angiography, intravascular ultrasound, optical coherence tomography, scanning electron microscopy, and histology. RESULTS: At follow-up, all anastomoses (n = 4) were fully patent (FitzGibbon grade A). Scanning electron microscopy demonstrated complete endothelial coverage of the anastomotic surface, and histology showed minimal streamlining intimal hyperplasia. The in vivo intravascular ultrasound and optical coherence tomography acquisitions confirmed histologic findings. Optical coherence tomography demonstrated 0.06-mm intimal coverage of the intraluminal part of the connector along the full circumference of the anastomosis. CONCLUSIONS: In this pilot study, the Excimer Laser Assisted Nonocclusive Anastomosis coronary connector showed an excellent healing response on the long-term in the porcine OPCAB model. Hence, this new concept might be a potential alternative to hand-sutured anastomosis in (minimally invasive) OPCAB surgery. PMID- 24758950 TI - Impact of sex on the risk to develop contrast-induced nephropathy after transcatheter aortic valve implantation. AB - OBJECTIVE: Contrast-induced nephropathy (CIN) is the third most common cause of acute renal failure and is associated with increased morbidity and in-hospital mortality. Some recent studies identified female sex as a risk factor of CIN. The aim of this study was to determine the relative impact of female sex on the development and clinical outcome of CIN in patients with preexisting renal impairment after transapical transcatheter aortic valve implantation (TAVI). METHODS: From February 2008 to February 2011, a total of 55 TAVI patients [82.4 (6.5) years] with preprocedural serum creatinine level of greater than 1.1 mg/dL were retrospectively investigated. The incidence of postprocedural CIN, lengths of intensive care unit and hospital stay, and short-term mortality among men and women were compared. Contrast-induced nephropathy was defined as a creatinine increase of greater than 0.5 mg/dL or greater than 25% from baseline within 3 days after contrast medium (CM) exposure. RESULTS: The women had significantly lower body surface area [1.8 (0.18) vs 1.95 (0.17) m2; P = 0.002), lower hemoglobin levels [11.5 (1.3) vs 12.7 (1.6) g/dL, P < 0.001], and lower estimated glomerular filtration rate [34.2 (9.7) vs 49.4 (12.3) mL/min per 1.73 m2, P = 0.002]. The amount of CM given was significantly higher in the women relative to body surface area [67.3 (42.5) vs 48.3 (16.6) mL/m2, P = 0.043]. The women received a higher number of blood cell transfusion units [4.4 (3.4) vs 2.1 (2.7) U, P = 0.006]. The frequency of CIN within 72 hours after CM exposure was significantly higher in the women (62.1% vs 26.9%, P = 0.009). A total of 31% of the women (n = 9) versus 7.7% of the men (n = 2) needed hemodialysis (P = 0.031). Analysis of the postoperative morbidity in terms of length of intensive care unit and hospital stay revealed no significant difference between the two groups. Mortality results reached a significant difference at 60 days, with 31% (n = 9) mortality in the women compared with 7.7% (n = 2) in the men (P = 0.031). CONCLUSIONS: Women with preexisting renal impairment are at higher risk than men for CIN, with resultant higher early mortality after transapical TAVI. PMID- 24758951 TI - Aortic valve replacement via right minithoracotomy versus median sternotomy: a propensity score analysis. AB - OBJECTIVE: The aim of this study was to define the relative role of a right minithoracotomy (RT) versus standard median sternotomy (ST) for open aortic valve replacement (AVR). METHODS: A retrospective analysis was performed of all 1348 patients undergoing isolated, open AVR at a single institution during a 14-year period. Because relatively few patients were technically suitable for redo AVR with the RT approach (n = 20), all redo patients (n = 209) were excluded, leaving 1139 patients available for analysis. Patients converting from RT to ST approach (n = 15) were analyzed separately. RESULTS: Relative to ST (n = 672), the RT patients (n = 452) were older with more stenosis but with more recent operation year, lower rate of congestive heart failure, higher ejection fraction, lower rate of endocarditis, and lower rate of renal disease than the ST AVR patients (all P < 0.0001). Right minithoracotomy AVR was associated with longer cardiopulmonary bypass times [157 (25) vs 131 (38), P = 0.0004] and clamp times [103 (20) vs 85 (27), P < 0.0001] but less transfusion (1.4 vs 3.4 U, P = 0.0003), less chest tube output (405 vs 950 mL, P < 0.0001), fewer reoperations for bleeding (0.4% vs 4%, P < 0.0001), shorter length of stay (6 vs 8 days, P = 0.03), and lower rate of atrial fibrillation (15% vs 20%, P = 0.03). Stroke, operative mortality, and survival were not significantly different between the groups. CONCLUSIONS: Given the biases of retrospective propensity-adjusted analysis, these data suggest that RT AVR is a safe alternative to ST AVR in selected patients, with advantages of avoiding sternotomy with associated bleeding, transfusion, and delayed wound healing, at the expense of longer pump and clamp times. PMID- 24758952 TI - Representing potential energy surfaces by high-dimensional neural network potentials. AB - The development of interatomic potentials employing artificial neural networks has seen tremendous progress in recent years. While until recently the applicability of neural network potentials (NNPs) has been restricted to low dimensional systems, this limitation has now been overcome and high-dimensional NNPs can be used in large-scale molecular dynamics simulations of thousands of atoms. NNPs are constructed by adjusting a set of parameters using data from electronic structure calculations, and in many cases energies and forces can be obtained with very high accuracy. Therefore, NNP-based simulation results are often very close to those gained by a direct application of first-principles methods. In this review, the basic methodology of high-dimensional NNPs will be presented with a special focus on the scope and the remaining limitations of this approach. The development of NNPs requires substantial computational effort as typically thousands of reference calculations are required. Still, if the problem to be studied involves very large systems or long simulation times this overhead is regained quickly. Further, the method is still limited to systems containing about three or four chemical elements due to the rapidly increasing complexity of the configuration space, although many atoms of each species can be present. Due to the ability of NNPs to describe even extremely complex atomic configurations with excellent accuracy irrespective of the nature of the atomic interactions, they represent a general and therefore widely applicable technique, e.g. for addressing problems in materials science, for investigating properties of interfaces, and for studying solvation processes. PMID- 24758953 TI - Evaluation and treatment of chronic cough. AB - Chronic cough is a frustrating and common problem, resulting in significant psychological and physical sequelae as well as enormous financial costs in terms of health care expense and time lost from work. Decreased QoL and depression are common. However, using a systematic approach, including assessing whether the patient uses ACE-I and cigarettes, excluding the presence of red flags and risk factors for life-threatening diseases, and obtaining and normal chest radiograph, more than 90% of cases of chronic cough are diagnosed as being caused by UACS, asthma, or GERD. It is recommended to address these conditions sequentially, starting with UACS. Nonasthmatic eosinophilic bronchitis and pertussis infections are unrecognized by primary care providers and should be considered after UACS, asthma, and GERD have been addressed. Finally, cough hypersensitivity syndrome is a new area of research and has been hypothesized to be the underlying factor in many cases of chronic cough, regardless of the inciting factor. More clinical research is needed to further elucidate the cough reflex pathway and the factors involved in modulating its sensitivity, which may eventually lead to new antitussive therapeutics. PMID- 24758954 TI - Low back pain. AB - Low back pain is a common, frequently recurring condition that often has a nonspecific cause. Most nonspecific acute low back pain will improve within several weeks with or without treatment. The diagnostic workup should focus on evaluation for evidence of systemic or pathologic causes. Psychosocial distress, poor coping skills, and high initial disability increase the risk for a prolonged disability course. All patients with acute or chronic low back pain should be advised to remain active. The treatment of chronic nonspecific low back pain involves a multidisciplinary approach targeted at preserving function and preventing disability. Surgical referral is indicated in the presence of severe or progressive neurologic deficits or signs and symptoms of cauda equina syndrome. PMID- 24758955 TI - Leg discomfort: beyond the joints. AB - Although simple characterization of discomfort as cramps, heaviness, shooting pains, and so forth can be misleading, history and examination are key to accurate diagnosis. Absence of both dorsalis pedis and posterior tibial pulses strongly suggests peripheral arterial disease (PAD), and the presence of either pulse makes PAD less likely. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are a common cause of lower extremity myalgias. Restless legs syndrome causes nocturnal discomfort but must be distinguished from confounding"mimics." Neurologic causes of leg symptoms include lumbar spinal stenosis, radiculopathy, distal symmetric polyneuropathy, and entrapment neuropathy. Many common causes of leg discomfort can be managed conservatively. PMID- 24758956 TI - Common dermatologic conditions. AB - When assessing a patient with a new dermatologic condition, developing a differential diagnosis is essential to ensure the condition is not elusive as a workup and potential therapy are considered. Subsequent narrowing of that differential based on history and physical examination can allow a more targeted approach to diagnostic testing and triage, and hasten an effective treatment and resolution. The authors hope to have provided useful historical and clinical clues to aid in the rapid differentiation of the more common diagnoses for alopecias and rashes of the face, intertriginous areas, and legs. PMID- 24758957 TI - Evaluation and treatment of shoulder pain. AB - Shoulder pain is a common symptom in the adult population. The most common cause of shoulder pain is SIS, reflecting a problem with the rotator cuff or subacromial bursa. Determining the cause of a patient's pain is usually a clinical diagnosis based on careful history taking and physical examination. Limited use of imaging studies will be needed in the setting of trauma, possible glenohumeral arthritis, or when a complete tendon tear is suspected. Therapy is based on pain control and therapeutic exercises in almost all cases. Despite the prevalence of shoulder pain, there is no consensus on the best way to achieve pain control or on the type of exercise most likely to achieve speedy recovery. PMID- 24758958 TI - Diagnosis and treatment of headache in the ambulatory care setting: a review of classic presentations and new considerations in diagnosis and management. AB - Headaches represent the most common constellation of neurologic disorders and are a very common cause of morbidity, lost work time, and decreased quality of life among sufferers. In this article, the diagnostic features, workup, and treatment of common, nuanced, and difficult-to-diagnose headache conditions were addressed. The future will hold a number of changes, with respect to both the diagnosis and treatment of headache disorders. As the aging population continues to grow, primary care providers will need to become increasingly familiar with differentiating between benign primary and more serious secondary headache disorders and will need to be able to treat the headache disorders unique to the elderly. With respect to therapeutic options, the future for treatment of the various headache disorders is promising. With the rise in popularity of complementary medical practices, there is likely to be more research on the roles of acupuncture, herbal and alternative remedies, massage therapy, and mind-body techniques. Further, new research is suggesting that neurostimulation may be useful in certain chronic, intractable headache conditions. Finally, the pathophysiology of headache disorders is still poorly understood and there is great hope that better understanding of the underlying mechanics of headache might contribute to improved treatment modalities and better quality of life for patients. PMID- 24758959 TI - Evaluation and treatment of colonic symptoms. AB - Important considerations for constipation include: 1. Initial evaluation should evaluate for fecal incontinence, fecal impaction, medication side effects, concerning symptoms, underlying medical or metabolic issues and irritable bowel syndrome. 2. History and examination should be used to determine if a defecatory disorder is most likely. a. If defecatory disorder is likely, testing with balloon expulsion or anal manometry can be considered and, if confirmed, treatment with biofeedback (if testing not available, it is reasonable to trial fiber and laxatives because many patients have a mixed disorder). b. If it is unlikely, proceed with trial of fiber and/or osmotic laxatives. 3. If continued symptoms, consider trial of newer agent (lubiprostone or linaclotide). 4. If ineffective, consider testing for colon transit time and referral to gastroenterology. PMID- 24758960 TI - Dyspepsia. AB - Dyspepsia is a complex disorder with several distinct pathophysiologic mechanisms that are still poorly understood. Patients who experience dyspepsia have a high burden of disease, with significant personal and economic costs. Although serious pathology presenting as dyspepsia is rare, clinicians need to be aware of alarm features that should trigger prompt referral for subspecialty care. Those without alarm features can be managed in a rational way with either empiric antisecretory therapy, test-and-treat for H pylori eradication, antidepressants, and psychotherapy, or a combination of these. Given the heterogeneity of symptoms and large variability in response to different treatments, more research into specific pathophysiologic mechanisms will likely help guide diagnosis and treatment choices in the future. PMID- 24758961 TI - Insomnia. AB - Insomnia, as the term is used by patients and in primary care, is a symptom: dissatisfaction with the quality or quantity of sleep obtained, despite attempts. For acute insomnia, reversal of the trigger (if possible) and treatment with safe, effective sleep medication are advised. For chronic insomnia, as with other types of symptoms, trying to distinguish between several potential underlying causes is key, because no single treatment approach is appropriate for all situations. Specific conditions such as restless legs syndrome, circadian rhythm disorders, and sleep apnea have specific treatment approaches. PMID- 24758962 TI - Diagnosing and treating dizziness. AB - Dizziness is a common presenting concern in primary care practice. The most useful diagnostic approach in distinguishing different types of dizziness is a thorough history and physical examination; additional tests are rarely necessary. Effective treatments exist for many causes of dizziness, and these treatments are often accomplished in the clinic or at home without the need for medication. PMID- 24758963 TI - Fatigue. AB - Fatigue is a common symptom in primary care with many causes ranging from benign to life threatening. Appropriate evaluation and management are guided by the patient's history, which provides valuable clues as to the source of the patient's symptoms. Ultimately a diagnosis may not be identified for many patients presenting with fatigue, and in these patients management is the most challenging. This article offers guidance in the management of patients presenting with fatigue including key aspects of the patient's history of present illness, the building of a differential diagnosis, rational evaluation in a patient with a nondiagnostic history, and management in the setting of a nondiagnostic work-up. PMID- 24758964 TI - Common anal problems. AB - Anal problems are pervasive, embarrassing and vexing to patients. Primary care providers should be well versed in addressing these concerns, which uncommonly require referral for specialty care. Additionally, anal symptoms and findings may herald previously undiagnosed underlying illness. PMID- 24758965 TI - Involuntary weight loss. AB - Involuntary weight loss remains an important and challenging clinical problem, with a high degree of morbidity and mortality. Because of the frequency of finding a serious underlying diagnosis, clinicians must be thorough in assessment, keeping in mind a broad range of possible causes. Although prediction scores exist, they have not been broadly validated; therefore, clinical judgment remains ever essential. PMID- 24758966 TI - Identifying and treating the causes of neck pain. AB - Future studies are needed to further understand the pathophysiology of mechanical neck pain. Robust scientific evidence is sparse on which noninvasive treatments are the most beneficial and how to better select patients for particular noninvasive or invasive treatments. PMID- 24758967 TI - Medically unexplained symptoms. AB - In summary, caring for patients with MUS is challenging for health care providers. Even defining somatization syndromes is complex and controversial, reflecting the medical community's limited understanding of the pathophysiology for this group of disorders. Although risk factors for MUS have been described and are well understood, little is known about how MUS can be prevented. Uncertainty in medicine, as in any human enterprise, is a given, but the difficulties in identification and treatment of patients with MUS highlight the limitations in understanding the intersection between physical and mental health. Patients come to their physician looking for clarity, understanding, and relief of debilitating symptoms. The understanding of MUS will evolve, and perhaps an organic cause not yet understood or described may emerge to lend clarity and therapeutic opportunities to some patients with somatic disorders. In the meantime, the most powerful tools available are the ability to communicate the limits of current understanding, acknowledge the difficulties faced by patients with this disorder, and reinforce the willingness and desire of clinicians to partner with patients as the focus shifts from diagnosis to symptom management. Thus, the physician-patient relationship, still in its rightful place at the heart of the practice of medicine, lies at the center of effective treatment of patients with MUS. PMID- 24758968 TI - Common symptoms in the ambulatory setting: evaluating common symptoms correctly: the core of internal medicine. PMID- 24758970 TI - A persistent cough related to aspiration of a nonradiopaque bone. AB - Aspiration of a foreign body by an adult often is not diagnosed until a month or more after the event, because of a lack of presenting symptoms indicative of an aspiration and low reliability, sensitivity, and specificity of plain film radiographs. Instead, the foreign body aspiration typically is diagnosed during the evaluation of other lung-related pathology. PMID- 24758971 TI - Spare change. PMID- 24758973 TI - Painful, discolored toes in a 42-year-old woman. PMID- 24758976 TI - Ethics, equity, and economics: a primer on women in medicine. AB - Women account for more than 70% of physician assistant (PA) students, 62% of practicing PAs, and 57% of faculty in PA programs. About half of all US medical students, 30% of actively practicing physicians, and 37% of faculty at academic medical centers are female. However, women in medicine are paid less than men for equal work effort and achieve fewer leadership positions within academia and medicine. Neglecting the skills and talents of women may lead to a workforce that fails to represent our patient and student populations. PMID- 24758975 TI - Brown recluse spider bite on the breast. AB - Brown recluse spiders are one of two types of spiders in the United States that can cause significant tissue damage and, in rare cases, death. Brown recluse spider bites are most often benign and self-limiting, but in a few cases can cause severe necrotic skin lesions. PMID- 24758977 TI - de Garengeot hernia: a unique surgical finding. AB - Femoral hernias occur in about 3% of all abdominal wall hernias. Herniation of the appendix through a femoral hernia (called de Garengeot hernia) is a much rarer finding, occurring in 0.8% to 1% of all cases. This unique surgical finding is most often found intraoperatively due to the similarities it shares with an irreducible inguinal or femoral hernia that requires emergent surgical intervention. When evaluating a patient with a persistent groin lump, consider de Garengeot hernia in the differential diagnosis. PMID- 24758978 TI - Depression and burnout symptoms among Air Force family medicine providers. AB - This study investigated the prevalence of depression and burnout symptoms among family medicine providers on active duty in the US Air Force. Results demonstrated that 84% of those surveyed scored positive for degrees of depression symptoms; only sex differences were significant. PMID- 24758979 TI - Acute leukemias. PMID- 24758980 TI - Hip pain and a limp in a 10-year-old girl. PMID- 24758981 TI - Identifying and treating adult survivors of sexual assault. AB - About 18% of women and 3% of men report being a victim of sexual assault, but fewer than one-third of victims seek immediate medical attention or psychological counseling. Over time, victims may experience physical and emotional reactions and turn to primary care providers, who should be prepared to identify survivors of sexual assault and provide thoughtful referrals for long-term follow-up. PMID- 24758982 TI - A painful urologic emergency. PMID- 24758983 TI - The letter. PMID- 24758984 TI - Lung ultrasound in the critically ill. AB - PURPOSE OF REVIEW: Lung ultrasound, which allows a bedside visualization of the lungs, is increasingly used in critical care. This review aims at highlighting a simple approach to this new discipline. RECENT FINDINGS: The 10 basic signs are the bat sign (indicating pleural line), lung sliding (yielding the seashore sign), the A line (horizontal artifact), the quad and sinusoid sign indicating pleural effusion regardless of its echogenicity, the tissue-like and shred sign indicating lung consolidation, the B line and lung rockets (artifacts indicating interstitial syndrome), abolished lung sliding with the stratosphere sign, suggesting pneumothorax, and the lung point, indicating pneumothorax. All these disorders were assessed using computed tomography (CT) as a gold standard with sensitivity and specificity ranging from 90 to 100%, allowing us to consider ultrasound as a reasonable bedside gold standard in the critically ill. We use a simple gray-scale unit (without Doppler) with a microconvex probe. SUMMARY: Lung ultrasound can be used for diagnosing acute respiratory failure (BLUE protocol), managing acute circulatory failure (Fluid Administration Limited by Lung Sonography protocol), and decreasing the use of radiograph or CT (the Lung Ultrasound in the Critically Ill Favoring Limitation of Radiation project). This can be extended from sophisticated ICUs to more austere settings, from neonates to bariatric adults without adaptation, trauma and several other disciplines (anesthesiology, emergency medicine, pulmonology, etc.). VIDEO ABSTRACT: http://links.lww.com/COCC/A8. PMID- 24758985 TI - The rationale for microcirculatory guided fluid therapy. AB - PURPOSE OF REVIEW: The ultimate purpose of fluid administration in states of hypovolemia is to correct cardiac output to improve microcirculatory perfusion and tissue oxygenation. Observation of the microcirculation using handheld microscopes gives insight into the nature of convective and diffusive defect in hypovolemia. The purpose of this article is to introduce a new platform for hemodynamic-targeted fluid therapy based on the correction of tissue and microcirculatory perfusion assumed to be at risk during hypovolemia. RECENT FINDINGS: Targeting systemic hemodynamic targets and/or clinical surrogates of hypovolemia gives inadequate guarantee for the correction of tissue perfusion by fluid therapy especially in conditions of distributive shock as occur in inflammation and sepsis. Findings are presented, which support the idea that only clinical signs of hypovolemia associated with low microcirculatory flow can be expected to benefit from fluid therapy and that fluid overload causes a defect in the diffusion of oxygen transport. SUMMARY: We hypothesized that the optimal amount of fluid needed for correction of hypovolemia is defined by a physiologically based functional microcirculatory hemodynamic platform where convection and diffusion need to be optimized. Future clinical trials using handheld microscopes able to automatically evaluate the microcirculation at the bedside will show whether such a platform will indeed optimize fluid therapy. PMID- 24758986 TI - Cryptococcus terricola is a promising oleaginous yeast for biodiesel production from starch through consolidated bioprocessing. AB - Starch is considered a potential feedstock for biofuel production, particularly in light of the large-scale landfilling of food waste and other starchy materials worldwide. Lipid accumulation by oleaginous yeast is a promising method for biodiesel production from starch. However, most oleaginous yeasts are grown on monosaccharides or oligosaccharides because they cannot directly utilize starch. We therefore investigated the starch-assimilation ability of 1,200 yeasts. We found that Cryptococcus terricola could be used for fuel production through consolidated bioprocessing. C. terricola JCM 24523 exhibited the highest lipid content of 61.96% on medium with 5% starch at 10 days. Fatty acid methyl ester analysis showed that this strain produced high proportions of C16:0 and C18 fatty acids when grown on starch, which are ideal for use in biodiesel. Considering the yield and cost, lipids derived from starch using C. terricola would be a promising alternative source for biodiesel production. PMID- 24758987 TI - The case for vaccinating against meningitis B. PMID- 24758988 TI - Taking the long view on the CREATE studies' findings. PMID- 24758989 TI - Influenza vaccination and Guillain-Barre syndrome. PMID- 24758990 TI - Influenza vaccination and Guillain-Barre syndrome. PMID- 24758991 TI - Influenza vaccination and Guillain-Barre syndrome. PMID- 24758992 TI - Access to antifungal medicines in resource-poor countries. PMID- 24758993 TI - Care bundles in intensive care units. PMID- 24758994 TI - Access to antifungal medicines in resource-poor countries - authors' reply. PMID- 24758995 TI - Imiquimod is not an effective drug for molluscum contagiosum. PMID- 24758996 TI - Care bundles in intensive care units - authors' reply. PMID- 24758997 TI - Twice-yearly ivermectin for onchocerciasis: the time is now. PMID- 24758998 TI - Rotavirus vaccination in Europe: drivers and barriers. AB - Rotavirus gastroenteritis is a vaccine-preventable disease that confers a high medical and economic burden in more developed countries and can be fatal in less developed countries. Two vaccines with high efficacy and good safety profiles were approved and made available in Europe in 2006. We present an overview of the status of rotavirus vaccination in Europe. We discuss the drivers (including high effectiveness and effect of universal rotavirus vaccination) and barriers (including low awareness of disease burden, perception of unfavourable cost effectiveness, and potential safety concerns) to the implementation of universal rotavirus vaccination in Europe. By February, 2014, national universal rotavirus vaccination had been implemented in Belgium, Luxembourg, Austria, Finland, Greece, Luxembourg, Norway, and the UK. Four other German states have issued recommendations and reimbursement is provided by sickness funds. Other countries were at various stages of recommending or implementing universal rotavirus vaccination. PMID- 24758999 TI - Reduced ability to recover from spindle disruption and loss of kinetochore spindle assembly checkpoint proteins in oocytes from aged mice. AB - Currently, maternal aging in women, based on mouse models, is thought to raise oocyte aneuploidy rates, because chromosome cohesion deteriorates during prophase arrest, and Sgo2, a protector of centromeric cohesion, is lost. Here we show that the most common mouse strain, C57Bl6/J, is resistant to maternal aging, showing little increase in aneuploidy or Sgo2 loss. Instead it demonstrates significant kinetochore-associated loss in the spindle assembly checkpoint protein Mad2 and phosphorylated Aurora C, which is involved in microtubule-kinetochore error correction. Their loss affects the fidelity of bivalent segregation but only when spindle organization is impaired during oocyte maturation. These findings have an impact clinically regarding the handling of human oocytes ex vivo during assisted reproductive techniques and suggest there is a genetic basis to aneuploidy susceptibility. PMID- 24759000 TI - Design, synthesis and biological evaluation of tasiamide analogues as tumor inhibitors. AB - Eighteen analogues of the marine cytotoxic linear peptide tasiamide were designed, synthesized and screened for their inhibitory activities against the growth of human nasopharyngeal carcinoma (KB) and human non-small cell lung tumor (A549) cell lines. The results indicated that minor modifications of the C terminus with aromatic groups were tolerated, with the IC50 values between 1.29 and 12.88 MUM against these two cancer cell lines. Truncation, minor modifications at the N-terminus or elimination of the N-methyl groups in N-Me-D Gln and/or N-Me-D-Phe residues resulted in inactive analogues. PMID- 24759002 TI - Practical aspects of removing the effects of elastic and thermal diffuse scattering from spectroscopic data for single crystals. AB - A method to remove the effects of elastic and thermal diffuse scattering (TDS) of the incident electron probe from electron energy-loss and energy-dispersive X-ray spectroscopy data for atomically resolved spectrum images of single crystals of known thickness is presented. By calculating the distribution of the probe within a specimen of known structure, it is possible to deconvolve the channeling of the probe and TDS from experimental data by reformulating the inelastic cross-section as an inverse problem. In electron energy-loss spectroscopy this allows valid comparisons with first principles fine-structure calculations to be made. In energy-dispersive X-ray spectroscopy, direct compositional analyses such as zeta factor and Cliff-Lorimer k-factor analysis can be performed without the complications of channeling and TDS. We explore in detail how this method can be incorporated into existing multislice programs, and demonstrate practical considerations in implementing this method using a simulated test specimen. We show the importance of taking into account the scattering of the probe in k factor analysis in a zone axis orientation. The applicability and limitations of the method are discussed. PMID- 24759001 TI - A new benzofuran glycoside and indole alkaloids from a sponge-associated rare actinomycete, Amycolatopsis sp. AB - Three new secondary metabolites, amycofuran (1), amycocyclopiazonic acid (2), and amycolactam (3), were isolated from the sponge-associated rare actinomycete Amycolatopsis sp. Based on combined spectroscopic analyses, the structures of 1-3 were determined to be a new benzofuran glycoside and new indole alkaloids related to cyclopiazonic acids, a class that has previously only been reported in fungi. The absolute configurations of 1 and 3 were deduced by ECD calculations, whereas that of 2 was determined using the modified Mosher method. Amycolactam (3) displayed significant cytotoxicity against the gastric cancer cell line SNU638 and the colon cancer cell line HCT116. PMID- 24759003 TI - Mechanism of repression of 11beta-hydroxysteroid dehydrogenase type 1 by growth hormone in 3T3-L1 adipocytes. AB - 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is an NADPH-dependent reductase that converts cortisone to cortisol in adipose tissue. We previously reported that GH and IGF-I decrease 11beta-HSD1 activity and mRNA levels in adipocytes. Hexose-6-phosphate dehydrogenase (H6PDH) is involved in the production of NADPH, which is a coenzyme for 11beta-HSD1. The aim of the present study was to clarify further the mechanism of repression of 11beta-HSD1 activity by GH using linsitinib, an IGF-I receptor inhibitor. The suppression of 11beta HSD1 mRNA by IGF-I was attenuated in the presence of 1 MUM linsitinib (17.2% vs. 53.3% of basal level, P<0.05). 11beta-HSD1 mRNA levels in cells treated with GH in the presence of 1 MUM linsitinib were not different from those in absence of linsitinib (35.9% vs. 33.9%). The increase in IGF-I mRNA levels with GH and 1 MUM linsitinib was not different from that in the absence of linsitinib (359% vs. 347%). H6PDH mRNA levels were significantly decreased in cells treated with IGF-I for 8 and 24 h (55.6% and 33.7%, P<0.05). In the presence of 1 MUM linsitinib, there was no repression of H6PDH mRNA (111.4%). H6PDH mRNA levels were significantly decreased in cells treated with GH in the absence of linsitinib for 24 h (55.9%, P<0.05), but not for 8 h (89.5%). The presence of 1 MUM linsitinib also prevented repression of H6PDH mRNA by GH over 24 h (107.8%). These results suggest that GH directly represses 11beta-HSD1 mRNA rather than acting via the IGF-I receptor, and that GH represses H6PDH through locally produced IGF-I. PMID- 24759004 TI - Estrogen decreases the expression of claudin-5 in vascular endothelial cells in the murine uterus. AB - Vascular endothelial (VE)-cadherin and claudin-5 are major components of the adherens and tight junctions of vascular endothelial cells, respectively, and decreases in their expression are associated with increases in endothelial paracellular permeability. In the uterus, estrogen induces endometrial edema. However, the in vivo effect of estrogen on endothelial paracellular permeability is unknown. Therefore, we studied the expression of VE-cadherin and claudin-5 in vascular endothelial cells in murine uteri stimulated by estrogen or progesterone. Ovariectomized mature mice were injected with estradiol-17beta (1 MUg/mouse) or progesterone (1 mg/mouse) at intervals of 24 hours for 6 days. The frozen transverse sections of the uteri of these mice and untreated mice were stained for CD31 (vascular endothelial cell marker) plus VE-cadherin or claudin-5 using a double-immunofluorescence method. Then, the percentages of VE-cadherin- or claudin-5-positive vessels among CD31-positive vessels were examined in the uterine endometria. VE-cadherin and claudin-5 were expressed in most CD31 positive vessels in the endometria of the untreated mice. Progesterone did not affect the expression of both VE-cadherin and claudin-5 and estradiol-17beta also did not affect the VE-cadherin expression, but estradiol-17beta significantly decreased the claudin-5 expression. This decreasing effect of estradiol-17beta was detected from 24 hours later when the water content per a uterus significantly increased. The present study indicates that estrogen, but not progesterone, decreases the expression of claudin-5 in vascular endothelial cells in the murine uterine endometrium from 24 hours later, suggesting that the decrease in the claudin-5 expression contributes to the endometrial edema late after the estrogen stimulation. PMID- 24759006 TI - [More attention should be paid to the application and extension of hematopoietic stem cell transplantation in lymphoma treatment]. PMID- 24759005 TI - Human islet mass, morphology, and survival after cryopreservation using the Edmonton protocol. AB - The aim of this study was to assess recovery, cell death, and cell composition of post-thaw cultured human islets. Cryopreserved islets were provided by the Clinical Islet Transplant Program, Edmonton, Canada. Islets were processed using media prepared in accordance with Pre-Edmonton and Edmonton protocols. Cryopreserved islets were rapidly thawed and cultured for 24 h, 3 d, 5 d, and 7 d, following which they were processed for histology. Islet quantification, integrity, morphology and tissue turnover were studied via hematoxylin and eosin stained sections. Ultrastructure was studied by electron microscopy and endocrine cell composition by immunohistochemistry. Using the Pre-Edmonton protocol, islet recovery was 50.1% and islet survival was 50% at 24 h while for the Edmonton protocol, the islet recovery was 69.4% (p<0.001) and islet survival, 50% at ~2.5 d. With an increasing culture duration although the physical integrity was retained there was an increasing loss of cohesivity both at light microscopic and at ultrastructure level regardless of the protocols used. Percentage islet survival and tissue turnover correlated negatively with culture duration in both protocols. The Edmonton protocol appears to preserve the islets better. However, culture duration adversely affects islet survival and quality, indicating the need for more optimal cryopreservation and culture techniques. PMID- 24759007 TI - [The shifting patterns of chronic lymphocytic leukemia treatment]. PMID- 24759008 TI - [Diagnosis and differential diagnosis of aggressive NK cell leukemia]. PMID- 24759009 TI - [The application value of PET-CT in lymphoma]. PMID- 24759010 TI - [Pathological diagnosis and research advances in aggressive B-cell lymphoma]. PMID- 24759011 TI - [Central nervous system involvement in diffuse large B-cell lymphoma: prevention and treatment]. PMID- 24759012 TI - [Treatment of elderly indolent lymphoma]. PMID- 24759013 TI - [Clinicopathological characteristics and prognostic analysis of 92 cases with primary gastrointestinal diffuse large B-cell lymphoma]. AB - OBJECTIVE: To analyze the clinical and pathological features, molecular biological markers and prognosis of primary gastrointestinal diffuse large B-cell lymphoma (DLBCL). METHODS: A retrospective study was conducted in 92 cases of primary gastrointestinal DLBCL. The data of clinical characteristics, pathological and immunohistochemical features were analyzed. The relationship between different factors at diagnosis and prognosis were studied. RESULTS: Of the 92 patients, the male-female ratio was 1.56:1 with a median age of 59(7-89) years. The most frequently involved site was stomach (50.0%), followed by small intestine (15.2%), colon (12.0%), ileocecum (10.9%) and multiple gastrointestinal tract involvements (9.8%). The ratio of non-germinal center B cell (non-GCB) subtype to germinal center B cell (GCB) was 2:1. Among the cases, Ki-67 had a high level expression with a median positive rate >80%. Positive expression of Bcl-2 was detected in 52.1% cases (25/48). Evidence of Helicobacter pylori (Hp) infections was detected in 34.0% cases with stomach involvement. Of the patients, 75 were included in a follow-up study with a median time of 48 months (3-130 months). The complete remission(CR)rate was 66.7%(50/75),the partial remission (PR) rate was 22.7% (17/75) and the overall response rate was 89.4% (67/75). The 1-, 3- and 5- year survival rates of the patients were 85.3%, 66.2% and 60.5%, respectively. The incidence of secondary malignancy after chemotherapy was 2.7%. The multivariate analysis indicated that primary colic DLBCL or multiple involvements of gastrointestinal tract and low serum albumin level (<35 g/L) at diagnosis were independently associated with poor outcome. Patients who received chemotherapy combined with rituximab (43 cases) had a higher CR rate (79.1% vs 46.9%, P=0.008) and 5-year overall survival (77.5% vs 53.1%, P=0.0045) than those without rituximab (32 case). CONCLUSION: Primary gastrointestinal DLBCL was a highly invasive and heterogeneous malignancy. In our data, the proportion of non GCB subtype was higher. Primary colic DLBCL and those with multiple involvements of gastrointestinal tract had poor survival. Low serum albumin at diagnosis indicated poor outcome. Rituximab treatment in addition to chemotherapy might help to improve the clinical outcome. Further prospective trails were needed to confirm our results. PMID- 24759014 TI - [Simultaneous presence of ins(17;15) and t(11;19) in a patient with acute promyelocytic leukemia]. PMID- 24759015 TI - [Efficacy of adjusted BACOD regimen on the treatment of relapsed refractory diffuse large B cell lymphoma]. AB - OBJECTIVE: To compare the efficacy and adverse events of adjusted BACOD (bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) regimen (continuous intravenous infusion) and conventional BACOD regimen (conventional intravenous drip) in the treatment of relapsed and refractory diffuse large B cell lymphoma (DLBCL). METHODS: Retrospective analysis of 63 cases of relapsed or refractory DLBCL patients was performed, 32 patients received conventional BACOD regimen and 31 patients received adjusted BACOD regimen. RESULTS: The response rates for adjusted group and conventional group were 87.1%(27/31)and 62.5%(20/32), respectively, during a median follow-up of 14(7-84) months. The difference was statistically significant between the two groups (P=0.025). The main adverse events were myelosuppression, gastrointestinal adverse reactions were rarely serious, and there were no serious liver and kidney toxicity. The median overall survival (OS) was 33 months for adjusted group and 12 months for conventional group, there was statistical differences (P=0.019). The median progression free survival (PFS) was 11 months and 8 months for two groups, the difference was not statistically significant (P=0.095). 1-year survival rates were 68.8% for adjusted group and 44.3% for conventional group, there were no statistical differences (P=0.055). The expected 3- and 5-year survival rates of adjusted group were significantly higher than that of conventional group (47.1% vs 12.8%, P=0.002; 37.7% vs 8.5%, P=0.006, respectively). CONCLUSION: Compared with the conventional BACOD regimen, the adjusted BCOAD regimen is effective and well tolerated in patients with relapsed or refractory DLBCL, the overall response rate and OS increased. PMID- 24759016 TI - [Distribution of lymphomas subtypes in Jiangsu Province: a multicenter analysis of 5 147 cases]. AB - OBJECTIVE: To investigate the epidemiological characteristics of lymphoma in Jiangsu province. METHODS: A total of 5 147 consecutive lymphoma samples collected from 18 hospitals in Jiangsu province from January 2007 to December 2013 and diagnosed according to the WHO classification were enrolled in this study. Basic epidemiological information including age, gender and lymphoma subtypes was analyzed. RESULTS: The median age of all lymphoma cases was 59(2-96) years, and gender ratio (M/F) was 1.6:1. The subtypes distribution analysis revealed that Hodgkin lymphoma (HL) accounted for 5.19% (n=241), whereas non Hodgkin's lymphoma (NHL) accounted for 94.81% (n=4 400). Further analysis displayed B-NHL formed 75.44% (n=3 501) of all cases and T/NK-NHL 16.51% (n=766), diffuse large B-cell lymphoma and NK/T-cell lymphoma were the major subtypes of B NHL and T/NK-NHL (53.50%, 1 873/3 501 and 31.85%, 244/766), respectively. CONCLUSION: Unique epidemiological characteristics of lymphoma in Jiangsu province was different from other regions in China and western country, which can provide strong theoretical basis for public health, clinical and basic research. PMID- 24759017 TI - [Clinical analysis of 135 newly diagnosed patients with Hodgkin lymphoma]. AB - OBJECTIVE: To investigate the clinical characteristics, therapeutic effects, long term survival and prognostic factors of the newly diagnosed patients with Hodgkin lymphoma (HL). METHODS: One hundred and thirty five newly diagnosed HL patients in West China hospital from January 1, 2000 to December 31, 2010 were analyzed retrospectively. Software SPSS18.0 was applied to determine the risk factors for therapeutic results and long term survivals. RESULTS: Of 135 patients, 78 cases were male and 57 female, the median age was 32(7-77) years old, and the median follow-up of 42(12-141) months. The peak age of HL was 20 to 30 years old and lymph node enlargement was the first presenting symptom in 69.63% of the patients. Among the all pathological types of HL, mixed-cellularity subtype (MC) and nodular sclerosing (NS) were the most common types, accounting for 59.7% and 34.0%, respectively. In MC subtypes, 66.2% of patients were male, while in NS subtypes, 61.4% were female. Among the 114 patients with complete follow-up data, 73 patients (64.0%) obtained complete remission and the total response rate was 77.2%. The 2-, 3- and 5-year overall survival (OS) rates were 91.2%, 88.0% and 80.9%, respectively. The progression free survival rates were 76%, 80.3% and 81.6%%, respectively. Among the patients with early unfavorable prognosis, 96.3% of them accepted full course chemotherapy and 13(48.1%) were combined with local radiotherapy. The 3- and 5- year survival rates of early unfavorable patients were higher than that of early favorable and advanced patients, but the difference was not statistically significant. Age>=45 years old and B symptom were adverse factors affecting curative effect for MC and NS subtypes, respectively. Furthermore, Age>=45 years, B symptoms and hepatomegaly were independent risk factors affecting the survival. CONCLUSION: HL is more common in young patients (age<45 years old) and usually diagnosed at the early stage, with predominance of MC subtypes. B symptoms were adverse prognostic factors of therapeutic effects. The standard- dose chemotherapy and suitable courses of treatment combined with radiotherapy may provide the best benefits for the HL patients. PMID- 24759018 TI - [Clinical features of rituximab plus chemotherapy as first-line treatment in patients with diffuse large B-cell lymphoma]. AB - OBJECTIVE: A prospective, multicenter and non-interventional prospective study was conducted to evaluate the clinical features of rituximab combined with chemotherapy (R-Chemo) as first-line treatment on newly diagnosed Chinese patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This was a single arm, prospective, observational multicenter and phase IV clinical trial for 279 patients, who were newly diagnosed as CD20-positive DLBCL from 24 medical centers in China 2011 and 2012, no special exclusion criteria were used. All patients received rituximab based R-Chemo regimes, such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone) and other regimes as the first-line treatment. The treatment strategies were determined by physicians and patients without detailed description for treatment course, dose, interval time and examination. Clinical response and safety of all patients were investigated in 120 days after completion of last dose of rituximab. RESULTS: Of 279 patients, 258 with stage I-IV who received at least 1 cycle of rituximab treatment and completed at least one time of tumor assessment were enrolled into intention-to-treat analysis, including 148 male and 110 female. The median age of all patients was 57.2(12.8-88.4) years. ECOG performance statuses of 0 or 1 were observed in 91.1% of patients, international prognostic index levels in the low risk and low-middle-risk groups in 76.4% of patients, the tumor diameters smaller than 7.5 cm in 69.0% of patients. All patients received 6 median cycles of R Chemo treatment every 24.4 days. R-CHOP treatment was shown to improve the clinical response with overall response rates of 94.2%. Common adverse events included anemia, marrow failure, leukopenia, thrombocytopenia, digestive diseases, infection and liver toxicity. All adverse events are manageable. CONCLUSION: Non-interventional clinical trial of R-Chemo remains the standard first-line treatment for newly diagnosed patients with DLBCL in real clinical practice, which is consistent with international treatment recommendations for DLBCL patients. R-Chemo can provide the clinical evidence and benefit as the first-line standard treatment for Chinese patients with DLBCL. PMID- 24759019 TI - [A phase II multicenter study to investigate R-ICE as a salvage therapy for relapsed diffuse large B-cell lymphoma]. AB - OBJECTIVE: To investigate the efficacy and safety of rituximab together with etoposide, carboplatin, and ifosfamide (R-ICE) as a salvage therapy for relapsed diffuse large B-cell lymphoma (DLBCL) after treatment with rituximab based first line chemotherapy (R-Chemo). METHODS: DLBCL patients with complete remission (CR) or complete remission unconfirmed (CRu) after 6-8 cycles of R-Chemo treatment but relapsed for first time after stopping treatment were included in this study. Three cycles of R-ICE regimen were given to the patients [1st day: rituximab, 375 mg/m2; 2nd-4th day: ifosfamide, 1 600 mg/m2; 3rd day: carboplatin, area under the curve (AUC) =5 (maximum dosage: 800 mg), 2nd-4th day: etoposide, 100 mg/m2]. The primary endpoint was overall response rate (ORR). The secondary endpoints were the 2-year progression-free survival (PFS), 2-year overall survival (OS), and toxicity. RESULTS: Thirty-two patients with median age at 55(range: 26-68) were recruited in this clinical study and the final analysis. After three cycles of R ICE salvage treatment, 16 patients (50.0%) achieved CR or CRu and 9 patients (28.1 %) achieved partial remission (PR). The ORR was 78.1%. The 2-year PFS and OS were 40.8% and 60.7%, respectively. Nineteen patients (59.4%) had 3/4 grade adverse events. The ratios of leukopenia neutropenia, anemia and thrombocytopenia in patients with 3/4 grades were 37.5%, 15.6%, and 37.5%, respectively. No patient died. CONCLUSION: R-ICE is an effective salvage therapy for R-Chemo relapsed DLBCL with manageable toxicities. PMID- 24759020 TI - [Analysis of survival and prognosis in 409 newly diagnosed patients with diffuse large B-cell lymphoma]. AB - OBJECTIVE: To Explore the poor prognostic factors of diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 409 newly diagnosed patients with DLBCL from January 2000 to December 2010 were collected, and the prognostic factors by univariate and multivariate stratification were analyzed . RESULTS: Of the 409 DLBCL patients, 244 were males and 165 females, the median age was 56(16 89) years old, the median follow-up time was 23(2-108) months. In univariate analysis, age, clinical stage, B symptoms, ECOG scores, the international prognostic index (IPI) scores, bone marrow involvement, low absolute lymphocyte count (ALC), high LDH, beta2-MG>2 times of normal, regimen and therapeutic effect had significant influence on OS and PFS (P<0.05). Multivariate analysis showed that stage III-IV and high LDH were the poor prognostic factors of OS and PFS (P<0.05). When IPI scores were included, low ALC and IPI 3-5 scores were the poor predictors of OS and PFS in CHOP-like group (232 cases), revised IPI (R-IPI) was an independent poor predictors of OS and PFS in RCHOP-like group (177 cases). CONCLUSION: Stage III-IV and high LDH have negative influence on OS and PFS in patients with DLBCL, low ALC and IPI 3-5 scores affect OS and PFS in CHOP-like group, R-IPI affects OS and PFS in RCHOP-like group. PMID- 24759021 TI - [Prognostic value of 18F-FDG PET-CT in Hodgkin lymphoma]. AB - OBJECTIVE: To determine the predictive value of interim and end-of-treatment 18F FDG PET-CT after first-line treatment in patients with Hodgkin lymphoma (HL). METHODS: The clinical data of 50 newly diagnosed HL patients were retrospectively analyzed. Baseline, interim and end-of-treatment PET-CT were performed, and then imaging results were analyzed for the survival of patients via software SPSS 13.0. RESULTS: Fifty patients received first-line treatment with ABVD (doxorubicin + bleomycin + vincristine + dacarbazine) or BEACOPP (bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine+ prednisone) regimen. Interim PET-CT of 35 patients were performed after 2-4 cycles of treatment, 46 patients received PET-CT scans at the end of treatment. After a median follow-up of 29.4 months (12.2-52.4 months), the 3-year progression-free survival (PFS) rates were 100% and 70% for the interim PET-CT negative (n=25) and positive (n=10) patients, respectively (P=0.004). The 3-year PFS rates were 100% and 60% for the post-treatment PET-CT negative (n=36) and positive (n=10) patients, respectively (P<0.01). CONCLUSION: Interim and end-of treatment PET-CT were correlated with 3-year PFS rates for HL patients. They may play an important role in predicting the outcome of HL. The relationship with OS can not be determined because of the short follow-up time. PMID- 24759022 TI - [Clinical analysis of 81 cases of malignant lymphoma treated with autologous hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigated the curative effect of autologous hematopoietic stem cell transplantation (ASCT) for malignant lymphoma. METHODS: The clinical data of 81 patients with malignant lymphoma received ASCT from April 1999 to October 2013 were retrospectively analyzed. Of 81 patients, 70 were non-Hodgkin's lymphoma (NHL) and 11 Hodgkin's lymphoma (HL). High dose of etoposide combined with G-CSF was used to mobilize peripheral hematopoietic stem cell. Preconditioning regimen was BEAM (carmustine + cytarabine + etoposide + melphalan). RESULTS: Enough peripheral blood stem cells were collected from all patients. All of the patients after transplantation achieved hematopoietic reconstitution, the median time of the absolute neutrophil count (ANC) recovery to >0.5*109/L time was 10(7-16) d, and the median time of platelet count recovery to >20*109/L was 10(6-17) d. With the follow-up of 23(2-139) months, progression free survival (PFS) was 72.7%, and overall survival (OS) was 88.6%. The median PFS and OS were not reached. Complete remission (CR) before ASCT was an independent prognostic factor of PFS. No transplant related death happened. CONCLUSION: ASCT was a safe and effective method for treatment of malignant lymphoma. PMID- 24759023 TI - [Clinical outcome of autologous stem cell transplantation as first-line treatment in 30 patients with high risk lymphoblastic lymphoma]. AB - OBJECTIVE: To investigate the treatment outcomes of autologous stem cell transplantation (ASCT) as first-line treatment in patients with high risk lymphoblastic lymphoma (LBL) and compare the effect of different induction regimen on prognosis. METHODS: Thirty LBL patients in complete remission received ASCT from 1996 to 2012 in our hospital were retrospectively analyzed. RESULTS: (1)Of the 30 patients, 25 were T-LBL and 5 B-LBL with a median age of 19(7-53) years old. Ratio of male to female is 23:7. Fourteen (46.7%) patients presented with bulky mediastinal masses and 15(50.0%) with bone marrow involvement. The distribution of stages was 2(6.7%), 5(16.7%) and 23 (76.6%)patients with stages II, III, and IV, respectively. The distribution according to age-adjusted international prognostic index (aaIPI) was 5(16.7%) patients in 1 score, 14(46.6%) in 2 scores and 11(36.7%) in 3 scores. (2)At a median follow-up of 32(range, 10-171) months, 17 patients were alive and 13 relapsed and died from LBL after ASCT. The estimated 5-year probability of DFS and OS was (50.4+/-10.7) % and (53.9 +/-10.2)% for all the patients. (3)According to the treatment regimens before ASCT, the patients were divided into NHL-type group (n=12) and ALL-type group (n=18). In NHL-type group, 9 patients relapsed and died, the estimated 5-year probability of DFS and OS was (22.2 +/-12.8) % and (33.3 +/ 13.6) %, respectively. Median DFS and OS time were 24 months and 36 months. In ALL-type group, 4 patients relapsed and died from lymphoma, the estimated 5-year probability of DFS and OS was (77.8 +/- 9.8) % and (77.8 +/- 9.8) %, respectively. Median DFS and OS time were not reached. For DFS and OS, ALL-type group were better than that of NHL-type group and the difference was significant (P=0.022 and P=0.049). CONCLUSION: The results showed that complete remission with intensive first-line ALL-type regimens and followed by ASCT consolidation may significantly improve long-term outcome for high risk LBL patients. PMID- 24759024 TI - [The immunophenotypic characteristics of 260 patients with CD5 + B cell lymphoproliferative disorders]. AB - OBJECTIVE: To explore the immunophenotypic characteristics of CD5+ B cell lymphoproliferative disorders (B-LPD) of Chinese patients. METHODS: Immunophenotyping of bone marrow and (or) of peripheral blood was performed in patients with B-LPD by four color multiparameter flow cytometry analysis using a panel of monoclonal antibodies, and the patients clinical data were retrospectively analyzed. The difference in immunophenotypes and the related clinical features were retrospectively analyzed. Fluorescence in situ hybridization (FISH) for t(11;14) detection was applied to diagnose or exclude mantle cell lymphoma. RESULTS: (1)A total 260 CD5+ B-LPD patients were enrolled in this study, including 186 chronic lymphocytic leukemia (CLL), 40 mantle cell lymphoma (MCL), other B-LPD including 5 splenic marginal zone lymphoma (SMZL), 2 B-cell prolymphocytic leukemia (B-PLL), 3 hairy cell leukemia (HCL). The other 26 cases (10%)were not classified and defined as unclassified B-LPD (BLPD-U). MCL patients were all positive for t(11;14) detected by FISH, while all the BLPD-U patients were negative for t(11;14). (2) All patients expressed CD19, CD20 and CD5. According to the immunophenotypic score system, 186 CLL patients scored 4-5, 99.5% of patients with CD23+, 11.3% with sIgM+, 10.2% with FMC7+, 44.1% with CD22+ and 51.1% with CD11c+. MCL patients scored 2-3, with 50% expressing CD23 and sIgM, 81.6% expressing FMC7, 92.1% expressing CD22 and 5.3% expressing CD11c. In aspect of BLPD-U and other B-LPD, the expression of CD23, sIgM, FMC7, CD22 and CD11c were 73.1% and 50%, 34.6% and 50%, 88.5% and 100%, 92.3% and 90%, 69.2% and 70%, respectively. (3)In comparison of CLL with MCL, there was a significant difference in the expression of CD23, sIgM, FMC7, CD22 and CD11c between the two groups (P<0.01). Between MCL and BLPD-U, similar expression type of CD23, sIgM, FMC7 and CD22 was found except CD11c, which was highly expressed in BLPD-U (P<0.001). The difference of CD11c expression was also statistically significant between MCL and other B-LPD (P<0.01). In comparison of MCL with other B-LPD, there was a significant difference in the expression of CD11c (P<0.01). The expression of CD23 and sIgM in MCL are 7%-21% and 82%-100% respectively in Western population, while the expression of other immunophenotypic markers is similar with our study. CONCLUSION: The significant high incidence of CD23 and low incidence of sIgM compared to the Western population was observed in Chinese patients, and CD11c coud serve as a useful marker to distinguish MCL from CLL and other CD5+ B-LPD. PMID- 24759025 TI - [Value of interim 18F-FDG PET-CT examination in evaluation of chemotherapy response and prognosis in patients with diffuse large B-cell lymphoma]. PMID- 24759026 TI - [Malignant lymphoma simultaneously combined with other solid tumors: four cases report and literature review]. PMID- 24759027 TI - [Double hit lymphoma: a case report and literatures review]. PMID- 24759028 TI - [Prognostic value of interim and post-therapy 18F-FDG PET-CT in patients with T cell lymphomas]. PMID- 24759029 TI - [New progress in the development of malignant lymphoma targeting drugs]. PMID- 24759030 TI - [The evolution and curative effect of diffuse large B cell lymphoma treatment in China]. PMID- 24759031 TI - [Progress of diagnosis and treatment in peripheral T cell lymphoma]. PMID- 24759032 TI - [Acute lymphoblastic leukemia complicated with esophageal fistula: a case report]. PMID- 24759033 TI - [Expert consensus on diagnosis of B cell chronic lymphoproliferative disorders in China (2014)]. PMID- 24759034 TI - [Interpretation of the expert consensus on the management of lymphoma with HBV infection]. PMID- 24759035 TI - [Progress on clinical trials of new drugs for lymphoma in the 55th annual meeting of American Society of Hematology]. PMID- 24759036 TI - [Report on new target drug of lymphoma in the 55th annual meeting of American Society of Hematology]. PMID- 24759037 TI - [MYC-driven aggressive B-cell lymphomas in the 55th annual meeting of American Society of Hematology]. PMID- 24759038 TI - [Report on recent treatment progress of chronic lymphocytic leukemia in the 55th annual meeting of American Society of Hematology]. PMID- 24759039 TI - [Report on follicular lymphoma in the 55th annual meeting of American Society of Hematology]. PMID- 24759041 TI - Fractal free energy landscapes in structural glasses. AB - Glasses are amorphous solids whose constituent particles are caged by their neighbours and thus cannot flow. This sluggishness is often ascribed to the free energy landscape containing multiple minima (basins) separated by high barriers. Here we show, using theory and numerical simulation, that the landscape is much rougher than is classically assumed. Deep in the glass, it undergoes a 'roughness transition' to fractal basins, which brings about isostaticity and marginal stability on approaching jamming. Critical exponents for the basin width, the weak force distribution and the spatial spread of quasi-contacts near jamming can be analytically determined. Their value is found to be compatible with numerical observations. This advance incorporates the jamming transition of granular materials into the framework of glass theory. Because temperature and pressure control what features of the landscape are experienced, glass mechanics and transport are expected to reflect the features of the topology we discuss here. PMID- 24759042 TI - Exciton diffusion in disordered small molecules for organic photovoltaics: insights from first-principles simulations. AB - Exciton diffusion in small molecules 3,6-bis(5-(benzofuran-2-yl)thiophen-2-yl) 2,5-bis(2-ethylhexyl)pyrrolo[3,4-c]pyrrole-1,4-dione [DPP(TBFu)2] is studied using first-principles simulations. We have examined dependence of exciton diffusion on structure disorder, temperature and exciton energy. We find that exciton diffusion length and diffusivity increase with structural order, temperature and the initial exciton energy. Compared to conjugated polymer poly(3 hexylthiophene) (P3HT), DPP(TBFu)2 small molecules exhibit a much higher exciton diffusivity, but a shorter lifetime. The exciton diffusion length in DPP(TBFu)2 is 50% longer than that in P3HT, yielding a higher exciton harvesting efficiency; the physical origin behind these differences is discussed. The time evolutions of exciton energy, electron-hole distance, and exciton localization are explored, and the widely speculated exciton diffusion mechanism is confirmed theoretically. The connection between exciton diffusion and carrier mobilities is also studied. Finally we point out the possibility to estimate exciton diffusivity by measuring carrier mobilities under AC electric fields. PMID- 24759040 TI - Effect of a high-protein diet on maintenance of blood pressure levels achieved after initial weight loss: the DiOGenes randomized study. AB - Randomized trials have shown significant blood pressure (BP) reductions after increased protein compared with carbohydrate intake, but the effect on BP maintenance after initial weight loss is unclear. We examined the effect of a high-protein diet on the maintenance of reduced BP after weight loss in 420 overweight adults from the Diet, Obesity and Genes study. After an 8-week weight loss period (>8% BW), subjects (42+/-6 years) were randomized to either a high protein diet (23-28 en% protein) or a lower-protein control diet (10-15 en% protein) for 26 weeks. BMI after weight loss was 30.3+/-4.3 kg m(-2), BP was 118/73 mm Hg and 28 subjects (6.5%) used antihypertensive agents. Systolic BP during 26 weeks of weight maintenance dietary intervention increased in both treatment groups, but it was 2.2 mm Hg less (95% CI: -4.6 to 0.2 mm Hg, P=0.08) in the high-protein group than in the lower-protein control group. In 191 (pre)hypertensive subjects (baseline systolic BP?120 mm Hg), a larger difference was observed (-4.2 mm Hg (-7.7, -0.7), P=0.02). The effect was attenuated after adjustment for initial BP (-3.4 mm Hg (-6.9, -0.03), P=0.048), and after additional adjustment for weight change (-2.7 mm Hg (-6.1, 0.4), P=0.11). Adjustment for 24-h urinary excretion of sodium and potassium did not change the results. Diastolic BP yielded similar results. These findings suggest that a BP reduction after weight loss is better maintained when the intake of protein is increased at the expense of carbohydrates. This effect is partly mediated by body weight. PMID- 24759044 TI - Differential effects of RNAi treatments on field populations of the western corn rootworm. AB - RNA interference (RNAi) mediated crop protection against insect pests is a technology that is greatly anticipated by the academic and industrial pest control communities. Prior to commercialization, factors influencing the potential for evolution of insect resistance to RNAi should be evaluated. While mutations in genes encoding the RNAi machinery or the sequences targeted for interference may serve as a prominent mechanism of resistance evolution, differential effects of RNAi on target pests may also facilitate such evolution. However, to date, little is known about how variation of field insect populations could influence the effectiveness of RNAi treatments. To approach this question, we evaluated the effects of RNAi treatments on adults of three western corn rootworm (WCR; Diabrotica virgifera virgifera LeConte) populations exhibiting different levels of gut cysteine protease activity, tolerance of soybean herbivory, and immune gene expression; two populations were collected from crop rotation-resistant (RR) problem areas and one from a location where RR was not observed (wild type; WT). Our results demonstrated that RNAi targeting DvRS5 (a highly expressed cysteine protease gene) reduced gut cysteine protease activity in all three WCR populations. However, the proportion of the cysteine protease activity that was inhibited varied across populations. When WCR adults were treated with double-stranded RNA of an immune gene att1, different changes in survival among WT and RR populations on soybean diets occurred. Notably, for both genes, the sequences targeted for RNAi were the same across all populations examined. These findings indicate that the effectiveness of RNAi treatments could vary among field populations depending on their physiological and genetic backgrounds and that the consistency of an RNAi trait's effectiveness on phenotypically different populations should be considered or tested prior to wide deployment. Also, genes that are potentially subjected to differential selection in the field should be avoided for RNAi-based pest control. PMID- 24759045 TI - Resistance selection, mechanism and stability of Spodoptera litura (Lepidoptera: Noctuidae) to methoxyfenozide. AB - Methoxyfenozide belongs to a group of biorational insecticides known as insect growth regulators which is used in the control lepidopteran insect pests. Here we report a field collected population of Spodoptera litura selected with methoxyfenozide for thirteen consecutive generations resulted in the development of 83.24 and 2358.6-fold resistance to methoxyfenozide as compared to parental field population and susceptible laboratory population, respectively. The outcomes of synergism studies revealed methoxyfenozide resistance in S. litura to be monooxygenases (MO) mediated with high synergistic ratio (4.83) with piperonyl butoxide (PBO), while S,S,S-tributyl phosphorotrithioate (DEF) showed no synergism with methoxyfenozide (SR=1). This methoxyfenozide resistant strain showed a high cross resistance to deltamethrin (28.82), abamectin (12.87) and little to emamectin benzoate (2.36), however no cross resistance of methoxyfenozide and other tested insecticides was recorded. The results depicted the methoxyfenozide resistance in S. litura to be unstable with high reversion rate which decreased from 2358.6 to 163.9-fold (as compared to susceptible strain) when reared for five generations without any insecticidal exposure. The present research supports the significance of MO-mediated metabolism in resistance to methoxyfenozide, which demands some tactics to tackle this problem. The resistance against methoxyfenozide in S. litura can be overcome by switching off its use for few generations or insecticides rotation having different mode of action. PMID- 24759046 TI - The effects of avermectin on amino acid neurotransmitters and their receptors in the pigeon brain. AB - The objective of this study was to examine the effects of avermectin (AVM) on amino acid neurotransmitters and their receptors in the pigeon brain. Four groups two-month-old American king pigeons (n=20/group) were fed either a commercial diet or an AVM-supplemented diet (20mg/kg.diet, 40 mg/kg.diet, or 60 mg/kg.diet) for 30, 60, or 90 days. The contents of aspartic acid (ASP), glutamate (GLU), glycine (GLY), and gamma-aminobutyric acid (GABA) in the brain tissues were determined using ultraviolet high-performance liquid chromatography (HPLC). The expression levels of the GLU and GABA receptor genes were analyzed using real time quantitative polymerase chain reaction (qPCR). The results indicate that AVM exposure significantly enhances the contents of GABA, GLY, GLU, and ASP in the cerebrum, cerebellum, and optic lobe. In addition, AVM exposure increases the mRNA expression levels of gamma-aminobutyric acid type A receptor (GABAAR), gamma aminobutyric acid type B receptor (GABABR), N-methyl-d-aspartate 1 receptor (NR1), N-methyl-d-aspartate 2A receptor (NR2A), and N-methyl-d-aspartate 2B receptor (NR2B) in a dose- and time-dependent manner. Moreover, we found that the most damaged organ was the cerebrum, followed by the cerebellum, and then the optic lobe. These results show that the AVM-induced neurotoxicity may be associated with its effects on amino acid neurotransmitters and their receptors. The information presented in this study will help supplement the available data for future AVM toxicity studies. PMID- 24759047 TI - Biochemical and toxicological properties of two acetylcholinesterases from the common bed bug, Cimex lectularius. AB - We examined the molecular and enzymatic properties of two acetylcholinesterases (AChEs; ClAChE1 and ClAChE2) from the common bed bug, Cimex lectularius. Native polyacrylamide gel electrophoresis followed by activity staining and Western blotting revealed that ClAChE1 is the main catalytic enzyme and is abundantly expressed in various tissues. Both ClAChEs existed in dimeric form connected by a disulfide bridge and were attached to the membrane via a glycophosphatidylinositol anchor. To determine their kinetic and inhibitory properties, both ClAChE1 and ClAChE2 were in vitro expressed in Sf9 cells using a baculovirus expression system. ClAChE1 showed higher catalytic efficiency toward acetylcholine, supporting the hypothesis that ClAChE1 plays a major role in postsynaptic transmission. An inhibition assay revealed that ClAChE1 is generally more sensitive to organophosphates and carbamates examined although ClAChE2 was >4000-fold more sensitive to malaoxon than ClAChE1. The relatively higher correlation between the in vitro ClAChE1 inhibition and the in vivo toxicity suggested that ClAChE1 is the more relevant toxicological target for organophosphates and carbamates. Although the physiological function of ClAChE2 remains to be elucidated, ClAChE2 also appears to have neuronal functions, as judged by its tissue distribution and molecular and kinetic properties. Our findings help expand our knowledge on insect AChEs and their toxicological properties. PMID- 24759048 TI - Vitamin E improved cypermethrin-induced damages in the ovary of rats; evidence for angiogenesis and p53 involvement. AB - This study aimed to investigate the protective effect of vitamin E (VitE) on cypermethrin (CPM)-induced damages in the ovary. Wistar rats were divided into seven groups (n=6) including; control-sham (c), CPM-received (CPM, 75 mg/kg, i.p.), and CPM and VitE-treated (VitE, 150 mg/kg, orally) for 7, 14 and 24 days. The antioxidant status determination and hormonal assays along with histological and immunofluorescent assessments were performed. The expression of p53 at mRNA level was also examined. The CPM administration affected the ovarian structure and functions as it elevated the follicular atresia and significantly (P<0.05) lowered the estradiol level, time dependently. VitE administration enhanced the CPM-reduced antioxidant capacity, gonadotropins and estradiol levels. Co administration of VitE and CPM remarkably attenuated the CPM-induced RNA damage in granulosa and theca cells and elevated the deranged angiogenesis. The CPM reduced micro and macro vessels distribution was significantly (P<0.05) elevated in the VitE-received animals. Expression of p53 at mRNA level was down regulated in the VitE-treated groups completely and relatively following 7 and 14 days, respectively. Our data showed that the CPM-induced biochemical and histological damages could be prevented by VitE. Moreover, protective effects of VitE attribute to its potency in enhancing the antioxidant capacity and promoting the gonadotropins secretion, which resulted in down regulation of p53 overexpression and RNA damage in follicular cells accomplished with improved angiogenesis. PMID- 24759049 TI - Enzymes mediating resistance to lambda-cyhalothrin in Eriopis connexa (Coleoptera: Coccinellidae). AB - Resistance to widely used insecticide, lambda-cyhalothrin, was recently reported in the predatory lady beetle Eriopis connexa (Germar) (Coleoptera: Coccinellidae). However, to understand whether metabolic mechanisms underlie such resistance, synergism bioassays and in vitro studies were carried out by using inhibitors and model substrates for enzymatic assays, respectively. The LD50s estimated for susceptible and resistant populations etag of lambda cyhalothrin/insect, and thus, a 22-fold difference in resistance ratio. Synergism ratios for the susceptible population with piperonyl butoxide (PBO), diethyl maleate (DEM), triphenyl phosphate (TPP), and S,S,S-tributylphosphorotrithioate (DEF) were respectively 33.8-, 0.24-, 0.35-, and 4.25-fold, while for the resistant population, they were 1463.0-, 0.79-, 0.85-, and 282.6-fold, respectively. The synergized resistance ratios were 0.50-, 2.00-, 6.75-, and 8.77 fold with PBO, DEF, DEM, and TPP, respectively, while resistance was virtually suppressed with DEF. The esterase exhibited 4.16-, 4.03-, and 5.38-fold greater activity towards formation of alpha-naphthol, beta-naphthol, and 4-nitrophenol in the resistant population of E. connexa than in the susceptible population. The activity of esterase depended on concentrations of DEF applied, either using alpha-naphthol or beta-naphthol, which completely inhibited the activity at 636 etaM. The PBO inhibited the beta-naphthol formation in approximately 50%, suggesting it as inhibitor of esterases. The activities of glutathione-S transferase were similar and corresponded to 0.36-0.47 etamol(-1) min(-1)MUg of protein, for S and R populations, respectively. Similarly, the activities of cytochrome P450-dependent microsomal monooxygenases were 0.04 and 0.05 etamol(-1) min(-1)MUg of protein. The native gel indicated that the formation of beta naphthol was completely inhibited by methyl-paraoxon, but only partially inhibited by eserine, TPP, and PBO. Although other studies with DEF and PBO have demonstrated strong inhibition of type B carboxylesterase associated with insecticide resistance, the results reported here do not rule out metabolism by cytochrome P450-dependent microsomal monooxygenases as a factor conferring E. connexa resistance to lambda-cyhalothrin and confirmed that PBO may also act by inhibiting esterases of insects. PMID- 24759050 TI - A novel function of sanshools: the alleviation of injury from metolachlor in rice seedlings. AB - Szechuan peppers are extensively used as a spice and in traditional medicine in Asia, primarily because of its active compounds, sanshools (S). However, there is only limited mention in agriculture, and there are no papers reporting its use as an herbicide safener. In this study, we provide the first evidence that S can effectively alleviate rice-seedling injury from metolachlor (M). We observed that the M-treated (0.25 MUM) rice seedlings, which were 56.0%, 66.0%, and 57.0% of the non-treated control in shoot height, root length, and fresh biomass, respectively, were recovered by S to 93.1%, 97.6%, and 94.8%, respectively. The emergence rate was enhanced to over 80% in the M+S treatment, whereas it was below 60% in the M treatment. This M+S mixture elevated the rice-seedling root activity to higher than 87.0% of the value for the non-treated control. The activity of glutathione transferases in the combined treatments approximately doubles that of the M treatment and quadruples that of the non-treated controls. This effect was positively correlated with the induced expression of OsGSTU3. Our results suggest that S may represent a new group of safeners and enable the possibility of using these compounds for improving plant production or protecting rice from the phytotoxicity of metolachlor. PMID- 24759051 TI - Physiological, biochemical and histological alterations induced by administration of imidacloprid in female albino rats. AB - Imidacloprid, a neonicotinoid the newest class of major insecticide has outstanding potency and systemic action for crop protection against piercing and sucking insects pests and also highly effective for control of flea on cats and dogs. The effect of oral administration of two doses of imidacloprid 10 and 20mg/kg/day for 60 days on biochemical parameters, histopathology and protein profile of female albino rat was assessed. Average feed intake was significantly reduced (P<0.01) at 20mg/kg/day. Relative weight of heart and spleen decreased significantly (P<0.05) at higher dose level. Non significant increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), acid phosphatase (ACP), alkaline phosphatase (AKP) activity was observed in both the imidacloprid treated groups. There was significant decrease (P<0.01, P<0.05) in acetyl cholinesterase (AChE) activity in plasma and brain of both the imidacloprid treated groups. Microscopically, liver tissue of rats treated with higher dose of imidacloprid showed marked dilation and congestion of central vein and degeneration of hepatocytes. The exposure to imidacloprid produced histopathological changes that could be correlated with changes in the biochemical profile of female albino rats. The blood plasma proteins were examined by SDS PAGE. There was no diagnostic difference in the pattern of plasma protein profile of control and treated rats. Based on the present physiological, biochemical and histological studies it is evident that imidacloprid did not produce any significant effects at 10mg/kg/day dose but induced toxicological effects at 20mg/kg/day to female rats. PMID- 24759052 TI - Target-site mechanism of ACCase-inhibitors resistance in American sloughgrass (Beckmannia syzigachne Steud.) from China. AB - American sloughgrass (Beckmannia syzigachne) is a troublesome weed in winter wheat field rotated with rice in China. Fenoxaprop-p-ethyl and pinoxaden were observed failing to control American sloughgrass in the same filed in Lujiang county in 2011 and 2012, respectively. Whole-plant bioassay was conducted to determine the resistance to fenoxaprop-p-ethyl, pinoxaden and other herbicides in American sloughgrass. Dose-response experiment indicated that Lujiang population was highly resistant to fenoxaprop-p-ethyl (199.8-fold), pinoxaden (76.2-fold), clodinafop-propargyl (334.1-fold) and sethoxydim (15.9-fold); moderately resistant to clethodim (6.3-fold), susceptible to mesosulfuron-methyl, flucarbazone-sodium, pyroxsulam and isoproturon. Partial gene of CT domain was cloned and sequenced to confirm the molecular mechanism of resistance to ACCase inhibiting herbicides. A Trp2027Cys mutation was found in Lujiang population according to the sequencing result. This mutation is the molecular mechanism of resistance to fenoxaprop-p-ethyl in Lujiang population. Furthermore the Trp2027Cys mutation very likely results in cross resistance to clodinafop propargyl and pinoxaden in Lujiang population. 103 mutant homozygotes were detected from the 108 plants tested using a rapid dCAPS method developed in this paper. This is the first report of pinoxaden resistance and a mutation at position of 2027 for American sloughgrass. PMID- 24759053 TI - Evaluation of toxicological impact of cartap hydrochloride on some physiological activities of a non-heterocystous cyanobacterium Leptolyngbya foveolarum. AB - The present study was aimed to the evaluation of toxicological impact of insecticide cartap hydrochloride on photosynthesis and nitrogen assimilation of a non-heterocystous cyanoprokaryote Leptolyngbya foveolarum isolated from paddy fields of Punjab, India. The microorganism tolerated commercial grade insecticide up to 80 ppm. Lower concentration (20 ppm) of cartap supported good growth with high dry weight of biomass, total protein content, photosynthetic pigments, photosynthesis and respiration compared to untreated control cultures while higher concentrations (40 and 60 ppm) inhibited these parameters in a dose dependent manner. Treatment of the microorganism with 60 ppm cartap lowered the content of photosynthetic pigments with maximum inhibitory effect on phycoerythrin (70% decrease) followed by allophycocyanin (66% decrease). Rates of photosynthesis and respiration were inhibited by 63% and 45%, respectively, while PS-I, II and whole chain activity were decreased by 45%, 67% and 40% respectively, compared to untreated control cultures. Cartap at 60 ppm decreased nitrate and nitrite uptake by 31% and 61%, respectively, whereas uptake of ammonium was slightly increased (18%) in cartap (60 ppm) treated cells. Nitrate and nitrite reductase, and glutamine synthetase activities of the microorganism decreased by 36-50% in 60 ppm cartap. The low levels of growth, photosynthetic pigments and activities of nitrogen assimilating enzymes in cells grown in nitrogen depleted medium supplement with insecticide indicated that insecticide may be used by the organism as a nitrogen source. PMID- 24759054 TI - Triazophos induced oxidative stress and histomorphological changes in liver and kidney of female albino rats. AB - Organophosphate (OP) pesticides toxic manifestations have been associated with enhanced generation of reactive oxygen species (ROS) which culminates into oxidative stress (OS). Triazophos (TZ), a broad spectrum OP, was used in the present study to investigate toxic effects on liver and kidney of female albino rats at three sub-chronic dose levels of 1/10th, 1/20th and 1/40th of LD50 for 30 days. Activity levels of different OS parameters viz: catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) and lipid peroxidation (LPO) were differentially altered in liver and kidney of TZ treated rats as compared to control rats. Histomorphological studies further revealed number of abnormalities as infiltration, vacuolization, enlarged sinusoids and necrosis in liver of TZ treated rats, while renal histoarchitecture of 1/10th and 1/20th of LD50 TZ treated rats showed high degeneration of glomeruli. Enhanced apoptosis was also observed in hepatocytes at dose levels of 1/10th and 1/20th of LD50 TZ treated female rats. The results infer that exposure of female albino rats to TZ leads to number of pathophysiological conditions in the liver and kidney at dose dependent manner. PMID- 24759055 TI - Anonymous HIV testing: what does it mean in policy and practice? A case study in Newfoundland and Labrador, Canada. AB - HIV infection is not a legally notifiable disease at the national level in Canada; however, provincial and territorial officials voluntarily undertake notification to the Public Health Agency of Canada. A case study involving four community-based sites in Newfoundland and Labrador found that the absence of clear legislation concerning HIV testing presented challenges for nurses who had to interpret and comply with provincial legislation and agency policy while meeting the needs of test-seekers. This ambiguous messaging is part of other conflicting information about the availability of anonymous HIV testing that, along with other factors, may contribute to under-testing and under-diagnosis in the province. From a social justice perspective, developing a national HIV strategy and amending legislation to facilitate anonymous HIV testing might provide clearer direction to nurses and agencies, and promote public health by improving service delivery and increasing testing in under-tested, higher-risk taking populations. PMID- 24759056 TI - Anxiety sensitivity in relation to sleep quality among HIV-infected individuals. PMID- 24759057 TI - Protective factors in the experience of pregnancy and motherhood among Brazilian adolescents living with HIV: A case-series report. AB - Pregnancy, motherhood, and HIV infection in adolescence are events with relevant biological, psychological, and social implications for mothers, their babies, and families. Our study aimed to identify protective factors of the experience of pregnancy and motherhood among young mothers living with HIV, highlighting similarities and differences. A mixed method multiple-case study was conducted with three young primiparous mothers (ages 17 to 19 years), whose babies were 4 to 6 months old. Participants were recruited from specialized care services in Porto Alegre, Brazil. Data were collected using social support and adherence-to treatment questionnaires and a semi-structured interview. The following protective factors were identified: positive feelings about motherhood, positive assessments of received care and couple relationships, disclosure of HIV diagnosis to family members, family support, and accountability for infant care. Longitudinal studies would enhance the understanding of these factors, particularly if carried out with adolescents of different ages and focused on coping strategies. PMID- 24759058 TI - A quantitative study of factors influencing quality of life in rural Mexican women diagnosed with HIV. AB - This quantitative study explored the level of Quality of Life (QoL) in indigenous Mexican women and identified psychosocial factors that significantly influenced their QoL, using face-to-face interviews with 101 women accessing care in an HIV clinic in Oaxaca, Mexico. Variables included demographic characteristics, levels of depression, coping style, family functioning, HIV-related beliefs, and QoL. Descriptive statistics were used to analyze participant characteristics, and women's scores on data collection instruments. Pearson's R correlational statistics were used to determine the level of significance between study variables. Multiple regression analysis examined all variables that were significantly related to QoL. Pearson's correlational analysis of relationships between Spirituality, Educating Self about HIV, Family Functioning, Emotional Support, Physical Care, and Staying Positive demonstrated positive correlation to QoL. Stigma, depression, and avoidance coping were significantly and negatively associated with QoL. The final regression model indicated that depression and avoidance coping were the best predictor variables for QoL. PMID- 24759059 TI - Psychosocial profile and lived experience of HIV-infected long-term nonprogressors: a mixed method study. AB - The goal of this mixed method study was to describe the psychosocial profile of HIV-infected persons identified as long-term nonprogressors (LTNP), and their experiences of nonprogression. Data were collected from 24 participants with a mean age of 48 years and a mean duration of infection of 14 years. Results show rather moderate levels of anxiety and depression symptoms and a modest mean score of social support. Participants adapted by using acceptance, positive restructuring, and active coping strategies. Seven themes marked the experience: (a) reacting to announcement and dealing with diagnosis, (b) valuing interpersonal relations and well-being, (c) making changes in life, (d) coping with stress, (e) dealing with health care, (f) beliefs about reasons for nonprogression, and (g) living positively while dreading progression. The findings enrich a field of knowledge that has had little attention so far and shed light on the psychosocial profile of LTNP and their experiences of nonprogression. PMID- 24759060 TI - Understanding HIV-related stigma among Indonesian nurses. AB - Evidence indicates widespread stigmatization of persons living with HIV (PLWH) in Indonesia. Such attitudes among health care workers could impede the country's policies for effective diagnosis and medical treatment of PLWH. Nonetheless, research to guide interventions to reduce stigma in health care settings is lacking. Also, the contributions of workplace, religion, and HIV knowledge to nurses' HIV-related stigma are poorly understood. Our cross-sectional study aimed to describe factors associated with nurses' stigmatizing attitudes toward PLWH. Four hundred nurses recruited from four hospitals in Jakarta, Indonesia, were surveyed using the Nurse AIDS Attitude Scale to measure stigma. Stigmatizing attitudes were significantly predicted by education, HIV training, perceived workplace stigma, religiosity, Islamic religious identification, and affiliation with the Islamic hospital. HIV knowledge was not a significant predictor of stigmatizing attitudes. Organization changes fostering workplace diversity are likely to substantially reduce stigmatizing attitudes in nurses. PMID- 24759061 TI - Stimulation with the Aureobasidium pullulans-produced beta-glucan effectively induces interferon stimulated genes in macrophage-like cell lines. AB - A beta-(1,3),(1,6)-D-glucan produced by A. pullulans (AP-PG) is known to be an immune stimulating agent. In this study, we demonstrate that the stimulation with AP-PG effectively induces the interferon (IFN) stimulated genes (ISGs) in macrophage-like cell lines. The ISGs, Mx1, ISG15, and viperin mRNAs were significantly increased in RAW264.7 cells after stimulation with AP-PG. The stimulation with AP-PG transiently induced IFN-beta mRNA. However, the expression of viperin mRNA was also increased after stimulation with AP-PG even when new protein synthesis was completely blocked by treatment with cycloheximide. Further, in IFN-alpha receptor knockdown RAW264.7 cells, AP-PG stimulation more effectively induced viperin mRNA compared with that of IFN-alpha stimulation. The phosphorylation of Ser 727 in STAT1 involved in the enhancement of STAT1 activation was immediately increased after stimulation with AP-PG. In addition, viperin mRNA expression induced after stimulation with IFN-alpha was significantly increased by combined stimulation with AP-PG. These results suggest that stimulation with AP-PG effectively induces the ISGs through the induction of IFN and the enhancement of STAT1-mediated transcriptional activation. PMID- 24759063 TI - Prevalence, incidence, and persistence of psychiatric and substance use disorders among mothers living with HIV. AB - OBJECTIVE: To evaluate prevalence, incidence, remission, and persistence of psychiatric and substance use disorders among HIV-infected mothers and identify biopsychosocial correlates. METHODS: HIV-infected mothers (n = 1223) of HIV exposed uninfected children enrolled in a prospective cohort study; HIV uninfected mothers (n = 128) served as a comparison group. Mothers provided sociodemographic and health information and completed the Client Diagnostic Questionnaire (CDQ). Prevalence of any psychiatric or substance use disorder at initial evaluation was compared between the 2 groups. Incident, remitting, and persisting disorders were identified for 689 mothers with HIV who completed follow-up CDQs. We used logistic regression to evaluate adjusted associations of biopsychosocial characteristics with presence, incidence, remission, and persistence of disorders. RESULTS: Thirty-five percent of mothers screened positive for any psychiatric or substance use disorder at initial evaluation, with no difference by maternal HIV status (P = 1.00). Among HIV-infected mothers, presence of any disorder was associated with younger age [adjusted odds ratio (aOR): 1.39; 95% CI: 1.09 to 1.75], single parenthood (aOR: 1.35; 95% CI: 1.08 to 1.68), and functional limitations (aOR: 2.29; 95% CI: 1.81 to 2.90). Incident disorders were associated with functional limitations (aOR: 1.92; 95% CI: 1.10 to 3.30). Among HIV-infected mothers with a disorder at initial evaluation (n = 238), 61% had persistent disorders. Persistent disorders were associated with lower income (aOR: 2.44; 95% CI: 1.33 to 4.76) and functional limitations (aOR: 3.19; 95% CI: 1.87 to 5.48). Receipt of treatment for any disorder was limited: 4.5% at study entry, 7% at follow-up, 5.5% at both entry and follow-up. CONCLUSIONS: Psychiatric and substance use disorders remain significant comorbid conditions among HIV-infected mothers and require accessible evidence-informed treatment. PMID- 24759065 TI - STI patients are effective recruiters of undiagnosed cases of HIV: results of a social contact recruitment study in Malawi. AB - BACKGROUND: Patients with newly diagnosed HIV may be part of social networks with elevated prevalence of undiagnosed HIV infection. Social network recruitment by persons with newly diagnosed HIV may efficiently identify undiagnosed cases of HIV infection. We assessed social network recruitment as a strategy for identifying undiagnosed cases of HIV infection. METHODS: In a sexually transmitted infection (STI) clinic in Lilongwe, Malawi, 3 groups of 45 "seeds" were enrolled: STI patients with newly diagnosed HIV, STI patients who were HIV uninfected, and community controls. Seeds were asked to recruit up to 5 social "contacts" (sexual or nonsexual). Mean number of contacts recruited per group was calculated. HIV prevalence ratios (PRs) and number of contacts needed to test to identify 1 new case of HIV were compared between groups using generalized estimating equations with exchangeable correlation matrices. RESULTS: Mean number of contacts recruited was 1.3 for HIV-infected clinic seeds, 1.8 for HIV uninfected clinic seeds, and 2.3 for community seeds. Contacts of HIV-infected clinic seeds had a higher HIV prevalence (PR: 3.2, 95% confidence interval: 1.3 to 7.8) than contacts of community seeds, but contacts of HIV-uninfected clinic seeds did not (PR: 1.1, 95% confidence interval: 0.4 to 3.3). Results were similar when restricted to nonsexual contacts. To identify 1 new case of HIV, it was necessary to test 8 contacts of HIV-infected clinic seeds, 10 contacts of HIV uninfected clinic seeds, and 18 contacts of community seeds. CONCLUSIONS: Social contact recruitment by newly diagnosed STI patients efficiently led to new HIV diagnoses. Research to replicate findings and guide implementation is needed. PMID- 24759064 TI - Combination antiretroviral treatment for women previously treated only in pregnancy: week 24 results of AIDS clinical trials group protocol a5227. AB - BACKGROUND: Women with HIV and prior exposure to combination antiretroviral therapy (cART) solely for prevention of mother-to-child transmission (pMTCT) need to know whether they can later be treated successfully with a commonly used regimen of efavirenz (EFV) and coformulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). METHODS: Nonpregnant women with plasma HIV-1 RNA of >=500 copies per milliliter, previously cART exposed for pMTCT only, were eligible if they were off ART for >=24 weeks before entry, were without evidence of drug resistance on standard genotyping, and were ready to start EFV plus FTC/TDF. The primary endpoint was virologic response (defined as plasma HIV RNA <400 copies/mL) at 24 weeks. RESULTS: Fifty-four women were enrolled between October 2007 and December 2009; 52 of 54 completed 24 weeks of follow-up. Median baseline CD4 T-cell count was 265/mm and baseline plasma HIV-1 RNA was 4.6 log10 copies per milliliter. Median prior cART duration was 14 weeks, and median time elapsed from the last pMTCT dose to entry was 22 months. Virologic response at 24 weeks was observed in 42 of 52 women or 81% (exact 95% confidence interval: 68% to 90%). There were no differences in response by country, by number, or class of prior pMTCT exposures. Although confirmed virologic failure occurred in 8 women, no virologic failures were observed in women reporting perfect early adherence. CONCLUSIONS: In this first prospective clinical trial studying combination antiretroviral retreatment in women with a history of pregnancy-limited cART, the observed virologic response to TDF/FTC and EFV at 24 weeks was 81%. Virologic failures occurred and correlated with self-reported nonadherence. PMID- 24759066 TI - Timing of maternal HIV testing and uptake of prevention of mother-to-child transmission interventions among women and their infected infants in Johannesburg, South Africa. AB - BACKGROUND: By 2011, South African prevention of mother-to-child transmission (PMTCT) of HIV programs had reduced perinatal HIV transmission at 6 weeks of age to 2.7%. We investigated the profile of newly diagnosed vertically infected children and their mothers to identify shortfalls in the PMTCT program. METHODS: In this operational follow-up study, fieldworkers enrolled mothers of newly diagnosed HIV-infected children up to 2 years of age at 5 major health care facilities in Johannesburg. Structured questionnaires and clinical record reviews were conducted and analyzed to describe the population and assess factors associated with PMTCT uptake. RESULTS: Two hundred eighty-nine mother-child pairs were enrolled. Timing of maternal HIV diagnosis influenced PMTCT access and feeding choices and was associated with infants' age at HIV diagnosis (7 vs. 11 vs. 31 weeks where mothers tested before, during, or after the pregnancy, respectively; P < 0.0001). Women diagnosed before pregnancy (12%) were older (median, 31 years) than those diagnosed during the index pregnancy (53%; median, 27 years). Women diagnosed after delivery (35%) were younger (median, 25 years, P < 0.0001), of lower parity, and less likely to be South African citizens. In 81 cases (29%), late maternal diagnosis precluded any PMTCT access. Where women were diagnosed during or before pregnancy, the recommended PMTCT guidelines for mother and infant were followed in 86 (61%) pairs. CONCLUSIONS: Failure to diagnose maternal HIV infection before delivery was the main reason for missing PMTCT prophylaxis and early infant testing. Timely maternal diagnosis enables PMTCT uptake, but implementation and follow-up gaps require attention to improve infant outcomes. PMID- 24759067 TI - Surface-functionalized hyperbranched poly(amido acid) magnetic nanocarriers for covalent immobilization of a bacterial gamma-glutamyltranspeptidase. AB - In this study, we synthesized water-soluble hyperbranched poly(amido acid)s (HBPAAs) featuring multiple terminal CO2H units and internal tertiary amino and amido moieties and then used them in conjunction with an in situ Fe2+/Fe3+ co precipitation process to prepare organic/magnetic nanocarriers comprising uniformly small magnetic iron oxide nanoparticles (NP) incorporated within the globular HBPAAs. Transmission electron microscopy revealed that the HBPAA-gamma Fe2O3 NPs had dimensions of 6-11 nm, significantly smaller than those of the pristine gamma-Fe2O3 (20-30 nm). Subsequently, we covalently immobilized a bacterial gamma-glutamyltranspeptidase (BlGGT) upon the HBPAA-gamma-Fe2O3 nanocarriers through the formation of amide linkages in the presence of a coupling agent. Magnetization curves of the HBPAA-gamma-Fe2O3/BlGGT composites measured at 300 K suggested superparamagnetic characteristics, with a saturation magnetization of 52 emu g-1. The loading capacity of BlGGT on the HBPAA-gamma Fe2O3 nanocarriers was 16 mg g-1 support; this sample provided a 48% recovery of the initial activity. The immobilized enzyme could be recycled 10 times with 32% retention of the initial activity; it had stability comparable with that of the free enzyme during a storage period of 63 days. The covalent immobilization and stability of the enzyme and the magnetization provided by the HBPAA-gamma-Fe2O3 NPs suggests that this approach could be an economical means of depositing bioactive enzymes upon nanocarriers for BlGGT-mediated bio-catalysis. PMID- 24759068 TI - Biocompatible Fe3O4 increases the efficacy of amoxicillin delivery against Gram positive and Gram-negative bacteria. AB - This paper reports the synthesis and characterization of amoxicillin- functionalized magnetite nanostructures (Fe3O4@AMO), revealing and discussing several biomedical applications of these nanomaterials. Our results proved that 10 nm Fe3O4@AMO nanoparticles does not alter the normal cell cycle progression of cultured diploid cells, and an in vivo murine model confirms that the nanostructures disperse through the host body and tend to localize in particular sites and organs. The nanoparticles were found clustered especially in the lungs, kidneys and spleen, next to the blood vessels at this level, while being totally absent in the brain and liver, suggesting that they are circulated through the blood flow and have low toxicity. Fe3O4@AMO has the ability to be easily circulated through the body and optimizations may be done so these nanostructures cluster to a specific target region. Functionalized magnetite nanostructures proved a great antimicrobial effect, being active against both the Gram positive pathogen S. aureus and the Gram negative pathogen E. coli. The fabricated nanostructures significantly reduced the minimum inhibitory concentration (MIC) of the active drug. This result has a great practical relevance, since the functionalized nanostructures may be used for decreasing the therapeutic doses which usually manifest great severe side effects, when administrated in high doses. Fe3O4@AMO represents also a suitable approach for the development of new alternative strategies for improving the activity of therapeutic agents by targeted delivery and controlled release. PMID- 24759069 TI - RutheniumII complexes bearing fused polycyclic ligands: from fundamental aspects to potential applications. AB - In this review, we first discuss the photophysics reported in the literature for mononuclear ruthenium complexes bearing ligands with extended aromaticity such as dipyrido[3,2-a:2',3'-c]phenazine (DPPZ), tetrapyrido[3,2-a:2',3'-c:3'',2'' h:2''',3'''-j]-phenazine (TPPHZ), tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3''' j]acridine (TPAC), 1,10-phenanthrolino[5,6-b]1,4,5,8,9,12-hexaazatriphenylene (PHEHAT) 9,11,20,22-tetraaza- tetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3''' n]pentacene (TATPP), etc. Photophysical properties of binuclear and polynuclear complexes based on these extended ligands are then reported. We finally develop the use of binuclear complexes with extended pi-systems for applications such as photocatalysis. PMID- 24759070 TI - Natural dibenzo-alpha-pyrones and their bioactivities. AB - Natural dibenzo-alpha-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities such as toxicity on human and animals, phytotoxicity as well as cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties. Dibenzo-alpha-pyrones are biosynthesized via the polyketide pathway in microorganisms or metabolized from plant-derived ellagitannins and ellagic acid by intestinal bacteria. At least 53 dibenzo-alpha-pyrones have been reported in the past few decades. This mini review aims to briefly summarize the occurrence, biosynthesis, biotransformation, as well as their biological activities and functions. Some considerations related to synthesis, production and applications of dibenzo-alpha-pyrones are also discussed. PMID- 24759071 TI - C5-azobenzene-substituted 2'-deoxyuridine-containing oligodeoxynucleotides for photo-switching hybridization. AB - A new photoisomeric nucleoside dUAz bearing an azobenzene group at the C5 position of 2'-deoxyuridine was designed and synthesized. Photoisomerization of dUAz in oligodeoxynucleotides can be achieved rapidly and selectively with 365 nm (forward) and 450 nm (backward) irradiation. Thermal denaturation experiments revealed that dUAz stabilized the duplex in the cis-form and destabilized it in the trans-form with mismatch discrimination ability comparable to thymidine. These results indicate that dUAz could be a powerful material for reversibly manipulating nucleic acid hybridization with spatiotemporal control. PMID- 24759072 TI - Catechins and procyanidins of Ginkgo biloba show potent activities towards the inhibition of beta-amyloid peptide aggregation and destabilization of preformed fibrils. AB - Catechins and procyanidins, together with flavonoid glycosides and terpene trilactones, are three important categories of components in the standard extract of Ginkgo biloba leaves (EGb761). In this research, catechins and proanthocyanidins were found to exist in both the extract of Ginkgo leaves and Ginkgo products. By comparing with reference compounds, six of them were identified as (+)-catechin, (-)-epicatechin, (-)-gallocatechin, (-) epigallocatechin and procyanidins B1 and B3. The activities of these polyphenols in the inhibition of Abeta42 aggregation and the destabilization of preformed fibrils were evaluated using biochemical assays, which showed that all six of the polyphenols, as well as a fraction of the extract of Ginkgo biloba leaves (EGb) containing catechins and procyanidins, exerted potent inhibitory activities towards Abeta42 aggregation and could also destabilize the performed fibrils. Catechins and procyanidins can therefore be regarded as the potent active constituents of EGb761 in terms of their inhibition of Abeta42 aggregation and destabilization of the fibrils. Although quantitative mass spectroscopic analysis revealed that the catechins and procyanidins are only present in low concentrations in EGb761, these components should be studied in greater detail because of their potent inhibitory effects towards Abeta42 aggregation and their ability to destabilize preformed fibrils, especially during the quality control of Ginkgo leaves and the manufacture of Ginkgo products. PMID- 24759074 TI - Development of simple sequence repeat (SSR) markers of sesame (Sesamum indicum) from a genome survey. AB - Sesame (Sesamum indicum), an important oil crop, is widely grown in tropical and subtropical regions. It provides part of the daily edible oil allowance for almost half of the world's population. A limited number of co-dominant markers has been developed and applied in sesame genetic diversity and germplasm identity studies. Here we report for the first time a whole genome survey used to develop simple sequence repeat (SSR) markers and to detect the genetic diversity of sesame germplasm. From the initial assembled sesame genome, 23,438 SSRs (>=5 repeats) were identified. The most common repeat motif was dinucleotide with a frequency of 84.24%, followed by 13.53% trinucleotide, 1.65% tetranucleotide, 0.3% pentanucleotide and 0.28% hexanucleotide motifs. From 1500 designed and synthesised primer pairs, 218 polymorphic SSRs were developed and used to screen 31 sesame accessions that from 12 countries. STRUCTURE and phylogenetic analyses indicated that all sesame accessions could be divided into two groups: one mainly from China and another from other countries. Cluster analysis classified Chinese major sesame varieties into three groups. These novel SSR markers are a useful tool for genetic linkage map construction, genetic diversity detection, and marker-assisted selective sesame breeding. PMID- 24759073 TI - The effect of DA-9701 on 5-hydroxytryptamine-induced contraction of feline esophageal smooth muscle cells. AB - Serotonin, or 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter found in blood platelets, the gastrointestinal (GI) tract, and the central nervous system (CNS) of animals and humans. The signaling pathways of 5-hydroxytryptamine (5-HT)-induced contractions in cat esophageal smooth muscle cell (ESMC)s have been identified, but the downstream components of the 5-HT signaling pathway remain unclear. DA-9701 is the standardized extract of the Pharbitis nil Choisy seed (Pharbitidis Semen, Convolvulaceae) and the root of Corydalis yahusuo W.T. Wang (Corydalis Tuber, Papaveraceae). DA-9701 is known to have strong gastroprokinetic effects and a good safety profile. In this study, we investigated the 5-HT signaling pathway at the G-protein level, and we explored the mechanisms by which DA-9701 induces smooth muscle contraction. Freshly isolated smooth muscle cells were harvested from the feline esophagus, and cells were permeabilized to measure their length. 5-HT produced esophageal smooth muscle contractions in a dose-dependent manner. Furthermore, 5-HT produced a relatively long-acting contraction. 5-HT binds to the 5-HT2, 5-HT3 and 5-HT4 receptors to induce smooth muscle contraction in feline ESMCs. These receptors, which are located in esophageal smooth muscle, are coupled to Galphaq, Galphao and Galphas. These G proteins activate PLC, which leads to Ca2+/calmodulin dependent MLCK activation, resulting in MLC20 phosphorylation and cell contraction. Conversely, DA-9701 inhibits 5-HT-induced contraction by inhibiting MLC20 phosphorylation. PMID- 24759075 TI - Antioxidant and antitumor activities of new synthesized aromatic C-nucleoside derivatives. AB - The carbohydrazide 1 was used as the precursor for the synthesis of a number of new aromatic C-nucleosides containing 1,3,4-oxadiazole 7, [1,3,4]oxadiazolo[2,3 a]isoindole 10b and pyrazole units 18. On the other hand, the thiosemicarbazone 20 was used as the key intermediate for synthesis of 1,3,4-oxadiazole and 1,2,4 triazole-3-thione derivatives 21 and 23. The antioxidant activities of the prepared compounds were evaluated. The carbohydrazide 1 in particular was found to have potent antioxidant and antitumor activity. PMID- 24759076 TI - Anti-amoebic properties of carbonyl thiourea derivatives. AB - Thiourea derivatives display a broad spectrum of applications in chemistry, various industries, medicines and various other fields. Recently, different thiourea derivatives have been synthesized and explored for their anti-microbial properties. In this study, four carbonyl thiourea derivatives were synthesized and characterized, and then further tested for their anti-amoebic properties on two potential pathogenic species of Acanthamoeba, namely A. castellanii (CCAP 1501/2A) and A. polyphaga (CCAP 1501/3A). The results indicate that these newly synthesized thiourea derivatives are active against both Acanthamoeba species. The IC50 values obtained were in the range of 2.39-8.77 ug.mL-1 (9.47-30.46 uM) for A. castellanii and 3.74-9.30 ug.mL-1 (14.84-31.91 uM) for A. polyphaga. Observations on the amoeba morphology indicated that the compounds caused the reduction of the amoeba size, shortening of their acanthopodia structures, and gave no distinct vacuolar and nuclear structures in the amoeba cells. Meanwhile, fluorescence microscopic observation using acridine orange and propidium iodide (AOPI) staining revealed that the synthesized compounds induced compromised membrane in the amoeba cells. The results of this study proved that these new carbonyl thiourea derivatives, especially compounds M1 and M2 provide potent cytotoxic properties toward pathogenic Acanthamoeba to suggest that they can be developed as new anti-amoebic agents for the treatment of Acanthamoeba keratitis. PMID- 24759077 TI - Transport through quantum wells and superlattices on topological insulator surfaces. AB - We investigate electron transmission coefficients through quantum wells and quantum superlattices on topological insulator surfaces. The quantum well or superlattice is not constituted by general electronic potential barriers but by Fermi velocity barriers which originate in the different topological insulator surfaces. It is found that electron resonant modes can be renormalized by quantum wells and more clearly by quantum superlattices. The depth and width of a quantum well and superlattice, the incident angle of an electron, and the Fermi energy can be used to effectively tune the electron resonant modes. In particular, the number N of periodic structures that constitute a superlattice can further strengthen these regulating effects. These results suggest that a device could be developed to select and regulate electron propagation modes on topological insulator surfaces. Finally, we also study the conductance and the Fano factor through quantum wells and quantum superlattices. In contrast to what has been reported before, the suppression factors of 0.4 in the conductance and 0.85 in the Fano factor are observed in a quantum well, while the transport for a quantum superlattice shows strong oscillating behavior at low energy and reaches the same saturated values as in the case of a quantum well at sufficiently large energies. PMID- 24759078 TI - The impact of ageing on the intestinal epithelial barrier and immune system. AB - The vast mucosal surface of the intestine is patrolled by a large number of lymphocytes forming the intestinal immune system. Like any other system in the body, this branch of the immune system is affected by ageing. Although our knowledge on the age-associated changes of the systemic immune system has improved over the past few years, our understanding of the mechanisms of senescence of both adaptive and innate immune system of the gastrointestinal (GI) tract is still largely incomplete. However, recent advances in the field have shown that the identification of the events underlying the ageing process in the gut may have important consequences on health and wellbeing far beyond the GI tract. The aim of this review is to summarise the impact of ageing on the intestinal immune system, including the gut epithelium and other components of the intestinal barrier that maintain intestinal immune homeostasis and shape antigen-specific immune responses. PMID- 24759080 TI - New management algorithms in multiple sclerosis. AB - PURPOSE OF REVIEW: Our current treatment algorithms include only IFN-beta and glatiramer as available first-line disease-modifying drugs and natalizumab and fingolimod as second-line therapies. Today, 10 drugs have been approved in Europe and nine in the United States making the choice of therapy more complex. The purpose of the review has been to work out new management algorithms for treatment of relapsing-remitting multiple sclerosis including new oral therapies and therapeutic monoclonal antibodies. RECENT FINDINGS: Recent large placebo controlled trials in relapsing-remitting multiple sclerosis have shown efficacy of new oral disease-modifying drugs, teriflunomide and dimethyl fumarate, with similar or better efficacy than the injectable disease-modifying drugs, IFN-beta and glatiramer acetate. In addition, the new oral drugs seem to have a favorable safety profile. Further, the monoclonal antibody alemtuzumab, which in clinical trials has shown superiority to subcutaneous IFN-beta 1a, has been approved in Europe, but not yet in the United States. SUMMARY: In de novo-treated patients, the injectables, IFN-beta and glatiramer acetate, will to a great extent be replaced by the new orals, dimethyl fumarate and teriflunomide. However, patients who are stable on an injectable with no or minor side-effects could continue their current therapy. Alemtuzumab should be used as a second-line therapy. PMID- 24759081 TI - Nudging the obese: a UK-US consideration. AB - Over recent years, nudge policies have become increasingly popular (if somewhat confused) internationally. This article attempts to clarify what a nudge entails, and critically summarises some of the nudge policies that have been proposed to motivate weight loss in the United Kingdom and the United States. Despite the fact that most of the evidence on nudge-related policy has so far been produced in the United States, and that the leading nudge champions are American, the United Kingdom, at least with respect to considering policy interventions of this kind at the national level, appears to be relatively advanced. That said, nudge interventions remain of marginal practical import everywhere, and are never going to solve completely the obesity problem. Nonetheless, even a marginal effect may extend and improve many lives, a result that would satisfy most behavioural economists. PMID- 24759079 TI - Dendritic-cell exosomes cross-present Toll-like receptor-ligands and activate bystander dendritic cells. AB - Dendritic cells (DCs) are the major sentinel, antigen-presenting and regulatory components of the immune system. One of the central DC functions is to rapidly sense and alert host immune system of a pathogen invasion. In the present study, we investigated the role of DC exosomes (DCex) in this sentinel function. We demonstrated that DCex could bind bacterial Toll-like-receptor ligands (TLR-Ls), and acquire their ability to strongly activate bystander DCs. Consequently, bystander DCs enhance the expression of transmembrane tumor necrosis factor, secretion of proinflammatory cytokines and cross-talk with natural killer cells leading to the elevated secretion of IFNgamma. These findings newly show that DCex can bind and cross-present TLR-Ls to innate-immunity effector cells, and indicate a potent mechanism to systemically alert the host immune system of pathogen invasion. They also suggest a potential novel strategy to generate effective vaccines by binding TLR-L-immune adjuvants to DCex. PMID- 24759082 TI - The use of polyimide-modified aluminum nitride fillers in AlN@PI/epoxy composites with enhanced thermal conductivity for electronic encapsulation. AB - Polymer modified fillers in composites has attracted the attention of numerous researchers. These fillers are composed of core-shell structures that exhibit enhanced physical and chemical properties that are associated with shell surface control and encapsulated core materials. In this study, we have described an apt method to prepare polyimide (PI)-modified aluminum nitride (AlN) fillers, AlN@PI. These fillers are used for electronic encapsulation in high performance polymer composites. Compared with that of untreated AlN composite, these AlN@PI/epoxy composites exhibit better thermal and dielectric properties. At 40 wt% of filler loading, the highest thermal conductivity of AlN@PI/epoxy composite reached 2.03 W/mK. In this way, the thermal conductivity is approximately enhanced by 10.6 times than that of the used epoxy matrix. The experimental results exhibiting the thermal conductivity of AlN@PI/epoxy composites were in good agreement with the values calculated from the parallel conduction model. This research work describes an effective pathway that modifies the surface of fillers with polymer coating. Furthermore, this novel technique improves the thermal and dielectric properties of fillers and these can be used extensively for electronic packaging applications. PMID- 24759083 TI - Targeted genomic rearrangements using CRISPR/Cas technology. AB - Genomic rearrangements are frequently observed in cancer cells but have been difficult to generate in a highly specific manner for functional analysis. Here we report the application of CRISPR/Cas technology to successfully generate several types of chromosomal rearrangements implicated as driver events in lung cancer, including the CD74-ROS1 translocation event and the EML4-ALK and KIF5B RET inversion events. Our results demonstrate that Cas9-induced DNA breaks promote efficient rearrangement between pairs of targeted loci, providing a highly tractable approach for the study of genomic rearrangements. PMID- 24759084 TI - Commercial sexual exploitation of minors: overlooked and underreported. PMID- 24759086 TI - Oxidizing to death: disulfiram for cancer cell killing. PMID- 24759087 TI - Symptoms of depression and anxiety after the disclosure of the diagnosis of Alzheimer disease. AB - BACKGROUND AND PURPOSE: Many people fear that the disclosure of the diagnosis of Alzheimer disease (AD) to patients will prompt depressive symptoms or catastrophic reactions. We aimed to prospectively evaluate the modification of anxiety and depressive symptoms 3 months after the disclosure of the diagnosis of AD. METHODS: A total of 100 consecutive newly diagnosed patients with AD (mild or moderate stage) and their caregivers were included. The evolution of symptoms of depression and anxiety was assessed with the Zung Self-Rating Depression Scale (Zung SDS) and the depression item of the Neuropsychiatric Inventory (NPI-d) and the anxiety item of the Neuropsychiatric Inventory (NPI-a). After 3 months, the caregivers were asked their opinions on the global effect of the disclosure using a Likert-type scale. RESULTS: At 3 months, there was no significant change in the mean NPI-d (P = .87) and Zung SDS (P = .18) and a significant reduction in the NPI-a (P = .05). The NPI-d worsened in 22% of patients, improved in 22%, and remained unchanged in 56%. The NPI-a worsened in 12% of patients, improved in 33%, and remained unchanged in 54%. The caregivers rated the global effect of the disclosure as negative in 8%, neutral in 71%, and positive in 21% of patients. None of the patients or their proxies reported suicide attempts or catastrophic reactions. CONCLUSIONS: The disclosure of AD is safe in most cases and may improve anxiety. Symptoms of depression and anxiety worsen only in a minority of patients. The fear of depression or catastrophic reaction should not prevent clinicians to disclose the diagnosis of AD. PMID- 24759085 TI - UV signaling pathways within the skin. AB - The effects of UVR on the skin include tanning, carcinogenesis, immunomodulation, and synthesis of vitamin D, among others. Melanocortin 1 receptor polymorphisms correlate with skin pigmentation, UV sensitivity, and skin cancer risk. This article reviews pathways through which UVR induces cutaneous stress and the pigmentation response. Modulators of the UV-tanning pathway include sunscreen agents, melanocortin 1 receptor activators, adenylate cyclase activators, phosphodiesterase 4D3 inhibitors, T-oligos, and microphthalmia-associated transcription factor regulators such as histone deacetylase inhibitors. UVR, as one of the most ubiquitous carcinogens, represents both a challenge and an enormous opportunity in skin cancer prevention. PMID- 24759089 TI - Autocrine VEGF/VEGFR1 signaling in a subpopulation of cells associates with aggressive osteosarcoma. AB - Osteosarcoma is the most common primary bone malignancy and accounts for more than half of primary skeletal malignancies in children and young adults. Although vascular endothelial growth factor (VEGF) expression in osteosarcoma has been associated with poor outcome, its role in the pathogenesis of osteosarcoma remains controversial. Here, VEGF and VEGFR1 expression in both human and murine osteosarcoma cells associated with increasing malignant potential. Autocrine VEGF/VEGFR1 signaling resulted in constitutive activation of VEGFR1 in highly aggressive osteosarcoma cells. In addition, survival and proliferation of highly aggressive osteosarcoma cells was dependent on autocrine VEGF/R1 signaling in vitro. The effect of VEGFR1 expression on in vivo tumor growth and angiogenesis was evaluated by immunoselecting subpopulations of osteosarcoma cells that express high or low levels of VEGFR1. Cell enriched for high VEGFR1 expression showed increased VEGF production, tumor growth, tumor angiogenesis, and osteolysis in vivo. In addition, it was demonstrated that VEGF and VEGFR1 are coexpressed by a subset of tumor cells in human osteosarcoma, similar to what was observed in the murine osteosarcoma cells. These results suggest that autocrine VEGF/VEGFR1 signaling in a subpopulation of tumor cells plays a pivotal role in osteosarcoma progression. IMPLICATIONS: Aggressive osteosarcoma phenotypes are mediated by autocrine VEGF/VEGFR1 signaling and improved stratification measures and novel anti-angiogenic strategies may benefit this specific tumor type. PMID- 24759088 TI - Neuropsychological and neuropsychiatric prediction of global cognitive status among older Spanish-speaking Hispanics and English-speaking whites. AB - BACKGROUND: Neuropsychological and depression measures have been found to predict cognitive functioning. We compared these associations among whites and Spanish speaking Hispanics. METHODS: Fifty-two pairs of whites and Hispanics were matched demographically and clinically in a cross-sectional study. Hierarchical regression analyses predicted Global Deterioration Scale (GDS) rating by baseline neuropsychological tests and depression symptoms. RESULTS: Neuropsychological tests predicted GDS better in whites; depression symptoms--specifically retardation--predicted well in Hispanics but not whites. Immediate recall of the New York University (NYU)-Paragraph Test and the Retardation item of the Hamilton Depression Rating Scale were associated with GDS in Hispanics and delayed recall of the NYU-Paragraph Test and Wechsler Adult Intelligence Scale-Digit Symbol in whites. Neuropsychological tests and depression symptoms predicted GDS differently in Hispanics and whites. DISCUSSION: These results suggest that other measures should be considered to increase the predictive accuracy of neuropsychological tests when assessing cognitive status in Spanish-speaking Hispanics. Additional studies of specific ethnic/racial and sociodemographic subgroups are warranted. PMID- 24759090 TI - RNA recognition by a human antibody against brain cytoplasmic 200 RNA. AB - Diverse functional RNAs participate in a wide range of cellular processes. The RNA structure is critical for function, either on its own or as a complex form with proteins and other ligands. Therefore, analysis of the RNA conformation in cells is essential for understanding their functional mechanisms. However, no appropriate methods have been established as yet. Here, we developed an efficient strategy for panning and affinity maturation of anti-RNA human monoclonal antibodies from a naive antigen binding fragment (Fab) combinatorial phage library. Brain cytoplasmic 200 (BC200) RNA, which is also highly expressed in some tumors, was used as an RNA antigen. We identified MabBC200-A3 as the optimal binding antibody. Mutagenesis and SELEX experiments showed that the antibody recognized a domain of BC200 in a structure- and sequence-dependent manner. Various breast cancer cell lines were further examined for BC200 RNA expression using conventional hybridization and immunoanalysis with MabBC200-A3 to see whether the antibody specifically recognizes BC200 RNA among the total purified RNAs. The amounts of antibody-recognizable BC200 RNA were consistent with hybridization signals among the cell lines. Furthermore, the antibody was able to discriminate BC200 RNA from other RNAs, supporting the utility of this antibody as a specific RNA structure-recognizing probe. Intriguingly, however, when permeabilized cells were subjected to immunoanalysis instead of purified total RNA, the amount of antibody-recognizable RNA was not correlated with the cellular level of BC200 RNA, indicating that BC200 RNA exists as two distinct forms (antibody-recognizable and nonrecognizable) in breast cancer cells and that their distribution depends on the cell type. Our results clearly demonstrate that anti RNA antibodies provide an effective novel tool for detecting and analyzing RNA conformation. PMID- 24759091 TI - Protein kinase A regulates gene-specific translational adaptation in differentiating yeast. AB - Cellular differentiation is driven by coordinately regulated changes in gene expression. Recent discoveries suggest that translation contributes as much as transcription to regulating protein abundance, but the role of translational regulation in cellular differentiation is largely unexplored. Here we investigate translational reprogramming in yeast during cellular adaptation to the absence of glucose, a stimulus that induces invasive filamentous differentiation. Using ribosome footprint profiling and RNA sequencing to assay gene-specific translation activity genome-wide, we show that prolonged glucose withdrawal is accompanied by gene-specific changes in translational efficiency that significantly affect expression of the majority of genes. Notably, transcripts from a small minority (<5%) of genes make up the majority of translating mRNA in both rapidly dividing and starved differentiating cells, and the identities of these highly translated messages are almost nonoverlapping between conditions. Furthermore, these two groups of messages are subject to condition-dependent translational privilege. Thus the "housekeeping" process of translation does not stay constant during cellular differentiation but is highly adapted to different growth conditions. By comparing glucose starvation to growth-attenuating stresses that do not induce invasive filamentation, we distinguish a glucose-specific translational response mediated through signaling by protein kinase A (PKA). Together, these findings reveal a high degree of growth-state specialization of the translatome and identify PKA as an important regulator of gene-specific translation activity. PMID- 24759092 TI - The Streptococcus suis transcriptional landscape reveals adaptation mechanisms in pig blood and cerebrospinal fluid. AB - Streptococcus suis (SS) is an important pathogen of pigs, and it is also recognized as a zoonotic agent for humans. SS infection may result in septicemia or meningitis in the host. However, little is known about genes that contribute to the virulence process and survival within host blood or cerebrospinal fluid (CSF). Small RNAs (sRNA) have emerged as key regulators of virulence in several bacteria, but they have not been investigated in SS. Here, using a differential RNA-sequencing approach and RNAs from SS strain P1/7 grown in rich medium, pig blood, or CSF, we present the SS genome-wide map of 793 transcriptional start sites and 370 operons. In addition to identifying 29 sRNAs, we show that five sRNA deletion mutants attenuate SS virulence in a zebrafish infection model. Homology searches revealed that 10 sRNAs were predicted to be present in other pathogenic Streptococcus species. Compared with wild-type strain P1/7, sRNAs rss03, rss05, and rss06 deletion mutants were significantly more sensitive to killing by pig blood. It is possible that rss06 contributes to SS virulence by indirectly activating expression of SSU0308, a virulence gene encoding a zinc binding lipoprotein. In blood, genes involved in the synthesis of capsular polysaccharide (CPS) and subversion of host defenses were up-regulated. In contrast, in CSF, genes for CPS synthesis were down-regulated. Our study is the first analysis of SS sRNAs involved in virulence and has both improved our understanding of SS pathogenesis and increased the number of sRNAs known to play definitive roles in bacterial virulence. PMID- 24759093 TI - Elastic network models capture the motions apparent within ensembles of RNA structures. AB - The role of structure and dynamics in mechanisms for RNA becomes increasingly important. Computational approaches using simple dynamics models have been successful at predicting the motions of proteins and are often applied to ribonucleo-protein complexes but have not been thoroughly tested for well-packed nucleic acid structures. In order to characterize a true set of motions, we investigate the apparent motions from 16 ensembles of experimentally determined RNA structures. These indicate a relatively limited set of motions that are captured by a small set of principal components (PCs). These limited motions closely resemble the motions computed from low frequency normal modes from elastic network models (ENMs), either at atomic or coarse-grained resolution. Various ENM model types, parameters, and structure representations are tested here against the experimental RNA structural ensembles, exposing differences between models for proteins and for folded RNAs. Differences in performance are seen, depending on the structure alignment algorithm used to generate PCs, modulating the apparent utility of ENMs but not significantly impacting their ability to generate functional motions. The loss of dynamical information upon coarse-graining is somewhat larger for RNAs than for globular proteins, indicating, perhaps, the lower cooperativity of the less densely packed RNA. However, the RNA structures show less sensitivity to the elastic network model parameters than do proteins. These findings further demonstrate the utility of ENMs and the appropriateness of their application to well-packed RNA-only structures, justifying their use for studying the dynamics of ribonucleo proteins, such as the ribosome and regulatory RNAs. PMID- 24759094 TI - Single cell genome analysis of an uncultured heterotrophic stramenopile. AB - A broad swath of eukaryotic microbial biodiversity cannot be cultivated in the lab and is therefore inaccessible to conventional genome-wide comparative methods. One promising approach to study these lineages is single cell genomics (SCG), whereby an individual cell is captured from nature and genome data are produced from the amplified total DNA. Here we tested the efficacy of SCG to generate a draft genome assembly from a single sample, in this case a cell belonging to the broadly distributed MAST-4 uncultured marine stramenopiles. Using de novo gene prediction, we identified 6,996 protein-encoding genes in the MAST-4 genome. This genetic inventory was sufficient to place the cell within the ToL using multigene phylogenetics and provided preliminary insights into the complex evolutionary history of horizontal gene transfer (HGT) in the MAST-4 lineage. PMID- 24759095 TI - Is Simpson grade I removal necessary in all cases of spinal meningioma? Assessment of postoperative recurrence during long-term follow-up. AB - It is generally accepted that the first choice of treatment for spinal meningiomas is "radical" surgical removal. However, Simpson grade I removal is sometimes difficult, especially in cases with ventral dural attachment, because of the risk of spinal cord damage or the difficulty of dural repair after radical resection. In addition, there is no consensus on a surgical strategy for radicality, whether or not Simpson grade I resection should be performed in all cases of spinal meningioma. In this study, we retrospectively analyzed clinical and radiological data of surgically treated 14 patients with spinal meningioma, to assess the influence of the Simpson grade to tumor recurrences during long term follow-up (median 8.2 years, 1.3-27.9). The number of patients in Simpson grades I, II, III, and IV were 2, 8, 0, and 3, respectively; Simpson grading was not applicable to one patient with non-dura-based meningioma. No postoperative permanent neurological worsening was encountered. The recurrence rate was 21.4% (3 out of 14 cases). Of these 3 recurrent cases, 1 was a case of non-dura-based meningioma and another was a case of neurofibromatosis type 2 (NF2); both of them are known as risk factors for recurrence after surgical removal of spinal meningiomas. Considering this background of these two recurrences, the clinical results of the present study are consistent with previous results. Therefore, we propose that surgeons do not always have to achieve Simpson grade I removal if dural repair is complicated and postoperative cerebrospinal fluid (CSF) leakage or neurological worsening are estimated after resection of dural attachment and repair of dural defect. PMID- 24759096 TI - Use of blunt scalp hooks for abdominal procedure in lumboperitoneal shunt placement: technical note. AB - In obese patients, we often find difficulty in laparotomy for placing a lumboperitoneal shunt catheter. The authors introduced an easy technique to get a sufficiently wide and shallow operative field through small abdominal incision in obese people. Four blunt scalp hooks and rubber bands, commonly used in craniotomy, were prepared. The fat layer and the rectus abdominis muscle layer were retracted and pulled up using these hooks. Blunt scalp hooks were useful for safe and effective retraction of abdominal wall, which made a sufficient and shallow operative field. PMID- 24759097 TI - Treatment of acute cerebral artery occlusion using the Penumbra system: our early experience. AB - Intravenous recombinant tissue-type plasminogen activator (rt-PA) therapy is highly recommended to patients who are diagnosed with ischemic stroke within 4.5 hours after the onset while mechanical clot retrieval can be attempted in patients who are not indicated for or cannot effectively receive intravenous rt PA therapy. In this article, we report early treatment outcomes and discuss the usefulness of mechanical clot retrieval using the Penumbra system (Penumbra Inc., Alameda, California, USA), especially in terms of technical cautions during the procedure and adaptability to elderly and high National Institutes of Health Stroke Scale (NIHSS) patients. We included 7 patients with thromboembolic occlusion. Pretreatment NIHSS score ranged from 11 to 36 (mean: 24.9). All patients achieved good recanalization [thrombolysis in cerebral infarction (TICI) grade 2a or greater] without complications. The NIHSS score at 30 days after the treatment ranged between 0 and 28 (mean: 12.4), and improved more than 10 points in 4 of the 7 patients (57.1%). To obtain good recanalization without complications, selection of suitable reperfusion catheter and careful manipulation of separator prefiguring the occluded distal vessels are essential. The improved NIHSS score at 30 days after the treatment may have led to favorable results, such as an increased participation in available rehabilitation programs and the alleviation of the burden of care. Our findings suggest that the Penumbra system might be effective for treatment in elderly patients or patients with high NIHSS score wherein rt-PA therapy is inadvisable or ineffective in ischemic stroke secondary to large vessel occlusion. Recanalization can improve their quality of life on condition that the procedure is performed successfully without serious complications. PMID- 24759098 TI - Utility of intraoperative fetal heart rate monitoring for cerebral arteriovenous malformation surgery during pregnancy. AB - We report two methods of intraoperative fetal heart rate (FHR) monitoring in cases of cerebral arteriovenous malformation surgery during pregnancy. In one case in her third trimester, cardiotocography was used. In another case in her second trimester, ultrasound sonography was used, with a transesophageal echo probe attached to her lower abdomen. Especially, the transesophageal echo probe was useful because of the advantages of being flexible and easy to attach to the mother's lower abdomen comparing with the usual doppler ultrasound probe. In both cases, the surgery was successfully performed and FHR was monitored safely and stably. The use of intraoperative FHR monitoring provides information about the influence of induced maternal hypotension and unexpected bleeding on fetus during surgery. These monitoring techniques would be especially emphasized in cerebrovascular surgery for the safe management of both mother and fetus. PMID- 24759099 TI - Functional role for Piezo1 in stretch-evoked Ca2+ influx and ATP release in urothelial cell cultures. AB - The urothelium is a sensory structure that contributes to mechanosensation in the urinary bladder. Here, we provide evidence for a critical role for the Piezo1 channel, a newly identified mechanosensory molecule, in the mouse bladder urothelium. We performed a systematic analysis of the molecular and functional expression of Piezo1 channels in the urothelium. Immunofluorescence examination demonstrated abundant expression of Piezo1 in the mouse and human urothelium. Urothelial cells isolated from mice exhibited a Piezo1-dependent increase in cytosolic Ca(2+) concentrations in response to mechanical stretch stimuli, leading to potent ATP release; this response was suppressed in Piezo1-knockdown cells. In addition, Piezo1 and TRPV4 distinguished different intensities of mechanical stimulus. Moreover, GsMTx4, an inhibitor of stretch-activated channels, attenuated the Ca(2+) influx into urothelial cells and decreased ATP release from them upon stretch stimulation. These results suggest that Piezo1 senses extension of the bladder urothelium, leading to production of an ATP signal. Thus, inhibition of Piezo1 might provide a promising means of treating bladder dysfunction. PMID- 24759101 TI - A molecular basis for the interplay between T cells, viral mutants, and human leukocyte antigen micropolymorphism. AB - Mutations within T cell epitopes represent a common mechanism of viral escape from the host protective immune response. The diverse T cell repertoire and the extensive human leukocyte antigen (HLA) polymorphism across populations is the evolutionary response to viral mutation. However, the molecular basis underpinning the interplay between HLA polymorphism, the T cell repertoire, and viral escape is unclear. Here we investigate the T cell response to a HLA-B*35:01 and HLA-B*35:08-restricted (407)HPVGEADYFEY(417) epitope from Epstein-Barr virus and naturally occurring variants at positions 4 and 5 thereof. Each viral variant differently impacted on the epitope's flexibility and conformation when bound to HLA-B*35:08 or HLA-B*35:01. We provide a molecular basis for understanding how the single residue polymorphism that discriminates between HLA-B*35:01/08 profoundly impacts on T cell receptor recognition. Surprisingly, one viral variant (P5-Glu to P5-Asp) effectively changed restriction preference from HLA B*35:01 to HLA-B*35:08. Collectively, our study portrays the interplay between the T cell response, viral escape, and HLA polymorphism, whereby HLA polymorphism enables altered presentation of epitopes from different strains of Epstein-Barr virus. PMID- 24759100 TI - Critical role for NAD glycohydrolase in regulation of erythropoiesis by hematopoietic stem cells through control of intracellular NAD content. AB - NAD glycohydrolases (NADases) catalyze the hydrolysis of NAD to ADP-ribose and nicotinamide. Although many members of the NADase family, including ADP ribosyltransferases, have been cloned and characterized, the structure and function of NADases with pure hydrolytic activity remain to be elucidated. Here, we report the structural and functional characterization of a novel NADase from rabbit reticulocytes. The novel NADase is a glycosylated, glycosylphosphatidylinositol-anchored cell surface protein exclusively expressed in reticulocytes. shRNA-mediated knockdown of the NADase in bone marrow cells resulted in a reduction of erythroid colony formation and an increase in NAD level. Furthermore, treatment of bone marrow cells with NAD, nicotinamide, or nicotinamide riboside, which induce an increase in NAD content, resulted in a significant decrease in erythroid progenitors. These results indicate that the novel NADase may play a critical role in regulating erythropoiesis of hematopoietic stem cells by modulating intracellular NAD. PMID- 24759102 TI - YCL047C/POF1 is a novel nicotinamide mononucleotide adenylyltransferase (NMNAT) in Saccharomyces cerevisiae. AB - NAD(+) is an essential metabolic cofactor involved in various cellular biochemical processes. Nicotinamide riboside (NR) is an endogenously produced key pyridine metabolite that plays important roles in the maintenance of NAD(+) pool. Using a NR-specific cell-based screen, we identified mutants that exhibit altered NR release phenotype. Yeast cells lacking the ORF YCL047C/POF1 release considerably more NR compared with wild type, suggesting that POF1 plays an important role in NR/NAD(+) metabolism. The amino acid sequence of Pof1 indicates that it is a putative nicotinamide mononucleotide adenylyltransferase (NMNAT). Unlike other yeast NMNATs, Pof1 exhibits NMN-specific adenylyltransferase activity. Deletion of POF1 significantly lowers NAD(+) levels and decreases the efficiency of NR utilization, resistance to oxidative stress, and NR-induced life span extension. We also show that NR is constantly produced by multiple nucleotidases and that the intracellular NR pools are likely to be compartmentalized, which contributes to the regulation of NAD(+) homeostasis. Our findings may contribute to the understanding of the molecular basis and regulation of NAD(+) metabolism in higher eukaryotes. PMID- 24759103 TI - New role for Kruppel-like factor 14 as a transcriptional activator involved in the generation of signaling lipids. AB - Sphingosine kinase 1 (SK1) is an FGF-inducible gene responsible for generation of sphingosine-1-phosphate, a critical lipid signaling molecule implicated in diverse endothelial cell functions. In this study, we identified SK1 as a target of the canonical FGF2/FGF receptor 1 activation pathway in endothelial cells and sought to identify novel transcriptional pathways that mediate lipid signaling. Studies using the 1.9-kb SK1 promoter and deletion mutants revealed that basal and FGF2-stimulated promoter activity occurred through two GC-rich regions located within 633 bp of the transcription start site. Screening for GC-rich binding transcription factors that could activate this site demonstrated that KLF14, a gene implicated in obesity and the metabolic syndrome, binds to this region. Congruently, overexpression of KLF14 increased basal and FGF2-stimulated SK1 promoter activity by 3-fold, and this effect was abrogated after mutation of the GC-rich sites. In addition, KLF14 siRNA transfection decreased SK1 mRNA and protein levels by 3-fold. Congruently, SK1 mRNA and protein levels were decreased in livers from KLF14 knock-out mice. Combined, luciferase, gel shift, and chromatin immunoprecipitation assays showed that KLF14 couples to p300 to increase the levels of histone marks associated with transcriptional activation (H4K8ac and H3K14ac), while decreasing repressive marks (H3K9me3 and H3K27me3). Collectively, the results demonstrate a novel mechanism whereby SK1 lipid signaling is regulated by epigenetic modifications conferred by KLF14 and p300. Thus, this is the first description of the activity and mechanisms underlying the function of KLF14 as an activator protein and novel regulator of lipid signaling. PMID- 24759104 TI - Kinetics, structure, and mechanism of 8-Oxo-7,8-dihydro-2'-deoxyguanosine bypass by human DNA polymerase eta. AB - DNA damage incurred by a multitude of endogenous and exogenous factors constitutes an inevitable challenge for the replication machinery. Cells rely on various mechanisms to either remove lesions or bypass them in a more or less error-prone fashion. The latter pathway involves the Y-family polymerases that catalyze trans-lesion synthesis across sites of damaged DNA. 7,8-Dihydro-8-oxo-2' deoxyguanosine (8-oxoG) is a major lesion that is a consequence of oxidative stress and is associated with cancer, aging, hepatitis, and infertility. We have used steady-state and transient-state kinetics in conjunction with mass spectrometry to analyze in vitro bypass of 8-oxoG by human DNA polymerase eta (hpol eta). Unlike the high fidelity polymerases that show preferential insertion of A opposite 8-oxoG, hpol eta is capable of bypassing 8-oxoG in a mostly error free fashion, thus preventing GC->AT transversion mutations. Crystal structures of ternary hpol eta-DNA complexes and incoming dCTP, dATP, or dGTP opposite 8 oxoG reveal that an arginine from the finger domain assumes a key role in avoiding formation of the nascent 8-oxoG:A pair. That hpol eta discriminates against dATP exclusively at the insertion stage is confirmed by structures of ternary complexes that allow visualization of the extension step. These structures with G:dCTP following either 8-oxoG:C or 8-oxoG:A pairs exhibit virtually identical active site conformations. Our combined data provide a detailed understanding of hpol eta bypass of the most common oxidative DNA lesion. PMID- 24759105 TI - Molecular and cellular mechanisms responsible for cellular stress and low-grade inflammation induced by a super-low dose of endotoxin. AB - Super-low-dose endotoxemia in experimental animals and humans is linked to low grade chronic inflammatory diseases. However, the underlying molecular and cellular mechanisms are not well understood. In this study, we examined the effects of a super-low dose of LPS on low-grade inflammation in macrophages as well as underlying mechanisms. We observed that a super-low dose of LPS induces mitochondrial fission and cell necroptosis in primary murine macrophages, dependent upon interleukin 1 receptor-associated kinase (IRAK-1). Mechanistically, our study reveals that a super-low dose of LPS causes protein ubiquitination and degradation of mitofusin 1 (Mfn1), a molecule required for maintaining proper mitochondrial fusion. A super-low dose of LPS also leads to dephosphorylation and activation of Drp1, a molecule responsible for mitochondrial fission and cell necroptosis. Furthermore, we demonstrated that a super-low dose of LPS activates receptor interacting protein 3 kinase (RIP3), a key molecule critical for the assembly of the necrosome complex, the initiation of Drp1 dephosphorylation, and necroptosis. The effects of a super-low dose of LPS are abolished in macrophages harvested from IRAK-1-deficient mice. Taken together, our study identified a novel molecular pathway that leads to cellular stress and necroptosis in macrophages challenged with a super-low dose of endotoxin. This may reconcile low-grade inflammation often associated with low grade endotoxemia. PMID- 24759107 TI - Quorum sensing activity of Aeromonas caviae strain YL12, a bacterium isolated from compost. AB - Quorum sensing is a well-studied cell-to-cell communication method that involves a cell-density dependent regulation of genes expression mediated by signalling molecules. In this study, a bacterium isolated from a plant material compost pile was found to possess quorum sensing activity based on bioassay screening. Isolate YL12 was identified using matrix-assisted laser desorption ionization time-of flight (MALDI-TOF) mass spectrometry and molecular typing using rpoD gene which identified the isolate as Aeromonas caviae. High resolution tandem mass spectrometry was subsequently employed to identify the N-acyl homoserine lactone profile of Aeromonas caviae YL12 and confirmed that this isolate produced two short chain N-acyl homoserine lactones, namely C4-HSL and C6, and the production was observed to be cell density-dependent. Using the thin layer chromatography (TLC) bioassay, both AHLs were found to activate C. violaceum CV026, whereas only C6-HSL was revealed to induce bioluminescence expression of E. coli [pSB401]. The data presented in this study will be the leading steps in understanding the role of quorum sensing in Aeromonas caviae strain YL12. PMID- 24759108 TI - Effect of angular velocity on sensors based on morphology dependent resonances. AB - We carried out an analysis to investigate the morphology dependent optical resonances shift (MDR) of a rotating spherical resonator. The spinning resonator experiences an elastic deformation due to the centrifugal force acting on it, leading to a shift in its MDR. Experiments are also carried out to demonstrate the MDR shifts of a spinning polydimethylsiloxane (PDMS) microsphere. The experimental results agree well with the analytical prediction. These studies demonstrated that spinning sensor based on MDR may experience sufficient shift in the optical resonances, therefore interfering with its desirable operational sensor design. Also the results show that angular velocity sensors could be designed using this principle. PMID- 24759109 TI - Novel paradigm for constructing masses in Dempster-Shafer evidence theory for wireless sensor network's multisource data fusion. AB - Dempster-Shafer evidence theory (DSET) is a flexible and popular paradigm for multisource data fusion in wireless sensor networks (WSNs). This paper presents a novel and easy implementing method computing masses from the hundreds of pieces of data collected by a WSN. The transfer model is based on the Mahalanobis distance (MD), which is an effective method to measure the similarity between an object and a sample. Compared to the existing methods, the proposed method concerns the statistical features of the observed data and it is good at transferring multi-dimensional data to belief assignment correctly and effectively. The main processes of the proposed method, which include the calculation of the intersection classes of the power set and the algorithm mapping MDs to masses, are described in detail. Experimental results in transformer fault diagnosis show that the proposed method has a high accuracy in constructing masses from multidimensional data for DSET. Additionally, the results also prove that higher dimensional data brings higher accuracy in transferring data to mass. PMID- 24759106 TI - Transcription factors NRF2 and NF-kappaB are coordinated effectors of the Rho family, GTP-binding protein RAC1 during inflammation. AB - The small GTPase protein RAC1 participates in innate immunity by activating a complex program that includes cytoskeleton remodeling, chemotaxis, activation of NADPH oxidase, and modulation of gene expression. However, its role in regulating the transcriptional signatures that in term control the cellular inflammatory profiles are not well defined. Here we investigated the functional and mechanistic connection between RAC1 and the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2), master regulator of the anti-oxidant response. Lipopolysaccharide and constitutively active RAC1(Q61L) mutant induced the anti-oxidant enzyme heme-oxygenase-1 (HO-1) through activation of NRF2. The use of KEAP1-insensitive NRF2 mutants indicated that RAC1 regulation of NRF2 is KEAP1-independent. Interestingly, NRF2 overexpression inhibited, whereas a dominant-negative mutant of NRF2 exacerbated RAC1-dependent activation of nuclear factor-kappaB (NF-kappaB), suggesting that NRF2 has an antagonistic effect on the NF-kappaB pathway. Moreover, we found that RAC1 acts through NF-kappaB to induce NRF2 because either expression of a dominant negative mutant of IkappaBalpha that leads to NF-kappaB degradation or the use of p65-NF-kappaB-deficient cells demonstrated lower NRF2 protein levels and basally impaired NRF2 signature compared with control cells. In contrast, NRF2-deficient cells showed increased p65-NF-kappaB protein levels, although the mRNA levels remain unchanged, indicating post-translational alterations. Our results demonstrate a new mechanism of modulation of RAC1 inflammatory pathway through a cross-talk between NF-kappaB and NRF2. PMID- 24759110 TI - Setup of galvanic sensors for the monitoring of gilded bronzes. AB - Traditional electrochemical techniques, such as linear polarization resistance (Rp), and electrochemical impedance spectroscopy (EIS), cannot be applied to gilded bronzes, as it may not be possible to interpret the results obtained due to the bimetallic nature of the studied material. The measurement of the macrocouple current generated by the gold/bronze galvanic couple can be used as an indicator of degradation processes. Nevertheless, this measurement cannot be performed directly on the original artifacts due to the systematic presence of short-circuits between the two metals. In the present work the use of galvanic sensors is proposed as a possible solution for the monitoring of gilded bronze artefacts. The sensors have been designed to simulate real gilded bronze surfaces in terms of composition and stratigraphy and have proved to be a reliable diagnostic tool for the in situ monitoring of the rates of deterioration of gilded bronze surfaces and to test new conservation treatments. Their set-up and application is reported and their performances discussed. PMID- 24759111 TI - A method for measuring the volume of transdermally extracted interstitial fluid by a three-electrode skin resistance sensor. AB - It is difficult to accurately measure the volume of transdermally extracted interstitial fluid (ISF), which is important for improving blood glucose prediction accuracy. Skin resistance, which is a good indicator of skin permeability, can be used to determine the volume of extracted ISF. However, it is a challenge to realize in vivo longitudinal skin resistance measurements of microareas. In this study, a three-electrode sensor was presented for measuring single-point skin resistance in vivo, and a method for determining the volume of transdermally extracted ISF using this sensor was proposed. Skin resistance was measured under static and dynamic conditions. The correlation between the skin resistance and the permeation rate of transdermally extracted ISF was proven. The volume of transdermally extracted ISF was determined using skin resistance. Factors affecting the volume prediction accuracy of transdermally extracted ISF were discussed. This method is expected to improve the accuracy of blood glucose prediction, and is of great significance for the clinical application of minimally invasive blood glucose measurement. PMID- 24759112 TI - WiSPH: a wireless sensor network-based home care monitoring system. AB - This paper presents a system based on WSN technology capable of monitoring heart rate and the rate of motion of seniors within their homes. The system is capable of remotely alerting specialists, caretakers or family members via a smartphone of rapid physiological changes due to falls, tachycardia or bradycardia. This work was carried out using our workgroup's WiSe platform, which we previously developed for use in WSNs. The proposed WSN architecture is flexible, allowing for greater scalability to better allow event-based monitoring. The architecture also provides security mechanisms to assure that the monitored and/or stored data can only be accessed by authorized individuals or devices. The aforementioned characteristics provide the network versatility and solidity required for use in health applications. PMID- 24759113 TI - Wearable biomedical measurement systems for assessment of mental stress of combatants in real time. AB - The Spanish Ministry of Defense, through its Future Combatant program, has sought to develop technology aids with the aim of extending combatants' operational capabilities. Within this framework the ATREC project funded by the "Coincidente" program aims at analyzing diverse biometrics to assess by real time monitoring the stress levels of combatants. This project combines multidisciplinary disciplines and fields, including wearable instrumentation, textile technology, signal processing, pattern recognition and psychological analysis of the obtained information. In this work the ATREC project is described, including the different execution phases, the wearable biomedical measurement systems, the experimental setup, the biomedical signal analysis and speech processing performed. The preliminary results obtained from the data analysis collected during the first phase of the project are presented, indicating the good classification performance exhibited when using features obtained from electrocardiographic recordings and electrical bioimpedance measurements from the thorax. These results suggest that cardiac and respiration activity offer better biomarkers for assessment of stress than speech, galvanic skin response or skin temperature when recorded with wearable biomedical measurement systems. PMID- 24759114 TI - An affordable open-source turbidimeter. AB - Turbidity is an internationally recognized criterion for assessing drinking water quality, because the colloidal particles in turbid water may harbor pathogens, chemically reduce oxidizing disinfectants, and hinder attempts to disinfect water with ultraviolet radiation. A turbidimeter is an electronic/optical instrument that assesses turbidity by measuring the scattering of light passing through a water sample containing such colloidal particles. Commercial turbidimeters cost hundreds or thousands of dollars, putting them beyond the reach of low-resource communities around the world. An affordable open-source turbidimeter based on a single light-to-frequency sensor was designed and constructed, and evaluated against a portable commercial turbidimeter. The final product, which builds on extensive published research, is intended to catalyze further developments in affordable water and sanitation monitoring. PMID- 24759115 TI - Angular rate optimal design for the rotary strapdown inertial navigation system. AB - Due to the characteristics of high precision for a long duration, the rotary strapdown inertial navigation system (RSINS) has been widely used in submarines and surface ships. Nowadays, the core technology, the rotating scheme, has been studied by numerous researchers. It is well known that as one of the key technologies, the rotating angular rate seriously influences the effectiveness of the error modulating. In order to design the optimal rotating angular rate of the RSINS, the relationship between the rotating angular rate and the velocity error of the RSINS was analyzed in detail based on the Laplace transform and the inverse Laplace transform in this paper. The analysis results showed that the velocity error of the RSINS depends on not only the sensor error, but also the rotating angular rate. In order to minimize the velocity error, the rotating angular rate of the RSINS should match the sensor error. One optimal design method for the rotating rate of the RSINS was also proposed in this paper. Simulation and experimental results verified the validity and superiority of this optimal design method for the rotating rate of the RSINS. PMID- 24759116 TI - Smartphone-based solutions for fall detection and prevention: challenges and open issues. AB - This paper presents a state-of-the-art survey of smartphone (SP)-based solutions for fall detection and prevention. Falls are considered as major health hazards for both the elderly and people with neurodegenerative diseases. To mitigate the adverse consequences of falling, a great deal of research has been conducted, mainly focused on two different approaches, namely, fall detection and fall prevention. Required hardware for both fall detection and prevention are also available in SPs. Consequently, researchers' interest in finding SP-based solutions has increased dramatically over recent years. To the best of our knowledge, there has been no published review on SP-based fall detection and prevention. Thus in this paper, we present the taxonomy for SP-based fall detection and prevention solutions and systematic comparisons of existing studies. We have also identified three challenges and three open issues for future research, after reviewing the existing articles. Our time series analysis demonstrates a trend towards the integration of external sensing units with SPs for improvement in usability of the systems. PMID- 24759117 TI - Tracking and recognition of multiple human targets moving in a wireless pyroelectric infrared sensor network. AB - With characteristics of low-cost and easy deployment, the distributed wireless pyroelectric infrared sensor network has attracted extensive interest, which aims to make it an alternate infrared video sensor in thermal biometric applications for tracking and identifying human targets. In these applications, effectively processing signals collected from sensors and extracting the features of different human targets has become crucial. This paper proposes the application of empirical mode decomposition and the Hilbert-Huang transform to extract features of moving human targets both in the time domain and the frequency domain. Moreover, the support vector machine is selected as the classifier. The experimental results demonstrate that by using this method the identification rates of multiple moving human targets are around 90%. PMID- 24759118 TI - An interactive control algorithm used for equilateral triangle formation with robotic sensors. AB - This paper describes an interactive control algorithm, called Triangle Formation Algorithm (TFA), used for three neighboring robotic sensors which are distributed randomly to self-organize into and equilateral triangle (E) formation. The algorithm is proposed based on the triangular geometry and considering the actual sensors used in robotics. In particular, the stability of the TFA, which can be executed by robotic sensors independently and asynchronously for E formation, is analyzed in details based on Lyapunov stability theory. Computer simulations are carried out for verifying the effectiveness of the TFA. The analytical results and simulation studies indicate that three neighboring robots employing conventional sensors can self-organize into E formations successfully regardless of their initial distribution using the same TFAs. PMID- 24759119 TI - Recent developments in hyperspectral imaging for assessment of food quality and safety. AB - Hyperspectral imaging which combines imaging and spectroscopic technology is rapidly gaining ground as a non-destructive, real-time detection tool for food quality and safety assessment. Hyperspectral imaging could be used to simultaneously obtain large amounts of spatial and spectral information on the objects being studied. This paper provides a comprehensive review on the recent development of hyperspectral imaging applications in food and food products. The potential and future work of hyperspectral imaging for food quality and safety control is also discussed. PMID- 24759120 TI - The effect of micronutrient supplements on male fertility. AB - PURPOSE OF REVIEW: To describe the beneficial effects of micronutrient supplementation on male fertility. RECENT FINDINGS: Several micronutrients have beneficial effects on sperm quality, as well on male fertility (e.g. pregnancy rate). A deliberate use of micronutrients might be helpful for infertile patients. Healthcare providers should be aware that supplements contain the studied dose. SUMMARY: Male sterility is becoming increasingly important because of various factors. In addition to the avoidable risk factors (alcohol and smoking), unchangeable factors are also likely involved in the genesis. Modern reproductive medicine methods help resulting in decent pregnancy rates in subfertile men. However, in addition to reproductive medicine methods, factors other than cessation of smoking and alcohol consumption can influence the fertility of men. Several studies have reported a significant increase in sperm quality and pregnancy rates when the men were supplemented by specific vitamins and micronutrients.The present review gives an overview of the study results and discusses specific legal requirements (e.g. 'upper limits'). PMID- 24759121 TI - Optimization algorithm for rate equations with an application to epitaxial graphene. AB - We describe an algorithm that searches the parameter space of rate theories to optimize the associated rate coefficients based on a fit to experimental (or any other) data. Beginning with an initial set of parameters, which may be estimated, partially calculated, or indeed random, the algorithm follows a path, calculating the error at each point, until a minimum error is reached. We illustrate our method by correcting a previously proposed rate theory for the nucleation and growth of graphene on Ru(0 0 0 1) and Ir(1 1 1) to account for the temperature dependence of the graphene island density. This quantity shows an exponential decrease as the temperature is raised, in contrast to the power law decrease predicted by conventional nucleation theory, which indicates that a qualitatively different mechanism is operative for graphene island formation. Other applications of our method are also discussed. PMID- 24759122 TI - Atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in hypertensive diastolic heart failure model rats. AB - OBJECTIVE: Clinical studies have suggested the beneficial effects of statin therapy on diastolic heart failure. However, the mechanism of the beneficial effects of statin on diastolic heart failure remains unknown. We examined the effect of atorvastatin on the cardiac function of Dahl salt-sensitive rat, a model of hypertensive diastolic heart failure. METHODS: Dahl salt-sensitive rats were divided into three groups: the low-salt group (given standard diet), the high-salt group (given 8% NaCl diet from 7 weeks of age), and the high-salt + atorvastatin (HS + Ato) group (given 8% NaCl diet from 7 weeks of age and atorvastatin from 17 weeks of age). We evaluated left ventricular hypertrophy (LVH), fibrosis, and function by using echocardiography and histology. We also examined the expression of molecules related to fibrosis in the hearts of Dahl salt-sensitive rats and cultured rat cardiac fibroblasts. RESULTS: Left ventricular hypertrophy, diastolic dysfunction, and cardiac fibrosis were observed in the high-salt group. Atorvastatin ameliorated cardiac fibrosis and normalized left ventricular diastolic function without altering blood pressure. Atorvastatin also decreased the expression of heat shock protein 47 (HSP47), an essential chaperone for type 1 collagen processing, without changing in expression of transforming growth factor beta. In rat cardiac fibroblast cells, atorvastatin also reduced HSP47 level induced by transforming growth factor beta. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl pyrophosphate and mimicked by Rho kinase inhibitor. CONCLUSION: Atorvastatin administration ameliorates cardiac fibrosis and improves left ventricular diastolic function in Dahl salt-sensitive rats. Lowering HSP47 by atorvastatin via inhibition of Rho-Rho kinase pathway is suggested as a mechanism. PMID- 24759123 TI - Measurement of pulse wave velocity in children: comparison of volumetric and tonometric sensors, brachial-femoral and carotid-femoral pathways. AB - BACKGROUND: Pulse wave velocity (PWV), a measure of arterial stiffness strongly predictive of cardiovascular risk in adults, is usually measured by sequential ECG-referenced carotid and femoral tonometry. A simplified technique, more suitable for use in children, employs simultaneous volumetric recording from a sensor applied over the carotid artery and a cuff applied over the femoral artery or arm and thigh pressure cuffs applied over the brachial and femoral arteries. The purpose of this study was to compare PWV computed over the carotid-femoral path (PWVcf) with that over the brachial-femoral path (PWVbf) using a volumetric system (Vicorder) and to compare values of PWVcf obtained by the volumetric and a tonometric method (SphygmoCor) in children. METHOD: Vicorder PWVcf and PWVbf were compared in 156 children (3-18 years, 110 with chronic kidney disease), and PWVcf by Vicorder was compared to PWVcf by SphygmoCor in a subset of 122 patients. RESULTS: PWVcf by Vicorder was moderately correlated with PWVcf by SphygmoCor (R = 0.50, P < 0.000). PWVbf and PWVcf Vicorder were more closely correlated (R = 0.75, P < 0.0001), but with a significant systematic difference. Applying a correction factor to PWVbf measurements gave results similar to those obtained over the carotid-femoral path. Within-patient coefficients of variation for repeated measures were 5.9, 7.8, and 8.5% for PWVbf (Vicorder), PWVcf (Vicorder) and PWVcf (SphygmoCor), respectively. All PWV values showed a similar relation to age. CONCLUSION: Volumetric methods appear reproducible and are easy to use in children, but values obtained by Vicorder and SphygmoCor are not interchangeable even when measured over the same pathway. PMID- 24759124 TI - Impact of antihypertensive combination and monotreatments on blood pressure variability: assessment by old and new indices. Data from a large ambulatory blood pressure monitoring database. AB - OBJECTIVES: High 24-h ambulatory blood pressure (ABP) variability is associated with poor cardiovascular outcomes. We analysed a large ABP monitoring database containing data from hypertensive patients treated with telmisartan/amlodipine combination or various monotherapies with the aim of quantifying the 24-h distribution of blood pressure (BP) reduction by treatment through the smoothness index and of developing and testing a new treatment-on-variability index (TOVI) to quantify the effects of treatment on both mean BP and BP variability. METHODS: ABP data were pooled from 10 studies (N = 4294) with a median follow-up of 60 days. Smoothness index was calculated by dividing the mean of treatment-induced hourly BP reductions by its SD. TOVI was calculated as the ratio of the mean of hourly BP reductions to weighted 24-h BP SD (weighted mean of daytime and night time SDs) under treatment. RESULTS: The SBP/DBP smoothness index and TOVI values of telmisartan/amlodipine combination were significantly (P < 0.0001) higher (smoothness index: 1.81/1.51; TOVI: 2.71/2.13) compared with telmisartan 80 mg (smoothness index: 1.12/0.90; TOVI: 1.55/1.23), amlodipine 10 mg (smoothness index: 1.33/1.09; TOVI: 2.09/1.58), valsartan 160 mg (smoothness index: 1.01/0.81; TOVI: 1.35/1.07), ramipril 10 mg (smoothness index: 0.83/0.63; TOVI: 1.11/0.87) and placebo (smoothness index: 0.23/0.18; TOVI: 0.34/0.30), indicating a smoother 24-h BP reduction profile (higher smoothness index) as well as the achievement of significantly lower and smoother BP levels over 24 h (higher TOVI) with the combination. CONCLUSION: As compared with various monotherapies, the telmisartan/amlodipine combination was associated with a smoother BP reduction over 24 h and with a more favourable balance between mean 24-h BP reduction and the degree of BP variability on treatment, reflecting both its effectiveness in lowering BP levels and its longer duration of action. The agreement between smoothness index and TOVI demonstrates that they are similarly effective in the differentiation of antihypertensive treatments, although providing conceptually different information, the clinical relevance of which needs to be tested by ad-hoc outcome studies. PMID- 24759125 TI - More rigorous protocol adherence to intensive structured management improves blood pressure control in primary care: results from the Valsartan Intensified Primary carE Reduction of Blood Pressure study. AB - OBJECTIVE: To examine protocol adherence to structured intensive management in the Valsartan Intensified Primary carE Reduction of Blood Pressure (VIPER-BP) study involving 119 primary care clinics and 1562 randomized participants. METHODS: Prospective criteria for assessing adherence to treatment prescription, uptitration, and visit attendance at 6, 10, 14, and 18 weeks postrandomization were applied to 1038 intervention participants. Protocol adherence scores of 1-5 (least to most adherent) were compared to blood pressure (BP) control during 26 weeks of follow-up. RESULTS: Mean age was 59.3 +/- 12.0 years, 963 (62%) were men, and 1045 (67%) had longstanding hypertension. Clinic attendance dropped from 91 (week 6) to 83% (week 26) and pharmacological instructions were followed for 93% (baseline) to 61% at week 14 (uptitration failures commonly representing protocol deviations). Overall, 26-week BP levels and BP target attainment ranged from 132 +/- 14/79 +/- 9 and 51% to 141 +/- 15/83 +/- 11 mmHg and 19% in those participants subject to the highest (n = 270, 26%) versus least (n = 148, 14%) per protocol adherence, respectively; adjusted relative risk (RR) 1.22 per unit protocol adherence score, 95% confidence interval (CI) 1.15-1.31; for achieving BP target (P < 0.001). Participants with a per protocol score of 4 or 5 (512/1038, 49.3%) were 1.54-fold (95% CI 1.31-1.81; P < 0.001) more likely to achieve their individual BP target compared with usual care. Clinics equipped with a practice nurse significantly influenced protocol adherence (adjusted RR 1.20, 95% CI 1.06-1.37; P = 0.004) and individual BP control (RR 1.21, 95% CI 1.04-1.41; P = 0.015). CONCLUSION: There is considerable potential for structured care management to improve BP control in primary care, especially when optimally applied. PMID- 24759126 TI - KCNJ5 gene somatic mutations affect cardiac remodelling but do not preclude cure of high blood pressure and regression of left ventricular hypertrophy in primary aldosteronism. AB - OBJECTIVE: Aldosterone exerts detrimental cardiovascular effects, and patients with an aldosterone-producing adenoma (APA) carrying somatic mutations in the KCNJ5 K(+) channel (mutAPA) have higher plasma aldosterone concentration than wild-type APA (wtAPA) patients. We therefore investigated whether mutAPA patients develop a more prominent cardiovascular damage than wtAPA patients. METHODS AND FINDINGS: From 257 consecutive primary aldosteronism patients, we identified 176 who had both a diagnosis of APA by the 'four corners' criteria and high-quality echocardiographic data. Of them, 129 with KCNJ5 sequencing information and long term follow-up data were compared for echocardiographic changes according to presence (mutAPA, 26%) or absence (wtAPA, 74%) of the KCNJ5 mutations. At baseline, the mutAPA were similar to the wtAPA for blood pressure (BP) and need for antihypertensive medications. However, they had higher left ventricular mass index (59 +/- 19 vs. 51 +/- 13 g/h(2.7); P < 0.05) and plasma aldosterone concentration [49 (32-68) vs. 36 (25-52) ng/dl); P = 0.048] than the wtAPA patients. In spite of their more prominent cardiac involvement, the mutAPA patients exhibited a fall of BP and plasma aldosterone similar to wtAPA, and a regression of left ventricular mass index. CONCLUSIONS: Compared to the wild-type APA patients those with KCNJ5 mutations showed more prominent cardiovascular damage. Notwithstanding this, their chances of being cured from the hyperaldosteronism and the high BP, and of regression of left ventricular hypertrophy after adrenalectomy, were not compromised by the presence of these mutations. PMID- 24759127 TI - Investigating multiple aspects of blood pressure control. PMID- 24759128 TI - Comment on "a novel tumor: specimen index for assessing adequacy of resection in early stage oral tongue cancer" by Montero PH, Palmer FL, Shuman AG et al. [Oral Oncol 2014;50(3):213-20]. PMID- 24759130 TI - Hemostasis: old system, new players, new directions. AB - Initiation of clotting cascade by tissue factor (TF): Factor VII (FVII) complex is essential for hemostasis however pathologic expression of TF leads to thrombosis. In contrast, the contact pathway factor XII, and to the smaller extent FXI are dispensable for normal hemostasis but still contribute to pathologic thrombosis. New data suggest that not only platelets but also leukocytes and red blood cells can actively participate to thrombosis. Growing evidence demonstrates that coagulation proteases not only regulate hemostasis and thrombosis but also contribute to the many cellular responses via activation of protease activated receptors (PARs). The reviews in this supplement summarize the latest findings related to TF and coagulation proteases, including novel models of hemostasis and thrombosis, new insights into mechanism of thrombosis and trauma induced coagulopathy, interplay between coagulation and innate immune system and pathophysiology of contact activation pathway. PMID- 24759131 TI - An overview of mathematical modeling of thrombus formation under flow. AB - In the last decade numerous mathematical models have been formulated to investigate specific components of the clotting system such as the tissue factor pathway of coagulation. Sophisticated, multiscale models were developed to better understand the interplay of flow-mediated transport, platelet deposition, and coagulation kinetics, and their overall effect on thrombus formation. Promotion of thrombus growth is partially due to the well-known pro-coagulant roles of platelets like the surface-dependent coagulation reactions. Iterations of theoretical model predictions and experiment have helped to elucidate anticoagulant roles of platelets as well. These roles include paving over the subendothelium and hindering transport of substrates to and from enzyme complexes which can strongly affect thrombus formation. In this review, we give a brief overview of theoretical models of thrombus formation under flow and some of the experiments that motivated them and were motivated by them. PMID- 24759132 TI - The procoagulant envelope virus surface: contribution to enhanced infection. AB - Many virus types are covered by a lipid bilayer. This structure called an envelope, is derived from the host cell and includes host- and virus-encoded proteins. Because envelope components first interact with the host, it is the trigger for infection, immunity and pathology. The roles of especially host derived constituents are poorly understood. Focusing on herpes simplex type 1 (HSV1) as a model, we have shown that the envelope acquires the physiological initiators of coagulation from the host cell; tissue factor (TF) and procoagulant phospholipid (proPL). Unlike resting cells, where TF and proPL accessibility is carefully restricted, their expression is constitutive on the purified virus enabling factor VIIa (FVIIa)-dependant factor Xa (FXa) and thrombin generation. Interestingly, HSV1-encoded glycoprotein C (gC) on the virus enhances FXa production. In addition to coagulation proteases, HSV1 also facilitates fibrinolytic plasmin generation. HSV1 TF and gC combine to optimally enhance cultured cell infection when both FVIIa and FXa are available through protease activated receptor (PAR) 2. Plasmin also increases infection through PAR2, whereas thrombin provides an additive effect via PAR1. Thus, depending on the host cell, TF and proPL may be a general feature of enveloped viruses, enabling coagulation protease activation and PAR-mediated effects on infection. PMID- 24759133 TI - Roles of PAR1 and PAR2 in viral myocarditis. AB - Viral myocarditis is estimated to cause ~20% of sudden death in people under the age of 40. A variety of viruses have been found to cause myocarditis including coxsackievirus B3 (CVB3). Many studies have been performed with CVB3 because there is a mouse model of CVB3-induced myocarditis. Studies have shown that the TLR3-IFNbeta pathway plays a central role in the innate immune response to CVB3 infection. Our laboratory studies the role of protease activated receptors (PAR) in different biological responses including viral infection. We examined the effect of a deficiency in either PAR1 or PAR2 on CVB3-induced myocarditis. Interestingly, we found that PAR1 knockout mice had increased cardiac injury whereas PAR2 knockout mice had decreased cardiac injury. Our studies support the notion that PARs modulate the innate immune response and can have both positive and negative effects on TLR-dependent responses. PMID- 24759134 TI - Coagulation and morbidity in treated HIV infection. AB - HIV infected patients are at increased risk for venous and arterial thromboembolic events. Multiple markers related to inflammation (IL-6, TNFrI, C reative protein) and coagulation (tissue factor expression, FVIII, thrombin, fibrinogen and D-dimer levels) are increased in HIV infection, and several are predictive of thrombotic risk and mortality in HIV disease. The mechanisms behind the risk for abnormal coagulation in HIV infection have not been fully elucidated, but may be related to a chronic immune activation and inflammatory state in both untreated and treated HIV infection. The contribution of traditional risk factors, including smoking and dyslipidemia, overly represented in HIV infected patients, must also be considered when assessing thrombotic risk in this setting. Currently, several interventional studies are aimed at reducing inflammation and cardiovascular risk in HIV disease and may provide insights into the determinants of clotting events in HIV infected patients. PMID- 24759135 TI - Acute traumatic coagulopathy: clinical characterization and mechanistic investigation. AB - Trauma remains the leading cause of death and morbidity worldwide and bleeding is the primary reason for this mortality. Over the past 11 years there has been a paradigm shift in our understanding of coagulopathy after trauma. Specifically its incidence, biological drivers, clinical sequelae have been elucidated. From this understanding a concurrent change in resuscitation practices has occurred. This manuscript will review the history of resuscitation after injury, the discovery and clinical and biological characterization of acute traumatic coagulopathy and the changes in resuscitation practices aimed at combating coagulopathy and inflammatory perturbation after trauma. Finally it will discuss the ongoing state of the science and suggest topics for continued biological and clinical study. PMID- 24759129 TI - Neurodevelopment, GABA system dysfunction, and schizophrenia. AB - The origins of schizophrenia have eluded clinicians and researchers since Kraepelin and Bleuler began documenting their findings. However, large clinical research efforts in recent decades have identified numerous genetic and environmental risk factors for schizophrenia. The combined data strongly support the neurodevelopmental hypothesis of schizophrenia and underscore the importance of the common converging effects of diverse insults. In this review, we discuss the evidence that genetic and environmental risk factors that predispose to schizophrenia disrupt the development and normal functioning of the GABAergic system. PMID- 24759136 TI - Crosstalk between the coagulation and complement systems in sepsis. AB - Sepsis is a potent activator of the hemostatic and complement systems. While local activation of these proteolytic cascades contributes to the host defense, their uncontrolled systemic activation has major tissue damaging effects that lead to multiple organ failure and death. We have extensively studied the activation of complement and coagulation cascades in experimental sepsis using baboons challenged with live bacteria, such as Gram-negative Escherichia coli or Gram-positive Staphylococcus aureus and Bacillus anthracis, or with the bacterial product peptidoglycan. We observed that these challenges rapidly induce disseminated intravascular coagulation and robust complement activation. We applied a potent C3 convertase inhibitor, compstatin, which prevented sepsis induced complement activation, reduced thrombocytopenia, decreased the coagulopathic responses, and preserving the endothelial anticoagulant properties. Overall, our work demonstrates that live bacteria and bacterial products activate the complement and coagulation cascades, and that blocking formation of complement activation products, especially during the organ failure stage of severe sepsis could be a potentially important therapeutic strategy. PMID- 24759137 TI - Adoptive transfer method to study platelet function in mouse models of disease. AB - Platelets play an important role in many physiological and pathological situations. However, the molecular mechanisms by which platelets contribute to health and disease are often ill-defined. One of the limiting factors to these studies is a fast but reliable method to generate animals with platelet-specific signaling defects. We here review recent approaches to establish an adoptive platelet transfer model in mice. PMID- 24759138 TI - Inflammation-associated activation of coagulation and immune regulation by the protein C pathway. AB - The inflammation-induced activation of the protein C pathway provides negative feedback inhibition of coagulation and exerts coagulation-independent anti inflammatory and cytoprotective effects. The balance between these activities of aPC modulates the outcome of diverse inflammatory diseases such as encephalitis, diabetes, and sepsis; and is affected by naturally occurring aPC-resistance of coagulation factor V Leiden. PMID- 24759139 TI - Biological basis and pathological relevance of microvascular thrombosis. AB - Microvascular thrombosis indicates a pathological occlusion of microvessels by fibrin- and/or platelet-rich thrombi. It is observed during systemic infections, cancer, myocardial infarction, stroke, neurodegenerative diseases and in thrombotic microangiopathies. Microvessel thrombosis can cause greatly differing symptoms that range from limited changes in plasma coagulation markers to severe multi-organ failure. Because microvessel thrombi are difficult to detect and often occur only transiently, their importance for disease development and host biology is likely markedly under-appreciated. Recently, clear indications for a biological basis of microvascular thrombosis have been obtained. During systemic infections microvessel thrombosis can mediate an intravascular innate immune response (immunothrombosis). This biological form of thrombosis is based on the generation of fibrin inside blood vessels and is critically triggered by neutrophils and their interactions with platelets which result in the release of neutrophil extracellular traps (extracellular nucleosomes). Immunothrombosis is critically supported by neutrophil elastase and the activator molecules of blood coagulation tissue factor and factor XII. Identification of the biological driving forces of microvascular thrombosis should help to elucidate the mechanisms promoting pathological vessel occlusions in both microvessels and large vessels. PMID- 24759140 TI - Fibrinogen and red blood cells in venous thrombosis. AB - Deep vein thrombosis and pulmonary embolism, collectively termed venous thromboembolism (VTE), affect over 1 million Americans each year. VTE is triggered by inflammation and blood stasis leading to the formation of thrombi rich in fibrin and red blood cells (RBCs). However, little is known about mechanisms regulating fibrin and RBC incorporation into venous thrombi, or how these components mediate thrombus size or resolution. Both elevated circulating fibrinogen (hyperfibrinogenemia) and abnormal fibrin(ogen) structure and function, including increased fibrin network density and resistance to fibrinolysis, have been observed in plasmas from patients with VTE. Abnormalities in RBC number and/or function have also been associated with VTE risk. RBC contributions to VTE are thought to stem from their effects on blood viscosity and margination of platelets to the vessel wall. More recent studies suggest RBCs also express phosphatidylserine, support thrombin generation, and decrease fibrinolysis. RBC interactions with fibrin(ogen) and cells, including platelets and endothelial cells, may also promote thrombus formation. The contributions of fibrin(ogen) and RBCs to the pathophysiology of VTE warrants further investigation. PMID- 24759142 TI - The role of the contact pathway in thrombus propagation. AB - The continued search for the ideal antithrombotic agent that would prevent or reduce thrombus growth inside blood vessels without an effect on the essential hemostatic functions of blood, including extraluminal thrombin generation and platelet activation, has been going in new directions in the past decade. These directions include studies suggesting that activation of the intrinsic coagulation cascade through contact activation of factor XII, and the resultant thrombin generation is a pathologic event that leads to undesirable consequences. Recent animal studies of contact pathway inhibitors in experimental thrombogenesis suggest that the contact activation pathway of blood coagulation may play a pathogenic role in thrombosis, and pharmacologic inhibition of contact activation may have antithrombotic effects. Development of reasonably potent selective inhibitors of contact activation pathway components or activities now allow for the conduct of studies in various animal species, including primates. These studies have generated interesting data that now support the hypothesis that thrombogenesis in humans may also involve the pathological activation of the intrinsic coagulation cascade. Moreover, baboons, mice, and rabbits, pretreated with antibodies that selectively inhibit factor XII activation, procoagulant factor XIIa activity, or all enzymatic activities of factor XIIa show significantly reduced propensity for occlusive thrombus propagation in various models of acute thrombogenesis on vascular grafts, membrane oxygenators, and even on injured arteries. Since contact activation of blood does not play a demonstrable role in normal hemostasis, and there has been no evidence generated to date suggesting that activation of factor XII has a physiologic function, current research now supports the original concept, developed over 2 decades ago, that temporal pharmacologic inhibition of thrombin generation through the contact pathway may have therapeutic potential and could produce beneficial antithrombotic activities without hemostasis impairment. PMID- 24759141 TI - Physiologic activities of the contact activation system. AB - The plasma contact activation (CAS) and kallikrein/kinin (KKS) systems consist of 4 proteins: factor XII, prekallikrein, high molecular weight kininogen, and the bradykinin B2 receptor. Murine genetic deletion of factor XII (F12(-/-)), prekallikrein (Klkb1(-/-)), high molecular weight kininogen (Kgn1(-/-)) and the bradykinin B2 receptor (Bdkrb2(-/-)) yield animals protected from thrombosis. With possible exception of F12(-/-) and Kgn1(-/-) mice, the mechanism(s) for thrombosis protection is not reduced contact activation. Bdkrb2(-/-) mice are best characterized and they are protected from thrombosis through over expression of components of the renin angiotensin system (RAS) leading to elevated prostacyclin with vascular and platelet inhibition. Alternatively, prolylcarboxypeptidase, a PK activator and degrader of angiotensin II, when deficient in the mouse leads to a prothrombotic state. Its mechanism for increased thrombosis also is mediated in part by components of the RAS. These observations suggest that thrombosis in mice of the CAS and KKS are mediated in part through the RAS and independent of reduced contact activation. PMID- 24759143 TI - The mechanism underlying activation of factor IX by factor XIa. AB - Factor XI (fXI) is the zymogen of a plasma protease, factor XIa (fXIa), that contributes to thrombin generation during blood coagulation by proteolytic conversion of factor IX (fIX) to factor IXabeta (fIXabeta). There is considerable interest in fXIa as a therapeutic target because it contributes to thrombosis, while serving a relatively minor role in hemostasis. FXI/XIa has a distinctly different structure than other plasma coagulation proteases. Specifically, the protein lacks a phospholipid-binding Gla-domain, and is a homodimer. Each subunit of a fXIa dimer contains four apple domains (A1 to A4) and one trypsin-like catalytic domain. The A3 domain contains a binding site (exosite) that largely determines affinity and specificity for the substrate fIX. After binding to fXIa, fIX undergoes a single cleavage to form the intermediate fIXalpha. FIXalpha then rebinds to the A3 domain to undergo a second cleavage, generating fIXabeta. The catalytic efficiency for the second cleavage is ~7-fold greater than that of the first cleavage, limiting fIXalpha accumulation. Residues at the N-terminus and C terminus of the fXIa A3 domain likely form the fIX binding site. The dimeric conformation of fXIa is not required for normal fIX activation in solution. However, monomeric forms of fXI do not reconstitute fXI-deficient mice in arterial thrombosis models, indicating the dimer is required for normal function in vivo. FXI must be a dimer to be activated normal by the protease fXIIa. It is also possible that the dimeric structure is an adaptation that allows fXI/XIa to bind to a surface through one subunit, while binding to its substrate fIX through the other. PMID- 24759144 TI - Red blood cells and thrombin generation in sickle cell disease. AB - The prothrombotic nature of sickle cell disease (SCD) is evidenced by the chronically elevated levels of almost all coagulation activation biomarkers, and an increased incidence of certain thrombotic events, including venous thromboembolism. Numerous studies have attempted to define the extent and elucidate the mechanism of the observed increase in thrombin generation in SCD patients in vivo. In general, these studies were performed using thrombin generation assays in platelet poor or platelet rich plasma and showed little difference in endogenous thrombin potential between the SCD cohort and healthy matched controls. In SCD, erythrocytes and monocytes have been demonstrated to exhibit procoagulant characteristics. Thus, the absence of these cellular components in standard thrombin generation assays may fail to reflect global hypercoagulability in the whole blood of patients with SCD. We were therefore surprised to see no difference in net thrombin generation in tissue factor initiated initiated clotting of whole blood from patients with SCD. However, we are continuing to reconcile these seemingly disparate observations by slight modifications of the whole blood model that include alternative coagulation triggers and a re-examination of the net thrombin generation when the protein/protein S system is simultaneously interrogated. PMID- 24759145 TI - Differential roles of tissue factor and phosphatidylserine in activation of coagulation. AB - It has been suggested that the main physiological trigger of coagulation, tissue factor, possesses limited procoagulant activity and occurs in an inactive or so called encrypted state. For the conversion of encrypted into decrypted tissue factor with sufficient procoagulant activity, four distinct models have been proposed: 1; dimer formation, 2; lipid rafts, 3; disulfide bonds, and 4; phosphatidylserine exposure. Pro and cons can be given for each of these mechanisms of tissue factor encryption/decryption, however, it seems most likely that two or more mechanisms act together in activating the procoagulant activity. The exposure of phosphatidylserine in the outer layer of cell membranes supports coagulation through enhanced formation of the tenase (factors IXa, VIIIa and X) and prothrombinase (factors Xa, Va and prothrombin) complexes. The proposed role for phosphatidylserine in decryption of tissue factor could contribute to the correct orientation of the tissue factor - factor VII complex. Overall, the contribution of both tissue factor and phosphatidylserine to coagulation seems distinct with tissue factor being the physiological activator and phosphatidylserine the driving force of propagation of coagulation. PMID- 24759146 TI - Coagulation in liver toxicity and disease: role of hepatocyte tissue factor. AB - The liver is the primary source of a number of circulating coagulation factors, and acute liver injury and chronic liver disease are each associated with alterations in blood coagulation. Current views of the connection between liver injury and coagulation extend beyond the impact of liver disease on synthesis of coagulation factors to include a role for coagulation factor activity in the initiation and progression of liver disease. Mechanisms of coagulation initiation in liver disease are not completely understood. Compared to other tissues, liver expresses very low levels of tissue factor (TF). Recent studies indicate that expression of TF by hepatocytes comprises the majority of liver procoagulant activity, and that hepatocyte TF activates coagulation induced by liver injury. This review will briefly cover the expression and regulation of TF by hepatocytes, the role of TF in coagulation triggered by liver toxicity, and the contribution of coagulation activity to the progression of liver disease. PMID- 24759147 TI - A mouse bleeding model to study oral anticoagulants. AB - New oral anticoagulants to reduce the incidence of thrombosis have recently become available. When compared to the existing therapy, warfarin, these novel agents have similar efficacy with a reduced risk of spontaneous bleeding. However, these novel agents have been associated with significant, even fatal, bleeding following trauma. Reversal agents are being developed that bind and neutralize these oral anticoagulants. However, these are not yet available. Another strategy is to increase thrombin generation by administration of "bypassing" agents such as prothrombin complex concentrates or factor VIIa. Several animal models have been used to model the hemostatic defect induced by the thrombin inhibitor dabigatran. A rat tail injury model, a rabbit cuticle bleeding model, and a rabbit kidney laceration model have all been reported to show increased bleeding, but with supratherapeutic doses of dabigatran. A mouse tail transection model has been reported to reflect increased bleeding at peak therapeutic dabigatran levels. We found that the Whinna saphenous vein hemostasis model reliably reflects a hemostatic defect at therapeutic levels of dabigatran. This model can potentially reflect the effects of reversal or bypassing agents. PMID- 24759148 TI - Developing individualized coagulation profiling of disease risk: thrombin generation dynamic models of the pro and anticoagulant balance. AB - Global assays and computational models have advanced research into the realm of individualized profiling of hemostatic states. This brief review will describe one computational approach which utilizes an integrated method that evaluates the dynamics of thrombin generation by defining interactions of the pro and anticoagulant proteins, enzymes and cofactors based upon individualized concentrations of select factors. This plasma composition based computational modeling can provide a mechanism based bridge between empirical global assays of coagulation and individualized risk prediction. PMID- 24759149 TI - Validating single-cell genomics for the study of renal development. AB - Single-cell genomics will enable studies of the earliest events in kidney development, although it is unclear if existing technologies are mature enough to generate accurate and reproducible data on kidney progenitors. Here we designed a pilot study to validate a high-throughput assay to measure the expression levels of key regulators of kidney development in single cells isolated from embryonic mice. Our experiment produced 4608 expression measurements of 22 genes, made in small cell pools, and 28 single cells purified from the RET-positive ureteric bud. There were remarkable levels of concordance with expression data generated by traditional microarray analysis on bulk ureteric bud tissue with the correlation between our average single-cell measurements and GUDMAP measurements for each gene of 0.82-0.85. Nonetheless, a major motivation for single-cell technology is to uncover dynamic biology hidden in population means. There was evidence for extensive and surprising variation in expression of Wnt11 and Etv5, both downstream targets of activated RET. The variation for all genes in the study was strongly consistent with burst-like promoter kinetics. Thus, our results can inform the design of future single-cell experiments, which are poised to provide important insights into kidney development and disease. PMID- 24759150 TI - Association between hemoglobin variability, serum ferritin levels, and adverse events/mortality in maintenance hemodialysis patients. AB - In recent times, therapy for renal anemia has changed dramatically in that iron administration has increased and doses of erythropoiesis-stimulating agents (ESAs) have decreased. Here we used a prospective, observational, multicenter design and measured the serum ferritin and hemoglobin levels every 3 months for 2 years in 1086 patients on maintenance hemodialysis therapy. The associations of adverse events with fluctuations in ferritin and hemoglobin levels and ESA and iron doses were measured using a Cox proportional hazards model for time dependent variables. The risks of cerebrovascular and cardiovascular disease (CCVD), infection, and hospitalization were higher among patients who failed to maintain a target-range hemoglobin level and who exhibited high-amplitude fluctuations in hemoglobin compared with patients who maintained a target-range hemoglobin level. Patients with a higher compared with a lower ferritin level had an elevated risk of CCVD and infectious disease. Moreover, the risk of death was significantly higher among patients with high-amplitude ferritin fluctuations compared with those with a low ferritin level. The risks of CCVD, infection, and hospitalization were significantly higher among patients who were treated with high weekly doses of intravenous iron compared with no intravenous iron. Thus, there is a high risk of death and/or adverse events in patients with hemoglobin levels outside the target range, in those with high-amplitude hemoglobin fluctuations, in those with consistently high serum ferritin levels, and in those with high-amplitude ferritin fluctuations. PMID- 24759151 TI - Modulation of heparan sulfate in the glomerular endothelial glycocalyx decreases leukocyte influx during experimental glomerulonephritis. AB - The glomerular endothelial glycocalyx is postulated to be an important modulator of permeability and inflammation. The glycocalyx consists of complex polysaccharides, the main functional constituent of which, heparan sulfate (HS), is synthesized and modified by multiple enzymes. The N-deacetylase-N sulfotransferase (Ndst) enzymes initiate and dictate the modification process. Here we evaluated the effects of modulation of HS in the endothelial glycocalyx on albuminuria and glomerular leukocyte influx using mice deficient in endothelial and leukocyte Ndst1 (TEKCre+/Ndst1flox/flox). In these mice, glomerular expression of a specific HS domain was significantly decreased, whereas the expression of other HS domains was normal. In the endothelial glycocalyx, this specific HS structure was not associated with albuminuria or with changes in renal function. However, glomerular leukocyte influx was significantly reduced during antiglomerular basement membrane nephritis, which was associated with less glomerular injury and better renal function. In vitro decreased adhesion of wild-type and Ndst1-deficient granulocytes to Ndst1 silenced glomerular endothelial cells was found, accompanied by a decreased binding of chemokines and L-selectin. Thus, modulation of HS in the glomerular endothelial glycocalyx significantly reduced the inflammatory response in antiglomerular basement membrane nephritis. PMID- 24759152 TI - Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury. AB - The contribution of miRNA to the pathogenesis of acute kidney injury (AKI) is not well understood. Here we evaluated an integrative network of miRNAs and mRNA data to discover a possible master regulator of AKI. Microarray analyses of the kidneys of mice treated with cisplatin were used to extract putative miRNAs that cause renal injury. Of them, miR-122 was mostly downregulated by cisplatin, whereas miR-34a was upregulated. A network integrating dysregulated miRNAs and altered mRNA expression along with target prediction enabled us to identify Foxo3 as a core protein to activate p53. The miR-122 inhibited Foxo3 translation as assessed using an miR mimic, an inhibitor, and a Foxo3 3'-UTR reporter. In a mouse model, Foxo3 levels paralleled the degree of tubular injury. The role of decreased miR-122 in inducing Foxo3 during AKI was strengthened by the ability of the miR-122 mimic or inhibitor to replicate results. Increase in miR-34a also promoted the acetylation of Foxo3 by repressing Sirt1. Consistently, cisplatin facilitated the binding of Foxo3 and p53 for activation, which depended not only on decreased miR-122 but also on increased miR-34a. Other nephrotoxicants had similar effects. Among targets of p53, Phlda3 was robustly induced by cisplatin, causing tubular injury. Consistently, treatment with miR mimics and/or inhibitors, or with Foxo3 and Phlda3 siRNAs, modulated apoptosis. Thus, our results uncovered an miR integrative network regulating toxicant-induced AKI and identified Foxo3 as a bridge molecule to the p53 pathway. PMID- 24759154 TI - Microalbuminuria: target for renoprotective therapy PRO. AB - Drug efficacy is ascertained using clinically meaningful outcomes that directly affect the well-being of patients. However, in studies of chronic kidney disease progression, clinically meaningful outcomes like end-stage renal disease take a long time to occur. The use of surrogate end points/markers as replacement for clinical outcomes is tempting as it may reduce sample size requirements, shorten follow-up time, facilitate trial conduct, and allow the performance of intervention trials in earlier stages of kidney disease to be carried out. We here reviewed recent data supporting the use of microalbuminuria as a valid surrogate end point in clinical trials of chronic kidney disease. We provide data that albuminuria is associated with worse renal prognosis and that pharmacological treatment aimed to reduce albuminuria levels delays the progression of renal disease and the occurrence of clinical outcomes. Furthermore, we review new studies showing that albumin is not only an inert molecule but also directly affects the function of several cell types in the kidney and may have a pathogenic role in renal disease. Accepting microalbuminuria as a surrogate marker for renal outcomes will lead to less resource-consuming hard outcome trials, will accelerate the development of drugs for chronic kidney disease, and enable earlier access of these drugs to individual patients. PMID- 24759153 TI - Minocycline prevents osmotic demyelination associated with aquaresis. AB - Overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome (ODS). Minocycline protects ODS associated with overly rapid correction of chronic hyponatremia with hypertonic saline infusion in rats. In clinical practice, inadvertent rapid correction frequently occurs due to water diuresis, when vasopressin action suddenly ceases. In addition, vasopressin receptor antagonists have been applied to treat hyponatremia. Here the susceptibility to and pathology of ODS were evaluated using rat models developed to represent rapid correction of chronic hyponatremia in the clinical setting. The protective effect of minocycline against ODS was assessed. Chronic hyponatremia was rapidly corrected by 1 (T1) or 10 mg/kg (T10) of tolvaptan, removal of desmopressin infusion pumps (RP), or administration of hypertonic saline. The severity of neurological impairment in the T1 group was significantly milder than in other groups and brain hemorrhage was found only in the T10 and desmopressin infusion removal groups. Minocycline inhibited demyelination in the T1 group. Further, immunohistochemistry showed loss of aquaporin-4 (AQP4) in astrocytes before demyelination developed. Interestingly, serum AQP4 levels were associated with neurological impairments. Thus, minocycline can prevent ODS caused by overly rapid correction of hyponatremia due to water diuresis associated with vasopressin action suppression. Increased serum AQP4 levels may be a predictive marker for ODS. PMID- 24759155 TI - Framing the issue of ageing and health care spending in Canada, the United Kingdom and the United States. AB - Political debates about the affordability of health care programmes in high income countries often point to population ageing as a threat to sustainability. Debates in the United States, in particular, highlight concerns about intergenerational equity, whereby spending on older people is perceived as a threat to spending on the young. This paper compares how the problem of health spending is defined in Canada, the United Kingdom and the United States by presenting the results of a content analysis of print media during the period 2005-2010. We found that population ageing was cited as an important source of health care cost increases in all three countries but was cited less frequently in Canadian newspapers than in the UK or US papers. Direct claims about intergenerational equity are infrequent among the articles we coded, but newspaper articles in the United States were more likely than those in Canada and the United Kingdom to claim that of high health care spending on older people takes resources away from younger people. In Canada a much larger percentage of articles in our sample either claimed that high health care spending is crowding out other types of government expenditure. Finally, we found that almost no articles in the United States challenged the view that population ageing causes health care spending, whereas in both Canada and the United Kingdom a small, but steady stream of articles challenged the idea that population ageing is to blame for health care spending increases. PMID- 24759156 TI - Onyx embolization of dural arteriovenous fistulas of the cavernous sinus through the superior pharyngeal branch of the ascending pharyngeal artery. AB - We report three cases of dural arteriovenous fistula (DAVF) of the cavernous sinus treated by Onyx injection through the superior pharyngeal branch of the ascending pharyngeal artery. The treatment of choice of DAVFs of the cavernous sinus is endovascular, and it is preferentially done via transvenous occlusion of the cavernous sinus. The cavernous sinus can be reached through either the inferior petrosal sinus or the superior ophthalmic vein. When these venous routes are occluded, the first attempt is to pass through the occluded inferior petrosal sinus, but sometimes this attempt can fail. In some cases there are small transosseous feeders to the fistula arising from the superior pharyngeal branch of the ascending pharyngeal artery. When all of the more conventional approaches are unattainable, this route can be attempted. In our experience, it allowed safe and rapid occlusion of the fistula. PMID- 24759157 TI - Considering iatrogenic psychosis after malignant glioma resection. AB - It is generally well known that medial temporal lobe resections have been associated with a variety of postoperative neuropsychiatric disturbances. Most of the neurosurgical literature on psychiatric disturbances after a temporal lobectomy concern patients with a strong history of epilepsy; however, relatively few articles have been reported due to a mesial temporal lobectomy following tumour removal. We report the case of a patient who underwent a gross total resection of a malignant astrocytoma in the temporal lobe who developed transient psychosis. Difficulties in diagnosing and predicting this condition are discussed as along with management considerations. PMID- 24759158 TI - Traumatic appendicitis misdiagnosed as a case of haemoperitoneum. AB - Acute appendicitis is one of the most common emergencies handled by a surgeon. Various aetiologies of acute appendicitis have been proposed but none have been proved. Trauma too has been proposed as a cause of acute appendicitis. Here we present a case of blunt trauma abdomen which was explored to rule out a perforation of hollow viscous organ and haemoperitoneum, but at the time of exploration a perforated appendicitis was found. The chronological order of events points towards blunt trauma as the probable cause of this appendicitis. This case also highlights the fact that even if trauma was not the cause of acute appendicitis, acute appendicitis should still be kept in the differential diagnosis of a patient presenting with pain in the right lower abdomen and a history of trauma. PMID- 24759159 TI - Overwhelming Capnocytophaga canimorsus infection in a patient with asplenia. AB - Patients with asplenia are prone to overwhelming infections due to encapsulated organisms. We report a 62-year-old man presenting with fever and weakness. His medical history was significant for splenectomy and owning a dog as pet. The patient on examination had evidence of animal bite and scratch marks on his lower extremity and developed dry gangrene of multiple digits of his upper extremity soon after admission. The patient's initial blood cultures were positive for Gram negative rods, but no organism was identified. Capnocytophaga canimorsus was the suspected organism and the patient's antibiotics were tailored accordingly, with good clinical recovery. The patient' blood cultures finally grew C canimorsus on day 20 for which the patient had already been treated with prior clinical judgement. Physicians should be aware of this organism in the setting of sepsis in patients with asplenia and use appropriate antibiotics until further results are obtained. PMID- 24759160 TI - Twelve-year-old boy with recurrent presentations of shortness of breath: an intraluminal tracheal tumour. AB - A 12-year-old boy was admitted with symptoms of recurrent shortness of breath since 12 months along with mild intermittent retrosternal chest pain that had developed 3 weeks ago prior to admission. He was previously treated for asthma with no improvement. Initial posteroanterior chest X-ray (CXR) revealed no abnormality on two occasions. Lateral CXR showed a mass lesion in the distal trachea which was subsequently confirmed by a CT scan of the chest. PMID- 24759161 TI - Delayed stenosis following stentriever use in acute stroke intervention. AB - We report two cases of delayed post-embolectomy stenosis-that is, a new stenosis in the vascular bed of a previous endovascular embolectomy. The first case was discovered incidentally in a patient returning after embolectomy for evaluation of cerebral aneurysms. The second case was discovered on an MR angiogram obtained to screen for stenosis. This was prompted by our experience with the first case. To our knowledge, this phenomenon has not been reported previously. PMID- 24759162 TI - Endovascular coil retrieval using a TrevoProVue stentriever. AB - A 65-year-old man with a left cavernous internal carotid artery cerebral aneurysm experienced a premature detachment of the first framing coil (10 mm * 40 cm Penumbra Complex Standard) during a coil embolization procedure. The coil herniated into the anterior cerebral artery and pericallosal artery. Multiple attempts to retrieve the coil using both a 2 and 4 mm Microsnare (Amplatz GooseNeck) failed. A Trevo ProVue retrievable stent was then used to retrieve the coil without any adverse events. This case report highlights a novel use of a stent for the removal of a foreign body from the cerebrovascular system. PMID- 24759163 TI - Littre's hernia with an impalpable testis in a boy: a diagnostic dilemma. AB - Littre's hernia is a rare clinical entity. The presence of a Littre's hernia in a 2-year-old boy with an impalpable testis is even rarer. We describe this interesting case with a review of the literature. PMID- 24759164 TI - Successful multidisciplinary treatment of hilar cholangiocarcinoma in a patient with complicated new-onset coronary artery disease. AB - We report a 69-year-old man suffering from hilar cholangiocarcinoma and concurrent new-onset complicated coronary artery disease. After implanting non drug-eluting coronary stents, combination chemotherapy with gemcitabine and S-1 under continuation of dual antiplatelet therapy was carried out and partial tumour response was achieved. Subsequently, extended right hepatectomy with partial resection of the Spiegel lobe and left hepaticojejunostomy was performed while continuing preoperative single antiplatelet therapy with aspirin. The patient recovered well without any thromboembolic or bleeding complications. Like the current case, neoadjuvant chemotherapy and subsequent curative resection under continuation of antiplatelet therapy, followed by preceding coronary intervention, is one of the preferred options for the treatment of hepatobiliary malignancy in patients with concurrent new-onset coronary artery disease. PMID- 24759165 TI - Retropharyngeal abscess complicating 'innocent' foreign body ingestion. AB - An adult patient presented to the emergency department with pharyngeal discomfort on swallowing, persisting several hours after lunch. Transnasal fibre-optic endoscopy performed by an otolaryngologist identified a hypopharyngeal foreign body, and the stalk of a dry leaf partially penetrating the mucosa was easily removed under general anaesthesia. Symptoms regressed completely and the patient was discharged. Two days later he presented again, reporting slight dysphagia without odynophagia or other associated symptoms. Meticulous physical examination by the same otolaryngologist revealed this time a slight asymmetry of the posterior pharyngeal wall. A history of recent pharyngeal trauma and findings on clinical examination raised clinical suspicion of retropharyngeal abscess which was supported by CT scan findings. The diagnosis was confirmed in the operating theatre where a purulent collection was drained under new general anaesthesia. PMID- 24759166 TI - Rare presentation of sebaceous hyperplasia. AB - A 23-year-old woman presented with an 8-month history of asymptomatic thickening of the central areola bilaterally and oily nipple discharge. On examination, there were yellowish-pink papules coalescing into plaques bilaterally. Biopsy showed ectopic sebaceous glands (Montgomery tubercles), known as bilateral areolar sebaceous hyperplasia. PMID- 24759167 TI - Acute appendicitis: a potential complication of video capsule endoscopy. AB - A 69-year-old man presented to our emergency room with malena and symptoms suggestive of anaemia. He was on chronic anticoagulation with warfarin for a mechanical aortic valve. He was haemodynamically stable. Laboratory investigations revealed a low haemoglobin level of 7.1 g/dL and a low-ferritin level of 6 ng/dL suggesting chronic gastrointestinal bleeding. Oesophagogastroduodenoscopy and colonoscopy were performed to identify the source of bleeding but were unfruitful. Video capsule endoscopy was performed. Fifteen hours after ingesting the capsule endoscope, the patient started having severe abdominal pain, nausea and vomiting. Abdominal X-ray did not show any bowel perforation. CT of the abdomen revealed impaction of the capsule endoscope at the appendiceal orifice and an inflamed appendix. The patient underwent laparoscopic appendectomy and made a good recovery. PMID- 24759168 TI - Fibroepithelial ureteral polyps presenting as ureteropelvic obstruction. AB - A 57-year-old woman presented with bilateral abdominal pain and flank discomfort. Imaging studies, consisting of CT scan, diethylene triamine pentaacetic acid renal scan with Lasix and a retrograde pyelogram, indicated an obstruction at the uteropelvic junction (UPJ), possibly due to fibroepithelial polyps within the ureter. A robotic pyeloplasty revealed a ureteral diverticulum and a thin, still attached fibroepithelial polyp of approximately 2 cm in length. The patient tolerated the procedure well and was discharged one day postpyeloplasty with no reported complications. This rare clinical scenario should be considered when formulating a diagnosis for a UPJ obstruction. PMID- 24759169 TI - 'Blaschkoid' giant wart in immunocompetent patient. PMID- 24759170 TI - Looking into the virulence of Candida parapsilosis: a diagnostic perspective. PMID- 24759171 TI - Induction of functional tissue-engineered skeletal muscle constructs by defined electrical stimulation. AB - Electrical impulses are necessary for proper in vivo skeletal muscle development. To fabricate functional skeletal muscle tissues in vitro, recapitulation of the in vivo niche, including physical stimuli, is crucial. Here, we report a technique to engineer skeletal muscle tissues in vitro by electrical pulse stimulation (EPS). Electrically excitable tissue-engineered skeletal muscle constructs were stimulated with continuous electrical pulses of 0.3 V/mm amplitude, 4 ms width, and 1 Hz frequency, resulting in a 4.5-fold increase in force at day 14. In myogenic differentiation culture, the percentage of peak twitch force (%Pt) was determined as the load on the tissue constructs during the artificial exercise induced by continuous EPS. We optimized the stimulation protocol, wherein the tissues were first subjected to 24.5%Pt, which was increased to 50-60%Pt as the tissues developed. This technique may be a useful approach to fabricate tissue-engineered functional skeletal muscle constructs. PMID- 24759172 TI - Trophic state and toxic cyanobacteria density in optimization modeling of multi reservoir water resource systems. AB - The definition of a synthetic index for classifying the quality of water bodies is a key aspect in integrated planning and management of water resource systems. In previous works [1,2], a water system optimization modeling approach that requires a single quality index for stored water in reservoirs has been applied to a complex multi-reservoir system. Considering the same modeling field, this paper presents an improved quality index estimated both on the basis of the overall trophic state of the water body and on the basis of the density values of the most potentially toxic Cyanobacteria. The implementation of the index into the optimization model makes it possible to reproduce the conditions limiting water use due to excessive nutrient enrichment in the water body and to the health hazard linked to toxic blooms. The analysis of an extended limnological database (1996-2012) in four reservoirs of the Flumendosa-Campidano system (Sardinia, Italy) provides useful insights into the strengths and limitations of the proposed synthetic index. PMID- 24759173 TI - Recombinant Clostridium difficile toxin fragments as carrier protein for PSII surface polysaccharide preserve their neutralizing activity. AB - Clostridium difficile is a Gram-positive bacterium and is the most commonly diagnosed cause of hospital-associated and antimicrobial-associated diarrhea. Despite the emergence of epidemic C. difficile strains having led to an increase in the incidence of the disease, a vaccine against this pathogen is not currently available. C. difficile strains produce two main toxins (TcdA and TcdB) and express three highly complex cell-surface polysaccharides (PSI, PSII and PSIII). PSII is the more abundantly expressed by most C. difficile ribotypes offering the opportunity of the development of a carbohydrate-based vaccine. In this paper, we evaluate the efficacy, in naive mice model, of PSII glycoconjugates where recombinant toxins A and B fragments (TcdA_B2 and TcdB_GT respectively) have been used as carriers. Both glycoconjugates elicited IgG titers anti-PSII although only the TcdB_GT conjugate induced a response comparable to that obtained with CRM197. Moreover, TcdA_B2 and TcdB_GT conjugated to PSII retained the ability to elicit IgG with neutralizing activity against the respective toxins. These results are a crucial proof of concept for the development of glycoconjugate vaccines against C. difficile infection (CDI) that combine different C. difficile antigens to potentially prevent bacterial colonization of the gut and neutralize toxin activity. PMID- 24759175 TI - Recombinant expression and functional characterization of martentoxin: a selective inhibitor for BK channel (alpha + beta4). AB - Martentoxin (MarTX), a 37-residue peptide purified from the venom of East-Asian scorpion (Buthus martensi Karsch), was capable of blocking large-conductance Ca2+ activated K+ (BK) channels. Here, we report an effective expression and purification approach for this toxin. The cDNA encoding martentoxin was expressed by the prokaryotic expression system pGEX-4T-3 which was added an enterokinase cleavage site by PCR. The fusion protein (GST-rMarTX) was digested by enterokinase to release hetero-expressed toxin and further purified via reverse phase HPLC. The molecular weight of the hetero-expressed rMarTX was 4059.06 Da, which is identical to that of the natural peptide isolated from scorpion venom. Functional characterization through whole-cell patch clamp showed that rMarTX selectively and potently inhibited the currents of neuronal BK channels (alpha + beta4) (IC50 = 186 nM), partly inhibited mKv1.3, but hardly having any significant effect on hKv4.2 and hKv3.1a even at 10 MUM. Successful expression of martentoxin lays basis for further studies of structure-function relationship underlying martentoxin or other potassium-channel specific blockers. PMID- 24759176 TI - Comments on Environmental and Sanitary Aspects of the Scorpionism by Tityus trivittatus in Buenos Aires City, Argentina. AB - Deaths by venomous animals are medical emergencies that can lead to death and thus constitute sanitary problems in some regions of the world. In the South of America, the accidents by these animals are a common sanitary problem especially in warm, tropical or subtropical regions, related with rural work in several countries. Argentina is located in the extreme South of South America and a minor part of the continental surface is in tropical or subtropical regions, where most of the accidents by venomous animals happen. However, in the big cities in the center and South of the country, with no relation to rural work, scorpionism, mostly due to the synanthropic and facultative parthenogenetic scorpion Tityus trivittatus, has become a sanitary problem in the last few decades. This scorpion is present in the biggest cities of Argentina and in the last decades has killed over 20 children in provinces of the center and north of the country, mostly in big cities. In addition, it seems that this species is growing and spreading in new regions of the cities. In this revision, some characteristics of this scorpion regarding its habitat, spreading in Buenos Aires city, combat measures and available treatments are discussed. PMID- 24759177 TI - Periodontal tissue regeneration by transplantation of rat adipose-derived stromal cells in combination with PLGA-based solid scaffolds. AB - Regeneration of damaged periodontium is challenging due to its multi-tissue composition. Mesenchymalstem cell-based approaches using adipose-derived stromal cells (ASCs) may contribute to periodontal reconstruction, particularly when combined with the use of scaffolds to maintain a space for new tissue growth. The aim of this study was to assess the regenerative potential of ASCs derived from inbred or outbred rats in combination with novel solid scaffolds composed of PLGA (Poly D,L-lactic-co-glycolic acid) (PLGA-scaffolds). Cultured ASCs seeded onto PLGA scaffolds (ASCs/PLGA) or PLGA-scaffolds (PLGA) alone were transplanted into periodontal fenestration defects created in F344 or Sprague Dawley (SD) rats. Micro-CT analysis showed a significantly higher percentage of bone growth in the ASCs/PLGA groups compared with the PLGA-alone groups at five weeks after surgery. Similarly, histomorphometric analysis demonstrated thicker growth of periodontal ligament and cementum layers in the ASCs/PLGA-groups compared with the PLGA-alone groups. In addition, transplanted DiI-labeled ASCs were observed in the periodontal regenerative sites. The present investigation demonstrated the marked ability of ASCs in combination with PLGA scaffolds to repair periodontal defects. PMID- 24759178 TI - The identification of affinity peptide ligands specific to the variable region of human antibodies. AB - Of all potential biological therapeutics, monoclonal antibody (mAb)-based therapies are becoming the dominant focus of clinical research. In particular, smaller recombinant antibody fragments such as single-chain variable fragments (scFv) have become the subject of intense focus. However, an efficient affinity ligand for antibody fragment purification has not been developed. In the present study, we designed a consensus sequence for the human antibody heavy or light chain-variable regions (Fv) based on the antibody sequences available in the ImMunoGeneTics information system (IMGT), and synthesized these consensus sequences as template Fv antibodies. We then screened peptide ligands that specifically bind to the repertoire-derived human Fv consensus antibody using a 12-mer-peptide library expressed-phage display method. Subsequently, 1 peptide for the VH template and 8 peptides for the VK template were selected as the candidate ligands after 4 rounds of panning the phage display. Using peptide-bead based immunoprecipitation, the code-4 and code-13 peptides showed recovery rates of the VH and VK templates that were 20-30% and 40-50%, respectively. Both peptides exhibited better recovery rates for trastuzumab scFv (approximately 40%). If it were possible to identify the best combination of VH and VK-binding peptides among the ligand peptides suitable for the human mAb Fv sequence, the result could be a promising purification tool that might greatly improve the cost efficiencies of the purification process. PMID- 24759180 TI - Evaluation of trunk stability in the sitting position using a new device. AB - The purpose of this study was to evaluate trunk stability in seated elderly and young individuals using a new device that inclines a seat while tracking the center of pressure (CoP). We evaluated the locus of CoP, locus length, locus length per second, enveloped area, root mean square area, and locus length per unit area (LNG/AREA). LNG/AREA, which reflects postural adjustments controlled by the spinal proprioceptive reflexes of the lower limbs, was not significantly different between young and elderly individuals. Our device measured trunk stability without influence from the lower extremities, which explains why LNG/AREA did not significantly differ between young and elderly individuals. These findings indicate that the new device can be used to quantify dynamic trunk stability. PMID- 24759179 TI - Expression of (pro)renin receptor in breast cancers and its effect on cancercell proliferation. AB - (Pro)renin receptor ((P)RR) is a specific receptor for renin and prorenin. The aim of the present study is to clarify expression of (P)RR and pathophysiological roles of (P)RR in human breast carcinomas. (P)RR expression was studied in 69 clinical cases of breast carcinoma by immunohistochemistry.Effects of (P)RR on cell proliferation were examined in cultured human breast carcinoma cells using (P)RR specific small interference RNA. Immunohistochemistry showed that(P)RR immunoreactivity was detected in the breast carcinoma cells in 50 of 69 cases of breast carcinoma (72%). The analysis on association between (P)RR immunoreactivity and clinicopathological parameters showed that the number of (P)RR positive cases was significantly greater in Ki-67 (a cell proliferation marker)>=10% group than in Ki-67<10% group (P=0.02). (P)RR was expressed in 4 types of human breast carcinoma cell lines. (P)RR specific small interference RNA inhibited proliferation of both MCF-7 (ERalpha positive) and SK-BR-3 (ERalpha negative) cells. The present study has shown, for the first time, the expression of (P)RR in human breast carcinoma tissues and cultured breast carcinoma cell lines. These findings have raised the possibility that the blockade of the (P)RR signaling may be a novel therapeutic strategy against breast carcinomas. PMID- 24759174 TI - Immunogenicity of a West Nile virus DIII-cholera toxin A2/B chimera after intranasal delivery. AB - West Nile virus (WNV) causes potentially fatal neuroinvasive disease and persists at endemic levels in many parts of the world. Despite advances in our understanding of WNV pathogenesis, there remains a significant need for a human vaccine. The domain III (DIII) region of the WNV envelope protein contains epitopes that are the target of neutralizing antibodies. We have constructed a chimeric fusion of the non-toxic cholera toxin (CT) CTA2/B domains to DIII for investigation as a novel mucosally-delivered WNV vaccine. Purification and assembly of the chimera, as well as receptor-binding and antigen delivery, were verified by western blot, GM1 ELISA and confocal microscopy. Groups of BALB/c mice were immunized intranasally with DIII-CTA2/B, DIII, DIII mixed with CTA2/B, or CTA2/B control, and boosted at 10 days. Analysis of serum IgG after 14 and 45 days revealed that mucosal immunization with DIII-CTA2/B induced significant DIII specific humoral immunity and drove isotype switching to IgG2a. The DIII-CTA2/B chimera also induced antigen-specific IgM and IgA responses. Bactericidal assays indicate that the DIII-CTA2/B immunized mice produced DIII-specific antibodies that can trigger complement-mediated killing. A dose escalation resulted in increased DIII-specific serum IgG titers on day 45. DIII antigen alone, in the absence of adjuvant, also induced significant systemic responses after intranasal delivery. Our results indicate that the DIII-CTA2/B chimera is immunogenic after intranasal delivery and merits further investigation as a novel WNV vaccine candidate. PMID- 24759181 TI - Acquisition of useful sero-diagnostic autoantibodies using the same patients'sera and tumor tissues. AB - Cancer tissues are comprised of various components including tumor cells and the surrounding tumor stroma, which consists of the extracellular matrix and inflammatory cells. Since the tumor stroma plays critical roles in tumor development, investigation of the tumor stroma in addition to tumor cells is important to identify useful tumor-associated markers. To discover novel and useful sero-diagnostic markers, a comparative study of tumor-associated autoantibodies (AAbs) in sera from lung adenocarcinoma (AC) patients was investigated by two-dimensional immunoblotting with AC cell lines or each autologous AC tissues. Autoantigens identified from tissue and cell line samples comprised 58 (45 antigens) and 53 spots (41 antigens), respectively. Thirty-six proteins including Transforming growth factor-beta-induced protein ig-h3 (BIGH3) and Hyaluronan and proteoglycan link protein 1 (HAPLN1) were detected only from tissues, 32 proteins only from cell lines, and 9 proteins from both. BIGH3 and HAPLN1 expressions were confirmed in the tumor stroma, but not in AC cell lines by immunostaining and immunoblotting. These data suggest that autologous tumor tissue and serum are important to coincidently detect AAbs derived from the tumor stroma in addition to tumor cells. PMID- 24759182 TI - Epigallocatechin gallate suppresses LPS endocytosis and nitric oxide production by reducing Rab5-caveolin-1 interaction. AB - Epigallocatechin gallate (EGCG) is the major polyphenol in green tea and the main bioactive compound responsible for the health benefits of tea consumption. The molecule exhibits antimicrobial and anti-inflammatory activities. However, little is known about the molecular mechanisms by which EGCG elicits those activities. In this study, we examined the effects of EGCG on lipopolysaccharide (LPS) endocytosis and LPS-induced NO production. We also investigated the mechanism with focus on the effect of EGCG on interaction between small GTPase Rab5 and caveolin-1. EGCG suppressed endocytosis of LPS and LPS-induced nitric oxide production in mouse macrophage-like cells (RAW 264). EGCG suppressed the Rab5 caveolin-1 interaction and reduced Rab5 activity. The results suggest that EGCG reduced LPS-induced innate immune responses through suppression of LPS endocytosis by interfering with Rab5-caveolin-1 interaction and by reducing Rab5 activity. PMID- 24759183 TI - Potentiation of osteoclastogenesis by adipogenic conversion of bone marrow derived mesenchymal stem cells. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are the indispensable component of the bone marrow, being the common precursors for adipocytes and osteoblasts. We show here that adipogenic differentiation resulted in increase in the production of adipocyte markers, such as adiponectin,fatty-acid binding proteins (FABP4), peroxisome proliferator-activated receptor gamma (PPARgamma), as well as the receptor activator of nuclear-kappaB ligand (RANKL). Co-culture of osteoclast precursors (OCPs) with BMSCs-derived adipocytes significantly enhanced osteoclast differentiation with low-dose RANKL, whose levels alone could not promote osteoclastogenesis. These results demonstrate for the first time that adipogenic differentiation of BMSCs plays a pivotal role in maintaining bone homeostasis. PMID- 24759184 TI - Increased activated natural killer T cells in the liver of patients with advanced stage primary biliary cirrhosis. AB - Although growing evidence suggests a major role for T cells in the pathogenesis of primary biliary cirrhosis (PBC), the roles of natural killer (NK) and natural killer T (NKT) cells, which predominate in the liver, in the pathogenesis of PBC remain unclear. We investigated the status of NK and NKT cells in the liver and peripheral blood samples obtained from 11 patients with asymptomatic PBC diagnosed as stage I or II (early PBC) and 7 patients with symptomatic PBC who underwent liver transplantation (advanced PBC) using flow cytometry and immunohistochemical staining. The proportions of NK and NKT cells were significantly decreased in the liver of patients with early PBC compared with normal donors. However, the proportion of CD56+ NKT cells was increased in the liver of patients with advanced PBC. Moreover, the proportion of activated Fas ligand (FasL)-positive NKT cells was significantly increased in the liver of patients with advanced PBC compared with early PBC (P=0.013). We also found increased expression of FasL on lymphocytes infiltrating around the injured bile duct in advanced PBC using immunohistochemical staining. Our results suggest that activated NKT cells may contribute to the biliary epithelial cell death resulting in the progression of PBC. PMID- 24759185 TI - Effect of five taste ligands on the release of CCK from an enteroendocrine cell line, STC-1. AB - Here, we investigated which taste ligand induces the CCK (cholecystokinin) release from intestinal STC-1 cells. We first developed a new assay to measure the release of CCK. The expression vector for CCK type A receptor (CCKAR) was permanently introduced into HEK293T cells and a cell line was established (CCKAR/HEK). Then, STC-1 cells were treated with taste ligands and the incubated buffer of STC-1 cells containing released CCK was applied to CCKAR/HEK cells.Since CCKAR couples to Gq-signaling, the CCK-induced receptor activation can be monitored by the method of Ca2+-imaging. Therefore, when CCK is released from STC-1 cells to culture medium with taste stimulation, Ca2+ activation of CCKAR/HEK should be observed. Among five different taste ligands (saccharin, Na glutamate, NaCl, denatonium benzoate, HCl), only denatonium benzoate and HCl induced the release of CCK in STC-1 cells. Thus, we found that only specific taste ligands induce the CCK release, and that other three taste ligands cannot induce the release of CCK despite of their ability to elevate the intracellular Ca2+ level in STC-1 cells. PMID- 24759186 TI - Update on pathology of antibody-mediated rejection in the lung allograft. AB - PURPOSE OF REVIEW: The determination of antibody-mediated rejection (AMR) in the pulmonary allograft remains a diagnostic challenge. Herein, we review the pathologic findings from recent studies, including the International Society of Heart and Lung Transplantation (ISHLT) summary statement on pulmonary AMR and preliminary data from the Banff allograft pathology study on AMR in lung transplant patients. RECENT FINDINGS: Some pathologic findings, including acute lung injury and neutrophilic capillary infiltration, are likely to be associated with pulmonary AMR but do not appear to be specific pathologic markers. The ISHLT statement on pulmonary AMR lists numerous pathologic findings that may be associated with donor-specific antibodies (DSAs). Other recent studies, including the Banff study on pulmonary AMR, have found correlations between clinical AMR, defined in part by the presence of DSAs, and nonspecific acute lung injury and capillary neutrophils with or without C4d deposition. SUMMARY: At this time, the diagnosis of lung transplant AMR requires multidisciplinary coordination and is ultimately determined by the managing clinician. In the full clinical context, including knowledge of serologic data for the presence or absence of DSAs, pathologic interpretation may provide valuable information that can guide therapy and support the clinical diagnosis. PMID- 24759187 TI - An impact of the ring substitution in nicorandil on its adsorption on silver nanoparticles. Surface-enhanced Raman spectroscopy studies. AB - The substituent effect on structure and surface activity of biologically active nicorandil was investigated by means of surface-enhanced Raman spectroscopy (SERS). Vibrational characterization was a basis for investigation of the adsorption profile of nicorandil and 1-methylnicorandil on silver nanoparticles. An assignment of SERS bands was performed by the comparison of the Raman spectra of both compounds in the solid state and in solutions, complemented by DFT calculations. Even though the nitro group was found to be the most attractive to the silver surface, the strong impact of the methyl substituent changed this preferable adsorption mechanism in 1-methylnicorandil. Protonation of the nitrogen atom in the pyridinium ring was also found to have an impact on absorption mechanism. PMID- 24759188 TI - Optical conductivity of curved graphene. AB - We compute the optical conductivity for an out-of-plane deformation in graphene using an approach based on solutions of the Dirac equation in curved space. Different examples of periodic deformations along one direction translates into an enhancement of the optical conductivity peaks in the region of the far- and mid-infrared frequencies for periodicities ~100 nm. The width and position of the peaks can be changed by dialling the parameters of the deformation profiles. The enhancement of the optical conductivity is due to intraband transitions and the translational invariance breaking in the geometrically deformed background. Furthermore, we derive an analytical solution of the Dirac equation in a curved space for a general deformation along one spatial direction. For this class of geometries, it is shown that curvature induces an extra phase in the electron wave function, which can also be explored to produce interference devices of the Aharonov-Bohm type. PMID- 24759189 TI - The effectiveness of stuttering treatments in Germany. AB - PURPOSE: Persons who stutter (PWS) should be referred to the most effective treatments available, locally or regionally. A prospective comparison of the effects of the most common stuttering treatments in Germany is not available. Therefore, a retrospective evaluation by clients of stuttering treatments was carried out. METHOD: The five most common German stuttering treatments (231 single treatment cases) were rated as to their perceived effectiveness, using a structured questionnaire, by 88 PWS recruited through various sources. The participants had received between 1 and 7 treatments for stuttering. RESULTS: Two stuttering treatments (stuttering modification, fluency shaping) showed favorable and three treatments (breathing therapy, hypnosis, unspecified logopedic treatment) showed unsatisfactory effectiveness ratings. The effectiveness ratings of stuttering modification and fluency shaping did not differ significantly. The three other treatments were equally ineffective. The differences between the effective and ineffective treatments were of large effect sizes. The typical therapy biography begins in childhood with an unspecified logopedic treatment administered extensively in single and individual sessions. Available comparisons showed intensive or interval treatments to be superior to extensive treatments, and group treatments to be superior to single client treatments. CONCLUSION: The stuttering treatment most often prescribed in Germany, namely a weekly session of individual treatment by a speech-language pathologist, usually with an assorted package of mostly unknown components, is of limited effectiveness. Better effectiveness can be expected from fluency shaping or stuttering modification approaches, preferably with an intensive time schedule and with group sessions. EDUCATIONAL OBJECTIVES: Readers will be able to: (a) discuss the five most prevalent stuttering treatments in Germany; (b) summarize the effectiveness of these treatments; and (c) describe structural treatment components that seem to be preferable across different kinds of treatments. PMID- 24759190 TI - Phonological encoding of young children who stutter. AB - PURPOSE: Several empirical studies suggest that children who stutter, when compared to typically fluent peers, demonstrate relatively subtle, yet robust differences in phonological encoding. Phonological encoding can be measured through the use of tasks that reflect the underlying mechanisms of phonological processing, such as phonological awareness. This study investigated the phonological encoding abilities of five- and six-year old children who stutter. METHODS: Young children who stutter were paired according to language ability, maternal education, and sex to their typically fluent peers. Participants completed multiple measures of phonological awareness abilities (i.e., sound matching, phoneme blending, elision), as well as measures of expressive and receptive vocabulary and articulation. RESULTS: Young children who stutter performed significantly less well than nonstuttering peers on tasks of elision and sound blending. No between-group differences were found in sound matching abilities or in any of the background language measures. CONCLUSIONS: Results suggest that young children who stutter have subtle, yet robust, linguistic differences in certain aspects of phonological encoding that may contribute to an unstable language planning system in young children who stutter. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) describe how phonological awareness can inform our understanding of phonological encoding; (b) summarize the findings of previously published studies that examined some aspects of phonological awareness in children who do and do not stutter; and (c) compare the results of the current study with other investigations of phonological awareness skills in children who stutter and their typically fluent peers. PMID- 24759191 TI - Birth weight and stuttering: Evidence from three birth cohorts. AB - PURPOSE: Previous studies have produced conflicting results with regard to the association between birth weight and developmental stuttering. This study sought to determine whether birth weight was associated with childhood and/or adolescent stuttering in three British birth cohort samples. METHODS: Logistic regression analyses were carried out on data from the Millenium Cohort Study (MCS), British Cohort Study (BCS70) and National Child Development Study (NCDS), whose initial cohorts comprised over 56,000 individuals. The outcome variables were parent reported stuttering in childhood or in adolescence; the predictors, based on prior research, were birth weight, sex, multiple birth status, vocabulary score and mother's level of education. Birth weight was analysed both as a categorical variable (low birth weight, <2500g; normal range; high birth weight, >=4000g) and as a continuous variable. Separate analyses were carried out to determine the impact of birth weight and the other predictors on stuttering during childhood (age 3, 5 and 7 and MCS, BCS70 and NCDS, respectively) or at age 16, when developmental stuttering is likely to be persistent. RESULTS: None of the multivariate analyses revealed an association between birth weight and parent reported stuttering. Sex was a significant predictor of stuttering in all the analyses, with males 1.6-3.6 times more likely than females to stutter. CONCLUSION: Our results suggest that birth weight is not a clinically useful predictor of childhood or persistent stuttering. PMID- 24759192 TI - Stuttering attitudes of students: Professional, intracultural, and international comparisons. AB - PURPOSE: The study sought to identify major-specific, training, and cultural factors affecting attitudes toward stuttering of speech-language pathology (SLP) students. METHOD: Eight convenience samples of 50 students each from universities in the USA and Poland filled out the Public Opinion Survey of Human Attributes Stuttering (POSHA-S) in English or Polish, respectively. USA samples included undergraduate and graduate students in SLP majors or non-SLP majors as well as a sample of non-SLP students who were Native Americans. Polish samples included SLP (logopedics), psychology, and mixed majors. RESULTS: SLP students held more positive attitudes than non-SLP students in both countries. Graduate students held more positive attitudes than undergraduate students in the USA, and this effect was stronger for SLP than for non-SLP students. Native American students' stuttering attitudes were similar to other American non-SLP students' attitudes. Polish student attitudes were less positive overall than those of their American student counterparts. CONCLUSION: SLP students' attitudes toward stuttering are affected by a "halo effect" of being in that major, by specific training in fluency disorders, and by various cultural factors, yet to be clearly understood. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) describe major factors affecting SLP students' attitudes toward stuttering; (b) describe similarities and differences in attitudes toward stuttering of students from the USA and Poland; (c) describe similarities and differences in attitudes toward stuttering of Native American students from the USA and non-Native American students. PMID- 24759193 TI - Business intelligence and nursing administration. PMID- 24759194 TI - Charting a new course: advancing the next generation of nursing-sensitive indicators. PMID- 24759195 TI - American organization of nurse executives nurse leader survey: compensation trends and satisfaction levels. AB - The American Organization of Nurse Executives conducted a salary survey of more than 4,600 nurse leaders, capturing information from 2012. About half of the salaries fall between $80,000 and $130,000. When correlating years of leadership to salary level, the 10-year mark appears to be the tipping point in terms of higher salaries for nurse leaders, with 52% of those with 11 to 20 years of experience and 64% of those with more than 20 years of experience reporting annual salaries equal to or greater than $120,000. Overall job satisfaction is high among nurse leaders, with 62% stating that they are very satisfied and another 29% responding that they are somewhat satisfied. PMID- 24759196 TI - The commitment to influential nursing administration research: an interview with Dr Donna Sullivan Havens. AB - This department highlights nursing leaders who have demonstrated a commitment to nursing leadership in research, practice, policy, education and theory. This interview profiles Donna Sullivan Havens, PhD, RN, FAAN, professor, The University of North Carolina at Chapel Hill. PMID- 24759197 TI - Measuring direct nursing cost per patient in the acute care setting. AB - OBJECTIVE: The objective of the study was to measure the variability of direct nursing cost for similar patients and to examine the characteristics of nurses assigned to different types of patients. BACKGROUND: There is no standard method for measuring direct nursing cost by patient. METHODS: Deidentified data were collected from 3 databases for patients admitted from January 2010 through December 2012 on 1 medical/surgical unit in a large Magnet hospital. Direct nursing care time and costs were calculated from the nurse-patient assignment. RESULTS: Variability in nursing intensity (0.36-13 hours) and cost per patient day ($132-$1,455) was significant for similar patients. Higher cost nurses were not assigned sicker patients (F3, 3029 = 87.09, P < .001, R = 0.124). Mean (SD) nursing direct cost per day was $96.48 ($55.73). CONCLUSIONS: Standard measurement of nursing cost per patient could be benchmarked across hospitals and inform nursing administration care delivery decisions. PMID- 24759198 TI - The Baptist Health High Risk Falls Assessment: a methodological study. AB - OBJECTIVE: The purpose of this study was to evaluate the psychometric properties of the Baptist Health High Risk Falls Assessment (BHHRFA). BACKGROUND: The cost of falls and the potential for increased patient morbidity and mortality necessitate the development of a psychometrically sound assessment. METHODS: Based on pilot data, a multisite study was conducted. Assessments were collected on 21 medical-surgical units, 1 rehabilitation unit, 1 psychiatric unit, and 3 critical care units (N = 241599). Sensitivity, specificity, and diagnostic odds ratios (DORs) were calculated. Clinical usefulness in terms of assessment performance time was addressed. RESULTS: Psychometric properties were within a desirable range for each site, critical care patients, and all participants (sensitivity, 0.64-1.00; specificity, 0.50-0.70; and DOR, 4.73-7.0). Although sensitivity at 1 site was high (0.84), specificity was low (0.37). CONCLUSIONS: Results suggest that the BHHRFA is clinically useful for adult inpatients across acute care settings. PMID- 24759199 TI - The Affordable Health Care Act annual wellness visits: the effectiveness of a nurse-run clinic in promoting adherence to mammogram and colonoscopy recommendations. AB - OBJECTIVE: The aim of this study was to determine the effectiveness of the nurse run annual wellness visit (AWV) in improving adherence to cancer screening recommendations for colonoscopies and/or mammograms. BACKGROUND: The Affordable Health Care Act provides Medicare beneficiaries access to AWVs. Nurse-run AWVs offer individualized education, reinforce health screening recommendations, and may enhance the patients' intent to complete the screenings. METHODS: A nonexperimental comparative study was conducted using data collected from chart audits comparing patients who only attended the AWV, patients who attended the AWV linked with a physician visit, and patients who have not attended an AWV. RESULTS: Patients who attended the AWV showed greater adherence to mammogram completion regardless of the link to the physician follow-up visit. Differences in adherence to colonoscopy recommendations were not significant, likely because of the low number of colonoscopies reported. CONCLUSIONS: Nurse-run AWV clinics are associated with adherence to mammograms and show promise of increasing colonoscopy compliance. PMID- 24759200 TI - Psychological competence: the key to leader empowering behaviors. AB - OBJECTIVE: The aim of this study was to examine the effects of specific cognitions or aspects of psychological empowerment on 5 major aspects of leader empowering behaviors. BACKGROUND: Leader empowering behaviors are linked to important employee outcomes such as work effectiveness. Psychologically empowered leaders are known to use more empowering behaviors in their practice. There is limited research examining what aspects of psychological empowerment are most associated with different aspects of leader empowering behaviors. METHODS: Data from a sample of 103 frontline and midlevel nurse leaders were analyzed after they participated in a leadership development program. RESULTS: Psychological competence was the strongest predictor of the total score for leader empowering behaviors and 4 of 5 subscale scores, and meaning was the 2nd strongest predictor. Autonomy was not a significant predictor. CONCLUSION: Psychological empowerment, particularly in the form of psychological competence, is an important leader characteristic and should be a focus of leadership development strategies. PMID- 24759201 TI - Impact of workplace mistreatment on patient safety risk and nurse-assessed patient outcomes. AB - OBJECTIVE: The aim of this study was to investigate the impact of subtle forms of workplace mistreatment (bullying and incivility) on Canadian nurses' perceptions of patient safety risk and, ultimately, nurse-assessed quality and prevalence of adverse events. BACKGROUND: Workplace mistreatment is known to have detrimental effects on job performance and in nursing may threaten patient care quality. METHODS: A total of 336 nurses from acute care settings across Ontario responded to a questionnaire that was mailed to their home address in early 2013, with a response rate of 52%. RESULTS: Bullying and incivility from nurses, physicians, and supervisors have significant direct and indirect effects on nurse-assessed adverse events (R = 0.03-0.06) and perceptions of patient care quality (R = 0.04 0.07), primarily through perceptions of increased patient safety risk. CONCLUSIONS: Bullying and workplace incivility have unfavorable effects on nurse assessed patient quality through their effect on perceptions of patient safety risk. PMID- 24759202 TI - What is the best?: simple versus visitor restricted rest period. AB - OBJECTIVE: The aim of this study was to compare a highly structured planned rest protocol that includes visitor and healthcare personnel restrictions with a simple planned rest period that encourages patients to rest during a designated time without restriction of visitors and healthcare personnel. BACKGROUND: Many hospitals acute care have begun to restrict visitors and nonessential health team interventions during specific times despite the lack of experimentally designed studies. METHODS: Using a convenience sample of 52 intermediate care unit patients, a randomized experimental design study compared a highly structured planned rest protocol with restriction of visitors/healthcare personnel to a simple planned rest period without restrictions. The primary outcome variable was the patient's perceived quality of rest after a 2-hour rest period. RESULTS: Intermediate care patients' perception of rest and sleep during a designated rest period was similar whether elaborate rest strategies were used, including visitor and healthcare personnel restrictions, or if it was only suggested they rest and the door to their room closed. CONCLUSIONS: The restriction of visitors and healthcare personnel during a 2-hour rest period did not improve the patient's perception of rest or how long it took them to go to sleep. PMID- 24759203 TI - Image is more than a uniform: the promise of assurance. AB - OBJECTIVE: The purpose of this qualitative study was to explore the meaning of the phrase "image of the nurse" in the context of the desired brand experience of assurance. BACKGROUND: A brand is a promise that lives in the minds of consumers. Nurses play a key role in delivering on the brand promise of a hospital. METHODS: Using focus groups, the authors applied a deductive approach to generate data. Discussion transcripts were analyzed by establishing codes and identifying themes. RESULTS: The most frequent comment from participants was that for nurses to communicate assurance, they must 1st be clean, well groomed, and understated in overall appearance. Nurse behaviors that reassure patients include being present with patients, helping patients know what to expect, and demonstrating a consistent team approach. CONCLUSIONS: Overall appearance and behaviors define the image of nurses and contribute significantly to the brand of assurance. PMID- 24759204 TI - Generational differences in work ethic among 3 generations of registered nurses. AB - OBJECTIVE: The purpose of this study was to understand if differences in dimensions of work ethic exist among 3 generations of nurses working in an inpatient setting at an acute care facility. BACKGROUND: Generational differences are linked with increased turnover, with work ethic frequently cited as an important difference. METHODS: The quantitative, quasi-experimental cross sectional study recruited inpatient registered nurses from 2 teaching hospitals in a southern US metropolitan area to complete the Multidimensional Work Ethic Profile online. RESULTS: The 285 completed surveys indicated that similarities exist among the 3 generations, with statistically significant differences only in leisure, hard work, and delay of gratification dimensions. CONCLUSIONS: Understanding differences in work ethic dimensions could lead to strategies for improving the generational conflict. These results also lead to the conclusion that work ethic differences may not be the cause of the generational conflict among nurses. PMID- 24759205 TI - The political economy of rationing health care in England and the US: the 'accidental logics' of political settlements. AB - This article considers how the 'accidental logics' of political settlements for the English National Health Service (NHS) and the Medicare and Medicaid programmes in the United States have resulted in different institutional arrangements and different implicit social contracts for rationing, which we define to be the denial of health care that is beneficial but is deemed to be too costly. This article argues that rationing is designed into the English NHS and designed out of US Medicare; and compares rationing for the elderly in the United States and in England for acute care, care at the end of life, and chronic care. PMID- 24759206 TI - Dendritic cells from aged subjects contribute to chronic airway inflammation by activating bronchial epithelial cells under steady state. AB - The mechanisms underlying the increased susceptibility of the elderly to respiratory infections are not well understood. The crosstalk between the dendritic cells (DCs) and epithelial cells is essential in maintaining tolerance as well as in generating immunity in the respiratory mucosa. DCs from aged subjects display an enhanced basal level of activation, which can affect the function of epithelial cells. Our results suggest that this is indeed the scenario as exposure of primary bronchial epithelial cells (PBECs) to supernatants from unstimulated DCs of aged subjects resulted in activation of PBECs. The expression of CCL20, CCL26, CXCL10, mucin, and CD54 was significantly increased in the PBECs exposed to aged DC supernatants, but not to young DC supernatants. Furthermore, aged DC supernatants also enhanced the permeability of the PBEC barrier. We also found that DCs from aged subjects spontaneously secreted increased levels of pro-inflammatory mediators, interleukin-6, tumor necrosis factor (TNF)-alpha, and metalloproteinase A disintegrin family of metalloproteinase 10, which can affect the functions of PBECs. Finally, we demonstrated that TNF-alpha, present in the supernatant of DCs from aged subjects, was the primary pro-inflammatory mediator that affected PBEC functions. Thus, age-associated alterations in DC-epithelial interactions contribute to chronic airway inflammation in the elderly, increasing their susceptibility to respiratory diseases. PMID- 24759207 TI - Phenotype and susceptibility to HIV infection of CD4+ Th17 cells in the human female reproductive tract. AB - Prevention of sexual acquisition of HIV in women requires a substantial increase in our knowledge about HIV-target cell availability and regulation in the female reproductive tract (FRT). In this study, we analyzed the phenotype and susceptibility to HIV infection of CD4(+) T cell in the endometrium (EM), endocervix (END), and ectocervix (ECT) of the FRT. We found that T helper type 17 (Th17) cells represent a major subset in FRT tissues analyzed and that Th17 cells were the main CD4(+) T-cell population expressing C-C motif chemokine receptor 5 (CCR5) and CD90. In premenopausal women, CD4(+) T cells and Th17 cells, in particular, were significantly lower in EM relative to END and ECT. Th17 cells were elevated in EM from postmenopausal women relative to premenopausal tissues but not changed in END and ECT. Susceptibility of CD4(+) T cells to HIV infection measured as intracellular p24 was lowest in the EM and highest in the ECT. Additionally, we found that Th17 cells co-expressing CCR5 and CD90 were the most susceptible to HIV infection. Our results provide valuable information for designing preventive strategies directed at targeting highly susceptible target cells in the FRT. PMID- 24759208 TI - Physiologic doses of depot-medroxyprogesterone acetate do not increase acute plasma simian HIV viremia or mucosal virus shedding in pigtail macaques. AB - OBJECTIVE: Epidemiologic studies remain inconclusive on whether the injectable contraceptive depot-medroxyprogesterone acetate (DMPA) increases mucosal HIV shedding and transmissibility. Nonhuman primate models may help to determine the effects of DMPA on acute HIV replication. DESIGN: We defined a physiologic dose of DMPA in macaques and assessed the impact of DMPA on acute simian HIV (SHIV) replication. METHODS: Pigtail macaques received 1-30 mg of DMPA intramuscularly followed by measurements of progesterone and medroxyprogesterone acetate (MPA). Vaginal epithelial thickness, number of cell layers and density of intraepithelial CD3 cells were measured. The effect of DMPA on SHIV viremia and genital virus shedding was investigated in six pigtail macaques infected during monthly treatment cycles with 3 mg DMPA. Six DMPA-untreated macaques were controls. RESULTS: Plasma MPA concentrations directly correlated with changes in epithelial thickness (correlation = 0.84; P < 0.001) and density of intraepithelial CD3 cells (correlation = 0.41; P = 0.02). A 3 mg DMPA dose recapitulated plasma MPA concentrations and changes in vaginal epithelial thickness seen in women. DMPA-treated and untreated macaques showed similar peak plasma viremia and RNA area under the curve values over 12 weeks (P = 0.94), although treated macaques had higher odds of having virus being detected in plasma (odds ratio 6.6, P = 0.02). Rectal and vaginal virus shedding was similar between treated and untreated macaques (P = 0.72 and P = 0.53, respectively). CONCLUSION: In this pigtail macaque model of DMPA and vaginal SHIV infection, we found little or no effect of DMPA on plasma viremia and mucosal virus shedding during acute infection. These results do not support a role of DMPA in increasing mucosal HIV shedding. PMID- 24759211 TI - Shared function knowledge: infants' attention to function information in communicative contexts. AB - Humans are specifically adapted to knowledge acquisition and transfer by social communication. According to natural pedagogy theory, infants are highly sensitive to signals that indicate a teacher's communicative intention and are biased to interpret communicative contexts as conveying relevant and generalizable knowledge that is also shared by other conspecifics. We investigated whether infants as young as 12 months interpret ostensively communicated object-directed emotion expressions as generalizable and shareable with others. Given that young infants pay particular attention to information about objects' functions, we were interested in whether the shareability assumption also holds for emotional attitudes toward functional features of unfamiliar objects. The results suggest that 12-month-olds (N=80) flexibly interpret another person's emotion displays toward unfamiliar artifacts either as object-centered and generalizable attitudes or as person-centered subjective attitudes, depending on the communicative characteristics of the learning context. Furthermore, the transfer of ostensively communicated information about the artifacts depended on their functional usability, which is consistent with infants' early sensitivity to function information in various areas of cognitive development. PMID- 24759210 TI - Single cell imaging of Bruton's tyrosine kinase using an irreversible inhibitor. AB - A number of Bruton's tyrosine kinase (BTK) inhibitors are currently in development, yet it has been difficult to visualize BTK expression and pharmacological inhibition in vivo in real time. We synthesized a fluorescent, irreversible BTK binder based on the drug Ibrutinib and characterized its behavior in cells and in vivo. We show a 200 nM affinity of the imaging agent, high selectivity, and irreversible binding to its target following initial washout, resulting in surprisingly high target-to-background ratios. In vivo, the imaging agent rapidly distributed to BTK expressing tumor cells, but also to BTK positive tumor-associated host cells. PMID- 24759209 TI - Principles and methods of integrative genomic analyses in cancer. AB - Combined analyses of molecular data, such as DNA copy-number alteration, mRNA and protein expression, point to biological functions and molecular pathways being deregulated in multiple cancers. Genomic, metabolomic and clinical data from various solid cancers and model systems are emerging and can be used to identify novel patient subgroups for tailored therapy and monitoring. The integrative genomics methodologies that are used to interpret these data require expertise in different disciplines, such as biology, medicine, mathematics, statistics and bioinformatics, and they can seem daunting. The objectives, methods and computational tools of integrative genomics that are available to date are reviewed here, as is their implementation in cancer research. PMID- 24759214 TI - [Comparison of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography image quality between commercial and in-house supply of FDG radiopharmaceuticals]. AB - OBJECTIVE: PET images are affected by scanner model, reconstruction conditions, injected dose, scan duration, patient health status and FDG radiopharmaceutical supply systems. The present study compares images of 40 patients using commercial and in-house FDG systems with one PET scanner (Aquiduo). METHODS: The PET images were evaluated using the physical indexes of NECpatient, NECdensity and SNRliver proposed by the Japanese guidelines for oncological FDG-PET/CT, and by visual assessment. RESULTS: There were no significant differences in the physical indexes between PET images generated using commercial and in-house FDG. The physical indexes were also acceptable according to the recommended Japanese guidelines. NECdensity was higher when a higher dose/body weight of commercial FDG was injected (correlation coefficient: r=0.576, p<0.001) and lower when BMI was lower and in-house FDG was injected (r=-0.786, p<0.0001). These results suggest that scan duration should be increased if the injected dose of commercial FDG/body weight is <5.5 MBq/kg, and if individuals with BMI >21.4 kg/m(2) are injected with in-house FDG. CONCLUSIONS: Scan duration should be varied depending on FDG supply systems to ensure more accurate image quality and quantitative values during evaluations of response to therapy and prognostic prediction. PMID- 24759215 TI - [A method of measuring presampled modulation transfer function using a rationalized approximation of geometrical edge slope]. AB - Several improvements were implemented in the edge method of presampled modulation transfer function measurements (MTFs). The estimation technique for edge angle was newly developed by applying an algorithm for principal components analysis. The error in the estimation was statistically confirmed to be less than 0.01 even in the presence of quantum noise. Secondly, the geometrical edge slope was approximated using a rationalized number, making it possible to obtain an oversampled edge response function (ESF) with equal intervals. Thirdly, the final MTFs were estimated using the average of multiple MTFs calculated for local areas. This averaging operation eliminates the errors caused by the rationalized approximation. Computer-simulated images were used to evaluate the accuracy of our method. The relative error between the estimated MTF and the theoretical MTF at the Nyquist frequency was less than 0.5% when the MTF was expressed as a sinc function. For MTFs representing an indirect detector and phase-contrast detector, good agreement was also observed for the estimated MTFs for each. The high accuracy of the MTF estimation was also confirmed, even for edge angles of around 10 degrees, which suggests the potential for simplification of the measurement conditions. The proposed method could be incorporated into an automated measurement technique using a software application. PMID- 24759212 TI - Dysregulated microRNA expression in serum of non-vaccinated children with varicella. AB - Circulating microRNAs (miRNAs) may play an important role in pathogen-host interactions and can serve as molecular markers for the detection of infectious diseases. To date, the relationship between circulating miRNAs and varicella zoster virus (VZV) caused varicella has not been reported. Using TaqMan Low Density Array (TLDA) analysis, expression levels of miRNAs in serum samples from 29 patients with varicella and 60 patients with Bordetella pertussis (BP), measles virus (MEV) and enterovirus (EV) were analyzed. The array results showed that 247 miRNAs were differentially expressed in sera of the varicella patients compared with healthy controls (215 up-regulated and 32 down-regulated). Through the following qRT-PCR confirmation and receiver operational characteristic (ROC) curve analysis, five miRNAs (miR-197, miR-629, miR-363, miR-132 and miR-122) were shown to distinguish varicella patients from healthy controls and other microbial infections with moderate sensitivity and specificity. A number of significantly enriched pathways regulated by these circulating miRNAs were predicted, and some of them were involved in inflammatory response, nervous system and respiratory system development. Our results, for the first time, revealed that a number of miRNAs were differentially expressed during VZV infection, and these five serum miRNAs have great potential to serve as biomarkers for the diagnosis of VZV infection in varicella patients. PMID- 24759216 TI - [Winston-lutz test and acquisition of flexmap using rotational irradiation]. AB - PURPOSE: IGRT (image guided radiation therapy) is a useful technique for implementing precisely targeted radiation therapy. Quality assurance and quality control (QA/QC) medical linear accelerators with a portal imaging system (electronic portal imaging device: EPID) are the key to ensuring safe IGRT. The Winston-Lutz test (WLT) provides an evaluation of the MV isocenter, which is the intersection of radiation, collimator, and couch isocenters. A flexmap can indicate a displacement of EPID from the beam center axis as a function of gantry angles which can be removed from the images. The purpose of this study was to establish a novel method for simultaneously carrying out WLT and acquiring a flexmap using rotational irradiation. We also observed long-term changes in flexmaps over a period of five months. METHOD: We employed rotational irradiation with a rectangular field (30*30 mm). First, the displacement of EPID from the beam center axis, indicated by the ball bearing (BB) center, was evaluated using an in-house program. The location of the BB center was then modified according to WLT. Second, a second irradiation was used to acquire a flexmap. We performed this examination regularly and evaluated long-term changes in the flexmap. RESULTS AND DISCUSSION: It proved feasible to perform WLT and flexmap measurements using our proposed methods. The precision of WLT using rotational irradiation was 0.1 mm. In flexmap analysis, the maximum displacement from the mean value for each angle was 0.4 mm over five months. CONCLUSION: We have successfully established a novel method of simultaneously carrying out WLT and flexmap acquisition using rotational irradiation. Maximum displacement from the mean in each angle was 0.4 mm over five months. PMID- 24759213 TI - HIV-1 latency in monocytes/macrophages. AB - Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established called the HIV-1 reservoir. Highly active antiretroviral therapy (HAART) has significantly improved the life of HIV-1 infected patients. However, complete eradication of HIV-1 from infected individuals is not possible without targeting latent sources of infection. HIV-1 establishes latent infection in resting CD4+ T cells and findings indicate that latency can also be established in the cells of monocyte/macrophage lineage. Monocyte/macrophage lineage includes among others, monocytes, macrophages and brain resident macrophages. These cells are relatively more resistant to apoptosis induced by HIV-1, thus are important stable hideouts of the virus. Much effort has been made in the direction of eliminating HIV-1 resting CD4+ T-cell reservoirs. However, it is impossible to achieve a cure for HIV-1 without considering these neglected latent reservoirs, the cells of monocyte/macrophage lineage. In this review we will describe our current understanding of the mechanism of latency in monocyte/macrophage lineage and how such cells can be specifically eliminated from the infected host. PMID- 24759217 TI - [Examination of the orbitomeatal basal line-anthropological basal line crossing angle and acanthiomeatal line-anthropological basal line crossing angle]. AB - Orbitomeatal basal line-anthropological basal line (OML-ABL), and the acanthiomeatal line (AML)-ABL crossing angles were measured using profile pictures. There were 219 volunteers in total: 42 people four years old, 44 people nine years old, 45 people 14 years old, 43 people 19 years old, and 45 people 40 years or older (48+/-7.4 years). The average OML-ABL crossing angle was 14.3 degrees in the 4-year-old group, while that of the 40-year or older group was 11.1 degrees. The deviation width of the 4-year-old group was 4.8 degrees, and that of the 40-year or older group was 2.4 degrees. The average AML-ABL crossing angle was 12.3 degrees in the 4-year-old group, while that of the 40-year or older group was 15.7 degrees. There were differences between males and females. The deviation width of the 4-year group was 5.4 degrees, and that of the 40-year or older group was 2.7 degrees. The results showed that 14.0 degrees for around 4 year-old, and 12.0 degrees for around 9- to 14-year-olds, could be used as OML ABL crossing angles as a practical proposition. PMID- 24759218 TI - [For practice a high quality screening CT colonography]. PMID- 24759219 TI - [JSRT Member" Mr. Toru Fujita"]. PMID- 24759220 TI - [History of physical science and technology in radiation therapy]. PMID- 24759221 TI - [9. Coronary artery disease (1): percutaneous coronary intervention]. PMID- 24759222 TI - [2. Basic of image reconstruction (2): fundamentals of iterative method]. PMID- 24759223 TI - [Asian Harmonization Working Party (AHWP) report]. PMID- 24759224 TI - [Role of Japanese Journal of Radiological Technology]. PMID- 24759225 TI - Surgical options to enhance intestinal function in patients with short bowel syndrome. AB - PURPOSE OF REVIEW: This review will provide the practitioner with an understanding of the spectrum of nontransplant surgical options for managing patients with short bowel syndrome (SBS). RECENT FINDINGS: Intestinal lengthening procedures are a promising therapy to allow autonomy from parenteral nutrition. The recently described serial transverse enteroplasty is an effective procedure that is easier to perform and has similar outcomes to the more standard longitudinal lengthening procedure described by Bianchi. SUMMARY: There are several surgical options for management of the SBS, including construction of intestinal valves or reversed intestinal segments, interposition of segments of colon, or intestinal lengthening procedures. The choice of technique is dictated by the patient's underlying pathophysiology and includes such factors as intestinal transit time, length of remnant bowel, presence of intact colon, and degree of small bowel dilation. Nontransplant surgical interventions are important adjuncts to the elimination of parenteral nutrition dependence and need for intestinal transplantation. PMID- 24759227 TI - Management of hepatoblastoma: an update. AB - PURPOSE OF REVIEW: To summarize the current standards and guidelines for the diagnosis and management of hepatoblastoma, a rare pediatric liver tumor. RECENT FINDINGS: Hepatoblastoma is the most common malignant liver tumor in childhood. International collaborative efforts have led to uniform implementation of the pretreatment extent of disease (PRETEXT) staging system as a means to establish consensus classification and assess upfront resectability. Additionally, current histopathological classification, in light of more advanced molecular profiling and immunohistochemical techniques and integration of tumor biomarkers into risk stratification, is reviewed. Multimodal therapy is composed of chemotherapy and surgical intervention. Achievement of complete surgical resection plays a key role in successful treatment for hepatoblastoma. Overall, outcomes have greatly improved over the past four decades because of advances in chemotherapeutic agents and administration protocols as well as innovations of surgical approach, including the use of vascular exclusion, ultrasonic dissection techniques, and liver transplantation. Challenges remain in management of high-risk patients as well as patients with recurrent or metastatic disease. SUMMARY: Eventually, a more individualized approach to treating the different types of the heterogeneous spectrum of hepatoblastoma, in terms of different chemotherapeutic protocols and timing as well as type and extent of surgery, may become the basis of successful treatment in the more complex or advanced types of hepatoblastoma. PMID- 24759226 TI - Maternal-fetal cellular trafficking: clinical implications and consequences. AB - PURPOSE OF REVIEW: Maternal-fetal cellular trafficking (MFCT) is the bidirectional passage of cells between mother and fetus during pregnancy. This results in the presence of fetal cells in the maternal circulation, known as fetal microchimerism, and maternal cells in the fetal circulation, known as maternal microchimerism. The biologic role of this transplacental cellular trafficking during pregnancy is not known, although it has been implicated in development of the fetal immune system, tolerance mechanisms during pregnancy, tissue repair in autoimmune disease and cancer, and immune surveillance. RECENT FINDINGS: Clinical utility of MFCT has been identified in prenatal testing for aneuploidies and prediction of pregnancy complications. Additionally, this transplacental passage of cells has been implicated in the delicate balance between immunologic priming and tolerance, which can influence the occurrence of autoimmune disease and transplantation outcomes. Ongoing studies are evaluating the utility of microchimerism in predicting the risk of graft rejection in transplantation. SUMMARY: In this review, we will discuss the clinical implications of MFCT in pregnancy, fetal surgery, autoimmune disease, transplantation, and cancer. PMID- 24759228 TI - Evaluation and management of atrioventricular block in children. AB - PURPOSE OF REVIEW: Pediatric brady-dysrhythmias and conduction disorders are uncommon, but timely recognition and evaluation are critical. This review will highlight the key diagnostic and management steps for first, second, and third degree atrioventricular heart block in pediatric patients. RECENT FINDINGS: There is a breadth of acquired and often reversible causes of atrioventricular block in childhood. Recent advances in diagnostics and pacing therapies have led to improved outcomes. SUMMARY: A thorough evaluation is required to determine when atrioventricular block requires treatment. In symptomatic or unstable patients, the management should focus on resuscitative measures, diagnostic testing, potential reversible causes, monitoring for progression, cardiac consultation and evaluating the need for definitive pacemaker placement. PMID- 24759229 TI - The state of affairs of neurologic monitoring by near-infrared spectroscopy in pediatric cardiac critical care. AB - PURPOSE OF REVIEW: The decreasing postoperative mortality in patients with congenital heart disease has enabled an increasing interest in preventing morbidity, especially from the central nervous system. Near-infrared spectroscopy, a noninvasive technology that provides an estimate of tissue oxygenation, has been introduced in the intensive care unit and has gained popularity over the last decade. This review aims to ascertain its ability to affect outcome. RECENT FINDINGS: Recent studies have started to incorporate cerebral near-infrared spectroscopy in the assessment, evolution, and outcomes of surgical patients with congenital heart disease. These studies often represent small single-center high-risk cohorts that are evaluated in a retrospective or an observational manner. Nevertheless, new data are starting to indicate that near infrared spectroscopy may be helpful not only in the assessment of critical care parameters, such as cardiac output performance or likelihood of adverse events, but, most notably, in the long-term neurological outcome. SUMMARY: In addition to additional corroborative trials from different centers, a critical question that remains to be answered is whether targeting cerebral near-infrared spectroscopy values, as part of goal-directed therapy protocols, can help to improve outcome overall. PMID- 24759230 TI - Pediatric pulmonary medicine: progress at the intersections. PMID- 24759232 TI - Panax red ginseng extract regulates energy expenditures by modulating PKA dependent lipid mobilization in adipose tissue. AB - Regulation of balance between lipid accumulation and energy consumption is a critical step for the maintenance of energy homeostasis. Here, we show that Panax red ginseng extract treatments increased energy expenditures and prevented mice from diet induced obesity. Panax red ginseng extracts strongly activated Hormone Specific Lipase (HSL) via Protein Kinase A (PKA). Since activation of HSL induces lipolysis in WAT and fatty acid oxidation in brown adipose tissue (BAT), these results suggest that Panax red ginseng extracts reduce HFD induced obesity by regulating lipid mobilization. PMID- 24759231 TI - Gleevec/imatinib, an ABL2 kinase inhibitor, protects tumor and endothelial cells from semaphorin-induced cytoskeleton collapse and loss of cell motility. AB - Class 3 semaphorins are axonal guidance mediators and regulators of angiogenesis and tumor progression. Semaphorin 3A and 3F (SEMA3A&F) act by depolymerizing F actin, resulting in cytoskeleton collapse. A key signaling step is that SEMA3A&F activates ABL2 tyrosine kinase, which activates p190RhoGAP, which in turn inactivates RhoA, thereby diminishing stress fiber formation and ensuing cell migration. We now demonstrate that Gleevec (imatinib, STI571), an ABL2 tyrosine kinase inhibitor, abrogates SEMA3A&F-induced stress fiber loss in glioblastoma cells and endothelial cells and diminishes their ability to inhibit migration. On the other hand, Sutent (sunitinib), a receptor tyrosine kinase inhibitor, did not rescue SEMA3A&F-induced collapsing activity. These results describe a novel property of Gleevec, its ability to antagonize semaphorins. PMID- 24759233 TI - Thermal expansion of free-standing graphene: benchmarking semi-empirical potentials. AB - The thermodynamical properties of free-standing graphene have been investigated under constant zero pressure as a function of temperature using Monte Carlo simulations. A variety of atomistic models have been used, including the simple three-body Stillinger potential and a series of bond-order many-body potentials based on the Tersoff-Brenner seminal models, with recent reparametrizations dedicated to graphene, extensions to medium-range or long-range dispersion corrections. In addition, we have also tested a tight-binding potential in the fourth-moment approximation. The simulations reveal significant discrepancies in the in-plane lattice parameter and the thermal expansion coefficient, which despite showing monotonically increasing variations with temperature, can be positive, negative or change sign at moderate temperature depending on the potential. Comparison with existing experimental and theoretical data obtained from complementary approaches indicates that empirical potentials limited to nearest-neighbour interactions give rather dispersed results, and that van der Waals corrections generally tend to flatten the variations of the in-plane lattice constant, in contradiction with experiment. Only the medium-range corrected potentials of Los and Fasolino, as well as the tight-binding model in the fourth-moment approximation, are reasonably close to the reference results near room temperature. Our results suggest that classical potentials should be used with caution for thermal properties. PMID- 24759234 TI - Fast epileptic discharges associated with ictal negative motor phenomena. AB - OBJECTIVE: Focal motor negative phenomena have been described in seizures primarily involving "negative" motor areas (opercular pre-motor and medial pre motor regions) and the rolandic region (post-central or pre-central). The localizing value of such signs and the mechanisms by which an epileptic discharge may generate negative phenomena remain debated. METHODS: Ictal positive and negative motor phenomena occurring during seizures affecting the rolandic area were studied in a patient having intracerebral recordings (stereo-electro encephalography, SEEG) for drug resistant epilepsy. RESULTS: During the video SEEG and EMG recording, nine positive and 27 negative motor seizures were recorded. All were generated within the same area (right opercular central area, Brodmann Area 4). The 2 different types of clinical seizure were differentiable by their power/frequency spectrum: positive motor seizures were associated with a prominent alpha-beta band discharge while negative motor seizures were associated with a gamma band discharge (>45Hz). CONCLUSIONS: We propose that within the primary motor cortex, high frequency sustained discharges may disrupt the ongoing excitatory drive to the peripheral motoneurons and produce negative motor signs, while sustained lower frequency discharges (alpha and beta bands) may activate the cortico-nuclear or cortico-spinal pathway and produce positive motor signs. SIGNIFICANCE: Both positive and negative ictal motor phenomena can be observed in the primary motor cortex depending on the properties of the epileptic discharge. PMID- 24759235 TI - Water and sanitation: addressing inequalities. PMID- 24759236 TI - Health disparities in Europe: hope for the future? PMID- 24759237 TI - Cigarette packaging in China--not going far enough. PMID- 24759238 TI - Do we underestimate the benefits of antidepressants? PMID- 24759240 TI - Abdisalan Noor: mapping malaria. PMID- 24759241 TI - Commission on Global Governance for Health: just another report? PMID- 24759242 TI - MDG 7c for safe drinking water in India: an illusive achievement. PMID- 24759243 TI - Commission on Global Governance for Health: just another report?--authors' reply. PMID- 24759244 TI - Commission on Global Governance for Health: just another report? PMID- 24759245 TI - North Korea: a challenge for global solidarity. PMID- 24759246 TI - Treatment of paracetamol overdose. PMID- 24759247 TI - North Korea: a challenge for global solidarity. PMID- 24759248 TI - Treatment of paracetamol overdose--authors' reply. PMID- 24759249 TI - Late effects of breast radiotherapy. PMID- 24759250 TI - Classification of mental disorders: a global mental health perspective. PMID- 24759251 TI - Henna tattoo: infection or allergy? PMID- 24759252 TI - Borders, centers, and margins: critical landscapes for migrant health. AB - Nurses in North America have a distinguished history of involvement in immigrant health due to the immigrant character of this region. The Western Hemisphere is a region composed of recent migrants from nearly every corner of the globe. Complicated economic, environmental, and social dynamics contribute to these various migration patterns and commensurate health-related issues-physical, psychological, and spiritual. Nurses attuned to health issues of newer immigrants' lives use newfound knowledge to shape the care they provide, and political advocacy. This article updates our understandings of migration, utilizing critical perspectives to analyze contemporary dynamics of migration and respective health issues. PMID- 24759253 TI - More than 50% of pregnant Japanese women with an intake of 150 MUg dietary folate per 1,000 kcal can maintain values above the cut-off. AB - Most Japanese pregnant women do not take the estimated average requirement (EAR) of folate for pregnant women, which is 400 MUg/d. Nevertheless, folate deficiencies have not been reported. We examined biomarkers for evaluating the status of folate in pregnant Japanese women. Apparently healthy pregnant Japanese women were cross-sectionally recruited from a private obstetric hospital. We measured nutritional biomarkers of folate in these women, as well as their folate intake. The numbers of subjects were 230 (49, 62, and 81, and 38 in the first (up to 15 wk), second (16-30 wk), and third (over 31 wk) trimesters of pregnancy, and 1 mo after delivery, respectively). Folate intakes (medians) in the first, second, and third trimesters, and 1 mo after delivery were 235+/-147 (194), 226+/ 83 (218), and 256+/-85 (254), and 300+/-105 (305) MUg/d, respectively. Folate concentrations in plasma and erythrocytes appeared to be valid indicators for assessing folate status, with cut-off values of 7 nmol/L and 300 nmol/L, respectively. Plasma folate concentrations (medians) in the first, second, and third trimesters, and 1 mo after delivery were 17.6+/-9.6 (16.7), 12.4+/-8.3 (9.4), and 12.1+/-8.4 (9.4), and 10.7+/-8.9 (7.9) nmol/L, respectively. Each of the folate values was over the cut-off value. Erythrocyte folate concentrations (medians) in the first, second, and third trimesters, and 1 mo after delivery were 358+/-108 (365), 389+/-154 (365), and 325+/-150 (315), and 308+/-158 (276) nmol/L, respectively. Each of the folate values was near or over the cut-off value. In conclusion, the data obtained demonstrated that the estimated average requirement of folate for pregnant Japanese women was ?250 MUg/d. PMID- 24759254 TI - Vitamin A determination in milk samples based on the luminol-periodate chemiluminescence system. AB - A simple and rapid flow injection (FI) method for the determination of retinyl acetate is reported based on its enhancing effect on the luminol-periodate chemiluminescence (CL) system in an alkaline medium. The detection limit (3s*blank) was 8.0*10-8 mol L-1, with an injection throughput of 90 h-1. The method allows linear increase of CL intensity over the retinyl acetate concentration range of 1.0-100*10-7 mol L-1 (R2=0.9996) with relative standard deviations of 2.4% (n=10) for 5.0*10-7 mol L-1. The key chemical and physical variables (reagent concentrations, flow rates, sample volume, and photomultiplier tube (PMT) voltage) were optimized and potential interferences were investigated. The method was successfully applied to human milk, fresh cow's milk and infant milk-based formulas and the results were in good agreement with the previously reported HPLC method. A brief discussion on the possible CL reaction mechanism is also presented. PMID- 24759255 TI - Formation of [nicotinamide-2H3]NAD+ from [2H4]nicotinamide and [2H4]nicotinic acid in human HepG2N cells and involvement of 2H/1H exchange at the redox site of NAD+/NADH. AB - To determine the rates of cellular NAD+ synthesis and breakdown, incorporation of stable isotope-labeled precursors into NAD+ should be quantified. Although with 2H (D)-labeled precursors [2,4,5,6-D4]nicotinamide ([D4]Nam) and [2,4,5,6 D4]nicotinic acid ([D4]NA), [D3]NAD+ is formed in human cells, why only three of four D atoms from [D4]Nam and [D4]NA are present in NAD+ remains unknown. Using a liquid chromatography-tandem mass spectrometry, we tested the involvement of D/1H (H) exchange at the redox site of NAD+/NADH (C-4 carbon of the pyridine ring) by oxidoreductases exhibiting opposite stereospecificity for the coenzymes in the 1 Da mass decrease in the cellular NAD+ formation. In all cells examined, [Nam D3]NAD+, but not [Nam-D4]NAD+, was obtained after the incubation with the D4 labeled precursors, whereas [Nam-D4]NAD+, but not [Nam-D3]NAD+, was synthesized from the same precursors with purified recombinant NAD+ biosynthetic enzymes. [D4]Nam group of [Nam-D4]NAD+ was converted to [D3]Nam group via [D4]NADH by in vitro sequential reduction and oxidation with oxidoreductases exhibiting opposite stereospecificity for the coenzymes. Furthermore, using [2,5,6-D3]Nam, which has H instead of D at the C-4 carbon, as a precursor of NAD+ in the cells, the 1-Da mass decrease in the nucleotide was not observed. Based on these observations, we conclude that following the synthesis of [Nam-2,4,5,6-D4]NAD+, cellular redox reactions of NAD+/NADH convert [Nam-2,4,5,6-D4]NAD+ to [Nam-2,5,6-D3]NAD+. Quantification of [Nam-2,5,6-D]NAD+ and [2,5,6-D3]Nam would successfully determine the rate of the NAD+ turnover and provide clues to understand regulatory mechanisms of cellular NAD+ concentrations. PMID- 24759256 TI - Daily ingestion of grains of paradise (Aframomum melegueta) extract increases whole-body energy expenditure and decreases visceral fat in humans. AB - We reported previously that a single ingestion of an alcohol extract of grains of paradise (GP, Aframomum melegueta), a species of the ginger family, increases energy expenditure (EE) through the activation of brown adipose tissue, a site of sympathetically mediated metabolic theromogenesis. The present study aimed to examine a daily ingestion of GP extract on whole-body EE and body fat in humans. Whole-body EE and body fat content were measured before and after daily oral ingestion of GP extract (30 mg/d) for 4 wk in 19 non-obese female volunteers aged 20-22 y in a single-blind, randomized, placebo-controlled, crossover design. Four week daily ingestion of GP and a placebo decreased and increased slightly the visceral fat area at the umbilicus level, respectively. The GP-induced change was significantly different from that induced by the placebo (p<0.05), and negatively correlated with the initial visceral fat area (r=-0.64, p<0.01). Neither GP nor placebo ingestion affected subcutaneous or total fat. The daily ingestion of GP, but not the placebo, increased whole-body EE (p<0.05). These results suggest that GP extract may be an effective and safe tool for reducing body fat, mainly by preventing visceral fat accumulation. PMID- 24759257 TI - The effect of the timing of meal intake on energy metabolism during moderate exercise. AB - Although the intake of carbohydrates is important for the supplementation of energy substrate utilized during exercise, fat oxidation is possibly prevented by an elevation of insulin, and whether or not the timing of the intake of meals affects energy metabolism during exercise has not been clarified. The purpose of this study was to investigate the effect of the timing of the intake of meals taken at different times before exercise on the carbohydrate and fat metabolism during aerobic exercise. The subjects were eight young trained athletes who performed cycling exercise at the lactate threshold (LT) intensity for 60 min. They performed under five conditions consisting of a no-meal (water) trial, and four meal trials that had a normal meal at 1, 2, 3, and 4 h before the exercise. There were no significant changes for any trial in respiratory exchange ratio, or carbohydrate or fat oxidation rates during exercise. The serum insulin level before exercise in the meal trials was more elevated, the shorter the time to the start of the exercise from meal intake. A tendency for higher blood glucose was shown during exercise with a shorter interval time in the meal trials. No alterations were demonstrated for the serum free fatty acids in any of the groups. These results showed that the timing of the pre-exercise meal taken within a 4-h period before exercise did not affect the energy metabolism of the trained subjects during exercise at LT intensity. PMID- 24759258 TI - Food restriction causes low bone strength and microarchitectural deterioration in exercised growing male rats. AB - The pathogenesis of bone disorders in young male athletes has not been well understood. We hypothesized that bone fragility is caused by low energy availability, due to insufficient food intake and excessive exercise energy expenditure in young male athletes. To examine this hypothesis, we investigated the influence of food restriction on bone strength and bone morphology in exercised growing male rats, using three-point bending test, dual-energy X-ray absormetry, and micro-computed tomography. Four-week-old male Sprague-Dawley rats were divided randomly into the following groups: the control (Con) group, exercise (Ex) group, food restriction (R) group, and food restriction plus exercise (REx) group after a 1-wk acclimatization period. Thirty-percent food restriction in the R and REx groups was carried out in comparison with that in the Con group. Voluntary running exercise was performed in the Ex and REx groups. The experimental period lasted 13 wk. At the endpoint of this experiment, the bone strength of the femurs and tibial BMD in the REx group were significantly lower than those in the Con group. Moreover, trabecular bone volume and cortical bone volume in the REx group were also significantly lower than those in the Con group. These findings indicate that food restriction causes low bone strength and microarchitectural deterioration in exercised growing male rats. PMID- 24759259 TI - Effects of acute and chronic boysenberry intake on blood pressure and endothelial function in spontaneous hypertensive rats. AB - The effects of acute or chronic intake of boysenberry juice or artificial vinegar on blood pressure (BP) and endothelial function were investigated in spontaneous hypertensive rats (SHR). A single administration of boysenberry juice (BJ, equivalent to 0.5 mL/kg body weight) or artificial boysenberry juice vinegar (BJV, equivalent to 0.5 mL BJ and 0.10 g acetic acid/kg body weight) decreased both systolic blood pressure (SBP) and diastolic blood pressure (DBP) significantly. Reductions in SBP of the control group compared with the BJ and BJV groups reached maxima of -16.8+/-4.3 and -28.4+/-7.3 mmHg 8 h after administration, respectively. Chronic SBP- and DBP-lowering effects were also observed upon daily feedings of both BJ and BJV at 4 wk. No significant differences were found in SBP or DBP between respective acute and chronic intake of BJ and BJV, except for the decrease in DBP after 4 wk of BJV intake. This suggests that the polyphenol constituents in BJ and BJV likely play a major role in lowering SBP and DBP under these conditions and that acetic acid added to BJ exerts a DBP-lowering effect after 4 wk of BJV intake. The polyphenolic constituents of these beverages might elevate plasma NO concentration via aortic endothelial nitric oxide synthase activation, but the effects of chronic intake on blood pressure might also be at least partly mediated by the renin-angiotensin system. These results may help explain the beneficial effects of boysenberry intake on cardiovascular health, such as reduced blood pressure and improved endothelial function. PMID- 24759260 TI - Insulin resistance in SHR/NDmc-cp rats correlates with enlarged perivascular adipocytes and endothelial cell dysfunction in skeletal muscle. AB - Ectopic adipose tissue in skeletal muscle is implicated in the development of insulin resistance, which is frequently induced by abnormal dietary habits such as excessive eating and a high-fat diet. However, the characteristics of ectopic adipocytes are unknown. In this study, we investigated the characteristics of ectopic adipocytes in the skeletal muscle of spontaneously hypertensive corpulent congenic (SHR/NDmc-cp) rats as a model of insulin resistance from excessive eating. SHR/NDmc-cp rats displayed overt insulin resistance with high plasma glucose, insulin, and triacylglycerol concentrations relative to control Wistar Kyoto (WKY) rats. In contrast, streptozotocin (STZ)-treated WKY rats had high glucose but low insulin concentrations. Ectopic adipocytes were found around blood vessels in the gastrocnemius in SHR/NDmc-cp rats. Areas of perivascular adipocytes and protein expression of resistin were greater in SHR/NDmc-cp rats than in control and STZ-treated WKY rats. The level of the phosphorylated (active) form of endothelial nitric oxide synthase in the gastrocnemius was lower in SHR/NDmc-cp rats than in the other groups. Insulin-resistant SHR/NDmc-cp rats showed enlarged perivascular adipocytes and greater endothelial cell dysfunction in the gastrocnemius. PMID- 24759261 TI - Effect of dietary gamma-aminobutyric acid on the nerve growth factor and the choline acetyltransferase in the cerebral cortex and hippocampus of ovariectomized female rats. AB - The brain protein synthesis and the plasma concentration of growth hormone (GH) is sensitive to the dietary gamma-aminobutyric acid (GABA) in ovariectomized female rats; however, the role of dietary GABA on biomarkers including nerve growth factor (NGF) and choline acetyltransferase for the function of cholinergic neurons remains unknown in ovariectomized female rats. The purpose of this study was to determine whether the dietary GABA affects the concentration and mRNA level of NGF, and the activity of choline acetyltransferase in the brains of ovariectomized female rats. Experiments were done on two groups of 24-wk-old ovariectomized female rats given 0 or 0.5% GABA added to a 20% casein diet. The concentrations of NGF and activities of choline acetyltransferase in the cerebral cortex and hippocampus, and mRNA level of NGF in the hippocampus increased significantly with the 20% casein+0.5% GABA compared with the 20% casein diet alone. In the hippocampus, the mRNA level of NGF significantly correlated with the NGF concentration (r=0.714, p<0.01). These results suggest that the administration of GABA to ovariectomized female rats is likely to control the mRNA level and concentration of NGF and cause an increase in the activity of choline acetyltransferase in the brains. PMID- 24759262 TI - Efficacy of habitual exercise for improving lipid profiles depends on the PPRAgamma genotype in Japanese males. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) responds to thiazolidinedione derivatives, which are ligands of PPARgamma, and affects insulin resistance. Recently, a PPARgamma study reported that in high-fat-diet induced obesity, the phosphorylation of PPARgamma prevented the transcription of specific PPARgamma targets that have anti-obesity effects. We previously reported that genetic variants of the fatty acid desaturase were associated with plasma lipid profiles and could contribute to dyslipidemia in Japanese males. The aim of this study was to investigate the anti-obesity effects of PPARgamma variants on lipid profiles. One hundred and thirty-eight (138) Japanese males participated in the study. Their serum lipid markers and the fatty acid composition of their red blood cell (RBC) membranes were determined. The stearoyl-CoA desaturase 1 (SCD1) indices were represented as the fatty acid product : precursor ratios. The participants were genotyped for the single-nucleotide polymorphism rs2938392 in the PPARgamma gene. The participants' fitness habits were also surveyed by questionnaire. The effects of habitual exercise on the measured lipid parameters were compared in each genotype group. No association between the genotypes in the PPARgamma gene and the biochemical data was found. However, the serum triglyceride levels and the SCD1 indices in RBC membranes were significantly higher in the participants who carried the major rs2938392 allele (A/A) and did not habitually exercise than in those who did exercise. These findings indicate that the risk for detrimental lipid profiles in the absence of habitual exercise depends on the PPARgamma genotype in Japanese males. PMID- 24759263 TI - A preliminary evaluation of efficacy and safety of Wharton's jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus. AB - INTRODUCTION: Stem cell therapy has recently been introduced to treat patients with type 2 diabetes mellitus (T2DM). However, no data are available on the efficacy and safety of allogeneic Wharton's Jelly-derived mesenchymal stem cell (WJ-MSC) transplantation in patients with T2DM. Here we performed a non-placebo controlled prospective phase I/II study to determine efficacy and safety of WJ MSC transplantation in T2DM. METHODS: Twenty-two patients with T2DM were enrolled and received WJ-MSC transplantation through one intravenous injection and one intrapancreatic endovascular injection (catheterization). They were followed up for 12 months after transplantation. The primary endpoints were changes in the levels of glycated hemoglobin and C-peptide and the secondary endpoints included insulin dosage, fasting blood glucose (FBG), post-meal blood glucose (PBG), inflammatory markers and T lymphocyte counts. RESULTS: WJ-MSC transplantation significantly decreased the levels of glucose and glycated hemoglobin, improved C peptide levels and beta cell function, and reduced markers of systemic inflammation and T lymphocyte counts. No major WJ-MSC transplantation-related adverse events occurred, but data suggest a temporary decrease in levels of C peptide and beta cell function at one month after treatment, possibly related to intrapancreatic endovascular injection. CONCLUSIONS: Our data demonstrate that treatment with WJ-MSCs can improve metabolic control and beta cell function in patients with T2DM. The therapeutic mechanism may involve improvements in systemic inflammation and/or immunological regulation. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR-ONC-10000985. Registered 23 September 2010. PMID- 24759265 TI - Drugs for hypertension. PMID- 24759264 TI - NeuroArray: a universal interface for patterning and interrogating neural circuitry with single cell resolution. AB - Recreation of neural network in vitro with designed topology is a valuable tool to decipher how neurons behave when interacting in hierarchical networks. In this study, we developed a simple and effective platform to pattern primary neurons in array formats for interrogation of neural circuitry with single cell resolution. Unlike many surface-chemistry-based patterning methods, our NeuroArray technique is specially designed to accommodate neuron's polarized morphologies to make regular arrays of cells without restricting their neurite outgrowth, and thus allows formation of freely designed, well-connected, and spontaneously active neural network. The NeuroArray device was based on a stencil design fabricated using a novel sacrificial-layer-protected PDMS molding method that enables production of through-structures in a thin layer of PDMS with feature sizes as small as 3 um. Using the NeuroArray along with calcium imaging, we have successfully demonstrated large-scale tracking and recording of neuronal activities, and used such data to characterize the spiking dynamics and transmission within a diode-like neural network. Essentially, the NeuroArray is a universal patterning platform designed for, but not limited to neuron cells. With little adaption, it can be readily interfaced with other interrogation modalities for high-throughput drug testing, and for building neuron culture based live computational devices. PMID- 24759268 TI - Snus usage: Harm induction or harm reduction? PMID- 24759267 TI - The hydroclimatic and ecophysiological basis of cloud forest distributions under current and projected climates. AB - BACKGROUND: Tropical montane cloud forests (TMCFs) are characterized by a unique set of biological and hydroclimatic features, including frequent and/or persistent fog, cool temperatures, and high biodiversity and endemism. These forests are one of the most vulnerable ecosystems to climate change given their small geographic range, high endemism and dependence on a rare microclimatic envelope. The frequency of atmospheric water deficits for some TMCFs is likely to increase in the future, but the consequences for the integrity and distribution of these ecosystems are uncertain. In order to investigate plant and ecosystem responses to climate change, we need to know how TMCF species function in response to current climate, which factors shape function and ecology most and how these will change into the future. SCOPE: This review focuses on recent advances in ecophysiological research of TMCF plants to establish a link between TMCF hydrometeorological conditions and vegetation distribution, functioning and survival. The hydraulic characteristics of TMCF trees are discussed, together with the prevalence and ecological consequences of foliar uptake of fog water (FWU) in TMCFs, a key process that allows efficient acquisition of water during cloud immersion periods, minimizing water deficits and favouring survival of species prone to drought-induced hydraulic failure. CONCLUSIONS: Fog occurrence is the single most important microclimatic feature affecting the distribution and function of TMCF plants. Plants in TMCFs are very vulnerable to drought (possessing a small hydraulic safety margin), and the presence of fog and FWU minimizes the occurrence of tree water deficits and thus favours the survival of TMCF trees where such deficits may occur. Characterizing the interplay between microclimatic dynamics and plant water relations is key to foster more realistic projections about climate change effects on TMCF functioning and distribution. PMID- 24759271 TI - Preface of the workshop on innovative personalized radioimmunotherapy (WIPR 2013). PMID- 24759272 TI - Comparative analysis of multiple myeloma treatment by CD138 antigen targeting with bismuth-213 and Melphalan chemotherapy. AB - INTRODUCTION: Multiple myeloma (MM) is a B-cell malignancy of terminally differentiated plasma cells within the bone marrow. Despite intense research to develop new treatments, cure is almost never achieved. Alpha-radioimmunotherapy (RIT) has been shown to be effective in vivo in a MM model. In order to define where alpha-RIT stands in MM treatment, the aim of this study was to compare Melphalan, MM standard treatment, with alpha-RIT using a [213Bi]-anti-mCD138 antibody in a syngeneic MM mouse model. METHODS: C57BL/KaLwRij mice were grafted with 1 * 10(6) 5T33 murine MM cells. Luciferase transfected 5T33 cells were used for in vivo localization. The first step of the study was to assess the dose response of Melphalan 21 days after engraftment. The second step consisted in therapeutic combination: Melphalan followed by RIT at day 22 or day 25 after engraftment. Toxicity (animal weight, blood cell counts) and treatment efficacy were studied in animals receiving no treatment, injected with Melphalan alone, RIT alone at day 22 or day 25 (3.7 MBq of [213Bi]-anti-CD138) and Melphalan combined with alpha-RIT. RESULTS: Fifty percent of untreated mice died by day 63 after MM engraftment. In mice treated with Melphalan alone, only the 200 MUg dose improved median survival. No animal was cured after Melphalan treatment whereas 60% of the mice survived with RIT alone at day 22 after tumor engraftment with only slight and reversible hematological radiotoxicity. No therapeutic effect was observed with alpha-RIT 25 days after engraftment. Melphalan and alpha-RIT combination does not improve overall survival compared to RIT alone, and results in increased leukocyte and red blood cell toxicity. CONCLUSIONS: Alpha-RIT seems to be a good alternative to Melphalan. Association of these two treatments provides no benefit. The perspectives of this work would be to evaluate RIT impact on the regimens incorporating the novel agents bortezomide, thalidomide and lenalidomide. PMID- 24759273 TI - Colchicine effect on P-glycoprotein expression and activity: in silico and in vitro studies. AB - Colchicine is a P-glycoprotein (P-gp) substrate that induces its expression, thus increasing the risk for unexpected pharmacokinetic interactions with this drug. Because increased P-gp expression does not always correlate with increased activity of this efflux pump, we evaluated the changes in both P-gp expression and activity induced by colchicine using an in vitro model. Caco-2 cells were incubated with 0.1-100 MUM colchicine up to 96 h. Cytotoxicity was evaluated by the MTT and LDH leakage assays, P-gp expression and activity were evaluated by flow cytometry and P-gp ATPase activity was measured in MDR1-Sf9 membrane vesicles. Furthermore, colchicine fitting in P-gp induction and competitive inhibition pharmacophore hypothesis, and docking studies evaluating the interaction between colchicine and P-gp drug binding pocket were tested in silico. Significant cytotoxicity was noted after 48 h. At 24 h a significant increase in P-gp expression was observed, which was not accompanied by an increase in transport activity. Moreover, colchicine significantly increased P-gp ATPase activity, demonstrating to be actively transported by the pump. New pharmacophores were constructed to predict P-gp modulatory activity. Colchicine fitted both the P-gp induction and competitive inhibition models. In silico, colchicine was predicted to bind to the P-gp drug-binding pocket suggesting a competitive mechanism of transport. These results show that colchicine induced P gp expression in Caco-2 cells but the activity of the protein remained unchanged, highlighting the need to simultaneously evaluate P-gp expression and activity. With the newly constructed pharmacophores, new drugs can be initially screened in silico to predict such potential pharmacokinetic interactions. PMID- 24759274 TI - Electrical tissue property imaging at low frequency using MREIT. AB - The tomographic imaging of tissue's electrical properties (e.g., conductivity and permittivity) has been greatly improved by recent developments in magnetic resonance (MR) imaging techniques, which include MR electrical impedance tomography (MREIT) and electrical property tomography. When the biological material is subjected to an external electric field, local changes in its electrical properties become sources of magnetic field perturbations, which are detectable by the MR signals. Controlling the external excitation and measuring the responses using an MRI scanner, we can formulate the imaging problem as an inverse problem in which unknown tissue properties are recovered from the acquired MR signals. This inverse problem is nonlinear; it involves the incorporation of Maxwell's equations and Bloch equations during data acquisition. Each method for visualizing internal conductivity and permittivity distributions has its own methodological limitations, and is restricted to imaging only a part of the ensemble or mean tissue structures or states. Therefore, imaging methods can be improved by developing complementary methods that can employ the beneficial aspects of various existing techniques. This paper focuses on recent progress in MREIT and discusses its distinct features in comparison with other imaging methods. PMID- 24759275 TI - Breast cancer histopathology image analysis: a review. AB - This paper presents an overview of methods that have been proposed for the analysis of breast cancer histopathology images. This research area has become particularly relevant with the advent of whole slide imaging (WSI) scanners, which can perform cost-effective and high-throughput histopathology slide digitization, and which aim at replacing the optical microscope as the primary tool used by pathologist. Breast cancer is the most prevalent form of cancers among women, and image analysis methods that target this disease have a huge potential to reduce the workload in a typical pathology lab and to improve the quality of the interpretation. This paper is meant as an introduction for nonexperts. It starts with an overview of the tissue preparation, staining and slide digitization processes followed by a discussion of the different image processing techniques and applications, ranging from analysis of tissue staining to computer-aided diagnosis, and prognosis of breast cancer patients. PMID- 24759277 TI - Visual and auditory brain-computer interfaces. AB - Over the past several decades, electroencephalogram (EEG)-based brain-computer interfaces (BCIs) have attracted attention from researchers in the field of neuroscience, neural engineering, and clinical rehabilitation. While the performance of BCI systems has improved, they do not yet support widespread usage. Recently, visual and auditory BCI systems have become popular because of their high communication speeds, little user training, and low user variation. However, building robust and practical BCI systems from physiological and technical knowledge of neural modulation of visual and auditory brain responses remains a challenging problem. In this paper, we review the current state and future challenges of visual and auditory BCI systems. First, we describe a new taxonomy based on the multiple access methods used in telecommunication systems. Then, we discuss the challenges of translating current technology into real-life practices and outline potential avenues to address them. Specifically, this review aims to provide useful guidelines for exploring new paradigms and methodologies to improve the current visual and auditory BCI technology. PMID- 24759278 TI - A brief history of tissue models for cardiac electrophysiology. AB - The last four decades have produced a number of significant advances in the developments of computer models to simulate and investigate the electrical activity of cardiac tissue. The tissue descriptions that underlie these simulations have been built from a combination of clever insight and careful comparison with measured data at multiple scales. Tissue models have not only led to greater insights into the mechanisms of life-threatening arrhythmias but have been used to engineer new therapies to treat the consequences of cardiac disease. This paper is a look back at the early years in the cardiac modeling and the challenges facing the field as models move toward the clinic. PMID- 24759276 TI - Brain-computer interfaces using sensorimotor rhythms: current state and future perspectives. AB - Many studies over the past two decades have shown that people can use brain signals to convey their intent to a computer using brain-computer interfaces (BCIs). BCI systems extract specific features of brain activity and translate them into control signals that drive an output. Recently, a category of BCIs that are built on the rhythmic activity recorded over the sensorimotor cortex, i.e., the sensorimotor rhythm (SMR), has attracted considerable attention among the BCIs that use noninvasive neural recordings, e.g., electroencephalography (EEG), and have demonstrated the capability of multidimensional prosthesis control. This paper reviews the current state and future perspectives of SMR-based BCI and its clinical applications, in particular focusing on the EEG SMR. The characteristic features of SMR from the human brain are described and their underlying neural sources are discussed. The functional components of SMR-based BCI, together with its current clinical applications, are reviewed. Finally, limitations of SMR-BCIs and future outlooks are also discussed. PMID- 24759279 TI - A shocking past: a walk through generations of defibrillation development. AB - Defibrillation is one of the most successful and widely recognized applications of electrotherapy. Yet the historical road to its first successful application in a patient and the innovative adaptation to an implantable device is marred with unexpected turns, political and personal setbacks, and public and scientific condemnation at each new idea. Driven by dedicated scientists and ever-advancing creative applications of new technologies, from electrocardiography to high density mapping and computational simulations, the field of defibrillation persevered and continued to evolve to the life-saving tool it is today. In addition to critical technological advances, the history of defibrillation is also marked by the plasticity of the theory of defibrillation. The advancing theories of success have propelled the campaign for reducing the defibrillation energy requirement, instilling hope in the development of a painless and harmless electrical defibrillation strategy. PMID- 24759280 TI - Hydrogels as carriers for stem cell transplantation. AB - Stem cells are a promising source for cell replacement therapy for several degenerative conditions. However, a number of limitations such as low cell survival, uncontrolled and/or low differentiation, induction of host immune response, and the risk of teratoma formation remain as challenges. In this review, we explore the utility of hydrogels as carriers for stem cell delivery and their potential to overcome some of the current limitations in stem cell therapy. We focus on in situ gelling hydrogels, and also discuss other strategies to modulate the immune response to promote controlled stem cell differentiation. Immunomodulatory hydrogels and gels designed to promote cell survival and integration into the host site will likely have a significant effect on enhancing the efficacy of stem cell transplantation as a therapy for debilitating degenerative diseases. PMID- 24759283 TI - Unobtrusive sensing and wearable devices for health informatics. AB - The aging population, prevalence of chronic diseases, and outbreaks of infectious diseases are some of the major challenges of our present-day society. To address these unmet healthcare needs, especially for the early prediction and treatment of major diseases, health informatics, which deals with the acquisition, transmission, processing, storage, retrieval, and use of health information, has emerged as an active area of interdisciplinary research. In particular, acquisition of health-related information by unobtrusive sensing and wearable technologies is considered as a cornerstone in health informatics. Sensors can be weaved or integrated into clothing, accessories, and the living environment, such that health information can be acquired seamlessly and pervasively in daily living. Sensors can even be designed as stick-on electronic tattoos or directly printed onto human skin to enable long-term health monitoring. This paper aims to provide an overview of four emerging unobtrusive and wearable technologies, which are essential to the realization of pervasive health information acquisition, including: (1) unobtrusive sensing methods, (2) smart textile technology, (3) flexible-stretchable-printable electronics, and (4) sensor fusion, and then to identify some future directions of research. PMID- 24759282 TI - Integrated circuits and electrode interfaces for noninvasive physiological monitoring. AB - This paper presents an overview of the fundamentals and state of the-art in noninvasive physiological monitoring instrumentation with a focus on electrode and optrode interfaces to the body, and micropower-integrated circuit design for unobtrusive wearable applications. Since the electrode/optrode-body interface is a performance limiting factor in noninvasive monitoring systems, practical interface configurations are offered for biopotential acquisition, electrode tissue impedance measurement, and optical biosignal sensing. A systematic approach to instrumentation amplifier (IA) design using CMOS transistors operating in weak inversion is shown to offer high energy and noise efficiency. Practical methodologies to obviate 1/f noise, counteract electrode offset drift, improve common-mode rejection ratio, and obtain subhertz high-pass cutoff are illustrated with a survey of the state-of-the-art IAs. Furthermore, fundamental principles and state-of-the-art technologies for electrode-tissue impedance measurement, photoplethysmography, functional near-infrared spectroscopy, and signal coding and quantization are reviewed, with additional guidelines for overall power management including wireless transmission. Examples are presented of practical dry-contact and noncontact cardiac, respiratory, muscle and brain monitoring systems, and their clinical applications. PMID- 24759284 TI - A review of multitaper spectral analysis. AB - Nonparametric spectral estimation is a widely used technique in many applications ranging from radar and seismic data analysis to electroencephalography (EEG) and speech processing. Among the techniques that are used to estimate the spectral representation of a system based on finite observations, multitaper spectral estimation has many important optimality properties, but is not as widely used as it possibly could be. We give a brief overview of the standard nonparametric spectral estimation theory and the multitaper spectral estimation, and give two examples from EEG analyses of anesthesia and sleep. PMID- 24759281 TI - Toward integrated molecular diagnostic system (i MDx): principles and applications. AB - Integrated molecular diagnostic systems ( iMDx), which are automated, sensitive, specific, user-friendly, robust, rapid, easy-to-use, and portable, can revolutionize future medicine. This review will first focus on the components of sample extraction, preservation, and filtration necessary for all point-of-care devices to include for practical use. Subsequently, we will look for low-powered and precise methods for both sample amplification and signal transduction, going in-depth to the details behind their principles. The final field of total device integration and its application to the clinical field will also be addressed to discuss the practicality for future patient care. We envision that microfluidic systems hold the potential to breakthrough the number of problems brought into the field of medical diagnosis today. PMID- 24759285 TI - Advancing our understanding of the glucose system via modeling: a perspective. AB - The glucose story begins with Claude Bernard's discovery of glycogen and milieu interieur, continued with Banting's and Best's discovery of insulin and with Rudolf Schoenheimer's paradigm of dynamic body constituents. Tracers and compartmental models allowed moving to the first quantitative pictures of the system and stimulated important developments in terms of modeling methodology. Three classes of multiscale models, models to measure, models to simulate, and models to control the glucose system, are reviewed in their historical development with an eye to the future. PMID- 24759286 TI - Dissecting heart failure through the multiscale approach of systems medicine. AB - Heart failure (HF) is a complex syndrome which can be the exit of different etiologies which lead to a common clinical picture. Treatment outcome is modest and new insights into pathophysiology are needed to improve effectively diagnosis, prognosis, and therapy. As a complex disease, it can really benefit from the new approach provided by molecular medicine where information about the cell program can deeply change the patient management. The comprehension of molecular mechanisms relies on new technologies which are able to provide data at the different levels of the cell workflow. A proper processing of these data is as essential as the generation of data itself, together with an integrative approach able to exploit observations at different scales, starting from the molecular levels up to an effective assessment of phenotype with cardiovascular and systemic parameters. In this paper, evidences concerning current understanding of HF, passing from one scale to another, are reported, to underline how functional genomics and systems biology perspective, fostered by the combination of biotechnologies and bioinformatic methods, may transform the concepts of diagnosis and, consequently, of treatment, toward the fulfillment of the invoked patient-specific medicine. PMID- 24759287 TI - Integration: the firm and the health care sector. AB - Integration in health care is a key goal of health reform in United States and England. Yet past efforts in the 1990s to better integrate the delivery system were of limited success. Building on work by Bevan and Janus on delivery integration, this article explores integration through the lens of economic theories of integration. Firms generally integrate to increase efficiency through economies of scale, to improve their market power, and resolve the transaction costs involved with multiple external suppliers. Using the United States and England as laboratories, we apply concepts of economic integration to understand why integration does or does not occur in health care, and whether expectations of integrating different kinds of providers (hospital, primary care) and health and social services are realistic. Current enthusiasm for a more integrated health care system expands the scope of integration to include social services in England, but retains the focus on health care in the United States. We find mixed applicability of economic theories of integration. Economies of scale have not played a significant role in stimulating integration in both countries. Managerial incentives for monopoly or oligopoly may be more compelling in the United States, since hospitals seek higher prices and more leverage over payers. In both countries the concept of transaction costs could explain the success of new payment and budgeting methods, since health care integration ultimately requires resolving transaction costs across different delivery organizations. PMID- 24759288 TI - Spin-correlations and magnetic structure in an Fe monolayer on 5d transition metal surfaces. AB - We present a detailed first principles study on the magnetic structure of an Fe monolayer on different surfaces of 5d transition metals. We use the spin-cluster expansion technique to obtain parameters of a spin model, and predict the possible magnetic ground state of the studied systems by employing the mean field approach and, in certain cases, by spin dynamics calculations. We point out that the number of shells considered for the isotropic exchange interactions plays a crucial role in the determination of the magnetic ground state. In the case of Ta substrate we demonstrate that the out-of-plane relaxation of the Fe monolayer causes a transition from ferromagnetic to antiferromagnetic ground state. We examine the relative magnitude of nearest neighbour Dzyaloshinskii-Moriya (D) and isotropic (J) exchange interactions in order to get insight into the nature of magnetic pattern formations. For the Fe/Os(0 0 0 1) system we calculate a very large D/J ratio, correspondingly, a spin spiral ground state. We find that, mainly through the leading isotropic exchange and Dzyaloshinskii-Moriya interactions, the inward layer relaxation substantially influences the magnetic ordering of the Fe monolayer. For the Fe/Re(0 0 0 1) system characterized by large antiferromagnetic interactions we also determine the chirality of the 120 degrees Neel-type ground state. PMID- 24759289 TI - Congenital respiratory epithelial cysts of the orbit: a rare cause of major orbital impairment. AB - Congenital respiratory epithelial cysts of the orbit are rare lesions with few reported cases. Extensive disease may cause an orbital apex syndrome, resulting in significant visual loss. Two such cases were described, the risk factors associated with surgical morbidity were identified, and the embryological origins of these cysts were reviewed. PMID- 24759290 TI - Transcranial orbital decompression for progressive compressive optic neuropathy after 3-wall decompression in severe graves' orbitopathy. AB - PURPOSE: To determine surgical outcomes after transcranial decompression of the superior orbit in patients with progressive compressive optic neuropathy (CON) secondary to Graves' orbitopathy (GO) who had previously been treated with 3-wall decompression. METHODS: Approval from the West Virginia University Institution Review Board was obtained. A retrospective review of 4 patients with GO who received bilateral transcranial decompression of the orbits for progressive compressive optic neuropathy after bilateral maximal extracranial 3-wall decompression was performed. The patients were treated by the Multidisciplinary Orbit and Skull Base Services at West Virginia University and the University of Michigan. RESULTS: Bilateral transcranial decompression of the orbit for GO was performed on 8 orbits in 4 patients. All 8 orbits had radiographic evidence of compression of the orbital apex, and all patients had been treated with steroids, orbital radiation, and bilateral 3-wall decompression. Preoperative vision ranged from 20/25 to 20/100, which improved to 20/25 or better in all eyes. The visual field mean deviation improved from a mean of -13.05 to -1.67 dB. Hertel measurements improved from a mean of 19.25 to 15.25 mm. Extraocular motility was essentially unchanged. Two patients were noted to have asymptomatic ocular pulsations. There were no other complications, and all patients remained stable during a follow-up period of 5 years (range 2-8 years). CONCLUSIONS: Transcranial decompression is an effective and safe method of salvaging vision when standard treatments fail. This is only the second report of transcranial decompression for refractory compressive optic neuropathy after decompression from a standard approach. PMID- 24759291 TI - Lacrimal sac movement under intrasac pressure changes observed with dacryoendoscopy. AB - PURPOSE: To examine movement of the intrasac cavity under intrasac pressure changes with dacryoendoscopy. METHODS: The authors examined 10 lacrimal sacs (3 right and 7 left) without lacrimal tract obstruction in 10 Japanese patients (3 men and 7 women) aged 35 to 86 years (average, 62.8 years). These were the contralateral sides of the sides with nasolacrimal duct obstruction that were treated with dacryocystorhinostomy. After enlarging a superior lacrimal punctum, a dacryoendoscope (FT-203F; FiberTech) was inserted. When the tip of the dacryoendoscope passed through the common internal ostium, the handgrip was rotated 90 degrees superiorly to face the tip inferiorly. Water was poured into the cavity throughout this process via the water channel of the dacryoendoscope. Then, with the water poured or suctioned from the same channel, namely causing positive or negative pressure changes in the intrasac cavity, movement of the lacrimal sac wall was examined with dacryoendoscopy. RESULTS: The lateral wall of the lacrimal sac moved with pressure changes fairly flexibly. Under positive pressure, the wall moved outward, but it moved inward under negative pressure. CONCLUSIONS: The present study demonstrated movement of the lacrimal sac wall with intrasac pressure changes, which was suggestive of its contribution to lacrimal drainage of the sac. PMID- 24759292 TI - Supramaximal levator resection for unilateral congenital ptosis: cosmetic and functional results. AB - PURPOSE: To analyze the cosmetic and functional results of a large series of patients with unilateral congenital ptosis without spontaneous compensatory ipsilateral frontalis hyperaction who underwent supramaximal levator resection (SMLPSr). METHODS: A multicenter retrospective review of 35 children (14 girls and 21 boys) of mean age 5.5+/-3.6 SD years with unilateral congenital ptosis who underwent surgery in 3 different countries: Italy, n=8; Argentina, n=11; and Brazil, n=16. Preoperative evaluation included measurements of upper eyelid margin reflex distance (MRD1) and levator palpebrae superioris muscle excursion, assessment of frontalis hyperaction, and ocular motility examination. At least 6 months postoperatively, photographs were used to measure the upper eyelid contour of OU. The spontaneous blinking amplitude and downward eyelid saccades of OU were quantified in a subset of 14 patients. Quantitative comparison among the 3 centers was performed with nonparametric 1-way analysis of variance (Kruskal Wallis). Paired t tests were used to compare the pre- and postoperative measurements, and p value<0.05 was statistically significant. RESULTS: The mean preoperative MRD1 of the operated eyes increased from 0.5+/-1.1 SD mm to 3.4+/ 0.84 SD mm (t=15.9; p<0.000001), consequently the eyelid positional asymmetry decreased from 3.1+/-1.21 mm to 0.1+/-0.86 SD mm (t=16.5; p<=0.000001). Twenty nine percent of eyelids had mild contour abnormalities and 31.4% showed some degree of lash ptosis. Spontaneous blinks were abnormal in 93% of the cases (eyelids). The amplitude of the abnormal blinks ranged from 12.9% to 65.4% (mean=37.1%) of the contralateral eyelids. Downward eyelid saccades were reduced in 79% of the eyelids. The amplitudes the saccades ranged from 2.2% to 84.6% (mean=54.8%). CONCLUSIONS: In unilateral congenital ptosis, SMLPSr effectively reduces the positional asymmetry between eyelids. Mild contour abnormalities and lash ptosis are the main complications of the surgery. Postoperatively, spontaneous blinks and downward saccades were reduced in most eyelids. The reduced postoperative eyelid kinetics indicates that only patients with normal upward Bell signs are good candidates for this procedure. PMID- 24759293 TI - Conjugated estrogens/bazedoxifene (Duavee) for menopausal symptoms and prevention of osteoporosis. PMID- 24759294 TI - Tasimelteon (Hetlioz) for non-24-hour sleep-wake disorder. PMID- 24759295 TI - In brief: enteric-coated aspirin as an antiplatelet drug. PMID- 24759297 TI - Initial experience of a rapid-insertion bone-anchored hearing system: series of 20 consecutive implants. AB - Objective: The loading of bone-anchored hearing system sound processors usually occurs two to three months after surgical implant. This study examined a new bone anchored hearing system coupling mechanism that permits loading at two weeks post implantation without compromising osseointegration. Methods: Twenty implants were implanted into 15 patients. The interval between operation and time of processor loading was recorded, along with the cause of any delay and any late complications. Results: Two patients were fitted with implants at seven and nine weeks. The delay was a result of administrative errors; the patients reported no skin problems. Of the remaining 17 implants, 8 processors were fitted at 2 weeks, 1 at 3 weeks, 4 at 4 weeks, 3 at 7 weeks and 1 at 8 weeks. For those nine implants fitted later than two weeks, the delay was because of incomplete skin healing. Conclusion: The Oticon Medical Xpress system allowed processor loading at two weeks post-operatively, providing skin healing was adequate. Early loading occurred in approximately half of the patients. All patients were fitted within the two to three months traditionally allowed. Prolonged skin healing time was the main reason for the delayed fitting of sound processors. PMID- 24759298 TI - In vitro effects of l-carnitine and glutamine on motility, acrosomal abnormality, and plasma membrane integrity of rabbit sperm during liquid-storage. AB - This study was designed to evaluate the in vitro effects of l-carnitine and glutamine (Gln) on the sperm quality parameters of liquid-stored rabbit semen maintained up to 24 h at 5 degrees C. Pooled and extended ejaculates were divided into two equal portions. l-Carnitine doses of 0.5, 1 and 2mM were added to the first portion, and glutamine was added at the same doses to the second portion. All samples were cooled to 5 degrees C and examined at 0, 6, 12 and 24 h of liquid storage. Supplementation of the semen extender with three different doses of l-carnitine provided significant increases in the percentage of motile sperm at 12 h (P<0.01), and 24h (P<0.001) and enabled significant protection of the sperm plasma membrane (P<0.01) at 12 and 24h of cool-storage, in comparison to the control samples. Only the 2mM dose of l-carnitine significantly (P<0.01) decreased the rate of acrosomal damage when compared to the control group. Furthermore, all doses of Gln caused a significant (P<0.01) decrease in acrosomal damage at 6h, and provided significant improvement (P<0.01) in sperm motility, acrosomal and plasma membrane integrities at 12 and 24h of liquid storage, when compared to the controls. In conclusion, the supplementation of liquid-stored rabbit semen with l-carnitine and Gln provided a protection for sperm against cool storage-induced functional and structural damages. PMID- 24759299 TI - Cryopreservation of hMSCs seeded silk nanofibers based tissue engineered constructs. AB - Long term cryopreservation of tissue engineering constructs is of paramount importance to meet off-the shelf requirements for medical applications. In the present study, the effect of cryopreservation using natural osmolytes such as trehalose and ectoin with and without conventional Me2SO on the cryopreservation of tissue engineered constructs (TECs) was evaluated. MSCs derived from umbilical cord were seeded on electrospun nanofibrous silk fibroin scaffolds and cultured to develop TECs. TECs were subjected to controlled rate freezing using nine different freezing solutions. Among these, freezing medium consisting of natural osmolytes like trehalose (40mM), ectoin (40mM), catalase (100MUg) as antioxidant and Me2SO (2.5%) was found to be the most effective. Optimality of the chosen cryoprotectants was confirmed by cell viability (PI live/dead staining), cell proliferation (MTT assay), microstructure analysis (SEM), membrane integrity (confocal microscopy) and in vitro osteogenic differentiation (ALP assay, RT-PCR and histology) study carried out with post-thaw cryopreserved TECs. The mechanical integrity of the cryopreserved scaffold was found to be unaltered. The performance of the freezing medium towards cryopreservation of TEC was superior than the performance achieved using conventional Me2SO and similar to the non cryopreserved TEC. Overall we have formulated an efficient freezing medium that may pave the way of long term preservation of TECs with maintaining its integrity, MSCs viability and differentiation potentiality. It was observed that the performance of freezing medium for cryopreservation of TECs was better than the Me2SO. PMID- 24759300 TI - Estimation of 24-hour urine phosphate excretion from spot urine collection: development of a predictive equation. AB - BACKGROUND: The management of hyperphosphatemia in patients with moderate to severe chronic kidney disease (CKD) includes dietary phosphate restriction and/or prescription of phosphate binders. Measuring phosphate intake in CKD is important for monitoring dietary adherence and for the effectiveness of therapeutic interventions. The 24-hour urine collection is the gold standard method for determining phosphate intake; however, timed urine collections are cumbersome and prone to error. We investigated the precision and accuracy of spot urine phosphate measurements, compared to 24-hour urine phosphate (24hUrP) collection. STUDY DESIGN, SETTING, AND PARTICIPANTS: We evaluated simultaneous spot and 24hUrP measurements, collected on multiple occasions, from 143 participants in the Phosphate Normalization Trial, a randomized trial of phosphate binders versus placebo among persons with an estimated glomerular filtration rate between 20-45 mL/minute per 1.73 m2. We used residual analyses and graphical methods to model the functional relationship of spot urine phosphate and creatinine measurements with 24hUrP. We used multiple linear regression to test whether additional covariates improved model prediction, including treatment assignment, age, sex, height, weight, urine collection time, and last meal time. We internally validated results using leave-one-out cross-validation, and externally validated in an independent replication cohort. RESULTS: A log-log relation between the spot urine phosphate-to-creatinine ratio and 24hUrP excretion yielded the best model fit. In addition to spot urine phosphate and creatinine concentrations, inclusion of age, sex, and weight significantly improved prediction of 24hUrP. Compared with a spot urine phosphate-to-creatinine ratio alone (r2 = 0.12, P < .001), the new equation more accurately predicted 24hUrP (leave-one-out validation r2 = 0.43, P < .001, independent validation r2 = 0.39, P < .001). CONCLUSION: We describe a novel equation to predict 24hUrP excretion using spot urine phosphate and creatinine, age, sex, and weight. The equation is more accurate and precise than the urine phosphate-to-creatinine ratio alone, and it provides a simple method for estimating 24hUrP excretion in patients with nondialysis-requiring CKD. PMID- 24759301 TI - The beneficial effects of weight reduction in overweight patients with chronic proteinuric immunoglobulin a nephropathy: a randomized controlled trial. AB - OBJECTIVE: This study was conducted to examine the effects of weight reduction on proteinuria, adipokines, and renal function in overweight immunoglobulin A nephropathy (IgAN) patients (body mass index > 23 kg/m2) with chronic proteinuria more than 6 months. DESIGN: This was a single-center, prospective, randomized controlled trial. The study was performed at the outpatient clinic at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, from July 2012 to February 2013. SUBJECTS: Twenty-six overweight patients with chronic proteinuric biopsy proven IgAN were randomized into a control group (n = 13) or a low-calorie normal protein diet group (n = 13). All patients received the maximum dosage of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and other antihypertensive agents to achieve a blood pressure less than 125/75 mmHg. INTERVENTION: The study intervention was a low-calorie diet (target energy per day as 500-kcal subtraction from total energy requirement) for a 6-month period. MAIN OUTCOME MEASURE: At baseline and after 6 months of a low-calorie diet, body weight, body content, and clinical and laboratory parameters were determined and compared. RESULTS: After initiating a low-calorie diet for 6 months, the normalized protein nitrogen appearance values were not different, indicating comparable protein intake. The low-calorie group had lower total daily calorie intake (1,307.1 +/- 171.8 vs. 1,772.2 +/- 315.4 kcal/d, P < .01) and significant reductions in body weight (-5.1 +/- 3.3%, P < .001), fat content (-12.7 +/- 14.1%, P < .05), and 24-hour urine protein (-45.2 +/- 15.4%, P < .001). Blood pressure and renal function parameters were unaltered. The low-calorie group had approximately 20% lower plasma levels of leptin but unchanged adiponectin. There were positive correlations between the amount of protein reduction and the changes of body weight, fat mass, and leptin. CONCLUSIONS: A 6-month low-calorie diet leads to weight reduction and results in diminished fat content and decreased proteinuria in overweight IgAN patients with chronic proteinuria. This beneficial effect might be mediated by changes in adipokines. PMID- 24759302 TI - Patient education. MyPlate for healthy eating with chronic kidney disease (MyPlate education for patients with chronic kidney disease receiving hemodialysis and peritoneal dialysis treatment). PMID- 24759303 TI - Efficient single-mode photon-coupling device utilizing a nanofiber tip. AB - Single-photon sources are important elements in quantum optics and quantum information science. It is crucial that such sources be able to couple photons emitted from a single quantum emitter to a single propagating mode, preferably to the guided mode of a single-mode optical fiber, with high efficiency. Various photonic devices have been successfully demonstrated to efficiently couple photons from an emitter to a single mode of a cavity or a waveguide. However, efficient coupling of these devices to optical fibers is sometimes challenging. Here we show that up to 38% of photons from an emitter can be directly coupled to a single-mode optical fiber by utilizing the flat tip of a silica nanofiber. With the aid of a metallic mirror, the efficiency can be increased to 76%. The use of a silicon waveguide further increases the efficiency to 87%. This simple device can be applied to various quantum emitters. PMID- 24759304 TI - Understanding weekly cycles in suicide: an analysis of Austrian and Swiss data over 40 years. AB - BACKGROUND: Seasonal as well as weekly cycles in suicide have been described, replicated and poorly understood for a long time. In Western countries, suicides are typically least frequent on weekends and most frequent on Mondays and Tuesdays. To improve understanding of this phenomenon a strategy is required which focuses on anomalous findings beyond the regular patterns. Here, we focused on instances where the weekly suicide patterns disappear or are interrupted. METHODS: We used data from Swiss and Austrian mortality statistics for the periods 1969-2010 and 1970-2010, respectively. First, the data were cross tabulated by days of the week and the available socio-demographic information (sex, age, religious affiliation and region). Second, time series of cumulated daily frequencies of suicide were analysed by seasonal Autoregressive Integrated Moving Average (ARIMA) models which included intervention effects accounting for Easter and Pentecost (Whit) holidays. RESULTS: First, the cross tabulations showed that weekly cycles may be smoothed above all in young persons and smoothed in drowning, jumping and car gas exhaustion suicides. Second, the ARIMA analyses displayed occasional preventive effects for holidays Saturdays and Sundays, and more systematic effects for holiday Mondays. There were no after effects on Tuesdays following holiday Mondays. CONCLUSIONS: In general, the weekend dip and the Monday backlog effect in suicide show striking similarities to the Advent season effect and are interpretable within the same template. The turning points between low and high frequencies possibly provide promising frames for the timing of prevention activities. PMID- 24759306 TI - Special issue in perinatal and pediatric bereavement. PMID- 24759307 TI - Should parents and families of stillborn babies be encouraged to see, hold, and have funerals for the babies? PMID- 24759312 TI - Impact of a pediatric quality of life program on providers' moral distress. AB - PURPOSE: To evaluate the impact of the introduction of a new pediatric palliative care program on the pattern of moral distress in pediatric healthcare providers (HCPs). STUDY DESIGN AND METHODS: We used a before and after cross-sectional survey design to study the impact of the Pediatric Quality of Life (QoL) Program on the moral distress of pediatric HCPs at a single center. Moral distress is measured in both intensity and frequency. The sample came from lists of all pediatric providers (nurses, physicians, social workers, therapists, dieticians, chaplains, administrators) serving the inpatient and outpatient pediatric areas of a southeastern academic tertiary medical center. RESULTS: The intensity of moral distress from situations focused on "individual responsibility" and "not in the best interest of the patient" were similar before and after program implementation, but the intensity of distress related to "work quality of life" decreased after program implementation. Situations causing moral distress when the "care given was not in the patient's best interest" occurred less frequently after program implementation. Providers disagreed with statements that "work related distress" impacted their personal or professional life. The number of providers who were considering leaving the institution within 6 months decreased following program implementation. CLINICAL IMPLICATIONS: After implementation of the Pediatric QoL Program, nurses and other providers encountered morally distressing situations less often. Providers also answered that they had greater comfort with and competence in providing care focused on patients' quality of life after completing the program. As palliative care programs include many activities that reduce moral distress, nurses should actively take advantage of participation in debriefing sessions and staff education to maximize their work quality of life. PMID- 24759313 TI - Combining regional expertise to form a bereavement support alliance. AB - Providing compassionate bereavement care for families experiencing perinatal loss is a standard of care in most healthcare organizations. In this article, we describe the development of The Alliance of Perinatal Bereavement Support Facilitators, begun over 25 years ago in Chicago by staff who identified the need to reach out to colleagues at other area institutions for advice and support in this work. This collaboration created a regional support network that has resulted in a long-lasting, active, sustainable organization of excellence focused on enhancing practice, education, and perinatal bereavement care. Alliance activities center around four main areas: education, networking/support, policy, and recognizing outstanding service to families. By continuing to draw upon the collective talent, wisdom, and expertise of its members, The Alliance still serves grieving families and provides mentoring for future interdisciplinary team members engaged in this work. The path taken to build this organization can be used by professionals in other specialties who are looking to create their own alliance infrastructure based on mutual benefit and interest. PMID- 24759314 TI - Nutritional considerations during bereavement. PMID- 24759315 TI - Online obituaries and memorials. PMID- 24759316 TI - Global perspectives on perinatal loss. PMID- 24759318 TI - Managing an indeterminate (category II) fetal heart rate tracing during labor. PMID- 24759319 TI - Opioids and cancer recurrence. AB - PURPOSE OF REVIEW: With the majority of deaths from cancer because of their metastases, strategies to reduce this from occurring are at the forefront of treatment. It has been hypothesized that morphine may result in an increase in cancer metastases, following many in-vitro and animal studies, but the evidence from human retrospective data is inconclusive. This article will explore the possible mechanisms by which opioids can impact on the natural history of the cancer cell and whether they are likely to be harmful in individuals with cancer. RECENT FINDINGS: Although there have been trials demonstrating benefits with regional anaesthesia techniques (opioid sparing) in the surgical population, it is not clear whether the source of the benefit arises directly from the avoidance of opioids or an added benefit afforded by regional anaesthesia. Research has shown that in particular cancer cell types, morphine may actually be beneficial and that the MU-opioid receptor (MOR) plays a role in cancer disease. With the crystal structure of the MOR having recently been elucidated, this may offer new opportunities for treatments aimed at reducing cancer metastasis. SUMMARY: The role opioids play in the development of cancer metastasis and recurrence is far from clear and appears to differ depending on the cancer cell type in question. Prospective randomized controlled trials are currently underway in humans to help clarify the situation further and there results are awaited with anticipation. The negative impact of pain on the immune system is well documented and it appears that appropriate analgesia is paramount in minimizing this. Opioids still constitute a central role in the management of moderate-to-severe cancer pain. PMID- 24759320 TI - Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. AB - Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. PMID- 24759322 TI - Elevated CO2 further lengthens growing season under warming conditions. AB - Observations of a longer growing season through earlier plant growth in temperate to polar regions have been thought to be a response to climate warming. However, data from experimental warming studies indicate that many species that initiate leaf growth and flowering earlier also reach seed maturation and senesce earlier, shortening their active and reproductive periods. A conceptual model to explain this apparent contradiction, and an analysis of the effect of elevated CO2--which can delay annual life cycle events--on changing season length, have not been tested. Here we show that experimental warming in a temperate grassland led to a longer growing season through earlier leaf emergence by the first species to leaf, often a grass, and constant or delayed senescence by other species that were the last to senesce, supporting the conceptual model. Elevated CO2 further extended growing, but not reproductive, season length in the warmed grassland by conserving water, which enabled most species to remain active longer. Our results suggest that a longer growing season, especially in years or biomes where water is a limiting factor, is not due to warming alone, but also to higher atmospheric CO2 concentrations that extend the active period of plant annual life cycles. PMID- 24759323 TI - Ecology: drought in the congo basin. PMID- 24759325 TI - Factor structure of the Chinese version of the Pittsburgh sleep quality index in breast cancer patients. AB - OBJECTIVE: The Pittsburgh Sleep Quality Index (PSQI) is used extensively to assess subjective sleep disturbance in cancer populations. Although previous studies on the PSQI suggested a better fit for a two- or three-factor model than the original one-factor model, none accounted for the indicator-specific effect between sleep duration and habitual sleep efficiency. This study evaluated the PSQI's dimensionality and its convergent validity with cancer-related psychopathological states in female breast cancer patients. METHODS: The PSQI was administered to 197 women with breast cancer. Confirmatory factor analysis examined the relative fit of one-, two-, three-, and revised one-factor models. The PSQI's convergent validity was evaluated via bivariate correlations between the PSQI factor scores and measures of anxiety, depression, fatigue, pain, and quality of life. RESULTS: Confirmatory factor analyses showed an adequate fit for the revised one-factor model with the PSQI global score as the overall index of sleep disturbance. Although the revised one- and two-factor solutions showed statistically equivalent model fits, the one-factor model was selected due to utility reasons. The severity of sleep dysfunction that the PSQI global score represented was positively correlated with anxiety, depression, fatigue, pain, and reduced quality of life. CONCLUSION: The results support the PSQI's original unidimensional structure, demonstrating that the PSQI global score is a valid and parsimonious measure for assessing and screening sleep dysfunction in cancer patients. PMID- 24759324 TI - Widespread decline of Congo rainforest greenness in the past decade. AB - Tropical forests are global epicentres of biodiversity and important modulators of climate change, and are mainly constrained by rainfall patterns. The severe short-term droughts that occurred recently in Amazonia have drawn attention to the vulnerability of tropical forests to climatic disturbances. The central African rainforests, the second-largest on Earth, have experienced a long-term drying trend whose impacts on vegetation dynamics remain mostly unknown because in situ observations are very limited. The Congolese forest, with its drier conditions and higher percentage of semi-evergreen trees, may be more tolerant to short-term rainfall reduction than are wetter tropical forests, but for a long term drought there may be critical thresholds of water availability below which higher-biomass, closed-canopy forests transition to more open, lower-biomass forests. Here we present observational evidence for a widespread decline in forest greenness over the past decade based on analyses of satellite data (optical, thermal, microwave and gravity) from several independent sensors over the Congo basin. This decline in vegetation greenness, particularly in the northern Congolese forest, is generally consistent with decreases in rainfall, terrestrial water storage, water content in aboveground woody and leaf biomass, and the canopy backscatter anomaly caused by changes in structure and moisture in upper forest layers. It is also consistent with increases in photosynthetically active radiation and land surface temperature. These multiple lines of evidence indicate that this large-scale vegetation browning, or loss of photosynthetic capacity, may be partially attributable to the long-term drying trend. Our results suggest that a continued gradual decline of photosynthetic capacity and moisture content driven by the persistent drying trend could alter the composition and structure of the Congolese forest to favour the spread of drought tolerant species. PMID- 24759321 TI - Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation. AB - The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing gammadelta T (gammadeltaT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23 dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL 23-dependent inflammatory cytokines by dermal gammadeltaT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses. PMID- 24759327 TI - Biocompatibility of antimicrobial melimine lenses: rabbit and human studies. AB - PURPOSE: Covalent immobilization of antimicrobial peptide melimine onto contact lenses can produce broad-spectrum antimicrobial lenses. The purpose of this study was to investigate the performance of melimine-coated contact lenses in an animal model and human clinical trial. METHODS: Melimine was covalently attached onto the surface of contact lenses via EDC (1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride) coupling. A rabbit model of daily contralateral wear of lenses for 22 days was conducted to assess the lens safety. A prospective, randomized, double-masked, one-day human clinical trial was used to evaluate subjective responses and ocular physiology during contralateral wear of melimine coated (test) and uncoated (control) lenses. Delayed reactions were monitored during follow-up visits after 1 and 4 weeks. Ex vivo retention of antimicrobial activity of worn lenses was assessed by reduction in numbers of viable Pseudomonas aeruginosa and Staphylococcus aureus. RESULTS: Melimine-coated lenses produced no ocular signs or symptoms that would indicate cytotoxicity during the lens wear of rabbits. No histological changes were found in rabbit corneas. During the human trial, no differences were observed in wettability, surface deposition, lens-fitting centration, movement, tightness, and corneal coverage between test and control lenses (p > 0.05). There were no significant differences in bulbar, limbal, or palpebral redness or conjunctival staining (p > 0.05). Mean corneal (extent, depth, and type) staining was higher for test lenses compared with that for control lenses (p < 0.05). There was no significant difference in subjective responses for lens comfort, dryness, and awareness (p > 0.05). No delayed reactions were associated with the test lenses. Worn test lenses retained more than 1.5 log inhibition against both bacterial types. CONCLUSIONS: Melimine coated contact lenses were worn safely by humans. However, they were associated with higher corneal staining. The melimine-coated lenses retained high antibacterial activity after wear. PMID- 24759329 TI - Development: Germ plasm 'fuels' vertebrate evolution. PMID- 24759330 TI - Microbial genetics: Amplified origins of antibiotic resistance. PMID- 24759331 TI - Distribution of lifetimes of kinetochore-microtubule attachments: interplay of energy landscape, molecular motors and microtubule (de-)polymerization. AB - Before a cell divides into two daughter cells, chromosomes are replicated resulting in two sister chromosomes embracing each other. Each sister chromosome is bound to a separate proteinous structure, called kinetochore (kt), that captures the tip of a filamentous protein, called microtubule (MT). Two oppositely oriented MTs pull the two kts attached to two sister chromosomes, thereby pulling the two sisters away from each other. Here we theoretically study an even simpler system, namely an isolated kt coupled to a single MT; this system mimics an in vitro experiment where a single kt-MT attachment is reconstituted using purified extracts from budding yeast. Our models not only account for the experimentally observed 'catch-bond-like' behavior of the kt-MT coupling, but also make new predictions on the probability distribution of the lifetimes of the attachments. In principle, our new predictions can be tested by analyzing the data collected in the in vitro experiments, provided that the experiment is repeated a sufficiently large number of times. Our theory provides a deep insight into the effects of (a) size, (b) energetics, and (c) stochastic kinetics of the kt-MT coupling on the distribution of the lifetimes of these attachments. PMID- 24759333 TI - Ultrasound scanning in the post-operative assessment of flexor tendon repairs: A useful tool in the hand clinic. PMID- 24759334 TI - The impact of hepatitis B on heart transplantation: 19 years of national experience in Korea. AB - BACKGROUND: Hepatitis B virus (HBV) infection is endemic in Korea. With an increasing number of heart transplantation, problems associated with hepatitis B reactivation are becoming an important issue. We aimed to evaluate the functional significance of HBV infection on outcomes of heart transplantation. MATERIAL AND METHODS: We reviewed all medical records of overall national heart transplantation recipients and donors who had HBV hepatitis at the time of the transplantation, from March 1994 to May 2013. We investigated the HBV serology status, HBV-DNA level of donors and recipients, liver function test, immunosuppressive agent and antiviral agent prescription, and hepatitis morbidity and mortality. RESULTS: 1) There were 12 HBsAg (+) recipients and 6 HBsAg (+) donors. Median duration of follow-up was 1715 days (minimum 162 days to maximum 6553 days). 2) Nine HBsAg (+) recipients (75%), who continued antiviral treatment, have survived without any hepatic event. Reactivation of HBV developed in 3 recipients at a median duration of 238 days after transplantation. They died of fulminant hepatitis despite antiviral rescue therapy. 3) In contrast, 6 recipients with immunity to HBV before the transplantation, who had received heart from HBV (+) donors, have survived without any liver-related event. CONCLUSIONS: HBV (+) recipients have perioperative results and long-term survival rates comparable to HBV (-) recipients. However, absence or cessation of antiviral prophylaxis indiscriminately brought reactivation of HBV, which rapidly progressed to hepatic failure and death. In contrast, HBV (+) hearts transplanted to HBV-immune recipients were maintained without hepatitis reactivation. Nineteen years of national experience strongly suggests that long-term antiviral prophylaxis is necessary for HBV (+) recipients. PMID- 24759335 TI - Abdominal pain in hypertriglyceridemia. PMID- 24759336 TI - Conservative management of razor blade ingestion. AB - A 30-year-old woman presented to the emergency department complaining of abdominal discomfort. An abdominal radiograph was done, revealing ten rectangular razor blades measuring 5 * 2 cm. The patient was taken to the operating room and a flexible esophago-gastroduodenoscopy was performed. Attempts at retrieval, using both a gastric overtube and an inverted hood, were unsuccessful due to the shape and size of the blades. She was transferred to a regular medical floor and managed conservatively with serial abdominal radiographs. Over the next week, she passed the razor blades transanally without further event-all were still wrapped in paper and chewing gum-and was cleared to be discharged home. PMID- 24759337 TI - Sphincteroplasty for anal incontinence. AB - Sphincteroplasty (SP) is the operation most frequently performed in patients suffering from moderate-to-severe anal incontinence (AI) who do not respond to conservative treatment. Other costly surgeries, such as artificial bowel sphincter (ABS) and electro-stimulated graciloplasty, have been more or less abandoned due to their high morbidity rate. Minimally invasive procedures are widely used, such as sacral neuromodulation and injection of bulking agents, but both are costly and the latter may cure only mild incontinence. The early outcome of SP is usually good if the sphincters are not markedly denervated, but its effect diminishes over time. SP is more often performed for post-traumatic than for idiopathic AI. It may also be associated to the Altemeier procedure, aimed at reducing the recurrence rate of rectal prolapse, and may be useful when AI is due either to injury to the sphincter, or to a narrowed rectum following the procedure for prolapse and haemorrhoids (PPH) and stapled transanal rectal resection (STARR). The outcome of SP is likely to be improved with biological meshes and post-operative pelvic floor rehabilitation. SP is more effective in males than in multiparous women, whose sphincters are often denervated, and its post-operative morbidity is low. In conclusion, SP, being both low-cost and safe, remains a good option in the treatment of selected patients with AI. PMID- 24759339 TI - The epidemiology of anal incontinence and symptom severity scoring. AB - For many patients, anal incontinence (AI) is a devastating condition that can lead to social isolation and loss of independence, contributing to a substantial economic health burden, not only for the individual but also for the allocation of healthcare resources. Its prevalence is underestimated because of poor patient reporting, with many unrecorded but symptomatic cases residing in nursing homes. Endosonography has improved our understanding of the incidence of post-obstetric sphincter tears that are potentially suitable for repair and those cases resulting from anorectal surgery, most notably after fistula and hemorrhoid operations. The clinical scoring systems assessing the severity of AI are discussed in this review, along with their limitations. Improvements in the standardization of these scales will advance our understanding of treatment response in an era where the therapeutic options have multiplied and will permit a better comparison between specific therapies. PMID- 24759338 TI - Internal anal sphincter augmentation and substitution. AB - There is an increasing recognition of the importance of internal anal sphincter (IAS) dysfunction presenting as passive faecal incontinence. This problem may manifest after anal sphincterotomy or following the more minimally invasive operations for haemorrhoids, as well as with advancing age. Because of the poor results of IAS plication and the beneficial outcomes with peri-urethral bulking agents in urology, these materials have been developed for use in IAS dysfunction. This review outlines the basic purported mechanisms of action, defining the materials in clinical use, their methods of deployment, complications and reported outcomes. There is still much that is unknown concerning the ideal agent or the volume and the technique of deployment, which will only be answered by powerful, prospective, randomized, controlled trials. The specific role of autologous stem cells designed to regenerate the sphincters in cases of functional impairment or muscle loss is yet to be seen. PMID- 24759340 TI - Solid pseudopapillary tumor: a rare neoplasm of the pancreas. AB - Solid pseudopapillary tumor is a rare primary neoplasm of the pancreas that typically affects young women. It is a relatively a benign tumor, with a favorable prognosis. We here report a 27-year-old woman with solid pseudopapillary neoplasm, who presented with mild jaundice, mildly elevated liver function tests and right upper quadrant pain. Ultrasound was suggestive of hemorrhagic hepatic adenoma; however, on magnetic resonance imaging, a heterogenous mass was found in the head of pancreas. Endoscopic ultrasound-guided fine needle aspiration (FNA) revealed tumor cells with papillary architecture and immunohistochemical analysis showing cells positive for markers including beta catenin, vimentin, alpha 1 antitrypsin etc. These findings were consistent with solid pseudopapillary neoplasm. The patient underwent pancreaticoduodenectomy. Post-surgical biopsy confirmed the FNA findings with tumor localized to the pancreas. The patient was not given any adjuvant therapy. She remained asymptomatic and showed no signs of disease after four months follow-up. It is important to differentiate this tumor from other pancreatic neoplasms, because this type is amenable to cure after complete surgical resection, even in cases with capsular invasion, unlike malignant tumors of the pancreas. PMID- 24759341 TI - Sarcomatoid carcinoma of the jejunum presenting as obscure gastrointestinal bleeding in a patient with a history of gliosarcoma. AB - Small bowel malignant tumors are rare and sarcomatoid carcinomas have rarely been reported at this site. We report a 56-year-old woman, with history of an excised gliosarcoma, who presented with recurrent obscure gastrointestinal bleeding. She underwent endoscopy and colonoscopy, which failed to identify the cause of the bleeding. The abdominal computed tomography scan located a tumor in the small bowel. Pathology revealed a jejunal sarcomatoid carcinoma. She developed tumor recurrence and multiple liver metastases shortly after surgery. Immunohistochemistry is required for accurate diagnosis. Sarcomatoid carcinoma is a rare cause of obscure gastrointestinal bleeding, which is associated with a poor prognosis. PMID- 24759343 TI - Association of procedure length on outcomes and adverse events of endoscopic retrograde cholangiopancreatography. AB - OBJECTIVE: The aims of this study were to determine the effects of length of procedure on endoscopic retrograde cholangiopancreatography (ERCP) outcomes and adverse events. METHODS: All ERCP procedures, performed by experienced advanced endoscopists, in patients without prior papillary intervention from 2006 to 2008 were reviewed. Procedures were arbitrarily divided into two groups: shorter procedures (SP), with a duration shorter than the overall mean procedure length, and longer procedures (LP), with a duration longer than overall mean procedure length. Length of procedure was defined as the time from endoscope insertion to endoscope removal. RESULTS: Two hundred and ninety-five procedures were included in the analysis. Mean procedure length was 45.6 +/- 30.1 min. One hundred and seventy-seven procedures (60%) were SP and 118 (40%) were LP. There were no differences between the groups with regard to patients' ages, genders, race, or trainee participation. SP cases were more likely to be biliary vs pancreatic or bi-ductal evaluations (P = 0.03). LP had significantly higher complexity scores (34% with >3 vs 13%; P = 0.046) and were more likely to require pre-cut papillotomy (39% vs 15%; P < 0.001). There was no significant difference between the groups in overall completion rates (91.5% LP vs 96% SP; P = 0.10) or adverse events (10.2% LP vs 6.2% SP; P = 0.21). However, LP cases were associated with higher rates of post-ERCP bleeding (4.2% vs 0.6%; P = 0.029). CONCLUSION: There was no significant difference in outcomes or overall adverse events between shorter and longer ERCP procedures. However, longer procedures were associated with higher procedure complexity, higher utilization of pre-cut technique, and increased risk of bleeding. PMID- 24759342 TI - The antegrade continence enema procedure and total anorectal reconstruction. AB - Patients may present with anal incontinence (AI) following repair of a congenital anorectal anomaly years previously, or require total anorectal reconstruction (TAR) following radical rectal extirpation, most commonly for rectal cancer. Others may require removal of their colostomy following sphincter excision for Fournier's gangrene, or in cases of severe perineal trauma. Most of the data pertaining to antegrade continence enema (the ACE or Malone procedure) comes from the pediatric literature in the management of children with AI, but also with supervening chronic constipation, where the quality of life and compliance with this technique appears superior to retrograde colonic washouts. Total anorectal reconstruction requires an anatomical or physical supplement to the performance of a perineal colostomy, which may include an extrinsic muscle interposition (which may or may not be 'dynamized'), construction of a neorectal reservoir, implantation of an incremental artificial bowel sphincter or creation of a terminal, smooth-muscle neosphincter. The advantages and disadvantages of these techniques and their outcome are presented here. PMID- 24759344 TI - An unexpected cause of acute liver failure. AB - A 66-year-old man presented with decompensated acute liver failure with no clear etiology. Eventually, a bone marrow biopsy revealed hemophagocytic cells, and he was diagnosed with hemophagocytic lymphohistiocytosis. This is an uncommon condition in adults, with high morbidity and mortality, and it is often indistinguishable from other forms of acute liver failure. Early clinical suspicion is critical to making the diagnosis, based on meeting at least four of nine specified criteria. PMID- 24759345 TI - Kayexalate-induced colonic ulcer. AB - A 61-year-old male presents to the emergency room with complaints of fatigue, dizziness and bright red blood per rectum (BRBPR) for 2 days. Past medical history was significant for gastroesophageal reflux disease, non-steroidal anti inflammatory drug (NSAID) induced ulcer, and end-stage renal disease (GFR < 30) status post 2 failed renal grafts. Pertinent medications include pantoprazole and sodium polystyrene sulfonate in sorbitol (Kayexalate 30 g/d orally). On esophagogastroduodenoscopy (EGD) there was a single shallow, flat, non-bleeding gastric ulcer (3 mm) in the pre-pyloric region of the stomach with no stigmata of bleeding. A colonoscopy was performed showing evidence of colitis and localized ulcerations in the cecum which were biopsied. Histopathology revealed basophilic, nonpolarizable, rhomboid-like crystals without evidence of necrosis. PMID- 24759346 TI - The use of a simple anal sling in the management of anal incontinence. AB - BACKGROUND. Many patients presenting with anal incontinence (AI) are frail, with attendant comorbidities precluding the use of complicated, expensive reconstructive techniques. In these cases, revisiting a simple approach-designed to provide some sort of effective barrier to stool-is worthwhile where the options include a customized peri-anal sling or the use of an anal plug. METHODS. Analysis of an unselected cohort of 33 patients (mean age 54 years; range 27-86 years) with AI is presented, these patients having undergone insertion of an elastic band peri-anal sling between December 2004 and December 2009. Pre- and post-operative assessment included the Jorge-Wexner score of incontinence, anorectal manometry and the Rockwood Fecal Incontinence Quality of Life (FIQoL) score. RESULTS. The follow-up period ranged from 50 to 108 months with a mean of 65 months. Early post-operative complications included spontaneous disruption of the sling at the fourth and seventh post-operative day in two patients and local infection in a further two cases. Late complications included skin erosion in two patients, (one occurring 3 years post-operatively) and breakage of the sling in a further seven patients. Explantation was performed in 13 cases, and re implantation in 10 patients. No differences were noted in resting or squeeze manometry, with significant improvement in the Jorge-Wexner scores in 32 cases and in all of the four Rockwood quality of life scales. CONCLUSIONS. An anal sling is an effective and simple surgical option for the management of selected cases presenting with anal incontinence. Longer-term data are awaited comparing this technique with other standard surgical alternatives. PMID- 24759347 TI - Conservative treatment for anal incontinence. AB - Anal incontinence (AI) in adults is a troublesome condition that negatively impacts upon quality of life and results in significant embarrassment and social isolation. The conservative management of AI is the first step and targets symptomatic relief. The reported significant improvement with conservative treatments for AI is close to 25% and involves prescribed changes in lifestyle habits, a reduced intake of foods that may cause or aggravate diarrhea or rectal urgency, and the use of specific anti-diarrheal agents. The use of a mechanical barrier in the form of an anal plug and the outcomes and principles of pelvic kinesitherapies and biofeedback options are outlined. This review discusses a gastroenterologist's approach towards conservative therapy in patients referred with anal incontinence. PMID- 24759348 TI - Adynamic and dynamic muscle transposition techniques for anal incontinence. AB - Gracilis muscle transposition is well established in general surgery and has been the main muscle transposition technique for anal incontinence. Dynamization, through a schedule of continuous electrical stimulation, converts the fatigue prone muscle fibres to a tonic fatigue-resistant morphology with acceptable results in those cases where there is limited sphincter muscle mass. The differences between gluteoplasty and graciloplasty, as well as the techniques and complications of both procedures, are outlined in this review. Overall, these techniques are rarely carried out in specialized units with experience, as there is a high revision and explantation rate. PMID- 24759349 TI - Sacral neuromodulation and peripheral nerve stimulation in patients with anal incontinence: an overview of techniques, complications and troubleshooting. AB - Sacral neuromodulation (SNM) therapy has revolutionized the management of many forms of anal incontinence, with an expanded use and a medium-term efficacy of 75% overall. This review discusses the technique of SNM therapy, along with its complications and troubleshooting and a discussion of the early data pertaining to peripheral posterior tibial nerve stimulation in incontinent patients. Future work needs to define the predictive factors for neurostimulatory success, along with the likely mechanisms of action of their therapeutic action. PMID- 24759350 TI - Temperature-controlled radiofrequency energy in patients with anal incontinence: an interim analysis of worldwide data. AB - BACKGROUND: Controlled delivery of radiofrequency energy (SECCA procedure) as treatment for anal incontinence (AI) was introduced 15 years ago. Since then, several clinical studies have emerged. This article evaluates the clinical response and sustainability of SECCA for patients with AI. METHODS: Only original clinical studies retrieved from PubMed and Medline were included. The outcome measures, faecal incontinence scores, definition of response, clinical results and anorectal evaluation were analysed. RESULTS: Ten studies were included, which involved 150 original patients. Three studies reported a long-term follow-up. The one-year follow-up shows a moderate effect, which declines somewhat over time. Only minor temporary side-effects are reported and none of the patients declined treatment. CONCLUSION: SECCA is a safe and well-tolerated procedure that is easy to perform without any serious short- or long-term complications, but with only a moderate clinical effect that declines over time. Results of randomized, sham controlled controlled trials are awaited. PMID- 24759351 TI - Isolated pancreatic tuberculosis masquerading as pancreatic cancer. AB - Isolated pancreatic tuberculosis (TB) remains a rarity despite the high incidence of tuberculosis in many of the African and Asian countries. Presentation as discrete pancreatic mass often masquerades as pancreatic neoplasm and diagnosis may require histology. Extra-hepatic portal hypertension due to splenic vein thrombosis complicating pancreatic TB has been reported in the literature. We report here a case of isolated pancreatic TB with pancreatic head mass mimicking neoplasm with extra-hepatic portal hypertension. The possibility of TB should be considered in the list of differential diagnoses of pancreatic mass and an endoscopic, ultrasound-guided biopsy might help to clinch the diagnosis of this potentially curable disease. PMID- 24759352 TI - Non-typhoidal salmonella: an unusual cause of spontaneous bacterial peritonitis in decompensated cirrhosis. AB - Salmonella typhimurium, a non-typhoidal salmonella, is an unusual cause of spontaneous bacterial peritonitis (SBP). It is usually reported in asymptomatic patients with normal or high ascitic fluid protein levels with underlying immunosuppression, as high opsonic activity in the ascitic fluid of these patients protects them from the usual organisms causing spontaneous bacterial peritonitis, unless they are exposed to a particularly virulent organism like salmonella. We report a case of culture-proven non-typhoidal salmonella in a patient with decompensated cirrhosis, with low protein and without any underlying immunosuppression, and no other source to explain its origin. PMID- 24759353 TI - Serous cystadenocarcinoma of the mesentery in a man: case report and review of literature. AB - In February 2007, a 41-year-old Japanese male was admitted to our hospital with increasing upper abdominal pain. A contrast-enhanced computed tomography (CT) scan of the abdomen demonstrated a well-demarcated, hypodense cystic mass with a thickened wall in the mesocolon. The laboratory results were within normal limits, except for increased carcinoembryonic antigen, carbohydrate antigen 19-9, DUPAN-2 and SPAN-1. The patient was diagnosed as having a mesenteric malignant cyst, and during a laparotomy, a right hemicolectomy with mesenteric cystectomy was performed without rupture in March 2007. In the microscopic findings, there was a well-differentiated adenocarcinoma in the inner surface of the cyst and in the fibrous connective tissue of the hypertrophic cystic wall. The tumor cells were immunohistochemically reactive to cytokeratin (CK) 7, CK18 and CK20. No remnant of the malignancy was detected in the resected margin of the colon, cyst, liver or peritoneum nor was an uptake detected in an 18[F]-fluorodeoxyglucose positron emission tomography/CT examination of other organs. Finally, the malignancy was concluded to be a serous cystadenocarcinoma of the mesentery. Nineteen months after the operation, the patient died from peritonitis carcinomatosa due to a small intestine rupture. This report suggests mesenteric cystadenocarcinomas originating in the ovary, oviduct and intestinal mucosa, but these were ruled out in our patient. In this report, we discuss a case of the malignant transformation of a cyst into adenocarcinoma, which to our knowledge has never been previously reported in a male patient. PMID- 24759354 TI - Abdominal aortic thrombosis and tuberculosis: an uncommon association. AB - Thrombosis of the abdominal aorta is an uncommon event and usually occurs in a diseased vessel. We report a case of a 42-year-old male who presented with abdominal distension and was found to have tuberculosis-related ascites and was incidentally found to have aortic thrombosis. The patient improved with four-drug anti-tubercular therapy and anticoagulation. The occurrence of non-occlusive thrombosis of the abdominal aorta in tuberculosis is unusual. PMID- 24759355 TI - Sources, concentrations, and exposure effects of environmental gestagens on fish and other aquatic wildlife, with an emphasis on reproduction. AB - Fish and other aquatic wildlife, including frogs, turtles, and alligators, have been used as vertebrate sentinels for the effects of endocrine disrupting and other emerging chemicals of concern found in aquatic ecosystems. Research has focused on the effects of estrogenic, androgenic, and thyroidogenic compounds, but there is a growing body of literature on the reproductive health exposure effects of environmental gestagens on aquatic wildlife. Gestagens include native progestogens, such as progesterone, and synthetic progestins, such as gestodene and levonorgestrel, which bind progesterone receptors and have critically important roles in vertebrate physiology, especially reproduction. Roles for progestogen include regulating gamete maturation and orchestrating reproductive behavior, both as circulating hormones and as secreted pheromones. Gestagens enter the aquatic environment through paper mill effluent, wastewater treatment plant effluent, and agricultural runoff. A number of gestagens have been shown to negatively affect reproduction, development, and behavior of exposed fish and other aquatic wildlife at ng/L concentrations, and these compounds have been measured in the environment at single to 375 ng/L. Given the importance of endogenous progestogens in the regulation of gametogenesis, secondary sex characteristics, and reproductive behavior in vertebrates and the documented exposure effects of pharmaceutical progestins and progesterone, environmental gestagens are an emerging class of contaminants that deserve increased attention from researchers and regulators alike. The potential for environmental gestagens to affect the reproductive health of aquatic vertebrates seems evident, but there are a number of important questions for researchers to address in this nascent field. These include identifying biomarkers of gestagen exposure; testing the effects of environmentally relevant mixtures; and determining what other physiological endpoints and taxa might be affected by exposure to environmental gestagens. PMID- 24759356 TI - Impacted dentures in the oesophagus. AB - OBJECTIVE: This study presents the incidence of denture impaction in the oesophagus, and discusses the difficulties of managing such cases. METHOD: A total of 262 patients with a history of foreign body ingestion (between 1999 and 2010) were reviewed; 46 of these patients had dentures impacted in the oesophagus. RESULTS: The cervical section of the oesophagus was the commonest site of impaction. Dysphagia and tracheal tenderness were the most consistent features when dentures became impacted in the upper oesophagus. In most cases, rigid oesophagoscopy enabled successful removal of the impacted denture. Locating an impacted denture hidden within the oesophageal mucosal folds sometimes proved difficult. CONCLUSION: In cases of impacted dentures in the oesophagus, a positive history helps in the diagnosis, but a high degree of clinical suspicion aids early detection. Conventional radiographs are important but may not always be of assistance. Early intervention reduces complications. Dentures that are poorly maintained and old are more likely to be swallowed accidentally. The inclusion of radiopaque filler within dentures would assist localisation following accidental swallowing. PMID- 24759357 TI - A new window into adolescents' worlds: the impact of online social interaction on risk behavior. PMID- 24759358 TI - Cyberbullying and psychological and behavioral health problems. PMID- 24759359 TI - A child rights and equity-based framework to advance policy and practice related to adolescent consent to vaccines. PMID- 24759361 TI - The global burden of mental and substance use disorders: changes in estimating burden between GBD1990 and GBD2010. AB - Background. The main aim of this paper is to compare and contrast the methodological approaches of the new Global Burden of Disease 2010 Study (GBD 2010) with the original study conducted for 1990 (GBD 1990), in terms of calculating burden for mental and substance use disorders. Methods. We reviewed the conceptual and methodological changes to GBD burden calculations in the GBD 2010 study, compared with previous studies. We then discuss the possible implications of these changes with respect to burden estimates for mental and substance use disorders. Results. It is not possible to compare burden estimates arising from the GBD 1990 study with the most recent burden estimates. There have been important advances in the categorisation and definition of mental disorders, and the input and computation of epidemiological models for disease distribution. There have also been major changes to conceptual and social value choices aimed at addressing concerns that arose following publication of earlier GBD studies. Conclusion. Advancements to the GBD conceptual framework and method of calculating burden estimates has led to more accurate and equitable consideration of the burden for mental and substance use disorders. Proposed annual updates of GBD estimates by the Institute of Health Metrics and Evaluation provide an opportunity to continue to advance the evidence base that underpins the quantification of disease burden. PMID- 24759360 TI - The authoring committee responds. PMID- 24759362 TI - Platypnoea orthodeoxia after hepatic surgery. AB - Platypnoea orthodeoxia is a rare clinical syndrome characterised by dyspnoea and deoxygenation exhibited in upright position with improvement in supine posture. Previously described aetiologies include cardiac (pericardial effusion or constrictive pericarditis), pulmonary (pneumonectomy, emphysema or amiodarone toxicity), abdominal (cirrhosis or ileus) or vascular (abdominal aortic aneurysm) causes. We report an unusual case of platypnoea orthodeoxia associated with patent foramen ovale and partial hepatic resection. PMID- 24759363 TI - 'Twenty-four-and-a-half' syndrome and contralateral hemifacial spasm due to pontine carvernoma. PMID- 24759365 TI - Unusual ECG pattern of the acute inferior wall infarction due to RCA occlusion with concomitant LAD and LCX disease. PMID- 24759364 TI - 'Dancing eyes, dancing feet syndrome' in small cell lung carcinoma. AB - A 60-year-old man presented with a 25-day history of acute onset instability of gait, tremulousness of limbs and involuntary eye movements. Examination revealed presence of opsoclonus, myoclonus and ataxia, without any loss of motor power in the limbs. Prompt investigations were directed towards identifying an underlying malignancy which is often associated with this type of clinical scenario. CT of the brain was normal and cerebrospinal fluid examination showed lymphocytic pleocytosis. A cavitatory lesion was found in the right lung base on the high resolution CT of the chest and histopathological examination of this lung mass showed small cell lung carcinoma. The patient was managed symptomatically with levetiracetam and baclofen and referred to oncology department for resection of the lung mass. PMID- 24759366 TI - Exposure to parasites increases promiscuity in a freshwater snail. AB - Under the Red Queen hypothesis, outcrossing can produce genetically variable progeny, which may be more resistant, on average, to locally adapted parasites. Mating with multiple partners may enhance this resistance by further increasing the genetic variation among offspring. We exposed Potamopyrgus antipodarum to the eggs of a sterilizing, trematode parasite and tested whether this altered mating behaviour. We found that exposure to parasites increased the number of snail mating pairs and the total number of different mating partners for both males and females. Thus, our results suggest that, in host populations under parasite mediated selection, exposure to infective propagules increases the rate of mating and the number of mates. PMID- 24759367 TI - A field study investigating effects of landmarks on territory size and shape. AB - Few studies have examined how landmarks affect territories' fundamental characteristics. In this field study, we investigated effects of landmarks on territory size, shape and location in a cichlid fish (Amatitlania siquia). We provided cans as breeding sites and used plastic plants as landmarks. During 10 min trials, we recorded locations where residents chased intruders and used those locations to outline and measure the territory. In two experiments, we observed pairs without landmarks and with either a point landmark (one plant) or linear landmark (four plants) placed near the nest can. We alternated which trial occurred first and performed the second trial 24 h after the first. Territories were approximately round without landmarks or with a point landmark but were significantly more elongated when we added a linear landmark. Without landmarks, nests were centrally located; however, with any landmark, pairs set territory boundaries closer to the landmark and thus the nest. Territory size was significantly reduced in the presence of any landmark. This reduction suggests that a smaller territory with well-defined boundaries has greater benefits than a larger territory with less well-defined borders. PMID- 24759368 TI - Identification of visual paternity cues in humans. AB - Understanding how individuals identify their relatives has implications for the evolution of social behaviour. Kinship cues might be based on familiarity, but in the face of paternity uncertainty and costly paternal investment, other mechanisms such as phenotypic matching may have evolved. In humans, paternal recognition of offspring and subsequent discriminative paternal investment have been linked to father-offspring facial phenotypic similarities. However, the extent to which paternity detection is impaired by environmentally induced facial information is unclear. We used 27 portraits of fathers and their adult sons to quantify the level of paternity detection according to experimental treatments that manipulate the location, type and quantity of visible facial information. We found that (i) the lower part of the face, that changes most with development, does not contain paternity cues, (ii) paternity can be detected even if relational information within the face is disrupted and (iii) the signal depends on the presence of specific information rather than their number. Taken together, the results support the view that environmental effects have little influence on the detection of paternity using facial similarities. This suggests that the cognitive dispositions enabling the facial detection of kinship relationships ignore genetic irrelevant facial information. PMID- 24759369 TI - Antennal lobe organization and pheromone usage in bombycid moths. AB - We investigated the neuroanatomy of the macroglomerular complex (MGC), which is involved in sex pheromone processing, in five species in the subfamily Bombycinae, including Ernolatia moorei, Trilocha varians, Rondotia menciana, Bombyx mandarina and Bombyx mori. The glomerulus located at the dorsal-most part of the olfactory centre shows the largest volume in moth species examined to date. Such normal glomerular organization has been observed in E. moorei and T. varians, which use a two-component mixture and includes the compound bombykal as a mating signal. By contrast, the other three species, which use another component as a single attractant, exhibited a modified arrangement of the MGC. This correlation between pheromone usage and neural organization may be useful for understanding the process of speciation. PMID- 24759370 TI - Seeing the body produces limb-specific modulation of skin temperature. AB - Vision of the body, even when non-informative about stimulation, affects somatosensory processing. We investigated whether seeing the body also modulates autonomic control in the periphery by measuring skin temperature while manipulating vision. Using a mirror box, the skin temperature was measured from left hand dorsum while participants: (i) had the illusion of seeing their left hand, (ii) had the illusion of seeing an object at the same location or (iii) looked directly at their contralateral right hand. Skin temperature of the left hand increased when participants had the illusion of directly seeing that hand but not in the other two view conditions. In experiment 2, participants viewed directly their left or right hand, or the box while we recorded both hand dorsum temperatures. Temperature increased in the viewed hand but not the contralateral hand. These results show that seeing the body produces limb-specific modulation of thermal regulation. PMID- 24759371 TI - Mitigating the squash effect: sloths breathe easily upside down. AB - Sloths are mammals renowned for spending a large proportion of time hanging inverted. In this position, the weight of the abdominal contents is expected to act on the lungs and increase the energetic costs of inspiration. Here, we show that three-fingered sloths Bradypus variegatus possess unique fibrinous adhesions that anchor the abdominal organs, particularly the liver and glandular stomach, to the lower ribs. The key locations of these adhesions, close to the diaphragm, prevent the weight of the abdominal contents from acting on the lungs when the sloth is inverted. Using ventilation rate and body orientation data collected from captive and wild sloths, we use an energetics-based model to estimate that these small adhesions could reduce the energy expenditure of a sloth at any time it is fully inverted by almost 13%. Given body angle preferences for individual sloths in our study over time, this equates to mean energy saving of 0.8-1.5% across individuals (with individual values ranging between 0.01 and 8.6%) per day. Given the sloth's reduced metabolic rate compared with other mammals and extremely low energy diet, these seemingly innocuous adhesions are likely to be important in the animal's energy budget and survival. PMID- 24759372 TI - Mysterious bio-duck sound attributed to the Antarctic minke whale (Balaenoptera bonaerensis). AB - For decades, the bio-duck sound has been recorded in the Southern Ocean, but the animal producing it has remained a mystery. Heard mainly during austral winter in the Southern Ocean, this ubiquitous sound has been recorded in Antarctic waters and contemporaneously off the Australian west coast. Here, we present conclusive evidence that the bio-duck sound is produced by Antarctic minke whales (Balaenoptera bonaerensis). We analysed data from multi-sensor acoustic recording tags that included intense bio-duck sounds as well as singular downsweeps that have previously been attributed to this species. This finding allows the interpretation of a wealth of long-term acoustic recordings for this previously acoustically concealed species, which will improve our understanding of the distribution, abundance and behaviour of Antarctic minke whales. This is critical information for a species that inhabits a difficult to access sea-ice environment that is changing rapidly in some regions and has been the subject of contentious lethal sampling efforts and ongoing international legal action. PMID- 24759373 TI - Cougars' key to survival through the Late Pleistocene extinction: insights from dental microwear texture analysis. AB - Cougars (Puma concolor) are one of only two large cats in North America to have survived the Late Pleistocene extinction (LPE), yet the specific key(s) to their relative success remains unknown. Here, we compare the dental microwear textures of Pleistocene cougars with sympatric felids from the La Brea Tar Pits in southern California that went extinct at the LPE (Panthera atrox and Smilodon fatalis), to clarify potential dietary factors that led to the cougar's persistence through the LPE. We further assess whether the physical properties of food consumed have changed over time when compared with modern cougars in southern California. Using dental microwear texture analysis (DMTA), which quantifies surface features in three dimensions, we find that modern and Pleistocene cougars are not significantly different from modern African lions in any DMTA attributes, suggesting moderate durophagy (i.e. bone processing). Pleistocene cougars from La Brea have significantly greater complexity and textural fill volume than Panthera atrox (inferred to have primarily consumed flesh from fresh kills) and significantly greater variance in complexity values than S. fatalis. Ultimately, these results suggest that cougars already used or adopted a more generalized dietary strategy during the Pleistocene that may have been key to their subsequent success. PMID- 24759374 TI - Factors influencing repeated seed movements by scatter-hoarding rodents in an alpine forest. AB - Scatter-hoarding rodents are effective dispersal agents for many plant species. Several studies have shown that rodents repeatedly re-cache seeds. The re-caching process often has a significant impact on final seedling establishment, but the factors determining its occurrence are poorly understood. In this study, we followed the fate of 3564 artificial seeds that varied in size, nutrient content and tannin content. Seeds cached closer to their original releasing plots were more likely to be re-cached, and to a further distance. Larger seeds were more likely to be re-cached than smaller ones, while nutrient and tannin content had little effect. Most plant species that depend on scatter-hoarding rodents for seed dispersal bear relatively large seeds, and large seeds are usually more likely to be dispersed and to establish seedlings, suggesting that the caching preferences of scatter-hoarding rodents may have played an important role in the evolution of large seeds. PMID- 24759375 TI - Reconstruction of historical exposures at a Welsh nickel refinery (1953-2000). AB - Past epidemiological studies of workers in a nickel refinery in Clydach, Wales, have shown evidence of large excess respiratory cancer mortality risks [lung cancer relative risk (RR) ~ 3; nasal cancer RR ~ 140] in those employed prior to 1930, with risks dropping dramatically in workers hired subsequently. The pre 1930 risks have generally been attributed to high exposures to mixtures of nickel compounds. More recent studies of this refinery's workers have focused on those first hired in 1953, when many of the operations that presumably gave rise to the high exposures were no longer in operation. While these studies have shown greatly decreased lung cancer risks overall (RR ~ 1.4), and no substantive evidence of increased nasal cancer risk, the absence of reliable exposure estimates have made it difficult to ascertain whether the increased lung cancer risks are nickel related or due to other factors. This study uses nickel measurements from the 1970s to the present, documentation of process changes, and dust measurements taken around the 1950s to construct an exposure matrix for the recent cohort. It provides evidence of at least 30-fold decreases in levels of nickel exposure from the 1950s to the present, with estimated inhalable nickel concentrations in the 1950s in excess of 5mg Ni m(-3). PMID- 24759376 TI - Concentration of bioaerosols in composting plants using different quantification methods. AB - BACKGROUND: Bioaerosols (organic dusts) containing viable and non-viable microorganisms and their metabolic products can lead to adverse health effects in exposed workers. Standard quantification methods of airborne microorganisms are mainly based on cultivation, which often underestimates the microbial burden. The aim of the study was to determine the microbial load in German composting plants with different, mainly cultivation-independent, methods. Second purpose was to evaluate which working areas are associated with higher or lower bioaerosol concentrations. METHODS: A total of 124 inhalable dust samples were collected at different workplaces in 31 composting plants. Besides the determination of inhalable dust, particles, and total cell numbers, antigen quantification for moulds (Aspergillus fumigatus, Aspergillus versicolor, Penicillium chrysogenum, and Cladosporium spp.) and mites was performed. Concentrations of beta-glucans as well as endotoxin and pyrogenic activities were also measured. The number of colony forming units (cfu) was determined by cultivation of moulds and actinomycetes in 36 additional dust samples. RESULTS: With the exception of particle numbers, concentrations of all determined parameters showed significant correlations (P < 0.0001; r Spearman: 0.40-0.80), indicating a close association between these exposure markers. Colony numbers of mesophilic moulds and actinomycetes correlated also significantly with data of cultivation-independent methods. Exposure levels showed generally large variations. However, all parameters were measured highest in dusty working areas like next to the shredder and during processing with the exception of Cladosporium antigens that were found in the highest concentrations in the delivery area. The lowest concentrations of dust, particles, antigens, and pyrogenic activity were determined in wheel loader cabins (WLCs), which were equipped with an air filtration system. CONCLUSION: It was possible to assess the microbial load of air in composting plants with different quantification methods. Since allergic and toxic reactions may be also caused by nonliving microorganisms, cultivation-independent methods may provide additional information about bioaerosol composition. In general, air filtration reduced the bioaerosol exposure shown in WLCs. Due to the fact that the mechanical processing of compost material, e.g. by shredding or sieving is associated with the generation of high bioaerosol concentrations, there is still a need of improved risk assessment and state-of-the-art protective measures in composting plants. PMID- 24759377 TI - Incidence of osteoporotic fractures in elderly women and men in Finland during 2005-2006: a population-based study. AB - BACKGROUND AND AIMS: Osteoporosis is a major health concern in elderly population. Low-trauma fractures offer one way of identifying these patients for treatment. Population-specific incidences of osteoporotic fractures are essential to validate tools for clinical decision making. MATERIAL AND METHODS: To evaluate population-based osteoporotic fracture incidences in Central Finland, we performed a manual search of low-trauma fractures 2005-2006 from the records of all the local health-care organizations treating trauma patients. We identified low-trauma fracture patients from radiology reports from five health centers serving the inhabitants of nine municipalities and from the patient records of two hospitals in Central Finland. The manually collected data were then compared against data from the Finnish Health Care Register. RESULTS: The crude incidence of all osteoporotic fractures in 2005-2006 in the population aged 50 years was 1254/100,000 person years: 694/100,000 person years in men and 1718/100,000 person years in women. Fracture numbers derived from register data were similar to those manually collected for hip and humerus fractures, but clearly smaller than those for wrist and ankle fractures. CONCLUSIONS: Population-based low trauma fracture incidences, reported here for Finland, constitute a basis for calibration of fracture risk evaluation tools (e.g. the World Health Organization fracture risk evaluation tool, FRAX). This study showed that register data underestimate the incidences of, in particular, distal radius and ankle fractures. PMID- 24759378 TI - Should asymptomatic retrosternal goitre be left untreated? A prospective single centre study. AB - BACKGROUND AND AIMS: Retrosternal goiter may cause symptoms of airway obstruction and dysphagia, but often it is asymptomatic and is increasingly detected incidentally with imaging investigations. Consensus has been reached that sternotomy is not necessary in most cases, as a collar incision normally suffices. Yet, surgery for retrosternal goiter is associated with more complications than cervical goiter. There is controversy over whether patients with asymptomatic retrosternal goiter should be operated. Proponents argue that retrosternal goiter may be a risk for thyroid cancer and may progress to later cause symptoms, although clear evidence is missing. PATIENTS AND METHODS: Between 1984 and 2012, 132 patients underwent surgery for benign retrosternal goiter. Preoperatively, the benign nature was clinically apparent and confirmed by fine needle cytology in most cases. RESULTS: Sternotomy was required in only 4 of the 132 operations. Three patients died in the postoperative period. The risk of morbidity and mortality was 16.7% in 60 patients with compression symptoms and 13.9% in 72 patients without compression symptoms (P = 0.808). Histology revealed no case of unsuspected cancer. CONCLUSION: Surgery for retrosternal goiters involves a higher risk for complications than do cervical goiters, and the risk does not differ between patients with and without symptoms. This, and the fact that no patient in this study had unsuspected cancer, calls into question the rationale for surgery in patients with asymptomatic retrosternal goiter without suspected cancer. PMID- 24759379 TI - Surveillance for hepatocellular carcinoma: evidence, guidelines and utilization. PMID- 24759380 TI - Iran needs to present a united front on science. PMID- 24759392 TI - Tamiflu report comes under fire. PMID- 24759393 TI - Chile quake defies expectations. PMID- 24759394 TI - Quantum communications leap out of the lab. PMID- 24759395 TI - RNA interference rebooted. PMID- 24759396 TI - Climate-change adaptation: Designer reefs. PMID- 24759397 TI - Renewable energy: Biofuels heat up. PMID- 24759401 TI - Health database: Restore public trust in care.data project. PMID- 24759402 TI - Russian science: US sanctions put research at risk. PMID- 24759403 TI - Mental health: Drug search on risky path. PMID- 24759404 TI - Research strategy: Ecology must seek universal principles. PMID- 24759405 TI - Mental health: More than neurobiology. PMID- 24759406 TI - Sensory systems: Do you hear what I see? PMID- 24759407 TI - Genetics: The vital Y chromosome. PMID- 24759409 TI - Guidelines for investigating causality of sequence variants in human disease. AB - The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development. PMID- 24759410 TI - Origins and functional evolution of Y chromosomes across mammals. AB - Y chromosomes underlie sex determination in mammals, but their repeat-rich nature has hampered sequencing and associated evolutionary studies. Here we trace Y evolution across 15 representative mammals on the basis of high-throughput genome and transcriptome sequencing. We uncover three independent sex chromosome originations in mammals and birds (the outgroup). The original placental and marsupial (therian) Y, containing the sex-determining gene SRY, emerged in the therian ancestor approximately 180 million years ago, in parallel with the first of five monotreme Y chromosomes, carrying the probable sex-determining gene AMH. The avian W chromosome arose approximately 140 million years ago in the bird ancestor. The small Y/W gene repertoires, enriched in regulatory functions, were rapidly defined following stratification (recombination arrest) and erosion events and have remained considerably stable. Despite expression decreases in therians, Y/W genes show notable conservation of proto-sex chromosome expression patterns, although various Y genes evolved testis-specificities through differential regulatory decay. Thus, although some genes evolved novel functions through spatial/temporal expression shifts, most Y genes probably endured, at least initially, because of dosage constraints. PMID- 24759413 TI - Hybrid shallow on-axis and deep off-axis hydrothermal circulation at fast spreading ridges. AB - Hydrothermal flow at oceanic spreading centres accounts for about ten per cent of all heat flux in the oceans and controls the thermal structure of young oceanic plates. It also influences ocean and crustal chemistry, provides a basis for chemosynthetic ecosystems, and has formed massive sulphide ore deposits throughout Earth's history. Despite this, how and under what conditions heat is extracted, in particular from the lower crust, remains largely unclear. Here we present high-resolution, whole-crust, two- and three-dimensional simulations of hydrothermal flow beneath fast-spreading ridges that predict the existence of two interacting flow components, controlled by different physical mechanisms, that merge above the melt lens to feed ridge-centred vent sites. Shallow on-axis flow structures develop owing to the thermodynamic properties of water, whereas deeper off-axis flow is strongly shaped by crustal permeability, particularly the brittle-ductile transition. About 60 per cent of the discharging fluid mass is replenished on-axis by warm (up to 300 degrees Celsius) recharge flow surrounding the hot thermal plumes, and the remaining 40 per cent or so occurs as colder and broader recharge up to several kilometres away from the axis that feeds hot (500 700 degrees Celsius) deep-rooted off-axis flow towards the ridge. Despite its lower contribution to the total mass flux, this deep off-axis flow carries about 70 per cent of the thermal energy released at the ridge axis. This combination of two flow components explains the seismically determined thermal structure of the crust and reconciles previously incompatible models favouring either shallower on axis or deeper off-axis hydrothermal circulation. PMID- 24759412 TI - Superconducting quantum circuits at the surface code threshold for fault tolerance. AB - A quantum computer can solve hard problems, such as prime factoring, database searching and quantum simulation, at the cost of needing to protect fragile quantum states from error. Quantum error correction provides this protection by distributing a logical state among many physical quantum bits (qubits) by means of quantum entanglement. Superconductivity is a useful phenomenon in this regard, because it allows the construction of large quantum circuits and is compatible with microfabrication. For superconducting qubits, the surface code approach to quantum computing is a natural choice for error correction, because it uses only nearest-neighbour coupling and rapidly cycled entangling gates. The gate fidelity requirements are modest: the per-step fidelity threshold is only about 99 per cent. Here we demonstrate a universal set of logic gates in a superconducting multi-qubit processor, achieving an average single-qubit gate fidelity of 99.92 per cent and a two-qubit gate fidelity of up to 99.4 per cent. This places Josephson quantum computing at the fault-tolerance threshold for surface code error correction. Our quantum processor is a first step towards the surface code, using five qubits arranged in a linear array with nearest-neighbour coupling. As a further demonstration, we construct a five-qubit Greenberger-Horne-Zeilinger state using the complete circuit and full set of gates. The results demonstrate that Josephson quantum computing is a high-fidelity technology, with a clear path to scaling up to large-scale, fault-tolerant quantum circuits. PMID- 24759411 TI - Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators. AB - The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease. PMID- 24759419 TI - Self-report symptoms differ between younger and older dizzy patients. AB - OBJECTIVE: To determine whether the responses of elders compared with younger patients differed significantly on a structured dizziness case history. STUDY DESIGN: Retrospective case reviews. SETTING: Outpatient balance function testing center. PATIENTS: Two-hundred thirty-three adults who underwent vestibular function testing and completed a structured case history. The mean age of the adult group (18-64 yr) was 46.4 years. The mean age of the old adult group (65 yr and older) was 76.2 years. MAIN OUTCOME MEASURE: Patient's self-reported symptoms on a structured case history questionnaire. RESULTS: Younger adults reported significantly more complaints of true vertigo and associated nausea and vomiting compared with older patients. Older patients tended to report symptoms of unsteadiness or falling. Despite the lack of vertiginous symptoms, BPPV was common in older adults. CONCLUSION: The clinician should be aware of differences in self-report dizziness symptoms in older patients. Older patients who do not have vertigo may be told that their symptoms are normal for their age, when, in fact, they may have an undiagnosed vestibular system impairment. PMID- 24759420 TI - In response to the letter to the editor: a step further in vestibular testing for patients with vestibular schwannoma. PMID- 24759421 TI - Lobular capillary hemangioma and external auditory canal. PMID- 24759422 TI - Re: Salzman et al. Osteonecrosis of the external auditory canal associated with oral bisphosphonate therapy: case report and literature review. Otol Neurotol 2013;34:209-13. PMID- 24759423 TI - A common case with common problems: laparoscopic treatment of small bowel obstruction (SBO). AB - BACKGROUND: Laparoscopic approach to patients with suspected small bowel obstruction (SBO) is not yet widely accepted nor clearly standardized; due to the absence of randomized trials, many questions still remain matter of debate. METHODS: By describing a single typical case of acute intestinal occlusive syndrome in a 82 years old woman, in which a SBO was suspected on the basis of previous surgical history and CT scan imaging, every single step of therapy is discussed, including the decision to perform explorative laparoscopy, the first trocar placement, the decision to continue by laparoscopy or to convert in laparotomy, and finally the small bowel resection and re-anastomosis. RESULTS: The decision to approach a suspected SBO by laparoscopy should be taken on the basis of a number of features which would predict the success rate, such as mild abdominal distention, proximal obstruction, partial obstruction, small bowel diameter less than 4 cm, previous appendenctomy, anticipated single band adhesion. In these cases laparoscopic approach may improve post-operative outcomes in terms of reduced postoperative ileus, hospitalization and wound infection rate. CONCLUSIONS: In selected, not unusual cases of SBO, a laparoscopic approach is feasible and effective. A growing Literature, mainly based upon retrospective series, is available. PMID- 24759424 TI - Isolation and characterization of purple non-sulfur bacteria, Afifella marina, producing large amount of carotenoids from mangrove microhabitats. AB - This study determined the effect of light intensity and photoperiod on the dry cell weight and total amount of carotenoids in four isolates of purple non-sulfur bacteria obtained from shaded and exposed microhabitats of a mangrove ecosystem in Kota Kinabalu, Sabah, Malaysia. The initial isolation of the bacteria was carried out using synthetic 112 medium under anaerobic conditions (2.5 klx) at 30 +/- 2 degrees C. On the basis of colony appearance, cell morphology, gram staining, motility test, and 16S rRNA gene sequencing analyses, all four bacteria were identified as Afifella marina. One of the bacterial isolates, designated as Af. marina strain ME, which was extracted from an exposed mud habitat within the mangrove ecosystem, showed the highest yield in dry cell weight (4.32+/- 0.03 g/l) as well as total carotenoids (0.783 +/- 0.002 mg/g dry cell weight). These values were significantly higher than those for dry cell weight (3.77 +/- 0.02g/l ) and total carotenoid content (0.706 +/- 0.008 mg/g) produced by the isolates from shaded habitats. Further analysis of the effect of 10 levels of light intensity on the growth characteristics of Af. marina strain ME showed that the optimum production of dry cell weight and total carotenoids was achieved at different light intensities and incubation periods. The bacterium produced the highest dry cell weight of 4.98 g/l at 3 klx in 72 h incubation, but the carotenoid production of 0.783 mg/g was achieved at 2.5 klx in 48 h incubation. Subsequent analysis of the effect of photoperiod on the production of dry cell weight and total carotenoids at optimum light intensities (3 and 2.5 klx, respectively) revealed that 18 and 24 h were the optimum photoperiods for the production of dry cell weight and total carotenoids, respectively. The unique growth characteristics of the Af. marina strain ME can be exploited for biotechnology applications. PMID- 24759425 TI - Nutrient removal and biofuel production in high rate algal pond using real municipal wastewater. AB - This study evaluated the growth and nutrient removal ability of an indigenous algal consortium on real untreated municipal wastewater in a high rate algal pond (HRAP). The HRAP was operated semicontinuously under different hydraulic retention times (HRT: 2, 4, 6, and 8 days). The average removal efficiencies of chemical oxygen demand, and total nitrogen and phosphate of real municipal wastewater were maintained at 85.44 +/- 5.10%, 92.74 +/- 5.82%, and 82.85 +/- 8.63%, respectively, in 2 day HRT. Algae dominated the consortium and showed high settling efficiency (99%), and biomass and lipid productivity of 0.500 +/- 0.03 g/l/day and 0.103 +/- 0.0083 g/l/day (2 day HRT), respectively. Fatty acid methyl ester analysis revealed a predominance of palmitate (C16:0), palmitoleate (C16:1), linoleate (C18:2), and linolenate (C18:3). Microalgal diversity analyses determined the presence of Chlorella, Scenedesmus, and Stigeoclonium as the dominant microalgae. The algal consortium provides significant value not only in terms of energy savings and nutrient removal but also because of its bioenergy potential as indicated by the lipid content (20-23%) and FAME profiling. PMID- 24759426 TI - Non-aflatoxigenicity of commercial Aspergillus oryzae strains due to genetic defects compared to aflatoxigenic Aspergillus flavus. AB - Aspergillus oryzae is generally recognized as safe, but it is closely related to A. flavus in morphology and genetic characteristics. In this study, we tested the aflatoxigenicity and genetic analysis of nine commercial A. oryzae strains that were used in Korean soybean fermented products. Cultural and HPLC analyses showed that none of the commercial strains produced detectable amount of aflatoxins. According to the molecular analysis of 17 genes in the aflatoxin (AF) biosynthetic pathway, the commercial strains could be classified into three groups. The group I strains contained all the 17 AF biosynthetic genes tested in this study; the group II strains deleted nine AF biosynthetic genes and possessed eight genes, including aflG, aflI, aflK, aflL, aflM, aflO, aflP, and aflQ; the group III strains only had six AF biosynthetic genes, including aflG, aflI, aflK, aflO, aflP, and aflQ. With the reverse transcription polymerase chain reaction, the group I A. oryzae strains showed no expression of aflG, aflQ and/or aflM genes, which resulted in the lack of AF-producing ability. Group II and group III strains could not produce AF owing to the deletion of more than half of the AF biosynthetic genes. In addition, the sequence data of polyketide synthase A (pksA) of group I strains of A. oryzae showed that there were three point mutations (two silent mutations and one missense mutation) compared with aflatoxigenic A. flavus used as the positive control in this study. PMID- 24759427 TI - In vitro activity of taurine-5-bromosalicylaldehyde Schiff base against planktonic and biofilm cultures of methicillin-resistant Staphylococcus aureus. AB - Staphylococcus aureus is a major human pathogen, implicated in both community and hospital acquired infections. The therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections is becoming more difficult because of multidrug resistance and strong biofilmforming properties. Schiff bases have attracted attention as promising antibacterial agents. In this study, we investigated the in vitro activity of taurine-5-bromosalicylaldehyde Schiff base (TBSSB) against MRSA. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentration (MBC) were determined using a microtiter broth dilution method. TBSSB effectively inhibited planktonic MRSA, with an MIC of 32 MUg/ml. The time-kill curve confirmed that TBSSB exhibited bactericidal activity against MRSA. TBSSB was also found to significantly inhibit MRSA biofilm formation at 24 h, especially at 1*MIC and sub-MIC levels. Furthermore, scanning electron microscopy and transmission electron microscopy showed remarkable morphological and ultrastructural changes on the MRSA cell surface, due to exposure to TBSSB. This study indicated that TBSSB may be an effective bactericidal agent against MRSA. PMID- 24759429 TI - Antibody-based delivery of IL2 and cytotoxics eradicates tumors in immunocompetent mice. AB - Antibody-drug conjugates are increasingly being used for cancer therapy, but little is known about their ability to promote anticancer immunity, which may lead to long-lasting remissions. We investigated the therapeutic effect of antibody-based pharmacodelivery of cemadotin, a cytotoxic drug, and IL2, a strong proinflammatory cytokine. Using the F8 antibody, which selectively localizes to the tumor neovasculature, combination treatment led to tumor eradication, in a process dependent on CD8(+) T cells and natural killer cells in the C1498 syngeneic mouse model of acute myelogenous leukemia. The clinical combination of antibody-drug conjugates and antibody-cytokine proteins should be facilitated by their orthogonal toxicity profiles. PMID- 24759430 TI - Vaccination of lambs against Haemonchus contortus infection with a somatic protein (Hc23) from adult helminths. AB - A somatic protein from adult Haemonchus contortus (Hc23), the most abundant component in a low molecular weight fraction with known immunizing effect against experimental haemonchosis, has been purified by immunochromatography. The immunoprophylactic value of Hc23 was tested in groups of 5-6 months old Assaf lambs using Al(OH)(3) or Escherichia coli lipopolysaccharide+inactivated Propionibacterium acnes as adjuvant and the results compared with uninfected control, uninfected and challenged or infected and challenged lambs. Immunization with Hc23 in either adjuvant elicited significant reductions in fecal egg counts after challenge with 15,000 L3s (70.67%-85.64%, respectively) and reduced (67.1% and 86%) abomasal worm counts (45 days post-challenge). Immunized lambs displayed higher peripheral eosinophil counts, were less anaemic and had weight gains than challenged controls. The results suggest that the Hc23 antigen can induce a partially protective response against haemonchosis in lambs. PMID- 24759432 TI - Letter to the editor regarding: negative pressure wound therapy. PMID- 24759431 TI - Cloning and expression of transgenes using linear vectors in Trypanosoma cruzi. AB - The identification of new targets for vaccine and drug development for the treatment of Chagas' disease is dependent on deepening our understanding of the parasite genome. Vectors for genetic manipulation in Trypanosoma cruzi basically include those that remain as circular episomes and those that integrate into the parasite's genome. Artificial chromosomes are alternative vectors to overcome problematic transgene expression often occurring with conventional vectors in this parasite. We have constructed a series of vectors named pTACs (Trypanosome Artificial Chromosomes), all of them carrying telomeric and subtelomeric sequences and genes conferring resistance to different selection drugs. In addition, one pTAC harbours a modified GFP gene (pTAC-gfp), and another one carries the ornithine decarboxilase gene from Crithidia fasciculata (pTAC-odc). We have encountered artificial chromosomes generated from pTACs in transformed T. cruzi epimastigotes for every version of the designed vectors. These extragenomic elements, in approximately 6-8 copies per cell, remained as linear episomes, contained telomeres and persisted after 150 and 60 generations with or without selection drugs, respectively. The linear molecules remained stable through the different T. cruzi developmental forms. Furthermore, derived artificial chromosomes from pTAC-odc could complement the auxotrophy of T. cruzi for polyamines. Our results show that pTACs constitute useful tools for reverse functional genetics in T. cruzi that will contribute to a better understanding of T. cruzi biology. PMID- 24759433 TI - Highly selective detection of oil spill polycyclic aromatic hydrocarbons using molecularly imprinted polymers for marine ecosystems. AB - Im*plications due to oil spills on marine ecosystems have created a great interest toward developing more efficient and selective materials for oil spill toxins detection and remediation. This research paper highlights the application of highly efficient molecularly imprinted polymer (MIP) adsorbents based on a newly developed functional crosslinker (N,O-bismethacryloyl ethanolamine, NOBE) for detection of highly toxic polycyclic aromatic hydrocarbons (PAHs) in seawater. The binding capacity of MIP for oil spill toxin pyrene is 35 mg/g as compared to the value of 3.65 mg/g obtained using a non-imprinted polymer (NIP). The selectivity of all three high molecular weight PAHs (pyrene, chrysene and benzo[a]pyrene) on the NOBE-MIP shows an excellent selective binding with only 5.5% and 7% cross-reactivity for chrysene and benzo[a]pyrene, respectively. Not only is this particularly significant because the rebinding solvent is water, which is known to promote non-selective hydrophobic interactions; the binding remains comparable under salt-water conditions. These selective and high capacity adsorbents will find wide application in industrial and marine water monitoring/remediation. PMID- 24759434 TI - Bioaccumulation and elimination kinetics of hydroxylated polybrominated diphenyl ethers (2'-OH-BDE68 and 4-OH-BDE90) and their distribution pattern in common carp (Cyprinus carpio). AB - Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have attracted wide concerns due to their toxicities and universal presence in wildlife and humans. The relatively high Kow values of OH-PBDEs imply these compounds may have a significant bioaccumulation potential, but so far, the existing data provide little information regarding the kinetics of uptake and depuration in any organisms. Here we exposed common carps separately to two OH-PBDEs, 2'-OH-BDE68 and 4-OH-BDE90, for 30 days (d) in a flow-through system, followed by a 60-d depuration period in clean water to investigate compound-specific bioaccumulation and tissue distribution. Two OH-PBDEs could accumulate in common carp, and the high concentration was observed in liver or kidney. The uptake rates (k1) of two OH-PBDEs ranged from 0.15 to 21.3 d(-1) in fish, and the elimination rates (k2) ranged from 0.027 to 0.075 d(-1), which leaded to their BCF values in 4.8-299.2 ranges. Half-lives ranged from 9.2 d to 25.6 d. The exposure concentration significantly affected BCF values but didn't change their relative compositions in liver, kidney and muscle after a long exposure time. To our knowledge, this is the first study to systematically assess uptake, depuration kinetics and tissue distribution for OH-PBDEs via a controlled experimental animal model. PMID- 24759435 TI - Current knowledge on adolescent driver distraction. PMID- 24759436 TI - Young driver distraction: state of the evidence and directions for behavior change programs. AB - Adolescent drivers are overrepresented in distraction-related motor vehicle crashes. A number of potential reasons for such an elevated risk include driving inexperience, high adoption of communication technology, increased peer involvement, and tendency to take risks, which render young drivers particularly vulnerable. Major legislative efforts in Graduated Licensing Systems that include passenger restrictions have shown positive effects. Restrictions on cell phone use are also being introduced; however, it is challenging to enforce such regulations. This article argues that such contextual, legislative interventions are an essential prevention strategy, but there is an unfilled need to introduce behavior change programs that may target adolescents, parents, and friends. A theoretical framework is applied in which risk and protective factors are identified from research within the contexts of community and jurisdiction. In the literature on distraction, social context and normative influences are key elements used to inform program design for adolescent drivers, with parental monitoring informing interventions targeting parents. Following from this assessment of the message content assessment, the design of strategies to deliver the messages is reviewed. In the current literature, school-based programs, simulations, and Web-delivered programs have been evaluated with supplementary strategies delivered by physicians and parents. Such developments are still at an early stage of development, and ultimately will need controlled implementation and evaluation studies. Of course, there is no likely single approach to prevent adolescent driver distraction. Complementary approaches such as the further development of technological interventions to manage phone use are needed. PMID- 24759438 TI - Driver distraction: a perennial but preventable public health threat to adolescents. AB - Although public health efforts have made some progress in reducing risk of adolescent motor vehicle crashes over the last three decades, new technologies and evolving behavior patterns have focused attention on the risk of distracted driving. For many of the same reasons that alcohol-impaired driving represents a distinct risk for adolescents, distracted driving has an elevated impact on this age group. Similarly, many of the strategies used to reduce alcohol-impaired driving among adolescents might be applied to driver distraction, including adults serving as role models with high standards of behavior. The unique challenge posed by the proliferation of new technological distractions may accelerate this risk behavior and may lend itself to innovative prevention efforts. PMID- 24759437 TI - Neural responses to exclusion predict susceptibility to social influence. AB - PURPOSE: Social influence is prominent across the lifespan, but sensitivity to influence is especially high during adolescence and is often associated with increased risk taking. Such risk taking can have dire consequences. For example, in American adolescents, traffic-related crashes are leading causes of nonfatal injury and death. Neural measures may be especially useful in understanding the basic mechanisms of adolescents' vulnerability to peer influence. METHODS: We examined neural responses to social exclusion as potential predictors of risk taking in the presence of peers in recently licensed adolescent drivers. Risk taking was assessed in a driving simulator session occurring approximately 1 week after the neuroimaging session. RESULTS: Increased activity in neural systems associated with the distress of social exclusion and mentalizing during an exclusion episode predicted increased risk taking in the presence of a peer (controlling for solo risk behavior) during a driving simulator session outside the neuroimaging laboratory 1 week later. These neural measures predicted risky driving behavior above and beyond self-reports of susceptibility to peer pressure and distress during exclusion. CONCLUSIONS: These results address the neural bases of social influence and risk taking; contribute to our understanding of social and emotional function in the adolescent brain; and link neural activity in specific, hypothesized, regions to risk-relevant outcomes beyond the neuroimaging laboratory. Results of this investigation are discussed in terms of the mechanisms underlying risk taking in adolescents and the public health implications for adolescent driving. PMID- 24759439 TI - Social norms and risk perception: predictors of distracted driving behavior among novice adolescent drivers. AB - PURPOSE: Adolescent drivers are at elevated crash risk due to distracted driving behavior (DDB). Understanding parental and peer influences on adolescent DDB may aid future efforts to decrease crash risk. We examined the influence of risk perception, sensation seeking, as well as descriptive and injunctive social norms on adolescent DDB using the theory of normative social behavior. METHODS: 403 adolescents (aged 16-18 years) and their parents were surveyed by telephone. Survey instruments measured self-reported sociodemographics, DDB, sensation seeking, risk perception, descriptive norms (perceived parent DDB, parent self reported DDB, and perceived peer DDB), and injunctive norms (parent approval of DDB and peer approval of DDB). Hierarchical multiple linear regression was used to predict the influence of descriptive and injunctive social norms, risk perception, and sensation seeking on adolescent DDB. RESULTS: 92% of adolescents reported regularly engaging in DDB. Adolescents perceived that their parents and peers participated in DDB more frequently than themselves. Adolescent risk perception, parent DDB, perceived parent DDB, and perceived peer DDB were predictive of adolescent DDB in the regression model, but parent approval and peer approval of DDB were not predictive. Risk perception and parental DDB were stronger predictors among males, whereas perceived parental DDB was stronger for female adolescents. CONCLUSIONS: Adolescent risk perception and descriptive norms are important predictors of adolescent distracted driving. More study is needed to understand the role of injunctive normative influences on adolescent DDB. Effective public health interventions should address parental role modeling, parental monitoring of adolescent driving, and social marketing techniques that correct misconceptions of norms related to around driver distraction and crash risk. PMID- 24759440 TI - Peer passenger influences on male adolescent drivers' visual scanning behavior during simulated driving. AB - PURPOSE: There is a higher likelihood of crashes and fatalities when an adolescent drives with peer passengers, especially for male drivers and male passengers. Simulated driving of male adolescent drivers with male peer passengers was studied to examine passenger influences on distraction and inattention. METHODS: Male adolescents drove in a high-fidelity driving simulator with a male confederate who posed either as a risk-accepting passenger or as a risk-averse passenger. Drivers' eye movements were recorded. The visual scanning behavior of the drivers was compared when driving alone with when driving with a passenger and when driving with a risk-accepting passenger with a risk-averse passenger. RESULTS: The visual scanning of a driver significantly narrowed horizontally and vertically when driving with a peer passenger. There were no significant differences in the times the drivers' eyes were off the forward roadway when driving with a passenger versus when driving alone. Some significant correlations were found between personality characteristics and the outcome measures. CONCLUSIONS: The presence of a male peer passenger was associated with a reduction in the visual scanning range of male adolescent drivers. This reduction could be a result of potential cognitive load imposed on the driver due to the presence of a passenger and the real or perceived normative influences or expectations from the passenger. PMID- 24759441 TI - Distracted driver behaviors and distracting conditions among adolescent drivers: findings from a naturalistic driving study. AB - PURPOSE: The proliferation of new communication technologies and capabilities has prompted concern about driving safety. This concern is particularly acute for inexperienced adolescent drivers. In addition to being early adopters of technology, many adolescents have not achieved the degree of automaticity in driving that characterizes experienced adults. Consequently, distractions may be more problematic in this group. Yet little is known about the nature or prevalence of distracted driving behaviors or distracting conditions among adolescent drivers. METHOD: Vehicles of 52 high-school age drivers (N=38 beginners and N=14 more experienced) were equipped for 6 months with unobtrusive event-triggered data recorders that obtain 20-second clips of video, audio, and vehicle kinematic information when triggered. A low recording trigger threshold was set to obtain a sample of essentially random driving segments along with those indicating rough driving behaviors. RESULTS: Electronic device use (6.7%) was the most common single type of distracted behavior, followed by adjusting vehicle controls (6.2%) and grooming (3.8%). Most distracted driver behaviors were less frequent when passengers were present. However, loud conversation and horseplay were quite common in the presence of multiple peer passengers. These conditions were associated with looking away from the road, the occurrence of serious events, and, to a lesser extent, rough driving (high g-force events). CONCLUSIONS: Common assumptions about adolescent driver distraction are only partially borne out by in-vehicle measurement. The association of passengers with distraction appears more complex than previously realized. The relationship between distractions and serious events differed from the association with rough driving. PMID- 24759443 TI - Keep your eyes on the road: young driver crash risk increases according to duration of distraction. AB - PURPOSE: Secondary task engagement that distracts the driver is a contributing factor to motor vehicle crashes among adults. However, the association between eye glance duration and crash risk with novice teenage drivers has not been determined. METHODS: Vehicles of 42 newly licensed teenage drivers were instrumented with cameras, accelerometers, Global Positioning System(s) (GPS), and other devices. Data were collected continuously for 18 months. Crashes and near crashes (CNCs) were identified by examining highly elevated gravitational force events. Video footage of the 6 seconds prior to each CNC and randomly sampled non-CNC road segments were coded for the duration of eye glances off the forward roadway and the presence of secondary task engagement. The likelihood (odds ratios) of CNC due to eye glance behavior was calculated by comparing the prevalence of secondary task engagement and duration of eyes off road prior to CNC with the prevalence and duration of eyes off road during non-CNC road segments. RESULTS: Crash risk increased with the duration of single longest glance during all secondary tasks (OR=3.8 for >2 s) and wireless secondary task engagement (OR=5.5 for >2 s). Single longest glance provided a more consistent estimate of crash risk than total time eyes off the forward roadway. CONCLUSIONS: Those eye glances away from the forward roadway involving secondary tasks increased the likelihood of CNC. The longer the duration of eye glance away from the road the greater the risk, regardless of type of secondary task. Education and policy discouraging secondary task engagement, particularly for prolonged periods, is warranted. PMID- 24759442 TI - Adolescence, attention allocation, and driving safety. AB - Motor vehicle crashes are the leading source of morbidity and mortality in adolescents in the United States and the developed world. Inadequate allocation of attention to the driving task and to driving hazards are important sources of adolescent crashes. We review major explanations for these attention failures with particular focus on the roles that brain immaturity and lack of driving experience play in causing attention problems. The review suggests that the potential for overcoming inexperience and immaturity with training to improve attention to both the driving task and hazards is substantial. Nevertheless, there are large individual differences in both attentional abilities and risky driving tendencies that pose challenges to novice driver policies. Research that can provide evidence-based direction for such policies is urgently needed. PMID- 24759444 TI - The impact of Michigan's text messaging restriction on motor vehicle crashes. AB - PURPOSE: The purpose of this study was to determine the effects of Michigan's universal text messaging restriction (effective July 2010) across different age groups of drivers and crash severities. METHODS: Changes in monthly crash rates and crash trends per 10,000 licensed drivers aged 16, 17, 18, 19, 20-24, and 25 50 years were estimated using time series analysis for three levels of crash severity: (1) fatal/disabling injury; (2) nondisabling injury; and (3) possible injury/property damage only (PDO) crashes for the period 2005-2012. Analyses were adjusted for crash rates of drivers' aged 65-99 years, Michigan's unemployment rate, and gasoline prices. RESULTS: After the introduction of the texting restriction, significant increases were observed in crash rates and monthly trends in fatal/disabling injury crashes and nondisabling injury crashes, and significant decreases in possible injury/PDO crashes. The magnitude of the effects where significant changes were observed was small. CONCLUSIONS: The introduction of the texting restriction was not associated with a reduction in crash rates or trends in severe crash types. On the contrary, small increases in the most severe crash types (fatal/disabling and nondisabling injury) and small decreases in the least severe crash types (possible injury/PDO) were observed. These findings extend the literature on the effects of cell phone restrictions by examining the effects of the restriction on newly licensed adolescent drivers and adult drivers separately by crash severity. PMID- 24759445 TI - Short-wavelength cone-opponent retinal ganglion cells in mammals. AB - In all of the mammalian species studied to date, the short-wavelength-sensitive (S) cones and the S-cone bipolar cells that receive their input are very similar, but the retinal ganglion cells that receive synapses from the S-cone bipolar cells appear to be quite different. Here, we review the literature on mammalian retinal ganglion cells that respond selectively to stimulation of S-cones and respond with opposite polarity to longer wavelength stimuli. There are at least three basic mechanisms to generate these color-opponent responses, including: (1) opponency is generated in the outer plexiform layer by horizontal cells and is conveyed to the ganglion cells via S-cone bipolar cells, (2) inputs from bipolar cells with different cone inputs and opposite response polarity converge directly on the ganglion cells, and (3) inputs from S-cone bipolar cells are inverted by S cone amacrine cells. These are not mutually exclusive; some mammalian ganglion cells that respond selectively to S-cone stimulation seem to utilize at least two of them. Based on these findings, we suggest that the small bistratified ganglion cells described in primates are not the ancestral type, as proposed previously. Instead, the known types of ganglion cells in this pathway evolved from monostratified ancestral types and became bistratified in some mammalian lineages. PMID- 24759446 TI - S-cone psychophysics. AB - We review the features of the S-cone system that appeal to the psychophysicist and summarize the celebrated characteristics of S-cone mediated vision. Two factors are emphasized: First, the fine stimulus control that is required to isolate putative visual mechanisms and second, the relationship between physiological data and psychophysical approaches. We review convergent findings from physiology and psychophysics with respect to asymmetries in the retinal wiring of S-ON and S-OFF visual pathways, and the associated treatment of increments and decrements in the S-cone system. Beyond the retina, we consider the lack of S-cone projections to superior colliculus and the use of S-cone stimuli in experimental psychology, for example to address questions about the mechanisms of visually driven attention. Careful selection of stimulus parameters enables psychophysicists to produce entirely reversible, temporary, "lesions," and to assess behavior in the absence of specific neural subsystems. PMID- 24759447 TI - Quantifying differences in the epidemic curves from three influenza surveillance systems: a nonlinear regression analysis. AB - Influenza surveillance enables systematic collection of data on spatially and demographically heterogeneous epidemics. Different data collection mechanisms record different aspects of the underlying epidemic with varying bias and noise. We aimed to characterize key differences in weekly incidence data from three influenza surveillance systems in Melbourne, Australia, from 2009 to 2012: laboratory-confirmed influenza notified to the Victorian Department of Health, influenza-like illness (ILI) reported through the Victorian General Practice Sentinel Surveillance scheme, and ILI cases presenting to the Melbourne Medical Deputising Service. Using nonlinear regression, we found that after adjusting for the effects of geographical region and age group, characteristics of the epidemic curve (including season length, timing of peak incidence and constant baseline activity) varied across the systems. We conclude that unmeasured factors endogenous to each surveillance system cause differences in the disease patterns recorded. Future research, particularly data synthesis studies, could benefit from accounting for these differences. PMID- 24759448 TI - Feasibility of HIV Universal Voluntary Counseling and Testing in a Thai General Practice Clinic. AB - An HIV transmission prevention program incorporating universal voluntary counseling and testing (UVCT) was conducted in a general practice (GP) clinic of a Thai hospital. Of the 494 participating patients, 356 (72%) accepted HIV-UVCT. Independent factors associated with HIV-UVCT acceptance included participating in the program after office hours (4-8 pm; P < .001), living with domestic partner with no marriage (P = .01), and having primary school education or less (P = .02). The main reasons for declining HIV-UVCT were time constraint (38%) and perceiving self as no risk (35%). Among the 356 patients undergoing HIV-UVCT, having moderate to high HIV risk (P < .001) and male sex (P = .01) were independently associated with low HIV risk perception. By HIV-UVCT, the rate of new HIV infection was 4 (1.1%) of 356 patients. Of these 4 newly diagnosed HIV infected patients, 3 (75%) were homosexual men. The findings suggest feasibility of HIV-UVCT in our GP clinic and factors to be considered for improving the program. PMID- 24759449 TI - A Case of Cerebellar Ataxia Associated with HIV Infection. AB - Cerebellar complications of HIV infection primarily manifested in ataxia, usually arise as the result of cerebellar lesions due to opportunistic infections, vasculitis or neoplastic processes. A 28 year old female known to have HIV infection for last four years, presented to our hospital with progressive unsteadiness in walking, slurring of speech and intention tremors for the last two months. There was no family history of similar complaints, and she was on Anti retroviral treatment for last one and a half years. The results of examination were notable for severe dysarthria, slow saccades, a conspicuous dysmetria and dysdiadokokinesia. She had no cognitive, sensory or motor deficits. MRI revealed diffuse cerebellar atrophy. Extensive laboratory work up failed to disclose a cause for subacute ataxia. Isolated cerebellar degeneration in an HIV patient is rare and should prompt a diagnostic work up. PMID- 24759450 TI - Pearly penile papules. PMID- 24759451 TI - Central solitary incisor in a 9-year-old girl: more than a cosmetic issue. PMID- 24759452 TI - Vitamin D deficiency in HIV: a shadow on long-term management? AB - Vitamin D deficiency in HIV infection has attracted much interest. The best known clinical outcomes of vitamin D deficiency are rickets (children) and osteomalacia (adults). Several non-skeletal disorders have also been linked to suboptimal vitamin D levels in the general population. The prevalence of vitamin D deficiency varies widely (6-100%) across diverse patient populations, with no evidence that it is higher in HIV-positive versus noninfected adults. Vitamin D deficiency may blunt immune restoration and exacerbate HIV complications (e.g. opportunistic infections, poor perinatal outcomes, wasting, HIV disease progression, AIDS events, and death). The nonnucleoside reverse transcriptase inhibitor efavirenz was associated with a relatively high risk of vitamin D deficiency; nevirapine, etravirine, and rilpivirine were noted to have less or no impact on vitamin D versus efavirenz in the limited data available. Protease inhibitors have either no or a low association with vitamin D deficiency. Nucleoside/nucleotide reverse transcriptase inhibitors (with the possible exception of zidovudine) also did not appear to be associated with vitamin D deficiency. Management of vitamin D deficiency in HIV-positive adults has not been rigorously evaluated; some guidelines recommend more vitamin D supplementation for HIV-positive adults on antiretrovirals versus the general population (e.g. 2-3 times higher vitamin D daily intake for the age group; loading dose up to 10,000 IU/day for 8-10 weeks and a maintenance dose of 800 2,000 IU/day). In conclusion, although vitamin D deficiency in HIV-positive adults can be prevalent, current evidence for its causes and impact is relatively weak. More data, particularly from large, controlled, long-term trials, regarding the benefits of correcting vitamin D levels in HIV-positive adults are needed. PMID- 24759453 TI - Morbidity in older HIV-infected patients: impact of long-term antiretroviral use. AB - The introduction of HAART has represented a major advance in the care of people with HIV. By markedly increasing life expectancy, HAART has significantly changed the pattern of HIV infection in developed countries, the "graying" of the HIV infected population being a powerful testament to its success. However, this has presented physicians with new challenges relating to the care of older patients with HIV, many of whom exhibit a "frailty syndrome" associated with increased comorbidity and chronic low-grade inflammation in a process which has recently been termed "inflammaging". This paper reviews the pattern of morbidity seen in older HIV-infected patients and examines the effects, both beneficial and deleterious, of antiretroviral therapy. The efficacy and tolerability of antiretroviral therapy is of particular importance in older patients, given the likelihood that increased frailty may magnify the consequences both of suboptimal viral suppression and of toxicity, and in view of the complications that may arise from the presence of comorbidities and resultant polypharmacy. The challenge is to maximize antiviral efficacy and minimize toxicity, while taking into account the often complex web of comorbidities that may be present in these patients. This challenge is being met through the refinement of existing antiretroviral therapy regimens, the development of new agents, and a growing focus on a more holistic approach to care, which acknowledges the importance of the overall "health picture" and of good communication and cooperation between treating physicians and patients. PMID- 24759455 TI - Invite an adversary to lunch. PMID- 24759454 TI - A red-shifted fluorescent substrate for aldehyde dehydrogenase. AB - Selection of cells positive for aldehyde dehydrogenase (ALDH) activity from a green-fluorescent background is difficult with existing reagents. Here we report a red-shifted fluorescent substrate for ALDH, AldeRed 588-A, for labelling viable ALDH(pos) cells. We demonstrate that AldeRed 588-A successfully isolates ALDH(hi) human haematopoietic stem cells from heterogeneous cord blood mononuclear cells. AldeRed 588-A can be used for multicolour applications to fractionate ALDH(pos) cells in the presence of green fluorophores including the ALDEFLUOR reagent and cells expressing enhanced green-fluorescent protein (eGFP). AldeRed 588-A stains ALDH(pos) murine pancreatic centroacinar and terminal duct cells, as visualized using fluorescent microscopy. AldeRed588-A provides a useful tool to select stem cells or study ALDH within a green-fluorescent background. PMID- 24759456 TI - Power napping for nurses. AB - An underutilized strategy for staying sharp and engaged in the course of a shift. PMID- 24759457 TI - Interview with Julie Sochalski. PMID- 24759458 TI - Interview with Julie Sochalski. PMID- 24759459 TI - Interruptions and errors. PMID- 24759460 TI - Straight talk about nursing. PMID- 24759463 TI - Chest physiotherapy for pneumonia in children. PMID- 24759464 TI - Cases of neural tube defects in Washington State. Many questions, few answers. PMID- 24759465 TI - Infections spread during children's clinic visits. PMID- 24759467 TI - Quitting smoking also improves mental health. PMID- 24759470 TI - The VAWA makes American Indian women safer. PMID- 24759471 TI - Childhood deaths from car accidents decrease. PMID- 24759473 TI - Heroin: life, death, and politics. PMID- 24759479 TI - Constructing a search strategy and searching for evidence. A guide to the literature search for a systematic review. AB - This article is the third in a new series on the systematic review from the Joanna Briggs Institute, an international collaborative supporting evidence-based practice in nursing, medicine, and allied health fields. The purpose of the series is to show nurses how to conduct a systematic review-one step at a time. This article details the major considerations surrounding search strategies and presents an example of a search using the PubMed platform (pubmed.gov). PMID- 24759480 TI - Noise in the ICU. PMID- 24759481 TI - Delineating the role of the part-time clinical nurse instructor. PMID- 24759482 TI - Lessons learned from litigation: the case of Bernard Travaglini. PMID- 24759483 TI - Intensive care. AB - The author finds his ideal of nursing care in an inpatient hospice. PMID- 24759484 TI - Multisensory integration, sensory substitution and visual rehabilitation. AB - Sensory substitution has advanced remarkably over the past 35 years since first introduced to the scientific literature by Paul Bach-y-Rita. In this issue dedicated to his memory, we describe a collection of reviews that assess the current state of neuroscience research on sensory substitution, visual rehabilitation, and multisensory processes. PMID- 24759486 TI - Analysis of infant lumbar puncture success rates: sitting flexed versus lateral flexed positions. AB - OBJECTIVES: The primary objective was to determine whether the sitting flexed position yields higher success rates of obtaining cerebrospinal fluid (CSF) for culture. The secondary objectives were to determine whether the sitting flexed position yields higher success rates of obtaining the following: CSF for cell count, non-traumatic CSF, and CSF on the first attempt. METHODS: The study investigator performed a retrospective chart review of infants 0 to 365 days of age who had a lumbar puncture (LP) performed from January 1 to December 31 of 2010. Data on the LP position and the number of attempts were abstracted from procedure notes. Twenty-one LPs were excluded because of incomplete data on LP position and/or number of attempts. Spinal fluid count results were obtained from electronic medical records. Non-traumatic LPs were defined in 2 categories: CSF red blood cell counts of 500 cells per cubic millimeter or less and 10,000 cells per cubic millimeter or less. RESULTS: One hundred thirty-two LPs were included: 30 sitting flexed and 102 lateral flexed. There were no differences in success rates between positions for the primary objective of obtaining CSF for culture and the secondary study objectives of obtaining CSF for cell count and non traumatic CSF. A significant secondary objective was that operators who performed the LP in the sitting flexed position were more likely to obtain CSF on the first attempt (odds ratio, 2.74; confidence interval, 1.17-6.45). CONCLUSIONS: The sitting flexed position was as successful as the lateral flexed position in the primary objective of obtaining CSF for culture and the secondary objectives of obtaining CSF for cell count and non-traumatic CSF. For the secondary objective of obtaining CSF on the first attempt, the sitting flexed position was associated with a higher rate of obtaining CSF on the first attempt in infants younger than 12 months. PMID- 24759487 TI - Fluoroscopy screen time during contrast enema for the evaluation and treatment of intussusception. AB - OBJECTIVE: The objective of this study was to describe fluoroscopy screen time (FST) for children undergoing contrast enema (CE) for suspected intussusception. METHODS: This is a single-center, retrospective cohort study of children younger than 7 years examined for intussusception by CE. We reviewed medical records for demographics, radiographic results, and FST. We used nonparametric descriptive statistical tests and calculated odds ratios (OR). RESULTS: The median FST for 457 included CEs was 116 seconds. The median FST for positive CEs (n = 194) was 138 seconds (95% confidence interval [CI], 126-152); for negative CEs (n = 250), 86 seconds (95% CI, 78-102); and for uncertain studies (n = 13), 138 seconds (95% CI, 89-208) (P < 0.01). There was no difference in median FST if symptoms were present 24 hours or less versus longer than 24 hours. There was no difference between contrast types. Median FST for successful reductions was 122 seconds (95% CI, 114-138). In cases of failed reductions, median FST for those undergoing surgery was 277 seconds (95% CI, 195-370) and 175 seconds (95% CI, 128-271) (P < 0.01) for those undergoing delayed repeat CE. The OR for receiving a repeat CE was 1.3 (95% CI, 1.1-1.4; P < 0.01) for every minute of FST. The OR for undergoing surgical reduction was 1.3 (95% CI, 1.2-1.5; P < 0.01) for every minute of FST and 3.7 (95% CI, 2.0-6.9; P < 0.01) for FST longer than 3 minutes. CONCLUSIONS: Fluoroscopy screen time for the evaluation and diagnosis of intussusception is shorter than that previously described. When an initial screening ultrasound is not available or nondiagnostic and the suspicion is high, further evaluation with a CE may be warranted because the radiation exposure is likely lower than that previously reported. PMID- 24759488 TI - Pediatric syncope: is detailed medical history the key point for differential diagnosis? AB - Syncope is a transient loss of consciousness as a result of global cerebral hypoperfusion. It is generally benign but may be a sign of pathology. The purpose of this study was to analyze the frequency of syncope due to cardiac, neurocardiogenic, neurologic, situational, psychiatric, and other causes and make a differential diagnosis of syncope types according to detailed medical history and further investigations. We examined prospectively 268 children presented to pediatric polyclinics as well as cardiology and neurology departments (age range, 1-18 years) with a primary complaint of syncope for the study. Cardiac syncope was diagnosed in 12 patients, neurocardiogenic syncope in 232, neurologic syncope in 9, psychiatric syncope in 9, situational in 4, and benign paroxysmal positional vertigo in 2. The neurologic syncope group consists of patients diagnosed with epilepsy after evaluation. Eight patients in the cardiac syncope group were found to have diseases such as long QT syndrome, and the remaining patients had hypertrophic cardiomyopathy, atrioventricular nodal reentry tachycardia, ventricular tachycardia, and a second-degree heart block that can cause sudden death. In conclusion, syncope is a common problem in childhood that requires hospitalization. Because it may be the first finding of an underlying malignant cardiac or neurologic disease, clinicians must be very careful during medical evaluation. An electrocardiogram and a medical history including the details of the event, chronic diseases, and familial diseases are among the most important steps for the right diagnosis and prognosis. Instead of a routine procedure, further diagnostic workup should be directed according to medical history for high yield. Convulsive movements may be defined in all types of syncope related with cerebral hypoxia, and this may lead to a misdiagnosis of seizure by the clinician. PMID- 24759489 TI - Oral, jaw, and neck injury in infants and children: from abusive trauma or intubation? AB - OBJECTIVES: The objective of this study was to identify the incidence of oral, jaw, and neck injury secondary to endotracheal intubation in young children. METHODS: This prospective observational study was conducted in the pediatric intensive care unit at a level 1 trauma center. From October 1998 to January 1999 and November 2007 to April 2008, all intubated patients younger than 3 years with no prior oral procedures were examined within 24 hours of intubation. A standardized form was used to record injuries. Separately, medical records were reviewed for prior injuries. Chi-square/Fisher exact test was used for statistical analysis. RESULTS: Of 105 patients included in the study, 12 had oral, jaw, or neck injury. One patient had a hard palate injury from a pen cap in his mouth during a seizure. Another broke a tooth biting the laryngoscope blade (the only injury directly attributable to intubation). The remaining 10 patients were determined to be those who experienced abusive trauma. The overall incidence of injury directly from intubation was 0.9%. Oral, jaw, and neck injuries were all significantly associated with abusive trauma (P < 0.001). Eleven patients had difficult intubations: 9 had no injuries, 1 experienced abusive trauma and the second was the patient who broke his tooth during intubation. CONCLUSIONS: Oral, jaw, or neck injury in young children is rarely caused by endotracheal intubation, regardless of difficulty during the procedure. PMID- 24759491 TI - Compliance of colleges and universities in the United States with nationally published guidelines for emergency and disaster preparedness. AB - OBJECTIVES: The aim of this study was to determine the compliance of colleges and universities in the United States with nationally published guidelines by the Federal Emergency Management Agency and the U.S. Department of Education for emergency and disaster preparedness at institutions of higher education. METHODS: A questionnaire was electronically distributed to the director of security personnel of 1167 institutions between January 2010 and August 2011. RESULTS: Two hundred twenty-three questionnaires were available for analysis. Although 96% of the institutions had an official emergency and disaster plan, 10% do not practice the plan, 27% have not conducted tabletop exercises, and 20% do not perform after action reports. Ninety-two percent of the institutions have a campus-wide communication system. Approximately half of the institutions include disaster preparedness as part of student/faculty employment orientation. Sixteen percent of the institutions have not included their local fire/police/emergency medical services in the development and implementation of their plan, and 31% of the institutions have not discussed preparedness with their local hospital. Whereas 96% of the institutions have established evacuation procedures, 19% have never practiced these procedures, 24% have not designated safe locations on campus, 44% have not designated safe locations in the surrounding community, and 50% do not have methods of transportation in the event of a campus-wide evacuation. CONCLUSIONS: Although most of the institutions in our study reported having an emergency and disaster plan based on national recommendations, areas for improvement were identified. PMID- 24759490 TI - Emergency department visits in the neonatal period in the United States. AB - OBJECTIVES: This study aimed to estimate the incidence of emergency department (ED) visits in the neonatal period in a nationally representative sample and to examine variation by race. METHODS: The National Hospital Ambulatory Medical Care Survey is a nationally representative survey of utilization of ambulatory care services including EDs. We studied all ED visits for patients who were younger than 28 days old from 2003 to 2008. Using the national birth certificate data, we calculated the visit rates by race. Emergency department visits were also characterized by age, insurance status, diagnosis category, region, and hospital type (safety-net vs non-safety-net hospitals). RESULTS: There was an average of 320,540 neonatal ED visits in the United States per year, with an estimated 7.6% of births visiting the ED within 28 days. Estimated rates of ED visits were highest among non-Hispanic blacks, with 14.4% (95% confidence interval [CI], 10.0 19.2) of newborns having an ED visit in the neonatal period, compared with 6.7% (95% CI, 4.9-7.2) for whites and 7.7% (95% CI, 5.7-9.8) for Hispanics. Hispanic and black neonates were more likely to be seen in safety-net hospitals (75.8% 78.2%) than white (57.1%) patients (P = 0.004). CONCLUSIONS: In this first nationally representative study of neonatal visits to the ED, visits were common, with the highest rates in non-Hispanic blacks. Hispanic and black neonates were more commonly seen in safety-net hospitals. Reasons for high visit rates deserve further study to determine whether hospital discharge practices and/or access to primary care are contributing factors. PMID- 24759492 TI - A prospective study of pediatric hand fractures and review of the literature. AB - OBJECTIVE: Hand fractures represent a leading cause of morbidity in children. However, little information exists correlating the mechanisms and environment of injury with outcomes and treatments. We examine the demographics, etiology, anatomic location, mechanism, and management of pediatric hand fractures in our center's hand unit. METHODS: We conducted a prospective observational study on all children with acute hand fractures evaluated in the Plastic Surgery Emergency Clinic during a 3-month period in 2010. Data pertaining to demographics, referral patterns, injury pattern, clinical outcomes, and other factors related to hand fractures were then analyzed and interpreted. RESULTS: Most children were referred by our institution's emergency department. More than 60% were boys, and nearly half were between 10 and 15 years old. The right and left hands were injured at equal rates. Most of the injuries (90%) occurred in the afternoon or evening. More than 85% occurred in urban, rather than rural, environments. Crush injuries were the leading cause in toddlers, whereas sports-related injuries became the major cause of injury in older groups. Proximal phalanges were the most common bone injured, and the fifth digit was the most commonly injured digit. More than 80% of the fractures were managed nonsurgically. CONCLUSIONS: The pattern of pediatric hand fracture in different age groups is highlighted in this article. The observations from this study will hopefully encourage further review with a larger cohort and a focus on preventative measures for pediatric hand fractures. PMID- 24759493 TI - Small longitudinal S incision and page turning style of annular ligament partial resection to treat stenosing tenosynovitis of thumb flexor tendon. AB - BACKGROUND: To present the treatment outcome for patients with stenosing tenosynovitis of thumb flexor tendon treated with a small S incision and page turning style of annular ligament partial resection. MATERIAL AND METHODS: During a 2-year period between August 2011 and July 2013, 12 consecutive patients (mean age, 45.8 years) with stenosing tenosynovitis of the thumb flexor tendon were prospectively enrolled into this study. All 12 patients underwent longitudinal S skin incision to expose annular ligament and thumb flexor tendon, and with page turning style of annular ligament partial resection to finish the operation. The average range of motion of metacarpophalangeal thumb joint, Quick disability of arm, shoulder, and hand and Short Musculoskeletal Function Assessment Dysfunction score of arm and hand were primary outcome measures. RESULTS: There were 9 cases of stiff metacarpophalangeal joint of thumb and 3 cases of snapping thumb for stenosing tenosynovitis. At 1-year follow-up, all stenosing tenosynovitis had healed by an average of 4 weeks. The average range of motion of the metacarpophalangeal joint was 37.1 degrees (range, 34-40 degrees ). No patients had recurrence, cicatricial contraction, or postoperative infection. The average disability of arm, shoulder, and hand was 0.3 out of 100 (range, 0-1.67), and average Short Musculoskeletal Functional Assessment Dysfunction score of arm and hand was 6.9 out of 40 (range, 0-15.6). All 12 patients stated that they were highly satisfied. CONCLUSIONS: Small S incision and page turning style of annular ligament partial resection for stenosing tenosynovitis of thumb flexor tendon is a safe, simple, and reliable alternative treatment with minimal soft-tissue irritation, good functional results and recovery can be expected. PMID- 24759494 TI - [Clinical features of six patients with pancreas metastasis from renal cell carcinoma]. AB - We retrospectively reviewed patients who underwent radical or partial nephrectomy and were followed up in Oji General Hospital from 1992 through 2012. A total of 6 patients had disease recurrence in the pancreas during follow-up. We investigated their clinical features and treatment outcomes. The median age at diagnosis was 75 years. The median interval from nephrectomy to the detection of pancreatic metastasis was 114 months. As local therapy for metastasis, surgical resection was selected for 4 patients. On the other hand, administration of medication, including interferon alpha and sunitinib was selected for 2 patients with other simultaneous metastatic sites. One of the 4 patients with surgical resection had disease recurrence in the residual pancreas and needed additional excision. At the median follow-up of 38 months after treatment of pancreatic metastasis, one patient remained alive without evidence of disease, 3 patients were alive with recurrent disease, and 2 patients had died of the disease. PMID- 24759495 TI - [A case of multiple bony pain due to metastatic malignant pheochromocytoma successfully treated with strontium-89]. AB - A 50-year-old woman complaining of right flank pain visited our hospital. Computed tomography revealed adrenal gland tumor measuring 10 cm in diameter, and multiple bone and liver metastases. It was diagnosed as a malignant pheochromocytoma by means of endocrinological examination and metaiodobenzylguanidine scintigraphy. Although 8 courses of cyclophosphamide, vincristine and dacarbazine therapy were performed, the tumor grew larger gradually, and the bony pain progressed and became uncontrollable with oxycodone hydrochloride. After zoredronic acid and strontium-89 were administered, the bony pain reduced, and the opioid usage could be reduced. In accordance with disease progression, the bony pain progressed again, but the readministration of strontium-89 could diminish the pain again. To our knowledge, this is the first case of malignant pheochromocytoma which strontium-89 was administered, and was effective. PMID- 24759496 TI - [Leiomyosarcoma of the inferior vena cava: a case report and review]. AB - A 37-year-old woman with an incidentally found abdominal mass was referred to our hospital. A fixed, non-tender mass was palpated in the right upper quadrum of her abdomen. There was no elevation of tumor markers. Computed tomography revealed a mass extending from the hepatic vein level to renal hilar level. The tumor completely obstructed the inferior vena cava (IVC). T1-weighted magnetic resonance imaging (MRI) showed that the mass was isointense with muscles. T2 weighted MRI image with contrast medium demonstrated collateral circulation. Upon diagnosis of the IVC tumor, we removed the right kidney and the tumor en bloc without reconstructing IVC. The tumor diameter was 11.6 * 5.5 * 4.7 cm. Pathological examination established a diagnosis of IVC leiomyosarcoma. She is alive without sign of recurrence after operation for seven months. There were 143 reports of IVC leiomyosarcoma in Japan. In 31% of them, IVC was not reconstructed. PMID- 24759497 TI - [Successful conservative management of blunt renal rupture in a girl]. AB - An 11-year-old girl visited the emergency room of our hospital with complaints of pain, nausea and gross hematuria after abdominal injury due to a fall from a fence. Computed tomography (CT) showed ruptured right kidney, hematoma, urinoma, and slight liver damage in S7 area. According to the Classification of Renal Injury by the Japanese Association for the Surgery of Trauma, this case was Type IIIb, but according to the American Association for the Surgery of Trauma Organ Injury Severity Scale for the Kidney, it was Type V. Because her vital signs were stable after admission, conservative management was initiated. There was no progression of anemia, and blood transfusion was not required. Right ureteral stenting was performed on the 4th hospital day because of an increase in fluid accumulation around the right kidney. Percutaneous drainage was performed on the 9th hospital day because of a further increase in fluid accumulation around the right kidney. After percutaneous drainage, fluid accumulation around the kidney was improved, and the drainage tube was removed on the 20th hospital day. The patient was discharged on the 22nd day. Although the decreased blood flow in the ruptured portion of the right kidney was observed in a subsequent CT scan, renal scintigraphy showed a relatively well maintained function of the right kidney (split renal function; right 38% and left 62%). She had no increase in blood pressure one year after renal injury. PMID- 24759498 TI - [A case report of metastatic renal cell carcinoma to the bladder]. AB - 70-year-old man was suffering from asymptomatic gross hematuria. Computed tomography demonstrated the mass in the right kidney, bladder, bone and lung. Cystoscopy revealed a solitary, nonpapillary lesion at the right side of the dome. At first, transuretheral resection of bladder tumor was performed. The pathological diagnosis was clear cell carcinoma of unknown origin. Sequentially, retroperitoneoscopic nephrectomy was performed. The pathological diagnosis of the right renal tumor was also clear cell carcinoma. The diagnosis was renal cell carcinoma metastasized to the bladder, bone and lung. To our knowledge, in Japan, this is the 45th case of metastasis to the bladder of renal cell carcinoma in the literature. PMID- 24759499 TI - [Castleman's disease of the kidney: a case report]. AB - Castleman's disease is a rare disorder characterized by benign proliferation of lymphoid tissue. A 61-year-old man was referred to our department for a renal mass incidentally detected by magnetic resonance imaging. Computed tomography showed a 18 * 20 * 14 mm mass in the upper pole of the right kidney, which enhanced at the early phase and washed out at the late phase. On the diagnosis of renal cell carcinoma, laparoscopic partial nephrectomy was performed. Pathological examinations revealed a hyaline-vascular type of Castleman's disease confined to the kidney. PMID- 24759500 TI - [Metastatic collecting duct carcinoma with relatively long-term survival treated with sunitinib: a case report]. AB - A 51-year-old man visited our hospital with a chief complaint of left renal mass detected by ultrasonography in another hospital. Enhanced computed tomography (CT) revealed a hypovascular tumor measuring about 9 cm in the left kidney, tumor thrombus in the inferior vena cava and paraaortic lymph nodes metastases. Radical left transperitoneal nephrectomy with removal of the thrombus from the left renal vein were performed. Paraaortic lymph nodes dissection was partially performed because of the solid adhesion to aorta. Histological examination revealed collecting duct carcinoma (CDC). He was treated with systemic chemotherapy (gemcitabine plus nedaplatin) followed by sunitinib. Duration of stable disease after initiation of therapy was seventeen months, and survival after surgery was 31 months. It would be worthwhile to prospectively evaluate the antitumor activity of tyrosine kinase inhibitors against metastatic CDC. PMID- 24759501 TI - [Upper tract urothelial carcinoma associated with giant hydronephrosis due to ligation of a ureter: a case report]. AB - A 73-year-old woman was referred to our hospital with a complaint of left lumbar backache. Computed tomography (CT) revealed left giant hydronephrosis containing high-density fluid suspected of hemorrhage in the renal pelvis and swelling of cervical and mediastinal lymph nodes. Positron emission tomography (PET)-CT showed a small high uptake lesion in the left kidney parenchyma, and cervical and mediastinal lymph nodes. Percutaneous pelvic puncture yielded discharge of hemorrhagic fluid with negative cytology. Preoperative diagnosis was left giant hydronephrosis due to ligation of a left ureter at uterine myomectomy 43 years ago with renal hemorrhage caused by recent back injury, and cervical and mediastinal lymph node involvement of unknown origin. Because severe lumbar backache persisted, we performed palliative left nephrectomy and biopsy of cervical lymph nodes. The pathological diagnosis was invasive urothelial carcinoma with squamous differentiation and lymph node involvement. PMID- 24759502 TI - [Metastatic ureteral tumor from colon cancer: a case report]. AB - A 53-year-old man was referred for further examination of left hydronephrosis. He had undergone high anterior resection for sigmoid colon cancer about 2 years previously. Retrograde pyelography demonstrated a filling defect in the middle portion of the left ureter. Brushing cytology of the lesion was class IV. Left nephroureterectomy was performed. Histology indicated metastatic adenocarcinoma from colon cancer. PMID- 24759503 TI - [A case of urachal carcinoma with multiple lung metastases treated by TS-1/CDDP chemotherapy]. AB - A 67-year-old woman presented with macroscopic hematuria and lower abdominal pain. Cystoscopy revealed a broad-stalk non-papillary tumor at the bladder dome. Computed tomography (CT) showed a tumor extending from the umbilicus to the bladder dome, together with multiple lung metastases. Serum carcinoembryonic antigen and cancer antigen (CA19-9) levels were elevated at 7.0 ng/ml and 180 U/ml, respectively. Transurethral resection of the tumor was performed and histopathology revealed adenocarcinoma. Therefore, the tumor was diagnosed as a stage IVB (Sheldon's category) urachal carcinoma. En bloc segmental resection of the urachal carcinoma with the bladder dome was performed, followed by chemotherapy with tegafur, gimestat, and otastat potassium (TS-1) and cisplatin. The disease remained stable for 8 months. However, a follow up CT scan after 11 chemotherapy cycles showed progression of the lung metastases. In spite of the change to a second-line gemcitabine and cisplatin chemotherapy regimen, the disease continued to progress after 4 cycles. PMID- 24759504 TI - [Small cell carcinoma in a vesical diverticulum: a case report]. AB - We report a case of small cell carcinoma located within the vesical diverticulum. A 73-year-old woman referred to our hospital with a chief complaint of gross hematuria. Cystoscopy confirmed a non-papillary tumor within the vesical diverticulum. Histopathologic diagnosis with transurethral resection of the tumor (TURBT) specimen was small cell carcinoma. Later, tumor recurrence occurred within the same diverticulum. TURBT and biopsy of the vesical mucosa were performed. After confirming that no tumor was detected outside of the diverticulum, partial cystectomy was done including an adequate margin around the diverticulum in September, 2010. Since the histopathologic finding of the specimen revealed urothelial carcinoma (UC) this time and microinvasion and venous invasion were detected, we performed an adjuvant chemotherapy according to the protocol of gemcitabine and cisplatin therapy. To our knowledge, this is the 4th case report of small cell carcinoma located in a vesical diverticulum in Japan. PMID- 24759505 TI - [Gangrene of the penis due to strangulation by a rubber band: a case report]. AB - We report a case of strangulation of the penis by a rubber band. A 79-year-old man placed a rubber band tightly around the corona of his glans penis in order to prevent urinary incontinence. After five days, he was taken to our hospital in an ambulance for high temperature and general malaise. We found the rubber band and removed it immediately. Gangrene of the penis continued and he did not recover from sepsis, so we performed partial penectomy. After the operation, he completely recovered. Penile strangulation using a soft constricting object such as a rubber band might result in severe complications and we should be careful. PMID- 24759506 TI - Comparative molecular analysis of bacterial communities inhabiting pristine and polluted with polycyclic aromatic hydrocarbons Black Sea coastal sediments. AB - Molecular analysis was applied to characterize bacterial community structure in sediment samples collected from pristine site and oil-polluted Black Sea harbor. Amplified Ribosomal DNA Restriction Analysis (ARDRA) revealed a high similarity in the restriction patterns of both samples thus not demonstrating the effect of the pollutant on the structure of the bacterial communities. Constructed 16S rRNA gene libraries gave more detailed assessment of members. Results showed that alpha- and gamma-Proteobacteria were dominant in the oil polluted site, whereas the pristine site was characterized by prevalence of Actinobacteria. The biodegradative potential of the adapted bacterial community in the oil-polluted sediments was demonstrated by the presence of the aromatic ring hydroxylating dioxygenase genes. PMID- 24759507 TI - Field experiments on remediation of coastal sediments using granulated coal ash. AB - Field experiments were carried out to evaluate the effect of Granulated Coal Ash (GCA) on remediation of coastal sediments in terms of removing phosphates and hydrogen sulfide. Phosphate concentrations in the sediment were kept below 0.2 mg/l after the application of GCA, whereas those in the control sites increased up to 1.0 mg/l. The concentration of hydrogen sulfide in the sediment was maintained at almost zero in the experimental sites (GCA application sites) for over one year, whereas it ranged 0.1-2.4 mg S L(-1) in control sites. Meanwhile, individual number of benthos increased in the experimental sites by several orders of magnitude compared to the control sites. The major process involved in hydrogen sulfide removal by GCA was thought to be the increase in pH, which suppresses hydrogen sulfide formation. From our findings, we concluded that GCA is an effective material for remediating organically enriched coastal sediment. PMID- 24759508 TI - Review of oil spill remote sensing. AB - Remote-sensing for oil spills is reviewed. The use of visible techniques is ubiquitous, however it gives only the same results as visual monitoring. Oil has no particular spectral features that would allow for identification among the many possible background interferences. Cameras are only useful to provide documentation. In daytime oil absorbs light and remits this as thermal energy at temperatures 3-8K above ambient, this is detectable by infrared (IR) cameras. Laser fluorosensors are useful instruments because of their unique capability to identify oil on backgrounds that include water, soil, weeds, ice and snow. They are the only sensor that can positively discriminate oil on most backgrounds. Radar detects oil on water by the fact that oil will dampen water-surface capillary waves under low to moderate wave/wind conditions. Radar offers the only potential for large area searches, day/night and foul weather remote sensing. PMID- 24759509 TI - Whole genome data for omics-based research on the self-fertilizing fish Kryptolebias marmoratus. AB - Genome resources have advantages for understanding diverse areas such as biological patterns and functioning of organisms. Omics platforms are useful approaches for the study of organs and organisms. These approaches can be powerful screening tools for whole genome, proteome, and metabolome profiling, and can be used to understand molecular changes in response to internal and external stimuli. This methodology has been applied successfully in freshwater model fish such as the zebrafish Danio rerio and the Japanese medaka Oryzias latipes in research areas such as basic physiology, developmental biology, genetics, and environmental biology. However, information is still scarce about model fish that inhabit brackish water or seawater. To develop the self fertilizing killifish Kryptolebias marmoratus as a potential model species with unique characteristics and research merits, we obtained genomic information about K. marmoratus. We address ways to use these data for genome-based molecular mechanistic studies. We review the current state of genome information on K. marmoratus to initiate omics approaches. We evaluate the potential applications of integrated omics platforms for future studies in environmental science, developmental biology, and biomedical research. We conclude that information about the K. marmoratus genome will provide a better understanding of the molecular functions of genes, proteins, and metabolites that are involved in the biological functions of this species. Omics platforms, particularly combined technologies that make effective use of bioinformatics, will provide powerful tools for hypothesis-driven investigations and discovery-driven discussions on diverse aspects of this species and on fish and vertebrates in general. PMID- 24759510 TI - Amount and type of derelict gear from the declining black pearl oyster aquaculture in Ahe atoll lagoon, French Polynesia. AB - Pearl oyster aquaculture is a major activity in French Polynesia atoll lagoons. After the economic decline that characterized the last decade, concerns recently rose about discarded installations and materials that supported aquaculture practices and by facilities abandoned after they had to close their activities. In May 2013, a first inventory of the type and amount of pearl farms derelict gear (PFDG) was achieved on 47 sites in Ahe lagoon. Surveys were conducted within and outside the boundaries of aquaculture concessions. Twenty types of PFDG littered the lagoon floor and the water column. The most impacted areas were near abandoned grafting houses with up to nine types of PFDG. Forty-five percent of the sites were impacted, including outside concessions. While management authorities are fully aware of the problem, this first assessment is a wake-up call to stimulate the cleaning of lagoons, enhance awareness among farmers, and identify potential ecological consequences on lagoon ecosystems. PMID- 24759511 TI - Simulated distribution and ecotoxicity-based assessment of chemically-dispersed oil in Tokyo Bay. AB - To assess risks of chemically-dispersed oil to marine organisms, oil concentrations in the water were simulated using a hypothetical spill accident in Tokyo Bay. Simulated oil concentrations were then compared with the short-term no observed effect concentration (NOEC), 0.01 mg/L, obtained through toxicity tests using marine diatoms, amphipod and fish. Area of oil concentrations higher than the NOEC were compared with respect to use and non-use of dispersant. Results of the simulation show relatively faster dispersion near the mouth of the bay compared to its inner sections which is basically related to its stronger water currents. Interestingly, in the inner bay, a large area of chemically-dispersed oil has concentrations higher than the NOEC. It seems emulsifying oil by dispersant increases oil concentrations, which could lead to higher toxicity to aquatic organisms. When stronger winds occur, however, the difference in toxic areas between use and non-use of dispersant is quite small. PMID- 24759512 TI - Impacts of recreational motorboats on fishes: a review. AB - A considerable amount of research has been conducted on the impacts of recreational boating activities on fishes but little or no synthesis of the information has been undertaken. This review shows that motor boats impact on the biology and ecology of fishes but the effects vary according to the species and even particular size classes. Direct hits on fishes by propellers are an obvious impact but this aspect has been poorly documented. Alterations in the wave climate and water turbidity may also influence fishes and their habitats, especially submerged and emergent plant beds. Sound generated by boat motors can also influence the communication and behaviour of certain species. Pollution arising from fuel spillages, exhaust emissions and antifouling paints all have detrimental effects on fishes. Finally, the use of recreational boats as vectors of aquatic invasive organisms is very real and has created major problems to the ecology of aquatic systems. PMID- 24759513 TI - A dynamical model of tumour immunotherapy. AB - A coupled ordinary differential equation model of tumour-immune dynamics is presented and analysed. The model accounts for biological and clinical factors which regulate the interaction rates of cytotoxic T lymphocytes on the surface of the tumour mass. A phase plane analysis demonstrates that competition between tumour cells and lymphocytes can result in tumour eradication, perpetual oscillations, or unbounded solutions. To investigate the dependence of the dynamic behaviour on model parameters, the equations are solved analytically and conditions for unbounded versus bounded solutions are discussed. An analytic characterisation of the basin of attraction for oscillatory orbits is given. It is also shown that the tumour shape, characterised by a surface area to volume scaling factor, influences the size of the basin, with significant consequences for therapy design. The findings reveal that the tumour volume must surpass a threshold size that depends on lymphocyte parameters for the cancer to be completely eliminated. A semi-analytic procedure to calculate oscillation periods and determine their sensitivity to model parameters is also presented. Numerical results show that the period of oscillations exhibits notable nonlinear dependence on biologically relevant conditions. PMID- 24759515 TI - Prevalence and correlates of HIV infection and sexually transmitted infections in female sex workers (FSWs) in Shanghai, China. AB - In 2009, we examined HIV and sexually transmitted infections (STIs) in 750 female sex workers (FSWs) in Shanghai using a cross-sectional survey. Participants (mean age 27 years) were interviewed and tested for HIV and selected STIs. Prevalence was: HIV 0.13%, chlamydia 14.7%, gonorrhoea 3.5% and syphilis 1.3%. In a demographic multivariate model, younger age, higher income and originating from provinces other than Zhejiang and Shanghai were independently associated with STI. In a social and sexual behavioural model, women working in small venues with fewer clients per week, use of drugs, and higher price charged per sex act indicated a greater risk for STI. Although HIV appears rare in Shanghai FSWs, chlamydial infection is common, especially in women aged <25 years (prevalence 19.6%). Since STI and HIV share similar risk factors, preventive intervention measures should be implemented immediately based on the venues and characteristics of FSWs to prevent future spread of HIV. PMID- 24759516 TI - Coagulation-flocculation for lignin removal from wastewater - a review. AB - Industrial discharge has tremendously increased inorganic pollutants in water bodies all over the world. Paper and pulp effluent is included in one of the most pollution generating discharges containing complex chemical compounds such as lignin. For clean and healthy water resources, the recovery of lignin from wastewater from the paper and pulp industry is of high importance. Available chemical and biological technologies for removal of lignin have certain drawbacks. Coagulation and flocculation is not only the economic but also the effective method for removal of lignin. The present review highlights available coagulants employed for removal of lignin from paper and pulp wastewater. Each coagulant is pH dependent and shows varied results with change in effluent characteristics. The hydrolysis products of aluminium-based coagulants, iron based coagulants and copper sulphate have positive charges. These positive charges promote formation of flocs through charged neutralisation or sweep flocculation. In the case of titanium-based coagulants, hydrolysis product is negatively charged and mode is heterocoagulation. Ninety percent recovery of lignin is achieved by using a mixture of oxotitanium sulphate and aluminium sulphate and 80% with aluminium sulphate. Virtually complete recovery of lignin is observed with oxotitanium sulphate. PMID- 24759517 TI - Dairy wastewater treatment using an activated sludge-microalgae system at different light intensities. AB - A microalgae-bacteria system was used for dairy industry wastewater treatment in sequenced batch mode in a photobioreactor. The research investigated the influence of two light intensities: 360 and 820 MUmol m(-2)s(-1) on treatment performances, microalgal cell recovery and dynamics of the protozoan community. Results showed that the light intensity of 360 MUmol m(-2)s(-1) was found to be insufficient to support photosynthetic activity after the increase of bacterial biomass leading to the decrease of organic matter and ammonium removal efficiencies from 95 to 78% and 95 to 41%, respectively. Maximum microalgal cells recovery was about 63%. Continuous modification in the protozoan community was also noticed during this test. Increasing the light intensity to 820 MUmol m( 2)s(-1) led to better microalgal cells recovery (up to 88%) and improved treatment performances. However, the decrease of protozoan richness to small flagellates and free-swimming ciliates was noticed. Moreover, the developed protozoan trophic network was found to be different from that identified in the conventional activated sludge system. The study emphasized that high increase of bacterial biomass promoted in nutrient- and organic matter-rich wastewater can strongly affect the treatment performances as a result of the shadow effect produced on the photoautotrophic microalgae aggregates. PMID- 24759518 TI - Innovative use of lamella clarifiers for central stormwater treatment in separate sewer systems. AB - Lamella settlers have been used in the past few years for the sedimentation of particles in wastewater and stormwater applications. A new and very innovative approach for the treatment of stormwater flows is proposed which extends the portfolio of solutions beyond traditional settling tanks. Surface runoff is stored in a sewer or a basin and finally treated in a small but continuously operated lamella clarifier. The low throughput flow will yield good treatment efficiency at a small footprint. The possibilities of using existing storage volume in a storm sewer, as well as the structural flexibility of the arrangement are decisive benefits. As a large operational advantage, the lamellae may be cleaned mechanically, e.g. by pivoting under water. Finally, the flow and the sludge which will be sent to the downstream treatment plant will be minimized. A new comparative simulation method is proposed in order to assess an equivalent degree of stormwater treatment, either by achieving an equal annual volume of treated stormwater or, more directly, an equal amount of spilled pollutant load. The new solution is compared with a traditional settling tank according to current German design rules. Additionally, a case study from a real installation will be presented. PMID- 24759519 TI - Performance and metabolic aspects of a novel enhanced biological phosphorus removal system with intermittent feeding and alternate aeration. AB - A novel enhanced biological phosphorus removal (EBPR) system, which combined the intermittent feeding design with an anaerobic selector, was examined using on line oxidation reduction potential (ORP), nitrate and ammonium probes. Two experimental periods were investigated: the aerobic and anoxic phases were set at 40 and 20 minutes respectively for period I, and set at 30 and 30 minutes for period II. Chemical oxygen demand (COD), biochemical oxygen demand (BOD5) and P removal were measured as high as 87%, 96% and 93% respectively, while total Kjeldahl nitrogen (TKN) and NH4(+) removal averaged 85% and 91%. Two specific denitrification rates (SDNRs), which corresponded to the consumption of the readily biodegradable and slowly biodegradable COD, were determined. SDNR-1 and SDNR-2 during period I were 0.235 and 0.059 g N g(-1) volatile suspended solids (VSS) d(-1) respectively, while the respective rates during period II were 0.105 and 0.042 g N g(-1) VSS d(-1). The specific nitrate formation and ammonium oxidizing rates were 0.076 and 0.064 g N g(-1) VSS d(-1) for period I and 0.065 and 0.081 g N g(-1) VSS d(-1) for period II respectively. The specific P release rates were 2.79 and 4.02 mg P g(-1) VSS h(-1) during period I and II, while the respective anoxic/aerobic uptake rates were 0.42 and 0.55 mg P g(-1) VSS h(-1). This is the first report on an EBPR scheme using the intermittent feeding strategy. PMID- 24759520 TI - Ecological characteristics of plankton and aquatic vegetation in Lake Qiluhu. AB - Investigations of the phytoplankton, zooplankton, zoobenthos and aquatic vegetation in Lake Qiluhu were carried out in February, 2009. Over the whole lake, 13 sampling sites were set up for the analysis of phytoplankton and zooplankton, and 22 profiles for the collection of macrophytes and zoobenthos. In the survey, 7 phyla, 65 algae species were identified. The average abundance of phytoplankton was 7.16 * 10(8) cells/L, and the dominant specie was Limnothrix redekei. No obvious surface accumulation of algae was detected. The concentration of Chlorophyll a ranged from 85 to 101 MUg/L, and the average value was 93 MUg/L. Nineteen species of zooplankton were observed, including 4 species of rotifers, 6 species of cladocerans and 9 species of copepods. Copepods were the dominant species, their abundance reaching 68%, whilst Cladocerans took second place with an abundance proportion of 28%. Six species of submerged vegetation were identified: Potamogeton Pectinatus, Myriophyllum, Elodea Canadensis, Ceratophyllum demersum and Potamogeton crispus. Amongst them, the dominant vegetation was P. Pectinatus, the biomass of which was up to 63% of the total biomass. Emerged macrophytes were cluster distributed across the whole lake, mainly consisting of Scirpus tabernaemontani, phragmites communis and cane shoots. Unfortunately, no living zoobenthos were found at the sites. The results indicated that, in Lake Qiluhu, the abundance of phytoplankton was maintained at a high level. The ecological function of submerged vegetation was gradually being lost because of its low standing crop and coverage, and the benthic animal habitat was severely damaged. PMID- 24759521 TI - Distillery fusel oil as an alternative carbon source for denitrification - from laboratory experiments to full-scale applications. AB - Industrial waste products may be a viable alternative to commercial external carbon sources. In this study, the properties of fusel oil (distillery waste product) were investigated in terms of temperature dependency of denitrification and acclimation period. Furthermore, results obtained during three different full scale trials were used to verify similarities with and differences from the results obtained under laboratory-scale conditions. Batch experiments with non acclimated biomass revealed a very strong temperature dependency of the denitrification process (theta = 1.15, R(2) = 0.92) in the range of examined process temperatures (13-22 degrees C). Fusel oil had minor (or no) effects on the behaviour of NO2-N and PO4-P. Significantly lower nitrate utilization rates were observed during acclimation to fusel oil in the full-scale bioreactors compared to a bench-scale reactor. This may primarily be attributed to lower doses of fusel oil, lower process temperatures and more complicated process configurations (resulting in non-optimal use of fusel oil for denitrification). Results obtained from both laboratory-scale experiments and full-scale trials suggested that an acclimation period of a few weeks would be required to reach the maximum denitrification capability of process biomass, even though positive effects of dosing can be observed almost immediately. PMID- 24759522 TI - Anaerobic model for high-solids or high-temperature digestion - additional pathway of acetate oxidation. AB - Current anaerobic digestion models cannot properly simulate processes that are operated under high solids concentrations or high temperatures. A modification to existing models has been implemented by adding important missing degradation pathways, to accommodate these systems without artificially recalibrating the model parameters. Specifically, we implemented the alternate acetate oxidizing mechanism that is more tolerant to ammonia than the standard aceticlastic pathway. Inhibition values were estimated and an empirical function has been used to apply ammonia inhibition. The model also relates metabolic activity to un ionised species such as undissociated acetic acid as substrate (although not obligatory for all organisms) and unionised ammonia as inhibitor. The model relies on an equilibrium chemistry module (e.g. including the phosphate buffer), resulting in more accurate pH predictions, which is crucial for proper modeling of CO2 and NH3 stripping. Calibration results from three case-studies modeling thermal hydrolysis and subsequent digestion of sludge are presented. PMID- 24759523 TI - Irreversible fouling of membrane bioreactors due to formation of a non-biofilm gel layer. AB - Extra-cellular polymeric substances (EPS), known to contribute to fouling in membrane bio-reactors (MBRs), are generally divided into bound and free EPS. The free EPS are able to form a gel layer on the membrane active surface. The mechanisms involved in formation of such layer and its effects on performance of the MBR membranes were studied. The free EPS, extracted by centrifugation and microfiltration, contained a significant amount of humic-like substances. Under static contact to the membrane, adsorption of humic-like substances to the membrane occurred and could be explained by conventional adsorption kinetics. Due to static adsorption, surface roughness of the membrane declined significantly, indicating that adsorbed matters to the membrane filled the cavities of the membrane surface. Filtration of the free EPS caused 50% water flux decline. The fouling resistance linearly increased with the amount of the humic-like substances retained during filtration as predicted by gel growth theory. A low pressure backwash could re-establish the water flux only up to 70%. PMID- 24759525 TI - Coupling acoustic devices for monitoring combined sewer network sediment deposits. AB - Combined sewer networks display some unique features that are not easily reproducible in the laboratory and have yet to be well understood. The transport of organic and mobile sediments, present in large quantities despite the use of optimal design practices, dramatically changes sewer flow patterns and the interaction between flow and sediment. To understand both the flow patterns and transport features of these complex environments, it is therefore necessary to install instrumentation in situ. For this paper, two distinct acoustic techniques were coupled in order to measure both the sediment interface and velocity. For this purpose, a 2 MHz rotating head acoustic profiler and a 10 MHz acoustic Doppler velocimeter (ADV) were jointly installed to survey the position of sediment deposits and measure velocity patterns. Results were compared with measurements recorded in different environments, where both coarser and finer soft deposits were present. These results typically showed good agreement between the interfaces detected using velocity measurements on coarse deposits, while the presence of soft deposits demonstrated the need for coupling measurements techniques that can correctly assess the sediment interface. PMID- 24759524 TI - Investigation of the shape change of bio-flocs and its influence on mass transport using particle image velocimetry. AB - In this laboratory study, an advanced flow visualization technique - particle image velocimetry (PIV) - was employed to investigate the change of shape of activated sludge flocs in water and its influence on the material transport characteristics of the flocs. The continuous shape change of the bio-flocs that occurred within a very short period of time could be captured by the PIV system. The results demonstrate that the fluid turbulence caused the shift of parts of a floc from one side to the other in less than 200 ms. During the continuous shape change, the liquid within the floc was forced out of the floc, which was then refilled with the liquid from the surrounding flow. For the bio-flocs saturated with a tracer dye, it was shown that the dye could be released from the flocs at a faster rate when the flocs were swayed around in water. The experimental results indicate that frequent shape change of bio-flocs facilitates the exchange of fluid and materials between the floc interior and the surrounding water. This mass transfer mechanism can be more important than molecular diffusion and internal permeation to the function and behavior of particle aggregates, including bio-flocs, in natural waters and treatment systems. PMID- 24759526 TI - Biotransformation potential of phytosterols under anoxic and anaerobic conditions. AB - The biotransformation potential of three phytosterols (campesterol, stigmasterol and beta-sitosterol) under denitrifying, sulfate-reducing and fermentative/methanogenic conditions was assessed. Using a group contribution method, the standard Gibbs free energy of phytosterols was calculated and used to perform theoretical energetic calculations. The oxidation of phytosterols under aerobic, nitrate-reducing, sulfate-reducing and methanogenic conditions was determined to be energetically feasible. However, using semi-continuously fed cultures maintained at 20-22 degrees C over 16 weekly feeding cycles (112 days; retention time, 21 days), phytosterol removal was observed under nitrate-reducing and sulfate-reducing conditions, but not under fermentative/methanogenic conditions. Under sulfate-reducing conditions, stigmast-4-en-3-one was identified as an intermediate of phytosterol biotransformation, a reaction more likely carried out by dehydrogenases/isomerases, previously reported to act on cholesterol under both oxic and anoxic (denitrifying) conditions. Further study of the biotransformation of phytosterols under anoxic/anaerobic conditions is necessary to delineate the factors and conditions leading to enhanced phytosterol biodegradation and the development of effective biological treatment systems for the removal of phytosterols from pulp and paper wastewaters and other phytosterol bearing waste streams. PMID- 24759527 TI - Removing organic matter from sulfate-rich wastewater via sulfidogenic and methanogenic pathways. AB - The simultaneous organic matter removal and sulfate reduction in synthetic sulfate-rich wastewater was evaluated for various chemical oxygen demand (COD)/sulfate ratios applied in a horizontal-flow anaerobic immobilized sludge (HAIS) reactor. At higher COD/sulfate ratios (12.5 and 7.5), the removal of organic matter was stable, likely due to methanogenesis. A combination of sulfate reduction and methanogenesis was clearly established at COD/sulfate ratios of 3.0 and 1.9. At a COD/sulfate ratio of 1.0, the organic matter removal was likely influenced by methanogenesis inhibition. The quantity of sulfate removed at a COD/sulfate ratio of 1.0 was identical to that obtained at a ratio of 1.9, indicating a lack of available electron donors for sulfidogenesis. The sulfate reduction and organic matter removal were not maximized at the same COD/sulfate ratio; therefore, competitive inhibition must be the predominant mechanism in establishing an electron flow. PMID- 24759528 TI - Hydrogen production from formic acid solution by modified TiO2 and titanate nanotubes in a two-step system under visible light irradiation. AB - Hydrogen gas is one of the most promising renewable energy sources, and the final product of hydrogen combustion is nothing but water. However, it is still a big challenge to produce hydrogen and store it. Many studies have been conducted into produce hydrogen from water using photocatalysts. Z-scheme photocatalysis is a two-photocatalyst system that comprises a hydrogen catalyst and an oxygen catalyst to produce hydrogen and oxygen respectively. Compared to the one-step system, the two-step system can promote the efficiency of water splitting. In addition, formic acid (FA) is a convenient hydrogen-storage material and can be safely handled in aqueous solutions. Therefore, this study investigated the photocatalytic conversion of FA solution to hydrogen using visible light with several types of hydrogen catalysts (CdS/titanate nanotubes (TNTs), CdS/TiO2, Pt/CdS/TNTs) and WO3 as the oxygen catalyst. The results showed that the yield of hydrogen with CdS/TNTs + WO3 was much higher than with CdS/TiO2 + WO3. Moreover, coating the photocatalysts with metal could further promote the reaction. The optimal platinum loading was 0.01 wt%, and the hydrogen production achieved was 852.5 MUmol . h(-1) with 20 vol% FA solution. PMID- 24759529 TI - Kinetics and thermodynamics of anaerobic ammonium oxidation process using Brocadia spp. dominated mixed cultures. AB - Anaerobic ammonium oxidation (anammox) is a recently discovered microbial process commonly applied to treat ammonium pollution in effluents with low organic carbon content. Modeling anammox processes is important for simulating and controlling full-scale plants. In this study, the anammox process was simulated using three models, and substrate and growth parameters obtained by different research groups. Two Brocadia spp.-dominated mixed cultures, one granular and the other flocculent, were used for this purpose. A very good correlation between experimental data using both sludges and model predictions was achieved by one of the models, obtaining correlation coefficients higher than 0.997. Other models and stoichiometric equations tested were unable to predict the anammox kinetics and stoichiometry. Furthermore, the thermodynamic behavior of the two mixed cultures was compared through the determination of the energy of activation of the anammox conversion at temperatures ranging from 9 to 40 degrees C. Optimum temperature for anammox activity was established at 30-35 degrees C in both cases. The energy of activation values calculated for granular sludge and flocculent sludge were 64 and 124 kJ mol(-1), respectively. PMID- 24759530 TI - Study on nitrogen load reduction efficiency of agricultural conservation management in a small agricultural watershed. AB - Different crops can generate different non-point source (NPS) loads because of their spatial topography heterogeneity and variable fertilization application rates. The objective of this study was to assess nitrogen NPS load reduction efficiency by spatially adjusting crop plantings as an agricultural conservation management (ACM) measure in a typical small agricultural watershed in the black soil region in northeast China. The assessment was undertaken using the Soil and Water Assessment Tool (SWAT). Results showed that lowland crops produce higher nitrogen NPS loads than those in highlands. It was also found that corn gave a comparatively larger NPS load than soybeans due to its larger fertilization demand. The ACM assessed was the conversion of lowland corn crops into soybean crops and highland soybean crops into corn crops. The verified SWAT model was used to evaluate the impact of the ACM action on nitrogen loads. The results revealed that the ACM could reduce NO3-N and total nitrogen loads by 9.5 and 10.7%, respectively, without changing the area of crops. Spatially optimized regulation of crop planting according to fertilizer demand and geological landscapes can effectively decrease NPS nitrogen exports from agricultural watersheds. PMID- 24759532 TI - Influence of shear on nitrification rates in a membrane bioreactor. AB - Grundfos BioBooster (GBB) installed and operated a membrane bioreactor (MBR) test plant in 2012. During the period it became evident that the nitrification rate was lower than expected and a study was carried out to investigate the possible reasons for the observed low-nitrification rate. Tests were conducted at a pilot plant and the effect of shear from the BioBooster membrane system and the pressure reduction component on the nitrification rate was investigated. The possible effect of selection of microbial communities caused by the filtration unit was also investigated. The results revealed an unchanged nitrification rate when exposed to shear from the filtration unit and the pressure reduction component. When testing the effect of selection, the nitrification rate was also unchanged. PMID- 24759531 TI - Effect of metal-ion doping on the characteristics and photocatalytic activity of TiO2 nanotubes for the removal of toluene from water. AB - Toluene is an extensively used reagent that could cause water pollution and endanger human health. In this work, an O3/UV/ion-doped TiO2 nanotubes process was investigated to obtain the optimum TiO2 nanotubes for effective toluene decomposition. Photocatalytic activity is found to be influenced by the doped-ion type by affecting the ionic radius, valence state, and configuration of the dopant. The calcination temperature and doping concentration, which change the weight fractions of the anatase phase (fA), the Brunauer-Emmett-Teller surface area (SBET), and the energy band gap (Eg) of the catalyst, also affect the photocatalytic activity. When TiO2 is doped with ions, SBET decreases and Eg becomes narrower. The photocatalytic activities of TiO2 for toluene removal increase after doping with Ag(+), Al(3+), Cu(2+), Fe(3+), Mn(2+), Ni(2+), V(5+), and Zn(2+). Moreover, the 1.0% Fe(3+)-doped TiO2 nanotubes calcined at 550 degrees C have the highest catalytic activity, with a toluene removal efficiency of 70.7%. PMID- 24759533 TI - Pollutant removal and membrane fouling in an anaerobic submerged membrane bioreactor for real sewage treatment. AB - Real sewage was continuously treated by a laboratory-scale anaerobic submerged membrane bioreactor (AnSMBR) for over 160 days. Results showed that around 90% of chemical oxygen demand, and 99% of turbidity and total suspended solids in the sewage could be removed by the AnSMBR system. Membrane flux sustained at 11 L/(m(2) h) was realized with biogas sparging. Small flocs from sludge deflocculation in the early operational period caused a high membrane fouling rate, and the high specific filtration resistance of the cake layer appeared mostly attributable to the osmotic pressure effect. The performance results were also compared with those in the literature for upflow anaerobic sludge blanket reactors and aerobic membrane bioreactors for sewage treatment, demonstrating that AnSMBR could provide a desirable alternative for sewage treatment. PMID- 24759534 TI - When the smoke disappears: dealing with extinguishing chemicals in firefighting wastewater. AB - Water is not enough. Nowadays, numerous chemicals are used for fire extinction. After use, however, these may unintentionally enter sewerage systems. In order to safely treat firefighting wastewater (FFWW), knowledge of the potential effects of these chemicals on biological treatment processes is essential. This study characterized and mimicked the composition of FFWW containing two powders, three foams and one foam degrader. Nitrogen (162-370 mg NH4(+)-N L(-1)) and phosphorus (173-320 mg PO4(3-)-P L(-1)) concentrations exceeded discharge limits, whereas chemical and biological oxygen demand, suspended solids and detergent concentrations remained sufficiently low. Adequate nutrient removal could be obtained through FeCl3 addition and nitrification/denitrification with acetate as substrate. In batch tests, residual nitrifying activities of 84, 81, 89, 95 and 93% were observed in the presence of powders, foams, foam degrader, synthetic and real FFWW, respectively. All categories showed higher denitrification rates than the control. Although the powders at first seemed to inhibit anammox activity at 82%, after pH correction anammox was fully feasible, allowing nitrogen removal through oxygen-limited nitrification/denitrification (OLAND). Detailed cost calculations indicated that OLAND could save 11% of capital and 68% of operational costs compared to nitrification/denitrification, identifying OLAND as the most recommendable process for nitrogen removal from firefighting wastewaters. PMID- 24759535 TI - Advanced anaerobic processes to enhance waste activated sludge stabilization. AB - The requirement for enhanced stabilization processes to obtain a more stable, pathogen-free sludge for agricultural use is an increasing challenge to comply with in the waste hierarchy. With this in mind, the Routes European project ('Novel processing routes for effective sewage sludge management') is addressed to assess innovative solutions with the aim of maximizing sludge quality and biological stability. In order to increase anaerobic stabilization performances, the sequential anerobic/aerobic process and the thermophilic digestion process, with or without integration of the thermal hydrolysis pre-treatment, were investigated as regards the effect on sludge stabilization, dewaterability and digestion performances. Thermal pre-treatment improved anaerobic digestion in terms of volatile solids reduction and biogas production, but digestate dewaterability worsened. Fluorescence in situ hybridization (FISH) quantification showed an increase of methanogens consistent with the increase of biogas produced. The aerobic post-treatment after mesophilic digestion had a beneficial effect on dewaterability and stability of the digested sludge even if was with a reduction of the potential energy recovery. PMID- 24759536 TI - Energy-efficient wastewater treatment via the air-based, hybrid membrane biofilm reactor (hybrid MfBR). AB - We used modeling to predict the energy and cost savings associated with the air based, hybrid membrane-biofilm reactor (hybrid MfBR). This process is obtained by replacing fine-bubble diffusers in conventional activated sludge with air supplying, hollow-fiber membrane modules. Evaluated processes included removal of chemical oxygen demand (COD), combined COD and total nitrogen (TN) removal, and hybrid growth (biofilm and suspended). Target concentrations of COD and TN were based on high-stringency water reuse scenarios. Results showed reductions in power requirements as high as 86%. The decrease mainly resulted from the dramatically lower air flows for the MBfR, resulting from its higher oxygen transfer efficiencies. When the MBfR was used for COD and TN removal, savings up to US$200/1,000 m(3) of treated water were predicted. Cost savings were highly sensitive to the costs of the membrane modules and electrical power. The costs were also very sensitive to membrane oxidation flux for ammonia, and the membrane life. These results suggest the hybrid MBfR may provide significant savings in energy and costs. Further research on the identified key parameters can help confirm these modeling predictions and facilitate scale-up. PMID- 24759537 TI - Comparing environmental impacts of tertiary wastewater treatment technologies for advanced phosphorus removal and disinfection with life cycle assessment. AB - Different technologies for tertiary wastewater treatment are compared in their environmental impacts with life cycle assessment (LCA). Targeting very low phosphorus concentration (50-120 MUg/L) and seasonal disinfection of wastewater treatment plant (WWTP) secondary effluent, this LCA compares high-rate sedimentation, microsieve, dual media filtration (all with UV disinfection), and polymer ultrafiltration or ceramic microfiltration membranes for upgrading the large WWTP Berlin-Ruhleben. Results of the LCA show that mean effluent quality of membranes is highest, but at the cost of high electricity and chemical demand and associated emissions of greenhouse gases or other air pollutants. In contrast, gravity-driven treatment processes require less electricity and chemicals, but can reach significant removal of phosphorus. In fact, dual media filter or microsieve cause substantially lower specific CO2 emissions per kg P removed from the secondary effluent (180 kg CO2-eq/kg P, including UV) than the membrane schemes (275 kg CO2-eq/kg P). PMID- 24759538 TI - Dynamics of pollutant discharge in combined sewer systems during rain events: chance or determinism? AB - A large database of continuous flow and turbidity measurements cumulating data on hundreds of rain events and dry weather days from two sites in Paris (called Quais and Clichy) and one in Lyon (called Ecully) is presented. This database is used to characterize and compare the behaviour of the three sites at the inter events scale. The analysis is probed through three various variables: total volumes and total suspended solids (TSS) masses and concentrations during both wet and dry weather periods in addition to the contributions of diverse-origin sources to event flow volume and TSS load values. The results obtained confirm the previous findings regarding the spatial consistency of TSS fluxes and concentrations between both sites in Paris having similar land uses. Moreover, masses and concentrations are proven to be correlated between Parisian sites in a way that implies the possibility of some deterministic processes being reproducible from one catchment to another for a particular rain event. The results also demonstrate the importance of the contribution of wastewater and sewer deposits to the total events' loads and show that such contributions are not specific to Paris sewer networks. PMID- 24759539 TI - Membrane biofouling mechanism in an aerobic granular reactor degrading 4 chlorophenol. AB - The membrane fouling of an aerobic granular reactor coupled with a submerged membrane in a sequencing batch reactor (SBR) was evaluated. The fouling analysis was performed by applying microscopy techniques to determine the morphology and structure of the fouling layer on a polyvinylidene fluoride membrane. It was found that the main cause of fouling was the polysaccharide adsorption on the membrane surface, followed by the growth of microorganisms to form a biofilm. PMID- 24759540 TI - Combined mesophilic anaerobic and thermophilic aerobic digestion process for high strength food wastewater to increase removal efficiency and reduce sludge discharge. AB - In this study, a process that combines the mesophilic anaerobic digestion (MAD) process with thermophilic aerobic digestion (TAD) for high-strength food wastewater (FWW) treatment was developed to examine the removal of organic matter and methane production. All effluent discharged from the MAD process was separated into solid and liquid portions. The liquid part was discarded and the sludge part was passed to the TAD process for further degradation. Then, the digested sludge from the TAD process was recycled back to the MAD unit to achieve low sludge discharge from the combined process. The reactor combination was operated in two phases: during Phase I, 40 d of total hydraulic retention time (HRT) was applied; during Phase II, 20 d was applied. HRT of the TAD process was fixed at 5 d. For a comparison, a control process (single-stage MAD) was operated with the same HRTs of the combined process. Our results indicated that the combined process showed over 90% total solids, volatile solids and chemical oxygen demand removal efficiencies. In addition, the combined process showed a significantly higher methane production rate than that of the control process. Consequently, the experimental data demonstrated that the combined MAD-TAD process was successfully employed for high-strength FWW treatment with highly efficient organic matter reduction and methane production. PMID- 24759541 TI - Interaction of colloidal nanoparticles with their local environment: the (ionic) nanoenvironment around nanoparticles is different from bulk and determines the physico-chemical properties of the nanoparticles. AB - The physico-chemical properties of colloidal nanoparticles (NPs) are influenced by their local environment, as, in turn, the local environment influences the physico-chemical properties of the NPs. In other words, the local environment around NPs has a profound impact on the NPs, and it is different from bulk due to interaction with the NP surface. So far, this important effect has not been addressed in a comprehensive way in the literature. The vicinity of NPs can be sensitively influenced by local ions and ligands, with effects already occurring at extremely low concentrations. NPs in the Huckel regime are more sensitive to fluctuations in the ionic environment, because of a larger Debye length. The local ion concentration hereby affects the colloidal stability of the NPs, as it is different from bulk owing to Debye Huckel screening caused by the charge of the NPs. This can have subtle effects, now caused by the environment to the performance of the NP, such as for example a buffering effect caused by surface reaction on ultrapure ligand-free nanogold, a size quenching effect in the presence of specific ions and a significant impact on fluorophore-labelled NPs acting as ion sensors. Thus, the aim of this review is to clarify and give an unifying view of the complex interplay between the NP's surface with their nanoenvironment. PMID- 24759542 TI - Biogenic gradients in algal density affect the emergent properties of spatially self-organized mussel beds. AB - Theoretical models highlight that spatially self-organized patterns can have important emergent effects on the functioning of ecosystems, for instance by increasing productivity and affecting the vulnerability to catastrophic shifts. However, most theoretical studies presume idealized homogeneous conditions, which are rarely met in real ecosystems. Using self-organized mussel beds as a case study, we reveal that spatial heterogeneity, resulting from the large-scale effects of mussel beds on their environment, significantly alters the emergent properties predicted by idealized self-organization models that assume homogeneous conditions. The proposed model explicitly considers that the suspended algae, the prime food for the mussels, are supplied by water flow from the seaward boundary of the bed, which causes in combination with consumption a gradual depletion of algae over the simulated domain. Predictions of the model are consistent with properties of natural mussel patterns observed in the field, featuring a decline in mussel biomass and a change in patterning. Model analyses reveal a fundamental change in ecosystem functioning when this self-induced algal depletion gradient is included in the model. First, no enhancement of secondary productivity of the mussels comparing with non-patterns states is predicted, irrespective of parameter setting; the equilibrium amount of mussels is entirely set by the input of algae. Second, alternate stable states, potentially present in the original (no algal gradient) model, are absent when gradual depletion of algae in the overflowing water layer is allowed. Our findings stress the importance of including sufficiently realistic environmental conditions when assessing the emergent properties of self-organized ecosystems. PMID- 24759543 TI - Is the Donnan effect sufficient to explain swelling in brain tissue slices? AB - Brain tissue swelling is a dangerous consequence of traumatic injury and is associated with raised intracranial pressure and restricted blood flow. We consider the mechanical effects that drive swelling of brain tissue slices in an ionic solution bath, motivated by recent experimental results that showed that the volume change of tissue slices depends on the ionic concentration of the bathing solution. This result was attributed to the presence of large charged molecules that induce ion concentration gradients to ensure electroneutrality (the Donnan effect), leading to osmotic pressures and water accumulation. We use a mathematical triphasic model for soft tissue to characterize the underlying processes that could lead to the volume changes observed experimentally. We suggest that swelling is caused by an osmotic pressure increase driven by both non-permeating solutes released by necrotic cells, in addition to the Donnan effect. Both effects are necessary to explain the dependence of the tissue slice volume on the ionic bath concentration that was observed experimentally. PMID- 24759544 TI - A semi-automated measurement technique for the assessment of radiolucency. AB - The assessment of radiolucency around an implant is qualitative, poorly defined and has low agreement between clinicians. Accurate and repeatable assessment of radiolucency is essential to prevent misdiagnosis, minimize cases of unnecessary revision, and to correctly monitor and treat patients at risk of loosening and implant failure. The purpose of this study was to examine whether a semi automated imaging algorithm could improve repeatability and enable quantitative assessment of radiolucency. Six surgeons assessed 38 radiographs of knees after unicompartmental knee arthroplasty for radiolucency, and results were compared with assessments made by the semi-automated program. Large variation was found between the surgeon results, with total agreement in only 9.4% of zones and a kappa value of 0.602; whereas the automated program had total agreement in 81.6% of zones and a kappa value of 0.802. The software had a 'fair to excellent' prediction of the presence or the absence of radiolucency, where the area under the curve of the receiver operating characteristic curves was 0.82 on average. The software predicted radiolucency equally well for cemented and cementless implants (p = 0.996). The identification of radiolucency using an automated method is feasible and these results indicate that it could aid the definition and quantification of radiolucency. PMID- 24759545 TI - Alterations in cholesterol and ganglioside GM1 content of lipid rafts in platelets from patients with Alzheimer disease. AB - The aim of this study was to investigate the changes in the protein, cholesterol, and ganglioside GM1 content of lipid rafts in platelets from patients with Alzheimer disease (AD), and identify potential blood biomarkers of the disease. A total of 31 Chinese patients with AD and 31 aged-matched control subjects were selected. Lipid rafts were isolated from platelets using Optiprep gradient centrifugation. The protein content of lipid rafts was evaluated using Micro BCA assay, the cholesterol content using molecular probes, ganglioside GM1 content using colorimetry and dot-blotting analysis. The results showed that the cholesterol and ganglioside GM1 content of lipid rafts from platelets was significantly higher in patients with AD than aged-matched control subjects, whereas the protein content of lipid rafts did not show any differences between the 2 groups. These results indicate that the increases in the cholesterol and ganglioside GM1 content of lipid rafts from the platelets of patients with AD might serve as a biochemical adjunct to the clinical diagnosis of AD. PMID- 24759546 TI - Normative data for 8 neuropsychological tests in older blacks and whites from the atherosclerosis risk in communities (ARIC) study. AB - Accurate assessment of cognitive impairment requires comparison of cognitive performance in individuals to performance in a comparable healthy normative population. Few prior studies have included a large number of black participants and few have excluded participants from the normative sample with subclinical/latent neurological disease or dementia. This study provides age, race, and education-specific normative data for 8 cognitive tests derived from 320 black and 392 white participants aged 61 to 82 years (mean 71 y) in the Atherosclerosis Risk in Communities (ARIC) study without clinical or subclinical/latent neurological disease. Normative data are provided for the Delayed Word Recall Test, Logical Memory Parts I and II, the Word Fluency Test, Animal Naming, the Trail Making Test Parts A and B and the Digit Symbol Substitution Test. Age, race, and education-specific mean and -1.5 SD scores are given in tabular form and graphically, as well as regression-based equations to derive adjusted score cut-points. These robust normative data should enhance comparison across studies of cognitive aging, where these measures are widely used, and improve interpretation of performance on these tests for the diagnosis of cognitive impairment not only within the ARIC cohort, but also among older blacks and whites with similar demographics. PMID- 24759547 TI - Mild cognitive impairment due to alzheimer disease is less likely under the age of 65. AB - Patients with amnestic mild cognitive impairment (aMCI) are considered to have a high risk for Alzheimer dementia (AD). Even high positive predictive values, however, cannot be guaranteed even by tests with high sensitivity and specificity when disease prevalence is low. If we regard the clinical criteria for aMCI as a test for predicting aMCI due to AD, the positive predictive value of the criteria will be low by definition in young patients with aMCI (age below 65 years) because of the low prevalence of AD in this age group. To test this hypothesis, we compared CSF biomarkers for AD between young (age below 65 years) and old (age 65 years or older) age groups of normal cognition, aMCI, and AD of the Alzheimer's Disease Neuroimaging Initiative database. Using these biomarkers, we observed that the prevalence of aMCI due to AD differed significantly between the young and the old. For example, only 28.2% young aMCI, but 63.2% old aMCI, had abnormal CSF amyloid measures consistent with AD pathology. As posited, the presence of aMCI due to AD was lower in young aMCI than in old aMCI. Given that the likelihood of aMCI due to AD is reduced in younger subjects, more attention to and evaluation of alternative diagnoses need to be considered in this group. PMID- 24759548 TI - Prediction of Efficacy of Vabicaserin, a 5-HT2C Agonist, for the Treatment of Schizophrenia Using a Quantitative Systems Pharmacology Model. AB - A quantitative systems pharmacology model that combines in vitro/preclinical neurophysiology data, human imaging data, and patient disease information was used to blindly predict steady-state clinical efficacy of vabicaserin, a 5-HT2C full agonist, in monotherapy and, subsequently, to assess adjunctive therapy in schizophrenia. The model predicted a concentration-dependent improvement of positive and negative syndrome scales (PANSS) in schizophrenia monotherapy with vabicaserin. At the exposures of 100 and 200 mg b.i.d., the predicted improvements on PANSS in virtual patient trials were 5.12 (2.20, 8.56) and 6.37 (2.27, 10.40) (mean (95% confidence interval)), respectively, which are comparable to the observed phase IIa results. At the current clinical exposure limit of vabicaserin, the model predicted an ~9-point PANSS improvement in monotherapy, and <4-point PANSS improvement adjunctive with various antipsychotics, suggesting limited clinical benefit of vabicaserin in schizophrenia treatment. In conclusion, the updated quantitative systems pharmacology model of PANSS informed the clinical development decision of vabicaserin in schizophrenia. PMID- 24759549 TI - Spatially and temporally reconfigurable assembly of colloidal crystals. AB - The self-assembly of colloidal crystals is important to the production of materials with functional optical, mechanical and conductive properties. Yet, self-assembly methods are limited by their slow kinetics and lack of structural control in space and time. Refinements such as templating and directed assembly partially address the problem, albeit by introducing fixed surface features such as templates or electrodes. A template-free method to reconfigure colloidal crystals simultaneously in three-dimensional space and time would better align work in colloidal assembly with materials applications. Here, we report a photo induced assembly method that yields regions either filled with colloidal crystals or completely devoid of colloids. The origin of the effect is found to be electrophoresis of colloids generated by photochemistry at an indium tin oxide coated substrate. Simple optical manipulations are applied to reconfigure these assembly and depletion regions. Thus, the method represents a new kind of template-free, reconfigurable three-dimensional photolithography. PMID- 24759550 TI - Seasonal pattern of lesion development in diseased Fraxinus excelsior infected by Hymenoscyphus pseudoalbidus. AB - Ash dieback is a recent widespread disease on ash (Fraxinus sp.) that is causing important economic and ecological losses throughout Europe. The disease is initiated by the ascomycetous fungus Hymenoscyphus pseudoalbidus (anamorph Chalara fraxinea). The main aim of this study was to investigate seasonal pattern of lesion development associated with ash dieback. We present data on the spread of 324 natural lesions in ash shoots, branches and stems surveyed over a 32 month period. Most lesions were active and showed the greatest rate of growth during the summer; however, lesions were active throughout the year. Tree mortality was high, with more than a third of the surveyed trees dying during the study. Although many lesions permanently ceased to develop, the rate at which new lesions emerged was greater than the rate at which lesions entered a resting phase. The most common cause for a lesion going into a permanent state of rest was that it had encountered a branch-base. Genotype analysis showed that multiple infections can occur in a single tree given that different genotypes were identified in different lesions as well as in single lesions. A weak positive correlation was noted between tree health and tree size and a weak negative correlation was noted between tree overall health and lesion activity. The lower limit for H. pseudoalbidus growth in culture was between 4.0 degrees C and 0.5 degrees C. PMID- 24759551 TI - Re: Cardiopulmonary resuscitation and automatic external defibrillator training in schools: "is anyone learning how to save a life?". PMID- 24759552 TI - A proposal of guidance for identification of Schizophyllum commune-associated sinobronchial allergic mycosis. PMID- 24759553 TI - Maternal intake of Natto, a Japan's traditional fermented soybean food, during pregnancy and the risk of eczema in Japanese babies. AB - BACKGROUND: There are reports that the maternal diet during pregnancy may affect development of babies' eczema. We sought to investigate the association between the maternal diet during pregnancy and the risk of eczema in infancy in Japan. METHODS: A birth cohort was set up at 2 hospitals in Chiba city. Dietary habits concerning fish, butter, margarine, yogurt and natto during pregnancy was obtained from mothers just after delivery. The intake frequencies of these foods were classified into four groups: 1) daily, 2) 2-3 times a week, 3) once a week and 4) once a month or less. Diagnosis of eczema at 6 months of age was made by the presence of an itchy rash that persisted more than two months. RESULTS: Valid data on 650 mother-baby pairs were obtained. No relationship between frequencies of the maternal intake of fish, margarine and yogurt during pregnancy and the onset rate of the babies' eczema were observed. For butter consumption, the incidence of babies' eczema was significantly higher in the group with daily intake than in those with an intake 2-3 times a week or less (p = 0.044). For natto, incidence of babies' eczema was significantly lower in the group with everyday intake than those eating it 2-3 times a week or less (p = 0.020). CONCLUSIONS: High frequency intake of natto during pregnancy possibly reduces the incidence of eczema in children at 6 months of age. PMID- 24759554 TI - A new reliable method for detecting specific IgE antibodies in the patients with immediate type wheat allergy due to hydrolyzed wheat protein: correlation of its titer and clinical severity. AB - BACKGROUND: Immediate-type wheat allergy caused by a specific hydrolyzed wheat protein (HWP-IWA), Glupearl 19S (GP19S), typically develops food-dependent exercise-induced anaphylaxis (FDEIA), but is different from conventional FDEIA, or simple wheat allergy in many aspects. The skin prick test (SPT) is considered to be the most effective method for diagnosis of HWP-IWA. As SPT is a relatively qualitative method, we developed quantitative and high-throughput test method for HWP-IWA. METHODS: An enzyme-linked immunosorbent assay (ELISA)-based GP19S specific IgE assay was tested using sera from 14 HWP-IWA and five conventional wheat-dependent exercise-induced anaphylaxis (CO-WDEIA) patients, as well as five healthy subjects. Then a validation study at five different institutions was carried out using sera from 10 HWP-IWA and five CO-WDEIA patients, as well as five healthy subjects different from the previous studies. RESULTS: The mean unit values converted from measured absorbance of ELISA were 68.3, 1.3 and 1.1 respectively. Furthermore, the validation study revealed reproducible results across all five institutions, with the standard deviation (SD) being 0.3-0.4 for the healthy group, 0.2-0.6 for the CO-WDEIA group, and 3.8-9.6 for HWP-IWA group except for one case. One case of HWP-IWA was excluded from analysis due to the high SD of 53.3 units, indicating that samples with a unit value > 100.0 will affect inter-laboratory reproducibility. CONCLUSIONS: Our findings suggest that the ELISA-based GP19S-specific IgE assay can be used to test HWP-IWA using venous blood samples, except for those with a unit value > 100.0. PMID- 24759555 TI - Exercise-induced wheezing among Japanese pre-school children and pupils. AB - BACKGROUND: Exercise-induced wheezing (EIW) may be a symptom of asthma and is a predictor of exercise-induced bronchoconstriction, transient narrowing of the lower airway following exercise in the presence or absence of diagnosed asthma. Population-based studies with a large sample of EIW in relation to age, sex, current asthma severity and medication usage have been sparse. METHODS: International Study of Asthma and Allergies in Childhood questionnaires were distributed at 885 nurseries, 535 primary schools, 321 junior high schools and 190 high schools, respectively, across Japan, and the corresponding data on 46,597, 41,216, 45,960 and 51,104 children were analyzed. RESULTS: Prevalence of EIW was 4.8, 4.7, 17.9 and 15.4% for each of the four educational facility types, respectively. Among 24,103 current asthmatics, 20.9, 28.7, 76.1 and 73.6% of subjects for the 4 educational facility groups reported to have experienced EIW, respectively. Severity of current asthma was associated with the risk of EIW; odds ratio (95% confidence interval) of children with asthma attack every day for having EIW once a week or more, using intermittent asthmatics as reference group, were 24.48 (19.33 to 31.01) adjusted for other covariates. Among current asthmatic kindergartners, increase in risk for EIW due to ascending severity of current asthma was mitigated by daily use of leukotriene receptor antagonist (p for interaction = 0.071). CONCLUSIONS: EIW was not rare among current asthmatic children. An increased risk for EIW was in accordance with increasing severity of current asthma and this relation was mitigated with leukotriene receptor antagonist daily use among kindergartners. PMID- 24759556 TI - Study on patients who underwent suspected diagnosis of allergy to amide-type local anesthetic agents by the leukocyte migration test. AB - BACKGROUND: There are problems in diagnosis of allergy to amide-type local anesthetic agents (ALAs), because definitive diagnosis is not obtained by in vivo tests, which are used for the diagnosis. Consequently, patients may be exposed to risk. There are few diagnoses based on in vitro tests, and there are almost no relevant studies. METHODS: Authors examined involvement of allergic reaction using the leukocyte migration test (LMT) through multiple standpoints in 43 patients who underwent suspected diagnosis of allergy to ALAs. RESULTS: Rate of LMT-positives was 54%, and especially the positive rate of lidocaine hydrochloride preparations was significantly high. In 15 positives to lidocaine hydrochloride preparations, all cases were indicated as positive in a test with drugs containing antiseptic agent, but only 3 cases were indicated as positive in a test with lidocaine hydrochloride alone. In addition, test with paraben was conducted in 4 cases; 2 cases were confirmed as positive. In relevance of histories of drug or food allergies, development rates of ALAs-allergies were the highest in both allergies, and were 35% and 13%, respectively. CONCLUSIONS: There is a high possibility that these adverse reactions were caused by pseudoallergy to drug. Even by allergic reactions, it was assumed that 80% of them might be caused by antiseptic agents such as paraben. In addition, it was suggested that ALAs, especially lidocaine hydrochloride preparations have high antigenicity (sensitizing property). Furthermore, it was considered that patients with past history of drug or food allergies have a high potential for manifestation of the reactions. PMID- 24759558 TI - Expressions and roles of periostin in otolaryngological diseases. AB - Periostin is a 90-kDa member of the fasciclin-containing family; it functions as part of matricellular proteins, and its production by airway epithelial cells is induced by IL-4 and IL-13. Periostin is secreted by fibroblasts and upregulated in the airway epithelia of patients with bronchial asthma; it is considered to contribute to remodeling under this pathological condition. However, despite many studies in diverse research areas, our overall understanding of this intriguing molecule is still inadequate. Here, we integrate the available evidence on periostin expression and its roles in otolaryngological diseases, including allergic rhinitis, chronic rhinosinusitis with nasal polyps, aspirin-induced asthma, organized hematoma, eosinophilic otitis media, and IgG4-related disease. Periostin might be involved as an important structural mediator in pathological processes such as insult and injury, Th2-driven inflammation, extracellular matrix restructuring, fibrosclerosis, tumor angiogenesis, and tissue remodeling. PMID- 24759557 TI - Factors contributing to an accelerated decline in pulmonary function in asthma. AB - Patients with asthma show a steeper age-related decline in pulmonary function than healthy subjects, which is often alleviated after the initiation of treatment with inhaled corticosteroids (ICS). However, there still are patients who develop irreversible airflow limitations despite receiving adequate ICS treatment. The identification of the characteristics of such patients and biomarkers of progression for airflow limitation, a functional consequence of airway remodeling, is considered important in the management of asthma. A variety of biomarkers are associated with the forced expiratory volume in 1s (FEV1) in asthma in a cross-sectional fashion. However, few biomarkers are known to reflect the decline in pulmonary function, particularly in patients with asthma who receive ICS treatment. Recently periostin, a matricellular protein that prolongs Th2/eosinophilic inflammation and reflects airway remodeling, was reported to be detected in serum. In a Kinki Hokuriku Airway disease Conference multicenter cohort study, we demonstrated that among several serum markers, high serum periostin level, particularly >=95ng/mL, was the only marker associated with a greater annual decline in FEV1 and a decline in FEV1 of >=30mL.yr-1. A variant (rs9603226) of the POSTN gene that encodes periostin was also involved in the frequency of a decline in FEV1 of >=30mL.yr-1. Our results suggest that the serum periostin level is a useful marker reflecting pulmonary function decline in patients with asthma receiving ICS. PMID- 24759559 TI - Serum periostin: a novel biomarker for asthma management. AB - Chronic airway inflammation and remodeling are fundamental features of asthma. Even with adequate inhaled corticosteroid (ICS) treatment, there are still patients who exhibit Th2/eosinophilic inflammation and develop airflow limitation, a functional consequence of airway remodeling. There are few biomarkers that are applicable in the clinical setting that reflect refractory Th2/eosinophilic inflammation and remodeling of the asthmatic airways. Therefore, establishing such biomarkers is essential for managing patients who suffer from these conditions. This review addresses the importance of serum periostin measurements by describing observations made in a KiHAC multicenter cohort with periostin used as a marker of pulmonary function decline and refractory Th2/eosinophilic inflammation in patients with asthma receiving long-term ICS treatment. Furthermore, serum periostin could be a companion diagnostic for targeted therapy against refractory Th2/eosinophilic inflammation. Finally, the distinct characteristics of serum periostin as compared to conventional biomarkers are addressed. PMID- 24759560 TI - Periostin in skin tissue and skin-related diseases. AB - Extracellular matrix (ECM) is not only involved in the maintenance of normal physiological tissue but also in interactions with other ECM components, tissue remodeling, and modulating immune responses. The skin provides a distinctive environment characterized by rich fibroblasts producing various ECM proteins, epithelial-mesenchymal interactions, and immune responses induced by external stimuli. Recently, periostin-a matricellular protein-has been highlighted for its pivotal functions in the skin. Analysis of periostin null mice has revealed that periostin contributes to collagen fibrillogenesis, collagen cross-linking, and the formation of ECM meshwork via interactions with other ECM components. Periostin expression is enhanced by mechanical stress or skin injury; this is indicative of the physiologically protective functions of periostin, which promotes wound repair by acting on keratinocytes and fibroblasts. Along with its physiological functions, periostin plays pathogenic roles in skin fibrosis and chronic allergic inflammation. In systemic sclerosis (SSc) patients, periostin levels reflect the severity of skin fibrosis. Periostin null mice have shown reduced skin fibrosis in a bleomycin-induced SSc mouse model, indicating a key role of periostin in fibrosis. Moreover, in atopic dermatitis (AD), attenuated AD phenotype has been observed in periostin null mice in a house dust mite extract induced AD mouse model. Th2 cytokine-induced periostin acts on keratinocytes to produce inflammatory cytokines that further enhance the Th2 response, thereby sustaining and amplifying chronic allergic inflammation. Thus, periostin is deeply involved in the pathogenesis of AD and other inflammation-related disorders affecting the skin. Understanding the dynamic actions of periostin would be key to dissecting pathogenesis of skin-related diseases and to developing novel therapeutic strategies. PMID- 24759561 TI - Depression symptoms, social support and overall health among HIV-positive individuals in Kenya. AB - In Kenya, there was a reported decline in HIV incidence and prevalence among those aged 15 to 64 years and children. Despite the decline, closer assessment of psychosocial issues like depression, contextual factors (family and community), and social support is necessary given the likely impact on overall health and HIV prevention. This paper examines an association between symptoms of depression and social support on overall health among HIV-positive participants recruited from an HIV clinic in Kenya. Descriptive statistics and logistic regression analyses were utilized. Findings reveal that compared to those with minimal depression (referent category) participants with mild, moderate, moderately severe/severe depression had higher odds of having poor health. For social support, compared with participants with no social support (referent category), participants with high social support had lower odds of having poor overall health in both unadjusted and multivariable-adjusted models. In conclusion, this study suggests that HIV clinics and interventions need to focus more on the psychological and/or mental health status of HIV-infected individuals while providing avenues such as social support groups that can be a buffer against the negative impact of HIV infection and depression on overall health outcomes. PMID- 24759562 TI - Assessing the role of peripheral CD8 T cells in neurocognitive impairment in HIV infected men who have sex with men: data from the MSM Neurocog Study. AB - Studies have suggested CD8 lymphocytes may be a possible marker for inflammation, which is believed to be a contributing factor to neurocognitive impairment. Individuals enrolled in the MSM Neurocog Study were analysed. Those with depression, anxiety or mood disorders were excluded. Individuals with neurocognitive impairment were identified using the Brief NeuroCognitive Screen and compared to those with normal scores. CD4 and CD8 T cell values and CD4:CD8 ratios were compared between groups. In all, 144 men, aged 18-50 years, were included in the analysis. Twenty were diagnosed with neurocognitive impairment. We were unable to identify any significant difference between current, nadir or peak CD4 and CD8 counts. CD4:CD8 ratios and CD4:CD8 ratio inversion (<1) were also found to be similar between both groups. However, neurocognitive impairment subjects were 8% more likely to have inversion of CD4:CD8 ratio and higher median peak CD8 cell counts reported compared to non-impaired subjects. Analysis of data from the MSM Neurocog Study, demonstrated trends in peripheral CD8 counts and CD4:CD8 ratios. However, we are unable to demonstrate any significant benefit. Plasma biomarkers of neurocognitive impairment in HIV-infected subjects would be of great benefit over current methods of invasive CSF analysis and technical neuroimaging used in the diagnosis of neurocognitive impairment. Future, prospective, longitudinal work with large numbers of neurocognitive impairment subjects is required to further investigate the role of peripheral CD8 T cells as markers of neurocognitive impairment. PMID- 24759563 TI - 2014 European Guideline on HIV testing. AB - Testing for HIV is one of the cornerstones in the fight against HIV spread. The 2014 European Guideline on HIV Testing provides advice on testing for HIV infection in individuals aged 16 years and older who present to sexually transmitted infection, genito-urinary or dermato-venereology clinics across Europe. It may also be applied in other clinical settings where HIV testing is required, particularly in primary care settings. The aim of the guideline is to provide practical guidance to clinicians and laboratories that within these settings undertake HIV testing, and to indicate standards for best practice. PMID- 24759565 TI - Constraint neighborhood projections for semi-supervised clustering. AB - Semi-supervised clustering aims to incorporate the known prior knowledge into the clustering algorithm. Pairwise constraints and constraint projections are two popular techniques in semi-supervised clustering. However, both of them only consider the given constraints and do not consider the neighbors around the data points constrained by the constraints. This paper presents a new technique by utilizing the constrained pairwise data points and their neighbors, denoted as constraint neighborhood projections that requires fewer labeled data points (constraints) and can naturally deal with constraint conflicts. It includes two steps: 1) the constraint neighbors are chosen according to the pairwise constraints and a given radius so that the pairwise constraint relationships can be extended to their neighbors, and 2) the original data points are projected into a new low-dimensional space learned from the pairwise constraints and their neighbors. A CNP-Kmeans algorithm is developed based on the constraint neighborhood projections. Extensive experiments on University of California Irvine (UCI) datasets demonstrate the effectiveness of the proposed method. Our study also shows that constraint neighborhood projections (CNP) has some favorable features compared with the previous techniques. PMID- 24759566 TI - Minimizing illumination differences for 3D to 2D face recognition using lighting maps. AB - Asymmetric 3D to 2D face recognition has gained attention from the research community since the real-world application of 3D to 3D recognition is limited by the unavailability of inexpensive 3D data acquisition equipment. A 3D to 2D face recognition system explicitly relies on 3D facial data to account for uncontrolled image conditions related to head pose or illumination. We build upon such a system, which matches relit gallery textures with pose-normalized probe images, using the gallery facial meshes. The relighting process, however, is based on an assumption of indoor lighting conditions and limits recognition performance on outdoor images. In this paper, we propose a novel method for minimizing illumination difference by unlighting a 3D face texture via albedo estimation using lighting maps. The algorithm is evaluated on challenging databases (UHDB30, UHDB11, FRGC v2.0) with drastic lighting and pose variations. The experimental results demonstrate the robustness of our method for estimating the albedo from both indoor and outdoor captured images, and the effectiveness and efficiency for illumination normalization in face recognition. PMID- 24759564 TI - Preemptive Tolerogenic Delivery of Donor Antigens for Permanent Allogeneic Islet Graft Protection. AB - We have previously developed a robust regimen for tolerance induction in murine models of islet cell transplantation using pre- and posttransplant infusions of donor splenocytes (SPs) treated with a chemical cross-linker ethylcarbodiimide (ECDI). However, the requirement for large numbers of fresh donor SPs for ECDI coupling impairs its clinical feasibility, and additionally, the compatibility of this tolerance regimen with commonly used immunosuppressive drugs is largely unknown. In the current study, we demonstrate that equivalent tolerance efficacy for islet cell transplantation can be successfully achieved not only with a significantly lower dose of ECDI-SPs than originally established but also with culture-expanded donor B-cells or with soluble donor antigens in the form of donor cell lysate, which is ECDI coupled to recipient SPs. We further demonstrate that tolerance induced by donor ECDI-SPs is dependent on a favorable apoptotic-to necrotic cell ratio post-ECDI coupling and is not affected by a transient course of conventional immunosuppressive drugs including tacrolimus and mycophenolate mofetil. While splenic antigen-presenting cells of the recipient play an important role in mediating the tolerogenic effects of donor ECDI-SPs, splenectomized recipients can be readily tolerized and appear to employ liver Kupffer cells for uptaking and processing of the ECDI-SPs. We conclude that infusion of donor ECDI-SPs is a versatile tolerance strategy that has a high potential for adaptation to clinically feasible regimens for tolerance trials for human islet cell transplantation. PMID- 24759567 TI - Measurement of ultrasonic scattering attenuation in austenitic stainless steel welds: realistic input data for NDT numerical modeling. AB - Multipass welds made of 316L stainless steel are specific welds of the primary circuit of pressurized water reactors in nuclear power plants. Because of their strong heterogeneous and anisotropic nature due to grain growth during solidification, ultrasonic waves may be greatly deviated, split and attenuated. Thus, ultrasonic assessment of the structural integrity of such welds is quite complicated. Numerical codes exist that simulate ultrasonic propagation through such structures, but they require precise and realistic input data, as attenuation coefficients. This paper presents rigorous measurements of attenuation in austenitic weld as a function of grain orientation. In fact attenuation is here mainly caused by grain scattering. Measurements are based on the decomposition of experimental beams into plane-wave angular spectra and on the modeling of the ultrasonic propagation through the material. For this, the transmission coefficients are calculated for any incident plane wave on an anisotropic plate. Two different hypotheses on the welded material are tested: first it is considered as monoclinic, and then as triclinic. Results are analyzed, and validated through comparison to theoretical predictions of related literature. They underline the great importance of well-describing the anisotropic structure of austenitic welds for UT modeling issues. PMID- 24759568 TI - European cancer mortality predictions for the year 2014. AB - BACKGROUND: From most recent available data, we projected cancer mortality statistics for 2014, for the European Union (EU) and its six more populous countries. Specific attention was given to pancreatic cancer, the only major neoplasm showing unfavorable trends in both sexes. PATIENTS AND METHODS: Population and death certification data from stomach, colorectum, pancreas, lung, breast, uterus, prostate, leukemias and total cancers were obtained from the World Health Organisation database and Eurostat. Figures were derived for the EU, France, Germany, Italy, Poland, Spain and the UK. Projected 2014 numbers of deaths by age group were obtained by linear regression on estimated numbers of deaths over the most recent time period identified by a joinpoint regression model. RESULTS: In the EU in 2014, 1,323,600 deaths from cancer are predicted (742,500 men and 581,100 women), corresponding to standardized death rates of 138.1/100,000 men and 84.7/100,000 women, falling by 7% and 5%, respectively, since 2009. In men, predicted rates for the three major cancers (lung, colorectum and prostate cancer) are lower than in 2009, falling by 8%, 4% and 10%, respectively. In women, breast and colorectal cancers had favorable trends (-9% and -7%), but female lung cancer rates are predicted to rise 8%. Pancreatic cancer is the only neoplasm with a negative outlook in both sexes. Only in the young (25-49 years), EU trends become more favorable in men, while women keep registering slight predicted rises. CONCLUSIONS: Cancer mortality predictions for 2014 confirm the overall favorable cancer mortality trend in the EU, translating to an overall 26% fall in men since its peak in 1988, and 20% in women, and the avoidance of over 250,000 deaths in 2014 compared with the peak rate. Notable exceptions are female lung cancer and pancreatic cancer in both sexes. PMID- 24759569 TI - Recurrent bovine tuberculosis in New Zealand cattle and deer herds, 2006-2010. AB - A retrospective cohort study was conducted to identify risk factors for bovine tuberculosis (bTB) recurrence in New Zealand cattle and deer herds identified as bTB-infected from 1 June 2006 to 1 November 2010. A Cox proportional hazards model identified a positive relationship between the daily hazard of bTB recurrence and: (1) the number of prior bTB episodes for two episodes [hazard ratio (HR) 3.22, 95% confidence interval (CI) 1.21-8.60], and for five episodes (HR 89.5, 95% CI 13.8-580), (2) more than one positive bTB case animal at the index episode (HR 2.25, 95% CI 1.19-4.25) and (3) the presence of cleared test positives at the final test of the index episode. The proportional hazards assumption was violated for the latter variable so a time-dependent covariate was introduced. Up to 2 years post-clearance, the daily hazard of bTB recurrence was greater in herds with test-positives at the final test (HR 2.59, 95% CI 1.30 5.13), but this effect was not observed more than 2 years' post-clearance (HR 1.05, 95% CI 0.28-3.91). We conclude that unresolved infection contributes to further bTB episodes in the first 2 years after herd clearance. PMID- 24759570 TI - Acute and chronic observations of complete atrioventricular block in rats. AB - The mechanisms of production, and gross, microscopic and electrocardiograhic findings of surgically-induced complete heart block (CHB) in the adult rat are presented. This is an effective in vivo model for establishing alternative methods to electronic pacemakers and for providing detailed information aimed at replacement, reduction and refinement of the technique. Sternal thoracotomy was employed to identify the epicardial fat pad by the aortic root, used as a landmark for cauterization of the atrioventricular (AV) node. Stable CHB was produced in 60 rats with a 70% survival rate. The best survival rate was observed in 8-week-old animals weighing 221 +/- 27.6 g. Heart rate before cauterization was 387 +/- 55 bpm, reduced after cauterization to 126 +/- 40 bpm in the survival and to 65 +/- 19 bpm in the non-survival groups. At 30 days findings were: elevated left ventricular end-diastolic pressure (21 +/- 5.4 mmHg, P < 0.05); maximal rate of rise of left ventricular pressure (LVP) during isovolumetric contraction (2192 +/- 235 mmHg/s, P < 0.05); maximal rate of decrease of LVP ( 1658 +/- 191 mmHg/s, P < 0.05); isovolumetric relaxation constant (5.7 +/- 0.8 ms, P < 0.05) with wet-to-dry lung-weight ratio (78.1 +/- 0.4, P < 0.05); heart weight/body weight (0.6 +/- 0.1, P < 0.05); heart volume (1.8 +/- 0.3 mL, P < 0.05); longitudinal diameter (20.2 +/- 1.91 mm, P < 0.05); and transversal diameter (17.0 +/- 1.4 mm, P < 0.05) with supported dilated cardiomyopathy which culminated in chronic heart failure. CHB hearts had increased preload and replacement of myofibrils by collagen. CHB was achieved reproducibly by cauterization of the rat AV node and/or His bundle. This led to electrophysiological, hemodynamic, and structural remodeling, and could be useful in long-term cardiac remodeling assessments and potential therapy development. PMID- 24759571 TI - Housing breeding mice in three different IVC systems: maternal performance and pup development. AB - A proper cage environment is essential for the welfare of laboratory mice, especially for females during the energy demanding lactation period and for pups during early development and growth. The most common housing system for laboratory mice is individually ventilated cages (IVCs) of which there are different layouts and ventilation strategies available on the market. The present study investigates the impact of cage environment in three different IVC types, on the maternal performance of females, and pup development and growth in C57BL/6NCrl and Crl:NMRI Foxn1 nu mice. The results show differences in in-cage climate, female body weight, pup growth, feed and water consumption, and nest quality between cage types. There was a distinct effect of genotype in these differences, with the main effects found in NMRI NU mice. The results indicate that IVC systems might need to be managed differently for mice of different types and/or different physiological status. Many of the differences seen between cage systems could be drawn to the physical construction of the cage, such as location of feed hopper and location of air inlet and outlet. In conclusion, IVC in-cage climate affects the maternal performance of female mice and pup growth, but with differences between the two strains tested. PMID- 24759572 TI - Oral self-administration of buprenorphine in the diet for analgesia in mice. AB - Postsurgical oral self-administration of analgesics in rodents is an interesting technique of providing analgesia, avoiding the negative effects of manipulation. Several strategies, using gelatin or nutella, have already been described. However, rodents require some habituation period to reach a good intake because of their neophobic behavior. The current study aimed to explore whether buprenorphine when mixed with an extruded diet offers a potential treatment option in the pain management of mice using a triple approach: by measuring the spontaneous intake in healthy animals; by using the hot-plate test; and finally by assessing the drug's ability to provide postoperative analgesia in a surgical intervention of moderate severity (intra-utero electroporation). Mice consumed during 20 hours, similar amounts of extruded diet alone, mixed with glucosaline, and mixed with buprenorphine (0.03 mg per pellet) or meloxicam (0.25 mg per pellet) both of which were diluted in glucosaline, showing that no neophobia was associated with these administrations. Relative increase from baseline latency (% maximal possible effect) in the hot-plate test at 20 h of administration was significantly higher for oral buprenorphine in diet 0.03 mg/pellet, and diet 0.15 mg/pellet, compared with placebo and no differences were found between those oral administrations and subcutaneous buprenorphine 0.1 mg/kg measured 3 h later. The treatment was also effective in attenuating the reductions in food consumption and body weight that occur after surgery. These data suggest that providing buprenorphine with the diet is a feasible and effective way of self administration of analgesia in mice and does not cause neophobia and may easily contribute to the refinement of surgical procedures. PMID- 24759573 TI - Reduced vergence adaptation is associated with a prolonged output of convergence accommodation in convergence insufficiency. AB - Convergence insufficiency (CI) is a developmental visual anomaly defined clinically by a reduced near point of convergence, a reduced capacity to view through base-out prisms (fusional convergence); coupled with asthenopic symptoms typically blur and diplopia. Experimental studies show reduced vergence parameters and tonic adaptation. Based upon current models of accommodation and vergence, we hypothesize that the reduced vergence adaptation in CI leads to excessive amounts of convergence accommodation (CA). Eleven CI participants (mean age=17.4+/-2.3 years) were recruited with reduced capacity to view through increasing magnitudes of base out (BO) prisms (mean fusional convergence at 40 cm=12+/-0.9Delta). Testing followed our previous experimental design for (n=11) binocularly normal adults. Binocular fixation of a difference of Gaussian (DoG) target (0.2 cpd) elicited CA responses during vergence adaptation to a 12Delta BO. Vergence and CA responses were obtained at 3 min intervals over a 15 min period and time course were quantified using exponential decay functions. Results were compared to previously published data on eleven binocular normals. Eight participants completed the study. CI's showed significantly reduced magnitude of vergence adaptation (CI: 2.9Delta vs. normals: 6.6Delta; p=0.01) and CA reduction (CI=0.21 D, Normals=0.55 D; p=0.03). However, the decay time constants for adaptation and CA responses were not significantly different. CA changes were not confounded by changes in tonic accommodation (Change in TA=0.01+/-0.2D; p=0.8). The reduced magnitude of vergence adaptation found in CI patients resulting in higher levels of CA may potentially explain their clinical findings of reduced positive fusional vergence (PFV) and the common symptom of blur. PMID- 24759574 TI - Synchronous HIV/AIDS-related Epstein-Barr Virus-associated smooth muscle tumors in a 20-year-old female. AB - We present a case of simultaneous endobronchial and adrenal Epstein-Barr Virus associated smooth muscle tumors in a 20-year-old female with AIDS. Blood Epstein Barr Virus polymerase chain reaction was negative at the time of diagnosis. PMID- 24759575 TI - PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. AB - Prostate cancer (PCa) is the second most common malignancy among men in the world. Castration-resistant prostate cancer (CRPC) is the lethal form of the disease, which develops upon resistance to first line androgen deprivation therapy (ADT). Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor (AR) signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of specific pathway inhibitors in advanced PCa. In addition, we will highlight current deficiencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors. PMID- 24759576 TI - The impact of male overweight on semen quality and outcome of assisted reproduction. AB - It is well-documented that male overweight and obesity causes endocrine disorders that might diminish the male reproductive capacity; however, reports have been conflicting regarding the influence of male body mass index (BMI) on semen quality and the outcome of assisted reproductive technology (ART). The aim of this study was to investigate whether increased male BMI affects sperm quality and the outcome of assisted reproduction in couples with an overweight or obese man and a non-obese partner. Data was prospectively collected from 612 infertile couples undergoing ART at a Danish fertility center. Self-reported information on paternal height and weight were recorded and BMI was calculated. The men were divided into four BMI categories: underweight BMI < 20 kg m(-2) normal BMI 20 24.9 kg m(-2), overweight BMI 25-29.9 kg m(-2) and obese BMI > 30 kg m(-2). Conventional semen analysis was performed according to the World Health Organization guideline and sperm DNA integrity was analyzed by the Sperm Chromatin Structure Assay (SCSA). No statistically significant effect of male BMI was seen on conventional semen parameters (sperm concentration, total sperm count, seminal volume and motility) or on SCSA-results. Furthermore, the outcome of ART regarding fertilization rate, number of good quality embryos (GQE ), implantation and pregnancy outcome was not influenced by the increasing male BMI. PMID- 24759577 TI - Improving intermittent androgen deprivation therapy: lessons learned from basic and translational research. AB - Intermittent androgen deprivation therapy (IADT) is an alternative to continuous androgen deprivation therapy (ADT) in prostate cancer patients with nonmetastatic disease. ADT is associated with numerous side effects such as hot flashes, sexual dysfunction, anemia, fatigue, loss of muscle mass, osteoporosis, metabolic syndrome and premature cardiovascular disease. IADT was developed with the intention of improving the quality of life and to delay progression of prostate cancer to castration resistance. The benefits of slightly improved quality of life by IADT compared to ADT were demonstrated in multiple clinical trials. IADT was noted to be noninferior to ADT in patients with biochemical recurrence of prostate cancer but in studies performed in patients with metastatic prostate cancer, the results were inconclusive. Our recent studies suggested that the administration of 5 alpha-reductase inhibitors during the off-cycle of IADT can significantly prolong the survival of mice bearing androgen-sensitive prostate tumors when off-cycle duration was short. This review discusses the survival benefit of 5 alpha-reductase inhibition in IADT in animal models and the potential translation of this finding into clinic. PMID- 24759578 TI - Tunica albuginea allograft: a new model of LaPeyronie's disease with penile curvature and subtunical ossification. AB - The pathophysiology of LaPeyronie's disease (PD) is considered to be multifactorial, involving genetic predisposition, trauma, inflammation and altered wound healing. However, these factors have not yet been validated using animal models. In this study, we have presented a new model obtained by tunica albuginea allograft. A total of 40, 16-week-old male rats were used. Of these, 8 rats served as controls and underwent a 10 * 2-mm-wide tunical excision with subsequent autografting, whereas the remaining 32 underwent the same excision with grafting of the defect with another rat's tunica. Morphological and functional testing was performed at 1, 3, 7 and 12 weeks after grafting. Intracavernous pressure, the degree of penile curvature and elastic fiber length were evaluated for comparison between the allograft and control groups. The tissues were obtained for histological examination. The penile curvature was significantly greater in the allografted rats as compared with the control rats. The erectile function was maintained in all rats, except in those assessed at 12 weeks. The elastin fiber length was decreased in the allografted tunica as compared to control. SMAD2 expression was detected in the inner part of the allograft, and both collagen-II- and osteocalcin-positive cells were also noted. Tunica albuginea (TA) allograft in rats is an excellent model of PD. The persistence of curvature beyond 12 weeks and the presence of ossification in the inner layer of the TA were similar to those observed in men with PD. Validation studies using this animal model would aid understanding of the PD pathophysiology for effective therapeutic interventions. PMID- 24759579 TI - Anti-angiogenesis in prostate cancer: knocked down but not out. AB - Angiogenesis is a very complex physiological process, which involves multiple pathways that are dependent on the homeostatic balance between the growth factors (stimulators and inhibitors). This tightly controlled process is stimulated by angiogenic factors, which are present within the tumor and surrounding tumor associated stromal cells. The dependence of tumor propagation, invasion and metastasis on angiogenesis makes the inhibitors of new blood vessel formation attractive drugs for treating the malignancies. Angiogenesis can be disrupted by several distinct mechanisms: by inhibiting endothelial cells, by interrupting the signaling pathways or by inhibiting other activators of angiogenesis. This strategy has shown therapeutic benefit in several types of solid tumors, leading to Food and Drug Administration (FDA) approval of anti-angiogenic agents in the treatment of kidney, non-small cell lung, colon and brain cancers. Although no angiogenesis inhibitors have been approved for patients with metastatic prostate cancer, therapies that target new blood vessel formation are still an emerging and promising area of prostate cancer research. PMID- 24759580 TI - Comparison of sperm retrieval and reproductive outcome in azoospermic men with testicular failure and obstructive azoospermia treated for infertility. AB - We assessed the rates of sperm retrieval and intracytoplasmic sperm injection outcomes, including the neonatal profile of infants conceived, in men with testicular failure. Three-hundred and sixty-five men with testicular failure who underwent micro-dissection testicular sperm extraction were included in this study. We compared their outcomes with 40 men with testicular failure who used donor sperm for injections due to failed retrieval, and 146 men with obstructive azoospermia who underwent percutaneous sperm retrieval. The retrieval rate in testicular failure was 41.4%, and the results were lower than the obstructed azoospermia (100%; adjusted odds ratio: 0.033; 95% CI: 0.007-0.164; P< 0.001). Live birth rates after sperm injections were lower in men with testicular failure (19.9%) compared with donor sperm (37.5%; adjusted OR: 0.377 (95% CI: 0.233 0.609, P< 0.001)) and obstructive azoospermia (34.2%; adjusted OR: 0.403 (95% CI: 0.241-0.676, P= 0.001). Newborn parameters of infants conceived were not significantly different among the groups. We concluded that the chances of obtaining sperm on retrieval and achieving a live birth after intracytoplasmic sperm injection (ICSI) are reduced in men with testicular failure. The profile of infants conceived after sperm injection does not seem to be negatively affected by testicular failure. PMID- 24759581 TI - Optimal treatment for castration-resistant prostate cancer. PMID- 24759582 TI - Sperm retrieval rates and ICSI outcomes for men with nonobstructive azoospermia and the health of resulting offspring. PMID- 24759583 TI - Solving a bottleneck in animal models of Peyronie's disease. PMID- 24759584 TI - Androgen receptor functions in prostate cancer development and progression. PMID- 24759585 TI - The metastatic castration-resistant prostate cancer treatment paradigm: more choices, more questions. PMID- 24759586 TI - Disposable circumcision suture device: clinical effect and patient satisfaction. AB - In our experience patients undergoing circumcision are mostly concerned about pain and penile appearances. We conducted a prospective randomized trial to assess the benefits of a new disposable circumcision suture device (DCSD). A total of 942 patients were equally divided into three groups (conventional circumcision, Shang ring and disposable suture device group). Patients in the DCSD group were anesthetized with compound 5% lidocaine cream, the others with a 2% lidocaine penile block. Operation time, intra-operative blood loss, incision healing time, intra-operative and post-operative pain, the penile appearance and overall satisfaction degree were measured. Operation time and intra-operative blood loss were significantly lower in the Shang ring and suture device groups compared to the conventional group (P < 0.001). Intra-operative pain was less in the suture device group compared with the other two groups (P < 0.001); whereas post-operative pain was higher in the conventional group compared to the other two groups (P < 0.001). Patients in the suture device (80.57%) and Shang ring (73.57%) groups were more satisfied with penile appearances compared with the conventional circumcision group (20.06%, P < 0.05). Patients in suture device group also healed markedly faster than the conventional group (P < 0.01). The overall satisfaction rate was better in the suture device group (78.66%) compared with the conventional (47.13%) and Shang ring (50.00%) groups (P < 0.05). The combination of DCSD and lidocaine cream resulted in shorter operation and incision healing times, reduced intra-operative and post-operative pain and improved patient satisfaction with the cosmetic appearances. PMID- 24759587 TI - Prevalence, correlates, attitude and treatment seeking of erectile dysfunction among type 2 diabetic Chinese men attending primary care outpatient clinics. AB - To investigate the prevalence, correlates, attitude and treatment seeking behavior of erectile dysfunction (ED) in type 2 diabetes mellitus (T2DM) patients in the primary care setting, a multi-center cross-sectional survey using a structured anonymous self-administered questionnaire was performed in 10 general outpatient clinics. Of the 603 subjects (91% response rate), the prevalence of ED men, as defined by the International Index of Erectile Function, was 79.1%. Most subjects had mild ED (28.9%), followed by mild-to-moderate ED (27.9%), then moderate ED (13.4%) and severe ED (9%). Nearly 55% of those with ED did not consider themselves as having ED. Less than 10% of them had ever sought medical treatment, although 76.1% of them wished to receive management from doctor(s) should they be diagnosed with ED. They considered the most important management from doctors to be clinical assessment (41.7%), followed by management of potential underlying cause (37.8%), referral to specialist (27.5%), education (23.9%), prescription of phosphodiesterase type 5 inhibitors (16.9%) and referral to counseling service (6.7%). The prevalence of ED was strongly associated with subjects who thought they had ED (odds ratio (OR) = 90.49 (20.00-409.48, P< 0.001)) and were from the older age group (OR = 1.043 (1.011-1.076, P= 0.008)). In conclusion, ED is highly prevalent among T2DM men. The majority of them wanted management from doctors should they have ED, but only a minority would actually voice out the request. Screening of ED among T2DM men using structural questionnaire allowed the diagnosis of more than half of the ED cases, which otherwise would have gone undiagnosed. PMID- 24759588 TI - New developments in the treatment of castration resistant prostate cancer. AB - In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer (CRPC) have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research. PMID- 24759589 TI - Cyr61: a potential therapeutic target for prostate cancer. PMID- 24759591 TI - The role of urethral pressure profile on treating premature ejaculation by tamsulosin. PMID- 24759592 TI - A strategy for rapid analysis of xenobiotic metabolome of Sini decoction in vivo using ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry combined with pattern recognition approach. AB - Xenobiotic metabolome identificatioqn of Chinese herbal prescription in biological systems is a very challenging task. In the present work, a reliable strategy based on the combination of ultra-performance liquid chromatography electrospray ionization quadrupole-time-of-flight mass spectrometry (UHPLC-ESI-Q TOFMS) and pattern recognition approach such as principal component analysis (PCA) and partial least squared discriminant analysis (PLS-DA) was proposed to rapidly discover and analyze the xenobiotic metabolome from Sini decoction (SND). Using the S- and VIP-plots of PLS-DA, 96 and 112 interest ions from positive and negative ion datasets were extracted as SND metabolome in rat urine following oral administration of SND. Among them, 53 absorbed prototype components of SND and 49 metabolites were identified, which provided essential data for further studying the relationship between the chemical components and pharmacological activity of SND. Our results indicated that hydrolysis and demethylation were the major metabolic pathways of diterpenoid alkaloids, while glucuronidation, sulfation, hydrolysis, reduction, demethylation, and hydroxylation were the main metabolic pathways of flavonoids, and hydrolysis was the metabolic pathway of gingerol-related compounds. No saponin-related metabolites were detected. PMID- 24759593 TI - Simple validated LC-MS/MS method for the determination of atropine and scopolamine in plasma for clinical and forensic toxicological purposes. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of atropine and scopolamine in 100MUL human plasma was developed and validated. Sample pretreatment consisted of protein precipitation with acetonitrile followed by a concentration step. Analytes and levobupivacaine (internal standard) were separated on a Zorbax XDB-CN column (75mm*4.6mm i.d., 3.5MUm) with gradient elution (purified water, acetonitrile, formic acid). The triple quadrupole MS was operated in ESI positive mode. Matrix effect was estimated for deproteinised plasma samples. Selected reaction monitoring (SRM) was used for quantification in the range of 0.10-50.00ng/mL. Interday precision for both tropanes and intraday precision for atropine was <10%, intraday precision for scopolamine was <14% and <18% at lower limit of quantification (LLOQ). Mean interday and intraday accuracies for atropine were within +/-7% and for scopolamine within +/-11%. The method can be used for determination of therapeutic and toxic levels of both compounds and has been successfully applied to a study of pharmacodynamic and pharmacokinetic properties of tropanes, where plasma samples of volunteers were collected at fixed time intervals after ingestion of a buckwheat meal, spiked with five low doses of tropanes. PMID- 24759594 TI - Ab initio molecular dynamics study of high-pressure melting of beryllium oxide. AB - We investigate, through first-principles molecular dynamics simulations, the high pressure melting of BeO in the range 0 <= p <= 100 GPa. The wurtzite (WZ), zinc blend (ZB), and rocksalt (RS) phases of BeO are considered. It is shown that below 40 GPa, the melting temperature for the WZ phase is higher than that for the ZB and RS phases. When the pressure is beyond 66 GPa, the melting temperature for the RS phase is the highest one, in consistent with the previously reported phase diagram calculated within the quasiharmonic approximation. We find that in the medium pressure range between 40 to 66 GPa, the ZB melting data are very close to those of RS, which results from the fact that the ZB structure first transforms to RS phase before melting. The ZB-RS-liquid phase transitions have been observed directly during the molecular dynamics runs and confirmed using the pair correlation functions analysis. In addition, we propose the melting curve of BeO in the form Tm = 2696.05 (1 + P/24.67)(0.42), the zero-pressure value of 2696.05 K falling into the experimental data range of 2693 ~ 2853 K. PMID- 24759596 TI - Spin regulation in composite spin-filter barrier devices. AB - Magnetic insulators are known to provide large effective Zeeman fields that are confined at an interface, making them especially powerful in modifying adjacent one- or two-dimensional electronic structures. Utilizing this phenomenon and the other important property of magnetic insulators--spin filtering--here we report the generation and subsequent detection of a large interface field, as large as tens of tesla in EuS/Al/EuS heterostructures with metallic coulomb islands confined within a magnetic insulator barrier. The unique energy profile across this sandwich structure produces spin-assisted charge transfer across the device, generating a spontaneous spin current and voltage. These unique properties can be practical for controlling spin flows in electronic devices and for energy harvesting. PMID- 24759590 TI - Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer. AB - Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17alpha-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17alpha-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity. PMID- 24759598 TI - Beyond EGFR TKI in EGFR-mutant non-small cell lung cancer patients: main challenges still to be overcome. AB - First line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is the standard treatment in advanced EGFR-mutant Non Small Cell Lung Cancer (NSCLC) patients, with an improvement in response rate, progression free survival, and quality of life compared with upfront chemotherapy. However, in the real world, EGFR mutation results often return positive once chemotherapy has been started. Different clinical strategies have been tested in this situation: reserve the EGFR TKI until tumor become resistant beyond chemotherapy, stop chemotherapy and switch to EGFR TKI, introduce the EGFR TKI as a maintenance treatment, or combined strategies such as intercalated or concurrent EGFR TKI plus chemotherapy. In this review, we aim to summarize the clinical evidence of first line treatment strategy with EGFR TKI and discuss the potential options in the sequence of treatment in EGFR-mutant patients. PMID- 24759597 TI - SAHA and S116836, a novel tyrosine kinase inhibitor, synergistically induce apoptosis in imatinib-resistant chronic myelogenous leukemia cells. AB - Limited treatment options are available for chronic myelogenous leukemia (CML) patients who develop imatinib mesylate (IM) resistance. Here we proposed a novel combination regimen, a co-administration of S116836, a novel small molecule multi targeted tyrosine kinase inhibitor that was synthesized by rational design, and histone deacetylases inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA), to overcome IM resistance in CML. S116836 at low concentrations used in the present study mildly downregulates auto-tyrosine phosphorylation of Bcr-Abl. SAHA, an FDA approved HDACi drug, at 1 MUM has modest anti-tumor activity in treating CML. However, we found a synergistic interaction between SAHA and S116836 in Bcr-Abl positive CML cells that were sensitive or resistant to IM. Exposure of KBM5 and KBM5-T315I cells to minimal or non-toxic concentrations of SAHA and S116836 synergistically reduced cell viability and induced cell death. Co-treatment with SAHA and S116838 repressed the expressions of anti-apoptosis proteins, such as Mcl-1 and XIAP, but promoted Bim expression and mitochondrial damage. Of importance, treatment with both drugs significantly reduced cell viability of primary human CML cells, as compared with either agent alone. Taken together, our findings suggest that SAHA exerts synergistically with S116836 at a non-toxic concentration to promote apoptosis in the CML, including those resistant to imatinib or dasatinib. PMID- 24759599 TI - Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. AB - Lung cancer is characterized by the highest incidence of solid tumor-related brain metastases, which are reported with a growing incidence during the last decade. Prognostic assessment may help to identify subgroups of patients that could benefit from more aggressive therapy of metastatic disease, in particular when central nervous system is involved. The recent sub-classification of non small cell lung cancer (NSCLC) into molecularly-defined "oncogene-addicted" tumors, the emergence of effective targeted treatments in molecularly defined patient subsets, global improvement of advanced NSCLC survival as well as the availability of refined new radiotherapy techniques are likely to impact on outcomes of patients with brain dissemination. The present review focuses on key evidence and research strategies for systemic treatment of patients with central nervous system involvement in non-small cell lung cancer. PMID- 24759600 TI - Application of ThinPrep bronchial brushing cytology in the early diagnosis of lung cancer: a retrospective study. AB - The majority of lung cancer patients are diagnosed at advanced stages of disease. This study evaluated the diagnostic value of ThinPrep (TP) bronchial brushing cytology in lung cancer. A total of 595 patients with suspicious lung cancer were enrolled in this study. The bronchial brushing samples were prepared by TP. The data were then compared to histology of lung tissue samples. Histologically, 479 of these 595 patients were diagnosed with lung cancer, including 223 cases of lung squamous cell carcinoma (SCC), 77 cases of lung adenocarcinoma (ADC), and 152 cases of small cell lung carcinoma (SCLC). The TP cytology revealed a total of 460 cases of lung cancer (including 232 SCCs, 91 ADCs, and 108 SCLCs). The TP cytological technique had 87.06% sensitivity and 62.93% specificity in the diagnosis of lung cancer. Specifically, TP cytology confirmed 195 of 223 SCCs, 47 of 77 ADCs, and 94 of 152 SCLCs. The TP cytology showed 87.44% sensitivity and 90.05% specificity for the diagnosis of SCC, with a Matthew's correlation coefficient (MCC) of 0.820; while the sensitivity was reduced to 61.04% and the specificity was 90.93% for the diagnosis of ADC, with a MCC of 0.464. For the diagnosis of SCLC, the sensitivity was 61.84% and the specificity was 96.84%, with a MCC of 0.648. Thus, this study demonstrated the usefulness of TP bronchial brushing cytology in the early diagnosis of lung cancer, especially the early stage of lung SCC. A prospective clinical trial will verify these data before being translated into the clinic. PMID- 24759601 TI - Appropriateness of administrative data for vaccine impact evaluation: the case of pneumonia hospitalizations and pneumococcal vaccine in Brazil. AB - Ten-valent pneumococcal conjugate vaccine (PCV10) was recently introduced into the Brazilian Immunization Programme. Secondary data are used as a measurement of community-acquired pneumonia (CAP) burden, but their completeness and reliability need to be ascertained. We performed probabilistic linkage between hospital primary data from active prospective population-based surveillance (APS) and hospital secondary data from the Hospital Information System administrative database of the National Unified Health System (SIH-SUS). Children aged 2-23 months hospitalized during January-December 2012 were identified. Incidence rates of hospitalized CAP were estimated. Agreement of case identification was measured by kappa index. A total of 1639 (26%) CAP cases were identified in APS and 1714 (35%) in SIH-SUS. Of these 3353 records, 1127 CAP cases were present in both databases. Kappa on CAP case identification was 0.72 (95% confidence interval 0.69-0.75). CAP hospitalization incidence using administrative (5285/100 000) and hospital (5054/100 000) primary data were similar (P = 0.184). Our findings suggest that administrative databases of hospitalizations are reliable sources to assess PCV10 impact in time-series analyses. PMID- 24759602 TI - Essix restoration: a novel approach for transitional teeth replacement. AB - Loss of teeth is a distressing situation. The patient may cultivate feeling of loss of an organ on loss of teeth. Especially when anterior teeth are lost appearance of the patient is compromised with altered pronunciation. This is a really embarrassing situation for people working as news readers, social workers, marketing executives, theatre artists or persons whose presentation in front of people is important as part of their work. Replacement of missing teeth immediately after loss is not possible always due to local and systemic physiological factors, age, pathological factors and unfavourable condition of soft tissue in a particular area. Various means are available for transitional replacement of teeth which may or may not require adjacent teeth preparation. Essix restoration is easy to fabricate and use the restoration option with great aesthetic value. PMID- 24759603 TI - Congenital malignant melanoma of the scalp in a 25-day-old neonate. AB - We present a case of congenital malignant melanoma of the scalp in a neonate. The child was born through caesarean section with a swelling, the size of a tennis ball, on the posterior scalp. At presentation to the clinic at 25 days after birth, the swelling had significantly increased in size and ulcerated. An excision was carried out but, because of extensive haemorrhage and haemodynamic instability, the procedure was limited to subtotal resection. Later on, completion of the excision and flap coverage of the wound were performed. After an initial stable course of a few months, the child came back with local recurrence. A re-excision was planned but the child developed pneumonia resulting in sepsis leading to the demise of the child. The report adds to the literature by describing a rare entity and challenges of managing large vascular scalp lesions with complete excision and defect coverage. PMID- 24759604 TI - Simultaneous bilateral triquetral fractures, acquired in two separate accidents within 9 h. PMID- 24759605 TI - Mantle cell lymphoma: a rare cause of a solitary duodenal mass. AB - Mantle cell lymphoma is a very aggressive lymphoma with a very poor prognosis. It commonly involves the gastrointestinal tract but rarely presents as primary gastrointestinal lymphoma. The most notable cases of primary gastrointestinal mantle cell lymphomas have been described as multiple lymphomatous polyposis and have a very poor prognosis. We report a case of primary gastrointestinal mantle cell lymphoma that was discovered by endoscopic biopsy of a single duodenal polyp in a 70-year-old woman who was previously treated for Helicobacter pylori gastritis. She presented with a 6-month history of indigestion, heartburn and abdominal bloating. A subsequent workup revealed one extranodal site of involvement, lymphatic involvement below the diaphragm and a normal bone marrow biopsy. We followed a wait-and-watch approach including serial CT scans and blood tests. Two years later, her symptoms have not progressed and her disease has remained stable. PMID- 24759606 TI - Autoimmune hepatitis: trust in transaminases. AB - A rational and appropriate evaluation of liver biochemical tests is essential, given the increased number of abnormal laboratory results in asymptomatic patients. Critical judgement allows early diagnosis in the absence of typical clinical signs. Autoimmune hepatitis is a rare disease with high clinical variability. We present a child investigated for unexplained increase in aminotransferases, discovered accidentally 2 months earlier in a standard laboratory panel approach. She was asymptomatic and no physical signs of chronic or acute liver disease were found. Laboratory investigation showed hypergammaglobulinaemia with selective elevation of IgG and a positive anti-liver cytosol type 1. Severe interface hepatitis was found on liver biopsy and treatment was initiated with steroids and azathioprine with good response. This case highlights the importance of trusting in any serum aminotransferase abnormality, even in asymptomatic children and emphasises the value of clinical suspicion and specific immunosuppressive therapy in prognosis. PMID- 24759607 TI - Isolated III cranial nerve palsy: a Hodgkin's lymphoma? AB - A 69-year-old woman developed ptosis and diplopia due to an isolated pupil involving left oculomotor nerve palsy. General examination was unremarkable. Initial workup showed a mild increase in cerebrospinal fluid proteins. Imaging studies were remarkable for a left oculomotor nerve enhancement in brain MRI and hyperfixation along the nerve's pathway in full body single-photon emission CT. Assuming the possible diagnosis of neurosarcoidosis, the patient was started on high-dose methylprednisolone. Three months later she developed pancytopenia. A bone marrow biopsy was performed and histopathology revealed infiltration by Hodgkin's lymphoma. Adriamycin, bleomycin, vinblastine, dacarbazine protocol chemotherapy was started and full haematological remission obtained after four cycles, despite mild oculomotor nerve palsy persisted. Isolated oculomotor palsy as the first presenting manifestation of a lymphoma is rare and alternative differential diagnosis must be considered in the absence of other lymphoma manifestations. In this case as with many rare initial manifestations of common diseases watchful waiting was crucial to the correct diagnosis and treatment strategy. PMID- 24759608 TI - Cutaneous horn: get to the bottom of it. AB - A 62-year-old man presented to our family practice office with a skin lesion that developed over 8-10 months. Over the past 2-3 months the lesion grew more quickly. A 2-3 cm, hard brown projection was noted on the dorsal aspect of his hand. A decision was made to excise the lesion and send it for pathological evaluation. The lesion was found to be a cutaneous horn with invasive squamous cell carcinoma at the base. The margins of the sample were free of cancer cells. Cutaneous horns are raised skin lesions made of dead keratin derived from base keratinocytes. They are frequently found in areas of the body that have had solar exposure. There are a wide variety of histopathological findings at the base of these lesions. They range from benign to premalignant to malignant. Cutaneous horns should be completely excised and sent for pathological evaluation. PMID- 24759609 TI - Bronchial atresia with finger-in-glove sign. PMID- 24759610 TI - Atorvastatin improves systolic function, but does not prevent the development of dilated cardiomyopathy in streptozotocin-induced diabetic rats. AB - BACKGROUND: Therapy with HMG-CoA reductase inhibitors (statins) has been associated with a significant reduction in the number of major cardiovascular (CV) events in diabetic patients. The mechanisms by which these drugs improve cardiac status remain unclear. We assessed the effects of atorvastatin (10 mg/kg/day) on CV function in streptozotocin (STZ)-induced diabetic rats. METHODS: Age-matched, nondiabetic rats were used as controls. Echocardiographic parameters, systolic blood pressure (SBP), endothelial-dependent relaxation, cardiac and vascular oxidative stress, perivascular fibrosis, and cholesterol levels were evaluated after a 4-week atorvastatin treatment period. RESULTS: In diabetic rats, SBP was higher than in controls. Atorvastatin decreased SBP in diabetic rats by 14% (n = 10, p < 0.05), and significantly increased stroke volume, ejection fraction, and cardiac output index. Whereas atorvastatin reduced left ventricular end systolic volume (LVESV) by 50% (p < 0.05), it failed to reduce left ventricular end diastolic volume (LVEDV). Total cholesterol was higher in diabetic rats than in controls and atorvastatin was ineffective in reducing cholesterol levels. The statin, however, decreased perivascular fibrosis and media thickness, and the markers of oxidative stress malondialdehyde (MDA) and 4-hidroxyalkenals (4-HAE) in aortic homogenates from diabetic rats. In addition, atorvastatin improved endothelial function by increasing the E MAX value of the acetylcholine-induced relaxation from 53.7 +/- 4.1% in untreated diabetic to 82.1 +/- 7.0% in treated diabetic rats (n = 10, p < 0.05). L-NAME fully abolished this improvement, suggesting that the increased vascular relaxation with atorvastatin is NO-dependent. CONCLUSIONS: Whereas atorvastatin does not reverse ventricular dilatation, it does have a positive hemodynamic effect on the CV system of diabetic rats. This hemodynamic benefit is independent of cholesterol levels, and is observed concomitantly with reduced oxidative stress, vascular remodeling, and improved endothelial function. Together, these results suggest that atorvastatin decreases the workload on the heart and improves systolic performance in type 1 diabetic rats by reducing oxidative stress, vascular tone, and systemic vascular resistance. PMID- 24759611 TI - Influence of typical angina versus inducible myocardial ischemia in the contemporary management of stable coronary artery disease. AB - OBJECTIVE: To investigate, in patients with known or suspected coronary artery disease (CAD) undergoing myocardial perfusion single-photon emission computed tomography (MPS),the interaction between patient symptoms and single-photon emission computed tomography (SPECT) results, and their effects on patient outcomes. Previous data have shown that medical treatment may be as beneficial as invasive treatment for most patients with stable CAD. Nonetheless, patient presentation with typical angina (TA) seems to still lead to more aggressive management, regardless of the amount of myocardial ischemia detected by noninvasive methods. METHODS: Over 33 +/- 20 months, 2958 patients undergoing stress/rest cardiac SPECT were followed. Summed stress, rest and difference scores (SSS, SRS and SDS, respectively) were analyzed. Abnormal SPECT was defined as a SSS>3, and ischemic SPECT as a SDS>1. During follow up, cardiac catheterization (CATH), myocardial revascularization (either percutaneous or surgical), myocardial infarction (MI) and all-cause death were evaluated. RESULTS: TA was found in 228 patients (7.7%). Comparing patients with TA with those without it, the former more often had had abnormal (43.0% versus 34.3%, p < 0.001) and ischemic SPECT (25.9% versus 13.6%, p < 0.001). Also, higher rates of MI (2.0% versus 0.6%, p < 0.001), CATH (10.1% versus 4.7%, p < 0.001) and revascularization (7.8% versus 3.0%, p < 0.001) were observed, while death was not significantly different (1.5% versus 1.0%, p = 0.2). Even in the absence of ischemia in SPECT, patients with TA had higher CATH and revascularization rates; death, again, was not significantly increased. CONCLUSION: Although patients with TA more often had ischemic SPECT, all-cause death was not significantly increased. Nonetheless, TA was associated with more frequent referrals for CATH and revascularization, even with nonischemic SPECT. This may suggest that despite current evidence, the management of stable patients with known or suspected CAD is influenced by symptom type. PMID- 24759612 TI - The children of dialysis: live-born babies from on-dialysis mothers in Italy--an epidemiological perspective comparing dialysis, kidney transplantation and the overall population. AB - BACKGROUND: A successful pregnancy is an exceptional event on dialysis. Few data are available comparing pregnancy rates on dialysis, transplantation and the overall population. The aim of the study was to assess the incidence of live births from mothers on chronic dialysis compared with the overall population and with kidney transplant patients. METHODS: The setting of the study is in Italy between 2000-12. Data on dialysis was aquired by phone inquiries that were carried out between June and September, 2013, involving all the public dialysis centres in Italy; the result was a 100% response rate. The date included was end stage renal disease, type of dialysis, residual glomerular filtration rate, changes in dialysis and therapy, hospitalization; week of birth, birth weight, centile; and outcome of mother and child. Information on transplantation was acquired by inquiry by the kidney and pregnancy study group who were contacted by phone or e-mail; the result was a 60% response rate. Data concerning prevalence of women in childbearing age (20-45) were obtained from the Italian Dialysis and Transplant Registries (2010-11 update). Official site of the Italian Ministry of Health. RESULTS: During the study period, 23 women on dialysis (three on peritoneal dialysis) delivered live-born babies and one woman delivered twins (24 babies). Three babies died in the first weeks-months of life (including one twin); 19 of 21 singletons with available data were pre-term (33.3% <34 weeks); the prevalence of children <10th gestational age-adjusted centile was 33.3%. Birth weight and gestational age were lower in children from on-dialysis mothers as compared with 110 pregnancies following kidney graft, (weight: 1200 versus 2500 g; gestational age: 30 versus 36 weeks; P < 0.001). Incidence of live-born babies was inferred as 0.7-1.1 per 1000 female dialysis patients aged 20-45 and 5.5-8.3 per 1000 grafted patients in the same age range (Italian live-birth rates: 72.5 per 1000 women aged 20-45 years). CONCLUSIONS: Having a baby while on dialysis is rare but not impossible, though early mortality remains high. There is a 'scale of probability' estimating that women on dialysis have a 10-fold lower probability of delivering a live-born baby than those who have undergone renal transplantation, who in turn have a 10-fold lower probability of delivering a live-born baby as compared with the overall population. PMID- 24759613 TI - Predicted deep-sea coral habitat suitability for the U.S. West coast. AB - Regional scale habitat suitability models provide finer scale resolution and more focused predictions of where organisms may occur. Previous modelling approaches have focused primarily on local and/or global scales, while regional scale models have been relatively few. In this study, regional scale predictive habitat models are presented for deep-sea corals for the U.S. West Coast (California, Oregon and Washington). Model results are intended to aid in future research or mapping efforts and to assess potential coral habitat suitability both within and outside existing bottom trawl closures (i.e. Essential Fish Habitat (EFH)) and identify suitable habitat within U.S. National Marine Sanctuaries (NMS). Deep-sea coral habitat suitability was modelled at 500 m*500 m spatial resolution using a range of physical, chemical and environmental variables known or thought to influence the distribution of deep-sea corals. Using a spatial partitioning cross validation approach, maximum entropy models identified slope, temperature, salinity and depth as important predictors for most deep-sea coral taxa. Large areas of highly suitable deep-sea coral habitat were predicted both within and outside of existing bottom trawl closures and NMS boundaries. Predicted habitat suitability over regional scales are not currently able to identify coral areas with pin point accuracy and probably overpredict actual coral distribution due to model limitations and unincorporated variables (i.e. data on distribution of hard substrate) that are known to limit their distribution. Predicted habitat results should be used in conjunction with multibeam bathymetry, geological mapping and other tools to guide future research efforts to areas with the highest probability of harboring deep-sea corals. Field validation of predicted habitat is needed to quantify model accuracy, particularly in areas that have not been sampled. PMID- 24759614 TI - Distinct tissue-specific requirements for the zebrafish tbx5 genes during heart, retina and pectoral fin development. AB - The transcription factor Tbx5 is expressed in the developing heart, eyes and anterior appendages. Mutations in human TBX5 cause Holt-Oram syndrome, a condition characterized by heart and upper limb malformations. Tbx5-knockout mouse embryos have severely impaired forelimb and heart morphogenesis from the earliest stages of their development. However, zebrafish embryos with compromised tbx5 function show a complete absence of pectoral fins, while heart development is disturbed at significantly later developmental stages and eye development remains to be thoroughly analysed. We identified a novel tbx5 gene in zebrafish- tbx5b--that is co-expressed with its paralogue, tbx5a, in the developing eye and heart and hypothesized that functional redundancy could be occurring in these organs in embryos with impaired tbx5a function. We have now investigated the consequences of tbx5a and/or tbx5b downregulation in zebrafish to reveal that tbx5 genes have essential roles in the establishment of cardiac laterality, dorsoventral retina axis organization and pectoral fin development. Our data show that distinct relationships between tbx5 paralogues are required in a tissue specific manner to ensure the proper morphogenesis of the three organs in which they are expressed. Furthermore, we uncover a novel role for tbx5 genes in the establishment of correct heart asymmetry in zebrafish embryos. PMID- 24759616 TI - 6Li-loaded directionally sensitive anti-neutrino detector for possible geo neutrinographic imaging applications. AB - Despite the latent and unique benefits of imaging uranium and thorium's distribution in the earth's interior, previously proposed experimental techniques used to identify the incoming geo-neutrino's direction are not applicable to practical imaging due to the high miss-identification in a neutrino's track reconstruction. After performing experimental studies and Monte-Carlo simulations, we confirmed that a significant improvement is possible in neutrino tracking identification with a (6)Li-loaded neutrino detector. For possible imaging applications, we also explore the feasibility of producing geo neutrinographic images of gigantic magmatic reservoirs and deep structure in the mantle. We anticipate and plan to apply these newly designed detectors to radiographic imaging of the Earth's interior, monitoring of nuclear reactors, and tracking astrophysical sources of neutrinos. PMID- 24759615 TI - Incomplete pneumolysin oligomers form membrane pores. AB - Pneumolysin is a member of the cholesterol-dependent cytolysin (CDC) family of pore-forming proteins that are produced as water-soluble monomers or dimers, bind to target membranes and oligomerize into large ring-shaped assemblies comprising approximately 40 subunits and approximately 30 nm across. This pre-pore assembly then refolds to punch a large hole in the lipid bilayer. However, in addition to forming large pores, pneumolysin and other CDCs form smaller lesions characterized by low electrical conductance. Owing to the observation of arc-like (rather than full-ring) oligomers by electron microscopy, it has been hypothesized that smaller oligomers explain smaller functional pores. To investigate whether this is the case, we performed cryo-electron tomography of pneumolysin oligomers on model lipid membranes. We then used sub-tomogram classification and averaging to determine representative membrane-bound low resolution structures and identified pre-pores versus pores by the presence of membrane within the oligomeric curve. We found pre-pore and pore forms of both complete (ring) and incomplete (arc) oligomers and conclude that arc-shaped oligomeric assemblies of pneumolysin can form pores. As the CDCs are evolutionarily related to the membrane attack complex/perforin family of proteins, which also form variably sized pores, our findings are of relevance to that class of proteins as well. PMID- 24759617 TI - British container breeding mosquitoes: the impact of urbanisation and climate change on community composition and phenology. AB - The proliferation of artificial container habitats in urban areas has benefitted urban adaptable mosquito species globally. In areas where mosquitoes transmit viruses and parasites, it can promote vector population productivity and fuel mosquito-borne disease outbreaks. In Britain, storage of water in garden water butts is increasing, potentially expanding mosquito larval habitats and influencing population dynamics and mosquito-human contact. Here we show that the community composition, abundance and phenology of mosquitoes breeding in experimental water butt containers were influenced by urbanisation. Mosquitoes in urban containers were less species-rich but present in significantly higher densities (100.4+/-21.3) per container than those in rural containers (77.7+/ 15.1). Urban containers were dominated by Culex pipiens (a potential vector of West Nile Virus [WNV]) and appear to be increasingly exploited by Anopheles plumbeus (a human-biting potential WNV and malaria vector). Culex phenology was influenced by urban land use type, with peaks in larval abundances occurring earlier in urban than rural containers. Among other factors, this was associated with an urban heat island effect which raised urban air and water temperatures by 0.9 degrees C and 1.2 degrees C respectively. Further increases in domestic water storage, particularly in urban areas, in combination with climate changes will likely alter mosquito population dynamics in the UK. PMID- 24759618 TI - The expanding repertoire of the IL-12 cytokine family in teleost fish: Identification of three paralogues each of the p35 and p40 genes in salmonids, and comparative analysis of their expression and modulation in Atlantic salmon Salmo salar. AB - Interleukin (IL)-12 family cytokines are heterodimers of an alpha-chain (p19, p28 and p35) and a beta-chain (p40 and Ebi3), present as IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Ebi3) and IL-35 (p35/Ebi3), and play key roles in immune responses in mammals. One p35 and up to three p40 genes have been cloned in some fish species. The identification of three active p35 genes, along with three p40 paralogues in salmonids in the current study further expands the repertoire of IL 12, IL-23 and IL-35 molecules in these species. The multiple p35 genes in teleost fish appear to have arisen via whole genome duplications. The different paralogues of the subunits are divergent, and differentially expressed and modulated by PAMPs and proinflammatory cytokines, hinting that distinct isoforms could be produced in response to infection. Therefore, the expanded IL-12 cytokine family may provide an unprecedented level of regulation to fine tune the immune response in fish. PMID- 24759619 TI - Meta-analytically informed network analysis of resting state FMRI reveals hyperconnectivity in an introspective socio-affective network in depression. AB - Alterations of social cognition and dysfunctional interpersonal expectations are thought to play an important role in the etiology of depression and have, thus, become a key target of psychotherapeutic interventions. The underlying neurobiology, however, remains elusive. Based upon the idea of a close link between affective and introspective processes relevant for social interactions and alterations thereof in states of depression, we used a meta-analytically informed network analysis to investigate resting-state functional connectivity in an introspective socio-affective (ISA) network in individuals with and without depression. Results of our analysis demonstrate significant differences between the groups with depressed individuals showing hyperconnectivity of the ISA network. These findings demonstrate that neurofunctional alterations exist in individuals with depression in a neural network relevant for introspection and socio-affective processing, which may contribute to the interpersonal difficulties that are linked to depressive symptomatology. PMID- 24759620 TI - Kobophenol A inhibits sodium nitroprusside-induced cardiac H9c2 cell death through suppressing activation of JNK and preserving mitochondrial anti-apoptotic Bcl-2 and Mcl-1. AB - Sodium nitroprusside (SNP) releases nitric oxide (NO), a powerful vasodilator, and thus widely used in intensive care unit for treating hypertension emergency. However, cardiac toxicity after SNP administration is a clinical problem. For finding a natural compound that suppressing SNP-induced cardiac toxicity, we tested the protective potential of kobophenol A (Kob A), purified from the root of Caragana sinica, against the toxic effects of SNP. The severe cardiac H9c2 cell death was induced by SNP (2 mM) treatment. Kob A ameliorated SNP-induced cardiac H9c2 cell death, and this protective effect of Kob A may be related to the inhibition of c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase activation following SNP administration. In addition, the downregulation of cellular Bcl-2 and Mcl-1 levels by SNP exposure was strongly abrogated in the presence of Kob A. These biological properties of Kob A might provide insights into developing new cardioprotectant against SNP-induced cardiac cell death. PMID- 24759621 TI - Epigenetic silencing of RASSF10 promotes tumor growth in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most malignant diseases and the five year survival rate remains less than 10%. RASSF10 is a newly identified member of the Ras-association family, but the regulation and the function of RASSF10 in ESCC remain unclear. Research methodologies such as methylation specific PCR (MSP), semi-quantitative RT-PCR, immunohistochemistry, Sodium bisulfite sequencing, and colony formation assay were utilized in this investigation. Loss of RASSF10 expression was found in KYSE150 cells and reduced expression was found in KYSE70 and KYSE180 cells. Expression of RASSF10 was found in KYSE140, KYSE450, KYSE510, TE1, TE3, and TE8 cell lines. Complete methylation was found in KYSE30 and KYSE150 cells, partial methylation was found in KYSE70, KYSE180, KYSE510, and TE1, and unmethylation was found in KYSE140, KYSE450, TE3, and TE8. Re-expression or increased expression was induced by 5-Aza-dC treatment. RASSF10 was methylated in 44.3% primary esophageal squamous cell carcinoma. RASSF10 inhibits cell proliferation and induces G2/M phase arrest in esophageal cancer cells. IN CONCLUSION: RASSF10 was frequently methylated in human esophageal squamous cell carcinoma and expression of RASSF10 was regulated by promoter region hypermethylation. RASSF10 may serve as a tumor suppressor of esophageal cancer. PMID- 24759622 TI - Novel biological radiochemotherapy approaches in locally advanced-stage cervical cancer management. AB - Biological anticancer agents that enhance radiochemotherapeutic effect are appealing in the modern medical treatment of uterine cervix cancer. In this concise review, the focus is on three classes of biological anticancer agents. The first class is ribonucleotide reductase inhibitors. These biological anticancer agents impede deoxyribonucleotide payout and stop new synthesis of DNA molecule building blocks. By disrupting deoxyribonucleotide supply and demand economics, ribonucleotide reductase inhibitors disrupt the repair of radiation- and chemotherapy-induced DNA damage and enhance cancer cell death. Angiogenesis inhibitors represent a second class of biological anticancer agents. Angiogenesis inhibitors are conceptually thought to normalize cancer tumor vasculature and modulate vascular endothelial growth factor signals. Consequences of normalized tumor vessel permeability are better oxygen supply for radiosensitization and improved tumor fluid dynamics imparting chemosensitization. A third class, cytolytic T-cell immune modulators, edits human immune system responses to cancer cell antigens. These biological anticancer agents exploit molecular signaling involved in immune detection and in immune eradication. Completed and planned clinical trials utilizing these agents are discussed relative to the future radiochemotherapeutic management of uterine cervix cancer. PMID- 24759623 TI - All eyes on the next generation of HIV vaccines: strategies for inducing a broadly neutralizing antibody response. AB - HIV-1 broadly neutralizing antibodies (BNAbs) develop after several years of infection through a recursive process of memory B cell adaptation and maturation against co-evolving virus quasispecies. Advances in single-cell sorting and memory B cell antibody cloning methods have identified many new HIV BNAbs targeting conserved epitopes on the HIV envelope (env) protein. 3D crystal structures and biophysical analyses of BNAbs bound to invariant virus structures expressed on monomeric gp120, epitope scaffolds, core structures, and native trimers have helped us to visualize unique binding interactions and paratope orientations that have been instrumental in guiding vaccine design. A paradigm shift in the approach to structure-based design of HIV-1 envelope immunogens came recently after several laboratories discovered that native viral envelopes or "env-structures" reverse-engineered to bind with high affinity to a handful of broadly neutralizing antibodies did not in fact bind the predicted germline precursors of these broadly neutralizing antibodies. A major challenge for HIV-1 B cell vaccine development moving forward is the design of new envelope immunogens that can trigger the selection and expansion of germline precursor and intermediate memory B cells to recapitulate B cell ontogenies associated with the maturation of a broadly neutralizing antibody response. Equally important for vaccine development is the identification of delivery systems, prime-boost strategies, and synergistic adjuvant combinations that can induce the magnitude and quality of antigen-specific T follicular helper (TFH) cell responses needed to drive somatic hypermutation (SHM) and B cell maturation against heterologous primary virus envelopes. Finding the combination of multi-protein envelope immunogens and immunization strategies that can evolve a potent broadly neutralizing antibody response portends to require a complex vaccine regimen that might be difficult to implement on any scale. This perspective strives to integrate recent insights into mechanisms associated with the evolution of an HIV 1 broadly neutralizing antibody response with current immunogen design and proffers a novel immunization strategy for skewing TH17/TFH cell responses that can drive B cell adaptation and affinity maturation associated with a broadly neutralizing antibody response. PMID- 24759624 TI - Immunotherapy in sarcoma: a new frontier. AB - Sarcomas are rare cancers of soft tissue and bone, and remain incurable when refractory to standard multimodality treatments. With the recent advances in immunotherapy for other solid tumors, there is heightened interest in the potential link of the immune system with sarcoma physiology. This review aims to summarize the ongoing laboratory and clinical research investigating the applications of immunotherapy in the treatment of sarcomas. With ongoing opportunities in vaccine therapy, adoptive transfer of immune cells, biochemotherapy, and immune checkpoint inhibitors, enrollment in immunotherapy clinical trials is an appealing option for sarcoma patients either in conjunction with traditional treatment modalities, or for those with few standard treatment options. PMID- 24759625 TI - Novel approaches and mechanisms in hematopoietic stem cell gene therapy. AB - Hematopoietic stem cell gene therapy is one of the most exciting clinical tools to emerge from the gene therapy stable. This technology combines the expansion capability of hematopoietic stem cells, capable of replacing the entire blood and immune system of an individual, with the capacity for long-term replacement of one or more gene copies using integrating gene therapy vectors. Hematopoietic stem cell gene therapy benefits significantly from the pre-existing experience of standard blood and marrow transplantation, whilst at the same time having the capacity to deliver a safer and more effective therapy to a wider range of diseases. In this review we summarize the potential of hematopoietic stem cell gene therapy to expand the scope of hematopoietic stem cell transplantation, including the evolution of vector delivery systems and the success and failures of current clinical experience with this treatment. In particular we deal with the incidence of vector mediated transformation in patients and the steps that have been taken to minimize this risk. Finally we discuss the innovations in preclinical development that are likely to drive the future of this field, including the expansion to many more genetic diseases, particularly those affecting the brain. PMID- 24759627 TI - Family history of frontotemporal lobar degeneration in Asia--an international multi-center research. AB - BACKGROUND: Previous studies in western countries have shown that about 30%-50% of patients with frontotemporal lobar degeneration (FTLD) have a positive family history, whereas the few epidemiological studies on FTLD done in Asia reported much lower frequencies. It is not clear the reason why the frequencies of FTLD with positive family history were lower in Asia. Furthermore, these findings were not from studies focused on family history. Therefore, it is necessary to conduct further studies on the family history of FTLD in Asia. This international multi center research aims to investigate the family histories in patients with FTLD and related neurodegenerative diseases such as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and motor neuron diseases in a larger Asian cohort. METHODS: Participants were collected from five countries: India, Indonesia, Japan, Taiwan, and Philippines. All patients were diagnosed with behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), progressive non-fluent aphasia (PA), frontotemporal dementia with motor neuron disease (FTD/MND), PSP, and corticobasal degeneration (CBD) according to international consensus criteria. Family histories of FTLD and related neurodegenerative diseases were investigated in each patient. RESULTS: Ninety-one patients were included in this study. Forty-two patients were diagnosed to have bvFTD, two patients had FTD/MND, 22 had SD, 15 had PA, one had PA/CBS, five had CBS and four patients had PSP. Family history of any FTLD spectrum disorder was reported in 9.5% in bvFTD patients but in none of the SD or PA. CONCLUSION: In contrast to patients of the western countries, few Asian FTLD patients have positive family histories of dementia. PMID- 24759626 TI - The genome sequence of a widespread apex predator, the golden eagle (Aquila chrysaetos). AB - Biologists routinely use molecular markers to identify conservation units, to quantify genetic connectivity, to estimate population sizes, and to identify targets of selection. Many imperiled eagle populations require such efforts and would benefit from enhanced genomic resources. We sequenced, assembled, and annotated the first eagle genome using DNA from a male golden eagle (Aquila chrysaetos) captured in western North America. We constructed genomic libraries that were sequenced using Illumina technology and assembled the high-quality data to a depth of ~40x coverage. The genome assembly includes 2,552 scaffolds >10 Kb and 415 scaffolds >1.2 Mb. We annotated 16,571 genes that are involved in myriad biological processes, including such disparate traits as beak formation and color vision. We also identified repetitive regions spanning 92 Mb (~6% of the assembly), including LINES, SINES, LTR-RTs and DNA transposons. The mitochondrial genome encompasses 17,332 bp and is ~91% identical to the Mountain Hawk-Eagle (Nisaetus nipalensis). Finally, the data reveal that several anonymous microsatellites commonly used for population studies are embedded within protein coding genes and thus may not have evolved in a neutral fashion. Because the genome sequence includes ~800,000 novel polymorphisms, markers can now be chosen based on their proximity to functional genes involved in migration, carnivory, and other biological processes. PMID- 24759629 TI - Association between serum trace element concentrations and the disease activity of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex, incompletely understood, etiology. Several genetic and environmental factors are suspected to be involved in its aetiology. Oxidative stress may be implicated in the pathogenesis of SLE and may be affected by trace element status. Zinc (Zn), copper (Cu) and selenium (Se) are essential components of several anti-oxidative enzymes and are also involved in several immune functions. The current study aimed to assess the relationship between serum concentrations of these trace elements and the clinical disease activity of SLE assessed using the SLE disease activity index (SLEDAI). Serum concentrations of albumin (Alb) (p = 0.001), Se (p = 0.001), Zn (p = 0.001) and the Zn to Cu ratio (Zn/Cu R) (p = 0.001) were lower in patients with SLE than the age- and sex-matched healthy controls. However, only Alb (p = 0.001) and Cu (p = 0.03) were negatively correlated with disease activity, which was supported by regression analysis. In summary, lower serum values of Alb, Zn, Se and Zn/Cu R were found in SLE patients compared with healthy controls; however, in addition to serum Alb concentrations, serum Cu concentrations were also negatively correlated with lupus disease activity. PMID- 24759630 TI - Bone marrow analysis of immune cells and apoptosis in patients with systemic lupus erythematosus. AB - OBJECTIVES: To examine the immune cell profile in the bone marrow of systemic lupus erythematosus (SLE) patients and to assess its clinical relevance. METHODS: Sixteen bone marrow samples from 14 SLE patients were compared with seven healthy control samples. The numbers of immune cells and apoptotic cells in the bone marrow were examined by immunohistochemistry. The association between immune cell subsets and clinical features was investigated. RESULTS: CD4+ T cells, macrophages and plasma cells were more common in the bone marrow of SLE patients than in healthy controls (p=0.001, p=0.004 and p<0.001, respectively). Greater numbers of CD4+ T cells and macrophages were associated with high-grade bone marrow damage. The percentage of apoptotic cells in bone marrow of SLE patients was significantly higher than that in controls (p<0.001) and was positively correlated with the number of plasmacytoid dendritic cells (p=0.013). Increased number of plasma cells along with high interleukin-6 expression was correlated with anti-double stranded DNA antibody levels and the SLE disease activity index (p=0.031 and 0.013, respectively). CONCLUSION: Bone marrow from SLE patients showed a distinct immune cell profile and increased apoptosis. This, coupled with a correlation with disease activity, suggests that the bone marrow may play a critical role in the pathogenesis of SLE. PMID- 24759631 TI - Immunomodulatory effects of H.P. Acthar Gel on B cell development in the NZB/W F1 mouse model of systemic lupus erythematosus. AB - H.P. Acthar Gel(r) (Acthar) is a highly purified repository gel preparation of adrenocorticotropic hormone (ACTH1-39), a melanocortin peptide that can bind and activate specific receptors expressed on a range of systemic lupus erythematosus (SLE)-relevant target cells and tissues. This study was performed to evaluate the effects of Acthar in a mouse model of SLE, using an F1 hybrid of the New Zealand Black and New Zealand White strains (NZB/W F1). Twenty-eight week old NZB/W F1 mice with established autoimmune disease were treated with Acthar, Placebo Gel (Placebo), or prednisolone and monitored for 19 weeks. Outcomes assessed included disease severity (severe proteinuria, >= 20% body weight loss, or prostration), measurement of serial serum autoantibody titers, terminal spleen immunophenotyping, and evaluation of renal histopathology. Acthar treatment was linked with evidence of altered B cell differentiation and development, manifested by a significant reduction in splenic B cell follicular and germinal center cells, and decreased levels of circulating total and anti-double-stranded DNA (IgM, IgG, and IgG2a) autoantibodies as compared with Placebo. Additionally, Acthar treatment resulted in a significant decrease of proteinuria, reduced renal lymphocyte infiltration, and attenuation of glomerular immune complex deposition. These data suggest that Acthar diminished pathogenic autoimmune responses in the spleen, peripheral blood, and kidney of NZB/W F1 mice. This is the first preclinical evidence demonstrating Acthar's potential immunomodulatory activity and efficacy in a murine model of systemic lupus erythematosus. PMID- 24759632 TI - A novel external fixator used to treat open comminuted fractures of the middle and distal phalanges with concomitant FDP avulsion injury. AB - The use of external fixators for treating comminuted hand fractures has become popular with commercially available or handmade fixators assembled in the operating theater. We present a case of a Zone I flexor digitorum profundus (FDP) avulsion fracture that was complicated by the presence of open, comminuted fractures of the distal and middle phalanges. The injury was treated using an external fixator constructed in the operating theater from readily available materials and with a 4-strand pullout suture technique tied over a button to repair the FDP avulsion. This technique facilitated treatment of the comminuted and contaminated fractures while allowing reconstruction of the Zone I FDP injury and allowing relatively early mobilization of the FDP repair. PMID- 24759633 TI - Donor Pretreatment With IL-1 Receptor Antagonist Attenuates Inflammation and Improves Functional Potency in Islets From Brain-Dead Nonhuman Primates. AB - Most pancreas and islet grafts are recovered from brain-dead (BD) donors. In this study we characterized the early inflammatory response induced by brain death in pancreata and islets from nonhuman primate donors and evaluated the effect of targeted anti-inflammatory intervention in the protection of pancreatic islets prior to transplantation. BD donors were monitored for 6 h and assigned to three experimental groups: group 1: BD-untreated donors (BD-UT) (n = 7), group 2: BD + donor pretreatment with IL-1ra (n = 6), and group 3: non-BD animals serving as controls (n = 7). We observed an IL-1ra-dependent reduction in the mobilization and activation of neutrophils from bone marrow and a significantly reduced accumulation of CD68(+) leukocytes in the pancreas and islets after brain death induction. Donor treatment with IL-1ra significantly decreased chemokine mRNA expression (MCP-1, IL-8, and MIP-1a) and attenuated the activation of circulating neutrophils and intraislet macrophages as demonstrated by a reduction in intracellular IL-1beta, IL-6, MCP-1, and MIP-1alpha expression. As a result, IL 1ra dramatically improved viability, mitochondrial membrane polarity, and islet engraftment in mice transplanted using a minimal islet mass. These results suggest that early immunomodulation targeting inflammation in the BD donor may represent an effective therapeutic strategy to improve islet quality and function prior to transplantation. PMID- 24759634 TI - The emerging biofuel crop Camelina sativa retains a highly undifferentiated hexaploid genome structure. AB - Camelina sativa is an oilseed with desirable agronomic and oil-quality attributes for a viable industrial oil platform crop. Here we generate the first chromosome scale high-quality reference genome sequence for C. sativa and annotated 89,418 protein-coding genes, representing a whole-genome triplication event relative to the crucifer model Arabidopsis thaliana. C. sativa represents the first crop species to be sequenced from lineage I of the Brassicaceae. The well-preserved hexaploid genome structure of C. sativa surprisingly mirrors those of economically important amphidiploid Brassica crop species from lineage II as well as wheat and cotton. The three genomes of C. sativa show no evidence of fractionation bias and limited expression-level bias, both characteristics commonly associated with polyploid evolution. The highly undifferentiated polyploid genome of C. sativa presents significant consequences for breeding and genetic manipulation of this industrial oil crop. PMID- 24759635 TI - The elemental composition of demospongiae from the Red Sea, Gulf of Aqaba. AB - Trace elements are vital for the growth and development of all organisms. Little is known about the elemental content and trace metal biology of Red Sea demosponges. This study establishes an initial database of sponge elemental content. It provides the necessary foundation for further research of the mechanisms used by sponges to regulate the uptake, accumulation, and storage of metals. The metal content of 16 common sponge species was determined using ICP measurements. A combination of statistical methods was used to determine the correlations between the metals and detect species with significantly high or low concentrations of these metals. Bioaccumulation factors were calculated to compare sponge metal content to local sediment. Theonella swinhoei contained an extremely high concentration of arsenic and barium, much higher (at least 200 times) than all other species and local sediment. Hyrtios erecta had significantly higher concentration of Al, Cr, Fe, Mn, Ti and V than all other species. This is due to sediment accumulation and inclusion in the skeleton fibers of this sponge species. Suberites clavatus was found to contain significantly higher concentration of Cd, Co, Ni and Zn than all other species and local sediment, indicating active accumulation of these metals. It also has the second highest Fe concentration, but without the comparably high concentrations of Al, Mn and Ti that are evident in H. erecta and in local sediment. These differences indicate active uptake and accumulation of Fe in S. clavatus, this was also noted in Niphates rowi. A significantly higher B concentration was found in Crella cyatophora compared to all other species. These results indicate specific roles of trace elements in certain sponge species that deserve further analysis. They also serve as a baseline to monitor the effects of anthropogenic disturbances on Eilat's coral reefs. PMID- 24759637 TI - A think aloud study comparing the validity and acceptability of discrete choice and best worst scaling methods. AB - OBJECTIVES: This study provides insights into the validity and acceptability of Discrete Choice Experiment (DCE) and profile-case Best Worst Scaling (BWS) methods for eliciting preferences for health care in a priority-setting context. METHODS: An adult sample (N = 24) undertook a traditional DCE and a BWS choice task as part of a wider survey on Health Technology Assessment decision criteria. A 'think aloud' protocol was applied, whereby participants verbalized their thinking while making choices. Internal validity and acceptability were assessed through a thematic analysis of the decision-making process emerging from the qualitative data and a repeated choice task. RESULTS: A thematic analysis of the decision-making process demonstrated clear evidence of 'trading' between multiple attribute/levels for the DCE, and to a lesser extent for the BWS task. Limited evidence consistent with a sequential decision-making model was observed for the BWS task. For the BWS task, some participants found choosing the worst attribute/level conceptually challenging. A desire to provide a complete ranking from best to worst was observed. The majority (18,75%) of participants indicated a preference for DCE, as they felt this enabled comparison of alternative full profiles. Those preferring BWS were averse to choosing an undesirable characteristic that was part of a 'package', or perceived BWS to be less ethically conflicting or burdensome. In a repeated choice task, more participants were consistent for the DCE (22,92%) than BWS (10,42%) (p = 0.002). CONCLUSIONS: This study supports the validity and acceptability of the traditional DCE format. Findings relating to the application of BWS profile methods are less definitive. Research avenues to further clarify the comparative merits of these preference elicitation methods are identified. PMID- 24759636 TI - MRI biomarkers identify the differential response of glioblastoma multiforme to anti-angiogenic therapy. AB - BACKGROUND: Although anti-angiogenic therapy (AATx) holds great promise for treatment of malignant gliomas, its therapeutic efficacy is not well understood and can potentially increase the aggressive recurrence of gliomas. It is essential to establish sensitive, noninvasive biomarkers that can detect failure of AATx and tumor recurrence early so that timely adaptive therapy can be instituted. We investigated the efficacy of MRI biomarkers that can detect response to different classes of AATxs used alone or in combination with radiation. METHODS: Murine intracranial glioma xenografts (NOD/SCID) were treated with sunitinib, VEGF-trap or B20 (a bevacizumab equivalent) alone or in combination with radiation. MRI images were acquired longitudinally before and after treatment, and various MRI parameters (apparent diffusion coefficient, T1w + contrast, dynamic contrast-enhanced [DCE], initial area under the contrast enhancement curve, and cerebral blood flow) were correlated to tumor cell proliferation, overall tumor growth, and tumor vascularity. RESULTS: Combinatorial therapies reduced tumor growth rate more efficiently than monotherapies. Apparent diffusion coefficient was an accurate measure of tumor cell density. Vascular endothelial growth factor (VEGF)-trap or B20, but not sunitinib, resulted in significant reduction or complete loss of contrast enhancement. This reduction was not due to a reduction in tumor growth or microvascular density, but rather was explained by a reduction in vessel permeability and perfusion. We established that contrast enhancement does not accurately reflect tumor volume or vascular density; however, DCE-derived parameters can be used as efficient noninvasive biomarkers of response to AATx. CONCLUSIONS: MRI parameters following therapy vary based on class of AATx. Validation of clinically relevant MRI parameters for individual AATx agents is necessary before incorporation into routine practice. PMID- 24759638 TI - Effect of pH on the anaerobic acidogenesis of agroindustrial wastewaters for maximization of bio-hydrogen production: a lab-scale evaluation using batch tests. AB - The aim of this study was to investigate the impact of pH on the production of bio-hydrogen and end-products from a mixture of olive mill wastewater, cheese whey and liquid cow manure (with a ratio of 55:40:5, v/v/v). Batch experiments were performed under mesophilic conditions (37 degrees C) at a range of pH from 4.5 to 7.5. The main end-products identified were acetic, propionic, butyric, lactic acid and ethanol. The highest hydrogen production yield was observed at pH 6.0 (0.642 mol H2/mol equivalent glucose consumed), whereas the maximum VFAs concentration (i.e. 13.43 g/L) was measured at pH 6.5. The composition of acidified effluent in acetic and butyric acid was similar at pH 6.0 and 6.5, albeit an increase of propionic acid was observed in higher pH. Lactic acid was identified as a major metabolite which presented an intense accumulation (up to 11 g/L) before its further bioconversion to butyric acid and hydrogen. PMID- 24759639 TI - Enhancing volatile fatty acid (VFA) and bio-methane production from lawn grass with pretreatment. AB - The bioconversion of fiber-based carbohydrates during anaerobic digestion (AD) is impeded due to the recalcitrant nature of the plant cell wall. Pretreatment of lignocellulose materials under mild conditions are needed to improve the digestibility at minimum cost. This study investigated the effects of different pretreatments, including ozone, soaking aqueous ammonia (SAA), combined ozone and SAA (OSAA), and size reduction to enhance volatile fatty acid (VFA) and bio methane production when lawn grass was used as substrate. To study VFA production, methanogenesis was selectively inhibited by sodium 2 bromoethanesulfonate to decouple the relation between VFA and bio-methane. The enzymatic hydrolysis of SAA (residence time 24h at 50 degrees C) and OSAA (10 min ozonation and 6h of SAA) in pretreatment of lawn grass sample resulted in 86.71% and 89.63% sugar recovery, respectively. The specific methane yields of the control, ozone, SAA, OSAA, and size-reduced grass samples were 402.5, 358.8, 481.0, 462.6, and 358.3 ml CH4/g volatile solid (VS), respectively. PMID- 24759640 TI - Catalytic pyrolysis of wood biomass in an auger reactor using calcium-based catalysts. AB - Wood catalytic pyrolysis using calcium-based materials was studied in an auger reactor at 450 degrees C. Two different catalysts, CaO and CaO.MgO were evaluated and upgraded bio-oils were obtained in both cases. Whilst acidity and oxygen content remarkable decrease, both pH and calorific value increase with respect to the non-catalytic test. Upgrading process was linked to the fact that calcium based materials could not only fix the CO2-like compounds but also promoted the dehydration reactions. In addition, process simulation demonstrated that the addition of these catalysts, especially CaO, could favour the energetic integration since a lowest circulation of heat carrier between combustor and auger reactor should be needed. An energy self-sustained system was obtained where thermal energy required for biomass drying and for pyrolysis reaction was supplied by non-condensable gas and char combustion, respectively. PMID- 24759641 TI - Hybrid sequential treatment of aromatic hydrocarbon-polluted effluents using non ionic surfactants as solubilizers and extractants. AB - A treatment train combining a biological and a physical approach was investigated for the first time in order to remediate polycyclic aromatic hydrocarbons (PAHs) polluted effluents. Given the hydrophobic nature of these contaminants, the presence of non-ionic surfactants is compulsory to allow their bioavailability. The presence of these surfactants also entails an advantage in order to ease contaminant removal by the formation of aqueous two-phase systems (ATPS). The segregation ability of environmentally benign salts such as potassium tartrate, citrate, and oxalate was discussed for extracting phenanthrene (PHE), pyrene (PYR), and benzo[a]anthracene (BaA). The biological remediation efficiency reached circa 60% for PHE and PYR, and more than 80% for BaA. The coupling of ATPS subsequent stage by using potassium citrate allowed increasing the total PAH remediation yields higher than 97% of PAH removal. The viability of the proposed solution was investigated at industrial scale by using the software tool SuperPro Designer. PMID- 24759642 TI - Performance of two-stage vegetable waste anaerobic digestion depending on varying recirculation rates. AB - Vegetable waste, which characterized by high moisture content, was evaluated as a substrate for biogas production. The effects of recirculation rate (RR) on the performance of two-stage anaerobic digestion were investigated. The system was operated at an organic loading rate of 1.7 g VS/L/d with varying RRs (0, 0.6, 1, and 1.4). Results demonstrated that volumetric biogas production rates in acidogenic reactor increased from approximately 0.2 7 L/L/d to 0.97 L/L/d, when pH is increased from approximately 5.1 to 6.7. These indicate that recirculation of alkaline effluent from the methanogenic reactor helps create a favorable condition for biogas production in the acidogenic reactor. The decrease in chemical oxygen demand (COD) concentrations from approximately 21,000 mg/L to 6800 mg/L was also observed in the acidogenic reactor. This condition may be attributed to dilution under recirculation. The dynamics between hydrolysis and methanogenesis under recirculation indicated that mass transfer capacity between two-stage reactors improved. PMID- 24759643 TI - Pretreatment of lignocellulosic biomass using Fenton chemistry. AB - In an attempt to mimic white-rot fungi lignin degradation via in vivo Fenton chemistry, solution phase Fenton chemistry (10 g biomass, 176 mmol hydrogen peroxide and 1.25 mmol Fe(2+) in 200 mL of water) was applied to four different biomass feedstocks. An enzymatic saccharification of Fenton pretreated biomass showed an average 212% increase relative to untreated control across all four feedstocks (P<0.05, statistically significant). A microbial fermentation of the same Fenton pretreated biomass showed a threefold increase in gas production upon a sequential co-culture with Clostridium thermocellum and Clostridium beijerinckii. These results demonstrate the use of solution phase Fenton chemistry as a viable pretreatment method to make cellulose more bioavailable for microbial biofuel conversion. PMID- 24759644 TI - Reaction mechanisms and rate constants of waste degradation in landfill bioreactor systems with enzymatic-enhancement. AB - Augmenting leachate before recirculation with peroxidase enzymes is a novel method to increase the available carbon, and therefore the food supply to microorganisms at the declining phase of the anaerobic landfill bioreactor operation. In order to optimize the enzyme-catalyzed leachate recirculation process, it is necessary to identify the reaction mechanisms and determine rate constants. This paper presents a kinetic model developed to ascertain the reaction mechanisms and determine the rate constants for enzyme catalyzed anaerobic waste degradation. The maximum rate of reaction (Vmax) for MnP enzyme catalyzed reactors was 0.076 g(TOC)/g(DS).day. The catalytic turnover number (k(cat)) of the MnP enzyme-catalyzed was 506.7 per day while the rate constant (k) of the un-catalyzed reaction was 0.012 per day. PMID- 24759645 TI - Exploiting composting biodiversity: study of the persistent and biotechnologically relevant microorganisms from lignocellulose-based composting. AB - The composting ecosystem is a suitable source for the discovery of novel microorganisms and secondary metabolites. This work analyzes the identity of microbial community that persists throughout lignocellulose-based composting, evaluates their metabolic activities and studies the capability of selected isolates for composting bioaugmentation. Bacterial species of the phyla Firmicutes, Actinobacteria and Proteobacteria and fungi of the phylum Ascomycota were ubiquitous throughout the composting. The species Arthrobacter russicus, Microbacterium gubbeenense, Ochrocladosporium frigidarii and Cladosporium lignicola are detected for the first time in this ecosystem. In addition, several bacterial and fungal isolates exhibited a wide range of metabolic capabilities such as polymers (lignocellulose, protein, lipids, pectin and starch) breakdown and phosphate-solubilization that may find many biotechnological applications. In particular, Streptomyces albus BM292, Gibellulopsis nigrescens FM1397 and FM1411, Bacillus licheniformis BT575, Bacillus smithii AT907 and Alternaria tenuissima FM1385 exhibited a great potential as inoculants for composting bioaugmentation. PMID- 24759646 TI - Evaluation of Paecilomyces variotii potential in bioethanol production from lignocellulose through consolidated bioprocessing. AB - The ascomycete Paecillomyces variotii was evaluated for the first time as a candidate species for the production of bioethanol from lignocellulose through consolidated bioprocessing (CBP) approaches. The examined strain (ATHUM 8891) revealed all the necessary phenotypic characteristics required for 2nd generation biofuel production. The fungus is able to efficiently ferment glucose and xylose to ethanol, with yields close to the theoretical maximum. Nitrogen supplementation greatly affected ethanol production with nitrate-nitrogen presenting the best results. Notably, ethanol yield on xylose fermentation was higher than that of glucose, while in co-fermentation of glucose-xylose mixtures no distinguished diauxic behavior was observed. Furthermore, the fungus seems to possess the necessary enzyme factory for the degradation of lignocellulosic biomass, as it was able to grow and produce ethanol on common agro-industrial derivatives. Overall, the results of our study indicate that P. variotii is a new and possibly powerful candidate for CBP applications. PMID- 24759647 TI - Bolus tracking with nanofilter-based multispectral videography for capturing microvasculature hemodynamics. AB - Multispectral imaging is a highly desirable modality for material-based analysis in diverse areas such as food production and processing, satellite-based reconnaissance, and biomedical imaging. Here, we present nanofilter-based multispectral videography (nMSV) in the 700 to 950 nm range made possible by the tunable extraordinary-optical-transmission properties of 3D metallic nanostructures. Measurements made with nMSV during a bolus injection of an intravascular tracer in the ear of a piglet resulted in spectral videos of the microvasculature. Analysis of the multispectral videos generated contrast measurements representative of arterial pulsation, the distribution of microvascular transit times, as well as a separation of the venous and arterial signals arising from within the tissue. Therefore, nMSV is capable of acquiring serial multispectral images relevant to tissue hemodynamics, which may have application to the detection and identification of skin cancer. PMID- 24759648 TI - Paediatricians and psychiatrists working together: what works best? PMID- 24759649 TI - 'Living with Teenagers': feasibility study of a peer-led parenting intervention for socially disadvantaged families with adolescent children. AB - OBJECTIVE: To develop and test the feasibility of a peer-led parenting intervention for parents of adolescent children. DESIGN: Formative evaluation using a mixed-method cohort design. SETTING: Socially deprived community sites in London, UK. PARTICIPANTS: Parents seeking help with managing behavioural difficulties of an index adolescent child (aged 11-17 years). INTERVENTION: A structured, group-based intervention ('Living with Teenagers') delivered by trained peer facilitators. MAIN OUTCOME MEASURES: We assessed feasibility in terms of uptake and completion rates (% parents completing >=5 sessions); social validity (assessed by service satisfaction measure and participant interviews); and potential for impact (assessed by parent-reported measures of adolescent behaviour and mental health, parenting satisfaction, expressed emotion, and disciplinary practices). RESULTS: Participants (n=41) were predominately (79%) from minority ethnic backgrounds and nearly half were lone parents. Most had not previously accessed a structured parenting programme. The completion rate was 71%. Significant changes (p<0.05) were observed in reduced parental concern about adolescent problems, increased parenting satisfaction and less negative expressed emotion. There were non-significant changes in disciplinary practices and adolescent mental health. Participants were highly satisfied with their service experience and endorsed the acceptability of the intervention's content, materials and peer-led format, while suggesting an expanded number of sessions and more skills practice and demonstrations. CONCLUSIONS: Peer-led parenting groups are feasible and potentially effective for supporting parents of adolescents living in socially disadvantaged communities. These findings warrant more rigorous testing under controlled conditions. PMID- 24759650 TI - Avidity of antibodies against infecting pneumococcal serotypes increases with age and severity of disease. AB - The incidence of invasive pneumococcal disease (IPD) rises with age. Among adult IPD patients, the avidity of antipneumococcal polysaccharide antibodies against the infecting serotype increased with age and severity of disease, indicating that susceptibility to IPD in the elderly may rather be due to flaws in other aspects of opsonophagocytosis. PMID- 24759652 TI - Haemoproteus ilanpapernai n. sp. (Apicomplexa, Haemoproteidae) in Strix seloputo from Singapore: morphological description and reassignment of molecular data. AB - Haemoproteus ilanpapernai Karadjian and Landau n. sp. from the Spotted Wood Owl, Strix seloputo, in Singapore is described from material from Ilan Paperna's collection of slides. The species was previously identified as Haemoproteus syrnii (Mayer, 1910). However, comparisons between the material from Strix seloputo and our own material from Strix aluco, the type host of H. syrnii, revealed morphological and molecular differences. H. ilanpapernai n. sp. differs morphologically from H. syrnii by the much smaller size of the gametocytes, the different position of the mature gametocytes in the erythrocyte (apical, subapical, or lateral in H. ilanpapernai vs. always lateral in H. syrnii), the effect on the erythrocyte nucleus (frequently tilted in H. ilanpapernai but not displaced laterally vs. straight and displaced laterally in H. syrnii) and characters of the pigment (aggregated in the gametocytes of H. ilanpapernai vs. dispersed in H. syrnii). A molecular analysis showed that the two species differ by 2.9% at the cyt b and 3.1% at the COI genes. PMID- 24759651 TI - Human antibody responses to the polyclonal Dryvax vaccine for smallpox prevention can be distinguished from responses to the monoclonal replacement vaccine ACAM2000. AB - Dryvax (Wyeth Laboratories, Inc., Marietta, PA) is representative of the vaccinia virus preparations that were previously used for preventing smallpox. While Dryvax was highly effective, the national supply stocks were depleted, and there were manufacturing concerns regarding sterility and the clonal heterogeneity of the vaccine. ACAM2000 (Acambis, Inc./Sanofi-Pasteur Biologics Co., Cambridge, MA), a single-plaque-purified vaccinia virus derivative of Dryvax, recently replaced the polyclonal smallpox vaccine for use in the United States. A substantial amount of sequence heterogeneity exists within the polyclonal proteome of Dryvax, including proteins that are missing from ACAM2000. Reasoning that a detailed comparison of antibody responses to the polyclonal and monoclonal vaccines may be useful for identifying unique properties of each antibody response, we utilized a protein microarray comprised of approximately 94% of the vaccinia poxvirus proteome (245 proteins) to measure protein-specific antibody responses of 71 individuals receiving a single vaccination with ACAM2000 or Dryvax. We observed robust antibody responses to 21 poxvirus proteins in vaccinated individuals, including 11 proteins that distinguished Dryvax responses from ACAM2000. Analysis of protein sequences from Dryvax clones revealed amino acid level differences in these 11 antigenic proteins and suggested that sequence variation and clonal heterogeneity may contribute to the observed differences between Dryvax and ACAM2000 antibody responses. PMID- 24759653 TI - Professor Alain Chabaud (13 March 1923-11 March 2013). PMID- 24759654 TI - The var3 genes of Plasmodium falciparum 3D7 strain are differentially expressed in infected erythrocytes. AB - Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important virulence factor encoded by a family of 59 var genes, including 56 var genes plus 3 small var3 genes. The var genes are among the most diverse sequences in the P. falciparum genome, but the var3 genes are found conserved in most P. falciparum strains. Previous studies have been mainly focused on the typical var genes, while the biological characteristics of the var3 genes remain unknown. In this study, the three var3 genes, PF3D7_0100300, PF3D7_0600400, and PF3D7_0937600, were found to be transcribed in the erythrocytic stages of P. falciparum, with a peak in the transcription level at 16 h post-invasion, but terminated immediately after 16 h post-invasion. The encoded protein of PF3D7_0600400 could be detected in both the late trophozoite stage and schizont stage, while the encoded proteins of PF3D7_0100300 and PF3D7_0937600 could only be detected in the late trophozoite stage and schizont stage, respectively. Thus, the var3 genes of the P. falciparum 3D7 strain were differentially expressed during the erythrocytic development of the parasite. PMID- 24759655 TI - Occupational ladder fall injuries - United States, 2011. AB - Falls remain a leading cause of unintentional injury mortality nationwide [corrected].Among workers, approximately 20% of fall injuries involve ladders. Among construction workers, an estimated 81% of fall injuries treated in U.S. emergency departments (EDs) involve a ladder. To fully characterize fatal and nonfatal injuries associated with ladder falls among workers in the United States, CDC's National Institute for Occupational Safety and Health (NIOSH) analyzed data across multiple surveillance systems: 1) the Census of Fatal Occupational Injuries (CFOI), 2) the Survey of Occupational Injuries and Illnesses (SOII), and 3) the National Electronic Injury Surveillance System occupational supplement (NEISS-Work). In 2011, work-related ladder fall injuries (LFIs) resulted in 113 fatalities (0.09 per 100,000 full-time equivalent [FTE] workers), an estimated 15,460 nonfatal injuries reported by employers that involved >=1 days away from work (DAFW), and an estimated 34,000 nonfatal injuries treated in EDs. Rates for nonfatal, work-related, ED-treated LFIs were higher (2.6 per 10,000 FTE) than those for such injuries reported by employers (1.2 per 10,000 FTE). LFIs represent a substantial public health burden of preventable injuries for workers. Because falls are the leading cause of work related injuries and deaths in construction, NIOSH, the Occupational Safety and Health Administration, and the Center for Construction Research and Training are promoting a national campaign to prevent workplace falls. NIOSH is also developing innovative technologies to complement safe ladder use. PMID- 24759656 TI - Indoor firing ranges and elevated blood lead levels - United States, 2002-2013. AB - Indoor firing ranges are a source of lead exposure and elevated blood lead levels (BLLs) among employees, their families, and customers, despite public health outreach efforts and comprehensive guidelines for controlling occupational lead exposure. There are approximately 16,000-18,000 indoor firing ranges in the United States, with tens of thousands of employees. Approximately 1 million law enforcement officers train on indoor ranges. To estimate how many adults had elevated BLLs (>=10 ug/dL) as a result of exposure to lead from shooting firearms, data on elevated BLLs from the Adult Blood Lead Epidemiology and Surveillance (ABLES) program managed by CDC's National Institute for Occupational Safety and Health (NIOSH) were examined by source of lead exposure. During 2002 2012, a total of 2,056 persons employed in the categories "police protection" and "other amusement and recreation industries (including firing ranges)" had elevated BLLs reported to ABLES; an additional 2,673 persons had non-work-related BLLs likely attributable to target shooting. To identify deficiencies at two indoor firing ranges linked to elevated BLLs, the Washington State Division of Occupational Safety and Health (WaDOSH) and NIOSH conducted investigations in 2012 and 2013, respectively. The WaDOSH investigation found a failure to conduct personal exposure and biologic monitoring for lead and also found dry sweeping of lead-containing dust. The NIOSH investigation found serious deficiencies in ventilation, housekeeping, and medical surveillance. Public health officials and clinicians should ask about occupations and hobbies that might involve lead when evaluating findings of elevated BLLs. Interventions for reducing lead exposure in firing ranges include using lead-free bullets, improving ventilation, and using wet mopping or high-efficiency particulate air (HEPA) vacuuming to clean. PMID- 24759657 TI - Benefits from immunization during the vaccines for children program era - United States, 1994-2013. AB - The Vaccines for Children (VFC) program was created by the Omnibus Budget Reconciliation Act of 1993 and first implemented in 1994. VFC was designed to ensure that eligible children do not contract vaccine-preventable diseases because of inability to pay for vaccine and was created in response to a measles resurgence in the United States that resulted in approximately 55,000 cases reported during 1989-1991. The resurgence was caused largely by widespread failure to vaccinate uninsured children at the recommended age of 12-15 months. To summarize the impact of the U.S. immunization program on the health of all children (both VFC-eligible and not VFC-eligible) who were born during the 20 years since VFC began, CDC used information on immunization coverage from the National Immunization Survey (NIS) and a previously published cost-benefit model to estimate illnesses, hospitalizations, and premature deaths prevented and costs saved by routine childhood vaccination during 1994-2013. Coverage for many childhood vaccine series was near or above 90% for much of the period. Modeling estimated that, among children born during 1994- 2013, vaccination will prevent an estimated 322 million illnesses, 21 million hospitalizations, and 732,000 deaths over the course of their lifetimes, at a net savings of $295 billion in direct costs and $1.38 trillion in total societal costs. With support from the VFC program, immunization has been a highly effective tool for improving the health of U.S. children. PMID- 24759658 TI - Surveillance systems to track progress toward global polio eradication - worldwide, 2012-2013. AB - In 2012, the World Health Assembly of the World Health Organization (WHO) declared completion of polio eradication a programmatic emergency. Polio cases are detected through surveillance of acute flaccid paralysis (AFP) cases and subsequent testing of stool specimens for polioviruses (PVs) at WHO-accredited laboratories within the Global Polio Laboratory Network (GPLN). AFP surveillance is supplemented by environmental surveillance, testing sewage samples from selected sites for PVs. Virologic surveillance, including genomic sequencing to identify isolates by genotype and measure divergence between isolates, guides Global Polio Eradication Initiative (GPEI) activities by confirming the presence of PV, tracking chains of PV transmission, and highlighting gaps in AFP surveillance quality. This report provides AFP surveillance quality indicators at national and subnational levels during 2012-2013 for countries that experienced PV cases during 2009-2013 in the WHO African Region (AFR) and Eastern Mediterranean Region (EMR), the remaining polio-endemic regions. It also summarizes the results of environmental surveillance and reviews indicators assessing the timeliness of reporting of PV isolation and of virus strain characterization globally. Regional-level performance indicators for timely reporting of PV isolation were met in five of six WHO regions in 2012 and 2013. Of 30 AFR and EMR countries that experienced cases of PV (wild poliovirus [WPV], circulating vaccine-derived poliovirus [cVDPV], or both) during 2009-2013, national performance indicator targets for AFP surveillance and collection of adequate specimens were met in 27 (90%) countries in 2012 and 22 (73%) in 2013. In 17 (57%) countries, >=80% of the population lived in subnational areas meeting both AFP performance indicators in 2012, decreasing to 13 (43%) in 2013. To achieve polio eradication and certify interruption of PV transmission, intensive efforts to strengthen and maintain AFP surveillance are needed at subnational levels, including in field investigation and prompt collection of specimens, particularly in countries with current or recent active PV transmission. PMID- 24759659 TI - Notes from the field: measles - California, January 1-April 18, 2014. AB - Measles is a highly contagious, acute viral illness that can lead to severe complications and death. Even patients who experience uncomplicated acute measles have a small risk for developing a devastating neurologic illness, subacute sclerosing panencephalitis, years after their infection. Measles was documented as eliminated (defined as interruption of continuous transmission lasting >=12 months) in the United States in 2000; however, importation of measles cases and limited local transmission continue to occur. During January 1-April 18, 2014, the California Department of Public Health received reports of 58 confirmed measles cases, the highest number reported for that period since 1995. Patients ranged in age from 5 months to 60 years. Three (5%) patients were aged <12 months, six (10%) were aged 1-4 years, 17 (29%) were aged 5-19 years, and 32 (55%) were aged >=20 years. As of April 18, there had been 12 hospitalizations, and no deaths had been reported. During 2000-2013, the median annual number of measles cases reported in California was nine (range = four to 40). PMID- 24759660 TI - Functions of liver natural killer cells are dependent on the severity of liver inflammation and fibrosis in chronic hepatitis C. AB - During chronic hepatitis C virus (HCV) infection, the role of intra-hepatic (IH) natural killer (NK) cells is still controversial. To clarify their functions, we investigated anti-viral and cytotoxic activity of NK cells in human fresh liver biopsies. We compared the functions of IH-NK cells in HCV-infected and NASH patients in physiological conditions as well as after stimulation using flow cytometric and immunohistochemical analyses. Interestingly, few IH-NK cells produced anti-viral cytokine IFN-gamma in HCV-infected patients similarly as in non-infected individuals. Spontaneous degranulation activity was extremely low in peripheral NK cells compared to IH-NK cells, and was significantly higher in IH NK cells from HCV-infected patients compared to non-infected individuals. Immunohistochemical analysis revealed that perforin granules were polarized at the apical pole of IH-NK cells. The presence of CD107a and perforin in IH-NK cells demonstrated that NK cells exerted a cytolytic activity at the site of infection. Importantly, IH-NK cell functions from HCV-infected patients were inducible by specific exogenous stimulations. Upon ex vivo K562 target cell stimulations, the number of degranulating NK cells was significantly increased in the pool of IH-NK cells compared to circulating NK cells. Interestingly, after stimulation, the frequency of IFN-gamma-producing IH-NK cells in HCV-infected patients was significantly higher at early stage of inflammation whereas the spontaneous IH-NK cell degranulation activity was significantly impaired in patients with highest inflammation and fibrosis Metavir scores. Our study highlights that some IH-NK cells in HCV-infected patients are able to produce INF gamma and degranulate and that those two activities depend on liver environment including the severity of liver injury. Thus, we conclude that critical roles of IH-NK cells have to be taken into account in the course of the liver pathogenesis associated to chronic HCV infection. PMID- 24759662 TI - Barrett's esophagus: review of diagnosis and treatment. AB - Barrett's esophagus (BE) is an acquired condition characterized by replacement of stratified squamous epithelium by a cancer predisposing metaplastic columnar epithelium. Endoscopy with systemic biopsy protocols plays a vital role in diagnosis. Technological advancements in dysplasia detection improves outcomes in surveillance and treatment of patients with BE and dysplasia. These advances in endoscopic technology radically changed the treatment for dysplastic BE and early cancer from being surgical to organ-sparing endoscopic therapy. A multimodal treatment approach combining endoscopic resection of visible and/or raised lesions with ablation techniques for flat BE mucosa, followed by long-term surveillance improves the outcomes of BE. Safe and effective endoscopic treatment can be either tissue acquiring as in endoscopic mucosal resection and endoscopic submucosal dissection or tissue ablative as with photodynamic therapy, radiofrequency ablation and cryotherapy. Debatable issues such as durability of response, recognition and management of sub-squamous BE and optimal management strategy in patients with low-grade dysplasia and non-dysplastic BE need to be studied further. Development of safer wide field resection techniques, which would effectively remove all BE and obviate the need for long-term surveillance, is another research goal. Shared decision making between the patient and physician is important while considering treatment for dysplasia in BE. PMID- 24759661 TI - Diagnosis and management of parastomal pyoderma gangrenosum. AB - Parastomal pyoderma gangrenosum (PPG) is an unusual neutrophilic dermatosis characterized by painful, necrotic ulcerations occurring in the area surrounding an abdominal stoma. It typically affects young to middle-aged adults, with a slight female predominance. The underlying etiology for PPG remains enigmatic but aberrant immune response to injury may play a pivotal role. The reported risk factors for the development of PPG include the presence of extra-intestinal manifestations, autoimmune disorders and obesity, along with local factors, such as the presence of parastomal hernia or pressure ulcer. PPG can develop at any time after the stoma construction. The histopathological features of PPG are not pathognomonic and its diagnosis is mainly based on clinical features. The management of PPG often requires a multidisciplinary approach, with a combination of local wound care and systemic medications. PMID- 24759663 TI - Update of liver fibrosis and steatosis with transient elastography (Fibroscan). AB - BACKGROUND: Assessment of liver fibrosis and steatosis is now almost indispensable in most of the chronic liver diseases in order to determine prognosis and need for treatment, and to monitor disease progression and response to treatment. Liver biopsy is limited by its invasiveness and patient acceptability. Transient elastography (TE; Fibroscan) is a non-invasive tool with satisfactory accuracy and reproducibility to estimate liver fibrosis. AIMS & METHODS: To review the existing evidence concerning the clinical applications of TE in major liver diseases, including chronic hepatitis B and -C, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, primary biliary cirrhosis and primary sclerosing cholangitis. RESULTS: As alanine aminotransferase (ALT) is one of the major confounding factors of liver stiffness in chronic hepatitis B, an ALT-based algorithm has been developed and higher liver stiffness measurements (LSM) cut-off values for different stages of liver fibrosis should be used in patients with elevated ALT levels up to five times the upper limit of normal. Furthermore, falsely-high LSM results up to the cirrhotic range may occur during ALT flare. TE is also useful predicting patient prognosis in the development of hepatocellular carcinoma (HCC), portal hypertension, postoperative complications in HCC patients and survival. Unfortunately, failed acquisition of TE is common in obese patients. Furthermore, obese patients may have higher LSM results, even in the same stage of liver fibrosis. To better evaluate NAFLD a new XL probe, with a larger probe with lower ultrasound frequency and deeper penetration, increases the success rate of TE in obese patients. The median LSM value with the XL probe was found to be lower than that by the conventional M probe, hence cut off values were approximately 1.2 to 1.3 kilopascals lower than those of the M probe, suggesting its adoption. Studies reveal that a novel ultrasonic controlled attenuation parameter is potentially useful to detect and quantify hepatic steatosis non-invasively. CONCLUSION: TE is a non-invasive, accurate and reproducible test of liver fibrosis and possibly hepatic steatosis and has been validated in a wide spectrum of liver diseases. TE is also useful to predict patient outcomes. PMID- 24759664 TI - Autoimmune pancreatitis. AB - Autoimmune pancreatitis (AIP) is a rare, heterogeneous, fibroinflammatory disorder of the pancreas. It has gained increasing recognition due to a presentation that can mimic difficult-to-treat disorders such as pancreatic cancer, cholangiocarcinoma and primary sclerosing cholangitis. In contrast, autoimmune pancreatitis is a benign disease that is very responsive to therapy with corticosteroids. There are two types of AIP. Type 1 disease is the most common worldwide and is associated with extrapancreatic manifestations and elevated levels of IgG4-positive cells. Type 2 AIP is characterized by a paucity of IgG4-positive cells and is more difficult to diagnose. This review provides an update on the diagnosis, pathophysiology and treatment of AIP, with special emphasis on the two subtypes. PMID- 24759666 TI - Use of antibacterial sutures for skin closure in controlling surgical site infections: a systematic review of published randomized, controlled trials. AB - OBJECTIVE: The objective of this article is to systematically analyse the randomized, controlled trials that compare the use of antibacterial sutures (ABS) for skin closure in controlling surgical site infections. METHODS: Randomized, controlled trials on surgical patients comparing the use of ABS for skin closure in controlling the surgical site infections were analysed systematically using RevMan(r) and combined outcomes were expressed as odds ratios (OR) and standardized mean differences (SMD). RESULTS: Seven randomized, controlled trials evaluating 1631 patients were retrieved from electronic databases. There were 760 patients in the ABS group and 871 patients in the simple suture group. There was moderate heterogeneity among trials (Tau(2) = 0.12; chi(2) = 8.40, df = 6 [P < 0.01]; I(2) = 29%). Therefore in the random-effects model, the use of ABS for skin closure in surgical patients was associated with a reduced risk of developing surgical site infections (OR, 0.16; 95% CI, 0.37, 0.99; z = 2.02; P < 0.04) and postoperative complications (OR, 0.56; 95% CI, 0.32, 0.98 z = 2.04; P = 0.04). The durations of operation and lengths of hospital stay were similar following the use of ABS and SS for skin closure in patients undergoing various surgical procedures. CONCLUSION: Use of ABS for skin closure in surgical patients is effective in reducing the risk of surgical site infection and postoperative complications. ABS is comparable with SS in terms of length of hospital stay and duration of operation. PMID- 24759665 TI - Clinical controversies in endoscopic ultrasound. AB - The field of diagnostic and therapeutic endoscopic ultrasound (EUS) is growing rapidly. Although EUS has enhanced our ability to diagnose and treat a wide variety of GI conditions, there are many controversial issues regarding the appropriate application of EUS techniques. In this review we discuss five controversial topics in EUS: the utility of EUS in staging of esophageal and gastric cancer; selection of appropriate needle gauge for fine needle aspiration (FNA); use of the stylet in FNA; and the emerging role of contrast agents in endoscopic ultrasound. PMID- 24759667 TI - Wedge and needle liver biopsies show discordant histopathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. AB - BACKGROUND: Controversy exists over whether or not single-needle liver biopsies are sufficient to compare histological parameters in patients with non-alcoholic fatty liver disease. AIMS: To identify sampling variability, we biopsied four liver specimens per patient, based on biopsy size (needle vs wedge) and location (left vs right lobe), immediately prior to bariatric Roux-en-Y gastric bypass surgery. METHODS: Ten prospectively enrolled, morbidly obese patients underwent 40 laparoscopy-guided biopsies; two needle and two wedge from each of 16 left and 16 right liver lobes. The Kappa coefficient for concordance compared histological parameters from left and right lobe needle- and wedge biopsies. Wedge biopsies were considered our 'Gold Standard'. RESULTS: Each patient had two wedge- and two needle liver biopsies. Kappa concordance between all needle and wedge biopsies from right and left lobes showed variability. Wedge- and needle liver biopsies from contralateral lobes had higher concordance with each other, compared to ipsilateral needle/wedge biopsy pairs. Contralateral wedge pairs had higher concordance than contralateral needle/needle pairs. There were no biopsy complications. CONCLUSIONS: Wedge biopsy pairs had the best Kappa concordance but contralateral needle/needle biopsy pairs had good Kappa concordance. There were no complications from the 40 needle- and wedge liver biopsies, confirming the safety of laporoscopic multi-biopsy in both liver lobes. PMID- 24759668 TI - An NSQIP evaluation of practice patterns and outcomes following surgery for anorectal abscess and fistula in patients with and without Crohn's disease. AB - BACKGROUND: Patients with Crohn's disease (CD) are believed to have more aggressive anorectal abscess and fistula disease. We assessed the types of procedures performed and perioperative complications associated with the surgical management of anorectal abscess and fistula disease in patients with and without CD. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database (ACS-NSQIP, 2005-2010) was used to calculate 30-day outcomes using regression modeling, accounting for demographics, comorbidities and surgical procedures. ICD-9 codes for anorectal abscess or fistula were used for initial selection. Patients were then stratified, based on the presence or absence of underlying CD. Local procedures included incision and drainage of abscesses, fistulotomy and seton placement. Cutaneous fistulas were considered simple, while all others were classified as complex (-vaginal, -urethral and vesical). RESULTS: A total of 7,218 patients (mean age 45 years; 64% male) met inclusion criteria, with underlying CD in 345 (4.8%). CD patients were more likely to have a seton placed (9.9 vs 8.2%, P < 0.001) and be on steroids (15.4 vs 4.3%, P < 0.001). Thirty-seven percent of CD patients underwent local procedures, while 46% had a proctectomy and 8% underwent diversion. Fistulotomy was more common in those without underlying CD (16 vs 11%, P < 0.001). The overall complication rate after local treatment was 4.9%, with no difference between patients with and without CD (7.7 vs 4.9%, P = 0.144). This was not affected by fistula type-simple (7.9 vs 3.9%, P = 0.194) vs complex (33 vs 7.1%, P = 0.21)-or when stratified by wound (3.8 vs 2.4%; P = 0.26) or systemic complications (3.8 vs 2.5%; P = 0.53). Yet, complications following emergency procedures were higher in patients with CD (21.4 vs 5.9%, P = 0.047). Factors significantly associated with increased complications were Crohn's disease (OR = 8.2), lack of functional independence (OR = 2.0), pre-operative weight loss (OR = 2.6) and pre-operative acute renal failure (OR = 5.6). Steroids were also associated with a 1.7-fold increase in complications, independent from CD. CONCLUSIONS: While most patients with anorectal abscess/fistula are treated with local procedures, proctectomy and diversion use is fairly common in those with underlying CD. Although complication rates following elective local procedures for anorectal abscess/fistula are similar in patients with and without CD, they are higher in patients on steroids and in CD patients undergoing emergent procedures. PMID- 24759669 TI - Surgical outcomes and their relation to the number of prior episodes of diverticulitis. AB - PURPOSE: We aimed to investigate the relationship between the number of prior episodes of diverticulitis and outcomes of sigmoid colectomy. METHODS: After institutional review board approval, a retrospective review was undertaken based on records of patients who underwent sigmoid resection with anastomosis for diverticulitis between 4 May 2007 and 29 February 2012. Patients were divided into two groups: 0-3 attacks (group 1) and >=4 attacks (group 2). Statistical analyses were performed to determine whether the groups differed on demographic, intra-operative and postoperative variables. RESULTS: We identified 247 patients who underwent sigmoid colectomy for diverticulitis (45 open, 202 laparoscopic). The two groups did not differ significantly in age, gender, American Society of Anesthesiologists score, past surgical history, body mass index, length of stay, use of a stoma or number of prior hospitalizations for diverticulitis. Group 1 had a higher rate of abscesses (30.6 vs 6.8%, P < 0.001) and fistulas (19.4 vs 0.9%, P < 0.001); a longer operative time (190.1 vs 166.3 min, P = 0.0024); and higher rates of postoperative complications (45.8 vs 23.3%, P < 0.001) and conversion (17.1 vs 4.4%, P = 0.0091). The most common surgical complications in groups 1 and 2 were wound infection (35 vs 10) and ileus (20 vs 8). Based on multivariate regression analysis, >=4 attacks were independently correlated with a lower complication rate (odds ratio = 0.512, 95% confidence interval = 0.266 0.987, P = 0.046). CONCLUSIONS: Patients who had >=4 previous attacks of diverticulitis had fewer postoperative complications. PMID- 24759670 TI - BRAF mutation in multiple primary cancer with colorectal cancer and stomach cancer. AB - AIMS: Recently, BRAF mutation testing has been introduced as a marker in differentiating Lynch syndrome from sporadic colorectal cancers or in predicting colorectal cancers with worse prognosis. Individuals with hereditary predisposition to cancer development are at an increased risk of developing multiple primary cancers. The purpose of this study is to identify mutation in the BRAF gene in multiple primary cancers with colorectal cancer and stomach cancer. METHODS: BRAF mutation was analysed in 45 patients with colorectal cancer and stomach cancer, synchronously or metachronously. RESULTS: Mean age was 64.07 years (range: 47-83 years). For the colorectal cancer, tumors were located at the sigmoid colon in eight patients (17.8%) and at the rectum in 22 patients (48.9%). Twenty-three patients (51.1%) had synchronous cancer. Four patients (8.9%) had family members with cancer. BRAF mutation was identified in three patients (6.7%). All three of these patients had metachronous cancers. The colorectal cancers were located in the sigmoid colon (1 patient) and the rectum (2 patients). CONCLUSIONS: BRAF mutation rate was low in the multiple primary cancer with colorectal cancer and stomach cancer. With only BRAF gene study, it was not possible to identify any correlation with family history of colorectal cancer. Further study means considering other genes - MSI, MSH2, MLH1, MSH6. PMID- 24759672 TI - Aborted sudden cardiac death in a 14-year-old athlete: the anomalous coronary artery. PMID- 24759673 TI - Lexical variation and change in british sign language. AB - This paper presents results from a corpus-based study investigating lexical variation in BSL. An earlier study investigating variation in BSL numeral signs found that younger signers were using a decreasing variety of regionally distinct variants, suggesting that levelling may be taking place. Here, we report findings from a larger investigation looking at regional lexical variants for colours, countries, numbers and UK placenames elicited as part of the BSL Corpus Project. Age, school location and language background were significant predictors of lexical variation, with younger signers using a more levelled variety. This change appears to be happening faster in particular sub-groups of the deaf community (e.g., signers from hearing families). Also, we find that for the names of some UK cities, signers from outside the region use a different sign than those who live in the region. PMID- 24759671 TI - Molecular genetic techniques for gene manipulation in Candida albicans. AB - Candida albicans is one of the most common fungal pathogen in humans due to its high frequency as an opportunistic and pathogenic fungus causing superficial as well as invasive infections in immunocompromised patients. An understanding of gene function in C. albicans is necessary to study the molecular basis of its pathogenesis, virulence and drug resistance. Several manipulation techniques have been used for investigation of gene function in C. albicans, including gene disruption, controlled gene expression, protein tagging, gene reintegration, and overexpression. In this review, the main cassettes containing selectable markers used for gene manipulation in C. albicans are summarized; the advantages and limitations of these cassettes are discussed concerning the influences on the target gene expression and the virulence of the mutant strains. PMID- 24759674 TI - Effect of a proteasome inhibitor plus steroids on HLA antibodies in sensitized patients awaiting a renal transplant. AB - BACKGROUND: This prospective monocentric study investigated the effect of corticosteroids plus bortezomib to reduce anti-HLA antibodies before renal transplantation. METHODS: Included were 23 patients with stable immunization against HLA and awaiting a kidney transplant (KT). Treatment consisted of bortezomib (1.3 mg/m) plus 40 mg of dexamethasone intravenously on days 1, 3, 8, and 10 (B+S). Class I and II anti-HLAs were determined using the single-antigen beads assay at day 0 (D0), month 1 (M1), M3, and M6. RESULTS: Antibodies against 96 class I and 76 class II antigens were investigated and patients had a mean number of 49 (+/- 21) antibodies against HLA on D0: 31 were against HLA class I and 17 were against HLA class II. At D0, the median was 10,734 (range, 1096 18,513) for the highest mean fluorescent intensity (hAb) anti-class I antibodies and 11,189 (range, 1276-19,176) for class II. By M3, 41% of patients had a greater than 25% decrease in class 1 hAbs and 60% by M6. By M3, 33% of patients had a greater than 25% decrease in class II hAbs and 42% by M6. At M6, 54% of anti-HLA antibodies had a sustained decrease by more than 25% and 36% were decreased by more than 50%. No predictive factors for decreased antibodies after bortezomib plus steroid therapy were identified. No serious adverse event was observed. Thereafter, 11 of 23 patients received successful transplants without having experienced acute rejection (follow-up, 18 months). CONCLUSIONS: B+S is an effective alternative therapy for reducing class I and II anti-HLA, regardless of other previous treatments. PMID- 24759675 TI - Raman phonon emission in a driven double quantum dot. AB - The compound semiconductor gallium-arsenide (GaAs) provides an ultra-clean platform for storing and manipulating quantum information, encoded in the charge or spin states of electrons confined in nanostructures. The absence of inversion symmetry in the zinc-blende crystal structure of GaAs however, results in a strong piezoelectric interaction between lattice acoustic phonons and qubit states with an electric dipole, a potential source of decoherence during charge sensitive operations. Here we report phonon generation in a GaAs double quantum dot, configured as a single- or two-electron charge qubit, and driven by the application of microwaves via surface gates. In a process that is a microwave analogue of the Raman effect, phonon emission produces population inversion of the two-level system and leads to rapid decoherence of the qubit when the microwave energy exceeds the level splitting. Comparing data with a theoretical model suggests that phonon emission is a sensitive function of the device geometry. PMID- 24759676 TI - Autoimmune manifestations in SCID due to IL7R mutations: Omenn syndrome and cytopenias. AB - B+NK+SCID (severe combined immunodeficiency) due to IL7Ralpha deficiency represents approximately 10% of American SCID cases. To better understand the spectrum of autoimmune disorders associated with IL7Ralpha deficiency, we describe two unrelated IL7Ralpha-deficient female SCID infants whose clinical picture was dominated by autoimmune manifestations: one with intrauterine Omenn syndrome (OS) and another with persistent thrombocytopenic purpura since 4months of age. The OS baby harbored a homozygous p.C118Y mutation in IL7R. She presented dense eosinophilic infiltrates in several organs, including pancarditis, which may have contributed to her death (on the 2nd day of life). B cells were observed in lymph nodes, spleen, bone marrow and thymus. The second patient harbored compound heterozygous p.C118Y and p.I121NfsX8 mutations. She underwent a successful unrelated cord blood transplant. In conclusion, early OS can be observed in patients with IL7R mutations, and autoimmune cytopenias could also complicate the clinical course of SCID babies with this type of defect. PMID- 24759677 TI - A single nucleotide polymorphism -35 kb T>C (rs9264942) is strongly associated with psoriasis vulgaris depending on HLA-Cw(*)06. AB - HLA class I molecules play a role both in viral infection control and in autoimmune diseases development. rs9264942T>C polymorphism in HLA-C gene was found to impact on HLA-C surface expression level and to be associated with HIV-1 control. It was found that these HLA alleles which protect against AIDS are associated with autoimmune disease e.g. psoriasis vulgaris (PsV). Whether rs9264942 SNP is associated with PsV was investigated here. rs9264942T>C was genotyped in 292 PsV patients, and 254 controls using TaqMan Genotyping Assay. PsV patients differed from controls in frequencies of rs9264942T>C alleles (p=3.62 * 10(-16)) and genotypes (5.67 * 10(-15)). However, rs9264942C allele was predisposing to PsV 3-fold weaker than HLA-Cw(*)06 (OR=5.04 vs. OR=15.61, respectively). In addition, this SNP was described earlier to be in strong linkage disequilibrium (LD) with another SNP, rs67384697 ins/del, which by affecting a microRNA binding is responsible for regulating HLA-C expression. However, typing for is cheaper and simpler than that for rs67384697, therefore we think it may substitute for it to some extent. PMID- 24759678 TI - Analysis of HLA-G gene polymorphism and protein expression in invasive breast ductal carcinoma. AB - The human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule predominantly expressed in trophoblastic placental cells to protect the fetus during pregnancy. However, evidence has shown that this molecule may be implicated in the immune escape mechanism of tumor cells. Thus, the aim of this study was to evaluate the frequency of 14-bp insertion/deletion HLA-G polymorphism, as well as the expression of this molecule in patients with invasive breast ductal carcinoma (IDC). A significant association between the expression of HLA-G and the presence of metastasis in lymph nodes (p=0.01) was observed and the expression of HLA-G was significantly higher in patients with shorter survival time (p=0.03). The analysis suggests that the polymorphism observed in patients with IDC may be inducing a higher expression of the HLA-G molecule, which may possibly contribute to shorter survival time and a worse clinical prognosis for such patients. PMID- 24759679 TI - Interrelations of graph distance measures based on topological indices. AB - In this paper, we derive interrelations of graph distance measures by means of inequalities. For this investigation we are using graph distance measures based on topological indices that have not been studied in this context. Specifically, we are using the well-known Wiener index, Randic index, eigenvalue-based quantities and graph entropies. In addition to this analysis, we present results from numerical studies exploring various properties of the measures and aspects of their quality. Our results could find application in chemoinformatics and computational biology where the structural investigation of chemical components and gene networks is currently of great interest. PMID- 24759681 TI - Body ownership and beyond: connections between cognitive neuroscience and linguistic typology. AB - During the past few decades, two disciplines that rarely come together-namely, cognitive neuroscience and linguistic typology-have been generating remarkably similar results regarding the representational domain of personal possessions. Research in cognitive neuroscience indicates that although the core self is grounded in body ownership, the extended self encompasses a variety of noncorporeal possessions, especially those that play a key role in defining one's identity. And research in linguistic typology indicates that many languages around the world contain a distinct grammatical construction for encoding what is commonly called "inalienable" possession-a category of owned objects that almost always includes body parts, but that also tends to include several other kinds of personally relevant entities. Both of these independent lines of investigation are summarized, and a number of interdisciplinary connections between them are discussed. PMID- 24759680 TI - Prevalence and correlates of vitamin K deficiency in children with inflammatory bowel disease. AB - Although vitamin K deficiency has been implicated in adult inflammatory bowel disease (IBD), its prevalence in pediatric IBD remains unknown. We carried out a cross-sectional study in 63 children with Crohn's disease (CD) and 48 with ulcerative colitis (UC) to assess the prevalence of vitamin K deficiency and to search for potential correlation between vitamin K status and pediatric IBD activity. Vitamin K status was assessed using protein induced by vitamin K absence-II (PIVKA-II; ELISA). Prevalence of vitamin K deficiency was 54.0% in CD and 43.7% in UC. Vitamin K deficiency was more common in patients with higher CD activity, in CD patients with higher mass Z-scores, and less common among children with CD treated with infliximab. Relation of vitamin K deficiency to pediatric IBD clinical course and treatment demand further research. PMID- 24759682 TI - In Situ Recruitment of Human Bone Marrow-Derived Mesenchymal Stem Cells Using Chemokines for Articular Cartilage Regeneration. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are a good cell source for regeneration of cartilage as they can migrate directly to the site of cartilage injury and differentiate into articular chondrocytes. Articular cartilage defects do not heal completely due to the lack of chondrocytes or BMSCs at the site of injury. In this study, the chemotaxis of BMSCs toward chemokines, which may give rise to a complete regeneration of the articular cartilage, was investigated. CCR2, CCR4, CCR6, CXCR1, and CXCR2 were expressed in normal BMSCs and were increased significantly upon treatment with proinflammatory cytokines. BMSC migration was increased by MIP-3alpha and IL-8 more than by MCP-1 or SDF-1alpha. IL-8 and MIP-3alpha significantly enhanced the chemotaxis of BMSCs compared with MCP-1, SDF-1alpha, or PBS. Human BMSC recruitment to transplanted scaffolds containing either IL-8 or MIP-3alpha significantly increased in vivo compared to scaffolds containing PBS. Furthermore, IL-8- and MIP-3alpha-containing scaffolds enhanced tissue regeneration of an osteochondral defect site in beagle knee articular cartilage. Therefore, this study suggests that IL-8 and MIP-3alpha are the candidates that induce the regeneration of damaged articular cartilage. PMID- 24759683 TI - Mitochondrial regulation of NADPH oxidase in hindlimb unweighting rat cerebral arteries. AB - Exposure to microgravity results in post-flight cardiovascular deconditioning and orthostatic intolerance in astronauts. Vascular oxidative stress injury and mitochondrial dysfunction have been indicated in this process. To elucidate the mechanism for this condition, we investigated whether mitochondria regulated NADPH oxidase in hindlimb unweighting (HU) rat cerebral and mesenteric arteries. Four-week HU was used to simulate microgravity in rats. Vascular superoxide generation, protein and mRNA levels of Nox2/Nox4, and the activity of NADPH oxidase were examined in the present study. Compared with control rats, the levels of superoxide increased in cerebral (P<0.001) but not in mesenteric vascular smooth muscle cells. The protein and mRNA levels of Nox2 and Nox4 were upregulated significantly (P<0.001 and P<0.001 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) in HU rat cerebral arteries but not in mesenteric arteries. NADPH oxidases were activated significantly by HU (P<0.001) in cerebral arteries but not in mesenteric arteries. Chronic treatment with mitochondria-targeted antioxidant mitoTEMPO attenuated superoxide levels (P<0.001), decreased the protein and mRNA expression levels of Nox2/Nox4 (P<0.01 and P<0.05 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) and the activity of NADPH oxidase (P<0.001) in HU rat cerebral arteries, but exerted no effects on HU rat mesenteric arteries. Therefore, mitochondria regulated the expression and activity of NADPH oxidases during simulated microgravity. Both mitochondria and NADPH oxidase participated in vascular redox status regulation. PMID- 24759684 TI - RNA interference-based therapy for spinocerebellar ataxia type 7 retinal degeneration. AB - Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disease characterized by loss of motor coordination and retinal degeneration with no current therapies in the clinic. The causative mutation is an expanded CAG repeat in the ataxin-7 gene whose mutant protein product causes cerebellar and brainstem degeneration and retinal cone-rod dystrophy. Here, we reduced the expression of both mutant and wildtype ataxin-7 in the SCA7 mouse retina by RNA interference and evaluated retinal function 23 weeks post injection. We observed a preservation of normal retinal function and no adverse toxicity with >=50% reduction of mutant and wildtype ataxin-7 alleles. These studies address an important safety concern regarding non-allele specific silencing of ataxin-7 for SCA7 retinal therapy. PMID- 24759685 TI - Allostatic load model associated with indoor environmental quality and sick building syndrome among office workers. AB - This study investigates whether indoor environmental quality (IEQ) influences allostatic load (AL) and whether AL can be a predictor for sick building syndrome (SBS). We also assessed and compared the associations between AL and SBS versus 8 hydroxydeoxyguanosine (8-OHdG) and SBS. A total of 115 office workers from 21 offices completed self-reported SBS questionnaires, and provided 11 biomarkers for their AL. Multiple linear regressions and logistic regression analysis were applied to examine the correlations between IEQ and AL or 8-OHdG and between AL or 8-OHdG and SBS, respectively. Our data revealed that the neuroendocrine system was correlated with CO2, the difference between indoor and outdoor CO2 levels (dCO2), and the indoor-outdoor ratio of CO2 (CO2 I/O). Metabolic system effects were associated with illumination. The relationships between illumination, CO2, dCO2, CO2 I/O and 8-OHdG were consistent with those and AL in specific systems. Furthermore, we found that risks for SBS syndromes were related with neuroendocrine and metabolic system of the AL. 8-OHdG was associated with eye dryness or irritation, eye tiredness and vomiting. We conclude that IEQ significantly influences AL and that AL can be a predictor for reporting SBS with information on system-specific effects. PMID- 24759686 TI - Subjective numeracy and preference to stay with the status quo. AB - BACKGROUND: Preference for the status quo, or clinical inertia, is a barrier to implementing treat-to-target protocols in patients with chronic diseases such as rheumatoid arthritis (RA). The objectives of this study were to examine the influence of subjective numeracy on RA-patient preference for the status quo and to determine whether age modifies this relationship. METHODS: RA patients participated in a single face-to-face interview. Numeracy was measured using the Subjective Numeracy Scale. Treatment preference was measured using Adaptive Conjoint Analysis. RESULTS: Of 205 eligible subjects, 156 agreed to participate. Higher subjective numeracy was associated with lower preference for the status quo in a regression model including race, employment, and use of biologics (adjusted odds ratio [95% confidence interval] = 0.71 [0.52-0.95], P = 0.02). Higher subjective numeracy was protective against status quo preferences among subjects younger than 65 years (adjusted odds ratio [95% confidence interval] = 0.64 (0.43-0.94), P = 0.02) but not among older subjects. CONCLUSIONS: Subjective numeracy is independently associated with younger, but not older, RA patients' preferences for the status quo. Our results add to the literature demonstrating age and numeracy differences in treatment preferences and medical decision-making processes. PMID- 24759687 TI - Are waiting list prioritization guidelines being followed in Australia? AB - OBJECTIVE: When waiting lists are used to ration treatments for nonemergency procedures, a prioritization rule is required to ensure that urgent patients are admitted first. This study investigates how the introduction of an explicit prioritization guideline affected the prioritization behavior of doctors, who previously had full discretion for assigning patients. DESIGN: The analysis exploits the publication of recommended priority categories in public hospitals. Taking the recommendations as a reference, deviations from the recommended priority assignments by doctors before and after the guideline publication are assessed. Multinomial logit models are used to control for patient and hospital characteristics. Heterogeneity in the impact of the guideline across patient characteristics is explored through interaction terms. SETTING: The state of New South Wales, Australia, between July 2004 and December 2010. PARTICIPANTS: Admissions via waiting lists in public hospitals (N = 753,010). MAIN OUTCOME MEASURE: Priority categories assigned by doctors. RESULTS: The guideline increased the likelihood that doctors would actually assign a semi-urgent priority to admissions with a recommended priority of semi-urgent by 11.7 percentage points (P < 0.000) and would assign a nonurgent priority to admissions with a recommended priority of non-urgent by 13.1 percentage points (P < 0.000). In contrast, the guideline lowered the likelihood of an urgent priority being assigned to admissions with a recommended priority of urgent by 13.7 percentage points (P < 0.000). Priority assignments are affected by payment status; specifically, a higher priority is given to paying patients, and this preferential treatment is not diminished by the presence of the guideline. CONCLUSION: The presence of a simple clinical priority guideline at the procedural level has not produced systematic, clinically based prioritization behaviors among doctors. The New South Wales priority guideline has curtailed assignments to the highest priority. This result raises a question concerning the usefulness of such a guideline in improving timely and equitable access to health care. PMID- 24759688 TI - A Protoberberine derivative HWY336 selectively inhibits MKK4 and MKK7 in mammalian cells: the importance of activation loop on selectivity. AB - A protoberberine derivative library was used to search for selective inhibitors against kinases of the mitogen-activated protein kinase (MAPK) cascades in mammalian cells. Among kinases in mammalian MAPK pathways, we identified a compound (HWY336) that selectively inhibits kinase activity of mitogen-activated protein kinase kinase 4 and 7 (MKK4 and MKK7). The IC50 of HWY336 was 6 uM for MKK4 and 10 uM for MKK7 in vitro. HWY336 bound to both kinases reversibly via noncovalent interactions, and inhibited their activity by interfering with access of a protein substrate to its binding site. The binding affinity of HWY336 to MKK4 was measured by surface plasmon resonance to determine a dissociation constant (Kd) of 3.2 uM. When mammalian cells were treated with HWY336, MKK4 and MKK7 were selectively inhibited, resulting in inhibition of c-Jun NH2-terminal protein kinases in vivo. The structural model of HWY336 bound to either MKK4 or MKK7 predicted that HWY336 was docked to the activation loop, which is adjacent to the substrate binding site. This model suggested the importance of the activation loop of MKKs in HWY336 selectivity. We verified this model by mutating three critical residues within this loop of MKK4 to the corresponding residues in MKK3. The mutant MKK4 displayed similar kinase activity as wild-type kinase, but its activity was not inhibited by HWY336 compared to wild-type MKK4. We propose that the specific association of HWY336 to the activation loop of MKK4/MKK7 is responsible for its selective inhibition. PMID- 24759689 TI - Antimicrobial activity of pantothenol against staphylococci possessing a prokaryotic type II pantothenate kinase. AB - Pantothenol is a provitamin of pantothenic acid (vitamin B5) that is widely used in healthcare and cosmetic products. This analog of pantothenate has been shown to markedly inhibit the phosphorylation activity of the prokaryotic type II pantothenate kinase of Staphylococcus aureus, which catalyzes the first step of the coenzyme A biosynthetic pathway. Since type II enzymes are found exclusively in staphylococci, pantothenol suppresses the growth of S. aureus, S. epidermidis, and S. saprophyticus, which inhabit the skin of humans. Therefore, the addition of this provitamin to ointment and skincare products may be highly effective in preventing infections by opportunistic pathogens. PMID- 24759690 TI - Providing quality family planning services: Recommendations of CDC and the U.S. Office of Population Affairs. AB - This report provides recommendations developed collaboratively by CDC and the Office of Population Affairs (OPA) of the U.S. Department of Health and Human Services (HHS). The recommendations outline how to provide quality family planning services, which include contraceptive services, pregnancy testing and counseling, helping clients achieve pregnancy, basic infertility services, preconception health services, and sexually transmitted disease services. The primary audience for this report is all current or potential providers of family planning services, including those working in service sites that are dedicated to family planning service delivery as well as private and public providers of more comprehensive primary care. The United States continues to face substantial challenges to improving the reproductive health of the U.S. population. Nearly one half of all pregnancies are unintended, with more than 700,000 adolescents aged 15-19 years becoming pregnant each year and more than 300,000 giving birth. One of eight pregnancies in the United States results in preterm birth, and infant mortality rates remain high compared with those of other developed countries. This report can assist primary care providers in offering family planning services that will help women, men, and couples achieve their desired number and spacing of children and increase the likelihood that those children are born healthy. The report provides recommendations for how to help prevent and achieve pregnancy, emphasizes offering a full range of contraceptive methods for persons seeking to prevent pregnancy, highlights the special needs of adolescent clients, and encourages the use of the family planning visit to provide selected preventive health services for women, in accordance with the recommendations for women issued by the Institute of Medicine and adopted by HHS. PMID- 24759692 TI - Dryinidae of the Oriental region (Hymenoptera: Chrysidoidea). AB - An updated revision of Oriental Dryinidae is presented. Seven subfamilies, 20 genera and 368 species are treated. Eight new species are described: Aphelopus zonalis Xu, Olmi & He, sp. nov. (China, Hainan); Anteon zoilum Xu, Olmi & He, sp. nov. (China, Yunnan), Anteon zonarium Xu, Olmi & He, sp. nov. (China, Yunnan), Anteon zopyrum Xu, Olmi & He, sp. nov. (China, Xizang), Anteon zoroastrum Xu, Olmi & He, sp. nov. (Malaysia, Malaya), Esagonatopus sinensis Xu, Olmi & He, sp. nov. (China, Yunnan), Gonatopus yunnanensis Xu, Olmi & He, sp. nov. (China, Yunnan); Ponomarenkoa ellenbergeri Olmi, Xu & He, sp. nov. (Myanmar amber). Descriptions, geographic distribution, known hosts, natural en-emies and type material of each species are presented, together with illustrations of the main morphological characters and keys to the subfamilies, genera and species. Complete lists of references concerning the Oriental Dryinidae and their hosts are given. New synonymies are proposed for Aphelopus albiclypeus Xu, He & Olmi, 1999 (=A. exnotaulices He & Xu, 2002, syn. nov.), A. orientalis Olmi, 1984 (=A. albopictoides Xu & He, 1999, syn. nov.), A. taiwanensis Olmi, 1991 (=A. compresssus Xu & Yao, 1997, syn. nov.), A. niger Xu & He, 1999 (=A. nigricornis Xu, He & Olmi, 1999, syn. nov.), A. penanganus Olmi, 1984 (=A.olmii He & Xu, 2002, syn. nov.), Anteon cacumen Xu & He, 1997 (=A. longwangshanense Xu & He, 1997, syn. nov.), A. hilare Olmi, 1984 (=A. corax Olmi, 1984, syn. nov., =A. javanum Olmi, 1984, syn. nov., =A. serratum Xu & He, 1999, syn. nov.), A. lankanum Olmi, 1984 (=A. planum Xu & He, 1999, syn. nov.), A. munitum Olmi, 1984 (=A. bauense Olmi, 1984, syn. nov.), A. parapriscum Olmi, 1991 (=A. alpinum He & Xu, 2002, syn. nov.), A. peterseni Olmi, 1984 (=A. scrupulosum He & Xu, 2002, syn. nov.), A. yuani Xu, He & Olmi, 1998 (=A. yuae He & Xu, 2002, syn. nov.), Lonchodryinus bimaculatus Xu & He, 1994 (=L. niger He & Xu, 2002, syn. nov.), L. ruficornis (Dalman, 1818) (=L. melaphelus Xu & He, 1994, syn. nov.), Dryinus indicus (Kieffer, 1914) (=Chlorodryinus koreanus Moczar, 1983, syn. nov., =Dryinus masneri Olmi, 2009, syn. nov.), D. stantoni Ashmead, 1904 (=D. undatomarginis Xu & He, 1998, syn. nov., =D. wuyishanensis He & Xu, 2002, syn. nov.), Adryinus jini Xu & Yang, 1995 (=A. platycornis Xu & He, 1995, syn. nov.), Gonatopus nigricans (R. Perkins, 1905 (=G. fulgori Nakagawa, 1906, syn. nov., =G. insulanus He & Xu, 1998, syn. nov., Pseudogonatopus sogatea Rohwer, 1920, syn. nov.; P. pusanus Olmi, 1984, syn. nov.), G. nudus (R. Perkins, 1912) (=G. yangi He & Xu, 1998, syn. nov.), G. pedestris Dalman, 1818 (=Epigonatopus sakaii Esaki & Hashimoto, 1933, syn. nov.), G. rufoniger Olmi, 1993 (=Neodryinus hishimonovorus Xu & He, 1997, syn. nov.), G. schen-klingi Strand, 1913 (=G. euscelidivorus Xu & He, 1999, syn. nov.). New combinations are proposed for Deinodryinus con-strictus (Olmi, 1998), comb. nov. (from Anteon), Dryinus asiaticus (Olmi, 1984), comb. nov. (from Alphadryinus), D. barbarus (Olmi, 1984), comb. nov. (from Mesodryinus), Gonatopus bengalensis (Olmi, 1984), comb. nov. (from Agona-topoides ), G. bicuspis (Olmi, 1993), comb. nov. (from Pseudogonatopus), G. borneanus (Olmi, 1984), comb. nov. (from Agonatopoides ); G. indicus (Olmi, 1987), comb. nov. (from Donisthorpina), G. insularis (Olmi, 1984), comb. nov. (from Agonatopoides), G. lankae (Ponomarenko, 1981), comb. nov. (from Pseudogonatopus), G. malesiae (Olmi, 1984), comb. nov. (from Pseudogonatopus), G. nepalensis (Olmi, 1986), comb. nov. (from Pseudogonatopus), G. pajanensis (Olmi, 1989), comb. nov. (from Agonatopoides), G. pyrillae (Mani, 1942), comb. nov. (from Agonatopoides), G. sarawakensis (Olmi, 1984), comb. nov. (from Pseudogonatopus), G. validus (Olmi, 1984), comb. nov. (from Pseudogonatopus). PMID- 24759693 TI - Porphyromonas gingivalis: a heartful oral pathogen? PMID- 24759694 TI - Outcomes of tailored angioplasty and/or stenting for symptomatic intracranial atherosclerosis: a prospective cohort study after SAMMPRIS. AB - BACKGROUND AND PURPOSE: High periprocedural complication rate is a key limitation of endovascular treatment of intracranial atherosclerotic disease (ICAD), despite potential risk reduction of recurrent stroke. Taking lessons from the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Arterial Stenosis (SAMMPRIS) trial, targeting a selected patient population, we prospectively evaluated the feasibility and safety of tailored angioplasty and/or stenting for patients with ICAD. METHODS: From November 2011 to October 2012, 158 patients with symptomatic ICAD caused by hypoperfusion combined with poor collateral flow were consecutively recruited into a prospective single center study. Patients were divided into three groups based on arterial access and lesion morphology: balloon mounted stent group (group BS) for smooth access and Mori A lesion, angioplasty plus self-expanding stent group (group AS) for tortuous access and Mori B or C lesion, and angioplasty group (group AG) for tortuous access and Mori A lesion. The primary endpoints were successful procedure rate and any vascular event within 30 days. RESULTS: Overall technical success rate was 96.3% (154/158). There were significant differences in the technical success rate: 89.7% (35/39) in group AG compared with 97.5% (79/81) in group BS and 100% (38/38) in group AS (p=0.042). The 30 day composite stroke, myocardial infarction, or death rate was 4.4% (7/158). Stroke within 30 days occurred in four patients in group BS and in three patients in group AS. CONCLUSIONS: Individualized treatment of ICAD using tailored devices according to arterial access and lesion morphology was feasible and safe in symptomatic patients caused by hypoperfusion with poor collateral flow. PMID- 24759696 TI - Semi-automatic breast ultrasound image segmentation based on mean shift and graph cuts. AB - Computerized tumor segmentation on breast ultrasound (BUS) images remains a challenging task. In this paper, we proposed a new method for semi-automatic tumor segmentation on BUS images using Gaussian filtering, histogram equalization, mean shift, and graph cuts. The only interaction required was to select two diagonal points to determine a region of interest (ROI) on an input image. The ROI image was shrunken by a factor of 2 using bicubic interpolation to reduce computation time. The shrunken image was smoothed by a Gaussian filter and then contrast-enhanced by histogram equalization. Next, the enhanced image was filtered by pyramid mean shift to improve homogeneity. The object and background seeds for graph cuts were automatically generated on the filtered image. Using these seeds, the filtered image was then segmented by graph cuts into a binary image containing the object and background. Finally, the binary image was expanded by a factor of 2 using bicubic interpolation, and the expanded image was processed by morphological opening and closing to refine the tumor contour. The method was implemented with OpenCV 2.4.3 and Visual Studio 2010 and tested for 38 BUS images with benign tumors and 31 BUS images with malignant tumors from different ultrasound scanners. Experimental results showed that our method had a true positive rate (TP) of 91.7%, a false positive (FP) rate of 11.9%, and a similarity (SI) rate of 85.6%. The mean run time on Intel Core 2.66 GHz CPU and 4 GB RAM was 0.49 +/- 0.36 s. The experimental results indicate that the proposed method may be useful in BUS image segmentation. PMID- 24759695 TI - Persistence of Functional Sensory Maps in the Absence of Cortical Layers in the Somsatosensory Cortex of Reeler Mice. AB - In rodents, layer IV of the primary somatosensory cortex contains the barrel field, where individual, large facial whiskers are represented as a dense cluster of cells. In the reeler mouse, a model of disturbed cortical development characterized by a loss of cortical lamination, the barrel field exists in a distorted manner. Little is known about the consequences of such a highly disturbed lamination on cortical function in this model. We used in vivo intrinsic signal optical imaging together with piezo-controlled whisker stimulation to explore sensory map organization and stimulus representation in the barrel field. We found that the loss of cortical layers in reeler mice had surprisingly little incidence on these properties. The overall topological order of whisker representations is highly preserved and the functional activation of individual whisker representations is similar in size and strength to wild-type controls. Because intrinsic imaging measures hemodynamic signals, we furthermore investigated the cortical blood vessel pattern of both genotypes, where we also did not detect major differences. In summary, the loss of the reelin protein results in a widespread disturbance of cortical development which compromises neither the establishment nor the function of an ordered, somatotopic map of the facial whiskers. PMID- 24759698 TI - Predicting the bioconcentration factor of highly hydrophobic organic chemicals. AB - Bioconcentration refers to the process of uptake and buildup of chemicals in living organisms. Experimental measurement of bioconcentration factor (BCF) is time-consuming and expensive, and is not feasible for a large number of chemicals of regulatory concern. Quantitative structure-activity relationship (QSAR) models are used for estimating BCF values to help in risk assessment of a chemical. This paper presents the results of a QSAR study conducted to address an important problem encountered in the prediction of the BCF of highly hydrophobic chemicals. A new QSAR model is derived using a dataset of diverse organic chemicals previously tested in a United States Environmental Protection Agency laboratory. It is noted that the linear relationship between the BCF and hydrophobic parameter, i.e., calculated octanol-water partition coefficient (ClogP), breaks down for highly hydrophobic chemicals. The parabolic QSAR equation, log BCF=3.036 ClogP-0.197 ClogP(2)-0.808 MgVol (n=28, r(2)=0.817, q(2)=0.761, s=0.558) (experimental log BCF range=0.44-5.29, ClogP range=3.16-11.27), suggests that a non-linear relationship between BCF and the hydrophobic parameter, along with inclusion of additional molecular size, weight and/or volume parameters, should be considered while developing a QSAR model for more reliable prediction of the BCF of highly hydrophobic chemicals. PMID- 24759697 TI - Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12. AB - Posterior amorphous corneal dystrophy (PACD) is a rare, autosomal dominant disorder affecting the cornea and iris. Next-generation sequencing of the previously identified PACD linkage interval on chromosome 12q21.33 failed to yield a pathogenic mutation. However, array-based copy number analysis and qPCR were used to detect a hemizygous deletion in the PACD linkage interval containing 4 genes encoding small leucine-rich proteoglycans (SLRPs): KERA, LUM, DCN, and EPYC. Two other unrelated families with PACD also demonstrated deletion of these SLRPs, which play important roles in collagen fibrillogenesis and matrix assembly. Given that these genes are essential to the maintenance of corneal clarity and the observation that knockout murine models display corneal phenotypic similarities to PACD, we provide convincing evidence that PACD is associated with haploinsufficiency of these SLRPs. PMID- 24759699 TI - Comparison of fecal pyruvate kinase isoform M2 and calprotectin in acute diarrhea in hospitalized children. AB - Fecal concentrations of pyruvate kinase isoform M2 (M2-PK) and calprotectin (FC) serve as biomarkers of inflammation of gastrointestinal mucosa. The value of M2 PK in discriminating between patients with viral and bacterial acute diarrhea (AD) is currently unknown. We analyzed M2-PK and FC concentrations in fifty hospitalized children with AD (29 of which were caused by rotavirus and 21 by Salmonella enteritidis) as well as 32 healthy subjects. There was no difference in the areas under the receiver operating characteristic curves plotted for the two tests in differentiating rotaviral from bacterial AD. The sensitivity and specificity of M2-PK at optimal cut-off (20 U/g) were 75.9% and 71.4%, respectively. M2-PK and FC had similar values in distinguishing between children with AD caused by rotavirus and Salmonella enteritidis. The performance of both tests in hospitalized patients did not meet the needs of everyday clinical practice. Moreover, no advantage of fecal tests over the measurement of CRP was documented. PMID- 24759700 TI - Will Coral Islands maintain their growth over the next century? A deterministic model of sediment availability at Lady Elliot Island, Great Barrier Reef. AB - A geomorphic assessment of reef system calcification is conducted for past (3200 Ka to present), present and future (2010-2100) time periods. Reef platform sediment production is estimated at 569 m3 yr-1 using rate laws that express gross community carbonate production as a function of seawater aragonite saturation, community composition and rugosity and incorporating estimates of carbonate removal from the reef system. Key carbonate producers including hard coral, crustose coralline algae and Halimeda are mapped accurately (mean R2 = 0.81). Community net production estimates correspond closely to independent census-based estimates made in-situ (R2 = 0.86). Reef-scale outputs are compared with historic rates of production generated from (i) radiocarbon evidence of island deposition initiation around 3200 years ago, and (ii) island volume calculated from a high resolution island digital elevation model. Contemporary carbonate production rates appear to be remarkably similar to historical values of 573 m3 yr-1. Anticipated future seawater chemistry parameters associated with an RCP8.5 emissions scenario are employed to model rates of net community calcification for the period 2000-2100 on the basis of an inorganic aragonite precipitation law, under the assumption of constant benthic community character. Simulations indicate that carbonate production will decrease linearly to a level of 118 m3 yr-1 by 2100 and that by 2150 aragonite saturation levels may no longer support the positive budgetary status necessary to sustain island accretion. Novel aspects of this assessment include the development of rate law parameters to realistically represent the variable composition of coral reef benthic carbonate producers, incorporation of three dimensional rugosity of the entire reef platform and the coupling of model outputs with both historical radiocarbon dating evidence and forward hydrochemical projections to conduct an assessment of island evolution through time. By combining several lines of evidence in a deterministic manner, an assessment of changes in carbonate production is carried out that has tangible geomorphic implications for sediment availability and associated island evolution. PMID- 24759701 TI - Highly competitive reindeer males control female behavior during the rut. AB - During the rut, female ungulates move among harems or territories, either to sample mates or to avoid harassment. Females may be herded by a male, may stay with a preferred male, or aggregate near a dominant male to avoid harassment from other males. In fission-fusion group dynamics, female movement is best described by the group's fission probability, instead of inter-harem movement. In this study, we tested whether male herding ability, female mate choice or harassment avoidance influence fission probability. We recorded group dynamics in a herd of reindeer Rangifer tarandus equipped with GPS collars with activity sensors. We found no evidence that the harassment level in the group affected fission probability, or that females sought high rank (i.e. highly competitive and hence successful) males. However, the behavior of high ranked males decreased fission probability. Male herding activity was synchronous with the decrease of fission probability observed during the rut. We concluded that male herding behavior stabilized groups, thereby increasing average group size and consequently the opportunity for sexual selection. PMID- 24759702 TI - A method to assess target gene involvement in angiogenesis in vitro and in vivo using lentiviral vectors expressing shRNA. AB - Current methods to study angiogenesis in cancer growth and development can be difficult and costly, requiring extensive use of in vivo methodologies. Here, we utilized an in vitro adipocyte derived stem cell and endothelial colony forming cell (ADSC/ECFC) co-culture system to investigate the effect of lentiviral-driven shRNA knockdown of target genes compared to a non-targeting shRNA control on cord formation using High Content Imaging. Cord formation was significantly reduced following knockdown of the VEGF receptor VEGFR2 in VEGF-driven cord formation and the FGF receptor FGFR1 in basic FGF (bFGF)-driven cord formation. In addition, cord formation was significantly reduced following knockdown of the transcription factor forkhead box protein O1 (FOXO1), a protein with known positive effects on angiogenesis and blood vessel stabilization in VEGF- and bFGF-driven cord formation. Lentiviral shRNA also demonstrated utility for stable knockdown of VEGFR2 and FOXO1 in ECFCs, allowing for interrogation of protein knockdown effects on in vivo neoangiogenesis in a Matrigel plug assay. In addition to interrogating the effect of gene knockdown in endothelial cells, we utilized lentiviral shRNA to knockdown specificity protein 1 (SP1), a transcription factor involved in the expression of VEGF, in U-87 MG tumor cells to demonstrate the ability to analyze angiogenesis in vitro in a tumor-driven transwell cord formation system and in tumor angiogenesis in vivo. A significant reduction in tumor-driven cord formation, VEGF secretion, and in vivo tumor angiogenesis was observed upon SP1 knockdown. Therefore, evaluation of target gene knockdown effects in the in vitro co-culture cord formation assay in the ADSC/ECFC co culture, ECFCs alone, and in tumor cells translated directly to in vivo results, indicating the in vitro method as a robust, cost-effective and efficient in vitro surrogate assay to investigate target gene involvement in endothelial or tumor cell function in angiogenesis. PMID- 24759703 TI - Coxsackievirus cloverleaf RNA containing a 5' triphosphate triggers an antiviral response via RIG-I activation. AB - Upon viral infections, pattern recognition receptors (PRRs) recognize pathogen associated molecular patterns (PAMPs) and stimulate an antiviral state associated with the production of type I interferons (IFNs) and inflammatory markers. Type I IFNs play crucial roles in innate antiviral responses by inducing expression of interferon-stimulated genes and by activating components of the adaptive immune system. Although pegylated IFNs have been used to treat hepatitis B and C virus infections for decades, they exert substantial side effects that limit their use. Current efforts are directed toward the use of PRR agonists as an alternative approach to elicit host antiviral responses in a manner similar to that achieved in a natural infection. RIG-I is a cytosolic PRR that recognizes 5' triphosphate (5'ppp)-containing RNA ligands. Due to its ubiquitous expression profile, induction of the RIG-I pathway provides a promising platform for the development of novel antiviral agents and vaccine adjuvants. In this study, we investigated whether structured RNA elements in the genome of coxsackievirus B3 (CVB3), a picornavirus that is recognized by MDA5 during infection, could activate RIG-I when supplied with 5'ppp. We show here that a 5'ppp-containing cloverleaf (CL) RNA structure is a potent RIG-I inducer that elicits an extensive antiviral response that includes induction of classical interferon-stimulated genes, as well as type III IFNs and proinflammatory cytokines and chemokines. In addition, we show that prophylactic treatment with CVB3 CL provides protection against various viral infections including dengue virus, vesicular stomatitis virus and enterovirus 71, demonstrating the antiviral efficacy of this RNA ligand. PMID- 24759704 TI - The impact of linked selection on plant genomic variation. AB - Understanding the forces that shape patterns of genetic variation across the genome is a major aim in evolutionary genetics. An emerging insight from analyses of genome-wide polymorphism and divergence data is that selection on linked sites can have an important impact on neutral genetic variation. However, in contrast to Drosophila, which exhibits a signature of recurrent hitchhiking, many plant genomes studied so far seem to mainly be affected by background selection. Moreover, many plants do not exhibit classic signatures of linked selection, such as a correlation between recombination rate and neutral diversity. In this review, I discuss the impact of genome architecture and mating system on the expected signature of linked selection in plants and review empirical evidence for linked selection, with a focus on plant model systems. Finally, I discuss the implications of linked selection for inference of demographic history in plants. PMID- 24759705 TI - Revision of the genus Coletinia (Zygentoma: Nicoletiidae) in the Iberian Peninsula, with descriptions of nine new species. AB - The discovery of several members of the genus Coletinia Wygodzinsky, 1980, from subterranean habitats (endogean and troglobiont), prompted the review of this genus in the Iberian Peninsula. Most of the samples came from caves of the Mediterranean basin of Spain, from Cadiz to the Tarragona province. As a result of this revision, nine new species have been established: C. herculea n. sp., an endogean from Cadiz; C. vergitana n. sp. from the Gador calcareous mountains in Almeria; C. calaforrai n. sp. from the gypsum karst in Almeria; C. intermedia n. sp. from caves in Murcia and Alicante; C. diania n. sp., found in the north of the province of Alicante; C. longitibia n. sp. and C. tessella n. sp., both troglobites from Valencia; C. redetecta n. sp. from Castellon caves and finally C. hernandoi n. sp., an endogean from Tarragona. Moreover, Coletinia maggii (Grassi, 1887) is reported for the first time in the Iberian Peninsula, and new data are presented regarding C. mendesi, C. tinautiand C. capolongoi that widen their geographic distribution and enhance the information about their anatomic characteristics and biology. These results increase the number of known species of this genus to 14 in the region and to 21 in the world. The new species are described and compared with the most closely related previously known species of the genus. Characters with the most taxonomic relevance are discussed using optical and scanning microscope studies. A key for the identification of the Iberian Coletinia species and a distribution map including all of them are also provided. PMID- 24759706 TI - Bruker biotyper matrix-assisted laser desorption ionization-time of flight mass spectrometry system for identification of Nocardia, Rhodococcus, Kocuria, Gordonia, Tsukamurella, and Listeria species. AB - We evaluated whether the Bruker Biotyper matrix-associated laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system provides accurate species-level identifications of 147 isolates of aerobically growing Gram-positive rods (GPRs). The bacterial isolates included Nocardia (n = 74), Listeria (n = 39), Kocuria (n = 15), Rhodococcus (n = 10), Gordonia (n = 7), and Tsukamurella (n = 2) species, which had all been identified by conventional methods, molecular methods, or both. In total, 89.7% of Listeria monocytogenes, 80% of Rhodococcus species, 26.7% of Kocuria species, and 14.9% of Nocardia species (n = 11, all N. nova and N. otitidiscaviarum) were correctly identified to the species level (score values, >= 2.0). A clustering analysis of spectra generated by the Bruker Biotyper identified six clusters of Nocardia species, i.e., cluster 1 (N. cyriacigeorgica), cluster 2 (N. brasiliensis), cluster 3 (N. farcinica), cluster 4 (N. puris), cluster 5 (N. asiatica), and cluster 6 (N. beijingensis), based on the six peaks generated by ClinProTools with the genetic algorithm, i.e., m/z 2,774.477 (cluster 1), m/z 5,389.792 (cluster 2), m/z 6,505.720 (cluster 3), m/z 5,428.795 (cluster 4), m/z 6,525.326 (cluster 5), and m/z 16,085.216 (cluster 6). Two clusters of L. monocytogenes spectra were also found according to the five peaks, i.e., m/z 5,594.85, m/z 6,184.39, and m/z 11,187.31, for cluster 1 (serotype 1/2a) and m/z 5,601.21 and m/z 11,199.33 for cluster 2 (serotypes 1/2b and 4b). The Bruker Biotyper system was unable to accurately identify Nocardia (except for N. nova and N. otitidiscaviarum), Tsukamurella, or Gordonia species. Continuous expansion of the MALDI-TOF MS databases to include more GPRs is necessary. PMID- 24759707 TI - Current status of epidemiology and diagnosis of human sarcocystosis. AB - Species of Sarcocystis are Apicomplexan parasites requiring intermediate and definitive hosts to complete their life cycle. Humans are one of many natural host species and may serve as both intermediate and definitive hosts. However, the extent and public health significance of human Sarcocystis infection are incompletely known. In this minireview, we provide an update on the epidemiology and diagnosis of human sarcocystosis and propose some tools that could contribute to a better understanding of the clinical significance and epidemiology of Sarcocystis infections. PMID- 24759708 TI - Isolation and identification of an Enterobacter cloacae strain producing a novel subtype of Shiga toxin type 1. AB - We describe here the isolation and identification of a Shiga toxin 1 (Stx1) producing Enterobacter cloacae strain, M12X01451, from a human clinical specimen. The bacterial isolate was identified as E. cloacae using a polyphasic approach that included phenotypic, genetic, and proteomic analyses. The M12X01451 stx1 was sequenced, and the holotoxin was found to share only 87% amino acid sequence identity with the nearest Stx1 subtype reference sequence. Sequence analysis of the regions immediately flanking stx1 displayed similarities with bacteriophage related sequences, suggesting a prophage origin. The stx1 gene was a stable element within the M12X01451 genome, as demonstrated by real-time PCR detection following successive subculturing of the bacterial isolate. Culture supernatant from M12X01451 was cytotoxic to Vero cells but was not neutralized by an anti Stx1 monoclonal antibody. In addition, Stx1 from M12X01451 demonstrated limited antigenicity with two commercially available lateral flow immunoassays. The M12X01451 Stx represents a new Stx1 subtype based on the degree of sequence dissimilarity with Stx1 subtype reference sequences and its limited reactivity with anti-Stx1 antibodies. PMID- 24759709 TI - CarbAcineto NP test for rapid detection of carbapenemase-producing Acinetobacter spp. AB - Multidrug-resistant Acinetobacter baumannii isolates, particularly those that produce carbapenemases, are increasingly reported worldwide. The biochemically based Carba NP test, extensively validated for the detection of carbapenemase producers among Enterobacteriaceae and Pseudomonas spp., has been modified to detect carbapenemase production in Acinetobacter spp. A collection of 151 carbapenemase-producing and 69 non-carbapenemase-producing Acinetobacter spp. were tested using the Carba NP test and a modified Carba NP protocol (the CarbAcineto NP test) in this study. The CarbAcineto NP test requires modified lysis conditions and an increased bacterial inoculum compared to those of the original Carba NP test. The Carba NP test detects metallo-beta-lactamase producers but failed to detect the production of other carbapenemase types among Acinetobacter spp. In contrast, the newly designed CarbAcineto NP test, which is rapid and reproducible, detects all types of carbapenemases with a sensitivity of 94.7% and a specificity of 100%. This cost-effective technique offers a reliable and affordable technique for identifying carbapenemase production in Acinetobacter spp., which is a marker of multidrug resistance in those species. Its use will facilitate the recognition of these carbapenemases and prevent their spread. PMID- 24759710 TI - Mechanical homogenization increases bacterial homogeneity in sputum. AB - Sputum obtained from patients with cystic fibrosis (CF) is highly viscous and often heterogeneous in bacterial distribution. Adding dithiothreitol (DTT) is the standard method for liquefaction prior to processing sputum for molecular detection assays. To determine if DTT treatment homogenizes the bacterial distribution within sputum, we measured the difference in mean total bacterial abundance and abundance of Burkholderia multivorans between aliquots of DTT treated sputum samples with and without a mechanical homogenization (MH) step using a high-speed dispersing element. Additionally, we measured the effect of MH on bacterial abundance. We found a significant difference between the mean bacterial abundances in aliquots that were subjected to only DTT treatment and those of the aliquots which included an MH step (all bacteria, P = 0.04; B. multivorans, P = 0.05). There was no significant effect of MH on bacterial abundance in sputum. Although our results are from a single CF patient, they indicate that mechanical homogenization increases the homogeneity of bacteria in sputum. PMID- 24759711 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry can accurately differentiate Aeromonas dhakensis from A. hydrophila, A. caviae, and A. veronii. AB - Among 217 Aeromonas isolates identified by sequencing analysis of their rpoB genes, the accuracy rates of identification of A. dhakensis, A. hydrophila, A. veronii, and A. caviae were 96.7%, 90.0%, 96.7%, and 100.0%, respectively, by the cluster analysis of spectra generated by matrix-assisted laser desorption ionization-time of flight mass spectrometry. PMID- 24759712 TI - Norovirus GII.4 detection in environmental samples from patient rooms during nosocomial outbreaks. AB - Norovirus (NoV) is an important cause of nosocomial gastroenteric outbreaks. This 5-month study was designed to characterize NoV contamination and airborne dispersal in patient rooms during hospital outbreaks. Air vents, overbed tables, washbasins, dust, and virus traps designed to collect charged particles from the air were swabbed to investigate the possibility of NoV contamination in patient rooms during outbreaks in seven wards and in an outbreak-free ward. Symptomatic inpatients were also sampled. Nucleic acid extracts of the samples were examined for NoV RNA using genogroup I (GI) and GII real-time reverse transcription-PCR (RT-PCR). The NoV strains were characterized by RT-PCR, sequencing, and phylogenetic analysis of the RNA-dependent RNA-polymerase-N/S capsid-coding region (1,040 nucleotides [nt]). Patient strains from two outbreaks in one ward were sequenced across the RNA-dependent-RNA-polymerase major capsid-coding region (2.5 kb), including the hypervariable P2 domain. In the outbreak wards, NoV GII was detected in 48 of 101 (47%) environmental swabs and 63 of 108 patients (58%); NoV genotype II.4 was sequenced from 18 environmental samples, dust (n = 8), virus traps (n = 4), surfaces (n = 6), and 56 patients. In contrast, NoV GII was detected in 2 (GII.4) of 28 (7%) environmental samples and in 2 (GII.6 and GII.4) of 17 patients in the outbreak-free ward. Sequence analyses revealed a high degree of similarity (>99.5%, 1,040 nt) between NoV GII.4 environmental and patient strains from a given ward at a given time. The strains clustered on 11 subbranches of the phylogenetic tree, with strong correlations to time and place. The high nucleotide similarity between the NoV GII.4 strains from patients and their hospital room environment provided molecular evidence of GII.4 dispersal in the air and dust; therefore, interventional cleaning studies are justified. PMID- 24759714 TI - Molecular test based on isothermal helicase-dependent amplification for detection of the Clostridium difficile toxin A gene. AB - The AmpliVue Clostridium difficile assay and a glutamate dehydrogenase (GDH) illumigene algorithm were evaluated using 308 diarrheal stool specimens of patients suspected of having C. difficile infection. Compared to the enriched toxigenic culture method, the sensitivities, specificities, and positive and negative predictive values of the AmpliVue C. difficile assay and the GDH illumigene-based algorithm were 91.7% (95% confidence interval [CI], 76.4 to 97.8), 100% (95% CI, 98.3 to 100), 100% (95% CI, 87 to 100), and 98.9% (95% CI, 96.6 to 99.7), respectively. PMID- 24759715 TI - Novel selective medium for isolation of Staphylococcus lugdunensis from wound specimens. AB - We compared a novel selective Staphylococcus lugdunensis (SSL) medium with routine media (blood and chocolate agars) for the detection of S. lugdunensis in 990 clinical specimens (from tissue, pus, or wound swabs). Significantly more S. lugdunensis isolates were detected on SSL medium (34/990) than on routine medium (7/990) (P = 0.001, McNemar's test). PMID- 24759716 TI - Determination of disk diffusion and MIC quality control guidelines for GSK2140944, a novel bacterial type II topoisomerase inhibitor antimicrobial agent. AB - GSK2140944 is a novel bacterial type II topoisomerase inhibitor in development for the treatment of conventional and biothreat pathogens, including Gram positive pathogens and methicillin-resistant Staphylococcus aureus. This quality control study was performed to establish ranges for selected control strains: S. aureus ATCC 29213 and ATCC 25923, Escherichia coli ATCC 25922, Haemophilus influenzae ATCC 49247, and Streptococcus pneumoniae ATCC 49619. The control ranges will be crucial for the accurate evaluation of GSK2140944 potency as it progresses through clinical trial development. PMID- 24759717 TI - Multiplex PCR assay for unequivocal differentiation of Actinobacillus pleuropneumoniae serovars 1 to 3, 5 to 8, 10, and 12. AB - An improved multiplex PCR, using redesigned primers targeting the serovar 3 capsule locus, which differentiates serovars 3, 6, and 8 Actinobacillus pleuropneumoniae isolates, is described. The new primers eliminate an aberrant serovar 3-indicative amplicon found in some serovar 6 clinical isolates. Furthermore, we have developed a new multiplex PCR for the detection of serovars 1 to 3, 5 to 8, 10, and 12 along with apxIV, thus extending the utility of this diagnostic PCR to cover a broader range of isolates. PMID- 24759718 TI - Retrospective study of etiologic agents associated with nonsuppurative meningoencephalitis in stranded cetaceans in the canary islands. AB - Nineteen natural cases of etiologically undetermined encephalitides in free ranging cetaceans were studied retrospectively. Histological examination of the brains revealed variable degrees of nonsuppurative encephalitis or meningoencephalitis, characterized predominantly by perivascular lymphohistiocytic infiltrates. A PCR assay was used on brain and other available tissues to detect the presence of morbillivirus, herpesvirus, West Nile virus, Toxoplasma gondii, and Brucella spp. In addition, immunohistochemical (IHC) staining was performed on selected tissues to determine the presence of morbilliviral antigens. Six animals (5 striped dolphins and 1 common dolphin) showed IHC and/or molecular evidence of morbilliviral antigens and/or genomes, mainly in brain tissue. Conventional nested PCR detected herpesviral DNA in brain tissue samples from two striped dolphins. There was no evidence of West Nile virus, T. gondii, or Brucella spp. in any of the brain tissue samples examined. The information presented here increases the number of confirmed morbillivirus positive cases within the Canarian archipelago from two previously reported cases to eight. Furthermore, a new nested-PCR method for the detection of morbillivirus is described here. Regarding herpesvirus, the phylogenetic analysis performed in the current study provides valuable information about a possible pathogenic branch of cetacean alphaherpesviruses that might be responsible for some fatal cases worldwide. PMID- 24759713 TI - Bacterial whole-genome sequencing revisited: portable, scalable, and standardized analysis for typing and detection of virulence and antibiotic resistance genes. AB - Multidrug-resistant nosocomial pathogens present a major burden for hospitals. Rapid cluster identification and pathogen profiling, i.e., of antibiotic resistance and virulence genes, are crucial for effective infection control. Methicillin-resistant Staphylococcus aureus (MRSA), in particular, is now one of the leading causes of nosocomial infections. In this study, whole-genome sequencing (WGS) was applied retrospectively to an unusual spike in MRSA cases in two intensive care units (ICUs) over the course of 4 weeks. While the epidemiological investigation concluded that there were two separate clusters, each associated with one ICU, S. aureus protein A gene (spa) typing data suggested that they belonged to single clonal cluster (all cases shared spa type t001). Standardized gene sets were used to extract an allele-based profile for typing and an antibiotic resistance and toxin gene profile. The WGS results produced high-resolution allelic profiles, which were used to discriminate the MRSA clusters, corroborating the epidemiological investigation and identifying previously unsuspected transmission events. The antibiotic resistance profile was in agreement with the original clinical laboratory susceptibility profile, and the toxin profile provided additional, previously unknown information. WGS coupled with allelic profiling provided a high-resolution method that can be implemented as regular screening for effective infection control. PMID- 24759719 TI - Mycoplasma genitalium infection is associated with microscopic signs of cervical inflammation in liquid cytology specimens. AB - Cervicitis is a common clinical finding often attributed to sexually transmitted infections (STIs), but no etiologic agent is identified in the majority of cases. In this study, we comparatively assessed inflammation among the common infectious etiologies of cervicitis and assessed the potential value of liquid cytology specimens for predicting STIs. Among 473 Louisiana women at low risk for acquiring STIs, the prevalences of Mycoplasma genitalium, Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis in liquid-based cytology specimens were 1.5, 2.1, 0.6, and 4.4%, respectively. N. gonorrhoeae and human papillomavirus 18 (HPV18) infections were significantly more common among subjects infected with M. genitalium. Using direct microscopy, we observed significant increases in leukocyte infiltrates among subjects with monoinfections with M. genitalium or C. trachomatis compared to women with no detectable STIs. Inflammation was highest among subjects with M. genitalium. Using a threshold of >= 2 leukocytes per epithelial cell per high-powered field, the positive predictive values for M. genitalium, C. trachomatis, N. gonorrhoeae, and T. vaginalis were 100, 70, 67, and 20%, respectively. Several novel M. genitalium genotypes were identified, all of which were predicted to be susceptible to macrolide antibiotics, suggesting that different strains may circulate among low risk women and that macrolide resistance is substantially lower than in high-risk populations. This study highlights the capacity of M. genitalium to elicit cervical inflammation and, considering the strong epidemiologic associations between M. genitalium and human immunodeficiency virus (HIV), provides a potential mechanism for acquisition and shedding of HIV via chronic leukocyte recruitment to the cervical mucosa. PMID- 24759720 TI - Validation of a microbead-based format for spoligotyping of Legionella pneumophila. AB - A 42-plex clustered regularly interspaced short palindromic repeat (CRISPR)-based typing technique (spoligotyping) was recently developed at the French National Reference Center for Legionella. It allows the subtyping of the Legionella pneumophila sequence type 1/Paris pulsotype. In this report, we present the transfer of the membrane-based spoligotyping technique to a microbead-based multiplexed format. This microbead-based high-throughput assay uses devices such as Luminex 200 or the recently launched Magpix system (Luminex Corp., Austin, TX). We designated this new technique LP-SPOL (for L. pneumophila spoligotyping). We used two sets of samples previously subtyped by the membrane-based spoligotyping method to set up and validate the transfer on the two microbead based systems. The first set of isolates (n = 56) represented the whole diversity of the CRISPR patterns known to date. These isolates were used for transfer setup (determination of spacer cutoffs for both devices). The second set of isolates (n = 245) was used to validate the transfer to the two microbead-based systems. The results obtained by the Luminex 200 system were 100% concordant with those obtained by the Magpix system for the 2 sets of isolates. In total, 10 discrepant results were observed when comparing the membrane-based method to the microbead based method. These discrepancies were further resolved by repeating either the membrane-based or the microbead-based assay. This new assay is expected to play an emerging role for surveillance of L. pneumophila, starting with one of the most frequent genotypes, the sequence type 1/Paris pulsotype. However, the generalization of this typing method to all L. pneumophila strains is not feasible, since not all L. pneumophila strains contain CRISPRs. PMID- 24759721 TI - Usefulness of Pneumotest-latex for direct serotyping of Streptococcus pneumoniae isolates in clinical samples. AB - This study evaluated the usefulness of the Pneumotest-Latex assay for serotyping Streptococcus pneumoniae isolates directly in clinical samples. With an agreement of 88.1% with a PCR-based reference method, this test can be a useful tool for this study purpose, especially in clinical laboratories that do not have access to nucleic acid amplification technologies. PMID- 24759722 TI - Comparison of ESwab with traditional swabs for detection of methicillin-resistant Staphylococcus aureus using two different walk-away commercial real-time PCR methods. AB - The ESwab system (Copan Diagnostics) was evaluated as a nasopharyngeal specimen collection device to be used for methicillin-resistant Staphylococcus aureus (MRSA) detection by the GeneXpert and BD Max MRSA assays. Different MRSA strains and dilutions of each strain were tested in triplicate. ESwabs proved to be a suitable collection system for the two assays tested. PMID- 24759723 TI - Molecular epidemiology and identification of a Staphylococcus aureus clone causing food poisoning outbreaks in Japan. AB - Molecular characterization of isolates from staphylococcal food poisoning (SFP) outbreaks in Japan showed that the dominant lineage causing SFP outbreaks is clonal complex 81 (CC81), a single-locus variant of sequence type 1, coagulase type VII, positive for sea and/or seb, and positive for seh. Among various CC lineages producing staphylococcal enterotoxin A, CC81 showed the highest toxin productivity. PMID- 24759724 TI - Pediatric multicenter evaluation of the Verigene gram-negative blood culture test for rapid detection of inpatient bacteremia involving gram-negative organisms, extended-spectrum beta-lactamases, and carbapenemases. AB - We evaluated the investigational use only (IUO) version of the rapid Verigene Gram-negative blood culture test (BC-GN), a microarray that detects 9 genus/species targets (Acinetobacter spp., Citrobacter spp., Enterobacter spp., Escherichia coli/Shigella spp., Klebsiella oxytoca, Klebsiella pneumoniae, Proteus spp., Pseudomonas aeruginosa, and Serratia marcescens) and 6 antimicrobial resistance determinants (blaCTX-M, blaKPC, blaNDM, blaVIM, blaIMP, and blaOXA) directly from positive blood cultures. BC-GN was performed on positive BacT/Alert Pediatric FAN and Bactec Peds Plus blood cultures with Gram negative organisms at two tertiary pediatric centers. Vitek MS (bioMerieux, Durham, NC) was used to assign gold standard organism identification. The Check MDR CT-102 microarray (Check Points B.V., Wageningen, Netherlands) was used as an alternative method for detecting resistance determinants. In total, 104 organisms were isolated from 97 clinical blood cultures. BC-GN correctly detected 26/26 cultures with Acinetobacter spp., P. aeruginosa, and S. marcescens, 5/6 with Citrobacter spp., 13/14 with Enterobacter spp., 23/24 with E. coli, 2/3 with K. oxytoca, 16/17 with K. pneumoniae, and 0/1 with Proteus spp. BC-GN appropriately reported negative BC-GN results in 8/13 blood cultures that grew organisms that were not represented on the microarray but failed to detect targets in 3/5 cultures that grew multiple Gram-negative organisms. BC-GN detected 5/5 and 1/1 clinical blood cultures with blaCTX-M and blaVIM. All 6 results were corroborated by Check MDR CT-102 microarray testing. The Verigene BC-GN test has the potential to expedite therapeutic decision making in pediatric patients with Gram-negative bacteremia. Sensitivity was satisfactory but may be suboptimal in mixed Gram negative blood cultures. PMID- 24759726 TI - Antimicrobial susceptibility of Campylobacter jejuni and Campylobacter coli isolates obtained in Montreal, Quebec, Canada, from 2002 to 2013. AB - From 2002 to 2013 in Montreal, Quebec, Canada, 38 Campylobacter coli isolates were more frequently erythromycin, tetracycline, and ciprofloxacin resistant than 440 Campylobacter jejuni subsp. jejuni isolates (18.4% versus 1.8%; P = 0.00005), of which the 148 isolates acquired abroad were more frequently erythromycin, tetracycline, and ciprofloxacin resistant than the 292 isolates acquired locally (5.4% versus 0%; P = 0.0001). PMID- 24759725 TI - Cross-infection of solid organ transplant recipients by a multidrug-resistant Klebsiella pneumoniae isolate producing the OXA-48 carbapenemase, likely derived from a multiorgan donor. AB - We describe two cases of bacteremic infections caused by a multidrug-resistant Klebsiella pneumoniae isolate producing the OXA-48 carbapenemase that occurred in two solid organ transplant (liver and kidney) recipients, which was apparently transmitted with the allografts. This finding underscores the risk of donor derived infections by multidrug-resistant Gram-negative pathogens in solid organ transplant recipients and emphasizes the need for rapid screening of organ donors for carriage of similar pathogens. PMID- 24759727 TI - Prevalence and duration of asymptomatic Clostridium difficile carriage among healthy subjects in Pittsburgh, Pennsylvania. AB - Previous studies suggested that 7 to 15% of healthy adults are colonized with toxigenic Clostridium difficile. To investigate the epidemiology, genetic diversity, and duration of C. difficile colonization in asymptomatic persons, we recruited healthy adults from the general population in Allegheny County, Pennsylvania. Participants provided epidemiological and dietary intake data and submitted stool specimens. The presence of C. difficile in stool specimens was determined by anaerobic culture. Stool specimens yielding C. difficile underwent nucleic acid testing of the tcdA gene segment with a commercial assay; tcdC genotyping was performed on C. difficile isolates. Subjects positive for C. difficile by toxigenic anaerobic culture were asked to submit additional specimens. One hundred six (81%) of 130 subjects submitted specimens, and 7 (6.6%) of those subjects were colonized with C. difficile. Seven distinct tcdC genotypes were observed among the 7 C. difficile-colonized individuals, including tcdC genotype 20, which has been found in uncooked ground pork in this region. Two (33%) out of 6 C. difficile-colonized subjects who submitted additional specimens tested positive for identical C. difficile strains on successive occasions, 1 month apart. The prevalence of C. difficile carriage in this healthy cohort is concordant with prior estimates. C. difficile-colonized individuals may be important reservoirs for C. difficile and may falsely test positive for infections due to C. difficile when evaluated for community-acquired diarrhea caused by other enteric pathogens. PMID- 24759728 TI - Sample sequencing of vascular plants demonstrates widespread conservation and divergence of microRNAs. AB - Small RNAs are pivotal regulators of gene expression that guide transcriptional and post-transcriptional silencing mechanisms in eukaryotes, including plants. Here we report a comprehensive atlas of sRNA and miRNA from 3 species of algae and 31 representative species across vascular plants, including non-model plants. We sequence and quantify sRNAs from 99 different tissues or treatments across species, resulting in a data set of over 132 million distinct sequences. Using miRBase mature sequences as a reference, we identify the miRNA sequences present in these libraries. We apply diverse profiling methods to examine critical sRNA and miRNA features, such as size distribution, tissue-specific regulation and sequence conservation between species, as well as to predict putative new miRNA sequences. We also develop database resources, computational analysis tools and a dedicated website, http://smallrna.udel.edu/. This study provides new insights on plant sRNAs and miRNAs, and a foundation for future studies. PMID- 24759729 TI - Core state preconception health indicators - pregnancy risk assessment monitoring system and behavioral risk factor surveillance system, 2009. AB - PROBLEM/CONDITION: Promoting preconception health can potentially improve women's health and pregnancy outcomes. Evidence-based interventions exist to reduce many maternal behaviors and chronic conditions that are associated with adverse pregnancy outcomes such as tobacco use, alcohol use, inadequate folic acid intake, obesity, hypertension, and diabetes. The 2006 national recommendations to improve preconception health included monitoring improvements in preconception health by maximizing public health surveillance (CDC. Recommendations to improve preconception health and health care-United States: a report of the CDC/ATSDR Preconception Care Work Group and the Select Panel on Preconception Care. MMWR 2006;55[No. RR-6]). REPORTING PERIOD COVERED: 2009 for 38 indicators; 2008 for one indicator. DESCRIPTION OF SURVEILLANCE SYSTEMS: The Pregnancy Risk Assessment Monitoring System (PRAMS) is an ongoing state- and population-based surveillance system designed to monitor selected self-reported maternal behaviors, conditions, and experiences that occur shortly before, during, and after pregnancy among women who deliver live-born infants. The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing state-based telephone survey of noninstitutionalized adults aged >=18 years in the United States that collects state-level data on health-related risk behaviors, chronic conditions, and preventive health services. This surveillance summary includes PRAMS data from 29 reporting areas (n = 40,388 respondents) and BRFSS data from 51 reporting areas (n = 62,875 respondents) for nonpregnant women of reproductive age (aged 18-44 years). To establish a comprehensive, nationally recognized set of indicators to be used for monitoring, evaluation, and response, a volunteer group of policy and program leaders and epidemiologists identified 45 core state preconception health indicators, of which 41 rely on PRAMS or BRFSS as data sources. This report includes 39 of the 41 core state preconception health indicators for which data are available through PRAMS or BRFSS. The two indicators from these data sources that are not described in this report are human immunodeficiency virus (HIV) testing within a year before the most recent pregnancy and heavy drinking on at least one occasion during the preceding month. Ten preconception health domains are examined: general health status and life satisfaction, social determinants of health, health care, reproductive health and family planning, tobacco and alcohol use, nutrition and physical activity, mental health, emotional and social support, chronic conditions, and infections. Weighted prevalence estimates and 95% confidence intervals (95% CIs)for 39 indicators are presented overall and for each reporting area and stratified by age group (18-24, 25-34, and 35-44 years) and women's race/ethnicity (non-Hispanic white, non-Hispanic black, non-Hispanic other, and Hispanic). RESULTS: This surveillance summary includes data for 39 of 41 indicators: 2009 data for 23 preconception health indicators that were monitored by PRAMS and 16 preconception health indicators that were monitored by BRFSS (one BRFSS indicator uses 2008 data). For two of the indicators that are included in this report (prepregnancy overweight or obesity and current overweight or obesity), separate measures of overweight and obesity were reported. All preconception health indicators varied by reporting area, and most indicators varied significantly by age group and race/ethnicity. Overall, 88.9% of women of reproductive age reported good, very good, or excellent general health status and life satisfaction (BRFSS). A high school/general equivalency diploma or higher education (social determinants of health domain) was reported by 94.7% of non-Hispanic white, 92.9% of non-Hispanic other, 91.1% of non Hispanic black, and 70.9% of Hispanic women (BRFSS). Overall, health-care insurance coverage during the month before the most recent pregnancy (health-care domain) was 74.9% (PRAMS). A routine checkup during the preceding year was reported by 79.0% of non-Hispanic black, 65.1% of non-Hispanic white, 64.3% of other, and 63.0% of Hispanic women (BRFSS). Among women with a recent live birth (2-9 months since date of delivery), selected PRAMS results for the reproductive health and family planning, tobacco and alcohol use, and nutrition domains included several factors. Although 43% of women reported that their most recent pregnancy was unintended (unwanted or wanted to be pregnant later), approximately half (53%) of those who were not trying to get pregnant reported not using contraception at the time of conception. Smoking during the 3 months before pregnancy was reported by 25.1% of women, and drinking alcohol 3 months before pregnancy was reported by 54.2% of women. Daily use of a multivitamin, prenatal vitamin, or a folic acid supplement during the month before pregnancy was reported by 29.7% of women. Selected BRFSS results included indicators pertaining to the nutrition and physical activity, emotional and social support, and chronic conditions domains among women of reproductive age. Approximately one fourth (24.7%) of women were identified as being obese according to body mass index (BMI) on the basis of self-reported height and weight. Overall, 51.6% of women reported participation in recommended levels of physical activity per U.S. Department of Health and Human Services physical activity guidelines. Non Hispanic whites reported the highest prevalence (85.0%) of having adequate emotional and social support, followed by other races/ethnicities (74.9%), Hispanics (70.5%), and non-Hispanic blacks (69.7%). Approximately 3.0% of persons reported ever being diagnosed with diabetes, and 10.2% of women reported ever being diagnosed with hypertension. INTERPRETATION: The findings in this report underscore opportunities for improving the preconception health of U.S. women. Preconception health and women's health can be improved by reducing unintended pregnancies, reducing risky behaviors (e.g., smoking and drinking) among women of reproductive age, and ensuring that chronic conditions are under control. Evidence-based interventions and clinical practice guidelines exist to address these risks and to improve pregnancy outcomes and women's health in general. The results also highlight the need to increase access to health care for all nonpregnant women of reproductive age and the need to encourage the use of essential preventive services for women, including preconception health services. In addition, system changes in community settings can alleviate health problems resulting from inadequate social and emotional support and environments that foster unhealthy lifestyles. Policy changes can promote health equity by encouraging environments that promote healthier options in nutrition and physical activity. Finally, variation in the preconception health status of women by age and race/ethnicity underscores the need for implementing and scaling up proven strategies to reduce persistent health disparities among those at highest risk. Ongoing surveillance and research in preconception health are needed to monitor the influence of improved health-care access and coverage on women's prepregnancy and interpregnancy health status, pregnancy and infant outcomes, and health disparities. PUBLIC HEALTH ACTION: Public health decision makers, program planners, researchers, and other key stakeholders can use the state-level PRAMS and BRFSS preconception health indicators to benchmark and monitor preconception health among women of reproductive age. These data also can be used to evaluate the effectiveness of preconception health state and national programs and to assess the need for new programs, program enhancements, and policies. PMID- 24759730 TI - Non-thermal atmospheric pressure plasma preferentially induces apoptosis in p53 mutated cancer cells by activating ROS stress-response pathways. AB - Non-thermal atmospheric pressure plasma (NTAPP) is an ionized gas at room temperature and has potential as a new apoptosis-promoting cancer therapy that acts by generating reactive oxygen species (ROS). However, it is imperative to determine its selectivity and standardize the components and composition of NTAPP. Here, we designed an NTAPP-generating apparatus combined with a He gas feeding system and demonstrated its high selectivity toward p53-mutated cancer cells. We first determined the proper conditions for NTAPP exposure to selectively induce apoptosis in cancer cells. The apoptotic effect of NTAPP was greater for p53-mutated cancer cells; artificial p53 expression in p53-negative HT29 cells decreased the pro-apoptotic effect of NTAPP. We also examined extra- and intracellular ROS levels in NTAPP-treated cells to deduce the mechanism of NTAPP action. While NTAPP-mediated increases in extracellular nitric oxide (NO) did not affect cell viability, intracellular ROS increased under NTAPP exposure and induced apoptotic cell death. This effect was dose-dependently reduced following treatment with ROS scavengers. NTAPP induced apoptosis even in doxorubicin-resistant cancer cell lines, demonstrating the feasibility of NTAPP as a potent cancer therapy. Collectively, these results strongly support the potential of NTAPP as a selective anticancer treatment, especially for p53 mutated cancer cells. PMID- 24759731 TI - Depletion of FKBP51 in female mice shapes HPA axis activity. AB - Psychiatric disorders such as depressive disorders and posttraumatic stress disorder are a major disease burden worldwide and have a higher incidence in women than in men. However, the underlying mechanism responsible for the sex dependent differences is not fully understood. Besides environmental factors such as traumatic life events or chronic stress, genetic variants contribute to the development of such diseases. For instance, variations in the gene encoding the FK506 binding protein 51 (FKBP51) have been repeatedly associated with mood and anxiety. FKBP51 is a negative regulator of the glucocorticoid receptor and thereby of the hypothalamic-pituitary-adrenal axis that also interacts with other steroid hormone receptors such as the progesterone and androgen receptors. Thus, the predisposition of women to psychiatric disorders and the interaction of female hormones with FKBP51 and the glucocorticoid receptor implicate a possible difference in the regulation of the hypothalamic-pituitary-adrenal axis in female FKBP51 knockout (51KO) mice. Therefore, we investigated neuroendocrine, behavioural and physiological alterations relevant to mood disorders in female 51KO mice. Female 51KOs and wild type littermates were subjected to various behavioural tests, including the open field, elevated plus maze and forced swim test. The neuroendocrine profile was investigated under basal conditions and in response to an acute stressor. Furthermore, we analysed the mRNA expression levels of the glucocorticoid receptor and corticotrophin release hormone in different brain regions. Overall, female 51KO mice did not display any overt behavioural phenotype under basal conditions, but showed a reduced basal hypothalamic-pituitary-adrenal axis activity, a blunted response to, and an enhanced recovery from, acute stress. These characteristics strongly overlap with previous studies in male 51KO mice indicating that FKBP51 shapes the behavioural and neuroendocrine phenotype independent of the sex of the individual. PMID- 24759734 TI - Sunitinib suppress neuroblastoma growth through degradation of MYCN and inhibition of angiogenesis. AB - Neuroblastoma, a tumor of the peripheral sympathetic nervous system, is the most common and deadly extracranial tumor of childhood. The majority of high-risk neuroblastoma exhibit amplification of the MYCN proto-oncogene and increased neoangiogenesis. Both MYCN protein stabilization and angiogenesis are regulated by signaling through receptor tyrosine kinases (RTKs). Therefore, inhibitors of RTKs have a potential as a treatment option for high-risk neuroblastoma. We used receptor tyrosine kinase antibody arrays to profile the activity of membrane bound RTKs in neuroblastoma and found the multi-RTK inhibitor sunitinib to tailor the activation of RTKs in neuroblastoma cells. Sunitinib inhibited several RTKs and demonstrated potent antitumor activity on neuroblastoma cells, through induction of apoptosis and cell cycle arrest. Treatment with sunitinib decreased MYCN protein levels by inhibition of PI3K/AKT signaling and GSK3beta. This effect correlates with a decrease in VEGF secretion in neuroblastoma cells with MYCN amplification. Sunitinib significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude mice and demonstrated an anti-angiogenic effect in vivo with a reduction of tumor vasculature and a decrease of MYCN expression. These results suggest that sunitinib should be tested as a treatment option for high risk neuroblastoma patients. PMID- 24759732 TI - Genetic polymorphism of cytochrome P450 4F2, vitamin E level and histological response in adults and children with nonalcoholic fatty liver disease who participated in PIVENS and TONIC clinical trials. AB - Vitamin E improved liver histology in children and adults with NAFLD who participated in TONIC and PIVENS clinical trials, but with significant inter individual variability in its efficacy. Cytochrome P450 4F2 (CYP4F2) is the major enzyme metabolizing Vit E, with two common genetic variants (V433M, rs2108622 and W12G, rs3093105) found to alter its activity. We investigated the relationship between CYP4F2 genotypes, alpha-tocopherol levels and histological improvement in these two trials. V433M and W12G variants were genotyped in TONIC (n = 155) and PIVENS (n = 213) DNA samples. The relationships between CYP4F2 genotypes, plasma alpha-tocopherol levels at baseline and weeks 48 (w48) and 96 (w96) and histological end points (overall improvement in liver histology and resolution of NASH) were investigated. As a result, the V433M genotype was significantly associated with baseline plasma alpha-tocopherol in the TONIC trial (p = 0.004), but not in PIVENS. Among those receiving Vit E treatment, CYP4F2 V433M genotype was associated with significantly decreased plasma alpha-tocopherol levels at w48 (p = 0.003 for PIVENS and p = 0.026 for TONIC) but not at w96. The w96 alpha tocopherol level was significantly associated with resolution of NASH (p = 0.006) and overall histology improvement (p = 0.021)in the PIVENS, but not in the TONIC trial. There was no significant association between CYP4F2 genotypes and histological end points in either trial. Our study suggested the a moderate role of CYP4F2 polymorphisms in affecting the pharmacokinetics of Vit E as a therapeutic agent. In addition, there may be age-dependent relationship between CYP4F2 genetic variability and Vit E pharmacokinetics in NAFLD. PMID- 24759735 TI - Fluoride and arsenic exposure impairs learning and memory and decreases mGluR5 expression in the hippocampus and cortex in rats. AB - Fluoride and arsenic are two common inorganic contaminants in drinking water that are associated with impairment in child development and retarded intelligence. The present study was conducted to explore the effects on spatial learning, memory, glutamate levels, and group I metabotropic glutamate receptors (mGluRs) expression in the hippocampus and cortex after subchronic exposure to fluoride, arsenic, and a fluoride and arsenic combination in rats. Weaned male Sprague Dawley rats were assigned to four groups. The control rats drank tap water. Rats in the three exposure groups drank water with sodium fluoride (120 mg/L), sodium arsenite (70 mg/L), and a sodium fluoride (120 mg/L) and sodium arsenite (70 mg/L) combination for 3 months. Spatial learning and memory was measured in Morris water maze. mGluR1 and mGluR5 mRNA and protein expression in the hippocampus and cortex was detected using RT-PCR and Western blot, respectively. Compared with controls, learning and memory ability declined in rats that were exposed to fluoride and arsenic both alone and combined. Combined fluoride and arsenic exposure did not have a more pronounced effect on spatial learning and memory compared with arsenic and fluoride exposure alone. Compared with controls, glutamate levels decreased in the hippocampus and cortex of rats exposed to fluoride and combined fluoride and arsenic, and in cortex of arsenic-exposed rats. mGluR5 mRNA and protein expressions in the hippocampus and mGluR5 protein expression in the cortex decreased in rats exposed to arsenic alone. Interestingly, compared with fluoride and arsenic exposure alone, fluoride and arsenic combination decreased mGluR5 mRNA expression in the cortex and protein expression in the hippocampus, suggesting a synergistic effect of fluoride and arsenic. These data indicate that fluoride and arsenic, either alone or combined, can decrease learning and memory ability in rats. The mechanism may be associated with changes of glutamate level and mGluR5 expression in cortex and hippocampus. PMID- 24759736 TI - Brd4 is essential for IL-1beta-induced inflammation in human airway epithelial cells. AB - BACKGROUND: Chronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-kappaB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as "readers" of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells. METHODS: Human primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL 1beta (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI 1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated. RESULT: H2O2 enhanced IL1beta induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters. CONCLUSION: Oxidative stress enhanced IL1beta induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in the regulation of inflammatory genes and provides a potential novel anti-inflammatory target. PMID- 24759737 TI - Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. AB - While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD) has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR) in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC) and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs) decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-gamma and IL 17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-gamma production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD. PMID- 24759738 TI - Genomic analysis of drug resistant gastric cancer cell lines by combining mRNA and microRNA expression profiling. AB - Understanding the mechanism underlying multidrug resistance and identifying effective targets that can overcome it is of critical importance. In this study, mRNA and miRNA expression profiling of the drug resistant sublines, SGC7901/VCR and SGC7901/ADR, and their parental gastric cancer cell line SGC7901 were performed. A significant number of genes and a limited subset of miRNAs were commonly dysregulated, which were further validated using qRT-PCR. GO and KEGG pathway analyses of the commonly dysregulated genes indicated that the MAPK signalling pathway may be involved in multidrug resistance, which was further validated using immunoblotting and MTT assay. Finally a primary multidrug resistance network in gastric cancer, consisting of the commonly dysregulated genes and miRNAs, was established and functional miRNA-mRNA pairs were identified. The commonly dysregulated genes and miRNAs identified in this study may represent good therapeutic targets and further study of these targets may increase our understanding of the mechanisms underlying multidrug resistance. PMID- 24759739 TI - A comprehensive genome-wide study on tissue-specific and abiotic stress-specific miRNAs in Triticum aestivum. AB - Productivity of wheat crop is largely dependent on its growth and development that, in turn, is mainly regulated by environmental conditions, including abiotic stress factors. miRNAs are key regulators of gene expression networks involved in diverse aspects of development and stress responses in plants. Using high throughput sequencing of eight small RNA libraries prepared from diverse abiotic stresses and tissues, we identified 47 known miRNAs belonging to 20 families, 49 true novel and 1030 candidate novel miRNAs. Digital gene expression analysis revealed that 257 miRNAs exhibited tissue-specific expression and 74 were associated with abiotic stresses. Putative target genes were predicted for miRNAs identified in this study and their grouping into functional categories indicated that the putative targets were involved in diverse biological processes. RLM-RACE of predicted targets of three known miRNAs (miR156, miR160 and miR164) confirmed their mRNA cleavage, thus indicating their regulation at post-transcriptional level by the corresponding miRNAs. Mapping of the sequenced data onto the wheat progenitors and closely related monocots revealed a large number of evolutionary conserved miRNAs. Additional expression profiling of some of these miRNAs in other abiotic stresses underline their involvement in multiple stresses. Our findings provide valuable resource for an improved understanding of the role of miRNAs in stress tolerance as well as plant development. PMID- 24759740 TI - Combinatorial communication in bacteria: implications for the origins of linguistic generativity. AB - Combinatorial communication, in which two signals are used together to achieve an effect that is different to the sum of the effects of the component parts, is apparently rare in nature: it is ubiquitous in human language, appears to exist in a simple form in some non-human primates, but has not been demonstrated in other species. This observed distribution has led to the pair of related suggestions, that (i) these differences in the complexity of observed communication systems reflect cognitive differences between species; and (ii) that the combinations we see in non-human primates may be evolutionary pre cursors of human language. Here we replicate the landmark experiments on combinatorial communication in non-human primates, but in an entirely different species, unrelated to humans, and with no higher cognition: the bacterium Pseudomonas aeruginosa. Using the same general methods as the primate studies, we find the same general pattern of results: the effect of the combined signal differs from the composite effect of the two individual signals. This suggests that advanced cognitive abilities and large brains do not necessarily explain why some species have combinatorial communication systems and others do not. We thus argue that it is premature to conclude that the systems observed in non-human primates are evolutionarily related to language. Our results illustrate the value of an extremely broad approach to comparative research. PMID- 24759741 TI - Incidence of TB and HIV in prospectively followed household contacts of TB index patients in South Africa. AB - OBJECTIVE: To report the incidence rates of TB and HIV in household contacts of index patients diagnosed with TB. DESIGN: A prospective cohort study in the Matlosana sub-district of North West Province, South Africa. METHODS: Contacts of index TB patients received TB and HIV testing after counseling at their first household visit and were then followed up a year later, in 2010. TB or HIV diagnoses that occurred during the period were determined. RESULTS: For 2,377 household contacts, the overall observed TB incidence rate was 1.3 per 100 person years (95% CI 0.9-1.9/100py) and TB incidence for individuals who were HIV infected and HIV seronegative at baseline was 5.4/100py (95% CI 2.9-9.0/100py) and 0.7/100py (95% CI 0.3-1.4/100py), respectively. The overall HIV incidence rate was 2.2/100py (95% CI 1.3-8.4/100py). CONCLUSIONS: In the year following a household case finding visit when household contacts were tested for TB and HIV, the incidence rate of both active TB and HIV infection was found to be extremely high. Clearly, implementing proven strategies to prevent HIV acquisition and preventing TB transmission and progression to disease remains a priority in settings such as South Africa. PMID- 24759743 TI - Career on the move: geography, stratification, and scientific impact. AB - Changing institutions is an integral part of an academic life. Yet little is known about the mobility patterns of scientists at an institutional level and how these career choices affect scientific outcomes. Here, we examine over 420,000 papers, to track the affiliation information of individual scientists, allowing us to reconstruct their career trajectories over decades. We find that career movements are not only temporally and spatially localized, but also characterized by a high degree of stratification in institutional ranking. When cross-group movement occurs, we find that while going from elite to lower-rank institutions on average associates with modest decrease in scientific performance, transitioning into elite institutions does not result in subsequent performance gain. These results offer empirical evidence on institutional level career choices and movements and have potential implications for science policy. PMID- 24759744 TI - Solid-state gas sensors for breath analysis: a review. AB - The analysis of volatile compounds is an efficient method to appraise information about the chemical composition of liquids and solids. This principle is applied to several practical applications, such as food analysis where many important features (e.g. freshness) can be directly inferred from the analysis of volatile compounds. The same approach can also be applied to a human body where the volatile compounds, collected from the skin, the breath or in the headspace of fluids, might contain information that could be used to diagnose several kinds of diseases. In particular, breath is widely studied and many diseases can be potentially detected from breath analysis. The most fascinating property of breath analysis is the non-invasiveness of the sample collection. Solid-state sensors are considered the natural complement to breath analysis, matching the non-invasiveness with typical sensor features such as low-cost, easiness of use, portability, and the integration with the information networks. Sensors based breath analysis is then expected to dramatically extend the diagnostic capabilities enabling the screening of large populations for the early diagnosis of pathologies. In the last years there has been an increased attention to the development of sensors specifically aimed to this purpose. These investigations involve both specific sensors designed to detect individual compounds and non specific sensors, operated in array configurations, aimed at clustering subjects according to their health conditions. In this paper, the recent significant applications of these sensors to breath analysis are reviewed and discussed. PMID- 24759745 TI - Modern analytical supercritical fluid chromatography using columns packed with sub-2 MUm particles: a tutorial. AB - This tutorial provides an overview of the possibilities, limitations and analytical conditions of modern analytical supercritical fluid chromatography (SFC) using columns packed with sub-2 MUm particles. In particular, it gives a detailed overview of commercially available modern SFC instrumentation and the detectors that can be employed (UV, MS, ELSD, FID, etc.). Some advice on the choice of the stationary phase dimensions and chemistries, the nature of the mobile phase (choice of organic modifier and additives) and its flow rate as well as the backpressure and temperature are also provided. Finally, several groups of potentially problematic compounds, including lipophilic compounds, hydrophilic substances and basic drugs, are discussed in detail. All these families of analytes can be resolved with SFC but require specific analytical conditions. PMID- 24759746 TI - High-precision quadruple isotope dilution method for simultaneous determination of nitrite and nitrate in seawater by GCMS after derivatization with triethyloxonium tetrafluoroborate. AB - Quadruple isotope dilution mass spectrometry (ID(4)MS) has been applied for simultaneous determination of nitrite and nitrate in seawater. ID(4)MS allows high-precision measurements and entails the use of isotopic internal standards ((18)O-nitrite and (15)N-nitrate). We include a tutorial on ID(4)MS outlining optimal experimental design which generates results with low uncertainties and obviates the need for direct (separate) evaluation of the procedural blank. Nitrite and nitrate detection was achieved using a headspace GCMS procedure based on single-step aqueous derivatization with triethyloxonium tetrafluoroborate at room temperature. In this paper the sample preparation was revised and fundamental aspects of this chemistry are presented. The proposed method has detection limits in the low parts-per-billion for both analytes, is reliable, precise, and has been validated using a seawater certified reference material (MOOS-2). Simplicity of the experimental design, low detection limits, and the use of quadruple isotope dilution makes the present method superior to the state of-the-art for determination of nitrite and nitrate, and an ideal candidate for reference measurements of these analytes in seawater. PMID- 24759747 TI - Multi-response optimization of the extraction and derivatization protocol of selected polar metabolites from apple fruit tissue for GC-MS analysis. AB - Given the complexity of the plant metabolome exhibiting a wide spectrum of physico-chemical properties, finding the best compromise for GC-MS analysis is a challenging exercise. In this study, the GC-MS protocol for extracting and analyzing polar metabolites from apple tissue is optimized. We found pure methanol extraction to be slightly better as compared to the two phase methanol/chloroform/water extraction in terms of introducing less degradation of the extracted metabolites while being comparable in extraction efficiency and repeatability. The methanol extraction was superior to the single phase methanol/chloroform/water extraction in all performance measures. A multi response optimization based on a desirability function was applied to optimize the derivatization. This procedure allows searching for optimal parameters while simultaneously considering overall detection enhancement of metabolites from various metabolic classes. A short oximation at a high temperature in combination with a low silylation temperature gave results similar to a longer oximation at low temperature in combination with a high silylation temperature. Increasing silylation time from 0.5 h to 2 h resulted in an improvement of the silylation reaction. PMID- 24759748 TI - Enhanced electrochemiluminescence based on Ru(bpy)32+-doped silica nanoparticles and graphene composite for analysis of melamine in milk. AB - A sensitive electrochemiluminescence (ECL) sensor for melamine analysis was fabricated based on Ru(bpy)3(2+)-doped silica (Ru(bpy)3(2+)@SiO2) nanoparticles and graphene composite. Spherical Ru(bpy)3(2+)@SiO2 nanoparticles with uniform size about 55 nm were prepared by the reverse microemulsion method. Since per Ru(bpy)3(2+)@SiO2 nanoparticle encapsulated a great deal of Ru(bpy)3(2+), the ECL intensity has been greatly enhanced, which resulted in high sensitivity. Due to its extraordinary electric conductivity, graphene improved the conductivity and accelerated the electron transfer rate. In addition, graphene could work as electronic channel improving the efficient luminophor amount participating in the ECL reaction, which further enhanced the ECL signal. This proposed sensor was used to melamine analysis and the ECL intensity was proportional to logarithmic melamine concentration range from 1*10(-13) M to 1*10(-8) M with the detect limit as low as 1*10(-13) M. In application to detect melamine in milk, satisfactory recoveries could be obtained, which indicated this sensor having potential application in melamine analysis in real samples. PMID- 24759749 TI - Mimicking Daphnia magna bioassay performance by an electronic tongue for urban water quality control. AB - Toxicity is one of the key parameters of water quality in environmental monitoring. However, being evaluated as a response of living beings (as their mobility, fertility, death rate, etc.) to water quality, toxicity can only be assessed with the help of these living beings. This imposes certain restrictions on toxicity bioassay as an analytical method: biotest organisms must be properly bred, fed and kept under strictly regulated conditions and duration of tests can be quite long (up to several days), thus making the whole procedure the prerogative of the limited number of highly specialized laboratories. This report describes an original application of potentiometric multisensor system (electronic tongue) when the set of electrochemical sensors was calibrated against Daphnia magna death rate in order to perform toxicity assessment of urban waters without immediate involvement of living creatures. PRM (partial robust M) and PLS (projections on latent structures) regression models based on the data from this multisensor system allowed for prediction of toxicity of unknown water samples in terms of biotests but in the fast and simple instrumental way. Typical errors of water toxicity predictions were below 20% in terms of Daphnia death rate which can be considered as a good result taking into account the complexity of the task. PMID- 24759750 TI - Ratiometric near-infrared chemosensor for trivalent chromium ion based on tricarboyanine in living cells. AB - A tricarboyanine derivative (IRPP) is applied as a ratiometric near-infrared chemosensor for detecting trivalent chromium ions (Cr(3+)) in living cells. Upon the addition of Cr(3+) to a solution of IRPP, large-scale shifts in the emission spectrum (from 755 nm to 561 nm) are observed. In the newly developed sensing system, these well-resolved emission peaks yield a sensing system that covers a linear range from 1.0*10(-7) to 1.0*10(-5) M with a detection limit of 2.5*10(-8) M. The experimental results show the response behavior of IRPP towards Cr(3+) is pH independent under neutral conditions (6.0-7.5). Most importantly, the fast response time (less than 3 min) and selectivity for Cr(3+) over other common metal ions provide a strong argument for the use of this sensor in real world applications. As a proof of concept, the proposed chemosensor has been used to detect and quantify Cr(3+) in river water samples and to image Cr(3+) in living cells with encouraging results. PMID- 24759751 TI - Mismatch repair gene MLH3 Pro844Leu and Thr942Ile polymorphisms and the susceptibility to cervical carcinoma and HPV infection: a case-control study in a Chinese population. AB - To investigate the association between MLH3 Pro844Leu, Thr942Ile polymorphisms and potential linkage with the risk of cervical carcinoma and potential effect on protein function, we carried out a case-control study with 400 cervical squamous cell carcinoma, 400 CIN3 and 1200 normal controls in a Chinese population. The results showed that there was an increased risk of cervical carcinoma and CIN3 associated with the genotype 844CT [OR 2.17 (1.61-2.94); P<0.001; OR 1.49 (1.08 2.07), P 0.017, respectively] and a decreased risk with the 942CT genotype [OR 0.56 (0.38-0.82); P<0.001; OR 0.37 (0.24-0.58), P<0.001, respectively]. Most 844CT genotypes were linkage CT(844)-CC(942), which increased the risk of cervical carcinoma and CIN3 [77/83, OR 2.04 (1.48-2.80), P<0.001; 55/61, OR 1.46 (1.03-2.06), P 0.035, respectively]. Most 942CT were linkage CC(844)-CT(942), which decreased the risk of cervical carcinoma [29/35, OR 0.60 (0.40-0.91); P 0.017; 18/24, OR 0.33 (0.20-0.55), P<0.001, respectively]. In some grouping, the 844CT and 942CT were further enriched; especially HR-HPV-positive subjects both in the CIN3 and the cervical carcinoma, the 844CT had greater enrichment. These results included that CT(844)-CC(942) was associated with a high risk of cervical carcinoma and CIN3, and the CC(844)-CT(942) decreased the risk. The 844CT had a higher level of enrichment in HR-HPV positive individuals, which is probably related to HR-HPV susceptibility. There was no significant difference of the MLH3 mRNA expression and these two amino acid substitutions did not impact on the protein function. PMID- 24759752 TI - Use of the Contingent Valuation Method in the assessment of a landfill mining project. AB - A comprehensive approach for the evaluation of the economic feasibility of landfill mining (LFM) should take into account not only the direct costs and revenues for the private investor, but also the social benefits or costs (generally called externalities), in such a way that projects generating major social benefits (and no significant private revenues) are not overlooked. With a view to contributing to the development of a common framework for the evaluation of LFM projects, this paper presents the results of a case study where the issue of the assessment of social benefits from a LFM project is addressed. In particular, the Contingent Valuation Method is applied for the monetary assessment of the community-perceived benefits from the remediation of an old uncontrolled waste deposit by means of LFM and the conversion of the area into a park. Based on the results of a survey carried out on a random sample of people living near the old landfill, the economic values of the individual willingness to pay (WTP) for LFM and the subsequent creation of a public park were calculated and the correlations with the relevant variables (distance from the landfill site, age, income, sex, education level) assessed. The results were then suitably extended and the monetary value of the welfare increase of the whole population resident in the area and potentially affected both by LFM and the creation of the park was calculated. PMID- 24759753 TI - Quantifying methane emission from fugitive sources by combining tracer release and downwind measurements - a sensitivity analysis based on multiple field surveys. AB - Using a dual species methane/acetylene instrument based on cavity ring down spectroscopy (CRDS), the dynamic plume tracer dispersion method for quantifying the emission rate of methane was successfully tested in four measurement campaigns: (1) controlled methane and trace gas release with different trace gas configurations, (2) landfill with unknown emission source locations, (3) landfill with closely located emission sources, and (4) comparing with an Fourier transform infrared spectroscopy (FTIR) instrument using multiple trace gasses for source separation. The new real-time, high precision instrument can measure methane plumes more than 1.2 km away from small sources (about 5 kg h(-1)) in urban areas with a measurement frequency allowing plume crossing at normal driving speed. The method can be used for quantification of total methane emissions from diffuse area sources down to 1 kg per hour and can be used to quantify individual sources with the right choice of wind direction and road distance. The placement of the trace gas is important for obtaining correct quantification and uncertainty of up to 36% can be incurred when the trace gas is not co-located with the methane source. Measurements made at greater distances are less sensitive to errors in trace gas placement and model calculations showed an uncertainty of less than 5% in both urban and open-country for placing the trace gas 100 m from the source, when measurements were done more than 3 km away. Using the ratio of the integrated plume concentrations of tracer gas and methane gives the most reliable results for measurements at various distances to the source, compared to the ratio of the highest concentration in the plume, the direct concentration ratio and using a Gaussian plume model. Under suitable weather and road conditions, the CRDS system can quantify the emission from different sources located close to each other using only one kind of trace gas due to the high time resolution, while the FTIR system can measure multiple trace gasses but with a lower time resolution. PMID- 24759754 TI - Realization of a spin-wave multiplexer. AB - Recent developments in the field of spin dynamics--like the interaction of charge and heat currents with magnons, the quasi-particles of spin waves--opens the perspective for novel information processing concepts and potential applications purely based on magnons without the need of charge transport. The challenges related to the realization of advanced concepts are the spin-wave transport in two-dimensional structures and the transfer of existing demonstrators to the micro- or even nanoscale. Here we present the experimental realization of a microstructured spin-wave multiplexer as a fundamental building block of a magnon based logic. Our concept relies on the generation of local Oersted fields to control the magnetization configuration as well as the spin-wave dispersion relation to steer the spin-wave propagation in a Y-shaped structure. Thus, the present work illustrates unique features of magnonic transport as well as their possible utilization for potential technical applications. PMID- 24759755 TI - Anion recognition by simple chromogenic and chromo-fluorogenic salicylidene Schiff base or reduced-Schiff base receptors. AB - This review contains extensive application of anion sensing ability of salicylidene type Schiff bases and their reduced forms having various substituents with respect to phenolic OH group. Some of these molecular systems behave as receptor for recognition or sensing of various anions in organic or aqueous-organic binary solvent mixture as well as in the solid supported test kits. Development of Schiff base or reduced Schiff base receptors for anion recognition event is commonly based on the theory of hydrogen bonding interaction or deprotonation of phenolic -OH group. The process of charge transfer (CT) or inhibition of excited proton transfer (ESIPT) or followed by photo-induced electron transfer (PET) lead to naked-eye color change, UV-vis spectral change, chemical shift in the NMR spectra and fluorescence spectral modifications. In this review we have tried to discuss about the anion sensing properties of Schiff base or reduced Schiff base receptors. PMID- 24759756 TI - Synthesis, characterization, structural analysis of metal(II) complexes of N' [(E)-3-Bromo-5-Chloro-2-hydroxybenzidene]-4-hydroxybenzohydrazide Multisubstituted Schiff base as a F(-) and Cu(2+) ions selective chemosensor. AB - New colorimetric chemosensor, N'-[(E)-3-Bromo-5-Chloro-2-hydroxybenzidene]-4 hydroxybenzohydrazide, containing OH and NH groups as binding sites have been synthesized and characterized by spectral UV, IR, NMR and ESR. The molecular structure of ligand is determined by X-ray crystallography and it has the monoclinic space group P21/c with cell parameters a=15.1058(6), b=14.3433(6), c=17.5800(8)A and Z=8. The electronic spectral measurements show that Co(2+), Ni(2+) and Zn(2+) complexes have tetrahedral geometry, while Cu(2+) complex has square planar geometry. Magnetic measurements show that Cu(2+), Co(2+) and Ni(2+) complexes have paramagnetic behavior and Zn(2+) complex has diamagnetic behavior. Anion binding studies carried out using (1)H NMR and UV-visible spectrophotometric titrations revealed that these receptors exhibit selective recognition towards F(-) over other halide anions. The selectivity for F(-) among the halides is attributed mainly to the hydrogen-bond interaction of the receptor with F(-). Receptor (5 * 10(-5)M) shows color change from colorless to yellow in the presence of tetrabutylammonium fluoride (TBAF, 1.5 * 10(-3)M). Moreover, F(-) induced color changes remain the same even in the presence of large excess of Cl( ), Br(-) and I(-). The binding constant is found to be higher towards F(-) ion and this may be due to presence of OH group, which offers extra binding site. Chromogenic receptor undergoes distinct color changes from colorless to green on gradual addition of Cu(2+) can be used as colorimetric probes for spectrophotometric and visual analysis of Cu(2+) in the presence of other transition metal ions such as Co(2+), Ni(2+) and Zn(2+). PMID- 24759757 TI - The use of contrast-enhanced post Mortem CT in the detection of cardiovascular deaths. AB - OBJECTIVES: To evaluate the diagnostic value of contrast enhanced post mortem computed tomography (PMCT) in comparison to non-enhanced post mortem CT in the detection of cardiovascular causes of death (COD). BACKGROUND: As autopsy rates decline, new methods to determine CODs are necessary. So contrast enhanced PMCT shall be evaluated in comparison to established non-enhanced PMCT in order to further improve the method. METHODS: In a prospective study, 20 corpses were examined using a 64-row multisclice CT (MSCT) before and after intraarterial perfusion with a newly developed, barium-bearing contrast agent and ventilation of the lungs. The cause of death was determined in enhanced and unenhanced scans and a level of confidence (LOC) was given by three experienced radiologists on a scale between 0 and 4. Results were compared to autopsy results as gold standard. Autopsy was performed blinded to PMCT-findings. RESULTS: The method allowed visualization of different types of cause of death. There was a significant improvement in LOC in enhanced scans compared to unenhanced scans as well as an improvement in the detection of COD. The cause of death could be determined in 19 out of 20 patients. CONCLUSIONS: PMCT is feasible and appears to be robust for diagnosing cardiovascular causes of death. When compared with unenhanced post mortem CT intraarterial perfusion and pulmonary ventilation significantly improve visualization and diagnostic accuracy. These promising results warrant further studies. PMID- 24759758 TI - Novel PPAR pan agonist, ZBH ameliorates hyperlipidemia and insulin resistance in high fat diet induced hyperlipidemic hamster. AB - Effective and safe pharmacological interventions for hyperlipidemia remains badly needed. By incorporating the key pharmacophore of fibrates into the natural scaffold of resveratrol, a novel structural compound ZBH was constructed. In present study, we found ZBH reserved approximately one third of the sirtuin 1 (SIRT1) activation produced by resveratrol at in-vitro enzyme activity assay, directly bound to and activated all three peroxisome proliferator-activated receptor (PPAR) subtypes respectively in PPAR binding and transactivation assays. Moreover, ZBH (EC50, 1.75 uM) activate PPARalpha 21 fold more efficiently than the well-known PPAR pan agonist bezafibrate (EC50 37.37 uM) in the cellular transactivation assays. In the high fat diet induced hyperlipidemic hamsters, 5 week treatment with ZBH significantly lowered serum triglyceride, total cholesterol, LDL-C, FFA, hyperinsulinemia, and improved insulin sensitivity more potently than bezafibrate. Meanwhile, serum transaminases, creatine phosphokinase and CREA levels were found not altered by ZBH intervention. Mechanism study indicated ZBH promoted the expression of PPARalpha target genes and SIRT1 mRNA. Hepatic lipogenesis was markedly decreased via down-regulation of lipogenic genes, and fatty acid uptake and oxidation was simultaneously increased in the liver and skeletal muscle via up-regulation of lipolysis genes. Glucose uptake and utilization was also significantly promoted in skeletal muscle. These results suggested that ZBH significantly lowered hyperlipidemia and ameliorated insulin resistance more efficiently than bezafibrate in the hyperlipidemic hamsters primarily by activating of PPARalpha, and SIRT1 promotion and activation. ZBH thus presents a potential new agent to combat hyperlipidemia. PMID- 24759759 TI - T cell contamination in flow cytometry gating approaches for analysis of innate lymphoid cells. AB - Innate lymphoid cells (ILCs) differ from T and B cells as they do not express genetically rearranged antigen receptors. The most prominent member of this group, NK cells, can be identified by numerous surface receptors such as natural cytotoxicity receptors (NCRs). However, novel groups of ILCs have recently been described and classified based on fate-determining transcription factors and cytokines being produced, similarly to T helper cells. Due to the lack of exclusive markers, ILCs are primarily defined by the paucity of lineage markers. Using RORc-fate-mapping mice, we found that the common lineage exclusion using CD3 yields an ILC population containing a large proportion of T cells with recombined TCR loci and low expression of CD3. Thus, we suggest adding CD5 as a marker for thorough elimination of T cells to avoid erroneous interpretations of ILC function in immunity. PMID- 24759761 TI - A.S.P.E.N. parenteral nutrition safety consensus recommendations: translation into practice. PMID- 24759760 TI - Pyrazinamide resistance, Mycobacterium tuberculosis lineage and treatment outcomes in San Francisco, California. AB - BACKGROUND: Pyrazinamide (PZA) is a first line agent for the treatment of active tuberculosis. PZA is also considered a potent companion drug for newer regimens under development. There are limited data on the demographic, clinical, and pathogen characteristics of PZA resistant tuberculosis. METHODS: Using a retrospective cohort study design, we evaluated all PZA resistant M. tuberculosis (M.tb) and M. bovis cases reported in San Francisco from 1991 to 2011. Demographic, clinical, and molecular data were analyzed. M.tb lineage was determined for all PZA resistant strains and compared to PZA susceptible strains. RESULTS: PZA resistance was identified in 1.8% (50 of 2,842) of mycobacterial isolates tested, corresponding to a case rate of 0.3 per 100,000 in the population. Monoresistant PZA infection was associated with the Hispanic population ([OR], 6.3; 95% [CI], 1.97-20.16) and 48% of cases were due to M. bovis. Infection with monoresistant PZA was also associated with extrapulmonary disease ([OR], 6.0; 95% [CI], 2.70-13.26). There was no statistically significant difference between treatment failure and mortality rates in patients infected with PZA monoresistance compared to pansusceptible controls (4% vs. 8%, p = 0.51), or those with PZA and MDR resistance (PZA-MDR) compared to MDR controls (18% vs. 29%, p = 0.40). PZA resistance was not associated with M.tb lineage. CONCLUSIONS: Across two decades of comprehensive epidemiologic data on tuberculosis in San Francisco County, PZA resistance was uncommon. PZA resistance caused predominantly extrapulmonary disease and was more common in Hispanics compared to other ethnicities, with nearly half the cases attributed to M. bovis. No association was found between PZA monoresistance and M.tb lineage. Treatment outcomes were not adversely influenced by the presence of PZA resistance. PMID- 24759762 TI - Randomized Study of Radiologic vs Endoscopic Placement of Gastrojejunostomies in Patients at Risk of Aspiration Pneumonia. AB - Objective: In patients at risk of aspiration pneumonia due to gastroesophageal reflux who require gastrojejunostomy feeding tubes, the tubes are placed either radiologically (RIGJ) or endoscopically (PEGJ). There is little published evidence of the superiority of one technique over the other. Methods: Patients referred for long-term jejunal feeding were randomly allocated to have a 14F RIGJ or 15F with 9F jejunal extension PEGJ inserted. A technetium-99m (99mTc) colloid study was done to determine the presence of gastroesophageal reflux and jejunogastric reflux after feeding tube placement. We recorded enteral feed and tube-related complications, in addition to tube-related morbidity and mortality to 90 days following placement. Results: Baseline characteristics were similar between groups, with gastroesophageal reflux demonstrated in 52%. Following enteral tube placement, gastroesophageal reflux was not observed by 99mTc studies or any difference in clinical outcome to 90 days after placement. No jejunal tubes were displaced in any of the 31 RIGJ tubes, while 9 tubes were displaced in the 34 PEGJ patients (P = .008). Reversible jejunal tube blockages occurred: 19 RIGJ (5 patients) and 61 PEGJ (11 patients) (P = .003, chi2 = 9.1). Conclusion: There was little difference between the 2 tubes for clinical outcomes. RIGJ tubes were less prone than PEGJ tubes to reversible blockage and displacement. It is likely that the better outcome for RIGJ tubes relates to their larger tube diameter and stiffness. PMID- 24759763 TI - Effects of chebulic acid on advanced glycation endproducts-induced collagen cross links. AB - Advanced glycation end-products (AGEs) have been implicated in the development of diabetic complications. We report the antiglycating activity of chebulic acid (CA), isolated from Terminalia chebula on breaking the cross-links of proteins induced by AGEs and inhibiting the formation of AGEs. Aminoguanidine (AG) reduced 50% of glycated bovine serum albumin (BSA) with glycolaldehyde (glycol-BSA) induced cross-links of collagen at a concentration of 67.8 +/- 2.5 mM, the level of CA required for exerting a similar antiglycating activity was 38.8 +/- 0.5 uM. Also, the breaking activity on collagen cross-links induced by glycol-BSA was potent with CA (IC50=1.46 +/- 0.05 mM), exhibiting 50-fold stronger breaking activity than with ALT-711, a well-known cross-link breaker (IC50=72.2 +/- 2.4 mM). IC50 values of DPPH. scavenging activity for CA and ascorbic acid (AA) were 39.2 +/- 4.9 and 19.0 +/- 1.2 ug dry matter (DM) mL(-1), respectively, and ferric reducing and antioxidant power (FRAP) activities for CA and AA were 4.70 +/- 0.06 and 11.4 +/- 0.1 mmol/FeSO4.7H2O/g DM, respectively. The chelating activities of CA, AG and ALT711 on copper-catalyzed oxidation of AA were compared, and in increasing order, ALT-711 (IC50 of 1.92 +/- 0.20 mM)1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups. CONCLUSION: Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is able to detect the initiation of ventilation induced brain injury. PMID- 24759766 TI - Why a falling drop does not in general behave like a rising bubble. AB - Is a settling drop equivalent to a rising bubble? The answer is known to be in general a no, but we show that when the density of the drop is less than 1.2 times that of the surrounding fluid, an equivalent bubble can be designed for small inertia and large surface tension. Hadamard's exact solution is shown to be better for this than making the Boussinesq approximation. Scaling relationships and numerical simulations show a bubble-drop equivalence for moderate inertia and surface tension, so long as the density ratio of the drop to its surroundings is close to unity. When this ratio is far from unity, the drop and the bubble are very different. We show that this is due to the tendency for vorticity to be concentrated in the lighter fluid, i.e. within the bubble but outside the drop. As the Galilei and Bond numbers are increased, a bubble displays underdamped shape oscillations, whereas beyond critical values of these numbers, over-damped behavior resulting in break-up takes place. The different circulation patterns result in thin and cup-like drops but bubbles thick at their base. These shapes are then prone to break-up at the sides and centre, respectively. PMID- 24759767 TI - Delineating the functional map of the interaction between nimotuzumab and the epidermal growth factor receptor. AB - Molecular details of epidermal growth factor receptor (EGFR) targeting by nimotuzumab, a therapeutic anti-cancer antibody, have been largely unknown. The current study delineated a functional map of their interface, based on phage display and extensive mutagenesis of both the target antigen and the Fv antibody fragment. Five residues in EGFR domain III (R353, S356, F357, T358, and H359T) and the third hypervariable region of nimotuzumab heavy chain were shown to be major functional contributors to the interaction. Fine specificity differences between nimotuzumab and other anti-EGFR antibodies were revealed. Mapping information guided the generation of a plausible in silico binding model. Knowledge about the epitope/paratope interface opens new avenues for the study of tumor sensitivity/resistance to nimotuzumab and for further engineering of its binding site. The developed mapping platform, also validated with the well-known cetuximab epitope, allows a comprehensive exploration of antigenic regions and could be expanded to map other anti-EGFR antibodies. PMID- 24759768 TI - Enhanced reduction of an azo dye using henna plant biomass as a solid-phase electron donor, carbon source, and redox mediator. AB - The multiple effects of henna plant biomass as a source of carbon, electron donor, and redox mediator (RM) on the enhanced bio-reduction of Orange II (AO7) were investigated. The results indicated that the maximum AO7 reduction rate in the culture with henna powder was ~6-fold that in the sludge control culture lacking henna. On the one hand, AO7 reduction can be advantageously enhanced by the release of available electron donors; on the other hand, the associated lawsone can act as a fixed RM and play a potential role in shuttling electrons from the released electron donors to the final electron acceptor, AO7. The soluble chemical oxygen demand (SCOD) during each experiment and the FTIR spectra suggested that the weakened AO7 reduction along with the retention of henna powder might not be attributed to the lack of fixed lawsone but rather to the insufficiency of electron donors. PMID- 24759769 TI - Characterization of liquid and solid product from pyrolysis of Pongamia glabra deoiled cake. AB - In the present study, a new feedstock, Pongamia glabra deoiled cake (PGDC), is reported for pyrolysis. Experiments were conducted in a laboratory scale fixed bed pyrolyzer at temperatures ranging from 350 to 600 degrees C with varying heating rates of 10, 20, 40 degrees C/min in nitrogen atmosphere. The highest liquid yield of 30.60% was observed at 500 degrees C with heating rate of 40 degrees Cmin(-1). The biochar obtained had a porous structure and was characterized by powder X-ray diffraction (XRD), Scanning electron microscopy (SEM) and Fourier Transform Infrared (FTIR) spectroscopy along with elemental analysis. The representative bio-oil sample was characterized by CHN analyzer, GC MS, NMR and FTIR spectroscopy. The bio-oil has a calorific value of 28.19MJ/kg and contains a higher amount of aliphatic compounds. The present investigation suggests that within the realm of biomass energy conversion technologies the PGDC can be used as a feedstock for pyrolysis conversion, thereby serving the demand of second generation biofuels. PMID- 24759770 TI - Neural processes in pseudo perceptual rivalry: an ERP and time-frequency approach. AB - Necker cube is one of the ambiguous figures that is physically a static image but can be alternately perceived in two different perspectives. A great deal of debate exists regarding ambiguous figures that induce spontaneous switching between rival percepts. To investigate the time course of neural processes underlying such perceptual rivalry, we recorded electroencephalograms associated with participants' perceptions of a Necker cube under ambiguous and unambiguous conditions, using a modified discontinuous-presentation method. Each condition consisted of two stimuli presented consecutively, starting with an unambiguous stimulus in both conditions. The second stimulus was either ambiguous (ambiguous condition) or unambiguous (control condition). We compared endogenous reversal activity of ambiguous stimuli with exogenous reversals. As a result, we found that the right-occipital beta-band activity (16-26 Hz) increased 100-150 ms and 350-450 ms after the onset of the ambiguous stimulus only when the perception of the ambiguous stimulus differed from that of the first stimulus. These results indicate that activity in the right-occipital total beta band reflects endogenous switching between rivaling percepts. PMID- 24759773 TI - Uniformity and nonuniformity of neural activities correlated to different insight problem solving. AB - Previous studies on the neural basis of insight reflected weak consistency except for the anterior cingulate cortex. The present work adopted the semantic and homophonic punny riddle to explore the uniformity and nonuniformity of neural activities correlated to different insight problem solving. Results showed that in the early period of insight solving, the semantic and homophonic punny riddles induced a common N350-500 over the central scalp. However, during -400 to 0 ms before the riddles were solved, the semantic punny riddles induced a positive event-related potential (ERP) deflection over the temporal cortex for retrieving the extensive semantic information, while the homophonic punny riddles induced a positive ERP deflection over the temporal cortex and a negative one in the left frontal cortex which might reflect the semantic and phonological information processing respectively. Our study indicated that different insight problem solving should have the same cognitive process of detecting cognitive conflicts, but have different ways to solve the conflicts. PMID- 24759772 TI - Eugenol and carvacrol excite first- and second-order trigeminal neurons and enhance their heat-evoked responses. AB - Eugenol and carvacrol from clove and oregano, respectively, are agonists of the warmth-sensitive transient receptor potential channel TRPV3 and the irritant sensitive transient receptor potential ankyrin (TRPA)-1. Eugenol and carvacrol induce oral irritation that rapidly desensitizes, accompanied by brief enhancement of innocuous warmth and heat pain in humans. We presently investigated if eugenol and carvacrol activate nociceptive primary afferent and higher order trigeminal neurons and enhance their heat-evoked responses, using calcium imaging of cultured trigeminal ganglion (TG) and dorsal root ganglion (DRG) neurons, and in vivo single-unit recordings in trigeminal subnucleus caudalis (Vc) of rats. Eugenol and carvacrol activated 20-30% of TG and 7-20% of DRG cells, the majority of which additionally responded to menthol, mustard oil and/or capsaicin. TG cell responses to innocuous (39 degrees ) and noxious (42 degrees C) heating were enhanced by eugenol and carvacrol. We identified dorsomedial Vc neurons responsive to noxious heating of the tongue in pentobarbital-anesthetized rats. Eugenol and carvacrol dose-dependently elicited desensitizing responses in 55% and 73% of heat-sensitive units, respectively. Responses to noxious heat were briefly enhanced by eugenol and carvacrol. Many eugenol- and carvacrol-responsive units also responded to menthol, cinnamaldehyde and capsaicin. These data support a peripheral site for eugenol and carvacrol to enhance warmth- and noxious heat-evoked responses of trigeminal neurons, and are consistent with the observation that these agonists briefly enhance warmth and heat pain on the human tongue. PMID- 24759771 TI - Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation. AB - Lateral hypothalamic (LH) stimulation produces antinociception in female rats in acute, nociceptive pain. Whether this effect occurs in neuropathic pain or whether male-female sex differences exist is unknown. We examined the effect of LH stimulation in male and female rats using conditions of nociceptive and neuropathic pain. Neuropathic groups received chronic constriction injury (CCI) to induce thermal hyperalgesia, a sign of neuropathic pain. Nociceptive rats were naive for CCI, but received the same thermal stimulus following LH stimulation. To demonstrate that CCI ligation produced thermal hyperalgesia, males and females received either ligation or sham surgery for control. Both males and females demonstrated significant thermal hyperalgesia following CCI ligation (p<0.05), but male sham surgery rats also showed a significant left-right difference not present in female sham rats. In the second experiment, rats randomly assigned to CCI or nociceptive groups were given one of three doses of the cholinergic agonist carbachol (125, 250, or 500 nmol) or normal saline for control, microinjected into the left LH. Paw withdrawal from a thermal stimulus (paw withdrawal latency; PWL) was measured every 5 min for 45 min. Linear mixed models analysis showed that males and females in both pain conditions demonstrated significant antinociception, with the 500-nmol dose producing the greatest effect across groups compared with controls for the left paw (p<0.05). Female CCI rats showed equivalent responses to the three doses, while male CCI rats showed more variability for dose. However, nociceptive females responded only to the 500-nmol dose, while nociceptive males responded to all doses (p<0.05). For right PWL, only nociceptive males showed a significant carbachol dose response. These findings are suggestive that LH stimulation produces antinociception in male and female rats in both nociceptive and neuropathic pain, but dose response differences exist based on sex and pain condition. PMID- 24759774 TI - Optimisation and assessment of three modern touch screen tablet computers for clinical vision testing. AB - Technological advances have led to the development of powerful yet portable tablet computers whose touch-screen resolutions now permit the presentation of targets small enough to test the limits of normal visual acuity. Such devices have become ubiquitous in daily life and are moving into the clinical space. However, in order to produce clinically valid tests, it is important to identify the limits imposed by the screen characteristics, such as resolution, brightness uniformity, contrast linearity and the effect of viewing angle. Previously we have conducted such tests on the iPad 3. Here we extend our investigations to 2 other devices and outline a protocol for calibrating such screens, using standardised methods to measure the gamma function, warm up time, screen uniformity and the effects of viewing angle and screen reflections. We demonstrate that all three devices manifest typical gamma functions for voltage and luminance with warm up times of approximately 15 minutes. However, there were differences in homogeneity and reflectance among the displays. We suggest practical means to optimise quality of display for vision testing including screen calibration. PMID- 24759775 TI - Prevalence of Sexual Violence Against Women in 23 States and Two U.S. Territories, BRFSS 2005. AB - Sexual violence (SV) is a significant public health problem. Using data from the 2005 Behavioral Risk Factor Surveillance System (BRFSS), this article provides state-specific 12-month SV prevalence data for women residing in 23 states and two territories. Overall, more than 500,000 women in the participating states experienced completed or attempted nonconsensual sex in the 12-month period prior to the survey. The collection of state-level data using consistent, uniform, and behaviorally specific SV definitions enables states to evaluate the magnitude of the problem within their state and informs the development and evaluation of state-level SV programs, policies, and prevention efforts. PMID- 24759776 TI - Pediatric colonoscopy in South China: a 12-year experience in a tertiary center. AB - OBJECTIVE: To investigate: 1) the demographics and clinical characteristics, 2) the findings, and 3) the safety and effectiveness in a cohort of Chinese pediatric patients undergoing colonoscopy. METHODS: The study participants were consecutive patients aged <=14 years old that underwent their first colonoscopy in the endoscopy center at the First Affiliated Hospital, Sun Yat-sen University between Jan. 1, 2001 and Dec. 31, 2012. Demographic, clinical, endoscopic, and pathological findings were collected. RESULTS: The cohort consisted of 322 patients, including 218 boys (67.7%) and 104 girls (32.3%). The median age was 8.0 years old and ranged from 9 months to 14 years old. Hematochezia (48.8%) and abdominal pain/discomfort (41.3%) were the most common presentations preceding pediatric colonoscopy. The caecal intubation success rate was 96.3%. No serious complications occurred during the procedures. A total of 227 patients (70.5%) received a positive diagnosis under endoscopy, including 138 patients with polyps and 53 patients with inflammatory bowel disease (IBD). Among the patients with polyps, 71.0% were juvenile polyps. Comparisons between years 2001-2006 and 2007 2012 showed that the IBD detection rate increased significantly (4.6% vs. 22.4%, P<0.001), while the opposite occurred for the polyp detection rate (73.1% vs. 27.6%, P<0.001). CONCLUSION: Colonoscopy in pediatric patients is a safe and effective procedure. Polyps are the primary finding during colonoscopy. In South China there has been an increase in pediatric patients diagnosed with IBD over the past decade. However, a large epidemiological study is needed to confirm our findings. PMID- 24759777 TI - Have historical climate changes affected Gentoo penguin (Pygoscelis papua) populations in Antarctica? AB - The West Antarctic Peninsula (WAP) has been suffering an increase in its atmospheric temperature during the last 50 years, mainly associated with global warming. This increment of temperature trend associated with changes in sea-ice dynamics has an impact on organisms, affecting their phenology, physiology and distribution range. For instance, rapid demographic changes in Pygoscelis penguins have been reported over the last 50 years in WAP, resulting in population expansion of sub-Antarctic Gentoo penguin (P. papua) and retreat of Antarctic Adelie penguin (P. adeliae). Current global warming has been mainly associated with human activities; however these climate trends are framed in a historical context of climate changes, particularly during the Pleistocene, characterized by an alternation between glacial and interglacial periods. During the last maximal glacial (LGM~21,000 BP) the ice sheet cover reached its maximum extension on the West Antarctic Peninsula (WAP), causing local extinction of Antarctic taxa, migration to lower latitudes and/or survival in glacial refugia. We studied the HRVI of mtDNA and the nuclear intron betafibint7 of 150 individuals of the WAP to understand the demographic history and population structure of P. papua. We found high genetic diversity, reduced population genetic structure and a signature of population expansion estimated around 13,000 BP, much before the first paleocolony fossil records (~1,100 BP). Our results suggest that the species may have survived in peri-Antarctic refugia such as South Georgia and North Sandwich islands and recolonized the Antarctic Peninsula and South Shetland Islands after the ice sheet retreat. PMID- 24759778 TI - Structural investigations of silicate-phosphate glasses containing MoO3 by FTIR, Raman and 31P MAS NMR spectroscopies. AB - Molybdenum is a transition metal (refers to the "d" block of the periodic table) whose atom has an incomplete d sub-shell. It is known that in silicate glasses molybdenum may exist under four oxidation states: Mo6+, Mo5+, Mo4+ and Mo3+, simultaneously molybdenum cations, depending on their content in the glass network, may either be a glass forming component, or act as a modifier. The contemporary literature data show studies conducted mostly on the structure of silicate, phosphate, borate and borosilicate glasses containing molybdenum ions, but not silicate-phosphate glasses. Therefore, the author has undertaken detailed studies using FTIR, Raman and 31P MAS NMR techniques in order to examine the effect of MoO3 addition into the structure of silicate-phosphate glasses from SiO2P2O5K2OCaOMgO system. On the basis of obtained results it was concluded that molybdenum ions in the analysed glasses act as a modifier, which follows from the gradual breakage of oxygen bridges, i.e. POP, SiOSi, and SiOP, and the following formation of connections such as Mo[MoO4]OSi and/or Mo[MoO4]OP. In summary, it is concluded that the increase of MoO3 content (up to 4.4 mol.%) in the structure of glasses of SiO2P2O5K2OMgOCaO system results in weakening of the structure and gradual increase of the degree of silico-oxygen and phosphor-oxygen frameworks depolymerisation. PMID- 24759779 TI - Antimicrobial and antioxidant activities of Mimusops elengi seed extract mediated isotropic silver nanoparticles. AB - The present study reports the use of Mimusops elengi (M. elengi) fruit extract for the synthesis of silver nanoparticles (Ag NPs). The synthesized Ag NPs was initially noticed through visual color change from yellow to reddish brown and further confirmed by surface plasmonic resonance (SPR) band at 429 nm using UV Visible spectroscopy. Morphology and size of Ag NPs was determined by Transmission Electron Microscopy (TEM) analysis. X-ray Diffraction (XRD) study revealed crystalline nature of Ag NPs. The prolonged stability of Ag NPs was due to capping of oxidized polyphenols which was established by Fourier Transform Infrared Spectroscopy (FTIR) study. The polyphenols present in M. elengi fruit extract was analyzed by High Pressure Liquid Chromatography (HPLC) and the results revealed the presence of ascorbic acid, gallic acid, pyrogallol and resorcinol. In order to study the role of these polyphenols in reducing Ag+ ions to Ag NPs, analyses of extracts before reduction and after reduction were carried out. In addition, the synthesized Ag NPs were tested for antibacterial and antioxidant activities against Staphylococcus aureus (S. Aureus) and Escherichia coli (E. coli). Ag NPs showed good antimicrobial activity against both gram positive (S. aureus) and gram negative (E. coli) bacteria. It also showed good antioxidant activity as compared to ascorbic acid as standard antioxidant. PMID- 24759780 TI - Theoretical exploration of control factors for the high-order harmonic generation (HHG) spectrum in two-color field. AB - In this work, the laser-parameter effects on the high-order harmonic generation (HHG) spectrum and attosecond trains by mixing two-color laser field, a visible light field of 800 nm and a mid-infrared (mid-IR) laser pulses of 2400 nm, are theoretically demonstrated for the first time. Different schemes are applied to discuss the function of intensity, carrier-envelope phase (CEP) and pulse duration on the generation of an isolated attosecond pulse. As a consequence, an isolated 16as pulse is obtained by Fourier transforming an ultrabroad XUV continuum of 208 eV with the fundamental field of duration of 6 fs, 9*10(14)W/cm2 of intensity, the duration of 12 fs, the CEPs of the two driving pulses of -pi and the relative strength ratio ?R=0.2. PMID- 24759781 TI - Social and economic conditions in childhood and the progression of functional health problems from midlife into old age. AB - BACKGROUND: Childhood living conditions have been found to predict health and mortality in midlife and in old age. This study examines the associations between social and economic childhood conditions and the onset and progression of functional health problems from midlife into old age, and the extent to which potential associations are mediated by educational attainment and smoking. METHODS: Data from the Level of Living Survey and the Swedish Panel Study of Living Conditions of the Oldest Old were merged to create a longitudinal data set with five repeated measures from 1968 to 2004 (n=1765, aged 30-50 years and free from functional health problems at baseline). Multilevel regression models were used to analyse retrospective reports of social and economic conditions in childhood (eg, conflicts or economic problems in the family) in relation to the progression of functional health problems over the 36-year period. RESULTS: Results showed that social and economic disadvantages in childhood were associated with an earlier onset and a faster progression of functional health problems from midlife into old age. Subsequent models showed that differences in educational attainment, but not smoking, explained much of the association between childhood disadvantages and trajectories of functional health problems. CONCLUSIONS: According to these results, adverse social and economic conditions in childhood affect the development of functional health problems from midlife into old age indirectly through less favourable life careers, including lower education. Creating equal opportunities for educational attainment may help reduce the long-term effects of disadvantaged childhood conditions and postpone functional health problems. PMID- 24759782 TI - Association between dietary intakes of PCBs and the risk of obesity: the SUN project. AB - BACKGROUND: Polychlorinated biphenyls (PCB) are persistent organic pollutants (POP) that are consumed because of their bioaccumulation through the food chain. Recent studies have suggested the implication of POPs in the development of metabolic diseases such as type 2 diabetes and obesity. However, this relationship is not entirely consistent, and has not been investigated in longitudinal studies. The purpose of this study was to prospectively examine the association between dietary intake of PCBs and the incidence of obesity in the Seguimiento Universidad de Navarra (SUN) Project. METHODS: Our study included 12 313 participants without obesity at baseline, who were followed-up for a median of 8.1 years. Dietary intakes of PCBs, expressed as WHO toxic equivalents, were assessed at baseline through a 136-item semiquantitative food-frequency questionnaire. The published concentration levels of PCBs measured in samples of food consumed in Spain were used to estimate intakes. Multivariable Cox regression models were fitted to estimate HRs and 95% CI for incident obesity. RESULTS: During follow-up, we observed 621 incident cases of obesity. After adjustment for total energy intake and additional adjustment for potential confounders, participants in the fifth quintile of PCBs intake were at higher risk of becoming obese (adjusted HR: 1.58; (95% CI 1.21 to 2.06)) compared to those in the first quintile. The linear trend test was statistically significant (p<0.001). CONCLUSIONS: Dietary intake of PCBs as estimated using a food frequency questionnaire was associated with a higher incidence of obesity. Nevertheless, further longitudinal studies are needed to confirm our results. PMID- 24759783 TI - Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4. AB - Mounting evidence indicates that oncogenic Ras can modulate cell autonomous inflammatory cytokine production, although the underlying mechanism remains unclear. Here we show that squamous cell carcinoma antigens 1 and 2 (SCCA1/2), members of the Serpin family of serine/cysteine protease inhibitors, are transcriptionally upregulated by oncogenic Ras via MAPK and the ETS family transcription factor PEA3. Increased SCCA expression leads to inhibition of protein turnover, unfolded protein response, activation of NF-kappaB and is essential for Ras-mediated cytokine production and tumour growth. Analysis of human colorectal and pancreatic tumour samples reveals a positive correlation between Ras mutation, enhanced SCCA expression and IL-6 expression. These results indicate that SCCA is a Ras-responsive factor that plays an important role in Ras associated cytokine production and tumorigenesis. PMID- 24759784 TI - Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1 induced glioblastoma cell apoptosis. AB - Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) is a divergent member of the transforming growth factor-beta (TGF-beta) superfamily. NAG-1 plays remarkable multifunctional roles in controlling diverse physiological and pathological processes including cancer. Like other TGF-beta family members, NAG-1 can play dual roles during cancer development and progression by negatively or positively modulating cancer cell behaviors. In glioblastoma brain tumors, NAG 1 appears to act as a tumor suppressor gene; however, the precise underlying mechanisms have not been well elucidated. In the present study, we discovered that overexpression of NAG-1 induced apoptosis in U87 MG, U118 MG, U251 MG, and T98G cell lines via the intrinsic mitochondrial pathway, but not in A172 and LN 229 cell lines. NAG-1 could induce the phosphorylation of PI3K/Akt and Smad2/3 in all six tested glioblastoma cell lines, except Smad3 phosphorylation in A172 and LN-229 cell lines. In fact, Smad3 expression and its phosphorylation were almost undetectable in A172 and LN-229 cells. The PI3K inhibitors promoted NAG-1-induced glioblastoma cell apoptosis, while siRNAs to Smad2 and Smad3 decreased the apoptosis rate. NAG-1 also stimulated the direct interaction between Akt and Smad3 in glioblastoma cells. Elevating the level of Smad3 restored the sensitivity to NAG-1-induced apoptosis in A172 and LN-229 cells. In conclusion, our results suggest that PI3K/Akt and Smad-dependent signaling pathways display opposing effects in NAG-1-induced glioblastoma cell apoptosis. PMID- 24759785 TI - Structural transition from helices to hemihelices. AB - Helices are amongst the most common structures in nature and in some cases, such as tethered plant tendrils, a more complex but related shape, the hemihelix forms. In its simplest form it consists of two helices of opposite chirality joined by a perversion. A recent, simple experiment using elastomer strips reveals that hemihelices with multiple reversals of chirality can also occur, a richness not anticipated by existing analyses. Here, we show through analysis and experiments that the transition from a helical to a hemihelical shape, as well as the number of perversions, depends on the height to width ratio of the strip's cross-section. Our findings provides the basis for the deterministic manufacture of a variety of complex three-dimensional shapes from flat strips. PMID- 24759786 TI - Universal ferroelectric switching dynamics of vinylidene fluoride trifluoroethylene copolymer films. AB - In this work, switching dynamics of poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] copolymer films are investigated over unprecedentedly wide ranges of temperature and electric field. Remarkably, domain switching of copolymer films obeys well the classical domain nucleation and growth model although the origin of ferroelectricity in organic ferroelectric materials inherently differs from the inorganic counterparts. A lower coercivity limit of 50 MV/m and 180 degrees domain wall energy of 60 mJ/m(2) are determined for P(VDF-TrFE) films. Furthermore, we discover in copolymer films an anomalous temperature-dependent crossover behavior between two power-law scaling regimes of frequency-dependent coercivity, which is attributed to the transition between flow and creep motions of domain walls. Our observations shed new light on the switching dynamics of semi-crystalline ferroelectric polymers, and such understandings are critical for realizing their reliable applications. PMID- 24759788 TI - Y chromosome gr/gr subdeletion is associated with lower semen quality in young men from the general Japanese population but not in fertile Japanese Men. AB - Several case-control studies have investigated whether Y chromosome haplogroups or deletions are associated with spermatogenic failure. However, the relationships between Y chromosome haplogroups or deletions and semen quality in general population have not been elucidated. In this study, we assessed relationships between Y chromosome haplogroups or deletions and semen parameters in 791 fertile Japanese men and 1221 young men from the general Japanese population. We found that the haplogroup D2 (M55 lineage) was significantly associated with lower semen parameters, especially total motile sperm count (P = 0.00051, beta = -0.097), in men from the general population but not in fertile men. In addition, we found that the gr/gr subdeletion was associated with semen quality and in particular, strongly associated with decreased sperm motility (P = 0.00041, beta = -3.14) and total motile sperm count (P = 0.00031, beta = -0.099) in men from the general population but not in fertile men. The combined analysis of fertile Japanese men and men from the general Japanese population showed that the haplogroup D2 (M55 lineage) and the gr/gr subdeletion were strongly associated with reduced sperm motility (P = 0.00056, beta = -2.71, and P = 7.7 * 10(-5), beta = -3.05, respectively) and that haplogroup O2b1 was strongly associated with elevated sperm motility (P = 0.00089, beta = 2.94). These observations add further support for the view that the gr/gr subdeletion diminishes sperm motility that consequently may result in male infertility. PMID- 24759787 TI - Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways. AB - Obese pregnant women have increased levels of proinflammatory cytokines in maternal circulation and placental tissues. However, the pathways contributing to placental inflammation in obesity are largely unknown. We tested the hypothesis that maternal body mass index (BMI) was associated with elevated proinflammatory cytokines in maternal and fetal circulations and increased activation of placental inflammatory pathways. A total of 60 women of varying pre-/early pregnancy BMI, undergoing delivery by Cesarean section at term, were studied. Maternal and fetal (cord) plasma were collected for analysis of insulin, leptin, IL-1beta, IL-6, IL-8, monocyte chemoattractant protein (MCP) 1, and TNFalpha by multiplex ELISA. Activation of the inflammatory pathways in the placenta was investigated by measuring the phosphorylated and total protein expression of p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase (JNK)-MAPK, signal transducer-activated transcription factor (STAT) 3, caspase-1, IL-1beta, IkappaB-alpha protein, and p65 DNA-binding activity. To determine the link between activated placental inflammatory pathways and elevated maternal cytokines, cultured primary human trophoblast (PHT) cells were treated with physiological concentrations of insulin, MCP-1, and TNFalpha, and inflammatory signaling analyzed by Western blot. Maternal BMI was positively correlated with maternal insulin, leptin, MCP-1, and TNFalpha, whereas only fetal leptin was increased with BMI. Placental phosphorylation of p38-MAPK and STAT3, and the expression of IL-1beta protein, were increased with maternal BMI; phosphorylation of p38-MAPK was also correlated with birth weight. In contrast, placental NFkappaB, JNK and caspase-1 signaling, and fetal cytokine levels were unaffected by maternal BMI. In PHT cells, p38-MAPK was activated by MCP-1 and TNFalpha, whereas STAT3 phosphorylation was increased following TNFalpha treatment. Maternal BMI is associated with elevated maternal cytokines and activation of placental p38-MAPK and STAT3 inflammatory pathways, without changes in fetal systemic inflammatory profile. Activation of p38-MAPK by MCP-1 and TNFalpha, and STAT3 by TNFalpha, suggests a link between elevated proinflammatory cytokines in maternal plasma and activation of placental inflammatory pathways. We suggest that inflammatory processes associated with elevated maternal BMI may influence fetal growth by altering placental function. PMID- 24759790 TI - Phosphorylation of CDK2 on threonine 160 influences silencing of sex chromosome during male meiosis. AB - In mammalian meiosis, the X and Y chromosomes are largely unsynapsed and transcriptionally silenced during the pachytene stage of meiotic prophase (meiotic sex chromosome inactivation), forming a specialized nuclear territory called sex or XY body. An increasing number of proteins and noncoding RNAs were found to localize to the sex body and take part in influencing expression of sex chromosome genes. Cyclin-dependent kinase 2 (Cdk2 (-/-)) spermatocytes show incomplete sex chromosome pairing. Here, we further showed that phosphorylation of CDK2 isoform 1 (p-CDK2(39) [39 kDa]) on threonine 160 localizes to the sites of asynapsis and the sex body, interacting with phosphorylated gamma-H2AX. Meanwhile, p-CDK2(39) is frequently mislocalized throughout the sex body, and meiotic sex chromosome inactivation is disrupted in PWK*C57BL/6J hybrid mice. Furthermore, pachytene spermatocytes treated with mevastatin (an inhibitor of p CDK2) showed overexpression of sex chromosome-linked genes. Our results highlight an important role for p-CDK2(39) in influencing silencing of the sex chromosomes during male meiosis by interacting with gamma-H2AX. PMID- 24759791 TI - Validation of CHA2DS2-VASc and HAS-BLED scores in Japanese patients with nonvalvular atrial fibrillation: an analysis of the J-RHYTHM Registry. AB - BACKGROUND: Recent European guidelines recommended the CHA2DS2-VASc score for thromboembolic and the HAS-BLED score for bleeding risk stratifications. We validated these scores in 7,384 Japanese patients with nonvalvular atrial fibrillation (NVAF) enrolled in the J-RHYTHM Registry. METHODS AND RESULTS: Of the study cohort, 6,387 patients taking warfarin and the other 997 not taking warfarin were prospectively examined for 2 years. Thromboembolic and major bleeding risks were stratified by modified CHA2DS2-VASc (mCHA2DS2-VASc) and HAS BLED (mHAS-BLED) scores, respectively. Of the patients with mCHA2DS2-VASc score 0, 1, and >=2, thromboembolism occurred in 2/141 (0.7%/year), 4/233 (0.9%/year), and 24/623 (1.9%/year), respectively, in the non-warfarin group, and in 1/346 (0.1%/year, P=0.19 vs. non-warfarin), 4/912 (0.2%/year, P=0.05), and 92/5,129 (0.9%/year, P=0.0005), respectively, in the warfarin group. When female sex was excluded from the score, thromboembolism occurred in 2/180 patients (0.6%/year), 5/245 (1.0%/year), and 23/572 (1.6%/year), respectively, in the non-warfarin group, and in 1/422 (0.1%/year, P=0.20 vs. non-warfarin), 5/1,096 (0.2%/year, P=0.02), and 91/4,869 (0.9%/year, P=0.0005), respectively, in the warfarin group. Patients with mHAS-BLED scores >=3 were at high risk for major bleeding irrespective of warfarin treatment (1.3 and 2.6%/year in the non-warfarin and warfarin groups, respectively). CONCLUSIONS: In Japanese NVAF patients, the mCHA2DS2-VASc score is useful for identifying patients at truly low risk of thromboembolism. Female sex may be excluded as a risk from the score. mHAS-BLED score >=3 is useful for identifying patients at high risk of major bleeding. PMID- 24759789 TI - Tissue-specific changes in molecular clocks during the transition from pregnancy to lactation in mice. AB - Circadian clocks regulate homeostasis and mediate responses to stressors. Lactation is one of the most energetically demanding periods of an adult female's life. Peripartum changes occur in almost every organ so the dam can support neonatal growth through milk production while homeostasis is maintained. How circadian clocks are involved in adaptation to lactation is currently unknown. The abundance and temporal pattern of core clock genes' expression were measured in suprachiasmatic nucleus, liver, and mammary from late pregnant and early lactation mice. Tissue-specific changes in molecular clocks occurred between physiological states. Amplitude and robustness of rhythms increased in suprachiasmatic nucleus and liver. Mammary rhythms of core molecular clock genes were suppressed. Attenuated rhythms appeared to be a physiological adaptation of mammary to lactation, because manipulation of timing of suckling resulting in significant differences in plasma prolactin and corticosterone had no effect on amplitude. Analysis of core clock proteins revealed that the stoichiometric relationship between positive (CLOCK) and negative (PER2) components remained 1:1 in liver but was increased to 4:1 in mammary during physiological transition. Induction of differentiation of mammary epithelial cell line HC11 with dexamethasone, insulin, and prolactin resulted in similar stoichiometric changes among positive and negative clock regulators, and prolactin induced phase shifts in HC11 Arntl expression rhythm. Data support that distinct mechanisms drive periparturient changes in mammary clock. Stoichiometric change in clock regulators occurs with gland differentiation. Suppression of mammary clock gene expression rhythms represents a physiological adaptation to suckling cues. Adaptations in mammary clock are likely needed in part to support suckling demands of neonates. PMID- 24759792 TI - Report of the American College of Cardiology (ACC) Scientific Sessions 2014, Washington, DC. AB - The American College of Cardiology (ACC) Scientific Session was held at the Walter E. Washington Convention Center in Washington, DC from March 29-31, 2014. The ACC Scientific Session is one of 3 major scientific cardiology meetings in the world, with over 20,000 attendees from 109 countries. There were over 2,200 oral and poster abstracts, and 22 late-breaking clinical trials (LBCTs), which are the focus of this report. Interestingly, in the CoreValve trials, transcatheter aortic valve replacement with a self-expanding transcatheter aortic valve bioprosthesis was associated with a higher survival rate at 1 year than surgical aortic valve replacement. Long-term results in a further study are needed. I hope the present report will encourage others to attend the ACC Scientific Session 2015 to be held in San Diego on March 14-16, 2015. PMID- 24759794 TI - Can coronary angioscopy predict drug-eluting stent thrombosis? PMID- 24759795 TI - Capacity and hypoxic response of subcutaneous adipose tissue blood flow in humans. AB - BACKGROUND: The blood flow capacity in subcutaneous adipose tissue in humans remains largely unknown, and therefore the aim of this study was to determine the physiological range of blood flow in this tissue. METHODS AND RESULTS: The subcutaneous adipose tissue blood flow (ATBF) was measured in 9 healthy young men by positron emission tomography using radiowater tracer. Subcutaneous ATBF was determined in regions adjacent to knee extensors at rest and during dynamic knee extensor exercise, and with 2 physiological perturbations: while breathing moderate systemic hypoxic air (14% O2) at rest and during exercise, and during intra-femoral artery infusion of high-dose adenosine infusion. ATBF was 1.3+/ 0.6ml.100g(-1).min(-1) at rest and increased with exercise (8.0+/-3.0ml.100g( 1).min(-1), P<0.001) and adenosine infusion (10.5+/-4.9ml.100g(-1).min(-1), P=0.001), but not when breathing moderate systemic hypoxic air (1.5+/-0.4ml.100g( 1).min(-1)). ATBF was similar during exercise and adenosine infusion, but vascular conductance was lower during adenosine infusion. Finally, ATBF during exercise in moderate systemic hypoxia was reduced (6.3+/-2.2ml.100g(-1).min(-1)) compared to normoxic exercise (P=0.004). CONCLUSIONS: The vasodilatation capacity of human subcutaneous adipose blood flow appears to be comparable to, or even higher, than that induced by moderate intensity exercise. Furthermore, the reduced blood flow response in subcutaneous adipose tissue during systemic hypoxia is likely to contribute, in part, to the redistribution of blood flow to exercising muscle in a condition of reduced oxygen availability. PMID- 24759793 TI - Transcriptome complexity in cardiac development and diseases--an expanding universe between genome and phenome. AB - With the advancement of transcriptome profiling by micro-arrays and high throughput RNA-sequencing, transcriptome complexity and its dynamics are revealed at different levels in cardiovascular development and diseases. In this review, we will highlight the recent progress in our knowledge of cardiovascular transcriptome complexity contributed by RNA splicing, RNA editing and noncoding RNAs. The emerging importance of many of these previously under-explored aspects of gene regulation in cardiovascular development and pathology will be discussed. PMID- 24759797 TI - Anomalous small angle x-ray scattering simulations: proof of concept for distance measurements for nanoparticle-labelled biomacromolecules in solution. AB - Anomalous small angle X-ray scattering can in principle be used to determine distances between metal label species on biological molecules. Previous experimental studies in the past were unable to distinguish the label-label scattering contribution from that of the molecule, because of the use of atomic labels; these labels contribute only a small proportion of the total scattering signal. However, with the development of nanocrystal labels (of 50-100 atoms) there is the possibility for a renewed attempt at applying anomalous small angle X-ray scattering for distance measurement. This is because the contribution to the scattered signal is necessarily considerably stronger than for atomic labels. Here we demonstrate through simulations, the feasibility of the technique to determine the end-to-end distances of labelled nucleic acid molecules as well as other internal distances mimicking a labelled DNA binding protein if the labels are dissimilar metal nanocrystals. Of crucial importance is the ratio of mass of the nanocrystals to that of the labelled macromolecule, as well as the level of statistical errors in the scattering intensity measurements. The mathematics behind the distance determination process is presented, along with a fitting routine than incorporates maximum entropy regularisation. PMID- 24759796 TI - Efficacy and safety of adjusted-dose prasugrel compared with clopidogrel in Japanese patients with acute coronary syndrome: the PRASFIT-ACS study. AB - BACKGROUND: Prasugrel is an antiplatelet agent that shows more prompt, potent, and consistent platelet inhibition than clopidogrel. The objective of this study was to confirm the efficacy and safety of prasugrel at loading/maintenance doses of 20/3.75 mg. METHODS AND RESULTS: Japanese patients (n=1,363) with acute coronary syndrome undergoing percutaneous coronary intervention were randomized to either prasugrel (20/3.75 mg) or clopidogrel (300/75 mg), both in combination with aspirin (81-330 mg for the first dose and 81-100 mg/day thereafter), for 24 48 weeks. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE) at 24 weeks, defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke. We compared the incidence of MACE between the 2 groups using point estimates. Safety outcomes included the incidence of bleeding events until 2 weeks after the last dose. The incidence of MACE at 24 weeks was 9.4% in the prasugrel group and 11.8% in the clopidogrel group (risk reduction 23%, hazard ratio 0.77, 95% confidence interval 0.56-1.07). The incidence of non-coronary artery bypass graft-related major bleeding was similar in both groups (1.9% vs. 2.2%). CONCLUSIONS: Prasugrel 20/3.75 mg was associated with a low incidence of ischemic events, similar to the results of TRITON-TIMI 38, and with a low risk of clinically serious bleeding in Japanese ACS patients. PMID- 24759799 TI - A comparison of vasopressin, terlipressin, and lactated ringers for resuscitation of uncontrolled hemorrhagic shock in an animal model. AB - AIM: The aim of this study is to compare the effect of lactated ringer (LR), vasopressin (Vaso) or terlipressin (Terli) on uncontrolled hemorrhagic shock (UHS) in rats. METHODS: 48 rats were divided into four treatment groups for UHS study. Vaso group was given bolus vasopressin (0.8 U/kg); the Terli group was given bolus terlipressin (15 mcg/kg); LR group was given LR and the sham group was not given anything. Mean arterial pressure (MAP), serum lactate level, plasma cytokine levels, lung injury and mortality are investigated for these different treatment groups. RESULTS: Compared with LR group, vasopressin and terlipressin treated groups were associated with higher MAP, lowered mortality rates, less lung injury, lowered serum lactate level, less proinflammatory and more anti inflammatory cytokine production at certain time points. Comparing between vasopressin and terlipressin treated groups, there is no statistical difference in mortality rates, lung injury, serum lactate level and cytokine level. However, there is a difference in the length of time in maintaining a restored level of MAP (80 to 110 mmHg). The terlipressin treated rats can maintain this restored level of MAP for 45 minutes, but the vasopressin treated rats can only maintain this restored level of MAP for 5 minutes before decreasing gradually to the MAP observed in LR group (40 mmHg). CONCLUSION: Early optimization of hemodynamics with terlipressin or vasopressin in an animal model of UHS was associated with improved hemodynamics and inflammatory cytokine profile than the LR control. Compared with vasopressin, terlipressin has the advantage of ease of use and sustained effects. PMID- 24759798 TI - Brain signature of chronic orofacial pain: a systematic review and meta-analysis on neuroimaging research of trigeminal neuropathic pain and temporomandibular joint disorders. AB - Brain neuroimaging has been widely used to investigate the bran signature of chronic orofacial pain, including trigeminal neuropathic pain (TNP) and pain related to temporomandibular joint disorders (TMD). We here systematically reviewed the neuroimaging literature regarding the functional and structural changes in the brain of TNP and TMD pain patients, using a computerized search of journal articles via PubMed. Ten TNP studies and 14 TMD studies were reviewed. Study quality and risk of bias were assessed based on the criteria of patient selection, the history of medication, the use of standardized pain/psychological assessments, and the model and statistics of imaging analyses. Qualitative meta analysis was performed by examining the brain regions which showed significant changes in either brain functions (including the blood-oxygen-level dependent signal, cerebral blood flow and the magnetic resonance spectroscopy signal) or brain structure (including gray matter and white matter anatomy). We hypothesized that the neuroimaging findings would display a common pattern as well as distinct patterns of brain signature in the disorders. This major hypothesis was supported by the following findings: (1) TNP and TMD patients showed consistent functional/structural changes in the thalamus and the primary somatosensory cortex, indicating the thalamocortical pathway as the major site of plasticity. (2) The TNP patients showed more alterations at the thalamocortical pathway, and the two disorders showed distinct patterns of thalamic and insular connectivity. Additionally, functional and structural changes were frequently reported in the prefrontal cortex and the basal ganglia, suggesting the role of cognitive modulation and reward processing in chronic orofacial pain. The findings highlight the potential for brain neuroimaging as an investigating tool for understanding chronic orofacial pain. PMID- 24759800 TI - Tyrosine phosphorylation of beta-catenin affects its subcellular localization and transcriptional activity of beta-catenin in Hela and Bcap-37 cells. AB - In order to investigate the relationship between tyrosine phosphorylation of beta catenin and transcriptional activity of beta-catenin in Hela and Bcap-37 cells, genistein (a tyrosine kinase inhibitor) was used to inhibit tyrosine phosphorylation in cells. Our results showed the total beta-catenin protein levels were mainly equal in Hela, Bcap-37 and HK-2 cells, beta-catenin was mainly present in nucleus in Hela and Bcap-37cells, while in HK-2 cell beta-catenin was mainly located in cytoplasm. Genistein could inhibit tyrosine phosphorylation of beta-catenin and downregulate nuclear beta-catenin expression in Hela and Bcap-37 cells. In addition, genistein suppressed Ki-67 promoter activity and Ki-67 protein level, thus promoted cell apoptosis. Furthermore, beta-catenin could increase the Ki-67 promoter activity in Hela and Bcap-37 cells. From these findings we conclude that tyrosine phosphorylation of beta-catenin can regulate the cellular distribution of beta-catenin and affect the transcriptional activity of beta-catenin. PMID- 24759801 TI - Scaling relationships between leaf mass and total plant mass across Chinese forests. AB - Biomass partitioning is important for illustrating terrestrial ecosystem carbon flux. West, Brown and Enquist (WBE) model predicts that an optimal 3/4 allometric scaling of leaf mass and total biomass of individual plants will be applied in diverse communities. However, amount of scientific evidence suggests an involvement of some biological and environmental factors in interpreting the variation of scaling exponent observed in empirical studies. In this paper, biomass information of 1175 forested communities in China was collected and categorized into groups in terms of leaf form and function, as well as their locations to test whether the allocation pattern was conserved or variable with internal and/or environmental variations. Model Type II regression protocol was adopted to perform all the regressions. The results empirically showed that the slopes varied significantly across diverse forested biomes, between conifer and broadleaved forests, and between evergreen and deciduous forests. Based on the results, leaf form and function and their relations to environments play a significant role in the modification of the WBE model to explore more accurate laws in nature. PMID- 24759802 TI - Detecting human presence at the border of the Northeastern Italian Pre-Alps. 14C dating at Rio Secco cave as expression of the first Gravettian and the late mousterian in the Northern Adriatic Region. AB - In the northern Adriatic regions, which include the Venetian region and the Dalmatian coast, late Neanderthal settlements are recorded in few sites and even more ephemeral are remains of the Mid-Upper Palaeolithic occupations. A contribution to reconstruct the human presence during this time range has been produced from a recently investigated cave, Rio Secco, located in the northern Adriatic region at the foot of the Carnic Pre-Alps. Chronometric data make Rio Secco a key site in the context of recording occupation by late Neanderthals and regarding the diffusion of the Mid-Upper Palaeolithic culture in a particular district at the border of the alpine region. As for the Gravettian, its diffusion in Italy is a subject of on-going research and the aim of this paper is to provide new information on the timing of this process in Italy. In the southern end of the Peninsula the first occupation dates to around 28,000 14C BP, whereas our results on Gravettian layer range from 29,390 to 28,995 14C years BP. At the present state of knowledge, the emergence of the Gravettian in eastern Italy is contemporaneous with several sites in Central Europe and the chronological dates support the hypothesis that the Swabian Gravettian probably dispersed from eastern Austria. PMID- 24759803 TI - Chemopreventive and therapeutic effects of nimbolide in cancer: the underlying mechanisms. AB - Cancer chemoprevention is a strategy taken to block, reverse or retard the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. Naturally occurring phytochemicals are becoming increasingly popular over synthetic drugs for several reasons, including safety, efficacy and easy availability. Nimbolide, a triterpene derived from the leaves and flowers of neem, is widely used in traditional medical practices for treating various human ailments. The neem limonoid exhibits multiple pharmacological effects among which its anticancer activity is the most promising. The preclinical and mechanistic studies carried over the decades have shown that nimbolide inhibits tumorigenesis and metastasis without any toxicity and unwanted side effects. Nimbolide exhibits anticancer activity through selective modulation of multiple cell signaling pathways linked to inflammation, survival, growth, invasion, angiogenesis and metastasis. The present review highlights the current knowledge on molecular targets that contribute to the observed anticancer activity of nimbolide related to (i) inhibition of carcinogenic activation and induction of antioxidant and carcinogen detoxification enzymes, (ii) induction of growth arrest and apoptosis; and (iii) suppression of proinflammatory signaling pathways related to cancer progression. PMID- 24759804 TI - Zinc oxide nanoparticles delay human neutrophil apoptosis by a de novo protein synthesis-dependent and reactive oxygen species-independent mechanism. AB - Inflammation is one of the major toxic effects reported in the literature following nanoparticle (NP) exposure. Knowing the importance of neutrophils to orchestrate inflammation, it is surprising that the direct role of NPs on neutrophil biology is poorly documented. Here, we investigated if ZnO NPs can alter neutrophil biology. We found that ZnO NPs increased the cell size, induced cell shape changes, activated phosphorylation events, enhanced cell spreading onto glass, but did not induce the generation of reactive oxygen species (ROS). Treatment of neutrophils with ZnO NPs markedly and significantly inhibited apoptosis and increased de novo protein synthesis, as demonstrated by gel electrophoresis of metabolically [(35)S]-labeled cells. Utilization of the protein synthesis inhibitor, cycloheximide, reversed such antiapoptotic effect. We conclude that ZnO NPs are activators of several human neutrophil functions and that they inhibit apoptosis by a de novo protein synthesis-dependent and ROS independent mechanism. This is the first example that a NP acts on the neo synthesis of polypeptides. PMID- 24759808 TI - Proposal for demonstrating the Hong-Ou-Mandel effect with matter waves. AB - The Hong-Ou-Mandel effect is a demonstration of destructive quantum interference between pairs of indistinguishable bosons, realised so far only with massless photons. Here we propose an experiment to realize this effect in the matter-wave regime using pair-correlated atoms produced via a collision of two Bose-Einstein condensates and subjected to two laser--induced Bragg pulses. We formulate a measurement protocol for the multimode matter-wave field, which--unlike the typical two-mode optical case-bypasses the need for repeated measurements under different displacement settings of the beam splitter, markedly reducing the number of experimental runs required to map out the interference visibility. Although the protocol can be used in related matter-wave schemes, we focus on condensate collisions. By simulating the entire experiment, we predict a Hong-Ou Mandel dip visibility of ~69%. This visibility highlights strong quantum correlations between the atoms, paving the way for a possible demonstration of a Bell inequality violation with massive particles in a related Rarity-Tapster setup. PMID- 24759805 TI - A pathogenesis related protein, VpPR-10.1, from Vitis pseudoreticulata: an insight of its mode of antifungal activity. AB - Previously, VpPR-10.1 was isolated and characterized from a cDNA library of a fungus-resistant accession of Chinese wild grape (Vitis pseudoreticulata). We found that expression of VpPR-10.1 is affected by the fungal pathogen Erysiphe necator. To investigate the biochemical basis of the nuclease activity of VpPR 10.1 and its role in antifungal resistance, we generated recombinant VpPR-10.1 as well as site-directed mutations targeting three conserved amino acid residues among plant PR-10 s: Lys55, Glu149, and Tyr151. We showed that wild-type recombinant VpPR-10.1 exhibits both RNase and DNase activities. Mutant VpPR10.1 Y151H essentially retained all these activities. In contrast, VpPR10.1-K55N, where Lys55 in the P-loop region is mutated to Asn, and VpPR10.1-E149G, where Glu149 is mutated to Gly, lost their nuclease activity, indicating that both residues play a critical role in catalyzing RNA and DNA degradation. Furthermore, VpPR10.1 and VpPR10.1-Y151H inhibited the growth of the cultured fungal pathogen Alternaria alternate. Through transient expression in grapevine, we also demonstrated that VpPR10.1-K55N and VpPR10.1-E149G compromised resistance to E. necator. Finally, we further found that VpPR-10.1 can lead to programmed cell death and DNA degradation when incubated with tobacco BY-2 suspension cells. We show here that Lys55 and Glu149, but not Tyr151, are required for the RNase, DNase and antifungal activities of VpPR-10.1. The strong correlation between the level of VpPR-10.1 nuclease activity and its antifungal property indicates that the former is the biochemical basis for the latter. Taken together, our experiments revealed that VpPR-10.1 is critical in mediating fungal resistance in grape, potentially playing a dual role by degrading pathogen RNA and inducing programmed death of host cells. PMID- 24759809 TI - Identification of fall risk predictors in daily life measurements: gait characteristics' reliability and association with self-reported fall history. AB - Background. Gait characteristics extracted from trunk accelerations during daily life locomotion are complementary to questionnaire- or laboratory-based gait and balance assessments and may help to improve fall risk prediction. Objective. The aim of this study was to identify gait characteristics that are associated with self-reported fall history and that can be reliably assessed based on ambulatory data collected during a single week. Methods. We analyzed 2 weeks of trunk acceleration data (DynaPort MoveMonitor, McRoberts) collected among 113 older adults (age range, 65-97 years). During episodes of locomotion, various gait characteristics were determined, including local dynamic stability, interstride variability, and several spectral features. For each characteristic, we performed a negative binomial regression analysis with the participants' self-reported number of falls in the preceding year as outcome. Reliability of gait characteristics was assessed in terms of intraclass correlations between both measurement weeks. Results. The percentages of spectral power below 0.7 Hz along the vertical and anteroposterior axes and below 10 Hz along the mediolateral axis, as well as local dynamic stability, local dynamic stability per stride, gait smoothness, and the amplitude and slope of the dominant frequency along the vertical axis, were associated with the number of falls in the preceding year and could be reliably assessed (all P < .05, intraclass correlation > 0.75). Conclusions. Daily life gait characteristics are associated with fall history in older adults and can be reliably estimated from a week of ambulatory trunk acceleration measurements. PMID- 24759811 TI - Se14, encoding a JmjC domain-containing protein, plays key roles in long-day suppression of rice flowering through the demethylation of H3K4me3 of RFT1. AB - Floral transition from the vegetative to the reproductive growth phase is a major change in the plant life cycle and a key factor in reproductive success. In rice (Oryza sativa L.), a facultative short-day plant, numerous flowering time and flower formation genes that control floral transition have been identified and their physiological effects and biochemical functions have been clarified. In the present study, we used a Se14-deficient mutant line (HS112) and other flowering mutant lines to investigate the photoperiodic response, chromosomal location and function in the photoperiod sensitivity of the Se14 gene. We also studied the interactive effects of this locus with other crucial flowering time genes. We found that Se14 is independent of the known photoperiod-sensitive genes, such as Hd1 and Ghd7, and is identical to Os03g0151300, which encodes a Jumonji C (JmjC) domain-containing protein. Expression analysis revealed that the expressions of RFT1, a floral initiator known as a "florigen-like gene", and Ehd1 were up regulated in HS112, whereas this up-regulation was not observed in the original variety of 'Gimbozu'. ChIP assays of the methylation states of histone H3 at lysine 4 (H3K4) revealed that the trimethylated H3K4 in the promoter region of the RFT1 chromatin was significantly increased in HS112. We conclude that Se14 is a novel photoperiod-sensitivity gene that has a suppressive effect on floral transition (flowering time) under long day-length conditions through the modification of chromatin structure by H3K4me3 demethylation in the promoter region of RFT1. PMID- 24759812 TI - Transanal endoscopic microsurgery: what indications in 2013? AB - Thanks to major advances in the field of surgical techniques and neoadjuvant chemoradiation therapy, along with more accurate pre-operative staging tools and the widespread introduction of population-based screening programs, treatment of rectal cancer has been evolving over the past few decades, moving towards a more tailored approach. This has brought a shift in the treatment algorithm of benign rectal lesions and selected early rectal cancers, for which today transanal endoscopic microsurgery (TEM) is accepted as an effective alternative to abdominal surgery. In 2013, topics of controversy are the role of TEM in the treatment of more advanced rectal cancers, in cases of complete pathological response after chemoradiation therapy and the role of TEM as a platform for single-port surgery and NOTES. This article reviews the current indications for TEM and the future perspectives of this approach in the treatment of rectal tumors. PMID- 24759813 TI - Immune response after laparoscopic colectomy for cancer: a review. AB - BACKGROUND AND AIM: Colorectal cancer (CRC) is the third leading cause of cancer mortality worldwide and laparoscopic colectomy has been established as equivalent to the open approach in terms of oncological results and patients' safety. Survival benefits have been reported in favor of laparoscopic colectomy (LC) in stage III CRC patients. Different immune responses after surgery, in terms of innate and cellular immunity, may potentially explain some of the reported differences. This review summarizes the literature on differences in immune response after the laparoscopic and the open approach for CRC. MATERIALS AND METHODS: A literature search of electronic databases was conducted and all studies published on 'colorectal cancer', 'laparoscopic and open colectomy' 'immune response' and 'surgical stress laparoscopy versus open' were collected. Among these, the ones referring to CRC and those that had any clinical relevance offering information on perioperative parameters were used. RESULTS: Despite the heterogeneity of studies, they support the view that innate immune response is activated to a greater degree in open colectomy (OC), which may be related to the more extensive trauma and surgical stress. On the other hand, cellular immunity is better preserved after LC. These differences are more pronounced in the immediate postoperative period. CONCLUSIONS: LC has been related to decreased up regulation of innate immunity and better-preserved cellular immunity. The latter may be related to better anti-tumor activity and may be beneficial in terms of oncological survival in a subgroup of LC patients. PMID- 24759814 TI - Managing Barrett's esophagus with radiofrequency ablation. AB - Barrett's esophagus (BE) is a well-established pre-malignant lesion for esophageal adenocarcinoma, a condition that carries a dismal five-year overall survival rate of less than 15%. Among several available methods to eliminate BE, radiofrequency ablation (RFA) provides the most efficient modality, since it has been demonstrated to successfully eradicate BE with or without dysplasia with acceptable safety, efficacy and durability profiles. In conjunction with proton pump therapy, this new technology has quickly become the standard care for patients with dysplastic BE. However, several technical questions remain about how to deploy RFA therapy for maximum effectiveness and long-term favorable outcomes for all stages of the disease. These include how to select patient for therapy, what the best protocol for RFA is, when to use other modalities, such as endoscopic mucosal resection, and what should be considered for refractory BE. This review addresses these questions with the perspective of the best available evidence matched with the authors' experience with the technology. PMID- 24759815 TI - Evidence-based review of the management of early gastric cancer. AB - Although standard gastrectomy remains the most definitive locoregional treatment for early gastric cancer, it carries significant perioperative morbidities. Surgical gastrectomy for resection of lymph nodes is not always required and endoscopic resection may be a treatment option for patients at negligible risk of lymph node metastasis. Furthermore, the criteria for endoscopic resection are expanding, along with the development of new technology, in both Eastern and western countries with high prevalence of early gastric cancer, where studies for endoscopic treatment modalities have been conducted. Within such a trend, however, it should be emphasized that early gastric cancer needs to be treated cautiously, especially in western countries, as several studies suggest that there may be differences in tumor biology and aggressiveness between Asian and non-Asian populations. PMID- 24759816 TI - Re-examination of the standardization of colon cancer surgery. AB - The standardization of colon cancer surgery has been an area of intense interest. The recent establishment of the complete mesocolic excision (CME) technique has defined the operative approach for colon cancer surgeries and enabled the collection of high-quality oncological specimens for histopathological evaluation. Standard for the Diagnosis and Treatment of Colorectal Cancer (2010), issued by the Ministry of Health of China, has provided legal bases for the treatment of colorectal cancers. However, certain confusions remain due to lack of detailed guidelines for operations. This raised the key question: "What is the standardized colon cancer surgery?" The present study re-examined the core ideas of General Rules for Clinical and Pathological Studies on Cancer of the Colon, Rectum and Anus (seventh edition) published by the Japanese Society for Cancer of the Colon and Rectum. CME-related studies published in English academic journals between April 2009 and July 2012 were surveyed and analysed. Several technical issues related to the requirement of R0 resection were analysed, including the theoretical basis for the safety range of bowel resection and the rational determination of the range of regional lymph node dissection. PMID- 24759817 TI - Total gastrectomy for locally advanced cancer: the pure laparoscopic approach. PMID- 24759818 TI - Open transinguinal preperitoneal mesh repair of inguinal hernia: a targeted systematic review and meta-analysis of published randomized controlled trials. AB - OBJECTIVE: The objective of this article is to systematically analyse the randomized, controlled trials comparing transinguinal preperitoneal (TIPP) and Lichtenstein repair (LR) for inguinal hernia. METHODS: Randomized, controlled trials comparing TIPP vs LR were analysed systematically using RevMan(r) and combined outcomes were expressed as risk ratio (RR) and standardized mean difference. RESULTS: Twelve randomized trials evaluating 1437 patients were retrieved from the electronic databases. There were 714 patients in the TIPP repair group and 723 patients in the LR group. There was significant heterogeneity among trials (P < 0.0001). Therefore, in the random effects model, TIPP repair was associated with a reduced risk of developing chronic groin pain (RR, 0.48; 95% CI, 0.26, 0.89; z = 2.33; P < 0.02) without influencing the incidence of inguinal hernia recurrence (RR, 0.18; 95% CI, 0.36, 1.83; z = 0.51; P = 0.61). Risk of developing postoperative complications and moderate-to-severe postoperative pain was similar following TIPP repair and LR. In addition, duration of operation was statistically similar in both groups. CONCLUSION: TIPP repair for inguinal hernia is associated with lower risk of developing chronic groin pain. It is comparable with LR in terms of risk of hernia recurrence, postoperative complications, duration of operation and intensity of postoperative pain. PMID- 24759819 TI - Postoperative ileus in colorectal surgery: is there any difference between laparoscopic and open surgery? AB - BACKGROUND: Postoperative ileus is a major complication of patients undergoing abdominal surgery. The purpose of this study was to determine the effects of operative time and the method of surgery on postoperative ileus. METHODS: After institutional review board approval, 121 patients were studied in two groups. Group 1 consisted of 86 patients with colorectal cancers and Group 2 included 35 patients with diverticulitis. Various surgical procedures were performed in both groups. In all patients, the nasogastric (NG) tube was removed after termination of surgery. Clear liquids were offered commencing on the first postoperative day, followed by a regular diet as tolerated. GI-1 was the postoperative time to toleration of clear liquids, whereas GI-2 was the postoperative time to first bowel movement or flatus and toleration of a regular diet. Statistical analysis was performed using a linear regression model by disease with the first bowel movement or flatus as the dependent variable and operative time and category as explanatory variables. RESULTS: Vomiting after oral feeding occurred in 18 (20.9%) patients with cancer and in 7 (20.0%) patients with diverticular disease. An NG tube was reinserted in 13 (15.1%) patients in the cancer group and in 3 (8.6%) patients in the diverticular disease group. In patients with cancer, the duration of operation was associated with GI-2 (P = 0.011), whereas in patients with diverticulitis, the duration of operation was associated with GI-1 (P = 0.001) and GI-2 (P = 0.044). In the diverticulitis group, a significant relationship was found between GI-2 and operative category (P = 0.03). CONCLUSION: Longer operations led to more prolonged postoperative ileus after both laparoscopy and laparotomy, regardless of malignant or benign pathology. In anticipation of and/or following longer operations, surgeons should consider measures to shorten postoperative ileus. PMID- 24759820 TI - Laparoscopic adjustable gastric banding: a report of 228 cases. AB - OBJECTIVE: To evaluate the surgical outcomes and complications after laparoscopic adjustable gastric banding (LAGB) in obese patients. METHODS: This retrospective study included 228 patients (73 males and 155 females, mean age, 32.5 +/- 10.3 years) who underwent LAGB at the Changhai Hospital of the Second Military Medical University from June 2003 to June 2011. The body weight and postoperative complications were followed up. RESULTS: The pre-operative mean body mass index (BMI) was 39.5 +/- 6.3 kg/m(2). Except in one case of inadequate exposure of the stomach, all laparoscopic procedures were successfully accomplished, with no conversion to open surgery. The mean operation time was 65.0 +/- 20.3 min. The mean hospital stay was 2.7 +/- 0.9 days. Early postoperative complications (<30 days) occurred in five cases (2.2%) and late complications (>30 days) occurred in 75 cases (32.9%), including 56 cases (24.6%) with band-associated complications. The percentage of excess weight loss (EWL%) at 1, 3 and 5 years was 40.5 +/- 30.5%, 59.5 +/- 41.5% and 58.9 +/- 46.4%, respectively. The percentages of patients with EWL% >25%, >50% and >75% were, respectively, 60%, 33% and 0% at 1 year follow-up, 43%, 39%, and 16% at 3 years follow-up and 40%, 34% and 16% at 5 years follow-up. CONCLUSION Although LAGB has low peri-operative mortality and morbidity rates, it is associated with a high late complication rate and unsatisfactory weight loss. It may be optional, but not the first choice, for the treatment of obesity. PMID- 24759821 TI - Laparoscopic reversal of Hartmann's procedure: safety and feasibility. AB - AIMS: The present study aimed to compare the surgical outcomes of patients receiving laparoscopic reversal of Hartmann's procedure (RHP) with those receiving open surgery. METHODS: Records of all patients with RHP performed in our unit (including laparoscopic and open surgery) between 2000 and 2012 were retrieved. Data were retrospectively reviewed and compared. RESULTS: Eighty-two RHPs were performed between 2000 and 2012. Thirty-five were performed with an open approach and 47 with a laparoscopic approach. Conversion rate was 28% in the laparoscopic group. There was no difference, between the two groups, in operation time or blood loss. The median length of stay was significantly shorter in the laparoscopic group (12 vs 14 days, P = 0.002) and fewer patients in the laparoscopic group had complications with post-operative paralytic ileus (2 vs 17%, P = 0.038). None of the patients in the laparoscopic group developed incisional hernia at the conclusion of follow-up, as opposed to five in the open group (0 vs 14%, P = 0.012). CONCLUSION: Laparoscopic RHP is safe and feasible, with more favorable surgical outcomes, when compared with open surgery. Conversion rate is acceptable. It should be the technique of choice for patients undergoing RHP. PMID- 24759822 TI - Mercury reduces avian reproductive success and imposes selection: an experimental study with adult- or lifetime-exposure in zebra finch. AB - Mercury is a global pollutant that biomagnifies in food webs, placing wildlife at risk of reduced reproductive fitness and survival. Songbirds are the most diverse branch of the avian evolutionary tree; many are suffering persistent and serious population declines and we know that songbirds are frequently exposed to mercury pollution. Our objective was to determine the effects of environmentally relevant doses of mercury on reproductive success of songbirds exposed throughout their lives or only as adults. The two modes of exposure simulated philopatric species versus dispersive species, and are particularly relevant because of the heightened mercury-sensitivity of developing nervous systems. We performed a dosing study with dietary methylmercury in a model songbird species, the zebra finch (Taeniopygia guttata), at doses from 0.3 - 2.4 parts per million. Birds were exposed to mercury either as adults only or throughout their lives. All doses of mercury reduced reproductive success, with the lowest dose reducing the number of independent offspring produced in one year by 16% and the highest dose, representing approximately half the lethal dose for this species, causing a 50% reduction. While mercury did not affect clutch size or survivorship, it had the most consistent effect on the proportion of chicks that fledged from the nest, regardless of mode of exposure. Among birds exposed as adults, mercury caused a steep increase in the latency to re-nest after loss of a clutch. Birds exposed for their entire lifetimes, which were necessarily the offspring of dosed parents, had up to 50% lower reproductive success than adult-exposed birds at low doses of methylmercury, but increased reproductive success at high doses, suggesting selection for mercury tolerance at the highest level of exposure. Our results indicate that mercury levels in prey items at contaminated sites pose a significant threat to populations of songbirds through reduced reproductive success. PMID- 24759825 TI - Advanced HIV disease at antiretroviral therapy (ART) initiation despite implementation of expanded ART eligibility guidelines during 2007-2012 in Khayelitsha, South Africa. PMID- 24759824 TI - Dependence on the CCR5 coreceptor for viral replication explains the lack of rebound of CXCR4-predicted HIV variants in the Berlin patient. AB - The "Berlin patient" is the first patient cured of HIV-1 infection after allogeneic transplantation with nonfunctional CCR5 coreceptor stem cells. We demonstrate that CXCR4-predicted minority viruses present prior to transplantation were unable to rebound after transplantation due to their dependence on CCR5 for replication and high genetic barrier toward CXCR4 usage. PMID- 24759826 TI - Artemisinin-based combination therapies are efficacious and safe for treatment of uncomplicated malaria in HIV-infected Ugandan children. AB - BACKGROUND: Artemisinin-based combination therapies (ACTs) are highly efficacious and safe, but data from human immunodeficiency virus (HIV)-infected children concurrently receiving antiretroviral therapy (ART) and ACTs are limited. METHODS: We evaluated 28-day outcomes following malaria treatment with artemether lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in 2 cohorts of HIV infected Ugandan children taking various ART regimens. In one cohort, children <6 years of age were randomized to lopinavir/ritonavir (LPV/r) or nonnucleoside reverse transcriptase inhibitor-based ART and treated with AL for uncomplicated malaria. In another cohort, children <12 months of age were started on nevirapine based ART if they were eligible, and randomized to AL or DP for the treatment of their first and all subsequent uncomplicated malaria episodes. RESULTS: There were 773 and 165 treatments for malaria with AL and DP, respectively. Initial response to therapy was excellent, with 99% clearance of parasites and <1% risk of repeat therapy within 3 days. Recurrent parasitemia within 28 days was common following AL treatment. The risk of recurrent parasitemia was significantly lower among children taking LPV/r-based ART compared with children taking nevirapine based ART following AL treatment (15.3% vs 35.5%, P = .009), and those treated with DP compared with AL (8.6% vs 36.2%, P < .001). Both ACT regimens were safe and well tolerated. CONCLUSIONS: Treatment of uncomplicated malaria with AL or DP was efficacious and safe in HIV-infected children taking ART. However, there was a high risk of recurrent parasitemia following AL treatment, which was significantly lower in children taking LPV/r-based ART compared with nevirapine based ART. PMID- 24759828 TI - Reply to Solari et al. PMID- 24759827 TI - Causes and determinants of mortality in HIV-infected adults with tuberculosis: an analysis from the CAMELIA ANRS 1295-CIPRA KH001 randomized trial. AB - BACKGROUND: Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)-infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival. METHODS: We assessed mortality rates, causes of death, and factors of mortality in Cambodian HIV-infected adults with CD4 count <=200 cells/uL and tuberculosis, randomized to initiate ART either 2 weeks (early ART) or 8 weeks (late ART) after tuberculosis treatment onset in the CAMELIA clinical trial. RESULTS: Six hundred sixty-one patients enrolled contributed to 1366.1 person-years of follow-up; 149 (22.5%) died. There were 8.3 deaths per 100 person-years (95% confidence interval [CI], 6.4-10.7) in the early ART group and 13.8 deaths per 100 person-years (95% CI, 11.2-16.9) in the late ART group (P = .002). Tuberculosis was the primary cause of death (28%), followed by other HIV-associated conditions (19%). Factors independently associated with mortality in the first 26 weeks were the age, body mass index, hemoglobin, interrupted or ineffective tuberculosis treatment before identification of drug resistance, disseminated tuberculosis, and nontuberculous mycobacterial disease. After 50 weeks in the trial, the most frequent causes of death were non-HIV related or tuberculosis related, including drug toxicity; factors associated with mortality were late ART, loss to follow-up, and absence of cotrimoxazole prophylaxis. CONCLUSIONS: Despite ART introduction, mortality remained high, with tuberculosis as the leading cause of death. Reducing tuberculosis-related mortality remains a challenge in resource-limited settings and requires innovative strategies. Clinical Trials Registration. NCT00226434. PMID- 24759829 TI - The forgotten component in the staging and management of HIV/hepatitis C virus coinfected patients. PMID- 24759831 TI - Reply to Patten et al. PMID- 24759832 TI - Tempered enthusiasm for fecal transplant. PMID- 24759833 TI - Phenolic glycolipid-I does not cross-react with visceral leishmaniasis sera in a Brazilian subset. PMID- 24759830 TI - Invasive pneumococcal disease in children can reveal a primary immunodeficiency. AB - BACKGROUND: About 10% of pediatric patients with invasive pneumococcal disease (IPD) die from the disease. Some primary immunodeficiencies (PIDs) are known to confer predisposition to IPD. However, a systematic search for these PIDs has never been carried out in children presenting with IPD. METHODS: We prospectively identified pediatric cases of IPD requiring hospitalization between 2005 and 2011 in 28 pediatric wards throughout France. IPD was defined as a positive pneumococcal culture, polymerase chain reaction result, and/or soluble antigen detection at a normally sterile site. The immunological assessment included abdominal ultrasound, whole-blood counts and smears, determinations of plasma immunoglobulin and complement levels, and the evaluation of proinflammatory cytokines. RESULTS: We included 163 children with IPD (male-to-female ratio, 1.3; median age, 13 months). Seventeen children had recurrent IPD. Meningitis was the most frequent type of infection (87%); other infections included pleuropneumonitis, isolated bloodstream infection, osteomyelitis, endocarditis, and mastoiditis. One patient with recurrent meningitis had a congenital cerebrospinal fluid fistula. The results of immunological explorations were abnormal in 26 children (16%), and a PID was identified in 17 patients (10%), including 1 case of MyD88 deficiency, 3 of complement fraction C2 or C3 deficiencies, 1 of isolated congenital asplenia, and 2 of Bruton disease (X linked agammaglobulinemia). The proportion of PIDs was much higher in children aged >2 years than in younger children (26% vs 3%; P < .001). CONCLUSIONS: Children with IPD should undergo immunological investigations, particularly those aged >2 years, as PIDs may be discovered in up to 26% of cases. PMID- 24759834 TI - Cost-effective mapping of benthic habitats in inland reservoirs through split beam sonar, indicator kriging, and historical geologic data. AB - Because bottom substrate composition is an important control on the temporal and spatial location of the aquatic community, accurate maps of benthic habitats of inland lakes and reservoirs provide valuable information to managers, recreational users, and scientists. Therefore, we collected vertical, split-beam sonar data (roughness [E1], hardness [E2], and bathymetry) and sediment samples to make such maps. Statistical calibration between sonar parameters and sediment classes was problematic because the E1:E2 ratios for soft (muck and clay) sediments overlapped a lower and narrower range for hard (gravel) substrates. Thus, we used indicator kriging (IK) to map the probability that unsampled locations did not contain coarse sediments. To overcome the calibration issue we tested proxies for the natural processes and anthropogenic history of the reservoir as potential predictive variables. Of these, a geologic map proved to be the most useful. The central alluvial valley and mudflats contained mainly muck and organic-rich clays. The surrounding glacial till and shale bedrock uplands contained mainly poorly sorted gravels. Anomalies in the sonar data suggested that the organic-rich sediments also contained trapped gases, presenting additional interpretive issues for the mapping. We extended the capability of inexpensive split-beam sonar units through the incorporation of historic geologic maps and other records as well as validation with dredge samples. Through the integration of information from multiple data sets, were able to objectively identify bottom substrate and provide reservoir users with an accurate map of available benthic habitat. PMID- 24759835 TI - Correlation of microRNA-16, microRNA-21 and microRNA-101 expression with cyclooxygenase-2 expression and angiogenic factors in cirrhotic and noncirrhotic human hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a classical example of inflammation linked cancer and is characterized by hypervascularity suggesting rich angiogenesis. Cycloxygenase-2 (COX-2) is a potent mediator of inflammation and is considered to upregulate angiogenesis. The aims of the study are (1) to analyze expression of Cox-2 mRNA, Cox-2 protein, miR-16, miR-21 and miR-101 in HCC and adjacent liver parenchyma in cirrhotic and noncirrhotic liver, (2) to investigate the relation between COX-2 expression, miR-21 expression and angiogenic factors in these tissues and (3) to investigate the association between miR-16 and miR 101 and COX-2 expression. METHODS: Tissue samples of HCC and adjacent liver parenchyma of 21 noncirrhotic livers and 20 cirrhotic livers were analyzed for COX-2 expression at the mRNA level (qRT-PCR) and at the protein level by Western blot and immunohistochemistry. Gene expression of VEGFA, VEGFR1, VEGFR2, Ang-1, Ang-2 and Tie-2 were correlated with COX-2 levels. miR-16, miR-21 and miR-101 gene expression levels were quantified in HCC tumor tissue. RESULTS: COX-2 mRNA and protein levels were lower in HCC as compared to adjacent liver parenchyma both in cirrhotic and noncirrhotic liver. COX-2 protein localized mainly in vascular and sinusoidal endothelial cells and in Kupffer cells. At the mRNA level but not at the protein level, COX-2 correlated with mRNA levels of angiogenic factors VEGFR1, Ang-1, and Tie2. miR-21 expression was higher in cirrhotic tissues versus noncirrhotic tissues. MiR-101 expression was lower in cirrhotic versus noncirrhotic adjacent liver parenchyma. None of the miRNAs correlelated with COX-2 expression. miR-21 correlated negatively with Tie-2 receptor in adjacent liver parenchyma. CONCLUSIONS: In human HCC, COX-2 mRNA but not COX-2 protein levels are associated with expression levels of angiogenic factors. MiR 21 levels are not associated with angiogenic molecules. MiR-16 and miR-101 levels do not correlate with COX-2 mRNA and protein levels. PMID- 24759836 TI - Induction of pluripotency in human somatic cells via a transient state resembling primitive streak-like mesendoderm. AB - During mammalian embryonic development, the primitive streak initiates the differentiation of pluripotent epiblast cells into germ layers. Pluripotency can be reacquired in committed somatic cells using a combination of a handful of transcription factors, such as OCT3/4, SOX2, KLF4 and c-MYC (hereafter referred to as OSKM), albeit with low efficiency. Here we show that during OSKM-induced reprogramming towards pluripotency in human cells, intermediate cells transiently show gene expression profiles resembling mesendoderm, which is a major component of the primitive streak. Based on these findings, we discover that forkhead box H1 (FOXH1), a transcription factor required for anterior primitive streak specification during early development, significantly enhances the reprogramming efficiency of human fibroblasts by promoting their maturation, including mesenchymal to epithelial transition and the activation of late pluripotency markers. These results demonstrate that during the reprogramming process, human somatic cells go through a transient state that resembles mesendoderm. PMID- 24759837 TI - Trypanosoma cruzi survival following cold storage: possible implications for tissue banking. AB - While Trypanosoma cruzi, the etiologic agent of Chagas disease, is typically vector-borne, infection can also occur through solid organ transplantation or transfusion of contaminated blood products. The ability of infected human cells, tissues, and cellular and tissue-based products (HCT/Ps) to transmit T. cruzi is dependent upon T. cruzi surviving the processing and storage conditions to which HCT/Ps are subjected. In the studies reported here, T. cruzi trypomastigotes remained infective 24 hours after being spiked into blood and stored at room temperature (N = 20); in 2 of 13 parasite-infected cultures stored 28 days at 4 degrees C; and in samples stored 365 days at -80 degrees C without cryoprotectant (N = 28), despite decreased viability compared to cryopreserved parasites. Detection of viable parasites after multiple freeze/thaws depended upon the duration of frozen storage. The ability of T. cruzi to survive long periods of storage at +4 and -80 degrees C suggests that T. cruzi-infected tissues stored under these conditions are potentially infectious. PMID- 24759838 TI - Capturing natural-colour 3D models of insects for species discovery and diagnostics. AB - Collections of biological specimens are fundamental to scientific understanding and characterization of natural diversity-past, present and future. This paper presents a system for liberating useful information from physical collections by bringing specimens into the digital domain so they can be more readily shared, analyzed, annotated and compared. It focuses on insects and is strongly motivated by the desire to accelerate and augment current practices in insect taxonomy which predominantly use text, 2D diagrams and images to describe and characterize species. While these traditional kinds of descriptions are informative and useful, they cannot cover insect specimens "from all angles" and precious specimens are still exchanged between researchers and collections for this reason. Furthermore, insects can be complex in structure and pose many challenges to computer vision systems. We present a new prototype for a practical, cost effective system of off-the-shelf components to acquire natural-colour 3D models of insects from around 3 mm to 30 mm in length. ("Natural-colour" is used to contrast with "false-colour", i.e., colour generated from, or applied to, gray scale data post-acquisition.) Colour images are captured from different angles and focal depths using a digital single lens reflex (DSLR) camera rig and two axis turntable. These 2D images are processed into 3D reconstructions using software based on a visual hull algorithm. The resulting models are compact (around 10 megabytes), afford excellent optical resolution, and can be readily embedded into documents and web pages, as well as viewed on mobile devices. The system is portable, safe, relatively affordable, and complements the sort of volumetric data that can be acquired by computed tomography. This system provides a new way to augment the description and documentation of insect species holotypes, reducing the need to handle or ship specimens. It opens up new opportunities to collect data for research, education, art, entertainment, biodiversity assessment and biosecurity control. PMID- 24759839 TI - Epigenetic regulation: basic concepts and relevance to neurologic disease. PMID- 24759840 TI - Brugada syndrome in spinal and bulbar muscular atrophy. AB - OBJECTIVE: The aim of this study was to clarify myocardial involvement and its clinical implications in subjects with spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease affecting both neuronal and nonneuronal tissues. METHODS: Two independent cardiologists evaluated ECGs from a total of 144 consecutive subjects with SBMA. We performed immunohistochemical, immunoblot, and quantitative real-time PCR analyses of autopsied myocardium. RESULTS: Abnormal ECGs were detected in 70 (48.6%) of 144 subjects. The most frequent findings were ST-segment abnormalities in V1-3 (19.4%), followed by ST-segment abnormalities in V5-6 (18.1%). We detected Brugada-type ECGs in 17 of 28 subjects with ST-segment abnormalities in V1-3. Of those, one subject presented with syncope that required an implantable cardioverter defibrillator and led to eventual sudden death, and another subject also died suddenly. No subjects with Brugada-type ECGs had mutations in SCN5A, CACNA1C, or CACNB2 genes. In autopsied cases, we detected nuclear accumulation of the mutant androgen receptor protein and decreased expression levels of SCN5A in the myocardium. CONCLUSIONS: Subjects with SBMA often show Brugada-type ECG. The accumulation of the pathogenic androgen receptor may have a role in the myocardial involvement in SBMA. PMID- 24759842 TI - Hydrocephalus in neuromyelitis optica. PMID- 24759843 TI - Comment: importance of cognitive reserve in traumatic brain injury. AB - The expectation for moderate to severe traumatic brain injury (TBI) is permanent damage and lasting deficits. However, in a multicenter investigation, Schneider et al.(1) show that by 1 year postinjury, one-fourth of patients with TBI achieve disability-free recovery (DFR), defined as a score of zero on the Disability Rating Scale. Of importance, cognitive reserve (CR) in the form of educational attainment was related to DFR. PMID- 24759841 TI - DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies. AB - OBJECTIVE: To investigate patients with DPAGT1 (UDP-N-acetylglucosamine-dolichyl phosphate N-acetylglucosaminephosphotransferase 1)-associated myasthenic syndrome. METHODS: We performed exome and Sanger sequencing, determined glycoprotein expression in patient muscles, assessed pathogenicity of the mutant proteins by examining their expression and enzymatic activity in transfected cells, evaluated structural changes in muscle and the neuromuscular junction, and examined electrophysiologic aspects of neuromuscular transmission in vitro. RESULTS: Patients 1 and 2, 16 and 14 years of age, had progressive fatigable weakness since infancy and are intellectually disabled. Patient 3, a less severely affected brother of patient 1, also has autistic features. Each patient harbors 2 novel heteroallelic mutations in DPAGT1, an enzyme subserving protein N glycosylation. Patients 1 and 3 harbor Met1Leu, which reduces protein expression, and His375Tyr, which decreases enzyme activity. Patient 2 carries Val264Met, which abolishes enzyme activity, and a synonymous Leu120Leu mutation that markedly augments exon skipping, resulting in some skipped and infrequent nonskipped alleles. Therefore, the nonskipped allele rescues the phenotype. Intracellular microelectrode studies indicate combined pre- and postsynaptic defects of neuromuscular transmission with evidence for somatic mosaicism in patient 2. Structural studies reveal hypoplastic endplates, fiber-type disproportion, tubular aggregates, and degeneration of muscle fiber organelles resulting in autophagocytosis. CONCLUSIONS: DPAGT1 myasthenia affects multiple parameters of neuromuscular transmission, causes fiber-type disproportion and an autophagic myopathy, and can be associated with intellectual disability. We speculate that hypoglycosylation of synapse-specific proteins causes defects in central as well as motor synapses. PMID- 24759844 TI - Separate prediction of intracerebral hemorrhage and ischemic stroke. AB - OBJECTIVES: To develop and validate 10-year cumulative incidence functions of intracerebral hemorrhage (ICH) and ischemic stroke (IS). METHODS: We used data on 27,493 participants from 3 population-based cohort studies: the Atherosclerosis Risk in Communities Study, median age 54 years, 45% male, median follow-up 20.7 years; the Rotterdam Study, median age 68 years, 38% male, median follow-up 14.3 years; and the Cardiovascular Health Study, median age 71 years, 41% male, median follow-up 12.8 years. Among these participants, 325 ICH events, 2,559 IS events, and 9,909 nonstroke deaths occurred. We developed 10-year cumulative incidence functions for ICH and IS using stratified Cox regression and competing risks analysis. Basic models including only established nonlaboratory risk factors were extended with diastolic blood pressure, total cholesterol/high-density lipoprotein cholesterol ratio, body mass index, waist-to-hip ratio, and glomerular filtration rate. The cumulative incidence functions' performances were cross-validated in each cohort separately by Harrell C-statistic and calibration plots. RESULTS: High total cholesterol/high-density lipoprotein cholesterol ratio decreased the ICH rates but increased IS rates (p for difference across stroke types <0.001). For both the ICH and IS models, C statistics increased more by model extension in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Improvements in C statistics were reproduced by cross validation. Models were well calibrated in all cohorts. Correlations between 10 year ICH and IS risks were moderate in each cohort. CONCLUSIONS: We developed and cross-validated cumulative incidence functions for separate prediction of 10-year ICH and IS risk. These functions can be useful to further specify an individual's stroke risk. PMID- 24759845 TI - Functional recovery after moderate/severe traumatic brain injury: a role for cognitive reserve? AB - OBJECTIVE: To evaluate the hypothesis that educational attainment, a marker of cognitive reserve, is a predictor of disability-free recovery (DFR) after moderate to severe traumatic brain injury (TBI). METHODS: Retrospective study of the TBI Model Systems Database, a prospective multicenter cohort funded by the National Institute on Disability and Rehabilitation Research. Patients were included if they were admitted for rehabilitation after moderate to severe TBI, were aged 23 years or older, and had at least 1 year of follow-up. The main outcome measure was DFR 1 year postinjury, defined as a Disability Rating Scale score of zero. RESULTS: Of 769 patients included, 214 (27.8%) achieved DFR at 1 year. In total, 185 patients (24.1%) had <12 years of education, while 390 (50.7%) and 194 patients (25.2%) had 12 to 15 years and >=16 years of education, respectively. DFR was achieved by 18 patients (9.7%) with <12 years, 120 (30.8%) with 12 to 15 years, and 76 (39.2%) with >=16 years of education (p < 0.001). In a logistic regression model controlling for age, sex, and injury- and rehabilitation-specific factors, duration of education of >=12 years was independently associated with DFR (odds ratio 4.74, 95% confidence interval 2.70 8.32 for 12-15 years; odds ratio 7.24, 95% confidence interval 3.96-13.23 for >=16 years). CONCLUSION: Educational attainment was a robust independent predictor of 1-year DFR even when adjusting for other prognostic factors. A dose response relationship was noted, with longer educational exposure associated with increased odds of DFR. This suggests that cognitive reserve could be a factor driving neural adaptation during recovery from TBI. PMID- 24759846 TI - Longitudinal follow-up of SWEDD subjects in the PRECEPT Study. AB - OBJECTIVE: To compare the clinical and imaging characteristics of those PRECEPT (Parkinson Research Examination of CEP-1347 Trial) subjects with a scan without evidence of dopaminergic deficit (SWEDD) to those with dopamine transporter (DAT) deficit scans at study baseline and during a 22-month follow-up. METHODS: Baseline (n = 799) and 22-month follow-up (n = 701) [(123)I] beta-CIT SPECT scans were acquired. The percent change in [(123)I] beta-CIT striatal binding ratio, the percentage of subjects requiring dopaminergic therapy, the change in Unified Parkinson's Disease Rating Scale (UPDRS) score, and the PRECEPT Study investigators' diagnosis at study termination were compared between SWEDD and DAT deficit subjects. RESULTS: SWEDD subjects (n = 91) compared with DAT deficit subjects (n = 708) showed reduced UPDRS score at baseline (18.7 [SD 8.5] vs 25.5 [SD 10.5], p < 0.05) and minimal change in both [(123)I] beta-CIT striatal binding ratio (-0.2% [SD 12.2] vs -8.5% [SD 11.9], p < 0.0001) and UPDRS score (0.5 [SD 6.9] vs 10.5 [SD 8.9], p < 0.0001) at follow-up assessments. At PRECEPT termination, the diagnosis by study investigators was changed from Parkinson disease (PD) to other disorders not associated with DAT deficit in 44% (95% confidence interval 34.2, 54.7) of SWEDD subjects compared with 3.6% (95% confidence interval 2.3, 5.1) of DAT deficit subjects. CONCLUSION: These results indicate that subjects identified as having a SWEDD, with DAT imaging within the normal range, have minimal evidence of clinical or imaging PD progression. These data strongly suggest that SWEDD subjects are unlikely to have idiopathic PD. PMID- 24759847 TI - Risk of cerebral arteriovenous malformation rupture during pregnancy and puerperium. AB - OBJECTIVE: To determine whether the risk of arteriovenous malformation (AVM) rupture is increased during pregnancy and puerperium. METHODS: Participants included 979 female patients with intracranial AVM admitted to Beijing Tiantan Hospital between 1960 and 2010. Two neurosurgery residents reviewed medical records for each case. Of them, 393 patients with ruptured AVM between 18 and 40 years of age were used for case-crossover analysis. Number of children born and clinical information during pregnancy and puerperium were retrieved to identify whether AVM rupture occurred during this period. RESULTS: Of the 979 women, 797 hemorrhages occurred during 25,578 patient-years of follow-up, yielding an annual hemorrhage rate of 3.11%. The annual AVM hemorrhage rate in patients aged 18 to 40 years (n = 579) was 2.78%, lower than the rate in other age groups (odds ratio = 0.75, 95% confidence interval 0.65-0.86, p < 0.05). Of the 393 patients with rupture of AVM aged 18 to 40 years, 12 hemorrhages occurred in 12 patients over 452 pregnancies, yielding a hemorrhage rate of 2.65% per pregnancy or 3.32% per year. Among the remaining 381 patients, 441 hemorrhages occurred during 10,627 patient-years of follow-up, yielding an annual hemorrhage rate of 4.14%. The odds ratio for rupture of AVM during pregnancy and puerperium, compared with the control period, was 0.71 (95% confidence interval 0.61-0.82). CONCLUSIONS: No increased risk of hemorrhage was found in patients with cerebral AVM during pregnancy and the puerperium. We therefore would not advise against pregnancy in women with intracranial AVM. PMID- 24759850 TI - Lipase-catalyzed asymmetric synthesis of oxathiazinanones through dynamic covalent kinetic resolution. AB - A domino addition-lactonization pathway has been applied to a dynamic covalent resolution protocol, leading to efficient oxathiazinanone formation as well as chiral discrimination. A new, double biocatalytic pathway has furthermore been proposed and evaluated where the initial product inhibition could be efficiently circumvented. PMID- 24759849 TI - Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG) protein in fulminant type 1 diabetes. AB - BACKGROUND: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear. PROCEDURES: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. RESULT: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Ialpha protein. The vesicles containing REG Ialpha protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Ialpha protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. CONCLUSION: The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Ialpha protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Ialpha in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells. PMID- 24759851 TI - Seasonal variation in the voluntary food intake of domesticated cats (Felis catus). AB - There are numerous reports about seasonal cycles on food intake in animals but information is limited in dogs and cats. A 4-year prospective, observational, cohort study was conducted to assess differences in food intake in 38 ad-libitum fed adult colony cats, of various breeds, ages and genders. Individual food intake was recorded on a daily basis, and the mean daily intake for each calendar month was calculated. These data were compared with climatic data (temperature and daylight length) for the region in the South of France where the study was performed. Data were analysed using both conventional statistical methods and by modelling using artificial neural networks (ANN). Irrespective of year, an effect of month was evident on food intake (P<0.001), with three periods of broadly differing intake. Food intake was least in the summer months (e.g. June, to August), and greatest during the months of late autumn and winter (e.g. October to February), with intermediate intake in the spring (e.g. March to May) and early autumn (e.g. September). A seasonal effect on bodyweight was not recorded. Periods of peak and trough food intake coincided with peaks and troughs in both temperature and daylight length. In conclusion, average food intake in summer is approximately 15% less than food intake during the winter months, and is likely to be due to the effects of outside temperatures and differences in daylight length. This seasonal effect in food intake should be properly considered when estimating daily maintenance energy requirements in cats. PMID- 24759853 TI - Reinventing the disc: a reminder to give credit to past giants. PMID- 24759852 TI - Family-based treatment of early childhood obsessive-compulsive disorder: the Pediatric Obsessive-Compulsive Disorder Treatment Study for Young Children (POTS Jr)--a randomized clinical trial. AB - IMPORTANCE: Cognitive behavior therapy (CBT) has been established as efficacious for obsessive-compulsive disorder (OCD) among older children and adolescents, yet its effect on young children has not been evaluated sufficiently. OBJECTIVE: To examine the relative efficacy of family-based CBT (FB-CBT) involving exposure plus response prevention vs an FB relaxation treatment (FB-RT) control condition for children 5 to 8 years of age. DESIGN, SETTING, AND PARTICIPANTS: A 14-week randomized clinical trial (Pediatric Obsessive-Compulsive Disorder Treatment Study for Young Children [POTS Jr]) conducted at 3 academic medical centers between 2006 and 2011, involving 127 pediatric outpatients 5 to 8 years of age who received a primary diagnosis of OCD and a Children's Yale-Brown Obsessive Compulsive Scale total score of 16 or higher. INTERVENTIONS: Participants were randomly assigned to 14 weeks of (1) FB-CBT, including exposure plus response prevention, or (2) FB-RT. MAIN OUTCOMES AND MEASURES: Responder status defined as an independent evaluator-rated Clinical Global Impression-Improvement scale score of 1 (very much improved) or 2 (much improved) and change in independent evaluator-rated continuous Children's Yale-Brown Obsessive Compulsive Scale total score. RESULTS Family-based CBT was superior to FB-RT on both primary outcome measures. The percentages of children who were rated as 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Improvement scale at 14 weeks were 72% for FB-CBT and 41% for FB-RT. The effect size difference between FB-CBT and FB-RT on the Clinical Global Impression-Improvement scale was 0.31 (95% CI, 0.17-0.45). The number needed to treat (NNT) with FB-CBT vs FB-RT was estimated as 3.2 (95% CI, 2.2-5.8). The effect size difference between FB-CBT and FB-RT on the Children's Yale-Brown Obsessive Compulsive Scale at week 14 was 0.84 (95% CI, 0.62-1.06). CONCLUSIONS AND RELEVANCE: A comprehensive FB-CBT program was superior to a relaxation program with a similar format in reducing OCD symptoms and functional impairment in young children (5-8 years of age) with OCD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00533806. PMID- 24759854 TI - Long-term effects of birth weight and breastfeeding duration on inflammation in early adulthood. AB - Chronic inflammation is a potentially important physiological mechanism linking early life environments and health in adulthood. Elevated concentrations of C reactive protein (CRP)--a key biomarker of inflammation--predict increased cardiovascular and metabolic disease risk in adulthood, but the developmental factors that shape the regulation of inflammation are not known. We investigated birth weight and breastfeeding duration in infancy as predictors of CRP in young adulthood in a large representative cohort study (n = 6951). Birth weight was significantly associated with CRP in young adulthood, with a negative association for birth weights 2.8 kg and higher. Compared with individuals not breastfed, CRP concentrations were 20.1%, 26.7%, 29.6% and 29.8% lower among individuals breastfed for less than three months, three to six months, 6-12 months and greater than 12 months, respectively. In sibling comparison models, higher birth weight was associated with lower CRP for birth weights above 2.5 kg, and breastfeeding greater than or equal to three months was significantly associated with lower CRP. Efforts to promote breastfeeding and improve birth outcomes may have clinically relevant effects on reducing chronic inflammation and lowering risk for cardiovascular and metabolic diseases in adulthood. PMID- 24759855 TI - On signals of phase transitions in salmon population dynamics. AB - Critical slowing down (CSD) reflects the decline in resilience of equilibria near a bifurcation and may reveal early warning signals (EWS) of ecological phase transitions. We studied CSD in the recruitment dynamics of 120 stocks of three Pacific salmon (Oncorhynchus spp.) species in relation to critical transitions in fishery models. Pink salmon (Oncorhynchus gorbuscha) exhibited increased variability and autocorrelation in populations that had a growth parameter, r, close to zero, consistent with EWS of extinction. However, models and data for sockeye salmon (Oncorhynchus nerka) indicate that portfolio effects from heterogeneity in age-at-maturity may obscure EWS. Chum salmon (Oncorhynchus keta) show intermediate results. The data do not reveal EWS of Ricker-type bifurcations that cause oscillations and chaos at high r. These results not only provide empirical support for CSD in some ecological systems, but also indicate that portfolio effects of age structure may conceal EWS of some critical transitions. PMID- 24759856 TI - The effects of island ontogeny on species diversity and phylogeny. AB - A major goal of island biogeography is to understand how island communities are assembled over time. However, we know little about the influence of variable area and ecological opportunity on island biotas over geological timescales. Islands have limited life spans, and it has been posited that insular diversity patterns should rise and fall with an island's ontogeny. The potential of phylogenies to inform us of island ontogenetic stage remains unclear, as we lack a phylogenetic framework that focuses on islands rather than clades. Here, we present a parsimonious island-centric model that integrates phylogeny and ontogeny into island biogeography and can incorporate a negative feedback of diversity on species origination. This framework allows us to generate predictions about species richness and phylogenies on islands of different ages. We find that peak richness lags behind peak island area, and that endemic species age increases with island age on volcanic islands. When diversity negatively affects rates of immigration and cladogenesis, our model predicts speciation slowdowns on old islands. Importantly, we find that branching times of in situ radiations can be informative of an island's ontogenetic stage. This novel framework provides a quantitative means of uncovering processes responsible for island biogeography patterns using phylogenies. PMID- 24759857 TI - Biogeographic, climatic and spatial drivers differentially affect alpha-, beta- and gamma-diversities on oceanic archipelagos. AB - Island biogeographic studies traditionally treat single islands as units of analysis. This ignores the fact that most islands are spatially nested within archipelagos. Here, we took a fundamentally different approach and focused on entire archipelagos using species richness of vascular plants on 23 archipelagos worldwide and their 174 constituent islands. We assessed differential effects of biogeographic factors (area, isolation, age, elevation), current and past climate (temperature, precipitation, seasonality, climate change velocity) and intra archipelagic spatial structure (archipelago area, number of islands, area range, connectivity, environmental volume, inter-island distance) on plant diversity. Species diversity of each archipelago (gamma) was additively partitioned into alpha, beta, nestedness and replacement beta-components to investigate the relative importance of environmental and spatial drivers. Multiple regressions revealed strong effects of biogeography and climate on alpha and gamma, whereas spatial factors, particularly number of islands, inter-island distance and area range, were key to explain beta. Structural equation models additionally suggested that gamma is predominantly determined by indirect abiotic effects via its components, particularly beta. This highlights that beta and the spatial arrangement of islands are essential to understand insular ecology and evolution. Our methodological framework can be applied more widely to other taxa and archipelago-like systems, allowing new insights into biodiversity origin and maintenance. PMID- 24759858 TI - Decision accuracy in complex environments is often maximized by small group sizes. AB - Individuals in groups, whether composed of humans or other animal species, often make important decisions collectively, including avoiding predators, selecting a direction in which to migrate and electing political leaders. Theoretical and empirical work suggests that collective decisions can be more accurate than individual decisions, a phenomenon known as the 'wisdom of crowds'. In these previous studies, it has been assumed that individuals make independent estimates based on a single environmental cue. In the real world, however, most cues exhibit some spatial and temporal correlation, and consequently, the sensory information that near neighbours detect will also be, to some degree, correlated. Furthermore, it may be rare for an environment to contain only a single informative cue, with multiple cues being the norm. We demonstrate, using two simple models, that taking this natural complexity into account considerably alters the relationship between group size and decision-making accuracy. In only a minority of environments do we observe the typical wisdom of crowds phenomenon (whereby collective accuracy increases monotonically with group size). When the wisdom of crowds is not observed, we find that a finite, and often small, group size maximizes decision accuracy. We reveal that, counterintuitively, it is the noise inherent in these small groups that enhances their accuracy, allowing individuals in such groups to avoid the detrimental effects of correlated information while exploiting the benefits of collective decision-making. Our results demonstrate that the conventional view of the wisdom of crowds may not be informative in complex and realistic environments, and that being in small groups can maximize decision accuracy across many contexts. PMID- 24759860 TI - On fossils, phylogenies and sequences of evolutionary change. PMID- 24759859 TI - Heterostyly accelerates diversification via reduced extinction in primroses. AB - The exceptional species diversity of flowering plants, exceeding that of their sister group more than 250-fold, is especially evident in floral innovations, interactions with pollinators and sexual systems. Multiple theories, emphasizing flower-pollinator interactions, genetic effects of mating systems or high evolvability, predict that floral evolution profoundly affects angiosperm diversification. However, consequences for speciation and extinction dynamics remain poorly understood. Here, we investigate trajectories of species diversification focusing on heterostyly, a remarkable floral syndrome where outcrossing is enforced via cross-compatible floral morphs differing in placement of their respective sexual organs. Heterostyly evolved at least 20 times independently in angiosperms. Using Darwin's model for heterostyly, the primrose family, we show that heterostyly accelerates species diversification via decreasing extinction rates rather than increasing speciation rates, probably owing to avoidance of the negative genetic effects of selfing. However, impact of heterostyly appears to differ over short and long evolutionary time-scales: the accelerating effect of heterostyly on lineage diversification is manifest only over long evolutionary time-scales, whereas recent losses of heterostyly may prompt ephemeral bursts of speciation. Our results suggest that temporal or clade specific conditions may ultimately determine the net effects of specific traits on patterns of species diversification. PMID- 24759861 TI - Frustrative reward omission increases aggressive behaviour of inferior fighters. AB - Animals use aggressive behaviour to gain access to resources, and individuals adjust their behaviour relative to resource value and own resource holding potential (RHP). Normally, smaller individuals have inferior fighting abilities compared with larger conspecifics. Affective and cognitive processes can alter contest dynamics, but the interaction between such effects and that of differing RHPs has not been adjudged. We investigated effects of omission of expected reward (OER) on competing individuals with contrasting RHPs. Small and large rainbow trout (Oncorhynchus mykiss) were conditioned to associate a light with reward. Thereafter, the reward was omitted for half of the fish prior to a contest between individuals possessing a 36-40% difference in RHP. Small control individuals displayed submissive behaviour and virtually no aggression. By contrast, small OER individuals were more aggressive, and two out of 11 became socially dominant. Increased aggression in small OER individuals was accompanied by increased serotonin levels in the dorsomedial pallium (proposed amygdala homologue), but no changes in limbic dopamine neurochemistry were observed in OER exposed individuals. The behavioural and physiological response to OER in fish indicates that frustration is an evolutionarily conserved affective state. Moreover, our results indicate that aggressive motivation to reward unpredictability affects low RHP individuals strongest. PMID- 24759862 TI - Cultural transmission of tool use by Indo-Pacific bottlenose dolphins (Tursiops sp.) provides access to a novel foraging niche. AB - Culturally transmitted tool use has important ecological and evolutionary consequences and has been proposed as a significant driver of human evolution. Such evidence is still scarce in other animals. In cetaceans, tool use has been inferred using indirect evidence in one population of Indo-Pacific bottlenose dolphins (Tursiops sp.), where particular dolphins ('spongers') use marine sponges during foraging. To date, evidence of whether this foraging tactic actually provides access to novel food items is lacking. We used fatty acid (FA) signature analysis to identify dietary differences between spongers and non spongers, analysing data from 11 spongers and 27 non-spongers from two different study sites. Both univariate and multivariate analyses revealed significant differences in FA profiles between spongers and non-spongers between and within study sites. Moreover, FA profiles differed significantly between spongers and non-spongers foraging within the same deep channel habitat, whereas the profiles of non-spongers from deep channel and shallow habitats at this site could not be distinguished. Our results indicate that sponge use by bottlenose dolphins is linked to significant differences in diet. It appears that cultural transmission of tool use in dolphins, as in humans, allows the exploitation of an otherwise unused niche. PMID- 24759863 TI - An island-wide predator manipulation reveals immediate and long-lasting matching of risk by prey. AB - Anti-predator behaviour affects prey population dynamics, mediates cascading effects in food webs and influences the likelihood of rapid extinctions. Predator manipulations in natural settings provide a rare opportunity to understand how prey anti-predator behaviour is affected by large-scale changes in predators. Here, we couple a long-term, island-wide manipulation of an important rodent predator, the island fox (Urocyon littoralis), with nearly 6 years of measurements on foraging by deer mice (Peromyscus maniculatus) to provide unequivocal evidence that prey closely match their foraging behaviour to the number of fox predators present on the island. Peromyscus maniculatus foraging among exposed and sheltered microhabitats (a measure of aversion to predation risk) closely tracked fox density, but the nature of this effect depended upon nightly environmental conditions known to affect rodent susceptibility to predators. These effects could not be explained by changes in density of deer mice over time. Our work reveals that prey in natural settings are cognizant of the dynamic nature of their predators over timescales that span many years, and that predator removals spanning many generations of prey do not result in a loss of anti-predator behaviour. PMID- 24759864 TI - Menstrual cycle phase alters women's sexual preferences for composers of more complex music. AB - Over 140 years ago Charles Darwin first argued that birdsong and human music, having no clear survival benefit, were obvious candidates for sexual selection. Whereas the first contention is now universally accepted, his theory that music is a product of sexual selection through mate choice has largely been neglected. Here, I provide the first, to my knowledge, empirical support for the sexual selection hypothesis of music evolution by showing that women have sexual preferences during peak conception times for men that are able to create more complex music. Two-alternative forced-choice experiments revealed that woman only preferred composers of more complex music as short-term sexual partners when conception risk was highest. No preferences were displayed when women chose which composer they would prefer as a long-term partner in a committed relationship, and control experiments failed to reveal an effect of conception risk on women's preferences for visual artists. These results suggest that women may acquire genetic benefits for offspring by selecting musicians able to create more complex music as sexual partners, and provide compelling support for Darwin's assertion 'that musical notes and rhythm were first acquired by the male or female progenitors of mankind for the sake of charming the opposite sex'. PMID- 24759865 TI - How sailfish use their bills to capture schooling prey. AB - The istiophorid family of billfishes is characterized by an extended rostrum or 'bill'. While various functions (e.g. foraging and hydrodynamic benefits) have been proposed for this structure, until now no study has directly investigated the mechanisms by which billfishes use their rostrum to feed on prey. Here, we present the first unequivocal evidence of how the bill is used by Atlantic sailfish (Istiophorus albicans) to attack schooling sardines in the open ocean. Using high-speed video-analysis, we show that (i) sailfish manage to insert their bill into sardine schools without eliciting an evasive response and (ii) subsequently use their bill to either tap on individual prey targets or to slash through the school with powerful lateral motions characterized by one of the highest accelerations ever recorded in an aquatic vertebrate. Our results demonstrate that the combination of stealth and rapid motion make the sailfish bill an extremely effective feeding adaptation for capturing schooling prey. PMID- 24759866 TI - Settling down of seasonal migrants promotes bird diversification. AB - How seasonal migration originated and impacted diversification in birds remains largely unknown. Although migratory behaviour is likely to affect bird diversification, previous studies have not detected any effect. Here, we infer ancestral migratory behaviour and the effect of seasonal migration on speciation and extinction dynamics using a complete bird tree of life. Our analyses infer that sedentary behaviour is ancestral, and that migratory behaviour evolved independently multiple times during the evolutionary history of birds. Speciation of a sedentary species into two sedentary daughter species is more frequent than speciation of a migratory species into two migratory daughter species. However, migratory species often diversify by generating a sedentary daughter species in addition to the ancestral migratory one. This leads to an overall higher migratory speciation rate. Migratory species also experience lower extinction rates. Hence, although migratory species represent a minority (18.5%) of all extant birds, they have a higher net diversification rate than sedentary species. These results suggest that the evolution of seasonal migration in birds has facilitated diversification through the divergence of migratory subpopulations that become sedentary, and illustrate asymmetrical diversification as a mechanism by which diversification rates are decoupled from species richness. PMID- 24759869 TI - Substitution reactions in metal-organic frameworks and metal-organic polyhedra. AB - Substitution reaction, as one of the most powerful and efficient chemical reactions, has been widely used in various syntheses, including those for the design and preparation of functional molecules or materials. In the past decade, a class of newly developed inorganic-organic hybrid materials, namely metal organic materials (MOMs), has experienced a rapid development. MOMs are composed of metal-containing nodes connected by organic linkers through strong chemical bonds, and can be divided into metal-organic frameworks (MOFs) and metal-organic polygons/polyhedra (MOPs) with infinite and discrete structural features, respectively. Recent research has shown that the substitution reaction can be used as a new strategy in the synthesis and modification of MOFs and MOPs, particularly for pre-designed ones with desired structures and functions, which are usually difficult to access by a direct one-pot self-assembly synthetic approach. This review highlights the implementation of the substitution reaction in MOFs and MOPs. Examples of substitution reactions at metal ions, organic ligands, and free guest molecules of MOFs and MOPs are listed and analyzed. The changes or modifications in the structures and/or properties of these materials induced by the substitutions, as well as the nature of the associated reaction, are discussed, with the conclusion that the substitution reaction is really feasible and powerful in synthesizing and tailoring MOMs. PMID- 24759868 TI - Clinical characteristics and outcomes associated with the natural history of early repolarization in a young, biracial cohort followed to middle age: the Coronary Artery Risk Development in Young Adults (CARDIA) study. AB - BACKGROUND: Early repolarization (ER), a common electrocardiographic phenotype, has been associated with increased mortality risk in middle-aged adults. Data are sparse on long-term follow-up and outcomes associated with ER in younger adults. METHODS AND RESULTS: We prospectively examined 5039 participants (mean age, 25 years at baseline, 40% black) from the Coronary Artery Disease Risk in Adults (CARDIA) cohort for 23 years. Twelve-lead ECGs were recorded and analyzed at years 0, 7, and 20 and coded as definite or probable ER using a standardized algorithm. Cox regression was used, and models were adjusted for important baseline and clinical covariates. Kaplan-Meier curves were created for presence of ER and total mortality and cardiovascular mortality. Participants with ER were more likely to be black, male, smoke, have higher systolic blood pressure, lower heart rate and body mass index, higher exercise duration, and longer PR, QRS, and QT intervals. ER was associated with total mortality (hazard ratio, 1.77; confidence interval, 1.38-2.28; P<0.01) and cardiovascular mortality (hazard ratio, 1.59; confidence interval, 1.01-2.50; P=0.04) in unadjusted analyses, but adjustment for age, sex, and race attenuated associations almost completely. Sex race stratified analyses showed no significant associations between ER and outcome for any of the subgroups except blacks. CONCLUSIONS: The presence of ER at any time point during 23 years of follow-up was not associated with adverse outcomes. Black race and male sex confound the unadjusted association of ER and outcomes, with no race-sex interactions noted. Additional studies are necessary to understand the factors associated with heightened risk of death in those who maintain ER into and beyond middle age. PMID- 24759867 TI - An intra-individual comparison of MRI, [18F]-FET and [18F]-FLT PET in patients with high-grade gliomas. AB - OBJECTIVES: Intra-individual spatial overlap analysis of tumor volumes assessed by MRI, the amino acid PET tracer [18F]-FET and the nucleoside PET tracer [18F] FLT in high-grade gliomas (HGG). METHODS: MRI, [18F]-FET and [18F]-FLT PET data sets were retrospectively analyzed in 23 HGG patients. Morphologic tumor volumes on MRI (post-contrast T1 (cT1) and T2 images) were calculated using a semi automatic image segmentation method. Metabolic tumor volumes for [18F]-FET and [18F]-FLT PETs were determined by image segmentation using a threshold-based volume of interest analysis. After co-registration with MRI the morphologic and metabolic tumor volumes were compared on an intra-individual basis in order to estimate spatial overlaps using the Spearman's rank correlation coefficient and the Mann-Whitney U test. RESULTS: [18F]-FLT uptake was negative in tumors with no or only moderate contrast enhancement on MRI, detecting only 21 of 23 (91%) HGG. In addition, [18F]-FLT uptake was mainly restricted to cT1 tumor areas on MRI and [18F]-FLT volumes strongly correlated with cT1 volumes (r = 0.841, p<0.001). In contrast, [18F]-FET PET detected 22 of 23 (96%) HGG. [18F]-FET uptake beyond areas of cT1 was found in 61% of cases and [18F]-FET volumes showed only a moderate correlation with cT1 volumes (r = 0.573, p<0.001). Metabolic tumor volumes beyond cT1 tumor areas were significantly larger for [18F]-FET compared to [18F]-FLT tracer uptake (8.3 vs. 2.7 cm3, p<0.001). CONCLUSION: In HGG [18F] FET but not [18F]-FLT PET was able to detect metabolic active tumor tissue beyond contrast enhancing tumor on MRI. In contrast to [18F]-FET, blood-brain barrier breakdown seems to be a prerequisite for [18F]-FLT tracer uptake. PMID- 24759871 TI - Application of hydrophobically modified water-soluble polymers for the dispersion of hydrophobic magnetic nanoparticles in aqueous media. AB - Hydrophobically modified water-soluble polymers (HMWSPs), comprised of a poly(sodium methacrylate) (PMANa) or poly(sodium acrylate) (PANa) backbone and pendent dodecyl methacrylate (DMA) or dodecyl acrylamide (DAAm) chains, respectively, were synthesized. The hydrophobic content of the copolymers, P(MANa co-DMA) and P(ANa-co-DAAm), is in the range of 0 to 25 mol%, while their weight average molar mass varies from ~10 000 up to ~75 000. Their self-assembly behavior in dilute aqueous solution was followed through Nile Red probing, DLS and TEM measurements. The critical micelle concentration (CMC) is mainly controlled by the hydrophobic content and not the molar mass of the copolymers. Above CMC, spherical and large-compound micelles are identified by DLS and TEM. Moreover, oleylamine coated CoFe2O4 nanoparticles (CoFe2O4@OAm MNPs) of 9.4 nm with a saturation magnetization Ms = 85 emu g(-1) were solvothermally prepared. The hydrophobic CoFe2O4@OAm MNPs were successfully encapsulated into the hydrophobic cores of the structures formed by the copolymers above CMC through a solvent mixing procedure, and in that way hydrophilic CoFe2O4@HMWSP nanohybrids resulted. For comparison purposes, two alternate phase transfer approaches were also used to convert CoFe2O4@OAm MNPs to hydrophilic ones: (a) addition of a coating layer by cetyltrimethyl ammonium bromide (CTAB) and (b) by the ligand exchange procedure with 2,3-dimercaptosuccinic acid (DMSA). NMR transverse relaxivity measurements of the aqueous suspensions of CoFe2O4@P(ANa-co-DAAm), CoFe2O4@CTAB and CoFe2O4@DMSA were recorded and the r2 relaxivity was determined. CoFe2O4@CTAB demonstrated the highest r2 relaxivity of 554.0 mM(-1) s(-1), while CoFe2O4@P(ANa-co-DAAm) and CoFe2O4@DMSA showed lower values of 313.6 mM(-1) s(-1) and 76.3 mM(-1) s(-1), respectively. PMID- 24759870 TI - An integrative theory-driven positive emotion regulation intervention. AB - Over the past fifteen years, positive psychology research has validated a set of happiness enhancing techniques. These techniques are relatively simple exercises that allow happiness seekers to mimic thoughts and behavior of naturally happy people, in order to increase their level of well-being. Because research has shown that the joint use of these exercises increases their effects, practitioners who want to help happiness seekers need validated interventions that combine several of these techniques. To meet this need, we have developed and tested an integrative intervention (Positive Emotion Regulation program - PER program) incorporating a number of validated techniques structured around a theoretical model: the Process Model of Positive Emotion Regulation. To test the effectiveness of this program and to identify its added value relative to existing interventions, 113 undergraduate students were randomly assigned to a 6 week positive emotion regulation pilot program, a loving-kindness meditation training program, or a wait-list control group. Results indicate that fewer participants dropped out from the PER program than from the Loving-Kindness Meditation training. Furthermore, subjects in the PER group showed a significant increase in subjective well-being and life satisfaction and a significant decrease in depression and physical symptoms when compared to controls. Our results suggest that the Process Model of Positive Emotion Regulation can be an effective option to organize and deliver positive integrative interventions. PMID- 24759873 TI - Early diagnosis of keratoconus: what difference is it making? PMID- 24759874 TI - Ocular adnexal lymphoma: validation of American Joint Committee on Cancer seventh edition staging guidelines. AB - BACKGROUND/AIMS: To validate the prognostic significance of the American Joint Committee on Cancer (AJCC) seventh edition staging criteria for ocular adnexal lymphoma (OAL) of all histologic subtypes. METHODS: Retrospective review of clinical records for all consecutive patients with OAL treated from November 1998 to December 2012. RESULTS: 130 patients were evaluated, 82 with primary and 34 with secondary OAL. Fourteen patients were excluded due to incomplete records. 71 women (61.2%) and 45 men (38.8%) had a median age of 61.5 years. Patients were followed for a median of 32.5 months. Treatment varied, in part, related to lymphoma histologic subtype. Overall, there were 17 recurrences (8 local and 9 distant) in patients with primary OAL. For primary OAL, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 55.9% and 85.8%, respectively. For primary OAL, while there was a trend towards decreased 5-year DFS for more aggressive subtypes, this was not statistically significant. More advanced Ann Arbor stage was associated with decreased 5-year DFS; however, this trend was not statistically significant. However, increased AJCC seventh edition T category was associated with decreased 5-year DFS (T1=67.8%, T2=59.2%, T3=28.6%, T4=33.3%; p=0.025). CONCLUSION: AJCC seventh edition T category was predictive of DFS in patients with OAL. PMID- 24759875 TI - Cataract surgery in small adult eyes. AB - AIM: To evaluate the clinical outcomes of phacoemulsification cataract surgery in microphthalmos. METHODS: Retrospective consecutive case series of eyes with axial length <20.9 mm, and requiring a high intraocular lens (IOL) power (>=30 or >=35 dioptres for anterior or posterior chamber fixation, respectively), with no history of previous ocular surgery, and undergoing planned phacoemulsification cataract surgery with IOL implantation at Moorfields Eye Hospital was investigated to observe the incidence of intraoperative and postoperative complications. RESULTS: During a 5-year study period, 47 of 22,093 eyes were treated in two locations (0.21%). Thirty-nine eyes met the study inclusion criteria. No serious intraoperative adverse events were recorded. Severe postoperative complications (retinal detachment and chronic postoperative uveitis) occurred in two cases. The postoperative corrected distance visual acuity (CDVA) was logMAR 0.30 or better in 24 eyes (62%), and only three eyes obtained worse vision. The overall ocular comorbitidy rate was 53%; 10 microphthalmic eyes (26%) presented with associated congenital or hereditary pathology, and had worse visual outcomes (p<0.0001). CONCLUSIONS: Microphthalmic eyes requiring high IOL power are rare, and their presence is often associated with other ocular congenital or acquired disorders. Overall, the clinical outcomes were satisfactory and the surgical procedure affected by a low complication rate. PMID- 24759876 TI - Visualisation of contrast-enhanced intraoperative optical coherence tomography with indocyanine green. AB - Optical coherence tomography (OCT)-based visualisation of ophthalmic anatomy has transformed the clinical practice of ophthalmology. The translation of OCT into the surgical theatre is currently being actively researched and may provide a paradigm shift in surgical practice. Enhanced visualisation of tissues and tissue planes may provide further iterative improvement in surgeon feedback. Contrast enhanced intraoperative OCT (iOCT) has been previously described with triamcinolone. In this report, we describe the OCT features and contrast enhancement noted with indocyanine green using iOCT in human subjects as well as an ex vivo analysis in porcine eyes. PMID- 24759877 TI - Choroidal schwannoma: a case series of five patients. AB - AIM: To report a case series of five patients diagnosed with choroidal schwannoma at the Liverpool Ocular Oncology Centre. METHODS: Patients with choroidal schwannoma were identified by searching the computerised database of the Liverpool Ocular Oncology Centre. RESULTS: The patients (3 males, 2 females) ranged in age from 15 years to 45 years. Three tumours were treated by enucleation, trans-scleral local resection, and combined bevacizumab and photodynamic therapy, respectively. Two were observed after confirmation of the diagnosis by biopsy. CONCLUSIONS: Choroidal schwannoma has a variety of clinical manifestations. Associated features include hard exudates, retinal feeder vessels and serous retinal detachment. Biopsy with immunohistochemistry is required for diagnosis. Tumours not amenable to resection may respond to photodynamic therapy. PMID- 24759878 TI - Intracameral recombinant tissue plasminogen activator (r-tPA) for refractory toxic anterior segment syndrome. PMID- 24759880 TI - Root anatomical phenes associated with water acquisition from drying soil: targets for crop improvement. AB - Several root anatomical phenes affect water acquisition from drying soil, and may therefore have utility in breeding more drought-tolerant crops. Anatomical phenes that reduce the metabolic cost of the root cortex ('cortical burden') improve soil exploration and therefore water acquisition from drying soil. The best evidence for this is for root cortical aerenchyma; cortical cell file number and cortical senescence may also be useful in this context. Variation in the number and diameter of xylem vessels strongly affects axial water conductance. Reduced axial conductance may be useful in conserving soil water so that a crop may complete its life cycle under terminal drought. Variation in the suberization and lignification of the endodermis and exodermis affects radial water conductance, and may therefore be important in reducing water loss from mature roots into dry soil. Rhizosheaths may protect the water status of young root tissue. Root hairs and larger diameter root tips improve root penetration of hard, drying soil. Many of these phenes show substantial genotypic variation. The utility of these phenes for water acquisition has only rarely been validated, and may have strong interactions with the spatiotemporal dynamics of soil water availability, and with root architecture and other aspects of the root phenotype. This complexity calls for structural-functional plant modelling and 3D imaging methods. Root anatomical phenes represent a promising yet underexplored and untapped source of crop breeding targets. PMID- 24759879 TI - Culture-independent evaluation of the appendix and rectum microbiomes in children with and without appendicitis. AB - PURPOSE: The function of the appendix is largely unknown, but its microbiota likely contributes to function. Alterations in microbiota may contribute to appendicitis, but conventional culture studies have not yielded conclusive information. We conducted a pilot, culture-independent 16S rRNA-based microbiota study of paired appendix and rectal samples. METHODS: We collected appendix and rectal swabs from 21 children undergoing appendectomy, six with normal appendices and fifteen with appendicitis (nine perforated). After DNA extraction, we amplified and sequenced 16S rRNA genes and analyzed sequences using CLoVR. We identified organisms differing in relative abundance using ANOVA (p<0.05) by location (appendix vs. rectum), disease (appendicitis vs. normal), and disease severity (perforated vs. non-perforated). RESULTS: We identified 290 taxa in the study's samples. Three taxa were significantly increased in normal appendices vs. normal rectal samples: Fusibacter (p = 0.009), Selenomonas (p = 0.026), and Peptostreptococcus (p = 0.049). Five taxa were increased in abundance in normal vs. diseased appendices: Paenibacillaceae (p = 0.005), Acidobacteriaceae GP4 (p = 0.019), Pseudonocardinae (p = 0.019), Bergeyella (p = 0.019) and Rhizobium (p = 0.045). Twelve taxa were increased in the appendices of appendicitis patients vs. normal appendix: Peptostreptococcus (p = 0.0003), Bilophila (p = 0.0004), Bulleidia (p = 0.012), Fusobacterium (p = 0.018), Parvimonas (p = 0.003), Mogibacterium (p = 0.012), Aminobacterium (p = 0.019), Proteus (p = 0.028), Actinomycineae (p = 0.028), Anaerovorax (p = 0.041), Anaerofilum (p = 0.045), Porphyromonas (p = 0.010). Five taxa were increased in appendices in patients with perforated vs. nonperforated appendicitis: Bulleidia (p = 0.004), Fusibacter (p = 0.005), Prevotella (p = 0.021), Porphyromonas (p = 0.030), Dialister (p = 0.035). Three taxa were increased in rectum samples of patients with appendicitis compared to the normal patients: Bulleidia (p = 0.034), Dialister (p = 0.003), and Porphyromonas (p = 0.026). CONCLUSION: Specific taxa are more abundant in normal appendices compared to the rectum, suggesting that a distinctive appendix microbiota exists. Taxa with altered abundance in diseased and severely diseased (perforated) samples may contribute to appendicitis pathogenesis, and may provide microbial signatures in the rectum useful for guiding both treatment and diagnosis of appendicitis. PMID- 24759881 TI - Gas film retention and underwater photosynthesis during field submergence of four contrasting rice genotypes. AB - Floods can completely submerge some rice (Oryza sativa L.) fields. Leaves of rice have gas films that aid O2 and CO2 exchange under water. The present study explored the relationship between gas film persistence and underwater net photosynthesis (PN) as influenced by genotype and submergence duration. Four contrasting genotypes (FR13A, IR42, Swarna, and Swarna-Sub1) were submerged for 13 days in the field and leaf gas films, chlorophyll, and the capacity for underwater PN at near ambient and high CO2 were assessed with time of submergence. At high CO2 during the PN assay, all genotypes initially showed high rates of underwater PN, and this rate was not affected by time of submergence in FR13A. This superior photosynthetic performance of FR13A was not evident in Swarna-Sub1 (carrying the SUB1 QTL) and the declines in underwater PN in both Swarna-Sub1 and Swarna were equal to that in IR42. At near ambient CO2 concentration, underwater PN declined in all four genotypes and this corresponded with loss of leaf gas films with time of submergence. FR13A retained leaf gas films moderately longer than the other genotypes, but gas film retention was not linked to SUB1. Diverse rice germplasm should be screened for gas film persistence during submergence, as this trait could potentially increase carbohydrate status and internal aeration owing to increased underwater PN, which contributes to submergence tolerance in rice. PMID- 24759883 TI - Functional trade-offs in succulent stems predict responses to climate change in columnar cacti. AB - Columnar cacti occur naturally in many habitats and environments in the Americas but are conspicuously dominant in very dry desert regions. These majestic plants are widely regarded for their cultural, economic, and ecological value and, in many ecosystems, support highly diverse communities of pollinators, seed dispersers, and frugivores. Massive amounts of water and other resources stored in the succulent photosynthetic stems of these species confer a remarkable ability to grow and reproduce during intensely hot and dry periods. Yet many columnar cacti are potentially under severe threat from environmental global changes, including climate change and loss of habitat. Stems in columnar cacti and other cylindrical-stemmed cacti are morphologically diverse; stem volume-to surface area ratio (V:S) across these taxa varies by almost two orders of magnitude. Intrinsic functional trade-offs are examined here across a broad range of V:S in species of columnar cacti. It is proposed that variation in photosynthetic gas exchange, growth, and response to stress is highly constrained by stem V:S, establishing a mechanistic framework for understanding the sensitivity of columnar cacti to climate change and drought. Specifically, species that develop stems with low V:S, and thus have little storage capacity, are expected to express high mass specific photosynthesis and growth rates under favourable conditions compared with species with high V:S. But the trade-off of having little storage capacity is that low V:S species are likely to be less tolerant of intense or long-duration drought compared with high V:S species. The application of stable isotope measurements of cactus spines as recorders of growth, water relations, and metabolic responses to the environment across species of columnar cacti that vary in V:S is also reviewed. Taken together, our approach provides a coherent theory and required set of observations needed for predicting the responses of columnar cacti to climate change. PMID- 24759882 TI - Reciprocal crosstalk between jasmonate and salicylate defence-signalling pathways modulates plant volatile emission and herbivore host-selection behaviour. AB - The jasmonic acid (JA) and salicylic acid (SA) signalling pathways, which mediate induced plant defence responses, can express negative crosstalk. Limited knowledge is available on the effects of this crosstalk on host-plant selection behaviour of herbivores. We report on temporal and dosage effects of such crosstalk on host preference and oviposition-site selection behaviour of the herbivorous spider mite Tetranychus urticae towards Lima bean (Phaseolus lunatus) plants, including underlying mechanisms. Behavioural observations reveal a dynamic temporal response of mites to single or combined applications of JA and SA to the plant, including attraction and repellence, and an antagonistic interaction between SA- and JA-mediated plant responses. Dose-response experiments show that concentrations of 0.001mM and higher of one phytohormone can neutralize the repellent effect of a 1mM application of the other phytohormone on herbivore behaviour. Moreover, antagonism between the two signal transduction pathways affects phytohormone-induced volatile emission. Our multidisciplinary study reveals the dynamic plant phenotype that is modulated by subtle changes in relative phytohormonal titres and consequences for the dynamic host-plant selection by an herbivore. The longer-term effects on plant-herbivore interactions deserve further investigation. PMID- 24759884 TI - A novel gene, MdSSK1, as a component of the SCF complex rather than MdSBP1 can mediate the ubiquitination of S-RNase in apple. AB - As a core factor in S-RNase-based gametophytic self-incompatibility (GSI), the SCF (SKP1-Cullin1-F-box-Rbx1) complex (including pollen determinant SLF, S-locus F-box) functions as an E3 ubiquitin ligase on non-self S-RNase. The SCF complex is formed by SKP1 bridging between SLF, CUL1, and Rbx1; however, it is not known whether an SCF complex lacking SKP1 can mediate the ubiquitination of S-RNase. Three SKP1-like genes from pollen were cloned based on the structural features of the SLF-interacting-SKP1-like (SSK) gene and the 'Golden Delicious' apple genome. These genes have a motif of five amino acids following the standard 'WAFE' at the C terminal and, in addition, contain eight sheets and two helices. All three genes were expressed exclusively in pollen. In the yeast two-hybrid and pull-down assays only one was found to interact with MdSFBB and MdCUL1, suggesting it is the SLF-interacting SKP1-like gene in apple which was named MdSSK1. In vitro experiments using MdSSK1, S2-MdSFBB1 (S2-Malus domestica S-locus-F-box brother) and MdCUL1 proteins incubated with S 2-RNase and ubiquitin revealed that the SCF complex ubiquitinylates S-RNase in vitro, while MdSBP1 (Malus domestica S-RNase binding protein 1) could not functionally replace MdSSK1 in the SCF complex in ubiquitinylating S-RNase. According to the above experiments, MdSBP1 is probably the only factor responsible for recognition with S-RNase, while not a component of the SCF complex, and an SCF complex containing MdSSK1 is required for mediating the ubiquitination of S-RNase. PMID- 24759885 TI - On the synthesis of alpha-amino sulfoxides. AB - A synthetic study on the preparation of N-Boc alpha-amino sulfoxides has revealed an unexpected instability which is believed to be due to alpha-elimination of the sulfoxide to give an iminium ion. Full synthetic details are reported on two main synthetic routes: lithiation and sulfinate trapping of N-Boc heterocycles and oxidation of N-Boc alpha-amino sulfides. Six novel alpha-amino sulfoxides were successfully prepared and isolated. It is speculated that four other alpha-amino sulfoxides were synthesised but could not be isolated due to their propensity to alpha-eliminate the sulfoxide. Ultimately, a stable, cyclic N-Boc alpha-amino sulfoxide was prepared and this successful synthesis relied on the alpha-amino sulfoxide being part of a bicyclic [3.1.0] fused ring system that could not undergo alpha-elimination of the sulfoxide. PMID- 24759886 TI - Physical and biological determinants of collective behavioural dynamics in complex systems: pulling chain formation in the nest-weaving ant Oecophylla smaragdina. AB - The evolution of nest weaving, the inclusion of larval silk in the nest walls, is considered one of the pinnacles of cooperative behaviour in social insects. Within the four ant genera in which this has evolved, Oecophylla are unique in being the only group that precedes the deposition of larval silk by actively manipulating the leaf substrate to form a nest chamber. Here we provide the first descriptions of the manipulation process within a complex-systems framework. Substrate manipulation involves individual ants selecting, grasping and attempting to pull the edge of the substrate. These individuals are then joined by nest mates at the work site, who either select a site beside the first individual or grasp the body of the first or preceding worker to form a chain of pulling ants that together drag and bend the substrate. Site selection by individual workers is not random when confronted with an artificial leaf, with individuals more likely to grasp a substrate at its tip rather than along a more broad edge. The activity of additional individuals is also not random, with their activity being grouped in both space and time. Additional individuals are more likely to join an existing biting individual or pulling group. The positive feedback associated with the early stages of pulling behaviour appears typical for many of the collective actions observed in social insects. PMID- 24759888 TI - Unexpected neutral aza-macrocycle complexes of sodium. AB - Highly unusual Na(+) complexes with neutral tri- and tetra-amines are isolable in good yield from the reaction of NaBAr(F) with the amine in organic media. Structural characterisation reveals primary Na-N bonding, including an unusual sandwich cation [Na(Me3tacn)2](+), derived from homoleptic N6-coordination via two Me3-tacn ligands, and the distorted 5-coordinate [Na(thf)(Me4cyclam)](+). PMID- 24759887 TI - A MAP3k1 SNP predicts survival of gastric cancer in a Chinese population. AB - OBJECTIVES: Genome-wide association studies (GWAS) have demonstrated that the single nucleotide polymorphism (SNP) MAP3K1 rs889312 is a genetic susceptibility marker significantly associated with a risk of hormone-related tumors such as breast cancer. Considering steroid hormone-mediated signaling pathways have an important role in the progression of gastric cancer, we hypothesized that MAP3K1 rs889312 may be associated with survival outcomes in gastric cancer. The purpose of this study was to test this hypothesis. METHODS: We genotyped MAP3K1 rs889312 using TaqMan in 884 gastric cancer patients who received subtotal or total gastrectomy. Kaplan-Meier survival analysis and Cox proportional hazard regression were used to analyze the association between MAP3K1 rs889312 genotypes and survival outcomes of gastric cancer. RESULTS: Our findings reveal that the rs889312 heterozygous AC genotype was significantly associated with an increased rate of mortality among patients with diffuse-type gastric cancer (log-rank P = 0.028 for AC versus AA/CC, hazard ratio [HR] = 1.32, 95% confidence interval [CI] = 1.03-1.69), compared to those carrying the homozygous variant genotypes (AA/CC). Additionally, univariate and multivariate Cox regression analysis demonstrate that rs889312 polymorphism was an independent risk factor for poor survival in these patients. CONCLUSIONS: In conclusion, we demonstrate that MAP3K1 rs889312 is closely correlated with outcome among diffuse-type gastric cancer. This raises the possibility for rs889312 polymorphisms to be used as an independent indicator for predicting the prognosis of diffuse-type gastric cancer within the Chinese population. PMID- 24759890 TI - Requests for euthanasia/physician-assisted suicide on the basis of mental suffering: vulnerable patients or vulnerable physicians? PMID- 24759889 TI - Durability of a vesicular stomatitis virus-based marburg virus vaccine in nonhuman primates. AB - The filoviruses, Marburg virus (MARV) and Ebola virus, causes severe hemorrhagic fever with high mortality in humans and nonhuman primates. A promising filovirus vaccine under development is based on a recombinant vesicular stomatitis virus (rVSV) that expresses individual filovirus glycoproteins (GPs) in place of the VSV glycoprotein (G). These vaccines have shown 100% efficacy against filovirus infection in nonhuman primates when challenge occurs 28-35 days after a single injection immunization. Here, we examined the ability of a rVSV MARV-GP vaccine to provide protection when challenge occurs more than a year after vaccination. Cynomolgus macaques were immunized with rVSV-MARV-GP and challenged with MARV approximately 14 months after vaccination. Immunization resulted in the vaccine cohort of six animals having anti-MARV GP IgG throughout the pre-challenge period. Following MARV challenge none of the vaccinated animals showed any signs of clinical disease or viremia and all were completely protected from MARV infection. Two unvaccinated control animals exhibited signs consistent with MARV infection and both succumbed. Importantly, these data are the first to show 100% protective efficacy against any high dose filovirus challenge beyond 8 weeks after final vaccination. These findings demonstrate the durability of VSV-based filovirus vaccines. PMID- 24759893 TI - Recent developments of direct rhenium-catalyzed [1,3]-transpositions of allylic alcohols and their silyl ethers. AB - The direct metal-catalyzed [1,3]-transposition of allylic alcohols and allylic silyl ethers is a synthetically useful isomerization process that occurs via [3,3]-sigmatropic rearrangement induced by high oxidation state oxometal complexes. The isomerization requires only a catalytic amount of promoter, and high chirality transfer can be achieved. Thus, it bears a significant potential to become a powerful tool in multistep synthesis. Although [1,3]-transposition of allylic alcohols has been known since the late 1960s, the development of synthetically useful protocols that allow for a high level of regio- and stereoselectivity control and their synthetic applications have emerged only recently. This tutorial review summarizes recently developed regioselective [1,3] transpositions of allylic alcohols and silyl ethers and their applications to natural product synthesis. PMID- 24759894 TI - Reply to the comment by Van der Deen et al.: "Possible methodological reason for the finding that 'Neither tax increase nor reimbursement reduced health disparities'". PMID- 24759895 TI - The receptor for advanced glycation end products (RAGE) affects T cell differentiation in OVA induced asthma. AB - The receptor for glycation end products (RAGE) has been previously implicated in shaping the adaptive immune response. RAGE is expressed in T cells after activation and constitutively in T cells from patients with diabetes. The effects of RAGE on adaptive immune responses are not clear: Previous reports show that RAGE blockade affects Th1 responses. To clarify the role of RAGE in adaptive immune responses and the mechanisms of its effects, we examined whether RAGE plays a role in T cell activation in a Th2 response involving ovalbumin (OVA) induced asthma in mice. WT and RAGE deficient wild-type and OT-II mice, expressing a T cell receptor specific for OVA, were immunized intranasally with OVA. Lung cellular infiltration and T cell responses were analyzed by immunostaining, FACS, and multiplex bead analyses for cytokines. RAGE deficient mice showed reduced cellular infiltration in the bronchial alveolar lavage fluid and impaired T cell activation in the mediastinal lymph nodes when compared with WT mice. In addition, RAGE deficiency resulted in reduced OT-II T cell infiltration of the lung and impaired IFNgamma and IL-5 production when compared with WT mice and reduced infiltration when transferred into WT hosts. When cultured under conditions favoring the differentiation of T cells subsets, RAGE deficient T cells showed reduced production of IFNgamma but increased production of IL-17. Our data show a stimulatory role for RAGE in T activation in OVA induced asthma. This role is largely mediated by the effects of RAGE on T cell proliferation and differentiation. These findings suggest that RAGE may play a regulatory role in T cell responses following immune activation. PMID- 24759897 TI - Electronic structure at nanocontacts of surface passivated CdSe nanorods with gold clusters. AB - We report the electronic structure of free standing and gold attached passivated CdSe nanorods. The goal is to assess the changes at the nanolevel after formation of contacts with gold clusters serving as electrodes and compare the results with experimental observations [Steiner et al., Phys. Rev. Lett., 2005, 95, 056805]. It is interesting to note that upon attaching gold clusters, the nanorods shorter than 27 A develop metallicity by means of metal induced gap states (MIGS). Longer nanorods exhibit a nanoscale Schottky barrier emerging at the center. For these nanorods, the interfacial region closest to the gold electrodes shows a finite density of states in the gap due to MIGS, which gradually decreases towards the center of the nanorod opening up a finite gap. Our theoretical results agree qualitatively with the experimental results of Steiner et al. This study attempts to identify the minimum length of a one-dimensional nanostructure to be used in an electronic device. An analysis of density of states and charge density brings out the role of hybridization of semiconductor states with metal states. Bader charge analysis indicates localized charge transfer from metal to semiconductor. PMID- 24759896 TI - Diversity and antimicrobial activity of culturable endophytic fungi isolated from moso bamboo seeds. AB - Bamboos, regarded as therapeutic agents in ethnomedicine, have been used to inhibit inflammation and enhance natural immunity for a long time in Asia, and there are many bamboo associated fungi with medical and edible value. In the present study, a total of 350 fungal strains were isolated from the uncommon moso bamboo (Phyllostachys edulis) seeds for the first time. The molecular diversity of these endophytic fungi was investigated and bioactive compound producers were screened for the first time. All the fungal endophytes were categorized into 69 morphotypes according to culturable characteristics and their internal transcriber spacer (ITS) regions were analyzed by BLAST search with the NCBI database. The fungal isolates showed high diversity and were divided in Ascomycota (98.0%) and Basidiomycota (2.0%), including at least 19 genera in nine orders. Four particular genera were considered to be newly recorded bambusicolous fungi, including Leptosphaerulina, Simplicillium, Sebacina and an unknown genus in Basidiomycetes. Furthermore, inhibitory effects against clinical pathogens and phytopathogens were screened preliminarily and strains B09 (Cladosporium sp.), B34 (Curvularia sp.), B35 (undefined genus 1), B38 (Penicillium sp.) and zzz816 (Shiraia sp.) displayed broad-spectrum activity against clinical bacteria and yeasts by the agar diffusion method. The crude extracts of isolates B09, B34, B35, B38 and zzz816 under submerged fermentation, also demonstrated various levels of bioactivities against bambusicolous pathogenic fungi. This study is the first report on the antimicrobial activity of endophytic fungi associated with moso bamboo seeds, and the results show that they could be exploited as a potential source of bioactive compounds and plant defense activators. In addition, it is the first time that strains of Shiraia sp. have been isolated and cultured from moso bamboo seeds, and one of them (zzz816) could produce hypocrellin A at high yield, which is significantly different from the other strains published. PMID- 24759898 TI - Fragmentation and exfoliation of 2-dimensional materials: a statistical approach. AB - The main advantage for applications of graphene and related 2D materials is that they can be produced on large scales by liquid phase exfoliation. The exfoliation process shall be considered as a particular fragmentation process, where the 2D character of the exfoliated objects will influence significantly fragmentation dynamics as compared to standard materials. Here, we used automatized image processing of Atomic Force Microscopy (AFM) data to measure, one by one, the exact shape and size of thousands of nanosheets obtained by exfoliation of an important 2D-material, boron nitride, and used different statistical functions to model the asymmetric distribution of nanosheet sizes typically obtained. Being the resolution of AFM much larger than the average sheet size, analysis could be performed directly at the nanoscale and at the single sheet level. We find that the size distribution of the sheets at a given time follows a log-normal distribution, indicating that the exfoliation process has a "typical" scale length that changes with time and that exfoliation proceeds through the formation of a distribution of random cracks that follow Poisson statistics. The validity of this model implies that the size distribution does not depend on the different preparation methods used, but is a common feature in the exfoliation of this material and thus probably for other 2D materials. PMID- 24759901 TI - Vicarious group-based rejection: creating a potentially dangerous mix of humiliation, powerlessness, and anger. AB - Rejection can convey that one is seen as inferior and not worth bothering with. Is it possible for people to feel vicariously rejected in this sense and have reactions that are similar to those following personal rejection, such as feeling humiliated, powerless, and angry? A study on personal rejection was followed by two main studies on vicarious group-based rejection. It was found that merely observing rejection of ingroup members can trigger feelings of humiliation that are equally intense as those experienced in response to personal rejection. Moreover, given that the rejection is explicit, vicariously experienced feelings of humiliation can be accompanied by powerlessness and anger. Potentially, this combination of emotions could be an important source of offensive action against rejecters. PMID- 24759902 TI - Role of the nano amorphous interface in the crystallization of Sb2Te3 towards non volatile phase change memory: insights from first principles. AB - The nano amorphous interface is important as it controls the phase transition for data storage. Yet, atomic scale insights into such kinds of systems are still rare. By first-principles calculations, we obtain the atomic interface between amorphous Si and amorphous Sb2Te3, which prevails in the series of Si-Sb-Te phase change materials. This interface model reproduces the experiment-consistent phenomena, i.e. the amorphous stability of Sb2Te3, which defines the data retention in phase change memory, and is greatly enhanced by the nano interface. More importantly, this method offers a direct platform to explore the intrinsic mechanism to understand the material function: (1) by steric effects through the atomic "channel" of the amorphous interface, the arrangement of the Te network is significantly distorted and is separated from the p-orbital bond angle in the conventional phase-change material; and (2) through the electronic "channel" of the amorphous interface, high localized electrons in the form of a lone pair are "projected" to Sb2Te3 from amorphous Si by a proximity effect. These factors set an effective barrier for crystallization and improve the amorphous stability, and thus data retention. The present research and scheme sheds new light on the engineering and manipulation of other key amorphous interfaces, such as Si3N4/Ge2Sb2Te5 and C/Sb2Te3, through first-principles calculations towards non volatile phase change memory. PMID- 24759900 TI - Adenosine stress cardiovascular magnetic resonance with variable-density spiral pulse sequences accurately detects coronary artery disease: initial clinical evaluation. AB - BACKGROUND: Adenosine stress cardiovascular magnetic resonance perfusion imaging can be limited by motion-induced dark-rim artifacts, which may be mistaken for true perfusion abnormalities. A high-resolution variable-density spiral pulse sequence with a novel density compensation strategy has been shown to reduce dark rim artifacts in first-pass perfusion imaging. We aimed to assess the clinical performance of adenosine stress cardiovascular magnetic resonance using this new perfusion sequence to detect obstructive coronary artery disease. METHODS AND RESULTS: Cardiovascular magnetic resonance perfusion imaging was performed during adenosine stress (140 MUg/kg per minute) and at rest on a Siemens 1.5-T Avanto scanner in 41 subjects with chest pain scheduled for coronary angiography. Perfusion images were acquired during injection of 0.1 mmol/kg Gadolinium diethylenetriaminepentacetate at 3 short-axis locations using a saturation recovery interleaved variable-density spiral pulse sequence. Significant stenosis was defined as >50% by quantitative coronary angiography. Two blinded reviewers evaluated the perfusion images for the presence of adenosine-induced perfusion abnormalities and assessed image quality using a 5-point scale (1 [poor] to 5 [excellent]). The prevalence of obstructive coronary artery disease by quantitative coronary angiography was 68%. The average sensitivity, specificity, and accuracy were 89%, 85%, and 88%, respectively, with a positive predictive value and negative predictive value of 93% and 79%, respectively. The average image quality score was 4.4+/-0.7, with only 1 study with more than mild dark-rim artifacts. There was good inter-reader reliability with a kappa statistic of 0.67. CONCLUSIONS: Spiral adenosine stress cardiovascular magnetic resonance results in high diagnostic accuracy for the detection of obstructive coronary artery disease with excellent image quality and minimal dark-rim artifacts. PMID- 24759903 TI - Space radiation risks for astronauts on multiple International Space Station missions. AB - Mortality and morbidity risks from space radiation exposure are an important concern for astronauts participating in International Space Station (ISS) missions. NASA's radiation limits set a 3% cancer fatality probability as the upper bound of acceptable risk and considers uncertainties in risk predictions using the upper 95% confidence level (CL) of the assessment. In addition to risk limitation, an important question arises as to the likelihood of a causal association between a crew-members' radiation exposure in the past and a diagnosis of cancer. For the first time, we report on predictions of age and sex specific cancer risks, expected years of life-loss for specific diseases, and probability of causation (PC) at different post-mission times for participants in 1-year or multiple ISS missions. Risk projections with uncertainty estimates are within NASA acceptable radiation standards for mission lengths of 1-year or less for likely crew demographics. However, for solar minimum conditions upper 95% CL exceed 3% risk of exposure induced death (REID) by 18 months or 24 months for females and males, respectively. Median PC and upper 95%-confidence intervals are found to exceed 50% for several cancers for participation in two or more ISS missions of 18 months or longer total duration near solar minimum, or for longer ISS missions at other phases of the solar cycle. However, current risk models only consider estimates of quantitative differences between high and low linear energy transfer (LET) radiation. We also make predictions of risk and uncertainties that would result from an increase in tumor lethality for highly ionizing radiation reported in animal studies, and the additional risks from circulatory diseases. These additional concerns could further reduce the maximum duration of ISS missions within acceptable risk levels, and will require new knowledge to properly evaluate. PMID- 24759904 TI - Ionic effects in self-propelled Pt-coated Janus swimmers. AB - Colloidal particles partially coated with platinum and dispersed in H2O2 solution are often used as model self-propelled colloids. Most current data suggest that neutral self-diffusiophoresis propels these particles. However, several studies have shown strong ionic effects in this and related systems, such as a reduction of propulsion speed by salt. We investigate these ionic effects in Pt-coated polystyrene colloids, and find here that the direction of propulsion can be reversed by addition of an ionic surfactant, and that although adding pH neutral salts reduces the propulsion speed, adding the strong base NaOH has little effect. We use these data, as well as measured reaction rates, to argue against propulsion by either neutral or ionic self-diffusiophoresis, and suggest instead that the particle's propulsion mechanism may in fact bear close resemblance to that operative in bimetallic swimmers. PMID- 24759905 TI - Eye movements, visual search and scene memory, in an immersive virtual environment. AB - Visual memory has been demonstrated to play a role in both visual search and attentional prioritization in natural scenes. However, it has been studied predominantly in experimental paradigms using multiple two-dimensional images. Natural experience, however, entails prolonged immersion in a limited number of three-dimensional environments. The goal of the present experiment was to recreate circumstances comparable to natural visual experience in order to evaluate the role of scene memory in guiding eye movements in a natural environment. Subjects performed a continuous visual-search task within an immersive virtual-reality environment over three days. We found that, similar to two-dimensional contexts, viewers rapidly learn the location of objects in the environment over time, and use spatial memory to guide search. Incidental fixations did not provide obvious benefit to subsequent search, suggesting that semantic contextual cues may often be just as efficient, or that many incidentally fixated items are not held in memory in the absence of a specific task. On the third day of the experience in the environment, previous search items changed in color. These items were fixated upon with increased probability relative to control objects, suggesting that memory-guided prioritization (or Surprise) may be a robust mechanisms for attracting gaze to novel features of natural environments, in addition to task factors and simple spatial saliency. PMID- 24759907 TI - Retrograde vs Conventional Dissection Technique in Pancreaticoduodenectomy: A Pilot Study. AB - IMPORTANCE: A retrograde dissection technique of pancreaticoduodenectomy in a caudocranial direction has been described recently. OBSERVATIONS: Fifteen consecutive patients who underwent retrograde pancreaticoduodenectomy were compared with 15 consecutive patients operated on through a conventional approach. The mean (SD) intraoperative blood loss was 407 (202) mL in the retrograde group compared with 423 (253) mL in the conventional group (P = .84). The mean (SD) operative duration was 255 (57) minutes in the retrograde group compared with 264 (54) minutes in the conventional group (P = .66). The overall morbidity was 7 of 15 patients (47%) in the retrograde group and 6 of 15 (40%) in the conventional group (P > .99). Neither group had a positive resection margin or a perioperative death. CONCLUSIONS AND RELEVANCE: The retrograde dissection technique had no significant difference in perioperative outcomes compared with the conventional dissection technique and could serve as an alternative dissection approach in pancreaticoduodenectomy. PMID- 24759906 TI - A module of human peripheral blood mononuclear cell transcriptional network containing primitive and differentiation markers is related to specific cardiovascular health variables. AB - Peripheral blood mononuclear cells (PBMCs), including rare circulating stem and progenitor cells (CSPCs), have important yet poorly understood roles in the maintenance and repair of blood vessels and perfused organs. Our hypothesis was that the identities and functions of CSPCs in cardiovascular health could be ascertained by analyzing the patterns of their co-expressed markers in unselected PBMC samples. Because gene microarrays had failed to detect many stem cell associated genes, we performed quantitative real-time PCR to measure the expression of 45 primitive and tissue differentiation markers in PBMCs from healthy and hypertensive human subjects. We compared these expression levels to the subjects' demographic and cardiovascular risk factors, including vascular stiffness. The tested marker genes were expressed in all of samples and organized in hierarchical transcriptional network modules, constructed by a bottom-up approach. An index of gene expression in one of these modules (metagene), defined as the average standardized relative copy numbers of 15 pluripotency and cardiovascular differentiation markers, was negatively correlated (all p<0.03) with age (R2 = -0.23), vascular stiffness (R2 = -0.24), and central aortic pressure (R2 = -0.19) and positively correlated with body mass index (R2 = 0.72, in women). The co-expression of three neovascular markers was validated at the single-cell level using mRNA in situ hybridization and immunocytochemistry. The overall gene expression in this cardiovascular module was reduced by 72+/-22% in the patients compared with controls. However, the compactness of both modules was increased in the patients' samples, which was reflected in reduced dispersion of their nodes' degrees of connectivity, suggesting a more primitive character of the patients' CSPCs. In conclusion, our results show that the relationship between CSPCs and vascular function is encoded in modules of the PBMCs transcriptional network. Furthermore, the coordinated gene expression in these modules can be linked to cardiovascular risk factors and subclinical cardiovascular disease; thus, this measure may be useful for their diagnosis and prognosis. PMID- 24759908 TI - The Proportion of Malignancy in Incidental Thyroid Lesions on 18-FDG PET Study: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To evaluate through a systematic review and meta-analysis the malignancy rates of thyroid incidentalomas identified in adults by 18 fluorodeoxyglucose positron emission tomography, computed tomography (18-FDG PET CT) imaging studies. DATA SOURCES: The literature search was conducted using OVID Medline, EMBASE, the Cochrane Library, Google Scholar, Pubmed, and reference list review (inception to April 2013) by 2 independent review authors. REVIEW METHODS: Studies with adults undergoing 18-FDG PET scan identifying a thyroid incidentaloma with definitive histological or cytological results reported were included. RESULTS: Thirty-one studies with a total of 197,296 PET studies and 3659 focal thyroid incidentalomas were identified with 1341 having definitive cytopathology or histopathology. The pooled proportion of malignancy was calculated as 19.8% (95% confidence interval [CI], 15.3%-24.7%) with 15.4% (95% CI, 11.4%-20.0%) of the total cases being papillary thyroid cancer. Distant metastases represented 1.1% (95% CI, 0.6%-1.8%) of the total cases. CONCLUSIONS: Our systematic review and meta-analysis suggests that the incidence of malignancy is high in thyroid incidentalomas identified through 18-FDG PET imaging studies. Thyroid incidentalomas identified through 18-FDG PET require thorough investigation. PMID- 24759909 TI - The Therapeutic Dilemma of Cochlear Nerve Deficiency: Cochlear or Brainstem Implantation? AB - OBJECTIVE: To compare the outcomes between 2 age-matched cohorts of children with cochlear nerve deficiency: those receiving auditory brainstem implants (group A) or cochlear implants (group B). STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Subjects were selected from a pool of 537 children fitted with cochlear implants (n = 443) or auditory brainstem implants (n = 94) over the past 14 years. Performance, examined with the Category of Auditory Performance scale, and complications were compared with a mean follow-up of 5 years. RESULTS: All children had bilateral profound sensorineural hearing loss and cochlear nerve deficiency. Magnetic resonance imaging documented an absent cochlear nerve (n = 12) and a small cochlear nerve (n = 8) in group A and an absent cochlear nerve (n = 11) and a small cochlear nerve (n = 9) in group B (P = 1.000). Children with cochlear implants had Category of Auditory Performance scores spanning from 0 to 3 levels of performance, and all required manual communication mode and visual supplementation. Children with auditory brainstem implants had Category of Auditory Performance scores spanning from 2 to 7, and most patients demonstrated behavioral responses irrespective of inner ear malformations and an absent cochlear nerve or small cochlear nerve (P < .001). CONCLUSIONS: In children with cochlear nerve deficiency, patients fitted with cochlear implants did not develop speech understanding and production. Those fitted with auditory brainstem implants had the opportunity to develop open-set speech perception, acquiring verbal language competence using oral communication exclusively and participating in mainstream education. The overall complication rate of auditory brainstem implants was not greater than that of cochlear implants. PMID- 24759910 TI - Amount and frequency of exercise affect glycaemic control more than exercise mode or intensity. PMID- 24759911 TI - The Exercise is Medicine Global Health Initiative: a 2014 update. AB - BACKGROUND: A third of the world's population does not engage in recommended levels of physical activity (PA), leading to substantial health and economic burdens. The healthcare sector offers a variety of resources that can help counsel, refer and deliver PA promotion programmes for purposes of primordial, primary, secondary and tertiary prevention. Substantial evidence already exists in support of multipronged PA counselling, prescription and referral strategies, in particular those linking healthcare and community-based resources. METHODS: The Exercise is Medicine (EIM) initiative was introduced in 2007 to advance the implementation of evidence-based strategies to elevate the status of PA in healthcare. In this article, we describe the evolution and global expansion of the EIM initiative, its components, their implementation, an evaluation framework and future initiative activities. RESULTS: Until now, EIM has a presence in 39 countries with EIM Regional Centers established in North America, Latin America, Europe, Africa, Southeast Asia, China and Australasia. The EIM Global Health Initiative is transitioning from its initial phase of infrastructure and awareness building to a phase of programme implementation, with an emphasis in low-to-middle income countries, where 80% of deaths due to non-communicable diseases already occur, but where a large gap in research and implementation of PA strategies exists. CONCLUSIONS: Broad implementation of PA counselling and referral systems, as clinical practice standard of care, has the potential to improve PA at the population level by complementing and leveraging other efforts and to contribute to achieving global targets for the reduction of inactivity and related morbidity and mortality. PMID- 24759912 TI - O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond. AB - Alzheimer disease (AD) is a growing problem for aging populations worldwide. Despite significant efforts, no therapeutics are available that stop or slow progression of AD, which has driven interest in the basic causes of AD and the search for new therapeutic strategies. Longitudinal studies have clarified that defects in glucose metabolism occur in patients exhibiting Mild Cognitive Impairment (MCI) and glucose hypometabolism is an early pathological change within AD brain. Further, type 2 diabetes mellitus (T2DM) is a strong risk factor for the development of AD. These findings have stimulated interest in the possibility that disrupted glucose regulated signaling within the brain could contribute to the progression of AD. One such process of interest is the addition of O-linked N-acetylglucosamine (O-GlcNAc) residues onto nuclear and cytoplasmic proteins within mammals. O-GlcNAc is notably abundant within brain and is present on hundreds of proteins including several, such as tau and the amyloid precursor protein, which are involved in the pathophysiology AD. The cellular levels of O GlcNAc are coupled to nutrient availability through the action of just two enzymes. O-GlcNAc transferase (OGT) is the glycosyltransferase that acts to install O-GlcNAc onto proteins and O-GlcNAcase (OGA) is the glycoside hydrolase that acts to remove O-GlcNAc from proteins. Uridine 5'-diphosphate-N acetylglucosamine (UDP-GlcNAc) is the donor sugar substrate for OGT and its levels vary with cellular glucose availability because it is generated from glucose through the hexosamine biosynthetic pathway (HBSP). Within the brains of AD patients O-GlcNAc levels have been found to be decreased and aggregates of tau appear to lack O-GlcNAc entirely. Accordingly, glucose hypometabolism within the brain may result in disruption of the normal functions of O-GlcNAc within the brain and thereby contribute to downstream neurodegeneration. While this hypothesis remains largely speculative, recent studies using different mouse models of AD have demonstrated the protective benefit of pharmacologically increased brain O-GlcNAc levels. In this review we summarize the state of knowledge in the area of O-GlcNAc as it pertains to AD while also addressing some of the basic biochemical roles of O-GlcNAc and how these might contribute to protecting against AD and other neurodegenerative diseases. PMID- 24759913 TI - Identification of protein kinase inhibitors with a selective negative effect on the viability of Epstein-Barr virus infected B cell lines. AB - Epstein-Barr virus (EBV) is a human herpesvirus, which is causally associated with the development of several B lymphocytic malignancies that include Burkitt's lymphomas, Hodgkin's disease, AIDS and posttransplant associated lymphomas. The transforming activity of EBV is orchestrated by several latent viral proteins that mimic and modulate cellular growth promoting and antiapoptotic signaling pathways, which involve among others the activity of protein kinases. In an effort to identify small molecule inhibitors of the growth of EBV-transformed B lymphocytes a library of 254 kinase inhibitors was screened. This effort identified two tyrosine kinase inhibitors and two MEK inhibitors that compromised preferentially the viability of EBV-infected human B lymphocytes. Our findings highlight the possible dependence of EBV-infected B lymphocytes on specific kinase-regulated pathways underlining the potential for the development of small molecule-based therapeutics that could target selectively EBV-associated human B lymphocyte malignancies. PMID- 24759914 TI - Thermoluminescent responses of Li3B7O12:Cu to proton beam. AB - A thermoluminescent (TL) phosphor Li3B7O12:Cu was irradiated by a proton beam at NIRS-HIMAC in Japan. Irradiation was performed at different water-equivalent depths using range shifters made of polymethyl methacrylate. The thermoluminescent responses of Li3B7O12:Cu were analysed, focusing on the TL efficiency and glow curve. The irradiated samples were heated from room temperature to 200 degrees C at 0.16 degrees C s(-1). The high-temperature area of the glow curve under proton irradiation changed in comparison with that under (60)Co gamma-ray irradiation. The relative TL efficiency of the main peak slightly varied between 0.8 and 1.1. The relationship between the relative TL efficiency of the main peak and the high-temperature area ratio (HTR) value, the relative TL ratio of the main peak to the high-temperature area, showed approximate linearity for proton dosimetry. Using correction based on the HTR method, the TL phosphor Li3B7O12:Cu can become a useful dosimetric tool for therapeutic proton beams. PMID- 24759915 TI - Dose distribution outside the target volume for 170-MeV proton beam. AB - Dose delivered outside the proton field during radiotherapy can potentially lead to secondary cancer development. Measurements with a 170-MeV proton beam were performed with passive detectors (track etched detectors and thermoluminescence dosemeters) in three different depths along the Bragg curve. The measurement showed an uneven decrease of the dose outside of the beam field with local enhancements. The major contribution to the delivered dose is due to high-energy protons with linear energy transfer (LET) up to 10 keV um(-1). However, both measurement and preliminary Monte Carlo calculation also confirmed the presence of particles with higher LET. PMID- 24759916 TI - RBE-LET relationship for proton and alpha irradiations studied with a nanodosimetric approach. AB - Relative Biological Effectiveness (RBE) values are used to characterise the biological efficiency of different radiation qualities relative to photon irradiations. The RBE-high linear energy transfer (LET) relation for ion irradiations presents general features that the authors propose to look at using a nanometric description of the energy deposition of these ion irradiations (protons and alphas of different energies). In this work, the simulation of the energy transfer points in the tracks was made by Monte Carlo method using the Geant4-DNA processes and a nanometric description of the target of interest for studying biological effects, the DNA molecule. Results were obtained concerning the sensitive volume to be considered for direct DNA clustered damages that could be related to late biological effects. PMID- 24759918 TI - Traumatic Hemoperitoneum. PMID- 24759920 TI - Evolving design rules for the inverse granular packing problem. AB - If a collection of identical particles is poured into a container, different shapes will fill to different densities. But what is the shape that fills a container as close as possible to a pre-specified, desired density? We demonstrate a solution to this inverse-packing problem by framing it in the context of artificial evolution. By representing shapes as bonded spheres, we show how shapes may be mutated, simulated, and selected to produce particularly dense or loose packing aggregates, both with and without friction. Moreover, we show how motifs emerge linking these shapes together. The result is a set of design rules that function as an effective solution to the inverse packing problem for given packing procedures and boundary conditions. Finally, we show that these results are verified by experiments on 3D-printed prototypes used to make packings in the real world. PMID- 24759917 TI - Reduction of selenite to red elemental selenium by Rhodopseudomonas palustris strain N. AB - The trace metal selenium is in demand for health supplements to human and animal nutrition. We studied the reduction of selenite (SeO3-2) to red elemental selenium by Rhodopseudomonas palustris strain N. This strain was cultured in a medium containing SeO3-2 and the particles obtained from cultures were analyzed using transmission electron microscopy (TEM), energy dispersive microanalysis (EDX) and X ray diffraction analysis (XRD). Our results showed the strain N could reduce SeO3-2 to red elemental selenium. The diameters of particles were 80-200 nm. The bacteria exhibited significant tolerance to SeO3-2 up to 8.0 m mol/L concentration with an EC50 value of 2.4 m mol/L. After 9 d of cultivation, the presence of SeO32- up to 1.0 m mol/L resulted in 99.9% reduction of selenite, whereas 82.0% (p<0.05), 31.7% (p<0.05) and 2.4% (p<0.05) reduction of SeO3-2 was observed at 2.0, 4.0 and 8.0 m mol/L SeO32- concentrations, respectively. This study indicated that red elemental selenium was synthesized by green technology using Rhodopseudomonas palustris strain N. This strain also indicated a high tolerance to SeO3-2. The finding of this work will contribute to the application of selenium to human health. PMID- 24759919 TI - Retrotransposon hypomethylation in melanoma and expression of a placenta-specific gene. AB - In the human placenta, DNA hypomethylation permits the expression of retrotransposon-derived genes that are normally silenced by methylation in somatic tissues. We previously identified hypomethylation of a retrotransposon derived transcript of the voltage-gated potassium channel gene KCNH5 that is expressed only in human placenta. However, an RNA sequence from this placental specific transcript has been reported in melanoma. This study examined the promoter methylation and expression of the retrotransposon-derived KCNH5 transcript in 25 melanoma cell lines to determine whether the acquisition of 'placental' epigenetic marks is a feature of melanoma. Methylation and gene expression analysis revealed hypomethylation of this retrotransposon in melanoma cell lines, particularly in those samples that express the placental KCNH5 transcript. Therefore we propose that hypomethylation of the placental-specific KCNH5 promoter is frequently associated with KCNH5 expression in melanoma cells. Our findings show that melanoma can develop hypomethylation of a retrotransposon derived gene; a characteristic notably shared with the normal placenta. PMID- 24759921 TI - Stochastic heterogeneous interaction promotes cooperation in spatial prisoner's dilemma game. AB - Previous studies mostly investigate player's cooperative behavior as affected by game time-scale or individual diversity. In this paper, by involving both time scale and diversity simultaneously, we explore the effect of stochastic heterogeneous interaction. In our model, the occurrence of game interaction between each pair of linked player obeys a random probability, which is further described by certain distributions. Simulations on a 4-neighbor square lattice show that the cooperation level is remarkably promoted when stochastic heterogeneous interaction is considered. The results are then explained by investigating the mean payoffs, the mean boundary payoffs and the transition probabilities between cooperators and defectors. We also show some typical snapshots and evolution time series of the system. Finally, the 8-neighbor square lattice and BA scale-free network results indicate that the stochastic heterogeneous interaction can be robust against different network topologies. Our work may sharpen the understanding of the joint effect of game time-scale and individual diversity on spatial games. PMID- 24759923 TI - NICE says drug for metastatic breast cancer is unaffordable for NHS. PMID- 24759922 TI - Wolbachia infection modifies the profile, shuttling and structure of microRNAs in a mosquito cell line. AB - MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in many biological processes such as development, cell signaling and immune response. Small RNA deep sequencing technology provided an opportunity for a thorough survey of the miRNA profile of a mosquito cell line from Aedes aegypti. We characterized the miRNA composition of the nucleus and the cytoplasm of uninfected cells and compared it with the one of cells infected with the endosymbiotic bacterium Wolbachia strain wMelPop-CLA. We found an overall increase of small RNAs between 18 and 28 nucleotides in both cellular compartments in Wolbachia-infected cells and identified specific miRNAs induced and/or suppressed by the Wolbachia infection. We discuss the mechanisms that the cell may use to shuttle miRNAs between the cytoplasm and the nucleus. In addition, we identified piRNAs that changed their abundance in response to Wolbachia infection. The miRNAs and piRNAs identified in this study provide promising leads for investigations into the host-endosymbiont interactions and for better understanding of how Wolbachia manipulates the host miRNA machinery in order to facilitate its persistent replication in infected cells. PMID- 24759924 TI - The old "nature-nurture debate" has been supplanted in recent years by research showing interaction between biology, and culture and environment. Editor's introduction. PMID- 24759925 TI - Genetic associations with intimate partner violence in a sample of hazardous drinking men in batterer intervention programs. AB - The etiology of intimate partner violence (IPV) is multifactorial. However, etiological theories of IPV have rarely included potential genetic factors. The purpose of the present study was to examine whether a cumulative genetic score (CGS) containing the monoamine oxidase A (MAOA) and the human serotonin transporter gene linked polymorphism (5-HTTLPR) was associated with IPV perpetration after accounting for the effects of alcohol problems, drug problems, age, and length of relationship. We obtained DNA from 97 men in batterer intervention programs in the state of Rhode Island. In the full sample, the CGS was significantly associated with physical and psychological aggression and injuries caused to one's partner, even after controlling for the effects of alcohol problems, drug problems, age, and length of relationship. Two of the men in the sample likely had Klinefelter's syndrome, and analyses were repeated excluding these two individuals, leading to similar results. The implications of the genetic findings for the etiology and treatment of IPV among men in batterer intervention programs are briefly discussed. PMID- 24759926 TI - Further investigation of genetics and intimate partner violence. AB - We thank Drs. Abbey, Bennett, DeWall, and Way for making truly outstanding points in their thoughtful commentaries. We agree with the feedback and advice from all of these distinguished scientists. Future work on genetics and intimate partner violence (IPV) should, when possible, include a larger number of genetic variants, closely examine gene by environment interactions, and study potential mechanisms explaining the connection between genetics and IPV. As with any research, but particularly with respect to studies on a controversial topic such as genetic correlates of IPV, extreme caution should be taken prior to generalizing results or deriving any practical applications from the data. Clearly, replication and extension of the findings in other populations is essential. Ultimately, we believe that it is worth pursuing this line of work given the possible contributions it may make to understanding the etiology, prevention, and treatment of IPV in the future. Finding solutions to IPV will require the collaboration of a diverse group of constituents from many disciplines. PMID- 24759927 TI - De novo transcriptome and small RNA analyses of two amorphophallus species. AB - Konjac is one of the most important glucomannan crops worldwide. The breeding and genomic researches are largely limited by the genetic basis of Amorphophallus. In this study, the transcriptomes of A. konjac and A. bulbifer were constructed using a high-throughput Illumina sequencing platform. All 108,651 unigenes with average lengths of 430 nt in A. konjac and 119,678 unigenes with average lengths of 439 nt were generated from 54,986,020 reads and 52,334,098 reads after filtering and assembly, respectively. A total of 54,453 transcripts in A. konjac and 55,525 in A. bulbifier were annotated by comparison with Nr, Swiss-Prot, KEGG, and COG databases after removing exogenous contaminated sequences. A total of 80,332 transcripts differentially expressed between A. konjac and A. bulbifer. The majority of the genes that are associated with konjac glucomannan biosynthetic pathway were identified. Besides, the small RNAs in A. konjac leaves were also obtained by deep sequencing technology. All of 5,499,903 sequences of small RNAs were obtained with the length range between 18 and 30 nt. The potential targets for the miRNAs were also predicted according to the konjac transcripts. Our study provides a systematic overview of the konjac glucomannan biosynthesis genes that are involved in konjac leaves and should facilitate further understanding of the crucial roles of carbohydrate synthesis and other important metabolism pathways in Amorphophallus. PMID- 24759928 TI - Vascular endothelial growth factor-receptor 1 inhibition aggravates diabetic nephropathy through eNOS signaling pathway in db/db mice. AB - The manipulation of vascular endothelial growth factor (VEGF)-receptors (VEGFRs) in diabetic nephropathy is as controversial as issue as ever. It is known to be VEGF-A and VEGFR2 that regulate most of the cellular actions of VEGF in experimental diabetic nephropathy. On the other hand, such factors as VEGF-A, -B and placenta growth factor bind to VEGFR1 with high affinity. Such notion instigated us to investigate on whether selective VEGFR1 inhibition with GNQWFI hexamer aggravates the progression of diabetic nephropathy in db/db mice. While diabetes suppressed VEGFR1, it did increase VEGFR2 expressions in the glomerulus. Db/db mice with VEGFR1 inhibition showed more prominent features with respect to, albuminuria, mesangial matrix expansion, inflammatory cell infiltration and greater numbers of apoptotic cells in the glomerulus, and oxidative stress than that of control db/db mice. All these changes were related to the suppression of diabetes-induced increases in PI3K activity and Akt phosphorylation as well as the aggravation of endothelial dysfunction associated with the inactivation of FoxO3a and eNOS-NOx. In cultured human glomerular endothelial cells (HGECs), high glucose media with VEGFR1 inhibition induced more apoptotic cells and oxidative stress than did high-glucose media alone, which were associated with the suppression of PI3K-Akt phosphorylation, independently of the activation of AMP activated protein kinase, and inactivation of FoxO3a and eNOS-NOx pathway. In addition, transfection with VEGFR1 siRNA in HGECs also suppressed PI3K-Akt-eNOS signaling. In conclusion, the specific blockade of VEGFR1 with GNQWFI caused severe renal injury related to profound suppression of the PI3K-Akt, FoxO3a and eNOS-NOx pathway, giving rise to the oxidative stress-induced apoptosis of glomerular cells in type 2 diabetic nephropathy. PMID- 24759930 TI - Towards a proactive therapy utilizing the modern spectrum of extracorporeal life support: a single-centre experience. AB - BACKGROUND: We describe a single-centre experience of extracorporeal life support (ELS) for patients with severe and refractory cardiogenic shock, refractory cardiac arrest and severe respiratory failure. METHODS: Between September 2007 and September 2012, 56 intra-hospital and 10 inter-hospital adult patients were supported. RESULTS: The median ELS duration was 3 (0.9 - 6) days in venoarterial and 9.2 (7.4 - 24.4) days in venovenous supported patients. At hospital discharge and follow-up (12 and 40 months), survival among the respiratory (venovenous) patients and cardiac (venoarterial) patients was 84% and 38%, respectively. Survival in severe refractory cardiogenic shock patients was related to early initiation of ELS (<8 hours of onset of failure). A delay in initiating venoarterial ELS (>8 hours) and increased pre-ELS pH and lactate levels were associated with death in all cardiomyopathy patients, independent of infarct size. CONCLUSIONS: Our results exemplify the benefits of ELS as a bridge to initial stabilization of critically ill patients. Potentially, the early application of ELS technology can lower mortality and morbidity in patients with a regressive pathology. PMID- 24759929 TI - EHD3-dependent endosome pathway regulates cardiac membrane excitability and physiology. AB - RATIONALE: Cardiac function is dependent on the coordinate activities of membrane ion channels, transporters, pumps, and hormone receptors to tune the membrane electrochemical gradient dynamically in response to acute and chronic stress. Although our knowledge of membrane proteins has rapidly advanced during the past decade, our understanding of the subcellular pathways governing the trafficking and localization of integral membrane proteins is limited and essentially unstudied in vivo. In the heart, to our knowledge, there are no in vivo mechanistic studies that directly link endosome-based machinery with cardiac physiology. OBJECTIVE: To define the in vivo roles of endosome-based cellular machinery for cardiac membrane protein trafficking, myocyte excitability, and cardiac physiology. METHODS AND RESULTS: We identify the endosome-based Eps15 homology domain 3 (EHD3) pathway as essential for cardiac physiology. EHD3 deficient hearts display structural and functional defects including bradycardia and rate variability, conduction block, and blunted response to adrenergic stimulation. Mechanistically, EHD3 is critical for membrane protein trafficking, because EHD3-deficient myocytes display reduced expression/localization of Na/Ca exchanger and L-type Ca channel type 1.2 with a parallel reduction in Na/Ca exchanger-mediated membrane current and Cav1.2-mediated membrane current. Functionally, EHD3-deficient myocytes show increased sarcoplasmic reticulum [Ca], increased spark frequency, and reduced expression/localization of ankyrin-B, a binding partner for EHD3 and Na/Ca exchanger. Finally, we show that in vivo EHD3 deficient defects are attributable to cardiac-specific roles of EHD3 because mice with cardiac-selective EHD3 deficiency demonstrate both structural and electric phenotypes. CONCLUSIONS: These data provide new insight into the critical role of endosome-based pathways in membrane protein targeting and cardiac physiology. EHD3 is a critical component of protein trafficking in heart and is essential for the proper membrane targeting of select cellular proteins that maintain excitability. PMID- 24759932 TI - Apolipoprotein A1 regulates coenzyme Q10 absorption, mitochondrial function, and infarct size in a mouse model of myocardial infarction. AB - HDL and apolipoprotein A1 (apoA1) concentrations inversely correlate with risk of death from ischemic heart disease; however, the role of apoA1 in the myocardial response to ischemia has not been well defined. To test whether apoA1, the primary HDL apolipoprotein, has an acute anti-inflammatory role in ischemic heart disease, we induced myocardial infarction via direct left anterior descending coronary artery ligation in apoA1 null (apoA1(-/-)) and apoA1 heterozygous (apoA1(+/-)) mice. We observed that apoA1(+/-) and apoA1(-/-) mice had a 52% and 125% increase in infarct size as a percentage of area at risk, respectively, compared with wild-type (WT) C57BL/6 mice. Mitochondrial oxidation contributes to tissue damage in ischemia-reperfusion injury. A substantial defect was present at baseline in the electron transport chain of cardiac myocytes from apoA1(-/-) mice localized to the coenzyme Q (CoQ) pool with impaired electron transfer (67% decrease) from complex II to complex III. Administration of coenzyme Q10 (CoQ10) to apoA1 null mice normalized the cardiac mitochondrial CoQ pool and reduced infarct size to that observed in WT mice. CoQ10 administration did not significantly alter infarct size in WT mice. These data identify CoQ pool content leading to impaired mitochondrial function as major contributors to infarct size in the setting of low HDL/apoA1. These data suggest a previously unappreciated mechanism for myocardial stunning, cardiac dysfunction, and muscle pain associated with low HDL and low apoA1 concentrations that can be corrected by CoQ10 supplementation and suggest populations of patients that may benefit particularly from CoQ10 supplementation. PMID- 24759933 TI - Tablets are preferred and more acceptable than powdered prenatal calcium supplements among pregnant women in Dhaka, Bangladesh. AB - Prenatal calcium supplementation is recommended by the WHO to decrease the risk of preeclampsia in women with low dietary calcium intake; yet, this recommendation has not been successfully implemented to date. One component of an effective population-based prenatal calcium intervention will be the selection of a widely accepted calcium vehicle to promote consistent, long-term consumption of the supplement. We aimed to evaluate preference and acceptability of 4 different options for delivering prenatal calcium (conventional tablets, chewable tablets, unflavored powder, and flavored powder) to pregnant women in urban Bangladesh. In a modified discrete-choice trial, pregnant women (n = 132) completed a 4-d "run in period" in which each delivery vehicle was sampled once, followed by a 21-d "selection period" during which participants were instructed to freely select a single delivery vehicle of their choice each day. Preference was empirically defined as the probability that each delivery vehicle was selected on a given day, and measured from participants' daily delivery vehicle selections; acceptability was assessed by using mid- and post-trial questionnaires. Conventional tablets demonstrated the highest probability of selection (62%); the probability of selection of chewable tablets (19%), flavored powder (12%), and unflavored powder (5%) were all significantly lower than for conventional tablets (P < 0.001). The palatability and product characteristics of the conventional tablets were more acceptable than for the other 3 delivery vehicles. Our rigorous methodologic approach used both quantitative and self-reported measures that consistently identified the most preferred and accepted prenatal calcium delivery form. Through observation of pregnant women's actual supplement use, and perceptions of acceptability (i.e., ease of use, palatability), we demonstrated that conventional tablets are likely to be the most accepted and successful calcium delivery vehicle in future field studies and scale-up of the WHO recommendation in Bangladesh. PMID- 24759931 TI - Quercetin supplementation attenuates the progression of cancer cachexia in ApcMin/+ mice. AB - Although there are currently no approved treatments for cancer cachexia, there is an intensified interest in developing therapies because of the high mortality index associated with muscle wasting diseases. Successful treatment of the cachectic patient focuses on improving or maintaining body weight and musculoskeletal function. Nutraceutical compounds, including the natural phytochemical quercetin, are being examined as potential treatments because of their anti-inflammatory, antioxidant, and anticarcinogenic properties. The purpose of this study was to determine the effect of quercetin supplementation on the progression of cachexia in the adenomatous polyposis coli (Apc)(Min/+) mouse model of colorectal cancer. At 15 wk of age, C57BL/6 and male Apc(Min/+) mice were supplemented with 25 mg/kg of quercetin or vehicle solution mix of Tang juice and water (V) daily for 3 wk. Body weight, strength, neuromuscular performance, and fatigue were assessed before and after quercetin or V interventions. Indicators of metabolic dysfunction and inflammatory signaling were also assessed. During the treatment period, the relative decrease in body weight in the Apc(Min/+) mice gavaged with V (Apc(Min/+)V; -14% +/- 2.3) was higher than in control mice gavaged with V (+0.6% +/- 1.0), control mice gavaged with quercetin (-2% +/- 1.0), and Apc(Min/+) mice gavaged with quercetin (Apc(Min/+)Q; -9% +/- 1.3). At 18 wk of age, the loss of grip strength and muscle mass shown in Apc(Min/+)V mice was significantly attenuated (P < 0.05) in Apc(Min/+)Q mice. Furthermore, Apc(Min/+)V mice had an induction of plasma interleukin-6 and muscle signal transducer and activator of transcription 3 phosphorylation, which were significantly (P < 0.05) mitigated in Apc(Min/+)Q mice, despite having a similar tumor burden. Quercetin treatment did not improve treadmill run-time-to-fatigue, hyperglycemia, or hyperlipidemia in cachectic Apc(Min/+) mice. Overall, quercetin supplementation positively affected several aspects of cachexia progression in mice and warrants further exploration as a potential anticachectic therapeutic. PMID- 24759935 TI - Direct hydrosilylation by a zirconacycle with beta-hydrogen. AB - Azasilazirconacycle Cp2Zr{kappa(2)-N(SiHMe2)SiHMeCH2} (1) and formaldehyde react through an uncatalyzed addition reaction (hydrosilylation) to form an exocyclic methoxysilyl-substituted zirconacycle. Although 1 contains 2-center-2-electron SiH groups, this transformation parallels the reactions of non-classical [Cp2ZrN(SiHMe2)2](+) ([2](+)) with carbonyls. Reactions of 1 with a series of nucleophilic and electrophilic agents were explored, as well as reactions of related beta-SiH-containing silazidozirconium compounds, to develop a rationale for the unexpected hydrosilylation. For example, carbon monoxide and 1 react at the Zr-C bond to form Cp2Zr{kappa(2)-OC(=CH2)SiHMeN(SiHMe2)} (7). The Lewis acid B(C6F5)3 also reacts at the Zr-C bond to give Cp2Zr{N(SiHMe2)SiHMeCH2B(C6F5)3} (8). OPEt3 and N,N-dimethylaminopyridine (DMAP) do not appear to interact with 1. In contrast, OPEt3 and DMAP react with non-classical compounds [2](+) and zwitterionic 8. PMID- 24759936 TI - Contractile and mechanical properties of epithelia with perturbed actomyosin dynamics. AB - Mechanics has an important role during morphogenesis, both in the generation of forces driving cell shape changes and in determining the effective material properties of cells and tissues. Drosophila dorsal closure has emerged as a reference model system for investigating the interplay between tissue mechanics and cellular activity. During dorsal closure, the amnioserosa generates one of the major forces that drive closure through the apical contraction of its constituent cells. We combined quantitation of live data, genetic and mechanical perturbation and cell biology, to investigate how mechanical properties and contraction rate emerge from cytoskeletal activity. We found that a decrease in Myosin phosphorylation induces a fluidization of amnioserosa cells which become more compliant. Conversely, an increase in Myosin phosphorylation and an increase in actin linear polymerization induce a solidification of cells. Contrary to expectation, these two perturbations have an opposite effect on the strain rate of cells during DC. While an increase in actin polymerization increases the contraction rate of amnioserosa cells, an increase in Myosin phosphorylation gives rise to cells that contract very slowly. The quantification of how the perturbation induced by laser ablation decays throughout the tissue revealed that the tissue in these two mutant backgrounds reacts very differently. We suggest that the differences in the strain rate of cells in situations where Myosin activity or actin polymerization is increased arise from changes in how the contractile forces are transmitted and coordinated across the tissue through ECadherin-mediated adhesion. Altogether, our results show that there is an optimal level of Myosin activity to generate efficient contraction and suggest that the architecture of the actin cytoskeleton and the dynamics of adhesion complexes are important parameters for the emergence of coordinated activity throughout the tissue. PMID- 24759937 TI - DNA hybridization detection with 100 zM sensitivity using piezoelectric plate sensors with an improved noise-reduction algorithm. AB - We have examined real-time, in situ hybridization detection of target DNA (tDNA) in a buffer solution and in urine using 8 MUm-thick lead magnesium niobate-lead titanate (PMN-PT) piezoelectric plate sensors (PEPSs) about 1.1-1.2 mm long and 0.45 mm wide with improved 3-mercaptopropyltrimethoxysilane (MPS) insulation and a new multiple-parabola (>50) resonance peak position fitting algorithm. With probe DNA (pDNA) immobilized on the PEPS surface and by monitoring the first width extension mode (WEM) resonance frequency shift we detected tDNA in real time at concentration as low as 1 * 10(-19) M in urine (100 zM) with a signal to noise ratio (SNR) of 13 without DNA isolation and amplification at room temperature in 30 min. The present multiple-parabola fitting algorithm increased the detection of SNR by about 10 times compared to those obtained using the raw data and by about 5 times compared to those obtained using single parabola fitting. The detection was validated by in situ follow-up detection and subsequent visualization of fluorescent reporter microspheres (FRMs) coated with reporter DNA complementary to the tDNA but different from the probe pDNA. PMID- 24759934 TI - The OPEP protein model: from single molecules, amyloid formation, crowding and hydrodynamics to DNA/RNA systems. AB - The OPEP coarse-grained protein model has been applied to a wide range of applications since its first release 15 years ago. The model, which combines energetic and structural accuracy and chemical specificity, allows the study of single protein properties, DNA-RNA complexes, amyloid fibril formation and protein suspensions in a crowded environment. Here we first review the current state of the model and the most exciting applications using advanced conformational sampling methods. We then present the current limitations and a perspective on the ongoing developments. PMID- 24759938 TI - Immunogenicity of a trivalent human papillomavirus L1 DNA-encapsidated, non replicable baculovirus nanovaccine. AB - Previously, we developed a non-replicating recombinant baculovirus coated with human endogenous retrovirus envelope protein (AcHERV) for enhanced cellular delivery of human papillomavirus (HPV) 16L1 DNA. Here, we report the immunogenicity of an AcHERV-based multivalent HPV nanovaccine in which the L1 segments of HPV 16, 18, and 58 genes were inserted into a single baculovirus genome of AcHERV. To test whether gene expression levels were affected by the order of HPV L1 gene insertion, we compared the efficacy of bivalent AcHERV vaccines with the HPV 16L1 gene inserted ahead of the 18L1 gene (AcHERV HP16/18L1) with that of AcHERV with the HPV 18L1 gene inserted ahead of the 16L1 gene (AcHERV-HP18/16L1). Regardless of the order, the bivalent AcHERV DNA vaccines retained the immunogenicity of monovalent AcHERV-HP16L1 and AcHERV HP18L1 DNA vaccines. Moreover, the immunogenicity of bivalent AcHERV-HP16/18L1 was not significantly different from that of AcHERV-HP18/16L1. In challenge tests, both bivalent vaccines provided complete protection against HPV 16 and 18 pseudotype viruses. Extending these results, we found that a trivalent AcHERV nanovaccine encoding HPV 16L1, 18L1, and 58L1 genes (AcHERV-HP16/18/58L1) provided high levels of humoral and cellular immunogenicity against all three subtypes. Moreover, mice immunized with the trivalent AcHERV-based nanovaccine were protected from challenge with HPV 16, 18, and 58 pseudotype viruses. These results suggest that trivalent AcHERV-HPV16/18/58L1 could serve as a potential prophylactic baculoviral nanovaccine against concurrent infection with HPV 16, 18, and 58. PMID- 24759939 TI - Assessment of coupling between trans-abdominally acquired fetal ECG and uterine activity by bivariate phase-rectified signal averaging analysis. AB - Couplings between uterine contractions (UC) and fetal heart rate (fHR) provide important information on fetal condition during labor. At present, couplings between UC and fHR are assessed by visual analysis and interpretation of cardiotocography. The application of computerized approaches is restricted due to the non-stationarity of the signal, missing data and noise, typical for fHR. Herein, we propose a novel approach to assess couplings between UC and fHR, based on a signal-processing algorithm termed bivariate phase-rectified signal averaging (BPRSA). METHODS: Electrohysterogram (EHG) and fetal electrocardiogram (fECG) were recorded non-invasively by a trans-abdominal device in 73 women at term with uneventful singleton pregnancy during the first stage of labor. Coupling between UC and fHR was analyzed by BPRSA and by conventional cross power spectral density analysis (CPSD). For both methods, degree of coupling was assessed by the maximum coefficient of coherence (CPRSA and CRAW, respectively) in the UC frequency domain. Coherence values greater than 0.50 were consider significant. CPRSA and CRAW were compared by Wilcoxon test. RESULTS: At visual inspection BPRSA analysis identified coupled periodicities in 86.3% (63/73) of the cases. 11/73 (15%) cases were excluded from further analysis because no 30 minutes of fECG recording without signal loss was available for spectral analysis. Significant coupling was found in 90.3% (56/62) of the cases analyzed by BPRSA, and in 24.2% (15/62) of the cases analyzed by CPSD, respectively. The difference between median value of CPRSA and CRAW was highly significant (0.79 [IQR 0.69-0.90] and 0.29 [IQR 0.17-0.47], respectively; p<0.0001). CONCLUSION: BPRSA is a novel computer-based approach that can be reliably applied to trans abdominally acquired EHG-fECG. It allows the assessment of correlations between UC and fHR patterns in the majority of labors, overcoming the limitations of non stationarity and artifacts. Compared to standard techniques of cross correlations, such as CPSD, BPRSA is significantly superior. PMID- 24759940 TI - Habitat of in vivo transformation influences the levels of free radical scavengers in Clinostomum complanatum: implications for free radical scavenger based vaccines against trematode infections. AB - BACKGROUND: Since free radical scavengers of parasite origin like glutathione-S transferase and superoxide dismutase are being explored as prospective vaccine targets, availability of these molecules within the parasite infecting different hosts as well as different sites of infection is of considerable importance. Using Clinostomum complanatum, as a model helminth parasite, we analysed the effects of habitat of in vivo transformation on free radical scavengers of this trematode parasite. METHODS: Using three different animal models for in vivo transformation and markedly different sites of infection, progenetic metacercaria of C. complanatum were transformed to adult ovigerous worms. Whole worm homogenates were used to estimate the levels of lipid peroxidation, a marker of oxidative stress and free radical scavengers. RESULTS: Site of in vivo transformation was found to drastically affect the levels of free radical scavengers in this model trematode parasite. It was observed that oxygen availability at the site of infection probably influences levels of free radical scavengers in trematode parasites. CONCLUSION: This is the first report showing that habitat of in vivo transformation affects levels of free radical scavengers in trematode parasites. Since free radical scavengers are prospective vaccine targets and parasite infection at ectopic sites is common, we propose that infections at different sites, may respond differently to free radical scavenger based vaccines. PMID- 24759941 TI - Hepatic branch vagus nerve plays a critical role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin A. AB - Orexin-A (a neuropeptide in the hypothalamus) plays an important role in many physiological functions, including the regulation of glucose metabolism. We have previously found that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage, which is suppressed by hypothalamic orexin-A. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system (sympathetic, parasympathetic and vagus nerve) is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic orexin-A-mediated suppression of post-ischemic glucose intolerance development and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Intrahypothalamic orexin-A (5 pmol/mouse) administration significantly suppressed the development of post-ischemic glucose intolerance and neuronal damage on day 1 and 3, respectively after MCAO. MCAO-induced decrease of hepatic insulin receptors and increase of hepatic gluconeogenic enzymes on day 1 after was reversed to control levels by orexin-A. This effect was reversed by intramedullary administration of the orexin-1 receptor antagonist, SB334867, or hepatic vagotomy. In the medulla oblongata, orexin-A induced the co-localization of cholin acetyltransferase (cholinergic neuronal marker used for the vagus nerve) with orexin-1 receptor and c-Fos (activated neural cells marker). These results suggest that the hepatic branch vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin-A. PMID- 24759942 TI - Pressure control during preparation of saphenous veins. AB - IMPORTANCE: Long-term patency of human saphenous veins (HSVs) used as autologous conduits for coronary artery bypass grafting (CABG) procedures remains limited because of vein graft failure (VGF). Vein graft failure has been reported to be as high as 45% at 12 to 18 months after surgery and leads to additional surgery, myocardial infarction, recurrent angina, and death. Preparation of HSVs before implantation leads to conduit injury, which may promote VGF. OBJECTIVES: To investigate whether pressure distension during vein graft preparation leads to endothelial injury and intimal thickening and whether limiting intraluminal pressure during pressure distension by using a pressure release valve (PRV) preserves endothelial function and prevents neointima thickening. DESIGN, SETTING, AND PARTICIPANTS: Segments of HSVs were collected in a university hospital from 13 patients undergoing CABG procedures immediately after harvest (unmanipulated [UM]), after pressure distension (after distension [AD]), and after typical intraoperative surgical graft preparation (after manipulation [AM]). Porcine saphenous veins (PSVs) from 7 healthy research animals were subjected to manual pressure distension with or without an in-line PRV that prevents pressures of 140 mm Hg or greater. Endothelial function of the HSVs and PSVs was determined in a muscle bath, endothelial integrity was assessed, and intimal thickening in PSVs was evaluated after 14 days in organ culture. MAIN OUTCOMES AND MEASURES: Endothelial function was measured in force, converted to stress, and defined as the percentage relaxation of maximal phenylephrine-induced contraction. Endothelial integrity was assessed by immunohistologic examination. Neointimal thickness was measured by histomorphometric analysis. RESULTS: Pressure distension of HSVs led to decreased mean (SEM) endothelial-dependent relaxation (5.3% [2.3%] for AD patients vs 13.7% [2.5%] for UM patients; P < .05) and denudation. In the AM group, the function of the conduits was further decreased (-3.2% [3.2%]; P < .05). Distension of the PSVs led to reduced endothelial-dependent relaxation (7.6% [4.4%] vs 61.9% [10.2%] in the control group; P < .05), denudation, and enhanced intimal thickening (15.0 [1.4] um vs 2.2 [0.8] um in the control group; P < .05). Distension with the PRV preserved endothelial-dependent relaxation (50.3% [9.6%]; P = .32 vs control), prevented denudation, and reduced intimal thickening (3.4 [0.8] um; P = .56 vs controls) in PSVs. CONCLUSIONS AND RELEVANCE: Use of a PRV during graft preparation limits intraluminal pressure generated by manual distension, preserves endothelial integrity, and reduces intimal hyperplasia. Integration of this simple device may contribute to improved long-term vein graft patency. PMID- 24759943 TI - Quantitative-proteomic comparison of alpha and Beta cells to uncover novel targets for lineage reprogramming. AB - Type-1 diabetes (T1D) is an autoimmune disease in which insulin-secreting pancreatic beta cells are destroyed by the immune system. An emerging strategy to regenerate beta-cell mass is through transdifferentiation of pancreatic alpha cells to beta cells. We previously reported two small molecules, BRD7389 and GW8510, that induce insulin expression in a mouse alpha cell line and provide a glimpse into potential intermediate cell states in beta-cell reprogramming from alpha cells. These small-molecule studies suggested that inhibition of kinases in particular may induce the expression of several beta-cell markers in alpha cells. To identify potential lineage reprogramming protein targets, we compared the transcriptome, proteome, and phosphoproteome of alpha cells, beta cells, and compound-treated alpha cells. Our phosphoproteomic analysis indicated that two kinases, BRSK1 and CAMKK2, exhibit decreased phosphorylation in beta cells compared to alpha cells, and in compound-treated alpha cells compared to DMSO treated alpha cells. Knock-down of these kinases in alpha cells resulted in expression of key beta-cell markers. These results provide evidence that perturbation of the kinome may be important for lineage reprogramming of alpha cells to beta cells. PMID- 24759945 TI - High-precision robotic microcontact printing (R-MUCP) utilizing a vision guided selectively compliant articulated robotic arm. AB - Increased realization of the spatial heterogeneity found within in vivo tissue microenvironments has prompted the desire to engineer similar complexities into in vitro culture substrates. Microcontact printing (MUCP) is a versatile technique for engineering such complexities onto cell culture substrates because it permits microscale control of the relative positioning of molecules and cells over large surface areas. However, challenges associated with precisely aligning and superimposing multiple MUCP steps severely limits the extent of substrate modification that can be achieved using this method. Thus, we investigated the feasibility of using a vision guided selectively compliant articulated robotic arm (SCARA) for MUCP applications. SCARAs are routinely used to perform high precision, repetitive tasks in manufacturing, and even low-end models are capable of achieving microscale precision. Here, we present customization of a SCARA to execute robotic-MUCP (R-MUCP) onto gold-coated microscope coverslips. The system not only possesses the ability to align multiple polydimethylsiloxane (PDMS) stamps but also has the capability to do so even after the substrates have been removed, reacted to graft polymer brushes, and replaced back into the system. Plus, non-biased computerized analysis shows that the system performs such sequential patterning with <10 MUm precision and accuracy, which is equivalent to the repeatability specifications of the employed SCARA model. R-MUCP should facilitate the engineering of complex in vivo-like complexities onto culture substrates and their integration with microfluidic devices. PMID- 24759944 TI - Fluorescein dye intercalated layered double hydroxides for chemically stabilized photoluminescent indicators on inorganic surfaces. AB - A new photoactive thin film of layered double hydroxide (LDH) nanocrystals containing fluorescein dyes (LDH-F) has been developed by self-assembly of the LDH nanocrystals and well-controlled intercalation of the dyes in organic media. XRD results and absorption spectra confirmed the highly oriented interlayer arrangement of the dianionic form of the fluorescein dyes in the LDH interlayers, in which the dye molecules were electrostatically immobilized between the positively charged LDH layers with a monolayer packing structure. An intensity weighted average PL lifetime was estimated to be 1.45 ns and fluorescence lifetime imaging microscopy revealed that the individual LDH nanocrystals on the LDH-F film had largely similar lifetimes, which were ascribed to the uniform loading of fluorescein dyes onto the LDH matrix without photoluminescence quenching. PMID- 24759946 TI - Whistleblower was unfairly dismissed in case lasting 12 years, tribunal rules. PMID- 24759947 TI - Metamagnetic behaviour in a new Cu(II)Re(IV) chain based on the hexachlororhenate(IV) anion. AB - A new chloro-bridged heterobimetallic Cu(II)Re(IV) chain of formula {Cu(pyim)(Him)2ReCl6}n.MeCN (.MeCN) has been prepared and magnetostructurally characterised. Compound is the first example of the [Re(IV)Cl6](2-) anion acting as a metalloligand towards a paramagnetic metal ion. PMID- 24759948 TI - Prevalence of cardiovascular risk factors in hemodialysis patients - The CORDIAL study. AB - BACKGROUND: There are scarce epidemiological data on cardiovascular risk profile of chronic hemodialysis patients in Brazil. OBJECTIVE: The CORDIAL study was designed to evaluate cardiovascular risk factors and follow up a hemodialysis population in a Brazilian metropolitan city. METHODS: All patients undergoing regular hemodialysis for chronic renal failure in all fifteen nephrology centers of Porto Alegre were considered for inclusion in the baseline phase of the CORDIAL study. Clinical, laboratory and demographic data were obtained in medical records and in structured individual interviews performed in all patients by trained researchers. RESULTS: A total of 1215 patients were included (97.3% of all hemodialysis patients in the city of Porto Alegre). Their average age was 58.3 years old, 59.5% were male and 62.8% were white. The prevalence of cardiovascular risk factors observed was 87.5% for hypertension, 84.7% for dyslipidemia, 73.1% for sedentary lifestyle, 53.7% for tobacco use, and 35.8% for diabetes. In a multivariate adjusted analysis, we found that sedentary lifestyle (p = 0.032, PR 1.08 - 95%CI: 1.01-1.15), dyslipidemia (p = 0.019, PR 1.08 - 95%CI: 1.01-1.14), and obesity (p < 0.001, PR 1.96 - 95%CI: 1.45-2.63) were more frequent in women; and hypertension (p = 0.018, PR 1.06 - 95%CI: 1.01-1.11) and tobacco use (p = 0.006, PR 2.7 - 95%CI: 1.79-4.17) were more often found among patients under 65 years old. Sedentary lifestyle was independently associated with time in dialysis less than 12 months (p < 0.001, PR 1.23 - 95% CI: 1.14 1.33). CONCLUSION: Hemodialysis patients in this southern metropolitan Brazilian city have a high prevalence of cardiovascular risk factors resembling many northern countries. PMID- 24759949 TI - NHETS - Necropsy Heart Transplantation Study. AB - BACKGROUND: Discrepancies between pre and post-mortem diagnoses are reported in the literature, ranging from 4.1 to 49.8 % in cases referred for necropsy, with important impact on patient treatment. OBJECTIVE: To analyze patients who died after cardiac transplantation and to compare the pre- and post-mortem diagnoses. METHODS: Perform a review of medical records and analyze clinical data, comorbidities, immunosuppression regimen, laboratory tests, clinical cause of death and cause of death at the necropsy. Then, the clinical and necroscopic causes of death of each patient were compared. RESULTS: 48 deaths undergoing necropsy were analyzed during 2000-2010; 29 (60.4 %) had concordant clinical and necroscopic diagnoses, 16 (33.3%) had discordant diagnoses and three (6.3%) had unclear diagnoses. Among the discordant ones, 15 (31.3%) had possible impact on survival and one (2.1%) had no impact on survival. The main clinical misdiagnosis was infection, with five cases (26.7 % of discordant), followed by hyperacute rejection, with four cases (20 % of the discordant ones), and pulmonary thromboembolism, with three cases (13.3% of discordant ones). CONCLUSION: Discrepancies between clinical diagnosis and necroscopic findings are commonly found in cardiac transplantation. New strategies to improve clinical diagnosis should be made, considering the results of the necropsy, to improve the treatment of heart failure by heart transplantation. PMID- 24759950 TI - Temporal variation in the prognosis and treatment of advanced heart failure - before and after 2000. AB - BACKGROUND: The treatment of heart failure has evolved in recent decades suggesting that survival is increasing. OBJECTIVE: To verify whether there has been improvement in the survival of patients with advanced heart failure. METHODS: We retrospectively compared the treatment and follow-up data from two cohorts of patients with systolic heart failure admitted for compensation up to 2000 (n = 353) and after 2000 (n = 279). We analyzed in-hospital death, re hospitalization and death in 1 year of follow-up. We used Mann-Whitney U test and chi-square test for comparison between groups. The predictors of mortality were identified by regression analysis through Cox proportional hazards model and survival analysis by the Kaplan-Meier survival analysis. RESULTS: The patients admitted until 2000 were younger, had lower left ventricular impairment and received a lower proportion of beta-blockers at discharge. The survival of patients hospitalized before 2000 was lower than those hospitalized after 2000 (40.1% vs. 67.4%; p<0.001). The independent predictors of mortality in the regression analysis were: Chagas disease (hazard ratio: 1.9; 95% confidence interval: 1.3-3.0), angiotensin-converting-enzyme inhibitors (hazard ratio: 0.6; 95% confidence interval: 0.4-0.9), beta-blockers (hazard ratio: 0.3; 95% confidence interval: 0.2-0.5), creatinine >= 1.4 mg/dL (hazard ratio: 2.0; 95% confidence interval: 1.3-3.0), serum sodium <= 135 mEq/L (hazard ratio: 1.8; 95% confidence interval: 1.2-2.7). CONCLUSIONS: Patients with advanced heart failure showed a significant improvement in survival and reduction in re hospitalizations. The neurohormonal blockade, with angiotensin-converting-enzyme inhibitors and beta-blockers, had an important role in increasing survival of these patients with advanced heart failure. PMID- 24759951 TI - Preclinical study of a biodegradable polymer-based stent with abluminal sirolimus release. AB - BACKGROUND: Bioabsorbable polymer stents with drug elution only on the abluminal surface may be safer than durable polymer drug-eluting stents. OBJECTIVE: To report the experimental findings with the InspironTM stent - a bioabsorbable polymer-coated stent with sirolimus release from the abluminal surface only, recently approved for clinical use. METHODS: 45 stents were implanted in the coronary arteries of 15 pigs. On day 28 after implantation, angiographic, intracoronary ultrasonographic and histomorphological data were collected. Five groups were analyzed: Group I (nine bare-metal stents); Group II (nine coated with bioabsorbable polymer on the luminal and abluminal surfaces); Group III (eight stents coated with bioabsorbable polymer on the abluminal surface); Group IV (nine stents with bioabsorbable polymer and sirolimus on the luminal and abluminal surfaces); and Group V (ten stents with bioabsorbable polymer and sirolimus only on the abluminal surface). RESULTS: The following results were observed for Groups I, II, III, IV and V, respectively: percentage stenosis of 29 +/- 20; 36 +/- 14; 33 +/- 19; 22 +/- 13 and 26 +/- 15 (p = 0.443); late lumen loss (in mm) of 1.02 +/- 0.60; 1.24 +/- 0.48; 1.11 +/- 0.54; 0.72 +/- 0.44 and 0.78 +/- 0.39 (p = 0.253); neointimal area (in mm(2)) of 2.60 +/- 1.99; 2.74 +/- 1.51; 2.74 +/- 1.30; 1.30 +/- 1.14 and 0.97 +/- 0.84 (p = 0.001; Groups IV and V versus Groups I, II and III); and percentage neointimal area of 35 +/- 25; 38 +/- 18; 39 +/- 19; 19 +/- 18 and 15 +/- 12 (p = 0.001; Groups IV and V versus Groups I, II and III). Injury and inflammation scores were low and with no differences between the groups. CONCLUSION: The InspironTM stent proved to be safe and was able to significantly inhibit the neointimal hyperplasia observed on day 28 after implantation in porcine coronary arteries. PMID- 24759952 TI - Tai Chi Chuan for cardiac rehabilitation in patients with coronary arterial disease. AB - BACKGROUND: Several studies have shown that Tai Chi Chuan can improve cardiac function in patients with heart disease. OBJECTIVE: To conduct a systematic review of the literature to assess the effects of Tai Chi Chuan on cardiac rehabilitation for patients with coronary artery disease. METHODS: We performed a search for studies published in English, Portuguese and Spanish in the following databases: MEDLINE, EMBASE, LILACS and Cochrane Register of Controlled Trials. Data were extracted in a standardized manner by three independent investigators, who were responsible for assessing the methodological quality of the manuscripts. RESULTS: The initial search found 201 studies that, after review of titles and abstracts, resulted in a selection of 12 manuscripts. They were fully analyzed and of these, nine were excluded. As a final result, three randomized controlled trials remained. The studies analyzed in this systematic review included patients with a confirmed diagnosis of coronary artery disease, all were clinically stable and able to exercise. The three experiments had a control group that practiced structured exercise training or received counseling for exercise. Follow-up ranged from 2 to 12 months. CONCLUSION: Preliminary evidence suggests that Tai Chi Chuan can be an unconventional form of cardiac rehabilitation, being an adjunctive therapy in the treatment of patients with stable coronary artery disease. However, the methodological quality of the included articles and the small sample sizes clearly indicate that new randomized controlled trials are needed in this regard. PMID- 24759954 TI - Multifunctional ScF3:Ln3+ (Ln = Tb, Eu, Yb, Er, Tm and Ho) nano/microcrystals: hydrothermal/solvothermal synthesis, electronic structure, magnetism and tunable luminescence properties. AB - A facile, hydrothermal/solvothermal route has been developed to synthesize a series of multifunctional lanthanide ion (Tb(3+), Eu(3+), Yb(3+), Tm(3+), Er(3+) and Ho(3+))-activated ScF3 nanocrystals. The morphology and size of ScF3 can be tuned in a controlled manner by altering the additives and volume ratios of H2O : EtOH in the initial solution. Under ultraviolet (UV), vacuum ultraviolet (VUV) or low-voltage electron-beam excitation, the as-obtained Tb(3+), Eu(3+) codoped ScF3 product exhibits multicolor photoluminescence (PL) and cathodoluminescence (CL), and possible luminescence mechanisms are discussed. Moreover, under 980 nm excitation, upconversion (UC) emissions have been achieved in Yb(3+)-Er(3+), Yb(3+)-Tm(3+), and Yb(3+)-Ho(3+) codoped ScF3. Ferromagnetic property of ScF3 is detected due to the nanocrystal defects. The results obtained indicate that the lanthanide ion-doped ScF3 nanocrystals exhibit multicolor UV/VUV PL, CL, and UC luminescence as well as ferromagnetic properties. Thus, they may have potential applications in PL areas, field emission display devices, bioseparation and magnetic resonance imaging. PMID- 24759953 TI - Lineage tracing of resident tendon progenitor cells during growth and natural healing. AB - Unlike during embryogenesis, the identity of tissue resident progenitor cells that contribute to postnatal tendon growth and natural healing is poorly characterized. Therefore, we utilized 1) an inducible Cre driven by alpha smooth muscle actin (SMACreERT2), that identifies mesenchymal progenitors, 2) a constitutively active Cre driven by growth and differentiation factor 5 (GDF5Cre), a critical regulator of joint condensation, in combination with 3) an Ai9 Cre reporter to permanently label SMA9 and GDF5-9 populations and their progeny. In growing mice, SMA9+ cells were found in peritendinous structures and scleraxis-positive (ScxGFP+) cells within the tendon midsubstance and myotendinous junction. The progenitors within the tendon midsubstance were transiently labeled as they displayed a 4-fold expansion from day 2 to day 21 but reduced to baseline levels by day 70. SMA9+ cells were not found within tendon entheses or ligaments in the knee, suggesting a different origin. In contrast to the SMA9 population, GDF5-9+ cells extended from the bone through the enthesis and into a portion of the tendon midsubstance. GDF5-9+ cells were also found throughout the length of the ligaments, indicating a significant variation in the progenitors that contribute to tendons and ligaments. Following tendon injury, SMA9+ paratenon cells were the main contributors to the healing response. SMA9+ cells extended over the defect space at 1 week and differentiated into ScxGFP+ cells at 2 weeks, which coincided with increased collagen signal in the paratenon bridge. Thus, SMA9-labeled cells represent a unique progenitor source that contributes to the tendon midsubstance, paratenon, and myotendinous junction during growth and natural healing, while GDF5 progenitors contribute to tendon enthesis and ligament development. Understanding the mechanisms that regulate the expansion and differentiation of these progenitors may prove crucial to improving future repair strategies. PMID- 24759955 TI - Experiment and computation: a combined approach to study the reactivity of palladium complexes in oxidation states 0 to IV. AB - As the accuracy of computational chemistry increases, and the advent of more powerful computers decreases the amount of time required to perform complex calculations, the use of this to investigate chemical systems becomes increasingly attractive. Particularly in combination with practical lab-based experimental and spectroscopic studies the application of in silico studies is a powerful tool for mechanistic investigations. In this review we demonstrate how a combined experimental and computational approach can yield mechanistic insight that could frequently not have been accessible to this high degree of certainty by utilising one of these two approaches alone. After an introduction describing the challenges of studying palladium-based chemistry, and how this combined approach can help to tackle these challenges (Section 1), we provide examples in which experiments have been used in tandem with computational chemistry. This discussion is categorised by palladium oxidation state for convenience: Pd(0) chemistry comprises discussion on oxidative addition in traditional Pd(0)/Pd(II) cross-coupling (Section 2); a section on odd oxidation state chemistry includes oxidation of Pd(0) to Pd(I) dimers, oxidative addition to Pd(I) dimers, oxidation of Pd(II) to Pd(III) dimers and subsequently reductive elimination from these Pd(III) dimers (Section 3); Pd(II) chemistry includes transmetallation, reductive elimination and the field of C-H activation relating to palladium catalysis (Section 4); and finally, a section on Pd(IV) chemistry focusses on reductive elimination from these complexes (Section 5). PMID- 24759956 TI - Dimeric phenanthroimidazole for blue electroluminescent materials: the effect of substituted position attached to biphenyl center. AB - Two isomers of 4,40-bis(1-phenyl-phenanthro[9,10-d]-imidazol-2-yl)biphenyl (BPPI), L-BPPI and Z-BPPI were prepared by tuning the substituted position on the biphenyl from para- to meta-coupling. Because of the conjugated degree change at the C2-position in the phenanthroimidazole block, the fluorescent color of L-BPPI (433 nm) and Z-BPPI (402 nm) showed an obvious blue-shift compared with that of BPPI (468 nm) in the films. Meanwhile, their non-doped devices exhibited more valuable and stable deep-blue emissions with a CIE coordinate of (0.16, 0.10) and (0.16, 0.11), respectively. Furthermore, some valuable information on structure properties was obtained by density functional theory calculations, and photophysical and electrochemical characterization. PMID- 24759957 TI - Multiple behaviour change intervention and outcomes in recently diagnosed type 2 diabetes: the ADDITION-Plus randomised controlled trial. AB - AIMS/HYPOTHESIS: The aim of this study was to assess whether or not a theory based behaviour change intervention delivered by trained and quality-assured lifestyle facilitators can achieve and maintain improvements in physical activity, dietary change, medication adherence and smoking cessation in people with recently diagnosed type 2 diabetes. METHODS: An explanatory randomised controlled trial was conducted in 34 general practices in Eastern England (Anglo Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care-Plus [ADDITION-Plus]). In all, 478 patients meeting eligibility criteria (age 40 to 69 years with recently diagnosed screen or clinically detected diabetes) were individually randomised to receive either intensive treatment (n = 239) or intensive treatment plus a theory-based behaviour change intervention led by a facilitator external to the general practice team (n = 239). Randomisation was central and independent using a partial minimisation procedure to balance stratifiers between treatment arms. Facilitators taught patients skills to facilitate change in and maintenance of key health behaviours, including goal setting, self-monitoring and building habits. Primary outcomes included physical activity energy expenditure (individually calibrated heart rate monitoring and movement sensing), change in objectively measured fruit and vegetable intake (plasma vitamin C), medication adherence (plasma drug levels) and smoking status (plasma cotinine levels) at 1 year. Measurements, data entry and laboratory analysis were conducted with staff unaware of participants' study group allocation. RESULTS: Of 475 participants still alive, 444 (93%; intervention group 95%, comparison group 92%) attended 1-year follow-up. There were no significant differences between groups in physical activity (difference: +1.50 kJ kg(-1) day(-1); 95% CI -1.74, 4.74), plasma vitamin C (difference: -3.84 MUmol/l; 95% CI -8.07, 0.38), smoking (OR 1.37; 95% CI 0.77, 2.43) and plasma drug levels (difference in metformin levels: -119.5 MUmol/l; 95% CI -335.0, 95.9). Cardiovascular risk factors and self-reported behaviour improved in both groups with no significant differences between groups. CONCLUSIONS/INTERPRETATION: For patients with recently diagnosed type 2 diabetes receiving intensive treatment in UK primary care, a facilitator-led individually tailored behaviour change intervention did not improve objectively measured health behaviours or cardiovascular risk factors over 1 year. TRIAL REGISTRATION: ISRCTN99175498 FUNDING: The trial is supported by the Medical Research Council, the Wellcome Trust, National Health Service R&D support funding (including the Primary Care Research and Diabetes Research Networks) and National Institute of Health Research under its Programme Grants for Applied Research scheme. The Primary Care Unit is supported by NIHR Research funds. Bio-Rad provided equipment for HbA1c testing during the screening phase. PMID- 24759958 TI - IL-6-dependent proliferation of alpha cells in mice with partial pancreatic-duct ligation. AB - AIMS/HYPOTHESIS: IL-6 was recently shown to control alpha cell expansion. As beta cells expand following partial pancreatic-duct ligation (PDL) in adult mice, we investigated whether PDL also causes alpha cells to expand and whether IL-6 signalling is involved. As alpha cells can reprogramme to beta cells in a number of beta cell (re)generation models, we examined whether this phenomenon also exists in PDL pancreas. METHODS: Total alpha cell volume, alpha cell size and total glucagon content were evaluated in equivalent portions of PDL- and sham operated mouse pancreases. Proliferation of glucagon(+) cells was assessed by expression of the proliferation marker Ki67. Inter-conversions between alpha and beta cells were monitored in transgenic mice with conditional cell-type-specific labelling. The role of IL-6 in regulating alpha cell proliferation was evaluated by in situ delivery of an IL-6-inactivating antibody. RESULTS: In response to PDL surgery, alpha cell volume in the ligated tissue was increased threefold, glucagon content fivefold and alpha cell size by 10%. Activation of alpha cell proliferation in PDL pancreas required IL-6 signalling. A minor fraction of alpha cells derived from beta cells, whereas no evidence for alpha to beta cell conversion was obtained. CONCLUSIONS/INTERPRETATION: In PDL-injured adult mouse pancreas, new alpha cells are generated mainly by IL-6-dependent self-duplication and seldom by reprogramming of beta cells. PMID- 24759959 TI - Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo. AB - AIMS/HYPOTHESIS: Insulin exerts a direct action on vascular cells, thereby affecting the outcome and progression of diabetic vascular complications. However, the mechanism through which insulin signalling is impaired in the endothelium of diabetic individuals remains unclear. In this work, we have evaluated the role of the AGE precursor methylglyoxal (MGO) in generating endothelial insulin resistance both in cells and in animal models. METHODS: Time course experiments were performed on mouse aortic endothelial cells (MAECs) incubated with 500 MUmol/l MGO. The glyoxalase-1 inhibitor S-p bromobenzylglutathione-cyclopentyl-diester (SpBrBzGSHCp2) was used to increase the endogenous levels of MGO. For the in vivo study, an MGO solution was administrated i.p. to C57BL/6 mice for 7 weeks. RESULTS: MGO prevented the insulin-dependent activation of the IRS1/protein kinase Akt/endothelial nitric oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, while extracellular signal-regulated kinase (ERK1/2) activation and endothelin-1 (ET-1) release were increased by MGO in MAECs. Similar results were obtained in MAECs treated with SpBrBzGSHCp2. In MGO- and SpBrBzGSHCp2-exposed cells, inhibition of ERK1/2 decreased IRS1 phosphorylation on S616 and rescued insulin dependent Akt activation and NO generation, indicating that MGO inhibition of the IRS1/Akt/eNOS pathway is mediated, at least in part, by ERK1/2. Chronic administration of MGO to C57BL/6 mice impaired whole-body insulin sensitivity and induced endothelial insulin resistance. CONCLUSIONS/INTERPRETATION: MGO impairs the action of insulin on the endothelium both in vitro and in vivo, at least in part through an ERK1/2-mediated mechanism. These findings may be instrumental in developing novel strategies for preserving endothelial function in diabetes. PMID- 24759960 TI - Overview of Clostridium difficile infection: implications for China. AB - The incidence and severity of Clostridium difficile infection (CDI) have dramatically increased in the Western world in recent years. In contrast, CDI is rarely reported in China, possibly due to under-diagnosis. This article briefly summarizes CDI incidence, management and preventive strategies. The authors intend to raise awareness of this disease among Chinese physicians and health workers, in order to minimize the medical and economic burden of a potential epidemic in the future. PMID- 24759961 TI - Bone loss in patients with the ileostomy and ileal pouch for inflammatory bowel disease. AB - Low bone mineral density (BMD) or low bone mass is common in patients with inflammatory bowel disease (IBD). Studies have shown that low BMD is also common in patients with ulcerative colitis (UC) even after colectomy and ileal pouch anal anastomosis (IPAA). The reported frequency of osteopenia ranged from 26-55% and that of osteoporosis ranged from 13-32% in patients with IPAA. Increasing age, low body mass index, lack of calcium supplementation and high inflammatory activity with villous atrophy in the ileo-anal pouch are risk factors for low bone mass in pouch patients. Bone loss is also common in patients with IBD and ostomy. Current professional society guidelines do not specifically address the need for surveillance in patients with ileal pouches or ostomy. A growing body of evidence suggests that patients with ileal pouch or ostomy are at an increased risk of bone loss. Pending prospective studies, screening and surveillance using dual energy X-ray absorptiometry (DEXA) along with calcium/vitamin D supplementation may be beneficial in those patients. PMID- 24759963 TI - A brief comment on liver resection for hepatocellular carcinoma. PMID- 24759964 TI - Value of transrectal ultrasonography for tumor node metastasis restaging in patients with locally advanced rectal cancer after neoadjuvant chemoradiotherapy. AB - OBJECTIVE: To explore the value of transrectal ultrasonography (TRUS) for tumor node metastasis (TNM) restaging for patients with locally advanced rectal cancer after neoadjuvant chemoradiotherapy (neo-CRT). METHODS: One hundred and forty nine patients with locally advanced rectal cancer (cT3-4 or cN+) who underwent TRUS after neo-CRT were retrospectively reviewed. TRUS restaging was compared with the results of post-operative pathological TNM findings. RESULTS: After neo CRT, the accuracy of TRUS for diagnosing T-staging was 30.9%, with 60.4% (90/149) of cases overestimated. The sensitivity of TRUS for T-staging (T0 vs T1 vs T2 vs T3 vs T4) were 16.3%, 0%, 12.5%, 42.6% and 75.0%, respectively. The accuracy of TRUS for diagnosing N-staging after neo-CRT was 81.2%, with the sensitivities of N0 and N+ were 93.3% and 31.0%, respectively. After neo-CRT, 27.5% (41/149) of patients achieved pathologically complete response (pCR). The sensitivity, specificity, positive predictive value and negative predictive values of TRUS for pCR were 17.1%, 99.1%, 87.5% and 75.9%, respectively. CONCLUSIONS: TRUS can be applied for restaging T4 and N0, and has potential for screening out patients with pCR in those with locally advanced rectal cancer after neo-CRT, although some stages are overestimated for T-staging and its sensitivity for predicting pCR is low. PMID- 24759965 TI - Cannulation time is a more accurate measure of cannulation difficulty in endoscopic retrograde cholangiopancreatography than the number of attempts. AB - BACKGROUND: Cannulation of the common bile duct (CBD) is the initial and sometime challenging step in endoscopic retrograde cholangiopancreatography (ERCP) procedure. Endoscopists often use cannulation attempts and cannulation time to grade cannulation difficulty, but a standard system has yet to be established. The objective of this study was to compare cannulation times with numbers of cannulation attempts, as measures of cannulation difficulty. METHODS: We conducted a prospective study in a tertiary referral center, enrolling 58 patients who were undergoing ERCP for a variety of indications. Cannulation time and the number of cannulation attempts were recorded for each patient. A subset of 14 ERCPs had two observers assessing attempts at cannulation. Cannulation time, number of attempts and inter-observer variability in assessment of attempts were compared and studied. RESULTS: The degree of agreement between two the methods (cannulation times and number of cannulation attempts) was unacceptable. There were considerable discrepancies between attempt tallies from two observers but the mean difference was statistically insignificant. CONCLUSION: The grade of cannulation difficulty for a given ERCP procedure may differ when different methods are used (total cannulation time vs number of attempts); thus, grading by different methods should not be used interchangeably. Cannulation time is a more objective and more accurate assessment tool for grading cannulation difficulty than the number of attempts to cannulate the papilla. PMID- 24759962 TI - Biomarkers in precision therapy in colorectal cancer. AB - Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe. Because CRC is also a major cause of cancer-related deaths worldwide, a lot of research has been focused on the discovery and development of biomarkers to improve the diagnostic process and to predict treatment outcomes. Up till now only a few biomarkers are recommended by expert panels. Current TNM criteria, however, cause substantial under- and overtreatment of CRC patients. Consequently, there is a growing need for new and efficient biomarkers to ensure optimal treatment allocation. An ideal biomarker should be easily translated into clinical practice, to identify patients who can be spared from treatment or benefit from therapy, ultimately resulting in precision medicine in the future. In this review we aim to provide an overview of a number of frequently studied biomarkers in CRC and, at the same time, we will emphasize the challenges and controversies that withhold the clinical introduction of these biomarkers. We will discuss both prognostic and predictive markers of chemotherapy, aspirin therapy as well as overall therapy toxicity. Currently, only mutant KRAS, mutant BRAF, MSI and the Oncotype DX(r) Colon Cancer Assay are used in clinical practice. Other biomarker studies showed insufficient evidence to be introduced into clinical practice. Divergent patient selection criteria, absence of validation studies and a large number of single biomarker studies are possibly responsible. We therefore recommend that future studies focus on combining key markers, rather than analysing single markers, standardizing study protocols, and validate the results in independent study cohorts, followed by prospective clinical trials. PMID- 24759966 TI - Changing approaches to rectal prolapse repair in the elderly. AB - AIM: The abdominal approach to rectal prolapse is associated with lower rates of recurrence but a higher chance of complications and has been traditionally reserved for younger patients. However, longer life expectancy and wider use of laparoscopic techniques necessitates another look at the abdominal approach in older patients. METHODS: This was a retrospective review of data from patients undergoing abdominal repair of rectal prolapse between 2005 and 2011. RESULTS: Forty-six abdominal repairs (laparoscopic or open suture rectopexy, sigmoidectomy and rectopexy and low anterior resection) were performed during the study period. Twenty-nine repairs (63%) were performed in patients under the age of 70 (average age 51) and 17 (37%) in patients older than 70 (average age 76; range 71-89). Most of the cases performed during the initial 3 years of the study were via laparotomy. However, in the last 4 years, the laparoscopic approach was used in 83% of younger patients and 69% of older patients. Average length of stay was 2.6 days for younger and 3.8 days for older patients. Both groups had similar rates of re-admission: 20% vs 23%. The rate of wound infection was higher in the younger patients (5% vs nil). However, rates of urinary tract infection, two instances (10%) vs four (30%), urinary retention, one instance (5%) vs two (15.4%), ileus, one instance (5%) vs two (15.4%) were higher in the older group. CONCLUSION: Wider use of laparoscopy has precipitated a change in the approach to rectal prolapse in older patients. Although associated with a slightly higher rate of post-operative complications, the abdominal approach to rectal prolapse is feasible, safe and effective in patients older than 70 years. PMID- 24759967 TI - Peliosis hepatis associated with hereditary haemorrhagic telangiectasia. AB - Hereditary haemorrhagic telangiectasia (HHT) is an autosomal, predominantly inherited disease characterized by diffuse telangiectases involving the skin, mucous membranes, lung, brain, gastrointestinal tract and liver. Peliosis hepatis is a rare, benign disorder causing sinusoidal dilatation and the presence of multiple blood-filled lacunar spaces within the liver. We report a case of an HHT patient with incidental magnetic resonance findings of focal hepatic peliosis. PMID- 24759968 TI - Low-grade appendiceal neoplasm presenting as a volvulus of the cecum. AB - Mucocele of the appendix is an uncommon disorder that is often asymptomatic, but can present similarly to acute appendicitis. Timely diagnosis and treatment is imperative due to the many complications that can result from the mucocele, such as perforation. Appendiceal mucoceles (AM) were previously thought to be either benign or malignant; however, a different pathological classification of AM is currently favored. Also, only a few cases of volvulus of a benign AM have been reported. Here, we present the first reported case of a low-grade appendiceal mucinous neoplasm resulting in a volvulus of the cecum. PMID- 24759969 TI - Gastric metastases of oral carcinoma resulting from percutaneous endoscopic gastrostomy placement via the introducer technique. AB - INTRODUCTION. Tumour cell implantation is a rare complication in patients with head and neck cancers, who have undergone percutaneous endoscopic gastrostomy (PEG) tube placement. It has not been reported in patients who underwent a PEG insertion via the radiological or introducer technique. We describe a novel case presentation of metastatic disease in a patient who underwent PEG placement via the introducer (Russell) technique which, to the best of our knowledge, has not not previously been described. CASE PRESENTATION. The patient was a 37-year-old Malay woman who developed metastatic squamous cell carcinoma deposits in her stomach and liver one month after a gastrostomy tube was removed following the completion of treatment for oropharyngeal carcinoma. CONCLUSION. Previous authors have advocated the use of alternative PEG insertion technique apart from the 'pull' technique to minimise the risk of tumour implantation from head and neck cancers. Our case report suggests that this risk is not totally eliminated when the PEG tube is inserted via the introducer technique. PMID- 24759970 TI - Neuronal adaptation translates stimulus gaps into a population code. AB - Neurons in sensory pathways exhibit a vast multitude of adaptation behaviors, which are assumed to aid the encoding of temporal stimulus features and provide the basis for a population code in higher brain areas. Here we study the transition to a population code for auditory gap stimuli both in neurophysiological recordings and in a computational network model. Independent component analysis (ICA) of experimental data from the inferior colliculus of Mongolian gerbils reveals that the network encodes different gap sizes primarily with its population firing rate within 30 ms after the presentation of the gap, where longer gap size evokes higher network activity. We then developed a computational model to investigate possible mechanisms of how to generate the population code for gaps. Phenomenological (ICA) and functional (discrimination performance) analyses of our simulated networks show that the experimentally observed patterns may result from heterogeneous adaptation, where adaptation provides gap detection at the single neuron level and neuronal heterogeneity ensures discriminable population codes for the whole range of gap sizes in the input. Furthermore, our work suggests that network recurrence additionally enhances the network's ability to provide discriminable population patterns. PMID- 24759971 TI - Green spaces and adverse pregnancy outcomes. AB - OBJECTIVE: The objective of this study was to evaluate the associations between proximity to green spaces and surrounding greenness and pregnancy outcomes, such as birth weight, low birth weight (LBW), very LBW (VLBW), gestational age, preterm deliveries (PTD) and very PTD (VPTD). METHODS: This study was based on 39,132 singleton live births from a registry birth cohort in Tel Aviv, Israel, during 2000-2006. Surrounding greenness was defined as the average of satellite based Normalised Difference Vegetation Index (NDVI) in 250 m buffers and proximity to major green spaces was defined as residence within a buffer of 300 m from boundaries of a major green space (5000 m(2)), based on data constructed from OpenStreetMap. Linear regression (for birth weight and gestational age) and logistic regressions models (for LBW, VLBW, PTD and VPTD) were used with adjustment for relevant covariates. RESULTS: An increase in 1 interquartile range greenness was associated with a statistically significant increase in birth weight (19.2 g 95% CI 13.3 to 25.1) and decreased risk of LBW (OR 0.84, 95% CI 0.78 to 0.90). Results for VLBW were in the same direction but were not statistically significant. In general, no associations were found for gestational age, PTD and VPTD. The findings were consistent with different buffer and green space sizes and stronger associations were observed among those of lower socioeconomic status. CONCLUSIONS: This study confirms the results of a few previous studies demonstrating an association between maternal proximity to green spaces and birth weight. Further investigation is needed into the associations with VLBW and VPTD, which has never been studied before. PMID- 24759972 TI - Encouraging and supporting smoking cessation in the workforce. PMID- 24759973 TI - Dobzhansky-muller and wolbachia-induced incompatibilities in a diploid genetic system. AB - Genetic incompatibilities are supposed to play an important role in speciation. A general (theoretical) problem is to explain the persistence of genetic diversity after secondary contact. Previous theoretical work has pointed out that Dobzhansky-Muller incompatibilities (DMI) are not stable in the face of migration unless local selection acts on the alleles involved in incompatibility. With local selection, genetic variability exists up to a critical migration rate but is lost when migration exceeds this threshold value. Here, we investigate the effect of intracellular bacteria Wolbachia on the stability of hybrid zones formed after the Dobzhansky Muller model. Wolbachia are known to cause a cytoplasmic incompatibility (CI) within and between species. Incorporating intracellular bacteria Wolbachia can lead to a significant increase of critical migration rates and maintenance of divergence, primarily because Wolbachia induced incompatibility acts to reduce frequencies of F1 hybrids. Wolbachia infect up to two-thirds of all insect species and it is therefore likely that CI co-occurs with DMI in nature. The results indicate that both isolating mechanisms strengthen each other and under some circumstances act synergistically. Thus they can drive speciation processes more forcefully than either when acting alone. PMID- 24759974 TI - Importance of gradients in membrane properties and electrical coupling in sinoatrial node pacing. AB - The sinoatrial node (SAN) is heterogeneous in terms of cell size, ion channels, current densities, connexins and electrical coupling. For example, Nav1.5 (responsible for INa) and Cx43 (responsible for electrical coupling) are absent from the centre of the SAN (normally the leading pacemaker site), but present in the periphery (at SAN-atrial muscle junction). To test whether the heterogeneity is important for the functioning of the SAN, one- and two-dimensional models of the SAN and surrounding atrial muscle were created. Normal functioning of the SAN (in terms of cycle length, position of leading pacemaker site, conduction times, activation and repolarization sequences and space constants) was observed when, from the centre to the periphery, (i) cell characteristics (cell size and ionic current densities) were changed in a gradient fashion from a central-type (lacking INa) to a peripheral-type (possessing INa) and (ii) coupling conductance was increased in a gradient fashion. We conclude that the heterogeneous nature of the node is important for its normal functioning. The presence of Nav1.5 and Cx43 in the periphery may be essential for the node to be able to drive the atrial muscle: Nav1.5 provides the necessary depolarizing current and Cx43 delivers it to the atrial muscle. PMID- 24759975 TI - The influence of bereavement on body mass index: results from a national Swedish survey. AB - BACKGROUND: Previous findings suggest that the loss of a family member is associated with health and mortality. The purpose of this study was to investigate the association between bereavement experiences and BMI, and whether there are socio-demographic differences in this association. OBJECTIVE: To investigate the association between bereavement experiences and BMI, and whether there are socio-demographic differences in this association. METHODS: We used cross-sectional data with retrospective questions from the Swedish Level of Living Survey (LNU) of 2000, including 5,142 individuals. The bereavement experiences examined in the study include the loss of a sibling, a parent or a spouse, and time since the death of a parent. BMI (kg/m2) was calculated using self-reported measurements of weight and height. The association between bereavement and BMI was evaluated through linear regressions. RESULTS: After controlling for possible confounders, most of the models detected an association between bereavement and BMI. The fully-adjusted model showed that loss of parents was associated with a 0.45 increase in BMI (SE = 0.20). The effect also seemed to be dependent on time since the loss and social class position. CONCLUSIONS: The present study is the first to examine associations between different types of familial losses and BMI. We find an association between the death of a family member and BMI, but it appears to be related to time since the death, type of bereavement experience and social class. PMID- 24759977 TI - Detection of zeptomole quantities of nonfluorescent molecules in a 10(1) nm nanochannel by thermal lens microscopy. AB - Nanofluidics in 10(1) nm space, whose scale is comparable to the electric double layer (EDL) and the size of biomolecules, promises novel functional analytical devices. However, the detection, which is indispensable to the integrated chemical system, is still challenging in such an ultra-small space. Previously, we reported a differential interference contrast thermal lens microscope (DIC TLM) based on the photothermal interferometry principle and succeeded in detection of nonfluorescent molecules in 10(2) nm spaces. However, the thermal diffusion into substrates becomes a problem for detection in 10(1) nm spaces. The DIC-TLM signals are significantly cancelled out in spaces much smaller than the confocal length (~10(2) nm), which makes DIC-TLM detection in 10(1) nm space quite difficult. To overcome this problem, we propose a new channel structure that benefits the thermal diffusion and sensitivity enhancement in DIC-TLM by employing TiO2 as a substrate material for compensating the signal cancellation effect. As a result, DIC-TLM detection of nonfluorescent molecules (800 molecules) was successfully demonstrated in a nanochannel with a depth of 50 nm. The developed detection method will contribute to the functional nanofluidic devices utilizing 10(1) nm spaces. PMID- 24759978 TI - Automated mosaicing of feature-poor optical coherence tomography volumes with an integrated white light imaging system. AB - We demonstrate the first automated, volumetric mosaicing algorithm for optical coherence tomography (OCT) that both accommodates 6-degree-of-freedom rigid transformations and implements a bundle adjustment step amenable to generating large fields of view with endoscopic and freehand imaging systems. Our mosaicing algorithm exploits the known, rigid connection between a combined white light and OCT imaging system to reduce the computational complexity of traditional volumetric mosaicing pipelines. Specifically, the search for 3-D point correspondences is replaced by two, 2-D processing steps: We first coregister a pair of white light images in 2-D and then generate a surface map based on the volumetric OCT data, which is used to convert 2-D image homographies into 3-D volumetric transformations. A significant benefit of our dual-modality approach is its tolerance for feature-poor datasets such as bladder tissue; in contrast, approaches to mosaic feature-rich volumes with significant variations in the local intensity gradient (e.g., retinal data containing prolific vasculature) are not suitable for such feature-poor datasets. We demonstrate the performance of our algorithm using ex vivo bladder tissue and a custom tissue-mimicking phantom. The algorithm shows excellent performance over the range of volume-to-volume transformations expected during endoscopic examination and comparable accuracy with several orders of magnitude superior run times than an open-source gold standard algorithm (N-SIFT). We anticipate the proposed algorithm can benefit bladder surveillance and surgical planning. Furthermore, its generality gives it broad applicability and potential to extend the use of OCT to clinical applications relevant to large organs typically imaged with freehand, forward viewing endoscopes. PMID- 24759976 TI - Rapid range expansion is not restricted by inbreeding in a sexually cannibalistic spider. AB - Few studies investigated whether rapid range expansion is associated with an individual's short-term fitness costs due to an increased risk of inbred mating at the front of expansion. In mating systems with low male mating rates both sexes share potential inbreeding costs and general mechanisms to avoid or reduce these costs are expected. The spider Argiope bruennichi expanded its range recently and we asked whether rapid settlement of new sites exposes individuals to a risk of inbreeding. We sampled four geographically separated subpopulations, genotyped individuals, arranged matings and monitored hatching success. Hatching success was lowest in egg-sacs derived from sibling pairs and highest in egg-sacs derived from among-population crosses, while within-population crosses were intermediate. This indicates that inbreeding might affect hatching success in the wild. Unlike expected, differential hatching success of within- and among population crosses did not correlate with genetic distance of mating pairs. In contrast, we found high genetic diversity based on 16 microsatellite markers and a fragment of the mitochondrial COI gene in all populations. Our results suggest that even a very recent settlement secures the presence of genetically different mating partners. This leads to costs of inbreeding since the population is not inbred. PMID- 24759979 TI - Design and optimization of an ultra wideband and compact microwave antenna for radiometric monitoring of brain temperature. AB - We present the modeling efforts on antenna design and frequency selection to monitor brain temperature during prolonged surgery using noninvasive microwave radiometry. A tapered log-spiral antenna design is chosen for its wideband characteristics that allow higher power collection from deep brain. Parametric analysis with the software HFSS is used to optimize antenna performance for deep brain temperature sensing. Radiometric antenna efficiency (eta) is evaluated in terms of the ratio of power collected from brain to total power received by the antenna. Anatomical information extracted from several adult computed tomography scans is used to establish design parameters for constructing an accurate layered 3-D tissue phantom. This head phantom includes separate brain and scalp regions, with tissue equivalent liquids circulating at independent temperatures on either side of an intact skull. The optimized frequency band is 1.1-1.6 GHz producing an average antenna efficiency of 50.3% from a two turn log-spiral antenna. The entire sensor package is contained in a lightweight and low-profile 2.8 cm diameter by 1.5 cm high assembly that can be held in place over the skin with an electromagnetic interference shielding adhesive patch. The calculated radiometric equivalent brain temperature tracks within 0.4 degrees C of the measured brain phantom temperature when the brain phantom is lowered 10 degrees C and then returned to the original temperature (37 degrees C) over a 4.6-h experiment. The numerical and experimental results demonstrate that the optimized 2.5-cm log spiral antenna is well suited for the noninvasive radiometric sensing of deep brain temperature. PMID- 24759980 TI - Liquid metal angiography for mega contrast X-ray visualization of vascular network in reconstructing in-vitro organ anatomy. AB - Visualization on the anatomical vessel networks plays a vital role in the physiological or pathological investigations. However, so far it still remains a big challenge to identify the fine structures of the smallest capillary vessel networks via conventional imaging ways. Here, the room temperature liquid metal angiography was proposed for the first time to generate mega contrast X-ray images for multiscale vasculature mapping. Particularly, gallium was adopted as the room temperature liquid metal contrast agent and infused into the vessels of in vitro pig hearts and kidneys. We scanned the samples under X-ray and compared the angiograms with those obtained via conventional contrast agent--the iohexol. As quantitatively demonstrated by the grayscale histograms and numerical indexes, the contrast of the vessels to the surrounding tissues in the liquid metal angiograms is orders higher than that of the iohexol enhanced images. And the angiogram has reached detailed enough width of 0.1 mm for the tiny vessels, which indicated that the capillaries can be clearly distinguished under the liquid metal enhanced images. Further, with tomography from the micro-CT, we also managed to reconstruct the 3-D structures of the kidney vessels. Tremendous clarity and efficiency of the method over existing approaches have been experimentally clarified. It was disclosed that the usually invisible capillary networks now become distinctively clear in the gallium angiograms. This basic mechanism has generalized purpose and can be extended to a wide spectrum of 3-D computational tomographic areas. It opens a new soft tool for quickly reconstructing high-resolution spatial channel networks for scientific researches as well as engineering practices where complicated and time-consuming resections are no longer a necessity. PMID- 24759981 TI - Human brain distinctiveness based on EEG spectral coherence connectivity. AB - The use of EEG biometrics, for the purpose of automatic people recognition, has received increasing attention in the recent years. Most of the current analyses rely on the extraction of features characterizing the activity of single brain regions, like power spectrum estimation, thus neglecting possible temporal dependencies between the generated EEG signals. However, important physiological information can be extracted from the way different brain regions are functionally coupled. In this study, we propose a novel approach that fuses spectral coherence-based connectivity between different brain regions as a possibly viable biometric feature. The proposed approach is tested on a large dataset of subjects (N = 108) during eyes-closed (EC) and eyes-open (EO) resting state conditions. The obtained recognition performance shows that using brain connectivity leads to higher distinctiveness with respect to power-spectrum measurements, in both the experimental conditions. Notably, a 100% recognition accuracy is obtained in EC and EO when integrating functional connectivity between regions in the frontal lobe, while a lower 97.5% is obtained in EC (96.26% in EO) when fusing power spectrum information from parieto-occipital (centro-parietal in EO) regions. Taken together, these results suggest that the functional connectivity patterns represent effective features for improving EEG based biometric systems. PMID- 24759982 TI - Nationwide i.v. fluid shortage threatens care. PMID- 24759983 TI - Performance of a Medipix3RX spectroscopic pixel detector with a high resistivity gallium arsenide sensor. AB - High resistivity gallium arsenide is considered a suitable sensor material for spectroscopic X-ray imaging detectors. These sensors typically have thicknesses between a few hundred MUm and 1 mm to ensure a high photon detection efficiency. However, for small pixel sizes down to several tens of MUm, an effect called charge sharing reduces a detector's spectroscopic performance. The recently developed Medipix3RX readout chip overcomes this limitation by implementing a charge summing circuit, which allows the reconstruction of the full energy information of a photon interaction in a single pixel. In this work, we present the characterization of the first Medipix3RX detector assembly with a 500 MUm thick high resistivity, chromium compensated gallium arsenide sensor. We analyze its properties and demonstrate the functionality of the charge summing mode by means of energy response functions recorded at a synchrotron. Furthermore, the imaging properties of the detector, in terms of its modulation transfer functions and signal-to-noise ratios, are investigated. After more than one decade of attempts to establish gallium arsenide as a sensor material for photon counting detectors, our results represent a breakthrough in obtaining detector-grade material. The sensor we introduce is therefore suitable for high resolution X-ray imaging applications. PMID- 24759984 TI - Adaptive quantification and longitudinal analysis of pulmonary emphysema with a hidden Markov measure field model. AB - The extent of pulmonary emphysema is commonly estimated from CT scans by computing the proportional area of voxels below a predefined attenuation threshold. However, the reliability of this approach is limited by several factors that affect the CT intensity distributions in the lung. This work presents a novel method for emphysema quantification, based on parametric modeling of intensity distributions and a hidden Markov measure field model to segment emphysematous regions. The framework adapts to the characteristics of an image to ensure a robust quantification of emphysema under varying CT imaging protocols, and differences in parenchymal intensity distributions due to factors such as inspiration level. Compared to standard approaches, the presented model involves a larger number of parameters, most of which can be estimated from data, to handle the variability encountered in lung CT scans. The method was applied on a longitudinal data set with 87 subjects and a total of 365 scans acquired with varying imaging protocols. The resulting emphysema estimates had very high intra subject correlation values. By reducing sensitivity to changes in imaging protocol, the method provides a more robust estimate than standard approaches. The generated emphysema delineations promise advantages for regional analysis of emphysema extent and progression. PMID- 24759985 TI - Application of tolerance limits to the characterization of image registration performance. AB - Deformable image registration is used increasingly in image-guided interventions and other applications. However, validation and characterization of registration performance remain areas that require further study. We propose an analysis methodology for deriving tolerance limits on the initial conditions for deformable registration that reliably lead to a successful registration. This approach results in a concise summary of the probability of registration failure, while accounting for the variability in the test data. The (beta, gamma) tolerance limit can be interpreted as a value of the input parameter that leads to successful registration outcome in at least 100beta% of cases with the 100gamma% confidence. The utility of the methodology is illustrated by summarizing the performance of a deformable registration algorithm evaluated in three different experimental setups of increasing complexity. Our examples are based on clinical data collected during MRI-guided prostate biopsy registered using publicly available deformable registration tool. The results indicate that the proposed methodology can be used to generate concise graphical summaries of the experiments, as well as a probabilistic estimate of the registration outcome for a future sample. Its use may facilitate improved objective assessment, comparison and retrospective stress-testing of deformable. PMID- 24759986 TI - PTEN-inhibition by zinc ions augments interleukin-2-mediated Akt phosphorylation. AB - Free zinc ions (Zn(2+)) participate in several signaling pathways. The aim of the present study was to investigate a potential involvement of Zn(2+) in the PI3K/Akt pathway of interleukin (IL)-2 signaling in T-cells. The IL-2 receptor triggers three major pathways, ERK1/2, JAK/STAT5, and PI3K/Akt. We have previously shown that an IL-2-mediated release of lysosomal Zn(2+) into the cytoplasm activates ERK1/2, but not STAT5. In the present study, Akt phosphorylation in response to IL-2 was abrogated by the Zn(2+) chelator N,N,N',N'-tetrakis-2(pyridyl-methyl)ethylenediamine, and was induced by treatment with Zn(2+) and the ionophore pyrithione. The latter were ineffective in cells that were treated with siRNA against the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that degrades the lipid second messenger PI(3,4,5)P3, which is produced by PI3K and leads to activation of Akt. Inhibition of recombinant PTEN by Zn(2+)in vitro yielded an IC50 of 0.59 nM. Considering a resting free cytoplasmic Zn(2+) level of 0.2 nM in the T-cell line CTLL-2, this seems ideally suited for dynamic regulation by cellular Zn(2+). Oxidation with H2O2 and supplementation with Zn(2+) led to similar changes in the CD spectrum of PTEN. Moreover, Zn(2+) partially prevented the oxidation of cysteines 71 and 124. Hence, we hypothesize that zinc signals affect the IL-2-dependent PI3K/Akt pathway by inhibiting the negative regulator PTEN through binding with a sub nanomolar affinity to cysteine residues that are essential for its catalytic activity. PMID- 24759988 TI - A regularized model-based optimization framework for pan-sharpening. AB - Pan-sharpening is a common postprocessing operation for captured multispectral satellite imagery, where the spatial resolution of images gathered in various spectral bands is enhanced by fusing them with a panchromatic image captured at a higher resolution. In this paper, pan-sharpening is formulated as the problem of jointly estimating the high-resolution (HR) multispectral images to minimize an objective function comprised of the sum of squared residual errors in physically motivated observation models of the low-resolution (LR) multispectral and the HR panchromatic images and a correlation-dependent regularization term. The objective function differs from and improves upon previously reported model-based optimization approaches to pan-sharpening in two major aspects: 1) a new regularization term is introduced and 2) a highpass filter, complementary to the lowpass filter for the LR spectral observations, is introduced for the residual error corresponding to the panchromatic observation model. To obtain pan sharpened images, an iterative algorithm is developed to solve the proposed joint minimization. The proposed algorithm is compared with previously proposed methods both visually and using established quantitative measures of SNR, spectral angle mapper, relative dimensionless global error in synthesis, Q, and Q4 indices. Both the quantitative results and visual evaluation demonstrate that the proposed joint formulation provides superior results compared with pre-existing methods. A software implementation is provided. PMID- 24759987 TI - allograft inflammatory factor 1 functions as a pro-inflammatory cytokine in the oyster, Crassostrea ariakensis. AB - The oyster Crassostrea ariakensis is an economically important bivalve species in China, unfortunately it has suffered severe mortalities in recent years caused by rickettsia-like organism (RLO) infection. Prevention and control of this disease is a priority for the development of oyster aquaculture. Allograft inflammatory factor-1 (AIF-1) was identified as a modulator of the immune response during macrophage activation and a key gene in host immune defense reaction and inflammatory response. Therefore we investigated the functions of C. ariakensis AIF-1 (Ca-AIF1) and its antibody (anti-CaAIF1) in oyster RLO/LPS-induced disease and inflammation. Ca-AIF1 encodes a 149 amino acid protein containing two typical Ca2+ binding EF-hand motifs and shares a 48-95% amino acid sequence identity with other animal AIF-1s. Tissue-specific expression analysis indicates that Ca-AIF1 is highly expressed in hemocytes. Significant and continuous up-regulation of Ca AIF1 is detected when hemocytes are stimulated with RLO/LPS (RLO or LPS). Treatment with recombinant Ca-AIF1 protein significantly up-regulates the expression levels of LITAF, MyD88 and TGFbeta. When anti-CaAIF1 antibody is added to RLO/LPS-challenged hemocyte monolayers, a significant reduction of RLO/LPS induced LITAF is observed at 1.5-12 h after treatment, suggesting that interference with Ca-AIF1 can suppress the inflammatory response. Furthermore, flow cytometric analysis indicated that anti-CaAIF1 administration reduces RLO/LPS-induced apoptosis and necrosis rates of hemocytes. Collectively these findings suggest that Ca-AIF1 functions as a pro-inflammatory cytokine in the oyster immune response and is a potential target for controlling RLO infection and LPS-induced inflammation. PMID- 24759989 TI - Scene text recognition in mobile applications by character descriptor and structure configuration. AB - Text characters and strings in natural scene can provide valuable information for many applications. Extracting text directly from natural scene images or videos is a challenging task because of diverse text patterns and variant background interferences. This paper proposes a method of scene text recognition from detected text regions. In text detection, our previously proposed algorithms are applied to obtain text regions from scene image. First, we design a discriminative character descriptor by combining several state-of-the-art feature detectors and descriptors. Second, we model character structure at each character class by designing stroke configuration maps. Our algorithm design is compatible with the application of scene text extraction in smart mobile devices. An Android based demo system is developed to show the effectiveness of our proposed method on scene text information extraction from nearby objects. The demo system also provides us some insight into algorithm design and performance improvement of scene text extraction. The evaluation results on benchmark data sets demonstrate that our proposed scheme of text recognition is comparable with the best existing methods. PMID- 24759990 TI - Receptive fields selection for binary feature description. AB - Feature description for local image patch is widely used in computer vision. While the conventional way to design local descriptor is based on expert experience and knowledge, learning-based methods for designing local descriptor become more and more popular because of their good performance and data-driven property. This paper proposes a novel data-driven method for designing binary feature descriptor, which we call receptive fields descriptor (RFD). Technically, RFD is constructed by thresholding responses of a set of receptive fields, which are selected from a large number of candidates according to their distinctiveness and correlations in a greedy way. Using two different kinds of receptive fields (namely rectangular pooling area and Gaussian pooling area) for selection, we obtain two binary descriptors RFDR and RFDG .accordingly. Image matching experiments on the well-known patch data set and Oxford data set demonstrate that RFD significantly outperforms the state-of-the-art binary descriptors, and is comparable with the best float-valued descriptors at a fraction of processing time. Finally, experiments on object recognition tasks confirm that both RFDR and RFDG successfully bridge the performance gap between binary descriptors and their floating-point competitors. PMID- 24759991 TI - Antiangiogenic treatment diminishes renal injury and dysfunction via regulation of local AKT in early experimental diabetes. AB - In view of increased vascular endothelial growth factor-A (VEGF-A) expression and renal dysfunction in early diabetes, we designed a study to test whether VEGF-A inhibition can prevent early renal injury and dysfunction. We investigated the relationship and mechanism between VEGF-A and AKT regulation. In vitro, VEGF-A small interfering RNA (siRNA) and AKT inhibitor MK-2206 were employed to podocytes and NRK-52 cells cultured in high glucose (30 mM). In vivo, the antiangiogenic drug endostatin was administered in 12 week-old streptozotocin induced male Sprague Dawley rats. The levels of VEGF-A, AKT, phosphorylated Ser473-AKT, phosphorylated Thr308-AKT, nephrin, angiotensin II (Ang II), angiotensin type II receptor 1 (ATR1) were examined using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis and immunohistochemistry. Interactions between phosphorylated Thr308-AKT and either nephrin in podocytes or Ang II in renal tubules were studied, respectively, using confocal immunofluorescence microscopy and immunoprecipitation. Silencing VEGF-A in podocytes upregulated phosphorylated Thr308-AKT and nephrin. Silencing VEGF-A in NRK-52E cells upregulated phosphorylated Thr308-AKT while downregulated Ang II and ATR1. MK-2206 enhanced VEGF-A expression in both podocytes and NRK-52E cells by inhibiting AKT activities. In diabetic rat kidneys, VEGF-A was upregulated and phosphorylated Thr308-AKT colocalized with either nephrin in podocytes or Ang II in renal tubules. With the endostatin treatment, the level of VEGF-A decreased while phosphorylated Thr308-AKT increased in both glomeruli and renal tubules. Treatment with endostatin upregulated nephrin in podocytes while downregulated Ang II and AT1R in renal tubules. Glomerular mesangial expansion was attenuated by the endostatin treatment, however, differences did not reach statistical significance. Endostatin ameliorated the interstitial fibrosis, urine albumin excretion rate (UAER) and albumin to creatinine ratio. We conclude that phosphorylated Thr308-AKT regulates VEGF-A expression by interacting with either nephrin in glomeruli or Ang II in renal tubules. Antiangiogenic treatment improves renal injury and function in early experimental diabetes. PMID- 24759992 TI - Human migration patterns in Yemen and implications for reconstructing prehistoric population movements. AB - Population migration has played an important role in human evolutionary history and in the patterning of human genetic variation. A deeper and empirically-based understanding of human migration dynamics is needed in order to interpret genetic and archaeological evidence and to accurately reconstruct the prehistoric processes that comprise human evolutionary history. Current empirical estimates of migration include either short time frames (i.e. within one generation) or partial knowledge about migration, such as proportion of migrants or distance of migration. An analysis of migration that includes both proportion of migrants and distance, and direction over multiple generations would better inform prehistoric reconstructions. To evaluate human migration, we use GPS coordinates from the place of residence of the Yemeni individuals sampled in our study, their birthplaces and their parents' and grandparents' birthplaces to calculate the proportion of migrants, as well as the distance and direction of migration events between each generation. We test for differences in these values between the generations and identify factors that influence the probability of migration. Our results show that the proportion and distance of migration between females and males is similar within generations. In contrast, the proportion and distance of migration is significantly lower in the grandparents' generation, most likely reflecting the decreasing effect of technology. Based on our results, we calculate the proportion of migration events (0.102) and mean and median distances of migration (96 km and 26 km) for the grandparent's generation to represent early times in human evolution. These estimates can serve to set parameter values of demographic models in model-based methods of prehistoric reconstruction, such as approximate Bayesian computation. Our study provides the first empirically-based estimates of human migration over multiple generations in a developing country and these estimates are intended to enable more precise reconstruction of the demographic processes that characterized human evolution. PMID- 24759993 TI - Wavelet domain feature extraction scheme based on dominant motor unit action potential of EMG signal for neuromuscular disease classification. AB - In this paper, two schemes for neuromuscular disease classification from electromyography (EMG) signals are proposed based on discrete wavelet transform (DWT) features. In the first scheme, a few high energy DWT coefficients along with the maximum value are extracted in a frame by frame manner from the given EMG data. Instead of considering only such local information obtained from a single frame, we propose to utilize global statistics which is obtained based on information collected from some consecutive frames. In the second scheme, motor unit action potentials (MUAPs) are first extracted from the EMG data via template matching based decomposition technique. It is well known that not all MUAPs obtained via decomposition are capable of uniquely representing a class. Thus, a novel idea of selecting a dominant MUAP, based on energy criterion, is proposed and instead of all MUAPs, only the dominant MUAP is used for the classification. A feature extraction scheme based on some statistical properties of the DWT coefficients of dominant MUAPs is proposed. For the purpose of classification, the K-nearest neighborhood (KNN) classifier is employed. Extensive analysis is performed on clinical EMG database for the classification of neuromuscular diseases and it is found that the proposed methods provide a very satisfactory performance in terms of specificity, sensitivity, and overall classification accuracy. PMID- 24759994 TI - Efavirenz promotes beta-secretase expression and increased Abeta1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND). AB - Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, causes neurological symptoms that interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HIV associated neurocognitive disorders (HAND) in patients on combination antiretroviral therapy (cART). Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human "Swedish" mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Abeta) production. Treatment with EFV or the EFV containing regimen generated significantly increased soluble amyloid beta (Abeta), and promoted increased beta-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Abeta - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Abeta generation while 3TC, AZT, or vehicle control did not. Finally, microglial Abeta phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Abeta promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Abeta peptide. PMID- 24759995 TI - Effects of siRNA on RET/PTC3 junction oncogene in papillary thyroid carcinoma: from molecular and cellular studies to preclinical investigations. AB - RET/PTC3 junction oncogene is typical of radiation-induced childhood papillary thyroid carcinoma (PTC) with a short latency period. Since, RET/PTC3 is only present in the tumour cells, thus represents an interesting target for specific therapy by small interfering RNA (siRNA). Our aim is to demonstrate in vitro and in vivo molecular and cellular effects of siRNA on RET/PTC3 knockdown for therapeutic application.First, we established a novel cell line stably expressing RET/PTC3 junction oncogene, named RP3 which was found tumorigenic in nude mice compared to NIH/3T3 mouse fibroblasts. Among four siRNAs and five concentrations tested against RET/PTC3, an efficient siRNA RET/PTC3 and an appropriate dose (50 nM) were selected which showed significant inhibition (p<0.001) of gene (RT-qPCR) and protein (Western blot) expressions. This siRNA was found efficient in RP3 cells (harbouring RET/PTC3) but non-efficient in BHP10-3 SCmice cell line (harbouring RET/PTC1) showing that a specific siRNA against fusion sequence is required to target the junction oncogene. In vitro siRNA RET/PTC3 showed significant (p<0.001) inhibitory effects on RP3 cell viability (MTT assay) and on invasion/migration (IncuCyte scratch test) with blockage of cell cycle at G0/G1 phase (flow cytometry) and induced apoptosis by caspase-3 and PARP1 cleavage (WB). After intravenous injection in nude mice, respective squalene (SQ) nanoparticles (NPs) of siRNA RET/PTC3 significantly (p<0.001) reduced RP3 tumour growth, oncogene and oncoprotein expressions, induced apoptosis and partially restored differentiation (decrease in Ki67). Hence, our findings highly support the use of siRNA RET/PTC3-SQ NPs as a new promising treatment for patients affected by PTC expressing RET/PTC3. PMID- 24759996 TI - Ambulatory measurement of three-dimensional foot displacement during treadmill walking using wearable wireless ultrasonic sensor network. AB - Techniques that could be used to monitor human motion precisely are helpful in various applications such as rehabilitation, gait analysis, and athletic performance analysis. This paper focuses on the 3-D foot trajectory measurements based on a wearable wireless ultrasonic sensor network. The system consists of an ultrasonic transmitter (mobile) and several receivers (anchors) with fixed known positions. In order not to restrict the movement of subjects, a radio frequency (RF) module is used for wireless data transmission. The RF module also provides the synchronization clock between mobile and anchors. The proposed system measures the time-of-arrival (TOA) of the ultrasonic signal from mobile to anchors. Together with the knowledge of the anchor's position, the absolute distance that the signal travels can be computed. Then, the range information defines a circle centered at this anchor with radius equal to the measured distance, and the mobile resides within the intersections of several such circles. Based on the TOA-based tracking technique, the 3-D foot trajectories are validated against a camera-based motion capture system for ten healthy subjects walking on a treadmill at slow, normal, and fast speeds. The experimental results have shown that the ultrasonic system has sufficient accuracy of net root-mean square error ( 4.2 cm) for 3-D displacement, especially for foot clearance with accuracy and standard deviation ( 0.62 +/-7.48 mm) compared to the camera-based motion capture system. The small form factor and lightweight feature of the proposed system make it easy to use. Such a system is also much lower in cost compared to the camera-based tracking system. PMID- 24759997 TI - Discrimination of tooth layers and dental restorative materials using cutting sounds. AB - Dental restoration begins with removing carries and affected tissues with air turbine rotary cutting handpieces, and later restoring the lost tissues with appropriate restorative materials to retain the functionality. Most restoration materials eventually fail as they age and need to be replaced. One of the difficulties in replacing failing restorations is discerning the boundary of restorative materials, which causes inadvertent removal of healthy tooth layers. Developing an objective and sensor-based method is a promising approach to monitor dental restorative operations and to prevent excessive tooth losses. This paper has analyzed cutting sounds of an air-turbine handpiece to discriminate between tooth layers and two commonly used restorative materials, amalgam and composite. Support vector machines were employed for classification, and the averaged short-time Fourier transform coefficients were selected as the features. The classifier performance was evaluated from different aspects such as the number of features, feature scaling methods, classification schemes, and utilized kernels. The total classification accuracies were 89% and 92% for cases included composite and amalgam materials, respectively. The obtained results indicated the feasibility and effectiveness of the proposed method. PMID- 24759999 TI - Nonasymptotic mean-field games. AB - Mean-field games have been studied under the assumption of very large number of players. For such large systems, the basic idea consists of approximating large games by a stylized game model with a continuum of players. The approach has been shown to be useful in some applications. However, the stylized game model with continuum of decision-makers is rarely observed in practice and the approximation proposed in the asymptotic regime is meaningless for networks with few entities. In this paper, we propose a mean-field framework that is suitable not only for large systems but also for a small world with few number of entities. The applicability of the proposed framework is illustrated through various examples including dynamic auction with asymmetric valuation distributions, and spiteful bidders. PMID- 24759998 TI - Linkage disequilibrium and genome-wide association mapping in tetraploid wheat (Triticum turgidum L.). AB - Association mapping is a powerful tool for the identification of quantitative trait loci through the exploitation of the differential decay of linkage disequilibrium (LD) between marker loci and genes of interest in natural and domesticated populations. Using a sample of 230 tetraploid wheat lines (Triticum turgidum ssp), which included naked and hulled accessions, we analysed the pattern of LD considering 26 simple sequence repeats and 970 mostly mapped diversity array technology loci. In addition, to validate the potential for association mapping in durum wheat, we evaluated the same genotypes for plant height, heading date, protein content, and thousand-kernel weight. Molecular and phenotypic data were used to: (i) investigate the genetic and phenotypic diversity; (ii) study the dynamics of LD across the durum wheat genome, by investigating the patterns of LD decay; and (iii) test the potential of our panel to identify marker-trait associations through the analysis of four quantitative traits of major agronomic importance. Moreover, we compared and validated the association mapping results with outlier detection analysis based on population divergence. Overall, in tetraploid wheat, the pattern of LD is extremely population dependent and is related to the domestication and breeding history of durum wheat. Comparing our data with several other studies in wheat, we confirm the position of many major genes and quantitative trait loci for the traits considered. Finally, the analysis of the selection signature represents a very useful complement to validate marker-trait associations. PMID- 24760000 TI - Limited utility of ITPA deficiency to predict early anemia in HCV patients with advanced fibrosis receiving Telaprevir. AB - BACKGROUND: Severe anemia is a common side effect of Pegylated Interferon + Ribavirin (PR) and Telaprevir (TVR) in hepatitis C virus (HCV) genotype 1 patients with advanced fibrosis or cirrhosis (F3-F4). Inosine triphosphatase (ITPA) genetic variants are associated with RBV- induced anemia and dose reduction. AIM: To test the association of ITPA polymorphisms rs1127354 and rs7270101 with hemoglobin (Hb) decline, need for RBV dose reduction (RBV DR), erythropoietin (EPO) support and blood transfusions during the first 12 weeks of TVR triple therapy. MATERIALS AND METHODS: 69 consecutive HCV-1 patients (mean age 57 years) with F3-F4 who received PR and TVR were genotyped for ITPA polymorphisms rs1127354 and rs7270101. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe). RESULTS: ITPA deficiency was absent in 48 patients (70%), mild in 12 (17%) and moderate in 9 patients (13%). Mean week 4 Hb decline was higher in non ITPA deficient patients (3,85 g/dL) than in mildly or moderately ITPA deficient patients (3,07 g/dL and 1,67 g/dL, p<0.0001). Grade 3-4 anemia developed in 81% non ITPA deficient patients versus 67% mild deficient and 55% moderate deficient patients (p = ns). Grade of ITPA deficiency was not associated with RbvDR (no deficiency: 60%, mild: 58%, moderate: 67%; p = ns), EPO use (no deficiency: 65%, mild: 58%, moderate:56%; p = ns) or need for blood transfusion (no deficiency: 27%, mild: 17%, moderate: 33%; p = ns). CONCLUSIONS: In patients with F3-F4 chronic hepatitis C receiving TVR based therapy, ITPA genotype does not impact on the management of early anemia. PMID- 24760002 TI - A randomized clinical trial of the immunogenicity of 7-valent pneumococcal conjugate vaccine compared to 23-valent polysaccharide vaccine in frail, hospitalized elderly. AB - BACKGROUND: Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly. METHODS: Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months. RESULTS: Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm. CONCLUSION: We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity. TRIAL REGISTRATION: The Australian Clinical Trials Registry ACTRN12607000387426. PMID- 24760001 TI - Insights into nasal carriage of Staphylococcus aureus in an urban and a rural community in Ghana. AB - The epidemiology of Staphylococcus aureus in the community in Ghana was never investigated prior to this study. The aims of the study were: i) to assess prevalence of nasal S. aureus carriage in Ghanaian people living in an urban and a rural area, and ii) to identify phenotypic and genotypic traits of strains isolated from the two communities. Nasal swabs were collected from healthy individuals living in an urban community situated in the suburb of the capital city, Accra (n = 353) and in a rural community situated in the Dangme-West district (n = 234). The overall prevalence of nasal carriage was 21% with a significantly higher prevalence in the urban (28%) than in the rural community (11%) (p<0.0001). The levels of antimicrobial resistance were generally low (<5%) except for penicillin (91%) and tetracycline (25%). The only two (0.3%) MRSA carriers were individuals living in the urban area and had been exposed to hospitals within the last 12 months prior to sampling. Resistance to tetracycline (p = 0.0009) and presence of Panton-Valentine leukocidin (PVL) gene (p = 0.02) were significantly higher among isolates from the rural community compared to isolates from the urban community. Eleven MLST clonal complexes (CC) were detected based on spa typing of the 124 S. aureus isolates from the two communities: CC8 (n = 36), CC152 (n = 21), CC45 (n = 21), CC15 (n = 18), CC121 (n = 6), CC97 (n = 6), CC30 (n = 5), CC5 (n = 5), CC508 (n = 4), CC9 (n = 1), and CC707 (n = 1). CC8 and CC45 were less frequent in the rural area than in the urban area (p = 0.02). These results reveal remarkable differences regarding carriage prevalence, tetracycline resistance, PVL content and clonal distribution of S. aureus in the two study populations. Future research may be required to establish whether such differences in nasal S. aureus carriage are linked to socio-economic differences between urban and rural communities in this African country. PMID- 24760003 TI - Arabidopsis thaliana glyoxalase 2-1 is required during abiotic stress but is not essential under normal plant growth. AB - The glyoxalase pathway, which consists of the two enzymes, GLYOXALASE 1 (GLX 1) (E.C.: 4.4.1.5) and 2 (E.C.3.1.2.6), has a vital role in chemical detoxification. In Arabidopsis thaliana there are at least four different isoforms of glyoxalase 2, two of which, GLX2-1 and GLX2-4 have not been characterized in detail. Here, the functional role of Arabidopsis thaliana GLX2-1 is investigated. Glx2-1 loss of-function mutants and plants that constitutively over-express GLX2-1 resemble wild-type plants under normal growth conditions. Insilico analysis of publicly available microarray datasets with ATTEDII, Mapman and Genevestigator indicate potential role(s) in stress response and acclimation. Results presented here demonstrate that GLX2-1 gene expression is up-regulated in wild type Arabidopsis thaliana by salt and anoxia stress, and by excess L-Threonine. Additionally, a mutation in GLX2-1 inhibits growth and survival during abiotic stresses. Metabolic profiling studies show alterations in the levels of sugars and amino acids during threonine stress in the plants. Elevated levels of polyamines, which are known stress markers, are also observed. Overall our results suggest that Arabidopsis thaliana GLX2-1 is not essential during normal plant life, but is required during specific stress conditions. PMID- 24760004 TI - Frequent mutations in EGFR, KRAS and TP53 genes in human lung cancer tumors detected by ion torrent DNA sequencing. AB - Lung cancer is the most common malignancy and the leading cause of cancer deaths worldwide. While smoking is by far the leading cause of lung cancer, other environmental and genetic factors influence the development and progression of the cancer. Since unique mutations patterns have been observed in individual cancer samples, identification and characterization of the distinctive lung cancer molecular profile is essential for developing more effective, tailored therapies. Until recently, personalized DNA sequencing to identify genetic mutations in cancer was impractical and expensive. The recent technological advancements in next-generation DNA sequencing, such as the semiconductor-based Ion Torrent sequencing platform, has made DNA sequencing cost and time effective with more reliable results. Using the Ion Torrent Ampliseq Cancer Panel, we sequenced 737 loci from 45 cancer-related genes to identify genetic mutations in 76 human lung cancer samples. The sequencing analysis revealed missense mutations in KRAS, EGFR, and TP53 genes in the breast cancer samples of various histologic types. Thus, this study demonstrates the necessity of sequencing individual human cancers in order to develop personalized drugs or combination therapies to effectively target individual, breast cancer-specific mutations. PMID- 24760005 TI - Specific activation of K-RasG12D allele in the bladder urothelium results in lung alveolar and vascular defects. AB - K-ras is essential for embryogenesis and its mutations are involved in human developmental syndromes and cancer. To determine the consequences of K-ras activation in urothelium, we used uroplakin-II (UPK II) promoter driven Cre recombinase mice and generated mice with mutated KrasG12D allele in the urothelium (UPK II-Cre;LSL-K-rasG12D). The UPK II-Cre;LSL-K-rasG12D mice died neonatally due to lung morphogenesis defects consisting of simplification with enlargement of terminal air spaces and dysmorphic pulmonary vasculature. A significant alteration in epithelial and vascular basement membranes, together with fragmentation of laminin, points to extracellular matrix degradation as the causative mechanism of alveolar and vascular defects. Our data also suggest that altered protease activity in amniotic fluid might be associated with matrix defects in lung of UPK II-Cre;LSL-K-rasG12. These defects resemble those observed in early stage human neonatal bronchopulmonary dysplasia (BPD), although the relevance of this new mouse model for BPD study needs further investigation. PMID- 24760007 TI - Evaluating relationships between wild Skeena river sockeye salmon productivity and the abundance of spawning channel enhanced sockeye smolts. AB - The enhancement of salmon populations has long been used to increase the abundance of salmon returning to spawn and/or to be captured in fisheries. However, in some instances enhancement can have adverse impacts on adjacent non enhanced populations. In Canada's Skeena watershed, smolt-to-adult survival of Babine Lake sockeye from 1962-2002 was inversely related to the abundance of sockeye smolts leaving Babine Lake. This relationship has led to the concern that Babine Lake smolt production, which is primarily enhanced by spawning channels, may depress wild Skeena (Babine and non-Babine) sockeye populations as a result of increased competition between wild and enhanced sockeye smolts as they leave their natal lakes and co-migrate to sea. To test this hypothesis we used data on Skeena sockeye populations and oceanographic conditions to statistically examine the relationship between Skeena sockeye productivity (adult salmon produced per spawner) and an index of Babine Lake enhanced smolt abundance while accounting for the potential influence of early marine conditions. While we had relatively high power to detect large effects, we did not find support for the hypothesis that the productivity of wild Skeena sockeye is inversely related to the abundance of enhanced sockeye smolts leaving Babine Lake in a given year. Importantly, life-time productivity of Skeena sockeye is only partially explained by marine survival, and likely is an unreliable measure of the influence of smolt abundance. Limitations to our analyses, which include: (1) the reliance upon adult salmon produced per spawner (rather than per smolt) as an index of marine survival, and (2) incomplete age structure for most of the populations considered, highlight uncertainties that should be addressed if understanding relationships between wild and enhanced sockeye is a priority in the Skeena. PMID- 24760006 TI - IKAP deficiency in an FD mouse model and in oligodendrocyte precursor cells results in downregulation of genes involved in oligodendrocyte differentiation and myelin formation. AB - The splice site mutation in the IKBKAP gene coding for IKAP protein leads to the tissue-specific skipping of exon 20, with concomitant reduction in IKAP protein production. This causes the neurodevelopmental, autosomal-recessive genetic disorder - Familial Dysautonomia (FD). The molecular hallmark of FD is the severe reduction of IKAP protein in the nervous system that is believed to be the main reason for the devastating symptoms of this disease. Our recent studies showed that in the brain of two FD patients, genes linked to oligodendrocyte differentiation and/or myelin formation are significantly downregulated, implicating IKAP in the process of myelination. However, due to the scarcity of FD patient tissues, these results awaited further validation in other models. Recently, two FD mouse models that faithfully recapitulate FD were generated, with two types of mutations resulting in severely low levels of IKAP expression. Here we demonstrate that IKAP deficiency in these FD mouse models affects a similar set of genes as in FD patients' brains. In addition, we identified two new IKAP target genes involved in oligodendrocyte cells differentiation and myelination, further underscoring the essential role of IKAP in this process. We also provide proof that IKAP expression is needed cell-autonomously for the regulation of expression of genes involved in myelin formation since knockdown of IKAP in the Oli-neu oligodendrocyte precursor cell line results in similar deficiencies. Further analyses of these two experimental models will compensate for the lack of human postmortem tissues and will advance our understanding of the role of IKAP in myelination and the disease pathology. PMID- 24760008 TI - Microsecond molecular dynamics simulations of Mg2+- and K+-bound E1 intermediate states of the calcium pump. AB - We have performed microsecond molecular dynamics (MD) simulations to characterize the structural dynamics of cation-bound E1 intermediate states of the calcium pump (sarcoendoplasmic reticulum Ca2+-ATPase, SERCA) in atomic detail, including a lipid bilayer with aqueous solution on both sides. X-ray crystallography with 40 mM Mg2+ in the absence of Ca2+ has shown that SERCA adopts an E1 structure with transmembrane Ca2+-binding sites I and II exposed to the cytosol, stabilized by a single Mg2+ bound to a hybrid binding site I'. This Mg2+-bound E1 intermediate state, designated E1*Mg2+, is proposed to constitute a functional SERCA intermediate that catalyzes the transition from E2 to E1*2Ca2+ by facilitating H+/Ca2+ exchange. To test this hypothesis, we performed two independent MD simulations based on the E1*Mg2+ crystal structure, starting in the presence or absence of initially-bound Mg2+. Both simulations were performed for 1 us in a solution containing 100 mM K+ and 5 mM Mg2+ in the absence of Ca2+, mimicking muscle cytosol during relaxation. In the presence of initially-bound Mg2+, SERCA site I' maintained Mg2+ binding during the entire MD trajectory, and the cytosolic headpiece maintained a semi-open structure. In the absence of initially-bound Mg2+, two K+ ions rapidly bound to sites I and I' and stayed loosely bound during most of the simulation, while the cytosolic headpiece shifted gradually to a more open structure. Thus MD simulations predict that both E1*Mg2+ and E*2K+ intermediate states of SERCA are populated in solution in the absence of Ca2+, with the more open 2K+-bound state being more abundant at physiological ion concentrations. We propose that the E1*2K+ state acts as a functional intermediate that facilitates the E2 to E1*2Ca2+ transition through two mechanisms: by pre-organizing transport sites for Ca2+ binding, and by partially opening the cytosolic headpiece prior to Ca2+ activation of nucleotide binding. PMID- 24760009 TI - A new polymorphism biomarker rs629367 associated with increased risk and poor survival of gastric cancer in chinese by up-regulated miRNA-let-7a expression. AB - BACKGROUND: Variant in pri-miRNA could affect miRNA expression and mature process or splicing efficiency, thus altering the hereditary susceptibility and prognosis of cancer. We aimed to assess miRNA-let-7 single nucleotide polymorphisms (SNP) associated with the risk and prognosis of gastric cancer (GC) as predicting biomarkers, and furthermore, its possible mechanisms. METHODS: A two-stage case control study was designed to screen four miRNA SNPs (pri-let-7a-2 rs629367 and rs1143770, pri-let-7a-1 rs10739971, pri-let-7f-2 rs17276588) in 107 GC patients, 107 atrophic gastritis (AG), and matched 124 controls using PCR-RFLP. Two promising SNPs were validated in another independent 1949 samples (including 579 gastric cancer patients, 649 atrophic gastritis and 721 controls) using Sequenom MassARRAY platform and sequencing. RESULTS: We found that pri-let-7a-2 rs629367 CC variant genotype was associated with increased risks of gastric cancer and atrophic gastritis by 1.83-fold and 1.86-fold, respectively. For gastric cancer prognosis, patients with rs629367 CC genotype had significantly poorer survival than patients with AA genotype (log-rank P = 0.004). We further investigated the let-7a expression levels in serum and found that let-7a expression elevated gradually for rs629367 AA, CA, CC genotype in the atrophic gastritis group (P = 0.043). Furthermore, we confirmed these findings in vitro study by overexpressing let-7a carrying pri-let-7a-2 wild-type A or polymorphic-type C allele (P<0.001). CONCLUSIONS: pri-let-7a-2 rs629367 CC genotype could increase the risks of gastric cancer as well as atrophic gastritis and was also associated with poor survival of gastric cancer, which possibly by affecting the mature let-7a expression, and could serve as a predicting biomarker for high-risk and poor prognosis of gastric cancer. PMID- 24760010 TI - Adenoviruses using the cancer marker EphA2 as a receptor in vitro and in vivo by genetic ligand insertion into different capsid scaffolds. AB - Adenoviral gene therapy and oncolysis would critically benefit from targeted cell entry by genetically modified capsids. This requires both the ablation of native adenovirus tropism and the identification of ligands that remain functional in virus context. Here, we establish cell type-specific entry of HAdV-5-based vectors by genetic ligand insertion into a chimeric fiber with shaft and knob domains of the short HAdV-41 fiber (Ad5T/41sSK). This fiber format was reported to ablate transduction in vitro and biodistribution to the liver in vivo. We show that the YSA peptide, binding to the pan-cancer marker EphA2, can be inserted into three positions of the chimeric fiber, resulting in strong transduction of EphA2-positive but not EphA2-negative cells of human melanoma biopsies and of tumor xenografts after intratumoral injection. Transduction was blocked by soluble YSA peptide and restored for EphA2-negative cells after recombinant EphA2 expression. The YSA peptide could also be inserted into three positions of a CAR binding-ablated HAdV-5 fiber enabling specific transduction; however, the Ad5T/41sSK format was superior in vivo. In conclusion, we establish an adenovirus capsid facilitating functional insertion of targeting peptides and a novel adenovirus using the tumor marker EphA2 as receptor with high potential for cancer gene therapy and viral oncolysis. PMID- 24760011 TI - In vivo substrates of the lens molecular chaperones alphaA-crystallin and alphaB crystallin. AB - alphaA-crystallin and alphaB-crystallin are members of the small heat shock protein family and function as molecular chaperones and major lens structural proteins. Although numerous studies have examined their chaperone-like activities in vitro, little is known about the proteins they protect in vivo. To elucidate the relationships between chaperone function, substrate binding, and human cataract formation, we used proteomic and mass spectrometric methods to analyze the effect of mutations associated with hereditary human cataract formation on protein abundance in alphaA-R49C and alphaB-R120G knock-in mutant lenses. Compared with age-matched wild type lenses, 2-day-old alphaA-R49C heterozygous lenses demonstrated the following: increased crosslinking (15-fold) and degradation (2.6-fold) of alphaA-crystallin; increased association between alphaA crystallin and filensin, actin, or creatine kinase B; increased acidification of betaB1-crystallin; increased levels of grifin; and an association between betaA3/A1-crystallin and alphaA-crystallin. Homozygous alphaA-R49C mutant lenses exhibited increased associations between alphaA-crystallin and betaB3-, betaA4-, betaA2-crystallins, and grifin, whereas levels of betaB1-crystallin, gelsolin, and calpain 3 decreased. The amount of degraded glutamate dehydrogenase, alpha enolase, and cytochrome c increased more than 50-fold in homozygous alphaA-R49C mutant lenses. In alphaB-R120G mouse lenses, our analyses identified decreased abundance of phosphoglycerate mutase, several beta- and gamma-crystallins, and degradation of alphaA- and alphaB-crystallin early in cataract development. Changes in the abundance of hemoglobin and histones with the loss of normal alpha crystallin chaperone function suggest that these proteins also play important roles in the biochemical mechanisms of hereditary cataracts. Together, these studies offer a novel insight into the putative in vivo substrates of alphaA- and alphaB-crystallin. PMID- 24760012 TI - Positive lymph node metastasis has a marked impact on the long-term survival of patients with hepatocellular carcinoma with extrahepatic metastasis. AB - BACKGROUND: The prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastasis is extremely poor. However, what is the main risk factor for survival remains unclear for these patients. We aimed to find out the relative frequency, incidence and locations of extrahepatic metastases and the risk factors of long-term survival of the patients. METHODS: 132 HCC patients with extrahepatic metastasis diagnosed by 18F-FDG PET/CT and conventional workup were enrolled into this study. The incidence and locations of extrahepatic metastases were summarized, and the related risk factors of overall survival were analyzed. RESULTS: The most frequent extrahepatic metastatic sites were lymph nodes in 72 (54.5%), bone in 33 (25.0%) and lung in 28 (21.2%) patients. On univariate analysis, prothrombin time, Child-Pugh grade, portal/hepatic vein invasion and lymph node metastasis were independent risk factors of overall survival. On multivariate analysis, lymph node metastasis was the only independent risk factor of overall survival. The cumulative survival rates at 1- and 3-years after diagnosis of extrahepatic metastasis of HCC were 34.4% and 9.3%, respectively. The median survival time was 7 months (range 1 ~38 months). The median survival time for patients with or without lymph node metastasis were 5 months (range 1~38 months) and 12 months (range 1~30 months), respectively (P = 0.036). CONCLUSIONS: This study showed lymph nodes to be the most frequent site of extrahepatic metastases for primary HCC. Lymph node metastasis was the main risk factor of overall survival in patients with HCC with extrahepatic metastasis. PMID- 24760013 TI - Influence of anodal transcranial direct current stimulation (tDCS) over the right angular gyrus on brain activity during rest. AB - Although numerous studies examined resting-state networks (RSN) in the human brain, so far little is known about how activity within RSN might be modulated by non-invasive brain stimulation applied over parietal cortex. Investigating changes in RSN in response to parietal cortex stimulation might tell us more about how non-invasive techniques such as transcranial direct current stimulation (tDCS) modulate intrinsic brain activity, and further elaborate our understanding of how the resting brain responds to external stimulation. Here we examined how activity within the canonical RSN changed in response to anodal tDCS applied over the right angular gyrus (AG). We hypothesized that changes in resting-state activity can be induced by a single tDCS session and detected with functional magnetic resonance imaging (fMRI). Significant differences between two fMRI sessions (pre-tDCS and post-tDCS) were found in several RSN, including the cerebellar, medial visual, sensorimotor, right frontoparietal, and executive control RSN as well as the default mode and the task positive network. The present results revealed decreased and increased RSN activity following tDCS. Decreased RSN activity following tDCS was found in bilateral primary and secondary visual areas, and in the right putamen. Increased RSN activity following tDCS was widely distributed across the brain, covering thalamic, frontal, parietal and occipital regions. From these exploratory results we conclude that a single session of anodal tDCS over the right AG is sufficient to induce large-scale changes in resting-state activity. These changes were localized in sensory and cognitive areas, covering regions close to and distant from the stimulation site. PMID- 24760014 TI - Contribution of IL-12/IL-35 common subunit p35 to maintaining the testicular immune privilege. AB - The testis is an organ with immune privilege. The comprehensive blood-testis barrier formed by Sertoli cells protects autoimmunogenic spermatozoa and spermatids from attack by the body's immune system. The interleukin (IL)-6/IL-12 family cytokines IL-12 (p35/p40), IL-23 (p19/p40), IL-27 (p28/Epstein-Barr virus induced gene 3 [EBI3]), and IL-35 (p35/EBI3) play critical roles in the regulation of various immune responses, but their roles in testicular immune privilege are not well understood. In the present study, we investigated whether these cytokines are expressed in the testes and whether they function in the testicular immune privilege by using mice deficient in their subunits. Expression of EBI3 was markedly increased at both mRNA and protein levels in the testes of 10- or 12-week-old wild-type mice as compared with levels in 2-week-old mice, whereas the mRNA expression of p40 was markedly decreased and that of p35 was conserved between these two groups. Lack of EBI3, p35, and IL-12 receptor beta2 caused enhanced infiltration of lymphocytes into the testicular interstitium, with increased interferon-gamma expression in the testes and autoantibody production against mainly acrosomal regions of spermatids. Spermatogenic disturbance was more frequently observed in the seminiferous tubules, especially when surrounded by infiltrating lymphocytes, of these deficient mice than in those of wild-type mice. In particular, p35-deficient mice showed the most severe spermatogenic disturbance. Immunohistochemical analyses revealed that endothelial cells and peritubular cells in the interstitium were highly positive for p35 at both ages, and CD163+ resident macrophages positive for p35 and EBI3, possibly producing IL-35, were also detected in the interstitium of 12-week-old mice but not those of 2-week-old mice. These results suggest that p35 helps in maintaining the testicular immune privilege, in part in an IL-35-dependent manner. PMID- 24760016 TI - Alexithymia influences brain activation during emotion perception but not regulation. AB - Alexithymia is a psychological construct that can be divided into a cognitive and affective dimension. The cognitive dimension is characterized by difficulties in identifying, verbalizing and analysing feelings. The affective dimension comprises reduced levels of emotional experience and imagination. Alexithymia is widely regarded to arise from an impairment of emotion regulation. This is the first functional magnetic resonance imaging (fMRI) study to critically evaluate this by investigating the neural correlates of emotion regulation as a function of alexithymia levels. The aim of the current study was to investigate the neural correlates underlying the two alexithymia dimensions during emotion perception and emotion regulation. Using fMRI, we scanned 51 healthy subjects while viewing, reappraising or suppressing negative emotional pictures. The results support the idea that cognitive alexithymia, but not affective alexithymia, is associated with lower activation in emotional attention and recognition networks during emotion perception. However, in contrast with several theories, no alexithymia related differences were found during emotion regulation (neither reappraisal nor suppression). These findings suggest that alexithymia may result from an early emotion processing deficit rather than compromised frontal circuits subserving higher-order emotion regulation processes. PMID- 24760015 TI - Fetal exposure to perfluorinated compounds and attention deficit hyperactivity disorder in childhood. AB - BACKGROUND: The association between exposure to perfluorinated compounds (PFCs) and attention deficit hyperactivity disorder (ADHD) diagnosis has been sparsely investigated in humans and the findings are inconsistent. OBJECTIVES: A matched case-control study was conducted to investigate the association between fetal exposure to PFCs and ADHD diagnosis in childhood. METHODS: The study base comprised children born in Malmo, Sweden, between 1978 and 2000 that were followed up until 2005. Children with ADHD (n = 206) were identified at the Department of Child and Adolescent Psychiatry. Controls (n = 206) were selected from the study base and were matched for year of birth and maternal country of birth. PFC concentrations were measured in umbilical cord serum samples. The differences of the PFC concentrations between cases and controls were investigated using Wilcoxon's paired test. Possible threshold effects (above the upper quartile for perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) and above limit of detection [LOD] for perfluorononanoic acid (PFNA)) were evaluated by conditional logistic regression. RESULTS: The median umbilical cord serum concentrations of PFOS were 6.92 ng/ml in the cases and 6.77 ng/ml in the controls. The corresponding concentrations of PFOA were 1.80 and 1.83 ng/ml. No associations between PFCs and ADHD were observed. Odds ratios adjusted for smoking status, parity, and gestational age were 0.81 (95% confidence interval [CI] 0.50 to 1.32) for PFOS, 1.07 (95% CI 0.67 to 1.7) for PFOA, and 1.1 (95% CI 0.75 to 1.7) for PFNA. CONCLUSIONS: The current study revealed no support for an association between fetal exposure to PFOS, PFOA, or PFNA and ADHD. PMID- 24760017 TI - Costs of a motivational enhancement therapy coupled with cognitive behavioral therapy versus brief advice for pregnant substance users. AB - OBJECTIVES: To determine and compare costs of a nurse-administered behavioral intervention for pregnant substance users that integrated motivational enhancement therapy with cognitive behavioral therapy (MET-CBT) to brief advice (BA) administered by an obstetrical provider. Both interventions were provided concurrent with prenatal care. METHODS: We conducted a micro-costing study that prospectively collected detailed resource utilization and unit cost data for each of the two intervention arms (MET-CBT and BA) within the context of a randomized controlled trial. A three-step approach for identifying, measuring and valuing resource utilization was used. All cost estimates were inflation adjusted to 2011 U.S. dollars. RESULTS: A total of 82 participants received the MET-CBT intervention and 86 participants received BA. From the societal perspective, the total cost (including participants' time cost) of the MET-CBT intervention was $120,483 or $1,469 per participant. In contrast, the total cost of the BA intervention was $27,199 or $316 per participant. Personnel costs (nurse therapists and obstetric providers) for delivering the intervention sessions and supervising the program composed the largest share of the MET-CBT intervention costs. Program set up costs, especially intervention material design and training costs, also contributed substantially to the overall cost. CONCLUSIONS: Implementation of an MET-CBT program to promote drug abstinence in pregnant women is associated with modest costs. Future cost effectiveness and cost benefit analyses integrating costs with outcomes and benefits data will enable a more comprehensive understanding of the intervention in improving the care of substance abusing pregnant women. PMID- 24760018 TI - Aminostyrylbenzofuran directly reduces oligomeric amyloid-beta and reverses cognitive deficits in Alzheimer transgenic mice. AB - Alzheimer's disease is an irreversible neurodegenerative disorder that is characterized by the abnormal aggregation of amyloid-beta into neurotoxic oligomers and plaques. Although many disease-modifying molecules are currently in Alzheimer clinical trials, a small molecule that inhibits amyloid-beta aggregation and ameliorates the disorder has not been approved to date. Herein, we report the effects of a potent small molecule, 6-methoxy-2-(4 dimethylaminostyryl) benzofuran (KMS88009), that directly disrupts amyloid-beta oligomerization, preserving cognitive behavior when used prophylactically and reversing declines in cognitive behavior when used therapeutically. KMS88009 exhibited excellent pharmacokinetic profiles with extensive brain uptake and a high level of safety. When orally administered before and after the onset of Alzheimer's disease symptoms, KMS88009 significantly reduced assembly of amyloid beta oligomers and improved cognitive behaviors in the APP/PS1 double transgenic mouse model. The unique dual mode of action indicates that KMS88009 may be a powerful therapeutic candidate for the treatment of Alzheimer's disease. PMID- 24760019 TI - Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. AB - The cell surface proteins CD133, CD24 and CD44 are putative markers for cancer stem cell populations in colon cancer, associated with aggressive cancer types and poor prognosis. It is important to understand how these markers may predict treatment outcomes, determined by factors such as radioresistance. The scope of this study was to assess the connection between EGFR, CD133, CD24, and CD44 (including isoforms) expression levels and radiation sensitivity, and furthermore analyze the influence of AKT isoforms on the expression patterns of these markers, to better understand the underlying molecular mechanisms in the cell. Three colon cancer cell-lines were used, HT-29, DLD-1, and HCT116, together with DLD-1 isogenic AKT knock-out cell-lines. All three cell-lines (HT-29, HCT116 and DLD-1) expressed varying amounts of CD133, CD24 and CD44 and the top ten percent of CD133 and CD44 expressing cells (CD133high/CD44high) were more resistant to gamma radiation than the ten percent with lowest expression (CD133low/CD44low). The AKT expression was lower in the fraction of cells with low CD133/CD44. Depletion of AKT1 or AKT2 using knock out cells showed for the first time that CD133 expression was associated with AKT1 but not AKT2, whereas the CD44 expression was influenced by the presence of either AKT1 or AKT2. There were several genes in the cell adhesion pathway which had significantly higher expression in the AKT2 KO cell-line compared to the AKT1 KO cell-line; however important genes in the epithelial to mesenchymal transition pathway (CDH1, VIM, TWIST1, SNAI1, SNAI2, ZEB1, ZEB2, FN1, FOXC2 and CDH2) did not differ. Our results demonstrate that CD133high/CD44high expressing colon cancer cells are associated with AKT and increased radiation resistance, and that different AKT isoforms have varying effects on the expression of cancer stem cell markers, which is an important consideration when targeting AKT in a clinical setting. PMID- 24760021 TI - Ovarian blood vessel occlusion as a surgical sterilization method in rats. AB - PURPOSE: To evaluate the female sterilization by occlusion of the ovarian blood flow, using the rat as experimental model. METHODS: Fifty-five females rats were divided into four groups: I (n=10), bilateral ovariectomy, euthanized at 60 or 90 days; II (n=5), opening the abdominal cavity, euthanized at 90 days; III (n=20), bilateral occlusion of the ovarian blood supply using titanium clips, euthanized at 60 or 90 days; and IV (n=20), bilateral occlusion of the ovarian blood supply using nylon thread, euthanized at 60 or 90 days. The estrous cycle was monitored by vaginal cytology. After euthanasia, the reproductive tissues were evaluated histologically. RESULTS: Ovarian atresia was identified macroscopically at 60 days after surgery in the rats in groups III and IV; however, most of the rats in group III maintained cyclicity. Histology of the tissues from group IV revealed that the ovarian tissue was replaced by dense fibrous connective tissue that was slightly vascularized and that intact follicles were absent by 90 days. CONCLUSION: Ovarian blood vessels occluded caused ischemia, leading to progressive tissue necrosis, and bilateral occlusion using a nylon ligature is a viable method for surgical sterilization. PMID- 24760020 TI - Amyloid-beta and proinflammatory cytokines utilize a prion protein-dependent pathway to activate NADPH oxidase and induce cofilin-actin rods in hippocampal neurons. AB - Neurites of neurons under acute or chronic stress form bundles of filaments (rods) containing 1?1 cofilin?actin, which impair transport and synaptic function. Rods contain disulfide cross-linked cofilin and are induced by treatments resulting in oxidative stress. Rods form rapidly (5-30 min) in >80% of cultured hippocampal or cortical neurons treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% of maximum response in ~6 h) occurs in a subpopulation (~20%) of hippocampal neurons upon exposure to soluble human amyloid-beta dimer/trimer (Abetad/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNFalpha, IL-1beta, IL-6) also induce rods at the same rate and within the same neuronal population as Abetad/t. Neurons from prion (PrP(C))-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or Abetad/t. Two pathways inducing rod formation were confirmed by demonstrating that NADPH-oxidase (NOX) activity is required for prion-dependent rod formation, but not for rods induced by glutamate or energy depletion. Surprisingly, overexpression of PrP(C) is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX dependent pathway. Persistence of PrP(C)-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrP(C)-dependent rods causes rod disappearance with a half-life of about 36 min. Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Abeta-binding membrane proteins induce synaptic dysfunction. PMID- 24760022 TI - Effects of subcutaneous carbon dioxide on calcitonin gene related peptide and substance P secretion in rat skin. AB - PURPOSE: To investigate the subcutaneous injection of carbon dioxide (CO2) on neuropeptides Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP) secretion in rat skin. METHODS: Fifty-six Wistar-EPM rats were distributed in two groups: one for CGRP analysis, the other for SP analysis. Each group was subdivided into four subgroups: control (Cont), control with needle (ContNd), CO2 injection (CO2Inj) and atmospheric air injection (AirInj) - with seven animals each. Sample analyses of partial skin were conducted by Western Blotting (WB). RESULTS: In SP group, there was a decrease in the amount of neuropeptides in subgroups CO2Inj and AirInj. Similarly, in CGRP group, there was a decrease in the amount of pro-CGRP neuropeptides (15 kDa) in subgroups CO2Inj and AirInj; Nevertheless, there was no decrease in the amount of CGRP (5 kDa) in any subgroups. CONCLUSION: Subcutaneous injection of CO2 and atmospheric air decreased the amount of Substance P and pro-Calcitonin Gene-Related Peptide (15 kDa) neuropeptides in rat skin. PMID- 24760023 TI - Spongy film of cellulosic polysaccharide as a dressing for aphthous stomatitis treatment in rabbits. AB - PURPOSE: To develop an experimental model of acute inflammation, like aphthous ulcers, in oral cavity of rabbits, and also, to evaluate the results of the application of a polysaccharide spongy film of molasses from sugar cane as assist treatment in the healing process. METHODS: Twenty adult rabbits weighting between 2.5 kg and 3.9 kg were divided into two groups: experimental and control infected ulcers were induced on the jugal mucosa by surgical excision. They were treated at the experimental group by curettage and dressing with spongy film of cellulosic polysaccharide film, whereas saline solution was used in the control group. Temporal evolution of the healing area, histopathology and bacteriological analysis were used to evaluate the healing process on the 3rd (D3), 7th (D7) and 11th days (D11). RESULTS: The healing time and bacteriological study showed no statistical differences on the group means. Analyzing the histopathology of the experimental group we verified epithelial hyperplasia from D3 to D11, instead in the control group there was a greater clutter of the epithelial cells from the D3 to D11. CONCLUSION: The experimental model used caused aphthous ulcers and the polysaccharide sponge film can be used as an aid in the symptomatic treatment and healing of the ulcerative lesions of the oral mucosa. PMID- 24760024 TI - Effects of cholecystectomy on the changes of motility of Beagle dogs' sphincter of Oddi. AB - PURPOSE: To observe the effect of cholecystectomy on the changes of motion pattern of Beagle dogs' sphincter of Oddi (SO), and investigate the modulatory role of nitric oxide (NO) and cholecystokinin (CCK) in the regulation of SO. METHODS: Pressure of common bile duct, SO motility, response to bolus injections of cholecystokinin (CCK, 20 ng/kg and 100 ng/kg), basal pressure (BP) and phasic contraction amplitude (PCA) were measured respectively by manometry in six Beagle dogs before and after cholecystectomy. RESULTS: After cholecystectomy, the pressure and diameter of common bile ducts (CBD) was significantly increased (p<0.01); BP and phasic contraction frequency (PCF) were also increased, however, no significant differences were found between the two groups; the SO motilities was not significantly changed. The relaxation responded to physiological dose of CCK (20ng/kg) was decreased, while bolus-dose of CCK (100ng/kg) induced rapid contractions and decreased PCA after cholecystectomy. The regulation pattern of SO pressure modulated by NO and its inhibitor had changed after cholecystectomy. CONCLUSION: After cholecystectomy in Beagle dogs, no obviously change of motion pattern of SO was observed through self-compensation, but these compensations may lead to some changes of regulation pattern of CCK and NO on SO. PMID- 24760025 TI - Analgesic comparison of systemic lidocaine, morphine or lidocaine plus morphine infusion in dogs undergoing fracture repair. AB - PURPOSE: To compare the postoperative analgesic effects of lidocaine, morphine and lidocaine plus morphine administered by constant rate infusion (CRI) and analyzing their effects on opioid requirements after orthopedic surgery in dogs. METHODS: Twenty-four dogs underwent fracture repairs were premedicated with IM acepromazine (0.05 mg/kg) combined with morphine (0.3mg/kg). Anesthesia was induced with IV propofol (4 to 5 mg/ kg) and maintained with isoflurane. The dogs were randomly assigned to 3 groups and administered a CRI IV of lidocaine (T-L), morphine (T-M) or lidocaine plus morphine (T-LM) at the same doses. Postoperative analgesia was assessed for 24 hours using a Visual Analog Scale (VAS) and the Glasgow Composite Pain Scale (GCPS). Rescue analgesia was performed if the evaluation score exceeded 50% of the VAS and/or 33% of the GCPS. RESULTS: The pain score and postoperative opioid requirements did not differ among the treatments. Rescue analgesia was administered to 1/8 dogs in the T-M and T-LM, and to 3/8 dogs in the T-L. CONCLUSION: Lidocaine, morphine or lidocaine/morphine CRI may be efficacious techniques for pain management in the first 24 hours post surgery. However, the two drugs administered together did not reduce the postoperative opioid requirement in dogs undergoing fracture repair. Key words: Anesthesia. Analgesics. Analgesics, Opioid. Lidocaine. Morphine. Dogs. PMID- 24760026 TI - Reconstruction of abdominal wall defects using small intestinal submucosa coated with gelatin hydrogel incorporating basic fibroblast growth factor. AB - PURPOSE: To construct a new biomaterial-small intestinal submucosa coated with gelatin hydrogel incorporating basic fibroblast growth factor, and to evaluate the new biomaterials for the reconstruction of abdominal wall defects. METHODS: Thirty six Sprague-Dawley rats were used in the animal experiments and randomly divided into three groups. The new biomaterial was constructed by combining small intestinal submucosa with gelatin hydrogel for basic fibroblast growth factor release. Abdominal wall defects were created in rats, and repaired using the new biomaterials (group B), compared with small intestinal submucosa (group S) and ULTRAPROTM mesh (group P). Six rats in each group were sacrificed at three and eight weeks postoperatively to examine the gross effects, inflammatory responses, collagen deposition and neovascularization. RESULTS: After implantation, mild adhesion was caused in groups B and S. Group B promoted more neovascularization than group S at three weeks after implantation, and induced significantly more amount of collagen deposition and better collagen organization than groups S and P at eight weeks after implantation. CONCLUSION: Small intestinal submucosa coated with gelatin hydrogel incorporating basic fibroblast growth factor could promote better regeneration and remodeling of host tissues for the reconstruction of abdominal wall defects. PMID- 24760027 TI - Comparative study of tissue reactivity to n-butyl-2-cyanoacrylate and nylon monofilament thread on pericranium-cutaneous flaps in rats. AB - PURPOSE: To study the repair of pericranium-cutaneous flaps fixed with suture anchored in a skull bone tunnel or N-butyl-2-cyanoacrylate adhesive in Wistar rats with emphasis on the cellular inflammatory response and the production of types I and III collagen. METHODS: The operated region in the cephalic region of Wistar rats was removed minutes before euthanasia, fixed in formalin, and subjected to histological preparation. Slides were stained with hematoxylin-eosin and Picrosirius. Standardized counts of polymorphonuclear and mononuclear cells, fibroblasts, and macrophages were performed, and the percentages of types I and III collagen were determined. Data collection occurred on days 3, 7, 14, 21, and 45 postoperatively. A value of p<0.05 was considered statistically significant. RESULTS: Quantitative analysis of the data showed more fibroblasts in the surgical adhesive group than in the nylon monofilament thread groups (p=0.0211). Qualitative analysis showed higher reactivity in the adhesive group, with a predominance of polymorphonuclear cells from days 3-45 and macrophages from days 3-7. The amount of type I collagen exceeded 80% in the treated and control groups at the end of the experiment. CONCLUSIONS: Subperiosteal detachment triggers a cellular inflammatory response that is amplified using soft tissue fixation methods. The adhesive n-butyl-2-cyanoacrylate was more reactive than the nylon monofilament thread anchored in the skull bone tunnel. PMID- 24760028 TI - The neuroprotective effect of Sulindac after ischemia-reperfusion injury in rats. AB - PURPOSE: To investigate the neuroprotective effects of Sulindac on the hippocampal complex after global cerebral ischemia/reperfusion (I/R) injury in rats. METHODS: Thirty one Sprague-Dawley rats were used, distributed into group I (sham) n:7 were used as control. For group II (n:8), III (n:8) and IV (n:8) rats, cerebral ischemia was performed via the occlusion of bilateral internal carotid artery for 45 minutes and continued with reperfusion process. 0.3 mL/kg/h 0.9 % sodium chloride was infused intraperitoneally to the Group II rats before ischemia, 5MUg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group III rats before ischemia and 5MUg/kg/h/0.3 ml sulindac was infused intraperitoneally to the Group IV rats after ischemia and before reperfusion process. The levels of MDA, GSH and MPO activity were measured in the left hippocampus tissue. The hippocampal tissue of all group members were taken for histopathological study. RESULTS: The MDA and MPO levels increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05). Beside these, the GSH levels decreased from group I (control) to group II (I/R) (P<0.05) and increased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05).The number of apoptotic neurons increased from group I (control) to group II (I/R) (P<0.05) and decreased from group II (I/R) to group III (presulindac + I/R) and IV (postsulindac + I/R) (P<0.05). CONCLUSION: The Sulindac may have neuroprotective effects on ischemic neural tissue to prevent the reperfusion injury after ischemia. PMID- 24760029 TI - Urethral dysfunction due to alloxan-induced diabetes. Urodynamic evaluation and action of sildenafil citrate. AB - PURPOSE: To evaluate the effect of diabetes mellitus and of sildenafil citrate on female urethral function. METHODS: Twenty nine female rats were divided into four groups: G1 - (n=9), normal rats; G2 - (n=6), normal rats treated with sildenafil citrate; G3 - (n=9) rats with alloxan-induced diabetes; G4 - (n=5) rats with alloxan-induced diabetes treated with sildenafil citrate. Under anesthesia, urodynamic evaluation was performed by cystometry and urethral pressure simultaneously. RESULTS: A significant increase in urethral pressure was observed during micturition. CONCLUSION: Sildenafil citrate can partially reduced urethral pressure in diabetic female rats. PMID- 24760030 TI - DNA damage and antioxidant status in medical residents occupationally exposed to waste anesthetic gases. AB - PURPOSE: To investigate the effects of occupational exposure to waste anesthetic gases on genetic material and antioxidant status in professionals during their medical residency. METHODS: The study group consisted of 15 medical residents from Anesthesiology and Surgery areas, of both genders, mainly exposed to isoflurane and to a lesser degree to sevoflurane and nitrous oxide; the control group consisted of 15 young adults not exposed to anesthetics. Blood samples were drawn from professionals during medical residency (eight, 16 and 22 months of exposure to waste anesthetic gases). DNA damage was evaluated by comet assay, and antioxidant defense was assessed by total thiols and the enzymes glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT). RESULTS: When comparing the two groups, DNA damage was significantly increased at all time points evaluated in the exposed group; plasma thiols increased at 22 months of exposure and GPX was higher at 16 and 22 months of exposure. CONCLUSION: Young professionals exposed to waste anesthetic gases in operating rooms without adequate scavenging system have increased DNA damage and changes in redox status during medical residency. There is a need to minimize exposure to inhalation anesthetics and to provide better work conditions. PMID- 24760031 TI - Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney disease and hypertension in humans. AB - Experimentally renal tissue hypoxia appears to play an important role in the pathogenesis of chronic kidney disease (CKD) and arterial hypertension (AHT). In this study we measured renal tissue oxygenation and its determinants in humans using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) under standardized hydration conditions. Four coronal slices were selected, and a multi gradient echo sequence was used to acquire T2* weighted images. The mean cortical and medullary R2* values ( = 1/T2*) were calculated before and after administration of IV furosemide, a low R2* indicating a high tissue oxygenation. We studied 195 subjects (95 CKD, 58 treated AHT, and 42 healthy controls). Mean cortical R2 and medullary R2* were not significantly different between the groups at baseline. In stimulated conditions (furosemide injection), the decrease in R2* was significantly blunted in patients with CKD and AHT. In multivariate linear regression analyses, neither cortical nor medullary R2* were associated with eGFR or blood pressure, but cortical R2* correlated positively with male gender, blood glucose and uric acid levels. In conclusion, our data show that kidney oxygenation is tightly regulated in CKD and hypertensive patients at rest. However, the metabolic response to acute changes in sodium transport is altered in CKD and in AHT, despite preserved renal function in the latter group. This suggests the presence of early renal metabolic alterations in hypertension. The correlations between cortical R2* values, male gender, glycemia and uric acid levels suggest that these factors interfere with the regulation of renal tissue oxygenation. PMID- 24760032 TI - Brain morphology in children with epilepsy and ADHD. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common comorbidity of childhood epilepsy, but the neuroanatomical correlates of ADHD in epilepsy have yet to be comprehensively characterized. METHODS: Children with new and recent-onset epilepsy with (n = 18) and without (n = 36) ADHD, and healthy controls (n = 46) underwent high resolution MRI. Measures of cortical morphology (thickness, area, volume, curvature) and subcortical and cerebellar volumes were compared between the groups using the program FreeSurfer 5.1. RESULTS: Compared to the control group, children with epilepsy and ADHD exhibited diffuse bilateral thinning in the frontal, parietal and temporal lobes, with volume reductions in the brainstem and subcortical structures (bilateral caudate, left thalamus, right hippocampus). There were very few group differences across measures of cortical volume, area or curvature. CONCLUSIONS: Children with epilepsy and comorbid ADHD exhibited a pattern of bilateral and widespread decreased cortical thickness as well as decreased volume of subcortical structures and brainstem. These anatomic abnormalities were evident early in the course of epilepsy suggesting the presence of antecedent neurodevelopmental changes, the course of which remains to be determined. PMID- 24760034 TI - AKAP12 mediates barrier functions of fibrotic scars during CNS repair. AB - The repair process after CNS injury shows a well-organized cascade of three distinct stages: inflammation, new tissue formation, and remodeling. In the new tissue formation stage, various cells migrate and form the fibrotic scar surrounding the lesion site. The fibrotic scar is known as an obstacle for axonal regeneration in the remodeling stage. However, the role of the fibrotic scar in the new tissue formation stage remains largely unknown. We found that the number of A-kinase anchoring protein 12 (AKAP12)-positive cells in the fibrotic scar was increased over time, and the cells formed a structure which traps various immune cells. Furthermore, the AKAP12-positive cells strongly express junction proteins which enable the structure to function as a physical barrier. In in vivo validation, AKAP12 knock-out (KO) mice showed leakage from a lesion, resulting from an impaired structure with the loss of the junction complex. Consistently, focal brain injury in the AKAP12 KO mice led to extended inflammation and more severe tissue damage compared to the wild type (WT) mice. Accordingly, our results suggest that AKAP12-positive cells in the fibrotic scar may restrict excessive inflammation, demonstrating certain mechanisms that could underlie the beneficial actions of the fibrotic scar in the new tissue formation stage during the CNS repair process. PMID- 24760035 TI - Neighbourhood factors and depression among adolescents in four Caribbean countries. AB - BACKGROUND: Past research suggests that perceived neighbourhood conditions may influence adolescents' emotional health. Relatively little research has been conducted examining the association of perceived neighbourhood conditions with depressive symptoms among Caribbean adolescents. This project examines the association of perceived neighbourhood conditions with levels of depressive symptoms among adolescents in Jamaica, the Bahamas, St. Kitts and Nevis, and St. Vincent. METHODS: Adolescents attending grade ten of the academic year 2006/2007 in Jamaica, the Bahamas, St. Vincent, and St. Kitts and Nevis were administered the Neighbourhood Characteristics Questionnaire along with the BDI-II. Social cohesion, attachment to the neighbourhood, neighbourhood quality, neighbourhood crime, and neighbourhood disorder scales were created by summing the relevant subscales of the Neighbourhood Characteristics Questionnaire. Multiple regression analyses were used to examine the relationships of perceived neighbourhood conditions to depressive symptoms. RESULTS: A wide cross-section of tenth grade students in each nation was sampled (n = 1955; 278 from Jamaica, 217 from the Bahamas, 737 St. Kitts and Nevis, 716 from St. Vincent; 52.1% females, 45.6% males and 2.3% no gender reported; 12 to 19 years, mean = 15.3 yrs, sd = .95 yr). Nearly half (52.1%) of all adolescents reported mild to severe symptoms of depression with 29.1% reporting moderate to severe symptoms of depression. Overall, Jamaican adolescents perceived their neighbourhoods in a more positive manner than those in the Bahamas, St. Vincent and St. Kitts and Nevis. Results of a series of hierarchical multiple regression analyses suggested that a different pattern of neighbourhood factors for each island were associated with depressive symptoms. However, neighbourhood factors were more highly associated with depressive symptoms for Jamaican students than for students in the other three islands. CONCLUSIONS: Neighbourhood factors appear to be partially associated with adolescents' self-reports of depressive symptoms. However, other factors may mitigate this relationship. PMID- 24760033 TI - Left and right amygdala - mediofrontal cortical functional connectivity is differentially modulated by harm avoidance. AB - BACKGROUND: The left and right amygdalae are key regions distinctly involved in emotion-regulation processes. Individual differences, such as personality features, may affect the implicated neurocircuits. The lateralized amygdala affective processing linked with the temperament dimension Harm Avoidance (HA) remains poorly understood. Resting state functional connectivity imaging (rsFC) may provide more insight into these neuronal processes. METHODS: In 56 drug-naive healthy female subjects, we have examined the relationship between the personality dimension HA on lateralized amygdala rsFC. RESULTS: Across all subjects, left and right amygdalae were connected with distinct regions mainly within the ipsilateral hemisphere. Females scoring higher on HA displayed stronger left amygdala rsFC with ventromedial prefrontal cortical (vmPFC) regions involved in affective disturbances. In high HA scorers, we also observed stronger right amygdala rsFC with the dorsomedial prefrontal cortex (dmPFC), which is implicated in negative affect regulation. CONCLUSIONS: In healthy females, left and right amygdalae seem implicated in distinct mPFC brain networks related to HA and may represent a vulnerability marker for sensitivity to stress and anxiety (disorders). PMID- 24760036 TI - Asthma and chronic obstructive pulmonary disease (COPD) prevalence and health services use in Ontario Metis: a population-based cohort study. AB - INTRODUCTION: Chronic respiratory diseases cause a significant health and economic burden around the world. In Canada, Aboriginal populations are at increased risk of asthma and chronic obstructive pulmonary disease (COPD). There is little known, however, about these diseases in the Canadian Metis population, who have mixed Aboriginal and European ancestry. A population-based study was conducted to quantify asthma and COPD prevalence and health services use in the Metis population of Ontario, Canada's largest province. METHODS: The Metis Nation of Ontario Citizenship Registry was linked to provincial health administrative databases to measure and compare burden of asthma and COPD between the Metis and non-Metis populations of Ontario between 2009 and 2012. Asthma and COPD prevalence, health services use (general physician and specialist visits, emergency department visits, hospitalizations), and mortality were measured. RESULTS: Prevalences of asthma and COPD were 30% and 70% higher, respectively, in the Metis compared to the general Ontario population (p<0.001). General physician and specialist visits were significantly lower in Metis with asthma, while general physician visits for COPD were significantly higher. Emergency department visits and hospitalizations were generally higher for Metis compared to non-Metis with either disease. All-cause mortality in Metis with COPD was 1.3 times higher compared to non-Metis with COPD (p = 0.01). CONCLUSION: There is a high burden of asthma and COPD in Ontario Metis, with significant prevalence and acute health services use related to these diseases. Lower rates of physician visits suggest barriers in access to primary care services. PMID- 24760037 TI - Cardiac function and outcome in patients with cardio-embolic stroke. AB - BACKGROUND: The relationship between whole spectrum of Ejection fraction (EF) and cardioembolic stroke (CES) outcome has not been fully described yet. Notably, it remains unclear whether borderline EF (41~49%) is related with poor outcome after CES. We sought to evaluate whether lower ejection fraction and borderline EF could predict the outcome in patients with CES. METHOD AND RESULTS: We evaluated the relationship between EF and functional outcome in 437 consecutive patients with CES. EF was introduced as continuous and categorical (EF<=40%, EF 41~49%, EF>=50%) variable. Patients with CES and the subgroup with AF were evaluated separately. Poor short-term outcome (modified Rankin Score>=3at discharge or death within 90 days after stroke onset) and long-term mortality were evaluated. A total of 165 patients (37.8%) had poor short-term outcomes. EF tends to be lower in patients with poor short-term outcome (56.8+/-11.0 vs. 54.8+/-12.0, p value 0.086). Overall cumulative death was136 (31.1%) in all CES patients and 106 (31.7%) in the AF subgroup. In a multivariable model adjusted for possible covariates, the hazard ratio for mortality significantly decreased by 3% for every 1% increase in ejection fraction in CES patients and 2% for every 1% increase in the AF subgroup. Reduced EF (EF<=40%) showed higher mortality (HR 2.61), and those with borderline EF (41~49%) had a tendency of higher mortality (HR 1.65, p-value 0.067)compared with those with normal EF. CONCLUSION: We found a strong association between lower EF and CES outcome. Echocardiographic evaluation helps to better determine the prognosis in CES patients, even in subgroup of patients with AF. PMID- 24760039 TI - A cationic copper(I) iodide cluster MOF exhibiting unusual ligand assisted thermochromism. AB - By employing a tridentate thiophosphoramide ligand, [(NHAQ)3P[double bond, length as m-dash]S] (AQ = 3-quinolinyl), a cationic MOF, {[Cu6I5(L(1))2](OH).3DMF.2.5MeOH}n, was synthesized. Photo-physical studies on the 2D-MOF showed an unusual thermochromic behaviour emitting a blue fluorescence at 298 K due to the AQ chromophore and an orange-yellow phosphorescence at 77 K due to the [Cu6I5](+) unit. PMID- 24760038 TI - IgG1 and IgG4 antibody responses to the Anopheles gambiae salivary protein gSG6 in the sympatric ethnic groups Mossi and Fulani in a malaria hyperhendemic area of Burkina Faso. AB - Human antibody response to the Anopheles gambiae salivary protein gSG6 has recently emerged as a potentially useful tool for malaria epidemiological studies and for the evaluation of vector control interventions. However, the current understanding of the host immune response to mosquito salivary proteins and of the possible crosstalk with early response to Plasmodium parasites is still very limited. We report here the analysis of IgG1 and IgG4 subclasses among anti-gSG6 IgG responders belonging to Mossi and Fulani from Burkina Faso, two ethnic groups which are known for their differential humoral response to parasite antigens and for their different susceptibility to malaria. The IgG1 antibody response against the gSG6 protein was comparable in the two groups. On the contrary, IgG4 titers were significantly higher in the Fulani where, in addition, anti-gSG6 IgG4 antibodies appeared in younger children and the ratio IgG4/IgG1 stayed relatively stable throughout adulthood. Both gSG6-specific IgG1 and IgG4 antibodies showed a tendency to decrease with age whereas, as expected, the IgG response to the Plasmodium circumsporozoite protein (CSP) exhibited an opposite trend in the same individuals. These observations are in line with the idea that the An. gambiae gSG6 salivary protein induces immune tolerance, especially after intense and prolonged exposure as is the case for the area under study, suggesting that gSG6 may trigger in exposed individuals a Th2-oriented immune response. PMID- 24760047 TI - Selection of apoptotic cell specific human antibodies from adult bone marrow. AB - Autoreactive antibodies that recognize neo-determinants on apoptotic cells in mice have been proposed to have protective, homeostatic and immunoregulatory properties, although our knowledge about the equivalent antibodies in humans has been much more limited. In the current study, human monoclonal antibodies with binding specificity for apoptotic cells were isolated from the bone marrow of healthy adults using phage display technology. These antibodies were shown to recognize phosphorylcholine (PC)-associated neo-determinants. Interestingly, three of the four identified apoptotic cell-specific antibody clones were encoded by VH3 region rearrangements with germline or nearly germline configuration without evidence of somatic hypermutation. Importantly, the different identified antibody clones had diverse heavy chain CDR3 and deduced binding surfaces as suggested by structure modeling. This may suggest a potentially great heterogeneity in human antibodies recognizing PC-related epitopes on apoptotic cells. To re-construct the postulated structural format of the parental anti-PC antibody, the dominant clone was also expressed as a recombinant human polymeric IgM, which revealed a substantially increased binding reactivity, with dose dependent and antigen-inhibitable binding of apoptotic cells. Our findings may have implication for improved prognostic testing and therapeutic interventions in human inflammatory disease. PMID- 24760048 TI - The cognitive mechanisms of the SNARC effect: an individual differences approach. AB - Access to mental representations of smaller vs. larger number symbols is associated with leftward vs. rightward spatial locations, as represented on a number line. The well-replicated SNARC effect (Spatial-Numerical Association of Response Codes) reveals that simple decisions about small numbers are facilitated when stimuli are presented on the left, and large numbers facilitated when on the right. We present novel evidence that the size of the SNARC effect is relatively stable within individuals over time. This enables us to take an individual differences approach to investigate how the SNARC effect is modulated by spatial and numerical cognition. Are number-space associations linked to spatial operations, such that those who have greater facility in spatial computations show the stronger SNARC effects, or are they linked to number semantics, such that those showing stronger influence of magnitude associations on number symbol decisions show stronger SNARC effects? Our results indicate a significant correlation between the SNARC effect and a 2D mental rotation task, suggesting that spatial operations are at play in the expression of this effect. We also uncover a significant correlation between the SNARC effect and the distance effect, suggesting that the SNARC is also related to access to number semantics. A multiple regression analysis reveals that the relative contributions of spatial cognition and distance effects represent significant, yet distinct, contributions in explaining variation in the size of the SNARC effect from one individual to the next. Overall, these results shed new light on how the spatial-numerical associations of response codes are influenced by both number semantics and spatial operations. PMID- 24760049 TI - Survival in HIV-infected patients after a cancer diagnosis in the cART Era: results of an italian multicenter study. AB - OBJECTIVES: We studied survival and associated risk factors in an Italian nationwide cohort of HIV-infected individuals after an AIDS-defining cancer (ADC) or non-AIDS-defining cancer (NADC) diagnosis in the modern cART era. METHODS: Multi-center, retrospective, observational study of HIV patients included in the MASTER Italian Cohort with a cancer diagnosis from January 1998 to September 2012. Malignancies were divided into ADC or NADC on the basis of the Centre for Disease Control-1993 classification. Recurrence of cancer and metastases were excluded. Survivals were estimated according to the Kaplan-Meier method and compared according to the log-rank test. Statistically significant variables at univariate analysis were entered in a multivariate Cox regression model. RESULTS: Eight hundred and sixty-six cancer diagnoses were recorded among 13,388 subjects in the MASTER Database after 1998: 435 (51%) were ADCs and 431 (49%) were NADCs. Survival was more favorable after an ADC diagnosis than a NADC diagnosis (10-year survival: 62.7%+/-2.9% vs. 46%+/-4.2%; p = 0.017). Non-Hodgkin lymphoma had lower survival rates than patients with Kaposi sarcoma or cervical cancer (10-year survival: 48.2%+/-4.3% vs. 72.8%+/-4.0% vs. 78.5%+/-9.9%; p<0.001). Regarding NADCs, breast cancer showed better survival (10-year survival: 65.1%+/-14%) than lung cancer (1-year survival: 28%+/-8.7%), liver cancer (5-year survival: 31.9%+/ 6.4%) or Hodgkin lymphoma (10-year survival: 24.8%+/-11.2%). Lower CD4+ count and intravenous drug use were significantly associated with decreased survival after ADCs or NADCs diagnosis. Exposure to cART was found to be associated with prolonged survival only in the case of ADCs. CONCLUSIONS: cART has improved survival in patients with an ADC diagnosis, whereas the prognosis after a diagnosis of NADCs is poor. Low CD4+ counts and intravenous drug use are risk factors for survival following a diagnosis of ADCs and Hodgkin lymphoma in the NADC group. PMID- 24760050 TI - Alkyl caffeates improve the antioxidant activity, antitumor property and oxidation stability of edible oil. AB - Caffeic acid (CA) is distributed widely in nature and possesses strong antioxidant activity. However, CA has lower solubility in non-polar media, which limits its application in fat-soluble food. To increase the lipophilicity of natural antioxidant CA, a series of alkyl caffeates were synthesized and their antioxidant and antitumor activities were investigated. The antioxidant parameters, including the induction period, acid value and unsaturated fatty acid content, of the alkyl caffeates in edible oil were firstly investigated. The results indicated that alkyl caffeates had a lower DPPH IC50 (14-23 uM) compared to CA, dibutyl hydroxy toluene (BHT) and Vitamin C (24-51 uM), and significantly inhibited four human cancer cells (SW620, SW480, SGC7901 and HepG2) with inhibition ratio of 71.4-78.0% by a MTT assay. With regard to the induction period and acid value assays, methyl and butyl caffeates had higher abilities than BHT to restrain the oxidation process and improve the stability of edible oil. The addition of ethyl caffeate to oil allowed maintenance of a higher unsaturated fatty acid methyl ester content (68.53%) at high temperatures. Overall, the alkyl caffeats with short chain length (n<5) assessed better oxidative stability than those with long chain length. To date, this is the first report to the correlations among the antioxidant activity, anticancer activity and oxidative stability of alkyl caffeates. PMID- 24760051 TI - An instrumented pendulum system for measuring energy absorption during fracture insult to large animal joints in vivo. AB - For systematic laboratory studies of bone fractures in general and intra articular fractures in particular, it is often necessary to control for injury severity. Quantitatively, a parameter of primary interest in that regard is the energy absorbed during the injury event. For this purpose, a novel technique has been developed to measure energy absorption in experimental impaction. The specific application is for fracture insult to porcine hock (tibiotalar) joints in vivo, for which illustrative intra-operative data are reported. The instrumentation allowed for the measurement of the delivered kinetic energy and of the energy passed through the specimen during impaction. The energy absorbed by the specimen was calculated as the difference between those two values. A foam specimen validation study was first performed to compare the energy absorption measurements from the pendulum instrumentation versus the work of indentation performed by an MTS machine. Following validation, the pendulum apparatus was used to measure the energy absorbed during intra-articular fractures created in 14 minipig hock joints in vivo. The foam validation study showed close correspondence between the pendulum-measured energy absorption and MTS-performed work of indentation. In the survival animal series, the energy delivered ranged from 31.5 to 48.3 Js (41.3+/-4.0, mean+/-s.d.) and the proportion of energy absorbed to energy delivered ranged from 44.2% to 64.7% (53.6%+/-4.5%). The foam validation results support the reliability of the energy absorption measure provided by the instrumented pendulum system. Given that a very substantial proportion of delivered energy passed--unabsorbed--through the specimens, the energy absorption measure provided by this novel technique arguably provides better characterization of injury severity than is provided simply by energy delivery. PMID- 24760052 TI - Interpersonal trust across six Asia-Pacific countries: testing and extending the 'high trust society' and 'low trust society' theory. AB - BACKGROUND: Trust is regarded as a necessary component for the smooth running of society, although societal and political modernising processes have been linked to an increase in mistrust, potentially signalling social and economic problems. Fukuyama developed the notion of 'high trust' and 'low trust' societies, as a way of understanding trust within different societies. The purpose of this paper is to empirically test and extend Fukuyama's theory utilising data on interpersonal trust in Taiwan, Hong Kong, South Korea, Japan, Australia and Thailand. This paper focuses on trust in family, neighbours, strangers, foreigners and people with a different religion. METHODS: Cross-sectional surveys were undertaken in 2009-10, with an overall sample of 6331. Analyses of differences in overall levels of trust between countries were undertaken using Chi square analyses. Multivariate binomial logistic regression analysis was undertaken to identify socio-demographic predictors of trust in each country. RESULTS: Our data indicate a tripartite trust model: 'high trust' in Australia and Hong Kong; 'medium trust' in Japan and Taiwan; and 'low trust' in South Korea and Thailand. Trust in family and neighbours were very high across all countries, although trust in people with a different religion, trust in strangers and trust in foreigners varied considerably between countries. The regression models found a consistent group of subpopulations with low trust across the countries: people on low incomes, younger people and people with poor self-rated health. The results were conflicting for gender: females had lower trust in Thailand and Hong Kong, although in Australia, males had lower trust in strangers, whereas females had lower trust in foreigners. CONCLUSION: This paper identifies high, medium and low trust societies, in addition to high and low trusting population subgroups. Our analyses extend the seminal work of Fukuyama, providing both corroboration and refutation for his theory. PMID- 24760053 TI - Imbalance between pro and anti-oxidant mechanisms in perivascular adipose tissue aggravates long-term high-fat diet-derived endothelial dysfunction. AB - BACKGROUND: The hypothesis of this study is that long-term high-fat diets (HFD) induce perivascular adipose tissue (PVAT) dysfunction characterized by a redox imbalance, which might contribute to aggravate endothelial dysfunction in obesity. METHODS AND RESULTS: C57BL/6J mice were fed either control or HFD (45% kcal from fat) for 32 weeks. Body weight, lumbar and mesenteric adipose tissue weights were significantly higher in HFD animals compared to controls. The anticontractile effect of PVAT in mesenteric arteries (MA) was lost after 32 week HFD and mesenteric endothelial-dependent relaxation was significantly impaired in presence of PVAT in HFD mice (Emax = 71.0+/-5.1 vs Emax = 58.5+/-4.2, p<0.001). The inhibitory effect of L-NAME on Ach-induced relaxation was less intense in the HFD group compared with controls suggesting a reduction of endothelial NO availability. Expression of eNOS and NO bioavailability were reduced in MA and almost undetectable in mesenteric PVAT of the HFD group. Superoxide levels and NOX activity were higher in PVAT of HFD mice. Apocynin only reduced contractile responses to NA in HFD animals. Expression of ec-SOD and total SOD activity were significantly reduced in PVAT of HFD mice. No changes were observed in Mn-SOD, Cu/Zn-SOD or catalase. The ratio [GSSG]/([GSH]+[GSSG]) was 2-fold higher in the mesenteric PVAT from HFD animals compared to controls. CONCLUSIONS: We suggest that the imbalance between pro-oxidant (NOX, superoxide anions, hydrogen peroxide) and anti-oxidant (eNOS, NO, ecSOD, GSSG) mechanisms in PVAT after long term HFD might contribute to the aggravation of endothelial dysfunction. PMID- 24760054 TI - Leg extension power is a pre-disaster modifiable risk factor for post-traumatic stress disorder among survivors of the Great East Japan Earthquake: a retrospective cohort study. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a common psychological problem following natural disasters. Although pre-disaster risk factors are important for early detection and proactive support, the examination of such has been limited to sociodemographic factors, which were largely unaffected by the disasters. We examined the association between pre-disaster physical functioning and lifestyle and PTSD symptoms five months after the earthquake in the Great East Japan Earthquake survivors who were participating in a pre-existing cohort study. METHODS: We designed a retrospective cohort study of a cooperative association in Sendai from August 2010 to August 2011. In 2010, lifestyle, physical condition, and sociodemographic factors were examined by self-reported questionnaires completed by 522 employees of this organization. We also measured the leg extension power of all the participants. PTSD symptoms were evaluated by the Japanese version of the Impact of Event Scale-Revised (IES-R-J) following the earthquake of 2011. RESULTS: In multivariate linear regression analysis, leg extension power (beta = -0.128, P = 0.025), daily drinking (beta = 0.203, P = 0.006), and depressive symptoms (beta = 0.139, P = 0.008) were associated with total score of the IES-R-J among men. Moreover, for the IES-R-J subscale, leg extension power was also negatively associated with Intrusion (beta = -0.114, P = 0.045) and Hyperarousal (beta = -0.163, P = 0.004) after adjusting for all other significant variables. For women, hypertension (beta = 0.226, P = 0.032) and depressive symptoms (beta = 0.205, P = 0.046) were associated with the total score of the IES-R-J. CONCLUSIONS: Leg extension power is a potentially modifiable pre-disaster risk factor among men for attenuating the severity of PTSD symptoms associated with great disasters such as the Great East Japan Earthquake among men. PMID- 24760056 TI - Surgical outcomes and prognostic factors in patients with synchronous colorectal liver metastases. AB - CONTEXT: Colorectal cancer is the second most prevalent cancer worldwide, and the liver is the most common site of metastases. Surgical resection of colorectal liver metastases provides the sole possibility of cure and the best odds of long term survival. Objectives To describe surgical outcomes and identify features associated with disease prognosis in patients submitted to synchronous colorectal cancer liver metastasis resection. METHODS: Retrospective study of 59 patients who underwent surgery for synchronous colorectal cancer liver metastasis. Actuarial survival and disease-free survival were assessed, depending on the prognostic variable of interest. RESULTS: Postoperative mortality and morbidity rates were 3.38% and 30.50% respectively. Five-year disease-free survival was estimated at 23.96%, and 5-year overall survival, at 38.45%. Carcinoembryonic antigen levels >= 50 ng/mL and presence of three or more liver metastasis were limiting factors for disease-free survival, but did not affect late survival. No patient with liver metastases and extrahepatic disease had disease-free interval longer than 20 months, but this had no significance or impact on long-term survival. None of the prognostic factors assessed had an impact on late survival, although no patients with more than three liver metastases survived beyond 40 months. CONCLUSIONS: Although Carcinoembryonic antigen levels and number of metastases are prognostic factors that limit disease-free survival, they had no impact on 5-year survival and, therefore, should not determine exclusion from surgical treatment. Resection is the best treatment option for synchronous colorectal liver metastases, and even for patients with multiple metastases, large tumors and extrahepatic disease, it can provide long-term survival rates over 38%. PMID- 24760057 TI - Biochemical nutritional profile of liver cirrhosis patients with hepatocellular carcinoma. AB - CONTEXT: Liver cirrhosis patients with hepatocellular carcinoma present nutritional alterations and metabolic disorders that negatively impact the prognosis. OBJECTIVE: The objective is to identify alterations in the metabolism of macro and micronutrients among liver cirrhosis patients with and without hepatocellular carcinoma and their relation to the Child-Turcote-Pugh score and Barcelona Clinic Liver Cancer staging. METHODS: Analytical transversal study, with 31 hepatocellular carcinoma patients and 48 liver cirrhosis patients. Laboratorial exams were carried out. The existence of an association between the biochemical parameters and the disease severity as well as the presence of hepatocellular carcinoma was assessed. RESULTS: The metabolic-nutritional profile of liver cirrhosis patients caused by the hepatitis C virus and hepatocellular carcinoma showed alterations, specifically the lipid (total cholesterol, HDL and triglycerides), protein (albumin, creatinine and uric acid), iron (transferrin, iron and ferritin saturation), hematocrit and hemoglobin, zinc and B12 vitamin profiles. There is a relation between nutritional biochemical markers and the Child-Turcote-Pugh, as well as Barcelona Clinic Liver Cancer staging. CONCLUSIONS: Considering the existence of alterations in the metabolism of nutrients in liver cirrhosis patients with and without hepatocellular carcinoma, and also that conventional nutritional assessment methods present limitations for this population, the biochemical laboratorial exams are valid to complement the diagnosis of the nutritional state in a quick and practical manner. PMID- 24760058 TI - Exhaled and plasma nitrite: a comparative study among healthy, cirrhotic and liver transplant patients. AB - CONTEXT: There is a relative lack of studies about exhaled nitrite (NO2-) concentrations in cirrhotic and transplanted patients. OBJECTIVE: Verify possible differences and correlations between the levels of NO2-, measured in plasma and exhaled breath condensate collected from patients with cirrhosis and liver transplant. METHOD: Sixty adult male patients, aged between 27 and 67 years, were subdivided into three groups: a control group comprised of 15 healthy volunteers, a cirrhosis group composed of 15 volunteers, and a transplant group comprised of 30 volunteers. The NO2- concentrations were measured by chemiluminescence. RESULTS: 1) The analysis of plasma NO2- held among the three groups showed no statistical significance. 2) The comparison between cirrhotic and control groups, control and transplanted and cirrhotic and transplanted was not statistically significant. 3) The measurements performed on of NO2- exhaled breath condensate among the three groups showed no statistical difference. 4) When comparing the control group samples and cirrhotic, control and transplanted and cirrhotic and transplanted, there was no significant changes in the concentrations of NO2-. CONCLUSION: No correlations were found between plasma and exhaled NO2-, suggesting that the exhaled NO2- is more reflective of local respiratory NO release than the systemic circulation. PMID- 24760059 TI - Control of hypertension after roux-en-y gastric bypass among obese diabetic patients. AB - CONTEXT: Hypertension is a common disorder in general practice and has a widely known association with type 2 diabetes mellitus. Low adhesion to clinical treatment may lead to poor results. Obesity surgery can bring early and relevant resolution rates of both morbidities. OBJECTIVE: To describe hypertension evolution after Roux-en-Y gastric bypass in patients with type 2 diabetes mellitus. METHOD: Descriptive observational study designed as a historical cohort of 90 subjects with hypertension and diabetes who underwent Roux-en-Y gastric bypass and were evaluated before and after surgery. RESULTS: It was observed a hypertension resolution rate of 85.6% along with markedly decrease in anti hypertensive usage. Mean resolution time was 3.2 months. Resolution was associated with homeostasis model assessment - insulin resistance, preoperative fasting insulin, anti-hypertensive usage, hypertension time, body mass index and percentage of weight loss. Resolution of hypertension was not statistically associated with diabetes remission within this sample. CONCLUSION: Roux-en-Y gastric bypass was a safe and effective therapeutic tool to achieve hypertension resolution in patients who also had diabetes mellitus. PMID- 24760060 TI - Functional assessment of older obese patients candidates for bariatric surgery. AB - CONTEXT: Obesity in the elderly is associated with exacerbation of functional decline (dependency), that occurs with aging, because of decreased muscle mass and strength, and increased joint dysfunction. Consequently, there is progressive loss of independence, autonomy, chronic pain and impaired quality of life. The weight loss can bring benefits in all these aspects, especially when accompanied by exercises. Elderly patients with morbid obesity may be submitted to surgical treatment, taking into account that the massive weight loss, eventually caused by bariatric surgery, may exacerbate the loss of muscle mass and nutritional complications that may bring harm to the overall health and quality of life of these patients. The functional assessment of elderly patients, candidates for bariatric surgery and the extent to which surgery can bring benefits to the patients, in the field of functionality, has still to be determined. OBJECTIVE: To describe profile functionality in obese elderly referred to a bariatric surgery program. METHODS: Patients with age >= 60 and BMI >= 35 underwent comprehensive geriatric assessment that evaluates co morbidities, medication use, ability to perform basic activities of daily living and instrumental activities of daily living, and the "Timedupandgo" test to evaluate mobility, whose cut-off point was <= 10 seconds. Statistical analysis was performed in order to see if there is a positive correlation of dependency with BMI and age (over or under 65 years). Results Forty subjects have completed evaluation. The mean age was 64.1 years (60-72) and 75% were women. They had an average weight of 121.1 kg (72.7 204) and a mean BMI of 47.2 kg/m2 (35.8-68.9). 16 patients (40%) have shown dependency for activities of daily living, 19 (47,5%) for instrumental activities of daily living and 20 patients (50%) had a "Timedupandgo" test over 10 seconds. Statistical analysis (t-Student, Mann-Whitney, Binary Logistic Regression) has shown positive correlation of dependency in activities of daily living for BMI >49 kg/m2, dependency in instrumental activities of daily living for BMI >46,5 kg/m2, and "Timedupandgo" test greater than 10 seconds for BMI >51 kg/m2 (P<0,05). No dependency difference was observed for patients over or under 65 years age. CONCLUSIONS: Functional decline is observed in almost half of the morbid obese patients over 60 years old. It is related to increasing BMI (BMI >46,5 kg/m2) but not related to age (60 to 65 years or over 65 years). Functional decline should be considered a co-morbidity in the elderly obese patients and should be assessed before bariatric surgery in this population. PMID- 24760061 TI - Low mortality rate in 97 consecutive pancreaticoduodenectomies: the experience of a group. AB - CONTEXT: Pancreaticoduodenectomy is the procedure of choice for resectable cancer of the periampullary region. These tumors account for 4% of deaths from cancer, being referred to as one of the lowest survival rates at 5 years. Surgery remains a complex procedure with substantial morbidity and mortality. Despite reports of up to 30% mortality rates, in centers of excellence it have been identified as less than 5%. Recent studies show that pancreaticojejunostomy represents the "Achilles' heel" of the procedure. OBJECTIVE: To evaluate the post-operative 30 days morbidity and mortality rates. METHODS: Retrospective analysis of 97 consecutive resected patients between July, 2000 and December, 2012. All patients were managed by the same group, and data were obtained from specific database service. The main objective was to evaluate the 30-day mortality rate, but we also studied data of surgical specimen, need for vascular resection and postoperative complications (gastric stasis, pancreatic fistula, pneumonia and reoperation rate). RESULTS: Thirty-day mortality rate was 2.1% (two patients). Complete resection with no microscopic residual tumor was obtained in 93.8% of patients, and in 67.3% of cases pathology did not detected metastatic nodes. Among postoperative complications were reported 6% of prolonged gastric stasis, 10.3% of pneumonia, 10.3% of pancreatic fistula and 1% of infection in the drain pathway. Two patients underwent reoperation due to bleeding and infected hematoma caused by pancreatic fistula, and another for intestinal obstruction because of adhesions at postoperative day 12. CONCLUSIONS: The pancreaticoduodenectomy as treatment procedure for periampullary cancers has a low morbidity and mortality rate in services with experience in Hepato-Pancreato-Biliary surgery, remaining as first-line treatment in resectable patients. PMID- 24760062 TI - Correlation between platelet count and both liver fibrosis and spleen diameter in patients with schistosomiasis mansoni. AB - CONTEXT: Studies have described the correlation between platelet count and the stages of fibrosis in chronic viral hepatitis, but few publications have studied this correlation in Schistosomiasis mansoni. OBJECTIVES: Therefore, this study aimed to correlate platelet count with both the periportal fibrosis pattern and spleen diameter evaluated by ultrasound exam in patients with Schistosomiasis mansoni. METHODS: Patients with Schistosomiasis mansoni were evaluated by abdominal ultrasound by a single examiner for the determination of periportal fibrosis pattern (Niamey classification) and spleen diameter. Platelet counts were performed in an automated cell counter. RESULTS: One hundred eighty-seven patients with Schistosomiasis mansoni (mean age: 50.2 years) were included in the study, 114 of whom (61%) were women. Based on the Niamey classification, the ultrasound analysis revealed that 37, 64, 64 and 22 patients exhibited patterns C, D, E and F, respectively. In these four groups, the mean number of platelets was 264, 196, 127 and 103 x 109/L and mean spleen diameter was 9.2, 11.9, 14.9 and 16.2 centimeters, respectively. A reduction in platelet count was significantly associated with both the progression of the periportal fibrosis and the increase in spleen size. CONCLUSIONS: Platelet count in patients with Schistosomiasis mansoni was inversely correlated with the severity of periportal fibrosis and spleen diameter. PMID- 24760063 TI - Adalimumab for maintenance therapy for one year in Crohn's disease: results of a Latin American single-center observational study. AB - CONTEXT: Adalimumab is a fully-human antibody that inhibits TNF alpha, with a significant efficacy for long-term maintenance of remission. Studies with this agent in Latin American Crohn's disease patients are scarce. OBJECTIVES: The objective of this study was to outline clinical remission rates after 12 months of adalimumab therapy for Crohn's disease patients. METHODS: Retrospective, single-center, observational study of a Brazilian case series of Crohn's disease patients under adalimumab therapy. Variables analyzed: demographic data, Montreal classification, concomitant medication, remission rates after 1, 4, 6 and 12 months. Remission was defined as Harvey-Bradshaw Index <= 4, and non-responder imputation and last-observation-carried-forward analysis were used. The influence of infliximab on remission rates was analyzed by Fischer and Chi-square tests (P<0.05). RESULTS: Fifty patients, with median age of 35 years at therapy initiation, were included. Remission rates after 12 months of therapy were 54% under non-responder-imputation and 88% under last-observation-carried-forward analysis. After 12 months, remission on patients with previous infliximab occurred in 69.23% as compared to 94.59% in infliximab-naive patients (P = 0.033). CONCLUSIONS: Adalimumab was effective in maintaining clinical remission after 12 months of therapy, with an adequate safety profile, and was also more effective in infliximab naive patients. PMID- 24760064 TI - Analysis of the survival of cirrhotic patients enlisted for liver transplantation in the pre- and post-MELD era in southern Brazil. AB - CONTEXT: Transplantation is the only cure for decompensated cirrhosis. Model for End-Stage Liver Disease (MELD) is used in liver allocation. OBJECTIVES: Comparing survival of enlisted populations in pre- and post-MELD eras and estimating their long-term survival. METHODS: This is a retrospective study of cirrhotics enlisted for transplantation during pre- and post-MELD eras. Survival curves were generated using Kaplan-Meier's model. Cox's model was used to determine risk factors for mortality. Exponential, Weibull's, normal-log and Gompertz's models were used to estimate long-term survival. RESULTS: The study included 162 patients enlisted in pre-MELD era and 184 in post-MELD period. Kaplan-Meier's survival curve of patients enlisted in post-MELD era was better than that of pre MELD period (P = 0.009). This difference remained for long-term estimates, with a survival of 53.54% in 5 years and 44.64% in 10 years for patients enlisted in post-MELD era and of 43.17% and 41.75% for pre-MELD period. Era in which patients had been enlisted (P = 0.010) and MELD score at enlistment (P<0.001) were independently associated to survival with hazard ratios of 0.664 (95% CI confidence interval = 0.487-0.906) and 1.069 (95% CI = 1.043-1.095). CONCLUSIONS: MELD-based transplantation policy is superior to chronology-based one, promoting better survival for enlisted patients, even in long-term. PMID- 24760065 TI - Biliary atresia: evaluation on two distinct periods at a reference pediatric service. AB - CONTEXT: Biliary atresia is a progressive, idiopathic, fibro-obliterative disease of the extrahepatic biliary tree that presents with biliary obstruction exclusively in the neonatal period. OBJECTIVES: To assess the differences regarding age at referral, age at surgery, duration of propaedeutics and waiting time for surgery between two groups of infants in different periods. METHODS: Retrospective study of infants diagnosed with biliary atresia on two periods: 1983-1993 and 1998-2011. RESULTS: Biliary atresia was diagnosed in 129 infants, being 48 in casuistic I and 81 in casuistic II. The median age at admission was 94 and 60 days, respectively (P = 0.0001). On evaluating patients who had undergone portoenterostomy before 120 days of age, no difference was observed regarding the duration of propaedeutics or waiting time for surgery (P = 0.15), but difference was found when comparing the age at surgery (P = 0.002). Among those infants with no biliary flow and without liver transplantation or death after 18 post-operative months, the estimated probability of survival was 44.6% and 38.7% in casuistics I and II, respectively. In casuistic I, all infants who showed biliary flow were alive during the observation period and, in casuistic II, 80.3% were alive after 7 years of follow-up. CONCLUSIONS: Even though patients were admitted and treated earlier, it is clear that surgery could be done sooner. Delay in referral and timely propaedeutics were the main contributors. PMID- 24760066 TI - Testosterone changes in patients with liver cirrhosis before and after orthotopic liver transplantation and its correlation with MELD. AB - CONTEXT: Hypogonadism is a common clinical situation in male patients with liver cirrhosis. OBJECTIVES: The aim of the present study was to evaluate the effects of orthotopic liver transplantation on testosterone, free testosterone and sex hormone-binding globulin in male with advanced liver disease and also to determine the relationship of these changes with Model for End-stage Liver Disease (MELD) score. METHODS: In a prospective study, serum levels of testosterone, free testosterone and sex hormone-binding globulin of 30 male adult patients with end-stage liver disease were measured 2 to 4 hours before and 6 months after orthotopic liver transplantation. RESULTS: Total testosterone levels increased after orthotopic liver transplantation and the number of patients with normal testosterone levels increased from 18 to 24. Free testosterone mean level in the pre-transplant group was 7.8 pg/mL and increased to 11.5 pg/mL (P = 0.10) and sex hormone-binding globulin level decreased after orthotopic liver transplantation returning to normal levels in MELD <= 18 - group (A) (P<0.05). CONCLUSIONS: Serum level changes of testosterone, free testosterone and sex hormone-binding globulin are more pronounced in cirrhotic males with MELD <= 18. Serum levels of testosterone and free testosterone increase and serum levels of sex hormone-binding globulin decrease after orthotopic liver transplantation. PMID- 24760067 TI - Anti-ulcer activity of leguminosae plants. AB - CONTEXT: Ulcer is the most common gastrointestinal disturbance resulting from an inadequate gastric mucosal defense. Several drugs are available in the market to address the disease; however, these drugs are associated with unnecessary side effects. OBJECTIVES: Previous research have confirmed the efficacy of plant extracts for possible treatment of the disease. This research aims to evaluate the anti-ulcer properties of medicinal plants. METHODS: Methanol extracts from the leaves of Intsia bijuga, Cynometra ramiflora, Tamarindus indica, Cassia javanica, Cassia fistula, Bauhini purpurea, Senna spectabilis, Senna siamea and Saraca thaipingensis were evaluated for their anti-ulcer activity using HCl ethanol as ulcerogen. RESULTS: All extracts showed inhibitory activity with I. bijuga, T. indica, S. spectabilis and S. thaipingensis exhibiting more than 50% inhibition. S. thaipingensis showed the highest activity at 80%. S. spectabilis and S. thaipingensis were partitioned further into hexane, ethyl acetate and aqueous fractions. The aqueous and ethyl acetate fractions of S. spectabilis showed significant increased in its activity while the hexane and ethyl acetate fractions of S. thaipingensis gave higher activity than its aqueous portions. CONCLUSIONS: We conclude that plant extracts are potential sources of new anti ulcer agents. PMID- 24760068 TI - Colonoscopy and carcinoembryonic antigen variations. AB - CONTEXT: Colonoscopy is essential for synchronous and metachronous cancer detection. Carcinoembryonic antigen is a colorectal cancer tumor marker, important as a follow-up tool in patients with previous colorectal cancer. False positive carcinoembryonic antigen elevation results in multiples exams and in patient anxiety. In literature, there is reference to transient carcinoembryonic antigen increase with colonoscopy. OBJECTIVE: To evaluate the influence of bowel preparation and colonoscopy in carcinoembryonic antigen blood levels. METHODS: We prospectively studied subjects that underwent routine colonoscopy in our institution. Blood samples were collected (1) before bowel cleaning, (2) before colonoscopy and (3) immediately after colonoscopy. Blood carcinoembryonic antigen levels were determined by "Sandwich" immunoassay. The statistical methods used were the paired t-test and ANOVA. RESULTS: Thirty-seven patients (22M/15F) were included; age range 28-84 (mean 56 years). Mean carcinoembryonic antigen values were 1.9, 2 and 1.8 for (1), (2) and (3), respectively. An increase in value (2) compared with (1) was observed in 20/37 patients (P = 0.018), mainly in younger patients and in patients requiring more endoluminal interventions. In 29/37 patients, the CEA value decreased from (2) to (3) (P = 1.3x10-7). CONCLUSIONS: A trend for carcinoembryonic antigen increase after bowel cleaning was observed, especially in younger patients and in patients with more endoluminal interventions, but without clinical meaning. PMID- 24760069 TI - Hepatitis and pneumonitis during adalimumab therapy in Crohn disease: mind the histoplasmosis! AB - CONTEXT: Tumor necrosis factor-alpha (TNF-alpha) inhibitor therapy plays a pivotal role in the management of moderate to severe inflammatory bowel disease. Because of the role of TNF-alpha in the host defenses, anti-TNF therapy has been associated with an increase the risks of granulomatous infections. OBJECTIVE: To report the first case of adalimumab-associated invasive histoplasmosis presenting as an acute hepatitis-like syndrome and febrile pneumonitis in a patient with Crohn's disease. METHOD: Case report of a patient with progressive histoplasmosis confirmed by percutaneous fine needle aspiration biopsy lung and urine Histoplasma antigen. RESULTS: We present the case of a young man with CD who developed pneumonia and acute hepatitis-like features caused by Histoplasma capsulatum infection during adalimumab therapy. To the best of our knowledge, this acute hepatitis-like manifestation has never been reported as a presentation of the histoplasmosis in patients with Crohn's disease. CONCLUSIONS: This case underscores the potential risk for serious infection that may arise in this setting and should alert clinicians to the need to consider the histoplasmosis diagnosis in patients presenting with acute hepatitis-like syndrome associated with prolonged febrile illness or pneumonitis during therapy with anti-TNF-alpha antibodies. PMID- 24760071 TI - A truncated form of rod photoreceptor PDE6 beta-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the gamma-subunit. AB - Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin alpha-subunit (GNAT1), and cGMP phosphodiesterase type 6 beta-subunit (PDE6B). In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB. The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization. Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation, the duplication, c.928 9_940dup resulting in a tyrosine to cysteine substitution at codon 314, a frameshift, and a premature termination (p.Tyr314Cysfs*50). To understand the mechanism of the PDE6beta1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6beta1-313. We found that PDE6beta1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory gamma-subunit (Pgamma), and interferes with the inhibition of normal PDE6alphabeta catalytic subunits by Pgamma. Moreover, both truncated forms of the PDE6beta protein, PDE6beta1-313 and PDE6beta1-314fs*50 expressed in rods of transgenic X. laevis are targeted to the phototransduction compartment. We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds Pgamma and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation. PMID- 24760072 TI - Genome-wide analysis of the bZIP transcription factors in cucumber. AB - bZIP proteins are one of the largest transcriptional regulators playing crucial roles in plant development, physiological processes, and biotic/abiotic stress responses. Despite the availability of recently published draft genome sequence of Cucumis sativus, no comprehensive investigation of these family members has been presented for cucumber. We have identified 64 bZIP transcription factor encoding genes in the cucumber genome. Based on structural features of their encoded proteins, CsbZIP genes could be classified into 6 groups. Cucumber bZIP genes were expanded mainly by segmental duplication rather than tandem duplication. Although segmental duplication rate of the CsbZIP genes was lower than that of Arabidopsis, rice and sorghum, it was observed as a common expansion mechanism. Some orthologous relationships and chromosomal rearrangements were observed according to comparative mapping analysis with other species. Genome wide expression analysis of bZIP genes indicated that 64 CsbZIP genes were differentially expressed in at least one of the ten sampled tissues. A total of 4 CsbZIP genes displayed higher expression values in leaf, flowers and root tissues. The in silico micro-RNA (miRNA) and target transcript analyses identified that a total of 21 CsbZIP genes were targeted by 38 plant miRNAs. CsbZIP20 and CsbZIP22 are the most targeted by miR165 and miR166 family members, respectively. We also analyzed the expression of ten CsbZIP genes in the root and leaf tissues of drought-stressed cucumber using quantitative RT-PCR. All of the selected CsbZIP genes were measured as increased in root tissue at 24th h upon PEG treatment. Contrarily, the down-regulation was observed in leaf tissues of all analyzed CsbZIP genes. CsbZIP12 and CsbZIP44 genes showed gradual induction of expression in root tissues during time points. This genome-wide identification and expression profiling provides new opportunities for cloning and functional analyses, which may be used in further studies for improving stress tolerance in plants. PMID- 24760073 TI - Your morals depend on language. AB - Should you sacrifice one man to save five? Whatever your answer, it should not depend on whether you were asked the question in your native language or a foreign tongue so long as you understood the problem. And yet here we report evidence that people using a foreign language make substantially more utilitarian decisions when faced with such moral dilemmas. We argue that this stems from the reduced emotional response elicited by the foreign language, consequently reducing the impact of intuitive emotional concerns. In general, we suggest that the increased psychological distance of using a foreign language induces utilitarianism. This shows that moral judgments can be heavily affected by an orthogonal property to moral principles, and importantly, one that is relevant to hundreds of millions of individuals on a daily basis. PMID- 24760074 TI - Training-dependent associative learning induced neocortical structural plasticity: a trace eyeblink conditioning analysis. AB - Studies utilizing general learning and memory tasks have suggested the importance of neocortical structural plasticity for memory consolidation. However, these learning tasks typically result in learning of multiple different tasks over several days of training, making it difficult to determine the synaptic time course mediating each learning event. The current study used trace-eyeblink conditioning to determine the time course for neocortical spine modification during learning. With eyeblink conditioning, subjects are presented with a neutral, conditioned stimulus (CS) paired with a salient, unconditioned stimulus (US) to elicit an unconditioned response (UR). With multiple CS-US pairings, subjects learn to associate the CS with the US and exhibit a conditioned response (CR) when presented with the CS. Trace conditioning is when there is a stimulus free interval between the CS and the US. Utilizing trace-eyeblink conditioning with whisker stimulation as the CS (whisker-trace-eyeblink: WTEB), previous findings have shown that primary somatosensory (barrel) cortex is required for both acquisition and retention of the trace-association. Additionally, prior findings demonstrated that WTEB acquisition results in an expansion of the cytochrome oxidase whisker representation and synaptic modification in layer IV of barrel cortex. To further explore these findings and determine the time course for neocortical learning-induced spine modification, the present study utilized WTEB conditioning to examine Golgi-Cox stained neurons in layer IV of barrel cortex. Findings from this study demonstrated a training-dependent spine proliferation in layer IV of barrel cortex during trace associative learning. Furthermore, findings from this study showing that filopodia-like spines exhibited a similar pattern to the overall spine density further suggests that reorganization of synaptic contacts set the foundation for learning-induced neocortical modifications through the different neocortical layers. PMID- 24760075 TI - Notch-1 signaling promotes the malignant features of human breast cancer through NF-kappaB activation. AB - The aberrant activation of Notch-1 signaling pathway has been proven to be associated with the development and progression of cancers. However, the specific roles and the underlying mechanisms of Notch-1 signaling pathway on the malignant behaviors of breast cancer are poorly understood. In this study, using multiple cellular and molecular approaches, we demonstrated that activation of Notch-1 signaling pathway promoted the malignant behaviors of MDA-MB-231 cells such as increased cell proliferation, colony formation, adhesion, migration, and invasion, and inhibited apoptosis; whereas deactivation of this signaling pathway led to the reversal of the aforementioned malignant cellular behaviors. Furthermore, we found that activation of Notch-1 signaling pathway triggered the activation of NF-kappaB signaling pathway and up-regulated the expression of NF kappaB target genes including MMP-2/-9, VEGF, Survivin, Bcl-xL, and Cyclin D1. These results suggest that Notch-1 signaling pathway play important roles in promoting the malignant phenotype of breast cancer, which may be mediated partly through the activation of NF-kappaB signaling pathway. Our results further suggest that targeting Notch-1 signaling pathway may become a newer approach to halt the progression of breast cancer. PMID- 24760077 TI - Multimorbidity and quality of preventive care in Swiss university primary care cohorts. AB - BACKGROUND: Caring for patients with multimorbidity is common for generalists, although such patients are often excluded from clinical trials, and thus such trials lack of generalizability. Data on the association between multimorbidity and preventive care are limited. We aimed to assess whether comorbidity number, severity and type were associated with preventive care among patients receiving care in Swiss University primary care settings. METHODS: We examined a retrospective cohort composed of a random sample of 1,002 patients aged 50-80 years attending four Swiss university primary care settings. Multimorbidity was defined according to the literature and the Charlson index. We assessed the quality of preventive care and cardiovascular preventive care with RAND's Quality Assessment Tool indicators. Aggregate scores of quality of provided care were calculated by taking into account the number of eligible patients for each indicator. RESULTS: Participants (mean age 63.5 years, 44% women) had a mean of 2.6 (SD 1.9) comorbidities and 67.5% had 2 or more comorbidities. The mean Charlson index was 1.8 (SD 1.9). Overall, participants received 69% of recommended preventive care and 84% of cardiovascular preventive care. Quality of care was not associated with higher numbers of comorbidities, both for preventive care and for cardiovascular preventive care. Results were similar in analyses using the Charlson index and after adjusting for age, gender, occupation, center and number of visits. Some patients may receive less preventive care including those with dementia (47%) and those with schizophrenia (35%). CONCLUSIONS: In Swiss university primary care settings, two thirds of patients had 2 or more comorbidities. The receipt of preventive and cardiovascular preventive care was not affected by comorbidity count or severity, although patients with certain comorbidities may receive lower levels of preventive care. PMID- 24760076 TI - Identification of BDNF sensitive electrophysiological markers of synaptic activity and their structural correlates in healthy subjects using a genetic approach utilizing the functional BDNF Val66Met polymorphism. AB - Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such "synaptogenic" therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error processing, as measured during a flanker task (ERN); and showed increased slow wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans. PMID- 24760078 TI - An association of genotypes and antimicrobial resistance patterns among Salmonella isolates from pigs and humans in Taiwan. AB - We collected 110 Salmonella enterica isolates from sick pigs and determined their serotypes, genotypes using pulsed-field gel electrophoresis (PFGE), and antimicrobial susceptibility to 12 antimicrobials and compared the data with a collection of 18,280 isolates obtained from humans. The pig isolates fell into 12 common serovars for human salmonellosis in Taiwan; S. Typhimurium, S. Choleraesuis, S. Derby, S. Livingstone, and S. Schwarzengrund were the 5 most common serovars and accounted for a total of 84% of the collection. Of the 110 isolates, 106 (96%) were multidrug resistant (MDR) and 48 (44%) had PFGE patterns found in human isolates. S. Typhimurium, S. Choleraesuis, and S. Schwarzengrund were among the most highly resistant serovars. The majority of the 3 serovars were resistant to 8-11 of the tested antimicrobials. The isolates from pigs and humans sharing a common PFGE pattern displayed identical or very similar resistance patterns and Salmonella strains that caused severe infection in pigs were also capable of causing infections in humans. The results indicate that pigs are one of the major reservoirs to human salmonellosis in Taiwan. Almost all of the pig isolates were MDR, which highlights the necessity of strictly regulating the use of antimicrobials in the agriculture sector in Taiwan. PMID- 24760079 TI - Identification and HLA-tetramer-validation of human CD4+ and CD8+ T cell responses against HCMV proteins IE1 and IE2. AB - Human cytomegalovirus (HCMV) is an important human pathogen. It is a leading cause of congenital infection and a leading infectious threat to recipients of solid organ transplants as well as of allogeneic hematopoietic cell transplants. Moreover, it has recently been suggested that HCMV may promote tumor development. Both CD4+ and CD8+ T cell responses are important for long-term control of the virus, and adoptive transfer of HCMV-specific T cells has led to protection from reactivation and HCMV disease. Identification of HCMV-specific T cell epitopes has primarily focused on CD8+ T cell responses against the pp65 phosphoprotein. In this study, we have focused on CD4+ and CD8+ T cell responses against the immediate early 1 and 2 proteins (IE1 and IE2). Using overlapping peptides spanning the entire IE1 and IE2 sequences, peripheral blood mononuclear cells from 16 healthy, HLA-typed, donors were screened by ex vivo IFN-gamma ELISpot and in vitro intracellular cytokine secretion assays. The specificities of CD4+ and CD8+ T cell responses were identified and validated by HLA class II and I tetramers, respectively. Eighty-one CD4+ and 44 CD8+ T cell responses were identified representing at least seven different CD4 epitopes and 14 CD8 epitopes restricted by seven and 11 different HLA class II and I molecules, respectively, in total covering 91 and 98% of the Caucasian population, respectively. Presented in the context of several different HLA class II molecules, two epitope areas in IE1 and IE2 were recognized in about half of the analyzed donors. These data may be used to design a versatile anti-HCMV vaccine and/or immunotherapy strategy. PMID- 24760081 TI - Acoustic telemetry validates a citizen science approach for monitoring sharks on coral reefs. AB - Citizen science is promoted as a simple and cost-effective alternative to traditional approaches for the monitoring of populations of marine megafauna. However, the reliability of datasets collected by these initiatives often remains poorly quantified. We compared datasets of shark counts collected by professional dive guides with acoustic telemetry data from tagged sharks collected at the same coral reef sites over a period of five years. There was a strong correlation between the number of grey reef sharks (Carcharhinus amblyrhynchos) observed by dive guides and the telemetry data at both daily and monthly intervals, suggesting that variation in relative abundance of sharks was detectable in datasets collected by dive guides in a similar manner to data derived from telemetry at these time scales. There was no correlation between the number or mean depth of sharks recorded by telemetry and the presence of tourist divers, suggesting that the behaviour of sharks was not affected by the presence of divers during our study. Data recorded by dive guides showed that current strength and temperature were important drivers of the relative abundance of sharks at monitored sites. Our study validates the use of datasets of shark abundance collected by professional dive guides in frequently-visited dive sites in Palau, and supports the participation of experienced recreational divers as contributors to long-term monitoring programs of shark populations. PMID- 24760082 TI - Dopamine precursor depletion influences pain affect rather than pain sensation. AB - Pain is a multidimensional experience, which includes sensory, cognitive, and affective aspects. Converging lines of evidence indicate that dopaminergic neurotransmission plays an important role in human pain perception. However, the precise effects of dopamine on different aspects of pain perception remain to be elucidated. To address this question, we experimentally decreased dopaminergic neurotransmission in 22 healthy human subjects using Acute Phenylalanine and Tyrosine Depletion (APTD). During APTD and a control condition we applied brief painful laser stimuli to the hand, assessed different aspects of pain perception, and recorded electroencephalographic responses. APTD-induced decreases of cerebral dopaminergic activity did not influence sensory aspects of pain perception. In contrast, APTD yielded increases of pain unpleasantness. The increases of unpleasantness ratings positively correlated with effectiveness of APTD. Our finding of an influence of dopaminergic neurotransmission on affective but not sensory aspects of phasic pain suggests that analgesic effects of dopamine might be mediated by indirect effects on pain affect rather than by direct effects on ascending nociceptive signals. These findings contribute to our understanding of the complex relationship between dopamine and pain perception, which may play a role in various clinical pain states. PMID- 24760084 TI - Increasing leaf vein density by mutagenesis: laying the foundations for C4 rice. AB - A high leaf vein density is both an essential feature of C4 photosynthesis and a foundation trait to C4 evolution, ensuring the optimal proportion and proximity of mesophyll and bundle sheath cells for permitting the rapid exchange of photosynthates. Two rice mutant populations, a deletion mutant library with a cv. IR64 background (12,470 lines) and a T-DNA insertion mutant library with a cv. Tainung 67 background (10,830 lines), were screened for increases in vein density. A high throughput method with handheld microscopes was developed and its accuracy was supported by more rigorous microscopy analysis. Eight lines with significantly increased leaf vein densities were identified to be used as genetic stock for the global C4 Rice Consortium. The candidate population was shown to include both shared and independent mutations and so more than one gene controlled the high vein density phenotype. The high vein density trait was found to be linked to a narrow leaf width trait but the linkage was incomplete. The more genetically robust narrow leaf width trait was proposed to be used as a reliable phenotypic marker for finding high vein density variants in rice in future screens. PMID- 24760083 TI - Resolving hot spots in the C-terminal dimerization domain that determine the stability of the molecular chaperone Hsp90. AB - Human heat shock protein of 90 kDa (hHsp90) is a homodimer that has an essential role in facilitating malignant transformation at the molecular level. Inhibiting hHsp90 function is a validated approach for treating different types of tumors. Inhibiting the dimerization of hHsp90 via its C-terminal domain (CTD) should provide a novel way to therapeutically interfere with hHsp90 function. Here, we predicted hot spot residues that cluster in the CTD dimerization interface by a structural decomposition of the effective energy of binding computed by the MM GBSA approach and confirmed these predictions using in silico alanine scanning with DrugScore(PPI). Mutation of these residues to alanine caused a significant decrease in the melting temperature according to differential scanning fluorimetry experiments, indicating a reduced stability of the mutant hHsp90 complexes. Size exclusion chromatography and multi-angle light scattering studies demonstrate that the reduced stability of the mutant hHsp90 correlates with a lower complex stoichiometry due to the disruption of the dimerization interface. These results suggest that the identified hot spot residues can be used as a pharmacophoric template for identifying and designing small-molecule inhibitors of hHsp90 dimerization. PMID- 24760087 TI - Neuropathy and cough may not be a fortuitous association. PMID- 24760085 TI - Biological characteristics of the MG-63 human osteosarcoma cells on composite tantalum carbide/amorphous carbon films. AB - Tantalum (Ta) is a promising metal for biomedical implants or implant coating for orthopedic and dental applications because of its excellent corrosion resistance, fracture toughness, and biocompatibility. This study synthesizes biocompatible tantalum carbide (TaC) and TaC/amorphous carbon (a-C) coatings with different carbon contents by using a twin-gun magnetron sputtering system to improve their biological properties and explore potential surgical implant or device applications. The carbon content in the deposited coatings was regulated by controlling the magnetron power ratio of the pure graphite and Ta cathodes. The deposited TaC and TaC/a-C coatings exhibited better cell viability of human osteosarcoma cell line MG-63 than the uncoated Ti and Ta-coated samples. Inverted optical and confocal imaging was used to demonstrate the cell adhesion, distribution, and proliferation of each sample at different time points during the whole culture period. The results show that the TaC/a-C coating, which contained two metastable phases (TaC and a-C), was more biocompatible with MG-63 cells compared to the pure Ta coating. This suggests that the TaC/a-C coatings exhibit a better biocompatible performance for MG-63 cells, and they may improve implant osseointegration in clinics. PMID- 24760088 TI - Cognitive assessment in severe dementia and lower levels of education: reducing negligence. PMID- 24760089 TI - Clinical and neurophysiologic characterization of an European family with hereditary sensory neuropathy, paroxysmal cough and gastroesophageal reflux. AB - In 2002, Spring et al reported a family with an autosomal dominant form of hereditary sensory neuropathy; patients also presented adult onset of gastroesophageal reflux and cough. Since then, no further families have been described. OBJECTIVE: To study a new Portuguese family with these characteristics. METHOD: To describe the clinical and neurophysiologic characteristics of one family with features of sensory neuropathy associated with cough and gastroesophageal erflux. RESULTS: Three of five siblings presented a similar history of paroxysmal cough (5th decade). About a decade later they experienced numbness and paraesthesia in the feet and in all cases there was evidence of an axonal sensory neuropathy. A history of gastroesophageal reflux of variable severity and age of onset was also present. DISCUSSION: Molecular genetic studies have demonstrated genetic heterogeneity between the hereditary sensory neuropathy type 1 subtypes. The identification of these families is of major importance because further work is required to identify the underlying genetic defect. PMID- 24760090 TI - Educational bias in the assessment of severe dementia: Brazilian cutoffs for severe Mini-Mental State Examination. AB - Cognitive assessment in advanced stages of Alzheimer's disease (AD) is limited by the imprecision of most instruments. OBJECTIVE: To determine objective cognitive responses in moderate and severe AD patients by way of the Severe Mini-Mental State Examination (SMMSE), and to correlate performances with Mini-Mental State Examination (MMSE) scores. METHOD: Consecutive outpatients in moderate and severe stages of AD (Clinical Dementia Rating 2.0 or 3.0) were evaluated and compared according to MMSE and SMMSE scores. RESULTS: Overall 400 patients were included, 67.5% females, mean age 76.6+/-6.7 years-old. There was no significant impact of age or gender over MMSE or SMMSE scores. Mean schooling was 4.4+/-2.5 years, impacting SMMSE scores (p=0.008). Scores on MMSE and SMMSE were significantly correlated (F-ratio=690.6325, p<0.0001). CONCLUSION: The SMMSE is influenced by schooling, but not by age or gender, and is an accurate test for assessment of moderate and severe AD. PMID- 24760091 TI - Lower mortality rate in people with dementia is associated with better cognitive and functional performance in an outpatient cohort. AB - We describe a three-year experience with patients with dementia. METHOD: clinical, cognitive and functional evaluation was performed by a multidisciplinary team for persons above 60 years. Mortality was assessed after three years. RESULTS: Mini-Mental State Examination (MMSE) (n=2,074) was 15.7 (8.4). Male patients MMSE (n=758) was 15.6 (8.3) and female's (n=1315) was 15.8 (8.3). Instrumental Activities of Daily Living Scale (n=2023) was 16.5 (7.6); females (n=1277) was 16.9 (7.2) and males (n=745) was 15.7(8.2). From these patients, 12.6% (n=209) died within three years. Baseline cognition of patients still alive was higher (p<0.001) than MMSE of those who died [MMSE=16.3 (8.1) vs. 10.6 (7.6)]. Mortality rate decreased 6% (IR=0.94) for each additional point on MMSE. Higher functional status decreases the mortality rate approximately 11% (IR=0.89) independently of age, gender, and education. CONCLUSION: Three-year mortality rates are dependent on baseline functional and cognitive status. PMID- 24760092 TI - Developmental dyscalculia in children and adolescents with idiopathic epilepsies in a Brazilian sample. AB - Epilepsy is one of the most prevalent chronic disorders of childhood which can threaten child development and mental health. Among cognitive disorders, dyscalculia is one of the most important. In this study, 39 children and adolescents with idiopathic epilepsy underwent clinical and neuropsychological assessment to determine the intellectual level, math skills, reading and writing performance and neuropsychological profile. It was observed that the mathematical ability was below schooling expectations in a higher frequency than expected. There were no significant differences in mathematical performance among groups divided by number of antiepileptic drugs used, duration of disease and types and frequency of seizures. There was a positive correlation with intelligence quotient and attentional and reading level. These results suggest the existence not only of dyscalculia, but the concurrence of attentional and reading problems for the poor mathematical performance in this population. PMID- 24760093 TI - Qualitative analysis of the Clock Drawing Test by educational level and cognitive profile. AB - The use of a qualitative scale for the Clock Drawing Test (CDT) may add information about the pattern of errors committed. OBJECTIVE: To translate and adapt the Modified Qualitative Error Analysis of Rouleau into Brazilian Portuguese and to examine the pattern of errors according to educational level and cognitive profile. METHOD: 180 adults (47-82 years) completed the CDT. Participants were stratified into age and educational levels and separated between those with and without changes in cognitive screening tests (Mini-Mental State Examination, Verbal Fluency). RESULTS: No significant differences were found in CDT scores among age groups. Among participants without cognitive impairment, those with lower education often presented graphic difficulties, conceptual deficits and spatial deficits. Participants with cognitive deficits, demonstrated more frequently conceptual and spatial errors. CONCLUSION: The qualitative analysis of the CDT may contribute to the identification of cognitive changes. Education level has to be taken into consideration during the analysis. PMID- 24760094 TI - Delayed latencies of auditory evoked potential P300 are associated with the severity of Parkinson's disease in older patients. AB - Electrophysiological methods could provide important information about the neurophysiological status in Parkinson's disease (PD). OBJECTIVE: To investigate the prolonged auditory P300 latency in PD and its association with the disease clinical stage. METHOD: Clinical profiles of 44 patients were evaluated and those in initial and advanced stages of PD were identified. The frequency of altered latencies, median of latencies in each stage, and correlation between latencies and motor and non-motor clinical features were analyzed. Latencies were considered altered when they were more than two standard deviations from the mean of controls, per age group. RESULTS: It was verified 10% of alterations in initial stages and 31% in advanced. There was correlation between latencies and non-motor clinical features. Subjects older than 65, in advanced stages, presented a significant increase of latencies. CONCLUSION: There was an association between PD severity and P300 prolonged latencies among subjects 65 years old or older. PMID- 24760095 TI - Electrophysiologic characteristics of tremor in Parkinson's disease and essential tremor. AB - Tremor in essential tremor (ET) and Parkinson's disease (PD) usually present specific electrophysiologic profiles, however amplitude and frequency may have wide variations. OBJECTIVE: To present the electrophysiologic findings in PD and ET. METHOD: Patients were assessed at rest, with posture and action. Seventeen patients with ET and 62 with PD were included. PD cases were clustered into three groups: predominant rest tremor; tremor with similar intensity at rest, posture and during kinetic task; and predominant kinetic tremor. RESULTS: Patients with PD presented tremors with average frequency of 5.29+/-1.18 Hz at rest, 5.79+/ 1.39 Hz with posture and 6.48+/-1.34 Hz with the kinetic task. Tremor in ET presented with an average frequency of 5.97+/-1.1 Hz at rest, 6.18+/-1 Hz with posture and 6.53+/-1.2 Hz with kinetic task. Seven (41.2%) also showed rest tremor. CONCLUSION: The tremor analysis alone using the methodology described here, is not sufficient to differentiate tremor in ET and PD. PMID- 24760096 TI - Laparoscopic assisted ventriculoperitoneal shunt revisions as an option for pediatric patients with previous intraabdominal complications. AB - Multiple shunt failure is a challenge in pediatric neurosurgery practice and one of the most feared complications of hydrocephalus. OBJECTIVE: To demonstrate that laparoscopic procedures for distal ventriculoperitoneal shunt failure may be an effective option for patients who underwent multiple revisions due to repetitive manipulation of the peritoneal cavity, abdominal pseudocyst, peritonitis or other situations leading to a "non reliable" peritoneum. METHOD: From March 2012 to February 2013, the authors reviewed retrospectively the charts of six patients born and followed up at our institution, which presented with previous intra peritoneal complications and underwent ventriculoperitoneal shunt revision assisted by video laparoscopy. RESULTS: After a mean follow-up period of nine months, all patients are well and no further shunt failure was identified so far. CONCLUSION: Laparoscopy assisted shunt revision in children may be, in selected cases, an effective option for patients with multiple peritoneal complications due to ventriculo-peritoneal shunting. PMID- 24760097 TI - Complete removal of the spinal nerve sheath tumors. Surgical technics and results from a series of 30 patients. AB - OBJECTIVE: Observe whether a microsurgical gross total removal (GTR) of a spinal nerve sheath tumors (SNSTs) is safe and decreases the tumor recurrence. METHOD: We identify 30 patients with 44 SNSTs. RESULTS: We operated upon 15 males and 15 females patients; mean age 40 years. GTR was achieved in 29 (96.6%) instances. Surgical mortality was 3.3% and the recurrence rate was 3.3%. The median follow up time was 6.2 years. CONCLUSION: The surgical approach used in this group of patients afford that the great majority of tumors could be totally removed with low mortality and low recurrence rates, proving to be safe and effective. PMID- 24760098 TI - Hysteria to conversion disorders: Babinski's contributions. AB - The main objective of this paper is to present the importance of hysteria on Babinski's oeuvre, and the conceptions of pithiatism from Babinski until the one of conversion disorder. Babinski gave a mental basis for hysteria in the place of Charcot's encephalopatic one, and several important semiotic tools to differentiate organic from hysterical manifestations based on studies from 1893 1917/8. His teachings were spread worldwide, and in Brazil they were also appreciated in the work on hysteria by Antonio Austregesilo, the first Brazilian neurology chairman. The neurobiological basis of hysteria conceived by Charcot is nowadays reappraised, and Babinski's neurosemiological contribution is everlasting. The patients believed to be hysterical, and the two outstanding neurologists, Charcot and Babinski, gave support for the development of the modern neurology. PMID- 24760099 TI - Claude Bernard: bicentenary of birth and his main contributions to neurology. AB - Claude Bernard (1813-1878) followed two main research paths: the chemical and physiological study of digestion and liver function, along with experimental section of nerves and studies on sympathetic nerves. Curare studies were, for example, of longstanding interest. His profound mental creativity and hand skillfulness, besides methodology quality, directed his experiments and findings, mainly at the College de France. His broader and epistemological concerns were carried out at the Sorbonne and later at the Museum national d'Histoire naturelle. His insight gave clues to define the " milieu interieur", later known as "homeostasis", and grasp the brain complexity. Bernard followed and surpassed his master Francois Magendie who also fought against dogmas and laid the foundations of experimental medicine, and its main heinous tool - vivisection. Bernard created the methodological bases of experimental medicine, and collected honors as a renowned researcher. PMID- 24760100 TI - Eyelid retraction is not a pathognomonic sign of Machado-Joseph disease in the context of spinocerebellar ataxias. PMID- 24760101 TI - Opinion. PMID- 24760102 TI - Factors affecting vocalization in Tengmalm's owl (Aegolius funereus) fledglings during post-fledging dependence period: scramble competition or honest signalling of need? AB - Begging behaviour of nestlings has been intensively studied for several decades as a key component of parent-offspring conflict. There are essentially two main theories to account for intensity of food solicitation among offspring: that intensity of begging is related to some form of scramble competition between nest mates or that it offers honest signalling of need to parents. The vast majority of studies which have addressed begging behaviour have been based on observations of, and experiments on, nestlings and have not considered begging behaviour, during the post-fledging period. Begging vocalizations in this post-fledging phase of dependence have rarely been studied, despite the importance of vocalizations as a communication method between offspring and parents, particularly for nocturnal species. We radiotracked 39 fledglings of the Tengmalm's owl (Aegolius funereus) in two years with different availability of prey: 2010 (n = 29 fledglings) and 2011 (n = 10 fledglings) and made 1320 nightly localizations in which we recorded presence or absence of begging calls. Within years, the most important measures related to the probability of vocalization were body condition at fledging, time of night, number of surviving siblings, age and weather conditions. Begging intensity increased with age in both years; however, in the year with low prey availability fledglings vocalized significantly more often. The main factor causing these differences between years was probably the different availability of prey, affecting breeding success, post fledging behaviour, and thus also both short- and long-term needs of offspring. We believe that our results suggest honest signalling of their fledgling's need. PMID- 24760103 TI - Entropic imaging of cataract lens: an in vitro study. AB - Phacoemulsification is a common surgical method for treating advanced cataracts. Determining the optimal phacoemulsification energy depends on the hardness of the lens involved. Previous studies have shown that it is possible to evaluate lens hardness via ultrasound parametric imaging based on statistical models that require data to follow a specific distribution. To make the method more system adaptive, nonmodel-based imaging approach may be necessary in the visualization of lens hardness. This study investigated the feasibility of applying an information theory derived parameter - Shannon entropy from ultrasound backscatter to quantify lens hardness. To determine the physical significance of entropy, we performed computer simulations to investigate the relationship between the signal-to-noise ratio (SNR) based on the Rayleigh distribution and Shannon entropy. Young's modulus was measured in porcine lenses, in which cataracts had been artificially induced by the immersion in formalin solution in vitro. A 35-MHz ultrasound transducer was used to scan the cataract lenses for entropy imaging. The results showed that the entropy is 4.8 when the backscatter data form a Rayleigh distribution corresponding to an SNR of 1.91. The Young's modulus of the lens increased from approximately 8 to 100 kPa when we increased the immersion time from 40 to 160 min (correlation coefficient r = 0.99). Furthermore, the results indicated that entropy imaging seemed to facilitate visualizing different degrees of lens hardening. The mean entropy value increased from 2.7 to 4.0 as the Young's modulus increased from 8 to 100 kPa (r = 0.85), suggesting that entropy imaging may have greater potential than that of conventional statistical parametric imaging in determining the optimal energy to apply during phacoemulsification. PMID- 24760104 TI - Inducible nitric oxide synthase inhibition reverses pulmonary arterial dysfunction in lung transplantation. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) after lung transplantation remains a significant cause of morbidity and mortality. Lung IRI induces nitric oxide synthesis (iNOS) and reactive nitrogen species, decreasing nitric oxide bioavailability. We hypothesized that ischemia-induced iNOS intensifies with reperfusion and contributes to IRI-induced pulmonary arterial regulatory dysfunction, which may lead to early graft failure and cause pulmonary edema. The aim of this study was to determine whether ischemia-reperfusion alters inducible and endothelial nitric oxide synthase expression, potentially affecting pulmonary perfusion. We further evaluated the role of iNOS in post-transplantation pulmonary arterial disorder. METHODS: We randomized 32 Sprague-Dawley rats into two groups. The control group was given a sham operation whilst the experimental group received orthotropic lung transplants with a modified three-cuff technique. Changes in lung iNOS, and endothelial nitric oxide synthase expression were measured after lung transplantation by enzyme-linked immunosorbent assay (ELISA). Vasoconstriction in response to exogenous phenylephrine and vasodilation in response to exogenous acetylcholine of pulmonary arterial rings were measured in vitro as a measure of vascular dysfunction. To elucidate the roles of iNOS in regulating vascular function, an iNOS activity inhibitor (N6-(1-iminoethyl)-L lysine, L-NIL) was used to treat isolated arterial rings. In order to test whether iNOS inhibition has a therapeutic effect, we further used L-NIL to pre treat transplanted lungs and then measured post-transplantation arterial responses. RESULTS: Lung transplantation caused upregulation of iNOS expression. This was also accompanied by suppression of both vasoconstriction and vasodilation of arterial rings from transplanted lungs. Removal of endothelium did not interfere with the contraction of pulmonary arterial rings from transplanted lungs. In contrast, iNOS inhibition rescued the vasoconstriction response to exogenous phenylephrine of pulmonary arterial rings from transplanted lungs. In addition, lung transplantation led to suppression of PaO2/FiO2 ratio, increased intrapulmonary shunt (Q s/Q t), and increase of lung wet to dry ratio (W/D), malondialdehyde and myeloperoxidase levels, all of which were reversed upon iNOS inhibition. Furthermore, inhibition of iNOS significantly rescued vascular function and alleviated edema and inflammatory cell infiltration in the transplanted lung. CONCLUSIONS: Our data suggest that lung transplantation causes upregulation of iNOS expression, and pulmonary vascular dysfunction. iNOS inhibition reverses the post-transplantational pulmonary vascular dysfunction. PMID- 24760106 TI - Access to 6H-naphtho[2,3-c]chromenes by a palladium-catalyzed reaction of 2 haloaryl allene with 2-alkynylphenol. AB - A palladium-catalyzed reaction of 2-haloaryl allene with 2-alkynylphenol is described, leading to 6H-naphtho[2,3-c]chromenes in good to excellent yields. This transformation proceeds efficiently with excellent chemoselectivity and regioselectivity. PMID- 24760105 TI - Catechin ameliorates cardiac dysfunction in rats with chronic heart failure by regulating the balance between Th17 and Treg cells. AB - OBJECTIVE: Disequilibrium of the cytokine network was reported to play an important role in the progression of chronic heart failure (CHF). Catechin exerts cardioprotection through treating many kinds of angiocardiopathy. However, the effects of catechin on CHF are currently unclear. Therefore, the main aim of this study was to investigate the efficacy of catechin on CHF rats as well as its relationship to immunoregulation. METHODS: CHF was induced in rats by ligation of the abdominal aorta. Myocardial function was evaluated by left ventricular systolic pressure and left ventricular end-diastolic pressure. The cytokine level was measured by enzyme-linked immunosorbent assay. Th17 and Treg levels in peripheral blood and spleen were analyzed by flow cytometry. RESULTS: The results showed that catechin treatment (50, 100 mg/kg/day) markedly improved myocardial function in rats treated with abdominal aortic coarctation. Severity of myocardial dysfunction in CHF rats significantly correlated with serum values of interleukin-17 (IL-17)/IL-10. Further results indicated catechin obviously inhibited immune activation, regulated unbalanced levels of IL-17/IL-10, and reversed abnormal polarization of TH17 as well as Treg in peripheral blood and spleen. CONCLUSIONS: Taken together, oral administration of catechin effectively suppressed abdominal aorta ligation-induced CHF in rats, which was closely associated with its modulation on Th17 and Treg. PMID- 24760107 TI - Anterior and intermediate pituitary tissues express claudin 4 in follicle stellate cells and claudins 2 and 5 in endothelial cells. AB - Follicle-stellate cells are pituitary non-granular cells that are arranged between secretory cells or organized in follicles with small lumens. Cells from the follicles exhibit the typical phenotype of a transporting epithelium, including apical microvilli with a cilium and tight junctions. Freeze-fracture electron microscopy images show that the tight junctions consist of 5-7 anastomosing strands and that cultured follicle-stellate cells develop a trans epithelial electrical resistance characteristic of "tight" epithelia. Here, we investigate the molecular composition of the tight junction from follicle stellate cells. We found that the rat anterior pituitary lobe expresses mRNAs for claudins 2, 4 and 5; the proteins of all these claudins are observed in the anterior lobe, whereas the intermediate lobe expresses claudins 2 and 5 and the posterior lobe contains only claudin 5. Follicle-stellate cells, identified by their protein marker S100beta, expresses claudin 4 in the apical membrane, in co localization with dipeptidyl-peptidase and near acetylated beta-tubulin. Claudin 4 partially co-localizes with E-cadherin, indicating that a fraction of the protein is located in the basolateral domain. Follicle-stellate-enriched cell cultures develop patches of polygonal cells expressing claudin 4 and E-cadherin, encircled by extensive monolayers of fusiform cells. Claudin 2 stains specifically blood vessels, identified by claudin 5 and VE-cadherin labels. Thus, follicles in the anterior pituitary consist of "tight" epithelia that can carry out intense vectorial transport, together with a high cation movement in blood vessels, possibly related to the ion requirements of excitable secretory cells for hormone secretion. PMID- 24760108 TI - Fc glycan-modulated immunoglobulin G effector functions. AB - Immunoglobulin G (IgG) molecules are glycoproteins and residues in the sugar moiety attached to the IgG constant fragment (Fc) are essential for IgG functionality such as binding to cellular Fc receptors and complement activation. The core of this sugar moiety consists of a bi-antennary heptameric structure of mannose and N-acetylglucosamine (GlcNAc), further decorated with terminal and branching residues including galactose, sialic acid, fucose, and GlcNAc. Presence or absence of distinct residues such as fucose and sialic acid can dramatically alter pro- and anti-inflammatory IgG activities which could be harnessed for immunotherapeutic purposes. Here we review recent advances in understanding the role of the IgG-Fc glycan during immune responses and for immunotherapy with a focus on sialic acid and intravenous immunoglobulin (IVIG) treatment. PMID- 24760109 TI - Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease. AB - Intravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent. PMID- 24760110 TI - Early systemic sclerosis: serum profiling of factors involved in endothelial, T cell, and fibroblast interplay is marked by elevated interleukin-33 levels. AB - PURPOSE: To assess the serum profile of factors involved in endothelial, T-cell, and fibroblast interplay in patients with Raynaud's phenomenon (RP) associated with nailfold vodeocapillaroscopy (NVC) scleroderma findings and/or systemic sclerosis (SSc) marker autoantibodies, recently labeled as early SSc patients. METHODS: Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), CCL2, CXCL8, IL-13, IL-33, and transforming growth factor-beta (TGF-beta) were measured in 24 early SSc patients, 48 definite SSc patients, and 24 osteoarthritis/fibromyalgia controls by multiplex suspension immunoassay. All SSc patients were investigated for the presence/absence of preclinical and clinical organ involvement, SSc marker autoantibodies, and NVC abnormalities. RESULTS: Serum sICAM-1, CCL2, CXCL8, and IL-13 were increased in all SSc patients as compared to controls, and paralleled the severity of the disease subset (early SSc < limited cutaneous SSc < diffuse cutaneous SSc; p < 0.0001). Surprisingly, IL-33 was significantly higher in early SSc patients as compared to both controls (p < 0.01) and definite SSc patients (p < 0.05). In early SSc there were no differences in the investigated markers according to the functional and serological features assessed. CONCLUSIONS: Our study suggests that an endothelial, T-cell and fibroblast activation can be present in patients with early SSc and it is associated with a distinct profile of circulating factors involved in the cross-talk of these cells. The marked increase of IL-33 in early SSc patients suggests new routes of investigation of cell-cell dynamics in target tissues predating overt disease manifestations, thus opening to new therapeutic approaches. PMID- 24760111 TI - Elevated double negative T cells in pediatric autoimmunity. AB - PURPOSE: Autoimmune diseases are thought to be caused by a loss of self-tolerance of the immune system. One candidate marker of immune dysregulation in autoimmune disease is the presence of increased double negative T cells (DNTs) in the periphery. DNTs are characteristically elevated in autoimmune lymphoproliferative syndrome, a systemic autoimmune disease caused by defective lymphocyte apoptosis due to Fas pathway defects. DNTs have also been found in the peripheral blood of adult patients with systemic lupus erythematosus (SLE), where they may be pathogenic. DNTs in children with autoimmune disease have not been investigated. METHODS: We evaluated DNTs in pediatric patients with SLE, mixed connective tissue disease (MCTD), juvenile idiopathic arthritis (JIA), or elevated antinuclear antibody (ANA) but no systemic disease. DNTs (CD3(+)CD56( )TCRalphabeta(+)CD4(-)CD8(-)) from peripheral blood mononuclear cells were analyzed by flow cytometry from 54 pediatric patients including: 23 SLE, 15 JIA, 11 ANA and 5 MCTD compared to 28 healthy controls. RESULTS: Sixteen cases (29.6 %) had elevated DNTs (>=2.5 % of CD3(+)CD56(-)TCRalphabeta(+) cells) compared to 1 (3.6 %) control. Medication usage including cytotoxic drugs and absolute lymphocyte count were not associated with DNT levels, and percentages of DNTs were stable over time. Analysis of multiple phenotypic and activation markers showed increased CD45RA expression on DNTs from patients with autoimmune disease compared to controls. CONCLUSION: DNTs are elevated in a subset of pediatric patients with autoimmune disease and additional investigations are required to determine their precise role in autoimmunity. PMID- 24760112 TI - Clinical trials of intravenous immunoglobulin for Alzheimer's disease. AB - The human polyclonal IgG antibody preparation known as Intravenous Immunoglobulin (IVIG) has been under study as a potential treatment for Alzheimer's disease (AD) since 2002. Preclinical and clinical studies have shown that IVIG has anti amyloid and immune modulatory properties relevant to treating neurodegenerative disorders. In early stage AD clinical trials, IVIG was found to reduce cognitive decline and increase brain glucose metabolism. Unfortunately, IVIG failed to meet primary outcome objectives in the North American Phase 3 clinical trial in mild to moderate AD. However, positive cognitive signals were observed in pre-planned subgroup analyses among APOE-epsilon4 carriers and moderately impaired AD patients. Biomarker studies revealed dose dependent increases in plasma and CSF immunoglobulins and decreases in beta amyloid-42 levels. In addition, IVIG treatment was generally safe and well-tolerated. These findings suggest that naturally occurring human anti-amyloid antibodies may play a physiologic role in the clearance of aggregated amyloid proteins. While the results of clinical trials to date do not provide support for the use of IVIG to treat AD at the doses tested, additional studies of IVIG's mechanisms are warranted and may guide the development of more effective therapies for AD in the future. PMID- 24760113 TI - A novel splice site mutation in the SERPING1 gene leads to haploinsufficiency by complete degradation of the mutant allele mRNA in a case of familial hereditary angioedema. AB - Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare autosomal-dominant and life-threatening disorder caused by mutations in SERPING1 gene. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. Here we report the case of a patient with HAE-C1INH without family history of angioedema. By sequencing the SERPING1 gene we detected a novel mutation (c.1249 + 5G > A) affecting the 5' donor splice site in intron 7. We analyzed the SERPING1 cDNA expecting a defect in splicing process but only the wild type allele was detected. SNP analysis of the cDNA sequence demonstrated that only one of the two alleles was present, indicating that the mRNA from the mutated allele was completely degraded. This study reinforces the concept of incomplete penetrance of this disorder since the patients' mother never presented any sign of angioedema despite carrying the same mutation. PMID- 24760115 TI - The science and arts of antibodies. PMID- 24760114 TI - Clinical and genetic characterization of Japanese sporadic cases of periodic Fever, aphthous stomatitis, pharyngitis and adenitis syndrome from a single medical center in Japan. AB - PURPOSE: To investigate clinical presentation, genetic background and cytokine profile of Japanese sporadic cases of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. METHODS: Nine PFAPA syndrome patients were recruited. DNA sequence analysis of auto inflammatory disorder susceptibility genes, MEFV, MVK, NLRP3, and TNFRSF1A, were performed. Serum cytokine levels and monocyte IL-1beta levels were measured by ELISA. RESULTS: The study population consisted of six males and three females (mean age of onset 26.8 months). Febrile episodes lasted 3-6 days with symptom-free intervals ranging from 2 to 12 weeks. Fever was accompanied by pharyngitis (n = 8), aphthous stomatitis (n = 4), and cervical adenitis (n = 5). White blood cells and C reactive protein were increased during the attack phase. Mean IgD serum levels were 7.32 +/- 9.51 mg/dl during the attack phase, and were mildly elevated in two patients. Heterozygous MEFV, NLRP3 and TNFRSF1A variants were detected in four, one and three cases, respectively. Serum TNF-alpha and IL-18 levels were elevated during the attack-free and attack periods compared with controls. Other cytokines, IL-1beta, IL-1ra, IL-6, and sTNFR1, were only increased during the attack phase. Oral prednisolone was administered to eight patients and immediately reduced fever. Tonsillectomy performed in five patients induced cessation of fever in four patients. One case with repeated fever attacks after tonsillectomy showed increased monocyte IL-1beta production, similar to the other active case with genetic variants of auto inflammatory disorder-associated genes. CONCLUSIONS: Japanese PFAPA syndrome patients may have cytokine regulation dysfunction as a result of genetic variants of auto inflammatory disorder associated genes. PMID- 24760116 TI - Mesenteric lymph reperfusion exacerbates spleen injury caused by superior mesenteric artery occlusion shock. AB - The intestinal lymph pathway plays an important role in the pathogenesis of organ injury following superior mesenteric artery occlusion (SMAO) shock. We hypothesized that mesenteric lymph reperfusion (MLR) is a major cause of spleen injury after SMAO shock. To test this hypothesis, SMAO shock was induced in Wistar rats by clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h. Similarly, MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h, followed by reperfusion for 2 h. In the MLR+SMAO group rats, both the SMA and MLD were clamped and then released for reperfusion for 2 h. SMAO shock alone elicited: 1) splenic structure injury, 2) increased levels of malondialdehyde, nitric oxide (NO), intercellular adhesion molecule-1, endotoxin, lipopolysaccharide receptor (CD14), lipopolysaccharide-binding protein, and tumor necrosis factor-alpha, 3) enhanced activities of NO synthase and myeloperoxidase, and 4) decreased activities of superoxide dismutase and ATPase. MLR following SMAO shock further aggravated these deleterious effects. We conclude that MLR exacerbates spleen injury caused by SMAO shock, which itself is associated with oxidative stress, excessive release of NO, recruitment of polymorphonuclear neutrophils, endotoxin translocation, and enhanced inflammatory responses. PMID- 24760117 TI - Oxidative stress and cellular immunity in patients with recurrent aphthous ulcers. AB - Recurrent aphthous ulcer (RAU) is an inflammatory condition of the oral mucosa characterized by painful, well-circumscribed, single or multiple round or ovoid ulcerations. The exact etiologic factor(s) of these ulcerations are not yet understood. The objective of this study was to evaluate inflammatory processes and free radical metabolism of 25 patients with RAUs compared to 25 healthy controls. The levels of malondialdehyde (MDA) and glutathione (GSH) were determined by high-performance liquid chromatography. Tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-10, and IL-12 were determined by ELISA. Nitric oxide (NO), myeloperoxidase (MPO), total antioxidant status (TAS), and total oxidant status (TOS) levels were measured spectroscopically in serum. The levels of MDA, GSH, TNF-alpha, IL-2, IL-12, MPO, and TOS, and oxidative stress index (OSI) were higher, and the levels of NO, IL-10, and TAS were lower in patients with RAU than in controls. Statistical analysis showed that GSH, TNF alpha, IL-2, IL-10, and OSI differed significantly in patients with RAU compared to controls. These parameters have important roles in oxidant/antioxidant defense. PMID- 24760118 TI - Cardiorespiratory fitness, pulmonary function and C-reactive protein levels in nonsmoking individuals with diabetes. AB - The objective of this study was to evaluate cardiorespiratory fitness and pulmonary function and the relationship with metabolic variables and C-reactive protein (CRP) plasma levels in individuals with diabetes mellitus (DM). Nineteen men with diabetes and 19 age- and gender-matched control subjects were studied. All individuals were given incremental cardiopulmonary exercise and pulmonary function tests. In the exercise test, maximal workload (158.3 +/- 22.3 vs 135.1 +/- 25.2, P=0.005), peak heart rate (HRpeak: 149 +/- 12 vs 139 +/- 10, P=0.009), peak oxygen uptake (VO2peak: 24.2 +/- 3.2 vs 18.9 +/- 2.8, P<0.001), and anaerobic threshold (VO2VT: 14.1 +/- 3.4 vs 12.2 +/- 2.2, P=0.04) were significantly lower in individuals with diabetes than in control subjects. Pulmonary function test parameters, blood pressure, lipid profile (triglycerides, HDL, LDL, and total cholesterol), and CRP plasma levels were not different in control subjects and individuals with DM. No correlations were observed between hemoglobin A1C (HbA1c), CRP and pulmonary function test and cardiopulmonary exercise test performance. In conclusion, the results demonstrate that nonsmoking individuals with DM have decreased cardiorespiratory fitness that is not correlated with resting pulmonary function parameters, HbA1c, and CRP plasma levels. PMID- 24760119 TI - Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy. AB - It is not known whether the addition of ezetimibe to statins adds cardiovascular protection beyond the expected changes in lipid levels. Subjects with coronary heart disease were treated with four consecutive 1-week courses of therapy (T) and evaluations. The courses were: T1, 100 mg aspirin alone; T2, 100 mg aspirin and 40 mg simvastatin/10 mg ezetimibe; T3, 40 mg simvastatin/10 mg ezetimibe, and 75 mg clopidogrel (300 mg initial loading dose); T4, 75 mg clopidogrel alone. Platelet aggregation was examined in whole blood. Endothelial microparticles (CD51), platelet microparticles (CD42/CD31), and endothelial progenitor cells (CD34/CD133; CDKDR/CD133, or CD34/KDR) were quantified by flow cytometry. Endothelial function was examined by flow-mediated dilation. Comparisons between therapies revealed differences in lipids (T2 and T3T1 and T4, P=0.001). Decreased platelet aggregation was observed after aspirin (arachidonic acid, T1=7.0 mmol/l when fasting or >=11.1 mmol/l during feeding were deemed hyperglycaemic. Patients with acute hyperglycaemia and HbA1c <6.5% (48 mmol/mol) were categorised as 'CIAH', those with known diabetes as 'recognised diabetes', and those with HbA1c >=6.5% but no previous diagnosis of diabetes as 'unrecognised diabetes'. The remainder were classified as 'normoglycaemic'. Hospital mortality, HbA1c and acute peak glycaemia were assessed using a logistic regression model. RESULTS: Of 1,000 patients, 498 (49.8%) had CIAH, 220 (22%) had recognised diabetes, 55 (5.5%) had unrecognised diabetes and 227 (22.7%) were normoglycaemic. The risk of death increased by approximately 20% for each increase in acute glycaemia of 1 mmol/l in patients with CIAH and those with diabetes and HbA1c levels <7% (53 mmol/mol), but not in patients with diabetes and HbA1c >=7%. This association was lost when adjusted for severity of illness. CONCLUSIONS: Critical illness-associated hyperglycaemia is the most frequent cause of hyperglycaemia in the critically ill. Peak glucose concentrations during critical illness are associated with increased mortality in patients with adequate premorbid glycaemic control, but not in patients with premorbid hyperglycaemia. Optimal glucose thresholds in the critically ill may, therefore, be affected by premorbid glycaemia. PMID- 24760121 TI - My paper 20 years later: Effect of positive end-expiratory pressure on right ventricular function in humans. AB - INTRODUCTION: In 1992, we published a report on the effect of positive end expiratory pressure (PEEP) on right ventricular (RV) function in humans. RESULTS: We measured RV volumes and pressures and pericardial pressure (Ppc) as PEEP was increased from zero to 15 cm H20 in 12 patients after thoracotomy, using a pulmonary arterial catheter equipped with a rapid responding thermistor that allowed measurement of RV ejection fraction (RVef), while Ppc was measured via a pericardial balloon catheter. RV end-diastolic volume (EDV) was estimated as the ratio of stroke volume (SV) to RVef, whereas RV end-systolic volume (ESV) were estimated as RV EDV-SV. PEEP increased Ppc and Pra, but RVef unaltered. There was no relation between either RV filling pressure (Pra-Ppc) and EDV or the change in RV filling pressure and EDV, although EDV varied significantly with PEEP (p < 0.05). The relations between EDV and both SV and RVef were weak (r = 0.54 and 0.55, respectively). RVef varied inversely with ESV (r = -0.77), although it showed no relation to transmural peak pulmonary artery pressure (r = 0.28). However, both absolute and relative changes in EDV corresponded closely with respective ESV values (r = 0.94). We concluded that EDV varies independently of changes in filling pressure and that changes in ESV occur independently of changes in ejection pressure. These data can be explained by assuming that the RV shape changes can dissociate changes in RV EDV from changes in RV wall stress (preload). Thus, changes in RV EDV may or may not alter SV but should proportionately change ESV to a degree dependent on election pressure and contractility. CONCLUSIONS: Subsequent studies confirmed our findings which can be summarized as 1) RV filling is independent of Pra; thus central venous pressure cannot be used to estimate RV preload; and 2) for cardiac output to increase by the Starling mechanism the RV must dilate increasing RV ESV. Since the pericardium limits absolute biventricular volume, there is a finite limit to which cardiac output can increase by the Starling mechanism defined not by left ventricular contractility but by RV function. And 3) if fluid loading causes Pra to increase without increasing cardiac output, then resuscitation should stop as the patient is going into acute cor pulmonale. These truths help bedside clinicians understand the echocardiographic and hemodynamic signatures of both RV failure and volume responsiveness. PMID- 24760122 TI - Rapid detection of thyroid cartilage fracture by ultrasound in a multiple trauma patient. PMID- 24760124 TI - Reactions of trinuclear platinum clusters with electrophiles: ionisation isomerism with [Pt3(MU2-I)(MU-PPh2)2(PPh3)3]I and [Pt3(MU-PPh2)2I2(PPh3)3]. Structures of [Pt3(MU2-Cl)(MU-PPh2)2(PPh3)3]PF6, [Pt3(MU-PPh2)2I2(PPh3)3] and of the Pt-Ag cluster [Pt3{MU3-AgBF4}(MU2-I)(MU-PPh2)2(PPh3)3]BF4. AB - A reaction of the 44 electron cluster [Pt3(MU-PPh2)3Ph(PPh3)2] (1) with wet AgBF4 afforded the cationic cluster [Pt3(MU2-OH)(MU-PPh2)2(PPh3)3]BF4 (3(BF4)) which slowly transformed into [Pt3(MU2-Cl)(MU-PPh2)2(PPh3)3]BF4 (4(BF4)) upon recrystallization from CH2Cl2. These 44 electron clusters have been characterized by (31)P{(1)H} NMR, and the crystal structure of 4(PF6) has been determined by X ray diffraction, as well as that of [Pt3(MU-PPh2)2I2(PPh3)3] (5), which was obtained by recrystallization of the known cluster [Pt3(MU2-I)(MU-PPh2)2(PPh3)3]I (2(I)) from toluene and represents a neutral formula isomer of the latter. In addition, we have prepared the adducts of cluster 1 containing the moieties [Cu(NCMe)2](+) and [Au(PPh3)](+) in 6 and 7, respectively, and on the basis of their spectroscopic data, it was concluded that these complexes have similar structures to that previously established for the adduct of 1 with Ag(TFA) (TFA = OC(O)CF3), [Pt3{MU3-Ag(TFA)}(MU-PPh2)3Ph(PPh3)2] (8). The cationic clusters in 3(BF4) and 4(BF4) react with Ag(TFA) to afford cationic adducts in [Pt3{MU3 Ag(TFA)}(MU2-X)(MU-PPh2)2(PPh3)3]BF4 (9(BF4), X = OH; 10(BF4), X = Cl). The structure of the mixed-metal cluster [Pt3(MU3-AgBF4)(MU2-I)(MU-PPh2)2(PPh3)3]BF4 (11(BF4)), obtained by reaction of the complex 2(I) with AgBF4, was determined by X-ray diffraction. PMID- 24760123 TI - Primary parapharyngeal tumours: a review of 21 cases. AB - BACKGROUND: The diagnostic and therapeutic procedures performed in a series of patients with primary parapharyngeal space (PPS) tumours treated at the ENT Departments of San Giovanni Bosco Hospital, Turin, and of the Pugliese-Ciaccio Hospital, Catanzaro, Italy, in the period 2001-2010 are evaluated. MATERIALS AND METHODS: The retrospective review included 20 patients, 11 male and 9 female, average age of 41 years operated on for 21 primary PPS tumours. The most common tumours found were neurogenic neoplasms, while those of salivary origin were the next most common. RESULTS: There were 14 paragangliomas (7 originating from carotid glomus, 5 from vagal and 2 from tympanicum), 1 sympathetic chain schwannoma and 6 pleomorphic adenomas. All the tumours were benign in nature and gave rise to few signs or symptoms. Patients underwent preoperative computed tomography (CT) scan or magnetic resonance imaging (MRI) or both. Most contrast enhanced masses were submitted to some type of angiography. Most of the surgeries were planned through imaging alone, as preoperative fine needle aspiration (FNA) biopsy was performed only in six cases. Four different approaches were adopted for tumour removal: transcervical, transcervical/transparotid, cervical transparotid-transmandibular and infratemporal fossa approach. There was no operative mortality, though neurologic morbidity was significant. Follow-up, extended to a maximum of 11 years, did not reveal any recurrences. In conclusion, neurogenic tumours may be the most common of PPS masses. Surgery is the mainstay treatment and external approaches offer the potential for satisfactory tumour resection. Of such external approaches, transcervical and cervical/transparotid are the most often used in benign forms. CONCLUSION: The number of perioperative complications encountered in this series confirms the difficulty of performing surgery in this complex area, even in benign cases. The chances of avoiding vascular damage and saving the trunks or most of the nerve fibres involved depend not only on the skill and experience of the surgeon but also on the anatomy of the lesion, the type of connection between the tumour and the nerve from which it originates and the distribution of neural fibres in or around the tumour mass. PMID- 24760125 TI - Strain measurement by cardiovascular magnetic resonance in pediatric cancer survivors: validation of feature tracking against harmonic phase imaging. AB - BACKGROUND: Left ventricular strain may be a more sensitive marker of left ventricular dysfunction than ejection fraction in pediatric cancer survivors after anthracycline therapy, but there is limited validation of strain measurement by feature tracking on cardiovascular magnetic resonance (MR) images. OBJECTIVE: To compare left ventricular circumferential and radial strain by feature tracking vs. harmonic phase imaging analysis (HARP) in pediatric cancer survivors. MATERIALS AND METHODS: Twenty-six patients (20.2 +/- 5.6 years old) underwent cardiovascular MR at least 5 years after completing anthracycline therapy. Circumferential and radial strain were measured at the base, midventricle and apex from short-axis myocardial tagged images by HARP, and from steady-state free precession images by feature tracking. RESULTS: Left ventricular ejection fraction more closely correlated with global circumferential strain by feature tracking (r = -0.63, P = 0.0005) than by HARP (r = -0.39, P = 0.05). Midventricular circumferential strain did not significantly differ by feature tracking or HARP (-20.8 +/- 3.4 vs. -19.5 +/- 2.5, P = 0.07), with acceptable limits of agreement. Midventricular circumferential strain by feature tracking strongly correlated with global circumferential strain by feature tracking (r = 0.87, P < 0.0001). Radial strain by feature tracking had poor agreement with HARP, particularly at higher values of radial strain. Intraobserver and interobserver reproducibility was excellent for feature tracking circumferential strain, but reproducibility was poor for feature tracking radial strain. CONCLUSION: Midventricular circumferential strain by feature tracking is a reliable and reproducible measure of myocardial deformation in patients status post anthracycline therapy, while radial strain measurements are unreliable. Further studies are necessary to evaluate potential relation to long-term outcomes. PMID- 24760126 TI - Imaging and quantification of trans-membrane protein diffusion in living bacteria. AB - The cytoplasmic membrane forms the barrier between any cell's interior and the outside world. It contains many proteins that enable essential processes such as the transmission of signals, the uptake of nutrients, and cell division. In the case of prokaryotes, which do not contain intracellular membranes, the cytoplasmic membrane also contains proteins for respiration and protein folding. Mutual interactions and specific localization of these proteins depend on two dimensional diffusion driven by thermal fluctuations. The experimental investigation of membrane-protein diffusion in bacteria is challenging due to their small size, only a few times larger than the resolution of an optical microscope. Here, we review fluorescence microscopy-based methods to study diffusion of membrane proteins in living bacteria. The main focus is on data analysis tools to extract diffusion coefficients from single-particle tracking data obtained by single-molecule fluorescence microscopy. We introduce a novel approach, IPODD (inverse projection of displacement distributions), to obtain diffusion coefficients from the usually obtained 2-D projected diffusion trajectories of the highly 3-D curved bacterial membrane. This method provides, in contrast to traditional mean-squared-displacement methods, correct diffusion coefficients and allows unravelling of heterogeneously diffusing populations. PMID- 24760131 TI - Poisoning by Talisia esculenta (A. St.-Hil.) Radlk in sheep and cattle. AB - Talisia esculenta is a tree that produces pitomba, a fruit consumed by human beings in several regions of Brazil. The current study reports 3 outbreaks of poisoning by leaves and fruits of T. esculenta affecting sheep and cattle and the experimental reproduction of the disease in sheep. In the first investigated outbreak, sheep ingested the leaves of the plant; another outbreak affected cattle and sheep that ingested leaves and fruits; and in a third outbreak, sheep ingested only the fruits. The animals developed severe nervous signs, but most recovered. Poisoning was reproduced experimentally in 5 sheep by the administration of 30-60 g of leaves/kg body weight and in 2 sheep with doses of 5 and 10 g of seeds/kg body weight, respectively. No significant necropsy or histologic lesions were found. PMID- 24760130 TI - Structural basis for the site-specific incorporation of lysine derivatives into proteins. AB - Posttranslational modifications (PTMs) of proteins determine their structure function relationships, interaction partners, as well as their fate in the cell and are crucial for many cellular key processes. For instance chromatin structure and hence gene expression is epigenetically regulated by acetylation or methylation of lysine residues in histones, a phenomenon known as the 'histone code'. Recently it was shown that these lysine residues can furthermore be malonylated, succinylated, butyrylated, propionylated and crotonylated, resulting in significant alteration of gene expression patterns. However the functional implications of these PTMs, which only differ marginally in their chemical structure, is not yet understood. Therefore generation of proteins containing these modified amino acids site specifically is an important tool. In the last decade methods for the translational incorporation of non-natural amino acids using orthogonal aminoacyl-tRNA synthetase (aaRS):tRNAaaCUA pairs were developed. A number of studies show that aaRS can be evolved to use non-natural amino acids and expand the genetic code. Nevertheless the wild type pyrrolysyl-tRNA synthetase (PylRS) from Methanosarcina mazei readily accepts a number of lysine derivatives as substrates. This enzyme can further be engineered by mutagenesis to utilize a range of non-natural amino acids. Here we present structural data on the wild type enzyme in complex with adenylated epsilon-N-alkynyl-, epsilon-N butyryl-, epsilon-N-crotonyl- and epsilon-N-propionyl-lysine providing insights into the plasticity of the PylRS active site. This shows that given certain key features in the non-natural amino acid to be incorporated, directed evolution of this enzyme is not necessary for substrate tolerance. PMID- 24760132 TI - Synergistic hemolysis between beta-lysin-producing Staphylococcus species and Rothia nasimurium in primary cultures of clinical specimens obtained from dogs. AB - Nonhemolytic isolates of catalase-positive, Gram-positive cocci were observed that produced strong synergistic hemolysis with colonies of Staphylococcus pseudintermedius and Staphylococcus schleiferi subsp. coagulans in primary cultures of clinical specimens from dogs. The isolates appeared similar to nonhemolytic staphylococci but were not identified with conventional biochemical tests or commercial biochemical test kits. Partial 16S ribosomal RNA gene sequences from each of 9 tested isolates were nearly identical to that of Rothia nasimurium. The isolates produced positive Christie-Atkins-Munch-Peterson test reactions with Staphylococcus aureus (ATCC strain 25923) and Staphylococcus intermedius Hajek (ATCC strain 49052). The latter was identified in the current study as S. pseudintermedius. Rothia nasimurium appears to be a previously unreported commensal organism in dogs. Its potential significance as an opportunistic contributor to polymicrobial infections in dogs is not known. PMID- 24760133 TI - Lack of association of ABCB4 insertion mutation with gallbladder mucoceles in dogs. AB - The etiology of canine gallbladder mucocele (GBM) has not yet been identified. However, several studies have linked GBM in dogs to particular breeds (Shetland Sheepdogs are commonly implicated), concurrent endocrine disease (hyperadrenocorticism and/or hypothyroidism), and a mutation in the canine ABCB4 gene (ABCB4 1583_1584G), particularly in Shetland Sheepdogs. The current study assessed ABCB4 1583_1584G, in a wider sample of dogs with GBM compared with age and breed-matched controls. ABCB4 1583_1584G was identified in 4 of 8 Shetland Sheepdogs and 13 of 28 other breeds with GBM. ABCB4 1583_1584G was also detected in 9 of 12 Shetland Sheepdogs and 23 of 37 other breeds that did not have GBM. No statistically significant association existed between ABCB4 1583_1584G and the presence of GBM for all dogs combined or for Shetland Sheepdogs alone. In contrast to previously reported findings, the current study did not identify a strong association between ABCB4 1583_1584G and GBM in Shetland Sheepdogs or other breeds. PMID- 24760128 TI - Developmental and pathological angiogenesis in the central nervous system. AB - Angiogenesis, the formation of new blood vessels from pre-existing vessels, in the central nervous system (CNS) is seen both as a normal physiological response as well as a pathological step in disease progression. Formation of the blood brain barrier (BBB) is an essential step in physiological CNS angiogenesis. The BBB is regulated by a neurovascular unit (NVU) consisting of endothelial and perivascular cells as well as vascular astrocytes. The NVU plays a critical role in preventing entry of neurotoxic substances and regulation of blood flow in the CNS. In recent years, research on numerous acquired and hereditary disorders of the CNS has increasingly emphasized the role of angiogenesis in disease pathophysiology. Here, we discuss molecular mechanisms of CNS angiogenesis during embryogenesis as well as various pathological states including brain tumor formation, ischemic stroke, arteriovenous malformations, and neurodegenerative diseases. PMID- 24760129 TI - Molecular chaperones are nanomachines that catalytically unfold misfolded and alternatively folded proteins. AB - By virtue of their general ability to bind (hold) translocating or unfolding polypeptides otherwise doomed to aggregate, molecular chaperones are commonly dubbed "holdases". Yet, chaperones also carry physiological functions that do not necessitate prevention of aggregation, such as altering the native states of proteins, as in the disassembly of SNARE complexes and clathrin coats. To carry such physiological functions, major members of the Hsp70, Hsp110, Hsp100, and Hsp60/CCT chaperone families act as catalytic unfolding enzymes or unfoldases that drive iterative cycles of protein binding, unfolding/pulling, and release. One unfoldase chaperone may thus successively convert many misfolded or alternatively folded polypeptide substrates into transiently unfolded intermediates, which, once released, can spontaneously refold into low-affinity native products. Whereas during stress, a large excess of non-catalytic chaperones in holding mode may optimally prevent protein aggregation, after the stress, catalytic disaggregases and unfoldases may act as nanomachines that use the energy of ATP hydrolysis to repair proteins with compromised conformations. Thus, holding and catalytic unfolding chaperones can act as primary cellular defenses against the formation of early misfolded and aggregated proteotoxic conformers in order to avert or retard the onset of degenerative protein conformational diseases. PMID- 24760134 TI - Spontaneous chronic T-cell leukemia in a male rhesus macaque ( Macaca mulatta). AB - Blood smears from a 24-year-old male rhesus macaque ( Macaca mulatta) used for cognitive function studies were evaluated. The macaque had an 8-month history of gradual weight loss and increasing lymphocytosis. Most of the lymphocytes present were small to medium and had a mature morphology. Based on the degree and duration of the lymphocytosis, and the appearance of the lymphocytes, a diagnosis of chronic lymphocytic leukemia was made. The animal tested negative for 4 viral diseases that are commonly associated with lymphoproliferative disorders in Old World monkeys. Over the course of 12 months, the lymphocytosis progressed from 18.4 to 384 * 103 lymphocytes/ul (reference range: 0.8-17 * 103 cells/ul), and euthanasia was elected. On histologic examination, cluster of differentiation (CD)3- and CD8-positive, CD79-negative neoplastic cells comprised 40-60% of the bone marrow, diffusely obscured the normal splenic architecture, and were present in the vascular channels in other organs. Findings were characteristic of T-cell lymphocytic leukemia. Naturally occurring T-cell lymphocytic leukemia has been rarely reported in rhesus macaques and, to the authors' knowledge, never in males. A persistent lymphocytosis characterized by a monomorphic population of CD3- and CD8-positive cytotoxic T-lymphocytes and the presence of neoplastic cells in the bone marrow led to a diagnosis in the current case. PMID- 24760135 TI - Significance of ERalpha, HER2, and CAV1 expression and molecular subtype classification to canine mammary gland tumor. AB - Canine mammary gland tumor (CMT) and human breast cancer (HBC) share many similarities regarding their risk factors, histological features, and behavior. Despite the increasing evidence of molecular marker expression as a prognostic indicator for HBC, few studies have applied this approach to CMT. The aim of the present study is to evaluate the significance of the expression of estrogen receptor-alpha (ERalpha), human epidermal growth factor receptor 2 (HER2), and caveolin-1 (CAV1) to the behavior and the clinical outcome of CMT. Additionally, the correlation between subtype classification (luminal A, luminal B, HER2 overexpressing, basal-like, and normal-like) and tumor behavior prognosis were assessed. Canine mammary gland tissues were immunohistochemically stained for ERalpha, HER2, and CAV1 and evaluated and classified into 5 subtypes on the basis of immunoreactivity. Although there were no statistically significant differences in the molecular marker immunoreactivity of different subtypes, the degree of positive staining for ERalpha, extranuclear ERalpha, HER2, and CAV1 showed significant correlations (P < 0.05) with the behavior and prognosis of the tumor. The current study indicates the prognostic value of immunohistochemical staining status of ERalpha, HER2, and CAV1 for CMT. In addition, some trends were seen in subtype classification on the prognosis of the tumor, implying that, although further analysis is needed, there is potential clinical application of 5-subtype classification for CMT. PMID- 24760136 TI - Altered glucose metabolism in mouse and humans conceived by IVF. AB - In vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation (OS) and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus natural birth under energy-balanced and high-fat-overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80 mU/m(2)/min), was lower in IVF patients (n = 14) versus control subjects (n = 20) after 3 days of an energy-balanced diet (30% fat). In response to 3 days of overfeeding (+1,250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P = 0.02). Mice conceived after either OS alone or IVF weighed significantly less at birth versus controls (P < 0.01). However, only mice conceived by IVF displayed increased fasting glucose levels, impaired glucose tolerance, and reduced insulin-stimulated Akt phosphorylation in the liver after 8 weeks of consuming either a chow or high-fat diet (60% fat). Thus, OS impaired fetal growth in the mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of the development of metabolic diseases later in life, in both mice and humans. PMID- 24760137 TI - Cerebral microvascular lesions on high-resolution 7-Tesla MRI in patients with type 2 diabetes. AB - Cerebral small vessel disease, including microvascular lesions, is considered to play an important role in the development of type 2 diabetes mellitus (T2DM) associated cognitive deficits. With ultra-high field MRI, microvascular lesions (e.g., microinfarcts and microbleeds) can now be visualized in vivo. For the current study, 48 nondemented older individuals with T2DM (mean age 70.3 +/- 4.1 years) and 49 age-, sex-, and education-matched control subjects underwent a 7 Tesla brain MRI scan and a detailed cognitive assessment. The occurrence of cortical microinfarcts and cerebral microbleeds was assessed on fluid-attenuated inversion recovery and T1-weighted and T2*-weighted images, respectively, compared between the groups, and related to cognitive performance. Microinfarcts were found in 38% of control subjects and 48% of patients with T2DM. Microbleeds were present in 41% of control subjects and 33% of patients (all P > 0.05). The presence and number of microinfarcts or microbleeds were unrelated to cognitive performance. This study showed that microvascular brain lesions on ultra-high field MRI are not significantly more common in well-controlled patients with T2DM than in control subjects. PMID- 24760138 TI - Liver-restricted Repin1 deficiency improves whole-body insulin sensitivity, alters lipid metabolism, and causes secondary changes in adipose tissue in mice. AB - Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue and maps within a quantitative trait locus (QTL) for body weight and triglyceride (TG) levels in the rat. The QTL has further been supported as a susceptibility locus for dyslipidemia and related metabolic disorders in congenic and subcongenic rat strains. Here, we elucidated the role of Repin1 in lipid metabolism in vivo. We generated a liver-specific Repin1 knockout mouse (LRep1(-/-)) and systematically characterized the consequences of Repin1 deficiency in the liver on body weight, glucose and lipid metabolism, liver lipid patterns, and protein/mRNA expression. Hyperinsulinemic-euglycemic clamp studies revealed significantly improved whole-body insulin sensitivity in LRep1(-/-) mice, which may be due to significantly lower TG content in the liver. Repin1 deficiency causes significant changes in potential downstream target molecules including Cd36, Ppargamma, Glut2 protein, Akt phosphorylation, and lipocalin2, Vamp4, and Snap23 mRNA expression. Mice with hepatic deletion of Repin1 display secondary changes in adipose tissue function, which may be mediated by altered hepatic expression of lipocalin2 or chemerin. Our findings indicate that Repin1 plays a role in insulin sensitivity and lipid metabolism by regulating key genes of glucose and lipid metabolism. PMID- 24760139 TI - Molecular signatures differentiate immune states in type 1 diabetic families. AB - Mechanisms associated with type 1 diabetes (T1D) development remain incompletely defined. Using a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially interleukin (IL)-1-dependent signatures associated with preonset and recent onset (RO) T1D relative to unrelated healthy control subjects (uHC). To better understand inherited susceptibility in T1D families, we conducted cross-sectional and longitudinal analyses of healthy autoantibody negative (AA(-)) high HLA-risk siblings (HRS) (DR3 and/or DR4) and AA(-) low HLA risk siblings (LRS) (non-DR3/non-DR4). Signatures, scored with a novel ontology based algorithm, and confirmatory studies differentiated the RO T1D, uHC, HRS, and LRS plasma milieus. Relative to uHC, T1D family members exhibited an elevated inflammatory state, consistent with innate receptor ligation that was independent of HLA, AA, or disease status and included elevated plasma IL-1alpha, IL-12p40, CCL2, CCL3, and CCL4 levels. Longitudinally, signatures of T1D progressors exhibited increasing inflammatory bias. Conversely, HRS possessing decreasing AA titers revealed emergence of an IL-10/transforming growth factor-beta-mediated regulatory state that paralleled temporal increases in peripheral activated CD4(+)/CD45RA(-)/FoxP3(high) regulatory T-cell frequencies. In AA(-) HRS, the familial innate inflammatory state also was temporally supplanted by immunoregulatory processes, suggesting a mechanism underlying the decline in T1D susceptibility with age. PMID- 24760140 TI - BH3-only molecule Bim mediates beta-cell death in IRS2 deficiency. AB - Irs2-deficient mice develop type 2-like diabetes due to a reduction in beta-cell mass and a failure of pancreatic islets to undergo compensatory hyperplasia in response to insulin resistance. In order to define the molecular mechanisms, we knocked down Irs2 gene expression in mouse MIN6 insulinoma cells. Insulin receptor substrate 2 (IRS2) suppression induced apoptotic cell death, which was associated with an increase in expression of the BH3-only molecule Bim. Knockdown (KD) of Bim reduced apoptotic beta-cell death induced by IRS2 suppression. In Irs2-deficient mice, Bim ablation restored beta-cell mass, decreased the number of TUNEL-positive cells, and restored normal glucose tolerance after glucose challenge. FoxO1 mediates Bim upregulation induced by IRS2 suppression, and FoxO1 KD partially inhibits beta-cell death induced by IRS2 suppression. These results suggest that Bim plays an important role in mediating the increase in beta-cell apoptosis and the reduction in beta-cell mass that occurs in IRS2-deficient diabetes. PMID- 24760141 TI - The pen is mightier than the keyboard: advantages of longhand over laptop note taking. AB - Taking notes on laptops rather than in longhand is increasingly common. Many researchers have suggested that laptop note taking is less effective than longhand note taking for learning. Prior studies have primarily focused on students' capacity for multitasking and distraction when using laptops. The present research suggests that even when laptops are used solely to take notes, they may still be impairing learning because their use results in shallower processing. In three studies, we found that students who took notes on laptops performed worse on conceptual questions than students who took notes longhand. We show that whereas taking more notes can be beneficial, laptop note takers' tendency to transcribe lectures verbatim rather than processing information and reframing it in their own words is detrimental to learning. PMID- 24760143 TI - When cognitive control is not adaptive. AB - In order to engage in goal-directed behavior, cognitive agents have to control the processing of task-relevant features in their environments. Although cognitive control is critical for performance in unpredictable task environments, it is currently unknown how it affects performance in highly structured and predictable environments. In the present study, we showed that, counterintuitively, top-down control can impair and interfere with the otherwise automatic integration of statistical information in a predictable task environment, and it can render behavior less efficient than it would have been without the attempt to control the flow of information. In other words, less can sometimes be more (in terms of cognitive control), especially if the environment provides sufficient information for the cognitive system to behave on autopilot based on automatic processes alone. PMID- 24760142 TI - A developmental pathway from early life stress to inflammation: the role of negative health behaviors. AB - Early life stressors are associated with elevated inflammation, a key physiological risk factor for disease. However, the mechanisms by which early stress leads to inflammation remain largely unknown. Using a longitudinal data set, we examined smoking, alcohol consumption, and body mass index (BMI) as health-behavior pathways by which early adversity might lead to inflammation during young adulthood. Contemporaneously measured early adversity predicted increased BMI and smoking but not alcohol consumption, and these effects were partially accounted for by chronic stress in young adulthood. Higher BMI in turn predicted higher levels of soluble tumor necrosis factor receptor type II (sTNF RII) and C-reactive protein (CRP), and smoking predicted elevated sTNF-RII. These findings establish that early adversity contributes to inflammation in part through ongoing stress and maladaptive health behavior. Given that maladaptive health behaviors portend inflammation in young adulthood, they serve as promising targets for interventions designed to prevent the negative consequences of early adversity. PMID- 24760144 TI - Gratitude: a tool for reducing economic impatience. AB - The human mind tends to excessively discount the value of delayed rewards relative to immediate ones, and it is thought that "hot" affective processes drive desires for short-term gratification. Supporting this view, recent findings demonstrate that sadness exacerbates financial impatience even when the sadness is unrelated to the economic decision at hand. Such findings might reinforce the view that emotions must always be suppressed to combat impatience. But if emotions serve adaptive functions, then certain emotions might be capable of reducing excessive impatience for delayed rewards. We found evidence supporting this alternative view. Specifically, we found that (a) the emotion gratitude reduces impatience even when real money is at stake, and (b) the effects of gratitude are differentiable from those of the more general positive state of happiness. These findings challenge the view that individuals must tamp down affective responses through effortful self-regulation to reach more patient and adaptive economic decisions. PMID- 24760145 TI - Orthographic coding in illiterates and literates. AB - We investigated how literacy modifies one of the mechanisms of the visual system that is essential for efficient reading: flexible position coding. To do so, we focused on the abilities of literates and illiterates to compare two-dimensional strings of letters (Experiment 1) and symbols (Experiment 2) in which the positions of characters had been manipulated. Results from two perceptual matching experiments revealed that literates were sensitive to alterations in characters' within-string position and identity, whereas illiterates are almost blind to these changes. We concluded that letter-position coding is a mechanism that emerges during literacy acquisition and that the recognition of sequences of objects is highly modulated by reading skills. These data offer new insights about the manner in which reading acquisition shapes the visual system by making it highly sensitive to the internal structure of sequences of characters. PMID- 24760146 TI - Recent aspects of self-oscillating polymeric materials: designing self oscillating polymers coupled with supramolecular chemistry and ionic liquid science. AB - Herein, we summarise the recent developments in self-oscillating polymeric materials based on the concepts of supramolecular chemistry, where aggregates of molecular building blocks with non-covalent bonds evolve the temporal or spatiotemporal structure. By utilising the rhythmic oscillation of the association/dissociation of molecular aggregates coupled with the redox oscillation by the BZ reaction, novel soft materials that express similar functions as those of living matter will be achieved. Further, from the viewpoint of materials science, our recent approach to prepare self-oscillating materials that operate long-term under mild conditions will be introduced. PMID- 24760148 TI - Acute-phase protein alpha1-antitrypsin--a novel regulator of angiopoietin-like protein 4 transcription and secretion. AB - The angiopoietin-like protein 4 (angptl4, also known as peroxisome proliferator activated receptor [PPAR]gamma-induced angiopoietin-related protein) is a multifunctional protein associated with acute-phase response. The mechanisms accounting for the increase in angptl4 expression are largely unknown. This study shows that human alpha1-antitrypsin (A1AT) upregulates expression and release of angplt4 in human blood adherent mononuclear cells and in primary human lung microvascular endothelial cells in a concentration- and time-dependent manner. Mononuclear cells treated for 1 h with A1AT (from 0.1 to 4 mg/ml) increased mRNA of angptl4 from 2- to 174-fold, respectively, relative to controls. In endothelial cells, the maximal effect on angptl4 expression was achieved at 8 h with 2 mg/ml A1AT (11-fold induction versus controls). In 10 emphysema patients receiving A1AT therapy (Prolastin), plasma angptl4 levels were higher relative to patients without therapy (nanograms per milliliter, mean [95% confidence interval] 127.1 [99.5-154.6] versus 76.8 [54.8-98.8], respectively, p = 0.045) and correlated with A1AT levels. The effect of A1AT on angptl4 expression was significantly diminished in cells pretreated with a specific inhibitor of ERK1/2 activation (UO126), irreversible and selective PPARgamma antagonist (GW9662), or genistein, a ligand for PPARgamma. GW9662 did not alter the ability of A1AT to induce ERK1/2 phosphorylation, suggesting that PPARgamma is a critical mediator in the A1AT-driven angptl4 expression. In contrast, the forced accumulation of HIF-1alpha, an upregulator of angptl4 expression, enhanced the effect of A1AT. Thus, acute-phase protein A1AT is a physiological regulator of angptl4, another acute-phase protein. PMID- 24760147 TI - Calpain-1 contributes to IgE-mediated mast cell activation. AB - Mast cells play a central role in allergy through secretion of both preformed and newly synthesized mediators. Mast cell mediator secretion is controlled by a complex network of signaling events. Despite intensive studies, signaling pathways in the regulation of mast cell mediator secretion remain incompletely defined. In this study, we examined the role of calpain in IgE-dependent mast cell activation. IgE-mediated activation of mouse bone marrow-derived mast cells enhanced calpain activity. Inhibition of calpain activity by a number of calpain inhibitors reduced IgE-mediated mast cell degranulation both in vitro and in vivo. Calpain inhibitors blocked IgE-mediated TNF and IL-6 production in vitro and reduced late-phase allergic response in vivo. Importantly, mouse calpain-1 null bone marrow-derived mast cells showed reduced IgE-mediated mast cell degranulation in vitro and in vivo, diminished cytokine and chemokine production in vitro, and impaired late-phase allergic response in vivo. Further studies revealed that calpain-1 deficiency led to specific attenuation of IkappaB-NF kappaB pathway and IKK-SNAP23 pathway, whereas calcium flux, MAPK, Akt, and NFAT pathway proceed normally in IgE-activated calpain-1 null mast cells. Thus, calpain-1 is identified as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation. PMID- 24760149 TI - TLR3 activation augments matrix metalloproteinase production through reactive nitrogen species generation in human lung fibroblasts. AB - Viral infection often triggers asthma exacerbation and contributes to airway remodeling. Cell signaling in viral infection is mainly mediated through TLR3. Many mediators are involved in airway remodeling, but matrix metalloproteinases (MMPs) are key players in this process in asthma. However, the role of TLR3 activation in production of MMPs is unknown. In this study, we examined the effects of polyinosinic-polycytidylic acid [poly(I:C)], a ligand for TLR3, on production of MMPs in human lung fibroblasts, with a focus on nitrosative stress in TLR3 modulation of MMP production. After lung fibroblasts were treated with poly(I:C), production of MMP-1, -2, and -9 and inducible NO synthase (iNOS) was assessed. The roles of NF-kappaB and IFN regulatory factor-3 (IRF-3) in the poly(I:C)-mediated production of MMPs and the responsiveness to poly(I:C) of normal lung fibroblasts and asthmatic lung fibroblasts were also investigated. Poly(I:C) augmented production of MMPs and iNOS in fibroblasts, and an iNOS inhibitor diminished this production of MMPs. Poly(I:C) stimulated translocation of NF-kappaB and IRF-3 into the nucleus in fibroblasts and inhibition of NF kappaB or IRF-3 abrogated the poly(I:C)-induced increase in both iNOS expression and release of MMPs. Poly(I:C)-induced production of iNOS and MMPs was greater in asthmatic fibroblasts than in normal fibroblasts. We conclude that viral infection may induce nitrosative stress and subsequent MMP production via NF kappaB- and IRF-3-dependent pathways, thus potentiating viral-induced airway remodeling in asthmatic airways. PMID- 24760150 TI - Impact of asymptomatic herpes simplex virus type 2 infection on mucosal homing and immune cell subsets in the blood and female genital tract. AB - HSV-2 infection is common and generally asymptomatic, but it is associated with increased HIV susceptibility and disease progression. This may relate to herpes mediated changes in genital and systemic immunology. Cervical cytobrushes and blood were collected from HIV-uninfected African/Caribbean women in Toronto, and immune cell subsets were enumerated blindly by flow cytometry. Immune differences between groups were assessed by univariate analysis and confirmed using a multivariate model. Study participants consisted of 46 women, of whom 54% were infected with HSV-2. T cell activation and expression of the mucosal homing integrin alpha4beta7 (19.60 versus 8.76%; p < 0.001) were increased in the blood of HSV-2-infected women. Furthermore, expression of alpha4beta7 on blood T cells correlated with increased numbers of activated (coexpressing CD38/HLA-DR; p = 0.004) and CCR5(+) (p = 0.005) cervical CD4(+) T cells. HSV-2-infected women exhibited an increase in the number of cervical CD4(+) T cells (715 versus 262 cells/cytobrush; p = 0.016), as well as an increase in the number and proportion of cervical CD4(+) T cells that expressed CCR5(+) (406 versus 131 cells, p = 0.001; and 50.70 versus 34.90%, p = 0.004) and were activated (112 versus 13 cells, p < 0.001; and 9.84 versus 4.86%, p = 0.009). Mannose receptor expression also was increased on cervical dendritic cell subsets. In conclusion, asymptomatic HSV-2 infection was associated with significant systemic and genital immune changes, including increased immune activation and systemic alpha4beta7 expression; correlation of the latter with highly HIV-susceptible CD4(+) T cell subsets in the cervix may provide a mechanism for the increased HIV susceptibility observed in asymptomatic HSV-2-infected women. PMID- 24760151 TI - Ezh2 regulates transcriptional and posttranslational expression of T-bet and promotes Th1 cell responses mediating aplastic anemia in mice. AB - Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome. IFN-gamma-producing Th1 CD4(+) T cells mediate the immune destruction of hematopoietic cells, and they are central to the pathogenesis. However, the molecular events that control the development of BM-destructive Th1 cells remain largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple cellular processes primarily by silencing gene expression. We recently reported that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the effects of Ezh2 inhibition in CD4(+) T cells using a mouse model of human AA. Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant decrease in the expression of Tbx21 and Stat4, which encode transcription factors T-bet and STAT4, respectively. Introduction of T-bet but not STAT4 into Ezh2-deficient T cells fully rescued their differentiation into Th1 cells mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells and directly activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent proteasome-mediated degradation of T-bet protein in Th1 cells. Our results demonstrate that Ezh2 promotes the generation of BM-destructive Th1 cells through a mechanism of transcriptional and posttranscriptional regulation of T-bet. These results also highlight the therapeutic potential of Ezh2 inhibition in reducing AA and other autoimmune diseases. PMID- 24760152 TI - Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils. AB - High-dose i.v. Ig (IVIG) is used to treat various autoimmune and inflammatory diseases; however, the mechanism of action remains unclear. Based on the K/BxN serum transfer arthritis model in mice, IVIG suppression of inflammation has been attributed to a mechanism involving basophils and the binding of highly sialylated IgG Fc to DC-SIGN-expressing myeloid cells. The requirement for sialylation was examined in the collagen Ab-induced arthritis (CAbIA) and K/BxN serum transfer arthritis models in mice. High-dose IVIG (1-2 g/kg body weight) suppressed inflammatory arthritis when given prophylactically. The same doses were also effective in the CAbIA model when given subsequent to disease induction. In this therapeutic CAbIA model, the anti-inflammatory effect of IVIG was dependent on IgG Fc but not F(ab')2 fragments. Removal of sialic acid residues by neuraminidase had no impact on the anti-inflammatory activity of IVIG or Fc fragments. Treatment of mice with basophil-depleting mAbs did not abrogate the suppression of either CAbIA or K/BxN arthritis by IVIG. Our data confirm the therapeutic benefit of IVIG and IgG Fc in Ab-induced arthritis but fail to support the significance of sialylation and basophil involvement in the mechanism of action of IVIG therapy. PMID- 24760153 TI - Kinetics of B cell responses to Plasmodium falciparum erythrocyte membrane protein 1 in Ghanaian women naturally exposed to malaria parasites. AB - Naturally acquired protective immunity to Plasmodium falciparum malaria takes years to develop. It relies mainly on Abs, particularly IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins on the infected erythrocyte surface. It is only partially understood why acquisition of clinical protection takes years to develop, but it probably involves a range of immune-evasive parasite features, not least of which are PfEMP1 polymorphism and clonal variation. Parasite-induced subversion of immunological memory and expansion of "atypical" memory B cells may also contribute. In this first, to our knowledge, longitudinal study of its kind, we measured B cell subset composition, as well as PfEMP1-specific Ab levels and memory B cell frequencies, in Ghanaian women followed from early pregnancy up to 1 y after delivery. Cell phenotypes and Ag-specific B cell function were assessed three times during and after pregnancy. Levels of IgG specific for pregnancy-restricted, VAR2CSA-type PfEMP1 increased markedly during pregnancy and declined after delivery, whereas IgG levels specific for two PfEMP1 proteins not restricted to pregnancy did not. Changes in VAR2CSA-specific memory B cell frequencies showed typical primary memory induction among primigravidae and recall expansion among multigravidae, followed by contraction postpartum in all. No systematic changes in the frequencies of memory B cells specific for the two other PfEMP1 proteins were identified. The B cell subset analysis confirmed earlier reports of high atypical memory B cell frequencies among residents of P. falciparum-endemic areas, and indicated an additional effect of pregnancy. Our study provides new knowledge regarding immunity to P. falciparum malaria and underpins efforts to develop PfEMP1-based vaccines against this disease. PMID- 24760154 TI - Transient systemic inflammation does not alter the induction of tolerance to gastric autoantigens by migratory dendritic cells. AB - It has been proposed that activation of dendritic cells (DCs) presenting self antigens during inflammation may lead to activation of autoreactive T cells and the development of autoimmunity. To test this hypothesis, we examined the presentation of the autoantigen recognized in autoimmune gastritis, gastric H(+)/K(+) ATPase, which is naturally expressed in the stomach and is constitutively presented in the stomach-draining lymph nodes. Systemic administration to mice of the TLR9 agonist CpG DNA, agonist anti-CD40 Ab, or TLR4 agonist LPS all failed to abrogate the process of peripheral clonal deletion of H(+)/K(+) ATPase-specific CD4 T cells or promote the development of autoimmune gastritis. We demonstrated that migratory DCs from the stomach-draining lymph nodes are the only DC subset capable of constitutively presenting the endogenous gastric H(+)/K(+) ATPase autoantigen in its normal physiological context. Analysis of costimulatory molecules indicated that, relative to resident DCs, migratory DCs displayed a partially activated phenotype in the steady state. Furthermore, migratory DCs were refractory to stimulation by transient exposure to TLR agonists, as they failed to upregulate costimulatory molecules, secrete significant amounts of inflammatory cytokines, or induce differentiation of effector T cells. Together, these data show that transient systemic inflammation failed to break tolerance to the gastric autoantigen, as migratory DCs presenting the gastric autoantigen remain tolerogenic under such conditions, demonstrating the robust nature of peripheral tolerance. PMID- 24760155 TI - MIF promotes B cell chemotaxis through the receptors CXCR4 and CD74 and ZAP-70 signaling. AB - Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine-like functions that plays a pivotal role in the pathogenesis of inflammatory diseases by promoting leukocyte recruitment. We showed that MIF promotes the atherogenic recruitment of monocytes and T cells through its receptors CXCR2 and CXCR4. Effects of MIF on B cell recruitment have not been addressed. In this study, we tested the involvement of MIF in B cell chemotaxis and studied the underlying mechanism. We show that MIF promotes primary murine B cell chemotaxis in a dose-dependent manner, comparable to the B cell chemokines CXCL13 and CXCL12. Splenic B cells express CXCR4 and the receptor CD74 but not CXCR2. Inhibition of CXCR4 or CD74 or a genetic deficiency of Cd74 in primary B cells fully abrogated MIF-mediated B cell migration, implying cooperative involvement of both receptors. MIF stimulation of B cells resulted in a rapid increase in intracellular Ca(2+) mobilization and F-actin polymerization. Intriguingly, the tyrosine kinase ZAP-70 was activated upon MIF and CXCL12 treatment in a CXCR4- and CD74-dependent manner. Pharmacological inhibition of ZAP-70 resulted in abrogation of primary B cell migration. Functional involvement of ZAP-70 was confirmed by small interfering RNA-mediated knockdown in Ramos B cell migration. Finally, primary B cells from ZAP-70 gene-deficient mice exhibited ablated transmigration in response to MIF or CXCL12. We conclude that MIF promotes the migration of B cells through a ZAP-70-dependent pathway mediated by cooperative engagement of CXCR4 and CD74. The data also suggest that MIF may contribute to B cell recruitment in vivo (e.g., in B cell-related immune disorders). PMID- 24760157 TI - Prevention and management of pressure ulcers in primary and secondary care: summary of NICE guidance. PMID- 24760158 TI - Should doctors prescribe cannabinoids? PMID- 24760159 TI - TV advertisement that linked alcohol with cancer was not misleading, says UK regulator. PMID- 24760160 TI - Emergency medicine team of the year. PMID- 24760161 TI - The horizontal Y-shaped graft with respective graft tension angles in anatomical two-bundle medial patellofemoral ligament reconstruction. AB - PURPOSE: Various techniques for medial patellofemoral ligament (MPFL) reconstruction have been described with two bundles of graft tensioned simultaneously. The present study was to introduce an anatomical reconstruction procedure using a horizontal Y-shaped graft with respective graft tension angles and report the preliminary results. METHODS: A surgical technique for MPFL reconstruction using a horizontal Y-shaped semitendinosus tendon autograft with two bundles tensioned at 0 degrees and 30 degrees of knee flexion was described in detail. The patellar stability was evaluated with the apprehension test and an axial computed tomography (CT) scan at 30 degrees of knee flexion. The knee function was evaluated using the Lysholm and Kujala scores. RESULTS: No recurrent dislocation or subluxation was reported for 45 patients at a mean of 33.7-month follow-up. On CT images, congruence angle, patellar tilt angle, lateral patellar angle and lateral displacement were restored to the normal range. At the last follow-up, the mean Lysholm score improved from 51.8+/-6.2 to 91.7+/-4.1 and mean Kujala score was from 53.4+/-5.3 to 90.9+/-6.6 (P<0.01). CONCLUSIONS: The present anatomical MPFL reconstruction technique with a horizontal Y-shaped two-bundle graft tensioned at respective knee flexion angles could not only recreate the fan shape of MPFL but also mimic the function bundles of native ligament. Clinical follow-up confirms the good restoration of the patellar stability and significant improvement of knee function without special complications. LEVEL OF EVIDENCE: Therapeutic, Level IV. PMID- 24760162 TI - Femoral shaft bowing in the coronal plane has more significant effect on the coronal alignment of TKA than proximal or distal variations of femoral shape. AB - PURPOSE: The aim of this study was to determine (1) variations in the shape of the proximal, middle, and distal femur in a series of Korean patients who had undergone total knee arthroplasty (TKA), (2) the preoperative relationship between these three parameters and the distal valgus cutting angle referenced off the femoral intramedullary guide, and (3) whether there was any relationship between femoral bowing and variations in the shape of the proximal or distal femur in the coronal plane. METHODS: The preoperative long-standing anteroposterior radiographs of 316 consecutive osteoarthritis patients who underwent primary TKA from 2009 to 2011 were examined. The femoral neck shaft angle, the femoral shaft bowing angle, and the mechanical lateral distal femoral angle were measured to assess the shape of the proximal, middle, and distal femur, respectively. The valgus cutting angle of the femur was defined as the angle between the distal anatomical and mechanical axes of the femur. RESULTS: The study population showed large variations in femoral shape. The mean femoral intramedullary guide angle was 6.5 degrees +/- 1.3 degrees (range: 4 degrees 13 degrees ). The femoral shaft bowing angle was the factor that showed the strongest correlation with this angle (P < 0.001). The mechanical lateral distal femoral angle showed only a weak correlation (P = 0.001), and the femoral neck shaft angle showed no correlation (n.s.). The femoral shaft bowing angle showed a weak correlation with the mechanical lateral distal femoral angle (P = 0.001), but was not significantly correlated with the femoral neck shaft angle (n.s.). Apparent femoral bowing (>3 degrees of lateral or medial bowing) was found in 42 (13.3 %) of cases (37 cases of lateral bowing and five of medial bowing). Cases with lateral apparent femoral bowing >3 degrees had a distal cutting angle of 8.6 degrees +/- 2.2 degrees relative to the femoral intramedullary guide. CONCLUSION: The femoral intramedullary guide angle was mainly influenced by femoral shaft bowing among femoral deformities in the coronal plane. Therefore, to increase the accuracy of distal femoral cut during TKA, it is necessary to confirm femoral deformities and to measure the femoral intramedullary guide angle preoperatively from coronal radiographs covering the whole femur. LEVEL OF EVIDENCE: IV. PMID- 24760163 TI - Holistic approach to understanding anterior knee pain. Clinical implications. AB - Anterior knee pain is one of the most frequent reasons for consultation within knee conditions. The aetiology is not well known, which explains the sometimes unpredictable results of its treatment. Normally, when we see a patient in the office with anterior knee pain, we only study and focus on the knee. If we do this, we are making a big mistake. We must not forget to evaluate the pelvis and proximal femur, as well as the psychological factors that modulate the course of the illness. Both the pelvifemoral dysfunction as well as the psychological factors (anxiety, depression, catastrophization and kinesiophobia) must be included in our therapeutic targets of the multidisciplinary treatment of anterior knee pain. We must not only focus on the knee, we must remember to "look up" to fully understand what is happening and be able to solve this difficult problem. The aetiology of anterior knee pain is multifactorial. Therefore, diagnosis and treatment of patellofemoral disorders must be individualized. Our findings stress the importance of tailoring physiotherapy, surgery and psycho educational interventions to each patient. PMID- 24760164 TI - Total patellectomy in knees without prior arthroplasty: a systematic review. AB - PURPOSE: Total patellectomy is a radical procedure and is only used as a last resort. The functional results reported in the literature are contradictory. The purpose of this review of the literature is to evaluate the functional outcome that can be expected after total patellectomy. METHODS: The systematic review was conducted in accordance with the PRISMA statement criteria using the PubMed/MEDLINE database, the EMBASE database, the Cochrane library databases, and the OVID database. Patellectomies were performed either alone or in conjunction with reinforcement of the extensor mechanism; they were longitudinal or transverse. Analysis was first descriptive and then comparative based on medians. RESULTS: Research identified 394 articles, of which 31 have been included in this review, describing a total of 1,416 knees with a mean follow-up of 7 years. The mean percentage of outcomes judged good or excellent per article was 68.8% (min max: 29-100%). The complication rate identified was 20.3% (7.6% without calcifications). The functional outcome was considered better in the group undergoing reinforcement of the extensor mechanism [median of percentages per article at 93, IQR = (74-95) vs. 67 (55-79) in the group patellectomy alone]. CONCLUSION: Total patellectomy gives good or excellent results in 85% of cases if reinforcement is performed with a longitudinal excision. LEVEL OF EVIDENCE: IV. PMID- 24760165 TI - Laparoscopic transabdominal inguinal hernia repair in community hospital settings: a general surgeon's last 10 years experience. AB - Numerous studies have documented the laparoscopic TransAbdominal Pre-Peritoneal (TAPP) approach as an excellent choice for inguinal hernia repair, especially with an experienced surgeon. A cohort population of patients who underwent TAPP laparoscopic surgery for inguinal hernias over the last 10 years, with follow-up, were evaluated, focusing on the feasibility, safety and benefits of this procedure in a community hospital setting. MATERIALS AND METHODS: A total of 533 patients underwent TAPP for inguinal hernias between January 2003 and March 2013 in two community hospitals in the Northeast of Italy-"Civil Hospital" in Vittorio Veneto (TV) and "Civil Hospital" in Adria (RO). RESULTS: The total number of hernias treated was 1,000. The overall mean operative time was 43.50 min (+/ 13.2). All but three of the procedures were done on a day surgery basis. There were no conversions to open repair or deaths in our series. We had two cases of small bowel obstruction and eight relapses (0.8 %) in our series. The mean follow up was 59.4 months (+/-5.6; range 3-120). No patients reported severe pain at 10 days, 21 patients (3.9 %) reported mild pain at 3-month follow-up. Over 90 % of the patients had a return of physical work capacity within 2 weeks, the remaining within 30 days. All patients were completely satisfied (numerical rating scale 10/10) 3 months after the operation. CONCLUSIONS: The analysis of the short- and long-term post-operative outcomes of our experience enabled us to conclude that in an appropriate setting, TAPP is feasible, effective, safe and beneficial for patients. It should be incorporated into general surgeons' expertise and selectively used for the management of patients with hernias, as long as adequate training is obtained and appropriate preparation performed. PMID- 24760166 TI - Effectiveness of muscle strengthening and description of protocols for preventing falls in the elderly: a systematic review. AB - BACKGROUND: Falls are a geriatric syndrome that is considered a significant public health problem in terms of morbidity and mortality because they lead to a decline in functional capacity and an impaired quality of life in the elderly. Lower limb muscle strengthening seems to be an effective intervention for preventing falls; however, there is no consensus regarding the best method for increasing lower limb muscle strength. OBJECTIVES: To analyze the effectiveness of lower limb muscle strengthening and to investigate and describe the protocols used for preventing falls in elderly subjects. METHOD: We performed a systematic review of randomized and controlled clinical trials published between 2002 and 2012 in the databases PubMed, EMBASE, Scopus, Web of Science, and PEDro that cited some type of lower limb muscle strengthening protocol and that evaluated the incidence of falls as the primary outcome exclusively in elderly subjects. Twelve studies met the inclusion criteria. Qualitative analysis was performed by independent reviewers applying the PEDro scale. RESULTS: The data obtained from the selected studies showed lower fall rates in the intervention groups compared to controls. Six studies described the lower limb muscle strengthening protocol in detail. High methodological quality was found in 6 studies (PEDro score >= 7/10 points). CONCLUSIONS: The methodological quality of the studies in this area appears to leave little doubt regarding the effectiveness of lower limb strengthening exercises for preventing falls in elderly subjects, however the interventions in these studies were poorly reported. PMID- 24760168 TI - A complex population structure of the cassava pathogen Xanthomonas axonopodis pv. manihotis in recent years in the Caribbean Region of Colombia. AB - Cassava bacterial blight, caused by Xanthomonas axonopodis pv. manihotis (Xam), is the most important bacterial disease affecting this crop. A continuous surveillance of the pathogen population dynamics is required to develop an efficient disease management program. During the 1990s, Xam populations showed high levels of genetic variation and relevant migratory processes that were important determinants of the distribution of the pathogen diversity in Colombia. Aiming to characterize the current population structure of the pathogen and the evolutionary forces that shape these populations, sampling collections were carried out from September 2008 until November 2010 in the Colombian Caribbean Region. One hundred and sixty bacterial isolates were characterized using amplified fragment length polymorphism (AFLP) markers. Additionally, a subset of effector genes were sequenced in some isolates to determine their usefulness in Xam population studies and to provide additional information to that obtained with AFLPs. Virulence patterns of ten isolates were determined in nine cassava accessions. Our results show a complex architecture of population and confirm migratory process previously reported in the Caribbean Region. Chinu, one of the locations sampled, presented remarkable features in population dynamics such as longer genetic distances, higher diversity indices, and a genetically differentiated population when it was compared with other locations. Virulence tests showed that MCOL2215, one of the most cultivated cassava varieties in the Caribbean coast, was susceptible to the majority of Xam isolates tested. This study shows the current condition of populations of Xam in the Caribbean Region of Colombia, and it contributes to improve the existing bacterial blight control practices. PMID- 24760167 TI - Plasmid-related quinolone resistance determinants in epidemic Vibrio parahaemolyticus, uropathogenic Escherichia coli, and marine bacteria from an aquaculture area in Chile. AB - Marine bacteria from aquaculture areas with industrial use of quinolones have the potential to pass quinolone resistance genes to animal and human pathogens. The VPA0095 gene, related to the quinolone resistance determinant qnrA, from clinical isolates of epidemic Vibrio parahaemolyticus conferred reduced susceptibility to quinolone after cloning into Escherichia coli K-12 either when acting alone or synergistically with DNA gyrase mutations. In addition, a plasmid-mediated quinolone resistance gene from marine bacteria, aac(6')-Ib-cr, was identical to aac(6')-Ib-cr from urinary tract isolates of E. coli, suggesting a recent flow of this gene between these bacteria isolated from different environments. aac(6')-Ib cr from E. coli also conferred reduced susceptibility to quinolone and kanamycin when cloned into E. coli K-12. PMID- 24760170 TI - Pyrosequencing reveals the microbial communities in the Red Sea sponge Carteriospongia foliascens and their impressive shifts in abnormal tissues. AB - Abnormality and disease in sponges have been widely reported, yet how sponge associated microbes respond correspondingly remains inconclusive. Here, individuals of the sponge Carteriospongia foliascens under abnormal status were collected from the Rabigh Bay along the Red Sea coast. Microbial communities in both healthy and abnormal sponge tissues and adjacent seawater were compared to check the influences of these abnormalities on sponge-associated microbes. In healthy tissues, we revealed low microbial diversity with less than 100 operational taxonomic units (OTUs) per sample. Cyanobacteria, affiliated mainly with the sponge-specific species "Candidatus Synechococcus spongiarum," were the dominant bacteria, followed by Bacteroidetes and Proteobacteria. Intraspecies dynamics of microbial communities in healthy tissues were observed among sponge individuals, and potential anoxygenic phototrophic bacteria were found. In comparison with healthy tissues and the adjacent seawater, abnormal tissues showed dramatic increase in microbial diversity and decrease in the abundance of sponge-specific microbial clusters. The dominated cyanobacterial species Candidatus Synechococcus spongiarum decreased and shifted to unspecific cyanobacterial clades. OTUs that showed high similarity to sequences derived from diseased corals, such as Leptolyngbya sp., were found to be abundant in abnormal tissues. Heterotrophic Planctomycetes were also specifically enriched in abnormal tissues. Overall, we revealed the microbial communities of the cyanobacteria-rich sponge, C. foliascens, and their impressive shifts under abnormality. PMID- 24760169 TI - Changes in sediment bacterial community in response to long-term nutrient enrichment in a subtropical seagrass-dominated estuary. AB - Florida Bay exhibits a natural gradient of strong P limitation in the east which shifts to weak P or even N limitation at the western boundary. This nutrient gradient greatly affects seagrass abundance and productivity across the bay. We assessed the effects of N and P additions on sediment bacterial community structure in relation to the existing nutrient gradient in Florida Bay. Sediment samples from 24 permanent 0.25 m(2) plots in each of six sites across Florida Bay were fertilized with granular N and P in a factorial design for 26 months. Sediment bacterial community structure was analyzed using PCR-denaturing gradient gel electrophoresis (DGGE) analysis of 16S ribosomal RNA (rRNA) genes and a cloning strategy from DGGE bands. The phylogenetic positions of 16S rRNA sequences mostly fell into common members found in marine sediments such as sulfate-reducing Deltaproteobacteria, Gammaproteobacteria, Spirochaetes, and Bacteriodetes. Twenty-eight common DGGE bands were found in all sediment samples; however, some DGGE bands were only found or were better represented in eastern sites. Bacterial community diversity (Shannon-Weiner index) showed similar values throughout all sediment samples. The N treatment had no effect on the bacterial community structures across the bay. Conversely, the addition of P significantly influenced the bacterial community structure at all but the most western site, where P is least limiting due to inputs from the Gulf of Mexico. P additions enhanced DGGE band sequences related to Cytophagales, Ectothiorhodospiraceae, and Desulfobulbaceae, suggesting a shift toward bacterial communities with increased capability to degrade polymeric organic matter. In addition, a band related to Deferribacteres was enhanced in eastern sites. Thus, indigenous environmental conditions were the primary determining factors controlling the bacterial communities, while the addition of P was a secondary determining factor. This P induced change in community composition tended to be proportional to the amount of P limitation obviated by the nutrient additions. PMID- 24760171 TI - Insights into biodegradation through depth-resolved microbial community functional and structural profiling of a crude-oil contaminant plume. AB - Small-scale geochemical gradients are a key feature of aquifer contaminant plumes, highlighting the need for functional and structural profiling of corresponding microbial communities on a similar scale. The purpose of this study was to characterize the microbial functional and structural diversity with depth across representative redox zones of a hydrocarbon plume and an adjacent wetland, at the Bemidji Oil Spill site. A combination of quantitative PCR, denaturing gradient gel electrophoresis, and pyrosequencing were applied to vertically sampled sediment cores. Levels of the methanogenic marker gene, methyl coenzyme-M reductase A (mcrA), increased with depth near the oil body center, but were variable with depth further downgradient. Benzoate degradation N (bzdN) hydrocarbon-degradation gene, common to facultatively anaerobic Azoarcus spp., was found at all locations, but was highest near the oil body center. Microbial community structural differences were observed across sediment cores, and bacterial classes containing known hydrocarbon degraders were found to be low in relative abundance. Depth-resolved functional and structural profiling revealed the strongest gradients in the iron-reducing zone, displaying the greatest variability with depth. This study provides important insight into biogeochemical characteristics in different regions of contaminant plumes, which will aid in improving models of contaminant fate and natural attenuation rates. PMID- 24760172 TI - Mixing analysis of PCS slurries in a horizontal scraped surface bioreactor. AB - Horizontal rotating reactors offer many advantages for enzymatic hydrolysis of viscous biomass slurries; however, they do not provide homogenous mixtures since motion is only in the angular direction. Multi-directional mixing is important for dispersing enzymes and carrying products away from reaction sites. The objective here was to experimentally quantify mixing times and axial dispersion coefficients in a horizontal rotating bioreactor. Mixing times were of the same order as reaction times, indicating that enzymatic hydrolysis could be as much controlled by diffusion and mixing effects as by the complex reaction mechanism. The dispersion coefficient for the highest solids slurry was 20* less than the lowest solids slurry, which is indicative of the difference in free water and the magnitude change of viscosity with relatively small addition of solids. The slow mixing times and low dispersion may be an acceptable tradeoff with significantly lower power requirements compared to a conventional vertical reactor. PMID- 24760173 TI - Synthesis and characterization of cysteine functionalized silver nanoparticles for biomolecule immobilization. AB - A facile method for the aqueous phase synthesis of cysteine-functionalized silver nanoparticles by potato extract has been reported in the present work. These functionalized nanoparticles were then used for the covalent immobilization of a biomolecule, alkaline phosphatase, on its surface through carbodiimide coupling. Different reaction parameters such as cysteine concentration, reducing agent concentration, temperature, pH and reaction time were varied during the nanoparticles' formation, and their effects on plasmon resonance were studied using Ultraviolet-visible spectroscopy. Fourier transform infrared spectroscopy was used to confirm the surface modification of silver nanoparticles by cysteine and the particle size analysis was done using particle size analyzer, which showed the average nanoparticles' size of 61 nm for bare silver nanoparticles and 201 nm for the enzyme-immobilized nanoparticles. The synthesized nanoparticles were found to be highly efficient for the covalent immobilization of alkaline phosphatase on its surface and retained 67% of its initial enzyme activity (9.44 U/mg), with 75% binding efficiency. The shelf life of the enzyme-nanoparticle bioconjugates was found to be 60 days, with a 12% loss in the initial enzyme activity. With a simple synthesis strategy, high immobilization efficiency and enhanced stability, these enzyme-coated nanoparticles have the potential for further integration into the biosensor technology. PMID- 24760174 TI - Effect of ozone exposure on the electrical characteristics of high-purity, large diameter semiconducting carbon nanotubes. AB - In this study, we have elucidated the interactions between ozone and carbon nanotubes by monitoring the characteristics of field-effect transistors based on polymer-sorted, large-diameter semiconducting carbon nanotubes. The drain-source current of these transistors initially increases with ozone exposure and then it progressively decreases with increasing exposure beyond 3 min. This non-monotonic dependence of the drain-source current can be ascribed to two competing processes. At short ozone exposure, p-doping of carbon nanotubes dominates; the drain-source current thus increases as a result of increasing hole concentration. This effect is most evidenced in a progressive threshold voltage shift towards positive voltages with increasing exposure to ozone. At extended ozone exposure, chemical oxidation of carbon nanotubes instead dominates. The drain-source current decreases as a result of decreasing hole mobility. This effect manifests itself in a monotonic decrease in the mobility of these devices as a function of ozone exposure. PMID- 24760175 TI - TiO2(B) nanoparticle-functionalized WO3 nanorods with enhanced gas sensing properties. AB - In this work, TiO2(B) nanoparticle (NP)-functionalized WO3 nanorods (NRs) were synthesized by a two-step solution strategy, with a hydrothermal process for WO3 NRs and hydrolyzation of Ti(OBu)4 for the functionalization of TiO2(B) NPs. Various techniques, including scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS), were employed to investigate the morphology, microstructure, crystalline nature and chemical composition of the prepared TiO2(B) NP functionalized WO3 NRs. SEM and TEM results revealed that the TiO2(B)-WO3 composite showed a rod-like nanostructure with a diameter in the range from 93 to 154 nm and a rough surface, which could increase the accessible surface area and the amount of surface active sites, thus improving the properties or performance of the as-prepared composite NRs. XRD and XPS analysis clearly verified that monoclinic TiO2(B) NPs, a metastable polymorph of TiO2, were successfully supported on the WO3 NRs. Gas sensing measurement results for several common reductive organic gases such as acetone, ethanol, ether, methanol and formaldehyde demonstrated that the sensor based on the as-obtained TiO2(B) NP functionalized WO3 NRs exhibited obviously enhanced responses compared with a pure WO3 NR based sensor, as well as fast response-recovery speeds, good reproducibility and good stability, indicating their promising application in gas sensors. The excellent gas sensing performance could be attributed to the unique 1D rod-like nanostructure with a rough surface, the existence of TiO2-WO3 heterojunctions and the catalytic effect of the TiO2(B) NPs. The as-prepared TiO2(B) NP-functionalized WO3 NRs will also have very good prospects in electrochromic devices and catalysis applications. PMID- 24760176 TI - Downregulation of miR-214 is specific of liver metastasis in colorectal cancer and could play a role determining the metastatic niche. PMID- 24760177 TI - Chicks of the great spotted cuckoo may turn brood parasitism into mutualism by producing a foul-smelling secretion that repels predators. AB - The great spotted cuckoo (Clamator glandarius) is an important brood parasite of carrion crows (Corvus corone corone) in northern Spain. We recently found that, unlike what is commonly known for cuckoo-host interactions, the great spotted cuckoo has no negative impact on average crow fitness in this region. The explanation for this surprising effect is a repulsive secretion that the cuckoo chicks produce when they are harassed and that may protect the brood against predation. Here, we provide details on the chemical composition of the cuckoo secretion, as well as conclusive evidence that the dominating volatile chemicals in the secretion are highly repellent to model species representative of common predators of the crows. These results support the notion that, in this particular system, the production of a repulsive secretion by the cuckoo chicks has turned a normally parasitic interaction into a mutualistic one. PMID- 24760178 TI - [Sexuality and depression among pregnant women with recurrent spontaneous abortion]. AB - PURPOSE: It was to compare pregnant women who experienced recurrent spontaneous abortion (RSA) and those who did not in terms of the prevalence of depressive symptoms and sexual behavior. METHODS: A prospective case-control study was carried out. The first group consisted of women with RSA and the second, of primigravidae. The Beck Depression Inventory (BDI), the Female Sexual Function Index (FSFI) and one more questionnaire, developed by the authors themselves, about emotional aspects resulting from sexual intercourse during pregnancy were applied. The Student t-test was used to compare quantitative variables with normal distribution, and categorical variables were compared by the chi-square test or Fisher's exact test. The level of significance was set at p<0.05. RESULTS: The BDI showed (19.9 versus 10.0%) approximately twice the incidence of depression in the RSA group. Regarding sexual function, the average scores of the FSFI were 21.1 and 16.4 (p<0.05) for the study and control groups, respectively, although no significant difference was observed only in the desire domain (average 3.4+/-1.3 for the RSA group and 3.7+/-1.1 for control group) (p=0.1). We observed that, regardless the presence or absence of an RSA history among the pregnant women, the higher the depression score, the lower the sexuality score (r=-0,3). CONCLUSIONS: The RSA pregnant group often experiences twice higher depression and more impaired sexual function. There is an inverse association between depression and sexual function. PMID- 24760179 TI - Arterial contour detectability in head CT angiography. AB - PURPOSE: Arterial contour extraction is essential for visualization and analysis of vasculature in CT angiography (CTA). A means for evaluating the detectability of artery contours CTA images is required. We developed and tested a new method for this purpose based on phase information from two-dimensional Fourier transforms of CTA images. The relationship between arterial contour detectability and a patient's ocular lens dose was evaluated in CTA images obtained with various tube voltages and currents. METHODS: A head phantom was designed for use as a target object containing a simulated vascular tree, filled with dilute contrast medium (10 mg iodine/ml). The head phantom was scanned using a 64 multidetector CT scanner with tube voltages of 80-140 kV and tube currents corresponding to volume CT dose index [Formula: see text] ranging from 24.4 to 72.8 mGy. Lens doses were measured using the planar silicon PIN-photodiode system. The quality of artery contours in the CTA source images was assessed using a computed detectability index. RESULTS: Lens dose increased proportionally with tube voltage and current. The use of 80 kV provided the highest contour detectability. However, for each tube voltage, the detectability of artery contours was almost constant across the CTDI(vol) values. These results were mostly consistent with the subjective recognition of artery contours on CTA images. CONCLUSIONS: A CTA protocol using 80 kV and 420 mA can reduce the radiation exposure to ocular lens by approximately 40 %, and improve the artery contour detectability compared with a routine protocol. PMID- 24760182 TI - Boron-doped graphene as a promising anode for Na-ion batteries. AB - The Na-ion battery has recently gained a lot of interest as a low-cost alternative to the current Li-ion battery technology. Its feasibility strongly depends on the development of suitable electrode materials. In the present work we propose a novel anode candidate, boron-doped graphene, for the Na-ion battery. Our first-principles calculations demonstrate that the sodiation of boron-doped graphene well preserves its structural integrity. The 2D-BC3 anode has the average sodiation voltage of 0.44 V in an appropriate range to avoid the safety concerns caused by the formation of dendritic deposits. The capacity of the 2D BC3 anode reaches ~2.04 times that of the graphite anode in a Li-ion battery and ~2.52 times that of hard carbon in a Na-ion battery. The high electronic mobility and Na mobility on boron-doped graphene indicates that it has a high potential to reach good rate performance. These suggest the promising potential of boron-doped graphene to serve as an anode for a rechargeable Na-ion battery. PMID- 24760181 TI - Collagen type III alpha 1 polymorphism (rs1800255, COL3A1 2209 G>A) assessed with high-resolution melting analysis is not associated with pelvic organ prolapse in the Dutch population. AB - INTRODUCTION AND HYPOTHESIS: The rs1800255, COL3A1 2209 G>A polymorphism in the alpha 1 chain of collagen type III has been associated with an increased risk of pelvic organ prolapse (POP). In one of our previous studies however, polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) misdiagnosed rs1800255, COL3A1 2209 G>A in 6 % of cases. The high-resolution melting (HRM) analysis on the contrary obtained a 100 % accordance for this specific polymorphism and was used in the present study to validate this risk factor for POP. METHODS: In this case-control study, women with and without symptoms of POP were included and compared. DNA was extracted from blood samples. HRM analysis was used to assess for the presence of the homozygous rs1800255. Groups were compared using the Pearson chi-square, Mann-Whitney, and t tests. The discrepancy between HRM and PCR-RFLP results was investigated using PCR-RFLP results available from our previous study. RESULTS: The study included 354 women: 272 patients with POP and 82 controls; 18 (7 %) cases versus 3 (4 %) controls had a homozygous rs1800255, COL3A1 2209 G>A polymorphism (odds ratio 1.9, 95 % confidence interval 0.5-6.9, compared to the wild type), and thus no association between POP and the homozygous polymorphism could be demonstrated. A discrepancy between HRM and PCR-RFLP results was found in 8 % of the samples. CONCLUSIONS: The previously found statistically significant association between the rs1800255, COL3A1 2209 G>A polymorphism as measured with PCR-RFLP and POP could no longer be demonstrated. This raises concerns regarding the results of other association studies using PCR-RFLP. PMID- 24760184 TI - The first tyrosyl radical intermediate formed in the S2-S3 transition of photosystem II. AB - The EPR "split signals" represent key intermediates of the S-state cycle where the redox active D1-Tyr161 (YZ) has been oxidized by the reaction center of the photosystem II enzyme to its tyrosyl radical form, but the successive oxidation of the Mn4CaO5 cluster has not yet occurred (SiYZ). Here we focus on the S2YZ state, which is formed en route to the final metastable state of the catalyst, the S3 state, the state which immediately precedes O-O bond formation. Quantum chemical calculations demonstrate that both isomeric forms of the S2 state, the open and closed cubane isomers, can form states with an oxidized YZ residue without prior deprotonation of the Mn4CaO5 cluster. The two forms are expected to lie close in energy and retain the electronic structure and magnetic topology of the corresponding S2 state of the inorganic core. As expected, tyrosine oxidation results in a proton shift towards His190. Analysis of the electronic rearrangements that occur upon formation of the tyrosyl radical suggests that a likely next step in the catalytic cycle is the deprotonation of a terminal water ligand (W1) of the Mn4CaO5 cluster. Diamagnetic metal ion substitution is used in our calculations to obtain the molecular g-tensor of YZ. It is known that the gx value is a sensitive probe not only of the extent of the proton shift between the tyrosine-histidine pair, but also of the polarization environment of the tyrosine, especially about the phenolic oxygen. It is shown for PSII that this environment is determined by the Ca(2+) ion, which locates two water molecules about the phenoxyl oxygen, indirectly modulating the oxidation potential of YZ. PMID- 24760183 TI - Prediction and analysis of canonical EF hand loop and qualitative estimation of Ca2+ binding affinity. AB - The diversity of functions carried out by EF hand-containing calcium-binding proteins is due to various interactions made by these proteins as well as the range of affinity levels for Ca2+ displayed by them. However, accurate methods are not available for prediction of binding affinities. Here, amino acid patterns of canonical EF hand sequences obtained from available crystal structures were used to develop a classifier that distinguishes Ca2+-binding loops and non Ca2+ binding regions with 100% accuracy. To investigate further, we performed a proteome-wide prediction for E. histolytica, and classified known EF-hand proteins. We compared our results with published methods on the E. histolytica proteome scan, and demonstrated our method to be more specific and accurate for predicting potential canonical Ca2+-binding loops. Furthermore, we annotated canonical EF-hand motifs and classified them based on their Ca2+-binding affinities using support vector machines. Using a novel method generated from position-specific scoring metrics and then tested against three different experimentally derived EF-hand-motif datasets, predictions of Ca2+-binding affinities were between 87 and 90% accurate. Our results show that the tool described here is capable of predicting Ca2+-binding affinity constants of EF hand proteins. PMID- 24760185 TI - Educational games for malaria diagnosis. PMID- 24760187 TI - Gene therapy boosts the bionic ear. AB - Close-field electroporation gene delivery using the cochlear implant electrode array enhances the bionic ear (Pinyon et al., this issue). PMID- 24760188 TI - Suppression of p21Rac signaling and increased innate immunity mediate remission in Crohn's disease. AB - In inflammatory bowel disease (IBD), large areas of apparently healthy mucosa lie adjacent to ulcerated intestine. Knowledge of the mechanisms that maintain remission in an otherwise inflamed intestine could provide important clues to the pathogenesis of this disease and provide rationale for clinical treatment strategies. We used kinome profiling to generate comprehensive descriptions of signal transduction pathways in inflamed and noninflamed colonic mucosa in a cohort of IBD patients, and compared the results to non-IBD controls. We observed that p21Rac1 guanosine triphosphatase (GTPase) signaling was strongly suppressed in noninflamed colonic mucosa in IBD. This suppression was due to both reduced guanine nucleotide exchange factor activity and increased intrinsic GTPase activity. Pharmacological p21Rac1 inhibition correlated with clinical improvement in IBD, and mechanistically unrelated pharmacological p21Rac1 inhibitors increased innate immune functions such as phagocytosis, bacterial killing, and interleukin-8 production in healthy controls and patients. Thus, suppression of p21Rac activity assists innate immunity in bactericidal activity and may induce remission in IBD. PMID- 24760189 TI - Close-field electroporation gene delivery using the cochlear implant electrode array enhances the bionic ear. AB - The cochlear implant is the most successful bionic prosthesis and has transformed the lives of people with profound hearing loss. However, the performance of the "bionic ear" is still largely constrained by the neural interface itself. Current spread inherent to broad monopolar stimulation of the spiral ganglion neuron somata obviates the intrinsic tonotopic mapping of the cochlear nerve. We show in the guinea pig that neurotrophin gene therapy integrated into the cochlear implant improves its performance by stimulating spiral ganglion neurite regeneration. We used the cochlear implant electrode array for novel "close field" electroporation to transduce mesenchymal cells lining the cochlear perilymphatic canals with a naked complementary DNA gene construct driving expression of brain-derived neurotrophic factor (BDNF) and a green fluorescent protein (GFP) reporter. The focusing of electric fields by particular cochlear implant electrode configurations led to surprisingly efficient gene delivery to adjacent mesenchymal cells. The resulting BDNF expression stimulated regeneration of spiral ganglion neurites, which had atrophied 2 weeks after ototoxic treatment, in a bilateral sensorineural deafness model. In this model, delivery of a control GFP-only vector failed to restore neuron structure, with atrophied neurons indistinguishable from unimplanted cochleae. With BDNF therapy, the regenerated spiral ganglion neurites extended close to the cochlear implant electrodes, with localized ectopic branching. This neural remodeling enabled bipolar stimulation via the cochlear implant array, with low stimulus thresholds and expanded dynamic range of the cochlear nerve, determined via electrically evoked auditory brainstem responses. This development may broadly improve neural interfaces and extend molecular medicine applications. PMID- 24760191 TI - Changing Bodies: Experiences of Women Who Have Undergone a Surgically Induced Menopause. AB - We aimed to explore the lived experiences of women who had a surgical menopause as a result of undergoing a hysterectomy with Bilateral Salpingo-Oopherectomy (BSO). We adopted a qualitative interview design using Interpretative Phenomenological Analysis (IPA), and recruited 7 women aged 47 to 59. We conducted synchronous online semistructured interviews using the MSN (Microsoft Network) Messenger program. In the findings, we examine the prominent and underresearched theme of body image change. We discuss the women's journey from a deep internal bodily change, the meaning of this changing body image, through to the thoughts and behaviors involved with self-presentation concerns and coping with body image changes. A woman's perceived attractiveness and appearance investment are important factors to consider regarding adaptation to change over this transition. The findings might have implications for interventions designed to enhance mental well-being and increase health behaviors in women experiencing gynecological illness and/or menopause. PMID- 24760190 TI - Aspirin and the risk of colorectal cancer in relation to the expression of 15 hydroxyprostaglandin dehydrogenase (HPGD). AB - Aspirin use reduces the risk of colorectal neoplasia, at least in part, through inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2) related pathways. Hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (15-PGDH, HPGD) is down-regulated in colorectal cancers and functions as a metabolic antagonist of PTGS2. We hypothesized that the effect of aspirin may be antagonized by low 15-PGDH expression in the normal colon. In the Nurses' Health Study and the Health Professionals Follow-Up Study, we collected data on aspirin use every 2 years and followed up participants for diagnoses of colorectal cancer. Duplication-method Cox proportional, multivariable-adjusted, cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for incident colorectal cancer according to 15-PGDH mRNA expression level measured in normal mucosa from colorectal cancer resections. Among 127,865 participants, we documented 270 colorectal cancer cases from which we could assess 15-PGDH expression. Compared with nonuse, regular aspirin use was associated with lower risk of colorectal cancer that developed within a background of colonic mucosa with high 15-PGDH expression [multivariable HR, 0.49; 95% confidence interval (CI), 0.34 to 0.71], but not with low 15-PGDH expression (multivariable HR, 0.90; 95% CI, 0.63 to 1.27) (P for heterogeneity = 0.018). Regular aspirin use was associated with lower incidence of colorectal cancers arising in association with high 15-PGDH expression, but not with low 15 PGDH expression in normal colon mucosa. This suggests that 15-PGDH expression level in normal colon mucosa may serve as a biomarker that may predict stronger benefit from aspirin chemoprevention. PMID- 24760192 TI - New gout test: enhanced ex vivo cytokine production from PBMCS in common gout patients and a gout patient with Kearns-Sayre syndrome. AB - Monosodium urate (MSU) monohydrate crystals synergize with various toll-like receptor (TLR) ligands to induce interleukin-(IL)-1beta production. Data are shown from a young male with mitochondriopathy in Kearns-Sayre syndrome (KSS) who developed gout and underwent urate-lowering therapy (ULT) versus a group of common gout patients. Peripheral blood mononuclear cells (PBMCs) are exposed in vitro to MSU crystals in the presence/absence of TLR2 ligands palmitic acid (C16:0) or palmitoyl-3-cysteine (Pam3Cys); proinflammatory cytokine production (IL-1beta, IL-6, IL-8) is assessed by specific ELISA's. MSU crystals alone failed to induce IL-1beta, IL-6, or IL-8 in both the KSS patient and gout controls. A strong synergy between MSU crystals and C16:0 or Pam3Cys for induction of IL-1 beta/IL-6 is found in gout patients, but in gout with KSS, we found even more response than in control gout patients. Pam3Cys exposure reveals an enhanced response in cells originating from the KSS patient, indicating a high producer phenotype in response to TLR2 stimulation. During ULT, serum urate levels dropped in the KSS case. The hyperresponse of TLR2 may be secondary to the high serum urate concentration of 0.92 mmol/l that was initially found in circulation in vivo. Within a 6-month period, the serum urate concentration dropped, and the in vitro stimulation tests improved but did not fully normalize yet. The ex vivo cytokine production in gout patients is promising a novel gout test; PBMCs' responses in the mitochondriopathic gout patient is enhanced when compared with common gout patients, indicating a supersensitive gout patient profile. The non inflammatory presentation in the KSS case with bulky gout is due to less inflammatory MSU crystals, i.e., specific crystal stereochemical/conformational properties. For developing gout attacks, the serum urate level and specific crystal properties both are of importance. Key Messages 1. Ex vivo cell tests are promising to serve as a novel gout lab test for screening purposes. 2. Ex vivo cellular responses are reduced following intraarticular glucocorticoid injection and/or urate-lowering therapy. 3. Crystal conformation properties play a role in the inflammatory in vivo and ex vivo response in gout. 4. A young male with Kearns-Sayre syndrome is described with less pronounced inflammatory PMBC responses to his own MSU crystals which explains the advanced stage of urate accumulation in this individual. PMID- 24760195 TI - Report details US administration's efforts to enlist outside support for Affordable Care Act. PMID- 24760193 TI - HLA-DRB1 frequency in patients with familial and sporadic rheumatoid arthritis in north east of Iran. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints that has a strong correlation with HLA-DRB1. Family history is considered a known risk factor for RA. The aims of this study were to compare the frequency of HLA-DRB1 alleles between patients with sporadic and familial RA and also between healthy controls with RA patients (sporadic and familial) and clarify if familial RA is more severe than sporadic RA. This study included 129 consecutive patients with sporadic and 48 cases with familial (first-degree siblings) RA who visited a rheumatology unit. Demographic data, including extra-articular involvement, mean disease activity according to DAS28 (ESR) criteria, and main laboratory findings, were compared between patients with sporadic and familial RA. HLA-DRB1 typing was carried out using the PCR-SSP method, and the frequency of each allele was determined in all cases and compared with the results of HLA-DRB1 frequencies in 72 healthy controls who were previously reported by our group in northeast Iran. Patients with sporadic and familial RA were matched in age and sex, most of the cases in both groups were females. The mean age of patients was 45 years. Ocular involvement was the most frequent extra-articular manifestation of our patients. There was no significant difference between the two groups in visual analogue scale (VAS) index, number of inflamed or tender joints, extra-articular involvements, and main laboratory findings. HLA-DRB1* 01 (55 %), 04 (48 %), and 03 (43 %) alleles were the most frequent alleles in both sporadic and familial diseases. The frequency of HLA-DRB1*11 and HLA-DRB1*13 was significantly higher in normal participants compared with RA (p = 0.001). There was no significant difference in the HLA-DRB1 allele's frequency between sporadic and familial RA. Therefore, familial aggregation was not associated with RA severity. PMID- 24760196 TI - Theoretical Loss and Gambling Intensity (Revisited): A Response to Braverman et al. (2013). AB - In this paper, we provide a brief response to Braverman et al. (J Gambl Stud. doi: 10.1007/s10899-013-9428-z , 2013b) critique of our 'Theoretical Loss' metric as a measure of monetary gambling intensity (Auer and Griffiths in J Gambl Stud. doi: 10.1007/s10899-013-9376-7 , 2013a; Auer et al. in Gaming Law Rev Econ 16:269 273, 2012). We argue that 'gambling intensity' and 'gambling involvement' are essentially the same construct as descriptors of monetary gambling activity. Additionally, we acknowledge that playing duration (i.e., the amount of time-as opposed to money-actually spent gambling) is clearly another important indicator of gambling involvement-something that we have consistently noted in our previous studies including our empirical studies on gambling using behavioural tracking data. Braverman and colleagues claim that the concept of Theoretical Loss is nullified when statistical analysis focuses solely on one game type as the house edge is constant across all games. In fact, they state, the correlation between total amount wagered and Theoretical Loss is perfect. Unfortunately, this is incorrect. To disprove the claim made, we demonstrate that in sports betting (i.e., a single game type), the amount wagered does not reflect monetary gambling involvement using actual payout percentage data (based on 52,500 independent bets provided to us by an online European bookmaker). After reviewing the arguments presented by Braverman and colleagues, we are still of the view that when it comes to purely monetary measures of 'gambling intensity', the Theoretical Loss metric is a more robust and accurate measure than other financial proxy measures such as 'amount wagered' (i.e., bet size) as a measure of what players are prepared to financially risk while gambling. PMID- 24760197 TI - Mortality analysis by neighbourhood in a city with high levels of industrial air pollution. AB - OBJECTIVES: Taranto, a city in south-eastern Italy, suffers serious environmental pollution from industrial sources. A previous cohort analysis found mortality excesses among neighbourhoods closest to industrial areas. Aim of this study was to investigate whether mortality also increased in other neighbourhoods compared to Apulia region. METHODS: Standardized mortality ratios were computed. Number of deaths and of person-years at risk by neighbourhood came from the previous cohort study for 1998-2008 period. Reference population was Apulia region excluding Taranto province. A meta-analysis was conducted across less close neighbourhoods computing summary SMR estimates and evaluating heterogeneity. RESULTS: For the entire city higher mortality values are confirmed for all causes, all malignant neoplasms and several specific sites, neurological, cardiac, respiratory and digestive diseases. High mortality values are not confined to neighbourhoods closest to industrial areas for lung cancer, cardiac, respiratory and digestive diseases, in both sexes, and among women for all malignant neoplasms and pancreatic cancer. CONCLUSIONS: Increased mortality risks can also be observed in Taranto neighbourhoods not directly adjacent to industrial areas. Spatial trend, impact of socio-economic factors and duration of residence should be further explored. PMID- 24760198 TI - The effect of atomic ions on model sigma-hole bonded complexes of AH3Y (A = C, Si, Ge; Y = F, Cl, Br). AB - A computational study of ionic X...AH3-Y complexes (X = F(-), Cl(-), Br(-), Li(+), Be(2+); A = C, Si, Ge; Y = F, Cl, Br) predicted optimized structures which are held together by a combination of attractive forces, including ion-dipole and ion-sigma-hole electrostatic interactions, and polarization forces. The trends (with variation in the halogen Y) for selected properties were rationalized by considering the electron density shifts due to the ion's electric field. Although it has been found previously that the trends for binding energies in neutral complexes follow the sigma-hole strength, the present study found that the dependence on the dipole polarizability of the A-Y bond can explain the trends for binding energies in these more strongly bound ionic complexes. PMID- 24760201 TI - Conjugated linolenic acids and their bioactivities: a review. AB - Conjugated linolenic acid (CLNA) is a mixture of positional and geometric isomers of octadecatrienoic acid (alpha-linolenic acid, cis9,cis12,cis15-18:3 n-3) found in plant seeds. Three 8,10,12-18:3 isomers and four 9,11,13-18:3 isomers have been reported to occur naturally. CLNA isomers such as punicic acid, alpha eleostearic acid and jacaric acid have been attributed to exhibit several health benefits that are largely based on animal and in vitro studies. This review has summarized and updated the evidence regarding the metabolism and bioactivities of CLNA isomers, and comprehensively discussed the recent studies on the effects of anti-carcinogenic, lipid metabolism regulation, anti-inflammatory, anti-obese and antioxidant activities of CLNA isomers. The available results may provide a potential application for CLNA isomers from natural sources, especially edible plant seeds, as effective functional food ingredients and dietary supplements for the above mentioned disease management. Further research, especially human randomized clinical trials, is warranted to investigate the detailed physiological effects, bioactivity and molecular mechanism of CLNA. PMID- 24760202 TI - A case of right double inferior vena cava with circumcaval ureter. AB - Congenital inferior vena cava (IVC) anomalies are silent and detected incidentally on imaging. Double IVC is the most common IVC anomaly and is usually characterized by the presence of an IVC on each side of the abdominal aorta. In contrast, right double IVC, which is defined as two post-renal IVCs positioned to the right of the abdominal aorta, is seldom recognized. We report a rare case of a complete right double IVC with a circumcaval ureter that was incidentally detected by CT and describe the embryological and clinical implications. PMID- 24760199 TI - Interaction of drug- and granulocyte-mediated killing of Pseudomonas aeruginosa in a murine pneumonia model. AB - BACKGROUND: Killing of bacterial pathogens by granulocytes is a saturable process, as previously demonstrated. There is virtually no quantitative information about how granulocytes interact with antimicrobial chemotherapy to kill bacterial cells. METHODS: We performed a dose-ranging study with the aminoglycoside plazomicin against Pseudomonas aeruginosa ATCC27853 in a granulocyte-replete murine pneumonia model. Plazomicin was administered in a humanized fashion (ie, administration of decrementing doses 5 times over 24 hours, mimicking a human daily administration profile). Pharmacokinetic profiling was performed in plasma and epithelial lining fluid. All samples were simultaneously analyzed with a population model. Mouse cohorts were treated for 24 hours; other cohorts treated with the same therapy were observed for another 24 hours after therapy cessation, allowing delineation of the therapeutic effect necessary to reduce the bacterial burden to a level below the half-saturation point. RESULTS: The mean bacterial burden (+/-SD) at which granulocyte-mediated kill was half saturable was 2.45 * 10(6) +/- 6.84 * 10(5) colony-forming units of bacteria per gram of tissue (CFU/g). Higher levels of plazomicin exposure reduced the bacterial burden to <5 log10 CFU/g, allowing granulocytes to kill an additional 1.0-1.5 log CFU/g over the subsequent 24 hours. CONCLUSIONS: For patients with large bacterial burdens (eg, individuals with ventilator-requiring hospital-acquired pneumonia), it is imperative to kill >=2 log10 CFU/g early after treatment initiation, to allow the granulocytes to contribute optimally to bacterial clearance. PMID- 24760203 TI - Organized thrombus in pulmonary arteries in patients with chronic thromboembolic pulmonary hypertension; imaging with cone beam computed tomography. AB - PURPOSE: To assess the usefulness of cone-beam CT (CBCT) during pulmonary angiography for the evaluation of organized thrombus at segmental or subsegmental arteries in patients with chronic thromboembolic pulmonary hypertension (CTEPH). MATERIALS AND METHODS: The segmental and/or subsegmental pulmonary arteries of 13 patients with CTEPH were evaluated by CBCT. We classified representative forms of organized thrombus into 4 types (type 1: webs, type 2: web and slits, type 3: slits, and type 4: narrowing or complete occlusion), and the distribution and frequency of the organized thrombus were evaluated. The relative detectability of these lesions using CBCT was compared with that in contrast-enhanced CT pulmonary angiography (CTPA). RESULTS: Type 1 lesions were most frequently observed in both segmental (30/65 = 46 %) and subsegmental branches (72/156 = 46 %). Type 2 lesions were relatively less frequent than type 1, but subsegmental branches were frequently involved (29/156 = 19 %). Type 3 lesions observed as a thin flap in 9/156 subsegmental branches (6 %). Comparing with CTPA, all 40 lesions in segmental branches were detectable in CTPA, whereas only 62 lesions among 90 lesions (69 %) in subsegmental branches could be observed by CTPA. CONCLUSION: CBCT is found to be useful for the treatment planning of balloon pulmonary angioplasty distal to segmental arteries. PMID- 24760205 TI - [Syncope and dizziness]. PMID- 24760206 TI - Highly active AuCo alloy nanoparticles encapsulated in the pores of metal-organic frameworks for hydrolytic dehydrogenation of ammonia borane. AB - Ultrafine AuCo alloy nanoparticles were successfully encapsulated in the pores of MIL-101 by using the double solvents method combined with the overwhelming reduction approach, which exert excellent catalytic activity for hydrolytic dehydrogenation of ammonia borane. PMID- 24760204 TI - A protective lipidomic biosignature associated with a balanced omega-6/omega-3 ratio in fat-1 transgenic mice. AB - A balanced omega-6/omega-3 polyunsaturated fatty acid (PUFA) ratio has been linked to health benefits and the prevention of many chronic diseases. Current dietary intervention studies with different sources of omega-3 fatty acids (omega 3) lack appropriate control diets and carry many other confounding factors derived from genetic and environmental variability. In our study, we used the fat 1 transgenic mouse model as a proxy for long-term omega-3 supplementation to determine, in a well-controlled manner, the molecular phenotype associated with a balanced omega-6/omega-3 ratio. The fat-1 mouse can convert omega-6 to omega-3 PUFAs, which protect against a wide variety of diseases including chronic inflammatory diseases and cancer. Both wild-type (WT) and fat-1 mice were subjected to an identical diet containing 10% corn oil, which has a high omega-6 content similar to that of the Western diet, for a six-month duration. We used a multi-platform lipidomic approach to compare the plasma lipidome between fat-1 and WT mice. In fat-1 mice, an unbiased profiling showed a significant increase in the levels of unesterified eicosapentaenoic acid (EPA), EPA-containing cholesteryl ester, and omega-3 lysophosphospholipids. The increase in omega-3 lipids is accompanied by a significant reduction in omega-6 unesterified docosapentaenoic acid (omega-6 DPA) and DPA-containing cholesteryl ester as well as omega-6 phospholipids and triacylglycerides. Targeted lipidomics profiling highlighted a remarkable increase in EPA-derived diols and epoxides formed via the cytochrome P450 (CYP450) pathway in the plasma of fat-1 mice compared with WT mice. Integration of the results of untargeted and targeted analyses has identified a lipidomic biosignature that may underlie the healthful phenotype associated with a balanced omega-6/omega-3 ratio, and can potentially be used as a circulating biomarker for monitoring the health status and the efficacy of omega-3 intervention in humans. PMID- 24760208 TI - The influence of calorie labeling on food orders and consumption: a review of the literature. AB - Obesity is a challenging public health problem that affects millions of Americans. Increasingly policy makers are seeking environmental and policy-based solutions to combat and prevent its serious health effects. Calorie labeling mandates, including the provision in the 2010 Patient Protection and Affordable Care Act that is set to begin in 2014, have been one of the most popular and most studied approaches. This review examines 31 studies published from January 1, 2007 through July 19, 2013. It builds on Harnack and French's 2008 review and assesses the evidence on the effectiveness of calorie labeling at the point of purchase. We find that, while there are some positive results reported from studies examining the effects of calorie labeling, overall the best designed studies (real world studies, with a comparison group) show that calorie labels do not have the desired effect in reducing total calories ordered at the population level. Moving forward, researchers should consider novel, more effective ways of presenting nutrition information, while keeping a focus on particular subgroups that may be differentially affected by nutrition policies. PMID- 24760209 TI - Copy number and sequence variation of leucine-rich repeat modules suggests distinct functional constraints operating on variable lymphocyte receptors expressed by agnathan T cell-like and B cell-like lymphocytes. AB - Unlike jawed vertebrates that use T cell and B cell receptors for antigen recognition, jawless vertebrates represented by lampreys and hagfish use variable lymphocyte receptors (VLR) as antigen receptors. VLRs generate high levels of diversity by assembling variable leucine-rich repeat (LRR) modules. Of the three VLRs thus far identified, VLRB is expressed on B cell-like lymphocytes and functions as antibodies, whereas VLRA and VLRC are expressed on T cell-like lymphocytes and function as membrane-bound receptors. In the present study, we show that the copy number of LRRV modules in lamprey and hagfish VLRB transcripts follows a binominal distribution with the success rates of 15.5 and 22.4 %, respectively. By contrast, the copy number distribution of LRRV modules in VLRA and VLRC transcripts deviates from the binominal distribution mainly because transcripts with two or less LRRV modules occur infrequently. Notably, the second LRRV module shows distinctive sequence signatures in VLRA and VLRC, but not in VLRB transcripts. These observations suggest that distinct functional constraints operate on VLRs expressed by agnathan T cell-like and B cell-like lymphocytes. PMID- 24760210 TI - Mixed-ligand hydroxocopper(II)/pyridazine clusters embedded into 3D framework lattices. AB - Rational combination of pyridazine, hydroxo and carboxylate bridging ligands led to the assembly of three types of mixed-ligand polynuclear Cu(II) clusters (A: [Cu2(MU-OH)(MU-pdz)(MU-COO)]; B: [Cu4(MU3-OH)2(MU-pdz)2]; C: [Cu5(MU-OH)2(MU pdz)4(MU-COO)2(MU-H2O)2]) and their integration into 3D framework structures. Mixed-ligand complexes [Cu2(MU-OH){TMA}(L)(H2O)] (1), [Cu4(MU3 OH)2{ATC}2(L)2(H2O)2].H2O (2) [Cu4(MU3-OH)2{TDC}3(L)2(H2O)2].7H2O (3) (L = 1,3 bis(pyridazin-4-yl)adamantane; TMA(3-) = benzene-1,3,5-tricarboxylate, ATC(3-) = adamantane-1,3,5-tricarboxylate, TDC(2-) = 2,5-thiophenedicarboxylate) and [Cu5(MU-OH)2{X}4(L)2(H2O)2].nH2O (X = benzene-1,3-dicarboxylate, BDC(2-), n = 5 (4) and 5-hydroxybenzene-1,3-dicarboxylate, HO-BDC(2-), n = 6 (5)) are prepared under hydrothermal conditions. Trigonal bridges TMA(3-) and ATC(3-) generate planar Cu(II)/carboxylate subtopologies further pillared into 3D frameworks (1: binodal 3,5-coordinated, doubly interpenetrated tcj-3,5-Ccc2; 2: binodal 3,8 coordinated tfz-d) by bitopic pyridazine ligands. Unprecedented triple bridges in 1 (cluster of type A) support short CuCu separations of 3.0746(6) A. The framework in 3 is a primitive cubic net (pcu) with multiple bis-pyridazine and TDC(2-) links between the tetranuclear nodes of type . Compounds 4 and 5 adopt uninodal ten-coordinated framework topologies (bct) embedding unprecedented centrosymmetric open-chain pentanuclear clusters of type C with two kinds of multiple bridges, Cu(MU-OH)(MU-pdz)2Cu and Cu(MU-COO)(MU-H2O)Cu (CuCu distances are 3.175 and 3.324 A, respectively). Magnetic coupling phenomena were detected for every type of cluster by susceptibility measurements of 1, 3 and 4. For binuclear clusters A in 1, the intracluster antiferromagnetic exchange interactions lead to a diamagnetic ground state (J = -17.5 cm(-1); g = 2.1). Strong antiferromagnetic coupling is relevant also for type B, which consequently results in a diamagnetic ground state (J1 = -110 cm(-1); J2 = -228 cm(-1), g = 2.07). For pentanuclear clusters of type C in 4, the exchange model is based on a strongly antiferromagnetically coupled central linear trinuclear Cu3 group (J1 = 125 cm(-1)) and two outer Cu centers weakly antiferromagnetically coupled to the terminal Cu ions of the triad (J2 = -12.5 cm(-1)). PMID- 24760207 TI - Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing. AB - Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p < .05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased beta2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), beta2-AR protein (2.5-fold), phosphorylation of beta-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased beta2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM MSCs- 21%? and NHKs- 60%?, p < .002), and resulted in a 10-fold (BM-MSCs) and 51 fold (NHKs) increase in release of IL-6 (p < .001) responses that were remarkably reduced by pretreatment with beta2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p < .05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs. PMID- 24760211 TI - Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals. AB - The oral bioavailability of many lipophilic bioactive agents (pharmaceuticals and nutraceuticals) is limited due to various physicochemical and physiological processes: poor release from food or drug matrices; low solubility in gastrointestinal fluids; metabolism or chemical transformation within the gastrointestinal tract; low epithelium cell permeability. The bioavailability of these agents can be improved by specifically designing food matrices that control their release, solubilization, transport, metabolism, and absorption within the gastrointestinal tract. This article discusses the impact of food composition and structure on oral bioavailability, and how this knowledge can be used to design excipient foods for improving the oral bioavailability of lipophilic bioactives. Excipient foods contain ingredients or structures that may have no bioactivity themselves, but that are able to promote the bioactivity of co-ingested bioactives. These bioactives may be lipophilic drugs in pharmaceutical preparations (such as capsules, pills, or syrups) or nutraceuticals present within food matrices (such as natural or processed foods and beverages). PMID- 24760212 TI - Genetic diversity among volunteer donors of bone marrow in southeastern Brazil, according to the HLA system. AB - CONTEXT AND OBJECTIVE: Checking the histocompatibility of the molecules of the human leukocyte antigen (HLA) system is vital for performing bone marrow transplantation with allogeneic material. The objective of this study was to characterize bone marrow donors according to gender, age, ethnicity and HLA groups at a regional hemotherapy center in Brazil. DESIGN AND SETTING: Descriptive study on registered donors at a regional hemotherapy center in a public university hospital in the southeastern region of Brazil. METHODS: The records of 66,780 donors who were registered between 2005 and June 2011 were consulted, and the variables studied were tabulated. RESULTS: There were equal numbers of male and female donors and 82.8% of them were under 45 years of age. In terms of ethnicity, 77.3% declared themselves to be white, 15.0% mixed race, 5.7% black and 2% others. In terms of immunogenetic characterization, the most frequent HLA-A allelic group was HLA-A*02, with 39.20% of the donors; in the HLA B allelic group, the most common was HLA-B*35, with 14.18%; while in the HLA-DRB1 allelic group, the most frequent was HLA-DRB1*03, with 17.03%. Comparison between these results and data from the Brazilian Bone Marrow Donor Registry (REDOME) showed that there were demographic and immunogenetic differences due to the history of immigration in the region of Ribeirao Preto, in southeastern Brazil. CONCLUSIONS: The results reinforce the importance of understanding the demographic and immunogenic profile of regions of Brazil, in order to reduce the waiting time for a histocompatible donor. PMID- 24760213 TI - Anemia in inflammatory bowel disease: prevalence, differential diagnosis and association with clinical and laboratory variables. AB - CONTEXT AND OBJECTIVES: Anemia is the most frequent extraintestinal complication of inflammatory bowel disease. This study aimed to: 1) determine the prevalence of anemia among patients with inflammatory bowel disease; 2) investigate whether routine laboratory markers are useful for diagnosing anemia; and 3) evaluate whether any association exists between anemia and clinical/laboratory variables. DESIGN AND SETTING: Cross-sectional at a federal university. METHODS: 44 outpatients with Crohn's disease and 55 with ulcerative colitis were evaluated. Clinical variables (disease activity index, location of disease and pharmacological treatment) and laboratory variables (blood count, iron laboratory, vitamin B12 and folic acid) were investigated. RESULTS: Anemia and/or iron laboratory disorders were present in 75% of the patients with Crohn's disease and in 78.2% with ulcerative colitis. Anemia was observed in 20.5% of the patients with Crohn's disease and in 23.6% with ulcerative colitis. Iron deficiency anemia was highly prevalent in patients with Crohn's disease (69.6%) and ulcerative colitis (76.7%). Anemia of chronic disease in combination with iron deficiency anemia was present in 3% of the patients with Crohn's disease and in 7% of the patients with ulcerative colitis. There was no association between anemia and disease location. In ulcerative colitis, anemia was associated with the disease activity index. CONCLUSIONS: Most patients present iron laboratory disorders, with or without anemia, mainly due to iron deficiency. The differential diagnosis between the two most prevalent types of anemia was made based on clinical data and routine laboratory tests. In ulcerative colitis, anemia was associated with the disease activity index. PMID- 24760214 TI - Carbamazepine for prevention of chemotherapy-induced nausea and vomiting: a pilot study. AB - CONTEXT AND OBJECTIVE: Nausea and vomiting are major inconveniences for patients undergoing chemotherapy. Despite standard preventive treatment, chemotherapy induced nausea and vomiting (CINV) still occurs in approximately 50% of these patients. In an attempt to optimize this treatment, we evaluated the possible effects of carbamazepine for prevention of CINV. DESIGN AND LOCATION: Prospective nonrandomized open-label phase II study carried out at a Brazilian public oncology service. METHODS: Patients allocated for their first cycle of highly emetogenic chemotherapy were continuously recruited. In addition to standard antiemetic protocol that was made available, they received carbamazepine orally, with staggered doses, from the third day before until the fifth day after chemotherapy. Considering the sparseness of evidence about the efficacy of anticonvulsants for CINV prevention, we used Simon's two-stage design, in which 43 patients should be included unless overall complete prevention was not achieved in 9 out of the first 15 entries. The Functional Living Index-Emesis questionnaire was used to measure the impact on quality of life. RESULTS: None of the ten patients (0%) presented overall complete prevention. In three cases, carbamazepine therapy was withdrawn because of somnolence and vomiting before chemotherapy. Seven were able to take the medication for the entire period and none were responsive, so the study was closed. There was no impact on the patients' quality of life. CONCLUSION: Carbamazepine was not effective for prevention of CINV and also had a deleterious side-effect profile in this population. PMID- 24760215 TI - Prevalence of risk factors for stuttering among boys: analytical cross-sectional study. AB - CONTEXT AND OBJECTIVE: There have been few studies on the risk factors for subgroups of stuttering. The aim of this study was to characterize the risk factors for developmental familial stuttering among boys who stutter and who do not stutter, such as disfluency types, associated quality and communication factors, emotional and physical stress, familial attitudes and personal reactions. DESIGN AND SETTING: Analytical cross-sectional study with a control group, performed at the Fluency Studies Laboratory of the Department of Speech and Hearing Disorders of a public university. METHODS: The parents of 40 age matched stuttering and non-stuttering boys took part in this study. The participants were divided into two groups: stuttering children (SC) and non stuttering children (NSC), with ages between 6 years 0 months and 11 years 11 months. Initially, all of the participants underwent a fluency assessment and then data were gathered using the Protocol for the Risk of Developmental Stuttering. RESULTS: There were no differences in the physical stress distribution factors and personal reactions between the groups. Inappropriate familial attitudes were presented by 95% of the SC and 30% of the NSC. Four risk factors analyzed were not shown by the NSC, namely stuttering-like disfluency, quality factors, physical stress and emotional stresses. CONCLUSIONS: The findings suggest that the presence of stuttering-like disfluency, associated quality and communication factors, emotional stress and inappropriate family attitudes are important risk factors for familial developmental stuttering among boys. PMID- 24760216 TI - Carotid body tumor: retrospective analysis on 22 patients. AB - CONTEXT AND OBJECTIVE: Carotid body tumors, or chemodectomas, are the most common head and neck paragangliomas, accounting for 80% of the cases. They may present minor symptoms; however, they deserve special attention in order to achieve accurate diagnosis and adequate treatment. The objectives of this study were to show the approach towards chemodectomas and evaluate the complications of the patients treated surgically without previous embolization. DESIGN AND SETTING: Retrospective study on chemodectomas followed up at the Head and Neck Surgery Service, Department of Surgery, Unicamp. METHODS: Twenty-two patients were evaluated between 1983 and 2009. The diagnosis was based on clinical findings and imaging methods. The epidemiological characteristics, lesion characteristics, diagnostic methods, treatment and complications were analyzed. RESULTS: The paragangliomas were classified as Shamblin I (9%), II (68.1%) and III (22.7%). Angiography, magnetic resonance imaging and computed tomography confirmed the diagnosis in 20 patients (90.9%). Five (22.7%) had significant bleeding during the surgery, while four (18.1%) had minor bleeding. Four patients (18.1%) developed neurological sequelae. Seven (31.8%) needed ligatures of the external carotid artery. Three patients (13.6%) underwent carotid bulb resection. The postoperative follow-up ranged from 3 months to 14 years without recurrences or mortality. CONCLUSIONS: In our experience and in accordance with the literature, significant bleeding and neurological sequelae may occur in chemodectoma cases, particularly in Shamblin III patients. The complications from treatment without previous embolization were similar to data in the literature data, from cases in which this procedure was applied prior to surgery. PMID- 24760218 TI - Disassembly of micelles in nanoscopic space to prepare concentric nanotubes with variable hydrophobic interiors. AB - Nanotubes with variable hydrophobic interiors were prepared by disassembling anionic micelles in the inner walls of positive charge bearing conjugated polymer nanotubes. PMID- 24760219 TI - Individual risk modelling for esophagectomy: a systematic review. AB - INTRODUCTION: A number of models have been applied to predict outcomes from esophagectomy. This systematic review aimed to compare their clinical credibility, methodological quality and performance. METHODS: A systematic review of the PubMed, EMBASE and Cochrane databases was performed in October 2012. Model and study quality were appraised using the framework of Minne et al. RESULTS: Twenty studies were included in total; these were heterogeneous, retrospective and conducted over a number of years; all models were generated via logistic regression. Overall mortality was high, and consequently not representative of current practice. Clinical credibility and methodological quality were variable, with frequent failure to perform internal validation and variable presentation of calibration and discrimination metrics. P-POSSUM demonstrated the best calibration and discrimination for predicting mortality. Other than the Southampton score (which has yet to be externally validated) and the Amsterdam score, no studies had utility in predicting complications. CONCLUSION: Whilst a number of models have been developed, adapted or trialled, due to numerous limitations, larger and more contemporary studies are required to develop and validate models further. The role of alternative techniques such as decision tree analysis and artificial neural networks is not known. PMID- 24760220 TI - A brief personal history of cancer immunotherapy at Stanford: if these walls could talk.... AB - This is a journey that began in medical school at Stanford in 1963 and that is still underway, now as faculty member here for the past 40 years. History is by its nature selective, and I chose highlights that reflect on the remarkable progress we have made using the immune system to treat cancer. We will never be satisfied until we eliminate suffering and early mortality from cancer, but the progress is indeed remarkable as are the people who have contributed to it. PMID- 24760221 TI - Polycyclic aromatic hydrocarbons, tobacco smoke, and epigenetic remodeling in asthma. AB - Environmental determinants including aerosolized pollutants such as polycyclic aromatic hydrocarbons (PAHs) and tobacco smoke have been associated with exacerbation and increased incidence of asthma. The influence of aerosolized pollutants on the development of immune dysfunction in asthmatics has been suggested to be mediated through epigenetic remodeling. Genome accessibility and transcription are regulated primarily through DNA methylation, histone modification, and microRNA transcript silencing. Epigenetic remodeling has been shown in studies to be associated with Th2 polarization and associated cytokine and chemokine regulation in the development of asthma. This review will present evidence for the contribution of the aerosolized pollutants PAH and environmental tobacco smoke to epigenetic remodeling in asthma. PMID- 24760222 TI - Digestion proteomics: tracking lactoferrin truncation and peptide release during simulated gastric digestion. AB - The extent to which nutritional and functional benefit is derived from proteins in food is related to its breakdown and digestion in the body after consumption. Further, detailed information about food protein truncation during digestion is critical to understanding and optimising the availability of bioactives, in controlling and limiting allergen release, and in minimising or monitoring the effects of processing and food preparation. However, tracking the complex array of products formed during the digestion of proteins is not easily accomplished using classical proteomics. We here present and develop a novel proteomic approach using isobaric labelling to mapping and tracking protein truncation and peptide release during simulated gastric digestion, using bovine lactoferrin as a model food protein. The relative abundance of related peptides was tracked throughout a digestion time course, and the effect of pasteurisation on peptide release assessed. The new approach to food digestion proteomics developed here therefore appears to be highly suitable not only for tracking the truncation and relative abundance of released peptides during gastric digestion, but also for determining the effects of protein modification on digestibility and potential bioavailability. PMID- 24760223 TI - Classification of normal and diseased liver shapes based on Spherical Harmonics coefficients. AB - Liver-shape analysis and quantification is still an open research subject. Quantitative assessment of the liver is of clinical importance in various procedures such as diagnosis, treatment planning, and monitoring. Liver-shape classification is of clinical importance for corresponding intra-subject and inter-subject studies. In this research, we propose a novel technique for the liver-shape classification based on Spherical Harmonics (SH) coefficients. The proposed liver-shape classification algorithm consists of the following steps: (a) Preprocessing, including mesh generation and simplification, point-set matching, and surface to template alignment; (b) Liver-shape parameterization, including surface normalization, SH expansion followed by parameter space registration; (c) Feature selection and classification, including frequency based feature selection, feature space reduction by Principal Component Analysis (PCA), and classification. The above multi-step approach is novel in the sense that registration and feature selection for liver-shape classification is proposed and implemented and validated for the normal and diseases liver in the SH domain. Various groups of SH features after applying conventional PCA and/or ordered by p value PCA are employed in two classifiers including Support Vector Machine (SVM) and k-Nearest Neighbor (k-NN) in the presence of 101 liver data sets. Results show that the proposed specific features combined with classifiers outperform existing liver-shape classification techniques that employ liver surface information in the spatial domain. In the available data sets, the proposed method can successful classify normal and diseased livers with a correct classification rate of above 90 %. The performed result in average is higher than conventional liver-shape classification method. Several standard metrics such as Leave-one-out cross-validation and Receiver Operating Characteristic (ROC) analysis are employed in the experiments and confirm the effectiveness of the proposed liver-shape classification with respect to conventional techniques. PMID- 24760224 TI - A more secure anonymous user authentication scheme for the integrated EPR information system. AB - Secure and efficient user mutual authentication is an essential task for integrated electronic patient record (EPR) information system. Recently, several authentication schemes have been proposed to meet this requirement. In a recent paper, Lee et al. proposed an efficient and secure password-based authentication scheme used smart cards for the integrated EPR information system. This scheme is believed to have many abilities to resist a range of network attacks. Especially, they claimed that their scheme could resist lost smart card attack. However, we reanalyze the security of Lee et al.'s scheme, and show that it fails to protect off-line password guessing attack if the secret information stored in the smart card is compromised. This also renders that their scheme is insecure against user impersonation attacks. Then, we propose a new user authentication scheme for integrated EPR information systems based on the quadratic residues. The new scheme not only resists a range of network attacks but also provides user anonymity. We show that our proposed scheme can provide stronger security. PMID- 24760227 TI - Direct synthesis of a mesoporous TiO2-RuO2 composite through evaporation-induced polymeric micelle assembly. AB - Here we report a direct synthesis of a mesoporous TiO2-RuO2 composite. Titanium tetraisopropoxide (TTIP) and RuCl3 are used as inorganic precursors for TiO2 and RuO2, respectively. Evaporation-induced assembly of spherical micelles made of an asymmetric poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) triblock copolymer enables the fabrication of a mesoporous TiO2-RuO2 composite with a uniform pore size of 30 nm. PMID- 24760225 TI - The effect of electronic medical record application on the length of stay in a Chinese general hospital: a department- and disease-focused interrupted time series study. AB - A key purpose of electronic medical records (EMR) introduced in medical institutions is to improve work efficiency. The average length of stay (LOS) is just an important indicator to evaluate work efficiency of medical care in hospitals. Recently, there have been reports about effects of EMR application on LOS in medical institutions, but they have been mostly based on the overall analysis of a region or a hospital and not of specific clinical departments and diseases or based on longer time periods. Therefore, in this study, we selected four clinical departments and four diseases with the largest number of inpatients from January 2004 to December 2012 in a Chinese 3A general hospital and used an interrupted time-series method by the departments and diseases to analyze the relationship of EMR application and LOS. Through our analyses, we concluded that, under unadjusted condition, LOS were all reduced (P < 0.001) after EMR application in four departments and for four diseases. After adjustment by gender, age or admission condition, LOS still all decreased after EMR application (P < 0.05) regardless of departments or diseases. The trend changes in LOS reversed from increasing to decreasing in the orthopedics department (coefficient: 0.016 to -0.079), the cardiovascular surgery department (coefficient: 0.007 to -0.126) and all departments overall (coefficient: 0.004 to -0.070), as well as for the intervertebral disc disorders (coefficient: 0.026 to 0.068). Furthermore, the decreasing trend gained a larger slope in the cardiology department (coefficient: -0.017 to -0.023), the neurology department (coefficient: -0.012 to -0.043) and for the coronary heart disease (coefficient: 0.010 to -0.018), the ventricular septal defect (coefficient: -0.024 to -0.059), and the cerebral infarction (coefficient: -0.031 to -0.040). Together, these findings indicate that EMR application coincided with a decrease in LOS and may have a contribution to the decrease. PMID- 24760228 TI - Cloning and characterization of the first GH10 and GH11 xylanases from Rhizopus oryzae. AB - The only available genome sequence for Rhizopus oryzae strain 99-880 was annotated to not encode any beta-1,4-endoxylanase encoding genes of the glycoside hydrolase (GH) family 10 or 11. Here, we report the identification and cloning of two such members in R. oryzae strain NRRL 29086. Strain 29086 was one of several selected fungi grown on wheat or triticale bran and screened for xylanase activity among other hydrolytic actions. Its high activity (138 U/ml) in the culture supernatant led to the identification of two activity-stained proteins, designated Xyn-1 and Xyn-2 of respective molecular masses 32,000 and 22,000. These proteins were purified to electrophoretic homogeneity and characterized. The specific activities of Xyn-1 and Xyn-2 towards birchwood xylan were 605 and 7,710 U/mg, respectively. Kinetic data showed that the lower molecular weight Xyn 2 had a higher affinity (K m=3.2 +/- 0.2 g/l) towards birchwood xylan than Xyn-1 by about 4-fold. The melting temperature (T m) of the two proteins, estimated to be in the range of 49.5-53.7 degrees C indicated that they are rather thermostable proteins. N-terminal and internal peptide sequences were obtained by chemical digestion of the purified xylanases to facilitate cloning, expression in Escherichia coli, and sequencing of the respective gene. The cloned Rhizopus xylanases were used to demonstrate release of xylose from flax shives-derived hemicellulose as model feedstock. Overall, this study expands the catalytic toolbox of GH10 and 11 family proteins that have applications in various industrial and bioproducts settings. PMID- 24760229 TI - Effects of pyruvate dehydrogenase subunits overexpression on the alpha ketoglutarate production in Yarrowia lipolytica WSH-Z06. AB - Yarrowia lipolytica WSH-Z06 harbours a promising capability to oversynthesize alpha-ketoglutarate (alpha-KG). Its wide utilization is hampered by the formation of high concentrations of pyruvate. In this study, a metabolic strategy for the overexpression of the alpha and beta subunits of pyruvate dehydrogenase E1, E2 and E3 components was designed to reduce the accumulation of pyruvate. Elevated expression level of alpha subunit of E1 component improved the alpha-KG production and reduced the pyruvate accumulation. Due to a reduction in the acetyl-CoA supply, neither the growth of cells nor the synthesis of alpha-KG was restrained by the overexpression of beta subunit of E1, E2 and E3 components. Furthermore, via the overexpression of these thiamine pyrophosphate (TPP)-binding subunits, the dependency of pyruvate dehydrogenase on thiamine was diminished in strains T1 and T2, in which alpha and beta subunits of E1 component were separately overexpressed. In these two recombinant strains, the accumulation of pyruvate was insensitive to variations in exogenous thiamine. The results suggest that alpha-KG production can be enhanced by altering the dependence on TPP of pyruvate dehydrogenase and that the competition for the cofactor can be switched to ketoglutarate dehydrogenase via separate overexpression of the TPP-binding subunits of pyruvate dehydrogenase. The results presented here provided new clue to improve alpha-KG production. PMID- 24760230 TI - Microbial management of arthropod pests of tea: current state and prospects. AB - Sustainable tea cultivation will rely increasingly on alternatives to conventional chemical insecticides for pest management that are environment friendly and reduce the amount of pesticide residues in made tea. Entomopathogens can provide effective control, conserve biodiversity, and serve as alternatives to chemical insecticides under several conditions. Due to their specificity for insects, these pathogens including viruses, bacteria, and fungi are ideal candidates for incorporation in the integrated pest management strategies for tea where their effects on other natural enemies will be minimal. Biological and ecological characteristics of several dominant natural entomopathogenic microorganisms have been well documented throughout the tea-growing countries particularly China, Japan, and India. But research to convert them to microbial insecticide formulations for tea pest control by evolving suitable techniques for production, standardization, formulation, and application has not progressed well except in Japan and China to some extent. Increased use of microbial control will depend on a variety of factors including improvements in the pathogens' virulence, formulation, delivery, etc. and an increased awareness of their attributes by growers and the general public. In this review, we provide an overview of microbial control of the key insect pests of tea and also the scope for future studies for their better utilization. PMID- 24760231 TI - Colorectal polyps and polyposis syndromes. AB - A polyp is defined as any mass protruding into the lumen of a hollow viscus. Colorectal polyps may be classified by their macroscopic appearance as sessile (flat, arising directly from the mucosal layer) or pedunculated (extending from the mucosa through a fibrovascular stalk). Colorectal polyps may also be histologically classified as neoplastic or as non-neoplastic (hyperplastic, hamartomatous, or inflammatory). The neoplastic polyps are of primary importance because they harbor a malignant potential, which represents a stage in the development of colorectal cancer. For this reason, it is essential to identify these polyps at a sufficiently early stage, when a simple outpatient procedure to remove them can interrupt the development of colorectal cancer and prevent disease and death. When invasive carcinoma arises in a polyp, careful consideration must be given to ensuring the adequacy of treatment. Although most neoplastic polyps do not evolve into cancer, it is well accepted that the majority of colorectal carcinomas evolve from adenomatous polyps; the sequence of events leading to this transformation is referred to as the adenoma-to-carcinoma sequence. The presence of a systemic process that promotes the development of multiple gastro-intestinal polyps is termed 'polyposis'. Hereditary gastro intestinal polyposis syndromes account for approximately 1% of all cases of colorectal cancer and are associated with a broad spectrum of extra-colonic tumors. Early detection and accurate classification of these syndromes are essential, in order to initiate a surveillance program for the early detection of cancer. Several polyposis syndromes have been described, each having its own genetic basis and characteristic polyp distribution, clinical presentation, and malignancy risk. Diagnostic modalities and treatment options for neoplastic polyps-as well as the most prevalent polyposis syndromes-are reviewed below. PMID- 24760232 TI - Field cancerization in the colon: a role for aberrant DNA methylation? AB - Colorectal cancer is the third most common cancer worldwide and arises secondary to the progressive accumulation of genetic and epigenetic alterations in normal colon cells, which results in a polyp-to-cancer progression sequence. It is known that individuals with a personal history of colon adenomas or cancer are at increased risk for metachronous colon neoplasms. One explanation for this increased risk could be field cancerization, which is a phenomenon in which the histologically normal tissue in an organ is primed to undergo transformation. Epigenetic alterations appear to be promising markers for field cancerization. In this review, we discuss field cancerization in the colon and the data supporting the use of methylated DNA as a biomarker for this phenomenon. PMID- 24760233 TI - Hyponatraemia and cirrhosis. AB - Hyponatraemia is a common complication of advanced cirrhosis related to an impairment in the renal capacity for eliminating solute-free water, causing a retention of water that is disproportionate to the retention of sodium, thus leading to a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatraemia is a non-osmotic hypersecretion of arginine vasopressin (AVP) or antidiuretic hormone from the neurohypophysis, related to circulatory dysfunction. Hyponatraemia in cirrhosis is associated with increased morbidity and mortality. Hyponatraemia is also associated with increased morbidity and impaired short-term survival after transplantation. The current standard of care based on restricting fluids to 1 1.5 L/day is rarely effective. Other approaches, such as albumin infusion and the use of vaptans-which act by specifically antagonizing the effects of AVP on the V2 receptors located in the kidney tubules-have been evaluated for their role in the management of hyponatraemia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatraemia; however their use in patients with end-stage liver disease is limited by hepatotoxic effects of some of these drugs. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited. PMID- 24760234 TI - Re-evaluation of indications and outcomes of endoscopic excision procedures for colorectal tumors: a review. AB - Endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) are useful therapeutic techniques for colorectal tumors. Currently, new techniques based on these procedures are available, such as endoscopic submucosal dissection with snare (ESD-S) and endoscopic mucosal resection with pre-cutting (EMR-P). For the excision of colorectal tumors, each of these techniques has been characterized as having a high total resection rate, low recurrence rate or low complication rate. In this study, we analysed clinical trials that had recently been published, to search for the most appropriate endoscopic treatment for colorectal tumors. Our search results revealed the following: for a tumor with a diameter less than 20 mm, the surgeon should choose ESD, ESD-S, EMR-P or EMR, depending on the condition of the tumor. On the other hand, to excise a tumor larger than 20 mm in diameter, ESD and ESD-S should be the first choices. However, if the patient has a high risk of complications due to ESD or ESD-S, the use of EMR-P would be suitable. Because of the high possibility of canceration in a tumor larger than 20 mm in diameter, EMR is not the optimal endoscopic treatment for the excision of a colorectal tumor, due to a low total resection rate and a high recurrence rate. PMID- 24760235 TI - Neoadjuvant therapy followed by local excision and two-stage total mesorectal excision: a new strategy for sphincter preservation in locally advanced ultra-low rectal cancer. AB - BACKGROUND: With the increased usage of neoadjuvant chemoradiotherapy, improved surgical technique and stapling devices, sphincter-preserving resection has become more frequent for patients with rectal cancer. However, as for locally advanced ultra-low rectal cancer, sphincter-preservation is still facing an enormous challenge. OBJECTIVE: To introduce an NLT strategy of sphincter preservation-neoadjuvant therapy (NT) followed by local excision (LE) and two stage total mesorectal excision (TME)-into the treatment of locally advanced ultra-low rectal cancer (lesions with anal sphincter invasion). METHODS: From October 2010 to October 2011, nine patients with locally advanced rectal cancer located less than 3 cm from the anal verge were treated by the NLT strategy. All patients had shown good clinical response to NT. The LE procedure was carried transanally 6-8 weeks after completion of the NT. TME was performed to dissect mesorectal lymph nodes 4-6 weeks after LE. RESULTS: Of the nine patients, the lesion was assessed as T2 in two, T3 in five, and T4 in two before NT, and lymph node metastasis was detected in five patients. The median distance from the tumor to the anal verge was 2.5 cm (range: 1-3 cm). The median follow-up was 27 months (range: 24-34 months). No distant metastasis was detected. Only one patient (11.1%) developed local recurrence at 12 months post-operatively and then underwent abdomino-perineal resection. The remaining eight patients had preserved long-term continence and the median Wexner score at two years post-operation was 4 (range: 2-6). CONCLUSION: The new NLT strategy can achieve sphincter preservation in some patients with ultra-low rectal cancer, with favorable oncological outcome and preservation of normal anal sphincter function. PMID- 24760236 TI - An experimental research into endostatin microbubble combined with focused ultrasound for anti-tumor angiogenesis in colon cancer. AB - OBJECTIVE: to evaluate the therapeutic effect of targeted endostatin-loaded microbubbles, combined with improved, focused, directional ultrasound radiation for inhibition of subcutaneous translocation in situ colon tumor angiogenesis in colon cancer. METHODS: 65 BALB/c nude mice with subcutaneous translocation in situ colon tumors were randomly divided into five groups. Group A was the control group, without any treatments. In Group B, the mouse was treated with ultrasonic radiation. In Group C, the mouse was treated with ultrasonic radiation combined with empty SonoVue microbubbles. In Group D, the mouse was treated with ultrasonic radiation combined with empty Targestar-SA microbubbles. In Group E, the mouse was treated with ultrasonic radiation combined with endostatin microbubbles. The tumor size was measured before and 1, 14, and 28 days after irradiation. The peak intensity (PI), regional blood volume (RBV) and regional blood flow (RBF) were recorded using contrast-enhanced ultrasound. The tumor tissue was removed for pathological examination; the tumor necrosis area and microvascular density (MVD) were evaluated by immunohistochemistry. RESULTS: Tumors in Groups C, D and E were significantly smaller than in Groups A and B at 28 days after irradiation, with Group E the smallest. PI, RBF and RBV of Groups C, D, and E were significantly decreased 28 days after radiation with Group E the lowest, and significantly lower than Groups A and B (all P < 0.05). The tumor tissue necrosis area of Group E was clearly greater while MVD was obviously lower than the other groups (all P < 0.01) at 28 days after treatment. CONCLUSION: The targeted endostatin microbubbles, combined with focused, directional ultrasound radiation can damage tumor microvasculature of subcutaneous colon translocation in situ colon cancer, as well as inhibit the tumor angiogenesis. PMID- 24760237 TI - Use of prototype two-channel endoscope with elevator enables larger lift-and snare endoscopic mucosal resection in a porcine model. AB - BACKGROUND: Flat and depressed lesions are becoming increasingly recognized in the esophagus, stomach, and colon. Various techniques have been described for endoscopic mucosal resection (EMR) of these lesions. AIMS: To evaluate the efficacy of lift-grasp-cut EMR using a prototype dual-channel forward-viewing endoscope with an instrument elevator in one accessory channel (dual-channel elevator scope) as compared to standard dual-channel endoscopes. METHODS: EMR was performed using a lift-grasp-cut technique on normal flat rectosigmoid or gastric mucosa in live porcine models after submucosal injection of 4 mL of saline using a dual-channel elevator scope or a standard dual-channel endoscope. With the dual channel elevator scope, the elevator was used to attain further lifting of the mucosa. The primary endpoint was size of the EMR specimen and the secondary endpoint was number of complications. RESULTS: Twelve experiments were performed (six gastric and six colonic). Mean specimen diameter was 2.27 cm with the dual channel elevator scope and 1.34 cm with the dual-channel endoscope (P = 0.018). Two colonic perforations occurred with the dual-channel endoscope, vs no complications with the dual-channel elevator scope. CONCLUSIONS: The increased lift of the mucosal epithelium, through use of the dual-channel elevator scope, allows for larger EMR when using a lift-grasp-cut technique. Noting the thin nature of the porcine colonic wall, use of the elevator may also make this technique safer. PMID- 24760238 TI - A study of laparoscopic extraperitoneal sigmoid colostomy after abdomino-perineal resection for rectal cancer. AB - OBJECTIVE: To established a procedure for laparoscopic extraperitoneal ostomy after abdomino-perineal resection (APR) and study safety aspects and complications. METHOD: From July 2011 to July 2012, 36 patients with low rectal cancer undergoing APR were included in the study and divided into extraperitoneal ostomy group (n = 18) and intraperitoneal ostomy group (n = 18). Short- and long term complications were compared between the two groups. All patients were followed up and the median duration was 17 months (range: 12-24). RESULTS: The rates of short-term complication related to colostomies were comparable between the two groups, except the rate for stoma edema was higher in the extraperitoneal group (33.3% vs 0%; P = 0.008). In the intraperitoneal ostomy group, two patients developed stoma prolapse, one had stoma stenosis, and two had parastomal hernia. In contrast, no long-term complications related to colostomies occurred in the extraperitoneal ostomy group. The rate of long-term complication was lower in the extraperitoneal ostomy group (0% vs 22.2%; P = 0.036). CONCLUSION: The laparoscopic extraperitoneal ostomy is a relatively simple and safe procedure, with fewer long-term complications related to colostomy. However the follow-up period was not too long and needs to be extended. PMID- 24760239 TI - Expanding the horizons of endoscopic ultrasound: diagnosis of non-digestive pathologies. AB - Endoscopic ultrasound (EUS) is mainly used for the evaluation and sampling of mediastinal and abdominal lymph nodes, luminal and submucosal lesions of the upper and lower gastrointestinal tract, as well as in the diagnostic approach for pancreatic, biliary and liver disease. However, several non-digestive pathologies may be encountered as well, expanding the diagnostic potential of EUS. In this article, we present nine examples of extra-digestive abnormalities detected by means of EUS, including pathologies of the thyroid gland, mediastinal and abdominal vessels, lungs, kidney and the urinary bladder. The purpose of this article is to review the capabilities of EUS beyond routine evaluation of gastrointestinal organs. PMID- 24760240 TI - Pediatric ileoileal intussusception with a lipoma lead point: a case report. AB - Intussusception is a common cause of mechanical bowel obstruction among children, with older children being more likely to have a pathological lead point. Intestinal neoplasms are rare and small intestinal lipomas are even less common. Herein we describe a case of a 7-year-old boy with ileoileal intussusception, with an ileal lipoma as the pathological lead point. Computed tomography was useful pre-operatively for revealing intussusception due to lipoma as the pathologic lead point. PMID- 24760241 TI - Krukenberg tumour as the initial presentation of Peutz-Jeghers syndrome. AB - Peutz-Jeghers syndrome (PJS) is an hereditary syndrome characterized by gastrointestinal polyposis and mucocutaneous pigmentation. PJS patients are at increased risk of developing various cancers, especially of the gastrointestinal and gynaecological tracts. Colonic adenocarcinoma is one of the more common tumours that occur in PJS. We report a young lady presenting with a large ovarian tumour, later diagnosed to have PJS with colonic signet cell adenocarcinoma and synchronous ovarian metastasis. PMID- 24760242 TI - Dermatological findings in early detection of complex regional pain syndrome. AB - IMPORTANCE: Complex regional pain syndrome (CRPS) is a chronic pain condition usually affecting the extremities. It mostly occurs in 3 distinct stages with intense pain being the hallmark feature in every stage. Skin abnormalities are common, and often necessary, in the clinical findings required to diagnose CRPS. OBSERVATIONS: A man in his 30s presented to the dermatology clinic with complaints of recurrent redness, swelling, and burning pain in his left arm. Based on this clinical presentation with normal findings from a neurological examination and unremarkable findings on diagnostic imaging, the diagnosis of CRPS was made. CONCLUSIONS AND RELEVANCE: It is important for dermatologists to understand and recognize CRPS as a neurological disorder with major dermatologic implications. The ability of dermatologists to identify and direct patients with this syndrome is a critical factor in determining the likelihood of favorable outcomes following diagnosis of CRPS. This report outlines and reviews a neurological condition presenting with clinically significant cutaneous changes. We illustrate the bias that dermatologists may have in exclusively associating patient complaints with dermatological implications. This stresses the necessity for dermatologists to perform comprehensive medical histories and physical examinations to minimize diagnostic error and improve patient care. PMID- 24760243 TI - Changes in trabecular bone density in incident pediatric Crohn's disease: a comparison of imaging methods. AB - This study of changes in dual energy x-ray absorptiometry (DXA) spine BMD following diagnosis and treatment for childhood Crohn's disease demonstrated that changes in conventional posteroanterior BMD results were confounded by impaired growth, and suggested that lateral spine measurements and strategies to estimate volumetric BMD were more sensitive to disease and treatment effects. INTRODUCTION: We previously reported significant increases in peripheral quantitative CT (pQCT) measures of trabecular volumetric bone mineral density (vBMD) following diagnosis and treatment of pediatric Crohn's disease (CD). The objective of this study was to compare pQCT trabecular vBMD and three DXA measures of spine BMD in this cohort: (1) conventional posteroanterior BMD (PA BMD), (2) PA-BMD adjusted for height Z (PA-BMDHtZ), and (3) width-adjusted volumetric BMD (WA-BMD) estimated from PA and lateral scans. METHODS: Spine DXA [lumbar (L1-4) for posteroanterior and L3 for lateral] and tibia pQCT scans were obtained in 65 CD subjects (ages 7-18 years) at diagnosis and 12 months later. BMD results were converted to sex, race, and age-specific Z-scores based on reference data in >650 children (ages 5-21 years). Multivariable linear regression models identified factors associated with BMD Z-scores. RESULTS: At CD diagnosis, all BMD Z-scores were lower compared with the reference children (all p values <0.01). The pQCT vBMD Z-scores (-1.46 +/- 1.30) were lower compared with DXA PA-BMD (-0.75 +/- 0.98), PA-BMDHtZ (-0.53 +/- 0.87), and WA-BMD (-0.61 +/- 1.10) among CD participants. Only PA-BMD Z-scores were correlated with height Z scores at baseline (R = 0.47, p < 0.0001). pQCT and WA-BMD Z-scores increased significantly over 12 months to -1.04 +/- 1.26 and -0.20 +/- 1.14, respectively. Changes in all four BMD Z-scores were positively associated with changes in height Z-scores (p < 0.05). Glucocorticoid doses were inversely associated with changes in WA-BMD (p < 0.01) only. CONCLUSIONS: Conventional and height Z-score adjusted PA DXA methods did not demonstrate the significant increases in trabecular vBMD noted on pQCT and WA-BMD scans. WA-BMD captured glucocorticoid effects, potentially due to isolation of the vertebral body on the lateral projection. Future studies are needed to identify the BMD measure that provides greatest fracture discrimination in CD. PMID- 24760244 TI - Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2 year open-label study. AB - Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug. INTRODUCTION: The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1-34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis. METHODS: Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N = 65) or quarterly intravenous IBN (N = 122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared. RESULTS: Baseline characteristics (overall mean +/- SD) were similar between groups in terms of age 67.9 +/- 7.4 years, body mass index 23.8 +/- 3.8 kg/m(2), BMD L1-L4 0.741 +/- 0.100 g/cm(2), and TBS 1.208 +/- 0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 % +/- 6.3 vs. +2.9 % +/- 3.3 and +4.3 % +/- 6.6 vs. +0.3 % +/- 4.1, respectively; P < 0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r (2) = 0.04) with no correlation between the changes in BMD and TBS over 24 months. CONCLUSIONS: In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN. PMID- 24760245 TI - Risk of fracture in patients with Guillain-Barre syndrome. AB - The aim of this study was to evaluate fracture risk in patients with Guillain Barre syndrome (GBS). No association with risk of fracture was observed for GBS patients compared with controls. Only GBS patients using pain treatment had a doubled risk of fracture. INTRODUCTION: Symptoms of Guillain-Barre syndrome (GBS) may vary from mild difficulty in walking to complete paralysis, which may increase the risk of fractures. Therefore, the aim of this study was to evaluate fracture risk in patients with GBS. METHODS: We conducted a retrospective cohort study using the UK Clinical Practice Research Datalink (1987-2012). Each patient with GBS was matched by year of birth, sex, and practice, up to six patients without a history of GBS. Outcome measure was any fracture. RESULTS: There were no associations between GBS and any fracture, adjusted hazard ratio (AHR) 1.01 (95 % confidence interval [CI] 0.77-1.33), or osteoporotic fracture, AHR 0.76 (95 % CI 0.50-1.17), compared with controls. Stratification to gender, age, and duration since diagnosis did not show an association either. Only for GBS patients using pain treatment, risk of fracture was doubled AHR 1.97 (95 % confidence CI 1.21-3.21) compared with controls. The risk of fracture in GBS patients exposed to pain treatment was equivalent to risk of fracture among controls exposed to pain treatment. CONCLUSIONS: No association with risk of fracture was observed for GBS patients compared with controls. Only GBS patients using pain treatment had a doubled risk of fracture, but their risk was equivalent to fracture risk among controls exposed to pain treatment. PMID- 24760246 TI - Suppressed bone turnover was associated with increased osteoporotic fracture risks in non-obese postmenopausal Chinese women with type 2 diabetes mellitus. AB - We found that type 2 diabetes mellitus (T2DM) was associated with increased fracture risks in non-obese postmenopausal Chinese women, and suppressed bone turnover might be the underlying mechanism. This is the first study evaluating and explaining the association of T2DM with osteoporotic fracture in Chinese population with such high homogeneity. INTRODUCTION: The aim of this study was to investigate the association of T2DM with osteoporotic fracture in postmenopausal Chinese women. METHODS: One thousand four hundred ten postmenopausal women were included and stratified into non-obese population [body mass index (BMI) < 25 kg/m(2)] and obese population (BMI >= 25 kg/m(2)). Each type of population was classified into diabetes group, impaired fasting glucose (IFG) group, and normal glucose group. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Serum C-terminal telopeptide of type I collagen (beta-CTX) and serum N-amino terminal prepeptide of type 1 procollagen (P1NP) were quantified. Vertebral fractures (VFs) and non-VFs were assessed by vertebral X-ray and questionnaire, respectively. RESULTS: Comparing to normal glucose group, diabetes group and IFG group both had lower levels of P1NP and beta-CTX, despite population types. Despite having non-decreased BMD, non-obese diabetic patients had higher risks of total fracture and VF than BMI-matched normal glucose subjects (both P < 0.05). Non-obese population was further classified by a mean value of P1NP or beta-CTX. Non-obese diabetic patients with low P1NP or high beta CTX had higher fracture risks (both P < 0.05), comparing to non-obese normal glucose subjects with high P1NP or high beta-CTX, respectively. CONCLUSIONS: Type 2 diabetic patients had suppressed bone turnover, which might explain the increased fracture risks, independent of BMD. IFG patients might also have poor bone quality and need early prevention. PMID- 24760247 TI - Osteomalacia mimicking spondyloarthropathy: a case report. AB - Osteomalacia is a metabolic bone disorder characterized by impaired mineralization of bone matrix. Symptoms of osteomalacia can be confused with other conditions such as spondyloarthropathy, polymyalgia rheumatica, polymyositis, and fibromyalgia. In this case, we report a patient with axial osteomalacia who developed low back pain, morning stiffness, and "grade 3 sacroiliitis" in pelvis X-ray, leading to the misdiagnosis as seronegative spondyloarthropathy. Serum biochemical studies revealed low serum phosphorus, low 25-hydroxy vitamin D3, normal calcium, elevated parathyroid hormone, and alkaline phosphatase levels. Her symptoms were relieved with vitamin D and calcium therapy. The diagnosis of osteomalacia should be considered in case of sacroiliitis and spondylitis. PMID- 24760249 TI - Performance of solid and liquid culture media for the detection of Mycobacterium tuberculosis in clinical materials: meta-analysis of recent studies. PMID- 24760248 TI - Effect of magnesium oxide on interfraction prostate motion and rectal filling in prostate cancer radiotherapy: analysis of a randomized clinical trial. AB - PURPOSE: To investigate whether magnesium oxide reduces the interfraction motion of the prostate and the amount of rectal filling and rectal gas, which influences prostate position during radiotherapy for prostate cancer. PATIENTS AND METHODS: From December 2008 to February 2010, 92 prostate cancer patients scheduled for intensity-modulated radiotherapy (77 Gy in 35 fractions) using fiducial marker based position verification were randomly assigned to receive magnesium oxide (500 mg twice a day) or placebo during radiotherapy. In a previous study, we investigated the effect on intrafraction motion and did not find a difference between the treatment arms. Here, we compared the interfraction prostate motion between the two treatment arms as well as the amount of rectal filling and rectal air pockets using pretreatment planning computed tomography and magnetic resonance imagingscans. RESULTS: There was no statistically significant difference between the treatment arms in translation and rotation of the prostate between treatment fractions, except for the rotation around the cranial caudal axis. However, the difference was less than 1 degrees and therefore considered not clinically relevant. There was no significant difference in the amount of rectal filling and rectal air pockets between the treatment arms. CONCLUSION: Magnesium oxide is not effective in reducing the interfraction prostate motion or the amount of rectal filling and rectal gas during external-beam radiotherapy. Therefore, magnesium oxide is not recommended in clinical practice for these purposes. PMID- 24760250 TI - Are hospitalizations for rotavirus gastroenteritis associated with meteorologic factors? AB - Local climatic factors might explain seasonal patterns of rotavirus infections, but few models have been proposed to determine the effects of weather conditions on rotavirus activity. Here, we study the association of meteorologic factors with rotavirus activity, as determined by the number of children hospitalized for rotavirus gastroenteritis on the Mediterranean island of Mallorca (Spain). We conducted a retrospective review of the medical records of children aged 0-5 years admitted for rotavirus gastroenteritis between January 2000 and December 2010. The number of rotavirus hospitalizations was correlated to temperature, humidity, rainfall, atmospheric pressure, water vapor pressure, wind speed, and solar radiation using regression and time-series techniques. A total of 311 patients were hospitalized for rotavirus gastroenteritis in the 11-year study period, with a seasonal pattern from December to June, and a peak incidence in February. After multiple regressions, weekly rotavirus activity could be explained in 82 % of cases (p < 0.001) with a one-week lag meteorologic model. Rotavirus activity was negatively associated to temperature and positively associated to atmospheric pressure, solar radiation, and wind speed. Temperature and solar radiation were the factors that contributed most to the model, with a peak rotavirus activity at 9 degrees C and 800 10KJ/m(2), respectively. In conclusion, hospitalization for rotavirus was strongly associated with mean temperature, but an association of rotavirus activity with solar radiation, atmospheric pressure, and wind speed was also demonstrated. This model predicted more than 80 % of rotavirus hospitalizations. PMID- 24760258 TI - Increased incorporation of antiplasmin into the fibrin network in patients with type 1 diabetes. AB - OBJECTIVE: Diabetes is associated with various vascular complications and is suggested to induce a prothrombotic state. In the current study, we characterized antiplasmin incorporation into fibrin in relation to other fibrinolytic compounds in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 236 patients with type 1 diabetes and 78 control subjects were investigated. The incorporation of antiplasmin into the fibrin network and the plasma levels of plasminogen activator inhibitor type 1 (PAI-1) activity, tissue plasminogen activator (tPA) activity, tPA/PAI-1 complex, plasmin-antiplasmin complex, antiplasmin, factor XIII, and d-dimer were measured. In addition, we used global assays to study fibrinolysis. RESULTS: The incorporation of antiplasmin into the fibrin network was significantly higher in patients with type 1 diabetes than in control subjects without diabetes (1.65 +/- 0.25 vs. 1.35 +/- 0.18 mg/L, respectively; P < 0.0001). The patients also had lower PAI-1 activity (2.19 units/mL [interquartile range 0.96-5.42] vs. 4.25 units/mL [1.95-9.0]; P = 0.0012) and antiplasmin level in plasma (78.5 +/- 13.3 vs. 83.2 +/- 15.4 mg/L; P < 0.05), resulting in a higher fibrinolytic capacity (shorter clot lysis time; P = 0.0090). We did not find any important sex differences regarding fibrinolysis in the patients or in the control subjects. CONCLUSIONS: Patients with type 1 diabetes incorporate more antiplasmin into the fibrin network than control subjects without diabetes do and have a reduced PAI-1 activity and a shorter clot lysis time. These results suggest that patients with type 1 diabetes produce a fibrin clot that is more resistant to fibrinolysis, which, however, may be counteracted by an increased fibrinolytic potential in plasma. PMID- 24760259 TI - Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial. AB - OBJECTIVE: Vitamin D deficiency in pregnancy is associated with an increased risk of gestational diabetes mellitus (GDM) and neonatal vitamin D deficiency. We conducted a double-blind, randomized controlled trial of low-dose (LD) versus high-dose (HD) vitamin D supplementation to investigate the effects of vitamin D supplementation on glucose metabolism during pregnancy. RESEARCH DESIGN AND METHODS: Women with plasma 25-hydroxyvitamin D (25OHD) levels <32 ng/mL before 20 weeks' gestation were randomized to oral vitamin D3 at 5,000 IU daily (HD) (n = 89) or the recommended pregnancy dose of 400 IU daily (LD) (n = 90) until delivery. The primary end point was maternal glucose levels on oral glucose tolerance test (OGTT) at 26-28 weeks' gestation. Secondary end points included neonatal 25OHD, obstetric and other neonatal outcomes, and maternal homeostasis model assessment of insulin resistance. Analysis was by intention to treat. RESULTS: There was no difference in maternal glucose levels on OGTT. Twelve LD women (13%) developed GDM versus seven (8%) HD women (P = 0.25). Neonatal cord 25OHD was higher in HD offspring (46 +/- 11 vs. 29 +/- 12 ng/mL, P < 0.001), and deficiency was more common in LD offspring (24 vs. 10%, P = 0.06). Post hoc analysis in LD women showed an inverse relationship between pretreatment 25OHD and both fasting and 2-h blood glucose level on OGTT (both P < 0.001). Baseline 25OHD remained an independent predictor after multiple regression analysis. CONCLUSIONS: HD vitamin D supplementation commencing at a mean of 14 weeks' gestation does not improve glucose levels in pregnancy. However, in women with baseline levels <32 ng/mL, 5,000 IU per day was well tolerated and highly effective at preventing neonatal vitamin D deficiency. PMID- 24760260 TI - Changes in subcutaneous fat cell volume and insulin sensitivity after weight loss. AB - OBJECTIVE: Large subcutaneous fat cells associate with insulin resistance and high risk of developing type 2 diabetes. We investigated if changes in fat cell volume and fat mass correlate with improvements in the metabolic risk profile after bariatric surgery in obese patients. RESEARCH DESIGN AND METHODS: Fat cell volume and number were measured in abdominal subcutaneous adipose tissue in 62 obese women before and 2 years after Roux-en-Y gastric bypass (RYGB). Regional body fat mass by dual-energy X-ray absorptiometry; insulin sensitivity by hyperinsulinemic-euglycemic clamp; and plasma glucose, insulin, and lipid profile were assessed. RESULTS: RYGB decreased body weight by 33%, which was accompanied by decreased adipocyte volume but not number. Fat mass in the measured regions decreased and all metabolic parameters were improved after RYGB (P < 0.0001). Whereas reduced subcutaneous fat cell size correlated strongly with improved insulin sensitivity (P = 0.0057), regional changes in fat mass did not, except for a weak correlation between changes in visceral fat mass and insulin sensitivity and triglycerides. The curve-linear relationship between fat cell size and fat mass was altered after weight loss (P = 0.03). CONCLUSIONS: After bariatric surgery in obese women, a reduction in subcutaneous fat cell volume associates more strongly with improvement of insulin sensitivity than fat mass reduction per se. An altered relationship between adipocyte size and fat mass may be important for improving insulin sensitivity after weight loss. Fat cell size reduction could constitute a target to improve insulin sensitivity. PMID- 24760261 TI - Weight loss, glycemic control, and cardiovascular disease risk factors in response to differential diet composition in a weight loss program in type 2 diabetes: a randomized controlled trial. AB - OBJECTIVE: To test whether a weight loss program promotes greater weight loss, glycemic control, and improved cardiovascular disease risk factors compared with control conditions and whether there is a differential response to higher versus lower carbohydrate intake. RESEARCH DESIGN AND METHODS: This randomized controlled trial at two university medical centers enrolled 227 overweight or obese adults with type 2 diabetes and assigned them to parallel in-person diet and exercise counseling, with prepackaged foods in a planned menu during the initial phase, or to usual care (UC; two weight loss counseling sessions and monthly contacts). RESULTS: Relative weight loss was 7.4% (95% CI 5.7-9.2%), 9.0% (7.1-10.9%), and 2.5% (1.3-3.8%) for the lower fat, lower carbohydrate, and UC groups (P < 0.001 intervention effect). Glycemic control markers and triglyceride levels were lower in the intervention groups compared with UC group at 1 year (fasting glucose 141 [95% CI 133-149] vs. 159 [144-174] mg/dL, P = 0.023; hemoglobin A1c 6.9% [6.6-7.1%] vs. 7.5% [7.1-7.9%] or 52 [49-54] vs. 58 [54-63] mmol/mol, P = 0.001; triglycerides 148 [134-163] vs. 204 [173-234] mg/dL, P < 0.001). The lower versus higher carbohydrate groups maintained lower hemoglobin A1c (6.6% [95% CI 6.3-6.8%] vs. 7.2% [6.8-7.5%] or 49 [45-51] vs. 55 [51-58] mmol/mol) at 1 year (P = 0.008). CONCLUSIONS: The weight loss program resulted in greater weight loss and improved glycemic control in type 2 diabetes. PMID- 24760262 TI - Distribution of C-peptide and its determinants in North American children at risk for type 1 diabetes. AB - OBJECTIVE: To determine basal and stimulated C-peptide percentiles in North American children and adolescents at risk for type 1 diabetes (T1D) and to examine factors associated with this distribution in the Diabetes Prevention Trial-Type 1 (DPT-1). RESEARCH DESIGN AND METHODS: We included 582 subjects aged 4-18 years at randomization in the DPT-1 trials. A 2-h oral glucose tolerance test (OGTT) was performed at baseline and every 6 months during the 5-year follow up period. The percentile values of C-peptide after baseline OGTT were estimated according to age, BMI Z score (BMIZ), and/or sex categories. Conditional quantile regression was used to examine the relationship between C-peptide percentiles and various independent variables. RESULTS: The basal and stimulated C-peptide levels increased significantly as age and BMIZ increased (P < 0.05). Both age and BMIZ had a stronger impact on the upper quartile of C-peptide distributions than the lower quartile. Sex was only significantly associated with stimulated C-peptide. Higher stimulated C-peptide levels were generally observed in girls compared with boys at the same age and BMIZ (P < 0.05). HLA type and number of positive antibodies and antibody titers (islet cell antibody [ICA], insulin autoantibody, GAD65A, and ICA512A) were not significantly associated with C-peptide distribution after adjustment for age, BMIZ, and sex. CONCLUSIONS: Age-, sex-, and BMIZ-specific C-peptide percentiles can be estimated for North American children and adolescents at risk for T1D. They can be used as an assessment tool that could impact the recommendations in T1D prevention trials. PMID- 24760263 TI - Prevention of recurrent foot ulcers with plantar pressure-based in-shoe orthoses: the CareFUL prevention multicenter randomized controlled trial. AB - OBJECTIVE: To assess the efficacy of in-shoe orthoses that were designed based on shape and barefoot plantar pressure in reducing the incidence of submetatarsal head plantar ulcers in people with diabetes, peripheral neuropathy, and a history of similar prior ulceration. RESEARCH DESIGN AND METHODS: Single-blinded multicenter randomized controlled trial with subjects randomized to wear shape- and pressure-based orthoses (experimental, n = 66) or standard-of-care A5513 orthoses (control, n = 64). Patients were followed for 15 months, until a study end point (forefoot plantar ulcer or nonulcerative plantar forefoot lesion) or to study termination. Proportional hazards regression was used for analysis. RESULTS: There was a trend in the composite primary end point (both ulcers and nonulcerative lesions) across the full follow-up period (P = 0.13) in favor of the experimental orthoses. This trend was due to a marked difference in ulcer occurrence (P = 0.007) but no difference in the rate of nonulcerative lesions (P = 0.76). At 180 days, the ulcer prevention effect of the experimental orthoses was already significant (P = 0.003) when compared with control, and the benefit of the experimental orthoses with respect to the composite end point was also significant (P = 0.042). The hazard ratio was 3.4 (95% CI 1.3-8.7) for the occurrence of a submetatarsal head plantar ulcer in the control compared with experimental arm over the duration of the study. CONCLUSIONS: We conclude that shape- and barefoot plantar pressure-based orthoses were more effective in reducing submetatarsal head plantar ulcer recurrence than current standard-of care orthoses, but they did not significantly reduce nonulcerative lesions. PMID- 24760264 TI - Complement factor 3 is associated with insulin resistance and with incident type 2 diabetes over a 7-year follow-up period: the CODAM Study. AB - OBJECTIVE: Immune dysregulation can affect insulin resistance (IR) and beta-cell function and hence contribute to development of type 2 diabetes mellitus (T2DM). The complement system, as a regulator of immune and inflammatory homeostasis, may be a relevant contributor therein. However, longitudinal studies focusing on complement as a determinant of T2DM and IR are scarce. Therefore, we prospectively investigated the association of plasma complement factor 3 (C3) with (estimates of) IR in muscle, liver, and adipocytes, as well as with glucose tolerance, including incident T2DM. RESEARCH DESIGN AND METHODS: Fasting C3, nonesterified fatty acids, glucose, and insulin (the latter two during oral glucose tolerance tests) were measured at baseline (n = 545) and after 7 years of follow-up (n = 394) in a prospective cohort study. RESULTS: Over the 7-year period, C3 levels (per 0.1 g/L) were longitudinally associated with higher homeostasis model assessment of IR (HOMA2-IR; beta = 15.2% [95% CI 12.9-17.6]), hepatic IR (beta = 6.1% [95% CI 4.7-7.4]), adipocyte IR (beta = 16.0% [95% CI 13.0-19.1]), fasting glucose (beta = 1.8% [95% CI 1.2-2.4]), 2-h glucose (beta = 5.2% [95% CI 3.7-6.7]), and area under the curve for glucose (beta = 3.6% [95% CI 2.7-4.6]). In addition, greater changes in C3 (per 0.1 g/L) were associated with greater changes in HOMA2-IR (beta = 0.08 [95% CI 0.02-0.15]) and greater changes in hepatic IR (beta = 0.87 [95% CI 0.12-1.61]) over 7 years, but not glucose tolerance. Moreover, baseline C3 was associated with the 7-year incidence of T2DM (odds ratio 1.5 [95% CI 1.1-2.0]). CONCLUSIONS: Changes in C3 were associated with changes in several measures of IR and may reflect progression of metabolic dysregulation, which eventually leads to abnormalities in glucose tolerance and T2DM. PMID- 24760265 TI - Aortic graft infection. PMID- 24760267 TI - In situ fabrication of graphene-carbon nanochain webs as anodes for Li-ion batteries. AB - Carbon nanochain webs-sandwiched graphene has been successfully fabricated via in situ polymerization and subsequent carbonization. Such a novel nano-micro structure not only provides high conductivity, but also improves the cycling stability and rate capability during Li-ion storage. It shows a charge capacity of 1103.2 mA h g(-1) at 0.05 A g(-1) after 50 cycles. PMID- 24760266 TI - Strategies for promoting HIV testing uptake: willingness to receive couple-based and collective HIV testing among a cross-sectional online sample of men who have sex with men in China. AB - OBJECTIVES: Low rates of HIV testing drive the rapidly growing HIV epidemic among men who have sex with men (MSM) in China. We examined the potential usefulness of couple-based and collective HIV testing strategies among Chinese MSM. METHODS: A cross-sectional online survey was conducted among 1113 MSM in 2013. Multivariable logistic regression analyses were conducted to identify factors associated with willingness to receive couple-based and collective testing. RESULTS: Acceptability of couple-based testing was very high among participants (86.1%), with a moderate level of interest in collective testing (43.2%). Being 'out' to others about one's sexual identity (adjusted OR (AOR)=1.48, 95% CI 1.01 to 2.17) and having ever had an HIV test (AOR=3.05, 95% CI 2.10 to 4.33) were associated with willingness to receive couple-based testing. Having multiple male anal sex partners in the past 3 months was associated with willingness to participate in collective testing (AOR=1.43, 95% CI 1.03 to 1.99). DISCUSSION: Couple-based and collective HIV testing could help better control the HIV epidemic among Chinese MSM if implemented and promoted in a culturally competent manner. PMID- 24760268 TI - The beneficial role of spiritual counseling in heart failure patients. AB - To ascertain the beneficial role of spiritual counseling in patients with chronic heart failure. This is a pilot study evaluating the effects of adjunct spiritual counseling on quality of life (QoL) outcomes in patients with heart failure. Patients were assigned to "religious" or "non-religious" counseling services based strictly on their personal preferences and subsequently administered standardized QoL questionnaires. A member of the chaplaincy or in-house volunteer organization visited the patient either daily or once every 2 days throughout the duration of their hospitalization. All patients completed questionnaires at baseline, at 2 weeks, and at 3 months. Each of the questionnaires was totaled, with higher scores representing positive response, except for one survey measure where lower scores represent improvement (QIDS-SR16). Twenty-three patients (n = 23, age 57 +/- 11, 11 (48 %) male, 12 (52 %) female, mean duration of hospital stay 20 +/- 15 days) completed the study. Total mean scores were assessed on admission, at 2 weeks and at 3 months. For all patients in the study, the mean QIDS-SR16 scores were 8.5 (n = 23, SD = 3.3) versus 6.3 (n = 18, SD = 3.5) versus 7.3 (n = 7, SD = 2.6). Mean FACIT-Sp-Ex (version 4) scores were 71.1 (n = 23, SD = 15.1) versus 74.7 (n = 18, SD = 20.9) versus 81.4 (n = 7, SD = 8.8). The mean MSAS scores were 2.0 (n = 21, SD = 0.6) versus 1.8 (n = 15, SD = 0.7) versus 2.5 (n = 4, SD = 0.7). Mean QoL Enjoyment and Satisfaction scores were 47.2 % (n = 23, SD = 15.0 %) versus 53.6 % (n = 18, SD = 16.4 %) versus 72.42 % (n = 7, SD = 22 %). The addition of spiritual counseling to standard medical management for patients with chronic heart failure patients appears to have a positive impact on QoL. PMID- 24760269 TI - Integrated 18F-FDG PET/perfusion CT for the monitoring of neoadjuvant chemoradiotherapy in rectal carcinoma: correlation with histopathology. AB - PURPOSE: The aim of this study was to prospectively monitor changes in the flow metabolic phenotype (DeltaFMP) of rectal carcinoma (RC) after neoadjuvant chemoradiotherapy (CRT) and to evaluate whether DeltaFMP of RC correlate with histopathological prognostic factors including response to CRT. METHODS: Sixteen patients with RC (12 men, mean age 60.7 +/- 12.8 years) underwent integrated (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/perfusion CT (PET/PCT), followed by neoadjuvant CRT and surgery. In 13 patients, PET/PCT was repeated after CRT. Perfusion [blood flow (BF), blood volume (BV), mean transit time (MTT)] and metabolic [maximum and mean standardized uptake values (SUVmax, SUVmean)] parameters as well as the FMP (BF * SUVmax) were determined before and after CRT by two independent readers and correlated to histopathological prognostic factors of RC (microvessel density, necrosis index, regression index, vascular invasion) derived from resected specimens. The diagnostic performance of DeltaFMP for prediction of treatment response was determined. RESULTS: FMP significantly decreased after CRT (p < 0.001), exploiting higher changes after CRT as compared to changes of perfusion and metabolic parameters alone. Before CRT, no significant correlations were found between integrated PET/PCT and any of the histopathological parameters (all p > 0.05). After CRT, BV and SUVmax correlated positively with the necrosis index (r = 0.67/0.70), SUVmax with the invasion of blood vessels (r = 0.62) and DeltaFMP with the regression index (r = 0.88; all p < 0.05). DeltaFMP showed high accuracy for prediction of histopathological response to CRT (AUC 0.955, 95 % confidence interval 0.833 1.000, p < 0.01) using a cut-off value of -75%. CONCLUSION: In RC, DeltaFMP derived from integrated (18)F-FDG PET/PCT is useful for monitoring the effects of neoadjuvant CRT and allows prediction of histopathological response to CRT. PMID- 24760270 TI - Automated quantitative pupillometry for the prognostication of coma after cardiac arrest. AB - BACKGROUND: Sedation and therapeutic hypothermia (TH) delay neurological responses and might reduce the accuracy of clinical examination to predict outcome after cardiac arrest (CA). We examined the accuracy of quantitative pupillary light reactivity (PLR), using an automated infrared pupillometry, to predict outcome of post-CA coma in comparison to standard PLR, EEG, and somato sensory evoked potentials (SSEP). METHODS: We prospectively studied over a 1-year period (June 2012-June 2013) 50 consecutive comatose CA patients treated with TH (33 degrees C, 24 h). Quantitative PLR (expressed as the % of pupillary response to a calibrated light stimulus) and standard PLR were measured at day 1 (TH and sedation; on average 16 h after CA) and day 2 (normothermia, off sedation: on average 46 h after CA). Neurological outcome was assessed at 90 days with Cerebral Performance Categories (CPC), dichotomized as good (CPC 1-2) versus poor (CPC 3-5). Predictive performance was analyzed using area under the ROC curves (AUC). RESULTS: Patients with good outcome [n = 23 (46 %)] had higher quantitative PLR than those with poor outcome [n = 27; 16 (range 9-23) vs. 10 (1 30) % at day 1, and 20 (13-39) vs. 11 (1-55) % at day 2, both p < 0.001]. Best cut-off for outcome prediction of quantitative PLR was <13 %. The AUC to predict poor outcome was higher for quantitative than for standard PLR at both time points (day 1, 0.79 vs. 0.56, p = 0.005; day 2, 0.81 vs. 0.64, p = 0.006). Prognostic accuracy of quantitative PLR was comparable to that of EEG and SSEP (0.81 vs. 0.80 and 0.73, respectively, both p > 0.20). CONCLUSIONS: Quantitative PLR is more accurate than standard PLR in predicting outcome of post-anoxic coma, irrespective of temperature and sedation, and has comparable prognostic accuracy than EEG and SSEP. PMID- 24760271 TI - The polymorphism interleukin-8 -251A/T is associated with a significantly increased risk of cancers from a meta-analysis. AB - Emerging evidences show that interleukin-8 (IL-8) has important regulatory functions in tumorigenesis. IL-8 -251A/T is a single nucleotide polymorphism in the promoter region of the IL-8 gene and affects IL-8 production. Analysis of previous studies on the association of -251A/T polymorphism with different cancer types remained to be illustrated. To further assess the effect of -251A/T polymorphism on cancer risks, we performed this meta-analysis, up to November 2013, of 12,917 cases with different cancer types and 17,689 controls from 47 published case-control designed studies. Statistical analyses were performed using STATA 11.0 software. Crude odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of associations. ORs with 95 % CIs for IL 8 -251A/T polymorphism and cancer were estimated using fixed- and random-effects models when appropriate. Significantly increased risks were found in overall under the models of A allele vs. T allele, AA vs. TT, and AA vs. AT/TT. Significantly elevated risks were observed in breast cancer under the models of A allele vs. T allele, AT vs. TT, AA/AT vs. TT, and AA vs. AT/TT, and in nasopharyngeal carcinoma under the models of AT vs. TT, AA/AT vs. TT, and AA vs. AT/TT. We found that significantly elevated risks were observed in the Asian population and hospital-based studies in all comparison models. Thus, this meta analysis indicates that IL-8 -251A/T polymorphism is associated with a significantly increased risk of cancers and may provide evidence-based medical certificate to study the cancer susceptibility. PMID- 24760272 TI - Influence of peripheral whole-blood microRNA-7 and microRNA-221 high expression levels on the acquisition of castration-resistant prostate cancer: evidences from in vitro and in vivo studies. AB - Prostate cancer (PC) is the more frequently diagnosed neoplasia in men in developed countries. The evolution of PC to castration-resistant prostate cancer (CRPC) represents real problems of clinical management, in consequence to the limited therapeutic options. MicroRNAs (miRNAs) are small noncoding RNAs that play an important role in gene expression and function regulation. The increased evidence that miRNAs are involved in cancer development and progression has made them potential biomarkers for cancer diagnosis, prognosis, and aggressiveness. Our purpose was to identify a miRNA expression profile associated with the development of CRPC. We firstly observed a miRNA expression profile differentially expressed between the castration-resistant (CR) PC3 cell line and the hormone-sensitive LnCaP cell line, where miR-7, miR-221, and miR-222 were upregulated in PC3 (11.3-fold increase, P = 0.012; 11.3-fold increase, P = 0.002; 8.6-fold increase, P = 0.002, respectively). We also observed that the trend of miR-1233 expression levels was higher in PC3 (3.7-fold increase, P = 0.057). These miRNAs differentially expressed in vitro were studied in a peripheral whole blood samples from PC patients. We observed that patients presenting an early CR acquisition (<= 20 months) had higher expression levels of miR-7 and miR-221 (P = 0.034 and P = 0.036, respectively). Furthermore, we found that patients diagnosed with high-Gleason score tumors and presenting simultaneous higher miR-7 expression levels have a significant reduce time to CR compared with patients who present lower miR-7 expression levels (11 vs. 51 months, log-rank test P = 0.004). We also found that patients diagnosed with high-Gleason score tumors and higher expression levels of miR-221 have an early CRPC compared to patients with lower miR-221 expression levels (10 vs. 46 months, log-rank test P = 0.012). We observed a significantly lower overall survival in patients with higher peripheral whole-blood expression levels of miR-7 (28 vs. 116 months, log-rank test P = 0.001). Our results suggest that miR-7 and miR-221 peripheral whole blood expression levels can be potential predictive biomarkers of CRPC development. PMID- 24760273 TI - LRG1 is an independent prognostic factor for endometrial carcinoma. AB - Endometrial cancer (EC) is one of the most common female malignancies. The patients with high-risk factors may have poor prognosis. Therefore, there is an urgent need to find a new molecule to more accurately predict survival of patients. Leucine-rich-alpha-2-glycoprotein1 (LRG1), one of leucine-rich repeat family, was closely associated with cancer metastasis and poor prognosis. The biological functions and the expression level of LRG1 remain obscure in EC. In this study, by immunohistochemical analysis of 242 EC patient tissues, we found that LRG1 expression was associated with stage and lymphatic metastasis in both test cohort (133 patients) and validation cohort (109 patients). Furthermore, to investigate the prognostic value of LRG1 in endometrial carcinoma, we analyzed the correlation between variables and overall survival with Cox proportional hazard regression. The result showed that LRG1 was an independent prognostic factor for overall survival of endometrial carcinoma patients. To further evaluate the prognostic efficiency of LRG1 in endometrial carcinoma, we compared the sensitivity and specificity of LRG1 in endometrial carcinoma prognosis by logistic regression. The result showed that LRG1 combining with other clinicopathological risk factors was a stronger prognostic model than clinicopathological risk factors alone or their combination. Thus, LRG1 potentially offered clinical value in directing personal treatment for endometrial carcinoma patients. PMID- 24760274 TI - Stat3 inhibits Beclin 1 expression through recruitment of HDAC3 in nonsmall cell lung cancer cells. AB - Recent studies have shown that Beclin 1, a key regulator of autophagic process, is frequently downregulated and may serve as an independent prognostic biomarker for nonsmall cell lung cancer. However, the molecular mechanisms underlying its downregulation remain poorly understood. The signal transducer and activator of transcription 3 (Stat3) is a transcription factor which plays a crucial role for multiple tumor growth and progression. Here, we demonstrate that Beclin 1 is a direct transcriptional target of Stat3 in lung cancer cells. Interleukin-6 (IL-6) treatment or transfection of a constitutively activated Stat3 in AGS and NCI H1650 cells inhibited Beclin 1 expression. At the molecular level, we further revealed that Stat3 could directly bind to the promoter region of Beclin 1 and repressed its transcription through recruiting histone deacetylase 3 (HDAC3). Collectively, our results suggest that the activated Stat3 may represent an important mechanism for Beclin 1 downregulation in nonsmall cell lung cancer development. PMID- 24760276 TI - [Interdisciplinary soft tissue sarcoma surgery. New strategies in diagnostic and treatment]. PMID- 24760275 TI - Prostaglandin E2 accelerates invasion by upregulating Snail in hepatocellular carcinoma cells. AB - Our previous studies showed that prostaglandin E2 (PGE2) promotes hepatoma cell growth and migration, as well as invasion; however, the precise mechanism remains elusive. Snail and p65 protein levels were detected in human samples with hepatocellular carcinoma (HCC) by immunohistochemistry (IHC) staining. HCC cell lines (Huh-7 and Hep3B) were used for in vitro experiments. PGE2/Akt/NF-kappaB pathway was investigated in Huh-7 and Hep3B cells after treatment with PGE2, EP4 receptor (EP4R) agonist, Akt inhibitor, and NF-kappaB inhibitor, respectively, by real-time reverse transcription (RT)-PCR, Western blotting, and immunofluorescence (IF) staining. In vitro cell invasion assay was performed to evaluate the effect of PGE2 on tumor invasiveness. Knockdown of EP4R was carried out in Huh-7 cells through plasmid-based small interfering RNA (siRNA) approach to confirm the regulation of PGE2 on Snail by EP4R. Dual luciferase reporter assay was performed to assess Snail promoter activity in Huh-7 cell after treatment with EP4R agonist. We found that the protein levels of Snail were higher in HCC tissues than those in control and that PGE2 and EP4R agonist treatment significantly increased Snail expression in Huh-7 and Hep3B cells. EP4R agonist also profoundly promoted invasiveness of Huh-7 cells. Knockdown of the EP4R by siRNA completely blocked the PGE2-induced upregulation of Snail expression and reduced invasiveness of Huh-7 cells. We failed to find that EP4R induced upregulation of Snail was reversed by inhibition of cAMP response element binding protein (CREB), a canonical downstream target of EP4R. Alternatively, EP4R agonist treatment significantly increased the levels of phosphorylated EGFR and Akt both in Huh-7 and Hep3B cells. AG1478, an EGFR inhibitor, blocked the phosphorylation of Akt. The levels of phosphorylated IkappaB increased in Huh-7 cells after treatment with EP4R agonist for 30 min. The levels of phosphorylated p65 started to increase in Huh-7 cells treated with EP4R agonist for 4 h, and p65 translocated into the nucleus. In EP4R-agonist-treated Hep3B, the levels of phosphorylated p65 were also increased compared to the control group. The phosphorylation levels of p65 were significantly decreased in Huh-7 and Hep3B cells after treatment with the Akt signaling inhibitor LY294002 and EP4R agonist for 24 h. Treatment with the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) at 10 MUM for 24 h blocked EP4R-agonist-induced Snail upregulation in Huh 7 and Hep3B cells. Furthermore, we obtained human Snail promoter sequence from TRED-Promoter Database and identified a putative binding site of NF-kappaB in the sequence through TFSEARCH analysis. Subsequently, we treated Huh-7 cells with EP4R agonist or EP4R agonist and PDTC (NF-kappaB antagonist) and found significantly increased Snail promoter activity after EP4R agonist treatment for 12 h. The increased Snail promoter activity could be partially abolished by additional PDTC treatment. In addition, p65 protein levels were found increased together with Snail in HCC tissues compared to normal liver tissues. In conclusion, PGE2 activates Akt/NF-kappaB signaling and then upregulates Snail via the EP4R/EGFR to promote migration and invasion in hepatoma cells. These findings may help future evaluation of novel chemo-preventive strategies for HCC. PMID- 24760277 TI - Small homologous blocks in phytophthora genomes do not point to an ancient whole genome duplication. AB - Genomes of the plant-pathogenic genus Phytophthora are characterized by small duplicated blocks consisting of two consecutive genes (2HOM blocks) and by an elevated abundance of similarly aged gene duplicates. Both properties, in particular the presence of 2HOM blocks, have been attributed to a whole-genome duplication (WGD) at the last common ancestor of Phytophthora. However, large intraspecies synteny-compelling evidence for a WGD-has not been detected. Here, we revisited the WGD hypothesis by deducing the age of 2HOM blocks. Two independent timing methods reveal that the majority of 2HOM blocks arose after divergence of the Phytophthora lineages. In addition, a large proportion of the 2HOM block copies colocalize on the same scaffold. Therefore, the presence of 2HOM blocks does not support a WGD at the last common ancestor of Phytophthora. Thus, genome evolution of Phytophthora is likely driven by alternative mechanisms, such as bursts of transposon activity. PMID- 24760278 TI - Two cases of pisiform bone impingement syndrome after proximal row carpectomy. AB - Proximal row carpectomy (PRC) is an established surgical procedure used to treat post-traumatic osteoarthritis of the wrist with sparing of the midcarpal joint and advanced aseptic necrosis such as lunatomalacia. Proximalization of the distal carpal row following PRC may lead to secondary problems such as radiocarpal impingement. At follow-up, two of our patients complained about ulnar sided wrist pain after proximal row carpectomy. Computed tomography (CT) scans were taken for both patients with an additional magnetic resonance imaging scan for one patient. The CT scan revealed clear osteolysis consistent with a pisiform bone impingement on the ulnar styloid process in both the cases, and also on the hamate in one patient. An impingement syndrome of this nature has not previously been described and should be kept in mind when patients report ulnocarpal symptoms after PRC. PMID- 24760280 TI - Oxygen vacancy formation and the ion migration mechanism in layered perovskite (Sr,La)3Fe2O(7-delta). AB - Metal oxides are widely used in devices such as sensors, fuel cells, and oxygen permeation membranes. Understanding the oxide ion migration mechanism would provide fundamental insights into the relationships between the structure and properties such as ionic conductivity. The Ruddlesden-Popper perovskite (Sr,La)n+1(Fe,Co)nO3n+1 (n = 2) has characteristic oxygen permeation and ion conduction properties, resulting from the layered perovskite structure. To elucidate the ion migration mechanism in Sr2.46La0.54Fe2O7-delta (SLF) we used a combination of experimental techniques [X-ray powder diffraction (XRPD) and enthalpy investigations of the oxygen vacancy formation reaction] and computational techniques [the bond valence sum (BVS) approach and ab initio density functional theory (DFT)]. The structural analyses of SLF by XRPD and DFT agreed well. They showed that the oxygen vacancies in SLF are located at the O1 oxygen site, which is on the vertex shared by two FeO6 octahedra in the perovskite layer. Enthalpy of the oxygen vacancy formation changed at 830 degrees C. This is similar to the ionic conduction behavior reported for Sr3Fe2O7. The XRPD study indicates that the host structural framework did not change with temperature, while the oxygen/vacancy arrangement in SLF did change at 830 degrees C. The BVS and DFT studies suggested a change in the ion migration pathway, in which the ion migration through O1 sites becomes more important at temperatures higher than 830 degrees C. PMID- 24760279 TI - Brain activation of the defensive and appetitive survival systems in obsessive compulsive disorder. AB - Several studies have shown that basic emotions are responsible for a significant enhancement of early visual processes and increased activation in visual processing brain regions. It may be possible that the cognitive uncertainty and repeated behavioral checking evident in Obsessive Compulsive Disorder (OCD) is due to the existence of abnormalities in basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional-laden stimuli. The objective of the present study was to test if patients with OCD show evidence of altered basic survival circuits, particularly those associated with the visual processing of the physical characteristics of emotional stimuli. Fifteen patients with OCD and 12 healthy controls underwent functional magnetic resonance imaging acquisition while being exposed to emotional pictures, with different levels of arousal, intended to trigger the defensive and appetitive basic survival circuits. Overall, the present results seem to indicate dissociation in the activity of the defense and appetitive survival systems in OCD. Results suggest that the clinical group reacts to basic threat with a strong activation of the defensive system mobilizing widespread brain networks (i.e., frontal, temporal, occipital-parietal, and subcortical nucleus) and blocking the activation of the appetitive system when facing positive emotional triggers from the initial stages of visual processing (i.e., superior occipital gyrus). PMID- 24760281 TI - New diagnostic method for lesions with transepidermal melanocytic migration. PMID- 24760285 TI - Mid-infrared free-electron laser tuned to the amide I band for converting insoluble amyloid-like protein fibrils into the soluble monomeric form. AB - A mid-infrared free-electron laser (FEL) is operated as a pulsed and linearly polarized laser with tunable wavelengths within infrared region. Although the FEL can ablate soft tissues with minimum collateral damage in surgery, the potential of FEL for dissecting protein aggregates is not fully understood. Protein aggregates such as amyloid fibrils are in some cases involved in serious diseases. In our previous study, we showed that amyloid-like lysozyme fibrils could be disaggregated into the native form with FEL irradiation specifically tuned to the amide I band (1,620 cm(-1)). Here, we show further evidence for the FEL-mediated disaggregation of amyloid-like fibrils using insulin fibrils. Insulin fibrils were prepared in acidic solution and irradiated by the FEL, which was tuned to either 1,620 or 2,000 cm(-1) prior to the experiment. The Fourier transform infrared spectroscopy (FT-IR) spectrum after irradiation with the FEL at 1,620 cm(-1) indicated that the broad peak (1,630-1,660 cm(-1)) became almost a single peak (1,652 cm(-1)), and the beta-sheet content was reduced to 25 from 40% in the fibrils, while that following the irradiation at 2,000 cm(-1) remained at 38%. The Congo Red assay as well as transmission electron microscopy observation confirmed that the number of fibrils was reduced by FEL irradiation at the amide I band. Size-exclusion chromatography analysis indicated that the disaggregated form of fibrils was the monomeric form. These results confirm that FEL irradiation at the amide I band can dissect amyloid-like protein fibrils into the monomeric form in vitro. PMID- 24760286 TI - Evaluation of diagnostic utility of multidetector computed tomography and magnetic resonance imaging in blunt pancreatic trauma: a prospective study. AB - BACKGROUND: Blunt pancreatic trauma is an uncommon injury with high morbidity and mortality. Retrospective analyses of computed tomography (CT) performance report CT to have variable sensitivity in diagnosing pancreatic injury. Both a prospective analysis of multidetector CT (MDCT) performance and diagnostic utility of magnetic resonance imaging (MRI) in acute blunt pancreatic injury remain unexplored. PURPOSE: To prospectively evaluate the utility of MDCT with MRI correlation in patients with blunt pancreatic trauma using intraoperative findings as the gold standard for analysis. MATERIAL AND METHODS: The contrast enhanced CT (CECT) scans of patients admitted with blunt abdominal trauma were prospectively evaluated for CT signs of pancreatic injury. Patients detected to have pancreatic injury on CT were assigned a CT grade of injury according to American Association for Surgery of Trauma classification. MRI was performed in patients not undergoing immediate laparotomy and MRI grade independent of CT grade was assigned. Surgical grade was taken as gold standard and accuracy of CT and MRI for grading pancreatic injury and pancreatic ductal injury (PDI) was calculated. A quantitative and qualitative comparison of MRI was also done with CT to determine the performance of MRI in acute pancreatic injury. RESULTS: Thirty out of 1198 patients with blunt trauma abdomen were detected to have pancreatic injury on CT, which was surgically confirmed in 24 patients. Seventeen underwent MRI and surgical correlation was available in 14 patients. CT and MRI correctly identified the grade of pancreatic injury in 91.7% (22/24) and 92.86% (13/14) patients, respectively. Both CT and MRI correctly identified PDI in 18/19 and 11/12 patients, respectively, with good inter-modality agreement of 88.9% (kappa value of 0.78). MRI also qualitatively added to the information provided by CT and increased diagnostic confidence in 58.8% of patients. CONCLUSION: MDCT performs well in grading pancreatic injury and evaluating pancreatic ductal injury. MRI is useful in evaluation of acute pancreatic trauma as it can increase diagnostic confidence and provide more qualitative information regarding the extent of injury. PMID- 24760287 TI - Evaluation of photo-reactive siderophore producing bacteria before, during and after a bloom of the dinoflagellate Lingulodinium polyedrum. AB - Evidence is increasing for a mutualistic relationship between phytoplankton and heterotrophic marine bacteria. It has been proposed that bacteria producing photoactive iron binding compounds known as siderophores could play an important role in such mutualistic associations by producing bioavailable iron utilizable by phytoplankton and in exchange receive autotrophically derived DOM. In order to understand the potential role photoactive siderophores might be playing in bacterial-algal mutualism or marine biogeochemistry in general, it is important to be able to detect and quantify their presence in various environments. One approach to accomplish that end is to make use of high sensitivity genomics technology (qPCR) to search for siderophore biosynthesis genes related to the production of photoactive siderophores. In this way one can access their "biochemical potential" and utilize this information as a proxy for the presence of these siderophores in the marine environment. In this report we studied the correlation of the presence of bacteria producing one of the three photoactive siderophores relative to total bacterial and dinoflagellate numbers from surface water at the Scripps Pier before, during, and after fall bloom of the dinoflagellate Lingulodinium polyedrum. We believe that these findings will aid us in gauging the importance of photoactive siderophores in the marine environment and in harmful algal bloom dynamics in particular. PMID- 24760288 TI - Effectiveness of a theoretically-based judgment and decision making intervention for adolescents. AB - Although adolescents demonstrate capacity for rational decision making, their tendency to be impulsive, place emphasis on peers, and ignore potential consequences of their actions often translates into higher risk-taking including drug use, illegal activity, and physical harm. Problems with judgment and decision making contribute to risky behavior and are core issues for youth in treatment. Based on theoretical and empirical advances in cognitive science, the Treatment Readiness and Induction Program (TRIP) represents a curriculum-based decision making intervention that can be easily inserted into a variety of content-oriented modalities as well as administered as a separate therapeutic course. The current study examined the effectiveness of TRIP for promoting better judgment among 519 adolescents (37 % female; primarily Hispanic and Caucasian) in residential substance abuse treatment. Change over time in decision making and premeditation (i.e., thinking before acting) was compared among youth receiving standard operating practice (n = 281) versus those receiving standard practice plus TRIP (n = 238). Change in TRIP-specific content knowledge was examined among clients receiving TRIP. Premeditation improved among youth in both groups; TRIP clients showed greater improvement in decision making. TRIP clients also reported significant increases over time in self-awareness, positive-focused thinking (e.g., positive self-talk, goal setting), and recognition of the negative effects of drug use. While both genders showed significant improvement, males showed greater gains in metacognitive strategies (i.e., awareness of one's own cognitive process) and recognition of the negative effects of drug use. These results suggest that efforts to teach core thinking strategies and apply/practice them through independent intervention modules may benefit adolescents when used in conjunction with content-based programs designed to change problematic behaviors. PMID- 24760293 TI - Subcellular localization of the magnetosome protein MamC in the marine magnetotactic bacterium Magnetococcus marinus strain MC-1 using immunoelectron microscopy. AB - Magnetotactic bacteria are a diverse group of prokaryotes that biomineralize intracellular magnetosomes, composed of magnetic (Fe3O4) crystals each enveloped by a lipid bilayer membrane that contains proteins not found in other parts of the cell. Although partial roles of some of these magnetosome proteins have been determined, the roles of most have not been completely elucidated, particularly in how they regulate the biomineralization process. While studies on the localization of these proteins have been focused solely on Magnetospirillum species, the goal of the present study was to determine, for the first time, the localization of the most abundant putative magnetosome membrane protein, MamC, in Magnetococcus marinus strain MC-1. MamC was expressed in Escherichia coli and purified. Monoclonal antibodies were produced against MamC and immunogold labeling TEM was used to localize MamC in thin sections of cells of M. marinus. Results show that MamC is located only in the magnetosome membrane of Mc. marinus. Based on our findings and the abundance of this protein, it seems likely that it is important in magnetosome biomineralization and might be used in controlling the characteristics of synthetic nanomagnetite. PMID- 24760296 TI - 26th ASMS Sanibel Conference on mass spectrometry-ion activation: fundamentals, applications and new frontiers. PMID- 24760295 TI - Metabolic de-isotoping for improved LC-MS characterization of modified RNAs. AB - Mapping, sequencing, and quantifying individual noncoding ribonucleic acids (ncRNAs), including post-transcriptionally modified nucleosides, by mass spectrometry is a challenge that often requires rigorous sample preparation prior to analysis. Previously, we have described a simplified method for the comparative analysis of RNA digests (CARD) that is applicable to relatively complex mixtures of ncRNAs. In the CARD approach for transfer RNA (tRNA) analysis, two complete sets of digestion products from total tRNA are compared using the enzymatic incorporation of (16)O/(18)O isotopic labels. This approach allows one to rapidly screen total tRNAs from gene deletion mutants or comparatively sequence total tRNA from two related bacterial organisms. However, data analysis can be challenging because of convoluted mass spectra arising from the natural (13)C and (15) N isotopes present in the ribonuclease-digested tRNA samples. Here, we demonstrate that culturing in (12)C-enriched/(13)C-depleted media significantly reduces the isotope patterns that must be interpreted during the CARD experiment. Improvements in data quality yield a 35 % improvement in detection of tRNA digestion products that can be uniquely assigned to particular tRNAs. These mass spectral improvements lead to a significant reduction in data processing attributable to the ease of spectral identification of labeled digestion products and will enable improvements in the relative quantification of modified RNAs by the (16)O/(18)O differential labeling approach. PMID- 24760294 TI - Analysis of the lipidome of xenografts using MALDI-IMS and UHPLC-ESI-QTOF. AB - Human tumor xenografts in immunodeficient mice are a very popular model to study the development of cancer and to test new drug candidates. Among the parameters analyzed are the variations in the lipid composition, as they are good indicators of changes in the cellular metabolism. Here, we present a study on the distribution of lipids in xenografts of NCI-H1975 human lung cancer cells, using MALDI imaging mass spectrometry and UHPLC-ESI-QTOF. The identification of lipids directly from the tissue by MALDI was aided by the comparison with identification using ESI ionization in lipid extracts from the same xenografts. Lipids belonging to PCs, PIs, SMs, DAG, TAG, PS, PA, and PG classes were identified and their distribution over the xenograft was determined. Three areas were identified in the xenograft, corresponding to cells in different metabolic stages and to a layer of adipose tissue that covers the xenograft. PMID- 24760298 TI - Gene expression profiling in the hippocampus of orchidectomized rats. AB - Evidence from the literature suggests that testosterone (T) plays an important role in the neural structure, physiology, and function of the hippocampus (HP). However, many of the genes involved and underlying mechanisms remain to be elucidated. To shed light on this issue, we explored the transcriptome of HP in orchidectomized (OOX) rats to identify T-dependent gene expression in rat HP. RNA from OOX and sham HP animals were processed and measured by the Applied Biosystems microarray platform. The results showed a total of 271 genes differentially expressed between OOX vs. sham animals. Overall, T depletion resulted in the upregulation of 98 genes, including genes associated with neurogenesis and behavior. Of particular interest was the downregulation of 173 genes, with known functions, including signal transduction or neurological system processes. Our data shows that T depletion results in significantly altered hippocampal gene expression profiles and constitutes a starting tool to elucidating the molecular mechanisms involved in the action of androgens in the physiology of the HP. PMID- 24760299 TI - Studies on the reactions of [AuCl4](-) with different nucleophiles in aqueous solution. AB - In order to distinguish between the different types of reactions that can occur between Au(III) species and simple nucleophiles, including iodide, bromide, nitrite, thiourea, pyridine and dimethyl sulfoxide, spectrophotometric techniques including stopped-flow and rapid-scan measurements were employed under specific reaction conditions. All experiments were performed in a 0.4 M NaCl aqueous solution to maintain a high chloride concentration and a constant ionic strength. The temperature dependence of the observed rate constants confirmed the associative nature of the ligand substitution reactions. The redox behaviour of the Au(III) species was studied by cyclic voltammetry and confirmed the reversible redox transitions at ca. 0.38 V (SCE, E = 0.1 V s(-1)). Results obtained during the reaction progress were attributed to the formation of Au(0). This oxidation state was observed for the reactions with thiourea, iodide and nitrite, whereas pyridine showed a potential shift only to Au(i) formation, while bromide showed potential shifts typical of ligand substitution reactions. The reaction with dimethyl sulfoxide was studied using (1)H NMR and ab initio (RMP2(full)/LANL2DZp) techniques, which revealed why Au(III) does not react with sulfoxide. The results are discussed in terms of the importance of the stability of the Au(III) species in aqueous solutions of the selected salts and bases. In this way, one could differentiate between a possible three-electron inner-sphere redox process and/or a substitution process during the rapid initial step of the reactions. PMID- 24760308 TI - Development of a new endoscope holder for head and neck surgery--from the technical design concept to implementation. AB - Endoscope holders are utilized by a variety of surgeons but are not commonplace in head and neck surgery. The SOLOASSIST active camera holder, which is currently used for abdominal surgery, will soon be adapted for head and neck surgery in collaboration with AKTORmed GmbH SOLO SURGERY (Barbing, Germany). In our pre feasibility study, we analyzed the use of the existing endoscope holder on anatomical specimens during head and neck surgery. Based on these results, we are proceeding towards the development of a new endoscope holder for head and neck surgery. First, we drafted the technical concepts and discussed the advantages and disadvantages of the system. Then, we used anatomic specimens to measure the forces that occur intraoperatively during sinus surgery. Next, we designed a computer-aided design (CAD) model. Finally, we developed the first production prototype and used it for a frontal skull base procedure on an anatomical specimen. We present the three most promising concepts for a new holder. The resulting total force (F res = ?(X (2) + Y (2) + Z (2))) was calculated to be 3.2 N during sinus surgery. We could observe all necessary intraoperative landmarks with the endoscope and its holder in a sinus and frontal skull base surgery. We developed a production prototype of a new endoscope holder and demonstrate satisfactory results in the use of anatomic specimens for skull base surgery. PMID- 24760309 TI - Clinical outcomes and quality of life in patients with nasal polyposis after functional endoscopic sinus surgery. AB - The majority of studies have shown that the use of functional endoscopic sinus surgery (FESS) leads to symptomatic improvement in 73-98.4 % of patients with chronic rhinosinusitis and nasal polyposis (NP). The aim of the study is to evaluate clinical outcomes and quality of life (QoL) in patients with NP after FESS. The prospective study included 85 consecutive adult patients (>=18 years) with NP who were operated on using FESS after failure of the medicamentous treatment and in certain cases of surgical treatment. QoL was assessed by Short Form-36 Health Survey (SF-36) questionnaire, and the symptom intensity was presented using visual analogue scale (VAS). The objective finding was presented as endoscopic and computerized tomography (CT) score. The intensity of each symptom, the values of symptom scores (major, minor and total), the values of dimension scales and summary scales of the QoL, as well as the values of endoscopic score through three periods of time (pre-surgery, 6 and 12 months after the surgery) were analyzed. Following the FESS, mean intensity values of all individual symptoms and symptom scores were significantly lower and the values of all dimension scales and summary scales of QoL were significantly higher (p < 0.05). There was no statistically significant difference in symptom intensity and QoL after 6 and 12 months of surgical treatment (p > 0.05). Endoscopic score was on average significantly lower after 6 and 12 months of FESS (p < 0.05), but the mean score value after 12 months of operation was significantly higher in relation to that after 6 months of surgery (p < 0.05). Nevertheless, the recurrence of NP was observed in 28 patients (32.9 %) in the follow-up period. In conclusion, FESS in NP patients results in significant improvement of symptom intensity, QoL and endoscopic score. While the intensity of symptoms and QoL showed a tendency to maintain between 6 and 12 months after surgery, endoscopic score showed a tendency of exacerbation in the same period. PMID- 24760310 TI - A comparative study of three-year weight loss and outcomes after laparoscopic gastric bypass in patients with "yellow light" psychological clearance. AB - The relationship between psychological factors and bariatric surgical outcomes is unclear. While some psychological contraindications to bariatric surgery are described, there is no consensus on preoperative psychological evaluation or on factors that can predict bariatric outcomes. Our aim was to determine whether full or reserved psychological clearance predicts early weight loss or compliance with follow-up. We found no clinically significant differences in short-term weight loss outcomes or in attendance at scheduled follow-up visits between patients receiving full or "green light" clearance versus "yellow light" clearance, meaning clearance with recommendations for ongoing therapy. Further research may identify psychological predictors of success following bariatric surgery and help optimize preoperative evaluation practices. PMID- 24760311 TI - IrO2 as a promoter of Pt-Ru for methanol electro-oxidation. AB - A multifunctional catalyst may represent a valid route to enhance methanol electro-oxidation. Ternary catalysts based on Pt modified with both Ru and Ir oxides show better performance for methanol electro-oxidation than bi-metallic Pt Ru catalysts. PMID- 24760312 TI - Alemtuzumab therapy for leukemic cutaneous T-cell lymphoma: diffuse erythema as a positive predictor of complete remission. PMID- 24760320 TI - A BODIPY-based reactive probe for the detection of Au(III) species and its application to cell imaging. AB - A BODIPY-based fluorescent probe bearing a pyridyl hydrazone motif responds selectively to Au(III) ions through an irreversible C=N bond hydrolysis reaction. PMID- 24760321 TI - Maternal stress predicts postpartum weight retention. AB - Postpartum weight retention (PPWR) is a significant contributor to the development of overweight and obesity in women of childbearing age. Stress may be a key mechanism making it more difficult for mothers to lose weight in the year following delivery. The aim of this study was to assess whether specific aspects of parenting stress and life stress influence postpartum weight retention in new mothers. Women in late pregnancy or up to 2 months postpartum (n = 123) were enrolled in the study and followed through the first year postpartum. Linear regression models evaluated the associations of parenting stress (isolation, attachment and depressive symptoms) as well as overall life stress at 2, 6, and 12 months postpartum with PPWR at 6 and 12 months. During the first year postpartum, higher depression and life stress were significantly associated with greater PPWR. As the effect of depression diminished, the effect of life stress became significant. Contrary to hypothesized relationships, fewer problems with attachment and less social isolation were significantly associated with greater PPWR. Higher gestational weight gain and African American race were also significantly associated with greater PPWR at both 6 and 12 months. Different types of stress predict weight retention in first time mothers during the first year postpartum. Understanding the relationships between parenting stress, concurrent life stress and PPWR can enhance the development of future interventions that specifically target self-identified stressors, leading to improved weight related outcomes. PMID- 24760322 TI - Leukemias involving abdominal and pelvic lymph nodes: evaluation with contrast enhanced MDCT. AB - PURPOSE: To clarify features of lymph nodes associated with leukemia purposing to offer help for imaging diagnosis and differential diagnosis of leukemia. MATERIALS AND METHODS: We retrospectively analyzed 47 patients with clinically proven leukemia involving the abdominal and pelvic lymph nodes. Of these 47 patients, 10 had acute myeloid leukemia, 9 had acute lymphocytic leukemia, and 28 had chronic lymphocytic leukemia. MDCT was used to determine lymph node features such as morphology, growth patterns, size, enhancement patterns, anatomical distribution, and manifestations in extramedullary organs. RESULTS: Incidence of leukemia was higher in men than in women. Enlarged lymph nodes were more frequently conglomerated in chronic lymphocytic leukemia (96.4%) than in acute myeloid leukemia (50%) and acute lymphocytic leukemia (55.6%; P < 0.05 for both). Lymph nodes associated with chronic lymphocytic leukemia were larger than those associated with acute myeloid and lymphocytic leukemias (P < 0.05 for both). The enlarged lymph nodes appeared homogeneous (80.9%) and homogeneous mixed with peripheral (19.1%). No statistically significant differences were observed between the three types of leukemias with respect to enhancement patterns (all P > 0.05). The lymph nodes commonly associated with these three leukemias were located in the lesser omentum, upper and lower para-aortic regions, and groin region. CONCLUSIONS: Our study showed that contrast-enhanced MDCT could accurately determine the enhancement patterns and anatomical distribution of lymph nodes associated with leukemia. Therefore, it is helpful for imaging diagnosis and differential diagnosis of leukemia. PMID- 24760323 TI - Clinical characteristics and imaging features of small bowel adenocarcinomas in Crohn's disease. AB - PURPOSE: Small bowel adenocarcinoma is uncommon in patients with Crohn's disease but has an extremely poor prognosis. There is a paucity of data on the clinical characteristics and radiologic features of this entity. We sought to update our institutional experience with small bowel adenocarcinoma occurring in the setting of Crohn's disease and to systematically re-examine pre-operative imaging findings. METHODS: Medical records were abstracted to identify all patients with Crohn's disease and small bowel adenocarcinoma who were evaluated at Mayo Clinic, Rochester, Minnesota and Mayo Clinic, Scottsdale, Arizona between 1976 and 2012. Clinical, demographic, and outcomes data were obtained for each patient. Pre diagnosis radiologic imaging was re-evaluated by two gastrointestinal radiologists. RESULTS: Thirty-four patients (21 males) were identified. Median ages at Crohn's disease and cancer diagnoses were 22.4 and 52.9 years, respectively. Median follow-up after cancer diagnosis was 272.0 days; 22 patients (64.7%) had persistent or recurrent adenocarcinoma at last follow-up. 1- and 2 year mortality rates were 29.6% and 48.0%. Pre-operative imaging studies were available for re-review in 14 cases. Features concerning for malignancy included annular mass, nodularity at the extraluminal margins of the mass, and perforation. Nearly all tumors arose in regions of chronic inflammation and caused luminal narrowing with pre-stenotic dilatation. CONCLUSIONS: Small bowel adenocarcinoma is rare in patients with Crohn's disease but results in significant mortality. CT or MR imaging findings can be suggestive of the pre operative diagnosis, but it is usually diagnosed at an advanced stage with laparotomy. PMID- 24760324 TI - Preliminary experience of a new perspective view technology for the detection of portal vein thrombus in hepatocellular carcinoma patients. AB - OBJECTIVE: To assess the feasibility and efficiency of a perspective view technology (Fly Thru) for the detection of portal vein tumor thrombus (PVTT) in hepatocellular carcinoma (HCC) patients. METHODS: Fly Thru was performed in 79 HCC patients. The images were reviewed off-site for evaluation of the imaging quality and diagnosis. Pathology and/or contrast-enhanced CT was used as the reference standard for PVTT. The diagnostic quality of the images, presences of PVTT, and patency of the target vessels were recorded by two-dimensional ultrasound (2DUS) and Fly Thru image. The diagnostic performances of resident and staff radiologists were compared between 2DUS with or without off-line Fly Thru. RESULTS: Fly Thru was performed successfully in 43 of 79 patients (54.4%). The Fly Thru Imaging quality was good in 30/43 patients (69.8%), suboptimal but diagnostic in 10/43 (23.2%), and non-diagnostic in the remaining 3/43 (7.0%). PVTTs were detected in 31 patients according to the reference standard, with 8 in the main portal vein, 15 in the first branch, and 8 in the second branch of the portal vein. The agreement was good between conventional 2DUS and Fly Thru (kappa = 0.783, p = 0.000). There was a significant association between the quality and the ability of Fly Thru in the detection of PVTTs (p = 0.001). The diagnostic performance for both readers between 2DUS with or without Fly Thru showed no statistically significant differences, except for the sensitivity for resident radiologist. The sensitivity of 2DUS (71.0%, 22/31) for resident radiologists was lower than that of Fly Thru as an adjunctive diagnostic tool (90.3%, 28/31) (p = 0.041). CONCLUSION: Fly Thru is of diagnostic quality and can provide useful information for the detection of PVTT in HCC patients. PMID- 24760327 TI - Molecular modeling of membrane tube pearling and the effect of nanoparticle adsorption. AB - The shape transformation of membrane tubes, also known as pearling, is thought to play an important role in a variety of cellular activities, like intracellular transport. Despite considerable experiments have investigating this phenomenon, the detailed molecular mechanism as well as how environmental factors affect the tube pearling instability is still ambiguous. In this work, we use computer simulation techniques to obtain a molecular-level insight into the tube pearling process. We find that the tube morphology is strongly determined by the water pressure inside membrane tubes. For example, the tube shrinkage and subsequent bending is observed when we decrease the inner water pressure. Contrarily, as we increase the inner water pressure, the tube pearling tends to occur in order to reduce the surface energy. Besides, our simulations show that the membrane tube pearling is regulated by the adsorption of nanoparticles (NPs) in two competing ways. One is that the NP adsorption can exert an additional membrane tension and thus promote the pearling and subsequent division of membrane tubes. On the other hand, the NP adsorption can locally rigidify the membrane and thus contrarily restrain the tube pearling. Therefore, the NP size, NP concentration and NP membrane adhesion strength will collectively regulate the tube pearling process. PMID- 24760326 TI - The role of Rho-kinases in IL-1beta release through phagocytosis of fibrous particles in human monocytes. AB - Long fibers, such as asbestos and carbon nanotubes (CNTs), are more potent activators of inflammatory and genotoxicity than short or tangled fibers. Fibrous particles trigger interleukin (IL)-1beta secretion and cause inflammatory diseases through NLRP3 inflammasomes in phagocytotic cells. However, the mechanism involved in fibrous particle-induced inflammation has not been well documented. In this study, we focused on GTPase effector Rho-kinases (ROCK1, and 2), which are known to be involved in a wide range of cellular functions such as adhesion, regulation of cytoskeleton, and phagocytosis. We examined whether ROCKs are associated with multi-walled CNT (MWCNT)- or asbestos-induced IL-1beta secretion in human monocytic THP-1 cells using a selective inhibitor and small interfering RNA. THP-1 cells were differentiated to macrophages by PMA and were exposed to MWCNTs, crocidolite asbestos or lipopolysaccharide (LPS) in the presence or absence of Y27632 (ROCK inhibitor) or Z-YVAD (caspase-1 inhibitor). Exposure of the cells to MWCNTs or asbestos provoked IL-1beta secretion, but this secretion was suppressed by both Y27632 and Z-YVAD, whereas LPS-induced IL-1beta secretion was inhibited only by Z-YVAD and not by Y27632. siRNA designed for knockdown of both ROCK1 and ROCK2 suppressed MWCNT- and asbestos-induced IL-1beta secretion, but did not change LPS-induced IL-1beta secretion. Moreover, Y27632 suppressed pro-IL-1beta protein levels and the release of activated-cathepsin B and activated-caspase-1 induced by MWCNTs or asbestos. In contrast, LPS-induced pro-IL-1beta protein was not suppressed by Y27632. These results suggest that ROCKs are involved in fibrous particle-induced inflammasome responses in THP-1 cells. PMID- 24760325 TI - Inactivation of two newly identified tobacco heavy metal ATPases leads to reduced Zn and Cd accumulation in shoots and reduced pollen germination. AB - Cadmium (Cd) is a non-essential heavy metal, which is classified as a "known human carcinogen" by the International Agency for Research on Cancer (IARC). Understanding the mechanisms controlling Cd distribution in planta is essential to develop phytoremediation approaches as well as for food safety. Unlike most other plants, tobacco (Nicotiana tabacum) plants translocate most of the Cd taken up from the soil, out of the roots and into the shoots, leading to high Cd accumulation in tobacco shoots. Two orthologs of the Arabidopsis thaliana HMA2 and HMA4 Zn and Cd ATPases that are responsible for zinc (Zn) and Cd translocation from roots to shoots were identified in tobacco and sequenced. These genes, named NtHMAalpha and NtHMAbeta, were more highly expressed in roots than in shoots. NtHMAalpha was expressed in the vascular tissues of both roots and leaves as well as in anthers. No visual difference was observed between wild type plants and plants in which the NtHMAalpha and NtHMAbeta genes were either mutated or silenced. These mutants showed reduced Zn and Cd accumulation in shoots as well as increased Cd tolerance. When both NtHMA genes were silenced, plant development was altered and pollen germination was severely impaired due to Zn deficiency. Interestingly, seeds from these lines also showed decreased Zn concentration but increased iron (Fe) concentration. PMID- 24760328 TI - Evaluating the Psychopathological Profile of Women Undergoing Reduction Mammaplasty With the Symptom Checklist-90-Revised. AB - BACKGROUND: Patients who desire reduction mammaplasty (RM) also may seek relief from social and emotional challenges that accompany their physical condition, including low self-confidence and impaired body image. Reduction mammaplasty is known to improve patients' physical and psychological well-being. It may be speculated that patients who undergo RM are motivated by psychological problems and have psychopathologies. Health care insurers reluctant to cover the expense of this surgery may cite mental health as a reason to deny coverage. OBJECTIVES: The authors assessed the psychopathological profile of patients who presented for RM, utilizing a validated instrument, and compared scores with standard norm values. METHODS: Preoperatively, 67 women were assessed with the Symptom Checklist-90-Revised (SCL-90-R), a validated instrument for evaluating a broad range of psychopathological problems and symptoms. The SCL-90-R provides a general psychoneurosis score, as well as scores for 8 symptom subscales. RESULTS: The mean patient age was 36 +/- 11.2 years. The mean (SD) total score on the SCL 90-R was 130 (38.7), which was not significantly higher than the norm score of 123. Only the subscores for somatization and sleep disturbance were significantly higher than the norm scores for these subscales. Compared with the norm score for women who presented with chronic pain, the total score for our study population was significantly lower. CONCLUSIONS: Patients who undergo RM have normal scores for psychoneurosis according to the SCL-90-R. Health care insurance coverage for RM should not be denied on the basis that the motivation for surgery relates to psychopathology. Additionally, psychological testing is not recommended for most patients who desire breast reduction surgery; rather, clinical judgment based on common sense should be applied. LEVEL OF EVIDENCE: 3. PMID- 24760329 TI - Recurrent abscesses of the neck: scrofuloderma. PMID- 24760336 TI - Factors that minimize postgastrectomy symptoms following pylorus-preserving gastrectomy: assessment using a newly developed scale (PGSAS-45). AB - BACKGROUND: Pylorus-preserving gastrectomy (PPG) is sometimes performed as a function-preserving surgery for the treatment of early gastric cancer. The aim of this study was to use an integrated assessment scale for postgastrectomy syndrome to determine the appropriate indicators and optimal methods for PPG. METHODS: The Postgastrectomy Syndrome Assessment Study (PGSAS) is a multicenter survey based on an integrated questionnaire (PGSAS-45) consisting of 45 items. Questionnaire responses were retrieved from a total of 2,520 patients, each of whom had undergone one of six different types of gastrectomy procedures; 313 responses from patients who had received PPG were analyzed here. RESULTS: The size of the proximal gastric remnant (less than one-quarter, about one-third, or more than one-half of the original size) significantly influenced the change in body weight, the scores for dissatisfaction at the meal, and dissatisfaction for daily life subscale (P = 0.030, P = 0.005, P = 0.034, respectively). The nausea score in patients who underwent hand-sewn anastomosis was significantly lower than in those who underwent anastomosis with a linear stapler (P = 0.006). The scores for diarrhea subscale, increased passage of stools, and sense of foods sticking differed significantly depending on the length of the preserved pyloric cuff (P = 0.047, P = 0.021, P = 0.046, respectively). CONCLUSIONS: The results suggest that preservation of a sufficient proximal gastric remnant is recommended when utilizing PPG as function-preserving surgery. PMID- 24760337 TI - Erratum to: Is a clear benefit in survival enough to modify patient access to the surgery service? A retrospective analysis in a cohort of gastric cancer patients. PMID- 24760338 TI - The tibialis anterior response revisited. AB - The idiomuscular response to direct percussion is rarely tested nowadays because of its uncertain mechanism and significance. While performing neurological examination, we observed a brisk ankle dorsiflexion response on direct muscle percussion of m. tibialis anterior in patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP). In contrast, in patients with upper motor neuron lesions, an ankle inversion response was seen. In this article we describe our findings in patients with bilateral lower limb weakness. We assessed 73 consecutive patients with bilateral lower limb weakness. A strong dorsiflexion response to percussion of m. tibialis anterior was seen in 11 out of 14 patients with AIDP (sensitivity 78.6%). None of the other patients showed a strong dorsiflexion response (specificity 100%). An inversion response was seen in 11 out of 13 patients with UMN involvement (sensitivity 92.3%). It was also noted in two of 46 patients without proven UMN involvement (specificity 96.7%). The idiomuscular response to percussion of m. tibialis anterior can be useful in the assessment of patients with lower limb weakness of unclear cause. PMID- 24760339 TI - TDP-43 in Alzheimer's disease is not associated with clinical FTLD or Parkinsonism. AB - Widespread deposition of TAR DNA-binding protein of 43 kDa (TDP-43), a major protein inclusion commonly found in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) can also be seen in a subset of cases with Alzheimer's disease (AD). Some of these AD cases have TDP-43 immunoreactivity in basal ganglia (BG) and substantia nigra (SN), regions that when affected can be associated with parkinsonian signs or symptoms, or even features suggestive of frontotemporal dementia. Here, we examined the presence of clinical features of FTLD, parkinsonian signs and symptoms, and BG atrophy on MRI, in 51 pathologically confirmed AD cases (Braak neurofibrillary tangle stage IV-VI) with widespread TDP-43 deposition, with and without BG and SN involvement. All 51 cases had presented with progressive cognitive impairment with prominent memory deficits. None of the patients demonstrated early behavioral disinhibition, apathy, loss of empathy, stereotyped behavior, hyperorality, and/or executive deficits. Furthermore, TDP-43 deposition in BG or SN had no significant association with tremor (p = 0.80), rigidity (p = 0.19), bradykinesia (p = 0.19), and gait/postural instability (p = 0.39). Volumes of the BG structures were not associated with TDP-43 deposition in the BG. The present study demonstrates that TDP-43 deposition in pathologically confirmed AD cases is not associated with a clinical manifestation suggestive of FTLD, or parkinsonian features. PMID- 24760340 TI - The quest for choice and the need for relational care in mental health work. AB - Since the revolutionary mood of the 1960s, patient-centered mental health care and a research emphasis on service users as experts by experience have emerged hand in hand with a view of service users as consumers. What happens to knowledge derived from firsthand experience when mental health users become experts and actively choose care? What kind of perspective do service users pursue on psychological distress? These are important questions in a field where psychiatric expertise on mental illness is socially structured and constrained as an intra-personal disturbance of the mind. We argue that experience experts have lost a coherent perspective on care and health. We illustrate this by rationally reconstructing how the interpersonal view of mental health first gained and then lost coherence between the conception of mental health, the practice of mental health care, and the user experience. Harry Stack Sullivan's interpersonal theory was a paradigm case for such coherence. The inclusion of mental health consumers as 'experts by experience' in the mental health field took place at the cost of Sullivan's coherent interpersonal theory. Service users who interact side by side with medical experts as experience experts are constrained by the evidence-based imperative and consumerism. Service users are caught up in a race among experts to gain knowledge about mental problems from a third-person perspective instead of from first-person experience. To make a contribution service users have more to gain from a research approach that appreciates that they are persons among persons rather than experts among experts. PMID- 24760342 TI - Theoretical study of thermoelectric properties of few-layer MoS2 and WSe2. AB - Molybdenum disulfide (MoS2) and tungsten diselenide (WSe2) are prototypical layered two-dimensional transition metal dichalcogenide materials, with each layer consisting of three atomic planes. We refer to each layer as a trilayer (TL). We study the thermoelectric properties of 1-4TL MoS2 and WSe2 using a ballistic transport approach based on the electronic band structures and phonon dispersions obtained from first-principles calculations. Our results show that the thickness dependence of the thermoelectric properties is different under n type and p-type doping conditions. Defining ZT1st peak as the first peak in the thermoelectric figure of merit ZT as doping levels increase from zero at 300 K, we found that ZT1st peak decreases as the number of layers increases for MoS2, with the exception of 2TL in n-type doping, which has a slightly higher value than 1TL. However, for WSe2, 2TL has the largest ZT1st peak in both n-type and p type doping, with a ZT1st peak value larger than 1 for n-type WSe2. At high temperatures (T > 300 K), ZT1st peak dramatically increases when the temperature increases, especially for n-type doping. The ZT1st peak of n-type 1TL-MoS2 and 2TL-WSe2 can reach 1.6 and 2.1, respectively. PMID- 24760344 TI - Revisiting the coordination chemistry for preparing manganese oxide nanocrystals in the presence of oleylamine and oleic acid. AB - By pyrolyzing manganese(II) acetate in 1-octadecene in the presence of oleylamine and oleic acid, manganese oxide nanocrystals were prepared. It was observed that both MnO and Mn3O4 nanocrystals were simultaneously formed by quickly heating the reaction mixture up to 250 degrees C, while a preheating procedure carried out at 100 degrees C led to uniform MnO nanocubes that developed into eight-arm MnO nanocrystals upon prolonged reaction. To understand the mechanisms for forming these two different kinds of manganese oxide nanocrystals, i.e., Mn3O4 and MnO, the coordination between oleic acid/oleylamine and Mn(2+) was investigated. The detailed investigations suggest that Mn(2+)-oleylamine coordination is kinetically driven and favorable for the formation of Mn3O4 nanocrystals due to the relatively low electronegativity of N from oleylamine, while Mn(2+)-oleate coordination is thermodynamically driven and can prevent the central metal ion (Mn(2+)) from being oxidized owing to the relatively high electronegativity of O from the oleate ligand. Following these new insights, by properly balancing the coordination of oleic acid and oleylamine to Mn(2+), the selective synthesis of MnO and Mn3O4 nanocrystals with uniform shapes was successfully achieved. PMID- 24760341 TI - Healthcare professionals' dilemmas: judging patient's decision making competence in day-to-day care of patients suffering from Korsakoff's syndrome. AB - Patient's decision making competence (PDMC) is a widely discussed subject. Issues of competence, autonomy, well-being and protection of the patient come up every day. In this article we analyse what role PDMC plays in Dutch legislation and what dilemmas healthcare professionals may experience, notably in patients suffering from Korsakoff's syndrome. Dilemmas emerge if professionals want to meet the requirements mentioned in Dutch law and the desires of their patients. The autonomy of the patient and the healthcare professionals' duty to take care of their patient's best interests, create a tension and lead to uncomfortable situations. Healthcare professionals describe difficulty finding a balance between these issues and assessing the degree of mental competence still present. In long term care situations, quality of the relationship between healthcare professionals and their patients seems to be of much more importance in decision making on minor issues of competence than simply relying on legal or house rules. In being committed to their cases, professionals will be more sensitive to individuals habits, abilities, welfare and dignity, which will make it easier to decide on issues of competence, and to find creative solutions to their dilemmas. PMID- 24760343 TI - Intra-operative perforation: a risk factor for prognosis of low rectal cancer after abdominoperineal resection. AB - This study was designed to explore the influence of intra-operative perforation on prognosis of low rectal cancer after APR and to investigate the risk factors of perforation. Perforation is not scarce during the procedure of abdominoperineal resection (APR). There is no consensus on perforation rate and related risk factor for APR. Data of 925 patients who received APR for low rectal cancer between January 2000 and August 2008 were reviewed. The intra-operative perforation rate was 7.4 % (68/925). The recurrence rate was 28.6 % in patients with intra-operative perforation compared with 6.8 % in patients with no perforation (P < 0.001); 5-year survival rate in patients with perforation was 41.4 and 66.3 % in patients with no perforation. Univariate analysis showed that intra-operative perforation affected recurrence rate and survival significantly (P < 0.001, P < 0.001); multivariate analysis revealed that intra-operative perforation was an independent prognostic factors for recurrence (RR: 3.087, P < 0.001), while not for survival (RR: 1.331, P = 0.051). Patients aged more than 70 years, T3 tumor and treated by general surgeon had higher perforation rate (P = 0.001, P = 0.004, P = 0.008). Intra-operative perforation affected the prognosis of low rectal cancer after APR significantly. Elderly patient aged more than 70 years, T3 tumor and general surgeon who performed operation were three risk factors of increased perforation rate. PMID- 24760345 TI - Copper-catalyzed olefinic C-H difluoroacetylation of enamides. AB - Copper-catalyzed olefinic difluoroacetylation of enamides via direct C-H bond functionalization using BrCF2CO2Et is reported for the first time. It constitutes an efficient radical-free method for the regioselective synthesis of beta difluoroester substituted enamides which exhibits broad substrate scope, and thus demonstrates its potent application in a late stage fluorination strategy. PMID- 24760347 TI - Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. AB - The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages. PMID- 24760348 TI - Outcome and reinfection after Staphylococcus aureus bacteraemia in individuals with and without HIV-1 infection: a case-control study. AB - OBJECTIVES: Individuals infected with HIV-1 are at an increased risk of Staphylococcus aureus bacteraemia (SAB). The aim of this study was to investigate mortality rate and risk of reinfection associated with SAB in HIV-1-infected individuals compared to individuals without HIV-1 infection. SETTING: University hospital treating a third of the estimated 5000 individuals with HIV infection in Denmark. PARTICIPANTS: HIV-1-infected (n=82) and sex-matched and age-matched uninfected (n=163) individuals with SAB in the time period 1 January 1995 to 31 December 2010. PRIMARY OUTCOME MEASURES: 30-day and 365-day mortality rate ratio and relative risk of reinfection. RESULTS: Individuals with HIV had an increased risk of death at day 30 (OR 11.90 (95% CI 2.15 to 65.85)) compared to individuals without HIV. Other factors associated with mortality were age, a foreign device and Pitt score. HIV-related factors did not associate to mortality. During follow up, there were 43 episodes of reinfection; in individuals with HIV infection at an incidence rate of 7.8 (95% CI 4.7 to 10.9)/100 person-years compared with 2.2 (95% CI 1.2 to 3.2)/100 person-years for individuals without HIV. In multivariate analysis, HIV status (OR 2.91 (95% CI 1.29 to 6.58) and injection drug use (OR 3.51 (95% CI 1.06 to 11.63) were independently associated with an increased risk of reinfection. CONCLUSIONS: HIV-1 infection is associated with an increased risk of 30-day mortality after SAB and a very high rate of reinfection. Age, a foreign device and Pitt score predicted outcome. For patients infected with HIV, neither CD4 T-lymphocyte counts nor plasma HIV RNA levels were associated with 30-day outcome. TRIAL REGISTRATION NUMBER: The study was approved by the Danish Data Protection Agency (record no. 2007-41-1196). PMID- 24760349 TI - Bee venom acupuncture for rheumatoid arthritis: a systematic review protocol. AB - INTRODUCTION: This systematic review aims to analyse the trial data on the effects of bee venom acupuncture (BVA) for rheumatoid arthritis (RA). METHODS AND ANALYSIS: The following 14 databases will be searched from their inception to March 2014: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), AMED, CINAHL, six Korean medical databases (OASIS, Korean Traditional Knowledge Portal, Korean Studies Information Service System, KoreaMed, Korean Medical Database and DBPIA) and three Chinese databases including CNKI (China National Knowledge Infrastructure), Wanfang and VIP. The methodological quality will be assessed using the Cochrane risk of bias tool. DISSEMINATION: The systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print. TRIAL REGISTRATION NUMBER: PROSPERO 2013: CRD42013005853. PMID- 24760350 TI - Aversive tension of adolescents with anorexia nervosa in daily course: a case controlled and smartphone-based ambulatory monitoring trial. AB - INTRODUCTION: Monitoring and reduction of aversive tension is a core issue in dialectical behaviour therapy of patients. It has been shown that aversive tension is increased in adult borderline personality disorder and is linked to low emotion labelling ability. However, until now there is no documented evidence that patients with anorexia nervosa suffer from aversive tension as well. Furthermore the usability of a smartphone application for ambulatory monitoring purposes has not been sufficiently explored. METHODS AND ANALYSIS: We compare the mean and maximum self-reported aversive tension in 20 female adolescents (12-19 years) with anorexia nervosa in outpatient treatment with 20 healthy controls. They are required to answer hourly, over a 2-day period, that is, about 30 times, four short questions on their smartphone, which ensures prompt documentation without any recall bias. At the close out, the participants give a structured usability feedback on the application and the procedure. ETHICS AND DISSEMINATION: The achieved result of this trial has direct relevance for efficient therapy strategies and is a prerequisite for trials regarding dialectical behaviour therapy in anorexia nervosa. The results will be disseminated through peer-review publications. The ethics committee of the regional medical association in Mainz, Germany approved the study protocol under the reference number 837.177.13. TRIAL REGISTRATION NUMBER: The trial is registered at the German clinical trials registration under the reference number DRKS00005228. PMID- 24760351 TI - Factors associated with anxiety and depression among type 2 diabetes outpatients in Malaysia: a descriptive cross-sectional single-centre study. AB - OBJECTIVE: To determine the prevalence and factors associated with anxiety and depression among type 2 diabetes outpatients in Malaysia. DESIGN: Descriptive, cross-sectional single-centre study with universal sampling of all patients with type 2 diabetes. SETTING: Endocrinology clinic of medical outpatient department in a Malaysian public hospital. PARTICIPANTS: All 169 patients with type 2 diabetes (men, n=99; women, n=70) aged between 18 and 90 years who acquired follow-up treatment from the endocrinology clinic in the month of September 2013. MAIN OUTCOME MEASURES: The validated Hospital Anxiety and Depression Scale (HADS), sociodemographic characteristics and clinical health information from patient records. RESULTS: Of the total 169 patients surveyed, anxiety and depression were found in 53 (31.4%) and 68 (40.3%), respectively. In multivariate analysis, age, ethnicity and ischaemic heart disease were significantly associated with anxiety, while age, ethnicity and monthly household income were significantly associated with depression. CONCLUSIONS: Sociodemographics and clinical health factors were important correlates of anxiety and depression among patients with diabetes. Integrated psychological and medical care to boost self determination and confidence in the management of diabetes would catalyse optimal health outcomes among patients with diabetes. PMID- 24760352 TI - Correlation of measured and calculated serum osmolality during mannitol or hypertonic saline infusion in patients after craniotomy: a study protocol and statistical analysis plan for a randomised controlled trial. AB - INTRODUCTION: Brain oedema is a major complication after craniotomy. Hyperosmolar agents have been used as the medical treatment for this condition. Measurement and estimation of serum osmolality during hyperosmolar agent infusion is of clinical importance to evaluate clinical efficacy, adjust dosage and avoid side effects. However, several studies have shown that calculated serum osmolality may lead to a systematic bias compared with direct measurement. In the present study, mannitol or hypertonic saline (HS) will be used in patients after elective craniotomy. We aim to determine the accuracy of serum osmolality estimation during the application of hyperosmolar agent. METHODS AND ANALYSIS: The study is a prospective, randomised, double-blinded, controlled, parallel-group design. Adult patients requiring the use of hyperosmolar agents for the prevention or treatment of postoperative brain oedema are enrolled and assigned randomly to one of the two treatment study groups, labelled as 'M group' and 'HS group'. Patients in the M and HS groups receive intravenous infusion of 125 mL of either 20% mannitol or 3.1% sodium chloride solution, respectively. Data will be collected immediately before the infusion of study agents, 15, 30, 60, 120, 240 and 360 min after the start of infusion of experimental agents, which includes serum osmolality, concentration of serum sodium, potassium, urea and glucose. Serum osmolality will be measured by means of freezing point depression. Estimated serum osmolality will also be calculated by using four formulas published previously. Osmole gap is calculated as the difference between the measured and the estimated values. The primary endpoint is the correlation of measured and estimated serum osmolality during hyperosmolar agent infusion. ETHICS AND DISSEMINATION: The study was approved by the International Review Board (IRB) of Beijing Tiantan Hospital, Capital Medical University. Study findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02037815. PMID- 24760354 TI - Validity of the International Classification of Diseases, 10th revision discharge diagnosis codes for hyponatraemia in the Danish National Registry of Patients. AB - OBJECTIVE: To examine the validity of the International Classification of Diseases, 10th revision (ICD-10) codes for hyponatraemia in the nationwide population-based Danish National Registry of Patients (DNRP) among inpatients of all ages. DESIGN: Population-based validation study. SETTING: All somatic hospitals in the North and Central Denmark Regions from 2006 through 2011. PARTICIPANTS: Patients of all ages admitted to hospital (n=819 701 individual patients) during the study period. The patient could be included in the study more than once, and our study did not restrict to patients with serum sodium measurements (total of n=2 186 642 hospitalisations). MAIN OUTCOME MEASURE: We validated ICD-10 discharge diagnoses of hyponatraemia recorded in the DNRP, using serum sodium measurements obtained from the laboratory information systems (LABKA) research database as the gold standard. One sodium value <135 mmol/L measured at any time during hospitalisation confirmed the diagnosis. We estimated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for ICD-10 codes for hyponatraemia overall and for cut-off points for increasing hyponatraemia severity. RESULT: An ICD-10 code for hyponatraemia was recorded in the DNRP in 5850 of the 2 186 642 hospitalisations identified. According to laboratory measurements, however, hyponatraemia was present in 306 418 (14%) hospitalisations. Sensitivity of hyponatraemia diagnoses was 1.8% (95% CI 1.7% to 1.8%). For sodium values <115 mmol/L, sensitivity was 34.3% (95% CI 32.6% to 35.9%). The overall PPV was 92.5% (95% CI 91.8% to 93.1%) and decreased with increasing hyponatraemia severity. Specificity and NPV were high for all cut off points (>=99.8% and >=86.2%, respectively). Patients with hyponatraemia without a corresponding ICD-10 discharge diagnosis were younger and had higher Charlson Comorbidity Index scores than patients with hyponatraemia with a hyponatraemia code in the DNRP. CONCLUSIONS: ICD-10 codes for hyponatraemia in the DNRP have high specificity but very low sensitivity. Laboratory test results, not discharge diagnoses, should be used to ascertain hyponatraemia. PMID- 24760353 TI - Can analyses of electronic patient records be independently and externally validated? The effect of statins on the mortality of patients with ischaemic heart disease: a cohort study with nested case-control analysis. AB - OBJECTIVE: To conduct a fully independent and external validation of a research study based on one electronic health record database, using a different electronic database sampling the same population. DESIGN: Using the Clinical Practice Research Datalink (CPRD), we replicated a published investigation into the effects of statins in patients with ischaemic heart disease (IHD) by a different research team using QResearch. We replicated the original methods and analysed all-cause mortality using: (1) a cohort analysis and (2) a case-control analysis nested within the full cohort. SETTING: Electronic health record databases containing longitudinal patient consultation data from large numbers of general practices distributed throughout the UK. PARTICIPANTS: CPRD data for 34 925 patients with IHD from 224 general practices, compared to previously published results from QResearch for 13 029 patients from 89 general practices. The study period was from January 1996 to December 2003. RESULTS: We successfully replicated the methods of the original study very closely. In a cohort analysis, risk of death was lower by 55% for patients on statins, compared with 53% for QResearch (adjusted HR 0.45, 95% CI 0.40 to 0.50; vs 0.47, 95% CI 0.41 to 0.53). In case-control analyses, patients on statins had a 31% lower odds of death, compared with 39% for QResearch (adjusted OR 0.69, 95% CI 0.63 to 0.75; vs OR 0.61, 95% CI 0.52 to 0.72). Results were also close for individual statins. CONCLUSIONS: Database differences in population characteristics and in data definitions, recording, quality and completeness had a minimal impact on key statistical outputs. The results uphold the validity of research using CPRD and QResearch by providing independent evidence that both datasets produce very similar estimates of treatment effect, leading to the same clinical and policy decisions. Together with other non-independent replication studies, there is a nascent body of evidence for wider validity. PMID- 24760355 TI - Smoker, ex-smoker or non-smoker? The validity of routinely recorded smoking status in UK primary care: a cross-sectional study. AB - OBJECTIVE: To investigate how smoking status is recorded in UK primary care; to evaluate whether appropriate multiple imputation (MI) of smoking status yields results consistent with health surveys. SETTING: UK primary care and a population survey conducted in the community. PARTICIPANTS: We identified 354 204 patients aged 16 or over in The Health Improvement Network (THIN) primary care database registered with their general practice 2008-2009 and 15 102 individuals aged 16 or over in the Health Survey for England (HSE). OUTCOME MEASURES: Age standardised and age-specific proportions of smokers, ex-smokers and non-smokers in THIN and the HSE before and after MI. Using information on time since quitting in the HSE, we estimated when ex-smokers are typically recorded as non-smokers in primary care records. RESULTS: In THIN, smoking status was recorded for 84% of patients within 1 year of registration. Of these, 28% were smokers (21% in the HSE). After MI of missing smoking data, the proportion of smokers was 25% (missing at random) and 20% (missing not at random). With increasing age, more were identified as ex-smokers in the HSE than THIN. It appears that those who quit before age 30 were less likely to be recorded as an ex-smoker in primary care than people who quit later. CONCLUSIONS: Smoking status was relatively well recorded in primary care. Misclassification of ex-smokers as non-smokers is likely to occur in those quitting smoking at an early age and/or a long time ago. Those with no smoking status information are more likely to be ex-smokers or non smokers than smokers. PMID- 24760356 TI - A group-based HIV and sexually transmitted infections prevention intervention for lesbian, bisexual, queer and other women who have sex with women in Calgary and Toronto, Canada: study protocol for a non-randomised cohort pilot study. AB - INTRODUCTION: The limited research that exists suggests that lesbian, bisexual queer (LBQ) and other women who have sex with women are at similar risk for sexually transmitted infections (STI) as heterosexual women. However, scant research has evaluated HIV and STI prevention strategies for LBQ women. The authors present the rationale and study protocol for developing and pilot testing a psychoeducational group-based HIV and STI prevention intervention with LBQ women in Calgary and Toronto, Canada. METHODS AND ANALYSIS: This is a multicentre non-randomised cohort pilot study. The target population is LBQ women in Calgary and Toronto, Canada. The authors aim to recruit 40 participants using purposive peer-driven recruitment methods. Participants will conduct a pretest followed by a 2-day group programme of six 2 h sessions addressing stigma, STI and HIV prevention, healthy relationships, safer sex self-efficacy, self-worth, social support and LBQ community engagement. Participants will conduct a post-test directly following the intervention and 6 weeks after the intervention. The primary outcome is safer sex practices; our prespecified index of clinically significant change is an effect size of 0.50. Secondary outcomes include: safer sex self-efficacy, STI testing frequency, STI knowledge, resilient coping, social support, sexual stigma, access to care, depression and self-esteem. We will conduct mixed-effects regression to calculate mean outcome pre-post test score change. ETHICS AND DISSEMINATION: Research ethics approval was attained from the Office of Research Ethics (REB: 29291), University of Toronto, Toronto, Ontario, Canada. Trial results will be published according to the Transparent Reporting of Evaluations with Non-randomised Designs (TREND) statement, regardless of the outcomes. TRIAL REGISTRATION NUMBER: This study is registered at http://clinicaltrials.gov, registration number NCT02067845. PMID- 24760357 TI - Validating childhood asthma in an epidemiological study using linked electronic patient records. AB - OBJECTIVE: To investigate the performance of parent-reported data in identifying physician-confirmed asthma. DESIGN AND SETTING: Validation study using linkage between the Avon Longitudinal Study of Parents and Children (ALSPAC) and electronic patient records held within the General Practice Research Database (GPRD). PARTICIPANTS: Participants were those eligible to participate in ALSPAC who also had a record in the GPRD; this included 765 individuals, just under 4% of ALSPAC-eligible participants. The analysis was based on 141 participants with complete parent-reported asthma data. PRIMARY AND SECONDARY OUTCOME MEASURES: The main GPRD outcome measure was whether a child had a diagnosis of asthma before they were nine. Parent-reported measures were doctor diagnosis of asthma (before mean age 7.5 years), various outcomes based on wheezing and breathlessness recorded longitudinally between 6 months and 8.5 years. Secondary outcomes were bronchial hyper-responsiveness (BHR), forced expiratory volume in 1 s/forced vital capacity ratio and skin prick test responses. RESULTS: Among the 141 participants with complete parent-reported data, 26 (18%) had an asthma diagnosis before age nine. Using general practitioner (GP)-recorded asthma as the gold standard, the question 'Has a doctor ever diagnosed your child with asthma?' was both sensitive (88.5%) and specific (95.7%). 'Ever wheezed' had the highest sensitivity (100%) but low specificity (60%). More specific definitions were obtained by restricting to those who had wheezed on more than one occasion, experienced frequent wheeze and/or wheezed after the age of 3, but these measures had low sensitivities. BHR only identified 50% of those with a GP-recorded diagnosis. CONCLUSIONS: Parental reports of a doctor's diagnosis agree well with a GP-recorded diagnosis. High specificity for asthma can be achieved by using detailed wheezing questions, although these definitions are likely to exclude mild cases of asthma. Our study shows that linkage between observational studies and electronic patient records has the potential to enhance epidemiological research. PMID- 24760358 TI - DSM-5 alcoholism: A 60-year perspective. PMID- 24760359 TI - Lifelong desquamation of the hands and feet. PMID- 24760360 TI - Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection. AB - Crack cocaine use is associated with impaired verbal memory in HIV-infected women more than uninfected women. To understand the neural basis for this impairment, this study examined the effects of crack cocaine use on activation of the prefrontal cortex (PFC) and strategic encoding during a verbal memory task in HIV infected women. Three groups of HIV-infected women from the Chicago Consortium of the Women's Interagency HIV Study were compared: current users of crack cocaine (n = 10), former users of cocaine (n = 11), and women who had never used cocaine (n = 9). Participants underwent functional magnetic resonance imaging during a verbal memory task and completed a neuropsychological test of verbal memory. On the neuropsychological test, current crack users performed significantly worse than other groups on semantic clustering, a measure of strategic encoding, p < 0.05. During encoding, activation in left anterior cingulate cortex (ACC) was lower in current and former cocaine users compared to never users. During recognition, activation in bilateral PFC, specifically left dorsal medial PFC and bilateral dorsolateral PFC, was lower in current and former users compared to women who had never used cocaine. Lower activation in left dorsolateral PFC was correlated with worse performance on the recognition task, p < 0.05. The verbal learning and memory deficits associated with cocaine use in women with HIV may be partially accounted for by alterations in ACC and PFC function. PMID- 24760361 TI - Pattern of neurocognitive function in patients receiving boosted protease inhibitor monotherapy: a detailed neuropsychological study. AB - It is unknown if, compared to a triple drug antiretroviral therapy, boosted protease inhibitor monotherapy leads to worse results in specific neuropsychological processes. In our study, we included patients virologically suppressed (>=1 year), on antiretroviral therapy, without concomitant major neurocognitive confounders, receiving boosted lopinavir or darunavir as monotherapy (n = 96) or as triple therapy with two nucleoside reverse transcriptase inhibitors (n = 95). All patients underwent a comprehensive neuropsychological test battery (14 neuropsychological measures, covering seven domains). Both groups were compared in average score distributions and rates of neuropsychological deficits. Similar comparisons were conducted only for patients with neurocognitive impairment. In the adjusted analysis, we found only small differences between groups in the entire sample: better verbal learning (p = 0.02; d = 0.28) and verbal recall scores (p < 0.01; d = 0.25) in patients on boosted protease inhibitor monotherapy and slightly better motor skills with dominant hand (p = 0.02; d = 0.23) scores in patients on triple therapy. No greater proportion of deficits in the protease inhibitor monotherapy group was found in any neuropsychological measure. In neurocognitively impaired patients, we found similar outcomes in verbal learning, verbal recall, and motor skills with dominant hand but with larger effect sizes. Close similarities in the neurocognitive pattern between groups question the clinical relevance of the number of neuroactive drugs included in the regimen. These results also suggest that peripheral viral load control may be a good indicator of brain protection. PMID- 24760362 TI - A 12-year-old Bella Donna. PMID- 24760363 TI - Cypermethrin-induced nigrostriatal dopaminergic neurodegeneration alters the mitochondrial function: a proteomics study. AB - Cypermethrin induces the slow and progressive degeneration of the nigrostriatal dopaminergic neurons in rats. Postnatal preexposure with low doses of cypermethrin is known to enhance the susceptibility of animals upon adulthood reexposure. The study was undertaken to delineate the role of mitochondria in cypermethrin-induced neurodegeneration. Indexes of dopaminergic neurodegeneration, microglial activation, and mitochondrial dysfunction and its proteome profile were assessed in controls and cypermethrin-treated rats. Cypermethrin increased nigral dopaminergic neurodegeneration and microglial activation while reduced mitochondrial membrane potential and complex I activity. Cypermethrin attenuated striatal dopamine content and differentially regulated the expressions of the nine striatal and ten nigral proteins. Western blot analyses showed that cypermethrin also increased c-Jun N-terminal kinase (JNK), caspase-3, tumor suppressor protein (p53), tumor necrosis factor-alpha (TNF alpha), p38 mitogen-activated protein kinase (p38 MAPK), and heme oxygenase-1 (HO 1) expressions and reduced B cell lymphoma-2 protein (Bcl-2) expression. Syndopa and minocycline rescued from cypermethrin induced augmentation in microglial activation and reductions in mitochondrial membrane potential and complex I activity, striatal dopamine content, and degeneration of nigral dopaminergic neurons. Syndopa and minocycline, respectively, modulated the expressions of four and six striatal and four and seven nigral proteins. Furthermore, they reinstated the expressions of JNK, caspase-3, Bcl-2, p53, p38 MAPK, TNF-alpha, and HO-1. The study demonstrates that cypermethrin induces mitochondrial dysfunction and alters mitochondrial proteome leading to oxidative stress and apoptosis, which regulate the nigrostriatal dopaminergic neurodegeneration. PMID- 24760365 TI - Probing crystal structure and mesoscale assembly of cellulose microfibrils in plant cell walls, tunicate tests, and bacterial films using vibrational sum frequency generation (SFG) spectroscopy. AB - This study reports that the noncentrosymmetry and phase synchronization requirements of the sum frequency generation (SFG) process can be used to distinguish the three-dimensional organization of crystalline cellulose distributed in amorphous matrices. Crystalline cellulose is produced as microfibrils with a few nanometer diameters by plants, tunicates, and bacteria. Crystalline cellulose microfibrils are embedded in wall matrix polymers and assembled into hierarchical structures that are precisely designed for specific biological and mechanical functions. The cellulose microfibril assemblies inside cell walls are extremely difficult to probe. The comparison of vibrational SFG spectra of uniaxially-aligned and disordered films of cellulose Ibeta nanocrystals revealed that the spectral features cannot be fully explained with the crystallographic unit structure of cellulose. The overall SFG intensity, the alkyl peak shape, and the alkyl/hydroxyl intensity ratio are sensitive to the lateral packing and net directionality of the cellulose microfibrils within the SFG coherence length scale. It was also found that the OH SFG stretch peaks could be deconvoluted to find the polymorphic crystal structures of cellulose (Ialpha and Ibeta). These findings were used to investigate the cellulose crystal structure and mesoscale cellulose microfibril packing in intact plant cell walls, tunicate tests, and bacterial films. PMID- 24760364 TI - Cytotoxic effect of p-Coumaric acid on neuroblastoma, N2a cell via generation of reactive oxygen species leading to dysfunction of mitochondria inducing apoptosis and autophagy. AB - p-Coumaric acid (p-CA), an ubiquitous plant phenolic acid, has been proven to render protection against pathological conditions. In the present study, p-CA was evaluated for its capacity to induce cytotoxic effect to neuroblastoma N2a cells and we report here the possible mechanism of its action. p-CA at a concentration of 150 MUmol/L, upon exposure for 72 h, stimulated 81.23 % of cells to apoptosis, as evidenced by flow cytometer studies mediated through elevated levels of ROS (7.5-fold over control). Excess ROS production activated structural injury to mitochondrial membrane, observed as dissipation of its membrane potential and followed by the release of cytochrome c (8.73-fold). Enhanced generation of intracellular ROS correlated well with the decreased levels (~60 %) of intracellular GSH. Sensitizing neuroblastoma cells for induction of apoptosis by p-CA identified p53-mediated upregulated accumulation of caspase-8 messenger RNA (2.8-fold). Our data report on autophagy, representing an additional mechanism of p-CA to induce growth arrest, detected by immunoblotting and fluorescence, correlated with accumulation of elevated levels (1.2-fold) of the LC3-II protein and acridine orange-stained autophagosomes, both autophagy markers. The present study indicates p-CA was effective in production of ROS-dependent mitochondrial damage-induced cytotoxicity in N2a cells. PMID- 24760367 TI - Exploring zinc coordination in novel zinc battery electrolytes. AB - The coordination of zinc ions by tetraglyme has been investigated here to support the development of novel electrolytes for rechargeable zinc batteries. Zn(2+) reduction is electrochemically reversible from tetraglyme. The spectroscopic data, molar conductivity and thermal behavior as a function of zinc composition, between mole ratios [80 : 20] and [50 : 50] [tetraglyme : zinc chloride], all suggest that strong interactions take place between chloro-zinc complexes and tetraglyme. Varying the concentration of zinc chloride produces a range of zinc chloro species (ZnClx)(2-x) in solution, which hinder full interaction between the zinc ion and tetraglyme. Both the [70 : 30] and [50 : 50] mixtures are promising electrolyte candidates for reversible zinc batteries, such as the zinc air device. PMID- 24760366 TI - Treatment of epileptic seizures in brain tumors: a critical review. AB - Epileptic seizures represent a common signal of intracranial tumors, frequently the presenting symptom and the main factor influencing quality of life. Treatment of tumors concentrates on survival; antiepileptic drug (AED) treatment frequently is prescribed in a stereotyped way. A differentiated approach according to epileptic syndromes can improve seizure control and minimize unwarranted AED effects. Prophylactic use of AEDs is to be discouraged in patients without seizures. Acutely provoked seizures do not need long-term medication except for patients with high recurrence risk indicated by distinct EEG patterns, auras, and several other parameters. With chronically repeated seizures (epilepsies), long term AED treatment is indicated. Non-enzyme-inducing AEDs might be preferred. Valproic acid exerts effects against progression of gliomatous tumors. In low grade astrocytomas with epilepsy, a comprehensive presurgical epilepsy work-up including EEG-video monitoring is advisable; in static non-progressive tumors, it is mandatory. In these cases, the neurosurgical approach has to include the removal of the seizure-onset zone frequently located outside the lesion. PMID- 24760370 TI - Dynamical estimation of neuron and network properties III: network analysis using neuron spike times. AB - Estimating the behavior of a network of neurons requires accurate models of the individual neurons along with accurate characterizations of the connections among them. Whereas for a single cell, measurements of the intracellular voltage are technically feasible and sufficient to characterize a useful model of its behavior, making sufficient numbers of simultaneous intracellular measurements to characterize even small networks is infeasible. This paper builds on prior work on single neurons to explore whether knowledge of the time of spiking of neurons in a network, once the nodes (neurons) have been characterized biophysically, can provide enough information to usefully constrain the functional architecture of the network: the existence of synaptic links among neurons and their strength. Using standardized voltage and synaptic gating variable waveforms associated with a spike, we demonstrate that the functional architecture of a small network of model neurons can be established. PMID- 24760371 TI - The influence of weather on health-related help-seeking behavior of senior citizens in Hong Kong. AB - It is believed that extreme hot and cold weather has a negative impact on general health conditions. Much research focuses on mortality, but there is relatively little community health research. This study is aimed at identifying high-risk groups who are sensitive to extreme weather conditions, in particular, very hot and cold days, through an analysis of the health-related help-seeking patterns of over 60,000 Personal Emergency Link (PE-link) users in Hong Kong relative to weather conditions. In the study, 1,659,716 PE-link calls to the help center were analyzed. Results showed that females, older elderly, people who did not live alone, non-subsidized (relatively high-income) users, and those without medical histories of heart disease, hypertension, stroke, and diabetes were more sensitive to extreme weather condition. The results suggest that using official government weather forecast reports to predict health-related help-seeking behavior is feasible. An evidence-based strategic plan could be formulated by using a method similar to that used in this study to identify high-risk groups. Preventive measures could be established for protecting the target groups when extreme weather conditions are forecasted. PMID- 24760368 TI - Role of Sost in Wnt signal pathway in osteoporosis rats and regulating effect of soybean isoflavones on Wnt signal pathway. AB - To explore the mechanism of soybean isoflavones (SI) on OVX-induced osteoporosis, we investigated the effect of SI on Wnt signaling that emerged as a novel key pathway for promoting bone formation. Results showed that SI decreased bone mineral elements loss, improved biomechanics parameters in OVX rats. Wnt3a activation can promote the dissociation of beta-catenin complexes, release of beta-catenin monomer and inhibition of beta-catenin monomer degradation. SI decreased sost mRNA and sclerosteosis protein expression in a dose-dependent manner, and increased beta-catenin proteins expression in femur of OVX rats. These data suggest that SI suppresses the canonical Wnt signal in OVX rats, partially through the enhancement of the dickkopf-1 production. OVX results in decreased estrogen level in rats. SI act as inhibitors of Wnt-mediated activation of by competitively binding to LRP5, and subsequently downregulating beta-catenin gene. PMID- 24760373 TI - Measuring sun damage at the grocery store: Mychelle Dermaceuticals and Whole Foods Market bring UV photography to aisle #7. PMID- 24760375 TI - A case of erythema multiforme followed by herpes zoster. PMID- 24760374 TI - Anxiolytic effects of oxytocin in cue-induced cocaine seeking behavior in rats. AB - RATIONALE: Oxytocin (OT) is a neuropeptide previously related to reward, learning, memory, and stress, events associated with cocaine addiction. OT has shown anxiolytic properties in different animal models of anxiety. Moreover, previous data have demonstrated an increase in mRNA OT levels within the nucleus accumbens (NAc) following acute and chronic cocaine exposure in rats. Therefore, OT might play a modulatory role in the rewarding properties of cocaine. OBJECTIVES: The present set of experiments aims to examine the role of OT on environmentally elicited cocaine-seeking behavior and whether OT could reduce anxiety associated with this behavior. METHODS: Separate groups of rats were trained in a cue-elicited cocaine-seeking behavior paradigm. Prior to the reinstatement phase, animals received microinfusions of artificial cerebrospinal fluid (aCSF), OT, OT agonist (TgOT), or OT antagonist (OTA) within the intracerebral ventricular intracerebroventricular (ICV) system. To test OT anxiolytic effects in reinstatement behavior, separate groups of animals were trained in a cue-elicited cocaine-seeking behavior protocol or in a cocaine conditioning paradigm. At the end of each behavioral training, all animals were ICV pretreated with aCSF or OT, and then exposed to an elevated plus maze. RESULTS: Results showed that OT and TgOT pretreatment significantly reduced reinstatement of cocaine-seeking behavior. Most significantly, OT treatment reduced the anxiety triggered by cue-induced reinstatement conditions and cocaine paired conditioned locomotion. CONCLUSIONS: The present study demonstrates for the first time that OT actions within the brain mediate the anxiety response triggered by cues previously paired with cocaine intake. PMID- 24760379 TI - Nutritional improvement following growing rod surgery in children with early onset scoliosis. AB - PURPOSE: We aimed to evaluate the nutritional status of children with early onset scoliosis (EOS) and to determine if treatment with growing rod instrumentation improves weight percentile. METHODS: Data was retrospectively collected on 88 EOS patients treated with growing rods at six institutions. Mean age at surgery was 5.8 years, and mean Cobb angle was 75 degrees . All patients were followed for at least 2 years (mean 4 years). Weights were converted to normative percentiles based on the patients' age and gender. RESULTS: Preoperatively, 47 % (41/88) of patients were <5 percentile for weight, thus failing to thrive. There was a significant increase in mean postoperative weight percentiles at latest follow-up (p = 0.004). 49 % of patients gained weight, with a mean of 18 percentile. A significant relationship exists between age at initial surgery and percentile weight gain (p < 0.005), with children <4 years old not demonstrating postoperative improvement. This relationship was not confounded by preoperative weight, preoperative Cobb angle, or years of follow-up (p > 0.05). Children with neuromuscular and syndromic diagnoses do not appear to improve their mean nutritional status after surgery when compared to patients with idiopathic or congenital/structural scoliosis (p = 0.006). CONCLUSION: Following growing rod treatment, there was significant improvement in nutritional status in approximately 50 % of patients, similar to that reported with VEPTR. Neuromuscular and syndromic patients did not experience nutritional improvement post-operatively. These findings support the theory that growing rods improve the clinical status of EOS patients, as nutritional improvement is one outcome of improved clinical status. The relationship between age at initial surgery and nutritional improvement is intriguing. PMID- 24760382 TI - Role of multivitamins, micronutrients and probiotics supplementation in management of HIV infected children. AB - OBJECTIVES: To assess the immuno-clinical response of micronutrients supplementation in human immunodeficiency virus (HIV) infected children (both on and without antiretroviral therapy) and to assess the role of probiotics in improvement of CD4 counts in HIV infected children not on antiretroviral therapy. METHODS: This was an open labeled randomized control study, conducted in Department of Pediatrics and Antiretrovial Therapy (ART) Center, S.N. Medical College, Agra. One hundred and twenty seven HIV infected children aged <= 15 y were included in the study. Enrolled children were randomized to receive micronutrients for 6 mo or probiotics for 3 mo. Children who did not receive supplements served as control. Change in WHO clinical stage, immunological stage, CD4 counts and body mass index (BMI) status were taken at the end of 6 mo. In probiotic group, mean CD4 count were taken as outcome measure. A detailed history, examination and WHO clinical staging were recorded for all the patients. RESULTS: In micronutrient supplemented group (not on ART), significant improvement was seen in WHO clinical staging (p = 0.049) when compared to controls after 6 mo. Probiotic supplemented group showed significant increase in CD4 counts compared to control group (p = 0.0022) in children >5 y. Control group showed significant decline in CD4 count in children <=5 y (-65.3 cells/mm(3), p=0.005) and in children >5 y (-87.9 cells/mm(3), p=0.05) after 12 wk of supplementation. CONCLUSIONS: Probiotics supplementation has shown significant improvement in CD4 counts. Micronutrients supplementation has shown significant delay in the progression towards advance stage of disease. PMID- 24760384 TI - Abstracts of the RANZCP (Royal Australian and New Zealand College of Psychiatrists) 2014 Congress. PMID- 24760383 TI - Quantification of dermatophyte viability for evaluation of antifungal effect by quantitative PCR. AB - Dermatophytosis is a common disease caused by dermatophyte fungi such as Trichophyton rubrum and Trichophyton mentagrophytes. A method of quantifying fungal viability in the lesions of dermatophytosis is indispensable for understanding the therapeutic process and outcome; however, no such method has yet been developed. The aim of this study was to develop a method for quantifying dermatophyte viability by quantitative polymerase chain reaction (qPCR). The internal transcribed spacer (ITS) and D1/D2 regions, including each of rRNA and rDNA, were chosen as the targets, and dermatophyte-specific primer pairs were designed corresponding to ITS and D1/D2 regions. The amounts of target RNA and DNA after heat or antifungal treatment were measured by qPCR and compared with colony-forming unit (CFU) counts. RNA and DNA could extract from dermatophytes by mechanical pulverization of conidia using a Multi-Beads Shocker cell disruptor. Our method was sufficiently sensitive to detect 10 copies by qPCR using both ITS and D1/D2 primer pairs. The most sensitive target was ITS-cDNA after heat or antifungal treatment, and essentially consistent with CFU counts. On the other hands, ITS-DNA and D1/D2-DNA were not decreased soon after heat or antifungal treatment, but those were decreased significantly and reflected the CFU counts after 48 h of antifungal treatment. We conclude that ITS-cDNA is useful mainly for quantifying dermatophyte viability at early responses, but ITS-DNA and D1/D2 DNA are also available for evaluation, which does not need an early response. PMID- 24760387 TI - Prognostic and predictive role of epidermal growth factor receptor mutation in recurrent pulmonary adenocarcinoma after curative resection. AB - OBJECTIVES: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment prolongs the progression-free survival of patients with advanced non-small-cell lung cancer harbouring EGFR mutations. This study aimed to evaluate the prognostic factors influencing survival after recurrence, and the effectiveness of EGFR-TKIs in patients with recurrent pulmonary adenocarcinoma after curative resection. METHODS: EGFR mutations were prospectively evaluated in 594 patients who underwent curative surgical resection for pulmonary adenocarcinoma. Among them, 138 patients who had postoperative recurrent disease were enrolled in the study. Potential prognostic factors for post-recurrence survival (PRS) were evaluated, and predictive factors of responsiveness to EGFR TKIs were also analysed. RESULTS: Among the 138 patients who had postoperative recurrent disease, EGFR mutations were identified in 73 (52.9%) patients. In multivariable analysis, never-smoking status [hazard ratio (HR), 0.522; P = 0.012], adjuvant radiotherapy (HR, 1.995; P = 0.016), disease-free interval of less than 1 year from initial resection to recurrence (HR, 2.382; P = 0.001), surgical treatment for recurrence (HR, 0.346; P = 0.002) and EGFR mutation (HR, 0.552; P = 0.013) were independent prognostic factors for PRS. Among patients treated with EGFR-TKI, EGFR mutation status was the only predictor of response to EGFR-TKI (P < 0.001), and patients with EGFR mutation showed better PRS (3- and 5 year survival rates after recurrence, 68.8 and 41.1%, respectively) than those without EGFR mutations (3- and 5-year survival rates after recurrence, 39.1 and 15.7%, respectively; P = 0.017). CONCLUSIONS: Our study demonstrated that EGFR mutation is an independent prognostic factor for PRS. Considering that EGFR mutations were the only independent predictors for response to EGFR-TKIs, selecting patients for EGFR-TKI therapy according to EGFR mutation status may lead to a better prognosis in patients with recurrent pulmonary adenocarcinoma. PMID- 24760386 TI - Overlapping genetic and environmental influences on nonsuicidal self-injury and suicidal ideation: different outcomes, same etiology? AB - IMPORTANCE: Nonsuicidal self-injury (NSSI) and suicidal self-injury are very harmful behaviors and are associated with several psychiatric disorders. In the recently developed fifth edition of the DSM, NSSI and suicidal behavior disorder are for the first time introduced as conditions in their own right instead of symptoms of other psychiatric disorders. It is unclear to what extent NSSI and suicidal self-injury share the same underlying biological mechanisms and are influenced by the same environmental factors. OBJECTIVE: To determine the relative importance of genetic and environmental influences on the variation in NSSI and suicidal ideation and their covariation. DESIGN, SETTING, AND PARTICIPANTS: Classical twin design using a sample of 10,678 male and female adult twins (mean [SD] age, 32.76 [6.99] years) from the Australian Twin Registry, a population-based twin registry. Between 1996 and 2009, the twins participated in semistructured telephone interviews that primarily focused on psychiatric disorders. MAIN OUTCOMES AND MEASURES: Lifetime presence of self reported NSSI and suicidal ideation. RESULTS The prevalences of NSSI and suicidal ideation were 4.7% and 26.5%, respectively, and individuals who engaged in self harm were much more likely to report suicidal ideation (odds ratio = 8.39; 95% CI, 6.84-10.29). Results from a bivariate genetic model indicated that genetic factors explain a substantial part of the variance in both NSSI (37% for men and 59% for women) and suicidal ideation (41% for men and 55% for women), while residual influences (including nonshared environmental influences and measurement error) explain the remainder of the variance. Shared (family) environment did not seem to play a role. Moreover, both behaviors were strongly correlated (r = 0.49 for men and 0.61 for women), and this correlation was largely explained by overlapping genetic influences (76% for men and 62% for women), whereas residual influences accounted for the remainder of the phenotypic correlation. CONCLUSIONS AND RELEVANCE: Results indicated that the substantial correlation between NSSI and suicidal ideation is largely driven by overlapping genetic factors, suggesting that the 2 behaviors share similar biological underpinnings. Overlapping residual influences also explain part of the covariance between the 2 traits. Future research should further investigate which genetic and environmental influences underlie the vulnerability to NSSI and suicidal ideation. PMID- 24760388 TI - Comparative tissue proteomics analysis of thoracic aortic dissection with hypertension using the iTRAQ technique. AB - OBJECTIVES: To identify differentially expressed proteins from the aortic tissue of thoracic aortic dissection (TAD) with hypertension and normal aorta and to explore the potential molecular pathogenesis of TAD. METHODS: Aortic tissue samples were collected from two groups of age- and gender-matched patients with TAD and normal aorta. These samples were subjected to isobaric tags for relative and absolute quantitation analysis to identify the proteins involved in TAD. Signalling pathways were analysed using the Metacore software, and the identified proteins were validated by western blotting. RESULTS: A total of 36 proteins were identified between two groups, with 19 of them being significantly down-regulated and 17 up-regulated in patients with TAD. Proteins including fibrillin-1, emilin 1, decorin, protein DJ-1 and histone H4 were validated by western blotting. The enrichment analysis performed using the Metacore process networks data showed that cell adhesion_cell-matrix interactions, proteolysis_extracellular matrix (ECM) remodelling and inflammation_interleukin 6 (IL-6) signalling were the main protein interaction networks involved in TAD. We further observed indications of increased transforming growth factor-beta (TGF-beta) signalling and impaired aortic wall remodelling, both of which may be molecular mechanisms for the pathogenesis of TAD. CONCLUSIONS: The differentially expressed proteins identified in our study are mainly involved in cell-matrix interaction, ECM remodelling and inflammation. These mechanisms, combined with the TGF-beta signalling pathway, may play an important role in the pathogenesis of TAD. PMID- 24760389 TI - Genomic organization and evolution of the trace amine-associated receptor (TAAR) repertoire in Atlantic salmon (Salmo salar). AB - There is strong evidence that olfaction plays a key role in the homing of salmonids to their natal spawning grounds, particularly in the freshwater phase. However, the physiological and genetic mechanisms behind this biological phenomenon are largely unknown. It has been shown that Pacific salmon respond to dissolved free amino acids from their natal streams. This indicates that amino acids comprise part of the olfcatory cues for imprinting and homing in salmonids. As trace amine-associated receptors (TAARs), a class of olfactory receptors that are close relatives of the G protein-coupled aminergic neurotransmitter receptors, recognize amino acid metabolites, we hypothesize that TAARs play an important role in salmon homing by recognizing olfactory cues. Therefore, to better understand homing in Atlantic salmon, we set out to characterize the TAAR genes in this species. We searched the first assembly of the Atlantic salmon genome for sequences resembling TAARs previously characterized in other teleosts. We identified 27 putatively functional TAAR genes and 25 putative TAAR pseudogenes, which cluster primarily on chromosome 21 (Ssa21). Phylogenetic analysis of TAAR amino acid sequences from 15 vertebrate species revealed the TAAR gene family arose after the divergence of jawed and jawless vertebrates. The TAARs group into three classes with salmon possessing class I and class III TAARs. Within each class, evolution is characterized by species-specific gene expansions, which is in contrast to what is observed in other olfactory receptor families (e.g., OlfCs and oras). PMID- 24760390 TI - Two genomic regions contribute disproportionately to geographic differentiation in wild barley. AB - Genetic differentiation in natural populations is driven by geographic distance and by ecological or physical features within and between natural habitats that reduce migration. The primary population structure in wild barley differentiates populations east and west of the Zagros Mountains. Genetic differentiation between eastern and western populations is uneven across the genome and is greatest on linkage groups 2H and 5H. Genetic markers in these two regions demonstrate the largest difference in frequency between the primary populations and have the highest informativeness for assignment to each population. Previous cytological and genetic studies suggest there are chromosomal structural rearrangements (inversions or translocations) in these genomic regions. Environmental association analyses identified an association with both temperature and precipitation variables on 2H and with precipitation variables on 5H. PMID- 24760391 TI - The long-term outcomes after curative resection for mass-forming intrahepatic cholangiocarcinoma associated with hepatitis C viral infection: a multicenter analysis by Osaka Hepatic Surgery Study Group. AB - BACKGROUND AND OBJECTIVES: Hepatitis C virus (HCV) infection plays an important role in the development of not only hepatocellular carcinoma (HCC) but also intrahepatic cholangiocarcinoma (ICC). The aim of this study was to identify the specific characteristics of HCV-related ICC. METHODS: Of 90 patients who underwent curative resection for mass-forming ICC, 33 patients had chronic HCV infection. We examined the relationship between HCV infection and the clinicopathologic findings and surgical outcomes. RESULTS: The incidence of simultaneous HCC was significantly higher in patients infected with HCV (30.3%) than in those without HCV infection (5.3%). Four patients were diagnosed with metachronous HCC after resection for HCV-related ICC. Patients with HCV infection had a significantly shorter overall survival time than patients without HCV infection, although there was no difference in ICC tumor-free survival rates between the two groups. Five HCC-related deaths occurred in patients with HCV infection, while none of patients without HCV infection died from HCC. Multivariate analysis indicated that HCV infection, tumor size >5 cm, multiple ICC tumors, and nodal metastases were predictors of poor prognosis in patients who underwent curative resection for mass-forming ICC. CONCLUSIONS: HCV infection was an adverse prognostic factor after curative resection for mass-forming ICC. PMID- 24760392 TI - [Transforming-growth-factor-beta-induced corneal dystrophies]. PMID- 24760394 TI - Toward high spatial resolution sampling and characterization of biological tissue surfaces using mass spectrometry. AB - Mass spectrometry has emerged as a powerful tool for the bioanalytical sciences because of its ability to characterize small and large biomolecules in vanishingly small amounts. A recurring motif in mass spectrometry aims to decipher the chemical composition of biological samples at the molecular level, requiring drastic improvements in the ability to interrogate well defined and highly spatially resolved areas of a sample surface. With the growth of novel ionization methods, numerous advances have been made in sampling biological tissue surfaces. Here, current advancements in ambient, inlet, and vacuum ionization methods are discussed with respect to the potential improvements in the goal of achieving high spatial resolution and/or fast surface analysis. Of similar importance is the need for improvements in applicable characterization strategies using high performance fragmentation technologies such as electron transfer dissociation and electron capture dissociation directly from surfaces, and gas-phase separation through ion mobility spectrometry and high resolution mass spectrometry. PMID- 24760393 TI - Rapid assessment of drug response in cancer cells using microwell array and molecular imaging. AB - Selection of personalized chemotherapy regimen for individual patients has significant potential to improve chemotherapy efficacy and to reduce the deleterious effects of ineffective chemotherapy drugs. In this study, a rapid and high-throughput in vitro drug response assay was developed using a combination of microwell array and molecular imaging. The microwell array provided high throughput analysis of drug response, which was quantified based on the reduction in intracellular uptake (2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D glucose) (2-NBDG). Using this synergistic approach, the drug response measurement was completed within 4 h, and only a couple thousand cells were needed for quantification. The broader application of this microwell molecular imaging approach was demonstrated by evaluating the drug response of two cancer cell lines, cervical (HeLa) and bladder (5637) cancer cells, to two distinct classes of chemotherapy drugs (cisplatin and paclitaxel). This approach did not require an extended cell culturing period, and the quantification of cellular drug response was 4-16 times faster compared with other cell-microarray drug response studies. Moreover, this molecular imaging approach had comparable sensitivity to traditional cell viability assays, i.e., the MTT assay and propidium iodide labeling of cellular nuclei;and similar throughput results as flow cytometry using only 1,000-2,000 cells. Given the simplicity and robustness of this microwell molecular imaging approach, it is anticipated that the assay can be adapted to quantify drug responses in a wide range of cancer cells and drugs and translated to clinical settings for a rapid in vitro drug response using clinically isolated samples. PMID- 24760395 TI - A highly sensitive method for in vitro testing of fluorinated drug candidates using high-resolution continuum source molecular absorption spectrometry (HR-CS MAS). AB - We report here the development, optimization, and evaluation of a highly sensitive method for the determination of fluorine in biological matrices employing highresolution continuum source molecular absorption spectrometry (HR CS MAS), suitable for pharmacological testing of fluorine-containing drug candidates. For this purpose, the most important parameters were studied in detail and subsequently optimized using a multivariate approach based on experimental design methodology. We developed a new approach employing a graphite tube lined with tantalum foil, thereby significantly enhancing sensitivity, while interferences from phosphorus monoxide (PO) molecular absorption due to the complex phosphate-rich matrix were completely eliminated. The limit of detection and the characteristic mass were 5.79 and 6.08 pg F, respectively. In order to evaluate the accuracy of the procedure, a recovery test was performed using spiked samples from three bioassays (i.e., DNA binding, protein binding, and cellular uptake) and the recovery rates ranged from 97.4 to 106.4%. The proposed method is applicable for preclinical in vitro testing of fluorinated drug molecules and thereby establishes HR-CS atomic absorption spectrometry instrumentation as a universal tool in medicinal chemistry. PMID- 24760396 TI - High-throughput absolute quantification of proteins using an improved two dimensional reversed-phase separation and quantification concatemer (QconCAT) approach. AB - Stable isotope dilution-selective reaction monitoring-mass spectrometry (SID-SRM MS) has been widely used for the absolute quantitative analysis of proteins. However, when performing the large-scale absolute quantification of proteins from a more complex tissue sample, such as mouse liver, in addition to a high throughput approach for the preparation and calibration of large amounts of stable-isotope-labelled internal standards, a more powerful separation method prior to SRM analysis is also urgently needed. To address these challenges, a high-throughput absolute quantification strategy based on an improved two dimensional reversed-phase (2D RP) separation and quantification concatemer (QconCAT) approach is presented in this study. This strategy can be used to perform the simultaneous quantification of hundreds of proteins from mouse liver within one week of total MS measurement time. By using calibrated synthesised peptides from the protein glutathione S-transferase (GST), large amounts of GST tagged QconCAT internal standards corresponding to hundreds of proteins can be accurately and rapidly quantified. Additionally, using an improved 2D RP separation method, a mixture containing a digested sample and QconCAT standards can be efficiently separated and absolutely quantified. When a maximum gradient of 72 min is employed in the first LC dimension, resulting in 72 fractions, identification and absolute quantification experiments for all fractions can be completed within one week of total MS measurement time. The quantification approach developed here can further extend the dynamic range and increase the analytical sensitivity of SRM analysis of complex tissue samples, thereby helping to increase the coverage of absolute quantification in a whole proteome. PMID- 24760397 TI - A homogeneous quenching resonance energy transfer assay for the kinetic analysis of the GTPase nucleotide exchange reaction. AB - A quenching resonance energy transfer (QRET) assay for small GTPase nucleotide exchange kinetic monitoring is demonstrated using nanomolar protein concentrations. Small GTPases are central signaling proteins in all eukaryotic cells acting as a "molecular switches" that are active in the GTP-state and inactive in the GDP-state. GTP-loading is highly regulated by guanine nucleotide exchange factors (GEFs). In several diseases, most prominently cancer, this process in misregulated. The kinetics of the nucleotide exchange reaction reports on the enzymatic activity of the GEF reaction system and is, therefore, of special interest. We determined the nucleotide exchange kinetics using europium labeled GTP (Eu-GTP) in the QRET assay for small GTPases. After GEF catalyzed GTP loading of a GTPase, a high time-resolved luminescence signal was found to be associated with GTPase bound Eu-GTP, whereas the non-bound Eu-GTP fraction was quenched by soluble quencher. The association kinetics of the Eu-GTP was measured after GEF addition, whereas the dissociation kinetics could be determined after addition of unlabeled GTP. The resulting association and dissociation rates were in agreement with previously published values for H-Ras(Wt), H-Ras(Q61G), and K Ras(Wt), respectively. The broader applicability of the QRET assay for small GTPases was demonstrated by determining the kinetics of the Ect2 catalyzed RhoA(Wt) GTP-loading. The QRET assay allows the use of nanomolar protein concentrations, as more than 3-fold signal-to-background ratio was achieved with 50 nM GTPase and GEF proteins. Thus, small GTPase exchange kinetics can be efficiently determined in a HTS compatible 384-well plate format. PMID- 24760398 TI - LC-MS/MS method for the simultaneous quantification of artesunate and its metabolites dihydroartemisinin and dihydroartemisinin glucuronide in human plasma. AB - Artesunate (AS), a hemisuccinate derivative of artemisinin, is readily soluble in water and can easily be used in formulations for parenteral treatment of severe malaria. AS is rapidly hydrolyzed to the active metabolite dihydroartemisinin (DHA) and primarily eliminated by biliary excretion after glucuronidation. To investigate systematically the AS metabolism and pharmacokinetics, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of AS and its metabolites DHA and DHA glucuronide (DHAG) in human plasma samples was developed. Compared to previous methods, our method includes for the first time the quantification of the glucuronide metabolite using a newly synthesized stable isotope-labeled analogue as internal standard. Sample preparation was performed with only 50 MUL plasma by high-throughput solid-phase extraction in the 96-well plate format. Separation of the analytes was achieved on a Poroshell 120 EC-C18 column (50*2.1 mm, 2.7 MUm, Agilent Technologies, Waldbronn, Germany). The method was validated according to FDA guidelines. Calibration curves were linear over the entire range from 1 to 2,500 nM (0.4 961.1 ng/mL), 165 to 16,500 nM (46.9-4,691.8 ng/mL), and 4 to 10,000 nM (1.8 4,604.7 ng/mL) for AS, DHA, and DHAG, respectively. Intra- and interbatch accuracy, determined as a deviation between nominal and measured values, ranged from -5.7 to 3.5% and from 2.7 to 5.8%, respectively. The assay variability ranged from 1.5 to 10.9% for intra- and interbatch approaches. All analytes showed extraction recoveries above 85%. The method was successfully applied to plasma samples from patients under AS treatment. PMID- 24760400 TI - CT-guided needle biopsy performed with modified coaxial technique in patients with refractory or recurrent lymphomas. AB - The aim of this study was to evaluate the role of computed tomography (CT)-guided core needle biopsy (CNB) performed by modified coaxial technique as an alternative tool to surgical biopsy in patients with refractory or recurrent lymphomas. Between May 2005 and May 2012, 57 CT-guided CNB of deep lesions were performed in patients with a previous diagnosis of lymphoma and suspected for refractory or recurrent disease. A modified coaxial technique was used in all cases and multiple samples were obtained for histological and immunohistochemical studies. A diagnosis of lymphoma with specification of subtype according to the World Health Organization (WHO) classification was established in 30/57 cases (52.6 %). The previous diagnosis of lymphoma was confirmed in 27/57 patients (47.4 %), whereas histological progression in 3/57 (5.3 %) and other malignant neoplasms in 17/57 (29.8 %) were found. Lymphoma without subtype specification was diagnosed in 6/57 (10.5 %), and no conclusive diagnosis could be established in 4/57 cases (7 %). Overall diagnostic accuracy was 82.5 %. In patients with a final diagnosis of malignant lymphoma, accuracy was 75 %. No complications occurred. Percutaneous CT-guided CNB is a safe, effective and reliable tool in the management of patients with refractory or recurrent lymphomas without superficial lymphadenopathy and can be considered as alternative to surgical sampling. PMID- 24760399 TI - Characterization of the enhanced peroxidatic activity of amyloid beta peptide hemin complexes towards neurotransmitters. AB - Binding of heme to the amyloid peptides Abeta40/42 is thought to be an initial step in the development of symptoms in the early stages of Alzheimer's disease by enhancing the intrinsic peroxidatic activity of heme. We found considerably higher acceleration of the reaction for the physiologically relevant neurotransmitters dopamine and serotonin than reported earlier for the artificial substrate 3,3',5,5'-tetramethylbenzidine (TMB). Thus, the binding of hemin to Abeta peptides might play an even more crucial role in the early stages of Alzheimer's disease than deduced from these earlier results. To mimic complex formation, a new surface architecture has been developed: The interaction between the truncated amyloid peptide Abeta1-16 and hemin immobilized on an aminohexanethiol spacer on a gold electrode has been analyzed by cyclic voltammetry. The resulting complex has a redox pair with a 25 mV more cathodic formal potential than hemin alone. PMID- 24760401 TI - Phase 1 study of the effect of icosapent ethyl on warfarin pharmacokinetic and anticoagulation parameters. AB - BACKGROUND AND OBJECTIVE: Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved to reduce triglyceride levels in patients with severe (>=5.65 mmol/L) hypertriglyceridemia. EPA, the active metabolite of IPE, is mainly metabolized via beta-oxidation, and studies suggest that omega-3 fatty acids such as EPA may have antithrombotic effects. The objective of this study was to evaluate the effect of IPE on the pharmacokinetic and anticoagulation pharmacodynamics of warfarin, a substrate of cytochrome P450 2C9-mediated metabolism. METHODS: Healthy adults received oral warfarin (25 mg) on day 1, oral IPE (4 g/day) on days 8-35, and co-administration on Day 29. Primary pharmacokinetic end points were area under the concentration-versus-time curve from zero to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)) for R- and S-warfarin; pharmacodynamic end points were area under the international normalized ratio (INR) effect-time curve after the warfarin dose (AUC(INR)) and maximum INR (INR(max)). RESULTS: Twenty-five subjects completed the study. AUC(0-infinity) and C max ratios of geometric means for both R- and S warfarin following co-administration of warfarin with versus without IPE were within the 90 % confidence intervals of 0.80-1.25. AUC(INR), INR(max), and ratios were also similar. CONCLUSIONS: IPE 4 g/day did not significantly change the single-dose AUC(0-infinity) or C(max) of R- and S-warfarin or the anticoagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg. Co-administration of these drugs was safe and well tolerated in this study of healthy adult subjects. PMID- 24760402 TI - Clinical pharmacokinetics of the nicotinic channel modulator dexmecamylamine (TC 5214) in subjects with various degrees of renal impairment. AB - BACKGROUND AND OBJECTIVE: Dexmecamylamine (TC-5214) is a nicotinic channel modulator that was evaluated as a potential adjunct treatment to an antidepressant for patients with major depressive disorder. Dexmecamylamine is almost completely eliminated via the kidneys, with more than 90 % of a given dose excreted unchanged in urine. The aim of this study was to assess the single-dose pharmacokinetics of dexmecamylamine in subjects with various degrees of renal impairment and subjects undergoing hemodialysis. METHODS: A single-dose, open label, parallel-group study was conducted at two study centers in the USA. There were four treatment groups with eight subjects in each, receiving a single dose of dexmecamylamine 8 mg (subjects with normal renal function and mild renal impairment) or TC-5412 2 mg [subjects with moderate renal impairment and end stage renal disease (ESRD)]. The pharmacokinetics of dexmecamylamine in plasma, urine, and dialysate were evaluated using non-compartmental analysis. RESULTS: The plasma pharmacokinetics of dexmecamylamine were influenced by renal function. The increase in dose-normalized area under the plasma concentration-time curve (AUC) was statistically significant with an approximately doubled exposure in subjects with moderate renal impairment compared with subjects with normal renal function. The maximum plasma concentration was not impacted by renal function. Plasma clearance of dexmecamylamine in ESRD subjects appeared negligible, with flat plasma concentration-time profiles. Hemodialysis had a relatively modest effect on reduction of dexmecamylamine plasma concentrations. There was no discernable relationship between renal clearance and urinary pH. CONCLUSION: Renal impairment increased the AUC, prolonged the elimination half-life, and decreased the clearance of dexmecamylamine following administration as a single oral dose. It is likely that renal function would need to be taken into account when setting the dose. Dexmecamylamine administration should be avoided or the dose significantly reduced in patients with severe renal impairment and ESRD. PMID- 24760404 TI - Concordant body stalk anomaly in a monoamniotic twin pregnancy at 9 weeks. PMID- 24760406 TI - Surgical treatment of sarcomas of the spine. AB - OPINION STATEMENT: Primary sarcomas of the spine are rare diseases and include osteosarcoma, chondrosarcoma, chordoma, and Ewing's sarcoma. Surgery for these lesions remains an important part of their treatment. Strong evidence exists for the en bloc resection of chondrosarcoma and chordoma since these lesions respond poorly to both chemotherapy and radiation. Weaker but important evidence suggests that osteosarcoma and Ewing's sarcoma may also benefit from wide excisions, but after the application of neoadjuvant therapy, which may significantly aid the surgical process as well as independently prolong the survival. The unacceptable morbidity associated with damage to the neural elements makes resection with wide margins difficult in the spine. Nevertheless, this can be achieved in many circumstances and can, on occasion, lead to long term disease-free survival and even cure. There are numerous techniques described for en bloc resections in the mobile spine and pelvis and these vary widely for the region of the spine involved and the preferences of the surgeon. There are constant principles that do apply to all cases. We think of these surgeries as consisting of 2 stages which can be done in 1 or multiple operations. In the first phase, a corridor free of tumor is removed from the bone and the neural elements to be protected are dissected free from surrounding tissues. In the second phase, the tumor and a margin of normal tissue is circumferentially dissected and delivered while sparing the neural structures. Patient selection, in terms of age, overall disease burden, personal preferences, and comorbidities need to be carefully taken into account to optimize the risk benefit ratio. Sarcomas of the spine are a challenging group of lesions to treat but they can also be the most rewarding. Our newly acquired insight into the pathogenesis of these lesions, as well as improved surgical techniques combined with better neoadjuvant and adjuvant therapies are leading to longer survival times as well as long term disease free survivors. PMID- 24760405 TI - Cost-effectiveness of integrated care in frail elderly using the ICECAP-O and EQ 5D: does choice of instrument matter? AB - Economic evaluations likely undervalue the benefits of interventions in populations receiving both health and social services, such as frail elderly, by measuring only health-related quality of life. For this reason, alternative preference-based instruments have been developed for economic evaluations in the elderly, such as the ICECAP-O. The aim of this paper is twofold: (1) to evaluate the cost-effectiveness using a short run time frame for an integrated care model for frail elderly, and (2) to investigate whether using a broader measure of (capability) wellbeing in an economic evaluation leads to a different outcome in terms of cost-effectiveness. We performed univariate and multivariate analyses on costs and outcomes separately. We also performed incremental net monetary benefit regressions using quality adjusted life years (QALYs) based on the ICECAP-O and EQ-5D. In terms of QALYs as measured with the EQ-5D and the ICECAP-O, there were small and insignificant differences between the instruments, due to negligible effect size. Therefore, widespread implementation of the Walcheren integrated care model would be premature based on these results. All results suggest that, using the ICECAP-O, the intervention has a higher probability of cost effectiveness than with the EQ-5D at the same level of WTP. In case an intervention's health and wellbeing effects are not significant, as in this study, using the ICECAP-O will not lead to a false claim of cost-effectiveness of the intervention. On the other hand, if differences in capability QALYs are meaningful and significant, the ICECAP-O may have the potential to measure broader outcomes and be more sensitive to differences between intervention and comparators. PMID- 24760407 TI - Gene expression in mycorrhizal orchid protocorms suggests a friendly plant-fungus relationship. AB - Orchids fully depend on symbiotic interactions with specific soil fungi for seed germination and early development. Germinated seeds give rise to a protocorm, a heterotrophic organ that acquires nutrients, including organic carbon, from the mycorrhizal partner. It has long been debated if this interaction is mutualistic or antagonistic. To investigate the molecular bases of the orchid response to mycorrhizal invasion, we developed a symbiotic in vitro system between Serapias vomeracea, a Mediterranean green meadow orchid, and the rhizoctonia-like fungus Tulasnella calospora. 454 pyrosequencing was used to generate an inventory of plant and fungal genes expressed in mycorrhizal protocorms, and plant genes could be reliably identified with a customized bioinformatic pipeline. A small panel of plant genes was selected and expression was assessed by real-time quantitative PCR in mycorrhizal and non-mycorrhizal protocorm tissues. Among these genes were some markers of mutualistic (e.g. nodulins) as well as antagonistic (e.g. pathogenesis-related and wound/stress-induced) genes. None of the pathogenesis or wound/stress-related genes were significantly up-regulated in mycorrhizal tissues, suggesting that fungal colonization does not trigger strong plant defence responses. In addition, the highest expression fold change in mycorrhizal tissues was found for a nodulin-like gene similar to the plastocyanin domain containing ENOD55. Another nodulin-like gene significantly more expressed in the symbiotic tissues of mycorrhizal protocorms was similar to a sugar transporter of the SWEET family. Two genes coding for mannose-binding lectins were significantly up-regulated in the presence of the mycorrhizal fungus, but their role in the symbiosis is unclear. PMID- 24760408 TI - Predicting Discontinuation of Pegylated Interferon as a Result of Lack of Efficacy in United States Veterans With Chronic Hepatitis C on Dual Therapy. AB - BACKGROUND: Many patients with chronic hepatitis C virus (HCV) being treated with pegylated interferon (peg-IFN) plus ribavirin (RBV) do not respond to therapy and do not clear the virus. Standard of care during the era of dual therapy was to discontinue the patient's therapy based on insufficient decreases in viral load after 12 and/or 24 weeks on therapy. OBJECTIVES: We identified patient characteristics that were significant predictors of discontinuation as a result of lack of efficacy (LOE) in a national database of US veterans with genotypes 1 and 4. METHODS: We identified US veterans who received care at Veterans Affairs medical centers in 2004-2009 and who had lab-confirmed HCV diagnoses and initiated therapy with peg-IFN plus RBV. Patients who discontinued therapy early were classified as either LOE or non-LOE discontinuers based on pharmacy refill patterns and laboratory response data. Predictors of LOE discontinuation were identified using univariate and multivariable Cox proportional hazards modeling. RESULTS: Of 321 238 HCV patients with an ICD-9 diagnosis code, 31 215 (9.7%) initiated dual therapy with peg-IFN plus RBV, and 10 333 (3.2%) met all inclusion criteria and were included in the analysis. Overall, 13.6% of the cohort was classified as LOE. Significant predictors of LOE discontinuation included treatment for drug abuse (hazard ratio [HR] = 2.18), age >65 years (HR = 1.75), antiretroviral therapy for HIV (HR = 1.48), black race (HR = 1.47), platelet count >100/mm3 (HR = 1.46), and drug therapy for insomnia (HR = 1.40). CONCLUSIONS: We identified risk factors for discontinuation caused by LOE. Future work should focus on determining whether these characteristics are also predictive of triple-therapy LOE discontinuations. PMID- 24760410 TI - [Metacognitive Therapy in the Treatment of Depression.] AB - Metacognitive Therapy (MCT) developed by A. Wells is one of the new developments of Behavior Therapy. It assumes that not the content of cognition is important for the treatment of psychological disorders. Instead of this from a metacognitive perspective persistent and unflexible patterns of thinking and focusing attention and therewith associated dysfunctional coping behaviors play a crucial role for their development and maintenance. These patterns are called Cog nitive Attentional Syndrome (CAS). In depres-sion the CAS consists of excessive rumination and worry, focusing attention on potential danger (threat monitoring) and maladaptive coping strategies, e. g. avoidance of social contact or substance abuse. The reason for the use of these strategies is the existence of positive metacognitions which highlight its benefit for the patient (e. g. "Rumination helps me to find a solution for my problems!"). Over time however negative metacognitive beliefs develop about the uncontrollability and danger of these processes (e. g., "Rumination is uncontrollable!"). They account for the continued use of these strategies and of further coping behaviors that backfire. The aim of MCT is to improve the metacognitive awareness of the patients and to regain flexible control over processes of thinking and focusing attention. The CAS is reduced, the underlying metacognitive beliefs are changed and alternative plans of cognitive processing are generated. The existing data suggest that regarding treatment outcome MCT is possibly superior to Cognitive Behavior Therapy. PMID- 24760409 TI - Acute over-the-counter pharmacological intervention does not adversely affect behavioral outcome following diffuse traumatic brain injury in the mouse. AB - Following mild traumatic brain injury (TBI), patients may self-treat symptoms of concussion, including post-traumatic headache, taking over-the-counter (OTC) analgesics. Administering one dose of OTC analgesics immediately following experimental brain injury mimics the at-home treated population of concussed patients and may accelerate the understanding of the relationship between brain injury and OTC pharmacological intervention. In the current study, we investigate the effect of acute administration of OTC analgesics on neurological function and cortical cytokine levels after experimental diffuse TBI in the mouse. Adult, male C57BL/6 mice were injured using a midline fluid percussion (mFPI) injury model of concussion (6-10 min righting reflex time for brain-injured mice). Experimental groups included mFPI paired with either ibuprofen (60 mg/kg, i.p.; n = 16), acetaminophen (40 mg/kg, i.p.; n = 9), or vehicle (15% ethanol (v/v) in 0.9% saline; n = 13) and sham injury paired OTC medicine or vehicle (n = 7-10 per group). At 24 h after injury, functional outcome was assessed using the rotarod task and a modified neurological severity score. Following behavior assessment, cortical cytokine levels were measured by multiplex ELISA at 24 h post-injury. To evaluate efficacy on acute inflammation, cortical cytokine levels were measured also at 6 h post-injury. In the diffuse brain-injured mouse, immediate pharmacological intervention did not attenuate or exacerbate TBI-induced functional deficits. Cortical cytokine levels were affected by injury, time, or their interaction. However, levels were not affected by treatment at 6 or 24 h post-injury. These data indicate that acute administration of OTC analgesics did not exacerbate or attenuate brain-injury deficits which may inform clinical recommendations for the at-home treated mildly concussed patient. PMID- 24760411 TI - [Resilience and psychological impairment in adulthood: the impact of age and social inequality]. AB - In a cross-sectional study the influence of social inequality on resilience and psychological distress was investigated in a sample of N=4 142 adults. A social stratum was created, including education, financial income and job-status, as well as age (>= 25 years). Multivariate analysis of variance (MANOVA) showed influences of gender, social status and age on resilience (RS-11) and psychological distress: depression (PHQ-2), anxiety (GAD-7), life satisfaction (FLZ(M)). In contrast to the most continuous influence of the social background in women across any age-group, older males (>= 65 years) were not affected by their social background. In both sexes members of the social underclass had the lowest resilience. The results indicate the need for specific intervention as to prevention. PMID- 24760412 TI - [Premature termination of inpatient psychotherapy]. AB - This systematic review examines the frequency and possible causes of premature termination of psychotherapeutic treatments. The literature search focused on adult patients who drop-out of acute and rehabilitative inpatient psychosomatic care in Germany. The weighted average drop-out-rate of the 15 included studies was 12.5%. Young age, unemployment, inability to work, the diagnosis of an eating disorder, a somatoform disorder or a personality disorder and a low impairment at intake show a relation to a higher risk for a premature termination of the treatment. Beside these sociodemographic and clinical variables, the motivation for treatment as well as treatment expectations seem to play a role in the prediction of attrition. PMID- 24760413 TI - [Conceptions of "transcultural competence" and their relevance for the psychiatric-psychotherapeutic care. Results of an interdisciplinary literature review]. AB - The concept of transcultural competence is increasingly discussed in Germany as a requirement for providing adequate psychiatric-psychotherapeutic care for persons with a migration background. To this day, understanding of this concept is heterogeneous. This overview aims at systemizing existing definitions of transcultural competence in psychology, medicine and related fields to improve understanding of the term in practice. 130 German and English language scientific papers were analyzed and were evaluated qualitatively with grounded theory method. The analysis produced 3 approaches: a technological approach, a component approach and a positioning-and-attitude approach. The suggested categorization of the understandings of the term transcultural competence allows for a detailed overview of the current definitions of this term and thus provides criteria for a better evaluation of implemented transcultural competence in fields of psychiatric-psychotherapeutic care. PMID- 24760415 TI - ROS1 translocations and amplifications in lung cancer brain metastases. PMID- 24760414 TI - Application of diffusion-weighted magnetic resonance imaging to predict the intracranial metastatic tumor response to gamma knife radiosurgery. AB - To evaluate the effect of stereotactic radiosurgery (SRS) on intracranial metastases with diffusion-weighted imaging/apparent diffusion coefficient maps. A total of 107 patients with 144 metastases larger than 1 cm in diameter were retrospectively reviewed. We calculated the DWI(Tumor/white matter) ratios (DWI(T/WM) ratio) between the metastases and the normal, contralateral frontal white matter at each time point. We also recorded the ADC values for metastases (ADCT values). The DWI(T/WM) ratio and ADCT values were assessed for correlation with the patients' tumor response, brain edema, and survival. A decrease in DWI(T/WM) ratios was seen in the controlled metastases, and an increase in the DWI(T/WM) ratio were seen in the metastases with poor tumor control. On the other hand, an increase in ADCT values was seen in the controlled metastases, and a decrease in ADCT values was seen in the metastases with poor control. The differences were significant (p value: 0.001 and 0.002, respectively). Sensitivity of a decrease in the DWI(T/WM) ratio to make an early prediction of tumor control was 83.9%, and specificity was 88.5%. When using the initial ADCT values of metastases to predict tumor response, sensitivity and specificity were 85.5 and 72.7%, respectively. DWI/ADC is a practical method for studying the efficacy of SRS and predicting early metastases response progression. A decrease signal on DWI and increased ADC values are indicators of good tumor control, and reflect the beneficial effect of SRS. PMID- 24760416 TI - Vasculature of the hive: heat dissipation in the honey bee (Apis mellifera) hive. AB - Eusocial insects are distinguished by their elaborate cooperative behavior and are sometimes defined as superorganisms. As a nest-bound superorganism, individuals work together to maintain favorable nest conditions. Residing in temperate environments, honey bees (Apis mellifera) work especially hard to maintain brood comb temperature between 32 and 36 degrees C. Heat shielding is a social homeostatic mechanism employed to combat local heat stress. Workers press the ventral side of their bodies against heated surfaces, absorb heat, and thus protect developing brood. While the absorption of heat has been characterized, the dissipation of absorbed heat has not. Our study characterized both how effectively worker bees absorb heat during heat shielding, and where worker bees dissipate absorbed heat. Hives were experimentally heated for 15 min during which internal temperatures and heat shielder counts were taken. Once the heat source was removed, hives were photographed with a thermal imaging camera for 15 min. Thermal images allowed for spatial tracking of heat flow as cooling occurred. Data indicate that honey bee workers collectively minimize heat gain during heating and accelerate heat loss during cooling. Thermal images show that heated areas temporarily increase in size in all directions and then rapidly decrease to safe levels (<37 degrees C). As such, heat shielding is reminiscent of bioheat removal via the cardiovascular system of mammals. PMID- 24760417 TI - Mouse pharmacokinetics and metabolism of the curcumin analog, 4-piperidinone,3,5 bis[(2-fluorophenyl)methylene]-acetate(3E,5E) (EF-24; NSC 716993). AB - PURPOSE: Curcumin, a keto-enol constituent of turmeric, has in vitro and in vivo antitumor activity. However, in vivo potency is low due to poor oral absorption. The mono-carbonyl analog, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone acetate (EF-24, NSC 716993), exhibited broad-spectrum activity in the NCI anticancer cell line screen and potent antiangiogenesis activity in a HUVEC cell migration assay. The purpose of this study was to characterize the preclinical pharmacology of EF-24 in mice. METHODS: EF-24 plasma stability, protein binding, pharmacokinetics, and metabolism were characterized utilizing an LC/MS/MS assay. RESULTS: An LC/MS/MS assay incorporated protein precipitation with methanol, reverse-phase HPLC separation under gradient elution using an aqueous methanol mobile phase containing 0.1 % formic acid, and positive electrospray ionization detection of the m/z 312 > 149 transition for EF-24. The assay was linear over the range 7.8-1,000 nM. Plasma protein binding was >98 % with preferential binding to albumin. EF-24 plasma disposition in mice after i.v. administration of a 10 mg/kg dose was best fit to a 3-compartment open model. The terminal elimination half-life and plasma clearance values were 73.6 min and 0.482 L/min/kg, respectively. EF-24 bioavailability was 60 and 35 % after oral and i.p. administration, respectively. NADPH-dependent metabolism of EF-24 loss in liver microsomal preparations yielded several metabolites consistent with EF-24 hydroxylation and reduction. PMID- 24760418 TI - Nanoporous TiO2 nanoparticle assemblies with mesoscale morphologies: nano-cabbage versus sea-anemone. AB - We report the novel synthesis of nanoporous TiO2 nanoparticle ensembles with unique mesoscale morphologies. Constituent nanoparticles evolved into multifaceted assemblies, exhibiting excellent crystallinity and enhanced photocatalytic activity compared with commercial TiO2. Such materials could be exploited for applications, like organic pollutant degradation. PMID- 24760419 TI - Robot-assisted level II-IV neck dissection through a modified facelift incision: initial North American experience. AB - BACKGROUND: Cosmesis is of increasing importance to the otolaryngology patient population. This is the first report of clinical outcomes of robot-assisted neck dissection by North American groups. METHODS: This is a retrospective case control study. Cases included three patients who underwent isolated, ipsilateral robot-assisted neck dissection. Operative time, estimated blood loss, lymph node retrieval, total drainage, hospital stay and complications from this group were compared against the outcomes of six consecutive patients who underwent conventional neck dissection. RESULTS: Operative times were longer in robot assisted neck dissection (mean 234 min) compared with the conventional neck dissection (mean 110 min). There were no significant differences between the two groups in other outcomes. CONCLUSIONS: Robot-assisted selective neck dissection of levels II-IV is feasible through a modified facelift incision. Our initial data suggest that this procedure is surgically sound. It should be applied by experienced surgeons who wish to avoid a cervical incision. PMID- 24760421 TI - pH-Dependent accumulation of anticancer compound on mycelia in fermentation of marine fungus. AB - The real-time distribution of anticancer 1403C in fermentation broth of marine fungus Halorosellinia sp. was investigated. It was closely related with pH variations, which was, 1403C in the supernatant decreased while that in the mycelia increased with pH rising. There was only 0.5 % of the total 1403C left in the supernatant when pH reached 7.0. The scanning electron microscope then provided information that compounds precipitated on the mycelia when pH rose. Then, the pH-regulation experiments proved that 1403C mainly secreted extracellular and easily dissolved in acidic condition but precipitated and absorbed on the mycelia with the increase of broth pH. Thereby, a pH-regulation strategy was proposed and applied to accumulate 1403C on the mycelia before draw off of fermentation broth. It significantly simplified purification process and is critical for 1403C preparation of industrial scale. PMID- 24760423 TI - Approval of high-risk medical devices in the US: implications for clinical cardiology. AB - Since 1976, the US Food and Drug Administration (FDA) has used the premarket approval (PMA) process to approve high-risk medical devices, including implantable cardioverter defibrillators (ICDs), coronary stents, and artificial heart valves. The PMA process is widely viewed as a rigorous evaluation of device safety and effectiveness, though recent recalls-most notably related to underperforming ICD leads-have raised concerns about whether physicians and patients should sometimes be more wary about devices approved via this pathway. The FDA must utilize a "least burdensome" approach to approve new medical devices, and many widely used device models have been approved as supplements to existing PMA-approved devices with limited clinical testing. A recent Supreme Court ruling has made it difficult for patients harmed by unsafe PMA-approved devices to seek damages in court. Cardiologists who utilize high-risk medical devices should be aware that FDA approval of new devices relies on variable levels of evidence and does not necessarily indicate improved effectiveness over existing models. Clinician and patient engagement in postmarket surveillance and comparative effectiveness research remains imperative. PMID- 24760422 TI - No causal association identified for human papillomavirus infections in lung cancer. AB - Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer. PMID- 24760424 TI - Pathophysiology, prevention, and treatment of commotio cordis. AB - Commotio cordis is increasing described and it is now clear that this phenomenon is an important cause of sudden cardiac death on the playing field. Victims are predominantly young, male, and struck in the left chest with a ball. An animal model has been developed and utilized to explore the important variables and mechanism of commotio cordis. Impact during a narrow window of repolarization causes ventricular fibrillation. Other important variables include location, velocity, shape, and hardness of the impact object. Biological characteristics such as gender, pliability of the chest wall, and genetic susceptibility also play a role in commotio cordis. The mechanism of ventricular fibrillation appears to be an increase in heterogeneity of repolarization caused by induced abnormalities of ion channels activated by abrupt increases in left ventricular pressure. In the setting of altered repolarization a trigger of ventricular depolarization (premature ventricular depolarization caused directly by the chest blow) initiates a spiral wave that quickly breaks down into ventricular fibrillation. Prevention of commotio cordis is possible. Improved recognition and resuscitation have led to an improvement in outcome. PMID- 24760426 TI - From modeling to measurement: developmental trends in genetic influence on adiposity in childhood. AB - OBJECTIVE: Evidence of increasing heritability of BMI over childhood can seem paradoxical given longer exposure to environmental influences. Genomic data were used to provide direct evidence of developmental increases in genetic influence. METHODS: BMI standard deviation scores (BMI-SDS) at ages 4 and 10 were calculated for 2,556 twin pairs in the Twins Early Development Study. Twin analyses estimated heritability of BMI-SDS at each age and the longitudinal genetic correlation. One randomly selected twin per pair was genotyped. Genome-wide complex trait analysis (GCTA) determined DNA-based heritability at each age and the longitudinal genomic correlation. Associations with a polygenic obesity risk score (PRS) using 28 obesity-related single nucleotide polymorphisms (SNPs) were assessed at each age, with bootstrapping to test the significance of the increase in variance explained. RESULTS: Twin-estimated heritability increased from age 4 (0.43; 95% CI: 0.35-0.53) to 10 (0.82; 0.74-0.88). GCTA-estimated heritability went from non-significant at 4 (0.20; -0.21 to 0.61) to significant at 10 (0.29; 0.01-0.57). Longitudinal genetic correlations derived from twins (0.58) and GCTA (0.66) were similar. The same PRS explained more variance at 10 than 4 years (R(2) Delta:0.024; 0.002-0.078). CONCLUSIONS: GCTA and PRS findings confirm twin based results suggesting increasing genetic influence on adiposity during childhood despite substantial genetic stability. PMID- 24760425 TI - Regulation of hematopoiesis in endosteal microenvironments. AB - After birth, the hematopoietic system develops along with bone formation in mammals. Osteolineage cells are derived from mesenchymal progenitor cells, and differentiate into several types of bone-forming cells. Of the various types of cell constituents in bone marrow, osteolineage cells have been shown to play important roles in hematopoiesis. Early studies have identified osteoblasts as a hematopoietic stem cell niche component. Since that time, the role of endosteal microenvironment as a critical regulator of hematopoietic stem/progenitor cell (HSC/HPC) behavior has been appreciated particularly under stress conditions, such as cytokine-induced HSC/HPC mobilization, homing/engraftment after bone marrow transplantation, and disease models of leukemia/myelodysplasia. Recent studies revealed that the most differentiated osteolineage cells, i.e., osteocytes, play important roles in the regulation of hematopoiesis. In this review, we provide an overview of recent advances in knowledge of regulatory hematopoietic mechanisms in the endosteal area. PMID- 24760427 TI - CT coronary angiography versus conventional invasive coronary angiography - the view of the referring physician. AB - PURPOSE: Assessment of experience gained by local referring physicians with the procedure of coronary computed tomographic angiography (CCTA) in the everyday clinical routine. MATERIALS AND METHODS: A 25-item questionnaire was sent to 179 physicians, who together had referred a total of 1986 patients for CCTA. They were asked about their experience to date with CCTA, the indications for coronary imaging, and their practice in referring patients for noninvasive CCTA or invasive catheter angiography. RESULTS: 53 questionnaires (30 %) were assessable, corresponding to more than 72 % of the patients referred. Of the referring physicians who responded, 94 % saw a concrete advantage of CCTA in the treatment of patients, whereby 87 % were 'satisfied' or 'very satisfied' with the reporting. For excluding coronary heart disease (CHD) where there was a low pre test probability of disease, the physicians considered CCTA to be superior to conventional coronary diagnosis (4.2 on a scale of 1 - 5) and vice versa for acute coronary syndrome (1.6 of 5). The main reasons for unsuitability of CCTA for CT diagnosis were claustrophobia and the absence of a sinus rhythm. The level of exposure to radiation in CCTA was estimated correctly by only 42 % of the referring physicians. 90 % of the physicians reported that their patients evaluated their coronary CT overall as 'positive' or 'neutral', while 87 % of the physicians whose patients had undergone both procedures reported that the patients had experienced CCTA as the less disagreeable of the two. CONCLUSION: CCTA is accepted by the referring physicians as an alternative imaging procedure for the exclusion of CHD and received a predominantly positive assessment from both the referring physicians and the patients. PMID- 24760428 TI - Imaging of appendicitis in adults. AB - Three imaging modalities are available for the diagnosis of acute appendicitis: ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI). Transabdominal ultrasound should be the first-line imaging test. Abdominal CT is superior to US and is required immediately in patients with atypical clinical presentation of appendicitis and suspected perforation. However, low-dose unenhanced CT is equal to standard-dose CT with intravenous contrast agents in the detection of five signs of acute appendicitis (thickened appendiceal wall more than 2 mm, cross-sectional diameter greater than 6 mm, periappendicitis, abscess, and appendicolith). MRI is necessary in pregnant women and young adults. This review illustrates the principles of state-of-the-art imaging techniques and their clinical relevance. KEY POINTS: * US is the basic diagnostic method in case of suspected appendicitis.* CT is necessary in patients with atypical presentation of appendicitis.* MRI should be the first-line imaging test in pregnant women. PMID- 24760429 TI - Serum S100beta is a better biomarker than neuron-specific enolase for sepsis associated encephalopathy and determining its prognosis: a prospective and observational study. AB - S100beta and neuron-specific enolase (NSE) are brain injury biomarkers, mainly used in brain trauma, cerebral stroke and hypoxic ischemia encephalopathy. The aim of this study was to study the clinical significance of serum S100beta and NSE in diagnosing sepsis-associated encephalopathy (SAE) and predicting its prognosis. This was a prospective and observational study. Clinical data of septic patients were collected within 24 h after ICU admission from May 2012 to April 2013. We evaluated the level of consciousness twice per day. SAE was defined as cerebral dysfunction in the presence of sepsis that fulfilled the exclusion criteria. The infection biochemical indicators, Glasgow coma scale (GCS) score, acute physiology and chronic health evaluation score II, serum NSE and S100beta were newly measured or evaluated for SAE patients. Finally, hospital mortality, bacteriological categories, length of ICU stay and length of hospital stay were also recorded for all enrolled patients. The data was analyzed with the Chi square test, two-sample t test or Mann-Whitney U test between two groups. The correlation between two factors was analyzed using the Pearson or Spearman analysis. Receiver operating characteristic (ROC) curves were used to determine the ability of S100beta and NSE in diagnosing SAE and predicting the hospital mortality. In addition, cut-off points were obtained from the curves to determine the highest sum of sensitivity and specificity. Of 112 enrolled patients, 48 patients were diagnosed with SAE. The serum S100beta and NSE concentrations in SAE patients were both significantly higher than in non-SAE patients 0.306 (IQR 0.157-0.880) MUg/L vs. 0.095 (IQR 0.066-0.177) MUg/L, 24.87 (IQR 31.73-12.73) ng/mL vs. 15.49 (IQR 9.88-21.46) ng/mL, P < 0.01]. GCS scores were related more closely to S100beta than NSE (-0.595 vs. -0.337). S100beta levels of 0.131 MUg/L diagnosed SAE with 67.2% specificity and 85.4% sensitivity in the ROC curve, the area under the curve was 0.824 (95% confidence interval 0.750-0.898). NSE levels of 24.15 ng/mL diagnosed SAE with 82.8% specificity and 54.2% sensitivity, and the area under the curve was 0.664 (95 % confidence interval 0.561-0.767). In addition, the area under the curve for S100beta for predicting hospital mortality was larger than for NSE (0.730 vs. 0.590). Serum S100beta concentrations in SAE patients were significantly higher than in non-SAE patients. These may be related to the severity of SAE and may predict the outcome of sepsis. The efficacy and sensitivity of serum S100beta in diagnosing SAE were high, but it had a low specificity. Moreover, compared to NSE, serum S100beta was better for both diagnosing SAE and predicting the outcome of sepsis. PMID- 24760430 TI - Anti-inflammatory effect of tanshinone I in neuroprotection against cerebral ischemia-reperfusion injury in the gerbil hippocampus. AB - Tanshinone I (TsI) is an important lipophilic diterpene extracted from Danshen (Radix Salvia miltiorrhizae) and has been used in Asia for the treatment of cerebrovascular diseases such as ischemic stroke. In this study, we examined the neuroprotective effect of TsI against ischemic damage and its neuroprotective mechanism in the gerbil hippocampal CA1 region (CA1) induced by 5 min of transient global cerebral ischemia. Pre-treatment with TsI protected pyramidal neurons from ischemic damage in the stratum pyramidale (SP) of the CA1 after ischemia-reperfusion. The pre-treatment with TsI increased the immunoreactivities and protein levels of anti-inflammatory cytokines [interleukin (IL)-4 and IL-13] in the TsI-treated-sham-operated-groups compared with those in the vehicle treated-sham-operated-groups; however, the treatment did not increase the immunoreactivities and protein levels of pro-inflammatory cytokines (IL-2 and tumor necrosis factor-alpha). On the other hand, in the TsI-treated-ischemia operated-groups, the immunoreactivities and protein levels of all the cytokines were maintained in the SP of the CA1 after transient cerebral ischemia. In addition, we examined that IL-4 injection into the lateral ventricle did not protect pyramidal neurons from ischemic damage. In conclusion, these findings indicate that the pre-treatment with TsI can protect against ischemia-induced neuronal death in the CA1 via the increase or maintenance of endogenous inflammatory cytokines, and exogenous IL-4 does not protect against ischemic damage. PMID- 24760431 TI - An analytical framework in the general coalescent tree setting for analyzing polymorphisms created by two mutations. AB - This paper presents an analytical framework for analyzing polymorphisms created by two mutation events in samples of DNA sequences modeled in the general coalescent tree setting. I developed the framework by deriving analytical formulas for the numbers of the topologies of the genealogies with two mutation events. This approach gives an advantage to analyze polymorphisms in large samples of DNA sequences at a non-recombining locus under vicarious evolutionary scenarios. Particularly the framework allows to estimate the probability of polymorphism data created by two mutation events as well as the ages of the events. Based on these results I extended the definition of the site frequency spectrum by classifying pairs of polymorphic sites into groups and presented analytical expressions for computing the expected sizes of these groups. Within the framework I also designed a Bayesian approach for inferring the haplotype of the most recent common ancestor at two polymorphic sites. Lastly, the framework was applied to polymorphism data from human APOE gene region under various demographic scenarios for ancestral human population and explored the signature of linkage disequilibrium for inferring the ancestral haplotype at two polymorphic sites. Interestingly enough, the results show that the most frequent haplotype at two completely linked polymorphic sites is not always the most likely candidate for the haplotype of the most recent common ancestor. PMID- 24760432 TI - Anatomical nomenclature and the use of eponyms. PMID- 24760433 TI - Assessing Patients' Preference for Integrating Herbal Medicine Within Primary Care Services in Saudi Arabia. AB - BACKGROUND: Family physician advice and follow-up may be important to reduce the negative aspects of locally marketed herbal remedies and improve the patient outcome. There is a lack of studies assessing the preference of Saudi patients for the integration of herbal medicine into primary care services. OBJECTIVES: To examine the knowledge, attitudes, and practice of Saudi patients toward herbal medicine and its integration into primary care services. METHODS: A cross sectional study was conducted between February and March 2013 among adult patients attending the family medicine clinics at a primary care center in Riyadh, Saudi Arabia. A self-administered questionnaire (27 items) was developed and administered to all patients. RESULTS: A total of 240 patients were included in the current analysis. The average age was 33.5 +/- 9.9 years, and 61% of the patients were women. Approximately 60% of the patients were aware of herbal medicine use and its possible side effects. More than 85% of the patients believed that herbal containers should be labeled with safety information. Approximately 71% of the patients had a favorable attitude toward integrated services. Approximately 65% of the patients used herbal remedies for themselves, and 42% used them for their children. Preference for integrated services was significantly associated with female sex, better knowledge, positive attitudes toward safety and regulations, and higher level of practice. CONCLUSIONS: A good knowledge and a very favorable attitude toward integrating herbal medicine into primary care services were found among a group of patients attending a primary care center in Saudi Arabia. PMID- 24760438 TI - Impact-insertion applicator improves reliability of skin penetration by solid microneedle arrays. PMID- 24760436 TI - Misuse and abuse of pregabalin and gabapentin: cause for concern? AB - Gabapentinoids (e.g. pregabalin and gabapentin) are widely used in neurology, psychiatry and primary healthcare but are increasingly being reported as possessing a potential for misuse. In fact, increasing levels of both prescriptions and related fatalities, together with an anecdotally growing black market, have been reported from a range of countries. This article reviews the current evidence base of this potential, in an attempt to answer the question of whether there is cause for concern about these drugs. Potent binding of pregabalin/gabapentin at the calcium channel results in a reduction in the release of excitatory molecules. Furthermore, gabapentinoids are thought to possess GABA-mimetic properties whilst possibly presenting with direct/indirect effects on the dopaminergic 'reward' system. Overall, pregabalin is characterized by higher potency, quicker absorption rates and greater bioavailability levels than gabapentin. Although at therapeutic dosages gabapentinoids may present with low addictive liability levels, misusers' perceptions for these molecules to constitute a valid substitute for most common illicit drugs may be a reason of concern. Gabapentinoid experimenters are profiled here as individuals with a history of recreational polydrug misuse, who self-administer with dosages clearly in excess (e.g. up to 3-20 times) of those that are clinically advisable. Physicians considering prescribing gabapentinoids for neurological/psychiatric disorders should carefully evaluate a possible previous history of drug abuse, whilst being able to promptly identify signs of pregabalin/gabapentin misuse and provide possible assistance in tapering off the medication. PMID- 24760437 TI - Anti-HIV drug development through computational methods. AB - Although highly active antiretroviral therapy (HAART) is effective in controlling the progression of AIDS, the emergence of drug-resistant strains increases the difficulty of successful treatment of patients with HIV infection. Increasing numbers of patients are facing the dilemma that comes with the running out of drug combinations for HAART. Computational methods play a key role in anti-HIV drug development. A substantial number of studies have been performed in anti-HIV drug development using various computational methods, such as virtual screening, QSAR, molecular docking, and homology modeling, etc. In this review, we summarize recent advances in the application of computational methods to anti-HIV drug development for five key targets as follows: reverse transcriptase, protease, integrase, CCR5, and CXCR4. We hope that this review will stimulate researchers from multiple disciplines to consider computational methods in the anti-HIV drug development process. PMID- 24760439 TI - Biliopancreatic diversion with duodenal switch improves insulin sensitivity and secretion through caloric restriction. AB - OBJECTIVE: To assess the rapid improvement of insulin sensitivity and beta-cell function following biliopancreatic diversion with duodenal switch (BPD-DS) and determine the role played by caloric restriction in these changes. METHODS: Standard meals were administrated before and on day 3, 4, and 5 after BPD-DS to measure total caloric intake, glucose excursion, insulin sensitivity, and secretion in matched type 2 diabetes and normoglycemic (NG) subjects. In a second set of study, other subjects with type 2 diabetes had the same meal tests prior to and after a 3-day caloric restriction identical to that observed after BPD-DS and then 3 days after actually undergoing BPD-DS. RESULTS: Improvement of HOMA-IR occurred at day 3 after BPD-DS in diabetes and after 3 days of caloric restriction. The disposition index (DI) improved rapidly in diabetes after BPD-DS and to a similar extent after caloric restriction. DI was higher and did not change after BPD-DS in NG. Changes in glucagon-like peptide-1, gastric inhibitory peptide, peptide tyrosine tyrosine, ghrelin, and pancreatic polypeptide levels were not associated with modulation of DI in the participants. CONCLUSIONS: Caloric restriction is the major mechanism underlying the early improvement of insulin sensitivity and beta-cell function after BPD-DS in type 2 diabetes. PMID- 24760440 TI - Calculated reciprocity? A comparative test with six primate species. AB - Little evidence of calculated reciprocity has been found in non-human primates so far. In this study, we used a simple experimental set-up to test whether partners pulled a sliding table to altruistically provide food to each other in short-term interactions. We tested 46 dyads of chimpanzees, bonobos, gorillas, orangutans, brown capuchin monkeys and spider monkeys to examine whether a subject's tendency to provide food to a partner was directly affected by the partner's previous behaviour, by the species, by the condition (i.e., whether the partner could access the food provided by the subject) and by the social tolerance levels within each dyad. Chimpanzees and orangutans were the only species pulling significantly more when the partner could retrieve the food altruistically provided. However, no species reciprocated food exchanges, as subjects' probability to pull was not affected by the previous number of the partner's pulls, with the possible exception of one orangutan dyad. Although subjects clearly knew how the apparatus worked and easily obtained food for themselves, individuals did not usually take the opportunity to provide food to their partners, suggesting that calculated reciprocity is not a common behaviour and that food exchanges are usually not reciprocated in the short-term within dyads. PMID- 24760442 TI - New components of the renin-angiotensin system: alamandine and the MAS-related G protein-coupled receptor D. AB - The renin-angiotensin system is an important component of the central and humoral mechanisms of blood pressure and hydro-electrolytic balance control. Angiotensin II is a key player of this system. Twenty-five years ago the first manuscripts describing the formation and actions of another peptide of the RAS, angiotensin (1-7), were published. Since then several publications have shown that angiotensin-(1-7) is as pleiotropic as angiotensin II, influencing the functions of many organs and systems. The identification of the ACE homologue ACE2 and, a few years later, Mas, as a receptor for angiotensin-(1-7) contributed a great deal to establish this peptide as a key player of the RAS. Most of the actions of angiotensin-(1-7) are opposite to those described for angiotensin II. This has led to the concept of two arms of the RAS: one comprising ACE/AngII/AT1R and the other ACE2/Ang-(1-7)/Mas. More recently, we have described the identification of a novel component of the RAS, alamandine, which binds to the Mas-related G protein coupled receptor D. This peptide is formed by decarboxylation of the Asp residue of angiotensin-(1-7), leading to the formation of Ala as the N-terminal amino acid. Alternatively, it can be formed by hydrolysis of Ang A, by ACE2. Its effects include vasorelaxation, central effects similar to those produced by angiotensin-(1-7), blunting of isoproterenol-induced heart fibrosis, and anti hypertensive action in SHR. The putative enzyme responsible for alamandine formation from angiotensin-(1-7) is under investigation. The identification of this novel component of the RAS opens new venues for understanding its physiological role and opens new putative therapeutic possibilities for treating cardiovascular diseases. PMID- 24760441 TI - Angiotensin II and vascular injury. AB - Vascular injury, characterized by endothelial dysfunction, structural remodelling, inflammation and fibrosis, plays an important role in cardiovascular diseases. Cellular processes underlying this include altered vascular smooth muscle cell (VSMC) growth/apoptosis, fibrosis, increased contractility and vascular calcification. Associated with these events is VSMC differentiation and phenotypic switching from a contractile to a proliferative/secretory phenotype. Inflammation, associated with macrophage infiltration and increased expression of redox-sensitive pro-inflammatory genes, also contributes to vascular remodelling. Among the many factors involved in vascular injury is Ang II. Ang II, previously thought to be the sole biologically active downstream peptide of the renin angiotensin system (RAS), is converted to smaller peptides, [Ang III, Ang IV, Ang (1-7)], that are functional and that modulate vascular tone and structure. The actions of Ang II are mediated via signalling pathways activated upon binding to AT1R and AT2R. AT1R activation induces effects through PLC-IP3-DAG, MAP kinases, tyrosine kinases, tyrosine phosphatases and RhoA/Rho kinase. Ang II elicits many of its (patho)physiological actions by stimulating reactive oxygen species (ROS) generation through activation of vascular NAD(P)H oxidase (Nox). ROS in turn influence redox-sensitive signalling molecules. Here we discuss the role of Ang II in vascular injury, focusing on molecular mechanisms and cellular processes. Implications in vascular remodelling, inflammation, calcification and atherosclerosis are highlighted. PMID- 24760444 TI - Locoregional therapies for metastatic colorectal carcinoma to the liver--an evidence-based review. AB - The liver is the most common visceral site of colorectal cancer metastasis and recurrence. Given that only 25% of patients with colorectal liver metastases are amenable to curative surgical resection at initial diagnosis, locoregional intra arterial therapies including hepatic arterial infusion chemotherapy, conventional transarterial chemoembolization, drug-eluting-bead transarterial chemoembolization, and radioembolization have increasingly developed as viable treatment options. The rationale, efficacy, safety, and toxicity of each of these therapies are reviewed and stratified based on current evidence. PMID- 24760443 TI - Fructose and uric acid: is there a role in endothelial function? AB - Population level data support that consumption of fructose and fructose-based sweeteners has dramatically increased and suggest that high dietary intake of fructose is an important factor in the development of the cardiorenal metabolic syndrome (CRS). The CRS is a constellation of cardiac, kidney and metabolic disorders including insulin resistance, obesity, metabolic dyslipidemia, high blood pressure, and evidence of early cardiac and kidney disease. The consequences of fructose metabolism may result in intracellular ATP depletion, increased uric acid production, oxidative stress, inflammation, and increased lipogenesis, which are associated with endothelial dysfunction. Endothelial dysfunction is an early manifestation of vascular disease and a driver for the development of CRS. A better understanding of fructose overconsumption in the development of CRS may provide new insights into pathogenesis and future therapeutic strategies. PMID- 24760445 TI - Identification of thyroid-receptor antagonists in water from the Guanting Reservoir, Beijing, China. AB - Thyroid hormone (TH) has long been known to be essential for normal brain development in both humans and animals, and increasing evidence suggests that environmental components may disrupt TH signaling. In the present study, two hybrid yeast bioassay and chemical analysis were used to evaluate and identify thyroid-receptor (TR) disruptors in water from the Guanting Reservoir, Beijing, China. Modified yeast bioassay showed that the water samples could affect TH signaling. The bioassay-derived amiodarone hydrochloride equivalents ranged from 33.8 +/- 3.3 to 308.5 +/- 31.8 ug/L. Solid-phase extraction was used to separate the organic extracts, which were subjected to bioassay and chemical analysis. The organic extracts significantly antagonized the TR, which accounted for >86.0 % of the total effects. Thus, organic extracts may play a major role in the TR disruption activity of the water. Phenols, organochlorine pesticides, and phthalate esters were detected in the organic extracts. Chemical analysis and toxic-equivalent calculation showed that a major cause of the TR antagonism of the water was dibutyl phthalate (80.1 to 122.7 %). PMID- 24760446 TI - Effects of Ce(III) and CeO2 nanoparticles on soil-denitrification kinetics. AB - Cerium (Ce)-based compounds, such as CeO2 nanoparticles (NPs), have received much attention in the last several years due to their popular applications in industrial and commercial uses. Understanding the impact of CeO2 NPs on nutrient cycles, a subchronic toxicity study of CeO2 NPs on soil-denitrification process was performed as a function of particle size (33 and 78 nm), total Ce concentration (50-500 mg L(-1)), and speciation [Ce(IV) vs. Ce(III)]. The antimicrobial effect on the soil-denitrification process was evaluated in both steady-state and zero-order kinetic models to assess particle- and chemical species specific toxicity. It was found that soluble Ce(III) was far more toxic than Ce(IV)O2 NPs when an equal total concentration of Ce was evaluated. Particle size-dependent toxicity, species-dependent toxicity, and concentration-dependent toxicity were all observed in this study for both the steady-state and the kinetic evaluations. Changes in physicochemical properties of Ce(IV)O2 NPs might be important in assessing the environmental fate and toxicity of NPs in aquatic and terrestrial environments. PMID- 24760447 TI - Predictive value of cardiovascular parameters in stages 1 and 2 of twin-to-twin transfusion syndrome. AB - OBJECTIVE: The Quintero staging of twin-to-twin transfusion syndrome (TTTS) does not include a comprehensive cardiovascular assessment. The aim of this study is to assess the predictive value of the myocardial performance index (MPI) and the Children's Hospital of Philadelphia (CHOP) score on recipient survival in Quintero stages 1 and 2 TTTS. METHODS: The cohort study was based on prospectively collected data between May 2008 and February 2013 in a population of stages 1 and 2 TTTS. Comparisons between groups were carried out using Student's t-test and chi(2)-test. A stepwise ascending multivariate logistic regression model was then built. RESULTS: A total of 73 pregnancies in stages 1 and 2 of Quintero's classification were treated with laser. Rates of recipient fetal losses were higher when MPI was above 0.43 ms (71.4% vs 28.6%, p = 0.022). Rate of CHOP score above 5 was higher in the fetal loss group (28.6% vs 5.1%, p = 0.022). After adjustment for Quintero stages 1 or 2, the risk of recipient loss rate is higher according to CHOP score [OR 7.6; 95% confidence interval (CI) 1.3 43.5] or MPI value (OR 3.7; 95% CI 1.0-13.9). CONCLUSION: The CHOP score and MPI are correlated with the recipient survival in stages 1 and 2 TTTS. PMID- 24760448 TI - Development of thermostable lyophilized inactivated polio vaccine. AB - PURPOSE: The aim of current study was to develop a dried inactivated polio vaccine (IPV) formulation with minimal loss during the drying process and improved stability when compared with the conventional liquid IPV. METHODS: Extensive excipient screening was combined with the use of a Design of Experiment (DoE) approach in order to achieve optimal results with high probability. RESULTS: Although it was shown earlier that the lyophilization of a trivalent IPV while conserving its antigenicity is challenging, we were able to develop a formulation that showed minimal loss of potency during drying and subsequent storage at higher temperatures. CONCLUSION: This study showed the potential of a highly stable and safe lyophilized polio vaccine, which might be used in developing countries without the need of a cold-chain. PMID- 24760449 TI - Isothermal microcalorimetry of pressurized systems I: a rapid method to evaluate pressurized metered dose inhaler formulations. AB - PURPOSE: The techniques available to study formulation stability in pressurized metered dose inhalers (pMDIs) are limited, due to the challenging conditions of working with high pressure propellants. Isothermal microcalorimetry is a valuable tool used to screen and aid in formulation development of solid and solution drug formulations; however there are currently no available methods to evaluate pMDIs. In this paper, we have developed a method that allows measurement of such pressurized systems. METHODS: Samples were prepared by cold filling ampoules with propellant (HFA 134a) and drugs of interest. Ampoule caps were fitted with a specific O-ring, coated with paraffin and pre-conditioned prior to measurement. Samples were equilibrated at 25 degrees C, placed in a Thermal Activity Monitor III (TAM III) system and measured isothermally at 25 degrees C for a period of at least 24 h. RESULTS: Using well-defined procedures and ampoule preparation techniques we were able to safely contain the volatile propellant and acquire a stable measurement baseline. We were able to rapidly determine, within 6 h, the physical stability of amorphous and crystalline drug forms of beclomethasone dipropionate and formoterol fumarate dihydrate when formulated with HFA 134a. CONCLUSIONS: Isothermal microcalorimetry in pressurized HFA propellant systems was shown to be a rapid screening tool to evaluate pMDI formulation physical stability. This method can potentially be applied to study pMDI formulation factors to expedite product development. PMID- 24760450 TI - [Total hip arthroplasty with a less invasive anterolateral approach]. AB - Soft tissue injury in total hip replacements has recently developed into a main topic of orthopaedic surgery. The M. glutaeus medius is at risk to be injured in Watson-Jones' approach to the hip. A special technique in positioning of the leg offers the possibility to save the integrity of the muscles. While profiling the femur shaft the leg is held underneath the opposite leg in outer rotation, hyperextention and forced adduction. The advantage in comparison to other less invasive techniques is the common supine position of the patient on the table. The different technical steps are easy to achieve. PMID- 24760451 TI - [Editorial for the Journal of Orthopaedics and Traumatology]. PMID- 24760452 TI - [Significance of Minimally Invasive Approaches during Primary Hip Arthroplasty - an Update]. AB - INTRODUCTION: Minimally invasive approaches to the hip joint during primary endoprosthetics have been for many years the focus of controversial discussion. Minimally invasive approaches offer soft tissue protecting implantations clear advantages regarding early postoperative functional results and reduced intraoperative blood loss. METHOD: On the basis of comprising literary research the available primary and secondary literature is evaluated - the advantages and disadvantages of minimally invasive approaches at the hip joint are discussed in relation to traditional approaches. RESULTS: The available primary and secondary literature verifies that the advantages of minimally invasive approaches at the hip joint include functional outcome in the early postoperative phase. In comparison to standard approaches there are no differences in the functional outcome after 12 months follow-up. Additionally, reduced length of operation, reduced blood loss and shorter stationary stay are confirmed. Studies relating to degrees of evidence I and II, which concern the medium- and long-term results of minimally invasive approaches in comparison to the established standard approaches, are not available. The available systematic reviews and meta-analyses merely allow a global evaluation of the primary literature on minimally invasive approaches, without thereby differentiating between the established standard approaches and the modified pendant according to minimally invasive criteria. There is a lack of knowledge with regard to in-vivo imaging data (MRI) as a potential evidence for reduction of muscular trauma by using minimally invasive approaches. CONCLUSION: Presently, the available literature does not allow definitive assessment regarding the significance of minimally invasive approaches at the hip joint. Future, random-controlled studies are necessary in order to compare the reliable (long-term) results of the established standard approaches with the hip approaches according to minimally invasive criteria. As long as sufficient long-term results regarding the complication and revision rates of minimally invasive approaches are not available, the method cannot be recommended as "gold standard." PMID- 24760454 TI - [Use of Bone Morphogenetic Proteins (BMPs) for the Treatment of Pseudarthroses - Efficiency and Therapy Failure]. AB - In the therapy for pseudarthroses of the proximal tibia, the human recombinant bone morphogenetic proteins (BMP-2 and BMP-7) have been used for several years. Despite their limited and specified use as local mediators of bone healing, no conclusions regarding the therapeutic success can be made beforehand. The regulatory mechanisms have turned out to be much more complex and patient specific than had been assumed before. To help understand the cell biological processes (signalling) and the current possibilities of predicting a successful use of BMP, this article summarises the relevant findings. PMID- 24760455 TI - [Bone substitutes - basic principles and clinical applications]. AB - Treatment of bone defects and non-unions frequently requires the transplantation of autologous bone. As an alternative, different kinds of bone substitutes have been used more often during the past years. These bone substitutes include synthetic materials, just as well as processed materials from human donors (allogen) or animals (xenogen). The relatively low hurdles in the approval process, compared to pharmaceutical drugs, have led to an almost unmanageable amount of different kinds of bone substitutes. Due to sparse clinical studies, evidence-based decisions for a specific product or a specific indication are hardly possible. Therefore, a deeper knowledge about basic properties of different bone substitutes is needed for a rational clinical decision. The present review aims to clarify the sometimes confusing nomenclature of bone substitutes and discuss their different biological properties. Generally, bone substitutes can be discriminated in osteogenic, osteoinductive and osteoconductive materials. The great majority of bone substitutes and especially synthetic materials serve as a matrix for bone growth and therefore possess mainly osteoconductive properties. The combination of these osteoconductive materials with osteogenic cells or osteoinductive growth factors, leads to composite materials with higher bone forming potential. Clinically, the quality and vitality of the recipient bone defect is of great importance. As a prerequisite for successful transplantation of bone substitutes or autologous bone, the recipient bone defect should be mechanically stable, free of infection with vital bone ends and intact soft tissue coverage. Bone defects in the spine, methaphyseal defects after trauma/tumour and diaphyseal segmental defects are typical indications for the application of bone substitutes. Unfortunately, the current literature does not allow concrete recommendations for specific bone substitutes or specific clinical indications. However, this review aims to discuss clinical benefits and limitations of bone substitutes for frequent indications to help clinicians in their decision making process. PMID- 24760453 TI - [The impact of capsular repair on the dislocation rate after primary total hip arthroplasty: a retrospective analysis of 1972 cases]. AB - BACKGROUND: Dislocation is the second most frequently encountered complication in primary total hip arthroplasty (THA) and occurs more commonly in the early postoperative rehabilitation phase. Sir Charnley recommended the "avoidance of resection of the capsule" and emphasised its contribution to hip joint stability in THA. Several authors, however, doubted its significance and considered resection of the capsule to be essential. Since 2002, some surgeons increasingly adopted a modified, less invasive technique of THA via Bauer approach, including the preservation and repair of the hip joint capsule with focus on maintaining its acetabular origin. Another group of surgeons applied the traditional technique including the resection of the joint capsule via an anterolateral approach. In this case-control study we investigated whether the dislocation rate can be reduced through joint capsule reconstruction and whether any negative impact on patient satisfaction, functional results or revision rate is observed. MATERIAL AND METHODS: All cases of primary THA performed in our institution in a timeframe between 2002 and 2009 were included with the only exceptions of resurfacing arthroplasty, dual mobility and tumour hip replacements. Joint capsule repair cases were gathered in the study group (SG), capsule resection cases in the control group (CG). Additional patient-related data were taken from the anaesthesia records. The WOMAC score and a questionnaire focusing on detection of dislocations and revision surgeries was sent out for each case. Further targeted research was conducted that included requesting records and reports from external hospitals. In the case of non-responding patients, all available data (operating room documentation, electronic files, archive, X-rays) were reviewed for incidents of dislocation and revision surgery. Groupings and classifications were exclusively performed by senior surgeons. SG and CG were compared regarding epidemiologic, implant-associated and surgery-specific data. Statistical evaluations were performed using the Chi-squared test and the Mann Whitney U test. RESULTS: 1972 cases of primary THA were included: 992 in the SG and 980 in the CG. The follow-up rates were 92.7 % in the SG and 76.4 % in the CG, the mean follow-up times 33.5 months and 73.4 months, respectively, with a follow-up of at least 12 months in all cases. In the SG, the dislocation rate was 0.3 % (n = 3) and thus significantly lower than the 2.55 % in the CG (n = 25, p < 0.001). Both the WOMAC score (SG: 1.46 +/- 1.73; CG: 1.53 +/- 1.80; p > 0.05) and the revision rate (SG: 5.24 %; CG: 6.84 %; p = 0.139) showed no significant differences. CONCLUSION: Preservation and repair of the hip joint capsule causes an 88-%-reduction of the dislocation rate in primary THA in this large series including 1972 cases, operated via the Bauer or the anterolateral approach. Several authors reported comparable results after THA using similar techniques of soft tissue and capsular repair through the posterior or posterolateral approach. Sparing and reconstructing the hip joint capsule therefore seems to reduce the dislocation rate after primary THA by one order of magnitude regardless of the surgical approach and, especially, if the acetabular origin is preserved. Capsule related specific complications such as an increased revision rate, malfunction or pain were neither recorded in our study nor by others. Thus, careful preservation and reconstruction of the hip joint capsule may be expressly recommended in primary THA. PMID- 24760456 TI - [Biomechanical modelling of the wrist joint]. AB - BACKGROUND: The hand represents one of the most complex joint mechanisms of the human body. The hand is also an important communication medium. The spectrum of today's hand injuries reaches from minor damage up to complex traumata with loss of several functional aspects. Enormous subsequent economic costs result. The therapeutic re-establishment of the equilibrium between maximum stress and the actual applied stress is the condition for a lifelong joint function. MATERIAL AND METHODS: A literature review about biomechanical wrist models was realised. The previous models found in the literature were systematically analysed as well as verifying their suitability for clinical use regarding pathological changes, therapy approaches and modelling/simulation approaches, respectively, of wrist injuries. RESULTS: The return of the wrist joint biomechanics to the normal condition is a key factor for a successful therapy. Furthermore, it is important for the re-establishment of an unimpaired joint function. Currently, there exist only simplified descriptions and models of the wrist joint, approximated by technical joints and furthermore, they are partially contradictory. Therefore, no uniform validated biomechanical wrist model exists as yet. CONCLUSION: Regarding the arising complex clinical problems, however, a valid biomechanical wrist joint model would be necessary as assistance, in order to improve the success of systematised therapies on the basis of computer-aided model-based planning and intervention. PMID- 24760457 TI - [Osteoporosis - inflammatory effects on bone metabolism and fracture risk]. AB - There is a large body of evidence that proinflammatory cytokines, particularly interleukin-1, interleukin-6, and tumour necrosis factor-alpha, play an important role in bone metabolism. Moreover, it is suspected that proinflammatory cytokines are also important in the pathogenesis of age- and estrogen deficiency-related bone loss. Although an accelerated decrease in bone mass is observed in patients with chronic inflammatory disorders, the definite meaning of proinflammatory cytokines in the aetiology of osteoporosis is still unclear. Some studies suggest a relationship between increased concentrations of proinflammatory cytokines and a decrease in bone mineral density, as well as an increased risk of fracture. In sum, the evidence is rather scarce and does not permit any clear conclusions about the effects of single cytokines in bone metabolism. To be able to define more exactly at which stage of the pathogenesis of osteoporosis parameters of a systemic inflammation take effect, further studies will be necessary, particularly for developing suitable diagnostic markers for clinicians. These diagnostic markers may be able to identify patients at risk for osteoporosis and therefore predict fracture risks. Thus, early interventions to preserve bone health, for example, by anti-cytokine therapy, could be more effective and efficient. PMID- 24760458 TI - [Thromboembolic complications 6 months after plate osteosynthesis of a mid clavicular fracture]. AB - A 32-year-old patient suffered from progredient intermittent claudication of the left arm 6 months after plate fixation of a midshaft clavicular fracture (OTA classification type A). The radiological analysis revealed a subacute stenosis of the left subclavian artery, caused by a granuloma at the tip of a protruding screw, which triggered recurrent emboli and symptoms. Reperfusion was achieved by catheter embolectomy and complete removal of the plate. The case shows that, when performing plate osteosynthesis of clavicular fractures, special consideration has to be given to the length and protrusion of the applied screws. Due to the anatomic proximity not only acute, but also subsequent irritation of the subclavian vessels is possible. PMID- 24760459 TI - [A diagnostic algorithm for painful total knee replacement]. AB - Total knee arthroplasty (TKA) is one of the most common procedures in orthopedic surgery and clinical success can be characterized by the revision rate and improvement of function, as well as the patients' satisfaction and pain. Despite the clinical success of primary TKA with 10-year survival rates as high as 95 %, about 20 % of the patients after TKA are not completely satisfied with their outcomes for several reasons. Obvious causes of failure might be identified with clinical examinations and standard radiographs only, whereas the unexplained painful TKA still remains a challenge for the surgeon. Failure can be classified into extra- and intraarticular disorders, the latter being divided into biological and mechanical origins. The onset of the pain after the operation and the differentiation between pain in motion and at rest are helpful to distinguish between mechanical and non-mechanical problems. An infection should be the first diagnosis to be ruled out in a painful TKA. It is generally accepted that a clear understanding of the failure mechanism in each case is required prior to considering revision surgery. METHOD: In this review a practical diagnostic algorithm is described for failure analysis in more detail. The evaluation of a painful TKA includes a detailed history with an extended analysis of the type of pain, thorough clinical examination including spine, hip and ankle, radiographic and laboratory analysis, as well as invasive examinations like joint aspiration and biopsies. CONCLUSION: This diagnostic algorithm offers an important tool for a sufficient failure analysis in almost all patients with painful TKA. PMID- 24760460 TI - Differential contribution of task conflicts to task switch cost and task mixing cost in alternating runs and cued task-switching: evidence from ex-Gaussian modeling of reaction time distributions. AB - Task switching involves switch cost (poorer performance switch trials than in task-repetition trials) and mixing cost (poorer performance in task-repetition trials than in trials from blocks without task switching). These are mainly studied with the alternating runs task-switching (ARTS) paradigm (in which the task changes every constant number of trials) or the cued task-switching (CTS) paradigm, in which the tasks change randomly. The authors tested the hypothesis that dealing with actual or potential conflicts regarding which task is currently required contribute to mixing cost in CTS more than in ARTS and contribute to switch costs more in ARTS than in CTS. This hypothesis was tested using ex Gaussian modeling of reaction time (RT) distributions, in which the heaviness of the right tail marks task conflicts (Steinhauser and Hubner in J Exp Psychol Human Percept Perform 35:1398-1412 2009). As predicted, a heavier RT-distribution tail marked switch cost more strongly in ARTS than in CTS and marked mixing costs more strongly in CTS than in ARTS. These results indicate that switch cost and mixing cost reflect different processes in different task-switching paradigms. PMID- 24760461 TI - Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis. AB - In this study, we aim to identify the genes responsible for colorectal cancer risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS single nucleotide polymorphisms (SNPs) with the expression of genes within a 2 Mb region (cis eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n = 47) and other of normal mucosa adjacent to colon cancer (n = 97, total 144). Paired tumor tissues (n = 97) were also analyzed but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93; r = 0.60); rs7136702 in 12q13.12 associated to DIP2B (r = 0.63) and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r = 0.47). For loci in chromosomes 11 and 12, we have found other SNPs in linkage disequilibrium that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r = 0.66) and rs61927768 for 12q13.12 (r = 0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein-protein interaction networks. PMID- 24760462 TI - De novo Stage IV breast cancer: breast conserving resection of the primary tumor? AB - Multiple retrospective reviews completed over the past decade suggest a survival advantage with resection of the intact primary tumor in women with metastatic breast cancer. However, these reviews are not without bias, and recently completed randomized trials do not support a significant survival benefit, although local control benefits may exist. Completion of ongoing trials is needed to reach a definitive conclusion regarding the merit of primary tumor resection for local control and survival. PMID- 24760463 TI - Development of appropriateness criteria for the surgical treatment of symptomatic lumbar degenerative spondylolisthesis (LDS). AB - PURPOSE: Spine surgery rates are increasing worldwide. Treatment failures are often attributed to poor patient selection and inappropriate treatment, but for many spinal disorders there is little consensus on the precise indications for surgery. With an aging population, more patients with lumbar degenerative spondylolisthesis (LDS) will present for surgery. The aim of this study was to develop criteria for the appropriateness of surgery in symptomatic LDS. METHODS: A systematic review was carried out to summarize the current level of evidence for the treatment of LDS. Clinical scenarios were generated comprising combinations of signs and symptoms in LDS and other relevant variables. Based on the systematic review and their own clinical experience, twelve multidisciplinary international experts rated each scenario on a 9-point scale (1 highly inappropriate, 9 highly appropriate) with respect to performing decompression only, fusion, and instrumented fusion. Surgery for each theoretical scenario was classified as appropriate, inappropriate, or uncertain based on the median ratings and disagreement in the ratings. RESULTS: 744 hypothetical scenarios were generated; overall, surgery (of some type) was rated appropriate in 27%, uncertain in 41% and inappropriate in 31%. Frank panel disagreement was low (7% scenarios). Face validity was shown by the logical relationship between each variable's subcategories and the appropriateness ratings, e.g., no/mild disability had a mean appropriateness rating of 2.3 +/- 1.5, whereas the rating for moderate disability was 5.0 +/- 1.6 and for severe disability, 6.6 +/- 1.6. Similarly, the average rating for no/minimal neurological abnormality was 2.3 +/- 1.5, increasing to 4.3 +/- 2.4 for moderate and 5.9 +/- 1.7 for severe abnormality. The three variables most likely (p < 0.0001) to be components of scenarios rated "appropriate" were: severe disability, no yellow flags, and severe neurological deficit. CONCLUSION: This is the first study to report criteria for determining candidacy for surgery in LDS developed by a multidisciplinary international panel using a validated method (RAM). The panel ratings followed logical clinical rationale, indicating good face validity. The work refines clinical classification and the phenotype of degenerative spondylolisthesis. The predictive validity of the criteria should be evaluated prospectively to examine whether patients treated "appropriately" have better clinical outcomes. PMID- 24760464 TI - Symptomatic epidural hematoma after lumbar decompression surgery. AB - BACKGROUND CONTEXT: Postoperative symptomatic epidural hematoma (SEH) is a serious complication of lumbar spine surgery. Despite its rarity, this uncommon complication may result in devastating neurological sequelae, including lower limb weakness. PURPOSE: A retrospective study was made to identify possible risk factors of postoperative spinal epidural hematoma by reviewing the clinical cases of this rare complication and analyzing the postoperative evaluations of patients. METHODS: From 2002 to 2010, out of 15,562 who underwent lumbar decompression procedure with/without instrumentation, 25 patients required reoperation for epidural hematoma after the initial spinal surgery. For the control group, another 75 patients were randomly selected from the pool of patients who received lumbar decompression surgery during the same period of time. The medical records of preoperative, intraoperative and postoperative factors were collected to determine possible risk factors by comparing between the cases and controls, and the postoperative evaluations of muscle power, intractable pain, saddle anesthesia, time to detection and time to evacuation were analyzed to find if there is any significant relation within the case group. Mann-Whitney U test, two-sample t test, chi (2) test and Fisher's exact test were used for statistical analysis. RESULTS: The incidence of postoperative symptomatic epidural hematoma is 0.16%. After the initial procedure, 20 (80%) patients developed progressive decrease in muscle power (MP <= 3), 14 (56%) patients had intractable pain (VAS >= 7), and 19 (76%) patients had saddle anesthesia. Preoperative diastolic blood pressure, intraoperative use of gelfoam for dura coverage and postoperative drain output were statistically significant risk factors (p < 0.01). Within the SEH case group, postoperative symptom of decreased muscle power had significant relation with blood loss, laminectomy level and fusion level (p = 0.016, 0.021, 0.010). If the symptom of decreased muscle power or perianal anesthesia was not improved after hematoma evacuation, there was a tendency for permanent leg weakness after 1-year follow-up (p = 0.001, 0.003). CONCLUSIONS: The findings suggest that preoperative diastolic blood pressure, intraoperative use of gelfoam for dura coverage and postoperative drain output are risk factors for symptomatic epidural hematoma after lumbar decompression surgery. Major blood loss and multilevel surgical procedure could result in poor recovery of muscle power. After spine decompression surgery, early detection and evacuation of hematoma are the key to avoid neurologic deterioration and have better clinical outcomes. PMID- 24760465 TI - Blood loss and operative duration using monopolar electrosurgery versus ultrasound scissors for surgical preparation during thoracoscopic ventral spondylodesis: results of a randomized, blinded, controlled trial. AB - PURPOSE: Monopolar electrosurgery is the gold standard for surgical preparation in thoracoscopic spine procedures. However, use of ultrasound scissors could decrease blood loss, accelerate the preparation time and improve patient safety, while minimizing operative costs. This trial compares both preparation techniques for ventral thoracoscopic spondylodesis. METHODS: The study design is an open, prospective, randomized, and double-blinded two-armed clinical trial performed in two centres. Forty-one patients with vertebral body fractures from T10 to L2 were included. Primary endpoint: preparation time. Secondary endpoints: blood loss, organ injuries, duration of hospitalization. RESULTS: Primary and secondary endpoints did not differ significantly between groups (p level 0.05). Increased blood loss (150 ml or more) was eliminated with ultrasound scissors (p = 0.0014). CONCLUSIONS: Primary and secondary endpoints did not differ significantly between the two preparation techniques. The use of either ultrasound scissors or electric scalpel offers safe and effective preparation for thoracoscopic spine surgery. PMID- 24760466 TI - Late-onset deep surgical-site infection after posterior lumbar interbody fusion in a patient treated with tocilizumab; unusual changes in inflammatory markers. AB - PURPOSE: To describe a case of late-onset deep surgical-site infection (SSI) after posterior lumbar interbody fusion in a patient treated with tocilizumab (TCZ) for rheumatoid arthritis (RA), with emphasis on the clinical symptoms and changes in inflammatory markers such as white blood cell (WBC) count and C reactive protein (CRP) level. CASE REPORT: A 74-year-old woman with 3-year history of RA underwent posterior lumbar interbody fusion at the L4/5/S1 level. After confirmation of no clinical symptom of SSI postoperatively, we decided to use TCZ for the patient after 2 months postoperatively. At 8 months after beginning of TCZ, she suffered from sudden onset of severe low back pain (LBP) with fever (38 degrees C) 1 day after administration of TCZ. Local tissues around the operative wound showed no sign of redness, warmth, or swelling. Increases in body temperature, WBC count, and CRP level were well suppressed by TCZ. Magnetic resonance imaging performed 2 weeks after onset of LBP revealed deep SSI. After surgical debridement and administration of the sensitive antibiotics, no clinical signs of recurrent spondylitis or osteolysis of vertebral body have been seen for 3 years. CONCLUSIONS: As TCZ strongly suppresses inflammatory reactions, detecting deep SSI based on local and systemic findings and laboratory data is quite difficult. Care must be taken regarding SSI when patients treated with TCZ complain of long-lasting LBP after lumbar surgery. PMID- 24760468 TI - Fetal biometry in the Korean population: reference charts and comparison with charts from other populations. AB - OBJECTIVE: The objectives of this article were to construct size charts for fetal biometry in the Korean population and to identify ethnic differences in fetal biometry. METHOD: A prospective, cross-sectional study was performed with 986 fetuses between 15 to 40 weeks of gestation. The following biometric variables were measured: biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and long bones lengths including the femur, tibia, humerus, and ulna. For each measurement, regression models were fitted to estimate the mean and standard deviation at each gestational age. The calculated centiles were compared with centiles from other populations using Z-scores. RESULTS: New charts for the Korean population were presented for the fetal biometric variables. Most of the parameters were similar to those for the Italian population. Also, in comparison with the North American and UK populations, Korean fetuses had greater BPD, HC, and AC in the first half of pregnancy but tended to measure progressively smaller with advancing gestational age. In comparison with the Hong Kong population, Korean fetuses had a longer femur length at any gestational age. CONCLUSION: We present size charts for fetal biometry for the Korean population using the recommended methodology, suggesting they are different from what is reported in other ethnicities. PMID- 24760469 TI - The comparison of fluid dynamics parameters in an Andersen cascade impactor equipped with and without a preseparator. AB - The fluid dynamic data in Andersen cascade impactor (ACI) are still lacking. Airflows and those affected parameters can be predicted in a preseparator and Andersen cascade impactor (ACI) by computational modeling. This study developed a validated computational fluid dynamic (CFD) model of an ACI and investigated the effects of the preseparator on the CFD parameters. Validation of the computational nozzle velocity for each of the stage 0 to stage 5 of the ACI stages was found to be within a 3.56% error. The flow field indicated that the preseparator accelerated the airflow velocity at the induction tube from 1.13 to 3.71 +/- 0.09 m/s and 2.40 to 8.68 +/- 0.16 m/s (at 28.3 and 60 L/min of flow rate, respectively). The preseparator produced a nozzle's wall shear stress ranged from 0.08 to 0.34 Pa on a collection plate, while the ex-preseparator spread wall shear from the plate's center was in a range of 0.11 to 0.37 Pa (at 28.3 L/min of flow rate). Moreover, the nozzle velocities increased along the distance from the middle of the collection plate to the periphery. The CFD explained the airflow of the preseparator equipped model by accelerating the airflow along the inlet port to maximize the trapping of desirable particles and the generation of a smooth wall shear stress at the collection plate to reduce the particle re-entrainment. While, the ex-preseparator generated an airflow that resulted in a higher wall shear stress occurring on the lower stages. PMID- 24760471 TI - Development and evaluation of Ca(+ 2) ion cross-linked carboxymethyl xanthan gum tablet prepared by wet granulation technique. AB - The objective of this work was to study the release behavior of prednisolone from calcium-cross-linked carboxymethyl xanthan gum (CMXG) tablets in dissolution medium having different pH values prevailing in the gastrointestinal lumen. Xanthan gum (XG) was derivatized to CMXG which was then cross-linked in situ with Ca(+2) ion during wet massing step of tablet preparation. Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry studies did not show any drug-polymer interaction although the drug underwent solid-state transformation during compression as evident from X-ray diffraction analysis. In vitro release study demonstrated that increase in the amount of Ca(+2) ion decreased the drug release, and beyond a certain amount, the drug release increased. While increase in both drug load and tablet crushing strength decreased the drug release, increase in exposure time in acid solution of pH 1.2 increased the overall release of the drug. The mechanism of drug release was non Fickian/anomalous. The results indicated that variation in the amount of Ca(+2) ion can modulate the drug release from CMXG matrix tablets as needed. PMID- 24760472 TI - Radial artery avulsion--a rare complication of transradial catheterization. AB - Transradial access is becoming the default mode of catheterization in a growing number of centers in the United States. The increasing utilization of transradial access has led to significant reduction in access site complications especially bleeding complications. We report a rare complication of transradial catheterization of radial artery avulsion, which was successfully treated in an endovascular fashion during the index procedure. (c) 2014 Wiley Periodicals, Inc. PMID- 24760470 TI - In vitro-controlled release delivery system for hydrogen sulfide donor. AB - Hydrogen sulfide (H2S) is having many potential pharmacological and physiological actions which reported that therapeutically useful concentration is low (100-160 MUM) and a higher concentration could be toxic. Most of its donors produce it on coming into contact with water. All of these problems could be solved by a controlled-release delivery system which does not utilize water in any of its development steps. Therefore, 12 sustained release formulations were prepared by dissolving sodium hydrogen sulfide (NaHS)-a model H2S donor-in polymer solutions, prepared by dissolving polymers (consisted of either polylactide (PLA) or polylactide co-glycolide (PLGA), containing free carboxylic acid or capped allyl ester end group) in a mixture of benzyl benzoate (BB) and benzyl alcohol (BA). The formulation was injected in simulated tear fluid (STF) from which samples were withdrawn at specified times and assayed for NaHS content. We found decrease in burst and overall release with increase in polymer concentration from 10 to 20% w/v. The formulations containing free end group showed significant (p < 0.05) reduction of burst release (11% vs 21%). However, the overall release or the average amount released per hour was found to be significantly (p < 0.05) increased for formulations containing polymers with free end group than those with capped end group. A sustained level of H2S was found to be maintained for 72 h which should be further increased to a month to make it a viable H2S donor delivery system in addition to investigating toxicity profile specifically for the purpose of subconjunctival ocular delivery. PMID- 24760473 TI - Pharmacologic sex hormones in pregnancy in relation to offspring obesity. AB - OBJECTIVE: To assess the association between in utero exposure to either diethylstilbestrol (DES) or an oral contraceptive in pregnancy and offspring obesity. METHODS: Using data from the Collaborative Perinatal Project (1959 1974), a multicenter prospective study of pregnant women and their offspring, we examined overweight or obesity among 34,419 children with height and weight data at age 7 years. Generalized linear models to estimate the adjusted odds ratio (aOR) for overweight or obesity (>=85th percentile) or obesity (>=95th percentile) in the offspring according to exposure during different months of pregnancy were used. RESULTS: Oral contraceptive use during pregnancy was positively associated with offspring overweight or obesity and obesity. The magnitude of association was strongest in the first 2 months of pregnancy for obesity (aOR 2.0, 95% CI: 1.1, 3.7). DES use was also associated with offspring overweight or obesity and obesity, with the association being strongest for exposure beginning between months 3 and 5 (e.g., for exposure beginning in months 3-4, the aOR for obesity was 2.8, 95% CI: 1.3, 6.3). CONCLUSIONS: Pharmacologic sex hormone use in pregnancy may be associated with childhood obesity. Whether contemporary, lower dose oral contraceptive formulations are similarly associated with increased risk of childhood obesity is unclear. PMID- 24760474 TI - RcLEA, a late embryogenesis abundant protein gene isolated from Rosa chinensis, confers tolerance to Escherichia coli and Arabidopsis thaliana and stabilizes enzyme activity under diverse stresses. AB - The late embryogenesis abundant (LEA) protein family is a large protein family that is closely associated with resistance to abiotic stresses in many organisms, such as plants, bacteria and animals. In this study, we isolated a LEA gene, RcLEA, which was cytoplasm-localized, from Rosa chinensis. RcLEA was found to be induced by high temperature through RT-PCR. Overexpression of RcLEA in Escherichia coli improved its growth performance compared with the control under high temperature, low temperature, NaCl and oxidative stress conditions. RcLEA was also overexpressed in Arabidopsis thaliana. The transgenic Arabidopsis showed better growth after high and low temperature treatment and exhibited less peroxide according to 3, 3-diaminobenzidine staining. However, RcLEA did not improve the tolerance to NaCl or osmotic stress in Arabidopsis. In vitro analysis showed that RcLEA was able to prevent the freeze-thaw-induced inactivation or heat-induced aggregation of various substrates, such as lactate dehydrogenase and citrate synthase. It also protected the proteome of E. coli from denaturation when the proteins were heat-shocked or subjected to acidic conditions. Furthermore, bimolecular fluorescence complementation assays suggested that RcLEA proteins function in a complex manner by making the form of homodimers. PMID- 24760475 TI - Impact of interventions designed to reduce medication administration errors in hospitals: a systematic review. AB - BACKGROUND: There is a need to identify effective interventions to minimize the threat posed by medication administration errors (MAEs). OBJECTIVE: Our objective was to review and critically appraise interventions designed to reduce MAEs in the hospital setting. DATA SOURCES: Ten electronic databases were searched between 1985 and November 2013. METHODS: Randomized controlled trials (RCTs) and controlled trials (CTs) reporting rates of MAEs or related adverse drug events between an intervention group and a comparator group were included. Data from each study were independently extracted and assessed for potential risk of bias by two authors. Risk ratios (RRs, with 95 % confidence intervals [CIs]) were used to examine the effect of an intervention. RESULTS: Six RCTs and seven CTs were included. Types of interventions clustered around four main themes: medication use technology (n = 4); nurse education and training (n = 3); changing practice in anesthesia (n = 2); and ward system changes (n = 4). Reductions in MAE rates were reported by five studies; these included automated drug dispensing (RR 0.72, 95 % CI 0.53-1.00), computerized physician order entry (RR 0.51, 95 % 0.40-0.66), barcode-assisted medication administration with electronic administration records (RR 0.71, 95 % CI 0.53-0.95), nursing education/training using simulation (RR 0.17, 95 % CI 0.08-0.38), and clinical pharmacist-led training (RR 0.76, 95 % CI 0.67-0.87). Increased or equivocal outcome rates were found for the remaining studies. Weaknesses in the internal or external validity were apparent for most included studies. LIMITATIONS: Theses and conference proceedings were excluded and data produced outside commercial publishing were not searched. CONCLUSIONS: There is emerging evidence of the impact of specific interventions to reduce MAEs in hospitals, which warrant further investigation using rigorous and standardized study designs. Theory-driven efforts to understand the underlying causes of MAEs may lead to more effective interventions in the future. PMID- 24760479 TI - Insurance cancellations in context: stability of coverage in the nongroup market prior to health reform. AB - Recent cancellations of nongroup health insurance plans generated much policy debate and raised concerns that the Affordable Care Act (ACA) may increase the number of uninsured Americans in the short term. This article provides evidence on the stability of nongroup coverage using US census data for the period 2008 11, before ACA provisions took effect. The principal findings are threefold. First, this market was characterized by high turnover: Only 42 percent of people with nongroup coverage at the outset of the study period retained that coverage after twelve months. Second, 80 percent of people experiencing coverage changes acquired other insurance within a year, most commonly from an employer. Third, turnover varied across groups, with stable coverage more common for whites and self-employed people than for other groups. Turnover was particularly high among adults ages 19-35, with only 21 percent of young adults retaining continuous nongroup coverage for two years. Given estimates from 2012 that 10.8 million people were covered in this market, these results suggest that 6.2 million people leave nongroup coverage annually. This suggests that the nongroup market was characterized by frequent disruptions in coverage before the ACA and that the effects of the recent cancellations are not necessarily out of the norm. These results can serve as a useful pre-ACA baseline with which to evaluate the law's long-term impact on the stability of nongroup coverage. PMID- 24760477 TI - Refractory and super-refractory status epilepticus--an update. AB - Status epilepticus is a medical emergency with a high mortality. Early recognition and initiation of treatment leads to a better response and may improve outcomes. Refractory status epilepticus is defined as recurrent seizure activity despite two appropriately selected and dosed antiepileptic drugs including a benzodiazepine. The term "super-refractory status epilepticus" was introduced during the London-Innsbruck Colloquium on status epilepticus in 2011 and refers to status epilepticus that continues or recurs 24 h or more after the initiation of treatment with anesthetic antiepileptic drugs. This includes cases in which seizure control is attained after induction of anesthesia but recurs on weaning the patient off the anesthetic agent. This article reviews the approach to refractory status epilepticus and super-refractory status epilepticus, including management as well as common pathophysiological causes of these entities. PMID- 24760476 TI - Mechanisms for alternative treatments in Parkinson's disease: acupuncture, tai chi, and other treatments. AB - At least 40% of patients with Parkinson's disease (PD) use one or more forms of alternative therapy (AT) to complement standard treatments. This article reviews the commonest forms of AT for PD, including acupuncture, tai chi, yoga, mindfulness, massage, herbal medicine, and cannabis. We discuss the current evidence for the clinical efficacy of each AT and discuss potential mechanisms, including those suggested by animal and human studies. With a few notable exceptions, none of the treatments examined were investigated rigorously enough to draw definitive conclusions about efficacy or mechanism. Tai chi, acupuncture, Mucuna pruriens, cannabinoids, and music therapy have all been proposed to work through specific mechanisms, although current evidence is insufficient to support or refute these claims, with the possible exception of Mucuna pruriens (which contains levodopa). It is likely that most ATs predominantly treat PD patients through general mechanisms, including placebo effects, stress reduction, and improved mood and sleep, and AT may provide patients with a greater locus of control regarding their illness. PMID- 24760480 TI - Catalytic, enantioselective vinylogous Michael reactions. AB - Recent progress in the field of catalytic, enantioselective vinylogous Michael reactions of latent dienolates is described which furnish optically highly enriched chiral 1,7-dioxo compounds of great utility in one synthetic operation. Emphasis is given to new catalysis modes which realise this challenging transformation with high regio- as well as enantioselectivity. PMID- 24760481 TI - The prevalence of knee injuries ipsilateral to tibial shaft fractures and their impact on clinical outcome. AB - OBJECTIVE: The purpose of this prospective study was to examine the prevalence of occult knee injuries in patients with ipsilateral tibial shaft fractures and determine their impact on clinical outcome. MATERIALS AND METHODS: Preoperative knee MRI examination was performed in 41 patients (42 knees) with isolated tibial shaft fractures. Menisci, cruciate ligaments, collateral ligaments, extensor mechanism, osteochondral lesions, bone contusions and knee effusion were evaluated. All patients were treated with reamed and locked intra-medullary tibial nailing without an additional surgical procedure for knee injuries. All patients were followed to at least fracture union and were evaluated with knee examination and Lysholm knee score. RESULTS: Of the 42 knees, 41 (97.6 %) showed at least one defined injury around the knee. There was only one patient who had totally normal knee MRI findings. One or more ligamentous injuries of the knee were identified in 35 (83.3 %) of the knees. Five patents (11.9 %) had medial meniscal tear in posterior horn. Extensor mechanism injuries were seen in two patients. Mild to marked joint effusion was observed in 35 (81 %) knees. Twenty two knees demonstrated bone bruise; femoral condyle (n = 7), tibial plateau (n = 12), patella (n = 2) and fibular head (n = 1). No patients had osteochondral lesion. Patients were followed with a mean of 13.2 +/- 3.6 (range 8-22) months. Clinical knee examination revealed Grade II (+) anterior drawer test in two patients. The mean Lysholm knee score was 99.1 +/- 2.14 (range 91-100) at the final follow-up. CONCLUSIONS: Ipsilateral intra-articular, extra-articular or combined knee injuries may occur at the time of injury with tibial shaft fractures. However, most of these injuries are not clinically relevant and heal without any sequel or remain asymptomatic late after fracture union. Routine use of preoperative knee MRI examination in patients with tibial shaft fractures is not necessary. PMID- 24760482 TI - Optimized outcome prediction in breast cancer by combining the 70-gene signature with clinical risk prediction algorithms. AB - Clinical guidelines for breast cancer treatment differ in their selection of patients at a high risk of recurrence who are eligible to receive adjuvant systemic treatment (AST). The 70-gene signature is a molecular tool to better guide AST decisions. The aim of this study was to evaluate whether adding the 70 gene signature to clinical risk prediction algorithms can optimize outcome prediction and consequently treatment decisions in early stage, node-negative breast cancer patients. A 70-gene signature was available for 427 patients participating in the RASTER study (cT1-3N0M0). Median follow-up was 61.6 months. Based on 5-year distant-recurrence free interval (DRFI) probabilities survival areas under the curve (AUC) were calculated and compared for risk estimations based on the six clinical risk prediction algorithms: Adjuvant! Online (AOL), Nottingham Prognostic Index (NPI), St. Gallen (2003), the Dutch National guidelines (CBO 2004 and NABON 2012), and PREDICT plus. Also, survival AUC were calculated after adding the 70-gene signature to these clinical risk estimations. Systemically untreated patients with a high clinical risk estimation but a low risk 70-gene signature had an excellent 5-year DRFI varying between 97.1 and 100 %, depending on the clinical risk prediction algorithms used in the comparison. The best risk estimation was obtained in this cohort by adding the 70-gene signature to CBO 2012 (AUC: 0.644) and PREDICT (AUC: 0.662). Clinical risk estimations by all clinical algorithms improved by adding the 70-gene signature. Patients with a low risk 70-gene signature have an excellent survival, independent of their clinical risk estimation. Adding the 70-gene signature to clinical risk prediction algorithms improves risk estimations and therefore might improve the identification of early stage node-negative breast cancer patients for whom AST has limited value. In this cohort, the PREDICT plus tool in combination with the 70-gene signature provided the best risk prediction. PMID- 24760483 TI - Supramolecular organization of photosynthetic membrane proteins in the chlorosome containing bacterium Chloroflexus aurantiacus. AB - The arrangement of core antenna complexes (B808-866-RC) in the cytoplasmic membrane of filamentous phototrophic bacterium Chloroflexus aurantiacus was studied by electron microscopy in cultures from different light conditions. A typical nearest-neighbor center-to-center distance of ~18 nm was found, implying less protein crowding compared to membranes of purple bacteria. A mean RC:chlorosome ratio of 11 was estimated for the occupancy of the membrane directly underneath each chlorosome, based on analysis of chlorosome dimensions and core complex distribution. Also presented are results of single-particle analysis of core complexes embedded in the native membrane. PMID- 24760484 TI - Traditional Chinese medicine versus western medicine as used in China in the management of rheumatoid arthritis: a randomized, single-blind, 24-week study. AB - This study is designed to compare the efficacy and safety of traditional Chinese medicine (TCM) with western medicine (WM) in the management of rheumatoid arthritis (RA). This is a 24-week, randomized, multicenter, single-blind study comparing TCM with WM (as used in China) carried out between June 2002 and December 2004 in nine research centers in China, involving 489 patients. Patients were randomized to receive TCM (n = 247), MTX and SSZ (n = 242). MTX was started at a dose of 5 mg to a final dose of 7.5-15 mg weekly. The maintenance dose was 2.5-7.5 mg weekly. The starting dose of SSZ was 0.25 g bid, increasing by 0.25 g a day once a week to a final dose of 0.5-1 g qid. The maintenance dose was 0.5 g tid to qid. Primary end point was the proportion of patients with response according to the American College of Rheumatology 20 % improvement criteria (ACR20) at weeks 24. At 24 weeks, ACR20 responses were 53.0 % in TCM group and 66.5 % in WM group, (P < 0.001) at 24 weeks. ACR 50 responses were 31.6 % of TCM group and 42.6 % in WM group, (P = 0.01). ACR70 responses were 12.6 % in TCM group and 17.4 % in WM group, (P = 0.14). Side effects were observed more frequently in WM group. In this study, ACR20, ACR50 responses at 24 weeks were significantly better in the WM treated group, by intention to treat (ITT) and per protocol analysis. The ACR 70 response showed no significant difference between the two groups. TCM, while effective in treating RA, appears to be less effective than WM in controlling symptoms, but TCM is associated with fewer side effects. PMID- 24760485 TI - Growth abnormalities in children and adolescents with juvenile idiopathic arthritis. AB - In patients with juvenile idiopathic arthritis (JIA) growth impairment and variance in body composition are well-known long-term complications. In the active phases of the disease, particular patients with systemic and polyarticular JIA reveal growth impairment. Some experience "catch-up" growth following reduction in disease activity and lower glucocorticoid doses. Although new therapeutic options are available, there are still 10-20 % of patients with severe forms of the disease who show continuous growth disturbance. Only few studies have specifically addressed body composition in JIA. Bone mass deficits in part could be related to the deficits of muscle mass. Study data on growth hormone treatment in short children with JIA are promising in respect of growth development, final height and body composition. The major goal for physicians is optimal disease control while maintaining normal growth and body composition. Early recognition of patients who develop prolonged growth and body composition disturbances is important as these abnormalities contribute to long-term morbidity and need to be addressed both diagnostically and therapeutically. PMID- 24760486 TI - Differential insertion of the atrioventricular valves: measurement protocol to detect various congenital heart defects. AB - OBJECTIVES: The objectives of this study were to develop reference values for the distance between the atrioventricular valves, called differential insertion of the atrioventricular valves (DIAVV), in normal fetuses using four-dimensional ultrasound with spatio-temporal image correlation and to explore if DIAVV measurement can differentiate between normal hearts and hearts with cardiac defects. METHODS: The DIAVV was analysed longitudinally following a measurement protocol in 74 fetuses between 15 and 36 weeks gestational age. The DIAVV was measured in an apical four-chamber view of the heart in end-diastole. Furthermore, the DIAVV was measured in 70 fetuses with cardiac defects. RESULTS: In total, 337 normal and 70 abnormal spatio-temporal image correlation volumes were examined. Longitudinal regression analysis revealed a positive relationship of the DIAVV with gestational age and fetal biometry (p < 0.0001). The DIAVV of fetuses with double outlet right ventricle, truncus arteriosus, atrioventricular septal defects, Ebstein and tetralogy of Fallot all differed from normal fetuses (p < 0.05). CONCLUSION: Measurement of the DIAVV is a promising tool; however, a well-defined measurement protocol should be followed to accomplish the correct plane and exact moment in the cardiac cycle. This study presents new nomograms following this measurement protocol and reports an abnormal DIAVV in a wide spectrum of congenital heart disease. PMID- 24760487 TI - The debate over eponyms. AB - Traditionally, important clinical or anatomic discoveries were labeled with the discoverer's name, to serve as both a means to recognize and reward the discoverer's contribution to the field but also because scientific names were often harder to remember and more difficult to communicate. Eponyms have been pervasive throughout anatomy and medicine over the last few centuries. Recently, some experts have argued that eponyms harbor significant limitations and have become antiquated. For instance, some eponyms fail to convey the characteristic findings associated with the disease or structure for which they are associated and eponyms are often times variable based on country and journal and in the grammatical form that is used. In fact, some individuals are going so far as to call for the removal of eponyms from published medical literature and medical textbooks going forward. In this article, we explore the arguments for and against the continued use of eponyms within medical education and practice, so that readers may understand both sides of the debate. PMID- 24760488 TI - Is sinus disease the cause of my headaches? An update on sinus disease and headache. AB - The interplay between head pain caused by sinus disease and primary headaches is complex. Classification of secondary headaches, attributed to disorders of the nose or paranasal sinuses has been recently updated. New treatments including office- based procedures are emerging for patients with chronic sinusitis. This paper briefly reviews sinus disease and headache. PMID- 24760490 TI - It IS a tumor -- current review of headache and brain tumor. AB - "Do I have a tumor?" This is a question in every person's mind when first confronted with a new-onset headache, a question that causes considerable anxiety among patients, leading them to seek medical evaluation. This publication reviews the current literature with respect to the epidemiology, pathophysiology presentation, and treatment of headaches in association with intracranial neoplasm. PMID- 24760489 TI - Breakthrough cancer pain. AB - Breakthrough pain is a distinct pain state that is common in patients with cancer pain and which is associated with significant morbidity in this group of patients. The aim of this article is to highlight important journal articles relating to breakthrough pain that have been published within the last year, including a systematic review of the epidemiology of breakthrough pain, the largest-ever study of the clinical features of breakthrough pain, and a network meta-analysis of the treatment of breakthrough pain. PMID- 24760491 TI - Preventive drugs in childhood and adolescent migraine. AB - While headaches in children are quite common, the study and characterization of headache disorders in the pediatric age group has historically been limited. In the absence of controlled studies on prophylactic treatment of the primary headache disorders in this age group, the diagnosis of childhood migraine rests on criteria similar to those in adults. Data from adult studies are often extrapolated and applied to children as well. Although it appears that many preventive agents are safe in children, none are currently FDA-approved for this age group. As a result, despite experiencing significant disability, the vast majority of children who present to their physician with migraine headache do not receive prophylactic therapy. Furthermore, controlled clinical trials investigating the use of both abortive and preventive medications in children have suffered from high placebo response rates. The shorter duration of headaches and other characteristic features seen in children are such that designing randomized controlled trials in this age group is more problematic and limiting. As such, treatment practices vary widely, even among specialists, due to the absence of evidence-based guidelines from clinical trials. PMID- 24760492 TI - Using animal models to understand cancer pain in humans. AB - Cancer pain is not a single entity but a complex pain state involving different pain syndromes, with inflammatory, neuropathic, compressive, and ischaemic mechanisms. Current therapeutic regimens are based largely on opioids, although opioid treatment can lead to many side effects. Studies using animal models of cancer pain are aimed at understanding cancer pain and developing novel therapies. The most frequently reported models are of bone cancer pain, predominantly modelling pain associated with tumour growth within bone marrow. Here we summarise recent findings from studies using animal models of cancer pain and discuss the methodological quality of these studies. PMID- 24760493 TI - Ultrasound-guided stellate ganglion block: safety and efficacy. AB - Cervical sympathetic and stellate ganglion blocks (SGB) provide a valuable diagnostic and therapeutic benefit to sympathetically maintained pain syndromes in the head, neck, and upper extremity. With the ongoing efforts to improve the safety of the procedure, the techniques for SGB have evolved over time, from the use of the standard blind technique, to fluoroscopy, and recently to the ultrasound (US)-guided approach. Over the past few years, there has been a growing interest in the ultrasound-guided technique and the many advantages that it might offer. Fluoroscopy is a reliable method for identifying bony surfaces, which facilitates identifying the C6 and C7 transverse processes. However, this is only a surrogate marker for the cervical sympathetic trunk. The ideal placement of the needle tip should be anterolateral to the longus colli muscle, deep to the prevertebral fascia (to avoid spread along the carotid sheath) but superficial to the fascia investing the longus colli muscle (to avoid injecting into the muscle substance). Identifying the correct fascial plane can be achieved with ultrasound guidance, thus facilitating the caudal spread of the injectate to reach the stellate ganglion at C7-T1 level, even if the needle is placed at C6 level. This allows for a more effective and precise sympathetic block with the use of a small injectate volume. Ultrasound-guided SGB may also improve the safety of the procedure by direct visualization of vascular structures (inferior thyroidal, cervical, vertebral, and carotid arteries) and soft tissue structures (thyroid, esophagus, and nerve roots). Accordingly, the risk of vascular and soft tissue injury may be minimized. PMID- 24760495 TI - Transcatheter aortic valve replacement program development: recommendations for best practice. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is an increasingly available therapy for the management of aortic stenosis in higher risk populations. Beyond addressing the procedural challenges, centers must attend to the unique requirements of developing TAVR programs from referral to follow-up. AIM: The aim of this article is to outline the recommendations for best practice for program development from centers with early and extensive experience. RECOMMENDATIONS: The guideline-recommended Heart Team approach requires interdisciplinary agreements, delineation of roles and responsibilities, and the development of the role of the TAVR Coordinator. To support appropriate case selection, the screening and evaluation must be organized in a comprehensive clinic visit. In addition to the multimodality imaging tests, the assessment of functional status and frailty is pivotal to the eligibility decision. Throughout the TAVR trajectory, careful attention must be afforded to the integration of geriatric best practices. Pre-procedure care requires patient and family education to manage expectations and facilitate early discharge planning. Peri procedural care planning, including equipment requirements, monitoring protocols, and emergency intervention agreements, contributes to procedural success. The aims of post-procedure care are to monitor the recovery, facilitate the rapid return to baseline status, and optimize length of stay. TAVR programs require data management strategies to facilitate and monitor program growth, support program evaluation, and meet the requirements for submission to national registries. CONCLUSION: TAVR represents a paradigm shift in the management of structural heart disease. Programmatic success and patient outcomes depend on the development of a comprehensive and collaborative program tailored to TAVR. PMID- 24760494 TI - Low-pressure/spinal fluid leak headache. AB - Low cerebrospinal fluid (CSF) pressure results in neurologic deficits, of which the most common manifestation is headache. Typically, the headache is postural - and specifically, orthostatic - in presentation. There are three hypotheses to explain the occurrence of headache associated with low CSF fluid. The first is traction on pain-sensitive intracranial and meningeal structures; the second is CSF hypovolemia; and the third is spinal loss of CSF resulting in increased compliance at the caudal end of the CSF space. Spontaneous intracranial hypotension (SIH), once believed to be rare, is now more commonly recognized. It is typically associated with orthostatic headache (although initially it may not be) and one or more other symptoms such as alterations in hearing, nausea, vomiting, neck stiffness, diplopia, and visual field cuts. Magnetic resonance imaging (MRI) of the brain with gadolinium is the first study of choice, which typically reveals diffuse pachymeningeal enhancement and, frequently, cerebellar tonsillar descent and posterior fossa crowding. Epidural blood patch (EBP) is the treatment of choice. Surgery and epidural fibrin glue injection are options for those who fail conservative therapy and/or EBP. PMID- 24760496 TI - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA): an overview and update for the cytopathologist. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a minimally invasive technique for evaluating the mediastinum and staging patients with lung cancer. In the hands of an experienced operator, the procedure is safe and provides excellent sensitivity, specificity, and predictive diagnostic values. In conjunction with endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), a nearly complete mediastinal evaluation can be performed in a minimally invasive fashion. This strategy results in improved lymph node staging, markedly reduced need for mediastinoscopy, and fewer futile thoracotomies compared with a traditional surgical staging procedure. The procedure is cost effective and provides excellent cytologic specimens that have proven well suited for ancillary testing, such as immunohistochemistry and tumor genotyping. EBUS-TBNA, initially used as a tool to sample the lymph nodes adjacent to the airway walls, has now become instrumental in sampling lesions in the mediastinum, hilum, and lung parenchyma, where previously more than 1 procedure would have been necessary. Looking forward, expanded use of this procedure is likely to revolutionize the access to cytology-proven staging and restaging of lung cancer and other thoracic malignancies in a minimally invasive fashion. PMID- 24760498 TI - The role of protein p16(INK4a) in glottic laryngeal squamous cell carcinoma. AB - Head and neck squamous cell cancer (HNSCC) includes tumors of various anatomical sites sharing the common etiological factors. However some differences in pathogenesis and prognosis of HNSCC have been hitherto documented. Laryngeal squamous cell carcinoma (LSCC) is one the most common type of the head and neck cancer. The majority of laryngeal cancers are located in the glottic area. P16 was recently documented to be important prognostic marker in many tumors including HNSCC. The aim of our study was to assess the significance of p16 expression in glottic LSCC. Fifty eight patients after surgical treatment of the glottic LSCC were enrolled in the retrospective study. The p16 expression was immunohistochemically detected and semiquantitatively evaluated in tumor tissue. The results were statistically correlated with clinical and pathological parameters. Protein p16 was expressed in glottic LSCC of 15 patients (25.9 %). Statistically significant higher p16 overexpression was proven in non-smokers in comparison with smokers (75 % versus 18 %; p =0.003). Recurrent cancer was diagnosed in 8 patients (13.8 %), and all these tumors were p16 negative. Our study shows, that p16 expression in glottic LSCC especially in subgroup of non smokers might be promising prognosticator of better clinical outcome in routine practice. The p16 status did not statistically correlate with cervical lymph node metastases or with grading and staging of cancers, respectively. The preliminary results suggest that p16 overexpression in glottic LSCC may identify patients at low risk of disease recurrence. However, the pathobiology of this tumor as well as predictive role of p16 expression in laryngeal cancer still remains to be better elucidated. PMID- 24760499 TI - Impact of diabetes mellitus duration on effect of lower extremity nerve decompression in 1,526 diabetic peripheral neuropathy patients. AB - BACKGROUND: Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus (DM). The aim of this study was to analyze DM duration in the prognosis of diabetic peripheral neuropathy of the lower extremity. METHODS: A total of 1,526 DPN patients who were treated with DELLON surgical nerve decompression were divided into a short DM duration group and long DM duration group using a length of 5 years as the standard duration. Before and 1.5 years after surgery, high-resolution ultrasound, quantitative sensory testing (QST), and nerve conduction velocity (NCV) were performed and compared to the normal control. RESULTS: Postoperative NCV of all the patients in either treatment group significantly increased (p < 0.05) and postoperative CSA significantly decreased (p < 0.05) compared with that before surgery. The CPT significantly increased compared with the preoperative value (p < 0.05). The postoperative WPT was significantly lower than the preoperative value (p < 0.01), and the postoperative VPT was significantly lower than the preoperative value (p < 0.05). Overall, the postoperative NCV, CSA, CPT, WPT, and VPT values from the short DM duration group were significantly different from that of the long DM duration group (p < 0.05). CONCLUSIONS: The duration of DM is critical to the prognosis of DPN of the lower extremity, and the data from this study suggest that an early diagnosis and subsequent surgery for DPN have important clinical value. PMID- 24760501 TI - Insulin increases mRNA abundance of the amino acid transporter SLC7A5/LAT1 via an mTORC1-dependent mechanism in skeletal muscle cells. AB - Abstract Amino acid transporters (AATs) provide a link between amino acid availability and mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activation although the direct relationship remains unclear. Previous studies in various cell types have used high insulin concentrations to determine the role of insulin on mTORC1 signaling and AAT mRNA abundance. However, this approach may limit applicability to human physiology. Therefore, we sought to determine the effect of insulin on mTORC1 signaling and whether lower insulin concentrations stimulate AAT mRNA abundance in muscle cells. We hypothesized that lower insulin concentrations would increase mRNA abundance of select AAT via an mTORC1 dependent mechanism in C2C12 myotubes. Insulin (0.5 nmol/L) significantly increased phosphorylation of the mTORC1 downstream effectors p70 ribosomal protein S6 kinase 1 (S6K1) and ribosomal protein S6 (S6). A low rapamycin dose (2.5 nmol/L) significantly reduced the insulin-(0.5 nmol/L) stimulated S6K1 and S6 phosphorylation. A high rapamycin dose (50 nmol/L) further reduced the insulin (0.5 nmol/L) stimulated phosphorylation of S6K1 and S6. Insulin (0.5 nmol/L) increased mRNA abundance of SLC38A2/SNAT2 (P <= 0.043) and SLC7A5/LAT1 (P <= 0.021) at 240 min and SLC36A1/PAT1 (P = 0.039) at 30 min. High rapamycin prevented an increase in SLC38A2/SNAT2 (P = 0.075) and SLC36A1/PAT1 (P >= 0.06) mRNA abundance whereas both rapamycin doses prevented an increase in SLC7A5/LAT1 (P >= 0.902) mRNA abundance. We conclude that a low insulin concentration increases SLC7A5/LAT1 mRNA abundance in an mTORC1-dependent manner in skeletal muscle cells. PMID- 24760502 TI - Differential psychophysiological interactions of insular subdivisions during varied oropharyngeal swallowing tasks. AB - Abstract The insula is a highly integrated cortical region both anatomically and functionally. It has been shown to have cognitive, social-emotional, gustatory, and sensorimotor functions. Insular involvement in both normal and abnormal swallowing behavior is well established, yet its functional connectivity is unclear. Studies of context-dependent connectivity, or the connectivity during different task conditions, have the potential to reveal information about synaptic function of the insula. The goal of this study was to examine the functional connectivity of specific insular regions (ventral anterior, dorsal anterior, and posterior) with distant cortical regions during four swallowing conditions (water, sour, e-stim, and visual biofeedback) using generalized psychophysiological interactions (gPPI). In 19 healthy adults, we found that the visual biofeedback condition was associated with the most and strongest increases in functional connectivity. The posterior insula/rolandic operculum regions had the largest clusters of increases in functional connectivity, but the ventral anterior insula was functionally connected to a more diverse array of cortical regions. Also, laterality assessments showed left lateralized increases in swallowing functional connectivity. Our results are aligned with reports about the insula's interconnectivity and extensive involvement in multisensory and cognitive tasks. PMID- 24760503 TI - Growth hormone secretagogue receptor deficiency in mice protects against obesity induced hypertension. AB - Abstract Growth hormone secretagogue receptor (GHS-R) signaling has been associated with growth hormone release, increases in food intake and pleiotropic cardiovascular effects. Recent data demonstrated that acute GHS-R antagonism leads to increases in mean arterial pressure mediated by the sympathetic nervous system in rats; a highly undesirable effect if GHS-R antagonism was to be used as a therapeutic approach to reducing food intake in an already obese, hypertensive patient population. However, our data in conscious, freely moving GHS-R deficient mice demonstrate that chronic absence of GHS-R signaling is protective against obesity-induced hypertension. GHS-R deficiency leads to reduced systolic blood pressure variability (SBPV); in response to acute high-fat diet (HFD)-feeding, increases in the sympathetic control of SBPV are suppressed in GHS-R KO mice. Our data further suggest that GHS-R signaling dampens the immediate HFD-mediated increase in spontaneous baroreflex sensitivity. In diet-induced obesity, absence of GHS-R signaling leads to reductions in obesity-mediated hypertension and tachycardia. Collectively, our findings thus suggest that chronic blockade of GHS R signaling may not result in adverse cardiovascular effects in obesity. PMID- 24760504 TI - Mathematical modeling supports the presence of neutrophil depriming in vivo. AB - Abstract Following migration into the intestinal mucosa in inflammatory bowel disease (IBD), neutrophils enter the intestinal lumen and are excreted. This provides a basis for quantification of disease activity by measuring excreted label following injection of In-111-labeled neutrophils. In severe pan-colitis, 50% of the injected In-111 is typically recovered in the feces, indicating that 50% of neutrophil turnover is via fecal excretion. Neutrophils have an intravascular lifespan of ~10 h and a distribution volume of ~10 L, so total body neutrophil turnover is 10.N/10 cells/h, where N is the peripheral blood neutrophil count (cells/L). Neutrophil loss via the colon in a patient with 50% fecal In-111 loss is therefore N/120 cells/min. Pan-colonic mucosal-blood flow in pan-colitis is 200 mL/min, which would deliver N/5 neutrophils to the colon per min. Therefore, 5/120, or 4%, of incoming neutrophils undergo migration into inflamed bowel. If the 96% of nonmigrating cells exit in a primed state, then at steady state >90% of circulating neutrophils would be primed if no depriming took place. As the highest level of priming seen in IBD is ~40%, this indicates that depriming within the circulation must take place. Using the above values in the steady state equation relating priming rate to depriming rate plus primed-cell destruction rate gives a mean depriming time of 35 min. We conclude that a very small proportion of neutrophils entering a site of inflammation migrate and that in vivo depriming must take place to limit the numbers of primed neutrophils in the circulation. PMID- 24760505 TI - Interaction between human placental microvascular endothelial cells and a model of human trophoblasts: effects on growth cycle and angiogenic profile. AB - Abstract Intrauterine growth restriction (IUGR) is a leading cause of perinatal complications, and is commonly associated with reduced placental vasculature. Recent studies demonstrated over-expression of IGF-1 in IUGR animal models maintains placental vasculature. However, the cellular environment of the placental chorionic villous is unknown. The close proximity of trophoblasts and microvascular endothelial cells in vivo alludes to autocrine/paracrine regulation following Ad-HuIGF-1 treatment. We investigated the co-culturing of BeWo Choriocarcinoma and Human Placental Microvascular Endothelial Cells (HPMVECs) on the endothelial angiogenic profile and the effect Ad-HuIGF-1 treatment of one cell has on the other. HPMVECs were isolated from human term placentas and cultured in EGM-2 at 37 degrees C with 5% CO2. BeWo cells were maintained in Ham's F12 nutrient mix with 10% FBS and 1% pen/strep. Co-cultured HPMVECS+BeWo cells were incubated in serum-free control media, Ad-HuIGF-1, or Ad-LacZ at MOI 0 and MOI 100:1 for 48 h. Non-treated cells and mono-cultured cells were compared to co-cultured cells. Angiogenic gene expression and proliferative and apoptotic protein expression were analysed by RT-qPCR and immunocytochemistry, respectively. Statistical analyses was performed using student's t-test with P < 0.05 considered significant. Direct Ad-HuIGF-1 treatment increased HPMVEC proliferation (n = 4) and reduced apoptosis (n = 3). Co-culturing HPMVECs+BeWo cells significantly altered RNA expression of the angiogenic profile compared to mono-cultured HPMVECs (n = 8). Direct Ad-HuIGF-1 treatment significantly increased Ang-1 (n = 4) in BeWo cells. Ad-HuIGF-1 treatment of HPMVECs did not alter the RNA expression of angiogenic factors. Trophoblastic factors may play a key role in placental vascular development and IGF-1 may have an important role in HPMVEC growth. PMID- 24760506 TI - Overexpression of apolipoprotein C-III decreases secretion of dietary triglyceride into lymph. AB - Abstract Apolipoprotein C-III (apoC-III) is not only predominantly synthesized by the liver but also by the small intestine. Because apoC-III is secreted from the intestine on the chylomicron along with lipid absorption, we questioned whether apoC-III might play a role in intestinal lipid absorption and/or transport. Using both wild-type (WT) and apoC-III transgenic (apoC-III Tg) mice, we showed that apoC-III Tg mice have decreased lymphatic lipid transport compared with WT mice in response to an intraduodenal infusion of radiolabeled lipid. This is associated with accumulation of radiolabeled lipids in the luminal compartment of the apoC-III Tg mice, indicating delayed lipid uptake from the lumen. The total amount of radioactive lipids in the mucosal compartment did not differ between apoC-III Tg and WT mice, but the lipid distribution analysis indicated a predominance of free fatty acids and monoacylglycerol in the mucosa of apoC-III Tg mice, implying impaired esterification capacity. Thus, the mechanisms underlying the reduced lymphatic lipid transport in apoC-III Tg mice involve both a delayed lipid uptake into enterocytes, as well as impaired esterification to form triglyceride in the mucosa. These data document a novel role for apoC-III in the uptake, re-esterification, and lymphatic transport of dietary lipids in the intestine. PMID- 24760507 TI - Increased AMP-activated protein kinase in skeletal muscles of Murphy Roth Large mice and its potential role in altered metabolism. AB - Abstract Wild-type Murphy Roth Large (MRL) mice have long been investigated for their superior healing ability when subjected to various wound and disease models. Despite this long history, the mechanisms causing their extraordinary healing ability remain undefined. As we have recently demonstrated that MRL mice with muscular dystrophy are resistant to the associated fibrosis and the Heber Katz group has demonstrated MRL mitochondrial mutations, we decided to investigate the skeletal muscle metabolic characteristics of the MRL mouse strain compared to the commonly utilized C57BL/6J control mouse strain. We now have evidence demonstrating an altered metabolism in the MRL quadriceps, triceps brachii, and diaphragm of 8-week-old animals compared to tissues from control animals. The MRL skeletal muscles have increased activated phosphorylated AMP activated protein kinase (pAMPK). The increased pAMPK signaling coincides with increased skeletal muscle mitochondrial content. These metabolic changes may compensate for insufficient oxidative phosphorylation which is demonstrated by altered quantities of proteins involved in oxidative phosphorylation and ex vivo metabolic investigations. We also demonstrate that the MRL muscle cells have increased metabolic physiologic reserve. These data further the investigations into this important and unique mouse strain. Why the MRL mice have increased pAMPK and how increased pAMPK and the resultant metabolic alterations affect the healing ability in the MRL mouse strain is discussed. Understanding the molecular mechanisms surrounding the super healing characteristics of these mice will lead to relevant clinical intervention points. In conclusion, we present novel data of increased mitochondrial content, pAMPK, and glycolytic indicators in MRL skeletal muscles. PMID- 24760508 TI - Motion processing across multiple topographic maps in the electrosensory system. AB - Abstract Animals can efficiently process sensory stimuli whose attributes vary over orders of magnitude by devoting specific neural pathways to process specific features in parallel. Weakly electric fish offer an attractive model system as electrosensory pyramidal neurons responding to amplitude modulations of their self-generated electric field are organized into three parallel maps of the body surface. While previous studies have shown that these fish use parallel pathways to process stationary stimuli, whether a similar strategy is used to process motion stimuli remains unknown to this day. We recorded from electrosensory pyramidal neurons in the weakly electric fish Apteronotus leptorhynchus across parallel maps of the body surface (centromedial, centrolateral, and lateral) in response to objects moving at velocities spanning the natural range. Contrary to previous observations made with stationary stimuli, we found that all cells responded in a similar fashion to moving objects. Indeed, all cells showed a stronger directionally nonselective response when the object moved at a larger velocity. In order to explain these results, we built a mathematical model incorporating the known antagonistic center-surround receptive field organization of these neurons. We found that this simple model could quantitatively account for our experimentally observed differences seen across E and I-type cells across all three maps. Our results thus provide strong evidence against the hypothesis that weakly electric fish use parallel neural pathways to process motion stimuli and we discuss their implications for sensory processing in general. PMID- 24760509 TI - Effects of transcranial direct current stimulation in combination with motor practice on dexterous grasping and manipulation in healthy older adults. AB - Abstract Transcranial anodal stimulation (tDCS) over primary motor cortex (M1) improves dexterous manipulation in healthy older adults. However, the beneficial effects of anodal tDCS in combination with motor practice on natural and clinically relevant functional manual tasks, and the associated changes in the digit contact forces are not known. To this end, we studied the effects of 20 min of tDCS applied over M1 for the dominant hand combined with motor practice (MP) in a sham-controlled crossover study. We monitored the forces applied to an object that healthy elderly individuals grasped and manipulated, and their performances on the Grooved Pegboard Test and the Key-slot task. Practice improved performance on the Pegboard test, and anodal tDCS + MP improved retention of this performance gain when tested 35 min later, whereas similar performance gains degraded in the sham group after 35 min. Interestingly, grip force variability on an isometric precision grip task performed with visual feedback of precision force increased following anodal tDCS + MP, but not sham tDCS + MP. This finding suggests that anodal tDCS over M1 might alter the descending drive to spinal motor neurons involved in the performance of isometric precision grip task under visual feedback leading to increased fluctuations in the grip force exerted on the object. Our results demonstrate that anodal stimulation in combination with motor practice helps older adults to retain their improved performance on a functionally relevant manual task in healthy older adults. PMID- 24760510 TI - EPO-receptor is present in mouse C2C12 and human primary skeletal muscle cells but EPO does not influence myogenesis. AB - Abstract The role and regulation of the pleiotropic cytokine erythropoietin (EPO) in skeletal muscle are controversial. EPO exerts its effects by binding its specific receptor (EPO-R), which activates intracellular signaling and gene transcription in response to internal and external stress signals. EPO is suggested to play a direct role in myogenesis via the EPO-R, but several studies have questioned the effect of EPO treatment in muscle in vitro and in vivo. The lack of certainty surrounding the use of nonspecific EPO-R antibodies contributes to the ambiguity of the field. Our study demonstrates that the EPO-R gene and protein are expressed at each stage of mouse C2C12 and human skeletal muscle cell proliferation and differentiation and validates a specific antibody for the detection of the EPO-R protein. However, in our experimental conditions, EPO treatment had no effect on mouse C2C12 and human muscle cell proliferation, differentiation, protein synthesis or EPO-R expression. While an increase in Akt and MAPK phosphorylation was observed, we demonstrate that this effect resulted from the stress caused by changing medium and not from EPO treatment. We therefore suggest that skeletal muscle EPO-R might be present in a nonfunctional form, or too lowly expressed to play a role in muscle cell function. PMID- 24760512 TI - The isovolumic relaxation to early rapid filling relation: kinematic model based prediction with in vivo validation. AB - Abstract Although catheterization is the gold standard, Doppler echocardiography is the preferred diastolic function (DF) characterization method. The physiology of diastole requires continuity of left ventricular pressure (LVP)-generating forces before and after mitral valve opening (MVO). Correlations between isovolumic relaxation (IVR) indexes such as tau (time-constant of IVR) and noninvasive, Doppler E-wave-derived metrics, such as peak A-V gradient or deceleration time (DT), have been established. However, what has been missing is the model-predicted causal link that connects isovolumic relaxation (IVR) to suction-initiated filling (E-wave). The physiology requires that model-predicted terminal force of IVR (Ft IVR) and model-predicted initial force of early rapid filling (Fi E-wave) after MVO be correlated. For validation, simultaneous (conductance catheter) P-V and E-wave data from 20 subjects (mean age 57 years, 13 men) having normal LV ejection fraction (LVEF>50%) and a physiologic range of LV end-diastolic pressure (LVEDP) were analyzed. For each cardiac cycle, the previously validated kinematic (Chung) model for isovolumic pressure decay and the Parametrized Diastolic Filling (PDF) kinematic model for the subsequent E wave provided Ft IVR and Fi E-wave respectively. For all 20 subjects (15 beats/subject, 308 beats), linear regression yielded Ft IVR = alpha Fi E-wave + b (R = 0.80), where alpha = 1.62 and b = 1.32. We conclude that model-based analysis of IVR and of the E-wave elucidates DF mechanisms common to both. The observed in vivo relationship provides novel insight into diastole itself and the model-based causal mechanistic relationship that couples IVR to early rapid filling. PMID- 24760511 TI - Fibulin-5 null mice with decreased arterial compliance maintain normal systolic left ventricular function, but not diastolic function during maturation. AB - Abstract The large arteries serve as compliant vessels that store energy during systole and return it during diastole. This function is made possible by the elastic fibers in the arterial wall that are assembled during late embryonic and early postnatal development from various proteins, including fibulin-5. Mice and humans with insufficient amounts of fibulin-5 have reduced arterial compliance as adults. Reduced compliance of the large arteries is correlated with hypertension, reduced cardiac function, and an increased risk of death from cardiac and cardiovascular disease. The goal of this study was to quantify arterial compliance, blood pressure, and left ventricular (LV) function from early postnatal development to young adulthood in fibulin-5 null (Fbln5-/-) mice to determine the effects of reduced arterial compliance during this critical period of elastic fiber assembly. We find that ascending aorta compliance is reduced as early as postnatal day (P) 7 and carotid artery compliance is reduced by P21 in Fbln5-/- mice. We did not find significant increases in systolic blood pressure by P60, but pulse pressures are increased by P21 in Fbln5-/- mice. LV systolic function, as measured by ejection fraction and fractional shortening, is unaffected in Fbln5-/- mice. However, LV diastolic function, as measured by tissue Doppler imaging, is compromised at all ages in Fbln5-/- mice. We propose that Fbln5-/- mice represent a suitable model for further studies to determine mechanistic relationships between arterial compliance and LV diastolic function. PMID- 24760513 TI - High-frequency oscillatory ventilation versus conventional ventilation: hemodynamic effects on lung and heart. AB - Abstract High-frequency oscillatory ventilation (HFOV) may improve gas exchange in patients who are inadequately ventilated by conventional mechanical ventilation (CV); however, the hemodynamic consequences of switching to HFOV remain unclear. We compared the effects of CV and HFOV on pulmonary vascular conductance and left ventricular (LV) preload and performance at different airway and filling pressures. In anesthetized dogs, we measured LV dimensions, aortic and pulmonary artery (PA) flow, and mean airway ( AW) and pericardial pressures. Catheter-tip pressure manometers measured aortic, LV, left atrial, and PA pressures. The pericardium and chest were closed. At LV end-diastolic pressure (PLVED) = 5 mmHg and 12 mmHg, PEEP was varied (6 cm H2O, 12 cm H2O, and 18 cm H2O) during CV. Then, at airway pressures equal to those during CV, HFOV was applied at 4 Hz, 10 Hz, and 15 Hz. Increased AW decreased pulmonary vascular conductance. As cardiac output increased, conductance increased. At PLVED = 12 mmHg, conductance was greatest during HFOV at 4 Hz. LV preload (i.e., ALV, our index of end-diastolic volume) was similar during HFOV and CV for all conditions. At PLVED = 12 mmHg, SWLV was similar during CV and HFOV, but, at PLVED = 5 mmHg and AW 10 cm H2O, SWLV was lower during HFOV than CV. Compared to pulmonary vascular conductance at higher frequencies, at PLVED = 12 mmHg, conductance was greater at HFOV of 4 Hz. Effects of CV and HFOV on LV preload and performance were similar except for decreased SWLV at PLVED = 5 mmHg. These observations suggest the need for further studies to assess their potential clinical relevance. PMID- 24760514 TI - The mouse cyclophosphamide model of bladder pain syndrome: tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors. AB - Abstract Painful bladder syndrome/Interstitial cystitis (PBS/IC) is a chronic disorder characterized clinically by recurring episodes of pelvic pain and increased urination frequency, significantly impairing patients' quality of life. Despite this, there is an unmet medical need in terms of effective diagnostics and treatment. Animal models are crucial in this endeavor. Systemic chronic administration of cyclophosphamide (CYP) in mice has been proposed as a relevant preclinical model of chronic bladder pain. However, molecular mechanisms underlying the pathogenesis of this model are lacking. Here, we show that mice, subjected to repetitive systemic injections of CYP, developed mild inflammatory response in bladder tissue characterized by submucosal edema, moderate increase in proinflammatory cytokine gene expression, and mastocytosis. No signs of massive inflammatory infiltrate, tissue hemorrhages, mucosal ulcerations and urothelium loss were observed. Instead, CYP treatment induced urothelium hyperplasia, accompanied by activation of proliferative signaling cascades, and a decrease in the expression of urothelium-specific markers. Metabotropic glutamate (mGlu) receptors have been implicated in chronic pain disorders. CYP administration induced differential changes in mGlu receptors mRNA levels in bladder tissue, without affecting gene expression at spinal cord level, pointing to the potential link between peripheral mGlu receptors and inflammation-induced bladder malfunction and hyperalgesia. Taken together, these data indicate that chronic CYP treatment in mice is a model of PBS mostly relevant to the major, nonulcerative subtype of the syndrome, characterized by a relatively unaltered mucosa and a sparse inflammatory response. This model can help to elucidate the pathogenetic mechanisms of the disease. PMID- 24760515 TI - Dextran induces differentiation of circulating endothelial progenitor cells. AB - Abstract Endothelial progenitor cells (EPCs) have been demonstrated to be effective for the treatment of cardiovascular diseases. However, the differentiation process from circulation to adhesion has not been clarified because circulating EPCs rarely attached to dishes in EPC cultures previously. Here we investigated whether immature circulating EPCs differentiate into mature adhesive EPCs in response to dextran. When floating-circulating EPCs derived from ex vivo expanded human cord blood were cultured with 5% and 10% dextran, they attached to fibronectin-coated dishes and grew exponentially. The bioactivities of adhesion, proliferation, migration, tube formation, and differentiated type of EPC colony formation increased in EPCs exposed to dextran. The surface protein expression rate of the endothelial markers vascular endothelial growth factor (VEGF)-R1/2, VE-cadherin, Tie2, ICAM1, VCAM1, and integrin alphav/beta3 increased in EPCs exposed to dextran. The mRNA levels of VEGF-R1/2, VE-cadherin, Tie2, endothelial nitric oxide synthase, MMP9, and VEGF increased in EPCs treated with dextran. Those of endothelium-related transcription factors ID1/2, FOXM1, HEY1, SMAD1, FOSL1, NFkB1, NRF2, HIF1A, EPAS1 increased in dextran-treated EPCs; however, those of hematopoietic- and antiangiogenic-related transcription factors TAL1, RUNX1, c-MYB, GATA1/2, ERG, FOXH1, HHEX, SMAD2/3 decreased in dextran exposed EPCs. Inhibitor analysis showed that PI3K/Akt, ERK1/2, JNK, and p38 signal transduction pathways are involved in the differentiation in response to dextran. In conclusion, dextran induces differentiation of circulating EPCs in terms of adhesion, migration, proliferation, and vasculogenesis. The differentiation mechanism in response to dextran is regulated by multiple signal transductions including PI3K/Akt, ERK1/2, JNK, and p38. These findings indicate that dextran is an effective treatment for EPCs in regenerative medicines. PMID- 24760516 TI - Combinatory effects of siRNA-induced myostatin inhibition and exercise on skeletal muscle homeostasis and body composition. AB - Abstract Inhibition of myostatin (Mstn) stimulates skeletal muscle growth, reduces body fat, and induces a number of metabolic changes. However, it remains unexplored how exercise training modulates the response to Mstn inhibition. The aim of this study was to investigate how siRNA-mediated Mstn inhibition alone but also in combination with physical activity affects body composition and skeletal muscle homeostasis. Adult mice were treated with Mstn-targeting siRNA and subjected to a treadmill-based exercise protocol for 4 weeks. Effects on skeletal muscle and fat tissue, expression of genes, and serum concentration of proteins involved in myostatin signaling, skeletal muscle homeostasis, and lipid metabolism were investigated and compared with Mstn(-/-) mice. The combination of siRNA-mediated Mstn knockdown and exercise induced skeletal muscle hypertrophy, which was associated with an upregulation of markers for satellite cell activity. SiRNA-mediated Mstn knockdown decreased visceral fat and modulated lipid metabolism similar to effects observed in Mstn(-/-) mice. Myostatin did not regulate its own expression via an autoregulatory loop, however, Mstn knockdown resulted in a decrease in the serum concentrations of myostatin propeptide, leptin, and follistatin. The ratio of these three parameters was distinct between Mstn knockdown, exercise, and their combination. Taken together, siRNA-mediated Mstn knockdown in combination with exercise stimulated skeletal muscle hypertrophy. Each intervention or their combination induced a specific set of adaptive responses in the skeletal muscle and fat metabolism which could be identified by marker proteins in serum. PMID- 24760517 TI - Influence of high ovarian hormones on QT interval duration in young African women. AB - Abstract The longer QT interval duration observed in women compared to men is usually attributed to sexual hormones. The aim of our study was to investigate, among black African women, the influence of hormonal variations during the menstrual cycle on the duration of the QT interval. Fourteen young black African women, healthy, sedentary, aged 24 +/- 1.7 years, with a regular menstrual cycle (28 +/- 1 days) were selected from 59 volunteers. At each phase of their menstrual cycle, menstrual 2.9 +/- 0.6 days, follicular 13 +/- 1.5 days, and luteal 23.1 +/- 1.4 days, an electrocardiogram was performed in supine position after a resting period of 30 min, to measure QT interval duration. QT interval was corrected by Bazett's (QTcb) and Fridericia's (QTcf) formulae. Then, blood samples were obtained to measure estradiol, progesterone, and serum electrolytes (K(+), Ca(2+), Mg(2+)). There was no significant difference in uncorrected QT intervals between the three phases of the menstrual cycle. It was the same for QTcb and QTcf. Moreover, during the menstrual cycle, we did not observe any correlation between each QT, QTcb, QTcf, and estradiol levels which raised during the follicular phase (356.61 +/- 160.77 pg/mL) and progesterone levels which raised during the luteal phase (16.38 +/- 5.88 ng/mL). Finally, the method of Bland and Altman demonstrated that the corrections of QT by Bazett and Fridericia formulae were not interchangeable. The results of this study showed that high levels of estradiol and progesterone in young black African women did not influence the QT, QTcb and QTcf intervals duration during the menstrual cycle. PMID- 24760518 TI - ACE2 deficiency increases NADPH-mediated oxidative stress in the kidney. AB - Abstract Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and hydrolyzes angiotensin II (Ang II) to Ang(1-7). Since Ang II is a strong activator of oxidative stress, we reasoned that ACE2 could be involved in the regulation of renal oxidative stress by governing the levels of Ang II. We, therefore, assessed levels of oxidative stress in kidney cortex of ACE2 knockout and wild-type littermate mice under baseline conditions. We found multiple markers of increased oxidative stress in ACE2KO mice. NADPH oxidase activity was increased in kidney cortex from ACE2KO mice as compared to WT (227 +/- 24% vs.100 +/- 19%, P < 0.001). However, kidney catalase and superoxide dismutase activities were not different between groups. Exogenous Ang II was degraded less efficiently by kidneys from ACE2KO mice than WT mice, and administration of an AT1R blocker (losartan 30 mg/kg/day) resulted in normalization of NADPH oxidase activity in the ACE2KO. These findings suggest that an AT1R-dependent mechanism contributes to increased ROS observed in the ACE2KO. This study demonstrates that genetic deficiency of ACE2 activity in mice fosters oxidative stress in the kidney in the absence of overt hypertension and is associated with reduced kidney capacity to hydrolyze Ang II. ACE2KO mice serve as a novel in vivo model to examine the role of overactivity of NADPH oxidase in kidney function. PMID- 24760519 TI - Effects of mild calorie restriction on anxiety and hypothalamic-pituitary-adrenal axis responses to stress in the male rat. AB - Abstract Chronic calorie restriction (CR) is one of the few interventions to improve longevity and quality of life in a variety of species. It also reduces behavioral indices of anxiety and influences some stress hormones under basal conditions. However, it is not known how CR influences hypothalamic-pituitary adrenal (HPA) axis function or if those on a CR diet have heightened HPA axis responses to stress. We hypothesized elevated basal glucocorticoid levels induced by CR would lead to exacerbated HPA axis responses to the psychological stress, restraint, in the male rat. We first confirmed rats fed 75% of their normal calorie intake for 3 weeks were less anxious than ad libitum-fed (AD) rats in the elevated plus maze test for anxiety. The anxiolytic effect was mild, with only grooming significantly attenuated in the open field and no measured behavior affected in the light/dark box. Despite elevated basal glucocorticoids, CR rats had very similar hormonal and central responses to 15-min restraint to the AD rats. Both CR and AD rats responded to restraint stress with a robust increase in glucocorticoids that was resolved by 60 min. Both groups also showed robust neuronal activation in the paraventricular nucleus of the hypothalamus and in other stress- and feeding-sensitive brain regions that was not substantially affected by calorie intake. Our findings thus demonstrate chronic mild CR is subtly anxiolytic and is not likely to affect HPA axis responses to psychological stress. These findings support research suggesting a beneficial effect of mild CR. PMID- 24760520 TI - Liver x receptors stimulate lipogenesis in bovine mammary epithelial cell culture but do not appear to be involved in diet-induced milk fat depression in cows. AB - Abstract Milk fat synthesis of ruminants can be inhibited by intermediates of ruminal fatty acid biohydrogenation including trans-10, cis-12 conjugated linoleic acid (CLA). These biohydrogenation intermediates signal a coordinated downregulation of genes involved in mammary FA synthesis, transport, and esterification. We have previously reported decreased mammary expression of sterol response element-binding protein 1 (SREBP1), SREBP1-activating proteins, and thyroid hormone-responsive spot 14 (S14) in the cow during diet-induced milk fat depression (MFD), and treatment with trans-10, cis-12 CLA. Liver x receptors (LXR) and retinoid x receptors (RXR) regulate lipogenesis and are known to bind polyunsaturated FA and LXR agonist increases lipid synthesis in mammary epithelial cell culture. The current studies investigated if biohydrogenation products of rumen origin inhibit mammary lipogenesis through LXR and/or RXR. Expression of LXRs was not different in lactating compared to nonlactating bovine mammary tissue, and expression of LXRs, RXRalpha, and selected LXR and RXR target genes was not changed in mammary tissue during diet-induced or CLA-induced MFD in the cow. In bovine mammary epithelial cell culture, LXR agonist stimulated lipogenesis and expression of LXRbeta, ATP-binding cassette 1 (ABCA1), SREBP1c, and S14, but LXR activation did not overcome CLA inhibition of lipogenesis and downregulation of LXRbeta, SREBP1c, and S14 expression. Lastly, expression of the LXR-regulated carbohydrate-responsive element-binding protein (ChREBP) was higher in lactating than nonlactating tissue and was decreased during CLA-induced MFD. We conclude that changes in mammary LXR expression in dairy cows are not involved in MFD and that trans-10, cis-12 CLA inhibition of lipogenesis and diet-induced MFD appears independent of direct LXR signaling. PMID- 24760521 TI - Tactile gating in a reaching and grasping task. AB - Abstract A multitude of events bombard our sensory systems at every moment of our lives. Thus, it is important for the sensory cortex to gate unimportant events. Tactile suppression is a well-known phenomenon defined as a reduced ability to detect tactile events on the skin before and during movement. Previous experiments found detection rates decrease just prior to and during finger abduction, and decrease according to the proximity of the moving effector. This study examined how tactile detection changes during a reach to grasp. Fourteen human participants used their right hand to reach and grasp a cylinder. Tactors were attached to the index finger, the fifth digit, and the forearm of both the right and left arm and vibrated at various epochs relative to a "go" tone. Results showed that detection rates at the forearm decreased before movement onset; whereas at the right index finger, right fifth digit and at the left index finger, left fifth digit, and forearm sites did not decrease like in the right forearm. These results indicate that the task affects gating dynamics in a temporally- and contextually dependent manner and implies that feed-forward motor planning processes can modify sensory signals. PMID- 24760522 TI - Dichotomous mechanisms of aortic stiffening in high-fat diet fed young and old B6D2F1 mice. AB - Abstract Advancing age is associated with increased stiffness of large elastic arteries as assessed by aortic pulse wave velocity (PWV). Greater PWV, associated with increased risk of cardiovascular diseases, may result from altered expression of the extracellular matrix proteins, collagen and elastin, as well as cross-linking of proteins by advanced glycation end products (AGEs). Indeed, aortic PWV is greater in old (28-31 months) normal chow (NC, 16% fat by kcal)-fed male B6D2F1 mice compared with young (Y: 5-7 months) NC-fed mice (397 +/- 8 vs. 324 +/- 14 cm/s, P < 0.05). Aging also induces a ~120% increase in total aortic collagen content assessed by picosirius red stain, a ~40% reduction in medial elastin assessed by Verhoeff's Van Geison stain, as well as a 90% greater abundance of AGEs in the aorta (P < 0.05). The typical American diet contains high dietary fat and may contribute to the etiology of arterial stiffening. To that end, we hypothesized that the age-associated detriments in arterial stiffening are exacerbated in the face of high dietary fat. In young animals, high-fat (40% fat by kcal) diet increases aortic stiffness by 120 +/- 18 cm/s relative to age-matched NC-fed mice (P < 0.001). High-fat was without effect on aortic collagen or AGEs content in young animals; however, elastin was greatly reduced (~30%) after high-fat in young mice. In old animals, high-fat increased aortic stiffness by 108 +/- 47 cm/s but was without effect on total collagen content, medial elastin, or AGEs. These data demonstrate that both aging and high fat diet increase aortic stiffness, and although a reduction in medial elastin may underlie increased stiffness in young mice, stiffening of the aorta in old mice after high-fat diet does not appear to result from a similar structural modification. PMID- 24760523 TI - Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells. AB - Abstract Alveolar fluid clearance is driven by vectorial Na(+) transport and promotes postnatal lung adaptation. The effect of insulin on alveolar epithelial Na(+) transport was studied in isolated alveolar cells from 18-19-day gestational age rat fetuses. Equivalent short-circuit currents (ISC) were measured in Ussing chambers and different kinase inhibitors were used to determine the pathway of insulin stimulation. In Western Blot measurements the activation of mediators stimulated by insulin was analyzed. The ISC showed a fast dose-dependent increase by insulin, which could be attributed to an increased ENaC (epithelial Na(+) channel) activity in experiments with permeabilized apical or basolateral membrane. 5-(N-Ethyl-N-isopropyl)amiloride inhibition of ISC was not affected, however, benzamil-sensitive ISC was increased in insulin-stimulated monolayers. The application of LY-294002 and Akti1/2 both completely blocked the stimulating effect of insulin on ISC. PP242 partly blocked the effect of insulin, whereas Rapamycin evoked no inhibition. Western Blot measurements revealed an increased phosphorylation of AKT after insulin stimulation. SGK1 activity was also increased by insulin as shown by Western Blot of pNDRG1. However, in Ussing chamber measurements, GSK650394, an inhibitor of SGK1 did not prevent the increase in ISC induced by insulin. The application of IGF-1 mimicked the effect of insulin and increased the ENaC activity. In addition, an increased autophosphorylation of the IGF-1R/IR was observed after insulin stimulation. We conclude that insulin rapidly increases epithelial Na(+) transport by enhancing the activity of endogenous ENaC through activation of PI3K/AKT in alveolar cells. PMID- 24760524 TI - Distinct mechanisms of spike timing-dependent LTD at vertical and horizontal inputs onto L2/3 pyramidal neurons in mouse barrel cortex. AB - Abstract Spike timing-dependent plasticity (STDP) is an attractive candidate to mediate the synaptic changes that support circuit plasticity in sensory cortices during development. STDP is prevalent at excitatory synapses, but it is not known whether the underlying mechanisms are universal, or whether distinct mechanisms underpin STDP at different synapses. Here, we set out to compare and contrast STDP at vertical layer 4 and horizontal layer 2/3 inputs onto postsynaptic layer 2/3 neurons in the mouse barrel cortex. We find that both vertical and horizontal inputs show STDP, but that they display different time windows for induction of timing-dependent long-term depression (t-LTD). Moreover, whereas t-LTD at vertical inputs requires presynaptic NMDA receptors and is expressed presynaptically, using paired recordings we find that t-LTD at horizontal inputs requires postsynaptic NMDA receptors and is expressed postsynaptically. These results demonstrate that similar forms of plasticity on the same postsynaptic neuron can be mediated by distinct mechanisms, and suggest that these forms of plasticity may enable these two types of cortical synapses to support different functions. PMID- 24760525 TI - Dietary supplementation with either saturated or unsaturated fatty acids does not affect the mechanoenergetics of the isolated rat heart. AB - Abstract It is generally recognized that increased consumption of polyunsaturated fatty acids, fish oil (FO) in particular, is beneficial to cardiac and cardiovascular health, whereas equivalent consumption of saturated fats is deleterious. In this study, we explore this divergence, adopting a limited purview: The effect of dietary fatty acids on the mechanoenergetics of the isolated heart per se. Mechanical indices of interest include left-ventricular (LV) developed pressure, stroke work, cardiac output, coronary perfusion, and LV power. The principal energetic index is whole-heart oxygen consumption, which we subdivide into its active and basal moieties. The primary mechanoenergetic index of interest is cardiac efficiency, the ratio of work performance to metabolic energy expenditure. Wistar rats were divided into three Diet groups and fed, ad libitum, reference (REF), fish oil-supplemented (FO), or saturated fatty acid supplemented (SFA) food for 6 weeks. At the end of the dietary period, hearts were excised, mounted in a working-heart rig, and their mechanoenergetic performance quantified over a range of preloads and afterloads. Analyses of Variance revealed no difference in any of the individual mechanoenergetic indices among the three Diet groups. In particular, we found no effect of prior dietary supplementation with either saturated or unsaturated fatty acids on the global efficiency of the heart. PMID- 24760526 TI - At the risk of repeating ourselves... Publishing data replication and negative data is good practice. PMID- 24760527 TI - Differential effects of oral and transdermal menopausal hormone therapy on prostacyclin and thromboxane in platelets. AB - Abstract Menopausal hormone therapies (MHT) may increase thrombotic risk but modulate endothelial function and reduce development of vascular lesions. This study compared effects of MHT on prostanoid-modulated adenosine triphosphate (ATP) secretion from platelets in relationship with endothelial reactive hyperemia (RH) index and carotid intima medial thickness (CIMT). Participants were healthy, recently menopausal women of the Kronos Early Estrogen Prevention Study (KEEPS) randomized to one of three treatments: oral conjugated equine estrogen (oCEE, 0.45 mg/day), transdermal 17beta-estradiol (tE2, 50 MUg/day) each with intermittent oral progesterone or placebo pills and patch (PL). Prostacyclin and thromboxane A2 were assessed by quantification of their stable metabolites (6 keto-prostaglandin F1alpha, 6-k-PGF1alpha; thromboxane B2, TXB2), using ELISA. Dense granule ATP secretion from activated platelets was determined by bioluminescence; RH and CIMT were determined by fingertip tonometry and ultrasound, respectively. After 48 months of treatment, platelet content of 6-k PGF1alpha and TXB2 was significantly lower in oCEE compared to the PL. Inhibition of ATP secretion by exogenous activation of cAMP associated with platelet 6-k PGF1alpha (r = -0.41, P = 0.04) and TXB2 (r = 0.71, P = 0.0005) only in the oCEE group. Serum and platelet content of 6-k-PGF1alpha and TXB2 associated positively in the PL and tE2 groups. Serum 6-k-PGF1alpha positively associated with RH in the oCEE group (r = 0.73, P = 0.02), while serum TXB2 positively associated with CIMT in the tE2 group (r = 0.64, P = 0.01). Thus, oCEE and tE2 differentially affect prostanoid-mediated platelet secretory pathways but alone would not account for an increased thrombotic risk for oral MHT. Furthermore, platelet derived prostanoids may contribute to RH and vascular remodeling in healthy menopausal women. PMID- 24760529 TI - Adenylyl cyclase 4 does not regulate collecting duct water and sodium handling. AB - Abstract Adenylyl cyclase (AC)-stimulated cAMP is a key mediator of collecting duct (CD) Na and water transport. AC isoforms 3, 4, and 6 are expressed in the CD. Our group demonstrated that AC6, but not AC3, is involved in regulating CD Na and water transport. However, the role of AC4 in such regulation remains unknown. Therefore, we generated mice with loxP-flanked critical exons in the Adcy4 gene and bred with mice expressing the aquaporin-2/Cre recombinase transgene to yield CD principal cell-specific knockout of AC4 (CD AC4 KO). Isolated inner medullary CD showed 100% genomic target gene recombination in CD AC4 KO mice, while microdissected cortical CD and renal papillary AC4 mRNA was significantly reduced in CD AC4 KO mice. CD AC4 KO had no effect on vasopressin (AVP)-stimulated cAMP generation in the inner medulla. Water intake, urine volume, and urine osmolality were similar between CD AC4 KO and control mice during normal or restricted water intake. Sodium intake, urinary Na excretion, and blood pressure on a normal-, high-, or low-Na diet were not affected by CD AC4 KO. Moreover, there were no differences in plasma AVP or plasma renin concentration between CD AC4 KO and control mice. In summary, these data suggest that CD AC4 does not play a role in the physiologic regulation of CD Na and water handling. PMID- 24760528 TI - Vitamin D deficiency causes airway hyperresponsiveness, increases airway smooth muscle mass, and reduces TGF-beta expression in the lungs of female BALB/c mice. AB - Abstract Vitamin D deficiency is associated with disease severity in asthma. We tested whether there is a causal association between vitamin D deficiency, airway smooth muscle (ASM) mass, and the development of airway hyperresponsiveness (AHR). A physiologically relevant mouse model of vitamin D deficiency was developed by raising BALB/c mice on vitamin D-deficient or -replete diets. AHR was assessed by measuring lung function responses to increasing doses of inhaled methacholine. Five-micron sections from formalin-fixed lungs were used for ASM measurement and assessment of lung structure using stereological methods. Transforming growth factor (TGF)-beta levels were measured in bronchoalveolar lavage fluid (BALF). Lungs were dissected from embryonic day (E) 17.5 vitamin D deficient and -replete fetal mice for quantification of ASM density and relative gene expression of TGF-beta signaling pathway molecules. Eight-week-old adult vitamin D-deficient female mice had significantly increased airway resistance and ASM in the large airways compared with controls. Vitamin D-deficient female mice had a smaller lung volume, volume of parenchyma, and alveolar septa. Both vitamin D-deficient male and female mice had reduced TGF-beta levels in BALF. Vitamin D deficiency did not have an effect on ASM density in E17.5 mice, however, expression of TGF-beta1 and TGF-beta receptor I was downregulated in vitamin D deficient female fetal mice. Decreased expression of TGF-beta1 and TGF-beta receptor I during early lung development in vitamin D-deficient mice may contribute to airway remodeling and AHR in vitamin D-deficient adult female mice. This study provides a link between vitamin D deficiency and respiratory symptoms in chronic lung disease. PMID- 24760530 TI - Ovine fetal swallowing responses to polyhydramnios. AB - Abstract Swallowing of amniotic fluid by late gestation fetuses increases when amniotic fluid volume (AFV) is elevated. Our objectives were to quantitatively characterize fetal swallowing when AFV is elevated above normal to polyhydramniotic levels and to explore the mechanisms that mediate these changes. Late gestation fetal sheep were studied under basal conditions and during intra amniotic infusion of lactated Ringer's solution. Control AFV averaged 631 +/- 214 mL (SE, n = 6), swallowed volume was 299 +/- 94 mL/day, and there were 5.7 +/- 1.8 bouts/day of rapid swallowing. During intra-amniotic infusion, AFV (3065 +/- 894 mL) and daily swallowed volume (699 +/- 148 mL/day) increased (P < 0.05) and the number of bouts reached a maximum of 13.7 +/- 2.0 bouts/day when AFV exceeded 1500 mL. Unexpectedly, the volume swallowed per bout (57.3 +/- 5.8 mL, n = 102) did not vary with AFV (r = 0.023, P = 0.81). Neither the number of swallows/day nor the volume/swallow changed consistently with elevated AFV. Daily swallowed volume increases and reaches a maximum of twice normal as AFV approaches polyhydramniotic levels. Mechanistically, the increase in swallowing was achieved primarily by an increase in the number of bouts of swallowing per day rather than the expected passive increase in volume per bout. This implies changes in fetal behavior as AFV was elevated. Furthermore, swallowed volume was four times more sensitive to increases in AFV than reported previously. PMID- 24760531 TI - Influence of CO2 on neurovascular coupling: interaction with dynamic cerebral autoregulation and cerebrovascular reactivity. AB - Abstract PaCO2 affects cerebral blood flow (CBF) and its regulatory mechanisms, but the interaction between neurovascular coupling (NVC), cerebral autoregulation (CA), and cerebrovascular reactivity to CO2 (CVR), in response to hypercapnia, is not known. Recordings of cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end-tidal CO2 (EtCO2) were performed in 18 subjects during normocapnia and 5% CO2 inhalation while performing a passive motor paradigm. Together with BP and EtCO2, a gate signal to represent the effect of stimulation was used as input to a multivariate autoregressive-moving average model to calculate their separate effects on CBFv. Hypercapnia led to a depression of dynamic CA at rest and during stimulation in both hemispheres (P < 0.02) as well as impairment of the NVC response, particularly in the ipsilateral hemisphere (P < 0.01). Neither hypercapnia nor the passive motor stimulation influenced CVR. Dynamic CA was not influenced by the motor paradigm during normocapnia. The CBFv step responses to each individual input (BP, EtCO2, stimulation) allowed identification of the influences of hypercapnia and neuromotor stimulation on CA, CVR, and NVC, which have not been previously described, and also confirmed the depressing effects of hypercapnia on CA and NVC. The stability of CVR during these maneuvers and the lack of influence of stimulation on dynamic CA are novel findings which deserve further investigation. Dynamic multivariate modeling can identify the complex interplay between different CBF regulatory mechanisms and should be recommended for studies involving similar interactions, such as the effects of exercise or posture on cerebral hemodynamics. PMID- 24760532 TI - Mapping the content of the Patient-Reported Outcomes Measurement Information System (PROMIS(r)) using the International Classification of Functioning, Health and Disability. AB - BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS ((r)) ) is a US National Institutes of Health initiative that has produced self reported item banks for physical, mental and social health. OBJECTIVE: To describe the content of PROMIS at the item level using the World Health Organization's International Classification of Functioning, Disability and Health (ICF). METHODS: All PROMIS adult items (publicly available as of 2012) were assigned to relevant ICF concepts. The content of the PROMIS adult item banks was then described using the mapped ICF code descriptors. RESULTS: The 1,006 items in the PROMIS instruments could all be mapped to ICF concepts at the second level of classification, with the exception of three items of global or general health that mapped across the first-level classification of ICF activity and participation component (d categories). Individual PROMIS item banks mapped from 1 to 5 separate ICF codes indicating one-to-one, one-to-many and many-to-one mappings between PROMIS item banks and ICF second-level classification codes. PROMIS supports measurement of the majority of major concepts in the ICF body functions (b) and activity and participation (d) components using PROMIS item banks or subsets of PROMIS items that could, with care, be used to develop customized instruments. Given that the focus of PROMIS is on measurement of person health outcomes, concepts in body structures (s) and some body functions (b), as well as many ICF environmental factor, have minimal coverage in PROMIS. DISCUSSION: The PROMIS-ICF mapped items provide a basis for users to evaluate the ICF-related content of specific PROMIS instruments and to select PROMIS instruments in ICF-based measurement applications. PMID- 24760533 TI - Vitamin D and health-related quality of life in a community sample of older Canadians. AB - PURPOSE: To assess how vitamin D status is associated with health-related quality of life (HRQOL) among older residents of Canada. DESIGN: We analysed baseline data of 1,493 Canadians aged 50 years and over in Alberta on HRQOL (EQ-5D-5L) and serum 25-hydroxyvitamin D (25(OH)D) as a measure of vitamin D status. We applied multivariable regression methods to examine the association between vitamin D status and each of the five dimensions and the summary index of the EQ-5D-5L. RESULTS: Participants with higher serum 25(OH)D levels were significantly less likely to report problems with mobility, usual activities, and depression and anxiety. Specifically, age- and gender-adjusted odds ratios for reporting problems with mobility, usual activities, and depression and anxiety were 0.58 (95 % confidence interval 0.44-0.78), 0.67 (0.50-0.89), and 0.67 (0.51-0.88) per 100 nmol/L increase in 25(OH)D, respectively. No significant associations were observed for problems with self-care and with pain and discomfort. HRQOL scores combining the responses of each of the five dimensions increased significantly with increasing serum 25(OH)D levels. CONCLUSIONS: This is the first study to reveal the importance of vitamin D for the five dimensions of HRQOL in a community-based sample. The observed associations of vitamin D and HRQOL call for intervention studies to strengthen the evidence of the potential benefits of vitamin D supplementation for HRQOL among older adults. PMID- 24760535 TI - Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion. AB - Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently - despite elusive mechanisms of action - bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5. PMID- 24760536 TI - Effect of testosterone on markers of mitochondrial oxidative phosphorylation and lipid metabolism in muscle of aging men with subnormal bioavailable testosterone. AB - OBJECTIVE: Recent studies have indicated that serum testosterone in aging men is associated with insulin sensitivity and expression of genes involved in oxidative phosphorylation (OxPhos), and that testosterone treatment increases lipid oxidation. Herein, we investigated the effect of testosterone therapy on regulators of mitochondrial biogenesis and markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels. METHODS: Skeletal muscle biopsies were obtained before and after treatment with either testosterone gel (n=12) or placebo (n=13) for 6 months. Insulin sensitivity and substrate oxidation were assessed by euglycemic hyperinsulinemic clamp and indirect calorimetry. Muscle mRNA levels and protein abundance and phosphorylation of enzymes involved in mitochondrial biogenesis, OxPhos, and lipid metabolism were examined by quantitative real-time PCR and western blotting. RESULTS: Despite an increase in lipid oxidation (P<0.05), testosterone therapy had no effect on insulin sensitivity or mRNA levels of genes involved in mitochondrial biogenesis (PPARGC1A, PRKAA2, and PRKAG3), OxPhos (NDUFS1, ETFA, SDHA, UQCRC1, and COX5B), or lipid metabolism (ACADVL, CD36, CPT1B, HADH, and PDK4). Consistently, protein abundance of OxPhos subunits encoded by both nuclear (SDHA and UQCRC1) and mitochondrial DNA (ND6) and protein abundance and phosphorylation of AMP-activated protein kinase and p38 MAPK were unaffected by testosterone therapy. CONCLUSION: The beneficial effect of testosterone treatment on lipid oxidation is not explained by increased abundance or phosphorylation-dependent activity of enzymes known to regulate mitochondrial biogenesis or markers of OxPhos and lipid metabolism in the skeletal muscle of aging men with subnormal bioavailable testosterone levels. PMID- 24760534 TI - Pilot clinical study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased risk for colorectal cancer. AB - Colorectal cancer (CRC) remains a significant cause of mortality. Inhibitors of cyclooxygenase (COX) and thus prostaglandin E2, are promising CRC preventives, but have significant toxicities. Ginger has been shown to inhibit COX, to decrease the incidence and multiplicity of adenomas, and decrease PGE2 concentrations in subjects at normal risk for CRC. This study was conducted to determine the effects of 2.0 g/d of ginger given orally on the levels of PGE2, leukotriene B4 (LTB4), 13-hydroxy-octadecadienoic acids, and 5-, 12-, & 15 hydroxyeicosatetraenoic acid, in the colonic mucosa of subjects at increased risk for CRC. We randomized 20 subjects to 2.0 g/d ginger or placebo for 28 d. At baseline and Day 28, a flexible sigmoidoscopy was used to obtain colon biopsies. A liquid chromatography mass spectrometry method was used to determine eicosanoid levels in the biopsies, and levels were expressed per amount of protein or free arachidonic acid (AA). There was a significant decrease in AA between baseline and Day 28 (P = 0.05) and significant increase in LTB4 (P = 0.04) when normalized to protein, in subjects treated with ginger versus placebo. No other changes in eicosanoids were observed. There was no difference between the groups in total adverse events (AE; P = 0.06). Ginger lacks the ability to decrease eicosanoid levels in people at increased risk for CRC. Ginger did appear to be both tolerable and safe; and could have chemopreventive effects through other mechanisms. Further investigation should focus on other markers of CRC risk in those at increased CRC risk. PMID- 24760537 TI - Treatment effectiveness of pasireotide on health-related quality of life in patients with Cushing's disease. AB - OBJECTIVE: Cushing's disease (CD) can significantly impair patients' health related quality of life (HRQOL). This study investigated the treatment effectiveness of pasireotide on HRQOL of CD patients, and assessed the relationships between HRQOL and urinary free cortisol (UFC) and CD-related signs and symptoms. DESIGN: In this phase III, randomized, double-blind study, patients with UFC >=1.5*upper limit of normal (ULN) received s.c. pasireotide 600 or 900 MUg twice daily. The trial primary endpoint was UFC at or below ULN at month 6 without dose titration. Open-label treatment continued through month 12. HRQOL was measured using the Cushing's Quality of Life Questionnaire (CushingQoL) instrument at baseline and follow-up visits until month 12 during which clinical signs and features of CD, and the Beck Depression Inventory II (BDI-II), were also collected. METHODS: Pearson's/Spearman's correlations between changes in CushingQoL and changes in clinical signs and symptoms were assessed. Changes in CushingQoL and the proportion of patients achieving a clinically meaningful improvement in CushingQoL were also compared among patients stratified by mean UFC (mUFC) control status (controlled, partially controlled, and uncontrolled) at month 6. Analyses were also conducted at month 12, with multivariable adjustment for baseline characteristics and CushingQoL. RESULTS: Change in CushingQoL was significantly correlated with changes in mUFC (r=-0.40), BMI (r=-0.39), weight (r=-0.41), and BDI-II (r=-0.54) at month 12 but not at month 6. The percentage of CushingQoL responders at month 12 based on month 6 mUFC control status were as follows: 63, 58.8, and 37.9% in the controlled, partially controlled, and uncontrolled groups respectively. Adjusted CushingQoL scores at month 12 were 58.3 for controlled patients (Delta=11.5 vs uncontrolled, P=0.012) and 54.5 for partially controlled patients (Delta=7.7 vs uncontrolled, P=0.170). CONCLUSIONS: Pasireotide treatment can result in a meaningful HRQOL improvement among those who complete a 12-month treatment period, most often among patients achieving biochemical control. PMID- 24760538 TI - Adiponectin gene variants and the risk of coronary heart disease: a 16-year longitudinal study. AB - OBJECTIVE: Circulating adiponectin levels have been shown to be associated with a risk of coronary heart disease (CHD). However, its primary role in protecting against the development of CHD remains controversial due to conflicting observations in prospective studies. To gain further insight into the primary role of adiponectin, our major objective was to investigate the relationship between single nucleotide polymorphisms (SNPs) of the adiponectin gene (ADIPOQ) and incident CHD in a population-based cohort with no CHD at baseline. DESIGN AND METHODS: We conducted a 16-year longitudinal study in 2196 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). During 33 862 person years of follow-up, 184 subjects developed CHD (cumulative incidence rate=5.4 per 1000 person-years). Nine ADIPOQ SNPs with potential functional relevance or shown to be associated with adiponectin levels and/or CHD were genotyped. RESULTS: Among the nine ADIPOQ SNPs, +276G>T (rs1501299) was independently associated with incident CHD in men but not in women, even after adjustments for traditional cardiovascular risk factors (Padjusted=5.5*10(-3) to 0.023; hazard ratio=1.39 1.54). Furthermore, there was a significant association of the T allele of +276G>T with a lower adiponectin level (P=0.027; beta (95% CI)=-0.05 (-0.10, 0.01). CONCLUSIONS: This study demonstrated that +276G>T may be an independent predictor of CHD development. Our findings suggest that low adiponectin levels, as may be influenced by +276G>T, confer a higher risk of CHD, in keeping with a role of hypoadiponectinaemia in the development of CHD in the general population. PMID- 24760539 TI - Small medullary thyroid carcinoma: post-operative calcitonin rather than tumour size predicts disease persistence and progression. AB - OBJECTIVE: Recently, small medullary thyroid carcinomas (smallMTCs; <=1.5 cm) are frequently diagnosed, occasionally as incidental findings in surgical specimens. Their clinical course varies. We examined tumour size as a predictor of clinical behaviour. DESIGN: A retrospective study. METHODS: A total of 128 smallMTC patients (35.2% males and 45% familial) were followed up for 0.9-30.9 years. According to tumour size (cm), patients were classified into four groups: group 1, 0.1-0.5 (n=33); group 2, 0.6-0.8 (n=33); group 3, 0.8-1.0 (n=29) and group 4, 1.1-1.5 (n=33). RESULTS: Pre- and post-operative calcitonin levels were positively associated with the tumour size (P<0.001). Capsular and lymph node invasion were more frequent in groups 3 and 4 (P<0.03); the stage was more advanced and the outcome was less favourable with an increasing tumour size (P<0.001). Groups 1 and 2 patients were more frequently cured (group 1, 87.8%; group 2, 72.7%; group 3, 68.9%; and group 4, 48.5%; P=0.002). The 10-year probability of lack of disease progression according to the tumour size differed between patients with tumour sizes of 0.1-1.0 and 1.1-1.5 cm (96.6%, 81.3%, x(2)=4.03, P=0.045 for log-rank test). Post-operative calcitonin was the only predictor significantly associated with the 10-year progression of disease. Post operative calcitonin levels >=4.65 pg/ml predicted disease persistence (sensitivity 93.8% and specificity 90%) and >=14.5 pg/ml predicted disease progression (sensitivity 100%, specificity 82%, receiver operating characteristic curve analysis). CONCLUSIONS: Tumour size may be of clinical importance only in patients with MTCs >1 cm in size. Post-operative calcitonin is a more important predictor than size for disease progression. PMID- 24760540 TI - Association of HDL-C and apolipoprotein A-I with the risk of type 2 diabetes in subjects with impaired fasting glucose. AB - OBJECTIVES: HDLs have many diverse functions. The goal of this study was to determine the association of HDL cholesterol (HDL-C) and apolipoprotein A-I (apoA I) with the development of type 2 diabetes (T2D). In particular, this study determined the association between the ratio of HDL-C to apoA-I (HA) and incident T2D. DESIGN AND METHODS: A total of 27 988 subjects with impaired fasting glucose (IFG) (18 266 men and 9722 women) aged 21-91 years (mean age 40.7 years) were followed for a mean duration of 2.81 years. RESULTS: Study subjects were divided into quartiles according to the baseline HA ratio. Age, male sex, current smoking, BMI, waist circumference, and high-sensitivity C-reactive protein decreased across the quartiles, and all metabolic profiles, including blood pressure, fasting glucose, insulin resistance as determined by homeostasis model assessment of insulin resistance, and lipid measurements such as total cholesterol, LDL cholesterol, non-HDL-C, and apoB, improved as the HA ratio increased. In addition, incident cases of T2D decreased as the HA ratio increased, independent of age, sex, BMI, current smoking, systolic blood pressure, HbA1c, fasting serum insulin, family history of diabetes, and serum triglyceride concentrations (HR (95% CI) of fourth quartile vs first quartile; 0.76 (0.67-0.86), P<0.0001). CONCLUSIONS: A higher HA ratio was associated with favorable metabolic profiles and a lower risk of T2D development in subjects with IFG. PMID- 24760541 TI - Treatment of osteogenesis imperfecta in adults. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous rare connective tissue disorder commonly caused by mutations in the collagen type I genes. Pharmacological treatment has been most extensively studied in children, and there are only few studies comprising adult OI patients. OBJECTIVES: i) To review the literature on the current medical management of OI in children and adults, and thereby identify unmet medical needs and ii) to present an overview of possible future treatment options. RESULTS: Individualization and optimization of OI treatment in adults remain a challenge, because available treatments do not target the underlying collagen defect, and available literature gives weak support for treatment decisions for adult patients. CONCLUSIONS: Bisphosphonates are still the most widely used pharmacological treatment for adult OI, but the current evidence supporting this is sparse and investigations on indications for choice and duration of treatment are needed. PMID- 24760542 TI - A room with a view of integrity and professionalism: personal reflections on teaching responsible conduct of research in the neurosciences. AB - Neuroscientists are increasingly put into situations which demand critical reflection about the ethical and appropriate use of research tools and scientific knowledge. Students or trainees also have to know how to navigate the ethical domains of this context. At a time when neuroscience is expected to advance policy and practice outcomes, in the face of academic pressures and complex environments, the importance of scientific integrity comes into focus and with it the need for training at the graduate level in the responsible conduct of research (RCR). I describe my experience teaching RCR in a graduate neuroscience program and identify three personal reflections where further dialogue could be warranted: (1) mobilizing a common set of competencies and virtues standing for professionalism in the neurosciences; (2) tailoring RCR for the neurosciences and empowering students through the active engagement of mentors; (3) soliciting shared responsibility for RCR training between disciplines, institutions and governmental or funding agencies. PMID- 24760543 TI - Determination of 10-chloromethyl-11-demethyl-12-oxo-calanolide A in rat plasma using liquid chromatography-tandem mass spectrometry and its application to pharmacokinetics. AB - A rapid and specific liquid chromatography-tandem mass spectrometry for the quantitation of 10-chloromethyl-11-demethyl-12-oxo-calanolide A (F18), a small molecule nonnucleoside reverse transcriptase inhibitor, was developed and validated in rat plasma. F18 was monitored by positive electrospray ionization in the selected reaction monitoring mode. The standard curve was linear over the range of 2-1000 ng/mL. The method was used to determine the plasma concentration of F18 after a single oral dose of 50 mg/kg in rats. PMID- 24760544 TI - PiRNAs link epigenetic modifications to reprogramming. AB - Cell reprogramming is a process involved in changing epigenetic landscapes, including histone modification, DNA methylation, and expression of non-coding RNAs; and reprogramming finally leads to changes in gene expression profile and cell fate. A great challenge to this field is to overcome epigenetic suppression exerted by highly differentiated cells of those key regions that are critical for establishment and maintenance of final cell types or induced pluripotent stem cells (iPSCs). As a new class of small non-coding RNAs, piwi-interacting RNAs (piRNAs) have been shown to play important roles in transposon silencing, transcriptional/post-transcriptional regulation, and epigenetic modifications. In this review, we discuss recent advances in which piRNAs were proposed or shown to be barriers to reprogramming suppression through epigenetic silencing, and it may be necessary to overcome this piRNA-derived barrier to achieve final cellular status during reprogramming. Therefore, gaining deeper insights into the mechanism(s) by which piRNAs mediate epigenetic regulation of gene expression, genome stability and chromatin status may offer a new avenue for efficient reprogramming of somatic cells toward a pluripotent state. PMID- 24760545 TI - Whole-brain mapping of behaviourally induced neural activation in mice. AB - The ability to visualize behaviourally evoked neural activity patterns across the rodent brain is essential for understanding the distributed brain networks mediating particular behaviours. However, current imaging methods are limited in their spatial resolution and/or ability to obtain brain-wide coverage of functional activity. Here, we describe a new automated method for obtaining cellular-level, whole-brain maps of behaviourally induced neural activity in the mouse. This method combines the use of transgenic immediate-early gene reporter mice to visualize neural activity; serial two-photon tomography to image the entire brain at cellular resolution; advanced image processing algorithms to count the activated neurons and align the datasets to the Allen Mouse Brain Atlas; and statistical analysis to identify the network of activated brain regions evoked by behaviour. We demonstrate the use of this approach to determine the whole-brain networks activated during the retrieval of fear memories. Consistent with previous studies, we identified a large network of amygdalar, hippocampal, and neocortical brain regions implicated in fear memory retrieval. Our proposed methods can thus be used to map cellular networks involved in the expression of normal behaviours as well as to investigate in depth circuit dysfunction in mouse models of neurobiological disease. PMID- 24760546 TI - Developing an inter-organizational community-based health network: an Australian investigation. AB - Networks in health care typically involve services delivered by a defined set of organizations. However, networked associations between the healthcare system and consumers or consumer organizations tend to be open, fragmented and are fraught with difficulties. Understanding the role and activities of consumers and consumer groups in a formally initiated inter-organizational health network, and the impacts of the network, is a timely endeavour. This study addresses this aim in three ways. First, the Unbounded Network Inter-organizational Collaborative Impact Model, a purpose-designed framework developed from existing literature, is used to investigate the process and products of inter-organizational network development. Second, the impact of a network artefact is explored. Third, the lessons learned in inter-organizational network development are considered. Data collection methods were: 16 h of ethnographic observation; 10 h of document analysis; six interviews with key informants and a survey (n = 60). Findings suggested that in developing the network, members used common aims, inter professional collaboration, the power and trust engendered by their participation, and their leadership and management structures in a positive manner. These elements and activities underpinned the inter-organizational network to collaboratively produce the Health Expo network artefact. This event brought together healthcare providers, community groups and consumers to share information. The Health Expo demonstrated and reinforced inter-organizational working and community outreach, providing consumers with community-based information and linkages. Support and resources need to be offered for developing community inter-organizational networks, thereby building consumer capacity for self-management in the community. PMID- 24760547 TI - Organic acids and protein compounds causing the photoluminescence properties of natural rubber membranes and the quenching phenomena from Au nanoparticle incorporation. AB - Natural rubber membranes were fabricated using latex from Hevea brasiliensis trees (clone RRIM 600) by casting, and controlling the time and temperature of thermal treatment. Three temperatures were used: 65, 80 and 120 degrees C and the corresponding annealing times of 6, 8, 10 and 12 h. The centrifugation of the latex produces the constituent phases: solid rubber (F1), serum or protein components (F2) and bottom fraction (F3). The photoluminescence properties could be correlated with organic acid components of latex. Natural rubber membranes were used as the active substrate (reducing agent) for the incorporation of colloidal Au nanoparticles synthesized by in situ reduction at different times. The intensity of photoluminescence bands assigned to the natural rubber decreases with the increase in amount of nanoparticles present on the membrane surface. It can be assumed that Au nanoparticles may be formed by reduction of the Au cation reacting with functional groups that are directly related to photoluminescence properties. However, the quenching of fluorescence may be attributed to the formation of a large amount of metal nanostructures on the natural rubber surface. PMID- 24760548 TI - Computational modeling of vibration-induced systemic hydration of vocal folds over a range of phonation conditions. AB - Predicting phonation conditions that are benign to voice health remains a biomechanically relevant problem. Our objective is to provide insight into vocal fold (VF) hydration based on continuum-based VF models that are able to compute VF stresses during phonation and a scheme for the extraction and generalization of such computational data based on the principle of linear superposition. Because VF tissue is poroelastic, spatial gradients of VF hydrostatic stresses computed for a given phonation condition determine VF interstitial fluid flow. The present approach transforms, based on linear superposition principles, the computed interstitial fluid velocities at the particular phonation to those at an arbitrary phonation condition. Intersititial fluid flow characteristics for a range of phonation conditions are compared. For phonation conditions with no or moderate collision, no dehydration per vibration cycle is predicted throughout the VF. For more severe collision conditions, tissue dehydration is restricted to a region close to the glottal surface. Interstitial fluid displacement in the VF is found to be heterogeneous and strongly dependent on the phonation condition. A phonation condition is found to exist for which dehydration peaks. The proposed method significantly expands the scope and relevance of conducting isolated numerical simulations of VF vibration. PMID- 24760549 TI - Fiat lux in understanding cardiac pacing, resynchronization and signalling by way of optogenetics. PMID- 24760550 TI - Purinergic receptors and atherosclerosis: emerging role for vessel wall P2Y12. PMID- 24760551 TI - A glimpse at cardiac ion channel macromolecular complexes. PMID- 24760552 TI - Lipoprotein (a) concentrations, apolipoprotein (a) phenotypes, and peripheral arterial disease in three independent cohorts. AB - AIMS: The relevance of lipoprotein(a) [Lp(a)] concentrations and low-molecular weight (LMW) apo(a) phenotypes in peripheral arterial disease (PAD) has only been investigated by few studies. Therefore, we analysed this association in three independent cohorts and performed a Mendelian Randomization approach using instrumental variable regression. METHODS AND RESULTS: Lp(a) concentrations, apo(a) phenotypes, and one SNP in the LPA gene (rs10455872) were measured in the CAVASIC study, including 241 male patients with intermittent claudication and 246 age- and diabetes-matched controls as well as in the two population-based studies KORA F3 (n = 3184) and KORA F4 (n = 3080). In KORA F3/F4, 109/80 persons suffered from intermittent claudication, 200/144 from PAD, and 128/103 showed an ankle brachial index (ABI) <0.9. In CAVASIC, adjusted logistic regression analyses revealed significant associations between an increase of log-Lp(a) per one standard deviation (SD) (OR = 1.28, P = 0.02) as well as LMW apo(a) phenotypes and symptomatic PAD (OR = 1.65, P = 0.03). Linear regression models with continuous ABI showed a significant association in the combined analyses of KORA F3/F4: an increase in log-Lp(a) per one SD (beta = -0.006, P = 0.005) and the presence of LMW apo(a) phenotypes (beta = -0.011, P = 0.02) or the minor allele of rs10455872 (beta = -0.016, P = 0.03) were associated with a decrease in ABI in the fully adjusted linear and instrumental variable regression models. CONCLUSION: Analyses in three independent populations showed significant associations of Lp(a) concentrations, LMW apo(a) phenotypes, and rs10455872 with PAD. This points to a causal relationship between Lp(a) and PAD since the genetically determined apo(a) phenotypes and SNP alleles are indeed associated with PAD. PMID- 24760554 TI - Obituary for prof. Roberto Passariello. PMID- 24760556 TI - An HPLC method for the quantitation of 3-pentylbenzo[c]thiophen-1(3H)-one in dog plasma and its application to a pharmacokinetic study. AB - A simple, sensitive and reproducible high-performance liquid chromatography (HPLC) assay method was developed for the estimation of 3-pentylbenzo[c]thiophen 1(3H)-one (S5 ), a potential anti-ischemic stroke agent, in dog plasma. The analytical procedure involves protein precipitation of S5 and nobiletin (internal standard) from dog plasma with acetonitrile. Chromatographic separation was achieved on Sapphire C18 analytical column with methanol-water (80:20, v/v) as mobile phase. The eluate was monitored using a UV detector set at 260 nm. The calibration curves were linear over the range of 0.2-20 ug/mL. Absolute recoveries of S5 were 79.2-86.1% from dog plasma. The intra- and inter-day relative standard deviation precisions were <7 and 5%, respectively. The method was successfully applied to the pharmacokinetic study of S5 in beagle dogs. PMID- 24760553 TI - Methylation potential associated with diet, genotype, protein, and metabolite levels in the Delta Obesity Vitamin Study. AB - Micronutrient research typically focuses on analyzing the effects of single or a few nutrients on health by analyzing a limited number of biomarkers. The observational study described here analyzed micronutrients, plasma proteins, dietary intakes, and genotype using a systems approach. Participants attended a community-based summer day program for 6-14 year old in 2 years. Genetic makeup, blood metabolite and protein levels, and dietary differences were measured in each individual. Twenty-four-hour dietary intakes, eight micronutrients (vitamins A, D, E, thiamin, folic acid, riboflavin, pyridoxal, and pyridoxine) and 3 one carbon metabolites [homocysteine (Hcy), S-adenosylmethionine (SAM), and S adenosylhomocysteine (SAH)], and 1,129 plasma proteins were analyzed as a function of diet at metabolite level, plasma protein level, age, and sex. Cluster analysis identified two groups differing in SAM/SAH and differing in dietary intake patterns indicating that SAM/SAH was a potential marker of nutritional status. The approach used to analyze genetic association with the SAM/SAH metabolites is called middle-out: SNPs in 275 genes involved in the one-carbon pathway (folate, pyridoxal/pyridoxine, thiamin) or were correlated with SAM/SAH (vitamin A, E, Hcy) were analyzed instead of the entire 1M SNP data set. This procedure identified 46 SNPs in 25 genes associated with SAM/SAH demonstrating a genetic contribution to the methylation potential. Individual plasma metabolites correlated with 99 plasma proteins. Fourteen proteins correlated with body mass index, 49 with group age, and 30 with sex. The analytical strategy described here identified subgroups for targeted nutritional interventions. PMID- 24760558 TI - High-precision determination of 13C-18O bonds in CO2 using multicollector peak hopping. AB - RATIONALE: Rapid development of the CO2 'clumped-isotope' temperature proxy (Delta47 ) has involved both resource- and labor-intensive analytical methods. We report strategies for measuring Delta47 on a conventional mass spectrometer, with the usual CO2 set of three Faraday collectors while reducing the time devoted to standardization with temperature-equilibrated CO2. METHODS: We measured Delta47 in CO2 on a mass spectrometer using only three Faraday cups by 'multicollector peak hopping', directing (46)CO2(+) and (47)CO2(+) ion beams into the Faraday cups normally used for m/z 44 and 45. Delta47 was calculated from the previously measured delta(13) C and delta(18) O values and we then measured (47)CO2(+)/(46)CO2(+). We invoke a protocol for correcting ion-beam intensities for secondary electrons to address common problems with compositional non linearity and both long- and short-term measurement stability. RESULTS: Our method eliminates the need for six Faraday cups for measuring Delta47, a possible advantage for many laboratories. In addition, by using a correction based on removing the effects of secondary electrons, we remove the Delta47 dependence on delta(47)CO2. As a result, our methods are robust against mass spectrometer operating conditions. CONCLUSIONS: Delta47 can be precisely measured on mass spectrometers currently employed for measuring delta(13) C and delta(18) O values without significant resource investment. Accounting for ion scatter during measurements of CO2 results in improved external precision and long-term stability, while significantly increasing the machine time available for sample analysis. PMID- 24760557 TI - Characterizing synthetic polymers and additives using new ionization methods for mass spectrometry. AB - RATIONALE: New inlet and vacuum ionization methods provide advantages of specificity, simplicity and speed for the analysis of synthetic polymers and polymer additives directly from surfaces such as fibers using mass spectrometry (MS) on different commercial mass spectrometers (Waters SYNAPT G2, Thermo LTQ Velos). METHODS: We compare inlet ionization methods with the recently discovered vacuum ionization method. This method, termed matrix assisted ionization vacuum (MAIV), utilizes the matrix 3-nitrobenzonitrile (3-NBN) for the analysis of synthetic polymers and additives without additional energy input by simply exposing the matrix:analyte:salt to the vacuum of the mass spectrometer. Matrix:analyte:salt samples can be introduced while dry (surfaces, e.g. glass slides, pipet tips) or slightly wet (e.g. filter paper, pipet tips). RESULTS: Compounds ionized by these methods can be analyzed in both positive and negative detection modes through cationization or deprotonation, respectively. The dynamic range of the experiment can be enhanced, as well as structural analysis performed, by coupling the vacuum ionization method with ion mobility spectrometry mass spectrometry (IMS-MS) and tandem mass spectrometric (MS/MS) fragmentation. CONCLUSIONS: The specificity of 3-NBN matrix to ionize small and large nonvolatile analyte molecules by MAIV makes this matrix a good choice for observing low-abundance additives in the presence of large amounts of synthetic polymer using MS. PMID- 24760559 TI - Determination of 13C/12 C ratios of endogenous urinary 5-amino-imidazole-4 carboxamide 1beta-D-ribofuranoside (AICAR). AB - RATIONALE: AICAR (5-aminoimidazole-4-carboxamide 1beta-D-ribofuranoside) is prohibited in sport according to rules established by the World Anti-Doping Agency. Doping control laboratories identify samples where AICAR abuse is suspected by measuring its urinary concentration and comparing the observed level with naturally occurring concentrations. As the inter-individual variance of urinary AICAR concentrations is large, this approach requires a complementary method to unambiguously prove the exogenous origin of AICAR. Therefore, a method for the determination of carbon isotope ratios (CIRs) of urinary AICAR has been developed and validated. METHODS: Concentrated urine samples were fractionated by means of liquid chromatography for analyte cleanup. Derivatization of AICAR yielding the trimethylsilylated analog was necessary to enable CIR determinations by gas chromatography/combustion/isotope ratio mass spectrometry. The method was tested for its repeatability and stability over time and a linear mixing model was applied to test for possible isotopic discrimination. A reference population of n = 63 males and females was investigated to calculate appropriate reference limits to differentiate endogenous from exogenous urinary AICAR. These limits were tested by an AICAR elimination study. RESULTS: The developed method fulfills all the requirements for adequate sports drug testing and was found to be fit for purpose. The investigated reference population showed a larger variability in the CIR of AICAR than of the endogenous steroids. Nevertheless, the calculated thresholds for differences between AICAR and endogenous steroids can be applied straightforwardly to evaluate suspicious doping control samples with the same statistical confidence as established e.g. for testosterone misuse. These thresholds enabled the detection of a single oral AICAR administration for more than 40 h. CONCLUSIONS: Determination of thee CIRs is the method of choice to distinguish between an endogenous and an exogenous source of urinary AICAR. The developed method will enable investigations into doping control samples with elevated urinary concentrations of AICAR and clearly differentiate between naturally produced/elevated and illicitly administered AICAR. PMID- 24760560 TI - Direct detection of brominated flame retardants from plastic e-waste using liquid extraction surface analysis mass spectrometry. AB - RATIONALE: The worldwide generation of plastic electronic waste (e-waste) is reaching epic proportions. The presence of toxic brominated flame retardants (BFRs) within these materials limits their ability to be recycled, resulting in large amounts of e-waste reaching landfills. METHODS: Liquid extraction surface analysis mass spectrometry (LESA-MS) employing a chip-based nanoelectrospray coupled to a triple quadrupole mass spectrometer represents a novel control technology for directing e-waste streams for recycling. LESA-MS allows direct sampling and analysis of solid material, capable of detecting BFRs including polybrominated diphenyl ethers (PBDEs) and tetrabromobisphenol A (TBBP-A), the two most common flame retardant additives currently in circulation. RESULTS: Authentic PBDE congeners and TBBP-A were deposited on glass and characterised by LESA-MS analysis. PBDEs are notoriously difficult to detect via electrospray; however, they were detected with ease by utilising a combination of nanoelectrospray and solvent doped with ammonium acetate. In situ detection of TBBP-A within plastic e-waste was also possible by performing LESA-MS on the surface of granulated material provided by a commercial waste depot. E-waste sample analysis was completely automated, with each sample analysed in less than 1 min. CONCLUSIONS: LESA-MS is fast, simple, and robust allowing unambiguous detection of a range of additives through tandem mass spectrometry. LESA-MS does not require dissolution of the solid matrix nor the sample to be present under vacuum and the use of separative techniques prior to analysis is not necessary. PMID- 24760561 TI - Electrospray ionization tandem mass spectrometry study of six isomeric cationic amphiphiles with ester/amide linker. AB - RATIONALE: Isomeric cationic amphiphiles differing only in the orientation of the linker group have been demonstrated to possess dramatically changed gene transfer efficacies. Studies aimed at understanding structure-stability correlations of such isomeric cationic amphiphiles at the molecular level are yet to be undertaken. Such studies may throw significant new insights into the mechanistic origin on their contrasting bioactivities. METHODS: Electrospray ionization mass spectrometry (ESI-MS) and multi-stage tandem mass spectrometric (MS(n)) experiments were performed on a LCQ ion trap mass spectrometer. The decomposition pathway was confirmed by high-resolution mass spectrometry data from a quadrupole time-of-flight (Q-TOF) mass spectrometer. Dissociation curves were drawn based on the intensities of precursor and product ions. RESULTS: The collision-induced dissociation (CID) spectra of the M(+) ion of each isomeric pair showed distinct product ions (3 pairs). Normal esters (1 and 3) showed abundant product ions with a neighboring group participation (NGP) reaction and reverse esters (lipid 2 and 4) showed McLafferty rearrangement product ions. The spectra of a normal amide (5) and a reverse amide (6) are similar to that found in the corresponding ester, except for the absence of the McLafferty rearrangement in 6. Dissociation curves revealed that normal esters/amide decompose at lower energy than those of corresponding reverse esters/amide. CONCLUSIONS: The lipids which easily decompose (flexible) show dramatically enhanced gene delivery capabilities and the lipids which decompose at higher collision energy (CE) values (rigid) are transfection incompetent. PMID- 24760562 TI - Automated non-stepwise preparation of bioanalytical calibration standards and quality controls using an ultra-low volume digitizing liquid dispenser. AB - RATIONALE: Stepwise preparation of calibration standards and quality controls (QCs) is one of the most routine and laborious steps in bioanalysis. An alternative non-contact dispenser using low picoliter digitized dispensing technology is evaluated for its application in non-stepwise preparation of calibration curve and QCs in bioanalysis. METHODS: Fluorescein was initially used to assess the accuracy and precision of dispense volumes with fluorescent measurement. Various concentrations of MX-1, an in-house proprietary small molecule compound, in neat solution and in dog plasma were prepared manually with calibrated pipettors and digitally by the digital dispenser. The plasma samples were extracted by protein precipitation. The resultant extracted samples and neat solutions of MX-1 were analyzed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) using an electrospray ionization (ESI) source in positive ion mode with selected reaction monitoring (SRM) of the mass transitions. RESULTS: In the three-day precision and accuracy assessment of dispensing volumes between 13 pL to 411.2 nL, the intra-day precision and accuracy ranged from 1.4% to 10.3% and 12.7% to 12.8%, respectively. The inter-day precision and accuracy ranged from 3.5% to 7.8% and -6.6% to 10.4%, respectively. For real analysis of in vivo study samples, all 49 samples analyzed showed a less than 5% difference between calibrations with digital and manual curve preparations. The resultant pharmacokinetic (PK) parameters were physiologically comparable as well. CONCLUSIONS: Using the digitized picoliter dispensing technology, high-speed automated precise and accurate dispense of a wide range of volumes can be achieved and tests for bioanalytical standards and QC preparations passed the stringent criteria set forth for regulated bioanalysis using LC/MS/MS-based technology. The digital dispenser has been found to be a useful tool in drug discovery for automatically preparing standards and QCs in seconds with low consumption of stock solutions and blank matrices. PMID- 24760564 TI - Generation of gas-phase zirconium fluoroanions by electrospray of an ionic liquid. AB - RATIONALE: New approaches for forming anions are sought that have strong abundance and no isobaric overlap, attributes that are compatible with the measurement of isotope ratios. Fluoroanions are particularly attractive because fluorine is monoisotopic, and thus will not have overlapping isobars with the isotope of interest. Since many elements do not have positive electron affinity values, they do not form stable negative atomic ions, and hence are not compatible with isotope ratio measurement using high sensitivity isotope ratio mass spectrometers such as accelerator mass spectrometers. METHODS: Zirconium fluoroanions were prepared using the fluorinating ionic liquid (IL) 1-ethyl-3 methylimidazolium fluorohydrogenate, which was used to generate abundant [ZrF5]( ) ions using electrospray ionization. The IL was dissolved in acetonitrile, combined with a dilute solution of either Zr(4+) or ZrO(2+), and then electrosprayed. Mass analysis and collision-induced dissociation experiments were conducted using a time-of-flight mass spectrometer. Cluster structures were predicted using density functional theory calculations. RESULTS: The fluorohydrogenate IL solutions generated abundant [ZrF5](-) ions starting from solutions of both Zr(4+) and ZrO(2+). The mass spectra also contained IL-bearing cluster ions, whose compositions indicated the presence of [ZrF6](2-) in solution, a conclusion supported by the structural calculations. Rinsing out the zirconium-IL solution with acetonitrile decreased the IL clusters, but enhanced [ZrF5](-), which was sorbed by the polymeric electrospray supply capillary, and then released upon rinsing. This reduced the ion background in the mass spectrum. CONCLUSIONS: The fluorohydrogenate-IL solutions are a facile way to form zirconium fluoroanions in the gas phase using electrospray. The approach has potential as a source of fluoroanions for isotope ratio measurements, which would enable high-sensitivity measurement of minor zirconium isotopes without overlapping isobars caused by the charge carrier (i.e., the monoisotopic fluorine atoms). PMID- 24760563 TI - Laser desorption ionization time-of-flight mass spectrometry of erbium-doped Ga Ge-Sb-S glasses. AB - RATIONALE: Rare earth-doped sulphide glasses in the Ga-Ge-Sb-S system present radiative emissions from the visible to the middle infrared range (mid-IR) range, which are of interest for a variety of applications including (bio)-chemical optical sensing, light detection, and military counter-measures. The aim of this work was to reveal structural motifs present during the fabrication of thin films by plasma deposition techniques as such knowledge is important for the optimization of thin film growth. METHODS: The formation of clusters in plasma plume from different concentrations of erbium-doped Ga5Ge20Sb10S65 glasses (0.05, 0.1, and 0.5 wt. % of erbium) using laser (337 nm) desorption ionization (LDI) was studied by time-of-flight mass spectrometry (TOF MS) in both positive and negative ion mode. The stoichiometry of the Ga(m)Ge(n)Sb(o)S(p)(+/-) clusters was determined via isotopic envelope analysis and computer modelling. RESULTS: Several Ga(m)Ge(n)Sb(o)S(p)(+/-) singly charged clusters were found but, surprisingly, only four species (Sb3S4(+/-), GaSb2S(p)(+/-) (p = 4, 5), Ga3Sb2S7(+/-) ) were common to both ion modes. For the first time, species containing rare earths (GaSb2SEr(+) and GaS6 Er2(+)) were identified in the plasma formed from rare earth-doped chalcogenide glasses, directly confirming the importance of gallium presence for rare earth bonding within the glassy matrix. CONCLUSIONS: The local structure of Ga-Ge-Sb-S glasses is at least partly different from the structure of species identified in plasma by mass spectrometry, as deduced from Raman scattering spectroscopy analysis; these glasses are mainly formed by [GeS4/2]/[GaS4/2] tetrahedra and [SbS3/2] pyramids. Extended X-ray absorption fine structure measurements show that Er(3+) ions in Ga Ge-Sb-S glasses are surrounded by 7 sulphur atoms. PMID- 24760565 TI - Identification of multiple constituents from seed of Vaccaria segetalis with an adsorbent-separation strategy based on liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - RATIONALE: Seeds of Vaccaria segetalis (Wang-Bu-Liu-Xing in Chinese) are mainly used in traditional Chinese medicine for the treatment of amenorrhea, breast infections, and edema. The study was designed to identify the components and metabolites of Wang-Bu-Liu-Xing. METHODS: A novel methodology combining an adsorbent-separation strategy with analysis by liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (LC/QTOF-MS/MS) was established to identify the components of Wang-Bu-Liu-Xing. The adsorbent-separation technique was applied on macroporous resin (adsorbents). Different concentrations of ethanol (30%, 60%, and 95%), which covered high-to-low polarity ranges, were chosen as the elution solvent, respectively. The QTOF mass spectrometer was operated in negative ion mode with an electrospray ionization source. RESULTS: A total of 52 components were successfully identified in the Wang-Bu-Liu-Xing decoction based on the fragmentation pathways and QTOF high-accuracy mass spectral analysis. To the best of our knowledge, several new saponins were reported for the first time. A total of 20 compounds, which included 10 prototypes and 10 metabolites, were also identified in rat plasma and urine after oral administration of Wang-Bu-Liu-Xing decoction. CONCLUSIONS: An integrated adsorbent-separation strategy is powerful and reliable for global detection and identification of complex components in herbal prescriptions. The components identified in rat biofluids may also provide helpful chemical information for further pharmacology and active mechanism study on this herb. PMID- 24760566 TI - The mobility of nitrogen across tree-rings of Norway spruce (Picea abies L.) and the effect of extraction method on tree-ring delta15N and delta13C values. AB - RATIONALE: The use of stable nitrogen (N) isotope ratios (delta(15)N values) in dendroecological studies is often preceded by an extraction procedure using organic solvents to remove mobile N compounds from tree-rings. Although these mobile N compounds may be capable of distorting potential environmental signals in the tree-ring delta(15)N values, recent investigations question the necessity of such an extraction. METHODS: We used an on-going experiment with simulated elevated N deposition previously labelled with (15)N, in conjunction with control trees, to investigate the necessity of extracting mobile N compounds (using a rapid extraction procedure) for tree-ring delta(15)N and delta(13)C studies, as well as N and C concentration analyses. In addition, we examined the magnitude of radial redistribution of N across tree-rings of Norway spruce (Picea abies). RESULTS: The (15)N label, applied in 1995/96, was found in tree-rings as far back as 1951, although the increased N availability did not cause any significant relative increase in tree growth. The rapid extraction procedure had no significant effect on tree-ring delta(15)N or delta(13)C values in either labelled or control trees, or on N concentration. The C concentrations, however, were significantly higher after extraction in control samples, with the opposite effect observed in labelled samples. CONCLUSIONS: Our results indicate that the extraction of mobile N compounds through the rapid extraction procedure is not necessary prior to the determination of Norway spruce delta(15)N or delta(13)C values in dendrochemical studies. delta(15)N values, however, must be interpreted with great care, particularly when used as a proxy for the N status of trees, due to the very high mobility of N within the tree stem sapwood of Norway spruce over several decades. PMID- 24760567 TI - Analysis of trace organic pollutants in wastewater to assess biodegradation using wrong-way-round ionization in liquid chromatography/tandem mass spectrometry. AB - RATIONALE: Monitoring the concentrations of pharmaceuticals and personal care products (PPCPs) in wastewater is an integral step toward understanding the fate of these contaminants in wastewater treatment plants (WWTPs). This paper aims to develop a method that allows for the simultaneous analysis of multiple classes of PPCPs that can be used as tracers to assess the performance of WWTPs. METHODS: Five PPCP tracers - carbamazepine (CBZ), 17alpha-ethinylestradiol (EE2), nonylphenol (NP), salicylic acid (SA), and trimethoprim (TMP) - were analyzed by liquid chromatography/triple quadrupole mass spectrometry (LC/MS/MS) using a highly basic mobile phase (pH 10.3). Conventionally, TMP (pKa 7.12) and CBZ (pKa 13.94) are analyzed in positive ion mode using an acidic mobile phase. However, the high pH mobile phase allowed the quantification of all the tracers by polarity switching, with TMP undergoing wrong-way-round (WWR) ionization. RESULTS: The instrument limits of detection for the five tracers, without solid phase extraction, were in the range of 1.3 to 5.9 ng/mL, except for NP, which was 238 ng/mL. The signal-to-noise (S/N) ratios for TMP and CBZ with the mobile phase at pH 10.3 were higher than the S/N ratios observed at pH 2.7 under positive electrospray ionization. The mechanism of WWR ionization for TMP was investigated, and we propose that a charge transfer from solvent clusters to TMP molecules due to electrolytic reactions at the surface of the droplet leads to WWR ionization in electrospray. CONCLUSIONS: A method to simultaneously analyze five representative PPCP tracers with a wide range of pKa values using WWR ionization in LC/MS/MS with polarity switching was developed. The method was successfully used to monitor the selected PPCPs in samples from full-scale WWTPs to assess their biodegradation under various treatment conditions. PMID- 24760568 TI - Internal energy distribution in electrospray ionization: towards the evaluation of a thermal-like distribution from the multiple-collision model. AB - RATIONALE: The internal energy deposition in ions that cross the desolvation region of an electrospray ionization (ESI) source affects the mass spectra that are obtained using in-source collision-induced dissociation (CID) or in tandem mass spectrometry (MS/MS) mode. It is thus important to evaluate the internal energy distributions of the ions in different parts of an ESI mass spectrometer. METHODS: The desolvation region is considered as a collision zone and a partially elastic multiple-collision model is used to account for the accumulation of internal energy in the ions. The ion survival yields (SY(Theo) of the theoretical mass spectra calculated by MassKinetics software are fitted with the experimental ion survival yields (SY(Exp)) of the substituted benzylpyridinium cations that have been obtained with an ESI source interfaced with a quadrupole mass spectrometer. The theoretical parameters used for fitting the calculation data with the experimental results are the center-of-mass collision energy (Ecom ) of the colliding ions and a term related to the pressure of the desolvation area of the ESI interface. RESULTS: In the proposed model, an average number of 'effective' collisions of close to 30 in the desolvation area is employed. The voltages applied to the orifice of this interface are correlated to a theoretical initial kinetic energy (E(init,Kin)) in the laboratory frame of the ions. In the present case, these theoretical initial kinetic energies range from 5.5 to 9 eV. The internal energy distributions evaluated from this model resemble the thermal distributions of ions having 'characteristic temperatures' between 1020 and 1550 K, and the results of calculations show that the mean internal energy of the ions increases linearly with the orifice voltage. CONCLUSIONS: The model used in this study can account for the energy build-up of the ions in an ESI interface and allows the change in the internal energy distribution of the electrosprayed ions in different regions of a mass spectrometer to be evaluated. PMID- 24760569 TI - Identification of alcohol-dependent clopidogrel metabolites using conventional liquid chromatography/triple quadrupole mass spectrometry. AB - RATIONALE: Clopidogrel (CLO) is a prodrug used to prevent ischemic events in patients undergoing percutaneous coronary intervention or with myocardial infarction. A previous study found ethyl clopidogrel (ECLO) is formed by transesterification of CLO when incubated with alcohol in human liver microsomes. We hypothesize that ECLO will be subject to further metabolism and developed an assay to identify its metabolites. METHODS: A liquid chromatography/triple quadrupole mass spectrometry (LC/MS/MS) method was developed to identify metabolites of ECLO. According to the predicted metabolic pathway of ECLO, precursor-product ion pairs were used to screen the possible metabolites of ECLO in human liver S9 fractions. Subsequently, the detected metabolites were characterized by the results of product ion scan. RESULTS: In the presence of alcohol, CLO was tranesterified to ECLO, which was further oxidized to form ethylated 2-oxo-clopidogrel and several ethylated thiol metabolites including the ethylated form of the H4 active metabolite. CONCLUSIONS: The ECLO formed by transesterification with alcohol is subject to metabolism by CYP450 enzymes producing ethylated forms of 2-oxo-clopidogrel and the active H4 thiol metabolite. PMID- 24760570 TI - The application of a new microfluidic device for the simultaneous identification and quantitation of midazolam metabolites obtained from a single micro-litre of chimeric mice blood. AB - RATIONALE: Improvements in the design of low-flow highly sensitive chromatographic ion source interfaces allow the detection and characterisation of drugs and metabolites from smaller sample volumes. This in turn improves the ethical treatment of animals by reducing both the number of animals needed and the blood sampling volumes required. METHODS: A new microfluidic device combining an ultra-high pressure liquid chromatography (UHPLC) analytical column with a nano-flow electrospray source is described. All microfluidic, gas and electrical connections are automatically engaged when the ceramic microfluidic device is inserted into the source enclosure. The system was used in conjunction with a hybrid quadrupole-time-of-flight mass spectrometer. RESULTS: The improved sensitivity of the system is highlighted in its application in the quantification and qualification of midazolam and its metabolites detected in whole blood from chimeric and wild-type mice. Metabolite identification and full pharmacokinetic profiles were obtained from a single micro-litre of whole blood at each sampling time and significant pharmacokinetic differences were observed between the two types of mice. CONCLUSIONS: Improvements in the enhanced ionisation efficiency from the microfluidic device in conjunction with nanoUHPLC/MS was sufficiently sensitive for the identification and quantification of midazolam metabolites from a single micro-litre of whole blood. Detection of metabolites not previously recorded from the chimeric mouse in vivo model was made. PMID- 24760571 TI - Isotopic niche (delta13S and delta15N values) of soil macrofauna in temperate forests. AB - RATIONALE: Stable isotope analysis (SIA) is used widely for reconstructing trophic links of vertebrate and invertebrate animals. Soil macrofauna form a substantial food source for a range of predators including amphibians, reptiles, birds and mammals. SIA-based estimations of their trophic niches require knowledge on the full range of isotopic signatures of potential preys. Considering the extremely high diversity of soil animals, this information is not easy to obtain. METHODS: We estimated a typical range of the isotopic signatures of soil macrofauna by compiling published and original data on soil macroinvertebrates in 11 temperate forests. We examined whether the baseline correction (i.e. subtracting delta(13)C or delta(15)N values of local litter) would decrease the between-site variability in the delta(13)C and delta(15)N values of soil animals. The dataset was subsequently used to estimate the frequency distribution of delta(13)C and delta(15)N values in saprophagous and predatory soil animals. RESULTS: The baseline correction reduced the between-site variability in delta(15)N, but not in delta(13)C values of soil animals. Over 95% of the taxa or individuals examined fell into an isotopic space with uncorrected delta(13)S values ranging from -27.9 to -22.50/00, and litter-normalized delta(15)N values from 0.8 to 9.60/00. Saprophagous and predatory soil animals were on average enriched in (13)C relative to plant litter by 3.5 and 2.70/00, respectively, which is likely to reflect the importance of saprotrophic microorganisms as the main energy source in soil food webs. The difference in delta(15)N values between saprophages and predators averaged 2.80/00, which fits the anticipated trophic enrichment per trophic level. CONCLUSIONS: Our results indicate that the range of possible delta(15)N values of soil macrofauna in temperate forest ecosystems can roughly be predicted based on the delta(15)N values of plant litter. On the other hand, no site-specific normalization is usually required when predicting the range of delta(13)C values of soil macroinvertebrates. PMID- 24760572 TI - Fully automated laser ablation liquid capture surface analysis using nanoelectrospray ionization mass spectrometry. AB - RATIONALE: Laser ablation provides for the possibility of sampling a large variety of surfaces with high spatial resolution. This type of sampling when employed in conjunction with liquid capture followed by nanoelectrospray ionization provides the opportunity for sensitive and prolonged interrogation of samples by mass spectrometry as well as the ability to analyze surfaces not amenable to direct liquid extraction. METHODS: A fully automated, reflection geometry, laser ablation liquid capture spot sampling system was achieved by incorporating appropriate laser fiber optics and a focusing lens into a commercially available, liquid extraction surface analysis (LESA((r)))-ready Advion TriVersa NanoMate system. RESULTS: Under optimized conditions about 10% of laser-ablated material could be captured in a droplet positioned vertically over the ablation region using the NanoMate robot-controlled pipette. The sampling spot size area with this laser ablation liquid capture surface analysis (LA/LCSA) mode of operation (typically about 120 um * 160 um) was approximately 50 times smaller than that achievable by direct liquid extraction using LESA((r)) (ca 1 mm diameter liquid extraction spot). The setup was successfully applied for the analysis of ink on glass and paper as well as the endogenous components in Alstroemeria Yellow King flower petals. In a second mode of operation with a comparable sampling spot size, termed laser ablation/LESA((r)), the laser system was used to drill through, penetrate, or otherwise expose material beneath a solvent resistant surface. Once drilled, LESA((r)) was effective in sampling soluble material exposed at that location on the surface. CONCLUSIONS: Incorporating the capability for different laser ablation liquid capture spot sampling modes of operation into a LESA((r))-ready Advion TriVersa NanoMate enhanced the spot sampling spatial resolution of this device and broadened the surface types amenable to analysis to include absorbent and solvent-resistant materials. PMID- 24760573 TI - Oxygen isotopic fractionation of O2 during adsorption and desorption processes using molecular sieve at low temperatures. AB - RATIONALE: Cryogenic trapping using molecular sieves is commonly used to collect O2 extracted from silicates for (17)O/(16)O and (18)O/(16)O analyses. However, gases which interfere with (17)O/(16)O analysis, notably NF3, are also trapped and their removal is essential for accurate direct measurement of the (17)O/(16)O ratio. It is also necessary to identify and quantify any isotopic fractionation associated with the use of cryogenic trapping using molecular sieves. METHODS: The oxygen isotopic compositions of O2 before and after desorption from, and adsorption onto, 13X and 5A molecular sieves (MS13X and MS5A) at 0 degrees C, -78 degrees C, -114 degrees C, and -130 degrees C were measured in order to determine the oxygen isotopic fractionation at these temperatures. We also investigated whether isotopic fractionation occurred when O2 gas was transferred sequentially into a second cold finger, also containing molecular sieve. RESULTS: It was confirmed that significant oxygen isotopic fractionation occurs between the gaseous O2 and that adsorbed onto molecular sieve, if desorption and adsorption are incomplete. As the fraction of released or untrapped O2 becomes smaller with decreasing trapping temperature (from 0 to -130 degrees C), the isotopic fractionation becomes larger. Approximately half of the total adsorbed O2 is released from the molecular sieve during desorption at -114 degrees C, which is the temperature recommended for separation from NF3 (retained on the molecular sieve), and this will interfere with (17)O/(16)O measurements. CONCLUSIONS: The use of a single cold finger should be avoided, because partial desorption is accompanied by oxygen isotopic fractionation, thereby resulting in inaccurate isotopic data. The use of a dual cold finger arrangement is recommended because, as we have confirmed, the transfer of O2 from the first trap to the second is almost 100%. However, even under these conditions, a small isotopic fractionation (0.18 +/- 0.050/00 in delta(17)O values and 0.26 +/- 0.060/00 in delta(18)O values) occurred, with O2 in the second trap being isotopically enriched in the heavier isotopes. PMID- 24760574 TI - Antigenic variability among two subtypes of human adenovirus serotype 7. AB - Human adenovirus type 7 (HAdV-7) is one of the major serotypes responsible for acute respiratory infection. It is important to investigate the antigenic variabilities of different HAdV-7 genomic subtypes for vaccine development. Phylogenetic analysis of global HAdV-7 strains and major antigen proteins showed that HAdV-7 could be classified into two subtypes. There were three highly variable regions (HVR1, HVR4, and HVR7) in the hexon protein that varied between subtypes. Within each of the subtypes, these regions were conserved. Two subtype HAdV-7 strains isolated in China were used to immunize mice for antigenic characterization. Mice immunized with one subtype strain showed 4-8-fold lower neutralizing antibody titers against another subtype strain. ELISA results showed that the variation in HVR1, 4, and 7 regions contributed to antigenic change, and it may be concluded that the three regions contain subtype-specific epitopes. In summary, strains of HAdV-7 could be divided into two subtypes using genome sequence and antigenic analysis; our results could be important for HAdV-7 vaccine development. PMID- 24760575 TI - Relationship between psychopathy, aggression, anger, impulsivity, and intermittent explosive disorder. AB - Intermittent explosive disorder (IED) in DSM-5 represents a disorder of recurrent, problematic, reactive (i.e., affective or impulsive), aggressive behavior that, over the lifetime, affects about 5-6% of individuals in the United States. While aggression is also observed in those with psychopathic personality, aggression in this context is frequently proactive rather than reactive, and neurobiological study suggests important differences between those with proactive aggression/psychopathy and those with reactive aggression. In this paper, we conducted two sets of analyses. First, a phenomenologic study to explore the frequency of psychopathic personality defined by the Psychopathology Checklist Screening Version (PCL-SV) among IED and comparator participants and to explore differences in measures of aggression, anger, and impulsivity as a function of IED and psychopathic personality. Second, we re-analyzed data from five published studies to determine if psychopathic personality accounted for differences between IED and comparator participants. The first study found that only a modest proportion of IED participants display clinically substantial features of psychopathy and that measures of trait aggression and anger, rather than those of psychopathy, are the strongest correlates of IED. The second study found little evidence for any impact of psychopathy on reported findings in IED compared with various control participants. PMID- 24760576 TI - Images in vascular medicine. Twenty-eight years later: A case of superior vena cava aneurysm secondary to cystic hygroma. PMID- 24760577 TI - Donor-matched mesenchymal stem cells from knee infrapatellar and subcutaneous adipose tissue of osteoarthritic donors display differential chondrogenic and osteogenic commitment. AB - Cell-based therapies have recently been proposed for the treatment of degenerative articular pathologies, such as early osteoarthritis, with an emphasis on autologous mesenchymal stem cells (MSCs), as an alternative to terminally differentiated cells. In this study, we performed a donor-matched comparison between infrapatellar fat pad MSCs (IFP-MSCs) and knee subcutaneous adipose tissue stem cells (ASCs), as appealing candidates for cell-based therapies that are easily accessible during surgery. IFP-MSCs and ASCs were obtained from 25 osteoarthritic patients undergoing total knee replacement and compared for their immunophenotype and differentiative potential. Undifferentiated IFP-MSCs and ASCs displayed the same immunophenotype, typical of MSCs (CD13+/CD29+/CD44+/CD73+/CD90+/CD105+/CD166+/CD31-/CD45-). IFP-MSCs and ASCs showed similar adipogenic potential, though undifferentiated ASCs had higher LEP expression compared to IFP-MSCs (p<0.01). Higher levels of calcified matrix (p<0.05) and alkaline phosphatase (p<0.05) in ASCs highlighted their superior osteogenic commitment compared to IFP-MSCs. Conversely, IFP-MSCs pellets showed greater amounts of glycosaminoglycans (p<0.01) and superior expression of ACAN (p<0.001), SOX9, COMP (p<0.001) and COL2A1 (p<0.05) compared to ASCs pellets, revealing a superior chondrogenic potential. This was also supported by lower COL10A1 (p<0.05) and COL1A1 (p<0.01) expression and lower alkaline phosphatase release (p<0.05) by IFP-MSCs compared to ASCs. The observed dissimilarities between IFP-MSCs and ASCs show that, despite expressing similar surface markers, MSCs deriving from different fat depots in the same surgical site possess specific features. Furthermore, the in vitro peculiar commitment of IFP-MSCs and ASCs from osteoarthritic donors towards the chondrogenic or osteogenic lineage may suggest a preferential use for cartilage and bone cell-based treatments, respectively. PMID- 24760579 TI - Inactivation of glycogen synthase kinase-3beta up-regulates beta-catenin and promotes chondrogenesis. AB - This study aimed to investigate whether inhibition of glycogen synthase kinase 3beta (GSK-3beta) could promote chondrocytes proliferation. The expression pattern of GSK-3beta was firstly determined by immunohistochemistry (IHC) in normal mouse. Tibias were then isolated and cultured for 6 days. The tibias were treated with dimethylsulfoxide (control) or GSK-3 inhibitor SB415286 (SB86). Length of tibias was measured until 6 days after treatment. These bones were either stained with alcian blue/alizarin red or analyzed by IHC. In addition, GSK 3beta and beta-catenin were analyzed by Western blot. Finally, cartilage-specific GSK-3beta deletion mice (KO) were generated. Efficiency of GSK-3beta deletion was determined through Western blot and IHC. After treated by inhibitor SB86, the overall length of growth plate was not changed. However, growth of tibia in SB86 group was increased by 31 %, the length of resting and proliferating was increased 13 % (P < 0.01), whereas the length of hypertrophic was decreased by 57 % (P < 0.01). Besides, the mineralized length was found to be significant longer than the control group (P < 0.05). In KO mice, growth plate and calvaria tissue both exhibit significant reduction of GSK-3beta (P < 0.05) whereas the lengths of tibias in KO were almost same compared with control mice. Finally, an increase amount of beta-catenin protein was observed in SB86 (P < 0.05). In addition, significantly increased beta-catenin was also found in the growth plate of KO mice (P < 0.05). Inhibition of GSK-3 could promote longitudinal growth of bone through increasing bone formation. Besides, the inactivation of GSK-3beta could lead to enhancing beta-catenin, therefore promote chondrocytes proliferation. PMID- 24760578 TI - Time and dose-dependent effects of chondroitinase ABC on growth of engineered cartilage. AB - Tissue engineering techniques have been effective in developing cartilage-like tissues in vitro. However, many scaffold-based approaches to cultivating engineered cartilage have been limited by low collagen production, an impediment for attaining native functional load-bearing tensile mechanical properties. Enzymatic digestion of glycosaminoglycans (GAG) with chondroitinase ABC (chABC) temporarily suppresses the construct's GAG content and compressive modulus and increases collagen content. Based on the promising results of these early studies, the aim of this study was to further promote collagen deposition through more frequent chABC treatments. Weekly dosing of chABC at a concentration of 0.15 U/mL resulted in a significant cell death, which impacted the ability of the engineered cartilage to fully recover GAG and compressive mechanical properties. In light of these findings, the influence of lower chABC dosage on engineered tissue (0.004 and 0.015 U/mL) over a longer duration (one week) was investigated. Treatment with 0.004 U/mL reduced cell death, decreased the recovery time needed to achieve native compressive mechanical properties and GAG content, and resulted in a collagen content that was 65 % greater than the control. In conclusion, the results of this study demonstrate that longer chABC treatment (one week) at low concentrations can be used to improve collagen content in developing engineered cartilage more expediently than standard chABC treatments of higher chABC doses administered over brief durations. PMID- 24760580 TI - Experimental and theoretical study of mechanoluminescence and lyoluminescence of Li3 PO4 : RE (RE = Dy and Tb) phosphors. AB - Li3 PO4 phosphors prepared by solid-state diffusion technique and lyoluminescence (LL) as well as mechanoluminescence (ML) studies are reported. Dy- and Tb activated phosphors show dosimetric characteristics using LL and ML techniques. The energy levels and hence trapping and detrapping of charge carriers in the material can be studied using ML. Li3 PO4 phosphor can be used in the dosimetric applications for ionizing radiation. By using the LL technique, the LL characteristics of Li3 PO4 may be useful for high radiation doses. We also report a more detailed theoretical understanding of the mechanism of LL and ML. PMID- 24760581 TI - Grey-matter volume as a potential feature for the classification of Alzheimer's disease and mild cognitive impairment: an exploratory study. AB - Specific patterns of brain atrophy may be helpful in the diagnosis of Alzheimer's disease (AD). In the present study, we set out to evaluate the utility of grey matter volume in the classification of AD and amnestic mild cognitive impairment (aMCI) compared to normal control (NC) individuals. Voxel-based morphometric analyses were performed on structural MRIs from 35 AD patients, 27 aMCI patients, and 27 NC participants. A two-sample two-tailed t-test was computed between the NC and AD groups to create a map of abnormal grey matter in AD. The brain areas with significant differences were extracted as regions of interest (ROIs), and the grey-matter volumes in the ROIs of the aMCI patients were included to evaluate the patterns of change across different disease severities. Next, correlation analyses between the grey-matter volumes in the ROIs and all clinical variables were performed in aMCI and AD patients to determine whether they varied with disease progression. The results revealed significantly decreased grey matter in the bilateral hippocampus/parahippocampus, the bilateral superior/middle temporal gyri, and the right precuneus in AD patients. The grey matter volumes were positively correlated with clinical variables. Finally, we performed exploratory linear discriminative analyses to assess the classifying capacity of grey-matter volumes in the bilateral hippocampus and parahippocampus among AD, aMCI, and NC. Leave-one-out cross-validation analyses demonstrated that grey-matter volumes in hippocampus and parahippocampus accurately distinguished AD from NC. These findings indicate that grey-matter volumes are useful in the classification of AD. PMID- 24760582 TI - Atrophic thyroid follicles and inner ear defects reminiscent of cochlear hypothyroidism in Slc26a4-related deafness. AB - Thyroid hormone is essential for inner ear development and is required for auditory system maturation. Human mutations in SLC26A4 lead to a syndromic form of deafness with enlargement of the thyroid gland (Pendred syndrome) and non syndromic deafness (DFNB4). We describe mice with an Slc26a4 mutation, Slc26a4 (loop/loop) , which are profoundly deaf but show a normal sized thyroid gland, mimicking non-syndromic clinical signs. Histological analysis of the thyroid gland revealed defective morphology, with a majority of atrophic microfollicles, while measurable thyroid hormone in blood serum was within the normal range. Characterization of the inner ear showed a spectrum of morphological and molecular defects consistent with inner ear pathology, as seen in hypothyroidism or disrupted thyroid hormone action. The pathological inner ear hallmarks included thicker tectorial membrane with reduced beta-tectorin protein expression, the absence of BK channel expression of inner hair cells, and reduced inner ear bone calcification. Our study demonstrates that deafness in Slc26a4 (loop/loop) mice correlates with thyroid pathology, postulating that sub-clinical thyroid morphological defects may be present in some DFNB4 individuals with a normal sized thyroid gland. We propose that insufficient availability of thyroid hormone during inner ear development plays an important role in the mechanism underlying deafness as a result of SLC26A4 mutations. PMID- 24760583 TI - Is tip apex distance as important as we think? A biomechanical study examining optimal lag screw placement. AB - BACKGROUND: Intertrochanteric hip fractures pose a significant challenge for the orthopaedic community as optimal surgical treatment continues to be debated. Currently, varus collapse with lag screw cutout is the most common mode of failure. Multiple factors contribute to cutout. From a surgical technique perspective, a tip apex distance less than 25 mm has been suggested to decrease the risk of cutout. We hypothesized that a low-center lag screw position in the femoral head, with a tip apex distance greater than 25 mm will provide equal, if not superior, biomechanical stability compared with a center-center position with a tip apex distance less than 25 mm in an unstable intertrochanteric hip fracture stabilized with a long cephalomedullary nail. QUESTIONS/PURPOSES: We attempted to examine the biomechanical characteristics of intertrochanteric fractures instrumented with long cephalomedullary nails with two separate lag screw positions, center-center and low-center. Our first research purpose was to examine if there was a difference between the center-center and low-center groups in cycles to failure and failure load. Second, we analyzed if there was a difference in fracture translation between the study groups during loading. METHODS: Nine matched pairs of femurs were assigned to one of two treatment groups: low-center lag screw position and center-center lag screw position. Cephalomedullary nails were placed and tip apex distance was measured. A standard unstable four-part intertrochanteric fracture was created in all samples. The femurs were loaded dynamically until failure. Cycles to failure and load and displacement data were recorded, and three-dimensional (3-D) motion was recorded using an Optotrak((r)) motion tracking system. RESULTS: There were no significant differences between the low-center and center-center treatment groups regarding the mean number of cycles to failure and mean failure load. The 3-D kinematic data showed significantly increased motion in the center-center group compared with the low-center group. At the time of failure, the magnitude of fracture translation was statistically significantly greater in the center-center group (20 +/- 2.8 mm) compared with the low-center group (15 +/- 3.4 mm; p = 0.004). Additionally, there was statistically significantly increased fracture gap distraction (center-center group, 13 +/- 2.8 versus low-center group, 7 +/- 4; p < 0.001) and shear fracture gap translation (center-center group, 12 +/- 2.3 mm; low-center group, 6 +/- 2.7 mm; p < 0.001). CONCLUSIONS: Positioning of the lag screw inferior in the head and neck was found to be at least as biomechanically stable as the center-center group although the tip apex distance was greater than 25 mm. CLINICAL RELEVANCE: Our findings challenge previously accepted principles of optimal lag screw placement. PMID- 24760585 TI - Prediction of substrate sites for protein phosphatases 1B, SHP-1, and SHP-2 based on sequence features. AB - Tyrosine phosphorylation plays crucial roles in numerous physiological processes. The level of phosphorylation state depends on the combined action of protein tyrosine kinases and protein tyrosine phosphatases. Detection of possible phosphorylation and dephosphorylation sites can provide useful information to the functional studies of relevant proteins. Several studies have focused on the identification of protein tyrosine kinase substrates. However, compared with protein tyrosine kinases, the prediction of protein tyrosine phosphatase substrates involved in the balance of protein phosphorylation level falls behind. This paper described a method that utilized the k-nearest neighbor algorithm to identity the substrate sites of three protein tyrosine phosphatases based on the sequence features of manually collected dephosphorylation sites. In the performance evaluation, both sensitivities and specificities could reach above 75% for all three protein tyrosine phosphatases. Finally, the method was applied on a set of known tyrosine phosphorylation sites to search for candidate substrates. PMID- 24760586 TI - Glycine modulates membrane potential, cell volume, and phagocytosis in murine microglia. AB - Phagocytes form engulfment pseudopodia at the contact area with their target particle by a process resembling cell volume (CV) regulatory mechanisms. We evaluated whether the osmoregulatory active neutral amino acid glycine, which contributes to CV regulation via activation of sodium-dependent neutral amino acid transporters (SNATs) improves phagocytosis in isotonic and hypertonic conditions in the murine microglial cell line BV-2 and primary microglial cells (pMG). In BV-2 cells and pMG, RT-PCR analysis revealed expression of SNATs (Slc38a1, Slc38a2), but not of GlyRs (Glra1-4). In BV-2 cells, glycine (5 mM) led to a rapid Na(+)-dependent depolarization of membrane potential (V mem). Furthermore, glycine increased CV by about 9%. Visualizing of phagocytosis of polystyrene microspheres by scanning electron microscopy revealed that glycine (1 mM) increased the number of BV-2 cells containing at least one microsphere by about 13%. Glycine-dependent increase in phagocytosis was suppressed by the SNAT inhibitor alpha-(methylamino)isobutyric acid (MeAIB), by replacing extracellular Na(+) with choline, and under hypertonic conditions, but not by the GlyR antagonist strychnine or the GlyR agonist taurine. Interestingly, hypertonicity induced suppression of phagocytosis was rescued by glycine. These findings demonstrate that glycine increases phagocytosis in iso- and hypertonic conditions by activation of SNATs. PMID- 24760587 TI - Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms. AB - Betaine is a methyl derivative of glycine first isolated from sugar beets. Betaine consumed from food sources and through dietary supplements presents similar bioavailability and is metabolized to di-methylglycine and sarcosine in the liver. The ergogenic and clinical effects of betaine have been investigated with doses ranging from 500 to 9,000 mg/day. Some studies using animal models and human subjects suggest that betaine supplementation could promote adiposity reductions and/or lean mass gains. Moreover, previous investigations report positive effects of betaine on sports performance in both endurance- and resistance-type exercise, despite some conflicting results. The mechanisms underlying these effects are poorly understood, but could involve the stimulation of lipolysis and inhibition of lipogenesis via gene expression and subsequent activity of lipolytic-/lipogenic-related proteins, stimulation of autocrine/endocrine IGF-1 release and insulin receptor signaling pathways, stimulation of growth hormone secretion, increased creatine synthesis, increases in protein synthesis via intracellular hyper-hydration, as well as exerting psychological effects such as attenuating sensations of fatigue. However, the exact mechanisms behind betaine action and the long-term effects of supplementation on humans remain to be elucidated. This review aims to describe evidence for the use of betaine as an ergogenic and esthetic aid, and discuss the potential mechanisms underlying these effects. PMID- 24760589 TI - The meta-analysis of crossover studies on exercise and appetite-related hormones. PMID- 24760590 TI - Significantly and practically meaningful differences in balance research: P values and/or effect sizes? AB - This paper examines statistical and practical significance when interpreting outcomes of balance research studies. The analysis has been restricted to studies differing in groups of interest and types of balance training; however, using equal parameters of task-oriented balance tests. While large samples differed significantly, no significant differences were found between small groups of athletes of different specializations. Likewise, the values did not differ significantly during stance on injured and non-injured legs. Nevertheless, moderate to large effect sizes indicate that the data are particularly meaningful in terms of sport and rehabilitation practice. On the contrary, visual feedback balance training in school-age children showed highly statistically significant changes, though the effects were trivial. Some discrepancy was also found between statistically significant changes after balance training in untrained subjects and small to high effect sizes. However, statistical significance of different balance training programs in physically active individuals and competitive athletes corresponded with calculated effect sizes. These findings signify that frequently used statistical significance in balance research does not imply that changes observed after the training are practically meaningful, or vice versa. Therefore, both P values and effect sizes should be used when interpreting results of cross-sectional and intervention balance studies. PMID- 24760591 TI - Considerations for the use of platelet-rich plasma in orthopedics. AB - The use of platelet-rich plasma (PRP) is expanding to numerous medical fields, including orthopedic surgery and sports medicine. The popularity of this new treatment option has prompted a rapid increase in research endeavors; however, the differences in application technique and the composition of PRP have made it difficult to compare results or make any firm conclusions regarding efficacy. The purpose of this article is twofold. First, to recommend details that should be provided in basic science and clinical PRP studies to allow meaningful comparisons between studies which may lead to a better understanding of efficacy. Second, to provide an understanding of the different PRP preparations and their clinical relevance. There are biochemical rationales for the use of PRP because it addresses several aspects of the healing process, including cell proliferation and tissue matrix regeneration, inflammation, nociception, infection, and hemostasis, all of which will be addressed. Given the current understanding of the importance the composition of PRP plays in tissue regeneration, it is likely that our future understanding of PRP will dictate 'customizing' the PRP preparation to the specific pathology of interest. The potential complications following PRP use are minor, and thus it appears to be a safe treatment option with a variety of potentially beneficial effects to injured musculoskeletal tissues. PMID- 24760593 TI - Feasibility of SaeboFlex upper-limb training in acute stroke rehabilitation: a clinical case series. AB - Upper-limb (UL) recovery following stroke is often poor. UL rehabilitation therefore continues to be a major focus for occupational therapy. Published evidence for the effectiveness of SaeboFlex training in acute stroke rehabilitation is scarce. The purpose of this study is to explore the feasibility and patient experience of SaeboFlex training in acute stroke. This feasibility study recruited stroke patients (< 84 days post-stroke) with moderate/severe UL weakness. They participated in SaeboFlex sessions for 12 weeks in addition to conventional rehabilitation. A battery of measures was taken at baseline, 4, 8 and 12 weeks. Eight participants were recruited. For the action research arm test score and UL Motricity Index, clinically significant improvements were noted in five out of seven (71%) and six out of seven participants (86%) respectively. Clinically significant improvements were also noted in secondary outcomes. Shoulder complications occurred in one participant. SaeboFlex training facilitated clinically significant improvements in UL function. It has the potential to improve participation and independence in ADLs, reduce carer burden and associated costs. Being a feasibility study with no control arm, we urge caution in interpreting these results. Future research is needed to evaluate the efficacy, optimum dosage and impact on dependency levels of SaeboFlex training as part of a randomized controlled trial. PMID- 24760592 TI - Validation of a sensitive LC/MS/MS method for the determination of telaprevir and its R-isomer in human plasma. AB - The purpose of this study was to validate a reversed-phase high-performance liquid chromatographic (HPLC), tandem mass spectrometry (MS/MS) assay for the determination of telaprevir and its R-diastereomer (VRT-127394) in acidified and nonacidified human plasma. The chromatographic baseline separation of telaprevir and telaprevir-R was performed on a Waters XBridge(TM) BEH Shield C18 , 2.1 * 75 mm column with a 2.5 um particle size, under isocratic conditions consisting of a mobile phase of 50:45:5 water-acetonitrile-isopropanol with 1% ammonia at 0.2 mL/min. This method utilized a stable isotope internal standard with 11 deuterium atoms on the structure of the telaprevir molecule (telaprevir-d11). An internal standard for the telaprevir-R (telaprevir-R-d11) was also prepared by incubating telaprevir-d11 in basic solution, which facilitated isomer inter-conversion. The detection and quantitation of telaprevir, telaprevir-R, telaprevir-IS and telaprevir-R-IS was achieved by positive ion electrospray (ESI+) MS/MS detection. The assay quantifiable limit was 5.0 ng/mL when 0.100 mL of acidified human plasma was extracted. Accuracy and precision were validated over the calibration range of 5.0-5000 ng/mL. It was demonstrated using patient samples that, contrary to previous recommendations, quantitation of telaprevir does not require acidified plasma. PMID- 24760595 TI - Hepatitis B virus infection reduces fertilization ability during in vitro fertilization and embryo transfer. AB - Whether hepatitis B virus (HBV) infection impairs human infertility is unclear. The present retrospective case-controlled study investigated the impact of HBV on sperm parameters, ovarian stimulation, and outcomes of in vitro fertilization (IVF) and embryo transfer. A total of 224 couples with at least one partner being HBsAg-seropositive undergoing their first IVF and embryo transfer cycle were identified, which included 77 couples with female partners being HBsAg seropositive, 136 couples with male partners being HBsAg-seropositive, and 11 couples with both partners being HBsAg-seropositive. A total of 448 both HBsAg seronegative couples served as controls. The percentage of normal sperm morphology was significantly lower in HBsAg-seropositive male partners than that in HBsAg-seronegative male partners (11.9 +/- 9.4% vs. 19.0 +/- 11.9%, P < 0.01). The duration of infertility was significantly prolonged in HBV-seropositive patients compared with HBV-seronegative patients (4.9 vs. 4.1 years, P < 0.01). Couples with female partners being HBsAg-seropositive had significantly lower top quality embryo rate than control group (22.4% vs. 31.6%, P < 0.01). In addition, the fertilization rates in groups with male or female partners being HBsAg seropositive were both significantly lower than the matched controls (80.2% vs. 82.8%, P < 0.05; 76.6% vs. 84.3%, P < 0.01, respectively). HBV infection was also found to be associated negatively with fertilization rate by logistic regression analysis (odds ratios: 0.410, 95% confidence interval: 0.186-0.906, P < 0.05). However, there was no significant difference in clinical pregnancy rates between HBsAg-seropositive and HBsAg-seronegative group. These results suggest that chronic HBV infection is likely to represent a significant cause of infertility. PMID- 24760594 TI - The elongation of primary cilia via the acetylation of alpha-tubulin by the treatment with lithium chloride in human fibroblast KD cells. AB - Primary cilium, an organelle found on nearly every cell in the human body, typically serves as the mechanical sensor of the cell. Lithium ion is known to promote the elongation of primary cilia in a variety of cell types, but it is unknown whether lithium is involved in the acetylation of alpha-tubulin which is essential for the assembly of primary cilia. In order to reveal the relationship between the elongation of primary cilia with lithium and the acetylation of alpha tubulin, we first observed the formation and structure of primary cilia in KD cells, a cell line deriving fibroblasts in human labium. Subsequently, by immunohistochemical and western blot analysis we elucidated that the length of primary cilia and acetylation of alpha-tubulin are regulated by lithium chloride (LiCl) in the medium in a time- and concentration-dependent manner. We next performed the RT-PCR, RNAi-based experiments and biochemical study using an inhibitor of glycogen synthase kinase-3betaGSK-3beta). We found that LiCl mobilizes the alpha-tubulin N-acetyltransferase 1 (alphaTAT1) in the signaling pathway mediating GSK-3beta and adenylate cyclase III. In conclusion, our results suggested that LiCl treatments activate alphaTAT1 by the inhibition of GSK-3beta and promote the alpha-tubulin acetylation, and then elongate the primary cilia. PMID- 24760596 TI - Nonpoint source pollution of urban stormwater runoff: a methodology for source analysis. AB - The characterization and control of runoff pollution from nonpoint sources in urban areas are a major issue for the protection of aquatic environments. We propose a methodology to quantify the sources of pollutants in an urban catchment and to analyze the associated uncertainties. After describing the methodology, we illustrate it through an application to the sources of Cu, Pb, Zn, and polycyclic aromatic hydrocarbons (PAH) from a residential catchment (228 ha) in the Paris region. In this application, we suggest several procedures that can be applied for the analysis of other pollutants in different catchments, including an estimation of the total extent of roof accessories (gutters and downspouts, watertight joints and valleys) in a catchment. These accessories result as the major source of Pb and as an important source of Zn in the example catchment, while activity-related sources (traffic, heating) are dominant for Cu (brake pad wear) and PAH (tire wear, atmospheric deposition). PMID- 24760598 TI - Photoperiodic induction of pre-migratory phenotype in a migratory songbird: identification of metabolic proteins in flight muscles. AB - Migratory birds need to undergo physiological changes during their preparation for migration. The current study characterized those changes in photoperiodic migratory black-headed buntings (Emberiza melanocephala), which initiate their northward spring migration in response to increasing day lengths. We measured differences in body mass, testis size and triglycerides levels in buntings between groups exposed to short (8 h light:16 h darkness, 8L:16D; SD) and long (16L:8D; LD) days, and identified proteins that showed significant differences between SD and LD in the flight muscle. To confirm that photostimulated changes were linked with migration, similar measurements were done on photoperiodic non migratory Indian weaverbirds (Ploceus philippinus), which share the habitat with buntings for almost half-a-year. Buntings were fattened and gained weight and had elevated serum triglyceride levels and recrudesced testes under LD, but not SD. The SDS-polyacrylamide gel electrophoresis revealed differences between SD and LD conditions in the flight muscle protein profiles of buntings, but not of weaverbirds. Two-dimensional gel electrophoresis of flight muscle of bunting separated three proteins, of which two were upregulated under LD condition. Mass spectroscopic analysis and a protein database search identified them as the fatty acid binding protein (FABP), myoglobin and creatine kinase (CK). Further semi quantitative and quantitative PCR assays revealed that FABP and myoglobin transcript levels in buntings, but not in weaverbirds, were upregulated under LD condition. However, there was no difference in CK mRNA levels between SD and LD in both the species. High FABP is perhaps linked with increased energy demands and high myoglobin with intense physical activity during migration. A difference in the CK protein, but not in mRNA levels between SD and LD may possibly indicate its photoperiodic regulation at the translational level. PMID- 24760600 TI - Influence of training status and eNOS haplotypes on plasma nitrite concentrations in normotensive older adults: a hypothesis-generating study. AB - The purpose of this study was to evaluate the relationship between 3 eNOS gene polymorphisms and training status (TS) in affecting plasma nitrite concentration (NO2) in normotensive adults over 50 years old. Resting blood pressure (BP) was measured in all participants (n = 101). Plasma was taken to analyze: lipid profile, nitrite concentration (NO2) and lipid peroxide levels (T-BARS). Also, genomic DNA was extracted from plasma for genotyping NOS3 polymorphisms (-786T>C; 894G>T; and VNTR in intron 4). TS was determined by one-mile walk test and Functional Fitness Test Battery from AAHPERD (TS1-regular TS; TS2-good TS; and TS3-very good TS). BP was not influenced by TS, but NO2 was 15% higher in TS3 (123 +/- 27 nM) compared to TS-2 (106 +/- 22 nM). No differences were found in plasma NO2 in the haplotype analyses. However, the presence of the C allele (T 786C) and ASP allele (Glu298Asp) was found to enhance the correlation between TS and NO2 levels (r = 0.492 in C/4b/ASP haplotype and r = 0.855 in C/4a/ASP haplotype). This study thus identifies NOS3 polymorphism-dependent sensitivity to the effects of physical training on plasma NO2. Maintenance of good levels of training status, in carriers of C allele for T-786C polymorphism, combined with ASP allele for Glu298Asp polymorphism, may result in an increase in the NO2 plasma concentrations, which may reflect improved NO bioavailability in older adult normotensive individuals. PMID- 24760601 TI - Tako tsubo and ischemic stroke in a patient with Alzheimer's disease. AB - BACKGROUND: Tako-tsubo cardiomyopathy (TTC), also known as "stress induced cardiomyopathy", is an acute cardiac condition characterized by transient myocardial dysfunction associated with a peculiar pattern of reversibile left ventricular ballooning that mimics myocardial infarction, but with normal coronary arteries. Tako-tsubo cardiomyopathy typically occurs in postmenopausal women and it is often triggered by physical or emotional stressful events. We report on a patient with Alzheimer's disease, who presented with TTC and an ischemic stroke. PMID- 24760599 TI - Linking physiological and cellular responses to thermal stress: beta-adrenergic blockade reduces the heat shock response in fish. AB - When faced with stress, animals use physiological and cellular strategies to preserve homeostasis. We were interested in how these high-level stress responses are integrated at the level of the whole animal. Here, we investigated the capacity of the physiological stress response, and specifically the beta adrenergic response, to affect the induction of the cellular heat shock proteins, HSPs, following a thermal stress in vivo. We predicted that blocking beta adrenergic stimulation during an acute heat stress in the whole animal would result in reduced levels of HSPs in red blood cells (RBCs) of rainbow trout compared to animals where adrenergic signaling remained intact. We first determined that a 1 h heat shock at 25 degrees C in trout acclimated to 13 degrees C resulted in RBC adrenergic stimulation as determined by a significant increase in cell swelling, a hallmark of the beta-adrenergic response. A whole animal injection with the beta2-adrenergic antagonist, ICI-118,551, successfully reduced this heat-induced RBC swelling. The acute heat shock caused a significant induction of HSP70 in RBCs of 13 degrees C-acclimated trout as well as a significant increase in plasma catecholamines. When heat-shocked fish were treated with ICI-118,551, we observed a significant attenuation of the HSP70 response. We conclude that circulating catecholamines influence the cellular heat shock response in rainbow trout RBCs, demonstrating physiological/hormonal control of the cellular stress response. PMID- 24760602 TI - Sinonasal lymphoma: case series and review of the literature. AB - BACKGROUND: Sinonasal lymphoma is a rare rhinologic entity. We present a case series and review the literature surrounding the diagnosis and management of this disease. METHODS: A pathology database spanning 22 years at a tertiary care center was searched for a diagnosis of lymphoma in the paranasal sinuses or the nasal cavity. Seventeen cases were identified, and retrospective chart review was performed. RESULTS: Maxillary and ethmoid sinuses were affected more frequently (n = 8 patients each) than sphenoid and frontal sinuses (n = 5 patients each). Histologically, the most common type was diffuse large B-cell lymphoma (53%, 9 patients), followed by extranodal natural killer/T-cell lymphoma (ENKL, 21%, 3 patients). Presenting symptoms included nasal obstruction and rhinorrhea (53%, 9 patients) and diplopia (18%, 3 patients); and radiographic imaging demonstrated a discrete mass (59%, 10 patients), sinus opacification (53%, 9 patients), and/or bony erosion (35%, 6 patients). Treatment included chemotherapy alone (71%, 12 patients), chemotherapy and radiation (6%, 1 patient), and radiation alone (6%, 1 patient). The 2-year and 5-year overall survival rates were 75% and 53%, respectively, whereas disease-free 2-year and 5-year survival rates were 70% and 49%, respectively. CONCLUSION: Lymphoma of the nasal cavity and paranasal sinuses is extremely rare, may mimic benign processes, and may manifest either in an isolated fashion or in conjunction with systemic disease. B-cell lymphomas, a more favorable diagnosis, account for a majority of cases, whereas ENKL is associated with rapid disease progression and death. Chemotherapy and radiation are the main therapies. Histologic diagnosis is of paramount importance, and clinicians must remain cognizant of this entity to differentiate it from other sinonasal malignancies. PMID- 24760603 TI - Timolol 0.1% gel versus timolol 0.5% eyedrops in the prophylaxis of ocular hypertension after phacoemulsification surgery. AB - PURPOSE: To determine the efficacy of timolol 0.1% gel in preventing increased intraocular pressure (IOP) after uncomplicated cataract surgery. METHODS: In this prospective, double-blinded, randomized study were enrolled 70 patients who underwent uncomplicated cataract surgery with phacoemulsification and intraocular lens implantation. After cataract surgery, 25 patients received a single instillation of timolol 0.1% gel (group A); 20 a single instillation of timolol 0.5% eyedrops (group B); and 25 no treatment (group C). The IOP was measured before surgery (T0) and 5 minutes (T1), 2 hours +/- 30 minutes (T2), 4 hours +/- 30 minutes (T3), and 24 hours +/- 180 minutes after surgery (T4). RESULTS: The patients in groups A and B had lower mean IOP values than those in group C at T2, T3, and T4; IOP was higher at T2 and T3 than at T1 in the control group. The IOP spikes in group C were higher than those observed in groups A and B: at T2, they were observed in 40% of the patients in group A, 30% in group B, and 76% in group C; and at T3, in respectively 20%, 10%, and 68%; and at T4, in respectively 4%, 0%, and 28%. CONCLUSIONS: Timolol 0.1% gel is as effective as timolol 0.5% eyedrops in reducing IOP and in limiting the occurrence of IOP spikes for up to 24 hours after phacoemulsification. PMID- 24760604 TI - Accidental foveal photocoagulation secondary to alexandrite laser. AB - PURPOSE: In recent years, we have seen an increase in the use of laser systems in the field of aesthetics (mainly depigmentation and hair removal). Alexandrite laser is the most widely used.Case report. METHODS: Case report. RESULTS: We describe a case of retinal injury (foveal photocoagulation) directly related to an alexandrite laser hair removal procedure. CONCLUSIONS: Hair removal by laser systems is a fast and efficient method. The use of lasers without adequate protective measures or by unqualified personnel increases the risk of ocular adverse effects. PMID- 24760605 TI - Treatment of macular edema secondary to retinal vein occlusion. PMID- 24760606 TI - Inhibitory effects of fucoxanthinol on the viability of human breast cancer cell lines MCF-7 and MDA-MB-231 are correlated with modulation of the NF-kappaB pathway. AB - Fucoxanthin is a carotenoid present in the chloroplasts of brown seaweeds. When ingested, it is metabolized mainly to fucoxanthinol in the gastrointestinal tract by digestive enzymes. These compounds have been shown to have many beneficial health effects. The present study was designed to evaluate the molecular mechanisms of action of fucoxanthin and/or of its metabolite fucoxanthinol against viability of estrogen-sensitive MCF-7 and estrogen-resistant MDA-MB-231 breast cancer cell lines. Fucoxanthin and fucoxanthinol reduced the viability of MCF-7 and MDA-MB-231 cells in dose- and time-dependent manners as a result of increased apoptosis. Furthermore, fucoxanthinol-induced apoptosis was more potent than that of fucoxanthin and correlated, for MDA-MB-231 cells, with inhibitory actions on members of the NF-kappaB pathway p65, p50, RelB, and p52. Being overexpressed and regulated by NF-kappaB in different types of cancers, the transcription factor SOX9 was also decreased at the nuclear level by fucoxanthin and fucoxanthinol in MDA-MB-231. Taken together, the current results suggest that fucoxanthinol and fucoxanthin could be potentially effective for the treatment and/or prevention of different types of cancers, including breast cancer. PMID- 24760607 TI - Red-shifted emission from 1,2-dioxetane-based chemiluminescent reactions. AB - Commercial chemiluminescent reagents emit across a broad portion of the electromagnetic spectrum (400-500 nm). A challenge to the use of chemiluminescence to monitor biological processes is the presence of interfering substances in the biological optical window. In the present study, longer wavelength emitting fluorophores (the organic dyes Alexa 568 and Alexa 647), and a semiconductor nanoparticle (QDOT800) were used to red-shift the emission from commercially available 1,2-dioxetane-based chemiluminescent substrate reactions. By adding non-conjugated fluorescent emitters into chemiluminescent reaction mixtures, an emission peak occurred at the predicted wavelength of the fluorescent emitter. The excitation and emission from QDOT800 was preserved in the presence of a 100 um-thick glass barrier separating it from the chemiluminescent reaction components. The maximum tissue phantom penetration by QDOT800 emission was 8.5 mm; in comparison, the native chemiluminescent emission at 500 nm was unable to penetrate the thinnest tissue phantom of 2.5 mm. The described method for red-shifted emissions from chemiluminescent reactions does not require direct interaction between the chemiluminescent reaction and the fluorescent emitters. This suggests that the mechanism of chemiluminescent excitation of fluorophores and QDOT800 is not exclusive to chemiluminescence resonance energy transfer or sensitized chemiluminescence, but rather by broad energization from the native chemiluminescent emission. PMID- 24760609 TI - Immobilized laccase on activated poly(vinyl alcohol) microspheres for enzyme thermistor application. AB - Poly(vinyl alcohol) (PVA) microspheres were prepared by inverse suspension crosslinked method, with glutaraldehyde as a crosslinking agent. PVA microspheres activated with aldehyde groups were employed for Trametes versicolor laccase immobilization. Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy were used to characterize the activated PVA microspheres and PVA microspheres with immobilized laccase (Lac/PVA microspheres), which show that laccase was successfully immobilized on the PVA microspheres. The optimum pH and temperature coupling conditions for the immobilized laccase were determined to be 3.3 and 30 degrees C, respectively. Residual activity was also investigated by soaking the immobilized laccase in organic solvents at different concentrations, proving it chemically stable. Immobilized laccase exhibited good storage stability at 4 degrees C. The enzyme biosensor showed good performance in 2,2 azinobis(3-ethylthiazoline-6-sulfonate) and bisphenol A, with concentration ranges of 2 to 8 mM and 0.05 to 0.25 mM, respectively. Therefore, PVA microspheres may have high potential as support for enzyme thermistor applications. PMID- 24760608 TI - Construction workers working in musculoskeletal pain and engaging in leisure-time physical activity: Findings from a mixed-methods pilot study. AB - BACKGROUND: While exercise has been shown to be beneficial for some musculoskeletal pain conditions, construction workers who are regularly burdened with musculoskeletal pain may engage less in leisure-time physical activity (LTPA) due to pain. In a small pilot study, we investigate how musculoskeletal pain may influence participation in LTPA among construction workers. METHODS: A sequential explanatory mixed-methods design was employed using a jobsite-based survey (n = 43) among workers at two commercial construction sites and one focus group (n = 5). RESULTS: Over 93% of these construction workers reported engaging in LTPA and 70% reported musculoskeletal pain. Fifty-seven percent of workers who met either moderate or vigorous LTPA guidelines reported lower extremity pain (i.e., ankle, knee) compared with 21% of those who did not engage in either LTPA (P = 0.04). Focus group analyses indicate that workers felt they already get significant physical activity out of their job because they are "moving all the time and not sitting behind a desk." Workers also felt they "have no choice but to work through pain and discomfort [as the worker] needs to do anything to get the job done." CONCLUSION: Pilot study findings suggest that construction workers not only engage in either moderate or vigorous LTPA despite musculoskeletal pain but workers in pain engage in more LTPA than construction workers without pain. PMID- 24760610 TI - Characterization of a family B DNA polymerase from the hyperthermophilic crenarchaeon Ignicoccus hospitalis KIN4/I and its application to PCR. AB - A family B DNA polymerase gene from the hyperthermophilic crenarchaeon Ignicoccus hospitalis KIN4/I was highly expressed under the control of T7lac promoter of pET 28ARG in Escherichia coli BL21-CodonPlus(DE3)-RIL cells. The produced I. hospitalis (Iho) DNA polymerase was purified by heat treatment followed by HisTrapTM HP column and HiTrapTM SP column chromatographies. The molecular mass of the purified Iho DNA polymerase was 88 kDa as estimated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The optimal pH for Iho DNA polymerase activity was 7.0 and the optimal temperature was 70 degrees C. Iho DNA polymerase was strongly activated by the presence of magnesium ion at an optimum concentration of 3 mM. The optimal concentration of KCl for Iho DNA polymerase activity was 60 mM. The half-life of the enzyme at 94 degrees C was about 2 h. The optimal conditions for polymerase chain reaction (PCR) were determined. Iho DNA polymerase possesses 3'->5' exonuclease activity, and the fidelity of the Iho DNA polymerase was similar to that of Pfu and Vent DNA polymerases. However, Iho DNA polymerase provided more enhanced efficiency of PCR amplification than Pfu and Vent DNA polymerases. Iho DNA polymerase could successfully amplify a 2-kb lambda DNA target with a 10-s extension time and could amplify a DNA fragment up to 8 kb lambda DNA. PMID- 24760611 TI - Influence of exercise intensity on training-induced tendon mechanical properties changes in older individuals. AB - This study compared the effects of low vs. high intensity training on tendon properties in an elderly population. Participants were pair-matched (gender, habitual physical activity, anthropometrics, and baseline knee extension strength) and then randomly assigned to low (LowR, i.e., ~40 % 1RM) or high (High R, i.e., ~80 % 1RM) intensity resistance training programmes for 12 weeks, 3* per week (LowR, n = 9, age 74 +/- 5 years; HighR, n = 8, age 68 +/- 6 years). Patellar tendon properties (stiffness [K], Young's modulus [YM], cross-sectional area [T CSA], and tendon length [T L]) were measured pre and post training using a combination of magnetic resonance imaging (MRI), B-mode ultrasonography, dynamometry, electromyography and ramped isometric knee extensions. With training K showed no significant change in the LowR group while it incremented by 57.7 % in the HighR group (p < 0.05). The 51.1 % group difference was significant (p < 0.05). These differences were still apparent when the data was normalized for T CSA and T L, i.e., significant increase in YM post-intervention in HighR (p < 0.05), but no change in LowR. These findings suggest that when prescribing exercise for a mixed genders elderly population, exercise intensities of <=40 % 1RM may not be sufficient to affect tendon properties. PMID- 24760613 TI - Incorporation of balls, tubes, and bowls in nanotechnology. AB - The development of nanotechnology has been spearheaded by the development and discovery of new materials. The earliest materials theorized to be used in nanotechnology were fullerenes and nanotubes. Although fullerenes and nanotubes have a rich history in the area of nanotechnology, fullerene fragments, which share some the same properties as fullerenes and nanotubes, show potential in the field of nanotechnology as well. Fullerene fragments were synthesized close to 20 years prior to the discovery of fullerenes; however due to their complex synthesis they remained in relative obscurity in the field of nanotechnology. More recently, improved syntheses of corannulene and other fullerene fragments on an industrial scale have led to their potential in industrial applications. With the mass production of corannulene finally being realized, many new structures and exciting properties are making its way into the chemical literature. PMID- 24760612 TI - Positive predictive value for malignancy of pure flat epithelial atypia diagnosis by percutaneous needle biopsy of the breast: management of FEA in ultrasonography. AB - BACKGROUND: Some reports suggest that the rate of definitive diagnosis of malignant tumors, namely, the final diagnosis being revised to a higher stage, in patients diagnosed as having flat epithelial atypia (FEA) by percutaneous needle biopsy of the breast (PNB) is as low as 0-3 %. However, other reports suggest that the rate is as high as 10 % or more, bringing confusion on this issue. We examined the positive predictive value for malignancy in the patients diagnosed as having pure FEA and the patients' radiolopathological characteristics observed in our hospital. METHODS: Of the patients who underwent PNB in our facility, those who were diagnosed as having pure FEA were recruited as the subjects of this study. RESULTS: Of the 4,197 consecutive patients who underwent PNB, 44 (1.0 %) were diagnosed as having pure FEA following a re-examination. Among 44 cases, 39 cases were selected as the subjects of this study. Among the 39 patients, six patients were diagnosed as having malignant lesions, two of whom had invasive carcinoma of no special type (papillotubular type), one had tubular carcinoma, one had ductal carcinoma in situ (DCIS) of high nuclear grade, one had DCIS of intermediate nuclear grade, and one had DCIS of low nuclear grade. The diameters of 6 malignant lesions were 10-30 mm at ultrasonography (US) examination. Five of the 39 patients had contralateral breast cancer. CONCLUSION: The positive predictive value for malignancy of pure FEA was 15.7 %. The patients with pure FEA may make a follow up without an excisional biopsy when the lesion sizes less than 10 mm on US examination. PMID- 24760614 TI - Gas-phase valence-electron photoemission spectroscopy using density functional theory. AB - We present a tutorial overview of the simulation of gas-phase valence-electron photoemission spectra using density functional theory (DFT), emphasizing both fundamental considerations and practical applications, and making appropriate links between the two. We explain how an elementary quantum mechanics view of photoemission couples naturally to a many-body perturbation theory view. We discuss a rigorous approach to photoemission within the framework of time dependent DFT. Then we focus our attention on ground-state DFT. We clarify the extent to which it can be used to mimic many-body perturbation theory in principle, and then provide a detailed discussion of the accuracy one can and cannot expect in practice with various approximate DFT forms. PMID- 24760615 TI - Solid-state NMR study of halogen-bonded adducts. AB - Nuclear magnetic resonance (NMR) spectroscopy offers unique insights into halogen bonds. NMR parameters such as chemical shifts, quadrupolar coupling constants, J coupling constants, and dipolar coupling constants are in principle sensitive to the formation and local structure of a halogen bond. Carrying out NMR experiments on halogen-bonded adducts in the solid state may provide several advantages over solution studies including (1) the absence of solvent which can interact with halogen bond donor sites and complicate spectral interpretation, (2) the lack of a need for single crystals or even long-range crystalline order, and (3) the potential to measure complete NMR interaction tensors rather than simply their isotropic values. In this chapter, we provide an overview of the NMR interactions and experiments which are relevant to the study of nuclei which are often found in halogen bonds (RX...Y) including (13)C, (35/37)Cl, (79/81)Br, (127)I, (77)Se, and (14/15)N. Experimental examples based on iodoperfluorobenzene halides, bis(trimethylammonium)alkane diiodide, and selenocyanate complexes, as well as haloanilinium halides, are discussed. Of particular interest is the sensitivity of the isotropic chemical shifts, the chemical shift tensor spans, and the halide nuclear electric quadrupolar coupling tensors to the halogen bond geometry in such compounds. Technical limitations associated with the NMR spectroscopy of covalently-bonded halogens are underlined. PMID- 24760617 TI - Detection of West Nile virus lineage 2 in the urine of acute human infections. AB - West Nile virus (WNV) lineage 2 emerged in Greece in 2010 and since then outbreaks in humans have been reported for four consecutive years. Laboratory diagnosis is based mainly on serology. A real-time RT-PCR was applied on urine samples obtained from 35 patients with acute WNV infection. WNV RNA was detected in 40% of the samples with cycle threshold (CT) values ranging from 26.95 to 39.89 (mean 33.11). WNV was isolated from two of four urine samples with low CT (<30). Viral load was not associated with patients' age, sex, day of illness, presence of WNV antibodies, and neurological symptoms. However, it seems that sample shipment and storage conditions are very important for virus detection and isolation. The usefulness of the WNV RNA detection in urine as a diagnostic tool of acute WNV infections is discussed. PMID- 24760618 TI - Work-related stress factors associated with problem drinking: A study of the Spanish working population. AB - BACKGROUND: Workers may drink to cope with stress or to overcome negative emotions arising from an aversive working context, but results of previous studies are inconclusive on the specific work features affecting alcohol use. METHODS: A cross-sectional study was designed with data on 13,005 working individuals from the Household Survey on Alcohol and Drugs in Spain (EDADES) 2007. We examined the associations between two drinking patterns and four measures of work-related stress factors. RESULTS: Moderate and high levels of exposure to a noxious working environment (OR = 2.15 [95% CI = 1.51-3.06] and OR = 2.23 [95% CI = 1.49-3.36]) and a high level of lack of social support (OR = 1.62 [95% CI = 1.16-2.28]) were associated with heavy drinking, and precariousness with binge drinking for both moderate (OR = 1.22 [95% CI = 1.01 1.46]) and high (OR = 1.33 [95% CI = 1.04-1.70]) levels (OR = 1.21; 95% CI = 1.04 1.40) in men. Significant associations among women were only found when stress factors were analyzed separately. CONCLUSIONS: Preventive practices in the workplace targeting alcohol abuse should consider specific production processes and organizational features. PMID- 24760619 TI - Soil organic matter and salinity affect copper bioavailability in root zone and uptake by Vicia faba L. plants. AB - Processes that control the mobility, transformation and toxicity of metals in soil are of special importance in the root-developing zone. For this reason, there is a considerable interest in understanding trace elements (TEs) behavior in soil, emphasising the processes by which plants take them up. Increased root zone salinity can affect plant TEs uptake and accumulation in plant tissue. Furthermore, copper (Cu) complexation by soil organic matter (SOM) is an effective mechanism of Cu retention in soils, controlling thus its bioavailability. Therefore, a greenhouse pot experiment was conducted to study the effects of soil Cu contamination in a saline environment on faba bean (Vicia faba L.) element uptake. Treatment with NaCl salinity was applied (control, 50 mM NaCl and 100 mM NaCl) on faba bean plants grown in a control and in a soil spiked with Cu (250 and 500 mg kg(-1)). Low and high SOM content trial variants were studied. Cu accumulation occurred in faba bean leaf, pod and seed. Cu contamination affected plant element concentrations in leaves (Na, Ca, Mg, Mn), pod (Zn, Mn) and seed (Mn, Mo, Zn). Root-zone salinity also affected faba bean element concentrations. Furthermore, Cu contamination-salinity and salinity-SOM interactions were significant for pod Cu concentration, suggesting that Cu phytoavailability could be affected by these interactions. Future research will be focused on the mechanisms of Cu translocation in plant and adaptation aspects of abiotic stress. PMID- 24760620 TI - Health hazard prospecting by modeling wind transfer of metal-bearing dust from mining waste dumps: application to Jebel Ressas Pb-Zn-Cd abandoned mining site (Tunisia). AB - This work presents a modeling approach to simulate spatial distribution of metal contamination in aerosols with evaluation of health hazard. This approach offers the advantage to be non-intrusive, less expensive than sampling and laboratory analyses. It was applied to assess the impact of metal-bearing dust from mining wastes on air quality for a nearby community and agricultural lands in Jebel Ressas (Tunisia) locality. Dust emission rates were calculated using existing parameterization adapted to the contamination source composed of mining wastes. Metal concentrations were predicted using a Gaussian model (fugitive dust model) with, as input: emission rates, dump physical parameters and meteorological data measured in situ for 30 days in summertime. Metal concentration maps were built from calculated PM10 particle concentrations. They evidence the areas where Pb and Cd concentrations exceeded WHO guidelines (0.5 and 0.005 ug/m(3), respectively). Maximum concentrations of Pb and Cd in PM10 are, respectively, of 5.74 and 0.0768 ug/m(3) for measured wind speed values up to 22 m/s. Preferential areas of contamination were determined in agricultural lands to the NW from the source dump where Pb and Cd exceeded guidelines up to a distance of 1,200 m. The secondary spreading directions were SW and E, toward the village. Health hazard prospecting shown that a major part of the village was exposed to contaminated dust and that daily hazard quotient (HQ) values reached locally 118 and 158, respectively, for Pb and Cd during the study period. However, HQ variations in the village are high, both temporally and geographically. PMID- 24760621 TI - Comparison of methods used to calculate typical threshold values for potentially toxic elements in soil. AB - The environmental quality of land can be assessed by calculating relevant threshold values, which differentiate between concentrations of elements resulting from geogenic and diffuse anthropogenic sources and concentrations generated by point sources of elements. A simple process allowing the calculation of these typical threshold values (TTVs) was applied across a region of highly complex geology (Northern Ireland) to six elements of interest; arsenic, chromium, copper, lead, nickel and vanadium. Three methods for identifying domains (areas where a readily identifiable factor can be shown to control the concentration of an element) were used: k-means cluster analysis, boxplots and empirical cumulative distribution functions (ECDF). The ECDF method was most efficient at determining areas of both elevated and reduced concentrations and was used to identify domains in this investigation. Two statistical methods for calculating normal background concentrations (NBCs) and upper limits of geochemical baseline variation (ULBLs), currently used in conjunction with legislative regimes in the UK and Finland respectively, were applied within each domain. The NBC methodology was constructed to run within a specific legislative framework, and its use on this soil geochemical data set was influenced by the presence of skewed distributions and outliers. In contrast, the ULBL methodology was found to calculate more appropriate TTVs that were generally more conservative than the NBCs. TTVs indicate what a "typical" concentration of an element would be within a defined geographical area and should be considered alongside the risk that each of the elements pose in these areas to determine potential risk to receptors. PMID- 24760623 TI - Multiple publications from a single study: ethical dilemmas. PMID- 24760622 TI - Soluble Klotho levels in adult renal transplant recipients are modulated by recombinant human erythropoietin. AB - BACKGROUND: Data on serum soluble Klotho levels in chronic kidney disease are contradictory and even less is known after renal transplantation. Experimental studies demonstrated that recombinant human erythropoietin (rhEPO) treatment mitigates Klotho reduction caused by renal damage. Therefore, this study aimed to determine serum Klotho levels in a cohort of kidney transplant recipients (KTR) and to evaluate whether rhEPO treatment can modulate, in vivo and in vitro, soluble Klotho. METHODS: 117 KTR and 22 healthy subjects (HS) were enrolled. In 17 KTR, rhEPO was discontinued for 5 weeks and Klotho levels were compared to 34 propensity score-matched controls. Moreover, we evaluated Klotho mRNA expression and protein secretion in HK-2 tubular cells treated with cyclosporin A (CyA) and rhEPO, alone or in combination. RESULTS: Serum Klotho levels in KTR were significantly higher than in HS (0.68 vs. 0.37, p = 0.002) and significantly associated with estimated glomerular filtration rate (r = -0.378, p = 0.003) and fibroblast growth factor 23 (r = -0.307, p < 0.0001). After 5 weeks of rhEPO discontinuation, treated KTR showed a sharper reduction of Klotho levels than controls (-0.56 vs. -0.11 ng/ml, p < 0.0001). In HK-2 cells CyA treatment induced a Klotho down-regulation that was mitigated by rhEPO pre-treatment. In the same experimental conditions, our results revealed that cells treated with CyA + rhEPO secreted higher soluble Klotho levels than those exposed to CyA or rhEPO alone. CONCLUSIONS: Our results demonstrate that KTR have higher serum Klotho levels than HS and that rhEPO treatment modulates these concentrations, suggesting a link between rhEPO and soluble Klotho in KTR. PMID- 24760625 TI - Impact of secondary hyperparathyroidism on ventricular mass regression after aortic valve replacement for aortic stenosis in hemodialysis-dependent patients. AB - In hemodialysis (HD)-dependent patients, secondary hyperparathyroidism induces cardiac hypertrophy. This study investigated whether parathyroid hormone (PTH) levels affect the degree of left ventricular (LV) mass regression in HD patients after aortic valve replacement (AVR) for aortic stenosis (AS). We retrospectively obtained preoperative and 2-year postoperative echocardiography and intact PTH measurements in 88 HD patients who underwent AVR, with bioprostheses (n = 35, 40%) and mechanical valves (n = 53, 60%) of effective orifice area >0.80 cm2/m2, between January 1997 and December 2010. The LV mass decreased significantly from 308 +/- 88 to 217 +/- 68 g at follow-up of 28 +/- 4 months after AVR (p < 0.001). The LV mass regression at follow-up was inversely related to preoperative PTH values (R = 0.44, p = 0.001). The LV mass regression at follow-up was significantly smaller in the patients (n = 47) with PTH >=100 pg/mL than in those (n = 41) with PTH <100 pg/mL throughout the study period (61 +/- 75 versus 108 +/ 49 g, p < 0.0001). After adjusting for female sex, hypertension, and baseline LV mass, high PTH values were found to be independent predictor of less LV mass regression at 2-year follow-up (beta = 0.23, r2 = 0.24, p = 0.02). In conclusion, the HD patients with high levels of PTH presented with less LV mass regression after AVR for AS without patient-prosthesis mismatch. Secondary hyperparathyroidism may impair regression of cardiac hypertrophy after AVR in HD patients with AS. PMID- 24760626 TI - Characterization of an anthraquinone fluor from the bioluminescent, pelagic polychaete Tomopteris. AB - Tomopteris is a cosmopolitan genus of polychaetes. Many species produce yellow luminescence in the parapodia when stimulated. Yellow bioluminescence is rare in the ocean, and the components of this luminescent reaction have not been identified. Only a brief description, half a century ago, noted fluorescence in the parapodia with a remarkably similar spectrum to the bioluminescence, which suggested that it may be the luciferin or terminal light-emitter. Here, we report the isolation of the fluorescent yellow-orange pigment found in the luminous exudate and in the body of the animals. Liquid chromatography-mass spectrometry revealed the mass to be 270 m/z with a molecular formula of C(15)H(10)O(5), which ultimately was shown to be aloe-emodin, an anthraquinone previously found in plants. We speculate that aloe-emodin could be a factor for resonant-energy transfer or the oxyluciferin for Tomopteris bioluminescence. PMID- 24760627 TI - Structures containing galectin-3 are recruited to the parasitophorous vacuole containing Trypanosoma cruzi in mouse peritoneal macrophages. AB - Trypanosoma cruzi has a complex life cycle where the infective forms for the vertebrate host are trypomastigotes and amastigotes. Both forms invade and lyse their parasitophorous vacuole (PV) membrane, entering into the cytoplasm of its host cells. Galectin-3 (Gal-3) is a protein abundantly distributed in macrophages and epithelial cells. Previous studies demonstrated that Gal-3 binds to a 45KDa mucin of trypomastigotes surface, enhancing its adhesion to the extracellular matrix and even its entry into cells. Gal-3 has another novel cytoplasmic function recently described: a vacuole lyses marker in intracellular bacteria. Considering (1) the importance of Gal-3 during T. cruzi early infection and (2) the importance of T. cruzi PV lyses for parasite differentiation and replication, this study intended to explore a possible recruitment of structures containing Gal-3 (G3CSs) to T. cruzi PVs. Microscopy analyses showed these G3CSs around PVs after 30 and 90 min of amastigotes and trypomastigotes infection, respectively. This recruitment was specific for T. cruzi PVs since we did not observe the same distribution at macrophages vacuoles containing fluorescent microspheres (FM). Concomitantly, this study intended to analyze the participation of actin cytoskeleton in T. cruzi PV maturation. We observed that actin filaments form a "belt-like" structure around trypomastigotes and amastigotes PVs, also labeled for Gal-3. At the time proposed for PV lysis, we observed an actin disassembling while LAMP-1 was recruited to PVs membrane. However, this pattern was maintained in macrophages derived from Gal-3 knockout mice, revealing that the actin belt structure forms independently from Gal-3. Taken together, these data suggest that G3CSs are recruited to vicinity of T. cruzi PV and that actin filaments localize and remain around T. cruzi PVs until the time of its lysis. PMID- 24760629 TI - Effects of 900 MHz radiofrequency radiation on skin hydroxyproline contents. AB - The present study aimed to investigate the possible effect of pulse-modulated radiofrequency radiation (RFR) on rat skin hydroxyproline content, since skin is the first target of external electromagnetic fields. Skin hydroxyproline content was measured using liquid chromatography mass spectrometer method. Two months old male wistar rats were exposed to a 900 MHz pulse-modulated RFR at an average whole body specific absorption rate (SAR) of 1.35 W/kg for 20 min/day for 3 weeks. The radiofrequency (RF) signals were pulse modulated by rectangular pulses with a repetition frequency of 217 Hz and a duty cycle of 1:8 (pulse width 0.576 ms). A skin biopsy was taken at the upper part of the abdominal costa after the exposure. The data indicated that whole body exposure to a pulse-modulated RF radiation that is similar to that emitted by the global system for mobile communications (GSM) mobile phones caused a statistically significant increase in the skin hydroxyproline level (p = 0.049, Mann-Whitney U test). Under our experimental conditions, at a SAR less than the International Commission on Non Ionizing Radiation Protection safety limit recommendation, there was evidence that GSM signals could alter hydroxyproline concentration in the rat skin. PMID- 24760628 TI - Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. AB - BACKGROUND: Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. OBJECTIVES: To assess the effectiveness and safety of late initiation of erythropoietin (EPO) between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL in July 2013. Additional searches included the Pediatric Academic Societies Annual Meetings from 2000 to 2013 (Abstracts2ViewTM) and clinical trials registries (www.clinicaltrials.gov; www.controlled-trials.com; and who.int/ictrp/en). For this update we moved one study from the early EPO review to this late EPO review. SELECTION CRITERIA: Randomised or quasi randomised controlled trials of late initiation of EPO treatment (started at >= eight days of age) versus placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: We include 30 studies (31 comparisons) randomising 1591 preterm infants. Literature searches in 2013 did not identify any new study for inclusion. For this update we moved one study enrolling 230 infants from the early EPO review to this late EPO review.Most included trials were of small sample size. The meta-analysis showed a significant effect of the use of one or more RBC transfusions (20 studies (n = 1142); typical risk ratio (RR) 0.71, 95% confidence interval (CI) 0.64 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I2 = 68%; RD I2 = 60%). We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant [typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants]. There was high heterogeneity for this outcome (I2 = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I2 = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I2 = 83%) and RD (I2 = 82%). Three trials enrolling 442 infants reported on ROP (stage >= 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was minimal heterogeneity for this outcome for RR (I2 = 18%) but high heterogeneity for RD (I2 = 79%). There were no significant differences in other clinical outcomes. There was no reduction in necrotizing enterocolitis in spite of a reduction in the use of RBC transfusions. Long-term neurodevelopmental outcomes were not reported. AUTHORS' CONCLUSIONS: Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (ml/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment to prevent donor exposure is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure. PMID- 24760630 TI - Hepatocellular carcinoma in Budd-Chiari syndrome: enhancement patterns at dynamic gadolinium-enhanced T1-weighted MR imaging. AB - The objective of this study was to analyze the enhancement patterns at dynamic gadolinium-enhanced T1-weighted MR imaging in patients of Hepatocellular Carcinoma (HCC) with associated Budd-Chiari syndrome (BCS). The MR imaging findings in 10 patients of HCC with associated BCS were compared to those of 32 other patients of HCC without BCS. During the arterial phase, significantly more lesions with BCS were hyperintense than lesions without BCS; during the equilibrium phase, significantly more lesions with BCS were slightly hyperintense or isointense than lesions without BCS (P < 0.05 for both). For HCC, contrast enhancement on MRI shows different enhancement patterns between patients of HCC with associated BCS and those without BCS. PMID- 24760631 TI - Plasma-derived human C1-esterase inhibitor does not prevent mechanical ventilation-induced pulmonary complement activation in a rat model of Streptococcus pneumoniae pneumonia. AB - Mechanical ventilation has the potential to cause lung injury, and the role of complement activation herein is uncertain. We hypothesized that inhibition of the complement cascade by administration of plasma-derived human C1-esterase inhibitor (C1-INH) prevents ventilation-induced pulmonary complement activation, and as such attenuates lung inflammation and lung injury in a rat model of Streptococcus pneumoniae pneumonia. Forty hours after intratracheal challenge with S. pneumoniae causing pneumonia rats were subjected to ventilation with lower tidal volumes and positive end-expiratory pressure (PEEP) or high tidal volumes without PEEP, after an intravenous bolus of C1-INH (200 U/kg) or placebo (saline). After 4 h of ventilation blood, broncho-alveolar lavage fluid and lung tissue were collected. Non-ventilated rats with S. pneumoniae pneumonia served as controls. While ventilation with lower tidal volumes and PEEP slightly amplified pneumonia-induced complement activation in the lungs, ventilation with higher tidal volumes without PEEP augmented local complement activation more strongly. Systemic pre-treatment with C1-INH, however, failed to alter ventilation-induced complement activation with both ventilation strategies. In accordance, lung inflammation and lung injury were not affected by pre-treatment with C1-INH, neither in rats ventilated with lower tidal volumes and PEEP, nor rats ventilated with high tidal volumes without PEEP. Ventilation augments pulmonary complement activation in a rat model of S. pneumoniae pneumonia. Systemic administration of C1-INH, however, does not attenuate ventilation-induced complement activation, lung inflammation, and lung injury. PMID- 24760632 TI - [Pathology features and management of small-size gastrointestinal stromal tumors]. AB - The incidence of gastrointestinal stromal tumor(GIST) is 1-2 per 100 000. Micro GIST with a size less than 1 cm are found in 3%-35% elderly population. These small-size GIST are usually located in the middle or upper stomach, with gain function KIT or PDGFRA mutation. In this review, the clinicopathological features and management of these small-size GISTs are discussed. PMID- 24760633 TI - [Interpretation on 2013 updated Chinese Consensus on the Diagnosis and Treatment of Gastrointestinal Stromal Tumors]. AB - The Gastrointestinal Stromal Tumor Experts Committee amended and complemented the Chinese Consensus on the Diagnosis and Treatment of Gastrointestinal Stromal Tumors(2013 version) based on the previous edition(2011 version) after broad consulation, repeat discussion on new results of clinical trials in recent years and the opinions of many experts. In the new consensus, the pathological diagnose was revised the most, including definition, diagnosis differential diagnosis, genotype, and recurrence risk classification. However, few modifications was made in surgical treatment and targeted therapy. It also describes the characteristics and difference between Chinese consensus and NCCN guideline so as to be more succinct as the reference of clinical practice and more suitable for Chinese patients. This article interpreted the key points of the update. PMID- 24760634 TI - [Treatment strategy for recurrent and metastatic gastrointestinal stromal tumors]. AB - Targeted therapy is the first line treatment for patients with recurrent/metastatic gastrointestinal stromal tumors(GIST). Sunitinib is effective for patients who have failed imatinib, specially with c-kit exon 9 gene mutation. Tyrosine kinase inhibitors combined with partial hepatectomy may increase the overall survival of GIST patients with liver metastasis. Selective patients with recurrent or metastatic GIST can benefit from surgical resection. Regorafenib and pazopanib can provide a significant improvement in progression free survival in patients after failure of standard treatment. PMID- 24760635 TI - [Diagnosis and treatment of wild-type gastrointestinal stromal tumors]. AB - Gastrointestinal stromal tumors(GIST) are the most common mesenchymal tumors of the gastrointestinal tract, and are mostly characterized by c-kit or PDGFRA gain of-function mutation. About 10%-15% of GIST do not harbor any mutations in the c kit and PDGFRA genes and are defined as wild-type GIST. There are significant differences in molecular mechanism and clinical characteristics between wild-type GIST and mutant GIST. Wild-type GIST should be considered as a family of diseases due to their extreme heterogeneity. Clinician should pay close attention to the diagnosis and treatment of wild-type GIST. PMID- 24760636 TI - [Role of molecular subtypes in gastrointestinal stromal tumors in a clinical setting]. AB - Gastrointestinal stromal tumors(GIST) are known for their molecular alterations in KIT or PDGFR genes, and have become the paradigm of molecularly targeted therapies for solid tumors. Recent researches of genotype and phenotype demonstrate that molecular subtypes can predict the response to treatment with tyrosine kinase inhibitors and are related with prognosis. Different strategies will be recommended according to different molecular subtypes of GIST in the future for treatment optimization and individualization. PMID- 24760637 TI - [Drug resistance mechanism and new therapy strategy progression in targeted treatment of gastrointestinal stromal tumors]. AB - Gastrointestinal stromal tumors(GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Most of these stromal tumors are characterized by mutations in the KTT or platelet-derived growth factor receptor alpha (PDGFRA) genes, resulting in the constitutive activation of tyrosine kinase signaling. Tyrosine kinase inhibitors(TKI), such as imatinib and sunitinib, provide the standard first-line and second-line therapy for patients with metastatic or unresectable GIST. Imatinib resistance has been a challenging problem in clinical practice and raised great concern. This review introduces the underlying mechanisms of imatinib resistance and advances of treatment strategies. Reasonable individual treatment with the guidance of molecular biology is promising to improve the efficacy and the quality of life for GIST patients. PMID- 24760638 TI - [A multicentre retrospective cohort study of patients with gastrointestinal stromal tumors in Shandong Province]. AB - OBJECTIVE: To investigate the clinicopathological features and prognosis of patients with gastrointestinal stromal tumor(GIST) after surgery in Shandong Province. METHODS: Clinicopathological data of GIST patients undergoing surgery from January 2001 to June 2013 in four university teaching hospitals in Shandong Province were reviewed. Pathology results were rechecked. Patients were followed up. The prognostic factors were evaluated by univariate and multivariate analyses with Log-rank test and Cox proportional hazard model. RESULTS: A total of 1039 GIST cases were enrolled, including 509 males and 530 females, with age from 18 to 87 years(median, 58). Ninety-three patients died of GIST during follow-up. The 1-, 3-, 5-year survival rates were 94.6%, 91.7% and 87.8%, respectively. Patients undergoing R0 resection had a higher 5-year overall survival rate than those undergoing R1 resection(88.8% vs 69.0%, P<0.05). For patients with intermediate risk of recurrence after surgery, the 5-year overall survival rate was 94.4% and 89.2% respectively in imatinib and non-imatinib intervention groups(P>0.05). For patients with high risk of recurrence after surgery, the 5-year overall survival rate was 76.8% and 67.7% respectively(P<0.05). Multivariate analysis revealed that tumor size(P<0.01, RR=1.988, 95%CI:1.497-2.641), mitotic count(P<0.01, RR=2.326, 95%CI:1.686-3.208) and tumor rupture(P<0.01, RR=3.032, 95%CI:1.732 5.308) were independent prognostic factors. CONCLUSIONS: Tumor size, mitotic count and tumor rupture affect the prognosis of patients after resection of primary GIST independently. The standard treatment of localized GIST is R0 resection. Adjuvant imatinib therapy can improve overall survival of patients with high risk of recurrence after surgery. The efficacy of imatinib for patients with intermediate risk of recurrence remains to be verified. PMID- 24760639 TI - [Clinical analysis of 156 patients with gastrointestinal stromal tumors receiving imatinib therapy]. AB - OBJECTIVE: To evaluate the impact of primary site, NIH risk and imatinib treatment on the prognosis of patients with gastrointestinal stromal tumors(GIST). METHODS: Clinicopathological data of 156 adult patients with GIST treated by imatinib in the Cancer Institute and Hospital of Tianjin Medical University from January 2006 to December 2010 were retrospectively analyzed. According to NIH risk classification, 30 patients were at moderate risk and 126 at high risk. Sixty-seven patients had advanced GIST. Prognosis of patients with different primary tumor site, different NIH risk and different treatment was compared respectively. RESULTS: Imatinib therapy was well tolerated in all the patients. Eighty-nine cases received radical operation and adjuvant imatinib treatment. Among 67 advanced GIST cases, 26 received radical operation and adjuvant imatinib treatment, 27 received palliative operation and adjuvant imatinib treatment, and 14 received simple adjuvant imatinib treatment without operation. All the patients had routine follow-up, ranging from 9 to 56(median 27) months. The overall survival (OS) rate was 96% in 1-year, 86% in 2-year, and 71% in 3-year. The OS rate was 95% in 1-year, 77% in 2-year, and 65% in 3-year for patients at high risk, and all 100% in 1-, 2-, 3-year for patients at moderate risk, the differences was statistically significant (P=0.001). The OS rate was 97% in 1-year, 90% in 2-year, and 84% in 3-year for patients with gastric GIST, and 95% in 1-year, 69% in 2-year, and 52% in 3-year for patients with non-gastric GIST, the difference was significant(P=0.000). The OS rate was 98% in 1-year, 95% in 2-year, and 90% in 3-year for patients undergoing radical resection and adjuvant imatinib therapy. For 67 advanced GIST patients with imatinib therapy, none had complete remission, 41 had part remission, 15 had stable disease, indicating 56 advanced GIST cases(83.6%) obtaining clinical benefit. The OS rate was 91% in 1-year, 58% in 2-year, and 43% in 3-year. CONCLUSIONS: The prognosis of high, and non-gastric and advanced GIST patients is poor. Radical resection combined with early imatinib treatment can improve the prognosis of GIST patients. PMID- 24760640 TI - [Clinicopathological analysis of 61 patients with rectal gastrointestinal stromal tumors]. AB - OBJECTIVE: To explore the clinicopathological characteristics, efficacy, and prognostic factors for patients with rectal gastrointestinal stromal tumor(GIST). METHODS: Clinicopathological and follow-up data of 61 patients with rectal GIST in our department from January 1990 to October 2012 were analyzed retrospectively and pathology specimens were reviewed. Kaplan-Meier method was used to calculate the survival. Univariate analysis and multivariate analysis were performed to investigate the influencing factors of prognosis with Log-rank test and Cox regression model. RESULTS: There were 42 male and 19 female patients with a median age of 59 years old. Eighteen cases(29.5%) were confirmed preoperatively as GIST by biopsy and 46 cases were diagnosed as GIST by first pathological examination. Fifteen cases(24.6%) were revised as GIST after re-examination of specimes among whom 14 cases had been diagnosed as leiomyoma or sarcoma, and 1 as neurolemmoma. Tumor location was above peritoneal reflection in 12 cases(19.7%) and below peritoneal reflection in 49(80.3%). Fifty-two patients underwent surgery, including 21 extended resections(lymph nodes clearance and combined organs resection simultaneously) and 31 local resections(tumor rejection or partial resection of rectal wall). Eleven patients received preoperative imatinib(400 mg/d). Forty-one cases received imatinib therapy after operation or biopsy diagnosis, including 25 cases who received palliative treatment for postoperative recurrence. Median follow-up time was 55(6 to 391) months and follow-up longer than 2 years was carried out in 46 patients. Overall survival rates of 1-, 2-, 3- , 5-year were 98%, 95.6%, 86.0% and 73.7% respectively. There were no significant differences between local resection group(96.4%, 92%, 83.3% and 77.3%) and extended resection group (100%, 94.7%, 89.50% and 82.6%)(chi(2)=0.004, P=0.947). Univariate analysis showed that survival was only associated with recurrence and metastasis (chi(2)=4.292, P=0.038). Multivariate Cox analysis showed postoperative survival was not associated with any factors(all P>0.05). The 3-year survival rate of patients with postoperative recurrence or metastasis receiving imatinib therapy was better as compared to those who did not received imatinib(82.7% vs. 71.4%). CONCLUSIONS: Rectal GIST are more common in the lower rectum. Surgery is the main treatment for rectal GIST. Local complete resection is the mainstay treatment. Extensive resection and lymph node clearance may not improve survival. Imatinib can improve the prognosis of patients with recurrence or metastasis. PMID- 24760642 TI - [Efficacy and prognosis of different treatments on 63 patients with small intestinal gastrointestinal stromal tumors]. AB - OBJECTIVE: To analyze the efficacy and prognosis of different treatments on small intestinal gastrointestinal stromal tumors(SIGIST). METHODS: Clinical data of 63 patients with SIGIST who were admitted to the Chinese PLA General Hospital from January 2004 to December 2013 were analyzed retrospectively. According to resection procedure and postoperative use of imatinib, patients were divided into R0 resection plus imatinib group (13 cases), R0 resection without imatinib group (42 cases), non-R0 resection plus imatinib group (7 cases), non-R0 resection without imatinib group (1 case). Survival was compared among groups. Result All the patients were followed up with a median length of 24 months(3 to 120 months), and the over survival (OS) rates at 1-year, 3-year, 5-year were 97%, 94% and 80%. In R0 resection plus imatinib group, R0 resection without imatinib group, and non R0 resection plus imatinib group, the progression free survival(PFS) time was 24, 24 and 23 months; the 1-year PFS were 100%, 97% and 83%; the 3-year PFS were 100%, 45% and 83%; the 5-year PFS were 100%, 28% and 42%. R0 resection plus imatinib group had significantly higher PFS(all P<0.05). The case of non-R0 resection without imatinib died 6 months after operation. Among 55 patients undergoing R0 resection, recurrence was found in 16 patients, whose recurrence rates of 1-year, 3-yeart and 5-year were 2%,43% and 58%. Local recurrence was found in 8 cases, hepatic recurrence in 3 cases and widespread recurrence in 5 cases, who received simple imatinib, operation plus imatinib and imatinib intervention, with median survival time of 66.5 months, 92.5 months and 48 months respectively. One patient initiatively abandoned treatment and died 17 months later. CONCLUSION: The total resection and postoperative imatinib administration can improve the prognosis and raise the progression free survival of patients with small intestinal stromal tumors. PMID- 24760641 TI - [Efficacy analysis of laparoscopic surgery for primary local gastric and intestinal gastrointestinal stromal tumors]. AB - OBJECTIVE: To investigate the feasibility and short-term efficacy of laparoscopic resection of primary local gastric and intestinal gastrointestinal stromal tumors(GIST). METHODS: Clinicopathological data of 26 patients with GIST, 20 located at the stomach and 6 at the intestine, undergoing laparoscopic complete resection from October 2010 to April 2013 were retrospectively analyzed. RESULTS: Hand-assisted laparoscopic surgery was performed in 3 patients with gastric GIST, while the other 23 underwent regular laparoscopic surgery. All the procedures were performed successfully without conversion to open operation. According to tumor location and growth types, gastric local resection was performed in 18 cases, distal gastrectomy in 2 cases and intestinal segmental resection in all 6 cases of intestinal GIST. The mean diameter of tumor was (4.5+/-1.6) cm. The mean operational time was(96.2+/-28.2) min, with a mean blood loss of (49.6+/-38.6) ml. Postoperative bowel function recovery time was (2.3+/-0.7) d and the length of postoperative hospital stay was (6.8+/-1.9) d. Bleeding from gastrointestinal tract developed in 1 patient after resection of intestinal GIST. Postoperative pathology indicated very low risk of GIST in 1(3.8%), low risk in 13(50.0%), intermediate in 9(34.6%) and high risk in 3(11.5%) patients, respectively. After a follow-up ranging form 3 to 32 months, no recurrence or death was found. CONCLUSION: Laparoscopic surgery of primary local GISTs from stomach or intestine is safe and feasible in selected patients, with less invasiveness, rapid recovery, and favorable short-term outcomes. PMID- 24760643 TI - [Retrospective clinical analysis of heterotopic pancreas misdiagnosed as gastrointestinal stromal tumors]. AB - OBJECTIVE: To improve the differential diagnosis and treatment between heterotopic pancreas and gastrointestinal stromal tumor. METHOD: Clinical and follow-up data of 14 cases who were diagnosed preoperatively as gastrointestinal stromal tumor whereas were confirmed as heterotopic pancreas in the gastrointestinal tract by postoperative pathological results in Renji Hospital from January 2007 to June 2013 were analyzed retrospectively. RESULT: There were 9 males and 5 females, aged ranged from 26 to 69 years old. Eight patients had upper abdominal pain, 2 presented with intestinal obstruction, and 4 were incidentally found on routine health check-up. The lesions located at the stomach in 11 cases, at the duodenum in 1 case, and at the jejunum in 2 cases. All the patients underwent operation. Postoperative pathology confirmed the diagnosis of heterotopic pancreas. Among these lesions, 10 cases presented with co-existence of pancreatic acinus and duct as main component with smooth muscle and few gastric mucosa tissues, 3 cases was mainly the pancreatic acinus and 1 case mainly the pancreatic duct and smooth muscle. CONCLUSIONS: Heterotopic pancreas may be misrocognized at gastrointestinal stromal tumors due to non-specific clinical manifestations and effective examination methods. Surgical procedure is the only one and the most effective treatment. Postoperative pathology examination is the most difinitive for differential diagnosis. PMID- 24760644 TI - [Efficacy analysis of endoscopic submucosal excavation for gastric gastrointestinal stromal tumors]. AB - OBJECTIVE: To assess the efficacy and safety of endoscopic submucosal excavation(ESE) for gastric gastrointestinal stromal tumors(GISTs). METHODS: Clinical data of 86 gastric GISTs patients undergoing ESE in our department from January 2007 to January 2013 were analyzed retrospectively. The whole tumor biopsy was used to determine the risk stratification. Complication of ESE was recorded and recurrence was investigated during regular follow-up. RESULTS: Tumors of all 86 cases were resected completely without residue proved by postoperative pathology. According to NIH risk stratification, 12 cases were very low risk, 30 low risk, 25 moderate risk, and 19 high risk. Tumor size, tumor depth, and tumor surface bleeding or edema were associated with the risk stratification of the GISTs(all P<0.05). Bleeding rate of ESE was 5.8%(5/86), including severe intraoperative bleeding in 1 case, postoperative delayed bleeding in 4 cases. The maximal tumor diameter was <2 cm in 1 case and >2 cm in 4 cases. The tumor were grade as moderate risk in 3 cases and high risk in 2 cases. The perforation rate was 10.5%(9/86), including tumors with a maximal diameter of <2 cm in 4 cases and >2 cm in 5 cases. The tumors were grade as moderate risk in 5 cases and high risk in 4 cases. Recurrence rate was 5.8%(5/86), including tumors with a maximal diameter <2 cm in 2 case and >2 cm in 3 cases. The tumors were grade as moderate risk in 4 cases and high risk in 1 cases. CONCLUSION: ESE is safe and effective for the treatment of gastric GISTs. The operative complication and postoperative recurrence may be associated with the tumor risk stratification. PMID- 24760645 TI - [Effect of early enteral nutrition on immune response and clinical outcomes after esophageal cancer surgery]. AB - OBJECTIVE: To evaluate the effect of early enteral nutrition(EEN) on immune response and clinical outcomes after esophageal cancer operation. METHODS: Sixty patients with esophageal cancer undergoing radical operation between March 2010 and July 2011 were randomly divided into two groups using envelope method: EEN group(n=30, administration of water and enteral nutrition early after operation) and TPN group(n=30, administration of total parenteral nutrition). Two groups both received 7-day nutrition support. Immune indexes(CD3(+), CD4(+), CD8(+), CD4(+)/CD8(+)) and serum nutritional indexes(albumin, pre-albumin, transferrin) were measured before operation and 1-, 3-, and 7-day after operation. The time to first flatus, length of postoperative hospital stay, total hospitalization cost, and postoperative complication were recorded. RESULTS: As compared to TPN group, the time to first flatus was significantly shorter in EEN group[(66.5+/-7.3) h vs. (75.1+/-6.8) h, P<0.01], as was hospital stay[(7.8+/-1.1) d vs. (9.3+/-1.3) d, P<0.01]. Total hospitalization cost[(36 210+/-3810) yuan vs. (39 731+/-4013) yuan, P<0.01] was lower in EEN group as compared to TPN group. There was no significant difference in postoperative complication rate between the two groups[13.3%(3/30) vs. 20.0%(6/30), P>0.05]. The levels of CD3(+), CD4(+), CD4(+)/CD8(+), albumin, prealbumin and transferrin were significantly higher in EEN group as compared to TPN group on postoperative day 3 and 7(all P<0.05), while CD8(+) was significantly lower in EEN group(P<0.05). CONCLUSION: EEN can promote early recovery of gastrointestinal function, improve nutritional and immune function, and therefore lead to fast postoperative recovery in esophageal cancer patients. PMID- 24760646 TI - [Relevant factor analysis on postoperative ileus following radical resection for colorectal cancer]. AB - OBJECTIVE: To investigate the associated factors for postoperative ileus following radical resection for colorectal cancer. METHODS: Clinical data of 1366 colorectal cancer patients undergoing radical resection by the same surgical team in our hospital from January 2000 to September 2011 were analyzed retrospectively. Univariate analysis and multivariate logistic regression analysis were used to identify the associated factors of postoperative ileus. RESULTS: A total of 70 patients(5.1%) developed postoperative ileus. Univariate and multivariate analyses showed that N2(OR=1.893, 95%CI:1.083-3.306), history of colorectal cancer resection(OR=4.899, 95%CI:1.490-16.110), preoperative obstruction (OR=2.616, 95%CI:1.297-5.280), right hemicolectomy(OR=2.024, 95%CI:1.052-3.894) and left hemicolectomy(OR=3.030, 95%CI:1.401-6.550) were risk factors for postoperative ileus following radical resection for colorectal cancer, while laparoscopic operation(OR=0.520, 95%CI:0.319-0.849) was protective. CONCLUSIONS: Postoperative ileus following radical resection for colorectal cancer is associated with surgical procedures. Laparoscopic colorectal resection can reduce the incidence of postoperative ileus. PMID- 24760647 TI - [Feasibility of radical laparoscopy-assisted gastrectomy for patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To assess the effect of radical laparoscopy-assisted gastrectomy(LG) for patients with chronic obstructive pulmonary disease (COPD). METHODS: Clinical data of 340 gastric cancer patients with COPD undergoing radical gastrectomy with lymphadenectomy at Southwest Hospital, Third Military Medical University between January 2010 and October 2013 were analyzed retrospectively. The clinical outcomes for the 262 patients with COPD who underwent LG(LG group) were compared with those of 78 patients with COPD who underwent open gastrectomy(OG group). During LG, pneumoperitoneum was maintained at an insuffiation pressure of 8 mmHg to 10 mmHg. The primary endpoint was postoperative pulmonary complication(PPC). To predict factors related to PPC, univariate and multivariate logistic analyses were carried out. RESULTS: Intraoperative blood loss was significantly less in the LG group [(131.2+/-14.7) ml] than in the OG group [(246.7+/-49.0) ml; t= 13.445, P=0.000], but operation time was significantly longer [(220.4+/-19.1) min vs. (194.2+/-31.5) min; t=6.877, P=0.000]. The findings showed PPC to be significantly less frequent in the LG group(5.3%,14/262) than in the OG group (15.4%, 12/78)(chi(2)=8.581, P=0.003). The severity of COPD was independent risk factor for PPC(P=0.031, HR=1.456, 95%CI:1.306-1.789). No independent predictor of PPCs was found in type of operative approach (open vs laparoscopic; P=0.126). CONCLUSION: The LG procedure with insuffiation pressure of pneumoperitoneum is tolerated for gastric cancer patients with mild or moderate COPD. PMID- 24760648 TI - [Clinical control study of laparoscopic versus open surgery for rectal cancer]. AB - OBJECTIVE: To evaluate the safety and short-term outcomes of laparoscopic assisted surgery for rectal cancer by comparing the efficacy of laparoscopy and open surgery. METHODS: Clinical data of patients with rectal cancer treated by laparoscopy or open surgery in Zhongshan Hospital from April 2011 to June 2012 were analyzed retrospectively, and the clinical outcomes between the two groups were compared. RESULTS: Ninety-six rectal cancer patients undergoing laparoscopic surgery(LS) were enrolled. A total of 216 rectal cancer patients underwent open surgery(OS). There was no operative death in both groups. In LS and OS group, the overall completion rates of TME were 86.4%(83/96) vs. 89.3%(193/216)(P>0.05) respectively, and the overall anal reservation rates were 78.1%(75/96) vs. 75.0%(162/216)(P>0.05) respectively. The mean distance to proximal resection margin and distal resection margin respectively were (10.3+/-4.1) cm vs.(10.0+/ 4.3) cm(P>0.05) and (3.4+/-0.9) cm vs. (3.6+/-1.4) cm(P>0.05) respectively. The mean number of harvested lymph nodes respectively were (12.8+/-5.2) vs.(13.7+/ 6.4)(P>0.05). Compared to OS, LS presented less blood loss [(98.0+/-28.7) ml vs. (175.0+/-41.0) ml, P<0.05], shorter postoperative hospital stay [(9.4+/-4.9) d vs.(11.6+/-6.2) d, P<0.05], quicker postoperative recovery of bowel function[(2.7+/-0.9) d vs. (3.4+/-0.9) d, P<0.05], shorter postoperative time to intake semi-solid[(3.7+/-1.2) d vs. (4.4+/-1.5) d, P<0.05], less postoperative complications(15.6% vs. 25.9%, P<0.05), but longer operative time[(155.7+/-48.4) min vs. (120.0+/-26.7) min, P<0.05]. Postoperative follow-up was 6 to 24 months, and the local recurrence of LS and OS was 2.1% and 2.3%(P>0.05). CONCLUSION: Laparoscopic surgery can obtain the same radical efficacy for rectal cancer as compared to open surgery. PMID- 24760649 TI - [Proximal gastrectomy versus total gastrectomy for adenocarcinoma of esophagogastric junction: a meta-analysis]. AB - OBJECTIVE: To compare the efficacy of proximal gastrectomy(PG) and total gastrectomy(TG) for adenocarcinoma of esophagogastric junction. METHODS: Clinical trials comparing PG with TG for adenocarcinoma of esophagogastric junction published from 1990 to 2012 were searched in Cochrane library, Medline, Embase and China National Knowledge Infrastructure (CNKI), Wanfang Data. Review manager 5.0 was used for meta-analysis and outcome measures included mortality and complication morbidity, as well as nutritional state. RESULTS: A total of 10 studies including 2481 patients were identified and analyzed. The results showed no significant differences in the mortality(OR=1.00, P=0.99) and complication morbidity(OR=2.14, P=0.12) between PG and TG. However, anastomotic stenosis(OR=5.40, P<0.01) and reflux esophagitis(OR=7.12, P=0.01) were more frequently observed in PG group. The nutritional state in TG group was comparable with PG group(WMD=2.09, P=0.57). CONCLUSION: TG is superior to PG in reducing the morbidity of anastomotic stenosis and reflux esophagitis. PMID- 24760650 TI - [Expression of phospholipase C epsilon-1 in gastric cancer and its association with prognosis]. AB - OBJECTIVE: To study the expression of phospholipase C epsilon-1(PLCE1) and its clinical significance in gastric cancer. METHODS: Surgical specimens were collected from 125 patients who underwent radical gastrectomy between 2005 and 2007 in the Zhejiang Provincial Peoples' Hospital. Expression level of PLCE1 protein was measured by immunohistochemistry in these 125 surgical specimens, which included primary gastric cancer and matched adjacent normal gastric mucosa tissues, and then 41 pairs of above specimens were selected randomly to examine the expression level of PLCE1 mRNA by quantitative reverse transcription PCR(qRT PCR). RESULTS: Immunohistochemistry and qRT-PCR showed that both protein and mRNA level of PLCE1 were up-regulated in gastric cancer compared with paired normal gastric mucosa. Univariate analysis demonstrated that the expression of PLCE1 was significantly associated with differentiation degree, invasion depth, lymph node metastasis, distant metastasis, and TNM stage (all P<0.01). The 5-year survival rate of positive PLCE1 group was significantly lower as compared to negative group (31.2% vs. 54.0%, P<0.01). However, the expression of PLCE1 was not an independent prognostic factor for gastric cancer (P>0.05). CONCLUSIONS: PLCE1 is up-regulated in gastric cancer, which is associated with the malignant biological behaviors of gastric cancer. High expression of PLCE1 suggests poor prognosis. PMID- 24760651 TI - [Anti-tumor effect of 5-FU-PLLA-CNTs on human gastric carcinoma cell lines in vitro]. AB - OBJECTIVE: To prepare cisPLLAtin-loaded polylactic acid/cnts, and to study the anti-tumor effect of 5-FU-PLLA-CNTs on human gastric carcinoma cell lines(MGC803 and MNK45). METHODS: 5-FU-PLLA-CNTs were prepared with ultrasound emulsification. The morphology of 5-FU-PLLA-CNTs was determined by scanning electron microscope(SEM), and its drug loading and drug release curve in vitro were detected by UV-Vis-NIR spectrophotometer. Cells were divided into experiment, positive control and negative control groups. CCK8 method was used to test the cytotoxic effect of 5-FU-PLLA-CNTs in different concentrations on MGC803 and MNK45 cell proliferation. Flow cytometry was employed to measure the apoptotic rate of MGC803 and MNK45 cells before and after the intervention of 5-FU-PLLA CNTs. RESULTS: Deep layer film of 5-FU-PLLA-CNTs was successfully established, whose drug-load rate was(4.54+/-0.43)%, entrapment rate was(21.56+/-2.36)%. In vitro release test showed release rate within 24 h of 5-FU-PLLA-CNTs was 23.9% in a as lowly increasing manner, and accumulating release rate was 85.3% at day 31. CCk8 experiment revealed, as compared to control group, 5-FU-PLLA-CNTs significantly inhibited the proliferation of two cell lines in dose-dependent and time-dependent manner. The best 5-FU-PLLA-CNTs concentration of inhibition for human gastric cancer cell lines was 1 mg/well. Flow cytometry indicated the apoptotic rate of MGC803 and MNK45 cells in experiment group treated by 1 mg/well 5-FU-PLLA-CNTs significantly increased as compared to negative control group (P<0.05), while the difference was not significant as compared to positive control group (P>0.05). CONCLUSION: The 5-FU-PLLA-CNTs has good drug sustained release capacity, and can significantly kill and inhibit the proliferation of MGC803 and MNK45 cell lines. PMID- 24760652 TI - [Correlation and clinical significance of expressions of HIF-1alpha and Sema4D in colorectal carcinoma tissues]. AB - OBJECTIVE: To compare the expressions of hypoxia-inducible factor 1 alpha(HIF 1alpha) and Semaphorin 4D(Sema4D) in colorectal carcinoma and normal colorectal tissues, and to investigate their correlation and clinical significance. METHODS: The expressions of HIF-1alpha and Sema4D were examined in 86 cases of colorectal carcinoma and 52 normal colorectal tissues by SP immunohistochemical staining. Correlation between these two expressions and association of the expressions with clinicopathological characters and prognosis were analyzed. RESULTS: The positive rates of HIF-1alpha and Sema4D protein in colorectal carcinoma tissues were significantly higher than those in normal colorectal tissues(58.1% vs. 7.7%, chi(2)=34.624, P<0.01; 60.5% vs. 11.5%, chi(2)=31.839, P<0.01). HIF-1alpha and Sema4D protein expressions were closely associated with colorectal carcinoma histological types(P=0.003, P=0.010), TNM staging (P=0.003, P=0.017) and lymphatic metastasis (P=0.003, P=0.020), and a significant correlation was observed between the expressions of HIF-1alpha and Sema4D protein (r=0.567, P<0.01). The 5-year overall survival rate was 37%. Univariate analysis showed that 5-year survival rates of patients with positive and negative HIF-1alpha protein expression were 24% and 56%(P=0.003), and those with positive and negative Sema4D protein expression were 23% and 59%(P=0.001). Multivariate Cox analysis showed that expression of Sema4D was an independent prognostic factor of colorectal cancer patients(P=0.026), while expression of HIF-1alpha was not(P=0.501). CONCLUSION: Combined detection of HIF-1alpha and Sema4D has the potential to predict the development trend of colorectal carcinoma and prognosis of patients. PMID- 24760653 TI - [Application of genetically engineered mice model in the research of gastrointestinal tumor]. AB - The gene knockout is based on the DNA homologous recombination and embryonic stem cell technology. It is an experimental method for modification of specific gene loci, which is one of the most direct means to clarifying gene functions. The similarity of genomes between mouse and human is as high as up to 95%. The life cycle of mice is relatively short, and easy to breed with stronger reproductive capacity. Therefore, the knockout mice are suitable for observing the whole process of disease pathogenesis. With genetic manipulation technology, researchers can produce the simulations of phenotypic effect by human genetic variation. This article focuses on genetically engineered mice models and their application in gastrointestinal cancer. PMID- 24760654 TI - Possible involvement of infection with human coronavirus 229E, but not NL63, in Kawasaki disease. AB - Although human coronavirus (HCoV)-NL63 was once considered a possible causative agent of Kawasaki disease based on RT-PCR analyses, subsequent studies could not confirm the result. In this study, this possibility was explored using serological tests. To evaluate the role of HCoV infection in patients with Kawasaki disease, immunofluorescence assays and virus neutralizing tests were performed. Paired serum samples were obtained from patients with Kawasaki disease who had not been treated with gamma-globulin. HCoV-NL63 and two antigenically different isolates of HCoV-229E (ATCC-VR740 and a new isolate, Sendai-H) were examined as controls. Immunofluorescence assays detected no difference in HCoV NL63 antibody positivity between the patients with Kawasaki disease and controls, whereas the rate of HCoV-229E antibody positivity was higher in the patients with Kawasaki disease than that in controls. The neutralizing tests revealed no difference in seropositivity between the acute and recovery phases of patients with Kawasaki disease for the two HCoV-229Es. However, the Kawasaki disease specimens obtained from patients in recovery phase displayed significantly higher positivity for Sendai-H, but not for ATCC-VR740, as compared to the controls. The serological test supported no involvement of HCoV-NL63 but suggested the possible involvement of HCoV-229E in the development of Kawasaki disease. PMID- 24760655 TI - Universal newborn screening for congenital CMV infection: what is the evidence of potential benefit? AB - Congenital CMV infection is a leading cause of childhood disability. Many children born with congenital CMV infection are asymptomatic or have nonspecific symptoms and therefore are typically not diagnosed. A strategy of newborn CMV screening could allow for early detection and intervention to improve clinical outcomes. Interventions might include antiviral drugs or nonpharmaceutical therapies such as speech-language therapy or cochlear implants. Using published data from developed countries, we analyzed existing evidence of potential benefit that could result from newborn CMV screening. We first estimated the numbers of children with the most important CMV-related disabilities (i.e. hearing loss, cognitive deficit, and vision impairment), including the age at which the disabilities occur. Then, for each of the disabilities, we examined the existing evidence for the effectiveness of various interventions. We concluded that there is good evidence of potential benefit from nonpharmaceutical interventions for children with delayed hearing loss that occurs by 9 months of age. Similarly, we concluded that there is fair evidence of potential benefit from antiviral therapy for children with hearing loss at birth and from nonpharmaceutical interventions for children with delayed hearing loss occurring between 9 and 24 months of age and for children with CMV-related cognitive deficits. We found poor evidence of potential benefit for children with delayed hearing loss occurring after 24 months of age and for children with vision impairment. Overall, we estimated that in the United States, several thousand children with congenital CMV could benefit each year from newborn CMV screening, early detection, and interventions. PMID- 24760656 TI - Open-label study assessing the long-term efficacy and safety of triple olmesartan/amlodipine/hydrochlorothiazide combination therapy for hypertension. AB - INTRODUCTION: To reduce cardiovascular risk associated with hypertension, the majority of patients require at least two drugs to control their blood pressure (BP), and many require three or more. METHODS: An open-label extension of a 10 week double-blind study assessed the long-term efficacy and safety of olmesartan/amlodipine/hydrochlorothiazide (OLM/AML/HCTZ) triple combination treatment in 2,509 patients with Grade 2-3 hypertension. After 8 weeks of single blind OLM/AML/HCTZ 20/5/12.5 mg treatment, patients at BP goal [seated systolic/diastolic BP (SeSBP/SeDBP) <140/90 mmHg, or <130/80 mmHg for patients with diabetes, or chronic kidney or cardiovascular disease] entered open-label treatment for 36 weeks. Patients not at goal received 8 weeks of randomized, double-blind treatment before entering open-label treatment. During open-label treatment, patients received OLM/AML/HCTZ 20/5/12.5, 40/5/12.5, 40/5/25, 40/10/12.5 or 40/10/25 mg with up- or down-titration as needed to achieve BP goals. RESULTS: During open-label treatment, mean SeSBP/SeDBP levels remained within the ranges 120-140 and 75-85 mmHg, respectively. At study end, significant reductions from baseline were seen in each group for SeSBP (37-43 mmHg) and SeDBP (22-27 mmHg), and 78.1% of patients overall achieved BP goal. Categorical analysis of patients by baseline SeSBP (150-159, 160-169, 170-179, 180-189, 190 to <200 mmHg) correlated with changes in SeSBP. Patients in the lowest baseline category (150-159 mmHg) showed a reduction of 34.3 mmHg, and those in the highest category (190 to <200 mmHg) showed a 59.4 mmHg reduction. At baseline, 90.8% of patients had Grade 2 or 3 hypertension, but at study end 91.9% had normal/high normal BP. The incidence of adverse events was similar across the treatment groups. CONCLUSION: In patients with Grade 2-3 hypertension, long-term treatment with OLM/AML/HCTZ triple combination therapy was well tolerated and effective. A high level of BP control and a substantial reduction in the level of hypertension severity were achieved. PMID- 24760657 TI - Human health risk assessment for ingestion exposure to groundwater contaminated by naturally occurring mixtures of toxic heavy metals in the Lao PDR. AB - This study constitutes the first systematic risk assessment in the Lao PDR of the safety of groundwater for consumption. Groundwater and hair samples were collected from seven Lao provinces to determine the quantitative health impact of heavy metals through ingestion exposure. Contamination levels for arsenic (As; 46.0 %) and barium (Ba; 16.2 %) exceeded World Health Organization (WHO) guidelines, especially in Mekong River floodplains. A USEPA assessment model for health risks from daily groundwater ingestion, with adjustments for local water consumption values, was applied to estimate the size of the population at risk for noncarcinogenic and carcinogenic health problems. As was the only element contributing to noncarcinogenic health risks in all contaminated areas. The populations of Bolikhamxai, Savannakhet, Saravane, Champasak, and Attapeu, moreover, were at risks of cancer. In addition to the As groundwater concentration factor, noncarcinogenic and carcinogenic risks were positively correlated with the average daily dose of As, exposure duration, and subject body weight. The level of As in hair correlated with groundwater consumption and average daily dose of As. 25.5 % of the population (n = 228) showed As levels in hair above the toxicity level. PMID- 24760658 TI - Using process-based models to filter out natural variability in observed concentrations of nitrogen and phosphorus in river water. AB - Advances in process-based modelling of loads of nitrogen and phosphorus carried by rivers have created new possibilities to interpret time series of water quality data. We examined how model runs with constant anthropogenic forcing can be used to estimate and filter out weather-driven variation in observational data and, thereby, draw attention to other features of such data. An assessment of measured and modelled nutrient concentrations at the outlets of 45 Swedish rivers provided promising results for total nitrogen. In particular, joint analyses of observational data and outputs from the catchment model S-HYPE strengthened the evidence that downward trends in nitrogen were due to mitigation measures in agriculture. Evaluation of modelled and observed total phosphorus concentrations revealed considerable bias in the collection or chemical analysis of water samples and also identified weaknesses in the model outputs. Together, our results highlight the need for more efficient two-way communication between environmental modelling and monitoring. PMID- 24760659 TI - PGE2 modulates the transcriptional activity of ERRa in prostate stromal cells. AB - The regulation of the transcriptional activity of the estrogen receptor-related receptor a (ERRa) has not yet been clearly documented. Aromatase is a direct target gene of ERRa, and we previously reported that prostaglandin E2 (PGE2) increased the expression of ERRa in the prostate stromal cell line WPMY-1, which ultimately promoted estradiol production by enhancing aromatase gene transcription. Here, we show that PGE2 also affects aromatase expression by regulating ERRa transcriptional activity in prostate stromal cells. When the cells were cultured in serum-free medium, the expression of aromatase was not proportional to the ERRa protein level, if no other stimulation occurred, indicating the absence of a factor that activates ERRa. PGE2 could upregulate aromatase and ERRa response element (ERRE)-reporter expression and also enhance ERRa phosphorylation and nuclear localization. PGE2 functions through the PGE2 receptors (EP) 2 and EP4, which couple to adenylate cyclase. The activation of adenylate cyclase with Forskolin mimicked the PGE2-mediated enhancement of extracellular signal-regulated kinase (ERK) phosphorylation and ERRa target gene expression. Experiments using specific signaling pathway inhibitors showed that both phosphatidylinositol 3-kinase (PI3K) and ERK are involved in ERRa activation, and the PI3K inhibitor was shown to abolish ERK activation. Our results suggest that PGE2 is a modulator of ERRa transcriptional activity. Furthermore, PGE2 activates the EP2/EP4-cAMP-PI3K-ERK signaling pathway, which enhanced ERRa transcriptional potentiality by increasing ERRa phosphorylation and nuclear translocation, subsequently promoting the expression of its target genes, such as aromatase. PMID- 24760660 TI - Oxidative stress in patients with thyroidectomy and thyroparathyroidectomy under replacement therapy. AB - Several studies have demonstrated an imbalance between free radicals and the antioxidative system in individuals with thyroid dysfunction. However, oxidative stress has not been evaluated in patients with thyroidectomy and thyroparathyroidectomy, who are under replacement therapy. The objective of this study was to evaluate the oxidative stress using malondialdehyde, nitric oxide, and catalase levels in patients with thyroidectomy and thyroparathyroidectomy. Nineteen patients with thyroidectomy, 20 patients with thyroparathyroidectomy, and 20 controls with no history of thyroid or parathyroid disease or surgery were included in the study. Serum malondialdehyde, nitric oxide, and catalase levels were examined. Levels of nitric oxide and malondialdehyde were elevated, and catalase levels decreased in patients with thyroidectomy and thyroparathyroidectomy compared with controls (p value for all the parameters: p<0.001). Free tetraiodothyronine was a potential predictor of malondialdehyde in the patient groups (p: 0.002). Catalase was negatively correlated with nitric oxide (p<0.01) and malondialdehyde (p<0.01). The results of the current study demonstrated that oxidative stress increased in patients with thyroidectomy and thyroparathyroidectomy despite the application of replacement therapies. PMID- 24760679 TI - Medically assisted nutrition for adult palliative care patients. AB - BACKGROUND: Many palliative care patients have a reduced oral intake during their illness. The management of this can include the provision of medically assisted nutrition with the aim of prolonging the length of life of a patient, improving their quality of life, or both. This is an updated version of the original Cochrane review published in Issue 4, 2008. OBJECTIVES: To determine the effect of medically assisted nutrition on the quality and length of life of palliative care patients. SEARCH METHODS: We identified studies from searching Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, CANCERLIT, Caresearch, Dissertation abstracts, SCIENCE CITATION INDEX and the reference lists of all eligible trials, key textbooks and previous systematic reviews. The date of the latest search was 26 March 2014. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) or prospective controlled trials (if no RCTs were found). DATA COLLECTION AND ANALYSIS: We found no RCTs or prospectively controlled trials that met the inclusion criteria. MAIN RESULTS: The original review identified four prospective non-controlled trials and the updated search in 2014 identified one more (plus an updated version of a Cochrane review on enteral feeding in motor neuron disease). There were five prospective non-controlled trials (including one qualitative study) that studied medically assisted nutrition in palliative care participants, and one Cochrane systematic review (on motor neuron disease that found no RCTs), but no RCTs or prospective controlled studies. AUTHORS' CONCLUSIONS: Since the last version of this review, we found no new studies. There are insufficient good-quality trials to make any recommendations for practice with regards to the use of medically assisted nutrition in palliative care patients. PMID- 24760678 TI - Medically assisted hydration for adult palliative care patients. AB - BACKGROUND: Many palliative care patients have reduced oral intake during their illness. The management of this can include the provision of medically assisted hydration with the aim of prolonging the life of a patient, improving their quality of life, or both. This is an updated version of the original Cochrane review published in Issue 2, 2008, and updated in February 2011. OBJECTIVES: To determine the effect of medically assisted hydration in palliative care patients on their quality and length of life. SEARCH METHODS: We identified studies by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, CANCERLIT, Caresearch, Dissertation abstracts, SCIENCE CITATION INDEX and the reference lists of all eligible studies, key textbooks and previous systematic reviews. The date of the latest search conducted on CENTRAL, MEDLINE and EMBASE was March 2014. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) or prospective controlled studies of medically assisted hydration in palliative care patients. DATA COLLECTION AND ANALYSIS: We identified six relevant studies for this update. These included three RCTs (222 participants), and three prospective controlled trials (360 participants). Two review authors independently assessed the studies for quality and validity. The small number of studies and the heterogeneity of the data meant that a quantitative analysis was not possible, so we included a description of the main findings. MAIN RESULTS: One study found that sedation and myoclonus (involuntary contractions of muscles) scores were improved more in the intervention group. Another study found that dehydration was significantly higher in the non-hydration group, but that some fluid retention symptoms (pleural effusion, peripheral oedema and ascites) were significantly higher in the hydration group. The other four studies (including the three RCTs) did not show significant differences in outcomes between the two groups. The only study that had survival as an outcome found no difference in survival between the hydration and control arms. AUTHORS' CONCLUSIONS: Since the last version of this review, we found one new study. The studies published do not show a significant benefit in the use of medically assisted hydration in palliative care patients; however, there are insufficient good-quality studies to inform definitive recommendations for practice with regard to the use of medically assisted hydration in palliative care patients. PMID- 24760681 TI - Indeterminate cystic fibrosis newborn screening results. PMID- 24760680 TI - Palindrome-mediated and replication-dependent pathogenic structural rearrangements within the NF1 gene. AB - Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susceptible to genomic rearrangements. A 197-bp long palindromic AT rich repeat (PATRR17) is located within intron 40 of the neurofibromatosis type 1 (NF1) gene (17q11.2). Through comprehensive NF1 analysis, we identified six unrelated patients with a rearrangement involving intron 40 (five deletions and one reciprocal translocation t(14;17)(q32;q11.2)). We hypothesized that PATRR17 may be involved in these rearrangements thereby causing NF1. Breakpoint cloning revealed that PATRR17 was indeed involved in all of the rearrangements. As microhomology was present at all breakpoint junctions of the deletions identified, and PATRR17 partner breakpoints were located within 7.1 kb upstream of PATRR17, fork stalling and template switching/microhomology-mediated break induced replication was the most likely rearrangement mechanism. For the reciprocal translocation case, a 51 bp insertion at the translocation breakpoints mapped to a short sequence within PATRR17, proximal to the breakpoint, suggesting a multiple stalling and rereplication process, in contrast to previous studies indicating a purely replication-independent mechanism for PATRR-mediated translocations. In conclusion, we show evidence that PATRR17 is a hotspot for pathogenic intragenic deletions within the NF1 gene and suggest a novel replication-dependent mechanism for PATRR-mediated translocation. PMID- 24760682 TI - Detection of Herpesvirus, Enterovirus, and Arbovirus infection in patients with suspected central nervous system viral infection in the Western Brazilian Amazon. AB - Acute infections of the central nervous system (CNS) can be caused by various pathogens. In this study, the presence of herpesviruses (HHV), enteroviruses (EVs), and arboviruses were investigated in CSF samples from 165 patients with suspected CNS viral infection through polymerase chain reaction (PCR) and reverse transcriptase PCR. The genomes of one or more viral agents were detected in 29.7% (49/165) of the CSF samples. EVs were predominant (16/49; 32.6%) followed by Epstein-Barr virus (EBV) (22.4%), Varicella-Zoster virus (VZV) (20.4%), Cytomegalovirus (CMV) (18.4%), herpes simplex virus (HSV-1) (4.1%), (HSV-2) (4.1%), and the arboviruses (14.3%). Four of the arboviruses were of dengue virus (DENV) and three of oropouche virus (OROV). The detection of different viruses in the CNS of patients with meningitis or encephalitis highlight the importance of maintaining an active laboratory monitoring diagnostics with rapid methodology of high sensitivity in areas of viral hyperendemicity that may assist in clinical decisions and in the choice of antiviral therapy. PMID- 24760683 TI - Study of luminescence and effect of Dy3+ on NaMgSO4 Cl:Ce chlorosulphate phosphor. AB - Chlorosulphate NaMgSO4 Cl phosphor doped with Ce(3+) and co-doped by Dy(3+) prepared by the wet chemical method was studied for its photoluminescence and thermoluminescence (TL) characteristics. The emission spectrum of Ce(3+) shows dominant peaks at 346 nm (excitation 270 nm) due to 5d -> 4f transition. Efficient energy transfer occurs from Ce(3+) -> Dy(3+) ions. Dy(3+) emission at 485 nm and 576 nm is due to (4) F9/2 -> (6) H15/2 and (4) F9/2 -> (6) H13/2 transitions of Dy(3+) ion respectively. The TL glow curves of NaMgSO4 Cl:Ce and Ce,Dy have been recorded for various concentrations at a heating rate of 2 degrees C/s irradiated by gamma-rays at a dose rate of 0.995 kGy/h for 1 Gy, which peaks at about 241 degrees C and 247-312 degrees C respectively. Further, in changing the concentration level, the general structure of the intensity is found to increase. The main property of this phosphor is its sensitivity even for low concentrations of rare earth ions and low gamma-ray dose. There is still scope for higher doses of gamma-radiation. The phosphor presented may be used as a lamp phosphor as well as for TL studies. PMID- 24760684 TI - Systematic review and meta-analysis of trainee- versus expert surgeon-performed colorectal resection. AB - BACKGROUND: The aim of this meta-analysis was to compare short-term and oncological outcomes following colorectal resection performed by surgical trainees and expert surgeons. METHODS: Systematic literature searches were made to identify articles on colorectal resection for benign or malignant disease published until April 2013. The primary outcome was the rate of anastomotic leak. Secondary outcomes were intraoperative variables, postoperative adverse event rates, and early and late oncological outcomes. Odds ratios (ORs), weighted mean differences (WMDs) and hazard ratios (HRs) for outcomes were calculated using meta-analytical techniques. RESULTS: The final analysis included 19 non randomized, observational studies of 14,344 colorectal resections, of which 8845 (61.7 per cent) were performed by experts and 5499 (38.3 per cent) by trainees. The overall rate of anastomotic leak was 2.6 per cent. Compared with experts, trainees had a lower leak rate (3.0 versus 2.0 per cent; OR 0.72, P = 0.010), but there was no difference between experts and expert-supervised trainees (3.2 versus 2.5 per cent; OR 0.77, P = 0.080). A subgroup of expert-supervised trainees had a significantly longer operating time for laparoscopic procedures (WMD 10.00 min, P < 0.001), lower 30-day mortality (OR 0.70, P = 0.001) and lower wound infection rate (OR 0.67, P = 0.040) than experts. No difference was observed in laparoscopic conversion, R0 resection or local recurrence rates. For oncological resection, there was no significant difference in cancer-specific survival between trainees and consultants (3 studies, 533 patients; hazard ratio 0.76, P = 0.130). CONCLUSION: In selected patients, it is appropriate for supervised trainees to perform colorectal resection. PMID- 24760685 TI - Anti-HBs response to hepatitis B immunoglobulin prophylaxis in liver transplant recipients. AB - BACKGROUND: Hepatitis B virus (HBV) recurrence after a liver transplant (LT) is a global issue. Several strategies have been adopted to prevent this recurrence. Most strategies recommend a combination of hepatitis B immunoglobulin (HBIG) and or nucleos(t)ide analogue. AIM OF THE STUDY: The aim of the study is to determine the anti-HBs response to HBIG among Indian patients who had undetectable pre transplant HBV DNA. METHODS: Seven adult HBV-related LT recipients of Indian origin with low pre-transplant HBV titres who had a liver transplant between August 2009 and June 2012 were included in the study. The protocol followed for post-liver transplant HBIG dose was titrated to achieve an anti-HBs titre of at least 100 IU/L. All recipients were on entecavir. Anti-HBs titre, and HBsAg status was checked at regular intervals. A retrospective analysis of the anti-HBs response to a loading and maintenance dose of HBIG was done. RESULTS: Seven adult HBV-related LT recipients on post-transplant prophylaxis with HBIG and nucleoside analogue (entecavir) fulfilled the criteria for the study. The median anti-HBs response to the anhepatic and loading dose of HBIG was high at 555 IU/L. In two, the response was less than 100 IU/L. The median dose of HBIG reduced at end of 1 month to 800 IU, and the median titre was 223 IU/L. For the next 11 months, the median requirement of HBIG was 3,000 and 4,000 IU, and the titre was low at 53.8 and 60.9 IU/L at end of 6 and 12 months, respectively. CONCLUSIONS: The anti-HBs response to HBIG was variable, and titres even below 100 IU/L did not result in HBV recurrence when HBIG was given in combination with entecavir. PMID- 24760687 TI - [Delayed antibiotic prescription for respiratory tract infections? - Delayed antibiotic prescription and no prescription lead to similar outcomes]. PMID- 24760686 TI - MicroRNA-1 (miR-1) inhibits chordoma cell migration and invasion by targeting slug. AB - Recent studies have revealed that expression of miRNA-1 (miR-1) is frequently down-regulated in several cancer types including chordoma. Identifying and validating novel targets of miR-1 is useful for understanding the roles of miR-1 in chordoma. We aimed to further investigate the functions of miR-1 in chordoma. Specifically, we assessed whether restoration of miR-1 affects cell migration and invasion in chordoma, and focused on the miR-1 potential target Slug gene. Migratory and invasive activities were assessed by wound healing and Matrigel invasion assays, respectively. Cell proliferation was determined by MTT assay. Slug expression was evaluated by Western blot, immunofluorescence, and immunohistochemistry. Restoration of miR-1 expression suppressed the migratory and invasive activities of chordoma cells. Transfection of miR-1 inhibited cell proliferation both time- and dose-dependently in chordoma. MiR-1 transfected cells showed inhibited Slug expression. Slug was over-expressed in chordoma cell lines and advanced chordoma tissues. In conclusion, we have shown that miR-1 directly targets the Slug gene in chordoma. Restoration of miR-1 suppressed not only proliferation, but also migratory and invasive activities, and reduced the Slug expression in chordoma cells. These results collectively indicate that miR 1/Slug pathway is a potential therapeutic target because of its crucial roles in chordoma cell growth and migration. PMID- 24760688 TI - [Internal medicine: challenging specialty with a wide range of diseases]. PMID- 24760689 TI - [Drug-induced liver injury as predominant cause of acute liver failure in a monocenter study]. AB - BACKGROUND AND AIM: Clinical course and mortality of acute liver failure (ALF) are determined by its causes. Traditionally, fulminant hepatitis B infection (HBV) was thought to be the predominant etiology of ALF in Germany. However, recent studies, conducted in American and European cohorts pointed to drug induced liver injury (DILI) as the major cause. Aim of this study was to identify currently predominant etiologies of ALF in a monocenter study at a leading transplant center in Germany. PATIENTS AND METHODS: The data of 161 patients admitted with ALF from 1/2002 to 12/2012 were analyzed retrospectively. All patients fulfilled the criteria of the "Acute Liver Failure Study Group Germany" (international normalized ratio (INR) >= 1.5, hepatic encephalopathy >= stage 1). RESULTS: DILI was the leading cause of ALF in this cohort. About 20 % of ALF patients with DILI died or received liver transplantats. Mortality rate was highest in ALF patients with unknown etiology and those without specific therapy available. CONCLUSIONS: In Europe ALF etiologies exhibit a North-South divide. In Germany the most common cause for ALF is idiosyncratic pharmacological intoxication followed by acute hepatitis B. PMID- 24760690 TI - [53-year-old patient with Raynaud's syndrome. polyneuropathia and fingertip necrosis]. PMID- 24760691 TI - [Free-floating right heart thrombi in pulmonary embolism: therapeutic options and differential diagnosis]. AB - BACKGROUND: There is little published evidence on the treatment of mobile masses in the right heart. We report the clinical courses of three consecutive patients presenting with acute pulmonary embolism and mobile masses in the right heart. HISTORY AND ADMISSION FINDINGS: Three women, aged 75, 72 and 52 years, were hospitalized within three months because of dyspnea and suspected pulmonary embolism. INVESTIGATIONS: Transthoracic echocardiography revealed right ventricular dysfunction and highly mobile masses, which were considered as in transit right heart thrombi in all cases. TREATMENT AND COURSE: All patients received immediate thrombolytic therapy (alteplase). No bleeding complications occurred. Thrombolysis was successful in the first two cases. However, the mass in the right ventricle did not disappear after thrombolysis in the third case and was removed surgically later on. The definite histological diagnosis was a myxoma of the right ventricle. CONCLUSION: According to literature, in-transit right heart thrombi are a potentially life-threatening complication of pulmonary embolism even in stable patients. Immediate thrombolysis is a valid therapeutic option and was successfully performed in 2 of our 3 patients. However, as case 3 suggests, differential diagnoses concerning mobile masses in the right heart, i. e. cardiac myxoma, should be taken into account and excluded by thoracic computed tomography . PMID- 24760692 TI - [Gastroesophageal reflux disease: surgical or medical treatment? - Medical]. PMID- 24760693 TI - [Gastroesophageal reflux disease: surgical or medical treatment? - Surgical]. PMID- 24760694 TI - [Intraductal papillary mucinous neoplasm of the pancreas]. AB - The diagnosis of cystic pancreatic lesions is raised more often within the last years. This is due to the fact that diagnostic opportunities and modalities such as endosonography (EUS), magnetic resonance imaging (MRI), magnetic resonance cholangio-pancreatography (MRCP), and computertomography (CT) have both improved and are more widely used. As such new recommendations were needed, since the knowledge on cystic pancreatic lesions has increased after the last consensus statement published in 2006. In this review the main aspects of the recent consensus statements for diagnosis and therapy or in some cases the surveillance strategy of intraductal papillary mucinous neoplasm will be summarized. Main duct IPMN will in most cases in surgically "fit" patients be resected, since the risk of malignancy is high in this entity. In patients with branch duct IPMN a careful "watch and wait" strategy can be applied if no "worrisome features" or "high-risk stigmata" can be detected. MRI is the imaging modality of choice, while EUS should be applied in centers with expertise. PMID- 24760695 TI - [Inflammatory osteoarthritis of the hands - challenges in diagnosis and therapy]. AB - Symptomatic osteoarthritis of the hand occurs in 5-20 % of the population >= 40 years. The diagnosis is made based on the clinical appearance, e. g. bony enlargements of small finger joints, pain and short morning stiffness. Laboratory or X-ray examinates can however be useful to exclude other rheumatic diseases. Non-pharmacological therapy options include patient education, physio- and occupational therapeutic exercise to strengthen the muscles and mobilisation. Topical non-steroidal anti-inflammatory drugs (NSAID) or capsaicin can be effective for mild to intermediate pain. Systemic therapeutics are paracetamol, NSAID or coxibs. Innovative therapy options are currently under investigation in clinical trials. PMID- 24760696 TI - [Helicobacter pylori: screen and treat?]. AB - Current evidence assigns to the Helicobacter pylori infection an essential role and major risk in gastric carcinogenesis. In high risk groups and populations a H. pylori screen-and-treat strategy is recommended and already implemented in some countries. A general screen-and-treat is the way to go as it may reduce the burden of gastric cancer for the community and prevent deleterious individual destinies. PMID- 24760697 TI - A novel molecular test for influenza B virus detection and lineage differentiation. AB - Contemporary influenza B viruses are classified into two groups known as Yamagata and Victoria lineages. The co-circulation of two viral lineages in recent years urges for a robust and simple diagnostic test for detecting influenza B viruses and for lineage differentiation. In this study, a SYBR green-based asymmetric PCR assay has been developed for influenza B virus detection. Apart from identifying influenza B virus, the assay contains sequence-specific probes for lineage differentiation. This allows identifying influenza B virus and detecting influenza B viral lineage in a single reaction. The test has been evaluated by a panel of respiratory specimens. Of 108 influenza B virus-positive specimens, 105 (97%) were positive in this assay. None of the negative control respiratory specimens were positive in the test (N = 60). Viral lineages of all samples that are positive in the assay (N = 105) can also be classified correctly. These results suggest that this assay has a potential for routine influenza B virus surveillance. PMID- 24760699 TI - Utilizing a nano-sorbent for the selective solid-phase extraction of vanillic acid prior to its determination by photoluminescence spectroscopy. AB - Vanillic acid (VA) is a phenolic acid, and acts as a natural antioxidant in fruits, vegetables and plants. The extraction and determination of trace levels of VA in plants is important, because stimulation of protein synthesis and activation of antioxidant enzymes occur in the presence of phenolic acids at trace levels. In this research, a photoluminescence spectroscopic method was developed for the quantification of VA in plant samples after separation and pre concentration. Selective extraction of VA from aqueous solution was performed using a solid-phase extraction column packed with nickel-aluminum layered double hydroxide as a nano-sorbent. After elution of extracted analyte from the column using 3 mL of a 3 mol/L NaOH solution, its concentration was determined spectrofluorometrically at lambda(em) = 357 nm with excitation at lambda(ex) = 280 nm. The spectrofluorometry method gave a linear response for VA within the range 20.0-900.0 ug/L, with a correlation coefficient of 0.9982. The limit of detection and sorption capacity were 7.6 ug/L and 66.2 mg/g, respectively. The method was validated by comparing the obtained results with gas chromatographic data. This method was used to determine VA in Chenopodium album and Prangos asperula plants. PMID- 24760698 TI - Key regulators control distinct transcriptional programmes in blood progenitor and mast cells. AB - Despite major advances in the generation of genome-wide binding maps, the mechanisms by which transcription factors (TFs) regulate cell type identity have remained largely obscure. Through comparative analysis of 10 key haematopoietic TFs in both mast cells and blood progenitors, we demonstrate that the largely cell type-specific binding profiles are not opportunistic, but instead contribute to cell type-specific transcriptional control, because (i) mathematical modelling of differential binding of shared TFs can explain differential gene expression, (ii) consensus binding sites are important for cell type-specific binding and (iii) knock-down of blood stem cell regulators in mast cells reveals mast cell specific genes as direct targets. Finally, we show that the known mast cell regulators Mitf and c-fos likely contribute to the global reorganisation of TF binding profiles. Taken together therefore, our study elucidates how key regulatory TFs contribute to transcriptional programmes in several distinct mammalian cell types. PMID- 24760701 TI - Red cell distribution width in relation to incidence of coronary events and case fatality rates: a population-based cohort study. AB - AIMS: High red cell distribution width (RDW) is a strong prognostic factor in patients with cardiovascular disease. We investigated the association between RDW and incidence of acute coronary events (CEs) and fatal outcome in subjects who subsequently experienced a first CE. METHODS AND RESULTS: RDW was measured in 26 820 subjects (aged 45-73 years, 61.6% women), without history of myocardial infarction or stroke, who participated in the Malmo Diet and Cancer study during 1991-1996. Cox proportional hazards model was used to analyse the association between RDW and CE. During a mean follow-up of 14 years, 1995 subjects had a first CE, of which 415 subjects died on the same day as the CE (fatal on day 1), another 86 died within 28 days (fatal in 28 days) and 1494 were non-fatal (survived >28 days). After adjustment for risk factors, baseline RDW was significantly associated with incidence of fatal CE (HR 1.82, CI 1.35 to 2.44) but not with non-fatal CE (HR 0.96, CI 0.82 to 1.12). Among all subjects with a CE during follow-up, the proportion who died on day 1 was 13.7%, 18.2%, 22.5% and 26.7%, respectively, for first, second, third and fourth quartiles of RDW. CONCLUSIONS: In this population-based study of subjects without history of CE or stroke, high RDW was associated with increased incidence of fatal CE. No relationship was observed for incidence of non-fatal CE. PMID- 24760700 TI - The safety and clinical usefulness of dobutamine stress echocardiography among octogenarians. AB - BACKGROUND: Increasing numbers of octogenarians are being referred for investigation of chest pain. While dobutamine stress echocardiography (DSE) has been shown to be useful in younger patients, its role among octogenarians remains unclear. This investigation aimed to investigate the safety and prognostic benefits of DSE on cardiac events and total mortality in octogenarians. METHODS: 550 consecutive patients aged >=80 years underwent DSE for suspected cardiac chest pain. All subjects were followed-up prospectively until March 2011, and the study end-points were a major cardiac event and total mortality. RESULTS: One hundred and eighty-three (33%) patients had a positive DSE result, 271 (49%) had a normal study, and 164 (30%) had fixed-wall motion abnormalities. During a mean follow-up of 2.14+/-1.13 years, there were 217 (39%) cardiac events and 63 (11%) deaths, of which 46 (73%) were cardiac. The absolute risk of cardiac events increased with burden of ischaemia on DSE, from 13%/year (none), to 26%/year (1-3 ischaemic (LV) segments), and 38%/year (>3 ischaemic LV segments), p<0.001. Any ischaemia was associated with an additional 13 cardiac events per 100 person years. In multivariate analysis, compared with non-ischaemic patients, the relative hazard of cardiac events for 1-3 and >3 ischaemic LV segments were 1.34 (95% CI 1.13 to 1.29) and 1.86 (95% CI 1.16 to 2.98), respectively. Addition of echocardiographic parameters to basic models improved the C statistic from 0.77 to 0.89 (p<0.001). CONCLUSIONS: Among octogenarians referred with suspected cardiac chest pain, DSE is safe and, importantly, identifies a subset at high risk of cardiac events. PMID- 24760702 TI - Advanced techniques in dobutamine stress echocardiography: focus on myocardial deformation analysis. PMID- 24760703 TI - Dual atrioventricular nodes. PMID- 24760704 TI - The multiparametric FRANCE-2 risk score: one step further in improving the clinical decision-making process in transcatheter aortic valve implantation. PMID- 24760705 TI - Failure to rescue as a source of variation in hospital mortality after hepatic surgery. AB - BACKGROUND: The mechanisms that underlie the association between high surgical volume and improved outcomes remain uncertain. This study examined the impact of complications and failure to rescue patients from these complications on mortality following hepatic resection. METHODS: The Nationwide Inpatient Sample was used to identify patients who had liver surgery between 2000 and 2010. Hospital volume was stratified into tertiles (low, intermediate and high). Rates of major complications, failure to rescue and mortality following hepatic surgery were compared. RESULTS: Some 9874 patients were identified. The major complication rate was 19.6 per cent in low-volume, 19.3 per cent in intermediate volume and 16.6 per cent in high-volume hospitals (P < 0.001). Most common major complications included respiratory insufficiency or failure (8.8 per cent), acute renal failure (4.2 per cent) and gastrointestinal bleeding (3.9 per cent), with each of these complications being less common in high-volume hospitals (P < 0.050). The incidence of major morbidity following hepatectomy remained the same over the past decade, but failure to rescue patients from these complications decreased (P = 0.011). The overall inpatient mortality rate following liver surgery was 3.2 per cent (3.8, 3.6 and 2.3 per cent for low-, intermediate- and high-volume hospitals respectively; P < 0.001). The rate of failure to rescue (death after a complication) was higher at low- and intermediate-volume hospitals (16.8 and 16.1 per cent respectively) compared with high-volume hospitals (11.8 per cent) (P = 0.032). After accounting for patient and hospital characteristics, patients treated at low-volume hospitals who had a complication were 40 per cent more likely to die than patients with a complication in a high-volume hospital (odds ratio 1.40, 95 per cent confidence interval 1.02 to 1.93). CONCLUSION: The risk of death following hepatic surgery is lower at high-volume hospitals. The reduction in mortality appears to be the result of both lower complication rates and a better ability in high-volume hospitals to rescue patients with major complications. PMID- 24760706 TI - Modulatory effect of whey proteins in some cytokines involved in wound healing in male diabetic albino rats. AB - The anti-inflammatory cytokines (interleukin (IL)-4 and IL-10) and the pro inflammatory cytokines (IL-1beta, IL-6, and tumor necroses factor-alpha (TNF alpha)) have important functions in wound healing. Thus, the aim of this study was to determine whether dietary supplementation with whey protein could enhance normal inflammatory responses during wound healing in diabetic rats. In this study, male albino rats were divided into a wounded control group, a wounded diabetic group, and a wounded diabetic group supplemented with whey protein orally at a dose of 100 mg/kg body weight. Tested rats showed increasing wound closure in rats treated with whey protein. In addition, after 4 days of wound, modulation in IL-4, IL-10, IL-1beta, IL-6, and TNF-alpha levels were detected. Statistical analysis of data showed significant difference between the whey protein-treated group and either control or diabetic groups (P < 0.05). Dietary supplementation with whey protein enhances the normal inflammatory responses during wound healing in diabetic rats by modulating the levels of some anti inflammatory and inflammatory cytokines. PMID- 24760707 TI - Accelerated dual-contrast first-pass perfusion MRI of the mouse heart: development and application to diet-induced obese mice. AB - PURPOSE: Gene-modified mice may be used to elucidate molecular mechanisms underlying abnormal myocardial blow flow (MBF). We sought to develop a quantitative myocardial perfusion imaging technique for mice and to test the hypothesis that myocardial perfusion reserve (MPR) is reduced in a mouse model of diet-induced obesity (DIO). METHODS: A dual-contrast saturation-recovery sequence with ky -t undersampling and a motion-compensated compressed sensing reconstruction algorithm was developed for first-pass MRI on a small-bore 7 Tesla system. Control mice were imaged at rest and with the vasodilators ATL313 and Regadenoson (n = 6 each). In addition, we imaged mice fed a high-fat diet (HFD) for 24 weeks. RESULTS: In control mice, MBF was 5.7 +/- 0.8 mL/g/min at rest and it increased to 11.8 +/- 0.6 mL/g/min with ATL313 and to 10.4 +/- 0.3 mL/g/min with Regadenoson. In HFD mice, we detected normal resting MBF (5.6 +/- 0.4 versus 5.0 +/- 0.3 on control diet), low MBF at stress (7.7 +/- 0.4 versus 10.4 +/- 0.3 on control diet, P < 0.05), and reduced MPR (1.4 +/- 0.2 versus 2.0 +/- 0.3 on control diet, P < 0.05). CONCLUSION: Accelerated dual-contrast first-pass MRI with motion-compensated compressed sensing provides spatiotemporal resolution suitable for measuring MBF in free-breathing mice, and detected reduced MPR in DIO mice. These techniques may be used to study molecular mechanisms that underlie abnormal myocardial perfusion. PMID- 24760708 TI - Unintentional pediatric ophthalmic tetrahydrozoline ingestion: case files of the medical toxicology fellowship at the University of California, San Francisco. PMID- 24760709 TI - Clinical signs of impending death in cancer patients. AB - BACKGROUND: The physical signs of impending death have not been well characterized in cancer patients. A better understanding of these signs may improve the ability of clinicians to diagnose impending death. We examined the frequency and onset of 10 bedside physical signs and their diagnostic performance for impending death. METHODS: We systematically documented 10 physical signs every 12 hours from admission to death or discharge in 357 consecutive patients with advanced cancer admitted to two acute palliative care units. We examined the frequency and median onset of each sign from death backward and calculated their likelihood ratios (LRs) associated with death within 3 days. RESULTS: In total, 203 of 357 patients (52 of 151 in the U.S., 151 of 206 in Brazil) died. Decreased level of consciousness, Palliative Performance Scale <=20%, and dysphagia of liquids appeared at high frequency and >3 days before death and had low specificity (<90%) and positive LR (<5) for impending death. In contrast, apnea periods, Cheyne-Stokes breathing, death rattle, peripheral cyanosis, pulselessness of radial artery, respiration with mandibular movement, and decreased urine output occurred mostly in the last 3 days of life and at lower frequency. Five of these signs had high specificity (>95%) and positive LRs for death within 3 days, including pulselessness of radial artery (positive LR: 15.6; 95% confidence interval [CI]: 13.7-17.4), respiration with mandibular movement (positive LR: 10; 95% CI: 9.1-10.9), decreased urine output (positive LR: 15.2; 95% CI: 13.4-17.1), Cheyne-Stokes breathing (positive LR: 12.4; 95% CI: 10.8 13.9), and death rattle (positive LR: 9; 95% CI: 8.1-9.8). CONCLUSION: We identified highly specific physical signs associated with death within 3 days among cancer patients. PMID- 24760710 TI - Isocitrate dehydrogenase 1 (IDH1) mutation in breast adenocarcinoma is associated with elevated levels of serum and urine 2-hydroxyglutarate. AB - Mutations in the IDH1 and IDH2 (isocitrate dehydrogenase) genes have been discovered across a range of solid-organ and hematologic malignancies, including acute myeloid leukemia, glioma, chondrosarcoma, and cholangiocarcinoma. An intriguing aspect of IDH-mutant tumors is the aberrant production and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), which may play a pivotal oncogenic role in these malignancies. We describe the first reported case of an IDH1 p.R132L mutation in a patient with hormone receptor-positive (HR+) breast adenocarcinoma. This patient was initially treated for locally advanced disease, but then suffered a relapse and metastasis, at which point an IDH1-R132 mutation was discovered in an affected lymph node. The mutation was subsequently found in the primary tumor tissue and all metastatic sites, but not in an uninvolved lymph node. In addition, the patient's serum and urine displayed marked elevations in the concentration of 2-HG, significantly higher than that measured in six other patients with metastatic HR+ breast carcinoma whose tumors were found to harbor wild-type IDH1. In summary, IDH1 mutations may impact a rare subgroup of patients with breast adenocarcinoma. This may suggest future avenues for disease monitoring through noninvasive measurement of 2-HG, as well as for the development and study of targeted therapies against the aberrant IDH1 enzyme. PMID- 24760712 TI - [Nonselective beta-blockers for arterial hypertension]. PMID- 24760713 TI - [What contribution makes DNA sequencing in clinical practice? - before widespread application DNA sequencing has to be optimized]. PMID- 24760711 TI - Medical expertise and patient involvement: a multiperspective qualitative observation study of the patient's role in oncological decision making. AB - BACKGROUND: Decision making in oncology poses intricate ethical questions because treatment decisions should account not only for evidence-based standards but also for the patient's individual values and preferences. However, there is a scarcity of empirical knowledge about patient involvement in oncological decision making. METHODS: Direct, nonparticipant observation was used as a qualitative research method to gain an understanding of the interplay between medical expertise and patient participation in oncological decision making. Based on a multiperspective approach, observations were performed in three settings (tumor conference, ward round, and outpatient clinic) in the oncology department of a German university hospital. The observation transcripts were analyzed using central features of qualitative data analysis. RESULTS: Major differences were identified regarding the decision-making processes in the three settings related to the patient's presence or absence. When the patient was absent, his or her wishes were cited only irregularly; however, patients actively advanced their wishes when present. Preselection of treatments by physicians was observed, narrowing the scope of options that were finally discussed with the patient. Dealing with decisions about risky treatments was especially regarded as part of the physician's professional expertise. CONCLUSION: The study reveals aspects of decision making for cancer patients that have been underexposed in the empirical and theoretical literature so far. Among these are the relevance of structural aspects for the decisions made and the practice of preselection of treatment options. It should be further discussed how far medical expertise reaches and whether therapeutic decisions can be made without consulting the patient. PMID- 24760714 TI - [Can an online risk assessment tool for identification of hereditary colorectal cancer reach the at-risk population and influence screening compliance?]. AB - BACKGROUND AND AIM: Lynch syndrome is a frequent autosomal dominant cancer predisposition leading to an estimated incidence of 3000-4000 new cancer diagnoses of colorectal and endometrial cancer in Germany per year. The underlying hereditary condition is largely underestimated and underrecognized by physicians. The usually young at-risk population, feeling insecure about their personal risk assessment, seeks information online. The aim of this study was to evaluate whether this online risk assessment tool for identification of increased risk for hereditary cancer predisposition reaches the target population and whether it succeeds in positively influencing intensified screening compliance. METHODS: The underlying algorithm for the test is based on the Bethesda and Amsterdam criteria and recent literature on polyposis syndromes. In the context of interrogating family and personal history, a total of five risk categories were defined. In addition to the cancers as defined in the above mentioned criteria, precursor lesions (polyps) were integrated into the risk estimate. Prior to launching, the algorithm was validated in family pedigrees of 102 mutation carriers with identified MLH-1 or MSH-2 mutations. RESULTS: During the time interval analysed, which was between October 2008 and April 2011 a total of 656 participants were included. Among these 19.1 % (125/656) belonged to the target population at increased familial or hereditary risk. 72.8 % (91/125) were yet healthy with known cancer-affected relatives. Merely 34.4 % (11/32) of the high-risk population were currently participating in a risk adjusted screening program. After completion of the online test 62.5 % (20/32) felt motivated to reconsider and adjust accordingly with increased surveillance. The test received an overall "good" evaluation (83 %) based on handling, performance and information content. CONCLUSION: This online risk-assessment tool was mainly completed by healthy (not cancer-affected) individuals with an increased risk for familial or hereditary colorectal cancer predisposition. The family pedigrees were comparable to these of known mutation carriers. The at-risk population was positively motivated to intensify screening strategies and the test received an overall positive evaluation. PMID- 24760715 TI - [71-year-old patient with loss of appetite, urge to defecate, and diarrhea]. PMID- 24760716 TI - [Early detection, negotiation and treatment of alcohol use disorders in primary care]. AB - Subjects with alcohol dependence or alcohol-related health problems frequently use the primary care system without receiving the correct diagnosis or specific interventions. Stigma, lack of knowledge and know-how with regards to diagnosis and treatment of alcohol-related disorders on the site of the health care professionals may contribute to the treatment gap. General anamnesis, clinical evaluation, and laboratory parameters can serve as indicators, and validated screening tests can further corroborate the hypothesis. However, a diagnosis should only be made according to ICD-10 criteria. Adequate counselling techniques substantially contribute to successful physician-patient interaction. Motivational Interviewing combines a positive, appreciative attitude with communicative techniques to create a motivation to change. It includes general approaches as open questions, appreciation of the patient, active listening, summarizing results as well as specific approaches such as change and confidence talk and dealing with resistance. Within a positive relationship, the conversation can lead to change. Brief interventions cover four to five sessions with a duration between five and sixty minutes. Brief interventions based on an empathic attitude und reflection of findings, a brief advice leaving the responsibility on the patient's side and supporting self-efficacy can improve alcohol-related disorders. The transtheoretical model of change may help the health care provider to adapt intervention strategies to the patient's state. Primary health care provides an adequate framework for screening, diagnosis and intervention for alcohol-related disorders with the aim of reduction or abstinence. Further institutions in addiction treatment such as self-help and clinical institutions may complement the treatment system. PMID- 24760717 TI - [Human babesiosis - a rare but potentially dangerous zoonosis]. AB - Human babesiosis is caused by the intraerythrocytic parasite of the genus Babesia (phylum Apicomplexa). Humans are commonly infected by the bite of Ixodid ticks. Rarely, transmission does occur perinatal or via contaminated blood transfusion. There is only insufficient data available on the clinical relevance in Europe, whereas there are known endemic states in the United States with an increasing importance of the disease in transfusion medicine. The following article gives an overview of the situation in Germany. Human babesiosis is a zoonotic disease with a worldwide increasing importance according to the increasing number of immunocompromised patients. Clinical symptoms have a wide range from asymptomatic to severe and letal cases. So far, the detection of the parasites in ticks and seroepidemiological data in Europe identified 3 humanpathogenic species: B. microti, B. divergens und B. venatorum (EU1-3). The relative small number of approximately 50 documented human cases is probably due to the lack of knowledge of the disease and the availability of diagnostic tools. Comprehensive systematic investigations of the prevalence in ticks, seroepidemiological data and improved diagnostic tests are urgently needed to evaluate the importance of the parasite. PMID- 24760718 TI - Natural prevalence of hepatitis C virus (HCV) variants resistant to protease and polymerase inhibitors in patients infected with HCV genotype 1 in Tunisia. AB - Hepatitis C virus (HCV) protease inhibitors (PIs) and polymerase inhibitors: nucleos(t)ide inhibitors (NS5B-NIs) and non-nucleos(t)ide inhibitors (NS5B-NNIs) have been recently developed to inhibit protease (NS3) or polymerase (NS5B) activities. The drawback of antiviral treatment is the emergence of resistance mutations to the drugs. The prevalence of such mutations conferring resistance to PIs, NS5B-NIs, and NS5B-NNIs before treatment has not been investigated so far in the Tunisian population. The aim of this study was to investigate the prevalence of known substitutions conferring resistance to HCV-PIs, NS5B-NIs, and NS5B-NNIs in 149 untreated patients naive of any novel or investigational anti-HCV drugs and infected with HCV genotype 1 (genotype 1a = 7; genotype 1b = 142). Twelve sequences (9.2%) of the 131/149 HCV NS3 sequences analyzed showed amino-acid substitutions associated with HCV PIs resistance mutations (T54S, n = 4 (3%); V55A, n = 2 (1.5%); Q80K, n = 4 (3%); R155K, n = 1 (0.7%); A156V, n = 1 (0.7%)). One (1%) of the 95/149 HCV NS5B sequences analyzed showed the substitution V321I conferring resistance to NS5B-NIs, while 34 of 95 (35.8%) showed substitutions conferring resistance to NS5B-NNIs (C316N, n = 2 (2%); M414L, n = 1 (1%); A421V, n = 8 (8.5%); M423A, n = 1 (1%); M423T, n = 2 (2%); I424V, n = 5 (5.2%); C445F, n = 1 (1%); I482T, n = 2 (2%); V494A, n = 1 (1%); P496A, n = 1 (1%); V499A, n = 15 (16%); S556G, n = 5 (5.2%)). Naturally occurring substitutions conferring resistance to NS3 or NS5B inhibitors exist in a substantial proportion of Tunisian treatment-naive patients infected with HCV genotype 1. Their influence on treatment outcome should be assessed. PMID- 24760719 TI - Reply to Fate of abstracts presented at the 2004-2008 International Liver Transplantation Society meetings. PMID- 24760720 TI - Study of the effect of varicocelectomy on sperm proteins expression in patients with varicocele and poor sperm quality by using two-dimensional gel electrophoresis. AB - PURPOSE: To compare proteomic profiles of spermatozoa from patients with varicocele and poor sperm quality before and after varicocelectomy. METHODS: This work was designed as a prospective and observational study. The study was based on 20 men with varicocele grade 3 and poor sperm quality undergoing varicocelectomy at the Fertility Unit of Royan institute in 2009. Two semen samples were collected, one before varicocelectomy and the other after surgery. Protein separation was done by two-dimensional protein electrophoresis, and analyzed by gel densitometry and mass spectrometry. Differential sperm protein expression levels were measured by gel densitometry. RESULTS: Comparison of the sperm parameters showed that sperm motility and concentration were increased after varicocelectomy. At the level of protein, a total of 3 protein spots were identified whose expression was significantly lower in sperm samples before varicocelectomy compared with after surgery including heat shock protein A5 (HSPA5), superoxide dismutase 1 (SOD1) and delta-subunit of the catalytic core of mitochondrial adenosine triphosphate synthase (ATP5D). CONCLUSIONS: High grade varicocoele affects sperm protein expression presumably because of increasing testicular temperature. These proteins play essential roles in sperm production, DNA integrity protection, and sperm motility. This novel study demonstrates that varicocelectomy can improve both sperm quality and proteins expression. PMID- 24760721 TI - Candidate gene expression patterns in rabbit preimplantation embryos developed in vivo and in vitro. AB - PURPOSE: The levels and timing of expression of genes like BCLXL, HDAC1 and pluripotency marker genes namely, OCT4, SOX2, NANOG and KLF4 are known to influence preimplantation embryo development. Despite this information, precise understanding of their influence during preimplantation embryo development is lacking. The present study attempts to compare the expression of these genes in the in vivo and in vitro developed preimplantation embryos. METHODS: The in vivo and in vitro developed rabbit embryos collected at distinct developmental stages namely, pronuclear, 2 cell, 4 cell, 8 cell, 16 cell, Morula and blastocyst were compared at the transcriptional and translational levels using Real Time PCR and immunocytochemical studies respectively. RESULTS: The study establishes the altered levels of candidate genes at the transcriptional level and translational level with reference to the zygotic genome activation (ZGA) phase of embryo development in the in vivo and in vitro developed embryos. The expression of OCT4, KLF4, NANOG and SOX2 genes were higher in the in vitro developed embryos whereas and HDAC1 was lower. BCLXL expression had its peak at ZGA in in vivo developed embryos. Protein expression of all the candidate genes was observed in the embryos. BCLXL, KLF4 and NANOG exhibited diffused localisation whereas HDAC1, OCT4, and SOX2 exhibited nuclear localisation. CONCLUSIONS: This study leads to conclude that BCLXL peak expression at the ZGA phase may be a requirement for embryo development. Further expression of all the candidate genes was influenced by ZGA phase of development at the transcript level, but not at the protein level. PMID- 24760722 TI - Human blastocysts exhibit unique microrna profiles in relation to maternal age and chromosome constitution. AB - PURPOSE: To determine microRNA (miRNA) expression in human blastocysts relative to advanced maternal age and chromosome constitution. METHODS: Cryopreserved human blastocysts were warmed and underwent a trophectoderm biopsy for comprehensive chromosomal screening. Select blastocysts were then lysed, reverse transcribed, and pre-amplified prior to running real-time PCR. Statistical analysis was performed using an internal constant housekeeping miRNA. Significant microRNA's of interest were then analyzed for their predicted genes and biological pathways. Additional cryopreserved blastocysts were warmed and stained for the SIRT1 protein for validation. RESULTS: Human blastocysts exhibit unique miRNA expression profiles in relation to maternal age and chromosome constitution. miR-93 was exclusively expressed in blastocysts from women in their forties and further up-regulated with an abnormal chromosome complement. Up regulated miR-93 resulted in an inverse down-regulation of targets like SIRT1, resulting in reduced oxidative defense. CONCLUSIONS: MiRNAs play an important role in aging as well as chromosome constitution and have downstream effects that regulate proteins which can compromise embryonic development. PMID- 24760723 TI - Risk factors for bleeding in hepatocellular adenoma. AB - BACKGROUND: Hepatocellular adenoma (HCA) is a benign hepatic lesion that may be complicated by bleeding, although the risk of bleeding is ill-defined. The aim of this study was to assess risk factors for bleeding in patients diagnosed with HCA. METHODS: Patients with HCA were included prospectively from January 2008 to July 2012. Patient characteristics were noted. Patients underwent dynamic magnetic resonance imaging (MRI) and/or computed tomography (CT) at presentation and during follow-up. Lesion characteristics on (follow-up) imaging were noted, and bleeding was graded as intratumoral (grade I), intrahepatic (grade II) or extrahepatic (grade III). The standard of reference for diagnosis was histopathology, or dynamic MRI and/or CT findings. Possible risk factors were included if mentioned in literature (lesion size, body mass index), or based on clinical experience (lesion location, visible vessels on imaging). RESULTS: A total of 45 patients (median age 39 (range 22-60) years; 44 women) with 195 lesions (median size 24 (10-250) mm) were evaluated. Bleeding occurred in 29 patients (64 per cent) and in 42 lesions (21.5 per cent) with a median size of 62 (10-160) mm. Size was a risk factor for bleeding (P < 0.001), with an increased number of bleeding events in lesions of 35 mm or more. Exophytic lesions (protruding from liver) had more bleeding (16 of 24, 67 per cent) than intrahepatic (9 of 82, 11 per cent) or subcapsular (17 of 89, 19 per cent) lesions (P < 0.001). Lesions in segments II and III had more bleeds than those in the right liver (11 of 32 versus 31 of 163; P = 0.049), as did lesions in which peripheral or central arteries were visualized on imaging (10 of 13 versus 32 of 182 lesions with no visible vascularization; P < 0.001). CONCLUSION: Risk factors for bleeding of HCA include diameter of 35 mm or more, visualization of lesional arteries, location in the left lateral liver, and exophytic growth. PMID- 24760724 TI - Low-rank plus sparse matrix decomposition for accelerated dynamic MRI with separation of background and dynamic components. AB - PURPOSE: To apply the low-rank plus sparse (L+S) matrix decomposition model to reconstruct undersampled dynamic MRI as a superposition of background and dynamic components in various problems of clinical interest. THEORY AND METHODS: The L+S model is natural to represent dynamic MRI data. Incoherence between k-t space (acquisition) and the singular vectors of L and the sparse domain of S is required to reconstruct undersampled data. Incoherence between L and S is required for robust separation of background and dynamic components. Multicoil L+S reconstruction is formulated using a convex optimization approach, where the nuclear norm is used to enforce low rank in L and the l1 norm is used to enforce sparsity in S. Feasibility of the L+S reconstruction was tested in several dynamic MRI experiments with true acceleration, including cardiac perfusion, cardiac cine, time-resolved angiography, and abdominal and breast perfusion using Cartesian and radial sampling. RESULTS: The L+S model increased compressibility of dynamic MRI data and thus enabled high-acceleration factors. The inherent background separation improved background suppression performance compared to conventional data subtraction, which is sensitive to motion. CONCLUSION: The high acceleration and background separation enabled by L+S promises to enhance spatial and temporal resolution and to enable background suppression without the need of subtraction or modeling. PMID- 24760725 TI - The German SCREEN project--design and evaluation of the communication strategy. AB - BACKGROUND: Skin cancer is the most common cancer in light-skinned populations worldwide. Primary and secondary preventive activities such as skin cancer screening are intended to reduce skin cancer burden. In 2003, a population-based skin cancer screening project [SCREEN (Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany)] was conducted in Northern Germany with more than 360,000 people screened. SCREEN was supported by a communication intervention that was aimed at informing the population about skin cancer, its risk factors and the screening intervention as well as preparing the health professionals for the project. Within SCREEN both physicians and practice nurses were educated in counselling. The aim of the present article is to describe and evaluate the communication strategy accompanying SCREEN. METHODS: Two computer-assisted telephone interview surveys were performed in April/May 2003 and May 2004. Participants had to be members of the statutory health insurance and be aged 20 years. They were asked about knowledge of skin cancer, perception of physicians' performance and skin cancer screening in general. Data are mainly presented in a descriptive manner. For statistical analyses, Mann Whitney U test and Pearson's chi-square test were used. RESULTS: Knowledge about sunburn in childhood and high ultraviolet exposure as skin cancer risk factors increased during SCREEN. Simultaneously, the awareness for early detection of skin cancer increased significantly from 41.3 to 74.0% (P < 0.001). A total of 21.5% of the interviewees participated in the skin cancer screening project, similar to the population-based participation rate reached. CONCLUSION: A comprehensive communication strategy accompanying a screening intervention improves the knowledge of potential screenees and may additionally increase the participation rate. PMID- 24760731 TI - Hand contamination with human rhinovirus in Bangladesh. AB - As one step in developing a measure of hand contamination with respiratory viruses, this study assessed if human rhinovirus (HRV) was detectable on hands in a low income non-temperate community where respiratory disease is a leading cause of child death. Research assistants observed residents in a low income community in Dhaka, Bangladesh. When they observed a resident sneeze or pick their nose, they collected a hand rinse and anterior nare sample from the resident. Samples were first tested for HRV RNA by real-time RT-PCR (rRT-PCR). A subset of rRT-PCR positive samples were cultured into MRC-5 and HeLa Ohio cells. Among 177 hand samples tested for HRV by real-time RT-PCR, 52 (29%) were positive. Among 15 RT PCR positive hand samples that were cultured, two grew HRV. HRV was detected in each of the sampling months (January, February, June, July, November, and December). This study demonstrates in the natural setting that, at least after sneezing or nasal cleaning, hands were contaminated commonly with potentially infectious HRV. Future research could explore if HRV RNA is present consistently and is associated sufficiently with the incidence of respiratory illness in communities that it may provide a proxy measure of respiratory viral hand contamination. PMID- 24760732 TI - Methodological quality of guidelines in gastroenterology. AB - BACKGROUND AND STUDY AIMS: Clinical guidelines are a common feature in modern endoscopy practice and they are being produced faster than ever. However, their methodological quality is rarely assessed. This study evaluated the methodological quality of current clinical guidelines in the field of gastroenterology, with an emphasis on endoscopy. MATERIALS AND METHODS: Practice guidelines published by the American College of Gastroenterology (ACG), American Gastroenterological Association (AGA), American Society for Gastrointestinal Endoscopy (ASGE), European Society of Gastrointestinal Endoscopy (ESGE), British Society of Gastroenterology (BSG), National Institute for Health and Care Excellence (NICE), and the Scottish Intercollegiate Guidelines Network (SIGN) were searched between September and October 2012 and evaluated using the AGREE II (Appraisal of Guidelines for Research and Evaluation) instrument (23 items, scores 1 - 7 for each item; higher scores mean better quality). RESULTS: A total of 100 guidelines were assessed. The mean number of items scoring 6 or 7 per guideline was 9.2 (out of 23 items). Overall, 99 % of guidelines failed to include the target population in the development process, and 96 % did not report facilitators and barriers to guideline application. In addition, 86 % did not include advice or tools, and 94 % did not present monitoring or auditing criteria. CONCLUSION: The global methodological quality of clinical guidelines in the field of gastroenterology is poor, particularly regarding involvement of the target population in the development of guidelines and in the provision of clear suggestions to practitioners. PMID- 24760733 TI - Facial color processing in the face-selective regions: an fMRI study. AB - Facial color is important information for social communication as it provides important clues to recognize a person's emotion and health condition. Our previous EEG study suggested that N170 at the left occipito-temporal site is related to facial color processing (Nakajima et al., [2012]: Neuropsychologia 50:2499-2505). However, because of the low spatial resolution of EEG experiment, the brain region is involved in facial color processing remains controversial. In the present study, we examined the neural substrates of facial color processing using functional magnetic resonance imaging (fMRI). We measured brain activity from 25 subjects during the presentation of natural- and bluish-colored face and their scrambled images. The bilateral fusiform face (FFA) area and occipital face area (OFA) were localized by the contrast of natural-colored faces versus natural colored scrambled images. Moreover, region of interest (ROI) analysis showed that the left FFA was sensitive to facial color, whereas the right FFA and the right and left OFA were insensitive to facial color. In combination with our previous EEG results, these data suggest that the left FFA may play an important role in facial color processing. PMID- 24760734 TI - Diagnosis and management of biliary complications in pediatric living donor liver transplant recipients. AB - The incidence of biliary complications (BCs) after living donor liver transplantation (LDLT) can reach 40%. Published data on the pediatric population are limited, and treatment protocols vary. Our aim was to describe the clinical scenario for BCs and treatment approaches after LDLT. Between October 1995 and December 2012, 489 pediatric LDLT procedures were performed. BCs developed in 71 patients (14.5%). Biliary strictures (BSs) developed in 45 (9.2%) patients, and bile leaks (BLs) developed in 33 patients (6.7%). The BL diagnosis was clinical in all cases, and 69.7% of the patients underwent surgery. Nearly half of the BS cases had clinical features or suggestive ultrasound findings. Liver biopsy findings suggested BSs in 51.7%. Percutaneous transhepatic cholangiography was performed in 95.6% of the BS patients. The success rate was 77% [mean number of percutaneous biliary interventions (PBIs) = 3.9 +/- 1.98, median drainage time = 8 months]. In conclusion, BL patients can be managed with conservative therapy, even though most of these patients will ultimately be treated with surgery. Diagnosing a BS requires a high degree of clinical suspicion because the available resources for its identification can fail in up to 50% of cases. A higher number of PBIs and the use of a drainage catheter for a longer time may be required to achieve better results with this technique. PMID- 24760735 TI - Blood clearance of Howell-Jolly bodies in an experimental autogenic splenic implant model. AB - BACKGROUND: Autogenic splenic implant (ASI) is one of the few alternatives for preservation of splenic tissue when total splenectomy is inevitable. The aim of this study was to determine the morphological and functional regeneration of ASIs, as indicated by the clearance of Howell-Jolly (HJ) bodies, in an experimental model. METHODS: Ninety-nine male Wistar rats were divided into three groups: sham-operated (group 1), total splenectomy alone (group 2), and total splenectomy combined with ASI (group 3). Animals in group 3 were further allocated to nine subgroups of nine rats each, and analysed at different time points (1, 4, 8, 12, 16, 20, 24, 28 and 32 weeks after surgery). Blood smears were prepared at predetermined times for detection of HJ bodies. Morphological regeneration of tissue in the ASI was analysed by histology. RESULTS: At 1 week, the regenerated mass corresponded to about 7 per cent of the tissue implanted, reaching approximately 54 per cent at 24 weeks. The HJ body levels were increased in groups 2 and 3 until 8 weeks after surgery, following which levels in the ASI group became similar to those in the sham-operated group. HJ bodies were difficult to detect when a level of 22.5 per cent of regenerated ASI mass was reached. CONCLUSION: Functional regeneration of ASIs occurred from 8 weeks after surgery. When 22.5 per cent of regenerated ASI mass was reached almost no HJ bodies could be observed in the bloodstream, resembling a spleen in situ. SURGICAL RELEVANCE: Splenectomy has been practised routinely, both in the emergency setting and as a therapeutic elective procedure. There is a correlation between asplenia/hyposplenia and the occurrence of fulminant sepsis, underlining the importance of developing surgical methods for preserving splenic function. Both clinical and experimental studies have shown at least partial morphological and functional regeneration of autogenic splenic implants (ASIs). Experimental studies investigating the immunoprotective effect of ASIs, based mostly on exposure of animals to various bacteria, have demonstrated that ASIs can increase the rate of bacterial clearance and decrease mortality from sepsis. Clinical studies have shown their ability to remove colloidal substances and altered erythrocyte corpuscular inclusions, such as Howell-Jolly, Heinz and Pappenheimer bodies, from the bloodstream. In this experimental study the functional and morphological regeneration of ASIs was studied over time in rats. PMID- 24760736 TI - Blind multirigid retrospective motion correction of MR images. AB - PURPOSE: Physiological nonrigid motion is inevitable when imaging, e.g., abdominal viscera, and can lead to serious deterioration of the image quality. Prospective techniques for motion correction can handle only special types of nonrigid motion, as they only allow global correction. Retrospective methods developed so far need guidance from navigator sequences or external sensors. We propose a fully retrospective nonrigid motion correction scheme that only needs raw data as an input. METHODS: Our method is based on a forward model that describes the effects of nonrigid motion by partitioning the image into patches with locally rigid motion. Using this forward model, we construct an objective function that we can optimize with respect to both unknown motion parameters per patch and the underlying sharp image. RESULTS: We evaluate our method on both synthetic and real data in 2D and 3D. In vivo data was acquired using standard imaging sequences. The correction algorithm significantly improves the image quality. Our compute unified device architecture (CUDA)-enabled graphic processing unit implementation ensures feasible computation times. CONCLUSION: The presented technique is the first computationally feasible retrospective method that uses the raw data of standard imaging sequences, and allows to correct for nonrigid motion without guidance from external motion sensors. PMID- 24760737 TI - The dependence of computed tomography number to relative electron density conversion on phantom geometry and its impact on planned dose. AB - A computed tomography number to relative electron density (CT-RED) calibration is performed when commissioning a radiotherapy CT scanner by imaging a calibration phantom with inserts of specified RED and recording the CT number displayed. In this work, CT-RED calibrations were generated using several commercially available phantoms to observe the effect of phantom geometry on conversion to electron density and, ultimately, the dose calculation in a treatment planning system. Using an anthropomorphic phantom as a gold standard, the CT number of a material was found to depend strongly on the amount and type of scattering material surrounding the volume of interest, with the largest variation observed for the highest density material tested, cortical bone. Cortical bone gave a maximum CT number difference of 1,110 when a cylindrical insert of diameter 28 mm scanned free in air was compared to that in the form of a 30 * 30 cm(2) slab. The effect of using each CT-RED calibration on planned dose to a patient was quantified using a commercially available treatment planning system. When all calibrations were compared to the anthropomorphic calibration, the largest percentage dose difference was 4.2 % which occurred when the CT-RED calibration curve was acquired with heterogeneity inserts removed from the phantom and scanned free in air. The maximum dose difference observed between two dedicated CT-RED phantoms was +/-2.1 %. A phantom that is to be used for CT-RED calibrations must have sufficient water equivalent scattering material surrounding the heterogeneous objects that are to be used for calibration. PMID- 24760738 TI - High expression of beta2-glycoprotein I is associated significantly with the earliest stages of hepatitis B virus infection. AB - Human beta2-glycoprotein I (beta2-GPI) binds to recombinant hepatitis B surface antigen (rHBsAg) and can bind specifically to annexin II, which is located on the cell membrane of human hepatoma SMMC-7721 cells. Viral envelope proteins are essential for mediating cellular entry. The aim of this study was to investigate the role of beta2-GPI in the early stages of hepatitis B virus (HBV) infection. Western blot and qRT-PCR analyses revealed that beta2-GPI expression was upregulated in HepG2.2.15 cells at both the mRNA and protein level and was almost non-existent in 293T and CHO cells. Furthermore, annexin II was expressed at lower levels in HepG2.2.15 cells compared to L02, HepG2, and SMMC-7721 cells. Additionally, ELISA analyses demonstrated that beta2-GPI enhanced the ability of HBsAg to bind to cell surfaces, and there was differential adhesion to L02, HepG2, HepG2.2.15, and 293T cells. Western blot and ELISA were then performed to assess the effects of HBV and the HBsAg domain on beta2-GPI expression in co transfected 293T cells. This study revealed that HBV and the large HBV envelope protein increased beta2-GPI expression. Further investigation indicated that beta2-GPI colocalized with HBsAg in the cytosol of HepG2.2.15 cells, with sodium taurocholate co-transporting polypeptide (NTCP) on the cell membrane in NTCP complemented HepG2 cells, and with annexin II in the cytosol of HepG2 and HepG2.2.15 cells. These data suggest that high expression of beta2-GPI enhances HBsAg binding to cell surfaces, thus contributing to virus particle transfer to the NTCP receptor and interaction with annexin II for viral membrane fusion. PMID- 24760739 TI - The good the bad and the ugly. PMID- 24760740 TI - Disentangling the discordance between epidemiological associations and physiological mechanisms. PMID- 24760741 TI - [Comparison of functional results with MRI findings after surgical treatment of transscaphoid perilunate fracture dislocations of the wrist: the role of scapholunate ligament lesions]. AB - PURPOSE: The aim of this study was to review the outcome of transscaphoid perilunate fracture dislocations by MRI to use the advantages of MRI to show the post-traumatic degenerative changes, the examination of cartilage, the integrity of the ligaments and the vascularisation of the carpal bones. A second aim of this study is to interpret the findings in correlation to the functional results and the individual perception of hand functionality (PRWE). PATIENTS AND METHODS: In this retrospective study, 20 patients (1 woman and 19 men), who were treated with open reduction and internal fixation at our institution, were reviewed at a mean of 67 (25-145) months postoperative. The mean age was 30 (12-73) years. The functional results were measured by range of motion (ROM), grip and pinch strength. The Mayo and Krimmer wrist scores were calculated and the SF-36 and the patient-rated wrist evaluation (PRWE) questionnaires were performed. Radiological findings included consolidation of the fracture and the radiological measures (revised carpal height, SL gap, SL and RL angle). An MRI, performed without a contrasting agent, was used to assess the degenerative changes of the joints, the vascularisation of the carpalia and the integrity of the SL ligament. Statistical data was calculated with SPSS. RESULTS: Range of motion and strength were reduced by 10-20% compared to the uninjured opposite side. Although the majority of the patients (85%) achieved good to very good results in the Mayo and Krimmer wrist scores, the MRI showed osteoarthritis in 95% of the cases in at least in 1 out of 5 patients evaluated intracarpal joints. MRI showed signs of complete SL ligament tears in 5 patients and a partial tear in 2 patients. The same group also showed the strongest degenerative changes. However, there was no correlation between patient satisfaction and imaging results. CONCLUSION: MRI findings, as well as X ray findings, do not correlate with the subjective and objective functional outcomes after surgical treatment of transscaphoid perilunate fracture dislocations. It can be assumed that SL ligament lesions seen in MRI play a major role over the long term course. PMID- 24760742 TI - Handedness preference and switching of peptide helices. Part I: Helices based on protein amino acids. AB - In this article, we review the relevant results obtained during almost 60 years of research on a specific aspect of stereochemistry, namely handedness preference and switches between right-handed and left-handed helical peptide structures generated by protein amino acids or appropriately designed, side-chain modified analogs. In particular, we present and discuss here experimental and theoretical data on three categories of those screw-sense issues: (i) right-handed/left handed alpha-helix transitions underwent by peptides rich in Asp, specific Asp beta-esters, and Asn; (ii) comparison of the preferred conformations adopted by helical host-guest peptide series, each characterized by an amino acid residue (e.g. Ile or its diastereomer aIle) endowed with two chiral centers in its chemical structure; and (iii) right-handed (type I)/left-handed (type II) poly (Pro)n helix transitions monitored for peptides rich in Pro itself or its analogs with a pyrrolidine ring substitution, particularly at the biologically important position 4. The unique modular and chiral properties of peptides, combined with their relatively easy synthesis, the chance to shape them into the desired conformation, and the enormous chemical diversity of their coded and non-coded alpha-amino acid building blocks, offer a huge opportunity to structural chemists for applications to bioscience and nanoscience problems. PMID- 24760743 TI - Lessons learned from adult clinical experience to inform evaluations of VEGF pathway inhibitors in children with cancer. AB - Agents targeting the vascular endothelial growth factor (VEGF) pathway have been studied in adults with cancer for nearly two decades. It is important to assess the lessons learned from this adult experience and to see how these lessons can help inform pediatric development of agents in this class. The benefit achieved from the use of VEGF pathway targeted agents for adult cancers has primarily been to delay for several months disease progression and less commonly time to death for conditions in which cure is not a reasonable expectation. VEGF pathway targeted agents have shown no efficacy when applied in the adjuvant setting. For adults with advanced cancer, prolongation of survival by 2-3 months is considered an important achievement in some settings. However, the primary goal of pediatric oncology clinical research is to identify treatments that allow children to be cured of their cancer and to grow to adulthood without treatment-induced limitations that lower their quality of survival. An important question for the pediatric oncology research community, pharmaceutical companies, and regulatory agencies to address in planning for future clinical trials is whether existing data support a role for VEGF pathway targeted agents in contributing to a therapeutic pathway to cure for children with cancer. PMID- 24760744 TI - Insights into molecular evolution from yeast genomics. AB - Enabled by comparative genomics, yeasts have increasingly developed into a powerful model system for molecular evolution. Here we survey several areas in which yeast studies have made important contributions, including regulatory evolution, gene duplication and divergence, evolution of gene order and evolution of complexity. In each area we highlight key studies and findings based on techniques ranging from statistical analysis of large datasets to direct laboratory measurements of fitness. Future work will combine traditional evolutionary genetics analysis and experimental evolution with tools from systems biology to yield mechanistic insight into complex phenotypes. PMID- 24760746 TI - Erythrovirus B19 and autoimmune thyroid diseases. Review of the literature and pathophysiological hypotheses. AB - Erythrovirus B19 (EVB19) has been incriminated, over recent years, in the onset and/or pathogenesis of many diseases, especially autoimmune thyroid diseases. This review of the literature (published over the last 40 years using Pubmed and Science Direct search engines) was designed to define the role of EVB19, particularly in autoimmune thyroid diseases.Two cases of subacute thyroiditis, one case of Graves' disease (associated with type 1 diabetes and rheumatoid arthritis), and one case of Hashimoto's thyroiditis following acute EVB19 infection were reported. A retrospective case-control study in a pediatric population demonstrated the role of EVB19 in Hashimoto's thyroiditis. Four retrospective studies of pathology slides (including PCR, immunohistochemistry or in situ hybridization) and a prospective case-control study on pathology slides demonstrated the presence of EVB19 in thyroid tissue of patients with benign multinodular goiter, Graves' disease, autoimmune thyroiditis (including Hashimoto's thyroiditis), and thyroid cancer. EVB19 can be demonstrated in the thyroid gland in a wide range of diseases. Although acute EVB19 infection could theoretically trigger autoimmune thyroid disease, there is currently no evidence that EVB19 plays a specific role in the pathophysiology of autoimmune thyroid diseases. PMID- 24760745 TI - Randomized clinical trial comparing Nordic pole walking and a standard home exercise programme in patients with intermittent claudication. AB - BACKGROUND: This was a randomized clinical trial to determine whether Nordic pole walking (NPW) is more effective in improving walking distance than a standard home exercise programme (HEP) in patients with intermittent claudication. METHODS: Fifty-two patients with stable claudication were allocated randomly to a standard HEP or NPW group, and asked to complete three 30-min walks per week for 12 weeks. Claudication distance (CD) and maximum walking distance (MWD) were measured at 0 (baseline), 4, 8 and 12 weeks. Patients in the NPW group were tested with (NPW+) and without (NPW-) poles. RESULTS: For NPW+, CD increased immediately from a median (range) of 124 (71-248) m to 148 (116-426) m, and MWD from 248 (149-900) to 389 (194-1099) m (P = 0.004 and P < 0.001 respectively). By 12 weeks, CD had further increased to 199 (118-550) m and MWD had more than doubled to 538 (250-1750) m (P < 0.001 and P = 0.001). For NPW-, CD at 12 weeks had increased significantly to 151 (100-328) m and MWD to 400 (200-900) m (P < 0.001 and P = 0.006 respectively). At 12 weeks the changes in the standard HEP group were not significant, despite excellent compliance: CD from 107 (56-332) to 153 (59-321) m and MWD from 355 (92-600) to 334 (149-874) m (P = 0.030 and P = 0.260 respectively). CONCLUSION: A 12-week exercise programme using Nordic poles significantly improved walking distance in claudicants compared with a standard HEP. REGISTRATION NUMBER: ISRCTN78168304 (http://www.controlled-trials.com). PMID- 24760747 TI - Curcumin ameliorates streptozotocin-induced heart injury in rats. AB - Heart failure (HF) is one of diabetic complications. This work was designed to investigate the possible modulatory effect of curcumin against streptozotocin induced diabetes and consequently HF in rats. Rats were divided into control, vehicle-treated, curcumin-treated, diabetic-untreated, diabetic curcumin-treated, and diabetic glibenclamide-treated groups. Animal treatment was started 5 days after induction of diabetes and extended for 6 weeks. Diabetic rats showed significant increase in serum glucose, triglycerides, total cholesterol, low density lipoprotein-cholesterol, very low density lipoprotein-cholesterol, nitric oxide, lactate dehydrogenase, cardiac malondialdehyde, plasma levels of interleukin-6, and tumor necrosis factor-alpha, and also showed marked decrease in serum high-density lipoprotein-cholesterol, cardiac reduced glutathione, and cardiac antioxidant enzymes (catalase, superoxide dismutase, and glutathione-S transferase). However, curcumin or glibenclamide treatment significantly mitigated such changes. In conclusion, curcumin has a beneficial therapeutic effect in diabetes-induced HF, an effect that might be attributable to its antioxidant and suppressive activity on cytokines. PMID- 24760748 TI - Home-made continuous positive airways pressure device may reduce mortality in neonates with respiratory distress in low-resource setting. AB - OBJECTIVE: To study the effectiveness of locally assembled low-cost version for continuous positive airway pressure (CPAP) delivery. PATIENTS: Babies with respiratory distress from two contiguous periods, one with CPAP therapy and the other without, were compared for following parameters: birth weight, gestational age, severity of respiratory distress, as assessed by Silverman-Anderson retraction score (SARS), maximum SARS, days taken for score to become 0, duration of oxygen therapy, hospital stay and the outcome. RESULTS: The profile of subjects was comparable in two groups. Severity of respiratory distress (SARS) was significantly higher in post-CPAP group. Time taken for SARS to become 0 and number of deaths were significantly lower, and the duration of oxygen administration and hospital stay were significantly higher in post-CPAP group. The cost of an individual disposable CPAP unit was ~Rs 160 (USD 3). CONCLUSION: A low-cost and locally assembled CPAP delivery system may reduce neonatal mortality among babies with respiratory distress. PMID- 24760749 TI - Protective association of milk intake on the risk of hip fracture: results from the Framingham Original Cohort. AB - Dairy foods are rich in bone-beneficial nutrients, yet the role of dairy foods in hip fracture prevention remains controversial. Our objective was to evaluate the association of milk, yogurt, cheese, cream, and milk + yogurt intakes with incident hip fracture in the Framingham Original Cohort. A total of 830 men and women from the Framingham Original Cohort, a prospective cohort study, completed a food-frequency questionnaire (1988 to 1989) and were followed for hip fracture until 2008. In this population-based study, Cox-proportional hazards regression was used to estimate hazard ratios (HR) by categories of energy-adjusted dairy intake (servings/wk), adjusting for standard confounders and covariates. The exposure was energy-adjusted intakes of milk, yogurt, cheese, cream, and milk + yogurt (servings/wk). Risk of hip fracture over the follow-up was the primary outcome; the hypothesis being tested was formulated after data collection. The mean age at baseline was 77 years (SD 4.9, range 68 to 96). Ninety-seven hip fractures occurred over the mean follow-up time of 11.6 years (range 0.04 to 21.9 years). The mean +/- SD (servings/wk) of dairy intakes at baseline were: milk = 6.0 +/- 6.4; yogurt = 0.4 +/- 1.3; cheese = 2.6 +/- 3.1; and cream = 3.4 +/- 5.5. Participants with medium (>1 and <7 servings/wk) or higher (>=7 servings/wk) milk intake tended to have lower hip fracture risk than those with low (<=1 serving/wk) intake (high versus low intake HR 0.58, 95% confidence interval [CI] 0.31-1.06, p = 0.078; medium versus low intake HR 0.61, 95% CI 0.36-1.08, p = 0.071; p trend = 0.178]. There appeared to be a threshold for milk, with 40% lower risk of hip fracture among those with medium/high milk intake compared with those with low intake (p = 0.061). A similar threshold was observed for milk + yogurt intake (p = 0.104). These associations were further attenuated after adjustment for femoral neck bone mineral density. No significant associations were seen for other dairy foods (p range = 0.117 to 0.746). These results suggest that greater intakes of milk and milk + yogurt may lower risk for hip fracture in older adults through mechanisms that are partially, but not entirely, attributable to effects on bone mineral density. PMID- 24760751 TI - Acceleration of self-consistent field convergence in ab initio molecular dynamics simulation with multiconfigurational wave function. AB - The Lagrange interpolation of molecular orbital (LIMO) method, which reduces the number of self-consistent field iterations in ab initio molecular dynamics simulations with the Hartree-Fock method and the Kohn-Sham density functional theories, is extended to the theory of multiconfigurational wave functions. We examine two types of treatments for the active orbitals that are partially occupied. The first treatment, as denoted by LIMO(C), is a simple application of the conventional LIMO method to the union of the inactive core and the active orbitals. The second, as denoted by LIMO(S), separately treats the inactive core and the active orbitals. Numerical tests to compare the two treatments clarify that LIMO(S) is superior to LIMO(C). Further applications of LIMO(S) to various systems demonstrate its effectiveness and robustness. PMID- 24760750 TI - Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study. AB - BACKGROUND: We investigated the spectrum, frequency, and risk factors for renal, gastrointestinal, and hepatic late adverse effects in survivors of childhood acute myeloid leukemia (AML) without relapse treated with chemotherapy alone according to three consecutive AML trials by the Nordic Society of Pediatric Hematology and Oncology (NOPHO). METHODS: A population-based cohort of children treated for AML according to the NOPHO-AML-84, -88, and -93 trials included 138 eligible survivors of whom 102 (74%) completed a questionnaire and 104 (75%) had a clinical examination and blood sampling performed. Eighty-five of 94 (90%) eligible sibling controls completed a similar questionnaire. Siblings had no clinical examination or blood sampling performed. RESULTS: At a median of 11 years (range 4-25) after diagnosis, renal, gastrointestinal, and hepatic disorders were rare both in survivors of childhood AML and in sibling controls, with no significant differences. Ferritin was elevated in 21 (21%) AML survivors but none had biochemical signs of liver damage. Viral hepatitis was present in three and cholelithiasis in two AML survivors. One adult survivor had hypertension, two had slightly elevated systolic blood pressure, and eight survivors had slightly elevated diastolic blood pressure. These persons all had normal creatinine and cystatin C levels. Marginal abnormalities in potassium, magnesium, calcium, or bicarbonate levels were found in 34 survivors. CONCLUSION: Survivors of childhood AML treated with chemotherapy only experienced few renal, gastrointestinal, and hepatic late effects. PMID- 24760752 TI - CD52 is a molecular target in advanced systemic mastocytosis. AB - Advanced systemic mastocytosis (SM) is an aggressive hematopoietic neoplasm with poor prognosis and short survival times. So far, no curative therapy is available for affected patients. We have identified the cell surface antigen CD52 (CAMPATH 1) as a molecular target expressed abundantly on the surface of primary neoplastic mast cells (MCs) in patients with advanced SM. In contrast, neoplastic MCs of patients with indolent SM and normal MCs expressed only low levels or did not express CD52. To study the mechanisms of CD52 expression and the value of this antigen as a potential therapeutic target, we generated a human MC cell line, designated MCPV-1, by lentiviral immortalization of cord blood-derived MC progenitor cells. Functional studies revealed that activated RAS profoundly promotes surface expression of CD52. The CD52-targeting antibody alemtuzumab induced cell death in CD52(+) primary neoplastic MCs obtained from patients with SM as well as in MCPV-1 cells. NSG mice xenotransplanted with MCPV-1 cells survived significantly longer after treatment with alemtuzumab (median survival: 31 d untreated vs. 46 d treated; P=0.0012). We conclude that CD52 is a novel marker and potential therapeutic target in neoplastic MCs in patients with advanced SM. PMID- 24760753 TI - A peptide panel investigation reveals the acceptor specificity of O-GlcNAc transferase. AB - O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) is widely distributed on nucleocytoplasmic proteins and participates in various physiological processes. But O-GlcNAc status on numerous proteins remains unknown. To better understand this modification, computational analysis combined with experimental study was performed in this work. Structural analysis of many O-GlcNAcylation sites indicated that the modification occurred predominantly in a random coil region. Frequency analysis on many O-GlcNAcylated peptides revealed a signature sequence, PPVS/TSATT, around the modification site (underlined, position 0). Based on the sequence, a peptide panel was designed to investigate key positions affecting O-GlcNAcylation of peptides and their amino acid preference. It was indicated that 3 positions (-2, -1, and +2) had an important role for this modification, where the presence of uncharged amino acids with small side chains could confer high reactivity. The amino acid preference at key positions was further investigated on bovine crystalline alpha via site-directed mutagenesis. The preferred amino acids were Pro > Ala > Gly at position -2, Ala > Thr > Val > Lys > Pro at position -1, and Ala > Gly > Arg > Glu at position +2. Altogether, these findings suggested that a substrate (peptide or protein) with Pro, Ala at position -2, and/or Val, Ala, Thr, Ser at position -1, and/or Ala, Ser, Pro, Thr, Gly at position +2 would have more chances for O-GlcNAcylation. To test the rule, 2 O-GlcNAcylation sites on sOGT (S52 and T449) were predicted and confirmed by Western blot. The present work systematically investigated the sequence signature for O-GlcNAcylation. The result will contribute to predicting the O-GlcNAc status of a protein and further functional studies. PMID- 24760754 TI - Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice. AB - The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B(-/-) mice [+7+/-2% vs. wild-type (WT), P = 0.05]. This was associated with increased extracellular signal-regulated kinase 2 phosphorylation and VEGFR2 activation (i.e., phosphorylated-Src/Src/VEGFR2 and dissociation of endothelial VEGFR2/VE-cadherin), together with higher infiltration of proangiogenic M2 macrophages within unchanged overall infiltration. In vitro, we showed that PTP1B inhibition or silencing using RNA interference increased VEGF induced migration and proliferation of mouse heart microvascular endothelial cells as well as fibroblast growth factor (FGF)-induced proliferation of rat aortic smooth muscle cells. At 8 d after MI in PTP1B(-/-) mice, increased LV capillary density (+21+/-3% vs. WT; P<0.05) and an increased number of small diameter arteries (15-50 MUm) were likely to participate in increased LV perfusion assessed by magnetic resonance imaging and improved LV compliance, indicating reduced diastolic dysfunction. In conclusion, PTP1B deficiency reduces MI-induced heart failure promptly after ischemia by enhancing angiogenesis, myocardial perfusion, and diastolic function. PMID- 24760755 TI - Selenoprotein P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. AB - Selenoprotein P (Sepp1) and its receptor, apolipoprotein E receptor 2 (apoER2), account for brain retaining selenium better than other tissues. The primary sources of Sepp1 in plasma and brain are hepatocytes and astrocytes, respectively. ApoER2 is expressed in varying amounts by tissues; within the brain it is expressed primarily by neurons. Knockout of Sepp1 or apoER2 lowers brain selenium from ~120 to ~50 ng/g and leads to severe neurodegeneration and death in mild selenium deficiency. Interactions of Sepp1 and apoER2 that protect against this injury have not been characterized. We studied Sepp1, apoER2, and brain selenium in knockout mice. Immunocytochemistry showed that apoER2 mediates Sepp1 uptake at the blood-brain barrier. When Sepp1(-/-) or apoER2(-/-) mice developed severe neurodegeneration caused by mild selenium deficiency, brain selenium was ~35 ng/g. In extreme selenium deficiency, however, brain selenium of ~12 ng/g was tolerated when both Sepp1 and apoER2 were intact in the brain. These findings indicate that tandem Sepp1-apoER2 interactions supply selenium for maintenance of brain neurons. One interaction is at the blood-brain barrier, and the other is within the brain. We postulate that Sepp1 inside the blood-brain barrier is taken up by neurons via apoER2, concentrating brain selenium in them. PMID- 24760756 TI - Objective assessment of attention in delirium: a narrative review. AB - OBJECTIVE: Inattention is a core feature of delirium, and valid assessment of attention is central to diagnosis. Methods of measuring attention in delirium can be divided into two broad categories: (i) objective neuropsychological testing; and (ii) subjective grading of behaviour during interview and clinical examination. Here, we review and critically evaluate studies of objective neuropsychological testing of attention in delirium. We examine the implications of these studies for delirium detection and monitoring in clinical practice and research, and how these studies inform understanding of the nature of attentional deficits in delirium. METHODS: Searches of MEDLINE and ISI Web of Knowledge databases were performed to identify studies in which objective tests of attention had been administered to patients with delirium, who had been diagnosed using DSM or ICD criteria. RESULTS: Sixteen publications were identified. The attention tests administered in these studies were grouped into the following categories: measures of attention span, vigilance tests, other pen-and-paper tests (e.g. Trail Making Test) and computerised tests of speeded reaction, vigilance and sustained attention. Patients with delirium showed deficits on all tasks, although most tasks were not considered pure measures of attention. Five papers provided data on differential diagnosis from dementia. Cancellation tests, spatial span tests and computerised tests of sustained attention discriminated delirium from dementia. Five studies presented reliability or validity statistics. CONCLUSIONS: The existing evidence base on objective assessment of attention in delirium is small. Objective testing of attention is underdeveloped but shows considerable promise in clinical practice and research. PMID- 24760757 TI - Performance of DFT+U method for prediction of structural and thermodynamic parameters of monazite-type ceramics. AB - We performed a density functional theory (DFT) study of the monazite-type ceramics using DFT+U method, where the Hubbard U parameters are derived ab initio, with the main goal in testing the predictive power of this computational method for modeling of f-electron materials that are of interest in nuclear waste management. We show that DFT+U approach with PBEsol as the exchange-correlation functional significantly improves description of structures and thermodynamic parameters of lanthanide-bearing oxides and monazites over commonly used standard DFT (PBE) approach. We found that it is essential to use the Hubbard U parameter derived for a given element and a given structure to reproduce the structural parameters of the measured materials. We obtained exceptionally good description of the structural parameters with U parameter derived using the linear response approach of Cococcioni and de Gironcoli (Phys. Rev. B 2005, 71, 035105). This shows that affordable methods, such as DFT+U with a clever choice of exchange correlation functional and the Hubbard U parameter can lead to a good description of f-electron materials. PMID- 24760758 TI - Yersinia pestis Ail recruitment of C4b-binding protein leads to factor I-mediated inactivation of covalently and noncovalently bound C4b. AB - The outer membrane protein Ail of Yersinia pestis mediates several virulence functions, including serum resistance. Here, we demonstrate that Ail binds C4b binding protein (C4BP), the primary fluid-phase regulator of the classical and lectin pathways. Non-covalent binding of C4 and C4b to Ail was also observed. C4BP bound to Ail can act as a cofactor to the serine protease factor I (fI) in the cleavage of fluid-phase C4b. Employing a panel of C4BP alpha-chain mutants, we observed that the absence of complement control protein domain 6 and 8 reduced binding to Ail. Immunoblot analysis of normal human serum (NHS)-treated bacteria revealed minimal C4b alpha'-chain complexes with bacterial outer membrane targets. Addition of the anti-C4BP monoclonal antibody MK104 to NHS restored C4b alpha' chain target complexes, suggesting that C4b binds covalently to targets on the Y. pestis surface. C4b bound to Ail noncovalently was also cleaved in a C4BP and fI-dependent manner, leaving the C4c fragment bound to Ail. MK104 also prevented the cleavage of noncovalently bound C4b. Collectively, these data suggest that when C4BP is bound to Ail, fI can cleave and inactivate C4b that has bound covalently to bacterial surface structures as well as C4b bound noncovalently to Ail. PMID- 24760759 TI - A bi-cistronic, reporter-encoding bovine viral diarrhea virus applied in a new, effective diagnostic test. AB - Infections with bovine viral diarrhea virus (BVDV) have a huge economic impact on cattle production and reproduction worldwide. A key factor for BVDV surveillance and eventual eradication is to efficiently detect infections and to monitor herd immunity. In this study, we generated a stable, bi-cistronic BVDV that encoded EGFP in addition to the viral proteins. Applying this recombinant virus, a new flow-cytometry-based virus neutralization test was established that enabled accurate and reliable detection of field-virus-infected and vaccinated animals. The test, which is simple and fast, is expected to support novel, effective screening procedures in eradication and vaccination programmes. PMID- 24760761 TI - Belief in life after death, salivary 3-methoxy-4-hydroxyphenylglycol, and well being among older people without cognitive impairment dwelling in rural Japan. AB - OBJECTIVES: Research has found that spirituality/religiosity has a salutary association with mental/physical health. However, the association of belief in life after death with well-being has rarely been studied, and the same is true of its association with biological indices, such as monoamine transmitters. Therefore, we examined the associations between well-being and religiosity, salivary 3-methoxy-4-hydroxyphenylglycol (sMHPG), and demographic characteristics. METHODS: The participants were 346 community-dwelling people, aged 65 years or older, without cognitive or mental deficits, in rural Japan. Measures of religiosity consisted of belief in life after death, attachment to life, and experiences related to death and religion. The measures were assessed by scales specifically suited for Japanese religious orientations. Participants' well-being was assessed by a life satisfaction scale containing two subscales. We also measured sMHPG, a major metabolite of noradrenaline that is thought to reflect certain psychological states, such as psychomotor retardation and effortful attention. RESULTS: One subscale of life satisfaction was positively associated with belief in life after death and sMHPG, and the other life satisfaction subscale was positively associated with education and death/religion related experiences (e.g., visiting family graves or loss of a friend). Gender differences were found in afterlife beliefs and each life satisfaction subscale. CONCLUSIONS: These results suggest that religiosity, including belief in life after death and death/religion-related experiences, is salubriously associated with mental health among older people, especially women, living in rural Japan. The basal level of sMHPG was positively associated with life satisfaction, but not with belief in life after death. PMID- 24760762 TI - The READY program: Building a global potential energy surface and reactive dynamic simulations for the hydrogen combustion. AB - READY (REActive DYnamics) is a program for studying reactive dynamic systems using a global potential energy surface (PES) built from previously existing PESs corresponding to each of the most important elementary reactions present in the system. We present an application to the combustion dynamics of a mixture of hydrogen and oxygen using accurate PESs for all the systems involving up to four oxygen and hydrogen atoms. Results at the temperature of 4000 K and pressure of 2 atm are presented and compared with model based on rate constants. Drawbacks and advantages of this approach are discussed and future directions of research are pointed out. PMID- 24760760 TI - Excessive production and extreme editing of human metapneumovirus defective interfering RNA is associated with type I IFN induction. AB - Type I IFN production is one of the hallmarks of host innate immune responses upon virus infection. Whilst most respiratory viruses carry IFN antagonists, reports on human metapneumovirus (HMPV) have been conflicting. Using deep sequencing, we have demonstrated that HMPV particles accumulate excessive amounts of defective interfering RNA (DIs) rapidly upon in vitro passage, and that these are associated with IFN induction. Importantly, the DIs were edited extensively; up to 70% of the original A and T residues had mutated to G or C, respectively. Such high editing rates of viral RNA have not, to our knowledge, been reported before. Bioinformatics and PCR assays indicated that adenosine deaminase acting on RNA (ADAR) was the most likely editing enzyme. HMPV thus has an unusually high propensity to generate DIs, which are edited at an unprecedented high frequency. The conflicting published data on HMPV IFN induction and antagonism are probably explained by DIs in virus stocks. The interaction of HMPV DIs with the RNA editing machinery and IFN responses warrants further investigation. PMID- 24760763 TI - Subacute antidiabetic and in vivo antioxidant effects of methanolic extract of Bridelia micrantha (Hochst Baill) leaf on alloxan-induced hyperglycaemic rats. AB - The methanolic leaf extract of Bridelia micrantha was tested for subacute antidiabetic and in vivo antioxidant effects in alloxan-induced hyperglycaemic rats. The subacute treatment of the extract (125, 250 and 500 mg/kg) produced 75, 68 and 63% reduction in fasting blood sugar level respectively, on day 14 of treatment. The extract produced time-dependent effect, but did not show a dose dependent effect. Its optimum antidiabetic activity was noted at the dose of 125 mg/kg and this was comparable to glibenclamide 2 mg/kg (positive control). The extract (125 mg/kg) showed good oral glucose tolerance test (OGTT) effect in both normoglycaemic and hyperglycaemic rats. The OGTT effect of the extract (125 mg/kg) did not differ significantly (p>0.05) from glibenclamide (2 mg/kg). The antioxidant effect of the extract was assayed through the determination of the level of thiobarbituric acid reactive substance (TBARS) and catalase activity. The extract produced a dose-dependent decrease in the serum level of TBARS and gave its optimum catalase activity at the dose of 500 mg/kg. This study suggests that the B. micrantha extract has antihyperglycaemic and antioxidant activities. Therefore, could be a potential source of novel antidiabetic and antioxidant agent for the management of diabetes mellitus. PMID- 24760764 TI - Pharmacognostical standardization and antidiabetic activity of Syzygium cumini (Linn.) barks (Myrtaceae) on streptozotocin-induced diabetic rats. AB - BACKGROUND: The objectives of the present study were phytochemical and pharmacological screening of bark of Syzygium cumini on streptozotocin (STZ) induced diabetic Wistar albino rats. METHODS: Dose selection was made on the basis of acute oral toxicity study (300-5,000 mg/kg b.w.) as per OECD guidelines. Rats were made diabetic by a single dose of STZ at 50 mg/kg b.w. intraperitoneally. The effect of Syzygium cumini extracts (500 mg/kg) on postprandial blood glucose level was determined in fasted diabetic and normal rats. Blood glucose levels were measured at 0, 30, and 90 min after the glucose administration in the OGTT study. The bark extracts were administered orally at the dose of 500 mg/kg for 21 days in the chronic study. Glibenclamide (2.5 mg/kg) was used as a standard drug for activity comparison. Statistical analyses were performed using one-way ANOVA followed by Bonferroni's multiple comparison tests. RESULTS: The phytochemical screening showed positive results for triterpenes/steroids, glycosides, carbohydrates, alkaloids, flavonoids, saponins, tannins and amino acids. Administration of Syzygium cumini extracts 30 min before oral glucose loading significantly suppressed (p<0.001) the rise in postprandial blood glucose levels in treated rats compared to control rats but less significant than glibenclamide. Daily, continuous oral treatment of STZ-induced diabetic with various extract of Syzygium cumini for 3 weeks resulted in significant reductions in fasting blood glucose levels compared with diabetic controls. The ethanol and aqueous extracts were most active. CONCLUSIONS: This study brings out the evidence regarding phytochemistry and pharmacological activities of Syzygium cumini. PMID- 24760765 TI - Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics. AB - While spinal muscular atrophy (SMA) is characterized by motor neuron degeneration, it is unclear whether and how much survival motor neuron (SMN) protein deficiency in muscle contributes to the pathophysiology of the disease. There is increasing evidence from patients and SMA model organisms that SMN deficiency causes intrinsic muscle defects. Here we investigated the role of SMN in muscle development using muscle cell lines and primary myoblasts. Formation of multinucleate myotubes by SMN-deficient muscle cells is inhibited at a stage preceding plasma membrane fusion. We found increased expression and reduced induction of key muscle development factors, such as MyoD and myogenin, with differentiation of SMN-deficient cells. In addition, SMN-deficient muscle cells had impaired cell migration and altered organization of focal adhesions and the actin cytoskeleton. Partially restoring SMN inhibited the premature expression of muscle differentiation markers, corrected the cytoskeletal abnormalities and improved myoblast fusion. These findings are consistent with a role for SMN in myotube formation through effects on muscle differentiation and cell motility. PMID- 24760766 TI - Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs. AB - Prader-Willi syndrome (PWS), a disorder of genomic imprinting, is characterized by neonatal hypotonia, hypogonadism, small hands and feet, hyperphagia and obesity in adulthood. PWS results from the loss of paternal copies of the cluster of SNORD116 C/D box snoRNAs and their host transcript, 116HG, on human chromosome 15q11-q13. We have investigated the mechanism of repression of the maternal SNORD116 cluster and 116HG. Here, we report that the zinc-finger protein ZNF274, in association with the histone H3 lysine 9 (H3K9) methyltransferase SETDB1, is part of a complex that binds to the silent maternal but not the active paternal alleles. Knockdown of SETDB1 in PWS-specific induced pluripotent cells (iPSCs) causes a decrease in the accumulation of H3K9 trimethylation (H3K9me3) at 116HG and corresponding accumulation of the active chromatin mark histone H3 lysine 4 dimethylation (H3K4me2). We also show that upon knockdown of SETDB1 in PWS specific iPSCs, expression of maternally silenced 116HG RNA is partially restored. SETDB1 knockdown in PWS iPSCs also disrupts DNA methylation at the PWS IC where a decrease in 5-methylcytosine is observed in association with a concomitant increase in 5-hydroxymethylcytosine. This observation suggests that the ZNF274/SETDB1 complex bound to the SNORD116 cluster may protect the PWS-IC from DNA demethylation during early development. Our findings reveal novel epigenetic mechanisms that function to repress the maternal 15q11-q13 region. PMID- 24760768 TI - Identification of a splicing variant that regulates type 2 diabetes risk factor CDKAL1 level by a coding-independent mechanism in human. AB - Single-nucleotide polymorphisms (SNPs) in CDKAL1 have been associated with the development of type 2 diabetes (T2D). CDKAL1 catalyzes 2-methylthio modification of adenosine at position 37 of tRNA(Lys)(UUU). A deficit of this modification causes aberrant protein synthesis, and is associated with impairment of insulin secretion in both mouse model and human. However, it is unknown whether the T2D associated SNPs in CDKAL1 are associated with downregulation of CDKAL1 by regulating the gene expression. Here, we report a specific splicing variant of CDKAL1 termed CDKAL1-v1 that is markedly lower in individuals carrying risk SNPs of CDKAL1. Interestingly, CDKAL1-v1 is a non-coding transcript, which regulates the CDKAL1 level by competitive binding to a CDKAL1-targeting miRNA. By direct editing of the genome, we further show that the nucleotides around the SNP regions are critical for the alternative splicing of CDKAL1-v1. These findings reveal that the T2D-associated SNPs in CDKAL1 reduce CDKAL1-v1 levels by impairing splicing, which in turn increases miRNA-mediated suppression of CDKAL1. Our results suggest that CDKAL1-v1-mediated suppression of CDKAL1 might underlie the pathogenesis of T2D in individuals carrying the risk SNPs. PMID- 24760769 TI - Glia are critical for the neuropathology of complex I deficiency in Drosophila. AB - Mitochondrial electron transport chain (ETC) disorders cause severe neurological disease, typically in the context of fatal encephalomyelopathies. Neuronal cell autonomous energy deficiency due to reduced mitochondrial adenosine triphosphate production is currently the leading hypothesis to explain the neurotoxicity in ETC disorders. To define the mechanisms underlying neuropathology in ETC disorders, we have modeled the most common type of ETC disorder, complex I deficiency, in Drosophila. Our model recapitulates important clinical features of the disease including neuronal loss, mitochondrial enlargement, motor dysfunction and early death. Using cell-type specific gene knockdown, we find that both neurons and glia contribute to the disease phenotype and that glia play a critical non-cell autonomous role in the development of neuronal toxicity. Our results open up an unexpected avenue of research, and could lead to the development of new treatment strategies. PMID- 24760770 TI - Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2. AB - Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4. PMID- 24760771 TI - Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a common and relentlessly progressive muscle disease. Some interventions have been identified that modestly slow progression and prolong survival, but more meaningful therapies are lacking. The goal of this study is to identify new therapeutic pathways for DMD using a zebrafish model of the disease. To accomplish this, we performed a non-biased drug screen in sapje, a zebrafish line with a recessive nonsense mutation in dystrophin. We identified 6 positive hits (out of 640 total drugs tested) by their ability to prevent abnormal birefringence in sapje. Follow-up analyses demonstrated that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provided the most substantial benefit. Morpholino-based experimentation confirmed that modulation of the serotonin pathway alone can prevent the dystrophic phenotype, and transcriptomic analysis revealed changes in calcium homeostasis as a potential mechanism. In all, we demonstrate that monoamine agonists can prevent disease in a vertebrate model of DMD. Given the safe and widespread use of SSRIs in clinical practice, our study identifies an attractive target pathway for therapy development. PMID- 24760773 TI - Entrapment of a neutral Tm(III)-based complex with two inner-sphere coordinated water molecules into PEG-stabilized vesicles: towards an alternative strategy to develop high-performance LipoCEST contrast agents for MR imaging. AB - Chemical exchange saturation transfer (CEST) probes issued from the encapsulation of a water proton paramagnetic shift reagent into the inner aqueous volume of lipid vesicles provide an emerging class of frequency-selective contrast agents with huge potential in the field of molecular magnetic resonance imaging (MRI). This work deals with the generation of such LipoCEST agents properly designed to optimize, under isotonic conditions, the chemical shift offset of the intra liposomal water protons as well as the number of exchangeable protons under reasonably low radiofrequency (RF) fields of saturation. The strategy lies in the loading of poly(ethylene glycol)-stabilized nanosized liposomes with uncharged lanthanide chelates, binding more than one water molecule in the first hydration sphere, exemplified here by [Tm(III)-DO3A (H2 O)2 ] complex. The key properties of the probes are demonstrated by complementary NMR investigations. The residence lifetime of the water molecules coordinated to the lanthanide center was outstandingly short (9.5 +/- 0.2 ns from (17) O NMR), and indeed relevant for effective LipoCEST responsiveness. The (1) H NMR CEST spectra (7.01 T magnetic field) prove that the theoretically expected optimal sensitivity can be approximated in the nanomolar concentration range, at reasonably low RF presaturation pulses (6.7-12 MUT) and saturation frequency offsets of the intra liposomal water protons beyond 10 ppm, making possible selective irradiation in biological environment. CEST-MRI images (7.01 T magnetic field and 10-12 MUT RF pulse) explicitly confirm the interest of these newly conceived LipoCEST agents, indeed among the most efficient ones developed so far under isosmotic conditions. PMID- 24760772 TI - Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate. AB - Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion. Mouse mutations in Fmn1 cause aberrant fusion of carpal digits. We report here that FlnB and Fmn1 physically interact, are co-expressed in chondrocytes in the growth plate and share overlapping expression in the cell cytoplasm and nucleus. Loss of FlnB leads to a dramatic decrease in Fmn1 expression at the hypertrophic-to ossification border. Loss of Fmn1-FlnB in mice leads to a more severe reduction in body size, weight and growth plate length, than observed in mice following knockout of either gene alone. Shortening of the long bone is associated with a decrease in chondrocyte proliferation and an overall delay in ossification in the double-knockout mice. In contrast to FlnB null, Fmn1 loss results in a decrease in the width of the prehypertrophic zone. Loss of both proteins, however, causes an overall decrease in the width of the proliferation zone and an increase in the differentiated hypertrophic zone. The current findings suggest that Fmn1 and FlnB have shared and independent functions. FlnB loss promotes prehypertrophic differentiation whereas Fmn1 leads to a delay. Both proteins, however, regulate chondrocyte proliferation, and FlnB may regulate Fmn1 function at the hypertrophic-to-ossification border, thereby explaining the overall delay in ossification. PMID- 24760774 TI - Echocardiographic follow-up and pregnancy outcome of fetuses with cardiac asymmetry at 18-22 weeks of gestation. AB - OBJECTIVE: The goal of our study was to evaluate the evolution of cardiac findings and assess the pregnancy outcome of fetuses with cardiac asymmetry at midgestation. METHODS: We reviewed all fetuses with cardiac asymmetry at echocardiograms performed at 18-22 weeks of gestation from 2006 to 2013. The data collected included the gestational age at diagnosis, serial echocardiographic findings, karyotype testing, and pregnancy outcome. Excluded were cases of classical hypoplastic left heart syndrome (HLHS) at initial echocardiogram (i.e., aortic (AO) and/or mitral atresia or dysplasia with normal intracardiac connections), heterotaxy syndrome, twin pregnancy, fetal growth restriction, and coarctation of the aorta. RESULTS: Our study included 278 fetuses with cardiac asymmetry (defined as Z-scores of left ventricle length or diameter of less than 2). A total of 202 (72%) fetuses had normal variations in cardiac growth by prenatal and neonatal echocardiography, 69 (25%) fetuses were confirmed to have HLHS variant by autopsy or neonatal echocardiography (with an overall survival of 4.3%), and seven (3%) fetuses were terminated before 24 weeks of gestation because of abnormal karyotypes. None of the cardiac measurements at the initial echocardiogram was significantly different between HLHS variant and normal cases. In the 69 fetuses ultimately diagnosed with HLHS variant, but not in the 202 normals, the Z-scores of all measured left heart structures decreased progressively between the first and the last prenatal echocardiograms (P < 0.01). CONCLUSIONS: The majority of the fetuses with cardiac asymmetry at 18-22 weeks have a good outcome. A minority of them progress to develop HLHS variant with advancing gestation. PMID- 24760775 TI - Tumor vasculature is regulated by FGF/FGFR signaling-mediated angiogenesis and bone marrow-derived cell recruitment: this mechanism is inhibited by SSR128129E, the first allosteric antagonist of FGFRs. AB - Tumor angiogenesis is accompanied by vasculogenesis, which is involved in the differentiation and mobilization of human bone marrow cells. In order to further characterize the role of vasculogenesis in the tumor growth process, the effects of FGF2 on the differentiation of human bone marrow AC133(+) cells (BM-AC133(+)) into vascular precursors were studied in vitro. FGF2, like VEGFA, induced progenitor cell differentiation into cell types with endothelial cell characteristics. SSR128129E, a newly discovered specific FGFR antagonist acting by allosteric interaction with FGFR, abrogated FGF2-induced endothelial cell differentiation, showing that FGFR signaling is essential during this process. To assess the involvement of the FGF/FRGR signaling in vivo, the pre-clinical model of Lewis lung carcinoma (LL2) in mice was used. Subcutaneous injection of LL2 cells into mice induced an increase of circulating EPCs from peripheral blood associated with tumor growth and an increase of intra-tumoral vascular index. Treatment with the FGFR antagonist SSR128129E strongly decreased LL2 tumor growth as well as the intra-tumoral vascular index (41% and 50% decrease vs. vehicle treated mice respectively, P < 0.01). Interestingly, SSR128129E treatment significantly decreased the number of circulating EPCs from the peripheral blood (53% inhibition vs. vehicle-treated mice, P < 0.01). These results demonstrate for the first time that the blockade of the FGF/FGFR pathway by SSR128129E reduces EPC recruitment during angiogenesis-dependent tumor growth. In this context, circulating EPCs could be a reliable surrogate marker for tumor growth and angiogenic activity. PMID- 24760776 TI - Prediction of IgG1 aggregation in solution. AB - Interest in monoclonal antibody aggregation is increasing as aggregates of biopharmaceuticals can cause an immunogenic response when injected into the body. In this work, a stoichiometric reaction model from concentration-time data is developed to predict the dimer ratio in stored antibody solutions over time. IgG1 was incubated at pH from 4.5 to 5.5, salt concentrations from 100 to 600 mmol/kg and protein concentrations of 10.6-26.3 g/L; samples were taken at intervals of 20 min to 5 h over time periods from 4 h to 7.6 days, and analyzed with size exclusion chromatography. The experiments showed the formation of dimers from monomers, but no higher order aggregates. Dilution of samples containing dimers led to the reversal of the dimerization reaction. Measurements of the concentrations of each component were made by fitting exponentially modified Gaussian peaks to the chromatograms used to measure the concentrations of the different forms of protein. This stoichiometric reaction model was able to predict the formation of dimers by the antibody studied. The equilibrium constant was found to be dependent on the salt concentration, and the kinetic constant showed a dependence on the pH of the solution. The prediction of the aggregation leads to a possibility of optimizing the conditions in order to prevent the dimer formation and to maximize the monomer concentration. PMID- 24760767 TI - Multi-ethnic fine-mapping of 14 central adiposity loci. AB - The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15 WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within +/- 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality. PMID- 24760777 TI - Silver-catalyzed oxidative activation of benzylic C-H bonds for the synthesis of difluoromethylated arenes. AB - A mild and catalytic method to form difluoromethylated arenes through the activation of benzylic C-H bonds has been developed. Utilizing AgNO3 as the catalyst, various arenes with diverse functional groups undergo activation/fluorination of benzylic C-H bonds with commercially available Selectfluor reagent as a source of fluorine in aqueous solution. The reaction is operationally simple and amenable to gram-scale synthesis. PMID- 24760778 TI - Incidence and zygosity of twin births following transfers using a single fresh or frozen embryo. AB - STUDY QUESTION: Are all twin births following single embryo transfer (SET) monozygotic? SUMMARY ANSWER: Between 1 in 10 and in 1 in 5 twins born after SET are the result of a concurrent natural conception. WHAT IS KNOWN ALREADY: The twinning rate after SET is higher than following natural conception. Most studies of twins following SET have incorrectly assumed monozygosity or have not been able to assess the zygosity. STUDY DESIGN, SIZE, DURATION: This study is a retrospective cohort study assessing the gender discordance of all live born twins following fresh or frozen SET. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 4701 patients in a large private IVF unit who gave birth following SET with a fresh or frozen embryo with complete follow-up. Of 137 viable twins at the 7-week ultrasound, 109 were delivered as twins. Gender discordance and Weinberg's differential rule were used to estimate dizygosity. Twin rates were compared for fresh and frozen transfers by insemination method and transfer day. MAIN RESULTS AND THE ROLE OF CHANCE: The overall live twin birth rate was 2.3% (109/4701). Based on the 7-week scan, 2 of the twins were monochorionic monoamniotic, 62 were monochorionic diamniotic and 45 were dichorionic diamniotic. There were a total of 12 gender discordant twins (11%), 7 from the Day 2/3 transfers and 5 from Day 5 transfers. Nine of the 12 discordant twins were from natural cycle frozen embryo transfers, the remaining 3 were from fresh cycles. LIMITATIONS, REASONS FOR CAUTION; To assess gender discordance only live born twins were studied. DNA fingerprinting of twins is a more accurate way to assess zygosity than measuring gender discordance. Same sex twins in this study are not necessarily monozygotic and the dizygotic rate in this study may therefore be higher. This rate was estimated using Weinberg's differential rule. WIDER IMPLICATIONS OF THE FINDINGS: As many as 1 in 5 twins born after SET may be the result of a concurrent natural conception. Couples therefore need to be counselled regarding the relative benefits and risks of intercourse in assisted reproduction technology cycles where spontaneous conception is possible. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 24760779 TI - Getting to the source: selective drug targeting of cancer stem cells. AB - Cancers are among the most important and most difficult to treat diseases of the 21st century. Conventional therapies include surgery, immunotherapy, and radiotherapy, as well many forms of drug treatments such as tamoxifen and Gleevec. However, these forms of treatment often do not eradicate the cancer stem cells, only managing to decrease the size of the tumor, allowing the cancer to return. The cancer stem cell hypothesis stipulates that malignancy is maintained through self-renewal of cancer stem cells (CSCs), which generate rapidly dividing progeny that comprise the tumors, and that are largely untouched by conventional therapies. Evidence for the central role of CSCs in many tumors has provided a paradigm shift in the way cancer chemotherapy may be addressed. Recent discoveries regarding the nature of the stem cell niche, and the key signaling pathways involved in stem cell self-renewal and differentiation from regenerative medicine, have provided key information that facilitates selective targeting of CSCs by small-molecule drugs. The growing body of biochemical knowledge on the nature of CSCs, and differences between them and normal adult stem cells essential for maintaining organisms, has augmented the increasing number of small molecules shown to control normal and aberrant stem cells. Here, we review small molecule approaches to the selective targeting of CSCs. PMID- 24760780 TI - Thermodynamics of micellization from heat-capacity measurements. AB - Differential scanning calorimetry (DSC), the most important technique for studying the thermodynamics of structural transitions of biological macromolecules, is seldom used in quantitative thermodynamic studies of surfactant micellization/demicellization. The reason for this could be ascribed to an insufficient understanding of the temperature dependence of the heat capacity of surfactant solutions (DSC data) in terms of thermodynamics, which leads to problems with the design of experiments and interpretation of the output signals. We address these issues by careful design of DSC experiments performed with solutions of ionic and nonionic surfactants at various surfactant concentrations, and individual and global mass-action model analysis of the obtained DSC data. Our approach leads to reliable thermodynamic parameters of micellization for all types of surfactants, comparable with those obtained by using isothermal titration calorimetry (ITC). In summary, we demonstrate that DSC can be successfully used as an independent method to obtain temperature-dependent thermodynamic parameters for micellization. PMID- 24760782 TI - Evidence of calcium-permeable AMPA receptors in dendritic spines of CA1 pyramidal neurons. AB - GluA2-lacking, calcium-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4 propionate receptors (AMPARs) have unique properties, but their presence at excitatory synapses in pyramidal cells is controversial. We have tested certain predictions of the model that such receptors are present in CA1 cells and show here that the polyamine spermine, but not philanthotoxin, causes use-dependent inhibition of synaptically evoked excitatory responses in stratum radiatum, but not s. oriens, in cultured and acute hippocampal slices. Stimulation of single dendritic spines by photolytic release of caged glutamate induced an N-methyl-d aspartate receptor-independent, use- and spermine-sensitive calcium influx only at apical spines in cultured slices. Bath application of glutamate also triggered a spermine-sensitive influx of cobalt into CA1 cell dendrites in s. radiatum. Responses of single apical, but not basal, spines to photostimulation displayed prominent paired-pulse facilitation (PPF) consistent with use-dependent relief of cytoplasmic polyamine block. Responses at apical dendrites were diminished, and PPF was increased, by spermine. Intracellular application of pep2m, which inhibits recycling of GluA2-containing AMPARs, reduced apical spine responses and increased PPF. We conclude that some calcium-permeable, polyamine-sensitive AMPARs, perhaps lacking GluA2 subunits, are present at synapses on apical dendrites of CA1 pyramidal cells, which may allow distinct forms of synaptic plasticity and computation at different sets of excitatory inputs. PMID- 24760781 TI - Development of dendritic tonic GABAergic inhibition regulates excitability and plasticity in CA1 pyramidal neurons. AB - Synaptic plasticity rules change during development: while hippocampal synapses can be potentiated by a single action potential pairing protocol in young neurons, mature neurons require burst firing to induce synaptic potentiation. An essential component for spike timing-dependent plasticity is the backpropagating action potential (BAP). BAP along the dendrites can be modulated by morphology and ion channel composition, both of which change during late postnatal development. However, it is unclear whether these dendritic changes can explain the developmental changes in synaptic plasticity induction rules. Here, we show that tonic GABAergic inhibition regulates dendritic action potential backpropagation in adolescent, but not preadolescent, CA1 pyramidal neurons. These developmental changes in tonic inhibition also altered the induction threshold for spike timing-dependent plasticity in adolescent neurons. This GABAergic regulatory effect on backpropagation is restricted to distal regions of apical dendrites (>200 MUm) and mediated by alpha5-containing GABA(A) receptors. Direct dendritic recordings demonstrate alpha5-mediated tonic GABA(A) currents in adolescent neurons which can modulate BAPs. These developmental modulations in dendritic excitability could not be explained by concurrent changes in dendritic morphology. To explain our data, model simulations propose a distally increasing or localized distal expression of dendritic alpha5 tonic inhibition in mature neurons. Overall, our results demonstrate that dendritic integration and plasticity in more mature dendrites are significantly altered by tonic alpha5 inhibition in a dendritic region-specific and developmentally regulated manner. PMID- 24760783 TI - Automatic scan test for detection of functional connectivity between cortex and muscles. AB - Postspike effects (PSEs) in averages of spike-triggered EMG snippets provide physiological evidence of connectivity between CMN cells and spinal motoneurons innervating skeletal muscles. They are typically detected by visual inspection of spike-triggered averages (SpTAs) or by multiple-fragment/single-snippet analyses [MFA (Poliakov AV, Schieber MH. J Neurosci Methods 79: 143-150, 1998) and SSA (Perel S, Schwartz AB, Ventura V. Neural Comput 26: 40-56, 2014)]; the latter are automatic tests that yield P values. However, MFA/SSA are only effective to detect PSEs that occur at about 6-16 ms posttrigger. Our first contribution is the scan test, an automatic test that has the same utility as SpTA, i.e., it can detect a wide range of PSEs at any latency, but it also yields a P value. Our second contribution is a thorough investigation of the statistical properties of PSE detection tests. We show that when the PSE is weak or the sample size is small, visual inspections of SpTAs have low power, because it is difficult to distinguish PSEs from background EMG variations. We also show that the scan test has better power and that its rate of spurious detections matches the chosen significance level alpha. This is especially important for investigators because, when a PSE is detected, this guarantees that the probability of a spurious PSE is less than alpha. Finally, we illustrate the operational characteristics of the PSE detection tests on 2,059 datasets from 5 experiments. The scan test is particularly useful to identify candidate PSEs, which can then be subject to further evaluation by SpTA inspection, and when PSEs are small and visual detection is ambiguous. PMID- 24760784 TI - The interplay of seven subthreshold conductances controls the resting membrane potential and the oscillatory behavior of thalamocortical neurons. AB - The signaling properties of thalamocortical (TC) neurons depend on the diversity of ion conductance mechanisms that underlie their rich membrane behavior at subthreshold potentials. Using patch-clamp recordings of TC neurons in brain slices from mice and a realistic conductance-based computational model, we characterized seven subthreshold ion currents of TC neurons and quantified their individual contributions to the total steady-state conductance at levels below tonic firing threshold. We then used the TC neuron model to show that the resting membrane potential results from the interplay of several inward and outward currents over a background provided by the potassium and sodium leak currents. The steady-state conductances of depolarizing Ih (hyperpolarization-activated cationic current), IT (low-threshold calcium current), and INaP (persistent sodium current) move the membrane potential away from the reversal potential of the leak conductances. This depolarization is counteracted in turn by the hyperpolarizing steady-state current of IA (fast transient A-type potassium current) and IKir (inwardly rectifying potassium current). Using the computational model, we have shown that single parameter variations compatible with physiological or pathological modulation promote burst firing periodicity. The balance between three amplifying variables (activation of IT, activation of INaP, and activation of IKir) and three recovering variables (inactivation of IT, activation of IA, and activation of Ih) determines the propensity, or lack thereof, of repetitive burst firing of TC neurons. We also have determined the specific roles that each of these variables have during the intrinsic oscillation. PMID- 24760785 TI - Activity of fixation neurons in the monkey frontal eye field during smooth pursuit eye movements. AB - We recorded the activity of fixation neurons in the frontal eye field (FEF) in trained monkeys and analyzed their activity during smooth pursuit eye movements. Fixation neurons were densely located in the area of the FEF in the caudal part of the arcuate gyrus facing the inferior arcuate sulcus where focal electrical stimulation suppressed the generation of saccades and smooth pursuit in bilateral directions at an intensity lower than the threshold for eliciting electrically evoked saccades. Whereas fixation neurons discharged tonically during fixation, they showed a variety of discharge patterns during smooth pursuit, ranging from a decrease in activity to an increase in activity. Of these, more than two-thirds were found to show a reduction in activity during smooth pursuit in the ipsilateral and bilateral directions. The reduction in activity of fixation neurons began at pursuit initiation and continued during pursuit maintenance. When catch-up saccades during the initiation of pursuit were eliminated by a step ramp target routine, the reduced activity of fixation neurons remained. The reduction in activity during pursuit was not dependent on the activity during fixation without a target. Based on these results, we discuss the role of the FEF at maintaining fixation in relation to various other brain areas. We suggest that fixation neurons in the FEF contribute to the suppression of smooth pursuit. These results suggest that FEF fixation neurons are part of a more generalized visual fixation system through which suppressive control is exerted on smooth pursuit, as well as saccades. PMID- 24760786 TI - Competitive interactions in sensorimotor cortex: oscillations express separation between alternative movement targets. AB - Choice behavior is influenced by factors such as reward and number of alternatives but also by physical context, for instance, the relative position of alternative movement targets. At small separation, speeded eye or hand movements are more likely to land between targets (spatial averaging) than at larger separation. Neurocomputational models explain such behavior in terms of cortical activity being preshaped by the movement environment. Here, we manipulate target separation, as a determinant of motor cortical activity in choice behavior, to address neural mechanisms of response selection. Specifically, we investigate whether context-induced changes in the balance of cooperative and competitive interactions between competing groups of neurons are expressed in the power spectrum of sensorimotor rhythms. We recorded magnetoencephalography while participants were precued to two possible movement target locations at different angles of separation (30, 60, or 90 degrees ). After a delay, one of the locations was cued as the target for a joystick pointing movement. We found that late delay-period movement-preparatory activity increased more strongly for alternative targets at 30 than at 60 or 90 degrees of separation. This nonlinear pattern was evident in slow event-related fields as well as in beta- and low gamma-band suppression. A comparable pattern was found within an earlier window for theta-band synchronization. We interpret the late delay effects in terms of increased movement-preparatory activity when there is greater overlap and hence less competition between groups of neurons encoding two response alternatives. Early delay-period theta-band synchronization may reflect covert response activation relevant to behavioral spatial averaging effects. PMID- 24760787 TI - Scaling and coordination deficits during dynamic object manipulation in Parkinson's disease. AB - The ability to reach for and dynamically manipulate objects in a dexterous fashion requires scaling and coordination of arm, hand, and fingertip forces during reach and grasp components of this behavior. The neural substrates underlying dynamic object manipulation are not well understood. Insight into the role of basal ganglia-thalamocortical circuits in object manipulation can come from the study of patients with Parkinson's disease (PD). We hypothesized that scaling and coordination aspects of motor control are differentially affected by this disorder. We asked 20 PD patients and 23 age-matched control subjects to reach for, grasp, and lift virtual objects along prescribed paths. The movements were subdivided into two types, intensive (scaling) and coordinative, by detecting their underlying self-similarity. PD patients off medication were significantly impaired relative to control subjects for both aspects of movement. Intensive deficits, reduced peak speed and aperture, were seen during the reach. Coordinative deficits were observed during the reach, namely, the relative position along the trajectory at which peak speed and aperture were achieved, and during the lift, when objects tilted with respect to the gravitational axis. These results suggest that basal ganglia-thalamocortical circuits may play an important role in fine motor coordination. Dopaminergic therapy significantly improved intensive but not coordinative aspects of movements. These findings are consistent with a framework in which tonic levels of dopamine in the dorsal striatum encode the energetic cost of a movement, thereby improving intensive or scaling aspects of movement. However, repletion of brain dopamine levels does not restore finely coordinated movement. PMID- 24760788 TI - Stance width changes how sensory feedback is used for multisegmental balance control. AB - A multilink sensorimotor integration model of frontal plane balance control was developed to determine how stance width influences the use of sensory feedback in healthy adults. Data used to estimate model parameters came from seven human participants who stood on a continuously rotating surface with three different stimulus amplitudes, with eyes open and closed, and at four different stance widths. Dependent variables included lower body (LB) and upper body (UB) sway quantified by frequency-response functions. Results showed that stance width had a major influence on how parameters varied across stimulus amplitude and between visual conditions. Active mechanisms dominated LB control. At narrower stances, with increasing stimulus amplitude, subjects used sensory reweighting to shift reliance from proprioceptive cues to vestibular and/or visual cues that oriented the LB more toward upright. When vision was available, subjects reduced reliance on proprioception and increased reliance on vision. At wider stances, LB control did not exhibit sensory reweighting. In the UB system, both active and passive mechanisms contributed and were dependent on stance width. UB control changed across stimulus amplitude most in wide stance (opposite of the pattern found in LB control). The strong influence of stance width on sensory integration and neural feedback control implies that rehabilitative therapies for balance disorders can target different aspects of balance control by using different stance widths. Rehabilitative strategies designed to assess or modify sensory reweighting will be most effective with the use of narrower stances, whereas wider stances present greater challenges to UB control. PMID- 24760790 TI - Chromophore based analyses of steady-state diffuse reflectance spectroscopy: current status and perspectives for clinical adoption. AB - Diffuse reflectance spectroscopy is a rapidly growing technology in the biophotonics community where it has shown promise in its ability to classify different tissues. In the steady-state domain a wide spectrum of clinical applications is supported with this technology ranging from diagnostic to guided interventions. Diffuse reflectance spectra provide a wealth of information about tissue composition; however, extracting biologically relevant information from the spectra in terms of chromophores may be more useful to gain acceptance into the clinical community. The chromophores that absorb light in the visible and near infrared wavelengths can provide information about tissue composition. The key characteristics of these chromophores and their relevance in different organs and clinical applications is the focus of this review, along with translating their use to the clinic. PMID- 24760792 TI - The metabolic pace-of-life model: incorporating ectothermic organisms into the theory of vertebrate ecoimmunology. AB - We propose a new heuristic model that incorporates metabolic rate and pace of life to predict a vertebrate species' investment in adaptive immune function. Using reptiles as an example, we hypothesize that animals with low metabolic rates will invest more in innate immunity compared with adaptive immunity. High metabolic rates and body temperatures should logically optimize the efficacy of the adaptive immune system--through rapid replication of T and B cells, prolific production of induced antibodies, and kinetics of antibody--antigen interactions. In current theory, the precise mechanisms of vertebrate immune function oft are inadequately considered as diverse selective pressures on the evolution of pathogens. We propose that the strength of adaptive immune function and pace of life together determine many of the important dynamics of host-pathogen evolution, namely, that hosts with a short lifespan and innate immunity or with a long lifespan and strong adaptive immunity are expected to drive the rapid evolution of their populations of pathogens. Long-lived hosts that rely primarily on innate immune functions are more likely to use defense mechanisms of tolerance (instead of resistance), which are not expected to act as a selection pressure for the rapid evolution of pathogens' virulence. PMID- 24760789 TI - Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys. AB - The subthalamic nucleus (STN) receives a dopaminergic innervation from the substantia nigra pars compacta, but the role of this projection remains poorly understood, particularly in primates. To address this issue, we used immuno electron microscopy to localize D1, D2, and D5 dopamine receptors in the STN of rhesus macaques and studied the electrophysiological effects of activating D1 like or D2-like receptors in normal and 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated parkinsonian monkeys. Labeling of D1 and D2 receptors was primarily found presynaptically, on preterminal axons and putative glutamatergic and GABAergic terminals, while D5 receptors were more significantly expressed postsynaptically, on dendritic shafts of STN neurons. The electrical spiking activity of STN neurons, recorded with standard extracellular recording methods, was studied before, during, and after intra-STN administration of the dopamine D1-like receptor agonist SKF82958, the D2-like receptor agonist quinpirole, or artificial cerebrospinal fluid (control injections). In normal animals, administration of SKF82958 significantly reduced the spontaneous firing but increased the rate of intraburst firing and the proportion of pause-burst sequences of firing. Quinpirole only increased the proportion of such pause-burst sequences in STN neurons of normal monkeys. In MPTP-treated monkeys, the D1-like receptor agonist also reduced the firing rate and increased the proportion of pause-burst sequences, while the D2-like receptor agonist did not change any of the chosen descriptors of the firing pattern of STN neurons. Our data suggest that dopamine receptor activation can directly modulate the electrical activity of STN neurons by pre- and postsynaptic mechanisms in both normal and parkinsonian states, predominantly via activation of D1 receptors. PMID- 24760791 TI - Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results. AB - BACKGROUND: Pain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases. METHODS: Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher's exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. RESULTS: One hundred forty-seven subjects were enrolled, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day. CONCLUSIONS: This multicenter phase III trial demonstrated that MRgFUS is a safe and effective, noninvasive treatment for alleviating pain resulting from bone metastases in patients that have failed standard treatments. PMID- 24760793 TI - Self-burial mechanics of hygroscopically responsive awns. AB - We present the results of a combined experimental and theoretical investigation of the mechanics of self-burial of some plant seeds whose morphologies respond to environmental changes in humidity. The seeds of Erodium and Pelargonium have hygroscopically responsive awns that play a critical role in their self-burial into soil. The awn, coiled in a dry state, uncoils to stretch linearly under highly humid condition because of a tilted arrangement of cellulose microfibrils in one of the layers of the awn's bilayered structure. By measuring the mechanical characteristics of the awns of Pelargonium carnosum, we find that the extensional force of the awn can be aptly modeled by the theory of elasticity for a coiled spring. We further show that although the resistance to the seed-head penetrating relatively coarse soils without spinning is large enough to block the digging seed, the rotation of the seed greatly reduces the soil's resistance down to a level the awn can easily overcome. Our mechanical analysis reveals that the self-burial of the seed is a sophisticated outcome of the helically coiled configuration of the awn. PMID- 24760794 TI - Insights from parasite-specific serological tools in eco-immunology. AB - Eco-immunology seeks evolutionary explanations for the tremendous variation in immune defense observed in nature. Assays to quantify immune phenotypes often are crucial to this endeavor. To this end, we suggest that more use could (and arguably should) be made of the veterinary and clinical serological toolbox. For example, measuring the magnitude and half-life of parasite-specific antibodies across a range of host taxa may provide new ways of testing theories in eco immunology. Here, we suggest that antibody assays developed in veterinary and clinical immunology and epidemiology provide excellent tools--or at least excellent starting points for development of tools--for tests of such hypotheses. We review how such assays work and how they may be optimized for new questions and new systems in eco-immunology. We provide examples of the application of such tools to eco-immunological studies of seabirds and mammals, and suggest a decision-tree to aid development of assays. We expect that addition of such tools to the eco-immunological toolbox will promote progress in the field and help elucidate how immune systems function and why they vary in nature. PMID- 24760795 TI - Developmental stress, song-learning, and cognition. AB - The evolution of enhanced cognitive ability has sometimes been attributed to sexual selection. An association between the mating success of males and their cognitive ability could arise either through male-male competition or through female choice. Specifically in the latter case, sexual selection would act more readily if males advertized their cognitive ability through display. Most traits involved in sexual display, however, seem unlikely to have any inherent relationship with cognition beyond that which arises through the effect of cognitive abilities on acquisition of resources and, in turn, the effect of resources on development of the display trait. In contrast, for displays whose development and expression require learning, a direct link with cognition is possible because of a shared dependence on brain function. The parallel effects of developmental stress on song-learning and cognition provide a compelling explanation for an association between attributes of the song and cognitive ability. We outline the hypothesis that sexually selected qualities of song serve as an indicator of cognitive abilities. We first present evidence that song learning is itself a challenging cognitive task. We then give evidence that sexual selection favors well-learned song. Next, we review evidence that song and cognitive ability both are affected by developmental stresses. We consider recent experimental data testing the relationship between song and cognitive ability. Finally, we suggest that the accuracy with which songs are learned may be an optimal indicator of other cognitive abilities. PMID- 24760796 TI - A computational fluid dynamics simulation study of coronary blood flow affected by graft placement?. AB - OBJECTIVES: To determine the effect of graft placement and orientation on flow rates through a partially obstructed coronary artery. METHODS: A numerical, parametric study of blood flow in the human coronary artery was conducted using computational fluid dynamics simulation. A cylindrical approximation of the coronary artery with varying degrees of stenosis, with and without a bypass graft, was modelled to determine trends in volumetric flow rates. Steady and transient simulations were conducted for geometric variations of percentage of blockage, length and shape of stenosis, graft position relative to the coronary blockage and graft orientation. Accurate simulations were performed using a non Newtonian fluid model and pressure-driven viscous flow. RESULTS: Simulations demonstrate, as expected, that total outlet flow rates of grafted arteries are consistently improved for upstream stenosis varying between 0 and 90% blockage. Grafts angled towards the artery provided increased total outflow. However, flow rates in the coronary artery upstream of the graft are substantially reduced in comparison with the non-grafted configuration due to competing flows. For some configurations (reduced blockage, graft placed close to long grafts), flow rates in the graft are below that of the flow rate through the stenosis. In general, a graft angled more towards the artery increased flow rates upstream of the graft. CONCLUSIONS: Placement and orientation of a graft may adversely affect upstream flow, with the degree of effect dependent on geometric factors of downstream position and graft angle. PMID- 24760797 TI - Morphological and molecular characterization of Parafurgasonia zhangi spec. nov. and Chilodonella acuta Kahl, 1931 (Protozoa, Ciliophora), from a soil habitat of Saudi Arabia. AB - The morphology and infraciliature of two soil ciliates, Parafurgasonia zhangi spec. nov. and Chilodonella acuta Kahl, 1931, collected from Saudi Arabia, were investigated by observations of both living cells and specimens after standard staining methods. P. zhangi differs from its congeners by the combination of the following features: excretory pore quite near posterior end of paroral membrane, 16 or 17 somatic kineties with about 11 kinetids in each one on dorsal side, paroral membrane gently curved and composed of about 15 dikinetids, and hypostomial organelle composed of four or five files of kinetids with four monokinetids each. The diagnosis of Chilodonella acuta was renewed to include characteristics revealed by the silver impregnation method: cells in vivo measuring 33-45) * 18-26) um, dorsal hump and tail-like podite present, two contractile vacuoles, seven left and five right kineties, 9-11 nematodesmal rods, and dorsal brush containing about 11 basal bodies. Phylogenetic analyses based on small-subunit rRNA gene sequences showed that P. zhangi was closer to species of the Colpodidiidae rather than the Furgasoniidae represented by Furgasonia blochmanni, and Chilodonella acuta clustered with its congener Chilodonella uncinata but was a well-outlined species of the genus. PMID- 24760798 TI - Methylobacterium pseudosasicola sp. nov. and Methylobacterium phyllostachyos sp. nov., isolated from bamboo leaf surfaces. AB - Two strains of Gram-negative, methylotrophic bacteria, isolated because of their abilities to promote plant growth, were subjected to a polyphasic taxonomic study. The isolates were strictly aerobic, motile, pink-pigmented, facultatively methylotrophic, non-spore-forming rods. The chemotaxonomic characteristics of the isolates included the presence of C18 : 1omega7c as the major cellular fatty acid. The DNA G+C contents of strains BL36(T) and BL47(T) were 69.4 and 69.8 mol%, respectively. 16S rRNA gene sequence analysis of strains BL36(T) and BL47(T) placed them under the genus Methylobacterium, with the pairwise sequence similarity between them and the type strains of closely related species ranging from 97.2 to 99.0%. On the basis of their phenotypic and phylogenetic distinctiveness and the results of DNA-DNA hybridization analysis, the isolates represent two novel species within the genus Methylobacterium, for which the names Methylobacterium pseudosasicola sp. nov. (type strain BL36(T) = NBRC 105203(T) = ICMP 17621(T)) and Methylobacterium phyllostachyos sp. nov. (type strain BL47(T) = NBRC 105206(T) = ICMP 17619(T)) are proposed. PMID- 24760799 TI - Oryzihumus terrae sp. nov., isolated from soil and emended description of the genus Oryzihumus. AB - A Gram-stain-positive, aerobic, non-flagellated bacterium, designated KIS22 12(T), was isolated from a soil sample of Baengnyeong Island in Onjin county, Republic of Korea. Cells were non-spore-forming cocci showing catalase-positive and oxidase-negative reactions. Growth of strain KIS22-12(T) was observed between 10 and 35 degrees C (optimum, 28-30 degrees C), between pH 5.0 and 9.0 (optimum, pH 7.0) and with 0-3% (w/v) NaCl. Strain KIS22-12(T) contained MK-8(H4) as the predominant menaquinone, and C17 : 1omega8c, iso-C15 : 0 and anteiso-C15 : 0 as the major fatty acids. Strain KIS22-12(T) contained diphosphatidylglycerol, phosphatidylinositol, one unknown aminophospholipid, one unknown aminolipid, two unknown phospholipids and one unknown lipid. The peptidoglycan type was A1gamma. The G+C content of the genomic DNA was 75.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain KIS22-12(T) formed a phyletic lineage with Oryzihumus leptocrescens KV-628(T). 16S rRNA gene sequence similarity between the two strains was 96.5%. On the basis of phenotypic, chemotaxonomic and molecular properties, strain KIS22-12(T) represents a novel species within the genus Oryzihumus, for which the name Oryzihumus terrae sp. nov. is proposed. The type strain is KIS22-12(T) ( = KACC 16543(T) = DSM 27161(T) = NBRC 109596(T)). An emended description of the genus Oryzihumus is also provided. PMID- 24760800 TI - Streptosporangium jomthongense sp. nov., an actinomycete isolated from rhizospheric soil and emendation of the genus Streptosporangium. AB - A novel actinomycete, strain 30EHS(T), was isolated from the rhizospheric soil under an elephant ear plant (Caladium bicolor) in Jomthong district, Bangkok, Thailand. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 30EHS(T) fell within the cluster of the genus Streptosporangium. Chemical composition analysis confirmed that the strain represented a member of the genus Streptosporangium even though this strain produced a tightly packed single spore on aerial hyphae. Phylogenetic analysis based on 16S rRNA gene sequences demonstrated that strain 30EHS(T) was most closely related to Streptosporangium fragile NBRC 14311(T) (98.1%), Streptosporangium carneum NBRC 15562(T) (97.8%) and Streptosporangium violaceochromogenes NBRC 15560(T) (97.4%). The DNA-DNA hybridization relatedness values between strain 30EHS(T) and the above three strains were below 70%. Based on combined data for phylogenetic analysis, DNA-DNA hybridization relatedness and physiological characteristics, it was concluded that strain 30EHS(T) should be classified as representing a novel species of the genus Streptosporangium. We propose the name Streptosporangium jomthongense sp. nov., with the type strain 30EHS(T) ( = BCC 53154(T) = NBRC 110047(T)). An emended description of the genus Streptosporangium is also proposed. PMID- 24760801 TI - Hemostasis and stem cell therapy in myocardial infarction. PMID- 24760802 TI - Current prevalence of hepatitis B infection among parturient women in Jakarta, Indonesia. AB - AIM: to determine the current prevalence of hepatitis B infection among parturient women in Jakarta, Indonesia. METHODS: a cross-sectional study was conducted in women giving birth between May and July 2009, recruited by consecutive sampling technique in 2 hospitals and 13 public health centers in Jakarta. Mothers with history of chronic liver disease were excluded. Data were collected by questionnaires including obstetric history, hepatitis B immunization history, and the presence of jaundice; maternal venous blood samples were taken before parturition for HBsAg determination that was performed by ELISA. RESULTS: of 1,009 parturient women screened for hepatitis B infection, 22 were found positive, giving an overall hepatitis B prevalence of 2.2%, previous 5.2% in 1985. None of the subjects had any symptoms of HBV infection. The highest HBsAg prevalence was found in the East Jakarta study site, with predominance in mothers aged <20 years and those with multi-parities. CONCLUSION: present prevalence of HBsAg among Indonesian parturient women in Jakarta was 2.2% and markedly reduced compared with prevalence in 1985. PMID- 24760803 TI - Hemostatic status of pre and post intracoronary injection of peripheral blood stem cells in patients with recent myocardial infarction. AB - AIM: to investigate hemostatic parameter changes, such as platelet aggregation, blood and plasma viscosity, prothrombin time, APTT, CRP and fibrinogen, before and after administration of stem cell therapy. METHODS: a total of 24 patients were enrolled. Peripheral blood stem cells (PBSCs) were harvested and injected into the infarct-related artery after 5 consecutive days of G-CSF administration. Recombinant human erythropoietin was administered at the time of intracoronary PBSCs injection. RESULTS: we were able to evaluate 11 from 24 of patients regarding hemostatic status pre-post stem cell injection. There were no significant difference between baseline vs 3 months in spontaneous aggregation (p=0.350), PT (p=0.793), aPTT (p=0.255) and TT (p=0.254). There were also no significant difference between baseline vs 3 months in plasma viscosity (p=0.442) and blood viscosity (p=0.843). Nevertheless the patient who had their blood and plasma viscosity above or below normal laboratory range return to normal level after the treatment. Both PT and APTT also show normalization value. Both Fibrinogen and CRP level show significant decrease between baseline and 3 months after treatment (p=0.009) and (p=0.04) respectively. CONCLUSION: combined G-CSF and EPO based-intracoronary infusion of PBSCs may open new perspective in the treatment of hypercoagulable state post AMI. PMID- 24760804 TI - Predictors of five days mortality in diabetic ketoacidosis patients: a prospective cohort study. AB - AIM: to determine the role of serum lactate and diabetic ketoacidosis (DKA) severity as predictors for five-days mortality in DKA patients. METHODS: a prospective cohort study was conducted in DKA patients admitted to emergency department (ED) at Cipto Mangunkusumo Hospital, Jakarta, Indonesia, during 2007 2008 periods. Predictors for 5 days mortality in DKA patients in this study including serum lactate and DKA severity (plasma glucose, arterial blood pH, serum bicarbonate, osmolality, anion gap, and alteration in sensorium) at admission. Cox's Proportional Hazard Regression Analysis was used to determine independent predictors for 5-days mortality among study population. RESULTS: sixty patients with diabetic ketoacidosis were enrolled in the study; in which 24 (40%) patients were died within 5 days after admission. In the multivariate analysis, the lactate level 4 mmol/L (HR, 3.09; 95% CI, 1.36-7.05) and altered in sensorium stuporous/comatose (HR, 3.38; 95% CI, 1.45-7.87) were identified as independent predictors for 5-days mortality in DKA adult patients. CONCLUSION: lactate level 4 mmol/L and altered in sensorium stuporous/comatose can be used to predict 5-days mortality in adult patients with DKA. PMID- 24760805 TI - Correlation between receptor activator of nuclear factor-kappabeta ligand (RANKL), and osteoprotegerin (OPG) with cartilage degradation in rheumatoid arthritis patients. AB - AIM: to analyze the correlation between Receptor activator of nuclear factor kappabeta ligand (RANKL), Osteoprotegrin (OPG) serum level with cartilage oligomeric matrix protein (COMP) serum level as a marker of cartilage degradation in rheumatoid arthritis patients. METHODS: a cross-sectional study was conducted on the subjects who came to the outpatient clinic of rheumatology in Cipto Mangunkusumo Hospital. Patients were diagnosed based on the American College of Rheumatology (ACR) 1987 revised criteria. All numerical data, both primary data and data transformation were not normally distributed, so we did bivariate analysis with Spearman correlation test. RESULTS: we collected the data of 60 RA patients with majority of the subject had active disease activity (78.3%). Methotrexate was the most widely disease modifying anti-rheumatoid drug (DMARD) used, either as a single drug (51.7%) or in combination with another DMARD (25.1%). Bivariate analysis was revealed that RANKL, OPG, and OPG/RANKL serum level have no significantly correlation with COMP serum level (p=0.52; p=0.25; p=0.2, respectively). CONCLUSION: RANKL and OPG serum level, had no correlation with cartilage degradation in rheumatoid arthritis patients. PMID- 24760806 TI - Level of circulating endothelial cells and expression of nuclear factor kappa beta of human's peripheral blood mononuclear cells in subjects with certain conditions. AB - AIM: to detect the levels of CEC and expression of NFkappaB in the three groups of subjects with certain conditions. METHODS: this study is an exploratory study using human peripheral blood samples. The study subjects comprised three groups, the group of 23 healthy people, a group of 35 people that has one or more risk factors for vascular disease and a group of 15 vascular disease patients (coronary heart disease, diabetes mellitus, stroke). CEC were isolated from peripheral blood mononuclear cells (PBMC). CEC level is identified through the measurement of CD45 and CD146 by flowcytometry method. NFkappaB expression is recognized by ELISA method (imgenex, USA). RESULTS: the highest average levels of CEC were found in the sick group (28.6%). The highest average expression of NFkappaB (924.9495) is found in the group with risk factors. The lowest average expression of NFkappaB and CEC is found in the healthy group. Statistical analysis of ANOVA at the interval confidence of 95% shows a significant difference (p=0.00) levels of CEC and NFkappaB expression between the healthy group with the group with the risk of cardiovascular disease (CVD) and patients with known CVD. CONCLUSION: increase of level CEC and NFkappaB expression has a strong relationship with vascular disease and its risk factors. PMID- 24760807 TI - An observational study to evaluate the safety and efficacy of telbivudine in adults with chronic hepatitis B. AB - AIM: to assess the safety and efficacy of telbivudine therapy in adult patients with CHB in Indonesia. METHODS: the study design was prospective cohort study. Multicenter study of adult CHB patients requiring oral antiviral therapy in daily practice setting. All patients received 600 mg of telbivudine daily for one year. Recruitment and decision to start telbivudine therapy was based on clinical indication as assessed by the participating physicians. The primary end-point was patient safety (adverse event or serious adverse events); while the secondary end points were HBeAg seroconversion, changes of serum HBV DNA levels and serum ALT normalization. Patients were assessed at week-24 and week-52 of treatment. RESULTS: a total of 176 cases were eligible for analysis, comprising 104 (59.8%) HBeAg-positive and 70 (40.2%) HBeAg-negative patients. Adverse events were reported in 7 (4.0%) patients, most of them were mild. HBeAg loss and seroconversion rate was 28.8% and 14.14% at week-52 respectively. Undetectable HBV DNA (PCR negativity) was 51.8% at week-24 and 62.7% at week-52. Median HBV DNA levels were significantly reduced from baseline to week-24 and week-52 treatment (both p<0.001; Wilcoxon's signed-rank test). Normalization of serum ALT activity occurred in 85 (73.28%) patients at week-52. CONCLUSION: Telbivudine therapy is generally safe and well tolerated among adult Indonesian patients with chronic hepatitis B. Treatment efficacy in terms of HBeAg loss and seroconversion, changes of HBV DNA levels and serum ALT normalization were similar to previous reported studies. PMID- 24760808 TI - Lower serum level of anti-tetanus toxin antibodies in patients with type 2 diabetes mellitus. AB - AIM: To evaluate the serum levels of anti-tetanus toxin antibodies (anti-TTA) in patients with type 2 diabetes mellitus (DM) and in a control group. METHODS: Totally, 100 patients with type 2 DM and 100 age- and sex-matched healthy individuals were enrolled to study. The presence of type 2 DM confirmed according to the clinical and para-clinical criteria such as fasting plasma glucose above 126 mg/dl. A peripheral blood sample was collected from all subjects. The serum samples of participants tested for the levels of anti-TTA by ELISA method. The serum antitoxin concentration 0.1 IU/mL was considered as a protective level of antibody. RESULTS: The seroprotective rate in healthy group was significantly higher than diabetic group (99% vs. 92%; p<0.02). The mean titer of anti-TTA in healthy group (5.32 +/- 0.26 IU/ml) was also significantly higher than diabetic patients (3.46 +/- 0.26 IU/ml; p>0.001). In diabetic men the mean titer of anti TTA was significantly higher in comparison to diabetic women (3.94 +/- 0.34 IU/ml vs 2.59 +/- 0.36 IU/ml; p<0.01). In diabetic patients the seroprotective rate and the mean titer of anti-TTA in subjects with age >40 years was also lower in comparison to those with age <40 years (89.23% vs 97.14%; p<0.15 and 4.57 +/- 0.38 IU/ml vs 2.86 +/- 0.32 IU/ml; P<0.002, respectively). The mean titer of anti TTA was significantly higher in patients with diabetes duration <5 years in comparison to patients with disease duration >5 years (3.91 +/- 0.35 IU/ml vs 2.85 +/- 0.38 IU/ml; p<0.04). CONCLUSION: these results showed lower levels of anti-TTA in patients with type 2 DM, in diabetic women, in patients aged >40 years and in diabetic patients with disease duration >5 years. PMID- 24760809 TI - Primary tuberculosis of the breast manifested as abscess: a rare case report. AB - Primary breast tuberculosis is a rare entity. We are reporting a case of primary breast tuberculosis, which presented as breast abscess. On histopathology, it was diagnosed as breast tuberculosis. Aspiration cytology was not done due breast abscess. Patient was put on anti-tubercular drugs. In follow up, after 3 months patient condition was improved. PMID- 24760810 TI - A rare manifestation of cysticercosis infestation. AB - There are many causes of urticaria, which may vary from infections to malignancy. Among the infections, infestations by cysticercosis (larval stage of the tapeworm called Taenia solium) is an important cause. The present report is of forty four years old female who presented with urticaria and swelling on face. The swelling was later diagnosed as cysticercosis by noninvasive ultrasonography. The urticaria subsided after the treatment of cysticercosis. We report this case for rarity of its presentation. PMID- 24760811 TI - Managing seasonal influenza: oseltamivir treatment policy in indonesia? AB - To manage cases of avian influenza A/H5N1 virus infection and in anticipation of a pandemic triggered by this virus, Indonesia purchased and distributed oseltamivir to the government health facilities. Oseltamivir is an antiviral drug that was developed for the treatment of influenza infections. Disease surveillance and research suggests that seasonal influenza (A/H1N1, A/H3N2 or B) results in considerable morbidity and mortality in Indonesia, where over 15% of influenza-like illness and severe acute respiratory illness patients test positive for the influenza virus. Indonesia currently limits oseltamivir for the management of avian influenza A/H5N1cases and in anticipation of a pandemic triggered by the A/H5N1 virus. We present the evidence for the use of oseltamivir in the treatment of seasonal influenza infections so that doctors have the option to prescribe the drug. We propose that the benefits of this approach will largely outweigh the risk of antiviral resistance. We recommend that oseltamivir be available for administration to patients with seasonal influenza infections, especially for those hospitalized and for groups with high risk of complications and adverse outcomes. Overall, this will reduce morbidity and mortality of seasonal influenza. PMID- 24760812 TI - Unilateral leg swelling. PMID- 24760813 TI - Endovascular treatment of intracranial aneurysms: diversity in treatment techniques of varying anatomical presentations. AB - We discuss and illustrate various endovascular treatment options for intracranial aneurysms, to reflect common technique used in endovascular treatment of brain aneurysm. We select five cases of various aneurysm types to show assortments of endovascular treatment (EVT) are performed. Selective catheterization of the intracranial aneurysms and endovascular treatments are technically feasible, offering a viable alternative to the surgical approach. We discuss the radiographic features, clinical presentation, and strategies of endovascular treatment of intracranial aneurysms. PMID- 24760814 TI - Non-invasive ventilation in acute respiratory failure. AB - One of the cornerstones of critical care medicine is support of the failing respiratory system. The 2 major components of managing respiratory failure are the acute intervention and the weaning process. Many of the studies to determine the optimal methods of ventilation and weaning have focused on non-invasive positive-pressure ventilation as an alternative to invasive ventilation, with various causes of acute respiratory failure. Non-invasive ventilation refers to the provision of ventilatory support to the lungs, without the use of an endotracheal airway. It has emerged as an important tool in the treatment of acute respiratory failure. Non-invasive positive ventilation has undergone a remarkable evolution over the past decades and is assuming an important role in the management of both acute and chronic respiratory failure. There is improvement in gas exchange, relief of respiratory muscle fatigue, and clinical outcome with reduced morbidity and mortality. Nevertheless, contraindications and failures need to be identified early, as delaying endotracheal intubation is associated with increased morbidity and mortality. Furthermore, although it is common practice to give intubation and mechanical ventilation, complications can result from the intubation process (damage to local tissue) and during the course of ventilation (pneumonia and sinusitis associated with ventilators), prolonging stay in intensive care, length of hospital stay and mortality in selected patients. PMID- 24760815 TI - Avoiding blunders involving 'immortal time'. PMID- 24760817 TI - Phycobilisome-Deficient Strains of Synechocystis sp. PCC 6803 Have Reduced Size and Require Carbon-Limiting Conditions to Exhibit Enhanced Productivity. AB - Reducing excessive light harvesting in photosynthetic organisms may increase biomass yields by limiting photoinhibition and increasing light penetration in dense cultures. The cyanobacterium Synechocystis sp. PCC 6803 harvests light via the phycobilisome, which consists of an allophycocyanin core and six radiating rods, each with three phycocyanin (PC) discs. Via targeted gene disruption and alterations to the promoter region, three mutants with two (pcpcT->C) and one (DeltaCpcC1C2:pcpcT->C) PC discs per rod or lacking PC (olive) were generated. Photoinhibition and chlorophyll levels decreased upon phycobilisome reduction, although greater penetration of white light was observed only in the PC-deficient mutant. In all strains cultured at high cell densities, most light was absorbed by the first 2 cm of the culture. Photosynthesis and respiration rates were also reduced in the DeltaCpcC1C2:pcpcT->C and olive mutants. Cell size was smaller in the pcpcT->C and olive strains. Growth and biomass accumulation were similar between the wild-type and pcpcT->C under a variety of conditions. Growth and biomass accumulation of the olive mutant were poorer in carbon-saturated cultures but improved in carbon-limited cultures at higher light intensities, as they did in the DeltaCpcC1C2:pcpcT->C mutant. This study shows that one PC disc per rod is sufficient for maximal light harvesting and biomass accumulation, except under conditions of high light and carbon limitation, and two or more are sufficient for maximal oxygen evolution. To our knowledge, this study is the first to measure light penetration in bulk cultures of cyanobacteria and offers important insights into photobioreactor design. PMID- 24760818 TI - Integrated Analysis Platform: An Open-Source Information System for High Throughput Plant Phenotyping. AB - High-throughput phenotyping is emerging as an important technology to dissect phenotypic components in plants. Efficient image processing and feature extraction are prerequisites to quantify plant growth and performance based on phenotypic traits. Issues include data management, image analysis, and result visualization of large-scale phenotypic data sets. Here, we present Integrated Analysis Platform (IAP), an open-source framework for high-throughput plant phenotyping. IAP provides user-friendly interfaces, and its core functions are highly adaptable. Our system supports image data transfer from different acquisition environments and large-scale image analysis for different plant species based on real-time imaging data obtained from different spectra. Due to the huge amount of data to manage, we utilized a common data structure for efficient storage and organization of data for both input data and result data. We implemented a block-based method for automated image processing to extract a representative list of plant phenotypic traits. We also provide tools for build in data plotting and result export. For validation of IAP, we performed an example experiment that contains 33 maize (Zea mays 'Fernandez') plants, which were grown for 9 weeks in an automated greenhouse with nondestructive imaging. Subsequently, the image data were subjected to automated analysis with the maize pipeline implemented in our system. We found that the computed digital volume and number of leaves correlate with our manually measured data in high accuracy up to 0.98 and 0.95, respectively. In summary, IAP provides a multiple set of functionalities for import/export, management, and automated analysis of high throughput plant phenotyping data, and its analysis results are highly reliable. PMID- 24760819 TI - Cytochrome P450 CYP81A12 and CYP81A21 Are Associated with Resistance to Two Acetolactate Synthase Inhibitors in Echinochloa phyllopogon. AB - Previous studies have demonstrated multiple herbicide resistance in California populations of Echinochloa phyllopogon, a noxious weed in rice (Oryza sativa) fields. It was suggested that the resistance to two classes of acetolactate synthase-inhibiting herbicides, bensulfuron-methyl (BSM) and penoxsulam (PX), may be caused by enhanced activities of herbicide-metabolizing cytochrome P450. We investigated BSM metabolism in the resistant (R) and susceptible (S) lines of E. phyllopogon, which were originally collected from different areas in California. R plants metabolized BSM through O-demethylation more rapidly than S plants. Based on available information about BSM tolerance in rice, we isolated and analyzed P450 genes of the CYP81A subfamily in E. phyllopogon. Two genes, CYP81A12 and CYP81A21, were more actively transcribed in R plants compared with S plants. Transgenic Arabidopsis (Arabidopsis thaliana) expressing either of the two genes survived in media containing BSM or PX at levels at which the wild type stopped growing. Segregation of resistances in the F2 generation from crosses of R and S plants suggested that the resistance to BSM and PX were each under the control of a single regulatory element. In F6 recombinant inbred lines, BSM and PX resistances cosegregated with increased transcript levels of CYP81A12 and CYP81A21. Heterologously produced CYP81A12 and CYP81A21 proteins in yeast (Saccharomyces cerevisiae) metabolized BSM through O-demethylation. Our results suggest that overexpression of the two P450 genes confers resistance to two classes of acetolactate synthase inhibitors to E. phyllopogon. The overexpression of the two genes could be regulated simultaneously by a single trans-acting element in the R line of E. phyllopogon. PMID- 24760820 TI - Reproducibility issues in science, is P value really the only answer? PMID- 24760821 TI - Revised evidence for statistical standards. PMID- 24760822 TI - Adaptive revised standards for statistical evidence. PMID- 24760823 TI - Ambiguous evidence for assigning DddQ as a dimethylsulfoniopropionate lyase and oceanic dimethylsulfide producer. PMID- 24760824 TI - A bottom-up control on fresh-bedrock topography under landscapes. AB - The depth to unweathered bedrock beneath landscapes influences subsurface runoff paths, erosional processes, moisture availability to biota, and water flux to the atmosphere. Here we propose a quantitative model to predict the vertical extent of weathered rock underlying soil-mantled hillslopes. We hypothesize that once fresh bedrock, saturated with nearly stagnant fluid, is advected into the near surface through uplift and erosion, channel incision produces a lateral head gradient within the fresh bedrock inducing drainage toward the channel. Drainage of the fresh bedrock causes weathering through drying and permits the introduction of atmospheric and biotically controlled acids and oxidants such that the boundary between weathered and unweathered bedrock is set by the uppermost elevation of undrained fresh bedrock, Zb. The slow drainage of fresh bedrock exerts a "bottom up" control on the advance of the weathering front. The thickness of the weathered zone is calculated as the difference between the predicted topographic surface profile (driven by erosion) and the predicted groundwater profile (driven by drainage of fresh bedrock). For the steady-state, soil-mantled case, a coupled analytical solution arises in which both profiles are driven by channel incision. The model predicts a thickening of the weathered zone upslope and, consequently, a progressive upslope increase in the residence time of bedrock in the weathered zone. Two nondimensional numbers corresponding to the mean hillslope gradient and mean groundwater-table gradient emerge and their ratio defines the proportion of the hillslope relief that is unweathered. Field data from three field sites are consistent with model predictions. PMID- 24760825 TI - E3 ubiquitin ligase Cullin-5 modulates multiple molecular and cellular responses to heat shock protein 90 inhibition in human cancer cells. AB - The molecular chaperone heat shock protein 90 (HSP90) is required for the activity and stability of its client proteins. Pharmacologic inhibition of HSP90 leads to the ubiquitin-mediated degradation of clients, particularly activated or mutant oncogenic protein kinases. Client ubiquitination occurs via the action of one or more E3 ubiquitin ligases. We sought to identify the role of Cullin-RING family E3 ubiquitin ligases in the cellular response to HSP90 inhibition. Through a focused siRNA screen of 28 Cullin-RING ligase family members, we found that CUL5 and RBX2 were required for degradation of several HSP90 clients upon treatment of human cancer cells with the clinical HSP90 inhibitor 17-AAG. Surprisingly, silencing Cullin-5 (CUL5) also delayed the earlier loss of HSP90 client protein activity at the same time as delaying cochaperone dissociation from inhibited HSP90-client complexes. Expression of a dominant-negative CUL5 showed that NEDD8 conjugation of CUL5 is required for client degradation but not for loss of client activity or recruitment of clients and HSP90 to CUL5. Silencing CUL5 reduced cellular sensitivity to three distinct HSP90 inhibitors, across four cancer types driven by different protein kinases. Our results reveal the importance of CUL5 in multiple aspects of the cellular response to HSP90 inhibition. PMID- 24760826 TI - Natural insertions in rice commonly form tandem duplications indicative of patch mediated double-strand break induction and repair. AB - The insertion of DNA into a genome can result in the duplication and dispersal of functional sequences through the genome. In addition, a deeper understanding of insertion mechanisms will inform methods of genetic engineering and plant transformation. Exploiting structural variations in numerous rice accessions, we have inferred and analyzed intermediate length (10-1,000 bp) insertions in plants. Insertions in this size class were found to be approximately equal in frequency to deletions, and compound insertion-deletions comprised only 0.1% of all events. Our findings indicate that, as observed in humans, tandem or partially tandem duplications are the dominant form of insertion (48%), although short duplications from ectopic donors account for a sizable fraction of insertions in rice (38%). Many nontandem duplications contain insertions from nearby DNA (within 200 bp) and can contain multiple donor sources--some distant- in single events. Although replication slippage is a plausible explanation for tandem duplications, the end homology required in such a model is most often absent and rarely is >5 bp. However, end homology is commonly longer than expected by chance. Such findings lead us to favor a model of patch-mediated double-strand-break creation followed by nonhomologous end-joining. Additionally, a striking bias toward 31-bp partially tandem duplications suggests that errors in nucleotide excision repair may be resolved via a similar, but distinct, pathway. In summary, the analysis of recent insertions in rice suggests multiple underappreciated causes of structural variation in eukaryotes. PMID- 24760828 TI - Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A. AB - Lytic immune effector function depends upon directed secretion of cytolytic granules at the immunological synapse (IS) and requires dynamic rearrangement of filamentous (F)-actin. Coronin 1A (Coro1A) is the hematopoietic-specific member of the Coronin family of actin regulators that promote F-actin disassembly. Here, we show that Coro1A is required for natural killer (NK) cell cytotoxic function in two human NK cell lines and ex vivo cells from a Coro1A-deficient patient. Using superresolution nanoscopy to probe the IS, we demonstrate that Coro1A promotes the deconstruction of F-actin density that facilitates effective delivery of lytic granules to the IS. Thus, we show, for the first time to our knowledge, a critical role for F-actin deconstruction in cytotoxic function and immunological secretion and identify Coro1A as its mediator. PMID- 24760829 TI - Single-molecule analysis reveals human UV-damaged DNA-binding protein (UV-DDB) dimerizes on DNA via multiple kinetic intermediates. AB - How human DNA repair proteins survey the genome for UV-induced photoproducts remains a poorly understood aspect of the initial damage recognition step in nucleotide excision repair (NER). To understand this process, we performed single molecule experiments, which revealed that the human UV-damaged DNA-binding protein (UV-DDB) performs a 3D search mechanism and displays a remarkable heterogeneity in the kinetics of damage recognition. Our results indicate that UV DDB examines sites on DNA in discrete steps before forming long-lived, nonmotile UV-DDB dimers (DDB1-DDB2)2 at sites of damage. Analysis of the rates of dissociation for the transient binding molecules on both undamaged and damaged DNA show multiple dwell times over three orders of magnitude: 0.3-0.8, 8.1, and 113-126 s. These intermediate states are believed to represent discrete UV-DDB conformers on the trajectory to stable damage detection. DNA damage promoted the formation of highly stable dimers lasting for at least 15 min. The xeroderma pigmentosum group E (XP-E) causing K244E mutant of DDB2 found in patient XP82TO, supported UV-DDB dimerization but was found to slide on DNA and failed to stably engage lesions. These findings provide molecular insight into the loss of damage discrimination observed in this XP-E patient. This study proposes that UV-DDB recognizes lesions via multiple kinetic intermediates, through a conformational proofreading mechanism. PMID- 24760831 TI - Charge gradient microscopy. AB - Here we present a simple and fast method to reliably image polarization charges using charge gradient microscopy (CGM). We collected the current from the grounded CGM probe while scanning a periodically poled lithium niobate single crystal and single-crystal LiTaO3 thin film on the Cr electrode. We observed current signals at the domains and domain walls originating from the displacement current and the relocation or removal of surface charges, which enabled us to visualize the ferroelectric domains at a scan frequency above 78 Hz over 10 MUm. We envision that CGM can be used in high-speed ferroelectric domain imaging and piezoelectric energy-harvesting devices. PMID- 24760830 TI - Structure of a mitochondrial cytochrome c conformer competent for peroxidase activity. AB - At the onset of apoptosis, the peroxidation of cardiolipin at the inner mitochondrial membrane by cytochrome c requires an open coordination site on the heme. We report a 1.45-A resolution structure of yeast iso-1-cytochrome c with the Met80 heme ligand swung out of the heme crevice and replaced by a water molecule. This conformational change requires modest adjustments to the main chain of the heme crevice loop and is facilitated by a trimethyllysine 72-to alanine mutation. This mutation also enhances the peroxidase activity of iso-1 cytochrome c. The structure shows a buried water channel capable of facilitating peroxide access to the active site and of moving protons produced during peroxidase activity to the protein surface. Alternate positions of the side chain of Arg38 appear to mediate opening and closing of the buried water channel. In addition, two buried water molecules can adopt alternate positions that change the network of hydrogen bonds in the buried water channel. Taken together, these observations suggest that low and high proton conductivity states may mediate peroxidase function. Comparison of yeast and mammalian cytochrome c sequences, in the context of the steric factors that permit opening of the heme crevice, suggests that higher organisms have evolved to inhibit peroxidase activity, providing a more stringent barrier to the onset of apoptosis. PMID- 24760832 TI - Therapeutic epitopes of Leptospira LipL32 protein and their characteristics. AB - Two LipL32-specific mouse monoclonal antibodies (mAbLPF1 and mAbLPF2) which neutralized Leptospira-mediated hemolysis in vitro and rescued hamsters from lethal Leptospira infection were produced. In this communication, locations and characteristics of the protective epitopes of the mAbs were studied by using a truncated LipL32 recombinant protein based-immunoassay and phage consensus mimotope identification and multiple alignments. The mAbLPF1 epitope consisted of P243, L244, I245, H246, L252 and Q253 on the LipL32 protein; it is mapped on the surface-exposed region of non-continuous beta13-turn and C-terminal amphipathic alpha6 helix with hydrophobic patch, contributing to phospholipid/host cell adhesion and membrane insertion on one side, and hydrophilic, acidic and basic amino acid residues on another side. The epitope peptide of the mAbLPF2 is linear 122PEEKSMPHW130 and located on surface-exposed alpha1 and alpha2 between beta7 and beta8 that bound to several host constituents. Both epitopes are highly conserved among the pathogenic and intermediately pathogenic Leptospira spp. and are absent from the LipL32 superfamily proteins of other microorganisms. This study not only enlightens the molecular mechanisms of the therapeutic mAbLPF1 and mAbLPF2, but also elaborates the potential of the two LipL32 regions as diagnostic and vaccine targets for leptospirosis. PMID- 24760833 TI - The neural correlates of working memory impairment in attention deficit/hyperactivity disorder. PMID- 24760834 TI - Progressive degeneration of dopaminergic neurons through TRP channel-induced cell death. AB - Progressive neurodegenerative diseases are among the most frequently occurring aging-associated human pathologies. In a screen for Caenorhabditis elegans mutant animals that lack their normal complement of dopaminergic neurons, we identified two strains with progressive loss of dopaminergic neurons during postembryonic life. Through whole-genome sequencing we show that both strains harbor dominant (d), gain-of-function mutations in the Transient Receptor Potential (TRP) mechanosensory channel trp-4, a member of the invertebrate and vertebrate TRPN type of the TRP family channels. Gain-of-function mutations in TRP channels have not been previously implicated in dopaminergic neuronal degeneration. We show that trp-4(d) induces cell death in dopamine neurons through a defined, calcium related downstream pathway. PMID- 24760836 TI - Nerve injury-induced neuropathic pain causes disinhibition of the anterior cingulate cortex. AB - Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. We performed multiple whole-cell recordings from neurons in layer 5 (L5) of the ACC of adult mice after chronic constriction injury of the sciatic nerve of the left hindpaw and observed a striking loss of connections between excitatory and inhibitory neurons in both directions. In contrast, no significant changes in synaptic efficacy in the remaining connected pairs were found. These changes were reflected on the network level by a decrease in the mEPSC and mIPSC frequency. Additionally, nerve injury resulted in a potentiation of the intrinsic excitability of pyramidal neurons, whereas the cellular properties of interneurons were unchanged. Our set of experimental parameters allowed constructing a neuronal network model of L5 in the ACC, revealing that the modification of inhibitory connectivity had the most profound effect on increased network activity. Thus, our combined experimental and modeling approach suggests that cortical disinhibition is a fundamental pathological modification associated with peripheral nerve damage. These changes at the cortical network level might therefore contribute to the neuropathic pain condition. PMID- 24760835 TI - Pain reduces sexual motivation in female but not male mice. AB - Chronic pain is often associated with sexual dysfunction, suggesting that pain can reduce libido. We find that inflammatory pain reduces sexual motivation, measured via mounting behavior and/or proximity in a paced mating paradigm, in female but not male laboratory mice. Pain was produced by injection of inflammogens zymosan A (0.5 mg/ml) or lambda-carrageenan (2%) into genital or nongenital (hind paw, tail, cheek) regions. Sexual behavior was significantly reduced in female mice experiencing pain (in all combinations); male mice similarly treated displayed unimpeded sexual motivation. Pain-induced reductions in female sexual behavior were observed in the absence of sex differences in pain related behavior, and could be rescued by the analgesic, pregabalin, and the libido-enhancing drugs, apomorphine and melanotan-II. These findings suggest that the well known context sensitivity of the human female libido can be explained by evolutionary rather than sociocultural factors, as female mice can be similarly affected. PMID- 24760837 TI - Role of GluK1 kainate receptors in seizures, epileptic discharges, and epileptogenesis. AB - Kainate receptors containing the GluK1 subunit have an impact on excitatory and inhibitory neurotransmission in brain regions, such as the amygdala and hippocampus, which are relevant to seizures and epilepsy. Here we used 2-amino-3 (3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a potent and selective agonist of kainate receptors that include the GluK1 subunit, in conjunction with mice deficient in GluK1 and GluK2 kainate receptor subunits to assess the role of GluK1 kainate receptors in provoking seizures and in kindling epileptogenesis. We found that systemic ATPA, acting specifically via GluK1 kainate receptors, causes locomotor arrest and forelimb extension (a unique behavioral characteristic of GluK1 activation) and induces myoclonic behavioral seizures and electrographic seizure discharges in the BLA and hippocampus. In contrast, the proconvulsant activity of systemic AMPA, kainate, and pentylenetetrazol is not mediated by GluK1 kainate receptors, and deletion of these receptors does not elevate the threshold for seizures in the 6 Hz model. ATPA also specifically activates epileptiform discharges in BLA slices in vitro via GluK1 kainate receptors. Olfactory bulb kindling developed similarly in wild type, GluK1, and GluK2 knock-out mice, demonstrating that GluK1 kainate receptors are not required for epileptogenesis or seizure expression in this model. We conclude that selective activation of kainate receptors containing the GluK1 subunit can trigger seizures, but these receptors are not necessary for seizure generation in models commonly used to identify therapeutic agents for the treatment of epilepsy. PMID- 24760838 TI - Crtc1 activates a transcriptional program deregulated at early Alzheimer's disease-related stages. AB - Cognitive decline is associated with gene expression changes in the brain, but the transcriptional mechanisms underlying memory impairments in cognitive disorders, such as Alzheimer's disease (AD), are largely unknown. Here, we aimed to elucidate relevant mechanisms responsible for transcriptional changes underlying early memory loss in AD by examining pathological, behavioral, and transcriptomic changes in control and mutant beta-amyloid precursor protein (APPSw,Ind) transgenic mice during aging. Genome-wide transcriptome analysis using mouse microarrays revealed deregulation of a gene network related with neurotransmission, synaptic plasticity, and learning/memory in the hippocampus of APPSw,Ind mice after spatial memory training. Specifically, APPSw,Ind mice show changes on a cAMP-responsive element binding protein (CREB)-regulated transcriptional program dependent on the CREB-regulated transcription coactivator 1 (Crtc1). Interestingly, synaptic activity and spatial memory induces Crtc1 dephosphorylation (Ser151), nuclear translocation, and Crtc1-dependent transcription in the hippocampus, and these events are impaired in APPSw,Ind mice at early pathological and cognitive decline stages. CRTC1-dependent genes and CRTC1 levels are reduced in human hippocampus at intermediate Braak III/IV pathological stages. Importantly, adeno-associated viral-mediated Crtc1 overexpression in the hippocampus efficiently reverses Abeta-induced spatial learning and memory deficits by restoring a specific subset of Crtc1 target genes. Our results reveal a critical role of Crtc1-dependent transcription on spatial memory formation and provide the first evidence that targeting brain transcriptome reverses memory loss in AD. PMID- 24760839 TI - Continuous postnatal neurogenesis contributes to formation of the olfactory bulb neural circuits and flexible olfactory associative learning. AB - The olfactory bulb (OB) is one of the two major loci in the mammalian brain where newborn neurons are constantly integrated into the neural circuit during postnatal life. Newborn neurons are generated from neural stem cells in the subventricular zone (SVZ) of the lateral ventricle and migrate to the OB through the rostral migratory stream. The majority of these newborn neurons differentiate into inhibitory interneurons, such as granule cells and periglomerular cells. It has been reported that prolonged supply of newborn neurons leads to continuous addition/turnover of the interneuronal populations and contributes to functional integrity of the OB circuit. However, it is not still clear how and to what extent postnatal-born neurons contribute to OB neural circuit formation, and the functional role of postnatal neurogenesis in odor-related behaviors remains elusive. To address this question, here by using genetic strategies, we first determined the unique integration mode of newly born interneurons during postnatal development of the mouse OB. We then manipulated these interneuron populations and found that continuous postnatal neurogenesis in the SVZ-OB plays pivotal roles in flexible olfactory associative learning and memory. PMID- 24760841 TI - The brain's temporal dynamics from a collective decision to individual action. AB - Social animals constantly make decisions together. What determines if individuals will subsequently adjust their behavior to align with collective choices? Here, using functional magnetic resonance imaging in humans, we characterize a novel temporal model of brain response from the time a collective decision is made to the time an individual action is required. We reveal that whether a behavioral modification will occur is determined not necessarily by the brain's response to the initial social influence, but by how that response (specifically in the orbitofrontal cortex; OFC) is mirrored at a later time when the individual selects their own action. This result suggests that the OFC may reconstitute an initial state of collective influence when individual action is subsequently needed. Importantly, these dynamics vary across individuals as a function of trait conformity and mediate the relationship between this personality characteristic and behavioral adjustment toward the group. PMID- 24760840 TI - Expression of Nampt in hippocampal and cortical excitatory neurons is critical for cognitive function. AB - Nicotinamide adenine dinucleotide (NAD(+)) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD(+) has been unclear. NAD(+) can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD(+) biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD(+) biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIalphaNampt(-/-) mice). CaMKIIalphaNampt(-/-) mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2-3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD(+) biosynthesis to mediate their survival and function. Studying this particular NAD(+) biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation. PMID- 24760842 TI - Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3alpha,5alpha-THP and reduces long-term operant ethanol self-administration. AB - Neuroactive steroids are endogenous neuromodulators capable of altering neuronal activity and behavior. In rodents, systemic administration of endogenous or synthetic neuroactive steroids reduces ethanol self-administration. We hypothesized this effect arises from actions within mesolimbic brain regions that we targeted by viral gene delivery. Cytochrome P450 side chain cleavage (P450scc) converts cholesterol to pregnenolone, the rate-limiting enzymatic reaction in neurosteroidogenesis. Therefore, we constructed a recombinant adeno-associated serotype 2 viral vector (rAAV2), which drives P450scc expression and neuroactive steroid synthesis. The P450scc-expressing vector (rAAV2-P450scc) or control GFP expressing vector (rAAV2-GFP) were injected bilaterally into the ventral tegmental area (VTA) or nucleus accumbens (NAc) of alcohol preferring (P) rats trained to self-administer ethanol. P450scc overexpression in the VTA significantly reduced ethanol self-administration by 20% over the 3 week test period. P450scc overexpression in the NAc, however, did not alter ethanol self administration. Locomotor activity was unaltered by vector administration to either region. P450scc overexpression produced a 36% increase in (3alpha,5alpha) 3-hydroxypregnan-20-one (3alpha,5alpha-THP, allopregnanolone)-positive cells in the VTA, but did not increase 3alpha,5alpha-THP immunoreactivity in NAc. These results suggest that P450scc overexpression and the resultant increase of 3alpha,5alpha-THP-positive cells in the VTA reduces ethanol reinforcement. 3alpha,5alpha-THP is localized to neurons in the VTA, including tyrosine hydroxylase neurons, but not astrocytes. Overall, the results demonstrate that using gene delivery to modulate neuroactive steroids shows promise for examining the neuronal mechanisms of moderate ethanol drinking, which could be extended to other behavioral paradigms and neuropsychiatric pathology. PMID- 24760843 TI - Motion integration for ocular pursuit does not hinder perceptual segregation of moving objects. AB - When confronted with a complex moving stimulus, the brain can integrate local element velocities to obtain a single motion signal, or segregate the elements to maintain awareness of their identities. The integrated motion signal can drive smooth-pursuit eye movements (Heinen and Watamaniuk, 1998), whereas the segregated signal guides attentive tracking of individual elements in multiple object tracking tasks (MOT; Pylyshyn and Storm, 1988). It is evident that these processes can occur simultaneously, because we can effortlessly pursue ambulating creatures while inspecting disjoint moving features, such as arms and legs, but the underlying mechanism is unknown. Here, we provide evidence that separate neural circuits perform the mathematically opposed operations of integration and segregation, by demonstrating with a dual-task paradigm that the two processes do not share attentional resources. Human observers attentively tracked a subset of target elements composing a small MOT stimulus, while pursuing it ocularly as it translated across a computer display. Integration of the multidot stimulus yielded optimal pursuit. Importantly, performing MOT while pursuing the stimulus did not degrade performance on either task compared with when each was performed alone, indicating that they did not share attention. A control experiment showed that pursuit was not driven by integration of only the nontargets, leaving the MOT targets free for segregation. Nor was a predictive strategy used to pursue the stimulus, because sudden changes in its global velocity were accurately followed. The results suggest that separate neural mechanisms can simultaneously segregate and integrate the same motion signals. PMID- 24760845 TI - Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder. AB - The ventral tegmental area (VTA) has been primarily implicated in reward motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS +/-20%, +/-40%, and +/-60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety. PMID- 24760844 TI - Developmental changes in the organization of functional connections between the basal ganglia and cerebral cortex. AB - The basal ganglia (BG) comprise a set of subcortical nuclei with sensorimotor, cognitive, and limbic subdivisions, indicative of functional organization. BG dysfunction in several developmental disorders suggests the importance of the healthy maturation of these structures. However, few studies have investigated the development of BG functional organization. Using resting-state functional connectivity MRI (rs-fcMRI), we compared human child and adult functional connectivity of the BG with rs-fcMRI-defined cortical systems. Because children move more than adults, customized preprocessing, including volume censoring, was used to minimize motion-induced rs-fcMRI artifact. Our results demonstrated functional organization in the adult BG consistent with subdivisions previously identified in anatomical tracing studies. Group comparisons revealed a developmental shift in bilateral posterior putamen/pallidum clusters from preferential connectivity with the somatomotor "face" system in childhood to preferential connectivity with control/attention systems (frontoparietal, ventral attention) in adulthood. This shift was due to a decline in the functional connectivity of these clusters with the somatomotor face system over development, and no change with control/attention systems. Applying multivariate pattern analysis, we were able to reliably classify individuals as children or adults based on BG-cortical system functional connectivity. Interrogation of the features driving this classification revealed, in addition to the somatomotor face system, contributions by the orbitofrontal, auditory, and somatomotor hand systems. These results demonstrate that BG-cortical functional connectivity evolves over development, and may lend insight into developmental disorders that involve BG dysfunction, particularly those involving motor systems (e.g., Tourette syndrome). PMID- 24760846 TI - Activation of dopaminergic D2/D3 receptors modulates dorsoventral connectivity in the hippocampus and reverses the impairment of working memory after nerve injury. AB - Dopamine plays an important role in several forms of synaptic plasticity in the hippocampus, a crucial brain structure for working memory (WM) functioning. In this study, we evaluated whether the working-memory impairment characteristic of animal models of chronic pain is dependent on hippocampal dopaminergic signaling. To address this issue, we implanted multichannel arrays of electrodes in the dorsal and ventral hippocampal CA1 region of rats and recorded the neuronal activity during a food-reinforced spatial WM task of trajectory alternation. Within-subject behavioral performance and patterns of dorsoventral neuronal activity were assessed before and after the onset of persistent neuropathic pain using the Spared Nerve Injury (SNI) model of neuropathic pain. Our results show that the peripheral nerve lesion caused a disruption in WM and in hippocampus spike activity and that this disruption was reversed by the systemic administration of the dopamine D2/D3 receptor agonist quinpirole (0.05 mg/kg). In SNI animals, the administration of quinpirole restored both the performance related and the task-related spike activity to the normal range characteristic of naive animals, whereas quinpirole in sham animals caused the opposite effect. Quinpirole also reversed the abnormally low levels of hippocampus dorsoventral connectivity and phase coherence. Together with our finding of changes in gene expression of dopamine receptors and modulators after the onset of the nerve injury model, these results suggest that disruption of the dopaminergic balance in the hippocampus may be crucial for the clinical neurological and cognitive deficits observed in patients with painful syndromes. PMID- 24760847 TI - Valence-specific effects of BDNF Val66Met polymorphism on dopaminergic stress and reward processing in humans. AB - Brain-derived neurotrophic factor (BDNF) levels in dopaminergic (DA) cells within the ventral tegmental area (VTA)/nucleus accumbens (NAc) circuitry appear to be a candidate mechanism for the neuroadaptive changes that follow stress and reward responses in animal models. However, the role of the BDNF gene variants in responses to salient cues through DA neurotransmission in humans remains unexplored. Here, we studied the effect of the common functional BDNF Val(66)Met (rs6265) polymorphism on rewarding experiences in the striatum and DA-mediated responses to stress. Seventy-two healthy controls were genotyped for the BDNF Val(66)Met polymorphism and underwent the monetary incentive delay task during an functional magnetic resonance imaging (fMRI) session. Forty-nine of them also underwent a sustained pain challenge with and without placebo administration with potential analgesic properties during PET measures of DA D2/3-receptor-mediated neurotransmission. Neuroimaging results revealed a significant effect of BDNF (Met(66) carriers > Val/Val) on brain responses during the anticipation of monetary losses, baseline D2/3 receptor availability, and pain-stress-induced DA release in the NAc. Conversely, BDNF Met(66) carriers showed no activation in response to monetary gains and a blunted DA response to the analgesic placebo in the NAc. These results provide initial human evidence regarding the effect of the BDNF Val(66)Met polymorphism on DA-mediated responses to stress, its cognitive regulation by positive expectations, and the anticipatory responses to monetary gains and losses in the VTA-NAc pathway. Our results are of relevance to the neurobiology of stress and reward interactions and the pathophysiology of stress related disorders. PMID- 24760848 TI - Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling. AB - A persistent and nonresolving inflammatory response to accumulating Abeta peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Abeta peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Abeta-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Abeta42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Abeta42-induced inflammatory factors and potentiated phagocytosis of Abeta42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Abeta42 driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-kappaB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1DeltaE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Abeta deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology. PMID- 24760850 TI - Source-reconstruction of event-related fields reveals hyperfunction and hypofunction of cortical circuits in antipsychotic-naive, first-episode schizophrenia patients during Mooney face processing. AB - Schizophrenia is characterized by dysfunctions in neural circuits that can be investigated with electrophysiological methods, such as EEG and MEG. In the present human study, we examined event-related fields (ERFs), in a sample of medication-naive, first-episode schizophrenia (FE-ScZ) patients (n = 14) and healthy control participants (n = 17) during perception of Mooney faces to investigate the integrity of neuromagnetic responses and their experience dependent modification. ERF responses were analyzed for M100, M170, and M250 components at the sensor and source levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 responses in FE-ScZ were within the normal range, whereas the M250 response was impaired. However, source localization revealed widespread elevated activity for M100 and M170 in FE-ScZ and delayed peak latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated by stimulus repetitions. The present findings suggest that neural circuits in FE-ScZ may be characterized by a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and abnormal spreading of activity, which is compatible with dysfunctional glutamatergic neurotransmission. PMID- 24760851 TI - Apathy in Parkinson's disease: neurophysiological evidence of impaired incentive processing. AB - Apathy is one of the most common and debilitating nonmotor manifestations of Parkinson's disease (PD) and is characterized by diminished motivation, decreased goal-directed behavior, and flattened affect. Despite its high prevalence, its underlying mechanisms are still poorly understood, having been associated with executive dysfunction, and impaired emotional processing and decision making. Apathy, as a syndrome, has recently been associated with reduced activation in the ventral striatum, suggesting that early- to middle-stage Parkinson's disease patients with this manifestation may have a compromised mesocorticolimbic dopaminergic pathway and impaired incentive processing. To test this hypothesis, we measured the amplitude of the feedback-related negativity, an event-related brain potential associated with performance outcome valence, following monetary gains and losses in human PD patients (12 women) and healthy controls (6 women) performing a gambling task. Early- to middle-stage PD patients presenting clinically meaningful symptoms of apathy were compared with nonapathetic PD patients and healthy controls. Patients with cognitive impairment, depression, and other psychiatric disturbances were excluded. Results showed that the amplitude of the feedback-related negativity, measured as the difference wave in the event-related brain potential between gains and losses, was significantly reduced in PD patients with apathy compared with nonapathetic patients and healthy controls. These findings indicate impaired incentive processing and suggest a compromised mesocorticolimbic pathway in cognitively intact PD patients with apathy. PMID- 24760849 TI - The role of Arp2/3 in growth cone actin dynamics and guidance is substrate dependent. AB - During development extrinsic guidance cues modulate the peripheral actin network in growth cones to direct axons to their targets. We wanted to understand the role of the actin nucleator Arp2/3 in growth cone actin dynamics and guidance. Since growth cones migrate in association with diverse adhesive substrates during development, we probed the hypothesis that the functional significance of Arp2/3 is substrate dependent. We report that Arp2/3 inhibition led to a reduction in the number of filopodia and growth cone F-actin content on laminin and L1. However, we found substrate-dependent differences in growth cone motility, actin retrograde flow, and guidance after Arp2/3 inhibition, suggesting that its role, and perhaps that of other actin binding proteins, in growth cone motility is substrate dependent. PMID- 24760852 TI - LMTK3 deficiency causes pronounced locomotor hyperactivity and impairs endocytic trafficking. AB - LMTK3 belongs to the LMTK family of protein kinases that are predominantly expressed in the brain. Physiological functions of LMTK3 and other members of the LMTK family in the CNS remain unknown. In this study, we performed a battery of behavioral analyses using Lmtk3(-/-) mice and showed that these mice exhibit abnormal behaviors, including pronounced locomotor hyperactivity, reduced anxiety behavior, and decreased depression-like behavior. Concurrently, the dopamine metabolite levels and dopamine turnover rate are increased in the striata of Lmtk3(-/-) mice compared with wild-type controls. In addition, using cultured primary neurons from Lmtk3(-/-) mice, we found that LMTK3 is involved in the endocytic trafficking of N-methyl-d-aspartate receptors, a type of ionotropic glutamate receptor. Altered membrane traffic of the receptor in Lmtk3(-/-) neurons may underlie behavioral abnormalities in the mutant animals. Together, our data suggest that LMTK3 plays an important role in regulating locomotor behavior in mice. PMID- 24760853 TI - Corticostriatal coordination through coherent phase-amplitude coupling. AB - The corticostriatal axis is the main input stage of the basal ganglia and is crucial for their role in motor behavior. Synchronized oscillations might mediate interactions between cortex and striatum during behavior, yet direct evidence remains sparse. Here, we show that, during motor behavior, low- and high frequency oscillations jointly couple cortex and striatum via cross-frequency interactions. We investigated neuronal oscillations along the corticostriatal axis in rats during rest and treadmill running. We found prominent theta and gamma oscillations in cortex and striatum, the peak frequencies of which scaled with motor demand. Theta and gamma oscillations were functionally coupled through phase-amplitude coupling. Furthermore, theta oscillations were phase coupled between structures. Together, local phase-amplitude coupling and corticostriatal theta phase coupling mediated the temporal correlation of gamma bursts between the cortex and striatum. The coordination of fast oscillations through coherent phase-amplitude coupling may be a general mechanism to regulate neuronal interactions along the corticostriatal axis and beyond. PMID- 24760854 TI - Slow oscillations in the mouse hippocampus entrained by nasal respiration. AB - Different types of network oscillations occur in different behavioral, cognitive, or vigilance states. The rodent hippocampus expresses prominent theta oscillations at frequencies between 4 and 12 Hz, which are superimposed by phase coupled gamma oscillations (30-100 Hz). These patterns entrain multineuronal activity over large distances and have been implicated in sensory information processing and memory formation. Here we report a new type of oscillation at near theta frequencies (2-4 Hz) in the hippocampus of urethane-anesthetized mice. The rhythm is highly coherent with nasal respiration and with rhythmic field potentials in the olfactory bulb: hence, we called it hippocampal respiration induced oscillations. Despite the similarity in frequency range, several features distinguish this pattern from locally generated theta oscillations: hippocampal respiration-induced oscillations have a unique laminar amplitude profile, are resistant to atropine, couple differently to gamma oscillations, and are abolished when nasal airflow is bypassed by tracheotomy. Hippocampal neurons are entrained by both the respiration-induced rhythm and concurrent theta oscillations, suggesting a direct interaction between endogenous activity in the hippocampus and nasal respiratory inputs. Our results demonstrate that nasal respiration strongly modulates hippocampal network activity in mice, providing a long-range synchronizing signal between olfactory and hippocampal networks. PMID- 24760855 TI - CNS axons globally increase axonal transport after peripheral conditioning. AB - Despite the inability of CNS axons to regenerate, an increased regenerative capacity can be elicited following conditioning lesion to the peripheral branch of dorsal root ganglia neurons (DRGs). By in vivo radiolabeling of rat DRGs, coupled to mass spectrometry and kinesin immunoprecipitation of spinal cord extracts, we determined that the anterograde transport of cytoskeleton components, metabolic enzymes and axonal regeneration enhancers, was increased in the central branch of DRGs following a peripheral conditioning lesion. Axonal transport of mitochondria was also increased in the central branch of Thy1 MitoCFP mice following a peripheral injury. This effect was generalized and included augmented transport of lysosomes and synaptophysin- and APP-carrying vesicles. Changes in axonal transport were only elicited by a peripheral lesion and not by spinal cord injury. In mice, elevated levels of motors and of polyglutamylated and tyrosinated tubulin were present following a peripheral lesion and can explain the increase in axonal transport induced by conditioning. In summary, our work shows that a peripheral injury induces a global increase in axonal transport that is not restricted to the peripheral branch, and that, by extending to the central branch, allows a rapid and sustained support of regenerating central axons. PMID- 24760856 TI - Decoding ventromedial hypothalamic neural activity during male mouse aggression. AB - The ventromedial hypothalamus, ventrolateral area (VMHvl) was identified recently as a critical locus for inter-male aggression. Optogenetic stimulation of VMHvl in male mice evokes attack toward conspecifics and inactivation of the region inhibits natural aggression, yet very little is known about its underlying neural activity. To understand its role in promoting aggression, we recorded and analyzed neural activity in the VMHvl in response to a wide range of social and nonsocial stimuli. Although response profiles of VMHvl neurons are complex and heterogeneous, we identified a subpopulation of neurons that respond maximally during investigation and attack of male conspecific mice and during investigation of a source of male mouse urine. These "male responsive" neurons in the VMHvl are tuned to both the inter-male distance and the animal's velocity during attack. Additionally, VMHvl activity predicts several parameters of future aggressive action, including the latency and duration of the next attack. Linear regression analysis further demonstrates that aggression-specific parameters, such as distance, movement velocity, and attack latency, can model ongoing VMHvl activity fluctuation during inter-male encounters. These results represent the first effort to understand the hypothalamic neural activity during social behaviors using quantitative tools and suggest an important role for the VMHvl in encoding movement, sensory, and motivation-related signals. PMID- 24760858 TI - Alpha power gates relevant information during working memory updating. AB - Human working memory (WM) is inherently limited, so we must filter out irrelevant information in our environment or our mind while retaining limited important relevant contents. Previous work suggests that neural oscillations in the alpha band (8-14 Hz) play an important role in inhibiting incoming distracting information during attention and selective encoding tasks. However, whether alpha power is involved in inhibiting no-longer-relevant content or in representing relevant WM content is still debated. To clarify this issue, we manipulated the amount of relevant/irrelevant information using a task requiring spatial WM updating while measuring neural oscillatory activity via EEG and localized current sources across the scalp using a surface Laplacian transform. An initial memory set of two, four, or six spatial locations was to be memorized over a delay until an updating cue was presented indicating that only one or three locations remained relevant for a subsequent recognition test. Alpha amplitude varied with memory maintenance and updating demands among a cluster of left frontocentral electrodes. Greater postcue alpha power was associated with the high relevant load conditions (six and four dots cued to reduce to three relevant) relative to the lower load conditions (four and two dots reduced to one). Across subjects, this difference in alpha power was correlated with condition differences in performance accuracy. In contrast, no significant effects of irrelevant load were observed. These findings demonstrate that, during WM updating, alpha power reflects maintenance of relevant memory contents rather than suppression of no-longer-relevant memory traces. PMID- 24760857 TI - Modulation dynamics in the orofacial sensorimotor cortex during motor skill acquisition. AB - The orofacial sensorimotor cortex is known to play a role in motor learning. However, how motor learning changes the dynamics of neuronal activity and whether these changes differ between orofacial primary motor (MIo) and somatosensory (SIo) cortices remain unknown. To address these questions, we used chronically implanted microelectrode arrays to track learning-induced changes in the activity of simultaneously recorded neurons in MIo and SIo as two naive monkeys (Macaca mulatta) were trained in a novel tongue-protrusion task. Over a period of 8-12 d, the monkeys showed behavioral improvements in task performance that were accompanied by rapid and long-lasting changes in neuronal responses in MIo and SIo occurring in parallel: (1) increases in the proportion of task-modulated neurons, (2) increases in the mutual information between tongue-protrusive force and spiking activity, (3) reductions in the across-trial firing rate variability, and (4) transient increases in coherent firing of neuronal pairs. More importantly, the time-resolved mutual information in MIo and SIo exhibited temporal alignment. While showing parallel changes, MIo neurons exhibited a bimodal distribution of peak correlation lag times between spiking activity and force, whereas SIo neurons showed a unimodal distribution. Moreover, coherent activity between pairs of MIo neurons was higher and centered around force onset compared with pairwise coherence of SIo neurons. Overall, the results suggest that the neuroplasticity in MIo and SIo occurring in parallel serves as a substrate for linking sensation and movement during sensorimotor learning, whereas the differing dynamic organizations reflect specific ways to control movement parameters as learning progresses. PMID- 24760859 TI - Effects of hippocampal state-contingent trial presentation on hippocampus dependent nonspatial classical conditioning and extinction. AB - Hippocampal local field potentials are characterized by two mutually exclusive states: one characterized by regular theta oscillations (~4-8 Hz) and the other by irregular sharp-wave ripples. Presenting stimuli during dominant theta oscillations leads to expedited learning, suggesting that theta indexes a state in which encoding is most effective. However, ripple-contingent training also expedites learning, suggesting that any discrete brain state, much like the external context, can affect learning. We trained adult rabbits in trace eyeblink conditioning, a hippocampus-dependent nonspatial task, followed by extinction. Trials were delivered either in the presence or absence of theta or regardless of hippocampal state. Conditioning in the absence of theta led to more animals learning, although learning was slower compared with a yoked control group. Contrary to expectations, conditioning in the presence of theta did not affect learning. However, extinction was expedited both when it was conducted contingent on theta and when it was conducted in a state contrary to that used to trigger trials during conditioning. Strong phase-locking of hippocampal theta-band responses to the conditioned stimulus early on during conditioning predicted good learning. No such connection was observed during extinction. Our results suggest that any consistent hippocampal oscillatory state can potentially be used to regulate learning. However, the effects depend on the specific state and task at hand. Finally, much like the external environment, the ongoing neural state appears to act as a context for learning and memory retrieval. PMID- 24760860 TI - Motor cortical correlates of arm resting in the context of a reaching task and implications for prosthetic control. AB - Prosthetic devices are being developed to restore movement for motor-impaired individuals. A robotic arm can be controlled based on models that relate motor cortical ensemble activity to kinematic parameters. The models are typically built and validated on data from structured trial periods during which a subject actively performs specific movements, but real-world prosthetic devices will need to operate correctly during rest periods as well. To develop a model of motor cortical modulation during rest, we trained monkeys (Macaca mulatta) to perform a reaching task with their own arm while recording motor-cortical single-unit activity. When a monkey spontaneously put its arm down to rest between trials, our traditional movement decoder produced a nonzero velocity prediction, which would cause undesired motion when applied to a prosthetic arm. During these rest periods, a marked shift was found in individual units' tuning functions. The activity pattern of the whole population during rest (Idle state) was highly distinct from that during reaching movements (Active state), allowing us to predict arm resting from instantaneous firing rates with 98% accuracy using a simple classifier. By cascading this state classifier and the movement decoder, we were able to predict zero velocity correctly, which would avoid undesired motion in a prosthetic application. Interestingly, firing rates during hold periods followed the Active pattern even though hold kinematics were similar to those during rest with near-zero velocity. These findings expand our concept of motor-cortical function by showing that population activity reflects behavioral context in addition to the direct parameters of the movement itself. PMID- 24760861 TI - Optogenetic-mediated release of histamine reveals distal and autoregulatory mechanisms for controlling arousal. AB - Histaminergic neurons in the tuberomammillary nucleus (TMN) are an important component of the ascending arousal system and may form part of a "flip-flop switch" hypothesized to regulate sleep and wakefulness. Anatomical studies have shown that the wake-active TMN and sleep-active ventrolateral preoptic nucleus (VLPO) are reciprocally connected, suggesting that each region can inhibit its counterpart when active. In this study, we determined how histamine affects the two branches of this circuit. We selectively expressed channelrhodopsin-2 (ChR2) in TMN neurons and used patch-clamp recordings in mouse brain slices to examine the effects of photo-evoked histamine release in the ventrolateral TMN and VLPO. Photostimulation decreased inhibitory GABAergic inputs to the ventrolateral TMN neurons but produced a membrane hyperpolarization and increased inhibitory synaptic input to the VLPO neurons. We found that in VLPO the response to histamine was indirect, most likely via a GABAergic interneuron. Our experiments demonstrate that release of histamine from TMN neurons can disinhibit the TMN and suppresses the activity of sleep-active VLPO neurons to promote TMN neuronal firing. This further supports the sleep-wake "flip-flop switch" hypothesis and a role for histamine in stabilizing the switch to favor wake states. PMID- 24760862 TI - Casein kinase 1 suppresses activation of REST in insulted hippocampal neurons and halts ischemia-induced neuronal death. AB - Repressor Element-1 (RE1) Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF) is a gene-silencing factor that is widely expressed during embryogenesis and plays a strategic role in neuronal differentiation. Recent studies indicate that REST can be activated in differentiated neurons during a critical window of time in postnatal development and in adult neurons in response to neuronal insults such as seizures and ischemia. However, the mechanism by which REST is regulated in neurons is as yet unknown. Here, we show that REST is controlled at the level of protein stability via beta-TrCP dependent, ubiquitin-based proteasomal degradation in differentiated neurons under physiological conditions and identify Casein Kinase 1 (CK1) as an upstream effector that bidirectionally regulates REST cellular abundance. CK1 associates with and phosphorylates REST at two neighboring, but distinct, motifs within the C terminus of REST critical for binding of beta-TrCP and targeting of REST for proteasomal degradation. We further show that global ischemia in rats in vivo triggers a decrease in CK1 and an increase in REST in selectively vulnerable hippocampal CA1 neurons. Administration of the CK1 activator pyrvinium pamoate by in vivo injection immediately after ischemia restores CK1 activity, suppresses REST expression, and rescues neurons destined to die. Our results identify a novel and previously unappreciated role for CK1 as a brake on REST stability and abundance in adult neurons and reveal that loss of CK1 is causally related to ischemia-induced neuronal death. These findings point to CK1 as a potential therapeutic target for the amelioration of hippocampal injury and cognitive deficits associated with global ischemia. PMID- 24760863 TI - Vasoactive intestinal polypeptide mediates circadian rhythms in mammalian olfactory bulb and olfaction. AB - Accumulating evidence suggests that the olfactory bulbs (OBs) function as an independent circadian system regulating daily rhythms in olfactory performance. However, the cells and signals in the olfactory system that generate and coordinate these circadian rhythms are unknown. Using real-time imaging of gene expression, we found that the isolated olfactory epithelium and OB, but not the piriform cortex, express similar, sustained circadian rhythms in PERIOD2 (PER2). In vivo, PER2 expression in the OB of mice is circadian, approximately doubling with a peak around subjective dusk. Furthermore, mice exhibit circadian rhythms in odor detection performance with a peak at approximately subjective dusk. We also found that circadian rhythms in gene expression and odor detection performance require vasoactive intestinal polypeptide (VIP) or its receptor VPAC2R. VIP is expressed, in a circadian manner, in interneurons in the external plexiform and periglomerular layers, whereas VPAC2R is expressed in mitral and external tufted cells in the OB. Together, these results indicate that VIP signaling modulates the output from the OB to maintain circadian rhythms in the mammalian olfactory system. PMID- 24760864 TI - Leptin-responsive GABAergic neurons regulate fertility through pathways that result in reduced kisspeptinergic tone. AB - The adipocyte-derived hormone leptin plays a critical role in the central transmission of energy balance to modulate reproductive function. However, the neurocircuitry underlying this interaction remains elusive, in part due to incomplete knowledge of first-order leptin-responsive neurons. To address this gap, we explored the contribution of predominantly inhibitory (GABAergic) neurons versus excitatory (glutamatergic) neurons in the female mouse by selective ablation of the leptin receptor in each neuronal population: Vgat Cre;Lepr(lox/lox) and Vglut2-Cre;Lepr(lox/lox) mice, respectively. Female Vgat Cre;Lepr(lox/lox) but not Vglut2-Cre;Lepr(lox/lox) mice were obese. Vgat Cre;Lepr(lox/lox) mice had delayed or absent vaginal opening, persistent diestrus, and atrophic reproductive tracts with absent corpora lutea. In contrast, Vglut2-Cre;Lepr(lox/lox) females exhibited reproductive maturation and function comparable to Lepr(lox/lox) control mice. Intracerebroventricular administration of kisspeptin-10 to Vgat-Cre;Lepr(lox/lox) female mice elicited robust gonadotropin responses, suggesting normal gonadotropin-releasing hormone neuronal and gonadotrope function. However, adult ovariectomized Vgat Cre;Lepr(lox/lox) mice displayed significantly reduced levels of Kiss1 (but not Tac2) mRNA in the arcuate nucleus, and a reduced compensatory luteinizing hormone increase compared with control animals. Estradiol replacement after ovariectomy inhibited gonadotropin release to a similar extent in both groups. These animals also exhibited a compromised positive feedback response to sex steroids, as shown by significantly lower Kiss1 mRNA levels in the AVPV, compared with Lepr(lox/lox) mice. We conclude that leptin-responsive GABAergic neurons, but not glutamatergic neurons, act as metabolic sensors to regulate fertility, at least in part through modulatory effects on kisspeptin neurons. PMID- 24760865 TI - Infralimbic BDNF/TrkB enhancement of GluN2B currents facilitates extinction of a cocaine-conditioned place preference. AB - Brain-derived neurotrophic factor (BDNF) regulates synaptic activity and behavioral flexibility, and reduction of BDNF strongly predicts psychiatric disorders and cognitive dysfunction. Restoration of BDNF-dependent activity could alleviate these impairments, but BDNF has limited clinical utility due to its pharmacokinetics. Here we demonstrate that activation of a primary BDNF target, the tropomyosin-related kinase B (TrkB) receptor, enhances the amplitude and prolongs the decay kinetics of N-methyl-d-aspartate receptor (NMDAR) currents in male rat infralimbic prefrontal pyramidal neurons. Moreover, these effects were prevented and reversed by blockade of NMDARs containing the GluN2B subunit. Our results show that this signaling cascade bidirectionally regulates extinction of a cocaine-induced conditioned place preference (CPP), a task that requires behavioral flexibility. Blockade of infralimbic TrkB receptors or GluN2B containing NMDARs disrupted consolidation of extinction of the CPP. In contrast, extinction was strengthened by potentiation of TrkB receptor activity with infralimbic infusions of BDNF or systemic injections of 7,8 dihydroxyflavone (7,8DHF), the newly synthesized TrkB receptor agonist. The 7,8DHF-induced enhancement of extinction was prevented by infralimbic infusions of a GluN2B specific receptor antagonist, demonstrating that TrkB receptor activation enhances extinction of cocaine-CPP via GluN2B-containing NMDARs. Together, infralimbic TrkB receptor activation strengthens GluN2B-containing NMDAR currents to support extinction learning. TrkB receptor agonists would therefore be useful as pharmacological adjuncts for extinction-based therapies for treatment of psychiatric disorders associated with reduced BDNF activity. PMID- 24760866 TI - The generation of antiphase oscillations and synchrony by a rebound-based vertebrate central pattern generator. AB - Many neural circuits are capable of generating multiple stereotyped outputs after different sensory inputs or neuromodulation. We have previously identified the central pattern generator (CPG) for Xenopus tadpole swimming that involves antiphase oscillations of activity between the left and right sides. Here we analyze the cellular basis for spontaneous left-right motor synchrony characterized by simultaneous bursting on both sides at twice the swimming frequency. Spontaneous synchrony bouts are rare in most tadpoles, and they instantly emerge from and switch back to swimming, most frequently within the first second after skin stimulation. Analyses show that only neurons that are active during swimming fire action potentials in synchrony, suggesting both output patterns derive from the same neural circuit. The firing of excitatory descending interneurons (dINs) leads that of other types of neurons in synchrony as it does in swimming. During synchrony, the time window between phasic excitation and inhibition is 7.9 +/- 1 ms, shorter than that in swimming (41 +/- 2.3 ms). The occasional, extra midcycle firing of dINs during swimming may initiate synchrony, and mismatches of timing in the left and right activity can switch synchrony back to swimming. Computer modeling supports these findings by showing that the same neural network, in which reciprocal inhibition mediates rebound firing, can generate both swimming and synchrony without circuit reconfiguration. Modeling also shows that lengthening the time window between phasic excitation and inhibition by increasing dIN synaptic/conduction delay can improve the stability of synchrony. PMID- 24760867 TI - Structural plasticity within the barrel cortex during initial phases of whisker dependent learning. AB - We report learning-related structural plasticity in layer 1 branches of pyramidal neurons in the barrel cortex, a known site of sensorimotor integration. In mice learning an active, whisker-dependent object localization task, layer 2/3 neurons showed enhanced spine growth during initial skill acquisition that both preceded and predicted expert performance. Preexisting spines were stabilized and new persistent spines were formed. These findings suggest rapid changes in connectivity between motor centers and sensory cortex guide subsequent sensorimotor learning. PMID- 24760868 TI - Activity-dependent tau protein translocation to excitatory synapse is disrupted by exposure to amyloid-beta oligomers. AB - Tau is a microtubule-associated protein well known for its stabilization of microtubules in axons. Recently, it has emerged that tau participates in synaptic function as part of the molecular pathway leading to amyloid-beta (Abeta)-driven synaptotoxicity in the context of Alzheimer's disease. Here, we report the implication of tau in the profound functional synaptic modification associated with synaptic plasticity. By exposing murine cultured cortical neurons to a pharmacological synaptic activation, we induced translocation of endogenous tau from the dendritic to the postsynaptic compartment. We observed similar tau translocation to the postsynaptic fraction in acute hippocampal slices subjected to long-term potentiation. When we performed live confocal microscopy on cortical neurons transfected with human-tau-GFP, we visualized an activity-dependent accumulation of tau in the postsynaptic density. Coprecipitation using phalloidin revealed that tau interacts with the most predominant cytoskeletal component present, filamentous actin. Finally, when we exposed cortical cultures to 100 nm human synthetic Abeta oligomers (Abetao's) for 15 min, we induced mislocalization of tau into the spines under resting conditions and abrogated subsequent activity dependent synaptic tau translocation. These changes in synaptic tau dynamics may rely on a difference between physiological and pathological phosphorylation of tau. Together, these results suggest that intense synaptic activity drives tau to the postsynaptic density of excitatory synapses and that Abetao-driven tau translocation to the spine deserves further investigation as a key event toward synaptotoxicity in neurodegenerative diseases. PMID- 24760869 TI - In vivo regulation of NGF-mediated functions by Nedd4-2 ubiquitination of TrkA. AB - Trk neurotrophin receptor ubiquitination in response to ligand activation regulates signaling, trafficking, and degradation of the receptors. However, the in vivo consequences of Trk ubiquitination remain to be addressed. We have developed a mouse model with a mutation in the TrkA neurotrophin receptor (P782S) that results in reduced ubiquitination due to a lack of binding to the E3 ubiquitin ligase, Nedd4-2. In vivo analyses of TrkAP782S indicate that defective ubiquitination of the TrkA mutant results in an altered trafficking and degradation of the receptor that affects the survival of sensory neurons. The dorsal root ganglia from the TrkAP782S knock-in mice display an increased number of neurons expressing CGRP and substance P. Moreover, the mutant mice show enhanced sensitivity to thermal and inflammatory pain. Our results indicate that the ubiquitination of the TrkA neurotrophin receptor plays a critical role in NGF mediated functions, such as neuronal survival and sensitivity to pain. PMID- 24760870 TI - Mice with compromised 5-HTT function lack phosphotyrosine-mediated inhibitory control over prefrontal 5-HT responses. AB - The activity of the prefrontal cortex is essential for normal emotional processing and is strongly modulated by serotonin (5-HT). Yet, little is known about the regulatory mechanisms that control the activity of the prefrontal 5-HT receptors. Here, we found and characterized a deregulation of prefrontal 5-HT receptor electrophysiological signaling in mouse models of disrupted serotonin transporter (5-HTT) function, a risk factor for emotional and cognitive disturbances. We identified a novel tyrosine kinase-dependent mechanism that regulates 5-HT-mediated inhibition of prefrontal pyramidal neurons. We report that mice with compromised 5-HTT, resulting from either genetic deletion or brief treatment with selective serotonin reuptake inhibitors during development, have amplified 5-HT1A receptor-mediated currents in adulthood. These greater inhibitory effects of 5-HT are accompanied by enhanced downstream coupling to Kir3 channels. Notably, in normal wild-type mice, we found that these larger 5 HT1A responses can be mimicked through inhibition of Src family tyrosine kinases. By comparison, in our 5-HTT mouse models, the larger 5-HT1A responses were rapidly reduced through inhibition of tyrosine phosphatases. Our findings implicate tyrosine phosphorylation in regulating the electrophysiological effects of prefrontal 5-HT1A receptors with implications for neuropsychiatric diseases associated with emotional dysfunction, such as anxiety and depressive disorders. PMID- 24760872 TI - Primary cutaneous tuberculosis in an elderly man. PMID- 24760871 TI - HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia. AB - Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia. PMID- 24760873 TI - Preventing the onset of major depressive disorder: a meta-analytic review of psychological interventions. AB - BACKGROUND: Depressive disorders are highly prevalent, have a detrimental impact on the quality of life of patients and their relatives and are associated with increased mortality rates, high levels of service use and substantial economic costs. Current treatments are estimated to only reduce about one-third of the disease burden of depressive disorders. Prevention may be an alternative strategy to further reduce the disease burden of depression. METHODS: We conducted a meta analysis of randomized controlled trials examining the effects of preventive interventions in participants with no diagnosed depression at baseline on the incidence of diagnosed depressive disorders at follow-up. We identified 32 studies that met our inclusion criteria. RESULTS: We found that the relative risk of developing a depressive disorder was incidence rate ratio = 0.79 (95% confidence interval: 0.69-0.91), indicating a 21% decrease in incidence in prevention groups in comparison with control groups. Heterogeneity was low (I(2) = 24%). The number needed to treat (NNT) to prevent one new case of depressive disorder was 20. Sensitivity analyses revealed no differences between type of prevention (e.g. selective, indicated or universal) nor between type of intervention (e.g. cognitive behavioural therapy, interpersonal psychotherapy or other). However, data on NNT did show differences. CONCLUSIONS: Prevention of depression seems feasible and may, in addition to treatment, be an effective way to delay or prevent the onset of depressive disorders. Preventing or delaying these disorders may contribute to the further reduction of the disease burden and the economic costs associated with depressive disorders. PMID- 24760874 TI - Estimating the coverage of mental health programmes: a systematic review. AB - BACKGROUND: The large treatment gap for people suffering from mental disorders has led to initiatives to scale up mental health services. In order to track progress, estimates of programme coverage, and changes in coverage over time, are needed. METHODS: Systematic review of mental health programme evaluations that assess coverage, measured either as the proportion of the target population in contact with services (contact coverage) or as the proportion of the target population who receive appropriate and effective care (effective coverage). We performed a search of electronic databases and grey literature up to March 2013 and contacted experts in the field. Methods to estimate the numerator (service utilization) and the denominator (target population) were reviewed to explore methods which could be used in programme evaluations. RESULTS: We identified 15 735 unique records of which only seven met the inclusion criteria. All studies reported contact coverage. No study explicitly measured effective coverage, but it was possible to estimate this for one study. In six studies the numerator of coverage, service utilization, was estimated using routine clinical information, whereas one study used a national community survey. The methods for estimating the denominator, the population in need of services, were more varied and included national prevalence surveys case registers, and estimates from the literature. CONCLUSIONS: Very few coverage estimates are available. Coverage could be estimated at low cost by combining routine programme data with population prevalence estimates from national surveys. PMID- 24760875 TI - Authors' response to: commentary by Johnson et al. PMID- 24760878 TI - A proposed model for community-assisted alcohol withdrawal in primary care in the UK Armed Forces. AB - Alcohol misuse and related morbidity continues to represent a challenge to the both the National Health Service (NHS) and the Defence Medical Services (DMS). A significant part of the management of patients who misuse alcohol involves planned assisted withdrawal for dependent drinkers. Traditionally, assisted alcohol withdrawal has been conducted in an in-patient setting owing to the perceived risks of carrying out this treatment. Current evidence shows that community-based approaches offer a safe and effective alternative to the traditional in-patient model with significant cost savings. This article proposes a model for community-assisted alcohol withdrawal (CAAW) for use within the DMS. It considers current guidelines and models already in operation within the NHS, offering evaluation and adjustments to fit the requirements that are applicable to the UK Armed Forces medical environment. PMID- 24760879 TI - Autophagic activation in vitrified-warmed mouse oocytes. AB - Vitrification involves the use of cryoprotectants (CPAs) and liquid nitrogen (LN2), which may cause osmotic damage and cryoinjury to oocytes. Autophagy is widely recognized as a survival or response mechanism elicited by various environmental and cellular stressors. However, the induction of autophagy in vitrified-warmed oocytes has not been examined. In this work, we investigated whether the vitrification-warming process induces autophagy in mouse oocytes. Metaphase II (MII) oocytes that were vitrified and stored in LN2 for at least 2 weeks were used in the study. In RT-PCR analyses, we observed that several Atg genes such as Atg5, Atg7, Atg12, LC3a (Map1lc3a), LC3b (Map1lc3b), and Beclin1 were expressed in MII mouse oocytes. Slight reduction in mRNA levels of Atg7 and Atg12 in vitrified-warmed oocytes was noted, and expression of these genes was not significantly influenced. Confocal live imaging analysis using oocytes from GFP-LC3 transgenic mice revealed that vitrified-warmed oocytes had a significantly higher number of GFP-LC3 puncta in comparison to fresh oocytes. The expression of BECLIN1 protein was also increased in vitrified-warmed oocytes. Treatment with 3-methyladenine, an inhibitor of autophagy, did not significantly affect the rates of oocyte survival, IVF, and embryonic development after warming and IVF. The results suggest that the observed autophagic activation in vitrified warmed oocytes is a natural adaptive response to cold stress. Collectively, we show for the first time that vitrified-warmed mouse oocytes exhibit autophagic activation during warming and that this response is not induced by CPA-containing solutions. The induction of autophagy by cold temperature is first reported herein. PMID- 24760880 TI - Lipids and oocyte developmental competence: the role of fatty acids and beta oxidation. AB - Metabolism and ATP levels within the oocyte and adjacent cumulus cells are associated with quality of oocyte and optimal development of a healthy embryo. Lipid metabolism provides a potent source of energy and its importance during oocyte maturation is being increasingly recognised. The triglyceride and fatty acid composition of ovarian follicular fluid has been characterised for many species and is influenced by nutritional status (i.e. dietary fat, fasting, obesity and season) as well as lactation in cows. Lipid in oocytes is a primarily triglyceride of specific fatty acids which differ by species, stored in distinct droplet organelles that re-localise during oocyte maturation. The presence of lipids, particularly saturated vs unsaturated fatty acids, in in vitro maturation systems affects oocyte lipid content as well as developmental competence. Triglycerides are metabolised by lipases that have been localised to cumulus cells as well as oocytes. Fatty acids generated by lipolysis are further metabolised by beta-oxidation in mitochondria for the production of ATP. beta oxidation is induced in cumulus-oocyte complexes (COCs) by the LH surge, and pharmacological inhibition of beta-oxidation impairs oocyte maturation and embryo development. Promoting beta-oxidation with l-carnitine improves embryo development in many species. Thus, fatty acid metabolism in the mammalian COC is regulated by maternal physiological and in vitro environmental conditions; and is important for oocyte developmental competence. PMID- 24760881 TI - Hypovirulence of the phytopathogenic fungus Botryosphaeria dothidea: association with a coinfecting chrysovirus and a partitivirus. AB - Botryosphaeria dothidea is an important pathogenic fungus causing fruit rot, leaf and stem ring spots and dieback, stem canker, stem death or stool mortality, and decline of pear trees. Seven double-stranded RNAs (dsRNAs; dsRNAs 1 to 7 with sizes of 3,654, 2,773, 2,597, 2,574, 1,823, 1,623, and 511 bp, respectively) were identified in an isolate of B. dothidea exhibiting attenuated growth and virulence and a sectoring phenotype. Characterization of the dsRNAs revealed that they belong to two dsRNA mycoviruses. The four largest dsRNAs (dsRNAs 1 to 4) are the genomic components of a novel member of the family Chrysoviridae (tentatively designated Botryosphaeria dothidea chrysovirus 1 [BdCV1]), a view supported by the morphology of the virions and phylogenetic analysis of the putative RNA dependent RNA polymerases (RdRps). Two other dsRNAs (dsRNAs 5 and 6) are the genomic components of a novel member of the family Partitiviridae (tentatively designated Botryosphaeria dothidea partitivirus 1 [BdPV1]), which is placed in a clade distinct from other established partitivirus genera on the basis of the phylogenetic analysis of its RdRp. The smallest dsRNA, dsRNA7, seems to be a noncoding satellite RNA of BdPV1 on the basis of the conservation of its terminal sequences in BdPV1 genomic segments and its cosegregation with BdPV1 after horizontal transmission. This is the first report of a chrysovirus and a partitivirus infecting B. dothidea and of a chrysovirus associated with the hypovirulence of a phytopathogenic fungus. IMPORTANCE: Our studies identified and characterized two novel mycoviruses, Botryosphaeria dothidea chrysovirus 1 (BdCV1) and Botryosphaeria dothidea partitivirus 1 (BdPV1), associated with the hypovirulence of an important fungus pathogenic to fruit trees. This is the first report of a chrysovirus and a partitivirus infecting B. dothidea and of a chrysovirus associated with the hypovirulence of a phytopathogenic fungus. BdCV1 appears to be a good candidate for the biological control of the serious disease induced by B. dothidea. Additionally, BdPV1 is placed in a clade distinct from the established genera. The BdCV1 capsid has two major structural proteins, and the capsid is distinct from that made up by a single polypeptide of the typical chrysoviruses. BdPV1 is the second partitivirus in which the putative capsid protein shares no significant identity with any mycovirus protein. A small accompanying dsRNA that is presumed to be a noncoding satellite RNA of BdPV1 is the first of its kind reported for a partitivirus. PMID- 24760883 TI - IRF7-dependent type I interferon production induces lethal immune-mediated disease in STAT1 knockout mice infected with lymphocytic choriomeningitis virus. AB - Following systemic infection with lymphocytic choriomeningitis virus (LCMV), STAT1 knockout (KO) mice but not wild-type, STAT2 KO, IRF9 KO, or IFNAR KO mice develop lethal disease perpetrated by CD4(+) T cells. IRF7 is a key transcriptional activator of type I IFN (IFN-I) during LCMV infection. Here, the role of IRF7 in the lethal host response to LCMV infection in STAT1 KO mice was examined. In contrast to STAT1 KO mice, STAT1/IRF7 double KO (DKO) mice survived LCMV infection with a reduced immune pathology in key organs, such as the liver and spleen. However, similar to STAT1 KO mice, STAT1/IRF7 DKO mice failed to control LCMV replication and spread. LCMV infection in STAT1 KO mice was associated with a significant elevation in the levels of a number of cytokines in serum, including IFN-Is, but this was largely absent in STAT1/IRF7 DKO mice, which had a modest increase in the levels of gamma interferon and CCL2 only. Since IRF7 is known to be a key transcriptional regulator of IFN-I gene expression, the possible role of IFN-I in lethal disease was examined further. STAT1/IFNAR DKO mice, in contrast to STAT1 KO mice, all survived infection with LCMV and exhibited little tissue immune pathology. Additionally, STAT1 KO mice that were deficient for either of the two IFN-I signaling molecules, STAT2 or IRF9, also survived LCMV infection. We conclude that the lethal immune-mediated disease resulting from LCMV infection in STAT1 KO mice is (i) dependent on IRF7 induced IFN-I production and (ii) driven by noncanonical IFN-I signaling via STAT2 and IRF9. IMPORTANCE: Here we report on the basis for the novel, fatal immune-mediated disease of STAT1 KO mice infected with LCMV. Our findings show that, surprisingly, the pathogenesis of this disease is dependent on IRF7 mediated type I interferon production. Moreover, our study identifies noncanonical type I interferon signaling via STAT2 and IRF9 to be essential for the type I IFN-driven fatal disease in LCMV-infected STAT1 KO mice. These results further highlight the significance of noncanonical type I IFN signaling in the pathogenesis of host-mediated injury following viral infection. PMID- 24760882 TI - Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF kappaB-dependent manner. AB - Characterizing the cellular factors that play a role in the HIV replication cycle is fundamental to fully understanding mechanisms of viral replication and pathogenesis. Whole-genome small interfering RNA (siRNA) screens have identified positive and negative regulators of HIV replication, providing starting points for investigating new cellular factors. We report here that silencing of the deubiquitinase cylindromatosis protein (CYLD), increases HIV infection by enhancing HIV long terminal repeat (LTR)-driven transcription via the NF-kappaB pathway. CYLD is highly expressed in CD4(+) T lymphocytes, monocyte-derived macrophages, and dendritic cells. We found that CYLD silencing increases HIV replication in T cell lines. We confirmed the positive role of CYLD silencing in HIV infection in primary human CD4(+) T cells, in which CYLD protein was partially processed upon activation. Lastly, Jurkat T cells latently infected with HIV (JLat cells) were more responsive to phorbol 12-myristate 13-acetate (PMA) reactivation in the absence of CYLD, indicating that CYLD activity could play a role in HIV reactivation from latency. In summary, we show that CYLD acts as a potent negative regulator of HIV mRNA expression by specifically inhibiting NF-kappaB-driven transcription. These findings suggest a function for this protein in modulating productive viral replication as well as in viral reactivation. IMPORTANCE: HIV transcription is regulated by a number of host cell factors. Here we report that silencing of the lysine 63 deubiquitinase CYLD increases HIV transcription in an NF-kappaB-dependent manner. We show that CYLD is expressed in HIV target cells and that its silencing increases HIV infection in transformed T cell lines as well as primary CD4(+) T cells. Similarly, reactivation of latent provirus was facilitated in the absence of CYLD. These data suggest that CYLD, which is highly expressed in CD4(+) T cells, can control HIV transcription in productive infection as well as during reactivation from latency. PMID- 24760884 TI - The human fetal glial cell line SVG p12 contains infectious BK polyomavirus. AB - The human fetal glial cell line SVG was generated in 1985 by transfecting primary fetal brain cells with a plasmid containing an origin-defective mutant of simian virus 40 (SV40). The cells, which express SV40 large T-antigen, support the replication of human JC polyomavirus (JCPyV) and have been used for JCPyV studies but also for other studies in which cells of neural origin were desirable. We intended to use the SVG p12 cells from ATCC for antiviral drug studies with JCPyV. However, during initial experiments, immunofluorescence microscopy controls unexpectedly revealed cells expressing the late viral proteins VP1, VP2/VP3, and agno. This was confirmed by Western blotting. Since our agnoprotein antiserum is specific for BKPyV agnoprotein, infection with BKPyV was suspected. Indeed, specific BKPyV PCR of SVG p12 supernatants revealed a viral load of >1 * 10(10) genomic equivalents/ml. Negative-staining electron microscopy showed characteristic polyomavirus virions, and infectious BKPyV was transmitted from SVG p12 supernatant to other cells. Long-range PCR covering the viral genome, followed by DNA sequencing, identified BKPyV strain UT as well as deletion derivatives. This was confirmed by next-generation sequencing. JCPyV (MAD-4) was found to infect apparently uninfected and BKPyV-infected SVG p12 cells. In total, 4 vials from 2 different ATCC lots of SVG p12 cells dating back to 2006 contained BKPyV, whereas the subclone SVG-A was negative. In conclusion, SVG p12 cells from ATCC contain infectious BKPyV. This may have affected results and interpretations of previous studies, and caution should be taken in future experiments. IMPORTANCE: This work reveals that one of the most frequently used cell lines for JC polyomavirus (JCPyV) research, the SV40-immortalized human fetal glial cell line SVG p12 obtained directly from ATCC, contains infectious BK polyomavirus (BKPyV) of strain UT and a spectrum of defective mutants. Strain UT has been previously found in urine and in tumors of different patients but is also frequently used for research. It is therefore not clear if BKPyV was present in the brain tissue used to generate the cell line or if this is a contamination. Although productive JCPyV infection of SVG cells was not dependent on prior BKPyV infection, the unnoticed presence of BKPyV may have influenced the results of studies using these cells. The interpretation of past results should therefore be reconsidered and cells tested for BKPyV before new studies are initiated. The frequently used subclone SVG-A did not contain BKPyV and could be a useful substitute. PMID- 24760885 TI - Protective properties of vaccinia virus-based vaccines: skin scarification promotes a nonspecific immune response that protects against orthopoxvirus disease. AB - The process of vaccination introduced by Jenner generated immunity against smallpox and ultimately led to the eradication of the disease. Procedurally, in modern times, the virus is introduced into patients via a process called scarification, performed with a bifurcated needle containing a small amount of virus. What was unappreciated was the role that scarification itself plays in generating protective immunity. In rabbits, protection from lethal disease is induced by intradermal injection of vaccinia virus, whereas a protective response occurs within the first 2 min after scarification with or without virus, suggesting that the scarification process itself is a major contributor to immunoprotection. importance: These results show the importance of local nonspecific immunity in controlling poxvirus infections and indicate that the process of scarification should be critically considered during the development of vaccination protocols for other infectious agents. PMID- 24760886 TI - Involvement of hepatitis C virus NS5A hyperphosphorylation mediated by casein kinase I-alpha in infectious virus production. AB - Nonstructural protein 5A (NS5A) of hepatitis C virus (HCV) possesses multiple functions in the viral life cycle. NS5A is a phosphoprotein that exists in hyperphosphorylated and basally phosphorylated forms. Although the phosphorylation status of NS5A is considered to have a significant impact on its function, the mechanistic details regulating NS5A phosphorylation, as well as its exact roles in the HCV life cycle, are still poorly understood. In this study, we screened 404 human protein kinases via in vitro binding and phosphorylation assays, followed by RNA interference-mediated gene silencing in an HCV cell culture system. Casein kinase I-alpha (CKI-alpha) was identified as an NS5A associated kinase involved in NS5A hyperphosphorylation and infectious virus production. Subcellular fractionation and immunofluorescence confocal microscopy analyses showed that CKI-alpha-mediated hyperphosphorylation of NS5A contributes to the recruitment of NS5A to low-density membrane structures around lipid droplets (LDs) and facilitates its interaction with core protein and the viral assembly. Phospho-proteomic analysis of NS5A with or without CKI-alpha depletion identified peptide fragments that corresponded to the region located within the low-complexity sequence I, which is important for CKI-alpha-mediated NS5A hyperphosphorylation. This region contains eight serine residues that are highly conserved among HCV isolates, and subsequent mutagenesis analysis demonstrated that serine residues at amino acids 225 and 232 in NS5A (genotype 2a) may be involved in NS5A hyperphosphorylation and hyperphosphorylation-dependent regulation of virion production. These findings provide insight concerning the functional role of NS5A phosphorylation as a regulatory switch that modulates its multiple functions in the HCV life cycle. IMPORTANCE: Mechanisms regulating NS5A phosphorylation and its exact function in the HCV life cycle have not been clearly defined. By using a high-throughput screening system targeting host protein kinases, we identified CKI-alpha as an NS5A-associated kinase involved in NS5A hyperphosphorylation and the production of infectious virus. Our results suggest that the impact of CKI-alpha in the HCV life cycle is more profound on virion assembly than viral replication via mediation of NS5A hyperphosphorylation. CKI-alpha-dependent hyperphosphorylation of NS5A plays a role in recruiting NS5A to low-density membrane structures around LDs and facilitating its interaction with the core for new virus particle formation. By using proteomic approach, we identified the region within the low-complexity sequence I of NS5A that is involved in NS5A hyperphosphorylation and hyperphosphorylation-dependent regulation of infectious virus production. These findings will provide novel mechanistic insights into the roles of NS5A associated kinases and NS5A phosphorylation in the HCV life cycle. PMID- 24760887 TI - Residue 41 of the Eurasian avian-like swine influenza a virus matrix protein modulates virion filament length and efficiency of contact transmission. AB - Position 41 of the influenza A virus matrix protein encodes a highly conserved alanine in human and avian lineages. Nonetheless, strains of the Eurasian avian like swine (Easw) lineage contain a change at this position: position 41 of A/swine/Spain/53207/04 (H1N1) (SPN04) encodes a proline. To assess the impact of this naturally occurring polymorphism on viral fitness, we utilized reverse genetics to produce recombinant viruses encoding wild-type M1 41P (rSPN04-P) and consensus 41A (rSPN04-A) residues. Relative to rSPN04-A, rSPN04-P virus displayed reduced growth in vitro. In the guinea pig model, rSPN04-P was transmitted to fewer contact animals than rSPN04-A and failed to infect guinea pigs that received a low-dose inoculum. Moreover, the P41A change altered virion morphology, reducing the number and length of filamentous virions, as well as reducing the neuraminidase activity of virions. The lab-adapted human isolate, A/PR/8/34 (H1N1) (PR8), is nontransmissible in the guinea pig model, making it a useful background in which to identify certain viral factors that enhance transmissibility. We assessed transmission in the context of single-, double-, and triple-reassortant viruses between PR8 and SPN04; PR8/SPN04 M, PR8/SPN04 M+NA, and PR8/SPN04 M+NA+HA, encoding either matrix 41 A or P, were generated. In each case, the virus possessing 41P transmitted less well than the corresponding 41A-encoding virus. In summary, we have identified a naturally occurring mutation in the influenza A virus matrix protein that impacts transmission efficiency and can alter virion morphology and neuraminidase activity. IMPORTANCE: We have developed a practical model for examining the genetics underlying transmissibility of the Eurasian avian-like swine lineage viruses, which contributed M and NA segments to the 2009 pandemic strain. Here, we use our system to investigate the impact on viral fitness of a naturally occurring polymorphism at matrix (M1) position 41 in an Easw isolate. Position 41 has been implicated previously in adaptation to laboratory substrates and to mice. Here we show that the polymorphism at M1 41 has a limited effect on growth in vitro but changes the morphology of the virus and impacts growth and transmission in the guinea pig model. PMID- 24760888 TI - Mutations in HIV-1 reverse transcriptase affect the errors made in a single cycle of viral replication. AB - The genetic variation in HIV-1 in patients is due to the high rate of viral replication, the high viral load, and the errors made during viral replication. Some of the mutations in reverse transcriptase (RT) that alter the deoxynucleoside triphosphate (dNTP)-binding pocket, including those that confer resistance to nucleoside/nucleotide analogs, affect dNTP selection during replication. The effects of mutations in RT on the spectrum (nature, position, and frequency) of errors made in vivo are poorly understood. We previously determined the mutation rate and the frequency of different types of mutations and identified hot spots for mutations in a lacZalpha (the alpha complementing region of lacZ) reporter gene carried by an HIV-1 vector that replicates using wild-type RT. We show here that four mutations (Y115F, M184V, M184I, and Q151M) in the dNTP-binding pocket of RT that had relatively small effects on the overall HIV-1 mutation rate (less than 3-fold compared to the wild type) significantly increased mutations at some specific positions in the lacZalpha reporter gene. We also show that changes in a sequence that flanks the reporter gene can affect the mutations that arise in the reporter. These data show that changes either in HIV 1 RT or in the sequence of the nucleic acid template can affect the spectrum of mutations made during viral replication. This could, by implication, affect the generation of drug-resistant mutants and immunological-escape mutants in patients. IMPORTANCE: RT is the viral enzyme that converts the RNA genome of HIV into DNA. Errors made during replication allow the virus to escape from the host's immune system and to develop resistance to the available anti-HIV drugs. We show that four different mutations in RT which are known to be associated with resistance to anti-RT drugs modestly increased the overall frequency of errors made during viral replication. However, the increased errors were not uniformly distributed; the additional errors occurred at a small number of positions (hot spots). Moreover, some of the RT mutations preferentially affected the nature of the errors that were made (some RT mutations caused an increase in insertion and deletion errors; others caused an increase in substitution errors). We also show that sequence changes in a region adjacent to a target gene can affect the errors made within the target gene. PMID- 24760889 TI - Phenylalanine residues at the carboxyl terminus of the herpes simplex virus 1 UL20 membrane protein regulate cytoplasmic virion envelopment and infectious virus production. AB - The herpes simplex virus type 1 (HSV-1) UL20 gene encodes a 222-amino-acid nonglycosylated envelope protein which forms a complex with viral glycoprotein K (gK) that functions in virion envelopment, egress, and virus-induced cell fusion. To investigate the role of the carboxyl terminus of the UL20 protein (UL20p) in cytoplasmic virion envelopment, a cadre of mutant viruses was constructed and characterized. The deletion of six amino acids from the carboxyl terminus of UL20p caused an approximately 1-log reduction in infectious virus production compared to that of the wild-type virus. Surprisingly, a phenylalanine-to-alanine replacement at amino acid position 210 caused a gain-of-function phenotype, increasing infectious virus production up to 1 log more than in the wild-type virus. In contrast, the replacement of two membrane-proximal phenylalanines with alanines caused drastic inhibition of infectious virion production and cytoplasmic virion envelopment. Prediction of the membrane topology of UL20p revealed that these two amino acid changes cause retraction of the carboxyl terminus of UL20p from the intracellular space. Confocal microscopy revealed that none of the engineered UL20 mutations affected intracellular transport of UL20p to trans-Golgi network membranes. In addition, a proximity ligation assay showed that none of the UL20 mutations affected UL20p colocalization and potential interactions with the UL37 protein recently found to interact with the gK/UL20 protein complex. Collectively, these studies show that phenylalanine residues within the carboxyl terminus of UL20p are involved in the regulation of cytoplasmic virion envelopment and infectious virus production. IMPORTANCE: We have shown previously that the UL20/gK protein complex serves crucial roles in cytoplasmic virion envelopment and that it interacts with the UL37 tegument protein to facilitate cytoplasmic virion envelopment. In this study, we investigated the role of phenylalanine residues within the carboxyl terminus of UL20p, since aromatic and hydrophobic amino acids are known to be involved in protein-protein interactions through stacking of their aromatic structures. Characterization of mutant viruses carrying phenylalanine (Phe)-to-alanine (Ala) mutations revealed that the two membrane-proximal Phe residues were critical for the proper UL20p membrane topology and efficient virion envelopment and infectious virus production. Surprisingly, a Phe-to-Ala change located approximately in the middle of the UL20p carboxyl terminus substantially enhanced cytoplasmic envelopment and overall production of infectious virions. This work revealed that Phe residues within the UL20p carboxyl terminus are involved in the regulation of cytoplasmic virion envelopment and infectious virus production. PMID- 24760890 TI - Structural analysis of respiratory syncytial virus reveals the position of M2-1 between the matrix protein and the ribonucleoprotein complex. AB - Respiratory syncytial virus (RSV), a member of the Paramyxoviridae family of nonsegmented, negative-sense, single-stranded RNA genome viruses, is a leading cause of lower respiratory tract infections in infants, young children, and the elderly or immunocompromised. There are many open questions regarding the processes that regulate human RSV (hRSV) assembly and budding. Here, using cryo electron tomography, we identified virus particles that were spherical, filamentous, and asymmetric in structure, all within the same virus preparation. The three particle morphologies maintained a similar organization of the surface glycoproteins, matrix protein (M), M2-1, and the ribonucleoprotein (RNP). RNP filaments were traced in three dimensions (3D), and their total length was calculated. The measurements revealed the inclusion of multiple full-length genome copies per particle. RNP was associated with the membrane whenever the M layer was present. The amount of M coverage ranged from 24% to 86% in the different morphologies. Using fluorescence light microscopy (fLM), direct stochastic optical reconstruction microscopy (dSTORM), and a proximity ligation assay (PLA), we provide evidence illustrating that M2-1 is located between RNP and M in isolated viral particles. In addition, regular spacing of the M2-1 densities was resolved when hRSV viruses were imaged using Zernike phase contrast (ZPC) cryo-electron tomography. Our studies provide a more complete characterization of the hRSV virion structure and substantiation that M and M2-1 regulate virus organization. IMPORTANCE: hRSV is a leading cause of lower respiratory tract infections in infants and young children as well as elderly or immunocompromised individuals. We used cryo-electron tomography and Zernike phase contrast cryo-electron tomography to visualize populations of purified hRSV in 3D. We observed the three distinct morphologies, spherical, filamentous, and asymmetric, which maintained comparable organizational profiles. Depending on the virus morphology examined, the amount of M ranged from 24% to 86%. We complemented the cryo-imaging studies with fluorescence microscopy, dSTORM, and a proximity ligation assay to provide additional evidence that M2-1 is incorporated into viral particles and is positioned between M and RNP. The results highlight the impact of M and M2-1 on the regulation of hRSV organization. PMID- 24760891 TI - Roles of major histocompatibility complex class II in inducing protective immune responses to influenza vaccination. AB - Major histocompatibility complex class II-deficient (MHC-II KO; Abeta(-/-)) mice were used to assess the roles of MHC-II molecules in inducing protective immune responses to vaccination. After vaccination with influenza A/PR8 virus-like particle (VLP) vaccine, in vivo and in vitro vaccine antigen-specific IgG isotype antibodies were not detected in MHC-II KO mice, which is quite different from CD4 T cell-deficient mice that induced vaccine-specific IgG antibodies. The deficiency in MHC-II did not significantly affect the induction of antigen specific IgM antibody in sera. MHC-II KO mice that were vaccinated with influenza VLP, whole inactivated influenza virus, or live attenuated influenza virus vaccines were not protected against lethal infection with influenza A/PR8 virus. Adoptive transfer of fractionated spleen cells from wild-type mice to MHC-II KO mice indicated that CD43(+) cell populations with MHC-II contributed more significantly to producing vaccine-specific IgG antibodies than CD43(-) B220(+) conventional B cell or CD4 T cell populations, as well as conferring protection against lethal infection. Bone marrow-derived dendritic cells from MHC-II KO mice showed a significant defect in producing interleukin-6 and tumor necrosis factor alpha cytokines. Thus, results indicate that MHC-II molecules play multiple roles in inducing protective immunity to influenza vaccination. Importance: Major histocompatibility complex class II (MHC-II) has been known to activate CD4 T helper immune cells. A deficiency in MHC-II was considered to be equivalent to the lack of CD4 T cells in developing host immune responses to pathogens. However, the roles of MHC-II in inducing protective immune responses to vaccination have not been well understood. In the present study, we demonstrate that MHC-II-deficient mice showed much more significant defects in inducing protective antibody responses to influenza vaccination than CD4 T cell-deficient mice. Further analysis showed that CD43 marker-positive immune cells with MHC-II, as well as an innate immunity-simulating adjuvant, could rescue some defects in inducing protective immune responses in MHC-II-deficient mice. These results have important implications for our understanding of host immunity-inducing mechanisms to vaccination, as well as in developing effective vaccines and adjuvants. PMID- 24760892 TI - Toll-like receptor 2-mediated innate immune responses against Junin virus in mice lead to antiviral adaptive immune responses during systemic infection and do not affect viral replication in the brain. AB - Successful adaptive immunity to virus infection often depends on the initial innate response. Previously, we demonstrated that Junin virus, the etiological agent responsible for Argentine hemorrhagic fever (AHF), activates an early innate immune response via an interaction between the viral glycoprotein and Toll like receptor 2 (TLR2). Here we show that TLR2/6 but not TLR1/2 heterodimers sense Junin virus glycoprotein and induce a cytokine response, which in turn upregulates the expression of the RNA helicases RIG-I and MDA5. NF-kappaB and Erk1/2 were important in the cytokine response, since both proteins were phosphorylated as a result of the interaction of virus with TLR2, and treatment with an Erk1/2-specific inhibitor blocked cytokine production. We show that the Junin virus glycoprotein activates cytokine production in a human macrophage cell line as well. Moreover, we show that TLR2-mediated immune response plays a role in viral clearance because wild-type mice cleared Candid 1 (JUNV C1), the vaccine strain of Junin virus, more rapidly than did TLR2 knockout mice. This clearance correlated with the generation of Junin virus-specific CD8(+) T cells. However, infected wild-type and TLR2 knockout mice developed TLR2-independent blocking antibody responses with similar kinetics. We also show that microglia and astrocytes but not neurons are susceptible to infection with JUNV C1. Although JUNV C1 infection of the brain also triggered a TLR2-dependent cytokine response, virus levels were equivalent in wild-type and TLR2 knockout mice. Importance: Junin virus is transmitted by rodents native to Argentina and is associated with both systemic disease and, in some patients, neurological symptoms. Humans become infected when they inhale aerosolized Junin virus. AHF has a 15 to 30% mortality rate, and patients who clear the infection develop a strong antibody response to Junin virus. Here we investigated what factors determine the immune response to Junin virus. We show that a strong initial innate immune response to JUNV C1 determines how quickly mice can clear systemic infection and that this depended on the cellular immune response. In contrast, induction of an innate immune response in the brain had no effect on virus infection levels. These findings may explain how the initial immune response to Junin virus infection could determine different outcomes in humans. PMID- 24760893 TI - Host and viral determinants of Mx2 antiretroviral activity. AB - Myxovirus resistance 2 (Mx2/MxB) has recently been uncovered as an effector of the anti-HIV-1 activity of type I interferons (IFNs) that inhibits HIV-1 at an early stage postinfection, after reverse transcription but prior to proviral integration into host DNA. The mechanistic details of Mx2 antiviral activity are not yet understood, but a few substitutions in the HIV-1 capsid have been shown to confer resistance to Mx2. Through a combination of in vitro evolution and unbiased mutagenesis, we further map the determinants of sensitivity to Mx2 and reveal that multiple capsid (CA) surfaces define sensitivity to Mx2. Intriguingly, we reveal an unanticipated sensitivity determinant within the C terminal domain of capsid. We also report that Mx2s derived from multiple primate species share the capacity to potently inhibit HIV-1, whereas selected nonprimate orthologs have no such activity. Like TRIM5alpha, another CA targeting antiretroviral protein, primate Mx2s exhibit species-dependent variation in antiviral specificity against at least one extant virus and multiple HIV-1 capsid mutants. Using a combination of chimeric Mx2 proteins and evolution-guided approaches, we reveal that a single residue close to the N terminus that has evolved under positive selection can determine antiviral specificity. Thus, the variable N-terminal region can define the spectrum of viruses inhibited by Mx2. Importance: Type I interferons (IFNs) inhibit the replication of most mammalian viruses. IFN stimulation upregulates hundreds of different IFN-stimulated genes (ISGs), but it is often unclear which ISGs are responsible for inhibition of a given virus. Recently, Mx2 was identified as an ISG that contributes to the inhibition of HIV-1 replication by type I IFN. Thus, Mx2 might inhibit HIV-1 replication in patients, and this inhibitory action might have therapeutic potential. The mechanistic details of how Mx2 inhibits HIV-1 are currently unclear, but the HIV-1 capsid protein is the likely viral target. Here, we determine the regions of capsid that specify sensitivity to Mx2. We demonstrate that Mx2 from multiple primates can inhibit HIV-1, whereas Mx2 from other mammals (dogs and sheep) cannot. We also show that primate variants of Mx2 differ in the spectrum of lentiviruses they inhibit and that a single residue in Mx2 can determine this antiviral specificity. PMID- 24760894 TI - Statistical linkage analysis of substitutions in patient-derived sequences of genotype 1a hepatitis C virus nonstructural protein 3 exposes targets for immunogen design. AB - Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4(+) and cytotoxic CD8(+) T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing diverse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41. IMPORTANCE: Despite much experimental work on HCV, a thorough statistical study of the HCV sequences for the purpose of immunogen design was missing in the literature. Such a study is vital to identify epistatic couplings among residues that can provide useful insights for designing a potent vaccine. In this work, ideas from random matrix theory were applied to characterize the statistics of substitutions within the diverse publicly available sequences of the genotype 1a HCV NS3 protein, leading to a group of sites for which HCV appears to resist simultaneous substitutions possibly due to deleterious effect on viral fitness. Our analysis leads to completely novel immunogen designs for HCV. In addition, the NS3 epitopes used in the recently proposed peptide-based vaccine IC41 were analyzed in the context of our framework. Our analysis predicts that alternative NS3 epitopes may be worth exploring as they might be more efficacious. PMID- 24760895 TI - Phosphorylation of herpes simplex virus 1 dUTPase upregulated viral dUTPase activity to compensate for low cellular dUTPase activity for efficient viral replication. AB - We recently reported that herpes simplex virus 1 (HSV-1) protein kinase Us3 phosphorylated viral dUTPase (vdUTPase) at serine 187 (Ser-187) to upregulate its enzymatic activity, which promoted HSV-1 replication in human neuroblastoma SK-N SH cells but not in human carcinoma HEp-2 cells. In the present study, we showed that endogenous cellular dUTPase activity in SK-N-SH cells was significantly lower than that in HEp-2 cells and that overexpression of cellular dUTPase in SK N-SH cells increased the replication of an HSV-1 mutant with an alanine substitution for Ser-187 (S187A) in vdUTPase to the wild-type level. In addition, we showed that knockdown of cellular dUTPase in HEp-2 cells significantly reduced replication of the mutant vdUTPase (S187A) virus but not that of wild-type HSV-1. Furthermore, the replacement of Ser-187 in vdUTPase with aspartic acid, which mimics constitutive phosphorylation, and overexpression of cellular dUTPase restored viral replication to the wild-type level in cellular dUTPase knockdown HEp-2 cells. These results indicated that sufficient dUTPase activity was required for efficient HSV-1 replication and supported the hypothesis that Us3 phosphorylation of vdUTPase Ser-187 upregulated vdUTPase activity in host cells with low cellular dUTPase activity to produce efficient viral replication.virus. Importance: It has long been assumed that dUTPase activity is important for replication of viruses encoding a dUTPase and that the viral dUTPase (vdUTPase) activity was needed if host cell dUTPase activity was not sufficient for efficient viral replication. In the present study, we showed that the S187A mutation in HSV-1 vdUTPase, which impaired its enzymatic activity, reduced viral replication in SK-N-SH cells, which have low endogenous cellular dUTPase activity, and that overexpression of cellular dUTPase restored viral replication to the wild-type level. We also showed that knockdown of cellular dUTPase in HEp 2 cells, which have higher dUTPase activity than do SK-N-SH cells, reduced replication of HSV-1 with the vdUTPase mutation but had no effect on wild-type virus replication. This is the first report, to our knowledge, directly showing that dUTPase activity is critical for efficient viral replication and that vdUTPase compensates for low host cell dUTPase activity to produce efficient viral replication. PMID- 24760897 TI - A novel use of transfer function estimation for early assessment of brain injury outcome. AB - Normal blood flow in the brain as a response to pressure fluctuations is commonly referred to as cerebral autoregulation. Linear, nonparametric models of cerebral autoregulation were estimated for 77 human subjects afflicted with brain injury, with mean arterial pressure used as input, and invasively measured regional cerebral blood flow used as output. The data were continuously monitored from the beginning of subject hospital stay. Mean transfer function gain as a function of frequency was calculated for each subject over a limited time window spanning 48 h, starting postsurgery. The mean transfer function gain of the cerebral autoregulation model provided a highly accurate, statistically significant, assessment of patient outcome. Subjects were accurately grouped by outcome, with a high significance ( ) across the entire measurement spectrum (0.005-0.25 Hz). In addition, the frequency band from 0.1 to 0.25 Hz contains particularly low variance in transfer function gain. This spectral region provides a highly statistically significant ( ) assessment of brain injury patient health that is useful for outcome prediction. PMID- 24760898 TI - Nonlinear state-space modeling of human motion using 2-D marker observations. AB - A novel method for the estimation of human kinematics, based on state-space modeling, is proposed. The state consists of the positions, orientations, velocities, and accelerations of an articulated model. Estimation is performed using the unscented Kalman filter (UKF) algorithm with a fixed-interval smoother. Impulsive acceleration at floor contact of the foot is estimated by implementing a contact constraint in the UKF evolution model. The constraint inserts an acceleration impulse into the model state. The estimation method was applied to marker-based motion analysis in a motion laboratory. Validation measurements were performed with a rigid test device and with human gait. A triaxial accelerometer was used to evaluate acceleration estimates. Comparison between the proposed method and the extended Kalman smoother showed a clear difference in the quality of estimates during impulsive accelerations. The proposed approach enables estimation of human kinematics during both continuous and transient accelerations. The approach provides a novel way of estimating acceleration at foot initial contact, and thus enables more accurate evaluation of loading from the beginning of the floor contact. PMID- 24760896 TI - Ezrin is a component of the HIV-1 virological presynapse and contributes to the inhibition of cell-cell fusion. AB - During cell-to-cell transmission of HIV-1, viral and cellular proteins transiently accumulate at the contact zone between infected (producer) and uninfected (target) cells, forming the virological synapse. Rearrangements of the cytoskeleton in producer and target cells are required for proper targeting of viral and cellular components during synapse formation, yet little is known about how these processes are regulated, particularly within the producer cell. Since ezrin-radixin-moesin (ERM) proteins connect F-actin with integral and peripheral membrane proteins, are incorporated into virions, and interact with cellular components of the virological presynapse, we hypothesized that they play roles during the late stage of HIV-1 replication. Here we document that phosphorylated (i.e., active) ezrin specifically accumulates at the HIV-1 presynapse in T cell lines and primary CD4(+) lymphocytes. To investigate whether ezrin supports virus transmission, we sought to ablate ezrin expression in producer cells. While cells did not tolerate a complete knockdown of ezrin, even a modest reduction of ezrin expression (~50%) in HIV-1-producing cells led to the release of particles with impaired infectivity. Further, when cocultured with uninfected target cells, ezrin-knockdown producer cells displayed reduced accumulation of the tetraspanin CD81 at the synapse and fused more readily with target cells, thus forming syncytia. Such an outcome likely is not optimal for virus dissemination, as evidenced by the fact that, in vivo, only relatively few infected cells form syncytia. Thus, ezrin likely helps secure efficient virus spread not only by enhancing virion infectivity but also by preventing excessive membrane fusion at the virological synapse. IMPORTANCE: While viruses, in principal, can propagate through successions of syncytia, HIV-1-infected cells in the majority of cases do not fuse with potential target cells during viral transmission. This mode of spread is coresponsible for key features of HIV-1 pathogenesis, including killing of bystander cells and establishment of latently infected T lymphocytes. Here we identify the ERM protein family member ezrin as a cellular factor that contributes to the inhibition of cell-cell fusion and thus to suppressing excessive syncytium formation. Our analyses further suggest that ezrin, which connects integral membrane proteins with actin, functions in concert with CD81, a member of the tetraspanin family of proteins. Additional evidence, documented here and elsewhere, suggests that ezrin and CD81 cooperate to prevent cytoskeleton rearrangements that need to take place during the fusion of cellular membranes. PMID- 24760899 TI - An armband wearable device for overnight and cuff-less blood pressure measurement. AB - 24-h blood pressure (BP) has significant prognostic value for cardiovascular risk screening, but the present BP devices are mainly cuff-based, which are unsuitable for long-term BP measurement, especially during nighttime. In this paper, we developed an armband wearable pulse transit time (PTT) system for 24-h cuff-less BP measurement and evaluated it in an unattended out-of-laboratory setting. Ten healthy young subjects participated in this ambulatory study, where PTT was measured at 30-min interval by this wearable system and the reference BP was measured by a standard oscillometric ambulatory BP monitor. Due to the misalignment of BP and PTT on their recording time caused by the different measurement principles of the two BP devices, a new estimation method has been proposed: transients in PTT were removed from the raw data by defined criteria, and then evenly interpolated, low-pass filtered, and resampled to synchronize at the time when BP was recorded. The results show that with the proposed method, the correlation between PTT and systolic BP (SBP) during nighttime with dynamic range of 21.8 +/- 14.2 mmHg has improved from -0.50 +/- 0.24 to -0.62 +/- 0.20 , and the difference between the estimated and reference SBP has improved from 0.7 +/- 10.7 to 2.8 +/- 8.2 mmHg with root mean square error reduced from 10.7 to 8.7 mmHg. In addition, the correlation between a very low frequency component of SBP and PTT obtained from the proposed method during nighttime is -0.80 +/- 0.10 and the difference is 2.4 +/- 5.7 mmHg for a dynamic BP range of 13.5 +/- 8.0 mmHg. It is therefore concluded from this study that the proposed wearable system has great potential to be used for overnight SBP monitoring, especially to measure the averaged SBP over a long period. PMID- 24760900 TI - Tackling speaking mode varieties in EMG-based speech recognition. AB - An electromyographic (EMG) silent speech recognizer is a system that recognizes speech by capturing the electric potentials of the human articulatory muscles, thus enabling the user to communicate silently. After having established a baseline EMG-based continuous speech recognizer, in this paper, we investigate speaking mode variations, i.e., discrepancies between audible and silent speech that deteriorate recognition accuracy. We introduce multimode systems that allow seamless switching between audible and silent speech, investigate different measures which quantify speaking mode differences, and present the spectral mapping algorithm, which improves the word error rate (WER) on silent speech by up to 14.3% relative. Our best average silent speech WER is 34.7%, and our best WER on audibly spoken speech is 16.8%. PMID- 24760901 TI - LOGISMOS-B: layered optimal graph image segmentation of multiple objects and surfaces for the brain. AB - Automated reconstruction of the cortical surface is one of the most challenging problems in the analysis of human brain magnetic resonance imaging (MRI). A desirable segmentation must be both spatially and topologically accurate, as well as robust and computationally efficient. We propose a novel algorithm, LOGISMOS B, based on probabilistic tissue classification, generalized gradient vector flows and the LOGISMOS graph segmentation framework. Quantitative results on MRI datasets from both healthy subjects and multiple sclerosis patients using a total of 16,800 manually placed landmarks illustrate the excellent performance of our algorithm with respect to spatial accuracy. Remarkably, the average signed error was only 0.084 mm for the white matter and 0.008 mm for the gray matter, even in the presence of multiple sclerosis lesions. Statistical comparison shows that LOGISMOS-B produces a significantly more accurate cortical reconstruction than FreeSurfer, the current state-of-the-art approach (p << 0.001). Furthermore, LOGISMOS-B enjoys a run time that is less than a third of that of FreeSurfer, which is both substantial, considering the latter takes 10 h/subject on average, and a statistically significant speedup. PMID- 24760902 TI - Maximum likelihood Doppler frequency estimation under decorrelation noise for quantifying flow in optical coherence tomography. AB - Recent hardware advances in optical coherence tomography (OCT) have led to ever higher A-scan rates. However, the estimation of blood flow axial velocities is limited by the presence and type of noise. Higher acquisition rates alone do not necessarily enable precise quantification of Doppler velocities, particularly if the estimator is suboptimal. In previous work, we have shown that the Kasai autocorrelation estimator is statistically suboptimal under conditions of additive white Gaussian noise. In addition, for practical OCT measurements of flow, decorrelation noise affects Doppler frequency estimation by broadening the signal spectrum. Here, we derive a general maximum likelihood estimator (MLE) for Doppler frequency estimation that takes into account additive white noise as well as signal decorrelation. We compare the decorrelation MLE with existing techniques using simulated and flow phantom data and find that it has better performance, achieving the Cramer-Rao lower bound. By making an approximation, we also provide an interpretation of this method in the Fourier domain. We anticipate that this estimator will be particularly suited for estimating blood flow in in vivo scenarios. PMID- 24760903 TI - ML-reconstruction for TOF-PET with simultaneous estimation of the attenuation factors. AB - In positron emission tomography (PET), attenuation correction is typically done based on information obtained from transmission tomography. Recent studies show that time-of-flight (TOF) PET emission data allow joint estimation of activity and attenuation images. Mathematical analysis revealed that the joint estimation problem is determined up to a scale factor. In this work, we propose a maximum likelihood reconstruction algorithm that jointly estimates the activity image together with the sinogram of the attenuation factors. The algorithm is evaluated with 2-D and 3-D simulations as well as clinical TOF-PET measurements of a patient scan and compared to reference reconstructions. The robustness of the algorithm to possible imperfect scanner calibration is demonstrated with reconstructions of the patient scan ignoring the varying detector sensitivities. PMID- 24760904 TI - HEp-2 cell classification using shape index histograms with donut-shaped spatial pooling. AB - We present a new method for automatic classification of indirect immunoflourescence images of HEp-2 cells into different staining pattern classes. Our method is based on a new texture measure called shape index histograms that captures second-order image structure at multiple scales. Moreover, we introduce a spatial decomposition scheme which is radially symmetric and suitable for cell images. The spatial decomposition is performed using donut-shaped pooling regions of varying sizes when gathering histogram contributions. We evaluate our method using both the ICIP 2013 and the ICPR 2012 competition datasets. Our results show that shape index histograms are superior to other popular texture descriptors for HEp-2 cell classification. Moreover, when comparing to other automated systems for HEp-2 cell classification we show that shape index histograms are very competitive; especially considering the relatively low complexity of the method. PMID- 24760905 TI - An iterative compensation approach without linearization of projector responses for multiple-projector system. AB - We aim to realize a new and simple compensation method that robustly handles multiple-projector systems without recourse to the linearization of projector response functions. We introduce state equations, which distribute arbitrary brightness among the individual projectors, and control the state equations according to the feedback from a camera. By employing the color-mixing matrix with gradient of projector responses, we compensate the controlled brightness input to each projector. Our method dispenses with cooperation among multiple projectors as well as time-consuming photometric calibration. Compared with existing methods, our method is shown to offer superior compensation performance and a more effective way of compensating multiple-projector systems. PMID- 24760906 TI - Mixed noise removal by weighted encoding with sparse nonlocal regularization. AB - Mixed noise removal from natural images is a challenging task since the noise distribution usually does not have a parametric model and has a heavy tail. One typical kind of mixed noise is additive white Gaussian noise (AWGN) coupled with impulse noise (IN). Many mixed noise removal methods are detection based methods. They first detect the locations of IN pixels and then remove the mixed noise. However, such methods tend to generate many artifacts when the mixed noise is strong. In this paper, we propose a simple yet effective method, namely weighted encoding with sparse nonlocal regularization (WESNR), for mixed noise removal. In WESNR, there is not an explicit step of impulse pixel detection; instead, soft impulse pixel detection via weighted encoding is used to deal with IN and AWGN simultaneously. Meanwhile, the image sparsity prior and nonlocal self-similarity prior are integrated into a regularization term and introduced into the variational encoding framework. Experimental results show that the proposed WESNR method achieves leading mixed noise removal performance in terms of both quantitative measures and visual quality. PMID- 24760907 TI - Cascade category-aware visual search. AB - Incorporating image classification into image retrieval system brings many attractive advantages. For instance, the search space can be narrowed down by rejecting images in irrelevant categories of the query. The retrieved images can be more consistent in semantics by indexing and returning images in the relevant categories together. However, due to their different goals on recognition accuracy and retrieval scalability, it is hard to efficiently incorporate most image classification works into large-scale image search. To study this problem, we propose cascade category-aware visual search, which utilizes weak category clue to achieve better retrieval accuracy, efficiency, and memory consumption. To capture the category and visual clues of an image, we first learn category-visual words, which are discriminative and repeatable local features labeled with categories. By identifying category-visual words in database images, we are able to discard noisy local features and extract image visual and category clues, which are hence recorded in a hierarchical index structure. Our retrieval system narrows down the search space by: 1) filtering the noisy local features in query; 2) rejecting irrelevant categories in database; and 3) preforming discriminative visual search in relevant categories. The proposed algorithm is tested on object search, landmark search, and large-scale similar image search on the large-scale LSVRC10 data set. Although the category clue introduced is weak, our algorithm still shows substantial advantages in retrieval accuracy, efficiency, and memory consumption than the state-of-the-art. PMID- 24760908 TI - Weighted KPCA degree of homogeneity amended nonclassical receptive field inhibition model for salient contour extraction in low-light-level image. AB - The stimulus response of the classical receptive field (CRF) of neuron in primary visual cortex is affected by its periphery [i.e., non-CRF (nCRF)]. This modulation exerts inhibition, which depends primarily on the correlation of both visual stimulations. The theory of periphery and center interaction with visual characteristics can be applied in night vision information processing. In this paper, a weighted kernel principal component analysis (WKPCA) degree of homogeneity (DH) amended inhibition model inspired by visual perceptual mechanisms is proposed to extract salient contour from complex natural scene in low-light-level image. The core idea is that multifeature analysis can recognize the homogeneity in modulation coverage effectively. Computationally, a novel WKPCA algorithm is presented to eliminate outliers and anomalous distribution in CRF and accomplish principal component analysis precisely. On this basis, a new concept and computational procedure for DH is defined to evaluate the dissimilarity between periphery and center comprehensively. Through amending the inhibition from nCRF to CRF by DH, our model can reduce the interference of noises, suppress details, and textures in homogeneous regions accurately. It helps to further avoid mutual suppression among inhomogeneous regions and contour elements. This paper provides an improved computational visual model with high performance for contour detection from cluttered natural scene in night vision image. PMID- 24760909 TI - Sparse spatial coding: a novel approach to visual recognition. AB - Successful image-based object recognition techniques have been constructed founded on powerful techniques such as sparse representation, in lieu of the popular vector quantization approach. However, one serious drawback of sparse space-based methods is that local features that are quite similar can be quantized into quite distinct visual words. We address this problem with a novel approach for object recognition, called sparse spatial coding, which efficiently combines a sparse coding dictionary learning and spatial constraint coding stage. We performed experimental evaluation using the Caltech 101, Caltech 256, Corel 5000, and Corel 10000 data sets, which were specifically designed for object recognition evaluation. Our results show that our approach achieves high accuracy comparable with the best single feature method previously published on those databases. Our method outperformed, for the same bases, several multiple feature methods, and provided equivalent, and in few cases, slightly less accurate results than other techniques specifically designed to that end. Finally, we report state-of-the-art results for scene recognition on COsy Localization Dataset (COLD) and high performance results on the MIT-67 indoor scene recognition, thus demonstrating the generalization of our approach for such tasks. PMID- 24760910 TI - Spatial filtering based on canonical correlation analysis for classification of evoked or event-related potentials in EEG data. AB - Classification of evoked or event-related potentials is an important prerequisite for many types of brain-computer interfaces (BCIs). To increase classification accuracy, spatial filters are used to improve the signal-to-noise ratio of the brain signals and thereby facilitate the detection and classification of evoked or event-related potentials. While canonical correlation analysis (CCA) has previously been used to construct spatial filters that increase classification accuracy for BCIs based on visual evoked potentials, we show in this paper, how CCA can also be used for spatial filtering of event-related potentials like P300. We also evaluate the use of CCA for spatial filtering on other data with evoked and event-related potentials and show that CCA performs consistently better than other standard spatial filtering methods. PMID- 24760911 TI - Segmentation and classification of gait cycles. AB - Gait abnormalities can be studied by means of instrumented gait analysis. Foot switches are useful to study the foot-floor contact and for timing the gait phases in many gait disorders, provided that a reliable foot-switch signal may be collected. Considering long walks allows reducing the intra-subject variability, but requires automatic and user-independent methods to analyze a large number of gait cycles. The aim of this work is to describe and validate an algorithm for the segmentation of the foot-switch signal and the classification of the gait cycles. The performance of the algorithm was assessed comparing its results against the manual segmentation and classification performed by a gait analysis expert on the same signal. The performance was found to be equal to 100% for healthy subjects and over 98% for pathological subjects. The algorithm allows determining the atypical cycles (cycles that do not match the standard sequence of gait phases) for many different kinds of pathological gait, since it is not based on pathology-specific templates. PMID- 24760912 TI - Balance testing with inertial sensors in patients with Parkinson's disease: assessment of motor subtypes. AB - In this study, the use of an instrumented balance test based on inertial sensors was evaluated in patients with Parkinson's disease (PD). We aimed to objectively characterize motor subtypes of PD [tremor dominant (TD) and postural instability gait difficulty (PIGD)], to help to quantitatively classify the PD subjects into motor subtypes. Subjects were studied performing postural tests, while wearing a device including a tri-axial accelerometer on the lower back, in four different experimental conditions that depended on feet position (feet-together or semi tandem) and vision (eyes open or closed). Postural measures, after a reliability check, were tested to identify their sensitivity to the disease, to the PD subtypes, and to the experimental conditions. The results highlight the possibility of distinguishing between the TD and PIGD subtypes by means of objective postural measures that are able to detect tremor and PIGD features and are able to classify a subject as TD or PIGD with good accuracy. Feet position influences frequency measures, whereas eyes closure influences the displacement measures and enhances differences between PD and control subjects, suggesting that postural displacement measures may be capable of detecting different adaptation processes to external sensory conditions between patients with PD and control subjects. PMID- 24760913 TI - Gesture therapy: an upper limb virtual reality-based motor rehabilitation platform. AB - Virtual reality platforms capable of assisting rehabilitation must provide support for rehabilitation principles: promote repetition, task oriented training, appropriate feedback, and a motivating environment. As such, development of these platforms is a complex process which has not yet reached maturity. This paper presents our efforts to contribute to this field, presenting Gesture Therapy, a virtual reality-based platform for rehabilitation of the upper limb. We describe the system architecture and main features of the platform and provide preliminary evidence of the feasibility of the platform in its current status. PMID- 24760914 TI - Demonstration of a semi-autonomous hybrid brain-machine interface using human intracranial EEG, eye tracking, and computer vision to control a robotic upper limb prosthetic. AB - To increase the ability of brain-machine interfaces (BMIs) to control advanced prostheses such as the modular prosthetic limb (MPL), we are developing a novel system: the Hybrid Augmented Reality Multimodal Operation Neural Integration Environment (HARMONIE). This system utilizes hybrid input, supervisory control, and intelligent robotics to allow users to identify an object (via eye tracking and computer vision) and initiate (via brain-control) a semi-autonomous reach grasp-and-drop of the object by the MPL. Sequential iterations of HARMONIE were tested in two pilot subjects implanted with electrocorticographic (ECoG) and depth electrodes within motor areas. The subjects performed the complex task in 71.4% (20/28) and 67.7% (21/31) of trials after minimal training. Balanced accuracy for detecting movements was 91.1% and 92.9%, significantly greater than chance accuracies (p < 0.05). After BMI-based initiation, the MPL completed the entire task 100% (one object) and 70% (three objects) of the time. The MPL took approximately 12.2 s for task completion after system improvements implemented for the second subject. Our hybrid-BMI design prevented all but one baseline false positive from initiating the system. The novel approach demonstrated in this proof-of-principle study, using hybrid input, supervisory control, and intelligent robotics, addresses limitations of current BMIs. PMID- 24760915 TI - Novel targeted sensory reinnervation technique to restore functional hand sensation after transhumeral amputation. AB - We present a case study of a novel variation of the targeted sensory reinnervation technique that provides additional control over sensory restoration after transhumeral amputation. The use of intraoperative somatosensory evoked potentials on individual fascicles of the median and ulnar nerves allowed us to specifically target sensory fascicles to reroute to target cutaneous nerves at a distance away from anticipated motor sites in a transhumeral amputee. This resulted in restored hand maps of the median and ulnar nerve in discrete spatially separated areas. In addition, the subject was able to use native and reinnervated muscle sites to control a robotic arm while simultaneously sensing touch and force feedback from the robotic gripper in a physiologically correct manner. This proof of principle study is the first to demonstrate the ability to have simultaneous dual flow of information (motor and sensory) within the residual limb. In working towards clinical deployment of a sensory integrated prosthetic device, this surgical method addresses the important issue of restoring a usable access point to provide natural hand sensation after upper limb amputation. PMID- 24760916 TI - Transparent muscle characterization using quantitative electromyography: different binarization mappings. AB - Evaluation of patients with suspected neuromuscular disorders is typically based on qualitative visual and auditory assessment of needle detected eletromyographic (EMG) signals; the resulting muscle characterization is subjective and highly dependent on the skill and experience of the examiner. Quantitative electromyography (QEMG) techniques were developed to extract motor unit potential trains (MUPTs) from needle detected EMG signals, and estimate features capturing motor unit potential (MUP) morphology and quantifying morphological consistency across MUPs belonging to the same MUPT. The aim of this study is to improve available methods for obtaining transparent muscle characterizations from features obtained using QEMG techniques. More specifically, we investigate the following. 1) Can the use of binarization mappings improve muscle categorization accuracies of transparent methods? 2) What are the appropriate binarization mappings in terms of accuracy and transparency? Results from four different sets of examined limb muscles (342 muscles in total) demonstrate that four out of the 10 investigated binarization mappings based on transparent characterization methods outperformed the multi-class characterizers based on Gaussian mixture models (GMM) and the corresponding binarization mappings based on GMM. This suggests that the use of an appropriate binarization mapping can overcome the decrease in categorization accuracy associated with quantizing MUPT features, which is necessary to obtain transparent characterizations. This performance gain can be attributed to the use of more relevant features and tuned quantization to obtain more specific binary characterizations. PMID- 24760923 TI - Fully automatic control of paraplegic FES pedaling using higher-order sliding mode and fuzzy logic control. AB - In this paper, a fully automatic robust control strategy is proposed for control of paraplegic pedaling using functional electrical stimulation (FES). The method is based on higher-order sliding mode (HOSM) control and fuzzy logic control. In FES, the strength of muscle contraction can be altered either by varying the pulse width (PW) or by the pulse amplitude (PA) of the stimulation signal. The proposed control strategy regulates simultaneously both PA and PW (i.e., PA/PW modulation). A HOSM controller is designed for regulating the PW and a fuzzy logic controller for the PA. The proposed control scheme is free-model and does not require any offline training phase and subject-specific information. Simulation studies on a virtual patient and experiments on three paraplegic subjects demonstrate good tracking performance and robustness of the proposed control strategy against muscle fatigue and external disturbances during FES induced pedaling. The results of simulation studies show that the power and cadence tracking errors are 5.4% and 4.8%, respectively. The experimental results indicate that the proposed controller can improve pedaling system efficacy and increase the endurance of FES pedaling. The average of power tracking error over three paraplegic subjects is 7.4+/-1.4% using PA/PW modulation, while the tracking error is 10.2+/-1.2% when PW modulation is used. The subjects could pedal for 15 min with about 4.1% power loss at the end of experiment using proposed control strategy, while the power loss is 14.3% using PW modulation. The controller could adjust the stimulation intensity to compensate the muscle fatigue during long period of FES pedaling. PMID- 24760925 TI - Comparing functional EMG characteristics between zero-order and first-order interface dynamics. AB - The optimal control scheme for powered prostheses can be determined using simulation experiments, for which an accurate model of prosthesis control is essential. This paper focuses on electromyographic (EMG) control signal characteristics across two different control schemes. We constructed a functional EMG model comprising three EMG signal characteristics-standard deviation, kurtosis, and median power frequency-using data collected under realistic conditions for prosthesis control (closed-loop, dynamic, anisometric contractions). We examined how the model changed when subjects used zero-order or first-order control. Control order had a statistically significant effect on EMG characteristics, but the effect size was small and generally did not exceed inter subject variability. Therefore, we suggest that this functional EMG model remains valid across different control schemes. PMID- 24760924 TI - Development of a biomimetic hand exotendon device (BiomHED) for restoration of functional hand movement post-stroke. AB - Significant functional impairment of the hand is common among stroke survivors and restoration of hand function should be prioritized during post-stroke rehabilitation. The goal of this study was to develop a novel biomimetic device to assist patients in producing complex hand movements with a limited number of actuators. The Biomimetic Hand Exoskeleton Device (BiomHED) is actuated by exotendons that mimic the geometry of the major tendons of the hand. Ten unimpaired subjects and four chronic stroke survivors participated in experiments that tested the efficacy of the system. The exotendons reproduced distinct spatial joint coordination patterns similar to their target muscle-tendon units for both subject groups. In stroke survivors, the exotendon-produced joint angular displacements were smaller, but not significantly different, than those of unimpaired subjects [Formula: see text]. Even with limited use of the BiomHED, the kinematic workspace of the index finger increased by 63%-1014% in stroke survivors. The device improved the kinematics of the tip-pinch task in stroke survivors and resulted in a significant reduction in the fingertip-thumb tip distance ( 17.9 +/-15.3 mm). This device is expected to enable effective "task oriented" training of the hand post-stroke. PMID- 24760926 TI - Identification of contaminant type in surface electromyography (EMG) signals. AB - The ability to recognize various forms of contaminants in surface electromyography (EMG) signals and to ascertain the overall quality of such signals is important in many EMG-enabled rehabilitation systems. In this paper, new methods for the automatic identification of commonly occurring contaminant types in surface EMG signals are presented. Such methods are advantageous because the contaminant type is typically not known in advance. The presented approach uses support vector machines as the main classification system. Both simulated and real EMG signals are used to assess the performance of the methods. The contaminants considered include: 1) electrocardiogram interference; 2) motion artifact; 3) power line interference; 4) amplifier saturation; and 5) additive white Gaussian noise. Results show that the contaminants can readily be distinguished at lower signal to noise ratios, with a growing degree of confusion at higher signal to noise ratios, where their effects on signal quality are less significant. PMID- 24760927 TI - Integrating language information with a hidden Markov model to improve communication rate in the P300 speller. AB - The P300 speller is a common brain-computer interface (BCI) application designed to communicate language by detecting event related potentials in a subject's electroencephalogram (EEG) signal. Information about the structure of natural language can be valuable for BCI communication systems, but few attempts have been made to incorporate this domain knowledge into the classifier. In this study, we treat BCI communication as a hidden Markov model (HMM) where hidden states are target characters and the EEG signal is the visible output. Using the Viterbi algorithm, language information can be incorporated in classification and errors can be corrected automatically. This method was first evaluated offline on a dataset of 15 healthy subjects who had a significant increase in bit rate from a previously published naive Bayes approach and an average 32% increase from standard classification with dynamic stopping. An online pilot study of five healthy subjects verified these results as the average bit rate achieved using the HMM method was significantly higher than that using the naive Bayes and standard methods. These findings strongly support the integration of domain specific knowledge into BCI classification to improve system performance and accuracy. PMID- 24760928 TI - A device for emulating cuff recordings of action potentials propagating along peripheral nerves. AB - This paper describes a device that emulates propagation of action potentials along a peripheral nerve, suitable for reproducible testing of bio-potential recording systems using nerve cuff electrodes. The system is a microcontroller based stand-alone instrument which uses established nerve and electrode models to represent neural activity of real nerves recorded with a nerve cuff interface, taking into consideration electrode impedance, voltages picked up by the electrodes, and action potential propagation characteristics. The system emulates different scenarios including compound action potentials with selectable propagation velocities and naturally occurring nerve traffic from different velocity fiber populations. Measured results from a prototype implementation are reported and compared with in vitro recordings from Xenopus Laevis frog sciatic nerve, demonstrating that the electrophysiological setting is represented to a satisfactory degree, useful for the development, optimization and characterization of future recording systems. PMID- 24760929 TI - Dexterous control of a prosthetic hand using fine-wire intramuscular electrodes in targeted extrinsic muscles. AB - Restoring dexterous motor function equivalent to that of the human hand after amputation is one of the major goals in rehabilitation engineering. To achieve this requires the implementation of a effortless human-machine interface that bridges the artificial hand to the sources of volition. Attempts to tap into the neural signals and to use them as control inputs for neuroprostheses range in invasiveness and hierarchical location in the neuromuscular system. Nevertheless today, the primary clinically viable control technique is the electromyogram measured peripherally by surface electrodes. This approach is neither physiologically appropriate nor dexterous because arbitrary finger movements or hand postures cannot be obtained. Here we demonstrate the feasibility of achieving real-time, continuous and simultaneous control of a multi-digit prosthesis directly from forearm muscles signals using intramuscular electrodes on healthy subjects. Subjects contracted physiologically appropriate muscles to control four degrees of freedom of the fingers of a physical robotic hand independently. Subjects described the control as intuitive and showed the ability to drive the hand into 12 postures without explicit training. This is the first study in which peripheral neural correlates were processed in real-time and used to control multiple digits of a physical hand simultaneously in an intuitive and direct way. PMID- 24760930 TI - Embedded human control of robots using myoelectric interfaces. AB - Myoelectric controlled interfaces have become a research interest for use in advanced prostheses, exoskeletons, and robot teleoperation. Current research focuses on improving a user's initial performance, either by training a decoding function for a specific user or implementing "intuitive" mapping functions as decoders. However, both approaches are limiting, with the former being subject specific, and the latter task specific. This paper proposes a paradigm shift on myoelectric interfaces by embedding the human as controller of the system to be operated. Using abstract mapping functions between myoelectric activity and control actions for a task, this study shows that human subjects are able to control an artificial system with increasing efficiency by just learning how to control it. The method efficacy is tested by using two different control tasks and four different abstract mappings relating upper limb muscle activity to control actions for those tasks. The results show that all subjects were able to learn the mappings and improve their performance over time. More interestingly, a chronological evaluation across trials reveals that the learning curves transfer across subsequent trials having the same mapping, independent of the tasks to be executed. This implies that new muscle synergies are developed and refined relative to the mapping used by the control task, suggesting that maximal performance may be achieved by learning a constant, arbitrary mapping function rather than dynamic subject- or task-specific functions. Moreover, the results indicate that the method may extend to the neural control of any device or robot, without limitations for anthropomorphism or human-related counterparts. PMID- 24760931 TI - Real-time and offline performance of pattern recognition myoelectric control using a generic electrode grid with targeted muscle reinnervation patients. AB - Targeted muscle reinnervation (TMR) is a surgical technique that creates myoelectric prosthesis control sites for high-level amputees. The electromyographic (EMG) signal patterns provided by the reinnervated muscles are well-suited for pattern recognition control. Pattern recognition allows for control of a greater number of degrees of freedom (DOF) than the conventional, EMG amplitude-based approach. Previous pattern recognition studies have shown benefit in placing electrodes directly over the reinnervated muscles. Localizing the optimal TMR locations is inconvenient and time consuming. In this contribution, we demonstrate that a clinically practical grid arrangement of electrodes yields real-time control performance that is equivalent to, or better than, the site-specific electrode placement for simultaneous control of multiple DOFs using pattern recognition. Additional findings indicate that grid-like electrode arrangement yields significantly lower classification errors for classifiers with a large number of movement classes ( > 9). These findings suggest that a grid electrode arrangement can be effectively used to control a multi-DOF upper limb prosthesis while reducing the time and effort associated with fitting the prosthesis due to clinical localization of control sites on amputee patients. PMID- 24760932 TI - Movement error rate for evaluation of machine learning methods for sEMG-based hand movement classification. AB - There has been increasing interest in applying learning algorithms to improve the dexterity of myoelectric prostheses. In this work, we present a large-scale benchmark evaluation on the second iteration of the publicly released NinaPro database, which contains surface electromyography data for 6 DOF force activations as well as for 40 discrete hand movements. The evaluation involves a modern kernel method and compares performance of three feature representations and three kernel functions. Both the force regression and movement classification problems can be learned successfully when using a nonlinear kernel function, while the exp- chi(2) kernel outperforms the more popular radial basis function kernel in all cases. Furthermore, combining surface electromyography and accelerometry in a multimodal classifier results in significant increases in accuracy as compared to when either modality is used individually. Since window based classification accuracy should not be considered in isolation to estimate prosthetic controllability, we also provide results in terms of classification mistakes and prediction delay. To this extent, we propose the movement error rate as an alternative to the standard window-based accuracy. This error rate is insensitive to prediction delays and it allows us therefore to quantify mistakes and delays as independent performance characteristics. This type of analysis confirms that the inclusion of accelerometry is superior, as it results in fewer mistakes while at the same time reducing prediction delay. PMID- 24760933 TI - Correlation analysis of electromyogram signals for multiuser myoelectric interfaces. AB - An inability to adapt myoelectric interfaces to a novel user's unique style of hand motion, or even to adapt to the motion style of an opposite limb upon which the interface is trained, are important factors inhibiting the practical application of myoelectric interfaces. This is mainly attributed to the individual differences in the exhibited electromyogram (EMG) signals generated by the muscles of different limbs. We propose in this paper a multiuser myoelectric interface which easily adapts to novel users and maintains good movement recognition performance. The main contribution is a framework for implementing style-independent feature transformation by using canonical correlation analysis (CCA) in which different users' data is projected onto a unified-style space. The proposed idea is summarized into three steps: 1) train a myoelectric pattern classifier on the set of style-independent features extracted from multiple users using the proposed CCA-based mapping; 2) create a new set of features describing the movements of a novel user during a quick calibration session; and 3) project the novel user's features onto a lower dimensional unified-style space with features maximally correlated with training data and classify accordingly. The proposed method has been validated on a set of eight intact-limbed subjects, left and-right handed, performing ten classes of bilateral synchronous fingers movements with four electrodes on each forearm. The method was able to overcome individual differences through the style-independent framework with accuracies of > 83% across multiple users. Testing was also performed on a set of ten intact limbed and six below-elbow amputee subjects as they performed finger and thumb movements. The proposed framework allowed us to train the classifier on a normal subject's data while subsequently testing it on an amputee's data after calibration with a performance of > 82% on average across all amputees. PMID- 24760934 TI - The extraction of neural information from the surface EMG for the control of upper-limb prostheses: emerging avenues and challenges. AB - Despite not recording directly from neural cells, the surface electromyogram (EMG) signal contains information on the neural drive to muscles, i.e., the spike trains of motor neurons. Using this property, myoelectric control consists of the recording of EMG signals for extracting control signals to command external devices, such as hand prostheses. In commercial control systems, the intensity of muscle activity is extracted from the EMG and used for single degrees of freedom activation (direct control). Over the past 60 years, academic research has progressed to more sophisticated approaches but, surprisingly, none of these academic achievements has been implemented in commercial systems so far. We provide an overview of both commercial and academic myoelectric control systems and we analyze their performance with respect to the characteristics of the ideal myocontroller. Classic and relatively novel academic methods are described, including techniques for simultaneous and proportional control of multiple degrees of freedom and the use of individual motor neuron spike trains for direct control. The conclusion is that the gap between industry and academia is due to the relatively small functional improvement in daily situations that academic systems offer, despite the promising laboratory results, at the expense of a substantial reduction in robustness. None of the systems so far proposed in the literature fulfills all the important criteria needed for widespread acceptance by the patients, i.e. intuitive, closed-loop, adaptive, and robust real-time ( 200 ms delay) control, minimal number of recording electrodes with low sensitivity to repositioning, minimal training, limited complexity and low consumption. Nonetheless, in recent years, important efforts have been invested in matching these criteria, with relevant steps forwards. PMID- 24760935 TI - Noninvasive, accurate assessment of the behavior of representative populations of motor units in targeted reinnervated muscles. AB - Targeted muscle reinnervation (TMR) redirects nerves that have lost their target, due to amputation, to remaining muscles in the region of the stump with the intent of establishing intuitive myosignals to control a complex prosthetic device. In order to directly recover the neural code underlying an attempted limb movement, in this paper, we present the decomposition of high-density surface electromyographic (EMG) signals detected from three TMR patients into the individual motor unit spike trains. The aim was to prove, for the first time, the feasibility of decoding the neural drive that would reach muscles of the missing limb in TMR patients, to show the accuracy of the decoding, and to demonstrate the representativeness of the pool of extracted motor units. Six to seven flexible EMG electrode grids of 64 electrodes each were mounted over the reinnervated muscles of each patient, resulting in up to 448 EMG signals. The subjects were asked to attempt elbow extension and flexion, hand open and close, wrist extension and flexion, wrist pronation and supination, of their missing limb. The EMG signals were decomposed using the Convolution Kernel Compensation technique and the decomposition accuracy was evaluated with a signal-based index of accuracy, called pulse-to-noise ratio (PNR). The results showed that the spike trains of 3 to 27 motor units could be identified for each task, with a sensitivity of the decomposition > 90%, as revealed by PNR. The motor unit discharge rates were within physiological values of normally innervated muscles. Moreover, the detected motor units showed a high degree of common drive so that the set of extracted units per task was representative of the behavior of the population of active units. The results open a path for a new generation of human machine interfaces in which the control signals are extracted from noninvasive recordings and the obtained neural information is based directly on the spike trains of motor neurons. PMID- 24760936 TI - Test-retest reliability of robotic assessment measures for the evaluation of upper limb recovery. AB - Rehabilitation robots have built-in technology and sensors that allow accurate measurement of movement kinematics and kinetics, which can be used to derive measures related to upper limb performance and highlight changes in motor behavior due to rehabilitation. This study aimed to assess the test-retest reliability of some robot-measured parameters by analyzing their intra-session and inter-session (day-by-day) variability. The study was carried out in two groups: 31 patients after stroke and 15 healthy subjects. Both groups practiced two different motor tasks consisting of point-to-point reaching movements in the shape of two geometrical figures that were selected for the assessment of global and directional (eight directions of the workspace) test-retest reliability. The reliability of six parameters measuring movement velocity, accuracy, efficiency and smoothness was assessed intra-session and inter-session by the ICC, SEM, and CV. Healthy subjects exhibited very high ICC values (> 0.85) and low SEM for all parameters. Patients had high ICC values and low SEM but their global reliability was generally lower compared to healthy subjects. In addition, their inter session reliability showed very high ICC values (> 0.91) and low SEM for all parameters. Direction analysis showed that in some parameters the reliability was generally high but not homogeneous in all directions. In addition, some directions showed systematic error. This study demonstrates that robot-measured parameters are reliable and can be considered ideal candidates for use in combination with impairment and functional clinical scales to evaluate motor improvement during robot-assisted neurorehabilitation. PMID- 24760937 TI - Estimation of human ankle impedance during the stance phase of walking. AB - Human joint impedance is the dynamic relationship between the differential change in the position of a perturbed joint and the corresponding response torque; it is a fundamental property that governs how humans interact with their environments. It is critical to characterize ankle impedance during the stance phase of walking to elucidate how ankle impedance is regulated during locomotion, as well as provide the foundation for future development of natural, biomimetic powered prostheses and their control systems. In this study, ankle impedance was estimated using a model consisting of stiffness, damping and inertia. Ankle torque was well described by the model, accounting for 98 +/-1.2% of the variance. When averaged across subjects, the stiffness component of impedance was found to increase linearly from 1.5 to 6.5 Nm/rad/kg between 20% and 70% of stance phase. The damping component was found to be statistically greater than zero only for the estimate at 70% of stance phase, with a value of 0.03 Nms/rad/kg. The slope of the ankle's torque-angle curve-known as the quasi stiffness-was not statistically different from the ankle stiffness values, and showed remarkable similarity. Finally, using the estimated impedance, the specifications for a biomimetic powered ankle prosthesis were introduced that would accurately emulate human ankle impedance during locomotion. PMID- 24760938 TI - Controlled nerve ablation with direct current: parameters and mechanisms. AB - Spastic hypertonus (muscle over-activity) often develops after spinal cord injury or stroke. Chemodenervating agents such as Botulinum toxin A (BtA) and phenol are often used to treat this condition. We have previously shown that the use of direct current (DC) to create controlled lesions of peripheral nerves may provide a means of reducing spastic hypertonus. Here, we explored a range of stimulation parameters that could be used clinically. Nerves were lesioned with DC in chronically implanted animals and the outcome was tracked over many months. In addition, we used DC to ablate nerves in animals with decerebrate rigidity (an animal model of spastic hypertonus) and we explored the possible mechanisms of DC nerve ablation. We found that nerve ablation with DC was effective in reducing hypertonus. Some stimulation paradigms were more likely to be clinically acceptable than others. Furthermore we showed that nerve regeneration occurs in the months following DC nerve ablation and we demonstrated that the ablation procedure is repeatable, much like BtA treatment. Regarding mechanism, our results did not support the hypothesis that DC caused nerve damage by overactivating sodium channels. Rather, the mechanism of damage seems to be related to changes in pH. PMID- 24760939 TI - Simulating transcranial direct current stimulation with a detailed anisotropic human head model. AB - Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique able to induce long-lasting changes in cortical excitability that can benefit cognitive functioning and clinical treatment. In order to both better understand the mechanisms behind tDCS and possibly improve the technique, finite element models are used to simulate tDCS of the human brain. With the detailed anisotropic head model presented in this study, we provide accurate predictions of tDCS in the human brain for six of the practically most-used setups in clinical and cognitive research, targeting the primary motor cortex, dorsolateral prefrontal cortex, inferior frontal gyrus, occipital cortex, and cerebellum. We present the resulting electric field strengths in the complete brain and introduce new methods to evaluate the effectivity in the target area specifically, where we have analyzed both the strength and direction of the field. For all cerebral targets studied, the currently accepted configurations produced sub-optimal field strengths. The configuration for cerebellum stimulation produced relatively high field strengths in its target area, but it needs higher input currents than cerebral stimulation does. This study suggests that improvements in the effects of transcranial direct current stimulation are achievable. PMID- 24760941 TI - Designing dynamical properties of brain-machine interfaces to optimize task specific performance. AB - Brain-machine interfaces (BMIs) are dynamical systems whose properties ultimately influence performance. For instance, a 2-D BMI in which cursor position is controlled using a Kalman filter will, by default, create an attractor point that "pulls" the cursor to particular points in the workspace. If created unintentionally, such effects may not be beneficial for BMI performance. However, there have been few empirical studies exploring how various dynamical effects of closed-loop BMIs ultimately influence performance. In this work, we utilize experimental data from two macaque monkeys operating a closed-loop BMI to reach to 2-D targets and show that certain dynamical properties correlate with performance loss. We also show that other dynamical properties represent tradeoffs between naturally competing objectives, such as speed versus accuracy. These findings highlight the importance of fine-tuning the dynamical properties of closed-loop BMIs to optimize task-specific performance. PMID- 24760940 TI - A multi-views multi-learners approach towards dysarthric speech recognition using multi-nets artificial neural networks. AB - Automatic speech recognition (ASR) can be very helpful for speakers who suffer from dysarthria, a neurological disability that damages the control of motor speech articulators. Although a few attempts have been made to apply ASR technologies to sufferers of dysarthria, previous studies show that such ASR systems have not attained an adequate level of performance. In this study, a dysarthric multi-networks speech recognizer (DM-NSR) model is provided using a realization of multi-views multi-learners approach called multi-nets artificial neural networks, which tolerates variability of dysarthric speech. In particular, the DM-NSR model employs several ANNs (as learners) to approximate the likelihood of ASR vocabulary words and to deal with the complexity of dysarthric speech. The proposed DM-NSR approach was presented as both speaker-dependent and speaker independent paradigms. In order to highlight the performance of the proposed model over legacy models, multi-views single-learner models of the DM-NSRs were also provided and their efficiencies were compared in detail. Moreover, a comparison among the prominent dysarthric ASR methods and the proposed one is provided. The results show that the DM-NSR recorded improved recognition rate by up to 24.67% and the error rate was reduced by up to 8.63% over the reference model. PMID- 24760942 TI - Feature extraction using extrema sampling of discrete derivatives for spike sorting in implantable upper-limb neural prostheses. AB - Next generation neural interfaces for upper-limb (and other) prostheses aim to develop implantable interfaces for one or more nerves, each interface having many neural signal channels that work reliably in the stump without harming the nerves. To achieve real-time multi-channel processing it is important to integrate spike sorting on-chip to overcome limitations in transmission bandwidth. This requires computationally efficient algorithms for feature extraction and clustering suitable for low-power hardware implementation. This paper describes a new feature extraction method for real-time spike sorting based on extrema analysis (namely positive peaks and negative peaks) of spike shapes and their discrete derivatives at different frequency bands. Employing simulation across different datasets, the accuracy and computational complexity of the proposed method are assessed and compared with other methods. The average classification accuracy of the proposed method in conjunction with online sorting (O-Sort) is 91.6%, outperforming all the other methods tested with the O-Sort clustering algorithm. The proposed method offers a better tradeoff between classification error and computational complexity, making it a particularly strong choice for on-chip spike sorting. PMID- 24760943 TI - Dynamical learning and tracking of tremor and dyskinesia from wearable sensors. AB - We have developed and evaluated several dynamical machine-learning algorithms that were designed to track the presence and severity of tremor and dyskinesia with 1-s resolution by analyzing signals collected from Parkinson's disease (PD) patients wearing small numbers of hybrid sensors with both 3-D accelerometeric and surface-electromyographic modalities. We tested the algorithms on a 44-h signal database built from hybrid sensors worn by eight PD patients and four healthy subjects who carried out unscripted and unconstrained activities of daily living in an apartment-like environment. Comparison of the performance of our machine-learning algorithms against independent clinical annotations of disorder presence and severity demonstrates that, despite their differing approaches to dynamic pattern classification, dynamic neural networks, dynamic support vector machines, and hidden Markov models were equally effective in keeping error rates of the dynamic tracking well below 10%. A common set of experimentally derived signal features were used to train the algorithm without the need for subject specific learning. We also found that error rates below 10% are achievable even when our algorithms are tested on data from a sensor location that is different from those used in algorithm training. PMID- 24760944 TI - Maximum likelihood estimation of motor unit firing pattern statistics. AB - Estimation of motor unit firing pattern statistics is a valuable method in physiological studies and a key procedure in electromyographic (EMG) decomposition algorithms. However, if any firings within the pattern are undetected or missed during the decomposition process, the estimation procedure can be disrupted. In order to provide an optimal solution, we present a maximum likelihood estimator of EMG firing pattern statistics, taking into account that some firings may be undetected. A model of the inter-discharge interval (IDI) probability density function with missing firings has been employed to derive the maximum likelihood estimator of the mean and standard deviation of the IDIs. Actual calculation of the maximum likelihood solution has been obtained by means of numerical optimization. The proposed estimator has been evaluated and compared to other previously developed algorithms by means of simulation experiments and has been tested on real signals. The new estimator was found to be robust and reliable in diverse conditions: IDI distributions with a high coefficient of variance or considerable skewness. Moreover, the proposed estimator outperforms previous algorithms both in simulated and real conditions. PMID- 24760945 TI - A 13.56-mbps pulse delay modulation based transceiver for simultaneous near-field data and power transmission. AB - A fully-integrated near-field wireless transceiver has been presented for simultaneous data and power transmission across inductive links, which operates based on pulse delay modulation (PDM) technique. PDM is a low-power carrier-less modulation scheme that offers wide bandwidth along with robustness against strong power carrier interference, which makes it suitable for implantable neuroprosthetic devices, such as retinal implants. To transmit each bit, a pattern of narrow pulses are generated at the same frequency of the power carrier across the transmitter (Tx) data coil with specific time delays to initiate decaying ringing across the tuned receiver (Rx) data coil. This ringing shifts the zero-crossing times of the undesired power carrier interference on the Rx data coil, resulting in a phase shift between the signals across Rx power and data coils, from which the data bit stream can be recovered. A PDM transceiver prototype was fabricated in a 0.35- MUm standard CMOS process, occupying 1.6 mm(2). The transceiver achieved a measured 13.56 Mbps data rate with a raw bit error rate (BER) of 4.3*10(-7) at 10 mm distance between figure-8 data coils, despite a signal-to-interference ratio (SIR) of -18.5 dB across the Rx data coil. At the same time, a class-D power amplifier, operating at 13.56 MHz, delivered 42 mW of regulated power across a separate pair of high-Q power coils, aligned with the data coils. The PDM data Tx and Rx power consumptions were 960 pJ/bit and 162 pJ/bit, respectively, at 1.8 V supply voltage. PMID- 24760946 TI - Adaptive covariance estimation of non-stationary processes and its application to infer dynamic connectivity from fMRI. AB - Time-varying covariance is an important metric to measure the statistical dependence between non-stationary biological processes. Time-varying covariance is conventionally estimated from short-time data segments within a window having a certain bandwidth, but it is difficult to choose an appropriate bandwidth to estimate covariance with different degrees of non-stationarity. This paper introduces a local polynomial regression (LPR) method to estimate time-varying covariance and performs an asymptotic analysis of the LPR covariance estimator to show that both the estimation bias and variance are functions of the bandwidth and there exists an optimal bandwidth to minimize the mean square error (MSE) locally. A data-driven variable bandwidth selection method, namely the intersection of confidence intervals (ICI), is adopted in LPR for adaptively determining the local optimal bandwidth that minimizes the MSE. Experimental results on simulated signals show that the LPR-ICI method can achieve robust and reliable performance in estimating time-varying covariance with different degrees of variations and under different noise scenarios, making it a powerful tool to study the dynamic relationship between non-stationary biomedical signals. Further, we apply the LPR-ICI method to estimate time-varying covariance of functional magnetic resonance imaging (fMRI) signals in a visual task for the inference of dynamic functional brain connectivity. The results show that the LPR ICI method can effectively capture the transient connectivity patterns from fMRI. PMID- 24760947 TI - Single-cycle-PLL detection for real-time FM-AFM applications. AB - In this paper we present a novel architecture for phase-locked loop (PLL) based high-speed demodulation of frequency-modulated (FM) atomic force microscopy (AFM) signals. In our approach, we use single-sideband (SSB) frequency upconversion to translate the AFM signal from the position sensitive detector to a fixed intermediate frequency (IF) of 10 MHz. In this way, we fully benefit from the excellent noise performance of PLL-based FM demodulators still avoiding the intrinsic bandwidth limitation of such systems. In addition, the upconversion to a fixed IF renders the PLL demodulator independent of the cantilever's resonance frequency, allowing the system to work with a large range of cantilever frequencies. To investigate if the additional noise introduced by the SSB upconverter degrades the system noise figure we present a model of the AM-to-FM noise conversion in PLLs incorporating a phase-frequency detector. Using this model, we can predict an upper corner frequency for the demodulation bandwidth above which the converted noise from the single-sideband upconverter becomes the dominant noise source and therefore begins to deteriorate the overall system performance. The approach is validated by both electrical and AFM measurements obtained with a PCB-based prototype implementing the proposed demodulator architecture. PMID- 24760948 TI - Microarray image denoising using complex Gaussian scale mixtures of complex wavelets. AB - Microarray images when contaminated with noise may severely affect the detection and quantification of gene expression. In this paper, we propose to use the complex Gaussian scale mixture (CGSM) model in complex wavelet domain for noise reduction in complementary DNA microarray images. Based on the joint information in the red and green channel microarray images, we model the complex wavelet coefficients of the channel images jointly using the CGSM, and subsequently perform image denoising using Bayes least square estimator in complex wavelet domain. The experimental results show that using the CGSM of complex wavelet coefficients provides better noise reduction of microarray images compared to other complex wavelet-based models. PMID- 24760949 TI - A learning-based semi-autonomous controller for robotic exploration of unknown disaster scenes while searching for victims. AB - Semi-autonomous control schemes can address the limitations of both teleoperation and fully autonomous robotic control of rescue robots in disaster environments by allowing a human operator to cooperate and share such tasks with a rescue robot as navigation, exploration, and victim identification. In this paper, we present a unique hierarchical reinforcement learning-based semi-autonomous control architecture for rescue robots operating in cluttered and unknown urban search and rescue (USAR) environments. The aim of the controller is to enable a rescue robot to continuously learn from its own experiences in an environment in order to improve its overall performance in exploration of unknown disaster scenes. A direction-based exploration technique is integrated in the controller to expand the search area of the robot via the classification of regions and the rubble piles within these regions. Both simulations and physical experiments in USAR like environments verify the robustness of the proposed HRL-based semi-autonomous controller to unknown cluttered scenes with different sizes and varying types of configurations. PMID- 24760950 TI - Can an Internet-based health risk assessment highlight problems of heart disease risk factor awareness? A cross-sectional analysis. AB - BACKGROUND: Health risk assessments are becoming more popular as a tool to conveniently and effectively reach community-dwelling adults who may be at risk for serious chronic conditions such as coronary heart disease (CHD). The use of such instruments to improve adults' risk factor awareness and concordance with clinically measured risk factor values could be an opportunity to advance public health knowledge and build effective interventions. OBJECTIVE: The objective of this study was to determine if an Internet-based health risk assessment can highlight important aspects of agreement between respondents' self-reported and clinically measured CHD risk factors for community-dwelling adults who may be at risk for CHD. METHODS: Data from an Internet-based cardiovascular health risk assessment (Heart Aware) administered to community-dwelling adults at 127 clinical sites were analyzed. Respondents were recruited through individual hospital marketing campaigns, such as media advertising and print media, found throughout inpatient and outpatient facilities. CHD risk factors from the Framingham Heart Study were examined. Weighted kappa statistics were calculated to measure interrater agreement between respondents' self-reported and clinically measured CHD risk factors. Weighted kappa statistics were then calculated for each sample by strata of overall 10-year CHD risk. Three samples were drawn based on strategies for treating missing data: a listwise deleted sample, a pairwise deleted sample, and a multiple imputation (MI) sample. RESULTS: The MI sample (n=16,879) was most appropriate for addressing missing data. No CHD risk factor had better than marginal interrater agreement (kappa>.60). High-density lipoprotein cholesterol (HDL-C) exhibited suboptimal interrater agreement that deteriorated (eg, kappa<.30) as overall CHD risk increased. Conversely, low density lipoprotein cholesterol (LDL-C) interrater agreement improved (eg, up to kappa=.25) as overall CHD risk increased. Overall CHD risk of the sample was lower than comparative population-based CHD risk (ie, no more than 15% risk of CHD for the sample vs up to a 30% chance of CHD for the population). CONCLUSIONS: Interventions are needed to improve knowledge of CHD risk factors. Specific interventions should address perceptions of HDL-C and LCL-C. Internet-based health risk assessments such as Heart Aware may contribute to public health surveillance, but they must address selection bias of Internet-based recruitment methods. PMID- 24760951 TI - Usage and effectiveness of a fully automated, open-access, Spanish Web-based smoking cessation program: randomized controlled trial. AB - BACKGROUND: The Internet is an optimal setting to provide massive access to tobacco treatments. To evaluate open-access Web-based smoking cessation programs in a real-world setting, adherence and retention data should be taken into account as much as abstinence rate. OBJECTIVE: The objective was to analyze the usage and effectiveness of a fully automated, open-access, Web-based smoking cessation program by comparing interactive versus noninteractive versions. METHODS: Participants were randomly assigned either to the interactive or noninteractive version of the program, both with identical content divided into 4 interdependent modules. At baseline, we collected demographic, psychological, and smoking characteristics of the smokers self-enrolled in the Web-based program of Universidad Nacional de Educacion a Distancia (National Distance Education University; UNED) in Madrid, Spain. The following questionnaires were administered: the anxiety and depression subscales from the Symptom Checklist-90 Revised, the 4-item Perceived Stress Scale, and the Heaviness of Smoking Index. At 3 months, we analyzed dropout rates, module completion, user satisfaction, follow-up response rate, and self-assessed smoking abstinence. RESULTS: A total of 23,213 smokers were registered, 50.06% (11,620/23,213) women and 49.94% (11,593/23,213) men, with a mean age of 39.5 years (SD 10.3). Of these, 46.10% (10,701/23,213) were married and 34.43% (7992/23,213) were single, 46.03% (10,686/23,213) had university education, and 78.73% (18,275/23,213) were employed. Participants smoked an average of 19.4 cigarettes per day (SD 10.3). Of the 11,861 smokers randomly assigned to the interactive version, 2720 (22.93%) completed the first module, 1052 (8.87%) the second, 624 (5.26%) the third, and 355 (2.99%) the fourth. Completion data was not available for the noninteractive version (no way to record it automatically). The 3-month follow-up questionnaire was completed by 1085 of 23,213 enrolled smokers (4.67%). Among them, 406 (37.42%) self-reported not smoking. No difference between groups was found. Assuming missing respondents continued to smoke, the abstinence rate was 1.74% (406/23,213), in which 22,678 were missing respondents. Among follow-up respondents, completing the 4 modules of the intervention increased the chances of smoking cessation (OR 1.95, 95% CI 1.27-2.97, P<.001), as did smoking 30 minutes (OR 1.58, 95% CI 1.04-2.39, P=.003) or 1 hour after waking (OR 1.93, 95% CI 1.27-2.93, P<.001) compared to smoking within the first 5 minutes after waking. CONCLUSIONS: The findings suggest that the UNED Web-based smoking cessation program was very accessible, but a high level of attrition was confirmed. This could be related to the ease of enrollment, its free character, and the absence of direct contact with professionals. It is concluded that, in practice, the greater the accessibility to the program, the lower the adherence and retention. Professional support from health services and the payment of a reimbursable fee could prevent high rates of attrition. PMID- 24760952 TI - Flavonoids from tartary buckwheat induce G2/M cell cycle arrest and apoptosis in human hepatoma HepG2 cells. AB - The cytotoxicity and antioxidant activity on human hepatoma cell line HepG2 of three flavonoids homogenous compounds from tartary buckwheat seeds and bran, namely quercetin, isoquercetin, and rutin, were investigated. The total antioxidant competency detection results indicated that the antioxidant capacity of quercetin was the strongest in a biological response system. A [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay showed that quercetin exhibited the strongest cytotoxic effects against the HepG2 cell line. Flow cytometric analysis indicated that quercetin significantly increased the production of reactive oxygen species, and led to the G2/M phase arrest accompanied by an increase of apoptotic cell death after 48 h of incubation. Quercetin-induced cell apoptosis was shown to involve p53 and p21 up-regulation, Cyclin D1, Cdk2, and Cdk7 down-regulation. These results suggested that the induction of G2/M arrest, apoptosis, and cell death by quercetin may associate with increased expression of p53 and p21, decrease of Cyclin D1, Cdk2, and Cdk7 levels, and generation of reactive oxygen species in cells. This study will help to better understand and fully utilize medicinal resources of plant flavonoids. PMID- 24760956 TI - Selective attention and facial expression recognition in patients with Parkinson's disease. AB - Parkinson's disease (PD) has been associated with facial expression recognition difficulties. However, this impairment could be secondary to the one produced in other cognitive processes involved in recognition, such as selective attention. This study investigates the influence of two selective attention components (inhibition and visual search) on facial expression recognition in PD. We compared facial expression and non-emotional stimuli recognition abilities of 51 patients and 51 healthy controls, by means of an adapted Stroop task, and by "The Face in the Crowd" paradigm, which assess Inhibition and Visual Search abilities, respectively. Patients scored worse than controls in both tasks with facial expressions, but not with the other nonemotional stimuli, indicating specific emotional recognition impairment, not dependent on selective attention abilities. This should be taken into account in patients' neuropsychological assessment given the relevance of emotional facial expression for social communication in everyday settings. PMID- 24760957 TI - The chance of survival and the functional outcome after in-hospital cardiopulmonary resuscitation in older people: a systematic review. AB - BACKGROUND: physicians are frequently confronted with the question whether cardiopulmonary resuscitation (CPR) is a medically appropriate treatment for older people. For physicians, patients and relatives, it is important to know the chance of survival and the functional outcome after CPR in order to make an informed decision. METHODS: a systematic search was performed in MEDLINE, Embase and Cochrane up to November 2012. Studies that were included described the chance of survival, the social status and functional outcome after in-hospital CPR in older people aged 70 years and above. RESULTS: we identified 11,377 publications of which 29 were included in this review; 38.6% of the patients who were 70 years and older had a return of spontaneous circulation. More than half of the patients who initially survived resuscitation died in the hospital before hospital discharge. The pooled survival to discharge after in-hospital CPR was 18.7% for patients between 70 and 79 years old, 15.4% for patients between 80 and 89 years old and 11.6% for patients of 90 years and older. Data on social and functional outcome after surviving CPR were scarce and contradictory. CONCLUSIONS: the chance of survival to hospital discharge for in-hospital CPR in older people is low to moderate (11.6-18.7%) and decreases with age. However, evidence about functional or social outcomes after surviving CPR is scarce. Prospective studies are needed to address this issue and to identify pre-arrest factors that can predict survival in the older people in order to define subgroups that could benefit from CPR. PMID- 24760960 TI - What makes death bad for us? PMID- 24760959 TI - Evaluating melanoma drug response and therapeutic escape with quantitative proteomics. AB - The evolution of cancer therapy into complex regimens with multiple drugs requires novel approaches for the development and evaluation of companion biomarkers. Liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM) is a versatile platform for biomarker measurement. In this study, we describe the development and use of the LC-MRM platform to study the adaptive signaling responses of melanoma cells to inhibitors of HSP90 (XL888) and MEK (AZD6244). XL888 had good anti-tumor activity against NRAS mutant melanoma cell lines as well as BRAF mutant cells with acquired resistance to BRAF inhibitors both in vitro and in vivo. LC-MRM analysis showed HSP90 inhibition to be associated with decreased expression of multiple receptor tyrosine kinases, modules in the PI3K/AKT/mammalian target of rapamycin pathway, and the MAPK/CDK4 signaling axis in NRAS mutant melanoma cell lines and the inhibition of PI3K/AKT signaling in BRAF mutant melanoma xenografts with acquired vemurafenib resistance. The LC-MRM approach targeting more than 80 cancer signaling proteins was highly sensitive and could be applied to fine needle aspirates from xenografts and clinical melanoma specimens (using 50 MUg of total protein). We further showed MEK inhibition to be associated with signaling through the NFkappaB and WNT signaling pathways, as well as increased receptor tyrosine kinase expression and activation. Validation studies identified PDGF receptor beta signaling as a potential escape mechanism from MEK inhibition, which could be overcome through combined use of AZD6244 and the PDGF receptor inhibitor, crenolanib. Together, our studies show LC-MRM to have unique value as a platform for the systems level understanding of the molecular mechanisms of drug response and therapeutic escape. This work provides the proof-of-principle for the future development of LC-MRM assays for monitoring drug responses in the clinic. PMID- 24760958 TI - qcML: an exchange format for quality control metrics from mass spectrometry experiments. AB - Quality control is increasingly recognized as a crucial aspect of mass spectrometry based proteomics. Several recent papers discuss relevant parameters for quality control and present applications to extract these from the instrumental raw data. What has been missing, however, is a standard data exchange format for reporting these performance metrics. We therefore developed the qcML format, an XML-based standard that follows the design principles of the related mzML, mzIdentML, mzQuantML, and TraML standards from the HUPO-PSI (Proteomics Standards Initiative). In addition to the XML format, we also provide tools for the calculation of a wide range of quality metrics as well as a database format and interconversion tools, so that existing LIMS systems can easily add relational storage of the quality control data to their existing schema. We here describe the qcML specification, along with possible use cases and an illustrative example of the subsequent analysis possibilities. All information about qcML is available at http://code.google.com/p/qcml. PMID- 24760961 TI - Cannabis use: signal of increasing risk of serious cardiovascular disorders. AB - BACKGROUND: Cannabis is known to be associated with neuropsychiatric problems, but less is known about complications affecting other specified body systems. We report and analyze 35 recent remarkable cardiovascular complications following cannabis use. METHODS AND RESULTS: In France, serious cases of abuse and dependence in response to the use of psychoactive substances must be reported to the national system of the French Addictovigilance Network. We identified all spontaneous reports of cardiovascular complications related to cannabis use collected by the French Addictovigilance Network from 2006 to 2010. We described the clinical characteristics of these cases and their evolution: 1.8% of all cannabis-related reports (35/1979) were cardiovascular complications, with patients being mostly men (85.7%) and of an average age of 34.3 years. There were 22 cardiac complications (20 acute coronary syndromes), 10 peripheral complications (lower limb or juvenile arteriopathies and Buerger-like diseases), and 3 cerebral complications (acute cerebral angiopathy, transient cortical blindness, and spasm of cerebral artery). In 9 cases, the event led to patient death. CONCLUSIONS: Increased reporting of cardiovascular complications related to cannabis and their extreme seriousness (with a death rate of 25.6%) indicate cannabis as a possible risk factor for cardiovascular disease in young adults, in line with previous findings. Given that cannabis is perceived to be harmless by the general public and that legalization of its use is debated, data concerning its danger must be widely disseminated. Practitioners should be aware that cannabis may be a potential triggering factor for cardiovascular complications in young people. PMID- 24760963 TI - Recreational marijuana use: is it safe for your patient? PMID- 24760962 TI - Effect of ischemic postconditioning on infarct size in patients with ST-elevation myocardial infarction treated by primary PCI results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) randomized trial. AB - BACKGROUND: Reduction of infarct size by ischemic postconditioning (IPost) has been reported in smaller proof-of-concept clinical studies, but has not been confirmed in other smaller studies. The principle needs to be evaluated in larger groups of ST-elevation myocardial infarction (STEMI) patients before being implemented in clinical practice. This study assessed the effect of ischemic postcoditioning (IPost) on infarct size in patients with STEMI treated by primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: Patients with first-time STEMI, <6 hours from symptom onset, referred to primary PCI were randomized to IPost or control groups. IPost was administered by 4 cycles of 1 minute reocclusion and 1-minute reperfusion, starting 1 minute after opening, followed by stenting. In the control group, stenting was performed immediately after reperfusion. The primary endpoint was infarct size measured by cardiac magnetic resonance after 4 months. A total of 272 patients were randomized. Infarct size (percent of left ventricular mass) after 4 months (median values and interquartile range) was 14.4% (7.7, 24.6) and 13.5% (8.1, 19.3) in the control group and IPost group, respectively (P=0.18). No significant impact of IPost was found when controlling for baseline risk factors of infarct size in a multivariate linear regression model (P=0.16). The effects of IPost on secondary endpoints, including markers of necrosis, myocardial salvage, and ejection fraction, as well as adverse cardiac events during follow-up, were consistently neutral. CONCLUSIONS: In contrast to several smaller trials reported previously, we found no significant effects of IPost on infarct size or secondary study outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov Unique identifier: NCT.No.PO1506. PMID- 24760964 TI - Cardiopulmonary resuscitation and public access defibrillation in the current era -can we do better yet? PMID- 24760965 TI - Physiological impact of transposable elements encoding DDE transposases in the environmental adaptation of Streptococcus agalactiae. AB - We have referenced and described Streptococcus agalactiae transposable elements encoding DDE transposases. These elements belonged to nine families of insertion sequences (ISs) and to a family of conjugative transposons (TnGBSs). An overview of the physiological impact of the insertion of all these elements is provided. DDE-transposable elements affect S. agalactiae in a number of aspects of its capability to adapt to various environments and modulate the expression of several virulence genes, the scpB-lmB genomic region and the genes involved in capsule expression and haemolysin transport being the targets of several different mobile elements. The referenced mobile elements modify S. agalactiae behaviour by transferring new gene(s) to its genome, by modifying the expression of neighbouring genes at the integration site or by promoting genomic rearrangements. Transposition of some of these elements occurs in vivo, suggesting that by dynamically regulating some adaptation and/or virulence genes, they improve the ability of S. agalactiae to reach different niches within its host and ensure the 'success' of the infectious process. PMID- 24760966 TI - Morphological and proteomic analysis of early stage air-liquid interface biofilm formation in Mycobacterium smegmatis. AB - We studied the early stages of pellicle formation by Mycobacterium smegmatis on the surface of a liquid medium [air-liquid interface (A-L)]. Using optical and scanning electron microscopy, we showed the formation of a compact biofilm pellicle from micro-colonies over a period of 8-30 h. The cells in the pellicle changed size and cell division pattern during this period. Based on our findings, we created a model of M. smegmatis A-L early pellicle formation showing the coordinate growth of cells in the micro-colonies and in the homogeneous film between them, where the accessibility to oxygen and nutrients is different. A proteomic approach utilizing high-resolution two-dimensional gel electrophoresis, in combination with mass spectrometry-based protein identification, was used to analyse the protein expression profiles of the different morphological stages of the pellicle. The proteins identified formed four expression groups; the most interesting of these groups contained the proteins with highest expression in the biofilm development phase, when the floating micro-colonies containing long and more robust cells associate into flocs and start to form a compact pellicle. The majority of these proteins, including GroEL1, are involved in cell wall synthesis or modification, mostly through the involvement of mycolic acid biosynthesis, and their expression maxima correlated with the changes in cell size and the rigidity of the bacterial cell wall observed by scanning electron microscopy. PMID- 24760967 TI - Comprehensive overexpression analysis of cyclic-di-GMP signalling proteins in the phytopathogen Pectobacterium atrosepticum reveals diverse effects on motility and virulence phenotypes. AB - Bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) is a ubiquitous bacterial signalling molecule produced by diguanylate cyclases of the GGDEF domain family. Elevated c-di-GMP levels or increased GGDEF protein expression is frequently associated with the onset of sessility and biofilm formation in numerous bacterial species. Conversely, phosphodiesterase-dependent diminution of c-di-GMP levels by EAL- and HD-GYP-domain proteins is often accompanied by increased motility and virulence. In this study, we individually overexpressed 23 predicted GGDEF, EAL or HD-GYP-domain proteins encoded by the phytopathogen Pectobacterium atrosepticum strain SCRI1043. MS-based detection of c-di-GMP and 5'-phosphoguanylyl-(3'-5')-guanosine in these strains revealed that overexpression of most genes promoted modest 1-10-fold changes in cellular levels of c-di-GMP, with the exception of the GGDEF-domain proteins ECA0659 and ECA3374, which induced 1290- and 7660-fold increases, respectively. Overexpression of most EAL domain proteins increased motility, while overexpression of most GGDEF domain proteins reduced motility and increased poly-beta-1,6-N-acetyl-glucosamine dependent flocculation. In contrast to domain-based predictions, overexpression of the EAL protein ECA3549 or the HD-GYP protein ECA3548 increased c-di-GMP concentrations and reduced motility. Most overexpression constructs altered the levels of secreted cellulases, pectinases and proteases, confirming c-di-GMP regulation of virulence in Pe. atrosepticum. However, there was no apparent correlation between virulence-factor induction and the domain class expressed or cellular c-di-GMP levels, suggesting that regulation was in response to specific effectors within the network, rather than total c-di-GMP concentration. Finally, we demonstrated that the cellular localization patterns vary considerably for GGDEF/EAL/HD-GYP proteins, indicating it is a likely factor restricting specific interactions within the c-di-GMP network. PMID- 24760969 TI - Regulation of gene expression at low temperature: role of cold-inducible promoters. AB - Psychrophilic micro-organisms are the most dominant flora in cold habitats. Their unique ability to survive and multiply at low temperatures (<5 degrees C) is based on their ability to modulate the rigidity of the membrane, to transcribe, to translate and to catalyse biochemical reactions at low temperature. A number of genes are known to be upregulated during growth at low temperature and cold inducible promoters are known to regulate the expression of genes at low temperature. In this review, we attempted to compile promoter sequences of genes that are cold-inducible so as to identify similarities and to compare the distinct features of each type of promoter when microbes are grown in the cold. PMID- 24760968 TI - Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection. AB - Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce IFN-gamma, H99gamma, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with WT Cryptococcus. Given that individuals with suppressed CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether antimicrobial peptides were produced in mice inoculated with H99gamma. Thus, we measured levels of antimicrobial peptides lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of lipocalin-2, S100A8, S100A9 and SAA3 as well as TLR4(+) and RAGE(+) macrophages and dendritic cells in mice inoculated with H99gamma compared with WT H99. Similar results were observed in the lungs of H99gamma-immunized, compared with heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22-deficient mice inoculated with H99gamma demonstrated antimicrobial peptide production and no change in survival rates compared with WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional. PMID- 24760970 TI - Actomyosin sliding is attenuated in contractile biomimetic cortices. AB - Myosin II motors embedded within the actin cortex generate contractile forces to modulate cell shape in essential behaviors, including polarization, migration, and division. In sarcomeres, myosin II-mediated sliding of antiparallel F-actin is tightly coupled to myofibril contraction. By contrast, cortical F-actin is highly disordered in polarity, orientation, and length. How the disordered nature of the actin cortex affects actin and myosin movements and resultant contraction is unknown. Here we reconstitute a model cortex in vitro to monitor the relative movements of actin and myosin under conditions that promote or abrogate network contraction. In weakly contractile networks, myosin can translocate large distances across stationary F-actin. By contrast, the extent of relative actomyosin sliding is attenuated during contraction. Thus actomyosin sliding efficiently drives contraction in actomyosin networks despite the high degree of disorder. These results are consistent with the nominal degree of relative actomyosin movement observed in actomyosin assemblies in nonmuscle cells. PMID- 24760971 TI - Loss of Ubp3 increases silencing, decreases unequal recombination in rDNA, and shortens the replicative life span in Saccharomyces cerevisiae. AB - Ubp3 is a conserved ubiquitin protease that acts as an antisilencing factor in MAT and telomeric regions. Here we show that ubp3? mutants also display increased silencing in ribosomal DNA (rDNA). Consistent with this, RNA polymerase II occupancy is lower in cells lacking Ubp3 than in wild-type cells in all heterochromatic regions. Moreover, in a ubp3? mutant, unequal recombination in rDNA is highly suppressed. We present genetic evidence that this effect on rDNA recombination, but not silencing, is entirely dependent on the silencing factor Sir2. Further, ubp3? sir2? mutants age prematurely at the same rate as sir2? mutants. Thus our data suggest that recombination negatively influences replicative life span more so than silencing. However, in ubp3? mutants, recombination is not a prerequisite for aging, since cells lacking Ubp3 have a shorter life span than isogenic wild-type cells. We discuss the data in view of different models on how silencing and unequal recombination affect replicative life span and the role of Ubp3 in these processes. PMID- 24760972 TI - Food-group and nutrient-density intakes by Hispanic and Latino backgrounds in the Hispanic Community Health Study/Study of Latinos. AB - BACKGROUND: Hispanics are a heterogeneous group of individuals with a variation in dietary habits that is reflective of their cultural heritage and country of origin. It is important to identify differences in their dietary habits because it has been well established that nutrition contributes substantially to the burden of preventable diseases and early deaths in the United States. OBJECTIVE: We estimated the distribution of usual intakes (of both food groups and nutrients) by Hispanic and Latino backgrounds by using National Cancer Institute methodology. DESIGN: The Hispanic Community Health Study/Study of Latinos is a population-based cohort study that recruited participants who were 18-74 y of age from 4 US cities in 2008-2011 (Miami, Bronx, Chicago, and San Diego). Participants who provided at least one 24-h dietary recall and completed a food propensity questionnaire (n = 13,285) were included in the analyses. Results were adjusted for age, sex, field center, weekend, sequencing, and typical amount of intake. RESULTS: Overall, Cubans (n = 2128) had higher intakes of total energy, macronutrients (including all subtypes of fat), and alcohol than those of other groups. Mexicans (n = 5371) had higher intakes of vitamin C, calcium, and fiber. Lowest intakes of total energy, macronutrients, folate, iron, and calcium were reported by Dominicans (n = 1217), whereas Puerto Ricans (n = 2176) had lowest intakes of vitamin C and fiber. Food-group servings reflected nutrient intakes, with Cubans having higher intakes of refined grains, vegetables, red meat, and fats and Dominicans having higher intakes of fruit and poultry, whereas Puerto Ricans had lowest intakes of fruit and vegetables. Central and South Americans (n = 1468 and 925, respectively) were characterized by being second in their reported intakes of fruit and poultry and the highest in fish intake in comparison with other groups. CONCLUSION: Variations in diet noted in this study, with additional analysis, may help explain diet-related differences in health outcomes observed in Hispanics and Latinos. PMID- 24760973 TI - The food metabolome: a window over dietary exposure. AB - The food metabolome is defined as the part of the human metabolome directly derived from the digestion and biotransformation of foods and their constituents. With >25,000 compounds known in various foods, the food metabolome is extremely complex, with a composition varying widely according to the diet. By its very nature it represents a considerable and still largely unexploited source of novel dietary biomarkers that could be used to measure dietary exposures with a high level of detail and precision. Most dietary biomarkers currently have been identified on the basis of our knowledge of food compositions by using hypothesis driven approaches. However, the rapid development of metabolomics resulting from the development of highly sensitive modern analytic instruments, the availability of metabolite databases, and progress in (bio)informatics has made agnostic approaches more attractive as shown by the recent identification of novel biomarkers of intakes for fruit, vegetables, beverages, meats, or complex diets. Moreover, examples also show how the scrutiny of the food metabolome can lead to the discovery of bioactive molecules and dietary factors associated with diseases. However, researchers still face hurdles, which slow progress and need to be resolved to bring this emerging field of research to maturity. These limits were discussed during the First International Workshop on the Food Metabolome held in Glasgow. Key recommendations made during the workshop included more coordination of efforts; development of new databases, software tools, and chemical libraries for the food metabolome; and shared repositories of metabolomic data. Once achieved, major progress can be expected toward a better understanding of the complex interactions between diet and human health. PMID- 24760974 TI - Protein leverage effects of beef protein on energy intake in humans. AB - BACKGROUND: The protein leverage hypothesis requires specific evidence that protein intake is regulated more strongly than energy intake. OBJECTIVE: The objective was to determine ad libitum energy intake, body weight changes, appetite profile, and nitrogen balance in response to 3 diets with different protein-to-carbohydrate + fat ratios over 12 consecutive days, with beef as a source of protein. DESIGN: A 3-arm, 12-d randomized crossover study was performed in 30 men and 28 women [mean +/- SD age: 33 +/- 16 y; body mass index (in kg/m2): 24.4 +/- 4.0] with the use of diets containing 5%, 15%, and 30% of energy (En%) from protein, predominantly from beef. RESULTS: Energy intake was significantly lower in the 30En%-protein condition (8.73 +/- 1.93 MJ/d) than in the 5En% protein (9.48 +/- 1.67 MJ/d) and 15En%-protein (9.30 +/- 1.62 MJ/d) conditions (P = 0.001), stemming largely from lower energy intake during meals (P = 0.001). Hunger (P = 0.001) and desire to eat (P = 0.001) ratings were higher and fullness ratings were lower (P = 0.001) in the 5En%-protein condition than in the 15En% protein and 30En%-protein conditions. Nitrogen excretion was lower in the 5En% protein condition (4.7 +/- 1.5 g/24 h; P = 0.001) and was higher in the 30En% protein condition (15.3 +/- 8.7 g/24 h; P = 0.001) compared with the 15En% protein condition (10.0 +/- 5.2 g/24 h). Nitrogen balance was maintained in the 5En%-protein condition and was positive in the 15En%- and 30En%-protein conditions (P = 0.001). CONCLUSIONS: Complete protein leverage did not occur because subjects did not consume to a common protein amount at the expense of energy balance. Individuals did underconsume relative to energy requirements from high-protein diets. The lack of support for protein leverage effects on a low protein diet may stem from the fact that protein intake was sufficient to maintain nitrogen balance over the 12-d trial. PMID- 24760975 TI - Processed foods: contributions to nutrition. AB - Both fresh and processed foods make up vital parts of the food supply. Processed food contributes to both food security (ensuring that sufficient food is available) and nutrition security (ensuring that food quality meets human nutrient needs). This ASN scientific statement focuses on one aspect of processed foods: their nutritional impacts. Specifically, this scientific statement 1) provides an introduction to how processed foods contribute to the health of populations, 2) analyzes the contribution of processed foods to "nutrients to encourage" and "constituents to limit" in the American diet as recommended by the Dietary Guidelines for Americans, 3) identifies the responsibilities of various stakeholders in improving the American diet, and 4) reviews emerging technologies and the research needed for a better understanding of the role of processed foods in a healthy diet. Analyses of the NHANES 2003-2008 show that processed foods provide both nutrients to encourage and constituents to limit as specified in the 2010 Dietary Guidelines for Americans. Of the nutrients to encourage, processed foods contributed 55% of dietary fiber, 48% of calcium, 43% of potassium, 34% of vitamin D, 64% of iron, 65% of folate, and 46% of vitamin B-12. Of the constituents to limit, processed foods contributed 57% of energy, 52% of saturated fat, 75% of added sugars, and 57% of sodium. Diets are more likely to meet food guidance recommendations if nutrient-dense foods, either processed or not, are selected. Nutrition and food science professionals, the food industry, and other stakeholders can help to improve the diets of Americans by providing a nutritious food supply that is safe, enjoyable, affordable, and sustainable by communicating effectively and accurately with each other and by working together to improve the overall knowledge of consumers. PMID- 24760977 TI - Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food. AB - BACKGROUND: Ghrelin, which is a stomach-derived hormone, increases with fasting and energy restriction and may influence eating behaviors through brain hedonic reward-cognitive systems. Therefore, changes in plasma ghrelin might mediate counter-regulatory responses to a negative energy balance through changes in food hedonics. OBJECTIVE: We investigated whether ghrelin administration (exogenous hyperghrelinemia) mimics effects of fasting (endogenous hyperghrelinemia) on the hedonic response and activation of brain-reward systems to food. DESIGN: In a crossover design, 22 healthy, nonobese adults (17 men) underwent a functional magnetic resonance imaging (fMRI) food-picture evaluation task after a 16-h overnight fast (Fasted-Saline) or after eating breakfast 95 min before scanning (730 kcal, 14% protein, 31% fat, and 55% carbohydrate) and receiving a saline (Fed-Saline) or acyl ghrelin (Fed-Ghrelin) subcutaneous injection before scanning. One male subject was excluded from the fMRI analysis because of excess head motion, which left 21 subjects with brain-activation data. RESULTS: Compared with the Fed-Saline visit, both ghrelin administration to fed subjects (Fed Ghrelin) and fasting (Fasted-Saline) significantly increased the appeal of high energy foods and associated orbitofrontal cortex activation. Both fasting and ghrelin administration also increased hippocampus activation to high-energy- and low-energy-food pictures. These similar effects of endogenous and exogenous hyperghrelinemia were not explicable by consistent changes in glucose, insulin, peptide YY, and glucagon-like peptide-1. Neither ghrelin administration nor fasting had any significant effect on nucleus accumbens, caudate, anterior insula, or amygdala activation during the food-evaluation task or on auditory, motor, or visual cortex activation during a control task. CONCLUSIONS: Ghrelin administration and fasting have similar acute stimulatory effects on hedonic responses and the activation of corticolimbic reward-cognitive systems during food evaluations. Similar effects of recurrent or chronic hyperghrelinemia on an anticipatory food reward may contribute to the negative impact of skipping breakfast on dietary habits and body weight and the long-term failure of energy restriction for weight loss. PMID- 24760978 TI - A population-based approach to define body-composition phenotypes. AB - BACKGROUND: Abnormal body compositions such as high adiposity (HA), low muscle mass (LM), or a combination of the 2 [high adiposity with low muscle mass (HA LM)] are relevant phenotypes, but data on their prevalence and impact on health are still limited. This is largely because of a lack of a consensus definition for these conditions. Of particular interest is the HA-LM phenotype, also termed "sarcopenic obesity," which may confer greater health risk. OBJECTIVE: We propose a new approach for operationalizing abnormal body-composition phenotypes in a representative adult population. DESIGN: Whole-body dual-energy X-ray absorptiometry data obtained from the 1999-2004 NHANES were analyzed for 13,236 subjects aged >=18 y (maximum weight and height of 136 kg and 1.96 m, respectively). Sex- and body mass index (BMI)-specific decile groups of appendicular skeletal muscle index (ASMI; kg/m2) and fat mass index (FMI; kg/m2) were developed. Cutoffs for HA and LM were incorporated into a diagnostic framework to characterize 4 specific body-composition phenotypes-low adiposity with high muscle mass, high adiposity with high muscle mass, low adiposity with low muscle mass, and HA-LM-and a subclassification of the phenotypes into classes I, II, and III. RESULTS: Abnormal phenotypes were prevalent across the age spectrum and BMI categories. The association between ASMI or FMI and age was modified by sex and BMI. The prevalence of HA-LM in the whole sample was 10.3% in women and 15.2% in men. The prevalence of all subclasses of HA-LM in obese women and men was 14.7% and 22.9%, respectively. HA-LM class III was more prevalent in obese men (2.3%) than in obese women (0.3%). CONCLUSIONS: We developed sex- and BMI-specific reference curves to harmonize the classification of body-composition phenotypes. The application of this classification will be particularly useful in the identification of cases of sarcopenic obesity. The association of these phenotypes with metabolic deregulation and increased disease risk awaits verification. PMID- 24760976 TI - Metabolomic patterns and alcohol consumption in African Americans in the Atherosclerosis Risk in Communities Study. AB - BACKGROUND: Effects of alcohol consumption on health and disease are complex and involve a number of cellular and metabolic processes. OBJECTIVE: We examined the association between alcohol consumption habits and metabolomic profiles. DESIGN: We conducted a cross-sectional study to explore the association of alcohol consumption habits measured by using a questionnaire with serum metabolites measured by using untargeted mass spectrometry in 1977 African Americans from the Jackson field center in the Atherosclerosis Risk in Communities Study. The whole sample was split into a discovery set (n = 1500) and a replication set (n = 477). Alcohol consumption habits were treated as an ordinal variable, with nondrinkers as the reference group and quartiles of current drinkers as ordinal groups with higher values. For each metabolite, a linear regression was conducted to estimate its relation with alcohol consumption habits separately in both sets. A modified Bonferroni procedure was used in the discovery set to adjust the significance threshold (P < 1.9 * 10-4). RESULTS: In 356 named metabolites, 39 metabolites were significantly associated with alcohol consumption habits in both discovery and replication sets. In general, alcohol consumption was associated with higher levels of most metabolites such as those in amino acid and lipid pathways and with lower levels of gamma-glutamyl dipeptides. Three pathways, 2-hydroxybutyrate related metabolites, gamma-glutamyl dipeptides, and lysophosphatidylcholines, which are considered to be involved in inflammation and oxidation, were associated with incident cardiovascular diseases. CONCLUSIONS: To our knowledge, this is the largest metabolomic study thus far conducted in nonwhites. Metabolomic biomarkers of alcohol consumption were identified and replicated. The results lend new insight into potential mediating effects between alcohol consumption and future health and disease. PMID- 24760980 TI - Enhanced cell volume regulation: a key mechanism in local and remote ischemic preconditioning. AB - We have previously shown that ischemic preconditioning (IPC) protection against necrosis in whole hearts and in both fresh and cultured cardiomyocytes, as well as the improved regulatory volume decrease to hypoosmotic swelling in cardiomyocytes, is abrogated through Cl(-) channel blockade, pointing to a role for enhanced cell volume regulation in IPC. To further define this cardioprotective mechanism, cultured rabbit ventricular cardiomyocytes were preconditioned either by 10-min simulated ischemia (SI) followed by 10-min simulated reperfusion (SR), by 10-min exposure/10-min washout of remote IPC (rIPC) plasma dialysate (from rabbits subjected to repetitive limb ischemia), or by adenoviral transfection with the constitutively active PKC-epsilon gene. These interventions were done before cardiomyocytes were subjected to either 60- or 75 min SI/60-min SR to assess cell necrosis (by trypan blue staining), 30-min SI to assess ischemic cell swelling, or 30-min hypoosmotic (200 mosM) stress to assess cell volume regulation. Necrosis after SI/SR and both SI- and hypoosmotic stress induced swelling was reduced in preconditioned cardiomyocytes compared with control cardiomyocytes (neither preconditioned nor transfected). These effects on necrosis and cell swelling were blocked by either Cl(-) channel blockade or dominant negative knockdown of inwardly rectifying K(+) channels with adenoviruses, suggesting that Cl(-) and K(+) movements across the sarcolemma are critical for cell volume regulation and, thereby, cell survival under hypoxic/ischemic conditions. Our results define enhanced cell volume regulation as a key common mechanism of cardioprotection by preconditioning in cardiomyocytes. PMID- 24760979 TI - The PTEN/PI3K/Akt signaling pathway mediates HMGB1-induced cell proliferation by regulating the NF-kappaB/cyclin D1 pathway in mouse mesangial cells. AB - Our previous experiment confirmed that high-mobility group box chromosomal protein 1 (HMGB1) was involved in the pathogenesis of Lupus nephritis (LN) by upregulating the proliferation of the mouse mesangial cell line (MMC) through the cyclin D1/CDK4/p16 system, but the precise mechanism is still unknown. Therefore, in the present study, we demonstrated that HMGB1 induced the proliferation of MMC cells in a time- and concentration-dependent manner, downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression, increased the level of Akt serine 473 phosphorylation, and induced p65 subunit nuclear translocation. The overexpression of PTEN prevented the upregulation of HMGB1 induced proliferation by blocking the activation of Akt. The knockdown of Akt by siRNA technology and blocking the nuclear factor-kappaB (NF-kappaB) pathway using pyrrolidine dithiocarbamate (PDTC) and SN50, inhibitors of NF-kappaB, both attenuated the HMGB1-induced proliferation by counteracting the activation of the cyclin D1. In addition, while sh-Akt partly blocked the nuclear translocation of the p65 subunit, PDTC did not affect the activation of the Akt induced by HMGB1 in MMC cells. These findings indicate that HMGB1 induced the proliferation of MMC cells by activating the PTEN/phosphoinositide-3-kinase (PI3K)/Akt/NF-kappaB signaling pathway. PMID- 24760981 TI - Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1alpha axis. AB - Slower, more oxidative muscle fibers are more resistant to the dystrophic pathology in Duchenne muscular dystrophy (DMD) patients as well as in the preclinical mdx mouse model of DMD. Therefore, one therapeutic strategy for DMD focuses on promoting expression of the slow, oxidative myogenic program. In the current study, we explored the therapeutic potential of stimulating the slow, oxidative phenotype in mdx mice by feeding 6-wk-old animals with the natural phenol resveratrol (RSV; ~100 mg.kg(-1).day(-1)) for 6 wk. Sirtuin 1 (SIRT1) activity and protein levels increased significantly, as well as peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) activity, in the absence of alterations in AMPK signaling. These adaptations occurred concomitant with evidence of a fast, glycolytic, to slower, more oxidative fiber type conversion, including mitochondrial biogenesis and increased expression of slower myosin heavy chain isoforms. These positive findings raised the question of whether increased exposure to RSV would result in greater therapeutic benefits. We discovered that an elevated RSV dose of ~500 mg.kg(-1).day(-1) across a duration of 12 wk was clearly less effective at muscle remodeling in mdx mice. This treatment protocol failed to influence SIRT1 or AMPK signaling and did not result in a shift towards a slower, more oxidative phenotype. Taken together, this study demonstrates that RSV can stimulate SIRT1 and PGC-1alpha activation, which in turn may promote expression of the slow, oxidative myogenic program in mdx mouse muscle. The data also highlight the importance of selecting an appropriate dosage regimen of RSV to maximize its potential therapeutic effectiveness for future application in DMD patients. PMID- 24760982 TI - Cav1.2 and Cav1.3 L-type calcium channels operate in a similar voltage range but show different coupling to Ca(2+)-dependent conductances in hippocampal neurons. AB - In the central nervous system, L-type voltage-gated calcium channels (LTCCs) come in two isoforms, namely Cav1.2 and Cav1.3 channels. It has been shown previously that these channels differ in biophysical properties, in subcellular localization, and in the coupling to the gene transcription machinery. In previous work on rat hippocampal neurons we have identified an excitatory cation conductance and an inhibitory potassium conductance as important LTCC coupling partners. Notably, a stimulus-dependent interplay of LTCC-mediated Ca(2+) influx and activation of these Ca(2+)-dependent conductances was found to give rise to characteristic voltage responses. However, the contribution of Cav1.2 and Cav1.3 to these voltage responses remained unknown. Hence, the relative contribution of the LTCC isoforms therein was the focus of the current study on hippocampal neurons derived from genetically modified mice, which either lack a LTCC isoform (Cav1.3 knockout mice) or express a dihydropyridine-insensitive LTCC isoform (Cav1.2DHP(-)-knockin mice). We identified common and alternate ion channel couplings of Cav1.2 and Cav1.3 channels. Whereas hyperpolarizing Ca(2+)-dependent conductances were coupled to both Cav1.2 and Cav1.3 channels, an afterdepolarizing potential was only induced by the activity of Cav1.2 channels. Unexpectedly, the activity of Cav1.2 channels was found at relatively hyperpolarized membrane voltages. Our data add important information about the differences between Cav1.2 and Cav1.3 channels that furthers our understanding of the physiological and pathophysiological neuronal roles of these calcium channels. Moreover, our findings suggest that Cav1.3 knockout mice together with Cav1.2DHP(-)-knockin mice provide valuable models for future investigation of hippocampal LTCC-dependent afterdepolarizations. PMID- 24760983 TI - Enhanced expression of Gqalpha and PLC-beta1 proteins contributes to vascular smooth muscle cell hypertrophy in SHR: role of endogenous angiotensin II and endothelin-1. AB - Vascular Gqalpha signaling has been shown to contribute to cardiac hypertrophy. In addition, angiotensin II (ANG II) was shown to induce vascular smooth muscle cell (VSMC) hypertrophy through Gqalpha signaling; however, the studies on the role of Gqalpha and PLC-beta1 proteins in VSMC hypertrophy in animal model are lacking. The present study was therefore undertaken to examine the role of Gqalpha/PLC-beta1 proteins and the signaling pathways in VSMC hypertrophy using spontaneously hypertensive rats (SHR). VSMC from 16-wk-old SHR and not from 12-wk old SHR exhibited enhanced levels of Gqalpha/PLC-beta1 proteins compared with age matched Wistar-Kyoto (WKY) rats as determined by Western blotting. However, protein synthesis as determined by [(3)H]leucine incorporation was significantly enhanced in VSMC from both 12- and 16-wk-old SHR compared with VSMC from age matched WKY rats. Furthermore, the knockdown of Gqalpha/PLC-beta1 in VSMC from 16 wk-old SHR by antisense and small interfering RNA resulted in attenuation of protein synthesis. In addition, the enhanced expression of Gqalpha/PLC-beta1 proteins, enhanced phosphorylation of ERK1/2, and enhanced protein synthesis in VSMC from SHR were attenuated by the ANG II AT1 and endothelin-1 (ET-1) ETA receptor antagonists losartan and BQ123, respectively, but not by the ETB receptor antagonist BQ788. In addition, PD98059 decreased the enhanced expression of Gqalpha/PLC-beta1 and protein synthesis in VSMC from SHR. These results suggest that the enhanced levels of endogenous ANG II and ET-1 through the activation of AT1 and ETA receptors, respectively, and MAP kinase signaling, enhanced the expression of Gqalpha/PLC-beta1 proteins in VSMC from 16-wk-old SHR and result in VSMC hypertrophy. PMID- 24760985 TI - Lysophosphatidic acid stimulation of NHE3 exocytosis in polarized epithelial cells occurs with release from NHERF2 via ERK-PLC-PKCdelta signaling. AB - The Na(+)/H(+) exchanger 3 (NHE3) is a brush border (BB) Na(+)/H(+) antiporter that accounts for the majority of physiologic small intestinal and renal Na(+) absorption. It is regulated physiologically and in disease via changes in endocytosis/exocytosis. Paradoxically, NHE3 is fixed to the microvillar (MV) actin cytoskeleton and has little basal mobility. This fixation requires NHE3 binding to the multi-PDZ domain scaffold proteins Na(+)/H(+) exchanger regulatory factor (NHERF)1 and NHERF2 and to ezrin. Coordinated release of NHE3 from the MV cytoskeleton has been demonstrated during both stimulation and inhibition of NHE3. However, the signaling molecules involved in coordinating NHE3 trafficking and cytoskeletal association have not been identified. This question was addressed by studying lysophosphatidic acid (LPA) stimulation of NHE3 in polarized renal proximal tubule opossum kidney (OK) cells that occurs via apical LPA5 receptors and is NHERF2 dependent and mediated by epidermal growth factor receptor (EGFR), Rho/Rho-associated kinase (ROCK), and ERK. NHE3 activity was determined by BCECF/fluorometry and NHE3 microvillar mobility by FRAP/confocal microscopy using NHE3-EGFP. Apical LPA (3 MUM)/LPA5R stimulated NHE3 activity, increased NHE3 mobility, and decreased the NHE3/NHERF2 association. The LPA stimulation of NHE3 was also PKCdelta dependent. PKCdelta was necessary for LPA stimulation of NHE3 mobility and NHE3/NHERF2 association. Moreover, the LPA induced translocation to the membrane of PKCdelta was both ERK and phospholipase C dependent with ERK acting upstream of PLC. We conclude that LPA stimulation of NHE3 exocytosis includes a signaling pathway that regulates fixation of NHE3 to the MV cytoskeleton. This involves a signaling module consisting of ERK-PLC PKCdelta, which dynamically and reversibly releases NHE3 from NHERF2 to contribute to the changes in NHE3 MV mobility. PMID- 24760986 TI - Cortisol increases CXCR4 expression but does not affect CD62L and CCR7 levels on specific T cell subsets in humans. AB - Glucocorticoids are well known to affect T cell migration, leading to a redistribution of the cells from blood to the bone marrow, accompanied by a concurrent suppression of lymph node homing. Despite numerous studies in this context, with most of them employing synthetic glucocorticoids in nonphysiological doses, the mechanisms of this redistribution are not well understood. Here, we investigated in healthy men the impact of cortisol at physiological concentrations on the expression of different migration molecules on eight T cell subpopulations in vivo and in vitro. Hydrocortisone (cortisol, 22 mg) infused during nocturnal rest when endogenous cortisol levels are low, compared with placebo, differentially reduced numbers of T cell subsets, with naive CD4(+) and CD8(+) subsets exhibiting the strongest reduction. Hydrocortisone in vivo and in vitro increased CXCR4 expression, which presumably mediates the recruitment of T cells to the bone marrow. Expression of the lymph node homing receptor CD62L on total CD3(+) and CD8(+) T cells appeared reduced following hydrocortisone infusion. However, this was due to a selective extravasation of CD62L(+) T cell subsets, as hydrocortisone affected neither CD62L expression on a subpopulation level nor CD62L expression in vitro. Corresponding results in the opposite direction were observed after blocking of endogenous cortisol synthesis by metyrapone. CCR7, another lymph node homing receptor, was also unaffected by hydrocortisone in vitro. Thus, cortisol seems to redirect T cells to the bone marrow by upregulating their CXCR4 expression, whereas its inhibiting effect on T cell homing to lymph nodes is apparently regulated independently of the expression of classical homing receptors. PMID- 24760984 TI - P2Y2 nucleotide receptor activation enhances the aggregation and self organization of dispersed salivary epithelial cells. AB - Hyposalivation resulting from salivary gland dysfunction leads to poor oral health and greatly reduces the quality of life of patients. Current treatments for hyposalivation are limited. However, regenerative medicine to replace dysfunctional salivary glands represents a revolutionary approach. The ability of dispersed salivary epithelial cells or salivary gland-derived progenitor cells to self-organize into acinar-like spheres or branching structures that mimic the native tissue holds promise for cell-based reconstitution of a functional salivary gland. However, the mechanisms involved in salivary epithelial cell aggregation and tissue reconstitution are not fully understood. This study investigated the role of the P2Y2 nucleotide receptor (P2Y2R), a G protein coupled receptor that is upregulated following salivary gland damage and disease, in salivary gland reconstitution. In vitro results with the rat parotid acinar Par-C10 cell line indicate that P2Y2R activation with the selective agonist UTP enhances the self-organization of dispersed salivary epithelial cells into acinar like spheres. Other results indicate that the P2Y2R-mediated response is dependent on epidermal growth factor receptor activation via the metalloproteases ADAM10/ADAM17 or the alpha5beta1 integrin/Cdc42 signaling pathway, which leads to activation of the MAPKs JNK and ERK1/2. Ex vivo data using primary submandibular gland cells from wild-type and P2Y2R(-/-) mice confirmed that UTP-induced migratory responses required for acinar cell self-organization are mediated by the P2Y2R. Overall, this study suggests that the P2Y2R is a promising target for salivary gland reconstitution and identifies the involvement of two novel components of the P2Y2R signaling cascade in salivary epithelial cells, the alpha5beta1 integrin and the Rho GTPase Cdc42. PMID- 24760987 TI - The single-biopsy approach in determining protein synthesis in human slow-turning over tissue: use of flood-primed, continuous infusion of amino acid tracers. AB - Muscle protein synthesis (MPS) rate is determined conventionally by obtaining two or more tissue biopsies during a primed, continuous infusion of a stable isotopically labeled amino acid. The purpose of the present study was to test whether tracer priming given as a flooding dose, thereby securing an instantaneous labeling of the tissue pools of free tracee amino acids, followed by a continuous infusion of the same tracer to maintain tracer isotopic steady state, could be used to determine the MPS rate over a prolonged period of time by obtaining only a single tissue biopsy. We showed that the tracer from the flood prime appeared immediately in the muscle free pool of amino acids and that this abundance could be kept constant by a subsequent continuous infusion of the tracer. When using phenylalanine as tracer, the flood-primed, continuous infusion protocol does not stimulate the MPS rate per se. In conclusion, the flood-primed, continuous infusion protocol using phenylalanine as tracer can validly be used to measure the protein synthesis rate in human in vivo experiments by obtaining only a single tissue biopsy after a prolonged infusion period. PMID- 24760989 TI - Improved cardiac function and dietary fatty acid metabolism after modest weight loss in subjects with impaired glucose tolerance. AB - Using a novel positron emission tomography (PET) method with oral administration of 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid (18FTHA), we recently demonstrated that subjects with impaired glucose tolerance (IGT) display an impairment in cardiac function associated with increased myocardial uptake of dietary fatty acids. Here, we determined whether modest weight loss induced by lifestyle changes might improve these cardiac metabolic and functional abnormalities. Nine participants with IGT, enrolled in a one-year lifestyle intervention trial, were invited to undergo determination of organ-specific postprandial dietary fatty acids partition using the oral 18FTHA method, and cardiac function and oxidative metabolic index using PET [11C]acetate kinetics with ECG-gated PET ventriculography before and after the intervention. The intervention resulted in significant weight loss and reduction of waist circumference, with reduced postprandial plasma glucose, insulin, and triglycerides excursion. We observed a significant increase in stroke volume, cardiac output, and left ventricular ejection fraction associated with reduced myocardial oxidative metabolic index and fractional dietary fatty acid uptake. Modest weight loss corrects the exaggerated myocardial channeling of dietary fatty acids and improves myocardial energy substrate metabolism and function in IGT subjects. PMID- 24760988 TI - Acylcarnitines activate proinflammatory signaling pathways. AB - Incomplete beta-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete beta-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed D,L isomers of C12- or C14-carnitine induced an NF-kappaB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant L-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25 MUM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified. PMID- 24760990 TI - Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements. AB - Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O2, cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo. PMID- 24760991 TI - Automated quantification of pancreatic beta-cell mass. AB - beta-Cell mass is a parameter commonly measured in studies of islet biology and diabetes. However, the rigorous quantification of pancreatic beta-cell mass using conventional histological methods is a time-consuming process. Rapidly evolving virtual slide technology with high-resolution slide scanners and newly developed image analysis tools has the potential to transform beta-cell mass measurement. To test the effectiveness and accuracy of this new approach, we assessed pancreata from normal C57Bl/6J mice and from mouse models of beta-cell ablation (streptozotocin-treated mice) and beta-cell hyperplasia (leptin-deficient mice), using a standardized systematic sampling of pancreatic specimens. Our data indicate that automated analysis of virtual pancreatic slides is highly reliable and yields results consistent with those obtained by conventional morphometric analysis. This new methodology will allow investigators to dramatically reduce the time required for beta-cell mass measurement by automating high-resolution image capture and analysis of entire pancreatic sections. PMID- 24760993 TI - Hypoxic signaling: some organs are more equal than others. Focus on "Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia". PMID- 24760992 TI - Mice lacking NOX2 are hyperphagic and store fat preferentially in the liver. AB - Chronic low-grade inflammation is an important contributor to the development of insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Obesity and high-fat feeding lead to infiltration of immune cells into metabolic tissues, promoting inflammation and insulin resistance. We hypothesized that macrophages from mice lacking NOX2 (Cybb), an essential component of the NADPH oxidase complex highly expressed in immune cells and associated with their inflammatory response, would be less inflammatory and that these mice would be protected from the development of high-fat-induced insulin resistance. Bone marrow-derived macrophages from NOX2 knockout (NOX2-KO) mice expressed lower levels of inflammatory markers (Nos2, Il6); however, NOX2-KO mice were hyperphagic and gained more weight than wild-type (WT) mice when fed either a chow or a high-fat (HF) diet. Surprisingly, NOX2-KO mice stored less lipid in epididymal white adipose tissue but more lipid in liver and had higher indexes of liver inflammation and macrophage infiltration than WT mice. Contrary to our hypothesis, HF-fed NOX2-KO mice were hyperinsulinemic and more insulin resistant than HF-fed WT mice, likely as a result of their higher hepatic steatosis and inflammation. In summary, NOX2 depletion promoted hyperphagia, hepatic steatosis, and inflammation with either normal or high-fat feeding, exacerbating insulin resistance. We propose that NOX2 participates in food intake control and lipid distribution in mice. PMID- 24760994 TI - Mercaptoacetate and fatty acids exert direct and antagonistic effects on nodose neurons via GPR40 fatty acid receptors. AB - beta-mercaptoacetate (MA) is a drug known to block mitochondrial oxidation of medium- and long-chain fatty acids (FAs) and to stimulate feeding. Because MA induced feeding is vagally dependent, it has been assumed that the feeding response is mediated by MA's antimetabolic action at a peripheral, vagally innervated site. However, MA's site of action has not yet been identified. Therefore, we used fluorescent calcium measurements in isolated neurons from rat nodose ganglia to determine whether MA has direct effects on vagal sensory neurons. We found that MA alone did not alter cytosolic calcium concentrations in nodose neurons. However, MA (60 MUM to 6 mM) significantly decreased calcium responses to both linoleic acid (LA; 10 MUM) and caprylic acid (C8; 10 MUM) in all neurons responsive to LA and C8. GW9508 (40 MUM), an agonist of the FA receptor, G protein-coupled receptor 40 (GPR40), also increased calcium levels almost exclusively in FA-responsive neurons. MA significantly inhibited this response to GW9508. MA did not inhibit calcium responses to serotonin, high K(+), or capsaicin, which do not utilize GPRs, or to CCK, which acts on a different GPR. GPR40 was detected in nodose ganglia by RT-PCR. Results suggest that FAs directly activate vagal sensory neurons via GPR40 and that MA antagonizes this effect. Thus, we propose that MA's nonmetabolic actions on GPR40 membrane receptors, expressed by multiple peripheral tissues in addition to the vagus nerve, may contribute to or mediate MA-induced stimulation of feeding. PMID- 24760995 TI - Regulation of the chemosensory control of breathing by Kolliker-Fuse neurons. AB - The Kolliker-Fuse region (KF) and the lateral parabrachial nucleus (LPBN) have been implicated in the maintenance of cardiorespiratory control. Here, we evaluated the involvement of the KF region and the LPBN in cardiorespiratory responses elicited by chemoreceptor activation in unanesthetized rats. Male Wistar rats (280-330 g; n = 5-9/group) with bilateral stainless-steel guide cannulas implanted in the KF region or the LPBN were used. Injection of muscimol (100 and 200 pmol/100 nl) in the KF region decreased resting ventilation (1,140 +/- 68 and 978 +/- 100 vs. saline: 1,436 +/- 155 ml.kg(-1).min(-1)), without changing mean arterial pressure (MAP) and heart rate (HR). Bilateral injection of the GABA-A antagonist bicuculline (1 nmol/100 nl) in the KF blocked the inhibitory effect on ventilation (1,418 +/- 138 vs. muscimol: 978 +/- 100 ml.kg( 1).min(-1)) elicited by muscimol. Muscimol injection in the KF reduced the increase in ventilation produced by hypoxia (8% O2) (1,827 +/- 61 vs. saline: 3,179 +/- 325 ml.kg(-1).min(-1)) or hypercapnia (7% CO2) (1,488 +/- 277 vs. saline: 3,539 +/- 374 ml.kg(-1).min(-1)) in unanesthetized rats. Bilateral injection of bicuculline in the KF blocked the decrease in ventilation produced by muscimol in the KF during peripheral or central chemoreflex activation. Bilateral injection of muscimol in the LPBN did not change resting ventilation or the increase in ventilation elicited by hypoxia or hypercapnia. The results of the present study suggest that the KF region, but not the LPBN, has mechanisms to control ventilation in resting, hypoxic, or hypercapnic conditions in unanesthetized rats. PMID- 24760996 TI - Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia. AB - Tissue hypoxia likely contributes to anemia-induced organ injury and mortality. Severe anemia activates hypoxia-inducible factor (HIF) signaling by hypoxic- and neuronal nitric oxide (NO) synthase- (nNOS) dependent mechanisms. However, organ specific hemoglobin (Hb) thresholds for increased HIF expression have not been defined. To assess organ-specific Hb thresholds for tissue hypoxia, HIF-alpha (oxygen-dependent degradation domain, ODD) luciferase mice were hemodiluted to mild, moderate, or severe anemia corresponding to Hb levels of 90, 70, and 50 g/l, respectively. HIF luciferase reporter activity, HIF protein, and HIF dependent RNA levels were assessed. In the brain, HIF-1alpha was paradoxically decreased at mild anemia, returned to baseline at moderate anemia, and then increased at severe anemia. Brain HIF-2alpha remained unchanged at all Hb levels. Both kidney HIF-1alpha and HIF-2alpha increased earlier (Hb ~70-90 g/l) in response to anemia. Liver also exhibited an early HIF-alpha response. Carotid blood flow was increased early (Hb ~70, g/l), but renal blood flow remained relatively constant, only increased at Hb of 50 g/l. Anemia increased nNOS (brain and kidney) and endothelia NOS (eNOS) (kidney) levels. Whereas anemia-induced increases in brain HIFalpha were nNOS-dependent, our current data demonstrate that increased renal HIFalpha was nNOS independent. HIF-dependent RNA levels increased linearly (~10-fold) in the brain. However, renal HIF-RNA responses (MCT4, EPO) increased exponentially (~100-fold). Plasma EPO levels increased near Hb threshold of 90 g/l, suggesting that the EPO response is sensitive. Collectively, these observations suggest that each organ expresses a different threshold for cellular HIF/NOS hypoxia responses. This knowledge may help define the mechanism(s) by which the brain and kidney maintain oxygen homeostasis during anemia. PMID- 24760997 TI - Metabolomics approach to assessing plasma 13- and 9-hydroxy-octadecadienoic acid and linoleic acid metabolite responses to 75-km cycling. AB - Bioactive oxidized linoleic acid metabolites (OXLAMs) include 13- and 9-hydroxy octadecadienoic acid (13-HODE + 9-HODE) and have been linked to oxidative stress, inflammation, and numerous pathological and physiological states. The purpose of this study was to measure changes in plasma 13-HODE + 9-HODE following a 75-km cycling bout and identify potential linkages to linoleate metabolism and established biomarkers of oxidative stress (F2-isoprostanes) and inflammation (cytokines) using a metabolomics approach. Trained male cyclists (N = 19, age 38.0 +/- 1.6 yr, wattsmax 304 +/- 10.5) engaged in a 75-km cycling time trial on their own bicycles using electromagnetically braked cycling ergometers (2.71 +/- 0.07 h). Blood samples were collected preexercise, immediately post-, 1.5 h post , and 21 h postexercise, and analyzed for plasma cytokines (IL-6, IL-8, IL-10, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, granulocyte colony-stimulating factor), F2-isoprostanes, and shifts in metabolites using global metabolomics procedures with gas chromatography mass spectrometry (GC-MS) and liquid chromatography mass spectrometry (LC-MS). 13-HODE + 9-HODE increased 3.1-fold and 1.7-fold immediately post- and 1.5 h postexercise (both P < 0.001) and returned to preexercise levels by 21-h postexercise. Post-75-km cycling plasma levels of 13-HODE + 9-HODE were not significantly correlated with increases in plasma cytokines but were positively correlated with postexercise F2 isoprostanes (r = 0.75, P < 0.001), linoleate (r = 0.54, P = 0.016), arachidate (r = 0.77, P < 0.001), 12,13-dihydroxy-9Z-octadecenoate (12,13-DiHOME) (r = 0.60, P = 0.006), dihomo-linolenate (r = 0.57, P = 0.011), and adrenate (r = 0.56, P = 0.013). These findings indicate that prolonged and intensive exercise caused a transient, 3.1-fold increase in the stable linoleic acid oxidation product 13 HODE + 9-HODE and was related to increases in F2-isoprostanes, linoleate, and fatty acids in the linoleate conversion pathway. These data support the use of 13 HODE + 9-HODE as an oxidative stress biomarker in acute exercise investigations. PMID- 24760998 TI - Insulin effects on glucose tolerance, hypermetabolic response, and circadian metabolic protein expression in a rat burn and disuse model. AB - Insulin controls hyperglycemia after severe burns, and its use opposes the hypermetabolic response. The underlying molecular mechanisms are poorly understood, and previous research in this area has been limited because of the inadequacy of animal models to mimic the physiological effects seen in humans with burns. Using a recently published rat model that combines both burn and disuse components, we compare the effects of insulin treatment vs. vehicle on glucose tolerance, hypermetabolic response, muscle loss, and circadian-metabolic protein expression after burns. Male Sprague-Dawley rats were assigned to three groups: cage controls (n = 6); vehicle-treated burn and hindlimb unloading (VBH; n = 11), and insulin-treated burn and hindlimb unloading (IBH; n = 9). With the exception of cage controls, rats underwent a 40% total body surface area burn with hindlimb unloading, then IBH rats received 12 days of subcutaneous insulin injections (5 units.kg(-1).day(-1)), and VBH rats received an equivalent dose of vehicle. Glucose tolerance testing was performed on day 14, after which blood and tissues were collected for analysis. Body mass loss was attenuated by insulin treatment (VBH = 265 +/- 17 g vs. IBH = 283 +/- 14 g, P = 0.016), and glucose clearance capacity was increased. Soleus and gastrocnemius muscle loss was decreased in the IBH group. Insulin receptor substrate-1, AKT, FOXO-1, caspase-3, and PER1 phosphorylation was altered by injury and disuse, with levels restored by insulin treatment in almost all cases. Insulin treatment after burn and during disuse attenuated the hypermetabolic response, increased glucose clearance, and normalized circadian-metabolic protein expression patterns. Therapies aimed at targeting downstream effectors may provide the beneficial effects of insulin without hypoglycemic risk. PMID- 24761001 TI - Competitive inhibition of SGLT2 by tofogliflozin or phlorizin induces urinary glucose excretion through extending splay in cynomolgus monkeys. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed a glucose lowering effect in type 2 diabetes patients through inducing renal glucose excretion. Detailed analysis of the mechanism of the glucosuric effect of SGLT2 inhibition, however, has been hampered by limitations of clinical study. Here, we investigated the mechanism of urinary glucose excretion using nonhuman primates with SGLT inhibitors tofogliflozin and phlorizin, both in vitro and in vivo. In cells overexpressing cynomolgus monkey SGLT2 (cSGLT2), both tofogliflozin and phlorizin competitively inhibited uptake of the substrate (alpha-methyl-d glucopyranoside; AMG). Tofogliflozin was found to be a selective cSGLT2 inhibitor, inhibiting cSGLT2 more strongly than did phlorizin, with selectivity toward cSGLT2 1,000 times that toward cSGLT1; phlorizin was found to be a nonselective cSGLT1/2 inhibitor. In a glucose titration study in cynomolgus monkeys under conditions of controlled plasma drug concentration, both tofogliflozin and phlorizin increased fractional excretion of glucose (FEG) by up to 50% under hyperglycemic conditions. By fitting the titration curve using a newly introduced method that avoids variability in estimating the threshold of renal glucose excretion, we found that tofogliflozin and phlorizin lowered the threshold and extended the splay in a dose-dependent manner without significantly affecting the tubular transport maximum for glucose (TmG). Our results demonstrate the contribution of SGLT2 to renal glucose reabsorption (RGR) in cynomolgus monkeys and demonstrate that competitive inhibition of cSGLT2 exerts a glucosuric effect by mainly extending splay and lowering threshold without affecting TmG. PMID- 24760999 TI - Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function. AB - Urinary bladder dysfunction presents a major problem in the clinical management of patients suffering from pathological conditions and neurological injuries or disorders. Currently, the etiology underlying altered visceral sensations from the urinary bladder that accompany the chronic pain syndrome, bladder pain syndrome (BPS)/interstitial cystitis (IC), is not known. Bladder irritation and inflammation are histopathological features that may underlie BPS/IC that can change the properties of lower urinary tract sensory pathways (e.g., peripheral and central sensitization, neurochemical plasticity) and contribute to exaggerated responses of peripheral bladder sensory pathways. Among the potential mediators of peripheral nociceptor sensitization and urinary bladder dysfunction are neuroactive compounds (e.g., purinergic and neuropeptide and receptor pathways), sensory transducers (e.g., transient receptor potential channels) and target-derived growth factors (e.g., nerve growth factor). We review studies related to the organization of the afferent limb of the micturition reflex and discuss neuroplasticity in an animal model of urinary bladder inflammation to increase the understanding of functional bladder disorders and to identify potential novel targets for development of therapeutic interventions. Given the heterogeneity of BPS/IC and the lack of consistent treatment benefits, it is unlikely that a single treatment directed at a single target in micturition reflex pathways will have a mass benefit. Thus, the identification of multiple targets is a prudent approach, and use of cocktail treatments directed at multiple targets should be considered. PMID- 24761000 TI - NADPH oxidase-derived reactive oxygen species contribute to impaired cutaneous microvascular function in chronic kidney disease. AB - Oxidative stress promotes vascular dysfunction in chronic kidney disease (CKD). We utilized the cutaneous circulation to test the hypothesis that reactive oxygen species derived from NADPH oxidase and xanthine oxidase impair nitric oxide (NO) dependent cutaneous vasodilation in CKD. Twenty subjects, 10 stage 3 and 4 patients with CKD (61 +/- 4 yr; 5 men/5 women; eGFR: 39 +/- 4 ml.min(-1).1.73 m( 2)) and 10 healthy controls (55 +/- 2 yr; 4 men/6 women; eGFR: >60 ml.min( 1).1.73 m(-2)) were instrumented with 4 intradermal microdialysis fibers for the delivery of 1) Ringer solution (Control), 2) 10 MUM tempol (scavenge superoxide), 3) 100 MUM apocynin (NAD(P)H oxidase inhibition), and 4) 10 MUM allopurinol (xanthine oxidase inhibition). Skin blood flow was measured via laser-Doppler flowmetry during standardized local heating (42 degrees C). N(g)-nitro-l-arginine methyl ester (L-NAME; 10 mM) was infused to quantify the NO-dependent portion of the response. Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum CVC achieved during sodium nitroprusside infusion at 43 degrees C. Cutaneous vasodilation was attenuated in patients with CKD (77 +/- 3 vs. 88 +/- 3%, P = 0.01), but augmented with tempol and apocynin (tempol: 88 +/- 2 (P = 0.03), apocynin: 91 +/- 2% (P = 0.001). The NO-dependent portion of the response was reduced in patients with CKD (41 +/- 4 vs. 58 +/- 2%, P = 0.04), but improved with tempol and apocynin (tempol: 58 +/- 3 (P = 0.03), apocynin: 58 +/- 4% (P = 0.03). Inhibition of xanthine oxidase did not alter cutaneous vasodilation in either group (P > 0.05). These data suggest that NAD(P)H oxidase is a source of reactive oxygen species and contributes to microvascular dysfunction in patients with CKD. PMID- 24761003 TI - Proteomic identification of early changes in the renal cytoskeleton in obstructive uropathy. AB - Bilateral ureteral obstruction (BUO) is associated with renal damage and impaired ability to concentrate urine and is known to induce alterations in an array of kidney proteins. The aim of this study was to identify acute proteomic alterations induced by BUO. Rats were subjected to BUO for 2, 6, or 24 h. Mass spectrometry-based proteomics was performed on the renal inner medulla, and protein changes in the obstructed group were identified. Significant changes were successfully identified for 109 proteins belonging to different biological classes. Interestingly, proteins belonging to the cytoskeleton and proteins related to cytoskeletal regulation were found to be biologically enriched in BUO using online-accessible tools. Western blots confirmed the selected results, demonstrating acute downregulation of proteins belonging to all three cytoskeletal components. The microfilament protein beta-actin and the intermediate filament proteins pankeratin and vimentin were all downregulated. beta-Tubulin, an important microtubular protein, was found to be significantly downregulated after 24 h. Also, there was significant upregulation of cofilin, an actin-binding protein known to be upregulated in other nephropathy models. Furthermore, both upregulation and downregulation of cytoskeletal motor and regulatory proteins were observed. These findings were confirmed by immunohistochemistry, which clearly showed alterations in labeling in the inner medulla. Interestingly, we were able to confirm selected results in mpkCCD cells exposed to mechanical stretch. Our findings add to the knowledge of BUO-induced acute changes in the renal cytoskeleton and suggest that these molecular changes are partly mediated by increased stretch of the cells during obstruction. PMID- 24761002 TI - Modulation of NCC activity by low and high K(+) intake: insights into the signaling pathways involved. AB - Modulation of Na(+)-Cl(-) cotransporter (NCC) activity is essential to adjust K(+) excretion in the face of changes in dietary K(+) intake. We used previously characterized genetic mouse models to assess the role of Ste20-related proline alanine-rich kinase (SPAK) and with-no-lysine kinase (WNK)4 in the modulation of NCC by K(+) diets. SPAK knockin and WNK4 knockout mice were placed on normal-, low-, or high-K(+)-citrate diets for 4 days. The low-K(+) diet decreased and high K(+) diet increased plasma aldosterone levels, but both diets were associated with increased phosphorylation of NCC (phospho-NCC, Thr(44)/Thr(48)/Thr(53)) and phosphorylation of SPAK/oxidative stress responsive kinase 1 (phospho-SPAK/OSR1, Ser(383)/Ser(325)). The effect of the low-K(+) diet on SPAK phosphorylation persisted in WNK4 knockout and SPAK knockin mice, whereas the effects of ANG II on NCC and SPAK were lost in both mouse colonies. This suggests that for NCC activation by ANG II, integrity of the WNK4/SPAK pathway is required, whereas for the low-K(+) diet, SPAK phosphorylation occurred despite the absence of WNK4, suggesting the involvement of another WNK (WNK1 or WNK3). Additionally, because NCC activation also occurred in SPAK knockin mice, it is possible that loss of SPAK was compensated by OSR1. The positive effect of the high-K(+) diet was observed when the accompanying anion was citrate, whereas the high-KCl diet reduced NCC phosphorylation. However, the effect of the high-K(+)-citrate diet was aldosterone dependent, and neither metabolic alkalosis induced by bicarbonate, nor citrate administration in the absence of K(+) increased NCC phosphorylation, suggesting that it was not due to citrate-induced metabolic alkalosis. Thus, the accompanying anion might modulate the NCC response to the high-K(+) diet. PMID- 24761004 TI - Neutral aminoaciduria in cystathionine beta-synthase-deficient mice; an animal model of homocystinuria. AB - The kidney is one of the major loci for the expression of cystathionine beta synthase (CBS) and cystathionine gamma-lyase (CTH). While CBS-deficient (Cbs(-/ )) mice display homocysteinemia/methioninemia and severe growth retardation, and rarely survive beyond the first 4 wk, CTH-deficient (Cth(-/-)) mice show homocysteinemia/cystathioninemia but develop with no apparent abnormality. This study examined renal amino acid reabsorption in those mice. Although both 2-wk old Cbs(-/-) and Cth(-/-) mice had normal renal architecture, their serum/urinary amino acid profiles largely differed from wild-type mice. The most striking feature was marked accumulation of Met and cystathionine in serum/urine/kidney samples of Cbs(-/-) and Cth(-/-) mice, respectively. Levels of some neutral amino acids (Val, Leu, Ile, and Tyr) that were not elevated in Cbs(-/-) serum were highly elevated in Cbs(-/-) urine, and urinary excretion of other neutral amino acids (except Met) was much higher than expected from their serum levels, demonstrating neutral aminoaciduria in Cbs(-/-) (not Cth(-/-)) mice. Because the bulk of neutral amino acids is absorbed via a B(0)AT1 transporter and Met has the highest substrate affinity for B(0)AT1 than other neutral amino acids, hypermethioninemia may cause hyperexcretion of neutral amino acids. PMID- 24761005 TI - Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations. AB - Unconjugated bilirubin is an endogenous circulating antioxidant, bound to albumin, and therefore is retained in the vascular compartment. Bilirubin has well-documented neurotoxic effects in infants; however, current evidence indicates mildly elevated bilirubin is associated with protection from cardiovascular disease and all-cause mortality in adults. Recent clinical studies show mildly elevated bilirubin is associated with protection from kidney damage and dysfunction, in addition to cardiovascular events and all-cause mortality in patients undergoing hemodialysis. This is the first review to examine the clinical evidence and summarize the potential mechanisms of action that link bilirubin to protection from kidney damage, subsequent kidney failure, and dialysis-related mortality. With this understanding, it is hoped that new therapies will be developed to prevent renal dysfunction and mortality from cardiovascular disease in at-risk individuals. PMID- 24761006 TI - Invited commentary: Parental smoking as a risk factor for adult tobacco use: can maternal smoking during pregnancy be distinguished from the social environmental influence during childhood? AB - Parental smoking is known to have prenatal health effects on developing fetuses, and postnatal exposure to secondhand smoke causes adverse health effects during childhood and beyond. Further, there is solid evidence that parental smoking during childhood is a potent risk factor for smoking in offspring. In this issue of the Journal, Rydell et al. (Am J Epidemiol. 2014;179(12):1409-1417) add to a growing body of evidence showing that maternal smoking during pregnancy is statistically associated with the long-term risk of tobacco use in offspring. The data revealed a strong signal between maternal smoking during pregnancy and tobacco use in young adulthood, an association that was largely concentrated in snus use but not cigarette smoking. This new study adds to a growing body of epidemiologic evidence that consistently points toward maternal smoking during pregnancy being associated with an increased risk of offspring tobacco use in later life. There is also evidence from animal models indicating that fetal exposure to maternal nicotine use in utero can have a durable impact on the neural pathways that affect lifetime sensitivity to nicotine. This is an important research topic that continues to yield a consistent signal despite an array of inferential challenges. PMID- 24761007 TI - Rydell et al. respond to "Parental smoking and adult tobacco use. PMID- 24761009 TI - Counterfeit medications and their negative impacts on health care. PMID- 24761008 TI - Exposure to maternal smoking during pregnancy as a risk factor for tobacco use in adult offspring. AB - Nicotine from maternal smoking during pregnancy can cross the placental barrier, possibly resulting in fetal brain sensitization, as indicated by studies in which prenatal exposure to maternal smoking was associated with an increased risk of tobacco use among adolescent offspring. We investigated whether this association persists beyond adolescence by studying cigarette smoking and the use of snus (Swedish oral moist snuff) among 983 young adults from a prospective cohort study conducted in Stockholm, Sweden, between 2006 and 2010. Self-reported questionnaire data were linked with data from national population-based registers from 1983 onward. Maternal smoking during pregnancy was consistently associated with snus use in offspring (e.g., for lifetime daily snus use, adjusted odds ratio = 2.04, 95% confidence interval: 1.32, 3.16; for use of >3 cans of snus per week vs. less, odds ratio = 3.85, 95% confidence interval: 1.57, 10.15). No association was apparent with offspring's smoking, age at onset of tobacco use, or changes in use between 2006 and 2010. These findings indicate that prenatal exposure to maternal smoking is associated with regular and heavy nicotine intake from smokeless tobacco rather than from smoking. This should be further explored in epidemiologic studies that simultaneously address the roles of genetics and social environments. PMID- 24761010 TI - Part-time and job-share careers among pharmacy practice faculty members. AB - Part-time and job-share policies may allow pharmacy practice faculty members to achieve work/life balance while pursuing their professional goals. Precedent for alternative work schedules within the health professions community can be found throughout the literature; however, little is known about part-time roles in academic pharmacy. The design and implementation of 3 different alternative faculty appointments are described and department chair and faculty perspectives are shared. Teaching, service, and scholarship responsibilities, as well as outcomes before and after changes in appointment, are described. Advantages and disadvantages, including advice for other colleges of pharmacy, are presented. Alternate appointments may be a key factor in retaining highly qualified faculty members who continue to bring their expertise to teaching, precepting, and scholarship within a college or school of pharmacy. PMID- 24761011 TI - Student pharmacists' clinical interventions in advanced pharmacy practice experiences at a community nonteaching hospital. AB - OBJECTIVE: To assess student pharmacists' clinical interventions in advanced pharmacy practice experiences (APPEs) at a community nonteaching hospital and evaluate completed interventions based on the type of documentation method used. METHODS: Clinical interventions of 120 fourth-year (P4) student pharmacists in advanced institutional, medication safety, or internal medicine APPEs were collected over a 31/2-year period. Clinical interventions were analyzed for cost savings, intervention type, and acceptance rates. A secondary analysis of paper based vs electronic-based documentation of completed interventions was performed. RESULTS: There were 2,170 clinical interventions attempted with an acceptance rate of 97%. The estimated cost savings was $280,297. A comparable number of interventions and cost savings per student was observed between paper-based and electronic-based documentation methods. CONCLUSION: Student pharmacists at a community nonteaching hospital have many opportunities for participation in patient-centered activities, and for interaction and collaboration with other healthcare professionals. They can significantly benefit patient care through clinical interventions, while also contributing to cost savings for the institution. PMID- 24761012 TI - Education in pediatrics in US colleges and schools of pharmacy. AB - OBJECTIVE: To determine the extent to which pediatrics is taught at US doctor of pharmacy (PharmD) programs and to characterize what is being taught and how. METHODS: A 40-question online survey instrument was sent to accredited and candidate-status US PharmD programs. RESULTS: Of 86 participating programs (67.2% response rate), 81 (94.2%) indicated that pediatric topics were included in their required classroom curricula (mean, 21.9 contact hours). A pediatric elective course was offered by 61.0% of programs (mean, 25.9 contact hours). Advanced pharmacy practice experiences (APPEs) in pediatrics were offered by 97.4% of programs, with an average of 27 students per program completing this practice experience annually. CONCLUSIONS: Almost all responding programs incorporated pediatrics in their required curricula. Pediatric elective courses provided an adequate mean number of contact hours, but 39.0% of programs did not offer an elective course. One-fifth of students completed a pediatric APPE prior to graduation. Continued expansion of pediatric-focused classroom and experiential curricula across US PharmD programs is recommended. PMID- 24761013 TI - Perceptions and use of iPad technology by pharmacy practice faculty members. AB - OBJECTIVES: To explore the potential of tablet technology to address the specific workload challenges of pharmacy practice faculty members and to evaluate tablet usage after a department-wide iPad initiative. METHODS: After conducting a needs assessment to determine pharmacy faculty attitudes towards tablet technology and to identify potential usage scenarios, all faculty members in a department of pharmacy practice received an iPad. After iPad distribution, training sessions and virtual tutorials were provided. An anonymous survey was administered to evaluate the pilot. RESULTS: The needs assessment survey revealed positive attitudes towards iPad technology, identified use scenarios, and led to a department-wide iPad pilot program. Most faculty members used iPads for connectivity with students (86%), paper/project annotation (68%), assessment (57%), and demonstration of tools used in practice (36%). For teaching, 61% of faculty members used iPads in seminars/laboratories, 57% used iPads in the experiential setting, and 43% used iPads in the classroom. Use of iPads for patient-care activities varied and depended on site support for mobile technology. The 23 faculty members with external practice sites used iPads to a greater extent and had more positive attitudes towards this technology compared with campus-based faculty members. CONCLUSION: Integration of tablet technology into the pharmacy education setting resulted in faculty-reported increased productivity and decreased paper waste. It also allowed faculty members to experiment with new teaching strategies in the classroom and experiential setting. Administrators at institutions exploring the use of tablet technology should allocate resources based on faculty needs and usage patterns. PMID- 24761014 TI - Factors associated with students' perception of preceptor excellence. AB - OBJECTIVES: To identify factors associated with preceptor excellence as rated by student pharmacists and to assess the correlation of excellent ratings with years as pharmacist, specialty certification, and faculty appointment status. METHODS: A retrospective analysis of student pharmacist evaluations of preceptors from May 2009 to May 2012 was completed to determine factors associated with preceptor excellence. RESULTS: Preceptors who showed an interest in teaching, related to the student as an individual, encouraged discussion, were accessible, provided feedback, served as a role model, were organized, and/or spent increased time with students were more likely to be rated excellent. CONCLUSION: Serving as role models and showing an interest in teaching demonstrated the strongest association with being an excellent preceptor. Identifying factors students associate with preceptor excellence may result in enhanced preceptor recruitment, development, and training. PMID- 24761015 TI - Measuring achievement goal orientations of pharmacy students. AB - OBJECTIVES: To measure the achievement goal orientations of pharmacy students attending a 3-year (accelerated) doctor of pharmacy (PharmD) program. METHODS: A 16-item survey based on the Achievement Goal Questionnaire (AGQ) was administered to first-year (P1) and second-year (P2) pharmacy students at the Appalachian College of Pharmacy (ACP). Students were instructed to indicate to what degree each statement was true for them using a 7-point Likert scale (1=not true of me, 7=very true of me). RESULTS: One hundred twenty of the 155 students (77%) completed the survey. Most students had mastery-approach, mastery-avoidance, performance-approach, and/or performance-avoidance goal orientations; few had work-avoidance goal orientations. Second-year students and male students had higher work-avoidance mean scores than did P1 students and female students (p<0.05). CONCLUSION: Pharmacy students were mastery- and performance-oriented learners, and most did not have work-avoidance goal orientations. Male students and P2 students had higher work-avoidance than did female students and P1 students, respectively. More longitudinal studies are needed to confirm these findings. PMID- 24761017 TI - Impact of student- versus instructor-directed case discussions on student performance in a pharmacotherapy capstone course. AB - OBJECTIVE: To evaluate the impact of incorporating student-directed (SD) vs instructor-directed (ID) active learning on student performance in a pharmacotherapy capstone course. DESIGN: This 9-credit course was redesigned from exclusively ID case discussions to a format in which half were SD and half were ID. Student performance on evaluation questions derived from SD sessions was compared with that from ID sessions. ASSESSMENT: Overall, students (n=299) performed better on ID-session questions than on SD-session questions (78.7% vs 75.3%, correctly answered, respectively; p<0.001). For written evaluations, students performed better on ID-session questions than on SD-session questions (79.8% vs 73.9%, respectively; p<0.001). For verbal evaluations, students performed better on SD-session questions than on ID-session questions (79.5% vs 74.5%, respectively; p<0.001). After the course revision, student confidence regarding their ability to think critically, solve problems, make decisions, and pursue lifelong learning was high, and student and faculty feedback was positive. CONCLUSION: Student performance in a pharmacotherapy capstone course remained acceptable when a combination of SD and ID active learning was used, but the addition of SD learning did not translate to better performance on course evaluations. PMID- 24761016 TI - Application of genomic principles to pharmacotherapy of cancer. AB - OBJECTIVES: To teach first-year (P1) pharmacy students to apply the principles of pharmacogenomics underlying clinical pharmacotherapeutics to cancer patients. DESIGN: Using polymerase chain reaction (PCR) and high-resolution melting analysis of deoxyribonucleic acid (DNA) from colorectal cancer cell lines to determine the presence of somatic mutations for an oncogenic marker, students formulated the proper course of treatment for a patient with similar tumor genomics. ASSESSMENT: In a postintervention survey, students highly rated the effectiveness of the laboratory session for learning pharmacogenomics, and subsequent examination scores reflected retention of principles and understanding of clinical application. CONCLUSION: The pharmacogenomic laboratory exercise prepared students to understand how genetic markers give clinical insight into the appropriate application of drugs in oncology pharmacotherapy. Further, the session inspired their interest in learning more about pharmacogenomics and their professional roles in personalized medicine. PMID- 24761018 TI - Using debate to teach pharmacy students about ethical issues. AB - OBJECTIVE: To create, implement, and evaluate debate as a method of teaching pharmacy undergraduate students about ethical issues. DESIGN: Debate workshops with 5 hours of contact with student peers and facilitators and 5 hours of self study were developed for second-year pharmacy students. Student development of various skills and understanding of the topic were assessed by staff members and student peers. ASSESSMENT: One hundred fifty students completed the workshops. The mean score for debating was 25.9 out of 30, with scores ranging from 23.2 to 28.7. Seventy percent of students agreed that the debates were a useful teaching method in the degree program. CONCLUSION: A series of workshops using debates effectively delivered course content on ethical issues and resulted in pharmacy students developing skills such as teamwork, peer assessment, communication, and critical evaluation. These findings suggest that pharmacy students respond favorably to a program using debates as a teaching tool. PMID- 24761019 TI - A collaborative approach to combining service, teaching, and research. AB - OBJECTIVE: To describe a faculty-student collaborative model and its outcomes on teaching, service, and scholarship. DESIGN: A Medicare Part D elective course was offered that consisted of classroom and experiential learning where pharmacy students participated in community outreach events to assist Medicare beneficiaries with Part D plan selection. The course training was expanded to include medication therapy management (MTM) and the administration of immunizations. At the completion of the course, students collaborated with faculty members on research endeavors. EVALUATION: During the first 6 years of this course, the class size more than doubled from 20 to 42 students, and all students participating in the course met the IPPE requirements for community outreach. Over that same period, the number of beneficiaries receiving assistance with their Part D plan grew from 72 to 610; and with the help of students starting in 2011, faculty members had 28 poster presentations at national conferences, 7 invited podium presentations at national/international meetings, and published 8 manuscripts in peer-reviewed journals. CONCLUSION: Through collaborative efforts, this model took an elective course and provided classroom and experiential learning for students, needed health services for the community, and opportunities to pursue wide ranging research projects for faculty members and students. PMID- 24761020 TI - High-fidelity simulation training in advanced resuscitation for pharmacy residents. AB - OBJECTIVE: To assess the impact of high-fidelity patient simulation on pharmacy resident knowledge, confidence, and competency with advanced resuscitation algorithms and interventions. DESIGN: An overview of the institutional cardiopulmonary arrest algorithm and a review of pertinent medications and calculations were presented to postgraduate year 1 (PGY1) pharmacy residents, followed by participation in 3 simulated clinical scenarios using a high-fidelity mannequin. ASSESSMENT: An improvement of pharmacy resident knowledge, confidence, and competency with advanced resuscitation skills was observed. In addition, pharmacy residents demonstrated high performance levels with skills requiring advanced competency and proactive interactions with the cardiac arrest team. CONCLUSION: Incorporating high-fidelity patient simulation into an advanced resuscitation training program can help pharmacy residents achieve competency through the active learning of practical skills. PMID- 24761021 TI - Practice experiences at a single institutional practice site to improve advanced pharmacy practice examination performance. AB - OBJECTIVE: To determine whether sequential assignment of students to the same facility for institutional practice experiences improves their advanced pharmacy practice experience (APPE) examination scores. DESIGN: Student volunteers were assigned to the same healthcare facility for all institutional introductory pharmacy practice experiences (IPPEs) and advanced pharmacy practice experiences (APPEs). Other students completed institutional IPPEs and APPEs at separate healthcare facilities, ranging from 2 to 4 different facilities per student. APPE examination scores of students assigned to the same facility for all institutional learning experiences were compared with those of students assigned to more than 1 institutional practice site. ASSESSMENT: Holding grade point average constant, students assigned to the same facility for institutional IPPEs and APPEs scored 3 percentage points higher on the APPE institutional examination compared with students assigned to separate facilities for these experiences. CONCLUSION: Assigning students to the same facility for both institutional IPPEs and APPEs positively influenced knowledge-based APPE examination performance. PMID- 24761022 TI - Analysis of compounded pharmaceutical products to teach the importance of quality in an applied pharmaceutics laboratory course. AB - OBJECTIVE: To assess the effectiveness of a product-analysis laboratory exercise in teaching students the importance of quality in pharmaceutical compounding. DESIGN: Second-year pharmacy students (N=77) participated in a pharmaceutical compounding laboratory exercise and subsequently analyzed their final product using ultraviolet (UV) spectrometry. ASSESSMENT: Reflection, survey instruments, and quiz questions were used to measure how well students understood the importance of quality in their compounded products. Product analysis showed that preparations compounded by students had an error range of 0.6% to 140%, with an average error of 23.7%. Students' reflections cited common sources of error, including inaccurate weighing, contamination, and product loss during both the compounding procedure and preparation of the sample for analysis. Ninety percent of students agreed that the exercise improved their understanding of the importance of quality in compounded pharmaceutical products. Most students (85.7%) reported that this exercise inspired them to be more diligent in their preparation of compounded products in their future careers. CONCLUSION: Integrating an analytical assessment during a pharmaceutical compounding laboratory can enhance students' understanding of quality of compounded pharmaceutical products. It can also provide students a chance to reflect on sources of error to improve their compounding technique in the future. PMID- 24761024 TI - Integrating science and practice in pharmacy curricula. AB - An integrated curriculum is one where the summation of different academic disciplines forms a coherent whole and, importantly, where the relationships between the different disciplines have been carefully and strategically considered when forming the composite. Within pharmacy curriculum integration is important in order to produce graduates who have the capacity to apply their knowledge to a range of complex problems where available information is often incomplete. This paper discusses the development of an integrated curriculum in which students are presented with an organized, logical sequence of material, but still challenged to make their own integrations and develop as integrative thinkers. An evidence-based model upon which an interdisciplinary undergraduate pharmacy curriculum can be built is presented. PMID- 24761023 TI - A pharmacy business management simulation exercise as a practical application of business management material and principles. AB - OBJECTIVE: To implement a pharmacy business management simulation exercise as a practical application of business management material and principles and assess students' perceived value. DESIGN: As part of a pharmacy management and administration course, students made various calculations and management decisions in the global categories of hours of operation, inventory, pricing, and personnel. The students entered the data into simulation software and a realistic community pharmacy marketplace was modeled. Course topics included accounting, economics, finance, human resources, management, marketing, and leadership. ASSESSMENT: An 18-item posttest survey was administered. Students' slightly to moderately agreed the pharmacy simulation program enhanced their knowledge and understanding, particularly of inventory management, cash flow statements, balance sheets, and income statements. Overall attitudes toward the pharmacy simulation program were also slightly positive and students also slightly agreed the pharmacy simulation program enhanced their learning of pharmacy business management. Inventory management was the only area in which students felt they had at least "some" exposure to the assessed business management topics during IPPEs/internship, while all other areas of experience ranged from "not at all" to "a little." CONCLUSION: The pharmacy simulation program is an effective active learning exercise and enhanced students' knowledge and understanding of the business management topics covered. PMID- 24761026 TI - What is missing in the Bachelor of Science clinical pharmacy program in China? PMID- 24761025 TI - In support of teaching basic diagnostics. PMID- 24761027 TI - Teaching aviation crew resource management in a pharmacy curriculum. PMID- 24761028 TI - Twitter as an in-class backchannel tool in a large required pharmacy course. PMID- 24761029 TI - A 256 pixel magnetoresistive biosensor microarray in 0.18MUm CMOS. AB - Magnetic nanotechnologies have shown significant potential in several areas of nanomedicine such as imaging, therapeutics, and early disease detection. Giant magnetoresistive spin-valve (GMR SV) sensors coupled with magnetic nanotags (MNTs) possess great promise as ultra-sensitive biosensors for diagnostics. We report an integrated sensor interface for an array of 256 GMR SV biosensors designed in 0.18 MUm CMOS. Arranged like an imager, each of the 16 column level readout channels contains an analog front- end and a compact SigmaDelta modulator (0.054 mm2) with 84 dB of dynamic range and an input referred noise of 49 nT/?Hz. Performance is demonstrated through detection of an ovarian cancer biomarker, secretory leukocyte peptidase inhibitor (SLPI), spiked at concentrations as low as 10 fM. This system is designed as a replacement for optical protein microarrays while also providing real-time kinetics monitoring. PMID- 24761030 TI - Miyaura Borylations of Aryl Bromides in Water at Room Temperature. AB - New technology for palladium-catalyzed cross-couplings between B2pin2 and aryl bromides leading to arylboronates is described. Micellar catalysis serves to enable borylations to take place in water as the only medium at ambient temperatures. PMID- 24761031 TI - Establishing a Causal Relationship between Interventions to Promote Self Determination and Enhanced Student Self-Determination. AB - Promoting the self-determination of adolescents with disabilities has become best practice in secondary education and transition services, but to date there have been no studies establishing a causal relationship between efforts to promote self-determination and enhancement of the self-determination of youth with disabilities. This article reports a randomized trial, placebo control group study of 371 high school students receiving special education services under the categorical areas of mental retardation or learning disabilities. Students were randomly assigned to an intervention or control group (by high school campus), with students in the intervention condition receiving multiple instructional components to promote self-determination. Latent growth curve analysis showed that although all students in the study showed improved self-determination over the three years of the study, students in the intervention group showed significantly greater growth, though specific intra-individual variables impacted this growth. Implications for research and intervention are discussed. PMID- 24761032 TI - Keto-Functionalized Polymer Scaffolds As Versatile Precursors to Polymer Side Chain Conjugates. AB - A new methacrylate monomer with a reactive ketone side-chain, 2-(4-oxo pentanoate) ethyl methacrylate (PAEMA), was synthesized and subsequently polymerized by reversible addition-fragmentation chain transfer (RAFT) polymerization to give a polymer with a narrow molecular weight distribution (PDI = 1.25). The polymer was chain extended with poly(ethylene glycol methyl ether acrylate) (PEGMA) to yield a block copolymer. Aminooxy containing small molecules and oligoethylene glycol were conjugated to the ketone functionality of the side chain in high yields. Cytotoxicity of the oxime-linked tetra(ethylene glycol) polymer to mouse fibroblast cells was investigated; the polymer was found to be non-cytotoxic up to 1 mg/mL. The ease with which this polymer is functionalized, suggests that it may be useful in forming tailored polymeric medicines. PMID- 24761033 TI - Diaporthe: a genus of endophytic, saprobic and plant pathogenic fungi. AB - Diaporthe (Phomopsis) species have often been reported as plant pathogens, non pathogenic endophytes or saprobes, commonly isolated from a wide range of hosts. The primary aim of the present study was to resolve the taxonomy and phylogeny of a large collection of Diaporthe species occurring on diverse hosts, either as pathogens, saprobes, or as harmless endophytes. In the present study we investigated 243 isolates using multilocus DNA sequence data. Analyses of the rDNA internal transcribed spacer (ITS1, 5.8S, ITS2) region, and partial translation elongation factor 1-alpha (TEF1), beta-tubulin (TUB), histone H3 (HIS) and calmodulin (CAL) genes resolved 95 clades. Fifteen new species are described, namely Diaporthe arengae, D. brasiliensis, D. endophytica, D. hongkongensis, D. inconspicua, D. infecunda, D. mayteni, D. neoarctii, D. oxe, D. paranensis, D. pseudomangiferae, D. pseudophoenicicola, D. raonikayaporum, D. schini and D. terebinthifolii. A further 14 new combinations are introduced in Diaporthe, and D. anacardii is epitypified. Although species of Diaporthe have in the past chiefly been distinguished based on host association, results of this study confirm several taxa to have wide host ranges, suggesting that they move freely among hosts, frequently co-colonising diseased or dead tissue. In contrast, some plant pathogenic and endophytic taxa appear to be strictly host specific. Given this diverse ecological behaviour among members of Diaporthe, future species descriptions lacking molecular data (at least ITS and HIS or TUB) should be strongly discouraged. PMID- 24761034 TI - Five new Penicillium species in section Sclerotiora: a tribute to the Dutch Royal family. AB - Current literature accepts 17 species in Penicillium section Sclerotiora. Several produce colonies in bright yellow to orange colours and have monoverticillate conidiophores, apart from P. herquei, P. malachiteum and P. nodositatum, which are biverticillate. The focus of this paper is to refine the concepts of the species currently accepted in the section and introduce five new species, named after the Dutch Royal family as P. vanoranjei, P. maximae, P. amaliae, P. alexiae and P. arianeae. Penicillium vanoranjei produces orange (Dutch = oranje) colonies in culture, and is named after Willem-Alexander Claus George Ferdinand, 'Zijne Koninklijke Hoogheid de Prins van Oranje' (translated from Dutch as: 'His Royal Highness the Prince of Orange') and his family, to coincide with his coronation. We review the current taxonomic positions of P. lilacinoechinulatum and P. nodositatum, both currently considered to be synonyms of P. bilaiae. Sequence data generated in this study show that both species are phylogenetically distinct. Penicillium lilacinoechinulatum is closely related to P. amaliae sp. nov., whereas P. nodositatum does not belong to Penicillium sensu stricto. All species were compared morphologically and phylogenetically, based on beta-tubulin and calmodulin DNA data. A table summarising the morphological characters of all species is included, together with photomicrographs and recommended DNA markers for identification. PMID- 24761035 TI - The expansion of Phytophthora clade 8b: three new species associated with winter grown vegetable crops. AB - Despite its association with important agricultural crops, Phytophthora clade 8b is a poorly studied group of species. The clade currently consists of three officially described species (Phytophthora porri, P. brassicae and P. primulae) that are host-specific pathogens of leek, cabbages and Primula spp., respectively. However, over the past few decades, several other clade 8b-like Phytophthoras have been found on a variety of different host plants that were all grown at low temperatures in winter seasons. In this study, a collection of 30 of these isolates was subjected to a phylogenetic study using two loci (the rDNA ITS region and the mitochondrial cox1 gene). This analysis revealed a clear clustering of isolates according to their host plants. To verify whether these isolates belong to separate species, a detailed morphological study was conducted. On the basis of genetic and morphological differences and host specificity, we now present the official description of three new species in clade 8b: Phytophthora cichorii sp. nov., P. dauci sp. nov. and P. lactucae sp. nov. Two other groups of isolates (Phytophthora taxon castitis and Phytophthora taxon parsley) might also represent new species but the data available at this time are insufficient for an official description. This brings Phytophthora clade 8b to a group of six species that are all host-specific, slow-growing and specifically infect herbaceous crops at low temperatures. PMID- 24761036 TI - Reappraisal of the genus Alternariaster (Dothideomycetes). AB - Alternariaster was erected in 2007 to accommodate Alternaria helianthi, a fungal species known to cause leaf spots on Helianthus annuus (sunflower). It was segregated from Alternaria based on conidial morphology. Recently an unknown alternaria-like dematiaceous fungus was found associated with leaf spots on Bidens sulphurea (yellow cosmos) in Brazil. Based on a multi-gene phylogeny of parts of the ITS and LSU genes, this fungus was placed within the Leptosphaeriaceae with Alternariaster helianthi as its closest neighbour. Additional genes sequenced, RPB2 and GAPDH, confirmed this close relationship. The fungus on B. sulphurea has smaller conidia, 50-97.5 * 12.5-20 MUm, compared to Al. helianthi, 80-160 * 18-30 MUm, and lacks oblique or transverse septa which can be present in Al. helianthi. Pathogenicity studies on 18 plant species belonging to the Compositae showed that the B. sulphurea fungus only infected B. sulphurea, whereas Al. helianthi infected H. annuus and Galinsoga quadriradiata, a yet unreported host of Al. helianthi. The fungus causing disease on B. sulphurea is hence closely related but phylogenetically, morphologically and pathologically distinct from Al. helianthi, and therefore newly described as Alternariaster bidentis. The collection of a second species in the genus Alternariaster and the multigene phylogenetic analysis of these two species, confirmed Alternariaster to be a well-delimited genus in the Leptosphaeriaceae rather than the Pleosporaceae, to which Alternaria belongs. PMID- 24761037 TI - Phylogeny of chrysosporia infecting reptiles: proposal of the new family Nannizziopsiaceae and five new species. AB - We have performed a phenotypic and phylogenetic study of a set of fungi, mostly of veterinary origin, morphologically similar to the Chrysosporium asexual morph of Nannizziopsis vriesii (Onygenales, Eurotiomycetidae, Eurotiomycetes, Ascomycota). The analysis of sequences of the D1-D2 domains of the 28S rDNA, including representatives of the different families of the Onygenales, revealed that N. vriesii and relatives form a distinct lineage within that order, which is proposed as the new family Nannizziopsiaceae. The members of this family show the particular characteristic of causing skin infections in reptiles and producing hyaline, thin- and smooth-walled, small, mostly sessile 1-celled conidia and colonies with a pungent skunk-like odour. The phenotypic and multigene study results, based on ribosomal ITS region, actin and beta-tubulin sequences, demonstrated that some of the fungi included in this study were different from the known species of Nannizziopsis and Chrysosporium and are described here as new. They are N. chlamydospora, N. draconii, N. arthrosporioides, N. pluriseptata and Chrysosporium longisporum. Nannizziopsis chlamydospora is distinguished by producing chlamydospores and by its ability to grow at 5 degrees C. Nannizziopsis draconii is able to grow on bromocresol purple-milk solids-glucose (BCP-MS-G) agar alkalinizing the medium, is resistant to 0.2 % cycloheximide but does not grow on Sabouraud dextrose agar (SDA) with 3 % NaCl. Nannizziopsis arthrosporioides is characterised by the production of very long arthroconidia. Nannizziopsis pluriseptata produces 1- to 5-celled sessile conidia, alkalinizes the BCP-MS-G agar and grows on SDA supplemented with 5 % NaCl. Chrysosporium longisporum shows long sessile conidia (up to 13 MUm) and does not produce lipase. PMID- 24761038 TI - Generic circumscriptions in Geoglossomycetes. AB - The class Geoglossomycetes is a recently created class of Ascomycota, currently comprised of one family (Geoglossaceae) and five genera (Geoglossum, Nothomitra, Sarcoleotia, Thuemenidium and Trichoglossum). These fungi, commonly known as earth tongues, have long been a subject of mycological research. However, the taxonomy within the group has historically been hindered by the lack of reliable morphological characters, uncertain ecological associations, and the inability to grow these fungi in culture. The phylogenetic relationships of Geoglossomycetes were investigated by conducting maximum likelihood and Bayesian analyses using a 4-gene dataset (ITS, LSU, MCM7, RPB1). Five well-supported monophyletic clades were found that did not correspond exactly with the currently recognised genera, necessitating a taxonomic revision of the group. Two new genera are proposed: Glutinoglossum to accommodate G. glutinosum and the newly described species G. heptaseptatum, and Sabuloglossum to accommodate S. arenarium. The type species of Thuemenidium, traditionally included within the Geoglossaceae, is confirmed as belonging to a separate lineage that is only distantly related to Geoglossomycetes. PMID- 24761039 TI - Disentangling the Trichoderma viridescens complex. AB - Trichoderma viridescens is recognised as a species complex. Multigene analyses based on the translation elongation factor 1-alpha encoding gene (tef1), a part of the rpb2 gene, encoding the second largest RNA polymerase subunit and the larger subunit of ATP citrate lyase (acl1) reveals 13 phylogenetic species with little or no phenotypic differentiation. This is the first use of acl1 in Trichoderma phylogenetics. The typification of T. viridescens s.str. is clarified and Hypocrea viridescens is replaced by the new name T. paraviridescens. Besides these two species, eleven are phylogenetically recognised and T. olivascens, T. viridarium, T. virilente, T. trixiae, T. viridialbum, T. appalachiense, T. neosinense, T. composticola, T. nothescens and T. sempervirentis are formally described and illustrated. Several species produce yellow diffusing pigment on cornmeal dextrose agar, particularly after storage at 15 degrees C, while T. olivascens is characterised by the formation of an olivaceous pigment. The results are compared with earlier publications on this group of species. PMID- 24761040 TI - Sodiomyces alkalinus, a new holomorphic alkaliphilic ascomycete within the Plectosphaerellaceae. AB - In this study we reassess the taxonomic reference of the previously described holomorphic alkaliphilic fungus Heleococcum alkalinum isolated from soda soils in Russia, Mongolia and Tanzania. We show that it is not an actual member of the genus Heleococcum (order Hypocreales) as stated before and should, therefore, be excluded from it and renamed. Multi-locus gene phylogeny analyses (based on nuclear ITS, 5.8S rDNA, 28S rDNA, 18S rDNA, RPB2 and TEF1-alpha) have displayed this fungus as a new taxon at the genus level within the family Plectosphaerellaceae, Hypocreomycetidae, Ascomycota. The reference species of actual Heleococcum members showed clear divergence from the strongly supported Heleococcum alkalinum position within the Plectosphaerellaceae, sister to the family Glomerellaceae. Eighteen strains isolated from soda lakes around the world show remarkable genetic similarity promoting speculations on their possible evolution in harsh alkaline environments. We established the pH growth optimum of this alkaliphilic fungus at c. pH 10 and tested growth on 30 carbon sources at pH 7 and 10. The new genus and species, Sodiomyces alkalinus gen. nov. comb. nov., is the second holomorphic fungus known within the family, the first one being Plectosphaerella - some members of this genus are known to be alkalitolerant. We propose the Plectosphaerellaceae family to be the source of alkaliphilic filamentous fungi as also the species known as Acremonium alcalophilum belongs to this group. PMID- 24761042 TI - Taxonomy and phylogeny of European Gymnopus subsection Levipedes (Basidiomycota, Omphalotaceae). AB - The systematic integrity of European Gymnopus subsect. Levipedes is verified based on anatomic-morphological characters with support from DNA sequences of ITS and translation elongation factor 1-alpha genes. Seven species (G. alpinus, G. aquosus, G. dryophilus - including var. lanipes, G. erythropus, G. fagiphilus, G. hybridus, and G. ocior) belonging to this subsection are included. We clarify the concepts of G. dryophilus and G. ocior, which were occasionally confused in older literature. Due to unavailability of previously selected neotype of G. dryophilus the substitute neotype specimen is selected. Gymnopus dryophilus var. lanipes is confirmed as a variety; no important differences from nominotypical variability were detected. All discriminative characters used for identification of these species are discussed in detail. An identification key is also provided. PMID- 24761041 TI - Multi-gene phylogenetic analyses reveal species limits, phylogeographic patterns, and evolutionary histories of key morphological traits in Entoloma (Agaricales, Basidiomycota). AB - Species from Entoloma subg. Entoloma are commonly recorded from both the Northern and Southern Hemispheres and, according to literature, most of them have at least Nearctic-Palearctic distributions. However, these records are based on morphological analysis, and studies relating morphology, molecular data and geographical distribution have not been reported. In this study, we used phylogenetic species recognition criteria through gene genealogical concordance (based on nuclear ITS, LSU, rpb2 and mitochondrial SSU) to answer specific questions considering species limits in Entoloma subg. Entoloma and their geographic distribution in Europe, North America and Australasia. The studied morphotaxa belong to sect. Entoloma, namely species like the notorious poisonous E. sinuatum (E. lividum auct.), E. prunuloides (type-species of sect. Entoloma), E. nitidum and the red-listed E. bloxamii. With a few exceptions, our results reveal strong phylogeographical partitions that were previously not known. For example, no collection from Australasia proved to be conspecific with the Northern Hemisphere specimens. Almost all North American collections represent distinct and sister taxa to the European ones. And even within Europe, new lineages were uncovered for the red-listed E. bloxamii, which were previously unknown due to a broad morphological species concept. Our results clearly demonstrate the power of the phylogenetic species concept to reveal evolutionary units, to redefine the morphological limits of the species addressed and to provide insights into the evolutionary history of key morphological characters for Entoloma systematics. New taxa are described, and new combinations are made, including E. fumosobrunneum, E. pseudoprunuloides, E. ochreoprunuloides and E. caesiolamellatum. Epitypes are selected for E. prunuloides and E. bloxamii. In addition, complete descriptions are given of some other taxa used in this study for which modern descriptions are lacking, viz. E. subsinuatum, E. whiteae, E. flavifolium, E. luridum, E. bloxamii, E. madidum, E. corneri, E. callidermum and E. coeruleoviride. PMID- 24761044 TI - Dual Roles of Gastric Gland Mucin-specific O-glycans in Prevention of Gastric Cancer. AB - Gastric gland mucin is secreted from gland mucous cells, including pyloric gland cells and mucous neck cells located in the lower layer of the gastric mucosa. These mucins typically contain O-glycans carrying terminal alpha1,4-linked N acetylglucosamine residues (alphaGlcNAc) attached to the scaffold protein MUC6, and biosynthesis of the O-glycans is catalyzed by the glycosyltransferase, alpha1,4-N-acetylglucosaminyltransferase (alpha4GnT). We previously used expression cloning to isolate cDNA encoding alpha4GnT, and then demonstrated that alphaGlcNAc functions as natural antibiotic against Helicobacter pylori, a microbe causing various gastric diseases including gastric cancer. More recently, it was shown that alphaGlcNAc serves as a tumor suppressor for differentiated type adenocarcinoma. This review summarizes these findings and identifies dual roles for alphaGlcNAc in gastric cancer. PMID- 24761043 TI - Fungal Planet description sheets: 154-213. AB - Novel species of microfungi described in the present study include the following from South Africa: Camarosporium aloes, Phaeococcomyces aloes and Phoma aloes from Aloe, C. psoraleae, Diaporthe psoraleae and D. psoraleae-pinnatae from Psoralea, Colletotrichum euphorbiae from Euphorbia, Coniothyrium prosopidis and Peyronellaea prosopidis from Prosopis, Diaporthe cassines from Cassine, D. diospyricola from Diospyros, Diaporthe maytenicola from Maytenus, Harknessia proteae from Protea, Neofusicoccum ursorum and N. cryptoaustrale from Eucalyptus, Ochrocladosporium adansoniae from Adansonia, Pilidium pseudoconcavum from Greyia radlkoferi, Stagonospora pseudopaludosa from Phragmites and Toxicocladosporium ficiniae from Ficinia. Several species were also described from Thailand, namely: Chaetopsina pini and C. pinicola from Pinus spp., Myrmecridium thailandicum from reed litter, Passalora pseudotithoniae from Tithonia, Pallidocercospora ventilago from Ventilago, Pyricularia bothriochloae from Bothriochloa and Sphaerulina rhododendricola from Rhododendron. Novelties from Spain include Cladophialophora multiseptata, Knufia tsunedae and Pleuroascus rectipilus from soil and Cyphellophora catalaunica from river sediments. Species from the USA include Bipolaris drechsleri from Microstegium, Calonectria blephiliae from Blephilia, Kellermania macrospora (epitype) and K. pseudoyuccigena from Yucca. Three new species are described from Mexico, namely Neophaeosphaeria agaves and K. agaves from Agave and Phytophthora ipomoeae from Ipomoea. Other African species include Calonectria mossambicensis from Eucalyptus (Mozambique), Harzia cameroonensis from an unknown creeper (Cameroon), Mastigosporella anisophylleae from Anisophyllea (Zambia) and Teratosphaeria terminaliae from Terminalia (Zimbabwe). Species from Europe include Auxarthron longisporum from forest soil (Portugal), Discosia pseudoartocreas from Tilia (Austria), Paraconiothyrium polonense and P. lycopodinum from Lycopodium (Poland) and Stachybotrys oleronensis from Iris (France). Two species of Chrysosporium are described from Antarctica, namely C. magnasporum and C. oceanitesii. Finally, Licea xanthospora is described from Australia, Hypochnicium huinayensis from Chile and Custingophora blanchettei from Uruguay. Novel genera of Ascomycetes include Neomycosphaerella from Pseudopentameris macrantha (South Africa), and Paramycosphaerella from Brachystegia sp. (Zimbabwe). Novel hyphomycete genera include Pseudocatenomycopsis from Rothmannia (Zambia), Neopseudocercospora from Terminalia (Zambia) and Neodeightoniella from Phragmites (South Africa), while Dimorphiopsis from Brachystegia (Zambia) represents a novel coelomycetous genus. Furthermore, Alanphillipsia is introduced as a new genus in the Botryosphaeriaceae with four species, A. aloes, A. aloeigena and A. aloetica from Aloe spp. and A. euphorbiae from Euphorbia sp. (South Africa). A new combination is also proposed for Brachysporium torulosum (Deightoniella black tip of banana) as Corynespora torulosa. Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa. PMID- 24761045 TI - Microfibril-associated glycoprotein-1 controls human ciliary zonule development in vitro. AB - The ciliary zonule in the eye, also known as Zinn's zonule, is composed of oxytalan fibers, which are bundles of microfibrils consisting mainly of fibrillin 1. However, it is still unclear which of the microfibril-associated molecules present in the ciliary zonule controls oxytalan fibers. Microfibril-associated glycoprotein-1 (MAGP-1) is the only microfibril-associated molecule identified in the human ciliary zonule. In the present study, we used siRNA against MAGP-1 in cultures of human non-pigmented ciliary epithelial cells to examine the extracellular deposition and appearance of fibrillin-1 employing Western blotting and immunofluorescence. MAGP-1 suppression led to a reduction of fibrillin-1 deposition. Immunofluorescence also confirmed that RNAi-mediated down-regulation of MAGP-1 led to suppression of fiber development. These results suggest that MAGP-1 plays a crucial role in the extracellular deposition of fibrillin-1 during formation of the human ciliary zonule. PMID- 24761046 TI - Coexpression of ang1 and tie2 in odontoblasts of mouse developing and mature teeth-a new insight into dentinogenesis. AB - Angiopoietin-1 regulates vascular angiogenesis and stabilization, and is reported to promote bone formation by facilitating angiogenesis. To estimate the role of Ang1 in odontogenesis, we explored the distribution of Ang1 and the receptor, Tie2 in the mouse developing and mature first molar of the mandible. At embryonic day 18, when differentiation of odontoblasts begins, immunosignals for Ang1 were intensely detected in the basement membrane and the distal side, which faced the basement membrane of odontoblasts. In situ hybridization revealed that Ang1 was expressed in odontoblasts and ameloblasts facing the basement membrane. Tie2 was localized in the distal side of odontoblasts. After birth, Ang1 was detected in the predentin, whereas both Ang1 and Tie2 were colocalized in odontoblasts and odontoblast processes. These distributions were retained up to 8 weeks. In contrast to odontoblasts, ameloblasts, cementoblasts and osteoblasts expressed Ang1 but did not express Tie2. Colocalization of Ang1 and Tie2 in odontoblasts and selective expression of Tie2 in odontoblasts among cells responsible for calcified tissue formation suggested the involvement of autocrine signals of Ang1 Tie2 in dentinogenesis. PMID- 24761047 TI - Upregulated Expression of AQP 7 in the Skeletal Muscles of Obese ob/ob Mice. AB - Aquaporin (AQP) is suggested to be regulated by leptin through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway. AQP7 and AQP9 are membrane proteins with water and glycerol channels, the latter of which is essential for triglyceride synthesis. We conjectured that the expression of AQP7 and AQP9 would be altered in the skeletal myofibers in obese leptin deficient ob/ob mice as compared with that of wild mice. RNA and protein levels were studied in the quadriceps femoris muscles of ob/ob and wild mice. Real time quantitative RT-PCR analysis showed that mouse AQP7 mRNA levels in skeletal muscles were significantly higher in ob/ob mice than in wild mice (P<0.01), whereas mouse AQP9 mRNA level was not different between the two groups (P>0.05). Histologically the type 1 myofibers of ob/ob mice contained numerous lipid droplets in oil red O stain samples. Immunohistochemical staining of ob/ob mouse muscles revealed enhanced expression of AQP7 at myofiber surface membranes, while AQP9 expression appeared to be similar to that of wild mice. The findings suggest that the upregulated expression of AQP7 in ob/ob mouse muscles facilitates the secretion of glycerol from myocytes. PMID- 24761048 TI - How Are Preferences Revealed? AB - Revealed preferences are tastes that rationalize an economic agent's observed actions. Normative preferences represent the agent's actual interests. It sometimes makes sense to assume that revealed preferences are identical to normative preferences. But there are many cases where this assumption is violated. We identify five factors that increase the likelihood of a disparity between revealed preferences and normative preferences: passive choice, complexity, limited personal experience, third-party marketing, and intertemporal choice. We then discuss six approaches that jointly contribute to the identification of normative preferences: structural estimation, active decisions, asymptotic choice, aggregated revealed preferences, reported preferences, and informed preferences. Each of these approaches uses consumer behavior to infer some property of normative preferences without equating revealed and normative preferences. We illustrate these issues with evidence from savings and investment outcomes. PMID- 24761050 TI - The Biofuels Tax Credit. PMID- 24761049 TI - Conversion Between Doubly and Triply Carboxylate-Bridged Di(ethylzinc) Complexes and Formation of the (MU-Oxo)tetrazinc Carboxylate [Zn4O(ArTolCO2)6]. AB - Ethylzinc 2,6-bis(p-tolyl)benzoate converts between two forms in solution. Through NMR spectroscopic techniques and X-ray crystallography, the species in equilibrium were identified as [Zn2(ArTolCO2)2(Et)2(THF)2] (1), [Zn2(ArTolCO2)3(Et)(THF)] (2), and diethyl zinc (ArTol = 2,6-bis(p-tolyl)phenyl). The equilibrium provides a model for understanding the speciation between doubly and triply m-terphenylcarboxylate-bridged diiron(II) and mononuclear iron(II) complexes. Evidence is presented for the occurrence of coordinatively unsaturated trigonal zinc species in solution. Both 1 and 2 decompose in air to form the T symmetric oxozinc carboxylate, [Zn4O(ArTolCO2)6] (3). PMID- 24761051 TI - Does Inherency Have a Place in Determinations of Obviousness? PMID- 24761052 TI - Biosimilarity and Interchangeability in the Biologics Price Competition and Innovation Act of 2009 and FDA's 2012 Draft Guidance for Industry. PMID- 24761053 TI - Epigenetic Patents: A Stressful Environment for an Emerging Science. PMID- 24761054 TI - New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France* AB - This article provides an overview of French legislative history, Parliamentary debates, and recent amendments in hESC research policy, as well as additional comparisons with laws across the European Union. Unlike policy discussions in the U.S., French dialogue on hESC research generally rejects the arbitrary division between the status of the embryo and hESCs, recognizing that hESC research necessarily requires the destruction of human embryos. Accordingly, French discourse debates the competing interests of science with secular ethical and civic considerations relating to the symbolic status of the embryo and society's duty to moderate what constitutes appropriate boundaries on research. Parliament recently amended France's hESC research laws to explicitly permit hESC research, signaling the beginning of reform efforts under President Hollande's new power structure, but the inclusion of secular moral considerations in the policy debate will likely restrain the extent of any future changes. PMID- 24761055 TI - Special issue on the teenage brain: Sensitivity to social evaluation. AB - Relative to childhood, peer relationships take on a heightened importance during adolescence. Might adolescents be highly attuned to information that concerns when and how they are being evaluated, and what their peers think of them? This review evaluates how continuing brain development - which influences brain function - partially explains or reflects adolescents' attunement to social evaluation. Though preliminary, evidence is mounting to suggest that while processing information relevant to social evaluation and the internal states of other people, adolescents respond with greater emotional intensity and corresponding nonlinear recruitment of socioaffective brain circuitry. This review highlights research findings that relate trajectories of brain development and social behavior, and discusses promising avenues of future research that will inform how brain development might lead adolescents sensitized to social evaluation. PMID- 24761056 TI - FLT PET-CT in evaluation of treatment response. AB - PURPOSE: Review published studies to investigate the value of clinical 3-deoxy-3 (18)F-fluorothymidine (FLT) positron emission tomography (PET) in predicting response to treatment. MATERIALS AND METHODS: Interrogate databases to identify suitable publications between 2007 and 2013 with a minimum of five patients. Articles within the inclusion criteria were reviewed with major findings reported leading to a descriptive analysis of FLT PET in therapy response. RESULTS: Lesions investigated included glioma, head and neck, esophageal, lung, breast, gastric, renal, rectal, sarcomas, germ cell, lymphomas, leukemia, and melanoma resulting in a total of 34 studies analyzed. A variety of therapies were applied and dissimilar PET protocols were widespread making direct comparison between studies challenging. Though baseline, early and late therapy scans were popular particularly in chemotherapy regimes. Most studies investigated showed significantly reduced FLT uptake during or after therapy compared with pretreatment scans. CONCLUSION: Current evidence suggests FLT PET has a positive role to play in predicting therapy response especially in brain, lung, and breast cancers where good correlation with Ki-67 is observed. However, careful attention must be placed in undertaking larger clinical trials where harmonization of scanning and analysis protocols are strictly adhered to fully assess the true potential of FLT PET in predicting response to treatment. PMID- 24761057 TI - Response assessment in metronomic chemotherapy: RECIST or PERCIST? AB - INTRODUCTION: Metronomic chemotherapy (MC) is a novel therapeutic variation for resistant cancers, wherein chemotherapeutic drugs are administrated in low doses with no prolonged drug-free break. It lessens the level of toxicity, is better tolerated and enhances the quality of life. This retrospective analysis was undertaken to evaluate whether anatomical (computed tomography [CT]) or functional (positron emission tomography [PET]) imaging be used for response assessment in patients on MC. MATERIALS AND METHODS: A total of 16 males and 27 females with age range of 12-83 years on MC who underwent PET/CT were assessed by new response evaluation criteria in solid tumors (RECIST 1.1) and PET response criteria in solid tumors (PERCIST 1.0). RESULTS: Concordance between RECIST 1.1 and PERCIST was seen in 32 (75%) patients. There was discordance in 11 (25%) patients. In patients with discordance, the results were confirmed by follow-up imaging. PET upstaged the disease in 81% of patients (9/11) and down-staged the disease in 19% of patients (2/11). CONCLUSIONS: Metabolic response accurately identified the disease status as assessed by clinical or imaging follow-up. Alteration in morphology takes time to manifest, which is demonstrated by CT or magnetic resonance; whereas in MC which brings about tumor dormancy, assessing metabolic response by PET would be more appropriate. MC is usually given in palliative setting but in few cases complete metabolic response was demonstrated in our study. In such a scenario this form of treatment has the potential to become an adjunct mode of treatment in some tumors. This needs to be evaluated with larger, homogenous patient population in a prospective mode. PMID- 24761059 TI - Evaluation of interobserver variability of parenchymal phase of Tc-99m mercaptoacetyltriglycine and Tc-99m dimercaptosuccinic acid renal scintigraphy. AB - OBJECTIVE: The aim of this study was to investigate the variability in the interpretation of parenchymal abnormalities and to assess the differences in interpretation of routine renal scintigraphic findings on posterior view of technetium-99m dimercaptosuccinic acid (pvDMSA) scans and parenchymal phase of technetium-99m mercaptoacetyltriglycine (ppMAG3) scans by using standard criterions to make standardization and semiquantitative evaluation and to have more accurately correlation. MATERIALS AND METHODS: Two experienced nuclear medicine physicians independently interpreted pvDMSA scans of 204 and ppMAG3 scans of 102 pediatric patients, retrospectively. Comparisons were made by visual inspection of pvDMSA scans, and ppMAG3 scans by using a grading system modified from Itoh et al. According to this, anatomical damage of the renal parenchyma was classified into six types: Grade 0-V. In the calculation of the agreement rates, Kendall correlation (tau-b) analysis was used. RESULTS: According to our findings, excellent agreement was found for DMSA grade readings (DMSA-GR) (tau-b = 0.827) and good agreement for MAG3 grade readings (MAG3-GR) (tau-b = 0.790) between two observers. Most of clear parenchymal lesions detected on pvDMSA scans and ppMAG3 scans identified by observers equally. Studies with negative or minimal lesions reduced correlation degrees for both DMSA-GR and MAG3-GR. CONCLUSION: Our grading system can be used for standardization of the reports. We conclude that standardization of criteria and terminology in the interpretations may result in higher interobserver consistency, also improve low interobserver reproducibility and objectivity of renal scintigraphy reports. PMID- 24761058 TI - F-18 fluoro-deoxy-glucose and F-18 sodium fluoride cocktail PET/CT scan in patients with breast cancer having equivocal bone SPECT/CT. AB - INTRODUCTION: Although single-photon emission computed tomography (SPECT)/computed tomography (CT) plays a major role in the characterization of equivocal lesions on bone scintigraphy, it remains equivocal in a fraction of these patients. We evaluated the additional value of cocktail F-18 sodium fluoride (18F-NaF) and F-18 fluorodeoxyglucose (18F-FDG) co-injection positron emission tomography (PET) (cocktail PET) in these patients. MATERIALS AND METHODS: Fifteen breast cancer patients, who had equivocal findings on the whole body bone scan (WBS) and SPECT/CT, were subjected to a cocktail PET/CT scan. The cocktail PET/CT was performed by co-administration of 18F-FDG and 18F-NaF in a ratio of about 2.4, with the total administered activity kept at approximately 10 mCi. RESULTS: Of the 15 patients, seven were with locally advanced breast cancer (LABC) and the other eight were referred because of suspicion of recurrent disease on follow-up. Of the seven patients with LABC, the cocktail PET scan was positive for all the lesions suspicious on WBS and SPECT/CT. Additionally, it showed uptake in the primary tumor and ipsilateral axillary lymph nodes as well as identified additional osseous, lymph nodal, and solid organ metastases in these patients. Similarly, of the eight patients studied for suspicion of recurrence, the cocktail PET scan was found to be positive in seven patients. In three patients, additional osseous lesions were noted. CONCLUSION: The cocktail PET/CT scan can characterize almost all the suspicious equivocal lesions on the bone scan and SPECT/CT. The distinct advantage of identifying lymph nodal and solid organ metastases allows it to be considered as a useful imaging modality in patients with equivocal bone SPECT/CT. PMID- 24761060 TI - Primary central nervous system lymphoma in an human immunodeficiency virus infected patient mimicking bilateral eye sign in brain seen in fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography. AB - Fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) has proven useful in the diagnosis, staging, and detection of metastasis and posttreatment monitoring of several malignancies in human immunodeficiency virus (HIV)-infected patients. It also has the ability to make the important distinction between malignancy and infection in the evaluation of central nervous system (CNS) lesions, leading to the initiation of the appropriate treatment and precluding the need for invasive biopsy. We report an interesting case of HIV positive 35-year-old woman presented with headache, disorientation, and decreased level of consciousness. She underwent whole body PET/CT which showed multiple lesions in the cerebrum which mimics bilateral eye in brain. A diagnosis of a primary CNS lymphoma was made and patient was started on chemotherapy. PMID- 24761062 TI - Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography imaging of an isolated subcutaneous loin metastasis from primary papillary carcinoma of the thyroid. AB - Differentiated thyroid cancer frequently metastasizes but generally spreads to regional cervical lymph nodes and, in advanced cases, to the lungs and/or skeleton. Metastases to the skin/subcutaneous tissue are rare. We report 45-year old male patient presented with a loin swelling which on biopsy showed a papillary carcinoma and referred for fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) to find out the primary disease. PET/CT showed abnormal FDG uptake within a loin metastasis and right lobe thyroid nodule. Fine-needle aspiration from nodule showed papillary carcinoma. Because thyroid cancer can rarely metastasize to the skin, attention should be given to that region during interpretation of the images. He was advised total thyroidectomy and metastasis excision. PMID- 24761061 TI - (18)F-FDG PET/CT for initial assessment and response monitoring in a case of high grade primary lymphoma of the thyroid gland: A case report and review of literature. AB - Thyroid lymphoma is a rare disease entity of elderly females. Chronic lymphocytic thyroiditis is said to be the precursor of thyroid lymphoma, suggesting a role of chronic antigen stimulation in the development of the disease. We present a case of male with lymphocytic thyroiditis who presented with painless progressive neck enlargement and pathology revealed features of high grade lymphoma. Staging and posttreatment (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) was performed. This report reemphasizes the role of (18)F-FDG PET/CT in the diagnosis, staging, and assessment of therapy response in patients with extranodal lymphoma, including the primary thyroid lymphoma. PMID- 24761063 TI - Tuberculosis the great mimicker: 18F-fludeoxyglucose positron emission tomography/computed tomography in a case of atypical spinal tuberculosis. AB - Tuberculosis (TB) has aptly been called the great mimicker. A 14-year-old boy, who had been treated for Hodgkin's Lymphoma 2 years back and had been in remission, underwent a whole body 18F-fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan, owing to a recent onset of backache and difficulty in walking. The study showed an FDG avid destructive lesion of the posterior elements of the sixth, seventh and eighth dorsal vertebrae along with a hypermetabolic collection in the adjacent paraspinal muscles with extension into the spinal canal, causing encasement of the thecal sac as well. Based on this constellation of findings, a diagnosis of atypical spinal TB was made, which was subsequently proven on histopathology. The present case illustrates that spinal TB, including the atypical form can be diagnosed on PET/CT even in clinically unsuspected cases. PMID- 24761064 TI - Malaria masquerading as relapse of Hodgkin's lymphoma on contrast enhanced (18)F fluorodeoxyglucose positron emission tomography/computed tomography: A diagnostic dilemma. AB - (18)Flurodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) is nowadays routinely used in management of lymphoma patients. We here present a case of Hodgkin's lymphoma which showed (18)F-FDG avid splenomegaly on PET/CT done for clinically suspected relapse. Further evaluation by peripheral smear examination revealed malaria. The patient was then started on anti-malarial medications and follow-up PET/CT revealed resolution of hypermetabolic splenomegaly. This report highlights that in endemic regions malaria can cause (18)F-FDG avid splenomegaly and might mimic relapse of lymphoma. PMID- 24761065 TI - A case of dual ectopy thyroid along the thyroglossal tract demonstrated on 99mTc Pertechnatate hybrid single photon emission computed tomography/computed tomography. AB - Ectopic thyroid tissue (ETT) refers to the presence of thyroid tissue in locations other than the normal anterior neck region between the second and fourth tracheal cartilages. Multiple ectopia of the thyroid is extremely rare. Here we report a case of 10-year-old girl with anterior midline neck swelling and hypothyroidism with dual ectopia of thyroid gland without orthotopic thyroid gland. Planar 99 m-technetium pertechnatate scan identified ETT corresponding to the palpable neck swelling. Single photon emission computed tomography/computed tomography (SPECT/CT) demonstrated ETT in two locations, one corresponding to the palpable mass and another in the in the sublingual location. This case thus demonstrates the important role of hybrid SPECT/CT in the identification of dual ectopia along the thyroglossal tract. PMID- 24761066 TI - Peritoneal and mediastinal highly differentiated follicular carcinoma of ovarian origin. AB - A 70-year-old female patient presented to her primary care doctor with persistent elevated alkaline phosphatase of suspected metastatic etiology. Computed tomography demonstrated epicardial and peritoneal nodules. Biopsy of one of the peritoneal nodules revealed thyroid tissue and extraovarian struma ovarii was considered. The patient had a history of remote total abdominal hysterectomy and bilateral salpingo-oophorectomy 31 years prior for endometriosis with no available pathology from that surgery. The patient recalls being told that she had a left ovarian cyst. A thyroid ultrasound was performed that demonstrated multiple nodules without concerning features; however, due to high clinical suspicion, a total thyroidectomy was performed. Upon full histological evaluation a 0.5 cm papillary microcarcinoma was found. Given the rarity of metastatic papillary cancer to the peritoneum and the small size and grade of the tumor, a diagnosis of highly differentiated follicular carcinoma of ovarian origin was favored. The patient was subsequently treated with radioiodine therapy. PMID- 24761067 TI - Myocardial perfusion SPECT in a case of retropulmonary looping of left coronary artery in a baby after arterial switch surgery. AB - Pediatric myocardial perfusion imaging (MPI) is not a routine investigation in an Indian setting due to under referrals and logistic problems. However, MPI is a frequently performed and established modality of investigation in adults for the identification of myocardial ischemia and viability. We report myocardial perfusion scintigraphy in a case of retropulmonary looping of left coronary artery in a baby after arterial switch surgery. Adenosine stress MPI revealed a large infarct involving anterior segment with moderate reversible ischemia of the lateral left ventricular segment. Coronary angiogram later confirmed left main coronary artery ostial occlusion with retrograde collateral supply from dilated right coronary artery. PMID- 24761068 TI - Rare case of trilateral retinoblastoma with spinal canal drop metastasis detected with fluorine-18 fluorodeoxyglucose positronemission tomography/computed tomography imaging. AB - Trilateral retinoblastoma (TRb) is a rare syndrome associating hereditary bilateral or unilateral retinoblastoma (Rb) with an intracranial neuroblastic tumor. The latter arises in the midline, most often in the pineal gland, less frequently in the suprasellar or parasellar region. The outcome is usually fatal because of secondary spinal dissemination. We report 10-year-old boy presented with a right eye proptosis and leukocoria, and the magnetic resonance imaging (MRI) showed right orbital mass lesion infiltrating optic nerve and diagnosis of retinoblastoma was made. He was referred for fluorodeoxyglucose-positron emission tomography/computed tomography (FDG PET/CT) to find out the extent of the disease. PET/CT showed abnormal FDG-uptake within right orbital mass lesion, suprasellar enhancing lesion and drop metastasis in the cervical spinal canal level. He was diagnosed as a case of TRb with spinal canal drop metastasis. He underwent chemotherapy and craniospinal irradiation. PMID- 24761069 TI - Horseshoe kidney mimicking cross-fused ectopia on (99m)Tc-EC renal dynamic scintigraphy. AB - The 'horseshoe kidney' is the most common renal fusion anomaly. In this disorder, two developed kidneys are connected to each other at the lower part and grow together. We report a case of horseshoe kidney mimicking cross-fused ectopia in (99m)Tc-EC renal dynamic scintigraphy. PMID- 24761070 TI - 18F-Fluoride bone positron emission tomography demonstrating changes related to finger clubbing and hypertrophic osteoarthropathy. AB - Hypertrophic pulmonary osteoarthropathy is manifested by clubbing and periostitis of bones. We present a very rare documentation of increased F18-sodium fluoride uptake in the distal phalanges of both hands correlating to clubbing of the fingers in a 55-year-old female patient with carcinoma of lung in whom bone positron emission tomography was performed for metastatic work-up. PMID- 24761071 TI - Carcinoma of unknown primary of neuroendocrine origin: Accurate detection of primary with (68)Ga-labelled [1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10 tetraacetic acid]-1-NaI3-Octreotide positron emission tomography/computed tomography enterography. AB - (68)Ga-labelled [1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid] 1-NaI3-Octreotide ((68)Ga-DOTANOC) positron emission tomography/computed tomography (PET/CT) is an excellent modality in patients with carcinoma of unknown primary of neuroendocrine origin. Most of the primary lesions are located in mid gut region where the lesions have poor resolution due to undistended and overlapping intestinal loops and motility-related artifacts. Although PET/CT enteroclysis, enterography and colonography have been described with (18)F fluorodeoxyglucose, PET/CT enterography with(68)Ga-DOTANOC has not been described in the literature. Here, we present a case where(68)Ga-DOTANOC PET/CT enterography was useful in identifying the primary neuroendocrine tumor lesion in small intestine with accurate delineation. PMID- 24761072 TI - Graves' disease with thyroid hemiagenesis: A rare abnormality with rarer presentation. PMID- 24761073 TI - Unilateral vocal cord paralysis: An unusual cause and rare imaging pattern seen on FDG PET/CT in a case of oropharyngeal cancer. PMID- 24761074 TI - Utility of single photon emission tomography/computed tomography in characterizing an additional focus of iodine uptake in post-treatment whole body iodine scan. PMID- 24761075 TI - Urinoma in a young child 6 months following dual cadaveric renal transplantation detected on technetium-99m ethylene dicysteine renal dynamic scan confirmed on SPECT/CT. PMID- 24761077 TI - A comprehensive predictive scoring method for difficult laparoscopic cholecystectomy. AB - CONTEXT: Laparoscopic cholecystectomy (LC) is the gold standard cholecystectomy. LC is the most common difficult laparoscopic surgery performed by surgeons today. The factors leading to difficult laparoscopic cholecystectomy can be predicted. AIMS: To develop a scoring method that predicts difficult laparoscopic cholecystectomy. SETTINGS AND DESIGN: Bidirectional prospective study in a medical college setup. MATERIALS AND METHODS: Following approval from the institutional ethical committee, cases from the three associated hospitals in a medical college setup, were collected using a detailed proforma stating the parameters of difficulty in laparoscopic cholecystectomy. Study period was between May 10 and June 12. Preoperative, sonographic and intraoperative criteria were considered. STATISTICAL ANALYSIS USED: Chi Square test and Receiver Operater Curve (ROC) analysis. RESULTS: Total 323 patients were included. On analysis, elderly patients, males, recurrent cholecystitis, obese patients, previous surgery, patients who needed preoperative Endoscopic retrograde cholangiopancreatography (ERCP), abnormal serum hepatic and pancreatic enzyme profiles, distended or contracted gall bladder, intra-peritoneal adhesions, structural anomalies or distortions and the presence of a cirrhotic liver on ultrasonography (USG) were identified as predictors of difficult LC. A scoring system tested against the same sample proved to be effective. A ROC analysis was done with area under receiver operator curve of 0.956. A score above 9 was considered difficult with sensitivity of 85% and specificity of 97.8%. CONCLUSIONS: This study demonstrates that a scoring system predicting the difficulty in LC is feasible. There is scope for further refinement to make the same less cumbersome and easier to handle. Further studies are warranted in this direction. PMID- 24761076 TI - Laparoscopic trans- and retroperitoneal adrenal surgery for large tumors. AB - BACKGROUND: Laparoscopic adrenalectomy for tumors larger than 6 cm is currently a matter of controversial discussion because of difficult mobilization from surrounding organs and a possible risk of capsule rupture. MATERIALS AND METHODS: Data of consecutive patients undergoing laparoscopic adrenalectomy between 1/1994 and 7/2012 were collected and analysed retrospectively. Intra- and postoperative morbidity in patients with tumors <=6 cm (group 1, n = 227) were compared to patients with tumors >6 cm, (group 2, n = 52). RESULTS: Incidence of adrenocortical carcinoma was significantly higher in group 2 patients (6.3% vs. 0.4%, P = 0.039) whereas the incidence of aldosterone-producing adenoma was lower (2% vs. 25%, P = 0.001). Mean duration of surgery was longer (105 min vs. 88 min, P = 0.03) and the estimated blood loss was higher (470 mL vs. 150 mL) in group 2 patients. Intraoperative bleeding rate (5.7% vs. 0.8%, P = 0.041), and the conversion rate were significantly higher (5.7% vs. 1.3%, P = 0.011) in group 2. Also, postoperative complication rate was significantly higher in group 2 (11.5% vs. 3.0%, P = 0.022). However, only two major complications occurred, one in each group. CONCLUSION: Minimally invasive adrenal surgery can be performed by an experienced surgeon even in patients with large tumors (>6 cm) with an increased but still acceptable intra- and postoperative morbidity. PMID- 24761078 TI - Laparoscopic resection for middle and low rectal cancer. AB - AIMS: The purpose of this study was to evaluate the technical feasibility, safety and oncological outcomes of laparoscopic resection for middle and low rectal cancers. MATERIALS AND METHODS: From January 2004 to December 2011, review of prospectively collected database revealed a series of 97 laparoscopic resections for middle and low rectal cancer within 10 cm from the anal verge. Five patients with multiple primary cancers were excluded. Operation time, intra-operative blood loss, surgical complications, duration of hospital stay, retrieved lymph nodes, tumour, node, metastasis (TNM) stage and recurrence were retrospectively analysed. RESULTS: Tumours were located within 5 cm of the anal verge in 28 patients (30.4%) and from 5 cm to 10 cm in 64 patients (69.6%). Abdominoperineal resection was performed in 12 patients (13%), and conversion to open surgery was necessary in four patients (4.3%). The mean operation time was 199.7 min (range 105-450 min) and the mean intra-operative blood loss was 169.9 mL (range 20-800 mL). The mean hospital stay was 11.8 days (range 5-45 days) and a mean of 12.2 lymph nodes were retrieved. The incidence of surgical complications was 11.9%, including anastomosis site leakage in five patients (5.4%). There were no mortalities resulting from laparoscopic surgery. The median follow-up period was 28.4 months (range 7-85 months). Recurrence occurred in eight patients (8.7%). CONCLUSIONS: Laparoscopic resection can be applied for middle and low rectal cancers with acceptable surgical and oncological outcomes. PMID- 24761080 TI - Preliminary experience with laparoscopic Foley's YV plasty for ureteropelvic junction obstruction in children. AB - INTRODUCTION: Laparoscopic dismembered pyeloplasty is an acceptable option for ureteropelvic junction (UPJ) obstruction in the paediatric population. We compared our results of laparoscopic dismembered and non-dismembered Foley's YV pyeloplasty. MATERIALS AND METHODS: Children presenting with hydronephrosis secondary to UPJ obstruction formed the study group. Foley's YV plasty was planned whenever it was observed that a tension free dismembered pyeloplasty was not possible in spite of all possible manoeuvres. Children were followed up for urinary infection, and renogram was repeated after 3 months. RESULTS: During the study period, 108 children (63 male and 45 female) with a mean age of 4.94 +/- 2.78 years underwent laparoscopic dismembered pyeloplasty and the remaining 11 children (5 male and 6 female) with a mean age of 4.00 +/- 1.776 years underwent laparoscopic Foley's YV plasty. There were no major peri-operative complications noted and conversion to open was not necessary in any child. Renogram done at 3 months post-operatively showed good drainage and improvement of renal function. CONCLUSIONS: Laparoscopic Foley's YV pyeloplasty is a safe and effective technique in appropriately selected cases of primary UPJ obstruction in children. PMID- 24761081 TI - Use of rigid tubal ligation scope: Serendipity in laparoscopic common bile duct exploration. AB - AIM: To assess the feasibility, safety of rigid tubal ligation scope in laparoscopic common bile duct (CBD) exploration. MATERIALS AND METHODS: Rigid nephroscope was used for laparoscopic CBD exploration until one day we tried the same with the rigid tubal ligation scope, which was passed easily into CBD both proximally and distally visualising the interior of the duct for presence of stone that were removed using endoscopic retrograde cholangiopancreaticography (ERCP) basket. This serendipity led us to use this scope for numerous patients from then on. A total of 62 patients, including male and female, underwent laparoscopic CBD exploration after choledochotomy with rigid tubal ligation scope between March 2007 and December 2012 followed by cholecystectomy. All the patients had both cholelithiasis and choledocholithiasis with minimum duct diameter of 12 mm. A total of 48 patients were given T-tube through choledochotomy and closed, and the remaining 14 patients had primary closure of choledochotomy. RESULTS: There were no intra-operative complications in any of the patients like CBD injury or portal vein injury. Post-operatively graded clamping of T-tube was done and was removed after 15 days in the patients who were given T-tube. None had retained the stone after T-tube cholangiography, which was done before removing the tube. Mean duration of follow up was 6 months. No patients had any complaints during the follow up. CONCLUSION: Laparoscopic CBD exploration is also feasible with rigid tubal ligation scope. With experienced surgeons, CBD injury is very minimal and stone clearance can be achieved in almost all patients. This rigid tubal ligation scope can be an alternative to other rigid and flexible scopes. PMID- 24761083 TI - Robotic assisted excision of retrovesical angiomyxoma in a male patient. AB - Angiomyxoma is a rare tumour found predominantly in pelvis of young females. Less than 150 cases have been reported, more than 90% in females and only few cases in males. Its surgical excision is a big challenge and usually leads to recurrence due to incomplete excision. We report a case of retrovesical Angiomyxoma in an elderly male. The aim of this report is to highlight the rarity of this disease, especially in males, and robotic assisted excision as an evolving option of treatment. PMID- 24761082 TI - Indian experience of robotics in gynecology. AB - AIMS: To study the role of robotics in various gynaecological cases, benign and malignant. MATERIALS AND METHODS: A total number of 80 cases have been analyzed. Operative time, estimated blood loss, hospital stay, complications, conversion rates have been retrospectively studied in all cases. Nodal yield, vaginal margin and paracervical clearance have been studied in all malignant cases. This investigation was conducted at a single minimal access surgery institute. RESULTS: Of total 80 cases, 29 were benign and 51 were malignant cases. In benign cases, total robotic hysterectomies were 24, 2 cases of tubotuboplasty, 1 case of endometriotic cyst excision, 1 case of metroplasty and 1 case of rectovaginal fistula. In 51 cases, 37 of radical hysterectomy, 9 exenterations and 6 were parametrectomy. In benign cases, mean operative time was 80 min, estimated blood loss was 20 ml, mean hospital stay was for 1 day, no major complications and no conversions. In malignant cases, mean operative time was 122 min, estimated blood loss was 50-100ml, 2 cases of ureteric fistulas and no conversions, nodal yield was 30, vaginal margin was 2.5-3.8 cm and para cervical clearance was 3-3.5 cm. CONCLUSIONS: Ours is the largest series of robotic surgery in gynecological procedures in India. Benign and malignant cases were addressed robotically showing the feasibility. PMID- 24761084 TI - Laparoscopic excision of cyst of canal of Nuck. AB - Hydrocele of the canal of Nuck is a rare condition in females. It results from the failure of obliteration of the distal portion of evaginated parietal peritoneum within the inguinal canal which forms a sac containing fluid. Patients generally present with inguinal swelling. We present a case of left sided cyst of canal of Nuck with left inguinal hernia in a 28-year-old female, which was diagnosed on ultrasonography. Patient underwent laparoscopic excision of cyst of canal of nuck with hernioplasty. Histopathology confirmed the diagnosis. To our knowledge, this is the first reported case of laparoscopic excision of a cyst (encysted hydrocele) of the canal of Nuck. PMID- 24761085 TI - Laparoscopic correction of intestinal malrotation in adult. AB - Intestinal malrotation is rare in adults. Patients may present with acute obstruction or chronic abdominal pain. These symptoms are caused by Ladd's bands and narrow mesentery resulting from incomplete gut rotation. Barium, computed tomography (CT) and magnetic resonance imaging (MRI), angiography and sometimes explorative laparotomy are used for diagnosis. Ladd's procedure is the treatment of choice but data about laparoscopic approach in adult is scarce. We report three cases of laparoscopic correction of adult malrotation presenting with chronic abdominal pain. The diagnosis is made by CT/MRI. Laparoscopic Ladd's procedure (release of bands, broadening of mesentery and appendicectomy) was performed via three ports. Procedure time 25-45 min. All patients were discharged on postoperative day 2. At 6 month follow-up, all are symptom free. Laparoscopic Ladd's procedure is an acceptable alternative to the open technique in treating chronic symptoms of intestinal malrotation in adults. PMID- 24761086 TI - Laparoscopic cholecystectomy in double gallbladder with dual pathology. AB - Double gallbladder is a rare embryological anomaly of clinical significance. Despite availability of modern imaging, only 50% of recently reported cases had preoperative diagnosis, which is desirable in every case to avoid serious operative complications. Double pathology in double gallbladder is extremely rare with only 3 reporting's available till date to the best of author's knowledge. With a preoperative diagnosis of double gallbladder, laparoscopic cholecystectomy can be safely and successfully performed with meticulous dissection, aided by operative cholangiogram. However in all such attempts a lower threshold should be kept for conversion to open surgery. Awareness about this anomaly amongst radiologists and surgeons is of crucial importance. Double gallbladder does not present with any specific symptom, neither it increases disease possibility in either lobe. Prophylactic cholecystectomy has no role in asymptomatic cases diagnosed accidentally. Author reports a case of a symptomatic young male with double gallbladder who presented with short history of dyspepsia, abdominal pain and fever. Definite preoperative diagnosis was reached with ultrasound scan and magnetic resonance cholangio pancreatography and subsequently dealt with laparoscopically. Calculous cholecystitis affected one lobe and acalculous empyema the other. While the 1st lobe drained though a cystic duct into common bile duct (CBD), the 2nd was without any communication with either CBD or its counterpart, thus remained as a blind vesicle. PMID- 24761088 TI - Single incision laparoscopic surgery - trans anal endoscopic microsurgery: A technological innovation. AB - Trans anal endoscopic microsurgery (TEM) first burst upon the scene several decades ago and then underwent a period of immersion. We have herein reported our experience in two cases who underwent TEM using laparoscopic techniques. The advent of single incision laparoscopic surgery (SILS) has made great inroads into various fields of general and gastrointestinal (GI) surgery. We decided to make use of the same technique in TEM for two patients who had large sessile villous adenomas of the rectum. We used this port and fixed it transanally to the edge of the anus. Carbon dioxide used for insufflation in laparoscopic surgery was used through one of the ports, and a telescope was inserted to the larger port. We made sure that the entire polyp was cut out completely until the circular muscle of the internal sphincter was clearly exposed. Next, the cut edges of the rectum were undermined between the mucosa and the circular muscles in order to bring the cut edges closer together. We were able to perform this SILS TEM in two cases. In both the cases, well differentiated villous adenoma (colonoscopically, biopsy proven before surgery) was confirmed after excision. The question has been raised whether TEM is the new laparoscopy for anorectal surgery. Increasingly, several reports are showing promise for treatment for early stage cancers and large rectal adenomas using TEM. Adoption of our technique using the SILS port that has not been previously described in medical literature, seems to be a promising tool for the future. TEM first burst upon the scene several decades ago and then under went a period of immersion. In recent years, with the onset of laparoscopic surgery, the thoughts and the ideas of using a laparoscopic surgical technique have invaded the area of colorectal cancer as well. We have herein reported our experience in two cases who underwent TEM using laparoscopic techniques. PMID- 24761087 TI - Laparoscopic extraction of fractured Kirschner wire from the pelvis. AB - Kirschner wire is a sharp stainless steel guide wire commonly used in fixation of fractured bone segments. There are case reports of migrated K wire from the upper limb into the spine and chest, and from the lower limb in to the abdomen and pelvis. Here, we present a case report of accidental intra-operative fracture of K wire during percutaneous femoral nailing for sub-trochanteric fracture of right femur, which migrated in to the pelvis when the orthopaedician tried to retrieve the broken segment of the K wire. This case highlights the use of laparoscopy as minimally invasive surgical option. PMID- 24761089 TI - SILS TEM: The new armamentarium in transanal endoscopic surgery. PMID- 24761091 TI - Water in flow and monk on move - stay clean. PMID- 24761090 TI - Structured Inequalities: Factors Associated with Spatial Disparities in Maternity Care in India. AB - Research on India documents considerable heterogeneity in health and health care across states. However, while regional differences are well established, factors underlying these differences have received little attention. This paper seeks to explain disparities in delivery care across districts by focusing on three factors: (1) Marriage and kinship patterns; (2) District wealth; (3) Governance and quality of services. Using data from nationally representative India Human Development Survey 2005 (IHDS) it examines the probability that the 11,905 women who had a child between 2000 and 2005 delivered in a hospital or received care from a doctor or a nurse while delivering at home. The results suggest that 47% of the variation in delivery care in India is between districts while 53% is between women within district. Although compositional differences in education and household wealth explain some of the variation between districts, marriage and kinship patterns, district wealth and governance each has a significant impact on shaping between-district variation in maternity care. PMID- 24761092 TI - Surgical scar revision: an overview. AB - Scar formation is an inevitable consequence of wound healing from either a traumatic or a surgical intervention. The aesthetic appearance of a scar is the most important criteria to judge the surgical outcome. An understanding of the anatomy and wound healing along with experience, meticulous planning and technique can reduce complications and improve the surgical outcome. Scar revision does not erase a scar but helps to make it less noticeable and more acceptable. Both surgical and non-surgical techniques, used either alone or in combination can be used for revising a scar. In planning a scar revision surgeon should decide on when to act and the type of technique to use for scar revision to get an aesthetically pleasing outcome. This review article provides overview of methods applied for facial scar revision. This predominantly covers surgical methods. PMID- 24761093 TI - Low-level laser therapy: an experimental design for wound management: a case controlled study in rabbit model. AB - BACKGROUND: There is a wide array of articles in medical literature for and against the laser effect on wound healing but without discrete effect determination or conclusion. This experimental study aims to evaluate the efficacy of low-level laser therapy on wound healing. MATERIALS AND METHODS: Thirty-four rabbits were randomly enrolled in two groups after creating a full thickness of 3 * 3 cm wound. The intervention group received low density laser exposure (4 J/cm(2)) on days 0, 3 and 6 with diode helium-neon low-intensity laser device (wl = 808 nm) and in control group moist wound dressing applied. Finally, wound-healing process was evaluated by both gross and pathological assessment. RESULTS: Fibrin formation was the same in the two groups (P = 0.4) but epithelialisation was much more in laser group (P = 0.02). Wound inflammation of the laser group was smaller than that of the control groups but statistical significance was not shown (P = 0.09). Although more smooth muscle actin was found in the wounds of the laser group but it was not statistically significant (P = 0.3). Wound diameter showed significant decrease in wound area in laser group (P = 0.003). CONCLUSION: According to our study, it seems that low-level laser therapy accelerates wound healing at least in some phases of healing process. So, we can conclude that our study also shows some hopes for low level laser therapy effect on wound healing at least in animal model. PMID- 24761094 TI - Combination therapy in the management of atrophic acne scars. AB - BACKGROUND: Atrophic acne scars are difficult to treat. The demand for less invasive but highly effective treatment for scars is growing. OBJECTIVE: To assess the efficacy of combination therapy using subcision, microneedling and 15% trichloroacetic acid (TCA) peel in the management of atrophic scars. MATERIALS AND METHODS: Fifty patients with atrophic acne scars were graded using Goodman and Baron Qualitative grading. After subcision, dermaroller and 15% TCA peel were performed alternatively at 2-weeks interval for a total of 6 sessions of each. Grading of acne scar photographs was done pretreatment and 1 month after last procedure. Patients own evaluation of improvement was assessed. RESULTS: Out of 16 patients with Grade 4 scars, 10 (62.5%) patients improved to Grade 2 and 6 (37.5%) patients improved to Grade 3 scars. Out of 22 patients with Grade 3 scars, 5 (22.7%) patients were left with no scars, 2 (9.1%) patients improved to Grade 1and 15 (68.2%) patients improved to Grade 2. All 11 (100%) patients with Grade 2 scars were left with no scars. There was high level of patient satisfaction. CONCLUSION: This combination has shown good results in treating not only Grade 2 but also severe Grade 4 and 3 scars. PMID- 24761095 TI - Commentary on: "Combination Therapy in the Management of Atrophic Acne Scars". PMID- 24761096 TI - Utility of gel nails in improving the appearance of cosmetically disfigured nails: experience with 25 cases. AB - BACKGROUND: Gel nails are a commonly used cosmetic procedure, though their use by dermatologists has not been evaluated. These can be used to improve the appearance of cosmetically disfigured nails where other treatment options have failed; the condition is self-limiting or irreversible; or to camouflage the dystrophy until healing. MATERIALS AND METHODS: A prospective, uncontrolled, open label study on 25 participants presenting with cosmetically disfigured nails was undertaken. Mycologically negative, consenting patients with various nail plate surface abnormalities like trachyonychia (n =8); superficial pitting (n =6); onychorrhexis (n =4); superficial pitting with onychoschizia (n =3); Beau's lines (n =3) and pterygium (n =1) were included. The patients received gel nail application using Ranara gel nail kit((r)). Extra care was taken to avoid any damage to cuticle. Standard pre- and post-treatment photographs were taken to assess improvement. Patient satisfaction score (1-10); Global assessment score of improvement (no improvement to excellent improvement) and any side effects reported were recorded. RESULTS: The average age of treated patients was 30.44+/ 11.39 years (range 18-60 years). A total of 69 nails were treated (average of 2.76 per patient). Post-procedure, the average patient satisfaction score was 9.08 +/- 0.86 (range 7-10). The Global assessment showed excellent improvement (40% cases); good improvement (56% cases) and mild improvement in the single case of pterygium treated. CONCLUSIONS: The use of Gel nails in patients with cosmetically disfiguring nail plate surface abnormalities (like trachyonychia, onychoschizia, pitting, etc.) was found to produce good to excellent improvement in most of the cases. The patient satisfaction with the procedure was rated as high. This, coupled with absence of side effects, make gel nails a valuable tool in improving cosmesis and satisfaction among patients presenting with nail plate surface abnormalities. Further studies with larger number of patients are required to assess the impact these prostheses can have. PMID- 24761097 TI - Treatment of port-wine stains with flash lamp pumped pulsed dye laser on Indian skin: a six year study. AB - CONTEXT: Port-wine stain (PWS) is one of the commonly encountered congenital cutaneous vascular lesions, with an equal sex distribution. Pulsed dye lasers (PDL) have revolutionized the treatment of both congential and acquired cutaneous vascular lesions. The pulsed dye lasers owing to its superior efficacy and safety profile have become the gold standard for the management of port-wine stains. AIMS: To evaluate the efficacy and side effects of pulsed dye laser for the management of Port-wine stain on Indian skin. MATERIALS AND METHODS: Seventy five patients of Fitzpatrick skin types IV&V with PWS underwent multiple treatments with PDL (V beam-Candela) over a period of six years at monthly intervals. Laser parameters were wavelength 595nm, spot sizes 7-10mm, fluence 6-12 j/cm2, pulse duration 0.45-10ms, along with cryogen cooling. Serial photographs were taken before and after every session. Clinical improvement scores of comparable photographs using a quartile grading (o=<20%, 1=21-40%, 2=41-60%, 3=61-80%, 4=>80%) were judged independently by two dermatologists after the series of treatment. Minimum number of treatments was 6 and maximum 17. They were followed up at six monthly intervals to observe re darkening of PWS. RESULTS: No patient showed total clearance.Grade3 improvement was observed in 70 % of children and 50% of adults after 8-10 sessions. Children showed better and faster response than adults. Thirty percent of patients developed post inflammatory hyper pigmentation which resolved over a period of six to eight weeks. Two patients had superficial scarring due to stacking of pulses. None of the patients showed re darkening of PWS till now. CONCLUSION: Pulsed dye laser is an effective and safe treatment for port-wine stain in Indian skin. PMID- 24761100 TI - "Something better than nothing" using the house hold electric chimney in the procedure room as an attempt to reduce the smell and biohazard. PMID- 24761098 TI - Propranolol for infantile haemangiomas: experience from a tertiary center. AB - AIM: Infantile haemangiomas are the most common tumor of infancy. We report the use of propranolol for treatment of problematic and complicated haemangiomas. PATIENTS AND METHODS: Propranolol was given to 52 children with mean age of 18.2 months at onset of treatment. After clinical and electrocardiographic evaluations, propranolol was administered with a starting dose of 2 mg/kg per day, given in 3 divided doses. Monthly follow up was done, response to oral propranolol therapy and any complications of therapy were recorded. Response to propranolol was classified as Complete Response, Excellent Response, Partial Response and Non Responder. RESULTS: Total 49 patients showed significant improvement after propranolol therapy out of which 4 patients were complete responder, 30 patients (56.7%) were excellent responders; 15 patients (28.8%) were partial responders. 3 patients (5.7%) had growth of haemangiomas despite propranolol therapy and were classified as non-responder. Side effect like hypotension, rashes, gastroesophageal reflux was reported by 3 patients. In our study mean duration of treatment was 6.5 months. At the end of treatment propranolol was stopped by with gradual tapering of dose over a period of 2 weeks. CONCLUSION: Propranolol administered orally at 2 mg/kg per day has rapid effective therapeutic effect in treatment of ulcerated haemangiomas and it appears to be a valuable and effective treatment option for infantile haemangiomas beyond the proliferative phase, and esthetically disfiguring haemangiomas. PMID- 24761099 TI - Autologous mini punch grafting: an experience of using motorized power punch in 10 patients. AB - BACKGROUND: Autologous mini punch grafting (MPG) is a safe, effective and easy technique that can be performed on any site with minimal side effects and good cosmetic results. Large areas of stable generalised vitiligo require more grafts and are time consuming. Hence multiple sessions of surgery need to be scheduled. We share our experience of using motorised power punches to increase the speed of surgery in large areas of stable vitiligo in 10 patients. MATERIALS AND METHODS: Ten patients in the age group of 12-55 years were treated with miniature punch grafting using power punches in single session on various sites. The power punches of 1-1.5 mm diameter were used to score donor and recipient sites, either of same or less than 0.2-0.3 mm size punches. The harvested grafts from donor site were then secured in the recipient beds and dressed. RESULTS: The average number of grafts harvested per session was 125-185, the duration of surgery ranged from 45 to 90 minutes. Perigraft pigment spread was seen at 3 weeks. Complete repigmentation was observed in 3-4 months in eight patients. Cobble stoning was observed in one patient, and all donor sites healed well with superficial scarring. CONCLUSION: We conclude that autologous MPG with motorised power punches for stable vitiligo, especially on large areas including difficult sites can be performed with ease in comparatively lesser time in a single session, greatly benefiting the patients. PMID- 24761101 TI - Commentary on: The Electric Household Chimney: A Cost Effective Alternative for Smoke Evacuator in the Operating Room. PMID- 24761102 TI - The management of helical rim keloids with excision, split thickness skin graft and intralesional triamcinolone acetonide. AB - Keloids of the helical rim are disfiguring. A cosmetically acceptable reconstruction is difficult especially in moderate to large sized lesions because the helical rim is a 3-dimensional structure with curved and thin cartilage. We report our experience in the management of moderate (4-10 cm) and large (>10 cm) helical rim keloids in five patients. Six helical rim keloids were reconstructed. There were four moderate (4-10 cm) and two large (>10 cm) helical rim keloids. Four were on the right helix and two on the left helix. One patient had bilateral helical rim keloids. The follow-up period ranged from 6 months to 4 years. No secondary surgical revision was required to improve the contour of the reconstructed helical rim. The aesthetic results were satisfactory in all the patients. PMID- 24761103 TI - Bindi tattoo on forehead: success with modified R-20 technique using low fluence q-switched nd yag laser: a case report. AB - Bindi tattoo on the forehead, is one of the cultural practice in Indian women from rural areas. Many patients are not pleased with the appearance of their tattoo and thus seek removal. The development of quality-switched lasers has revolutionized the removal of unwanted tattoos. However, despite multiple treatment sessions, the efficacy is often found to be limited. We herein report a case of green-blue bindi tattoo which failed to clear after 8 sessions of Q switched Nd YAG laser. The tattoo significantly cleared with R-20 method using low fluence Q-switched Nd YAG Laser. R-20 technique seems to be an effective method of tattoo removal and might be a boon for patients who are reluctant to pursue laser treatment because of fear of expenditure, side effects and uncertainty of result. We report efficacy of R-20 technique for a bindi tattoo on forehead. PMID- 24761104 TI - Novel Method of Treatment of Post-Q-Switched Nd-YAG Laser Depigmentation with Trichloroacetic Acid: A Report of Two Cases. PMID- 24761105 TI - Lasers are not Effective for Melasma in Darkly Pigmented Skin. PMID- 24761106 TI - Scalp roller therapy in resistant alopecia areata. PMID- 24761107 TI - Alopecia areata-successful outcome with microneedling and triamcinolone acetonide. PMID- 24761108 TI - Superficial large Basal cell carcinoma over face, reconstructed by v-y plasty. PMID- 24761109 TI - Baker's Dozen on the Scalp: An Interesting Case of Multiple Trichilemmal Cyst. PMID- 24761110 TI - A comment on A Study of Donor Area in Follicular Unit Hair Transplantation. PMID- 24761111 TI - Practice pearl: using 'Namazi Solution' for decreasing the formation of bruises in liposuction. PMID- 24761113 TI - Evaluation of antiepileptic activity of chloroform extract of Acalypha fruticosa in mice. AB - AIM: The aim of the present study is to evaluate the antiepileptic activity of chloroform extract of aerial parts of Acalypha fruticosa in mice. MATERIALS AND METHODS: The antiepileptic activity of chloroform extract of A. fruticosa at the doses of 30, 100 and 300 mg/kg, p.o. was evaluated by maximum electroshock (MES), pentylenetetrazole (PTZ) and isoniazid (INH)-induced convulsions in mice. Statistical analysis was carried out by one-way analysis of variance followed by Dunnett's test. RESULTS: In MES method, the chloroform extract significantly protected the mice from convulsions induced by electroshock method in a dose dependent manner and exhibited more activity at the dose of 300 mg/kg when compared with diazepam treated animals. In PTZ method, the extract inhibited convulsions in mice potent than phenobarbitone sodium. In INH method, it delayed the latency of convulsions in mice in a dose-dependent manner but failed to protect the mice against mortality. CONCLUSION: The chloroform extract exhibited significant and dose-dependent antiepileptic activity, which may be due to the presence of antioxidant principles like flavanoids. PMID- 24761112 TI - Anticarcinogenic effect of saffron (Crocus sativus L.) and its ingredients. AB - Conventional and newly emerging treatment procedures such as chemotherapy, catalytic therapy, photodynamic therapy and radiotherapy have not succeeded in reversing the outcome of cancer diseases to any drastic extent, which has led researchers to investigate alternative treatment options. The extensive repertoire of traditional medicinal knowledge systems from various parts of the world are being re-investigated for their healing properties Crocus sativus L., commonly known as saffron, is the raw material for one of the most expensive spice in the world, and it has been used in folk medicine for centuries. Chemical analysis has shown the presence of more than 150 components in saffron stigmas. The more powerful components of saffron are crocin, crocetin and safranal. Studies in animal models and with cultured human malignant cell lines have demonstrated antitumor and cancer preventive activities of saffron and its main ingredients, possible mechanisms for these activities are discussed. More direct evidence of anticancer effectiveness of saffron as chemo-preventive agent may come from trials that use actual reduction of cancer incidence as the primary endpoint. This review discusses recent literature data and our results on the cancer chemopreventive activities of saffron and its main ingredients. PMID- 24761114 TI - The effect of 30% ethanolic extract of Indian propolis on replica of human dentin compared against commercially available desensitizing agent: A methodological SEM study in vitro. AB - OBJECTIVE: This study evaluated the ability of 30% ethanolic extract of Indian propolis on dentinal tubule occlusion comparatively against CPP-ACP containing desensitizing agent GC tooth mousse. METHODOLOGY: The specimens were prepared from 30 freshly extracted sound human third molars stored in 10% formalin (pH 7.0) at a room temperature. From each specimen, a sectioned sample (5 mm length * 5 mm width * 3.5 mm depth) was obtained including the cervical area. Samples were smoothened and wet-polished with 1000- and 1200-grit aluminum oxide abrasive paper and diamond pastes, in order to stimulate the clinical aspect of hypersensitive dentin cervical surfaces. All the specimens were randomly assigned to three groups (n = 10), according to dentin surface treatments. Negative control: Untreated specimens (n = 4) and pretreated with 6% citric acid (n = 6); Test Group: 30% ethanolic extract of Indian propolis (n = 10); Positive Group: GC Tooth Mousse (n =10). All the specimens were prepared for SEM analysis. RESULTS: GC tooth mousse promoted tubule occlusion by crystal-like deposits in the lumen of the tubules. While propolis created a thin, smooth layer over dentin surface. CONCLUSION: According to the SEM analysis, both desensitizing agent were able to occlude the dentinal tubules. PMID- 24761115 TI - Aphrodisiac activity of polyherbal formulation in experimental models on male rats. AB - OBJECTIVE: To investigate the aphrodisiac potential of polyherbal formulations prepared from different parts of Tribulus terrestris, Curculigo orchioides, Allium tuberosum, Cucurbita pepo, Elephant creeper, Mucuna pruriens, and Terminalia catappa in Albino rats in specified ratio as suspension. MATERIALS AND METHODS: The different concentrations of prepared polyherbal formulations i.e. 150, 300, and 600 mg/kg and sildenafil citrate as standard (5 mg/kg) and vehicle (control) were administered orally to rats (n = 6 animals per group) for 3 weeks. Mating behavior parameters in male rats was monitored in first week and third week week of treatment pairing with receptive females. After termination of drug treatment, the mating performance, hormonal analysis, sperm count, and testes body weight ratio were also evaluated. RESULTS: The polyherbal formulation showed a significant increase in mating behavior as well as mating performance, serum hormonal levels, sperm count, and testes-body weight ratio with dose-dependent relationship as compared to vehicle control. But the dose of 600 mg/kg of polyherbal formulation assumes closer resemblance of above parameters with the standard used. CONCLUSION: The results of the study strongly suggest that the polyherbal formulations have a good aphrodisiac activity on rats in the above experimental models, which may be an alternative weapon for various sexual dysfunctions in future. PMID- 24761116 TI - Inhibitory effects by ayurvedic plants on prostate enlargement induced in rats. AB - BACKGROUND: Ayurveda recommends several plants and plant preparation for conditions of urogenital disorders as per its principles. OBJECTIVES: Ayurvedic plants Tamala (Cinnamomum tamala); Daruhalad (Berberis aristata); Ativish (Aconitum heterophyllum) were studied for mechanisms of prostatic hyperplasia induced in rats. MATERIALS AND METHODS: Prostatic enlargement was induced in castrated rats by testosterone injection s.c. for 21 days and simultaneously plants were dosed orally daily. On day 22 rats were sacrificed and prostate was removed; weight and volume of prostate was measured; histopathology performed. Inflammation was induced by injecting carrageenan in rat hind paw and inhibition was studied by measuring rat paw oedema at different time points. RESULTS: Tamala showed significant effect where it reduced prostatic enlargement and improved hyperplastic changes, while Daruhalad and Ativisha did not show any significant effect. All of them showed mild to moderate anti-inflammatory activity. CONCLUSION: Study concludes that Tamala may benefit in prostate disorder by virtue of inhibition of androgen mechanisms in prostate and modulating inflammatory mediators in prostate. Daruhalad and Ativisha did not show any effect in this model of prostate enlargement while the anti-inflammatory effect may propose one of the useful properties when included in various formulations. PMID- 24761117 TI - Effect on eNOS/NO Pathway in MIRI rats with preconditioning of GFPC from Dang Gui Si Ni decoction. AB - OBJECTIVE: In order to discover whether the eNOS/NO (endothelial nitric oxide synthase/nitric oxide) pathway is involved in the protective mechanisms of ischemic myocardium of DGSND (Dang Gui Si Ni Decoction) in MIRI (myocardial ischemia-reperfusion injury) SD rats. MATERIALS AND METHODS: We made I/R (ischemia-reperfusion) model by ligating the left anterior-descending branch of the coronary artery (LAD) for 30 min and releasing the ligature for 120 min. eNOS (nitric oxide synthase) mRNA (message ribonucleic acid) and iNOS (inducible nitric oxide synthase) mRNA were measured by the methods of real-time RT-PCR (Real time Polychainase Chain Reaction), peNOS (phosphorylated eNOS) and iNOS protein were measured by the means of western blot. RESULTS: In PPC group, real time RT-PCR and western-blot analysis showed that eNOS mRNA and peNOS protein increased markedly (P < 0.05); iNOS mRNA and protein decreased significantly (P < 0.05). CONCLUSION: These results indicate that ischemic preconditioning (IPC) of GFPC from DGSND plays a protective role in I/R heart through regulating the eNOS/NO signal pathway, which could increase the eNOS gene expression and decrease the expression of iNOS mRNA. PMID- 24761118 TI - Presence of monoterpene synthase in four Labiatae species and Solid-Phase Microextraction- Gas chromatography-Mass Spectroscopy analysis of their aroma profiles. AB - BACKGROUND: The family Lamiaceae (Labiatae) has included some medicinal plants. some monoterpene synthases, including linalool and limonene synthases, have been cloned and functionally characterized from several plants of Labiatae family. MATERIALS AND METHODS: In this study, presence of linalool and limonene synthases, in four species of Labiatae family including Nepeta cataria, Lavandula angustifolia, Hyssopus officinalis and Salvia sclarea has been determined by molecular biological techniques together with the Head space SPME - GC-MS analysis of the aroma profile of these species. RESULTS: Indicated that none of the plant species produced distinguishable bands with primer pairs related to d limonene synthase. Distinguishable bands around 1800 bp in cDNA samples of L. angustifolia, H. officinalis and S. sclarea were observed regarding to the presence of linalool synthase. Head space SPME-GC-MS analysis of the aroma profiles of the above-mentioned plants showed that linalool (31.0%), linalyl acetate (18.2%), were found as the major compounds of L. angustifolia, while geraniol (5.5%), nerol (34.0%) and alpha- citral (52.0%) were identified as the main compounds of the N. cataria. The major components of H. officinalis and S. sclarea oils were determined as cis-pinocamphone (57.3%), and linalool (19.0%), linalyl acetate (51.5%), respectively. CONCLUSION: H. officinalis was rich of cyclic monoterpenes, L. angustifolia, N. cataria and S. sclarea showed considerable amount of linear monoterpenes. The aroma profile of the above mentioned plants contained low concentration of sesquiterpenes except N. cataria, which indicated no sesquiterpene. The profiles of the main components of these plants are in agreement with molecular assays. PMID- 24761119 TI - Development and validation of a high performance thin layer chromatographic method for determination of 1, 8-Cineole in Callistemon Citrinus. AB - A new, simple, precise, rapid, and selective high performance thin layer chromatographic (HPTLC) method has been developed and validated for the estimation of 1, 8-cineole in volatile oil of leaves of Callistemon Citrinus obtained by hydro distillation. The method was validated as per ICH guidelines and can be utilized for routine analysis. The retention factor for 1, 8-cineole was found to be 0.52. The linearity was found to be in the range of 3 MUg-12 MUg. The recovery obtained for 1, 8-cineole was 98%, which is satisfactory. The result obtained in validation indicate the accuracy, reproducibility, and reliability of the developed HPTLC method for determination of 1, 8-cineole. PMID- 24761120 TI - Biphasic effect of Solanum nigrum fruit aqueous extract on vascular mesenteric beds in non-diabetic and streptozotocin-induced diabetic rats. AB - BACKGROUND: In Asia, Solanum nigrum fruit is traditionally used to manage, control, and treat diabetes. OBJECTIVE: This study was carried out to investigate the endothelium and nitric oxide roles in Solanum nigrum-induced vasorelaxation in non-diabetic and diabetic rat vessels. MATERIALS AND METHODS: Diabetes was induced by a single i.p. injection of streptozotocin. Eight weeks later, superior mesenteric arteries of non-diabetic and diabetic groups were isolated and perfused according to the McGregor method. Solanum nigrum fruit extract (SNE) at concentrations of 0.00001 to 0.6 mg/ml was added to the medium and perfusion pressure was recorded. RESULTS: Baseline perfusion pressure of diabetic group was significantly higher than non-diabetic rats in both intact and denuded endothelium. The low concentrations of SNE have vasodilatory effect in the diabetic and non-diabetic, but high concentrations of SNE produce initial significant contractions, followed by secondary relaxations in normal and diabetic rats. We observed vasorelaxation at low and high concentrations of SNE in both diabetic and non-diabetic groups after endothelium denudation. SNE induced vasorelaxation in diabetic group is mediated by both endothelium and smooth muscle, but the relaxatory effect of SNE in non-diabetic group is not mediated by endothelium, and SNE has direct action on the smooth muscle. CONCLUSION: Although the part of SNE-induced relaxation in diabetic vessel was mediated by endothelium, nitric oxide didn't play any role in this action, and maybe we can use SNE in the management of diabetes vessel complications in future. PMID- 24761121 TI - Pioglitazone, quercetin and hydroxy citric acid effect on hepatic biomarkers in Non Alcoholic Steatohepatitis. AB - BACKGROUND: Non alcoholic steatohepatitis (NASH), severe form of diseases belonging to the spectrum of the Non alcoholic fatty liver disease (NAFLD). It is an asymptomatic disease which leads to fibrosis and finally to cirrhosis, an end stage liver disease. OBJECTIVE: To study the effect of pioglitazone, quercetin and hydroxy citric acid on hepatic biomarkers and various biochemical parameters in experimentally induced non alcoholic steatohepatitis (NASH). MATERIALS AND METHODS: Male Wister rats were divided into 8 groups. The activities of alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) and gamma-Glutamyl Transferase (GGT) were assayed in serum. The levels of various other biochemical parameters such as serum albumin, total bilirubin, creatinine, urea, uric acid and glucose were also estimated in experimental NASH. RESULTS: The NASH group produced severe liver injury by significantly increasing the serum levels of ALT, AST, GGT and LDH compared with that of the control. However, the experimental NASH rats treated with pioglitazone, with quercetin and with hydroxy citric acid showed an obvious decrease in ALT, AST, GGT and LDH levels when compared with that of NASH induced group. A significant increase in the levels of albumin, creatinine, urea, uric acid, glucose and total bilirubin was noticed in experimentally induced NASH group (group 2) when compared to rats in control group (group 1). CONCLUSION: It could be inferred from this study that, pioglitazone, quercetin and hydroxy citric acid may afford protection to the liver against NASH, as evidenced by the results of this study on the levels of various biochemical parameters such as glucose, urea, uric acid, creatinine and bilirubin. Whereas from the results of hepatic marker enzymes, it is evident that optimal protection was observed after quercetin treatment against experimental NASH whereas pioglitazone and hydroxy citric acid also confers protection to some extent against NASH. PMID- 24761122 TI - Margaritaria discoidea (Euphorbiaceae) stem bark extract attenuates allergy and Freund's adjuvant-induced arthritis in rodents. AB - BACKGROUND: Various parts of Margaritaria discoidea find use in traditional medicine in the treatment of pain and oedema. This study evaluated the anti allergic, anti-inflammatory and anti-arthritic effects of a 70% (v/v) aqueous ethanol extract of the stem bark of Margaritaria discoidea, MDE in rodents. MATERIALS AND METHODS: Systemic anaphylaxis was induced by the injection of compound 48/80 into mice and their survival rate was monitored to evaluate the anti-allergic action of the extract. The effect of MDE assessed on the maximal and total oedema responses in the mouse carrageenan-induced paw oedema was used to evaluate the anti-inflammatory action of the extract while the Freund's adjuvant-induced arthritis model was employed to study the anti-arthritic effects of MDE. RESULTS: MDE dose-dependently increased the time for compound 48/80 induced mortality in mice. MDE suppressed the mean maximal swelling and the total paw swellings induced over 6 h in the carrageenan-induced paw oedema when administered either prophylactically or therapeutically. MDE caused a reduction in serum levels of TNFalpha and IL-6 and significantly suppressed Freund's adjuvant-induced arthritis. CONCLUSION: Margaritaria discoidea suppresses allergy and exhibits anti-inflammatory activity in mice. In addition it attenuates Freund's adjuvant-induced arthritis through a reduction in serum levels of TNFalpha and IL-6 in rats. PMID- 24761123 TI - Anti-allodynic and Anti-hyperalgesic effects of an ethanolic extract and xylopic acid from the fruits of Xylopia aethiopica in murine models of neuropathic pain. AB - BACKGROUND: Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders including headache and neuralgia. An animal model of vincristine-induced sensory neuropathy was developed after repeated intraperitoneal injection in rats and used in the present work to study the effects of the ethanolic extract of X. aethiopica (XAE) and its diterpene xylopic acid (XA) in vincristine-induced neuropathic pain. MATERIALS AND METHODS: Vincristine (0.1 mg kg(-1) day(-1)) was administered during two cycles of five consecutive days to induce chemotherapy-induced neuropathic pain. Static tactile anti-allodynic, anti-hyperalgesic, and cold anti-allodynic effects of XAE (30-300 mg kg(-1)) and XA (10-100 mg kg(-1)) were assessed using Von Frey filaments of bending forces of 4, 8, and 15 g, the Randall-Selitto paw pressure test, and cold water (4.5 degrees C), respectively. RESULTS: Administration of vincristine caused the development of allodynia and hyperalgesia with no significant motor deficit, spontaneous pain, and foot deformity. XAE (30-300 mg kg(-1)) and XA (10 100 mg kg(-1)) exhibited anti-hyperalgesic, tactile, and cold anti-allodynic properties with XA exhibiting greater potency than XAE. Pregabalin (10-100 mg kg( 1)) used as control produced similar effect. CONCLUSION: These findings establish the anti-allodynic and anti-hyperalgesic effects of the ethanolic fruit XAE and its major diterpene XA in vincristine-induced neuropathtic pain. PMID- 24761124 TI - Comparative study of antidiabetic activity of Cajanus cajan and Tamarindus indica in alloxan-induced diabetic mice with a reference to in vitro antioxidant activity. AB - BACKGROUND: Oxidative stress not only develops complications in diabetic (type 1 and type 2) but also contributes to beta cell destruction in type 2 diabetes in insulin resistance hyperglycemia. Glucose control plays an important role in the pro-oxidant/antioxidant balance. Some antidiabetic agents may by themselves have antioxidant properties independently of their role on glucose control. OBJECTIVE: The present investigation draws a comparison of the protective antioxidant activity, total phenol content and the antihyperglycemic activity of the methanolic extract of Cajanus cajan root (MCC) and Tamarindus indica seeds (MTI). MATERIALS AND METHODS: Antidiabetic potentials of the plant extracts were evaluated in alloxan-induced diabetic Swiss albino mice. The plant extracts at the doses of 200 and 400 mg/kg body weight was orally administered for glucose tolerance test during 1-hour study and hypoglycemic effect during 5-day study period in comparison with reference drug Metformin HCl (50 mg/kg). In vitro antioxidant potential of MCC and MTI was investigated by using 1, 1- diphenyl-2 picrylhydrazyl (DPPH) free radical scavenging activity at 517 nm. Total phenolic content, total antioxidant capacity and reducing power activity was also assayed. RESULTS: There was a significant decrease in fasting serum glucose level (P < 0.001), reduction in blood glucose level (P < 0.001) in 5-days study, observed in the alloxan-induced diabetic mice. The reduction efficacy of blood glucose level of both the extracts is proportional to their dose but MCC is more potent than MTI. Antioxidant study and quantification of phenolic compound of both the extracts revealed that they have high antioxidant capacity. CONCLUSION: These studies showed that MCC and MTI have both hypoglycemic and antioxidant potential but MCC is more potent than MTI. The present study suggests that both MCC and MTI could be used in managing oxidative stress. PMID- 24761125 TI - Anticonvulsant activity of Morus alba and its effect on brain gamma-aminobutyric acid level in rats. PMID- 24761126 TI - BAYESIAN WAVELET-BASED CURVE CLASSIFICATION VIA DISCRIMINANT ANALYSIS WITH MARKOV RANDOM TREE PRIORS. AB - Discriminant analysis is an effective tool for the classification of experimental units into groups. When the number of variables is much larger than the number of observations it is necessary to include a dimension reduction procedure into the inferential process. Here we present a typical example from chemometrics that deals with the classification of different types of food into species via near infrared spectroscopy. We take a nonparametric approach by modeling the functional predictors via wavelet transforms and then apply discriminant analysis in the wavelet domain. We consider a Bayesian conjugate normal discriminant model, either linear or quadratic, that avoids independence assumptions among the wavelet coefficients. We introduce latent binary indicators for the selection of the discriminatory wavelet coefficients and propose prior formulations that use Markov random tree (MRT) priors to map scale-location connections among wavelets coefficients. We conduct posterior inference via MCMC methods, we show performances on our case study on food authenticity and compare results to several other procedures.. PMID- 24761127 TI - Acute Effects of Competitive Exercise on Risk-Taking in a Sample of Adolescent Male Athletes. AB - Exercise acutely reduces cravings for tobacco and alcohol, but the mechanism accounting for this relationship is not fully understood. To explore exercise's effects on general risk-taking, we compared the performances of 20 adolescent male athletes on the balloon analog risk task (BART) immediately after periods of exercise (playing tennis) and rest. Statistically significant risk-taking effects were observed post-exercise. The established attenuating effect of exercise on desire for substance use did not extend to impulses for other risk behaviors in this study. In future studies, the moderating effects of participant characteristics and type of risk behavior should be considered. PMID- 24761128 TI - Safety and Effectiveness of NovaSure(r) Endometrial Ablation After Placement of Essure(r) Micro-Inserts. AB - Objective: In-office NovaSure(r) after Essure(r) is a clinical paradigm for which physicians are seeking information. A PubMed search (July 2011) revealed no peer reviewed articles describing this treatment sequence. To address the paucity of data on this topic, patients who had undergone Essure followed by NovaSure in a private practice office between July 1, 2008 and December 31, 2009 were evaluated. The objective was to evaluate safety and feasibility of in-office NovaSure after Essure, and to determine if the effectiveness of either procedure was altered by this treatment sequence. Design: This was a retrospective cohort study of 117 women (ages 24-52). Methods: Patients underwent Essure followed by NovaSure in two in-office sessions, separated by a median of 14 days. All patients had menorrhagia and desired permanent sterilization. A postprocedure patient questionnaire was administered to assess satisfaction and perceived effectiveness. Results: Among patients who underwent Essure followed by NovaSure, 83/117 (71%) returned for a 3-month hysterosalpingogram (HSG). Satisfactory placement and tubal occlusion were noted in 79/83 (95%) of these patients. Amenorrhea or spotting was observed in 72/97 (74%) of patients, 22/97 (23%) reported a satisfactory decrease in menstrual flow, and 3/97 (3%) reported ablation failure. Essure followed by NovaSure did not decrease the effectiveness of either procedure, and no adverse events were attributed to the combination of the two procedures. Patients reported high levels of satisfaction with both procedures. Conclusions: In women seeking permanent birth control and menorrhagia reduction, in-office Essure followed by NovaSure appeared to be safe, effective, and associated with high patient satisfaction. (J GYNECOL SURG 28:1). PMID- 24761129 TI - Hysteroscopic Removal of Cervical Ectopic Pregnancy Following Failed Intramuscular/Intra-Sac Methotrexate: A Case Report. AB - Background: Cervical pregnancy is a diagnosis associated with significant morbidity, specifically life-threatening hemorrhage that potentially requires hysterectomy to prevent maternal death. Conservative and fertility-sparing management strategies are poorly described in the literature, and there is no clear standard of care. Case: The patient was a 34-year-old gravida 1, para 0 who had conceived spontaneously after laparoscopic treatment of endometriosis, and was found to have cervical pregnancy. She received both intramuscular and intra sac methotrexate, with no resolution of the ectopic pregnancy. The pregnancy was removed hysteroscopically. Results: Subsequently, the patient was able to achieve a normal clinical pregnancy with ovulation induction/intrauterine insemination. This pregnancy was carried to term. Conclusions: Although cervical pregnancy is particularly hazardous and potentially fatal, conservative/fertility-sparing management of these pregnancies can be successful. (J GYNECOL SURG 28:369). PMID- 24761130 TI - Vaginal Hysterectomy by Electrosurgery for Benign Indications Associated with Previous Cesarean Section. AB - Background: Vaginal hysterectomies have been associated with difficulties in patients who have had cesarean sections prior to such hysterectomies. However, the Purohit technique may obviate the problems and make it easier to perform these operations. Objectives: This research tested an approach designed to facilitate vaginal hysterectomy in patients with previous cesarean sections in the absence of fixed adhesions of uterine corpi to previous anterior abdominal scarring. Design/Method: An observational study was conducted in a private general hospital between February 2010 and June 2012. All candidates for hysterectomy for benign indications who had had previous cesarean sections were examined for the presence of clinical and sonographic signs of fixed adhesions of uterine corpi to anterior abdominal-wall incisions caused by prior cesarean sections. Candidates who had such adhesions were not given vaginal hysterectomies. Results: Sixty-four (64) consecutive candidates were selected for vaginal hysterectomies. Of these patients, 26 (40.62%) had 1 cesarean section, 33 (51.56 %) had 2 cesarean sections, and 5 (7.81%) had 3 cesarean sections. Four (4) patients had had prior pelvic operations. The uteri were smaller than 12 weeks' gestation-size in 62 (96.87%) cases. In 26 (40.62 %) cases, there were no obstruction to accessing the anterior cul-de-sacs and vaginal hysterectomies were performed using the Purohit technique. In 38 (59.37 %) cases, dense uterovesical adhesions obstructed access to the anterior cul-de-sacs and a posterioanterior approach was used to perform vaginal hysterectomy in these patients. Vaginal hysterectomy was completed in all 64 cases. Vaginal salpingo-oophorectomy was performed in 3 (4.68%) cases. The mean operative time was 78.59+/-33.15 (35-190) minutes. The mean weight of specimen uteri was 161.01+/-108.87 (50-550) g. No patients needed conversions or blood transfusions. No patients had bladder, ureteric, or thermal injuries. Finally, there were no other major postoperative complications. Conclusions: In the absence of fixed adhesions of the uterine corpus to previous anterior abdominal scarring, vaginal hysterectomy for benign indications associated with previous cesarean section may be accomplished safely. The posterioanterior approach during vaginal hysterectomy may avoid unintended bladder injury in the presence of dense uterovesical adhesions caused by previous cesarean sections. (J GYNECOL SURG 29:7). PMID- 24761131 TI - Current Role of Robotic Hysterectomy. AB - Background: While robotic surgery for gynecologic indications received U.S. government approval in 2005, and has been rapidly and widely adopted, it is currently unclear how often this approach to hysterectomy is utilized. Objective: The aim of this research was to assess length of stay (LOS), mortality, indications, and current use of robotic hysterectomy, compared to other types of hysterectomy. Methods: A retrospective study of hysterectomies performed in New York State (NYS) in 2011 was performed. Data, including indication for surgery, age, procedure, LOS, and discharge status were obtained from the NYS Department of Health Statewide Planning and Research Cooperative System (SPARCS). Outcome Measures: LOS and mortality rate, were calculated according to institution, procedure, and indication for surgery. Results: For 22073 hysterectomies performed in NYS, the mean LOS was 2.9 days, and there were 29 (0.13%) deaths. The mean LOS for abdominal (12774 cases, 3.9 days) hysterectomies was longer than for laparoscopic (3927 cases, 1.6 days), robotic (2814 cases, 1.6 days), or vaginal (2558 cases, 1.7 days) hysterectomies (p<0.05). The adjusted mortality rates for abdominal (0.20%), laparoscopic (0.03%), robotic (0.07%), and vaginal (0.04%) hysterectomies were not significantly different. Overall, robotic surgery was performed in 29% of hospitals, by 11% of physicians and in 13% of cases. A robotic approach was utilized in 35% of patients with uterine cancer, 13% with endometriosis, 11% with excessive bleeding, 8% with leiomyomata, and 8% with pelvic relaxation. Conclusions: Despite the advantages in reduced LOS for robotic and other minimally invasive types of hysterectomies, the abdominal route is still predominant in most institutions. (J GYNECOL SURG XX:1). PMID- 24761132 TI - Ensemble Clustering using Semidefinite Programming. AB - We consider the ensemble clustering problem where the task is to 'aggregate' multiple clustering solutions into a single consolidated clustering that maximizes the shared information among given clustering solutions. We obtain several new results for this problem. First, we note that the notion of agreement under such circumstances can be better captured using an agreement measure based on a 2D string encoding rather than voting strategy based methods proposed in literature. Using this generalization, we first derive a nonlinear optimization model to maximize the new agreement measure. We then show that our optimization problem can be transformed into a strict 0-1 Semidefinite Program (SDP) via novel convexification techniques which can subsequently be relaxed to a polynomial time solvable SDP. Our experiments indicate improvements not only in terms of the proposed agreement measure but also the existing agreement measures based on voting strategies. We discuss evaluations on clustering and image segmentation databases. PMID- 24761133 TI - Changes in Attitudes, Intentions, and Behaviors toward Tobacco and Marijuana during U.S. Students' First Year of College. AB - Tobacco and marijuana are commonly used by college students and have negative health effects. The purpose of the study was to understand how students' attitudes, intentions, and behaviors toward tobacco and marijuana change during freshman year and to examine how attitude and intention predict use of these substances. College students completed phone interviews before and after freshman year. The identical interviews assessed students' attitudes, intentions, and behaviors toward both substances. Attitude was measured on a 0-6 scale (6 = most positive), intention on a 0-5 scale (5 = very likely to use), and behavior by lifetime use (yes or no) and current use (past-28-days). Overall, 275 participants completed both interviews. Attitudes increased (tobacco 0.9 to 1.2, p < 0.01; marijuana 1.9 to 2.3, p < 0.01). Intentions increased (tobacco 0.4 to 0.8, p = 0.03; marijuana 0.7 to 1.1, p < 0.01). 12.2% initiated tobacco, 13.5% initiated marijuana. Only intention predicted tobacco initiation, while both attitude and intention predicted marijuana initiation. Attitudes, intentions, and behaviors changed significantly towards favored use. Predictors of use varied by substance, suggesting that different prevention approaches may be beneficial. PMID- 24761134 TI - Chernoff's density is log-concave. AB - We show that the density of Z = argmax{W (t) - t2}, sometimes known as Chernoff's density, is log-concave. We conjecture that Chernoff's density is strongly log concave or "super-Gaussian", and provide evidence in support of the conjecture. PMID- 24761135 TI - Lexical access and vocabulary development in very young bilinguals. AB - This study compares lexical access and expressive and receptive vocabulary development in monolingual and bilingual toddlers. More specifically, the link between vocabulary size, production of translation equivalents, and lexical access in bilingual infants was examined as well as the relationship between the Communicative Development Inventories and the Computerized Comprehension Task. Twenty-five bilingual and 18 monolingual infants aged 24 months participated in this study. The results revealed significant differences between monolingual and bilinguals' expressive vocabulary size in L1 but similar total vocabularies. Performance on the Computerized Comprehension Task revealed no differences between the two groups on measures of both reaction time and accuracy, and a strong convergent validity of the Computerized Comprehension Task with the Communicative Development Inventories was observed for both groups. Bilinguals with a higher proportion of translation equivalents in their expressive vocabulary showed faster access to words in the Computerized Comprehension Task. PMID- 24761136 TI - Post-traumatic epilepsy: an overview. AB - Post-traumatic seizures (PTS) and post-traumatic epilepsy (PTE) are complications from traumatic brain injury (TBI). PTE refers to recurrent and unprovoked PTS that occur at least 1 week after TBI. Seizures during the first week after TBI are considered provoked, an acute complication from head injury, while seizures occurring 1 week after TBI are considered a manifestation of PTE and if only a single seizure occurs it is known as late PTS. EEG and neuroimaging help in the diagnosis of PTE. Predictors for PTE include TBI severity, presence of intracranial bleeding and early PTS. Several clinical trials have demonstrated that antiepileptic drugs are effective in reducing the frequency of acute PTS, but do not appear to alter the natural history of late PTS or PTE. PMID- 24761137 TI - Comparison of Artemisia annua Bioactivities between Traditional Medicine and Chemical Extracts. AB - The present work investigates the efficacy of using Artemisia annua in traditional medicine in comparison with chemical extracts of its bioactive molecules. In addition, the effects of location (Egypt and Jericho) on the bioactivities of the plant were investigated. The results showed that water extracts of Artemisia annua from Jericho have stronger antibacterial activities than organic solvent extracts. In contrast, water and organic solvent extracts of the Artemisia annua from Egypt do not have anti-bacterial activity. Furthermore, while the methanol extract of EA displayed high anticancer affects, the water extract of Egypt and the extracts of Jericho did not show significant anticancer activity. Finally, the results showed that the methanol and water extracts of Jericho had the highest antioxidant activity, while the extracts of Egypt had none. The current results validate the scientific bases for the use of Artemisia annua in traditional medicine. In addition, our results suggest that the collection location of the Artemisia annua has an effect on its chemical composition and bioactivities. PMID- 24761138 TI - Gastric Cancer Arising from an Upside-Down Stomach through a Paraesophageal Hiatal Hernia. AB - We report the rare case of an elderly patient with an advanced gastric cancer arising from an upside-down stomach through a paraesophageal hiatal hernia (PEH). An 82-year-old man presented with appetite loss and anemia. Upper gastrointestinal endoscopy revealed a type 1 tumor located in the middle body of the stomach. An upper gastrointestinal series and computed tomography showed organoaxial rotation of the stomach, which was located in the mediastinum, through a PEH, indicating an upside-down stomach. The preoperative diagnosis was gastric cancer arising from an upside-down stomach through a PEH. The patient underwent total gastrectomy with lymph node dissection and closure of the hernial orifice. Although a large PEH is a chronic disorder, gastric malignancies should be considered in patients with PEH manifested as an upside-down stomach due to its anatomical characteristics, and careful preoperative diagnosis is mandatory. PMID- 24761139 TI - A differential diagnosis for left atrial mass on transthoracic echocardiography: hiatus hernia. AB - Hiatus hernia is a common medical condition. An elderly woman being investigated for dyspnoea of unknown aetiology had a transthoracic echocardiogram as part of her investigations. This alarmingly demonstrated a large left atrial mass. Further assessment with cardiac magnetic resonance imaging revealed a large hiatus hernia compressing the left atrium and no intra-cardiac mass. The case succinctly highlights gastrointestinal pathology simulating cardiac symptoms and masses. PMID- 24761140 TI - Calcinosis cutis confined to the dermis after intravenous administration of a calcium preparation: a case report and review of the Japanese literature. AB - A 61-year-old female received intravenous injection of calcium chloride after common iliac artery bypass surgery. A red flare appeared at the site of the intravenous infusion on the left forearm and gradually progressed to induration. Seven weeks later, she was referred to the Department of Dermatology for management. Physical examination showed an indurated plaque measuring 13 * 65 mm in size, with linearly distributed ulcers covered by yellowish-white substance, surrounded by reddish skin. Laboratory tests showed no significant abnormalities including serum calcium, phosphate and thyroid hormones. Cultures were negative for microorganisms. Histopathological examination showed calcium deposition confined to the dermis. The lesion healed spontaneously within 2 months with scar formation. A review of the Japanese literature showed confinement of calcium deposits to the dermis in most of the reported cases. We speculate that the pathomechanism of dermal calcinosis includes needle-induced tissue injury with capillary destruction, leading to release of excess calcium between collagen fibers, and its binding to phosphate in the dermis and deposition as calcium phosphate crystals. PMID- 24761141 TI - A rare case of male bullous lupus erythematosus complicated with subsequent annular hypopigmentation. AB - A 57-year-old male had been suffering from an itchy map-shaped symmetrical erosive erythema with a crust that was attached to his upper arm and buttock, and occasionally he suffered from spiking fever. Laboratory examinations showed neither anti-desmoglein 1/3 antibodies nor anti-BP 180 antibodies, and he fulfilled the criteria for a diagnosis of systemic lupus erythematosus (SLE). Histologically, there was eosinophilic necrosis of keratinocytes, liquefaction and degradation with severe lymphocyte infiltration into the epidermis and subepidermal blister formation, suggestive of a variant of SLE, bullous lupus erythematosus (BLE). One month after remission of BLE, peculiar annular hypopigmentation appeared on the peripheral borders. An immunohistochemical analysis showed a decrease in Melan A-positive melanocytes and concomitant pigment incontinentia, with dense infiltration of CD8(+) T cells and IL-17A(+) Th17 cells. An ultrastructural analysis revealed a decrease, but not a complete disappearance, of both melanocytes and melanosomes, and no impairment in melanosomal transfer. In this case report, we would like to introduce the development of annular depigmentation complicated with BLE, and discuss the effects of lupus condition on melanocyte damage based on immunohistological and electromicroscopic findings of those vitiliginous lesions. PMID- 24761142 TI - Disseminated cryptococcosis-induced skin ulcers in a patient with autoimmune hepatitis. AB - We report the case of a 68-year-old woman with autoimmune hepatitis (AIH) who had leg ulcers induced by disseminated cryptococcosis. She had received prednisolone for her AIH at 20 mg/day for maintenance. On the initial visit, she complained of a painful ulcer that had round, shallow pockets with erythema and erythematous subcutaneous indurations on the right thigh. Several metacarpophalangeal joints and wrist joints were swollen, with tenderness and stiffness in the morning for over 3 h. Her serum rheumatoid factor was high. Since other autoimmune disorders such as rheumatoid arthritis can present with AIH, it was necessary to distinguish it from ulcers due to rheumatoid arthritis, although the characteristic features of these ulcers seemed to be different. A biopsy specimen from the erythematous skin showed globe-shaped organisms in the dermis and subcutaneous tissues; vasculitis and phlebostasis were not observed. The results from computed tomography scans and sputum culture led to the diagnosis of disseminated cryptococcosis. The administration of fluconazole, fosfluconazole, and voriconazole for about 2 months improved the cryptococcal pneumonia, but the size of the skin ulcer enlarged. The administration was changed to itraconazole, which reduced the size. Cryptococcal infections occur more commonly in immunocompromised hosts, including patients under immunosuppressive therapies such as corticosteroids. The possibility that the skin ulcers in immunocompromised hosts may be caused by cryptococcosis should be considered. PMID- 24761144 TI - The course of incidental intraorbital cavernous hemangioma in a patient with myasthenia gravis treated with cyclosporine: a case report. AB - A 69-year-old woman presented with generalized myasthenia gravis and a left orbital cavernous hemangioma (OCH), which elevated the optic nerve and displaced the external eye muscles. Cyclosporine treatment induced a gradual size reduction in the OCH, and consequently contributed to improved external ocular symptoms in combination with immunosuppressant effects. PMID- 24761143 TI - Severe gangrene accompanied by varicella zoster virus-related vasculitis mimicking rheumatoid vasculitis. AB - Herpes zoster infection occurs more frequently and severely in immunosuppressed populations. However, the condition sometimes presents with atypical clinical manifestations of the skin, which makes it difficult to reach a correct diagnosis. We experienced a case of acral gangrene caused by varicella zoster virus (VZV)-related vasculitis in a rheumatoid arthritis (RA) patient. Histologically, necrotic vasculitis was observed; however, there were initially no findings in the epidermis suggestive of a viral infection. We thought that the skin ulcer was related to rheumatoid vasculitis. However, an immunohistochemical analysis for VZV confirmed VZV infection in the vascular endothelium of the dermis, leading to effective treatment with intravenous acyclovir. Since various pathogenic skin phenotypes are observed in RA patients, modified according to the status of immunosuppression, clinicians must recognize the variation in typical and atypical manifestations in order to manage these patients. PMID- 24761145 TI - Improvement of freezing of gait in patients with Parkinson's disease by imagining bicycling. AB - Freezing of gait (FOG) is one of the factors that reduce the quality of life in patients with Parkinson's disease (PD). Imagining bicycling before gait start provided improvement in FOG in 2 PD patients. Imagining and mimicking bicycling after the initiation of gait allowed the rhythmic gait to continue without interruption. We suggest that imagining and mimicking bicycling, which are nonexternal cues, could serve as a helpful therapeutic approach for the intractable freezing and interruption of gait of PD patients. PMID- 24761146 TI - Biological characteristics of a cerebellar mass regrowing after removal in a patient with lhermitte-duclos disease: emission tomography studies. AB - Lhermitte-Duclos disease is a rare disorder characterized by a slowly enlarging mass in the cerebellum. The exact nature of this lesion remains unclear, but it has been variously characterized as hypertrophy, hamartoma or benign neoplasm. Single-photon emission computed tomography (SPECT) with (123)I-iomazenil and (99m)Tc-ethyl cysteinate dimer (ECD) display central benzodiazepine receptors that are widely distributed in the normal brain cortex, a combination of brain perfusion, enzymatic activity and blood-brain barrier function, respectively. This report describes the case of a 30-year-old man who developed Lhermitte Duclos disease. The mass regrew after a subtotal removal 13 years earlier. The cerebellar lesion exhibited hyperperfusion and hypermetabolism on blood flow and a metabolic rate of oxygen imaging on (15)O-gas positron emission tomography (PET), as well as a hyperactivity and a defect in the uptake on (99m)Tc-ECD and (123)I-iomazenil SPECT imaging, respectively. The present Lhermitte-Duclos lesion might have the biological characteristics of both hypertrophy and neoplasm, from the perspective of results from (15)O-gas PET, (99m)Tc-ECD and (123)I-iomazenil SPECT. PMID- 24761147 TI - Intravascular lymphomatosis mimicking primary central nervous system lymphoma: a case report and literature review. AB - We herein report a 75-year-old female patient with intravascular lymphomatosis (IVL) who presented with fever of unknown origin. Examination, including contrast enhanced CT and (67)Ga scintigraphy, failed to show any lesions. Her blood levels of lactate dehydrogenase and soluble interleukin-2 receptors were high, suggesting a lymphomatous tumor. A bone marrow puncture was negative, and a random skin biopsy revealed a monoclonal proliferation of naked, large lymphocytes in the vascular space of the subcutaneous tissue, confirming the diagnosis of IVL. MRI, performed 7 weeks after admission, showed a brain mass mimicking primary central nervous system lymphoma. The mass was considered to be a collection of malignant lymphocyte cells invading from the vessels. Without the random skin biopsy, this case may have been misdiagnosed as primary central nervous system lymphoma. PMID- 24761148 TI - Pterygium: nonsurgical treatment using topical dipyridamole - a case report. AB - PURPOSE: We report a case of a symptomatic, inflamed pterygium treated nonsurgically with topical dipyridamole and followed for 12 months. CASE REPORT: A 35-year-old woman presented with a stage II to III, V3, C3, K2, P1 (using Johnston, Williams & Sheppard's classification) pterygium in her right eye. She complained of a foreign body sensation, dryness, burning, and persistent uncontrolled blinking. A raised lesion was observed on the nasal conjunctiva that was 1.5 mm in size. It extended slightly onto the nasal cornea. There was moderate vascularity of the lesion that obscured the underlying scleral vessels. Moderate conjunctival hyperemia was detected at and medial to the pterygium. The cornea, anterior chamber, and external anatomy were otherwise unremarkable. The eye was initially treated twice daily with a topical application of dipyridamole in a normal saline solution, which was later reduced to once daily. RESULTS: There was a marked improvement in both the pterygium and the patient's symptoms. The tissue regressed from the limbal region of the cornea, had decreased in length from 1.5 to 1.0 mm, and decreased in height from approximately 1.0 to approximately 0.3 mm. Conjunctival hyperemia and vascularization resolved completely, and the underlying scleral vessels could once again be visualized. At 12 months, the pterygium was graded as stage 0 to I, V0, C2, K0, P0. CONCLUSIONS: To our knowledge, this is the first case of successful management of a pterygium and associated symptoms using topical dipyridamole. Further investigation is required to clarify the potential role of dipyridamole in the treatment of pterygia and pingueculae. PMID- 24761149 TI - Spontaneous Resolution of Long-Standing Macular Detachment due to Optic Disc Pit with Significant Visual Improvement. AB - PURPOSE: To report a case of spontaneous resolution of a long-standing serous macular detachment associated with an optic disc pit, leading to significant visual improvement. CASE PRESENTATION: A 63-year-old female presented with a 6 month history of blurred vision and micropsia in her left eye. Her best-corrected visual acuity was 6/24 in the left eye, and fundoscopy revealed serous macular detachment associated with optic disc pit, which was confirmed by optical coherence tomography (OCT). The patient was offered vitrectomy as a treatment alternative, but she preferred to be reviewed conservatively. Three years after initial presentation, neither macular detachment nor subretinal fluid was evident in OCT, while the inner segment/outer segment (IS/OS) junction line was intact. Her visual acuity was improved from 6/24 to 6/12 in her left eye, remaining stable at the 6-month follow-up after resolution. CONCLUSION: We present a case of spontaneous resolution of a long-standing macular detachment associated with an optic disc pit with significant visual improvement, postulating that the integrity of the IS/OS junction line may be a prognostic factor for final visual acuity and suggesting OCT as an indicator of visual prognosis and the probable necessity of a surgical management. PMID- 24761150 TI - Corneal and scleral dellen after an uneventful pterygium surgery and a febrile episode. AB - INTRODUCTION: We describe a patient with corneal and scleral dellen, which occurred after an uneventful pterygium excision without adjunctive therapy and a subsequent febrile episode. CASE REPORT: A 43-year-old woman presented with a history of recurrent irritation in her right eye and a diagnosis of pterygium. The pterygium was excised under local anesthesia with the bare scleral technique and without the use of antimetabolites. No complications occurred until 14 days after surgery when corneal and sclera dellen appeared; this was 2 days after a concomitant febrile episode (39 degrees C). Tobramycin and dexamethasone eye drops given after surgery were withdrawn and topical lubricants and antibiotic ointment, in combination with oral L-amino acids, were administered along with eye patching. One week later, the corneal dellen had completely healed and, 4 weeks later, the thinned sclera appeared regularly thick and white in color. Three months after surgery, a small recurrent pterygium was diagnosed, which remained stable without signs of inflammation for additional 18 months. CONCLUSIONS: Corneal and scleral dellen might be a late complication of uneventful pterygium surgery without antimetabolites and a subsequent febrile episode. PMID- 24761151 TI - Acupuncture Relieves the Excessive Excitation of Hypothalamic-Pituitary-Adrenal Cortex Axis Function and Correlates with the Regulatory Mechanism of GR, CRH, and ACTHR. AB - It had been indicated in the previous studies that acupuncture relieved the excessive excitation of hypothalamic-pituitary-adrenal cortex axis (HPAA) function induced by stress stimulation. But the changes in glucocorticoid receptor (GR) induced by acupuncture have not been detected clearly. The objective of the study was to observe the impacts of acupuncture on the protein expressions of corticotrophin releasing hormone (CRH), adrenocorticotropic hormone receptor (ACTHR), and GR under the physiological and stress states. The results showed that under the stress state, acupuncture upregulated the protein expression of GR in the hippocampus, hypothalamic paraventricular nucleus (PVN), and pituitary gland, downregulated the protein expression of GR in the adrenal cortex, and obviously reduced the protein expressions of CRH and ACTHR. Under the physiological state, acupuncture promoted GR protein expression in the hippocampus and CRH protein expression in the hippocampus and PVN. The results explained that acupuncture regulated the stress reaction via promoting the combination of glucocorticoids (GC) with GR, and GR protein expression. The increase of GR protein expression induced feedback inhibition on the overexpression of CRH and ACTHR, likely decreased GC level, and caused the reduction of GR protein expression in the adrenal cortex. PMID- 24761153 TI - Misdiagnosed hypomanic symptoms in patients with treatment-resistant major depressive disorder in Italy: results from the improve study. AB - BACKGROUND: Undiagnosed and therefore inadequately treated hypomanic symptoms may be a leading cause of drug resistance in depression diagnosed as unipolar (major depressive disorder, MDD). The purpose of the IMPROVE study was to identify the rate of misdiagnoses in patients with treatment-resistant MDD by screening for the presence of previous hypomanic episodes, and to study the characteristics of those patients with a positive history of hypomania. METHODS: Patients attending 29 psychiatric units throughout Italy with a diagnosis of MDD who were resistant to anti-depressant treatment were included in this multicentre, observational single visit study. The Hypomania Checklist 32 (HCL-32) was administered to detect underlying bipolarity. RESULTS: Among the 466 enrolled patients, 256 (57.40%) were positive at screening for a previous hypomanic episode (HCL-32 >=12), therefore suggesting a misdiagnosis. These patients scored higher than those with a negative history in both the "active/elated hypomania" (11.27+/-3.11 vs 3.57+/-3.05; P<0.0001) and "irritable/risk-taking hypomania" (2.87+/-2.03 vs 2.06+/-1.73; P<0.001) HCL-32 sub-scales. Patients with a positive history of hypomania were younger, had a higher number of previous depressive episodes and a higher frequency of comorbid conditions compared to those with a negative history. CONCLUSIONS: This study suggests that screening for hypomania in MDD resistant patients facilitates identification of a notable proportion of undiagnosed cases of bipolar spectrum disorder. Patients with a positive history of hypomania at screening had a demographic/clinical bipolar-like profile that included young age, higher number of previous depressive episodes and higher frequency of comorbid conditions. They also had both higher active and irritable hypomania symptom scores. PMID- 24761152 TI - THE IMPACT OF RACISM ON CLINICIAN COGNITION, BEHAVIOR, AND CLINICAL DECISION MAKING. AB - Over the past two decades, thousands of studies have demonstrated that Blacks receive lower quality medical care than Whites, independent of disease status, setting, insurance, and other clinically relevant factors. Despite this, there has been little progress towards eradicating these inequities. Almost a decade ago we proposed a conceptual model identifying mechanisms through which clinicians' behavior, cognition, and decision making might be influenced by implicit racial biases and explicit racial stereotypes, and thereby contribute to racial inequities in care. Empirical evidence has supported many of these hypothesized mechanisms, demonstrating that White medical care clinicians: (1) hold negative implicit racial biases and explicit racial stereotypes, (2) have implicit racial biases that persist independently of and in contrast to their explicit (conscious) racial attitudes, and (3) can be influenced by racial bias in their clinical decision making and behavior during encounters with Black patients. This paper applies evidence from several disciplines to further specify our original model and elaborate on the ways racism can interact with cognitive biases to affect clinicians' behavior and decisions and in turn, patient behavior and decisions. We then highlight avenues for intervention and make specific recommendations to medical care and grant-making organizations. PMID- 24761154 TI - How Is Pain Influenced by Cognition? Neuroimaging Weighs In. AB - Neuroimaging can inform cognitive theories to the extent that particular patterns of brain activity are sensitively and specifically associated with particular types of cognitive processes. We illustrate the utility of neuroimaging data in one specific case: understanding cognitive influences on pain. We first argue that pain self-reports are often inadequate to fully characterize pain experience and the processes that underlie it. Then, we describe how neuroimaging measures have been used to corroborate the effects of psychological manipulations on pain by focusing on placebo treatments and demonstrating effects on the best available correlates of pain experience. In addition, using placebo analgesia as an example, we argue that brain evidence is useful for building psychological theories likely to yield valid and generalizable predictions, because biologically informed theories are grounded in the constraints inherent in the relevant physiological systems. Finally, we suggest that neuroimaging findings will become increasingly useful for constraining psychological inference as brain patterns diagnostic of particular types of mental events are identified and characterized. In our view, the relationships between biological findings and cognitive theory are empirically based and must develop through an iterative process of synthesis across studies, topics, and methods. PMID- 24761155 TI - Atypical primary pulmonary meningioma: a report of a case suspected of being a lung metastasis. AB - Primary extracranial and extraspinal meningiomas are very rare tumours, and primary pulmonary ones are even more uncommon. They present as a solitary pulmonary nodule, and most of them are benign, except for three cases. We describe a primitive atypical pulmonary meningioma first suspected of being a metastasis in a patient during follow-up ten years after therapy for breast cancer. PMID- 24761156 TI - Transforming children's palliative care-from ideas to action: highlights from the first ICPCN conference on children's palliative care. AB - The International Children's Palliative Care Network (ICPCN) held its first international conference on children's palliative care, in conjunction with Tata Memorial Centre, in Mumbai, India, from 10-12 February 2014. The theme of the conference, Transforming children's palliative care-from ideas to action, reflected the vision of the ICPCN to live in a world where every child who needs it, can access palliative care, regardless of where they live. Key to this is action, to develop service provision and advocate for children's palliative care. Three pre-conference workshops were held on 9 February, aimed at doctors, nurses, social workers, and volunteers, and focused around the principles of children's palliative care, and in particular pain and symptom management. The conference brought together 235 participants representing 38 countries. Key themes identified throughout the conference included: the need for advocacy and leadership; for education and research, with great strides having been taken in the development of an evidence base for children's palliative care, along with the provision of education; the importance of communication and attention to spirituality in children, and issues around clinical care, in particular for neonates. Delegates were continually challenged to transform children's palliative care in their parts of the world and the conference culminated in the signing of the ICPCN Mumbai Declaration. The Declaration calls upon governments around the world to improve access to quality children's palliative care services and made a call on the Belgian government not to pass a bill allowing children to be euthanised in that country. The conference highlighted many of the ongoing developments in children's palliative care around the world, and as she closed the conference, Joan Marston (ICPCN CEO) challenged participants to take positive action and be the champions that the children need, thus transforming children's palliative care. PMID- 24761157 TI - The development and evaluation of a holistic needs assessment and care planning learning package targeted at cancer nurses in the UK. AB - A project team from the United Kingdom Oncology Nursing Society developed a blended e-learning website to facilitate nurses to further develop their confidence and competencies in a range of skills related to assessing the holistic needs of people with cancer. The project team identified three areas which were integral to an holistic needs assessment (HNA) implementation project. These were project support information, project management skills, and practical competencies delivered in a blended e-learning package containing a series of accessible video presentations, supporting documents, and practical activities. The team worked with internal and external partners to ensure that a robust and inspiring programme was created. www.hnaforcancer.com was launched in October 2012 as a blended learning programme that incorporates e-learning on core subjects. These subjects are packaged as videoed presentations with supporting learning material and can be accessed via the UKONS website. By the end of the programme participants were equipped to identify and explore the essential requirements for HNA and care planning, more able to recognise potential need, and initiate care to prevent or minimise the risk of complications. Participants had also developed confidence and competency in new skills, including basic project management. PMID- 24761158 TI - Non-medical prescribing of chemotherapy: engaging stakeholders to maximise success? AB - AIM: This study report examines the views and experiences of professional stakeholders about non-medical prescribing (NMP) of chemotherapy. BACKGROUND: The introduction of open formulary NMP has created opportunities to radically change health-care delivery. For chemotherapy services, the most recent advice from the National Chemotherapy Advisory Group [Department of Health (2009) Chemotherapy Services in England, ensuring quality and safety: a report from the National Chemotherapy Advisory Group, London Her Majesty's Stationary Office] clearly endorses the development of nurse- or pharmacist-led chemotherapy clinics. This is very much welcomed but is based on very limited evidence as to their effectiveness. DESIGN: A fourth-generation evaluation study. METHODS: A purposeful sample of 23 stakeholders connected with the chemotherapy service was used. A serial data collection technique with individual interviews followed by uni-professional focus groups was adopted. Finally, a multi-professional focus group was held to determine the strategic way forward. Data were collected in 2009-2010. RESULTS: The study illuminated the key features necessary to maximise success of NMP in chemotherapy clinics and captures the importance of good working relationships. Whilst different practice models will emerge, fundamental and core to services is the need for good team working, established and effective communication strategies, and most importantly avoiding isolation in practice. This study additionally reinforced any evaluation takes place within preexisting political contexts and in particular medical dominance. Not all medical colleagues agreed with or wanted NMP for their patients, highlighting difficulties of developing new models of working within a resisting culture. CONCLUSION: No objections to NMP of chemotherapy were found, but, clearly, the context of practice needs to be agreed and supportedby all professional stakeholders. What is already known about this topicOpen formulary non-medical prescribing has been rapidly introduced over the past decade.Little research has been conducted in acute care and none in the chemotherapy setting.Cancer policy recommends the introduction of nurse-led chemotherapy clinics.What this paper addsNon-medical prescribing (NMP) in chemotherapy is appropriate with the right model of practice.Well-established professional relationships are a key to success.NMP is not appropriate in isolation of the multidisciplinary team (MDT).Implications for practice and/or policyNurses need to demonstrate the value of non-medical prescribing in chemotherapy using available metrics.Models of practice need to ensure good communication channels, MDT working, and transparency of prescribing. PMID- 24761159 TI - Is it safe for pregnant health-care professionals to handle cytotoxic drugs? A review of the literature and recommendations. AB - The information related to health risks to foetuses due to the handling of chemotherapeutic agents by nurses during pregnancy is limited. The risks involved can be reduced significantly if nurses adhere to standard safety precautions while handling cytotoxic drugs. Nurses in patient areas where chemotherapy is administered are at constant low-level risk of exposure. The authors tried to gather evidence in this article from the recent literature to help to formalise policies for pregnant mothers working in these settings. PMID- 24761160 TI - Patient's perception of a nurse-led Trastuzumab pathway. AB - This paper presents the development of a pathway at a cancer unit in Northern England. The pathway aimed to ensure that patients with early breast cancer who were receiving Trastuzumab did so in a safe manner. This was achieved by developing a multiprofessional pathway, which crossed traditional boundaries to ensure the patient received the best care available. This paper describes the patient's perception of the pathway obtained through a patient satisfaction survey and suggestions for its future direction. PMID- 24761161 TI - Chemotherapy-Induced Nausea and Vomiting. AB - Despite treatment advances, nausea and vomiting, especially anticipatory nausea and vomiting, delayed nausea and vomiting and nausea alone, are still the most common, expected and feared side effects among patients receiving chemotherapy. Of the 70 to 80% of cancer patients who experience chemotherapy-induced nausea and vomiting many will delay or refuse future chemotherapy treatments and contemplate stopping all treatments because of fear of further nausea and vomiting. The purpose of this chapter is to provide an overview of the patho psychophysiology of CINV, the recommended guidelines for standard treatment, and highlight newer targeted treatment approaches. PMID- 24761162 TI - Synthesis of Nanogel-Protein Conjugates. AB - The covalent conjugation of bovine serum albumin (BSA) to disulfide cross-linked polymeric nanogels is reported. Polymeric nanogel precursors were synthesized via a reversible addition-fragmentation chain transfer (RAFT) random copolymerization of poly(ethylene glycol) methyl ether methacrylate (PEGMA) and pyridyl disulfide methacrylate (PDSMA). Reaction of the p(PEGMA-co-PDSMA) with dithiothreitol resulted in the formation of nanogels. PDSMA serves as both a crosslinking agent and a reactive handle for the surface modification of the nanogels. Lipophilic dye, DiI, was sequestered within the nanogels by performing the crosslinking reaction in the presence of the hydrophobic molecule. Thiol-enriched BSA was conjugated to nanogels loaded with DiI via a disulfide reaction between the BSA and the surface exposed nanogel pyridyl disulfides. Conjugation was confirmed by fast protein liquid chromatography, dynamic light scattering, and agarose and polyacrylamide gel electrophoresis. We expect that this methodology is generally applicable to the preparation of nanogel-protein therapeutics. PMID- 24761163 TI - Evidence-based Practices Addressed in Community-based Children's Mental Health Clinical Supervision. AB - CONTEXT: Clinical supervision is the principal method of training for psychotherapeutic practice, however there is virtually no research on supervision practice in community settings. Of particular interest is the role supervision might play in facilitating implementation of evidence-based (EB) care in routine care settings. OBJECTIVE: This study examines the format and functions of clinical supervision sessions in routine care, as well as the extent to which supervision addresses psychotherapeutic practice elements common to EB care for children with disruptive behavior problems, who represent the majority of patients served in publicly-funded routine care settings. METHODS: Supervisors (n=7) and supervisees (n=12) from four publicly-funded community-based child mental health clinics reported on 130 supervision sessions. RESULTS: Supervision sessions were primarily individual in-person meetings lasting one hour. The most common functions included case conceptualization and therapy interventions. Coverage of practice elements common to EB treatments was brief. DISCUSSION: Despite the fact that most children presenting to public mental health services are referred for disruptive behavior problems, supervision sessions are infrequently focused on practice elements consistent with EB treatments for this population. Supervision is a promising avenue through which training in EB practices could be supported to improve the quality of care for children in community-based "usual care" clinics. PMID- 24761164 TI - Does Syndrome Differentiation Matter? A Meta-Analysis of Randomized Controlled Trials in Cochrane Reviews of Acupuncture. AB - BACKGROUND: One of the basic and important principles of Traditional Chinese Medicine theory is syndrome differentiation, which is widely utilized for individual diagnosis and in the application of acupuncture treatment. However, the impact of syndrome differentiation on therapeutic effect is unclear because of insufficient supportive clinical evidence. OBJECTIVE: The aim of this study was to analyze current Cochrane Database systematic reviews of acupuncture and to evaluate differences in therapeutic effects of acupuncture treatment when syndrome differentiation is utilized, compared to when this approach is not utilized. METHODS: Cochrane Database systematic reviews of acupuncture were included if the reviews had sufficient data to perform subgroup analyses by syndrome differentiation applied during acupoints' selection. Searching was conducted across all available articles of the Cochrane Library, and the search concluded in July 2011. RESULTS: Forty-four trials from five Cochrane reviews were included in 10 subgroup meta-analyses. Seven meta-analyses showed that there were no differences between trials using fixed acupoints prescriptions and trials using individualized treatment based on relevant symptom improvements in cases of acute stroke, depression, epilepsy, migraine, and peripheral joint osteoarthritis (OA). The remaining 3 meta-analyses showed that acupuncture with fixed prescriptions was superior to individualized acupuncture for pain relief of peripheral joint OA, compared to sham control. CONCLUSIONS: The available evidence showed no significant difference between acupuncture treatment with or without syndrome differentiation. Large, well-designed trials are warranted to address the use of syndrome differentiation for specific diseases or conditions in order to confirm if there are any advantages of using syndrome differentiation to achieve better therapeutic effects with acupuncture. PMID- 24761165 TI - The Feasibility and Effects of Acupuncture on Quality of Life Scores During Chemotherapy in Ovarian Cancer: Results from a Pilot, Randomized Sham-Controlled Trial. AB - BACKGROUND: Within a pilot trial regarding chemotherapy-induced neutropenia, the secondary aim of the main study was explored. This involved measuring the effects as shown on two key measurement scales reflecting quality of life (QoL)-of verum versus sham acupuncture on patients with ovarian cancer during chemotherapy. OBJECTIVE: The aim of this substudy was to determine the feasibility of determining the effects of verum acupuncture versus sham acupuncture on QoL in patients with ovarian cancer during chemotherapy. DESIGN: This was a randomized, sham-controlled trial. SETTING: The trial was conducted at two cancer centers. PATIENTS: Patients with ovarian cancer (N=21) who were receiving chemotherapy primarily intravenous carboplatin and paclitaxel-participated in this substudy. INTERVENTION: The participants were given either active or sham acupuncture 1 week prior to cycle 2 of chemotherapy. There were ten sessions of acupuncture, with manual and electro-stimulation over a 4-week period. MAIN OUTCOME MEASURES: The European Organization for Research and Treatment of Cancer-Quality-of-Life Questionnaire-Core 30 Item (EORTC-QLQ-C30) and the Quality of Life Questionnaire Ovarian Cancer Module-28 Item (QLQ-OV28) were administered to the patients at baseline and at the end of their acupuncture sessions. RESULTS: Of the original 21, 15 patients (71%) completed the study, and 93% of them completed the questionnaires. The EORTC-QLQ-C30 subscores were improved in the acupuncture arm, including the mean scores of social function (SF), pain, and insomnia (p=0.05). However, after adjusting for baseline differences, only the SF score was significantly higher in the active acupuncture arm, compared with the sham acupuncture arm (p=0.03). CONCLUSIONS: It appears feasible to conduct a randomized sham-controlled acupuncture trial measuring QoL for patients with ovarian cancer who are undergoing chemotherapy. Acupuncture may have a role in improving QoL during chemotherapy. PMID- 24761166 TI - Diminished Ovarian Reserve, Clomid, and Traditional Chinese Medicine: A Case Study. AB - BACKGROUND: Infertility caused by diminished ovarian reserve (DOR) can result from an endocrinological imbalance. A rise in follicle stimulating hormone (FSH) and decrease in antral follicle count (AFC) for women age <=35 can lower pregnancy rates to <5%, and increase miscarriage rates to >75%. Chinese medicine may improve FSH and AFC levels in patients with DOR. It is common for women to seek adjunctive Traditional Chinese Medicine (TCM) treatment with biomedical clomid treatment. OBJECTIVE: This article reports the case of a female with DOR who had completed three multiple, serial clomid cycles from September to December 2005, and for whom clomid failed. DESIGN SETTING AND PATIENT: This is a case study of a 34-year-old patient with a 5-year history of infertility caused by DOR. She was treated in a private practice in Bellevue, WA. INTERVENTION: TCM treatment-including acupuncture and herbal therapy-lasted from from January 2007 to April 2007. MAIN OUTCOME MEASURES: The main outcomes sought were improvements in this patient's reproductive hormone panel, including tests for FSH, estradiol, and AFC levels; in addition a pregnancy outcome was desired. RESULTS: After 4 months of TCM treatment, the patient returned to biomedical care. Pregnancy was not achieved during three more clomid cycles, although she had improvements her levels of FSH (from 14.5 mIU/mL to 8.7 mIU/mL) and AFC (from 10-12 to 16-18 total). After 3 more cycles with clomid, her FSH level increased to 16.8 mIU/mL and her AFC level was <10. CONCLUSIONS: After three failed clomid cycles, a patient with DOR had improved FSH and AFC levels when she received TCM treatment. However, this patient was still unable to conceive although three more clomid cycles were attempted. More research is needed to discern demographically which patients benefit best from multiple, serial clomid interventions. In addition, it is important to investigate more-integrative treatments for patients with DOR, including assisted reproductive techniques, acupuncture, and Chinese herbs. PMID- 24761167 TI - Adherence to, and Satisfaction with, the Self-Acupressure Intervention in the LIFE Weight-Loss Maintenance Study. AB - BACKGROUND: The LIFE study was a randomized controlled trial assessing the impact of a self-acupressure intervention, Tapas Acupressure Technique(r) (TAT(r)), on weight-loss maintenance. The primary analysis showed no significant difference between TAT and social support (SS) for weight-loss maintenance, while exploratory post hoc tests suggested that, among participants with highest initial weight-loss, those in the TAT condition regained less weight than those in the SS condition. OBJECTIVE: The aim of the current study was to assess adherence to, and satisfaction with, the experimental self-acupressure intervention in the LIFE weight loss maintenance trial. DESIGN: This was a secondary analysis of adherence and satisfaction patterns in a large randomized controlled trial. SETTING: The study was conducted at a prominent health maintenance organization in the Pacific Northwest. SUBJECTS: This study involved 142 obese participants who had lost >10 pounds in a conventional weight-loss program and who were randomized to the experimental acupressure intervention. INTERVENTIONS: The experimental intervention (n=142) arm consisted of instruction and application of a self-acupressure intervention, the Tapas Acupressure Technique(r) (TAT(r)). OUTCOME MEASURES: The outcome sought was self-reported satisfaction and frequency of TAT practice. RESULTS: Sixty-six percent of TAT participants attended at least 6 of 8 intervention sessions. More than 80% of participants reported practicing TAT at home, on average, at least 2 days per week. Sixty two percent reported practicing <10 minutes per session, while 27% reported practicing 10-20 minutes per session. Higher satisfaction scores were significantly correlated with less weight regain (p=0.001). Frequency of TAT practice was not significantly associated with changes in weight, stress, insomnia, depression, or quality of life. CONCLUSIONS: These data suggest moderate acceptance of, and adherence to, the TAT intervention. Further research is required to identify and achieve optimal home-practice levels of self acupressure techniques. PMID- 24761168 TI - Acupuncture's Cardiovascular Actions: A Mechanistic Perspective. AB - Over the last several decades, there has been an explosion of articles on acupuncture, including studies that have begun to explore mechanisms underlying its analgesic and cardiovascular actions. Modulation of cardiovascular function is most effective during manual and low-frequency, low-intensity electroacupuncture (EA) at a select set of acupoints situated along meridians located over deep somatic nerves on the upper and lower extremities. Stimulation at these acupoints activates underlying sensory neural pathways that project to a number of regions in the central nervous system (CNS) that ultimately regulate autonomic outflow and hence cardiovascular function. A long-loop pathway involving the hypothalamus, midbrain, and medulla underlies EA modulation of reflex increases in blood pressure (BP). Actions of excitatory and inhibitory neurotransmitters in the supraspinal CNS underlie processing of the somatic input and adjustment of autonomic outflow during EA. Acupuncture also decreases elevated blood pressure through actions in the thoracic spinal cord. Reflexes that lower BP likewise are modulated by EA through its actions on sympathetic and parasympathetic nuclei in the medulla. The autonomic influence of acupuncture is slow in onset but prolonged in duration, typically lasting beyond the period of stimulation. Clinical studies suggest that acupuncture can be used to treat cardiac diseases, such as myocardial ischemia and hypertension, associated with overactivity of the sympathetic nervous system. PMID- 24761169 TI - The Antidepressant Effect of Laser Acupuncture: A Comparison of the Resting Brain's Default Mode Network in Healthy and Depressed Subjects During Functional Magnetic Resonance Imaging. AB - BACKGROUND: It has been suggested that the antidepressant effect of laser acupuncture involves modulation of the default mode network (DMN) or resting state network (RSN). In this study, the authors investigated changes in the DMN during laser acupuncture in depressed and nondepressed participants. OBJECTIVE: To aim of this study was to determine if the modulation of the DMN effects by laser acupuncture in depressed participants are different from those of nondepressed participants. DESIGN: Randomized stimulation was performed with laser acupuncture on four putative antidepressant acupoints (LR 14, LR 8, CV 14, and HT 7) in a block on-off design, while the blood oxygenation level-dependent (BOLD) fMRI response was recorded from each subject's whole brain on a 3T scanner. DMN patterns of the participants were identified, using an independent component analysis. The identified DMN components from both the nondepressed group and the depressed group were then analytically compared using SPM5. SETTING: This study took place at a research institute. SUBJECTS: Ten nondepressed participants and 10 depressed participants (DS) as confirmed by the Hamilton Depression Rating Scale (HAM-D) participated in this study. INTERVENTION: Low Intensity Laser Acupuncture. MAIN OUTCOME MEASURES: Significant DMN patterns in one group were greater than those in the other group. RESULTS: The nondepressed participants had significant modulation of DMN in the frontal region at the medial frontal gyrus (verum laser>rest, p<0.001) for three acupoints (LR 14, LR 8, and CV 14). For the depressive participants, the DMN modulation occurred at the inferior parietal cortex and the cerebellum (verum laser>rest, p<0.001). CONCLUSIONS: Laser acupuncture on LR 8, LR 14, and CV 14 stimulated both the anterior and posterior DMN in both the nondepressed and depressed participants. However, in the nondepressed participants, there was consistently outstanding modulation of the anterior DMN at the medial frontal gyrus across all three acupoints. In the depressed participants, there was wider posterior DMN modulation at the parieto-temporal-limbic cortices. This is part of the antidepressant effect of laser acupuncture. PMID- 24761170 TI - Pressure Pain Sensitivity and Insular Combined Glutamate and Glutamine (Glx) Are Associated with Subsequent Clinical Response to Sham But Not Traditional Acupuncture in Patients Who Have Chronic Pain. AB - BACKGROUND: Clinical trials of acupuncture in chronic pain have largely failed to demonstrate efficacy of traditional over sham acupuncture. However, it should be noted that sham acupuncture is not inert. OBJECTIVE: To determine if experimental pressure pain assessment and chemical neuroimaging can identify differential responsiveness to sham as opposed to traditional acupuncture. PATIENTS AND INTERVENTION: Fifty patients with fibromyalgia were randomized to either 9 traditional (TA) or sham (SA) acupuncture treatments over a period of 4 weeks. Both participants and assessors were blinded. MAIN OUTCOME MEASURES: The main outcome measures were pressure-pain sensitivity at the thumbnail, insular glutamate+glutamine (Glx), and clinical pain. RESULTS: PATIENTS WITH LOW PAIN SENSITIVITY (LPS), BUT NOT WITH HIGH PAIN SENSITIVITY (HPS), HAD A SIGNIFICANTLY REDUCED CLINICAL PAIN RESPONSE TO SA (CHANGE IN MEAN [STANDARD DEVIATION (SD)]: HPS -8.65 [7.91]; LPS -2.14 [6.68]; p=0.03). This relationship was not the case for TA (HPS -6.90 [4.51]; LPS -6.41 [9.25]; p=0.88). SA-treated patients who were more sensitive also had greater baseline levels of insular Glx than patients who were less sensitive (Glx mean [SD]: HPS 11.3 [1.18]; LPS 10.2 [0.54]; p=0.04). CONCLUSIONS: Pressure-pain testing may identify patients who are less likely to respond to SA. This effect may relate to the levels of brain excitatory neurotransmitters. PMID- 24761171 TI - Acupuncture for Treating Anxiety and Depression in Women: A Clinical Systematic Review. AB - BACKGROUND: Anxiety and depression are high in prevalence, especially in the female population, whose incidence is approximately double that of the male population. In addition, these conditions are difficult to treat and have high relapse rates and medication side-effects. There is evidence to suggest that acupuncture may be an effective treatment modality. OBJECTIVE: The aim of this review is to summarize the existing evidence on acupuncture as a therapy for anxiety and depression in women and to present a novel method for assessing acupuncture trial quality. METHODS: Published randomized controlled trials were included, whereby acupuncture was compared with any control procedure in subjects with anxiety and/or depression. Two authors extracted data independently. A novel acupuncture trial quality-assessment tool was developed to analyze the literature quality. RESULTS: Six articles used the desired inclusion and exclusion criteria. The quality of research varied heavily. Five studies were properly randomized. Three were double-blinded. Three used individualized acupuncture. Four studies were of at least reasonable quality. One was of marginal quality, and one was of poor quality. There was a significant difference between acupuncture and at least one control in all six trials. CONCLUSIONS: With respect to six reviewed studies, there is high-level evidence to support the use of acupuncture for treating major depressive disorder in pregnancy. PMID- 24761172 TI - Acupoint Stimulation for Acne: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Acupoint stimulation-including acupuncture, moxibustion, cupping, acupoint injection, and acupoint catgut embedding-has shown a beneficial effect for treating acne. However, comprehensive evaluation of current clinical evidence is lacking. OBJECTIVE: The aim of this review was to assess the effectiveness and safety of all acupoint stimulation techniques used to treat acne vulgaris. DESIGN: A systematic review was conducted. It included only randomized controlled trials on acupoint stimulation for acne. Six electronic databases were searched for English and Chinese language studies. All searches ended in May 2012. Studies were selected for eligibility and assessed for quality. RevMan 5.1 software was used for data analysis with an effect estimate presented as risk ratios (RR) or mean difference (MD) with a 95% confidence interval (CI). PATIENTS: Studies with subjects who were diagnosed with acne vulgaris, or papulopustular, inflammatory, adolescent, or polymorphic acne-regardless of gender, age, and ethnicity-were included. INTERVENTION: Interventions included any acupoint stimulation technique such as acupuncture, moxibustion, cupping, acupoint injection, and acupoint catgut embedding-compared with no treatment, placebo, or conventional pharmaceutical medication. MAIN OUTCOME MEASURE: Reduction of signs and symptoms and presence of adverse effects were examined. RESULTS: Forty-three trials involving 3453 patients with acne were included. The methodological quality of trials was generally poor in terms of randomization, blinding, and intention-to treat analysis. Meta-analyses showed significant differences in increasing the number of cured patients between acupuncture plus herbal medicine and herbal medicine alone (RR: 1.60; 95% CI: 1.19-2.14; P=0.002), and between acupuncture plus herbal facial mask and herbal facial mask alone (RR: 2.14; 95% CI: 1.29 3.55; P=0.003). Cupping therapy was significantly better than pharmaceutical medications for increasing the number of cured patients (RR: 2.11; 95% CI: 1.45 3.07; P<0.0001). Serious adverse events were not reported in all included trials. CONCLUSIONS: Acupoint stimulation therapies combined with other treatments appears to be effective for acne. However, further large, rigorously designed trials are needed to confirm these findings. PMID- 24761173 TI - The Role of Scalp Acupuncture for Relieving the Chronic Pain of Degenerative Osteoarthritis: A Pilot Study of Egyptian Women. AB - BACKGROUND: Osteoarthritis (OA) is a common chronic and painful condition secondary to deterioration of cartilage. OA-related pain can be managed pharmacologically together with complementary therapies, such as acupuncture. OBJECTIVE: The aim of this trial was to evaluate the effectiveness of Yamamoto New Scalp Acupuncture (YNSA) for relieving pain associated with OA in Egyptian women. DESIGN AND SETTING: At the Female Outpatient Pain Clinic, of the National Research Centre, in Cairo, Egypt, between March 2008 and June 2009, 30 females (ages 27-80) presenting with chronic pain caused by OA were studied. INTERVENTION: The affected YNSA points were treated for 20 minutes in a single session. MAIN OUTCOME MEASURE: Pain was assessed by a visual analogue scale (VAS) prior to, and 1 hour after, the intervention. RESULTS: PREINTERVENTION VAS SCORES WERE: 3-10 (mean 7.43+/-1.9; P>0.05). Postintervention VAS scores ranged from 0 to 8 (mean 3.37+/-2.1) with a statistically significant positive correlation between these scores and pretreatment values (P=0.01). Postintervention VAS scores were significantly related to pain locations. Post-hoc analysis showed statistically significant lower postintervention VAS scores for cervical OA, compared to those of lumbosacral OA. CONCLUSIONS: YNSA acupuncture is effective in immediate pain relief among females suffering from degenerative OA. PMID- 24761174 TI - Recurrent Pregnancy Loss and Traditional Chinese Medicine. AB - BACKGROUND: Recurrent pregnancy loss (RPL) can present with coexistent subfertility caused by diminished ovarian reserve (DOR). Recent texts suggest that Traditional Chinese Medicine (TCM) may improve pregnancy outcomes for women with RPL. OBJECTIVE: This article reports the outcome of the treatment of a female of advanced maternal age. She had diagnoses of DOR and RPL. DESIGN SETTING AND PATIENT: This 42-year-old patient with DOR and RPL presented in a private acupuncture practice, located in Bellevue, WA. INTERVENTION: The patient received TCM treatment that involved weekly acupuncture and Chinese herbal therapy from June 2006 to May 2007. MAIN OUTCOME MEASURES: The outcome sought was a live birth after 24 weeks of gestation. RESULTS: After another miscarriage in September 2006, this patient conceived a viable pregnancy in December 2006, after 6 months of treatment. She continued treatment through 20 weeks and delivered a healthy son at 39.5 weeks of gestation. CONCLUSIONS: Subfertile women with RPL may benefit from TCM treatment. More research is needed to examine the safety and effectiveness of TCM as a treatment for RPL. PMID- 24761175 TI - Research on Acupuncture in Pregnancy and Childbirth: The U.S. Contribution. AB - BACKGROUND: Along with an increasing use of acupuncture to treat pregnancy and childbirth concerns comes a need to assess the current state of related research, which is a critical step in defining a research agenda. OBJECTIVE: The goal of this article is to analyze the U.S. contribution to obstetric acupuncture research against the backdrop of professional positions and relevant historical events. METHODS: Original obstetric acupuncture research articles published post 1998 (147) and pre-1998 (62) were reviewed. Studies were placed into topical categories (e.g., breech correction, labor, and delivery), and the current authors identified region of study origin, study focus and type, gestational timing of treatment, general study outcomes, and adverse events. U.S. study characteristics were analyzed relative to those of other regions. RESULTS: The number of obstetric acupuncture publications more than tripled from pre- to post 1998, and the United States ranked third (behind the European region and China) in published articles. One case study indicated a serious adverse effect. Most post-1998 U.S. articles focused on pregnancy concerns; those conducted in early pregnancy involved acupressure. Acupuncture benefits varied by study topic. CONCLUSIONS: U.S. studies reflected greater effort toward treating pregnancy related problems, compared to childbirth and postpartum concerns. The U.S. research contribution is discussed within the context of health care system structure, professional concerns, funding, and the role of conventional biomedical care in advancing a successful research agenda. PMID- 24761176 TI - Inhibitory Effect of Acupuncture on Vibration-Induced Finger Flexion Reflex in Humans: Comparisons Among Radial, Median, and Ulnar Nerve Stimulation. AB - BACKGROUND: Vibration-induced finger flexion reflex (VFR) is inhibited with acupuncture to TE 5 or LI 4 at the skin innervated by the radial nerve. OBJECTIVE: The aim of this study was to determine if acupoints in regions innervated by the radial nerve are specific to inhibit VFR. MATERIALS AND METHODS: This experiment was performed using a crossover design with 3 acupuncture groups (needle insertion to the right LU 11, PC 9, or SI 1) and a control group (no needle treatment). Each acupoint was randomly needled on separate days. Ten healthy volunteers were recruited for this study. VFR was induced by applying vibration on the volar side of the right middle fingertip. An acupuncture needle was inserted in the acupoint and retained for 5 minutes. For the main outcome measure, maximum finger flexion force (MFFF) was measured during vibration and was compared among four groups. RESULTS: MFFFs in the acupuncture groups were significantly lower (p<0.05) than that in the control group. However, no significant difference was observed in MFFFs in the three intervention groups after acupuncture to LU 11, PC 9, and SI 1. CONCLUSIONS: Acupuncture to the right LU 11, PC 9, or SI 1 point inhibited the ipsilateral VFR, which suggests that afferent inputs from the radial nerve with needle insertion were not specific, compared with those from the median and ulnar nerves to suppress neuronal activities in the VFR reflex circuits. PMID- 24761177 TI - Acupuncture Evoked Response in Contralateral Somatosensory Cortex Reflects Peripheral Nerve Pathology of Carpal Tunnel Syndrome. AB - BACKGROUND: Most neuroimaging studies exploring brain response to different acupoints have been performed in healthy adults. OBJECTIVE: The aim of this study was to compare brain responses to acupuncture at local versus distal acupoints in patients with carpal tunnel syndrome (CTS), who have chronic pain, versus healthy controls (HC) and correlate these responses with median nerve function. MATERIALS AND METHODS: Brain response to electroacupuncture (EA; 2Hz) was evaluated with event-related functional MRI (fMRI) in patients with CTS (n=37) and age-matched HC (n=30). EA was applied at acupoints local (PC 7 to TW 5) and distal (SP 6 to LV 4) to the CTS lesions. RESULTS: Brain response in both groups and acupoints included activation of the bilateral secondary somatosensory cortex (S2) and insula, and the contralesional primary somatosensory cortex (cS1). Deactivation was noted in ipsilesional primary somatosensory cortex (S1). A significant difference between local and distal acupoints was found in cS1 for HC, but not CTS. Furthermore, cS1 activation by EA at local acupoints was negatively correlated with median nerve peak sensory latency in HC, but was positively correlated in CTS. No correlation was found for EA at distal acupoints for either group. CONCLUSIONS: Brain response to EA differs between CTS and HC and, for local acupoint stimulation, is associated with median nerve function, reflecting the peripheral nerve pathophysiology of CTS. PMID- 24761178 TI - Safety of Noninvasive Electrical Stimulation of Acupuncture Points During a Routine Neonatal Heel Stick. AB - BACKGROUND: Hospitalized infants may undergo frequent painful procedures with inadequate pain relief. Alternative pain relief interventions are needed. OBJECTIVE: The aim of this research was to determine the safety of noninvasive electrical stimulation of acupuncture points (NESAP) in neonates who were receiving routine heel sticks. DESIGN: This was a descriptive study performed to assess the safety of using a transcutaneous electrical nerve stimulation (TENS) unit to deliver NESAP to neonates. SETTING/SUBJECTS: The subjects were healthy newborn infants<3 days old before hospital discharge. INTERVENTION: The intervention was NESAP delivered via a TENS unit, administered before, during, and after heel stick. The electrodes of the TENS unit were applied at four acupuncture points. Settings were gradually increased: 6 infants received 1.0 mA, 2 Hz; the second 6 infants received 2.0 mA, 10 Hz; and the last 18 infants received 3.5 mA, 10 Hz. MAIN OUTCOME MEASURES: THREE MAIN MEASURES WERE USED: (1) skin assessment (2) vital signs; (3) pain scores using the Premature Infant Pain Profile (PIPP). RESULTS: There were no significant changes in vital signs during and after NESAP. There were no changes in PIPP scores in the first 12 infants after initiation of NESAP. A slight but nonsignificant increase in PIPP scores (from 2.65 to 3.5 on a scale of 0-18) occurred in the last 18 infants. There were no adverse events during or after NESAP. CONCLUSIONS: NESAP is safe for infants with low settings on a TENS unit. PMID- 24761179 TI - Acupuncture as an Adjunct Treatment for Primary Dysmenorrhea: A Comparative Study. AB - BACKGROUND: Primary dysmenorrhea occurs 40%-50% in women of reproductive age. Acupuncture may assist treatment of menstrual pain. OBJECTIVE: This study compared the effects of the acupuncture program Chongmai, or Thoroughfare Vessel (TV), to sham acupuncture on primary dysmenorrhea. METHODS: The current authors selected 3 groups of 10 patients each with primary dysmenorrhea for this comparative, prospective longitudinal study. The first group was treated at the TV points, the second group underwent sham acupuncture, and the third group (control) did not receive any kind of acupuncture. All groups were allowed to use steroidal anti-inflammatory drugs (NSAIDs). Menstrual pain was measured using a visual analogue scale (VAS). The results were analyzed using a Student's-t test in GraphPad Prism 5.0. Acupuncture needles were applied at the following TV acupuncture points: (1) Gongsun (SP 4); (2) Qichong (ST30); (3) Neiguan (PC 6); and (4) Baihuanshu (BL 30), the metameric action point of the pelvic area. Electrical stimulation was applied through each needle at 120 Hz for 40 minutes. RESULTS: TV acupuncture, sham acupuncture, and/or NSAIDs substantially reduced pain in all 10 patients in each respective group (100%). TV acupuncture treatment reduced the symptoms of primary dysmenorrhea, and symptoms were reduced for at least 6 months. Application of needles at simulated points away from the TV acupuncture program did not reduce pain significantly. CONCLUSIONS: TV acupuncture treatment can reduce the symptoms of primary dysmenorrhea, and the effect can last for 6 months. PMID- 24761181 TI - Abstracts and Commentaries on Key Articles in the Literature. PMID- 24761180 TI - An Historical Review and Perspective on the Impact of Acupuncture on U.S. Medicine and Society. AB - BACKGROUND: It took almost 300 years for Europe and 400 years for the United States to finally appreciate the therapeutic value of acupuncture. Findings from basic medical research that acupuncture stimulation causes release of endorphins, serotonin, enkephalins, and gamma-amino-butyric acid (GABA; a major inhibitory neurotransmitter of the brain), norepinephrine, and dopamine helped to explain the acupuncture effect on a biomedical and pharmacological basis that was acceptable to the Western medical establishment. CONTEXT: In the United States, there is significantly increased familiarity with acupuncture and U.S. patients have sought acupuncture treatment to relieve stress-related syndromes, to enhance the immune system, to reduce insomnia, to improve athletic performance, and to address Alzheimer's disease, as well as for cardiac and poststroke therapy. This article briefly reviews the history of acupuncture in the United States and discusses the potential of this modality in the the future. DISCUSSION: Acupuncture can be combined with conventional Western medicine for pain management in patient with cancer to reduce dosages of narcotic medications, side effects, adverse reactions, and the possibility of narcotic addiction. Because of acupuncture's increased popularity, acupuncture training schools have been set up in the United States, and some insurance companies cover acupuncture therapy. CONCLUSIONS: By studying both Eastern and Western medicine and using them in a complementary fashion, we open ourselves to many discoveries for the benefit of humanity. PMID- 24761182 TI - Medical Acupuncture: Past, Present, and Future. PMID- 24761183 TI - Insurance Reimbursement: An Expert Discussion on Best Practices and Avoiding Pitfalls. AB - Medical Acupuncture's Editor-in-Chief, Richard C. Niemtzow, MD, PhD, MPH, and Marshall Sagar, DO, DABMA, FAAMA, conducted a Roundtable Discussion with experienced medical acupuncturists-Claudia Cooke, MD, FACP, MPH, Aaron Michelfelder, MD, FAAFP, FAAMA, and Ali Safayan, MD-to discuss best insurance billing strategies related to their scope of practice and geographical locations, and related to compliance with the eventual changes from the Affordable Healthcare Act. This Roundtable offers valuable insight for frequently asked questions from both new and seasoned medical acupuncturists. The Journal welcomes further comments from the readership. PMID- 24761184 TI - Efficacy and Safety of Needle Acupuncture for Treating Gynecologic and Obstetric Disorders: An Overview. AB - Background: Acupuncture is being used increasingly to treat gynecologic and obstetric disorders. Objective: The aim of this review was to determine the efficacy and safety of acupuncture for treating pelvic and low-back pain during pregnancy, pain during labor, primary dysmenorrhea, and menopausal symptoms. Design: This is an overview of systematic reviews (SRs) and randomized controlled trials (RCTs). Search strategy: A literature search was conducted, in July 2010, in MEDLINE,(r) the Cochrane Database of Systematic Reviews, CENTRAL, the Database of Abstracts of Reviews of Effects, and Tripdatabase. Selection criteria: Published SRs and RCTs found during the literature search were included as well as RCTs that were published after completion of the literature search. Analysis: Data from SRs and RCTs that provided quantitative information were pooled. Results: Eight SRs and nine RCTs were included. One SR and 4 RCTs showed that acupuncture reduced pelvic and low-back pain, compared to physiotherapy or usual prenatal care. Results were contradictory when interventions were compared with sham acupuncture. With respect to reduction of pain during labor, two SRs showed no differences between acupuncture and sham acupuncture. None of the three SRs included on primary dysmenorrhea produced conclusive results. Two SRs of studies on menopausal symptoms showed no differences between acupuncture and sham acupuncture. A meta-analysis of three additional RCTs identified a favorable effect of acupuncture for reducing frequency and intensity of hot flashes. Adverse effects were mild and infrequent. Conclusions: Evidence for the efficacy of needle acupuncture for treating the disorders evaluated remains inconclusive. The intervention showed promising results for reducing pelvic and back pain during pregnancy and climacteric vasomotor symptoms, although well-designed studies are needed to make the results more precise and reliable. PMID- 24761185 TI - Traditional Chinese Medicine as a Basis for Treating Psychiatric Disorders: A Review of Theory with Illustrative Cases. AB - Background: Integrative medicine is becoming increasingly accepted in the global scheme of health care. Traditional Chinese Medicine (TCM) is often included among integrative medicine modalities. Objective: This article provides a background for integration of acupuncture and other TCM-derived approaches to managing psychiatric conditions. Methods: Classical theories of TCM that pertain to psychiatric conditions are reviewed, focusing on concepts of energetic imbalance, the implications of mind-body-spirit connections, and treatment strategies that involve TCM modalities. An example of correlation between TCM patterns of disharmony and the Western diagnosis of generalized anxiety disorder (GAD) is given, along with an illustrative case in which counseling, medications, and acupuncture were combined in treatment. TCM principles are incorporated in certain energy psychology modalities, such as Emotional Freedom Technique (EFT). A case is presented demonstrating the integration of energy psychology with acupuncture, Qigong and hypnosis as an avenue for releasing pathogenic emotions. In classical TCM theory, assessing and treating spiritual disharmonies is fundamental for dealing with emotional disorders. Practical application in a clinical case is described. Conclusions: TCM offers a cogent theoretical basis for assessing and clinically managing patients presenting with mental health issues. TCM principles integrate well with other systems, including Western medicine. PMID- 24761186 TI - Tongue Inspection in TCM: Observations in a Study Sample of Patients Living with HIV. AB - Background: One of the principal diagnostic methods in Traditional Chinese Medicine (TCM) is the inspection of the tongue. This method involves examination of the shape, size, color, and texture of the tongue body and coat and helps reveal the state of organ functions and progression of conditions. Literature on tongue observations for patients who have human immunodeficiency virus (HIV) is minimal. Objective: The goal of this study was to provide a clinical "snapshot" of initial tongue assessments of 159 patients living with HIV, who participated in an acupuncture clinical trial for chronic nausea. The aim was to explore the similarities and differences observed in tongue assessments. Design: This study was part of a prospective, randomized, controlled, double-blinded (subjects and evaluators), parallel-groups, acupuncture clinical trial for treating chronic nausea. Setting: The study was conducted at a large urban New York City academic health center. Patients: The patients in this study were 159 individuals who had HIV infections and who had histories of chronic nausea for >=3 months. Main Outcome Measures: Initial tongue assessments were recorded for seven basic characteristics: (1) tongue color; (2) tongue shape; (3) tongue body quality; (4) coat color; (5) coat weight; (6) coat surface; and (7) tongue action. Results: The overall tongue picture seen in these patients was that the tongue was swollen and toothmarked, had a pink body with cracks, and had a thick, dry white coat. Conclusions: The HIV disease itself and the use of long term medications affect the Blood, Qi, Yin, and Yang. The observation of the tongue provides a window into the process of the disease and, ultimately, insight for clinical care. This sample population snapshot illustrates the complex processes seen in long-term chronic conditions managed by pharmacologic medications. PMID- 24761187 TI - Positioning Standardized Acupuncture Points on the Whole Body Based on X-Ray Computed Tomography Images. AB - Objective: The goal of this research was to position all the standardized 361 acupuncture points on the entire human body based on a 3-dimensional (3D) virtual body. Materials and Methods: Digital data from a healthy Korean male with a normal body shape were obtained in the form of cross-sectional images generated by X-ray computed tomography (CT), and the 3D models for the bones and the skin's surface were created through the image-processing steps. Results: The reference points or the landmarks were positioned based on the standard descriptions of the acupoints, and the formulae for the proportionalities between the acupoints and the reference points were presented. About 37% of the 361 standardized acupoints were automatically linked with the reference points, the reference points accounted for 11% of the 361 acupoints, and the remaining acupoints (52%) were positioned point-by-point by using the OpenGL 3D graphics libraries. Based on the projective 2D descriptions of the standard acupuncture points, the volumetric 3D acupoint model was developed; it was extracted from the X-ray CT images. Conclusions: This modality for positioning acupoints may modernize acupuncture research and enable acupuncture treatments to be more personalized. PMID- 24761188 TI - Scientific Basis of Auriculotherapy: State of the Art. AB - Background: Using a modern scientific basis, this article examines clinical findings and experimentally reproducible data that demonstrate reliably the objective reality of the auriculotherapy procedures initiated by Paul Nogier, MD, of Lyon, France. Objective: The aims of this review are to: (1) identify the Chinese acupoints and all relevant related subjects; (2) offer a critical analysis of different auricle cartographies or ear maps; and (3) evaluate evidence for auriculotherapy with respect to the constant progress of our knowledge of nervous-system organization. Discussion: Acupuncture points have lower electrical impedance than nonacupoints. This was demonstrated by Niboyet and Terral, utilizing a sinusoidal current with the technical arrangements of different equivalent circuits made at Unit 103 of the French National Institute of Health and Medical Research (INSERM), Montpellier, France. This work demonstrated that physical behavior associated with acupuncture corresponds to a specific histologic structure located within the dermis termed the neurovascular complex (NVC). The concept of using sham points for testing acupuncture needs to be criticized. A reproducible experimental model of analgesia has been produced using the hind limb of a rabbit; this model is a proven demonstration of the positive action of acupuncture on pain. Acupuncture analgesia is a technique that has been used effectively by Chinese researchers in the 1970s for surgical applications. The different ear maps may have to be significantly modified because of the paucity of scientific validation of most of the localizations of organs or functions and, particularly, of nervous structures. Increased knowledge about complex nervous interactions should facilitate formulation of some scientifically acceptable hypothesis to explain the action of auriculotherapy. Conclusions: More scientific research should be performed to improve the scientific credibility of auriculotherapy. PMID- 24761190 TI - Conformational Substates of Myoglobin Intermediate Resolved by Picosecond X-ray Solution Scattering. AB - Conformational substates of proteins are generally considered to play important roles in regulating protein functions, but an understanding of how they influence the structural dynamics and functions of the proteins has been elusive. Here, we investigate the structural dynamics of sperm whale myoglobin associated with the conformational substates using picosecond X-ray solution scattering. By applying kinetic analysis considering all of the plausible candidate models, we establish a kinetic model for the entire cycle of the protein transition in a wide time range from 100 ps to 10 ms. Four structurally distinct intermediates are formed during the cycle, and most importantly, the transition from the first intermediate to the second one (B -> C) occurs biphasically. We attribute the biphasic kinetics to the involvement of two conformational substates of the first intermediate, which are generated by the interplay between the distal histidine and the photodissociated CO. PMID- 24761189 TI - Protein identification problem from a Bayesian point of view. AB - We present a generic Bayesian framework for the peptide and protein identification in proteomics, and provide a unified interpretation for the database searching and the de novo peptide sequencing approaches that are used in peptide identification. We describe several probabilistic graphical models and a variety of prior distributions that can be incorporated into the Bayesian framework to model different types of prior information, such as the known protein sequences, the known protein abundances, the peptide precursor masses, the estimated peptide retention time and the peptide detectabilities. Various applications of the Bayesian framework are discussed theoretically, including its application to the identification of peptides containing mutations and post translational modifications. PMID- 24761191 TI - Acute Intravenous Injection Toxicity Study of Escherichia coli-Derived Recombinant Human Bone Morphogenetic Protein-2 in Rat. AB - STUDY DESIGN: Prospective in vivo toxicity study. PURPOSE: To evaluate the conducted acute toxicity study of Escherichia coli (E. coli)-derived recombinant human bone morphogenetic protein-2 (rhBMP-2) with 6-weeks old Sprague-Dawley rats. OVERVIEW OF LITERATURE: rhBMP-2 has well-known osteoinductivity and it is used as a bone graft substitute. E. coli-derived rhBMP-2 can be mass-produced with relatively low costs. E. coli-derived rhBMP-2 facilitates osteoblastic differentiation and bone formation in vitro and in vivo. However, studies regarding side effects or toxicity of E. coli-derived rhBMP-2 have not been published. Thus, we conducted the acute toxicity study of E. coli-derived rhBMP-2 on 6-weeks old Sprague-Dawley rats. METHODS: One mg of BMP-2 was diluted in 0.285 mL of glycine buffer to prepare high BMP-2 concentrations (3.5 mg/mL). Intermediate (0.9 mg/mL) or low (0.35 mg/mL) concentrations of BMP-2 solution was prepared by serial dilutions. The compound was administrated at a dose of 0, 0.7, 1.8, 7 mg/kg by single intravenous injection to five of male and female rats. After the injection, the gross general observations including changes of body weight and histopathological analysis was performed for 14 days. RESULTS: No animal was found dead during the experiment and the body weight changes were both statistically insignificant in the control and experimental groups. No abnormal sign was shown in general observations and autopsy examinations. CONCLUSIONS: Thus, the lethal dose of E. coli-derived rhBMP-2 should be higher than 7 mg/kg with a single intravenous injection. PMID- 24761192 TI - Outcomes of fluoroscopically guided lumbar transforaminal epidural steroid injections in degenerative lumbar spondylolisthesis patients. AB - STUDY DESIGN: A prospective cohort. PURPOSE: To report the short and long term outcomes of fluoroscopically guided lumbar transforaminal epidural steroid injection (TFESI) in degenerative lumbar spondylolisthesis (DLS) patients. OVERVIEW OF LITERATURE: TFESI has been widely used for the treatment of lumbosacral radicular pains. However, to our knowledge, there has been no study which has evaluated the outcomes of TFESI in patients with DLS. METHODS: The DLS patients received fluoroscopically guided lumbar TFESI with 80 mg of methylprednisolone and 2 mL of 1% lidocaine hydrochloride. Patients were evaluated by an independent observer before the initial injection, at 2 weeks, at 6 weeks, at 3 months, and at 12 months after the injections. Visual analog scale (VAS), Roland 5-point pain scale, standing tolerance, walking tolerance, and patient satisfaction scale were evaluated for outcomes. RESULTS: Thirty three DLS patients treated with TFESI, who were completely followed up, were included in this study. The average number of injections per patient was 1.9 (range from 1 to 3 injections per patient). Significant improvements in VAS and Roland 5-point pain scale were observed over the follow up period from 2 weeks to 12 months. However, the standing and walking tolerance were not significantly improved after 2 weeks. At 2 weeks, the patient satisfaction scale was highest, although, these outcomes declined with time. The DLS patients with one level of spinal stenosis showed significantly better outcome than the DLS patients with two levels of spinal stenosis. Five patients (13%) underwent surgical treatment during the 3 to 12 months follow up. CONCLUSIONS: TFESI provides short term improvements in VAS and Roland 5-point pain scale, standing tolerance, walking tolerance and patient satisfaction scale in DLS patients. In the long term, it improves VAS but limits the improvements in Roland 5-point pain scale, standing tolerance, walking tolerance and patient satisfaction scale. PMID- 24761193 TI - Demineralized bone matrix, as a graft enhancer of auto-local bone in posterior lumbar interbody fusion. AB - STUDY DESIGN: A case controlled study with prospective data collection. PURPOSE: To evaluate the early influence and the final consequence of demineralized bone matrix (DBM) on auto-local bone as a graft enhancer in posterior lumbar interbody fusion (PLIF). OVERVIEW OF LITERATURE: DBM is known as an osteoinductive material; however, it has not been clearly recognized to enhance auto-local bone with a small amount. METHODS: Patients who had a PLIF were allocated into two groups. Group I (70 cases) used auto-local bone chips and group II (44 cases) used DBM as an additive to auto-local bone, 1 mL per a segment. Group selection was alternated. Early assessment was performed by computed tomography at 6 months and final assessment was done by simple radiography after 24 months at least. The degree of bone formation was assessed by 4 grade scale. RESULTS: The subjects of both groups were homogenous and had similar Oswestry Disability Index at final assessment. The ratio of auto-local bone chips and DBM was 6:1. The degree of bone formation at 6 months after surgery was superior in group II. However, there was no significant difference between the two groups at the final assessment. CONCLUSIONS: DBM was not recognized to enhance auto-local bone with small amount. PMID- 24761194 TI - Spinous process osteotomy to facilitate the access to the spinal canal when decompressing the spinal canal in patients with lumbar spinal stenosis. AB - STUDY DESIGN: Retrospective study. PURPOSE: The main purpose of this study was to investigate the union-rate of the spinous process after performing a spinous process osteotomy and whether union affects the clinical results after surgery. OVERVIEW OF LITERATURE: In the present study, spinous process osteotomy was used to facilitate access to the spinal canal when performing a decompressive procedure for lumbar spinal stenosis. The aim of this study was to evaluate the union rate of the spinous process and its effect on the clinical results of the procedure. METHODS: All patients were included in the study that underwent a decompressive procedure through spinous process osteotomy be between January 1, 2007 and December 31, 2007. Operation protocols were reviewed. A computed tomography (CT) scan was performed to evaluate the union of the osteotomies of the spinous process. According to the CT-scans, patients were divided into three groups: "complete-union," "partial-union," and "non-union." Patients reported their clinical results through a self-administered questionnaire. RESULTS: The mean period of follow up was 21.6 months (range, 16-28 months). A total of 44% of the performed osteotomies were considered as united. Ten patients (18%) were classified as "complete-union," 30 patients (55%) as "partial-union," and 15 patients (27%) as "non-union." The "complete-union" group showed better clinical results and scored significantly better in the Oswestry Disability Index and EQ 5D. However, no statistical difference was found in the pain-scores. There were no differences between the "partial-union" group and the "no-union" group. CONCLUSIONS: We found a radiologic union for 60 out of 135 (44%) spinous process osteotomies. PMID- 24761195 TI - A new electrophysiological method for the diagnosis of extraforaminal stenosis at L5-s1. AB - STUDY DESIGN: A retrospective study. PURPOSE: To examine the effectiveness of using an electrodiagnostic technique as a new approach in the clinical diagnosis of extraforaminal stenosis at L5-S1. OVERVIEW OF LITERATURE: We introduced a new effective approach to the diagnosis of extraforaminal stenosis at the lumbosacral junction using the existing electrophysiological evaluation technique. METHODS: A consecutive series of 124 patients with fifth lumbar radiculopathy were enrolled, comprising a group of 74 patients with spinal canal stenosis and a second group of 50 patients with extraforaminal stenosis at L5-S1. The technique involved inserting a pair of needle electrodes into the foraminal exit zone of the fifth lumbar spinal nerves, which were used to provide electrical stimulation. The compound muscle action potentials from each of the tibialis anterior muscles were recorded. RESULTS: The distal motor latency (DML) of the potentials ranged from 11.2 to 24.6 milliseconds in patients with extraforaminal stenosis. In contrast, the DML in patients with spinal canal stenosis ranged from 10.0 to 17.2 milliseconds. After comparing the DML of each of the 2 groups and at the same time comparing the differences in DML between the affected and unaffected side of each patient, we concluded there were statistically significant differences (p<0.01) between the 2 groups. Using receiver operating characteristic curve analysis, the cutoff values were calculated to be 15.2 milliseconds and 1.1 milliseconds, respectively. CONCLUSIONS: This approach using a means of DML measurement enables us to identify and localize lesions, which offers an advantage in diagnosing extraforaminal stenosis at L5-S1. PMID- 24761196 TI - Clinical findings and results of surgical resection of thoracolumbar osteoid osteoma. AB - STUDY DESIGN: Descriptive, cases series study. PURPOSE: To evaluate clinical findings and results of treatment of patients with spinal osteoid osteoma who underwent surgery. OVERVIEW OF LITERATURE: Osteoid osteoma is a benign tumor with spinal involvement rate of about 10%. It is manifested during adolescence with symptoms such as painful scoliosis. To treat the problem, operation on the patients and excising the nidus are suggested. METHODS: This descriptive study was conducted on 11 patients with spinal osteoid osteoma at our orthopedic educational center. All patients were treated through open surgery and nidus curettage. All samples were pathologically confirmed. Imaging methods (spiral computed tomography-scan) was used in preoperative planning. Scoliosis and other clinical findings were studied. RESULTS: The study was conducted on 11 patients comprising 6 females (54.5%) and 5 males (45.5%) with the mean age of 14.6 years. Mean deviation of scoliosis resulting from spinal osteoid osteoma was 22.8 degrees. There was more scoliosis in the involvement of the lumbar vertebra. In comparison with adults, scoliosis was more severe in youths. There was one case of vertebra body involvement with manifestation of painful scoliosis. Due to lack of careful preoperative examination, the surgery was repeated for this case. No sign of recurrence was observed in patients who underwent open surgery and all scoliosis in the follow-up had improved. CONCLUSIONS: Based on our findings, surgical excision of spinal ostoeid osteoma was successful and complete recovery was achieved in spinal deformity in the course of follow-up. Scoliosis is often seen during adolescence and lumbar involvement is more severe. PMID- 24761197 TI - C2 pars/pedicle screws in management of craniocervical and upper cervical instability. AB - STUDY DESIGN: A retrospective study. PURPOSE: To evaluate the efficacy and the safety of craniocervical and upper cervical stabilization by using C2 pars/pedicle screw fixations. OVERVIEW OF LITERATURE: The management of craniocervical and upper cervical instability has progressed over the past two decades due to good achievements in the instrumentation and the increased awareness on spinal anatomy and biomechanics. However, there is insufficient studies or solid conclusions on this topic, thus, we tried to investigate and present our findings. METHODS: Twenty-two patients were operated upon and were followed up from March 2008 to October 2010. One patient had craniocervical instability (post-surgical), 15 patients had atlantoaxial instability of different etiologies (trauma, tumors, inflammatory and degenerative) and 6 patients had hangman fractures. Patients' ages ranged from 18 to 52 years old. with 5 female patients and 17 male patients. RESULTS: Radiological follow ups performed immediately post-operation showed good screw positioning and complete reductions in nearly all the cases. All patients were followed up for more than one year. Sound fusions were observed among all patients. CONCLUSIONS: The use of pars/pedicle screws is a very effective, sound, safe and easy surgical modality for treating craniocervical, atlantoaxial and upper cervical instabilities. Increasing studies for the biomechanics of this important region and longer periods of follow-ups are necessary to document the usefulness of this modality when treating such patients. PMID- 24761198 TI - Role of coflex as an adjunct to decompression for symptomatic lumbar spinal stenosis. AB - STUDY DESIGN: Prospective cohort study. PURPOSE: To assess whether additional implantation of Coflex following spinal decompression provided better clinical outcomes compared to decompression alone for symptomatic lumbar spinal stenosis (LSS) and to determine whether improvement in clinical outcomes correlated with changes in the radiological indices studied. OVERVIEW OF LITERATURE: Literature on benefits of additional Coflex implantation compared to decompression alone for symptomatic LSS is limited. METHODS: Patients with symptomatic LSS who met the study criteria were offered spinal decompression with Coflex implantation. Those patients who accepted Coflex implantation were placed in the Coflex group (n=22); while those opting for decompression alone, were placed in the comparison group (n=24). Clinical outcomes were assessed preoperatively, six-months, one-year and two-years postoperatively, using the Oswestry disability index, 100 mm visual analogue scale (VAS)-back pain and VAS-leg pain, and short form-36 (SF-36). Radiological indices (disc height, foraminal height and sagittal angle) were assessed preoperatively, six months, one year, and two years postoperatively. RESULTS: Both groups showed statistically significant (p<0.001) improvement in all the clinical outcome indicators at all points in time as compared to the preoperative status. However, improvement in the Coflex group was significantly greater (p<0.001) than the comparison group. Changes in the radiological indices did not correlate significantly with the improvement in clinical outcome indicators. CONCLUSIONS: Additional Coflex implantation after spinal decompression in symptomatic LSS offers better clinical outcomes than decompression alone in the short-term. Changes in radiological indices do not correlate with the improvements in clinical outcomes after surgery for symptomatic LSS. PMID- 24761199 TI - Clinical and radiological outcomes of segmental spinal fusion in transforaminal lumbar interbody fusion with spinous process tricortical autograft. AB - STUDY DESIGN: A retrospective study. PURPOSE: To investigate clinical and radiological outcomes when using spinous process as a tricortical autograft for segmental spinal fusion in transforaminal lumbar interbody fusion (TLIF). OVERVIEW OF LITERATURE: Interbody spinal fusion is one of the important procedures in spinal surgery. Many types of autografts are harvested at the expense of complications. Clinical and radiographic results of patients who underwent TLIF with intraoperative harvested spinous process autograft in Prasat Neurological Institue, Bangkok, Thailand, were assessed as new technical innovation. METHODS: Between October 2005 to July 2009, 30 cases of patients who underwent TLIF with spinous process tricortical autograft were included. Clinical evaluations were assessed by visual analog scales (VAS) and Prolo functional and economic scores at the preoperation and postoperation and at 2 years postoperation. Static and dynamic plain radiograph of lumbar spine were reviewed for achievement of fusion. RESULTS: Initial successful fusion time in lumbar interbody fusion with spinous process tricortical autograft was 4.72 months (range, 3.8-6.1 months) postoperation and 100% fusion rate was reported at 2 years. Our initial successful fusion time in lumbar interbody fusion was compared to the other types of grafts in previous literatures. CONCLUSIONS: The use of intraoperative harvested spinous process tricortical autograft has overcome many disadvantages of harvesting autograft with better initial successful fusion time (4.72 months). VAS and Prolo scores showed some improvement in the outcomes between the preoperative and postoperative periods. PMID- 24761200 TI - Surgical management of pyogenic discitis of lumbar region. AB - STUDY DESIGN: Retrospective review of patients who had pyogenic discitis and were managed surgically. PURPOSE: To analyze the bacteriology, pathology, management and outcome of pyogenic discitis of the lumbar region treated surgically. OVERVIEW OF LITERATURE: Surgical management of pyogenic discitis is still an infrequently used modality of treatment. METHODS: A total of 42 patients comprised of 33 males and 9 females who had pyogenic discitis with a mean age of 51.61 years (range, 16-75 years) were included in this study. All the cases were confirmed as having pyogenic discitis by pus culture report and histopathological examination. The mean follow-up period was 41.9 months. RESULTS: Debridement and posterior lumbar interbody fusion with autologous iliac bone graft was done in all cases. Thirteen (30.95%) patients had other medical co-morbidities. Five cases had a previous operation of the spine, and three cases had a history of vertebral fracture. Three patients were operated for gynaecological problems, and four cases had a history of urological surgery. L4-5 level was the most frequent site of pyogenic discitis. The most common bacterium isolated was Staphylococcus aureus (S. aureus). Radiologically good fusion was seen in the majority of patients. CONCLUSIONS: Pyogenic discitis should be suspected in people having pain and local tenderness in the spinal region with a rise in inflammatory parameters in blood. The most common bacterium was S. aureus, but there were still a greater number of patients infected with other types of bacteria. Therefore, antibiotics therapy should be started only after isolating the bacteria and making the culture sensitivity report. PMID- 24761201 TI - Role of decompression in late presentation of cervical spinal cord disorders. AB - STUDY DESIGN: Prospective study conducted at Jawaharlal Nehru Medical College, Datta Meghe Institute of Medical Sciences, Wardha, India. PURPOSE: To show the efficacy of decompression in the late presentation of cervical spinal cord disorders. OVERVIEW OF LITERATURE: Studies by various authors have shown that early spinal decompression results in better neurological outcomes. METHODS: From January 2003 to January 2005, 11 of the 41 patients with cervical spinal cord compression, meeting the inclusion criteria, underwent anterior decompression; interbody graft placement and stabilization by anterior cervical locking plate. The neurologic and functional outcomes were recorded. RESULTS: Five patients had spinal cord injury and 6 patients had compressive cervical myelopathy. Complications included 1 death and 1 plate loosening. No patient lost their preoperative neurological status. One patient had no improvement, 2 patients showed full recovery. The mean follow-up is 28.3 month. At the of rehabilitation, 6 were able to walk without support), 2 could walk with support, and 1 needed a wheelchair. The average American Spinal Injury Association motor score on admission to the hospital, 32.8 (standard deviation [SD], 30.5); admission to rehabilitation, 38.6 (SD, 32.4); discharge from rehabilitation, 46.2 (SD, 33.7). The most recent follow-up was 64.0 (SD, 35.3). CONCLUSIONS: The anterior approach for cervical decompression allows for adequate decompression. This decompression is the best chance offered in even late reported cases, including posttraumatic cases where there is no evidence of cord transactions. The use of anterior cervical plates reduces the chances of graft loosening, extruding, or collapsing. PMID- 24761202 TI - Effectiveness of preemptive analgesia using a frequency rhythmic electrical modulation system in patients having instrumented fusion for lumbar stenosis. AB - STUDY DESIGN: A randomized prospective study. PURPOSE: To assess postoperative analgesic requirements after Phyback therapy preemptively in patients undergoing lumbar stabilization. OVERVIEW OF LITERATURE: Frequency Rhythmic Electrical Modulation System is the latest method of preemptive analgesia. METHODS: Forty patients were divided into two groups. Patients who were to receive tramadol were allocated to "group A" and those who were to receive Phyback therapy were allocated to "group B." In patients with a visual analog scale score of >4 or a verbal rating scale score of >2, 75 mg of diclofenac IM was administered. The amount of analgesic consumption, the bolus demand dosage, and the number of bolus doses administered were recorded. Patient satisfaction was evaluated using the visual analog patient satisfaction scale. RESULTS: There were statistically significant differences in the visual analog scale and verbal rating scale scores in the fourth, sixth, 12th, and 24th hours. The number of bolus infusions was significantly lower in group B. The amount of analgesic consumption was higher in group A. There was a significant difference between the two groups in the number of bolus infusions and the total amount of analgesic consumption, and this comparison showed better results for group B. CONCLUSIONS: Application of Phyback therapy reduced postoperative opioid consumption and analgesic demand, and it contributed to reducing patients' level of pain and increased patient satisfaction. Moreover, the application of preemptive Phyback therapy contributed to reducing preoperative pain which may have reduced patient anxiety. PMID- 24761203 TI - Intraoperative Life Threatening Acute Lung Injury Due to Multiple Septic Pulmonary Emboli during Transpedicular Biopsy and Kyphoplasty. AB - A 55-year-old gentleman was presented to our clinic two months after a trivial fall with persistent pain, gibbus at the thoraco-lumbar junction and intact neurology. Radiological and laboratory investigations suggested osteoporotic fracture or metastasis. Due to unremitting pain, a plan was made to do transpedicular biopsy and kyphoplasty. Biopsy needles were inserted into both pedicles and an attempt at aspiration was made. Since the aspirate was dry, 5 to 6 mL of saline was injected through one needle and an attempt at aspiration was made through the other. Three-millilitres of sero-sanguineous material mixed with pus came out and kyphoplasty was deferred. After extubation, the patient developed severe bronchospasm and was transferred to the intensive care unit. Investigations confirmed multiple septic pulmonary emboli and the patient recovered completely after treatment. This report highlights that confirmation of the diagnosis is essential before performing any procedure that increases the intravertebral pressure and the place should have appropriate facilities to manage complications. PMID- 24761204 TI - Cervical perineural cyst masquerading as a cervical spinal tumor. AB - Tarlov (perineural) cysts of the nerve roots are common and usually incidental findings during magnetic resonance imaging of the lumbosacral spine. There are only a few case reports where cervical symptomatic perineural cysts have been described in the literature. We report such a case where a high cervical perineural cyst was masquerading as a cervical spinal tumor. PMID- 24761205 TI - Literature review and clinical presentation of cervical spondylitis due to salmonella enteritidis in immunocompetent. AB - A 48-year-old woman was presented to our clinic with some fever and neck pains for about one month. Based on the symptoms and results of image, an empirical diagnosis of tuberculous cervical spondylitis was made. The pain was not significantly decreased after anti-tuberculosis therapy. And, 3 weeks later, she was re-admitted to our hospital for the unbearable pain. An exploration of the C4/5 by the anterior medial approach was recommended to evaluate the germ and debridement. Bacteriological tests showed that the pathogen was Salmonella Enteritidis. The pain was relieved significantly after operation and sensitive antibiotic treatments. Infections with Salmonella Typhi or Salmonella Paratyphi have been well-documented, while there are few reports of cervical spondylitis caused by Salmonella Enteritidis. We reported a case of a healthy woman with whom pyogenic cervical spondylitis of Salmonella Enteritidis was corroborated and treated and reviewed according to previous reports about spondylitis caused by Salmonella Enteritidis in the literature. PMID- 24761206 TI - Risk factors for recurrent lumbar disc herniations. AB - The most common complication after lumbar discectomy is reherniation. As the first step in reducing the rate of recurrence, many studies have been conducted to find out the factors that may increase the reherniation risk. Some reported factors are age, sex, the type of lumbar disc herniation, the amount of fragments removed, smoking, alcohol consumption and the length of restricted activities. In this review, the factors studied thus far are summarized, excepting factors which cannot be chosen or changed, such as age or sex. Apart from the factors shown here, many other risk factors such as diabetes, family history, history of external injury, duration of illness and body mass index are considered. Few are agreed upon by all. The reason for the diverse opinions may be that many clinical and biomechanical variables are involved in the prognosis following operation. For the investigation of risk factors in recurrent lumbar disc herniation, large scale multicenter prospective studies will be required in the future. PMID- 24761207 TI - Comparison of pyogenic spondylitis and tuberculous spondylitis. AB - Pyogenic spondylitis and tuberculous spondylitis are common causes of spinal infection. It is difficult to differentiate tuberculous spondylitis and pyogenic spondylitis clinically and radiologically. Recently magnetic resonance imaging has been reported to be beneficial for early diagnosis and differential diagnosis of the spondylitis, and is being used extensively for diagnosis. However, the diagnosis must be considered in combination with corresponding changes in clinical manifestations, radiological findings, blood and tissue cultures and histopathological findings. Conservative treatments, including antimicrobial medications, are started initially. Surgical treatments, which include anterior or posterior approach, single-stage or two-stage surgery, with or without instrumentation, may be performed as indicated. PMID- 24761208 TI - Pedicle screw nut loosening: potentially avoidable causes of spine instrumentation failure. PMID- 24761209 TI - Surgery or chemoradiation for stage IB cervical cancer? How cost effectiveness impacts a complex decision. PMID- 24761210 TI - Creating and field-testing the questionnaire for the assessment of knowledge about cervical cancer and its prevention among schoolgirls and female students. AB - OBJECTIVE: The aim of this study was to develop and validate a questionnaire used to assess the level of general knowledge about cervical cancer, its primary and secondary prevention, and to identify sources of information about the disease among schoolgirls and female students. METHODS: THE QUESTIONNAIRE DEVELOPMENT PROCESS WAS DIVIDED INTO FOUR PHASES: generation of issues; construction of a provisional questionnaire; testing of the provisional questionnaire for acceptability and relevance; field-testing, which aimed at ensuring reliability and validity of the questionnaire. Field-testing included 305 respondents of high school female Caucasian students, who filled out the final version of the questionnaire. RESULTS: After phase 1, a list of 65 issues concerning knowledge about cervical cancer and its prevention was generated. Of 305, 155 were schoolgirls (mean age+/-SD, 17.8+/-0.5) and 150 were female students (mean age+/ SD, 21.7+/-1.8). The Cronbach alpha coefficient for the whole questionnaire was 0.71 (range for specific questionnaire sections, 0.60 to 0.81). Test-retest reliability ranged from 0.89 to 0.94. CONCLUSION: The Cervical-Cancer-Knowledge Prevention-64 has been successfully developed to measure the level of knowledge about cervical cancer. The results confirm the validity, reliability and applicability of the created questionnaire. PMID- 24761211 TI - The relationship between positive peritoneal cytology and the prognosis of patients with FIGO stage I/II uterine cervical cancer. AB - OBJECTIVE: The purpose of this study was to assess whether peritoneal cytology has prognostic significance in uterine cervical cancer. METHODS: Peritoneal cytology was obtained in 228 patients with carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics [FIGO] stages IB1-IIB) between October 2002 and August 2010. All patients were negative for intraperitoneal disease at the time of their radical hysterectomy. The pathological features and clinical prognosis of cases of positive peritoneal cytology were examined retrospectively. RESULTS: Peritoneal cytology was positive in 9 patients (3.9%). Of these patients, 3/139 (2.2%) had squamous cell carcinoma and 6/89 (6.7%) had adenocarcinoma or adenosquamous carcinoma. One of the 3 patients with squamous cell carcinoma who had positive cytology had a recurrence at the vaginal stump 21 months after radical hysterectomy. All of the 6 patients with adenocarcinoma or adenosquamous carcinoma had disease recurrence during the follow-up period: 3 with peritoneal dissemination and 2 with lymph node metastases. There were significant differences in recurrence-free survival and overall survival between the peritoneal cytology-negative and cytology-positive groups (log-rank p<0.001). Multivariate analysis of prognosis in cervical cancer revealed that peritoneal cytology (p=0.029) and histological type (p=0.004) were independent prognostic factors. CONCLUSION: Positive peritoneal cytology may be associated with a poor prognosis in adenocarcinoma or adenosquamous carcinoma of the uterine cervix. Therefore, the results of peritoneal cytology must be considered in postoperative treatment planning. PMID- 24761212 TI - Cost-utility analysis of treatments for stage IB cervical cancer. AB - OBJECTIVE: To analyze the cost-utility of two common clinical practices for stage IB cervical cancer patients from provider and societal viewpoints. METHODS: A DECISION TREE MODEL WAS CONDUCTED TO EXAMINE VALUE FOR EXPENDITURE BETWEEN THE FOLLOWING: (1) radical hysterectomy with pelvic lymph node dissection (RHPLND) with or without postoperative adjuvant therapy according to the risk of recurrence and (2) concurrent chemoradiotherapy (CCRT). The relevant studies were identified to extract the probability data, and meta-analysis was performed. Direct medical costs were estimated from hospital database and medical records review. Direct non-medical costs and utility parameters were obtained through interviews with patients to estimate quality-adjusted life years (QALYs) outcome. The time horizon was according to the life expectancy of Thai women. RESULTS: From provider viewpoint, RHPLND and CCRT resulted in approximate costs of US $5,281 and US $5,218, respectively. The corresponding costs from societal viewpoint were US $6,533 and US $6,335, respectively. QALYs were 16.40 years for RHPLND and 15.94 years for CCRT. The estimated incremental cost effectiveness ratio of RHPLND in comparison to CCRT from provider and societal viewpoints were US $100/QALY and US $430/QALY, respectively. RHPLND had more cost-effectiveness than CCRT if patients did not need adjuvant therapy. The most effective parameter in model was a direct medical cost of CCRT. At the current ceiling ratio in Thailand, RHPLND provides better value for money than CCRT, with a probability of 75%. CONCLUSION: RHPLND is an efficient treatment for stage IB cervical cancer. This advantage is only for patients who require no adjuvant treatment. PMID- 24761213 TI - Survival analysis of endometrial cancer patients with cervical stromal involvement. AB - OBJECTIVE: Stage II endometrial cancer is relatively uncommon. There is no consensus for appropriate adjuvant therapy in endometrial cancer patients with cervical stromal involvement (International Federation of Gynecology and Obstetrics [FIGO] stage II). This study investigates how adjuvant treatments and tumor characteristics influence overall survival (OS) and disease-free survival (DFS) in stage II patients in order to establish better treatment guidelines. METHODS: This multi-institution, Institutional Review Board approved, study is a retrospective review of 40 endometrial cancer patients with cervical stromal involvement treated from 1993 to 2009. Kaplan-Meier estimates were used to evaluate OS and DFS. RESULTS: OS was 85% at three years and 67% at five years. There were no significant differences in age, histology, depth of invasion, comorbid conditions, surgical staging or recurrence between patients who received radiation therapy (RT) and those who did not. However, patients with FIGO grade 1 cancers were less likely to receive RT (p=0.007). Patients treated with RT had a similar 5 year OS (n=33, 69%) to those treated with surgery only (n=7, 60%, p=0.746). There were no OS differences when evaluating by grade, histology, or depth of invasion between patients who did and did not receive RT. Four patients recurred: three were locoregional failures only, and one failed locally and distant. CONCLUSION: Patients receiving RT had higher grade tumors. Despite this, OS was comparable between the RT and the no RT cohorts. Local failure was the predominant pattern of failure. Endometrial cancer patients with cervical stromal involvement likely receive better locoregional control with the addition of adjuvant RT and we continue to advocate for RT in most cases. PMID- 24761214 TI - Comparison of laparoscopy and laparotomy for the management of early-stage ovarian cancer: surgical and oncological outcomes. AB - OBJECTIVE: To investigate the surgical and oncological outcomes of laparoscopic surgery compared with laparotomy for the treatment of early-stage ovarian cancer. METHODS: Data from patients who underwent surgical management for early-stage ovarian cancer between 2006 and 2012 were retrospectively reviewed. All patients presented with stage I or II disease, and underwent comprehensive staging surgery consisting of a total hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, omentectomy, and peritoneal cytology. RESULTS: Seventy-seven patients who underwent laparoscopic surgery (24 patients) or laparotomy (53 patients) were identified. Surgery for none of the patients was converted from laparoscopy to laparotomy. The mean operation time was shorter and the estimated blood loss was lower in the laparoscopy group than in the laparotomy group, though the differences were not statistically significant (193 min vs. 224 min, p=0.127; 698 mL vs. 973 mL, p=0.127). There were no differences in the intraoperative or postoperative complications. During a mean follow-up period of 31 months, tumor recurrence occurred in 4 patients: 2 (8.3%) in the laparoscopy group and 2 (3.8%) in the laparotomy group. The mean disease-free survival was 59 months after laparoscopy and 66 months after laparotomy (p=0.367). CONCLUSION: Laparoscopic surgery seems to be adequate and feasible for the treatment of early-stage ovarian cancer with comparable results to laparotomy in terms of the surgical outcomes and oncological safety. PMID- 24761215 TI - Clinicopathologic features of epithelial ovarian carcinoma in younger vs. older patients: analysis in Japanese women. AB - OBJECTIVE: The purpose of this study was to clarify the clinical features of epithelial ovarian carcinoma (EOC) in younger vs. older patients in Japan. METHODS: We collected data on 1,562 patients with EOC treated at multiple institutions in the Tokai Ovarian Tumor Study Group, and analyzed them retrospectively. All patients were divided into 2 groups: group A (<=40 years old) and group B (>40 years old). The data were analyzed to evaluate prognostic factors and the distribution of features in each group. Patients were subjected to univariate and multivariate analyses to evaluate overall survival (OS). RESULTS: The median follow-up time was 45.1 months (range, 1 to 257 months). Patients in group A had a significantly higher rate of stage I disease (67.3% vs. 42.6%, respectively; p<0.001) and the mucinous type (36.7% vs. 13.5%, respectively; p<0.001) than those in group B. There was a significant difference of OS between the 2 groups (p=0.013). However, upon stratification according to the stage, there were no significant differences in the OS between the 2 groups (group A vs. B: stage I, p=0.533; stage II-IV, p=0.407). Multivariate analysis revealed that younger age was not an independent prognostic factor for OS. CONCLUSION: On the basis of our data, younger patients had a different clinical profile than older patients, particularly regarding the stage of the disease and pathological distribution; however, they showed a similar long-term prognosis, even upon stratification according to the stage. PMID- 24761216 TI - Use of colony-stimulating factor in patients with ovarian cancer receiving paclitaxel and carboplatin in Japan. AB - OBJECTIVE: To assess the use of colony-stimulating factors (CSFs) in patients with ovarian cancer who receive adjuvant paclitaxel and carboplatin chemotherapy in clinical practice and to assess whether the frequency of CSF use differs among hospitals in Japan. METHODS: CSF use in patients with ovarian cancer who received first-line paclitaxel and carboplatin was analyzed retrospectively using data from the Japanese hospitalization payment system. RESULTS: A total of 1,050 patients at 104 hospitals were identified. The median age was 60 years (range, 22 to 88 years). Of these, 163 patients (15.5%) were diagnosed with neutropenia and 134 patients (12.8%) received CSFs. Among the patients who received CSFs, 125 (93%) received them for the treatment of neutropenia without fever and 1 received them for febrile neutropenia. In total, CSFs were administered for 272 cycles of chemotherapy. Among them, CSFs were used as treatment for neutropenia without fever in 259 cycles (95%), as prophylaxis (primary or secondary) in 12 cycles (4%), and as treatment for febrile neutropenia in 1 cycle. Among hospitals, a median of 4.0% of patients received CSFs with an interquartile range of 25% (Q1, 0%; Q3, 25%). A logistic random effects model showed that the variation in the proportion of patients receiving CSFs among the 104 hospitals was 2.0 (p<0.001), suggesting that the use of CSFs varied across hospitals. CONCLUSION: Most patients received CSFs for neutropenia without fever. Standardized and evidence based use of CSFs is critically required among hospitals in Japan. PMID- 24761217 TI - Metronomic oral paclitaxel shows anti-tumor effects in an orthotopic mouse model of ovarian cancer. AB - OBJECTIVE: The purpose of this study was to compare the in vivo anti-tumor efficacy of a mucoadhesive, lipid-based, oral paclitaxel formulation (DHP107) with traditional, intraperitoneal (IP) paclitaxel using an orthotopic mouse model of chemotherapy-sensitive SKOV3ip1 ovarian cancer. METHODS: To determine the optimal therapeutic dose of oral paclitaxel, DHP107 was administered per os to female athymic nude mice at 0, 25, or 50 mg/kg twice per week. Control mice received 100 uL saline once per week. IP injections of paclitaxel at 5 mg/kg once per week were used for comparison. To evaluate the potential therapeutic effect of metronomic DHP107 chemotherapy, mice received DHP107 50 mg/kg once per week per os, which was compared with 25 mg/kg twice per week and with vehicle-treated controls. RESULTS: Low-dose DHP107 (25 mg/kg) twice per week was as effective as IP paclitaxel (5 mg/kg once a week) but high-dose DHP107 (50 mg/kg once per week) was less effective at inhibiting tumor growth in an orthotopic mouse model (88%, 82%, and 36% decrease in tumor weight, respectively). Mice that received 25 mg/kg DHP107 twice per week or 50 mg/kg DHP107 once per week per os had a significant decrease in tumor weight compared with vehicle-treated controls (p<0.01, both doses). CONCLUSION: Metronomic oral chemotherapy with DHP107 showed anti-tumor efficacy in vivo similar to IP paclitaxel in an orthotopic mouse model. PMID- 24761218 TI - Adjuvant therapy for endometrial cancer. AB - Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. PMID- 24761219 TI - Building a successful fertility preservation program at a major cancer center. AB - Over 150,000 reproductive age individuals face fertility-threatening cancer treatments each year. Improved detection and treatment of cancer in reproductive age patients have greatly increased the long-term survival and made it possible for these individuals to consider their long-term quality-of-life after cancer including having biologic offspring. Various methods of fertility preservation (FP) are now available for both males and females. In order to maximize FP options available to patients facing imminent gonadotoxic therapies, it is crucial that women have quick access to FP care and that providers expedite FP strategies. The overarching goal of a clinical FP program is to help patients and their physicians consider the impact of treatment on future fertility and facilitate FP efforts in what is often a limited time period before cancer treatment begins. PMID- 24761220 TI - Consideration of EphA2 in relation to epithelial-mesenchymal transition in uterine endometrial cancer. PMID- 24761221 TI - Asymmetric synthesis of chiral cycloalkenone derivatives via palladium catalysis. AB - The palladium-catalyzed oxidative desymmetrization of meso dibenzoates yields gamma-benzoyloxy cycloalkenones in good yields and with excellent levels of enantioselectivity. These compounds serve as precursors to a broad range of substituted cycloalkenones, including well-established synthetic building blocks and elaborated cycloalkanone derivatives. The ability to prepare both enantiomers of the oxidative desymmetrization products enables a unified strategy toward stereochemically diverse epoxyquinoid natural products. PMID- 24761222 TI - The Journal of Therapeutic Ultrasound: broadening knowledge in a rapidly growing field. AB - The Journal of Therapeutic Ultrasound has been established to provide an open access, online venue for the exponentially growing body of work in biomedical ultrasound therapy. PMID- 24761223 TI - The impact of vaporized nanoemulsions on ultrasound-mediated ablation. AB - BACKGROUND: The clinical feasibility of using high-intensity focused ultrasound (HIFU) for ablation of solid tumors is limited by the high acoustic pressures and long treatment times required. The presence of microbubbles during sonication can increase the absorption of acoustic energy and accelerate heating. However, formation of microbubbles within the tumor tissue remains a challenge. Phase shift nanoemulsions (PSNE) have been developed as a means for producing microbubbles within tumors. PSNE are emulsions of submicron-sized, lipid-coated, and liquid perfluorocarbon droplets that can be vaporized into microbubbles using short (<1 ms), high-amplitude (>5 MPa) acoustic pulses. In this study, the impact of vaporized phase-shift nanoemulsions on the time and acoustic power required for HIFU-mediated thermal lesion formation was investigated in vitro. METHODS: PSNE containing dodecafluoropentane were produced with narrow size distributions and mean diameters below 200 nm using a combination of sonication and extrusion. PSNE was dispersed in albumin-containing polyacrylamide gel phantoms for experimental tests. Albumin denatures and becomes opaque at temperatures above 58 degrees C, enabling visual detection of lesions formed from denatured albumin. PSNE were vaporized using a 30-cycle, 3.2-MHz, at an acoustic power of 6.4 W (free-field intensity of 4,586 W/cm(2)) pulse from a single-element, focused high power transducer. The vaporization pulse was immediately followed by a 15-s continuous wave, 3.2-MHz signal to induce ultrasound-mediated heating. Control experiments were conducted using an identical procedure without the vaporization pulse. Lesion formation was detected by acquiring video frames during sonication and post-processing the images for analysis. Broadband emissions from inertial cavitation (IC) were passively detected with a focused, 2-MHz transducer. Temperature measurements were acquired using a needle thermocouple. RESULTS: Bubbles formed at the HIFU focus via PSNE vaporization enhanced HIFU-mediated heating. Broadband emissions detected during HIFU exposure coincided in time with measured accelerated heating, which suggested that IC played an important role in bubble-enhanced heating. In the presence of bubbles, the acoustic power required for the formation of a 9-mm(3) lesion was reduced by 72% and the exposure time required for the onset of albumin denaturation was significantly reduced (by 4 s), provided that the PSNE volume fraction in the polyacrylamide gel was at least 0.008%. CONCLUSIONS: The time or acoustic power required for lesion formation in gel phantoms was dramatically reduced by vaporizing PSNE into bubbles. These results suggest that PSNE may improve the efficiency of HIFU-mediated thermal ablation of solid tumors; thus, further investigation is warranted to determine whether bubble-enhanced HIFU may potentially become a viable option for cancer therapy. PMID- 24761224 TI - MR-guided focused ultrasound technique in functional neurosurgery: targeting accuracy. AB - BACKGROUND: The purpose of this study was to describe targeting accuracy in functional neurosurgery using incisionless transcranial magnetic resonance (MR) guided focused ultrasound technology. METHODS: MR examinations were performed before and 2 days after the ultrasound functional neurosurgical treatment to visualize the targets on T2-weighted images and determine their coordinates. Thirty consecutive targets were reconstructed: 18 were in the central lateral nucleus of the medial thalamus (central lateral thalamotomies against neurogenic pain), 1 in the centrum medianum thalamic nucleus (centrum medianum thalamotomy against essential tremor), 10 on the pallido-thalamic tract (pallido-thalamic tractotomies against Parkinson's disease), and 1 on the cerebello-thalamic tract (cerebello-thalamic tractotomy against essential tremor). We describe a method for reconstruction of the lesion coordinates on post-treatment MR images, which were compared with the desired atlas target coordinates. We also calculated the accuracy of the intra-operative target placement, thus allowing to determine the global, planning, and device accuracies. We also estimated the target lesion volume. RESULTS: We found mean absolute global targeting accuracies of 0.44 mm for the medio-lateral dimension (standard deviation 0.35 mm), 0.38 mm for the antero-posterior dimension (standard deviation 0.33 mm), and 0.66 mm for the dorso-ventral dimension (standard deviation 0.37 mm). Out of the 90 measured coordinates, 83 (92.2%) were inside the millimeter domain. The mean three dimensional (3D) global accuracy was 0.99 mm (standard deviation 0.39 mm). The mean target volumes, reconstructed from surface measurements on 3D T1 series, were 68.5 mm(3) (standard deviation 39.7 mm(3)), and 68.9 mm(3) (standard deviation 40 mm(3)) using an ellipsoidal approximation. CONCLUSION: This study demonstrates a high accuracy of the MR-guided focused ultrasound technique. This high accuracy is due not only to the device qualities but also to the possibility for the operator to perform on-going real-time monitoring of the lesioning process. A precise method for determination of targeting accuracy is an essential component and basic requirement of the functional neurosurgical activity, allowing an on-going control of the performed therapeutic work indispensable for any target efficiency analysis and the maintenance of a low risk profile. PMID- 24761225 TI - Telling it like it is. PMID- 24761226 TI - Measurement of ultrasonic phase and group velocities in human dental hard tissue. AB - BACKGROUND: The development of ultrasound for use in dental tissues is hampered by the complex, multilayered nature of the teeth. The purpose of this preliminary study was to obtain the phase and group velocities associated with several directions of ultrasonic wave propagation in relation to the tooth structure, which would then lead to the determination of the elastic constants in dental hard tissue. Knowledge of these elastic constants can be used to feed back into numerical models (such as finite element) in order to simulate/predict ultrasonic wave propagation and behavior in the teeth. This will help to optimize ultrasonic protocols as potential noninvasive therapeutic tools for novel dental regenerative therapies. METHODS: An extracted human second molar was used to determine time-of-flight information from A-scan signatures obtained at various angles of inclination and rotation using a scanning acoustic microscope at 10 MHz. Phase and group velocities and associated slowness curves were calculated in order to determine the independent elastic constants in the human teeth. RESULTS: Results show that as the tooth was inclined at three azimuthal angles (Thetain = 0 degrees , 15 degrees , and 30 degrees ) and rotated from Phiin = 0 degrees to 360 degrees in order to cover the whole perimeter of the tooth, slowness curves constructed from the computed phase and group velocities versus angle of rotation confirm the inhomogeneous and anisotropic nature of the tooth as indicated by the nonuniform appearance of uneven circular shape patterns of the measurements when compared to those produced in a control isotropic fused quartz sample. CONCLUSIONS: This study demonstrates that phase and group velocities of ultrasound as determined by acoustic microscopy change and are dependent on the direction of the tooth structure. Thus, these results confirm that the tooth is indeed a multilayered anisotropic structure underscoring that there is no single elastic constant sufficient to represent the complex structure of the tooth. The findings underline the importance to take into account these crucial characteristics in order to develop and optimize therapeutic as well as diagnostic applications of ultrasound in dental tissue repair, and further studies are warranted to analyze ultrasound transmission at various frequencies and intensities in different teeth to develop appropriate models for ultrasound biophysical behavior in dental tissues. PMID- 24761227 TI - High-intensity focused ultrasound plus concomitant radiotherapy: a new weapon in oncology? AB - The potential impact of high-intensity focused ultrasound (HIFU) to general medicine and oncology seems very high. However, while in the research area, the development of this technique is very rapid and unchallenged. The direct application of HIFU to human tumour therapy is hampered by various technical difficulties, which may confine its role to a marginal device in the surgery armamentarium. To deploy the full potential of focused ultrasound in oncology, it seems necessary to review the basic relationship between HIFU and external beam radiotherapy. This is the aim of the present work. PMID- 24761228 TI - Fusiform correlates of facial memory in autism. AB - Prior studies have shown that performance on standardized measures of memory in children with autism spectrum disorder (ASD) is substantially reduced in comparison to matched typically developing controls (TDC). Given reported deficits in face processing in autism, the current study compared performance on an immediate and delayed facial memory task for individuals with ASD and TDC. In addition, we examined volumetric differences in classic facial memory regions of interest (ROI) between the two groups, including the fusiform, amygdala, and hippocampus. We then explored the relationship between ROI volume and facial memory performance. We found larger volumes in the autism group in the left amygdala and left hippocampus compared to TDC. In contrast, TDC had larger left fusiform gyrus volumes when compared with ASD. Interestingly, we also found significant negative correlations between delayed facial memory performance and volume of the left and right fusiform and the left hippocampus for the ASD group but not for TDC. The possibility of larger fusiform volume as a marker of abnormal connectivity and decreased facial memory is discussed. PMID- 24761230 TI - The influence of decreased levels of high density lipoprotein cholesterol on hematological indices in sickle cell disease patients. AB - BACKGROUND: Changes in lipoproteins levels in sickle cell disease (SCD) patients are well-known, but the physiological ramifications of the low levels observed have not been entirely resolved. AIM: The aim of this study is to evaluate the impact of decreased levels of high density lipoprotein cholesterol (HDL-c) on hematological indices in steady state SCD patients. SUBJECTS AND METHODS: The study was conducted on 84 SCD patients on steady clinical state, 36 males and 48 females with a mean age 21 (6) years. All those who have had blood transfusion within 4 months, infection, chronic kidney disease, and inflammatory episodes were excluded. Full blood count, total cholesterol, HDL-c, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, and triglyceride were assayed. Hematological indices of SCD patients with decreased levels of HDL-c were compared with those with normal HDL-c levels. RESULTS: The SCD patients with decreased levels of HDL-c presented with lower levels of hemoglobin (P < 0.01), hematocrit (P < 0.001), total leukocyte count (P = 0.02), red blood cell count (P < 0.01), absolute neutrophil count (P = 0.04), absolute monocyte count (P < 0.01), and triglyceride (P = 0.02). Of the 47 SCD with decreased levels of HDL-c, 82.9% (39/47) have had blood transfusion while 48.6% (18/37) out of 37 SCD with normal HDL-c have had blood transfusion. CONCLUSION: SCD patients with decreased levels of HDL-c had more severe anemia, higher leukocyte and platelet counts than those with normal HDL-c levels. The low HDL-c marker may assist in the prediction of adverse clinical events in these patients. PMID- 24761229 TI - Inhibition of Rgs10 Expression Prevents Immune Cell Infiltration in Bacteria induced Inflammatory Lesions and Osteoclast-mediated Bone Destruction. AB - Regulator of G-protein Signaling 10 (Rgs10) plays an important function in osteoclast differentiation. However, the role of Rgs10 in immune cells and inflammatory responses, which activate osteoclasts in inflammatory lesions, such as bacteria-induced periodontal disease lesions, remains largely unknown. In this study, we used an adeno-associated virus (AAV-) mediated RNAi (AAV-shRNA-Rgs10) knockdown approach to study Rgs10's function in immune cells and osteoclasts in bacteria-induced inflammatory lesions in a mouse model of periodontal disease. We found that AAV-shRNA-Rgs10 mediated Rgs10 knockdown impaired osteoclastogenesis and osteoclast-mediated bone resorption, in vitro and in vivo. Interestingly, local injection of AAV-shRNA-Rgs10 into the periodontal tissues in the bacteria induced inflammatory lesion greatly decreased the number of dendritic cells, T cells and osteoclasts, and protected the periodontal tissues from local inflammatory damage and bone destruction. Importantly, AAV-mediated Rgs10 knockdown also reduced local expression of osteoclast markers and pro inflammatory cytokines. Our results demonstrate that AAV-shRNA-Rgs10 knockdown in periodontal disease tissues can prevent bone resorption and inflammation simultaneously. Our data indicate that Rgs10 may regulate dendritic cell proliferation and maturation, as well as the subsequent stimulation of T-cell proliferation and maturation, and osteoclast differentiation and activation. Our study suggests that AAV-shRNA-Rgs10 can be useful as a therapeutic treatment of periodontal disease. PMID- 24761231 TI - Knowledge of first aid skills among students of a medical college in mangalore city of South India. AB - BACKGROUND: The adequate knowledge required for handling an emergency without hospital setting at the site of the accident or emergency may not be sufficient as most medical schools do not have formal first aid training in the teaching curriculum. AIM: The aim of this study is to assess the level of knowledge of medical students in providing first aid care. SUBJECTS AND METHODS: This cross sectional study was conducted during May 2011 among 152 medical students. Data was collected using a self-administered questionnaire. Based on the scores obtained in each condition requiring first aid, the overall knowledge was graded as good, moderate and poor. RESULTS: Only 11.2% (17/152) of the total student participants had previous exposure to first aid training. Good knowledge about first aid was observed in 13.8% (21/152), moderate knowledge in 68.4% (104/152) and poor knowledge in 17.8% (27/152) participants. Analysis of knowledge about first aid management in select conditions found that 21% (32/152) had poor knowledge regarding first aid management for shock and for gastro esophageal reflux disease and 20.4% (31/152) for epistaxis and foreign body in eyes. All students felt that first aid skills need to be taught from the school level onwards and all of them were willing to enroll in any formal first aid training sessions. CONCLUSION: The level of knowledge about first aid was not good among majority of the students. The study also identified the key areas in which first aid knowledge was lacking. There is thus a need for formal first aid training to be introduced in the medical curriculum. PMID- 24761232 TI - Radiobiological impact of planning techniques for prostate cancer in terms of tumor control probability and normal tissue complication probability. AB - BACKGROUND: The radiobiological models describe the effects of the radiation treatment on cancer and healthy cells, and the radiobiological effects are generally characterized by the tumor control probability (TCP) and normal tissue complication probability (NTCP). AIM: The purpose of this study was to assess the radiobiological impact of RapidArc planning techniques for prostate cancer in terms of TCP and normal NTCP. SUBJECTS AND METHODS: A computed tomography data set of ten cases involving low-risk prostate cancer was selected for this retrospective study. For each case, two RapidArc plans were created in Eclipse treatment planning system. The double arc (DA) plan was created using two full arcs and the single arc (SA) plan was created using one full arc. All treatment plans were calculated with anisotropic analytical algorithm. Radiobiological modeling response evaluation was performed by calculating Niemierko's equivalent uniform dose (EUD)-based Tumor TCP and NTCP values. RESULTS: For prostate tumor, the average EUD in the SA plans was slightly higher than in the DA plans (78.10 Gy vs. 77.77 Gy; P = 0.01), but the average TCP was comparable (98.3% vs. 98.3%; P = 0.01). In comparison to the DA plans, the SA plans produced higher average EUD to bladder (40.71 Gy vs. 40.46 Gy; P = 0.03) and femoral heads (10.39 Gy vs. 9.40 Gy; P = 0.03), whereas both techniques produced NTCP well below 0.1% for bladder (P = 0.14) and femoral heads (P = 0.26). In contrast, the SA plans produced higher average NTCP compared to the DA plans (2.2% vs. 1.9%; P = 0.01). Furthermore, the EUD to rectum was slightly higher in the SA plans (62.88 Gy vs. 62.22 Gy; P = 0.01). CONCLUSION: The SA and DA techniques produced similar TCP for low-risk prostate cancer. The NTCP for femoral heads and bladder was comparable in the SA and DA plans; however, the SA technique resulted in higher NTCP for rectum in comparison with the DA technique. PMID- 24761233 TI - Perception of male gender preference among pregnant igbo women. AB - BACKGROUND: Male gender preference is a dominant feature of Igbo culture and could be the reason behind women seeking fetal gender at ultrasound. AIM: The aim of this study is to investigate the perception of prenatal ultrasound patients of male gender preference in a patriarchal and gender sensitive society. SUBJECTS AND METHODS: The study was a cross-sectional survey, which targeted pregnant women who presented for prenatal ultrasound at four selected hospitals in Anambra State. A convenience sample size of 790 pregnant women constituted the respondents. The data collection instrument was a 13-item semi-structured self completion questionnaire designed in line with the purpose of the study. Descriptive and inferential statistical analyses were carried out with statistical significance being considered at P < 0.05. RESULTS: Most of the women (88.4%, 698/790) were aware that fetal gender can be determined during the prenatal ultrasound while just over half of them (61.0%, 482/790) wanted fetal gender disclosed to them during prenatal ultrasound. More than half (58.6%, 463/790) of the women desired to have male babies in their present pregnancies while 20.1% (159/790) desired female babies and 21.3% (168/790) did not care if the baby was male or female. Some of the women (22.2%, 175/790) wanted to have male babies in their present pregnancies for various reasons predominant of which was protecting their marriages and cementing their places in their husbands' hearts. Male gender preference was strongly perceived. There was considerable anxiety associated with prenatal gender determination and moderate loss of interest in the pregnancy associated with disclosure of undesired fetal gender. Socio-demographic factors had significant influence on perception of male gender preference. CONCLUSION: Male gender preference is strongly perceived among Igbo women and its perception is significantly influenced by socio-demographic factors. Male gender preference may be responsible for Igbo women seeking fetal gender at ultrasound. PMID- 24761234 TI - Computer vision syndrome and associated factors among medical and engineering students in chennai. AB - BACKGROUND: Almost all institutions, colleges, universities and homes today were using computer regularly. Very little research has been carried out on Indian users especially among college students the effects of computer use on the eye and vision related problems. AIM: The aim of this study was to assess the prevalence of computer vision syndrome (CVS) among medical and engineering students and the factors associated with the same. SUBJECTS AND METHODS: A cross sectional study was conducted among medical and engineering college students of a University situated in the suburban area of Chennai. Students who used computer in the month preceding the date of study were included in the study. The participants were surveyed using pre-tested structured questionnaire. RESULTS: Among engineering students, the prevalence of CVS was found to be 81.9% (176/215) while among medical students; it was found to be 78.6% (158/201). A significantly higher proportion of engineering students 40.9% (88/215) used computers for 4-6 h/day as compared to medical students 10% (20/201) (P < 0.001). The reported symptoms of CVS were higher among engineering students compared with medical students. Students who used computer for 4-6 h were at significantly higher risk of developing redness (OR = 1.2, 95% CI = 1.0-3.1,P = 0.04), burning sensation (OR = 2.1,95% CI = 1.3-3.1, P < 0.01) and dry eyes (OR = 1.8, 95% CI = 1.1-2.9, P = 0.02) compared to those who used computer for less than 4 h. Significant correlation was found between increased hours of computer use and the symptoms redness, burning sensation, blurred vision and dry eyes. CONCLUSION: The present study revealed that more than three-fourth of the students complained of any one of the symptoms of CVS while working on the computer. PMID- 24761235 TI - Clinico-Electroencephalography Pattern and Determinant of 2-year Seizure Control in Patients with Complex Partial Seizure Disorder in Kano, Northwestern Nigeria. AB - BACKGROUND: Complex partial seizures (CPS) may present with milder symptoms mimicking normal function of an adult person making the diagnosis delayed or often missed. There is a need for an in-depth training in epileptology to understand the various pattern of electro-clinical presentation of CPS. Ability to predict seizure control on first diagnosis can be very useful in the management of patients with CPS. However, there is a paucity of data on CPS in North-western Nigeria. AIM: This study aimed to describe the clinical and EEG characteristics of CPS and evaluate independent determinant of 2-year seizure control among adults with partial epilepsy in Kano, North-western Nigeria. SUBJECTS AND METHODS: Out of all patients diagnosed with epilepsy (PWE) at the adult neurology clinic of two tertiary hospitals in Kano over a period of 41/2 years, those with CPS were prospectively studied. Diagnosis of CPS was based on both clinical and EEG findings. Patients were followed-up for a minimum period of 2-year to determine their seizure control status. Data were analyzed using STATA version 10. RESULTS: Total of 158 (105 males, 53 females) were enrolled. Their age ranged between 15 and 85 (median = 30.5) years. Sixty six (66/158,41.7%) had aura and 64 of them (64/158, 41.1%) had automatism. The most common aura and automatism were abnormal epigastric sensation and oro-alimentary respectively. Twenty eight (28/158, 18%) had associated behavioral manifestations. EEG abnormality was recorded in 56 (56/158, 53.9%). Adequate seizure control was achieved in 55% (70/128) on anti-epileptic drugs (AEDs). Duration of epilepsy, before the commencement of AEDs was identified as an independent determinant of 2 year seizure control. CONCLUSION: Abnormal epigastric sensation and oroalimentary automatism were the most common clinical complaint. Duration epilepsy over 3 years or less was identified as an independent predictor of 2-year seizure control. PMID- 24761236 TI - Job satisfaction and its influential factors in dental academic members in tehran, iran. AB - BACKGROUND: Assessment of job satisfaction of the faculty members and its underlying factors may increase career fulfillment and raise the educational and research productivity, leading to higher quality of dental services at the community level, ultimately improving public oral health status. AIM: This study assessed job satisfaction and its influential factors in dental academic members in Tehran. SUBJECTS AND METHODS: The job satisfaction level of 203 faculty members was assessed using a Likert scale questionnaire from 0 to 4, with 4 representing very satisfied and 0 not at all satisfied. The analysis of variance was used to compare the responses among dental faculty members of three different universities. The impact of age, gender, academic rank, employment status and the date of employment on the overall faculty job satisfaction was identified by multiple linear regression analysis. RESULTS: The mean professional satisfaction score among faculty members was 1.5 (0.5) out of four. Among the studied underlying factors, only the date of employment was seen to have a statistically significant impact on the faculties' overall job satisfaction (P= 0.05). There was no difference in job compensation observed between the three dental faculties. Dissatisfying aspects of the academic work included educational and research policies, monetary strategies, quality of leadership and administration, promotion and tenure policies, job security, educational environment, equipments, and facilities. The only satisfying factor was the interaction between faculty colleagues and students. CONCLUSION: Faculty members of Tehran Dental Schools are dissatisfied with their work environments in Tehran Dental Schools. Issues such as salary and remuneration, facilities, equipments, promotion and tenure policies are strongly believed to account for the dissatisfaction. PMID- 24761237 TI - Established Osteoporosis and Gaps in the Management: Review from a Teaching hospital. AB - BACKGROUND: International osteoporosis foundation described severe or established osteoporosis as an osteoporotic individual with a fragility fracture. Orthopaedic surgeons frequently manage fractures, but we believe that large gaps are prevalent in the medical management of osteoporosis after fractures are fixed. AIM: The aim of this analysis is to assess the investigations and gaps in the management of osteoporosis in patients admitted with a fragility fracture of femur at King Fahd Hospital of the University, AlKhobar, Saudi Arabia. MATERIALS AND METHODS: A retrospective analysis of all admission and discharge; medical and pharmacy records database of patients over >= 50 years with fragility fracture between January 2001 and December 2011. The outcome measures assessed were investigations such as serum calcium, phosphorous, alkaline phosphatase, parathormone, 25 hydroxy vitamin D (25OHD) levels and a dual energy X-ray absorptiometry (DEXA). Secondly once the fracture was fixed what medications were prescribed, calcium and vitamin D, antiresorptives and anabolic agents. RESULTS: There were 207 patients admitted during the study period with an average age of 69.2 (12.1) years and 118 were females. In 169 (81.6%) patients, the fracture site was proximal femur. Vitamin D (25OHD) was requested in 31/207 (14.9%). DEXA scan was ordered in 49/207 (24.1%). A total of 78/207 (37.6%) patients received calcium and vitamin D3 and 94/207 (45.4%) either got calcium or vitamin D3. Bisphosphonates was used in 35, miacalcic nasal spray in 25 and anabolic agent teriparatide was prescribed in 21 patients. Post-fixation 126/207 (60.8%) patients did not receive any anti-osteoporotic medication. In untreated group, there were 87 males and 39 females. CONCLUSIONS: The study found that in patients, who sustained a fragility fracture, confirmation of osteoporosis by DEXA was very low and ideal treatment for severe osteoporosis was given out to few patients. More efforts are needed to fill this large gap in the correct management of osteoporosis related fractures by orthopaedic surgeons. PMID- 24761238 TI - Acrochordons as a cutaneous sign of metabolic syndrome: a case-control study. AB - BACKGROUND: Acrochordons (known as skin tags) are benign skin tumors. A few studies with contradictory results have been reported regarding the abnormalities of carbohydrate and/or lipid metabolisms in patients with skin tags. AIM: The aim of this study is to determine if the presence of acrochordons could be a marker of Metabolic syndrome by comparing with a control group. SUBJECTS AND METHODS: A total of 110 patients having two or more acrochordons and age- and gender-matched 110 controls were included in the study. Localization, size and the total number of acrochordons were recorded in the patient group. Age, sex, body mass index (BMI), waist circumference, smoking status, fasting plasma glucose (FPG), impaired glucose tolerance (IGT) test, insulin resistance, serum lipids and liver enzyme levels were estimated in cases and controls. Arterial blood pressures were measured in two groups. RESULTS: A total of 58 patients and 12 controls were diagnosed with overt diabetes mellitus (DM). 15% (16/110) of patients and 8% (9/110) of controls had an IGT test. The difference was statistically significant for the diagnosis of DM and not significant for the IGT. The mean levels of FPG, BMI, insulin resistance, total cholesterol, low-density lipoprotein cholesterol and triglyceride were significantly higher in patients than those in controls. Serum levels of high-density lipoprotein were less in patients. Patients with acrochordons had higher systolic and diastolic blood pressures than controls. CONCLUSION: Acrochordons may represent a cutaneous sign for Metabolic syndrome. Changing the life-style of these patients may have a beneficial role. PMID- 24761239 TI - Sexual activity and urological morbidities among nigerian menopausal women: findings from a community based survey. AB - BACKGROUND: Menopause represents the end of women reproductive career and it is at this time they begin to manifest morbidities such as urinary incontinence. AIM: To document proximate determinants of sexual activity and urological morbidities of menopausal women. SUBJECTS AND METHODS: This was a community survey conducted among 254 menopausal women Mokola in Ibadan, Nigeria in 2008. Respondents were selected using cluster sampling technique. Interviewer administered questionnaires were used to obtain information on their characteristics, pattern of urological and sexual activities. Descriptive, bivariate and multivariable tests were performed with Statistical Package for the Social Sciences 15.0 (Chicago, IL USA) and statistical significance was set at P value less than 0.05. RESULTS: The mean age of subjects was 60.3 (standard deviation = 10.2 years). About 33.5% (85/254) was still sexually active. About 68% (173/254) reported a reduction in sexual frequency since menopause while 31.5% (80/254) reported no change. The mean self-rated sexual performance score was 4.3 based on a numerical scale where 10 is the maximum obtainable. Significant predictors of reduction in sexual activity were age at menopause and education. Those between 45 and 49 years were less likely than those at 55 years or more (odds ratio [OR] = 0.21; 95% confidence interval OR = 0.05-0.87) while women with at least secondary education were thrice less likely than those with none to report a reduction in sexual activity after menopause. Less than a tenth reported urinary incontinence as a complaint. Urge incontinence was the most commonly reported followed by dysuria and stress incontinence. Less than a quarter of them had requested for a form of treatment. CONCLUSION: Sexual performance of Nigerian menopausal women is associated with age at menopause and education. Non-fistulous urinary incontinence is now being mentioned as a complaint contrary to the widely held view that it is part of the aging process. Therefore, awareness creation on management opportunities should be shared with them. PMID- 24761240 TI - Postpartum resumption of sexual activity, sexual morbidity and use of modern contraceptives among nigerian women in jos. AB - BACKGROUND: Postpartum sexual abstinence until when the child is weaned from breast milk is deeply rooted in most cultures in Nigeria. AIM: The study aimed at describing the current sexual practices of postpartum women, sexual morbidity, contraceptive prevalence and predictive factors for early postpartum sexual intercourse and associated sexual problems in our setting. SUBJECTS AND METHODS: This cross-sectional study was conducted among consecutive 340 women at a child welfare clinic 14 weeks after childbirth. Questionnaires were administered between January 2012 and June 2012 to ascertain their socio-demographic and obstetric features, sexual activity, time to coital resumption, reasons for resumption and non-resumption of intercourse, sexual problems encountered and contraceptive usage. Statistical analysis was performed using the SPSS version 16 for windows (SPSS Inc., Chicago, IL, USA). RESULTS: Sexual intercourse was resumed by 67.6% (230/340) of women with a mean time to resuming intercourse of 8.2 (2.9) weeks postpartum and a median time of 8.0 weeks. About 3.5% (8/230) did so within the puerperium. Sexual intercourse was initiated mainly (77.4% [178/230]) by their husbands and only 19.1% (44/230) of them were using modern contraceptives. About 62.6% (144/230) of women experienced sexual morbidities including vaginal dryness/insufficient lubrication, dyspareunia and vaginal discharge. Socio-demographic and obstetric features, menstrual and breastfeeding status were not predictive of early resumption of coitus. Vaginal delivery (OR: 3.6, 95% CI: 1.3-10.0, P = 0.01,) and previous episiotomy (OR: 2.4, 95% CI: 2.0 6.1, P = 0.04,) were predictive of sexual morbidity. CONCLUSION: Women in our setting resume sexual intercourse early after childbirth without the use of contraception and often with associated sexual morbidity. Emphasis on sexual and contraceptive education during the immediate postpartum period is therefore imperative. PMID- 24761241 TI - Epidemiology and clinical parameters of adult human immunodeficiency virus/acquired immunodeficiency syndrome at the initiation of antiretroviral therapy in South eastern Nigeria. AB - BACKGROUND: Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has continued to ravage the teeming populations in Nigeria, with disastrous consequences. Despite many studies and progress on HIV/AIDS in Africa, the data on the status of the patients at the commencement of therapy is lacking. AIM: The aim of this study is to determine the demographic, clinical and some laboratory features of adult HIV/AIDS patients, seen at the commencement of antiretroviral therapy (ART) in Nnamdi Azikiwe University Teaching Hospital, Nnewi, south-east Nigeria between July 2002 and October 2004. SUBJECTS AND METHODS: The study was a cross-sectional, descriptive study. Adult patients living with HIV/AIDS were studied using an interview administered questionnaire. Data was analyzed using Epi Info 2008 version 3.5.1. RESULTS: A total of 400 respondents participated in this study. The mean age was 36.8 (8.8) years. Almost 60% patients were married and the HIV concordance rate was 53.3% (136/255). Nearly 30% of the families had at least one child positive for HIV. The most common associated risky behavior was injection administered in patent medicine stores 74.5%(302/400) and the most common clinical symptom was respiratory. Of the 400 patients recruited in this study, 19 (4.8%) were lost to follow-up on the 6 months' visit, giving a follow-up rate of 95.2% (381/400). There was statistically significant difference in the mean body weight (P = 0.02), mean total white blood cell count (P < 0.001) and mean CD4(+) count (P < 0.001) at presentation and after 6 months of ART therapy. CONCLUSION: HIV/AIDS patients present late and body weight, CD4(+) count and total white blood cell count seemed to recover quickly on commencement of ART. The prevalence of concordance among couples and mother to child transmission rates tended to be high. Administration of injectable at patent medicine stores and multiple sexual partners are the most significant risk factors. PMID- 24761242 TI - Treatment Outcome and Follow-up of Tuberculosis Patients Put on Directly Observed Treatment Short-course Under Rural Health Training Center, Paithan, Aurangabad in India. AB - BACKGROUND: Revised National Tuberculosis Control Program (RNTCP) was found successful in achieving its objectives; still there is concern of relapse cases and defaulters. AIM: The aim of this study is to know the treatment outcome, to assess the reasons for relapse, default, death of patient and to assess the follow-up status of tuberculosis (TB) patients put on directly observed treatment short-course (DOTS). SUBJECTS AND METHODS: This cross-sectional survey was conducted in 140 TB patients put on DOTS during year 2005-2007 under Rural Health Training Center, Paithan. The personal interview was carried out by an investigator with pre-tested questionnaire during month of July-August 2008. RESULTS: Out of total 140, 125 TB cases could be traced: Category I 48% (60/125), Category II 16% (20/125) and Category III 36% (45/125). Cure rate among Category I was calculated to be 61.7% (37/60). Defaulters were observed to be 18.3% (11/60), 25% (5/20) and 20% (9/45) among Category I, Category II and Category III respectively. Death rate was higher (5%) among patients of Category II. During the follow-up visit, 82.4% (103/125) were found to be alive while 17.6% (22/125) dead. A total of 18 deaths were related with TB and its sequelae. Around 20% (5/25) defaulted because of feeling of well-being. During the follow-up visit, 5.8% (6/103) were again put on DOTS. CONCLUSIONS: Defaulters were high in present study. The majority of patients left the treatment due to feeling well. This can be tackled by effective counseling. Higher percentage of the patients showed improvement in their weight after completion of DOTS treatment. More emphasis was to be given toward existing TB patients to get successful results of RNTCP. PMID- 24761243 TI - Knowledge and use of personal protective measures against mosquito borne diseases in a resettlement colony of delhi. AB - BACKGROUND: Mosquito borne diseases (MBDs) are major public health problem in India. State of Delhi is endemic for dengue and other MBDs. The increasing incidence of MBDs in Delhi in recent years warrants a pro-active approach for their prevention. Knowledge and use of personal protective measures (PPMs) presents an effective strategy for prevention and control of MBDs. AIM: The present study was conducted to assess the knowledge and use of PPMs against MBDs in an urban resettlement colony of Delhi. SUBJECTS AND METHODS: It was a cross sectional study carried out in a resettlement colony of Delhi. A total of 100 families were selected by systematic random sampling. Data was collected using semi-structured questionnaire and supplemented by spot survey by the investigator in the community. The results were analyzed in SPSS version 16.0 (Chicago Illinios, USA). RESULTS: Out of the 100 respondents, 65% (65/100), 58%(58/100) and 13% (13/100) had heard about dengue, malaria and chikungunya, respectively. Nearly, one-fifth (20/100; 20%) of the participants reported incorrect breeding sites for mosquitoes. The knowledge regarding PPMs was very high (93/100; 93%) and about (90/100; 90%) families were actually using at least one of the PPMs. However, very few families were using them correctly (1/90; 1.1%) and adequately (5/90; 5.6%). The most common PPM being used by the study population was liquid vaporizers (54/90; 60%). Nearly one-third (29/90; 32.2%) of the participants reported side-effects due to PPMs with irritation to smell being the most common reported side-effect. On house visit, adult mosquitoes were seen in 67% (67/100) of the houses, while potential mosquito breeding sites were found in and around 56% (56/100) houses. CONCLUSIONS: There were crucial gaps in knowledge and practices of participants with regard to prevention and control of MBDs. Thus, there is a need to intensify efforts toward creating public knowledge and mobilizing community about correct use of preventive measures against MBDs. PMID- 24761244 TI - Hemolyzed Samples Should be Processed for Coagulation Studies: The Study of Hemolysis Effects on Coagulation Parameters. AB - BACKGROUND: Rejecting hemolyzed specimens received for coagulation studies is advised by the Clinical and Laboratory Standards Institute. Receiving such specimens is a common phenomenon in many laboratories. The true impact of hemolysis on coagulation studies is little studied in clinical practice. AIM: The aim of this work is to study the changes occurring in readings of prothrombin time (PT) and activated partial thromboplastin time (aPTT) in hemolyzed samples. SUBJECTS AND METHODS: A total of 45 blood samples were collected from two groups of healthy donors and patient population. Samples were run for PT and aPTT and then were hemolyzed and again rerun for PT and aPTT. GraphPad Prism 5 (Version 5, USA) was the software used for statistical analysis and paired "t" test was applied with significance level at 0.05. RESULTS: There was trend of increase in the readings of PT and aPTT in normal population and there was trend of decrease in the reading in patient population. The difference between paired samples from group one was not statistically significant, but it was significant in samples from second group. CONCLUSION: Samples sent for routine screening of coagulation studies with visible hemolysis can be processed for coagulation. There was no difference observed in hemolyzed and non-hemolyzed samples. PMID- 24761245 TI - The Relaxant Effect of Seed's Essential Oil and Oleo-Gum-Resin of Ferula Assa Foetida on Isolated Rat's Ileum. AB - BACKGROUND: In Iranian folk medicine, several plants are used for treatment of gastrointestinal disorders, such as diarrhea and spasm. One of these herbal medications are the essential oil yielded from seeds of Ferula assa-foetida L. and an oleo-gum-resin known as asafetida, which is exudated from its root. F. assa-foetida grows wildly in south and central mountains of Iran. AIM: In this study, relaxant effect of asafoetida and seed's essential oil of F. assa-foetida was investigated in isolated rat's ileum in three doses. MATERIALS AND METHODS: A total of 5 cm of ileum was removed and sets for recording its isotonic contractions. The amplitude of contractions induced by different doses of asafoetida and essential oil before and after exposing the specimens with cumulative logarithmic concentrations of acetylcholine (Ach) was evaluated. The relaxant effect of asafoetida and seed's essential oil of F. assa-foetida was investigated in isolated rat's ileum in three doses (0.1 0.2 and 0.3%). All statistical analysis was by GraphPad Prism 5 (San Diego, California) and comparisons were made by means of the analysis of variances followed by Tukey's test. The statistical significance was considered as P < 0.05. RESULTS: Asafoetida produced an antispasmodic effect on Ach induced contraction in 0.2% and 0.3% concentrations. Our findings also showed that essential oil has significant antispasmodic action against cumulative concentrations of 10(-12) up to 10(-2) M Ach. In spasmolytic evaluation, our findings showed that the essential oil derived from F. assa-foetida seed in concentrations of 0.2% and 0.3% significantly reduced Ach (10(-4) M) induced contractions. Exposure to the 0.2% and 0.3% asafoetida, reduced the percentage of maximum contraction induced by 10(-4) M Ach to 43% and 12% respectively, which this reduction was statistically significant. CONCLUSION: The results of the present study, supports the traditional claim of asafoetida as an antispasmodic therapeutic. PMID- 24761246 TI - Common mental disorders: a challenge among people living with human immunodeficiency virus infection/acquired immunodeficiency syndrome in udupi, India. AB - BACKGROUND: Globally, the prevalence of common mental disorders (CMD) is greater among people living with human immunodeficiency virus/acquired immunodeficiency syndrome (PLHA) as opposed to the general population. There is relatively limited research on mental health in PLHA in India and this study seeks to gain insight in this area. AIM: The aim of this study is to find the prevalence of CMD among PLHA in Udupi district. SUBJECTS AND METHODS: In this cross-sectional study, 227 PLHA were selected using a convenience sampling method and interviewed at a district antiretroviral treatment center. The Kessler Psychological Distress Scale (K10 scale) and the General Health Questionnaire (GHQ-12) were used to measure distress and stress, respectively to assess CMD. Statistical analysis was performed with categorical variables expressed as frequencies and percentages. Continuous variables were measured using mean and standard deviation. Univariate and multivariate analyses using binomial logistic regression was carried out. SPSS version 15 (SPSS Inc., Chicago, IL, USA) was used to analyze the data. RESULTS: The K10 Psychological Distress Scale indicated that 78.9% (n = 179/227) of participants suffered from mild to severe mental disorder and it was higher among divorced, separated or widowed PLHA followed by the married participants versus unmarried individuals. The GHQ-12 scale showed 68.3% (n = 155/227) suffering from mild to severe mental stress with the female gender developing stress 2.3 times more often. CONCLUSION: High levels of distress were seen among PLHA. They should be periodically screened for CMD and provided early psychological intervention at the point of contact with health professionals. Psychological care needs to be integrated along with the clinical care. PMID- 24761247 TI - Assessment of a group of nigerian dental students' education on medical emergencies. AB - BACKGROUND: The training of dental students in the management of medical emergencies is of utmost importance as they may encounter some of these emergencies at some point in their career. AIM: The aim of this study was to evaluate the medical emergency education in a Nigerian Dental School. SUBJECTS AND METHODS: This descriptive cross-sectional study was carried out among 124 final year dental students of the University of Benin, Benin City. Data was collected using a self-administered questionnaire. The questionnaire elicited information on demography, knowledge of inclusion of a medical emergency in the dental curriculum, knowledge of guidelines on medical emergency formulated by any dental authority, opinion on the comprehensiveness of the present training on medical emergency, type of medical emergency training received, previous encounter with a medical emergency, previous participation in emergency drills and knowledge of the content of an emergency kit. Descriptive statistics was carried out on the collected data. RESULTS: Only 58.1% (72/124) respondents were aware of the inclusion of a medical emergency in the dental curriculum and fewer, 17.7% (22/124), were aware of guidelines on medical emergency formulated by any dental authority. Fifty-two out of all the respondents (41.9%) claimed not to have received any form of training on medical emergency. Only 22.6% (28/123) had previously participated in an emergency drills and just 34.7% (43/124) had ever seen an emergency kit. CONCLUSIONS: It can be concluded from this study that the level of training and level of knowledge on medical emergencies of the studied dental students is below desirable standard. It is therefore necessary to put proper strategies in place to strengthen their identified areas of weakness. PMID- 24761248 TI - The prevalence and outcome of asymptomatic chlamydial infection screening among infertile women attending gynecological clinic in ibadan, South west Nigeria. AB - BACKGROUND: Chlamydial trachomatis infection is the most common cause of tubal infertility among women world-wide. Serological diagnosis of Chlamydial infection that may suggest previous, persistent or on-going infection is now incorporated into routine pre-treatment evaluation of infertile women including assisted conception. AIM: The aim of this study is to determine the prevalence and predictors of asymptomatic Chlamydial infection screening among infertile women and also to compare the screening outcome with findings on hysterosalpingogram (HSG). SUBJECTS AND METHODS: This was an observational study conducted among 132 infertile women that were attending Adeoyo Maternity Hospital Ibadan. A total volume of 2-3 ml of venous blood was collected for Chlamydia serology using ImmunoComb Bivalent immunoglobulin G kit (Code 50416002) and the results were compared with their HSG. Other information collected was socio-demographics and clinical parameters. Descriptive, bivariate and multivariate tests were performed using Statistical Package for the Social Sciences 15.0 (Chicago, IL USA) and statistical significance was set at (P < 0.05). RESULTS: A total of 130 women were studied with a mean age of 31.6 years (standard deviation = 4.7). Majority - 72.0% (95/132) - had been infertile for 5 years or less. The prevalence of Chlamydial trachomatis was 20.5% (27/132). Bivariate analysis between the biosocial variables and serology result showed a significant association with education (P < 0.01) and religion (P < 0.01). Logistic regression analysis revealed that Muslim women were 3.6 times more likely than Christians to have positive Chlamydial serology result (95% confidence interval odds ratio = 1.18 11.11). Of those with HSG result (64), the accuracy of the test kit showed low sensitivity - 44.2% (19/43) and negative predictive value 40.0% (16/40) (but, high specificity - 76.2%(16/21), and positive predictive value - 79.2% (19/24). CONCLUSION: Asymptomatic Chlamydial infection is common among infertile women and it positively predict HSG blockage. The serological test may prove invaluable in predicting the presence of tubal blockage; therefore, prophylactic antibiotics may be justified to be included in their care. PMID- 24761249 TI - Computer use and vision-related problems among university students in ajman, United arab emirate. AB - BACKGROUND: The extensive use of computers as medium of teaching and learning in universities necessitates introspection into the extent of computer related health disorders among student population. AIM: This study was undertaken to assess the pattern of computer usage and related visual problems, among University students in Ajman, United Arab Emirates. MATERIALS AND METHODS: A total of 500 Students studying in Gulf Medical University, Ajman and Ajman University of Science and Technology were recruited into this study. Demographic characteristics, pattern of usage of computers and associated visual symptoms were recorded in a validated self-administered questionnaire. Chi-square test was used to determine the significance of the observed differences between the variables. The level of statistical significance was at P < 0.05. The crude odds ratio (OR) was determined using simple binary logistic regression and adjusted OR was calculated using the multiple logistic regression. RESULTS: The mean age of participants was 20.4 (3.2) years. The analysis of racial data reveals that 50% (236/471) students were from Middle East, 32% (151/471) from other parts of Asia, 11% (52/471) from Africa, 4% (19/471) from America and 3% (14/471) from Europe. The most common visual problems reported among computer users were headache - 53.3% (251/471), burning sensation in the eyes - 54.8% (258/471) and tired eyes - 48% (226/471). Female students were found to be at a higher risk. Nearly 72% of students reported frequent interruption of computer work. Headache caused interruption of work in 43.85% (110/168) of the students while tired eyes caused interruption of work in 43.5% (98/168) of the students. When the screen was viewed at distance more than 50 cm, the prevalence of headaches decreased by 38% (50-100 cm - OR: 0.62, 95% of the confidence interval [CI]: 0.42-0.92). Prevalence of tired eyes increased by 89% when screen filters were not used (OR: 1.894, 95% CI: 1.065-3.368). CONCLUSION: High prevalence of vision related problems was noted among university students. Sustained periods of close screen work without screen filters were found to be associated with occurrence of the symptoms and increased interruptions of work of the students. There is a need to increase the ergonomic awareness among students and corrective measures need to be implemented to reduce the impact of computer related vision problems. PMID- 24761250 TI - Acute uterine inversion: a simple modification of hydrostatic method of treatment. AB - BACKGROUND: Hydrostatic method for reducing acute uterine inversion is simple method, if advocated properly. AIM: The aim of this study is to reduce the failures in technique in O'Sullivan's method in acute puerperal uterine inversion hence reducing maternal mortality and morbidity. SUBJECTS AND METHODS: This study was conducted over a f 6 year period s from 2007 to 2013. Women with acute uterine inversion immediately after delivered were included in the study. Repositioning of acute uterine inversion in six patients in emergency was done using trans-urethral resection of prostate set (TURP set), used in endoscopic resection of prostate, and two 3 L saline bags. RESULTS: The repositioning was successful in all requiring no anesthesia. CONCLUSIONS: This technique modification is improvisation of hydrostatic pressure with a trans-urethral resection of prostate set (TURP set) and 3 L saline bags and it is simple and effective and will definitely save women's lives; thus, reducing maternal morbidity and mortality. PMID- 24761251 TI - Hashimotos Thyroiditis with Coexistent Papillary Carcinoma and Non-hodgkin Lymphoma-thyroid. AB - Lymphocytic thyroiditis and hashimoto's thyroiditis (HT) are the two main forms of autoimmune thyroiditis among which the latter is most frequent. A vast majority of cases of papillary carcinoma and primary thyroid lymphoma (PTL) arise in the setting of HT. A case of 32-year-old female who presented with thyroid enlargement, post-thyroidectomy showed hashimoto's thyroiditis (HT) with coexistent papillary carcinoma and non-hodgkin lymphoma (NHL). The immunohistochemistry was positive for CD 20, CD 45, bcl 2 for lymphoma, low and high molecular cytokeratin for papillary carcinoma. The staging studies showed no evidence of metastasis. It is thus concluded that papillary carcinoma and NHL can coexist with HT. The thyroid lymphoma or papillary carcinoma has to be thought off, whenever patients presents with sudden enlargement in a known case of HT. A patient presenting with concomitant primary thyroid lymphoma and papillary thyroid carcinoma must be judiciously evaluated, since, the treatment has to prioritize the tumor with worst stage at the time of diagnosis. PMID- 24761252 TI - Reservoir complete denture in a patient with xerostomia secondary to radiotherapy for oral carcinoma: a case report and review of literature. AB - Xerostomia refers to a subjective sensation of dry mouth. A variety of factors can cause xerostomia including radiotherapy (RT) given for the treatment of oral carcinoma. Depending on the cause, treatment is provided to a patient suffering from xerostomia. In severe xerostomia salivary substitutes can be used and if the xerostomic patient is edentulous, then reservoir space for artificial salivary substitute can be created in partial as well as complete upper or lower dentures. The methods advocated so far for incorporating reservoir space in mandibular complete denture are costly, time consuming and require extra-laboratory steps. Therefore, the purpose of this article is to report a simpler method for fabrication of mandibular reservoir denture in a 67-year-old edentulous male patient suffering from xerostomia due to RT for oral carcinoma. PMID- 24761253 TI - Mucoepidermoid lung carcinoma in child. AB - Mucoepidermoid carcinoma (MEC) is a rare malignant tumor arising from the bronchial gland. A case of 6-year-old male child who presented with fever, hemoptysis and wheezing since 1month is reported. Chest X-ray showed features suggestive of foreign body with post-obstructive pneumonia and was treated for the same with medication without much improvement. Subsequently computerized tomography scan chest was carried out, which showed oval mass with speculated margin in right hilar region with distal segmental atelectasis. Bronchoscopy showed small growth with nodularity in the apical segmental bronchus of the right lower lobe with mucosal erosion and hence carried out broncho-alveolar lavage showed few atypical squamous cells. Patient underwent right lower lobectomy, which showed a grey white oval mass with solid and cystic areas in the right hilar region with extension in to the lung parenchyma. Histology of the tumor showed mixed solid and cystic areas with sheets of epidermoid cells and mucus filled cysts of irregular size. Areas of solid growth were composed of squamoid and intermediate cells. Hence, the final diagnosis of mucoepidermoid carcinoma (MEC) intermediate grade of the lung was made. Early diagnosis can be accomplished if the clinician is alert to persistent pneumonia, coughing and tumor obstruction on image studies. MEC is a comparatively rare low-grade tumor, which reportedly carries a good prognosis with early surgical intervention. PMID- 24761254 TI - Gorlin-goltz syndrome. AB - The Gorlin-Goltz syndrome (GGS) (the nevoid basal cell carcinoma syndrome) is a rare autosomal dominant syndrome caused due to mutations in the patched gene found on chromosome arm 9 q. It shows high penetrance and variable expressivity; is characterized by basal cell carcinomas, odontogenic keratocysts, palmar and/or plantar pits and ectopic calcifications of the falx cerebri. Until date, very few cases of GGS have been reported in India. Early diagnosis and treatment as well as genetic counseling are essential for this syndrome. A rare case report of a patient with characteristic features of GGS diagnosed at a rural dental college of Gujarat, India is presented here. This case report draws attention of the valuable role of dentist in diagnosis and early management of this syndrome. PMID- 24761255 TI - Unilateral closed lip schizencephaly with septo-optic dysplasia. AB - Schizencephaly is a rare malformation of the central nervous system. Both genetic and non-genetic etiologies like prenatal infections or ischemia have been postulated. Clinical manifestations most often include varying degrees of developmental delay, motor impairment and seizures. It can be associated with septo-optic dysplasia (SOD), optic nerve hypoplasia and absence of septum pellucidum, pachygyria, polymicrogyria, heterotopia and arachnoid cysts. We report a case of unilateral closed lip schizencephaly with SOD. PMID- 24761256 TI - A clinicopathological study of women with adnexal masses presenting with acute symptoms. AB - BACKGROUND: Abdominal pain is one of the most common presentations of adnexal pathology in gynecology. Early diagnosis and intervention is essential especially in adolescent girls and reproductive age group women to conserve reproductive function. AIM: The purpose of the following study is to assess the clinicopathologic outcome of women with adnexal masses presenting with acute pain. SUBJECTS AND METHODS: A retrospective study of women with adnexal masses who had surgical intervention for acute symptoms from June 2007 to May 2012 was undertaken. During the study period, a total of 57 women were operated for adnexal masses as emergency. RESULTS: Of the 57 women operated for adnexal masses as emergency, the most common pathology was teratoma 26% (15/57) followed by corpus luteal hemorrhage (16%) and endometriosis (14%). Laparoscopy was the initial surgical approach in just over 50% of patients, but surgery was completed laparoscopically only in about one-third of patients. Conservative surgery in the form of ovarian cystectomy was possible in 70% of patients. CONCLUSION: Complications of adnexal masses such as torsion and hemorrhage are common causes of acute abdominal pain. Timely diagnosis of the adnexal pathology and surgical intervention will help to preserve the reproductive outcome. Conservative surgery was possible in 70% of our study group. PMID- 24761257 TI - Legislation Alone is Enough to Combat Antibiotic Misuse? Certainly Not! PMID- 24761258 TI - Disclosure of parental HIV infection to children and psychosocial impact on children in China: a qualitative study. AB - This qualitative study aims to investigate parental HIV disclosure and psychological impact from the perspectives of their children. In-depth individual interviews with 47 children who had lost one or both parents to AIDS were conducted in China. All transcripts were coded using the software ATLAS.ti 5. Results showed that few of children knew of parental HIV status before the death of their parents. The main disclosers were the children's current caregivers. Some children knew about their parent's HIV infection based on their own observations or through overheard conversation, or their interactions with villagers. Both positive and negative psychological outcomes related to parental HIV disclosure were reported. Psychological counseling is needed for both parents and children to dealing with the parental HIV infection. PMID- 24761259 TI - Coronary Revascularization Using Bilateral Internal Thoracic Arteries: Safe with Skeletonization? AB - Substantial evidence exists to support a long-term survival benefit with bilateral internal thoracic artery (BITA) revascularization in coronary artery bypass grafting. However, this technique remains grossly underutilized worldwide and especially in the United States. In this review, we discuss evidence for the advantages of BITA grafting as well as the associated the risk of sternal wound complications. We then review a growing body of literature that suggests 'skeletonization' of the internal thoracic artery during harvest confers a protective benefit against sternal wound infection in patients receiving BITA. PMID- 24761260 TI - Caffeine, Alcohol, and Youth: A Toxic Mix. PMID- 24761261 TI - Effects of Caffeine Consumption by Women and Men on the Outcome of In Vitro Fertilization. AB - OBJECTIVE: The objective of this study was to estimate the association between caffeine consumption and in vitro fertilization (IVF) outcomes. METHODS: A total of 2474 couples were prospectively enrolled prior to undergoing their first cycle of IVF, contributing a total of 4716 IVF cycles. Discrete survival analysis adjusting for observed confounders was applied to quantify the relation between caffeine consumption and livebirth. Secondary outcomes of interest were oocyte retrieval, peak estradiol level, implantation rate, and fertilization rate. RESULTS: Overall, caffeine consumption by women was not significantly associated with livebirth (ptrend=0.74). Compared with women who do not drink caffeine, the likelihood of livebirth was not significantly different for women who drank low (>0-800 mg/week; odds ratio [OR]=1.00, 95% confidence interval [CI])=0.83-1.21), moderate (>800-1400 mg/week; OR=0.89, 95% CI=0.71-1.12), or high levels of caffeine (>1400 mg/week; OR=1.07, 95% CI=0.85-1.34). Greater caffeine intake by women was associated with a significantly lower peak estradiol level (ptrend=0.03), but was not associated with the number of oocytes retrieved (ptrend=0.75), fertilization rate (ptrend=0.10), or implantation rate (ptrend=0.23). There was no significant association between caffeine intake by men and livebirth (ptrend=0.27), fertilization (ptrend=0.72), or implantation (ptrend=0.24). The individual effects of consumption of coffee, tea, or soda by women or men were not related to livebirth. CONCLUSION: Caffeine consumption by women or men was not associated with IVF outcomes. PMID- 24761262 TI - Gender Differences in Subjective and Physiological Responses to Caffeine and the Role of Steroid Hormones. AB - BACKGROUND: We have shown previously that male and female adolescents differ in their responses to caffeine, but to date, the mechanisms underlying these gender differences are unknown. OBJECTIVE: The purpose of this study was to test the hypothesis that differences in circulating steroid hormones mediate gender differences in response to caffeine. METHODS: Subjective and physiological responses to caffeine were tested in adolescents using a double-blind, placebo controlled, crossover design. Participants were tested every 2 weeks for 8 weeks and received placebo and caffeine (2 mg/kg) twice each. Females were tested with placebo and caffeine in each phase of their menstrual cycle. Salivary concentrations of testosterone, estradiol, and progesterone were also measured. RESULTS: Males showed greater positive subjective effects than females. In females, higher levels of estradiol were associated with little or no subjective responses to caffeine, but lower levels of estradiol were associated with negative subjective responses to caffeine relative to placebo. There were gender differences in cardiovascular responses to caffeine, with males showing greater decreases in heart rate after caffeine administration than females, but females showing greater increases in diastolic blood pressure than males after caffeine administration. These gender differences may be related to steroid hormone concentrations. Blood pressure responses to caffeine were lower in males when estradiol was high, but higher in females when estradiol was high. CONCLUSIONS: When taken together, these findings suggest that males and females differ in their responses to caffeine and that these differences may be mediated by changes in circulating steroid hormones. PMID- 24761263 TI - Alcohol and Caffeine: The Perfect Storm. AB - Although it is widely believed that caffeine antagonizes the intoxicating effects of alcohol, the molecular mechanisms underlying their interaction are incompletely understood. It is known that both caffeine and alcohol alter adenosine neurotransmission, but the relationship is complex, and may be dose dependent. In this article, we review the available literature on combining caffeine and alcohol. Ethical constraints prohibit laboratory studies that would mimic the high levels of alcohol intoxication achieved by many young people in real-world settings, with or without the addition of caffeine. We propose a possible neurochemical mechanism for the increase in alcohol consumption and alcohol-related consequences that have been observed in persons who simultaneously consume caffeine. Caffeine is a nonselective adenosine receptor antagonist. During acute alcohol intake, caffeine antagonizes the "unwanted" effects of alcohol by blocking the adenosine A1 receptors that mediate alcohol's somnogenic and ataxic effects. The A1 receptor-mediated "unwanted" anxiogenic effects of caffeine may be ameliorated by alcohol-induced increase in the extracellular concentration of adenosine. Moreover, by means of interactions between adenosine A2A and dopamine D2 receptors, caffeine-mediated blockade of adenosine A2A receptors can potentiate the effects of alcohol-induced dopamine release. Chronic alcohol intake decreases adenosine tone. Caffeine may provide a "treatment" for the withdrawal effects of alcohol by blocking the effects of upregulated A1 receptors. Finally, blockade of A2A receptors by caffeine may contribute to the reinforcing effects of alcohol. PMID- 24761264 TI - Evaluating Dependence Criteria for Caffeine. AB - Background: Although caffeine is the most widely used mood-altering drug in the world, few studies have operationalized and characterized Diagnostic and Statistical Manual IV (DSM-IV) substance dependence criteria applied to caffeine. Methods: As a part of a nosological study of substance use disorders funded by the National Institute on Drug Abuse, we assessed caffeine use and dependence symptoms among high school and college students, drug treatment patients, and pain clinic patients who reported caffeine use in the last 7 days and also reported use of alcohol, nicotine, or illicit drugs within the past year (n=167). Results: Thirty-five percent met the criteria for dependence when all seven of the adopted DSM dependence criteria were used. Rates of endorsement of several of the most applicable diagnostic criteria were as follows: 26% withdrawal, 23% desire to cut down or control use, and 44% continued use despite harm. In addition, 34% endorsed craving, 26% said they needed caffeine to function, and 10% indicated that they talked to a physician or counselor about problems experienced with caffeine. There was a trend towards increased caffeine dependence among those dependent on nicotine or alcohol. Within a subgroup that had used caffeine, alcohol, and nicotine in the past year, 28% fulfilled criteria for caffeine dependence compared to 50% for alcohol and 80% for nicotine. Conclusion: The present study adds to a growing literature suggesting the reliability, validity, and clinical utility of the caffeine dependence diagnosis. Recognition of caffeine dependence in the DSM-V may be clinically useful. PMID- 24761265 TI - The Effects of Dietary Caffeine Use and Abstention on Blood Oxygen Level Dependent Activation and Cerebral Blood Flow. AB - BACKGROUND: Caffeine is a known vasoconstrictor that reduces resting cerebral blood flow (CBF) throughout the brain. This effect may be problematic in functional magnetic resonance imaging (fMRI) research, as the blood oxygen level dependent (BOLD) signal is a complex interaction of CBF and other factors that are dependent on changes in neural activity. It is unknown whether changes in the BOLD signal during an fMRI experiment could be affected by subjects' recent use or abstinence from dietary caffeine. METHODS: Here, we report two similar studies (n=45 and 17) that measure the effects of caffeine on BOLD activation, BOLD time course parameters, and CBF. Using a factorial design, low, moderate, and high caffeine consumers received either caffeine (250 mg) or placebo during normal caffeine use (satiated state) or after 30 hours of abstention (abstinent state). The fMRI of a reaction time task and resting-state CBF were collected. RESULTS: In general, acute caffeine administration reduced the time to peak and full width at half maximum of the BOLD time course, and CBF across both studies. Caffeine also produced a small reduction in BOLD activation. The majority of these reductions across measures were moderated by neither the level of caffeine use, nor the abstinent or satiated state. CONCLUSIONS: These results suggest that dietary caffeine use does not produce a significant effect on task-related BOLD activation. PMID- 24761266 TI - Alcohol Mixed with Energy Drink Use and Sexual Risk-Taking: Casual, Intoxicated, and Unprotected Sex. AB - OBJECTIVE: This study examined the confluence of several behaviors common to U.S. young adults: caffeinated energy drink use, alcohol use, and sexual risk-taking. The author examined relationships between the use of energy drinks mixed with alcohol (AmEDs) and three sexual risk behaviors: casual sex (i.e., intercourse with a nonexclusive and/or nonromantic partner), intoxicated sex (i.e., intercourse while under the influence of alcohol and/or illicit drugs), and unprotected sex (i.e., intercourse without use of a condom). METHOD: Logistic regression analyses were employed to analyze data from a cross-sectional survey of 648 sexually active undergraduate students at a large public university. RESULTS: After controlling for risk-taking norms and frequency of noncaffeinated alcohol use, AmED use was associated with elevated odds of casual sex and intoxicated sex but not unprotected sex. CONCLUSIONS: Although further studies are needed to test for event-level relationships, AmED use should be considered a possible risk factor for potentially health-compromising sexual behaviors. PMID- 24761267 TI - Effects of Alcohol, Coffee, and Tobacco, Alone or in Combination, on Physiological Parameters and Anxiety in a Young Population. AB - OBJECTIVE: The objective was to evaluate the effects of a single dose of alcohol, caffeine, and nicotine, alone or in combination, on physiological parameters (systolic and diastolic blood pressure [SBP and DBP] and heart rate [HR]) and state-trait anxiety in healthy young volunteers. METHOD: The procedure reproduces the conditions under which the subjects (n=76) usually ingest alcohol (through an alcoholic beverage), caffeine (through a cup of coffee), and nicotine (by smoking a cigarette), separately or in combination, according to their consumption habits of each individual. SBP and DBP, HR, and state anxiety (SA) were registered before (phase 1) and after (phase 2) treatment. RESULTS: Intake of alcohol or alcohol-nicotine reduced DBP. Comparisons between control and combined treatment (coffee-alcohol-nicotine) groups revealed a decrease in HR in the former group but not in the latter. The coffee consumers alone exhibited a tendency toward an increase in SA, while the control group showed a tendency toward a decrease in this measure. When Phase 1 and Phase 2 were compared, a decrease was observed in SBP (alcohol and coffee-alcohol groups), DBP (alcohol and alcohol-nicotine groups), HR (all groups, except coffee-alcohol and coffee-alcohol-nicotine groups), and SA (coffee-alcohol-nicotine group). CONCLUSIONS: (i) A low dose of alcohol, either alone or in combination with a cigarette, decreases DBP but not SBP; (ii) the polyconsumption of coffee, alcohol, and nicotine blocks the adaptation response (the reduction in HR in control subjects in the second phase); (iii) an increase of SA is observed after consuming coffee, while the opposite occurs in control subjects (a decrease of SA). PMID- 24761268 TI - Caffeine Enhances Heart Rate Variability in Middle-Aged Healthy, But Not Heart Failure Subjects. AB - BACKGROUND: In chronic heart failure (CHF) due to left ventricular dysfunction, diminished heart rate variability (HRV) is an independent predictor of poor prognosis. Caffeine has been shown to increase HRV in young healthy subjects. Such an increase may be of potential benefit to patients with CHF. OBJECTIVE: We hypothesized that intravenous infusion of caffeine would increase HRV in CHF, and in age-matched healthy control subjects. METHODS: On two separate days, 11 patients (1F) with CHF (age=51.3+/-4.6 years; left ventricular ejection fraction=18.6+/-2.7%; mean+/-standard error) and 10 healthy control subjects (age=48.0+/-4.0) according to a double-blind randomization design, received either saline or caffeine (4 mg/kg) infusion. We assessed HRV over 7 minutes of supine rest (fast Fourier Transform analysis) to determine total spectral power as well as its high-frequency (HF) (0.15-0.50 Hz) and low-frequency (LF) (0.05 0.15 Hz) components, and recorded muscle sympathetic nerve activity (MSNA) directly from the peroneal nerve (microneurography). RESULTS: In healthy control subjects, compared with saline, caffeine reduced both heart rate and sympathetic nerve traffic (p<=0.003) and increased the ratio of HF/total power (p<=0.05). Baseline LF power and the ratio LF/HF were significantly lower in CHF compared with controls (p=0.02), but caffeine had no effect on any element of HRV. CONCLUSIONS: Caffeine increases cardiac vagal heart rate modulation and reduces MSNA in middle-aged healthy subjects, but not in those with CHF. PMID- 24761270 TI - Combined Effects of Ephedrine-Containing Dietary Supplements, Caffeine, and Nicotine on Morphology and Ultrastructure of Rat Hearts. AB - Cigarette smokers have an increased risk for coronary artery disease. Nicotine present in cigarettes can adversely affect the cardiovascular system via stimulation of both sympathetic and parasympathetic neurons. Caffeine, another cardiovascular and central nervous system (CNS) stimulant, is commonly found in Ephedra and Ephedra-free dietary supplements. These caffeine-containing supplements also have been linked to cardiovascular toxicities. Although no longer on the U.S market, Ephedra-containing supplements are another source of cardiovascular and CNS stimulants, namely the ephedrine alkaloids. Together caffeine, nicotine, and ephedrine can individually stress the cardiovascular system, and an overlap of these agents is predicted in smokers and dieters. To understand the collective effects of these stimulants on the heart morphology and ultrastructure, rats were exposed to synthetic combinations of nicotine (0.2 mg/kg/day), ephedrine (0-30 mg/kg/day), and/or caffeine (0-24 mg/kg/day) as well as an extract from a caffeine-containing Ephedra supplement (Metabolife 356). After exposure for 3 days, the hearts were removed and examined for hypersensitivity myocarditis and myocardial necrosis. None of the drugs tested alone affected heart tissue morphology, nor were atypical cardiac cells observed. However, in combination, significant interactions were found between caffeine and ephedrine; the interventricular septum was most susceptible, with a significant increase in atypical cardiac cells observed. Nicotine pretreatment caused greater susceptibility to cardiotoxicity associated with combinations of caffeine + ephedrine or Metabolife, particularly in the left ventricle wall. These results indicate that sympathomimetic combinations present in Ephedra supplements may have produced cardiotoxicity reported in consumers of these products. Moreover, the presence of nicotine exacerbates these toxic effects. PMID- 24761269 TI - Differential Effect of Caffeine Consumption on Diverse Brain Areas of Pregnant Rats. AB - BACKGROUND: It has previously been shown that during gestation, the mother's brain has an increase in glial fibrillary acidic protein (GFAP)-immunoreactivity (-ir) and a decrease in the mRNA level of A1 adenosine receptor. Little is known about the A2A adenosine receptor in the maternal brain, and whether caffeine consumption throughout gestational period modifies GFAP and adenosine receptor density in specific brain areas. This study was undertaken to investigate the protein density of GFAP and adenosine receptors (A1 and A2A subtypes) in different regions of pregnant rat brain and the possible effect of caffeine on these proteins. METHODS: For this purpose, we examined the GFAP-, A1- and A2A-ir in the cingulate cortex (Cg2), dentate gyrus (DG), medial preoptic area (mPOA), secondary somatosensory cortex (S2), and striatum (Str) of pregnant Wistar rats (drug-free tap water or water with 1g/L diluted caffeine). RESULTS: We show a consistent and highly significant reduction of GFAP-ir in caffeine-treated pregnant rats in most of the areas analyzed. Our data demonstrate that caffeine consumption induces a significant increase of A2A-ir in Str. Concerning A1 receptor, the observed changes are dependent on the region analyzed; this receptor density is increased in Cg2, DG, and mPOA and decreased in the somatosensory cortex and Str. The results were confirmed by Western blotting. CONCLUSIONS: Our results suggest that chronic caffeine exposure could modify the physiolological situation of gestation by a reorganization of the neural circuits and the adenosine neuromodulator system. PMID- 24761271 TI - A Preliminary Study on the Effects of Self-Reported Dietary Caffeine on Pain Experience and Postoperative Analgesia. AB - BACKGROUND: Caffeine reduces the amount of analgesic medications necessary to provide postoperative pain (POP) relief and augments treatments for headaches and dental pain. Despite considerable evidence of its beneficial effects, little is understood about the role of dietary caffeine consumption on baseline pain sensitivity or POP following oral surgery. METHOD: Baseline experimental pain testing (quantitative sensory testing [QST]) using four stimulus modalities was conducted on 30 healthy adults (53% females) before surgical extraction of four third molars. Self-reported caffeine ingestion was reported before QST, and on the day of surgery, preoperative and postoperative caffeine plasma concentrations (CPC) were measured by mass spectrometry. POP ratings were obtained at timed intervals. RESULTS: In QST, compared to subjects who self-reported no caffeine intake, those who self-reported caffeine ingestion demonstrated a higher pain sensitivity, particularly, on ramp and hold sustained heat at 44 degrees C and 46 degrees C, as well as a lower heat pain threshold and tolerance (p=0.05). Differences approached significance (p=0.06) in POP between subjects with CPC above 300 ng/mL and those with CPC below 300 ng/mL. Specifically, those with >300 ng/mL CPC had a slightly lower POP (mean 2.43, range 0-5) compared to those with <300 ng/mL CPC whose POP ratings were slightly higher (mean 2.89) with a greater variability (range 0-9.5). CONCLUSIONS: Self-reported, dietary caffeine intake was associated with higher QST ratings with lower threshold and tolerance particularly on heat pain modalities. External factors (i.e., analgesic dosage) may have played a role in the analgesic effects of caffeine on POP in oral surgery, especially in individuals with CPC exceeding 300 ng/mL who reported lower pain. PMID- 24761273 TI - Coffee Consumption Associated with Increased Mortality of Women with Breast Cancer. AB - BACKGROUND: There has been some speculation that caffeine consumption may affect breast cancer. Most case-control studies have not documented evidence of a caffeine-breast cancer incidence link; however, there has been very little analysis of the possible effects of caffeine consumption on breast cancer survival. METHODS: We examined overall a 20-year survival of 96 women treated for breast cancer between 1990 and 1994. As part of their health history, these women were asked about coffee drinking. RESULTS: Fifty-three women drank one cup a day (79.2% survival), 22 women had two cups a day (72.7% survival), and 21 women drank three or more cups a day (42.9% survival). The effect of coffee consumption on survival was significant (p=0.006, the log rank test). To exclude the effects of lymph node involvement, age at diagnosis, and smoking history, Cox regression was performed. The effect of coffee was significant (p=0.001), independent of the effects of lymph node involvement (p=0.012) and age at diagnosis (p=0.014), and unrelated to a smoking history (p=0.721). CONCLUSION: Fatigued breast cancer survivors have an abnormal proinflammatory cytokine activity, an average of 5 years after diagnosis, as well as significant serum cortisol derangements compared to other survivors. One possible interpretation of our results suggests that there is an abnormal hypothalamic-pituitary-adrenal axis functioning in breast cancer patients with persistent fatigue, who might be using coffee to self medicate. In other words, coffee consumption in the present study might be a surrogate marker for fatigue. Because of the paucity of data regarding caffeine intake, poor sleep, fatigue, and breast cancer survival, further studies could be worthwhile. PMID- 24761274 TI - Caffeine and Substance Use Disorders. PMID- 24761275 TI - Caffeinated Alcohol, Sensation Seeking, and Injury Risk. AB - BACKGROUND: College students who consume caffeinated alcoholic beverages (CaffAlc) are at increased injury risk. This study examines the extent to which a sensation-seeking personality accounts for the relationship between consumption of CaffAlc and negative outcomes. METHODS: A Web-based survey was administered to stratified random samples of 4907 college students from eight North Carolina universities in Fall 2009. Sensation seeking was assessed using the Brief Sensation-Seeking Scale (BSSS) (alpha=0.81). Data were analyzed using linear and logistic regression. RESULTS: 3390 students (71.2%) reported past 30-day drinking, of whom 786 (23.2%) consumed CaffAlc. CaffAlc past 30-day drinkers had higher BSSS scores (3.8 vs. 3.4; p<0.001), compared to non-CaffAlc drinkers. Consumption of CaffAlc was associated with more frequent binge drinking (p<0.001) and drunken days in a typical week (p<0.001), even after adjusting for the BSSS score. CaffAlc students were more likely to be taken advantage of sexually (adjusted odds ratio [AOR]=1.70, p=0.012), drive under the influence of alcohol (AOR=2.00, p<0.001), and ride with a driver under the influence of alcohol (AOR=1.87, p<0.001). Injury requiring medical treatment was more prevalent among CaffAlc students with higher BSSS-8 scores (interaction p=0.024), even after adjustment for drinking levels and student characteristics. CONCLUSIONS: Sensation seeking does not fully account for the increase in risky drinking among college students who consume CaffAlc, nor does it moderate the relationship between CaffAlc and drinking behaviors. Sensation seeking moderates the risk of alcohol-associated injury requiring medical treatment among college students who consume CaffAlc. Those with strong sensation-seeking dispositions are at the highest risk of alcohol-associated injury requiring medical treatment. PMID- 24761276 TI - Caffeine Withdrawal and Dependence: A Convenience Survey Among Addiction Professionals. AB - AIMS: Caffeine withdrawal was included in the research appendix of the DSM-IV to encourage additional research to assist with determining its status for the next version of the manual. Caffeine dependence was not included because of a lack of empirical research at the time of publication. This study assessed the beliefs of addiction professionals about the clinical importance of caffeine withdrawal and dependence. METHODS: A 6-item survey was developed and delivered electronically to the members of six professional organizations that focus on addiction. Open ended comments were also solicited. Five hundred members responded. RESULTS: The majority (95%) thought that cessation of caffeine could produce a withdrawal syndrome, and that caffeine withdrawal can have clinical importance (73%); however, only half (48%) thought that caffeine withdrawal should be included in the Diagnostic and Statistical Manual of Mental Disorders (DSM). A majority (58%) believed that some people develop caffeine dependence; however, only 44% indicated that it should be in the DSM. Comments suggested that trepidation about inclusion of caffeine diagnoses was due to the concerns about the field of psychiatry being criticized for including common disorders with a relatively low clinical severity. Others, however, expressed an urgent need to take caffeine related problems more seriously. CONCLUSIONS: The majority of addiction professionals believe that caffeine withdrawal and dependence disorders exist and are clinically important; however, these professionals are divided in whether caffeine withdrawal and dependence should be included in DSM. Wider dissemination of the extant literature on caffeine withdrawal and additional research on caffeine dependence will be needed to provide additional guidance to policymakers and healthcare workers. PMID- 24761272 TI - The Impact of Caffeine on the Behavioral Effects of Ethanol Related to Abuse and Addiction: A Review of Animal Studies. AB - The impact of caffeine on the behavioral effects of ethanol, including ethanol consumption and abuse, has become a topic of great interest due to the rise in popularity of the so-called energy drinks. Energy drinks high in caffeine are frequently taken in combination with ethanol under the popular belief that caffeine can offset some of the intoxicating effects of ethanol. However, scientific research has not universally supported the idea that caffeine can reduce the effects of ethanol in humans or in rodents, and the mechanisms mediating the caffeine-ethanol interactions are not well understood. Caffeine and ethanol have a common biological substrate; both act on neurochemical processes related to the neuromodulator adenosine. Caffeine acts as a nonselective adenosine A1 and A2A receptor antagonist, while ethanol has been demonstrated to increase the basal adenosinergic tone via multiple mechanisms. Since adenosine transmission modulates multiple behavioral processes, the interaction of both drugs can regulate a wide range of effects related to alcohol consumption and the development of ethanol addiction. In the present review, we discuss the relatively small number of animal studies that have assessed the interactions between caffeine and ethanol, as well as the interactions between ethanol and subtype-selective adenosine receptor antagonists, to understand the basic findings and determine the possible mechanisms of action underlying the caffeine ethanol interactions. PMID- 24761277 TI - Paraxanthine: Connecting Caffeine to Nitric Oxide Neurotransmission. AB - Recent results obtained in our laboratory indicate that paraxanthine, the main metabolite of caffeine in humans, produces a significantly stronger locomotor activation in rats than caffeine. Furthermore, paraxanthine also produced a very significant increase in striatal extracellular concentrations of dopamine. Searching for an additional mechanism other than adenosine antagonism responsible for these psychostimulant-like effects, it was found that paraxanthine, but not caffeine, inhibited cGMP-preferring phosphodiesterases. Furthermore, interrupting nitric oxide neurotransmision (inhibiting nitric oxide synthase) significantly decreased both the locomotor-activating and the dopamine-releasing effects of paraxanthine. These results open up some obvious questions about the role of paraxanthine in the pharmacological effects of caffeine. PMID- 24761278 TI - Caffeine Content Labeling: A Missed Opportunity for Promoting Personal and Public Health. AB - Current regulation of caffeine-containing products is incoherent, fails to protect consumers' interests, and should be modified in multiple ways. We make the case for one of the regulatory reforms that are needed: all consumable products containing added caffeine should be required by the Food and Drug Administration (FDA) to include caffeine quantity on their labels. Currently, no foods or beverages that contain caffeine are required to include caffeine content on their labels. Strengthening these lax labeling requirements could prevent direct caffeine-induced harm, protect those most vulnerable to caffeine-related side effects, and enhance consumer autonomy and effective caffeine use. Consumers have an interest in regulating their intake of caffeine and thus, ought to know how much caffeine their foods and beverages contain. PMID- 24761280 TI - Effect of Caffeinated Soft Drinks on Salivary Flow. AB - BACKGROUND: Soft drinks containing caffeine have been associated with more aggressive forms of dental decay. Cariogenicity of caffeinated soft drinks may be attributed to the effect of caffeine on salivary flow. This study assessed whether caffeinated soft drinks produced short-term oral dryness in healthy adults. METHODS: The authors collected saliva on two separate days from 35 participants before and one hour after drinking a soft drink. On one of the days the soft drink was caffeinated and on the other day it was not. Saliva collection involved 15 minutes unstimulated whole saliva, 5 minutes paraffin-stimulated whole saliva, and 10 seconds labial minor salivary gland output. RESULTS: Unstimulated and stimulated flow rates slightly increased and minor gland output slightly decreased one hour after the soft drink consumption regardless of caffeine content. These changes were not statistically significant (two-period two-treatment crossover trial using two-stage Grizzle model, p>0.05). A linear mixed model statistic did not show the caffeine effect on salivary flow rate. CONCLUSIONS: Caffeinated soft drink consumption had no significant effect on salivary flow rate after one hour by any of the three measures employed in this study. Caffeine's contribution to the cariogenicity of soft drinks is likely by centrally-mediated effects on consumption patterns. PMID- 24761282 TI - Chronic Caffeine Administration Attenuates Vascular Injury-Induced Neointimal Hyperplasia in Rats. AB - Background: Inflammation is considered to be a major initiator to angioplasty induced vascular restenosis. Proinflammatory cytokines stimulate vascular smooth muscle cell (VSMC) migration and proliferation leading to neointimal hyperplasia. It has been reported that chronic caffeine use suppresses the production of proinflammatory cytokine TNF-alpha (tumor necrosis factor Alpha) and alters adenosine receptor expression in human neutrophils, indicating that caffeine may attenuate vascular injury-induced inflammation and subsequent neointimal hyperplasia. Our current study was designed to test the hypothesis that chronic caffeine treatment decreases vascular injury-induced neointimal hyperplasia by suppressing VSMC migration and proliferation. Methods and Results: The experiments were carried out using both in vivo (rat carotid artery injury model) and in vitro (VSMCs isolated from rat aorta) models. Male Sprague-Dawley rats that received chronic caffeine treatment (10 and 20 mg/kg per day, through oral gavage) showed a significant decrease in neointimal hyperplasia when compared to rats that received vehicle. To understand the underlying mechanisms, we tested if caffeine inhibits fetal bovine serum (FBS)-induced VSMC migration and proliferation. We found that caffeine substantially suppressed FBS-induced VSMC migration and proliferation. The attenuation of FBS-stimulated cell migration is dose dependent. Conclusion: Together, our results suggest that chronic treatment with high concentrations of caffeine attenuates vascular injury-induced neointimal hyperplasia by suppressing smooth muscle cell migration and proliferation in rats. PMID- 24761279 TI - Caffeine Use Disorder: A Comprehensive Review and Research Agenda. AB - Caffeine is the most commonly used drug in the world. Although consumption of low to moderate doses of caffeine is generally safe, an increasing number of clinical studies are showing that some caffeine users become dependent on the drug and are unable to reduce consumption despite knowledge of recurrent health problems associated with continued use. Thus, the World Health Organization and some health care professionals recognize caffeine dependence as a clinical disorder. In this comprehensive literature review, we summarize published research on the biological evidence for caffeine dependence; we provide a systematic review of the prevalence of caffeine dependence and rates of endorsement of clinically meaningful indicators of distress and functional impairment among habitual caffeine users; we discuss the diagnostic criteria for Caffeine Use Disorder-a condition for further study included in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.); and we outline a research agenda to help guide future clinical, epidemiological, and genetic investigations of caffeine dependence. Numerous controlled laboratory investigations reviewed in this article show that caffeine produces behavioral and physiological effects similar to other drugs of dependence. Moreover, several recent clinical studies indicate that caffeine dependence is a clinically meaningful disorder that affects a nontrivial proportion of caffeine users. Nevertheless, more research is needed to determine the reliability, validity, and prevalence of this clinically important health problem. PMID- 24761281 TI - Caffeine at Moderate Doses Can Inhibit Acupuncture-Induced Analgesia in a Mouse Model of Postoperative Pain. AB - BACKGROUND: The use of acupuncture in the treatment of pain conditions has been extensively investigated. However, the influence of dietary ingredients on acupuncture-induced analgesia (AA) remains unexplored. Recently, the role of adenosine receptors in AA has been shown, and caffeine, one of the world's most commonly consumed dietary ingredients, is an antagonist of these receptors. In this study, the postincisional pain model was used to investigate caffeine's influence on AA. METHOD: Mice submitted to plantar incision surgery were treated with acupuncture needling after administration of acute or chronic caffeine. Acupuncture needling was performed using two different types of stimuli, manual acupuncture and electroacupuncture bilaterally in the acupoint SP6. RESULTS: We found that acute preadministration of caffeine (10 mg/kg, i.p.) completely reversed AA in both types of acupuncture. In the chronic preadministration, we used two doses that mimicked the average daily caffeine consumption in Western countries and China. Interestingly, the Western dose of caffeine (70 mg/kg/day) administered during 8 days in the drinking water reversed AA and the Chinese dose (4 mg/kg/day) administered during the same period did not. CONCLUSIONS: These results indicate that the use of caffeine can inhibit the analgesic effect of different forms of acupuncture. In addition, our findings suggest that doses of caffeine relevant to dietary human intake levels could be a confounding factor in the context of acupuncture research. PMID- 24761283 TI - Continuous noninvasive monitoring of changes in human skin optical properties during oral intake of different sugars with optical coherence tomography. AB - The objective of this study was to evaluate the effects of blood glucose concentration (BGC) on in vivo human skin optical properties after oral intake of different sugars. In vivo optical properties of human skin were measured with a spectral domain optical coherence tomography (SD-OCT). Experimental results show that increase of BGC causes a decrease in the skin attenuation coefficient. And the maximum decrements in mean attenuation coefficient of skin tissue after drinking glucose, sucrose and fructose solution are 47.0%, 36.4% and 16.5% compared with that after drinking water, respectively (p < 0.05). The results also show that blood glucose levels of the forearm skin tissue are delayed compared with finger-stick blood glucose, and there are significant differences in the time delays after oral intake of different sugars. The time delay between mean attenuation coefficient and BGC after drinking glucose solution is evidently larger than that after drinking sucrose solution, and that after drinking sucrose solution is larger than that after drinking fructose solution. Our pilot studies indicate that OCT technique is capable of non-invasive, real-time, and sensitive monitoring of skin optical properties in human subjects during oral intake of different sugars. PMID- 24761285 TI - Nanosecond laser pulse stimulation of spiral ganglion neurons and model cells. AB - Optical stimulation of the inner ear has recently attracted attention, suggesting a higher frequency resolution compared to electrical cochlear implants due to its high spatial stimulation selectivity. Although the feasibility of the effect is shown in multiple in vivo experiments, the stimulation mechanism remains open to discussion. Here we investigate in single-cell measurements the reaction of spiral ganglion neurons and model cells to irradiation with a nanosecond-pulsed laser beam over a broad wavelength range from 420 nm up to 1950 nm using the patch clamp technique. Cell reactions were wavelength- and pulse-energy-dependent but too small to elicit action potentials in the investigated spiral ganglion neurons. As the applied radiant exposure was much higher than the reported threshold for in vivo experiments in the same laser regime, we conclude that in a stimulation paradigm with nanosecond-pulses, direct neuronal stimulation is not the main cause of optical cochlea stimulation. PMID- 24761284 TI - Optical stimulation enables paced electrophysiological studies in embryonic hearts. AB - Cardiac electrophysiology plays a critical role in the development and function of the heart. Studies of early embryonic electrical activity have lacked a viable point stimulation technique to pace in vitro samples. Here, optical pacing by high-precision infrared stimulation is used to pace excised embryonic hearts, allowing electrophysiological parameters to be quantified during pacing at varying rates with optical mapping. Combined optical pacing and optical mapping enables electrophysiological studies in embryos under more physiological conditions and at varying heart rates, allowing detection of abnormal conduction and comparisons between normal and pathological electrical activity during development in various models. PMID- 24761286 TI - Accurate position tracking of optically trapped live cells. AB - Optical trapping is a powerful tool in Life Science research and is becoming common place in many microscopy laboratories and facilities. There is a growing need to directly trap the cells of interest rather than introduce beads to the sample that can affect the fundamental biological functions of the sample and impact on the very properties the user wishes to observe and measure. However, instabilities while tracking large inhomogeneous objects, such as cells, can make tracking position, calibrating trap strength and making reliable measurements challenging. These instabilities often manifest themselves as cell roll or re orientation and can occur as a result of viscous drag forces and thermal convection, as well as spontaneously due to Brownian forces. In this paper we discuss and mathematically model the cause of this roll and present several experimental approaches for tackling these issues, including using a novel beam profile consisting of three closely spaced traps and tracking a trapped object by analysing fluorescence images. The approaches presented here trap T cells which form part of the adaptive immune response system, but in principle can be applied to a wide range of samples where the size and inhomogeneous nature of the trapped object can hinder particle tracking experiments. PMID- 24761287 TI - Effect of temperature and fixation on the optical properties of atherosclerotic tissue: a validation study of an ex-vivo whole heart cadaveric model. AB - Atherosclerotic plaque composition can be imaged using the optical attenuation coefficient derived from intravascular optical coherence tomography (OCT) data. The relation between optical properties and tissue type has been established on autopsy tissues. In this study, we validate an ex-vivo model for the effect of temperature and tissue fixation on optical parameters. We studied the optical attenuation of human coronary arteries at three temperatures, before and after formalin fixation. We developed an en-face longitudinal display of attenuation data of the OCT pullbacks. Using the unfixed, body-temperature condition image as a standard, and after extensive registration with other condition images, we quantify the differences in optical attenuation and the backscattered intensity. The results suggest that tissue fixation and temperature do not introduce systematic errors in studies of arterial optical properties. PMID- 24761288 TI - Photonic integrated Mach-Zehnder interferometer with an on-chip reference arm for optical coherence tomography. AB - Optical coherence tomography (OCT) is a noninvasive, three-dimensional imaging modality with several medical and industrial applications. Integrated photonics has the potential to enable mass production of OCT devices to significantly reduce size and cost, which can increase its use in established fields as well as enable new applications. Using silicon nitride (Si3N4) and silicon dioxide (SiO2) waveguides, we fabricated an integrated interferometer for spectrometer-based OCT. The integrated photonic circuit consists of four splitters and a 190 mm long reference arm with a foot-print of only 10 * 33 mm(2). It is used as the core of a spectral domain OCT system consisting of a superluminescent diode centered at 1320 nm with 100 nm bandwidth, a spectrometer with 1024 channels, and an x-y scanner. The sensitivity of the system was measured at 0.25 mm depth to be 65 dB with 0.1 mW on the sample. Using the system, we imaged human skin in vivo. With further optimization in design and fabrication technology, Si3N4/SiO2 waveguides have a potential to serve as a platform for passive photonic integrated circuits for OCT. PMID- 24761289 TI - Multiple-object geometric deformable model for segmentation of macular OCT. AB - Optical coherence tomography (OCT) is the de facto standard imaging modality for ophthalmological assessment of retinal eye disease, and is of increasing importance in the study of neurological disorders. Quantification of the thicknesses of various retinal layers within the macular cube provides unique diagnostic insights for many diseases, but the capability for automatic segmentation and quantification remains quite limited. While manual segmentation has been used for many scientific studies, it is extremely time consuming and is subject to intra- and inter-rater variation. This paper presents a new computational domain, referred to as flat space, and a segmentation method for specific retinal layers in the macular cube using a recently developed deformable model approach for multiple objects. The framework maintains object relationships and topology while preventing overlaps and gaps. The algorithm segments eight retinal layers over the whole macular cube, where each boundary is defined with subvoxel precision. Evaluation of the method on single-eye OCT scans from 37 subjects, each with manual ground truth, shows improvement over a state-of-the art method. PMID- 24761290 TI - Contact-free monitoring of circulation and perfusion dynamics based on the analysis of thermal imagery. AB - Acute circulatory disorders are commonly associated with systemic inflammatory response (SIRS) and sepsis. During sepsis, microcirculatory perfusion is compromised leading to tissue hypoperfusion and potentially to multiple organ dysfunction. In the present study, acute lung injury (ALI), one of the major causes leading to SIRS and sepsis, was experimentally induced in six female pigs. To investigate the progress of body temperature distribution, measurements with a long-wave infrared camera were carried out. Temperature centralization was evidenced during ALI owing to impairments of peripheral perfusion. In addition, statistical analysis demonstrated strong correlations between (a) standard deviation of the skin temperature distribution (SD) and shock index (SI) (p<0.0005), (b) SD and mean arterial pressure (MAP) (p<0.0005), (c) DeltaT/Deltax and SI (p<0.0005), as well as between (d) DeltaT/Deltax and MAP (p<0.0005). For clarification purposes, DeltaT/Deltax is a parameter implemented to quantify the spatial temperature gradient. This pioneering study created promising results. It demonstrated the capacity of infrared thermography as well as of the indexes, SD and DeltaT/Deltax, to detect impairments in both circulation and tissue perfusion. PMID- 24761291 TI - Spectral OCT with speckle contrast reduction for evaluation of the healing process after PRK and transepithelial PRK. AB - We evaluate Spectral OCT (SOCT) with a speckle contrast reduction technique using resonant scanner for assessment of corneal surface changes after excimer laser photorefractive keratectomy (PRK) and we compare healing process between conventional PRK and transepithelial PRK. The measurements were performed before and after the surgery. Obtained results show that SOCT with a resonant scanner speckle contrast reduction is capable of providing information regarding the healing process after PRK. The main difference between the healing processes of PRK and TransPRK, assessed by SOCT, was the time to cover the stroma with epithelium, which was shorter in the TransPRK group. PMID- 24761292 TI - Motion-artifact-robust, polarization-resolved second-harmonic-generation microscopy based on rapid polarization switching with electro-optic Pockells cell and its application to in vivo visualization of collagen fiber orientation in human facial skin. AB - Polarization-resolved second-harmonic-generation (PR-SHG) microscopy is a powerful tool for investigating collagen fiber orientation quantitatively with low invasiveness. However, the waiting time for the mechanical polarization rotation makes it too sensitive to motion artifacts and hence has hampered its use in various applications in vivo. In the work described in this article, we constructed a motion-artifact-robust, PR-SHG microscope based on rapid polarization switching at every pixel with an electro-optic Pockells cell (PC) in synchronization with step-wise raster scanning of the focus spot and alternate data acquisition of a vertical-polarization-resolved SHG signal and a horizontal polarization-resolved one. The constructed PC-based PR-SHG microscope enabled us to visualize orientation mapping of dermal collagen fiber in human facial skin in vivo without the influence of motion artifacts. Furthermore, it implied the location and/or age dependence of the collagen fiber orientation in human facial skin. The robustness to motion artifacts in the collagen orientation measurement will expand the application scope of SHG microscopy in dermatology and collagen related fields. PMID- 24761293 TI - Repeatability of in vivo 3D lamina cribrosa microarchitecture using adaptive optics spectral domain optical coherence tomography. AB - We demonstrate the repeatability of lamina cribrosa (LC) microarchitecture for in vivo 3D optical coherence tomography (OCT) scans of healthy, glaucoma suspects, and glaucomatous eyes. Eyes underwent two scans using a prototype adaptive optics spectral domain OCT (AO-SDOCT) device from which LC microarchitecture was semi automatically segmented. LC segmentations were used to quantify pore and beam structure through several global microarchitecture parameters. Repeatability of LC microarchitecture was assessed qualitatively and quantitatively by calculating parameter imprecision. For all but one parameters (pore volume) measurement imprecision was <4.7% of the mean value, indicating good measurement reproducibility. Imprecision ranged between 27.3% and 54.5% of the population standard deviation for each parameter, while there was not a significant effect on imprecision due to disease status, indicating utility in testing for LC structural trends. PMID- 24761294 TI - Robust efficient estimation of heart rate pulse from video. AB - We describe a simple but robust algorithm for estimating the heart rate pulse from video sequences containing human skin in real time. Based on a model of light interaction with human skin, we define the change of blood concentration due to arterial pulsation as a pixel quotient in log space, and successfully use the derived signal for computing the pulse heart rate. Various experiments with different cameras, different illumination condition, and different skin locations were conducted to demonstrate the effectiveness and robustness of the proposed algorithm. Examples computed with normal illumination show the algorithm is comparable with pulse oximeter devices both in accuracy and sensitivity. PMID- 24761295 TI - Non-invasive respiratory monitoring using long-period fiber grating sensors. AB - In non-invasive ventilation, continuous monitoring of respiratory volumes is essential. Here, we present a method for the measurement of respiratory volumes by a single fiber-grating sensor of bending and provide the proof-of-principle by applying a calibration-test measurement procedure on a set of 18 healthy volunteers. Results establish a linear correlation between a change in lung volume and the corresponding change in a local thorax curvature. They also show good sensor accuracy in measurements of tidal and minute respiratory volumes for different types of breathing. The proposed technique does not rely on the air flow through an oronasal mask or the observation of chest movement by a clinician, which distinguishes it from the current clinical practice. PMID- 24761296 TI - Non-invasive prediction of hemoglobin levels by principal component and back propagation artificial neural network. AB - To facilitate non-invasive diagnosis of anemia, specific equipment was developed, and non-invasive hemoglobin (HB) detection method based on back propagation artificial neural network (BP-ANN) was studied. In this paper, we combined a broadband light source composed of 9 LEDs with grating spectrograph and Si photodiode array, and then developed a high-performance spectrophotometric system. By using this equipment, fingertip spectra of 109 volunteers were measured. In order to deduct the interference of redundant data, principal component analysis (PCA) was applied to reduce the dimensionality of collected spectra. Then the principal components of the spectra were taken as input of BP ANN model. On this basis we obtained the optimal network structure, in which node numbers of input layer, hidden layer, and output layer was 9, 11, and 1. Calibration and correction sample sets were used for analyzing the accuracy of non-invasive hemoglobin measurement, and prediction sample set was used for testing the adaptability of the model. The correlation coefficient of network model established by this method is 0.94, standard error of calibration, correction, and prediction are 11.29g/L, 11.47g/L, and 11.01g/L respectively. The result proves that there exist good correlations between spectra of three sample sets and actual hemoglobin level, and the model has a good robustness. It is indicated that the developed spectrophotometric system has potential for the non invasive detection of HB levels with the method of BP-ANN combined with PCA. PMID- 24761297 TI - Multi-modal hard x-ray imaging with a laboratory source using selective reflection from a mirror. AB - Multi-modal hard x-ray imaging sensitive to absorption, refraction, phase and scattering contrast is demonstrated using a simple setup implemented with a laboratory source. The method is based on selective reflection at the edge of a mirror, aligned to partially reflect a pencil x-ray beam after its interaction with a sample. Quantitative scattering contrast from a test sample is experimentally demonstrated using this method. Multi-modal imaging of a house fly (Musca domestica) is shown as proof of principle of the technique for biological samples. PMID- 24761298 TI - Statistical intensity variation analysis for rapid volumetric imaging of capillary network flux. AB - We present a novel optical coherence tomography (OCT)-based technique for rapid volumetric imaging of red blood cell (RBC) flux in capillary networks. Previously we reported that OCT can capture individual RBC passage within a capillary, where the OCT intensity signal at a voxel fluctuates when an RBC passes the voxel. Based on this finding, we defined a metric of statistical intensity variation (SIV) and validated that the mean SIV is proportional to the RBC flux [RBC/s] through simulations and measurements. From rapidly scanned volume data, we used Hessian matrix analysis to vectorize a segment path of each capillary and estimate its flux from the mean of the SIVs gathered along the path. Repeating this process led to a 3D flux map of the capillary network. The present technique enabled us to trace the RBC flux changes over hundreds of capillaries with a temporal resolution of ~1 s during functional activation. PMID- 24761299 TI - Comparison of adaptive optics scanning light ophthalmoscopic fluorescein angiography and offset pinhole imaging. AB - Recent advances to the adaptive optics scanning light ophthalmoscope (AOSLO) have enabled finer in vivo assessment of the human retinal microvasculature. AOSLO confocal reflectance imaging has been coupled with oral fluorescein angiography (FA), enabling simultaneous acquisition of structural and perfusion images. AOSLO offset pinhole (OP) imaging combined with motion contrast post-processing techniques, are able to create a similar set of structural and perfusion images without the use of exogenous contrast agent. In this study, we evaluate the similarities and differences of the structural and perfusion images obtained by either method, in healthy control subjects and in patients with retinal vasculopathy including hypertensive retinopathy, diabetic retinopathy, and retinal vein occlusion. Our results show that AOSLO OP motion contrast provides perfusion maps comparable to those obtained with AOSLO FA, while AOSLO OP reflectance images provide additional information such as vessel wall fine structure not as readily visible in AOSLO confocal reflectance images. AOSLO OP offers a non-invasive alternative to AOSLO FA without the need for any exogenous contrast agent. PMID- 24761300 TI - Wide-field in vivo background free imaging by selective magnetic modulation of nanodiamond fluorescence. AB - The sensitivity and resolution of fluorescence-based imaging in vivo is often limited by autofluorescence and other background noise. To overcome these limitations, we have developed a wide-field background-free imaging technique based on magnetic modulation of fluorescent nanodiamond emission. Fluorescent nanodiamonds are bright, photo-stable, biocompatible nanoparticles that are promising probes for a wide range of in vitro and in vivo imaging applications. Our readily applied background-free imaging technique improves the signal-to background ratio for in vivo imaging up to 100-fold. This technique has the potential to significantly improve and extend fluorescent nanodiamond imaging capabilities on diverse fluorescence imaging platforms. PMID- 24761301 TI - Clinical superficial Raman probe aimed for epithelial tumor detection: Phantom model results. AB - A novel clinical Raman probe for sampling superficial tissue to improve in vivo detection of epithelial malignancies is compared to a non-superficial probe regarding depth response function and signal-to-noise ratio. Depth response measurements were performed in a phantom tissue model consisting of a polyethylene terephthalate disc in an 20%-Intralipid((r)) solution. Sampling ranges of 0-200 and 0-300 MUm were obtained for the superficial and non superficial probe, respectively. The mean signal-to-noise ratio of the superficial probe increased by a factor of 2 compared with the non-superficial probe. This newly developed superficial Raman probe is expected to improve epithelial cancer detection in vivo. PMID- 24761302 TI - Optical coherence tomography can assess skeletal muscle tissue from mouse models of muscular dystrophy by parametric imaging of the attenuation coefficient. AB - We present the assessment of ex vivo mouse muscle tissue by quantitative parametric imaging of the near-infrared attenuation coefficient ut using optical coherence tomography. The resulting values of the local total attenuation coefficient ut (mean +/- standard error) from necrotic lesions in the dystrophic skeletal muscle tissue of mdx mice are higher (9.6 +/- 0.3 mm(-1)) than regions from the same tissue containing only necrotic myofibers (7.0 +/- 0.6 mm(-1)), and significantly higher than values from intact myofibers, whether from an adjacent region of the same sample (4.8 +/- 0.3 mm(-1)) or from healthy tissue of the wild type C57 mouse (3.9 +/- 0.2 mm(-1)) used as a control. Our results suggest that the attenuation coefficient could be used as a quantitative means to identify necrotic lesions and assess skeletal muscle tissue in mouse models of human Duchenne muscular dystrophy. PMID- 24761304 TI - In vivo imaging and tracking of individual nanodiamonds in drosophila melanogaster embryos. AB - In this work, we incorporate and image individual fluorescent nanodiamonds in the powerful genetic model system Drosophila melanogaster. Fluorescence correlation spectroscopy and wide-field imaging techniques are applied to individual fluorescent nanodiamonds in blastoderm cells during stage 5 of development, up to a depth of 40 um. The majority of nanodiamonds in the blastoderm cells during cellularization exhibit free diffusion with an average diffusion coefficient of (6 +/- 3) * 10(-3) um(2)/s, (mean +/- SD). Driven motion in the blastoderm cells was also observed with an average velocity of 0.13 +/- 0.10 um/s (mean +/- SD) um/s and an average applied force of 0.07 +/- 0.05 pN (mean +/- SD). Nanodiamonds in the periplasm between the nuclei and yolk were also found to undergo free diffusion with a significantly larger diffusion coefficient of (63 +/- 35) * 10( 3) um(2)/s (mean +/- SD). Driven motion in this region exhibited similar average velocities and applied forces compared to the blastoderm cells indicating the transport dynamics in the two cytoplasmic regions are analogous. PMID- 24761303 TI - Imaging the eye fundus with real-time en-face spectral domain optical coherence tomography. AB - Real-time display of processed en-face spectral domain optical coherence tomography (SD-OCT) images is important for diagnosis. However, due to many steps of data processing requirements, such as Fast Fourier transformation (FFT), data re-sampling, spectral shaping, apodization, zero padding, followed by software cut of the 3D volume acquired to produce an en-face slice, conventional high speed SD-OCT cannot render an en-face OCT image in real time. Recently we demonstrated a Master/Slave (MS)-OCT method that is highly parallelizable, as it provides reflectivity values of points at depth within an A-scan in parallel. This allows direct production of en-face images. In addition, the MS-OCT method does not require data linearization, which further simplifies the processing. The computation in our previous paper was however time consuming. In this paper we present an optimized algorithm that can be used to provide en-face MS-OCT images much quicker. Using such an algorithm we demonstrate around 10 times faster production of sets of en-face OCT images than previously obtained as well as simultaneous real-time display of up to 4 en-face OCT images of 200 * 200 pixels(2) from the fovea and the optic nerve of a volunteer. We also demonstrate 3D and B-scan OCT images obtained from sets of MS-OCT C-scans, i.e. with no FFT and no intermediate step of generation of A-scans. PMID- 24761305 TI - Reduced interhemispheric functional connectivity of children with autism spectrum disorder: evidence from functional near infrared spectroscopy studies. AB - Autism spectrum disorder (ASD) is a neuro-developmental disorder, which has been associated with atypical neural synchronization. In this study, functional near infrared spectroscopy (fNIRS) was used to study the differences in functional connectivity in bilateral inferior frontal cortices (IFC) and bilateral temporal cortices (TC) between ASD and typically developing (TD) children between 8 and 11 years of age. As the first report of fNIRS study on the resting state functional connectivity (RSFC) in children with ASD, ten children with ASD and ten TD children were recruited in this study for 8 minute resting state measurement. Compared to TD children, children with ASD showed reduced interhemispheric connectivity in TC. Children with ASD also showed significantly lower local connectivity in bilateral temporal cortices. In contrast to TD children, children with ASD did not show typical patterns of symmetry in functional connectivity in temporal cortex. These results support the feasibility of using the fNIRS method to assess atypical functional connectivity of cortical responses of ASD and its potential application in diagnosis. PMID- 24761306 TI - Speckle contrast optical tomography: A new method for deep tissue three dimensional tomography of blood flow. AB - A novel tomographic method based on the laser speckle contrast, speckle contrast optical tomography (SCOT) is introduced that allows us to reconstruct three dimensional distribution of blood flow in deep tissues. This method is analogous to the diffuse optical tomography (DOT) but for deep tissue blood flow. We develop a reconstruction algorithm based on first Born approximation to generate three dimensional distribution of flow using the experimental data obtained from tissue simulating phantoms. PMID- 24761307 TI - Screening hypochromism (sieve effect) in red blood cells: a quantitative analysis. AB - Multiwavelength UV-visible spectroscopy, Kramers-Kronig analysis, and several other experimental and theoretical tools have been applied over the last several decades to fathom absorption and scattering of light by suspensions of micron sized pigmented particles, including red blood cells, but a satisfactory quantitative analysis of the difference between the absorption spectra of suspension of intact and lysed red blood cells is still lacking. It is stressed that such a comparison is meaningful only if the pertinent spectra are free from, or have been corrected for, scattering losses, and it is shown that Duysens' theory can, whereas that of Vekshin cannot, account satisfactorily for the observed hypochromism of suspensions of red blood cells. PMID- 24761308 TI - Earthquake-related injuries in the pediatric population: a systematic review. AB - BACKGROUND: Children are a special population, particularly susceptible to injury. Registries for various injury types in the pediatric population are important, not only for epidemiological purposes but also for their implications on intervention programs. Although injury registries already exist, there is no uniform injury classification system for traumatic mass casualty events such as earthquakes. OBJECTIVE: To systematically review peer-reviewed literature on the patterns of earthquake-related injuries in the pediatric population. METHODS: On May 14, 2012, the authors performed a systematic review of literature from 1950 to 2012 indexed in Pubmed, EMBASE, Scopus, Web of Science, and Cochrane Library. Articles written in English, providing a quantitative description of pediatric injuries were included. Articles focusing on other types of disasters, geological, surgical, conceptual, psychological, indirect injuries, injury complications such as wound infections and acute kidney injury, case reports, reviews, and non-English articles were excluded. RESULTS: A total of 2037 articles were retrieved, of which only 10 contained quantitative earthquake related pediatric injury data. All studies were retrospective, had different age categorization, and reported injuries heterogeneously. Only 2 studies reported patterns of injury for all pediatric patients, including patients admitted and discharged. Seven articles described injuries by anatomic location, 5 articles described injuries by type, and 2 articles described injuries using both systems. CONCLUSIONS: Differences in age categorization of pediatric patients, and in the injury classification system make quantifying the burden of earthquake-related injuries in the pediatric population difficult. A uniform age categorization and injury classification system are paramount for drawing broader conclusions, enhancing disaster preparation for future disasters, and decreasing morbidity and mortality. PMID- 24761309 TI - The contribution of badgers to confirmed tuberculosis in cattle in high-incidence areas in England. AB - The role of badgers in the transmission and maintenance of bovine tuberculosis (TB) in British cattle is widely debated as part of the wider discussions on whether badger culling and/or badger vaccination should play a role in the government's strategy to eradicate cattle TB. The key source of information on the contribution from badgers within high-cattle-TB-incidence areas of England is the Randomised Badger Culling Trial (RBCT), with two analyses providing estimates of the average overall contribution of badgers to confirmed cattle TB in these areas. A dynamical model characterizing the association between the estimated prevalence of Mycobacterium bovis (the causative agent of bovine TB) among badgers culled in the initial RBCT proactive culls and the incidence among sympatric cattle herds prior to culling is used to estimate the average overall contribution of badgers to confirmed TB herd breakdowns among proactively culled areas. The resulting estimate based on all data (52%) has considerable uncertainty (bootstrap 95% confidence interval (CI): 9.1-100%). Separate analyses of experimental data indicated that the largest estimated reduction in confirmed cattle TB achieved inside the proactive culling areas was 54% (overdispersion adjusted 95% CI: 38-66%), providing a lower bound for the average overall contribution of badgers to confirmed cattle TB. Thus, taking into account both results, the best estimate of the average overall contribution of badgers is roughly half, with 38% being a robustly estimated lower bound. However, the dynamical model also suggested that only 5.7% (bootstrap 95% CI: 0.9-25%) of the transmission to cattle herds is badger-to-cattle with the remainder of the average overall contribution from badgers being in the form of onward cattle-to cattle transmission. These estimates, confirming that badgers do play a role in bovine TB transmission, inform debate even if they do not point to a single way forward. PMID- 24761310 TI - West nile virus transmission in winter: the 2013 great salt lake bald eagle and eared grebes mortality event. AB - West Nile Virus (WNV) infection has been reported in over 300 species of birds and mammals. Raptors such as eagles, hawks and falcons are remarkably susceptible, but reports of WNV infection in Bald Eagles (Haliaeetus leucocephalus) are rare and reports of WNV infection in grebes (Podicipediformes) even rarer. We report an unusually large wild bird mortality event involving between 15,000-20,000 Eared Grebes (Podiceps nigricollis) and over 40 Bald Eagles around the Great Salt Lake, Utah, in November-December 2013. Mortality in grebes was first reported in early November during a period when the area was unseasonably warm and the grebes were beginning to gather and stage prior to migration. Ten out of ten Eared Grebes collected during this period were WNV RT PCR and/or isolation positive. This is the first report of WNV infection in Eared Grebes and the associated mortality event is matched in scale only by the combined outbreaks in American White Pelican (Pelecanus erythrorhynchos) colonies in the north central states in 2002-2003. We cannot be sure that all of the grebes were infected by mosquito transmission; some may have become infected through contact with WNV shed orally or cloacally from other infected grebes. Beginning in early December, Bald Eagles in the Great Salt Lake area were observed to display neurological signs such as body tremors, limb paralysis and lethargy. At least 43 Bald Eagles had died by the end of the month. Nine of nine Bald Eagles examined were infected with WNV. To the best of our knowledge, this is the largest single raptor mortality event since WNV became endemic in the USA. Because the majority of the eagles affected were found after onset of below freezing temperatures, we suggest at least some of the Bald Eagles were infected with WNV via consumption of infected Eared Grebes or horizontal transmission at roost sites. PMID- 24761311 TI - Polyglutamine Disease Modeling: Epitope Based Screen for Homologous Recombination using CRISPR/Cas9 System. AB - We have previously reported the genetic correction of Huntington's disease (HD) patient-derived induced pluripotent stem cells using traditional homologous recombination (HR) approaches. To extend this work, we have adopted a CRISPR based genome editing approach to improve the efficiency of recombination in order to generate allelic isogenic HD models in human cells. Incorporation of a rapid antibody-based screening approach to measure recombination provides a powerful method to determine relative efficiency of genome editing for modeling polyglutamine diseases or understanding factors that modulate CRISPR/Cas9 HR. PMID- 24761312 TI - HD-PRO-TRIADTM Validation: A Patient-reported Instrument for the Symptom Triad of Huntington's Disease. AB - BACKGROUND: Few valid, disease-specific measures of health-related quality of life (HRQOL) capture the spectrum of symptoms associated with Huntington's disease (HD). The HD-PRO-TRIADTM is a new, HD-specific, patient-reported outcome (PRO) instrument of the HD symptom triad (cognitive decline, emotional/behavioral dyscontrol, and motor dysfunction) designed for clinical research and practice. The objective was to validate the HD-PRO-TRIADTM through a cross-sectional sample of individuals with HD and caregivers. METHODS: Development of the HD-PRO-TRIADTM has been described elsewhere. A total of 132 individuals with HD and 40 HD caregivers, comprising 29 dyads, participated in the cross-sectional psychometric validation of this instrument. Participants provided responses to the HD-PRO TRIADTM and other HRQOL and disease severity instruments (EuroQOL 5D, Short Form 12, Neuro-QOL Item Banks, PROMIS Global Health, and self-reported Unified Huntington's Disease Rating Scale Total Functional Capacity and Independence Scales). Internal consistency, construct validity, and patient-caregiver proxy consistency were evaluated. RESULTS: Internal consistency of the three domains and overall HD-PRO-TRIADTM instrument was supported by Cronbach's alpha values >=0.94. Construct validity was supported by significant correlations between HD PRO-TRIADTM domain scores and other measures of the same domains (e.g., significant positive correlations between HD-PRO-TRIADTM Anxiety with Neuro-QOL Anxiety), as well as slightly weaker but still strong correlations with other HRQOL instruments (e.g., HD-PRO-TRIADTM Anxiety and UHDRS Independence; all p<0.01). Consistency between patient self-report and caregiver proxy report was supported by an intra-class correlation coefficient >=0.92 for all three domains and the overall instrument. DISCUSSION: These data indicate that HD-PRO-TRIADTM is a reliable and valid HRQOL instrument that captures the typical triad of HD symptoms. PMID- 24761313 TI - Immune Enteral Nutrition Can Improve Outcomes in Medical-Surgical Patients with ARDS: A Prospective Randomized Controlled Trial. AB - OBJECTIVE: To determine if early continuous enteral feeding of a diet containing eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), docosahexaenoic acid, and antioxidants in surgical-medical patients with ARDS improves Lung Injury Score (LIS), gas exchange, Multiple Organ Dysfunction (MOD) Score, ICU length of stay, and days on mechanical ventilation. METHODS: Prospective randomized 2 center double-blind controlled trial of 17 ARDS patients whom continuously tube fed the experimental diet (n=9) or an isonitrogenous, isocaloric standard diet (n=8) at a minimum caloric delivery of 90% of basal energy expenditure. RESULTS: In the experimental group, there was a decrease in lung injury score (p < 0.003) and lower ventilation variables (p < 0.001). Patients in the experimental group had a statistically significant decrease in 28-day MOD score (p < 0.05). The length of ICU stay was significantly decreased in the experimental group (12.8 vs. 17.5 days; p = 0.01). The study was underpowered to detect any survival benefits between the two groups. CONCLUSION: An EPA and GLA supplemented diet contributes to improved gas exchange in addition to decrease LIS, MOD scores and length of ICU stay in patients with ARDS. An EPA+GLA-enriched enteral diet may be an effective tool in the medical management of ARDS. PMID- 24761315 TI - Alpha Test of a Videogame to Increase Children's Vegetable Consumption. AB - OBJECTIVE: This is a report of an alpha test with a computer of one episode of a casual videogame smartphone application, called Kiddio Food FightTM (Archimage Inc., Houston, TX), targeted at training parents to increase their 3-5-year-old child's vegetable consumption. SUBJECTS AND METHODS: This was a qualitative study using semistructured interviews. Sixteen parents from three ethnic groups living with their 3-5-year-old child were recruited. Parents provided screening information and informed consent and played the videogame. Afterward, semistructured intensive interviews were conducted about their experience. RESULTS: Parents generally liked the game. Their suggestions included a reduced list of values, rewording of reasons statements, an improved storyline, and feedback during and at the end of the game. The scoring system was ignored or confusing. Problems with the tool bar and game navigation caused problems in performance. A tutorial was requested. CONCLUSIONS: Kiddio Food Fight could have positive acceptance among parents with minor modifications. A videogame play could help parents learn effective vegetable parenting practices. PMID- 24761314 TI - How to Assess Gaming-Induced Benefits on Attention and Working Memory. AB - Our daily actions are driven by our goals in the moment, constantly forcing us to choose among various options. Attention and working memory are key enablers of that process. Attention allows for selective processing of goal-relevant information and rejecting task-irrelevant information. Working memory functions to maintain goal-relevant information in memory for brief periods of time for subsequent recall and/or manipulation. Efficient attention and working memory thus support the best extraction and retention of environmental information for optimal task performance. Recent studies have evidenced that attention and working memory abilities can be enhanced by cognitive training games as well as entertainment videogames. Here we review key cognitive paradigms that have been used to evaluate the impact of game-based training on various aspects of attention and working memory. Common use of such methodology within the scientific community will enable direct comparison of the efficacy of different games across age groups and clinical populations. The availability of common assessment tools will ultimately facilitate development of the most effective forms of game-based training for cognitive rehabilitation and education. PMID- 24761316 TI - Fun and Games and Boredom. AB - Serious videogames use entertainment to teach, train, or change behavior. What began in the 1970s as tentative attempts to create learning software is now a recognized videogame genre and an emerging health science. Although more research is needed, a growing body of literature suggests serious videogames can be effective. Support for serious videogames, however, is not universal. An informal Web search reveals numerous skeptics. Critics question serious videogames' entertainment value and, thus, their viability. "How can serious videogames attract and maintain players," the argument goes, "if they aren't as much fun as commercial titles, or even any fun at all?" This article examines the argument that, to be effective, serious videogames should be overtly fun and comparable to commercial off-the-shelf videogames. It explores differences between game developer- and researcher-led projects and discusses ways serious videogames can avoid boring and alienating players. It concludes that direct comparisons between serious and commercial game entertainment values may be misdirected. PMID- 24761317 TI - Acceptability of an Online Health Videogame to Improve Diet and Physical Activity in Elementary School Students: "Fitter Critters" AB - OBJECTIVE: Interest in health videogames to stimulate health behavior change is increasing, yet little research exists on their use. This study tested the acceptability of an online health videogame called "Fitter CrittersTM" (Megazoid Games, Collegeville, PA) for improving healthy diet and activity in elementary school students. SUBJECTS AND METHODS: In October and November 2011, fifth grade students (n=97) from a school in central Massachusetts played the game for 1 week during their health class. Measures of nutrition and activity knowledge, attitudes, and self-efficacy were completed prior to playing the game and again on the final day along with a videogame acceptability questionnaire. RESULTS: The videogame was highly acceptable to participants as measured by the acceptability questionnaire mean rating of 4.52 (SD=0.60), where 1=strongly disagree and 5=strongly agree; 73% of students played the game at least once outside of class. Significant increases in positive attitudes toward healthy eating (P<0.001) and healthy eating self-efficacy (P=0.02) and marginally significant increases in nutrition knowledge (P=0.08) were observed. CONCLUSIONS: The "Fitter Critters" health videogame engages students in learning about healthy eating and activity. Further research should assess whether the positive changes observed in knowledge, attitudes, and self-efficacy translate into behavior change. PMID- 24761319 TI - Using a Computer Game to Teach Young Children About Their Brains. AB - OBJECTIVE: Neuroscience is often considered too advanced of a subject to teach young children; however, helping children to understand the connection between their body and brain can promote a positive attitude towards proper care of the brain. This study investigated if playing a computer game increased knowledge and interest in the brain compared with more traditional methods of learning. SUBJECTS AND METHODS: Participants included 169 children, 4-6 years old, attending either preschool or an afterschool program. Comparisons were made among computer game, story, and control groups. Outcomes included knowledge about brain function and interest in learning about the brain. Students were assessed after a single exposure and after multiple exposures to the game. RESULTS: Results indicated that the computer game generated greater knowledge gains and higher levels of interest compared with both the story and control groups. Results were consistent across single exposure and multiple exposure data. Students in the game condition had significantly higher posttest knowledge scores compared with students in both the story (beta=-0.40, t163=-5.450, P<0.001) and control condition (beta=-0.57, t163=-7.812, P<0.001). For general interest items, students in the game condition reported higher levels of interest compared with the control group (beta=-0.24, t164=-2.82, P<0.01). For content-specific interest, students in the game condition reported higher levels compared with the story group (t109=2.05, P<0.05). CONCLUSIONS: This study highlights the potential value computer games play in presenting scientific and health-related content about the brain to young children. PMID- 24761318 TI - Videogames to Promote Physical Activity in Older Adults with Schizophrenia. AB - Older adults with schizophrenia need physical activity interventions to improve their physical health. The purpose of this report is to describe the preliminary acceptability of a videogame-based physical activity program using the KinectTM for Xbox 360 game system (Microsoft, Redmond, WA) in older adults with schizophrenia. PMID- 24761320 TI - Structure of Corrective Feedback for Selection of Ineffective Vegetable Parenting Practices for Use in a Simulation Videogame. AB - A serious videogame is being developed to train parents of preschool children in selecting and using parenting practices that are likely to encourage their child to eat more vegetables. The structure of feedback to the parents on their selection may influence what they learn from the game. Feedback Intervention Theory provides some guidance on the design of such messages. The structure of preferred performance feedback statements has not been investigated within serious videogames. Two feedback formats were tested for a player's preferences within the context of this videogame. Based on Feedback Intervention Theory, which proposes that threat to self-concept impairs feedback response, three statement (a nonaffirming comment sandwiched between two affirming comments, called "Oreo" feedback, which should minimize threat to self-concept) and two statement (a nonaffirming comment followed by an affirming comment) performance feedbacks were tailored to respondents. Tailoring was based on participants' report of frequency of use of effective and ineffective vegetable parenting practices and the reasons for use of the ineffective practices. Participants selected their preference between the two forms of feedback for each of eight ineffective vegetable parenting practices. In general, mothers (n=81) (no male respondents) slightly preferred the "Oreo" feedback, but the pattern of preferences varied by demographic characteristics. Stronger relationships by income suggest the feedback structure should be tailored to family income. Future research with larger and more diverse samples needs to test whether perceived threat to self-concept mediates the response to feedback and otherwise verify these findings. PMID- 24761321 TI - Computational Intelligence and Game Design for Effective At-Home Stroke Rehabilitation. AB - OBJECTIVE: The aim of this article is to describe a game engine that has all the characteristics needed to support rehabilitation at home. The low-cost tracking devices recently introduced in the entertainment market allow measuring reliably at home, in real time, players' motion with a hands-free approach. Such systems have also become a source of inspiration for researchers working in rehabilitation. Computer games appear suited to guide rehabilitation because of their ability to engage the users. However, commercial videogames and game engines lack the peculiar functionalities required in rehabilitation: Games should be adapted to each patient's functional status, and monitoring the patient's motion is mandatory to avoid maladaptation. Feedback on performance and progression of the exercises should be provided. Lastly, several tracking devices should be considered, according to the patient's pathology and rehabilitation aims. SUBJECTS AND METHODS: We have analyzed the needs of the clinicians and of the patients associated in performing rehabilitation at home, identifying the characteristics that the game engine should have. RESULTS: The result of this analysis has led us to develop the Intelligent Game Engine for Rehabilitation (IGER) system, which combines the principles upon which commercial games are designed with the needs of rehabilitation. IGER is heavily based on computational intelligence: Adaptation of the difficulty level of the exercise is carried out through a Bayesian framework from the observation of the patient's success rate. Monitoring is implemented in fuzzy systems and based on rules defined for the exercises by clinicians. Several devices can be attached to IGER through an input abstraction layer, like the Nintendo(r) (Kyoto, Japan) WiiTM Balance BoardTM, the Microsoft(r) (Redmond, WA) Kinect, the Falcon from Novint Technologies (Albuquerque, NM), or the Tyromotion (Graz, Austria) Timo(r) plate balance board. IGER is complemented with videogames embedded in a specific taxonomy developed to support rehabilitation progression through time. CONCLUSIONS: A few games aimed at postural rehabilitation have been designed and developed to test the functionalities of the IGER system. The preliminary results of tests on normal elderly people and patients with the supervision of clinicians have shown that the IGER system indeed does feature the characteristics required to support rehabilitation at home and that it is ready for clinical pilot testing at patients' homes. PMID- 24761323 TI - Are Pediatricians "Game"? Reducing Childhood Obesity by Training Clinicians to Use Motivational Interviewing Through Role-Play Simulations with Avatars. AB - The results of a feasibility study funded by a National Institutes of Health Small Business Innovation Research Phase 1 grant to assess the potential of using online, avatar-based simulation technology to increase pediatricians' use of motivational interviewing techniques to reduce childhood obesity are promising, with potentially positive implications for individual and public health outcomes. PMID- 24761322 TI - Disentangling Fun and Enjoyment in Exergames Using an Expanded Design, Play, Experience Framework: A Narrative Review. AB - With exergames (as with physical activity in general), more intense and longer duration game play should accrue more health benefits. Exergames, however, appear to be played for relatively short durations, often at medium or lower intensities. Ostensibly games are played for fun or enjoyment. Enhancing the fun or enjoyment experienced during exergame play should enhance the intensity and duration of physical activity, and thereby the health benefits. Research, reviewed herein, indicates fun and/or enjoyment in games are inherently laden with psychosocial, physiological, and embodiment substrates. Physical activity may also have separate or closely related psychosocial, physiological, and embodiment enjoyment substrates. Research is needed to integrate these levels of experience and to identify the game mechanics that enhance, and even maximize, the fun or enjoyment experienced in exergames, to thereby increase the health benefit. PMID- 24761324 TI - Feasibility of Computer-Based Videogame Therapy for Children with Cerebral Palsy. AB - OBJECTIVES: Standing and gait balance problems are common in children with cerebral palsy (CP), resulting in falls and injuries. Task-oriented exercises to strengthen and stretch muscles that shift the center of mass and change the base of support are effective in improving balance. Gaming environments can be challenging and fun, encouraging children to engage in exercises at home. The aims of this project were to demonstrate the technical feasibility, ease of use, appeal, and safety of a computer-based videogame program designed to improve balance in children with CP. MATERIALS AND METHODS: This study represents a close collaboration between computer design and clinical team members. The first two phases were performed in the laboratory, and the final phase was done in subjects' homes. The prototype balance game was developed using computer-based real-time three-dimensional programming that enabled the team to capture engineering data necessary to tune the system. Videogame modifications, including identifying compensatory movements, were made in an iterative fashion based on feedback from subjects and observations of clinical and software team members. RESULTS: Subjects (n=14) scored the game 21.5 out of 30 for ease of use and appeal, 4.0 out of 5 for enjoyment, and 3.5 on comprehension. There were no safety issues, and the games performed without technical flaws in final testing. CONCLUSIONS: A computer-based videogame incorporating therapeutic movements to improve gait and balance in children with CP was appealing and feasible for home use. A follow-up study examining its effectiveness in improving balance in children with CP is recommended. PMID- 24761325 TI - Perceptions of a Videogame-Based Dance Exercise Program Among Individuals with Parkinson's Disease. AB - OBJECTIVE: Physical therapy, including exercise, improves gait and quality of life in Parkinson's disease (PD). Many programs promoting physical activity have generated significant short-term gains, but adherence has been a problem. A recent evidence-based analysis of clinical trials using physical therapy in PD patients produced four key treatment recommendations: cognitive movement strategies, physical capacity, balance training, and cueing. We have attempted to incorporate all four of these features together through a dance exercise program using the dance videogame "Dance Dance Revolution" (DDR) (Konami Digital Entertainment, El Segundo, CA). SUBJECTS AND METHODS: Sixteen medically stable participants with mild to moderate PD were given the opportunity to try DDR with supervision by a research staff member. Feedback about the advantages and disadvantages of DDR as a form of physical activity was elicited through focus groups using the nominal group technique. RESULTS: Of 21 advantages and 17 disadvantages elicited, the most frequently cited advantages were "fun" and "easy to use," followed by "improves balance or coordination," "challenging," and "full body aerobic activity." Common concerns were the distracting or confusing interface, cost, and possible technical issues. DISCUSSION: Interactive dance exercise was appealing to participants with PD and may help promote adherence to physical activity. Concerns regarding familiarity with the technology may be addressed with simplification of the interface or additional training for participants. Results support a larger longitudinal study of DDR in PD. PMID- 24761326 TI - "Creature-101": A Serious Game to Promote Energy Balance-Related Behaviors Among Middle School Adolescents. AB - BACKGROUND: Considering adolescents' heavy use of media, serious videogames may provide an engaging and innovative way to achieve positive impact on adolescents' diet and physical activity. The objective of this study was to evaluate the efficacy of playing a serious game, "Creature-101" (developed by Teachers College, Columbia University [New York, NY] and Stottler Henke Inc. [San Mateo, CA]), at promoting energy balance-related behaviors (EBRBs) such as increasing fruits and vegetables intake, water intake, and physical activity and decreasing processed snacks intake, sweetened beverages intake, and recreational screen time. SUBJECTS AND METHODS: This pre-post intervention-control study (n=590) was conducted in New York City low-income public middle schools. The students (11-13 years of age, 51.6 percent male) played "Creature-101" online in science/health education classes (seven sessions, 30 minutes each session for 1 month). "Creature-101" used behavioral theories as the framework for "creature care" in a world "Tween." Students were provided with scientific evidence that promoted energy balance through minigames, educational videos, and slideshows and were motivated with interactive dialogues with game characters. Students also assessed their own behaviors, created their own "real life" food and activity goals, and reported their progress. A self-reported, validated, online instrument that measured frequency and amount of targeted behaviors was administered at baseline and post-intervention. RESULTS: Analysis of covariance compared post-test means between groups with pretest scores as covariates. Intervention students reported significant decreases in frequency and amount of consumption of sweetened beverages and processed snacks compared with the controls. No changes were observed for the other behaviors. CONCLUSIONS: "Creature-101" was effective at reducing consumption of sweetened beverages and processed snacks, which are related to obesity risks, indicating that the game shows promise at promoting EBRBs. PMID- 24761327 TI - A Serious Exergame for Patients Suffering from Chronic Musculoskeletal Back and Neck Pain: A Pilot Study. AB - INTRODUCTION: Over recent years, the popularity of videogames has gone beyond youth and gamers and is slowly entering the field of professional healthcare. Exergames are an attractive alternative to physical therapy. The primary aim of this pilot study was to explore the user experience (usability, satisfaction, level of motivation, and game experience) of the patient with the "PlayMancer" exergame. The secondary aim was to explore the progression of the performed motor skills (walking velocity, overhead reach ability, and cervical range of motion) and the clinical changes (to physical condition, disability, and pain intensity) in a group of patients with chronic musculoskeletal pain using an exergame for 4 weeks. MATERIALS AND METHODS: In the European PlayMancer project, an exergame for physical rehabilitation of chronic pain patients was developed. This exergame is controlled by relevant motions of the patient's body captured by a motion suit and several infrared cameras. In three different integrated minigames, the patient can train the following motor skills: Walking velocity, overhead reaching, and neck mobility. RESULTS: Ten patients participated in this study and completed the 4 weeks of gaming. Patients rated the usability of the exergames as good (score of 78.5 [standard deviation 9.7; range, 60.0-97.5]) on the System Usability Scale, and the game motivated all patients to perform their exercises. Patients enjoyed playing and were pleased with both the game environment and the game play. Overall, the patients made a progression in the examined motor skills during the minigames over the 4 weeks of gaming. CONCLUSIONS: The "PlayMancer" exergame is a potential tool for achieving physical rehabilitation because it motivates patients to perform their exercises and as a result increases their motor skills and physical condition. PMID- 24761328 TI - Design Parameters in Multimodal Games for Rehabilitation. AB - Objectives: The repetitive and sometimes mundane nature of conventional rehabilitation therapy provides an ideal opportunity for development of interactive and challenging therapeutic games that have the potential to engage and motivate the players. Certain game design parameters that may encourage patients to actively participate by making the games more enjoyable have been identified. In this article, we describe a formative study in which we designed and evaluated some of these parameters with healthy subjects. Materials and Methods: The "operant conditioning" and "scoring" design parameters were incorporated in a remake of a classic labyrinth game, "Marble Maze." A group of participants (n=37) played the game twice: Once in the control condition without both modalities and then with either one of the parameters or with both. Measures of game duration and number of fails in the game were recorded along with survey questionnaires to measure player perceptions of intrinsic motivation on the game. Results: Longer playtimes, higher levels of interest/enjoyment, and effort to play the game were recorded with the introduction of these parameters. Conclusions: This study provides an understanding on how game design parameters can be used to motivate and encourage people to play longer. With these positive results, future aims are to test the parameters with stroke patients, providing much clearer insight as to what influences these parameters have on patients undergoing therapy. The ultimate goal is to utilize game design in order to maintain longer therapeutic interaction between a patient and his or her therapy medium. PMID- 24761329 TI - Medicare Resources That You Should Use. AB - Wound care scientists, manufacturers, and wound care professionals should take time to visit the Centers for Medicare & Medicaid Services' website. It is easy to navigate and contains information for all wound care stakeholders. This article reviews some of the most popular Medicare website pages that should prove useful to wound care stakeholders. The links to those pages are also provided. PMID- 24761330 TI - Medicare Coverage: You Cannot Play the Game If You Do Not Know the Rules. AB - WOUND CARE STAKEHOLDERS SHOULD REMEMBER THAT MEDICARE REIMBURSEMENT REQUIRES THREE PARTS: a relevant code, a published Medicare payment rate, and positive coverage or coverage based upon medical necessity. Qualified healthcare professionals, scientists, and manufacturers should establish a monthly routine, where they personally review revisions to pertinent National Coverage Determinations (NCDs) and Local Coverage Determinations (LCDs). These documents provide specific guidelines for positive coverage by the specific Medicare Administrative Contractor that processes the Medicare claims in a specific jurisdiction. When given an opportunity to provide comments on draft coverage determinations, wound care stakeholders should take advantage of the opportunity of educating the contractor medical director. After a LCD has become active, wound care stakeholders can and should request revisions, through the LCD Reconsideration Process, when new clinical evidence becomes available. PMID- 24761331 TI - HCPCS Coding: An Integral Part of Your Reimbursement Strategy. AB - The first step to a successful reimbursement strategy is to ensure that your wound care product has the most appropriate Healthcare Common Procedure Coding System (HCPCS) code (or billing) for your product. The correct HCPCS code plays an essential role in patient access to new and existing technologies. When devising a strategy to obtain a HCPCS code for its product, companies must consider a number of factors as follows: (1) Has the product gone through the Food and Drug Administration (FDA) regulatory process or does it need to do so? Will the FDA code designation impact which HCPCS code will be assigned to your product? (2) In what "site of service" do you intend to market your product? Where will your customers use the product? Which coding system (CPT(r) or HCPCS) applies to your product? (3) Does a HCPCS code for a similar product already exist? Does your product fit under the existing HCPCS code? (4) Does your product need a new HCPCS code? What is the linkage, if any, between coding, payment, and coverage for the product? Researchers and companies need to start early and place the same emphasis on a reimbursement strategy as it does on a regulatory strategy. Your reimbursement strategy staff should be involved early in the process, preferably during product research and development and clinical trial discussions. PMID- 24761332 TI - CPT(r) Codes: What Are They, Why Are They Necessary, and How Are They Developed? AB - Qualified healthcare professionals (QHPs) need to identify the professional services they provide and to report those services in a way that can be universally understood by institutions, private and government payers, researchers, and others interested parties. The QHPs' data are used to track healthcare utilization, identify services for payment, and to gather statistical healthcare information about populations. Each year, in the United States, healthcare insurers process over 5 billion claims for payment.1 To ensure that healthcare data are captured accurately and consistently and that health claims are processed properly for Medicare, Medicaid, and other health programs, a standardized coding system for medical services and procedures is essential. The Current Procedural Terminology (CPT(r)) system, developed by the American Medical Association (AMA), is used for just these purposes. The AMA system provides a standard language and numerical coding methodology to accurately communicate across many stakeholders, including patients, the medical, surgical, diagnostic, and therapeutic services provided by QHPs. The CPT descriptive terminology and associated code numbers provide the most widely accepted medical nomenclature used to report medical procedures and services for processing claims, conducting research, evaluating healthcare utilization, and developing medical guidelines and other forms of healthcare documentation. PMID- 24761333 TI - ICD-9-CM to ICD-10-CM Codes: What? Why? How? AB - The wound care industry will gain many benefits when International Classification of Diseases (ICD)-10-Clinical Modification (CM) is implemented. One of the main benefits is that the disease classifications will be consistent with current clinical practice and medical technology advances. The new classification codes will be very granular, which means the level of specificity will greatly improve. Numerous new codes will represent more specific anatomic sites, etiologies, comorbidities, and complications, and will improve the ability to demonstrate severity of illness. For instance, the new feature of laterality is directly built into the new codes: separate codes will distinguish right, left, and bilateral, where needed. The increased granularity will provide better analysis of disease patterns and outbreak of disease. Additionally, the United States will finally be using the same diagnosis coding system as the rest of the world. This article will describe what the ICD-9-CM/ICD-10-CM codes are, why they are so important, and how clinicians and researchers will convert from ICD-9-CM to ICD 10-CM effective October 1, 2014. PMID- 24761334 TI - Medicare Payment Systems: A Look Back and a Look Forward. AB - Medicare is the major payer for patients with chronic wounds. Over the past 50 years, the Medicare payment systems have undergone numerous changes. At the beginning of the Medicare program, providers were paid based on fee-for-service. In 1997, many of the Medicare payment systems were converted to prospective payment systems (PPSs). Currently, Medicare is conducting many demonstration payment programs to provide the best quality outcomes, at the lowest total cost of care (not necessarily the lowest cost product or procedure), and with patient satisfaction. While the demonstration payment programs are being tested, providers may receive parallel Medicare payments: payment through current PPS and through the demonstration payment program. Wound care providers and manufacturers need to prepare now for the future payment systems. PMID- 24761335 TI - Electronic Health Records, Registries, and Quality Measures: What? Why? How? AB - The transition from volume-based healthcare to value-based care is advancing via the reporting of quality measures, initially as a part of "pay for performance" within Medicare's Physician Quality Reporting System (PQRS) initiative. However, "value-based purchasing" requirements within the Affordable Care Act will increase the percentage of reimbursement linked to the reporting of quality measures. Currently, only five PQRS measures are relevant to wound care, and the venous ulcer care measure will be retired this year. PQRS measures in wound care can only be reported via claims or qualified patient registries, and no wound care measures are endorsed by the National Quality Forum (NQF). The recent Health Informational Technology for Economic and Clinical Health (HITECH) Act promoting the adoption of electronic health records (EHRs) requires quality reporting by clinicians wishing to access EHR adoption money. These clinicians will be able to comply with the next stage of "meaningful use" of EHRs, beginning in 2015, by submitting data to a qualified registry, and registry submission may eventually be required by Medicare for reimbursement of some wound care products and procedures. Other specialties are using registries to track adverse events, measure compliance with practice guidelines, and for comparative effectiveness data. Evidence-based measures should be developed as electronic measures that can be submitted directly from the clinicians' EHR. New wound care measures should undergo testing for NQF endorsement. The not-for-profit U.S. Wound Registry is a qualified patient registry that is available for PQRS reporting, measure testing, and future registry submission requirements. The lack of tested wound care quality measures threatens the entire wound care industry, as quality-based reimbursement is not limited to physician payment. Quality measures are an increasingly important part of many Medicare payment systems, including those for acute care hospitals, hospital-based outpatient wound care departments, and accountable care organizations. PMID- 24761337 TI - Using an Agent-Based Model to Examine the Role of Dynamic Bacterial Virulence Potential in the Pathogenesis of Surgical Site Infection. AB - OBJECTIVE: Despite clinical advances, surgical site infections (SSIs) remain a problem. The development of SSIs involves a complex interplay between the cellular and molecular mechanisms of wound healing and contaminating bacteria, and here, we utilize an agent-based model (ABM) to investigate the role of bacterial virulence potential in the pathogenesis of SSI. APPROACH: The Muscle Wound ABM (MWABM) incorporates muscle cells, neutrophils, macrophages, myoblasts, abstracted blood vessels, and avirulent/virulent bacteria to simulate the pathogenesis of SSIs. Simulated bacteria with virulence potential can mutate to possess resistance to reactive oxygen species and increased invasiveness. Simulated experiments (t=7 days) involved parameter sweeps of initial wound size to identify transition zones between healed and nonhealed wounds/SSIs, and to evaluate the effect of avirulent/virulent bacteria. RESULTS: The MWABM reproduced the dynamics of normal successful healing, including a transition zone in initial wound size beyond which healing was significantly impaired. Parameter sweeps with avirulent bacteria demonstrated that smaller wound sizes were associated with healing failure. This effect was even more pronounced with the addition of virulence potential to the contaminating bacteria. INNOVATION: The MWABM integrates the myriad factors involved in the healing of a normal wound and the pathogenesis of SSIs. This type of model can serve as a useful framework into which more detailed mechanistic knowledge can be embedded. CONCLUSION: Future work will involve more comprehensive representation of host factors, and especially the ability of those host factors to activate virulence potential in the microbes involved. PMID- 24761336 TI - Transforming Growth Factor Beta Signaling in Cutaneous Wound Healing: Lessons Learned from Animal Studies. AB - SIGNIFICANCE: Wound healing is a complex physiological process involving a multitude of growth factors, among which transforming growth factor beta (TGF beta) has the broadest spectrum of effects. Animal studies have provided key information on the mechanisms of TGF-beta action in wound healing and have guided the development of therapeutic strategies targeting the TGF-beta pathway to improve wound healing and scarring outcome. RECENT ADVANCES: Development of tissue-specific expression systems for overexpression or knockout of TGF-beta signaling pathway components has led to novel insight into the role of TGF-beta signaling in wound healing. This work has also identified molecules that might serve as molecular targets for the treatment of pathological skin conditions such as chronic wounds and excessive scarring (fibrosis). CRITICAL ISSUES: Many of the mouse models with genetic alterations in the TGF-beta signaling pathway develop an underlying skin abnormality, which may pose some limitations on the interpretation of wound-healing results obtained in these animals. Also, TGF beta's pleiotropic effects on many cell types throughout all phases of wound healing present a challenge in designing specific strategies for targeting the TGF-beta signaling pathway to promote wound healing or reduce scarring. FUTURE DIRECTIONS: Further characterization of TGF-beta signaling pathway components using inducible tissue-specific overexpression or knockout technology will be needed to corroborate results obtained in mouse models that display a skin phenotype, and to better understand the role of TGF-beta signaling during distinct phases of the wound-healing process. Such studies will also provide a better understanding of how TGF-beta mediates its autocrine, paracrine, and double paracrine effects on cellular responses in vivo during wound healing. PMID- 24761338 TI - Bottom-Up Mass Spectrometry-Based Proteomics as an Investigative Analytical Tool for Discovery and Quantification of Proteins in Biological Samples. AB - OBJECTIVE: The objective of this overview is to introduce bottom-up mass spectrometry (MS)-based proteomics approaches and strategies, widely used in other biomedical research fields, to the wound-healing research community. APPROACHES: TWO MAJOR PROTEOMICS WORKFLOWS ARE DISCUSSED: gel-based and gel-free chromatographic separation to reduce the complexity of the sample at protein and peptide level, respectively, prior to nano-liquid chromatography-tandem mass spectrometry analysis. Other strategies to discover less abundant proteins present in the sample, are also briefly discussed along with label-free and label incorporated methods for protein quantification. Overall, the experimental workflows are designed and continually improved to increase the number of proteins identifiable and quantifiable. DISCUSSION: Recent advances and improvements in all areas of proteomics workflow from sample preparation, to acquisition of massive amounts of data, to bioinformatics analysis have made this technology an indispensable tool for in-depth large-scale characterization of complex proteomes. This technology has been successfully applied in studies focusing on biomarker discovery, differential protein expression, protein-protein interactions, and post-translational modifications in complex biological samples such as cerebrospinal fluid, serum and plasma, and urine from patients. The publications from these studies have reported greater number of identified proteins, novel biomarker candidates, and post-translational modifications previously unknown. CONCLUSIONS: The qualitative and quantitative protein analysis of the protein population of wound tissues or fluids at different stages is important in wound healing research. Given the complexities and analytical challenges of these samples, MS-based proteomic workflows further improved with recent advances offer a powerful and attractive technology for this purpose. PMID- 24761339 TI - Treatment of Radiation Injury. AB - Significance: Radiation exposure as a result of radiation treatment, accident, or terrorism may cause serious problems such as deficiency due to necrosis or loss of function, fibrosis, or intractable ulcers in the tissues and organs. When the skin, bone, oral mucous membrane, guts, or salivary glands are damaged by ionizing radiation, the management and treatment are very lengthy and difficult. Critical Issues: In severe and irreversible injuries, surgery remains the mainstay of treatment. Several surgical procedures, such as debridement, skin grafting, and local and free-vascularized flaps, are widely used. Recent Advances: In specific cases of major morbidity or in high-risk patients, a newly developed therapy using a patient's own stem cells is safe and effective. Adipose tissue, normally a rich source of mesenchymal stem cells, which are similar to those from the bone marrow, can be harvested, since the procedure is easy, and abundant tissue can be obtained with minimal invasiveness. Future Directions: Based on the molecular basis of radiation injuries, several prospective treatments are under development. Single-nucleotide polymorphisms focus on an individual's sensitivity to radiation in radiogenomics, and the pathology of radiation fibrosis or the effect of radiation on wound healing is being studied and will lead to new insight into the treatment of radiation injuries. Protectors and mitigators are being actively investigated in terms of the timing of administration or dose. PMID- 24761340 TI - Breast Reconstruction After Radiotherapy. AB - It was once common practice in the treatment of breast cancer for total mastectomy and axillary lymph node dissection to be conventionally performed. However, breast-conserving surgery is increasingly being performed with marked improvement in a multidisciplinary treatment approach, including surgery, chemotherapy, irradiation, and antihormonal therapy. We must choose the optimal reconstructive methods with the reduction of the excision range. Furthermore, we also consider the local chronic radiation injury after adjuvant radiotherapy on breast reconstruction. As for breast reconstruction, the use of autologous tissues or artificial prostheses is common. However, after radiotherapy or if radiotherapy is planned, the complications such as infection, skin necrosis, or exposure of the implant are increased in breast reconstruction with implants. Therefore, the breast is reconstructed with autologous tissue mainly with radiotherapy using an autologous flap transfer. Meanwhile, the autologous fat transfer with adipose-derived regenerative cells for repair and regeneration has recently been investigated in reconstructive surgery. We discuss the autologous flap and fat transfer for breast reconstruction. PMID- 24761342 TI - Surgical Reconstruction of Radiation Injuries. AB - Significance: Patients with cancer receive benefits from radiation therapy; however, it may have adverse effects on normal tissue such as causing radiation induced ulcer and osteoradionecrosis. The most reliable method to treat a radiation ulcer is wide excision of the affected tissue, followed by coverage with well-vascularized tissue. As usual, radiation-induced skin ulcers are due to therapeutic irradiation for residual cancer or lymph nodes; the locations of radiation ulcers are relatively limited, including the head, neck, chest wall, lumbar, groin, and sacral areas. Thus, suitable reconstructive methods vary according to functional and aesthetic conditions. I reviewed the practices and surgical results for radiation ulcers over the past 30 years, and present the recommended surgical methods for these hard-to-heal ulcers. Recent Advances: At a minimum, flaps are required to treat radiation ulcers. Surgeons can recommend earlier debridement, followed by immediate coverage with axial-pattern musculocutaneous and fasciocutaneous flaps. Free flaps are also a useful soft tissue coverage option. The choice of flap varies with the location and size of the wounds. Critical Issues: The most crucial procedure is the complete resection of the radiation-affected area, followed by coverage with well-vascularized tissue. Future Directions: Recent developments in perforator flap techniques, which are defined as flaps with a blood supply from isolated perforating vessels of a stem artery, have allowed the surgeons to successfully resurface these difficult wounds with reduced morbidity. PMID- 24761341 TI - Radiation-Induced Bystander Response: Mechanism and Clinical Implications. AB - Significance: Absorption of energy from ionizing radiation (IR) to the genetic material in the cell gives rise to damage to DNA in a dose-dependent manner. There are two types of DNA damage; by a high dose (causing acute or deterministic effects) and by a low dose (related to chronic or stochastic effects), both of which induce different health effects. Among radiation effects, acute cutaneous radiation syndrome results from cell killing as a consequence of high-dose exposure. Recent advances: Recent advances in radiation biology and oncology have demonstrated that bystander effects, which are emerged in cells that have never been exposed, but neighboring irradiated cells, are also involved in radiation effects. Bystander effects are now recognized as an indispensable component of tissue response related to deleterious effects of IR. Critical issues: Evidence has indicated that nonapoptotic premature senescence is commonly observed in various tissues and organs. Senesced cells were found to secrete various proteins, including cytokines, chemokines, and growth factors, most of which are equivalent to those identified as bystander factors. Secreted factors could trigger cell proliferation, angiogenesis, cell migration, inflammatory response, etc., which provide a tissue microenvironment assisting tissue repair and remodeling. Future directions: Understandings of the mechanisms and physiological relevance of radiation-induced bystander effects are quite essential for the beneficial control of wound healing and care. Further studies should extend our knowledge of the mechanisms of bystander effects and mode of cell death in response to IR. PMID- 24761343 TI - The Celution(r) System: Automated Processing of Adipose-Derived Regenerative Cells in a Functionally Closed System. AB - Objective: To develop a closed, automated system that standardizes the processing of human adipose tissue to obtain and concentrate regenerative cells suitable for clinical treatment of thermal and radioactive burn wounds. Approach: A medical device was designed to automate processing of adipose tissue to obtain a clinical grade cell output of stromal vascular cells that may be used immediately as a therapy for a number of conditions, including nonhealing wounds resulting from radiation damage. Results: The Celution(r) System reliably and reproducibly generated adipose-derived regenerative cells (ADRCs) from tissue collected manually and from three commercial power-assisted liposuction devices. The entire process of introducing tissue into the system, tissue washing and proteolytic digestion, isolation and concentration of the nonadipocyte nucleated cell fraction, and return to the patient as a wound therapeutic, can be achieved in approximately 1.5 h. An alternative approach that applies ultrasound energy in place of enzymatic digestion demonstrates extremely poor efficiency cell extraction. Innovation: The Celution System is the first medical device validated and approved by multiple international regulatory authorities to generate autologous stromal vascular cells from adipose tissue that can be used in a real time bedside manner. Conclusion: Initial preclinical and clinical studies using ADRCs obtained using the automated tissue processing Celution device described herein validate a safe and effective manner to obtain a promising novel cell based treatment for wound healing. PMID- 24761344 TI - Immunonutrition: Role in Wound Healing and Tissue Regeneration. AB - Significance: The role of immunonutrition in wound healing has been an area of both interest and controversy for many years. Although deficiencies in certain nutrients have long been known to impair healing, supplementation of specific immune modulating nutrients has not consistently yielded improvements in wound healing. Still, the prospect of optimizing nutrition to assist the immune system in wound repair bears great significance in both medical and surgical fields, as the costs of wound care and repair cannot be ignored. Recent Advances: Recent studies have rekindled efforts to elucidate the roles of specific immunonutrients, and we now have a better understanding of the conditionally essential role of various nutrients such as arginine, which becomes essential in certain clinical situations such as for the trauma patient or patients at high risk for malnutrition. Immunonutrition in its current formulation usually includes supplementation with arginine, glutamine, omega-3 fatty acids, vitamins, and trace minerals, and its use has often been associated with decreased infectious complications and sometimes with improvements in wound healing. Critical Issues: A key to understanding the role of immunonutrition in wound healing is recognizing the distinct contributions and importance of the various elements utilized. Future Directions: Critical areas for future study include identifying the specific populations, timing, and ideal composition of immunomodulating diets in order to optimize the wound healing process. PMID- 24761345 TI - Malnutrition as a Precursor of Pressure Ulcers. AB - Significance: Numerous studies have reported associations between declining nutrition status and risk for pressure ulcers. Oral eating problems, weight loss, low body weight, undernutrition, and malnutrition are associated with an increased risk for pressure ulcers. Moreover, inadequate nutrient intake and low body weight are associated with slow and nonhealing wounds. However, the biologic significance of deterioration in nutrition status and consistent methodologies to quantify malnutrition and diminished micronutrient stores as predictors of skin breakdown remains controversial. Recent Advances: The Academy of Nutrition and Dietetics (Academy) and the American Society for Parenteral and Enteral Nutrition (ASPEN) Consensus Statement: Characteristics Recommended for the Identification and Documentation of Adult Malnutrition provide a standardized and measureable set of criterion for all health professionals to use to identify malnutrition. The Agency for Healthcare Research and Quality identified malnutrition as one of the common geriatric syndromes associated with increased risk for institutionalization and mortality that may be impacted by primary and secondary preventions. Critical Issues: The purpose of this article is to examine the Academy/ASPEN consensus statement on characteristics of adult malnutrition in the context of the National Pressure Ulcer Advisory Panel (NPUAP)/European Pressure Ulcer Advisory Panel (EPUAP) Guidelines on the Prevention and Treatment of Pressure Ulcers. Future Directions: Moreover, clinicians, and in particular, registered dietitians have the opportunity to integrate the Characteristics of Malnutrition with the NPUAP/EPUAP 2009 Prevention and Treatment Clinical Practice Guidelines, into clinical assessment and documentation using the Nutrition Care Process. Consensus guidelines will provide consistent research criteria yielding more useful data than presently available. PMID- 24761346 TI - Early Enteral Nutrition for Burn Injury. AB - Significance: Nutrition has been recognized as a critical component of acute burn care and ultimate wound healing. Debate remains over the appropriate timing of enteral nutrition and the benefit of supplemental trace elements, antioxidants, and immunonutrition for critically ill burn patients. Pharmacotherapy to blunt the metabolic response to burn injury plays a critical role in effective nutritional support. Recent Advances: Further evidence is demonstrating long-term benefits from pharmacologic immunomodulation given the prolonged metabolic response to injury that may last for over a year following the initial insult. Critical Issues: The majority of evidence regarding early enteral feeding comes from mixed populations and smaller studies. However, on balance, available evidence favors early feeding. Data regarding immunonutrition does not support the routine use of these products. Limited data regarding use of antioxidants and trace elements support their use. Future Directions: Further evaluation of anti inflammatory mediators of the immune response, such as statins, will likely play a role in the future. Further data are needed on the dosing and route of micronutrients as well as the utility of immunonutrition. Finally, little is known about nutrition in the obese burn patient making this an important area for investigation. PMID- 24761347 TI - Exercise, Obesity, and Cutaneous Wound Healing: Evidence from Rodent and Human Studies. AB - Significance: Impaired cutaneous wound healing is a major health concern. Obesity has been shown in a number of studies to impair wound healing, and chronic nonhealing wounds in obesity and diabetes are a major cause of limb amputations in the United States. Recent Advances: Recent evidence indicates that aberrant wound site inflammation may be an underlying cause for delayed healing. Obesity, diabetes, and other conditions such as stress and aging can result in a chronic low-level inflammatory state, thereby potentially affecting wound healing negatively. Critical Issues: Interventions which can speed the healing rate in individuals with slowly healing or nonhealing wounds are of critical importance. Recently, physical exercise training has been shown to speed healing in both aged and obese mice and in older adults. Exercise is a relatively low-cost intervention strategy which may be able to be used clinically to prevent or treat impairments in the wound-healing process. Future Directions: Little is known about the mechanisms by which exercise speeds healing. Future translational studies should address potential mechanisms for these exercise effects. Additionally, clinical studies in obese humans are necessary to determine if findings in obese rodent models translate to the human population. PMID- 24761348 TI - Electrical Stimulation Technologies for Wound Healing. AB - Objective: To discuss the physiological bases for using exogenously applied electric field (EF) energy to enhance wound healing with conductive electrical stimulation (ES) devices. Approach: To describe the types of electrical currents that have been reported to enhance chronic wound-healing rate and closure. Results: Commercial ES devices that generate direct current (DC), and mono and biphasic pulsed current waveforms represent the principal ES technologies which are reported to enhance wound healing. Innovation: Wafer-thin, disposable ES technologies (wound dressings) that utilize mini or micro-batteries to deliver low-level DC for wound healing and antibacterial wound-treatment purposes are commercially available. Microfluidic wound-healing chips are currently being used with greater accuracy to investigate the EF effects on cellular electrotaxis. Conclusion: Numerous clinical trials described in subsequent sections of this issue have demonstrated that ES used adjunctively with standard wound care (SWC), enhances wound healing rate faster than SWC alone. PMID- 24761349 TI - Bacterial Inhibition by Electrical Stimulation. AB - Significance: Much evidence shows that electrical stimulation (ES) promotes the wound healing process. The inhibitory effect of ES on bacterial growth has been proposed as a mechanism to explain the useful effects of ES on wound healing. Bacterial burden has been associated with chronic wounds. The extensive use of antibiotics can lead to the spread of multiple drug resistant bacteria. Whether biophysical energies, such as ES, can be used as a treatment modality against pathogenic microorganisms remains an open question. Recent Advances: The research literature provides evidence for useful effects of ES in terms of inhibition of bacterial growth. The type of ES, its polarity, and the intensity of the current play a major role in establishment of antibacterial effects. Both direct current (DC) and high voltage pulse current are more effective at inhibiting bacterial growth than are other types of ES. The exact mechanism underlying the antibacterial effects of ES is not clear. Critical Issues: Available evidence indicates that microampere DC (MUADC) is better than other ES types for inhibition of bacterial growth. The results of most studies also support the application of cathodal current for bacterial growth inhibition. The current intensity of ES would appear to be tolerable by humans if used clinically for treatment of infected wounds. Future Directions: The cathodal MUADC appears to be more effective for inhibition of microorganism growth. Further research, especially in vivo, is necessary to clarify the inhibitory effects of ES on wound bacterial infections. PMID- 24761350 TI - Vascular Endothelial Growth Factor Release Following Electrical Stimulation in Human Subjects. AB - Significance: Angiogenesis is an important phenomenon involved in the healing of chronic wounds, and it is mainly mediated by the release of vascular endothelial growth factor (VEGF) from endothelial cells. Electrical stimulation (ES) is a well-documented treatment used to assist the healing of chronic wounds. Due to the importance of VEGF in the healing process, and the need to know the mechanisms of action of ES involved in the process, this report aimed to determine by a literature review whether the VEGF release occurs following ES in human subjects. Recent Advances: The findings of this literature review suggest that ES releases VEGF, and this effect may be responsible for promoting angiogenesis after ES. Critical Issues: Despite the findings of this literature review on the release of VEGF by ES on wound healing are promising, a large number of studies are needed to confirm such effects. Future Directions: Further studies should be conducted to identify the best parameters and treatment schedule of ES to be used for the VEGF release. PMID- 24761351 TI - High-Voltage Pulsed Current Electrical Stimulation in Wound Treatment. AB - Significance: A range of studies point to the efficacy of electrical stimulation (ES) in wound treatment, but the methodology of its application has not been determined to date. This article provides a critical review of the results of clinical trials published by researchers using high-voltage pulsed current (HVPC) to treat chronic wounds. In describing the methodology of the trials, the article gives special attention to electric stimulus parameters, the frequency of procedures and total treatment duration. Recent Advances: HVPC is a monophasic pulsed electric current that consists of double-peaked impulses (5-200 MUs), at very high peak-current amplitude (2-2.5 A), and high voltage (up to 500 V), at a frequency of 1-125 pulses per second. HVPC can activate "skin battery" and cellular galvanotaxis, and improves blood flow and capillary density. Critical Issues: HVPC efficacy was evaluated in conservatively treated patients with diabetic foot, venous leg and pressure ulcers (PUs), and in some patients with surgically treated venous insufficiency. Future Directions: The efficacy of HVPC as one of several biophysical energies promoting venous leg ulcer (VLU) and PU healing has been confirmed. Additional studies are needed to investigate its effect on the healing of other types of soft tissue defects. Other areas that require more research include the identification of the therapeutic effect of HVPC on infected wounds, the determination of the efficacy of cathodal versus anodal stimulation, and the minimal daily/weekly duration of HVPC required to ensure optimal promotion of wound healing. PMID- 24761352 TI - Electrostimulation: Current Status, Strength of Evidence Guidelines, and Meta Analysis. AB - Significance: Delayed healing of skin wounds is a serious problem for the patients, clinicians, and society. The application of interventions with proven effectiveness to increase wound healing is relevant. Recent Advances: This article summarizes the results of effect studies with the application of electrostimulation (ES) as additional treatment to standard wound care (SWC). Therefore, five published narrative reviews are discussed. In addition, 15 studies with a clear randomized controlled trial design are analyzed systematically and the results are presented in four forest plots. The healing rate is expressed in the outcome measure percentage area reduction in 4 weeks of treatment (PAR4). This leads to a continuous measure with mean differences between the percentage healing in the experimental group (SWC plus ES) and in the control group (SWC alone or SWC plus placebo ES). Adding ES to SWC in all wound types increases PAR4 by an extra 26.7% (95% confidence interval [CI] 15.6, 37.8); adding unidirectional ES to SWC increases PAR4 by 30.8% (95% CI 20.9, 40.6) and adding unidirectional ES to the treatment of pressure ulcers increases PAR4 by 42.7% (95% CI 32.0, 53.3). Critical Issues: There is a discrepancy between the proven effectiveness of ES as additional treatment to SWC and the application of ES in real practice. Possible drawbacks are the lack of clinical expertise concerning the proper application of ES and the extra time effort and necessary equipment that are needed. Future Directions: Clinicians concerned about the optimal treatment of patients with delayed wound healing should improve their practical competency to be able to apply ES. PMID- 24761353 TI - Harnessing the Electric Spark of Life to Cure Skin Wounds. AB - Significance: Skin wounds cause great distress and are a huge economic burden, particularly with an increasingly aging population that heals poorly. There is an urgent need for better therapies that improve repair. Intracellular signaling pathways that regulate wound repair are activated by growth factors, hormones, and cytokines released at the wound. In addition, endogenous electric fields (EFs) are generated by epithelia in response to injury and are an important cue that coordinates cell behavior at wounds. Electrical stimulation (ES), therefore, holds the potential to be effective therapeutically in treating wounds. Recent Advances: ES of wounds is an old idea based on observations of the natural occurrence of EF at wound sites. However, it is now receiving increasing attention, because (1) the underpinning mechanisms are being clarified; (2) devices that measure skin wound currents are in place; and (3) medical devices that apply EF to poorly healing wounds are in clinical use with promising results. Critical Issues: Several signaling proteins transduce the EF influence to cells. However, a bigger picture of the EF-proteome is needed in order to understand this complex process and target it in a controlled manner. Future Directions: Dissecting the signaling pathways driving electrical wound healing will allow further identification of key molecular switches that control the cellular response to EFs. These findings herald the development of a new concept, the use of hydrogel electrodes impregnated with small molecules that target signaling pathways to explore the potential of dual electric-pharmacological therapies to repair wounds. PMID- 24761354 TI - Dissecting the Molecular Mechanisms of Electrotactic Effects. AB - Significance: Steady electric fields (EFs) surround cells and tissues in vivo and may regulate cellular behavior during development, wound healing, or tissue regeneration. Application of exogenous EFs of similar magnitude as those found in vivo can direct migration, growth, and division in most cell types, ranging from bacteria to mammalian cells. These EF effects have therapeutic potential, for instance, in accelerating wound healing or improving nerve repair. EFs are thought to signal through the plasma membrane to locally activate or recruit components of the cytoskeleton and the polarity machinery. How EFs might function to steer polarity is, however, poorly understood at a molecular level. Recent Advances: Here, we review recent work introducing genetically tractable systems, such as yeast and Dictyostelium cells, that begin to identify proteins and pathways involved in this response both at the level of ion transport at the membrane and at the level of cytoskeleton regulation. Critical Issues: These studies highlight the complexity of these EF effects and bring important novel views on core polarity regulation. Future Directions: Future work pursuing initial screening in model organisms should generate broad mechanistic understanding of electrotactic effects. PMID- 24761355 TI - Recent Developments in Electrotaxis Assays. AB - Significance: A wide range of cell types can migrate in response to physiological or externally applied direct current electric field (dcEF), a process termed electrotaxis. In particular, electrotaxis of epithelial cells to wound-generated dcEF for mediating wound healing is a well-accepted mechanism. In addition, various immune cells have been demonstrated to undergo electrotaxis, suggesting a link between electrotaxis and inflammatory responses in wound healing. Electrotaxis research will generate important insight into the electrical guiding mechanism for cell migration thereby providing the scientific basis to further develop clinical applications for wound care. Development of advanced electrotaxis assays will critically enable in-depth experimental electrotaxis studies in vitro. Recent Advances: Recently, a number of new electrotaxis assays or new uses of previously developed assays for electrotaxis studies have been reported. These new developments provide improved solutions for experimental throughput, configuration of three-dimensional cell migration environments and coexisting guiding signals, measurements of collective electrotactic cell migration, and sorting electrotactic populations. Critical Issues: These new developments face the challenge of playing a more important role to better understand the biological mechanisms underlying electrotaxis, in addition to making a stronger impact on relevant applications. Future Directions: On one hand, specific electrotaxis assays should be further developed to improve its function and tested for a broader range of experimental conditions and electrotactic populations. On the other hand, joint efforts among electrotaxis researchers are needed to integrate the unique features of specific electrotaxis assays, allowing more advanced and efficient electrotaxis analyses to answer both basic science and clinical questions. PMID- 24761356 TI - Therapeutic Application of Electric Fields in the Injured Nervous System. AB - Significance: Nervous system injuries, both in the peripheral nervous system (PNS) and central nervous system are a major cause for pain, loss-of-function, and impairment of daily life. As nervous system injuries commonly heal slowly or incompletely, new therapeutic approaches may be required. Recent Advances: The observation that cultured neurons are able to respond to exogenous electric fields (EFs) by sprouting more neurites and directing growth along the field, along with the presence of endogenous EFs in the developing vertebrate nervous system have led to the suggestion of the use of EFs in a regenerative therapeutic setting. This review discusses the effects of EFs on nervous cells, and their use in the treatment of nervous injuries in the eye, limb nerves, and the spinal cord. Exogenous EFs have been shown to be neuroprotective in various injury models of the eye, including traumatic injury, congenital degenerative retinopathy, and glaucoma. In the PNS, EFs are able to stimulate regrowth and functional recovery in damaged limb nerves. In the spinal cord, axonal regeneration and improved quality of life may be achieved using EF stimulation. Critical Issues: The optimal paradigm for electrical stimulation has not been determined, and the mechanisms behind the effect of EF are still largely unknown. Future Directions: Although the therapeutic use of EFs in the nervous system is still in its infancy, it is a promising therapeutic avenue for otherwise hard to treat injuries. The cellular/molecular mechanisms of such regulation need to be fully investigated, and the efficiency of applied EFs during wound healing needs to be optimized in a systematic approach in both animal models and future clinical trials. PMID- 24761357 TI - Clinical Trials Involving Biphasic Pulsed Current, MicroCurrent, and/or Low Intensity Direct Current. AB - Significance: This invited critical review will summarize an expansive body of literature regarding electrical stimulation (ES) and wound healing. Several clinical reports have been published in which ES has been evaluated as a therapy to speed the closure of chronic wounds. Different forms of ES have been applied in varying ways and described using inconsistent terminology by researchers and clinicians around the world. It is important to compile this research and to critically appraise the findings so that clinicians who are not familiar with this field can interpret the research. Recent Advances: More recently, ES has been delivered at subsensory levels (termed microcurrent in this review) using very small electrical devices contained within wound dressing. While these newer technologies have obvious technical advances, what research has been published to date about these new devices has not produced findings that suggest this form of ES can accelerate wound closure. Critical Issues: Reviewing a collection of published reports on this subject reveals that not all forms of ES produce beneficial results. Rather, only certain ES protocols such as monophasic pulsed current applied to the wound and biphasic pulsed current current that is applied for 2 h daily to periulcer skin at intensities which produce motor responses have consistently demonstrated positive results. Future Directions: Optimal stimulus parameters and treatment schedule for ES used to treat chronic wounds need to be determined. Researchers publishing in this field should provide detailed information about their ES treatment protocol and use a similar terminology to describe the ES waveform and stimulus parameters. PMID- 24761358 TI - The Electrical Response to Injury: Molecular Mechanisms and Wound Healing. AB - Significance: Natural, endogenous electric fields (EFs) and currents arise spontaneously after wounding of many tissues, especially epithelia, and are necessary for normal healing. This wound electrical activity is a long-lasting and regulated response. Enhancing or inhibiting this electrical activity increases or decreases wound healing, respectively. Cells that are responsible for wound closure such as corneal epithelial cells or skin keratinocytes migrate directionally in EFs of physiological magnitude. However, the mechanisms of how the wound electrical response is initiated and regulated remain unclear. Recent Advances: Wound EFs and currents appear to arise by ion channel up-regulation and redistribution, which are perhaps triggered by an intracellular calcium wave or cell depolarization. We discuss the possibility of stimulation of wound healing via pharmacological enhancement of the wound electric signal by stimulation of ion pumping. Critical Issues: Chronic wounds are a major problem in the elderly and diabetic patient. Any strategy to stimulate wound healing in these patients is desirable. Applying electrical stimulation directly is problematic, but pharmacological enhancement of the wound signal may be a promising strategy. Future Directions: Understanding the molecular regulation of wound electric signals may reveal some fundamental mechanisms in wound healing. Manipulating fluxes of ions and electric currents at wounds might offer new approaches to achieve better wound healing and to heal chronic wounds. PMID- 24761359 TI - Electrical Stimulation of Wound Healing: A Review of Animal Experimental Evidence. AB - Significance: Electrical stimulation (ES) is a therapeutic intervention that may help specialists facilitate wound healing rates. The purpose of this section is to compile the available animal research regarding the effectiveness of ES on the injury potential, healing rate, cellular and molecular proliferation, mechanical properties, and survival rate of skin flaps. Recent Advances: Regardless of the type of ES current and polarity used, most of the animal experimental evidence suggests that application of ES can facilitate wound healing. However, treatment time should be sufficiently long to attain good mechanical strength of regenerated tissue, because tensile strength is not consistent with augmented collagen deposition. ES improves the survival rate and skin blood flow of animal flaps, but clinical studies are needed to substantiate the findings from these animal experiments. Critical Issues: Impaired or delayed healing is a major clinical problem that can lead to wound chronicity. ES with various strategies has been used to facilitate the healing process, but many aspects remain controversial. Despite much research, no consensus exists regarding the detailed effects of ES on wound healing. Nevertheless, ES has been approved by the Center for Medicare and Medicine Services for reimbursement of the treatment of some chronic ulcers. Future Directions: Exogenous ES may promote the directional migration of cells and signaling molecules via electrotaxis; however, its underlying mechanism is still poorly understood. Future studies that further elucidate the mechanisms regulating electrotaxis will be necessary to optimize the use of ES in different wound states. PMID- 24761360 TI - Human Wound-Healing Research: Issues and Perspectives for Studies Using Wide Scale Analytic Platforms. AB - Significance: Revealing the basic mechanisms in the healing process and then regulating these processes for faster healing or to avoid negative outcomes such as infection or scarring are fundamental to wound research. The normal healing process is basically known, but to thoroughly understand the very complex aspects involved, it is necessary to characterize the course of events at a higher resolution with the latest molecular techniques and methodologies. Recent Advances: Various animal models are used in wound-healing research. Rodent and pig models are the ones most often used, probably because of pre-existing sophisticated research methodologies and as the proper care and ethical use of these species are highly developed and organized to serve science throughout the world. Critical Issues: Since several animal models are used, their anatomical and physiological differences varyingly affect the translation of results on healing mechanisms. Hence, to avoid species-specific misinformation, more ways to study wound healing directly in humans are needed. Future Directions: Fortunately, novel techniques have enabled high-end molecular-level research even from small samples of tissue. Since these methods require only a small amount of patient skin, they make it possible to study wound healing directly in humans. PMID- 24761361 TI - The Ontogeny of Skin. AB - Significance: During gestation, fetal skin progresses from a single layer derived from ectoderm to a complex, multi-layer tissue with the stratum corneum (SC) as the outermost layer. Innate immunity is a conferred complex process involving a balance of pro- and anti-inflammatory cytokines, structural proteins, and specific antigen-presenting cells. The SC is a part of the innate immune system as an impermeable physical barrier containing anti-microbial lipids and host defense proteins. Postnatally, the epidermis continually replenishes itself, provides a protective barrier, and repairs injuries. Recent Advances: Vernix caseosa protects the fetus during gestation and facilitates development of the SC in the aqueous uterine environment. The anti-infective, hydrating, acidification, and wound-healing properties post birth provide insights for the development of strategies that facilitate SC maturation and repair in the premature infant. Critical Issues: Reduction of infant mortality is a global health priority. Premature infants have an incompetent skin barrier putting them at risk for irritant exposure, skin compromise and life-threatening infections. Effective interventions to accelerate skin barrier maturation are compelling. Future Directions: Investigations to determine the ontogeny of barrier maturation, that is, SC structure, composition, cohesiveness, permeability, susceptibility to injury, and microflora, as a function of gestational age are essential. Clinicians need to know when the premature skin barrier becomes fully competent and comparable to healthy newborn skin. This will guide the development of innovative strategies for optimizing skin barrier development. PMID- 24761362 TI - The Role of Stem Cells During Scarless Skin Wound Healing. AB - Significance: In early gestation, fetal skin wounds undergo regeneration and healing without a scar. This phenomenon is intrinsic to early fetal skin but disappears during late gestation. Adult wounds undergo repair via a fibroproliferative response that leads to incomplete regeneration of the original tissue and a resultant scar. This outcome can have devastating effects for patients and is a significant financial burden to the healthcare system. Recent Advances: Studies have demonstrated the possible role of several stem cells in wound healing. In particular, epidermal stem cells and mesenchymal stem cells have been implicated in wound repair and regeneration. Recently, stem cells with adult epidermal stem cell markers have been found in fetal skin dermis. These cells are thought to play a role in scarless fetal wound healing. Critical Issues: Despite numerous studies on scarless fetal wound healing, the exact mechanism is still largely unknown. Although inflammation is greatly reduced, the stem cell profile of regenerating fetal skin wounds remains unknown. Without a detailed understanding of stem cell differences between fetal and adult wounds, the ability to prevent or treat both normal and pathologic excessive scarring, in the form of keloids and hypertrophic scars, is limited. Future Directions: Further studies on differences between fetal and adult skin-specific stem cells may elucidate the mechanism of scarless wound healing in the early fetus. With this knowledge, the potential to reduce scarring in adult wounds may be achieved. PMID- 24761363 TI - Dressings and Products in Pediatric Wound Care. AB - Significance: The increasing complexity of medical and surgical care provided to pediatric patients has resulted in a population at significant risk for complications such as pressure ulcers, nonhealing surgical wounds, and moisture associated skin damage. Wound care practices for neonatal and pediatric patients, including the choice of specific dressings or other wound care products, are currently based on a combination of provider experience and preference and a small number of published clinical guidelines based on expert opinion; rigorous evidence-based clinical guidelines for wound management in these populations is lacking. Recent Advances: Advances in the understanding of the pathophysiology of wound healing have contributed to an ever-increasing number of specialized wound care products, most of which are predominantly marketed to adult patients and that have not been evaluated for safety and efficacy in the neonatal and pediatric populations. This review aims to discuss the available data on the use of both more traditional wound care products and newer wound care technologies in these populations, including medical-grade honey, nanocrystalline silver, and soft silicone-based adhesive technology. Critical Issues: Evidence-based wound care practices and demonstration of the safety, efficacy, and appropriate utilization of available wound care dressings and products in the neonatal and pediatric populations should be established to address specific concerns regarding wound management in these populations. Future Directions: The creation and implementation of evidence-based guidelines for the treatment of common wounds in the neonatal and pediatric populations is essential. In addition to an evaluation of currently marketed wound care dressings and products used in the adult population, newer wound care technologies should also be evaluated for use in neonates and children. In addition, further investigation of the specific pathophysiology of wound healing in neonates and children is indicated to promote the development of wound care dressings and products with specific applications in these populations. PMID- 24761364 TI - Management of Traumatic Wounds and a Novel Approach to Delivering Wound Care in Children. AB - Significance: The costs and morbidity of pediatric traumatic wounds are not well known. The literature lacks a comprehensive review of the volume, management, and outcomes of children sustaining soft tissue injury. We briefly review the existing literature for traumatic wounds such as open fractures and burns. Such injuries require dedicated wound care and we propose a novel approach for more efficient and more effective delivery of dedicated pediatric wound care. Recent Advances: New pediatric literature is emerging regarding the long-term effects of wound care pain in traumatic injuries-especially burns. A variety of wound dressings and alternative management techniques exist and are geared toward reducing wound care pain. Our institution utilizes a unique model to provide adequate sedation and pain control through a dedicated pediatric wound care unit. We believe that this model reduces the cost of wound care by decreasing emergency department and operating room visits as well as hospital length of stay. Critical Issues: First, medical costs related to pediatric traumatic wound care are not insignificant. The need for adequate pain control and sedation in children with complex wounds is traditionally managed with operating room intervention. Afterward, added costs can be from a hospital stay for ongoing acute wound management. Second, morbidities of complex traumatic wounds are shown to be related to the acute wound care received. Future Directions: Further guidelines are needed to determine the most effective and efficient care of complex traumatic soft tissue injuries in the pediatric population. PMID- 24761366 TI - Structured Dietary Interventions in the Treatment of Severe Pediatric Obesity: A Pilot Study. AB - BACKGROUND: Structured dietary interventions have been associated with improved outcomes in adult weight-control programs, but virtually no research has focused on children. Thus, we conducted an uncontrolled pilot study to determine the potential utility of structured approaches to enhance the dietary component of family-based treatment of severe pediatric obesity (body mass index [BMI] >97th percentile for age and sex). METHOD: Children aged 8-12 years participated with a parent or guardian. Individualized menu plans were provided (MENU, n=12) alone, or along with meals and snacks for the child (MENU+MEAL, n=6). All families received up to $30/week reimbursement for foods included in the menus. RESULTS: Median BMI change was -1.2 kg/m2 for MENU (n=12), and -1.8 kg/m2 for MENU+MEAL (n=6). Both approaches were associated with significant reductions in BMI (p<0.05). CONCLUSION: Structured dietary interventions for severe pediatric obesity are acceptable to families and warrant further development. PMID- 24761365 TI - Homeobox Gene Deregulation: Impact on the Hallmarks of Cancer. AB - Homeobox genes comprise a super-family of evolutionarily conserved genes that play essential roles in controlling body plan specification and cell fate determination. Substantial evidence indicates that leukemogenesis is driven by abnormal expression of homeobox genes that control hematopoiesis. In solid tumors, aberrant expression of homeobox genes has been increasingly found to modulate diverse processes such as cell proliferation, cell death, metastasis, angiogenesis and DNA repair. This review discusses how homeobox genes are deregulated in solid tumors and the functional significance of this deregulation in the hallmarks of cancer. PMID- 24761367 TI - Understanding Eating and Exercise Behaviors in Post Roux-en-Y Gastric Bypass Patients: A Quantitative and Qualitative Study. AB - BACKGROUND: Weight regain following gastric bypass (GB) surgery continues to plague many individuals across the United States. However, understanding long term eating and exercise behaviors to promote and sustain a lower weight following GB surgery is limited. METHOD: The purpose of this study was to explore the perceptions and attitudes of eating and exercise behaviors associated with weight maintenance in post-GB patients (n=24) 2 or more years postsurgery. Demographic, anthropometric, and food record data were collected. Focus groups and personal interviews were used to understand behaviors and support systems associated with weight stabilization. Focus groups were audio-taped, transcribed, and organized into common themes. RESULTS: All participants were female, with a mean of 6 years postsurgery, and had a mean age of 51.8+/-10.5 years. The majority were married (71%) and had a college degree (58%). Although the average weight regain postsurgery was estimated at 16.2+/-12.7 kg, most of the women (75%) had maintained a significant weight loss of at least 50% of their excess body weight. Themes associated with weight regain emerging from the focus groups included variable family support and a return to "old eating habits." CONCLUSION: Focus group participants identified lack of long-term emotional support from family members and limited community support for weight loss surgery patients. PMID- 24761368 TI - The Patient Journey to Gastric Band Surgery: A Qualitative Exploration. AB - AIMS: This study explored the views and experiences of obese people preparing to undergo laparoscopic gastric banding (LAGB) leading up to the time of surgery. BACKGROUND: Weight loss surgery (WLS) is the most successful intervention available for the treatment of morbid obesity, and LAGB is among the most commonly used procedures in bariatric surgery. So far, the patient experience of deciding to undergo LAGB has been explored rarely and predominantly retrospectively. DESIGN: Semi-structured interviews took place with 23 patients about to undergo LAGB between June 2011 and March 2012. Data were analyzed using thematic analysis. Demographic and quality of life data situated the sample within the LAGB patient population. RESULTS: Three overarching themes were described. Participants were "living with obesity," including the physical, social, and psychological challenges and consequences of being obese. These created in them a "desire to change," expressed in multiple unsuccessful attempts to lose weight, and a quest for information, finally focusing on WLS. Eventually, "expectations toward LAGB" were formed, mainly to hand back a measure of control that enabled them to achieve, as well as ultimately to maintain, weight loss. This active process resulted in the patients' decision to undergo LAGB. When combined, these themes outline a distinct patient journey toward gastric banding. CONCLUSION: Knowledge of the patient journey can inform both selection and care of patients awaiting gastric band surgery and is required by all health professionals working with this patient group. PMID- 24761369 TI - Integrative Complementary Medicine for Treatment of Bariatric Perioperative Symptoms: Patients' Experiences and Staff Evaluations. AB - BACKGROUND: A unique integrative complementary medicine (CM) pilot program was launched in a general surgery department at a public teaching hospital in Israel. In addition to standard supportive care, CM treatments are used to support patients undergoing laparoscopic sleeve gastrectomy (LSG) in coping with perioperative distresses. We examined the experiences of patients and how the nursing staff evaluate these treatments. METHODS: Qualitative semi-structured open-ended interviews were used. RESULTS: Most patients reported that the treatments helped them to cope better with preoperative anxiety, and facilitated postoperative breathing and pain relief. Nurses reported that CM treatments enabled them to reduce doses of analgesics. Both patients and nurses suggested that preoperative CM treatment facilitated a better postoperative CM-associated outcome. CONCLUSIONS: Integrative perioperative CM treatments improved pain and anxiety care in patients undergoing LSG. More research is needed to examine CM efficacy in improving standard LSG perioperative supportive care and to evaluate cost effectiveness. PMID- 24761370 TI - Nutritional Implications of Obesity: Before and After Bariatric Surgery. PMID- 24761371 TI - Management of Failed Laparoscopic Roux-en-Y Gastric Bypass. AB - Background: Laparoscopic Roux-en-Y gastric bypass (LRYGB) has emerged as the gold standard for the management of morbid obesity. Accordingly, patients who fail to lose weight after LRYGB present a difficult problem for the bariatric surgeons. A literature review was performed to evaluate the management options for this select bariatric population. Methods: A literature search was conducted in the EMBASE and MEDLINE databases using the most comprehensive timeline. All relevant articles were identified and full texts were obtained and reviewed. Results: Thirteen articles were retrieved based on key word searches. Management for weight failure following LRYGB included revision using the following options: laparoscopic adjustable gastric banding, pouch/anastomotic revision with or without endoluminal techniques, laparoscopic distal Roux-en-Y gastric bypass, and laparoscopic biliopancreatic diversion with duodenal switch. Laparoscopic sleeve gastrectomy may be considered in patients who fail LRYGB with nutritional deficiencies. Conclusion: Failed LRYGB should be managed based on the patient presentation and diagnostic evaluation. Patients may present with significant nutritional deficiencies/complications, failure to lose weight, or weight recidivism. A treatment algorithm is proposed based on the literature to guide bariatric surgeons with respect to management options. However, given the paucity of research with respect to this problem, additional studies are needed to provide more insight on the optimal surgical management. PMID- 24761372 TI - Strategies for assessing diffusion anisotropy on the basis of magnetic resonance images: comparison of systematic errors. AB - Diffusion weighted imaging uses the signal loss associated with the random thermal motion of water molecules in the presence of magnetic field gradients to derive a number of parameters that reflect the translational mobility of the water molecules in tissues. With a suitable experimental set-up, it is possible to calculate all the elements of the local diffusion tensor (DT) and derived parameters describing the behavior of the water molecules in each voxel. One of the emerging applications of the information obtained is an interpretation of the diffusion anisotropy in terms of the architecture of the underlying tissue. These interpretations can only be made provided the experimental data which are sufficiently accurate. However, the DT results are susceptible to two systematic error sources: On one hand, the presence of signal noise can lead to artificial divergence of the diffusivities. In contrast, the use of a simplified model for the interaction of the protons with the diffusion weighting and imaging field gradients (b matrix calculation), common in the clinical setting, also leads to deviation in the derived diffusion characteristics. In this paper, we study the importance of these two sources of error on the basis of experimental data obtained on a clinical magnetic resonance imaging system for an isotropic phantom using a state of the art single-shot echo planar imaging sequence. Our results show that optimal diffusion imaging require combining a correct calculation of the b-matrix and a sufficiently large signal to noise ratio. PMID- 24761373 TI - An Arbitrary Waveform Wearable Neuro-stimulator System for Neurophysiology Research on Freely Behaving Animals. AB - Portable wireless neuro-stimulators have been developed to facilitate long-term cognitive and behavioral studies on the central nervous system in freely moving animals. These stimulators can provide precisely controllable input(s) to the nervous system, without distracting the animal attention with cables connected to its body. In this study, a low power backpack neuro-stimulator was developed for animal brain researches that can provides arbitrary stimulus waveforms for the stimulation, while it is small and light weight to be used for small animals including rats. The system consists of a controller that uses an RF link to program and activate a small and light microprocessor-based stimulator. A Howland current source was implemented to produce precise current controlled arbitrary waveform stimulations. The system was optimized for ultra-low power consumption and small size. The stimulator was first tested for its electrical specifications. Then its performance was evaluated in a rat experiment when electrical stimulation of medial longitudinal fasciculus induced circling behavior. The stimulator is capable of delivering programmed stimulations up to +/- 2 mA with adjusting steps of 1 MUA, accuracy of 0.7% and compliance of 6 V. The stimulator is 15 mm * 20 mm * 40 mm in size, weights 13.5 g without battery and consumes a total power of only 5.l mW. In the experiment, the rat could easily carry the stimulator and demonstrated the circling behavior for 0.1 ms current pulses of above 400 MUA. The developed system has a competitive size and weight, whereas providing a wide range of operation and the flexibility of generating arbitrary stimulation patterns ideal for long-term experiments in the field of cognitive and neuroscience research. PMID- 24761374 TI - Real-time Detection of Precursors to Epileptic Seizures: Non-Linear Analysis of System Dynamics. AB - We propose a novel approach for detecting precursors to epileptic seizures in intracranial electroencephalograms (iEEG), which is based on the analysis of system dynamics. In the proposed scheme, the largest Lyapunov exponent of the discrete wavelet packet transform (DWPT) of the segmented EEG signals is considered as the discriminating features. Such features are processed by a support vector machine (SVM) classifier to identify whether the corresponding segment of the EEG signal contains a precursor to an epileptic seizure. When consecutive EEG segments contain such precursors, a decision is made that a precursor is in fact detected. The proposed scheme is applied to the Freiburg dataset, and the results show that seizure precursors are detected in a time frame that unlike other existing schemes is very much convenient to patients, with sensitivity of 100% and negligible false positive detection rates. PMID- 24761375 TI - The effect of high voltage, high frequency pulsed electric field on slain ovine cortical bone. AB - High power, high frequency pulsed electric fields known as pulsed power (PP) has been applied recently in biology and medicine. However, little attention has been paid to investigate the application of pulse power in musculoskeletal system and its possible effect on functional behavior and biomechanical properties of bone tissue. This paper presents the first research investigating whether or not PP can be applied safely on bone tissue as a stimuli and what will be the possible effect of these signals on the characteristics of cortical bone by comparing the mechanical properties of this type of bone pre and post expose to PP and in comparison with the control samples. A positive buck-boost converter was applied to generate adjustable high voltage, high frequency pulses (up to 500 V and 10 kHz). The functional behavior of bone in response to pulse power excitation was elucidated by applying compressive loading until failure. The stiffness, failure stress (strength) and the total fracture energy (bone toughness) were determined as a measure of the main bone characteristics. Furthermore, an ultrasonic technique was applied to determine and comprise bone elasticity before and after pulse power stimulation. The elastic property of cortical bone samples appeared to remain unchanged following exposure to pulse power excitation for all three orthogonal directions obtained from ultrasonic technique and similarly from the compression test. Nevertheless, the compressive strength and toughness of bone samples were increased when they were exposed to 66 h of high power pulsed electromagnetic field compared to the control samples. As the toughness and the strength of the cortical bone tissue are directly associated with the quality and integrity of the collagen matrix whereas its stiffness is primarily related to bone mineral content these overall results may address that although, the pulse power stimulation can influence the arrangement or the quality of the collagen network causing the bone strength and toughness augmentation, it apparently did not affect the mineral phase of the cortical bone material. The results also confirmed that the indirect application of high power pulsed electric field at 500 V and 10 kHz through capacitive coupling method was safe and did not destroy the bone tissue construction. PMID- 24761376 TI - Vessel Segmentation in Retinal Images Using Multi-scale Line Operator and K-Means Clustering. AB - Detecting blood vessels is a vital task in retinal image analysis. The task is more challenging with the presence of bright and dark lesions in retinal images. Here, a method is proposed to detect vessels in both normal and abnormal retinal fundus images based on their linear features. First, the negative impact of bright lesions is reduced by using K-means segmentation in a perceptive space. Then, a multi-scale line operator is utilized to detect vessels while ignoring some of the dark lesions, which have intensity structures different from the line shaped vessels in the retina. The proposed algorithm is tested on two publicly available STARE and DRIVE databases. The performance of the method is measured by calculating the area under the receiver operating characteristic curve and the segmentation accuracy. The proposed method achieves 0.9483 and 0.9387 localization accuracy against STARE and DRIVE respectively. PMID- 24761377 TI - Design and construction of an optical computed tomography scanner for polymer gel dosimetry application. AB - Polymer gel dosimeter is the only accurate three dimensional (3D) dosimeter that can measure the absorbed dose distribution in a perfect 3D setting. Gel dosimetry by using optical computed tomography (OCT) has been promoted by several researches. In the current study, we designed and constructed a prototype OCT system for gel dosimetry. First, the electrical system for optical scanning of the gel container using a Helium-Neon laser and a photocell was designed and constructed. Then, the mechanical part for two rotational and translational motions was designed and step motors were assembled to it. The data coming from photocell was grabbed by the home-built interface and sent to a personal computer. Data processing was carried out using MATLAB software. To calibrate the system and tune up the functionality of it, different objects was designed and scanned. Furthermore, the spatial and contrast resolution of the system was determined. The system was able to scan the gel dosimeter container with a diameter up to 11 cm inside the water phantom. The standard deviation of the pixels within water flask image was considered as the criteria for image uniformity. The uniformity of the system was about +/-0.05%. The spatial resolution of the system was approximately 1 mm and contrast resolution was about 0.2%. Our primary results showed that this system is able to obtain two dimensional, cross-sectional images from polymer gel samples. PMID- 24761378 TI - A Novel CAD System for Mitosis detection Using Histopathology Slide Images. AB - Histopathology slides are one of the most applicable resources for pathology studies. As observation of these kinds of slides even by skillful pathologists is a tedious and time-consuming activity, computerizing this procedure aids the experts to have faster analysis with more case studies per day. In this paper, an automatic mitosis detection system (AMDS) for breast cancer histopathological slide images is proposed. In the proposed AMDS, the general phases of an automatic image based analyzer are considered and in each phase, some special innovations are employed. In the pre-processing step to segment the input digital histopathology images more precisely, 2D anisotropic diffusion filters are applied to them. In the training segmentation phase, the histopathological slide images are segmented based on RGB contents of their pixels using maximum likelihood estimation. Then, the mitosis and non-mitosis candidates are processed and hence that their completed local binary patterns are extracted object-wise. For the classification phase, two subsequently non-linear support vector machine classifiers are trained pixel-wise and object-wise, respectively. For the evaluation of the proposed AMDS, some object and region based measures are employed. Having computed the evaluation criteria, our proposed method performs more efficient according to f-measure metric (70.94% for Aperio XT scanner images and 70.11% for Hamamatsu images) than the methods proposed by other participants at Mitos-ICPR2012 contest in breast cancer histopathological images. The experimental results show the higher performance of the proposed AMDS compared with other competitive systems proposed in Mitos-ICPR2012 contest. PMID- 24761379 TI - Vesselness-guided Active Contour: A Coronary Vessel Extraction Method. AB - Vessel extraction is a critical task in clinical practice. In this paper, we propose a new approach for vessel extraction using an active contour model by defining a novel vesselness-based term, based on accurate analysis of the vessel structure in the image. To achieve the novel term, a simple and fast directional filter bank is proposed, which does not employ down sampling and resampling used in earlier versions of directional filter banks. The proposed model not only preserves the performance of the existing models on images with intensity inhomogeneity, but also overcomes their inability both to segment low contrast vessels and to omit non-vessel structures. Experimental results for synthetic images and coronary X-ray angiograms show desirable performance of our model. PMID- 24761380 TI - The diabetic patient in Ramadan. AB - During the month of Ramadan, all healthy, adult Muslims are required to fast from dawn to sunset. Fasting during Ramadan involves abstaining from food, water, beverages, smoking, oral drugs, and sexual intercourse. Although the Quran exempts chronically ill from fasting, many Muslims with diabetes still fast during Ramadan. Patients with diabetes who fast during the month of Ramadan can have acute complications. The risk of complications in fasting individuals with diabetes increases with longer periods of fasting. All patients with diabetes who wish to fast during Ramadan should be prepared by undergoing a medical assessment and engaging in a structured education program to undertake the fast as safely as possible. Although some guidelines do exist, there is an overwhelming need for better designed clinical trials which could provide us with evidence-based information and guidance in the management of patients with diabetes fasting Ramadan. PMID- 24761381 TI - Simultaneous hepatosplenic T-cell lymphoma and myelofibrosis. AB - Hepatosplenic T-cell lymphoma (HSTL) is a rare T-cell neoplasm of the lymphoid system. This type of lymphoma is characterized by sinusoidal infiltration of spleen, liver, bone marrow and lymph nodes by neoplastic lymphocytes. Here, we discuss a patient who had a left axillary lymph node biopsy with characteristic histological and immunohistochemical features of HSTL. In addition, infiltrating neoplastic T-cells and simultaneous characteristic features of myelofibrosis (MF) were also present in the bone marrow biopsy specimen. In contrast to secondary MF, primary MF is a progressive disease and may significantly affect the prognosis of coexisting HSTL. There are few reports in the literature talking about mild bone marrow fibrosis in association with T cell lymphoma, however marked increase in bone marrow fibrosis and HSTL never being reported. This case is shedding light on HSTL and marked increase in bone marrow fibrosis. PMID- 24761382 TI - Acinetobacter baumannii bacteremia, a rare complication of endoscopic retrograde cholagiopancreatography! AB - Bacteremia is a severe and sometimes fatal complication following endoscopic retrograde cholagiopancreatography (ERCP). Several bacteria have been implicated, with Enterobacteriaceae being the most common. We report a case of post-ERCP multi-drug resistant Acinetobacter baumannii bacteremia. PMID- 24761383 TI - Preoperative splenic artery embolization in klippel-Trenaunay syndrome with massive splenomegaly: A case report. AB - The authors describe a case of Klippel-Trenaunay syndrome (KTS) with massive splenomegaly in a 29-year-old woman. Preoperative splenic artery embolization using the "double embolization technique" (a combination of distal selective splenic artery embolization and proximal splenic artery occlusion) facilitated open splenectomy. PMID- 24761384 TI - Renal confined sarcoidosis: Natural history and diagnostic challenge. AB - A 69 year old male referred to nephrology clinic for uncontrolled hypertension. During his follow up over two years, he developed renal disease and hypercalcemia. He was found to have monoclonal gammopathy (MGUS). Urinalysis was negative except for Monoclonal IgG on immunoelectrophoresis. Workup for malignancy was negative including chest X-ray and bone marrow biopsy. He progressed into renal failure and ended up on dialysis. Interestingly, the renal biopsy showed non-caseating granulomas, and the patient was diagnosed with renal confined sarcoidosis which is extremely rare. PPD was negative. He was treated with Prednisone 60 mg daily. Surprisingly, his kidney disease was not responsive to steroids. Despite improvement in his calcium with treatment, his kidney function did not improve and he remained on hemodialysis but needed to stay on small dose of Prednisone to keep his calcium under control. Our case is the first in the literature that demonstrates the natural history of renal-confined sarcoidosis. In addition, the presence of MGUS created a diagnostic challenge and delayed diagnosis of sarcoidosis. Although the renal biopsy did not show direct damage from MGUS, a potential relation between renal sarcoidosis and MGUS is worth studied. PMID- 24761385 TI - A concurrent episode of two neoplasms in a toddler-age child. AB - Childhood neoplasms are relatively rare and represent only about 1- 2% of the total incidence of neoplasms in United States. Concurrent episode of childhood cancer is uncommon and usually related to a cancer genetic syndrome. Li Fraumeni Syndrome refers to an autosomal dominant condition that is manifested by the development of certain cancers in early childhood and an increased lifetime risk for developing multiple primary cancers including sarcoma, breast cancer, leukemia, bone cancer, and others. We report a case of a 21-month-old girl who was found to have orbital embryonal rhabdomyosarcoma and adrenocortical tumor concurrently. PMID- 24761386 TI - Development of a chamber system for rapid, high yield and cost-effective purification of deoxyribonucleic acid fragments from agarose gel. AB - BACKGROUND: There are several methods commonly practicing for deoxyribonucleic acid (DNA) purification from agarose gel. In most laboratories, especially in developing countries, present methods for recovering of DNA fragments from the gel are mostly involved organic solvents. However, manual purification using organic solvents are toxic, labor intensive, time consuming and prone to contamination owing to several handling steps. The above mentioned burdens as well as cost and long time to import them, especially in developing countries, prompted us to design and develop a chamber system for rapid, non-toxic, cost effective and user friendly device for polymerase chain reaction (PCR) products purification from agarose gel. MATERIALS AND METHODS: The device was made from plexiglass plates. After amplification of two fragments of 250 and 850 bp, PCR products were electrophoresed. Subsequently, the desired bands were excised and purified with three method: HiPer Mini chamber, phenol extraction method and spin column procedure. To assess the suitability of the purified DNAs, restriction digestion was applied. RESULTS: Results showed that the yield of recovered DNA in our method was above 95%, whereas the yields obtained with conventional phenol extraction and spin column methods were around 60%. CONCLUSION: In conclusion, the current method for DNA elution is quick, inexpensive and robust and it does not require the use of toxic organic solvents. In addition, the purified DNA was well has suited for further manipulations such as restriction digestion, ligation, cloning, sequencing and hybridization. PMID- 24761387 TI - Relationship between breast arterial calcification on mammography with CT Calcium scoring and coronary CT angiography results. AB - BACKGROUND: Mammography as a non invasive method has been suggested to be helpful in predicting coronary artery disease. This study aimed to investigate whether presence and severity of breast artery calcification (BAC) on mammograms is associated with computed tomography coronary angiography (CTCA) finding such as coronary artery calcium (CAC) score and the severity of coronary artery stenosis. MATERIALS AND METHODS: This cross-sectional study was performed on 150 women aged >40 years who were referred for CTCA. Women who had undergone screening mammography during the first year after CTCA entered the study. CAC score was determined and the severity of coronary artery stenosis was classified into normal, non-significant stenosis, or significant stenosis. Based on the severity of BAC, patients were also grouped into normal, mild, moderate, or severe groups. Then, the correlation between BAC severity and CAC score was determined. Patients with different BAC severity were also compared regarding the relative frequency of different grades of coronary artery stenosis. RESULTS: Mean age of subjects with BAC (n: 35) was significantly higher than patients without BAC (n: 115) (68.03 +/- 6.16 versus 54.36 +/- 7.63 years, P < 0.0001). Although the relative frequency of different grades of coronary artery stenosis was significantly higher in women with BAC (P < 0.0001), after controlling for age, there was no significant difference between patients with different severity of BAC in the mean of CAC score (P: 0.09). In addition, the correlation between BAC severity and CAC score was not statistically significant (R: 0.09, P: 0.26). CONCLUSION: We concluded that presence and severity of BAC have no significant correlation with CAC score on CTCA. PMID- 24761388 TI - Factor V Leiden does not have a role in cryptogenic ischemic stroke among Iranian young adults. AB - BACKGROUND: Different risk factors have been suggested for ischemic stroke in young adults. In a group of these patients despite of extensive diagnostic work up, the primary cause remains unknown. Coagulation tendency is accounted as a possible cause in these patients. Previous studies on factor V Leiden (FVL) as the main cause of inherited thrombophilia for clarifying the role of FVL in stroke have resulted in controversial findings. The current study investigates the role of this factor in ischemic stroke among Iranians. MATERIALS AND METHODS: This case-control study was performed between September 2007 and December 2008 in Isfahan, Iran. The case group comprised of 22 patients of which 15 were males and 7 were females with age range of <=50 years, diagnosed as ischemic stroke without classic risk factors and the control group consisted of 54 healthy young adults. After filling consent form, venous blood samples were obtained and sent to the laboratory for genetic examination. RESULTS: No FVL mutation was found in the case group. There was one carrier of the mutation as heterozygous in the control group (relative frequency = 1.85%). CONCLUSIONS: Based on our study, FVL might not be considered as an independent risk factor for ischemic stroke in Iranian individuals who are not suffering from other risk factors of ischemic stroke. PMID- 24761389 TI - Trigeminal nerve stimulation: A new way of treatment of refractory seizures. AB - BACKGROUND: Refractory epilepsy is a significant problem in clinical practice. Sometimes, multiple antiepileptic drugs are required to control the attacks. To avoid various complications ensuring from these drugs, new methods of treatment such as vagus nerve stimulation (VNS) have been recommended. Trigeminal nerve stimulation (TNS) is a new method under evaluation. The purpose of this paper is to determine whether this method is effective or not. MATERIALS AND METHODS: Percutaneous simulation of supraorbital branches of the trigeminal nerve by an electrical device was planned in 18 patients over a six-month period. Participants who fulfilled the research criteria were selected randomly from epileptic patients referred to the clinic. (November 2011-December 2012). T-test was used for data analysis. RESULTS: Only eight of 18 patients stayed in the study during all 6 months. A 47.9% reduction in daily seizure frequency was seen in this group (P = 0.022). Other subjects left the study earlier. In this group, seizure frequency increased by 10.6% (P = 0.82). CONCLUSIONS: The mechanism of the antiepileptic effects of TNS is not yet clear. In animal studies, it is suggested that the trigeminal nucleus and its projection to nucleus tractus solitarius (NTS) and the locus ceruleus, are involved in seizure modulation. Although in comparison with seizure frequency prior to the study there was significant seizure reduction, according to the usual criteria for VNS i.e. 50% seizure frequency reduction, the effect of TNS per se may not yet be adequate for treatment of seizures. Trigeminal nerve stimulation may be an effective "adjuvant" method for treatment of intractable seizure. PMID- 24761390 TI - Cloning, expression, purification and characterisation of Erwinia carotovora L asparaginase in Escherichia coli. AB - BACKGROUND: For the past 30 years, bacterial L-asparaginases have been used as therapeutic agents in the treatment of acute childhood lymphoblastic leukemia. It is found in a variety of organisms such as microbes, plants and mammals. Their intrinsic low-rate glutaminase activity, however, causes serious side-effects, including neurotoxicity, hepatitis, coagulopathy and other dysfunctions. Erwinia carotovora asparaginase shows decreased glutaminase activity, so it is believed to have fewer side-effects in leukemia therapy. Our aim was to clone, express, purify and characterize E. carotovora asparaginase. MATERIALS AND METHODS: L asparaginase from E. carotovora NCYC 1526 (ErA) was cloned and expressed in Escherichia coli strain BL21 (DE3). The enzyme was purified to homogeneity by affinity chromatography. Various conditions were tested to maximize the production of recombinant asparaginase in E. coli. RESULTS: A new L. asparaginase from E. carotovora NCYC 1526 (ErA) was successfully cloned, expressed and purified in E. coli BL21 (DE3). The specific activity of the enzyme was 430 IU/mg. CONCLUSION: The results of the present work form the basis for a new engineered form of ErA for future therapeutic use, which could be extended with crystallographic studies. PMID- 24761391 TI - Involvement of beta-adrenergic receptor of nucleus tractus solitarius in changing of baroreflex sensitivity by estrogen in female rats. AB - BACKGROUND: Arterial baroreflex (ABR) is an important factor in preventing of blood pressure fluctuations that determined by baroreflex sensitivity (BRS). Estrogen is an ovarian hormone that has influence on ABR. The mechanism of this effect of estrogen unknown and may be mediated by beta-adrenergic receptor of nucleus tractus solitarius (NTS), an important area in regulation of baroreflex. Therefore, in this study changing of BRS by estrogen after blockade beta adrenergic receptor of NTS in ovariectomized rats (Ovx) and Ovx treated with estrogen (Est) was examined. MATERIALS AND METHODS: After ovariectomy, all female rats divided to Ovx and Ovx + Est groups and two series of experiments were performed. In the first experiment, phenylephrine was [intravenously, IV] injected in both the Ovx and Ovx + Est groups, and mean arterial pressure (MAP), heart rate (HR), and BRS were evaluated (n = 8 for each group). In the second experiment, each of Ovx and Ovx + Est groups divided into saline and propranolol (pro) groups, saline and pro stereotaxically were microinjected into NTS, respectively. Further, phenylephrine (IV) was injected in all groups and BRS was evaluated. RESULTS: BRS significantly increased in estrogen-treated groups (Ovx + Est) compared to Ovx groups (P < 0.01). The blockade beta-adrenergic receptor of NTS by pro did not significantly changed BRS in both Ovx and Ovx + Est groups. CONCLUSION: We concluded that there aren't any intraction between estrogen and beta-adrenergic receptor of NTS in BRS. PMID- 24761392 TI - Effects of intra-operative end-tidal carbon dioxide levels on the rates of post operative complications in adults undergoing general anesthesia for percutaneous nephrolithotomy: A clinical trial. AB - BACKGROUND: A retrospective study has shown lesser days of hospital stay in patients with increased levels of intra-operative end-tidal carbon dioxide (ETCO2). It is probable that hypercapnia may exert its beneficial effects on patients' outcome through optimization of global hemodynamic and tissue oxygenation, leading to a lower rate of post-operative complications. This study was designed to test the hypothesis that higher values of intra-operative ETCO2 decrease the rate of post-operative complications. MATERIALS AND METHODS: In this randomized, double-blind clinical trial, 78 adult patients scheduled for percutaneous nephrolithotomy (PCNL) were prospectively enrolled and randomly divided into three groups. ETCO2 was set and maintained throughout the procedure at 31-33, 37-39 and 43-45 mmHg in the hypocapnia, normocapnia and hypercapnia groups, respectively. The rates of post-operative complications were compared among the three groups. RESULTS: Seventy-five patients completed the study (52 male and 23 female). Ten (38.5%), four (16%) and two (8.3%) patients developed post-operative vomiting in the hypocapnia, normocapnia and hypercapnia groups, respectively (P = 0.025). The nausea score was significantly lower in the hypercapnic group compared with the other groups (3.9 +/- 1.8, 3.2 +/- 2.1 and 1.3 +/- 1.8 in the hypocapnia, normocapnia and hypercapnia groups, respectively; P = 0.000). Time to return of spontaneous respiration and awakening were significantly decreased in the hypercapnia group compared with the other groups (P < 0.01). CONCLUSION: Mild intra-operative hypercapnia has a protecting effect against the development of post-operative nausea and vomiting and decreases the duration of emergence and recovery from general anesthesia. PMID- 24761393 TI - Comparison of SYBR Green and TaqMan methods in quantitative real-time polymerase chain reaction analysis of four adenosine receptor subtypes. AB - BACKGROUND: Real-time polymerase chain reaction (PCR) is based on the revolutionary method of PCR. This technique is the result of PCR enormous sensitivity and real-time monitoring combination. In quantitative gene expression analysis, two methods have more popularity, SYBR Green and TaqMan, SYBR Green is relatively cost benefit and easy to use and technically based on binding the fluorescent dye to double-stranded deoxyribonucleic acid (dsDNA) where TaqMan method has more expensive and based on dual labeled oligonucleotide and exonuclease activity of Taq polymerase enzyme. Specificity is the most important concern with the usage of any non-specific dsDNA-binding Dyes such as SYBR Green whiles more specificity showed by labeled oligonucleotide method such as TaqMan. In this study, we compared two common RT PCR methods, TaqMan and SYBR Green in measurement gene expression profile of adenosine receptors. MATERIALS AND METHODS: Gene expression profiles of A1, A2A, A2B and A3 Adenosine receptors were analyzed by optimized TaqMan and SYBR Green quantitative RT PCR in breast cancer tissues. Primary expression data was normalizing by B. actin reference gene. RESULTS: Efficiencies were calculated more than 95% for TaqMan and SYBR Green methods in all genes. The correlations between means of normalized data of each gene in two methods were positive and significant (P < 0.05). CONCLUSION: Data analysis showed that with the use of high performance primer and by use proper protocols and material we can make precise data by SYBR Green as TaqMan method. In other word by optimization of SYBR Green method, its performance and quality could be comparable to TaqMan method. PMID- 24761394 TI - Comparing clinical efficacy of Symbicort versus Pulmicort in reducing asthma symptom and improving its control. AB - BACKGROUND: Recently, higher efficacy of the combination of long-acting beta2 adrenoceptor agonist and inhaled corticosteroids on controlling asthma symptoms has been hypothesized. This study aimed to examine the clinical effects of the combination of Budesonide with formoterol (Symbicort) and Budesonide (Pulmicort) alone in persistent asthma. MATERIALS AND METHODS: In a randomized double-blinded clinical trial, 76 patients with definite diagnosis of moderate-to-severe asthma were randomized to receive Pulmicort 180 mcg/inhalation two puffs twice daily, or receive Symbicort 80/4.5 mg/inhalation two puffs twice daily, or receive Symbicort 160/4.5 mg/inhalation two puffs twice daily for 3 months. All participants were initially evaluated by spirometry for assessing respiratory parameters and also the level of asthma control was assessed by Asthma Control Test (ACT). RESULTS: More significant improvement in spirometry parameters, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, as well as in peak expiratory flow (PEF) in both groups of Symbicort with the regimens 80/4.5 mg/inhalation or 160/4.5 mg/inhalation 2 puffs twice daily compared with Pulmicort group, ACT score was significantly improved in Symbicort group with the regimens 160/4.5 mg/inhalation compared with both Symbicort groups with lower dosage and Pulmicort group. Response to treatment in PEF parameter and also in ACT level was significantly more in those who received Symbicort with the regimens 160/4.5 mg/inhalation compared with other two interventional groups adjusted for gender and age. CONCLUSION: Symbicort with the regimens 160/4.5 mg/inhalation has higher efficacy in reducing asthma symptom and improving its control compared with low doses of this drug and with Pulmicort. PMID- 24761395 TI - Anti-inflammatory effect of Helichrysum oligocephalum DC extract on acetic acid - Induced acute colitis in rats. AB - BACKGROUND: Helichrysum oligocephalum DC. from Asteraceae family is an endemic plant growing wild in Iran. This study was carried out to investigate the effect of H. oligocephalum hydroalcoholic extract (HOHE) on ulcerative colitis (UC) induced by acetic acid (AA) in rats. MATERIALS AND METHODS: Rats were grouped (n = 6) and fasted for 24 h before colitis induction. Treatments were started 2 h before the induction of colitis and continued for two consecutive days with different doses of HOHE (100, 200, and 400 mg/kg) orally (p.o.) and intraperitoneally (i.p.). The colon tissue was removed and tissue damages were scored after macroscopic and histopathologic assessments. RESULTS: Among the examined doses of HOHE, 100 mg/kg was the most effective dose that reduced the extent of UC lesions and resulted in significant alleviation. Weight/length ratio as an index of tissue inflammation and extravasation was also diminished in the treatment group administered HOHE at a dose of 100 mg/kg, and the results showed correlation with macroscopic and histopathologic evaluations. These data suggest that HOHE (100 mg/kg) administered either p.o. or i.p. was effective in diminishing inflammation and ulcer indices in this murine model of acute colitis in a non-dose-related manner. CONCLUSIONS: H. oligocephalum could be considered as a suitable anticolitis alternative; however, further studies are needed to support this hypothesis for clinical setting. PMID- 24761396 TI - Large ovarian leiomyoma in young woman. AB - Leiomyoma is benign mesenchymal tumor, that frequently occur in uterus but it rarely happens in ovary. Ovarian leiomyomas are seen concomitantly with uterine leiomyoma in about 78% of cases. They often discover incidentally but their most clinical manifestations are abdominal pain and palpable mass. Herein, we reported a large ovarian leiomyoma in a 22-year-old woman with abdominal pain and palpable mass at lower abdominal region. Computed tomography scan revealed large adnexal mass. Microscopic appearance was typical for leiomyoma but because its rarity in ovary the immunohistochemical staining was done. Major differential diagnostic considerations for this tumor in ovary are fibroma/thecoma, sclerosing stromal tumor, and leiomyosarcoma. The immunohistochemical staining with desmin, inhibin, and alpha-smooth muscle actin are helpful to rule out this differential diagnosis. PMID- 24761397 TI - The effect of intravenous infusion of paracetamol before anesthesia induction on the core and peripheral temperature changes and post-operative shivering in patients undergoing general anesthesia. AB - BACKGROUND: Post-operative shivering is an unpleasant complication that various drugs are used to prevent and treat. It is tried to advice a suitable drug with the least side-effects. This study was carried out to examine the effect of intravenous Apotel on the post-operative shivering and core and peripheral body temperature. MATERIALS AND METHODS: This clinical trial conducted in Al Zahra and Kashani Hospitals in Isfahan in 2012 on 64 patients undergoing upper limbs surgery with general anesthesia, which divided in two equal groups. In the first group, before induction, 15 mg/kg and up to 1 g paracetamol was infused in 100 cc normal saline within 20 min and control group was infused 100 cc normal saline during 20 min. Post-operative shivering and pain were recorded in the same time in addition to the core and peripheral temperature. The results were analyzed by SPSS ve.20 software. RESULTS: In patients receiving Apotel, the core and peripheral temperature were significantly lower (P < 0.05). At 10 min after entering in recovery, 10 patients in the control group and 2 in the intervention group suffered from shivering (31.2% vs. 6.2%), which was significantly different (P = 0.02). Nineteen patients (29.7%) suffered from shivering in recovery (14 patients in the control group and 5 patients in the intervention group (43.8% vs. 15.6%)). In Apotel receiving group, the incidence of shivering in recovery was significantly lower (P = 0.014). CONCLUSION: Given the beneficial effects of Apotel in post-operative shivering and pain reduction, using the drug as a pre drug is recommended in patients undergoing surgery with general anesthesia. PMID- 24761398 TI - The mutation of the rdxA gene in metronidazole-resistant Helicobacter pylori clinical isolates. AB - BACKGROUNDS: Antibiotic resistance is an increasing problem throughout the developed world, and knowledge about different resistance mechanisms is consequential for efficient treatment of bacterial infections. Although metronidazole has been frequently used in treatment regimens for H. pylori infection, but antibiotic resistance is now a major contributing factor in treatment failure. Nevertheless metronidazole has been greatly used as a critical component of combination therapies for H. pylori infection. OBJECTIVE: This study is trying to describe the mutational mechanisms of metronidazole resistance in H. pylori in our clinical isolates in Isfahanian patients, Iran and compare with the findings of previous studies in world. MATERIALS AND METHODS: MIC values of metronidazole for H. pylori strains were determined by E- test. Both rdxA and glmM genes used for confirmation of isolates as H. pylori and then amplification of another rdxA oligonucleotide pair was done. Finally, the six resistant strains were sent to sequencing for other processing and further analysis was done by software. RESULTS: The result of six clinical isolates in comparison with 26695, J99 and 69A as a sensitive and resistant reference strains showed plenty of mutations. No frame shift and nonsense mutation was seen in our clinical isolates. CONCLUSION: An interesting finding in metronidazole-resistant strains in our study was the detection of one mutation not previously described in the literature in the rdxA gene and this W(209)R substitution presumably plays a role in inducing metronidazole resistance. PMID- 24761399 TI - Mechanism of vasorelaxation induced by Achillea wilhelmsii in rat isolated thoracic aorta. AB - BACKGROUND: Achillea wilhelmsii (A. wilhelmsii) is used in Iraninan folk medicine for the treatment of hypertension; also, in previous reports, the hypotensive and antihypertensive effects of this plant have been indicated. The aim of the present study is to investigate the vasorelaxant effect of the hydroalcholic extract of A. wilhelmsii and its underlying mechanisms in isolated rat aorta. MATERIALS AND METHODS: The effect of the hydroalcholic A. wilhelmsii extract was tested on the contractile response of Wistar rat aorta induced by potassium chloride (KCl) and phenylephrine (PE) using a pressure transducer that is connected to the PowerLab. RESULTS: The cumulative concentrations of A. wilhelmsii (0.5-8 mg/ml) induced a vasorelaxation both in endothelium-intact and endothelium-denuded aortas precontracted by high K(+) (6 * 10(-2) M) or 10(-6) M PE. A. wilhelmsii, at a concentration of 4 mg/ml, reduced Ca(2+)-induced contraction (P < 0.001 vs. control) after PE or KCl had generated a stable contraction in the Ca(2+)-free solution. Furthermore, after incubation with diltiazem, the vasorelaxant effect of A. wilhelmsii reduced in the endothelium denuded aortas precontracted by PE or KCl (P < 0.001 vs. control). In contrast, A. wilhelmsii-induced relaxation was not affected by glibenclamide, BaCl2, ruthenium red, methylene blue, or heparin. CONCLUSIONS: The results showed that A. wilhelmsii had a vasorelaxation effect, which was not endothelium-dependent. The relaxation was mediated by inhibition of extracellular Ca(2+) influx through voltage- and receptor-operated Ca(2+) channels (VDDCs and ROCCs) in vascular smooth muscle cells. PMID- 24761400 TI - Long-term results of laparoscopic common bile duct exploration by choledochotomy for choledocholithiasis: 15-year experience from a single center. AB - PURPOSE: The aim of this study is to assess the long-term results of laparoscopic common bile duct exploration (LCBDE) and validate its effectiveness as a primary treatment modality for CBD stone. METHODS: A retrospective review of the medical records of 157 patients who underwent LCBDE from 1997 to 2011 was conducted. All LCBDE were performed by choledochotomy. Clinical demographics, operative outcome, recurrence rate of CBD stones, and long-term bile duct complications were analyzed. The mean follow-up period was 51.9 months. RESULTS: LCBDE was completed in 152 patients (96.8%) and 5 patients (3.2%) had open conversion. The male/female ratio was 78/79 and mean age was 67.3 years. Stone clearance was successful in 149 of 152 patients (98.0%). Nonlethal complications were noted in 11 patients (7.2%), including bile leakage in 6 patients (3.9%). Recurrent CBD stones developed in 9 of 152 patients (5.9%). Preoperative endoscopic sphincterotomy (P = 0.492) and choledochotomy repair type (T-tube drainage vs. primary closure, P = 0.740) were not significantly related to stone recurrence. There were no signs of any type of biliary injury or stricture observed in any of the patients during the follow-up period. CONCLUSION: LCBDE can be performed without increased risk of long-term complications such as bile duct stricture and recurrent CBD stones. LCBDE is a safe and effective treatment option for choledocholithiasis in terms of long-term outcome as well as short-term outcome. PMID- 24761402 TI - Leptomeningeal carcinomatosis from gastric cancer: single institute retrospective analysis of 9 cases. AB - PURPOSE: The aim of this study is to investigate the clinical features and outcomes of 9 consecutive patients who suffered with leptomeningeal carcinomatosis (LMC) originating from gastric cancer. METHODS: Between January 1995 and December 2010, we retrospectively reviewed the medical records of 9 patients with gastric LMC who had been treated at St. Vincent's Hospital, The Catholic University of Korea. RESULTS: With the exception of 1 patient, the primary gastric cancer was Borrmann type III or IV, and 5 cases had poorly differentiated or signet ring cell histology. TNM stage of the primary gastric cancer was III in 6 patients. The median interval from diagnosis of the primary malignancy to the diagnosis of LMC was 9 months. Headache (6 cases), altered mental status (4 cases), and dysarthria (3 cases) were presenting symptoms of LMC. Computed tomography findings were abnormal in 4 of 7 cases, while magnetic resonance imaging revealed abnormality in 4 of 5 cases. Radiation therapy was administered to 5 patients and intrathecal chemotherapy was administered to only 1 patient. Median overall survival duration from the diagnosis of LMC was 3 months. CONCLUSION: LMC originating from gastric cancer had a fatal clinical course and treatment strategies remain challenging. PMID- 24761401 TI - Which method of pancreatic surgery do medical consumers prefer among open, laparoscopic, or robotic surgery? A survey. AB - PURPOSE: The consumers' preferences are not considered in developing or implementing new medical technologies. Furthermore, little efforts are made to investigate their demands. Therefore, their preferred surgical method and the factors affecting that preference were investigated in pancreatic surgery. METHODS: Six-hundred subjects including 100 medical personnel (MP) and 500 lay persons (LP) were surveyed. Questionnaire included basic information on different methods of distal pancreatectomy; open surgery (OS), laparoscopic surgery (LS), and robotic surgery (RS). Assuming they required the operation, participants were told to indicate their preferred method along with a reason and an acceptable cost for both benign and malignant conditions. RESULTS: For benign disease, the most preferred method was LS. Limiting the choice to LS and RS, LS was preferred for cost and well-established safety and efficacy. OS was favored in malignant disease for the concern for radicality. Limiting the choice to LS and RS, LS was favored for its better-established safety and efficacy. The majority thought that LS and RS were both overpriced. Comparing MP and LP responses, both groups preferred LS in benign and OS in malignant conditions. However, LP more than MP tended to prefer RS under both benign and malignant conditions. LP thought that LS was expensive whereas MP thought the cost reasonable. Both groups felt that RS was too expensive. CONCLUSION: Though efforts for development of novel techniques and broadening indication should be encouraged, still more investments and research should focus on LS and OS to provide optimal management and satisfaction to the patients. PMID- 24761403 TI - Low molecular-weight heparin for thromboprophylaxis in patients undergoing gastric cancer surgery: an experience from one Korean institute. AB - PURPOSE: This study evaluated the efficacy for preventing venous thromboembolism (VTE) and adverse effects of low-molecular-weight heparin (LMWH) in order to launch a prospective clinical trial in Korea. METHODS: We reviewed the medical records of 108 consecutive patients who underwent gastric cancer surgery. These patients were divided into 2 groups according to the type of thromboprophylaxis: group A, LMWH combined with intermittent pneumatic compression (IPC); group B, IPC alone. The postoperative outcomes of the two groups were compared. RESULTS: Symptomatic VTE was observed in only 1 patient (0.9%) from group B. Postoperative bleeding was more common in group A than in group B (10.9% vs. 7.5%), although the difference was not significant (P = 0.055). Most bleeding episodes were minor and managed conservatively without intervention. Only a high body mass index was associated with a significantly increased risk of postoperative bleeding (odds ratio, 1.45; 95% confidence interval, 1.12-2.43; P = 0.051). CONCLUSION: A 40 mg of enoxaparin sodium is a safe and feasible dose for prevention of VTE. With the results of this study, we are planning a prospective randomized clinical trial to investigate the clinical efficacy of LMWH thromboprophylaxis in gastric cancer patients in Korea. PMID- 24761404 TI - Comparative study of oncologic outcomes for laparoscopic vs. open surgery in transverse colon cancer. AB - PURPOSE: Laparoscopic resection for transverse colon cancer is a technically challenging procedure that has been excluded from various large randomized controlled trials of which the long-term outcomes still need to be verified. The purpose of this study was to evaluate long-term oncologic outcomes for transverse colon cancer patients undergoing laparoscopic colectomy (LAC) or open colectomy (OC). METHODS: This retrospective review included patients with transverse colon cancer who received a colectomy between January 2006 and December 2010. Short term and five-year oncologic outcomes were compared between these groups. RESULTS: A total of 131 patients were analyzed in the final study (LAC, 84 patients; OC, 47 patients). There were no significant differences in age, gender, body mass index, tumor location, operative procedure, or blood loss between groups, but the mean operative time in LAC was significantly longer (LAC, 246.8 minutes vs. OC, 213.8 minutes; P = 0.03). Hospital stay was much shorter for LAC than OC (9.1 days vs. 14.5 days, P < 0.01). Postoperative complication rates were not statistically different between the two groups. In terms of long-term oncologic data, the 5-year disease-free survival and overall survival were not statistically different between both groups, and subgroup analysis according to cancer stage also revealed no differences. CONCLUSION: LAC for transverse colon cancer is feasible and safe with comparable short- and long-term outcomes. PMID- 24761405 TI - Single port laparoscopic appendectomy in children using glove port and conventional rigid instruments. AB - PURPOSE: To further improve the advantages of minimally invasive surgery, single port laparoscopic techniques continue to be developed. We report our initial experience with single port laparoscopic appendectomy (SPLA) in children and compare its outcomes to those of conventional laparoscopic appendectomy (CLA). METHODS: Clinical data were prospectively collected for SPLA cases performed at Chung-Ang University Hospital by a single surgeon between March 2011 and December 2011, including operative time, perioperative complications, conversion rate, and length of hospital stay. Each case of SPLA was performed using conventional laparoscopic instruments through Glove port placed into the single umbilical incision. To compare outcomes, a retrospective review was performed for those patients who underwent CLA between March 2010 and December 2010. RESULTS: Thirty one patients underwent SPLA and 114 patients underwent CLA. Mean age (10.5 years vs. 11.1 years, P = 0.43), weight (48.2 kg vs. 42.9 kg, P = 0.27), and operation time (41.8 minutes vs. 37.9 minutes, P = 0.190) were comparable between both groups. Mean hospital stay was longer for CLA group (2.6 days vs. 3.7 days, P = 0.013). There was no conversion to conventional laparoscopic surgery in SPLA group. In CLA group, there were nine complications (7.9%) with 3 cases of postoperative ileuses and 6 cases wound problems. There was one complication (3.2%) of umbilical surgical site infection in SPLA group (P = 0.325). CONCLUSION: The results of this study demonstrated that SPLA using conventional laparoscopic instruments is technically feasible and safe in children. SPLA using conventional laparoscopic instruments might be popularized by eliminating the need for specially designed instruments. PMID- 24761406 TI - Risk factor analysis of new brain lesions associated with carotid endarterectmy. AB - PURPOSE: Carotid endarterectomy (CEA) is the standard treatment for carotid artery stenosis. New brain ischemia is a major concern associated with CEA and diffusion weighted imaging (DWI) is a good imaging modality for detecting early ischemic brain lesions. We aimed to investigate the surgical complications and identify the potential risk factors for the incidence of new brain lesions (NBL) on DWI after CEA. METHODS: From January 2006 to November 2011, 94 patients who had been studied by magnetic resonance imaging including DWI within 1 week after CEA were included in this study. Data were retrospectively investigated by review of vascular registry protocol. Seven clinical variables and three procedural variables were analyzed as risk factors for NBL after CEA. RESULTS: The incidence of periprocedural NBL on DWI was 27.7%. There were no fatal complications, such as ipsilateral disabling stroke, myocardial infarction or mortality. A significantly higher incidence of NBL was found in ulcer positive patients as opposed to ulcer negative patients (P = 0.029). The incidence of NBL after operation was significantly higher in patients treated with conventional technique than with eversion technique (P = 0.042). CONCLUSION: Our data shows CEA has acceptable periprocedural complication rates and the existence of ulcerative plaque and conventional technique of endarterectomy are high risk factors for NBL development after CEA. PMID- 24761407 TI - Very early-onset peritoneal recurrence following curative total gastrectomy for Borrmann 4 gastric cancer. AB - Peritoneal dissemination is one of the treatment failures following gastric cancer surgery. We present a case with very early peritoneal recurrence, detected 8 days following curative surgery. A 39-year-old man, with Borrmann-4 advanced gastric cancer with signet ring cell type, underwent curative open total gastrectomy. However, focal peritoneal nodules on the left side of the diaphragmatic surface, which did not exist at the initial operation, were incidentally found during the reoperation for a postoperative intestinal obstruction via a laparoscopic approach. The pathologic result of the biopsied nodule revealed signet ring cell carcinoma. The patient underwent combination chemotherapy for several months without tumor regression. He suffered from intestinal obstruction again due to carcinomatosis peritonei, and died 9 months following initial surgery. Through this case report, we can carefully suspect that very early progression of cancer cells to carcinomatosis can occur in just several days after an operation. PMID- 24761408 TI - Primary malignant rhabdoid tumor of greater omentum in 10-year-old girl. AB - Contrary to metastatic tumors of the omentum, primary tumors of the omentum are very rare. A 10-year-old girl presented with low abdominal pain. Imaging studies showed a multiseptated hemorrhagic tumor. The mass from the omentum was removed completely and confirmed as a malignant rhabdoid tumor. Despite aggressive chemotherapy, she died after 9 months due to disease progression. We report one case of primary malignant rhabdoid tumor of the omentum for the first time. PMID- 24761409 TI - Bone mineral density and bone turnover markers in patients on long-term suppressive levothyroxine therapy for differentiated thyroid cancer. AB - PURPOSE: Current management for patients with differentiated thyroid cancer includes near total thyroidectomy and radioactive iodine therapy followed by administration of supraphysiological doses of levothyroxine (L-T4). Although hyperthyroidism is a well known risk factor for osteoporosis, the effects of L-T4 treatment on bone mineral density (BMD) in patients with thyroid cancer do not appear to be as significant as with endogenous hyperthyroidism. In this study, we evaluated the impact of long-term suppressive therapy with L-T4 on BMD and bone turn over markers in Korean female patients receiving L-T4 suppressive therapy. METHODS: We enrolled 94 female subjects (mean age, 50.84 +/- 11.43 years) receiving L-T4 after total or near total thyroidectomy and radioactive iodine therapy for thyroid cancer (mean follow-up period, 12.17 +/- 4.27 years). The subjects were divided into three groups by thyroid stimulating hormone (TSH) level (group 1 with TSH level <=0.001 uIU/mL, group 2 with TSH level between 0.001 and 0.17 uIU/mL, group 3 with TSH level >0.17 uIU/mL) and four groups by quartile of free T4 level. L-T4 dosage, BMD (examined by dual-energy x-ray absorptiometry), and bone turnover markers were evaluated according to TSH and free T4 levels. RESULTS: No significant decrease was detected in BMD or bone turnover markers according to TSH level or free T4 level. Also, the prevalence of osteoporosis and osteopenia was not different among groups. CONCLUSION: Long-term L-T4 suppressive therapy after thyroid cancer management did not affect bone density or increase the prevalence of osteoporosis even though TSH levels were supraphysiologically suppressed. PMID- 24761410 TI - The comparison of oncologic and clinical outcomes of laparoscopic liver resection for hepatocellular carcinoma. AB - PURPOSE: We evaluate the operative outcome and oncologic outcome of laparoscopic liver resection for hepatocellular carcinoma (HCC), and compare with open liver resection. METHODS: From January 2004 to December 2012, clinical data of 70 patients who underwent laparoscopic liver resection for HCC (laparoscopic liver resection group, lapa-group) were collected and analyzed retrospectively. Control group (open liver resection group, open-group) were retrospectively matched, and compared with lapa-group. RESULTS: Laparoscopic major liver resections were performed in 4 patients. Laparoscopic anatomical resections and nonanatomical resections were performed in 39 patients, and 31 patients, respectively. Mean operative time was shorter in lapa-group (215.5 +/- 121.84 minutes vs. 282.30 +/- 80.34 minutes, P = 0.001), mean intraoperative transfusion rate and total amount were small in lapa-group (24.28%, 148.57 +/- 3,354.98 mL vs. 40.78%, 311.71 +/- 477.01 mL). Open conversion occurred in 6 patients (8.57%) because of bleeding, inadequate resection, invisible mass on intraoperative ultrasonography, and tumor rupture. In lapa-group and open-group, 3-year disease-free survival rates were 58.3% +/- 0.08%, and 62.6% +/- 0.06%, respectively (P = 0.773). In lapa-group and open-group 3-year overall survival rates were 65.3% +/- 0.8%, and 65.7% +/- 0.6%, respectively (P = 0.610). CONCLUSION: Laparoscopic liver resection for HCC is feasible and safe in a large number of patients, with reasonable operative and oncologic results. PMID- 24761411 TI - Antichemosensitizing effect of resveratrol in cotreatment with oxaliplatin in HCT116 colon cancer cell. AB - PURPOSE: Although oxaliplatin is one of the most widely used chemotherapeutic agents for the treatment of advanced stages of colorectal cancers in clinic, cancer cells often develop oxaliplatin drug resistance. Thus, overcoming oxaliplatin drug resistance is a major issue in the successful treatment for advanced stages of colorectal malignancy. In order to maximize oxaliplatin therapy, we examined whether resveratrol, a natural phytochemical known to have chemopreventive effects on cancers, can have a chemosensitizing effect upon cotreatment with oxaliplatin. Survivin, a small inhibitor of apoptosis protein (IAP), expression is examined using HCT116 colon cancer cells. METHODS: In order to examine resveratrol chemosensitizing effect upon oxaliplatin cotreatment, survivin transcripts and protein expression, cell proliferation, and apoptotic responses were evaluated using HCT116 cells. Reverse transcription polymerase chain reaction (RT-PCR), Western blot, crystal violet staining analyses were performed. For survivin specific inhibition, YM155 molecule was used. RESULTS: Although oxaliplatin significantly suppressed survivin transcripts and protein expression level in HCT116 cells, resveratrol cotreatment induced restoration of survivin expression level of both transcripts and protein. Apoptotic induction by oxaliplatin only treatment was nullified upon resveratrol cotreatment. Induction of survivin restoration upon resveratrol cotreatment also occurred when survivin specific inhibitor, YM155, was used. In addition to survivin restoration, resveratrol cotreatment also induced restoration of Bcl-2/caspase-3 expression suppressed by oxaliplatin only treatment. CONCLUSION: Resveratrol has an antichemosensitizing effect upon cotreatment with oxaliplatin in HCT colon cancer cells. This antichemosensitizing effect of resveratrol can be cell-type specific. However, clinical use of resveratrol cotreatment with oxaliplatin should be approached cautiously. PMID- 24761412 TI - Robotic and laparoscopic pelvic lymph node dissection for rectal cancer: short term outcomes of 21 consecutive series. AB - PURPOSE: The aim of this study is to describe our initial experience and assess the feasibility and safety of robotic and laparoscopic lateral pelvic node dissection (LPND) in advanced rectal cancer. METHODS: Between November 2007 and November 2012, extended minimally invasive surgery for LPND was performed in 21 selected patients with advanced rectal cancer, including 11 patients who underwent robotic LPND and 10 who underwent laparoscopic LPND. Extended lymphadenectomy was performed when LPN metastasis was suspected on preoperative magnetic resonance imaging even after chemoradiation. RESULTS: All 21 procedures were technically successful without the need for conversion to open surgery. The median operation time was 396 minutes (range, 170-581 minutes) and estimated blood loss was 200 mL (range, 50-700 mL). The median length of stay was 10 days (range, 5-24 days) and time to removal of the urinary catheter was 3 days (range, 1-21 days). The median total number of lymph nodes harvested was 24 (range, 8 43), and total number of lateral pelvic lymph nodes was 7 (range, 2-23). Six patients (28.6%) developed postoperative complications; three with an anastomotic leakages, two with ileus and one patient with chyle leakage. Two patients (9.5%) developed urinary incontinence. There was no mortality within 30 days. During a median follow-up of 14 months, two patients developed lung metastasis and there was no local recurrence. CONCLUSION: Robotic and laparoscopic LPND is technically feasible and safe. Minimally invasive techniques for LPND in selected patients can be an acceptable alternative to an open LPND. PMID- 24761414 TI - Long-term outcome of crossover femoro-femoro-popliteal bypass using side-to-side anastomosis in ilio-femoral occlusive disease. AB - PURPOSE: During crossover femoro-femoro-popliteal sequential bypass (CFFPB) surgery in ilio-femoral occlusive disease, proximal anastomosis of the femoro popliteal bypass is usually performed distal to the distal anastomosis of the crossover femoro-femoral bypass. If not, it is done with a piggyback configuration. Another method is a side-to-side anastomosis. Its benefit is that this is the only anastomosis made. And it is less bulky compared with the piggyback configuration. This study was aimed to investigate the long-term outcome of CFFPB using side-to-side anastomosis. METHODS: From Sep 2006 to Aug 2012, 21 patients who underwent CFFPB using side-to-side anastomosis were enrolled. Externally supported polytetrafluoroethylene graft was used as a conduit in all patients. Patient demographic data and procedure details were investigated. Primary graft patency was calculated using the Kaplan-Meier method. RESULTS: The mean age of patients was 79 years (range, 62-81 years) and males were 17 (81%). Fifteen patients (71%) had critical limb ischemia. Inflow arteries comprised of 16 common femoral artery (CFA), 4 superficial femoral artery (SFA), and 1 deep femoral artery (DFA). Side-to-side anastomosis was performed on the CFA in 11, SFA in 2, and DFA in 8 patients. During the mean follow-up period of 21 months (1-60 months), 8 patients died. The 1-, 3-, and 5-year primary patency rates were 76%, 63%, and 63%. CONCLUSION: Long-term patency of CFFPB using side to-side anastomosis was acceptable. It can be one of the treatment options for patients with ilio-femoral occlusive disease. PMID- 24761413 TI - Comparison of outcomes according to the operation for type A esophageal atresia. AB - PURPOSE: The purpose was to evaluate outcomes according to different operative strategies of type A esophageal atresia (EA). METHODS: All patients who underwent surgery for type A EA between 1980 and 2011 were included. Patients were divided into 2 groups: E-E group included patients who received esophageal end-to-end anastomosis, whereas E-G group included patients who received esophago-gastric tube anastomosis. RESULTS: Twenty-two patients were included. The median gestational age was 37.5 weeks. The median birth weight was 2.5 kg. Twenty-one patients underwent gastrostomy as initial procedures, and one patient underwent primary esophageal end-to-end anastomosis. The median gap between both esophageal ends was six vertebral distance (VD). Seven patients underwent primary anastomosis of the esophagus, and 14 patients underwent gastric replacement. Three patients (13.6%) had anastomotic leakage and 10 patients (45.5%) had anastomotic stenosis. Most of the patients (90.9%) had gastroesophageal reflux, but only two patients required antireflux surgery. The median VD was significantly shorter in E-E group than in E-G group (3 VD vs. 6 VD). Stenosis was significantly more often in E-E group, but there was no significant difference in leakage and reflux symptoms. CONCLUSION: The treatment for type A EA can include E-E anastomosis or E-G anastomosis, depending on the length of the end-to-end interval after performing gastrostomy. Appropriate tension and blood flow in the anastomosis site are essential for preventing postoperative stenosis and leakage, and esophageal replacement with gastric tube is believed to be feasible and safe in cases where excessive tension is present. PMID- 24761415 TI - Clinical significance of type I endoleak on completion angiography. AB - PURPOSE: Type I endoleak is known to be associated with sac enlargement and occasional rupture, therefore, the treatment of type I endoleak is recommended at the time of diagnosis. The aim of this study was to identify the significance of early type I endoleak found on completion angiography. METHODS: Between January 2000 and December 2012, a total of 86 patients underwent endovascular abdominal aortic aneurysm repair (EVAR) and 10 patients (11.6%) were diagnosed with type Ia endoleak on completion angiography. Clinical and radiologic data were reviewed retrospectively. RESULTS: Of the 10 patients, two underwent EVAR with custom-made stent-grafts in the initial stage and both of them needed immediate treatment: one case involved open repair while the other involved insertion of an additional stent-graft. In 8 patients, the amount of leakage decreased after repeated balloon molding. They were managed conservatively and followed up with computed tomography angiography within 2 weeks after EVAR. In 7 of the 8 cases, type Ia endoleaks disappeared. In one patient with a persistent endoleak and a folded posterior wall of the stent-graft, coil embolization was performed 1 week after EVAR. With a median follow-up of 12 months (range, 1-61 months), no patients showed recurrence of type I endoleak or sac expansion. CONCLUSION: Type I endoleaks diagnosed on completion angiography sealed spontaneously in 7 of 10 patients (70.0%). In cases of decreased amounts of leakage after balloon molding, simple observation may be an alternative to repetitive procedures. The long-term follow-up of patients with self-sealed type I endoleaks is mandatory. PMID- 24761416 TI - Systemic metastasis of hepatocellular carcinoma responsive to multidisciplinary treatment including debulking surgery. AB - The lung, followed by regional lymph node and bone, is the most common site for extrahepatic metastasis of hepatocellular carcinoma (HCC). Metastatic skin lesion of HCC is rare, and it is a sign of poor prognosis, indicating the strong possibility of metastases in other regions of the body. We report the case of a 52-year-old male with multiple metastases, including skin metastasis of HCC, which were treated with multidisciplinary therapy. PMID- 24761417 TI - Use of meso-Rex shunt with transposition of the coronary vein for the management of extrahepatic portal vein obstruction. AB - The meso-Rex shunt is used to safely and effectively treat patients with portal hypertension due to extrahepatic portal vein obstruction. In the standard meso Rex shunt technique, the patient's own internal jugular vein is used as a vascular autograft. Inevitably, such a procedure requires neck exploration and sacrifice of the internal jugular vein. Here, we present a case of a 20-year-old man with idiopathic extrahepatic portal vein obstruction, who was treated with a new technique of transposition of the coronary vein, which is enlarged in most cases of portal hypertension, as an alternative to the standard meso-Rex shunt technique. The transposition of the coronary vein into the Rex recessus is more efficient and less invasive than harvesting an autologous vein graft. Therefore, this technique simplifies the procedure and should be used when possible. PMID- 24761418 TI - Atypia of undetermined significance on thyroid fine needle aspiration: surgical outcome and risk factors for malignancy. AB - PURPOSE: This study was performed to analyze the surgical pathology results of the "atypia of undetermined significance" (AUS) category from thyroid fine needle aspiration (FNA) and to describe the characteristics to distinguish a malignant from a benign nodule. METHODS: A retrospective analysis was done on 116 patients who underwent thyroid surgery from December 2008 to December 2012, following a diagnosis of AUS from preoperative thyroid FNA. We investigated the age, gender, size and site of the nodules, ultrasonographic criteria, cytological features, the number of atypia results after repeated FNAs, surgical method, and final pathologic results. RESULTS: Sixty-five out of 116 patients underwent total thyroidectomy and the rest had partial thyroidectomy. The final pathologic results were 41 malignancies (35.3%) and 75 benign diseases (64.7%). AUS was divided into group 1: 'cannot rule out malignancy' or group 2: 'cannot rule out follicular neoplasm'. After surgery, group 1 revealed papillary thyroid cancer in most cases and group 2 revealed follicular adenoma in most cases. Age over 40 years, ultrasonographic findings suggestive of malignancy, more than 2 results of atypia from repeated FNAs and nodules less than 2 centimeters were risk factors for malignancy on univariate analysis. Multivariate analysis showed that ultrasonographic findings suggestive of malignancy was a significant risk factor for malignancy. CONCLUSION: For proper evaluation of the risk for malignancy in thyroid AUS patients, the ultrasonographic criteria should be considered along with other clinicopathological findings such as age, nodule size, number of atypia, cytologic features. PMID- 24761419 TI - The pattern and significance of the calcifications of papillary thyroid microcarcinoma presented in preoperative neck ultrasonography. AB - PURPOSE: To analyze the incidence and patterns of calcification of papillary thyroid microcarcinoma (PTMC) on neck ultrasonography (NUS) and assess the clinical implications of calcification, especially for neck node metastasis. METHODS: The clinical data of 379 patients with PTMC who underwent thyroidectomy between January and December 2011 were retrospectively analyzed. PTMC lesions were classified into four subgroups according to their calcification patterns on preoperative NUS: microcalcification, macrocalcification, rim calcification, and noncalcification. The clinicopathologic characteristics were compared between the patients with and without calcification, and among the four subgroups. RESULTS: Calcifications were detected on NUS in 203 patients (53.5%) and central neck node metastasis was observed in 119 patients (31.3%). Calcification was associated with larger tumor size (0.68 cm vs. 0.54 cm), higher rate of lymph node metastasis (38.6% vs. 23.2%) and higher lymph node ratio (0.11 vs. 0.06) compared to noncalcification (All P < 0.05). In addition, the extent of calcification correlated with lesion size (0.67 cm vs. 0.69 cm vs. 0.85 cm). Further, the likelihood of lymph node metastasis also correlated with the extent of calcification in the order of non-, micro- and macrocalcification (23.3%, 36.8%, and 44.1%, respectively). The calcification rate was higher in patients with lymph node metastasis than those without it (65.5% vs.47.7%) (All P < 0.05). CONCLUSION: PTMC patients positive for calcification on NUS had a higher rate of lymph node metastasis, and a higher lymph node ratio compared to noncalcification patients. Calcification patterns should be assessed carefully in patients with PTMC by preoperative NUS. PMID- 24761420 TI - Can the model for end-stage liver disease score replace the indocyanine green clearance test in the selection of right hemihepatectomy in Child-Pugh class A? AB - PURPOSE: To identify the correlation of the model for end-stage liver disease (MELD) scores with the assessment of the risk of hepatic function after hemihepatectomy in patients with hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV). METHODS: A case-control study was performed based on data for 141 consecutive patients who underwent curative right hepatic resection between January 2006 and June 2010. RESULTS: All patients were Child-Pugh class A. The mean age of the patients was 50 years (range, 29-73 years). The group included 114 men (80.9%) and 27 women (19.1%). The distribution of MELD scores (median, 7; range, 6-14) and indocyanine green retention rate at 15 minutes (ICG R15) (median, 9.2%; range, 1.1%-19.5%) showed no significant correlation (P = 0.615). Only one perioperative death (0.7%) occurred within 30 days, which was the result of liver failure by hepatic artery dissection during the Pringle maneuver. Hepatic dysfunction occurred in 25 patients (17.7%) after liver resection. In multivariate analysis, male gender, increased HBV DNA level, and elevated serum aspartate transaminase level were significantly related with hepatic dysfunction. Tumor size and satellite nodule were closely associated with tumor recurrence in HBV-related HCC after right hemihepatectomy and satellite nodule was a predisposing factor for mortality in those patients. CONCLUSION: MELD score does not accurately predict hepatic function after right hemihepatectomy in patients with resectable HBV-related HCC. MELD scores were not correlated with the ICG-R15 values in patients with Child-Pugh class A. PMID- 24761421 TI - Solid pseudopapillary tumor of the pancreas in children: 15-year experience at a single institution with assays using an immunohistochemical panel. AB - PURPOSE: The aim of this study was to analyze the clinicopathological characteristics of solid pseudopapillary tumor (SPT) of the pancreas and to utilize an immunohistochemical panel to identify specific markers of the disease. METHODS: Eleven patients diagnosed with and treated for SPT of the pancreas over the past 15 years were retrospectively analyzed. RESULTS: The 11 patients consisted of 8 females and 3 males, of mean age at operation of 13.5 years (range, 10 to 18 years). The most frequent presenting symptom was abdominal pain and/or mass. One patient was referred with hemoperitoneum due to traumatic tumor rupture. The lesions were located in the body, head and tail of the pancreas in four, four, and three patients, respectively. Mean tumor diameter was 7.9 cm (range, 2.5 to 15 cm). Surgical procedures included distal pancreatectomy with splenectomy in four patients, pylorus preserving pancreaticoduodenectomy in four, distal pancreatectomy in two, and subtotal pancreatectomy with splenectomy in one. Mean follow-up was 60.5 months (range, 15 to 126 months). All patients remain alive without tumor recurrence. Immunohistochemical staining showed that all tumors were positive for beta-catenin, progesterone receptor (PR), vimentin, and CD99. However, all tumors were negative for E-cadherin and cytokeratin 7 expression. CONCLUSION: Patients with SPT of the pancreas have an excellent prognosis after surgical excision. Immunohistochemically, E-cadherin/beta catenin, PR, vimentin, and CD99 would help establish the diagnosis of SPT of the pancreas, although the results of immunohistochemical staining were found to have an indistinct complex immunoprofile. PMID- 24761423 TI - Predictive factors and the prognosis of recurrence of colorectal cancer within 2 years after curative resection. AB - PURPOSE: Because predicting recurrence intervals and patterns would allow for appropriate therapeutic strategies, we evaluated the clinical and pathological characteristics of early and late recurrences of colorectal cancer. METHODS: Patients who developed recurrence after undergoing curative resection for colorectal cancer stage I-III between January 2000 and May 2006 were identified. Early recurrence was defined as recurrence within 2 years after primary surgery of colorectal cancer. Analyses were performed to compare the clinicopathological characteristics and overall survival rate between the early and late recurrence groups. RESULTS: One hundred fifty-eight patients experienced early recurrence and 64 had late recurrence. Multivariate analysis revealed that the postoperative elevation of carbohydrate antigen 19-9 (CA 19-9), venous invasion, and N stage correlated with the recurrence interval. The liver was the most common site of early recurrence (40.5%), whereas late recurrence was more common locally (28.1%), or in the lung (32.8%). The 5-year overall survival rates for early and late recurrence were significantly different (34.7% vs. 78.8%; P < 0.001). Survival rates after the surgical resection of recurrent lesions were not different between the two groups. CONCLUSION: Early recurrence within 2 years after surgery was associated with poor survival outcomes after colorectal cancer recurrence. An elevated postoperative CA 19-9 level, venous invasion, and advanced N stage were found to be significant risk factors for early recurrence of colorectal cancer. PMID- 24761422 TI - Circulating cell-free DNA as a promising biomarker in patients with gastric cancer: diagnostic validity and significant reduction of cfDNA after surgical resection. AB - PURPOSE: The aim of this study is to determine whether levels of circulating free DNA (cfDNA) increase according to cancer progression, whether they are restored after surgical resection, and to evaluate cfDNA in gastric cancer patients as a useful biomarker. METHODS: A case-control study design was used. Thirty gastric cancer patients and 34 healthy subjects were enrolled from two hospitals in South Korea. The plasma cfDNA of patients with gastric cancer were obtained before surgery and 24 hours after surgery, and then analyzed by a quantitative, real time polymerase chain reaction. Plasma samples were also obtained from the control group. RESULTS: The mean levels of cfDNA in the healthy control group, patients with early gastric cancer, and with advanced gastric cancer were 79.78 +/- 8.12 ng/mL, 106.88 +/- 12.40 ng/mL, and 120.23 +/- 10.08 ng/mL, respectively (P < 0.01). Sensitivity was 96.67% and specificity was 94.11% when the cutoff value was 90 ng/mL. Variables representing the tumor burden such as tumor size, T stage, TNM stage, and curative resection are also associated with the levels of cfDNA. The levels of cfDNA in the 24-hour-after-surgery group decreased significantly (112.17 +/- 13.42 ng/mL vs. 77.93 +/- 5.94 ng/mL, P < 0.001) compared to the levels of cfDNA in the preoperation group. CONCLUSION: The changes in the levels of cfDNA can act as reliable biomarkers to detect cancer early, to predict tumor burden, estimate curative resection and even prognosis. PMID- 24761424 TI - Psychological attitude to self-appraisal of stoma patients: prospective observation of stoma duration effect to self-appraisal. AB - PURPOSE: In recent years, many psychological problems in patients with stomas have been addressed in a number of studies. But there are only a few studies that use objective measures to take into account self-appraisal by patients with permanent or temporary stomas. The aim of this study is to compare the psychological attitude of patients with permanent and temporary stomas and to determine the most appropriate psychological supportive care. METHODS: Sixty-five patients, who received a stoma between January 2009 and March 2012, were classified into two groups with either permanent or temporary stomas and were observed prospectively. We developed a questionnaire with the aid of a psychiatrist to analyze the grade of psychological attitude of self-appraisal of patients. The questionnaire was categorized into three parts; body image scale, self-esteem scale, and depression scale. Patients responded to the questionnaire 4 weeks after the operation and the answers of each group were compared. RESULTS: Out of 65 patients, 42 received temporary stomas and 23 received permanent stomas. There was no significant mean difference between permanent and temporary stoma patients in the body image scale, the self-esteem scale, and the depression scale. However, patients with a permanent stoma tended to have a worse body image and lower self-esteem on some specific items within the questionnaires. CONCLUSION: Patients with stomas have negative attitudes toward themselves and some meaningful differences were found between different types of stoma applied. Surgeons should be concerned about postoperative psychological support for patients with stomas. PMID- 24761425 TI - Relining technique for continuous sac enlargement and modular disconnection secondary to endotension after endovascular aortic aneurysm repair. AB - Endotension is an unpredictable late complication of endovascular aortic aneurysm repair (EVAR). This case report will discuss the successful treatment of enlarged aneurysmal sac due to endotension using the relining technique. An 81-year-old male complained of nondecreasing huge aneurysm sac. He had undergone EVAR for infrarenal abdominal aortic aneurysm 7 years prior and no endoleak was found through follow-up. Initially computed tomography-guided sac aspiration was tried, but in vain, Relining using the double barrel technique and tubular endograft for modular diconnection, which was unexpectedly found in the original endograft, were performed sucessfully. During follow-up after the relining procedure, the size of aneurysm sac continued to decrease in size. The relining technique is effective mothod for treating endotension. PMID- 24761426 TI - Mammary duct ectasia with bloody nipple discharge in a child. AB - Mammary duct ectasia is a rare disease in children and often presents as a cystic mass with bloody nipple discharge. The pathophysiology of mammary duct ectasia is unclear, and the differential diagnosis of other cystic masses with hemorrhage, such as complicated lymphangioma, is necessary. Here, we report a 14-month-old boy who exhibited unilateral mammary duct ectasia with bloody nipple discharge that was treated with surgical excision. Because some authors have reported that mammary duct ectasia can be often be resolved without surgery, conservative therapy should be considered first when a child presents with a cystic mass with bloody nipple discharge. However, the optimal duration of follow-up and timing of surgical excision have not yet been established. PMID- 24761427 TI - Material Mismatch Effect on the Fracture of a Bone-Composite Cement Interface. AB - The interfacial mechanics at the bone-implant interface is a critical issue for implant fixation and the filling of bone defects created by tumors and/or their excision. Our previous study found that micron and nano sizes MgO particles improved the fracture toughness of bone-cement interfaces under tension loading. The strength of bonding of different types of bone with different types of implants may not be the same. The aims of this research were to determine the influences of material mismatch due to bone orientation and a magnesium oxide (MgO) filler material for PMMA bone cement on the mechanical strength between bone and bone cement specimens. This research studied the longitudinal and transverse directions bovine cortical bone as different bone materials and poly Methyl MethAcrylate (PMMA) bone cement with and without MgO additives as different implant materials. The scope of work for this study was: (1) to determine the bending strength and modulus of different bone and bone cement specimens, (2) to determine whether inclusion of MgO particles on PMMA has any influence on these mechanical properties of PMMA, and (3) to determine whether bone orientation and inclusion of MgO particles with PMMA has any influence on the interface strength between bone and PMMA. This study showed that bone orientation has statistically significant effect on the bonding strength between bone and bone cement specimens (P value<0.05). This study also found that while MgO additive decreased the bending strength and modulus of PMMA bone cement, but the inclusion of MgO additives with PMMA bone cement has no statistically significant effect on the bonding strength between bone and bone cement specimens (P value>0.05). PMID- 24761428 TI - Targeted CNS Delivery Using Human MiniPromoters and Demonstrated Compatibility with Adeno-Associated Viral Vectors. AB - Critical for human gene therapy is the availability of small promoter tools to drive gene expression in a highly specific and reproducible manner. We tackled this challenge by developing human DNA MiniPromoters using computational biology and phylogenetic conservation. MiniPromoters were tested in mouse as single-copy knock-ins at the Hprt locus on the X Chromosome, and evaluated for lacZ reporter expression in CNS and non-CNS tissue. Eighteen novel MiniPromoters driving expression in mouse brain were identified, two MiniPromoters for driving pan neuronal expression, and 17 MiniPromoters for the mouse eye. Key areas of therapeutic interest were represented in this set: the cerebral cortex, embryonic hypothalamus, spinal cord, bipolar and ganglion cells of the retina, and skeletal muscle. We also demonstrated that three retinal ganglion cell MiniPromoters exhibit similar cell-type specificity when delivered via adeno-associated virus (AAV) vectors intravitreally. We conclude that our methodology and characterization has resulted in desirable expression characteristics that are intrinsic to the MiniPromoter, not dictated by copy number effects or genomic location, and results in constructs predisposed to success in AAV. These MiniPromoters are immediately applicable for pre-clinical studies towards gene therapy in humans, and are publicly available to facilitate basic and clinical research, and human gene therapy. PMID- 24761429 TI - Qualitative assessment of pain management in patients undergoing computed tomography-guided transthoracic lung biopsy. AB - BACKGROUND: Unpublished questionnaire data collected by the authors' institution (Toronto General Hospital, Toronto, Ontario) indicates that patients often experience significant pain while undergoing lung biopsy, yet receive only a fraction of the maximum allowable dosage of analgesic. OBJECTIVES: To qualitatively assess current pain management practices from the patient perspective. Patient education and patient satisfaction were also evaluated. METHODS: From March through June 2012, participants were contacted via telephone within one week of their procedure until data saturation was reached. The semistructured interviews were based on a study-specific interview template. Thematic analysis of qualitative study data was used to identify recurring interview topics. RESULTS: A consecutive sample of 16 outpatients who had undergone image-guided transthoracic lung biopsy at the authors' institution were interviewed. None of the study participants reported noteworthy pain associated with the insertion of lung biopsy needles. The most significant pain was caused by positioning within the computed tomography scanner, particularly among participants who were in the prone position. All participants reported high satisfaction with the amount of analgesic received. Potential complications and recovery period details were identified as areas for improved patient education. CONCLUSIONS: At the authors' institution, pain associated with lung biopsy needle insertion was well controlled. Positional pain is common for patients required to be in the prone position. Potential solutions include increasing awareness of positional pain and instituting additional supportive equipment. PMID- 24761430 TI - The 27-item coping strategies questionnaire-revised: confirmatory factor analysis, reliability and validity in Italian-speaking subjects with chronic pain. AB - BACKGROUND: Increasing attention is being devoted to cognitive-behavioural measures to improve interventions for chronic pain. OBJECTIVE: To develop an Italian version of the Coping Strategies Questionnaire - Revised (CSQ-R), and to validate it in a study involving 345 Italian subjects with chronic pain. METHODS: The questionnaire was developed following international recommendations. The psychometric analyses included confirmatory factor analysis; reliability, assessed by internal consistency (Cronbach's alpha) and test-retest reliability (intraclass correlation coefficients); and construct validity, assessed by calculating the correlations between the subscales of the CSQ-R and measures of pain (numerical rating scale), disability (Sickness Impact Profile - Roland Scale), depression (Center for Epidemiological Studies - Depression Scale) and coping (Chronic Pain Coping Inventory) (Pearson's correlation). RESULTS: Confirmatory factor analysis revealed that the CSQ-R model had an acceptable data model fit (comparative fit index and normed fit index >=0.90, root mean square error of approximation <=0.08). Cronbach's alpha was satisfactory (CSQ-R 0.914 to 0.961), and the intraclass correlation coefficients were good/excellent (CSQ-R 0.850 to 0.918). As expected, the correlations with the numerical rating scale, Sickness Impact Profile - Roland Scale, Center for Epidemiological Studies - Depression Scale and Chronic Pain Coping Inventory highlighted the adaptive and maladaptive properties of most of the CSQ-R subscales. CONCLUSION: The CSQ-R was successfully translated into Italian. The translation proved to have good factorial structure, and its psychometric properties are similar to those of the original and other adapted versions. Its use is recommended for clinical and research purposes in Italy and abroad. PMID- 24761432 TI - Rapid electrodeposition of a gold-Prussian blue nanocomposite with ultrahigh electroactivity for dual-potential amperometric biosensing of uric acid. AB - We report a new and efficient protocol for rapid electrodeposition of a gold Prussian blue ((Au-PB)REd) nanocomposite with ultrahigh electroactivity on an Au electrode by cyclic voltammetry in 0.1 M aqueous K2SO4 containing 1 mM K3Fe(CN)6, 1 mM HAuCl4, and 0.1 mM Fe2(SO4)3, and an electrochemical quartz crystal microbalance and scanning electron microscopy were utilized to investigate the electrodeposition. The (Au-PB)REd/Au electrode was then cast-coated with a urate oxidase (UOx)-poly(anilineboronic acid) (PABA)-Pt nanoparticle (PtNP) bionanocomposite and chitosan (CS) for high-performance amperometric biosensing of uric acid (UA) in the dual-potential mode. The UOx-PABA-PtNP bionanocomposite was prepared through chemical oxidation of anilineboronic acid (ABA) by sodium chloroplatinate in the presence of UOx. The thus-fabricated CS/UOx-PABA-PtNP/(Au PB)REd/Au enzyme electrode worked well under optimized conditions through both oxidation and reduction determination of enzyme-generated H2O2, which responded linearly to UA concentrations from 0.3 MUM to 0.65 mM with a sensitivity of 223 MUA mM(-1) cm(-2) and a limit of detection (LOD) of 0.2 MUM (0.7 V vs. SCE), and from 0.2 MUM to 0.25 mM with a sensitivity of 247 MUA mM(-1) cm(-2) and a LOD of 0.1 MUM (-0.05 V vs. SCE), being superior to most analogues hitherto reported for biosensing of UA. PMID- 24761431 TI - Fourier transform infrared spectroscopy to quantify collagen and elastin in an in vitro model of extracellular matrix degradation in aorta. AB - Extracellular matrix (ECM) is a key component and regulator of many biological tissues including aorta. Several aortic pathologies are associated with significant changes in the composition of the matrix, especially in the content, quality and type of aortic structural proteins, collagen and elastin. The purpose of this study was to develop an infrared spectroscopic methodology that is comparable to biochemical assays to quantify collagen and elastin in aorta. Enzymatically degraded porcine aorta samples were used as a model of ECM degradation in abdominal aortic aneurysm (AAA). After enzymatic treatment, Fourier transform infrared (FTIR) spectra of the aortic tissue were acquired by an infrared fiber optic probe (IFOP) and FTIR imaging spectroscopy (FT-IRIS). Collagen and elastin content were quantified biochemically and partial least squares (PLS) models were developed to predict collagen and elastin content in aorta based on FTIR spectra. PLS models developed from FT-IRIS spectra were able to predict elastin and collagen content of the samples with strong correlations (RMSE of validation = 8.4% and 11.1% of the range respectively), and IFOP spectra were successfully used to predict elastin content (RMSE = 11.3% of the range). The PLS regression coefficients from the FT-IRIS models were used to map collagen and elastin in tissue sections of degraded porcine aortic tissue as well as a human AAA biopsy tissue, creating a similar map of each component compared to histology. These results support further application of FTIR spectroscopic techniques for evaluation of AAA tissues. PMID- 24761433 TI - Synthesis of Cu2ZnSnS4 thin films directly onto conductive substrates via selective thermolysis using microwave energy. AB - Copper zinc tin sulfide (CZTS) thin films were deposited from homogeneous solutions of precursors and directly onto conductive films via selective thermolysis by microwave heating. Microwave energy is absorbed strongly by conductive films, which enables preferential heating to a sufficiently high temperature for the deposition of CZTS exclusively on the conductive layer without homogeneous nucleation of CZTS in the liquid phase or heterogeneous nucleation of CZTS on uncoated portions of substrates. PMID- 24761434 TI - Enzymatic preparation of a redox-responsive hydrogel for encapsulating and releasing living cells. AB - Horseradish peroxidase-mediated oxidative cross-linking of a thiolated poly(ethylene glycol) is promoted in the absence of exogenous hydrogen peroxide, by adding a small amount of a phenolic compound under physiological conditions. The prepared hydrogel can encapsulate and release living mammalian cells. PMID- 24761436 TI - Disseminated histoplasmosis in peripheral blood smear. PMID- 24761435 TI - Epstein-Barr virus-associated lymphocytosis masquerading as lymphoma. PMID- 24761437 TI - [What is the cause of postoperative dysphagia?]. PMID- 24761438 TI - [What are the advantages of coating?]. PMID- 24761439 TI - [Autoimmune pancreatitis -- rituximab for the prevention of relapses?]. PMID- 24761440 TI - [VEGF-level as a marker for pancreatic cancer]. PMID- 24761441 TI - [New group of patients identified]. PMID- 24761442 TI - [Are mesenchymal stem cells a therapeutic option?]. PMID- 24761443 TI - [Disease activity is easily evaluated with MRI]. PMID- 24761444 TI - [Primary disease presentation associated with colitis patterns]. PMID- 24761445 TI - [Spleen tyrosine kinase inhibitor guarantees gastrointestinal transit]. PMID- 24761446 TI - [Postoperative recurrence: adalimumab is an effective standard medication]. PMID- 24761447 TI - [Prospective multicentric phase III study]. PMID- 24761448 TI - [First-degree relatives of colorectal cancer patients: how many can we protect?]. PMID- 24761449 TI - [Friedrich Schiller and medicine]. PMID- 24761450 TI - Stephen Brady Thacker, 1947-2013. PMID- 24761451 TI - Hemophagocytosis by neoplastic plasma cells in multiple myeloma. PMID- 24761454 TI - Author's reply to Koppisch et al. PMID- 24761452 TI - Neutrophil numerals. PMID- 24761455 TI - Xanthine oxidase inhibition for the treatment of cardiovascular disease: a systematic review and meta-analysis. PMID- 24761457 TI - A challenging crossroad for emergency medicine: the epidemics of pain and pain medication deaths. PMID- 24761456 TI - Evidence-based narratives to improve recall of opioid prescribing guidelines: a randomized experiment. AB - OBJECTIVES: Physicians adopt evidence-based guidelines with variable consistency. Narratives, or stories, offer a novel dissemination strategy for clinical recommendations. The study objective was to compare whether evidence-based narrative versus traditional summary improved recall of opioid prescribing guidelines from the American College of Emergency Physicians (ACEP). METHODS: This was a prospective, randomized controlled experiment to compare whether narrative versus summary promoted short-term recall of six themes contained in the ACEP opioid guideline. The experiment was modeled after the free-recall test, an established technique in studies of memory. At a regional conference, emergency physicians (EPs) were randomized to read either a summary of the guideline (control) or a narrative (intervention). The fictional narrative was constructed to match the summary in content and length. One hour after reading the text, participants listed all content that they could recall. Two reviewers independently scored the responses to assess recall of the six themes. The primary outcome was the total number of themes recalled per participant. Secondary outcomes included the proportion of responses in each study arm that recalled individual themes and the proportion of responses in each arm that contained falsely recalled or extraneous information. RESULTS: Ninety-five physicians were randomized. Eighty-two physicians completed the experiment, for a response rate of 86%. The mean of the total number of themes recalled per participant was 3.1 in the narrative arm versus 2.0 in the summary arm (difference = 1.1, 95% confidence interval [CI] = 0.6 to 1.7). For three themes, the proportion of responses that recalled the theme was significantly greater in the narrative arm compared to the summary arm, with the differences ranging from 20% to 51%. For one theme, recall was significantly greater in the summary arm. For two themes, there was no statistically significant difference in recall between the arms. In the summary arm, 54% of responses were found to contain falsely recalled or extraneous information versus 21% of responses in the narrative arm (difference = 33%, 95% CI = 14% to 53%). CONCLUSIONS: Physicians exposed to a narrative about opioid guidelines were more likely to recall guideline content at 1 hour than those exposed to a summary of the guidelines. Future studies should examine whether the incorporation of narratives in dissemination campaigns improves guideline adoption and changes clinical practice PMID- 24761458 TI - Weaning the normal infant. PMID- 24761459 TI - EQ-5D-Y as a health-related quality of life measure in children and adolescents with functional disability in Sweden: testing feasibility and validity. AB - AIM: The EQ-5D-Y is a newly developed generic instrument measuring health-related quality of life in children and adolescents. The aim of the study was to test the feasibility and validity of the EQ-5D-Y in a Swedish patient sample of children and adolescents with functional motor, orthopaedic and medical disabilities and to compare the results with a general population sample. METHODS: Two samples of children and adolescents answered the EQ-5D-Y and a core set of internationally standardised instruments, variables and socio-demographic questions. Patients with functional disability (n = 71, aged seven to 17 years) and individuals from the general population (n = 407, aged eight to 16 years) were included in this study. RESULTS: There was a low number of missing answers. Significantly more problems were reported in all dimensions in the patient sample, and the mean visual analogue scale (VAS) score was significantly lower. Any problems were reported by 83% of the patients and by 37% of the general population. In the patient sample, 21% reported problems at the most severe level, compared with 1.5% in the general population sample. By subgroup analyses by diagnoses, the frequency of reported problems in the different dimensions varied. CONCLUSION: Even though feasibility and discriminative validity of the EQ-5D-Y were supported in our study, further studies are needed including more patients and patient groups. PMID- 24761460 TI - Nitric oxide, IL-6 and IL-13 are increased in the exhaled breath condensates of children with allergic rhinitis. AB - AIM: To evaluate nitric oxide and interleukin (IL)-6, IL-8 and IL-13 in the exhaled breath of children with allergic rhinitis (AR), before and after intranasal allergen exposure. METHODS: A total of 49 children with AR - comprising 20 who also had episodic asthma (AR+A) and 29 without asthma (AR) - were compared with 34 healthy controls. Nitric oxide concentrations in exhaled air (eNO) and IL-6, IL-8 and IL-13 in exhaled breath condensates (EBC) were measured in winter, outside the natural allergen exposure season, before and after an intranasal allergen challenge. RESULTS: The mean concentrations of eNO, IL-6 and IL-13 were significantly higher in the two AR groups. The concentration of IL-8 was below the assay detection limit in all EBC samples. The intranasal allergen challenge increased IL-13/EBC levels in both AR groups, but did not influence mean concentrations of eNO, IL-6 or IL-8. No challenge-related changes in IL-13/EBC were observed in the allergen-exposed controls or placebo-exposed children. CONCLUSION: Despite local application, the intranasal allergen challenge increased IL-13/EBC concentration in the AR children. As EBC reflects the status of lower airway segments, our observation may support the 'united airways' hypothesis, suggesting a functional link between the upper and lower airways. PMID- 24761461 TI - Differences in the prevalence of metabolic disorders between prepubertal boys and girls from 5 to 8 years of age. AB - AIM: To determine the prevalence of metabolic abnormalities, and differences between the sexes, in prepubertal overweight and normal weight children aged from 5 to 8 years, without any signs of health impairments or metabolic disturbances at the time of recruitment. METHODS: General health status and inflammatory markers were assessed in 100 overweight and 51 normal weight children, who were living in Germany and had undergone mandatory medical examinations. The study comprised of 81 girls and 70 boys. RESULTS: Despite being recruited as healthy, 73% of the overweight children and 16% of the normal weight children were found to suffer from one or more metabolic abnormalities, such as hypertension or insulin resistance. Girls with a body mass index (BMI) percentile of >=80th showed an increased susceptibility to metabolic disorders, and a similar effect was found for boys with a BMI percentile of >=95th. Plasma levels of proinflammatory markers, such as plasminogen activator inhibitor-1 and leptin, were also significantly higher in overweight than normal weight children. CONCLUSION: Metabolic and cardiovascular abnormalities and pro-inflammatory markers were prevalent in overweight prepubertal children. The prevalence rates appeared to differ between the sexes. PMID- 24761462 TI - The O(2)-sensing TRPA1 channel illustrates the significance of vagal nerves in cardio-respiratory adaptation to hypoxia. PMID- 24761463 TI - Motor unit activity after eccentric exercise and muscle damage in humans. AB - It is well known that unaccustomed eccentric exercise leads to muscle damage and soreness, which can produce long-lasting effects on muscle function. How this muscle damage influences muscle activation is poorly understood. The purpose of this brief review is to highlight the effect of eccentric exercise on the activation of muscle by the nervous system, by examining the change in motor unit activity obtained from surface electromyography (EMG) and intramuscular recordings. Previous research shows that eccentric exercise produces unusual changes in the EMG-force relation that influences motor performance during isometric, shortening and lengthening muscle contractions and during fatiguing tasks. When examining the effect of eccentric exercise at the single motor unit level, there are substantial changes in recruitment thresholds, discharge rates, motor unit conduction velocities and synchronization, which can last for up to 1 week after eccentric exercise. Examining the time course of these changes suggests that the increased submaximal EMG after eccentric exercise most likely occurs through a decrease in motor unit conduction velocity and an increase in motor unit activity related to antagonist muscle coactivation and low-frequency fatigue. Furthermore, there is a commonly held view that eccentric exercise produces preferential damage to high-threshold motor units, but the evidence for this in humans is limited. Further research is needed to establish whether there is preferential damage to high-threshold motor units after eccentric exercise in humans, preferably by linking changes in motor unit activity with estimates of motor unit size using selective intramuscular recording techniques. PMID- 24761464 TI - In the spotlight: rising stars in long term and post-acute care. Part 3. PMID- 24761465 TI - PEPPER gives corporate compliance guidance. PMID- 24761466 TI - Where creating an open culture starts. PMID- 24761467 TI - [Why infusion surgery did not start clinical transfusiology?]. AB - The article is devoted to the history of blood transfusion in the XVII century. The theoretical basis of the method was the publication in 1628 in London W. Harvey hypothesis about the circulation of blood, and the practical - conducted in 1656 in Oxford K. Wren experiments to inject of various liquids into the bloodstream. Methods for blood transfusions from animals to animals in February April 1667 developed in England R. Lower and E. King. The priority of the first transfusion of blood from the animal to man belongs to France. June 15, 1667 in Paris J.-B. Denis and barber-surgeon P. Emmerez using the Lower-King method transfused blood of a lamb to patients suffering from anemia. During the 2nd half of 1667 -- the spring of 1668 R. Lower, E. King and S. Pepis in England, J.-B. Denis and P. Emmerez in France, G. Riva and P.Manfredi in Italy, B. Kauffmann and M. Portmann in Germany had several successful blood transfusions. A total of 19 procedures done 10 sick people and 2 healthy man, but in the spring of 1668 public opinion related the death of a patient to the procedure. The Paris court held in April 1668 limited the blood transfusions, which in 1678 has been discontinued by law, without offering no impact on its renewal in the XIX century. PMID- 24761469 TI - [How to convey a bad news to your patients--a psycho-oncological approach]. PMID- 24761468 TI - The use of immobilized yeast technology for the production of rose and white sparkling wine from grape varieties of the Zitsa region, in Greece. AB - The use of immobilized yeast technology and its advantages in sparkling wine production was chosen for rose and white sparkling wine production, aiming at the study and brand development of a traditional local sparkling wine, mainly rose, which is produced from grape varieties cultivated at a local scale with the "rural" method, in Zitsa region, Ioannina, Greece. In all cases the double-layer immobilization method was used. Sodium alginate was used in the same concentration in all cases, for the external layer of the beads. Preliminary comparison of sodium alginate, carrageenan, and glycerine used for the internal core, showed that with 2% concentration of sodium alginate loaded with 2.10(9) cells/g of gel and 2,65 g of beads in each bottle cell release was not observed and the wine remained absolutely free of yeast cells even one month after fermentation completion. Organoleptic properties of the sparkling wine produced with immobilized yeast compared with sparkling wine produced with free yeast were found similar. PMID- 24761470 TI - Improving comprehension and accuracy of health questionnaires using pictorial descriptions (response to the editor). PMID- 24761471 TI - [Clarifying evidence of pharmacological effects of Kampo medicine]. PMID- 24761472 TI - [Pharmacological effects of kampo medicine]. PMID- 24761473 TI - HIV/AIDS: the labour market implications of compulsory testing. AB - OBJECTIVE: It is intended in this brief paper to outline the policy direction that ought to be followed regarding the phenomenon of HIV/AIDS and the workplace. In essence, this is a viewpoint instructed by data and research and not anecdotal evidence. METHODS: This is not primary research as it utilizes secondary material from existing literature as well as data from government sources. The method is a strict narrative regarding the data and frequencies and there there are no sophisticated statistical packages used for data analysis. RESULTS: On examining the data, it is clear that young women are disproportionately represented in the HIV and unemployment data. CONCLUSION: It is therefore likely that if testing for the purposes of employment is allowed to continue, it will create a disincentive to seek employment and thus will help to drive the infection underground. PMID- 24761474 TI - An unassuming revelation: Cuba's social policy toward the AIDS epidemic. AB - The thrust of this essay is nestled in Cuba's complimentary approach to the treatment of HIV/AIDS virus. In a comprehensive and comparative fashion, the contents herein give credence to a developing nation that demonstrates expedience and emphasizes a history of continuity with remarkable results. Underlying the report is a journey that enlightens the reader to a process rich in application and outcome during a period in which the plaque of HIV has transformed the Caribbean and Latin America community. Meanwhile, it also speaks to a collaborative effort inclusive of government , medical agencies, laboratories, international organizations and the public toward a common good. The country, nonetheless, is not without its shortcomings and therefore monetary constraints and matters of confidentiality and discrimination are pivotal to the presentation. In fact, an elaborate characterization accentuates a 50-year old commercial interdiction as a deterrent that contributes to the disruption of affordability and accessibility to the exchange of goods, services and information. Against all likelihood, a contrasting analysis of regional states inclusive of the United States of America documents Cuba's astonishing success in restricting HIV/AIDS. The Cuban model as described is an exemplary work in progress but likewise the fulfillment of the socialist philosophy toward humanity. PMID- 24761475 TI - [Awarded IADR distinguished scientist on salivary research 2013]. PMID- 24761476 TI - [A girl with flu like symptoms. What does the tongue reveal?]. PMID- 24761477 TI - [BMG sees a data protection breach in AKR]. PMID- 24761478 TI - [Online account invoice requires safe general practice electronic data processing. Is your data well protected?]. PMID- 24761479 TI - [Old, demented, in need of nursing care - and diabetic. Complications unavoidable?]. PMID- 24761481 TI - [Community acquired pneumonia: prognosis assessment and therapy. When must the patient be hospitalized?]. PMID- 24761480 TI - [When injectable diabetes therapy becomes necessary. Insulin or GLP-1 analogs?]. PMID- 24761482 TI - [Caresses]. PMID- 24761483 TI - [Naturopathy consultation. Hypo- and hypermenorrhea]. PMID- 24761484 TI - [ Smoking ban is good for the heart]. PMID- 24761485 TI - [Pesticides can cause dementia]. PMID- 24761486 TI - [Manual medicine handcraft, medicine enchantment?]. PMID- 24761487 TI - [Manual medicine--a powerful "hands on" facility to treat somatic and segmental dysfunction with musculosceletal pain, increased muscule tension, restrictions of fascia and posture asymmetries]. PMID- 24761488 TI - [Concept of treatment of low back pain]. PMID- 24761489 TI - [Manual therapy for insertional tendinosis]. PMID- 24761490 TI - [Antihypertensive treatment for patients 80 years and older]. PMID- 24761491 TI - [Acute abdomen: diagnostic approach]. PMID- 24761492 TI - [Novel adjuvants in vaccine development]. PMID- 24761493 TI - World Environment Day and its impact on pollution-free environment. PMID- 24761494 TI - Evaluation of oxidative stress and anti-oxidant status in essential hypertension. AB - The present study was planned to access the role of oxidative stress and anti oxidant status in essential hypertension. Malondialdehyde is one of the by products of lipid peroxidase and so extent of lipid peroxidation was measured by estimating malondialdehyde levels, nitrite concentration was used as an index of nitric oxide synthesis and anti-oxidant status was measured in terms of total antioxidant capacity. One hundred and eighty cases with essential hypertension and 60 volunteers as healthy controls were selected for the study. The subjects under study were grouped as pregeriatric (35-50 years) and geriatric (51-65 years). These cases were further subdivided into group I (mild), group II (moderate) and group III (severe), depending upon the levels of blood pressure. The study results showed statistically significant increased levels of serum malondialdehyde in all the groups of essential hypertensive patients when compared to that of healthy controls (p < 0.001), whereas levels of serum nitric oxide and total anti-oxidant capacity were significantly decreased in all groups of essential hypertensive patients when compared to those of controls (p < 0.001). These clear findings of the present study focuses the attention towards an alteration in the status of oxidants and anti-oxidant parameters indicating an impact of free radical action in the pathogenesis of essential hypertension. PMID- 24761496 TI - Study of C-reactive protein and C3 complement as acute phase reactants in unstable angina. AB - Prevalence rates of coronary artery disease are reported to be very high in Asian Indians. Traditional risk factors alone fail to explain the high rates of coronary artery disease in Indians. Acute phase reactants C-reactive protein and C3 in Indian subjects with unstable angina were evaluated and compared them with suitable controls to test the hypothesis that a relationship exists between acute phase reactants and unstable angina. Forty cases of unstable angina and forty suitable controls were enrolled for the study. Cases of unstable angina had significantly increased level of CRP as compared to control group (p = 0.01098). Statistically significant difference was found between case and control groups in TLC (p = 0.0037) and ESR (p = 0.0368), TLC and ESR being more in case group as compared to control group. C-reactive protein was significantly correlated with TLC, ESR and C3 in case group and TLC and ESR in control group. C3 was significantly correlated with all the other three inflammatory markers. C reactive protein, TLC and ESR in case group while no correlation was observed with any variable in control group. The present study concludes that a relationship exists between acute phase reactants studied and unstable angina. PMID- 24761495 TI - Peripheral neuropathy in diabetes. AB - Peripheral neuropathy is common complication of diabetes. The prevalence of peripheral neuropathy among diabetic patients on the basis of loss of vibration sensation had been studied. Detailed clinical history of each patient including age, gender, duration of diabetes, foot ulcer and biothesiometry was recorded in 211 diabetic patients between 20 and 80 years of age. It was observed that all patients under 30 years age (n = 8) felt vibration below 15 volts (no risk zone); 77% (24 out of 31) of the patients in the age group of 30-39 years were in the no risk zone, and 23% (n = 7) had mild peripheral neuropathy. Sixty per cent of the patients between 40 and 50 years (n = 44) were in the no risk zone, while 32% (n = 24) had mild peripheral neuropathy, 5% (n = 4) had moderate neuropathy and 3% (n = 2) had severe peripheral neuropathy. Amongst patients above 50 years of age, 31% (n = 31) were in no risk zone, 34% (n = 34) had mild peripheral neuropathy, 22% (n = 20) had moderate peripheral neuropathy and 13% (n = 13) had severe peripheral neuropathy. Of the patients with diabetes for less than 5 years, 58% had no neuropathy, and only 3% had severe neuropathy. Of the patients with diabetes for 5 to 15 years, 50% had no neuropathy, 30% had mild, and 10% had severe peripheral neuropathy. When patients with diabetes for over 15 years were studied, only 6% had no neuropathy and 19% had severe peripheral neuropathy. The study re-establishes that the severity of peripheral neuropathy increases with age and vibration perception decreses progressively with increased duration of diabetes. Vibration perception threshold testing helps to identify the high risk subjects who require special counselling and education to protect their feet. PMID- 24761497 TI - Distribution of certain risk factors among dyslipidaemic patients, morbid with first episode coronary heart disease. AB - The objectives of the study were to determine dyslipidaemia prevalence in first episode coronary heart disease cases and to determine the pattern of distribution of risk factors in this temporal relationship. This hospital based retrospective cohort study was conducted at Basaveshwara Teaching Hospital, Gulbarga, during January 2012. Data for the 3 year period (January 2005-December 2007) were collected from the case sheets of cardiac care unit admissions. Out of the 1,373 admissions to the cardiac care unit over the 36 months period, 462 case sheets were examined as these were the ones with first episode coronary heart disease aetiology. Also, lipid profile was available for 102 patients only and hence they were included in the study (n = 102). Only first episode coronary heart disease cases were considered. The labelling of dyslipidaemia was done according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Statistical analysis was done using Fisher-Exact, Chi-square and other appropriate tests. Dyslipidaemia was present in 67.6% of first episode coronary heart disease cases. Age, sex and occupational profiles were enumerated and cross tabulated to examine their influence on dyslipidaemia. In this study, increasing age profile did not show an association with the propensity towards developing an abnormal lipid profile. Males showed a greater predisposition towards developing dyslipidaemia (70.8%). With respect to occupation, males involved in semi-skilled labour had a higher degree of lipid profile abnormality (87.5%). Dyslipidaemia among working women was higher (75%) when compared to housewives (40%). This association was found to be statistically significant (p = 0.025). History of diabetes, hypertension, alcohol and smoking habits were also considered for the analysis. Heart disease patients with history of diabetes showed a high prevalence of dyslipidaemia (100%), the association being statistically significant (p = 0.008). Lipid profiling among hypertensives showed an aberration, wherein the prevalence of an abnormal profile was lower (54.5%). This association was found to be statistically significant (p=0.05). The influence of alcohol consumption on lipid profile showed an unequivocal association in this study (63.6%), when compared with patients who did not consume alcohol (69.6%). However, an association for dyslipidaemia was forthcoming among smokers (73.7%). This study shows significant association of dyslipidaemia with diabeties, history of alcohol consumption and the working profile of a woman. PMID- 24761498 TI - Latex agglutination test (LAT) for the diagnosis of typhoid fever. AB - The efficacy of latex agglutination test in the rapid diagnosis of typhoid fever was studied and the result compared with that of blood culture. This study included 80 children suffering from typhoid fever, among which 40 were confirmed by blood culture isolation and 40 had possible typhoid fever based on high Widal's titre (a four-fold rise in the titre of antibody to typhi "O" and "H" antigen was considered as a positive Widal's test result). Eighty children, 40 with febrile illness confirmed to be other than typhoid and 40 normal healthy children were used as negative controls. The various groups were: (i) Study group ie, group I had 40 children confirmed by culture isolation of Salmonella typhi(confirmed typhoid cases). (ii) Control groups ie, (a) group II with 40 febrile controls selected from paediatrics ward where cause other than S typhi has been established, (b) group III with 40 afebrile healthy controls that were siblings of the children admitted in paediatric ward for any reason with no history of fever and TAB vaccination in the last one year, and (c) group IV with 40 children with high Widal's titre in paired sera sample. Widal's test with paired sera with a one week interval between collections were done in all 40 patients. Latex aggtutination test which could detect 900 ng/ml of antigen as observed in checker board titration, was positive in all 40 children from group I who had positive blood culture and in 30 children from group IV who had culture negative and had high Widal's titre positive. Latex agglutination test was positive in 4 children in group II and none in group III. Using blood culture positive cases as true positive and children in groups II and III as true negative, the test had a sensitivity of 100% and specificity of 96%. Latex agglutination test was found to be significantly sensitive (100%) and specific (96%) and could detect 75% more cases in group IV (possible typhoid cases). Thus latex agglutination test can be used for rapid diagnosis of typhoid fever though it cannot replace conventional blood culture required for isolation of organism to report the antibiotic sensitivity. PMID- 24761499 TI - Myocardial infarction increases progressive visual field defects in well treated early primary open angle glaucoma--a prospective case control study. AB - The purpose of the study was to evaluate the progression of glaucomatous field damage in patients with stable primary open angle glaucoma after an attack of myocardial infarction. In this case control study, 62 open angle glaucoma patients were selected and regularly followed up. Among 62 patients, 9 had an attack of myocardial infarction. The intra-ocular pressure and visual field progression of both the groups (myocardial infarction versus no myocardial infarction) were analysed. Three (33.3%) out of 9 patients who had suffered from myocardial infarction showed progressive visual field loss whereas only 9 (16.9%) out of 53 patients who did not suffer from myocardial infarction, showed progressive field changes. Both the groups had stable target intra-ocular pressure between 14 and 16 mm Hg. Myocardial infarction may adversely influence the progression of primary open angle glaucoma which is suspected to result from ischaemia induced neuronal loss and only control of intraocular pressure is not the only solution. We have to look for other drugs that prevents ischaemia induced neuronal damage. PMID- 24761500 TI - Clinical profiles and symptoms of childhood depression. AB - The identification of depression poses significant clinical challenges to physicians, parents and teachers. Symptoms of depression may differ from those of the adult depression. Clinical depression varies in the nature and intensity of its presenting symptoms. It may present with the cardinal symptoms of major depressive disorder. It often goes unidentified and undiagnosed when it presents as masked depression or depressive equivalents. PMID- 24761501 TI - Gastric xanthoma with hyperplastic polyp: a case report. AB - Gastric xanthoma is uncommon lesion with a variably reported frequency. Hyperplastic polyps are commonest epithelial polyps in stomach. A rare case of simultaneous presence of xanthoma with hyperplastic polyp is reported. A 70-year old female presented with dyspepsia and heartburn. Upper gastro-intestinal endoscopy showed multiple sessile small whitish polyps in stomach. Histopathological examination of the polyps-showed features of xanthoma with hyperplastic polyp in the mucosa with areas of intestinal metaplasia and occasional H pylori. There was no evidence of malignancy in the present case. PMID- 24761503 TI - Transverse myelitis in antiphospholipid antibody negative systemic lupus erythematosus. AB - Acute transverse myelitis is a well known neurological complication occurring in systemic lupus erythematosus. Many prior studies have shown a link between transverse myelitis and the presence of antiphospholipid antibodies. Earlier theories have linked thrombotic tendency to be the culprit in such manifestations but currently there is evidence to support other causative mechanisms. A case of a young female diagnosed as systemic lupus erythematosus has been reported who presented with acute transverse myelitis and was found to be seronegative for antiphospholipid antibody. It is important to pay heed to and accordingly treat complications like acute transverse myelitis that occur regardless of antiphospholipid antibody positivity in a systemic lupus erythematosus setting. PMID- 24761502 TI - Acute presentation of idiopathic thrombocytopenic purpura in postmenopausal woman. AB - A healthy 50 years old woman who had no past history of bruising or menometrorrhagia was admitted with complaints of cutaneous petechiae all over the body for 5 days and gum bleeding for 3 days. She presented with isolated thrombocytopenia, an otherwise unremarkable peripheral smear and physical examination showed evidence of bleeding consistent with low platelet count. After excluding other causes of thrombocytopenia, diagnosis of idiopathic thrombocytopenic purpura was made. She was given intravenous steroids and marked improvement in signs and symptoms was noted. PMID- 24761504 TI - Glandular odontogenic cyst: a case report. AB - A case of glandular odontogenic cyst was diagnosed in a 33-year-old man. The cyst was located in the angle of the mandible, underneath the left molars. This case has been presented for its rarity of location in posterior mandible and presentation as intra-oral papillary growth. PMID- 24761505 TI - Facial diplegia: a clinical dilemma. AB - Bilateral facial paralysis is a rare clinical entity and presents as a diagnostic challenge. Unlike its unilateral counterpart facial diplegia is seldom secondary to Bell's palsy. Occurring at a frequency of 0.3% to 2% of all facial palsies it often indicates ominous medical conditions. Guillian-Barre syndrome needs to be considered as a differential in all given cases of facial diplegia where timely treatment would be rewarding. Here a case of bilateral facial palsy due to Guillian-Barre syndrome with atypical presentation is reported. PMID- 24761506 TI - [Collaboration, a great opportunity]. PMID- 24761507 TI - [Nurses should move into positions of influence]. PMID- 24761508 TI - [Fighting violence against women]. PMID- 24761509 TI - [The College of Nursing wishes to develop new skills]. PMID- 24761510 TI - [Using touch to prevent pain during the removal of a drain]. AB - A study was carried out in 2010-2011 to assess the effectiveness of "conscious touch" in preventing the pain caused by the removal of the Redon drain in patients having undergone a hip replacement. The results show that the pain rating is significantly lower in patients having received this touch. This study opens the way for further research work on the prevention of pain during nursing procedures. PMID- 24761512 TI - [Life after cancer. Thinking of life after cancer for living better with the disease]. PMID- 24761511 TI - [Management of crime victims in a forensic unit]. AB - The medico-legal process is often upsetting for victims of crime. Following a sexual assault, the medical and gynaecological examination can be a source of anxiety. The reception and management of the victims is personalised thanks to the work of the multi-disciplinary team. After the medico-legal examination, the victims are directed, depending on their needs, towards a medical, social or psychological follow-up. PMID- 24761513 TI - [The post-cancer period, a conceptual and epidemiological approach]. AB - The post-cancer period constitutes a growing issue due to increased cancer incidence and the improvements in treatments. There are numerous related concepts: survivor, remission, cure, etc. The consequences of the disease on the reprisal of a social and family life must be taken into account. PMID- 24761514 TI - [The needs of families faced with cancer]. AB - A cancer diagnosis overturns the whole family dynamic, with long-term consequences. A tool called Disque des besoins has been created for use in family interviews. PMID- 24761515 TI - [Reconciling cancer and work]. AB - Cancer leads to financial and social insecurity for those suffering from the disease. Cancer plans include this public health issue, developing support programmes to help patients preserve their social life despite the disease. A project led by a hospital's social services department helps patients in their return to work. PMID- 24761516 TI - [The post-cancer period, legal aspects]. PMID- 24761517 TI - [Family relationships faced with the ordeal of cancer]. AB - A child's cancer affects the whole family and has repercussions on each member. The disease favours the creation of intense, close bonds and support strategies between the parents and child, from which it is often difficult to withdraw. A specific consultation, away from the care environment, provides support for the patients and their family. PMID- 24761518 TI - [Psychological support in response to a child's cancer]. AB - Martin was five and a half when he was diagnosed with a form of ear, nose and throat cancer. His experience of the disease and its treatment fills him with terror and he has terrible temper tantrums. His parents' experience of the disease is one of isolation and the fear of his death. Psychological support enables each of them to talk about their experience and to re-establish a balance, both on an individual and family level. PMID- 24761519 TI - [Supporting children when a parent has cancer]. PMID- 24761520 TI - [Preserving one's self-image despite cancer]. AB - Cancer and the side effects of the treatments affect a patient's self-image. The assistance of a personal image consultant and socio-aesthetician can help the patient restore their appearance and become more accepting of themselves. It enables them to be more at ease in their relationships with others and reinforces self-esteem. PMID- 24761521 TI - [Sexual health for patients suffering from cancer]. AB - Patients suffering from cancer generally see their sex life deteriorate. Their self-image, the way their body is seen and their relationships with others are profoundly changed. Inviting the patient to evoke their difficulties helps them to regain a fulfilling sex life despite the disease. PMID- 24761522 TI - [Preserving fertility after cancer]. AB - The survival rate after cancer is increasing and the side effects of the treatments on fertility can be anticipated. Various techniques exist for men, women as well as for children. PMID- 24761523 TI - [Cancer, the role of volunteers in maintaining social ties]. PMID- 24761524 TI - [Geriatric oncology is just a premise]. PMID- 24761525 TI - [Bibliography. Life after cancer]. PMID- 24761526 TI - [Building ethical competency, essential for research nurses]. AB - A growing number of nurses are designing and implementing research protocols in France. However, their research training is still heterogeneous. This observation raises the need to underline the ethical specificities of research in nursing science and to encourage any researchers exploring this field to develop the ethical skills required to manage the research process. PMID- 24761527 TI - [Interactive digital applications, social research and professional applications]. PMID- 24761528 TI - Tiotropium: a new therapeutic option in asthma. AB - Although bronchial hyperresponsiveness to cholinergic agents is a main feature of asthma, the role of anticholinergic drugs in chronic asthma management has been largely underestimated. Several single-dose studies comparing acute bronchodilation induced by ipratropium bromide with salbutamol have shown that salbutamol is more effective than ipratropium in treating asthma. Recently, tiotropium has been studied in asthma, when added to low-medium dose inhaled corticosteroids (ICS) in unselected moderate asthmatics or in patients with uncontrolled asthma, or with COPD and history of asthma. Later, studies on patients with Arg/Arg beta2-receptor polymorphism demonstrated a similar efficacy of tiotropium in comparison with salmeterol, when both were added to ICS. More recently, pivotal long-term studies have been performed on severe asthmatics uncontrolled under ICS/LABA combination, showing the efficacy of tiotropium in improving lung function and in increasing the time until the first severe asthma exacerbation. These data support the use of tiotropium on top of ICS/LABA combination in moderate-severe asthmatic patients. New studies are going to be published on the use of tiotropium in mild and moderate asthmatics, when added to low or medium dose ICS, in comparison with ICS alone or with ICS/LABA combination. These data might extend the indication for using tiotropium in asthma. Therefore, tiotropium represents now a valid therapeutic option, in addition to the current therapy available for severe asthmatics, and in alternative to LABA in selected asthma populations. The specific asthma phenotype which may be appropriate for tiotropium treatment should still be defined. PMID- 24761529 TI - Health-related quality of life, lung function and dyspnea rating in COPD patients. AB - BACKGROUND AND AIM: COPD is a progressive and irreversible disease, thus assessing the impact of the disease on health-related quality of life (HRQOL) is important in the management of COPD. The aim of this study was to examine the relationship between HRQOL, lung function and dyspnea rating in patients with stable COPD. METHODS: One hundred COPD patients (mean age = 64.76 +/- 11.43 years) were recruited for this cross-sectional study. Lung function test was measured using a FlowScreen portable spirometry. Dyspnea rating was measured using the baseline dyspnea index (BDI). HRQOL was assessed using the SF-36v2 which summarized two components; physical health component summary (PHCS) and mental health component summary (MHCS). THE RESULTS: The mean value of lung function (Forced expiratory volume in 1 second, FEV1% predicted) was 58.19 +/- 30.24 and dyspnea rating was 6.85 +/- 2.68. The lung function was significantly correlated with MHCS (r=.294, p < 0.05) but not with the PHCS (p > 0.05). The dyspnea rating was significantly correlated with both PHCS (r=.730, p < 0.05) and MHCS (r = .324, p < 0.05). Regression analysis indicated that dyspnea rating emerged as the most significant predictor for PHCS and MHCS accounting for 54% and 12% of the variances respectively. CONCLUSIONS: The findings show that dyspnea rating is an important factor in predicting HRQOL of patients with COPD. This indicates that dyspnea rating influences HRQOL to a greater extent than the physiological measurement of lung function. Therefore, focusing on such predictors at an early stage may provide meaningful benefits in the management of COPD. PMID- 24761530 TI - Grading the severity of obstruction in patients with chronic obstructive pulmonary disease and morbid obesity. AB - AIM: To evaluate the severity of airway obstruction in patients affected by chronic obstructive pulmonary disease (COPD) in the presence of concomitant restriction due to morbid obesity. METHODS: Lung function test, six-minute walking distance (6MWD) test, body mass index measurement (BMI), and determination of dyspnoea using the Modified Medical Research Council Dyspnoea Scale (MMRC) were performed on each patient referred to our department according to their individual respiratory diagnosis or symptoms. Analysis was performed on smokers or ex-smokers patients, with both dyspnoea and chronic productive cough, showing non fully reversible airflow obstruction, with normal-weight (NW: BMI 22 to 24 kg/m2) or morbid-obesity (MO: BMI > or = 40 kg/m2). RESULTS: In 33 COPD patients, spirometric data differ between NW and MO only in fixed FEV1/FVC ratio (50 +/- 9 and 62 +/- 7, respectively; p = 0.0001) and FEV1/SVC % of predicted (57 +/- 15 and 71 +/- 11, respectively; p = 0.005). Furthermore, SVC was found to exceed FVC only in NW (2.82 +/- 0.7 L and 2.08 +/- 0.9 L, respectively; p = 0.03). NW and MO differ significantly also in MMRC (3.4 +/- 0.9 vs 2.4 +/- 1, respectively; p = 0.004), 6MWD in metres (226 +/- 100 and 331 +/-110, respectively, p = 0.007), 6MWD as % predicted (49 +/- 22 and 81 +/- 23, respectively; p = 0.0003), and BODE index (5.8 +/- 2 and 3.6 +/- 2, respectively; p = 0.003). CONCLUSIONS: There is a significant overgrading of obstruction in morbidly obese patients affected by COPD. Therefore, we suggest that an alternative grading system be used for patients with mixed ventilatory dysfunction. PMID- 24761531 TI - Training and practice in bronchoscopy a national survey in Italy. AB - BACKGROUND AND AIM: Bronchoscopy is performed in a variety of different settings in Italy. The surveys conducted so far have highlighted the heterogeneity of the procedures and the frequent inability to adhere to the guidelines. The aim of this survey was to analyse procedures, training, and opinions of Italian respiratory physicians performing interventional bronchology in the clinical practice. METHODS: The study was conducted retrospectively on 300 pulmonologists. From January to June 2008, these were invited to participate in an email survey to be sent out monthly to each participant for four consecutive months. RESULTS: Two hundred and one respiratory physicians took part in the study, most of whom (83.5%) work in either Pulmonology or Interventional Pulmonology Units. The year before the survey, 21.2% of the participants had performed fewer than 100 examinations, 42.3% 100 to 300, and 36.6% more than 300 bronchoscopies; 53.9% were familiar with the international guidelines on the topic. Among the responders, 34.1% had received less than 6 months training, 55.3% considered further training in rigid bronchoscopy, laser procedures and thoracoscopy, invaluable for their professional activity. Adequate training for transbronchial needle aspirates, was reported by 49.6% of respondents. CONCLUSIONS: Our data show that interventional bronchoscopy procedures are regularly performed according to current recommendations by over half of the Italian Pulmonologists participating in our survey. The need for more comprehensive basic education and training was put forward by the majority of physicians. PMID- 24761532 TI - Tuberculous pancreatitis complicated by ruptured splenic artery pseudoaneurysm. AB - Tuberculosis involving the pancreas is rare. We report a patient with pancreatic tuberculosis complicated by haemorrhage from a splenic artery pseudoaneurysm. As far as we are aware, the development of a splenic artery pseudoaneurysm in association with a large caseating mass of tuberculous pancreatic lymph nodes has not been reported previously. We review the literature and discuss the varied presentations of tuberculosis involving the pancreas or the pancreatic bed and its draining lymph nodes. PMID- 24761533 TI - Recurrent pneumomediastinum in a patient with rheumatoid arthritis. AB - Spontaneous pneumomediastinum (SPM); also known as mediastinal emphysema, is a rare and usually benign self-resolving appearance of extraluminal air in the mediastinum without any underlying trigger. This is an uncommon disorder mostly seen in the young males and classic clinical presentation is with chest pain, dyspnea, cough and appearance of subcutaneous emphysema. Although several connective tissue disorders have been reported in association with SPM, it is a rare occurrence in rheumatoid arthritis (RA) with only small number of cases reported in literature. We report a 69 years old male with RA who developed recurrent asymptomatic episodes of SPM detected over a period of one year. The recurrent but benign episodes of SPM in this patient reestablish the usual uncomplicated course of this unusual clinical entity even in the rare recurrent cases. PMID- 24761534 TI - Intramedullary thoracic spinal metastasis from small-cell lung cancer. AB - Lung cancer with intramedullary spinal cord metastasis (ISCM) is a rare event exhibiting dismal prognosis. In the present paper, we describe a 74-year-old male who developed bilateral leg weakness with associated backache and non-productive cough. Chest imaging evaluation demonstrated pronounced bilateral mediastinal lymphadenopathy and a nodular opacity in the right lower lobe. The patient was diagnosed with small cell lung cancer through bronchoscopic procedures. Magnetic resonance imaging of the spinal cord with contrast-enhancement revealed an intramedullary lesion consistent with metastasis at the T5-T6 level. Despite chemotherapy and thoracic spine radiotherapy, he eventually succumbed to the disease 3 months after diagnosis. A brief overview of the current literature is also provided laying emphasis on the therapeutic strategies of this unusual extrathoracic metastatic disease. PMID- 24761535 TI - TBNA for the treatment of non complicated bronchogenic cyst. PMID- 24761536 TI - Seasonal variation and homes: understanding the social experiences of older adults. AB - There has been limited research on the importance of seasons in the lives of older adults. Previous research has highlighted seasonal fluctuations in physical functioning--including limb strength, range of motion, and cardiac death--the spread of influenza in seasonal migration patterns. In addition, older adults experience isolation for various reasons, such as decline of physical and cognitive ability, lack of transportation, and lack of opportunities for social interaction. There has been much attention paid to the social isolation of older adults, yet little analysis about how the isolation changes throughout the year. Based on findings from an ethnographic study of older adults (n = 81), their family members (n = 49), and supportive professionals (n = 46) as they embark on relocation from their homes, this study analyzes the processes of moving for older adults. It examines the seasonal fluctuations of social isolation because of the effect of the environment on the social experiences of older adults. Isolation occurs because of the difficulty inclement weather causes on social interactions and mobility. The article concludes with discussion of the ways that research and practice can be designed and implemented to account for seasonal variation. PMID- 24761537 TI - Individualized plans of care to improve outcomes among children and adults with chronic illness: a systematic review. AB - BACKGROUND: Adults and children with chronic illness often require services from multiple providers. Individualized plans of care (IPCs) are sometimes developed to improve care coordination. However, their association with improved outcomes is unknown. METHODS: We searched literature published between January 2001 and October 2011, using Medline, CINAHL, EMBASE, PsychINFO, and bibliographic review. Eligible studies involved an IPC with input from the patient and/or family of individuals with chronic illness, evaluated outcomes, and were conducted in the United States. We assessed evidence quality using Oxford Centre for Evidence Based Medicine criteria. RESULTS: 15 studies met inclusion criteria. Studies were heterogeneous regarding populations and outcomes examined and were generally low quality. Most described IPC use within a multifaceted care coordination intervention. The strongest evidence links IPC use and symptom improvement in depressed adults; the weakest evidence exists for outcomes in children. Vague descriptions of the IPCs' limited analysis. CONCLUSIONS: Current evidence supporting an association between IPC use and improved outcomes, particularly among children, is sparse. Well-designed evaluations of clearly described IPCs are needed to examine who should be involved in their development, what they should include, and how often they should be updated to improve outcomes of care for this vulnerable population. PMID- 24761538 TI - Centralized care management support for "high utilizers" in primary care practices at an academic medical center. AB - Although evidence of effectiveness is limited, care management based outside primary care practices or hospitals is receiving increased attention. The University of Michigan (UM) Complex Care Management Program (CCMP) provides care management for uninsured and underinsured, high-utilizing patients in multiple primary care practices. To inform development of optimal care management models, we describe the CCMP model and characteristics and health care utilization patterns of its patients. Of a consecutive series of 49 patients enrolled at CCMP in 2011, the mean (SD) age was 48 (+/- 14); 23 (47%) were women; and 29 (59%) were White. Twenty-eight (57%) had two or more chronic medical conditions, 39 (80%) had one or more psychiatric condition, 28 (57%) had a substance abuse disorder, and 11 (22%) were homeless. Through phone, e-mail, and face-to-face contact with patients and primary care providers (PCPs), care managers coordinated health and social services and facilitated access to medical and mental health care. Patients had a mean (SD) number of hospitalizations and emergency room (ER) visits in 6 months prior to enrollment of2.2 (2.5) and 4.2 (4.3), respectively, with a nonstatistically significant decrease in hospitalizations, hospital days, and emergency room visits in 6 months following enrollment in CCMP. Centralized care management support for primary care practices engages high-utilizing patients with complex medical and behavioral conditions in care management that would be difficult to provide through individual practices and may decrease health care utilization by these patients. PMID- 24761539 TI - Physical and mental health: from youth to age in Ohio prisons. AB - Who cares about health care in prisons? You do if you have a son or a granddaughter in prison. Maybe you care anyway if you have had to wait a long time to see a doctor or if you could not have the treatment you needed because it cost too much. Maybe you have run into the attitude, "You ain't bleedin', you ain't needin'." Maybe you have found it hard to face the future with little or no hope that you could ever be in a better place. Or maybe you, like some older prisoners, have been able to develop new interests, new skills, to review your life and review it, and to redefine what matters. PMID- 24761540 TI - Closely approaching advanced age in a supermax prison. AB - When a Social Security recipient reaches the age of 50 years, he or she is classified as "closely approaching advanced age." Todd Ashker is passing this tipping point at Pelican Bay State Prison in California, a supermaximum security facility. My wife and I have corresponded with Mr. Ashker for more than half a dozen years. Although I cannot verify the details of his account, we believe that his representation of facts is generally reliable. He is one of the spokespersons for prisoners who conducted two hunger strikes in 2011 protesting conditions of their confinement. Another, sixty-day hunger strike took place in 2013. Thus, what follows is a story of resilience as well as victimization. PMID- 24761541 TI - Eleven blogs on aging. PMID- 24761542 TI - Marilyn Mesi Pona. PMID- 24761543 TI - Insulin patch pumps: a new tool for Type 2. PMID- 24761545 TI - Carbohydrate restriction: an option for diabetes management. PMID- 24761544 TI - Fast and fresh: lunch ideas. PMID- 24761547 TI - Vegetables. PMID- 24761546 TI - Diabetes quiz. How much do you know about vitamins? PMID- 24761549 TI - Cottage cheese pancakes. PMID- 24761548 TI - Medication therapy: getting help and support. PMID- 24761550 TI - Way too much of a good thing... PMID- 24761551 TI - Creating our future. PMID- 24761552 TI - Early childhood nutrition in an American Indian community: educational strategy for obesity prevention. AB - Prevailing infant and toddler feeding practices in an American Indian community were assessed to explore the feasibility of improvement by implementation of a maternal education program. A survey of prevailing nutritional practice was the basis for design of an instruction program on infant nutrition for mothers during pregnancy. Follow-up assessments provided information on feasibility, and requirements for an effective program. Failure to sustain breast-feeding, low fruit and vegetable intake, low fiber intake, consumption of sweetened beverages, low milk consumption and low vitamin D intake were identified as persisting problems. We conclude that infant and toddler feeding practices are comparable to national trends, but suboptimal and conducive to promoting early obesity and diabetes in a susceptible community. A successful education-based intervention strategy beginning in pregnancy appears feasible if psychosocial, environmental, and economic barriers can be addressed. PMID- 24761553 TI - Crisis. PMID- 24761554 TI - In adults with type 2 diabetes mellitus, are patients with poor control more likely to develop venous thromboembolism compared to patients with good control? PMID- 24761555 TI - Oklahoma Health Care Authority's (OHCA) Medical Professional Services unit. PMID- 24761557 TI - Rising above. ASHE recognizes the best in collaborative building. PMID- 24761558 TI - "The University of Texas MD Anderson Cancer Center: Alkek Tower expansion. PMID- 24761559 TI - Penrose hospital: emergency department renovation. PMID- 24761560 TI - South Georgia Medical Center: operating suite HVAC upgrade. PMID- 24761561 TI - Energy alternatives. On-site power generation technologies for health care facilities. PMID- 24761562 TI - Sizable difference. How regulations and technologies have influenced space planning. PMID- 24761563 TI - Big savings in small packages. Compact designs, higher precision controls and automation help new-era boilers rack up energy savings. PMID- 24761564 TI - Handling textiles in the hospital environment. PMID- 24761565 TI - Surface safety. Best practices in surface and medical device disinfection. PMID- 24761566 TI - Reg ready. Keeping up with Joint Commission standards changes. PMID- 24761567 TI - Winning floors. Developing a game plan that improves aesthetics and safety. PMID- 24761568 TI - A strong symbol of peace. PMID- 24761569 TI - The money structure of dentistry. PMID- 24761570 TI - Ethical superiority of dentists versus auto mechanics. PMID- 24761571 TI - Author reply: To PMID 23977750. PMID- 24761572 TI - Writing off copayments. PMID- 24761573 TI - Author's reply: To PMID 24283029. PMID- 24761574 TI - What we owe the next generation. PMID- 24761576 TI - Letter of Congratulations from Oklahoma Governor Mary Fallin. PMID- 24761575 TI - Let's discuss the future. PMID- 24761577 TI - Legislative action is a sophisticated enterprise. AB - Backroom deals and cash payoffs are fine depictions of political power in the movies. But they are ineffective in today's highly complex interaction between oral health and public policy. Three recent examples of the work of the California Dental Association's Government Affairs Council demonstrate the range of approaches that are needed to be successful. A mass-action campaign drew attention to the needs of underserved Californians and demonstrated dentists' willingness to help. Education, including visiting model programs, provided information legislators require to understand complex issues. Tightly niched grass-roots contacts from key constituents demonstrated not only interest but informed engagement. PMID- 24761578 TI - Can power be shared? AB - Dental insurance began with a partnership between dental service organizations and state dental associations with a view toward expanding the number of Americans receiving oral health care and as a means for permitting firms and other organizations to offer employee benefits. The goals have been achieved, but the alliance between dentistry and insurance has become strained. A lack of dialogue has fostered mutual misconceptions, some of which are reviewed in this paper. It is possible that the public, the profession, and the dental insurance industry can all be strengthened, but only through power-sharing around the original common objective. PMID- 24761579 TI - Power, ethics, and corporate dentistry. AB - The North Carolina Dental Association recently sought to place clear statutory limits on the influence of corporate, nondental interests over dentists practices' decision-making. This report describes the two-year legislative battle with well-funded and politically connected parties that ultimately resulted in laws that protect patients' rights to be treated by a dentist free of outside commercial interests. PMID- 24761580 TI - Legal dimensions of power in the dental office. AB - Hostile workplace environments and sexual harassment depend on unequal power. It is the legal responsibility of the employer (the dentist practice owner) to protect against, investigate, and take appropriate action to prevent the abuse of power in the office. This article discusses harassment by dentists, staff members, and patient, vendors, and other third parties. Six direct steps for managing this issue are presented. PMID- 24761581 TI - Dental student indebtedness: Where did it come from and where will it lead? AB - Today's dental school graduates are burdened by an ever-increasing amount of student loan debt from both their undergraduate and predoctoral educations. Although considered to be multifactorial in origin, this article explores the microeconomic theory of supply and demand as a source for rising tuition costs and subsequent educational debt. The historical context for the cost of a dental education is provided, and serious questions are posed about how this indebtedness might impact the future of the profession. PMID- 24761582 TI - Ethical obliqations and the dental office team. AB - A hypothetical case of alleged sexual misconduct in a practice with high employee turnover and stress is analyzed by three experts. This case commentary examines the ethical role expectations of an office manager who is not directly involved but becomes aware of the activities. The commentators bring the perspectives of a dental hygienist, academic administrator, and attorney; a teacher of behavioral sciences in a dental school; and a general dentist with many years of practice experience. PMID- 24761583 TI - Entrepreneurship in nursing. PMID- 24761584 TI - Serving as nurse of the day. PMID- 24761585 TI - The Jonas Nurse Leaders Scholar Program and the future of nursing in Oklahoma. PMID- 24761586 TI - Humor is awesome. PMID- 24761587 TI - Regeneration room: innovation to address staff RN retention. PMID- 24761588 TI - Advocacy: time to take another look? AB - In conclusion, patient advocacy is an ethical duty of each professional nurse. It is incumbent upon us, regardless of practice venue, to assure that we give thought to, take a second look at, our awesome responsibility and blessing to be advocates. PMID- 24761589 TI - Mercy emergency medicine co-workers rush to aid in the Philippines. PMID- 24761590 TI - Oklahoma Nurses Association 2014 legislative agenda and priorities. PMID- 24761591 TI - [Neuroanatomical basis for traumatic coma: clinical and magnetic resonance correlates]. AB - In this paper, the relationship between brain lesion localization (verified by magnetic resonance imaging (MRI)) and the severity of traumatic brain injury (TBI) and its outcomes is presented. Magnetic resonance studies in different modes (T1, T2, FLAIR, DWI, DTI, T2 * GRE, SWAN) were performed in 162 patients with acute TBI. Statistical analysis was done using Statistica 6, 8 software and R programming language. A new advanced MRI-based classification of TBI was introduced implying the assessment of hemispheric and brainstem traumatic lesions level and localization. Statistically significant correlations were found between the Glasgow coma and outcome scales scores (p < 0.001), and the proposed MRI grading scale scores, which means a high prognostic value of the new classification. The knowledge of injured brain microanatomy coming from sensitive neuroimaging, in conjunction with the assessment of mechanisms, aggravating factors and clinical manifestation of brain trauma is the basis for the actual predictive model of TBI. The proposed advanced MRI classification contributes to this concept development. PMID- 24761592 TI - [EEG-correlates of consciousness recovery after traumatic brain injury]. AB - The aim of studies of patients in long-term posttraumatic unconscious state (PUS) was to outline prognostically significant EEG-markers of consciousness condition and an assessment of its dynamics orientation. We analysed outcomes of dynamic (from days to 16 years after trauma) EEG studies in 196 patients in TBI-caused PUS and different degrees of mental recovery: from chronic unconscious state up to clear consciousness. These results were compared to clinical protocols and data of MRI. It is revealed that dynamic features of EEC pattern (with the analysis of equivalent dipolar sources of separate components) allow to characterize the severity of patient's current state, to reveal the brain structures with the most expressed dysfunction, to define a zone of local cortical damage, and also the general direction of development of a traumatic illness (as though dynamics of a homeostasis of a brain). Frequency characteristics of EEG power spectrum (average frequency--an effective frequency strip) in a background and at reactions find the greatest predictive importance, especially at their assessment in 2-3 months after a trauma. The background interhemispheric EEG coherence (first of all, frontal) as the integrative characteristic of system brain activity, and its change at reactions to external incentives most reflect degree of consciousness oppression, dynamics and potential of its restoration. It was shown the high informational of the researches EEG changes to indifferent and functionally significant signs for an assessment of CNS functionality, and also of PUS pathogenesis. PMID- 24761593 TI - [Neurotransmitter basis of consciousness and uncosciousness states]. AB - Plenty of different studies are dedicated to consciousness recovery problem, such as neuroanatomical, neurophysiological, neuropsychiatric, neurosurgical, neurological points of view. However, neurotransmitter dysfunction is one of the main difficulties for consciousness and other neurological functions recovery after brain trauma. There are a lot of pharmacological agents modulating brain neurotransmitter activity, but no one precise clinical indication. So, the neurotransmitter mechanisms of consciousness recovery in patients with brain pathologies are very actual for studying with updating methods. This review concerns to the current understanding of unconsciousness, neuroanatomical and neurotransmitter bases of the last one. PMID- 24761594 TI - [Recovery of consciousness as manifestation of neuroplasticity]. AB - Prolonged impairment of consciousness is one of the most fearsome syndromes during diseases and traumas of nervous system. Traumatic brain injury (TBI) is the cause of coma with outcome in vegetative state in approximately half of cases which allows considering this etiopathogenetic form of consciousness impairment as one of the models for studying its morphofunctional nature because the pathogenesis of TBI is mostly understood. Particularly, it has been showed that in the basis of clinical picture of TBI lie, on the one hand, morphological (diffuse axonal injury of subcortical white matter, necrotic changes in cortex, thalamus) and functional (diaschisis) disturbances and on the other--processes of sanogenesis occurring within the borders of neuroplasticity. The aim of our research was to investigate clinical and neurophysiological markers of consciousness recovery in patients with vegetative state (VS) after severe TBI by comparison of clinical changes dynamics and brain bioelectrical activity. In all patients we have evaluated neurological status, Glasgow coma scale, performed registration and spectral-coherent analysis of electroencephalography and also registration and analysis of somatosensory potentials, studied motor thresholds, amplitude-time characteristics of evoked motor potentials during transcranial magnetic stimulation, repeatedly conducted MRI or CT. The electroencephalography in most of the patients revealed theta- and delta-rhythm sometimes with signs of paroxysmal activity and interhemispheric asymmetry or low-amplitude EEG. It is estimated that reliable positive changes in amplitude-time characteristics of multimodal evoked potentials, reliable decrease of motor thresholds mostly in left hemisphere and increase of motor evoked potentials amplitude are in 5-7 preceded by clinical improvement in patients with TBI. PMID- 24761595 TI - [The evidence-based neurointensive care: what's next?]. AB - The work is devoted to the analysis of modern trends of process of cognition in neurointensive care. In particular, considered the emergence and development of the method of "evidence-based medicine" in the treatment of patients with diseases and injuries of the brain. Demonstrated the positive features of the method. However, the authors are focused on the limitations of evidence-based approach, the main of which are the lack of an individualized treatment plan and the paucity of information obtained from materials of randomized controlled trials. The authors propose to combine the "evidence" data and the "classical style" of treatment, which involves individual clinical judgment based on knowledge of the pathophysiology and pathomorphology, intelligent use of technology, retrospective analysis of the beneficial and adverse effects of certain methods, creation of a special data bank of "natural" course of events, the development of individual prognostic model. The authors believe that the use of standards is more appropriate during acute illness and trauma, and the classic style is better for chronic situation. PMID- 24761596 TI - [Productive mental disorders in post-traumatic disturbances of consciousness]. AB - Productive mental disorders (PMD) are the result of pathological mental activity. Alongside with deficient disorders PMD are the main characteristics of post traumatic disturbances of consciousness. PMD can be represented by different types of excitation, mistaken judgments (including paranoidal ones, confabulations, false orientation), false perception (psychosensory, in particular, illusory and hallucinatory phenomena) and affective disorders. Occurrence and signs of PMD were studied in 417 patients with brain injuries and their consequences. It was found that occurrence of PMD in clear consciousness (in form of delirium, confusion etc) is often a sign of deterioration of cerebral and/or somatic situation and requires urgent diagnostic and therapeutic measures. In another situation with PMD being revealed during emergence from coma, they are regarded as a prognostically favorable sign and require some correction only in case of long-term (more than 1-3 weeks) course. It was determined that PMD are characterized by: (a) a gradual (after emergence from unconsciousness) aggravation and complications of clinical symptoms till achieved orientation in the surroundings with their possible partial or complete regress; (b) the highest frequency and intensity with prevailed signs of dysfunction of any of cerebral hemispheres and the lowest frequency in case of relatively symmetric bilateral and profound brain damage; b) a great variety and severity in adult patients (compared with children and elderly). Irritation of different brain structures and their disconnection as well as pathological neuroplasticity in prolonged forms--are considered the basis for PMD occurrence. PMID- 24761597 TI - [Significance of executive functioning in children with severe traumatic brain injury at different stages of consciousness recovery. Neuropsychological approach]. AB - INTRODUCTION: Severe traumatic brain injury leads to a sharp increase in the number of children with severe disabilities. Early identification of higher mental functions disorders allows to develop rehabilitation programs and to increase effectiveness of intervention. The aim of this study was to investigate the executive function in children with severe traumatic brain injury at different stages of consciousness recovery and to develop the protocol of early neuropsychological assessment and intervention. PATIENTS AND METHODS: 62 children in age from 4 to 17 years with sTBI (Glasgow Coma Scale (GCS) < or = 8) were studied. 11 of them were studied in a vegetative state and minimal consciousness state with functional magnetic resonance imaging (fMRI) and with neurobehavioral scales. 51 children were evaluated with Paediatric Luria Neuropsychological Battery test which was adapted for early stage of recovery. RESULTS AND CONCLUSIONS: The MRI data analysis has shown structural brain damage: bilateral cortical contusions of the frontal lobes and diffuse axonal injuries were the most frequent lesions. Assessment of neuropsychological outcomes has shown that the most destroyed functions at the early recovery period were executive functions, processing speed (neurodynamics of metal activity) and memory functions (modal-nonspecific memory). Early identification of higher mental functions disorders with analysis of patient's behavior by neurobehavioral scales allowed to develop a protocol of monitoring and rehabilitation methods for early stage of recovery. PMID- 24761598 TI - [Team work as the way to back up consciousness]. AB - Conception of unconsciousness after brain injury had changed considerably due to high technologies. Nowadays some patients considered by clinicians as unconscious are admitted to awareness with neurovisual techniques. Physiologic and neurophysiologic signals' combining brings forward robust quantification of patients' clinical state too. These "Third Person View" approaches leave the question of patient's experience content open because of determined stimuli paradigms. Yet patient's response pattern becomes formed not only with brain deficits but by questions-stimuli, context, and inquiring person. Rehabilitation team work is sourcing of phenomenology knowledge of patient's processes due to "First-Second Person View" approach and chance to real-time change. Restoration of consciousness comes of building-up patients' contacts with their own bodies, other persons and outward things. The basic principle of this approach is feedback assignement to any minimal movement or vegetative signal of the patient. The net of feedbacks with the patient and inter-professional ones builds up the team as Non-linear Complex System. Characteristics of "Team-Patient" system status are energy, entropy, and complexity. Impairment of consciousness as the absence of linear contact with a patient may appear together with a loss of essential functions (low energy), vegetative-visceral fits (excessive energy and low order), motor agitation (excessive energy and order), and etc. Techniques of team work are different in these cases for resulting optimization of the system condition. System complexity rise is a powerful tool to arouse apatient with impairment of consciousness. System self-organization is a key process for awareness formation. Analysis of complex communication process in patient--team system may be useful for creation of the general theory of consciousness. PMID- 24761599 TI - [Recovery of consciousness: process-oriented approach]. AB - Traditionally psychological neurorehabilitation of neurosurgical patients is provided subject to availability of clear consciousness and minimal potential to communicate verbally. Cognitive and emotional disorders, problems in social adaptation, neurotic syndromes are normally targets in such cases. We work with patients having survived severe brain damage being in different states of consciousness: vegetative state, minimal state of consciousness, mutism, confusion, posttraumatic Korsaroff syndrom. Psychologist considers recovery of consciousness as the target besides traditional tasks. Construction of communication with patient is central part of such job, where the patient remains unable to contact verbally, yet it is impossible to consider potential aphasia. This is a non-verbal "dialogue" with patient created by psychologist with gradual development and involving other people and objects of environment. Inline with modern neuroscientific achievements demonstrating ability to recognize by patients with severe brain injury (A. Owen, S. Laureys, M. Monti, M. Coleman, A. Soddu, M. Boly and others) we base upon psychological science, on psychotherapeutic approaches containing instruments inevitable to work with patients in altered states of consciousness and creation of non-verbal communication with patient (Jung, Reich, Alexander, Lowen, Keleman, Arnold and Amy Mindell, S. Tomandl, D. Boadella, A. Langle, P. Levin etc). This article will include 15 years of experience to apply Process-oriented approach by A. Mindell to recovery of consciousness of neurosurgical patients based on work with "minimal signals" (micro moves, breath, mimic reactions etc.), principle of feedback, psychosomatic resonance, empathy. PMID- 24761600 TI - [An existential-phenomenological approach to consciousness]. AB - The human beings are characterized as subjects. Their essence is understood as Person. A treatment which does not consider the subjective and the Person would not correspond their essence. For a feeling and autonomous being, consciousness plays a role but cannot fully correspond the being a person. This has a therapeutic impact on the treatment of unconscious patients and gives the treatment a specific access. Some instructions for the therapeutic application of the phenomenological-existential concept and the phenomenological attitude towards unconscious or brain traumatized patients are given. The role of consciousness for being human is briefly reflected from an existential perspective. PMID- 24761601 TI - [Brain injury: existential view to the restoration of the patient's contact with the self and the world]. AB - We present conceptual changes in psychological rehabilitation after severe brain injury. Traditional clinical approach reduces the person's inner life to level of consciousness, considers psychological processes only from the deficit point of view. We consider the experience of coming out of coma (non-existence) from the point of fundamental components of existence, i.e. anchoring with the world, with life, with self, with the future (Langle, 2003). In aspect of experience these components form the matrix of Patient-World and Patient-Self recovery phases. While working with BI patients, we have defined following phases: 0-phase: experiencing existence, the feeling "I exist here". The main target of psychotherapy is consolidation and reinforcement of the feeling of existence through the feeling of one's body boundaries (and extension), and finding resources for surviving. 1-phase: "be-able-to-exist-in-the world". The patient comes across reality of external world. We mean first of all the perception of the factual side of the world. 2-phase: loving life. The work is concentrated on the recovery of patient's ability to address himself and others so as to be able to experience emotions and live through his own wishes. 3-phase: restoration of patient's self-image and substantiation of own value. It means self-perception and selfrespect despite all the losses and deficits because of trauma. 4-phase: finding the sense. It is necessary to help the patient to make the existential change to avoid dependent position, don't consider himself as the victim of circumstances. This conception is used on different stages of recovery starting from severe disordered consciousness to socialization stage. PMID- 24761602 TI - [III-rd international conference "basic and applied aspects of mental recovery after traumatic brain injury: a multidisciplinary approach"]. PMID- 24761603 TI - [Hypoxia-responsive factor PHD2 and angiogenic diseases]. AB - Prolyl-4-hydroxylase domain (PHDs) family is one of the most important regulatory factors in hypoxic stress. PHD2 plays a critical role in cells and tissues adaptation to the low oxygen environment. Its hydroxylation activity regulates the stability and transcriptional activity of the hypoxia-inducible factor 1 (HIF 1), which is the key factor in response to hypoxic stress. Subsequently, PHD2 acts as an important factor in oxygen homeostasis. Studies have shown that PHD2, through its regulation on HIF-1, plays an important role in the post-ischemic neovascularization. Furthermore, under hypoxic condition, PHD2 also regulates other pathways that positively regulate angiogenesis factors HIF-1 independently. Moreover, recently, several evidences have also shown that PHD2 also affects tumor growth and metastasis in a tumor microenvironment. Based on these facts, PHD2 have been considered as a potential therapeutic target both in treating ischemic diseases and tumors. Here, we review the molecular regulation mechanism of PHD2 and its physiological and pathological functions. We focus on the role of PHD2 in both therapeutic angiogenesis for ischemic disease and tumor angiogenesis, and the current progress in utilizing PHD2 as a therapeutic target. PMID- 24761604 TI - [Research progress of the small molecule covalent inhibitors]. AB - Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues. PMID- 24761605 TI - [Research progress of chemistry and anti-cancer activities of natural products from Chinese Garcinia plants]. AB - Garcinia plants are one of the rich sources of natural xanthones and benzophenones which have attracted a great deal of attention from the scientists in the fields of chemistry and pharmacology. Recently, many structurally unique constituents with various bioactivities, especially anti-tumor activity, have been isolated from Garcinia plants. This concise review focused on the anti cancer activity natural products isolated from Chinese Garcinia plants, and the research finding by authors and collaborators over the past several years were cited. PMID- 24761606 TI - [An overview of effects of traditional medicine on pharmacokinetics of western medicine]. AB - Traditional medicine (herb medicine) began to prevail again over last two decades, and it is about 70% of the world population taking herb medicine as supplement or alternative medicine according to a recent survey. The consumption of herb medicine increased exponentially in Canada, Australia and Europe during last 10 years. Since concomitant administration of herbal and western medicine has become a trend, it requires paying close attention to the problem. Herb-drug interactions have been extensively investigated worldwide, and there is an increasing concern about the clinical herb-drug interaction. In this review we introduced the current progress in the herb-drug interactions including evidence based clinical studies and establishment of levels of evidence for herb-drug interaction; and in the related mechanisms including the induction and inhibition of metabolic enzymes, inhibition and induction of transport and efflux proteins, alteration of gastrointestinal functions, and alteration in renal elimination. We also analyzed both the achievements and the challenges faced in the concomitant administration of traditional Chinese medicine and western medicine. PMID- 24761607 TI - [Progress in the study of core-crosslinked polymeric micelles in drug delivery system]. AB - The core-crosslinked polymeric micelles were used as a new drug delivery system, which can decrease the premature drug release in blood circulation, improve the stability of the micelles, and effectively transport the drug into the therapy sites. Then the drug bioavailability increased further, while the side effect reduced. Most drugs were physically entrapped or chemically covalent with the polymer in the internals of micelles. Based on the various constitutions and properties of polymeric micelles as well as the special characteristics of body microenvironment, the environment-responsive or active targeting core-crosslinked micelles were designed and prepared. As a result, the drug controlled release behavior was obtained. In the present paper, the research progress of all kinds of core-crosslinked micelles which were published in recent years is introduced. Moreover, the characteristic and application prospect of these micelles in drug delivery system are analyzed and summarized. PMID- 24761608 TI - [XCT790 inhibits rat vascular smooth muscle cells proliferation through down regulating the expression of estrogen-related receptor alpha]. AB - Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in several pathological processes of cardiovascular diseases. In this study, the effects of XCT790, a potent and selective inverse agonist of estrogen-related receptor alpha (ERRalpha), on rat VSMCs proliferation and related signal pathways were investigated. The proliferative activity of VSMCs was determined by CCK-8 assay. The mRNA levels of ERRalpha, PGC-1alpha, OPN and MCAD were assayed by RT PCR. The protein levels of ERRalpha, ERK2 and p-ERK1/2 were evaluated by Western blotting. ELISA was used to assess the protein expression of VEGF. The results showed that XCT790 (5-20 micromol x L(-1)) inhibited rat VSMCs proliferation, and the expression of ERRalpha and its target genes, as well as p-ERK1/2, were also inhibited. XCT790 inhibited VSMCs proliferation in a dose-dependent manner at the dose range from 5 to 20 micromol x L(-1) and in a time-dependent manner at the dose range from 10 to 20 micromol x L(-1). These findings demonstrate that XCT790 inhibits rat VSMCs proliferation by down-regulating the gene level of ERRalpha and thus inhibiting the ERK signal pathway, suggesting that ERRalpha may be a novel potential target for therapeutic approaches to inhibit VSMCs proliferation, which plays an important role in several cardiovascular diseases. PMID- 24761610 TI - [Inhibitions of SphK1 inhibitor SKI II on cell cycle progression and cell invasion of hepatoma HepG2 cells]. AB - Sphingosine kinase 1 (SphK1) plays critical roles in cell biological functions. Here we investigated the effects of SphK1 inhibitor SKI II on hepatoma HepG2 cell cycle progression and invasion. Cell survival was determined by SRB assay, cell cycle progression was assayed by flow cytometry, the ability of cell invasion was measured by Matrigel-Transwell assay and protein expression was detected by Western blotting. The results showed that SKI II markedly inhibited HepG2 cell survival in a dose-dependent manner, induced G1 phase arrest in HepG2 cell and inhibited cell invasion. SKI II markedly decreased the expressions of G1-phase related proteins CDK2, CDK4 and Cdc2 and the levels of cell invasion-associated proteins MMP2 and MMP9. The results showed that SKI II inhibited cell cycle progression and cell invasion, implying SphK1 as a potential target for hepatoma treatment. PMID- 24761609 TI - [The synergistic effect of lidamycin and rituximab on human B cell lymphoma]. AB - This study aimed to investigate the synergistic effect of lidamycin (LDM) and rituximab on human B cell lymphoma Ramos cells. Cell proliferation was measured using MTS assay, cell apoptosis was analyzed by Annexin V-FITC/PI assay, the expression of apoptosis related proteins was analyzed by Western blotting, and the in vivo lymphoma inhibition was verified using BALB/c mice inoculated via tail vein using Ramos cells which stably expressed pEGFP-N1 plasmid. The results showed that, after the pretreatment with rituximab for 48 h, rituximab and LDM showed significantly synergistic effects on cell proliferation. Cells in combined treatment group had a higher apoptosis rate than that in LDM treatment group. Compared with the LDM treatment group, the expression of apoptosis-related proteins such as Cleaved caspase-3, Cleaved caspase-7, Cleaved caspase-9 and Cleaved PARP in combined treatment groups increased, and expression of cIAP-2 and Bcl-2 decreased. The result of in vivo experiment showed that, in the combined treatment group, the survival time of BALB/c mice was significantly longer than the mice in control group and LDM treatment group, and the degree of tumor accumulation and metastasis to lymph nodes and spleen was lower. PMID- 24761611 TI - [1H NMR based metabonomics study on the antidepressant effect of genipin in rat hippocampus]. AB - The purpose of this study is to explore depression metabolic markers in rat hippocampus and to investigate the anti-depressant effect of genipin and its mechanisms using nuclear magnetic resonance (NMR) metabonomics. Chronic unpredictable mild stress (CUMS) procedure was conducted to establish the depressive rat model. At the beginning of the third week, genipin low dose (25 mg x kg(-1)), middle dose (50 mg x kg(-1)), high dose (100 mg x kg(-1)), and venlafaxine (50 mg x kg(-1)) were given to the CUMS rats separately once daily for two weeks except control and model groups. Rat hippocampus was analyzed by 1H NMR based metabonomics after drug administration for 2 weeks. Significant differences in the metabolic profile of rat hippocampus of the CUMS treated group and the control group were observed with metabolic effects of CUMS including decreasing in glycine and N-acetylaspartate, increasing in inositol, glutamate, lactate, glutamine, taurine and alanine. Genipin showed ideal antidepressive effects at a dose of 50 mg x kg(-1) in rats, decrease of inositol, glutamate, lactate, alanine were observed, while glycine and N-acetylaspartate were increased. Important influence has been found on normal nervous system function of these significant changed metabolites, which suggests that the antidepressant effect of genipin may be played by enhancing the activity of neurons in hippocampus, repairing and improving the function of the neuron. The metabonomics approach is an effective tool for the investigation of the anti-depressant effect and pharmacologic mechanisms of genipin. PMID- 24761613 TI - [A new indole alkaloid from the stems of Brucea mollis]. AB - Eight compounds were isolated from the stems of Brucea mollis by various chromatographic techniques such as column chromatography on silica gel and Sephadex LH-20, and preparative HPLC, and their structures were elucidated as bruceolline O (1), 1-(1-beta-glucopyranosyl)-1H-indole-3-carbaldehyde (2), canthin-6-one (3), 11-hydroxycanthin-6-one (4), 9-methoxycanthin-6-one (5), 4 methoxycanthin-6-one (6), infractin (7), and beta-carboline-1-propionic acid (8). The cytotoxic activities of compounds 1-8 against HCT-8 and A549 human cell lines were determined, but none of them exhibited significant activity (IC 50 > 10 micromol x L(-1)). Among them, compound 1 is a new indole alkaloid, and compounds 2 and 5-7 were isolated from this plant for the first time. PMID- 24761612 TI - [Design, synthesis and anti-proliferative activity of novel coumarin derivatives linking Schiff base and aryl nitrogen mustard]. AB - To explore novel coumarin derivatives with more potent anti-proliferative activity, a series of novel compounds were designed and synthesized by linking Schiff base and N, N-bis (2-chloroethyl) amine pharmacophore of nitrogen mustards to the coumarin's framework. Their structures were confirmed by 1H NMR, MS and element analysis techniques. In vitro anti-proliferative activities were evaluated against HepG2, DU145 and MCF7 cell lines by the standard MTT assay. The results showed that some of the target compounds exhibited strong anti proliferative activities against selected tumor cells, and compounds 7c, 7f, 7g, 7h and 7q were better than or equal to the activities of positive control, they deserved further development. PMID- 24761614 TI - [Identification of tetracenomycin X from a marine-derived Saccharothrix sp. guided by genes sequence analysis]. AB - The crude extracts of the fermentation broth from a marine sediment-derived actinomycete strain, Saccharothrix sp. 10-10, showed significant antibacterial activities against drug-resistant pathogens. A genome-mining PCR-based experiment targeting the genes encoding key enzymes involved in the biosynthesis of secondary metabolites indicated that the strain 10-10 showed the potential to produce tetracenomycin-like compounds. Further chemical investigation of the cultures of this strain led to the identification of two antibiotics, including a tetracenomycin (Tcm) analogs, Tcm X (1), and a tomaymycin derivative, oxotomaymycin (2). Their structures were identified by spectroscopic data analysis, including UV, 1D-NMR, 2D-NMR and MS spectra. Tcm X (1) showed moderate antibacterial activities against a number of drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) pathogens, with the MIC values in the range of 32-64 microg x mL(-1). In addition, 1 also displayed significant cytotoxic activities against human cancer cell lines, including HL60 (leukemia), HepG2 (liver), and MCF-7 (breast) with the IC 50 values of 5.1, 9.7 and 18.0 micromol x L(-1), respectively. Guided by the PCR-based gene sequence analysis, Tcm X (1) and oxotomaymycin (2) were identified from the genus of Saccharothrix and their 13C NMR data were correctly assigned on the basis of 2D NMR spectroscopic data analysis for the first time. PMID- 24761615 TI - [LC-FT-ICR-MS analysis of the prototypes and metabolites in rat plasma after administration of huang-lian-jie-du decoction]. AB - To obtain chemical constituent information of rat plasma after oral administration of Huang-Lian-Jie-Du Decoction (HLJDD), a LC-FT-ICR-MS method has been established, and both positive and negative ions scan modes were include in the analysis. By comparing their retention time, high resolution mass data of HLJDD extracts, blank plasma and dosed plasma, 38 constituents, including 22 prototype compounds and 16 metabolites, were detected in rat plasma after oral administration of HLJDD. In the 22 prototype compounds, 16 constituents were determined unambiguously by comparing with references. In the analysis of metabolites, phase II reactions like glucuronidation and sulfation were the major biotransformation pathways of HLJDD. M11 was observed as the only phase I metabolite in present experiment. The results will be beneficial for the further pharmacokinetics and pharmacological evaluations of HLJDD. PMID- 24761616 TI - [Identification of bufadienolides profiling in cinobufacino by HPLC-DAD-FT-ICR-MS method]. AB - Cinobufacino injection is a significant anti-tumor medicine for the treatment of various tumors in clinic, which was made from water extraction of the skin of Bufo bufo gargarizans. In present paper, HPLC-DAD-FT-ICR-MS method was used to identify the major bufadienolides in cinobufacino for the first time. Solid-phase extraction with dichloromethane and silica was used to enrich the total bufadienolides in cinobufacino. Based on the UV and high resolution MS/MS data, 33 bufadienolides were analyzed and characterized. Among them, eight compounds were identified by comparing with standard references unambiguously. This study elucidated the major bufadienolides in cinobufacino, which provided material foundation of cinobufacino and will be benefit for the further pharmacological research. PMID- 24761617 TI - [Quantitative determination of bosentan by proton nuclear magnetic resonance with internal standard method]. AB - The study aims to establish a quantitative nuclear magnetic resonance (QNMR) method for the determination of the absolute content of bosentan. Proton nuclear magnetic resonance spectroscopy [1H NMR] spectra were obtained in CDCl3 with the internal standard dimethyl terephthalate and zg30 pulse sequence by using a Bruker AVANCE II 400 spectrometer. The content of bosentan is determined with QNMR in comparison with the result obtained by mass balance method. The result is 96.25% by QNMR and 96.54% by mass balance method. A rapid and accurate QNMR method has been established for the quantitative determination of the absolute content of bosentan. The study provides a new way for the quality control and calibration of a new reference standard material, it could be the complementary with the mass balance method for the assay of standard reference. PMID- 24761618 TI - [Enhancers on the transmembrane transport of chlorogenic acid]. AB - To investigate the influence of the difference enhancers on the transport mechanism of chlorogenic acid (CGA) across Caco-2 cells model, a RP-HPLC method was adopted to detect the concentrations of CGA. At the concentrations of 20 to 80 microg x mL(-1), the difference of absorption rate constants (K(a)) was not statistically significant. At the concentrations of 40 and 20 microg x mL(-1), the ratios of apparent permeability coefficients (P(app)) of the apical to basolateral and the basolateral to apical were 1.14 and 1.18, respectively. With the effect of enhancers K(a) and P(app) increased, the absorption half-life (T1/2) decreased. CGA passed through the Caco-2 cell membrane mainly by passive transport. It showed that monocarboxylic acid transporter (MCT) could be involved in the across membrane transport process of CGA. Borneol had no effect on the cell membrane transport processes. The order of increasing absorption of CGA caused by the enhancers was sodium lauryl sulphate > sodium taurocholate > carbomer. PMID- 24761619 TI - [Repeated injection of mitoxantrone containing thermosensitive liposomes in rat induced ABC phenomenon]. AB - To investigate whether accelerated blood clearance (ABC) phenomenon could be induced after repeated injection of mitoxantrone thermosensitive liposomes, LC MS/MS and enzyme linked immunosorbent assay (ELISA) were used to measure the concentration of mitoxantrone and the anti-polyethylene glycol (PEG) IgM levels in rat plasma, separately. The drug was rapidly cleared away after the second administration. The anti-PEG IgM was detected after the first dose which was neutralized quickly after the second dose. It is proved that repeated administration of mitoxantrone thermosensitive liposomes in rat caused the ABC phenomenon. PMID- 24761620 TI - [Identification of radix et rhizoma clematidis and its adulterants using DNA barcoding]. AB - This study provides the candidate sequences in the identification of Radix et Rhizoma Clematidis and its adulterants using DNA barcoding. We amplified and sequenced the region psbA-trnH, with the data of 284 sequences from GenBank, the differential intra- and inter-specific divergences, genetic distance, barcoding gap were used to evaluate five barcodes, and the identification efficiency was assessed using BLAST1 and Nearest Distance methods. The results showed that psbA trnH barcodes performed high identification efficiency and inter-specific divergences among the five different DNA barcodes. Analysis of the barcoding gap and NJ tree showed psbA-trnH was superior to other barcodes. Based on the identification and PCR amplification efficiency, psbA-trnH can be the ideal barcode to identify Radix et Rhizoma Clematidis and its adulterants accurately. PMID- 24761621 TI - [Effect of Tibetan medicine zuotai on the activity, protein and mRNA expression of CYP1A2 and NAT2]. AB - To study the effect of Tibetan medicine Zuotai on the activity, protein and mRNA expression of CYP1A2 and NAT2, three different doses (1.2, 3.8 and 12 mg x kg( 1)) of Zuotai were administrated orally to rats once a day or once daily for twelve days, separately. Rats were administrated orally caffeine (CF) on the second day after Zuotai administration, and the urine concentration of CF metabolite 5-acetylamino-6-formylamino-3-methyl-uracil (AFMU), 1-methyluric acid (1U), 1-methylxanthine (1X), 1, 7-dimethylxanthine (17U) at 5 h after study drug administration was determined by RP-HPLC. The activity of CYP1A2 and NAT2 was evaluated by the ratio of metabolites (AFMU+1X+1U)/17U and the ratio of AFMU/(AFMU+1X+1U), respectively. The protein and mRNA expression of CYP1A2 and NAT2 were determined by ELISA and RT-PCR method, respectively. After single administration of Zuotai 3.8 mg x kg(-1) and repeated administration of Zuotai 3.8 and 12 mg x kg(-1), the activity of CYP1A2 and NAT2 decreased significantly compared with control group and there was no significant difference between other dose group and control group. The protein expression of CYP1A2 was significant lower than that in control group after repeated administration of Zuotai 12 mg x kg(-1), and the mRNA expression of CYP1A2 decreased significantly compared with that of control group after single administration of Zuotai 3.8 mg x kg(-1) and repeated admistration of Zuotai 12 mg x kg(-1), separately. The protein expression of NAT2 decreased significantly compared with that of control group after single and repeated administration of Zuotai 3.8 mg x kg(-1), respectively, and the mRNA expression of CYP1A2 decreased significantly compared with control group after single administration of Zuotai 3.8 mg x kg(-1). This study found that Tibetan medicine Zuotai had significant effect on the activity, protein and mRNA expression of CYP1A2 and NAT2. PMID- 24761622 TI - [Action of Euphorbia humifusa effective fraction on membrane biosynthesis and the gene expression of proteases MEP and SUB of Trichophyton rubrum]. AB - This study is to investigate the effect of Euphorbia humifusa effective fraction (EHEF) on the CYP51 enzyme activity, the lanosterol content and the MEP, SUB gene expression of Trichophyton rubrum. Trichophyton rubrum was treated by EHEF for 7 days at 26 degrees C. The activity of CYP51 enzyme of Trichophyton rubrum in the cell membrane was determined by using ELISA kit, and the lanosterol content was investigated by using high performance liquid chromatography (HPLC), and the MEP, SUB gene expression of Trichophyton rubrum was detected with the reverse transcription polymerase chain reaction (RT-PCR) method. Results showed that EHEF can decrease the membrane CYP51 enzyme activity, and it also can accumulate the fungal lanosterol in a dose-dependent manner, and it also can decrease the gene expression of MEP and SUB. The antifungal mechanism of EHEF may be related to the inhibition on CYP51 enzyme activity, and to the effects on fungal cell membrane ergosterol biosynthesis. It may also play an antifungal effect by inhibiting the MEP, SUB gene expression of fungal proteases. PMID- 24761623 TI - [Determination of sulfur dioxide residues in sulfur fumigated Chinese herbs with headspace gas chromatography]. AB - This paper aims to establish a method for the determination of sulfur dioxide in sulfur fumigation Chinese herbs. Sample powder and hydrochloric acid solution were isolated by paraffin layer in order to avoid early reactions, with the generation of sulfur dioxide, headspace with airtight needle was used to transfer sulfur dioxide into gas chromatograph, and detected with thermal conductivity detector. The analytical performance was demonstrated by the analysis of 12 herbs, spiked at four concentration levels. In general, the recoveries ranging from 70% to 110%, with relative standard deviations (RSDs) within 15%, were obtained. The limit of detection (LOD) was below 10 mg x kg(-1). Standard addition can be used for low recovery samples. The method is simple, less time consuming, specific and sensitive. Methods comparison revealed that gas chromatography is better than traditional titration in terms of method operability, accuracy and specificity, showing good application value. PMID- 24761624 TI - [Overview and prospect of syndrome differentiation of hypertension in traditional Chinese medicine]. AB - This article is to overview the literature of syndrome differentiation of traditional Chinese medicine on hypertension. According to the theory of disease in combination with syndrome, we concluded syndrome types of hypertension in four aspects, including national standards, industry standards, teaching standards and personal experience. Meanwhile, in order to provide new methods and approaches for normalized research, we integrated modern testing methods and statistical methods to analyze syndrome differentiation for the treatment of hypertension. PMID- 24761625 TI - [Advances on chemical constituents and pharmacological activity of genus Scilla]. AB - The genus Scilla consists of 90 species widely distributed in Europe, Asia and Africa, one and its variant of which can be found in China Some species of the genus have been used in traditional medicine to treat various diseases related to inflammation and pain. Phytochemical studies have demonstrated the presence of triterpene and tritepenoid saponins derived from eucosterol, bufadienolides, alkaloids, stilbenoids and lignan in the plants of this genus. Various bioactivities such as antimicrobial, anti-inflammatory, antioxidant, anti-tumor and glycosidase inhibitory activities, have been reported. In this review, the advance of chemical constituents and pharmacological activities of the Scilla species are summarized for further development and utilization of the resource. PMID- 24761626 TI - [Analysis and discussion about current development of relevant studies on "traditional Chinese medicine components"]. AB - As traditional Chinese medicine components have become a hotspot in the field of traditional Chinese medicine study, they have followed a development trend of diversity and false identification. In studies on a new modem product, we shall encourage the diversified development mode, but avoid the false concept identification of traditional Chinese medicine components. In this paper, by analyzing the current development of traditional Chinese medicine components and problems, we discussed the standardization of traditional Chinese medicine components, with the aim of reducing and avoiding the situations to study non traditional Chinese medicine components as traditional Chinese medicine components. PMID- 24761627 TI - [Advance in studies on effective components in wheat bran and their pharmacological activities]. AB - Wheat bran, as the testa of wheat, has a long history of medication. Modern studies have discovered that wheat bran contains dietary fiber, phenolic compounds, proteins, vitamins, minerals and many other compounds, and boasts wide pharmacological activities such as blood glucose reduction, hypertension reduction, lipid reduction, anti-oxidation, anti-bacteria, anti-inflammatory, antivirus, prevention of colon cancer and mutations, immunomodulation and adsorption of heavy metals. With great development and utilization values, wheat bran has long attracted wide attention from Chinese and foreign scholars. The paper summarizes the latest advance in domestic and foreign studies on effective components in wheat bran and their pharmacological effect, and gives a brief introduction of the limiting factors in the comprehensive development and utilization of wheat bran, in order to provide new preference for the development and utilization of abundant wheat bran resources in China. PMID- 24761628 TI - [Research progress of traditional mineral Chinese medicine]. AB - Traditional mineral Chinese medicine is a characteristic part of Chinese medicine, in the development of traditional Chinese medicine has its unique role. With the development of science and technology and the increase of the medical level, traditional mineral medicine research is gradually thorough and wide ranging. In recent years, traditional mineral Chinese medicine research mainly includes the physical properties of mineral medicine, structure, chemical composition, pharmacology and treatment mechanism research. The above several aspects of research in the mineral medicine has important practical and theoretical significance. The above several aspects of research status and the problems existing in the research were briefly summarized and reviewed in this paper, and its development were discussed, to provide reference for further studies in the future. PMID- 24761629 TI - [Expression analyses of BcUGT3 and BcUGT6, and their in vitro expression in Escherichia coli]. AB - The tissue-specific and MeJA-induced transcriptional levels of BcUGT3 and BcUGT6 in Bupleurum chinense were analyzed in the present study. The transcriptional levels of BcUGT3 in root, leaf, flower and fruit were similar and they all were higher than those in stem. The transcriptional level of BcUGT6 was the highest in leaf and the lowest in flower among in all tested tissues. With non-treated adventitious roots as control, BcUGT6's transcriptional levels were elevated to nearly 2 folds for 2 h, 8 h, 24 h, 2 d and 4 d in MeJA-treated adventitious roots of B. chinense. It showed that the transcriptional level of BcUGT6 was slightly affected by MeJA. While, BcUGT3's transcriptional levels were gradually elevated, and till 4 d after MeJA treatment, the expression level was about 7 folds than that of non-treated control. Using pET-28a (+), the expressions of two genes was investigated. Induced by IPTG, the target proteins were expressed in E. coli and then purified. All the results obtained in the present study will be helpful for follow-up bio-function analysis of BcUGT3 and BcUGT6. PMID- 24761630 TI - [Study of production of sesquiterpenes of Aquilaria senensis stimulated by Lasiodiplodia theobromae]. AB - To investigate the mechanism of agarwood formation in Aquilaria sinensis induced by Lasiodiplodia theobromae, the fermentation liquor of L. theobromae was analyzed qualitatively and quantitatively by gas chromatography-mass spectrometry (GC-MS). JAs were detected in the fermentation liquor. The effect of the fermentation liquor on the abundance of sesquiterpenes in the callus of A. sinensis was analyzed by solid phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS). And the fermentation liquor stimulated alpha-guaiene, alpha-humulene and delta-guaiene biosynthesis in calli. It was inferred that L. theobromae produced JAs, which resulted in a significant increase of sesquiterpenes in A. sinensis. PMID- 24761631 TI - [Effects of agarwood formation induced by Fusarium sp. A2 on distribution and community composition of endophytic fungi in leaves of Aquilaria sinensis]. AB - The aim of the paper is to observe the distribution of the endophytic fungi in leaves of Aquilaria sinensis by using permanent paraffin-cut section, optical microscope photography and histochemistry. Total DNA was extracted with modified CTAB method and rDNA ITS regions of plant and endophytic fungi were amplified with eukaryotic universal primers. The rDNA ITS amplicon was characterized by RFLP analysis, sequencing of rDNA ITS library and phylogenetic analyses using PAUP by maximum parsimony. Fusarium sp. A2 was used to induce the formation of resinous in A. sinensis trees. As a result, endophytic fungi mainly distributed in spongy and phloem in leaf. Endophytic fungi distributed in the phloem in agarwood-producing tree and had a relatively high abundance. Phoma sp. and Collectrotrichum sp. were the absolute advantage species in the leaf tissues of non-resinous and agarwood-producing tree, respectively. Collectrotrichum sp. was the only fungal species detected both in the two types of A. sinensis with different levels of abundance. The culture-independent molecular method can be used to identify fungal species directly and rapidly from the plant tissues. Endophytic fungal communities in non-resinous and agarwood-producing A. sinensis leaf tissues were quite different. PMID- 24761632 TI - [Comparative study on distribution of endophytic fungi in Eucommia barks from different habitats]. AB - A total of 152 strains of endophytic fungi were isolated from the barks of Eucommia ulmoides in three regions (Lueyang country, Zunyi country, Cili country). Based on morphological characteristics and analysis of ITS sequences, these strains were identified into 8 genera. Thereinto Phomopsis, Diaporthe and Alternaria were common genera to Eucommia barks from different sites. But the dominant genus was different: Alternaria was the dominant genus in the barks from Cili country, and Phomopsis was the dominant genus from Zunyi country, then Diaporthe was the one from Lueyang country. According to the similarity coefficient, the composition of the endophytic fungi was distinctly different between the barks from three sites. The diversity and species richness in Lueyang country and Cili country were found higher than those in Zunyi country. The evenness of endophytic fungi was 0.936 5 in Lueyang county, which was higher than 0.737 1 or 0.641 0 in Cili county or Zunyi county, respectively. After phylogenic analysis and calculating the genetic distances of typical strains belong to Phomopsis and its perfect stage--Diaporthe, there was very high genetic diversity in the two genera from our study. In conclusion, the community structure and diversity of endophytic fungi were significant different in Eucommia barks from the three habitats. PMID- 24761633 TI - [Cloning and analysis of reverse transcriptase(RT) of Ty1-copia retrotransposons in Dendrobium officinale]. AB - Using universal primer Ty1-copia retrotransposon RT,43 Ty1-copia like retrotransposon RT with high heterogeneity, stop codon mutation and frameshift mutation were amplified by PCR from genomic DNA of Zhejiang Lin'an (C15) and Yunnan Guangnan (A39) of Dendrobium officinale. The length of these sequences varied from 260 to 266 bp, and was rich in AT and consistency ranged from 47.1% to 97.7%. Different c/s-acting regulatory elements induced by low temperature, heat, light, all kinds of plant growth regulating substances and the starting transcription signals, corresponding to CAAT box, TATA box conserved sequences and some other regulatory elements. When being translated into amino acids, ten sequences presented stop codon mutation, five sequences presented frameshift mutation, and thirty-seven sequences presented conserved sequence "SLYGKQ" mutation. Six categories were identified through phylogenic analysis after alignment analyses of their amino acid sequences, and with other plants (eg. Triticum aestivum, Eleocharis quinqueflora) having high homology, which indicated that horizontal transmission of retrotransposon occurred among the plants in the past. PMID- 24761634 TI - [Study on preparation of salvianolic acid phospholipid compound]. AB - To prepare salvianolic acid phospholipid compound. With the compound of salvianolic acids and soybean phospholipid as the index, mono-factor experiment and orthogonal design experiment were conducted to screen its technical parameters. According to the results, the optimal preparation conditions of salvianolic acid phospholipid compound were that THF were taken as the reaction solvent, the concentration time was 3 h, the reactant concentration was 5 g x L( 1), the mass ratio of salvianolic acids and phospholipid was 1: 1.5, and the reaction temperature was 40 degrees C. The oil/water partition coefficient of the prepared salvianolic acid phospholipid compound significant increased in water and buffers with different pH values. The results of phase analysis such as DSC, XRD and FTIR indicated that salvianolic acids existed in phospholipid in an amorphous state. PMID- 24761635 TI - [Preparation and optimization of zhitong micro-emulsion formula]. AB - To prepare Zhitong micro-emulsion in this study, with the empirical formula of Zhitong preparation as the model medicine, the essential oil in the formula as the oil phase, and the water decoction as the water phase. The types of surfactant and co-surfactant were investigated. The changes in micro-emulsion conductivity and construction, the water percentage in the micro-emulsion system, the changing curve of conductivity and the fine pseudo-ternary phase diagram of micro-emulsion were drawn to determine the surfactant-co-surfactant mass ratio (K(m)). Subsequently, the D-mixture design was used to optimize Zhitong Micro emulsion formula, with particle size and surface tension of micro-emulsion as the indexes. Finally, efforts were made to determine part of physical parameters of Zhitong micro-emulsion and preliminarily detect its stability. The results showed that the micro-emulsion was optimal with the EL-35-tween 20 ratio of 4:1 in surfactant, whereas the absolute ethyl alcohol was recommended as the co surfactant. The ratio between surfactant and co-surfactant (K(m)) was 1.5. The finalized micro-emulsion formula contains 12% surfactant, 8% co-surfactant, 70% 1 g x mL(-1) water decoction and 8% oil. The results of the preliminary stability experiment showed a better stability of Zhitong micro-emulsion. PMID- 24761636 TI - [Study on simplification of extraction kinetics model and adaptability of total flavonoids model of Scutellariae radix]. AB - Because of irregular shapes of Chinese herbal pieces, we simplified the previously deduced general extraction kinetic model for TCMs, and integrated particle diameters of Chinese herbs that had been hard to be determined in the final parameter "a". The reduction of the direct determination of particle diameters of Chinese herbs was conducive to increase the accuracy of the model, expand the application scope of the model, and get closer to the actual production conditions. Finally, a simplified model was established, with its corresponding experimental methods and data processing methods determined. With total flavonoids in Scutellariae Radix as the determination index, we conducted a study on the adaptability of total flavonoids extracted from Scutellariae Radix with the water decoction method in the model. The results showed a good linear correlation among the natural logarithm value of the mass concentration of total flavonoids in Scutellariae Radix, the time and the changes in the natural logarithm of solvent multiple. Through calculating and fitting, efforts were made to establish the kinetic model of extracting total flavonoids from Scutellariae Radix with the water decoction method, and verify the model, with a good degree of fitting and deviation within the range of the industrial production requirements. This indicated that the model established by the method has a good adaptability. PMID- 24761637 TI - [Study on preparation of sagittatoside B with epimedin B converted from cellulase]. AB - To prepare sagittatoside B with epimedin B Hydrolyzed from cellulase. With the conversion ratio as the index, the effects of pH value, temperature, reaction time, dosage of enzyme and concentration of substrates on the conversion ratio were detected. L9 (3(4)) orthogonal design was adopted to optimize the preparation process. Hydrolyzed products were identified by MS, 1H-NMR, and 13C NMR. The results showed that the optimum reaction conditions for the enzymatic hydrolysis were that the temperature was 50 degrees C, the reaction medium was pH 5.6 acetic acid-sodium acetate buffer solution, the concentration of substrates was 20 g x L(-1), the mass ratio between enzyme and substrate was 3: 5, and the relative molecular mass of the reaction product was 646.23. NMR data proved that the product was sagittatoside B. The process is simple and reliable under mild reaction conditions, thus suitable for industrial production. PMID- 24761638 TI - [Determination of dissolution of liuwei dihuang concentrated pills based on multi index components]. AB - With the content of gallic acid, loganin, paeoniflorin and paeonol as the indexes, to screen out dissolution determination conditions, establish the dissolution determination method for multi-index components in Liuwei Dihuang concentrated pills, calculate and map the accumulative dissolution curve, and then compare the dissolution of products from different pharmaceutical factories through the similarity factor (f2). According to the results, the optimum dissolution determination conditions were the paddle method, with 250 mL 0.1 mol x L(-1) hydrochloric acid as the dissolution medium, and a rotation rate of 100 r x min(-1). The similarity factor values (f2) of the dissolution curves of the four main components of Liuwei Dihuang concentrated pills from different pharmaceutical factories were mostly less than 50. This demonstrated a significant difference in the dissolution of Liuwei Dihuang concentrated pills from different pharmaceutical factories, and provided scientific basis for improving the equality evaluation of Liuwei Dihuang concentrated pills. PMID- 24761639 TI - [A new flavone C-glycoside from leaves of Lophatherum gracile]. AB - Several kinds of column chromatography method were used to investigate the chemical constituents of the leaves of Lophatherum gracile. The structures of the isolated compounds were identified based on their physicochemical properties and spectral data. A new flavone C-glycoside was isolated and its structure was identified as 3'-methoxyl-luteolin 6-C-beta-D-galactopyranosiduronic acid (1 --> 2) -alpha-L-arabinopyranoside (1). PMID- 24761640 TI - [Chemical constituents from tubers of Cremastra appendiculata]. AB - Compounds were isolated through various chromatographic techniques and their structures were identified by spectroscopic data analysis and comparison with those reported in the literatures. Thirteen compounds were obtained from the petroleum ether and ethyl acetate extracts. Their structures were identified as 4,4'-dimethoxy-9,9', 10,10'-tetrahydro-(1, 1'-biphenanthrene) -2, 2', 7, 7' tetrol (1), 4, 4', 7, 7'-tetrahydroxy -2,2'-dimethoxy-1, 1'-biphenanthrene (2), 3, 5-dihydroxy-2, 4-dimethoxyphenanthrene (3), physcion (4), chrysophanol (5), emodin (6), genkwanin (7), quercetin (8), quercetin 3'-O-beta-D-glucopyranoside (9), 3-methoxy-4-hydroxy phenylethanol (10), syringic acid (11), vanillin (12), and p-hydroxybenzaldehyde (13), respectively. Compounds 1-3 and 5-12 are reported from this genus for the first time. PMID- 24761641 TI - [Chemical constituents from Chenopodium ambrosioides]. AB - Twelve compounds were isolated from the herb of Chenopodium ambrosioides, and their structures were identified by spectroscopic methods as kaempferol-7-O-alpha L-rhamnopyranoside (1), kaempferol-3,7-di-O-alpha-L-rhamnopyranoside (2), patuletin (3), quercetin-7-O-alpha-L-rhamnopyranoside (4), grasshopper ketone (5), 4-hydroxy-4-methyl-2-cyclohexen-1-one (6), syringaresinol (7), benzyl beta-D glucopyranoside (8), dendranthemoside B (9), N-trans-feruloyl tyramine (10), N trans-feruloyl 4'-O-methyldopamine (11), and 4-hydroxy-N-[2-(4-hydroxyphenyl) ethyl] benzamide (12). Among them,compounds 3, 6-8,10, and 12 were isolated from the genus Chenopodium for the first time, and compounds 2-12 were isolated from this plant for the first time. PMID- 24761642 TI - [Chemical constituents from leaves of Ilex latifolia]. AB - Nine compounds were isolated from the leaves of Ilex latifolia. Their structures were respectively identified as 5-hydroxy-6, 7, 8, 4'-tetramethoxyflavone (1), tangeretin (2), nobiletin (3), 5-hydroxy-6, 7, 8, 3', 4'-pentamethoxyflavone (4), 5, 6, 7, 8, 4'-pentamethoxyflavonol (5), 5, 6, 7, 8, 3', 4'-hexamethoxy-flavonol (6), 5-hydroxy-3', 4', 7-trimethoxyflavanone (7), soyacerebroside I (8), and soyacerebroside II (9) by their physicochemical properties and spectroscopic data Compounds 1-9 were isolated from this plant for the first time. PMID- 24761643 TI - [Analysis of monosaccharide compositions in polysaccharides from exopleura of Ginkgo biloba]. AB - A high-performance liquid chromatography method of pre-column derivatization with 1-phenyl-3-methyl-5 -pyrazolone (PMP) has been established for determination of 6 kinds of monosaccharides simultaneously. A special Agilent HC-C18 column (4. 6 mm x 250 mm, 5 microm), optimized for the separation of PMP derivatives, was used at ambient temperature of 40 degrees C. The PMP derivatives elution was performed with a mixture of 0.1 mol x L(-1) phosphate buffer (pH 6. 8) and acetonitrile in a ratio of 84: 16 at a flow rate of 1 mL x min(-1), and UV absorbance of the effluent was monitored at 245 nm. The results showed that the polysaccharides from exopleura of Ginkgo biloba were acidic heteropolysaccharides mainly containing mannose, rhamnose, D-galacturonic acid, glucose, galactose, arabinose, with the molar ratio of 0.032: 0.14: 0.296: 0.403:0.106: 0.046. PMID- 24761644 TI - [A NIR qualitative and quantitative model of 8 kinds of carbonate-containing mineral Chinese medicines]. AB - The aim of this paper is to apply near infrared spectroscopy techniques to construct a rapid identification method for 8 kinds of mineral Chinese Medicines containing carbonates. The qualitative model using clustering analysis method in OPUS software can identify accurately 8 kinds of carbonate-containing mineral Chinese medicines. The near-infrared quantitative model was established by using partial least squares method (PLS) for 7 mineral Chinese Medicines in which main component is calcium carbonate. Compared with the results by EDTA titration, the established quantitative analysis model for calcium carbonate content showed a good prediction result that when the content is between 47.61% -99.17%, the average relative deviation of the prediction result is 0.24% and the average recovery rate was 100.3%. The results also showed that the model using near infrared spectroscopy can get not only a rapid identification of the 8 mineral Chinese medicines containing carbonates, but also an accurate and reliabe content determination of calcium carbonate for the 7 mineral Chinese medicines which contain the component. PMID- 24761645 TI - [A high throughput coupled with high performance liquid chromatography-tandem mass spectrometry method for determination of aflatoxin B1, B2, G1, G2 in 10 traditional Chinese medicines]. AB - As the dilution procedure was applied, a simple, rapid and cost-effective high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of aflatoxin B1, B2, G1, and G2 was successfully by performed in a total 83 samples of 10 traditional Chinese medicines (TCMs), which were collected from 5 different hospital pharmacies and 5 different medical stores in Guangzhou city. Matrix effects of these 10 TCMs were ranged from 80.23% to 115.5% in low, intermediate and high concentration levels, indicating that the negative effect was overcome in this study. Meanwhile, the analysis method was proved to be stable and reliable during the whole analysis using Semen Armeniacae Amarum spiked 3 concentration levels of standard solution as quality control samples and the RSD < 6.6% was obtained. The contamination levels of 83 investigated samples were 13.89% and 17.02% in hospital pharmacies and medical stores, respectively. The result was presented to provide relevant reference and supplement to those researchers in TCMs analysis and screening. PMID- 24761646 TI - [Study on efficacy of liujunzi decoction combined with zuojin pills in treating acute radioactive duodenitis and their mechanism]. AB - OBJECTIVE: To evaluate the therapeutic effect of Liujunzi decoction combined with Zuojin pills in treating the radioactive duodenitis and their mechanism, and compare with clinical routine acid suppressants combined with mucous membrane protective preparations to study the mechanism of their efficacy. METHOD: According to the study of Williams J P and characteristics of duodenitis, and by reference to the radiation enteritis modeling standard, we took the lead in establishing the mouse radioactive duodenal injury model. The model mice were randomly divided into the control group (n = 26), traditional Chinese medicine (TCM) group (n = 16) and the western medicine (oral administration with famotidine 0.5 mL + almagate suspension 0.3 mL per mouse, once a day) group (n = 16). After the standard administrating, such objective indexes as general condition, weight, changes in health score, pathology and expression of inflammatory factors were observed to evaluate the efficacy. RESULT: The radioactive duodenitis model of mice was successfully established with 12 Gy. Mice in the control group suffered from weight loss, anorexia, low fluid intake, loose stools, and occasionally mucous bloody stool, poor spirit, dim fur, lack of exercise and arch back. Mice in drug intervention groups were generally better than those in the pure irradiation group. The IL-6, IL-1beta, TNF-alpha mRNA expressions in spleen and mesenteric lymph node tissues in TCM and western medicine groups showed a declining trend compared with the control group. Their concentrations in peripheral blood serum also slightly changed. The TCM group revealed notable advantage in reducing inflammatory factors. The microscopic observation showed that a better mucosa repair in intervention groups than the pure irradiation group. The improved Chiu's scoring method showed a statistical significance in the difference between TCM and western medicine groups (P < 0.05). CONCLUSION: Liujunzi decoction combined with Zuojin pills could treat acute radiation enteritis, regulate organic immunity, and inhibit acute injury, promote local tissue repair, with the potential to resist such adverse effects as radiation intestinal fibrosis. The regulation of inflammatory factor release is one of efficacy generation mechanisms. PMID- 24761647 TI - [Effect of formula of removing both phlegm and blood stasis on inflammatory reaction in Chinese mini-swine with coronary atherosclerosis]. AB - OBJECTIVE: To observe the effect of formula of removing both phlegm and blood stasis (TYTZ) in inhibiting the inflammatory reaction in Chinese mini-swine with coronary atherosclerosis. METHOD: Totally 36 Chinese mini-swine were randomly divided to six groups: the normal control group, the model group, the Shujiangzhi group and TYTZ groups with does of 2.0, 1.0 and 0.5 g x kg(-1), and six each in every group. Except for the normal control group, all of other groups were fed with high-fat diet for 2 weeks. Interventional balloons are adopted to injure their left anterior descending artery endothelium. After the operation, they were fed with high-fat diet for 8 weeks to prepare the coronary atherosclerosis model. In the 8th week after the operation and administration, the intravascular ultrasound was adopted to observe the coronary artery plaque burden of each group and the pathological morphology of coronary artery. Such inflammatory factors as high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were detected by ELISA. The expression of NF-kappaB p65 nuclear translocation was observed by the immunohistochemical method. RESULT: Compared with the normal control group, the model group showed significant increase in the coronary artery plaque burden at the end of the experiment (P < 0.01), notably abnormal structural changes in atherosclerotic vascular tissues, luminal stenosis, a large number of foam cells and inflammatory cell infiltration, remarkable growth of hs-CRP, TNF-alpha and IL-6 levels (P < 0.01). The immunohistochemical staining also showed the significant increase in the NF kappaB p65 nuclear translocation of coronary artery of Chinese mini-swine in the model group. Compared with the model group, TYTZ could significantly attenuate atherosclerotic plaque burden (P < 0.01), inhibit the coronary luminal stenosis, reduce inflammatory cell infiltration, decrease such inflammatory cell factors as hs-CRP, TNF-alpha and IL-6 in serum, and inhibit the NF-kappaB p65 nuclear translocation of coronary artery (P < 0.05 or P < 0.01). CONCLUSION: TYTZ can reduce the downstream inflammatory reaction by controlling NF-kappaB p65 nuclear translocation, so as to inhibit the occurrence and development of coronary atherosclerotic plaque in Chinese mini-swine. PMID- 24761648 TI - [Experimental study on Dendrobium candidum polysaccharides on promotion of hair growth]. AB - OBJECTIVE: To observe the effect and mechanism of Dendrobium candidum polysaccharides (DCP) in promoting hair growth, in order to lay a foundation for the development and utilization of D. candidum. METHOD: The water-extraction and alcohol-precipitation method was adopted to extract DCP, and the phenol-sulphuric acid method was used to determine its content. Thirty C57BL6J mice were collected to establish the hair loss model with hair removal cream. They were randomly divided into the control group, the positive control group and the DCP group, and given 0.2 mL of ultra-pure water, minoxidil tincture and DCP (5.0 g x L(-1)) 21 days. The mice hair growth scoring standard was adopted to evaluate the hair growth of C57BL/6J mice at 7, 14 d. The hairs in unit hair-losing areas of treated C57BL/6J mice at 21 d were weighed to evaluate the effect of DCP on the promotion of hair growth. MTT assay and RT-PCR method were used to evaluate the effect of DCP on the proliferatin of HaCaT cells and the mRNA expression of VEGF in HaCaT cells. RESULT: The extraction percent of DCP was 29.87%, and its content was 79.65%. The average scores for the hair growth and weight of C57BL/6J mice of DCP group were much higher than the control group. The survival rate and mRNA expression of VEGF of HaCaT cells were much higher than the control group. CONCLUSION: DCP has the effect in promoting hair growth. Its mechanism may be related to the up-regulation of the mRNA expression of VEGF. PMID- 24761649 TI - [Effect of sodium houttuyfonate in enhancing imipenem's activity against Pseudomonas aeruginosa biofilms]. AB - OBJECTIVE: To investigate the resistant effect of houttuyfonate sodium (SH) combined with imipenem (IMP) against Pseudomonas aeruginosa (Pa) biofilms. METHOD: The two-fold dilution method was used to examine the minimum inhibitory concentration (MIC) of the tested drug. The crystal violet staining was applied to detect the effect of the combination of 1/2MIC, 1MIC, 2MIC of SH, single IMP, 1/2MIC of SH and IMP of various concentrations on the clearance rate of adherent bacteria, growth of biofilms and alginate production. Fluorescein diacetate (FDA) propidium iodide (PI) doubling staining assay was employed to observe the bacterial viability and morphological changes after membrane dispersion of each drug group. RESULT: Sodium houttuyfonate could enhance the effect of IMP against pseudomonas aeruginosa biofilms. Particularly, the combination group with the concentration of 2MIC showed the highest effect, with P < 0.001 compared with the negative control group. The above results were proved by the bacterial viability and biofilm morphology under fluorescence microscope. CONCLUSION: After being combined with imipenem, sodium houttuyfonate shows a higher effect against biofilms. It is expected that the combination of the two drugs could improve the clinical efficacy of associated infections. PMID- 24761650 TI - [Effect of formula of removing both phlegm and blood stasis in improving hemorheology and blood fat of mini-swine with coronary heart disease of phlegm stasis cementation syndrome]. AB - OBJECTIVE: To observe effect of formula of removing both phlegm and blood stasis (TYTZ) in improving hemorheology and blood fat of mini-swine with coronary heart disease of phlegm-stasis cementation syndrome. METHOD: Thirty-six Chinese mini swine were randomly divided to six groups: the normal control group, the model group, the Shujiangzhi group and TYTZ groups with doses of 2.0, 1.0 and 0.5 g x kg(-1), with six mice in each group. Except for the normal control group, all of other groups were fed with high-fat diet for 2 weeks. Interventional balloons are adopted to injure their left anterior descending artery endothelium. After the operation, they were fed with high-fat diet for 8 weeks to prepare the coronary heart disease model of phlegm-stasis cementation syndrome. In the 8th week after the operation and administration, the changes in hemorheological parameters, serum lipid level, myocardial ischemia level and range were observed. RESULT: Compared with the normal control group, the model group showed significant increase in serum TC, TG, LDL-C and VLDL-C levels (P < 0.01), whole blood viscosity under the shear rate of 5 s (-1) and 60 s (-1) (P < 0.01), and myocardial ischemia degree and range (P < 0.01). Compared with the model group, TYTZ groups revealed significant decrease in myocardial ischemia degree and range (P < 0.01), serum TC, TG, LDL-C and VLDL-C levels (P < 0.05 or P < 0.01) and whole blood viscosity under the shear rate of 5 s(-1) and 60 s(-1) (P < 0.05). CONCLUSION: TYTZ could improve the abnormal hemorheology in Chinese mini-swine with coronary heart disease of phlegm-stasis cementation syndrome, and regulate serum lipid, with a certain efficacy for coronary heart disease of phlegm-stasis cementation syndrome. PMID- 24761651 TI - [Pharmacological study on free anthraquinones compounds in rhubarb in rats with experimental acute pancreatitis]. AB - OBJECTIVE: To verify the pharmacological hypothesis of prescriptions by studying the targeted distribution of major components in stewed rhubarb in the rat model with acute pancreatitis (AP). METHOD: Normal SD rats (control group, n = 5) and the AP model induced with intraperitoneal cerulein (model group, n = 5) were taken as the experimental objects. Rats of the two groups were orally administered with stewed rhubarb granules (20 g x kg(-1)). Their heart, liver, spleen, lung, kidney and pancreas were collected two hours after the administration. Such constituents as emodin, chrysophanol, physcion, rhein and aloe-emodin and their concentrations in each tissue homogenate were detected by high performance liquid chromatography-mass-mass. RESULT: Aloe-emodin and physcion in stewed rhubarb whose concentrations in liver and kidney of normal rats were higher than that in pancreatic tissues, while the distribution spectrums and concentrations of the remaining components in pancreatic tissues had no significant difference with that of other organs. The concentrations of emodin, aloe-emodin, rhein and chrysophanol in stewed rhubarb in pancreatic tissues of the AP model group were higher than that in other tissues and organs, while their concentrations in pancreatic, renal and splenic tissues were notably higher than that in the normal group. CONCLUSION: In the conditions of AP, effective components in stewed rhubarb show a targeted distribution feature in pancreas, which provides experimental basis for the pharmacological hypothesis of prescriptions. PMID- 24761652 TI - [Studies on pharmacokinetics features of characteristic active ingredients of daidai flavone extract in different physiological status]. AB - In order to explore the clinical hypolipidemic features of Daidai flavone extract, the pharmacokinetics features of characteristic active ingredients of Daidai flavone extract in normal and hyperlipemia rats were studied and compared. The study established the quantitative determination method of naringin and neohesperidin in plasma by UPLC-MS. Study compared the pharmacokinetics differences of naringin and noehesperidin in normal and hyperlipemia rats on the basis of establishment of hyperlipemia model. Results indicated that the pharmacokinetics features of characteristic active ingredients of Daidai flavone extract in normal and hyperlipemia rats showed significant differences. The C(max) of naringin and neohesperidin in hyperlipemia rats plasma after oral administration of Daidai flavone extract increased obviously, while t1/2, MRT and AUC0-24 h decreased, compared to normal rats. But t(max) showed no differences to that of normal rats. The results further proved Daidai flavone extract would have better hypolipidemic effect in the hyperlipemia pathological status. And the characteristic active ingredients naringin and noehesperidin were the material base of Daidai flavone extract to express the hypolipidemic effect. PMID- 24761653 TI - [Pharmacokinetics and brain distribution of ginsenosides after administration of sailuotong]. AB - Sailuotong (SLT) is a compound preparation composed of ginseng, ginkgo and saffron for the treatment of vascular dementia In order to identify its material foundation and provide evidence for therapeutic regimen, the pharmacokinetics and brain distribution of ginsenosides were investigated after intragastric administration of SLT. An LC-MS/MS method was developed for the determination of 7 ginsenosides in rat plasma simultaneously. Statistical analysis of obtained data demonstrated that the method has achieved the desired linearity, precision, accuracy and sensitivity. After administration of SLT at 60 mg x kg(-1) dose, 7 ginsengosides were all absorbed into systematic circulation. The quantitative and statistical analysis of gensenosides in plasma showed that protopanaxdiol saponins exhibited higher concentration and longer half life than protopanaxatriol saponins. The mean value of half life of ginsenosides Rg1, Re, Rb1, Rb2/b3, Rc and Rd were 15.26, 2.46, 18.41, 27.70, 21.86 and 61.58 h respectively. The peak concentration of them were 7.15, 2.83, 55.32, 30.22, 21.42, 8.81 microg x L(-1) respectively. The determination of brain distribution at different time after dosing revealed ginsenosides entered into brain promptly but the concentration declined along with time rapidly. The ginsenosides with higher concentration in brain were Rg1, Re, Rb1 and Rc. These findings demonstrated ginsenosides could be absorbed in blood and penetrated into brain rapidly. Some ginsenosides, especially Rg1 and Re, might be the main components directly effecting neurocyte in brain taking advantage of their better brain distribution. While ginsenosides of mostly protopanaxdiol saponins might protect brain mainly depending on peripheral efficacy in virtue of their long residence in blood, by which higher concentration could be reached after multiple dosing. PMID- 24761654 TI - [1H-NMR based metabonomic approach to evaluate detoxification effect of vinegar processed Euphorbia kansui]. AB - Euphorbia kansui (EK) is a toxic herbal drug, and often used after vinegar processing to reduce its toxicity. In present study, a 1H-NMR based metabonomic approach was used to evaluate the detoxification effect of vinegar-processed EK. The water extracts of EK and VEK were administered orally to male SD rats at doses of 9 g x kg(-1) x d(-1) for 1 week, respectively, and one more week observation was further conducted. The control group was orally given with saline. Histopathological studies of liver samples on the 8th and 15th day were conducted, and the metabolites of rat urine and liver were analysed by 1H-NMR. Histopathological studies of liver samples from EK and VEK treated rats showed no negative impacts. In metabonomic analyses of urines, changes of metabolites indicated liver damages, kidney lesions and imbalance of gut microbes in the second week. VEK-treated rats showed a quite lower toxicity compared with EK treated ones. The present study revealed that the metabonomic approach might be helpful for the evaluation of toxicity of EK and detoxic effect of VEK. PMID- 24761655 TI - [Study on supply and demand relation based on two stages division of market of Chinese materia medica]. AB - The complex production processes and long industrial chain in traditional Chinese medicine (TCM) market result in difficulty in Chinese market microstructure research. Based on the defining the logical relationships among different concepts. This paper divides TCM market into two stages as Chinese materia medica resource market and traditional Chinese Patent Medicines market. Under this foundation, we investigated the supply capacity, approaching rules and motivation system of suppliers in TCM market, analyzed the demand situation in the perspective of demand side, and evaluated the purchasing power in terms of population profile, income, and insurance. Furthermore we also analyzed the price formation mechanism in two stages of TCM market. We hope this study can make a positive and promotion effect on TCM market related research. PMID- 24761656 TI - [Present situation of science and technology of traditional Chinese medicine in China]. AB - This paper explains the status of science and technology of traditional Chinese medicine in China. Basic conclusions are as follows: policy environment is improved step by step, R&D funds and R&D personnel in traditional Chinese medicine field are increased continuously, and a lot of achievements have been got in traditional Chinese medicine field. PMID- 24761657 TI - [Thinking and practice of study on material basis of parched Chinese herbal medicines and their quality evaluation]. AB - Though parched Chinese herbal medicines contain less effective or index components, their pharmacological actions do not reduce or even become improved to some extent. However, the current studies related to material basis could not explain the changes in property, flavour and efficacy of parched Chinese herbal medicines. Meanwhile, due to the lack of objective and specific evaluation indexes, the quality evaluation could not reflect features of parched Chinese herbal pieces. Therefore, how to break the bottleneck for the studies on parched Chinese herbal pieces, make further innovation and conduct in-depth studies on the material basis of parched Chinese herbal medicines are common problems that medical scholars are facing. According to the findings in the previous studies, the author proposed to explain the material basis of parched Chinese herbal medicines by studying Maillard reaction and establish specific quality evaluation indexes according to the features of parched Chinese herbal pieces, and conducted relevant studies. PMID- 24761658 TI - [On plant stem cells and animal stem cells]. AB - A comparison of plant and animal stem cells can highlight core aspects of stem cell biology. In both kingdoms, stem cells are defined by their clonogenic properties and are maintained by intercellular signals. The signaling molecules are different in plants and animals stem cell niches, but the roles of argonaute and polycomb group proteins suggest that there are some molecular similarities. PMID- 24761659 TI - [Theory and research of dryness in traditional Chinese medicine]. AB - Dryness is the inherent performance in traditional Chinese medicine. Dryness with a specific efficacy and side effect can be reduced suitably by processing and compatibility in the clinical application. Nowadays domestic scholars have developed research of dryness in traditional Chinese medicine. However, it remains problems such as evaluation index of dryness not clear. This paper takes medical literature mining technology to analyze the historical origin and features of dryness theory. Combing the modern literatures to explicate the dryness' research status and existing problems. Putting forward the traditional Chinese medicine and research should adopt multidisciplinary knowledge and study the system of comprehensive evaluation. Dryness is expected to further application in traditional Chinese medicine clinical research. PMID- 24761660 TI - [Genetic potential and selection index of yield-related traits in 2-year-old licorice (Glycyrrhiza uralensis) populations]. AB - OBJECTIVE: To evaluate genetic potential and selection index of yield-related traits in 2-year-old populations, and provide a basis for high-yield breeding of licorice (Glycyrrhiza uralensis). METHODS: Four genotype licorice populations were transplanting in four different environment using complete randomized block design with three replication, and the 10 yield-related traits, including plant height (PH), stem diameter (SD), tiller number (TN), taproot length (TRL), root length (RL), root diameter (RD), diameter of 20 cm below the root head (D20), taperingness (TR), lateral root number (LRN) and root fresh weight (RFW) were measured in field. Genetic potential and selection index of yield-related traits were evaluated using theories of quantitative genetics. RESULTS: The genetic potential were higher for the three traits of PH (X1), TRL (X4) and RL (X5) that showed through genetic parameter of broad sense heritability (h2), genetic variation coefficient (GCV) and relative genetic advance (RGA). Among them, selection relative value increased by 45.94% through combination of PH and RL (Y1 = 0.21X1 + 0.08X5) compared with the direct selection for RFW (Y1). CONCLUSION: It can realize effective indirectly selection for yield traits, RFW of licorice by PH and RL or their combination. That is, for selection of high-yield licorice, select big and high plants firstly, and then single out long root length materials. PMID- 24761661 TI - [Study on the optimum combinations of plant hormone in callus culture of Thermopsis lanceolata]. AB - OBJECTIVE: To explore the effects of different hormone combinations on callus induction of Thermopsis lanceolata. METHODS: The effects of different hormone concentrations and ratio on callus induction and subculture multiplication of Thermopsis lanceolata were investigated by orthogonal design methods. RESULTS: The optimal medium of callus induction for hypocotyls explants was MS + 2, 4-D (0.5 mg/L) + BA (1.0 mg/L) + NAA (1.0 mg/L) + IAA (0.5 mg/L). The best medium of callus subculture multiplication for hypocotyl explants was MS with 2,4-D (0.1 mg/L) + BA (0.1 mg/L) + NAA (0.2 mg/L) + IAA (0.5 mg/L) . In the process of callus subculture multiplication, the effect extent of four kinds of hormones for hypocotyl explants was BA > 2,4-D > IAA > NAA. The growth curve of callus culture optimal hormone combination was "S" curve. CONCLUSION: The rapid callus culture system for Thermopsis lanceolata is established for the first time. It provides a new way for protecting and utilizing Thermopsis lanceolata species resources through the modern biotechnology. PMID- 24761662 TI - [Comparative study of antitumor activity of cantharidin and cantharis peptides]. AB - OBJECTIVE: To prepare cantharidin and cantharidin peptides from Mylabris and compare their antitumor activity. METHODS: Cantharis peptides was prepared by bionic enzymolysis approach and cantharidin was prepared by alkaline water supersonic extraction. The inhibitory effects of both compounds on BEL-7402 cells proliferation of human liver cancer were tested by Prestoblue method. The influence of both compounds on the grown of tumor, thymus, spleen of S180 tumor bearing mice were detected. RESULTS: Cantharis peptides and cantharidin could inhibit the proliferation of BEL-7402 cells (P < 0.05) in vivo, and the inhibitory effect of cantharis peptide was 12.54% lower than that of cantharidin. At the same time, they could inhibit the grown of S180 sarcoma (P < 0.05), and the inhibitory effect of cantharidin was higher than that of cantharis peptides (5.93%). Furthermore, cantharis peptides could't inhibit the grown of thymus and spleen. CONCLUSION: Both cantharis peptides and cantharidin have antineoplastic activity, but cantharidin peptides have no immunosuppression. PMID- 24761663 TI - [Effect of transplantation on growth and oxymatrine content of Sophora flavescens]. AB - OBJECTIVE: To study the effect of transplantation on the growth and oxymatrine content of Sophora flavescens and provide foundation for popularization and cultivation of Sophora flavescens in South China. METHODS: Sophora flavescens which was usually planted in North China and Northwest China was planted in a non traditional location, Zhongshan city, Guangdong Province in South China to test its adaptability. The growth characters, such as plant height, leaf area, dry weight of root, diameter and length of root and so on were measured from 2010 to 2012. The oxymatrine content of one-year old and two-year old root of Sophora flavescens were determined by HPLC. Nine major growth indexes for one-year old Sophora flavescens were comprehensively analyzed and evaluated by the methods of weighted gray relational and hierarchy evaluation of fuzzy mathematics. RESULTS: The weighted relevancy of introduced and reference cultivars was 0.8545. The introduced cultivar was rather adaptable to the geography environment in Zhongshan. Its quality was very close to the reference cultivars. Oxymatrine content of root of one-year old and two-year old Sophora flavescens was 13.2784 mg/g (as much as origin) and 16.4779 mg/g (less than origin 28.67%), respectively. These were 10.65% and 37.32% higher than the quality standard which were set up in the Chinese Pharmacopoeia (2010 edition). CONCLUSION: Sophora flavescens performs quite well in the newly introducing region. It is suitable to be cultivated and extended in South China. PMID- 24761664 TI - [Correlation analysis of major agronomic characters and the polysaccharide contents in Dendrobium officinale]. AB - OBJECTIVE: In order to provide theoretical and technological basis for the germplasm innovation and variety breeding in Dendrobium officinale, a study of the correlation between polysaccharide content and agronomic characters was conducted. METHODS: Based on the polysaccharide content determination and the agronomic characters investigation of 30 copies (110 individual plants) of Dendrobium officinale germplasm resources, the correlation between polysaccharide content and agronomic characters was analyzed via path and correlation analysis. RESULTS: Correlation analysis results showed that there was a significant negative correlation between average spacing and polysaccharide content, the correlation coefficient was -0.695. And the blade thickness was positively correlated with the polysaccharide content, but the correlation was not significant. The path analysis results showed that the stem length was the maximum influence factor to the polysaccharide, and it was positive effect, the direct path coefficient was 1.568. CONCLUSION: According to thess results, the polysaccharide content can be easily and intuitively estimated by the agronomic characters investigating data in the germpalsm resources screening and variety breeding. Therefore, it is a visual and practical technology guidance in quality variety breeding of Dendrobium officinale. PMID- 24761665 TI - [Quick identification and discrimination of sun-dried and sulfur-fumigated cimicifugae rhizoma by Fourier transform infrared spectroscopy]. AB - OBJECTIVE: To develop a method for quick identification of sun-dried and sulfur fumigated Cimicifugae Rhizoma by Fourier transform infrared spectroscopy (FTIR). METHODS: The alcoholic and aqueous extracts of sun-dried and sulfur-fumigated Cimicifugae Rhizoma were analyzed and compared by FTIR combined with second derivative infrared spectroscopy. RESULTS: FTIR spectra showed that there were some differences in the positions of infrared absorption peaks and the relative intensities in the alcoholic and aqueous extracts of sun-dried and sulfur fumigated Cimicifugae Rhizoma, and the second derivative IR spectra clearly enhanced the spectral resolution of their differences. FTIR spectra showed that the new absorption peaks of Cimicifugae Rhizoma appeared and a part of original absorption peaks disappeared after sulfur-fumigation in aqueous extracts, while a lot of new absorption peaks appeared and the intensities of almost all absorption peaks significantly decreased after sulfur-fumigation in alcoholic extracts. Second derivative IR spectra showed that both sun-dried and sulfur-fumigated Cimicifugae Rhizoma extracted by water differed significantly from each other ranging from about 3 950 to 3 940 cm(-1), 3 850 to 3 800 cm(-1), 1 800 to 1 750 cm(-1), as well as from 1 400 to 1 350 cm(-1); Differences also existed between sun-dried and sulfur-fumigated Cimicifugae Rhizoma extracted by ethanol ranging from about 3 980 to 3 960 cm(-1), 3 850 to 3 800 cm(-1), and 1 500 to 1 460 cm( 1). CONCLUSION: The FTIR method combined with the second derivative IR spectrum can be used to analyze and distinguish sun-dried and sulfur-fumigated Cimicifugae Rhizoma quickly and accurately. The developed method provides an efficient approach for the quality control of Chinese herbal medicines with its simplicity and strong specificity. PMID- 24761666 TI - [HPLC fingerprint and chemical pattern recognition of liposoluble chemical components for euodiae fructus]. AB - OBJECTIVE: To establish a method of HPLC fingerprint and chemical pattern recognition of liposoluble chemical components for quality evaluation of Euodiae Fructus. METHODS: The HPLC chromatographic separation was performed on a C18 column (250 mm x 4.6 mm, 5 microm). The mobile phase was a mixture of acetonitrile-0.5% acetic acid in gradient elution with flow rate of 1 mL/min. The detection wavelength was set at 249 nm, and the column temperature was 30 degrees C. RESULTS: There were 9 common peaks in the HPLC fingerprint of 34 batches of Euodiae Fructus samples. The results of cluster analysis and principal component analysis showed that the liposoluble chemical components of Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang and Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang were more similar than that of Euodia rutaecarpa (Juss.) Benth. CONCLUSION: The results provide new experimental and theoretical basis for quality control and evaluation of Euodiae Fructus. PMID- 24761667 TI - [Microstructure characteristics and identification significance of leaf epidermis of medicinal plants from Sabia genus]. AB - OBJECTIVE: To study the feasibility and significance of the method to identify medicinal plants through the observation and statistics of 9 species of Sabia medical plants from Guizhou province. METHODS: Leaf epidermis characteristics were observed, measured by optical microscope and analyzed by SPSS 17.0 software. RESULTS: All of these plants had some differences in indumentum, cell morphology and size, and had significant difference in the length and circumference of lower epidermis cells. CONCLUSION: The method combining microscopic observation with statistics can be used as the classification and identification basis of medicinal plants and materials of Sabia genus. PMID- 24761668 TI - [Study on triterpenoid saponins in the rhizome of Anemone hofengensis]. AB - OBJECTIVE: To study the triterpenoid saponins in the rhizome of Anemone hofengensis. METHODS: The constituents were separated with various chromatographic techniques and their structures were elucidated by physicochemical properties and spectral data. RESULTS: Five compounds were isolated and identified as 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-alpha-L-arabino pyranosyl-oleanolic acid (1), 3-O-alpha-L-rhamnopyranosyl-(1 --> 2)-beta-D glucopyranosyl-(1 --> 2)-alpha-L-rhamnopyranosyl-oleanolic acid 28-O-alpha-L rhamnopyranosyl-(1 --> 4) -beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranoside (2), 3-O-alpha-L-rhamnopyranosyl-(1 --> 2) [beta-D-glucopyranosyl-(1 --> 4)] alpha-L-rhamnopyranosyl-oleanolic acid-28-O-beta-D-glucopyranosyl-(1 --> 6)-beta D-gluco-pyranoside (3), 3-O-beta-D-glucopyranosyl-(1 --> 2)-beta-D-xylopyranosyl oleanolic acid 28-O-beta-D-glucopyranosyl-(1 --> 6)-beta-D-glucopyranoside (4), oleanolic acid-28-O-alpha-L-rhamnopyra-nosyl-(1 --> 4)-beta-D-glucopyranosyl-(1 - > 6)-beta-D-glucopyranoside (5). CONCLUSION: Compound 1 - 5 are isolated from this plant for the first time. PMID- 24761669 TI - [Study on the chemical constituents of Gastrodia elata]. AB - OBJECTIVE: To study the chemical constituents of Gastrodia elata. METHODS: The compounds were isolated by silica gel column chromatography and recrystallization and their structures were elucidated by spectral analysis. RESULTS: The structures of 14 compounds were identified as: p-hydroxybenzyl alcohol (1), p hydroxybenzaldehyde (2), 3, 4-dihydroxybenzaldehyde (3), 4, 4'-dihydroxy, dibenzyl ether (4), 4-hydroxymethyl benzyl-4'-hydroxy-3'-(4"-hydroxy benzl) benzyl ether (5), 4-ethoxybenzyl alcohol (6), anisic alcohol (7), bis(3, 4 dihydroxyphenyl) methane (8), 4, 4'-dihydroxydiphenyl methane (9), 2, 4-bis(4' hydroxy-benzyl)-phenol (10), 4-( methoxymenthyl) benzene-1, 2-diol (11), p methylphenyl-1 -O-beta-D-glucopyranoside (12), N6-(4'-hydroxybenzl) -adenosine (13) and beta-sitosterol (14). CONCLUSION: Compounds 6 - 8 and 11 are isolated from this plant for the first time. PMID- 24761670 TI - [Chemical constituents of ethyl acetate fraction from Hypericum hengshanense]. AB - OBJECTIVE: To study the constituents of ethyl acetate fraction form Hypericum hengshanense. METHODS: The constituents were isolated and purified by chromatography on silica gel and their structures were elucidated by MS and NMR spectral analysis. RESULTS: Ten compounds were isolated and identified as: hyperoside (1), hypericin (2), quercetin (3), quercitrin (4), sesamin (5), betulonic acid (6), rutin (7), kaempferol (8), beta-daucosterol (9), beta sitosterol (10). CONCLUSION: All compounds are obtained from this plant for the first time. PMID- 24761671 TI - [Study on chemical constituents of Citrullus vulgaris Schrad vine (II)]. AB - OBJECTIVE: To study the chemical constituents of ethyl acetate fraction of Citrullus vulgaris Schrad vine. METHODS: Compounds were isolated and purified by polyamide column chromatography, silica gel column chromatography, thin layer chromatography and sephadex gel column chromatography. Their structures were elucidated on the basis of physicochemical properties and spectral data. RESULTS: Ten compounds were isolated from Citrullus vulgaris Schrad vine and elucidated as: pentadecanoic acid (1), monopentadecanoin (2), 2, 3-dihydroxypropyl nonadecoate (3), lignoceric acid-2, 3-dihydroxy-propanenyl ester (4), lancerebroside 5 (5), salicylic acid (6), 4-hydroxybenzoic acid (7), hydroquinone (8), succinic acid (9) and vanillic acid (10). CONCLUSION: Compounds 1 - 10 are obtained from Citrullus vulgaris Schrad vine for the first time. PMID- 24761672 TI - [GC-MS analysis of chemical constituents of volatile oil from flowers of Rhododendron mucronatum]. AB - OBJECTIVE: To analyze the chemical constituents of volatile oil from flowers of Rhododendron mucronatum. METHODS: The volatile oil was extracted by water-steam distillation and analyzed by GC-MS. RESULTS: Forty-nine compounds, which occupied 79.55% of total constituents, were identified. The major constituents were linalool, beta-eudesmene, phytol, benzyl benzoate, benzyl salicylate and nonyl aldehyde. CONCLUSION: The chemical constituents of volatile oil, which contain many bioactive constituents, are mainly composed of terpenes, esters, and alkanes. PMID- 24761673 TI - [Isolation and structure elucidation of chemical constituents from Pinellia ternata]. AB - OBJECTIVE: To isolate and identify the chemical constituents of ethanol extract of Pinellia ternata. METHODS: The constituents were isolated by silica-gel, Sephadex LH-20 chromatography and HPLC techniques. The structures were identified by spectroscopic analysis including 2D NMR techniques and chemical properties. RESULTS: Nine compounds were obtained and identified as uridine (1), 5'-S-methyl 5'-thioadenosine (2), adenine (3), chrysophanol (4), 5-hydroxymethylfurfural (5), nicotinamide (6), (2S)-1-O-(9Z, 12Z-octadecadienoyl)-3-O-beta galactopyranosylglycerol (7), daucosterol (8), beta-sitosterol (9). CONCLUSION: Compounds 2, 6, 7 are isolated from this plant for the first time. PMID- 24761674 TI - [Effects of extracts from ziziphi spinosae semen and schisandrae chinensis fructus on amino acid neurotransmitter in rats with insomnia induced by PCPA]. AB - OBJECTIVE: To observe the effects of extract from Ziziphus Spinosa Semen and Schisandrae Chinensis Fructus on the content of amino acid neurotransmitter in the hypothalamus of insomnia rats induced by P-Chlorophenylalanine (PCPA) and its mechanism. METHODS: The model of insomnia rats were established by PCPA intraperitoneal injection, after the modeling, all the therapeutic group were treated with corresponding drug for one week. The hypothalamus pathological changes of the rats were observed. The contents of GABA, Glu in the hypothalamus were detected by Elisa. The GABA, Glu protein expression were detected by immunohistochemical. GABA(A), R(alpha1) and GABA(A)R(gamma2) mRNA expressions were detected by RT-PCR. RESULTS: Compared with model group, the content of GABA in the hypothalamus of rats increased obviously in the alcohol-water group (P < 0.05 or P < 0.01), while the content of Glu decreased obviously (P < 0.05 or P < 0.01). CONCLUSION: The extract from Ziziphus Spinosae Semen and Schisandrae Chinensis Fructus has obviously Sedative-hypnotic effect. Its mechanism may be related to regulating the content of amino acid neurotransmitter in the hypothalamus of rats. PMID- 24761675 TI - [Antiproliferative effect of cycloartane-type triterpenoid from myrrh against human prostate cancer cells]. AB - OBJECTIVE: To investigate the antiproliferative effect of cycloartan-24-ene 1alpha, 2alpha, 3beta-triol from Myrrh against human prostate cancer cells. METHODS: Morphological changes of compound-treated human prostate PC3 cells were determined by staining cells with Hoechst. The cell cycle progression and apoptosis were evaluated using flow cytometry assay. Apoptosis related protein levels were analyzed using Western blotting. RESULTS: Treatment of PC3 cells with cycloartan-24-ene-1alpha,2alpha,3beta-triol caused an increase ratio of apoptotic cells, which was verified by flow cytometry. It was also found that cycloartan-24 ene-1alpha,2alpha, 3beta-triol arrested cell cycle at the G0/G1 phase. Apoptosis related proteins, such as BCL-2, BAX, Caspase-3 and Caspase-9 were changed. CONCLUSION: These observes data indicate that cycloartan-24-ene 1alpha,2alpha,3beta-triol inhibit the proliferation of PC3 cells via induction of apoptosis and cell cycle arrest. PMID- 24761676 TI - [Effects of chlorogenic acid on the viability and HIF-1alpha mRNA expression of PC12 cells exposed to hypoxia]. AB - OBJECTIVE: To investigate the effects of chlorogenic acid on the viability and HIF-1alpha mRNA expression of PC12 cells exposed to hypoxia. METHODS: PC12 cells were cultured in trigas incubator in order to establish the hypoxic condition. The effects of chlorogenic acid on the cells were evaluated by morphological observation, cell viability and LDH release assays as well as the examination of mRNA expression level of HIF-1alpha. RESULTS: Chlorogenic acid significantly improved the viability of cells exposed to hypoxia, decreased LDH release, arrested the cell cycle on G1 phase, and increased the gene expression level of HIF-1alpha. CONCLUSION: Chlorogenic acid protects PC12 cells from hypoxic damage by improving the expression of HIF-1alpha. PMID- 24761677 TI - [Pharmacological study on hemostasis, analgesic and anti inflammation effects of the alcohol extract of Hibiscus tiliaceus]. AB - OBJECTIVE: To study the effects of hemostasis, analgesic and anti inflammation of the alcohol extract of Hibiscus tiliaceus and offer pharmacological and experimental basis for its safe and effective use in clinic. METHODS: The effects of hemostasist were observed with tail breaking method, capillary tube method and slide method; Hot board and body distortion induced by acetic acid methods were applied in mice analgesia experiment, the mice model of acute auricle swelling induced by dmi ethylbenzene and capillary permeability induced by acetic acid were applied to observe the anti inflammatory effects. RESULTS: The alcohol extract of Hibiscus tiliaceus could significantly reduce the bleeding time and the clotting time, delay the plant reaction time and reduce the writhing times of the mice, and it also had effect on inhibiting swelling of mice ear and the permeability of the capillary. CONCLUSION: These results suggest that the alcohol extract of Hibiscus tiliaceus has the effects of hemostasis, analgesic and anti inflammation. PMID- 24761678 TI - [Study on antidepressant effect of kuanxinjieyutang combined aerobic exercise]. AB - OBJECTIVE: To observe antidepressant effects of Kuanxinjieyutang (KXJYT), short term aerobic exercise and their joint intervention and its possible mechanism. METHODS: Ninty-six SPF male KM mice were randomly divided into control group, imipramine, low dose (KXJYT 1.8 g crude drugs/kg bw/time/day), high dose (3.6 g crude drugs/kg bw/time/day), exercise group (swimming 30 min/times/day), joint group (low dose and swimming ), with 8 days intervention. The antidepressant effect was evaluated by forced swimming, tail suspension test and overhead cross maze test. After mice were killed, brain monoamine neurotransmitter levels of mice were detected by ELISA, and BDNF expression in brain was analyzed by Western blotting. RESULTS: High dose group showed antidepressant effect like imipramine while low dose didn't. Exercise group showed similar or better antidepressant effect than imipramine. Joint group showed better interaction antidepressant effect. Brain NE, DA of high dose group and brain NE, DA and 5-HT content of exercise group increased significantly, similar to imipramine. Brain NE,DA and 5 HT content of Joint group were significantly higher than those of imipramine. The protein expression of BDNF in brain was more in imipramine, high dose,exercise and joint groups than that of control group, sports group was higher than that of low dose and high dose group, joint group was obviously higher than other groups. CONCLUSION: Moderate KXJYT, short-term aerobic exercise and their joint intervention have obvious antidepressant effect on mild depression. Its mechanism may be related to increasing brain NE and 5-HT content, and inducing brain BDNF expression, which may affect the nerve regeneration and plasticity, improve cognitive function. PMID- 24761679 TI - [Optimization of extraction technology for typhae pallen from tangwang mixture by central composite design-response surface method]. AB - OBJECTIVE: To optimize the extraction process of Typhae Pollen from Tangwang Mixture. METHODS: Using extraction rate and the content of isorhamnetin-3-O neohesperidoside as the evaluation indicator, the extraction ways of Typhae Pollen was determined by comparing water and alcohol extraction technology. Among the water extraction technology, investigated the effect of single extraction and mix extraction, and whether Typhae Pollen wrappes during extracting. Taking ethanol concentration, the amount of solvent and extraction time as investigate factors, using the multiple linear regression and binomial formula fitting, extraction process was optimized by response surface method. RESULTS: The optimum extraction technology was as follows: extracted 3 times with 8-fold the amount of 60% ethanol for 60 minutes each time. CONCLUSION: The optimized ethanol extracted technology is reasonable and can be applied for the large-scale production. PMID- 24761680 TI - [Optimized extraction technology of flavonoid compounds with anti-SMMC-7721 tumor activities in bark of Juglans mandshurica by orthogonal experimental design based on dose-effect fusion evaluation method]. AB - OBJECTIVE: To optimize the extraction technology of total flavonoids with antineoplastic activities in Juglans mandshurica, and explore the correlation between total flavonoids and pharmacodynamics indicators. METHODS: The quantity of antineoplastic components, ratio of extraction and cell inhibition rate were taken as the comprehensive indexes to optimize the main factors that influence the extraction of effective components by orthogonal experiment design. SPSS 17.0 software was used to analyze the Pearson correlation between effective components and pharmacodynamics indexes. RESULTS: The best extracting condition of total flavonoids were as follows: the ratio of 60% ethanol to Juglans mandshurica was 20: 1, extracting for 3 times, each time for 2 hour at 70 degrees C. Flavonoids extraction yield and cell inhibition rate was positively related in the straight line. CONCLUSION: This study provides a new insight into the optimization of extraction technology for traditional Chinese medicine, and lays a safe and reliable experimental basis for the clinical application of Juglans mandshurica. PMID- 24761681 TI - [Optimal extraction technology for genistein in Flemingia macrophylla with response surface method]. AB - OBJECTIVE: To optimize extraction techniques for genistein in Flemingia macrophylla by using response surface method. METHODS: Based on the single factor experiment, extraction temperature, extraction time and solvent ratio served as the response factor while the extraction rate of genistein served as the response value. Based on multiple linear regression and binomial expression, response surface method was employed to optimize the extracting process, and predicative analysis was conducted. RESULTS: The effects of factors in the descending order were as follows: extraction temperature, extraction time and solvent ratio. The optimal extraction technology was as follows: extraction temperature 80 degrees C, extraction time 3.5 h and solvent ratio 20 mL/g. Under these conditions, the extraction rate of genistein reached 0.161 mg/g. CONCLUSION: The results are agreed with model predictions. The technology can be used as the extraction process of genistein in Flemingia macrophylla. PMID- 24761682 TI - [Optimization of preparation technology of LIUWEI cataplasm, a kind of Zhuang national herbs]. AB - OBJECTIVE: To optimize preparation process of liuwei cataplasm, a Zhuang folk medical herb popularly applied as a kind of rheumatism, rheumatoid drug in Guangxi Zhuang Autonomous Region. METHODS: Orthogonal design test was employed to optimise matrix proportion and molding technology of liuwei cataplasma with glossiness, adhesive power, matrix residue, skin following and repeatedly exposing as indexes. RESULTS: Optimum matrix ratio of PANA, pressure sensitive adhesive, CNC-Na, gelatin, dihydroxyaluminium aminoacetate and glycerol was 0.5:1.0:0.4:0.1:0.3:3.0. Optimized parameters of technology were as follows: stiring speed 600 r/min, refining temperature 60 degrees C and drug loading of Liuwei extract 13.04%. CONCLUSION: Optimized liuwei cataplasm has a good adhesive power, exipcients and glossiness, meanwhile drug loading is large and no skin residue. The process is simple, stable and viable. PMID- 24761683 TI - [Study on formulation of Scutellaria baicalensis extract phospholipid complex nasal preparation]. AB - OBJECTIVE: To screen suitable nasal dosage forms of Scutellaria baicalensis extract phospholipid complex. METHODS: Used the permeable performance of hyorrinis mucosa, nasal irritation and other evaluation indexes to screen five different formulations. RESULTS: The submicroemulsion's apparent permeability coefficient was the largest, irritant was the smallest, and drug loading was higher than those of other formulations, which could meet the requirements of intranasal administration. CONCLUSION: The optimum formulation of Scutellria baicalensis extract phospholipid complex nasal preparation is submicroemulsion. PMID- 24761684 TI - Modified sequential Helicobacter pylori eradication therapy using high dose omeprazole and amoxicillin in the initial phase in the extensive metaboliser Turkish patients for CYP2C19 polymorphism is ineffective. AB - AIM: To investigate whether the sequential therapy composed of high dose omeprazole and high dose amoxicillin in the first step was effective in eradication of H. pylori and whether there was a relation between effectiveness of the therapy and CYP2C19 gene polymorphism. METHOD: 134 dyspeptic patients with H. pylori were administered a modified sequential therapy composed of omeprazole 40 mg t.i.d. and amoxicillin 1000 mg t.i.d, for the first five days followed by omeprazole 20 mg b.d., metronidazole 500 mg t.i.d. and tetracycline 500 mg t.i.d, for the next five days. CYP2C19 genotype status was determined in patients. Hp eradication status was investigated by C14 UNT four weeks after treatment. RESULTS: The eradication rates were 64.9% in ITT and 74.3% in PP analysis. In subgroup analyses, eradication rates were 73.8% and 60.8% (p: 0.145) in ITT for peptic ulcer and non-ulcer dyspepsia patients respectively and 86.1% and 69.1% (p: 0.052) in PP analysis for peptic ulcer and non-ulcer dyspepsia patients respectively. The difference was not significant. As for the CYP2C19 gene status, 81.5% of the patients had HoEM and 17.3% of the patients had HeEM, and eradication rates were 72% and 75% in ITT analysis for HoEM and HeEM respectively (p: 0.803) and 73.9% and 85.7% in PP analysis for HoEM and HeEM respectively (p: 0.347). There was not a significant difference in H. pylori eradication rates between the two groups. CONCLUSION: This modified high-dose sequential therapy was ineffective in a Turkish sample, nearly all of whom had EM in terms of CYP2C19 gene status. PMID- 24761685 TI - Gastrostomy use in children: a 3-year single centre experience. AB - AIM: Monocentric retrospective paediatric study describing indications for gastrostomy and major complications, compared to literature data as part of a quality check. METHODS: Records of all gastrostomy patients consulting at the UZ Ghent paediatric gastro-enterology department between January 2007-December 2009 were reviewed in December 2010 regarding indication, age and weight at tube insertion, insertion method, major complications and current gastrostomy tube type. RESULTS: 178 patients were included of which 165 (93%) were placed using the endoscopic pull technique, the others were placed surgically (n = 13). Neurodevelopmental disability with oral motor dysfunction was the major indication (113, 63%). Other indications were failure to thrive due to concomitant disease (65, 37%). Median age at tube insertion was 3yr (interquartile range (IQR) 0.6-9) with median tube time of 3.9 yr (IQR 1.9-7.2). Immediate complications were 1 peritonitis and 1 post-insertion fever episode. Late complications (10, 5.6%) were 1 gastrocolic fistula, 1 dislocation and 8 buried bumpers after 4 yr (range 35-10.4) of tube insertion. The incidence of buried bumper increased significantly with increasing PEG tube time (P < 0.01). Gastro-oesophageal reflux disease (GORD) led to Nissen fundoplication in 45 (25.3%) patients. The proportion of patients receiving a fundoplication remained about 20% over time but the time lapse between the 2 procedures decreased significantly. CONCLUSION: The development of buried bumper is associated to prolonged PEG tube use. In case of important GORD laparoscopic Nissen procedure and PEG placement can be performed simultaneously without increasing complication rate. PMID- 24761686 TI - Clinical significance of bowel wall thickening on computed tomography in HIV infected patients: association of anemia and hypoalbuminemia. PMID- 24761687 TI - A facebook survey to obtain alcohol-related information by young people and adolescents. An Italian study. AB - BACKGROUND: Alcohol consumption by adolescents and young adults is an issue of significant public concern. Internet-based Social Networking sites, such as Facebook, are potential avenues to reach young people easily. OBJECTIVE: to underline the innovation in proposing surveys to collect health-related information regarding young people alcohol consumption and other substances abuse by using Social Networking Websites, particularly Facebook. METHODS: A questionnaire investigating modalities of alcohol consumption, drinking patterns' risk behaviors and other substances abuse was proposed through a "Facebook event" to young Italian Facebook users aged between 16 and 32. Each Facebook user invited to the event was free to participate, to answer to the questionnaire and to invite his "Facebook friends". RESULTS: During the 89 days of permanence on the Social Network, 1846 Facebook users participated the event and 732 of them decided spontaneously to answer the questionnaire. The frequency of answering was 8.2 people per day. About 200 users wrote a positive comment to the initiative on the wall of the event. Sixty% of subjects participating the survey were females. Ninety-one% of people answering the questionnaire were alcohol consumers. More than 50% of alcohol consumers were also smokers. Approximately 50% of subjects were binge drinkers. Illegal drugs were used by the 22.2% of the interviewed people. CONCLUSIONS: Facebook resulted an efficient and rapid tool to reach young people from all over Italy and to propose surveys in order to investigate alcohol consumption and alcohol-related health problems in the youth. PMID- 24761688 TI - Diagnosing and treating pediatric Crohn's disease patients: is there a difference between adult and pediatric gastroenterologist's practices ? Results of the BELCRO cohort. PMID- 24761689 TI - Characteristics, treatment, and virologic responses of chronic hepatitis C patients treated with peginterferon alfa-2a and ribavirin in belgium: a sub analysis of the PROPHESYS study. AB - BACKGROUND AND STUDY AIMS: PROPHESYS was a prospective, international cohort study of monoinfected, treatment-naive chronic hepatitis C patients treated with a combination of peginterferon alfa-2a or alfa-2b and ribavirin.It included worldwide 7,163 patients from 19 countries (including 384 patients from Belgium alone) and demonstrated that sustained virologic response rates in the real world were similar to those achieved in well-controlled clinical trials. The objective of this sub-analysis was to present an overview of the baseline characteristics, anti-hepatitis C drug treatment, and virologic responses of the patients treated in Belgium, infected with HCV genotype 1, 2, 3, or 4, and administered pegin terferon alfa-2a. Moreover, the impact of ribavirin dosage on the response to treatment was studied. PATIENTS AND METHODS: 356 patients were included in this sub-analysis. All variables were summarized using descriptive statistics. RESULTS: Compared to the published data of the whole study population (1), the Belgian data presented some significant differences in terms of genotype distribution and response to treatment (e.g. lower prevalence of HCV genotype 1 infection, lower virologic response rates in HCV genotype 2 patients). Deviations from existing recommendations were identified (e.g. higher dose of ribavirin in HCV genotype 2 or 3 patients). Patients who received less than 80% of the target dose of ribavirin experienced a significantly weaker response to treatment. CONCLUSION: This sub-analysis provided an interesting profile of the Belgian experience in the treatment of chronic hepatitis C. PMID- 24761690 TI - Depth of remission in Crohn's disease patients seen in a referral centre : associated factors and impact on disease outcome. AB - INTRODUCTION: Our goals were to assess the prevalence of biological and tissue remission in routine practice in Crohn's disease, and to evaluate the correlation between biological or tissue remission and clinical or demographic characteristics as well as their impact on disease outcome. METHODS: We performed a retrospective monocenter study. Biological remission was defined by a CRP < 5 mg/I. Tissue remission was defined by the absence of ulcer at endoscopy and/or absence of signs of acute inflammation at MRI. Association with demographic, clinical and laboratory markers was studied by logistic regression models and rates of relapses, hospitalizations and surgeries were compared using the logrank test. RESULTS: Among the 263 patients included, 147 were in clinical remission; 102/147 (69%) were in biological remission. Fifty-six patients also had morphological evaluation: 37 (66%) were in tissue remission. Biological remission was associated with older age, higher hemoglobin and lower BMI. Tissue remission was associated with older age, lower platelets count, absence of previous surgery, and the use of immunosuppressant. Time-to-relapse was significantly longer in patients with biological remission and in patients with tissue remission as compared to patients without biological or tissue remission. CONCLUSIONS: Among the patients in clinical remission seen as outpatients, two thirds were either in biological and/or tissue remission. Biological and/or tissue remission was associated with a better outcome than clinical remission alone. PMID- 24761691 TI - Belgian consensus on chronic pancreatitis in adults and children: statements on diagnosis and nutritional, medical, and surgical treatment. AB - Chronic pancreatitis (CP) is an inflammatory disorder characterized by inflammation and fibrosis, resulting in a progressive and irreversible destruction of exocrine and endocrine pancreatic tissue. Clinicians should attempt to classify patients into one of the six etiologic groups according to the TIGARO classification system. MRI/MRCP, if possible with secretin enhancement, is considered the imaging modality of choice for the diagnosis of early-stage disease.In CP, pain is the most disabling symptom, with a significant impact on quality of life. Pain should be assessed using the Izbicki score and preferably treated using the "pain ladder" approach. In painful CP, endoscopic therapy (ET) can be considered as early as possible. This procedure can be combined with extracorporeal shock-wave lithotripsy (ESWL) in the presence of large (> 4 mm), obstructive stone(s) in the pancreatic head, and with ductal stenting in the presence of a single main pancreatic duct (MPD) stricture in the pancreatic head with a markedly dilated MPD. Pancreatic stenting should be pursued for at least 12 months in patients with persistent pain relief. On-demand stent exchange should be the preferred strategy. The simultaneous placement of multiple, side-by-side, pancreatic stents can be recommended in patients with MPD strictures persisting after 12 months of single plastic stenting. We recommend surgery in the following cases: a) technical failure of ET ; b) early (6 to 8 weeks) clinical failure ; c) definitive biliary drainage at a later time point; d) pancreatic ductal drainage when repetitive ET is considered unsuitable for young patients; e) resection of an inflammatory pancreatic head when pancreatic cancer cannot be ruled out; f) duodenal obstruction. Duodenopancreatectomy or oncological distal pancreatectomy should be considered for patients with suspected malignancy. Pediatricians should be aware of and systematically search for CP in the differential diagnosis of chronic abdominal pain. As malnutrition is highly prevalent in CP patients, patients at nutritional risk should be identified in order to allow for dietary counseling and nutritional intervention using oral supplements. Patients should follow a healthy balanced diet taken in small meals and snacks, with normal fat content. Enzyme replacement therapy is beneficial to symptomatic patients, but also in cases of subclinical insufficiency. Regular follow-up should be considered in CP patients, primarily to detect subclinical maldigestion and the development of pancreatogenic diabetes. Screening for pancreatic cancer is not recommended in CP patients, except in those with the hereditary form. PMID- 24761692 TI - A challenging alfa-fetoprotein in a cirrhotic patient. AB - A 57-year-old Italian man was admitted to our Hospital for investigation of a progressively raising alfa-fetoprotein (AFP) on the background of chronic hepatitis B infection. At abdominal imaging,liver morphology was suspected for advanced fibrosis but without any focal lesion. Clinical and ultrasonographic examinations were negative for testicular masses. When the patient was screened for gastroesophageal varices, upper intestinal endoscopy did not show signs of portal hypertension, while it revealed a gastric lesion which was histologically characterized as hepatoid adenocarcinoma of the stomach (HAS), with strong immunohistochemical positivity for AFP. The patient underwent subtotal gastrectomy and AFP fell within the normal range. This is a very rare case in which AFP-producing gastric cancer (AFPPGC), in the form of HAS, presented in a patient with chronic liver disease. Physicians should be particularly aware of AFPPGC when following patients with liver disorders due to the common use of AFP in this setting. PMID- 24761693 TI - Ectopic liver tissue in two distinct anatomical regions: a case report. AB - Extrahepatic liver tissue (ELT) is a rare clinical finding. Few cases are described. The reported location is almost exclusively confined to the subdiaphragmatic region with the gallbladder being the most frequent localisation. This paper describes a unique case with not only two localisations of ectopic liver tissue, but also in anatomical regions where ELT has never been described before. PMID- 24761694 TI - Venous thrombosis in a child with ulcerative colitis in remission: a case report. AB - Over the past 70 years, an association between venous thromboembolism and inflammatory bowel disease has been described. We report on a thirteen year old boy with ulcerative colitis and venous thrombosis. Literature on incidence of venous thromboembolism in inflammatory bowel disease (IBD) is reviewed as well as the possible pathogenetic mechanisms of this 'hypercoagulable state': role of acquired risk factors, inflammation, coagulation abnormalities and platelets. Finally, treatment of IBD and thrombosis is discussed. PMID- 24761695 TI - Irvingia gabonensis (African mango): innocent magic formula? PMID- 24761696 TI - Aorto-gastric fistula caused by an esophageal stent used in the treament of bariatric surgery's complications. PMID- 24761697 TI - Non-surgical treatment of a giant ileal lipoma by endoloop ligation (loop-and-let go). PMID- 24761698 TI - Retrieval of impacted esophageal stent in the ileum with double balloon enteroscopy: a novel technique. PMID- 24761699 TI - The Istanbul protocol (manual on the effective investigation and documentation of torture and other cruel, inhuman or degrading treatment or punishment): implementation and education in Israel. AB - All victims of violence encountered in our emergency rooms and clinics need to be recognized and documented as such. Although there has been progress in the implementation of rules concerning (domestic) violence against women, children and the elderly, the management of cases where patients have been subjected to violence while under the custody of legal enforcement agencies, or patients who have been victims of torture, is still not sufficiently standardized. We describe the Istanbul Protocol of the United Nations, an excellent tool that can help physicians and health professionals recognize and treat cases of torture or institutional violence. PMID- 24761700 TI - Testamentary capacity of the schizophrenic patient. AB - Testamentary capacity refers to an individual's capability to write his or her own will. Psychiatrists are required occasionally to give expert opinions regarding the testamentary capacity of individuals with a medical history or suspected diagnosis of a mental illness. This may stem from the patient/lawyer/ family initiative to explore the current capacity to testate in anticipation of a possible challenge, or may be sought when testamentary capacity of a deceased has been challenged. In this article we examine the medico-legal construct of testamentary capacity of the schizophrenic patient, and discuss the various clinical situations specific to schizophrenic patients, highlighting their impact on the medical opinion regarding testamentary capacity through examining the rulings of Israel's Supreme Court in a specific case where the testamentary capacity of a mentally ill individual who was challenged postmortem, and provide a workable framework for the physician to evaluate the capacity of a schizophrenic patient to write a will.. PMID- 24761701 TI - The role of cardiac computed tomography in infants with congenital heart disease. AB - BACKGROUND: Patients with complex congenital heart disease (CHD) have a high incidence of extracardiac vascular and non-vascular malformations. Those additional abnormalities may have an impact on the precise planning of surgical or non-surgical treatment. OBJECTIVES: To assess the role of electrocardiography gated CT-angiography (ECG-CTA) in the routine evaluation of CHD in neonates and infants particularly for the assessment of extracardiac findings. METHODS: The study cohort comprised 40 consecutive patients who underwent trans-thoracic echocardiography (TTE) and ECG-CTA. TTE and ECG-gated CTA findings regarding extracardiac vascular structures, coronary arteries and airways were compared with surgical or cardiac catheterization findings. Scans were evaluated for image quality using a subjective visual scale (from 1 to 4). Effective radiation dose was calculated for each scan. RESULTS: Median age was 28 +/- 88 days and mean weight 3.7 +/- 1.5 kg. Diagnostic quality was good or excellent (visual image score 3-4) in 39 of 40 scans (97.5%). ECG-CTA provided important additional information on extracardiac vascular structures and airway anatomy, complementing TTE in 75.6% of scans. Overall sensitivity of ECG-gated CTA for detecting extracardiac findings as compared with operative and cardiac catheterization findings was 97.6%. The calculated mean effective radiation dose was 1.4 +/- 0.07 mSv (range 1.014-2.3 mSv). CONCLUSIONS: ECG-CTA is an accurate modality for demonstrating extracardiac structures in complex CHD. It provides important complementary information to TTE with regard to extracardiac vascular structures and coronary artery anatomy. This modality may obviate the need for invasive cardiac catheterization, thus exposing the patient to a much lower radiation dose. PMID- 24761702 TI - National survey of postoperative pain control after cesarean delivery. AB - BACKGROUND: Postoperative pain is a common problem after cesarean deliveries. OBJECTIVES: To characterize common obstetric anesthesia practices after cesarean deliveries in Israel in order to standardize postoperative pain relief protocols. METHODS: A questionnaire was completed during an interview with every obstetric anesthesia unit in all 25 delivery wards in Israel. Data were gathered on intraoperative anesthesia and analgesia protocols as well as postoperative pain relief protocols. A sub-analysis compared units whose director completed a formal obstetric anesthesia training program with those whose directors did not. RESULTS: Neuraxial morphine was used routinely in 12% of hospitals. No unit providing intrathecal morphine complied with American Society of Anesthesiologists guidelines for respiratory monitoring after use of neuraxial opioids. Additionally, non-steroidal anti-inflammatory drugs (NSAIDs) .were used routinely in only half the wards, while patient-controlled analgesia was used infrequently. Postoperative verbal analog scores were not recorded routinely in 71% of units on postoperative day 1. The unit director's training significantly influenced the unit protocols. CONCLUSIONS: Intrathecal morphine, the gold standard of care in cesarean deliveries, is rarely used, mainly due to shortage of staff and lack of formal obstetric anesthesia training. In addition, NSAIDs are also underused. There is a need for more formal training for obstetric anesthesiologists in Israel. PMID- 24761703 TI - Blood pressure in obese and overweight children and adolescents. AB - BACKGROUND: The prevalence of obesity in children and adolescents has increased dramatically in the last few decades. Primary hypertension, a known secondary complication among obese adults, has been considered rare in children. OBJECTIVES: To investigate the prevalence of hypertension and its relation to body mass index (BMI) in obese children aged 9-17 years in Israel. METHODS: Weight, height, BMI, and systolic and diastolic blood pressure (BP) (twice) were measured in children attending general and pediatric endocrine clinics. Obesity was defined as BMI > or = 95th percentile and overweight as BMI > or = 85th percentile. Pre-hypertension and hypertension were defined as systolic and/or diastolic BP > or = 90th percentile for age, gender and height and BP > or = 95th percentile respectively. In children with pre-hypertension or hypertension, repeated measurements were performed. RESULTS: We evaluated 264 children of whom 152 had BMI > or = 85th percentile (study group). Their mean age was 12.5 years. The prevalence of elevated BP (both pre-hypertension and hypertension) in the study group was 44.1% and 31% at the first and second measurements respectively, compared to 11.6% and 1.9% in the normal-weight group. Hypertension was documented in 17.2% of the study group at the second measurement. CONCLUSIONS: Elevated BP was diagnosed in 31% of overweight and obese children and adolescents. Increased awareness and early diagnosis and treatment are essential. PMID- 24761704 TI - Association between cardiac manifestations and antiphospholipid antibody type and level in a cohort of Serbian patients with primary and secondary antiphospholipid syndrome. AB - BACKGROUND: Antiphospholipid syndrome (APS, also known as Hughes syndrome) may manifest itself as a primary or secondary disease, most commonly with systemic lupus erythemathosus (SLE) and various cardiac manifestations. OBJECTIVES: To report the first results from the Serbian National Cohort study, which was started in January 2000. METHODS: Our study included 374 patients: 260 primary APS patients and 114 SLE patients with secondary APS. Antiphospholipid antibody (aPL) analysis included detection of anticardiolipin antibodies (aCL) (immunoglobulin G and M), beta2-glycoprotein 1, and lupus anticoagulant. Echocardiography was performed in all patients, and data on myocardial infarction, unstable angina, chronic cardiomyopathy and acute heart failure were collected. RESULTS: There were 30.7% secondary APS patients and 9.2% primary APS patients with pseudo-infective endocarditis (P = 0.0001). Cardiac manifestations were observed in 28.7% of patients who had more than one type of antibody (category I), in 24.1% with category IIa, in 23.1% with category IIb, and in 27.8% with category IIc (P = 0.78). Age was confirmed as a significant factor for cardiac manifestations in APS patients (52.3 and 43.3 years, respectively, P = 0.001). aCL IgG and IgM positivity was related to valvular changes in all APS patients and high levels of those antibodies increased the risk of these manifestations. CONCLUSIONS: Patients with secondary APS had a higher prevalence ofvalvular lesions, and some aPL types and high levels of aPL were risk factors for specific cardiac manifestations in APS patients. PMID- 24761705 TI - Concomitant occurrence of pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease. AB - Erythema nodosum and pyoderma gangrenosum are common skin manifestations in inflammatory bowel diseases. Curiously, these two cutaneous features have seldom been reported to occur simultaneously. We present three patients affected with inflammatory bowel disease with concomitant erythema nodosum and pyoderma gangrenosum. PMID- 24761707 TI - Physician: make a boundary for thyself--keep out of partisan politics! PMID- 24761708 TI - Varicella pneumonia in a woman receiving methotrexate for psoriatic arthritis. PMID- 24761706 TI - Analgesia following cesarean delivery: "Sometimes it takes a painful experience to make us change our ways" (proverbs 20:30). PMID- 24761709 TI - Port site metastases in squamous cell carcinoma of the gallbladder. PMID- 24761710 TI - Methylprednisolone-induced liver injury: a diagnostic challenge. PMID- 24761711 TI - Beneficial effect of sauna therapy on severe antihistamine-resistant chronic urticaria. PMID- 24761712 TI - A novel simulation-based training program to improve clinical teaching and mentoring skills. AB - BACKGROUND: Physicians are often insufficiently trained in bedside teaching and mentoring skills. OBJECTIVES: To develop, implement and assess a simulation-based training program designed to improve clinical teaching among physicians. METHODS: We developed a one-day tutor training program based on six simulated scenarios with video-based debriefing. The program's efficacy was assessed using questionnaires completed by the participating physicians and their students. Main outcome measures were self-perceived teaching skills at baseline, after participation in the program, and following completion of the tutor role. Secondary outcome measures were the students' perceptions regarding their tutor skills. RESULTS: Thirty-two physicians (mean age 35.5 years, 56% females) participated in the program. Self-assessment questionnaires indicated statistically significant improvement following the program in 13 of 20 measures of teaching skills. Additional improvement was observed upon completion of the tutor role, leading to significant improvement in 19 of the .20 measures. Questionnaires completed by their students indicated higher scores in all parameters as compared to a matched control group of tutors who did not participate in the program, though not statistically significant. Most participants stated that the program enhanced their teaching skills (88%), they implement program-acquired skills when teaching students (79%), and they would recommend it to their peers (100%). Satisfaction was similar among participants with and without previous teaching experience. CONCLUSIONS: A novel one-day simulation-based tutor training program was developed and implemented with encouraging results regarding its potential to improve clinical teaching and mentoring skills. PMID- 24761713 TI - Imaging prior to endoscopic ear surgery: clinical note. AB - Cholesteatoma is an epidermoid cyst that is characterized by independent and progressive growth with destruction of adjacent tissues, especially the bone tissue, and tendency to recurrence. Treatment of cholesteatoma is essentially surgical. The choice of surgical technique depends on the extension of the disease, and preoperative otoscopic and radiological findings can be decisive in planning the optimal surgical approach. Cholesteatoma confined to the middle ear cavity and its extensions can be eradicated by use of the minimally invasive transmeatal endoscopic approach. Computerized tomography of the temporal bones fails to distinguish a cholesteatoma from the inflammatory tissue, granulations, fibrosis or mucoid secretions in 20-70% of cases showing opacification of the middle ear and mastoid. Using the turbo-spin echo (TSE), also known as non-echo planar imaging (non-EPI) diffusion-weighted (DW) magnetic resonance imaging, cholesteatoma can be distinguished from other tissues and from mucosal reactions in the middle ear and mastoid. Current MRI sequences can support the clinical diagnosis of cholesteatoma and ascertain the extent of the disease more readily than CT scans. The size determined by the TSE/HASTE (half-Fourier acquisition single-shot turbo-spin echo) DW sequences correlated well with intraoperative findings, with error margins lying within 1 mm. Our experience with more than 150 endoscopic surgeries showed that lesions smaller than 8 mm confined to the middle ear and its extension, as depicted by the non-EPI images, can be managed with transmeatal endoscopic approach solely. We call upon our otolaryngologist and radiologist colleagues to use the newest MRI modalities in the preoperative evaluation of candidates for cholesteatoma surgery. PMID- 24761714 TI - Large choledocholiathis extracted by endoscopic retrograde cholangiopancreatography after large-balloon sphincteroplasty. PMID- 24761715 TI - Simultaneous bilateral quadriceps tendons rupture in a patient with polyneuropathy. PMID- 24761716 TI - Acceptance of the offer of intra-articular corticosteroid injection at the knee joint. PMID- 24761717 TI - Does estrogen stimulate the pathogenic sort of anticardiolipin antibodies? PMID- 24761718 TI - Modelling risk aversion to support decision-making for controlling zoonotic livestock diseases. AB - Zoonotic infectious livestock diseases are becoming a significant burden for both animal and human health and are rapidly gaining the attention of decision-makers who manage public health programmes. If control decisions have only monetary components, governments are generally regarded as being risk-neutral and the intervention strategy with the highest expected benefit (lowest expected net costs) should be preferred. However, preferences will differ and alternative intervention plans will prevail if (human) life and death outcomes are involved. A rational decision framework must therefore consider risk aversion in the decision-maker and controversial values related to public health. In the present study, risk aversion and its impact on both the utility for the monetary component and the utility for the non-monetary component is shown to be an important element when dealing with emerging zoonotic infectious livestock diseases and should not be ignored in the understanding and support of decision making. The decision framework was applied to several control strategies for the reduction of human cases of brucellosis (Brucella melitensis) originating from sheep in Turkey. PMID- 24761719 TI - Veterinarians as practitioners and as key players in epidemiological surveillance: two tasks, two paradigms to be reconciled. AB - Veterinary practitioners are often involved in epidemiological surveillance systems, where their task is to detect animals suspected of suffering from diseases subject to surveillance and to include them in surveillance. However, these two tasks--practising veterinary medicine and taking part in surveillance- are based on different paradigms. Faced with a sick animal, a practitioner tries to maximise the probability of a correct diagnosis, whereas, when implementing surveillance, a veterinarian is required to maximise the inclusion of suspected cases in surveillance systems. Based on an analysis of the difficulties and problems posed by these coexisting tasks, the authors propose potential solutions through veterinary education and training. The implementers and coordinators of epidemiological surveillance systems must take these factors into account. PMID- 24761720 TI - A quantitative analysis of the supply and demand of veterinary manpower in India: implications for policy decisions. AB - The objective of this study was to estimate and forecastthe supply and demand of veterinary manpower in India. Intake numbers of veterinary students and numbers of graduates and postgraduates were collected for the period 1997 to 2007. Based on the annual growth rate, the demand and supply for the years 2015 and 2020 were predicted. Between 1997 and 2002 the average annual number of veterinary graduates was 1,675. This increased to 1,707 between 2002 and 2007, with a marginal growth rate of 1.87%. With a growth rate of 1.87% in graduates, and 4.5% growth rate in the Indian livestock sector, the number of additional graduates required to fill the gap between supply and demand for the years 2015 and 2020 would be 1,710 and 2,364, respectively. The annual postgraduate requirement for education and research and development is 310. However, between 2002 and 2007 the average annual number of veterinary postgraduates was 995, with a growth rate of 5.3% when compared with the period between 1997 and 2002, indicating a more than three-fold surplus. With a 5.3% growth rate in postgraduates and 4.5% growth rate in the livestock sector, the surplus postgraduates available by 2015 and 2020 will be 1,027 and 1,316, respectively. The study revealed that India is training fewer veterinary graduates and more postgraduates than the system requires. Therefore, it is recommended that attention and resources be directed to the expansion of professional undergraduate veterinary education, while postgraduate veterinary education should be contained and consolidated. PMID- 24761721 TI - Veterinary urban hygiene: a challenge for India. AB - India is confronted with many hygiene problems in urban areas that are related to animal populations. While some of these issues have been present for many years, others are only now emerging. A livestock census in 2003 and another in 2007 revealed that populations of crossbred cattle, goats and poultry are all increasing in urban areas, since this enables easy market access, which, in turn, reduces transportation costs and adds to profits. The canine population has increased along with the human population, largely due to a lack of control measures such as impounding stray animals and euthanasia. These increases in populations of both food-producing animals and stray animals in cities exacerbate such public health hazards as the transmission of zoonoses, vector-borne diseases, occcupational health hazards and environmental pollution, as well as compromising animal welfare. At present, public health hazards due to urban animal husbandry practices are considerably under-estimated. To improve veterinary-related urban hygiene and to facilitate livestock production operations in urban areas, there is an urgent need to develop sound, science based strategies enforced through stringent regulations. The use of One Health teams may provide an answer to these highly integrated public health problems. PMID- 24761722 TI - Veterinarian challenges to providing a multi-agency response to farm animal welfare problems in Ireland: responding to the human factor. AB - In 2012, the authors undertook a study of the challenges facing government and private veterinarians in responding to the human element of farm animal welfare incidents (i.e. the personal problems and difficulties of farmers that can result in farm animal neglect). This paper reports their findings and examines the role of veterinarians in responding to the difficulties of farmers. It also looks at their experiences of attempting to build a multi-agency approach involving veterinary and human support services. This paper builds on a study whereby the authors considered how social, health and attitudinal factors, as well as mental health problems, contribute to farm animal welfare incidents in Ireland. An early warning system involving relevant agencies is in place to identify and prevent farm animal welfare problems before they become critical. The literature provides examples of private veterinarians combining with support services where there are indicators of animal and human abuse. Yet there are no research examples of government or private veterinarians linking with support services to resolve farm animal welfare cases where there are social, health, and/or mental health difficulties with the herd owner. Four focus groups were conducted with government veterinarians (n = 18) and three with private veterinarians (n = 12). Government veterinarians made contact with support services to seek advice on how best to respond to the human element of farm animal welfare incidents, and/or to seek support for the herd owner. Contact between government and private veterinarians was driven by the former. Communication between agencies was influenced by individual efforts and personal contacts. Formal structures and guidelines, perceived professional capabilities in determining herd owner needs, and client confidentiality concerns among support services and private veterinarians were less influential. The fear of losing clients and the financial implications of this were also cited by private veterinarians. Family, neighbours and local support groups assisted in reaching an on-farm solution. The paper concludes with the requirements for a multi-agency approach in Ireland: the provision of tailored information and guidelines targeting government and private veterinarians and support services, and a comprehensive structure for relationship-building, planning, and cross-reporting between all the relevant agencies. PMID- 24761723 TI - Applying the OIE Terrestrial Animal Health Code to the welfare of animals exported from Australia. AB - Australia has implemented a through-chain regulatory framework to address animal welfare issues in the livestock export trade. The framework places the responsibility for ensuring that the welfare of exported animals meets internationally accepted standards on those who hold the licences issued for the export of Australian livestock. It applies to all livestock (cattle, buffalo, sheep, goats, camels) exported from Australia, either for immediate slaughter or for feeding and eventual slaughter. The development of the framework began when the Australian Standards for the Export of Livestock were implemented in December 2004, to safeguard animal welfare from the point when the animals are selected for export up until the moment when they are offloaded in the destination country. The framework has recently been extended to incorporate animal welfare requirements through to the point of slaughter in the destination country. The requirements draw on, and are consistent with, the animal welfare chapters of the World Organisation for Animal Health (OIE) Terrestrial Animal Health Code. PMID- 24761724 TI - Gastrointestinal campylobacteriosis in industrialised countries: comparison of the disease situation with salmonellosis, and microbiological contamination assessment. AB - The science-based assessment of foodborne zoonotic risk is used to evaluate the public health impact of a hazard and to guide public decision-making on control measures. Key information for the hazard characterisation and microbiological contamination assessment phases of risk assessment may be obtained from the collection and structured statistical analysis of international data. This approach was used for the hazard characterisation phase of a risk assessment of gastrointestinal campylobacteriosis and salmonellosis in 30 industrialised countries over the period 2005-2009. The results showed an overall increase in the annual ratio campylobacteriosis/salmonellosis (R(moy) > 2), despite significant differences among countries (P < 0.0001). For countries with complete data over 20 years, the results showed significantly higher exposure to campylobacteriosis among certain population segments (men, children under 5 years of age and adults aged between 20 and 30), as well as in summer. A number of paired factors (Campylobacter species/animal species-meat type) are observed in this consumer exposure. However, the overall rate of bacterial transfer in meat supply chains varies widely, with far lower values for cattle (0.16) and pigs (0.24) than for poultry (0.60) and chickens (1.17). A lack of harmonised epidemiological data on the contamination status of foodstuffs (frequency, level, site, and species) further hampers the accurate identification of critical points of contamination and of the spread of the hazard throughout the food chain. PMID- 24761725 TI - Assessing the relationship between farming practices, laboratory analyses and post-mortem findings: a case study in pig fattening. AB - European Union legislation on animal production associated with food safety requires the collection and management of information and data about the farm, the herd and the individual animal. This paper describes the technical steps of the generation, collection and interpretation of data from 296 pig-fattening farms, belonging to two farming associations and using indoor production systems (56 management parameters). The paper also describes post-mortem findings and the results of enzyme-linked immunosorbent assays (ELISA) for antibodies to salmonellae, Trichinella spp. and Yersinia spp. A total of nearly 30 million data points were collected and analysed for this study. The results of the ELISA were negative for Trichinella spp.; for salmonellae and Yersinia spp., both negative and positive results were obtained. Analysis of the farm management parameters showed no significant differences; therefore, the cut-off levels for salmonellae and Yersinia spp. were increased, in order to identify farms with a greater hygiene burden. Post-mortem findings, possibly related to 'farm hygiene', were used in the analysis. As a result, three farms with particular management decisions were identified as potentially having contributed to the high burden of pathogens detected using ELISA. A relationship between laboratory results and farm management parameters assessed from yes/no answers could not be established in this study without further work on the available data set. PMID- 24761726 TI - Illegal import of bushmeat and other meat products into Switzerland on commercial passenger flights. AB - Illegal imports of meat can present substantial risks to public and animal health. Several European countries have reported considerable quantities of meat imported on commercial passenger flights. The objective of this study was to estimate the quantity of meat illegally imported into Switzerland, with a separate estimation for bushmeat. Data were obtained by participation in intervention exercises at Swiss international airports and by analysing data on seizures during the four-year period 2008 to 2011. The study revealed that a wide array of animal species was imported into Switzerland. From the database, the average annual weight of meat seized during the period analysed was 5.5 tonnes, of which 1.4% was bushmeat. However, in a stochastic model the total annual inflow of illegal meat imports was estimated at 1,013 tonnes (95% CI 226 to 4,192) for meat and 8.6 tonnes (95% CI 0.8 to 68.8) for bushmeat. Thus, even for a small European country such as Switzerland the quantities of illegally imported meat and meat products are substantial and the consequences for public and animal health could be high. To reduce the risk, it is essential that surveillance at European airports is harmonised and that passenger information campaigns clarify the consequences of the illegal import of meat, particularly bushmeat. PMID- 24761727 TI - Data management systems for the bovine viral diarrhoea eradication programme in Switzerland. AB - A programme to eradicate bovine viral diarrhoea was launched in Switzerland in 2008 with the aim of eradicating the causal virus. During the first year of the programme, the entire population of 1.6 million cattle were tested for the presence of the virus; in the following three years an additional 1.8 million calves were tested. The complexity of information generated during the eradication programme, together with a tight schedule, made computerised data management a necessity. To organise, coordinate and supervise the programme, extensions were made to the computerised information system ISVet, of the Swiss Veterinary Service, which provides automated documents for both the Veterinary Service and private veterinarians. Specific data are accessible by user groups via the BVD-Web platform, ISVet and the Swiss animal movement database. The functionalities of the structure and the reports needed to control the progress of the programme are described in detail. The authors also discuss the major advantages, disadvantages and pitfalls when planning an eradication programme using a national centralised database over a distributed computer network. PMID- 24761728 TI - Risk assessment for the design of a risk-based surveillance programme for fish farms in Switzerland (in accordance with Council Directive 2006/88/EC of the European Union). AB - Swiss aquaculture farms were assessed according to their risk of acquiring or spreading viral haemorrhagic septicaemia (VHS) and infectious haematopoietic necrosis (IHN). Risk factors for the introduction and spread of VHS and IHN were defined and assessed using published data and expert opinions. Among the 357 aquaculture farms identified in Switzerland, 49.3% were categorised as high risk, 49.0% as medium risk and 1.7% as low risk. According to the new Directive 2006/88/EC for aquaculture of the European Union, the frequency of farm inspections must be derived from their risk levels. A sensitivity analysis showed that water supply and fish movements were highly influential on the output of the risk assessment regarding the introduction of VHS and IHN. Fish movements were also highly influential on the risk assessment output regarding the spread of these diseases. PMID- 24761729 TI - Seroepidemiological survey of bovine brucellosis in cattle under a traditional production system in western Ethiopia. AB - Bovine brucellosis, an important bacterial zoonosis, is usually associated with intensive systems of production. A cross-sectional study was conducted in western Ethiopia to determine the seroprevalence of bovine brucellosis in cattle undertraditional extensive husbandry. Sera collected from 1,152 cattle originating from 164 herds were screened, using the Rose Bengal test, and all positive sera were then examined, using complement fixation as a confirmatory test. Based on the results of two-step testing, the apparent seroprevalences were 1% (95% confidence interval [CI]: 0.5%, 1.7%) at the animal level and 4.9% (95% CI: 1.6%, 8.2%) at the herd level. A random-effects binary logistic regression model was used to examine potential risk factors, using 'herd' as a random effect. Herd size (p = 0.009) and abortion (p = 0.015) were significant risk factors for animal-level seropositivity, after controlling for other factors. Although bovine brucellosis was found at a low prevalence in the indigenous cattle population, the disease should be considered in any future expansion of dairy cattle production involving improved breeds. PMID- 24761730 TI - Epizootiological investigation of the most important infectious equine diseases in Greece. AB - During the period 2001 to 2008, a total of 7,872 equine sera were tested at the Centre of Veterinary Institutes of Athens. Antibodies against seven infectious diseases of equids were determined: equine infectious anaemia (EIA), African horse sickness (AHS), equine viral arteritis (EVA), West Nile encephalitis (WNE), glanders, piroplasmosis and dourine. Tests for the four viral diseases found 4.5% seropositivity for EIA, 0% for AHS, 3.3% for EVA and 4% for WNE. All sera tested for glanders antibodies were negative. Tests for piroplasmosis detected antibodies against T. equi and B. caballi in 12.9% and 1.3% of the sera, respectively. No sample tested positive for dourine. The results of this epidemiological survey provide strong evidence that Greece is free from the diseases of AHS, glanders and dourine. PMID- 24761731 TI - The efficiency of wire nets in enhancing the biosecurity of poultry in Brazil. AB - The aim of this study was to evaluate the efficiency of the use of wire nets of various mesh sizes to enhance biosecurity in the poultry industry in Brazil by preventing other bird species from entering chicken houses. The Brazilian poultry industry is technologically advanced and employs updated technology. The current Brazilian guidelines recommend the use of 25.40 mm mesh. However, scientific evidence of the efficiency of the nets recommended by these guidelines is lacking. In this study, a bird biometric methodology was developed to evaluate bird species. The methodology was based on the body dimensions of the animal, and it employed a new statistical design to analyse the data. Three groups of bird species were designated according to their importance. The value of this criterion (the importance of the species) was estimated by assessing the ability of birds to pass through the net. The paradigm was used to study 23 wild avian species that are naturally present in Brazil. The best results were observed for nets with a mesh size < or = 19.11 mm. This mesh size was able to efficiently restrain all of the species studied. However, in the same test, the net with 25.40 mm mesh could not restrain 11 bird species, one of which was Passer domesticus, which is found worldwide. On the basis of these results, the use of 19.11 mm mesh should be strongly recommended in order to achieve biosecurity of poultry houses. PMID- 24761732 TI - Bayesian estimation of the seroprevalence of brucellosis in humans and livestock in Kyrgyzstan. AB - Kyrgyzstan reported 77.5 new cases of human brucellosis per 100,000 inhabitants in 2007, which is one of the highest incidences in the world. However, because this number is based on official records, it is very likely that the incidence is underreported. The diagnostic tests most commonly used in Kyrgyzstan are the Rose Bengal test in ruminants and the Huddleson test in humans. The sensitivity and specificity of these tests have never been evaluated under field conditions in Kyrgyzstan, where the strains circulating in livestock and humans are unknown. Therefore, a representative national cross-sectional serological study was undertaken in humans, cattle, sheep and goats to assess the true seroprevalence and to compare different serologicaltests. In the year of study (2006), few animals were vaccinated against brucellosis in Kyrgyzstan. A total of 5,229 livestock sera and 1,777 human sera from three administrative regions were collected during spring 2006 and submitted to a range of serological tests. The true seroprevalence of brucellosis, estimated using Bayesian methodology, was 7% (95% credibility interval 4%-9%) in humans, 3% (1%-5%) in cattle, 12% (7%-23%) in sheep and 15% (7%-30%) in goats. The Rose Bengal test was confirmed as a useful screening test in livestock and humans, although its sensitivity was lower than that of other tests. The estimates of specificity of all tests were significantly higher than those for sensitivity. The high seroprevalence of brucellosis in humans, cattle and small ruminants in Kyrgyzstan was confirmed. Bayesian statistical approaches were demonstrated to be useful for simultaneously deriving test characteristics and true prevalence estimates in the absence of a gold standard. PMID- 24761733 TI - Chlamydial infections in Chinese livestock. AB - The occurrence and impact of chlamydial infections in Western livestock is well documented in the international literature, but less is known aboutthese infections in livestock in the People's Republic of China. China's livestock production and its share in the global market have increased significantly in recent decades. In this review, the relevant English and Chinese literature on the epidemiology of chlamydial infections in Chinese livestock is considered, and biosecurity measures, prophylaxis and treatment of these infections in China's livestock are compared with Western practices. Chlamydial infections are highly prevalent in Chinese livestock and cause important economic losses, as they do in the rest of the world. Surveillance data and diagnostic results of abortion outbreaks in cattle, sheep and goats highlight the importance of virulent chlamydial infections in China's major ruminant species in many of China's provinces, autonomous regions and municipalities. Data from many of China's provincial divisions also indicate the widespread presence of chlamydial infections in industrially reared swine across the country. Less is known about chlamydial infections in yak, buffalo and horses, but available reports indicate a high prevalence in China's populations. In these reports, chlamydiosis was related to abortions in yak and pneumonia in horses. In Western countries, chlamydial infections are principally treated with antibiotics. In China, however, traditional medicine is often used in conjunction with antibiotics or used as an alternative treatment. PMID- 24761734 TI - Diarrhoeagenic Escherichia coli and salmonellae in calves and lambs in Kashmir absence, prevalence and antibiogram. AB - Polymerase chain reaction assays and culture were used to investigate 728 faecal samples from 404 calves (286 diarrhoeic, 118 healthy) and 324 lambs (230 diarrhoeic, 94 healthy) in Kashmir, India, for the presence of enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli (EAEC), diffusely adherent E. coli (DAEC) and salmonellae. Antimicrobial sensitivity patterns were also investigated. In total, 23 ETEC isolates were obtained from the diarrhoeic calves and 12 from diarrhoeic lambs. Most (74%) of the isolates from calves harboured the gene encoding heat-labile enterotoxin I, whereas 75% of the isolates from lambs possessed only the gene encoding for heat-stable enterotoxin a. The ETEC isolates belonged to 20 serogroups, among which serogroups O15 (five isolates) and O8 (four isolates) were the most frequent. Salmonella Typhimurium or S. Enteritidis was identified in three samples from diarrhoeic lambs. The ETEC isolates and the salmonellae showed multidrug resistance. No EAEC or DAEC was detected in any of the samples. PMID- 24761735 TI - Antibiotic resistance of Clostridium perfringens isolates from broiler chickens in Egypt. AB - The use of antibiotic feed additives in broiler chickens results in a high prevalence of resistance among their enteric bacteria, with a consequent emergence of antibiotic resistance in zoonotic enteropathogens. Despite growing concerns about the emergence of antibiotic-resistant strains, which show varying prevalences in different geographic regions, little work has been done to investigate this issue in the Middle East. This study provides insight into one of the world's most common and financially crippling poultry diseases, necrotic enteritis caused by Clostridium perfringens. The study was designed to determine the prevalence of antibiotic resistance in C. perfringens isolates from clinical cases of necrotic enteritis in broiler chickens in Egypt. A total of 125 isolates were obtained from broiler flocks in 35 chicken coops on 17 farms and were tested using the disc diffusion method. All 125 isolates were resistant to gentamicin, streptomycin, oxolinic acid, lincomycin, erythromycin and spiramycin. The prevalence of resistance to other antibiotics was also high: rifampicin (34%), chloramphenicol (46%), spectinomycin (50%), tylosin-fosfomycin (52%), ciprofloxacin (58%), norfloxacin (67%), oxytetracycline (71%), flumequine (78%), enrofloxacin (82%), neomycin (93%), colistin (94%), pefloxacin (94%), doxycycline (98%) and trimethoprim-sulfamethoxazole (98%). It is recommended that C. perfringens infections in Egypt should be treated with antibiotics for which resistant isolates are rare at present; namely, amoxicillin, ampicillin, cephradine, fosfomycin and florfenicol. PMID- 24761736 TI - Detection of sheep-associated malignant catarrhal fever from clinical cases in Ethiopian cattle. AB - Mucoid nasal discharge, loss of weight, decreased milk production, diarrhoea, salivation, dyspnoea, fever, lacrimation, bilateral corneal opacity and bloody urine were observed in cattle located in the Arbe Gona district of southern Ethiopia. The disease was associated with a high case fatality rate: diseased cattle died within four to five days after showing clinical signs. The clinical presentation, gross pathological observations, histopathological findings and epidemiological data strongly suggested malignant catarrhal fever. Subsequently, the ovine herpesvirus type 2 (OvHV-2) DNA polymerase (UL30) gene was detected in pathological tissue samples using pan-herpesvirus nested polymerase chain reaction (PCR) and real-time PCR. As far as the authors are aware, this is the first report of a diagnostic investigation resulting in the detection of ovine OvHV-2 in cattle and confirming the existence of sheep-associated malignant catarrhal fever in Ethiopia. PMID- 24761737 TI - Chytridiomycosis: a global threat to amphibians. AB - Chytridiomycosis, which is caused by Batrachochytrium dendrobatidis, is an emerging infectious disease of amphibians. The disease is one of the main causes of the global decline in amphibians. The aetiological agent is ubiquitous, with worldwide distribution, and affects a large number of amphibian species in several biomes. In the last decade, scientific research has substantially increased knowledge of the aetiological agent and the associated infection. However, important epidemiological aspects of the environment-mediated interactions between the aetiological agent and the host are not yet clear. The objective of the present review is to describe chytridiomycosis with regard to the major features of the aetiological agent, the host and the environment. PMID- 24761738 TI - Prevalence of ovine footrot in the tropical climate of southern India and isolation and characterisation of Dichelobacter nodosus. AB - The present communication records the first determination of the prevalence of footrot in the unexpected situation of the tropical climate of Andhra Pradesh and Tamil Nadu, two states in southern India where the maximum temperature rises to 42 degrees C. In total, 73 outbreaks of footrot in Nellore brown sheep were investigated in 11 districts of Andhra Pradesh and one district of Tamil Nadu during the period March 2009 to March 2011.The overall prevalence of ovine footrot was 15%, with severity scores of 2 to 4 (lesion severity scale 0 to 4). The outbreaks occurred mostly during the rainy season, which is usually from June to December. From a total of 1,050 samples of lesions in naturally infected sheep, 478 (45.5%) were positive for Dichelobacter nodosus. Serogrouping of the isolates revealed six serogroups: A, B, C, E, F and I. Among the positive samples, 448 (93.7%) were a single serogroup and 30 (6.3%) carried a mixed infection with two serogroups. Taking single and mixed infections together, serogroup B was most frequent at 50.4% and was found in all districts, followed by serogroup I in 29.3% of samples, A in 14%, F in 6.7% and C in 5.6%. Serogroup E was detected in only one sample. Serogroups A and F were detected for the first time in India. All of 58 D. nodosus isolates in a sub-sample representing different serogroups were found to be virulent, based on the production of thermostable proteases and the presence of the integrase A gene intA. Thus, the present paper reporting isolation and characterisation of D. nodosus confirms the occurrence of virulent footrot in the tropical climate of southern India. PMID- 24761739 TI - Cross-sectional study of cattle lice infestation in the region of Nabeul in north east Tunisia. AB - This cross-sectional study is the first to estimate the prevalence of cattle pediculosis in Tunisia. A total of 39 cattle farms in the region of Nabeul in north-east Tunisia were visited and lice were collected by intensively brushing 789 cattle. The prevalence was estimated to be 20.5% on the farms (8/39) and 4.7% in animals (37/789). Collected parasites were examined under a stereomicroscope and three lice species were identified: Bovicola bovis, Linognathus vituli and Haematopinus eurysternus. Thirty-two animals were infested with the chewing lice B. bovis (4%), three with H. eurysternus (0.4%) and two with L. vituli (0.2%). The infestation prevalence was higher in calves under eight months of age (21.6%)than in adults (0.8%). Decision-makers in animal health should consider this parasitic disease in their control and eradication programmes. PMID- 24761740 TI - Recent molecular biology methods for foulbrood and nosemosis diagnosis. AB - Honey-bee colony losses are an increasing problem in Western countries. There are many different causes, including infections due to various pathogens. Molecular biology techniques have been developed to reliably detect and identify honey-bee pathogens. The most sensitive, specific and reliable is the quantitative real time polymerase chain reaction (qPCR) methodology. This review of the literature describes various studies where qPCR was used to detect, identify and quantify four major honey-bee pathogens: the bacteria Paenibacillus larvae and Melissococcus plutonius (the causative agents of American foulbrood and European foulbrood, respectively) and the microsporidia Nosema apis and N. ceranae (the causative agents of nosemosis). The application of qPCR to honey-bee pathogens is very recent, and techniques are expected to improve rapidly, leading to potential new prospects for diagnosis and control. Thus, qPCR techniques could shortly become a powerful tool for investigating pathogenic infections and increasing our understanding of colony losses. PMID- 24761741 TI - High-throughput sequencing in veterinary infection biology and diagnostics. AB - Sequencing methods have improved rapidly since the first versions of the Sanger techniques, facilitating the development of very powerful tools for detecting and identifying various pathogens, such as viruses, bacteria and other microbes. The ongoing development of high-throughput sequencing (HTS; also known as next generation sequencing) technologies has resulted in a dramatic reduction in DNA sequencing costs, making the technology more accessible to the average laboratory. In this White Paper of the World Organisation for Animal Health (OIE) Collaborating Centre for the Biotechnology-based Diagnosis of Infectious Diseases in Veterinary Medicine (Uppsala, Sweden), several approaches and examples of HTS are summarised, and their diagnostic applicability is briefly discussed. Selected future aspects of HTS are outlined, including the need for bioinformatic resources, with a focus on improving the diagnosis and control of infectious diseases in veterinary medicine. PMID- 24761743 TI - Synthesis of the PMB ether of 5,6-epoxyisoprostane E2 through aldol reaction of the alpha-bromocyclopentanone. AB - 5,6-Epoxyisoprostane E2 was synthesized via bromohydrination of the cyclopentene and aldol reaction of the alpha-bromocyclopentanone with the epoxyaldehyde. High regioselectivity in the bromohydrination was attained with recrystallized NBS and pyridine in aqueous DMSO. The enolate for the aldol reaction was generated by adding t-BuLi to the mixture of the alpha-bromocyclopentanone and ZnI2. This aldol protocol was applied successfully to several cyclopentanones and aldehydes. PMID- 24761744 TI - Needs-driven versus market-driven pharmaceutical innovation: the consortium for the development of a new medicine against malaria in Brazil. AB - The prevailing model for encouraging innovation based on patents and market oriented raises at least two economic and ethical issues: it imposes barriers on individuals and developing countries governments' access to medicines by defining prices that do not match their income, and the unavailability of new or appropriate products to address the health problems of these populations. In the last decade, this scenario has undergone some changes due to the emergence of new actors, the contribution of aid resources, the introduction to the market of new products against neglected diseases, the development of new governmental healthcare policies and research programs, etc. One example of such initiatives is the Fixed-Dose Artesunate Combination Therapy (FACT) project consortium, which brought together institutions with different natures from both the North and the South, for the development of two antimalarial fixed-dose combinations recommended by the WHO - artesunate-amodiaquine (ASAQ) and artesunate-mefloquine (ASMQ). This paper proposes to describe and analyze the ASMQ consortium, which is the result of a new pharmaceutical development approach, based on a different paradigm - needs-driven instead of market-driven -, collaborative, with strategic participation of institutions from the South, funded by alternative resources (public and philanthropic). Thus, it represents an interesting object of study for bioethical debates on intellectual property and innovation, and its analysis is justified in light of the current debate on ways of stimulating needs-driven pharmaceutical innovation. PMID- 24761745 TI - Radiation resistance and loss of crystal violet binding activity in Yersinia enterocolitica suspended in raw ground pork exposed to gamma radiation and modified atmosphere. AB - Virulence of many foodborne pathogens is directly linked to genes carried on self replicating extra-chromosomal elements, which can transfer genetic material, both vertically and horizontally, between bacteria of the same and different species. Pathogenic Yersinia enterocolitica harbors a 70-kb virulence plasmid (pYV) that encodes genes for low calcium response, crystal violet (CV) binding, Congo red uptake, autoagglutination (AA), hydrophobicity (HP), type III secretion channels, host immune suppression factors, and biofilm formation. Ionizing radiation and modified atmosphere packaging (MAP) are used to control foodborne pathogens and meat spoilage. In this study, the effect of gamma radiation and modified atmosphere (air, 100% N2 , 75% N2 : 25% CO2 , 50% N2 : 50% CO2 , 25% N2 : 75% CO2 , 100% CO2 ) were examined by using the CV binding phenotype, for the presence or absence of pYV in Y. enterocolitica, suspended in raw ground pork. All Y. enterocolitica serovars used (O:3, O:8, and O5,27) were more sensitive to radiation as the CO2 concentration increased above 50%. Crystal violet binding following a radiation dose of 1.0 kGy, which reduced the Y. enterocolitica serovars >5 log, was greatest in the presence of air (ca. 8%), but was not affected by N2 or CO2 concentration (ca. 5%). Following release from modified atmosphere after irradiation, the loss of CV binding rose from 5% to 8% immediately following irradiation to >30% after outgrowth at 25 degrees C for 24 h. These results, using Y. enterocolitica as a model system, indicate that the risk of foodborne illness could be affected by the loss of virulence factors when postprocess intervention technologies are used. PRACTICAL APPLICATION: Provides gamma radiation D10 data for inactivation data for Y. enterocolitica irradiated under modified atmosphere and information to risk assessors regarding the difference between pathogen presence versus actual virulence. PMID- 24761746 TI - Measuring risk, managing values: health technology and subjectivity in Denmark. AB - Based on fieldwork among Danes with a diagnosed risk of type 2 diabetes or cardiovascular disease, this paper investigates how the technological possibilities of diagnosing and monitoring invisible risks shape understandings of health and form subjectivity. It focuses on the experiences of being diagnosed with a risk condition in the form of high blood pressure or elevated blood glucose and the ensuing use of measuring devices. It argues that measurements of these conditions can be seen as 'formative processes' that produce and maintain a view of health as something that can best be known through the use of medical technology. The numerical values such measurements yield are seen as true indicators of health, and doing something about risk conditions is felt to be a personal imperative. The formative processes illustrated in this paper are motivational and thought provoking. The informants do not experience new symptoms after being diagnosed; rather they reflect upon their health in a new way and numbers become associated with personal responsibility and morality. However, because numbers influence subjective experiences, they can come to take up too much space in everyday life. Therefore, people have reservations about how often they should measure their values at home. The formative processes of being diagnosed with a risk condition are thus about subjectivity both in the sense of being subject to the demands of living with an illness and of being a subject who acts to keep life from being colonized by concerns about health. PMID- 24761747 TI - Does type of disability make a difference in affiliate stigma among family caregivers of individuals with autism, intellectual disability or physical disability? AB - BACKGROUND: Studies have shown that beyond public and self stigma, stigma can also impact family members. Only scant research has examined the internalised aspects of stigma, known as affiliate stigma, among family caregivers of individuals with disabilities. This study examined affiliate stigma among family caregivers of individuals with developmental disabilities via a comparison between caregivers of individuals with intellectual disabilities (ID), autism spectrum disorders (ASD) and physical disabilities (PD) in Israel. METHODS: Family caregivers (n = 171) of individuals with developmental disabilities, mainly ID (22.4%), ASD (32.9%) and PD (27.1%), completed a self-report structured questionnaire including the Affiliate Stigma Scale and background variables. RESULTS: Results supported a one-factor structure for the Affiliate Stigma Scale. Overall, affiliate stigma was relatively low in this sample, but was found to be higher among caregivers of individuals with ASD when compared with caregivers of individuals with ID or PD. CONCLUSION: Findings from this study point to the importance of supporting caregivers of individuals with ASD to decrease their feelings of stigma. It is also important to further develop scales measuring affiliate stigma in order to capture the multi-dimensional nature of the concept. PMID- 24761748 TI - Stabilization of thin liquid films by repulsive van der Waals force. AB - Using high-speed video recording of bubble rise experiments, we study the stability of thin liquid films trapped between a rising bubble and a surfactant free liquid-liquid meniscus interface. Using different combinations of nonpolar oils and water that are all immiscible, we investigate the extent to which film stability can be predicted by attractive and repulsive van der Waals (vdW) interactions that are indicated by the relative magnitude of the refractive indices of the liquid combinations, for example, water (refractive index, n = 1.33), perfluorohexane (n = 1.23), and tetradecane (n = 1.43). We show that, when the film-forming phase was oil (perfluorohexane or tetradecane), the stability of the film could always be predicted from the sign of the vdW interaction, with a repulsive vdW force resulting in a stable film and an attractive vdW force resulting in film rupture. However, if aqueous electrolyte is the film-forming bulk phase between the rising air bubble and the upper oil phase, the film always ruptured, even when a repulsive vdW interaction was predicted. We interpret these results as supporting the hypothesis that a short-ranged hydrophobic attraction determines the stability of the thin water film formed between an air phase and a nonpolar oil phase. PMID- 24761749 TI - Benchmark theoretical study of the pi-pi binding energy in the benzene dimer. AB - We establish a new estimate for the binding energy between two benzene molecules in the parallel-displaced (PD) conformation by systematically converging (i) the intra- and intermolecular geometry at the minimum, (ii) the expansion of the orbital basis set, and (iii) the level of electron correlation. The calculations were performed at the second-order Moller-Plesset perturbation (MP2) and the coupled cluster including singles, doubles, and a perturbative estimate of triples replacement [CCSD(T)] levels of electronic structure theory. At both levels of theory, by including results corrected for basis set superposition error (BSSE), we have estimated the complete basis set (CBS) limit by employing the family of Dunning's correlation-consistent polarized valence basis sets. The largest MP2 calculation was performed with the cc-pV6Z basis set (2772 basis functions), whereas the largest CCSD(T) calculation was with the cc-pV5Z basis set (1752 basis functions). The cluster geometries were optimized with basis sets up to quadruple-zeta quality, observing that both its intra- and intermolecular parts have practically converged with the triple-zeta quality sets. The use of converged geometries was found to play an important role for obtaining accurate estimates for the CBS limits. Our results demonstrate that the binding energies with the families of the plain (cc-pVnZ) and augmented (aug-cc-pVnZ) sets converge [within <0.01 kcal/mol for MP2 and <0.15 kcal/mol for CCSD(T)] to the same CBS limit. In addition, the average of the uncorrected and BSSE-corrected binding energies was found to converge to the same CBS limit much faster than either of the two constituents (uncorrected or BSSE-corrected binding energies). Due to the fact that the family of augmented basis sets (especially for the larger sets) causes serious linear dependency problems, the plain basis sets (for which no linear dependencies were found) are deemed as a more efficient and straightforward path for obtaining an accurate CBS limit. We considered extrapolations of the uncorrected (DeltaE) and BSSE-corrected (DeltaEcp) binding energies, their average value (DeltaEave), as well as the average of the latter over the plain and augmented sets (DeltaEave) with the cardinal number of the basis set n. Our best estimate of the CCSD(T)/CBS limit for the pi-pi binding energy in the PD benzene dimer is De = -2.65 +/- 0.02 kcal/mol. The best CCSD(T)/cc-pV5Z calculated value is -2.62 kcal/mol, just 0.03 kcal/mol away from the CBS limit. For comparison, the MP2/CBS limit estimate is -5.00 +/- 0.01 kcal/mol, demonstrating a 90% overbinding with respect to CCSD(T). The spin component-scaled (SCS) MP2 variant was found to closely reproduce the CCSD(T) results for each basis set, while scaled opposite spin (SOS) MP2 yielded results that are too low when compared to CCSD(T). PMID- 24761750 TI - Promoting self-management and adherence with strength and balance training for older people with long-term conditions: a mixed-methods study. AB - RATIONALE, AIMS AND OBJECTIVES: In the context of an ageing population, increasing numbers of older people with long-term conditions are presenting to secondary health care facilities in the United Kingdom having experienced a fall or fall-related injury. Despite such observations, falls and long-term conditions have traditionally been regarded as entirely separate entities. The purpose of this study was to explore the process of behaviour change in a small sample of older people with the fall-associated chronic liver disease primary biliary cirrhosis (PBC) receiving either a standard or an enhanced programme of strength and balance training (SBT). METHODS: A qualitatively driven mixed-methods approach was employed that juxtaposed semi-structured interviews with graphical representations of patient-reported outcome measures collected during the course of an experimental case series in nine older people with the fall-associated chronic liver disease PBC. RESULTS: Participants receiving both the standard and enhanced intervention completed the programme of SBT as instructed throughout the course of the case series. However, only the enhanced intervention, which focused on self-determination and self-management support, was associated with continued active participation on completion of the programme. CONCLUSIONS: Longer, but not necessarily more intensive, periods of clinical intervention are necessary to support individuals at risk of falling to move through the incremental stages of behaviour change. Effective self-management support should focus on the development of a wide range of strategies and behaviours to empower older people with long-term conditions develop an ongoing active commitment to SBT. PMID- 24761751 TI - Strategy to improve photovoltaic performance of DSSC sensitized by zinc prophyrin using salicylic acid as a tridentate anchoring group. AB - Three new zinc porphyrin dyes attached to ethynyl benzoic acid as an electron transmission and anchoring group have been designed, synthesized, and well characterized. The performances of their sensitized solar cells have been investigated by optical, photovoltaic, and electrochemical methods. The photoelectric conversion efficiency of the solar cells sensitized by the dye with salicylic acid as an anchoring group demonstrated obvious enhancement when compared with that sensitized by the dye with carboxylic acid as an anchoring group. The density functional theory calculations and the electrochemical impedance spectroscopies revealed that tridentate binding modes could increase the efficiency of electron injection from dyes to the TiO2 nanoparticles by more electron pathways. PMID- 24761752 TI - Lectin-tagged fluorescent polymeric nanoparticles for targeting of sialic acid on living cells. AB - In this study, we fabricated lectin-tagged fluorescent polymeric nanoparticles approximately 35 nm in diameter using biocompatible polymers conjugated with lectins for the purpose of detecting sialic acid on a living cell surface, which is one of the most important biomarkers for cancer diagnosis. Through cellular experiments, we successfully detected sialic acid overexpression on cancerous cells with high specificity. These fluorescent polymeric nanoparticles can be useful as a potential bioimaging probe for detecting diseased cells. PMID- 24761753 TI - Comparison of three artificial models of the magnetohydrodynamic effect on the electrocardiogram. AB - The electrocardiogram (ECG) is often acquired during magnetic resonance imaging (MRI), but its analysis is restricted by the presence of a strong artefact, called magnetohydrodynamic (MHD) effect. MHD effect is induced by the flow of electrically charged particles in the blood perpendicular to the static magnetic field, which creates a potential of the order of magnitude of the ECG and temporally coincident with the repolarisation period. In this study, a new MHD model is proposed by using MRI-based 4D blood flow measurements made across the aortic arch. The model is extended to several cardiac cycles to allow the simulation of a realistic ECG acquisition during MRI examination and the quality assessment of MHD suppression techniques. A comparison of two existing models, based, respectively, on an analytical solution and on a numerical method-based solution of the fluids dynamics problem, is made with the proposed model and with an estimate of the MHD voltage observed during a real MRI scan. Results indicate a moderate agreement between the proposed model and the estimated MHD model for most leads, with an average correlation factor of 0.47. However, the results demonstrate that the proposed model provides a closer approximation to the observed MHD effects and a better depiction of the complexity of the MHD effect compared with the previously published models, with an improved correlation (+5%), coefficient of determination (+22%) and fraction of energy (+1%) compared with the best previous model. The source code will be made freely available under an open source licence to facilitate collaboration and allow more rapid development of more accurate models of the MHD effect. PMID- 24761754 TI - Owner-reported coughing and nasal discharge are associated with clinical findings, arterial oxygen tension, mucus score and bronchoprovocation in horses with recurrent airway obstruction in a field setting. AB - REASONS FOR PERFORMING STUDY: In clinical practice, veterinarians often depend on owner-reported signs to assess the clinical course of horses with recurrent airway obstruction (RAO). OBJECTIVES: To test whether owner-reported information on frequency of coughing and observation of nasal discharge are associated with clinical, cytological and bronchoprovocation findings in RAO-affected horses in nonstandardised field conditions. STUDY DESIGN: Cross-sectional study comparing healthy and RAO-affected horses. METHODS: Twenty-eight healthy and 34 RAO affected Swiss Warmblood horses were grouped according to owner-reported 'coughing frequency' and 'nasal discharge'. Differences between these groups were examined using clinical examination, blood gas analyses, endoscopic mucus scores, cytology of tracheobronchial secretion and bronchoalveolar lavage fluid, and airway hyperresponsiveness determined by plethysmography with histamine bronchoprovocation. RESULTS: Frequently coughing horses differed most markedly from healthy control animals. Histamine bronchoprovocation-derived parameters were significantly different between the healthy control group and all RAO groups. Mucus grades and tracheobronchial secretion and bronchoalveolar lavage fluid neutrophil percentages had particularly high variability, with overlap of findings between groups. Owner satisfaction with the clinical status of the horse was high, even in severely affected horses. CONCLUSIONS: Owner-reported coughing and nasal discharge are associated with specific clinical and diagnostic findings in RAO-affected horses in field settings. While airway hyperresponsiveness differentiates best between healthy horses and asymptomatic RAO-affected horses, the absence of coughing and nasal discharge does not rule out significant neutrophilic airway inflammation. Owner satisfaction with the clinical status of the horse was uninformative. PMID- 24761756 TI - Public perceptions and alcohol policies: six case studies that examine trends and interactions. PMID- 24761755 TI - Selectively promiscuous opioid ligands: discovery of high affinity/low efficacy opioid ligands with substantial nociceptin opioid peptide receptor affinity. AB - Emerging clinical and preclinical evidence suggests that a compound displaying high affinity for MU, kappa, and delta opioid (MOP, KOP, and DOP) receptors and antagonist activity at each, coupled with moderate affinity and efficacy at nociceptin opioid peptide (NOP) receptors will have utility as a relapse prevention agent for multiple types of drug abuse. Members of the orvinol family of opioid ligands have the desired affinity profile but have typically displayed substantial efficacy at MOP and or KOP receptors. In this study it is shown that a phenyl ring analogue (1d) of buprenorphine displays the desired profile in vitro with high, nonselective affinity for the MOP, KOP, and DOP receptors coupled with moderate affinity for NOP receptors. In vivo, 1d lacked any opioid agonist activity and was an antagonist of both the MOP receptor agonist morphine and the KOP receptor agonist ethylketocyclazocine, confirming the desired opioid receptor profile in vivo. PMID- 24761757 TI - Trends in public opinion on alcohol issues during a period of increasing access to alcohol: Ontario, Canada, 1996-2011. AB - INTRODUCTION AND AIMS: The aim of our paper is to present trend data concerning public opinion on alcohol policy in the Canadian province of Ontario over a 16 year period (1996-2011), to assess if the level of support for alcohol control policies changed over this period and if any changes in public support for alcohol policy parallel real changes in alcohol distribution in Ontario. DESIGN AND METHODS: Selected policy-related items from 10 probability surveys of Ontario adults were analysed by means of logistic regression. RESULTS: A significant decline was found for attitudes supporting restricting corner stores sales and government control of liquor stores. A weaker decline was seen for attitudes towards reducing the number of places to buy alcohol. However, an increasing trend for attitudes favouring the status quo or greater control through taxes and hours of sale was found. There was no significant trend for attitudes towards maintaining the current level or reducing the number of liquor or beer stores. While there was some variation in trends in support by demographic characteristics and drinking level, not one sector stood out. DISCUSSION AND CONCLUSIONS: A gradual erosion of support is evident and concurrent with gradual increase in access to alcohol in Ontario during the time-period under study. The decline in support for alcohol control measures seems to be a general rather than a focused development. It appears that this was largely due to a shift in a greater percentage supporting the status quo, not a move towards increasing access to alcohol. PMID- 24761759 TI - The small scale clinical psychiatric case registers. PMID- 24761758 TI - Second-hand drinking may increase support for alcohol policies: new results from the 2010 National Alcohol Survey. AB - INTRODUCTION AND AIMS: The harms of second-hand smoke motivated tobacco control legislation. Documenting the effects of harms from others' drinking might increase popular and political will for enacting alcohol policies. We investigated the individual-level relationship between having experienced such harms and favouring alcohol policy measures, adjusting for other influences. DESIGN AND METHODS: We used the landline sample (n = 6957) of the 2010 National Alcohol Survey, a computer-assisted telephone interview survey based on a random household sample in the USA. Multivariable regression models adjusted for personal characteristics, including drinking pattern (volume and heavy drinking), were used to investigate the ability of six harms from others' drinking to predict a three-item measure of favour for stronger alcohol policies. RESULTS: Adjusting for demographics and drinking pattern, number of harms from others' drinking predicted support for alcohol policies (P < 0.001). In a similar model, family- and aggression-related harms, riding with a drink driver and being concerned about another's drinking all significantly influenced favour for stronger alcohol policy. DISCUSSION: Although cross-sectional data cannot prove a causal influence or directionality, the association found is consistent with the hypothesis that experiencing harms from others' drinking (experienced by a majority) makes one more likely to favour alcohol policies. Other things equal, women, racial/ethnic minorities, lower-income individuals and lighter drinkers tend to be more supportive of alcohol controls and policies. CONCLUSIONS: Studies that estimate the impact of harms from other drinkers on those victimised are important and now beginning. Next we need to learn how such information could affect decision makers and legislators. PMID- 24761760 TI - Smokeless tobacco increases aneuploidy in oral HPV16 E6/E7-transformed keratinocytes in vitro. AB - BACKGROUND: The scope of this work was to study synergism between human papillomavirus (HPV) infection and tobacco in vitro, both known to be independent risk factors for oral cancer. METHODS: HPV-positive and HPV-negative oral keratinocytes and oral HPV-negative fibroblasts were exposed to smokeless tobacco extract (STE) prepared from the Scandinavian (STE1) and US-type (STE2) snuff. Cell cycle profiles were determined with flow cytometry, and HPV E6/E7 mRNA expression in HPV-positive cells was assayed using RT-qPCR. RESULTS: The exposure of HPV-positive keratinocytes with STE2 increased the number of aneuploid cells from 27% to 80% of which 44% were in S-phase, while none of the diploid cells were in S-phase. The changes after STE1 exposure were less than seen after STE2: from 27% to 31% of which 34% were in S-phase. STE had no effect on HPV16 E6/E7 expression in HPV-positive keratinocytes. In oral spontaneously transformed, HPV negative keratinocytes, the number of aneuploid cells at G2-M stage increased after STE1 and STE2 exposure from 3% to 9% and 7%, respectively. In HPV-negative oral fibroblasts, the number of cells at G2-M phase increased from 11% to 21% after STE1 and 29% after STE2 exposure. CONCLUSIONS: The effect of STE varied in the cell lines studied. STE2 increased significantly the proportion of aneuploid cells in HPV-positive oral keratinocytes, but not HPV16 E6/E7 expression. This indicates that tobacco products may enhance the effects of HPV 16 and the risk of DNA aneuploidy increasing risk to malignant transformation. PMID- 24761761 TI - Aneurysmal subarachnoid hemorrhage with concomitant posterior communicating artery fenestration. AB - Fenestrations of the posterior communicating artery (PCoA) are extremely rare. Associated aneurysms have only been documented three times in the literature, and none associated with a subarachnoid hemorrhage. We describe a 52-year-old female who presented with a subarachnoid hemorrhage secondary to a ruptured saccular aneurysm at the proximal limb of a fenestrated right PCoA. The patient was also found to have bilateral middle cerebral artery (MCA) aneurysms. Surgical management included surmising the etiology of the subarachnoid hemorrhage with subsequent clipping of both the right PCoA and MCA aneurysm. The potential embryological mechanisms leading to a PCoA fenestration are discussed. PMID- 24761762 TI - Association between fat amount of dairy products with pulse wave velocity and carotid intima-media thickness in adults. AB - BACKGROUND: Examine the relation between consumption of low-fat vs. whole-fat dairy products with the carotid intima-media thickness and pulse wave velocity. FINDINGS: METHODS: Cross-sectional and multi-center study. A total of 265 subjects were selected by stratified random sampling. MEASUREMENTS: Information about dairy products was assessed using a semi-quantitative food-frequency questionnaire. Carotid intima-media thickness (IMT) was measured by carotid ultrasonography. Pulse wave velocity (PWV) was measured using the SphygmoCor System. RESULTS: Subjects (age 55.8 +/- 12.2) had mean values of IMT 0.68 +/- 0.10 mm and PWV 7.60 +/- 2.0 m/sec. The relationship between PWV and IMT with whole-fat and low-fat dairy intake groups, adjusted for age, sex, energy intake and other confounders revealed lower values of PWV in subjects with a consumption higher than 125 g/day of low-fat dairy and in those who did not intake whole-fat dairy. In a risk-factor adjusted regression model, an increase in PWV of 0.109 m/sec (95% CI: 0.006 -0.213) was estimated for every 100 g/day increase in whole fat dairy intake. Similarly, a decrease in PWV of 0.101 m/sec (95% CI: -0.178 0.023) was estimated for every 100 g/day increase in low-fat dairy intake, (p = 0.038 and p = 0.011 respectively). While for every 100 g/day increase in low-fat dairy intake, the estimate decrease of IMT was 0.005 mm (95% CI: -0.010 -0.001), p = 0.011. CONCLUSIONS: PWV and IMT showed an inverse association with the intake of low-fat dairy and a positive association with the intake of whole-fat dairy, so the amount of fat in dairy products can play an important role in arterial stiffness and subclinical atherosclerosis. PMID- 24761763 TI - Vitamin D effects on B cell function in autoimmunity. AB - Vitamin D seems to be implicated in the pathophysiology of autoimmune disorders as a natural immune modulator. Beneficial effects of vitamin D have been associated with different cells of the immune system; however, thus far, B cells seem to be somewhat neglected. In this paper, we describe the possible direct effects of vitamin D on B cells, with a focus on antibody production and the more recently identified regulatory B (Breg ) cells. B cells upregulate the vitamin D receptor (VDR) upon activation. Furthermore, due to regulated expression of the metabolizing enzymes CYP27B1 and CYP24A1, B cells have the potential to control the local availability of active vitamin D. B cells, therefore, may participate in vitamin D-mediated immune homeostasis, including plasma cell generation. Whether or not other B cell subsets, such as Breg cells, are equally responsive to vitamin D remains to be established. PMID- 24761764 TI - Diagnostic and prognostic utilities of multimarkers approach using procalcitonin, B-type natriuretic peptide, and neutrophil gelatinase-associated lipocalin in critically ill patients with suspected sepsis. AB - BACKGROUND: We investigated the diagnostic and prognostic utilities of procalcitonin (PCT), B-type natriuretic peptide (BNP), and neutrophil gelatinase associated lipocalin (NGAL) in critically ill patients with suspected sepsis, for whom sepsis was diagnosed clinically or based on PCT concentrations. METHODS: PCT, BNP, and NGAL concentrations were measured in 340 patients and were followed up in 109 patients. All studied biomarkers were analyzed according to the diagnosis, severity, and clinical outcomes of sepsis. RESULTS: Clinical sepsis and PCT-based sepsis showed poor agreement (kappa = 0.2475). BNP and NGAL showed significant differences between the two groups of PCT-based sepsis (P = 0.0001 and P < 0.0001), although there was no difference between the two groups of clinical sepsis. BNP and NGAL were significantly different according to the PCT staging and sepsis-related organ failure assessment subscores (P < 0.0001, all). BNP and PCT concentrations were significantly higher in the non-survivors than in the survivors (P = 0.0002) and showed an equal ability to predict in-hospital mortality (P = 0.0001). In the survivors, the follow-up NGAL and PCT concentrations were significantly lower than the initial values (148.7 ng/mL vs. 214.5 ng/mL, P < 0.0001; 0.61 ng/mL vs. 5.56 ng/mL, P = 0.0012). CONCLUSIONS: PCT based sepsis diagnosis seems to be more reliable and discriminating than clinical sepsis diagnosis. Multimarker approach using PCT, BNP, and NGAL would be useful for the diagnosis, staging, and prognosis prediction in the critically ill patients with suspected sepsis. PMID- 24761766 TI - Self-service kiosk for testing sunglasses. AB - BACKGROUND: Sunglasses users may only be assured on their ultraviolet protection by purchasing certified products, however they are not able to check if sunglasses are still ultraviolet (UV) protected as they age, unless they resort themselves to a professional who is qualified for using a spectrophotometer and is acknowledged on the standards for providing a report for the user. Current literature establishes safe limits on the exposure of the eyes relatively to the ultraviolet radiation exposure for the UVA and UVB ranges (280 nm - 400 nm). The UV protection is category dependent. Sunglasses are categorized from 0 to 4 and the categories are determined by the lenses transmission's percentage on the visible range (380 nm - 780 nm). METHODS: In order to overcome inaccessibility of such measurements on sunglasses, a prototype for testing ultraviolet protection on sunglasses, according to Brazilian Standards, has been developed for amateur use. The system consists of assembling UVA and UVB light sources and two UV responsive photodiode sensors, with Erythema action response for measuring UV protection; for categories measurements, combination of white light and LEDs were used for the visible range, as well as a light sensor having spectral response similar to the human eye. Electronics has been developed for controlling the measurements and software has been implemented for providing the report as well as for the user's interface. RESULTS: All the system was embedded as a self service touch screen kiosk and provides transmittance measurements that are within the deviation limit required by NBR15111, i.e., 0.25%. Measurements were performed in over 45 sunglasses and compared to CARY 5000 - VARIAN spectrophotometer and present a good correlation for the measurements of transmittance in the visible spectral range (r2 = 0.9999) and in the ultraviolet range (r2 = 0.9997). CONCLUSIONS: The prototype identifies the UV protection, for non-corrective sunglasses, according to category of the lens and is available for the public. In addition to educating the population about the importance of wearing protected sunglasses, the prototype has also allowed the public to have access to information about the quality of protection of their own sunglasses in an easy and free testing method. PMID- 24761765 TI - Comparative epidemiology of human metapneumovirus- and respiratory syncytial virus-associated hospitalizations in Guatemala. AB - BACKGROUND: Human metapneumovirus (HMPV) is an important cause of acute respiratory infections (ARI), but little is known about how it compares with respiratory syncytial virus (RSV) in Central America. OBJECTIVES: In this study, we describe hospitalized cases of HMPV- and RSV-ARI in Guatemala. METHODS: We conducted surveillance at three hospitals (November 2007-December 2012) and tested nasopharyngeal and oropharyngeal swab specimens for HMPV and RSV using real-time reverse transcription-polymerase chain reaction. We calculated incidence rates, and compared the epidemiology and outcomes of HMPV-positive versus RSV-positive and RSV-HMPV-negative cases. RESULTS: We enrolled and tested specimens from 6288 ARI cases; 596 (9%) were HMPV-positive and 1485 (24%) were RSV-positive. We observed a seasonal pattern of RSV but not HMPV. The proportion HMPV-positive was low (3%) and RSV-positive high (41%) for age <1 month, whereas these proportions were similar (~20%) by age 2 years. The annual incidence of hospitalized HMPV-ARI was 102/100 000 children aged <5 years [95% confidence interval (CI): 75-178], 2.6/100 000 persons aged 5-17 years (95%CI: 1.2-5.0), and 2.6/100 000 persons aged >= 18 years (95%CI: 1.5-4.9). Among children aged <5 years, HMPV-positive cases were less severe than HMPV-RSV-negative cases after adjustment for confounders [odds ratio (OR) for intensive care = 0.63, 95% CI 0.47-0.84]; OR for death = 0.46, 95% CI 0.23-0.92). CONCLUSIONS: Human metapneumovirus is a substantial contributor to ARI hospitalization in Guatemala, but HMPV hospitalizations are less frequent than RSV and, in young children, less severe than other etiologies. Preventive interventions should take into account the wide variation in incidence by age and unpredictable timing of incidence peaks. PMID- 24761767 TI - The decision-making process leading to deep brain stimulation in men and women with parkinson's disease - an interview study. AB - BACKGROUND: Deep brain stimulation (DBS) is an established treatment for patients with advanced parkinson's disease (PD). Research shows that women are under represented among patients undergoing DBS surgery. This may be due to gender biased selection of patients, but patients' wishes and attitudes may also contribute. This study investigated the decision making process to undergo DBS from the patient's perspective, and explored any gender patterns in the participants' decision-making. METHODS: All patients operated on with DBS for PD at the University Hospital of Northern Sweden between January 2002 and April 2010 were invited to an interview study. In this way 39 patients were recruited, 31 men and eight women. Three additional women, operated elsewhere, were recruited to acheive a more gender-balanced sample. In a mixed-method analysis, the interviews were analysed according to the constant comparison technique in grounded theory and descriptive statistics was used to present demographics and compare categories. RESULTS: Three different approaches to DBS were identified among the patients. 'Taking own initiative', included 48% of the patients and implied that the patients' own initiatives and arguments had been crucial for having surgery. 'Agreeing when offered', and accepting DBS when suggested by doctors embraced 43%. The third approach, 'Hesitating and waiting' included < 10% of the patients. Most of the men were either 'taking own initiative' or 'agreeing when offered'. The 11 women were evenly distributed in all three approaches. Among the interviewed, more women than men expressed strong fear of complications and more women consulted friends and relatives prior to deciding about DBS. Half of the patients had held a leadership position at work or in another organisation, and among patients 'taking own initiative' the proportion with leadership experiences was 80%. At time for surgery ten men but no woman were professionally active. CONCLUSION: This study suggests that many patients with advanced PD have to argue and struggle with their clinicians in order to be referred to a DBS-team. The study further suggests that patients' wishes, behaviour and position in society may all contribute to the skewed gender distribution among patients treated with DBS. PMID- 24761769 TI - Motion artifact removal from photoplethysmographic signals by combining temporally constrained independent component analysis and adaptive filter. AB - BACKGROUND: The calculation of arterial oxygen saturation (SpO2) relies heavily on the amplitude information of the high-quality photoplethysmographic (PPG) signals, which could be contaminated by motion artifacts (MA) during monitoring. METHODS: A new method combining temporally constrained independent component analysis (cICA) and adaptive filters is presented here to extract the clean PPG signals from the MA corrupted PPG signals with the amplitude information reserved. The underlying PPG signal could be extracted from the MA contaminated PPG signals automatically by using cICA algorithm. Then the amplitude information of the PPG signals could be recovered by using adaptive filters. RESULTS: Compared with conventional ICA algorithms, the proposed approach is permutation and scale ambiguity-free. Numerical examples with both synthetic datasets and real-world MA corrupted PPG signals demonstrate that the proposed method could remove the MA from MA contaminated PPG signals more effectively than the two existing FFT-LMS and moving average filter (MAF) methods. CONCLUSIONS: This paper presents a new method which combines the cICA algorithm and adaptive filter to extract the underlying PPG signals from the MA contaminated PPG signals with the amplitude information reserved. The new method could be used in the situations where one wants to extract the interested source automatically from the mixed observed signals with the amplitude information reserved. The results of study demonstrated the efficacy of this proposed method. PMID- 24761768 TI - Role of malignant ascites on human mesothelial cells and their gene expression profiles. AB - BACKGROUND: Malignant ascites is often present at diagnostic in women with advanced ovarian cancer (OC) and its presence is associated with a worse outcome. Human peritoneal mesothelial cells (HPMCs) are key components of malignant ascites. Although the interplay between HPMCs and OC cells is believed to be critical for tumor progression, it has not been well characterized. The purpose of this study was to assess the effect of ascites on HPMCs and clarify the role of HPMCs in OC progression. METHODS: Human OC ascites and benign peritoneal fluids were assessed for their ability to stimulate HPMC proliferation. Conditioned medium from ascites- and benign fluid-stimulated HPMCs were compared for their ability to attenuate apoptosis induced by TNF-related apoptosis inducing ligand (TRAIL). We conducted a comparative analysis of global expression changes in ascites-stimulated HPMCs using Agilent oligonucleotide microarrays. RESULTS: As compared to benign peritoneal fluids, malignant ascites stimulated the proliferation of HPMCs. TRAIL-induced apoptosis was attenuated in OC cells exposed to conditioned medium from ascites-stimulated HPMCs as compared to OC cells exposed to conditioned medium from benign fluid-stimulated HPMCs. A total of 649 genes were differentially expressed in ascites-stimulated HPMCs. Based on a ratio of more than 1.5-fold and a P < 0.05, 484 genes were up-regulated and 165 genes were down-regulated in ascites-exposed HPMCs. Stimulation of HPMCs with OC ascites resulted in differential expression of genes mainly associated with the regulation of cell growth and proliferation, cell death, cell cycle and cell assembly and organization, compared to benign peritoneal fluids. Top networks up regulated by OC ascites included Akt and NF-kappaB survival pathways whereas vascular endothelial growth factor (VEGF) pathway was down-regulated. CONCLUSIONS: The results of this study not only provide evidence supporting the importance of the interplay between cancer cells and HPMCs but also define the role that the tumor environment plays in these interactions. PMID- 24761770 TI - The effect of erythropoietin to pulmonary injury and mast cells secondary to acute pancreatitis. AB - BACKGROUND: Acute pancreatitis is a life-threatening necroinflammatory disease that is characterized by systemic inflammatory response syndrome and acute lung injury even in its very first days. Erythropoietin (EPO) is a hormone considered as an antiapoptotic and cytoprotective with observed receptors of anti inflammatory effect on organs apart from the liver and the kidneys. In this study, the effects of EPO on pulmonary mast cells and on secondary injury caused by acute pancreatitis are investigated. METHODS: Twenty one Wistar Albino rats were divided into three groups--sham, control, and EPO groups-with 7 rats per group. Pancreatitis was induced by administering 4.5% sodium taurocholate into the pancreatic duct. A 1000 U/kg/day dosage (three times) of EPO was administered to the EPO group. Blood urea nitrogen (BUN), creatinine, amylase, and troponin I in the serum were studied; and lung, kidney, brain, and heart tissues were examined histopathologically. RESULTS: There were no histopathological changes in the other organ tissues except for the lung tissue. Compared to the control group, the EPO group showed significantly reduced alveolar hemorrhage, septal neutrophil infiltration, lung wall thickness score, and mast cell count in the lung tissue. CONCLUSIONS: Administration of EPO reduces the mast cell count and lung wall thickness, and it reduces the alveolar hemorrhage and septal infiltration induced by acute pancreatitis. PMID- 24761771 TI - Identification of breast cancer patients with a high risk of developing brain metastases: a single-institutional retrospective analysis. AB - BACKGROUND: The objective of this study was to identify breast cancer patients with a high risk of developing brain metastases who may benefit from pre-emptive medical intervention. METHODS: Medical records of 352 breast cancer patients with local or locoregional disease at diagnosis were retrospectively analysed. The brain metastasis-free survival was estimated using the Kaplan-Meier method and patient groups were compared using the log rank test. The simultaneous relationship of multiple prognostic factors was assessed using Cox's proportional hazard regression analysis. The Fisher exact test was used to test the difference of proportions for statistical significance. RESULTS: On univariate analysis, statistically highly significant unfavourable risk factors for the brain metastasis-free survival were negative ER status, negative PR status, and triple negative tumor subtype. Young age at diagnosis (<=35 years) and advanced disease stage were not statistically significant (p = 0.10). On multivariate analysis, the only independent significant factor was the ER status (negative ER status; hazard radio (95% confidence interval), 5.1 (1.8-14.6); p = 0.003). In the subgroup of 168 patients with a minimum follow-up of 24 months, 49 patients developed extracranial metastases as first metastatic event. Of those, 7 of 15 (46.6%) with a negative ER status developed brain metastases compared to 5 of 34 (14.7%) with a positive ER status (Fisher exact test, p = 0.03). The median time interval (minimum-maximum) between the diagnosis of extracranial and brain metastases was 7.5 months (1-30 months). CONCLUSIONS: Breast cancer patients with extracranial metastasis and negative ER status exhibited an almost 50% risk of developing brain metastasis during their course of disease. Future studies are highly desired to evaluate the efficacy of pre-emptive medical intervention such as prophylactic treatment or diagnostic screening for high risk breast cancer patients. PMID- 24761772 TI - Intramolecular charge transfer effects on the diradical character and second hyperpolarizabilities of open-shell singlet X-pi-X (X = donor/acceptor) systems. AB - We investigate the effect of the quadrupole-type intramolecular charge transfer (ICT) in open-shell singlet donor-pi-donor (D-pi-D) molecules on the singlet open shell (diradical) character and the longitudinal second hyperpolarizabilities gamma (the third-order nonlinear optical (NLO) properties at the molecular scale). For this investigation we used the para-quinodimethane (PQM) with point charges (pc's) model calculated with the unrestricted coupled cluster method including single and double excitations with a perturbative treatment of the triple excitations (UCCSD(T)). In this model, the diradical character y and the amount of the ICT, that is, the D-pi-D nature, can be varied primarily by changing the exocyclic carbon-carbon bond (C-C) lengths and the external pc's Q, respectively. It turns out that the increase in the D-pi-D nature decreases the y values, moves the y values (ymax) giving the maximum gamma (gammamax) to the large y region, and enhances the gammamax values, for example, the gammamax of the singlet diradical PQM with Q = -2.8 au reaches twice that of the singlet diradical PQM without any pc's. This result indicates that open-shell singlet D pi-D systems with ICT are promising candidates for a new class of third-order NLO molecules, whose gamma values are more enhanced than those of conventional closed shell D-pi-D systems and of symmetric open-shell singlet systems without the ICT. To confirm this tendency, we examine the boron-disubstituted PQM dianion model, which is found to exhibit further enhancement of gamma as compared to the PQM model with intermediate diradical character due to the synergy effects of the intermediate open-shell singlet nature and the strong field-induced ICT nature in the dianionic state of the D-pi-D system. Further investigation of the acceptor pi-acceptor (A-pi-A) type ICT effect in the PQM-pc model shows that both D-pi-D and A-pi-A type symmetric ICTs give similar effects on the relationship between y and gamma, though there are some differences originating in the orbital contraction and extension induced by the pc's. The present results contribute to understanding the third-order NLO properties of open-shell symmetric ICT systems and thus to constructing new design guidelines for highly efficient third-order NLO systems. PMID- 24761774 TI - Extraction of high-quality DNA from ethanol-preserved tropical plant tissues. AB - BACKGROUND: Proper conservation of plant samples, especially during remote field collection, is essential to assure quality of extracted DNA. Tropical plant species contain considerable amounts of secondary compounds, such as polysaccharides, phenols, and latex, which affect DNA quality during extraction. The suitability of ethanol (96% v/v) as a preservative solution prior to DNA extraction was evaluated using leaves of Jatropha curcas and other tropical species. RESULTS: Total DNA extracted from leaf samples stored in liquid nitrogen or ethanol from J. curcas and other tropical species (Theobroma cacao, Coffea arabica, Ricinus communis, Saccharum spp., and Solanum lycopersicon) was similar in quality, with high-molecular-weight DNA visualized by gel electrophoresis. DNA quality was confirmed by digestion with EcoRI or HindIII and by amplification of the ribosomal gene internal transcribed spacer region. Leaf tissue of J. curcas was analyzed by light and transmission electron microscopy before and after exposure to ethanol. Our results indicate that leaf samples can be successfully preserved in ethanol for long periods (30 days) as a viable method for fixation and conservation of DNA from leaves. The success of this technique is likely due to reduction or inactivation of secondary metabolites that could contaminate or degrade genomic DNA. CONCLUSIONS: Tissue conservation in 96% ethanol represents an attractive low-cost alternative to commonly used methods for preservation of samples for DNA extraction. This technique yields DNA of equivalent quality to that obtained from fresh or frozen tissue. PMID- 24761773 TI - Health-related quality of life and socioeconomic status: inequalities among adults with a chronic disease. AB - BACKGROUND: A number of studies have shown an association between health-related quality of life (HRQL) and socioeconomic status (SES). Indicators of SES usually serve as potential confounders; associations between SES and HRQL are rarely discussed in their own right. Also, few studies assess the association between HRQL and SES among those with a chronic disease. The study focuses on the question of whether people with the same state of health judge their HRQL differently according to their SES, and whether a bias could be introduced by ignoring these differences. METHODS: The analyses were based on a representative sample of the adult population in Germany (n = 11,177). HRQL was assessed by the EQ-5D-3 L, i.e. the five domains (e.g. 'moderate or severe problems' concerning mobility) and the Visual Analog Scale (VAS). SES was primarily assessed by educational level; age, sex and family status were included as potential confounders. Six chronic diseases were selected, each having a prevalence of at least 1% (e.g. diabetes mellitus). Multivariate analyses were conducted by logistic and linear regression. RESULTS: Among adults with a chronic disease, most 'moderate or severe problems' are reported more often in the low (compared with the high) educational group. The same social differences are seen for VAS values, also in subgroups characterized by 'moderate or severe problems'. Gender specific analyses show that for women the associations with VAS values can just be seen in the total sample. For men, however, they are also present in subgroups defined by 'moderate or severe problems' or by the presence of a chronic disease; some of these differences exceed 10 points on the VAS scale. CONCLUSIONS: Low SES groups seem to be faced with a double burden: first, increased levels of health impairments and, second, lower levels of valuated HRQL once health is impaired. These associations should be analysed and discussed in their own right, based on interdisciplinary co-operation. Social epidemiologists could include measures of HRQL in their studies more often, for example, and health economists could consider assessing whether recommendations based on HRQL scales might include a social bias. PMID- 24761775 TI - Fused glycoluril-tetrathiafulvalene molecular clips as receptors for neutral electron acceptor guests. AB - Glycoluril-based molecular clips incorporating tetrathiafulvalene (TTF) sidewalls have been synthesized, and the efficient binding ability in solution of this host architecture toward m-dinitrobenzene through donor-acceptor interaction has been demonstrated. PMID- 24761776 TI - The road traffic crashes as a neglected public health concern; an observational study from Iranian population. AB - OBJECTIVE: Traffic crashes are multifactorial events caused by human factors, technical issues, and environmental conditions. The present study aimed to determine the role of human factors in traffic crashes in Iran using the proportional odds regression model. METHODS: The database of all traffic crashes in Iran in 2010 (n = 592, 168) registered through the "COM.114" police forms was investigated. Human risk factors leading to traffic crashes were determined and the odds ratio (OR) of each risk factor was estimated using an ordinal regression model and adjusted for potential confounding factors such as age, gender, and lighting status within and outside of cities. RESULTS: The drivers' mean age +/- standard deviation was 34.1 +/- 14.0 years. The most prevalent risk factors leading to death within cities were disregarding traffic rules and regulations (45%), driver rushing (31%), and alcohol consumption (12.3%). Using the proportional odds regression model, alcohol consumption was the most significant human risk factor in traffic crashes within cities (OR = 6.5, 95% confidence interval [CI], 4.88-8.65) and outside of cities (OR = 1.73, 95% CI, 1.22-3.29). CONCLUSIONS: Public health strategies and preventive policies should be focused on more common human risk factors such as disregarding traffic rules and regulations, drivers' rushing, and alcohol consumption due to their greater population attributable fraction and more intuitive impacts on society. PMID- 24761777 TI - Fe-based metallopolymer nanowall-based composites for Li-O2 battery cathode. AB - Metallopolymer nanowalls were prepared through a simple wet-chemical process using reduced graphene oxides as heterogeneous nucleation aids, which also help to form conductive electron paths. The nanowalls grow vertically on graphene surface with 100-200 nm in widths and ~20 nm in thickness. The Fe-based metallopolymer nanowall-based electrode shows best performance as O2 cathode exhibiting high round-trip efficiencies and stable cycling performance among other transition metal containing metallopolymer counterparts. The electrode delivers discharge-charge capacities of 1000 mAh/g for 40 cycles and maintains round-trip efficiencies >78% at 50 mA/g. The 1(st)-cycle round-trip efficiencies are 79%, 72%, and 65% at current densities of 50, 200, and 400 mA/g, respectively. The NMR analysis of the Fe-based metallopolymer based electrode after 40 cycles reveals slow formation of the side products, CH3CO2Li and HCO2Li. PMID- 24761778 TI - Stabilizing catalytically active nanoparticles by ligand linking: toward three dimensional networks with high catalytic surface area. AB - A general approach for the linking of Pt nanoparticles (NPs) with bifunctional amine ligands (organic molecules with two amine groups) is presented that allows for the preparation of NP catalysts without inorganic supports and high densities of the catalytically active metal. Advantage was taken of the use of "unprotected" NPs, which enables us to prepare different ligand-functionalized NPs from the same particle batch and thus to relate changes of the resulting material properties exclusively to the influence of the ligand. Three bifunctional ligands with similar functional groups (amines) but different hydrocarbon skeletons were used and compared to monofunctional ligands of similar molecular structures (alkyl and aryl amines) showing significantly different material properties. Monofunctional molecules with minor steric demand cover almost completely the NP surface and lead to two-dimensional assembling of the NPs. In contrast, the use of bifunctional amine ligands leads to the formation of porous, three-dimensional NP networks (ligand-linked NPs) with a high density of ligand free surface atoms, thus enabling for the application as catalytic materials. The stabilizing effect of bifunctional ligands serves as an alternative to the use of inorganic support materials and enables for catalytic applications of ligand-linked NP networks. PMID- 24761779 TI - Comment on "Fungicide field concentrations exceed FOCUS surface water predictions: urgent need of model improvement". PMID- 24761780 TI - A comparison of three doses of omeprazole in the treatment of equine gastric ulcer syndrome: A blinded, randomised, dose-response clinical trial. AB - REASONS FOR PERFORMING THE STUDY: A previous study demonstrated that a dose effect between 1.6 and 4.0 mg/kg bwt of omeprazole per os s.i.d. is present in the treatment of equine gastric ulceration. In the same study, healing of glandular ulceration appeared inferior to healing of squamous ulceration. However, several limitations were recognised in that study and further investigation is warranted. OBJECTIVES: To further investigate the presence of a dose relationship in the treatment of gastric ulceration under conditions that may favour omeprazole efficacy such as administration prior to exercise and after a brief fast, and potential differences between the response of squamous and glandular ulceration to omeprazole therapy. STUDY DESIGN: A blinded, randomised, dose-response clinical trial. METHODS: Sixty Thoroughbred racehorses with grade >=2/4 squamous and/or glandular ulceration were identified by gastroscopy. Horses were randomly assigned to receive either 1.0, 2.0 or 4.0 mg/kg bwt of enteric coated omeprazole per os s.i.d. 1-4 h prior to exercise. Gastroscopy was repeated at approximately 28 days. RESULTS: The lower doses studied (1.0 and 2.0 mg/kg bwt) were noninferior to the reference dose (4.0 mg/kg bwt) in the treatment of squamous ulceration. Healing was greater in squamous ulceration than glandular ulceration (86% vs. 14%; P<0.0001). Improvement in ulcer grade was more likely in squamous lesions than glandular lesions (96% vs. 34%; P<0.0001). Worsening of the glandular ulcer grade was observed in 36% of horses. CONCLUSIONS: The results of this study suggest that, under the conditions studied, where omeprazole is administered before exercise and following a brief fast, doses of omeprazole as low as 1 mg/kg bwt per os s.i.d. may be as effective as higher doses. The proportion of glandular ulceration that heals with 28 days of omeprazole therapy is less than that of squamous ulceration. PMID- 24761781 TI - Impact of formulation and saliva on acid milk gel friction behavior. AB - Rheological analysis is commonly used to evaluate mechanical properties in studies of food behavior. However, rheological analysis is often insufficient to describe food texture as evaluated by descriptive sensory analysis. Additionally, traditional rheometry does not account for changes in food behavior as a function of saliva incorporation into the food during mastication. The objectives of this study were to evaluate friction behavior of acid milk gels with and without the addition of saliva, and to determine relationships between frictional behaviors and mechanical and sensory behaviors. Acid milk gels were prepared with 12.5% total solids comprising nonfat dry milk, whey protein isolate, waxy maize starch, and gelatin in different ratios. The addition of starch was found to have significant impact on acid milk gel frictional behavior. Addition of saliva resulted in a change in frictional behavior over the entire sliding speed range measured. Correlations were found between rheological, tribological, and sensory behavior, suggesting that an underlying mechanism may impact both viscosity and friction behavior. Additional study is needed to further explore the links between food structure, rheology, tribology, and sensory texture. PRACTICAL APPLICATION: Application of tribology in food science allows measurement of friction behavior of foods. Matching both rheological and tribological behavior is important to creating reduced-fat or reduced-sugar products with similar mouthfeel to the original product. PMID- 24761782 TI - N-carbamidoyl-4-((3-ethyl-2,4,4-trimethylcyclohexyl)methyl)benzamide enhances staurosporine cytotoxic effects likely inhibiting the protective action of Magmas toward cell apoptosis. AB - We recently demonstrated that Magmas overexpression protects GH-secreting rat pitutitary adenoma cell lines from apoptosis by inhibiting cytochrome c release from mitochondria after treatment with staurosporine, strongly suggesting a role of Magmas in preventing apoptosis. The aim of this study was to produce a drug that, by inhibiting Tim16, may sensitize chemoresistant tumor cell to proapoptotic stimuli. We synthesized six compounds and challenged their sensitizing effects toward the proapoptotic effects of staurosporine in the TT cell line, derived from a human medullary thyroid carcinoma. We found that compound 5, devoid of the planarity in the aliphatic part of the lead 1, is not cytotoxic but enhances the proapoptotic effects of staurosporine by reducing MMP activation. Compound 5 may be useful for cancer treatment in association with chemotherapeutic drugs, possibly allowing a reduction of the chemotherapeutic agent effective dose. PMID- 24761783 TI - Coupled exposure to ingredients of cosmetic products: III. Ultraviolet filters. AB - BACKGROUND: The use of cosmetics exposes consumers to mixtures of ingredients, many of which are potential allergens. Ultraviolet (UV) filters are used not just in sunscreens, but also in other products. Many UV filters are known contact allergens and photoallergens. OBJECTIVE: To examine the pattern of co-exposure to UV filters in cosmetics. METHODS: A survey of products marketed in Germany, conducted in 2006-2009 by the Chemical and Veterinary Investigation Office in Karlsruhe, identified 4447 products (of all 5667 cosmetic products examined) (i) that were categorizable according to Annex I to the Cosmetics Directive, and (ii) with information on the presence of UV filters or zinc oxide. The occurrence and co-occurrence of UV filters were analysed and presented in tabular and graphical format. RESULTS: UV filters or zinc oxide were present in 22.5% of all 4447 products, ranging from almost 100% in sunscreens to a few per cent in, for example, some hair products; they were absent in two product categories. Frequently, several different UV filters were included in one product, for example in sunscreens (median 4) and in perfumes (median 3). The overall most frequent UV filters were butyl methoxydibenzoylmethane and titanium dioxide, combined mostly with octocrylene in sunscreens and with ethylhexyl methoxycinnamate in creams. CONCLUSIONS: The frequent co-occurrence of UV filters in cosmetic products possibly facilitates sensitization, and may explain why patients often react to chemically unrelated UV filters. PMID- 24761784 TI - The effects of thoracic surgery operations on quality of life: a multicenter study. AB - OBJECTIVE: Some treatment modalities may cause losses in patients' life comfort because of the treatment process. Our aim is to determine the effects of thoracic surgery operations on patients' quality of life. MATERIALS AND METHODS: This is a multicenter and prospective study. A hundred patients, who had undergone posterolateral thoracotomy (PLT) and/or lateral thoracotomy (LT), were included in the study. A quality of life questionnaire (SF-36) was used to determine the changes in life comfort. SF-36 was performed before the operation, on the first month, third month, sixth month and twelfth month after the operation. RESULTS: Seventy-two percent (n = 72) of the patients were male. PLT was performed in 66% (n = 66) of the patients, and LT was performed in 34% (n = 34) of the patients. The types of resections in patients were pneumonectomy in four patients, lobectomy in 59 patients and wedge resection in 11 patients. No resection was performed in 26 patients. Thoracotomy caused deteriorations in physical function (PF), physical role (RP), bodily pain (BP), health, vitality and social function scores. The deteriorations observed in the third month improved in the sixth and twelfth months. The PF, RP, BP and MH scores of the patients with lung resection were much more worsened compared with the patients who did not undergo lung resection. CONCLUSION: Thoracic surgery operations caused substantial dissatisfaction in life comfort especially in the third month postoperatively. The worsening in physical function, physical role, pain and mental health is much more in patients with resection compared with the patients who did not undergo resection. PMID- 24761785 TI - Arecoline is cytotoxic for human endothelial cells. AB - BACKGROUND: Oral submucous fibrosis is a pre-malignant fibrotic condition caused by areca nut use and involves reduced mucosal vascularity. Arecoline is the principal areca nut alkaloid and is cytotoxic for epithelium and fibroblasts. Endothelial cell cycle arrest is reported on exposure to arecoline, as is cytotoxicity for endothelial-lung carcinoma hybrid cells. We here describe cytotoxicity for primary human endothelial cultures from seven separate donors. MATERIALS AND METHODS: Human umbilical vein endothelial cells were exposed to increasing concentrations of arecoline and examined by: phase-contrast microscopy, haemocytometer counts, transmission electron microscopy, lactate dehydrogenase release and the methyl-thiazol-tetrazolium assay. RESULTS: Vacuolation and detachment of endothelium were observed at and above arecoline concentrations of 333 MUg/ml or more. Ultrastructural features of cellular stress were seen after 24-h treatment with 111 MUg/ml arecoline and included reduced ribosomal studding of endoplasmic reticulum, increased autophagolysosomal structures, increased vacuolation and reduced mitochondrial cristae with slight swelling. Similar changes were seen at 4 h with arecoline at 333 MUg/ml or above, but with more severe mitochondrial changes including increased electron density of mitochondrial matrix and greater cristal swelling, while by 24 h, these cells were frankly necrotic. Haemocytometer counts were paralleled by both lactate dehydrogenase release and the methyl-thiazol-tetrazolium assays. CONCLUSIONS: Arecoline is cytotoxic via necrosis for endothelium, while biochemical assays indicate no appreciable cellular leakage before death and detachment, as well as no clear effect on mitochondrial function in viable cells. Arecoline toxicity may thus contribute to reduced vascularity in oral submucous fibrosis. PMID- 24761787 TI - Psychometric characteristics of the Child Occupational Self-Assessment (COSA), Part Two: Refining the psychometric properties. PMID- 24761786 TI - The effects of social and health consequence framing on heavy drinking intentions among college students. AB - OBJECTIVES: Many interventions targeting college student drinking have focused on negative health effects of drinking heavily; however, some research suggests that social factors may have a stronger influence on the drinking behaviour of young people. Moreover, few studies have examined message framing effects in the context of alcohol consumption. This study investigated the effects of social and health consequence framing on college students' intentions to engage in heavy drinking. DESIGN: This study used a 2 * 2 experimental design with an appended control condition. METHODS: One hundred and twenty-four college students (74 women; M(age) = 18.9) participated in this study for course credit. Participants read vignettes that were ostensibly written by a recent graduate from the university, who described an episode of drinking in which he or she experienced either social or health consequences. These consequences were framed as either a gain (i.e., positive consequences of not drinking heavily) or a loss (i.e., negative consequences of drinking heavily). After reading the vignette, participants completed a measure of heavy drinking intentions. RESULTS: Regression analyses revealed that social consequences were associated with lower heavy drinking intentions when framed as a loss and that health consequences were associated with lower heavy drinking intentions when framed as a gain. These effects were stronger among those who reported higher (vs. lower) levels of previous drinking. CONCLUSIONS: Results suggest that interventions that focus on the negative health effects of heavy drinking may be improved by instead emphasizing the negative social consequences of drinking heavily and the positive health consequences of avoiding this behaviour. Statement of contribution What is already known on this subject? Previous studies have shown that gain frames are more effective than loss frames when highlighting the health consequences of health risk behaviours, such as heavy drinking. The heavy drinking behaviour of young people is influenced by social factors (e.g., perceived social consequences). However, little is known about framing effects for social consequences of heavy drinking. What does this study add? This study builds on previous research by demonstrating that a loss frame is more effective than a gain frame when highlighting the social consequences of health risk behaviour. Framing effects are strongest for those with more previous drinking experience. PMID- 24761788 TI - Men with intellectual disabilities with a history of sexual offending: empathy for victims of sexual and non-sexual crimes. AB - BACKGROUND: The objectives were (a) to compare the general empathy abilities of men with intellectual disabilities (IDs) who had a history of sexual offending to men with IDs who had no known history of illegal behaviour; and (b) to determine whether men with IDs who had a history of sexual offending had different levels of specific victim empathy towards their own victim, in comparison with an unknown victim of sexual crime, and a victim of non-sexual crime, and make comparisons with non-offenders. METHODS: Men with mild IDs (n=35) were asked to complete a measure of general empathy and a measure of specific victim empathy. All participants completed the victim empathy measure in relation to a hypothetical victim of a sexual offence, and a non-sexual crime, while additionally, men with a history of sexual offending were asked to complete this measure in relation to their own most recent victim. RESULTS: Men with a history of sexual offending had significantly lower general empathy, and specific victim empathy towards an unknown sexual offence victim, than men with no known history of illegal behaviour. Men with a history of sexual offending had significantly lower victim empathy for their own victim than for an unknown sexual offence victim. Victim empathy towards an unknown victim of a non-sexual crime did not differ significantly between the two groups. CONCLUSIONS: The findings suggest that it is important include interventions within treatment programmes that attempt to improve empathy and perspective-taking. PMID- 24761790 TI - Systemic Negligence: Why It Is Morally Important for Developing World Bioethics. AB - In the context of clinical and non-clinical biomedical practices, negligence is usually understood as a lapse of a specific professional duty by a healthcare worker or by a medical facility. This paper tries to delineate systemic negligence as another kind of negligence in the context of health systems, particularly in developing countries, that needs to be recognized and addressed. Systemic negligence is not just a mere collection of stray incidences of medical errors and system failures in a health system, but is proposed in this paper as a more pervasive kind of neglect. Several non-medical factors, such as lack of social and political will, also contribute to it and hence is more difficult to address in a health system. This paper argues that recognizing systemic negligence and including it research agenda have special moral importance for researchers in developing world bioethics, public health ethics and for health activists in the developing world. For, it can be a potent health system barrier, and can seriously impair efforts to ensure patient safety, particularly in the weaker health systems. As it erodes accountability in a health system, addressing it is also important for the twin goals of ensuring patient safety and improving health system performance. Above all, it needs to be addressed because the tolerance of its persistence in a health system seems to undervalue health as a social good. PMID- 24761789 TI - Survival and swimming behavior of insecticide-exposed larvae and pupae of the yellow fever mosquito Aedes aegypti. AB - BACKGROUND: The yellow fever mosquito Aedes aegypti is essentially a container inhabiting species that is closely associated with urban areas. This species is a vector of human pathogens, including dengue and yellow fever viruses, and its control is of paramount importance for disease prevention. Insecticide use against mosquito juvenile stages (i.e. larvae and pupae) is growing in importance, particularly due to the ever-growing problems of resistance to adult targeted insecticides and human safety concerns regarding such use in human dwellings. However, insecticide effects on insects in general and mosquitoes in particular primarily focus on their lethal effects. Thus, sublethal effects of such compounds in mosquito juveniles may have important effects on their environmental prevalence. In this study, we assessed the survival and swimming behavior of A. aegypti 4th instar larvae (L4) and pupae exposed to increasing concentrations of insecticides. We also assessed cell death in the neuromuscular system of juveniles. METHODS: Third instar larvae of A. aegypti were exposed to different concentrations of azadirachtin, deltamethrin, imidacloprid and spinosad. Insect survival was assessed for 10 days. The distance swam, the resting time and the time spent in slow swimming were assessed in 4th instar larvae (L4) and pupae. Muscular and nervous cells of L4 and pupae exposed to insecticides were marked with the TUNEL reaction. The results from the survival bioassays were subjected to survival analysis while the swimming behavioral data were subjected to analyses of covariance, complemented with a regression analysis. RESULTS: All insecticides exhibited concentration-dependent effects on survival of larvae and pupae of the yellow fever mosquito. The pyrethroid deltamethrin was the most toxic insecticide followed by spinosad, imidacloprid, and azadirachtin, which exhibited low potency against the juveniles. All insecticides except azadirachtin reduced L4 swimming speed and wriggling movements. A similar trend was also observed for swimming pupa, except for imidacloprid, which increased the swimming activity of pupa. Curiously, the insecticides did not affect cell damage in the neuromuscular system of larvae and pupae. CONCLUSIONS: Deltamethrin and spinosad were the main compounds to exhibit lethal effects, which allowed the control of A. aegypti larvae and pupae, and impair their swimming potentially compromising foraging and predation likelihood. PMID- 24761791 TI - A review of the management of childhood immune thrombocytopenia: how can we provide an evidence-based approach? AB - Most children with immune thrombocytopenia (ITP) have transiently low platelet counts and do not suffer from bleeding. Treatments with steroids, immunosuppression or splenectomy are not thought to be curative and may create more problems than the low platelet count. Consequently, many children do not receive treatment unless there is bleeding. However, although registry data looks promising, this approach outcome is not consistent between countries, or even between centres in the same country, leading to confusion for both physicians and families. Reaching a consensus for the management of paediatric ITP is further complicated by the lack of a diagnostic test and by the heterogeneity of the disease; for example, although most children remain relatively asymptomatic and go into an early remission, some patients have significant bleeding and others do not go into spontaneous remission. This review assesses the available evidence to guide physicians and families on making management decisions, showing the wide range of treatment choices, and the different approaches between countries and considers methods by which further information could be acquired to provide a more stratified approach to management. PMID- 24761793 TI - Predictably selective (sp3)C-O bond formation through copper catalyzed dehydrogenative coupling: facile synthesis of dihydro-oxazinone derivatives. AB - An intramolecular dehydrogenative (sp(3))C-O bond formation in salicylamides can be initiated by an active Cu/O2 species to generate pharamaceutically relevant dihydro-oxazinones. Experimental findings suggest that stereoelectronic parameters in both coupling partners are controlling factors for site selectivity in bond formation. Mechanistic investigations including isotope labeling, kinetic studies helped to propose a catalytic cycle. The method provides a convenient synthesis of an investigational new medicine CX-614, which has potential in finding treatment for Parkinson's and Alzheimer's diseases. PMID- 24761794 TI - Cytotoxic clinical isolates of Pseudomonas aeruginosa identified during the Steroids for Corneal Ulcers Trial show elevated resistance to fluoroquinolones. AB - BACKGROUND: To determine the relationship between type three secretion genotype and fluoroquinolone resistance for P. aeruginosa strains isolated from microbial keratitis during the Steroids for Corneal Ulcers Trial (SCUT) and for two laboratory strains, PA103 and PAO1. METHODS: Confirmed P. aeruginosa isolates from the SCUT were divided into exoU(+) or exoU(-). The exoU(+) strains contained the gene encoding ExoU, a powerful phospholipase toxin delivered into host cells by the type three secretion system. Isolates were then assessed for susceptibility to fluoroquinolone, cephalosporin, and aminoglycoside antibiotics using disk diffusion assays. Etest was used to determine the MIC of moxifloxacin and other fluoroquinolones. Laboratory isolates in which the exoU gene was added or deleted were also tested. RESULTS: A significantly higher proportion of exoU(+) strains were resistant to ciprofloxacin (p = 0.001), gatifloxacin (p = 0.003), and ofloxacin (p = 0.002) compared to exoU(-) isolates. There was no significant difference between exoU(+) or exoU(-) negative isolates with respect to susceptibility to other antibiotics except gentamicin. Infections involving resistant exoU(+) strains trended towards worse clinical outcome. Deletion or acquisition of exoU in laboratory isolates did not affect fluoroquinolone susceptibility. CONCLUSIONS: Fluoroquinolone susceptibility of P. aeruginosa isolated from the SCUT is consistent with previous studies showing elevated resistance involving exoU encoding (cytotoxic) strains, and suggest worse clinical outcome from infections involving resistant isolates. Determination of exoU expression in clinical isolates of P. aeruginosa may be helpful in directing clinical management of patients with microbial keratitis. PMID- 24761796 TI - Response to Comment on "Fungicide field concentrations exceed FOCUS surface water predictions: urgent need of model improvement". PMID- 24761795 TI - Reconsidering the safety in numbers effect for vulnerable road users: an application of agent-based modeling. AB - OBJECTIVE: Increasing levels of active transport provide benefits in relation to chronic disease and emissions reduction but may be associated with an increased risk of road trauma. The safety in numbers (SiN) effect is often regarded as a solution to this issue; however, the mechanisms underlying its influence are largely unknown. We aimed to (1) replicate the SiN effect within a simple, simulated environment and (2) vary bicycle density within the environment to better understand the circumstances under which SiN applies. METHODS: Using an agent-based modeling approach, we constructed a virtual transport system that increased the number of bicycles from 9% to 35% of total vehicles over a period of 1,000 time units while holding the number of cars in the system constant. We then repeated this experiment under conditions of progressively decreasing bicycle density. RESULTS: We demonstrated that the SiN effect can be reproduced in a virtual environment, closely approximating the exponential relationships between cycling numbers and the relative risk of collision as shown in observational studies. The association, however, was highly contingent upon bicycle density. The relative risk of collisions between cars and bicycles with increasing bicycle numbers showed an association that is progressively linear at decreasing levels of density. CONCLUSIONS: Agent-based modeling may provide a useful tool for understanding the mechanisms underpinning the relationships previously observed between volume and risk under the assumptions of SiN. The SiN effect may apply only under circumstances in which bicycle density also increases over time. Additional mechanisms underpinning the SiN effect, independent of behavioral adjustment by drivers, are explored. PMID- 24761792 TI - Illustrating the interplay between the extracellular matrix and microRNAs. AB - The discovery of cell surface receptors that bind to extracellular matrix (ECM) components marked a new era in biological research. Since then there has been an increasing appreciation of the importance of studying cells in the context of their extracellular environment. Cell behaviour is profoundly affected by the ECM, whose synthesis and turnover must be finely balanced in order to maintain normal function and prevent disease. In the last decade, microRNAs (miRNAs) have emerged as key regulators of ECM gene expression. As new technologies for the identification and validation of miRNA targets continue to be developed, a growing body of data supporting the role of miRNAs in regulating the ECM biology has arisen from a variety of cell and animal models along with clinical studies. However, more recent findings suggest an intriguing interplay between the ECM and miRNAs: not only can miRNAs control the composition of the ECM, but also the ECM can affect the expression of specific miRNAs. Here we discuss how miRNAs contribute to the synthesis, maintenance and remodelling of the ECM during development and disease. Furthermore, we bring to light evidence that points to a role for the ECM in regulating miRNA expression and function. PMID- 24761797 TI - Controlling of 6 nm sized and 10 nm pitched dot arrays ordered along narrow guide lines using PS-PDMS self-assembly. AB - We have studied graphoepitaxy to make nanodots or nanolines ordered along electron beam (EB)-drawn resist guide using block copolymers (BCPs) of polystyrene-polydimethylsiloxane (PS-PDMS). We found out that the number n of ordered molecular dot arrays in the line gap increases stepwise with the gap between guide lines. The n self-assembled dot arrays were ordered in a gap between n and n+1 times the mean PDMS pitch and self-assembled with no guide pattern. According to the ordering characteristics, 6 nm sized and 10 nm pitched PDMS dot arrays were formed using the BCP self-assembly with the guide lines. PMID- 24761798 TI - Pathways to soot oxidation: reaction of OH with phenanthrene radicals. AB - Energetics and kinetics of the oxidation of possible soot surface sites by hydroxyl radicals were investigated theoretically. Energetics were calculated by employing density functional theory. Three candidate reactions were selected as suitable prototypes of soot oxidation by OH. The first two, OH + benzene and OH + benzene-phenol complex, did not produce pathways that lead to substantial CO expulsion. The third reaction, OH attack on the phenanthrene radical, had multiple pathways leading to CO elimination. The kinetics of the latter reaction system were determined by solving the master equations with the MultiWell suite of codes. The barrierless reaction rates of this system were computed using the VariFlex program. The computations were carried out over the ranges 1500-2500 K and 0.01-10 atm. At higher temperatures, above 2000 K, the oxidation of phenanthrene radicals by OH followed a chemically activated path. At temperatures lower than 2000 K, chemical activation was not sufficient to drive the reaction to products; reaction progress was impeded by intermediate adducts rapidly de energizing before reaching products. In such cases, the reaction system was modeled by treating the accumulating adducts as distinct chemical species and computing their kinetics via thermal decomposition. The overall rate coefficient of phenanthrene radical oxidation by OH forming CO was found to be insensitive to pressure and temperature and is approximately 1 * 10(14) cm(3) mol(-1) s(-1). The oxidation of phenanthrene radicals by OH is shown to be controlled by two main processes: H atom migration/elimination and oxyradical decomposition. H atom migration and elimination made possible relatively rapid rearrangement of the aromatic edge to form oxyradicals with favorable decomposition rates. The reaction then continues down the fastest oxyradical pathways, eliminating CO. PMID- 24761800 TI - Observing the role of graphene in boosting the two-electron reduction of oxygen in graphene-WO3 nanorod photocatalysts. AB - The new role of graphene (GR) in boosting the two-electron reduction of O2 to H2O2 has been first identified in the GR-WO3 nanorod (NR) nanocomposite photocatalysts, which are fabricated by a facile, solid electrostatic self assembly strategy to integrate the positively charged branched poly(ethylenimine) (BPEI)-GR (BGR) and negatively charged WO3 NRs at room temperature. Photoactivity test shows that, as compared to WO3 NRs, BGR-WO3 NRs with an appropriate addition ratio of GR exhibit remarkably enhanced and stable visible-light photoactivity toward the degradation of Rhodamine B. Besides the common roles of GR observed in the GR-based composite photocatalysts in the literature, including enhancing the visible-light absorption intensity, improving the lifetime and transfer of photogenerated charge carriers, and increasing the adsorption capacity for reactants, we have observed the new role of GR in boosting the two-electron reduction of O2 to H2O2 in this specific BGR-WO3 NR photocatalyst system. Importantly, this new role of GR does contribute to the overall photoactivity enhancement of BGR-WO3 NR nanocomposites. The synergistic contribution of GR on improving the photoactivity of WO3 NRs and the underlying reaction mechanism have been analyzed by the structure-photoactivity correlation analysis and controlled experiments using radicals scavengers. PMID- 24761799 TI - Prevalence of malaria and anaemia among HIV infected pregnant women receiving co trimoxazole prophylaxis in Tanzania: a cross sectional study in Kinondoni Municipality. AB - BACKGROUND: HIV-infected pregnant women are particularly more susceptible to the deleterious effects of malaria infection particularly anaemia. In order to prevent opportunistic infections and malaria, a policy of daily co-trimoxazole prophylaxis without the standard Suphadoxine-Pyrimethamine intermittent preventive treatment (SP-IPT) was introduced to all HIV infected pregnant women in the year 2011. However, there is limited information about the effectiveness of this policy. METHODS: This was a cross sectional study conducted among HIV infected pregnant women receiving co-trimoxazole prophylaxis in eight public health facilities in Kinondoni Municipality from February to April 2013. Blood was tested for malaria infection and anaemia (haemoglobin <11 g/dl). Data were collected on the adherence to co-trimoxazole prophylaxis and other risk factors for malaria infection and anaemia. Pearson chi-square test, Fischer's exact test and multivariate logistic regression were used in the statistical analysis. RESULTS: This study enrolled 420 HIV infected pregnant women. The prevalence of malaria infection was 4.5%, while that of anaemia was 54%. The proportion of subjects with poor adherence to co-trimoxazole was 50.5%. As compared to HIV infected pregnant women with good adherence to co-trimoxazole prophylaxis, the poor adherents were more likely to have a malaria infection (Adjusted Odds Ratio, AOR = 6.81, 95% CI = 1.35-34.43, P = 0.02) or anaemia (AOR = 1.75, 95% CI = 1.03 2.98, P = 0.039). Other risk factors associated with anaemia were advanced WHO clinical stages, current malaria infection and history of episodes of malaria illness during the index pregnancy. CONCLUSION: The prevalence of malaria was low; however, a significant proportion of subjects had anaemia. Good adherence to co-trimoxazole prophylaxis was associated with reduction of both malaria infection and anaemia among HIV infected pregnant women. PMID- 24761801 TI - Nonpharmacologic approaches for pain management during labor compared with usual care: a meta-analysis. AB - OBJECTIVES: To assess the effects of nonpharmacologic approaches to pain relief during labor, according to their endogenous mechanism of action, on obstetric interventions, maternal, and neonatal outcomes. DATA SOURCE: Cochrane library, Medline, Embase, CINAHL and the MRCT databases were used to screen studies from January 1990 to December 2012. STUDY SELECTION: According to Cochrane criteria, we selected randomized controlled trials that compared nonpharmacologic approaches for pain relief during labor to usual care, using intention-to-treat method. RESULTS: Nonpharmacologic approaches, based on Gate Control (water immersion, massage, ambulation, positions) and Diffuse Noxious Inhibitory Control (acupressure, acupuncture, electrical stimulation, water injections), are associated with a reduction in epidural analgesia and a higher maternal satisfaction with childbirth. When compared with nonpharmacologic approaches based on Central Nervous System Control (education, attention deviation, support), usual care is associated with increased odds of epidural OR 1.13 (95% CI 1.05-1.23), cesarean delivery OR 1.60 (95% CI 1.18-2.18), instrumental delivery OR 1.21 (95% CI 1.03-1.44), use of oxytocin OR 1.20 (95% CI 1.01-1.43), labor duration (29.7 min, 95% CI 4.5-54.8), and a lesser satisfaction with childbirth. Tailored nonpharmacologic approaches, based on continuous support, were the most effective for reducing obstetric interventions. CONCLUSION: Nonpharmacologic approaches to relieve pain during labor, when used as a part of hospital pain relief strategies, provide significant benefits to women and their infants without causing additional harm. PMID- 24761802 TI - Assessment of physical strain in younger and older subjects using heart rate and scalings of perceived exertion. AB - Physical strain is usually evaluated physiologically by using the heart rate (HR) or psychologically using scaled perceived exertion (PE). In order to explore the relationship between these approaches, we compared the series of both measurements taken simultaneously during work on a bicycle ergometer. A total of 29 participants aged between 27 and 41, 42 and 56, and 57 and 71 years took part in 28 minutes of cycling with systematically increased and decreased load as well as in 7 hours of continuous cycling with low to medium exertion, interrupted by brief peak loads at high to very high exertion levels. Results revealed that, while both measurements are suitable to capture physical strain, HR is not as specific as PE. The older participants further perceived comparable physical loads as more demanding as the younger participants. With an aging workforce, results have potential implications for the organisation of work places. PRACTITIONER SUMMARY: The organisation of work processes is a key issue in the prevention of strain and hence of interest to ergonomists. Our study suggests that workers can, independent of age, perform physical work all day as long as they work at subjectively equal, moderate intensities. PMID- 24761803 TI - Estrogen and progesterone receptor status in breast cancer: a cross-sectional study of 450 women in Kerala, South India. AB - BACKGROUND: Hormone receptor status is an important prognostic and therapeutic tool in breast cancer. The objectives of our study were to create a database of breast cancer patients in Central Kerala between January 2010 and December 2012 and analyze the proportions of estrogen receptor and progesterone receptor positivity in premenopausal and postmenopausal women with breast cancer. METHODS: Estrogen and progesterone receptor status were evaluated by immunohistochemistry. The chi-square test was used for statistical analysis. RESULTS: The median age at diagnosis was 50 years while the mean age was 51.92 (SD = 11.78). 56.1% of premenopausal and 47.4% of postmenopausal patients were found to be ER positive, while PR positivity was 47.7% and 34.7% respectively in the premenopausal and postmenopausal age groups. CONCLUSIONS: The proportions of ER and PRnegative tumors were found to be lower than reported in earlier studies on Indian populations. Contrary to expectations, the proportions of ER and PRpositivity were found to be higher in the premenopausal age group. PMID- 24761804 TI - Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper. AB - BACKGROUND: Allergen immunotherapy (AIT) has been thoroughly documented in randomized controlled trials (RCTs). It is the only immune-modifying and causal treatment available for patients suffering from IgE-mediated diseases such as allergic rhinoconjunctivitis, allergic asthma and insect sting allergy. However, there is a high degree of clinical and methodological heterogeneity among the endpoints in clinical studies on AIT, for both subcutaneous and sublingual immunotherapy (SCIT and SLIT). At present, there are no commonly accepted standards for defining the optimal outcome parameters to be used for both primary and secondary endpoints. METHODS: As elaborated by a Task Force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) Immunotherapy Interest Group, this Position Paper evaluates the currently used outcome parameters in different RCTs and also aims to provide recommendations for the optimal endpoints in future AIT trials for allergic rhinoconjunctivitis. RESULTS: Based on a thorough literature review, the TF members have outlined recommendations for nine domains of clinical outcome measures. As the primary outcome, the TF recommends a homogeneous combined symptom and medication score (CSMS) as a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner. All outcomes, grouped into nine domains, are reviewed. CONCLUSION: A standardized and globally harmonized method for analysing the clinical efficacy of AIT products in RCTs is required. The EAACI TF highlights the CSMS as the primary endpoint for future RCTs in AIT for allergic rhinoconjunctivitis. PMID- 24761805 TI - Antimicrobial and antiinsectan phenolic metabolites of Dalea searlsiae. AB - Continued interest in the chemistry of Dalea spp. led to investigation of Dalea searlsiae, a plant native to areas of the western United States. Methanol extractions of D. searlsiae roots and subsequent chromatographic fractionation afforded the new prenylated and geranylated flavanones malheurans A-D (1-4) and known flavanones (5 and 6). Known rotenoids (7 and 8) and isoflavones (9 and 10) were isolated from aerial portions. Structure determination of pure compounds was accomplished primarily by extensive 1D- and 2D-NMR spectroscopy. The absolute configurations of compounds 1-5, 7, and 8 were assigned using electronic circular dichroism spectroscopy. Antimicrobial bioassays revealed significant activity concentrated in the plant roots. Compounds 1-6 exhibited MICs of 2-8 MUg/mL against Streptococcus mutans, Bacillus cereus, and oxacillin-sensitive and resistant Staphylococcus aureus. Aerial metabolites 7-10 were inactive against these organisms, but the presence of 7 and 8 prompted investigation of the antiinsectan activity of D. searlsiae metabolites toward the major crop pest Spodoptera frugiperda (fall armyworm). While compounds 1-10 all caused significant reductions in larval growth rates, associated mortality (33-66%) was highest with flavanone 4 and rotenoids 7 and 8. These findings suggest a differential allocation of antimicrobial and antiinsectan plant resources to root and aerial portions of the plant, respectively. PMID- 24761806 TI - Assessment of microbiological contamination of fresh, minimally processed, and ready-to-eat lettuces (Lactuca sativa), Rio de Janeiro State, Brazil. AB - This study aimed to assess the microbiological contamination of lettuces commercialized in Rio de Janeiro, Brazil, in order to investigate detection of norovirus genogroup II (NoV GII), Salmonella spp., total and fecal coliforms, such as Escherichia coli. For NoV detection samples were processed using the adsorption-elution concentration method associated to real-time quantitative polymerase chain reaction (qPCR). A total of 90 samples of lettuce including 30 whole fresh lettuces, 30 minimally processed (MP) lettuces, and 30 raw ready-to eat (RTE) lettuce salads were randomly collected from different supermarkets (fresh and MP lettuce samples), food services, and self-service restaurants (RTE lettuce salads), all located in Rio de Janeiro, Brazil, from October 2010 to December 2011. NoV GII was not detected and PP7 bacteriophage used as internal control process (ICP) was recovered in 40.0%, 86.7%, and 76.7% of those samples, respectively. Salmonella spp. was not detected although fecal contamination has been observed by fecal coliform concentrations higher than 10(2) most probable number/g. E. coli was detected in 70.0%, 6.7%, and 30.0% of fresh, MP, and RTE samples, respectively. This study highlights the need to improve hygiene procedures at all stages of vegetable production and to show PP7 bacteriophage as an ICP for recovering RNA viruses' methods from MP and RTE lettuce samples, encouraging the evaluation of new protocols that facilitate the establishment of methodologies for NoV detection in a greater number of food microbiology laboratories. PRACTICAL APPLICATION: The PP7 bacteriophage can be used as an internal control process in methods for recovering RNA viruses from minimally processed and ready-to-eat lettuce samples. PMID- 24761807 TI - Pulmonary involvement in patients with Behcet's disease: report of 15 cases. AB - BACKGROUND AND OBJECTIVES: Behcet's disease (BD) is a multisystem vasculitis, and pulmonary involvement in BD can have complex clinical manifestations. We aimed to analyze the clinical and radiological features, as well as the outcomes, of BD patients with pulmonary manifestation. METHOD: We retrospectively reviewed the medical records of 106 patients with BD diagnosed in our institute between January 2000 and January 2013. Patients with pulmonary vascular or parenchymal abnormalities on chest radiography, thorax computed tomography, magnetic resonance imaging or pulmonary scintigraphy were included in this study. RESULTS: Fifteen patients (14%) were identified to have pulmonary involvement. Pulmonary artery aneurysms (PAA) was observed in six patients, and all of them had concomitant thrombi, attenuation or occlusion of PAs, and five of them also had radiographic parenchymal changes. Three patients had solely pulmonary artery thrombus (PAT) without PAA. For the six patients with isolated radiographic parenchyma changes, pulmonary infiltration resolved with immunosuppressant therapy in four subjects; the lesion remained unchanged in one subject with radiographic interstitial changes, and acid-fast bacilli were found in the remaining subject. Patients with PAA or PAT had more frequency of hemoptysis and extra-pulmonary vascular lesions compared with isolated parenchymal involvement. Radiographic parenchyma changes are nonspecific, with ill-defined ground-glass opacity being the most common pulmonary radiographic parenchymal changes. Patients with isolated parenchymal changes had better prognosis than those with PAA or PAT. CONCLUSIONS: BD with pulmonary involvement can have a wide spectrum of abnormal clinical and radiographic manifestations, and multiple pulmonary lesions can exit in the same patient. PMID- 24761808 TI - No evidence for Helicobacter pylori in oral lichen planus. AB - OBJECTIVES: Oral lichen planus is a T-cell-mediated mucosal disease of unknown etiology. Numerous predisposing factors have been put forward in the etiology of this disease. This includes stress, drugs, genetic susceptibility, certain viruses, and bacterial infections. Recently, there have been studies published on possible role of Helicobacter pylori infection in pathogenesis of mucocutaneous diseases including oral lichen planus (OLP). The aim of this study was to detect immunohistochemically the presence of Helicobacter pylori in oral lichen planus. MATERIALS AND METHODS: Paraffin-embedded tissue blocks of 50 cases of OLP and 10 cases of normal buccal mucosal biopsies and 6 endoscopic biopsies of patients with peptic ulcer (control group) were sectioned and stained by hematoxylin and eosin. Serial sections of same were stained immunohistochemically using Anti Helicobacter pylori antibody and observed under microscope for presence or absence of Helicobacter pylori. RESULTS: Except for the control group, none of the cases of OLP and normal buccal mucosal biopsies showed positivity for Helicobacter pylori. CONCLUSION: As we did not detect the presence of Helicobacter pylori in any of the OLP cases, we question the role of these organisms in the pathogenesis of OLP planus if any. PMID- 24761809 TI - 'Double-Hit' cytogenetic status may not be predicted by baseline clinicopathological characteristics and is highly associated with overall survival in B cell lymphoma patients. AB - 'Double-Hit' (DH) B cell non-Hodgkin lymphomas are characterized by the presence of a MYC rearrangement and additional rearrangement(s) most commonly involving BCL2 and/or BCL6. Patients with DH lymphomas are unlikely to achieve long-term survival when treated with standard immunochemotherapy alone. DH gene rearrangements can be identified through metaphase karyotyping or more sensitive fluorescence in situ hybridization (FISH), although the latter is not routinely performed. We report 53 cases of B cell lymphoma that underwent diagnostic metaphase karyotying or FISH for MYC rearrangements. DH lymphoma was detected in 17 cases. No baseline factor, including age, serum lactate dehydrogenase, stage, International Prognostic Index or histology predicted for DH status. The median overall survival was significantly shorter for DH compared to non-DH lymphoma patients (8.2 vs. 56.8 months, P < 0.001). DH status retained the most statistically significant association with overall survival on multivariate Cox regression analysis. DH status could not be inferred by baseline disease- or patient-related characteristics and was most predictive of overall survival in this cohort of B cell lymphoma patients. These findings support the practice of routine performance of FISH for DH gene rearrangements on B cell lymphoma specimens in order to effectively identify DH patients who may benefit from risk adapted therapy. PMID- 24761810 TI - Elevated p53 protein expression; a predictor of relapse in rare chronic myeloid malignancies in children? AB - BACKGROUND: Alterations in the tumor suppressor gene TP53 have been associated with poor outcome in adult hematological malignancies. We have earlier reported an increased expression of the TP53 encoded protein p53, in bone marrow samples from pediatric patients with aggressive leukemia. Our aim was now to evaluate p53 protein expression at different time points before and after hematopoietic stem cell transplantation (HSCT) as a predictor of relapse in a group of children diagnosed with MDS, JMML and CML, and also investigate if potential alterations in expression could be correlated to mutations in TP53. PROCEDURE: Paraffin embedded bone marrow samples from 33 pediatric patients diagnosed with MDS, JMML and CML between 1997 and 2010 were collected retrospectively from time of diagnosis and pre and post HSCT. Immunohistochemistry (IHC) was performed on tissue microarrays (TMA) with antibodies to p53 and p21. DNA sequencing of exon 2 11 of TP53 was performed in 7 patients with JMML and 5 patients with MDS. RESULTS: Elevated p53 protein expression at diagnosis predicted for relapse, odds ratio (OR) 1.19 (95% CI: 1.02-1.40, p = .028). Sequencing of TP53 did not reveal any mutations in the 12 patients analyzed and p53 expression correlated positively to p21 expression indicating a functional p53/p21 protein pathway. CONCLUSION: Elevated p53 protein expression at diagnosis may be an indicator of relapse in children with MDS, JMML and CML. PMID- 24761811 TI - Peripheral T-cell lymphoma in a child with cutaneous involvement. PMID- 24761812 TI - Improving health behaviours of Latina mothers of youths and adults with intellectual and developmental disabilities. AB - BACKGROUND: Latina mothers who care for children with intellectual and developmental disabilities (IDD) over the lifespan struggle to take care of their own health needs in the context of their caregiving experience. Services are typically aimed at the persons with IDD and not their family caregivers. Yet, attending to family caregiver needs may contribute to better long-term care of persons with IDD who remain at home. To address this unmet need, we developed a culturally sensitive health education intervention for Latina mothers who care for youth and adults with IDD. The aim of the intervention is to improve maternal health-related self-efficacy and health behaviours, and to reduce stress. METHOD: A randomised control design was employed to determine preliminary efficacy of the intervention. Paired sample t-tests were conducted to examine within-group changes from baseline to 3-month post-test. Repeated-measures analysis of covariance was used to examine the group-by-time interaction effects. RESULTS: Intervention participants showed greater increases between pre- and post-test in health-related self-efficacy; self-care, nutrition and overall health behaviours. Both groups reported decreases in depressive symptoms and caregiver burden. CONCLUSIONS: While additional research is needed to determine long-term effects and to replicate findings, our results suggest that this culturally sensitive health intervention is a promising way to increase health behaviours which may lead to overall good health for Latina mothers who care for children with IDD across the lifespan. PMID- 24761813 TI - Transsulfuration is an active pathway for cysteine biosynthesis in Trypanosoma rangeli. AB - BACKGROUND: Cysteine, a sulfur-containing amino acid, plays an important role in a variety of cellular functions such as protein biosynthesis, methylation, and polyamine and glutathione syntheses. In trypanosomatids, glutathione is conjugated with spermidine to form the specific antioxidant thiol trypanothione (T[SH]2) that plays a central role in maintaining intracellular redox homeostasis and providing defence against oxidative stress. METHODS: We cloned and characterised genes coding for a cystathionine beta-synthase (CbetaS) and cysteine synthase (CS), key enzymes of the transsulfuration and assimilatory pathways, respectively, from the hemoflagellate protozoan parasite Trypanosoma rangeli. RESULTS: Our results show that T. rangeli CbetaS (TrCbetaS), similar to its homologs in T. cruzi, contains the catalytic domain essential for enzymatic activity. Unlike the enzymes in bacteria, plants, and other parasites, T. rangeli CS lacks two of the four lysine residues (Lys26 and Lys184) required for activity. Enzymatic studies using T. rangeli extracts confirmed the absence of CS activity but confirmed the expression of an active CbetaS. Moreover, CbetaS biochemical assays revealed that the T. rangeli CbetaS enzyme also has serine sulfhydrylase activity. CONCLUSION: These findings demonstrate that the RTS pathway is active in T. rangeli, suggesting that this may be the only pathway for cysteine biosynthesis in this parasite. In this sense, the RTS pathway appears to have an important functional role during the insect stage of the life cycle of this protozoan parasite. PMID- 24761814 TI - The opiate dilemma. PMID- 24761815 TI - Assessing the present state and potential of Medicaid controlled substance lock in programs. AB - Nonmedical use of prescription medications--particularly controlled substances- has risen dramatically in recent decades, resulting in alarming increases in overdose-related health care utilization, costs, and mortality. The Centers for Disease Control and Prevention estimate that 80% of abused and misused controlled substances originate as legal prescriptions. As such, policymakers and payers have the opportunity to combat nonmedical use by regulating controlled substance accessibility within legal prescribing and dispensing processes. One common policy strategy is found in Medicaid controlled substance lock-in programs. Lock in programs identify Medicaid beneficiaries exhibiting high-risk controlled substance seeking behavior and "lock in" these patients to, typically, a single prescriber and pharmacy from which they may obtain Medicaid-covered controlled substance prescriptions. Lock-in restrictions are intended to improve care coordination between providers, reduce nonmedical use behaviors, and limit Medicaid costs stemming from nonmedical use and diversion. Peer-reviewed and gray literature have been examined to assess the current prevalence and design of Medicaid lock-in programs, as well as the current evidence base for informing appropriate program design and understanding program effectiveness. Forty-six state Medicaid agencies currently operate lock-in programs. Program design varies widely between states in terms of defining high-risk controlled substance use, the scope of actual lock-in restrictions, and length of program enrollment. Additionally, there is a remarkable dearth of peer-reviewed literature evaluating the design and effectiveness of Medicaid lock-in programs. Nearly all outcomes evidence stemmed from publicly accessible internal Medicaid program evaluations, which largely investigated cost savings to the state. Lock-in programs are highly prevalent and poised to play a meaningful role in curbing the prescription drug abuse epidemic. However, achieving these ends requires a concerted effort from the academic and policy communities to rigorously evaluate the effect of lock-in programs on patient outcomes, determine optimal program design, and explore opportunities to enhance lock-in program impact through coordination with parallel controlled substance policy efforts, namely prescription drug-monitoring programs. PMID- 24761816 TI - Implementation of an opioid management initiative by a state Medicaid program. AB - BACKGROUND: The utilization of prescription opioids has increased over the last 2 decades. Associated with this is the misuse of prescription opioids for nonmedical purposes. Medicaid programs have struggled with developing strategies that balance best practice models, appropriate utilization, and reduction in costs associated with the opioid medication class. OBJECTIVE: To examine the impact of a 2-year stepwise initiative to reduce utilization and therapy costs of long-acting opioid analgesics (LAOA) by addressing issues of high dose, daily dose, and preferred therapeutic alternatives. METHODS: Utilization data from the Massachusetts Medicaid pharmacy program for LAOAs were reviewed and compared for 2 time periods. The calendar year prior to the initiative, 2002, was used as a base year and represents a time period when there were no restrictions in place for members to obtain long-acting opioids. The calendar year 2005 was the comparison year representing a time period after the multiple steps of the initiative had been implemented. A retrospective claims-based analysis was performed to determine the impact of restrictions on LAOAs, defined as brand and generic versions of oxycodone ER, morphine ER, methadone, and fentanyl transdermal system. The primary measure was the percentage of change of unique utilizers, paid claims, and average daily dose for each LAOA following the implementation of the opioid management initiative. Secondary measures included a cost analysis. RESULTS: Compared with 2002, the overall number of LAOA unique utilizers declined 17.8% (P < 0.0001), and the overall number of claims declined by 4.1% (P < 0.0001), while Medicaid pharmacy benefit member enrollment remained relatively stable. Average daily dose declined in methadone and morphine ER and increased in oxycodone ER and fentanyl transdermal system. The 2005 overall cost of LAOAs decreased 8.0% compared with the overall cost in 2002. The per-member per-month (PMPM) cost for opioid users in 2002 was $110.57 ($120.04 when adjusted to 2005 dollars) compared with $123.75 in 2005. In comparison, the overall PMPM for all members in 2002 was $3.52 ($3.82 when adjusted to 2005 dollars) compared with $3.59 in 2005. CONCLUSIONS: Our study successfully demonstrated that a state Medicaid program initiative can result in a significant overall decrease in opioid class utilization specifically for the targeted, more costly agents. This was achieved via the implementation of a Therapeutic Class Management multidisciplinary workgroup that established a prior authorization process implementing limits on dose, as well as identified preferred less costly agents. It further facilitated the direct opportunity for pharmacy-prescriber collaboration for LAOA medication management. PMID- 24761817 TI - Complexity of pain management among patients with nociceptive or neuropathic neck, back, or osteoarthritis diagnoses. AB - BACKGROUND: Approaches to pain management are diverse, requiring prescribers to evaluate an array of clinical issues and potential solutions. In addition to the difficult task of selecting a treatment option, pain treatment may be further complicated by multiple prescribers, multiple medications, and multiple mechanisms of pain origination. OBJECTIVE: To describe patient demographics (e.g., age, gender); comorbidities; office visits (e.g., physician, chiropractor, physical therapy, psychiatry, allergist); number of different prescribers overall prescription use; pain medications as classified by the World Health Organization's (WHO) pain ladder; adjuvant medications; nonpharmacologic procedures; and potential drug interactions in a broad sample of patients with nociceptive or neuropathic neck or back diagnoses, or osteoarthritis diagnoses, in a commercial population. METHODS: This claims-data analysis used a cross sectional cohort comparison with a fixed 2-year observation period from September 1, 2006, to August 31, 2008, for patients in the PharMetrics national managed care database. The assigned cohorts were neuropathic-related neck/back diagnoses (NEURO); neuropathic and nociceptive neck/back diagnoses (NEURO/NOCI); nociceptive neck/back diagnoses without a neuropathic-related diagnosis (NOCI); and only osteoarthritis (OA) diagnoses. All analyses were conducted by cohort. The analysis included the following patient-descriptive variables: patient demographics, comorbidities, office visits, most frequent medical providers and number of different prescribers, all medications, pain medications as classified by the WHO pain ladder, adjuvant medications, adjuvant procedures and potential drug interactions. The goal for selecting these variables was to describe a range of data that might provide insight into the complexity of pain management decisions faced by clinicians. RESULTS: The study included 85,014 patients, classified as NEURO (n = 2,375), NEURO/NOCI (n = 37,019), NOCI (n = 39,496), and OA (n = 6,124). The most frequently occurring comorbidities (observed in > 40% of patients) included cardiovascular and neuropathic pain conditions. Considering all types of medication claims observed among all cohorts, the overall mean prescription claim count for the 2-year observation period was 57.9 claims (standard deviation 56.2). Weak opioids (WHO pain relief ladder rung 2) accounted for the majority of pain medication claims across all cohorts. Across cohorts, 25.7% of patients had 10 or more days of overlapping drug availability (for inducers or inhibitors of the cytochrome P450 system concomitantly), a measure of potential for drug interactions. CONCLUSIONS: Choosing the appropriate pain treatment involves assessing currently used medications for existing illnesses and deciding on the appropriate types of pain medications. However, potentially serious drug-drug interactions are a consequence of multiple drug use, and such a potential requires thoughtful consideration by those involved in patient care. PMID- 24761818 TI - The prevalence of opioid-related major potential drug-drug interactions and their impact on health care costs in chronic pain patients. AB - BACKGROUND: Literature has shown that chronic pain patients prescribed opioids are at an increased risk for experiencing drug-drug interactions as a result of polypharmacy. In addition, chronic, noncancer pain patients who experience drug drug interactions have been shown to have greater health care utilization and costs. However, no study has focused on the health economics of major clinically significant drug-drug interactions associated with long-acting opioids. OBJECTIVES: To (a) estimate the prevalence of major drug-drug interactions among patients prescribed a long-acting opioid and (b) evaluate the potential impact of major drug-drug interactions on health care costs. METHODS: This study was a retrospective cohort analysis using claims data from the MarketScan Commercial Claims and Encounter Database between 2008 and 2010. Patients with at least 1 prescription for a long-acting opioid for >= 30 days were placed into cohorts according to the expected clinical impact of the potential drug-drug interaction: major versus none. Propensity score matching was used to mitigate differences in baseline characteristics between the cohorts. Health care costs were based on payments for all covered health care services, which consisted of inpatient and outpatient medical, emergency department, and outpatient prescription costs. RESULTS: Among 57,752 chronic, noncancer pain patients who met all inclusion and exclusion criteria, 5.7% (3,302) were exposed to a potential major drug-drug interaction. The costs associated with a potential interaction versus no potential interaction were significantly more after baseline characteristics of the cohorts were normalized by propensity score matching. Monthly health care costs in the 90-day post-index period were significantly greater ($3,366 vs. $2,757, a $609 difference) in patients exposed to a potential drug-drug interaction of major clinical significance, compared with those not exposed to a drug-drug interaction. The higher health care costs were mainly driven by outpatient and inpatient medical costs. CONCLUSIONS: Exposure to potential drug drug interactions may result in unnecessary and unintended health care costs. Physicians should be made aware of commonly administered cytochrome P450 (CYP450) metabolized drugs in the chronic pain patient and consider prescribing non-CYP450 metabolized opioid and nonopioid analgesics. Managed care's use of utilization management tools to avoid these exposures may reduce costs. PMID- 24761819 TI - Adherence patterns for abiraterone acetate and concomitant prednisone use in patients with prostate cancer. AB - BACKGROUND: With the growing use of oral anticancer medications, understanding adherence patterns has become increasingly important. Abiraterone acetate (AA) is a prodrug of abiraterone, a novel androgen biosynthesis inhibitor. AA is approved for use in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer. OBJECTIVE: To evaluate AA and concomitant prednisone utilization and adherence patterns for patients with prostate cancer in the United States. METHODS: This study used data from 2 administrative health care claims databases--Dataset 1: Truven Health Analytics MarketScan (December 2010 to August 2012) and Dataset 2: Symphony Health Solutions' ProMetis Lx (June 2009 to March 2013). To evaluate the consistency of medication-taking behavior, adherence was measured using medication possession ratio (MPR), which was calculated as the sum of days of supply divided by the days on therapy in patients with at least 2 AA prescriptions. Additional outcomes included the proportion of patients taking prednisone, mean and median daily dose of AA, and concomitant prednisone use. Adherence was also studied by age, health care plan type, or previous recent chemotherapy subgroups. RESULTS: 515 patients (mean age: 72.2) and 3,228 patients (mean age: 72.2) with at least 1 AA claim were selected from Dataset 1 and Dataset 2, respectively. The mean (median) daily AA dose per person per prescription was 998.8 (1,000) mg for Dataset 1 and 994.2 (1,000) mg for Dataset 2, which is within 1% of the recommended daily dose (1,000 mg). Mean (median) MPR was 93% (98%; n = 492) in Study Population 1 and 93% (100%; n = 2,449) in Study Population 2. The mean (median) daily prednisone dose per person per prescription was similar in both datasets with 10.1 (10.0; n = 488) mg and 10.6 (10.0; n = 2,425) mg in Dataset 1 and 2, respectively. Similar adherence patterns were observed for patients in different age groups, for patients with commercial health care plans versus patients with Medicare coverage, and for patients with recent chemotherapy compared with patients without. CONCLUSIONS: Results from 2 observational studies reported high levels of adherence to AA dosing and administration patterns consistent with prescribing information. These findings provide useful insights into the treatment patterns in patients with prostate cancer treated with AA and can contribute to the current discussion in oncologic research and practice. PMID- 24761820 TI - Health care utilization and costs by site of service for nonmetastatic breast cancer patients treated with trastuzumab. AB - BACKGROUND: Adjuvant trastuzumab treatment is administered to early stage breast cancer patients in physician office (POV) or hospital outpatient (HOP) settings. OBJECTIVE: To identify treatment patterns, utilization, and costs by site of care (POV vs. HOP) of patients with adjuvant treatment of breast cancer with trastuzumab. METHODS: This retrospective analysis identified adult, female breast cancer patients who initiated trastuzumab treatment (index date) from a large U.S. claims database. Inclusion criteria also required >= 2 claims for both trastuzumab (from July 1, 2006, to July 31, 2012) and breast cancer (during 6 month pre-index baseline period), no evidence of metastatic breast cancer or other cancers in the baseline period, and continuous enrollment with commercial or Medicare Advantage coverage 6 months pre- and post-index, except that patients who died during follow-up were retained. Patients with evidence of trastuzumab receipt during the baseline period or more than 1 site of care during follow-up were excluded. Patients were stratified by site of care and were followed from index date to 30 days after the last trastuzumab infusion prior to a gap >= 90 days, death, disenrollment, or end-of-study period. Differences in treatment patterns between the POV and HOP cohorts were assessed by t-test and chi-square test. The relationship between site of care and health care costs was modeled with a generalized linear model with gamma distribution and log link, and the number of trastuzumab infusions was modeled with negative binomial regression controlling for log follow-up time. All models were adjusted for age, baseline comorbidity score, and insurance type. RESULTS: Of the 3,439 breast cancer patients identified, 77.6% (2,669) received adjuvant trastuzumab in the POV setting. Mean age (53.7 years) and baseline comorbidity score (3.91) were similar among cohorts; a higher percentage of POV versus HOP patients had commercial insurance (91.1% vs. 86.4%, P < 0.001). Compared with the POV cohort, HOP patients had a shorter mean duration of trastuzumab treatment (324.8 vs. 343.0 days, P < 0.001); more treatment gaps (30-59 day gap: 67.4% vs. 24.1%, P < 0.001); and fewer trastuzumab infusions per month (1.37 vs. 1.98, P < 0.001) during follow-up. In multivariate analysis, the monthly count of trastuzumab infusions in the HOP cohort was lower than the POV cohort (incidence rate ratio = 0.693; 95% CI = 0.672-0.715). Adjusted per patient per month total health care costs were 53.6 % higher in the HOP setting (cost ratio = 1.536, 95% CI = 1.472 1.604). CONCLUSIONS: Breast cancer patients treated with adjuvant trastuzumab in the HOP setting had a shorter duration of trastuzumab treatment and fewer trastuzumab infusions but incurred higher monthly total costs than patients treated in the POV setting. PMID- 24761821 TI - Prescriber perceptions of a near real-time fax alert program for potential drug drug interactions. AB - BACKGROUND: Health systems have developed interventions to reduce harm associated with drug-drug interactions. Pharmacy benefit managers are in an important position to identify the coprescribing of medications known to interact, since they process data on a large portion of prescription claims in the United States. Electronic health records and electronic prescribing also include alerts through their systems' clinical decision support. However, limited data are available that assess prescribers' perceptions of processes that screen for potential drug drug interactions (PDDIs). OBJECTIVE: To determine prescribers' perceptions of near real-time fax alerts for PDDIs. METHODS: This was a 6-month prospective study where a pharmacy benefit manager distributed evidence-based summaries of 18 different PDDIs that included references and suggested management strategies. Fax alerts were individualized letters sent to the prescriber of the second drug of a PDDI pair for an individual patient. A 16-item questionnaire to assess prescribers' perceptions of the intervention accompanied each individualized PDDI evidence-based summary. RESULTS: A total of 8,075 fax alerts were distributed with 977 returning questionnaires, yielding a 12.1% response rate. There were 848 (86.8%) responses completed by physicians, and 71 (7.3%) completed by nurse practitioners. The most common PDDI fax alerts sent were for warfarin-statin (3,511, 43.5%) and warfarin-thyroid (2,111, 26.1%) interactions. 42.6% of respondents agreed or strongly agreed that fax alerts were a good way to communicate with them. However, 37.5% of respondents either agreed or strongly agreed that the fax alert was a "waste of my time." In contrast, respondents thought notification of carbamazepine-macrolide (mean 1.5 +/- 0.71), ciprofloxacin-tizanidine (mean 2.3 +/- 1.0), and statin-macrolide (mean 2.3 +/- 1.1) was not a waste of time. Also, 59.1% of respondents either disagreed or strongly disagreed that they would prefer to receive a telephone call when interactions like this occur. Half (50.5%) of the respondents indicated their computer systems provided drug interaction alerts. Prescribers who had previously received alerts and specialists were less likely to respond to the questionnaire (OR = 0.685, P <= 0.0001 and OR = 0.851, P = 0.0205, respectively). CONCLUSIONS: The positive response to fax alerts by physicians varies by the component drugs of the PDDI alerts. PMID- 24761822 TI - Outcomes and treatment patterns of adding a third agent to 2 OADs in patients with type 2 diabetes. AB - BACKGROUND: Patients with uncontrolled type 2 diabetes mellitus (T2DM), despite therapy with 2 oral antidiabetic drugs (OADs), may add a third OAD or a glucagon like peptide-1 receptor agonist (GLP-1) or initiate insulin therapy. The transition to insulin has been shown to be delayed in current practice, potentially through clinical inertia--the failure of health care providers to initiate or advance therapy when indicated. Patients and physicians may be resistant to insulin therapy because of beliefs about side effects and limitations to patients' lifestyle, while patients may consider that starting injectable therapy signifies a considerable worsening of their disease and may feel they have "failed" to manage it effectively. OBJECTIVE: To describe current treatment patterns and outcomes among adult patients with T2DM in the United States who were treated with 2 OADs and added a third antidiabetic drug. METHODS: This retrospective study followed patients with T2DM who added a third OAD (the "3OAD" cohort), insulin ("+Insulin"), or a GLP-1 ("+GLP-1") between July 2000 and March 2009. Patients were followed for up to 2 years. Baseline characteristics and follow-up outcomes--including blood glucose level (HbA1c), hypoglycemia, and health care costs--were examined. Treatment persistence was assessed to determine how long patients continued with their prescribed medications without discontinuing or switching. RESULTS: A total of 51,771 patients adding a third agent to their 2OAD regimen were included in this study. Most patients added a third OAD (n = 41,052) over insulin (n = 6,904) or GLP-1 (n = 3,815). At baseline, +Insulin patients were older, with higher comorbidity burden and higher HbA1c. During follow-up, 3OAD patients were more likely to be persistent with their treatment than +Insulin or +GLP-1 patients, but +Insulin patients had the greatest HbA1c reduction from baseline, while continuing with insulin treatment was associated with higher HbA1c reduction. Among 3OAD patients, most of those who switched a third agent initiated insulin, and those who switched early during the follow-up period had greater HbA1c reduction than those who continued with the 3OAD treatment regimen. Average annual health care costs declined in +Insulin patients but increased among 3OAD and +GLP-1 patients. Treatment persistence and HbA1c reduction in +GLP-1 patients were low. CONCLUSIONS: This study found that in current practice, physicians seem to be reluctant to prescribe injectable agents for patients with uncontrolled T2DM despite combination OAD therapy. Despite higher treatment persistence among patients adding a third OAD, this persistence did not translate into better glycemic control and may not necessarily be a long-term cost-saving solution. These data indicate a need for more evidence-based and patient-centered treatment decisions for patients unable to achieve and maintain glycemic targets on multiple OADs. PMID- 24761823 TI - Evaluation of allergic rhinitis and asthma control in a Portuguese community pharmacy setting. AB - BACKGROUND: Allergic rhinitis and asthma (ARA) are frequent respiratory diseases that often coexist, causing a high social and economic impact. It is important to maintain ARA disease control to reduce the disease burden. OBJECTIVE: To assess control in patients with 1 or both pathologies through the application of validated questionnaires at community pharmacies. METHODS: A cross-sectional study was conducted in the pharmacies of the Portuguese county of Covilha (located in the central region of Portugal with about 53,000 inhabitants). Subjects aged between 18 and 70 years who presented a prescription for an asthma and/or allergic rhinitis medication were invited to participate in the study by responding to a questionnaire that included the Control of Allergic Rhinitis and Asthma Test (CARAT). The CARAT is a validated tool to simultaneously assess the control of ARA with scores that range from 0 to 30 points, 0 meaning the worst and 30 meaning the best possible control of disease. RESULTS: Of the 224 participants, 58% were female and the median age was 48.5 years. The median CARAT score was 19 (mean = 17.8 +/- 6.4), and 87% of participants had a score < 25, indicating noncontrolled disease. Female participants, the elderly, and those with less school education responded with scores that demonstrated significantly less disease control. CONCLUSIONS: Using a simple self-assessment questionnaire, such as the CARAT, pharmacists can help identify patients with uncontrolled ARA disease, which is an important first step to change patients' knowledge about their disease, with an ultimate goal of improving ARA outcomes. PMID- 24761824 TI - Critic appraisal. Postoperative sensitivity with indirect restorations. AB - Postoperative sensitivity is characterized by short and sharp pain, and often experienced after cementation of indirect restorations. Factors associated with the occurrence of post-cementation sensitivity include type of cement, removal of smear layer by acid-etching, aggressive tooth preparation, inadequate provisional restorations, and patient's age. Its prevention is based on either interfering with mechanoreceptor activity or occluding the dentinal tubules. Regarding the latter, application of dentin desensitizers may be effective for blocking the tubules and significantly reducing dentin permeability and consequently postoperative sensitivity. This Critical Appraisal will present available clinical data where traditional materials such as zinc phosphate and glass ionomer cements (GIC) as well as self-adhesive resin-based cements were used. PMID- 24761826 TI - Rapid and quantitative detection of prostate specific antigen with a quantum dot nanobeads-based immunochromatography test strip. AB - Convenient and fast testing using an immunochromatography test strip (ICTS) enables rapid yes/no decisions regarding a disease to be made. However, the fundamental limitations of an ICTS, such as a lack of quantitative and sensitive analysis, severely hampers its application in reliable medical testing for the early detection of cancer. Herein, we overcame these limitations by integrating an ICTS with quantum dot nanobeads (QD nanobeads), which were fabricated by encapsulating QDs within modified poly(tert-butyl acrylate-co-ethyl acrylate-co methacrylic acid) and served as a robust signal-generating reagent for the ICTS. Prostate specific antigen (PSA) was used as a model analyte to demonstrate the performance of the QD nanobeads-based ICTS platform. Under optimized conditions, the concentration of PSA could be determined within 15 min with high sensitivity and specificity using only 40 MUL of sample. The detection limit was enhanced by ~12-fold compared with that of an ICTS that used QDs encapsulated by commercial 11-mercaptoundecanoic acid (QDs@MUA) as the signal-generating reagent. At the same time, the possible clinical utility of this approach was demonstrated by measurements recorded from PSA-positive patient specimens. Our data suggest that the QD nanobeads-based ICTS platform is not only rapid and low-cost but also highly sensitive and specific for use in quantitative point-of-care diagnostics; thus, it holds promise for becoming a part of routine medical testing for the early cancer of detection. PMID- 24761825 TI - Duration of injury correlates with necrosis in caerulein-induced experimental acute pancreatitis: implications for pathophysiology. AB - Pancreatic acinar cell necrosis is indicative of severe pancreatitis and the degree of necrosis is an index of its outcome. We studied whether the dose and duration of injury correlates with severity, particularly in terms of necrosis, in caerulein-induced acute pancreatitis (AP) in Swiss albino mice. In addition to control group 1 (G1), groups 2 and 3 received four injections of caerulein every hour but were sacrificed at five hours (G2) and nine hours (G3) respectively, and group 4 received eight injections and was sacrificed at nine hours (G4). The severity of pancreatitis was assessed histopathologically and biochemically. The histopathological scores of pancreatitis in groups 3 and 4 were significantly higher than in groups 1 and 2 (4 vs. 1, 4 vs. 2, 3 vs. 1, 3 vs. 2; P < 0.05). TUNEL-positive apoptotic cells were significantly higher in groups 2 and 3 compared with groups 1 and 4 (P < 0.05). Necrosis was significantly more in group 4 than other groups (37.49% (4.68) vs. 19.97% (1.60) in G2; 20.36% (1.56) in G3; P = 0.006 for G 2 vs. 4 and P = 0.019 for G 3 vs. 4). Electron microscopy revealed numerous autophagosomes in groups 2 and 3 and mitochondrial damage and necrosis in group 4. The pancreatic and pulmonary myeloperoxidase activity in group 4 was significantly higher than that in the other groups (P < 0.01). Hence, severity of pancreatitis is a function of the dose of injurious agent, while inflammation is both dose and duration dependent, which may also explain the wide spectrum of severity of AP seen in clinical practice. PMID- 24761827 TI - The prevalence of distraction among passenger vehicle drivers: a roadside observational approach. AB - OBJECTIVE: Distracted driving contributes to a large proportion of motor vehicle crashes, yet little is known about the prevalence of distracted driving and the specific types of distracting behaviors. The objective of this study was to estimate the prevalence of driver distraction using a roadside observational study design. METHODS: A cross-sectional survey involving direct roadside observation was conducted at 11 selected intersections. Trained investigators observed a sample of passenger vehicles and recorded distraction-related behaviors, driver characteristics, and contextual factors such as vehicle speed and traffic flow. RESULTS: Of the 3,265 drivers observed, the prevalence of distracted driving was 32.7%. Among those involved in a distracting activity, the most frequently observed distractions included interacting with another passenger (53.2%, where passengers were present), talking on the phone (31.4%), external vehicle distractions (20.4%), and texting/dialing a phone (16.6%). The prevalence of talking on the phone was higher among females than males (38.6% vs. 24.3%), whereas external vehicle distractions were higher among males than females (25.8% vs. 24.3%). Drivers <30 years were observed being engaged in any distracting activity, interacting with other passengers, and texting/dialing more frequently than drivers aged 30-50 and >50 years. Drivers were engaged in distracting behaviors more frequently when the car was stopped. CONCLUSIONS: When using similar methodology, roadside observational studies generate comparable prevalence estimates of driver distraction as naturalistic driving studies. Driver distraction is a common problem among passenger vehicle drivers. Despite the increased awareness on the dangers of texting and cell phone use while driving, these specific activities were 2 of the most frequently observed distractions. There is a continued need for road safety education about the dangers of distracted driving, especially for younger drivers. PMID- 24761828 TI - Kinetic mechanism at the branchpoint between the DNA synthesis and editing pathways in individual DNA polymerase complexes. AB - Exonucleolytic editing of incorrectly incorporated nucleotides by replicative DNA polymerases (DNAPs) plays an essential role in the fidelity of DNA replication. Editing requires that the primer strand of the DNA substrate be transferred between the DNAP polymerase and exonuclease sites, separated by a distance that is typically on the order of ~30 A. Dynamic transitions between functional states can be quantified with single-nucleotide spatial precision and submillisecond temporal resolution from ionic current time traces recorded when individual DNAP complexes are held atop a nanoscale pore in an electric field. In this study, we have exploited this capability to determine the kinetic relationship between the translocation step and primer strand transfer between the polymerase and exonuclease sites in complexes formed between the replicative DNAP from bacteriophage Phi29 and DNA. We demonstrate that the pathway for primer strand transfer from the polymerase to exonuclease site initiates prior to the translocation step, while complexes are in the pre-translocation state. We developed a mathematical method to determine simultaneously the forward and reverse translocation rates and the rates of primer strand transfer in both directions between the polymerase and the exonuclease sites, and we have applied it to determine these rates for Phi29 DNAP complexes formed with a DNA substrate bearing a fully complementary primer-template duplex. This work provides a framework that will be extended to determine the kinetic mechanisms by which incorporation of noncomplementary nucleotides promotes primer strand transfer from the polymerase site to the exonuclease site. PMID- 24761829 TI - To what extent does the anxiety scale of the Four-Dimensional Symptom Questionnaire (4DSQ) detect specific types of anxiety disorder in primary care? A psychometric study. AB - BACKGROUND: Anxiety scales may help primary care physicians to detect specific anxiety disorders among the many emotionally distressed patients presenting in primary care. The anxiety scale of the Four-Dimensional Symptom Questionnaire (4DSQ) consists of an admixture of symptoms of specific anxiety disorders. The research questions were: (1) Is the anxiety scale unidimensional or multidimensional? (2) To what extent does the anxiety scale detect specific DSM IV anxiety disorders? (3) Which cut-off points are suitable to rule out or to rule in (which) anxiety disorders? METHODS: We analyzed 5 primary care datasets with standardized psychiatric diagnoses and 4DSQ scores. Unidimensionality was assessed through confirmatory factor analysis (CFA). We examined mean scores and anxiety score distributions per disorder. Receiver operating characteristic (ROC) analysis was used to determine optimal cut-off points. RESULTS: Total n was 969. CFA supported unidimensionality. The anxiety scale performed slightly better in detecting patients with panic disorder, agoraphobia, social phobia, obsessive compulsive disorder (OCD) and post traumatic stress disorder (PTSD) than patients with generalized anxiety disorder (GAD) and specific phobia. ROC-analysis suggested that >=4 was the optimal cut-off point to rule out and >=10 the cut-off point to rule in anxiety disorders. CONCLUSIONS: The 4DSQ anxiety scale measures a common trait of pathological anxiety that is characteristic of anxiety disorders, in particular panic disorder, agoraphobia, social phobia, OCD and PTSD. The anxiety score detects the latter anxiety disorders to a slightly greater extent than GAD and specific phobia, without being able to distinguish between the different anxiety disorder types. The cut-off points >=4 and >=10 can be used to separate distressed patients in three groups with a relatively low, moderate and high probability of having one or more anxiety disorders. PMID- 24761830 TI - Churg-Strauss syndrome: a new endotype of severe asthma? Results of 14 Turkish patients. AB - INTRODUCTION: Churg-Strauss syndrome (CSS) is a rare multisystem vasculitis. Considering the variation of autoimmune diseases in different races, it is of interest to determine whether any outstanding features exist for Turkish patients with CSS. OBJECTIVE: The aim of this study was to evaluate the clinical and serological features of the disease, the treatment, and long-term follow-up details, and to investigate possible etiological factors of Turkish CSS patients. METHODS: The study included 14 patients who were diagnosed with CSS, and followed by our department between 2004 and 2012. Possible etiological factors, initial symptoms, clinical presentations, treatment, as well as outcomes were documented. The study was approved by the local ethics. RESULTS: All patients fulfilled the American College of Rheumatology criteria. Initial symptoms were worsening asthma (n = 14; 100%) and skin lesions (n = 6; 43%). All patients had a diagnosis of asthma and nasal polyps, whereas 57.1% had aspirin hypersensitivity at the time of diagnosis. The lungs (100%) and skin (43%) were most commonly involved. Peripheral eosinophilia dominated on initial presentations of all patients. Initial treatments included oral methyl prednisolone in all cases, whereas cyclophosphamide and azathioprine were used in three cases. Relapses were detected in five cases. None of the cases were able to stop the oral corticosteroid treatment. No fatalities were observed. CONCLUSION: We herein describe a new severe asthma endotype in connection with CSS. We suggest that physicians who deal with uncontrolled severe asthma cases should consider CSS in the presence of nasal polyps, aspirin hypersensitivity, and especially peripheral blood eosinophilia over 10%. PMID- 24761831 TI - Poly(N-isopropylacrylamide)/poly(dopamine) capsules. AB - Polymer capsules are an interesting concept considered in nanobiotechnology. Approaches that facilitate their assembly remain sought after. Poly(dopamine) (PDA) has been considered and successfully applied in this context. We recently demonstrated that PDA could be copolymerized with different types of poly(N isopropylacrylamide) (pNiPAAm) to assemble mixed films on planar substrates. Herein, we transferred this approach onto colloidal substrates and characterized the film thickness depending on the film composition and template particles size. While the membrane of capsules assembled using 5 MUm template particles exhibited strong dependency on the film composition, smaller templates led to capsules with similar membrane thickness. We then compared the permeability of different capsules using fluorescently labeled dextran and fluorescein. We found that the permeability of capsules was heavily dependent on the polymer composition and the template particle size. These fundamental findings contribute to the potential of these capsules, assembled in one-step, for biomedical applications. PMID- 24761832 TI - Using the essential oil of Aloysia triphylla (L'Her.) Britton to sedate silver catfish (Rhamdia quelen) during transport improved the chemical and sensory qualities of the fish during storage in ice. AB - Exposure of silver catfish to 40 MUL/L of the essential oil of Aloysia triphylla (AT) during in vivo transport delayed the onset and resolution of rigor mortis as well as the degradation of IMP into HxR compared to the control. The fish that were treated with 30 or 40 MUL/L of AT received lower sensory demerit scores after 10 d of storage in ice compared to the control, and the fish that were treated with 40 MUL/L of AT had a longer sensory shelf life than did the control. These results indicated that using AT as a sedative in the water in which the silver catfish were transported extended their freshness and increased their shelf life during refrigerated storage. PRACTICAL APPLICATION: Interest in natural anesthetics, such as Aloysia triphylla, has increased in the field of commercial aquaculture because they reduce the number of fish lesions acquired during capture, handling, and transportation. Fish sedated with the essential oil of A. triphylla at 40 MUL/L during transport before slaughter exhibited a delay in the loss of freshness and an increased shelf life in ice. In addition to improving animal welfare before slaughter, the essential oil appears to be a promising product for improving fish conservation in the food industry. PMID- 24761833 TI - Potent airway smooth muscle relaxant effect of cynatratoside B, a steroidal glycoside isolated from Cynanchum stauntonii. AB - The dried roots of Cynanchum stauntonii in having cough-relieving efficacy are commonly included in traditional antitussive formulas. The active components in a C. stauntonii root extract responsible for airway relaxation were isolated using an ex vivo bioassay-guided fractionation method, in which subfractions were evaluated for their inhibitory effects on the contraction of isolated rat tracheal rings by isometric tension measurements. A steroidal glycoside, cynatratoside B (1), identified by LC-MS and NMR spectroscopic analysis, was shown to have potent inhibition on acetylcholine- and carbachol-induced tracheal contractions. The present data provide scientific evidence to support the traditional use of C. stauntonii as an antitussive herbal medicine. PMID- 24761835 TI - Illumination, lighting technologies, and indoor environmental quality. PMID- 24761834 TI - Residue behaviour of six pesticides in button crimini during home canning. AB - The effect of home canning (including washing, boiling, cooling, adding solution and sterilisation) on residue levels of imidacloprid, diflubenzuron, abamectin, pyriproxyfen and beta-cypermethrin and chlorothalonilin on button crimini was assessed. Residues of imidacloprid, diflubenzuron, abamectin and pyriproxyfen were measured by UPLC-MS/MS; the residues of beta-cypermethrin and chlorothalonil were measured by GC. Results showed that washing resulted in a 3.8% reduction of the initial residue level of imidacloprid (p <= 0.05). From washing to sterilisation the processing effect was significant compared with raw crimini (p <= 0.05), but processing through cooling and adding solution had no effect. For diflubenzuron, from raw crimini to sterilisation the processing effect was significant by comparison with the initial level (p <= 0.05); the processing effect was not obvious between two sequential steps, and the sequential steps have list: washing and boiling, boiling and cooling, boiling and adding of solution, cooling and adding solution. The changes in abamectin levels were also significant from raw crimini to sterilisation compared with raw crimini (p <= 0.05), but the changes were not obvious from boiling to adding solution and amongst them. For pyriproxyfen, washing resulted in a 39% reduction, but changes were not obvious from washing to sterilisation, p <= 0.05 between two consecutive steps. The whole procedure could significantly decrease residues of beta cypermethrin (p <= 0.05); washing could significantly reduce residues of beta cypermethrin; the effects of last procedures were complicated, and p <= 0.05 between two consecutive steps. Washing resulted in an 80% reduction of chlorothalonil; after washing there were no detectable residues. After the whole process, the processing factors for imidacloprid, diflubenzuron, abamectin, pyriproxyfen, beta-cypermethrin and chlorothalonil were 0.40, 0.22, 0.04, 0.85, 0.28 and 0, respectively. PMID- 24761836 TI - Fluorine 18 fluorodeoxyglucose PET/CT volume-based indices in locally advanced non-small cell lung cancer: prediction of residual viable tumor after induction chemotherapy. AB - PURPOSE: To study whether volume-based indices of fluorine 18 fluorodeoxyglucose positron emission tomographic (PET)/computed tomographic (CT) imaging is an accurate tool to predict the amount of residual viable tumor after induction chemotherapy in patients with locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed consent. Twenty-two patients with locally advanced NSCLC underwent surgery after induction chemotherapy. All had pre- and posttreatment FDG PET/CT scans. CT largest diameter, CT volume, maximum standardized uptake value (SUVmax), mean SUV (SUVmean), metabolic tumor volume (TV), and total lesion glycolysis of primary tumor were calculated. Changes in tumor measurements were determined by dividing follow-up by baseline measurement (ratio index). Amounts of residual viable tumor, necrosis, fibrous tissue, inflammatory infiltrate, and Ki-67 proliferative index were estimated on resected tumor. Correlations between imaging indices and histologic parameters were estimated by using Spearman correlation coefficients or Mann-Whitney tests. RESULTS: No baseline or posttreatment indices correlated with percentage of residual viable tumor. TV ratio was the only index that correlated with percentage of residual viable tumor (r = 0.61 [95% confidence interval: 0.24, 0.81]; P = .003). Conversely, SUVmax and SUVmean ratios were only indices correlated with Ki-67 (r = 0.62 [95% confidence interval: 0.24, 0.82]; P = .003; and r = 0.60 [95% confidence interval: 0.21, 0.81]; P = .004, respectively). Total lesion glycolysis ratio was moderately correlated with residual viable tumor (r = 0.53 [95% confidence interval: 0.13, 0.78]; P = .01) and with Ki-67 (r = 0.57 [95% confidence interval: 0.18, 0.80]; P = .006). No ratios were correlated with presence of inflammatory infiltrate or foamy macrophages. CONCLUSION: TV and total lesion glycolysis ratios were the only indices correlated with residual viable tumor after induction chemotherapy in locally advanced NSCLC. PMID- 24761837 TI - What explains gray matter atrophy in long-standing multiple sclerosis? AB - PURPOSE: To identify the measures of focal and diffuse white matter (WM) abnormalities that are related to whole-brain, deep, and cortical gray matter (GM) atrophy in long-standing multiple sclerosis (MS). MATERIALS AND METHODS: The institutional review board approved the study; all subjects gave written informed consent. Magnetic resonance (MR) imaging was performed at 3 T in 208 patients with MS of long-standing duration (disease duration >= 10 years) and in 60 healthy control subjects. Normalized GM volume (NGMV), normalized WM volume (NWMV), normalized deep GM volume (NDGMV), cortical thickness, and normalized lesion volume (NLV) were quantified. Tissue integrity of normal-appearing WM (NAWM) and lesions was measured by using diffusion-tensor MR imaging. Multivariate associations between measures of GM atrophy and WM abnormalities were assessed in the patient group by using multiple linear regression. RESULTS: NGMV, NDGMV, and cortical thickness were reduced in patients with MS (all P < .001). The final model for NGMV consisted of NWMV, NLV, and patient age and sex (adjusted R(2) = 0.58, P < .001). NWMV, NLV, and patient sex were the explanatory variables for NDGMV (adjusted R(2) = 0.75, P < .001). The model for cortical thickness consisted of fractional anisotropy of NAWM, NLV, and patient age and sex (adjusted R(2) = 0.32, P < .001). The relationship between GM atrophy and WM abnormalities was weaker in primary and secondary progressive disease than in relapsing-remitting disease. CONCLUSION: Whole-brain and deep GM atrophy were particularly explained by WM atrophy and lesion volume, while cortical atrophy was associated with NAWM integrity loss. The weaker relationship between GM atrophy and WM abnormalities in patients with progressive disease might indicate a more independent neurodegenerative disease process in these patients. PMID- 24761839 TI - The intelligent clinical laboratory as a tool to increase cancer care management productivity. AB - Studies of the causes of cancer, early detection, prevention or treatment need accurate, comprehensive, and timely cancer data. The clinical laboratory provides important cancer information needed for physicians which influence clinical decisions regarding treatment, diagnosis and patient monitoring. Poor communication between health care providers and clinical laboratory personnel can lead to medical errors and wrong decisions in providing cancer care. Because of the key impact of laboratory information on cancer diagnosis and treatment the quality of the tests, lab reports, and appropriate lab management are very important. A laboratory information management system (LIMS) can have an important role in diagnosis, fast and effective access to cancer data, decrease redundancy and costs, and facilitate the integration and collection of data from different types of instruments and systems. In spite of significant advantages LIMS is limited by factors such as problems in adaption to new instruments that may change existing work processes. Applications of intelligent software simultaneously with existing information systems, in addition to remove these restrictions, have important benefits including adding additional non-laboratory generated information to the reports, facilitating decision making, and improving quality and productivity of cancer care services. Laboratory systems must have flexibility to change and have the capability to develop and benefit from intelligent devices. Intelligent laboratory information management systems need to benefit from informatics tools and latest technologies like open sources. The aim of this commentary is to survey application, opportunities and necessity of intelligent clinical laboratory as a tool to increase cancer care management productivity. PMID- 24761838 TI - Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide. AB - Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5.5 months and median overall survival was 29.5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM. PMID- 24761840 TI - Bladder cancer biomarkers: review and update. AB - As the recurrence and mortality rates of bladder cancer are high, research is needed to find suitable biomarkers for early detection, evaluation of prognosis, and surveillance of drug responses. We performed a computerized search of the Medline/PubMed databases with the key words bladder cancer, biomarker, early detection, prognosis and drug response. Several markers were identified at DNA, RNA and protein levels with different sensitivities and specificities. Only a few of the potential bladder cancer biomarkers have been approved for clinical use. Efforts now should be concentrated on finding a panel of markers with acceptable sensitivity and specificity for early detection of bladder cancer. PMID- 24761841 TI - Plant extracts and plant-derived compounds: promising players in a countermeasure strategy against radiological exposure. AB - Radiation exposure leads to several pathophysiological conditions, including oxidative damage, inflammation and fibrosis, thereby affecting the survival of organisms. This review explores the radiation countermeasure properties of fourteen (14) plant extracts or plant-derived compounds against these cellular manifestations. It was aimed at evaluating the possible role of plants or its constituents in radiation countermeasure strategy. All the 14 plant extracts or compounds derived from it and considered in this review have shown some radioprotection in different in vivo, ex-vivo and or in vitro models of radiological injury. However, few have demonstrated advantages over the others. C. majus possessing antioxidant, anti-inflammatory and immunomodulatory effects appears to be promising in radioprotection. Its crude extracts as well as various alkaloids and flavonoids derived from it, have shown to enhance survival rate in irradiated mice. Similarly, curcumin with its antioxidant and the ability to ameliorate late effect of radiation exposure, combined with improvement in survival in experimental animal following irradiation, makes it another probable candidate against radiological injury. Furthermore, the extracts of P. hexandrum and P. kurroa in combine treatment regime, M. piperita, E. officinalis, A. sinensis, nutmeg, genistein and ginsan warrants further studies on their radioprotective potentials. However, one that has received a lot of attention is the dietary flaxseed. The scavenging ability against radiation-induced free radicals, prevention of radiation-induced lipid peroxidation, reduction in radiation cachexia, level of inflammatory cytokines and fibrosis, are some of the remarkable characteristics of flaxseed in animal models of radiation injury. While countering the harmful effects of radiation exposure, it has shown its ability to enhance survival rate in experimental animals. Further, flaxseed has been tested and found to be equally effective when administered before or after irradiation, and against low doses (<= 5 Gy) to the whole body or high doses (12 13.5 Gy) to the whole thorax. This is particularly relevant since apart from the possibility of using it in pre-conditioning regime in radiotherapy, it could also be used during nuclear plant leakage/accidents and radiological terrorism, which are not pre-determined scenarios. However, considering the infancy of the field of plant-based radioprotectors, all the above-mentioned plant extracts/plant derived compounds deserves further stringent study in different models of radiation injury. PMID- 24761842 TI - Triple negative breast cancer. AB - Triple-negative breast cancers (TNBC), characterized by absence of the estrogen receptor (ER) and progesterone receptor (PR) and lack of overexpression of human epidermal growth factor receptor 2 (HER2), have a poor prognosis. To overcome therapy limitations of TNBC, various new approaches are needed. This mini-review focuses on discovery of new targets and drugs which might offer new hope for TNBC patients. PMID- 24761843 TI - Implementation of proteomics for cancer research: past, present, and future. AB - Cancer is the leading cause of the death, accounts for about 13% of all annual deaths worldwide. Many different fields of science are collaborating together studying cancer to improve our knowledge of this lethal disease, and find better solutions for diagnosis and treatment. Proteomics is one of the most recent and rapidly growing areas in molecular biology that helps understanding cancer from an omics data analysis point of view. The human proteome project was officially initiated in 2008. Proteomics enables the scientists to interrogate a variety of biospecimens for their protein contents and measure the concentrations of these proteins. Current necessary equipment and technologies for cancer proteomics are mass spectrometry, protein microarrays, nanotechnology and bioinformatics. In this paper, we provide a brief review on proteomics and its application in cancer research. After a brief introduction including its definition, we summarize the history of major previous work conducted by researchers, followed by an overview on the role of proteomics in cancer studies. We also provide a list of different utilities in cancer proteomics and investigate their advantages and shortcomings from theoretical and practical angles. Finally, we explore some of the main challenges and conclude the paper with future directions in this field. PMID- 24761844 TI - Cryptotanshinone induces inhibition of breast tumor growth by cytotoxic CD4+ T cells through the JAK2/STAT4/ perforin pathway. AB - Cryptotanshinone (CPT), is a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miotiorrhiza bunge. Numerous researchers have found that it could work as a potent antitumor agent to inhibit tumor growth in vitro, buith there has been much less emphasis on its in vivo role against breast tumors. Using a mouse tumor model of MCF7 cells, we showed that CPT strongly inhibited MCF7 cell growth in vivo with polarization of immune reactions toward Th1-type responses, stimulation of naive CD4+ T cell proliferation, and also increased IFN-gamma and perforin production of CD4+ T cells in response to tumor activated splenocytes. Furthermore, data revealed that the cytotoxic activity of CD4+ T cells induced by CPT was markedly abrogated by concanamycin A(CMA), a perforin inhibitor, but not IFN-gamma Ab. On the other hand, after depletion of CD4+ T cells or blocked perforin with CMA in a tumor-bearing model, CPT could not effectively suppress tumor growth, but this phenomenon could be reversed by injecting naive CD4+ T cells. Thus, our results suggested that CPT mainly inhibited breast tumor growth through inducing cytotoxic CD4+ T cells to secrete perforin. We further found that CPT enhanced perforin production of CD4+ T cells by up-regulating JAK2 and STAT4 phosphorylation. These findings suggest a novel potential therapeutic role for CPT in tumor therapy, and demonstrate that CPT performs its antitumor functions through cytotoxic CD4+ T cells. PMID- 24761845 TI - Cytotoxic T lymphocytes elicited by dendritic cell-targeted delivery of human papillomavirus type-16 E6/E7 fusion gene exert lethal effects on CaSki cells. AB - Human papillomavirus (HPV) is the primary etiologic agent of cervical cancer. Consideration of safety and non human leukocyte antigen restriction, protein vaccine has become the most likely form of HPV therapeutic vaccine, although none have so far been reported as effective. Since tumor cells consistently express the two proteins E6 and E7, most therapeutic vaccines target one or both of them. In this study, we fabricated DC vaccines by transducing replication-defective recombinant adenoviruses expressing E6/E7 fusion gene of HPV-16, to investigate the lethal effects of specific cytotoxic T lymphocytes (CTL) against CaSki cells in vitro. Mouse immature dendritic cells (DC) were generated from bone marrow, and transfected with pAd-E6/E7 to prepare a DC vaccine and to induce specific CTL. The surface expression of CD40, CD68, MHC II and CD11c was assessed by flow cytometry (FCM), and the lethal effects of CTL against CaSki cells were determined by DAPI, FCM and CCK-8 methods. Immature mouse DC was successfully transfected by pAd-E6/E7 in vitro, and the transfecting efficiency was 40%-50%. A DC vaccine was successfully prepared and was used to induce specific CTL. Experimental results showed that the percentage of apoptosis and killing rate of CaSki cells were significantly increased by coculturing with the specific CTL (p <0.05). These results illustrated that a DC vaccine modified by HPV-16 E6/E7 gene can induce apoptosis of CaSki cells by inducing CTL, which may be used as a new strategy for biological treatment of cervical cancer. PMID- 24761846 TI - Ginsenoside Rg1 induces apoptosis through inhibition of the EpoR-mediated JAK2/STAT5 signalling pathway in the TF-1/ Epo human leukemia cell line. AB - Ginsenoside Rg1 is one effective anticancer and antioxidant constituent of total saponins of Panax ginseng (TSPG), which has been shown to have various pharmacological effects. Our previous study demonstrated that Rg1 had anti-tumor activity in K562 leukemia cells. The aim of this study was designed to investigate whether Rg1 could induce apoptosis in TF-1/Epo cells and further to explore the underlying molecular mechanisms. Here we found that Rg1 could inhibit TF-1/Epo cell proliferation and induce cell apoptosis in vitro in a concentration and time dependent manner. It also suppressed the expression of EpoR on the surface membrane and inhibited JAK2/STAT5 pathway activity. Rg1 induced up regulation of Bax, cleaved caspase-3 and C-PAPR protein and down-regulation of Bcl-2 and AG490, a JAK2 specific inhibitor, could enhance the effects of Rg1. Our studies showed that EpoR-mediated JAK2/STAT5 signaling played a key role in Rg1 induced apoptosis in TF-1/Epo cells. These results may provide new insights of Rg1 protective roles in the prevention a nd treatment of leukemia. PMID- 24761847 TI - Comparison of crude and age-specific incidence rates of breast, ovary, endometrium and cervix cancers in Iran, 2005. AB - BACKGROUND: Cancer accounts for 12.6% of total deaths in the world (just after heart disease). MATERIALS AND METHODS: Frequency and age-specific incidence rates of breast and gynecologic cancers in Iran are calculated based on the dataset of the National Cancer Registry of Iran in 2005. RESULTS: Gynecologic and breast cancer accounted for 7.6% and 25.6% of total cancer cases, respectively. Ovarian cancer was the most frequent gynecologic cancer followed by endometrium. Endometrial cancer revealed the highest age specific incidence rate followed by ovary (after 59 years). CONCLUSIONS: Regarding disease burden, breast and gynecologic cases account for 33.4% of total cancer patients. The age specific incidence rate is a useful guide in epidemiologic and future plans. PMID- 24761848 TI - Survival results and prognostic factors in T4 N0-3 non-small cell lung cancer patients according to the AJCC 7th edition staging system. AB - BACKGROUND: The American Joint Committee on Cancer (AJCC) published a new staging system (7th edition) in 2009. In our study, we evaluated the survival results and prognostic factors among T4 local advanced non-small cell lung cancer (LA-NSCLC) patients in a large heterogeneous group, in accordance with this new system. MATERIALS AND METHODS: We retrospectively evaluated the files of 122 T4 N0-3 M0 LA-NSCLC patients, identified according to the new staging system, treated at two centers between November 2003 and June 2012. Variables correlating with univariate survival at p<0.20 were later included in multivariate Cox regression analysis. Here, selection of relevant predictors of survival was carried out in accordance with the likelihood ratio formula with p<0.05 regarded as significant. RESULTS: The median age was 60 and the median follow-up period was 17.4 months. Median overall survival (OS) was 18.3 months, the 1 year overall survival (OS) rate was 72%, and the 5 year OS rate was 28%. Statistically significant predictors of survival were (p<0.20) ECOG-PS (Eastern Cooperative Oncology Group Performance Status), age, T4 factor subgroup, stage and primary treatment in OS univariate analysis. On multivariate analysis for OS ECOG-PS (p=0.001), diagnostic stage (p=0.021), and primary treatment (p=0.004) were significant. In the group receiving non-curative treatment, the median OS was 11.0 months, while it was 19.0 months in the definitive RT group and 26.6 months in the curative treatment group. There was a significant difference between the non-curative group and the groups which had definitive RT and curative operations (respectively p<0.001 and p=0.001) in terms of OS, but not between the groups which had definitive RT and curative operations. The median event free survival (EFS) rate was 9.9 months, with rates of 46% and 19% at 3 and 5 years, respectively. On univariate analysis of EFS rate with ECOG-PS, weight loss and staging, statistical significance was found only for thorax computerized tomography (CT)+18F-fluorodeoxy-glucose positron emission tomography-CT (PET-CT) use, stage and primary treatment (p<0.20). In multivariate analysis with EFS, only the primary treatment was statistically significant (p=0.001). In the group receiving non-curative treatment, the median EFS was 10.5 months while in the curative operation group it was 14.7 months. When all the primary treatment groups were taken into consideration, grade III/IV side effect was observed in 57 patients (46.6%). Esophagitis was most prominent among those that received definitive radiotherapy. CONCLUSIONS: Independent prognostic factors among these 122 heterogeneous LA-NSCLC T4 N0-3 M0 patients were age at diagnosis, ECOG-PS, stage and primary treatment, the last also being a significant prognostic indicator of EFS. Our findings point to the importance of appropriate staging and a multidisciplinary approach with modern imaging methods in this patient group. In those with T4 lesions, treatment selection and the effective use of curative potential should be the most important goal of clinical care. PMID- 24761849 TI - Breast and cervical cancer screening and associated factors among older adult women in South Africa. AB - BACKGROUND: Little is known about the cancer screening prevalence and correlates in older adults from different racial backgrounds. In the context of heightened efforts for prevention and early diagnosis, we collected information on screening for two major types of cancers: cervical and breast cancer in order to establish their prevalence estimates and correlates among older South African women who participated in the Study of Global Ageing and Adults Health (SAGE) in 2008. MATERIALS AND METHODS: We conducted a national population-based cross-sectional study with a multi-stage stratified cluster sample of 3,840 individuals aged 50 years or older in South Africa in 2008. In this analysis, we only considered the female subsample of (n=2202). The measures used included socio-demographic characteristics, health variables, anthropometric and blood pressure measurements. Multivariable regression analysis was performed to assess the association of socio-demographic factors, health variables and cancer screening. RESULTS: Overall, regarding cervical cancer screening, 24.3% ever had a Papanicolaou (PAP) smear test, and regarding breast cancer screening, 15.5% ever had a mammography. In multivariate logistic regression analysis, younger age, higher education, being from the White or Coloured population group, urban residence, greater wealth, and suffering from two or more chronic conditions were associated with cervical cancer screening, and higher education, being from the White or Indian/Asian population group, greater wealth, having a health insurance, and suffering from two or more chronic conditions were associated with breast cancer screening. CONCLUSIONS: Cancer screening coverage remains low among elderly women in South Africa in spite of the national guideline recommendations for regular screening in order to reduce the risk of dying from these cancers if not detected early. There is a need to improve accessibility and affordability of early cervical and breast cancer screening for all women to ensure effective prevention and management of cervical and breast cancer. PMID- 24761850 TI - Canola oil influence on azoxymethane-induced colon carcinogenesis, hypertriglyceridemia and hyperglycemia in Kunming mice. AB - Azoxymethane (AOM) is a potent genotoxic carcinogen which specifically induces colon cancer. Hyperlipidemia and diabetes have several influences on colon cancer development, with genetic and environmental exposure aspects. Here, we investigated plasma lipid and glucose concentrations in Kunming mice randomized into four groups; control (no AOM or oil exposure), AOM control, AOM + pork oil, and AOM + canola oil. Aberrant crypt foci (ACF), plasma cholesterol, plasma triglyceride, plasma glucose and organ weight were examined 32 weeks after AOM injection. Results revealed that AOM exposure significantly increased ACF number, plasma triglyceride and glucose level. Further, male mice displayed a much higher plasma triglyceride level than female mice in the AOM control group. Dietary fat significantly inhibited AOM-induced hypertriglyceridemia, and canola oil had stronger inhibitory effect than pork oil. AOM-induced hyperglycemia had no sex difference and was not significantly modified by dietary fat. However, AOM itself not change plasma cholesterol level. AOM significantly increased liver and spleen weight in male mice, but decreased kidney weight in female mice. On the other hand, mice testis weight decreased when fed canola oil. AOM could induce colorectal carcinogenesis, hypertriglyceridemia and hyperglycemia in Kunming mice at the same time, with subsequent studies required to investigate their genome association. PMID- 24761851 TI - Epigenetic regulation of human riboflavin transporter 2(hRFT2) in cervical cancers from Uighur women. AB - In the present study, we studied the hypermethylation of the human riboflavin transporter 2 (hRFT2) gene and regulation of protein expression in biopsies from resected tissues from Uighur cervical squamous cell carcinoma (CSCC) patients and their neighboring normal tissues. hRFT2 gene promoter region methylation sequences were mapped in cervical cancer cell line SiHa by bisulfite-sequencing PCR and quantitative detection of methylated DNA from 30 pairs of Uighur's CSCCs and adjacent normal tissues by MassARRAY (Sequenom, San Diego, CA, USA) and hRFT2 protein expression was analyzed by immunohistochemistry. In SiHa, we identified 2 CG sites methylated from all of 12CpG sites of the hRFT2 gene. Analysis of the data from quantitative analysis of single CpG site methylation by Sequenom MassARRAY platform showed that the methylation level between two CpG sites (CpG 2 and CpG 3) from CpG 1~12 showed significant differences between CSCC and neighboring normal tissues. However, the methylation level of whole target CpG fragments demonstrated no significant variation between CSCC (0.476 +/- 0.020) and neighboring normal tissues (0.401 +/- 0.019, p>0.05). There was a tendency for translocation the hRFT2 proteins from cytoplasm/membrane to nucleus in CSCC with increase in methylation of CpG 2 and CpG 3 in hRFT2gene promoter regions, which may relate to the genesis of CSCC. Our results suggested that epigenetic modifications are responsible for aberrant expression of the hRFT2 gene, and may help to understand mechanisms of cervical carcinogenesis. PMID- 24761852 TI - Experimental study on residual tumor angiogenesis after cryoablation. AB - OBJECTIVE: To explore the mechanism and significance of tumor angiogenesis by observing changes of micro-vessel density (MVD) and expression of vascular endothelial growth factor (VEGF) in residual tumor tissues after cryoablation. MATERIALS AND METHODS: A total of 18 nude mice xenograft models with transplanted lung adenocarcinoma cell line A549 were established and randomly divided into 3 groups when the maximum diameter of tumor reached 1 cm: control, cisplatin (DDP) and cryoablation. The nude mice were sacrificed after 21-d cryoablation to obtain the tumor tissues. Then immunohistochemistry was applied to determine MVD and the expression of VEGF in tumor tissues. RESULTS: The tumor volumes of control group, DDP group and cryoablation group were 1.48 +/- 0.14 cm3, 1.03 +/- 0.12 cm3 and 0.99 +/- 0.06 cm3 respectively and the differences were significant (P < 0.01), whereas MVD values were 21.1 +/- 0.86, 24.7 +/- 0.72 and 29.2 +/- 0.96 (P < 0.01) and the positive expression rates of VEGF were 36.2 +/- 1.72%, 39.0 +/- 1.79% and 50.8 +/- 2.14% (P < 0.01), respectively, showing that MVD was proportional to the positive expression of VEGF (r = 0.928, P < 0.01). CONCLUSIONS: Cryoablation can effectively inhibit tumor growth, but tumor angiogenesis significantly increases in residual tumors, with high expression of VEGF playing an important role in the residual tumor angiogenesis. PMID- 24761853 TI - Epidemiological and clinicopathological characteristics of lung cancer in a teaching hospital in Iran. AB - BACKGROUND: Lung cancer is one of the most commonly diagnosed cancers and the most frequent cause of cancer-related death worldwide. In Iran, it ranks second and third as the cancer-causing death in men and women, respectively. We carried out this study to find out the demographic, clinical, and histological characteristics and risk factors of lung cancer in a referral tertiary center in Iran. MATERIALS AND METHODS: A retrospective study was conducted on cases of primary lung cancer based on the results of registered cancer reports of cytological and pathological specimens between March 2001 and March 2012. Demographic variables, clinical manifestations, histology and location of tumors were determined based on the data found in the medical records of each patient. Definite or probable etiologic factors were identified. Data analysis was performed with SPSS version 16 and a p-value <= 0.05 was considered as significant. RESULTS: A total of 203 patients, with a mean age of 65.7 years (SD=11.2), with primary lung cancer were identified, 81.3% being men. Of the total, 110 cases (54.2%) were living in urban areas. In 53.2% of cases, the site of tumor was on the right side and in 72.9% of cases the lesion was centrally located. The histological types of lung cancer were squamous cell carcinoma (SCC) in 107 cases (52.7%), adenocarcinoma (AC) in 30 cases (14.8%), and small cell carcinoma (SC) in 27 cases (13.3%). Significant correlations between the gender and residence, smoking, and the histological type and location (central or peripheral) of tumor were found. The percentage of smokers was 75.2% in men and 15.8% in women. CONCLUSIONS: Smoking was the most important risk factor and squamous cell carcinoma the most common histological type of lung cancer in our study. Male sex and being a smoker was associated with histological types of SCC while being nonsmoker had relationship with adenocarcinoma. PMID- 24761854 TI - Lack of prognostic value of mean corpuscular volume with capecitabine therapy in metastatic breast cancer. AB - BACKGROUND: Capecitabine is an oral fluoropyrimidine derivative which is frequently used alone or in combination regimens for the treatment of metastatic breast cancer. Although overall and progression free survivals have increased in recent years with the use of new generation drugs, predictive factors that would further improve the outcomes are needed. Previous studies have demonstrated the relation between post-treatment increase in mean corpuscular volume (MCV) and predicting therapy response as well as survival. The present study investigated the clinical impact of MCV elevation in metastatic breast cancer patients treated with capecitabine. MATERIALS AND METHODS: The data of a total of 82 patients from three centers followed between June 2005 and June 2013 were retrospectively analyzed. The demographic data and hormone receptor status of the patients, as well as initial examination before and after treatment and data concerning progression were recorded. MCV >= 100 fl was considered as macrocytosis. Capecitabine was given at a dose of 2500 mg/m2 daily for 14 days every three weeks. Pre-treatment and post-treatment MCV and other parameters of complete blood count were recorded. Post-treatment initial evaluation was performed after 2 cycles of therapy. RESULTS: The median age of the patients was 46.5 years (range 26-72 years) and 54% were premenopausal. Performance status was ECOG 0 and 1 in 81 (99%) patients. The median number of cycles for capecitabine therapy was 5 (min-max: 2-18). The median DeltaMCV level (post-treatment values at sixth week - baseline) was 6.4. Whilst DeltaMCV was >= 6.4 in 42 patients, it was <6.4 in 40 patients. Clinical benefit (complete response+partial response+stable disease) was observed in 37 (88%) of 42 patients with a median DeltaMCV >= 6.4 and in 30 (75%) of 40 patients with DeltaMCV <6.4 with no statistically significant difference (p=0.158). No significant difference was determined between the group with DeltaMCV >= 6.4 and the group with DeltaMCV <6.4 in terms of progression free survival (11 vs 12 months) (p=0.55) and overall survival (20 months vs. 24 months) (p=0.11). CONCLUSIONS: The identification of new predictive markers in metastatic breast cancer is very important. In some recent studies, increase in MCV has been suggested as a marker in tumor response. In the present study, however, no significant difference was determined between tumor response and increase in MCV. Further studies including higher numbers of patients are needed to determine whether increase in MCV is a predictive marker or not. PMID- 24761855 TI - Hypofractionated radiotherapy for breast cancers--preliminary results from a tertiary care center in eastern India. AB - BACKGROUND: The standard radiotherapy (RT) fractionation practiced in India and worldwide is 50 Gy in 25 fractions over 5 weeks to the chest wall or whole breast followed by tumour bed boost in case of breast conservation (BCS). A body of validated data exists regarding hypofractionation in breast cancer. We here report initial results for 135 patients treated at our center with the START-B type of fractionation. MATERIALS AND METHODS: From May 2011 till July 2012, women with all stages of breast cancer (excluding metastatic), who had undergone BCS or mastectomy were planned for 40 Gy in 15 fractions over 3 weeks to chest wall/whole breast and supraclavicular fossa (where indicated) followed by tumour bed boost in BCS patients. Planning was done using Casebow's technique. The primary end point was to assess the acute toxicity and the cosmetic outcomes. Using cosmetic scales; patients were assessed during radiotherapy and at subsequent follow up visits with the radiation oncologist. RESULTS: Of the 135 patients, 62 had undergone BCS and 73 mastectomy. Median age of the population was 52 years. Some 80% were T1 and T2 tumours in BCS whereas most patients in mastectomy group were T3 and T4 tumours (60%). 45% were node negative in BCS group whilst it was 23% in the mastectomy group. Average NPI scores were 3.9 and 4.9, respectively. Most frequently reported histopathology report was infiltrating ductal carcinoma (87%), grade III being most common (58%), and 69% were ER positive tumours, and 30% were Her 2 Neu positive. Triple negative tumours accounted for 13% and their mean age was young (43 yrs.) The maximum acute skin toxicity at the end of treatment was Grade 1 in 94% of the mastectomy group patients and 71% in BCS patients. Grade 2 toxicity was 6% in mast group and 23% in BCS group. Grade 3 was 6% in BCS group, no grade 3 toxicity in mastectomy patients and there was no grade 4 skin toxicity in any case. Post RT at 1 month; 39% of BCS patients had persisting Grade I skin reaction which was only 2% in mastectomy patients. At 3 months post RT, 18% patients had persisting hyperpigmentation. At 6 months 8% patients had persisting erythema in the BCS group only. Some 3% BCS and 8% mastectomy patients had lymph edema till the date of evaluation. Cosmetic outcome in BCS patients remained good to excellent 6 months post surgery and radiotherapy. 1 patient of BCS and 3 patients of mast had developed metastatic disease at the time of evaluation. CONCLUSIONS: Hypofractionated RT is well tolerated in Indian population with reduced acute skin toxicity and good cosmetic outcome. Regimens such as these should be encouraged in other centers to increase machine output time. The study is on going to assess long term results. PMID- 24761856 TI - Targeted efficacy of dihydroartemisinin for translationally controlled protein expression in a lung cancer model. AB - OBJECTIVE: Lung cancer is one of the malignant tumors with greatest morbidity and mortality around the world. The keys to targeted therapy are discovery of lung cancer biomarkers to facilitate improvement of survival and quality of life for the patients with lung cancer. Translationally controlled tumor protein (TCTP) is one of the most overexpressed proteins in human lung cancer cells by comparison to the normal cells, suggesting that it might be a good biomarker for lung cancer. MATERIALS AND METHODS: In the present study, the targeted efficacy of dihydroartemisinin (DHA) on TCTP expression in the A549 lung cancer cell model was explored. RESULTS AND CONCLUSIONS: DHA could inhibit A549 lung cancer cell proliferation, and simultaneously up-regulate the expression of TCTP mRNA, but down-regulate its protein expression in A549 cells. In addition, it promoted TCTP protein secretion. Therefore, TCTP might be used as a potential biomarker and therapeutic target for non-small cell lung cancers. PMID- 24761857 TI - Association between the pre-mir-218 polymorphism and cancer risk in the Chinese population: a meta-analysis. AB - BACKGROUND: Several recent studies have explored associations between pre-mir-218 polymorphism (rs11134527) and cancer risk. However, published data are still inconclusive. To obtain a more precise estimation of the relationship in the Chinese population, we carried out a meta-analysis for the first time. MATERIALS AND METHODS: Through retrieval from the PubMed, Medline, Embase, Web of Science databases, China National Knowledge Infrastructure and the Chinese BioMedical Literature Database, a total of four studies were analyzed with 3,561 cases and 3,628 controls for SNP pre-mir-218 rs11134527. We calculated odds ratios (ORs) and 95% confidence intervals (95%CIs) to explore the strength of associations. RESULTS: The results showed that the rs11134527 polymorphism was associated with decreased cancer risk in GG versus AA and GG versus AA+AG models tested ( GG vs AA: OR=0.82, 95%CI: 0.71-0.94; GG vs AA+AG: OR=0.84, 95%CI: 0.74-0.96), and significantly decreased cervical cancer risk was observed in GG versus AA and GG versus AA+AG models (GG vs AA: OR=0.79, 95%CI: 0.66-0.94; GG vs AA+AG: OR=0.80, 95%CI: 0.68-0.94). However, no significant association between the rs11134527 polymorphism and hepatocellular carcinoma risk was observed in all comparison models tested (AG vs AA: OR=0.94, 95%CI: 0.79-1.11; GG vs AA: OR=0.88, 95%CI: 0.70-1.10; GG+AG vs AA: OR=0.92, 95%CI: 0.79-1.08; GG vs AA+AG: OR=0.91, 95%CI: 0.75-1.11). CONCLUSION: The findings suggest that pre-miR-218 rs11134527 polymorphism may have some relation to cancer development in Chinese. However, well-designed studies with larger sample size and more detailed data are needed to confirm these conclusions. PMID- 24761858 TI - Importance of postoperative stimulated thyroglobulin level at the time of 131I ablation therapy for differentiated thyroid cancer. AB - BACKGROUND: Serum thyroglobulin detection plays an essential role during the follow-up of thyroid cancer patients treated with total/near total thyroidectomy and radioiodine ablation. The aim of this retrospective study was to evaluate the relationship between stimulated serum thyroglobulin (Tg) level at the time of high dose 131I ablation and risk of recurrence, using a three-level classification in patients with differentiated thyroid cancer (DTC) according to the ATA guidelines. Also we investigated the relationship between postoperative stimulated Tg at the time of ablation and DxWBS results at 8-10 months thereafter. MATERIALS AND METHODS: Patients with radioiodine accumulation were regarded as scan positive (scan +). If there was no relevant pathological radioiodine accumulation or minimal local accumulation in the thyroid bed region, this were regarded as scan negative (scan-) at the time of DxWBS. We classified patients in 3 groups as low, intermediate and high risk group for assessment of risk of recurrence according to the revised ATA guidelines. Also, we divided patients into 3 groups based on the stimulated serum Tg levels at the time of 131I ablation therapy. Groups 1-3 consisted of patients who had Tg levels of <= 2 ng/ml, 2-10 ng/ml, and >= 10 ng/ml, respectively. RESULTS: A total of 221 consecutive patients were included. In the high risk group according to the ATA guideline, while 45.5% of demonstrated Scan(+) Tg(+), 27.3% of patients demonstrated Scan(-) Tg(-); in the intermediate group, the figures were 2.3% and 90.0% while in the low risk group, they were 0.6% and 96.4%. In 9 of 11 patients with metastases (81.8%), stimulated serum Tg level at the time of radioiodine ablation therapy was over 10, however in 1 patient (9.1%) it was < 2 ng/mL and in one patient it was 2-10 ng/mL (p = 0.005). Aggressive subtypes of DTC were found in 8 of 221 patients and serum Tg levels were <= 2 ng/ml in 4 of these 8. CONCLUSIONS: We conclude that TSH-stimulated serum thyroglobulin level at the time of ablation may not determine risk of recurrence. Therefore, DxWBS should be performed at 8-12 months after ablation therapy. PMID- 24761859 TI - Knowledge about cervical cancer early warning signs and symptoms, risk factors and vaccination among students at a medical school in Al-Ahsa, Kingdom of Saudi Arabia. AB - BACKGROUND: Cervical cancer is the second most common cancer among females and also the most preventable. In the literature there is abundant evidence that awareness regarding cervical cancer and its prevention is low in the developing countries. Medical students are the future health professionals and can play an important role in increasing awareness among the general population. To assess the knowledge regarding symptoms, risk factors and prevention of cervical carcinoma among medical students in th Kingdom of Saudi Arabia, the present study was planned. MATERIALS AND METHODS: This cross-sectional study was conducted using a self-administered questionnaire with students at the College of Medicine, King Faisal University, Al-Ahsa, KSA, from December 2012 to May 2013. RESULTS: The responses of 188 students (males 111, females 77) in their second, third, fourth, and fifth years were recorded and used in the data analysis. The majority of the students were not aware of the early warning signs, symptoms and risk factors. On average, only 43.7% males and 56% of females were aware about the early signs and symptoms whereas 51.4% males and 57.8% females had knowledge about the risk factors of cervical cancers. Some 55% males and 46.8% females were unable to select the correct answer regarding human papilloma virus (HPV) infection as the cause of cervical cancer. Majority of the students (67%) were not aware about the availability of vaccine against HPV. CONCLUSIONS: Lack of knowledge regarding early signs and symptoms, risk factors and prevention of cervical cancer was observed in the present study. PMID- 24761860 TI - New insights into autonomic nerve preservation in high ligation of the inferior mesenteric artery in laparoscopic surgery for colorectal cancer. AB - AIM: To take a deeper insight into the relationship between the root of the inferior mesenteric artery (IMA) and the autonomic nerve plexuses around it by cadaveric anatomy and explore anatomical evidence of autonomic nerve preservation in high ligation of the IMA in laparoscopic surgery for colorectal cancer. METHODS: Anatomical dissection was performed on 11 formalin-fixed cadavers and 12 fresh cadavers. Anatomical evidence-based autonomic nerve preservation in high ligation of the IMA was performed in 22 laparoscopic curative resections of colorectal cancer. RESULTS: As the upward continuation of the presacral nerves, the bilateral trunks of SHP had close but different relationships with the root of the IMA. The right trunk of SHP ran relatively far away from the root of IMA. When the apical lymph nodes were dissected close to the root of the IMA along the fascia space in front of the anterior renal fascia, the right trunk of SHP could be kept in suit under the anterior renal fascia. The left descending branches to SHP constituted a natural and constant anatomical landmark of the relationship between the root of IMA and the left autonomic nerves. Proximal to this, the left autonomic nerves surrounded the root of the IMA. Distally, the left trunk of the SHP departed from the root of IMA under the anterior renal fascia. When high ligation of the IMA was performed distal to it, the left trunk of SHP could be preserved. The distance between the left descending branches to SHP and the origin of IMA varied widely from 1.3 cm to 2.3 cm. CONCLUSIONS: The divergences of the bilateral autonomic nerve preservation around the root of the IMA may contribute to provide anatomical evidence for more precise evaluation of the optimal position of high ligation of the IMA in the future. PMID- 24761861 TI - Diagnosis and therapy of primary hepatic neuroendocrine carcinoma: clinical analysis of 10 cases. AB - BACKGROUND: Primary hepatic neuroendocrine carcinoma (PHNEC) is rarer than extrahepatic gastrointestinal neuroendocrine carcinoma (NEC). It is difficult to make a correct diagnosis and poses a challenge for management. MATERIALS AND METHODS: Ten PHNEC patients were admitted to our hospital from June 2006 to June 2011. Laboratory tests and imaging scans were performed for diagnosis and exclusion of extrahepatic NEC. All patients were AFP - and CA199- . Seven patients had solid tumors with cystic changes on ultrasonography, CT and/or MRI. For the initial treatment, four patients received combined-therapy and six monotherapy. Considering overall treatment, six patients received combined therapy and four patients monotherapy. Staging criteria of primary hepatocellular carcinoma (PHC, AJCC 7th edition) were used to differentiate the stage of all patients: 3 patients were stage I, 2 stage II, 4 patients stage III and 1 stage IV. All patients were followed up and clinical data were gathered. RESULTS: The median follow-up duration was 38.5 months. The 1-year, 2-year, 3-year and 6-year disease-free survival was 80.0%, 46.2% and 46.2% and 0% respectively. The overall survival rates were 100%, 67.1%, 67.1% and 33.6% respectively. Patients in early stages (I/II) had similar disease-free and overall survival as those in advanced stages (III/IV). Patients with monotherapy had significant shorter disease-free and overall survival than the patients with combination-therapy. CONCLUSIONS: PHNEC has a unique specificity during its occurrence and development. The staging criteria of PHC might not be suitable for the PHENT. More convenient and effective features need to be found in imaging and laboratory detection. Surgical resection, TACE, chemotherapy and radiofrequency ablation should be performed in combination and actively for patients with PHNEC or recurrence to get the best effectiveness; they might extend the disease-free and overall survival. PMID- 24761862 TI - Perception of patients with cancer towards support management services and use of complementary alternative medicine--a single institution hospital-based study in Saudi Arabia. AB - BACKGROUND: To evaluate the perception of cancer patients toward treatment services and influencing factors and to inquire about the use of complementary alternative medicine (CAM). MATERIALS AND METHODS: Information was obtained through pre-tested structured questionnaires completed by cancer patients during treatment at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. RESULTS: Of 242 patients, 137 (64.6%) accepted to enter this study. Most were Saudi (n=93, 68%), female (n= 80, 58%), educated at university (n=71, 52%), married (n=97, 72%) and with breast cancer (n=36, 26%). One-hundred (73%) patients were satisfied with the services provided; 61% were Saudi. Ninety-four (68%) respondents were satisfied with the explanation of their cancer. Twenty-eight (21.6%) patients received CAM, of them 54.0% received herbal followed by rakia (21.0%), nutritional supplements/vitamins (7.0%) and Zamam water (18.0%), with significant differences among them (p =0.004). Seven (5%) patients believed this therapy could be used alone; 34 (25%) patients believed it could be used with other treatments, regardless of whether they themselves used this therapy. Fifty three (53%) satisfied patients felt they received enough support; 31 (58%) patients received support from family and friends; 22 (41.6%) patients received support from the health-care team. Patients who received information about their disease from their physicians and those who felt they had enough support were more satisfied. The patients who took alternative treatment were older age, mostly female and highly educated but values did not reach significance. CONCLUSIONS: We stress enhancing the educational and supportive aspects of cancer patient services to improve their treatment satisfaction and emphasize the need for increasing the educational and awareness programs offered to these patients. PMID- 24761863 TI - Diabetes mellitus and HbA1c levels associated with high grade prostate cancer. AB - PURPOSE: The aim of this study to analyze the association between history of diabetes mellitus (DM) with risk of prostate cancer (PCa) and cancer grade among men undergoing radical prostatectomy for PCa. MATERIALS AND METHODS: 50 patients with DM and 50 patients without DM who undervent radical prostatectomy (RP) were included in the study. Age at biopsy, height, weight, digital rectal examination (DRE), pre-biopsy PSA levels, prostate volume, histopathologic diagnosis after surgery and gleason scores were collected data from all patients. Histologic material obtained at biopsy was given a Gleason score; tumours with a Gleason score >= 7 were considered high grade and <7 were considered low grade. RESULTS: The mean age at the time of biopsy was 63.7 in patients with DM and 61.6 in patients without DM. Diabetic men had significantly lower PSA levels (p=0.01). Mean PSA level 7.04 +/- 2.85 in patients with DM and 8.7 +/- 2.86 in patients without DM, respectively. Also, diabetic men had higher RP tumor grade than men without DM (p=0.04). We found that HbA1c levels were higher in patients who have high grade prostate cancer (p<0.05). CONCLUSIONS: Diabetic men undergoing RP have lower PSA levels and have significantly higher grade PCa. We must be careful for screening PCa in patients with DM. Although the patients had lower PSA levels, they might have high grade disease. PMID- 24761864 TI - Expression and prognostic roles of TRPV5 and TRPV6 in non-small cell lung cancer after curative resection. AB - PURPOSE: We investigated the expression of epithelial Ca2+ channel transient receptor potential vanilloid (TRPV) 5 and 6 in non-small-cell lung cancer (NSCLC) and assessed their prognostic role in patients after surgical resection. MATERIALS AND METHODS: From January 2008 to January 2009, 145 patients who had undergone surgical resection of NSCLCs were enrolled in the study. Patient clinical characteristics were retrospectively reviewed. Fresh tumor samples as well as peritumor tissues were analyzed for TRPV5/6 expression using immune histochemistry (IHC) and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Patients were grouped based on their TRPV5 and TRPV6 levels in the tumor tissues, followed up after surgery, and statistically analyzed to examine the prognostic roles of TRPV5 and TRPV6 on patients' survival after surgical resection of NSCLCs. RESULTS: Using IHC, among the 145 patients who had undergone surgical resection of NSCLCs, strong protein expression (grade >= 2) of TRPV5 and TRPV6 was observed in a lower percentage of primary tumor tissues than in non-tumor tissues of same patients. Similar findings were obtained with the RT PCR test for mRNA levels. Decreased overall mRNA levels of TRPV5 and TRPV6 were associated with a worse overall survival rate (p=0.004 and p=0.003 respectively) and shorter recurrence-free survival (p?0.001 and p?0.001 respectively). The combining effect of TRPV5 and TRPV6 on survival was further investigated using multivariate analysis. The results showed that a combination of low expression of TRPV5 and TRPV6 could be an independent predictor of poor recurrence-free survival (p=0.002). CONCLUSIONS: Decreased expression of TRPV5/6 in tumor tissues was observed in NSCLC patients and was associated with shorter median survival time after surgical resection. Combined expression of TRPV5 and TRPV6 in tumor tissues demonstrated promising prognostic value in NSCLC patients. PMID- 24761865 TI - Aflatoxin B1 promotes cell growth and invasion in hepatocellular carcinoma HepG2 cells through H19 and E2F1. AB - H19 is an imprinted oncofetal gene, and loss of imprinting at the H19 locus results in over-expression of H19 in cancers. Aflatoxin B1(AFB1) is regarded as one of the most dangerous carcinogens. Exposure to AFB1 would most easily increase susceptibility to diseases such as hepatocellular carcinoma(HCC) but any possible relationship between AFB1 and H19 is not clear. In present study, we found that AFB1 could up-regulate the expression of H19 and promote cell growth and invasion by hepatocellular carcinoma HepG2 cells. Knocking down H19 RNA co ld reverse the effects of AFB1 on cell growth and invasion. In addition, AFB1 induced the expression of E2F1 and its knock-down could down-regulate H19 expression and suppress cell growth and invasion in hepatocellular carcinoma HepG2 cells. Furthermore, E2F1 over-expression could up-regulate H19 expression and promote cell growth and invasion, with binding to the H19 promoter being demonstrated by chromatin immunoprecipitation assays (ChIP). In summary, our results suggested that aflatoxin B1 could promote cell growth and invasion in hepatocellular carcinoma HepG2 cells through actions on H19 and E2F1. PMID- 24761866 TI - The exonuclease 1 Glu589Lys gene polymorphism and cancer susceptibility: evidence based on a meta-analysis. AB - BACKGROUND: Published studies on the association between the exonuclease 1 (EXO1) Glu589Lys polymorphism and cancer susceptibility have yielded conflicting results. Thus, a meta-analysis of published studies was performed to assess the possible association. MATERIALS AND METHODS: All eligible case-control studies published up to January 2013 on the association between the EXO1 Glu589Lys polymorphism and cancer susceptibility were identified by searching PubMed, Web of Science, Science Direct and hand search. Either fixed-effect or random-effect models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs) using the Comprehensive Meta-Analysis software version 2.2. RESULTS: A total of 4,391 cancer cases and 4,339 controls from 10 studies were included. Overall, no significant association between the EXO1 Glu589Lys polymorphism and cancer susceptibility was observed in either genetic model. However; in subgroup analyses by cancer type, a significant association between EXO1 Glu589Lys and lung cancer risk was found (Lys vs Glu: OR=1.23, 95%CI=1.07- 1.41, p heterogeneity=0.05). Further, subgroup analysis by ethnicity indicated that there was a statistically increased cancer risk in Asians (Lys vs Glu: OR=1.42, 95%CI=1.30-1.55, p heterogeneity=0.07; Lys/Lys vs Glu/Glu: OR=1.93, 95%CI=1.20-3.12, p heterogeneity=0.01; Lys/Lys+Glu/Lys vs Glu/Glu: OR=1.52, 95%CI=1.37-1.68, p heterogeneity=0.42; Lys/Lys vs Glu/Lys+Glu/Glu: OR=1.68, 95%CI=1.07-2.65, p heterogeneity=0.02). However, significant association was absent in Caucasians. CONCLUSIONS: This meta-analysis suggests, for the first time, that the EXO1 Glu589Lys polymorphism is not associated with overall cancer susceptibility, although marginal associations were found for lung cancer and Asian subgroups. Additional well-designed studies with larger sample size focusing on different ethnicities and cancer types are needed to confirm these findings. PMID- 24761867 TI - Outcomes of triple-negative versus non-triple-negative breast cancers managed with breast-conserving therapy. AB - BACKGROUND: Triple negative breast cancer is associated with aggressive behavior and high risk of local and regional failure. Aggressive surgical intervention is considered suitable. This makes role of breast conserving therapy (BCT) debatable in these patients. The objective of this study was to compare outcome of BCT for triple negative versus non-triple negative breast cancer. MATERIALS AND METHODS: Medical records of patients who underwent breast conserving therapy from 1999 to 2009 at Shaukat Khanum Cancer Hospital and had complete receptor status information were extracted. Patients were divided into triple negative breast cancer (TNBC) and non-TNBC. Patient characteristics, medical treatment modalities and adverse events were compared. Expected five year locoregional recurrence free, disease free and overall survival was calculated. The Cox proportional hazard model was used to identify independent predictors of outcome. RESULTS: A total of 194 patients with TNBC and 443 with non-TNBC were compared. Significant difference was present for age at presentation (p<0.0001), family history (p=0.005), grade (p<0.0001) and use of hormonal therapy (p<0.0001). The number of locoregional failures, distant failures and mortalities were not significantly different. No significant difference was present in 5 year locoregional recurrence free (96% vs 92%, p=0.3), disease free (75% vs 74%, p=0.7) and overall survival (78% vs 83%, p=0.2). On multivariate analysis, tumor size, nodal involvement and hormonal treatment were independent predictors of negative events. CONCLUSIONS: Breast conserving therapy has comparable outcomes for triple negative and non-triple negative breast cancers. PMID- 24761868 TI - Blending of soybean oil with selected vegetable oils: impact on oxidative stability and radical scavenging activity. AB - BACKGROUND: Soybean oil may protect against cancer of the breast and prostate. It may also exert beneficial influence in combination with other oils. Here, blends (20%, v/v) of sea buckthorn oil (SEBO), camellia oil (CAO), rice bran oil (RBO), sesame oil (SEO) and peanut oil (PEO) with soybean oil (SBO) were formulated. MATERIALS AND METHODS: Oxidative stability (OS) and radical scavenging activity (RSA) of SBO and blends stored under oxidative conditions (60 degrees C) for 24 days were studied. By blending with different kinds oils, levels of polyunsaturated fatty acids (PUFA) decreased, while monounsaturated fatty acid (MUFA) content increased. Progression of oxidation was followed by measuring peroxide value (PV), p-anisidine (PAV), conjugated dienes (CD) and conjugated trienes (CT). RESULTS: Inverse relationships were noted between PV and OS at termination of storage. Levels of CD and CT in SBO, and blends, increased with increase in time. The impact of SEO as additives on SBO oxidation was the strongest followed by RBO, CAO, SEBO and PNO. CONCLUSIONS: Oxidative stability of oil blends was better than SBO, most likely as a consequence of changes in fatty acids and tocopherols' profile, and minor bioactive lipids found in selected oils. The results suggest that these oil blends could contribute as sources of important antioxidant related to the prevention of chronic diseases associated to oxidative stress, such as in cancer and coronary artery disease. PMID- 24761869 TI - Expression of ERCC1, MSH2 and PARP1 in non-small cell lung cancer and prognostic value in patients treated with platinum-based chemotherapy. AB - PURPOSE: To evaluate the prognostic value of the expression of excision repair cross-complementation group l (ERCC1), MutS protein homolog 2 (MSH2) and poly ADP ribose polymerase 1 (PARP1) in non-small-cell lung cancer patients receiving platinum-based postoperative adjuvant chemotherapy. METHODS: Immunohistochemistry was applied to detect the expression of ERCC1, MSH2 and PARP1 in 111 cases of non small cell lung cancer paraffin embedded surgical specimens. Through og-rank survival analysis, we evaluated the prognostic value of the ERCC1, MSH2, PARP1 and the related clinicopathological factors. COX regression analysis was used to determine whether ERCC1, MSH2 and PARP1 were independent prognostic factors. RESULTS: In the enrolled 111 non-small cell lung cancer patients, the positive expression rate of ERCC1, MSH2 and RARP1 was 33.3%, 36.9% and 55.9%, respectively. ERCC1 (P<0.001) and PARP1 (P=0.033) were found to be correlated with the survival time while there was no correlation for MSH2 (P=0.298). Patients with both ERCC1 and PARP1 negative cancer had significantly longer survival time than those with ERCC1 (P=0.042) or PARP1 (P=0.027) positive alone. Similalry, the survival time of patients with both ERCC1 and PARP1 positive cancer was shorter than those with ERCC1 (P=0.048) or PARP1 (P=0.01) positive alone. CONCLUSION: Patients with ERCC1 or PARP1 negative non-small cell lung cancer appear to benefit from platinum-based postoperative adjuvant chemotherapy. PMID- 24761870 TI - Physical activity and cancer prevention: awareness and meeting the recommendations among adult Saudis. AB - BACKGROUND: There is a scarcity of information about the proportion of the adult Saudi population that meet the recommended guidelines of physical activity (PA) to reduce cancer risk. Moreover, their awareness about the role of PA in cancer prevention is unclear. OBJECTIVES: This cross-sectional study aimed at estimating the proportion of adult Saudis meeting the PA guidelines, specifically those recommended by American Cancer Society (ACS) for cancer prevention, and to assess the public awareness about the role of PA in cancer prevention. MATERIALS AND METHODS: Using a multistage sampling method, 2,127 adult Saudis of both genders were recruited from 6 urban and 4 rural primary health care centers in Al Hassa, Saudi Arabia. Participants were personally interviewed to gather information about their sociodemographic characteristics, searching activity about PA and cancer, and the time spent in leisure time PA (moderate and vigorous)/week using the Global Physical Activity Questionnaire with show cards. Finally, items about the role of PA in cancer risk reduction were inquired. RESULTS: Of the included participants, 11.6% met the recommendations for cancer prevention (>= 45 minutes of moderate-vigorous PA activity/>= 5 days/week or 225 minutes/week). Multivariate regression showed that being male (AOR=1.49, CI=1.09-2.06), <20 years of age (AOR=3.11, CI=2.03-4.76), and unemployed (AOR=2.22, CI=1.57-3.18) were significant predictors for meeting PA recommendations for cancer prevention. Only 11.4% of the sample indicated correctly the frequency and duration of PA required for an average adult to be physically active and while >70% of them indicated the role of PA in prevention of hypertension, coronary heart disease and lowering elevated blood cholesterol, only 18.6% and 21.7% correctly mentioned the role of PA in reducing colon and breast cancer risk, respectively. Poor knowledge was found among those with less than college education and aged >= 50 years. The level of knowledge was significantly positively correlated with total leisure time PA of the participants. CONCLUSIONS: A minority of adult Saudis in Al Hassa was aware about the role of PA in cancer prevention and engaged in sufficient LTPA for cancer risk reduction benefits, highlighting the need for public health actions to include policies and programs that address factors deterring their participation in LTPA and increasing their awareness with remedies to manage the prevalent misconceptions. PMID- 24761871 TI - What is the most effective strategy for improving the cancer screening rate in Japan? AB - BACKGROUND: Cancer screening rates in Japan are much lower than those in Western countries. This study evaluated the relationship between cancer screening rates and strategies used to improve screening rates, and determined which strategy is the most effective. MATERIALS AND METHODS: All municipalities are responsible for conducting gastric, lung, colorectal, cervical, and breast cancer screenings in Japan. Of the 1,746 municipalities in total, 92-99% were included in the analyses for each cancer screening. Using national data in 2009, the correlations between cancer screening rates and strategies for improving screening rates of all municipalities, both large (populations of over 30,000) and small (populations of under 30,000), were determined. The strategies used were as follows: sending personal invitation letters, personal visits by community health workers, use of a clinical setting for screening, and free screening. RESULTS: Of all four strategies used to improve cancer screening rates, sending personal invitation letters had the highest correlations with all screening rates, with the exception of breast cancer screening. The partial correlation coefficients linking this strategy with the screening rates in all municipalities were 0.28, 0.32, 0.30, and 0.26 for gastric, lung, colorectal, and cervical cancer screening, respectively. In large municipalities, the correlations between the number of examinees in a clinical setting and the screening rates were also relatively high, particularly for cervical cancer screening (r=0.41). CONCLUSIONS: Sending personal invitation letters appears to be particularly effective in improving cancer screening rates in all municipalities. All municipalities should implement a system that sends personal invitation letters for cancer screening. In large municipalities, increasing the availability of screening in a clinical setting is also effective in improving cancer screening rates. PMID- 24761872 TI - Expression of Fas/FasL in CD8+ T and CD3+ Foxp3+ Treg cells--relationship with apoptosis of circulating CD8+ T cells in hepatocellular carcinoma patients. AB - AIMS: Dysfunction of the host immune system in cancer patients can be due to a number of factors, including lymphocyte apoptosis. Several studies showed that Foxp3+T cells take part in inducing this process by expressing FasL in tumor patients. However, the relationship between apoptosis, CD8+T cells and Foxp3+T cells in HCC patients is still unclear. The present study was designed to investigate the correlation between apoptosis levels and Fas/FasL expression in CD8+T lymphocytes and Foxp3+T cells in patients with HCC. METHODS: CD8+T cells and CD3+Foxp3+T cells were tested from peripheral blood of HCC patients and normal controls and subjected to multicolor flow cytometry. The expression of an apoptosis marker (annexin V) and the death receptor Fas in CD8+T cells and FasL in CD3+Foxp3+T cells were evaluated. Serum TGF-beta1 levels in patients with HCC were measured by enzyme-linked immunosorbent assay. The relationship between apoptosis and Fas expression, as well as FasL expression in CD3+Foxp3+T cells was then evaluated. RESULTS: The frequency of CD8+T cells binding annexin V and Fas expression in CD8+T cells, were all higher in HCC patients than normal controls and the proportion of apoptotic CD8+T cells correlated with their Fas expression. Serum TGF-beta1 levels correlated inversely with CD3+Foxp3+T cells. CONCLUSIONS: Fas/FasL interactions might lead to excessive turnover of CD8+T cells and reduce anti-tumor immune responses in patients with HCC. Further investigations of apoptosis induction in Fas+CD8+T cells in vitro are required. PMID- 24761873 TI - EGF reverses multi-drug resistance via the p-ERK pathway in HepG2/ADM and SMMC7721/ADM hepatocellular carcinoma models. AB - AIM: To investigate signaling pathways for reversal of EGF-mediated multi-drug resistance (MDR) in hepatocellular carcinoma (HCC) models. MATERIALS AND METHODS: HCC MDR cell strain HepG2/adriamycin (ADM) and SMMC7721/ADM models were established using a method of exposure to medium with ADM between low and high concentration with gradually increasing concentration. Drug sensitivity and reversal of multi-drug resistance by EGF were determined and the cell cycle distribution and apoptosis were analyzed by flow cytometry. Phosphorylation of ERK1, ERK2, ERK5 and expression of Bim were detected by Western blotting. RESULTS: The results showed that HepG2/ADM and SMMC7721/ADM cells were resistant not only to ADM, but also to multiple anticancer drugs. When used alone, EGF had no anti-tumor activity in HepG2/ADM and SMMC7721/ADM cells in vitro, while it increased the cytotoxicity of ADM. EGF induced cell apoptosis and G0/G1 phase cell cycle arrest in HepG2/ADM And SMMC7721/ADM cells, while enhancing activity of p-ERKs and up-regulated expression of BimEL. CONCLUSIONS: EGF might enhance the chemosensitivity of HepG2/ADM and SMMC7721/ADM cells via up-regulating p-ERKs and BimEL protein. PMID- 24761874 TI - Serum levels of trace elements in patients with prostate cancer. AB - BACKGROUND: Trace elements are major components of biological structures; however, excessive levels of these elements can be toxic. MATERIALS AND METHODS: In the present study, serum levels of trace elements were measured in 30 patients with newly diagnosed as prostate cancer and 32 healthy volunteer by using furnace atomic absorption spectrophotometry. RESULTS: It was found that there was an increase in serum levels of Co, Cu, Mg and Pb (p<0.05), whereas a decrease in serum levels of Fe, Mn, and Zn levels in patients with prostate cancer (p<0.05). CONCLUSIONS: These changes may be important in the pathogenesis of prostate cancers; however, further prospective studies are needed to identify relationships between prostate cancer and trace elements. PMID- 24761875 TI - Lack of association of intron 3 16 bp polymorphism of TP53 with breast cancer among Iranian-Azeri patients. AB - BACKGROUND: p53 gene is a well-known tumor suppressor gene that has several polymorphisms in both its exons and introns. It has been suggested that intron 3 16 bp duplication polymorphism may affect the gene function resulting in reduction or suppression of p53 anti tumor activity. In most case control studies a duplicated allele has been noticeably more frequent in cases rather than controls but there are also conflicting results. The aim of this study was to assess the association of intron 3 16 bp duplication polymorphism of p53 with breast cancer risk among Iranian-Azeri population. We also analyzed the clinicopathological information of patients as an epidemiological description of breast cancer in the north-west of Iran. MATERIALS AND METHODS: This case-control study was performed on 221 breast cancer patients and 170 controls. Genomic DNA was extracted from peripheral blood samples and tumor tissues. p53 PIN3 genotype was determined using electrophoresis of PCR products on 8% non-denaturing polyacrylamide gels and silver staining. RESULTS: In the control and case groups, respectively, 62.9% and 61.1% had no 16 bp insertion (A1A1 genotype), 7.1% and 7.7% had insertion in both p53 alleles (A2A2) and 30% and 31.2% were heterozygous (A1A2). There was no significant difference between genotype frequencies as well as allelic frequencies in two case and control groups. CONCLUSIONS: According to the result of the present study, the intron 3 16 bp duplication polymorphism of p53 could not be assessed as a marker of risk factor for predisposition to breast cancer in Azeri population. However, a high frequency of A2 allele (22.1%) in our population suggested that intron 3 16 bp duplication polymorphism may be a valuable marker for study in other cancers with well designed large groups. PMID- 24761876 TI - Mini-array of multiple tumor-associated antigens (TAAs) in the immunodiagnosis of esophageal cancer. AB - Sera of cancer patients may contain antibodies that react with a unique group of autologous cellular antigens called tumor-associated antigens (TAAs). The present study aimed to determine whether a mini-array of multiple TAAs would enhance antibody detection and be a useful approach in esophageal cancer detection and diagnosis. Our mini-array of multiple TAAs consisted of eleven antigens, p53, pl6, Impl, CyclinB1, C-myc, RalA, p62, Survivin, Koc, CyclinD1 and CyclinE full length recombinant proteins. Enzyme-linked immunosorbent assays (ELISA) were used to detect autoantibodies against eleven selected TAAs in 174 sera from patients with esophageal cancer, as well as 242 sera from normal individuals. In addition, positive results of ELISA were confirmed by Western blotting. In a parallel screening trial, with the successive addition of antigen to a final total of eleven TAAs, there was a stepwise increase in positive antibody reactions. The eleven TAAs were the best parallel combination, and the sensitivity and specificity in diagnosing esophageal cancer was 75.3% and 81.0%, respectively. The positive and negative predictive values were 74.0% and 82.0%, respectively, indicating that the parallel assay of eleven TAAs raised the diagnostic precision significantly. In addition, the levels of antibodies to seven antigens, comprising p53, Impl, C-myc, RalA, p62, Survivin, and CyclinD1, were significantly different in various stages of esophageal cancer, which showed that autoantibodies may be involved in the pathogenesis and progression of esophageal cancer. All in all, this study further supports our previous hypothesis that a combination of antibodies might acquire higher sensitivity for the diagnosis of certain types of cancer. A customized mini-array of multiple carefully-selected TAAs is able to enhance autoantibody detection in the immunodiagnosis of esophageal cancer and autoantibodies to TAAs might be reference indicators of clinical stage. PMID- 24761877 TI - Glycididazole sodium combined with radiochemotherapy for locally advanced nasopharyngeal carcinoma. AB - BACKGROUND: To evaluate efficacy and side effects of glycididazole sodium (CMNa) combined with chemotherapy (cisplatin plus 5-FU/folic acid, PLF) and radiotherapy in treating patients with locally advanced nasopharyngeal carcinoma. MATERIALS AND METHODS: Patients with III~IV stage nasopharyngeal carcinoma (NPC),were randomly divided into treatment group (46 patients) and control group (45 patients). Both groups received radiotherapy concomitant with PLF chemotherapy. The treatment group at the same time was given CMNa (800 mg/m2 before radiotherapy), by l h intravenous drip, three times a week. RESULTS: When the dose of radiation was over 60 Gy, complete response rates of nasopharyngeal tumor and lymph node metastases in treatment group were significantly higher than in the control group (93.5% vs 77.8%; 89.1% vs 93.5%, p<0.05). Three months after radiotherapy, complete response rate of nasopharynx cancer and lymph node metastases in treatment group was both 97.8%, again higher than in the control group (84.4% and 82.2%) (p<0.05). In the treatment group, 1, 3, 5 year disease free survival rates were 95.7%, 86.7% and 54.5%; and in control group, the corresponding disease-free survival rates were 93.3%, 66.2% and 38.6%, respectively, the difference being statistically significant (log-rank =5.887, p=0.015). One, 3, 5 year overall survival rates in two groups of patients were 97.8%, 93.5%, 70.4% and 95.5%, 88.07%, 48.4%, respectively, again with a statistically significant difference (log-rank=6.470, p=0.011). Acute toxicity and long-term radiotherapy related toxicity in the two groups did not differ (p>0.05). CONCLUSIONS: Glycididazole sodium could improve curative effects without increasing adverse reactions when treating patients with locally advanced nasopharyngeal carcinoma. PMID- 24761878 TI - Pretreatment neutrophil/lymphocyte ratio as a prognostic aid in colorectal cancer. AB - BACKGROUND: Colorectal cancers(CRC) are the third most common cancer in the western world, with surgery preferred for management of non-metastatic disease and post surgical treatment usually arranged according to the TNM staging system. However, there is still prognostic variation between patients who have the same stage. It is increasingly recognized that variations within disease course and clinical outcome in colorectal cancer patients are influenced by not only oncological characteristics of the tumor itself but also host response factors. Recent studies have shown correlation between the inflammatory response and clinical outcomes in various cancers. The neutrophil/lymphocyte ratio (NLR) has been described as a marker for immune response to various stimuli including cancer. MATERIAL-METHODS: Two hundred eighty-one CRC patients were included in our retrospective analysis, separated into two groups according to a cut-off value for the NLR. Patient data including age, gender, vertical penetration, anatomic location, and differentiation of the tumor, TNM stage, survival rate, and disease-free survival were analyzed for correlations with the NLR. RESULTS: Using ROC curve analysis, we determined a cut-off value of 2.2 for NLR to be best to discriminate between patient survival in the whole group. In univariate analysis, high pretreatment NLR (p=0.001, 95%CI 1.483-4.846), pathologic nodal stage (p<0.001, 95%CI 1.082- 3.289) and advanced pathologic TNM stage (p<0.001, 95%CI 1.462-4.213) were predictive of shorter survival. In multivariate analysis, advanced pathologic TNM stage (p=0.001, 95%CI 1.303-26.542) and high pretreatment NLR (p=0.005, 95%CI 1.713-6.378) remained independently associated with poor survival. CONCLUSIONS: High pre-treatment NLR is a significant independent predictor of shorter survival in patients with colorectal cancer. This parameter is a simple, easily accessible laboratory value for identifying patients with poorer prognosis. PMID- 24761879 TI - Elevated serum neutrophil to lymphocyte and platelet to lymphocyte ratios could be useful in lung cancer diagnosis. AB - BACKGROUND: Lung cancer (LC) is still the primary cause of cancer deaths worldwide, and late diagnosis is a major obstacle to improving lung cancer outcomes. Recently, elevated preoperative or pretreatment neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) detected in peripheral blood were identified as independent prognostic factors associated with poor survival with various cancers, including colon cancer, esophageal cancer, gastric cancer and breast cancer. OBJECTIVE: The aim of this study was to examine whether MPV, NLR and PLR could be useful inflammatory markers to differentiate lung cancer patients from healthy controls. An investigation was also made of the relationship between these markers and other prognostic factors and histopathological subgroups. MATERIALS AND METHODS: Retrospectively eighty-one lung cancer patients and 81 age-sexes matched healthy subjects included into the study. Patients with hypertension, hematological and renal disease, heart failure, chronic infection, hepatic disorder and other cancer were excluded from the study. The preoperative or pretreatment blood count data was obtained from the recorded computerized database. RESULTS: NLR and PLR values were significantly higher in the LC patients compared to the healthy subjects.( NLR: 4.42 vs 2.45 p=0.001, PLR: 245.1 vs 148.2 p=0.002) MPV values were similar in both groups (7.7 vs 7.8). No statistically significant relationship was determined between these markers (MPV, NLR and PLR) and histopathological subgroups and TNM stages. CONCLUSIONS: NLR and PLR can be useful biomarkers in LC patients before treatment. Larger prospective studies are required to confirm these findings. PMID- 24761880 TI - Talin-1 correlates with reduced invasion and migration in human hepatocellular carcinoma cells. AB - BACKGROUND: Talin-1 is a cytoskeleton protein that participates in cell migration and plays a role in tumor formation, migration, and metastasis in different types of cancer. Chinese investigators have observed that the levels of Talin-1 protein and mRNA expression in HCC tissues are significantly lower than in the adjacent non-cancerous tissue. However, Japanese investigators have reported that Talin-1 is upregulated in HCC. Tln2 as homologous gene of Tln-1, which encodes a very similar protein, but the role of Talin-2 is very little known in primary liver cancer (PLC). We investigated whether the expression of Talin-1 in PLC may be associated with the histological subtype as well as the role of Talin-1 in tumor cell invasion and migration using human hepatocellular carcinoma cell lines. MATERIALS AND METHODS: We measured the mRNA expression levels of Talin-1 and Talin-2 in five human liver cancer cell lines and normal human liver cell (LO2 cell line) by real-time PCR and the protein expression levels of Talin-1 by Western blot. Migration and invasion of the cells were assessed using transwell assays and cell scratch experiments, respectively, and proliferation was assessed by soft AGAR colony formation. RESULTS: Talin-1 and Talin-2 expression differed significantly between the five human liver cancer cell lines and LO2 cell line (p<0.05). Compared with the LO2 cell line, the invasion and migration capabilities of the five cancer cell lines differed significantly (p<0.05). Similarly, the colony-forming ability differed (p<0.05). CONCLUSIONS: High levels of Talin-1 expression are correlated with reduced invasion and migration as well as decreased malignancy in human liver cancer cell lines; the suppression of Talin-1 promotes invasion and migration. In addition, Talin-2 may be correlated with invasion and migration in human hepatocellular carcinoma. PMID- 24761881 TI - Genotype CC of rs1800947 in the C-reactive protein gene may increase susceptibility to colorectal cancer: a meta-analysis. AB - BACKGROUND: Single nucleotide polymorphisms of C-reactive protein (CRP) have been shown to be related to circulating CRP level, risk and prognosis in cancer patients. However, accumulating evidence of rs1800947 involvement in risk of cancer is inconsistent. Thus, a meta-analysis was performed to obtain a more precise relationship. MATERIALS AND METHODS: The pooled odds ratio (OR) and its 95% confidence interval were assessed in 10 eligible articles with 12 studies containing 5,601 cancer cases and 8,669 cancer-free controls. RESULTS: No significant association was observed overall and in subgroups in comparison of genotype GC vs GG (PH=0.847, OR=0.939, 95%CI=0.810-1.087), GC/CC vs GG (PH=0.941, OR=1.021, 95%CI=0.901-1.157) and allele C vs G (PH=0.933, OR=1.026, 95%CI=0.909 1.159). However, statistically significance was evident in comparison of genotype CC vs GG in cancer risk (PH=0.586, OR=2.854, 95%CI= 1.413-5.763), especially in colorectal cancer (PH=0.481, OR=4.527, 95%CI= 1.664- 12.315). CONCLUSIONS: Genotype CC of rs1800947 in the CRP gene is strongly associated with increased cancer risk, particularly in colorectal cancer. PMID- 24761882 TI - Profile of colorectal polyps: a retrospective study from King Fahad Hospital, Madinah, Saudi Arabia. AB - AIM: To evaluate the predominant colorectal polyps in the Almadinah region of Saudi Arabia. MATERIALS AND METHODS: In this iretrospective study, we analyzed pathology reports of colonoscopies performed in King Fahad Hospital, Madinah, Saudi Arabia during the period 2006 to 2013. Data based on patient age, gender, size, site and type of polyps and the degree of dysplasia were analyzed by software SPSS 17 and compared with other published studies from different geographic regions of the world. RESULTS: During these years, 224 patients had colonic polyps, of whom 149 (66.5%) were men and 75 (33.5%) were women. The most common types of polyps were adenomatous (166), followed by hyperplastic polyps (24), juvenile (18), inflammatory (13), lipomatous (2) and one patient with Peutz Jegher polyps. Tubulovillous adenoma was the commonest adenomatous polyp (102), followed by tubular (41) and villous (23) types. The sigmoid colon was the most commonly involved region (36.6%). Dysplasia was significantly associated with female patients who had large size tubulovillous polyps located in the left colon. CONCLUSIONS: The type and distribution of colorectal polyps in Saudi Arabia is very similar to Western countries. Patient gender, and size, histological type and location of polyps are closely related to dysplastic change in colonic polyps. PMID- 24761883 TI - Differentiated thyroid carcinoma risk factors in French Polynesia. AB - BACKGROUND: To investigate differentiated thyroid cancer risk factors in natives of French Polynesia is of interest because of the very high incidence of this cancer in the archipelago. MATERIALS AND METHODS: To assess the role of various potential risk factors of thyroid cancer in the natives of French Polynesia we performed a case-control study. The study included almost all the French Polynesians diagnosed with differentiated thyroid carcinoma between 1981 and 2003 (n=229) and 373 French Polynesian control individuals from the general population without cancer. RESULTS: Thyroid radiation dose received from nuclear fallout before the age of 15, a personal history of neck or/and head medical irradiation, obesity, tallness, large number of children, an artificial menopause, a familial history of thyroid cancer, a low dietary iodine intake, and having a spring as the main source of drinking water were found to be significant risk factors. No roles of smoking habits, alcohol consumption, iodine containing drugs, and exposure to pesticides were evidenced. CONCLUSIONS: Except for smoking, differentiated thyroid carcinoma risk factors in natives of French Polynesia are similar to those in other populations. Our finding on the role of having a spring as a drinking water origin is coherent with some other studies and could be due to geological factors. PMID- 24761884 TI - Drainage alone or combined with anti-tumor therapy for treatment of obstructive jaundice caused by recurrence and metastasis after primary tumor resection. AB - AIM: To compare drainage alone or combined with anti-tumor therapy for treatment of obstructive jaundice caused by recurrence and metastasis after primary tumor resection. MATERIALS AND METHODS: We collect 42 patients with obstructive jaundice caused by recurrence and metastasis after tumor resection from January 2008 - August 2012, for which percutaneous transhepatic catheter drainage (pTCD)/ percutaneous transhepatic biliary stenting (pTBS) were performed. In 25 patients drainage was combined with anti-tumor treatment, antineoplastic therapy including intra/postprodure local treatment and postoperative systemic chemotherapy, the other 17 undergoing drainage only. We assessed the two kinds of treatment with regard to patient prognosis. RESULTS: Both treatments demonstrated good effects in reducing bilirubin levels in the short term and promoting liver function. The time to reobstruction was 125 days in the combined group and 89 days in the drainage only group; the mean survival times were 185 and 128 days, the differences being significant. CONCLUSIONS: Interventional drainage in the treatment of the obstructive jaundice caused by recurrence and metastasis after tumor resection can decrease bilirubin level quickly in a short term and promote the liver function recovery. Combined treatment prolongs the survival time and period before reobstruction as compared to drainage only. PMID- 24761885 TI - CD3+ CD4+ and CD3+ CD8+ lymphocyte subgroups and their surface receptors NKG2D and NKG2A in patients with non-small cell lung cancer. AB - BACKGROUND: To explore the prevalence of lymphocyte subgroups CD3+ CD4+ and CD3+ CD8+ and their surface receptors NKG2D and NKG2A in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 40 patients with NSCLC were divided into different groups according to different clinical factors (TNM staging, pathological patterns and genders) for assessment of relations with CD3+ CD4+ and CD3+ CD8+ and the surface receptors NKG2D and NKG2A of T lymphocytes in peripheral blood by flow cytometry. RESULTS: Patients in the advanced group had evidently lower levels of CD3+ CD4+ but markedly higher levels of CD3+ CD8+ in peripheral blood than those with early lesions (p<0.05). In addition, NSCLC patients in the advanced group had obviously higher CD3+ CD4+ NKG2D and CD3+ CD8+ NKG2A expression rates but lower CD3+ CD4+ NKG2A and CD3+ CD8+ NKG2D expression rates (p<0.05). However, there were no significant differences between NSCLC patients with different genders and pathological patterns in expression levels of lymphocyte subgroups CD3+ CD4+ and CD3+ CD8+ and their surface receptors NKG2D and NKG2A. CONCLUSIONS: Unbalanced expression of surface receptors NKG2D and NKG2A in CD3+ CD4+ and CD3+ CD8+ lymphocytes may be associated with a poor prognosis, greater malignancy and immunological evasion by advanced cancers, related to progression of lung cancer. PMID- 24761886 TI - Risk factors for appendiceal metastasis with epithelial ovarian cancer. AB - PURPOSE: To investigate the risk factors for appendiceal metastasis of epithelial ovarian cancer and compare findings with the previous studies. MATERIALS AND METHODS: One hundred and thirty-four patients with epithelial ovarian cancer were assessed in this study. All of them had undergone a surgical procedure including appendectomy. Of these, 21 (15.7%) patients who had appendiceal metastasis were analyzed as the case group and the patients with no metastasis were the controls, compared according to stage, grade, histology of tumor, preoperative Ca125 levels, presence of ascites, peritoneal cytology, diameter and site of tumor considered as risk factors. RESULTS: We found statistically significant differences between the groups in terms of stage, grade, right-sided tumor location, presence of ascites, diameter of tumor >= 10 cm and positive peritoneal cytology (p<0.05). In the logistic regression model, stage, grade, presence of ascites, right-sided location and diameter of tumor were independent risk factors. ROC curve analysis showed that stage, grade and diameter of the tumor were discriminative factors for appendiceal metastasis. CONCLUSIONS: In epithelial ovarian cancer, stage, grade, presence of ascites, right-sided location and large tumor size have importance for estimation of risk of appendiceal metastasis. As we compare our findings with previous studies, there is no definite recommendation for the risk factors of appendiceal metastasis in epithelial ovarian cancer and more studies are needed. PMID- 24761887 TI - Counts of Slackia sp. strain NATTS in intestinal flora are correlated to serum concentrations of equol both in prostate cancer cases and controls in Japanese men. AB - BACKGROUND: Isoflavones, which are included in soybeans, have been suggested to protect against prostate cancer. Equol, one of isoflavones, is an intestinally derived bacterial metabolite of daidzein. A newly identified equol-producing bacterium, Slackia sp. strain NATTS, with a high equol-producing activity was isolated from human feces in Japanese adults. Counts of Slackia sp. strain NATTS in intestinal flora have not been assessed with regard to prostate cancer risk. In this study, we investigated the association of serum isoflavones and counts of Slackia sp. strain NATTS with prostate cancer risk in a case-control study. MATERIALS AND METHODS: Concentrations of isoflavones and counts of Slackia sp. strain NATTS in feces were measured from 44 patients with prostate cancer and 28 hospital controls. The risk of prostate cancer was evaluated in terms of odds ratios (ORs) and 95% confidence intervals (CIs) by the logistic regression analysis. RESULTS: The detection proportions of Slackia sp. strain NATTS in cases and controls were 34.1% and 25.0%, respectively. Counts of Slackia sp. strain NATTS were significantly correlated with serum concentrations of equol both in cases and controls (Spearman correlation coefficients, rs=0.639 and rs=0.572, p<0.01, respectively). Serum concentrations of genistein, daidzein, glycitein, and equol were not significantly associated with risk of prostate cancer. CONCLUSIONS: This study found that counts of Slackia sp. strain NATTS correlated with serum concentrations of equol both in prostate cancer cases and controls, but serum isoflavone concentrations were not associated with risk of prostate cancer in our patients. PMID- 24761888 TI - Impact of AhR, CYP1A1 and GSTM1 genetic polymorphisms on TP53 R273G mutations in individuals exposed to polycyclic aromatic hydrocarbons. AB - This study was to undertaken to investigate the impacts of AhR, CYP1A1, GSTM1 genetic polymorphisms on the R273G mutation in exon 8 of the tumor suppressor p53 gene (TP53) among polycyclic aromatic hydrocarbons (PAHs) exposed to coke-oven workers. One hundred thirteen workers exposed to PAH and 82 control workers were recruited. We genotyped for polymorphisms in the AhR, CYP1A1, GSTM1, and TP53 R273G mutation in blood by PCR methods, and determined the levels of 1 hydroxypyrene as PAH exposure marker in urine using the high pressure liquid chromatography assay. We found that the distribution of alcohol users and the urinary excretion of 1-OHP in the exposed workers were significantly higher than that of the control workers (p=0.004, p<0.001, respectively). Significant differences were observed in the p53 genotype distributions of smoking subjects (p=0.01, 95%CI: 1.23-6.01) and PAH exposure (p=0.008, 95%CI: 1.24-4.48), respectively. Further, significant differences were observed in the p53 exon 8 mutations for the genetic polymorphisms of Lys/Arg for AhR (p=0.02, 95%CI: 0.70 15.86), Val/Val for CYP1A1 (p=0.04, 95%CI: 0.98-19.09) and null for GSTM1 (p=0.02, 95%CI: 1.19-6.26), respectively. Our findings indicated that polymorphisms of PAH metabolic genes, such as AhR, CYP1A1, GSTM1 polymorphisms may interact with p53 genetic variants and may contribute to PAH related cancers. PMID- 24761889 TI - Modification of a smoking motivation questionnaire for Chinese medical students. AB - INTRODUCTION: Smoking prevalence among the medical students is high in China. Therefore, understanding the smoking motivations of medical students is crucial for smoking control, but currently there are no scales questionnaires customized for probing the smoking motivations of medical students. This aim of study was to test and modify a questionnaire for investigating smoking motivations among medical students. METHODS: A cross-sectional survey was conducted among 1,125 medical students at Xuzhou Medical College in China in 2012.The model fit and validity was assessed by confirmatory factor analysis (CFA) and the reliability was tested by single-item reliability, composite reliability, and item-total correlation. RESULTS: The prevalence of smoking was 9.84 % among study population. In the modified scales, the global fit indices identified a CFI value of 0.96, TLI was 0.96, and the RMSEA was 0.063. CFA supported the two dimensional structure of the instrument. The average variance extracted ranged from 0.45 to 0.62. All single-item reliability scores were greater than 0.20, and the composite reliability ranged from 0.74 to 0.91. CONCLUSION: Modified scales could be the preliminary instrument used in evaluating the smoking motivations of medical students. However, it should be further assessed using other forms and methods of validity and reliability, additional motivations of smoking, and the survey of other medical colleges in China. PMID- 24761890 TI - Changes in economic status of households associated with catastrophic health expenditures for cancer in South Korea. AB - BACKGROUND: Cancer imposes significant economic challenges for individuals, families, and society. Households of cancer patients often experience income loss due to change in job status and/or excessive medical expenses. Thus, we examined whether changes in economic status for such households is affected by catastrophic health expenditures. MATERIALS AND METHODS: We used the Korea Health Panel Survey (KHPS) Panel 1st-4th (2008- 2011 subjects) data and extracted records from 211 out of 5,332 households in the database for this study. To identify factors associated with catastrophic health expenditures and, in particular, to examine the relationship between change in economic status and catastrophic health expenditures, we conducted a generalized linear model analysis. RESULTS: Among 211 households with cancer patients, 84 (39.8%) experienced catastrophic health expenditures, while 127 (40.2%) did not show evidence of catastrophic medical costs. If a change in economic status results from a change in job status for head of household (job loss), these households are more likely to incur catastrophic health expenditure than households who have not experienced a change in job status (odds ratios (ORs)=2.17, 2.63, respectively). A comparison between households with a newly-diagnosed patient versus households with patients having lived with cancer for one or two years, showed the longer patients had cancer, the more likely their households incurred catastrophic medical costs (OR=1.78, 1.36, respectively). CONCLUSIONS: Change in economic status of households in which the cancer patient was the head of household was associated with a greater likelihood that the household would incur catastrophic health costs. It is imperative that the Korean government connect health and labor policies in order to develop economic programs to assist households with cancer patients. PMID- 24761891 TI - Methylation of SFRPs and APC genes in ovarian cancer infected with high risk human papillomavirus. AB - BACKGROUND: Secreted frizzled-related protein (SFRP) genes, new tumor suppressor genes, are negative regulators of the Wnt pathway whose alteration is associated with various tumors. In ovarian cancer, SFRPs genes promoter methylation can lead to gene inactivation. This study investigated mechanisms of SFRP and adenomatous polyposis coli (APC) genes silencing in ovarian cancer infected with high risk human papillomavirus. MATERIALS AND METHODS: DNA was extracted from 200 formalin fixed paraffin-embedded ovarian cancer and their normal adjacent tissues (NAT) and DNA methylation was detected by methylation specific PCR (MSP). High risk human papillomavirus (HPV) was detected by nested PCR with consensus primers to amplify a broad spectrum of HPV genotypes. RESULTS: The percentages of SFRP and APC genes with methylation were significantly higher in ovarian cancer tissues infected with high risk HPV compared to NAT. The methylated studied genes were associated with suppression in their gene expression. CONCLUSION: This finding highlights the possible role of the high risk HPV virus in ovarian carcinogenesis or in facilitating cancer progression by suppression of SFRP and APC genes via DNA methylation. PMID- 24761892 TI - Incidence and mortality of female breast cancer in Jiangsu, China. AB - OBJECTIVES: The aim of this study was to describe and analyze the incidence and mortality of female breast cancer in Jiangsu Province of China. METHODS: Incidence and mortality data for female breast cancer and corresponding population statistics from eligible cancer registries in Jiangsu from 2006 to 2010 were collected and analyzed. Crude rates, age-specific rates and age standardized rates of incidence and mortality were calculated, and annual present changes (APCs) were estimated to describe the time trends. RESULTS: From 2006 to 2010, 11,013 new cases and 3,068 deaths of female breast cancer were identified in selected cancer registry areas of Jiangsu. The annual average crude incidence and age-standardized incidence by world population (ASW) were 25.2/ and 17.9/100,000 respectively. The annual average crude and ASW for mortality rates were 7.03/ and 4.81/100,000. The incidence was higher in urban areas than that in rural areas, and this was consistent in all age groups. No significant difference was observed in mortality between urban and rural areas. Two peaks were observed when looking at age-specific rates, one at 50-59 years and another at over 85 years. During the 5 years, incidence and mortality increased with APCs of 4.47% and 6.89%, respectively. Compared to the national level, Jiangsu is an area with relatively low risk of female breast cancer. CONCLUSION: Breast cancer has become a main public health problem among Chinese females. More prevention and control activities should be conducted to reduce the burden of this disease, even in relatively low risk areas like Jiangsu. PMID- 24761893 TI - Comparison of two methods to extract DNA from formalin-fixed, paraffin-embedded tissues and their impact on EGFR mutation detection in non-small cell lung carcinoma. AB - OBJECTIVE: Molecular pathology tests are often carried for clinicopathological diagnosis and pathologists have established large collections of formalin-fixed, paraffin-embedded tissue (FFPE) banks. However, extraction of DNA from FFPE is a laborious and challenging for researchers in clinical laboratories. The aim of this study was to compare two widely used DNA extraction methods: using a QIAamp DNA FFPE kit from Qiagen and a Cobas Sample Preparation Kit from Roche, and evaluated the effect of the DNA quality on molecular diagnostics. METHODS: DNA from FFPE non-small cell lung carcinoma tissues including biopsy and surgical specimens was extracted with both QIAamp DNA FFPE and Cobas Sample Preparation Kits and EGFR mutations of non-small cell lung carcinomas were detected by real time quantitative PCR using the extracted DNA. RESULTS AND CONCLUSION: Our results showed that DNA extracted by QIAamp and Cobas methods were both suitable to detect downstream EGFR mutation in surgical specimens. Howover, Cobas method could yield more DNA from biopsy specimens, and gain much better EGFR mutation results. PMID- 24761894 TI - Psychometric analysis of a Persian version of the European Organization for Research and Treatment of Cancer OG25 Quality of Life Questionnaire in oesophagogastric cancer patients. AB - BACKGROUND: Health-related quality of life (HRQL) is a fundamental outcome in oncology patients and quality of life (QOL) assessment requires clinically relevant questionnaires. The purpose of this study was translation and definition of measurement properties and the clinical validity of Quality of Life Questionnaire (QLQ) -OG25 module in Persian patients with oesophagus, oesophagogastric junction (OGJ) or gastric cancers. MATERIALS AND METHODS: The translation procedure followed European Organization for Research and Treatment of Cancer (EORTC) guidelines. Both EORTC QLQ-OG25 and a core questionnaire (EORTC QLQ-C30) were administered to patients with oesophagus (150), OG junction (93) and gastric (32) cancer undergoing multi-modal treatments. Convergent and discriminant validity, Cronbach's alpha coefficient and known-groups comparisons were used to examine reliability and validity. RESULTS: In all, 275 patients (mean age 62 years) completed both questionnaires. Compliance rate was high and the questionnaire module was well accepted. We found good reliability for multi item subscales of QLQ-OG25 (Cronbach's alpha coefficients 0.76-0.89). About 73% had TNM staging and scales distinguished between clinically distinct groups of patients. However, patients in palliative group experienced compromised functional status and worse treatment-associated symptoms than those in the potentially curative group. Test-retest scores were consistent. Multi-trait scaling analysis demonstrated good convergent and discriminant validity. CONCLUSIONS: Overall, the Persian version of QLQ-OG25 demonstrated psychometric and clinical validity that supports its application as a supplement to the original tool (EORTC QLQ-C30) when assessing HRQL in patients with upper gastrointestinal (GI) cancer both in curative and palliative phases. PMID- 24761895 TI - Distribution and haplotype associations of XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln polymorphisms with nasopharyngeal carcinoma in the Malaysian population. AB - BACKGROUND: DNA repair pathways play a crucial role in maintaining the human genome. Previous studies associated DNA repair gene polymorphisms (XPD Lys751Gln, XRCC1 Arg280His and XRCC1 Arg399Gln) with nasopharyngeal carcinoma. These non synonymous polymorphisms may alter DNA repair capacity and thus increase or decrease susceptibility. The present study aimed to determine the genotype distribution of XPD codon 751, XRCC1 codon 280 and codon 399 polymorphisms and haplotype associations among NPC cases and controls in the Malaysian population. MATERIALS AND METHODS: We selected 157 NPC cases and 136 controls from two hospitals in Kuala Lumpur, Malaysia for this study. The polymorphisms studied were genotyped by PCR-RFLP assay and allele and genotype frequencies, haplotype and linkage disequilibrium were determined using SNPstat software. RESULTS: For the XPD Lys751Gln polymorphism, the frequency of the Lys allele was higher in cases than in controls (94.5% versus 85.0%). For the XRCC1 Arg280His polymorphism, the frequency of Arg allele was 90.0% and 89.0% in cases and controls, respectively and for XRCC1 Arg399Gln the frequency of the Arg allele was 72.0% and 72.8% in cases and controls respectively. All three polymorphisms were in linkage disequilibrium. The odds ratio from haplotype analysis for these three polymorphisms and their association with NPC was 1.93 (95%CI: 0.90-4.16) for haplotype CGC vs AGC allele combinations. The global haplotype association with NPC gave a p-value of 0.054. CONCLUSIONS: Our study provides an estimate of allele and genotype frequencies of XRCC1Arg280His, XRCC1 Arg399Gln and XPD Lys751Gln polymorphisms in the Malaysian population and showed no association with nasopharyngeal cancer. PMID- 24761896 TI - Knockdown of GCF2/LRRFIP1 by RNAi causes cell growth inhibition and increased apoptosis in human hepatoma HepG2 cells. AB - BACKGROUND: GC-binding factor 2 (GCF2) is a transcriptional regulator that represses transcriptional activity of the epidermal growth factor receptor (EGFR) by binding to a specific GC-rich sequence in the EGFR gene promoter. In addition to this function, GCF2 has also been identified as a tumor-associated antigen and regarded as a potentially valuable serum biomarker for early human hepatocellular carcinoma (HCC) diagnosis. GCF2 is high expressed in most HCC tissues and cell lines including HepG2. This study focused on the influence of GCF2 on cell proliferation and apoptosis in HepG2 cells. MATERIALS AND METHODS: GCF2 expression at both mRNA and protein levels in HepG2 cells was detected with reverse transcription (RT) PCR and Western blotting, respectively. RNA interference (RNAi) technology was used to knock down GCF2 mRNA and protein expression. Afterwards, cell viability was analyzed with a Cell Counting Kit-8 (CCK-8), and cell apoptosis and caspase 3 activity by flow cytometry and with a Caspase 3 Activity Kit, respectively. RESULTS: Specific down-regulation of GCF2 expression caused cell growth inhibition, and increased apoptosis and caspase 3 activity in HepG2 cells. CONCLUSIONS: These primary results suggest that GCF2 may influence cell proliferation and apoptosis in HepG2 cells, and also provides a molecular basis for further investigation into the possible mechanism at proliferation and apoptosis in HCC. PMID- 24761897 TI - Computer tomography and magnetic resonance image manifestations of primary hepatic neuroendocrine cell carcinomas. AB - AIM: This study aims to investigate the manifestation of CT, MRI and dynamic enhanced scans for primary hepatic neuroendocrine cell carcinoma. METHODS: CT or MRI arterial and venous phase scan images of 19 cases of pathologically confirmed PHNEC were retrospectively analyzed. RESULTS: 14 cases (73.68%) with single lesion, 5 cases (26.3%) with multiple lesions, with an average diameter of 13.2 cm. Some 12 cases (63.16%) showed inhomogeneous enhancement, seven cases (36.8%) showed homogeneous enhancement, 13 cases (68.4%) demonstrated significant enhancement in the arterial phase, 13 cases (68.4%) had significantly enhanced portal venous phase including 7 cases (36.8 %) with portal venous phase density or signal above the arterial phase and 5 cases (26.3%) with the portal vein density or signal below the arterial phase. Seven cases (36.8%) had continued strengthened separate shadows in the center of the lesion. Thrombosis were not seen in portal veins. CONCLUSION: CT and MRI images of liver cell neuroendocrine carcinoma have certain characteristics that can provide valuable information for diagnosis and differential diagnosis. PMID- 24761898 TI - Diet patterns and risk of squamous cell oesophageal carcinoma: a case-control study in Uruguay. AB - BACKGROUND: Oesophageal cancer presents high incidence rates in the so-called Brazilian-Uruguayan belt. MATERIALS AND METHODS: The present study included 1,170 participants (234 cases and 936 controls) which were analyzed by unconditional multiple logistic regression in order to examine risk of oesophageal squamous cell carcinoma (OESCC) associated with several food groups. RESULTS: Boiled red meat (OR 2.59, 95%CI 1.69-3.97), lamb meat (OR 1.64, 95%CI 1.07-2.51), processed meat (OR 1.49, 95%CI 1.01-2.21), whole milk (OR 1.78, 1.19-1.68), fresh vegetables and fruits (OR 0.42, 95%CI 0.27-0.63), mate consumption (OR 2.04, 95%CI 1.32- 3.16), and black tea (OR 0.10, 95%CI 0.04-0.28) were significantly associated with risk of OESCC. CONCLUSIONS: Hot beverages (mate) and hot foods (boiled meat) appear to be important determinants in the risk of OESCC, allowing the penetration of carcinogens in tobacco and alcohol into the oesophageal mucosa. PMID- 24761899 TI - Two decades of experience with ductal carcinoma in situ of the breast in the Cancer Institute of Tehran, Iran. AB - BACKGROUND: Breast cancer screening and higher quality mammography have resulted in an increase in the diagnosis of ductal carcinoma in situ worldwide. We compared the incidence and other factors in our cases of ductal carcinoma in situ between two recent decades. MATERIALS AND METHODS: Medical records of cases of ductal carcinoma in situ who had been admitted to the surgery wards of the Cancer Institute of Tehran, Iran were evaluated from March 1993 to March 2003 as phase 1, and from April 2003 to April 2013 as phase 2. RESULTS: Ratio of ductal carcinoma in situ to overall breast cancer was 1.27 and 3.93 in phases 1 and 2, respectively. Rates of excisional or incisional biopsies versus core needle biopsies and clinically versus mammographically detected cases as well as median size of tumors dropped between the 2 phases while a substantial rise in the number of patients attending for screening was seen in this time period. Surgical treatments followed a trend from modified radical mastectomy and axillary lymphatic dissection toward breast conserving surgery and sentinel node dissection or no axillary intervention. CONCLUSIONS: Our study shows a considerable trend toward earlier detection of breast cancer and evolution of treatment strategies toward standard less invasive surgery of DCIS in Iran. PMID- 24761900 TI - ATAD2 is highly expressed in ovarian carcinomas and indicates poor prognosis. AB - The purpose of this study was to explore the expression of ATAD2 in ovarian tumor tissue as well as its relationship with degree of malignancy. Tumor tissue from 110 cases of ovarian cancer was collected in accordance with the Declaration of Helsinki for evaluation of ATAD2 expression immunohistochemistry, quantitative PCR (qPCR) and Western blotting. The correlation between the ATAD2 expression and and the prognosis of ovarian cancer was evaluated by Cox regression model. In addition, HO-8910 and OVCAR-3 cells were transfected with two siRNAs targeting ATAD2. Cell viability was evaluated with MTT assay, and cell migration by transwell migration assay. ATAD2 was shown to be highly expressed in 65.5% (72/110) of ovarian cancer cases, both at transcriptional and protein levels. Moreover, highly expression was positively correlated with degree of malignancy. Knock-down of ATAD2 in HO-8910 and OVCAR-3 cells was found to reduce cell migration. In addition, follow-up visits of the patients demonstrated that the 5 year survival rate was lower in patients with high expression of ATAD2. Our study suggested that ovarian tumor tissue may have highly expressed ATAD2, which is associated with tumor stage, omentum-metastasis, ascites and CA-125. Increased ATAD2 may play important roles in tumor proliferation and migration. ATAD2 could serve in particular as a prognostic marker and a therapeutic target for ovarian cancer. PMID- 24761901 TI - Mortality characteristics and prediction of female breast cancer in China from 1991 to 2011. AB - AIMS: To analyze time-dependent changes in female breast cancer (BC) mortality in China, forecast the trend in the ensuing 5 years, and provide recommendations for prevention and management. MATERIALS AND METHODS: Mortality data of breast cancer in China from 1991 to 2011 was used to describe characteristics and distribution, such as the changes of the standardized mortality rate, urban-rural differences and age differences. Trend-surface analysis was used to study the geographical distribution of mortality. In addition, curve estimation, time series modeling, Gray modeling (GM) and joinpoint regression were performed to estimate and predict future trends. RESULTS: In China, the mortality rate of breast cancer has increased yearly since 1991. In addition, our data predicted that the trend will continue to increase in the ensuing 5 years. Rates in urban areas are higher than those in rural areas. Over the past decade, all peak ages for death by breast cancer have been delayed, with the first death peak occurring at 55 to 65 years of age in urban and rural areas. Geographical analysis indicated that mortality rates increased from Southwest to Northeast and from West to East. CONCLUSIONS: The standardized mortality rate of breast cancer in China is rising and the upward trend is predicted to continue for the next 5 years. Since this can cause an enormous health impact in China, much better prevention and management of breast cancer is needed. Consequently, disease control centers in China should place more focus on the northeastern, eastern and southeastern parts of China for breast cancer prevention and management, and the key population should be among women between ages 55 to 65, especially those in urban communities. PMID- 24761902 TI - Efficacy of high dose radiotherapy in post-operative treatment of glioblastoma multiform--a single institution report. AB - BACKGROUND: Glioblastoma multiform (GBM) is a highly aggressive tumor with median survival of approximately 14 months. Management consists of maximal surgical resection followed by post-operative chemoradiation with concurrent then adjuvant temozolamide. The standard radiotherapy dose is 60 Gy in 2-Gy fractions recommended by the radiation therapy oncology group (RTOG). With the vast majority of tumor recurrences occurring within the previous irradiation field and the poor outcome associated with standard therapy, regimens designed to deliver higher radiation doses to improve local control and enhance survival are needed. In this study, we report a single institutional experience in treatment of 68 consecutive patients with GBM, treated with resection, and given post-operative radiotherapy followed by concurrent and/or adjuvant chemotherapy. RESULTS: Of the 80 patients who entered this study, 68 completed the treatment course; 45 (66.2%) males and 23 (33.8%) females with a mean age at diagnosis of 49.0 +/- 12.9 (21 75) years. At a median follow up of 19 months, 39 (57.3%) patients had evidence of tumor progression and 36 (52.9%) had died. The median over all survival for all patients was 16 months and progression free survival for all patients was 6.02 months. All potential prognostic factors were analyzed to evaluate their effects on overall survival. Age <= 50 year, concurrent and adjuvant chemotherapy and extent of surgery had significant p values. We found lower progression rate among patients who received higher doses of radiotherapy (>60 Gy). Higher radiation doses improved progression free survival (p=0.03). Despite increasing overall survival, this elevation was not significant. CONCLUSIONS: This study emphasize that higher radiation doses of (>60 Gy) can improve local control and potentially survival, so we strongly advise prospective multi centric studies to evaluate the role of higher doses of radiotherapy on GBM patient outcome. PMID- 24761903 TI - Endometrial adenocarcinoma: clinicopathologic and survival characteristics in Yazd, Iran. AB - BACKGROUND: Endometrial adenocarcinoma is the most common gynecological cancer in the Western world and its incidence appears to be rising. However, population based studies on endometrial cancer providing survival estimates by age, histology, and stage in Asia have been sparse. The aim of this study was to evaluate the clinicopathological data and survival for patients with endometrial adenocarcinoma treated at three institutions in Yazd, Iran. MATERIALS AND METHODS: Medical and anatomicopathological records at the Department of Pathology and Radiotherapy of the Shahid Sadoughi University of Medical Sciences and Madar private hospital, between 2005 and 2012 were reviewed. All cases of endometrial adenocarcinoma were included. The Kaplan-Maier method was used for survival analysis and Cox proportional hazards model for multiple regression analysis. RESULTS: The study included 84 patients. Stages I, II, III, and IV were identified in 65.4%, 21.5%, 11.9% and 1.2%, respectively. Disease-free survival rate was 73.9 +/- 3.77 months (95% confidence interval, 64.51-83.22 months) and relapse occurred in 12.3% of the patients. The overall survival rate was 78. 2 +/ 3.65 months (95% confidence interval, 71.0-85.3 months). A multivariate analysis revealed that stage and grade were associated with overall survival. CONCLUSIONS: In this survival analysis of patients with endometrial cancer, we found that the prognosis of endometrial cancer was fair but strongly varied by stage and grade, and moderately varied by histology and age. PMID- 24761904 TI - Antitumor constituents from Anthriscus sylvestris (L.) Hoffm. AB - Bioassay-guided chemical investigation of the roots of Anthriscus sylvestris (L.) Hoffm. resulted in the isolation of nine compounds, whose structures were determined by spectroscopic methods. Compound 1 was isolated from this plant for the first time and compounds 3 and 9 were first found from this genus. Different polar fractions of A. sylvestris extract and compounds 1, 6-8 and 9 were evaluated for antitumor activities against HepG2 (human hepatocellular carcinoma), MG-63 (human osteosarcoma cells), B16 (melanoma cells) and HeLa (human cervical carcinoma cells) lines by the MTT method. The petroleum ether fraction of A. sylvestris extract exhibited excellent inhibitory activity with an IC50 value of 18.3 MUg/ml. Among the isolates from the petroleum ether fraction, compound 7 showed significant inhibition against the growth of the four tumor cells with IC50 values ranging from 12.2-43.3 MUg/ml. PMID- 24761905 TI - Genetic variations in TERT-CLPTM1L genes and risk of lung cancer in a Chinese population. AB - BACKGROUND: This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) in telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane1-like (CLPTM1L) and lung cancer risk in a Chinese population. METHODS: We performed a hospital-based case-control study, including 980 lung cancer cases and 1000 cancer-free controls matched for age and sex. Each case and control was interviewed to collect information by well-trained interviewers. A total of 5 ml of venous blood was collected for genotype testing of TERT rs2736098 and CLPTM1L rs401681 using TaqMan methodology. RESULTS: The results revealed that the variant homozygote TERT rs2736098TT was associated with an increased risk of lung cancer (OR=2.017, 95%CI=1.518-2.681), especially lung adenocarcinoma (OR=2.117, 95%CI=1.557-3.043) and small cell carcinoma (OR=1.979, 95%CI: 1.174-3.334), compared with the TERT rs2736098CC genotype. Similar results were observed in non-smokers. CONCLUSION: The TERT rs2736098 polymorphism might affect the susceptibility to lung cancer in Chinese populations. The associations need to be verified in larger and different populations. PMID- 24761906 TI - Lack of any impact of histopathology type on prognosis in patients with early stage adenocarcinoma and squamous cell carcinoma of the uterine cervix. AB - BACKGROUND: The aim of this study was to evaluate the prognosis of patients with stage IA-IIB cervical carcinoma and to investigate a possible correlation of histology with prognosis. MATERIALS AND METHODS: Two hundred fifty one patients with adenocarcinoma and squamous cell carcinoma (SCC) histology for FIGO (International Federation of Gynecology and Obstetrics) stage IA-IIB uterine cervical carcinomas at the Radiation Oncology Clinic of GH Okmeydani Training and Research Hospital between January 1996 and December 2006 were selected, analyzed retrospectively and evaluated in terms of general characteristics and survival. Disease-free survival (DFS) and overall survival (OS) was calculated using the Kaplan-Meier method and differences were compared with the log-rank test. Multivariate analysis using a Cox-proportional hazards model was used to adjust for prognostic factors and to estimate hazard ratio (HR) with 95% confidence interval (CI). RESULTS: There was no differences between the two tumour types in age, stage, pelvic nodal metastasis, parametrial invasion, surgical margin status, DSI, LVSI, maximal tumor diameter, grade, and treatment modalities. 5 year OS and DFS were 73% and 77%, versus 64% and 69%, for SCC and adenocarcinoma, respectively (p> 0.05). Multivariate analysis revealed independent prognostic factors including pelvic nodal metastasis and resection margin status for OS (p=0.008, p=0.002, respectively). CONCLUSIONS: Prognosis of FIGO stage IA-IIB cervical cancer patients was found to be the same for those with adenocarcinoma and SCC. PMID- 24761907 TI - Esophageal cancer, gastric cancer and the use of pesticides in the southwestern of Turkey. AB - BACKGROUND: Esophageal and gastric cancer generally have a poor prognosis and may share common risk factors. It has been demonstrated that the pesticide usage may contribute to development of many cancer types. In this study, the relation between amount of pesticides used in agriculture and esophageal and gastric cancer incidence was researched. MATERIALS AND METHODS: Findings from the data bank of the Ministry of Health Provincial Health Directorate Cancer Records Center between the years of 1998-2010 were used. All patients who were diagnosed with gastric and esophageal cancer histopathologically were included. Data for annual pesticide usage were obtained from Provincial Agriculture Directorate for the same time period. Statistical analysis was performed using the Spearman test. RESULTS: One thousand eight hundred and ninety-six patients were involved in the study, 1,233 males (65%) and 663 females (35%), 230 with esophageal cancer (12.1%) and 1,666 with gastric cancer (87.9%). No statistically significant relation was apparent between pesticide amount used and esophageal cancer (p: 0.87). CONCLUSIONS: In our study, there was no relationship between pesticide usage and esophageal or gastric cancer. However, the time between pesticide usage and cancer development was not known, qualifying the comparison. PMID- 24761908 TI - Cleistocalyx nervosum extract ameliorates chemical-induced oxidative stress in early stages of rat hepatocarcinogenesis. AB - PURPOSE: To study the effect of Cleistocalyx nervosum extract (CE) on diethylnitrosamine (DEN) and phenobarbital (PB) induced oxidative stress in early stages of rat hepatocarcinogenesis. MATERIALS AND METHODS: Male Wistar rats were divided into 4 groups, with Group 1 as a negative control and Group 2 was a positive control receiving DEN injections once a week and PB in drinking water for 6 weeks. Two weeks before DEN initiation and PB treatment, Groups 3 and 4, were fed with 500 and 1000 mg/kg of CEs, respectively, for 8 weeks. RESULTS: A number of GST-P-positive foci, preneoplastic lesions, in the liver were markedly increased in carcinogen administered rats, but was comparatively decreased in rats treated with 1000 mg/kg of CE. The CE reduced malondialdehyde in serum and in the livers of rats treated with DEN and PB. Moreover, CE significantly increased the activities of glutathione peroxidase and catalase in rat liver. CONCLUSIONS: CE appeared to exert its chemopreventive effects by modulating antioxidant status during DEN and PB induced early stages of hepatocarcinogenesis in rats. PMID- 24761909 TI - Mortality of urinary tract cancer in Inner Mongolia 2008- 2012. AB - The aim of this study was to determine the mortality rate and burden of urinary tract cancers among residents of Inner Mongolia. We analyzed mortality data reported by the Death Registry System from 2008 to 2012. The rate of mortality due to urinary tract cancer was 2.04 per 100,000 person-years for the total population, 2.91 for men, and 1.11 for women. Therefore, the mortality rate for men was 2.62-fold the mortality rate for women, constituting a statistically significant difference (p<0.001). Over the period 2008 through 2012, the total potential years of life lost was 1388.1 person-years for men and 777.1 person years for women, and the average years of life lost were 7.71 years per male decedent and 12.0 years per female decedent. Mortality due to urinary tract cancers is substantially greater among the elderly population. Further, the mortality rate associated with urinary tract cancers is greater for elderly men than it is for elderly women. Therefore, in Inner Mongolia, urinary tract cancers appear to pose a greater mortality risk for men than they do for women. PMID- 24761910 TI - Up-regulating of RASD1 and apoptosis of DU-145 human prostate cancer cells induced by formononetin in vitro. AB - Prostate cancer is one of the most prevalent malignant cancers in men. The isoflavone formononetin is a main active component of red clover plants. In the present study, we assessed the effect of formononetin on human prostate cancer DU 145 cells in vitro, and elucidated possible mechanisms. DU-145 cells were treated with different concentrations of formononetin and cell proliferation was assessed by MTT assay, cell apoptosis by Hoechst 33258 and flow cytometry, and protein levels of RASD1, Bcl-2 and Bax by Western blotting. The results showed that formononetin inhibited the proliferation of DU-145 cells in a dose-dependent manner. DU-145 cells treated with different concentrations of formononetin displayed obvious morphological changes of apoptosis under fluorescence microscopy. In addition, formononetin increased the proportion of early apoptotic DU-145 cells, down-regulated the protein levels of Bcl-2 and up-regulated those of RASD1 and Bax. The level of RASD1 reached its maximum at 48 h post-treatment, and rapidly decreased thereafter. Together, we present evidence that formononetin triggered cell apoptosis through the mitochondrial apoptotic pathway by up regulating RASD1. PMID- 24761911 TI - Family history attributes and risk factors for breast cancer in Turkey. AB - BACKGROUND: When dealing with breast cancer, early detection is closely associated with determining and closely monitoring high risk groups. The aim of this study was to determine the preventable risk factors that are specific for our country, and to understand which risk factors were most predominant. MATERIALS AND METHODS: The study was planned as a case-control design. Women diagnosed with breast cancer who visited the Surgery, Obstetrics and Gynaecology, and Radiation Oncology outpatient clinics of the Izmir Dokuz Eylul University (DEU) School of Medicine were accepted as the case group. Then a control group matched for age was established among females who visited the outpatient clinics on the same days. A questionnaire prepared by the researchers was implemented using a face-to-face interview technique. The Mann-Whitney U test was used in the comparisons of the group averages, and the Pearson chi-square test in the comparisons between groups. In order to determine the dominant risk factors, binary logistical regression test was implemented. RESULTS: A total of 138 patients, 69 cases and 69 controls, were included in the study. A significant difference can be detected between the groups in terms of BMI, smoking, breast cancer prevalence among first degree family members, presence of breast cancer among distant family members, existence of other types of cancers among family members and the age of onset of menopause (p<0.05). Logistical regression analysis revealed that the presence of breast cancer among first degree relatives increased the risk of developing breast cancer 5.7 times. CONCLUSIONS: Although some results of this study are compatible with findings in the literature, some are not. In order to determine unique risk factors, there is a clear need for large-scale studies. PMID- 24761912 TI - Parental age-related risk of retinoblastoma in Iranian children. AB - BACKGROUND: Retinoblastoma is a rare malignant intraocular neoplasm. About 90% of cases feature a germline mutation in the RB1 gene and these will develop retinoblastoma during their early childhood. An association between mutations in germline cells and aging has been demonstrated. This suggests a higher incidence of childhood cancer including retinoblastoma among children of older parents. MATERIALS AND METHODS: In the present study we aimed to determine the association of paternal and maternal age with an increased risk of retinoblastoma in a case control study in Iranian population. The study was carried out on 240 persons who were born during 1984-2012 in Mahak and Mofid hospitals in Tehran, Iran. The statistical analysis included studying the mean age of parents and in order to know whether parental age of patients is different from parental age of control group, (t-test) compare averages test is used perfectly. By binary logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: The results of statistical analysis including the study of mean parental age by the use of (t-test) compare averages test showed a significant difference between parental ages of patients and controls. Logistic regression showed that coefficients were significant for maternal but not paternal age. CONCLUSIONS: Our findings indicate that advanced maternal age can increase the risk of retinoblastoma in offspring, but the paternal age has no significant effect. PMID- 24761913 TI - Metaplastic breast carcinoma: a heterogeneous disease. AB - The aim of this study is to evaluate clinicopathologic characteristics and the multi-disciplinary treatment results of metaplastic breast cancer (MBC) patients treated in a single institute. Seventeen female patients with MBC treated in our department between June 2000 and January 2012 were identified and retrospectively evaluated. The median age at diagnosis was 46 years (range, 26-66 years). The median tumor size at diagnosis was 3.5 cm (range 1.5-12 cm). Six (35%) patients underwent breast conservation surgery and 11 (65%) mastectomy. Axillary lymph node metastasis was found in 6 (35%) patients. Twelve (71%) had triple negative tumors. Postoperative RT and systemic adjuvant treatment was given to all patients accordingly to stage and biological characteristics. Median follow-up time was 27 months (range, 12-151 months). At the time of this analysis, 14 (82%) patients were alive with no evidence of disease, and 1 (6%) was alive with disease. The 3-year OS was 91% and 5-year 80%, and DFS rates were 76% and 76%, respectively. Despite the young age of our patients with mostly high grade tumors, larger tumor size and higher rates of lymph node metastasis, the survival outcomes in our study are favorable in comparison with previously reported series. PMID- 24761914 TI - The G801A polymorphism in the CXCL12 gene and risk of breast carcinoma: evidence from a meta-analysis including 2,931 subjects. AB - More and more evidence indicates that the G801A polymorphism in the CXCL12 gene might be associated with susceptibility to breast carcinoma in humans being. However, individually published results have been inconsistent. The purpose of this meta-analysis was to investigate the association between the G801A polymorphism in the CXCL12 gene and breast carcinoma risk. A complete search strategy was done by the electronic databases including PubMed and Chinese Biomedical Literature Database. A meta-analysis including seven individual studies was carried out in order to explore the association between the G801A polymorphism in the CXCL12 gene polymorphisms and breast carcinoma. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95%CIs) between the G801A polymorphism in the CXCL12 gene and breast carcinoma risk were assessed by the random-effects model. A significant relationship between the G801A polymorphism in the CXCL12 gene and breast carcinoma was discovered in an allelic genetic model (OR: 1.214, 95%CI: 1.085- 1.358, p=0.001), a homozygote model (OR: 1.663, 95%CI: 1.240-2.232, p=0.001), a heterozygote model (OR: 1.392, 95%CI: 1.190-1.629, p=0.000), a recessive genetic model (OR: 1.407, 95%CI: 1.060 1.868, p=0.018) and a dominant genetic model (OR: 1.427, 95%CI: 1.228-1.659, p=0.000). On sub-group analysis based on ethnicity, significance was observed between the European group and the mixed group. A significant relationship was found between the G801A polymorphism in the CXCL12 gene and breast carcinoma risk. Individuals with the A allele of the G801A polymorphism in the CXCL12 gene are under a higher risk for breast carcinoma. PMID- 24761915 TI - The 765G>C polymorphism in the cyclooxygenase-2 gene and gastric cancer risk: an update by meta-analysis. AB - BACKGROUND: The 765G>C polymorphism in cyclooxygenase-2 (COX-2) gene has been extensively investigated for association with gastric cancer (GC). However, the results of different studies have been inconsistent. The aim of this study is to comprehensively evaluate the genetic risk of -765G>C polymorphism in the COX-2 gene for GC. MATERIALS AND METHODS: We searched Pubmed, Embase, Medline, CNKI database, Wanfang database, Weipu database, and Chinese Biomedical database, covering all publications (last search been performed on Jan 10, 2014). Statistical analyses were performed using Revman 5.2 and STATA 10.0 software. RESULTS: A total of 1,874 cases and 3,005 controls in 10 case-control studies were included in this meta-analysis. The results indicated that the variant C allele carriers (GC+CC) had a 69% increased risk of GC when compared with the homozygote GG (odds ratio (OR)=1.69, 95% confidence interval (CI), 1.10-2.61 for GC+CC vs GG). In the subgroup analysis by ethnicity, significant elevated risks were associated with C allele carriers in Asians (OR=1.75, 95%CI=1.40-2.18, and p<0.00001) and in Indians (OR=8.38, 95%CI=4.34-16.16, and p<0.00001) but not in Caucasians (OR=1.07, 95%CI=0.81-1.42, and p=0.62) or in Dutch (OR=0.53, 95%CI= 0.33-0.87, and p= 0.01).In the subgroup analysis by Helicobacter pylori (H. pylori) status, a significantly increased risk was identified among H. pylori (+) (OR=3.58, 95%CI=2.33-3.50, and p<0.00001) and H. pylori (-) (OR=2.32, 95%CI=1.46 3.69, and p=0.0004). CONCLUSIONS: This meta-analysis suggested that the -765G>C polymorphism in the COX-2 gene could be a risk factor for GC in Asians and Indians. PMID- 24761916 TI - Situation of HPV16 E2 gene status during radiotherapy treatment of cervical carcinoma. AB - BACKGROUND: Human papillomavirus (HPV) integration within the E2 gene has been proposed as a critical event in cervical carcinogenesis. This study concerned whether HPV16 status and E2 gene intactness are predictive of radiation response in patients with cervical cancer. MATERIALS AND METHODS: Biopsies of 44 patients with cervical cancer were collected before or after radiotherapy. The presence of HPV16 was assessed by polymerase chain reaction (PCR) using specific primers for the L1 region. E2 disruption was detected by amplifying the entire E2 gene. RESULTS: HPV16 DNA was found in 54.5% of the clinical samples. Overall, 62.5% of the HPV16 positive tumors had integrated viral genome and 37.5% had episomal genome. There was a tendency of increase of HPV16 E2 negative tumors compared with HPV16 L1 ones in advanced stages (75% versus 20% in stage III respectively). Detection of E2 gene appeared influenced by the radiotherapy treatment, as the percentage of samples containing an intact HPV16 E2 was more frequent in pretreated patients compared to radiotherapy treated patients (66.6% versus 20%). The radiation therapy caused an eight-fold [OR= 8; CI=1.22-52.25; p=0.03] increase in the risk of HPV16 genome disruption. The integration status is influenced by the irradiation modalities, interestingly E2 disruption being found widely after radiotherapy treatment (75%) with a total fractioned dose of 50 Gy. CONCLUSIONS: This study reveals that the status of the viral DNA may be used as a marker to optimize the radiation treatment. PMID- 24761917 TI - Underutilization of curative treatment among patients with non small cell lung cancer: experience from a tertiary care centre in India. AB - BACKGROUND: Lung cancer is one of the commonest and most lethal cancers throughout the world. The majority of the patients present at advance stage and are not suitable for curative intent treatment. Even among patients with localized disease, there has been underutilization of curative treatment modalities. The aim of this study was to analyze the radical treatment utilization rates in patients with non small cell lung cancer (NSCLC) treated at our centre. MATERIALS AND METHODS: We analyzed case records of 104 patients with a pathologically confirmed diagnosis of NSCLC having stage 1-3B disease who were treated at our centre over last 3 years, to assess the utilization of curative treatment modalities i.e. surgery or radical radiotherapy. RESULTS: The median age of this cohort was 58 years. Out of 104 patients only 33 (31.7%) received curative intent treatment, 14 undergoing curative resection and 19 receiving radical doses of radiotherapy. The baseline characteristics of both the groups (with or without radical treatment) were not different. Major factors associated with underutilization with curative treatment were progressive disease or loss of follow up after chemotherapy and inappropriate use of TKI and/ or palliative radiotherapy in patients with stage 1-3B disease. Patients who did not receive radical treatment had inferior PFS and OS than those who received radical treatment. CONCLUSIONS: In our practice we observed gross underutilization of curative intent treatment modalities in patients with NSCLCs which is associated with inferior survival. PMID- 24761918 TI - Self-disclosure of breast cancer diagnosis by Iranian women to friends and colleagues. AB - BACKGROUND: Breast cancer (BC) is the most common form of cancer in Iranian women, and it remains a major health problem. An increasing number of young women are being diagnosed with BC, and therefore, there is an increasing likelihood that more women will survive breast cancer for many years. Many opine that self disclosure of BC diagnosis is important because talking about cancer helps people to make sense of their experiences; in fact, self-disclosure appears to play an important role in many health outcomes. However, this has not yet been studied in BC patients in Iran. Therefore, this study aimed to explore the status of self disclosure of BC diagnosis by Iranian women to friends and colleagues. MATERIALS AND METHODS: All BC records for 2001-2011 of employed women were studied at five hospitals in Mashhad. Data about the self-disclosure of BC diagnosis were gathered through telephone interviews, and the participants filled out a questionnaire about their status of self-disclosure of BC diagnosis to various groups of people. RESULTS: The mean age of employed women at the time of diagnosis was 44.3 +/- 6.7 years. Over 60% self-disclosed to work colleagues and over 90% to bosses/managers. Seventy per cent reported that they had support from their family and husband's family, while 95% reported that they had support from parents, siblings, children and friends. CONCLUSIONS: Most employed women self disclosed freely to family, friends, colleagues and bosses/managers. Apparently, self-disclosure of breast cancer diagnosis may have negative effects at work. About half of patients reported that they had support from family, managers and colleagues; however, for nearly 28% of employed women, disclosure had less positive effects. In particular, it altered their perception of others, produced difficulties with work and family and diminished closeness with the people who were told. However, the stigma of BC is far less than it once was. PMID- 24761919 TI - Anti-tumor effects and apoptosis induction by Realgar bioleaching solution in Sarcoma-180 cells in vitro and transplanted tumors in mice in vivo. AB - BACKGROUND: Realgar which contains arsenic components has been used in traditional Chinese medicine (TCM) as an anticancer drug. However, neither Realgar nor its formula are soluble in water. As a result, high dose of Realgar has to be administered to achieve an effective blood medicine concentration, and this is associated with adverse side effects. The objective of the present study was to increase the solubility of a formula using hydrometallurgy technology as well as investigating its effects on in vitro and in vivo cell proliferation and apoptosis in Sarcoma-180 cell line. MATERIALS AND METHODS: Antiproliferative activity of Realgar Bioleaching Solution (RBS) was evaluated by MTT assay. Further, effects of RBS on cell proliferation and apoptosis were studied using flow cytometry and transmission electron microscopy. Kunming mice were administered RBS in vivo, where arsenic specifically targeted solid tumors. RESULTS: The results indicated that RBS extract potently inhibited the tumor growth of Sarcoma-180 cell line in a dose-dependent manner. Flow cytometry and transmission electron microscopy further indicated that RBS significantly induced cell apoptosis through the inhibition of cell cycle pathway in a dose-dependent manner. Further, on RBS administration to mice, arsenic was specifically targeted to solid tumors CONCLUSIONS: RBS could substitute for traditional Realgar or its formula to work as a potent tool in cancer treatment. PMID- 24761920 TI - Association of DR4 (TRAIL-R1) polymorphisms with cancer risk in Caucasians: an updated meta-analysis. AB - Death receptor 4 (TRAIL-R1 or DR4) polymorphisms have been associated with cancer risk, but findings have been inconsistent. To estimate the relationship in detail, a meta-analysis was here performed. A search of PubMed was conducted to investigate the association between DR4 C626G, A683C and A1322G polymorphisms and cancer risk, using odds ratios (ORs) with 95% confidence intervals. The results suggested that DR4 C626G and A683C polymorphisms were indeed associated with cancer risk (for C626G, dominant model, OR 0.991, 95%CI 0.866-1.133, p=0.015; for A683C, additive model, OR=1.140, 95%CI: 0.948-1.370, p=0.028; dominant model, OR=1.156, 95%CI: 0.950-1.406, p=0.080) in the Caucasian subgroup. However, the association was not significant between DR4 polymorphism A1322G with cancer risk in Caucasians (For A1322G, additive model: OR 1.085, 95%CI 0.931-1.289, p=0.217; dominant model: OR 1.379, 95%CI 0.934-2.035, p=0.311; recessive model: OR 1.026, 95%CI 0.831-1.268 p=0.429.). In summary, our finding suggests that DR4 polymorphism C626G and A683 rather than A1322G are associated with cancer risk in Caucasians. PMID- 24761921 TI - Model-based survival estimates of female breast cancer data. AB - BACKGROUND: Statistical methods are very important to precisely measure breast cancer patient survival times for healthcare management. Previous studies considered basic statistics to measure survival times without incorporating statistical modeling strategies. The objective of this study was to develop a data-based statistical probability model from the female breast cancer patients' survival times by using the Bayesian approach to predict future inferences of survival times. MATERIALS AND METHODS: A random sample of 500 female patients was selected from the Surveillance Epidemiology and End Results cancer registry database. For goodness of fit, the standard model building criteria were used. The Bayesian approach is used to obtain the predictive survival times from the data-based Exponentiated Exponential Model. Markov Chain Monte Carlo method was used to obtain the summary results for predictive inference. RESULTS: The highest number of female breast cancer patients was found in California and the lowest in New Mexico. The majority of them were married. The mean (SD) age at diagnosis (in years) was 60.92 (14.92). The mean (SD) survival time (in months) for female patients was 90.33 (83.10). The Exponentiated Exponential Model found better fits for the female survival times compared to the Exponentiated Weibull Model. The Bayesian method is used to obtain predictive inference for future survival times. CONCLUSIONS: The findings with the proposed modeling strategy will assist healthcare researchers and providers to precisely predict future survival estimates as the recent growing challenges of analyzing healthcare data have created new demand for model-based survival estimates. The application of Bayesian will produce precise estimates of future survival times. PMID- 24761922 TI - Colorectal cancer screening practices of primary care providers: results of a national survey in Malaysia. AB - The incidence of colorectal cancer has been increasing in many Asian countries including Malaysia during the past few decades. A physician recommendation has been shown to be a major factor that motivates patients to undergo screening. The present study objectives were to describe the practice of colorectal cancer screening by primary care providers in Malaysia and to determine the barriers for not following recommendations. In this cross sectional study involving 132 primary care providers from 44 Primary Care clinics in West Malaysia, self administered questionnaires which consisted of demographic data, qualification, background on the primary care clinic, practices on colorectal cancer screening and barriers to colorectal cancer screening were distributed. A total of 116 primary care providers responded making a response rate of 87.9%. About 21% recommended faecal occult blood test (FOBT) in more than 50% of their patients who were eligible. The most common barrier was "unavailability of the test". The two most common patient factors are "patient in a hurry" and "poor patient awareness". This study indicates that colorectal cancer preventive activities among primary care providers are still poor in Malaysia. This may be related to the low availability of the test in the primary care setting and poor awareness and understanding of the importance of colorectal cancer screening among patients. More awareness programmes are required for the public. In addition, primary care providers should be kept abreast with the latest recommendations and policy makers need to improve colorectal cancer screening services in health clinics. PMID- 24761923 TI - Incidence and clinical outcomes of non-endometrioid carcinoma of endometrium: Siriraj Hospital experience. AB - BACKGROUND: To study the incidence of non-endometrioid carcinoma of endometrium and compare the clinical characteristics and treatment outcomes with endometrioid carcinoma patients. MATERIALS AND METHODS: This study included 236 patients with endometrial carcinoma at Siriraj Hospital whom were diagnosed and treated from 2003 through 2006. The clinical characteristics, pathological features, treatment and clinical outcomes were collected from the medical records. The 5-year survival was calculated according to 2009 FIGO staging. RESULTS: Non-endometrioid carcinoma of endometrium accounted for 10.2% of all endometrial carcinomas (24/236 patients). The 5 -year survival rate was significantly lower in the non endometrioid group compared to the endometrioid group (77.3% vs 96%, p<0.001) and clinical data pointed to greater malignancy. CONCLUSIONS: Non-endometrioid carcinoma of endometrium is relative rare but is more aggressive, has more distant metastasis at diagnosis with a worse survival rate than endometrioid carcinoma. Only patients in stage IA with no residual disease on a hysterectomy specimen may not need adjuvant treatment. PMID- 24761925 TI - Association between the TP53BP1 rs2602141 A/C polymorphism and cancer risk: a systematic review and meta-analysis. AB - BACKGROUND: The p53-binding protein 1 (TP53BP1) gene may be involved in the development of cancer through disrupting DNA repair. However, investigation of associations between TP53BP1 rs2602141 A/C polymorphism and cancer have yielded contradictory and inconclusive outcomes. We therefore performed a meta-analysis to evaluate the association between the TP53BP1 rs2602141 A/C polymorphism and cancer susceptibility. MATERIALS AND METHODS: Published literature from PubMed, Medline, the Cochrane Library, EMbase, Web of Science, Google (scholar), CBMDisc, Chongqing VIP database, and CNKI database were retrieved. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed or random effects models. Publication bias was estimated using funnel plots, Begg's and Egger's test. RESULTS: A total of seven studies (3,018 cases and 5,548 controls) were included in the meta-analysis. Our results showed that the genotype distribution of TP53BP1 rs2602141 A/C was not associated with cancer risk overall. However, on subgroup analysis, we found that TP53BP1 rs2602141 A/C was associated with cancer risk within an allele model (A vs C, OR=1.14, 95%CI: 1.01 1.29) and a codominant model (AA vs CC, OR=1.36, 95%CI: 1.06-1.74) in Asians rather than in Caucasians. Subgroup analysis by cancer type, genotype, and with or without adjustment for controls showed no significant association. CONCLUSIONS: The findings suggested an association between rs2602141 A/C polymorphism in TP53BP1 gene and increased risk of cancer in Asians. PMID- 24761924 TI - Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. AB - Oxaliplatin is a first-line therapy for colorectal cancer, but cancer cell resistance to the drug compromises its efficacy. To explore mechanisms of drug resistance, we treated colorectal cancer cells (HCT116 and SW620) long-term with oxaliplatin and established stable oxaliplatin-resistant lines (HCT116-OX and SW620-OX). Compared with parental cell lines, IC50s for various chemotherapeutic agents (oxaliplatin, cisplatin and doxorubicin) were increased in oxaliplatin resistant cell lines and this was accompanied by activation of nuclear factor erythroid-2 p45-related factor 2 (Nrf2) and NADPH quinone oxidoreductase 1 (NQO1). Furthermore, luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner. Luteolin also inhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and GSTalpha1/2] expression and decreased reduced glutathione in wild type mouse small intestinal cells. There was no apparent effect in Nrf2-/- mice. Luteolin combined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined index values below 1), indicating a synergistic effect. Therefore, adaptive activation of Nrf2 may contribute to the development of acquired drug-resistance and luteolin could restore sensitivity of oxaliplatin-resistant cell lines to chemotherapeutic drugs. Inhibition of the Nrf2 pathway may be the mechanism for this restored therapeutic response. PMID- 24761926 TI - Multicenter epidemiologic study on hepatocellular carcinoma in Turkey. AB - BACKGROUND: Hepatocellular cancer (HCC) is one of the important health problems in Turkey, being very common and highly lethal. The aim of this study was to determine clinical, demographic features and risk factors. MATERIALS AND METHODS: Nine hundred and sixth-three patients with HCC from 13 cities in Turkey were included in this study. RESULTS: Only 205 (21%) of the 963 patients were women, with a male:female predominance of 4.8:1 and a median age of 61 years. The etiologic risk factors for HCC were hepatitis B in 555 patients (57.6%), 453 (81%) in men, and 102 (19%) in women, again with male predominance, hepatitis C in 159 (16.5%), (14.9% and 22.4%, with a higher incidence in women), and chronic alcohol abuse (more than ten years) in 137 (14.2%) (16.8% and 4.9%, higher in males). The Child-Pugh score paralleled with advanced disease stage amd also a high level of AFP. CONCLUSIONS: According to our findings the viral etiology (hepatitis B and hepatitis C infections) in the Turkish population was the most important factor in HCC development, with alcohol abuse as the third risk factor. The Child-Pugh classification and AFP levels were determined to be important prognostic factors in HCC patients. PMID- 24761927 TI - Pre-operative evaluation of ovarian tumors by risk of malignancy index, CA125 and ultrasound. AB - PURPOSE: To evaluate the diagnostic performances of risk of malignancy index (RMI), CA-125 and ultrasound score in differentiating between benign and borderline or malignant ovarian tumors and find the best diagnostic test for referral of suspected malignant ovarian cases to gynaecologic oncologists. MATERIALS AND METHODS: This prospective study covered 467 women with pelvic tumors scheduled for surgery at our hospital between July 2011 and July 2013. The RMI was obtained from ultrasound score, CA125 and menopausal status. The diagnostic values of each parameter and the RMI were determined and compared using Statistical Packages for Social Sciences Version 14.0.1. RESULTS: In our study, 61% of ovarian tumors were malignant in the post-menopausal age group. RMI with a cut-off 150 had sensitivity of 84% and specificity of 97% in detecting ovarian cancer. CA-125>30 had a sensitivity of 84% and a specificity of 83%. An ultrasound score more than 2 had a sensitivity of 96% and specificity of 81%. RMI had the least false malignant cases thus avoiding unnecessary laparotomies. Ultrasound when used individually had the best sensitivity but poor specificity. CONCLUSIONS: Our study has demonstrated the RMI to be an easy, simple and applicable method in the primary evaluation of patients with pelvic masses. It can be used to refer suspected malignant patients to be operated by a gynaecologic oncologist. Other models of preoperative evaluation should be developed to improve the detection of early stage invasive, borderline and non epithelial ovarian cancers. PMID- 24761928 TI - Optimizing nutrition support in cancer care. AB - Involvement of a multidisciplinary team in cancer care may have added benefits over the existing system of patient management. A paradigm shift in the current patient management would allow more focus on nutritional support, in addition to clinical care. Malnutrition, a common problem in cancer patients, needs special attention from the early days of cancer care to improve quality of life and treatment outcomes. Patient management teams with trained oncology dietitians may provide quality personalized nutritional care to cancer patients. PMID- 24761929 TI - Remeasuring man. AB - Samuel George Morton (1799-1851) was the most highly regarded American scientist of the early and middle 19th century. Thanks largely to Stephen Jay Gould's book The Mismeasure of Man, Morton's cranial capacity measurements of different races is now held up as a prime example of and cautionary tale against scientific racism. A team of anthropologists recently reevaluated Morton's work and argued that it was Gould, not Morton, who was biased in his analysis. This article is a reexamination of the Morton and Gould controversy. It argues that most of Gould's arguments against Morton are sound. Although Gould made some errors and overstated his case in a number of places, he provided prima facia evidence, as yet unrefuted, that Morton did indeed mismeasure his skulls in ways that conformed to 19th century racial biases. Gould's critique of Morton ought to remain as an illustration of implicit bias in science. PMID- 24761930 TI - Fundamental resolution limits during electron-induced direct-write synthesis. AB - In this study, we focus on the resolution limits for quasi 2-D single lines synthesized via focused electron-beam-induced direct-write deposition at 5 and 30 keV in a scanning electron microscope. To understand the relevant proximal broadening effects, the substrates were thicker than the beam penetration depth and we used the MeCpPt(IV)Me3 precursor under standard gas injection system conditions. It is shown by experiment and simulation how backscatter electron yields increase during the initial growth stages which broaden the single lines consistent with the backscatter range of the deposited material. By this it is shown that the beam diameter together with the evolving backscatter radius of the deposit material determines the achievable line widths even for ultrathin deposit heights in the sub-5-nm regime. PMID- 24761932 TI - Motorcyclists' perceptions and experiences of riding and risk and their advice for safety. AB - OBJECTIVE: To examine the knowledge, observations, and perceptions of motorcycle riders on the risks of on-road motorcycling and potential safety measures to give insight and guidance in developing policies, programs, and legislation to improve the safety of motorcyclists. METHODS: Individual and focus group interviews were conducted with dealers and a cross section of motorcyclists from selected regions across New Zealand. The interviews were analyzed and coded to identify common themes and diverse perspectives on why people rode motorcycles, riders' perceptions on risk, and possible safety strategies for on-road motorcycling. FINDINGS AND DISCUSSION: Motorcycling has major benefits for riders, although most riders perceived that the risks could be severe and they were susceptible to injury. Their observations on the threats and barriers to safety focused on 3 components: the rider, the motorcycle, and the environment. Risks included inexperience, not riding to the conditions, choice of motorcycle, protective clothing and conspicuity, and speed. The underlying risk of being on 2 wheels was accentuated by the availability of high-power motorcycles. The threats perceived in the environment included the behavior of other road users, especially car drivers, and the poor road conditions and surrounds encountered. CONCLUSIONS: Riders identified risks that have been recognized in the road safety literature as well as risks for which there are no engineering or scientific solutions. To effectively increase motorcyclist safety, recognition of the commonalities and the differences between motorcyclists' perspectives and proposed strategies is needed. This approach is more likely to engage riders and thus support positive behavior change among riders and drivers. PMID- 24761931 TI - Chronic brain inflammation causes a reduction in GluN2A and GluN2B subunits of NMDA receptors and an increase in the phosphorylation of mitogen-activated protein kinases in the hippocampus. AB - Neuroinflammation plays a key role in the initiation and progression of neurodegeneration in Alzheimer's disease (AD). Chronic neuroinflammation results in diminished synaptic plasticity and loss of GluN1 N-methyl-D-aspartate (NMDA) receptors in the hippocampus, leading to the cognitive deficits that are the most common symptoms of AD. Therefore, it is suggested that chronic inflammation may alter expression levels of GluN2A and GluN2B subunits of NMDA receptors and associated intracellular signalling. Chronic neuroinflammation was induced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle in Fischer 344 rats. The status of hippocampus-dependent memory was evaluated in control rats and rats chronically infused with LPS. Microglial activation in the hippocampus was examined using immunohistochemical staining. Western blot analysis was used to measure membrane levels of GluN2A and GluN2B subunits of NMDA receptors and mitogen-activated protein kinase (MAPK) in the hippocampi of these rats, and immunofluorescent double labeling was used to assess the cellular location of MAPK. Microglial activation was observed in the hippocampi of rats that showed memory impairments with chronic LPS infusion. Chronic LPS infusion reduced the levels of GluN2A and GluN2B and increased the levels of phosphorylated MAPKs in the hippocampus. MAPK-positive immunoreactivity was observed mostly in the neurons and also in non-neuronal cells. Reductions in GluN2A and GluN2B subunits of NMDA receptors coupled with altered MAPK signaling, in response to inflammatory stimuli may be related to the cognitive deficits observed in AD. PMID- 24761933 TI - Insertion approach: bolstering the reproducibility of electrochemical signal amplification via DNA superstructures. AB - For more than a decade, the backfilling approach for the immobilization of DNA probes has been routinely adopted for the construction of functional interfaces; however, reliably reproducing electrochemical signal amplification by this method is a challenge. In this research, we demonstrate that the insertion approach significantly bolsters the reproducibility of electrochemical signal amplification via DNA superstructures. The combination of the backfilling approach and the DNA superstructure formation poses a big challenge to reliably reproducing electrochemical signal amplification. In order to use the detection of Hg(2+) as a prototype of this new strategy, a thymine-rich DNA probe that is specific to mercury ion was applied in this study. The presence of Hg(2+) induces the folding of the DNA probes and inhibits the formation of DNA superstructures. By using electroactive probes ([Ru(NH3)6](3+)) that are electrostatically adsorbed onto the double strands, differential pulse voltammetry (DPV) could quantitatively confirm the presence of Hg(2+). A limit of detection (LOD) and a limit of quantification (LOQ) (LOQ) as low as 0.3 and 9.5 pM, respectively, were achieved. Furthermore, excellent selectivity and real sample analysis demonstrated the promising potential of this approach in future applications. PMID- 24761934 TI - Observation of a brine layer on an ice surface with an environmental scanning electron microscope at higher pressures and temperatures. AB - Observation of a uranyl-salt brine layer on an ice surface using backscattered electron detection and ice surface morphology using secondary-electron detection under equilibrium conditions was facilitated using an environmental scanning electron microscope (ESEM) at temperatures above 250 K and pressures of hundreds of Pa. The micrographs of a brine layer over ice grains prepared by either slow or shock freezing provided a complementary picture of the contaminated ice grain boundaries. Fluorescence spectroscopy of the uranyl ions in the brine layer confirmed that the species exists predominately in the solvated state under experimental conditions of ESEM. PMID- 24761935 TI - Metal-organic frameworks with mechanically interlocked pillars: controlling ring dynamics in the solid-state via a reversible phase change. AB - Metal-organic framework (MOF) materials have been prepared that contain a mechanically interlocked molecule (MIM) as the pillaring strut between two periodic Zn-carboxylate layers. The MIM linker is a [2]rotaxane with a [24]crown 6 (24C6) macrocycle and an aniline-based axle with terminal pyridine donor groups. The single-crystal X-ray structures of MOFs UWDM-2 (1,4-diazophenyl dicarboxylate) and UWDM-3 (1,4-biphenyl-dicarboxylate) show that both frameworks are large enough to contain the free volume required for rotation of the interlocked 24C6 macrocycle, but the frameworks are interpenetrated (UWDM-2, three-fold, and UWDM-3, two-fold). In particular, for UWDM-3 the 24C6 rings of the pillaring MIM are positioned directly inside the square openings of neighboring zinc dicarboxylate layers. Variable-temperature (VT) (2)H SSNMR demonstrated that the 24C6 macrocycles in UWDM-2 and UWDM-3 can only undergo restricted motions related to ring flexibility or partial rotation but are incapable of undergoing free rotation. VT-powder X-ray diffraction studies showed that upon activation of UWDM-3, by removing solvent, a phase change occurs. The new beta-phase of UWDM-3 retained crystallinity, and (2)H SSNMR demonstrated that the 24C6 macrocyclic ring of the pillared MIM strut is now free enough to undergo full rotation. Most importantly, the phase change is reversible; the beta version of the MOF can be reverted to the original alpha state by resolvation, thus demonstrating, for the first time, that the dynamics of a MIM inside a solid material can be controlled by a reversible phase change. PMID- 24761936 TI - Solid-phase extraction for selective determination of bisphenol A in drinks and fruits by dummy surface molecularly imprinted polymer with direct synthetic method. AB - A reliable and selective method was developed for the determination of bisphenol A (BPA) in drinks and fruit using dummy surface molecularly imprinted polymer (DSMIP) as a solid-phase extraction (SPE)-enrichment and separation sorbent coupled with high-performance liquid chromatography (HPLC). Tetrabromobisphenol A (TBBPA), whose structure is similar to BPA, was selected as a dummy template molecule. DSMIP has a higher selectivity for BPA than surface non-imprinted polymer (SNIP) when used as sorbents for SPE. Potential factors affecting the extraction efficiency, including conditioning, sample loading, washing and elution, and the breakthrough volume were optimised. Under the optimum experimental conditions, the recoveries of BPA in drinks and fruit were in the range from 98% to 105% with relative standard deviations (RSDs) below 7%, and a limit of detection (LOD) of 3 ng ml(-1). The developed extraction protocol eliminated the effect of template leakage on quantitative analysis and could be applied to the trace determination of BPA in complicated functional samples. PMID- 24761937 TI - Diarrhea incidence and intestinal infections among rotavirus vaccinated infants from a poor area in Brazil: a spatial analysis. AB - BACKGROUND: Acute diarrhea is the second leading cause of mortality among children under 5 years of age in developing countries. The pathogen most strongly associated with diarrhea is rotavirus followed by enteric pathogens such as bacteria, helminthes and protozoan. Adequate sanitation and water supply contribute to decrease acute diarrhea incidence of most etiologic agents, although vaccination remains the most important intervention to control rotavirus acute diarrhea. This study aimed to describe environmental conditions and analyze spatially the acute diarrhea and intestinal infection among rotavirus vaccinated infants from Laranjeiras-Sergipe, Brazil. METHODS: Children were enrolled between 2 and 11 months of age and followed through 12 months. Demographic, socioeconomic and environmental data were obtained from a questionnaire, and immunization data were obtained from children vaccination card. Children stool samples were collected each month in order to run laboratory analyses. The household spatial localization was obtained by using a Global Positioning System (GPS). Spatial analysis was performed using the TerraView computer program and Kernel intensity estimation. RESULTS: A total of 1,113 stool samples were collected with 80 being diarrhea associated. Diarrhea incidence rate was 0.5 +/- 1.0 episodes/child/year. The overall infection rates by Ascaris lumbricoides, Endolimax nana, Giardia lamblia and rotavirus were 5.1%, 3.0%, 0.9% and 2.6%, respectively. 3.8% of diarrhea-associated stool samples were positive for rotavirus and 11.3% were positive for helminths and protozoans. There were some changes on spatial distribution of intestinal infections and diarrhea episodes along the four trimesters evaluated. CONCLUSIONS: The studied infants live equally in precarious conditions of sanitation which probably explain the significant rates of parasitic infections appearing in early life. The low acute diarrhea incidence in the studied rotavirus vaccinated population and the low number of symptomatic rotavirus infection may indicate vaccination efficacy to prevent acute diarrhea among young children in a poor environmental sanitary setting. PMID- 24761938 TI - Hemodynamic changes in child acute respiratory distress syndrome with airway pressure release ventilation: a case series. AB - BACKGROUND: Airway pressure release ventilation (APRV) is widely used in adult critical care settings. However, information on the use of APRV in the pediatric population is limited. METHODS: All patients admitted to the medical-surgical pediatric intensive care unit with a diagnosis of acute respiratory distress syndrome (ARDS) who received APRV for at least 12 h between 2007 and 2009 were reviewed. RESULTS: Thirteen patients with a variety of etiologies of ARDS were included, with a mean weight of 18.2 +/- 15.0 kg, a mean age of 68 +/- 57 months and a predicted mortality (based on Pediatric Index of Mortality version 2) of 23.9 +/- 13.8%. Patients were placed on APRV for a median of 4 days (range 1-10 days). There was no change in blood gas parameters after 1 h or 12 h of APRV when compared with pre-APRV. There was no statistical difference in hemodynamic parameters, including mean arterial blood pressure, central venous blood pressure and heart rate, while the patients were on APRV. CONCLUSION: APRV could be safely used in pediatric ARDS patients, without significant hemodynamic compromise or side effects. PMID- 24761939 TI - Longterm effects of bile duct injuries on health-related quality of life: is a meta-analysis reliable? PMID- 24761940 TI - Reply to Dominguez-Rosado et al. PMID- 24761942 TI - Tuning micropillar tapering for optimal friction performance of thermoplastic gecko-inspired adhesive. AB - We present a fabrication method and friction testing of a gecko-inspired thermoplastic micropillar array with control over the tapering angle of the pillar sidewall. A combination of deep reactive ion etching of vertical silicon pillars and subsequent maskless chemical etching produces templates with various widths and degrees of taper, which are then replicated with low-density polyethylene. As the silicon pillars on the template are chemically etched in a bath consisting of hydrofluoric acid, nitric acid, and acetic acid (HNA), the pillars are progressively thinned, then shortened. The replicated polyethylene pillar arrays exhibit a corresponding increase in friction as the stiffness is reduced with thinning and then a decrease in friction as the stiffness is again increased. The dilution of the HNA bath in water influences the tapering angle of the silicon pillars. The friction of the replicated pillars is maximized for the taper angle that maximizes the contact area at the tip which in turn is influenced by the stiffness of the tapered pillars. To provide insights on how changes in microscale geometry and contact behavior may affect friction of the pillar array, the pillars are imaged by scanning electron microscopy after friction testing, and the observed deformation behavior from shearing is related to the magnitude of the macroscale friction values. It is shown that the tapering angle critically changes the pillar compliance and the available contact area. Simple finite element modeling calculations are performed to support that the observed deformation is consistent with what is expected from a mechanical analysis. We conclude that friction can be maximized via proper pillar tapering with low stiffness that still maintains enough contact area to ensure high adhesion. PMID- 24761945 TI - Graphene-wrapped polyaniline nanowire arrays on nitrogen-doped carbon fabric as novel flexible hybrid electrode materials for high-performance supercapacitor. AB - We report the synthesis of reduced graphene oxide (RGO) sheet wrapped polyaniline (PANI) nanowire arrays grown on nitrogen-doped carbon fiber cloth (eCFC). The RGO coating layer is important to accommodate volume change and mechanical deformation of the coated PANI nanowires arrays during the long-term charge/discharge processes. The resulting hierarchical symmetric supercapacitor based on RGO/PANI/eCFC composites shows an enhanced capacitive behavior with a maximum energy density of 25.4 Wh kg(-1), a maximum power density of 92.2 kW kg( 1) and a specific capacitance of 1145 F g(-1), which is higher than that of PANI/eCFC (1050 F g(-1)) and GO/PANI/eCFC (940 F g(-1)). Moreover, the assembled supercapacitor exhibits excellent charge/discharge rates and a good cycling stability, retaining over 94% of its initial capacitance after 5000 cycles. PMID- 24761944 TI - Pedestrian fatalities resulting from train-person collisions. AB - OBJECTIVE: Train-person collisions have a significant impact in our society, due to their negative economic and psychological effects. This work aims to study fatalities resulting from train-person collisions in Portugal. METHODS: A retrospective study was conducted based on the analysis of autopsy reports related to train-person fatalities performed in the North Branch of the National Institute of Legal Medicine and Forensic Sciences. RESULTS: Suicide was responsible for most of the cases, and males were more often involved in train person collisions than females. Victims, between 40 and 59 years old, were found to be involved in a high percentage (39%) of the cases, and people older than 65 accounted for a significant percentage (40%) of the accidents. No seasonality was observed in suicide cases, but a decrease in accident numbers was registered in summer. Regarding weekday and time of day, afternoon and non-rush hour were the times when most suicides were observed, whereas accidents did not showed a specific weekday or time of day, except for rush hour, during which they were more frequent. Alcohol-positive blood analysis accounting for 25% of the cases. CONCLUSIONS: Differences from other European studies were found, which may be related to the different cultures of the countries/regions, as well as to the differences in the railway systems. More extensive studies must be performed in order to develop strategies to prevent train-person collisions. PMID- 24761946 TI - Will your article be found? Authors choose a confusing variety of words to describe dental survival analyses. AB - OBJECTIVES: Identify the words and phrases that authors used to describe time-to event outcomes of dental treatments in patients. MATERIALS AND METHODS: A systematic handsearch of 50 dental journals with the highest Citation Index for 2008 identified articles reporting dental treatment with time-to-event statistics (included "case" articles, n = 95), without time-to-event statistics (active "control" articles, n = 91), and all other articles (passive "control" articles n = 6796). The included and active controls were read, identifying 43 English words across the title, aim and abstract, indicating that outcomes were studied over time. Once identified, these words were sought within the 6796 passive controls. Words were divided into six groups. Differences in use of words were analyzed with Pearson's chi-square across these six groups, and the three locations (title, aim, and abstract). RESULTS: In the abstracts, included articles used group 1 (statistical technique) and group 2 (statistical terms) more frequently than the active and passive controls (group 1: 35%, 2%, 0.37%, P < 0.001 and group 2: 31%, 1%, 0.06%, P < 0.001). The included and active controls used group 3 (quasi-statistical) equally, but significantly more often than the passive controls (82%, 78%, 3.21%, P < 0.001). In the aims, use of target words was similar for included and active controls, but less frequent for groups 1-4 in the passive controls (P < 0.001). In the title, group 2 (statistical techniques) and groups 3-5 (outcomes) were similar for included and active controls, but groups 2 and 3 were less frequent in the passive controls (P < 0.001). Significantly more included articles used group 6 words (stating the study duration) (54%, 30%, P = 0.001). CONCLUSION: All included articles used time-to-event analyses, but two thirds did not include words to highlight this in the abstract. There is great variation in the words authors used to describe dental time-to-event outcomes. Electronic identification of such articles would be inconsistent, with low sensitivity and specificity. Authors should improve the reporting quality. Journals should allow sufficient space in abstracts to summarize research, and not impose unrealistic word limits. Readers should be mindful of these problems when searching for relevant articles. Additional research is required in this field. PMID- 24761947 TI - Commentary on 'Is mini-mental score examination scoring a new predictor of uncontrolled hypertension?'. PMID- 24761948 TI - Epidemiology of infective endocarditis in a large Belgian non-referral hospital. AB - OBJECTIVES: Guidelines for diagnosis of infective endocarditis are largely based upon epidemiological studies in referral hospitals. Referral bias, however, might impair the validity of guidelines in non-referral hospitals. Recent studies in non-referral care centres on infective endocarditis are sparse. We conducted a retrospective epidemiological study on infective endocarditis in a large non referral hospital in a Belgian city (Kortrijk). METHODS: The medical record system was searched for all cases tagged with a putative diagnosis of infective endocarditis in the period 2003-2010. The cases that fulfilled the modified Duke criteria for probable or definite infective endocarditis were included. RESULTS: Compared to referral centres, an older population with infective endocarditis, and fewer predisposing cardiac factors and catheter-related infective endocarditis is seen in our population. Our patients have fewer prosthetic valve endocarditis as well as fewer staphylococcal endocarditis. Our patients undergo less surgery, although mortality rate seems to be highly comparable with referral centres, with nosocomial infective endocarditis as an independent predictor of mortality. CONCLUSION: The present study suggests that characteristics of infective endocarditis as well as associative factors might differ among non referral hospitals and referral hospitals. PMID- 24761949 TI - Importance of preoperative anaesthetic consultation in perioperative medicine. AB - This report describes two patients for whom the preoperative, anaesthetic consultation led to postponing planned surgery because of important, undiagnosed health problems. In one of the two cases, this consultation was even life-saving. However, actual literature cannot prove any advantage on the outcome of the individual patient. The only proven advantages in favour of pre-operative consultation are a reduced length of stay in the hospital and a reduction in the cost of preoperative testing. PMID- 24761950 TI - Isolation, purification, and structural features of a polysaccharide from Phellinus linteus and its hypoglycemic effect in alloxan-induced diabetic mice. AB - Phellinus linteus is a medicinal mushroom that has been used in Oriental countries for centuries for its antitumor, antioxidant, immunomodulatory, and biological activity on hyperglycemia. A water-soluble crude polysaccharide was extracted using hot water from P. linteus mycelia grown under submerged culture. An orthogonal experiment was used to optimize the extraction conditions of P. linteus mycelia polysaccharides (PLP). The crude polysaccharide was purified using DEAE Sephadex A-50 and Sephadex G-200 chromatography. Fourier transform infrared (FT-IR) spectroscopy and nuclear magnetic resonance ((1) H NMR) spectroscopy were used to investigate the structure of the purified P. linteus polysaccharide (PLP-I), revealing that it was mainly a branched-type glycan with both alpha- and beta-linkages and a pyranoid sugar ring conformation. PLP orally administered at 100 mg/kg body weight/d could significantly reduce the blood glucose level by 35.60% in alloxan-induced diabetic mice. The results of an oral glucose tolerance test (OGTT) revealed that PLP had an effect on glucose disposal after 28 d of treatment. The result revealed that PLP from a submerged culture of P. linteus mycelia possessed potent hypoglycemic properties. The polysaccharide may be useful as a functional food additive and a hypoglycemic agent. PMID- 24761951 TI - The power of partnerships: a message for all radiologists. PMID- 24761952 TI - Cardiac MR imaging to probe tissue composition of the heart by using T1 mapping. PMID- 24761953 TI - Radiation dose reduction in renal colic protocol CT: are we doing enough to ensure adoption of best practices? PMID- 24761954 TI - State of the art: dual-energy CT of the abdomen. AB - Recent technologic advances in computed tomography (CT)--enabling the nearly simultaneous acquisition of clinical images using two different x-ray energy spectra--have sparked renewed interest in dual-energy CT. By interrogating the unique characteristics of different materials at different x-ray energies, dual energy CT can be used to provide quantitative information about tissue composition, overcoming the limitations of attenuation-based conventional single energy CT imaging. In the past few years, intensive research efforts have been devoted to exploiting the unique and powerful opportunities of dual-energy CT for a variety of clinical applications. This has led to CT protocol modifications for radiation dose reduction, improved diagnostic performance for detection and characterization of diseases, as well as image quality optimization. In this review, the authors discuss the basic principles, instrumentation and design, examples of current clinical applications in the abdomen and pelvis, and future opportunities of dual-energy CT. PMID- 24761958 TI - Case 205: renal stone ileus. AB - History An 80-year-old woman presented to the on-call surgical team with a 2-day history of abdominal distention and vomiting. Clinical examination revealed a distended tympanic abdomen with generalized tenderness but no evidence of peritoneal signs at physical examination. Relevant surgical history included previous intervention for renal stones, cholecystectomy, and cardiovascular and respiratory comorbidities. Abdominal radiography was performed in the emergency department, and computed tomography (CT) was performed based on the radiographic findings. PMID- 24761959 TI - Is volumetric functional MR imaging superior to current anatomic imaging response criteria for hepatocellular carcinoma after intraarterial therapy? PMID- 24761961 TI - Jay J. Listinsky, MD, PhD. PMID- 24761962 TI - Christopher Michael McManus, MD. PMID- 24761965 TI - Acrylamide in roasted barley grains: presence, correlation with colour and decrease during storage. AB - We investigated the presence of acrylamide in roasted barley grains, and assessed the correlation between acrylamide concentration and colour, and also examined acrylamide decrease during storage. Acrylamide concentrations in 45 commercially available roasted barley grains were analysed. The mean and standard deviation were 0.24 and 0.08 mg kg(-1), respectively. The CIE colour parameter a* value had little correlation with acrylamide concentration in roasted barley grains; however, the L* and b* values showed correlations with acrylamide concentration in the grains, yielding a correlation coefficient of 0.42 and 0.40, respectively. Darker-coloured roasted barley grains with lower L* values may contain lower amounts of acrylamide. Although acrylamide concentration decreased by 40% in the grains, and decreased by 36% in the milled grains (teabag form) after 309 days of storage at room temperature a significant difference in the rate of acrylamide decrease was not observed between the grain and teabag forms. The data obtained in this study are of importance to the risk assessment and management of acrylamide exposure in Japan. PMID- 24761964 TI - Variation in allelic expression associated with a recombination hotspot in Zea mays. AB - Gene expression is a complex process, requiring precise spatial and temporal regulation of transcription factor activity; however, modifications of individual cis- and trans-acting modules can be molded by natural selection to create a sizeable number of novel phenotypes. Results from decades of research indicate that developmental and phenotypic divergence among eukaryotic organisms is driven primarily by variation in levels of gene expression that are dictated by mutations, either in structural or regulatory regions, of genes. The relative contributions and interplay of cis- and trans-acting regulatory factors to this evolutionary process, however, remain poorly understood. Analysis of eight genes in the Bz1-Sh1 interval of Zea mays (maize) indicates significant allele-specific expression biases in at least one tissue for all genes, ranging from 1.3-fold to 36-fold. All detected effects were cis-regulatory in nature, although genetic background may also influence the level of expression bias and tissue specificity for some allelic combinations. Most allelic pairs exhibited the same direction and approximate intensity of bias across all four tissues; however, a subset of allelic pairs show alternating dominance across different tissue types or variation in the degree of bias in different tissues. In addition, the genes showing the most striking levels of allelic bias co-localize with a previously described recombination hotspot in this region, suggesting a naturally occurring genetic mechanism for creating regulatory variability for a subset of plant genes that may ultimately lead to evolutionary diversification. PMID- 24761966 TI - Editorial comment to activity of axitinib in patients with metastatic renal cell carcinoma previously treated with both vascular endothelial growth factor receptor tyrosine-kinase inhibitor and mammalian target of rapamycin inhibitor. PMID- 24761967 TI - Fabrication of a flexible UV band-pass filter using surface plasmon metal-polymer nanocomposite films for promising laser applications. AB - We introduce a strategy for the fabrication of silver/polycarbonate (Ag/PC) nanocomposite flexible films of (20 +/- 0.01) MUm thickness with different filling factor of surface plasmon metal using customized solution cast-thermal evaporation method. Structural characterizations confirmed the good crystallinity with cubic phase of Ag nanoparticles in PC films. Moreover, the microstructural evolutions of nanocomposite films are investigated by transmission electron microscopy, which indicates that the metal fraction is in the form of fractals. Additionally, the surface plasmonic behavior of nanocomposite films has been explored in detail to examine the distribution of Ag nanoparticles in PC film by spectroscopic technique. Furthermore, the obtained transmittance spectral features of this nanocomposite film are suitable for the applications of band pass filter at 320 nm UV range, which is highly desirable for a HeCd laser. PMID- 24761968 TI - Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma: a multicentre phase II study. AB - There is a lack of published data examining non-cytotoxic options for the frontline treatment of patients with high-tumour burden (HTB) indolent non Hodgkin lymphoma (iNHL). We completed a multicentre phase II study for patients with untreated HTB iNHL (NCT00369707) consisting of three induction cycles of weekly bortezomib and rituximab followed by an abbreviated consolidation. Forty two patients were treated and all were evaluable; the most common histology was follicular lymphoma (FL) (n = 33, 79%). Patient characteristics included median age 62 years (40-86); 38% bulky disease; 19% malignant effusions; 91% advanced stage disease; and median FL International Prognostic Index (FLIPI) score was 3. Therapy was well tolerated with few grade 3/4 toxicities including minimal neurotoxicity. On intent-to-treat, the overall response rate (ORR) at end of therapy was 70% with a complete remission (CR) rate of 40% (FL: ORR 76%, CR 44%). With 50-month median follow-up, 4-year progression-free survival (PFS) was 44% with 4-year overall survival (OS) of 87% (FL: 44% and 97%, respectively). Four year PFS for FLIPI 0-2 vs. 3-5 was 60% vs. 26% respectively (P = 0.02), with corresponding OS rates of 92% and 81% respectively (P = 0.16). Collectively, bortezomib/rituximab is a non-cytotoxic therapeutic regimen that was well tolerated and resulted in long-term survival rates approximating prior rituximab/cytotoxic chemotherapy series for untreated HTB FL. PMID- 24761969 TI - Photonic crystal kinase biosensor. AB - We have developed a novel biosensor for kinases that is based on a kinase responsive polymer hydrogel, which enables label-free screening of kinase activity via changes in optical properties. The hydrogel is specifically designed to swell reversibly upon phosphorylation of a target peptide, triggering a change in optical diffraction from a crystalline colloidal array of particles impregnated into the hydrogel. Diffraction measurements, and charge staining, confirmed the responsive nature of the hydrogel. Moreover, the change in diffraction of the hydrogel upon treatment with kinase exhibited a time- and dose dependent response. A theoretical model for ionic polymer networks describes the observed optical response well and can be used to quantify the extent of phosphorylation. PMID- 24761970 TI - Time-domain T-wave alternans is strongly associated with a history of ventricular fibrillation in patients with Brugada syndrome. AB - AIMS: T-wave alternans (TWA) is an indicator of vulnerability to ventricular arrhythmias and is useful for predicting sudden cardiac death (SCD) in patients with various structural heart diseases. We evaluated whether high levels of time domain TWA on ambulatory ECG (AECG) are associated with a history of ventricular fibrillation (VF) in Brugada syndrome (BrS) patients. METHODS AND RESULTS: We examined the associations among VF history, family history of SCD, spontaneous type 1 electrocardiogram (ECG), late potentials, VF induction by programmed electrical stimulation, and TWA in 45 BrS patients (44 males; mean age, 45 +/- 15 years). TWA analyzed from 24-h AECG recordings using the modified moving average method was positive in 13 of 43 patients (30%). Patients with a history of VF had a significantly higher incidence of a positive TWA test (82% vs. 13%; P < 0.001) and spontaneous type 1 ECG (92% vs. 38%; P = 0.007) than those without VF history. Multivariate analysis indicated that positive TWA (OR 7.217; 95% CI 2.503-35.504; P = 0.002) and spontaneous type 1 ECG (OR 5.530; 95% CI 1.651 34.337; P = 0.020) were closely associated with VF history. Spontaneous type 1 ECG had high sensitivity (92%) but low specificity (63%). Positive TWA was a reliable marker with high sensitivity and specificity (82% and 88%, respectively). CONCLUSION: Elevated time-domain TWA on AECG confirms arrhythmia risk in symptomatic BrS patients without the need for provocative stimuli. PMID- 24761971 TI - Tolerance to acetic acid is improved by mutations of the TATA-binding protein gene. AB - Screening a library of overexpressing mutant alleles of the TATA-binding gene SPT15 yielded two Saccharomyces cerevisiae strains (MRRC 3252 and 3253) with enhanced tolerance to acetic acid. They were also tolerant to propionic acid and hydrogen peroxide. Transcriptome profile analysis identified 58 upregulated genes and 106 downregulated genes in MRRC 3252. Stress- and protein synthesis-related transcription factors were predominantly enriched in the upregulated and downregulated genes respectively. Eight deletion mutants for some of the highly downregulated genes were acetic acid-tolerant. The level of intracellular reactive oxygen species was considerably lessened in MRRC 3252 and 3253 upon exposure to acetic acid. Metabolome profile analysis revealed that intracellular concentrations of 5 and 102 metabolites were increased and decreased, respectively, in MRRC 3252, featuring a large increase of urea and a significant decrease of amino acids. The dur1/2Deltamutant, in which the urea degradation gene DUR1/2 is deleted, displayed enhanced tolerance to acetic acid. Enhanced tolerance to acetic acid was also observed on the medium containing a low concentration of amino acids. Taken together, this study identified two SPT15 alleles, nine gene deletions and low concentration of amino acids in the medium that confer enhanced tolerance to acetic acid. PMID- 24761973 TI - Slow research: thoughts for a movement in global health. PMID- 24761972 TI - Microfluidic bead suspension hopper. AB - Many high-throughput analytical platforms, from next-generation DNA sequencing to drug discovery, rely on beads as carriers of molecular diversity. Microfluidic systems are ideally suited to handle and analyze such bead libraries with high precision and at minute volume scales; however, the challenge of introducing bead suspensions into devices before they sediment usually confounds microfluidic handling and analysis. We developed a bead suspension hopper that exploits sedimentation to load beads into a microfluidic droplet generator. A suspension hopper continuously delivered synthesis resin beads (17 MUm diameter, 112,000 over 2.67 h) functionalized with a photolabile linker and pepstatin A into picoliter-scale droplets of an HIV-1 protease activity assay to model ultraminiaturized compound screening. Likewise, trypsinogen template DNA-coated magnetic beads (2.8 MUm diameter, 176,000 over 5.5 h) were loaded into droplets of an in vitro transcription/translation system to model a protein evolution experiment. The suspension hopper should effectively remove any barriers to using suspensions as sample inputs, paving the way for microfluidic automation to replace robotic library distribution. PMID- 24761974 TI - The politics and anti-politics of infectious disease control. PMID- 24761975 TI - The politics and anti-politics of the global fund experiment: understanding partnership and bureaucratic expansion in Uganda. AB - After a decade of operations, the Global Fund is an institutional form in flux. Forced to cancel its eleventh round of funding due to a shortfall in donor pledges, the Fund is currently in firefighting mode, overhauling its leadership, governance structures, and operations. Drawing on a case study of Uganda, we look at how the original Global Fund vision to be a simple financial instrument has played out at the country level. Even prior to the cancellation of round 11, the proliferation of partners required to sustain the Global Fund to Fight AIDS, Tuberculosis and Malaria experiment led to increasing bureaucratization and an undermining of the Fund's own intentions to award life-saving grants according to need. Understanding these effects through the ethnographic material presented here may be one way of reflecting on the Fund's structure and practices as it struggles to reinvent itself in the face of criticism that it has impeded resource distribution. PMID- 24761976 TI - De-politicizing parasites: reflections on attempts to control the control of neglected tropical diseases. AB - Large amounts of funding are being allocated to the control of neglected tropical diseases. Strategies primarily rely on the mass distribution of drugs to adults and children living in endemic areas. The approach is presented as morally appropriate, technically effective, and context-free. Drawing on research undertaken in East Africa, we discuss ways in which normative ideas about global health programs are used to set aside social and biological evidence. In particular, there is a tendency to ignore local details, including information about actual drug take up. Ferguson's 'anti-politics' thesis is a useful starting point for analyzing why this happens, but is overly deterministic. Anti-politics discourse about healing the suffering poor may shape thinking and help explain cognitive dissonance. However, use of such discourse is also a means of strategically promoting vested interests and securing funding. Whatever the underlying motivations, rhetoric and realities are conflated, with potentially counterproductive consequences. PMID- 24761977 TI - Epidemics and the politics of knowledge: contested narratives in Egypt's H1N1 response. AB - This article explores the politics of knowledge involved in understanding and responding to epidemics in an era of global health governance and biosecurity. It develops and applies an approach focused on how multiple, competing narratives about epidemics are constructed, mobilized and interact, and selectively justify pathways of intervention and response. A detailed ethnographic case study of national and local responses to H1N1 influenza, so-called swine flu, in Egypt reveals how global narratives were reworked by powerful actors in a particular political context, suppressing and delegitimizing the alternative narratives of the Zabaleen (Coptic Christian) people whose lives and livelihoods centered on raising pigs and working with them to control urban waste. The case study illustrates important ways in which geographies and politics of blame around epidemics emerge and are justified, their political contexts and consequences, and how they may feed back to shape the dynamics of disease itself. PMID- 24761978 TI - Fetal age determination through biparietal diameter: a simple method of cranial reconstruction using multipurpose silicone. AB - In forensic medicine, gestational age of fetal remains is a crucial information in several contests, but the classic methods are inadequate when early gestational age needs to be assessed. In the author's experience, the measurement of the biparietal diameter provides more accurate information for this purpose. The status of the fetal head is therefore critical. This work describes an easy technique that allows to reconstruct the cranial volume of the fetus using multipurpose silicone given both the flexibility of the fetal head structure and the inorganic nature of the silicone itself. In conclusion, the determination of the biparietal diameter achieved through the above-described technique permitted a more accurate estimation of the dating of pregnancy in judicial cases where the fetal remains were incomplete and disrupted. PMID- 24761979 TI - CD45RA-Foxp3high but not CD45RA+Foxp3low suppressive T regulatory cells increased in the peripheral circulation of patients with head and neck squamous cell carcinoma and correlated with tumor progression. AB - BACKGROUND: T regulatory cells (Tregs) contribute to the progression of head and neck squamous cell carcinoma (HNSCC) by suppressing antitumor immunity. However, little is known regarding the functional heterogeneity of Tregs in HNSCC patients. METHODS: Using multicolor flow cytometry, the frequency of three Treg subsets, separated on the basis of CD45RA and Foxp3, from the peripheral circulation of newly-presenting HNSCC patients (19 oral cavity squamous cell carcinoma, 20 hypopharyngeal squamous cell carcinoma, 18 nasopharyngeal squamous cell carcinoma, 19 oropharyngeal squamous cell carcinoma, and 36 laryngeal squamous cell carcinoma) were assessed with regard to 31 healthy donors and clinicopathological features. Moreover, the functional capacity of each Treg subsets was evaluated based on CD45RA and CD25 expression. RESULTS: The frequency of Tregs in the peripheral circulation of HNSCC patients as a whole cohort was higher than in healthy donors (P < 0.0001). However, the frequency of Tregs was similar between patients with oral cavity squamous cell carcinoma and healthy donors (P = 0.269). Further dividing Tregs into three subsets based on Foxp3 and CD45RA expression revealed that the frequency of CD45RA-Foxp3high Tregs and CD45RA-Foxp3lowCD4+ T cells in patients with HNSCC developing from different subsites was higher than in healthy donors (P < 0.0001, P < 0.0001), whereas the frequency of CD45RA+Foxp3low Tregs was lower than in healthy donors (P < 0.0001). Functionally study revealed that CD45RA-CD25+++ Tregs significantly inhibit the proliferation of CD4+CD25- T cells (P < 0.001) and secrete lower levels of cytokines (P < 0.01) compared with CD45RA-CD25++CD4+ T cells. Importantly, the frequency of CD45RA-Foxp3high Tregs positively correlate with tumor stage (P < 0.0001) and nodal status (P < 0.0001). CONCLUSIONS: CD45RA-Foxp3high Tregs increase in the peripheral circulation of HNSCC patients, and correlate with tumor stage and nodal status; suggesting a role in tumor progression which may be manipulated by future immunotherapy. PMID- 24761980 TI - Successful treatment with L-asparaginase-based regimen for primary pulmonary NK/T cell lymphoma: a case report and review of the literature. AB - OBJECTIVE: To evaluate the treatment of primary pulmonary NK/T cell lymphoma. METHOD: A case report and review of the literature. The tissue material was obtained by transbronchial biopsy, and the diagnosis was confirmed by pathology. He received five cycles of chemotherapy with L-asparaginase-based regimen. RESULT: He remained complete remission for 2 years following the initial diagnosis. CONCLUSION: Primary pulmonary NK/T cell lymphoma is an aggressive disease. It is usually associated with poor outcome in the literature. L asparaginase based regimen was effective for our newly diagnosed patient. PMID- 24761981 TI - Phenytoin and sodium valproate but not levetiracetam induce bone alterations in female mice. AB - Adverse effects on the bone are amongst the potentially adverse clinical consequences with antiepileptic drugs (AEDs). This study compared the effects of 3 AEDs (phenytoin (PHT), sodium valproate (SVP), and levetiracetam (LTM)) on the bones of a Swiss strain of albino female mice. Drugs were administered daily for 4 months at doses that produced plasma concentrations corresponding to the clinically relevant therapeutic ranges. PHT and SVP (but not LTM) significantly lowered the bone mineral density (BMD) of lumbar vertebrae (L2-L4) as evaluated by dual-energy X-ray absorptiometry (DEXA) scan. The findings were supported by histopathology of vertebral (lumbar) bone and analysis of bone turnover markers. While both PHT and SVP reduced alkaline phosphatase (ALP) and hydroxyproline (HxP) in lumbar vertebrae, and elevated tartarate-resistant acid phosphatase (TRAP) and urinary excretion of calcium, LTM did not affect any of these markers of bone turnover, indicating that the drug might be a safer option in female epileptic patients prone to bone changes. PMID- 24761983 TI - Additional benefit of combined therapy with melatonin and apoptotic adipose derived mesenchymal stem cell against sepsis-induced kidney injury. AB - This study tested whether combined therapy with melatonin and apoptotic adipose derived mesenchymal stem cells (A-ADMSCs) offered additional benefit in ameliorating sepsis-induced acute kidney injury. Adult male Sprague-Dawley rats (n = 65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal-ligation and puncture (CLP), CLP-melatonin, CLP-A-ADMSC, and CLP melatonin-A-ADMSC. Circulating TNF-alpha level at post-CLP 6 hr was highest in CLP and lowest in SC groups, higher in CLP-melatonin than in CLP-A-ADMSC and CLP melatonin-A-ADMSC groups (all P < 0.001). Immune reactivity as reflected in the number of splenic helper-, cytoxic-, and regulatory-T cells at post-CLP 72 hr exhibited the same pattern as that of circulating TNF-alpha among all groups (P < 0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP melatonin than in CLP-A-ADMSC and CLP-melatonin-A-ADMSC groups, and higher in CLP A-ADMSC than in CLP-melatonin-A-ADMSC groups (all P < 0.001). Changes in protein expressions of inflammatory (RANTES, TNF-1alpha, NF-kappaB, MMP-9, MIP-1, IL 1beta), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF-beta) markers, reactive-oxygen-species (NOX-1, NOX-2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all P < 0.001). Expressions of antioxidants (GR+, GPx+, HO-1, NQO 1+) were lowest in SC group and highest in CLP-melatonin-A-ADMSC group, lower in CLP than in CLP-melatonin and CLP-A-ADMSC groups, and lower in CLP-melatonin- than in CLP-A-ADMSC-tretaed animals (all P < 0.001). In conclusion, combined treatment with melatonin and A-ADMSC was superior to A-ADMSC alone in protecting the kidneys from sepsis-induced injury. PMID- 24761984 TI - Is mini-mental score examination scoring a new predictor of uncontrolled hypertension? AB - Essential hypertension is an important risk factor for target organ damage. The brain is among the target organs infrequently visited. The authors evaluated whether an abnormal Mini-Mental Score Examination (MMSE) score predicts uncontrolled hypertension even if office blood pressure is normal. Seventy-seven hypertensive patients were included. The cognitive function of each patient was assessed using MMSE and a customized brain magnetic resonance imaging study. Patients were classified into normal cognitive function group and mild, moderate, and severe cognitive impairment groups. A significance level of P=.05 was used. There was a higher percentage of uncontrolled BP in every cognitive impairment class. In patients older than 65 years, MMSE score had a sensitivity and specificity of 94% and 83%, respectively, in the prediction of uncontrolled hypertension. MMSE is a simple test to run in the clinic to predict whether patients have well-controlled blood pressure. PMID- 24761982 TI - Follow-up in healthy schoolchildren and in adolescents with Down syndrome: psycho environmental and genetic determinants of physical activity and its impact on fitness, cardiovascular diseases, inflammatory biomarkers and mental health; the UP&DOWN study. AB - BACKGROUND: An objective diagnosis of sedentary behaviour as well as of the physical activity and fitness levels in youth and to better understand how lifestyle is associated with cardiovascular disease risk factors and other phenotypes is of clinical and public health interest, and might be informative for developing intervention studies focused on the promotion of physical activity in these population. The aim of this methodological paper is to describe the design and assessment in the UP&DOWN study. METHODS/DESIGN: The UP&DOWN study is a multi-center follow-up design where 2225 Spanish primary and secondary schoolchildren from Cadiz and Madrid, respectively, as well as 110 Spanish adolescents with Down syndrome from Madrid and Toledo were recruited to be assessed. Nine main measurement categories are assessed: i) socio-demographic and early determinants; ii) environmental determinants; iii) physical activity and sedentary behaviour; iv) health-related fitness; v) blood pressure and resting heart rate; vi) mental health; vii) dietary patterns; viii) blood samples; and ix) genetic analysis. During the 3-yr follow-up study, socio-demographic and early determinants, and genetic analysis are only assessed in the first year. Blood sampling is assessed in the first year and the third year (2nd follow-up), and all the other measurements are assessed every year. DISCUSSION: The findings of the UP&DOWN study may help the Health Information Systems and policy makers to identify the target population for primary prevention and health promotion policies, and to develop and test preventive strategies. Moreover, these data will allow following the trends at population level, as well as to modify/adapt/create new evidence-based physical activity guidelines at national level. The findings will also serve as a scientific platform for interventional studies. PMID- 24761986 TI - Weight and body mass index (BMI): current data for Austrian boys and girls aged 4 to under 19 years. AB - BACKGROUND: BMI reference charts are widely used to diagnose overweight, obesity and underweight in children and adolescents. AIM: To provide up-to-date national reference values for Austria. METHODS: A cross-sectional sample of over 14 500 children and adolescents (4-19 years) stratified by provinces according to age- and sex-specific population proportions was drawn via schooling institutions (kindergartens, schools and vocational colleges). The generalized additive models for location, scale and shape were used for a flexible estimation of percentile curves. RESULTS: Austrian boys and girls have higher average weight compared with previous prevalence data. BMI centiles matching BMI values at age 18 years, which are used for defining thinness, overweight and obesity in adults, were calculated. In Austria, using reference values as thresholds, ~18% of boys and 12% of girls are overweight (with thresholds passing through BMI 25.00-29.99 kg/m(2) in adults) and 5% of boys and 3% of girls are obese (with thresholds passing through BMI >=30.00 kg/m(2) in adults). CONCLUSION: Overweight and obesity are common in Austria and their prevalence is increasing (using the same IOTF reference for international comparison). Up-to-date national BMI reference values are provided to classify children and adolescents according to the proposed overweight and obesity thresholds. PMID- 24761985 TI - Barriers to mental health service use among distressed family caregivers of lung cancer patients. AB - Although family caregivers of patients with lung and other cancers show high rates of psychological distress, they underuse mental health services. This qualitative study aimed to identify barriers to mental health service use among 21 distressed family caregivers of lung cancer patients. Caregivers had not received mental health services during the patient's initial months of care at a comprehensive cancer centre in New York City. Thematic analysis of interview data was framed by Andersen's model of health service use and Corrigan's stigma theory. Results of our analysis expand Andersen's model by providing a description of need variables (e.g. psychiatric symptoms), enabling factors (e.g. finances), and psychosocial factors associated with caregivers' non-use of mental health services. Regarding psychosocial factors, caregivers expressed negative perceptions of mental health professionals and a desire for independent management of emotional concerns. Additionally, caregivers perceived a conflict between mental health service use and the caregiving role (e.g. prioritising the patient's needs). Although caregivers denied stigma associated with service use, their anticipated negative self-perceptions if they were to use services suggest that stigma may have influenced their decision to not seek services. Findings suggest that interventions to improve caregivers' uptake of mental health services should address perceived barriers. PMID- 24761987 TI - Epidemiology of systemic mastocytosis in Denmark. AB - Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of mast cells. Systemic mastocytosis (SM), in which abnormal mast cells are present in tissues beyond the skin, is divided into seven subcategories with varying degrees of severity and prognosis. Very little is known about the epidemiology of SM and its subcategories. This retrospective cohort study of 548 adults with SM diagnosed 1997-2010 was constructed using linked Danish national health registries. The most common subtype of mastocytosis was indolent SM (including urticaria pigmentosa) (n = 450; 82%), followed by SM with subtype unknown (n = 61; 11%), SM with associated clonal haematological non-mast cell lineage disease (n = 24; 4%), aggressive SM (n = 8; 2%), and mast cell leukaemia (n = 5; 1%). The incidence rate for SM (all subtypes including urticaria pigmentosa) was 0.89 per 100 000 per year. Cumulative incidence was 12.46 per 100 000, and the 14-year limited-duration prevalence as of 1 January, 2011 was 9.59 per 100 000. This nationwide cohort from Denmark is the first population-based epidemiological study of mastocytosis. In this cohort of patients aged 15 years and older, SM was found to be overall relatively rare with notable variation by subtype for patient characteristics, survival and epidemiological measures. PMID- 24761988 TI - Disseminated Scedosporium prolificans infection in an 'extensive metaboliser': navigating the minefield of drug interactions and pharmacogenomics. AB - We report a case of non-fatal disseminated Scedosporium prolificans infection, including central nervous system disease and endophthalmitis, in a relapsed acute myeloid leukaemia patient with extensive CYP2C19 metabolism. Successful treatment required aggressive surgical debridement, three times daily voriconazole dosing and cimetidine CYP2C19 inhibition. In addition, the unique use of miltefosine was employed due to azole-chemotherapeutic drug interactions. Prolonged survival following disseminated S. prolificans, adjunctive miltefosine and augmentation of voriconazole exposure with cimetidine CYP2C19 inhibition has not been reported. PMID- 24761989 TI - Studies of (-)-pironetin binding to alpha-tubulin: conformation, docking, and molecular dynamics. AB - A comprehensive conformational analysis for the anticancer agent pironetin (1) was achieved by molecular modeling using density functional theory calculations at the B3PW91/DGTZVP level in combination with calculated and experimental (1)H (1)H coupling constants comparison. Two solvent-dependent conformational families (L and M) were revealed for the optimum conformations. Docking studies of the pironetin-tubulin complex determined a quantitative model for the hydrogen-bond interactions of pironetin through the alphaAsn249, alphaAsn258, and alphaLys352 amino groups in alpha-tubulin, which supported the formation of a covalent adduct between the alphaLys352 and the beta carbon atom of the alpha,beta-unsaturated lactone. Saturation-transfer difference NMR spectroscopy confirmed that pironetin binds to tubulin, while molecular dynamics exposed a distortion of the tubulin secondary structure at the H8 and H10 alpha-helices as well as at the S9 beta sheet, where alphaLys352 is located. A large structural perturbation in the M loop geometry between the alphaIle274 and alphaLeu285 residues, an essential region for molecular recognition between alpha-alpha and beta-beta units of protofilaments, was also identified and provided a rationale for the pironetin inhibitory activity. PMID- 24761990 TI - Compliance work for food contact materials: feasibility of the legally required safety assessment of an epoxy/amine-based coating for domestic water pipe restoration. AB - Options were explored for fulfilling the legally required safety assessment for a widely applied epoxy/amine coating used for restoring corroded domestic drinking water supply systems. The coating was made up of two components mixed shortly before application, the first mainly consisting of bisphenol A diglycidyl ether (BADGE), the second of various amines. The analytically identified starting substances were all authorised, but only constituted a small proportion of the low molecular mass material left after curing and potentially migrating into water. Reaction products synthesised from constituents of the starting components (expected oligomers) could not be eluted from GC even after derivatisation, indicating that standard GC-MS screening would miss most potential migrants. They were detectable by size exclusion chromatography (SEC) after acetylation. HPLC with MS or fluorescence detection was possible for constituents including a BADGE moiety, but phenalkamines could not be detected with adequate sensitivity. Possibilities for determining long-term migration relevant for chronic toxicity are discussed. Analysis in water shortly after application of the coating overestimates migration if migration decreases over time and requires detection limits far out of reach. Analysis of a solvent extract of the coating is easier and provides an upper estimate of what could migrate into the drinking water over the years. However, to satisfy the regulatory requirements, components of the complex mixture need to be identified at lower proportions than those accessible. In vitro testing of the whole mixture for genotoxicity is expected to fail because of the required sensitivity and the glycidyl functions probably wrongly resulting in positive tests. The difficulties in dealing with this situation are discussed. PMID- 24761991 TI - Genetic diversity of the unicellular nitrogen-fixing cyanobacteria UCYN-A and its prymnesiophyte host. AB - Symbiotic interactions between nitrogen-fixing prokaryotes and photosynthetic eukaryotes are an integral part of biological nitrogen fixation at a global scale. One of these partnerships involves the cyanobacterium UCYN-A, which has been found in partnership with an uncultivated unicellular prymnesiophyte alga in open-ocean and coastal environments. Phylogenetic analysis of the UCYN-A nitrogenase gene (nifH) showed that the UCYN-A lineage is represented by three distinct clades, referred to herein as UCYN-A1, UCYN-A2 and UCYN-A3, which appear to have overlapping and distinct geographic distributions. The relevance of UCYN A's genetic diversity to its symbiosis and ecology was explored through combining flow cytometric cell sorting and molecular techniques to determine the host identity, nifH expression patterns and host cell size of one newly discovered clade, UCYN-A2, at a coastal site. UCYN-A2 nifH expression peaked during daylight hours, which is consistent with expression patterns of the UCYN-A1 clade in the open ocean. However, the cell size of the UCYN-A2 host was significantly larger than UCYN-A1 and host, suggesting adaptation to different environmental conditions. Like the UCYN-A1 host, the UCYN-A2 host was closely related to the genus Braarudosphaera; however, the UCYN-A1 and UCYN-A2 host rRNA sequences clustered into two distinct clades suggesting co-evolution of symbiont and host. PMID- 24761992 TI - Safe and effective means of detecting and quantitating Shiga-like toxins in attomole amounts. AB - Shiga-like toxins (verotoxins) are a class of AB5 holotoxins that are primarily responsible for the virulence associated with Shiga-like toxin producing Escherichia coli (STEC) infections. The holotoxins are composed of a pentamer of identical subunits (B subunit) responsible for delivering the catalytic subunit (A subunit) to a host cell and facilitating endocytosis of the toxin into the cell. The B subunits are not associated with toxicity. We developed a multiple reaction monitoring method based on analyzing conserved peptides, derived from the tryptic digestion of the B subunits. Stable-isotope-labeled analogues were prepared and used as internal standards to identify and quantify these characteristic peptides. We were able to detect and quantify Shiga toxins (Stx), Shiga-like toxin type 1 (Stx1) and type 2 (Stx2) subtypes, and to distinguish among most of the known subtypes. The limit of detection for digested pure standards was in the low attomole range/injection (~10 attomoles), which corresponded to a concentration of 1.7 femtomol/mL. A matrix effect was observed when dilute samples were digested in the buffer, Luria broth, or mouse plasma (LOD ~ 30 attomol/injection = 5 femtomol/mL). In addition, we determined that the procedures necessary to perform our mass spectrometry-based analysis completely inactivate the toxins present in the sample. This is a safe and effective method of detecting and quantitating Stx, Stx1, and Stx2, since it does not require the use of intact toxins. PMID- 24761993 TI - Renal dysfunction and clinical outcomes of patients undergoing ICD and CRTD implantation: data from the Israeli ICD registry. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy (CRT) reduce mortality in patients with heart failure (HF) and left ventricular dysfunction. However, their efficacy in patients with chronic kidney disease (CKD) is controversial. OBJECTIVE: We examined the association between renal dysfunction and clinical outcomes in patients undergoing ICD and CRT defibrillator (CRTD) implantation. METHODS: Data were collected from the Israeli ICD registry. Estimated glomerular filtration rate (eGFR) at implantation was assessed using the modification of diet in renal disease formula. Primary outcome was all-cause mortality. Secondary outcomes included the composite endpoints of death or HF and death or ventricular arrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]); any hospitalizations; first appropriate and inappropriate ICD therapy. RESULTS: During the study period (July 2010-November 2012), 2,811 patients were implanted with ICD or CRTD. One-year follow-up data were available for 730 ICD patients and 453 CRTD patients. Patients with eGFR < 30 mL/minute/1.73 m(2) (n = 54, 4.6%) were older, had a higher prevalence of diabetes, hypertension, or ischemic heart disease. eGFR <30 mL/minute/1.73 m(2) was associated with increased mortality risk in ICD (HR 5.4; 95% CI 1.5-19.2), but not in CRTD patients (HR 0.9; 95% CI 0.1-7.5). Renal dysfunction was associated with the composite endpoints of death or HF and death or VT/VF in ICD, but not in CRTD patients. Mean eGFR during follow-up decreased by 8.0 +/- 4.3 mL/minute/1.73 m(2) in ICD patients (P = 0.06) and by 1.8 +/- 1.3 mL/minute/1.73 m(2) in patients with CRTD (P = 0.2). CONCLUSION: Based on this retrospective analysis, CKD is associated with adverse prognosis after ICD implantation, but not after CRTD implantation. GFR decreased in patients with ICD, but not in CRTD patients. PMID- 24761994 TI - Efficient water oxidation using nanostructured alpha-nickel-hydroxide as an electrocatalyst. AB - Electrochemical water splitting is a clean technology that can store the intermittent renewable wind and solar energy in H2 fuels. However, large-scale H2 production is greatly hindered by the sluggish oxygen evolution reaction (OER) kinetics at the anode of a water electrolyzer. Although many OER electrocatalysts have been developed to negotiate this difficult reaction, substantial progresses in the design of cheap, robust, and efficient catalysts are still required and have been considered a huge challenge. Herein, we report the simple synthesis and use of alpha-Ni(OH)2 nanocrystals as a remarkably active and stable OER catalyst in alkaline media. We found the highly nanostructured alpha-Ni(OH)2 catalyst afforded a current density of 10 mA cm(-2) at a small overpotential of a mere 0.331 V and a small Tafel slope of ~42 mV/decade, comparing favorably with the state-of-the-art RuO2 catalyst. This alpha-Ni(OH)2 catalyst also presents outstanding durability under harsh OER cycling conditions, and its stability is much better than that of RuO2. Additionally, by comparing the performance of alpha-Ni(OH)2 with two kinds of beta-Ni(OH)2, all synthesized in the same system, we experimentally demonstrate that alpha-Ni(OH)2 effects more efficient OER catalysis. These results suggest the possibility for the development of effective and robust OER electrocatalysts by using cheap and easily prepared alpha-Ni(OH)2 to replace the expensive commercial catalysts such as RuO2 or IrO2. PMID- 24761995 TI - Simultaneous determination of seven constituents in Si-Ni-San decoction and a compatibility comparison study using HPLC-UV. AB - A simple and accurate HPLC-UV method was developed for simultaneous determination of seven constituents in Si-Ni-San decoction. Separation was performed on a Hypersil C18 column and detection was set with gradient wavelength at 240 nm (0 26 min) and 210 nm (26-30 min). The mobile phase consisted of 0.03% phosphoric acid in water (v/v), and acetonitrile was used with a flow rate of 1.0 (- 1). This method provides good linearity (r>0.9992), precision (RSD < 1.9%), repeatability (RSD < 2.9%), stability (RSD < 2.9%) and recovery (97.6-102.0%), which has been successfully applied to quantitative determination of the seven constituents in Si-Ni-San decoction and different compatibility groups. PMID- 24761996 TI - Scalable spheroid model of human hepatocytes for hepatitis C infection and replication. AB - Developing effective new drugs against hepatitis C (HCV) virus has been challenging due to the lack of appropriate small animal and in vitro models recapitulating the entire life cycle of the virus. Current in vitro models fail to recapitulate the complexity of human liver physiology. Here we present a method to study HCV infection and replication on spheroid cultures of Huh 7.5 cells and primary human hepatocytes. Spheroid cultures are constructed using a galactosylated cellulosic sponge with homogeneous macroporosity, enabling the formation and maintenance of uniformly sized spheroids. This facilitates easy handling of the tissue-engineered constructs and overcomes limitations inherent of traditional spheroid cultures. Spheroids formed in the galactosylated cellulosic sponge show enhanced hepatic functions in Huh 7.5 cells and maintain liver-specific functions of primary human hepatocytes for 2 weeks in culture. Establishment of apical and basolateral polarity along with the expression and localization of all HCV specific entry proteins allow for a 9-fold increase in viral entry in spheroid cultures over conventional monolayer cultures. Huh 7.5 cells cultured in the galactosylated cellulosic sponge also support replication of the HCV clone, JFH (Japanese fulminant hepatitis)-1 at higher levels than in monolayer cultures. The advantages of our system in maintaining liver-specific functions and allowing HCV infection together with its ease of handling make it suitable for the study of HCV biology in basic research and pharmaceutical R&D. PMID- 24761997 TI - IL-32 was involved in cigarette smoke-induced pulmonary inflammation in COPD. AB - PURPOSE: Previous study has proven the overexpression of interleukin 32 (IL-32) in lungs with chronic obstructive pulmonary disease (COPD). But the soluble IL-32 levels and the role of IL-32 in smokers and COPD are still unclear. METHODS: In this study, we enrolled 133 subjects who were divided into three groups: nonsmokers, control smokers and smokers with COPD. We detected the IL-32 levels in serum and induced sputum of all subjects. The pulmonary function, PaO2 and smoking exposure index were also collected. Moreover, macrophages were isolated and stimulated by cigarette smoke extraction (CSE). A special siRNA was used to suppress the IL-32 expression. RESULTS: There was no significant difference in IL 32 serum levels among the three groups. The IL-32 levels of induced sputum in COPD patients were markedly higher than control smokers and nonsmokers. The IL-32 levels in induced sputum of COPD patients were negatively correlated with forced expiratory volume (FEV1)/forced vital capacity and FEV1%. Moreover, a low concentration CSE could stimulate IL-32 expression and promote the release of several inflammatory factors (such as IL-6 and tumor necrosis factor-alpha). A special siRNA could significantly suppress the release of these inflammatory factors. CONCLUSIONS: This study revealed the critical role of IL-32 in pulmonary inflammation of COPD and smoker-associated diseases. PMID- 24761999 TI - Privacy and confidentiality: perspectives of mental health consumers and carers in pharmacy settings. AB - OBJECTIVES: The study aims to explore within the community pharmacy practice context the views of mental health stakeholders on: (1) current and past experiences of privacy, confidentiality and support; and (2) expectations and needs in relation to privacy and confidentiality. METHODS: In-depth interviews and focus groups were conducted in three states in Australia, namely Queensland, the northern region of New South Wales and Western Australia, between December 2011 and March 2012. KEY FINDINGS: There were 98 participants consisting of consumers and carers (n = 74), health professionals (n = 13) and representatives from consumer organisations (n = 11). Participants highlighted a need for improved staff awareness. Consumers indicated a desire to receive information in a way that respects their privacy and confidentiality, in an appropriate space. Areas identified that require improved protection of privacy and confidentiality during pharmacy interactions were the number of staff having access to sensitive information, workflow models causing information exposure and pharmacies' layout not facilitating private discussions. Challenges experienced by carers created feelings of isolation which could impact on care. CONCLUSIONS: This study explored mental health stakeholders' experiences and expectations regarding privacy and confidentiality in the Australian community pharmacy context. A need for better pharmacy staff training about the importance of privacy and confidentiality and strategies to enhance compliance with national pharmacy practice requirements was identified. Findings provided insight into privacy and confidentiality needs and will assist in the development of pharmacy staff training material to better support consumers with sensitive conditions. PMID- 24761998 TI - Macrophagic and microglial responses after focal traumatic brain injury in the female rat. AB - BACKGROUND: After central nervous system injury, inflammatory macrophages (M1) predominate over anti-inflammatory macrophages (M2). The temporal profile of M1/M2 phenotypes in macrophages and microglia after traumatic brain injury (TBI) in rats is unknown. We subjected female rats to severe controlled cortical impact (CCI) and examined the postinjury M1/M2 time course in their brains. METHODS: The motor cortex (2.5 mm left laterally and 1.0 mm anteriorly from the bregma) of anesthetized female Wistar rats (ages 8 to 10 weeks; N = 72) underwent histologically moderate to severe CCI with a 5-mm impactor tip. Separate cohorts of rats had their brains dissociated into cells for flow cytometry, perfusion fixed for immunohistochemistry (IHC) and ex vivo magnetic resonance imaging or flash-frozen for RNA and protein analysis. For each analytical method used, separate postinjury times were included for 24 hours; 3 or 5 days; or 1, 2, 4 or 8 weeks. RESULTS: By IHC, we found that the macrophagic and microglial responses peaked at 5 to 7 days post-TBI with characteristics of mixed populations of M1 and M2 phenotypes. Upon flow cytometry examination of immunological cells isolated from brain tissue, we observed that peak M2-associated staining occurred at 5 days post-TBI. Chemokine analysis by multiplex assay showed statistically significant increases in macrophage inflammatory protein 1alpha and keratinocyte chemoattractant/growth-related oncogene on the ipsilateral side within the first 24 hours after injury relative to controls and to the contralateral side. Quantitative RT-PCR analysis demonstrated expression of both M1- and M2 associated markers, which peaked at 5 days post-TBI. CONCLUSIONS: The responses of macrophagic and microglial cells to histologically severe CCI in the female rat are maximal between days 3 and 7 postinjury. The response to injury is a mixture of M1 and M2 phenotypes. PMID- 24762000 TI - Impairment of pulmonary vascular reserve and right ventricular systolic reserve in pulmonary arterial hypertension. AB - BACKGROUND: Exercise capacity is impaired in pulmonary arterial hypertension (PAH). We hypothesized that cardiovascular reserve abnormalities would be associated with impaired hemodynamic response to pharmacological stress and worse outcome in PAH. METHODS: Eighteen PAH patients (p) group 1 NYHA class II/III and ten controls underwent simultaneous right cardiac catheterization and intravascular ultrasound at rest and during low dose-dobutamine (10 mcg/kg/min) with trendelenburg (DST). We estimated cardiac output (CO), pulmonary vascular resistance (PVR) and capacitance (PC), and PA elastic modulus (EM). We concomitantly measured tricuspid annular plane systolic excursion (TAPSE), RV myocardial peak systolic velocity (Sm) and isovolumic myocardial acceleration (IVA) in PAH patients. Based on the rounded mean + 2 SD of the increase in mPAP in our healthy control group during DST (2.8 + 1.8 mm Hg), PAH p were divided into two groups according to mean PA pressure (mPAP) response during DST, 1: DeltamPAP > 5 mm Hg and 2: DeltamPAP <= 5 mm Hg. Cardiovascular reserve was estimated as the change (delta, Delta) during DST compared with rest, including DeltamPAP with respect to DeltaCO (DeltamPAP/DeltaCO). All patients were prospectively followed up for 2 years. RESULTS: PAH p showed significant lower heart rate and CO increase than controls during DST, with a significant mPAP and pulse PAP increase and higher DeltamPAP/DeltaCO (p < 0.05). Neither hemodynamic, IVUS and echocardiographic data were different between both PAH groups at rest. In group 1, DST caused a higher DeltaEM, DeltamPAP/DeltaCO, DeltaPVR, and DeltaTAPSE than group 2, with a lower IVA increase and a negative DeltaSV (p < 0.05). TAPSE correlated with mPAP and RVP (p < 0.05) and, IVA and Sm correlated with CO (p < 0.05). DeltaEM correlated with DeltamPAP and DeltaIVA with DeltaCO (p < 0.05). There were two deaths/pulmonary transplantations in group 1 and one death in group 2 during the follow-up (p > 0.05). CONCLUSIONS: Pulmonary vascular reserve and RV systolic reserve are significantly impaired in patients with PAH. The lower recruitable cardiovascular reserve is significantly related to a worse hemodynamic response to DST and it could be associated with a poor clinical outcome. PMID- 24762002 TI - Midwives and nonmedically indicated induction of labor. PMID- 24762003 TI - Relative quantification in imaging of a peptide on a mouse brain tissue by matrix assisted laser desorption ionization. AB - It is well-known that the number of analyte ions generated by matrix-assisted laser desorption ionization (MALDI) is not directly proportional to the analyte concentration at the irradiated spot. This is an obstacle to acquiring quantitatively meaningful maps for materials in a tissue by MALDI imaging. The problem worsens as the matrix suppression due to contaminants in the sample increases. In this work, we use a peptide as an example and show that we can overcome this problem by utilizing three guidelines derived from our recent studies on the generation of reproducible MALDI spectra. First is to acquire MALDI spectra under a temperature-controlled condition. Second is to keep the matrix suppression below an experimentally determined limit, and the third is to construct the image map using the peptide-to-matrix ion abundance ratio rather than the peptide ion abundance. The strategy works well for contaminated tissue samples and generates quantitatively meaningful maps. Also, it is demonstrated that a preposterous map can be generated when the peptide ion abundance is used in the construction of the map. PMID- 24762004 TI - Bile-induced peptidoglycan remodelling in Salmonella enterica. AB - Changes in the peptidoglycan (PG) structure of Salmonella enterica are detected in the presence of a sublethal concentration of sodium deoxycholate (DOC): (i) lower proportions of Braun lipoprotein (Lpp)-bound muropeptides; (ii) reduced levels of muropeptides cross-linked by L(meso)-diaminopimelyl-D(meso) diaminopimelic acid (L-D) peptide bridges (3-3 cross-links). Similar structural changes are found in S. enterica cultures adapted to grow in the presence of a lethal concentration of DOC, suggesting that reduced anchoring of Braun protein to PG and low occurrence of 3-3 cross-links may increase S. enterica resistance to bile. This view is further supported by additional observations: (i) A triple mutant lacking L,D-transpeptidases YbiS, ErfK, and YcfS, which does not contain Lpp anchored to PG, is hyper-resistant to bile; (ii) enhanced 3-3 cross-linking upon overexpression of YnhG transpeptidase causes a decrease in bile resistance. These observations suggest that remodelling of the cell wall may be added to the list of adaptive responses that permit survival of S. enterica in the presence of bile. PMID- 24762006 TI - Abstracts of the 18th Annual Meeting of French Society of Pharmacology and Therapeutics, 81th Annual Meeting of Society of Physiology, 35th Pharmacovigilance Meeting, 15th APNET Seminar, 12th CHU CIC Meeting and 9th Annual Meeting of Physiology, Pharmacology and Therapeutics, 22-24 April 2014, Poitiers, France. PMID- 24762005 TI - Regional difference of optimal contact force to prevent acute pulmonary vein reconnection during radiofrequency catheter ablation for atrial fibrillation. AB - BACKGROUND: Regional differences in optimal contact force (CF) to prevent acute pulmonary vein reconnection (APVR) during catheter ablation for atrial fibrillation (AF) remain unclear. OBJECTIVE: The purpose of this study was to evaluate regional difference in optimal CF during AF ablation. METHODS: This single-center observational study evaluated data from 57 consecutive drug refractory AF patients (mean age, 62 +/- 11 years; 43 males) who underwent initial pulmonary vein isolation (PVI) using the THERMOCOOL(r) SMARTTOUCHTM (Biosense Webster, Diamond Bar, CA, USA) catheter from June to August 2013. APVR was defined as the time-dependent reconnection >20 minutes after initial PVI and/or reconnection evoked by intravenous adenosine administration (20 mg). Point by-point relationships between the reconnected points and their CF values were evaluated. RESULTS: Total 72 gaps causing APVR were observed. Of a total of 4,421 ablation points, 285 (6.4%) were associated with APVR. The average CF value of the points with APVR was significantly lower than that of those without (APVR vs. no APVR; 7.5 +/- 6.7 g vs. 9.9 +/- 8.4 g; P < 0.0001). The areas under the curve and optimal CF values differed between segments (range 0.593-0.761 and 10-22 g, respectively). The optimal CF value was highest in bottom of the right PV and posterosuperior right PV segments (22 g) and lowest in posteroinferior right PV segment (10 g). CONCLUSIONS: There was a regional difference in optimal CF values to prevent APVR, and the optimal CF value to prevent APVR with >95% probability was 10-22 g, depending on the individual peri-PV segments. PMID- 24762001 TI - Functional plasticity of the N/OFQ-NOP receptor system determines analgesic properties of NOP receptor agonists. AB - Despite high sequence similarity between NOP (nociceptin/orphanin FQ opioid peptide) and opioid receptors, marked differences in endogenous ligand selectivity, signal transduction, phosphorylation, desensitization, internalization and trafficking have been identified; underscoring the evolutionary difference between NOP and opioid receptors. Activation of NOP receptors affects nociceptive transmission in a site-specific manner, with antinociceptive effects prevailing after peripheral and spinal activation, and pronociceptive effects after supraspinal activation in rodents. The net effect of systemically administered NOP receptor agonists on nociception is proposed to depend on the relative contribution of peripheral, spinal and supraspinal activation, and this may depend on experimental conditions. Functional expression and regulation of NOP receptors at peripheral and central sites of the nociceptive pathway exhibits a high degree of plasticity under conditions of neuropathic and inflammatory pain. In rodents, systemically administered NOP receptor agonists exerted antihypersensitive effects in models of neuropathic and inflammatory pain. However, they were largely ineffective in acute pain while concomitantly evoking severe motor side effects. In contrast, systemic administration of NOP receptor agonists to non-human primates (NHPs) exerted potent and efficacious antinociception in the absence of motor and sedative side effects. The reason for this species difference with respect to antinociceptive efficacy and tolerability is not clear. Moreover, co-activation of NOP and MU opioid peptide (MOP) receptors synergistically produced antinociception in NHPs. Hence, both selective NOP receptor as well as NOP/MOP receptor agonists may hold potential for clinical use as analgesics effective in conditions of acute and chronic pain. PMID- 24762007 TI - Effect of fuel and kiln type on the polycyclic aromatic hydrocarbon (PAH) levels in smoked shrimp, a Beninese food condiment. AB - Smoked shrimp is a food condiment widely used in Beninese local cooking practices. A previous study revealed that this product is highly contaminated with polycyclic aromatic hydrocarbons (PAH). The present study explored possibilities to reduce PAH levels in shrimp smoked using cottage industry smoking techniques with barrel and chorkor kilns, by replacing wood by charcoal from Acacia auriculiformis and Mangifera indica, as fuels. Results showed that only shrimp smoked using acacia charcoal in a chorkor kiln had PAH levels (benzo[a]pyrene = 5 ug kg(-1) and sum of benzo[a]pyrene, chrysene, benzo[a]anthracene and benzo[b]fluoranthene = 28 ug kg(-1)) in accordance with a European standard of 5 and 30 ug kg(-1), respectively, and suitable physicochemical characteristics for good storage (moisture content = 11.9% +/- 1.5%; water activity = 0.46 +/- 0.03). However, further investigations still needs to be done to reduce the duration of product contact with combustion gasses in order to reduce the PAH content of smoked shrimp to safer levels, largely below standards. PMID- 24762009 TI - QSARs for aquatic toxicity: celebrating, extending and displaying the pioneering contributions of Ferguson, Konemann and Veith. AB - Significant advances were made in the development of quantitative structure activity relationships (QSARs) relating molecular structure to aquatic toxicity by three studies over 30 years ago by Ferguson in 1939, Konemann in 1981, and Veith and colleagues in 1983. We revisit the original concepts and data from these studies and review these contributions from the bases of current perspectives on the hypothesized mechanism of baseline narcotic toxicity and the underlying thermodynamic and kinetic aspects. The relationships between LC50, octanol-water partition coefficient, aqueous solubility, chemical activity and chemical volume fraction in lipid phases are outlined including kinetic influences on measured toxicities. These relationships provide a compelling and plausible explanation of the success of these and other QSARs for aquatic toxicity. Suggestions are made for further advances in these QSARs to improve assessments of toxicity by baseline narcotic toxicity and selective modes of action, especially using emerging quantum chemical computational capabilities. PMID- 24762008 TI - Monoterpene glycoside ESK246 from Pittosporum targets LAT3 amino acid transport and prostate cancer cell growth. AB - The L-type amino acid transporter (LAT) family consists of four members (LAT1-4) that mediate uptake of neutral amino acids including leucine. Leucine is not only important as a building block for proteins, but plays a critical role in mTORC1 signaling leading to protein translation. As such, LAT family members are commonly upregulated in cancer in order to fuel increased protein translation and cell growth. To identify potential LAT-specific inhibitors, we established a function-based high-throughput screen using a prefractionated natural product library. We identified and purified two novel monoterpene glycosides, ESK242 and ESK246, sourced from a Queensland collection of the plant Pittosporum venulosum. Using Xenopus laevis oocytes expressing individual LAT family members, we demonstrated that ESK246 preferentially inhibits leucine transport via LAT3, while ESK242 inhibits both LAT1 and LAT3. We further show in LNCaP prostate cancer cells that ESK246 is a potent (IC50 = 8.12 MUM) inhibitor of leucine uptake, leading to reduced mTORC1 signaling, cell cycle protein expression and cell proliferation. Our study suggests that ESK246 is a LAT3 inhibitor that can be used to study LAT3 function and upon which new antiprostate cancer therapies may be based. PMID- 24762010 TI - Measurement tools for the diagnosis of nasal septal deviation: a systematic review. AB - OBJECTIVE: To perform a systematic review of measurement tools utilized for the diagnosis of nasal septal deviation (NSD). METHODS: Electronic database searches were performed using MEDLINE (from 1966 to second week of August 2013), EMBASE (from 1966 to second week of August 2013), Web of Science (from 1945 to second week of August 2013) and all Evidence Based Medicine Reviews Files (EBMR); Cochrane Database of Systematic Review (CDSR), Cochrane Central Register of Controlled Trials (CCTR), Cochrane Methodology Register (CMR), Database of Abstracts of Reviews of Effects (DARE), American College of Physicians Journal Club (ACP Journal Club), Health Technology Assessments (HTA), NHS Economic Evaluation Database (NHSEED) till the second quarter of 2013. The search terms used in database searches were 'nasal septum', 'deviation', 'diagnosis', 'nose deformities' and 'nose malformation'. The studies were reviewed using the updated Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. RESULTS: Online searches resulted in 23 abstracts after removal of duplicates that resulted from overlap of studies between the electronic databases. An additional 15 abstracts were excluded due to lack of relevance. A total of 8 studies were systematically reviewed. CONCLUSIONS: Diagnostic modalities such as acoustic rhinometry, rhinomanometry and nasal spectral sound analysis may be useful in identifying NSD in anterior region of the nasal cavity, but these tests in isolation are of limited utility. Compared to anterior rhinoscopy, nasal endoscopy, and imaging the above mentioned index tests lack sensitivity and specificity in identifying the presence, location, and severity of NSD. PMID- 24762011 TI - H5-based DNA constructs derived from selected highly pathogenic H5N1 avian influenza virus induce high levels of humoral antibodies in Muscovy ducks against low pathogenic viruses. AB - BACKGROUND: H5 low pathogenic avian influenza virus (LPAIV) infection in domestic ducks is a major problem in duck producing countries. Their silent circulation is an ongoing source of potential highly pathogenic or zoonotic emerging strains. To prevent such events, vaccination of domestic ducks might be attempted but remains challenging. Currently licensed vector vaccines derived from H5N1 HPAIV possess clade 0, clade 2.2 or clade 2.3.4 HA sequences: selection of the best HA candidate inducing the largest cross protection is a key issue. For this purpose, DNA immunization of specific pathogen free Muscovy ducks was performed using different synthetic codon optimized (opt) or native HA genes from H5N2 LPAIV and several H5N1 HPAIV clade 2.1, 2.2.1 and 2.3.4. Humoral cross-immunity was assessed 3 weeks after boost by hemagglutination inhibition (HI) and virus neutralization (VN) against three French H5 LPAIV antigens. FINDINGS: Vaccination with LP H5N2 HA induced the highest VN antibody titre against the homologous antigen; however, the corresponding HI titre was lower and comparable to HI titres obtained after immunization with opt HA derived from clades 2.3.4 or 2.1. Compared to the other HPAIV-derived constructs, vaccination with clade 2.3.4 opt HA consistently induced the highest antibody titres in HI and VN, when tested against all three H5 LPAIV antigens and H5N2 LPAIV, respectively: differences in titres against this last strain were statistically significant. CONCLUSION: The present study provides a standardized method to assess cross-immunity based on HA immunogenicity alone, and suggests that clade 2.3.4-derived recombinant vaccines might be the optimal candidates for further challenge testing to vaccinate domestic Muscovy ducks against H5 LPAIV. PMID- 24762013 TI - Evaluation of thromboelastography for prediction of clinical bleeding in thrombocytopenic dogs after total body irradiation and hematopoietic cell transplantation. AB - OBJECTIVE: To determine whether thromboelastography is more accurate than conventional methods of evaluating hemostasis for the prediction of clinical bleeding in thrombocytopenic dogs following total body irradiation (TBI) and bone marrow transplantation (BMT). ANIMALS: 10 client-owned thrombocytopenic dogs with multicentric lymphoma. PROCEDURES: Results of a kaolin-activated thromboelastography assay, platelet count, and buccal mucosal bleeding time were evaluated for correlation to clinical bleeding. RESULTS: Maximum amplitude, derived via thromboelastography, was the only hemostatic variable with significant correlation to clinical bleeding. Buccal mucosal bleeding time had a high sensitivity but poor specificity for identifying dogs with clinical bleeding. CONCLUSIONS AND CLINICAL RELEVANCE: Compared with buccal mucosal bleeding time and platelet count, thromboelastography was more reliable at identifying thrombocytopenic dogs with a low risk of bleeding and could be considered to help guide the use of transfusion products in dogs undergoing TBI and BMT. PMID- 24762014 TI - Gross anatomy of the deep perivertebral musculature in horses. AB - OBJECTIVE: To determine the gross morphology of the multifidus, longus colli, and longus thoracis muscles in the cervical and cranial thoracic portions of the equine vertebral column. SAMPLE: 15 horse cadavers. PROCEDURES: The vertebral column was removed intact from the first cervical vertebra (C1) to the seventh thoracic vertebra (T7). After removing the superficial musculature, detailed anatomic dissections of the multifidus, longus colli, and longus thoracis muscles were performed. RESULTS: The multifidus cervicis muscle consisted of 5 bundles/level arranged in lateral, medial, and deep layers from C2 caudally into the thoracic portion of the vertebral column. Fibers in each bundle attached cranially to a spinous process then diverged laterally, attaching caudally on the dorsolateral edge of the vertebral lamina and blending into the joint capsule of an articular process articulation after crossing 1 to 4 intervertebral joints. The longus colli muscle had ventral, medial, and deep layers with 5 bundles/level from C1 to C5 that attached cranially to the ventral surface of the vertebral body, diverged laterally and crossed 1 to 4 intervertebral joints, then attached onto a vertebral transverse process as far caudally as C6. The longus thoracis muscle consisted of a single, well-defined muscle belly from C6 to T5-T6, with intermediate muscular attachments onto the ventral aspects of the vertebral bodies, the intervertebral symphyses, and the craniomedial aspects of the costovertebral joint capsules. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that there were multiple, short bundles of the multifidus cervicis, multifidus thoracis, and longus colli muscles; this was consistent with a function of providing sagittal plane intersegmental vertebral column stability. PMID- 24762015 TI - Pharmacokinetics of dexmedetomidine after intravenous administration of a bolus to cats. AB - OBJECTIVE: To characterize the pharmacokinetics of dexmedetomidine after IV administration of a bolus to conscious healthy cats. ANIMALS: 5 healthy adult spayed female cats. PROCEDURES: Dexmedetomidine was administered IV as a bolus at 3 doses (5, 20, or 50 MUg/kg) on separate days in a random order. Blood samples were collected immediately before and at various times for 8 hours after drug administration. Plasma dexmedetomidine concentrations were determined with liquid chromatography-mass spectrometry. Compartment models were fitted to the concentration-time data by means of nonlinear regression. RESULTS: A 2 compartment model best fit the concentration-time data after administration of 5 MUg/kg, whereas a 3-compartment model best fit the data after administration of 20 and 50 MUg/kg. The median volume of distribution at steady-state and terminal half-life were 371 mL/kg (range, 266 to 435 mL/kg) and 31.8 minutes (range, 30.3 to 39.7 minutes), respectively, after administration of 5 MUg/kg; 545 mL/kg (range, 445 to 998 mL/kg) and 56.3 minutes (range, 39.3 to 68.9 minutes), respectively, after administration of 20 MUg/kg; and 750 mL/kg (range, 514 to 938 mL/kg) and 75.3 minutes (range, 52.2 to 223.3 minutes), respectively, after administration of 50 MUg/kg. CONCLUSIONS AND CLINICAL RELEVANCE: The pharmacokinetics of dexmedetomidine was characterized by a small volume of distribution and moderate clearance and had minimal dose dependence within the range of doses evaluated. These data will help clinicians design dosing regimens once effective plasma concentrations are established. PMID- 24762016 TI - Relationship between plasma dexmedetomidine concentration and sedation score and thermal threshold in cats. AB - OBJECTIVE: To characterize the relationship between plasma dexmedetomidine concentration and the temperature difference between the thermal threshold and skin temperature (DeltaT) and between plasma dexmedetomidine concentration and sedation score in healthy cats. ANIMALS: 5 healthy adult spayed female cats. PROCEDURES: Cats received IV administrations of saline (0.9% NaCl) solution, dexmedetomidine (5, 20, or 50 MUg/kg), or acepromazine (0.1 mg/kg). Blood samples were collected and thermal threshold and sedation score were determined before and at various times up to 8 hours after drug administration. In addition, cats received an IV infusion of dexmedetomidine that targeted a concentration achieving 99% of the maximum effect on DeltaT. RESULTS: No change in DeltaT over time was found for the saline solution and acepromazine treatments; DeltaT increased for 45 minutes when cats received dexmedetomidine at 5 and 20 MUg/kg and for 180 minutes when cats received dexmedetomidine at 50 MUg/kg. No change in sedation score over time was found for saline solution. Sedation score increased for 120 minutes after cats received acepromazine and for 60, 120, and 180 minutes after cats received dexmedetomidine at 5, 20, and 50 MUg/kg, respectively. The plasma dexmedetomidine concentration-effect relationships for the effect on DeltaT and sedation score were almost identical. The plasma dexmedetomidine concentration after infusion was lower than targeted, and DeltaT was not significantly affected. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine administration to cats resulted in thermal analgesia and also profound sedation. These data may be useful for predicting the course of thermal analgesia and sedation after dexmedetomidine administration to cats. PMID- 24762017 TI - Pharmacokinetics of subcutaneous versus intramuscular administration of ceftiofur crystalline-free acid to bearded dragons (Pogona vitticeps). AB - OBJECTIVE: To compare pharmacokinetics after a single IM or SC injection of ceftiofur crystalline-free acid (CCFA) to bearded dragons (Pogona vitticeps). ANIMALS: 8 adult male bearded dragons. PROCEDURES: In a preliminary experiment, doses of 15 and 30 mg/kg, SC, were compared in 2 animals, and 30 mg/kg resulted in a more desirable pharmacokinetic profile. Then, in a randomized, complete crossover experimental design, each bearded dragon (n = 6) received a single dose of 30 mg of CCFA/kg IM or SC; the experiment was repeated after a 28-day washout period with the other route of administration. Blood samples were collected at 10 time points for 288 hours after injection. Plasma concentrations of ceftiofur and desfuroylceftiofur metabolites were measured via reverse-phase high-performance liquid chromatography. Data were analyzed with a noncompartmental model. RESULTS: No adverse effects were observed. Plasma concentrations greater than a target minimum inhibitory concentration of 1 MUg/mL were achieved by 4 hours after administration by both routes. Mean plasma concentrations remained > 1 MUg/mL for > 288 hours for both routes of administration. CONCLUSIONS AND CLINICAL RELEVANCE: A single dose of CCFA (30 mg/kg) administered IM or SC to bearded dragons yielded plasma concentrations of ceftiofur and its metabolites > 1 MUg/mL for > 288 hours. The SC route would be preferred because of less variability in plasma concentrations and greater ease of administration than the IM route. Future studies should include efficacy data as well as evaluation of the administration of multiple doses. PMID- 24762018 TI - Effects of tylosin administration on C-reactive protein concentration and carriage of Salmonella enterica in pigs. AB - OBJECTIVE: To evaluate the effects of tylosin on C-reactive protein concentration, carriage of Salmonella enterica, and antimicrobial resistance genes in commercial pigs. ANIMALS: 120 pigs on 2 commercial farms. PROCEDURES: A cohort of sixty 10-week-old pigs in 4 pens/farm (15 pigs/pen) was randomly selected. Equal numbers of pigs were given feed containing tylosin (40 MUg/g of feed) for 0, 6, or 12 weeks. C-reactive protein concentrations were measured, microbial culture for S enterica in feces was performed, and antimicrobial resistance genes in feces were quantified. RESULTS: No significant associations were detected between C-reactive protein concentration or S enterica status and tylosin treatment. During the 12 weeks of tylosin administration, increased levels of 6 antimicrobial resistance genes did not occur. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment of pigs with tylosin did not affect C-reactive protein concentration or reduce carriage or load of S enterica. There was no evidence that pigs receiving tylosin had increased carriage of the 6 antimicrobial resistance genes measured. IMPACT FOR HUMAN MEDICINE: S enterica is a public health concern. Use of the antimicrobial growth promoter tylosin did not pose a public health risk by means of increased carriage of S enterica. PMID- 24762019 TI - Description of thoracoscopy and associated short-term cardiovascular and pulmonary effects in healthy cattle. AB - OBJECTIVE: To describe the optimal thoracoscopic approach to the bovine pleural cavity and evaluate the short-term effects of thoracoscopy on cardiovascular and pulmonary function of healthy cattle. SAMPLE: 6 healthy adult Holstein cows (12 hemithoraxes). PROCEDURES: For each cow, thoracoscopy was performed in both the left and right hemithoraxes with a 24-hour interval between procedures. Cows were sedated and restrained in a standing position for each thoracoscopic examination. Examination of each hemithorax lasted for 30 minutes. Arterial blood gas variables, heart rate, and respiratory rate were assessed at predetermined times before, during, and after the procedures to monitor cardiovascular and pulmonary function. Thoracic ultrasonography was performed immediately and at 24 hours and 1 week after each thorascopic examination to evaluate the extent of residual pneumothorax. RESULTS: Insertion of the laparoscope into the pleural cavity at the ninth intercostal space 15 cm ventral to the transverse processes of the thoracic vertebrae provided optimal visibility of structures in both the left and right hemithoraxes. Most structures of the pleural cavity were equally visible from both sides except the esophagus and the dorsal branch of the vagus nerve, which were best observed in the left hemithorax, and the pericardium, which was best observed in the right hemithorax. Mild increases in heart and respiratory rates and moderate decreases in arterial oxygen saturation and Pao2 were detected during the procedures. CONCLUSIONS AND CLINICAL RELEVANCE: Standing thoracoscopy was well tolerated in healthy adult dairy cattle and needs to be evaluated in cattle with pulmonary disease. PMID- 24762020 TI - Accuracy of noninvasive, single-plane fluoroscopic analysis for measurement of three-dimensional femorotibial joint poses in dogs. AB - OBJECTIVE: To compare accuracy of a noninvasive single-plane fluoroscopic technique with radiostereometric analysis (RSA) for determining 3-D femorotibial poses in a canine cadaver with normal stifle joints. SAMPLE: Right pelvic limb from a 25-kg adult mixed-breed dog. PROCEDURES: A CT scan of the limb was obtained before and after metal beads were implanted into the right femur and tibia. Orthogonal fluoroscopic images of the right stifle joint were acquired to simulate a biplanar fluoroscopic acquisition setup. Images were obtained at 5 flexion angles from 110 degrees to 150 degrees to simulate a gait cycle; 5 cycles were completed. Joint poses were calculated from the biplanar images by use of RSA with CT-derived beaded bone models and compared with measurements obtained by use of CT-derived nonbeaded bone models matched to single-plane, lateral-view fluoroscopic images. Single-plane measurements were performed by 2 observers and repeated 3 times by the primary observer. RESULTS: Mean absolute differences between the single-plane fluoroscopic analysis and RSA measurements were 0.60, 1.28, and 0.64 mm for craniocaudal, proximodistal, and mediolateral translations, respectively, and 0.63 degrees , 1.49 degrees , and 1.58 degrees for flexion-extension, abduction-adduction, and internal-external rotations, respectively. Intra- and interobserver repeatability was strong with maximum mean translational and rotational SDs of 0.52 mm and 1.36 degrees , respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that single-plane fluoroscopic analysis performed by use of CT-derived bone models is a valid, noninvasive technique for accurately measuring 3-D femorotibial poses in dogs. PMID- 24762021 TI - Accuracy of noninvasive, single-plane fluoroscopic analysis for measurement of three-dimensional femorotibial joint poses in dogs treated by tibial plateau leveling osteotomy. AB - OBJECTIVE: To compare accuracy of a noninvasive single-plane fluoroscopic analysis technique with radiostereometric analysis (RSA) for determining 3-D femorotibial poses in a canine cadaver stifle joint treated by tibial-plateau leveling osteotomy (TPLO). SAMPLE: Left pelvic limb from a 25-kg adult mixed breed dog. PROCEDURES: A CT scan of the left pelvic limb was performed. The left cranial cruciate ligament was transected, and a TPLO was performed. Radiopaque beads were implanted into the left femur and tibia, and the CT scan was repeated. Orthogonal fluoroscopic images of the left stifle joint were acquired at 5 stifle joint flexion angles ranging from 110 degrees to 150 degrees to simulate a gait cycle; 5 gait cycles were completed. Joint poses were calculated from the biplanar images by use of a digitally modified RSA and were compared with measurements obtained by use of hybrid implant-bone models matched to lateral view fluoroscopic images. Single-plane measurements were performed by 2 observers and repeated 3 times by the primary observer. RESULTS: Mean absolute differences between results of the single-plane fluoroscopic analysis and modified RSA were 0.34, 1.05, and 0.48 mm for craniocaudal, proximodistal, and mediolateral translations, respectively, and 0.56 degrees , 0.85 degrees , and 1.08 degrees for flexion-extension, abduction-adduction, and internal-external rotations, respectively. Intraobserver and interobserver mean SDs did not exceed 0.59 mm for all translations and 0.93 degrees for all rotations. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that single-plane fluoroscopic analysis by use of hybrid implant-bone models may be a valid, noninvasive technique for accurately measuring 3-D femorotibial poses in dogs treated with TPLO. PMID- 24762022 TI - Comparison of tear pH in dogs, horses, and cattle. AB - OBJECTIVE: To determine baseline tear pH in dogs, horses, and cattle by use of a microelectrode. ANIMALS: 28 dogs, 24 horses, and 29 cattle. PROCEDURES: Under manual restraint, tears were collected from each subject's left eye with cotton spears. A Schirmer tear test was performed in the right eye. Tears were extracted from the spears by centrifugation. Tear volume was measured, pH was determined with a microelectrode, and total solids (TS) concentration was measured by refractometry. RESULTS: Mean +/- SD pH of tears in cattle, dogs, and horses was 8.32 +/- 0.14, 8.05 +/- 0.26, and 7.84 +/- 0.30, respectively. Tear pH was significantly higher in cattle versus dogs and horses and in dogs versus horses. Mean +/- SD TS concentration in horses, cattle, and dogs was 2.04 +/- 1.29 g/dL, 1.07 +/- 0.60 g/dL, and 0.33 +/- 0.18 g/dL, respectively. Total solids concentration was significantly higher in horses versus cattle and dogs and in cattle versus dogs. Schirmer tear test results for all animals were within the species reference range. CONCLUSIONS AND CLINICAL RELEVANCE: Tear pH in all 3 species differed from that of published blood pH values and the pH of common topically administered ophthalmic medications. These fndings may have implications for variations in ocular flora and defense mechanisms, susceptibility to ocular disease, and success or comfort of topical treatment. PMID- 24762024 TI - Mechanical properties of various suture materials and placement patterns tested with surrogate in vitro model constructs simulating laryngeal advancement tie forward procedures in horses. AB - OBJECTIVE: To compare the mechanical properties of laryngeal tie-forward (LTF) surrogate constructs prepared with steel fixtures and No. 5 braided polyester or braided polyethylene by use of a standard or a modified suture placement technique. SAMPLE: 32 LTF surrogate constructs. PROCEDURES: Surrogate constructs were prepared with steel fixtures and sutures (polyester or polyethylene) by use of a standard or modified suture placement technique. Constructs underwent single load-to-failure testing. Maximal load at failure, elongation at failure, stiffness, and suture breakage sites were compared among constructs prepared with polyester sutures by means of the standard (n = 10) or modified (10) technique and those prepared with polyethylene sutures with the standard (6) or modified (6) technique. RESULTS: Polyethylene suture constructs had higher stiffness, higher load at failure, and lower elongation at failure than did polyester suture constructs. Constructs prepared with the modified technique had higher load at failure than did those prepared with the standard technique for both suture materials. All sutures broke at the knot in constructs prepared with the standard technique. Sutures broke at a location away from the knot in 13 of 16 constructs prepared with the modified technique (3 such constructs with polyethylene sutures broke at the knot). CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested LTF surrogate constructs prepared with polyethylene sutures or the modified technique were stronger than those prepared with polyester sutures or the standard technique. PMID- 24762025 TI - Efficacy of a flexible schedule for administration of a Leptospira borgpetersenii serovar Hardjo bacterin to beef calves. AB - OBJECTIVE: To determine whether a flexible vaccination regimen provides protection against challenge exposure with a virulent Leptospira borgpetersenii serovar Hardjo isolate. ANIMALS: Fifty-five 4-week-old calves seronegative for antibodies against L borgpetersenii serovar Hardjo. PROCEDURES: Calves were assigned to 3 groups and administered 2 doses of adjuvant (control calves; n = 11), 1 dose of serovar Hardjo bacterin and 1 dose of adjuvant (22), or 2 doses of the serovar Hardjo bacterin (22); there was a 16-week interval between dose administrations. Three weeks after the second dose, all calves were challenge exposed by use of conjunctival instillation of a heterologous strain of L borgpetersenii serovar Hardjo for 3 consecutive days. Urine samples for leptospiral culture were collected for 5 weeks after challenge exposure; at that time, all calves were euthanized and kidney samples collected for leptospiral culture. RESULTS: Antibody titers increased in both leptospiral-vaccinated groups of calves. A significant increase in antibody titers against L borgpetersenii serovar Hardjo was detected after administration of the second dose of L borgpetersenii serovar Hardjo bacterin and challenge exposure. In 10 of 11 adjuvant-treated control calves, serovar Hardjo was isolated from both urine and kidney samples. Leptospira borgpetersenii serovar Hardjo was not isolated from the urine or kidney samples obtained from any of the 21 remaining calves that received 1 dose of bacterin or the 20 remaining calves that received 2 doses of bacterin. CONCLUSIONS AND CLINICAL RELEVANCE: Protection in young calves was induced by vaccination with 1 or 2 doses of a serovar Hardjo bacterin. PMID- 24762026 TI - Efficacy of a multifactorial intervention on therapeutic adherence in patients with chronic obstructive pulmonary disease (COPD): a randomized controlled trial. AB - BACKGROUND: Therapeutic adherence of patients with chronic obstructive pulmonary disease (COPD) is poor. This study evaluated the effectiveness of a multifactorial intervention on improving the therapeutic adherence in chronic obstructive pulmonary disease (COPD) patients with scheduled inhalation therapy. METHODS: The study design consisted of a randomised controlled trial in a primary care setting. 146 patients diagnosed with COPD were randomly allocated into two groups using the block randomisation technique. One-year follow-ups with three visits were performed. The intervention consisted of motivational aspects related to adherence (beliefs and behaviour) in the form of group and individual interviews, cognitive aspects in the form of information about the illness and skills in the form of training in inhalation techniques. Cognitive-emotional aspects and training in inhalation techniques were reinforced during all visits of the intervention group. The main outcome measure was adherence to the medication regimen. Therapeutic adherence was determined by the percentage of patients classified as good adherent as evaluated by dose or pill count. RESULTS: Of the 146 participants (mean age 69.8 years, 91.8% males), 41.1% reported adherence (41.9% of the control group and 40.3% of the intervention group). When multifactorial intervention was applied, the reported adherence was 32.4% for the control group and 48.6% for the intervention group, which showed a statistically significant difference (p = 0.046). Number needed to treat is 6.37. In the intervention group, cognitive aspects increased by 23.7% and skilled performance of inhalation techniques increased by 66.4%. The factors related to adherence when multifactorial intervention was applied were the number of exacerbations (OR = 0.66), visits to health centre (OR = 0.93) and devices (OR = 2.4); illness severity (OR = 0.67), beta-2-adrenergic (OR = 0.16) and xantine (OR = 0.19) treatment; activity (OR = 1.03) and impact (OR = 1.03) scales of the Saint George Respiratory Questionnaire. CONCLUSION: Application of the multifactorial intervention designed for this study (COPD information, dose reminders, audio visual material, motivational aspects and training in inhalation techniques) resulted in an improvement in therapeutic adherence in COPD patients with scheduled inhalation therapy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18841601. PMID- 24762028 TI - Freeing Pseudomonas putida KT2440 of its proviral load strengthens endurance to environmental stresses. AB - 2.6% of the genome of the soil bacterium Pseudomonas putida KT2440 encodes phage related functions, but the burden of such opportunistic DNA on the host physiology is unknown. Each of the four apparently complete prophages borne by this strain was tested for stability, spontaneous excision and ability to cause lysis under various stressing conditions. While prophages P3 (PP2266-PP2297) and P4 (PP1532-1584) were discharged from the genome at a detectable rate, their induction failed otherwise to yield infective viruses. Isogenic P. putida KT2440 derivatives bearing single and multiple deletions of each of the prophages were then subjected to thorough phenotypic analyses, which generally associated the loss of proviral DNA with an increase of physiological vigour. The most conspicuous benefit acquired by prophage-less cells was a remarkable improvement in tolerance to UV light and other insults to DNA. This was not accompanied, however, with an upgrade of recA-mediated homologous recombination. The range of tolerance to DNA damage gained by the prophage-free strain was equivalent to the UV resistance endowed by the TOL plasmid pWW0 to the wild-type bacterium. While the P. putida's prophages are therefore genuinely parasitic, their detrimental effects can be offset by acquisition of compensatory traits through horizontal gene transfer. PMID- 24762027 TI - The effect of hyperpolarization-activated cyclic nucleotide-gated ion channel inhibitors on the vagal control of guinea pig airway smooth muscle tone. AB - BACKGROUND AND PURPOSE: Subtypes of the hyperpolarization-activated cyclic nucleotide-gated (HCN) family of cation channels are widely expressed on nerves and smooth muscle cells in many organ systems, where they serve to regulate membrane excitability. Here we have assessed whether HCN channel inhibitors alter the function of airway smooth muscle or the neurons that regulate airway smooth muscle tone. EXPERIMENTAL APPROACH: The effects of the HCN channel inhibitors ZD7288, zatebradine and Cs(+) were assessed on agonist and nerve stimulation evoked changes in guinea pig airway smooth muscle tone using tracheal strips in vitro, an innervated tracheal tube preparation ex vivo or in anaesthetized mechanically ventilated guinea pigs in vivo. HCN channel expression in airway nerves was assessed using immunohistochemistry, PCR and in situ hybridization. KEY RESULTS: HCN channel inhibition did not alter airway smooth muscle reactivity in vitro to exogenously administered smooth muscle spasmogens, but significantly potentiated smooth muscle contraction evoked by the sensory nerve stimulant capsaicin and electrical field stimulation of parasympathetic cholinergic postganglionic neurons. Sensory nerve hyperresponsiveness was also evident in in vivo following HCN channel blockade. Cs(+) , but not ZD7288, potentiated preganglionic nerve-dependent airway contractions and over time induced autorhythmic preganglionic nerve activity, which was not mimicked by inhibitors of potassium channels. HCN channel expression was most evident in vagal sensory ganglia and airway nerve fibres. CONCLUSIONS AND IMPLICATIONS: HCN channel inhibitors had a previously unrecognized effect on the neural regulation of airway smooth muscle tone, which may have implications for some patients receiving HCN channel inhibitors for therapeutic purposes. PMID- 24762029 TI - Sensitivity and specificity of substrate mapping: an in silico framework for the evaluation of electroanatomical substrate mapping strategies. AB - BACKGROUND: Voltage mapping is an important tool for characterizing proarrhythmic electrophysiological substrate, yet it is subject to geometric factors that influence bipolar amplitudes and thus compromise performance. The aim of this study was to characterize the impact of catheter orientation on the ability of bipolar amplitudes to accurately discriminate between healthy and diseased tissues. METHODS AND RESULTS: We constructed a 3-dimensional, in silico, bidomain model of cardiac tissue containing transmural lesions of varying diameter. A planar excitation wave was stimulated and electrograms were sampled with a realistic catheter model at multiple positions and orientations. We carried out validation studies in animal experiments of acute ablation lesions mapped with a clinical mapping system. Bipolar electrograms sampled at higher inclination angles of the catheter with respect to the tissue demonstrated improvements in both sensitivity and specificity of lesion detection. Removing low-voltage electrograms with concurrent activation of both electrodes, suggesting false attenuation of the bipolar electrogram due to alignment with the excitation wavefront, had little effect on the accuracy of voltage mapping. CONCLUSIONS: Our results demonstrate possible mechanisms for the impact of catheter orientation on voltage mapping accuracy. Moreover, results from our simulations suggest that mapping accuracy may be improved by selectively controlling the inclination of the catheter to record at higher angles with respect to the tissue. PMID- 24762030 TI - Chilling to zero degrees disrupts pollen formation but not meiotic microtubule arrays in Triticum aestivum L. AB - Throughout the wheat-growing regions of Australia, chilling temperatures below 2 degrees C occur periodically on consecutive nights during the period of floral development in spring wheat (Triticum aestivum L.). In this study, wheat plants showed significant reductions in fertility when exposed to prolonged chilling temperatures in controlled environment experiments. Among the cultivars tested, the Australian cultivars Kite and Hartog had among the lowest levels of seed set due to chilling and their responses were investigated further. The developmental stage at exposure, the chilling temperature and length of exposure all influenced the level of sterility. The early period of booting, and specifically the +4 cm auricle distance class, was the most sensitive and corresponded to meiosis within the anthers. The response of microtubules to chilling during meiosis in Hartog was monitored, but there was little difference between chilled and control plants. Other abnormalities, such as plasmolysis and cytomixis increased in frequency, were associated with death of developing pollen cells, and could contribute to loss of fertility. The potential for an above-zero chilling sensitivity in Australian spring wheat varieties could have implications for exploring the tolerance of wheat flower development to chilling and freezing conditions in the field. PMID- 24762032 TI - Using (19)F NMR to probe biological interactions of proteins and peptides. AB - Fluorine is a valuable probe for investigating the interactions of biological molecules because of its favorable NMR characteristics, its small size, and its near total absence from biology. Advances in biosynthetic methods allow fluorine to be introduced into peptides and proteins with high precision, and the increasing sensitivity of NMR spectrometers has facilitated the use of (19)F NMR to obtain molecular-level insights into a wide range of often-complex biological interactions. Here, we summarize the advantages of solution-state (19)F NMR for studying the interactions of peptides and proteins with other biological molecules, review methods for the production of fluorine-labeled materials, and describe some representative recent examples in which (19)F NMR has been used to study conformational changes in peptides and proteins and their interactions with other biological molecules. PMID- 24762033 TI - Assessment of treatment-seeking behavior and healthcare utilization in an international cohort of subjects with overactive bladder. AB - Abstract Objective: To assess the association between incontinence severity, treatment-seeking behavior, and healthcare resource utilization (HRU) among participants with overactive bladder (OAB) in eight countries. RESEARCH DESIGN AND METHODS: A cross-sectional online survey of subjects >=18 years old in Australia, Europe, and North America, who had a past OAB diagnosis and/or experienced >=1 urinary incontinence (UI) episode in the preceding 12 months, were eligible to participate. Subjects contacted for the survey were primarily from a voluntary medication monitoring registry, MediGuard. Predominantly stress incontinence subjects were excluded. Incontinence severity was assessed by the number of UI episodes over 3 days and grouped as 0 ('dry'), 1-2, 3-4, and >=5 UI episodes/day. Subject demographics, employment status, comorbidities, treatment seeking behavior (past OAB diagnosis; spoken to healthcare provider [HCP]), and HRU (diagnostic tests; HCP visits in 6 months before screening) were analyzed by incontinence severity. RESULTS: Overall, 1341 subjects with OAB (mean age 54.5 years; 70.7% female) were surveyed; 20.2%, 47.7%, 18.8%, and 13.3% of subjects reported 0, 1-2, 3-4, and >=5 UI episodes/day, respectively. Employment status and comorbidities were significantly (p < 0.05) associated with incontinence severity. The two measures of treatment-seeking behavior were significantly (p < 0.05) associated with incontinence severity groups; the proportion of subjects with a past diagnosis of OAB were 35.8%, 44.8%, 52.4%, and 64.0% in the 0, 1-2, 3 4, and >=5 UI episodes/day groups, respectively; and 59.0%, 63.6%, 65.9%, and 78.1% of subjects in the respective UI severity groups talked to a HCP about their OAB symptoms. Multivariate linear regression analyses showed a positive and consistent association between incontinence severity and HRU; subjects reported a mean of 2.7, 4.1, 4.4, and 7.7 diagnostic tests overall (p < 0.001), and a mean of 1.4, 2.2, 2.7, and 4.0 HCP visits in the 0, 1-2, 3-4, and >=5 UI episodes/day groups, respectively (p < 0.001). A potential limitation of the study is the cross-sectional survey methodology which limits the ability to draw causal inferences from the results. Additionally, since this is a web-based survey it is possible respondents who have access to/are familiar with technology were more likely to be enrolled. CONCLUSIONS: Incontinence severity was positively associated with both treatment-seeking behavior and HRU among subjects with OAB. PMID- 24762031 TI - Thyroglobulin as a biomarker of iodine deficiency: a review. AB - BACKGROUND: Thyroglobulin, produced exclusively by the thyroid gland, has been proposed to be a more sensitive biomarker of iodine status than thyrotropin or the thyroid hormones triiodothyronine and thyroxine. However, evidence on the usefulness of thyroglobulin (Tg) to assess iodine status has not been extensively reviewed, particularly in pregnant women and adults. SUMMARY: An electronic literature search was conducted using the Cochrane CENTRAL, Web of Science, PubMed, and Medline to locate relevant studies on Tg as a biomarker of iodine status. Since urinary iodine concentration (UIC) is the recommended method to assess iodine status in populations, only studies that clearly reported both Tg and UIC were included. For the purpose of this review, a median Tg <13 MUg/L and a median UIC >=100 MUg/L (UIC >=150 MUg/L for pregnant women) were used to indicate adequate iodine status. We excluded studies conducted in subjects with either known thyroid disease or those with thyroglobulin antibodies. The search strategy and selection criteria yielded 34 articles of which nine were intervention studies. The majority of studies (six of eight) reported that iodine deficient pregnant women had a median Tg >=13 MUg/L. However, large observational studies of pregnant women, including women with adequate and inadequate iodine status, as well as well-designed intervention trials that include both Tg and UIC, are needed. In adults, the results were equivocal because iodine-deficient adults were reported to have median Tg values of either <13 or >=13 MUg/L. Only studies in school-aged children showed that iodine-sufficient children typically had a median Tg <13 MUg/L. Some of the inconsistent results may be partially explained by the use of different methodological assays and failure to assess assay accuracy using a certified reference material. CONCLUSIONS: These data suggest that Tg does hold promise as a biomarker of iodine deficiency. However, it is associated with limitations. A median Tg cutoff of 13 MUg/L warrants further investigation, particularly in adults or pregnant women, as there is a lack of both observational and intervention studies in these groups. PMID- 24762034 TI - Vaginal breech birth: can we move beyond the Term Breech Trial? AB - Since the publication of the Term Breech Trial in 2000, planned cesarean has become the preferred mode of birth for women whose fetus is in a breech presentation. Over the past 20 years, however, subsequent evidence has not shown conclusively that cesarean birth is safer than vaginal birth for a fetus in a breech presentation when certain criteria are met. Many obstetric organizations support the option of planned vaginal birth for women with a breech presentation under strict prelabor selection criteria and intrapartum management guidelines. The growing trend toward cesarean unfortunately has left midwives and other intrapartum care providers in training with dwindling opportunities to competently master skills for vaginal breech birth. Although simulation training offers opportunities to practice infrequently encountered skills such as vaginal breech birth, it is unknown if this alternative will provide sufficient experience for future generations of clinicians. As a result, women with a breech presentation at term who desire a trial of labor often have limited choices. This article reviews the controversies surrounding the ideal mode of birth created by the Term Breech Trial. Criteria for vaginal breech birth are summarized and the role of simulation explored. Implications for midwifery practice when a breech presentation is diagnosed are also included. PMID- 24762035 TI - Nickel allergy induced systemic reaction to an intracardiac amplatzer device. AB - Nickel hypersensitivity is reported in about 10-15% of the general population and manifests mainly with dermatological signs. Chest discomfort, palpitations, signs and symptoms of pericarditis, and migraine are symptoms reported in rare cases of nickel hypersensitivity after implantation of a cardiac device made of nickel. We present the case of a patient with a nickel allergy from an Amplatzer device in which the removal of the device produced resolution of the symptoms. PMID- 24762036 TI - Endovascular treatment for nontraumatic rupture of the descending thoracic aorta: long-term results. AB - BACKGROUND: This study evaluated the long-term results of thoracic endovascular aortic repair (TEVAR) of nontraumatic rupture of the descending thoracic aorta. METHODS: This was a retrospective and observational single-center study. During the 10-year study period, 21 patients (6 males) with an average age of 66.1 +/- 12.4 (range 31-81) years underwent emergency TEVAR for nontraumatic rupture of the descending thoracic aorta. The underlying aortic pathologies causing the rupture were degenerative aneurysms in 11 patients, complicated type B dissection in nine, and erosion hemorrhage due to neoplasia in one patient. RESULTS: The 30 day mortality rate was 9.5% (2/21). Two patients died postoperatively: one from a repeat aortic rupture and the other from pneumonia. Two patients underwent early endovascular reintervention. After a median follow-up of 65.6 +/- 50.4 (range 1.5 44) months, 10 patients died, resulting in a late mortality of 52.6% (10/19). Six patients (31.5%) developed major complications requiring late reintervention. There was no mortality with reintervention. CONCLUSIONS: Endovascular treatment of the descending thoracic aorta in patients with nontraumatic rupture is a promising treatment option in an emergency setting with a relatively low mortality rate. Despite encouraging early results, TEVAR is associated with a high reintervention rate and poor survival due to nonaortic or procedure-related mortality in the long term. PMID- 24762037 TI - Development of a single endovascular device for aortic valve replacement and ascending aortic repair. AB - BACKGROUND AND AIM OF THE STUDY: Transcatheter aortic valve implantation (TAVI) is contraindicated in the presence of an ascending aortic aneurysm. Our aim was to design a composite endovascular device enabling ascending aortic repair and TAVI. METHODS: From 2007 to 2013, among 1196 patients with severe aortic stenosis screened for TAVI, 79 nonbicuspid patients had ascending aortic diameter >45 mm. Proximal aortic geometry was assessed in those with computed tomography angiography. RESULTS: All together, 51 patients (35 males, aged 85 +/- 8 years; 19 TAVI, 10 open Wheat procedures, 22 managed conservatively) were included. The required annular diameter for implantation of currently available TAVI prostheses was met in 41% (21/51). Novel prosthetic valves appropriate for annular range up to 30 mm would extend device applicability to 78% (40/51). Proximal and distal diameters of the graft-covering portion ranging between 30 and 46 mm would enable 10% graft oversizing in all but six patients. In 88% (45/51) the required minimum 10 mm distance between aortic valve annulus and coronary artery ostia was found. Mean distance between left and right coronary artery ostia and sinotubular junction was 2.6 +/- 1.5 and 3.2 +/- 1.7 mm, respectively. CONCLUSIONS: Novel composite endovascular valved grafts may extend the application of transcatheter techniques to patients denied TAVI due to a concomitant ascending aneurysm. The location of coronary arteries in relation to the sinotubular junction must be addressed in designing these composite valve grafts. PMID- 24762038 TI - One and a half ventricle repair in association with tricuspid valve repair according to "peacock tail" technique in patients with Ebstein's malformation and failing right ventricle. AB - OBJECTIVES: The aim of this study was to evaluate the outcome in a series of patients with Ebstein's anomaly and a failing right ventricle (RV) undergoing tricuspid valve (TV) repair and bidirectional Glenn cavopulmonary anastomosis (BDG). MATERIALS AND METHOD: Between January 2006 and September 2013, 11 consecutive patients diagnosed with severe forms of Ebstein's anomaly and a failing RV underwent TV surgery and BDG. The mean age was 16.5 +/- 7 years. Most frequently found symptoms were cyanosis, dyspnea, and arrhythmias. The azygos or hemiazygos veins were left open. The TV was repaired using the "peacock tail" technique, which consisted of total detachment of the anterior and posterior leaflets of the TV and rotation in both directions reimplanting them to the true annulus. The mean follow-up was 3.8 +/- 2.4 years (range three months to six years). RESULTS: Hospital mortality was 9% (one patient). TV repair was possible in 10 patients. None of the patients had AV block postoperatively. At one year after surgery, the indexed RV and RA diameter were reduced significantly versus the preoperative data (p = 0.003 and p < 0.001). The mean TVR and indexed TV area were 1.2 +/- 0.42 and 1.6 +/- 0.6 (mm/m2), significantly lower than preoperatively (p = 0.001 and p = 0.008, respectively). The mean NYHA functional class, SaO2 , and cardiothoracic ratio were significantly improved. CONCLUSIONS: The peacock tail technique for TV repair in combination with BDG in patients with Ebstein's malformation and depressed RV function results in TV preservation, a low incidence of recurrent regurgitation, favorable functional status and RV function, and resolution of cyanosis. PMID- 24762039 TI - Perventricular device closure of congenital ventricular septal defects. AB - Ventricular septal defect (VSD) is a common congenital heart disease. Open surgical repair with cardiopulmonary bypass (CPB) and sternotomy is the classic treatment. Percutaneous device closure is a minimally invasive alternative in treating selected VSDs, but it is limited by vascular access as well as radiation exposure especially in pediatric patients. Hybrid perventricular device closure of VSDs was designed to combine the advantages of both approaches allowing direct access to the defect without CPB and has gained wider acceptance in recent years. Under transesophageal echocardiography guidance, it could effectively close muscular, perimembranous, and even doubly committed defects. It is a safe and effective option for selected patients with congenital VSDs. In this article, we reviewed the application and results of this technique. PMID- 24762040 TI - Prevalence of low bone mass and vitamin D deficiency in beta-thalassemia major. AB - Low bone mass, a major cause of morbidity in patients with beta-thalassemia major (beta-TM), is multifactorial. There is lack of data about the current prevalence of low bone mass in patients with beta-TM. The aims of this study are to examine the current prevalence of low bone mass in beta-TM patients and the association between demographic characteristics, markers of iron overload, endocrinopathies, glycemic status and bone mineral density (BMD) as well as to study the 25-OH vitamin D status of the patients and its relationship with BMD. Our institution serves the largest cohort of beta-TM patients in the UK. From 99 patients (49 males, 50 females) with a mean +/- standard deviation (SD) age of 36 +/- 9 years, 55.5% had low BMD for their age as defined by Z-score BMD <-2.0 either at the lumbar spine (43.9%) or at the hip (25.5%). The only statistically significant association on the multivariate analysis was between hypogonadism and low BMD at the lumbar spine. In our study, 29.9% of patients had vitamin D deficiency, 65.7% had vitamin D insufficiency and 12.4% had optimal levels. No association between vitamin D status and low bone mass was found. Our study demonstrated a much lower prevalence of low bone mass in adults with beta-TM compared to previous studies. Further studies are needed to examine whether this suggests a widespread improvement across patients with beta-TM possibly due to advances in therapeutics. Most patients had suboptimal 25-OH-vitamin D levels, but no association between vitamin D status and bone mass was demonstrated. PMID- 24762041 TI - Spin-crossover and massive anisotropy switching of 5d transition metal atoms on graphene nanoflakes. AB - In spin crossover phenomena, the magnetic moment of a molecule is switched by external means. Here we theoretically predict that several 5d-transition metals (TMs) adsorbed on finite graphene flakes undergo a spin crossover, resulting from multiple adsorption minima, that are absent in the zero-dimensional limit of benzene and the two-dimensional limit of graphene. The different spin states are stable at finite temperature and can be reversibly switched with an electric field. The system undergoes a change in magnetic anisotropy upon spin crossover, which facilitates read-out of the spin state. The TM-decorated nanoflakes thus act as fully controlled single-ion magnetic switches. PMID- 24762042 TI - Development of an ototoxicity model in the adult CBA/CaJ mouse and determination of a golden window of corticosteroid intervention for otoprotection. AB - OBJECTIVE: To investigate the effect of timing of dexamethasone administration on auditory hair cell survival following an ototoxic insult with kanamycin and furosemide. STUDY DESIGN: Controlled experimental study. SETTING: Translational science experimental laboratory. METHODS: 5-6 week old CBA/CaJ mice, divided into 6 groups, were injected with kanamycin (1 mg/g SC) followed by furosemide (0.5 mg/g IP). Dexamethasone (0.1 mg/g IP) was injected at either 1 hour prior to insult, +1 hr, +6 hr, +12 hr, or +72 hr post insult. Temporal bones harvested on day 7 underwent Organ of Corti dissection. Immunohistochemical staining was performed using antibodies to myosin 7a, phalloidin, and TO-PRO. RESULTS: Hair cell counts demonstrate a uniform ototoxicity model with total loss of outer hair cells (OHCs) and near-total loss of inner hair cells (IHCs). The group pre treated with dexamethasone showed a statistically significant improvement in counts compared to controls (p = 0.004). Counts from the other experimental groups given dexamethasone after the insult were highly variable but demonstrated some apical and middle turn inner hair cell survival. CONCLUSION: Treatment of systemic dexamethasone prior to ototoxic insult attenuates hair cell loss in a reliable, novel, ototoxicity model using kanamycin and furosemide in CBA/CaJ mice. Dosing with dexamethasone following ototoxic insult shows promising yet variable response in hair cell survival. PMID- 24762043 TI - The YXXPhi motif within the severe acute respiratory syndrome coronavirus (SARS CoV) 3a protein is crucial for its intracellular transport. AB - BACKGROUND: The SARS coronavirus (SARS-CoV) 3a protein functions as an ion channel, induces apoptosis and is important for viral pathogenesis. It is expressed on the cell surface and contains a tyrosine-based sorting motif and a di-acidic motif, which may be crucial for its intracellular trafficking. However the role of these motifs is not fully understood in the case of 3a protein. METHODS: The subcellular distribution of the 3a protein was studied by immunofluorescence staining of cells transfected with wild type and mutant constructs along with markers for different intracellular compartments. Semi quantitative RT-PCR was performed to estimate the mRNA where as western blotting was carried out to detect protein levels of wild type and mutant 3a proteins. In vitro transcription- translation was performed to estimate cell free protein synthesis. RESULTS: While the wild type 3a protein is efficiently transported to the plasma membrane, the protein with mutations in the tyrosine and valine residues within the YXXV motif (DeltaYXXPhi) accumulated in the Golgi compartment. However the 3a protein with mutations within the EXD di-acidic motif (DeltaEXD) showed an intracellular distribution similar to the wild type protein. Increased retention of the DeltaYXXPhi protein in the Golgi compartment also increased its association with lipid droplets. The DeltaYXXPhi protein also expressed at significantly lower levels compared to the wild type 3a protein, which was reversed with Brefeldin A and Aprotinin. CONCLUSIONS: The data suggest that the YXXPhi motif of the SARS-CoV 3a protein is necessary for Golgi to plasma membrane transport, in the absence of which the protein is targeted to lysosomal degradation compartment via lipid droplets. PMID- 24762044 TI - Evidence for the sequential folding mechanism in RNase H from an ensemble-based model. AB - The number of distinct protein folding pathways starting from an unfolded ensemble, and hence, the folding mechanism is an intricate function of protein size, sequence complexity, and stability conditions. This has traditionally been a contentious issue particularly because of the ensemble nature of conventional experiments that can mask the complexity of the underlying folding landscape. Recent hydrogen-exchange experiments combined with mass spectrometry (HX-MS) reveal that the folding of RNase H proceeds in a hierarchical fashion with distinct intermediates and following a single discrete path. In our current work, we provide computational evidence for this unique folding mechanism by employing a structure-based statistical mechanical model. Upon calibrating the energetic terms of the model with equilibrium measurements, we predict multiple intermediate states in the folding of RNase H that closely resemble experimental observations. Remarkably, a simplified landscape representation adequately captures the folding complexity and predicts the possibility of a well-defined sequence of folding events. We supplement the statistical model study with both explicit solvent molecular simulations of the helical units and electrostatic calculations to provide structural and energetic insights into the early and late stages of RNase H folding that hint at the frustrated nature of its folding landscape. PMID- 24762045 TI - A novel mode of lactate metabolism in strictly anaerobic bacteria. AB - Lactate is a common substrate for major groups of strictly anaerobic bacteria, but the biochemistry and bioenergetics of lactate oxidation is obscure. The high redox potential of the pyruvate/lactate pair of E0 ' = -190 mV excludes direct NAD(+) reduction (E0 ' = -320 mV). To identify the hitherto unknown electron acceptor, we have purified the lactate dehydrogenase (LDH) from the strictly anaerobic, acetogenic bacterium Acetobacterium woodii. The LDH forms a stable complex with an electron-transferring flavoprotein (Etf) that exhibited NAD(+) reduction only when reduced ferredoxin (Fd(2-) ) was present. Biochemical analyses revealed that the LDH/Etf complex of A. woodii uses flavin-based electron confurcation to drive endergonic lactate oxidation with NAD(+) as oxidant at the expense of simultaneous exergonic electron flow from reduced ferredoxin (E0 ' ~ -500 mV) to NAD(+) according to: lactate + Fd(2-) + 2 NAD(+) -> pyruvate + Fd + 2 NADH. The reduced Fd(2-) is regenerated from NADH by a sequence of events that involves conversion of chemical (ATP) to electrochemical ( Delta MU ~ Na + ) and finally redox energy (Fd(2-) from NADH) via reversed electron transport catalysed by the Rnf complex. Inspection of genomes revealed that this metabolic scenario for lactate oxidation may also apply to many other anaerobes. PMID- 24762046 TI - Impact of the first eight months of orthodontic treatment with a fixed appliance on the families of adolescent patients. AB - OBJECTIVE: To evaluate the impact of the first 8 months of orthodontic treatment with a fixed appliance on the families of adolescent patients and to examine the evaluative properties of the Family Impact Scale (FIS). MATERIALS AND METHODS: The study involved a sample of 94 parents/caregivers of adolescents undergoing orthodontic treatment with a fixed appliance. The participants were asked to answer the Brazilian version of the FIS before treatment (T1) and 8 months after the bonding of the fixed appliance (T2). Statistical analysis was carried out using the Wilcoxon signed rank test and the Bonferroni correction for the overall score and FIS subscales. Responsiveness of the measure and the minimal clinically important difference (MCID) were also assessed. RESULTS: Among the 94 participants initially admitted to the present study, two were excluded as a result of treatment dropout and failure to return the second questionnaire. Thus, a sample of 92 parents/caregivers participated (response rate: 97.8%). Among the 92 participants, 70 were the mothers of patients, 16 were fathers, and six were other family members. Statistically significant improvements were found in the overall score (P < .001) as well as in both parental activity and parental emotions subscales (P < .001). The reductions in scores were associated with effect sizes showing moderate clinically meaningful changes in the overall FIS and in the parental/family activity, parental emotions, and family conflict subscales. The MCID was 2.66 for the overall FIS. CONCLUSION: The first 8 months of orthodontic treatment with a fixed appliance had a positive impact on the families of adolescents. PMID- 24762048 TI - Bioaccumulation of perfluorinated alkyl acids: observations and models. AB - In this review, we consider the two prevailing hypotheses for the mechanisms that control the bioaccumulation of perfluorinated alkyl acids (PFAAs). The first assumes that partitioning to membrane phospholipids, which have a higher affinity for charged species than neutral storage lipids, can explain the high bioaccumulation potential of these compounds. The second assumes that interactions with proteins--including serum albumin, liver fatty acid binding proteins (L-FABP), and organic anion transporters--determine the distribution, accumulation and half-lives of PFAAs. We consider three unique phenomena to evaluate the two models: (1) observed patterns of tissue distribution in the laboratory and field, (2) the relationship between perfluorinated chain length and bioaccumulation, and (3) species- and gender-specific variation in elimination half-lives. Through investigation of these three characteristics of PFAA bioaccumulation, we show the strengths and weaknesses of the two modeling approaches. We conclude that the models need not be mutually exclusive, but that protein interactions are needed to explain some important features of PFAA bioaccumulation. Although open questions remain, further research should include perfluorinated alkyl substances (PFASs) beyond the long-chain PFAAs, as these substances are being phased out and replaced by a wide variety of PFASs with largely unknown properties and bioaccumulation behavior. PMID- 24762047 TI - Clinical study of the pronator quadratus muscle: anatomical features and feasibility of pronator-sparing surgery. AB - BACKGROUND: No clinical data for the relationship of pronator quadratus (PQ) muscle to distal radius had been reported. The aim of this study was to investigate the anatomical features of the PQ muscle related to plate osteosynthesis for distal radius fractures in clinical cases. The feasibility of PQ muscle sparing surgery was investigated as well. METHODS: Fifty two distal radius fractures (23-A2) were enclosed in this study. The whole width of the muscle and the distance from the distal edge of the muscle to the joint surface of the distal radius were measured. The distance from the fracture site of the radius to the joint surface was measured as well. RESULTS: The average width of the pronator quadratus muscle was 37.6 mm. The average distance from the pronator quadratus muscle to the lunate fossa surface was 12.2 mm, and the average distance from the pronator quadratus muscle to the scaphoid fossa surface was 13.6 mm. The average distance from the lunate fossa of the distal radius to the fracture site was 12.2 mm (range, 7.3-17 mm), and the scaphoid fossa of the distal radius to the fracture site was 13.2 mm (range, 9.4-18.8 mm). CONCLUSIONS: This PQ muscle sparing surgery is feasible and can be performed without difficulty. The data might provide a useful basis for the preservation of pronator quadratus muscle applied to a functionally reduced fracture regarding the potential efficacy of conventional volar plate osteosynthesis. PMID- 24762049 TI - Incomplete cure of tachycardia-induced cardiomyopathy secondary to rapid atrial fibrillation by heart rate control without sinus conversion. AB - BACKGROUND: It is uncertain whether rate or rhythm control is more favorable for patients experiencing tachycardia-induced cardiomyopathy (TIC) secondary to rapid atrial fibrillation (AF). METHODS AND RESULTS: We compared the electrophysiological and hemodynamic properties and outcome after AF ablation in 20 patients with a history of decompensated TIC who maintained sinus rhythm or had paroxysmal AF (group 1), 32 with a history of decompensated TIC who had persistent or longstanding persistent AF (group 2), 377 without TIC who had paroxysmal AF (group 3), and 225 without TIC who had persistent or longstanding persistent AF (group 4). The corrected sinus node recovery time was more prolonged in group 2 than in groups 1, 3, or 4 (1,066 +/- 946 vs. 416 +/- 188, 450 +/- 322 and 590 +/- 329 milliseconds; P < 0.001, respectively). The mean left atrial pressure in group 2 was greater than that in groups 1, 3, or 4 (13.9 +/- 6.5 vs. 7.5 +/- 3.1, 8.2 +/- 4.1 and 10.8 +/- 4.2 mmHg; P < 0.001, respectively). The left ventricular ejection fraction assessed after the recovery from the decompensation was more decreased in group 2 than in group 1; however, it almost returned to normal if sinus rhythm was maintained after the AF ablation in group 2. The presence of a history of TIC did not predict an AF recurrence after the ablation. CONCLUSIONS: Heart rate control during AF without sinus conversion may result in an incomplete cure of TIC, suggesting the advantages of rhythm control with ablation in patients with TIC. PMID- 24762050 TI - Blocking the janus-activated kinase pathway reduces tumor necrosis factor alpha induced interleukin-18 bioactivity by caspase-1 inhibition. AB - INTRODUCTION: Our objective was to examine the role of the janus-activated kinase (JAK) pathway in the modulation of tumor necrosis factor-alpha (TNF)-induced-IL 18 bioactivity by reduction of caspase-1 function. METHODS: Caspase-1 expression in rheumatoid arthritis (RA) synovial fibroblasts treated with TNF was assessed by qRT-PCR and Western blot. Interleukin (IL)-18 was assessed by enzyme-linked immunosorbent assay (ELISA) in cell lysates and conditioned media and detected by immunofluorescence (IF) staining in RA synovial fibroblasts. The critical pathways for TNF-induced caspase-1 expression were determined by using chemical inhibitors of signaling followed by TNF stimulation. IL-18 bioactivity was assessed using human myelomonocytic KG-1 cells. RESULTS: TNF induced RA synovial fibroblast caspase-1 expression at the protein level in a time-dependant manner (P < 0.05). Blocking the JAK pathway reduced TNF-induced-caspase-1 expression at the transcriptional and protein levels by approximately 60% and 40%, respectively (P < 0.05). Blocking the JAK pathway reduced TNF-induced-caspase-1 expression at the transcriptional, protein, and activity levels by approximately 60%, 40%, and 53%, respectively (P < 0.05). We then confirmed by IF that TNF-induced IL-18 and investigated roles of the ERK1/2 and JAK pathways. Blocking the JAK pathway, TNF induced intracytoplasmic granular IL-18 expression suggesting a defect of caspase 1. Finally, blocking the JAK pathway, we observed a reduction of IL-18 bioactivity by 52% in RA synovial fibroblasts (P < 0.05). CONCLUSIONS: These results provide a new way to regulate TNF-induced-IL-18 bioactivity by blocking capase-1. These data present a novel role for JAK inhibition in RA patients and emphasize JAK inhibition use as a new therapeutic option in RA management. PMID- 24762051 TI - Induced carbon reallocation and compensatory growth as root herbivore tolerance mechanisms. AB - Upon attack by leaf herbivores, many plants reallocate photoassimilates below ground. However, little is known about how plants respond when the roots themselves come under attack. We investigated induced resource allocation in maize plants that are infested by the larvae Western corn rootworm Diabrotica virgifera virgifera. Using radioactive (11) CO(2), we demonstrate that root attacked maize plants allocate more new (11) C carbon from source leaves to stems, but not to roots. Reduced meristematic activity and reduced invertase activity in attacked maize root systems are identified as possible drivers of this shoot reallocation response. The increased allocation of photoassimilates to stems is shown to be associated with a marked thickening of these tissues and increased growth of stem-borne crown roots. A strong quantitative correlation between stem thickness and root regrowth across different watering levels suggests that retaining photoassimilates in the shoots may help root-attacked plants to compensate for the loss of belowground tissues. Taken together, our results indicate that induced tolerance may be an important strategy of plants to withstand belowground attack. Furthermore, root herbivore-induced carbon reallocation needs to be taken into account when studying plant-mediated interactions between herbivores. PMID- 24762052 TI - Infiltration of the thyroid gland by T-cell prolymphocytic leukemia. AB - BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is rare, accounting for only 0.06% of all malignant lymphomas, and is classified as a T-cell mature lymphoma. The disease affects mainly elderly patients and is characterized by splenomegaly, lymphadenopathy, skin infiltration, and a high leukocyte count, but thyroid filtration has never been detected as far as we could determine. We report here a case of infiltration of the thyroid gland by T-PLL. PATIENT FINDINGS: An 89-year old woman who had been treated for Hashimoto's thyroiditis for 20 years presented with a progressively enlarging thyroid mass accompanied by dyspnea and dysphasia. Atypical lymphocytes with irregular nuclei were observed in the peripheral blood. An open biopsy of the thyroid provided pathological evidence of T-PLL, and bone marrow examination showed infiltration by T-PLL. The diagnosis was therefore infiltration of the thyroid gland by T-PLL. Chemotherapy was initiated, but six months after termination, recurrence of neck swelling was observed. The patient was then treated with radiotherapy, but she died of a major stroke 15 months after onset. SUMMARY AND CONCLUSION: This is the first report of T-PLL infiltration of the thyroid gland, reminding physicians to keep in mind a broad differential diagnosis when encountering a patient with diffuse thyroid lesions and abnormal lymphocytes in the peripheral blood. PMID- 24762053 TI - Revealing the atomic restructuring of Pt-Co nanoparticles. AB - We studied Pt-Co bimetallic nanoparticles during oxidation in O2 and reduction in H2 atmospheres using an aberration corrected environmental transmission electron microscope. During oxidation Co migrates to the nanoparticle surface forming a strained epitaxial CoO film. It subsequently forms islands via strain relaxation. The atomic restructuring is captured as a function of time. During reduction cobalt migrates back to the bulk, leaving a monolayer of platinum on the surface. PMID- 24762055 TI - Protection from outpatient sudden cardiac death following ICD removal using a wearable cardioverter defibrillator. AB - BACKGROUND: An implantable cardioverter defibrillator (ICD) is effective in preventing sudden cardiac death (SCD). Once an ICD is removed and reimplantation is not feasible, a wearable cardioverter defibrillator (WCD) may be an alternative option. We determined the effectiveness of WCD for SCD prevention in patients who were discharged after ICD removal. METHODS: A retrospective study was conducted on all WCD (LifeVest, ZOLL, Pittsburgh, PA, USA) patients who underwent ICD removal due to cardiac device infections (CDIs) at two referral centers between January 1, 2005 and December 31, 2009. Clinical characteristics, device information, and WCD data were analyzed. Sudden cardiac arrest was defined as all sustained ventricular tachycardia (VT) and ventricular fibrillation occurring within a single 24-hour period. RESULTS: Ninety-seven patients (mean age 62.8 +/- 13.3, male 80.4%) were included in the study. The median duration of antibiotic use was 14.7 days (interquartile range [IQR] 10-30). The median daily WCD use was 20 hours/day and the median length of use was 21 days (IQR 5-47). A total of three patients were shocked by WCD. Two patients had four episodes of sustained VT, successfully terminated by the WCD. A third patient experienced two inappropriate treatments due to oversensitivity of the signal artifact. Three patients experienced sudden death outside the hospital while not wearing the device. Five patients died while hospitalized. CONCLUSION: WCD can prevent SCD, until ICD reimplantation is feasible in patients who underwent device removals for CDI. However, patient compliance is essential for the effective use of this device. PMID- 24762056 TI - Peptidylarginine deiminases: novel drug targets for prevention of neuronal damage following hypoxic ischemic insult (HI) in neonates. AB - Neonatal hypoxic ischaemic (HI) injury frequently causes neural impairment in surviving infants. Our knowledge of the underlying molecular mechanisms is still limited. Protein deimination is a post-translational modification caused by Ca(+2) -regulated peptidylarginine deiminases (PADs), a group of five isozymes that display tissue-specific expression and different preference for target proteins. Protein deimination results in altered protein conformation and function of target proteins, and is associated with neurodegenerative diseases, gene regulation and autoimmunity. In this study, we used the neonatal HI and HI/infection [lipopolysaccharide (LPS) stimulation] murine models to investigate changes in protein deimination. Brains showed increases in deiminated proteins, cell death, activated microglia and neuronal loss in affected brain areas at 48 h after hypoxic ischaemic insult. Upon treatment with the pan-PAD inhibitor Cl amidine, a significant reduction was seen in microglial activation, cell death and infarct size compared with control saline or LPS-treated animals. Deimination of histone 3, a target protein of the PAD4 isozyme, was increased in hippocampus and cortex specifically upon LPS stimulation and markedly reduced following Cl amidine treatment. Here, we demonstrate a novel role for PAD enzymes in neural impairment in neonatal HI Encephalopathy, highlighting their role as promising new candidates for drug-directed intervention in neurotrauma. Hypoxic Ischaemic Insult (HI) results in activation of peptidylarginine deiminases (PADs) because of calcium dysregulation. Target proteins undergo irreversible changes of protein bound arginine to citrulline, resulting in protein misfolding. Infection in synergy with HI causes up-regulation of TNFalpha, nuclear translocation of PAD4 and change in gene regulation as a result of histone deimination. Pharmacological PAD inhibition significantly reduced HI brain damage. PMID- 24762057 TI - Inhibitory receptor immunoglobulin-like transcript 4 was highly expressed in primary ductal and lobular breast cancer and significantly correlated with IL-10. AB - BACKGROUND: Immunoglobulin-like transcript 4 (ILT4) is an inhibitory molecule involved in immune response and has recently been identified to be strongly inducible by IL-10. The aim of the present study was to examine the associations of ILT4 expression with clinicopathological characteristics and IL-10 expression in primary ductal and lobular breast cancer. METHODS: We studied the expression of ILT4 in 4 cancer cell lines, 117 primary tumor tissues and 97 metastatic lymph nodes from patients with primary ductal and lobular breast cancer by reverse transcription-polymerase chain reaction, western blot or immunohistochemistry analysis. Additionally, IL-10 expression was also investigated using immunohistochemistry in primary tumor tissues. Then the relationship between ILT4 expression and clinicopathological characteristics/IL-10 expression was evaluated. RESULTS: ILT4 was highly expressed in all 4 human breast cancer cell lines on both mRNA and protein levels. In primary tumor tissues, ILT4 or IL-10 was expressed in the cell membrane, cytoplasm, or both; the positive rate of ILT4 and IL-10 expression was 60.7% (71/117) and 80.34% (94/117), respectively. ILT4 level was significantly correlated with IL-10 (r =0.577; p<0.01). Furthermore, the expression of ILT4 or IL-10 was associated with less number of Tumor Infiltrating Lymphocytes (TILs) (p=0.004 and 0.018, respectively) and more lymph node metastasis (p=0.046 and 0.035, respectively). CONCLUSION: Our data demonstrated the association of ILT4 and IL-10 expression in human breast cancer, suggesting their important roles in immune dysfunction and lymph node metastases. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1692652692107916. PMID- 24762059 TI - Association between glycemic indices and beta cell function in patients with newly diagnosed type 2 diabetes. AB - OBJECTIVE: To identify the relationship between glycemic indices and beta cell function in patients with newly diagnosed type 2 diabetes. METHODS: The cross sectional analysis included 61 patients with newly diagnosed type 2 diabetes who received continuous glucose monitoring (CGM) for 72 hours. The association between beta cell function and glycemic indices including A1C and glycemic variability was investigated. RESULTS: A1C (r = -0.405, p = 0.001) and standard deviation of blood glucose (SDBG, r = -0.274, p = 0.032) were significantly correlated to HOMA-beta cell function (HBCI), whereas mean amplitude of glycemic excursions (MAGE, r = -0.210, p = 0.104) was not informative. After multiple confounders adjustments, A1C (beta = -7.35, p < 0.001), MAGE (beta = -4.64, p = 0.040), and SDBG (beta = -12.3, p = 0.012) were associated with HBCI. CONCLUSION: A1C and glycemic variability were both associated with beta cell function in patients with newly diagnosed type 2 diabetes. The main limitations of the present study are the cross-sectional design in nature and the limited sample size. PMID- 24762058 TI - Activation of GPR18 by cannabinoid compounds: a tale of biased agonism. AB - BACKGROUND AND PURPOSE: GPR18 is a candidate cannabinoid receptor, but its classification as such is controversial. The rationale of the study presented herein was to consider the effects of N-arachidonoyl glycine (NAGly) and cannabinoids via differential G-protein coupled pathways, in addition to beta arrestin signalling. Cellular localization of GPR18 receptors was also examined. EXPERIMENTAL APPROACH: Calcium mobilization and ERK1/2 phosphorylation were quantified in a cell line stably expressing GPR18 (HEK293/GPR18 cells). In addition, using the DiscoveRx PathHunter CHO-K1 GPR18 beta-arrestin cell line, recruitment of beta-arrestin was quantified. KEY RESULTS: Concentration-dependent increases in intracellular calcium and ERK1/2 phosphorylation were observed in the presence of NAGly, abnormal cannabidiol (AbnCBD), O-1602, O-1918 and Delta(9) tetrahydrocannabinol (Delta(9)-THC) in HEK293/GPR18 cells. The initial rise in intracellular calcium in the presence of NAGly, O1918 and THC was blocked by either Galpha(q) or Galpha(i/o) inhibition. The ERK1/2 phosphorylation was inhibited by Pertussis toxin and N-arachidonoyl-L-serine (NARAS). Recruitment of beta-arrestin in the PathHunter CHO-K1 GPR18 cell line revealed a differential pattern of GPR18 activation; of all the ligands tested, only Delta(9)-THC produced a concentration-dependent response. The localization of GPR18 receptors within the HEK293/GPR18 cells is both intracellular, and on the plasma membrane. CONCLUSIONS AND IMPLICATIONS: These findings suggest that GPR18 activation involves several signal transduction pathways indicative of biased agonism, thereby providing a plausible explanation for the apparent discrepancies in GPR18 activation found in the literature. Additionally, the results presented herein provide further evidence for GPR18 as a candidate cannabinoid receptor. PMID- 24762060 TI - Relationship status and health: Does the use of different relationship indicators matter? AB - Studies that analyse the association between relationship status and health usually disregard non-marital relationships. The present study examines if the use of different relationship indicators leads to different associations between relationship status and physical and mental health. The database used for this analysis is the Survey of Health and Ageing in Europe, a large population-based survey of Europeans aged 50 and over and their cohabitants. This study combines cross-sectional and retrospective data of 13 European countries. The sample size is 9298 men and 11,631 women for grip strength and 9609 men and 12,333 women for depression. Generalised estimating equations are used. For men, the goodness-of fit measure quasi-likelihood under the independence model criterion indicates that marital status is a better predictor than cohabitation status or partnership status for predicting grip strength. However, for grip strength of women, there are only small differences in the model fit between the different relationship indicators. For both men and women, the partnership status (marriage, cohabitation or dating relationship) shows the best model fit for explaining depression. The results suggest that future health research could benefit from the use of relationship indicators other than marital status, particularly regarding mental health. PMID- 24762062 TI - Avoiding re-inventing the wheel in a people-centered approach to REDD+. AB - One important debate regarding Reducing Emissions from Deforestation and Forest Degradation (REDD+) in developing countries concerns the manner in which its implementation might affect local and indigenous communities. New ways to implement this mechanism without harming the interests of local communities are emerging. To inform this debate, we conducted a qualitative research synthesis to identify best practices (BPs) from people-centered approaches to conservation and rural development, developed indicators of BPs, and invited development practitioners and researchers in the field to assess how the identified BPs are being adopted by community-level REDD+ projects in Latin America. BPs included: local participation in all phases of the project; project supported by a decentralized forest governance framework; project objectives matching community livelihood priorities; project addressing community development needs and expectations; project enhancing stakeholder collaboration and consensus building; project applying an adaptive management approach; and project developing national and local capacities. Most of the BPs were part of the evaluated projects. However, limitations of some of the projects related to decentralized forest governance, matching project objectives with community livelihood priorities, and addressing community development needs. Adaptive management and free and prior informed consent have been largely overlooked. These limitations could be addressed by integrating conservation outcomes and alternative livelihoods into longer-term community development goals, testing nested forest governance approaches in which national policies support local institutions for forest management, gaining a better understanding of the factors that will make REDD+ more acceptable to local communities, and applying an adaptive management approach that allows for social learning and capacity building of relevant stakeholders. Our study provides a framework of BPs and indicators that could be used by stakeholders to improve REDD+ project design, monitoring, and evaluation, which may help reconcile national initiatives and local interests without reinventing the wheel. PMID- 24762061 TI - Fate and uptake of pharmaceuticals in soil-earthworm systems. AB - Pharmaceuticals present a potential threat to soil organisms, yet our understanding of their fate and uptake in soil systems is limited. This study therefore investigated the fate and uptake of (14)C-labeled carbamazepine, diclofenac, fluoxetine, and orlistat in soil-earthworm systems. Sorption coefficients increased in the order of carbamazepine < diclofenac < fluoxetine < orlistat. Dissipation of (14)C varied by compound, and for orlistat, there was evidence of formation of nonextractable residues. Uptake of (14)C was seen for all compounds. Depuration studies showed complete elimination of (14)C for carbamazepine and fluoxetine treatments and partial elimination for orlistat and diclofenac, with greater than 30% of the (14)C remaining in the tissue at the end of the experiment. Pore-water-based bioconcentration factors (BCFs), based on uptake and elimination of (14)C, increased in the order carbamazepine < diclofenac < fluoxetine and orlistat. Liquid chromatography-tandem mass spectrometry and liquid chromatography-Fourier transform mass spectrometry indicated that the observed uptake in the fluoxetine and carbamazepine treatments was due to the parent compounds but that diclofenac was degraded in the test system so uptake was due to unidentifiable transformation products. Comparison of our data with outputs of quantitative structure-activity relationships for estimating BCFs in worms showed that these models tend to overestimate pharmaceutical BCFs so new models are needed. PMID- 24762063 TI - Infliximab's influence on anastomotic strength and degree of inflammation in intestinal surgery in a rabbit model. AB - BACKGROUND: Infliximab, a TNF-alpha inhibitor, is a potent anti-inflammatory drug in the treatment of inflammatory bowel diseases. Recent studies have investigated the effect of infliximab treatment on postoperative complications such as anastomotic leakage, however, with conflicting results and conclusions. The purpose of this study was to investigate whether a single dose infliximab has an adverse effect on the anastomotic healing process, observed as reduced anastomotic breaking strength and histopathologically verified lower grade of inflammatory response, in the small intestine of a rabbit. METHODS: Thirty New Zealand rabbits (median weight 2.5 kg) were allocated to treatment with an intravenous bolus of either 10 mg/kg infliximab (n = 15) or placebo (n = 15). One week later all rabbits underwent two separate end-to-end anastomoses in the jejunum under general anesthesia. At postoperative day three, the anastomotic breaking strength was determined and histopathological changes were examined. RESULTS: The mean value of anastomotic breaking strength in the placebo group was 1.89 +/- 0.36 N and the corresponding value was 1.81 +/- 0.33 N in the infliximab treated rabbits. There was no statistically significant difference between the groups (p = 0.51). The infliximab-treated rabbits had a significant lower degree of inflammatory infiltration response compared to the placebo group (p = 0.047). CONCLUSIONS: Our conclusion, limited by the small sample sizes in both groups, is that a single dose of infliximab, given one week prior to surgery, does not have an impact on the anastomotic breaking strength on the third postoperative day in the small intestine of rabbits. PMID- 24762064 TI - Beneficial effects of pioglitazone and metformin in murine model of polycystic ovaries via improvement of chemerin gene up-regulation. AB - BACKGROUND: Polycystic ovary syndrome (PCO) is recognized as the most common endocrinopathy in female. Chemerin is a novel adipocytokine that is expressed in ovary and upregulated in adipose tissue of obese, PCO patients. To date there is no report about the regulation of ovarian chemerin gene expression after PCO induction and treatment by insulin sensitizing drugs including pioglitazone and metformin. Thirty female rats were divided into six experimental groups with five rats in each group including control group, PCO group (i.m injection of 4 mg estradiol benzoate for 40 days), metformin treated (200 mg/kg/day for 21 days), pioglitazone treated (20 mg/kg/day, for 21 days), PCO + metformin and PCO + pioglitazone. PCO was detected by microscopic observation of vaginal smear and treatment by metformin and pioglitazone was initiated one week after that. Ovarian chemerin expression was analyzed by real time PCR and western blotting. RESULTS: Our results demonstrated that PCO induction resulted in elevation of chemerin mRNA and protein levels in ovary in concomitant with incidence of insulin resistance and increasing androgen and progesterone production. We observed that metformin and pioglitazone attenuated ovarian chemerin expression and improved insulin resistance and abnormal steroid production in PCO rats. CONCLUSION: Based on data presented here we concluded that alteration of ovarian chemerin expression may has important role in PCO development and manipulation of chemerin expression or signaling by pioglitazone or metformin can be a novel therapeutic mechanism in the treatment of PCO patients by these drugs. PMID- 24762065 TI - Modeled occupational exposures to gas-phase medical laser-generated air contaminants. AB - Exposure monitoring data indicate the potential for substantive exposure to laser generated air contaminants (LGAC); however the diversity of medical lasers and their applications limit generalization from direct workplace monitoring. Emission rates of seven previously reported gas-phase constituents of medical laser-generated air contaminants (LGAC) were determined experimentally and used in a semi-empirical two-zone model to estimate a range of plausible occupational exposures to health care staff. Single-source emission rates were generated in an emission chamber as a one-compartment mass balance model at steady-state. Clinical facility parameters such as room size and ventilation rate were based on standard ventilation and environmental conditions required for a laser surgical facility in compliance with regulatory agencies. All input variables in the model including point source emission rates were varied over an appropriate distribution in a Monte Carlo simulation to generate a range of time-weighted average (TWA) concentrations in the near and far field zones of the room in a conservative approach inclusive of all contributing factors to inform future predictive models. The concentrations were assessed for risk and the highest values were shown to be at least three orders of magnitude lower than the relevant occupational exposure limits (OELs). Estimated values do not appear to present a significant exposure hazard within the conditions of our emission rate estimates. PMID- 24762067 TI - What potential do heterobivalent inhibitors have for the treatment of severe allergic reactions? PMID- 24762069 TI - Intestinal microbiota: unexpected alliance with tumor therapy. AB - Evaluation of: Iida N, Dzutsev A, Stewart CA et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967-970 (2013). Intestinal microbiota is essential for host physiological processes, including the maintenance of epithelial barrier and immune functions. However, paradoxically, the intestinal microbiota can promote various types of experimental carcinogenesis. The paper under evaluation demonstrates that disruption of the microbiota impairs the response of tumors to CpG oligonucleotide immunotherapy and platinum chemotherapy in a context-dependent manner. Thus, intestinal microbiota may have a great impact on the tumor response to chemotherapy and/or immunotherapy. PMID- 24762066 TI - Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer. AB - INTRODUCTION: Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy. METHODS: Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. RESULTS: A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. CONCLUSIONS: ALDH1 expression is a useful predictor of chemoresistance. The up-regulation of ALDH1 after NAC predicts poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells. TRIAL REGISTRATION: ACTRN12605000588695. PMID- 24762070 TI - PROSTVAC(r) targeted immunotherapy candidate for prostate cancer. AB - Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC(r) demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response. PMID- 24762071 TI - Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. AB - Alemtuzumab, a humanized monoclonal antibody that targets CD52, was recently approved in the EU and Canada for the treatment of patients with active relapsing remitting multiple sclerosis. Alemtuzumab induces rapid depletion of circulating B- and T-lymphocytes followed by repopulation that leads to a distinctive lymphocyte profile, including an increased proportion of regulatory T-lymphocytes and memory B- and T-lymphocytes. In early open-label studies, alemtuzumab treatment reduced the number of clinical relapses and new MRI lesions in participants with secondary progressive MS. However, most participants had continued worsening of disability, which led to the evaluation of alemtuzumab in patients with early stages of disease in the Genzyme (MA, USA)-sponsored clinical development program in MS. In one Phase II and two Phase III trials, alemtuzumab reduced the number of clinical relapses versus the active comparator, subcutaneous IFN-beta-1a, in treatment-naive and treatment-experienced participants with relapsing-remitting multiple sclerosis. Two of these trials showed reduction in risk of confirmed worsening of disability, and all showed reduction in cerebral atrophy. Safety issues include infusion reactions that are mitigated by pretreatment with corticosteroids in addition to symptomatic management with antihistamines; mild to moderate infections; and autoimmune adverse events. In this context, post-marketing risk mitigation strategies will be needed so that potential adverse events can be identified and managed early and effectively. PMID- 24762072 TI - Benefits of a continuous therapy for cancer patients with a novel adoptive cell therapy by cascade priming (CAPRI). AB - A growing body of evidence shows that immune cells are pivotal in the fight against cancer. First, association studies have identified immune-protective immune response genes against cancer. Second, the presence of immune cells in the respective malignant tumor correlated with a better prognosis for the patients. Third, adoptive cell therapy (ACT) showed, in recent reports, an efficient reduction or even cure for malignant tumors. The focus of this review is a novel in vitro ACT technique, using the patient's cascade-primed immune cells. The cascade-priming procedure stimulates APCs from the peripheral blood. Stimulated APCs digest and present tumor material better and differentiate naive cytotoxic T lymphocyte effector cells against the patient's cancer. The principle and the impressive results of the cascade-primed immune cell treatment in patient case series is compared with the ACT concepts of lymphokine-activated killer, macrophage-activated killer, macrophage-activated killer-dendritic cell, cytokine induced killer and tumor-infiltrating lymphocyte methods. PMID- 24762073 TI - Potential use of TNF-alpha inhibitors in systemic sclerosis. AB - Systemic sclerosis (SSc) is a rare connective tissue disease characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities and variable involvement of organs. TNF-alpha has a central role in initial host response to infections and in the pathogenesis of various systemic immune mediated diseases. Serum levels of TNF-alpha are elevated in patients with SSc and favor the development of pulmonary fibrosis and pulmonary arterial hypertension. Inflammatory arthritis can occur in patients with SSc. Infliximab and etanercept may improve the inflammatory arthritis and disability in SSc. TNF alpha inhibitors reduce the systemic inflammation, improve the endothelial function decreasing the risk of pulmonary arterial hypertension progression and of acute cardiovascular and/or cerebrovascular events. Physicians need to be aware of the potential risks of tuberculosis reactivation and opportunistic infections. Randomized controlled trials with TNF-alpha inhibitors in patients with SSc are needed to confirm the potential role of these agents in the treatment of SSc. PMID- 24762074 TI - Monoclonal antibodies against human cancer stem cells. AB - Cancer stem cells (CSCs) are a subpopulation of tumor cells that display self renewal and tumor initiation capacity and the ability to give rise to the heterogenous lineages of cancer cells that comprise the tumor. CSCs exhibit intrinsic mechanisms of resistance to modern cancer therapeutics, allowing them to survive current cancer therapies and to initiate tumor recurrence and metastasis. Various cell surface and transmembrane proteins expressed by CSCs, including CD44, CD47, CD123, EpCAM (CD326), CD133, IGF receptor I, and proteins of the Notch and Wnt signaling pathways have been identified. Recently, monoclonal antibodies and antibody constructs raised against these CSC proteins have shown efficacy against CSCs in human cancer xenograft mice, and some of them have demonstrated antitumor activity in clinical studies. Since current cancer therapies fail to eliminate CSCs, leading to cancer recurrence and progression, selective targeting of CSCs with monoclonal antibodies and antibody constructs may represent a novel therapeutic strategy against cancer. PMID- 24762077 TI - Current and future therapeutic approach for Waldenstrom's macroglobulinemia. AB - Waldenstrom's macroglobulinemia is a rare B-cell malignancy defined by medullar infiltration by clonal lymphoplasmocytic cells and monoclonal IgM secretion. Treatment is reserved for symptomatic patients. The main first-line treatment strategies combine immunotherapy (principally the anti-CD20 monoclonal antibody rituximab) with chemotherapeutic agents, including alkylating agents, purine analogs and/or bortezomib. The overall response rate to these conventional treatments is between 70 and 90%, but a cure cannot be expected. For patients with relapsed or refractory disease, drugs that were not used for first-line treatment and other agents such as immunomodulators can be tried, but the response rate is generally lower and the responses are shorter lived. Recently, advances in our understanding of the biology of Waldenstrom's macroglobulinemia have led to the development of new drugs targeting hyperactive pathways. This review focuses on current treatment options and on new therapeutic developments. PMID- 24762075 TI - Optimizing NKT cell ligands as vaccine adjuvants. AB - NKT cells are a subpopulation of T lymphocytes with phenotypic properties of both T and NK cells and a wide range of immune effector properties. In particular, one subset of these cells, known as invariant NKT cells (iNKT cells), has attracted substantial attention because of their ability to be specifically activated by glycolipid antigens presented by a cell surface protein called CD1d. The development of synthetic alpha-galactosylceramides as a family of powerful glycolipid agonists for iNKT cells has led to approaches for augmenting a wide variety of immune responses, including those involved in vaccination against infections and cancers. Here, we review basic, preclinical and clinical observations supporting approaches to improving immune responses through the use of iNKT cell-activating glycolipids. Results from preclinical animal studies and preliminary clinical studies in humans identify many promising applications for this approach in the development of vaccines and novel immunotherapies. PMID- 24762076 TI - Immunotherapeutic approaches for the treatment of eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a clinical pathologic disease characterized by symptoms of esophageal dysfunction and eosinophilia of the esophagus. When the diagnosis is confirmed, it is important to treat the eosinophilic inflammation not only to control the presenting symptoms, but also to prevent acute and chronic complications. The pathogenesis of EoE is most likely a mixed IgE and non IgE food-mediated reaction, where Th2 cytokines drive esophageal eosinophilia as in other atopic diseases. Hence, it is not surprising that therapy is based on inflammation control, with steroids (oral or topical) and/or food antigen avoidance. However, these treatment options are not specific, reduce the quality of life of patients and have significant side effects, therefore, there is an ongoing effort to design more specific immunotherapies. In this review, we review standard and immunotherapeutic options for EoE treatment, such as anti-IL-5, anti TNFalpha, anti-IgE, anti-CRTH, oral allergy desensitization and environmental immunotherapy. PMID- 24762080 TI - Development of atrial fibrillation after atrial flutter ablation: more a question of when than whether. PMID- 24762078 TI - Dendritic cell-based vaccines: clinical applications in breast cancer. AB - Recent evidence suggests that the immune system is involved in the carcinogenesis process and the antitumor immune responses impact the clinical outcome, thus emphasizing the concept of cancer immune surveillance. In this context, dendritic cells (DCs) seem to play a crucial role, as they are the most potent antigen presenting cells (APCs) and are able to stimulate naive T lymphocytes and to generate memory T lymphocytes. Immunotherapy with DC-based vaccines is a very attractive approach to treat cancer, offering the potential for high tumor specific cytotoxicity. Although breast cancer (BC) is traditionally considered a poorly immunogenic tumor, increasing numbers of both preclinical and clinical studies demonstrate that vaccination with DCs is capable of inducing an antitumor specific response, while being well tolerated and safe. However, clinical objective responses are still disappointing and many reasons may explain the difficulty of developing effective DC-based therapies for BC. In this review, we discuss the characteristics of DCs, and the major clinical indications for DC based immunotherapy in BC with related drawbacks. PMID- 24762081 TI - SLCO1B1, SLCO2B1, and SLCO1B3 polymorphisms and susceptibility to bladder cancer risk. AB - A variety of carcinogens are excreted in urine and may be actively transported by organic anion-transporting polypeptides that encoded by SLCOs. In this study, we evaluated whether single nucleotide polymorphisms (SNPs) in SLCO1B1, SLCO2B1, and SLCO1B3 are associated with bladder cancer susceptibility. Our results, for the first time, indicated that polymorphisms of SLCO1B1 rs2306283 might be associated with bladder cancer risk. Therefore, SNPs in SLCO1B1 may be potential biomarkers for assessing the risk of bladder cancer. PMID- 24762082 TI - Importance of glutamine metabolism in leukemia cells by energy production through TCA cycle and by redox homeostasis. AB - Some cancer cells depend on glutamine despite of pronounced glycolysis. We examined the glutamine metabolism in leukemia cells, and found that HL-60 cells most depended on glutamine in the 4 acute myelogenous leukemia (AML) cell lines examined: growth of HL-60 cells was most suppressed by glutamine deprivation and by inhibition of glutaminolysis, which was rescued by tricarboxylic acid (TCA) cycle intermediate, oxaloacetic acid. Glutamine is also involved in antioxidant defense function by increasing glutathione. Glutamine deprivation suppressed the glutathione content and elevated reactive oxygen species most evidently in HL-60 cells. Glutamine metabolism might be a therapeutic target in some leukemia. PMID- 24762084 TI - Nanostructured clathrate phonon glasses: beyond the rattling concept. AB - Using first-principles calculations, we investigated the thermoelectric properties of a newly synthesized Si-based ternary clathrate K8Al8Si38, composed of ~1 nm hollow cages with a metal atom inside. This compound contains solely Earth abundant elements. We found that, similar to other nanostructured type I clathrates, this system is a semiconductor and has a low thermal conductivity (~1 W/mK). It was long believed that the mere presence of rattling centers was responsible for the low lattice thermal conductivity of type I clathrates. We found instead that the cage structural disorder induced by atomic substitution plays a crucial role in determining the conductivity of these materials, in addition to the dynamics of the guest atoms. Our calculations showed that the latter is substantially affected by the charge transfer between the metal and the cages. Our results provide design rules for the search of new types of promising nanocage structured thermoelectric materials. PMID- 24762083 TI - Quantum mechanics/molecular mechanics study of oxygen binding in hemocyanin. AB - We report a combined quantum mechanics/molecular mechanics (QM/MM) study on the mechanism of reversible dioxygen binding in the active site of hemocyanin (Hc). The QM region is treated by broken-symmetry density functional theory (DFT) with spin projection corrections. The X-ray structures of deoxygenated (deoxyHc) and oxygenated (oxyHc) hemocyanin are well reproduced by QM/MM geometry optimizations. The computed relative energies strongly depend on the chosen density functional. They are consistent with the available thermodynamic data for oxygen binding in hemocyanin and in synthetic model complexes when the BH&HLYP hybrid functional with 50% Hartree-Fock exchange is used. According to the QM(BH&HLYP)/MM results, the reaction proceeds stepwise with two sequential electron transfer (ET) processes in the triplet state followed by an intersystem crossing to the singlet product. The first ET step leads to a nonbridged superoxo CuB(II)-O2(*-) intermediate via a low-barrier transition state. The second ET step is even more facile and yields a side-on oxyHc complex with the characteristic Cu2O2 butterfly core, accompanied by triplet-singlet intersystem crossing. The computed barriers are very small so that the two ET processes are expected to very rapid and nearly simultaneous. PMID- 24762085 TI - Educating the next generation of pulmonary fellows in transbronchial needle aspiration. Leading the blind to see. AB - Transbronchial needle aspiration (TBNA) remains an invaluable diagnostic tool in the evaluation of mediastinal and hilar abnormalities, specifically in the evaluation of patients with lung cancer. Training in TBNA has remained integral in pulmonary fellowship programs, but unfortunately the training methods, volumes, and outcomes have been variable. This has subsequently led to wide variations in practice patterns, diagnostic yield, and operator confidence. The introduction of endobronchial ultrasound-guided TBNA appears to have stimulated a resurgence in training and performance of TBNA. However, with this new technology, many questions have surfaced regarding training methods, volumes, and who should receive training. Within this context, we describe the history, current state, and future directions of the education of TBNA during pulmonary fellowship training. PMID- 24762087 TI - Preimplantation genetic diagnosis for cystic fibrosis: the Montpellier center's 10-year experience. AB - This study provides an overview of 10 years of experience of preimplantation genetic diagnosis (PGD) for cystic fibrosis (CF) in our center. Owing to the high allelic heterogeneity of CF transmembrane conductance regulator (CFTR) mutations in south of France, we have set up a powerful universal test based on haplotyping eight short tandem repeats (STR) markers together with the major mutation p.Phe508del. Of 142 couples requesting PGD for CF, 76 have been so far enrolled in the genetic work-up, and 53 had 114 PGD cycles performed. Twenty-nine cycles were canceled upon in vitro fertilization (IVF) treatment because of hyper- or hypostimulation. Of the remaining 85 cycles, a total of 493 embryos were biopsied and a genetic diagnosis was obtained in 463 (93.9%), of which 262 (without or with a single CF-causing mutation) were transferable. Twenty-eight clinical pregnancies were established, yielding a pregnancy rate per transfer of 30.8% in the group of seven couples with one member affected with CF, and 38.3% in the group of couples whose both members are carriers of a CF-causing mutation [including six couples with congenital bilateral absence of the vas deferens (CBAVD)]. So far, 25 children were born free of CF and no misdiagnosis was recorded. Our test is applicable to 98% of couples at risk of transmitting CF. PMID- 24762086 TI - Sox7 is regulated by ETV2 during cardiovascular development. AB - Vasculogenesis/angiogenesis is one of the earliest processes that occurs during embryogenesis. ETV2 and SOX7 were previously shown to play a role in endothelial development; however, their mechanistic interaction has not been defined. In the present study, concomitant expression of Etv2 and Sox7 in endothelial progenitor cells was verified. ETV2 was shown to be a direct upstream regulator of Sox7 that binds to ETV2 binding elements in the Sox7 upstream regulatory region and activates transcription. We observed that SOX7 over-expression can mimic ETV2 and increase endothelial progenitor cells in embryonic bodies (EBs), while knockdown of Sox7 is able to block ETV2-induced increase in endothelial progenitor cell formation. Angiogenic sprouting was increased by ETV2 over-expression in EBs, and it was significantly decreased in the presence of Sox7 shRNA. Collectively, these studies support the conclusion that ETV2 directly regulates Sox7, and that ETV2 governs endothelial development by regulating transcriptional networks which include Sox7. PMID- 24762089 TI - Spatial patterns of breeding success of grizzly bears derived from hierarchical multistate models. AB - Conservation programs often manage populations indirectly through the landscapes in which they live. Empirically, linking reproductive success with landscape structure and anthropogenic change is a first step in understanding and managing the spatial mechanisms that affect reproduction, but this link is not sufficiently informed by data. Hierarchical multistate occupancy models can forge these links by estimating spatial patterns of reproductive success across landscapes. To illustrate, we surveyed the occurrence of grizzly bears (Ursus arctos) in the Canadian Rocky Mountains Alberta, Canada. We deployed camera traps for 6 weeks at 54 surveys sites in different types of land cover. We used hierarchical multistate occupancy models to estimate probability of detection, grizzly bear occupancy, and probability of reproductive success at each site. Grizzly bear occupancy varied among cover types and was greater in herbaceous alpine ecotones than in low-elevation wetlands or mid-elevation conifer forests. The conditional probability of reproductive success given grizzly bear occupancy was 30% (SE = 0.14). Grizzly bears with cubs had a higher probability of detection than grizzly bears without cubs, but sites were correctly classified as being occupied by breeding females 49% of the time based on raw data and thus would have been underestimated by half. Repeated surveys and multistate modeling reduced the probability of misclassifying sites occupied by breeders as unoccupied to <2%. The probability of breeding grizzly bear occupancy varied across the landscape. Those patches with highest probabilities of breeding occupancy-herbaceous alpine ecotones-were small and highly dispersed and are projected to shrink as treelines advance due to climate warming. Understanding spatial correlates in breeding distribution is a key requirement for species conservation in the face of climate change and can help identify priorities for landscape management and protection. PMID- 24762088 TI - miR-125b induces cellular senescence in malignant melanoma. AB - BACKGROUND: Micro RNAs (miRs) have emerged as key regulators during oncogenesis. They have been found to regulate cell proliferation, differentiation, and apoptosis. Mir-125b has been identified as an oncomir in various forms of tumours, but we have previously proposed that miR-125b is a suppressor of lymph node metastasis in cutaneous malignant melanoma. Our goal was therefore to further examine this theory. METHODS: We used in-situ-hybridization to visualise miR-125b expression in primary tumours and in lymph node metastasis. Then using a miRVector plasmid containing a miR-125b-1 insert we transfected melanoma cell line Mel-Juso and then investigated the effect of the presence of a stable overexpression of miR-125b on growth by western blotting, flow cytometry and beta galactosidase staining. The tumourogenicity of the transfected cells was tested using a murine model and the tumours were further examined with in-situ hybridization. RESULTS: In primary human tumours and in lymph node metastases increased expression of miR-125b was found in single, large tumour cells with abundant cytoplasm. A stable overexpression of miR-125b in human melanoma cell line Mel-Juso resulted in a G0/G1 cell cycle block and emergence of large cells expressing senescence markers: senescence-associated beta-galactosidase, p21, p27 and p53. Mel-Juso cells overexpressing miR-125b were tumourigenic in mice, but the tumours exhibited higher level of cell senescence and decreased expression of proliferation markers, cyclin D1 and Ki67 than the control tumours. CONCLUSIONS: Our results confirm the theory that miR-125b functions as a tumour supressor in cutaneous malignant melanoma by regulating cellular senescence, which is one of the central mechanisms protecting against the development and progression of malignant melanoma. PMID- 24762090 TI - Follow-up of breast papillary lesion on core needle biopsy: experience in African American population. AB - BACKGROUND: The optimal course of clinical follow-up after a diagnosis of breast papillary lesion on a core needle biopsy (CNB) remains elusive. In particular, no reports in literature have addressed this question in African-American population. We describe our experience with breast papillary lesions in a primarily African-American population. METHODS: A search of our database for breast papillary lesions diagnosed on CNB between September 2002 and September 2012 was conducted. Cases were categorized into benign, atypical, and malignant. CK5/6 and CK903 stains were performed when necessary. RESULTS: A total of 64 breast papillary lesions were diagnosed on CNB, including 55 (86%) benign papillary lesions, 6 (9%) atypical lesions, and 3 (5%) intraductal papillary carcinomas. Of these 64 patients, 29 patients (25 African-Americans, 3 Hispanics, 1 Asian American) underwent lumpectomy within 6 months after CNB. Pathology of the lumpectomy showed: five of the 25 (20%) benign papillary lesions on needle biopsy were upgraded to intraductal or invasive papillary carcinoma; 2 of the 3 atypical papillary lesion cases on core biopsy were upgraded (67%), one into intraductal papillary carcinoma, the other invasive papillary carcinoma; the only case of malignant papillary lesion on CNB remained as intraductal papillary carcinoma on lumpectomy. The rate of upgrade in lumpectomy/mastectomy was 25%. CK5/6 and CK903 immunostains were performed on all seven core needle biopsies that were later upgraded. CONCLUSIONS: In our predominantly African-American urban population, 25% of benign or atypical papillary lesions diagnosed on CNB was upgraded in the final excisional examination. Early excision of all papillary lesions diagnosed on CNB may be justified in this patient population. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7950117821177201. PMID- 24762091 TI - Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism. AB - 1. Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS. 2. The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. 3. The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p = 0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p = 0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud's syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p = 0.037, p = 0.042, p = 0.039 and p = 0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p = 0.017). 4. The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease. PMID- 24762092 TI - Fate of antibiotic resistance genes and class 1 integrons in soil microcosms following the application of treated residual municipal wastewater solids. AB - Substantial quantities of antibiotic resistance genes (ARGs) are discharged with treated residual municipal wastewater solids and subsequently applied to soil. The objective of this work was to determine the decay rates for ARGs and class 1 integrons following simulated land application of treated wastewater solids. Treated residual solids from two full-scale treatment plants were applied to sets of triplicate soil microcosms in two independent experiments. Experiment 1 investigated loading rates of 20, 40, and 100 g kg(-1) of residual solids to a sandy soil, while experiment 2 investigated a loading rate of 40 g kg(-1) to a silty-loamy soil. Five ARGs (erm(B), sul1, tet(A), tet(W), and tet(X)), the integrase of class 1 integrons (intI1), 16S rRNA genes, 16S rRNA genes of all Bacteroides spp., and 16S rRNA genes of human-specific Bacteroides spp. were quantified using real-time polymerase chain reaction. ARGs and intI1 quantities declined in most microcosms, with statistically significant (P < 0.05) half-lives varying between 13 d (erm(B), experiment 1, 100 g kg(-1)) and 81 d (intI1, experiment 1, 40 g kg(-1)). These kinetic rates were much slower than have been previously reported for unit operations used to treat wastewater solids (e.g., anaerobic digestion). This research suggests that the design and operation of municipal wastewater treatment facilities with the explicit goal of mitigating the release of ARGs should focus on using technologies within the treatment facility, rather than depending on attenuation subsequent to land application. PMID- 24762093 TI - Fungemia in a Spanish hospital: the role of Candida parapsilosis over a 15-year period. AB - BACKGROUND: Candida parapsilosis is one of the main causes of fungemia in tertiary-care hospitals. Few studies have analysed the changes in its distribution over a long period. We compared the distribution of C. parapsilosis with that of other fungi over a 15-y period in a tertiary hospital. METHODS: The susceptibility of C. parapsilosis was analysed using the new species-specific clinical breakpoints. The C. parapsilosis complex species were differentiated molecularly. RESULTS: From January 1997 to December 2011, 360 isolates causing 350 episodes of fungemia were isolated. C. parapsilosis was the second most frequently isolated species (20%); only 1 C. orthopsilosis was identified and there were no C. metapsilosis. The remaining episodes were caused by C. albicans (43.1%), C. tropicalis (14.4%), C. glabrata (11.7%), and other fungal species (10.8%). The incidence of candidemia increased more than two-fold between 2009 and 2011 (from 3.3 to 7.4 cases/100,000 population), and C. parapsilosis and C. glabrata fungemia increased throughout the period. C. parapsilosis was the most frequent species in children under 15 y (57.1%). All C. parapsilosis isolates were susceptible to anidulafungin, micafungin, flucytosine, amphotericin B, and posaconazole, while 98.5% were susceptible to caspofungin, 97.1% to voriconazole, 95.6% to fluconazole, and 76.5% to itraconazole. CONCLUSIONS: This long-term study showed a slight increase in the incidence of candidemia during the years of the study and a trend towards an increase in C. parapsilosis. Because of its high frequency and intrinsic low susceptibility to echinocandins, the prevalence and susceptibility of C. parapsilosis should be monitored, especially in children. PMID- 24762096 TI - Toward a unified picture of the water self-ions at the air-water interface: a density functional theory perspective. AB - The propensities of the water self-ions, H3O(+) and OH(-), for the air-water interface have implications for interfacial acid-base chemistry. Despite numerous experimental and computational studies, no consensus has been reached on the question of whether or not H3O(+) and/or OH(-) prefer to be at the water surface or in the bulk. Here we report a molecular dynamics simulation study of the bulk vs interfacial behavior of H3O(+) and OH(-) that employs forces derived from density functional theory with a generalized gradient approximation exchange correlation functional (specifically, BLYP) and empirical dispersion corrections. We computed the potential of mean force (PMF) for H3O(+) as a function of the position of the ion in the vicinity of an air-water interface. The PMF suggests that H3O(+) has equal propensity for the interface and the bulk. We compare the PMF for H3O(+) to our previously computed PMF for OH(-) adsorption, which contains a shallow minimum at the interface, and we explore how differences in solvation of each ion at the interface vs in the bulk are connected with interfacial propensity. We find that the solvation shell of H3O(+) is only slightly dependent on its position in the water slab, while OH(-) partially desolvates as it approaches the interface, and we examine how this difference in solvation behavior is manifested in the electronic structure and chemistry of the two ions. PMID- 24762095 TI - Large-scale fungal diversity assessment in the Andean Yungas forests reveals strong community turnover among forest types along an altitudinal gradient. AB - The Yungas, a system of tropical and subtropical montane forests on the eastern slopes of the Andes, are extremely diverse and severely threatened by anthropogenic pressure and climate change. Previous mycological works focused on macrofungi (e.g. agarics, polypores) and mycorrhizae in Alnus acuminata forests, while fungal diversity in other parts of the Yungas has remained mostly unexplored. We carried out Ion Torrent sequencing of ITS2 rDNA from soil samples taken at 24 sites along the entire latitudinal extent of the Yungas in Argentina. The sampled sites represent the three altitudinal forest types: the piedmont (400 700 m a.s.l.), montane (700-1500 m a.s.l.) and montane cloud (1500-3000 m a.s.l.) forests. The deep sequence data presented here (i.e. 4 108 126 quality-filtered sequences) indicate that fungal community composition correlates most strongly with elevation, with many fungi showing preference for a certain altitudinal forest type. For example, ectomycorrhizal and root endophytic fungi were most diverse in the montane cloud forests, particularly at sites dominated by Alnus acuminata, while the diversity values of various saprobic groups were highest at lower elevations. Despite the strong altitudinal community turnover, fungal diversity was comparable across the different zonal forest types. Besides elevation, soil pH, N, P, and organic matter contents correlated with fungal community structure as well, although most of these variables were co-correlated with elevation. Our data provide an unprecedented insight into the high diversity and spatial distribution of fungi in the Yungas forests. PMID- 24762094 TI - Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). AB - AIMS: AWARD-5 was an adaptive, seamless, double-blind study comparing dulaglutide, a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist, with placebo at 26 weeks and sitagliptin up to 104 weeks. The study also included a dose-finding portion whose results are presented here. METHODS: Type 2 diabetes (T2D) patients on metformin were randomized 3 : 1 : 1 to seven dulaglutide doses, sitagliptin (100 mg), or placebo. A Bayesian algorithm was used for randomization and dose selection. Patients were adaptively randomized to dulaglutide doses using available data on the basis of a clinical utility index (CUI) of glycosylated haemoglobin A1c (HbA1c) versus sitagliptin at 52 weeks and weight, pulse rate (PR) and diastolic blood pressure (DBP) versus placebo at 26 weeks. The algorithm randomly assigned patients until two doses were selected. RESULTS: Dulaglutide 1.5 mg was determined to be the optimal dose. Dulaglutide 0.75 mg met criteria for the second dose. Dulaglutide 1.5 mg showed the greatest Bayesian mean change from baseline (95% credible interval) in HbA1c versus sitagliptin at 52 weeks -0.63 (-0.98 to -0.20)%. Dulaglutide 2.0 mg showed the greatest placebo adjusted mean change in weight [-1.99 (-2.88 to -1.20) kg] and in PR [0.78 (-2.10 to 3.80) bpm]. Dulaglutide 1.5 mg showed the greatest placebo-adjusted mean change in DBP [-0.62 (-3.40 to 2.30) mmHg]. CONCLUSIONS: The Bayesian algorithm allowed for an efficient exploration of a large number of doses and selected dulaglutide doses of 1.5 and 0.75 mg for further investigation in this trial. PMID- 24762098 TI - Hairy cell leukemia presenting initially with symptoms of Behcet's disease. AB - Vasculitis is relatively uncommon in lymphoproliferative disease and may predate the diagnosis of lymphoproliferative disease. Many vasculitides have been associated with hairy cell leukemia (HCL), including polyarteritis nodosa (PAN) and leukocytoclastic vasculitis. We herein report a case whose initial presentation was like Behcet's disease (BD) (arthritis, oral and genital ulcerations, papulopustular skin lesions) in addition to pancytopenia, but turned out to have HCL. Because of the overlap between their symptoms, like oral ulcerations, skin lesions, arthritis and constitutional findings, HCL and BD may mimic each other. We should keep in mind other reasons for vasculitis such as lymphoproliferative disease, especially whose who have hematological abnormalities such as pancytopenia. PMID- 24762097 TI - Computed tomographic characteristics of collateral venous pathways in dogs with caudal vena cava obstruction. AB - Collateral venous pathways develop in dogs with obstruction or increased blood flow resistance at any level of the caudal vena cava in order to maintain venous drainage to the right atrium. The purpose of this retrospective study was to describe the sites, causes of obstruction, and configurations of venous collateral pathways for a group of dogs with caudal vena cava obstruction. Computed tomography databases from two veterinary hospitals were searched for dogs with a diagnosis of caudal vena cava obstruction and multidetector row computed tomographic angiographic (CTA) scans that included the entire caudal vena cava. Images for each included dog were retrieved and collateral venous pathways were characterized using image postprocessing and a classification system previously reported for humans. A total of nine dogs met inclusion criteria and four major collateral venous pathways were identified: deep (n = 2), portal (n = 2), intermediate (n = 7), and superficial (n = 5). More than one collateral venous pathway was present in 5 dogs. An alternative pathway consisting of renal subcapsular collateral veins, arising mainly from the caudal pole of both kidneys, was found in three dogs. In conclusion, findings indicated that collateral venous pathway patterns similar to those described in humans are also present in dogs with caudal vena cava obstruction. These collateral pathways need to be distinguished from other vascular anomalies in dogs. Postprocessing of multidetector-row CTA images allowed delineation of the course of these complicated venous pathways and may be a helpful adjunct for treatment planning in future cases. PMID- 24762099 TI - Therapeutic strategies for cytomegalovirus infection in haematopoietic transplant recipients: a focused update. AB - INTRODUCTION: Cytomegalovirus (CMV) remains a significant cause of morbidity and mortality in immunocompromised patients, particularly following allogeneic haematopoietic transplantation. One of the principal factors leading to this increased risk is the loss of T-cell immunity. AREAS COVERED: In a recent review, we assessed the treatment strategies for prophylaxis and pre-emptive treatment of CMV, particularly where relevant to the high-risk patient populations following allogeneic haematopoietic transplantation. This review is a focused update to our previous article and presents a more detailed analysis of the developments in drugs, vaccines and adoptive T-cell therapies since that time. Relevant studies were selected from PubMed and clinicaltrials.gov. The search terms include allogeneic transplant, cytomegalovirus, multidrug-resistant virus and adoptive T cell therapy. EXPERT OPINION: The current randomised controlled studies evaluating pharmacological agents for CMV should inform as to whether these provide significant clinical benefits. Adoptive cell therapy provides a more physiological approach to the problem of lack of CMV-specific immunity. Recent reports add to the evidence that culture-based techniques can create cellular products that are safe and efficacious, although without Phase III data to definitively support their routine application and the difficulty of satisfying GMP standards. PMID- 24762101 TI - Spin-dependent quantum interference in nonlocal graphene spin valves. AB - Up to date, all spin transport experiments on graphene were done in a semiclassical regime, disregarding quantum transport properties such as phase coherence and interference. Here we show that in a quantum coherent graphene nanostructure the nonlocal voltage is strongly modulated. Using nonlocal measurements, we separate the signal in spin-dependent and spin-independent contributions. We show that the spin-dependent contribution is about 2 orders of magnitude larger than the spin-independent one, when corrected for the finite polarization of the electrodes. The nonlocal spin signal is not only strongly modulated but also changes polarity as a function of the applied gate voltage. By locally tuning the carrier density in the constriction via a side gate electrode we show that the constriction plays a major role in this effect. Our results show the potential of quantum coherent graphene nanostructures for the use in future spintronic devices. PMID- 24762100 TI - Protective mechanical ventilation in the non-injured lung: review and meta analysis. PMID- 24762102 TI - Will Choosing Wisely(r) improve quality and lower costs of care for patients with critical illness? AB - In 2009, a group of experts convened by the Institute of Medicine estimated that 30% of health care costs amounted to waste, including a substantial share from nonbeneficial and often harmful services. Professional organizations and medical ethicists subsequently called on specialty groups to generate "top five" lists of expensive tests or treatments without known benefits. Responding to this call, the American Board of Internal Medicine launched its Choosing Wisely campaign, with the top-five Choosing Wisely lists for pulmonary medicine and critical care released in 2014. In order for the critical care list to have an impact on costs and quality, two things must occur: providers whose practice is discordant with the list must adhere to the list when making decisions, and those decisions must lead to improvements in the quality of care at lower costs. Although the campaign addresses some limitations of past efforts to improve quality and reduce waste, we believe it will do little to change provider behavior. Even if the top-five list for critical care were to change the behavior of providers, its ultimate impact on costs and quality will be lower than anticipated. Here we suggest several strategies for stakeholders to increase the impact of the critical care top-five list, and further discuss that despite limitations of the campaign it is still imperative for advancing best practice in critical care. PMID- 24762103 TI - Why do farmers and veterinarians not report all bovine abortions, as requested by the clinical brucellosis surveillance system in France? AB - BACKGROUND: Since 2005, France has been officially free of brucellosis, an infectious disease that causes abortion in cattle and can be transmitted from cattle to humans. Recent animal and human cases have drawn attention to the need to prevent infection of humans and animals from any primary outbreaks. In order to detect any new outbreaks as soon as possible, a clinical surveillance system requires farmers and veterinarians to report each abortion and to test the aborting cow for brucellosis. However, under-reporting limits the sensitivity of this system. Our objective was to identify the barriers and motivations influencing field actors in their decision to report or not to report bovine abortions. We used a qualitative approach with semi-structured interviews of 12 cattle farmers and their eight veterinarians. RESULTS: Our analysis showed that four main themes influence the decision-making process of farmers and veterinarians: 1) the perceived risk of brucellosis and other abortive diseases; 2) the definition of a suspected case of brucellosis and other abortive diseases adopted by field actors, which is less sensitive than the mandatory definition; 3) the cost-benefit analysis conducted by actors, taking into account regulatory and health aspects, economic and financial losses, technical and practical factors; 4) the level of cooperation within the socio-technical network. We discussed how early detection may be improved by revising the definition of abortion, extending the time frame for notification and generalising the differential diagnosis of the causes of abortion. CONCLUSIONS: In contrast to quantitative approaches, qualitative studies can identify the factors (including unknown factors) influencing the decision-making process of field actors and reveal why they take those factors into consideration. Our qualitative study sheds light on the factors underlying the poor sensitivity of clinical brucellosis surveillance system for cattle in France, and suggests that early detection may be improved by considering actors' perceptions. We believe our findings may provide further insight into ways of improving other clinical surveillance systems and thus reduce the risk of disease. PMID- 24762104 TI - The actin/MKL1 signalling pathway influences cell growth and gene expression through large-scale chromatin reorganization and histone post-translational modifications. AB - In addition to soluble factors, mechanical constraints and extracellular matrix stiffness are important regulators of cell fate that are mediated by cytoskeletal modifications. The EMT (epithelial-mesenchymal transition) that occurs during normal development and malignant progression is a typical example of the phenotypic switch associated with profound actin remodelling and changes in gene expression. For instance, actin dynamics control motile cell functions in EMT, in part, through regulating the subcellular localization of the myocardin-related transcription factor MKL1 (megakaryoblastic leukaemia translocation 1), a co activator of SRF (serum-responsive factor). In the present paper, we show that MKL1 participates also to the control of the cellular switch between growth and quiescence. Experimental disconnection between MKL1 and G-actin (globular actin), by using an MKL1 mutant or enhancing the F (filamentous)-/G-actin ratio, generates a widely open chromatin state and a global increase in biosynthetic activity, classically associated with cell growth. Conversely, G-actin accumulation favours nuclear condensation and cell quiescence. These large-scale chromatin changes rely upon extensive histone modifications, exemplified by that of H3K9 (H3 Lys9) shifting from trimethylation, a heterochromatin mark, to acetylation, a mark of euchromatin. The present study provides the first evidence for a global reversible hetero/euchromatinization phenomenon triggered by the actin/MKL1 signalling pathway. PMID- 24762105 TI - Involvement of ectodomain Leu 214 in ATP binding and channel desensitization of the P2X4 receptor. AB - P2X receptors are trimeric ATP-gated cation permeable ion channels. When ATP binds, the extracellular head and dorsal fin domains are predicted to move closer to each other. However, there are scant functional data corroborating the role of the dorsal fin in ligand binding. Here using site-directed mutagenesis and electrophysiology, we show that a dorsal fin leucine, L214, contributes to ATP binding. Mutant receptors containing a single substitution of alanine, serine, glutamic acid, or phenylalanine at L214 of the rat P2X4 receptor exhibited markedly reduced sensitivities to ATP. Mutation of other dorsal fin side chains, S216, T223, and D224, did not significantly alter ATP sensitivity. Exposure of L214C to sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES(-)) or (2 aminoethyl) methanethiosulfonate hydrobromide in the absence of ATP blocked responses evoked by subsequent ATP application. In contrast, when MTSES(-) was applied in the presence of ATP, no current inhibition was observed. Furthermore, L214A also slightly reduced the inhibitory effect of the antagonist 2',3'-O (2,4,6-trinitrophenyl)-ATP, and the blockade was more rapidly reversible after washout. Certain L214 mutants also showed effects on current desensitization in the continued presence of ATP. L214I exhibited an accelerated current decline, whereas L214M exhibited a slower rate. Taken together, these data reveal that position L214 participates in both ATP binding and conformational changes accompanying channel opening and desensitization, providing compelling evidence that the dorsal fin domain indeed has functional properties that are similar to those previously reported for the body domains. PMID- 24762106 TI - Wnt of the two horizons: putting stem cell self-renewal and cell fate determination into context. AB - The canonical Wnt/beta-catenin pathway has long been associated with self-renewal and expansion of embryonic stem cells (ESCs). Recent studies have brought into question some earlier assumptions concerning the functional role that canonical Wnt signaling plays in self-renewal mechanisms by demonstrating clear effects on differentiation. In addition, Wnt is crucial for cell fate determination during embryogenesis. The seemingly contradictory data compiled over several years now point to a more complex system of organismal development by which the downstream effects of Wnt activity are largely determined by the context in which signaling occurs. This review will assess seemingly contradictory findings regarding Wnt signaling in either self-renewal or differentiation in ESCs and then explicate cellular scenarios that determine the context by which Wnt ligands exert their differential effects. Both physiological embryonic development and pathogenic adult carcinogenesis provide opportunities to gleam illuminating insights from stem or stem-like progenitor cells that place Wnt signaling at the center of important cellular decisions to expand or differentiate. The impact of heterogeneity, concentration, metabolic state, and the array of accessible interacting cofactors from various signaling pathways that regulate these functions in ESCs will be critically examined, and implications for early embryonic development and cancer biology will be explored. PMID- 24762107 TI - Distinct male reproductive strategies in two closely related oak species. AB - Reproductive strategies of closely related species distributed along successional gradients should differ as a consequence of the trade-off between competition and colonization abilities. We compared male reproductive strategies of Quercus robur and Q. petraea, two partly interfertile European oak species with different successional status. In the studied even-aged stand, trees of the late successional species (Q. petraea) grew faster and suffered less from intertree competition than trees of the early-successional species (Q. robur). A large scale paternity study and a spatially explicit individual-based mating model were used to estimate parameters of pollen production and dispersal as well as sexual barriers between species. Male fecundity was found to be dependent both on a tree's circumference and on its environment, particularly so for Q. petraea. Pollen dispersal was greater and more isotropic in Q. robur than in Q. petraea. Premating barriers to hybridization were strong in both species, but more so in Q. petraea than in Q. robur. Hence, predictions based on the competition colonization trade-off are well supported, whereas the sexual barriers themselves seem to be shaped by colonization dynamics. PMID- 24762108 TI - Sustained exposure to the investigational Kisspeptin analog, TAK-448, down regulates testosterone into the castration range in healthy males and in patients with prostate cancer: results from two phase 1 studies. AB - BACKGROUND/OBJECTIVE: Kisspeptin-54, an endogenous naturally occurring ligand of the G protein-coupled receptor-54, stimulates GnRH-gonadotropin secretion and suppresses metastases in animal models of cancer but is subject to rapid degradation and inactivation. TAK-448 is an investigational oligopeptide analog of the fully active 10-amino acid C terminus of kisspeptin-54. This phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of TAK-448 in healthy subjects and patients with prostate cancer (PC). DESIGN: Healthy subjects aged 50 years or older received TAK-448 sc as a single-bolus or 2-hour infusion (0.01-6 mg/d; part A) and as a 14-day sc administration (0.01-1 mg/d; part B). In a subsequent, open-label, phase 1 study in PC patients aged 40-78 years, TAK-448 was given as a 1-month depot formulation. RESULTS: Eighty-two healthy subjects received TAK-448; 30 received placebo. Grades 1-2 adverse events were reported in 26% of subjects during TAK-448 treatment. All dosing regimens resulted in dose proportional exposures. The maximum observed plasma concentration occurred after 0.25-0.5 hours, and median terminal elimination half-life was 1.4-5.3 hours. T increased approximately 1.3- to 2-fold by 48 hours after a single bolus or 2 hour injections, whereas during the 14-day infusion, at doses above 0.1 mg/d, T dropped to below-baseline values by 60 hours and reached a subsequently sustained below-castration level by day 8. In PC patients, T decreased to less than 20 ng/dL in four of five patients dosed with 12 or 24 mg TAK-448 sc-depot injections. The prostate-specific antigen decreased greater than 50% in all patients dosed with 24 mg. CONCLUSIONS: Continuous TAK-448 infusion was well tolerated by healthy males and resulted in sustained T suppression. Depot injection in patients with PC similarly reduced T and resulted in prostate specific antigen responses. PMID- 24762109 TI - Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial. AB - CONTEXT: The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined. OBJECTIVE: The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years. DESIGN: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: The study was conducted at two US pediatric endocrine centers. SUBJECTS: Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset. INTERVENTION(S): Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age. MAIN OUTCOME MEASURES: The main outcome measures for this report were median ages at Tanner breast stage >=2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed. RESULTS: Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not. CONCLUSIONS: In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome. PMID- 24762110 TI - The effect of prepubertal calcium carbonate supplementation on skeletal development in Gambian boys-a 12-year follow-up study. AB - CONTEXT: Calcium intake during growth is essential for future bone health but varies widely between individuals and populations. The impact on bone of increasing calcium intake is unknown in a population where low calcium intake, stunting, and delayed puberty are common. OBJECTIVE: To determine the effect of prepubertal calcium supplementation on mean age at peak velocity for bone growth and mineral accrual. DESIGN AND SETTING: Prospective follow-up of boys in rural Gambia, West Africa, who had participated in a double-blind, randomized, placebo controlled trial of calcium supplementation. PARTICIPANTS: Eighty boys, initially aged 8.0-11.9 years, were followed up for 12 years. INTERVENTIONS: Subjects received 1 year of calcium carbonate supplementation (1000 mg daily, 5 d/wk). MAIN OUTCOME MEASURES: Dual-energy x-ray absorptiometry measurements were carried out for whole body (WB), lumbar spine, and total hip bone mineral content, bone area (BA), and WB lean mass. Super imposition by translation and rotation models was made to assess bone growth. RESULTS: Age at peak velocity was consistently earlier in the calcium group compared to the placebo group, for WB bone mineral content (mean, -6.2 [SE, 3.1]; P = .05), WB BA (mean, -7.0 [SE, 3.2] mo; P = .03), lumbar spine and total hip BA. By young adulthood, supplementation did not change the amount of bone accrued (mineral or size) or the rate of bone growth. CONCLUSIONS: Twelve months of prepubertal calcium carbonate supplementation in boys with a low calcium diet advanced the adolescent growth spurt but had no lasting effect on bone mineral or bone size. There is a need for caution when applying international recommendations to different populations. PMID- 24762111 TI - Seated saline suppression testing for the diagnosis of primary aldosteronism: a preliminary study. AB - CONTEXT: Failure of aldosterone suppression by sodium loading during fludrocortisone suppression testing (FST) or saline suppression testing (SST) confirms primary aldosteronism (PA). We previously found recumbent SST (RSST) to lack sensitivity. Aldosterone levels can be higher upright (e.g. seated) than recumbent in patients with PA and upright levels are used during FST. We therefore hypothesized that seated SST (SSST) is more sensitive than RSST, especially for posture-responsive PA. SETTING AND DESIGN: Of 66 patients who underwent FST (upright plasma aldosterone levels measured at 10am basally and after 4 days fludrocortisone 0.1 mg 6-hourly and oral salt loading), 31 underwent SST (aldosterone levels measured basally at 8am and after infusion of 2 L normal saline over 4h) both recumbent and seated in randomized order and at least 2 weeks apart. RESULTS: FST confirmed PA in 23 of 31 patients (day 4 upright aldosterone level >165 pmol/L), excluded PA in three and was originally "inconclusive" in five. However, one with "inconclusive" FST had PA confirmed by lateralizing AVS and was reclassified "unilateral PA". Of 24 with confirmed PA (eight unilateral, 11 bilateral, and five undetermined subtype), 23 (96%) tested positive by SSST (4-h aldosterone level >165 pmol/L) compared with 8 (33%) by RSST (4-h plasma aldosterone level >140 pmol/L) (P < .001). RSST missed one unilateral, all bilateral, and four with as-yet undetermined subtype. RSST was positive in 7 of 10 (70%) posture-unresponsive vs one of 14 (7.1%) posture responsive patients (P < .005). CONCLUSION: These preliminary results suggest that seated SST may be superior to recumbent SST in terms of sensitivity for detecting PA, especially posture-responsive forms, and may represent a reliable alternative to FST. PMID- 24762112 TI - Increased body mass index, elevated C-reactive protein, and short telomere length. AB - CONTEXT: Obesity is associated with short telomere length. The cause of this association is unknown. OBJECTIVE: We hypothesized that genetically increased body mass index (BMI) is associated with telomere length shortening and that low grade inflammation might contribute through elevated C-reactive protein. SETTING AND DESIGN: We studied 45,069 individuals from the Copenhagen General Population Study with measurements of leukocyte telomere length, BMI, and C-reactive protein in a Mendelian randomization study. Using the three obesity-associated polymorphisms FTO rs9939609, MC4R rs17782313, and TMEM18 rs6548238, and the CRP promoter polymorphism rs3091244 in instrumental variable analyses, we estimated the associations between genetically increased BMI and telomere length and between genetically increased C-reactive protein and telomere length. RESULTS: In multivariable-adjusted observational analyses, telomere length decreased with seven base pairs (95% confidence interval, -9--5) per unit increase in BMI, and further adjustment for C-reactive protein attenuated this association to -5 base pairs (-8--3). In accordance, instrumental variable analysis showed a non significant telomere length shortening of six base pairs (-37-25) per unit increase in genetically determined BMI. Furthermore, in observational analyses, telomere length decreased with nine base pairs (-16--2) for a doubling in C reactive protein, supported by the instrumental variable analyses showing a corresponding genetically determined decrease of 66 base pairs (-124--7). CONCLUSIONS: High BMI is associated with short telomere length observationally. This might possibly be mediated through elevated C-reactive protein, given that genetically elevated C-reactive protein levels are associated with short telomere length. PMID- 24762113 TI - Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations. AB - CONTEXT: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common. OBJECTIVE: The aim was to identify underlying genetic causes of short stature with advanced bone age. SETTING AND DESIGN: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation. RESULTS: Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c.2026+1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function. CONCLUSIONS: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation. PMID- 24762114 TI - No adverse affect in clinical outcome using low preablation diagnostic (131)i activity in differentiated thyroid cancer: refuting thyroid-stunning effect. AB - CONTEXT: Published studies of thyroid stunning due to preablation (131)I scanning in the treatment of differentiated thyroid cancer after thyroidectomy had shown inconsistent clinical impact. OBJECTIVE: The objective of the study was to evaluate the clinical outcome in patients who were given a low diagnostic (131)I activity (1.1 mCi or 40 MBq) 6 days prior to radioiodine ablation (RAI). DESIGN/SETTING: Two cohorts of patients were treated in a cancer referral center in 2004-2011. The eligibility criteria were as follows: 1) diagnosis of differentiated thyroid cancer; 2) total or near total thyroidectomy; 3) no distant metastasis; and 4) receiving 82.4 mCi or greater (3050 MBq) therapeutic (131)I activity. PATIENTS/INTERVENTIONS: Three hundred five consecutive patients treated in 2004-2008 (group A) had a diagnostic activity 1.1 mCi of (131)I prior to RAI. The second cohort treated in 2009-2011 (group B) consisted of 237 patients who did not undergo diagnostic (131)I scanning prior to RAI. MAIN OUTCOME MEASURES: The tumor recurrence rate at 3 years and quantitative assessment using diagnostic whole-body radioiodine scans and TSH-stimulated thyroglobulin levels at 3-12 months after RAI were measured. RESULTS: The 3-year recurrence-free survival rates were 96.4% in both groups, with 4.3% in group A and 3.4% in group B having tumor recurrence (P = .91). The ablation success rates measured by diagnostic whole-body radioiodine scans were 97.6% and 100% and by stimulated thyroglobulin were 85.3% and 85.8% in group A and B, respectively (P = .62). CONCLUSIONS: The use of low diagnostic (131)I activity (1.1 mCi) given 6 days prior to RAI was safe and convenient without adversely affecting the long term clinical outcome. PMID- 24762115 TI - Tumor aerobic glycolysis: new insights into therapeutic strategies with targeted delivery. AB - INTRODUCTION: Cancer cells acclimatize to the harsh tumor microenvironment by altering cellular metabolism in favor of aerobic glycolysis. This process provides a source of energy and also generates essential components for macromolecular biosynthesis, which enables cellular survival. As the dependence of cancer cells on glycolysis affects tumorigenesis, it has become an attractive target for therapeutic intervention. Several preclinical studies have shown the effectiveness of using biological targets from the glycolytic pathway for anticancer therapy. AREAS COVERED: This review provides an insight into the glycolytic pathway, highlighting potential targets for glycolytic inhibition. We then discuss recent advancement in delivery strategies that have the potential to circumvent some of the problems posed by current glycolytic inhibitors, enabling resurrection of abandoned therapeutic agents. EXPERT OPINION: Targeting the glycolysis pathway is a tactical approach for cancer therapy. However, the current nonspecific therapeutic strategies have several drawbacks such as poor bioavailability, unfavorable pharmacokinetic profile and associated nonspecific toxicity, thereby limiting preclinical investigation. In recent years, nanoparticle systems have received recognition for the delivery of therapeutic agents directly to the tumor tissue. Thus, it is envisaged that this strategy can be expanded for the delivery of current glycolytic inhibitors specifically to tumor tissues providing improved anticancer activity. PMID- 24762116 TI - Practical science communication strategies for graduate students. AB - Development of skills in science communication is a well-acknowledged gap in graduate training, but the constraints that accompany research (limited time, resources, and knowledge of opportunities) make it challenging to acquire these proficiencies. Furthermore, advisors and institutions may find it difficult to support graduate students adequately in these efforts. The result is fewer career and societal benefits because students have not learned to communicate research effectively beyond their scientific peers. To help overcome these hurdles, we developed a practical approach to incorporating broad science communication into any graduate-school time line. The approach consists of a portfolio approach that organizes outreach activities along a time line of planned graduate studies. To help design the portfolio, we mapped available science communication tools according to 5 core skills essential to most scientific careers: writing, public speaking, leadership, project management, and teaching. This helps graduate students consider the diversity of communication tools based on their desired skills, time constraints, barriers to entry, target audiences, and personal and societal communication goals. By designing a portfolio with an advisor's input, guidance, and approval, graduate students can gauge how much outreach is appropriate given their other commitments to teaching, research, and classes. The student benefits from the advisors' experience and mentorship, promotes the group's research, and establishes a track record of engagement. When graduate student participation in science communication is discussed, it is often recommended that institutions offer or require more training in communication, project management, and leadership. We suggest that graduate students can also adopt a do-it-yourself approach that includes determining students' own outreach objectives and time constraints and communicating these with their advisor. By doing so we hope students will help create a new culture of science communication in graduate student education. PMID- 24762117 TI - QT interval prolongation in end-stage liver disease cannot be explained by nonhepatic factors. AB - INTRODUCTION: QT interval prolongation in patients with end-stage liver disease (ESLD) is common. However, electrolyte abnormalities, renal insufficiency, treatment with QT-prolonging drugs, and other factors known to prolong QT interval independently of liver disease occur frequently in ESLD. Moreover, elevated heart rate may be present in ESLD and result in spurious QTc prolongation if the Bazett formula is used for rate correction. It thus remains unclear whether QT prolongation in ESLD is directly caused by liver failure, or indirectly by these confounding factors. METHODS: Medical records of all patients (n = 437) who received orthotopic liver transplantation (OLTx) at our institution between 2008 and 2011 were reviewed. Data from 51 patients with available pre OLTx dobutamine stress echo (DSE), post-OLTx ECG and without nonhepatic factors affecting QT interval duration were analyzed. For each patient, QT versus RR regression line was calculated from ECG tracings obtained during DSE. The QT interval on post-OLTx ECG was compared with the pre-OLTx QT predicted by the regression line for the same RR interval. RESULTS: QT interval shortened significantly post-OLTx (from 394 +/- 47 to 364 +/- 45 ms at RR interval 750 +/- 144 ms; P < 0.002) when compared using the regression method. Corrected QT intervals calculated by Bazett and Fridericia formulas also shortened. Patients with prolonged QT pre-OLTx had significantly higher INR and lower serum albumin. CONCLUSION: ESLD impairs ventricular repolarization even in the absence of other known factors affecting repolarization. QT prolongation in ESLD is associated with impaired synthetic liver function. PMID- 24762118 TI - Dynamical transition and heterogeneous hydration dynamics in RNA. AB - Enhanced dynamical fluctuations of RNAs, facilitated by a network of water molecules with strong interactions with RNA, are suspected to be critical in their ability to respond to a variety of cellular signals. Using atomically detailed molecular dynamics simulations at various temperatures of purine (adenine) and preQ1 sensing riboswitch aptamers, which control gene expression by sensing and binding to metabolites, we show that water molecules in the vicinity of RNAs undergo complex dynamics depending on the local structures of the RNAs. The overall lifetimes of hydrogen bonds (HBs) of surface-bound waters are more than at least 1-2 orders of magnitude longer than those of bulk water. Slow hydration dynamics, revealed in the non-Arrhenius behavior of the relaxation time, arises from high activation barriers to break water HBs with a nucleotide and by reduced diffusion of water. The relaxation kinetics at specific locations in the two RNAs show a broad spectrum of time scales reminiscent of glass-like behavior, suggesting that the hydration dynamics is highly heterogeneous. Both RNAs undergo dynamic transition at T = TD ? 200 K, as assessed by the mean-square fluctuation of hydrogen atoms ?x(2)?, which undergoes an abrupt harmonic-to anharmonic transition at TD. The near-universal value of TD found for these RNAs and previously for tRNA is strongly correlated with changes in hydration dynamics as T is altered. Hierarchical dynamics of waters associated with the RNA surface, revealed in the motions of distinct classes of water with well-separated time scales, reflects the heterogeneous local environment on the molecular surface of RNA. At low temperatures, slow water dynamics predominates over structural transitions. Our study demonstrates that the complex interplay of dynamics between water and the local environment in the RNA structures could be a key determinant of the functional activities of RNA. PMID- 24762120 TI - Iron complexes derived from {nacnac-(CH2py)2}- and {nacnac-(CH2py)(CHpy)}n ligands: stabilization of iron(II) via redox noninnocence. AB - Nacnac-based tetradentate chelates, {nacnac-(CH2py)2}(-) ({nn(PM)2}(-)) and {nacnac-(CH2py)(CHpy)}(n) ({nn(PM)(PI)}(n)) have been investigated in iron complexes. Treatment of Fe{N(TMS)2}2(THF) with {nn(PM)2}H afforded {nn(PM)2}FeN(TMS)2 [1-N(TMS)2], which led to {nn(PM)2}FeCl (1-Cl) from HCl and to {nn(PM)2}FeN3 (1-N3) upon salt metathesis. Dehydroamination of 1-N(TMS)2 was induced by L (L = PMe3, CO) to afford {nn(PM)(PI)}Fe(PMe3)2 [2-(PMe3)2] and {nn(PM)(PI)}FeCO (3-CO). Substitution of 2-(PMe3)2 led to {nn(PM)(PI)}Fe(PMe3)CO [2-(PMe3)CO], and exposure to a vacuum provided {nn(PM)(PI)}Fe(PMe3) (3-PMe3). Metathesis routes to {nn(PM)(PI)}FeL2 (2-L2; L = PMe3, PMe2Ph) and {nn(PM)(PI)}FeL (3-L; L = PMePh2, PPh3) from [{nn(PM)(PI)}(2-)]Li2 and FeBr2(THF)2 in the presence of L proved feasible, and 1e(-) and 2e(-) oxidation of 2-(PMe3)2 afforded 2(+)-(PMe3)2 and 2(2+)-(PMe3)2 salts. Mossbauer spectroscopy, structural studies, and calculational assessments revealed the dominance of iron(II) in both high-spin (1-X) and low-spin (2-L2 and 3-L) environments, and the redox noninnocence (RNI) of {nn(PM)(PI)}(n) [2-L2, 3-L, n = 2-; 2(+)-(PMe3)2, n = 1-; 2(2+)-(PMe3)2, n = 0]. A discussion regarding the utility of RNI in chemical reactivity is proffered. PMID- 24762119 TI - Combination therapy with metformin plus sulphonylureas versus metformin plus DPP 4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. AB - AIMS: To compare the risk of major adverse cardiovascular events (MACE) and mortality for combination therapies with metformin and either sulphonylurea (SU) or dipeptidyl peptidase-4 inhibitor (DPP-4i). METHODS: Data were from the UK Clinical Practice Research Datalink (CPRD). Patients with type 2 diabetes were selected if initiated with combination therapies comprising metformin plus SU or DPP-4i 2007-2012. The co-primary endpoints were all-cause mortality and MACE (myocardial infarction or stroke). Times to endpoints were compared using Cox proportional hazards models. Additional analyses were performed on subsets matched directly on key characteristics and by propensity score. RESULTS: A total of 33 983 patients were prescribed SU and 7864 DPP-4i, and 5447 patients in each cohort could be matched directly and 6901 by propensity score. In the main analysis, there were 716 MACE events and 1217 deaths. Crude event rates for MACE were 11.3 events per 1000 person-years (pkpy) for SU, versus 5.3 pkpy for DPP-4i. For all-cause mortality, rates were 16.9 versus 7.3 pkpy, respectively. Following adjustment, there was a significant increase in the adjusted hazard ratio (aHR) for all-cause mortality in those exposed to SU across all analytical models: aHR = 1.357 (95% CI 1.076-1.710) for all subjects, 1.850 (1.245-2.749) directly matched and 1.497 (1.092-2.052) propensity-matched. For MACE, aHR was 1.710 (1.280-2.285) for all subjects, 1.323 (0.832-2.105) directly matched and 1.547 (1.076-2.225) propensity-matched. CONCLUSIONS: There was a reduction in all-cause mortality for patients treated with metformin combined with DPP-4i versus metformin plus SU, and a similar trend for MACE. PMID- 24762121 TI - Behcet's disease. PMID- 24762122 TI - Directed ortho metalation strategies. Effective regioselective routes to 1,2-, 2,3-, and 1,2,3-substituted naphthalenes. AB - The regioselective synthesis of 2,3-di- and 1,2,3-trisubstituted naphthalenes via Directed ortho Metalation (DoM) strategies of N,N-diethyl-O-naphthyl-2-carbamate (1) is presented. Sequential LiTMP metalation-electrophile quench and s BuLi/TMEDA (or t-BuLi)-electrophile quench of naphthyl-2-carbamate 1 provides a general route to contiguously substituted naphthalenes (6) with full regioselectivity. Further derivatization via ipso-halodesilylation and Suzuki Miyaura cross-coupling leads ultimately to substituted halonaphthalenes and benzonaphthopyranones (9). PMID- 24762123 TI - Correlates of female sexual functioning: adult attachment and differentiation of self. AB - INTRODUCTION: Female sexual functioning is affected by a range of factors including motivation, psychological well-being, and relationship issues. In understanding female sexual dysfunction (FSD), there has been a tendency to privilege diagnostic and medical over relationship issues. AIM: To investigate the association between women's experience of intimacy in close relationships operationalized in terms of attachment and degree of differentiation of self-and FSD. METHODS: Two hundred thirty sexually active Australian women responded to an invitation to complete a set of validated scales to assess potential correlates of sexual functioning. MAIN OUTCOME MEASURES: The Female Sexuality Function Index, the Experiences in Close Relationships Scale, the Differentiation of Self Inventory, as well as a set of study-specific questions were subject to hierarchical multiple regression analyses. RESULTS: Relational variables of attachment avoidance and to a lesser degree, attachment anxiety were associated with FSD. Participants with lower levels of differentiation of self were more likely to report sexual difficulties. The inability to maintain a sense of self in the presence of intimate others was the strongest predictors of sexual problems. A history of sexual abuse in adulthood and higher levels of psychological distress were also associated with sexual difficulties. CONCLUSIONS: The findings provide support for a relational understanding of female sexual functioning. Attachment avoidance, attachment anxiety, and degree of differentiation of self are shown to be associated with sexual difficulties. The findings support the need to focus on relational and psychological factors in women's experience of sex. PMID- 24762124 TI - Ventriculoarterial decoupling in human septic shock. AB - INTRODUCTION: Septic shock is the most severe manifestation of sepsis. It is characterized as a hypotensive cardiovascular state associated with multiorgan dysfunction and metabolic disturbances. Management of septic shock is targeted at preserving adequate organ perfusion pressure without precipitating pulmonary edema or massive volume overload. Cardiac dysfunction often occurs in septic shock patients and can significantly affect outcomes. One physiologic approach to detect the interaction between the heart and the circulation when both are affected is to examine ventriculoarterial coupling, which is defined by the ratio of arterial elastance (Ea) to left ventricular end-systolic elastance (Ees). In this study, we analyzed ventriculoarterial coupling in a cohort of patients admitted to ICUs who presented with vs without septic shock. METHODS: In this retrospective cross-sectional opportunity study, we measured routine hemodynamics using indwelling arterial and pulmonary arterial catheters and transthoracic echocardiograms in 25 septic patients (group S) and 25 non-septic shock patients (group C) upon ICU admission. Ees was measured by echocardiography using a single beat (EesSB) method. Ea was calculated as 0.9 systolic arterial pressure/stroke volume, and then the Ea/EesSB ratio was calculated (normal value <1.36). RESULTS: In group S, 21 patients had an Ea/EesSB ratio >1.36 (uncoupled). The four patients with Ea/EesSB ratios <=1.36 had higher EesSB values than patients with Ea/EesSB ratios >1.36 (P = 0.007), although Ea measurements were similar in both groups (P = 0.4). In group C, five patients had uncoupled Ea/EesSB ratios. No correlation was found between EesSB and left ventricular ejection fraction and between Ea/EesSB ratio and mixed venous oxygen saturation in septic shock patients. CONCLUSIONS: Upon admission to the ICU, patients in septic shock often display significant ventriculoarterial decoupling that is associated with impaired left ventricular performance. Because Ea/Ees decoupling alters cardiovascular efficiency and cardiac energetic requirements independently of Ea or Ees, we speculate that septic patients with ventriculoarterial uncoupling may benefit from therapy aimed at normalizing the Ea/Ees ratio. PMID- 24762126 TI - Will a novel semi-quantitative scale for classification of structural brain MRI improve patient care and research in children with cerebral palsy? PMID- 24762125 TI - Palladium-catalyzed hydroxylation of aryl and heteroaryl halides enabled by the use of a palladacycle precatalyst. AB - A method for the hydroxylation of aryl and heteroaryl halides, promoted by a catalyst based on a biarylphosphine ligand tBuBrettPhos (L5) and its corresponding palladium precatalyst (1), is described. The reactions allow the cross-coupling of both potassium and cesium hydroxides with (hetero)aryl halides to afford a variety of phenols and hydroxylated heteroarenes in high to excellent yield. PMID- 24762127 TI - Conformational analysis of the anti-HIV Nikavir prodrug: comparisons with AZT and Thymidine, and establishment of structure-activity relationships/tendencies in other 6'-derivatives. AB - A comprehensive theoretical conformational analysis of the anti-HIV Nikavir prodrug was carried out; this prodrug has noticeable advantage over the approved drug AZT. The whole conformational parameters (chi, alpha, beta, gamma, delta, phi, P and numax) were analysed as well as the NBO natural atomic charges. The calculations were carried out by means of DFT/B3LYP and ab initio MP2 methods with full relaxation of all geometrical parameters. The search located at least 67 stable structures, 4 of which were within a 1 kcal/mol electronic energy range of the global minimum. By MP2 it corresponds to the calculated values of the exocyclic torsional angles chi=-108.0 degrees , beta=14.5 degrees , gamma=76.7 degrees and epsilon=71.5 degrees . The results obtained are in accordance to those found in related anti-HIV nucleoside analogues. Comparisons of the conformers with those determined in the common anti-HIV drug AZT were carried out. A detailed analysis of the lowest vibrations (<200 cm(-1)) in the best conformer of Nikavir was carried out. The most stable hydrated cluster of this conformer with 20 explicit water molecules was determined. Calculations in five of its 6'-derivatives were performed to identify structural trends that might correlate with the anti-HIV activity of these compounds. Ten structure-activity relationships/tendencies were established that can help for the design of new drugs. Several recommendations for this design were expressed. PMID- 24762130 TI - Ways of knowing: realism, non-realism, nominalism and a typology revisited with a counter perspective for nursing science. AB - In this paper, we reconsider the context of Barbara Carper's alternative ways of knowing, a prominent discourse in modern nursing theory in North America. We explore this relative to the concepts of realism, non-realism and nominalism, and investigate the philosophical divisions behind the original typology, particularly in relationship to modern scientific enquiry. We examine forms of knowledge relative to realist and nominalist positions and make an argument ad absurdum against relativistic interpretations of knowledge using the example of Borge's Chinese Emporium of Benevolent Knowledge. We propose a contentious postpositivist practical classification for nursing knowledge that demonstrates and supports the idea that knowledge has both individual and subjective components. This classification supports the practical application of nursing knowledge within the paradigm of realist postpositivist science. PMID- 24762128 TI - Reversible effects of photodamage directed toward mitochondria. AB - When the initial effect of photodynamic therapy (PDT) involves mitochondrial photodamage, an early effect is loss of the mitochondrial membrane potential (DeltaPsim ). Using murine hepatoma 1c1c7 cells and a photosensitizing agent known to target mitochondria, we examined loss of DeltaPsim , initiation of apoptosis and loss of viability as a function of time and light dose. There was a correlation between loss of viability and the rapid disappearance of DeltaPsim, as detected by the potential-sensitive probe Mitotracker Orange (MTO). Loss of DeltaPsim was, however, reversible even with a substantial loss of viability. Unless there was a supralethal level of photodamage, 1c1c7 cells recovered their mitochondrial membrane potential, even if the cell population was on the pathway to apoptosis and cell death. These results indicate that when mitochondria are the initial PDT target, a qualitative estimate of photokilling can be provided by assessing the initial loss of DeltaPsim. PMID- 24762131 TI - Nonlinear-optical properties of alpha-diiminedithiolatonickel(II) complexes enhanced by electron-withdrawing carboxyl groups. AB - We report the synthesis, characterization, nonlinear-optical (NLO) properties, and density functional theory (DFT) calculations for three nickel diiminedithiolate complexes [Ni(4,4'-R2carboxy-bpy)(L)] [R = methyl, L = 1,2 benzenedithiolate (bdt), 1; R = ethyl, L = 5,6-dihydro-1,4-dithine-2,3-dithiolate (dddt), 2; R = ethyl, L = 1-(N-methylindol-5-yl)ethene-1,2-dithiolate (mi-5edt), 3]. The crystal structure of 1 shows a square-planar coordination for the nickel ion and bond distances consistent with a diiminedithiolate description for the complex. For all complexes, the cyclic voltammetry measurements show two reversible reduction processes (-1.353/-1.380 V and -0798/-0.830 V, respectively) and an anodic wave (+0.372/+0.601 V). The UV-vis spectra present a band around 600-700 nm (epsilon = 4880-6000 dm(3) mol(-1) cm(-1)) mainly attributed to a charge-transfer highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) transition, which shows a large negative solvatochromic shift, characteristic of push-pull complexes, and is responsible for the NLO properties of these molecules. The charge-transfer character of this electronic transition is confirmed by DFT calculations, with the HOMO mainly centered on the dithiolate moiety and the LUMO on the bpy ligand, with important contribution given by the carboxyl groups (~13%). Small contributions from the nickel(II) ion are present in both of the frontier orbitals. The carboxyl groups enhance the optical properties of this class of complexes, confirmed by comparison with the corresponding unsubstituted compounds. The second-order NLO properties have been measured by an electric-field-induced second-harmonic-generation technique using a 10(-3) M solution in N,N-dimethylformamide and working with a 1.907 MUm incident wavelength, giving for MUbeta1.907 (MUbeta0) values of -1095 (-581), 2760 (-954), and -1650 (-618) * 10(-48) esu for 1-3, respectively. These values are among the highest in the class of square-planar push-pull complexes, similar to those found for dithionedithiolate compounds. Moreover, spectroelectrochemical experiments demonstrate the possibility of using these complexes as redox switchable NLO chromophores. PMID- 24762132 TI - Effect of sterol side chain on ion channel formation by amphotericin B in lipid bilayers. AB - Amphotericin B (AmB) is one of the most efficient antimycotic drugs used in clinical practice. AmB interacts with membrane sterols increasing permeability of fungal membranes; however, it is still unclear how AmB selectively recognizes the fungal sterol, ergosterol (Erg), over other sterols in cell membranes. In this study, we investigated the effect of an Erg side chain on AmB activity by testing a series of Erg analogues that shared the same alicyclic structure as Erg but varied in the side chain structure by using the K(+) influx assay. The results clearly showed that the sterol side chain is essential for AmB selectivity toward Erg and for the activity of AmB-sterol ion channels. In agreement with our previous findings showing the direct interaction between the drug and Erg, these data suggested that AmB directly recognizes the sterol side chain structure, consequently promoting the formation of ion channels by AmB. Furthermore, the C24 methyl group and Delta22 double bond in the side chain of Erg are equally important for the interaction with AmB. Conformational analysis revealed that the C24 methyl group contributes to the interaction by increasing the van der Waals (VDW) contact area of the side chain, while the Delta22 double bond restricts the side chain conformation to maximize the VDW contact with the rigid AmB aglycone. This study provides direct experimental evidence of the mechanism of AmB selectivity toward fungal Erg. PMID- 24762129 TI - Divergent transcriptional responses to low temperature among populations of alpine and lowland species of New Zealand stick insects (Micrarchus). AB - In widespread and genetically structured populations, temperature variation may lead to among-population differentiation of thermal biology. The New Zealand stick insect genus Micrarchus contains four species that inhabit different thermal environments, two of which are geographically widespread. RNA-Seq and quantitative PCR were used to investigate the transcriptional responses to cold shock among lowland and alpine species to identify cold-responsive transcripts that differ between the species and to determine whether there is intraspecific geographical variation in gene expression. We also used mitochondrial DNA, nuclear 28S ribosomal DNA and transcriptome-wide SNPs to determine phylogeographic structure and the potential for differences in genetic backgrounds to contribute to variation in gene expression. RNA-Seq identified 2160 unigenes that were differentially expressed as a result of low-temperature exposure across three populations from two species (M. hystriculeus and M. nov. sp. 2), with a majority (68% +/- 20%) being population specific. This extensive geographical variation is consistent across years and is likely a result of background genetic differences among populations caused by genetic drift and possibly local adaptation. Responses to cold shock shared among alpine M. nov. sp. 2 populations included the enrichment of cuticular structure-associated transcripts, suggesting that cuticle modification may have accompanied colonization of low-temperature alpine environments and the development of a more cold-hardy phenotype. PMID- 24762133 TI - The impact of depression and ghrelin on body weight in migraineurs. AB - BACKGROUND: Comorbidity of migraine with anxiety and depression may play a role in the link between migraine and obesity. We examined the moderating and mediating roles of ghrelin in the relationship between depression (and anxiety) and body weight in newly diagnosed migraineurs. METHODS: Participants were 63 newly diagnosed migraine patients (using the ICHD-II criteria) and 42 healthy volunteers. Body mass index (BMI) was calculated by measuring height and weight. Ghrelin was assessed at fasting. Depression was assessed with the Hamilton Depression scale, and anxiety with the Hamilton Anxiety scale. RESULTS: The data did not support the mediating role of ghrelin in the relationship between depression (or anxiety) and BMI for either the migraine or the control group. The interaction between ghrelin and depression as well as anxiety was significant for the migraine group, but not for the control group. Depressed (or anxious) migraineurs had a positive association between ghrelin and BMI, whereas for the non-depressed (or non-anxious) migraineurs this association was negative. CONCLUSIONS: Depression and anxiety moderated the effect of ghrelin on BMI for migraineurs. Management of anxiety and depression might be regarded as part of migraine treatment. PMID- 24762134 TI - Predictive validity of the UK clinical aptitude test in the final years of medical school: a prospective cohort study. AB - BACKGROUND: The UK Clinical Aptitude Test (UKCAT) was designed to address issues identified with traditional methods of selection. This study aims to examine the predictive validity of the UKCAT and compare this to traditional selection methods in the senior years of medical school. This was a follow-up study of two cohorts of students from two medical schools who had previously taken part in a study examining the predictive validity of the UKCAT in first year. METHODS: The sample consisted of 4th and 5th Year students who commenced their studies at the University of Aberdeen or University of Dundee medical schools in 2007. Data collected were: demographics (gender and age group), UKCAT scores; Universities and Colleges Admissions Service (UCAS) form scores; admission interview scores; Year 4 and 5 degree examination scores. Pearson's correlations were used to examine the relationships between admissions variables, examination scores, gender and age group, and to select variables for multiple linear regression analysis to predict examination scores. RESULTS: Ninety-nine and 89 students at Aberdeen medical school from Years 4 and 5 respectively, and 51 Year 4 students in Dundee, were included in the analysis. Neither UCAS form nor interview scores were statistically significant predictors of examination performance. Conversely, the UKCAT yielded statistically significant validity coefficients between .24 and .36 in four of five assessments investigated. Multiple regression analysis showed the UKCAT made a statistically significant unique contribution to variance in examination performance in the senior years. CONCLUSIONS: Results suggest the UKCAT appears to predict performance better in the later years of medical school compared to earlier years and provides modest supportive evidence for the UKCAT's role in student selection within these institutions. Further research is needed to assess the predictive validity of the UKCAT against professional and behavioural outcomes as the cohort commences working life. PMID- 24762135 TI - The community speaks: understanding ethical values in allocation of scarce lifesaving resources during disasters. AB - INTRODUCTION: Pandemic influenza or other crises causing mass respiratory failure could easily overwhelm current North American critical care capacity. This threat has generated large-scale federal, state, and local efforts to prepare for a public health disaster. Few, however, have systematically engaged the public regarding which values are most important in guiding decisions about how to allocate scarce healthcare resources during such crises. METHODS: The aims of this pilot study were (1) to test whether deliberative democratic methods could be used to promote engaged discussion about complex, ethically challenging healthcare-related policy issues and (2) to develop specific deliberative democratic procedures that could ultimately be used in a statewide process to inform a Maryland framework for allocating scarce healthcare resources during disasters. Using collaboratively developed focus group materials and multiple metrics for assessing outcomes, we held 5-hour pilot community meetings with a combined total of 68 community members in two locations in Maryland. The key outcomes used to assess the project were (1) the comprehensibility of the background materials and ethical principles, (2) the salience of the ethical principles, (3) the perceived usefulness of the discussions, (4) the degree to which participants' opinions evolved as a result of the discussions, and (5) the quality of participant engagement. RESULTS: Most participants were thoughtful, reflective, and invested in this pilot policy-informing process. Throughout the pilot process, changes were made to background materials, the verbal introduction, and pre- and post-surveys. Importantly, by holding pilot meetings in two distinct communities (an affluent suburb and inner city neighborhood), we discerned that participants' ethical reflections were framed in large part by their place-based life experiences. CONCLUSION: This pilot process, coupled with extensive feedback from participants, yielded a refined methodology suitable for wider-scale use and underscored the need for involvement of diverse communities in a statewide engagement process on this critical policy issue. PMID- 24762136 TI - Symbiosomes: temporary moonlighting organelles. AB - Symbiosomes are a unique structural entity that performs the role of biological nitrogen fixation, an energy-demanding process that is the primary entryway of fixed nitrogen into the biosphere. Symbiosomes result from the infection of specific rhizobial strains into the roots of an appropriate leguminous host plant forming an organ referred to as a nodule. Within the infected plant cells of the nodule, the rhizobia are encased within membrane-bounded structures that develop into symbiosomes. Mature symbiosomes create an environment that allows the rhizobia to differentiate into a nitrogen-fixing form called bacteroids. The bacteroids are surrounded by the symbiosome space, which is populated by proteins from both eukaryotic and prokaryotic symbionts, suggesting this space is the quintessential component of symbiosis: an inter-kingdom environment with the single purpose of symbiotic nitrogen fixation. Proteins associated with the symbiosome membrane are largely plant-derived proteins and are non-metabolic in nature. The proteins of the symbiosome space are mostly derived from the bacteroid with annotated functions of carbon metabolism, whereas relatively few are involved in nitrogen metabolism. An appreciable portion of both the eukaryotic and prokaryotic proteins in the symbiosome are also 'moonlighting' proteins, which are defined as proteins that perform roles unrelated to their annotated activities when found in an unexpected physiological environment. The essential functions of symbiotic nitrogen fixation of the symbiosome are performed by co-operative interactions of proteins from both symbionts some of which may be performing unexpected roles. PMID- 24762137 TI - The expression of the tumour suppressor HBP1 is down-regulated by growth factors via the PI3K/PKB/FOXO pathway. AB - Growth factors inactivate the FOXO (forkhead box O) transcription factors through PI3K (phosphoinositide 3-kinase) and PKB (protein kinase B). By comparing microarray data from multiple model systems, we identified HBP1 (high-mobility group-box protein 1) as a novel downstream target of this pathway. HBP1 mRNA was down-regulated by PDGF (platelet-derived growth factor), FGF (fibroblast growth factor), PI3K and PKB, whereas it was up-regulated by FOXO factors. This observation was confirmed in human and murine fibroblasts as well as in cell lines derived from leukaemia, breast adenocarcinoma and colon carcinoma. Bioinformatics analysis led to the identification of a conserved consensus FOXO binding site in the HBP1 promoter. By luciferase activity assay and ChIP, we demonstrated that FOXO bound to this site and regulated the HBP1 promoter activity in a PI3K-dependent manner. Silencing of HBP1 by shRNA increased the proliferation of human fibroblasts in response to growth factors, suggesting that HBP1 limits cell growth. Finally, by analysing a transcriptomics dataset from The Cancer Genome Atlas, we observed that HBP1 expression was lower in breast tumours that had lost FOXO expression. In conclusion, HBP1 is a novel target of the PI3K/FOXO pathway and controls cell proliferation in response to growth factors. PMID- 24762138 TI - Prevalence of bluetongue virus infection and associated risk factors among cattle in North Kordufan State, Western Sudan. AB - BACKGROUND: Bluetongue virus causes febrile disease in sheep and a fatal hemorrhagic infection in North American White-tailed deer. However, in cattle the disease is typically asymptomatic and no clinical overt disease is associated with bluetongue infection. Bluetongue virus activity has been detected in Khartoum, Sennar and South Darfur states of the Sudan. Currently, no information is available in regard to previous exposure of livestock to Bluetongue virus in North Kordufan State, the largest livestock producing region in the country. The present study was conducted to determine the prevalence of bluetongue antibodies and to identify the potential risk factors associated with the presence of bluetongue antibodies among cattle in North Kordufan State, Sudan. A total of 299 bovine blood samples were collected randomly from six localities in North Kordufan State and were tested by enzyme-linked immunosorbent assay (ELISA) for detection of BTV-specific immunoglobulin G (IgG) antibodies. RESULTS: The serological evidence of Bluetongue virus infection was observed in 58 out of 299 cows, accounting for a 19.4% prevalence rate among cattle in North Kordufan State. Older cattle (>2 years of age) had four times the odds to be infected with BTV compared to young cattle (OR = 4.309, CI = 1.941-9.567, p-value = 0.01). Application of preventive measures, such as spraying or dipping with insecticide protects cattle against Bluetongue infection. Application of vector control measures decreased the odds for bluetongue seropositivity by 7 times (OR = 7.408, CI = 3.111-17.637, p-value = 0.01). CONCLUSIONS: The results of this study indicated that age and application of routine insecticides are influential risk factors for seroprevalence of Bluetongue in cattle. Surveillance of Bluetongue virus should be extended to include other susceptible animals and to study the distribution of the insect vectors in the region to better predict and respond to BTV outbreak in the State of North Kordufan, Sudan. PMID- 24762139 TI - What is the impact of SOCS3, IL-35 and IL17 in immune pathogenesis of recurrent pregnancy loss? AB - OBJECTIVE: To investigate the plasma levels of interleukin-4 (IL-4), IL-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta), IL-17, IL-35 and suppressor of cytokine signaling 3 (SOCS3) in the women with history of idiopathic recurrent pregnancy loss (RPL) and in the fertile controls. METHODS: This study was conducted with 60 idiopathic RPL cases and 40 age-matched fertile controls. Mid follicular plasma levels of IL-17, IFN-gamma, TNF-alpha, TGF-beta, IL-6, IL-4, IL 10, SOCS3 and IL-35 were assayed by an enzyme linked immunosorbent assay. RESULTS: The mean age of RPL and control cases were 31.6 +/- 0.6 and 32.1 +/- 0.7 years, respectively. While plasma IL-35 and SOCS3 levels of RPL group were significantly lower than that of the control group; IFN-gamma, TNF-alpha, IL-4, IL-6, IL-10, IL-17 and TGF-beta levels of RPL group were significantly higher than that of the control group. The comparison of cytokine ratios between RPL and control groups indicated significantly high TNF-alpha/IL-10, TNF-alpha/IL-4, IFN gamma/IL-10, IFN-gamma/IL-6 and IFN-gamma/IL-4 ratios in the RPL group. IL-35/IL 17 ratio was significantly low in the RPL group compared to that in the control group. Overstimulation of TNF-alpha presented moderate influence on recurrent miscarriage risk. CONCLUSION: Decreased SOCS3 and IL-35 plasma levels and increased Th1/Th2 cytokine ratios in RPL cases pointed out the supression of anti inflammatory process and this supression might play an important role in the pathogenesis of idiopathic RPL. PMID- 24762140 TI - Fat and thin actors, Roscoe 'Fatty' Arbuckle 1887-1933. PMID- 24762142 TI - Cyclic aldimines as superior electrophiles for Cu-catalyzed decarboxylative Mannich reaction of beta-ketoacids with a broad scope and high enantioselectivity. AB - A novel Cu-catalyzed enantioselective decarboxylative Mannich reaction of cyclic aldimines with beta-ketoacids is described. The cyclic structure of these aldimines, in which the C?N bond is constrained in the Z geometry, appears to be important, allowing Mannich condensation to proceed in high yields with excellent enantioselectivities. A chiral chroman-4-amine was synthesized from the decarboxylative Mannich product in several steps without loss of enantioselectivity. PMID- 24762141 TI - Combination of 13-Cis retinoic acid and lovastatin: marked antitumor potential in vivo in a pheochromocytoma allograft model in female athymic nude mice. AB - Currently, there are no reliably effective therapeutic options for metastatic pheochromocytoma (PCC) and paraganglioma. Moreover, there are no therapies that may prevent the onset or progression of tumors in patients with succinate dehydrogenase type B mutations, which are associated with very aggressive tumors. Therefore, we tested the approved and well-tolerated drugs lovastatin and 13-cis retinoic acid (13cRA) in vitro in an aggressive PCC mouse cell line, mouse tumor tissue-derived (MTT) cells, and in vivo in a PCC allograft nude mouse model, in therapeutically relevant doses. Treatment was started 24 hours before sc tumor cell injection and continued for 30 more days. Tumor sizes were measured from outside by caliper and sizes of viable tumor mass by bioluminescence imaging. Lovastatin showed antiproliferative effects in vitro and led to significantly smaller tumor sizes in vivo compared with vehicle treatment. 13cRA promoted tumor cell growth in vitro and led to significantly larger viable tumor mass and significantly faster increase of viable tumor mass in vivo over time compared with vehicle, lovastatin, and combination treatment. However, when combined with lovastatin, 13cRA enhanced the antiproliferative effect of lovastatin in vivo. The combination-treated mice showed slowest tumor growth of all groups with significantly slower tumor growth compared with the vehicle-treated mice and significantly smaller tumor sizes. Moreover, the combination-treated group displayed the smallest size of viable tumor mass and the slowest increase in viable tumor mass over time of all groups, with a significant difference compared with the vehicle- and 13cRA-treated group. The combination-treated tumors showed highest extent of necrosis, lowest median microvessel density and highest expression of alpha-smooth muscle actin. The combination of high microvessel density and low alpha-smooth muscle actin is a predictor of poor prognosis in other tumor entities. Therefore, this drug combination may be a well-tolerated novel therapeutic or preventive option for malignant PCC. PMID- 24762143 TI - Geriatric fractures about the hip: divergent patterns in the proximal femur, acetabulum, and pelvis. AB - Geriatric acetabular, pelvis, and subtrochanteric femur fractures are poorly understood and rapidly growing clinical problems. The purpose of this study was to describe the epidemiologic trends of these injuries as compared with traditional fragility fractures about the hip. From 1993 to 2010, the Nationwide Inpatient Sample (NIS) recorded more than 600 million Medicare-paid hospital discharges. This retrospective study used the NIS to compare patients with acetabular fractures (n=87,771), pelvic fractures (n=522,831), and subtrochanteric fractures (n=170,872) with patients with traditional hip fractures (intertrochanteric and femoral neck, n=3,495,742) with regard to annual trends over an 18-year period in incidence, length of hospital stay, hospital mortality, transfers from acute care institutions, and hospital charges. Traditional hip fractures peaked in 1996 and declined by 25.7% by 2010. During the same 18-year period, geriatric acetabular fractures increased by 67%, subtrochanteric femur fractures increased by 42%, and pelvic fractures increased by 24%. Hospital charges, when controlling for inflation, increased roughly 50% for all fracture types. Furthermore, transfers from outside acute care hospitals for definitive management stayed elevated for acetabular fractures as compared with traditional hip fractures, suggesting a greater need for tertiary care of acetabular fractures. Geriatric acetabular fractures are rapidly increasing, whereas traditional hip fractures continue to decline. Patients with these injuries are more likely to be transferred from their hospital of presentation to another acute care institution, possibly increasing costs and complications. This is likely related to their complexity and the lack of consensus regarding optimal management. PMID- 24762144 TI - Torsional properties of distal femoral cortical defects. AB - The optimal management of pathologic long bone lesions remains a challenge in orthopedic surgery. The goal of the current study was to investigate the effect of defect depth on the torsional properties of the distal femur. A laterally placed distal metaphyseal cylindrical defect was milled in the cortex of the distal femur in 20 composite models. The proximal extent of the defects was constant. By decreasing the radius of the cylinder that intersected this predefined cord, 4 different radii defining 4 different depths of resection of the distal femur were created for testing: 17%, 33%, 50%, and 67% cortical defects, when normalized to the width of the femur at the level of resection. Each femur was mounted into a hydraulic axial/torsion materials testing machine and each specimen underwent torsional stiffness testing and torsional failure in external rotation. The specimens with less than a 33% cortical loss consistently demonstrated a superiorly oriented spiral fracture pattern, while the specimens with greater than a 50% cortical loss consistently demonstrated an inferiorly oriented transverse fracture pattern. The cortical defects were all statistically (P<.05) less stiff in torsion as the defect grew larger. There was a strong linear correlation between the mean torsional stiffness and cortical defect size (r(2)=0.977). This observation is supported by finite element analysis. The amount of femur remaining is crucial to stability. This biomechanical analysis predicts a critical loss of torsional integrity when a cortical defect approaches 50% of the width of the femur. PMID- 24762145 TI - Placing femoral intramedullary nails in severely bowed femurs. AB - The authors describe a novel technique of anterograde femoral intramedullary nail fixation for hip fracture using the starting guide pin as a blocking screw. This cost-effective technique uses fluoroscopic radiography to ensure the guidewire is within the posterior aspect of the femur on a lateral view, thereby minimizing the risk of anterior cortical femoral fractures. PMID- 24762146 TI - Total knee arthroplasty after high tibial osteotomy. AB - High tibial osteotomy may be indicated in the treatment of varus knee in young, active patients. The preservation of proprioception and native joint and biomechanics is crucial for functional recovery in these patients. However, deterioration of initial good results can occur with time. In such cases, revision with total knee arthroplasty is indicated. However, this is a more surgically demanding option compared with a primary prosthesis. Accurate preoperative planning is mandatory to decrease the risk of intraoperative complications. A precise surgical technique, which is crucial to improving functional outcomes, includes hardware removal, joint exposition, tibial deformities due to previous osteotomy, and managing soft tissue mismatches. Possible technical challenges and surgical solutions exist for each of these aspects. However, several studies report lower functional results compared with primary implants. Thus, patients should be informed before high tibial osteotomy about its failure rate, the difficult surgical aspects of an additional prosthesis, and less satisfactory clinical results. PMID- 24762147 TI - Influence of nail prominence and insertion point on anterior knee pain after tibial intramedullary nailing. AB - Chronic anterior knee pain is the most common complication after tibial nail insertion. Its etiology remains unknown, and multifactorial sources have been suggested. The authors believe that nail prominence and the insertion point of the nail are important in the development of anterior knee pain. The purpose of this retrospective study was to evaluate the roles of the insertion point and nail prominence in anterior knee pain after tibial intramedullary nailing using a transtendinous approach and a common nail type. A total of 108 patients with tibial shaft fractures underwent reamed intramedullary nailing using a transtendinous approach between 2006 and 2009. Mean follow-up was 26.8+/-5.0 months. A visual analog scale (0-100) was used to estimate anterior knee pain severity while patients performed 7 activities retrospectively. Radiographic assessments, including nail prominence and insertion point, were performed. Sixty (55.6%) patients experienced knee pain (group P) and 48 (44.4%) did not (group N). Significant differences were not found between the groups with respect to demographics, nail diameters, or fracture classifications. Less superior and more anterior nail prominences in radiographic assessments were significantly associated with anterior knee pain. When the insertion point was over the bottom half of the anterior cortex, the influence of anterior nail prominence was more obvious. Nail removal resulted in diminished pain during the 7 assessed activities. Nail insertion should be over the bottom half of the anterior cortex, with minimal anterior nail prominence. If anterior knee pain occurs, removal of the nail should be considered. PMID- 24762148 TI - Incidence of syndesmotic injury. AB - Injury to the tibiofibular syndesmosis can occur with ankle sprain or fracture. The incidence of syndesmotic injury has not been specifically studied at a population level. Data on syndesmotic injury were obtained from the Healthcare Cost and Utilization Project (HCUP), a federal-state-private partnership. It is administered by the Agency for Healthcare Research and Quality, a division of the US Department of Health and Human Services. Two HCUP databases were queried for 8 states: the State Inpatient Database and the State Emergency Department Database. The first 6 International Classification of Diseases, Ninth Edition (ICD-9) code diagnoses were searched for codes that are used for syndesmotic injury (ie, 845.03). These data, along with data from the 2010 US census, were used to yield incidence rates for syndesmosis injury, as well as for various demographic groups. National estimates of injury totals were also calculated. In the 8 states, there were a total of 1821 syndesmotic injuries. Given the population of these states, the incidence rate of syndesmotic injury was 2.09 syndesmotic injuries per 100,000 person-years. This incidence correlates to an estimated 6445 syndesmotic injuries per year in the United States. These data provide some baseline numbers as to the incidence of syndesmotic injury in the United States. Although the incidence was low relative to some other injuries, the fact that syndesmotic injuries tend to occur in younger patients may have a greater effect in terms of productive years of life lost. PMID- 24762149 TI - Biologic augmentation of foot and ankle arthrodeses with an allogeneic cancellous sponge. AB - This case series was conducted to assess the safety and efficacy of using an allogeneic cancellous bone sponge for augmentation of foot and ankle arthrodeses. Twenty-five patients were prospectively enrolled in the study prior to undergoing fusion and were then followed for 12 months postoperatively. There were 45 joints: 7 ankles, 12 subtalars, 12 talonaviculars, 6 calcaneocuboids, 1 naviculocuneiform, 6 first tarsometatarsals, and 1 second tarsometatarsal. Patient-reported outcomes of pain (visual analog scale) and function (American Orthopaedic Foot and Ankle Society score) were obtained preoperatively and postoperatively at 6 and 12 months. No complications were noted intraoperatively or during the follow-up period. Three months postoperatively, radiographic osseous union was noted in 52% (13/25) of patients, which further increased to 96% (24/25) of patients at 6 and 12 months. There was no statistically significant difference in union time between joints [H(6)=11.5; P=.08]. Statistically significant improvements in pain (P<=.002) and function (P<.001) were observed across assessments. This study demonstrated that the cancellous bone sponge appears to be a safe and efficacious product. Randomized controlled trials are warranted to determine if the allogeneic cancellous sponge improves fusion rate, pain, and function. PMID- 24762150 TI - Minimally invasive plate osteosynthesis using a helical plate for metadiaphyseal complex fractures of the proximal humerus. AB - Minimally invasive plate osteosynthesis (MIPO) has been used for humeral shaft fractures, but concerns exist about soft tissue injuries. The purpose of this study was to report the surgical technique and clinical outcomes of MIPO using a helical plate for metadiaphyseal complex humeral shaft fractures. Twelve patients with acute displacement involving proximal and middle third humeral shaft fractures (AO type C) were treated using the MIPO technique with a helical plate. Fracture union, complications, and functional outcomes were evaluated using the Constant-Murley score and Mayo Elbow Performance Score (MEPS) at final follow-up. All fractures united at an average of 17.9 weeks. No major complications, such as neurovascular injury, infection, and nonunion, were observed. Mean Constant Murley and MEPS scores at final follow-up were 88.6 and 97.9, respectively. A MIPO technique using a helical plate can be a useful surgical option for metadiaphyseal complex fractures of the humeral shaft. PMID- 24762151 TI - Effect of depression on femoral head avascular necrosis from femoral neck fracture in patients younger than 60 years. AB - The purpose of this study was to determine the effect of depression on femoral head avascular necrosis (AVN) from femoral neck fracture in patients younger than 60 years and the relationship between depression and postoperative quality of life. The Beck Depression Inventory-II (BDI-II) was completed by 641 patients (352 men and 289 women; average age, 41.7+/-10.2 years; range, 20-60 years) postoperatively. Patients were divided into groups according to BDI-II score: a depressed group (BDI-II score of 14 or higher) and a nondepressed group (BDI-II score lower than 14). They were followed for an average of 28 months (range, 24 37 months). The postoperative diagnosis was confirmed by typical radiographs and single photon-emission computed tomography. Quality of life among patients was assessed using the Short Form-36 (SF-36) questionnaire. The overall incidences of depression and AVN were 30.6% (196 of 641) and 20.9% (134 of 641), respectively. Ninety-four (48.0%) patients in the depressed group and 40 (9.0%) patients in the nondepressed group ultimately developed AVN. Symptoms of depression significantly affected AVN. In addition, depression predicted patients' quality of life, as did sex, partner status, employment status, living alone, frequency of exercise, severity of fractures, and length of hospital stay. In a multiple linear regression model analyzing all of these variables, depression was the best independent predictor of quality of life. Depression in patients younger than 60 years with femoral neck fractures may increase postoperative femoral head AVN risk and greatly affect patients' quality of life. PMID- 24762152 TI - Safety of bilateral total knee arthroplasty in morbidly obese patients. AB - There has been an increase in the prevalence of morbid obesity and the demand for total knee arthroplasty (TKA). Physicians must help patients with bilateral knee arthritis to make informed decisions regarding whether to undergo staged, sequential, or simultaneous TKA. The purpose of this study was to evaluate the perioperative complications of 2-team simultaneous bilateral TKA in the morbidly obese. The authors performed a retrospective review of the records at a single tertiary hospital from 1997 to 2007 and identified 35 morbidly obese (body mass index [BMI] greater than 40 kg/m(2)) patients who had undergone unilateral TKA, as well as 42 morbidly obese and 79 nonobese (BMI less than 30 kg/m(2)) patients who underwent simultaneous bilateral TKA. Clinical, operative, and postoperative variables and complication rates were recorded. Clinical variables were similar between the morbidly obese TKA patients. The bilateral group had significantly increased operative times (132.4 vs 115.5 minutes; P<.01), intravenous fluids (2556.1 vs 2114.7 mL; P=.03), percentage transfused (64.2% vs 11.4%; P<.01), days in the hospital (3.6 vs 3.2 days; P=.03), and discharge rates to rehabilitation facility (72.7% vs 48.6%; P=.01). Major and minor complications were few and comparable, with the need for manipulation under anesthesia in unilateral TKA (11.4%; P=.04) as the only significant difference between groups, including when comparing bilateral nonobese TKAs with bilateral morbidly obese TKAs. The authors feel that morbidly obese patients may undergo 2-team simultaneous bilateral TKA after careful discussion regarding some of the differences in short-term outcomes. PMID- 24762153 TI - Radiographic predisposing factors for degenerative spondylolisthesis. AB - This study was a retrospective radiographic study involving analysis of computed tomography scans obtained for patients with degenerative spondylolisthesis of the L4-L5 segment and a control group. The purpose of the study was to identify radiological predisposing factors for degenerative spondylolisthesis of the L4-L5 segment. The authors reviewed all computed tomography scans (N=3370) performed at their institution between January 2005 and December 2008. Eighty-four patients with degenerative spondylolisthesis were identified and compared with a control group regarding facet joint orientation, the presence of sacralization of the L5 vertebra, the presence of major degenerative changes in the L5-S1 disk space, and the location of the intercrestal line. There was a statistically significant difference between the 2 groups regarding facet joint orientation, with more sagittal facet joints in the degenerative spondylolisthesis group (56 degrees and 54 degrees in the right and left facets, respectively, in the study group, and 46 degrees and 42 degrees in the right and left facets, respectively, in the control group) (P<.001). There was no statistically significant difference between the 2 groups regarding the presence of sacralization of the L5 vertebra, the presence of major degenerative changes in the L5-S1 disk space, and the location of the intercrestal line relative to the lumbar spine. There is an association between sagittal orientation of the facet joints at the L4-L5 segment and degenerative spondylolisthesis at the same level. PMID- 24762154 TI - Horizontal versus vertical orientation of the loop for tension band wiring of transverse patella fractures. AB - Conventional operative treatments of patella fractures are frequently associated with implant failure or displacement. Recent biomechanical studies showed that the orientation of the wire loop and the site of the wire twist can affect the fixation strength. The purpose of this study was to compare the clinical outcome of the tension band technique with loops in different orientations and different knot positions. For this retrospective study, 72 patella fractures (71 patients) were fixed with figure-of-eight configurations in combination with 2 K-wires. Patients were divided into 3 groups according to the orientation of tension band construct. A total of 40 patella fractures were placed with figure-of-eight configurations in a vertical orientation either with 1 wire twist (group 1; 16 patella fractures) or with 2 wire twists at the adjacent corners (group 2; 24 patella fractures). Thirty-two patella fractures were placed with figure-of-eight configurations in a horizontal orientation with 2 wire twists at the adjacent corners (group 3). Range of motion, complication rates, and knee scoring scales (Hospital for Special Surgery and Lysholm) were assessed during serial follow-up. Satisfactory reductions were achieved in all groups, but functional results in the early stage were different. Group 3 had better Hospital for Special Surgery and Lysholm scores at 3 months postoperatively; however, at 6 months and 1 year postoperatively, all groups had similar scores. At the 1-year follow-up, all groups achieved acceptable flexion and range of motion. The overall complication rate was lower in the horizontal group (12.5%). Placing the figure-of-eight tension band construct in a horizontal orientation can provide functional benefits in the early stage after patella fractures. PMID- 24762155 TI - Arthroscopic findings of coexisting lesions with greater tuberosity fractures. AB - Proximal humerus fractures comprise approximately 5% of all fractures, with isolated greater tuberosity fractures accounting for approximately 20% of proximal humerus fractures. Although performing shoulder arthroscopy in situations including a fracture is technically demanding, it allows surgeons the opportunity to identify and treat other coexisting lesions that could have otherwise been missed. The incidence of these pathologies in combination with greater tuberosity fractures has not been established. This study aimed to identify the various types of pathologies that may coexist with greater tuberosity fractures but not be detected before fixation. Displaced 2-part greater tuberosity fractures were treated arthroscopically in the authors' department. All patients initially underwent diagnostic arthroscopy during which other coexisting pathologies were detected and assessed, including rotator cuff tears, labral tears (Bankart or superior labral anterior posterior lesions), or long head of the biceps pathologies. Twenty-four patients underwent arthroscopic (n=10) or arthroscopic-assisted (n=14) greater tuberosity reduction and fixation. Thirteen (54.2%) fragments were fully displaced. Four (16.7%) patients had fracture dislocation of the glenohumeral joint. The concomitant soft-tissue pathologies were identified and treated arthroscopically in 22 (92%) patients. Arthroscopic evaluation before greater tuberosity fracture fixation revealed a high percentage of concomitant soft tissue pathologies. These pathologies may be overlooked otherwise, but they are easily detected arthroscopically, enabling their treatment during the same procedure. PMID- 24762156 TI - Effects of total knee and hip arthroplasty on body weight. AB - Patients frequently report functional and subjective improvement following total hip (THA) and knee arthroplasty (TKA), but these improvements do not correlate with decreased body weight at 1- and 2-year follow-up. The purpose of this retrospective study was to investigate changes in body weight following THA and TKA at longer follow-up than the 1- to 2-year follow-up frequently reported in the literature. A retrospective review of patients undergoing THA and TKA, as well as other commonly performed lower extremity orthopedic surgeries, was completed for January 2002 to October 2011 at a single tertiary care facility. Adults who underwent a single lower extremity orthopedic procedure during that time period were included in the study. Patients undergoing THA and TKA were analyzed for clinically and statistically significant weight changes at 1- and minimum 2-year follow-up. At a mean follow-up of 4.82 years, TKA resulted in a statistically significant decrease in mean body weight (1.47 kg; P=.0109). This finding was unique to TKA. The proportion of individuals who experienced clinically significant weight loss between the 1- and minimum 2-year follow-up was higher than the proportion of individuals who gained clinically significant weight over the same time period following THA and TKA. The results of this study suggest that clinically significant weight loss may continue for several years beyond the 1- and 2-year follow-up that is frequently reported in the literature. PMID- 24762157 TI - Allergy/hypersensitivity reactions as a predisposing factor to complex regional pain syndrome I in orthopedic patients. AB - Several predisposing conditions have been associated with complex regional pain syndrome I (CRPS I). The purpose of this study was to determine the relationship between a history of allergy/hypersensitivity reactions and CRPS I in orthopedic patients. Orthopedic patients with CRPS I (n=115) who experienced pain relief after a successful sympathetic nerve blockade were identified for study inclusion; a control group (n=115) matched to the CRPS I group by age, sex, and location of injury was also included. All patients in the study had an average age of 42 years. In the CRPS I group, all participants were Caucasian and the majority (80.8%) were women. The skin of patients with CRPS I was described as fair (57.7%), mottled (57.7%), or sensitive (80.8%). Of the patients with CRPS I, 78 (67.8%) reported a statistically significant history of allergies compared with the 39 (33.9%) patients in the control group (P<.0001). Patients with CRPS I who experienced complete pain relief for at least 1 month following a single sympathetic nerve block were asked to answer a questionnaire (n=35), and some then underwent immediate hypersensitivity testing using a skin puncture technique (n=26). Skin hypersensitivity testing yielded an 83.3% positive predictive value with an accuracy of 76.9%. Based on these results, a positive history for allergy/hypersensitivity reactions is a predisposing condition for CRPS I in this subset of orthopedic patients. These hypersensitivity reactions may prove important in gaining a better understanding in the pathophysiology of CRPS I as a regional pain syndrome. PMID- 24762158 TI - Arthroscopic biceps tenodesis compared with repair of isolated type II SLAP lesions in patients older than 35 years. AB - This study compared arthroscopic biceps tenodesis with biceps repair for isolated type II superior labrum anterior and posterior (SLAP) lesions in patients older than 35 years. The authors identified isolated type II SLAP lesions that were surgically managed over a 5-year period. Minimum 2-year follow-up data were available for 22 patients who underwent biceps repair (repair group) and for 15 patients who underwent a primary biceps tenodesis (tenodesis group). Mean age at surgery was 45.2+/-5.5 years in the repair group and 52.0+/-8.0 years in the tenodesis group. In the repair group, functional outcome improved from baseline to final follow-up using the American Shoulder and Elbow Surgeons (ASES) (47.5 to 87.4, respectively; P<.0001) and University of California, Los Angeles (UCLA) scores (18.5 to 31.2, respectively; P<.0001). In the tenodesis group, similar findings were observed for the ASES (43.4 to 89.9, respectively; P<.0001) and UCLA scores (19.0 to 32.7, respectively; P<.0001). No difference was found in functional outcome between the groups. Full range of motion recovery was delayed by approximately 3 months in the repair group compared with the tenodesis group (P=.0631). Two patients in the repair group required a secondary capsular release. Seventy-seven percent of patients in the repair group and 100% of patients in the tenodesis group were satisfied and returned to normal activity (P=.0673). In the current study, individuals older than 35 years with an isolated type II SLAP lesion had a shorter postoperative recovery, a more predictable functional outcome, and a higher rate of satisfaction and return to activity with a biceps tenodesis compared with a biceps repair. Based on these observations, biceps tenodesis is preferable to biceps repair for isolated type II SLAP lesions in nonoverhead athletes older than 35 years. PMID- 24762159 TI - Anatomy of the sural nerve and its relation to the achilles tendon by ultrasound examination. AB - Sural nerve injury is a relatively common complication after surgery on the Achilles tendon. Studies to determine the course of the sural nerve have been performed on cadaveric specimens. The purpose of this cross-sectional study was to use ultrasound to determine the relations of the sural nerve in a healthy population. The authors performed ultrasound examination of the posterior triangle of the ankle and Achilles tendon to determine the course of the sural nerve relative to the Achilles tendon in healthy participants. The mean distance between the nerve and the tendon was 21.48, 11.47, 5.8, and 0.81 mm lateral to the Achilles tendon as measured at the insertion and 4, 8, and 11 cm proximally, respectively. Male participants tended to have a nerve that was initially more lateral to the Achilles insertion compared with women. The distance between the sural nerve and the Achilles tendon was found to be lower in older participants, with the nerve passing significantly closer to the tendon at all levels (P<.01). Three anatomical variants were reported, with the nerve crossing the lateral border of the Achilles low or high or with multiple branches yet to converge. The course of the sural nerve can be visualized and plotted relative to the Achilles tendon using ultrasound examination in healthy participants. Older patients may be at an increased risk of iatrogenic nerve injury because the nerve courses closer to the Achilles tendon than that in young patients. Intraoperative ultrasound examination may be a useful modality to prevent sural nerve injury during Achilles tendon surgery. PMID- 24762160 TI - Prediction of prognosis in patients with cervical spinal cord injury without radiologic evidence of trauma using MRI. AB - The purpose of this study was to investigate whether pre- to postoperative changes of increased signal intensity (ISI) of the spinal cord as seen on T2 weighted magnetic resonance imaging (MRI) reflect the surgical outcome in patients with cervical spinal cord injury without radiologic evidence of trauma (SCIWORET). In this study, 54 patients with SCIWORET who underwent expansive laminoplasty were retrospectively analyzed. All patients underwent MRI at an average of 1.9 days (range, 1-5 days) after injury and 7.9 days (range, 6-10 days) postoperatively. The pre- and postoperative range and degree of ISI were measured on computer software using the same sagittal view on T2-weighted MRI. Then, the post-preoperative ratio of range and degree of ISI were calculated. Pre and postoperative neurologic evaluations were performed according to the criteria proposed by the Japanese Orthopedic Association (JOA). A significant negative correlation existed between the ratio of range of ISI and the recovery rate (r=-0.504, P<.01). The ratio of degree of ISI negatively correlated with the recovery rate, but this was not statistically significant. Patients were divided into 2 groups according to the ratio of degree of ISI: group A included patients with a ratio of degree of ISI of <=1 (n=24) and group B included patients with a ratio of degree of ISI of >1 (n=30). Patients' mean recovery rate was 65.0%+/ 6.3% in group A and 52.4%+/-7.4% in group B. A significant difference was found between the 2 groups (P<.001, Student's t test) when comparing recovery rate. The pre- to postoperative changes of the range and degree of ISI significantly reflected prognosis for surgical outcome in patients with SCIWORET. PMID- 24762161 TI - Civilian gunshot injuries of the humerus. AB - An institutional review board-approved retrospective study was performed at a level 1 trauma center to evaluate the adequacy of current treatment guidelines in the management of humerus fractures following civilian gunshot injuries. Fifty four patients with a humerus shaft fracture from a low-velocity gunshot wound were included in the study. Twenty-nine patients were treated nonoperatively, while 25 patients had operative treatment, with 14 undergoing plate fixation, 6 having application of an external fixator, 3 receiving an intramedullary rod, and 2 having irrigation and debridement with fracture immobilization provided by a brace. Patient demographics and injury data, radiographic analyses, and treatment complications were recorded. Healing of soft tissue and bony injuries, including fracture alignment in patients treated nonoperatively, was also evaluated. Fifty two of 54 patients had minor soft tissue damage and were treated successfully with minimal local wound care. Two patients with larger wounds required extended wound care with repeated irrigation and debridement. Overall, 47 of 54 fractures healed with the primary mode of treatment, and 7 patients went on to nonunion requiring further intervention. Of the patients treated nonoperatively, the average deformity was 16.5 degrees +/-7.4 degrees in the coronal plane and 4.4 degrees +/-4.0 degrees in the sagittal plane. This study supports the view that the majority of humerus fractures following civilian gunshot wounds may be treated nonoperatively, with a select group of patients requiring surgical stabilization. PMID- 24762162 TI - Intra-articular nodular fasciitis of the knee in a pediatric patient. AB - The differential diagnosis for an intra-articular lesion in the knee of a pediatric patient is broad. Diagnostic considerations include pigmented villonodular synovitis (PVNS)-the most common intra-articular tumor-and a variety of both benign and malignant tumors, including lipomas, hemangiopericytomas, nodular fasciitis, parosteal osteosarcomas, and fibromyxoid sarcomas. If there is concern over possible malignant lesions, a tumor surgeon should be consulted. Precise pathologic diagnosis is ideal for identifying these enigmatic lesions and for determining the appropriate treatment plan. This article presents the case of a 13-year-old boy who presented with 1-month duration of knee pain and no history of trauma to the extremity. Physical examination revealed pain along the medial and lateral joint lines, pain with range of motion, and limited range of motion of the affected knee. Magnetic resonance imaging revealed a 3*1*3-cm lesion in the posterolateral corner that was believed to be localized PVNS. Arthroscopically, there was no evidence of PVNS, but a posterolateral soft tissue mass was found and removed, which was pathologically diagnosed as a rare, benign, intra-articular nodular fasciitis. When working with intra-articular masses, it is important to assess the likelihood of malignancy and to both consult a tumor surgeon and use the appropriate surgical tumor principles when malignancy is a concern. Additionally, the pathology team should be consulted prior to surgery and be on standby during arthroscopic evaluation of the knee to help with precise diagnosis of the intra-articular mass. Discussing the case with the pathologist with imaging studies present is helpful and often aids in the diagnosis of the lesion. PMID- 24762163 TI - Understanding acute apophyseal spinous process avulsion injuries. AB - Apophyseal spinous process avulsion injury was first described in 1941. Since then, there have been sparse additional reports in the literature. The authors report their second case, involving an elite adolescent tennis player. The patient underwent surgical excision of the avulsed spinous process 12 weeks after initial presentation and experienced complete resolution of back pain. The authors provide the first reported histopathological analysis of the avulsion fracture site in the literature for both of their cases. The avulsion injury of the interspinous ligament was characterized by hypercellular fibrocartilage tissue, similar to that seen in severe Osgood-Schlatter's disease. The key physical examination finding in patients with avulsion spinous process fractures is acute tenderness directly over the fracture site that worsens with flexion rather than extension (unlike in spondylolysis). Patients should have routine radiographs, including dynamic flexion-extension views, magnetic resonance imaging, and computed tomography. The authors conclude that after 6 months of nonsurgical management for an athlete, surgical excision should be offered as an alternative. In both of their cases, nonsurgical management failed. Surgical excision offers definitive and simple treatment, as well as early return to athletic activities. Both patients were allowed to return to their competitive level of performance 6 weeks after surgery. PMID- 24762164 TI - Palladium-catalyzed C(sp2)-H arylation using formamide as a transformable directing group. AB - A new process for the ortho arylation of formanilides through palladium-catalyzed C-H activation is described. Formamide is reported as a transformable directing group in the transition-metal-catalyzed C-H functionalization reaction. The resulting biarylformanilide products can be readily transformed to the corresponding biarylisocyanides or N-heterocycles. PMID- 24762165 TI - Generic characterization of apolar metabolites in red chili peppers (Capsicum frutescens L.) by orbitrap mass spectrometry. AB - The aim of the present study was to develop a generic analytical method for the identification and quantitation of apolar plant metabolites in biomass using liquid chromatography-photodiode array-accurate mass mass spectrometry (LC-PDA amMS). During this study, a single generic sample preparation protocol was applied to extract apolar plant metabolites. Compound identification was performed using a single generic screening method for apolar compounds without the need for dedicated fractionation. Such a generic approach renders vast amounts of information and is virtually limited by only the solubility and detector response of the metabolites of interest. Method validation confirmed that this approach is applicable for quantitative purposes. Furthermore, an identification-quantitation strategy based on amMS and molar extinction coefficients was used for carotenoids, eliminating the need for reference standards for each carotenoid. To challenge the validated method, chili peppers (Capsicum frutescens L.) were analyzed to unravel their complex phytochemical composition (carotenoids, glycolipids, glycerolipids, capsaicinoids, lipid soluble vitamins). PMID- 24762167 TI - HLA-A, HLA-B and HLA-DRB1 allele and haplotype diversity among volunteer bone marrow donors from Croatia. AB - The determination of human leucocyte antigen (HLA)-A, HLA-B and HLA-DRB1 alleles in the routine procedure of a volunteer hematopoietic stem cell (HSC) donor's registration in the Croatian Bone Marrow Donor Registry (CBMDR) is performed to enhance the odds of finding a suitable HLA compatible donor for patients in need of a HSC transplantation worldwide. However, besides its original purpose, it also provides valuable information about the HLA polymorphism among Croats. The aim of the present study was to analyse the HLA allele and haplotype frequencies in a sample of 4000 donors from CBMDR. The distribution of HLA-A, HLA-B and HLA DRB1 alleles did not demonstrate significant differences from the data reported for other European populations. The higher frequency of B*40:02 allele in comparison with B*40:01 and DRB1*11:04 in comparison with DRB1*11:01 is interesting because it represents a difference in comparison with the Western and Northern European populations which are a main source of donors for Croatian patients. The haplotype frequencies show a greater variation and difference in comparison with data from other registries and populations; however, due to a lack of high-resolution haplotype data, comparison was possible only with a very limited number of other populations. PMID- 24762166 TI - Guideline-concordant administration of prothrombin complex concentrate and vitamin K is associated with decreased mortality in patients with severe bleeding under vitamin K antagonist treatment (EPAHK study). AB - INTRODUCTION: In vitamin K antagonist (VKA)-treated patients with severe hemorrhage, guidelines recommend prompt VKA reversal with prothrombin complex concentrate (PCC) and vitamin K. The aim of this observational cohort study was to evaluate the impact of guideline concordant administration of PCC and vitamin K on seven-day mortality. METHODS: Data from consecutive patients treated with PCC were prospectively collected in 44 emergency departments. Type of hemorrhage, coagulation parameters, type of treatment and seven-day mortality mortality were recorded. Guideline-concordant administration of PCC and vitamin K (GC-PCC-K) were defined by at least 20 IU/kg factor IX equivalent PCC and at least 5 mg of vitamin K performed within a predefined time frame of eight hours after admission. Multivariate analysis was used to assess the effect of appropriate reversal on seven-day mortality in all patients and in those with intracranial hemorrhage (ICH). RESULTS: Data from 822 VKA-treated patients with severe hemorrhage were collected over 14 months. Bleeding was gastrointestinal (32%), intracranial (32%), muscular (13%), and "other" (23%). In the whole cohort, seven day mortality was 13% and 33% in patients with ICH. GC-PCC-K was performed in 38% of all patients and 44% of ICH patients. Multivariate analysis showed a two-fold decrease in seven-day mortality in patients with GC-PCC-K (odds ratio (OR) = 2.15 (1.20 to 3.88); P = 0.011); this mortality reduction was also observed when only ICH was considered (OR = 3.23 (1.53 to 6.79); P = 0.002). CONCLUSIONS: Guideline concordant VKA reversal with PCC and vitamin K within eight hours after admission was associated with a significant decrease in seven-day mortality. PMID- 24762168 TI - The Norwegian version of the Severe Respiratory Insufficiency Questionnaire. AB - The aims of this study were to translate and adapt the Severe Respiratory Insufficiency (SRI) questionnaire into Norwegians and to test its reliability and validity.Data were collected from a cross-sectional survey and were linked to the Norwegian Registry of patients receiving long-term mechanical ventilation (LTMV). Of 193 potential participants, 127 responded to the SRI questionnaire. Reliability as measured with Cronbach's alpha varied between 0.68 and 0.88 for the subscales and was 0.94 for SRI-sum score. Construct validity was obtained with high correlations between subscales in SF-36 and SRI. The SRI questionnaire discriminated well between universally accepted clinical differences among categories of patients receiving LTMV by significant dissimilarities in SRI-sum score and SRI subscales. The Norwegian version of SRI has well-documented psychometric properties regarding reliability and validity. It might be used in clinical practice and in international studies for assessing health-related quality of life in patients receiving LTMV. PMID- 24762169 TI - How does the protein environment optimize the thermodynamics of thiol sulfenylation? Insights from model systems to QM/MM calculations on human 2-Cys peroxiredoxin. AB - Protein thiol/sulfenic acid oxidation potentials provide a tool to select specific oxidation agents, but are experimentally difficult to obtain. Here, insights into the thiol sulfenylation thermodynamics are obtained from model calculations on small systems and from a quantum mechanics/molecular mechanics (QM/MM) analysis on human 2-Cys peroxiredoxin thioredoxin peroxidase B (Tpx-B). To study thiol sulfenylation in Tpx-B, our recently developed computational method to determine reduction potentials relatively compared to a reference system and based on reaction energies reduction potential from electronic energies is updated. Tpx-B forms a sulfenic acid (R-SO(-)) on one of its active site cysteines during reactive oxygen scavenging. The observed effect of the conserved active site residues is consistent with the observed hydrogen bond interactions in the QM/MM optimized Tpx-B structures and with free energy calculations on small model systems. The ligand effect could be linked to the complexation energies of ligand L with CH3S(-) and CH3SO(-). Compared to QM only calculations on Tpx-B's active site, the QM/MM calculations give an improved understanding of sulfenylation thermodynamics by showing that other residues from the protein environment other than the active site residues can play an important role. PMID- 24762170 TI - Residual plasma in red blood cells and transfusion-related acute lung injury. AB - BACKGROUND: Transfusion-related acute lung injury (TRALI) is the most common cause of death from blood transfusion and red blood cells (RBCs) now account for approximately 50% of these fatalities. RBCs from female donors have been implicated in large series and HLA Class II antibodies to cognate recipient antigens identified in small series and case reports. The absolute volume of residual plasma in these RBCs is unknown. STUDY DESIGN AND METHODS: Two confirmed cases of RBC-associated TRALI in which the implicated donors had Class II antibodies were investigated, and the antibody strength against recipient cognate antigens was assessed using a fluorescent bead assay. RBCs in additive solution (AS) were studied on Day 42 of liquid storage to calculate residual anticoagulated plasma. RESULTS: Both RBC units were stored in AS-1 and were from female donors who had anti-HLA Class II antibodies of high strength against cognate antigens in the recipients. Anti-DR4 was identified in both cases. Nineteen AS-1 RBC units manufactured from whole blood donations using a hard spin had a mean (+/-1SD) residual plasma content of 38 +/- 8 mL, and 26 AS-3 RBC units manufactured using a soft spin had 66 +/- 13 mL (p < 0.01). CONCLUSION: RBCs continue to be manufactured from female donors of unknown or even known anti-HLA status. The residual plasma content of these RBCs may approach 100 mL. A combination of a high-strength antibody and large residual plasma volume could explain severe or even fatal RBC-associated TRALI. PMID- 24762171 TI - Jordanian women's dissatisfaction with childbirth care. AB - BACKGROUND: Dissatisfaction with childbirth care can have a negative impact on a woman's health and well-being, as well as her relationships with her infant. AIM: To investigate the prevalence and associated factors of dissatisfaction with intrapartum care by Jordanian women. METHOD: A descriptive cross-sectional study was used. Participants (n = 320) who were 7 weeks post-partum were recruited from five maternal and child health centres in Irbid city in northern Jordan. Participants provided personal and obstetric information, and completed the Satisfaction with Childbirth Care Scale. RESULTS: The majority of women (75.6%) were dissatisfied with their intrapartum care. Dissatisfaction was associated with the attendance of unknown and unwanted persons during childbirth, experiencing labour as more painful than expected, and perceptions of inadequate help from healthcare providers to manage pain during labour. LIMITATIONS: Findings are limited to Jordanian women accessing public sector perinatal health services. CONCLUSION: The high percentage of women reporting dissatisfaction with intrapartum care in this study is of concern. Women's perception of pain and expectations of staff during labour and birth need to be addressed through education and improved communication by staff. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Development of national evidence-based policies and quality assurance systems would help reduce the rate of obstetric interventions and give greater emphasis to respect for women's preferences during labour and birth. PMID- 24762172 TI - Molecular footprints of the Holocene retreat of dwarf birch in Britain. AB - Past reproductive interactions among incompletely isolated species may leave behind a trail of introgressed alleles, shedding light on historical range movements. Betula pubescens is a widespread native tetraploid tree species in Britain, occupying habitats intermediate to those of its native diploid relatives, B. pendula and B. nana. Genotyping 1134 trees from the three species at 12 microsatellite loci, we found evidence of introgression from both diploid species into B. pubescens, despite the ploidy difference. Surprisingly, introgression from B. nana, a dwarf species whose present range is highly restricted in northern, high-altitude peat bogs, was greater than introgression from B. pendula, which is morphologically similar to B. pubescens and has a substantially overlapping range. A cline of introgression from B. nana was found extending into B. pubescens populations far to the south of the current B. nana range. We suggest that this genetic pattern is a footprint of a historical decline and/or northwards shift in the range of B. nana populations due to climate warming in the Holocene. This is consistent with pollen records that show a broader, more southerly distribution of B. nana in the past. Ecological niche modelling predicts that B. nana is adapted to a larger range than it currently occupies, suggesting additional factors such as grazing and hybridization may have exacerbated its decline. We found very little introgression between B. nana and B. pendula, despite both being diploid, perhaps because their distributions in the past have rarely overlapped. Future conservation of B. nana may partly depend on minimization of hybridization with B. pubescens, and avoidance of planting B. pendula near B. nana populations. PMID- 24762173 TI - Toxicity and cosmetic outcome of hypofractionated whole-breast radiotherapy: predictive clinical and dosimetric factors. AB - PURPOSE: The objective of this study is to evaluate toxicity and cosmetic outcome in breast cancer patients treated with adjuvant hypo fractionated radiotherapy to the whole breast, and to identify the risk factors for toxicity. METHODS AND MATERIALS: Two hundred twelve women with early breast cancer underwent conserving surgery were enrolled in the study. The patients received 40.05 Gy in 15 daily fractions, 2.67 Gy per fraction. The boost to the tumor bed was administered with a total dose of 9 Gy in 3 consecutive fractions in 55 women. Physician-rated acute and late toxicity and cosmetic outcome (both subjective and objective) were prospectively assessed during and after radiotherapy. RESULTS: In our population study the mean age was 63 with the 17% (36 pts) of the women younger than 50 years.The median follow-up was 34 months. By the end of RT, 35 patients out of 212 (16%) no acute toxicity, according to the RTOG criteria, while 145 (68%) and 31 patients (15%) developed grade 1 and grade 2 acute skin toxicity, respectively.Late skin toxicity evaluation was available for all 212 patients with a minimum follow up of 8 months. The distribution of toxicity was: 39 pts (18%) with grade 1 and 2 pts (1%) with grade 2. No worse late skin toxicity was observed.Late subcutaneous grade 0-1 toxicity was recorded in 208 patients (98%) and grade 2 toxicity in 3 patients (2%), while grade 3 was observed in 1 patient only. At last follow up, a subjective and objective good or excellent cosmetic outcome was reported in 93% and 92% of the women, respectively. At univariate and multivariate analysis, the late skin toxicity was correlated with the additional boost delivery (p=0.007 and p=0.023). Regarding the late subcutaneous tissue, a correlation with diabetes was found (p=0.0283). CONCLUSION: These results confirm the feasibility and safety of the hypofractionated radiotherapy in patients with early breast cancer. In our population the boost administration was resulted to be a significant adverse prognostic factor for acute and late toxicity. Long-term follow up is need to confirm this finding. PMID- 24762174 TI - Validation of a novel, tissue-based simulator for robot-assisted radical prostatectomy. AB - PURPOSE: To create a tissue-based simulator that allows practice of key steps of robot-assisted radical prostatectomy (RARP) in a sequential fashion. MATERIALS AND METHODS: A model was created from female porcine genitourinary tract tissue to represent the male pelvic genitourinary anatomy. The following steps of RARP were simulated: dorsal venous complex ligation, division of bladder neck, seminal vesicle dissection, prostatic pedicle ligation with nerve sparing, urethral division, bladder neck reconstruction, and vesicourethral anastomosis. Ten novices and 10 experts performed RARP on the model. Face validity was calculated by ratings of realism. Content validity was calculated by experts' rating of usefulness of the model as a training tool. Construct validity was calculated by comparison of time to complete the simulator and rating of performance on the objective structured assessment of technical skill (OSATS) questionnaire, between novices and experts. RESULTS: The model was determined to have good face and content validity with an average score of 3.7/5 and 4.8/5, respectively. The mean time for completion of the simulator was 121.5 minutes for the novice and 62 minutes for the expert group (P<0.001), and the mean overall OSATS performance ratings were 4.6/5 for experts and 2.6/5 for novices (P<0.001), yielding good construct validity. CONCLUSIONS: We created and validated a realistic, tissue based simulator to allow for training of key surgical steps of RARP in a sequential fashion. Ultimately, this simulator could be incorporated into urology training, credentialing, and facilitate surgeon transitioning from open prostatectomy to RARP. PMID- 24762175 TI - The metabolism of neonicotinoid insecticide thiamethoxam by soil enrichment cultures, and the bacterial diversity and plant growth-promoting properties of the cultured isolates. AB - A soil enrichment culture (SEC) rapidly degraded 96% of 200 mg L(-1) neonicotinoid insecticide thiamethoxam (TMX) in MSM broth within 30 d; therefore, its metabolic pathway of TMX, bacterial diversity and plant growth-promoting rhizobacteria (PGPR) activities of the cultured isolates were studied. The SEC transformed TMX via the nitro reduction pathway to form nitrso, urea metabolites and via cleavage of the oxadiazine cycle to form a new metabolite, hydroxyl CLO tri. In addition, 16S rRNA gene-denaturing gradient gel electrophoresis analysis revealed that uncultured rhizobacteria are predominant in the SEC broth and that 77.8% of the identified bacteria belonged to uncultured bacteria. A total of 31 cultured bacterial strains including six genera (Achromobacter, Agromyces, Ensifer, Mesorhizobium, Microbacterium and Pseudoxanthomonas) were isolated from the SEC broth. The 12 strains of Ensifer adhaerens have the ability to degrade TMX. All six selected bacteria showed PGPR activities. E. adhaerens TMX-23 and Agromyces mediolanus TMX-25 produced indole-3-acetic acid, whereas E. adhaerens TMX-23 and Mesorhizobium alhagi TMX-36 are N2-fixing bacteria. The six-isolated microbes were tolerant to 200 mg L(-1) TMX, and the growth of E. adhaerens was significantly enhanced by TMX, whereas that of Achromobacter sp. TMX-5 and Microbacterium sp.TMX-6 were enhanced slightly. The present study will help to explain the fate of TMX in the environment and its microbial degradation mechanism, as well as to facilitate future investigations of the mechanism through which TMX enhances plant vigor. PMID- 24762177 TI - QSPR prediction of chromatographic retention times of pesticides: partition and fractal indices. AB - The high-performance liquid-chromatographic retentions of red-wine pesticide residues are modeled by structure-property relationships. The effect of different types of features is analyzed: geometric, lipophilic, etc. The properties are fractal dimensions, partition coefficient, etc., in linear and nonlinear correlation models. Biological plastic evolution is an evolutionary perspective conjugating the effect of acquired characters and relations that emerge among the principles of evolutionary indeterminacy, morphological determination and natural selection. It is applied to design the co-ordination index that is used to characterize pesticide retentions. The parameters used to calculate the co ordination index are the molar formation enthalpy, molecular weight and surface area. The morphological and co-ordination indices barely improve the correlations. The fractal dimension averaged for non-buried atoms, partition coefficient, etc. distinguishes the pesticide molecular structures. The structural and constituent classification is based on nonplanarity, and the number of cycles, and O, S, N and Cl atoms. Different behavior depends on the number of cycles. PMID- 24762176 TI - Cyhalofop-p-butyl mobility and distribution of residues in soil at various depths. AB - This study was conducted to evaluate cyhalofop-p-butyl mobility in a sandy loam soil and subsequent distribution of residues at various depths under field conditions. Soil samples were taken from 0 to 150 cm depths at 3-90 d after rains in lysemeter of 1 and 2 m depths. Cyhalofop-p-butyl application at two rates and subsequent precipitation had a significant impact on soil, physico-chemical properties and herbicide mobility. Precipitation caused substantial mobility of cyhalofop-p-butyl in the soil and 1.1-7.6 MUg L(-1) of cyhalofop-p-butyl was found in leachates. Cyhalofop-p-butyl residues in the leachates were probably due to preferential flow through the soil. Cyhalofop-p-butyl residues were detected in significant amounts from the soil up to 10 d, later, residues were found below the detection limit but its three transformation products viz., cyhalofop acid, diacid, and phenol were detected. PMID- 24762178 TI - A sensitive enzyme-linked immunosorbent assay amplified by biotin-streptavidin system for detecting non-steroidal anti-inflammatory drug ketoprofen. AB - A sensitive biotin-streptavidin-amplified enzyme-linked immunosorbent assay (BA ELISA) method was developed for detecting non-steroidal anti-inflammatory drug ketoprofen. Compared with traditional ELISA method, the sensitivity of proposed immunoassay was enhanced by the biotin-streptavidin system. Under the optimal condition, the median inhibitory concentration (IC50) was 0.25 ng mL(-1), with minor cross-reactivity to a number of structural analogs. This developed assay was successfully applied to detect the ketoprofen residues in different fish samples, and good recoveries (72.6-105.5%) were obtained. The results indicated that this immunoassay method could specifically detect trace ketoprofen residues and could be widely used for routine monitoring of food samples. PMID- 24762179 TI - Effect of Tinospora cordifolia on the reduction of ultraviolet radiation-induced cytotoxicity and DNA damage in PC12 cells. AB - The safety of Tinospora cordifolia and its potential to protect against ultraviolet radiation-induced cytotoxicity and DNA damage in PC12 cells were investigated. To evaluate the safety of T. cordifolia, cell viability and agarose gel electrophoresis were carried out using PC12 cells treated with 0 to 100 MUg mL(-1) of methanol extract of T. cordifolia. T. cordifolia extracts did not show cytotoxicity ranging 0 to 100 MUg mL(-1). In addition, T. cordifolia extracts significantly increased cell viability at 1 ng, 10 ng and 1 MUg mL(-1) concentrations in serum-deprived medium compared to control. To confirm the protective role against UV-induced damage, PC12 cells alone or in the presence of 10 ng, 100 ng, or 1 MUg mL(-1) of T. cordifolia extract were exposed to 250, 270 and 290 nm of UV radiation, which corresponded to doses of 120, 150 and 300 mJ cm(-2), respectively. Treatment with T. cordifolia extracts significantly increased the cell survival rate irradiated at 290 nm. In addition, T. cordifolia extracts significantly reduced cyclobutane pyrimidine dimer formation induced by UV irradiation at all wavelengths. In conclusion, T. cordifolia is not toxic and safe for cells. Our findings can support its application as phototherapy in the medical sector. PMID- 24762180 TI - Chloromuconolactone dehalogenase ClcF of actinobacteria. AB - This work investigated the distribution of the clcF gene in actinobacteria isolated from different ecotopes. The gene encodes chloromuconolactone dehalogenase (CMLD) ClcF, the enzyme found to date in only one representative of Gram-positive bacteria, Rhodococcus opacus 1CP, adapted to 2-chlorophenol (2CP). Using primers specific to the clcF gene, from the DNA matrix of rhodococcal strains closely related to species Rhodococcus wratislaviensis (P1, P12, P13, P20, G10, KT112, KT723, BO1) we obtained PCR products whose nucleotide sequences were 100% identical to that of the clcF gene from strain R. opacus 1CP. CMLDs isolated from the biomass of strains Rhodococcus spp. G10 and P1 grown on 2CP did not differ by their subunit molecular mass deduced from the known amino acid sequence of the clcF gene from the ClcF of strain R. opacus 1CP. Matrix-assisted laser dissociation/ionization time-of-flight mass spectrometry showed the presence of a peak with m/z 11,194-11,196 Da both in whole cells and in protein solutions with a ClcF activity. Thus, we have first time shown the distribution of ClcF among actinobacteria isolated from geographically distant habitats. PMID- 24762181 TI - Tributyltin distribution and producing androgenic activity in water, sediment, and fish muscle. AB - This study investigated the concentrations of Tributyltin (TBT) in water, sediment, and fish muscle samples taken from Kaohsiung Harbor and Kaoping River estuary, Taiwan. TBT concentrations in water and sediment samples ranged from less than 18.5 to 34.1 ng Sn L(-1) and from 2.44 to 29.7 ng Sn g(-1) weight per weight (w/w), respectively. Concentrations in the TBT-contaminated fish muscle samples ranged from 10.8 to 79.6 ng Sn g(-1) w/w. The TBT concentrations in fish muscle were higher than those in water and sediment samples. The fish muscle/water TBT bioconcentration factor (BCF) ranged from 590 to 3363 L kg(-1). Additionally, the water samples were assessed for androgenic activity with an MCF7-AR1 human breast cancer cell line. The androgenic activity ranged from 0.94 to 3.1 ng-dihydrotestosterone per litre water (ng-DHT L(-1)). Higher concentrations of TBT in water and sediment samples occurred in the dry season, but the androgenic activity had higher values in the rainy season. PMID- 24762182 TI - Pilot-scale field study for ammonia removal from lagoon biogas using an acid wet scrubber. AB - The anaerobic activities in swine slurry storage and treatment generate biogas containing gaseous ammonia component which is a chemical agent that can cause adverse environmental impacts when released to the atmosphere. The aim of this pilot plant study was to remove ammonia from biogas generated in a covered lagoon, using a sulfuric acid wet scrubber. The data showed that, on average, the biogas contained 43.7 ppm of ammonia and its concentration was found to be exponentially related to the air temperature inside the lagoon. When the air temperature rose to 35 degrees C and the biogas ammonia concentration reached 90 ppm, the mass transfer of ammonia/ammonium from the deeper liquid body to the interface between the air and liquid became a limiting factor. The biogas velocity was critical in affecting ammonia removal efficiency of the wet scrubber. A biogas flow velocity of 8 to 12 mm s(-1) was recommended to achieve a removal efficiency of greater than 60%. Stepwise regression revealed that the biogas velocity and air temperature, not the inlet ammonia concentration in biogas, affected the ammonia removal efficiency. Overall, when 73 g L(-1) (or 0.75 M) sulfuric acid solution was used as the scrubber solution, removal efficiencies varied from 0% to 100% with an average of 55% over a 40-d measurement period. Mass balance calculation based on ammonium-nitrogen concentration in final scrubber liquid showed that about 21.3 g of ammonia was collected from a total volume of 1169 m(3) of biogas, while the scrubber solution should still maintain its ammonia absorbing ability until its concentration reaches up to 1 M. These results showed promising use of sulfuric acid wet scrubber for ammonia removal in the digester biogas. PMID- 24762183 TI - Biodegradation of three tetracyclines in swine wastewater. AB - Tetracyclines (TCs), including tetracycline (TC), oxytetracycline (OTC), and chlortetracycline (CTC), are amongst the most common antibiotics used in animal husbandry. Residual amounts of these antibiotics in the environment are a concern because they contribute to selection of resistant bacteria. In this study, we investigated the biodegradation of three TCs in swine wastewater. In batch experiments, OTC and CTC were completely degraded at d 18 and 20, respectively, but TC was remained at 7.1% after 20 d incubation. The degradation rates of TCs in the wastewater were in the order of OTC > CTC > TC. Degradation of the TCs was enhanced by the addition of enzyme extract from spent mushroom compost (SMC) of Pleurotus eryngii. The degradation rates were higher with the addition of extract containing microcapsules than suspended enzyme extract in swine wastewater. In the bioreactor experiment, the addition of extract-containing microcapsules enhanced the removal rates of the three TCs, and adding TCs twice maintained enzyme activity in the swine wastewater. Of the microorganism strains isolated from the wastewater samples, strain HL2 (identified as Xanthobacter flavus) showed the best degrading ability. PMID- 24762184 TI - Oligonuclear Fe complexes (Fe, Fe4, Fe6, Fe9) derived from tritopic pyridine bis hydrazone ligands-structural, magnetic, and Mossbauer studies. AB - Tri-topic pyridine bis-hydrazone ligands produce polynuclear complexes with Fe(II) and Fe(III) salts with varying nuclearity and metal ion oxidation states. Mononuclear, tetranuclear, hexanuclear, and nonanuclear examples are discussed using structural, magnetic and Mossbauer data. In one case, although X-ray data suggest a [3 * 3] Fe9 grid (space group P42/n), careful examination of the structure, in conjunction with magnetic and Mossbauer data, indicates an unusual situation where the corner and center sites are present at unit occupancy, whereas side site occupancy is ~0.6. PMID- 24762185 TI - Bruxism and genetics: a review of the literature. AB - People who suffer from bruxism (teeth-grinding) often ask their dentists whether their condition is hereditary. The purpose of this study is to enable dentists to provide an 'evidence-based' answer to this question. The biomedical literature was searched using PubMed, and 32 publications were identified, of which nine proved relevant to the research question. The references cited by the publications identified yielded one further publication, bringing the total number of publications included in the analysis to 10. Four publications related to family studies, five related to twin studies and one related to a DNA analysis. With the exception of one of the twin studies, all the included studies concluded that bruxism appears to be (in part) genetically determined. Dentists whose patients ask them about bruxism can therefore tell them that teeth-grinding does indeed 'run in families'. PMID- 24762186 TI - Do sun- versus shade-grown kiwifruits perform differently upon storage? An overview of fruit maturity and nutraceutical properties of whole and fresh-cut produce. AB - Fresh-cut produce represents a good method to save about 25% of the kiwifruit not useful to meet the fresh fruit-marketing standard due to improper size and shape. For that reason, fresh-cut kiwifruit has been extensively studied. However, the comprehension of the influence of some aspects of cultivation might further increase the shelf life as well as the nutritional values of that fruit. This study explored the hypothesis that kiwifruits grown fully exposed to sunlight or partially shaded differently perform upon storage as whole fruit and as minimally processed produce. Flesh firmness (FF), total solids soluble (SSC), ascorbate (AAT), flavonoids (TFO), and phenols (TF) contents were evaluated in sliced and whole fruit upon 3 days of storage at 4 degrees C after 75 days of cold chamber storage at 0 degrees C. The activities of two enzymes related to the softening process, polygalacturonase (PG) and pectinmethylesterase (PME), were evaluated as well. FF and SSC were constitutively higher in sun-exposed fruit, and those characteristics remained higher during the storage as whole fruit. Greater constitutive content of AAT, TFO, and TP was found in sun-exposed whole fruit, although after cutting the reduction in their content was significantly lower in shaded fruits. PME and PG activities were higher only in whole shaded fruits, whereas no relevant differences occurred after cutting. In summary, sun-exposed fruits were more suitable for the fresh-fruit market, whereas the shaded counterpart displayed a good predisposition for use as fresh-cut produce, maintaining similar fruit maturity properties but higher nutraceutical values when sliced than fruit grown under full sun. PMID- 24762188 TI - Characterization of phosphorylation- and RNA-dependent UPF1 interactors by quantitative proteomics. AB - Human up-frameshift 1 (UPF1) is an ATP-dependent RNA helicase and phosphoprotein implicated in several biological processes but is best known for its key function in nonsense-mediated mRNA decay (NMD). Here we employed a combination of stable isotope labeling of amino acids in cell culture experiments to determine by quantitative proteomics UPF1 interactors. We used this approach to distinguish between RNA-mediated and protein-mediated UPF1 interactors and to determine proteins that preferentially bind the hypo- or the hyper-phosphorylated form of UPF1. Confirming and expanding previous studies, we identified the eukaryotic initiation factor 3 (eIF3) as a prominent protein-mediated interactor of UPF1. However, unlike previously reported, eIF3 binds to UPF1 independently of UPF1's phosphorylation state. Furthermore, our data revealed many nucleus-associated RNA binding proteins that preferentially associate with hyper-phosphorylated UPF1 in an RNase-sensitive manner, suggesting that UPF1 gets recruited to mRNA and becomes phosphorylated before being exported to the cytoplasm as part of the mRNP. PMID- 24762189 TI - Hyperoxia affects the regional pulmonary ventilation/perfusion ratio: an electrical impedance tomography study. AB - BACKGROUND: The way in which hyperoxia affects pulmonary ventilation and perfusion is not fully understood. We investigated how an increase in oxygen partial pressure in healthy young volunteers affects pulmonary ventilation and perfusion measured by thoracic electrical impedance tomography (EIT). METHODS: Twelve semi-supine healthy male volunteers aged 21-36 years were studied while breathing room air and air-oxygen mixtures (FiO2) that resulted in predetermined transcutaneous oxygen partial pressures (tcPO2) of 20, 40 and 60 kPa. The magnitude of ventilation (DeltaZv) and perfusion (DeltaZQ)-related changes in cyclic impedance variations, were determined using an EIT prototype equipped with 32 electrodes around the thorax. Regional changes in ventral and dorsal right lung ventilation (V) and perfusion (Q) were estimated, and V/Q ratios calculated. RESULTS: There were no significant changes in DeltaZv with increasing tcPO2 levels. DeltaZQ in the dorsal lung increased with increasing tcPO2 (P = 0.01), whereas no such change was seen in the ventral lung. There was a simultaneous decrease in V/Q ratio in the dorsal region during hyperoxia (P = 0.04). Two subjects did not reach a tcPO2 of 60 kPa despite breathing 100% oxygen. CONCLUSION: These results indicate that breathing increased concentrations of oxygen induces pulmonary vasodilatation in the dorsal lung even at small increases in FiO2. Ventilation remains unchanged. Local mismatch of ventilation and perfusion occurs in young healthy men, and the change in ventilation/perfusion ratio can be determined non-invasively by EIT. PMID- 24762190 TI - Phosphoric acid catalyzed diastereo- and enantioselective synthesis of substituted 1,3-diaminotetralins. AB - The reaction of anilines and phenylacetaldehydes in the presence of chiral phosphoric acid afforded optically active 1,2-trans, 2,3-cis 1,3-diaminotetralins in high yields with excellent diastereo- and enantioselectivities. The trans/cis product was readily isomerized to a trans/trans stereoisomer with no significant loss of enantiomeric purity. PMID- 24762192 TI - Copper-catalyzed oxidative C-O bond formation of 2-acyl phenols and 1,3 dicarbonyl compounds with ethers: direct access to phenol esters and enol esters. AB - A copper-catalyzed oxidative coupling of 2-carbonyl-substituted phenols and 1,3 dicarbonyl compounds with a wide range of dibenzyl or dialkyl ethers is described. This protocol provides an efficient preparation of phenol esters and enol esters in good yields with high chemoselectivity. This method represents an alternative protocol for classical esterification reactions. PMID- 24762191 TI - Arsenic trioxide inhibits transforming growth factor-beta1-induced fibroblast to myofibroblast differentiation in vitro and bleomycin induced lung fibrosis in vivo. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-beta1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition. METHODS: To identify the mechanism of Arsenic trioxide's (ATO)'s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-beta1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as alpha smooth muscle actin (alpha-SMA) and alpha-1 type I collagen. RESULTS: Treatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-beta1-induced alpha-smooth muscle actin (alpha-SMA) and alpha-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-beta1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-beta1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF beta1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung alpha-1 type I collagen mRNA and protein expression. CONCLUSIONS: In summary, these data indicate that low concentrations of ATO inhibit TGF-beta1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis. PMID- 24762193 TI - Goals of telephone nursing work--the managers' perspectives: a qualitative study on Swedish Healthcare Direct. AB - BACKGROUND: Swedish Healthcare Direct (SHD) receives 6 million calls yearly and aims at increased public sense of security and healthcare efficiency. Little is known about what SHD managers perceive as the primary goals of telephone nursing (TN) work and how the organisation matches goals of health promotion and equitable healthcare, so important in Swedish healthcare legislation. The aim of the study was to explore and describe what the SHD managers perceive as the goals of TN work and how the managers view health promotion and implementation of equitable healthcare with gender as example at SHD. METHODS: The study was qualitative using an exploratory and descriptive design. All 23 managers employed at SHD were interviewed and data analysis used deductive directed content analysis. RESULTS: The findings reveal four themes describing the goals of TN work as recommended by the SHD managers. These are: 'create feelings of trust', 'achieve patient safety', 'assess, refer and give advice', and 'teach the caller'. Most of the managers stated that health promotion should not be included in the goals, whereas equitable healthcare was viewed as an important issue. Varying suggestions for implementing equitable healthcare were given. CONCLUSIONS: The interviewed managers mainly echoed the organisational goals of TN work. The managers' expressed goal of teaching lacked the caller learning components highlighted by telenurses in previous research. The fact that health promotion was not seen as important indicates a need for SHD to clarify its goals as the organisation is part of the Swedish healthcare system, where health promotion should always permeate work. Time used for health promotion and dialogues in a gender equitable manner at SHD is well invested as it will save time elsewhere in the health care system, thereby facing one of the challenges of European health systems. PMID- 24762194 TI - Gestational diabetes mellitus and later cardiovascular disease: a Swedish population based case-control study. AB - OBJECTIVE: To identify if gestational diabetes mellitus (GDM) is a clinically useful marker of future cardiovascular disease (CVD) risk and if GDM combined with other risks (smoking, hypertension or body mass) identifies high-risk groups. DESIGN: Population-based matched case-control study. SETTING: National Swedish register data from 1991 to 2008. POPULATION: A total of 2639 women with a cardiovascular event and matched controls. METHODS: Conditional logistic regression examined associations with CVD before and after adjustment for conventional risk factors and confounders. Effect modification for the association of GDM with CVD by body mass index (BMI), smoking and chronic hypertension was assessed by stratification and interaction testing. Adjustment for diabetes post-pregnancy evaluated its mediating role. MAIN OUTCOME MEASURES: Inpatient diagnoses or causes of death identifying ischemic heart disease, ischemic stroke, atherosclerosis or peripheral vascular disease. RESULTS: The adjusted odds ratios (and 95% confidence intervals) for the association of CVD with GDM are 1.51 (1.07-2.14), 2.23 (2.01-2.48) for smoking, 1.98 (1.71-2.29) for obesity and 5.10 (3.18-8.18) for chronic hypertension. In stratified analysis the association of CVD with GDM was only seen among women with BMI >=25, with an odds ratio of 2.39 (1.39-4.10), but only women with a BMI <30 accounted for this increased risk. Adjustment for post-pregnancy diabetes attenuated it somewhat to 1.99 (1.13-3.52). CONCLUSIONS: In the absence of other recognised cardiovascular risk factors, such as smoking, obesity or chronic hypertension, GDM is a useful marker of raised CVD risk among women with BMI between 25 and 29. PMID- 24762196 TI - Neurobiological model of obsessive-compulsive disorder: evidence from recent neuropsychological and neuroimaging findings. AB - Obsessive-compulsive disorder (OCD) was previously considered refractory to most types of therapeutic intervention. There is now, however, ample evidence that selective serotonin reuptake inhibitors and behavior therapy are highly effective methods for treatment of OCD. Furthermore, recent neurobiological studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function. A large number of previous neuroimaging studies using positron emission tomography, single-photon emission computed tomography or functional magnetic resonance imaging (fMRI) have identified abnormally high activities throughout the frontal cortex and subcortical structures in patients with OCD. Most studies reported excessive activation of these areas during symptom provocation. Furthermore, these hyperactivities were decreased after successful treatment using either selective serotonin reuptake inhibitors or behavioral therapy. Based on these findings, an orbitofronto-striatal model has been postulated as an abnormal neural circuit that mediates symptomatic expression of OCD. On the other hand, previous neuropsychological studies of OCD have reported cognitive dysfunction in executive function, attention, nonverbal memory, and visuospatial skills. Moreover, recent fMRI studies have revealed a correlation between neuropsychological dysfunction and clinical symptoms in OCD by using neuropsychological tasks during fMRI. The evidence from fMRI studies suggests that broader regions, including dorsolateral prefrontal and posterior regions, might be involved in the pathophysiology of OCD. Further, we should consider that OCD is heterogeneous and might have several different neural systems related to clinical factors, such as symptom dimensions. This review outlines recent neuropsychological and neuroimaging studies of OCD. We will also describe several neurobiological models that have been developed recently. Advanced findings in these fields will update the conventional biological model of OCD. PMID- 24762195 TI - Beneficial effects of cerium oxide nanoparticles in development of chondrocyte seeded hydrogel constructs and cellular response to interleukin insults. AB - The harsh inflammatory environment associated with injured and arthritic joints represents a major challenge to articular cartilage repair. In this study, we report the effect of cerium oxide nanoparticles, or nanoceria, in modulating development of engineered cartilage and in combating the deleterious effects of interleukin-1alpha. Nanoceria was found to be biocompatible with bovine chondrocytes up to a concentration of 1000 MUg/mL (60,000 cells/MUg of nanoceria), and its presence significantly improved compressive mechanical properties and biochemical composition (i.e., glycosaminoglycans) of engineered cartilage. Raman microspectroscopy revealed that individual chondrocytes with internalized nanoceria have increased concentrations of proline, procollagen, and glycogen as compared with cells without the nanoparticles in their vicinity. The inflammatory response due to physiologically relevant quantities of interluekin 1alpha (0.5 ng/mL) is partially inhibited by nanoceria. To the best of the authors' knowledge, these results are the first to demonstrate a high potential for nanoceria to improve articular cartilage tissue properties and for their long term treatment against an inflammatory reaction. PMID- 24762197 TI - Periosteal PTHrP regulates cortical bone modeling during linear growth in mice. AB - The modeling of long bone surfaces during linear growth is a key developmental process, but its regulation is poorly understood. We report here that parathyroid hormone-related peptide (PTHrP) expressed in the fibrous layer of the periosteum (PO) drives the osteoclastic (OC) resorption that models the metaphyseal diaphyseal junction (MDJ) in the proximal tibia and fibula during linear growth. PTHrP was conditionally deleted (cKO) in the PO via Scleraxis gene targeting (Scx Cre). In the lateral tibia, cKO of PTHrP led to a failure of modeling, such that the normal concave MDJ was replaced by a mound-like deformity. This was accompanied by a failure to induce receptor activator of NF-kB ligand (RANKL) and a 75% reduction in OC number (P <= 0.001) on the cortical surface. The MDJ also displayed a curious threefold increase in endocortical osteoblast mineral apposition rate (P <= 0.001) and a thickened cortex, suggesting some form of coupling of endocortical bone formation to events on the PO surface. Because it fuses distally, the fibula is modeled only proximally and does so at an extraordinary rate, with an anteromedial cortex in CD-1 mice that was so moth eaten that a clear PO surface could not be identified. The cKO fibula displayed a remarkable phenotype, with a misshapen club-like metaphysis and an enlargement in the 3D size of the entire bone, manifest as a 40-45% increase in the PO circumference at the MDJ (P <= 0.001) as well as the mid-diaphysis (P <= 0.001). These tibial and fibular phenotypes were reproduced in a Scx-Cre-driven RANKL cKO mouse. We conclude that PTHrP in the fibrous PO mediates the modeling of the MDJ of long bones during linear growth, and that in a highly susceptible system such as the fibula this surface modeling defines the size and shape of the entire bone. PMID- 24762198 TI - Polymorphisms of inflammation-related genes and colorectal cancer risk: a population-based case-control study in China. AB - The previous studies found that chronic inflammation related to an increased risk of colorectal cancer (CRC). This study aims to explore the associations of polymorphisms in inflammation-related genes (IL10, IL10RA, IL6R, TNFRSF1A, TNFRSF1B, LTA and IL4) and their interactions with the risk of colorectal cancer among Chinese population. A population-based case-control study including 299 cases and 296 controls was conducted from January 2001 to December 2009. Multivariate unconditional logistic regression was used to analyse the association of nine SNPs in inflammation-related genes with the risk of CRC, colon cancer and rectal cancer, respectively. Generalized multifactor dimensionality reduction (GMDR) was implemented to explore the gene-gene interactions among all SNPs on CRC. A decreased risk of colorectal cancer in subjects with rs1800872 AC genotype of IL10 (OR = 0.643, 95%CI = 0.453, 0.912) or AC/CC genotype (OR = 0.636, 95%CI = 0.457, 0.885) was observed, compared with those with AA genotype. Meanwhile, similar associations were observed between rs1800872 and rectal cancer. Additionally, in rs1061624 of TNFRSF1B gene, AG genotype (OR=0.566; 95% CI= 0.362, 0.885) and AG/GG genotype (OR=0.638; 95% CI=0.420, 0.971) were significantly associated with a decreased risk of rectal cancer, respectively. Our findings indicated that mutants in IL10 and TNFRSF1B genes may change the CRC risk. However, there is no interaction between inflammation-related genes on CRC risk. PMID- 24762199 TI - Prognostic value of vascular endothelial growth factors A and C in oral squamous cell carcinoma. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) family members play a major role in angiogenesis and vascularization. VEGF-A promotes tumor angiogenesis by stimulating the growth of tumor vascular endothelial cells. In addition, VEGF-C has been identified as a potent inducer of lymphangiogenesis in tumor and lymph node metastasis. Previous studies have investigated the association between clinicopathological factors and the expression of VEGF-A and VEGF-C in oral squamous cell carcinoma cancer (OSCC), but the results are contradictory. In this study, we investigated the relationship between VEGF-A and VEGF-C expression and OSCC clinicopathological factors and prognosis. METHODS: Expression of VEGF-A and VEGF-C was evaluated in surgical specimens from 61 patients with OSCC and three human oral cancer cell lines (OSC-19, OSC-20 and HOC313) by immunohistochemical staining and enzyme-linked immunosorbent assay, respectively. We also determined the relationship between the 5-year survival rate and clinicopathological factors, such as TNM classification (Union for International Cancer Control, UICC), lymph node metastasis, recurrence, histological differentiation, location, and mode of invasion. RESULTS: VEGF-A expression correlated significantly with lymph node metastasis. VEGF-C expression was associated with lymph node metastasis, recurrence, and a poorer 5-year survival rate. A multivariate analysis demonstrated that VEGF-C is an independent prognostic factor for patients with OSCC. VEGF-C expression was significantly up-regulated in HOC313 cells compared to OSC-19 and OSC-20 cells. CONCLUSIONS: These results indicate that VEGF-C may be a predictive factor for OSCC outcome, lymph node metastasis, and recurrence. Moreover, VEGF-C may be an important factor in the development of new therapies for OSCC patients. PMID- 24762200 TI - Predicting driving ability using DriveSafe and DriveAware in people with cognitive impairments: a replication study. AB - BACKGROUND/AIM: Previously developed cut-off scores for off-road assessments, DriveSafe and DriveAware, were applied to data from a new sample. Our aim was to determine whether results from previous research are replicable in a different population, to further investigate the psychometric properties of the tools. METHODS: Using a retrospective cohort design, we analysed data from DriveSafe and DriveAware gathered in three driving centres in Sydney (N = 90). We calculated sensitivity and specificity of DriveSafe and DriveAware data for predicting results of on-road testing. RESULTS: Sensitivity and specificity for this study were very similar to those documented previously. The lower cut-off produced specificity of 96%, identical to previous calculations. The upper cut-off score yielded sensitivity of 91% compared with 93% previously. When scores from DriveSafe and DriveAware were trichotomised (i.e. 'pass,' 'fail,' and 'requires on-road testing'), they predicted on-road performance of about half of drivers with >= 90% accuracy. CONCLUSION: Findings will add to the body of evidence suggesting that not all drivers referred to occupational therapy driving assessors require expensive, time-consuming and potentially high risk on-road assessments. PMID- 24762201 TI - The Sec translocon mediated protein transport in prokaryotes and eukaryotes. AB - Protein transport via the Sec translocon represents an evolutionary conserved mechanism for delivering cytosolically-synthesized proteins to extra-cytosolic compartments. The Sec translocon has a three-subunit core, termed Sec61 in Eukaryotes and SecYEG in Bacteria. It is located in the endoplasmic reticulum of Eukaryotes and in the cytoplasmic membrane of Bacteria where it constitutes a channel that can be activated by multiple partner proteins. These partner proteins determine the mechanism of polypeptide movement across the channel. During SRP-dependent co-translational targeting, the ribosome threads the nascent protein directly into the Sec channel. This pathway is in Bacteria mainly dedicated for membrane proteins but in Eukaryotes also employed by secretory proteins. The alternative pathway, leading to post-translational translocation across the Sec translocon engages an ATP-dependent pushing mechanism by the motor protein SecA in Bacteria and a ratcheting mechanism by the lumenal chaperone BiP in Eukaryotes. Protein transport and biogenesis is also assisted by additional proteins at the lateral gate of SecY/Sec61alpha and in the lumen of the endoplasmic reticulum or in the periplasm of bacterial cells. The modular assembly enables the Sec complex to transport a vast array of substrates. In this review we summarize recent biochemical and structural information on the prokaryotic and eukaryotic Sec translocons and we describe the remarkably complex interaction network of the Sec complexes. PMID- 24762202 TI - Computational method to identify druggable binding sites that target protein protein interactions. AB - Protein-protein interactions are implicated in the pathogenesis of many diseases and are therefore attractive but challenging targets for drug design. One of the challenges in development is the identification of potential druggable binding sites in protein interacting interfaces. Identification of interface surfaces can greatly aid rational drug design of small molecules inhibiting protein-protein interactions. In this work, starting from the structure of a free monomer, we have developed a ligand docking based method, called "FindBindSite" (FBS), to locate protein-protein interacting interface regions and potential druggable sites in this interface. FindBindSite utilizes the results from docking a small and diverse library of small molecules to the entire protein structure. By clustering regions with the highest docked ligand density from FBS, we have shown that these high ligand density regions strongly correlate with the known protein protein interacting surfaces. We have further predicted potential druggable binding sites on the protein surface using FBS, with druggability being defined as the site with high density of ligands docked. FBS shows a hit rate of 71% with high confidence and 93% with lower confidence for the 41 proteins used for predicting druggable binding sites on the protein-protein interface. Mining the regions of lower ligand density that are contiguous with the high scoring high ligand density regions from FBS, we were able to map 70% of the protein-protein interacting surface in 24 out of 41 structures tested. We also observed that FBS has limited sensitivity to the size and nature of the small molecule library used for docking. The experimentally determined hotspot residues for each protein protein complex cluster near the best scoring druggable binding sites identified by FBS. These results validate the ability of our technique to identify druggable sites within protein-protein interface regions that have the maximal possibility of interface disruption. PMID- 24762204 TI - Parallel signatures of selection in temporally isolated lineages of pink salmon. AB - Studying the effect of similar environments on diverse genetic backgrounds has long been a goal of evolutionary biologists with studies typically relying on experimental approaches. Pink salmon, a highly abundant and widely ranging salmonid, provide a naturally occurring opportunity to study the effects of similar environments on divergent genetic backgrounds due to a strict two-year semelparous life history. The species is composed of two reproductively isolated lineages with overlapping ranges that share the same spawning and rearing environments in alternate years. We used restriction-site-associated DNA (RAD) sequencing to discover and genotype approximately 8000 SNP loci in three population pairs of even- and odd-year pink salmon along a latitudinal gradient in North America. We found greater differentiation within the odd-year than within the even-year lineage and greater differentiation in the southern pair from Puget Sound than in the northern Alaskan population pairs. We identified 15 SNPs reflecting signatures of parallel selection using both a differentiation based method (BAYESCAN) and an environmental correlation method (BAYENV). These SNPs represent genomic regions that may be particularly informative in understanding adaptive evolution in pink salmon and exploring how differing genetic backgrounds within a species respond to selection from the same natural environment. PMID- 24762205 TI - Multicenter matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) identifies proteomic differences in breast-cancer-associated stroma. AB - MALDI mass spectrometry imaging (MSI) has rapidly established itself as a powerful biomarker discovery tool. To date, no formal investigation has assessed the center-to-center comparability of MALDI MSI experiments, an essential step for it to develop into a new diagnostic method. To test such capabilities, we have performed a multicenter study focused on biomarkers of stromal activation in breast cancer. MALDI MSI experiments were performed in two centers using independent tissue banks, infrastructure, methods, and practitioners. One of the data sets was used for discovery and the other for validation. Areas of intra- and extratumoral stroma were selected, and their protein signals were compared. Four protein signals were found to be significantly associated with tumor associated stroma in the discovery data set measured in Munich. Three of these peaks were also detected in the independent validation data set measured in Leiden, all of which were also significantly associated with intratumoral stroma. Hierarchical clustering displayed 100% accuracy in the Munich MSI data set and 80.9% accuracy in the Leiden MSI data set. The association of one of the identified mass signals (PA28) with stromal activation was confirmed with immunohistochemistry performed on 20 breast tumors. Independent and international MALDI MSI investigations could identify validated biomarkers of stromal activation. PMID- 24762203 TI - Review: Hippocampal sclerosis in epilepsy: a neuropathology review. AB - Hippocampal sclerosis (HS) is a common pathology encountered in mesial temporal lobe epilepsy (MTLE) as well as other epilepsy syndromes and in both surgical and post-mortem practice. The 2013 International League Against Epilepsy (ILAE) classification segregates HS into typical (type 1) and atypical (type 2 and 3) groups, based on the histological patterns of subfield neuronal loss and gliosis. In addition, granule cell reorganization and alterations of interneuronal populations, neuropeptide fibre networks and mossy fibre sprouting are distinctive features of HS associated with epilepsies; they can be useful diagnostic aids to discriminate from other causes of HS, as well as highlighting potential mechanisms of hippocampal epileptogenesis. The cause of HS remains elusive and may be multifactorial; the contribution of febrile seizures, genetic susceptibility, inflammatory and neurodevelopmental factors are discussed. Post mortem based research in HS, as an addition to studies on surgical samples, has the added advantage of enabling the study of the wider network changes associated with HS, the long-term effects of epilepsy on the pathology and associated comorbidities. It is likely that HS is heterogeneous in aspects of its cause, epileptogenetic mechanisms, network alterations and response to medical and surgical treatments. Future neuropathological studies will contribute to better recognition and understanding of these clinical and patho-aetiological subtypes of HS. PMID- 24762206 TI - Distinguishing migration from isolation using genes with intragenic recombination: detecting introgression in the Drosophila simulans species complex. AB - BACKGROUND: Determining the presence or absence of gene flow between populations is the target of some statistical methods in population genetics. Until recently, these methods either avoided the use of recombining genes, or treated recombination as a nuisance parameter. However, genes with recombination contribute additional information for the detection of gene flow (i.e. through linkage disequilibrium). METHODS: We present three summary statistics based on the spatial arrangement of fixed differences, and shared and exclusive polymorphisms that are sensitive to the presence and direction of gene flow. Power and false positive rate for tests based on these statistics are studied by simulation. RESULTS: The application of these tests to populations from the Drosophila simulans species complex yielded results consistent with migration between D. simulans and its two endemic sister species D. mauritiana and D. sechellia, and between populations D. mauritiana on the islands of the Mauritius and Rodrigues. CONCLUSIONS: We demonstrate the sensitivity of the developed statistics to the presence and direction of gene flow, and characterize their power as a function of differentiation level and recombination rate. The properties of these statistics make them especially suitable for analyzing high throughput sequencing data or for their integration within the approximate Bayesian computation framework. PMID- 24762208 TI - Solvent-dependent decarboxylation of 1,3-dimethylimdazolium-2-carboxylate. AB - 1,3-Dimethylimidazolium-2-carboxylate 1 is stable in both pure water and pure acetonitrile. However, in mixtures of the two solvents, this compound suffers a rapid decarboxylation/protonaton reaction, forming 1,3-dimethylimidazolium cation 2. A series of kinetic and mechanistic experiments, along with DFT calculations, were carried out to understand the mechanism of this process and to elucidate the role of solvation on the stability of 1. These findings demonstrate that the decomposition process is a reversible decarboxylation forming the corresponding N heterocyclic carbene (1,3-dimethylimidazolylidene, 3), followed by a rapid protonation of 3 by water or other protic species. The length and strength of the C-C bond between in the imidazolium ring and the carboxylate group (denoted C(NHC)-CO2) of 1 is remarkably dependent on the polarity of the solvent. Density functional theory (DFT) calculations predict a ca. 20 kcal/mol change in the barrier to decarboxylation in going from the gas phase to (SMD-simulated) water. Thus, addition of water has two effects on the stability of 1. At low concentrations, it provides a proton source for the trapping of the carbene 3 and accelerates decomposition. At higher concentrations, it increases the polarity of the medium. slowing the decarboxylation process and likewise the overall decomposition rate. PMID- 24762209 TI - Scoring systems predict the prognosis of acute-on-chronic hepatitis B liver failure: an evidence-based review. AB - Acute-on-chronic hepatitis B liver failure is a devastating condition that is associated with mortality rates of over 50% and is consequent to acute exacerbation of chronic hepatitis B in patients with previously diagnosed or undiagnosed chronic liver disease. Liver transplantation is the definitive treatment to lower mortality rate, but there is a great imbalance between donation and potential recipients. An early and accurate prognostic system based on the integration of laboratory indicators, clinical events and some mathematic logistic equations is needed to optimize treatment for patients. As parts of the scoring systems, the MELD was the most common and the donor-MELD was the most innovative for patients on the waiting list for liver transplantation. This review aims to highlight the various features and prognostic capabilities of these scoring systems. PMID- 24762207 TI - Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. AB - SIGNIFICANCE: Blood forming, hematopoietic stem cells (HSCs) mostly reside in the bone marrow in a quiescent, nonmotile state via adhesion interactions with stromal cells and macrophages. Quiescent, proliferating, and differentiating stem cells have different metabolism, and accordingly different amounts of intracellular reactive oxygen species (ROS). Importantly, ROS is not just a byproduct of metabolism, but also plays a role in stem cell state and function. RECENT ADVANCES: ROS levels are dynamic and reversibly dictate enhanced cycling and myeloid bias in ROS(high) short-term repopulating stem cells, and ROS(low) quiescent long-term repopulating stem cells. Low levels of ROS, regulated by intrinsic factors such as cell respiration or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity, or extrinsic factors such as stem cell factor or prostaglandin E2 are required for maintaining stem cell self renewal. High ROS levels, due to stress and inflammation, induce stem cell differentiation and enhanced motility. CRITICAL ISSUES: Stem cells need to be protected from high ROS levels to avoid stem cell exhaustion, insufficient host immunity, and leukemic transformation that may occur during chronic inflammation. However, continuous low ROS production will lead to lack of stem cell function and opportunistic infections. Ultimately, balanced ROS levels are crucial for maintaining the small stem cell pool and host immunity, both in homeostasis and during stress situations. FUTURE DIRECTIONS: Deciphering the signaling pathway of ROS in HSC will provide a better understanding of ROS roles in switching HSC from quiescence to activation and vice versa, and will also shed light on the possible roles of ROS in leukemia initiation and development. PMID- 24762210 TI - Assessing the effectiveness of 30% sodium chloride aqueous solution for the preservation of fixed anatomical specimens: a 5-year follow-up study. AB - Anatomical specimens used in human or veterinary anatomy laboratories are usually prepared with formaldehyde (a cancerous and teratogenic substance), glycerin (an expensive and viscous fluid), or ethanol (which is flammable). This research aimed to verify the viability of an aqueous 30% sodium chloride solution for preservation of anatomical specimens previously fixed with formaldehyde. Anatomical specimens of ruminant, carnivorous, equine, swine and birds were used. All were previously fixed with an aqueous 20% formaldehyde solution and held for 7 days in a 10% aqueous solution of the same active ingredient. During the first phase of the experiment, small specimens of animal tissue previously fixed in formaldehyde were distributed in vials with different concentrations of formaldehyde, with or without 30% sodium chloride solution, a group containing only 30% sodium chloride, and a control group containing only water. During this phase, no contamination was observed in any specimen containing 30% sodium chloride solution, whether alone or in combination with different concentrations of formaldehyde. In the second phase of the experiment, the 30% sodium chloride solution, found to be optimal in the first phase of the experiment, was tested for its long-term preservation properties. For a period of 5 years, the preserved specimens were evaluated three times a week for visual contamination, odors, and changes in color and texture. There was no visual contamination or decay found in any specimen. Furthermore, no strange odors, or changes in color or softness were noted. The 30% sodium chloride solution was determined to be effective in the preservation of anatomic specimens previously fixed in formaldehyde. PMID- 24762211 TI - First description of NDM-1-, KPC-2-, VIM-2- and IMP-4-producing Klebsiella pneumoniae strains in a single Chinese teaching hospital. AB - A total of 180 non-duplicate carbapenem-resistant Klebsiella pneumoniae isolates were recovered from patients hospitalized between December 2010 and January 2012 at a Chinese hospital. Eight KPC-2, four NDM-1, one VIM-2, and five KPC-2 plus IMP-4 producers were identified and all were multidrug resistant due to the presence of other resistance determinants, including extended-spectrum beta lactamases (CTX-M-15, SHV-12), 16S rRNA methylases (armA, rmtB) and plasmid mediated quinolone-resistance determinants (qnrA, B, S, aac(6')-Ib-cr). Nine K. pneumoniae clones (Kpn-A1/ST395, Kpn-A3/ST11, Kpn-A2/ST134, Kpn-B/ST263, Kpn C/ST37, Kpn-D/ST39, Kpn-E/ST1151, Kpn-F/ST890, Kpn-G/ST1153) were identified. bla KPC-2 was located on transferable ~65 kb IncL/M (ST395, ST11, ST134, ST39) and ~100 kb IncA/C (ST37, ST1153, ST890) plasmids, respectively. On the other hand, bla NDM-1 was associated with a ~70 kb IncA/C plasmid (ST263). However, non typable plasmids of ~40 kb containing bla VIM-2 were detected in the ST1151 clone. This work reports the first co-occurrence of four diverse types of carbapenemase of K. pneumoniae clones from a single hospital in China. IncA/C, IncL/M, and other successful plasmids may be important for the dissemination of carbapenemases, producing a complex epidemiological picture. PMID- 24762212 TI - Variation of urinary protein to creatinine ratio during the day in women with suspected pre-eclampsia. AB - OBJECTIVE: To investigate the stability throughout the day of the protein to creatinine ratio (PCR) in spot urine, to demonstrate whether the PCR is a valid alternative for 24-hour protein investigation in pregnant women. DESIGN: Prospective study. SETTING: Tertiary referral university centre. POPULATION: Women suspected of having pre-eclampsia, admitted to the Erasmus Medical Centre. METHODS: Twenty-four-hour urine collections and simultaneously three single voided 5-ml aliquots were obtained at 8 a.m., 12 a.m. (noon) and 5 p.m. A PCR was measured in each specimen and compared with the 24-hour protein excretion. MAIN OUTCOME MEASURES: The 24-hour proteinuria and PCR measured in spontaneous voids. RESULTS: The PCRs correlated strongly with each other and with the 24-hour protein excretion but did show variation throughout the day (mean coefficient of variation 36%; 95% confidence interval 31-40%). The coefficient of variation was unrelated to the degree of 24-hour proteinuria. Receiver operating characteristics curves to discriminate between values below and greater than or equal to the threshold of 0.3 g protein per 24-hour had an area under the curve of respectively 0.94 (8 a.m.), 0.96 (noon) and 0.97 (5 p.m.). Sensitivities at 8 a.m., noon and 5 p.m. were respectively 89%, 96% and 94%; specificities were 75%, 78% and 78% with the proposed PCR cut-off of 30 mg/mmol (0.26 g/g) (National Institute for Health and Care Excellence guidelines).There is no evidence of a difference between the three measurement times regarding the sensitivities and specificities. CONCLUSION: The PCR determined in spot urine varies throughout the day but is a valid alternative for 24-hour urine collections in pregnant women. It is especially useful to rapidly identify clinically relevant proteinuria. PMID- 24762213 TI - A promoter polymorphism (rs3806798) of interleukin-15 gene is associated with chronic hepatitis B virus infection in the Chinese Han population. AB - This study aimed to investigate the association between the polymorphisms of IL 15 gene and susceptibility to chronic hepatitis B virus (HBV) infection in the Chinese Han population. A total of 234 patients with chronic HBV infection and 150 age- and sex-matched healthy controls in the Chinese population were enrolled in this case-control study. Genotyping of ten single nucleotide polymorphisms (SNPs) in the IL-15 gene was carried out via Sequenom MassARRAY system. The association analysis demonstrated that SNP rs3806798 (A/T) had a significant difference in the distribution between patients and healthy controls (P = 0.033). Moreover, a significantly increased risk of HBV infection was found to be associated with IL-15 rs3806798 A allele among male patients and HBeAg-negative patients, compared with IL-15 rs3806798 T allele (P = 0.003; P = 0.046, respectively). Furthermore, haplotype analysis revealed that haplotype ATAGG (rs3806798, rs12508866, rs1519551, rs6819823 and rs2857261, respectively) in block 1 was significantly associated with HBV infection (P = 0.022). In conclusion, we found an association between IL-15 rs3806798 and the risk of chronic HBV infection in a sample of Chinese Han population. PMID- 24762214 TI - Intrathecal local anaesthetics in ambulatory surgery. PMID- 24762215 TI - Verbalized desire for death or euthanasia in advanced cancer patients receiving palliative care. AB - OBJECTIVE: We aimed to address the prevalence of desire-to-die statements (DDSs) among terminally ill cancer patients in an acute palliative care unit. We also intended to compare the underlying differences between those patients who make desire-to-die comments (DDCs) and those who make desire-for-euthanasia comments (EUCs). METHOD: We conducted a one-year cross-sectional prospective study in all patients receiving palliative care who had made a DDC or EUC. At inclusion, we evaluated symptom intensity, anxiety and depression, and conducted a semistructured interview regarding the reasons for these comments. RESULTS: Of the 701 patients attended to during the study period, 69 (9.8%; IC 95% 7.7-12.3) made a DDS: 51 (7.3%) a DDC, and 18 (2.5%) an EUC. Using Edmonton Symptom Assessment Scale (ESAS) DDC group showed higher percentage of moderate-severe symptoms (ESAS > 4) for well-being (91 vs. 25%; p = 0.001), depression (67 vs. 25%; p = 0.055), and anxiety (52 vs. 13%; p = 0.060) than EUC group. EUC patients also considered themselves less spiritual (44 vs. 84%; p = 0.034). The single most common reason for a DDS was pain or physical suffering, though most of the reasons given were nonphysical. SIGNIFICANCE OF RESULTS: Almost 10% of the population receiving specific oncological palliative care made a DDC (7.3%) or EUC (2.5%). The worst well-being score was lower in the EUC group. The reasons for both a DDC and EUC were mainly nonphysical. We find that emotional and spiritual issues should be identified and effectively addressed when responding to a DDS in terminally ill cancer patients. PMID- 24762218 TI - Abstracts of the WFH 2014 World Congress, May 11-15, 2014, Melbourne, Australia. PMID- 24762217 TI - Immunohistochemical assessment of ATG7, LC3, and p62 in ameloblastomas. AB - BACKGROUND: To investigate the roles of autophagy in tumorigenesis, cytodifferentiation, and prognosis of odontogenic tumors, we analyzed the immunohistochemical expression of ATG7, LC3, and p62 in odontogenic tissues. METHODS: Tissue specimens of nine dental follicles and 69 ameloblastomas were immunohistochemically examined with antibodies against ATG7, LC3, and p62. RESULTS: Immunohistochemical reactivity for ATG7, LC3, and p62 was detected in many odontogenic epithelial cells and several endothelial cells and fibroblasts in dental follicles and ameloblastomas. ATG7 reactivity in ameloblatomas was significantly higher than that in dental follicles. Expression of ATG7, LC3, and p62 was found markedly in neoplastic cells near the basement membrane rather than central polyhedral cells in ameloblastomas. Reactivity for these molecules was significantly higher in unicystic ameloblastomas than in solid ameloblastomas. Granular cells in granular cell ameloblastomas showed obvious reactivity for the autophagy- related molecules, and LC3 reactivity in granular cell ameloblastomas was significantly higher than in other ameloblastoma variations. Recurrent ameloblastomas showed significantly lower reactivity of LC3 and p62 than primary ameloblastomas. CONCLUSIONS: Expression of ATG7, LC3, and p62 in dental follicles and ameloblastomas suggests that autophagy regulation might be affected by microenvironment alterations during tumorigenesis. The molecular machinery for autophagy is possibly involved in tissue architecture, neoplastic cell differentiation, and prognosis of the benign epithelial odontogenic tumor. PMID- 24762216 TI - Vascular calcification in patients with type 2 diabetes: the involvement of matrix Gla protein. AB - BACKGROUND: Matrix Gla protein (MGP) is an important inhibitor of calcification. The objective of the present study of patients with type 2 diabetes and normal or slightly altered kidney function was to evaluate levels of inactive, dephospho uncarboxylated MGP(dp-ucMGP) and total uncarboxylated MGP(t-ucMGP) and assess their links with biological and clinical parameters (including peripheral vascular calcification). METHODS: The DIACART study is a cross-sectional cohort study of 198 patients with type 2 diabetes and normal or slightly altered kidney function. Matrix Gla protein levels were measured with an ELISA and all patients underwent multislice spiral computed tomography scans to score below-knee arterial calcification. RESULTS: In the study population as a whole, the mean dp ucMGP and t-ucMGP levels were 627 +/- 451 pM and 4868 +/- 1613 nM, respectively. Glomerular filtration rate, age and current vitamin K antagonist use were independently associated with dp-ucMGP levels. When the study population was divided according to the median peripheral arterial calcification score, patients with the higher score displayed significantly lower t-ucMGP and significantly higher dp-ucMGP levels. Furthermore, plasma dp-ucMGP was positively associated with the peripheral arterial calcification score (independently of age, gender, previous cardiovascular disease and t-ucMGP levels). CONCLUSIONS: High dp-ucMGP levels were independently associated with below-knee arterial calcification score in patients with type 2 diabetes and normal or slightly altered kidney function. The reversibility of the elevation of dp-ucMGP levels and the latter's relationship with clinical events merit further investigation. PMID- 24762220 TI - Comparison of equipment prescriptions in the toilet/bathroom by occupational therapists using home visits and digital photos, for patients in rehabilitation. AB - BACKGROUND/AIM: Home visits, used by occupational therapists to facilitate independence and enhance safety, are effective but costly and time consuming. This research aims to establish the level of agreement in equipment prescribed by occupational therapists using: digital photographs only, and using home visits and digital photographs, respectively. METHOD: Quasi-experimental methodological design conducted in private dwellings in the community in Adelaide with rehabilitation patients and their family members. The equipment recommended by occupational therapists for the toilet and bathroom using similar methods (both digital photographs from previous data; n = 5) was compared with equipment recommended using different methods (conventional home visits vs. digital photographs; n = 14). RESULTS: Percent agreement for equipment prescribed between groups, that is digital only and home visit/photography, respectively, were: 72.5/83.9% for toilet; 87.4/88.3% for bathroom and 83/87% for toilet and bathroom. Variability of agreement in the equipment prescribed showed that some items of equipment were incongruently prescribed, by both methods for toilet and bathroom areas. CONCLUSION: Using digital photographs taken by family members, patient information, and an equipment list is a reliable method of making accurate equipment prescriptions in the toilet and bathroom areas. To enhance accuracy, in-depth patient information via face-to-face interview and measurements of physical environment should be included. PMID- 24762221 TI - Reductive iron assimilation and intracellular siderophores assist extracellular siderophore-driven iron homeostasis and virulence. AB - Iron is an essential nutrient and prudent iron acquisition and management are key traits of a successful pathogen. Fungi use nonribosomally synthesized secreted iron chelators (siderophores) or reductive iron assimilation (RIA) mechanisms to acquire iron in a high affinity manner. Previous studies with the maize pathogen Cochliobolus heterostrophus identified two genes, NPS2 and NPS6, encoding different nonribosomal peptide synthetases responsible for biosynthesis of intra- and extracellular siderophores, respectively. Deletion of NPS6 results in loss of extracellular siderophore biosynthesis, attenuated virulence, hypersensitivity to oxidative and iron-depletion stress, and reduced asexual sporulation, while nps2 mutants are phenotypically wild type in all of these traits but defective in sexual spore development when NPS2 is missing from both mating partners. Here, it is reported that nps2nps6 mutants have more severe phenotypes than both nps2 and nps6 single mutants. In contrast, mutants lacking the FTR1 or FET3 genes encoding the permease and ferroxidase components, respectively, of the alternate RIA system, are like wild type in all of the above phenotypes. However, without supplemental iron, combinatorial nps6ftr1 and nps2nps6ftr1 mutants are less virulent, are reduced in growth, and are less able to combat oxidative stress and to sporulate asexually, compared with nps6 mutants alone. These findings demonstrate that, while the role of RIA in metabolism and virulence is overshadowed by that of extracellular siderophores as a high-affinity iron acquisition mechanism in C. heterostrophus, it functions as a critical backup for the fungus. PMID- 24762222 TI - Positive and negative roles for soybean MPK6 in regulating defense responses. AB - It has been well established that MPK6 is a positive regulator of defense responses in model plants such as Arabidopsis and tobacco. However, the functional importance of soybean MPK6 in disease resistance has not been investigated. Here, we showed that silencing of GmMPK6 in soybean using virus induced gene silencing mediated by Bean pod mottle virus (BPMV) caused stunted growth and spontaneous cell death on the leaves, a typical phenotype of activated defense responses. Consistent with this phenotype, expression of pathogenesis related (PR) genes and the conjugated form of salicylic acid were significantly increased in GmMPK6-silenced plants. As expected, GmMPK6-silenced plants were more resistant to downy mildew and Soybean mosaic virus compared with vector control plants, indicating a negative role of GmMPK6 in disease resistance. Interestingly, overexpression of GmMPK6, either transiently in Nicotiana benthamiana or stably in Arabidopsis, resulted in hypersensitive response (HR) like cell death. The HR-like cell death was accompanied by increased PR gene expression, suggesting that GmMPK6, like its counterpart in other plant species, also plays a positive role in cell death induction and defense response. Using bimolecular fluorescence complementation analysis, we determined that GmMKK4 might function upstream of GmMPK6 and GmMKK4 could interact with GmMPK6 independent of its phosphorylation status. Taken together, our results indicate that GmMPK6 functions as both repressor and activator in defense responses of soybean. PMID- 24762223 TI - Combined inhibition of NF-kappaB and Bcl-2 triggers synergistic reduction of viability and induces apoptosis in melanoma cells. AB - Constitutive activation of nuclear factor kappaB (NF-kappaB) characterizes melanoma cells. To explore the molecular mechanism of melanoma cell survival by constitutive NF-kappaB activation, we used the NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ), which directly binds to NF-kappaB. DHMEQ abrogated constitutive NF-kappaB activity, which included RelA (p65)/p50 in melanoma cell lines G361 and HMV-II; however, the reduction of the viability was marginal. Expression of c-FLIP was not observed in the melanoma cell lines tested, and DHMEQ could not repress the expression of the Bcl-2 family proteins Bcl-2 and Bcl-xL. Concomitant treatment with DHMEQ and the inhibitor of antiapoptotic Bcl-2 family proteins, GX15-070, triggered synergistic reduction of the viability and induced apoptosis of G361 cells. These results indicate that abrogation of the NF-kappaB pathway alone is not sufficient to suppress the survival of melanoma cells. The NF-kappaB and the antiapoptotic Bcl-2 pathways cooperatively support the survival, and the dual targeting triggers synergistic reduction of the viability and induces apoptosis of melanoma cells. PMID- 24762224 TI - Phase II study of bevacizumab, capecitabine, and oxaliplatin followed by bevacizumab plus erlotinib as first-line therapy in metastatic colorectal cancer. AB - This phase II trial investigated the efficacy of an induction regimen of bevacizumab, capecitabine plus oxaliplatin (XELOX) followed by maintenance therapy with bevacizumab plus erlotinib as first-line therapy in patients with metastatic colorectal cancer. Patients with metastatic colorectal cancer received intravenous bevacizumab 7.5 mg/kg plus oxaliplatin 130 mg/m(2) on day 1 followed by oral capecitabine 1,000 mg/m(2) twice daily on days 1-14 every 3 weeks for six cycles. In the absence of disease progression, patients then received bevacizumab 7.5 mg/kg every 3 weeks plus oral erlotinib 150 mg once daily. The primary study endpoint was progression-free survival. In the intention-to-treat population (n = 90), the median progression-free survival was 9.2 [95% confidence interval (CI): 7.9-11.9] months, and the median overall survival was 25.8 (95% CI: 18.0-30.9) months. In the patient subpopulation who received both induction and maintenance therapy (n = 52), median progression-free survival was 11.1 (95% CI: 9.0-15.7) months, and the median overall survival was 29.5 (95% CI: 23.7-36.7) months. KRAS status did not predict efficacy. The most common grade 3/4 adverse events were diarrhea, asthenia, and neutropenia. XELOX-bevacizumab for 6 cycles followed by bevacizumab-erlotinib maintenance therapy has been shown to be a highly active and well-tolerated first-line regimen in patients with metastatic colorectal cancer. PMID- 24762225 TI - Cancer/testis antigen HCA587-derived long peptide vaccine generates potent immunologic responses and antitumor effects in mouse model. AB - The cancer/testis antigen HCA587 (also known as MAGE-C2), one of the most immunogenic tumor antigens, is overexpressed in a wide spectrum of malignant tumors and can serve as a target for immunotherapy. In this study, we synthesized 14 overlapping (25-35 amino acids) long peptides representing the sequence of the most immunogenic part of the HCA587 protein and evaluated the antigen-specific immune responses and antitumor effects generated by immunization with the synthetic long peptide (SLP) vaccine in a mouse model. HCA587 SLPs in combination with adjuvants CFA and CpG ODN induced potent T-cell responses, which were dominated by type 1 cytokine IFN-gamma-producing CD4(+) T cells as measured by ELISPOT and intracellular cytokine staining assay. Moreover, HCA587 SLP vaccination conferred protection against challenge with HCA587-expressing B16 melanoma in a therapeutic setting. Our findings may provide a scientific basis for the use of HCA587-derived long overlapping peptide vaccine for the treatment of patients with cancer in future clinical trials. PMID- 24762226 TI - Propofol inhibits proliferation and invasion of osteosarcoma cells by regulation of microRNA-143 expression. AB - Propofol is one of the extensively commonly used intravenous anesthetic agents. Previous studies have indicated that propofol has the ability to influence the biological behavior of several human cancer cells. However, the effect of propofol on osteosarcoma and its related molecular mechanisms are still not clear. Here we found that propofol significantly elevated the expression of miR 143, inhibited cell proliferation and invasion, and promoted apoptosis in osteosarcoma cell line MG63. Propofol also efficiently decreased protein expression of matrix metalloproteinase 13 (MMP-13). Moreover, the overexpression of miR-143 decreased MMP-13 protein level. Finally, the neutralization of miR-143 by anti-miR-143 antibody reversed the effect of propofol on cell proliferation, apoptosis, and invasion and upregulated MMP-13 expression in MG63 cells. Taken together, propofol may have antitumor potential in osteosarcoma, which is partly due to the downregulation of MMP-13 expression by miR-143. PMID- 24762227 TI - Synergistic antitumoral effect of IL-12 gene cotransfected with antiangiogenic genes for angiostatin, endostatin, and saxatilin. AB - Previously, it was reported that the cotransfection of angiostatin K1-3, endostatin, and saxatilin genes using cationic liposomes significantly inhibited tumor progression. IL-12 is a well-known immune modulator that promotes Th1-type antitumor immune responses and also induces antiangiogenic effects. In this study, we have examined the antitumoral function of the IL-12 gene cotransfected with antiangiogenic genes for angiostatin K1-3, endostatin, and saxatilin by O,O' dimyristyl-N-lysyl glutamate (DMKE) cationic liposomes in a mouse tumor model. According to our results, the administration of the IL-12 gene or the genes for angiostatin K1-3, endostatin, and saxatilin exhibited effective inhibition of B16BL6 melanoma growth in mice. In particular, intravenous administration of the IL-12 gene along with intratumoral administration of the three antiangiogenic genes synergistically inhibited the B16BL6 tumor growth. These results suggest that systemically expressed IL-12 enhances antitumoral efficacy of locally expressed antiangiogenic proteins. PMID- 24762228 TI - Stromal cell-derived factor-1 (SDF-1)/CXCR4 axis enhances cellular invasion in ovarian carcinoma cells via integrin beta1 and beta3 expressions. AB - Accumulating evidence has showed that stromal cell-derived factor-1 (SDF-1/CXCR4 axis played important roles in cancer metastases, but the detailed function in ovarian cancer is still largely unknown. In the present study, we determined the location of CXCR4 and lipid rafts, a specialized structure on cell membrane, in ovarian cancer tissues and ovarian cancer cell line SKOV3 cells by immunofluorescence. To analyze the role of SDF-1/CXCR4 and lipid rafts in tumor cell migration and invasion, Transwell assay and wound healing assay were also performed. Cytoflowmetry was carried out to determine the participation of integrins. Our data showed that CXCR4 and GM1 (marker of lipid rafts) were expressed in both ovarian cancer tissue and SKOV3 cells, and SDF-1 promoted the invasion and migration of SKOV3 cells, which was mediated by complete lipid rafts. Further studies uncovered that SDF-1 upregulated the expression of integrin beta1 and beta3, two molecules closely related with cancer metastasis. These results indicated that SDF-1 might promote the invasion and metastasis of ovarian cancer by regulating these two integrin molecules. PMID- 24762229 TI - Drug administration via enteral feeding tubes in residential care facilities for individuals with intellectual disability: an observational study. AB - BACKGROUND: The administration of oral medication to patients with an enteral feeding tube (EFT) is challenging. Compliance to guidelines concerning medication administration via EFT has been investigated extensively in the hospital setting. However, studies in residential care facilities (RCFs) for individuals with intellectual disability (ID) are very limited. Therefore, the present study aimed to collect direct observational data on drug administration practices to residents with EFT in multiple RCFs. METHOD: This cross-sectional, observational study was conducted in six Belgian RCFs for individuals with ID. Observations of medication preparation and administration through EFT were carried out in two randomly selected units per participating RCF, on 2 days per unit during all daytime drug rounds, using a direct observation method. Afterwards, the recorded observations were compared with international guidelines on drug preparation and administration through EFT. RESULTS: In total, 862 drug preparations and 268 administrations in 48 residents with EFT were witnessed. Mixing together multiple drugs, not diluting liquid formulations with at least an equal amount of water, not shaking suspensions/emulsions before use, and not selecting the most appropriate dosage form were the most common deviations from medication preparation guideline recommendations. For medication administration, not flushing the EFT with at least 15 mL water was the most common deviation. We also observed high variability in working methods regarding medication preparation and administration via EFT, even between staff members of the same unit. CONCLUSION: This study found that current guidelines concerning medication preparation and administration through EFT are often not followed in Belgian RCFs for individuals with ID. Further research aimed at understanding why current guidelines are not followed seems warranted. PMID- 24762230 TI - Overexpression of metabolic markers PKM2 and LDH5 correlates with aggressive clinicopathological features and adverse patient prognosis in tongue cancer. AB - AIMS: Pyruvate kinase M2 (PKM2) and lactate dehydrogenase 5 (LDH5) are two metabolic and oncogenic markers of cancer. In this study, we sought to investigate their expression patterns and prognostic value in tongue squamous cell carcinoma (TSCC). METHODS AND RESULTS: The expression and subcellular localization of PKM2 and LDH5 in TSCC cell lines were determined by Western blot and immunofluorescence. PKM2 and LDH5 abundance was examined by immunohistochemistry in 63 TSCC tumour specimens; their association with multiple clinicopathological parameters and overall patient survival was assessed. The protein levels of PKM2 and LDH5 were both significantly higher in TSCC cells than in an immortalized oral epithelial cell line. Overexpression of PKM2 associated significantly with cervical node metastasis (P = 0.0373), while elevated LDH5 levels correlated significantly with tumour size (P = 0.0094), pathological grade (P = 0.0052), cervical node metastasis (P = 0.0023) and clinical stage (P = 0.0024). Patients with tumours showing an increase in either PKM2 or LDH5 expression displayed significantly reduced overall survival, while patients with tumours overexpressing both proteins showed the worst prognosis with lowest overall survival. Furthermore, PKM2 and LDH5 were identified as independent prognostic predictors for overall patient survival in TSCC. CONCLUSION: Our data indicate that overexpression of PKM2 and LDH5 associates with key clinicopathological features and unfavourable prognosis in TSCC. PMID- 24762231 TI - Two types of heterometallic one-dimensional alignment composed of acetamidate bridged dirhodium and pivalamidate-bridged diplatinum complexes. AB - Two types of heterometallic one-dimensional chains, [{Rh2(acam)4}{Pt2(piam)2(NH3)4}2]n(CF3SO3)4n.2nMeOH (2, where acam = acetamidate, piam = pivalamidate) and [{Rh2(acam)4}{Pt2(piam)2(NH3)4}]n(CF3CO2)2n.2nEtOH (3), have been synthesized and characterized by single-crystal X-ray analyses. The chain structures in 2 and 3 are composed of two kinds of dinuclear complexes, [Rh2(acam)4] (i.e., [Rh2]) and [Pt2(piam)2(NH3)4] (i.e., [Pt2]), where Rh and Pt atoms are axially linked by metal-metal bonds. In 2 and 3, each complex is one dimensionally aligned as -{[Rh2]-[Pt2]-[Pt2]}n- or -{[Rh2]-[Pt2]}n-, respectively, in which different alignments are caused by different isomers of [Pt2] that are HH (head-head) and HT (head-tail) orientation of piam ligands and their hydrogen bonding modes. Considering the crystal structures and X-ray photoelectron spectra (XPS) measurements in 2 and 3, the oxidation states of the metal atoms are -{[Rh2(II,II)]-[Pt2(II,II)]-[Pt2(II,II)]}n- and -{[Rh2(II,II)] [Pt2(II,II)]}n-, which are unchanged from those in the starting compounds. The diffuse reflectance spectra show that LUMOs are M-M sigma-type orbitals. The gap between filled and vacant sigma-type orbitals in 3 is narrower than that in 2, and is attributed to the relative higher destabilized filled sigma-type orbitals caused by lower numbers of linking platinum atoms. PMID- 24762232 TI - Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature. AB - CONTEXT: Fluoroquinolone antibiotics have been used for several decades and are effective antimicrobials. Despite their usefulness as antibiotics, a growing body of evidence has accumulated in the peer-reviewed literature that shows fluoroquinolones can cause pathologic lesions in tendon tissue (tendinopathy). These adverse effects can occur within hours of commencing treatment and months after discontinuing the use of these drugs. In some cases, fluoroquinolone usage can lead to complete rupture of the tendon and substantial subsequent disability. OBJECTIVE: To discuss the cause, pharmacology, symptoms, and epidemiology of fluoroquinolone-associated tendinopathy and to discuss the clinical implications with respect to athletes and their subsequent physiotherapy. DATA SOURCES: We searched MEDLINE, Cumulative Index to Nursing and Allied Health (CINAHL), Allied and Complementary Medicine Database (AMED), and SPORTDiscus databases for available reports of fluoroquinolone-related tendinopathy (tendinitis, tendon pain, or rupture) published from 1966 to 2012. Search terms were fluoroquinolones or quinolones and tendinopathy, adverse effects, and tendon rupture. Included studies were written in or translated into English. Non-English-language and non English translations of abstracts from reports were not included (n = 1). STUDY SELECTION: Eligible studies were any available reports of fluoroquinolone-related tendinopathy (tendinitis, tendon pain, or rupture). Both animal and human histologic studies were included. Any papers not focusing on the tendon-related side effects of fluoroquinolones were excluded (n = 71). DATA EXTRACTION: Data collected included any cases of fluoroquinolone-related tendinopathy, the particular tendon affected, type of fluoroquinolone, dosage, and concomitant risk factors. Any data outlining the adverse histologic effects of fluoroquinolones also were collected. DATA SYNTHESIS: A total of 175 papers, including 89 case reports and 8 literature reviews, were identified. CONCLUSIONS: Fluoroquinolone tendinopathy may not respond well to the current popular eccentric training regimes and may require an alternative, staged treatment approach. Clinicians, athletes, athletic trainers, and their medical support teams should be aware of the need to discuss and possibly discontinue these antibiotics if adverse effects arise. PMID- 24762233 TI - Susceptibility to eating disorders among collegiate female student-athletes. AB - CONTEXT: Research has suggested that the prevalence of young women with eating disorders (EDs) is increasing, but determining the exact prevalence of EDs within the female student-athlete (FS-A) population is difficult. Looking at certain traits may help us to identify their level of susceptibility to developing an ED. OBJECTIVE: To determine the susceptibility of FS-As to EDs in relation to self concept, including self-esteem and body image. DESIGN: Cross-sectional study. SETTING: Athletic training and health centers at National Collegiate Athletic Association Division I, II, and III institutions via e-mail questionnaire correspondence. PATIENTS OR OTHER PARTICIPANTS: A total of 439 FS-As from 17 participating institutions completed the questionnaires. The sample was primarily white (83.1%) and underclass (61.8%). MAIN OUTCOME MEASURE(S): The questionnaire consisted of 4 parts: 3 subscales of the Eating Disorder Inventory-2, the Rosenberg Self-Esteem Scale, the Body Cathexis Scale, and demographic items. RESULTS: A total of 6.8% of FS-As were susceptible to anorexia and 1.8% were susceptible to bulimia. The majority of FS-As (61%) reported normal self-esteem levels, whereas 29.4% had high self-esteem. Overall, 64.5% were satisfied and 23% were very satisfied with their body image. CONCLUSIONS: These results are generally positive in that they suggest FS-As have high levels of self-concept and are at low risk to develop EDs. However, these findings do not mean that all concerns should be dismissed. Although more than 90% of the respondents were not susceptible to an ED, there are still FS-As who may be. Athletic departments should evaluate their FS-As' levels of self-concept so that their susceptibility to EDs can be addressed. The emotional aspect of health care should be included in providing holistic care for student-athletes. Athletic trainers often are the primary health care providers for FS-As, so they should be made aware of this concern. PMID- 24762234 TI - A predictive model to estimate knee-abduction moment: implications for development of a clinically applicable patellofemoral pain screening tool in female athletes. AB - CONTEXT: Prospective measures of high external knee-abduction moment (KAM) during landing identify female athletes at increased risk of patellofemoral pain (PFP). A clinically applicable screening protocol is needed. OBJECTIVE: To identify biomechanical laboratory measures that would accurately quantify KAM loads during landing that predict increased risk of PFP in female athletes and clinical correlates to laboratory-based measures of increased KAM status for use in a clinical PFP injury-risk prediction algorithm. We hypothesized that we could identify clinical correlates that combine to accurately determine increased KAM associated with an increased risk of developing PFP. DESIGN: Descriptive laboratory study. SETTING: Biomechanical laboratory. PATIENTS OR OTHER PARTICIPANTS: Adolescent female basketball and soccer players (n = 698) from a single-county public school district. MAIN OUTCOME MEASURE(S): We conducted tests of anthropometrics, maturation, laxity, flexibility, strength, and landing biomechanics before each competitive season. Pearson correlation and linear and logistic regression modeling were used to examine high KAM (>15.4 Nm) compared with normal KAM as a surrogate for PFP injury risk. RESULTS: The multivariable logistic regression model that used the variables peak knee-abduction angle, center-of-mass height, and hip rotational moment excursion predicted KAM associated with PFP risk (>15.4 NM of KAM) with 92% sensitivity and 74% specificity and a C statistic of 0.93. The multivariate linear regression model that included the same predictors accounted for 70% of the variance in KAM. We identified clinical correlates to laboratory measures that combined to predict high KAM with 92% sensitivity and 47% specificity. The clinical prediction algorithm, including knee-valgus motion (odds ratio [OR] = 1.46, 95% confidence interval [CI] = 1.31, 1.63), center-of-mass height (OR = 1.21, 95% CI = 1.15, 1.26), and hamstrings strength/body fat percentage (OR = 1.80, 95% CI = 1.02, 3.16) predicted high KAM with a C statistic of 0.80. CONCLUSIONS: Clinical correlates to laboratory-measured biomechanics associated with an increased risk of PFP yielded a highly sensitive model to predict increased KAM status. This screening algorithm consisting of a standard camcorder, physician scale for mass, and handheld dynamometer may be used to identify athletes at increased risk of PFP. PMID- 24762235 TI - Proteomic analysis of Daphnia magna hints at molecular pathways involved in defensive plastic responses. AB - BACKGROUND: Phenotypic plasticity in defensive traits occurs in many species when facing heterogeneous predator regimes. The waterflea Daphnia is well-known for showing a variety of these so called inducible defences. However, molecular mechanisms underlying this plasticity are poorly understood so far. We performed proteomic analysis on Daphnia magna exposed to chemical cues of the predator Triops cancriformis. D. magna develops an array of morphological changes in the presence of Triops including changes of carapace morphology and cuticle hardening. RESULTS: Using the 2D-DIGE technique, 1500 protein spots could be matched and quantified. We discovered 179 protein spots with altered intensity when comparing Triops exposed animals to a control group, and 69 spots were identified using nano-LC MS/MS. Kairomone exposure increased the intensity of spots containing muscle proteins, cuticle proteins and chitin-modifying enzymes as well as enzymes of carbohydrate and energy metabolism. The yolk precursor protein vitellogenin decreased in abundance in 41 of 43 spots. CONCLUSION: Identified proteins may be either directly involved in carapace stability or reflect changes in energy demand and allocation costs in animals exposed to predator kairomones. Our results present promising candidate proteins involved in the expression of inducible defences in Daphnia and enable further in depth analysis of this phenomenon. PMID- 24762237 TI - Overview of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. PMID- 24762236 TI - Soft tissue influence on ex vivo mobility in the hip of Iguana: comparison with in vivo movement and its bearing on joint motion of fossil sprawling tetrapods. AB - The reconstruction of a joint's maximum range of mobility (ROM) often is a first step when trying to understand the locomotion of fossil tetrapods. But previous studies suggest that the ROM of a joint is restricted by soft tissues surrounding the joint. To expand the limited informative value of ROM studies for the reconstruction of a fossil species' locomotor characteristics, it is moreover necessary to better understand the relationship of ex vivo ROM with the actual in vivo joint movement. To gain insight into the relationship between ex vivo mobility and in vivo movement, we systematically tested for the influence of soft tissues on joint ROM in the hip of the modern lizard Iguana iguana. Then, we compared the ex vivo mobility to in vivo kinematics of the hip joint in the same specimens using X-ray sequences of steady-state treadmill locomotion previously recorded. With stepwise removal of soft tissues and a repeated-measurement protocol, we show that soft tissues surrounding the hip joint considerably limit ROM, highlighting the problems when joint ROM is deduced from bare bones only. We found the integument to have the largest effect on the range of long-axis rotation, pro- and retraction. Importantly, during locomotion the iguana used only a fragment of the ROM that was measured in our least restrictive dissection situation (i.e. pelvis and femur only conjoined by ligaments), demonstrating the discrepancy between hip joint ROM and actual in vivo movement. Our study emphasizes the necessity for caution when attempting to reconstruct joint ROM or even locomotor kinematics from fossil bones only, as actual in vivo movement cannot be deduced directly from any condition of cadaver mobility in Iguana and likely in other tetrapods. PMID- 24762238 TI - Edoxaban or standard therapy with warfarin for stroke prevention in patients with atrial fibrillation? PMID- 24762239 TI - ROOBY trial data demonstrates revascularization had no impact on POAF. PMID- 24762240 TI - On ROOBY trial data and the impacts of revascularization: reply from the author. PMID- 24762241 TI - Use your head and your heart: a brain injury biomarker shows promise in assessing myocarditis. PMID- 24762242 TI - Cardiac patching and the regeneration of infarcted myocardium: where do we go from here? AB - EVALUATION OF: Serpooshan V, Zhao M, Metzler SA et al. The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function postmyocardial infarction. Biomaterials 34, 9048-9055 (2013). The decline of cardiac function in the post-myocardial infarcted (MI) heart is due to two essential problems: massive loss of contractile cardiomyocytes, and loss of structural and mechanical tissue integrity due to ongoing remodeling of scar tissue, often leading to left ventricular dilation. Serpooshan et al. demonstrate that an engineered acellular type I collagen patch with optimized mechanical properties, grafted onto the epicardium of infarcted adult murine hearts following ligation of the left anterior descending artery, significantly improves cardiac function and reduces left ventricular remodeling 4 weeks postinjury. While these short-term results are encouraging and, like in other studies, prove the relevance of mechanically supporting the injured myocardium, optimization of the approach in terms of time and manner of intervention, as well as origin of the biomaterial, is needed to warrant future clinical application. PMID- 24762244 TI - Telehealth for heart failure management: patient empowered self-care or surveillance by the nanny state? PMID- 24762243 TI - Highlights from the British Society for Heart Failure 16(th) Annual Autumn Meeting: 'Making sense of acute heart failure'. AB - 16th Annual Autumn Meeting of the British Society of Heart Failure: 'Making sense of acute heart failure', London, UK, 28-29 November 2013 The 16th Annual Autumn Meeting of the British Society of Heart Failure entitled 'Making sense of acute heart failure' took place on the 28-29 November 2013 at the Queen Elizabeth II Conference Centre in London. This year saw the 1000th member join the British Society of Heart Failure and over 700 delegates from the UK, Europe and North America attended this year's meeting. Professionals from a range of backgrounds were present including physicians, nurses, scientists, trainees and representatives from industry. The symposium, which is accredited by the Royal College of Physicians and the Royal College of Nursing, highlighted that although we have recently seen substantial progress in the management and outcomes of patients with chronic heart failure, acute heart failure management and outcomes have not changed significantly over almost a generation. PMID- 24762245 TI - Assessing coronary target lesion length: the Goldilocks approach. PMID- 24762246 TI - Alirocumab for hyperlipidemia: physiology of PCSK9 inhibition, pharmacodynamics and Phase I and II clinical trial results of a PCSK9 monoclonal antibody. AB - Statins have been the cornerstone of lipid therapy for the last two decades, but despite significant clinical efficacy in the majority of patients, a large residual risk remains for the development of initial or recurrent atherosclerotic cardiovascular disease. In addition, owing to side effects, a significant percentage of patients cannot tolerate any statin dose or a high enough statin dose to reach their recommended LDL cholesterol goals. Monoclonal antibodies (mAbs) to PCSK9 have recently been shown to be highly efficacious in lowering LDL cholesterol, while demonstrating a favorable adverse event profile in early clinical trials. This review of alirocumab (formerly REGN727/SAR236553) explains the physiology and pharmacodynamics of PCSK9 inhibition with a mAb, as well as the Phase I and II clinical trial results of alirocumab and the ongoing Phase III trial designs. Several mAbs to PCSK9 are currently in development and approval may be 1-3 years away. We will focus this review on alirocumab, but mAbs to PCSK9 are the most promising cholesterol-lowering medication since statins and have the potential to significantly reduce further the occurrence of atherosclerotic cardiovascular disease. PMID- 24762247 TI - Cangrelor for treatment during percutaneous coronary intervention. AB - Dual antiplatelet therapy consisting of aspirin and a P2Y12-receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention (PCI). The current P2Y12-receptor antagonists are only available for oral administration and exhibit a delayed onset of action. Furthermore, several days are required for platelet function to return to normal following cessation of therapy. Cangrelor is an intravenous ATP analog that directly, selectively and reversibly inhibits P2Y12 receptors on platelets. A 30-MUg/kg bolus dose followed by a 4-MUg/kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration. Cangrelor also demonstrates a fast offset as normal platelet function is restored 1-2 h after cessation of the infusion. Three large, double-blind, randomized trials - CHAMPION PLATFORM, CHAMPION PCI and CHAMPION PHOENIX - assessed the efficacy and safety of cangrelor compared with clopidogrel (during or immediately after PCI) or placebo in the setting of PCI. In the most recent CHAMPION PHOENIX trial, cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding. Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset, cangrelor may provide benefit in certain patients undergoing PCI. PMID- 24762248 TI - Prevalence of renal dysfunction according to the type of atrial fibrillation and anticoagulation treatment in patients who attended primary care in Spain. AB - AIM: To determine the prevalence of renal dysfunction according to the type of atrial fibrillation (AF) and anticoagulation treatment in patients attended in primary care in Spain. METHODS & PARTICIPANTS: The VAL-FAAP study was a national, descriptive, epidemiological and cross-sectional study that included patients of both sexes, >=18 years of age, with a previous diagnosis of AF by an ECG, attended in a primary-care setting. Renal function was defined by estimated glomerular filtration rate (eGFR), calculated by the modification of diet in renal disease-4 formula. RESULTS: A total of 3287 patients with atrial fibrillation were included (mean age: 71.9 +/- 10.1 years; 52.3% male). Overall, 31.6% of patients had an eGFR <60 ml/min/1.73m(2) and 1.6% <30 ml/min/1.73m(2). The proportion of patients with permanent AF increased as the eGFR decreased. Similarly, as congestive heart failure, hypertension, age >=75 years (doubled), diabetes mellitus, stroke (doubled), vascular disease, age 65-74 years, sex category (CHA2DS2-VASc) increased, chronic kidney disease was more frequent. A third of patients with CHA2DS2-VASc >=2 had moderate renal dysfunction; however, 35.5% of them did not receive anticoagulants (compared with 31.5% of those with CHA2DS2-VASc >=2 and normal renal function). CONCLUSION: Chronic kidney disease is common in patients with AF, particularly in those patients with permanent AF or CHA2DS2-VASc >=2. Although indicated, 35.5% of patients with AF, a CHA2DS2 VASc >=2 and moderate renal dysfunction did not receive appropriate anticoagulation, despite the high risk of stroke. PMID- 24762249 TI - Using galectin-3 to reduce heart failure rehospitalization. AB - Increasing attention is being paid towards reducing short-term heart failure readmissions in recent years. Biomarkers such as galectin-3 are likely to play pivotal roles in future heart failure management strategies as they can provide objective information on various pathophysiologic processes involved in heart failure. Galectin-3 is a biomarker of inflammation and fibrosis, which is strongly associated with adverse remodeling of the myocardium and subsequent left ventricular dysfunction. Clinically, elevated galectin-3 levels are associated with increased risk for short- and long-term risk for mortality and heart failure readmission. Galectin-3 can provide incremental predictive value for adverse events over natriuretic peptides. Although significant work is still required to further define the role of galectin-3, it has the potential to become an important part of future heart failure management algorithms by helping to provide an individualized risk profile, which can be used to optimize resource allocation and improve treatment outcomes. PMID- 24762250 TI - Vitamin K antagonist use for all patients with hypertrophic cardiomyopathy and atrial fibrillation: analysis of the literature and guideline review. AB - Hypertrophic cardiomyopathy (HCM), which was first described in 1958, occurs in approximately one in 500 people. Patients with HCM are at an increased risk of atrial fibrillation, which is not only poorly tolerated in this population, but also increases their risk of an embolic event. The incidence of stroke in HCM patients with atrial fibrillation is approximately 21-23%. Given the high risk of stroke, antithrombotic therapy with warfarin is recommended in national guidelines. This therapy should be used without regard to other risk factors for stroke that may be present. Anticoagulation with the new oral anticoagulants may be considered as an alternative; although, specific data for patients with HCM is not available. The purpose of this review is to remind practitioners of the importance of stroke prophylaxis with oral anticoagulants in this population. PMID- 24762251 TI - Prevention and prophylaxis of respiratory syncytial virus in pediatric cardiology: a UK perspective. AB - Respiratory syncytial virus (RSV) is a common infection, causing bronchiolitis in over 70% of infants each year and almost all children by the age of 2. It is the leading cause of acute lower respiratory tract infections and admissions to hospital worldwide. Previously healthy infants may have a prolonged cough or wheezing following RSV infection but up to 20% of those with congenital cardiac disease will be hospitalized and have significant morbidity and mortality. For this reason, it is generally recommended that many such infants should receive prophylaxis against RSV infection with palivizumab. This paper reviews the current state of knowledge about RSV affecting children with congenital heart disease from the perspective of those living in the UK and the current protection offered to such children. We also discuss the plans for the future of protection against RSV. PMID- 24762252 TI - Biobanks for cardiovascular epidemiology and prevention. AB - Biobanks for medical research are organized collections of biological samples associated with personal data and information on their donors, to be stored for an indefinite period of time. The storage of biological samples has varied considerably over time, ranging from the informal storage of tissue specimens in a researcher's freezer in the past, to the present well-structured formal repositories. Large-scale population-related biobanks are being set up in several countries and will allow not only research into individual diseases, but also approaches to a wide range of health-related issues, such as physical activity, eating, drinking, education and pollution, among others. The purpose of this article is to discuss how biobanks have improved research in cardiovascular disease epidemiology and prevention, by describing the most relevant population based epidemiological studies that used set-up biobanks and stored samples for research. The selection of epidemiological studies and biobanks was based on their dimensions and their contribution to the field. PMID- 24762254 TI - Individualized cardiovascular risk assessment by cardiovascular magnetic resonance. AB - Cardiovascular magnetic resonance (CMR) is gaining clinical importance in preventive medicine. Evidence on diagnostic accuracy and prognostic value, in addition to the development of faster imaging, increased availability of equipment and imaging expertise have led to a wide-spread use of CMR in a growing number of clinical indications. The first part of this review summarizes the role of CMR biomarkers for risk assessment focusing on the patients groups that benefit from the use of CMR. In the second part, the future directions for CMR are discussed and their role in prevention of cardiovascular disease. PMID- 24762253 TI - Targeting mitochondria for cardioprotection: examining the benefit for patients. AB - Mitochondria are critical for sustaining life, not only as the essential powerhouses of cells but as critical mediators of cell survival and death. Mitochondrial dysfunction has been identified as a key perturbation underlying numerous pathologies including myocardial ischemia-reperfusion injury and the subsequent development of impaired left ventricular systolic function and compensatory cardiac hypertrophy. This article outlines the role of mitochondrial dysfunction in these important cardiac pathologies and highlights current cardioprotective strategies and their clinical efficacy in acute myocardial infarction and heart failure patients. Finally, we explore novel mitochondrial targets and evaluate their potential future translation for clinical cardioprotection. PMID- 24762255 TI - Optimal aspirin dose in acute coronary syndromes: an emerging consensus. AB - Numerous clinical trials testing the efficacy of aspirin for the secondary prevention of cardiovascular disease have been published. We reviewed the literature pertaining to aspirin dose in acute coronary syndrome patients. Clinical trials assessing the comparative efficacy of different doses of aspirin are scarce. This complex antiplatelet therapy landscape makes it difficult to identify the best aspirin dose for optimizing efficacy and minimizing risk of adverse events, while complying with the various guidelines and recommendations. Despite this fact, current evidence suggests that aspirin doses of 75-100 mg/day may offer the optimal benefit:risk ratio in acute coronary syndrome patients. PMID- 24762256 TI - 'Today and more than ever, I FEEL LIKE A RESEARCHER': successful online learning collaborations between librarians and a Graduate School. AB - This article describes the development and delivery of an online module at the University of Nottingham on the literature review process. In particular, it discusses how academic librarians collaborated with researcher developers at the Graduate School at the University to deliver a highly successful online learning experience for students. The article provides an overview of the course, a discussion on the experiences of both the tutors and participants involved, concentrating specifically on those in Medicine and Health Sciences. Details about future international collaborations and development of the course are also provided. PMID- 24762257 TI - Genetic detection of Dobrava-Belgrade hantavirus in the edible dormouse (Glis glis) in central Serbia. AB - Hantaviruses are endemic in the Balkans, particularly in Serbia, where sporadic cases and/or outbreaks of hantaviral human disease have been reported repeatedly, and evidenced serologically. Here, we present genetic detection of Dobrava Belgrade virus (DOBV) hantaviral sequences in wild rodents trapped in central Serbia. All the animals were pre-screened serologically by indirect immunofluorescence (IF) test and only those with a positive finding of hantaviral antigens were further tested by polymerase chain reaction. Of the total of 104 trapped animals, 20 were found to be IF positive and of those three were positive for hantaviral RNA: one Microtus arvalis for Tula virus, and one each of Apodemus agrarius and Glis glis for DOBV. Phylogenetic analysis of the obtained sequences implies putative DOBV spillover infection of A. agrarius and G. glis from Apodemus flavicollis. However, future investigations should help to identify the most common natural host and geographical distribution of DOBV in its reservoir hosts in Serbia. PMID- 24762258 TI - Direct remote asymmetric bisvinylogous 1,4-additions of cyclic 2,5-dienones to nitroalkenes. AB - Here we report that cyclic 2,5-dienones can act as bisvinylogous precursors through in situ generation of linear trienamine species with a cinchona-derived primary amine, and exclusively remote epsilon-regioselective 1,4-additions to nitroalkenes were accomplished in moderate to high enantioselectivity. Moreover, a diversity of complex spirocyclic frameworks could be efficiently constructed in an enantioenriched manner from these multifunctional 1,4-adducts via subsequent vinylogous iminium and even cascade iminium catalysis of the same amine. PMID- 24762260 TI - Exploring family relationships through associations of comfort, relatedness states, and life closure in hospice patients: A pilot study. AB - OBJECTIVE: Research at the end of life tends to focus on the dying patient's symptoms, often overlooking issues associated with family interactions. However, many families struggle just to maintain or initiate these valuable connections. The purpose of our pilot study was to explore family relationships at the end of life and investigate associations among perceived comfort, relatedness states, and life closure. METHOD: This descriptive study used a cross-sectional design, and a convenience sample (n = 30; 18 women; mean age = 71 years) was recruited from patients admitted to a large not-for-profit hospice in northeastern Ohio. In person interviews using the Hospice Comfort Questionnaire, Relatedness States Visual Analog Scales, and the Life-Closure Scale provided data for analyses. RESULTS: Family interactions that were not associated with the physical tasks of caregiving were related to life closure (r = 0.36, p = 0.001), and life closure and comfort were highly correlated (r = 0.69, p < 0.001). Participants residing in an inpatient setting had higher levels of involvement (t[18] = -2.07, p = 0.05) and comfort in relationships (t[28] = -2.06, p = 0.05) than those in the home setting. SIGNIFICANCE OF RESULTS: This is the first known study investigating the associations among comfort, relatedness, and life closure at the end of life. The majority of participants had high levels of involvement and comfort in their relationships, and they preferred interactions that required minimal effort. Studies that focus on both patients' and family members' perceptions of relationships are needed as well as outcome studies that test simple interventions. PMID- 24762259 TI - A decline in inflammation is associated with less depressive symptoms after a dietary intervention in metabolic syndrome patients: a longitudinal study. AB - BACKGROUND: Metabolic syndrome (MetS) and depression have become two prevalent diseases worldwide, whose interaction needs further investigation. Dietary treatment for weight loss in patients with MetS may improve depressive manifestations, however, the precise interactive pathways remain uncertain. Therefore, the aim of this study was to examine the effects of a hypocaloric diet designed to reduce MetS features on self-perceived depression and the possible underlying factors. METHODS: Sixty subjects (Age: 50 +/- 1 y; BMI: 36.1 +/- 0.6 kg/m(2)) with MetS were selected from the RESMENA study (control and intervention) after they completed the 6-months hypocaloric treatment and rated for depressive symptoms using the Beck Depression Inventory (BDI). Anthropometric and biochemical measurements including leptin, C-reactive protein (CRP) and insulin levels were evaluated. RESULTS: Depressive symptoms decreased during the weight loss intervention, with no differences between both dietary groups (control group -4.2 +/- 0.8 vs RESMENA group -3.2 +/- 0.6, P = 0.490). The number of criteria of the MetS was higher among subjects with more somatic-related depressive symptoms at baseline (B = 1.032, P-trend = 0.017). After six months of dietary treatment, body weight decreased in all subjects (-8.7%; confidence interval (95% CI) = 7.0-9.7) and also self-perceived depression (-37.9%; 95% CI = 2.7-4.9), as well as circulating leptin (-20.1%; 95% CI = 1.8-6.8), CRP (-42.8%; 95% CI = 0.6-3.0) and insulin (-37.7%; 95% CI = 4.1-7.2) concentrations. The decrease in BDI was significantly associated with declines in body fat mass (B = 0.34, 95% CI = 0.11-0.56) and also with the decrease in leptin (B = 0.16, 95% CI = 0.04-0.28) and CRP (B = 0.24, 95% CI = 0.01-0.46) concentrations. CONCLUSIONS: The decrease in depressive manifestations after a weight loss intervention was related with adiposity, CRP and leptin in subjects with MetS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01087086. PMID- 24762261 TI - Urban liveability: emerging lessons from Australia for exploring the potential for indicators to measure the social determinants of health. AB - It has long been recognised that urban form impacts on health outcomes and their determinants. There is growing interest in creating indicators of liveability to measure progress towards achieving a wide range of policy outcomes, including enhanced health and wellbeing, and reduced inequalities. This review aimed to: 1) bring together the concepts of urban 'liveability' and social determinants of health; 2) synthesise the various liveability indicators developed to date; and 3) assess their quality using a health and wellbeing lens. Between 2011 and 2013, the research team reviewed 114 international academic and policy documents, as well as reports related to urban liveability. Overall, 233 indicators were found. Of these, 61 indicators were regarded as promising, 57 indicators needed further development, and 115 indicators were not useful for our purposes. Eleven domains of liveability were identified that likely contribute to health and wellbeing through the social determinants of health. These were: crime and safety; education; employment and income; health and social services; housing; leisure and culture; local food and other goods; natural environment; public open space; transport; and social cohesion and local democracy. Many of the indicators came from Australian sources; however most remain relevant from a 'global north' perspective. Although many indicators were identified, there was inconsistency in how these domains were measured. Few have been validated to assess their association with health and wellbeing outcomes, and little information was provided for how they should be applied to guide urban policy and practice. There is a substantial opportunity to further develop these measures to create a series of robust and evidence-based liveability indices, which could be linked with existing health and wellbeing data to better inform urban planning policies within Australia and beyond. PMID- 24762262 TI - Frequent hypermethylation of WNT pathway genes in laryngeal squamous cell carcinomas. AB - BACKGROUND: Aberrations in the function of the WNT signaling pathway have been recently implicated in the pathogenesis of head and neck cancer, and the hypermethylation of several WNT cascade inhibitors were shown to be useful in disease prognosis. However, the extent of deregulation of WNT pathway by DNA hypermethylation has not been studied in detail in laryngeal cancer so far. The aim of this study was to establish the frequency of methylation of WNT pathway negative regulators in laryngeal squamous cell carcinomas and evaluate its prognostic significance. METHODS: Twenty-six laryngeal squamous cell carcinoma cell lines and samples obtained from twenty-eight primary laryngeal carcinoma patients were analyzed. The methylation status of DKK1, LKB1, PPP2R2B, RUNX3, SFRP1, SFRP2, and WIF-1 was assessed using the methylation-specific polymerase chain reaction. RESULTS: Frequent hypermethylation of DKK1, PPP2R2B, SFRP1, SFRP2, and WIF-1 was detected, and a high methylation index was usually observed. Half of the cell lines analyzed and seventy percent of primary laryngeal carcinoma cases were characterized by the methylation of at least four genes. The hypermethylation of PPP2R2B or WIF-1 was associated with longer survival in laryngeal carcinoma cell lines. Moreover, the concurrent methylation of PPP2R2B and SFRP1 differentiated primary from recurrent laryngeal carcinoma cell lines. CONCLUSIONS: Frequent hypermethylation of WNT pathway negative regulators is observed in laryngeal squamous cell carcinomas. The possible prognostic significance of the methylation of DKK1, PPP2R2B, and SFRP1 needs to be evaluated in further prospective studies. PMID- 24762263 TI - Analysis of stress fractures associated with lameness in Thoroughbred flat racehorses training on different track surfaces undergoing nuclear scintigraphic examination. AB - REASONS FOR PERFORMING STUDY: There is limited information regarding the impact of training track surface on the occurrence of stress fractures. OBJECTIVES: To evaluate the impact of training track surface on the proportion of long bone and pelvic stress fractures associated with lameness in Thoroughbred horses in flat race training undergoing nuclear scintigraphic examination. STUDY DESIGN: Retrospective study. METHODS: Scintigraphic examinations of Thoroughbred flat racehorses were evaluated from 2 hospitals (hospital A [Toronto Equine Hospital], 2003-2009, and hospital B [George D. Widener Hospital for Large Animals, School of Veterinary Medicine, University of Pennsylvania], 1994-2006). Horses admitted to hospital A trained at a single track, at which the main training surface changed from dirt to synthetic on 27 August 2006. Two distinct populations existed at hospital B: horses that trained on dirt (numerous trainers) and those that trained on turf (single trainer). All scintigraphic images were evaluated by a blinded reviewer. Fisher's exact test and logistic regression were used when appropriate, and significance was set at P<0.05. RESULTS: When reviewing 528 scintigraphic examinations from hospital A (257 dirt and 271 synthetic, numerous trainers), there was a greater proportion of stress fractures detected in scintigraphic examinations from horses training on a synthetic surface (31.7%) in comparison to scintigraphic examinations from horses training on a dirt surface (23.0%) at an earlier point in time (P = 0.03). There was a greater proportion of hindlimb/pelvic and tibial stress fractures diagnosed in horses from the synthetic surface-trained group than from the dirt-trained group at hospital A (P<0.04 and P = 0.03, respectively). CONCLUSIONS: This study provides evidence that training surface may affect the proportion of stress fractures diagnosed, but other factors, such as training philosophy, appear to be important. Future prospective investigations to fully elucidate the relationship between training track surface and the proportion of stress fractures and other nonfatal musculoskeletal injuries are warranted. PMID- 24762264 TI - Eighteen-month follow-up of a play-based intervention to improve the social play skills of children with attention deficit hyperactivity disorder. AB - BACKGROUND/AIM: There is a well-documented need for interventions to successfully address the social difficulties of children with attention deficit hyperactivity disorder. This study aimed to further the development of a previously conducted pilot of a play-based intervention. To achieve this, children's social play outcomes pre-post and 18-month following the intervention were examined by raters unaware of the study's purpose. Additionally, parents' experiences of the intervention were explored. METHODS: Participants included five children with attention deficit hyperactivity disorder who had participated in a play-based intervention and their typically developing playmates; parents of children with attention deficit hyperactivity disorder also participated. Children and their playmates attended an 18-month follow-up play session and parents participated in semi-structured interviews. The Test of Playfulness was used to measure children's play outcomes in the context of social play with a peer, pre-post and 18-months following the intervention. Wilcoxon signed-ranks (Z) and Cohen's-d were used to measure effect. Thematic analysis was used to analyse reoccurring themes from parents' interviews. RESULTS: Children's social play outcomes improved pre-post intervention (Z = 2.02; P = 0.04; d = 1.6) and were maintained 18-month post intervention (Z = 0.14; P = 0.89; d = -0.4). Core themes included: the intervention as an enjoyable experience, a common language for talking about play/social interactions, an observable change in children's skills, transference of skills and the need for support to refresh learnt lessons over time. CONCLUSIONS: The intervention demonstrated preliminary and long-term efficacy in developing the social play skills of children with attention deficit hyperactivity disorder. Further research is required to optimise intervention feasibility and parent involvement prior to conducting a large-scale research. PMID- 24762265 TI - Polysulfone membranes coated with polymerized 3,4-dihydroxy-l-phenylalanine are a versatile and cost-effective synthetic substrate for defined long-term cultures of human pluripotent stem cells. AB - Clinical and industrial applications of human pluripotent stem cells (hPSC) require large amounts of cells that have been expanded under defined conditions. Labor-intensive techniques and ill-defined or expensive compounds and substrates are not applicable. Here we describe a chemically defined synthetic substrate consisting of polysulfone (PSF) membranes coated with polymerized 3,4-dihydroxy-l phenylalanine (DOPA). DOPA/PSF is inexpensive and can be easily produced at various shapes and sizes. DOPA/PSF supports long-term self-renewal of undifferentiated human embryonic (hESC) and human induced pluripotent stem cells (hiPSC) under defined conditions. Pluripotency is maintained for at least 10 passages. Adhesion of hPSC to DOPA/PSF is mainly mediated by a specific integrin heterodimer. Proliferation and gene expression patterns on DOPA/PSF and control substrates are comparable. Labor-intensive cultivation methods and use of serum or coating with proteins are not required. Together, these features make DOPA/PSF attractive for applications where large-scale expansion of human pluripotent stem cells under defined conditions is essential. PMID- 24762266 TI - Knowledge exchange and integrated services: experiences from an integrated community intellectual (learning) disability service for adults. AB - BACKGROUND: This paper examines knowledge exchange dynamics in a specialist integrated intellectual (learning) disability service, comprising specialist healthcare provision with social care commissioning and management, and considers their significance in terms of integrated service delivery. METHODS: A qualitative study focusing on knowledge exchange and integrated services. Semi structured interviews (n = 25) were conducted with members of an integrated intellectual disability service in England regarding their perceptions of knowledge exchange within the service and the way in which knowledge exchange impinges on the operation of the integrated service. RESULTS: Exchange of 'explicit' (codifiable) knowledge between health and care management components of the service is problematic because of a lack of integrated clinical governance and related factors such as IT and care record systems and office arrangements. Team meetings and workplace interactions allowed for informal exchange of explicit and 'tacit' (non-codifiable) knowledge, but presented challenges in terms of knowledge exchange completeness and sustainability. CONCLUSIONS: Knowledge exchange processes play an important role in the functioning of integrated services incorporating health and care management components. Managers need to ensure that knowledge exchange processes facilitate both explicit and tacit knowledge exchange and do not rely excessively on informal, 'ad hoc' interactions. Research on integrated services should take account of micro-scale knowledge exchange dynamics and relationships between social dynamics and physical factors. PMID- 24762267 TI - A message from WFH president Alain Weill: broad perspectives for a new era. PMID- 24762268 TI - Haemophilia care - beyond the treatment guidelines. AB - Care for people with haemophilia (PWH) has improved much over the last two decades leading to near normal lives for those receiving early regular prophylaxis with clotting factor concentrates (CFC). Yet, there are significant limitations of those practices. In the absence of a well-defined optimal prophylaxis protocol, there are wide variations in practices with a two to threefold difference in doses. In those parts of the world where there are constraints on the availability of CFC, episodic replacement remains the norm for most patients even though it is evident that this does not change the natural history of the disease over a wide range of doses. Suitable prophylactic protocols therefore need to be developed wherever possible at these doses. Finally, there are only limited data on long-term outcomes in haemophilia from anywhere in the world. The practice of documenting specific outcomes as part of the regular evaluation of PWH needs to be established and the appropriate instruments used to assess them. Definitions of clinical events and endpoints of interventions in clinical studies are being developed to help such data collection. The correlations between different replacement therapy protocols and specific outcomes will help define what is best at different dose levels. Such data will allow better health planning and treatment choices throughout the world. PMID- 24762269 TI - With blood in the joint - what happens next? Could activation of a pro inflammatory signalling axis leading to iRhom2/TNFalpha-convertase-dependent release of TNFalpha contribute to haemophilic arthropathy? AB - One of the main complications of haemophilia A is haemophilic arthropathy (HA), a debilitating disease with a significant negative impact on motility and quality of life. Despite major advances in the treatment of haemophilia A, many patients still suffer from HA. We wish to develop new treatments for HA, but must first better understand its causes. Our laboratory studies molecular scissors that release the pro-inflammatory cytokine tumour necrosis factor alpha (TNFalpha) from cells. TNFalpha is considered the 'fire alarm' of the body - it helps to fight infections, but can also cause diseases such as inflammatory arthritis. We know that the molecular scissors, called TNFalpha convertase (TACE), and its newly discovered regulator termed iRhom2 can be rapidly activated by small amounts of cytokines, growth factors, and pro-inflammatory mediators present in the blood. We hypothesize that the rapid activation of TACE could help explain one of the unsolved mysteries regarding the development of HA, which is how even small amounts of blood can provoke a persistent inflammatory response. We propose that once blood enters the joint, iRhom2 and TACE are activated to release TNFalpha and that this could promote the development of HA in a similar manner to that in which it promotes rheumatoid arthritis (RA). We are currently using immune cells stimulated with blood degradation products, and mouse models of HA, to test this hypothesis. If successful, our study could provide the rationale for testing anti-TNF antibodies, which are already used to treat RA, for the treatment of HA. In addition, they might uncover iRhom2 and TACE as attractive new candidate targets for the treatment of HA. PMID- 24762270 TI - Primary haemostasis: newer insights. AB - At the same time as biophysical and omics approaches are drilling deeper into the molecular details of platelets and other blood cells, as well as their receptors and mechanisms of regulation, there is also an increasing awareness of the functional overlap between human vascular systems. Together, these studies are redefining the intricate networks linking haemostasis and thrombosis with inflammation, infectious disease, cancer/metastasis and other vascular pathophysiology. The focus of this state-of-the-art review is some of the newer advances relevant to primary haemostasis. Of particular interest, platelet specific primary adhesion-signalling receptors and associated activation pathways control platelet function in flowing blood and provide molecular links to other systems. Platelet glycoprotein (GP)Ibalpha of the GPIb-IX-V complex and GPVI not only initiate platelet aggregation and thrombus formation by primary interactions with von Willebrand factor and collagen, respectively, but are also involved in coagulation, leucocyte engagement, bacterial or viral interactions, and are relevant as potential risk markers in a range of human diseases. Understanding these systems in unprecedented detail promises significant advances in evaluation of individual risk, in new diagnostic or therapeutic possibilities and in monitoring the response to drugs or other treatment. PMID- 24762271 TI - Novel products for haemostasis - current status. AB - Currently, new clotting factor concentrates are becoming available or are in advanced clinical studies that will significantly improve the treatment of patients with Haemophilia A or Haemophilia B. Various technologies are applied to extend half-life and/or allow for alternative routes of administration, e.g. subcutaneous route. Today, the advances for recombinant factor IX are significantly with half-life extensions to up to 100 h, allowing substitution intervals of 1-2 weeks. For recombinant factor VIII (FVIII) products the effect so far is only moderate, as the half-life extension is limited to about 15-18 h by the clearance of FVIII through its binding to von Willebrand factor. However, novel products applying new technologies with significantly extended half-life are already at the horizont, as a bispecific antibody that mimics FVIII. The pharmacokinetic improvements of the new products will lead to a revision of our current treatment regimens, with regard to intended trough levels, number of tolerated bleeds and likely will drive a greater individualization of regimens. Clearly, the potential of anti drug antibody response for these modified proteins must not be higher than with our current products. Another challenge are the increasingly diverse biochemical characteristics of the new products, that have to be considered when determining potencies and also when monitoring treatment in patients with the various available assays. Despite these challenges, the new products will significantly improve treatment and quality of life for our patients with haemophilia. PMID- 24762272 TI - Novel products for haemostasis. AB - The primary major issue in haemophilia treatment remains the development of inhibitors. Recently two novel bypassing products have been developed. First, a humanized bispecific antibody against FIXa and FX, termed hBS23, was produced utilizing these two molecules placed into a spatially appropriate position to mimic FVIIIa, and recently this mimetic activity and the pharmacokinetics of the original antibody were improved by engineering the charge properties of the variable region within the immunoglobulin. Using the new antibody, termed ACE910, a phase 1 study in 64 Japanese and Caucasian healthy adults was performed and data from this trial suggested that the product had medically acceptable safety and tolerability profiles. The other new bypassing agent is named MC710, and consists of a mixture of plasma-derived FVIIa and FX. Preclinical studies using in vitro and in vivo haemophilia B inhibitor monkey models indicated that the haemostatic effects of FVIIa and FX were enhanced by simultaneous administration. Results from phase I and II clinical studies suggested that MC710 had equal or greater pharmacokinetic (PK), pharmacodynamic (PD), efficacy and safety profiles than conventional bypassing agents in the treatment of joint bleeding in haemophilia patients with inhibitors. Another significant current issue in this context is the increased medical cost of conventional treatment due to the higher consumption of concentrates. Biosimilar products may offer advantages in these circumstances and may offer a less expensive alternative. Regulatory issues, however, together with acceptability of biosimilar materials and reimbursement policies as well as supply and demand incentives remain to be considered. Rare bleeding disorders (RBDs) have attracted less attention from the pharmaceutical industry than haemophilia or von Willebrand disease due to the limited number of patients involved. Many cases of this type have been treated, therefore, using fresh frozen plasma (FFP) or prothrombin complex concentrates (PCCs) which carry serious risks of infections, allergic reactions and fluid overload. Several specific plasma-derived or recombinant products including fibrinogen, FVIIa, FXI and FXIII have now become available, however, and a phase III clinical study of recombinant FXIIIa has recently been completed demonstrating safety and efficacy of substances of this nature. PMID- 24762273 TI - Monitoring of modified factor VIII and IX products. AB - The dawning era of novel recombinant factor VIII and factor IX concentrates, many of which have been bioengineered to achieve prolonged activity, brings with it the need to consider the most appropriate clinical laboratory approaches for potency assignment, as well as the measurement of postinfusion levels. This session will highlight the known limitations and inconsistencies between existing assay methodologies with respect to currently available products, and discuss some of the early data with respect to the novel agents. PMID- 24762274 TI - Current status of haemophilia gene therapy. AB - After many reports of successful gene therapy studies in small and large animal models of haemophilia, we have, at last, seen the first signs of success in human patients. These very encouraging results have been achieved with the use of adeno associated viral (AAV) vectors in patients with severe haemophilia B. Following on from these initial promising studies, there are now three ongoing trials of AAV-mediated gene transfer in haemophilia B all aiming to express the factor IX gene from the liver. Nevertheless, as discussed in the first section of this article, there are still a number of significant hurdles to overcome if haemophilia B gene therapy is to become more widely available. The second section of this article deals with the challenges relating to factor VIII gene transfer. While the recent results in haemophilia B are extremely encouraging, there is, as yet, no similar data for factor VIII gene therapy. It is widely accepted that this therapeutic target will be significantly more problematic for a variety of reasons including accommodating the larger factor VIII cDNA, achieving adequate levels of transgene expression and preventing the far more frequent complication of antifactor VIII immunity. In the final section of the article, the alternative approach of lentiviral vector-mediated gene transfer is discussed. While AAV mediated approaches to transgene delivery have led the way in clinical haemophilia gene therapy, there are still a number of potential advantages of using an alternative delivery vehicle including the fact that ex vivo host cell transduction will avoid the likelihood of immune responses to the vector. Overall, these are exciting times for haemophilia gene therapy with the likelihood of further clinical successes in the near future. PMID- 24762275 TI - Genomics of bleeding disorders. AB - Molecular genetic tools are widely applied in inherited bleeding disorders. New genes involved in haemorrhagic disorders have been identified by genome wide linkage analysis on families with a specific phenotype. LMNA1 or MCFD in combined FV/FVIII-deficiency and VKORC1 in vitamin K coagulation factor deficiency type 2 are two examples. Identification of the causative gene mutation has become standard for most bleeding disorders. Knowledge of the causative mutation allows genetic counselling in affected families and most importantly adds to the pathophysiological understanding of phenotypes. Haemophilia A represents a model as the F8 gene mutation predicts the risk of developing an inhibitor and more recently also the bleeding phenotype. In this review novel genetic diagnostic strategies for bleeding disorders are outlined and inhibitor formation is presented as an example for clinical relevant phenotype/genotype correlation studies. PMID- 24762277 TI - von Willebrand disease and platelet disorders. AB - The diagnosis and management of bleeding disorders is made difficult by the complexity and variety of disorders, clinical symptoms and bleeding type and severity. von Willebrand disease (VWD) and platelet disorders are disorders of primary haemostasis and together represent the most common inherited bleeding disorders. In this article, we describe the diagnosis of VWD and platelet disorders and the treatment options for VWD. PMID- 24762276 TI - Genetic testing in bleeding disorders. AB - The aim of molecular genetic analysis in families with haemophilia is to identify the causative mutation in an affected male as this provides valuable information for the patient and his relatives. For the patient, mutation identification may highlight inhibitor development risk or discrepancy between different factor VIII assays. For female relatives, knowledge of the familial mutation can facilitate carrier status determination and prenatal diagnosis. Recent advances in understanding mutations responsible for haemophilia and methods for their detection are presented. For reporting of such mutations, participation in external quality assessment ensures that essential patient and mutation details are routinely included and that pertinent information is incorporated in the interpretation. PMID- 24762278 TI - Laboratory aspects of von Willebrand disease: test repertoire and options for activity assays and genetic analysis. AB - The deficiency or abnormal function of von Willebrand factor (VWF) causes von Willebrand disease (VWD), the most frequent inherited bleeding disorder. The laboratory diagnosis of VWD can be difficult as the disease is heterogeneous and an array of assays is required to describe the phenotype. Basic classification of quantitative (type 1 and 3) and qualitative (type 2) VWD variants requires determination of VWF antigenic (VWF:Ag) levels and assaying of VWF ristocetin cofactor (VWF:RCo) activity, determining the capacity of VWF to interact with the platelet GPIb-receptor. Knowing the VWF:RCo activity is essential for identifying, subtyping and monitoring VWD, but the assay is poorly standardized and many protocols do not fulfil the clinical need in all situations. This has led to the development of novel activity assays, independent of ristocetin, with enhanced assay characteristics. Results from the first independent clinical evaluations are promising, showing that they are reliable and suitable for VWD diagnosis. The qualitative type 2 VWF deficiency can be further divided into four different subtypes (A, B, M and N) using specific assays that explore other activities or the size distribution of VWF multimers. These methods are discussed herein. However, in a number of patients it may be difficult to correctly classify the VWD phenotype and genetic analysis may provide the best option to clarify the disorder, through mutation identification. PMID- 24762279 TI - Rare bleeding disorders - bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency. AB - Rare bleeding disorders (RBDs) are inherited deficiencies of coagulation factors such as fibrinogen, factor (F) II, FV, FVII, combined FV+FVIII, FX, FXI and FXIII. These disorders usually have a low prevalence in the general population and constitute approximately 3-5% of all coagulation disorders. However, in some countries they may have the same prevalence as haemophilia B due to the practice of consanguineous marriage. The clinical picture of RBDs is highly variable and can vary markedly from mild to severe, making both diagnosis and optimal treatment quite challenging. This review focuses on: (i) the efforts to establish a bleeding assessment tool adequate to RBDs, (ii) the optimal management of patients affected with FXI deficiency and (iii) the correlation between clinical severity and laboratory diagnosis when determining the minimum coagulant activity required to prevent bleeding in each RBD. PMID- 24762280 TI - Epidemiological aspects of inhibitor development redefine the clinical importance of inhibitors. AB - Inhibitor development is a serious complication of treatment with coagulation products. Presently, 25-30% of all newly diagnosed patients with severe haemophilia A are diagnosed with inhibitors. An increasing number of genetic and non-genetic risk factors have been reported to be involved, although the impact of them in understanding the aetiology is still limited. Much attention has been focused on factor VIII products, but more recent studies show very little, if any, difference between class plasma and recombinant factor VIII products. More intensive treatment and higher dosing are probably more important factors. More than 10% of the inhibitors diagnosed in the last decade are of low titre. A first goal should be to understand their importance. It is argued that the impact of different risk factors should be studied in high-titre inhibitors to prevent dilution by non-significant low-titre inhibitors. PMID- 24762282 TI - Inhibitors - genetic and environmental factors. AB - It is known that a large number of both genetic and environmental factors contribute to the risk of inhibitor development, but underlying pathogenetic mechanisms are still under investigation. The clinical research on inhibitors towards factor VIII (FVIII) is challenged by the fact that this is an infrequent event occurring in a rare disease. Therefore, it is widely accepted that complementary studies involving animal models can provide important insights into the pathogenesis and treatment of this complication. In this respect, mouse models have been studied for clues to FVIII immunogenicity, natural history of immunity and for different approaches to primary and secondary tolerance induction. In the clinical setting, the type of FVIII product used and the occurrence of product switching are considered important factors which may have an influence on inhibitor development. The evaluation of data currently available in the literature does not prove unequivocally that a difference in the immunogenicity exists between particular FVIII products (e.g. recombinant vs. plasma-derived, full length vs. B-domainless). In addition, national products switches have occurred and, in this context, switching was not associated with an enhanced inhibitor risk. In contrast with severe haemophilia A, patients with moderate and mild haemophilia A receive FVIII treatment infrequently for bleeds or surgery. In this condition the inhibitor risk is low but remains present lifelong, requiring continuous vigilance, particularly after intensive FVIII exposure. PMID- 24762281 TI - Inhibitors - cellular aspects and novel approaches for tolerance. AB - The immune response against therapeutic clotting factors VIII and IX (FVIII and FIX) is a major adverse event that can effectively thwart their effectiveness in correcting bleeding disorders. Thus, a significant number of haemophilia patients form antibodies, called inhibitors, which neutralize the procoagulant functions of therapeutic cofactors FVIII (haemophilia A) or FIX (haemophilia B). Understanding the cellular and molecular aspects of inhibitor formation is critical to designing tolerogenic therapies for clinical use. This review will focus on the basis of the immune response to FVIII, in particular, and will discuss emerging efforts to not only reduce immunogenicity but also to prevent and/or reverse inhibitor formation. PMID- 24762283 TI - Laboratory testing for factor inhibitors. AB - Inhibitor assays are performed when patients present with unexplained prolonged routine coagulation test times and unexpected and/or unusual bleeding (potential for acquired haemophilia) as well as being a part of normal congenital haemophilia management and monitoring, particularly when bleeding occurs on therapy, or when increments in factor levels post-factor replacement remain lower than expected. In this article, we will describe the assays used, as well as their development, pitfalls in testing such as inter-laboratory variability and false negative/positive results, as well as some strategies for overcoming these pitfalls and potential alternative test approaches. The inter-laboratory coefficient of variation often approaches (and sometimes exceeds) 50%, as evidenced by various external quality assessment groups, and this variability has not improved over recent years. Additional important considerations include appropriate interpretation of test results, repeat testing for confirmation, and assessment of recovery as part of the diagnostic process. PMID- 24762284 TI - Changing paradigm of prophylaxis with longer acting factor concentrates. AB - Beginning in the 1960s the care of persons with haemophilia began to improve dramatically through a series of transformative improvements in care: development of lyophilized factor concentrates, home care programmes, prophylaxis and (due to the tragedy of HIV/hepatitis) the development of virally safer plasma-derived and recombinant factor concentrates. Prophylaxis, if commenced early and given in sufficient dose/frequency has been shown to allow persons with haemophilia to maintain excellent joints and lead normal lives. Yet the relatively short half lives of factor (F) VIII and IX concentrates leads to the need for frequent venous access. This remains a significant burden for patients with haemophilia on prophylaxis causing in many cases reduced patient adherence to prophylaxis and negative longterm outcomes. The last 5 years have witnessed a flourish of new bioengineered longer acting FVIII and IX concentrates manufactured using different technologies (pegylation or fusion to Fc/albumin). These products (especially the longer acting FIX concentrates) are likely to have profound implications on prophylaxis. With these longer acting factor concentrates prophylaxis regimens will almost certainly change. This will involve changes in what trough levels are targeted and how frequently factor is administered. It is hoped that these changes may improve patients' adherence to prophylaxis and their quality of life. These long-acting factor concentrates will undoubtedly have cost repercussions and will raise important questions regarding how decisions about choosing one longer acting concentrate over another, and whether these products are interchangeable, are made. This article will review what changes may ensue with the advent of these new longer acting factor concentrates. PMID- 24762285 TI - Prophylaxis in real life scenarios. AB - Prophylaxis has become the standard mantra of care for those individuals with severe haemophilia A and B. Primary prophylaxis is advocated to prevent the occurrence of symptomatic acute spontaneous haemarthroses and to preserve joint structure and function. Typically, twice or thrice weekly infusions of factor VIII or IX concentrates are integral to this treatment approach. Secondary prophylaxis is initiated after the relentless cycle of progressive joint damage has been triggered by prior haemarthroses and is intended to preserve existing joint health by preventing additional spontaneous bleeding events. Event-driven prophylaxis involves the administration of clotting factor concentrates to prevent acute traumatic bleeds, which are anticipated to occur in association with surgical or physical trauma. This regimen enhances the effectiveness of primary or secondary prophylaxis protocols or on-demand approaches to replacement therapy. Besides the marked reduction in the so-called annual bleed rate, prophylaxis regimens frequently increase personal self-confidence to embark on a more active and physical lifestyle; however, in reality, prophylaxis must be individualized in accordance with bleeding phenotypes, with the unique pharmacokinetic profile of administered replacement clotting factor concentrates, with the specific clinical scenario, and with the degree of intensity anticipated for any physical activity. The introduction of extended half-life replacement products will also influence how these prophylaxis regimens will be accomplished. The following scenarios will discuss how prophylaxis regimens can be implemented to protect the individual from developing spontaneous and activity-induced acute bleeding complications and to maintain an improved quality of life. PMID- 24762286 TI - Assessment of outcomes. AB - Effective healthcare delivery necessitates evaluation of the effect of interventions in the form of outcome assessment. Treatment effect includes measurement of how the patient feels, functions and survives following healthcare interventions. In haemophilia, which is a rare bleeding disorder, outcome assessment was characterized by a lack of validated outcome measurement tools and the challenges of hemophilia study design to collect outcome data. The aim of this communication is to share current thinking and, through practical examples, provide a state of the art practice in the assessment of hemophilia outcomes from a healthcare provider, patient/family and funder perspective. This discussion is timely and particularly relevant to the care of people with hemophilia on the eve of a number of novel hemophilia treatment products which are about to be licensed for use, specifically the long-acting factor VIII and factor IX concentrates. The first section by Dr Blanchet gives an overview of the tools currently available for assessment of structure/function, patient activities and patient participation in hemophilia healthcare delivery, pointing out the challenge of developing new tools and appropriate validation of currently available tools. The second section by Mr Brian O'Mahony emphasizes the essential collaboration and partnership between healthcare providers and people with hemophilia in collating the outcome data. In the third and final section, Mr Leigh McJames, gives a funder's perspective of the desirable outcomes of hemophilia care. PMID- 24762287 TI - Enhancing haemophilia care through registries. AB - Clinical registries or databases have an increasing role in the management of inherited bleeding disorders. Initially, research-based registries provided valuable data and now national databases are increasingly being developed with multiple stakeholders, including persons with haemophilia (PWH) and payers, to enable improvements and efficiencies in care. Registries are extending to international collaborations to collect adverse event data and comparisons of national approaches to the management of haemophilia to improve the availability of product to PWH. PMID- 24762288 TI - Medical co-morbidities and practice. AB - All-oral treatments of hepatitis C (HCV) have been trialled in patients with hereditary bleeding disorders and found to be effective. Further refinements of dosing and duration are being established. Importantly for patient acceptability these regimens are interferon-free. Cohort studies in older patients with haemophilia direct the need for attention to weight control, exercice, assessment of cardiovascular risk, especially hypertension and detection of osteoporosis. Where patients live a long way from a comprehensive care centre, telemedicine connections can engage centre experts with the patient and his/her local practitioners in devising and monitoring care plans. PMID- 24762289 TI - Joint WFH-ISTH session: issues in clinical trial design. AB - Haemophilia therapy is experiencing an unprecedented expansion in the number and novelty of clotting factor concentrates. Every product must be licensed by regulatory authorities, primarily on the basis of its safety and efficacy profiles. The low prevalence of haemophilia, and other inherited bleeding disorders, presents a significant challenge to patient recruitment for preauthorization clinical trials, especially given the low frequency of inhibitory antibodies, the major adverse event related to clotting factor exposure. Other challenges include a lack of harmonization between the major regulatory authorities in certain key areas, the selection of laboratory monitoring methodologies and the difficulty in obtaining high-quality phase IV safety data following authorization. These aspects will be reviewed in this session, which will also highlight the roles played by the World Federation of Hemophilia and International Society on Thrombosis and Haemostasis in the promotion of these discussions. PMID- 24762290 TI - Nicotinic alpha4beta2 acetylcholine receptors and cognitive function in Parkinson's disease. AB - BACKGROUND: Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD. METHODS: Twenty-five non-demented patients with IPD underwent a 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize alpha4beta2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction. RESULTS: In the CERAD, the IPD patients exhibited deficits in non-verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of alpha4beta2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region). CONCLUSIONS: These significant correlations between the results of the CERAD subtests and the cerebral alpha4beta2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD. PMID- 24762292 TI - Looking beneath the surface to determine what makes DNA damage deleterious. AB - Apurinic/apyrimidinic and oxidized abasic sites are chemically reactive DNA lesions that are produced by a variety of damaging agents. The effects of these molecules that lack a Watson-Crick base on polymerase enzymes are well documented. More recently, multiple consequences of the electrophilic nature of abasic lesions have been revealed. Members of this family of DNA lesions have been shown to inactivate repair enzymes and undergo spontaneous transformation into more deleterious forms of damage. Abasic site reactivity provides insight into the chemical basis for the cytotoxicity of DNA damaging agents that produce them and are valuable examples of how looking beneath the surface of seemingly simple molecules can reveal biologically relevant chemical complexity. PMID- 24762294 TI - External quality assessment of patient HLA-B*57:01 testing prior to abacavir prescription. AB - Hypersensitivity reactions to the drug abacavir are strongly associated with possession of HLA-B*57:01. Hence, patients with HIV/AIDS who may be prescribed abacavir should be tested for this HLA allele and the drug withheld from those that possess B*57:01. The UK National External Quality Assessment Service for Histocompatibility and Immunogenetics has operated a scheme for B*57:01 testing since 2008 which, in 2013, involved 47 participants from 12 countries. A total of 24 B*57:01-positive, 2 B*57:03-positive and 22 B*57-negative blood samples (including 2 B*58 samples) were distributed to between 28 and 47 laboratories each year over 6 years. Participants, who were unaware of the samples' HLA types, tested and reported on their B*57/B*57:01 status. A total of 1868 reports were assessed over the 6 years. Of the 880 reports on B*57:01 samples, 93.4% were correctly assigned as B*57:01, 2.8% were assigned as groups of B*57 alleles including B*57:01, and 3.3% were reported as B*57 positive only. Over the 6 years, there were four (0.46%) false B*57:01 negative reports. All the B*57:03 positive and B*57-negative samples, involving 72 and 916 assignments, respectively, were essentially reported as B*57:01 negative. Thus, there were no false B57:01 positive assignments. The reporting of B*57:01 status over the last 3 years of the scheme was 99.8% sensitive and 100% specific. Over the last year, it was 100% sensitive and 100% specific. PMID- 24762295 TI - Insight in the phase separation peculiarities of poly(dialkylaminoethyl methacrylate)s. AB - The thermoresponsive and pH-sensitive behavior of poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA), poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA), and poly(N,N-diisopropylaminoethyl methacrylate) (PDiPAEMA) is compared by use of different techniques. We employed temperature- and pH-dependent turbidimetry, fluorescence spectroscopy (of the polarity indicator 4-(dicyanomethylene)-2 methyl-6-(4-dimethylaminostyryl)-4H-pyran, 4HP, which is sometimes also abbreviated as DCM), and IR spectroscopy (of the carbonyl band). Within specific pH windows, all polymers showed phase separation at elevated temperatures (showing a lower critical solution temperature behavior, an LCST behavior). By increasing the hydrophobicity of the dialkylaminoethyl substituent, the phase separation is shifted to lower pH (at constant temperatures; pH(PDMAEMA) > pH(PDEAEMA) > pH(PDiPAEMA)) or to lower temperatures (at constant pH; T(PDMAEMA) > T(PDEAEMA) > T(PDiPAEMA)). While PDMAEMA does not exhibit pronounced changes in polarity upon phase separation (as seen by fluorescence spectroscopy), PDEAEMA and PDiPAEMA provide a nonpolar surrounding for the 4HP uptake above their collapse. In addition, PDiPAEMA causes the sharpest transition (as seen by the 4HP probe), although the carbonyl hydration experiences a more gradual (sigmoidal) transition for all polymers (as seen by IR). These observations allow a distinction of the phase separation mechanisms. While the LCST properties of PDMAEMA are mainly caused by backbone/carbonyl interactions, its rather polar dimethylaminoethyl group does not inflict pronounced hydrophobicity, but promotes a higher water content within the phase-separated polymer. In contrast, the phase separation of PDEAEMA and PDiPAEMA is mainly influenced by the less polar dialkylaminoethyl groups, leading to drastic changes in the hydrophobicity around the cloud points. Further, the IR data suggest that the diisopropylaminoethyl groups of PDiPAEMA tend to backfold to the carbonyl groups/backbone to minimize water-polymer contact already in its soluble state. Finally, this study might lead to advanced lasing applications of the laser dye 4HP. PMID- 24762293 TI - Successes and challenges in phenotype-based lead discovery for prion diseases. AB - Creutzfeldt-Jakob disease (CJD) is a rare but invariably fatal neurodegenerative disease caused by misfolding of an endogenous protein into an alternative pathogenic conformation. The details of protein misfolding and aggregation are not well understood nor are the mechanism(s) by which the aggregated protein confers cellular toxicity. While there is as yet no clear consensus about how best to intervene therapeutically in CJD, prion infections can be propagated in cell culture and in experimental animals, affording both in vitro and in vivo models of disease. Here we review recent lead discovery efforts for CJD, with a focus on our own efforts to optimize 2-aminothiazole analogues for anti-prion potency in cells and for brain exposure in mice. The compounds that emerged from this effort were found to be efficacious in multiple animal models of prion disease even as they revealed new challenges for the field, including the emergence of resistant prion strains. PMID- 24762297 TI - Pnicogen-bonded anionic complexes. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to investigate the pnicogen-bonded complexes H2YP:X(-), for X,Y = Cl, NC, F, CCH, and CH3. Of the 36 possible complexes, only 21 are unique equilibrium structures. All substituents form (H2XPX)(-) complexes with symmetric X-P-X bonds. The P-A ion-molecule pnicogen bonds in these and some additional complexes have partial covalent character, while some P-A' covalent bonds have partial ion-molecule character. A and A' are the atoms of X and Y, respectively, which are directly bonded to P. Complexes with these types of bonds include the symmetric complexes (H2XPX)(-), H2(CH3)P:F(-), H2(CCH)P:F(-), H2FP:NC(-), H2FP:Cl(-), H2FP:CN(-), and H2(NC)P:Cl( ). Charge transfer from A to the P-A' sigma* orbital stabilizes H2YP:X(-) complexes and leads to a reduction of the negative charge on X. For fixed X, the smallest negative charge occurs in the symmetric complex. Then, for a given X, the order of decreasing negative charge with respect to Y is CH3 > CCH > CN (bonded through C) > F > NC (bonded through N) > Cl, which is also the order of decreasing P-A distance. EOM-CCSD spin-spin coupling constants (1p)J(P-A) differentiate between shorter ion-molecule pnicogen bonds with partial covalent character and longer P...A ion-molecule pnicogen bonds. Similarly, coupling constants (1)J(P-A') differentiate between longer covalent P-A' bonds with partial ion-molecule character and shorter P-A' covalent bonds. PMID- 24762296 TI - Development and evaluation of the first high-throughput SNP array for common carp (Cyprinus carpio). AB - BACKGROUND: A large number of single nucleotide polymorphisms (SNPs) have been identified in common carp (Cyprinus carpio) but, as yet, no high-throughput genotyping platform is available for this species. C. carpio is an important aquaculture species that accounts for nearly 14% of freshwater aquaculture production worldwide. We have developed an array for C. carpio with 250,000 SNPs and evaluated its performance using samples from various strains of C. carpio. RESULTS: The SNPs used on the array were selected from two resources: the transcribed sequences from RNA-seq data of four strains of C. carpio, and the genome re-sequencing data of five strains of C. carpio. The 250,000 SNPs on the resulting array are distributed evenly across the reference C.carpio genome with an average spacing of 6.6 kb. To evaluate the SNP array, 1,072 C. carpio samples were collected and tested. Of the 250,000 SNPs on the array, 185,150 (74.06%) were found to be polymorphic sites. Genotyping accuracy was checked using genotyping data from a group of full-siblings and their parents, and over 99.8% of the qualified SNPs were found to be reliable. Analysis of the linkage disequilibrium on all samples and on three domestic C.carpio strains revealed that the latter had the longer haplotype blocks. We also evaluated our SNP array on 80 samples from eight species related to C. carpio, with from 53,526 to 71,984 polymorphic SNPs. An identity by state analysis divided all the samples into three clusters; most of the C. carpio strains formed the largest cluster. CONCLUSIONS: The Carp SNP array described here is the first high-throughput genotyping platform for C. carpio. Our evaluation of this array indicates that it will be valuable for farmed carp and for genetic and population biology studies in C. carpio and related species. PMID- 24762298 TI - Epigenetic regulation of cytokine expression in systemic lupus erythematosus with special focus on T cells. AB - Epigenetic events play a central role in the priming, differentiation and subset determination of T lymphocytes. Through their influence on chromatin conformation and DNA-accessibility to transcription factors and RNA polymerases, epigenetic marks allow or prevent gene expression and control cellular functions including cytokine expression. CpG-DNA methylation and post-translational modifications to histone tails are the two most well accepted epigenetic mechanisms. The involvement of epigenetic mechanisms in the pathogenesis of systemic lupus erythematosus (SLE) has been suggested by the development of lupus-like symptoms by individuals who received procainamide or hydralazine treatment resulting in a reduction of CpG-DNA methylation. To date, a growing body of literature indicates that the deregulation of cytokine expression through epigenetic disturbances can result in altered immune responses and autoimmune reactions. Over the past decade, various global and regional epigenetic alterations have been reported in immune cells from patients with SLE and other autoimmune disorders. More recently, the molecular mechanisms that result in epigenetic disturbances have been addressed, and deregulated transcription factor networks have been demonstrated to mediate epigenetic alterations in B and T lymphocytes from SLE patients. A better understanding of the molecular events that contribute to epigenetic alterations and subsequent immune imbalance is essential for the establishment of disease biomarkers and identification of potential therapeutic targets. PMID- 24762300 TI - Decoding the cryptic genomes of fungi: the promise of novel antibiotics. PMID- 24762299 TI - Influence of fossoriality on inner ear morphology: insights from caecilian amphibians. AB - It is widely accepted that a relationship exists between inner ear morphology and functional aspects of an animal's biology, such as locomotor behaviour. Animals that engage in agile and spatially complex behaviours possess semicircular canals that morphologically maximise sensitivity to correspondingly complex physical stimuli. Stemming from the prediction that fossorial tetrapods require a well developed sense of spatial awareness, we investigate the hypothesis that fossoriality leads to inner ear morphology that is convergent with other spatially adept tetrapods. We apply morphometrics to otic capsule endocasts of 26 caecilian species to quantify aspects of inner ear shape, and compare these with a sample of frog and salamander species. Our results reveal caecilians (and also frogs) possess strongly curved canals, a feature in common with spatially adept species. However, significantly shorter canals in caecilians suggest reduced sensitivity, possibly associated with reduced reliance on vestibulo-ocular reflexes in this group of visually degenerate tetrapods. An elaboration of the sacculus of caecilians is interpreted as a unique adaptation among amphibians to increase sensitivity to substrate-borne vibrations transmitted through the head. This study represents the first quantitative analyses of inner ear morphology of limbless fossorial tetrapods, and identifies features within a new behavioural context that will contribute to our understanding of the biological consequences of physical stimuli on sensory function and associated morphological evolution. PMID- 24762301 TI - Do nonhuman primate or bat adenoviruses pose a risk for human health? PMID- 24762302 TI - Spread of Klebsiella pneumoniae carbapenemase-2-producing Klebsiella pneumoniae clones in Asia. PMID- 24762304 TI - Microbiology of surgical site infections after gastrointestinal surgery in the south region of The Netherlands. AB - AIM: To give an overview of the microbiology of blood and wound samples from surgical site infections (SSIs) after gastrointestinal surgery, as well as the antimicrobial susceptibility of the microorganisms involved, and to discuss the appropriateness of the prophylactic antibiotics administered. MATERIALS & METHODS: During a 3.5-year study period, wound swabs and blood samples of patients with an SSI were taken in the first 48 h after surgery until 30 days thereafter. RESULTS: Most pathogens were isolated from wound swabs. Escherichia coli (25%) and Pseudomonas aeruginosa (10%) were the most frequently found microorganisms. Both microorganisms showed a slight tendency towards a decrease in susceptibility for the tested antibiotics, although after correction, this was not significant. CONCLUSION: The comparison between wound swabs taken in the first 48 h after a surgical procedure and swabs in the 30 days thereafter provides important information concerning the microbiology of SSIs and the development of antibiotic resistance of the causative agents over time. PMID- 24762305 TI - Is minocycline a solution for multidrug-resistant Acinetobacter baumannii? AB - Minocycline is an old, safe, second-line antimicrobial agent that has drawn attention over the last few years as a possible therapeutic option against multidrug-resistant Acinetobacter baumannii (MDR-AB) clinical isolates. Recent in vitro and in vivo results indicate that minocycline is a valid, alternative treatment option for minocycline-susceptible MDR-AB. Although effective alone, its administration as monotherapy should be avoided. Combinations with other antimicrobials can reduce the MIC of each component, present synergism and minimize the risk for drug resistance. Owing to its limited solubility in urine, it should be avoided for urinary pathogens. The present article reports all available information regarding its use as a therapeutic option against MDR-AB. PMID- 24762306 TI - Mitigation of human-pathogenic fungi that exhibit resistance to medical agents: can clinical antifungal stewardship help? AB - Reducing indiscriminate antimicrobial usage to combat the expansion of multidrug resistant human-pathogenic bacteria is fundamental to clinical antibiotic stewardship. In contrast to bacteria, fungal resistance traits are not understood to be propagated via mobile genetic elements, and it has been proposed that a global explosion of resistance to medical antifungals is therefore unlikely. Clinical antifungal stewardship has focused instead on reducing the drug toxicity and high costs associated with medical agents. Mitigating the problem of human pathogenic fungi that exhibit resistance to antimicrobials is an emergent issue. This article addresses the extent to which clinical antifungal stewardship could influence the scale and epidemiology of resistance to medical antifungals both now and in the future. The importance of uncharted selection pressure exerted by agents outside the clinical setting (agricultural pesticides, industrial xenobiotics, biocides, pharmaceutical waste and others) on environmentally ubiquitous spore-forming molds that are lesserstudied but increasingly responsible for drug-refractory infections is considered. PMID- 24762307 TI - New insights into the interaction of Mycobacterium tuberculosis and human macrophages. AB - Mycobacterium tuberculosis is a facultative intracellular pathogen. It infects macrophages where it avoids elimination by interfering with host defense mechanisms. Until recently, it was assumed that the acidification of phagosomes is the major strategy of macrophages to eliminate M. tuberculosis. However, there is emerging evidence demonstrating that human macrophages are equipped with additional antimicrobial effector functions. Specifically, autophagy, efferocytosis and antimicrobial peptides have been identified as mechanisms to restrict mycobacterial proliferation. Here we review recent findings on effector functions of human macrophages and mechanisms of the pathogen to interfere with them. PMID- 24762308 TI - Master manipulators: an update on Legionella pneumophila Icm/Dot translocated substrates and their host targets. AB - Macrophages are the front line of immune defense against invading microbes. Microbes, however, have evolved numerous and diverse mechanisms to thwart these host immune defenses and thrive intracellularly. Legionella pneumophila, a Gram negative pathogen of amoebal and mammalian phagocytes, is one such microbe. In humans, it causes a potentially fatal pneumonia referred to as Legionnaires' disease. Armed with the Icm/Dot type IV secretion system, which is required for virulence, and approximately 300 translocated proteins, Legionella is able to enter host cells, direct the biogenesis of its own vacuolar compartment, and establish a replicative niche, where it grows to high levels before lysing the host cell. Efforts to understand the pathogenesis of this bacterium have focused on characterizing the molecular activities of its many effectors. In this article, we highlight recent strides that have been made in understanding how Legionella effectors mediate host-pathogen interactions. PMID- 24762310 TI - Promises and failures of gallium as an antibacterial agent. AB - Gallium has a long history as a diagnostic and chemotherapeutic agent. The pharmacological properties of Ga(III) rely on chemical mimicry; when Ga(III) is exogenously supplied to living cells it can replace Fe(III) within target molecules, thereby perturbing bacterial metabolism. Ga(III)-induced metabolic distresses are dramatic in fast-growing cells, like bacterial cells. Interest in the antibacterial properties of Ga(III) has been raised by the compelling need for novel drugs to combat multidrug-resistant bacteria and by the shortage of new antibiotic candidates in the pharmaceutical pipeline. Ga(III) activity has been demonstrated, both in vitro and in animal models of infections, on several bacterial pathogens, also including intracellular and biofilm-forming bacteria. Ga(III) activity is affected by iron availability and the metabolic state of the cell, being maximal in iron-poor media and in respiring cells. Synergism between Ga(III) and antibiotics holds promise as last resort therapy for infections sustained by pandrug-resistant bacteria. PMID- 24762309 TI - Towards an understanding of the role of Clostridium perfringens toxins in human and animal disease. AB - Clostridium perfringens uses its arsenal of >16 toxins to cause histotoxic and intestinal infections in humans and animals. It has been unclear why this bacterium produces so many different toxins, especially since many target the plasma membrane of host cells. However, it is now established that C. perfringens uses chromosomally encoded alpha toxin (a phospholipase C) and perfringolysin O (a pore-forming toxin) during histotoxic infections. In contrast, this bacterium causes intestinal disease by employing toxins encoded by mobile genetic elements, including C. perfringens enterotoxin, necrotic enteritis toxin B-like, epsilon toxin and beta toxin. Like perfringolysin O, the toxins with established roles in intestinal disease form membrane pores. However, the intestinal disease associated toxins vary in their target specificity, when they are produced (sporulation vs vegetative growth), and in their sensitivity to intestinal proteases. Producing many toxins with diverse characteristics likely imparts virulence flexibility to C. perfringens so it can cause an array of diseases. PMID- 24762311 TI - Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. AB - The normal intestinal microbiota plays a major role in the maintenance of health and disease prevention. In fact, the alteration of the intestinal microbiota has been shown to contribute to the pathogenesis of several pathological conditions, including obesity and insulin resistance, among others. Recent studies have revealed profound alterations of the gut microbial flora in patients and animals with chronic kidney disease (CKD). Alterations in the composition of the microbiome in CKD may contribute to the systemic inflammation and accumulation of gut-derived uremic toxins, which play a central role in the pathogenesis of accelerated cardiovascular disease and numerous other CKD-associated complications. This review is intended to provide a concise description of the potential role of the CKD-associated changes in the gut microbiome and its potential role the pathogenesis of inflammation and uremic toxicity. In addition, the potential efficacy of pre- and pro-biotics in the restoration of the microbiome is briefly described. PMID- 24762313 TI - The ethics of pay-for-performance. PMID- 24762314 TI - Regulation in primary care. AB - Professional bodies have long overseen the maintenance of standards of training and practice within the different healthcare professions. Organisational regulation of healthcare in England comprises two main elements: regulation of the quality and safety of care offered by healthcare providers, currently undertaken by the Care Quality Commission (CQC); and regulation of the market in healthcare services, currently the responsibility of Monitor and the Department of Health. The eighth in the series, this article considers the expanding roles of newer bodies, particularly in relation to primary care. The cost-effectiveness of these new arrangements is unknown - and possibly unknowable. PMID- 24762315 TI - Evaluating improvement. AB - Evaluating quality improvement interventions requires a variety of methods. These range from quantitative methods, such as randomised controlled trials, to quasi experimental (controlled before-and-after and interrupted time series) and uncontrolled before-and-after studies, including clinical audits, to determine whether improvement interventions have had an effect. Qualitative methods are often also used to understand how or why an intervention was successful and which components of a complex or multifaceted intervention were most effective. Finally, mixed methods designs such as action research or case study methods are widely used to design and evaluate improvement interventions. PMID- 24762312 TI - Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections. AB - Dengue viruses (DENV) cause significantly more human disease than any other arbovirus, with hundreds of thousands of cases leading to severe disease in thousands annually. Antibodies and T cells induced by primary infection with DENV have the potential for both positive (protective) and negative (pathological) effects during subsequent DENV infections. In this review, we summarize studies that have examined T-cell responses in humans following natural infection and vaccination. We discuss studies that support a role for T cells in protection against and those that support a role for the involvement of T cells in the pathogenesis of severe disease. The mechanisms that lead to severe disease are complex, and T-cell responses are an important component that needs to be further evaluated for the development of safe and efficacious DENV vaccines. PMID- 24762316 TI - Colorectal cancer--applying a gender lens. AB - BACKGROUND: Colorectal cancer (CRC) is a major global health problem with survival varying according to stage at diagnosis. The incidence of CRC is much higher in patients with lower bowel symptoms. The symptoms are non-specific and are commonly experienced in the general population. Biological and environmental factors account for the high incidence and poor prognosis of CRC in men. OBJECTIVE: To review the behavioural factors influencing patient delay in seeking help for lower bowel symptoms using a gender lens. METHODS: An extensive literature search was performed using various databases including Medline, PubMed, CINAHL Plus, EMBASE and PsycINFO (1993-2013). Various search terms including rectal bleeding, prevalence, colorectal cancer, consultation, help seeking, gender differences and men were used. A systematic methodology including systematic data extraction and narrative synthesis was applied. RESULTS: Thirty two studies were included in the review. All studies except four were quantitative. Although there is some evidence that men delay more compared with women, there has not been any major improvement in the help-seeking behaviour for such symptoms over the past two decades. Several behavioural and demographic factors were associated with low rates of help-seeking. CONCLUSION: There are limited studies focusing on men's help-seeking behaviour for lower bowel symptoms. To facilitate timely help-seeking in men, it is important to understand their patterns of helpseeking for such symptoms. Further research to understand men's help-seeking behaviour is warranted. PMID- 24762317 TI - Exploring consumer values of comparative performance information for hospital choice. AB - BACKGROUND: In many countries, market orientation in healthcare has resulted in the publication of comparative performance information (CPI). Most of the research in this field is oriented towards the content and the presentation format of CPI while little is known about how consumers value CPI and the use of this information. AIM: The aim of this study was to clarify the perceived value that CPI brings for consumers of healthcare. Methods Qualitative research using six focus group interviews. Twenty-seven healthcare consumers were recruited using a mailing list and by personal invitation. Data from focus group interviews were transcribed and thematic analysis undertaken. RESULTS: Most participants were unaware of CPI, and valued alternative sources of information more than CPI. Through discussion with other consumers and by means of examples of CPI, respondents were able to express the values and perceived effects of CPI. Numerous underlying values hindered consumers' use of CPI, and therefore clarification of consumer values gave insights into the current non-usage of CPI. CONCLUSIONS: CPI is marginally valued, partly because of conflicting values expressed by consumers and, as such, it does not yet provide a useful information source on hospital choice beyond consumers' current selection routines in healthcare. Future research should be more focused on the values of consumers and their impact on the use of CPI. PMID- 24762318 TI - Engaging with clinical commissioning: the attitudes of general practitioners in East Lancashire. AB - BACKGROUND: Clinical commissioning is the centrepiece of government health reforms. Engagement with the reforms is important if they are to bring about improvements in the quality of healthcare. This is important in any healthcare system, not just the UK National Health Service (NHS). This study draws on data from a specially commissioned survey, exploring the extent to which general practitioners (GPs) in East Lancashire are engaged with clinical commissioning. Aim The aim of this study was to assess levels of engagement with clinical commissioning using a Clinical Commissioning Engagement Scale (CCES). METHODS: A six-point Likert scale CCES was distributed to all GPs within the boundary of East Lancashire Clinical Commissioning Group (CCG). The GPs are distributed across five localities that vary in terms of geography, demography and previous commissioning experience. The CCES aimed to capture comparative levels of engagement across twelve items, three for each of four dimensions of engagement: (1) personal attitude, (2) perceived capacity, (3) perceived capability and (4) opportunity. Eighty-five returns were received, representing a response rate of 35.3%. A full analysis of the data was conducted using SPSS v. 19. RESULTS: The results demonstrate concern for capacity and capability across the localities, where mean scores are universally well below the midpoint of the scale. However, attitude and opportunity were relatively positive indicators with mean scores above midpoint for all localities. CONCLUSION: The findings highlight the potential challenges for CCGs in engaging GPs and in particular responding to perceived problems of capability and capacity. Further research is required to shed light on whether East Lancashire is typical of other CCGs. PMID- 24762319 TI - Understanding the dementia diagnosis gap in Norfolk and Suffolk: a survey of general practitioners. AB - BACKGROUND: The National Health Service (NHS) has announced its new target to increase the 'shockingly low dementia diagnosis rate' in England from the current level of 45% to 66% by end of March 2015. Clinical commissioning groups (CCGs) in England have committed to meeting this target. The Norfolk and Suffolk dementia diagnosis rate (DDR) is below the rate for England in some areas; across the CCGs included in this study, the average DDR was 39.9% with a standard deviation of 5.3. AIMS: This study aimed to explore and understand the low DDR in Norfolk and Suffolk and to learn what might be needed to support general practitioners (GPs) to meet the targets set by the UK Department of Health. METHODS: An online survey was developed including questions from the National GP Audit 2009. The link to the online survey was sent via email to all GPs in four participating CCGs in Norfolk and Suffolk. SPSS was used for descriptive analysis. Chi-square tests were conducted to identify significant differences in response rates between groups of GPs. RESULTS: The survey was completed by 28% (N = 113) of 400 GPs in 108 practices across three CCGs receiving the survey link. There was a significant difference in response rates from GPs in each CCG, but there were no significant differences in terms of their answers to the questions in the survey. GP respondents expressed confidence in their ability to identify cases of dementia for onward referral to memory services. Participating GPs also acknowledged the benefits to patients and their carers of a timely dementia diagnosis at an early stage of the disease. However, they reported concerns about the quality and availability of post-diagnostic support services for people with dementia and their carers. In this survey, GPs' attitudes were more positive about diagnosing dementia than those responding to the National Audit 2009. CONCLUSIONS: Despite GPs' attitudes being more positive than in 2009 about diagnosing dementia, the Norfolk and Suffolk DDR remains low. This may reflect lack of GP confidence in the quality and availability of post-diagnostic support services. This study has identified a need to map the existing post-diagnostic support services for people with dementia and to identify gaps in services. This could lead to the development of a resource which might enable GPs to provide relevant advice to newly diagnosed patients and their carers, facilitate signposting to support services, and give GPs confidence to increase the DDR in their area. PMID- 24762320 TI - The impact of pay-for-performance on the workload of family practices in Estonia. AB - BACKGROUND: The quality system in Estonia is a payfor-performance scheme, rewarding family doctors for the quality of care they provide. This study examines the impact of the quality system on the workload of family doctors in Estonia. AIM: The aim of this study was to explore differences in the workload of family doctors participating in the clinical quality system and those not participating. METHODS: The study was conducted using a database from the Estonian Health Insurance Fund, which consists of health-related data for 96% of the Estonian population. The study compared the workload of Estonian family physicians in two groups: those participating in the quality system and those not. RESULTS: During the observation period 2005-2011, the proportion of family doctors participating in the clinical quality system increased from 48.2% to 69.2%. The total number of visits in primary care increased also and there was a difference in workload between the two groups. Doctors participating in the quality system performed more primary (initial) and secondary (follow-up) visits. The number of visits per doctor was also higher for those participating in the quality system. There was a shift to visits carried out by nurses, which showed an increased workload for nurses in the quality system during the observation period compared with a stable workload for those outside the system. The number of home visits decreased in both groups. CONCLUSION: Pay-for-performance had a notable impact on the workload of the primary care team and its members. Paying more attention to detecting chronic diseases in their early stages, recalling patients for general health check-ups and immunising children may have an effect on health status, but also requires increased staff levels. PMID- 24762322 TI - Active ageing and occupational therapy align. PMID- 24762321 TI - A longitudinal examination of mothers' and fathers' social information processing biases and harsh discipline in nine countries. AB - This study examined whether parents' social information processing was related to their subsequent reports of their harsh discipline. Interviews were conducted with mothers (n = 1,277) and fathers (n = 1,030) of children in 1,297 families in nine countries (China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand, and the United States), initially when children were 7 to 9 years old and again 1 year later. Structural equation models showed that parents' positive evaluations of aggressive responses to hypothetical childrearing vignettes at Time 1 predicted parents' self-reported harsh physical and nonphysical discipline at Time 2. This link was consistent across mothers and fathers, and across the nine countries, providing support for the universality of the link between positive evaluations of harsh discipline and parents' aggressive behavior toward children. The results suggest that international efforts to eliminate violence toward children could target parents' beliefs about the acceptability and advisability of using harsh physical and nonphysical forms of discipline. PMID- 24762323 TI - Zoledronic acid and geranylgeraniol regulate cellular behaviour and angiogenic gene expression in human gingival fibroblasts. AB - The mevalonate pathway (MVP) and the anti-angiogenic effect of bisphosphonates have been shown to play a role in the pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study determined the effect of the bisphosphonate, zoledronic acid and the replenishment of the MVP by geranylgeraniol on human gingival fibroblasts. Cell viability, apoptosis, morphological analysis using transmission electron microscopy, and gene expression for vascular endothelial growth factor A, bone morphogenic protein 2, ras homologue gene family member B, epiregulin and interferon-alpha were conducted. Results showed cellular viability was decreased in the presence of zoledronic acid and the co-addition of zoledronic acid with geranylgeraniol restored cell viability to control levels. Caspase 3/7 was detected in zoledronic acid-treated cells indicating apoptosis. Transmission electron microscopy revealed dilation of the rough endoplasmic reticulum with zoledronic acid and the appearance of multiple lipid-like vesicles following the addition of geranylgeraniol. Zoledronic acid significantly (P < 0.05, FR > +/- 2) up regulated vascular endothelial growth factor A, bone morphogenic protein 2, ras homologue gene family member B and epiregulin at one or more time points but not interferon-alpha. Addition of geranylgeraniol resulted in a reduction in the expression of all five genes compared with zoledronic-acid-treated human gingival fibroblasts. The study concluded geranylgeraniol partially reversed the effects of zoledronic acid in human gingival fibroblasts both at the cellular and genetic levels, suggesting the regulation of these genes is mediated via the mevalonate pathway. PMID- 24762324 TI - Volunteers trained in palliative care at the hospital: an original and dynamic resource. AB - OBJECTIVE: Volunteers trained in palliative care are increasingly present in acute care units in general hospitals. Nevertheless, there still are few available data on this topic, especially concerning the integration of volunteers outside the palliative structures. Our present study aimed to describe the experience of volunteers trained in palliative care in the context of a primary care hospital. In particular, the difficulties and the benefits of this specific position were evaluated according to volunteers' own perceptions and words. METHOD: We employed a qualitative method. Various aspects of the volunteer's role were explored by means of semistructured questions, addressing their activity, their motivations, and their feelings. Participants were volunteers (n = 19) trained in palliative care and working at a university hospital. After giving written consent, they completed the semistructured questionnaire at home. Content analysis was used to identify the main categories of answers and the principal themes reported by the volunteers. RESULTS: The main difficulties were related to uncertainty of the context. As every situation is different, volunteers could not define their role once and for all. However, they derived great satisfaction from their activity. A supporting frame and a good balance between constraints and autonomy were facilitating factors. Besides, the complexity related to the context contributed to make the position valuable and challenging. SIGNIFICANCE OF RESULTS: Integrating a voluntary service in a primary care hospital is partly based on active participation of the volunteers in developing their position in a more adequate way. In return, this relative autonomy implies a rigorous and supportive attitude from the institution. PMID- 24762325 TI - Adverse health in parents of children with disabilities and chronic health conditions: a meta-analysis using the parenting stress index's health sub-domain. AB - BACKGROUND: Compared with parents of same-aged children without disabilities, parents of children with disabilities and with chronic health conditions (CHC) show higher levels of stress and depression. Fewer studies, however, examine the physical health of these parents, and studies report mixed findings. Many studies, however, report mother's self-reported health using the Health Sub domain of Abidin's Parenting Stress Index (PSI). We therefore conducted a meta analysis comparing the physical health of parents of children with developmental disabilities (DD) and CHC vs. parents of children without DD/CHC in studies utilising this measure. METHODS: Eligible studies used the long form of the PSI and reported results from the 5-item Health sub-domain. Group comparison effect sizes were synthesised in a meta-analysis, and we also examined the potential relations of child, parent, and study characteristics. Our search yielded 19 eligible studies. RESULTS: Compared with parents of children without DD/CHC, parents of children with DD/CHC reported higher PSI health problem scores, with a weighted mean effect size of 0.39 (95% CI = 0.23-0.55). Effect sizes ranged from 0.13 to 1.46 and there was evidence of heterogeneity in the effect sizes (tau2 = 0.07; Q18 = 48.64, P < 0.01; I2 = 63.0%). Studies with higher numbers of reporting quality indicators generally reported larger effects and more recent studies showed smaller effects. Although several child and parent characteristics were moderately associated with effect sizes, none reached statistical significance. CONCLUSIONS: Practitioners should be alerted to the need for health prevention and treatment in this at-risk parent group. PMID- 24762326 TI - Microglia are selectively activated in endocrine and cardiovascular control centres in streptozotocin-induced diabetic rats. AB - Type 1 and 2 diabetes are associated with dysfunction in multiple hormone systems, as well as increased sympathetic nerve activity, which may contribute to the development of diabetic complications. In other pathologies, such as myocardial infarction, increased sympathetic drive is associated with neuroinflammation and microglial activation in the hypothalamic paraventricular nucleus (PVN), a brain region that regulates sympathetic drive and multiple endocrine responses. In the present study, we used immunohistochemistry to study microglial and neuronal activation in the PVN and related brain regions in streptozotocin (STZ)-induced diabetic rats. As expected, STZ treatment was associated with elevated blood glucose within 1 week. STZ injections also caused neuronal activation in the PVN and superoptic nucleus (SON) but not in the nucleus tractus solitarius (NTS), which was evident by 6 weeks. STZ-treated rats showed increased plasma osmolarity, which would be expected to activate PVN and SON neurones. There was no apparent increase in histochemical markers of microglial activation, including phospho-p38, phospho-extracellular signal regulated kinase, P2X4 receptor or interleukin 1-beta even at 10 weeks after STZ treatment. However, we did see a significant increase in the percentage of microglia with an activated morphology in the PVN, SON and NTS, although not in surrounding hypothalamic, brainstem or cortical regions. These morphological changes included a significant reduction in microglial process length and were evident by 8 weeks but not 6 weeks. The delayed onset of microglial changes compared to neuronal activation in the PVN and SON suggests the over-excitation of neurones as a mechanism of microglial activation. This delayed microglial activation may, in turn, contribute to the endocrine dysregulation and the elevated sympathetic nerve activity reported in STZ-treated rats. PMID- 24762327 TI - One-step Real-time Food Quality Analysis by Simultaneous DSC-FTIR Microspectroscopy. AB - This review discusses an analytical technique that combines differential scanning calorimetry and Fourier-transform infrared (DSC-FTIR) microspectroscopy, which simulates the accelerated stability test and detects decomposition products simultaneously in real time. We show that the DSC-FTIR technique is a fast, simple and powerful analytical tool with applications in food sciences. This technique has been applied successfully to the simultaneous investigation of: encapsulated squid oil stability; the dehydration and intramolecular condensation of sweetener (aspartame); the dehydration, rehydration and solidification of trehalose; and online monitoring of the Maillard reaction for glucose (Glc)/asparagine (Asn) in the solid state. This technique delivers rapid and appropriate interpretations with food science applications. PMID- 24762328 TI - Clinical and Foundational Briefs: A New Category of Publication. PMID- 24762329 TI - Geometry-induced asymmetric capillary flow. AB - When capillary flow occurs in a uniform porous medium, the depth of penetration is known to increase as the square root of time. However, we demonstrate in this study that the depth of penetration in multi-section porous layers with variation in width and height against the flow time is modified from this diffusive-like response, and liquids can pass through porous systems more readily in one direction than the other. We show here in a model and an experiment that the flow time for a negative gradient of cross-sectional widths is smaller than that for a positive gradient at the given total height of porous layers. The effect of width and height of local layers on capillary flow is quantitatively analyzed, and optimal parameters are obtained to facilitate the fastest flow. PMID- 24762330 TI - Tracking the commute home from school utilizing GPS and heart rate monitoring: establishing the contribution to free-living physical activity. AB - BACKGROUND: Active school commuting is widely regarded as a key opportunity for youth to participate in physical activity (PA). However, the accurate measurement of the commute home from school and its contribution to total free-living moderate-to-vigorous PA (MVPA) is relatively unexplored. METHODS: Seventy-five adolescents (38 males, 37 females) wore an integrated GPS and heart rate device during after-school hours for 4 consecutive weekdays. RESULTS: Active commuters were significantly more active (11.72 minutes MVPA) than passive commuters (3.5 minutes MVPA) during their commute home from school (P = .001). The commute home of walkers and cyclists on average contributed 35% of their total free-living PA. However, there was no significant difference in the overall free-living PA levels of passive and active commuters (P > .05). A total 92.7% of the youth living within 1.5 miles of the school actively commuted, compared with 16.7% of the youth who lived further away. Socioeconomic differences in commuting patterns were also evident. CONCLUSIONS: The findings highlighted the significant proportion of total free-living PA that was attributed to active commuting home from school. The study demonstrates the usefulness of utilizing GPS and heart rate data to accurately track young people's after-school PA. Demographic influences and implications for future research are discussed. PMID- 24762331 TI - Acanthosis nigricans in obese Chinese children. AB - OBJECTIVES. To investigate the demographic characteristics and insulin resistance in local overweight/obese Chinese children with and without acanthosis nigricans, and the associations of acanthosis nigricans with insulin resistance and other cardiometabolic co-morbidities. DESIGN. Case series with cross-sectional analyses. SETTING. A regional hospital in Hong Kong. PATIENTS. Chinese children assessed between January 2006 and December 2010 at Tseung Kwan O Hospital for being overweight or obese. MAIN OUTCOME MEASURES. The demographics, anthropometric data, acanthosis nigricans status, and biochemical results were analysed. RESULTS. A total of 543 overweight/obese children were studied with 64% being boys and 29% had insulin resistance. Adolescents aged 12 to 18 years, compared with children aged 5 to 11 years, were more likely to have acanthosis nigricans (63% vs 47%; P<0.001) and insulin resistance (37% vs 25%; P=0.005). Compared with overweight children, those who were obese were more likely to have the two conditions: acanthosis nigricans (59% vs 44%; P=0.005) and insulin resistance (35% vs 19%; P=0.001). Compared with those without acanthosis nigricans, those with the condition had significantly higher mean values for systolic blood pressures (P<0.001), 2-hour post-oral glucose tolerance test glucose level (P=0.021), fasting insulin level (P<0.001), homeostasis model of assessment-insulin resistance (P<0.001), fasting triglyceride level (P<0.001), and alanine aminotransferase level (P=0.002), but a lower high-density lipoprotein cholesterol level (P<0.001). Those with acanthosis nigricans were also more likely to have insulin resistance (P<0.001), hypertension (P=0.021), fatty liver (P=0.001), and abnormal glucose homeostasis (P=0.003). CONCLUSION. Obese Chinese children and adolescents with acanthosis nigricans had a higher chance of having insulin resistance and cardiometabolic co-morbidities. Acanthosis nigricans is an important clinical feature warranting early attention and evaluation to facilitate timely interventions and monitoring. PMID- 24762332 TI - The clinical utility of conventional karyotyping in the detection of cytogenetic abnormalities in soft tissue tumours: an Asian institutional experience. AB - OBJECTIVES: To assess the clinical utility of conventional karyotyping as a diagnostic tool in soft tissue tumours amidst the increasing use of molecular cytogenetics. DESIGN: Case series. SETTING: Singapore General Hospital, an Asian institution. PARTICIPANTS: A total of 35 participants (18 male and 17 female) aged 15 to 81 years were included in this study. Conventional karyotyping of 35 consecutive fresh soft tissue tumour specimens was performed over 4 years and the results were analysed. RESULTS: Of the 35 cases of soft tissue tumours reviewed, chromosome abnormalities were detected in 22 (63%) cases, 11 (31%) showed a normal karyotype, and 2 (6%) had culture failure. Of the 22 cases with abnormal karyotype, nine (41%) cases showed recurring aberrations: Ewing's sarcomas (n=2), desmoplastic small round cell tumour (n=1), synovial sarcomas (n=3), myxoid liposarcomas (n=2), and lipoma (n=1). One lipoma case had a t(2;12)(q23;q15) in which 2q23 breakpoint was not reported before. Chromosomal aberration involving 12q15 breakpoint has been shown in a previous study to be indicative of a lipoma like liposarcoma. Another lipoma case had addition of 5q15 and 9p13 together with a balanced aberration of t(12;13) (q13;q12) which were novel aberrations. One synovial sarcoma case showed t(3;7)(q21;p13) which was an uncharacteristic aberration. CONCLUSION: Conventional karyotyping demonstrated utility as a genome wide screening tool for soft tissue tumours and an adjunct diagnostic tool in the event histopathology results were doubtful. With the more widespread use of karyotyping, novel recurring chromosomal aberrations may be discovered. PMID- 24762333 TI - "Doctor, please tell me it's nothing serious": an exploration of patients' worrying and reassuring cognitions using stimulated recall interviews. AB - BACKGROUND: Many patients who consult their GP are worried about their health, but there is little empirical data on strategies for effective reassurance. To gain a better understanding of mechanisms for effective patient reassurance, we explored cognitions underlying patients' worries, cognitions underlying reassurance and factors supporting patients' reassuring cognitions. METHODS: In a qualitative study, we conducted stimulated recall interviews with 21 patients of 12 different GPs shortly after their consultation. We selected consultations in which the GPs aimed to reassure worried patients and used their videotaped consultation as a stimulus for the interview. The interviews were analysed with thematic coding and by writing interpretive summaries. RESULTS: Patients expressed four different core cognitions underlying their concerns: 'I have a serious illness', 'my health problem will have adverse physical effects', 'my treatment will have adverse effects' and 'my health problem will negatively impact my life'. Patients mentioned a range of person-specific and context specific cognitions as reasons for these core cognitions. Patients described five core reassuring cognitions: 'I trust my doctor's expertise', 'I have a trusting and supporting relationship with my doctor', 'I do not have a serious disease', 'my health problem is harmless' and 'my health problem will disappear.' Factors expressed as reasons for these reassuring cognitions were GPs' actions during the consultation as well as patients' pre-existing cognitions about their GP, the doctor-patient relationship and previous events. Patients' worrying cognitions were counterbalanced by specific reassuring cognitions, i.e. worrying and reassuring cognitions seemed to be interrelated. CONCLUSIONS: Patients described a wide range of worrying cognitions, some of which were not expressed during the consultation. Gaining a thorough understanding of the specific cognitions and tailoring reassuring strategies to them should be an effective way of achieving reassurance. The identified reassuring cognitions can guide doctors in applying these strategies in their daily practice. PMID- 24762334 TI - Acute response and subcellular movement of HSP27, alphaB-crystallin and HSP70 in human skeletal muscle after blood-flow-restricted low-load resistance exercise. AB - AIM: Heat-shock proteins (HSP) are important chaperones for stressed and damaged proteins. Low-load blood-flow-restricted resistance exercise (BFRE) is generally believed not to induce significant muscle damage, but is hitherto unverified with intracellular markers. Consequently, the aim of this study was to investigate the HSP response after BFRE in human skeletal muscle. METHODS: Nine healthy volunteers performed five sets to failure of unilateral knee extension at 30% of 1RM with partial blood-flow restriction. The contralateral leg performed the same work with free blood flow. Muscle biopsies were collected before exercise, 1, 24 and 48 h after exercise and analysed for HSP27, alphaB-crystallin, HSP70, desmin, glycogen content and myosin heavy chain by immunohistochemistry, ELISA and western blotting. RESULTS: One hour after exercise, HSP27 and alphaB-crystallin levels were reduced in the cytosolic and increased in the cytoskeletal fraction in the BFRE leg. HSP70 showed a delayed response and was increased over 48 h in the BFRE leg. Immunohistochemical analyses showed higher staining intensity of HSP70 in type 1 fibres in the BFRE leg at 24 and 48 h post-exercise. PAS staining showed decreased glycogen levels after BFRE, and interestingly, glycogen was still depleted 48 h after exercise in the same fibres displaying high HSP70 staining (type 1 fibres). CONCLUSION: Translocation of HSP27 and alphaB crystallin from cytosol to cytoskeletal structures indicates that cytoskeletal proteins are stressed during BFRE. However, overt signs of myofibrillar disruptions were not observed. Interestingly, the stress response was more pronounced in type 1 than in type 2 fibres and coincided with low glycogen levels. PMID- 24762335 TI - Developmental association of prosocial behaviour with aggression, anxiety and depression from infancy to preadolescence. AB - BACKGROUND: Research on associations between children's prosocial behaviour and mental health has provided mixed evidence. The present study sought to describe and predict the joint development of prosocial behaviour with externalizing and internalizing problems (physical aggression, anxiety and depression) from 2 to 11 years of age. METHOD: Data were drawn from the National Longitudinal Survey of Children and Youth (NLSCY). Biennial prosocial behaviour, physical aggression, anxiety and depression maternal ratings were sought for 10,700 children aged 0 to 9 years at the first assessment point. RESULTS: While a negative association was observed between prosociality and physical aggression, more complex associations emerged with internalizing problems. Being a boy decreased the likelihood of membership in the high prosocial trajectory. Maternal depression increased the likelihood of moderate aggression, but also of joint high prosociality/low aggression. Low family income predicted the joint development of high prosociality with high physical aggression and high depression. CONCLUSIONS: Individual differences exist in the association of prosocial behaviour with mental health. While high prosociality tends to co-occur with low levels of mental health problems, high prosociality and internalizing/externalizing problems can co-occur in subgroups of children. Child, mother and family characteristics are predictive of individual differences in prosocial behaviour and mental health development. Mechanisms underlying these associations warrant future investigations. PMID- 24762336 TI - pH sensitive quantum dot-anthraquinone nanoconjugates. AB - Semiconductor quantum dots (QDs) have been shown to be highly sensitive to electron or charge transfer processes, which may alter their optical properties. This feature can be exploited for different sensing applications. Here, we demonstrate that QD-anthraquinone conjugates can function as electron transfer based pH nanosensors. The attachment of the anthraquinones on the surface of QDs results in the reduction of electron hole recombination, and therefore a quenching of the photoluminescence intensity. For some anthraquinone derivatives tested, the quenching mechanism is simply caused by an electron transfer process from QDs to the anthraquinone, functioning as an electron acceptor. For others, electron transfer and energy transfer (FRET) processes were found. A detailed analysis of the quenching processes for CdSe/ZnS QD of two different sizes is presented. The photoluminescence quenching phenomenon of QDs is consistent with the pH sensitive anthraquinone redox chemistry. The resultant family of pH nanosensors shows pKa ranging ~5-8, being ideal for applications of pH determination in physiological samples like blood or serum, for intracellular pH determination, and for more acidic cellular compartments such as endosomes and lysosomes. The nanosensors showed high selectivity towards many metal cations, including the most physiologically important cations which exist at high concentration in living cells. The reversibility of the proposed systems was also demonstrated. The nanosensors were applied in the determination of pH in samples mimicking the intracellular environment. Finally, the possibility of incorporating a reference QD to achieve quantitative ratiometric measurements was investigated. PMID- 24762337 TI - Victims, bullies, and their defenders: a longitudinal study of the coevolution of positive and negative networks. AB - The complex interplay between bullying/victimization and defending was examined using a longitudinal social network approach (stochastic actor-based models). The (co)evolution of these relations within three elementary schools (Grades 2-5 at Time 1, ages 8-11, N = 354 children) was investigated across three time points within a year. Most bullies and defenders were in the same grade as the victims, although a substantial number of bullies and defenders were in other grades (most often one grade higher). Defenders were usually of the same gender as the victims, whereas most bullies were boys, with boys bullying both boys and girls. In line with goal-framing theory, multiplex network analyses provided evidence for the social support hypothesis (victims with the same bullies defended each other over time) as well as the retaliation hypothesis (defenders run the risk of becoming victimized by the bullies of the victims they defend). In addition, the analysis revealed that bullies with the same victims defended each other over time and that defenders of bullies initiated harassment of those bullies' victims. This study can be seen as a starting point in unraveling the relationship dynamics among bullying, victimization, and defending networks in schools. PMID- 24762339 TI - DSSC anchoring groups: a surface dependent decision. AB - Electrodes in dye sensitised solar cells are typically nanocrystalline anatase TiO2 with a majority (1 0 1) surface exposed. Generally the sensitising dye employs a carboxylic anchoring moiety through which it adheres to the TiO2 surface. Recent interest in exploiting the properties of differing TiO2 electrode morphologies, such as rutile nanorods exposing the (1 1 0) surface and anatase electrodes with high percentages of the (0 0 1) surface exposed, begs the question of whether this anchoring strategy is best, irrespective of the majority surface exposed. Here we address this question by presenting density functional theory calculations contrasting the binding properties of two promising anchoring groups, phosphonic acid and boronic acid, to that of carboxylic acid. Anchor electrode interactions are studied for the prototypical anatase (1 0 1) surface, along with the anatase (0 0 1) and rutile (1 1 0) surfaces. Finally the effect of using these alternative anchoring groups to bind a typical coumarin dye (NKX 2311) to these TiO2 substrates is examined. Significant differences in the binding properties are found depending on both the anchor and surface, illustrating that the choice of anchor is necessarily dependent upon the surface exposed in the electrode. In particular the boronic acid is found to show the potential to be an excellent anchor choice for electrodes exposing the anatase (0 0 1) surface. PMID- 24762340 TI - Enhanced auditory arousal increases intake of less palatable and healthier foods. AB - Two experiments were conducted to test a prediction of the arousal hypothesis that increased arousal will increase intake of less palatable and healthy foods. In both experiments, arousal was manipulated by adjusting the volume of a movie (soft, loud volume) while participants consumed foods. In Experiment 1, participants ate fresh (palatable) or stale (less palatable) popcorn during a 9 minute movie played at a soft or loud volume. Experiment 2 used the same procedures with healthier foods (carrot sticks and apple slices). Partial support for the arousal hypothesis in Experiment 1 showed that participants consumed more stale but not fresh popcorn in the loud (high arousal) versus soft (low arousal) volume group. These findings suggest that low but not high palatable foods are susceptible to manipulations of arousal. Consistent with this interpretation, Experiment 2 showed that high but not low environmental arousal increased intake of the fruits and vegetables, which are typically rated as lower in palatability compared to high fat foods. These results show that high arousal in an eating typical environment increases intake of less palatable foods, and healthy foods (i.e., fruits and vegetables). Increasing the availability of healthier foods in a loud food environment can have a positive impact on increasing intake of fruits and vegetables in that environment. PMID- 24762341 TI - Intestinal parasitic infestation in combatants and their families: a hospital based study in Mid-Western Regional Police Hospital, Nepal. AB - OBJECTIVE: To find out the scenario of intestinal parasitic infestation in combatants and their families in the setting of Mid-Western Regional Police Hospital (MWRPH), Nepal. STUDY DESIGN: Cross-sectional study. METHODS: All 2005 patients presented with the complaint of abdominal pain, diarrhoea, frequent defecation, blood in stool, or black stool from August 2007 to February 2011 were offered a stool examination. About 10g of fresh stool was collected in a clean, dry bottle. Two slides from each specimen were examined applying light microscope in 10 and 40 uvf at Banke, Nepalgunj hospital laboratory. RESULT: Among 2005 patients, 928 (46.28%) were infested with either helminths and/or protozoa. 96% were single infestation. The most common infestation was Ascaris lumbricoides (48.06%) and the second was hook worm (18.97%). Most common protozoal infestations were Entamoeba histolytica (12.92%) and Giardia lamblia (9.49%). Helminthic infestations peaked in cool months and protozoal infestations were rather steady throughout the year. CONCLUSION: Very high parasitic infestation in least developed mid- western Nepal may need urgent public health intervention. PMID- 24762342 TI - Association between socio-demographics and alcohol dependence among individuals living in an Indian setting. AB - BACKGROUND: Alcohol use is on the rise worldwide and urgent steps are required to curb this growing burden of alcohol consumption. Alcohol drinking leads to serious social, physical and mental consequences. OBJECTIVE: The objective of this pilot study is to examine association between socio-demographics and severity of alcohol dependence among individuals obtaining treatment at alcohol de-addiction center. METHODS: This pilot cross sectional study was conducted in September 2013 in South India. A convenient sample of 100 participants was enrolled. Individuals aged 30 years and above, receiving treatment from de addiction center and providing written informed consent were eligible for the study. A modified version of previously validated questionnaires was used for gathering information on socio-demographic characteristics, severity of alcohol dependence (using Alcohol Dependent Scale [ADS] and Short Alcohol Dependence Data questionnaire [SADD]), motivational incentives for alcohol quitting and challenges faced while quitting alcohol. RESULTS: All participants were males with mean age of 43 years (SD = 6.5 years). Significant association was seen between ADS and annual income (p = 0.001), education (p = 0.001), occupation (p < 0.0001) and work timing (p < 0.0001). Similar results were seen with SADD scores. Family support (100%) and health (60%) were reported to be the most important motivating factors for quitting alcohol. DISCUSSION: Results showed an urgent need of interventions that are family centered and focus on unskilled, less educated individuals having high work stress. Public health interventions should not only be home based, but should also include worksite awareness initiatives. A national policy is needed to promote alcohol quitting and to bring awareness regarding the consequences of alcohol consumption on individual's life. PMID- 24762343 TI - Development of evidence-based health policy documents in developing countries: a case of Iran. AB - BACKGROUND: Evidence-based policy documents that are well developed by senior civil servants and are timely available can reduce the barriers to evidence utilization by health policy makers. This study examined the barriers and facilitators in developing evidence-based health policy documents from the perspective of their producers in a developing country. METHODS: In a qualitative study with a framework analysis approach, we conducted semi-structured interviews using purposive and snowball sampling. A qualitative analysis software (MAXQDA 10) was used to apply the codes and manage the data. This study was theory-based and the results were compared to exploratory studies about the factors influencing evidence-based health policy-making. RESULTS: 18 codes and three main themes of behavioral, normative, and control beliefs were identified. Factors that influence the development of evidence-based policy documents were identified by the participants: behavioral beliefs included quality of policy documents, use of resources, knowledge and innovation, being time-consuming and contextualization; normative beliefs included policy authorities, policymakers, policy administrators, and co-workers; and control beliefs included recruitment policy, performance management, empowerment, management stability, physical environment, access to evidence, policy making process, and effect of other factors. CONCLUSION: Most of the cited barriers to the development of evidence based policy were related to control beliefs, i.e. barriers at the organizational and health system levels. This study identified the factors that influence the development of evidence-based policy documents based on the components of the theory of planned behavior. But in exploratory studies on evidence utilization by health policymakers, the identified factors were only related to control behaviors. This suggests that the theoretical approach may be preferable to the exploratory approach in identifying the barriers and facilitators of a behavior. PMID- 24762344 TI - Non-adherence to medication in outpatient setting in Nigeria: the effect of employment status. AB - BACKGROUND: Non-adherence to prescribed medication and health regimen has been identified as responsible for poor health outcomes. This study investigates the reasons for medication non-adherence in outpatient setting among malaria patients in Nigeria. METHODS: This research adopted quantitative research methods. A well structured questionnaire was completed by 440 respondents with minimum age of 18 years. The aim of the questionnaire was to get respondents' reasons for non adherence to medication. The demographic details of the respondents were also captured. RESULTS: Age, gender, educational level, marital status and medication payment were found not to influence non-adherence while employment was a significant variable. Respondents also indicated fear of death, nauseating smell of drugs, religious beliefs, the side effects of medication, the fear of taking counterfeit drugs or drugs that are past their expiry dates as also responsible for non-adherence. CONCLUSION: The results highlighted reasons for poor adherence in southwest Nigeria. Interventions can be targeted towards these reasons. PMID- 24762345 TI - Effects of social capital on general health status. AB - This paper discusses the concept of social capital as a potential factor in understanding the controversial relationship between income inequality and individual health status, arguing a positive, important role for social capital. Most of the health research literature focuses on individual health status and reveals that social capital increases individual health. However, the difficulty in measuring social capital, together with what may be the nearly impossible task of attributing causality, should relegate the concept to a more theoretical role in health research. Nonetheless, social capital receives academic attention as a potentially important factor in health research. This paper finds that the mixed results of empirical research on income inequality and health status remain a problem in the context of defining a stable relationship between socioeconomic status and health status. Clearly, further research is needed to elaborate on the income inequality and health relationship. In addition, focused, rigorous examination of social capital in a health context is needed before health researchers can comfortably introduce it as a concept of influence or significance. PMID- 24762346 TI - Association between awareness of patient rights and patient's education, seeing bill, and age: a cross-sectional study. AB - BACKGROUND: Considering the controversial results of previous reports on awareness of bill of patients' rights in different regions, as well as the fact that no report is available on the awareness of patients of their rights in teaching hospitals of Sari, we conducted the present study. MATERIALS & METHODS: This is a cross-sectional Study conducted in teaching hospitals of Sari in 2011. The study population consisted of 336 patients recruited from 4 hospitals affiliated with Mazandaran University of Medical Sciences in Sari, through calculating the selection quota of each hospital. Data were collected through face-to-face interview on discharge, using a two-section questionnaire based on the bill of patient rights and with verified reliability and validity. Data analysis was accomplished on SPSS soft- ware version 10. RESULTS: 55.4% of patients were women and 44.6% were men. The patients' mean age was 40.93 +/- 15.04 years and the mean length of stay was 4.6 +/- 3.34 days. Most patients had elementary education (36%) or were illiterate (25%). The majority (63.4%) had not seen the bill of patients' rights. 58.9% had poor knowledge, 12% had intermediate knowledge, and 29.1% had good knowledge. As for the articles of the bill, the poorest awareness correlated to the 9th article (the right to participate or refrain from participating in research). We found a significant relationship between awareness of the bill, and the patient's education, seeing the bill, and age (p < 0.0005). CONCLUSION: The results of the present study indicate that patients are not sufficiently aware of their rights, and this problem requires comprehensive planning to be resolved. PMID- 24762347 TI - Factors associated with posttraumatic stress disorder and its coping styles in parents of preterm and full-term infants. AB - INTRODUCTION: Birth of a premature infant and subsequent neonatal intensive care leads to psychological distress and trauma in parents. A large proportion of mothers show signs of trauma long after discharge from hospital. Fathers of premature infants are known to experience more stress than fathers of full-term infants. The sorrow experienced by parents of preterm infants is significantly higher than that experienced by parents of full-term infants because they have not been adequately prepared for the experience of birth, and need to cope with the stress caused by the clinical state and intensive care of the infant. METHOD: This was a descriptive-comparative study conducted in medical centers of Qom, Iran in 2012. In this study, 82 couples (164 mothers and fathers), participated in two groups as parents of preterm and full-term infants and completed demographic, midwifery, posttraumatic stress disorder, Spielberg anxiety questionnaires, and the Coping Inventory with Stressful Situation within 2 months after birth of their infant. Data were analyzed using Chi-square, Fisher's exact, Mann-Whitney, independent t tests, logistic regression, and Repeated measures ANOVA in SPSS-18 software. RESULTS: Posttraumatic stress disorder in preterm group mothers was significantly higher than in term group mothers (P=0.03), but no significant difference in this disorder was observed between fathers in these groups. There was a significant difference in coping styles with stress between mothers in the two groups (P < 0.001) and between fathers in the two groups (P < 0.001). Logistic model showed a significant correlation between posttraumatic stress and housing and coping strategies with stress in mothers. CONCLUSION: Parents of premature infants are more exposed to psychological disorders, and there is a need to adopt educational approaches to improve parents' coping ability with preterm infant's circumstance. PMID- 24762348 TI - Which factors influence functional patients improvements during rehabilitation? AB - BACKGROUND: Rehabilitation in patients with disabilities is an important aspect of tertiary prevention. Severity of disability, evaluated by global measures of autonomy, are essential for functional outcome evaluation. AIM: To determine the effectiveness of a rehabilitation programme in terms of percentage functional improvement (PFI); to verify the role of gender, age and length of stay (LOS), by motor and cognitive domains, on PFI. DESIGN: longitudinal study. SETTING: An intensive rehabilitation hospital. POPULATION: 305 inpatients. METHODS: The disability has been investigated using the Functional Independence Measure (FIM). Percentage differences between discharge and admission were calculated for FIM score. Wilcoxon matched pair test for the six areas and the two domains of the FIM score were calculated. The effect of LOS, gender and age on PFI were studied with Robust regression. RESULTS: Neurological and Orthopaedic patients had improvements on Motor and Cognitive domains. The greatest gains were in the Self Care, Sphintere Control, Transfer and Locomotion Areas (p <= 0.001). LOS was associated (p < 0.001) with PFI while age resulted borderline significant (p=0.049) in the cognitive domain in Neurological patients. CONCLUSION: The rehabilitation improved the overall conditions of neurological and orthopaedic patients. LOS emerged as the most important determinant in PFI. PMID- 24762349 TI - The National Health Insurance Scheme (NHIS) in the Dormaa Municipality, Ghana: why some residents remain uninsured? AB - The paper presents a quantitative investigation on the national health insurance scheme (nhis) in dormaa municipality, Ghana: why some residents remain uninsured? Since its implementation has been a little over a decade now. The aim is to identify the obstacles to enrollment by the public which would enable policy direction to ensure that all residents are registered with the scheme. A descriptive and cross-sectional study was conducted between May and July, 2013. Both purposive and simple random sampling technique were used to select 210 respondents and data obtained through self-administered and face-to-face interviews guided by structured questionnaire. chi square (X2) test of independence was adopted to show the association between socioeconomic and demographic features and membership. Findings from the research suggest that residents' decision to enrol have significant associated with gender, education, number of children, place of residence, employment and income. It was also observed that membership is highly affected by premium level. The discussion of the findings and recommendations offered, if incorporated into the policy guideline of NHIS could maintain and at the same time increase enrollment level which would guarantee quality, accessible and affordable basic health care protection for the good people of Ghana. PMID- 24762350 TI - Responses of trace elements to aerobic maximal exercise in elite sportsmen. AB - Trace elements are chemical elements needed in minute quantities for the proper growth, development, and physiology of the organism. In biochemistry, a trace element is also referred to as a micronutrient. Trace elements, such as nickel, cadmium, aluminum, silver, chromium, molybdenum, germanium, tin, titanium, tungsten, scandium, are found naturally in the environment and human exposure derives from a variety of sources, including air, drinking water and food. The Purpose of this study was investigated the effect of aerobic maximal intensity endurance exercise on serum trace elements as well-trained individuals of 28 wrestlers (age (year) 19.64+/-1.13, weight (Kg) 70.07 +/- 15.69, height (cm) 176.97 +/- 6.69) during and after a 2000 meter Ergometer test protocol was used to perform aerobic (75 %) maximal endurance exercise. Trace element serum levels were analyzed from blood samples taken before, immediately after and one hour after the exercise. While an increase was detected in Chromium (Cr), Nickel (Ni), Molybdenum (Mo) and Titanium (Ti) serum levels immediately after the exercise, a decrease was detected in Aluminum (Al), Scandium (Sc) and Tungsten (W) serum levels. Except for aluminum, the trace elements we worked on showed statistically meaningful responses (P < 0.05 and P < 0.001). According to the responses of trace elements to the exercise showed us the selection and application of the convenient sport is important not only in terms of sportsman performance but also in terms of future healthy life plans and clinically. PMID- 24762352 TI - Evaluating the scale-up of antiretroviral treatment sites in KwaZulu-Natal province of South Africa: achievements and challenges from 2005 to 2010. AB - In order to provide care to the increasing number of people infected with HIV, there is a need for scaling up the number of treatment sites. For the public health officials and planners, there is a need for a defined methodology to do this taking into consideration the national targets as enacted by the National Department of Health (NDOH) of South Africa. This commentary is about an evaluation conducted to review the progress made by the Province of KwaZulu-Natal in scaling-up antiretroviral treatment sites (ART). Overall, the prediction that 54 ART facilities were required for equitable distribution of antiretroviral treatment in KwaZulu-Natal had been exceeded as 89 ART sites had been established by 2010. In conclusion, the predicted number of ART sites by Wilson and Blower method was largely exceeded within 5 years of their prediction. Two major challenges are still lurking into the ART program, the accessibility by those who need it and the shortage of professional human resources particularly pharmacy staff. Innovative strategies are needed to address the shortage of health professionals and related disparities in order to increase access to ART. PMID- 24762351 TI - Quality of life, social desirability and their relationship in opium addicted persons in southeast of Iran. AB - BACKGROUND & AIM: Addiction leads to many problems which may adversely affect addicted people, their families and impose health care agencies with many challenges. This study aimed to examined quality of life (QoL), social desirability and their relationship among opium addicted persons in southeast of Iran. MATERIAL & METHODS: In a cross-sectional study conducted from September 2012 to January 2013, 123 addicted people were studied. Date collection tools were; checklist of demographic data, Iranian version of the 36-item short form QoL (SF-36) and Marlowe-Crowne Social Desirability Scale (MC-SDS). RESULTS: While mean score of QoL was 60.4+/-29.5, mean score of social desirability were 14.2+/ 3.7. Low, moderate and high levels of social desirability were observed in 4.9%, 90.2% and 4.9% of participants, respectively. Pearson's correlation were not significant between mean score of social desirability and mean score of QoL (p=0.969, r=0.004). CONCLUSION: Addicted participants of present study showed a moderate level of QoL and social desirability, without any significant relationship between QoL and social desirability. Further research is suggested in addicts with social and cultural differences. PMID- 24762353 TI - Being at peace as an important factor in acquiring teaching competency by Iranian nurse teachers: a qualitative study. AB - It is imperative to understand the factor that influence teaching competency. Therefore, it is necessary to study those that have an impact on the process of acquiring teaching competency. Competent nurse teachers have an important role in the achievement of nursing students and improving the quality of nursing education. However, few researches have focused specifically on the process of acquiring teaching competency in nurse teachers and its related factors. This study as a part of more extensive research aims to explore the factors influencing acquisition of teaching competency by Iranian nurse teachers. Grounded theory was chosen as the method. Eleven teachers from three nursing schools in Tehran were recruited. Data was generated by semi structured interviews during May 2011 to March 2013 and was analyzed through using constant comparison. Three main categories were emerged including "individual characteristics" (spirituality, professional interest, ethical conducts, knowledge expansion and reflective practice), "organizational factors" (management of educational systems, solidarity culture, student characteristics) and "socio-cultural factors" (social situations, and public definition of nursing). Nurse teachers who deal peacefully with the nursing profession and colleagues are responsible and committed to acquiring teaching competency. A suitable organization in nursing educational systems that is structured and ordered also encourages a peaceful approach by nurse teachers. PMID- 24762354 TI - Violence against women by their intimate partners in Shahroud in northeastern region of Iran. AB - BACKGROUND: Violence against women is one of the worst consequences of cultural, political, and socio-economic inequalities between men and women. Intimate Partner Violence (IPV) has been identified as an important cause of morbidity from multiple mental, physical, sexual, and reproductive health outcomes. Nonetheless, the prevalence and related factors of this international problem have not been investigated extensively in some parts of the world. The aims of this research were to determine the prevalence of physical and mental violence perpetrated by men against their intimate partners and to assess the associated factors of partner violence among women in Shahroud in northeastern region of Iran in 2010. METHODS: This Cross-Sectional study was conducted in Shahroud, in northeast of Iran in 2010. Cluster sampling was done from primary health service institutions, universities, public schools and governmental organizations throughout the city and six hundred married women completed the study. A structured questionnaire with 34 items was designed in three parts to assess the physically (10 items) and mentally (15 items) violent acts by a current intimate male partner and identify collative behaviors (9 items) of victims. The Logistic regression analysis was applied to determine the net effect of background variables on the IPV occurrence within the past year. RESULTS: About 20% of the participants experienced at least one type of physical violence. Increased risk of physical violence was positively associated with the younger age of the couple (OR=3.08, P<0.05), lower education (OR=2.28, P<0.01) and having a semi-manual skilled occupation of husband (OR=3.62, P<0.05), husband's heavy cigarette smoking (OR=2.62, P<0.01), and his drug abuse (OR=2.1, P<0.05). About 85% of the women had experienced mental harassment within the past twelve months. Logistic Regression Analysis found that lower education (OR=3.06, P<0.01) and having semi manual skilled occupation (OR=3.8, P<0.05) of husband, increasing years of marriage (OR=2.8, P<0.01), husband's heavy cigarette smoking (OR=2.3, P<0.01) and his abusing the use of drugs (OR=3.4, P<0.01) had significant associations with women's experience of mental violence. CONCLUSIONS: Some socioeconomic characteristics such as educational level, occupational status of men, heavy smoking and drug abusing are associated with the occurrence of violence against one's intimate partner. Since IPV is usually unreported, healthcare providers should be aware of the risk factors associated with domestic violence to be able to design preventive measures against its negative health outcomes in women. PMID- 24762355 TI - Relationship between Revised Graduated Index (R-GINDEX) of prenatal care utilization & preterm labor and low birth weight. AB - Prenatal care refers to accurate and consistent performance of the principles important to maintain healthy pregnancy outcomes and also for mother and child health. One of the new indices to assess the adequacy of care is Revised Graduated Index of Prenatal Care Utilization (R-GINDEX).The study aims to assess the relationship between quantitative prenatal care factors and preterm labor and low birth weight using R-GINDEX. This historical cohort study has been conducted on 420 mothers during the first two years after delivery in 2010. The adequacy of care was calculated by R-GINDEX. Based on this index, participants have been divided into three care groups including inadequate, adequate and intensive care groups. A significant relationship has been found between R-GINDEX and preterm birth and low birth weight (P<0.05). Thus the probability of premature labor in inadequate care group (RR=3.93) and low birth weight (RR= 2.53) was higher than that of the adequate and intensive care group. The results showed that the quantity of prenatal care is effective in reducing preterm birth and low birth weight. PMID- 24762356 TI - Relationship between addiction relapse and self-efficacy rates in injection drug users referred to Maintenance Therapy Center of Sari, 1391. AB - BACKGROUND & PURPOSE: Self-efficacy is the belief that one has the ability to implement the behaviors needed to produce a desired effect. There has been growing interest in the role of self-efficacy as a predictor and/or mediator of treatment outcome in number of domains. In numerous studies of substance abuse treatment, self-efficacy has emerged as an important predictor of outcome, or as a mediator of treatment effects. In the event of a slip, highly self-efficacious persons are inclined to regard the slip as a temporary setback and to reinstate control, whereas those who have low self-efficacy are more likely to proceed to a full-blown relapse. This study was carried out to determine relationship between relapse and self-efficacy and other factors in injected drug users. MATERIALS & METHODS: We conducted this study in 200 addicts in the center of counseling behavioral disease in health center of sari city (methadone maintenance therapy center or MMTC). A cross-sectional study was carried out on all of these addicts. RESULTS: The average age in addictions was 38 and its range was 20-60.72%of them were married and the first drug used was opium. All of them had relapse at least one time .we found a relationship between relapse and self-efficacy as well as the relationship between self-efficacy with the age of the first of drug use, dose, and procrastination for treatment, marriage, employment and job was significant. CONCLUSION: This study found that there was a significant difference between relapse and self-efficacy as well as other related factors. It is important to include drug users and common society organizations representing them in every stage of the governmental policy and program development process to make them responsive to the needs of the community. PMID- 24762357 TI - Cultural and socio-economic factors on changes in aging among Iranian women. AB - The aim of the study is to determine the cultural and socio-economic factors that influence changes in aging among Iranian women. This qualitative study was part of a more extensive study designed according to grounded theory method. A purposeful, snowball and theoretical sampling technique was used. Data collection instruments were interviews and field notes. Duration of interviews differed and ranged from 38 to 110 minutes. Data collection process, coding and analysis were performed simultaneously. Collected data were analyzed using the recommended method by Corbin and Straus (1998 and 2008). The factors were formed from 6 subcategories: cultural and socio-economic status in the past, urban/rural life, companionship status, beliefs and attitudes, higher responsibilities of women and women's financial capability. This study explained the various aspects of cultural and socio-economic changes in the elderly participants based on their real experiences. PMID- 24762358 TI - Assessing the association between the degree of pain and socioeconomic status among older persons in Ghana. AB - OBJECTIVES: The current study sought to examine the association between the degree of pain and socioeconomic status among older male and female Ghanaians. METHOD: Data were drawn from the 2007-08 World Health Organization Global Ageing and Adult Health (SAGE) survey conducted in Ghana (Young adults=803, Adults=1689 and Older adults=2616). This includes bodily aches Ghanaians experienced in the last 30 days. Analyses of the association of pain with predisposing and enabling factors were carried out by means of ordinal logistic regression analysis. RESULTS: In the age-adjusted model, pain was statistically significantly associated with the cohabitating group as its marginal effect suggests that respondents in that category were less likely to experience pain as related to the others in women. CONCLUSION: This study established that Ghanaian men go through more pain than their women counterparts. This article is premier to our knowledge to apply ordered logistic for the degree of pain. PMID- 24762359 TI - Risky sexual behavior among rural female adolescents in Malaysia: a limited role of protective factors. AB - PURPOSE: This paper presents the findings of a cross-sectional survey on the risk and protective factors of premarital sexual behavior among rural female adolescents in Peninsular Malaysia. METHODS: We investigated data on 770 female respondents aged 13-17 years in rural areas to identify predictive factors for premarital sexual intercourse. Data were analyzed using bivariate and multivariate regression. Specific socio-demographic factors, psychological and family domains, peer delinquency, and knowledge and attitudes about sexuality were considered in risky sexual behaviors in rural Malay girls. The effects of other covariates for premarital sexual intercourse were controlled by logistic regression model. RESULTS: Of the 770 rural female students, about 3.2% of respondents reported experience of sexual intercourse in the past three months. Out of those sexually active girls, 36% were 17 years old and 20% stated having sexual intercourse with more than one partner, and 72% did not use contraception during the most recent sexual intercourse. Midnight activities, peer-sexual disorder, self-evaluation, and attitude toward sexual health were significant predictors of sexual intercourse in rural girls in Malaysia. CONCLUSION: The finding highlights the impact of psychological factors and peer group influences on the challenges of premarital sexual behavior among rural girls and the notion of school-based sexual health education for adolescents. This study triggers other researchers take into account a comprehensive view of protective factors operating in adolescents' risky sexual behaviors in Asian culture seeing that family domain variables, unexpectedly, exerted no predicting influence on sexually active female teens in rural areas in Malaysia. PMID- 24762360 TI - Environmental factors in an Ontario community with disparities in colorectal cancer incidence. AB - OBJECTIVE: In Ontario, there are significant geographical disparities in colorectal cancer incidence. In particular, the northern region of Timiskaming has the highest incidence of colorectal cancer in Ontario while the southern region of Peel displays the lowest. We aimed to identify non-nutritional modifiable environmental factors in Timiskaming that may be associated with its diverging colorectal cancer incidence rates when compared to Peel. METHODS: We performed a systematic review to identify established and proposed environmental factors associated with colorectal cancer incidence, created an assessment questionnaire tool regarding these environmental exposures, and applied this questionnaire among 114 participants from the communities of Timiskaming and Peel. RESULTS: We found that tobacco smoking, alcohol consumption, residential use of organochlorine pesticides, and potential exposure to toxic metals were dominant factors among Timiskaming respondents. We found significant differences regarding active smoking, chronic alcohol use, reported indoor and outdoor household pesticide use, and gold and silver mining in the Timiskaming region. CONCLUSIONS: This study, the first to assess environmental factors in the Timiskaming community, identified higher reported exposures to tobacco, alcohol, pesticides, and mining in Timiskaming when compared with Peel. These significant findings highlight the need for specific public health assessments and interventions regarding community environmental exposures. PMID- 24762361 TI - On pump coronary artery bypass graft surgery versus off pump coronary artery bypass graft surgery: a review. AB - There are two basic ways of performing coronary artery bypass graft surgery (CABG): on pump CABG and off pump CABG. Off pump CABG is relatively a newer procedure to on-pump CABG and does not require the use of the cardiopulmonary bypass machine. On pump CABG is the more traditional method of performing bypass surgery. However its resultant inflammatory effects cause renal dysfunction, gastrointestinal distress and cardiac abnormalities which have forced the surgeons to look for alternatives to the procedure. An extensive literature search revealed that on pump CABG causes better revascularization as compared to off pump CABG while off pump CABG has a much lower post operative morbidity and mortality especially in high risk patients. We suggest that the technique used should depend on the ease of the surgeon doing the operation as both the methods seem almost equally efficient according to the review. PMID- 24762362 TI - Clinical assessment of dizzy patients: the necessity and role of diagnostic tests. AB - Over administration of diagnostic tests in health care settings is a critical issue, imposing a great deal of expenditure on health sector. Vertigo and dizziness are common complaints of many patients who seek medical advice, and the vast majority of them undergo several evaluations, including Brain Magnetic Resonance Imaging (MRI), Laboratory tests, Pure Tone Audiometry (PTA), and Electrocardiography (ECG). The aim of this study was to investigate the performing rate of these diagnostic tests, and to evaluate their necessity and medical indications. This study was conducted on 270 dizzy patients referred to Apadana Dizziness and Vertigo Clinic, Ahvaz, Iran, from July 2008 to February 2013. Of these, 71.9% were diagnosed with peripheral lesions while laboratory assessment (58.1%) and brain MRI (38.1%) were the most requested tests. Age was an important factor, affecting the frequency of performing the ECG and Brain MRI. Medications were still administered widely even to those who seemed to respond well enough to vestibular rehabilitation. These findings revealed that many unnecessary and time-consuming diagnostic tests were performed, which had minor contribution to the final diagnosis and treatment of the patients. Therefore, a modification in the assessment methods of the dizzy patients with emphasis on history and clinical presentation seems essential. PMID- 24762363 TI - Uterine contractions' pattern in active phase of labor as a predictor of failure to progress. AB - BACKGROUND: Failure to progress remains a key indication for cesarean section which caused by different factors including uterine contractions. If it is diagnosed in the primary phase of labor, a better prognosis can thus be made. The purpose of this study was to find a possible correlation between pattern of uterine contraction and progression of labor. METHOD: During this study, 120 women referred for delivery to an educational hospital's maternity ward in the North of Iran in 2010 were included. Uterine contractions of mothers were recorded in dilatation of 4 to7 cm for an hour. In this way, F/R ratio which means the time that a contraction needs to return from its peak to baseline (Fall) divided to the time for a contraction to rise to its peak (Rise) was calculated. All of the participants were followed until delivery, vaginal delivery or caesarean section. RESULTS: Mean and standard deviation of fall to raise ratio was 1.54+/-0.26 in mothers with vaginal delivery versus 1.74+/-0.21 for others underwent caesarean section (OR = 0.44, 95% CI: 0.005- 0.42, P < 0.001). Sensitivity, specificity, and predictive values (positive and negative) of mentioned ratio were 68.32%, 70.01%, 69.55%, and 68.91%, respectively. CONCLUSION: By considering acceptable predictive value of uterine contractions' pattern in the active phase of labor, it could help to timely diagnosis of failure to progress and consequently suitable intervention which probably maintain better health of both mother and fetus. PMID- 24762364 TI - Hypertension among rural population in four states: Sudan 2012. AB - BACKGROUND: Hypertension is emerging as an alarming public-health problem causes organ damage. OBJECTIVES: To identify prevalence of hypertension and predictor factors among rural population in four states in Sudan. METHODS: A community based cross-sectional study was conducted in sixteen rural areas in Sudan during April 2012. A total of 3020 adult were interviewed using structured questionnaire and blood pressure was measured before and after the interview. Hypertension was taken as >=140 mmHg and >=90 mmHg for systole and diastole respectively. ANALYSIS: Descriptive statistic was presented; Sex and mean of systolic and diastolic blood pressure were tested using ANOVA for individuals on antihypertensive medication. Predictor factors to hypertension were tested by logistic regression. RESULTS: Prevalence of hypertension among rural population was 15.8%. Overall means of systolic and diastolic blood pressure were 128.6 +/- 17.7 and 81.5 +/- 11.6 respectively while the means among hypertensive individuals was 154.74 +/-14.4 and 97.98+/-8.4 respectively Known hypertensive individuals were 20.1%; out of whom 71.7% were hypertensive and 22.4% have Target Organ Damage. Those on anti-hypertensive medications were 76.4% and normotensive were 55.1%. Individuals having both diabetes and hypertension were 3.3% and 80.2% were hypertensive. Log regression model showed age, smoking, diabetes and family hypertension were predictors of hypertension by 3.6%, 34.9%, 49.7% and 56.8% respectively (P-value < 0.05). CONCLUSION: Prevalence of hypertension among rural Sudan was 15.8%. Family history was the strongest predictor of hypertension. PMID- 24762365 TI - Patients discharged against medical advice from a psychiatric hospital in Iran: a prospective study. AB - AIM: Self- discharged patients are at high risk for readmission and ultimately higher cost for care.We intended to find the proportion of patients who leave hospital against medical advice and explore some of their characteristics. METHODS: This prospective study of discharge against medical advice was conducted in psychiatric wards of Zare hospital in Iran, 2011. A psychologist recorded some information on a checklist based on the documented information about the patient who wanted to leave against medical advice. The psychologist interviewed these patients and recorded the reasons for discharge against medical advice. Descriptive statistics were calculated for the variables. RESULTS: The rate of premature discharge was 34.4%. Compared to patients with regular discharges, patients with premature discharge were significantly more likely to be male, self employed, to have co morbid substance abuse and first admission and positive family history of psychiatric disorder. Disappearance of symptoms was the most frequent reason for premature discharge. CONCLUSION: The 34.4% rate of premature discharge observed in our study is higher than rate reported in other studies. One possible explanation is our teaching hospital serves a low-income urban area and most patients had low socioeconomic status. Further studies are needed to compare teaching and non-teaching hospital about the rate of premature discharge and the reasons of patients who want to leave against medical advice. PMID- 24762366 TI - Effect of dance labor on the management of active phase labor pain & clients' satisfaction: a randomized controlled trial study. AB - BACKGROUND: There are a wide variety of non- pharmacologic pain relief techniques for labor which include pelvic movement, upright position, back massage and partner support during the first stage of labor. The effectiveness of dance labor which is a combination of these techniques- has not been evaluated. AIM: This study aimed to evaluate the effectiveness of dance labor in pain reduction and woman's satisfaction during the first stage of labor. METHODS: 60 primiparous women aged 18-35 years old were randomly assigned to dance labor and control groups. In the dance labor group, women were instructed to do standing upright with pelvic tilt and rock their hips back and forth or around in a circle while their partner massaged their back and sacrum for a minimum of 30 minutes. In the control group, the participants received usual care during physiologic labor. Pain and satisfaction scores were measured by Visual Analogue Scale. Data were analyzed by using the t. test and Chi-square. FINDINGS: Mean pain score in the dance labor group was significantly lower than the control group (P < 0.05). The mean satisfaction score in the dance labor group was significantly higher than in the control group (P < 0.05). CONCLUSION: Dance labor which is a complementary treatment with low risk can reduce the intensity of pain and increase mothers, satisfaction with care during the active phase of labor. PMID- 24762367 TI - The frequency of smoking and common factors leading to continuation of smoking among health care providers in tertiary care hospitals of Karachi. AB - BACKGROUND: The primary objective of the study was to find out the frequency of tobacco smoking among health care providers in tertiary care hospitals of Karachi. The secondary objective was to identify the common factors responsible for the continuation of smoking. METHOD: This cross sectional study was conducted in the wards and out-patient departments of three selected tertiary hospitals of Karachi. A total of 180 health care providers were enrolled in the study using proportionate stratified sampling. Postgraduate students, house officers and trainees were excluded from the study. Data were collected from randomly selected health care providers using survey methodology. SPSS v. 20.0 was used to enter and analyze the data. RESULTS: Fifty two participants out of 180 were smokers for past one year (28.9%). Among them, 21 (11.7%) smoked more than 5 cigarettes per day. Twenty smokers (11.1%) were found to smoke due to peer influence. It was found that those who were influenced by their peers were 8.33 times more prone to be addicted to smoking than those who were less influenced. Similarly, the likelihood of addiction increased up to 76.9% with the lack of incentives. CONCLUSION: Our results clearly indicate that a large number of health care providers smoke which should be a serious concern. Hence our health agencies should take immediate action in order to curtail the heaving burden of smoking and its related health consequences. PMID- 24762368 TI - Re-birth after coronary bypass graft surgery: a hermeneutic-phenomenological study. AB - Although coronary artery bypass graft surgery has significant effects on reducing the symptoms of coronary artery disease, there is not enough knowledge and understanding of lived experience of patients after surgery. Understanding lived experience of this group of patients would be helpful for healthcare staff to provide better services to the patients. The aim of this study was to describe with a deeper understanding, the lived experiences of patients after Coronary Artery Bypass Graft Surgery. Using a hermeneutic phenomenological approach and a Van-Manen analysis method, in-depth semi-structured interviews were conducted with eleven participants who had lived experienced of at least six months post - coronary artery bypass graft surgery. Re-birth was the main theme that emerged in the process of data analysis. This theme was derived from four sub-themes including "feels younger", ''vigorous heart'', ''intrepid life'' and ''oriented to be healthy''. Life after a coronary artery bypass graft surgery is often appreciated as a re-birth by persons with these experiences as surgery did not only provide a feeling of wellness, but also added a sensation of youthfulness and improvement in the quality of life for these participants. In addition, they would actively participate in health promotional activities such as; adherence to medication and diet regimes, changes in lifestyle to maintain their health. PMID- 24762369 TI - The comparison of the effect of Transactional Model-based Teaching and Ordinary Education Curriculum- based Teaching programs on stress management among teachers. AB - BACKGROUND & OBJECTIVES: Regarding the effect of teachers' stress on teaching and learning processes, the researchers decided to provide a stress management program based on Transactional Model to solve this teachers' problems. Thus, this study is going to investigate the effect of Transactional Model- based Teaching and the Ordinary Education Curriculum- based Teaching programs on Yazd teachers. METHODS: The study was a semi- experimental one. The sample population (200 people) was selected using categorized method. The data were collected via PSS Questionnaire and a questionnaire which its validity and reliability had been proved. Eight teaching sessions were hold for 60-90 min. Evaluation was performed in three steps. The data were described and analyzed using SPSS software version 15. Value of P<0.05 was considered as significant. RESULTS: The participants were 200 people of Yazd teachers of primary schools. Mean age of group 1 and 2 was 42.05+/-5.69 and 41.25+/-5.89 respectively. Independent T- Test indicated a significant mean score (p=0.000) due to perceived stress of interference groups in post interference step and follow-up one respectively. CONCLUSION: Results showed a decreasing effect of both programs, but the Transactional Model- based interference indicated to decrease stress more than the other. PMID- 24762370 TI - Organizational entrepreneurship and administrators of hospitals: case study of Iran. AB - Due to rapid changes of technology and scientific advances in health systems and need for fast planning in health care, entrepreneurial spirit among employers and employees is a crucial element. According to the field of entrepreneurship research has not been solved and where learning and innovation for healthcare organizations due to the nature of the work required. This study aims to examine the entrepreneurial activities within the hospitals affiliated to Tehran University of Medical Sciences, Iran. To achieve the aim of the study, a questionnaire containing 29 items regarding the areas of innovation, creative behavior, flexibility, empowerment, rewarding systems and the management support was distributed among the hospitals' managers. Establishment of a culture of entrepreneurship in healthcare organizations led to the development unit controlled, changing the culture of the hospital. The analysis of the data showed that the majority of the managers agreed with all five areas of entrepreneurship namely the existence of innovation and innovative behavior, flexibility, decision making, rewarding and encouraging system, as well as management supportive system of personnel's new ideas. In fact, the managers generally had positive attitude towards entrepreneurship in their organizations The Pearson correlation test also showed that there is a significant relationship between the areas of entrepreneurship and the managers' age as well as their working experience (P<0.05). Entrepreneurial activities in healthcare can be improved through providing a suitable environment, adjusting reward and encouragement systems, giving more authority to subordinates, promoting awareness and education, and mobilizing managers to attract appropriate opportunities for organization. Further active involvement of employees, more stable in front of changes and increased ability managers to capture opportunities in domestic and foreign situation. PMID- 24762373 TI - Practicing by smartphone. PMID- 24762371 TI - The comparison of the effects of education provided by nurses on the quality of life in patients with congestive heart failure (CHF) in usual and home-visit cares in Iran. AB - AIM: Quality of life (QOL) can be considered as a quality indicator of health care systems and nurses can play an important role to improve QOL in patients with congestive heart failure (CHF). The aim of this study was to determine the effects of education provided by nurses on the QOL in patients with CHF in home visit care compared to usual care. METHOD: In a single-blind randomized controlled trial conducted from September 2011 to June 2012, 110 patients with CHF were randomly assigned into two groups. While patients in group I were received usual education at the time of hospital discharge, patients in Group II, in addition to usual education, were received special education regards to their illness by nurses who visited patients in their homes. The 36-item short-form (SF 36) questionnaire was used to evaluate the patient's QOL at the time of discharge and also six months after hospital discharge. RESULTS: At the time of hospital discharge, mean score of all 8 sub-score of SF-36 questionnaire was 63.4+/-7.8 in patients of group II and 61.1+/-6.4 in patients of group I, respectively (P> 0.05). QOL was decreased in group I and increased in group II compared to the time of hospital discharge. After six months, mean score of QOL was higher in group II than in group I. CONCLUSIONS: QOL of patients with CHF were decreased after hospital discharge. Education provided by nurses in home-visit care could improve the QOL in patients with CHF, based on the findings of this study. PMID- 24762372 TI - Cytokeratin expression of engrafted three-dimensional culture tissues using epithelial cells derived from porcine periodontal ligaments. AB - OBJECTIVE: This study investigated the differentiation and proliferation of epithelial cells derived from periodontal ligaments after three-dimensional culture using collagen gel with fibroblasts in vitro and in vivo. METHODS: Epithelial cells and fibroblasts were derived from porcine periodontal ligaments. Epithelial cells were labeled using a fluorescent red membrane marker (PKH-26GL) and were seeded onto collagen gel with fibroblasts, followed by incubation in an air-liquid interface for 7 days. Three-dimensional cultures were grafted onto the backs of nude mice and removed at 1, 7, and 14 days after surgery (in vivo model). Unfixed sections (5 MUm) were used to detect the presence of red fluorescent cells. Paraffin sections were analyzed histologically and immunohistochemically. Specimens were compared with three-dimensional culture tissues at 8, 14 and 21 days (in vitro model). RESULTS: Grafted three-dimensional cultures formed a stratified epithelial structure similar to skin in vivo. Epithelial cells were sequenced in basal-layer-like structures at 14 days in vivo. Immunohistochemical findings showed that the expression of cytokeratin was detected in the epithelial layer in in vitro and in vivo models. Ck8 + 18 + 19 was expressed in the upper epithelial layer in the in vitro model at 14 and 21 days, but not in vivo. Involucrin was expressed in the certified layers in vitro at 14 days, but not in vivo. Laminin was detected at the dermo-epidermal junction in vivo at 7 and 14 days, but not in vitro. CONCLUSION: These results suggest that differentiation of three-dimensional culture tissues differs in vivo and in vitro. PMID- 24762374 TI - Miniscrew-supported posterior intrusion for treatment of anterior open bite. PMID- 24762375 TI - Miniscrew anchorage for the correction of midline discrepancies. PMID- 24762376 TI - A "smart" elastics reminder. PMID- 24762377 TI - Treatment of a complex malocclusion in a growing skeletal Class II patient. PMID- 24762378 TI - A traction arch for impacted mandibular canines and premolars. PMID- 24762379 TI - Closure of maxillary spaces during retention. PMID- 24762380 TI - Factors in rehospitalisation for severe pressure ulcer care in spinal cord injury/disorders. AB - OBJECTIVE: Repeated hospital admissions (RHA) for ongoing pressure ulcer (PU) care remains a significant challenge in the clinical management of the spinal cord injury/disorders (SCI/D) population. The current study investigated the significance of risk factors for PU treatment and RHA. METHOD: A retrospective chart review of veterans admitted to the Louis Stokes Cleveland Department of Veterans Affairs Medical Center (LSCDVAMC) Spinal Cord Injury (SCI) unit for Category III or IV PUs was carried out. A random sample of 105 individuals with SCI/D, evaluated by the Wound Care Team (WCT) from 2006 to 2009 was assessed. Multiple PU development risk factors were extracted from the electronic health record system using standardised data collection forms and entered into the Spinal Cord Injury Pressure Ulcer Database (SCIPUD). Potential associations with RHA were analysed. RESULTS: Twenty variables were initially identified as potentially related to PU development. Descriptive statistics and statistically significant associations between risk factors and RHA were determined. Demographic factors showed no significant association with RHA. Duration of injury, power wheelchair use and sub-optimally managed spasticity (SMS) were significantly associated with higher RHA. Sub-optimally managed neurogenic bowel (SMNB) at admission was significantly associated with reduced RHA. CONCLUSION: Factors previously found to be predictive of initial PU development may not, in fact, be predictive of RHA. Some protective trends were observed, such as polypharmacy and marital status, but these did not reach statistical significance in this preliminary study of admission characteristics, warranting further research. DECLARATION OF INTEREST: There were no external sources of funding for this study. The authors have no conflicts of interests to declare. PMID- 24762381 TI - Aqueous oxygen peroxide treatment of VLUs in a primary care-based randomised, double-blind, placebo-controlled trial. AB - OBJECTIVE: To evaluate a novel aqueous oxygen peroxide (AOP) wound therapy (BioxyQuell) in a multi-centre, primary care-based, randomised, double-blind, placebo-controlled, parallel-group trial, monitoring long-term healing outcomes over 12 months. METHOD: Sixty-one patients with chronic, stable venous leg ulceration were treated with either AOP solution or sterile water placebo applied as a lavage over 2 weeks. The patients' wounds were dressed weekly and assessed fortnightly over the following 6 weeks. Patients who completed the initial 8-week trial were invited into a 10-month follow-up trial. The primary endpoints of the study were wound healing at 8 weeks, 12 weeks, 6 months and 12 months, and wound size reduction during the treatment phase. Secondary endpoints were reductions in wound bioburden and pain. RESULTS: Patients treated with AOP were more likely to heal at 6 months (p=0.014) and 12 months (p=0.006), but not at 8 weeks (p=0.979) or 12 weeks (p=0.263). Patients treated with AOP had greater wound area reduction (p=0.015), reductions in pain measured on a 100-point scale (p=0.001) and wound bioburden reduction (p=0.005) during the treatment phase. CONCLUSION: The addition of AOP treatment provides substantial benefits to patients with chronic venous leg ulceration compared with current best practice. PMID- 24762382 TI - Negative pressure wound therapy in the management of postoperative infections after musculoskeletal tumour surgery. AB - OBJECTIVE: The aim of the present retrospective study was to report on the effectiveness of the negative pressure wound therapy (NPWT) in the treatment of infected wounds after musculoskeletal tumour surgery. METHOD: A total of 12 patients (10 male, 2 female, mean age 44.9 years with 9 early and 3 late infections) were included in the study. Patient parameters measured include age, gender, tumour diagnosis and localisation, pathogen organism, foam used, pressure height and modus, number of NPWT dressings changes, total duration of NPWT, need for secondary wound closure, length of hospitalisation, complications, and follow up. RESULTS: The NPWT dressings were changed on average 6.7 (SD+/-6.9) times after a mean duration of 5.6 (SD+/-2.4) days. The total duration of NPWT was 37.7 (SD+/-32.9) days. The mean hospital stay was 77.5 (SD+/-58.8) days. In 7 out of 12 cases, a split-thickness skin graft transplantation was performed. In these cases, no seroma or hematoma formation beneath the skin graft could be observed. At a mean follow-up 39.2 (range: 9-73) months, no reinfection or infection persistence was apparent. CONCLUSION: NPWT can be of valuable assistance in the treatment of infected wounds following musculoskeletal tumour surgery. The patients should be informed about the long treatment period. PMID- 24762383 TI - Nutrition-related status and granulation tissue colour of pressure ulcers evaluated by digital image analysis in older patients. AB - OBJECTIVE: Granulation tissue colour may be an indicator for nutritional assessment in pressure ulcer (PU) care. This study evaluated the relationship between nutritional status, anaemia and diabetes, and granulation tissue colour of PUs by colour analysis of digital photographs in the clinical setting. METHOD: The cross-sectional study included 42 older patients with 51 full-thickness PUs from 10 institutions. Patient demographics, wound status, nutritional status and dietary intakes were obtained from medical charts. From a wound image, the granulation red index was processed by computer software and the proportion of pixels exceeding the threshold intensity of 80 for the granulation tissue surface (%GRI80) was calculated. RESULTS: Haemoglobin levels were positively associated with %GRI80 levels (p=0.007) in the crude model, but not in the adjusted model (p=0.260). The interaction term between diabetes and protein intake was significantly associated with %GRI80 levels in the adjusted models (p=0.010). At protein intakes of 0.95 g/kg or higher, diabetic wounds exhibited lower %GRI80 levels than non-diabetic wounds (p=0.002). At protein intakes of less than 0.95 g/kg, %GRI80 levels did not differ between diabetic and non-diabetic patients (p=0.247). Protein intakes of 0.95 g/kg or higher were associated with higher %GRI80 levels in non-diabetic patients (p=0.015), but not in diabetic patients (p=0.127). CONCLUSION: Granulation tissue colour, evaluated by the objective and quantitative analysis of digital photography, is related to haemoglobin level, diabetes and dietary intakes in clinical settings. PMID- 24762384 TI - Telemedicine - the future? PMID- 24762385 TI - Motor skills and calibrated autism severity in young children with autism spectrum disorder. AB - In addition to the core characteristics of autism spectrum disorder (ASD), motor skill deficits are present, persistent, and pervasive across age. Although motor skill deficits have been indicated in young children with autism, they have not been included in the primary discussion of early intervention content. One hundred fifty-nine young children with a confirmed diagnosis of ASD (n = 110), PDD-NOS (n = 26), and non-ASD (n = 23) between the ages of 14-33 months participated in this study.1 The univariate general linear model tested the relationship of fine and gross motor skills and social communicative skills (using calibrated autism severity scores). Fine motor and gross motor skills significantly predicted calibrated autism severity (p < .05). Children with weaker motor skills have greater social communicative skill deficits. Future directions and the role of motor skills in early intervention are discussed. PMID- 24762386 TI - Narratives of athletic identity after acquiring a permanent physical disability. AB - Individuals with acquired physical disabilities report lower levels of athletic identity. The objective of this study was to further explore why athletic identity may be lost or (re)developed after acquiring a physical disability. Seven women and four men (range = 28-60 years) participated in approximately 1 hour-long semistructured interviews; data were subjected to a narrative analysis. The structural analysis revealed three narrative types. The nonathlete narrative described physical changes in the body as reasons for diminished athletic identity. The athlete as a future self primarily focused on present sport behavior and performance goals such that behavior changes diminished athletic identity. The present self as athlete narrative type focused on the aspects of their present sport involvement, such as feedback from other athletes and skill development, which supported their athletic identity. Implications of these narrative types with respect to sport promotion among people with acquired physical disabilities are discussed. PMID- 24762387 TI - The correlates of body mass index and risk factors for being overweight among preschoolers with motor delay. AB - This cross-sectional study investigated the correlates of body mass index (BMI) and risk factors for overweight among 91 children with motor delay (MD) aged 9-73 months. Anthropometric measurements and questionnaires regarding multiple risk factors were obtained. Simple correlations between BMI percentile classifications and potential predictors were examined using Spearman's rank/Pearson's correlations and chi2 analysis. Multiple predictors of overweight were analyzed using logistic regression. BMI was correlated positively with higher caloric intake (rs = .21, p < .05) and negatively with passive activity (rs = ?.21, p < .05). When multiple predictors were considered, more severe dysphagia (odds ratio [OR], 2.81, p = .027, 95% confidence interval [CI], 1.13-7.03) and antiepileptic drug use (OR, 19.11, p = .008, 95% CI, 2.14-170.81) had significant partial effects on overweight status. Agencies supporting early development should consider caregiver education regarding the potential implication of feeding style and medication on BMI. PMID- 24762388 TI - Negotiated meanings of disability simulations in an adapted physical activity course: learning from student reflections. AB - Disability simulations have been used as a pedagogical tool to simulate the functional and cultural experiences of disability. Despite their widespread application, disagreement about their ethical use, value, and efficacy persists. The purpose of this study was to understand how postsecondary kinesiology students experienced participation in disability simulations. An interpretative phenomenological approach guided the study's collection of journal entries and clarifying one-on-one interviews with four female undergraduate students enrolled in a required adapted physical activity course. The data were analyzed thematically and interpreted using the conceptual framework of situated learning. Three themes transpired: unnerving visibility, negotiating environments differently, and tomorrow I'll be fine. The students described emotional responses to the use of wheelchairs as disability artifacts, developed awareness of environmental barriers to culturally and socially normative activities, and moderated their discomfort with the knowledge they could end the simulation at any time. PMID- 24762389 TI - Influence of service-learning on kinesiology students' attitudes toward P-12 students with disabilities. AB - Employing a grounded theory approach, the purpose of this study was to qualitatively examine the influence of service-learning (SL) on undergraduate kinesiology students' attitudes toward and experiences working with P-12 students with disabilities. Fourteen (9 female, 5 male) kinesiology students enrolled in an adapted physical education class participated in one of three focus group interviews regarding their experiences of working with P-12 students with disabilities. All interview data were analyzed following procedures outlined by Strauss and Corbin (1998). The following five themes represent the participants' experiences and attitudes toward P-12 students with disabilities after their involvement in a SL project: (a) initial reactions, (b) selection of P-12 students, (c) preconceived attitudes, (d) the benefits of SL, and (e) positive experience. All 14 of the participants who volunteered to share their experiences indicated that the SL experience positively affected their attitudes toward individuals with disabilities. PMID- 24762392 TI - Effectiveness of a Tai Chi intervention for improving functional fitness and general health among ethnically diverse older adults with self-reported arthritis living in low-income neighborhoods: a cohort study. AB - BACKGROUND AND PURPOSE: Tai Chi (TC) is a form of low to moderate physical activity that has been shown to significantly impact health and functional fitness among older adults; the impact of TC on the health and functional fitness of older adults with arthritis is not well understood. The purpose of this study was to assess the effectiveness of a 16-week TC intervention for improving functional fitness and self-reported general health among older adults with arthritis who were born outside Canada and were residing in low-income neighborhoods. METHODS: A 16-week intervention was conducted among older adults residing in 1 of 2 specified low-income neighborhoods in Canada. The analysis was limited to those who self-reported having arthritis (n = 102). Participants were encouraged to attend 2 moderate-intensity TC sessions per week for a total of 120 minutes. Functional fitness and health were assessed at baseline and at 16 weeks. RESULTS: Average attendance was 1.1 sessions per week. Functional fitness assessment results indicated that right-hand grip strength (25.6 +/- 8.2 to 26.7 +/- 7.8 kg), left-hand grip strength (24.9 +/- 7.3 to 26.8 +/- 7.1 kg), 30-second arm curl (15.6 +/- 5.0 to 18.6 +/- 5.7 repetitions/30 s), Timed Up-and-Go (7.4 +/ 2.6 to 6.9 +/- 2.6 s), and 30-second chair stand (12.0 +/- 3.9 to 15.4 +/- 5.8 s) improved significantly (P < 0.05) from baseline to 16 weeks. Results from the Short Form-36 indicate that physical functioning (73.1 +/- 19.9 to 80.3 +/- 19.4; P = 0.001), general health (61.5 +/- 20.9 to 66.0 +/- 20.4; P = 0.03), vitality (61.5 +/- 18.9 to 67.5 +/- 20.2; P = 0.008), and mental health (74.3 +/- 16.5 to 78.5 +/- 17.7; P = 0.04) also improved significantly over the intervention period. Improvements in physical health and physical function scores were clinically meaningful. DISCUSSION AND CONCLUSIONS: Participating in TC for 16 weeks led to significant improvements in functional fitness and components of physical and mental health among older adults with self-reported arthritis. Tai Chi seems to be a valuable mode of physical activity for this population. PMID- 24762393 TI - Characterization of the anti-influenza activity of the Chinese herbal plant Paeonia lactiflora. AB - Bai Shao (BS, the root of Paeonia lactiflora Pall.), a common Chinese herb in many recipes used to treat viral infection and liver diseases, is recognized for its ability to nourish menstruation, its Yin convergence, and as an antiperspirant. However, the mechanism and components for its antiviral function remain to be elucidated. In this study, an ethanolic extract of BS was further partitioned into aqueous and organic parts (EAex) for in vitro functional study and in vivo efficacy testing. EAex exhibited an IC50 of 0.016 +/- 0.005 mg/mL against influenza virus A/WSN/33 (H1N1), with broad-spectrum inhibitory activity against different strains of human influenza A viruses, including clinical oseltamivir-resistant isolates and an H1N1pdm strain. The synthesis of both viral RNA and protein was profoundly inhibited when the cells were treated with EAex. A time-of-addition assay demonstrated that EAex exerted its antiviral activity at various stages of the virus replication cycle. We addressed its antiviral activity at virus entry and demonstrated that EAex inhibits viral hemagglutination and viral binding to and penetration into host cells. In vivo animal testing showed that 200 mg/kg/d of EAex offered significant protection against viral infection. We conclude that BS possesses antiviral activity and has the potential for development as an anti-influenza agent. PMID- 24762394 TI - Physical activity counseling by primary care physicians: attitudes, knowledge, implementation, and perceived success. AB - BACKGROUND: In physical activity (PA) counseling, primary care physicians (PCPs) play a key role because they are in regular contact with large sections of the population and are important contact people in all health-related issues. However, little is known about their attitudes, knowledge, and perceived success, as well as about factors associated with the implementation of PA counseling. METHODS: We collected data from 4074 PCPs including information on physician and practice characteristics, attitudes toward cardiovascular disease (CVD) prevention, and measures used during routine practice to prevent CVD. Here, we followed widely the established 5 A's strategy (Assess, Advise, Agree, Assist, Arrange). RESULTS: The majority (87.2%) of PCPs rated their own level of competence in PA counseling as 'high,' while 52.3% rated their own capability to motivate patients to increase PA as 'not good.' Nine of ten PCPs routinely provided at least 1 measure of the modified 5 A's strategy, while 9.5% routinely used all 5 intervention strategies. CONCLUSIONS: The positive attitude toward PA counseling among PCPs should be supported by other stakeholders in the field of prevention and health promotion. An example would be the reimbursement of health counseling services by compulsory health insurance, which would enable PCPs to invest more time in individualized health promotion. PMID- 24762395 TI - p53 is positively regulated by miR-542-3p. AB - The tumor suppressor p53 and miRNAs are linked through a complex network. Several miRNAs modulate p53 expression, while p53 regulates the transcription and/or biogenesis of several other miRNAs. Here, we report the development of a cell based assay used with a library of human miRNA mimics in a high-throughput screen for miRNAs that modulate p53 expression. Overexpression of miRNA (miR)-542-3p in cancer cells elevated p53 expression, stimulated the expression of p53 targets, and inhibited cell proliferation. Mechanistically, miR-542-3p increased p53 protein stability by weakening interactions between p53 and its negative regulator MDM2. Furthermore, miR-542-3p suppressed ribosome biogenesis by downregulating a subset of ribosomal proteins such as RPS23, leading to upregulation of RPL11 and stabilization of p53. The 3'untranslated region in the RPS23 transcript contained a miR-542-3p-binding site, suggesting that RPS23 is a direct target of miR-542-3p. Our results define miR-542-3p as an important new positive regulator of p53 with potential applications in cancer treatment. PMID- 24762396 TI - Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis. AB - The mechanisms by which Myc overexpression or Pten loss promotes prostate cancer development are poorly understood. We identified the chromatin remodeling protein, ING4, as a crucial switch downstream of Myc and Pten that is required for human prostate epithelial differentiation. Myc-induced transient expression of ING4 is required for the differentiation of basal epithelial cells into luminal cells, while sustained ING4 expression induces apoptosis. ING4 expression is lost in >60% of human primary prostate tumors. ING4 or Pten loss prevents epithelial cell differentiation, which was necessary for tumorigenesis. Pten loss prevents differentiation by blocking ING4 expression, which is rescued by ING4 re expression. Pten or ING4 loss generates tumor cells that co-express basal and luminal markers, indicating prostate oncogenesis occurs through disruption of an intermediate step in the prostate epithelial differentiation program. Thus, we identified a new epithelial cell differentiation switch involving Myc, Pten, and ING4, which when disrupted leads to prostate tumorigenesis. Myc overexpression and Pten loss are common genetic abnormalities in prostate cancer, whereas loss of the tumor suppressor ING4 has not been reported. This is the first demonstration that transient ING4 expression is absolutely required for epithelial differentiation, its expression is dependent on Myc and Pten, and it is lost in the majority of human prostate cancers. This is the first demonstration that loss of ING4, either directly or indirectly through loss of Pten, promotes Myc-driven oncogenesis by deregulating differentiation. The clinical implication is that Pten/ING4 negative and ING4-only negative tumors may reflect two distinct subtypes of prostate cancer. PMID- 24762398 TI - Quantum walks with tuneable self-avoidance in one dimension. AB - Quantum walks exhibit many unique characteristics compared to classical random walks. In the classical setting, self-avoiding random walks have been studied as a variation on the usual classical random walk. Here the walker has memory of its previous locations and preferentially avoids stepping back to locations where it has previously resided. Classical self-avoiding random walks have found numerous algorithmic applications, most notably in the modelling of protein folding. We consider the analogous problem in the quantum setting - a quantum walk in one dimension with tunable levels of self-avoidance. We complement a quantum walk with a memory register that records where the walker has previously resided. The walker is then able to avoid returning back to previously visited sites or apply more general memory conditioned operations to control the walk. We characterise this walk by examining the variance of the walker's distribution against time, the standard metric for quantifying how quantum or classical a walk is. We parameterise the strength of the memory recording and the strength of the memory back-action on the walker, and investigate their effect on the dynamics of the walk. We find that by manipulating these parameters, which dictate the degree of self-avoidance, the walk can be made to reproduce ideal quantum or classical random walk statistics, or a plethora of more elaborate diffusive phenomena. In some parameter regimes we observe a close correspondence between classical self avoiding random walks and the quantum self-avoiding walk. PMID- 24762399 TI - Experience on palliative medicine clinical clerkships: Reflections of two sixth year medical students. PMID- 24762397 TI - The potential role of Kv4.3 K+ channel in heart hypertrophy. AB - Transient outward K+ current (I(to)) plays a crucial role in the early phase of cardiac action potential repolarization. Kv4.3 K(+) channel is an important component of I(to). The function and expression of Kv4.3 K(+) channel decrease in variety of heart diseases, especially in heart hypertrophy/heart failure. Int his review, we summarized the changes of cardiac Kv4.3 K(+) channel in heart diseases and discussed the potential role of Kv4.3 K(+) channel in heart hypertrophy/heart failure. In heart hypertrophy/heart failure of mice and rats, down regulation of Kv4.3 K(+) channel leads to prolongation of action potential duration (APD), which is associated with increased [Ca(2+)](I), activation of calcineurin and heart hypertrophy/heart failure.However, in canine and human, Kv4.3 K(+) channel does not play a major role in setting cardiac APD. So, in addition to Kv4.3 K(+) channel/APD/[Ca(2+)](I) pathway, there exits another mechanism of Kv4.3 K(+) channel in heart hypertrophy and heart failure: downregulation of Kv4.3 K(+) channels leads to CaMKII dissociation from Kv4.3-CaMKII complex and subsequent activation of the dissociated CaMKII , which induces heart hypertrophy/heart failure. Upregulation of Kv4.3K(+) channel inhibits CaMKII activation and its related harmful consequences. We put forward a new point-of-view that Kv4.3 K(+) channel is involved in heart hypertrophy/heart failure independently of its electric function, and drugs inhibiting or upregulating Kv4.3 K(+) channel might be potentially harmful or beneficial to hearts through CaMKII. PMID- 24762400 TI - Adherence barriers to chronic dialysis in the United States. AB - Hemodialysis patients often do not attend their scheduled treatment session. We investigated factors associated with missed appointments and whether such nonadherence poses significant harm to patients and increases overall health care utilization in an observational analysis of 44 million hemodialysis treatments for 182,536 patients with ESRD in the United States. We assessed the risk of hospitalization, emergency room visit, or intensive-coronary care unit (ICU-CCU) admission in the 2 days after a missed treatment relative to the risk for patients who received hemodialysis. Over the 5-year study period, the average missed treatment rate was 7.1 days per patient-year. In covariate adjusted logistic regression, the risk of hospitalization (odds ratio [OR], 3.98; 95% confidence interval [95% CI], 3.93 to 4.04), emergency room visit (OR, 2.00; 95% CI, 1.87 to 2.14), or ICU-CCU admission (OR, 3.89; 95% CI, 3.81 to 3.96) increased significantly after a missed treatment. Overall, 0.9 missed treatment days per year associated with suboptimal transportation to dialysis, inclement weather, holidays, psychiatric illness, pain, and gastrointestinal upset. These barriers also associated with excess hospitalization (5.6 more events per patient year), emergency room visits (1.1 more visits), and ICU-CCU admissions (0.8 more admissions). In conclusion, poor adherence to hemodialysis treatments may be a substantial roadblock to achieving better patient outcomes. Addressing systemic and patient barriers that impede access to hemodialysis care may decrease missed appointments and reduce patient morbidity. PMID- 24762403 TI - The periaqueductal grey and its role in respiratory regulation. PMID- 24762402 TI - Length polymorphism in heme oxygenase-1 and risk of CKD among patients with coronary artery disease. AB - The length polymorphism of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with cardiovascular events and mortality in high-risk populations. Experimental data suggest that heme oxygenase-1 protects against kidney disease. However, the association between this polymorphism and long-term risk of CKD in high-risk patients is unknown. We analyzed the allelic frequencies of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter in 386 patients with coronary artery disease recruited from January 1999 to July 2001 and followed until August 31, 2012. The S allele represents short repeats (<27), and the L allele represents long repeats (>=27). The primary renal end points consisted of sustained serum creatinine doubling and/or ESRD requiring long-term RRT. The secondary end points were major adverse cardiovascular events and mortality. At the end of study, the adjusted hazard ratios (95% confidence intervals) for each L allele in the additive model were 1.99 (1.27 to 3.14; P=0.003) for the renal end points, 1.70 (1.27 to 2.27; P<0.001) for major adverse cardiovascular events, and 1.36 (1.04 to 1.79; P=0.03) for mortality. With cardiac events as time-dependent covariates, the adjusted hazard ratio for each L allele in the additive model was 1.91 (1.20 to 3.06; P=0.01) for the renal end points. In conclusion, a greater number of guanosine thymidine dinucleotide repeats in the heme oxygenase-1 gene promoter is associated with higher risk for CKD, cardiovascular events, and mortality among patients with coronary artery disease. PMID- 24762404 TI - A Multi-Session Attribution Modification Program for Children with Aggressive Behaviour: Changes in Attributions, Emotional Reaction Estimates, and Self Reported Aggression. AB - BACKGROUND: Research suggests that aggressive children are prone to over attribute hostile intentions to peers. AIMS: The current study investigated whether this attributional style can be altered using a Cognitive Bias Modification of Interpretations (CBM-I) procedure. METHOD: A sample of 10-12-year olds selected for displaying aggressive behaviours was trained over three sessions to endorse benign rather than hostile attributions in response to ambiguous social scenarios. RESULTS: Compared to a test-retest control group (n = 18), children receiving CBM-I (n = 16) were less likely to endorse hostile attributions and more likely to endorse benign attributions in response to a new set of ambiguous social situations. Furthermore, aggressive behaviour scores reduced more in the trained group than in the untrained controls. Children who received attribution training also reported less perceived anger and showed a trend to report more self-control than those in the control group. CONCLUSIONS: Implications of these findings are discussed. PMID- 24762401 TI - Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. AB - Tissue injury initiates an inflammatory response through the actions of immunostimulatory molecules referred to as damage-associated molecular patterns (DAMPs). DAMPs encompass a group of heterogenous molecules, including intracellular molecules released during cell necrosis and molecules involved in extracellular matrix remodeling such as hyaluronan, biglycan, and fibronectin. Kidney-specific DAMPs include crystals and uromodulin released by renal tubular damage. DAMPs trigger innate immunity by activating Toll-like receptors, purinergic receptors, or the NLRP3 inflammasome. However, recent evidence revealed that DAMPs also trigger re-epithelialization upon kidney injury and contribute to epithelial-mesenchymal transition and, potentially, to myofibroblast differentiation and proliferation. Thus, these discoveries suggest that DAMPs drive not only immune injury but also kidney regeneration and renal scarring. Here, we review the data from these studies and discuss the increasingly complex connection between DAMPs and kidney diseases. PMID- 24762408 TI - Characterization of the early inflammatory infiltrate at the feeding site of infected sand flies in mice protected from vector-transmitted Leishmania major by exposure to uninfected bites. AB - BACKGROUND: Mice exposed to sand fly saliva are protected against vector transmitted Leishmania major. Although protection has been related to IFN-gamma producing T cells, the early inflammatory response orchestrating this outcome has not been defined. METHODOLOGY/PRINCIPAL FINDINGS: Mice exposed to uninfected P. duboscqi bites and naive mice were challenged with L. major-infected flies to characterize their early immune response at the bite site. Mostly, chemokine and cytokine transcript expression post-infected bites was amplified in exposed compared to naive mice. In exposed mice, induced chemokines were mostly involved in leukocyte recruitment and T cell and NK cell activation; IL-4 was expressed at 6 h followed by IFN-gamma and iNOS2 as well as IL-5 and IL-10 expression. In naive animals, the transcript expression following Leishmania-infected sand fly bites was suppressed. Expression profiles translated to an earlier and significantly larger recruitment of leukocytes including neutrophils, macrophages, Gr+ monocytes, NK cells and CD4+ T cells to the bite site of exposed compared to naive mice post-infected bites. Additionally, up to 48 hours post infected bites the number of IFN-gamma-producing CD4+ T cells and NK cells arriving at the bite site was significantly higher in exposed compared to naive mice. Thereafter, NK cells become cytolytic and persist at the bite site up to a week post-bite. CONCLUSION/SIGNIFICANCE: The quiet environment induced by a Leishmania-infected sand fly bite in naive mice was significantly altered in animals previously exposed to saliva of uninfected flies. We propose that the enhanced recruitment of Gr+ monocytes, NK cells and CD4 Th1 cells observed at the bite site of exposed mice creates an inhospitable environment that counters the establishment of L. major infection. PMID- 24762409 TI - Coupling of lever arm swing and biased Brownian motion in actomyosin. AB - An important unresolved problem associated with actomyosin motors is the role of Brownian motion in the process of force generation. On the basis of structural observations of myosins and actins, the widely held lever-arm hypothesis has been proposed, in which proteins are assumed to show sequential structural changes among observed and hypothesized structures to exert mechanical force. An alternative hypothesis, the Brownian motion hypothesis, has been supported by single-molecule experiments and emphasizes more on the roles of fluctuating protein movement. In this study, we address the long-standing controversy between the lever-arm hypothesis and the Brownian motion hypothesis through in silico observations of an actomyosin system. We study a system composed of myosin II and actin filament by calculating free-energy landscapes of actin-myosin interactions using the molecular dynamics method and by simulating transitions among dynamically changing free-energy landscapes using the Monte Carlo method. The results obtained by this combined multi-scale calculation show that myosin with inorganic phosphate (Pi) and ADP weakly binds to actin and that after releasing Pi and ADP, myosin moves along the actin filament toward the strong-binding site by exhibiting the biased Brownian motion, a behavior consistent with the observed single-molecular behavior of myosin. Conformational flexibility of loops at the actin-interface of myosin and the N-terminus of actin subunit is necessary for the distinct bias in the Brownian motion. Both the 5.5-11 nm displacement due to the biased Brownian motion and the 3-5 nm displacement due to lever-arm swing contribute to the net displacement of myosin. The calculated results further suggest that the recovery stroke of the lever arm plays an important role in enhancing the displacement of myosin through multiple cycles of ATP hydrolysis, suggesting a unified movement mechanism for various members of the myosin family. PMID- 24762410 TI - Interleukin 33: a switch-hitting cytokine. AB - For many years IL-33 has been widely studied in the context of T helper type 2 (Th2)-driven inflammatory disorders. Interestingly, IL-33 has now emerged as a cytokine with a plethora of pleiotropic properties. Depending on the immune cells targeted by IL-33, it is reported to not only promote Th2 immunity, but also to induce T helper type 1 (Th1) immunity. Furthermore, recent studies have revealed that IL-33 can activate CD8(+) T cells. These new studies provide evidence for its beneficial role in antiviral and antitumor immunity. Here we review the evidence of IL-33 to drive protective T cell immunity plus its potential use as an adjuvant in vaccination and tumor therapy. PMID- 24762412 TI - Impact of duration of rupture of membranes on outcomes of premature infants. AB - OBJECTIVE: The primary aim of the study was to determine how the risk of adverse outcomes was related to the duration of the latency period and gestational age at birth following preterm premature rupture of the fetal membranes (PPROM). STUDY DESIGN: Retrospective review of infants discharged from 330 neonatal intensive care units. We defined four subgroups based on gestational age: 23 to 25, 26 to 28, 29 to 31 and 32 to 34 weeks. Each gestational age group was evaluated by duration of ROM: <24 h, 1 to 7 days, 8 to 14 days, 15 to 21 days, 21 to 28 days and >28 days and compared with a referent group (PPROM of >24 h but <7 days). RESULT: In all, 239 808 non-anomalous infants 23 to 34 weeks' gestational age were identified; 37 233 (15.5%) had rupture of membranes (ROM) >24 h. Compared with a reference group (PPROM of >24 h but <7 days), the risk of mortality for PPROM of 8 to 14, 15 to 21 and 21 to 28 days varied depending on gestational age at birth. Only PPROM >28 days was consistently associated with increased mortality and decreased likelihood of survival without morbidity in all gestational age subgroups. CONCLUSION: PPROM for >28 days is associated with an increased risk of death and morbidity. PMID- 24762411 TI - Emission of volatile organic compounds from medical equipment inside neonatal incubators. AB - OBJECTIVE: To determine emission of volatile organic compounds (VOCs) from plastic medical equipment within an incubator. STUDY DESIGN: Air samples from incubators before and after adding medical equipment were analyzed using EPA TO 15 methodology. Headspace analysis was used to identify VOC emissions from each medical equipment item. Air changes per hour (ACH) of each incubator were determined and used to calculate the emission rate of identified VOCs. RESULTS: Cyclohexanone was identified in all incubator air samples. At 28 degrees C, the mean concentration before and after adding medical equipment items was 2.1 +/- 0.6 and 57.2 +/- 14.9 MUg m(-3),respectively (P<0.01). Concentrations increased to a mean of 83.8 +/- 23.8 MUg m(-)(3) (P<0.01) at 37(o)C and 93.0 +/- 45.1 MUg m(-)(3) (P=0.39) after adding 50% humidity. Intravenous tubing contributed 89% of cyclohexanone emissions. ACH were determined with access doors closed and open with means of 11.5 +/- 1.7 and 44.1 +/- 6.7 h(-1), respectively. Cyclohexanone emission rate increased from a mean of 102.2 MUg h(-1) at 28( degrees C to 148.8 MUg h(-1) (P<0.01) at 37 degrees C. CONCLUSION: Cyclohexanone was quantified in all incubator air samples containing plastic medical equipment. The concentration of cyclohexanone within the incubator was inversely related to ACH in the closed mode. The cyclohexanone concentration as well as the emission rate increased with higher temperature. PMID- 24762413 TI - Does simulation booster impact retention of resuscitation procedural skills and teamwork? AB - OBJECTIVE: The Neonatal Resuscitation Program (NRP) has transitioned to a simulation-based format. We hypothesized that immersive simulation differentially impacts similar trainee populations' resuscitation knowledge, procedural skill and teamwork behavior. STUDY DESIGN: Residents from NICU and non-NICU programs were randomized to either control or a booster simulation 7 to 10 months after NRP. Procedural skill and teamwork behavior instruments were validated. Individual resident's resuscitation performance was assessed at 15 to 18 months. Three reviewers rated videos. RESULT: Fifty residents were assessed. Inter-rater reliability was good for procedural skills (0.78) and team behavior (0.74) instruments. The intervention group demonstrated better procedural skills (71.6 versus 64.4) and teamwork behaviors (18.8 versus 16.2). The NICU program demonstrated better teamwork behaviors (18.6 versus 15.5) compared with non-NICU program. CONCLUSION: A simulation-enhanced booster session 9 months after NRP differentiates procedural skill and teamwork behavior at 15 months. Deliberate practice with simulation enhances teamwork behaviors additively with residents' clinical resuscitation exposure. PMID- 24762414 TI - Causes of hemolysis in neonates with extreme hyperbilirubinemia. AB - OBJECTIVE: We instituted a quality improvement process to enhance our capacity to diagnose genetic hemolytic conditions in neonates with extreme hyperbilirubinemia. STUDY DESIGN: During a 1-year period, whenever the total serum bilirubin (TSB) was >25 mg dl(-1) a special evaluation was performed. If we deemed an erythrocyte membrane defect likely, based on red blood cell morphology, EMA-flow cytometry was performed. Otherwise 'next-generation' sequencing was performed using a panel of genes involved in neonatal hyperbilirubinemia. RESULT: Ten neonates had a TSB ? 25 mg dl(-1). Two others were evaluated as part of this process at the request of their attending neonatologists, because each had a TSB >14 mg dl(-1) in the first hours after birth and required phototherapy for ? 1 week. Explanations for the jaundice were found in all 12 neonates. Five had hereditary spherocytosis, three of which also had ABO hemolytic disease. Two had pyruvate kinase deficiency. One had severe G6PD deficiency. The other four had ABO hemolytic disease. CONCLUSION: On the basis of the present small case series, we suggest that among neonates with extreme hyperbilirubinemia, it can be productive to pursue a genetic basis for hemolytic disease. PMID- 24762415 TI - Potential toxic effect of trifloxystrobin on cellular microstructure, mRNA expression and antioxidant enzymes in Chlorella vulgaris. AB - This study investigated the effects of trifloxystrobin that one strobilurin used widely in the world as an effective fungicidal agent to control Asian soybean rust on aquatic unicellular algae Chlorella vulgaris. We determined the potential toxic effect of trifloxystrobin on C. vulgaris, and found median inhibition concentration (IC(50)) value 255.58 (95% confidence interval, 207.81-330.29)MUgL( 1). In addition, the algal cells were obviously depressed or shrunk at different concentrations by electron microscopy. In the study, a real-time polymerase chain reaction (PCR) assay showed changes in transcript abundances of three photosynthetic genes, psaB, psbC, and rbcL, and one energy gene, ATPs. The results showed that trifloxystrobin reduced the transcript abundances of the three genes and enhanced expression of ATPs after 48 and 96 h. The lowest abundances of psaB, psbC and rbcL transcripts in response to trifloxystrobin exposure were 58%, 79% and 60% of those of the control, respectively. For the potential toxic influences, trifloxystrobin could decrease the soluble protein and total antioxidant contents (T-AOC), and increase superoxide dismutase (SOD) and peroxidase (POD) activity with a gradual concentration-response relationship. Overall, the present study demonstrated that trifloxystrobin could affect the activities of antioxidant enzymes, disrupts photosynthesis in C. vulgaris, and damage cellular structure. PMID- 24762416 TI - Early cellular responses against tributyltin chloride exposure in primary cultures derived from various brain regions. AB - Tributyltin (TBT) is a potent biocide and commonly used in various industrial sectors. Humans are mainly exposed through the food chain. We have previously demonstrated tin accumulation in brain following TBT-chloride (TBTC) exposure. In this study, effect of TBTC on dissociated cells from different brain regions was evaluated. Cytotoxicity assay (MTT), mode of cell death (Annexin V/PI assay), oxidative stress parameters (ROS and lipid peroxidation), reducing power of the cell (GSH), mitochondrial membrane potential (MMP) and intracellular Ca(2+) were evaluated to ascertain the effect of TBTC. Expression of glial fibrillary acidic protein (GFAP) was measured to understand the effect on astroglial cells. TBTC as low as 30 nM was found to reduce GSH levels, whereas higher doses of 300 and 3000 nM induced ROS generation and marked loss in cell viability mainly through apoptosis. Striatum showed higher susceptibility than other regions, which may have further implications on various neurological aspects. PMID- 24762418 TI - Use of medication prescribed for emotional or behavioral difficulties among children aged 6-17 years in the United States, 2011-2012. AB - Mental health problems are common chronic conditions in children (1-3). Medication is often prescribed to treat the symptoms of these conditions (4-7). Few population-based studies have examined the use of prescription medication to treat mental health problems among younger as well as older school-aged children (8-10). This report describes the sociodemographic characteristics of children aged 6-17 years prescribed medication or taking medication during the past 6 months for emotional or behavioral difficulties, and describes parental reports of the perceived benefit of this medication. PMID- 24762417 TI - A quality control mechanism coordinates meiotic prophase events to promote crossover assurance. AB - Meiotic chromosome segregation relies on homologous chromosomes being linked by at least one crossover, the obligate crossover. Homolog pairing, synapsis and meiosis specific DNA repair mechanisms are required for crossovers but how they are coordinated to promote the obligate crossover is not well understood. PCH-2 is a highly conserved meiotic AAA+-ATPase that has been assigned a variety of functions; whether these functions reflect its conserved role has been difficult to determine. We show that PCH-2 restrains pairing, synapsis and recombination in C. elegans. Loss of pch-2 results in the acceleration of synapsis and homolog dependent meiotic DNA repair, producing a subtle increase in meiotic defects, and suppresses pairing, synapsis and recombination defects in some mutant backgrounds. Some defects in pch-2 mutants can be suppressed by incubation at lower temperature and these defects increase in frequency in wildtype worms grown at higher temperature, suggesting that PCH-2 introduces a kinetic barrier to the formation of intermediates that support pairing, synapsis or crossover recombination. We hypothesize that this kinetic barrier contributes to quality control during meiotic prophase. Consistent with this possibility, defects in pch 2 mutants become more severe when another quality control mechanism, germline apoptosis, is abrogated or meiotic DNA repair is mildly disrupted. PCH-2 is expressed in germline nuclei immediately preceding the onset of stable homolog pairing and synapsis. Once chromosomes are synapsed, PCH-2 localizes to the SC and is removed in late pachytene, prior to SC disassembly, correlating with when homolog-dependent DNA repair mechanisms predominate in the germline. Indeed, loss of pch-2 results in premature loss of homolog access. Altogether, our data indicate that PCH-2 coordinates pairing, synapsis and recombination to promote crossover assurance. Specifically, we propose that the conserved function of PCH 2 is to destabilize pairing and/or recombination intermediates to slow their progression and ensure their fidelity during meiotic prophase. PMID- 24762424 TI - Voluntary water intake during and following moderate exercise in the cold. AB - Exercising in cold environments results in water losses, yet examination of resultant voluntary water intake has focused on warm conditions. The purpose of the study was to assess voluntary water intake during and following exercise in a cold compared with a warm environment. Ten healthy males (22 +/- 2 years, 67.8 +/ 7.0 kg, 1.77 +/- 0.06 m, VO2peak 60.5 +/- 8.9 ml.kg-1.min-1) completed two trials (7-8 days). In each trial subjects sat for 30 min before cycling at 70% VO2peak (162 +/- 27W) for 60 min in 25.0 +/- 0.1 degrees C, 50.8 +/- 1.5% relative humidity (RH; warm) or 0.4 +/- 1.0 degrees C, 68.8 +/- 7.5% RH (cold). Subjects then sat for 120 min at 22.2 +/- 1.2 degrees C, 50.5 +/- 8.0% RH. Ad libitum drinking was allowed during the exercise and recovery periods. Urine volume, body mass, serum osmolality, and sensations of thirst were measured at baseline, postexercise and after 60 and 120 min of the recovery period. Sweat loss was greater in the warm trial (0.96 +/- 0.18 l v 0.48 +/- 0.15 l; p < .0001) but body mass losses over the trials were similar (1.15 +/- 0.34% (cold) v 1.03 +/- 0.26% (warm)). More water was consumed throughout the duration of the warm trial (0.81 +/- 0.42 l v 0.50 +/- 0.49 l; p = .001). Cumulative urine output was greater in the cold trial (0.81 +/- 0.46 v 0.54 +/- 0.31 l; p = .036). Postexercise serum osmolality was higher compared with baseline in the cold (292 +/- 2 v 287 +/- 3 mOsm.kg-1, p < .0001) and warm trials (288 +/- 5 v 285 +/- 4 mOsm.kg-1; p = .048). Thirst sensations were similar between trials (p > .05). Ad libitum water intake adjusted so that similar body mass losses occurred in both trials. In the cold there appeared to a blunted thirst response. PMID- 24762431 TI - Gender differences in attitudes and beliefs associated with bystander behavior and sexual assault. AB - Sexual violence is a significant problem on many college campuses. Bystander education programs have been found to train individuals to act to prevent sexual and partner violence and improve the responses of peers to survivors. Limited evidence suggests that gender differences exist between males and females regarding both attitudes toward, and use of, bystander behavior, with females reporting more supportive attitudes and greater use of bystander behavior. The purpose of this study is to compare male and female college students on attitudes toward date rape, bystander efficacy, intention to act as a bystander, and actual use of bystander behaviors. A secondary aim explored gender differences in theoretically driven bystander behaviors and barriers to acting as a bystander. A convenience sample of 157 full-time undergraduate students aged 18-24 years completed survey measures of attitudes related to sexual and partner violence and willingness to help. Analysis of variance and chi-square were used to compare gender differences in scores. Significant gender differences were found for date rape attitudes, efficacy, and intention to act as a positive bystander. Men reported more rape-supportive attitudes and greater intention to act as a bystander than women, whereas women reported greater levels of bystander efficacy than men. The findings can be used in tailoring gender-specific components of bystander education programs for sexual assault prevention and intervention. PMID- 24762432 TI - Detection of hydrogen sulfide through photoluminescence quenching of penicillamine-copper nanocluster aggregates. AB - We have developed a one-pot, inexpensive, simple and rapid method to synthesize photoluminescent copper nanocluster (Cu NC) aggregates from Cu(2+) ions in 65% (v v(-1)) dimethylformamide aqueous solution containing penicillamine (PA) as a capping and reducing agent. As-prepared PA-Cu NC aggregates emit at 580 nm when excited at 326 nm, with a quantum yield of 2.0%. The photoluminescence of PA-Cu NC aggregates originate from ligand-to-metal charge transfer, which is supported by a long lifetime (126.5 ns) and a large Stokes shift (254 nm). As-prepared PA Cu NC aggregates have different emission wavelengths with the same excitation wavelength in various organic-aqueous solutions. The PA-Cu NC aggregates are highly selective and sensitive to the detection of hydrogen sulfide (H2S), based on analyte-induced photoluminescence quenching through the formation of CuS nanoparticles. The probe allows the detection of H2S, with a linear range of 1 100 MUM and a limit of detection (signal-to-noise ratio = 3) of 500 nM. The practicality of this probe has been validated through the analysis of hot spring water samples. PMID- 24762433 TI - Intermediate-band dynamics of quantum dots solar cell in concentrator photovoltaic modules. AB - We report for the first time a successful fabrication and operation of an InAs/GaAs quantum dot based intermediate band solar cell concentrator photovoltaic (QD-IBSC-CPV) module to the IEC62108 standard with recorded power conversion efficiency of 15.3%. Combining the measured experimental results at Underwriters Laboratory (UL(r)) licensed testing laboratory with theoretical simulations, we confirmed that the operational characteristics of the QD-IBSC-CPV module are a consequence of the carrier dynamics via the intermediate-band at room temperature. PMID- 24762434 TI - Estrogen promotes Leydig cell engulfment by macrophages in male infertility. AB - Male infertility accounts for almost half of infertility cases worldwide. A subset of infertile men exhibit reduced testosterone and enhanced levels of estradiol (E2), though it is unclear how increased E2 promotes deterioration of male fertility. Here, we utilized a transgenic mouse strain that overexpresses human CYP19, which encodes aromatase (AROM+ mice), and mice with knockout of Esr1, encoding estrogen receptor alpha (ERalphaKO mice), to analyze interactions between viable Leydig cells (LCs) and testicular macrophages that may lead to male infertility. In AROM+ males, enhanced E2 promoted LC hyperplasia and macrophage activation via ERalpha signaling. E2 stimulated LCs to produce growth arrest-specific 6 (GAS6), which mediates phagocytosis of apoptotic cells by bridging cells with surface exposed phosphatidylserine (PS) to macrophage receptors, including the tyrosine kinases TYRO3, AXL, and MER. Overproduction of E2 increased apoptosis-independent extrusion of PS on LCs, which in turn promoted engulfment by E2/ERalpha-activated macrophages that was mediated by AXL-GAS6-PS interaction. We further confirmed E2-dependant engulfment of LCs by real-time 3D imaging. Furthermore, evaluation of molecular markers in the testes of patients with nonobstructive azoospermia (NOA) revealed enhanced expression of CYP19, GAS6, and AXL, which suggests that the AROM+ mouse model reflects human infertility. Together, these results suggest that GAS6 has a potential as a clinical biomarker and therapeutic target for male infertility. PMID- 24762435 TI - Mesenchymal gene program-expressing ovarian cancer spheroids exhibit enhanced mesothelial clearance. AB - Metastatic dissemination of ovarian tumors involves the invasion of tumor cell clusters into the mesothelial cell lining of peritoneal cavity organs; however, the tumor-specific factors that allow ovarian cancer cells to spread are unclear. We used an in vitro assay that models the initial step of ovarian cancer metastasis, clearance of the mesothelial cell layer, to examine the clearance ability of a large panel of both established and primary ovarian tumor cells. Comparison of the gene and protein expression profiles of clearance-competent and clearance-incompetent cells revealed that mesenchymal genes are enriched in tumor populations that display strong clearance activity, while epithelial genes are enriched in those with weak or undetectable activity. Overexpression of transcription factors SNAI1, TWIST1, and ZEB1, which regulate the epithelial-to mesenchymal transition (EMT), promoted mesothelial clearance in cell lines with weak activity, while knockdown of the EMT-regulatory transcription factors TWIST1 and ZEB1 attenuated mesothelial clearance in ovarian cancer cell lines with strong activity. These findings provide important insights into the mechanisms associated with metastatic progression of ovarian cancer and suggest that inhibiting pathways that drive mesenchymal programs may suppress tumor cell invasion of peritoneal tissues. PMID- 24762436 TI - Epigenetic reprogramming induces the expansion of cord blood stem cells. AB - Cord blood (CB) cells that express CD34 have extensive hematopoietic capacity and rapidly divide ex vivo in the presence of cytokine combinations; however, many of these CB CD34+ cells lose their marrow-repopulating potential. To overcome this decline in function, we treated dividing CB CD34+ cells ex vivo with several histone deacetylase inhibitors (HDACIs). Treatment of CB CD34+ cells with the most active HDACI, valproic acid (VPA), following an initial 16-hour cytokine priming, increased the number of multipotent cells (CD34+CD90+) generated; however, the degree of expansion was substantially greater in the presence of both VPA and cytokines for a full 7 days. Treated CD34+ cells were characterized based on the upregulation of pluripotency genes, increased aldehyde dehydrogenase activity, and enhanced expression of CD90, c-Kit (CD117), integrin alpha6 (CD49f), and CXCR4 (CD184). Furthermore, siRNA-mediated inhibition of pluripotency gene expression reduced the generation of CD34+CD90+ cells by 89%. Compared with CB CD34+ cells, VPA-treated CD34+ cells produced a greater number of SCID-repopulating cells and established multilineage hematopoiesis in primary and secondary immune-deficient recipient mice. These data indicate that dividing CB CD34+ cells can be epigenetically reprogrammed by treatment with VPA so as to generate greater numbers of functional CB stem cells for use as transplantation grafts. PMID- 24762437 TI - Intrinsic TGF-beta signaling promotes age-dependent CD8+ T cell polyfunctionality attrition. AB - Advanced age is associated with immune system deficits that result in an increased susceptibility to infectious diseases; however, specific mediators of age-dependent immune dysfunction have not been fully elucidated. Here we demonstrated that aged mice exhibit poor effector CD8+ T cell polyfunctionality, primarily due to CD8+ T cell-extrinsic deficits, and that reduced CD8+ T cell polyfunctionality correlates with increased susceptibility to pathogenic diseases. In aged animals challenged with the parasite Encephalitozoon cuniculi, effector CD8+ T cell survival and polyfunctionality were suppressed by highly elevated TGF-beta1. Furthermore, TGF-beta depletion reduced effector CD8+ T cell apoptosis in both young and aged mice and enhanced effector CD8+ T cell polyfunctionality in aged mice. Surprisingly, intrinsic blockade of TGF-beta signaling in CD8+ T cells was sufficient to rescue polyfunctionality in aged animals. Together, these data demonstrate that low levels of TGF-beta1 promote apoptosis of CD8+ effector T cells and high TGF-beta1 levels associated with age result in both CD8+ T cell apoptosis and an altered transcriptional profile, which correlates with loss of polyfunctionality. Furthermore, elevated TGF-beta levels are observed in the elderly human population and in aged Drosophila, suggesting that TGF-beta represents an evolutionarily conserved negative regulator of the immune response in aging organisms. PMID- 24762438 TI - The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. AB - The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1alpha and HIF, respectively. In normoxia, AMPK induces PGC 1alpha, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dube (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1alpha-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK dependent HIF activation and the subsequent Warburg metabolic transformation. PMID- 24762439 TI - Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination. AB - Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3beta (GSK3beta) in nerves of mutant mice. Treatment with GSK3beta inhibitors, lithium, or 4-benzyl-2-methyl 1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling. PMID- 24762440 TI - ZEB1 sensitizes lung adenocarcinoma to metastasis suppression by PI3K antagonism. AB - Epithelial tumor cells that have undergone epithelial-to-mesenchymal transition (EMT) are typically prone to metastasis and drug resistance and contribute to a poor clinical outcome. The transcription factor ZEB1 is a known driver of EMT, and mediators of ZEB1 represent potential therapeutic targets for metastasis suppression. Here, we have shown that phosphatidylinositol 3-kinase-targeted (PI3K-targeted) therapy suppresses metastasis in a mouse model of Kras/Tp53 mutant lung adenocarcinoma that develops metastatic disease due to high expression of ZEB1. In lung adenocarcinoma cells from Kras/Tp53-mutant animals and human lung cancer cell lines, ZEB1 activated PI3K by derepressing miR-200 targets, including amphiregulin (AREG), betacellulin (BTC), and the transcription factor GATA6, which stimulated an EGFR/ERBB2 autocrine loop. Additionally, ZEB1 dependent derepression of the miR-200 and miR-183 target friend of GATA 2 (FOG2) enhanced GATA3-induced expression of the p110alpha catalytic subunit of PI3K. Knockdown of FOG2, p110alpha, and RHEB ameliorated invasive and metastatic propensities of tumor cells. Surprisingly, FOG2 was not required for mesenchymal differentiation, suggesting that mesenchymal differentiation and invasion are distinct and separable processes. Together, these results indicate that ZEB1 sensitizes lung adenocarcinoma cells to metastasis suppression by PI3K-targeted therapy and suggest that treatments to selectively modify the metastatic behavior of mesenchymal tumor cells are feasible and may be of clinical value. PMID- 24762442 TI - The association between time spent in vigorous physical activity and dietary patterns in adolescents: a cross-sectional study. AB - BACKGROUND: Physical activity interventions targeting weight status have yielded mixed results. This variability may be attributed to compensatory changes in dietary patterns after increasing physical activity (PA) levels. Therefore, we sought to determine whether dietary patterns varied with time spent in vigorous intensity PA in youth. METHODS: Cross-sectional analysis of 330 youth enrolled in a school-based prospective cohort in central Alberta. Physical activity was assessed with waist mounted accelerometers (Actical) worn for 7 days. Main outcomes included consumption of unhealthy foods and the unhealthy food index obtained from a validated web-based 24-hour dietary recall instrument. Secondary outcomes included macronutrient intake, food group (Canada's Food Guide to Healthy Eating) intake, and diet quality. RESULTS: Compared with youth participating in < 7 min/ day of vigorous physical activity, those achieving >= 7 min/day displayed no change in healthy or unhealthy food consumption. However, linear regression suggests a modest association between diet quality and vigorous intensity PA. CONCLUSION: These data demonstrate that in this cohort of Canadian youth, time spent being physically active is associated with healthier dietary patterns and not with increased consumption of unhealthy foods. PMID- 24762441 TI - Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. AB - Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GLP1 analogs, it remains unclear whether the glucose- and body weight-lowering effects of long-acting GLP1R agonists are via direct action on CNS GLP1R or the result of downstream activation of afferent neuronal GLP1R. We generated mice with either neuronal or visceral nerve-specific deletion of Glp1r and then administered liraglutide, a long-acting GLP1R agonist. We found that neither reduction of GLP1R in the CNS nor in the visceral nerves resulted in alterations in body weight or food intake in animals fed normal chow or a high fat diet. Liraglutide treatment provided beneficial glucose-lowering effects in both chow- and high-fat-fed mice lacking GLP1R in the CNS or visceral nerves; however, liraglutide was ineffective at altering food intake, body weight, or causing a conditioned taste aversion in mice lacking neuronal GLP1R. These data indicate that neuronal GLP1Rs mediate body weight and anorectic effects of liraglutide, but are not required for glucose-lowering effects. PMID- 24762444 TI - Effectiveness of collage activity based on a life review in elderly cancer patients: A preliminary study. AB - OBJECTIVE: Much of the cancer rehabilitation research that has been conducted has consisted of relatively early recovery-of-function rehabilitation, and little attention has been paid to the psychosocial aspects of palliative rehabilitation. The aim of the present preliminary study was to examine the "narratives" of elderly cancer patients that emerged as a result of a life review performed in association with collage activity and to assess the effectiveness of this intervention. METHOD: We conducted a collage activity based on a life review in two sessions. Some 11 cancer patients who were 65 years of age or older and receiving palliative care participated. Evaluations using the Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-Sp) Scale, the Hospital Anxiety and Depression Scale (HADS), and the Self-Efficacy Scale for Terminal Cancer (SESTC) were administered before and immediately after the intervention. RESULTS: The mean scores for the FACIT-Sp and affect regulation efficacy on the SESTC significantly increased, while the mean HADS score significantly decreased. Regarding the impressions after completion of the intervention, generally favorable evaluations were heard from families and medical staff members as well as from the subjects. SIGNIFICANCE OF RESULTS: A collage activity based on a life review may be effective for improving spiritual well-being, mitigating anxiety and depression, and improving self-efficacy. The collage itself was also useful in facilitating interactions with others, including family members, and the activity provided psychological support for families. PMID- 24762448 TI - Dietary availability in elderly Portuguese households. AB - OBJECTIVE: To identify dietary availability and its time trends in elderly Portuguese households. DESIGN: A set of four cross-sectional studies based on the Household Budget Surveys was used. The dietary data were described using the daily per capita availability of food and beverages, energy and selected nutrients (macronutrients, different lipid fractions and simple sugars). Differences between elderly household types and time trends were studied. SETTING: Portuguese Household Budget Survey data from 1989/1990, 1994/1995, 2000/2001 and 2005/2006. SUBJECTS: Households with members aged >=65 years were selected and categorized as solitary elderly female, solitary elderly male or couple (composed of one elderly female and one elderly male). RESULTS: While cereals, fats/oils, potatoes and sugar/sugar products decreased, an increase occurred in milk/milk products, fruits, bottled water, fruit/vegetable juices and soft drinks (P<0.05). The highest values for foods and beverages were mostly found in couples, while the lowest ones were from solitary males. Exceptions were observed for cereals, eggs, milk/milk products, vegetables, fruits and non alcoholic beverages, higher in solitary females; and for sugar/sugar products and alcoholic beverages, higher in solitary males. Over time, total energy and carbohydrates decreased while proteins and saturated fatty acids increased (P<0.001). Lipids increased in solitary males and couples (P<0.05). Simple sugars increased in solitary males but decreased in solitary females and couples (P<0.05). CONCLUSIONS: The increases in fruits and vegetables in solitary females accord with a healthier food pattern, but overall imbalances in the macronutrient profile for all elderly households may imply a decreasing diet quality. PMID- 24762449 TI - Analytic bond-order potentials for the bcc refractory metals Nb, Ta, Mo and W. AB - Bond-order potentials (BOPs) are based on the tight-binding approximation for determining the energy of a system of interacting atoms. The bond energy and forces are computed analytically within the formalism of the analytic BOPs. Here we present parametrizations of the analytic BOPs for the bcc refractory metals Nb, Ta, Mo and W. The parametrizations are optimized for the equilibrium bcc structure and tested for atomic environments far from equilibrium that had not been included in the fitting procedure. These tests include structural energy differences for competing crystal structures; tetragonal, trigonal, hexagonal and orthorhombic deformation paths; formation energies of point defects as well as phonon dispersion relations. Our tests show good agreement with available experimental and theoretical data. In practice, we obtain the energetic ordering of vacancy, [1 1 1], [1 1 0], and [1 0 0] self-interstitial atom in agreement with density functional theory calculations. PMID- 24762450 TI - Inflammation, ageing and chronic disease. AB - Acute inflammatory responses are essential for pathogen control and tissue repair but can also cause severe collateral damage. Tight regulation of the response is required to minimize host injury, but in the face of chronic infections and age associated immune dysregulation, inflammatory processes may exert multiple detrimental effects on the organism. The signs of low level systemic inflammation commonly detectable in elderly people are associated with many chronic diseases of ageing and may even contribute to their causation. The purpose of this article is to review recent literature from the past two years providing new data on the inter-relationships between inflammatory status and chronic diseases of ageing. PMID- 24762451 TI - Free fatty acid receptor 3 is a key target of short chain fatty acid. What is the impact on the sympathetic nervous system? AB - Nervous system (NS) activity participates in metabolic homeostasis by detecting peripheral signal molecules derived from food intake and energy balance. High quality diets are thought to include fiber-rich foods like whole grain rice, breads, cereals, and grains. Several studies have associated high consumption of fiber-enriched diets with a reduced risk of diabetes, obesity, and gastrointestinal disorders. In the lower intestine, anaerobic fermentation of soluble fibers by microbiota produces short chain fatty acids (SCFAs), key energy molecules that have a recent identified leading role in the intestinal gluconeogenesis, promoting beneficial effects on glucose tolerance and insulin resistance. SCFAs are also signaling molecules that bind to specific G-protein coupled receptors (GPCRs) named Free Fatty Acid Receptor 3 (FFA3, GPR41) and 2 (FFA2, GPR43). However, how SCFAs impact NS activity through their GPCRs is poorly understood. Recently, studies have demonstrated the presence of FFA2 and FFA3 in the sympathetic NS of rat, mouse and human. Two studies have showed that FFA3 activation by SCFAs increases firing and norepinephrine (NE) release from sympathetic neurons. However, the recent study from the Ikeda Laboratory revealed that activation of FFA3 by SCFAs impairs N-type calcium channel (NTCC) activity, which contradicts the idea of FFA3 activation leading to increased action potential evoked NE release. Here we will discuss the scope of the latter study and the putative physiological role of SCFAs and FFAs in the sympathetic NS. PMID- 24762452 TI - Bilateral Central Retinal Vein Occlusion in a patient with Ulcerative Colitis and Antiphospholipid Antibody Syndrome. PMID- 24762454 TI - Revisiting infant gastroesophageal reflux disease guidelines: considering obesity. PMID- 24762453 TI - Provider awareness alone does not improve transition readiness skills in adolescent patients with inflammatory bowel disease. AB - OBJECTIVE: Adolescent patients with chronic health conditions must gradually assume responsibility for their health. Self-management skills are needed for a successful transfer from adolescent to adult health care, but the development of these skills could be resource intensive. Pediatric providers are already instrumental in teaching patients about their health and may improve these skills. The aim of the study was to evaluate whether informal education of pediatric providers regarding transition improves inflammatory bowel disease (IBD) patient self-management skills. METHODS: Consecutive patients with IBD older than 10 years who presented to the outpatient setting were administered a survey regarding self-management behaviors in 2008 and 2011. During this time, several conferences on transition were presented to the providers. RESULTS: In 2008, 294 patients completed the survey (82%) compared with 121 patients (89%) in 2011. The patient groups were comparable with respect to sex (boys 50% vs 42%), mean age (16.7 vs 16.2 years), and type of IBD (Crohn 68% vs 66%). The 13- to 15 year-olds reported calling in refills (11%, 8%, respectively), scheduling clinic appointment (0, 1%), preparing questions (13%, 5%), and taking the main role in talking during clinic visits (15%, 24%). The 16- to 18-year-olds reported calling in refills (13%, 27%), scheduling clinic appointments (9%, 6%), preparing questions (9%, 16%), and taking the main role in talking in clinic visits (36%, 45%). Responsibility for behaviors gradually increases with age, but did not differ significantly between 2008 and 2011. CONCLUSIONS: Increasing awareness around transition readiness for pediatric providers had an insignificant effect on the self-management skills of patients with IBD. A more formal or structured approach is likely required to improve transition skills in adolescent patients. PMID- 24762455 TI - Celiac Disease in a Child Presenting With Recurrent Rectal Prolapse. PMID- 24762456 TI - Extensive Thoracic Injury From Button Battery Ingestion. PMID- 24762457 TI - Role of pediatric endoscopic retrograde cholangiopancreatography in an era stressing less-invasive imaging modalities. AB - BACKGROUND: The significance of pediatric endoscopic retrograde cholangiopancreatography (ERCP) according to age or disease variation is inconclusive. This study aimed to evaluate the usefulness of pediatric ERCP in diagnosing or treating small children with pancreaticobiliary disorders, including choledochal cyst (CC) and biliary atresia (BA). METHODS: From 1980 to 2011, 235 ERCPs were performed in 220 pediatric patients (median age, 2 years) at our institution. Underlying pathology was CC in 92 patients (3 years), BA in 62 patients (55 days), and others in 66 patients. Success and complication rates, and ERCP findings were retrospectively analyzed. RESULTS: The overall success rate was 96%. Rates for individual pathologies were 99% for CC, 92% for BA, and 96% for others. The success rate was 100% among children >3 years, but 92% when limited to infants. Post-ERCP hyperamylasemia and duodenal perforation occurred in 9% and 0.4% of cases, respectively. Regarding preoperative evaluation of the pancreaticobiliary system in CC, ERCP clearly delineated pancreaticobiliary maljunction (79%) and the pancreatic duct (94%), whereas it visualized the common bile duct and intrahepatic bile duct at relatively low rates (77% and 33%, respectively). ERCP successfully identified 16 cases (18%) with non-BA of 90 patients with suspected BA. Moreover, ERCP demonstrated only pancreatic duct in 70% of all BA. CONCLUSIONS: ERCP among children including infants with CC and BA can be performed with fairly satisfactory results. Although pediatric ERCP can also help describe the pancreaticobiliary system in detail, its indication should be deliberately considered when anatomical information from less-invasive imaging modalities is insufficient. PMID- 24762458 TI - Do pediatricians apply the 2009 NASPGHAN-ESPGHAN guidelines for the diagnosis and management of gastroesophageal reflux after being trained? AB - BACKGROUND: According to a recent survey, the 2009 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition-European Society for Pediatric Gastroenterology, Hepatology, and Nutrition gastroesophageal reflux guidelines are poorly adhered to by European primary care pediatricians. The main issue raised from the survey was the prescription of unnecessary acid suppressive medications, especially in infants. No inquiry into the reasons was made. The primary objective of the present study was to assess the applicability of the guidelines in European primary care pediatricians undergoing specific trainings. METHODS: One hundred pediatricians involved in the previous survey agreed to participate and were randomly divided into 2 groups: one group was trained in the guidelines through an online podcast and the other group was trained through a synopsis. During the following 3 months, each involved pediatrician was asked to enroll every consecutive infant, child, or adolescent with suggestive reflux symptoms. For every enrolled patient, pediatricians filled in a report concerning their diagnostic and therapeutic choices. RESULTS: A total of 382 patients (boys/girls 186/196, infants/children/adolescents 194/123/65) were enrolled by pediatricians. Infants with unexplained crying and/or distressed behavior who were prescribed proton-pump inhibitors were 3.7% compared with 45.2% of the survey data obtained before the training (P < 0.05). Infants with uncomplicated recurrent regurgitation and vomiting who were prescribed proton-pump inhibitors were 4.5% against 37.1% of the baseline survey data (P < 0.05). The overall rate of children managed in full compliance with the guidelines was 46.1% after the training compared with 1.8% before the training (P < 0.05). No significant differences were seen between pediatricians from podcast and synopsis group. CONCLUSIONS: The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition-European Society for Pediatric Gastroenterology, Hepatology, and Nutrition gastroesophageal reflux guidelines have good applicability, despite that they are presently poorly adhered to by European primary care pediatricians. Simple, inexpensive trainings were proven to be effective in increasing adherence by pediatricians. The increase in compliance clearly favors the role of continuous medical education through simple educational tools and subsequent assessment of practice. PMID- 24762459 TI - Validity and reliability of the Japanese version of the Newest Vital Sign: a preliminary study. AB - Health literacy (HL) refers to the ability to obtain, process, and understand basic health information and services, and is thus needed to make appropriate health decisions. The Newest Vital Sign (NVS) is comprised of 6 questions about an ice cream nutrition label and assesses HL numeracy skills. We developed a Japanese version of the NVS (NVS-J) and evaluated the validity and reliability of the NVS-J in patients with chronic pain. The translation of the original NVS into Japanese was achieved as per the published guidelines. An observational study was subsequently performed to evaluate the validity and reliability of the NVS-J in 43 Japanese patients suffering from chronic pain. Factor analysis with promax rotation, using the Kaiser criterion (eigenvalues >=1.0), and a scree plot revealed that the main component of the NVS-J consists of three determinative factors, and each factor consists of two NVS-J items. The criterion-related validity of the total NVS-J score was significantly correlated with the total score of Ishikawa et al.'s self-rated HL Questionnaire, the clinical global assessment of comprehensive HL level, cognitive function, and the Brinkman index. In addition, Cronbach's coefficient for the total score of the NVS-J was adequate (alpha = 0.72). This study demonstrated that the NVS-J has good validity and reliability. Further, the NVS-J consists of three determinative factors: "basic numeracy ability," "complex numeracy ability," and "serious-minded ability." These three HL abilities comprise a 3-step hierarchical structure. Adequate HL should be promoted in chronic pain patients to enable coping, improve functioning, and increase activities of daily living (ADLs) and quality of life (QOL). PMID- 24762461 TI - Use of microsomal triglyceride transfer protein inhibitors in patients with homozygous familial hypercholesterolemia: translating clinical trial experience into clinical practice. AB - Homozygous familial hypercholesterolemia (HoFH) is associated with severe hypercholesterolemia and premature cardiovascular morbidity and mortality. The most frequent cause of HoFH is loss of function mutations in the gene for the low density lipoprotein receptor, resulting in reduced clearance of low-density lipoprotein (LDL) cholesterol from the circulation. Patients with HoFH have attenuated responsiveness to lipidlowering therapies such as statins, cholesterol absorption inhibition, and bile acid binding resins because of impaired LDL receptor expression. Lomitapide is a novel microsomal triglyceride transfer protein inhibitor that does not depend on the ability to upregulate LDL receptors on the surface of hepatocytes. Lomitapide reduces production of apolipoprotein B containing lipoproteins, significantly reduces serum levels of LDL cholesterol, and is approved for use in patients with HoFH in the United States and the European Union. PMID- 24762460 TI - Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes? AB - Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease. PMID- 24762463 TI - Reassessing the importance of complete versus incomplete coronary revascularization. AB - Coronary revascularization may be performed for relief of anginal symptoms or, in specific patient subgroups, to reduce the incidence of myocardial infarction and mortality. Achieving complete revascularization of all significantly obstructed coronary segments has been an established goal of coronary bypass graft surgery (CABG) and more recent data demonstrate a salutary effect of complete revascularization following percutaneous coronary intervention (PCI) on long-term clinical outcomes as well. Incomplete coronary revascularization is associated with increased mortality following both CABG and PCI, as well as with an increased incidence of myocardial infarction, repeat revascularization, and major adverse cardiovascular or cerebrovascular events following PCI. The relationship between completeness of revascularization and late adverse clinical outcomes is both qualitative and quantitative as reflected by the residual SYNTAX score (angiographic lesion complexity) following PCI. Thus, complete revascularization has evolved as an important objective for either CABG or PCI and the ability to achieve complete revascularization should enter into the decision algorithm for choice of revascularization modality. PMID- 24762462 TI - Acute and chronic cardiovascular effects of hyperkalemia: new insights into prevention and clinical management. AB - The plasma pool of potassium is a partial reflection of the overall body, transient cellular shifts, and potassium elimination regulated by the kidneys. Potassium concentrations elevating above the upper limit of normal (> 5.0 mEq/L) have become more common in cardiovascular practice due to the growing population of patients with chronic kidney disease and the broad applications of drugs that modulate potassium excretion by either reducing production of angiotensin II (angiotensin-converting enzyme inhibitors, direct renin inhibitors, beta adrenergic receptor antagonists), blocking angiotensin II receptors (angiotensin receptor blockers), or antagonizing the action of aldosterone on mineralocorticoid receptors (mineralocorticoid receptor antagonists). In addition, acute kidney injury, critical illness, crush injuries, and massive red blood cell transfusions can result in hyperkalemia. Progressively more severe elevations in potassium are responsible for abnormalities in cardiac depolarization and repolarization and contractility. Untreated severe hyperkalemia results in sudden cardiac death. Traditional management steps have included reducing dietary potassium and discontinuing potassium supplements; withdrawal of exacerbating drugs; acute treatment with intravenous calcium gluconate, insulin, and glucose; nebulized albuterol; correction of acidosis with sodium bicarbonate for short-term shifts out of the plasma pool; and, finally, gastrointestinal ion exchange with oral sodium polystyrene sulfonate in sorbitol, which is mainly used in the hospital and is poorly tolerated due to gastrointestinal adverse effects. This review explores hyperkalemia as a complication in cardiovascular patients and highlights new acute, chronic, and preventative oral therapies (patiromer calcium, cross-linked polyelectrolyte, ZS 9) that could potentially create a greater margin of safety for vulnerable patients with combined heart and kidney disease. PMID- 24762464 TI - Emerging treatment options for refractory angina pectoris: ranolazine, shock wave treatment, and cell-based therapies. AB - A challenge of modern cardiovascular medicine is to find new, effective treatments for patients with refractory angina pectoris, a clinical condition characterized by severe angina despite optimal medical therapy. These patients are not candidates for surgical or percutaneous revascularization. Herein we review the most up-to-date information regarding the modern approach to the patient with refractory angina pectoris, from conventional medical management to new medications and shock wave therapy, focusing on the use of endothelial precursor cells (EPCs) in the treatment of this condition. Clinical limitations of the efficiency of conventional approaches justify the search for new therapeutic options. Regenerative medicine is considered the next step in the evolution of organ replacement therapy. It is driven largely by the same health needs as transplantation and replacement therapies, but it aims further than traditional approaches, such as cell-based therapy. Increasing knowledge of the role of circulating cells derived from bone marrow (EPCs) on cardiovascular homeostasis in physiologic and pathologic conditions has prompted the clinical use of these cells to relieve ischemia. The current state of therapeutic angiogenesis still leaves many questions unanswered. It is of paramount importance that the treatment is delivered safely. Direct intramyocardial and intracoronary administration has demonstrated acceptable safety profiles in early trials, and may represent a major advance over surgical thoracotomy. The combined efforts of bench and clinical researchers will ultimately answer the question of whether cell therapy is a suitable strategy for treatment of patients with refractory angina. PMID- 24762465 TI - Prevention and treatment of no-reflow phenomenon by targeting the coronary microcirculation. AB - The coronary no-reflow phenomenon refers to the post-percutaneous coronary intervention (PCI) state in which, despite successful revascularization of the epicardial conduit coronary arteries, substantial regions of the myocardium do not receive adequate perfusion. In most cases, the underlying mechanism can be attributed to alterations in the microvascular circulation caused by factors intrinsic or extrinsic to the coronary microcirculation. Because the no-reflow phenomenon is associated with poor clinical outcomes, it is of great importantance to identify and apply effective strategies for reducing post-PCI morbidity and mortality. Successful prevention strategies aim to ad dress increased vasoreactivity, intravascular platelet aggregation, microvascular inflammation, and down-stream plaque particle embolization. This review provides an updated overview on the pathomechanism of no-reflow and the current available prevention strategies from the perspective of coronary microcirculation. Although large randomized clinical trials have not yet identified any effective treatment, studying the coronary microcirculation may reveal new therapeutic targets for successful amelioration of the adverse clinical consequences from no-reflow phenomenon. PMID- 24762467 TI - Notes from the American College of Cardiology board of governors meeting. PMID- 24762466 TI - L-carnitine for the treatment of acute myocardial infarction. AB - Although the therapeutic strategies available for treating acute myocardial infarction (AMI) have evolved dramatically in recent decades, coronary artery disease remains the leading cause of death in our society, and the rates of recurrent myocardial infarction and mortality are still unacceptably high. Therefore, exploration of alternative therapeutic strategies for AMI is of utmost importance. One such strategy is to target metabolic pathways via L-carnitine supplementation. L-carnitine is a physiologically essential metabolic cofactor that has been shown to provide a plethora of benefits when administered after AMI. L-carnitine has been shown to lessen infarct size, to reduce ventricular arrhythmias, left ventricular dilation, and heart failure incidence, as well as improve survival. These benefits may, in part, be related to its ability to boost glucose oxidation in ischemic tissues, while moderating increases in fatty acyl coenzyme A levels that can impair mitochondrial efficiency and promote oxidative stress and inflammation. This article summarizes the evidence pertinent to the therapeutic use of L-carnitine for AMI. PMID- 24762468 TI - Who should be at the helm? A discussion on team-based care. PMID- 24762469 TI - Left main coronary artery perforation during percutaneous coronary intervention in a patient with noninfectious aortitis. AB - Noninfectious aortitis is increasingly recognized as an important cause of aortic aneurysms and dissection. Coronary involvement in noninfectious aortitis has been reported in several case reports and is marked by a high mortality. Here, we describe the case of a 72-year-old patient suffering from aortitis with involvement of the left main coronary artery trunk, who underwent percutaneous coronary intervention (PCI), which was complicated by left coronary artery perforation. Active inflammatory disease of the vessel wall may cause excessive tissue frailty and therefore has to be considered as a risk factor for perforation during PCI. PMID- 24762470 TI - Evaluation of long-term cardiovascular effects. PMID- 24762471 TI - Nonischemic dilated cardiomyopathy. PMID- 24762472 TI - Sulphonylurea usage in melioidosis is associated with severe disease and suppressed immune response. AB - BACKGROUND: Melioidosis is a problem in the developing tropical regions of Southeast Asia and Northern Australia where the the Gram negative saprophytic bacillus Burkholderia pseudomallei is endemic with the risk of fulminant septicaemia. While diabetes mellitus is a well-established risk factor for melioidiosis, little is known if specific hypoglycemic agents may differentially influence the susceptibility and clinical course of infection with B. pseudomallei (Bp). METHODOLOGY/PRINCIPAL FINDINGS: In this cohort study, patients with pre-existing diabetes and melioidosis were retrospectively studied. OUTCOME MEASURES: mortality, length of stay and development of complications (namely hypotension, intubation, renal failure and septicaemia) were studied in relation to prior diabetic treatment regimen. Peripheral blood mononuclear cells (PBMC) from diabetic patients and healthy PBMC primed with metformin, glyburide and insulin were stimulated with purified Bp antigens in vitro. Immune response and specific immune pathway mediators were studied to relate to the clinical findings mechanistically. Of 74 subjects, 44 (57.9%) had sulphonylurea-containing diabetic regimens. Patient receiving sulphonylureas had more severe septic complications (47.7% versus 16.7% p = 0.006), in particular, hypotension requiring intropes (p = 0.005). There was also a trend towards increased mortality in sulphonylurea users (15.9% versus 3.3% p = 0.08). In-vitro, glyburide suppressed inflammatory cytokine production in a dose-dependent manner. An effect of the drug was the induction of IL-1R-associated kinase-M at the level of mRNA transcription. CONCLUSION/SIGNIFICANCE: Sulphonylurea treatment results in suppression of host inflammatory response and may put patients at higher risk for adverse outcomes in melioidosis. PMID- 24762473 TI - Fabrication of highly ordered/switchable polymer nanogratings for nano-actuators using nanoimprint lithography. AB - Polymer micro/nano-actuators are attracting tremendous interest due to their potential applications in micro/nano-mechanical systems and lab-on-a-chip systems. To achieve this, thin films of stimuli-responsive polymers are required to be patterned at the micro/nanometer scale, and also to possess highly ordered orientation in the responsive component. We demonstrate here that nanoscale patterning and uniaxial alignment of liquid crystalline mesogens can be simultaneously achieved by nanoimprint lithography performed in the liquid crystalline mesophase. Photoactive azobenzene mesogens were aligned parallel to the nanogratings imprinted in the films. The degree of alignment depended on the extent of nanoconfinement. The nanogratings expanded in the direction perpendicular to the film upon exposure to uniform UV irradiation, because of trans-to-cis isomerization. In addition, the reversible deformation amplitude strongly depended on the degree of alignment of the photoactive azobenzene mesogens. PMID- 24762474 TI - Evolutionary game dynamics in populations with heterogenous structures. AB - Evolutionary graph theory is a well established framework for modelling the evolution of social behaviours in structured populations. An emerging consensus in this field is that graphs that exhibit heterogeneity in the number of connections between individuals are more conducive to the spread of cooperative behaviours. In this article we show that such a conclusion largely depends on the individual-level interactions that take place. In particular, averaging payoffs garnered through game interactions rather than accumulating the payoffs can altogether remove the cooperative advantage of heterogeneous graphs while such a difference does not affect the outcome on homogeneous structures. In addition, the rate at which game interactions occur can alter the evolutionary outcome. Less interactions allow heterogeneous graphs to support more cooperation than homogeneous graphs, while higher rates of interactions make homogeneous and heterogeneous graphs virtually indistinguishable in their ability to support cooperation. Most importantly, we show that common measures of evolutionary advantage used in homogeneous populations, such as a comparison of the fixation probability of a rare mutant to that of the resident type, are no longer valid in heterogeneous populations. Heterogeneity causes a bias in where mutations occur in the population which affects the mutant's fixation probability. We derive the appropriate measures for heterogeneous populations that account for this bias. PMID- 24762475 TI - Molecular mechanisms of hypoxic responses via unique roles of Ras1, Cdc24 and Ptp3 in a human fungal pathogen Cryptococcus neoformans. AB - Cryptococcus neoformans encounters a low oxygen environment when it enters the human host. Here, we show that the conserved Ras1 (a small GTPase) and Cdc24 (the guanine nucleotide exchange factor for Cdc42) play an essential role in cryptococcal growth in hypoxia. Suppressor studies indicate that PTP3 functions epistatically downstream of both RAS1 and CDC24 in regulating hypoxic growth. Ptp3 shares sequence similarity to the family of phosphotyrosine-specific protein phosphatases and the ptp3Delta strain failed to grow in 1% O2. We demonstrate that RAS1, CDC24 and PTP3 function in parallel to regulate thermal tolerance but RAS1 and CDC24 function linearly in regulating hypoxic growth while CDC24 and PTP3 reside in compensatory pathways. The ras1Delta and cdc24Delta strains ceased to grow at 1% O2 and became enlarged but viable single cells. Actin polarization in these cells, however, was normal for up to eight hours after transferring to hypoxic conditions. Double deletions of the genes encoding Rho GTPase Cdc42 and Cdc420, but not of the genes encoding Rac1 and Rac2, caused a slight growth retardation in hypoxia. Furthermore, growth in hypoxia was not affected by the deletion of several central genes functioning in the pathways of cAMP, Hog1, or the two-component like phosphorylation system that are critical in the cryptococcal response to osmotic and genotoxic stresses. Interestingly, although deletion of HOG1 rescued the hypoxic growth defect of ras1Delta, cdc24Delta, and ptp3Delta, Hog1 was not hyperphosphorylated in these three mutants in hypoxic conditions. RNA sequencing analysis indicated that RAS1, CDC24 and PTP3 acted upon the expression of genes involved in ergosterol biosynthesis, chromosome organization, RNA processing and protein translation. Moreover, growth of the wild-type strain under low oxygen conditions was affected by sub-inhibitory concentrations of the compounds that inhibit these biological processes, demonstrating the importance of these biological processes in the cryptococcal hypoxia response. PMID- 24762476 TI - Myths. PMID- 24762477 TI - The metaphysical combat with death in the terminally ill and the psychedelic trail. PMID- 24762478 TI - Understanding coping with cancer: how can qualitative research help? AB - Research in psycho-oncology investigates the psycho-social and emotional aspects of cancer and how this is related to health, well-being and overall patient care. Coping with cancer is a prime focus for researchers owing to its impact on patients' psychological processing and life in general. Research so far has focused mainly on quantitative study designs such as questionnaires to examine the coping strategies used by cancer patients. However, in order to gain a rich and deep understanding of the reasons, processes and types of strategies that patients use to deal with cancer, qualitative study designs are necessary. Few studies have used qualitative designs such as semi-structured interviews to explore coping with cancer. The current paper aims to review the suitability and benefits of using qualitative research designs to understand coping with cancer with the help of some key literature in psycho-oncology research. PMID- 24762479 TI - Role of concurrent chemoradiation in inoperable carcinoma esophagus: a prospective study. AB - INTRODUCTION: The treatment of choice in cancer esophagus is controversial. Radiation therapy oncology group, Eastern cooperative oncology group and Cochrane studies have shown superiority of concurrent chemoradiation in inoperable carcinoma esophagus. In these studies full dose cisplatin was given every 3 weeks along with radiotherapy and hence had some toxicity. So, we started treating inoperable carcinoma esophagus patients with low dose weekly cisplatin given concurrently with radiotherapy aiming at low toxicity and similar results. MATERIALS AND METHODS: A total of 31 cases of inoperable cases of carcinoma esophagus were treated with once weekly cisplatin 30 mg/m 2 along with radiotherapy 60 Gy in 30 fractions in 6 weeks on Telecobalt/Linear accelerator. RESULTS: We could achieve lower toxicity with 80%, 35% and 19% with 1, 2, and 3 year's survival with a median survival of 18 months. So, we conclude that this regimen is better than 3 weekly chemotherapy regimen as is better tolerated with less toxicity and similar outcome. PMID- 24762480 TI - The investigation of epsilon toxin effects on different cancerous cell lines and its synergism effect with methotrexate. AB - BACKGROUND: The overall goal of this study is to use a bacterial toxin as drug delivery agents for chemotherapy drugs and overcome the development of resistance to these medicines. COR-L105 and MDA-MB 231 which are epithelial-like were used in this study. Cytotoxicity assays were performed by 3-(4, 5-dimethyl-2 thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) as metabolic indicator. The toxin was essential to kill 50% (CT50) and IC 50 value (inhibition growth value) for methotrexate were determined as optical density at 540 nm. Epsilon toxin loaded PLGA nanoparticles were prepared using non-aqueous technique. Surface morphology, in vitro drug release, and encapsulation efficiency of the nanoparticles was determined. RESULTS: Results confirmed that using non-toxic concentration of epsilon toxin, resistance to cancerous cell decreased significantly, which could be an important result in cancer therapy. The synergistic effect of MTX and epsilon toxin showed that bio toxins can be used as supplement with chemical drugs and increase the effect of chemotherapy. The results illustrated that application of PLGA as drug delivery system due to its controlled release properties was beneficial. CONCLUSION: These finding proposed that due to the ease of local accessibility of lung tumors with aerosol drug delivery, biotoxins can directly be used with chemotherapy drugs in aerosol form. PMID- 24762481 TI - Image guidance in prostate cancer - can offline corrections be an effective substitute for daily online imaging? AB - PURPOSE: This aim of this study was to determine if a less resource-intensive and established offline correction protocol - the No Action Level (NAL) protocol was as effective as daily online corrections of setup deviations in curative high dose radiotherapy of prostate cancer. MATERIALS AND METHODS: A total of 683 daily megavoltage CT (MVCT) or kilovoltage CT (kvCBCT) images of 30 patients with localized prostate cancer treated with intensity modulated radiotherapy were evaluated. Daily image-guidance was performed and setup errors in three translational axes recorded. The NAL protocol was simulated by using the mean shift calculated from the first five fractions and implemented on all subsequent treatments. Using the imaging data from the remaining fractions, the daily residual error (RE) was determined. The proportion of fractions where the RE was greater than 3,5 and 7 mm was calculated, and also the actual PTV margin that would be required if the offline protocol was followed. RESULTS: Using the NAL protocol reduced the systematic but not the random errors. Corrections made using the NAL protocol resulted in small and acceptable RE in the mediolateral (ML) and superoinferior (SI) directions with 46/533 (8.1%) and 48/533 (5%) residual shifts above 5 mm. However; residual errors greater than 5mm in the anteroposterior (AP) direction remained in 181/533 (34%) of fractions. The PTV margins calculated based on residual errors were 5mm, 5mm and 13 mm in the ML, SI and AP directions respectively. CONCLUSION: Offline correction using the NAL protocol resulted in unacceptably high residual errors in the AP direction, due to random uncertainties of rectal and bladder filling. Daily online imaging and corrections remain the standard image guidance policy for highly conformal radiotherapy of prostate cancer. PMID- 24762482 TI - Evaluation of ER, PR and HER-2 receptor expression in breast cancer patients presenting to a semi urban cancer centre in Western India. AB - BACKGROUND: Hormone receptor expression has been reported to be low in breast cancer patients from developing countries. The pattern of receptor expression from urban and rural areas is not well studied. MATERIALS AND METHODS: This is a retrospective analysis of 206 consecutive breast cancer patients presenting to a semi urban cancer centre from 2009-2010. The demographic and clinical variables included age, residential area (rural, semi urban, or urban), menopausal status, and clinical stage. The pathological variables included tumor type, the presence of ductal carcinoma in situ, lymphovascular invasion, and expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) receptors by immunohistochemical (IHC) analysis. RESULTS: The majority of patients were postmenopausal with the median age of 50 years. Invasive ductal carcinoma was the most common subtype (94%). The ER status was available in 101 (49.3%), PR in 99 (48.0%), and HER2 in 82 (39.8%) cases. In patients in whom this data were available, ER was positive in 44.6%, PR in 40.4%, and HER2 in 34.2%. Out of the 82 patients in whom data on all three receptors were available, 34.1% patients had triple negative tumors. Analysis of our data showed a trend toward increasing ER and PR expression with age but this was not statistically significant. The average age of menopause was between 40-50 years of age. CONCLUSION: This report is an important documentation of the pathological characteristics in a predominantly rural/semi urban population of Indian breast cancer patients. Further studies from other centers with a similar background are required to confirm these results. PMID- 24762483 TI - Critical neurological structure sparing radiosurgery of vestibular schwannoma: dosimetric comparison of different techniques and dose prescription methods. AB - AIM: To investigate potential sparing of critical neurological structures (CNSs) during radiosurgery of vestibular schwannoma (VS) employing different techniques and dose prescription methods. MATERIALS AND METHODS: Fused CT and MRI datasets of eight patients with unilateral VS representing a wide range of target volume (0.48 to 12.08 cc; mean = 3.56 cc), shape and proximity to CNSs such as cochlea, trigeminal nerve and brainstem were re-planned employing static conformal field (SCF), dynamic conformal arc (DCA) and intensity modulated radiosurgery (IMRS) techniques. For every patient, five plans were created for a fixed margin dose of 12 Gy prescribed at 80% in three plans (SCF_80%, DCA_80%, and IMRS_80%) and 50% in another two plans (SCF_50% and DCA_50%). All plans were compared using standard dosimetric indices. RESULTS: Primary goal of every plan to cover >=99% of target volume with 12 Gy was fulfilled for all patients with minimum significant dose to target (D99) >=11.99 Gy. Best conformity index (CI Paddick = 0.62 +/- 0.12) was observed in SCF_80% and DCA_80% plans whereas; sharpest dose gradient index of 3.40 +/- 0.40 was resulted from DCA_50%. All five plans resulted similar maximum dose to brainstem (11.04 +/- 2.23 to 11.53 +/- 1.10 Gy), cochlea (9.02 +/- 1.79 to 10.15 +/- 1.26 Gy) and trigeminal nerve (11.55 +/- 1.38 to 12.19 +/- 2.12 Gy). Among 80% prescription plans, IMRS_80% reduces mean and D5 (P < 0.05) to all CNSs. Prescription of dose at 50% isodose sharpened the dose gradient and significantly (P < 0.05) reduced mean dose and D5 to all CNSs at the cost of target conformity (P = 0.01). Mean dose to cochlea and trigeminal nerve were least at 4.53 +/- 0.86 and 6.95 +/- 2.02 Gy from SCF_50% and highest at 6.65 +/- 0.70 and 8.40 +/- 2.11 Gy from DCA_80% plans respectively. CONCLUSION: This dosimetric data provides a guideline for choosing optimum treatment option and scope of inter institutional dosimetric comparison for further improvement in radiosurgery of Vestibular Schwannoma (VS). PMID- 24762484 TI - A single institution retrospective analysis of malignant melanoma. AB - BACKGROUND: The incidence of melanoma is rising at a rate greater than any other malignancy, although much of this increase is due to the more frequent diagnosis of patients with the earlier stages of melanoma. OBJECTIVE: In this study, patient and tumor-related characteristics and their effects on survival were evaluated. MATERIALS AND METHODS: The data was drawn from the patients' records with histologically proven primary cutaneous melanomas treated at the Ankara Oncology Hospital between January 2003 and December 2010. Sixty-nine patients (48 men and 21 women) were included in this study. 17 of the patients had already distant metastases at the time of diagnosis. While 45 of all patients had undergone surgery alone, 17 had received only palliative radiotherapy, and 7 had received primary radiotherapy. Survival curves were determined from the time of diagnosis. RESULTS: A total of 69 cutaneous melanoma cases were evaluated. While there was a predominance of males in all body sites, especially in the head and neck regions, the number of male patients was 5 times higher than females. Diseases located on the head tended to present a significantly higher rate in older patients (P = 0.009). Overall survival rates for 1 and 3 years were 79% and 44%, respectively. Distant metastatic melanoma was significantly related with poor prognosis (P < 0.001). Anatomic location showed a borderline significancy as a prognostic factor for overall survival (P = 0.053). CONCLUSION: Cutaneous melanomas developing at different body sites are associated with distinct patterns of survival outcomes. In this retrospective analysis, melanomas of the head and neck and limb, which are regional melanoma, appear to have better survival outcomes. PMID- 24762485 TI - Anti-cancer effects of CME-1, a novel polysaccharide, purified from the mycelia of Cordyceps sinensis against B16-F10 melanoma cells. AB - BACKGROUND: Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In melanoma, several signaling pathways are constitutively activated. Among these, the mitogen-activated protein kinase (MAPKs) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Therefore, the inhibition of MAPK signaling might be a crucial role for the treatment of melanoma cancer. AIMS: We examined the anticancer effect of CME-1, a novel water soluble polysaccharide fraction, isolated from Cordyceps sinensis mycelia on B16 F10 melanoma cells. MATERIALS AND METHODS: B16-F10 cells were exposed to different concentrations of CME-1 (250, 500 and 800 MUg/ml) for 24 h in 5% CO2 incubator at 37 degrees C. Western blot analysis was performed to detect the expression of MMP-1, p-p38 MAPK, p-ERK1/2, and IkB-alpha in B16-F10 cells. Cell migration test was performed by wound healing migration assay. RESULTS: CME-1 suppresses cell migration in a concentration-dependent manner. Western blotting analysis revealed that CME-1 led to the reduction on the expression levels of MMP 1 and down regulated the expression of phosphorylated extracellular signal regulated kinase (ERK1/2 and p38 mitogen-activated protein kinase (p38 MAPK). CME 1 restored the IkB-degradation in B16F10 cells. CONCLUSIONS: These results indicate that CME-1 inhibited MMP-1 expressions in B16F10 melanoma cells through either NF-kB or ERK/p38 MAPK down regulation thereby inhibiting B16F10 cell migration. Therefore, we proposed that CME-1 might be developed as a therapeutic potential candidate for the treatment of cancer metastasis. PMID- 24762486 TI - Clinicopathological, immunohistochemical factors and recurrence associated with extrathyroidal extension in papillary thyroid microcarcinoma. AB - BACKGROUND AND AIMS: Extrathyroidal extension (ETE) is one of the most important factors correlated to poor outcome of papillary thyroid carcinoma (PTC). However, the role of ETE in the prognosis of papillary thyroid microcarcinoma (PTMC) and the factor associated with ETE of PTMC are unclear. We investigated clinicopathological, immunohistochemical factors associated with ETE of PTMC to identify whether PTMC with ETE would have more adverse prognostic factors and higher risk for recurrence. SETTING AND DESIGN: We enrolled patients performed thyroidectomy due to PTC between January 2003 and June 2008 and selected patients diagnosed with PTMC among them. We investigated numerous clinicopathological, immunohistochemical factors of selected patients. MATERIALS AND METHODS: Data from 325 patients diagnosed with conventional PTMC by intraoperative frozen section and final pathology were recorded retrospectively. STATISTICAL ANALYSIS USED: A chi2 test or an independent two-sample t-test, multiple logistic regression analysis, the Kaplan-Meier method, and log-rank test. RESULTS: Thirty four percent of patients (325 of 952) had PTMC on final pathology. Among them, the number of patients with and without ETE was 91 and 234, respectively. On both univariate and multivariate analysis; ETE of PTMC correlated with size (P < 0.001); tumor, node, and metastasis (TNM) staging (P = 0.001); multifocality (P = 0.001); lymph node metastasis (P < 0.001); radioactive iodine (RAI) therapy (P = 0.001); and recurrence (P = 0.037). CONCLUSIONS: ETE of conventional PTMC is associated with size, multifocality, lymph node metastasis, and recurrence. More extensive surgery should be considered for patients having ETE identified by intraoperative frozen sections, preoperative imaging, and intraoperative finding and other high risk factors. PMID- 24762487 TI - Implementation of a wedged-dynamic arc therapy technique for head and neck cancer. AB - INTRODUCTION: In this study, we designed and evaluated a wedged dynamic arc therapy (W-DAT) to provide the desirable concaved-shape dose distribution to cover the target in the treatment of head and neck sequence cell carcinoma. MATERIALS AND METHODS: Eight patients were treated using W-DAT. The dose prescriptions were 70 Gy and 54 Gy, in 35 fractions, to the sites of the gross planning target volume (PTV1) and the microscopic (PTV2) diseases respectively. This technique consists of four wedged half-arcs of moving multi-leaf collimator leaves to fit PTV1 and shield brain stem at all gantry rotations. These were combined with two anterior-posterior conformal fields of different weighing to improve the dose uniformity. Another two anterior-posterior conformal fields were designed to cover the PTV2. All of the eight fields were half blocked by the normal jaws so there is no dose overlap at the interface between the two targets. RESULTS: Referring to radiation therapy oncology group protocol 0615, 95% of the PTV1 was covered by more than 95% (66.50 Gy) of the prescribed dose, with very low dose inhomogeneity index of 0.0670 +/- 0.0007. The maximum dose to 1% of the planning organ at risk volumes-brainstem didn't exceed 56.10 +/- 2.17 Gy while the two parotids were well spared as they received a mean dose of 21.97 +/- 3.24 Gy. Isocentric ion chamber measurements showed good agreement with the treatment planning system calculated dose with the maximum deviation of 2.40% while film measurements yielded lesser than 4.20% of the pixels failed the acceptance gamma criteria of (3 mm, 3%). CONCLUSION: W-DAT technique was approved in our department as the standard choice for the radical treatment of head and neck sequence cell carcinoma. PMID- 24762488 TI - Amelioration of doxorubicin induced cardio-and hepato-toxicity by carotenoids. AB - AIM OF STUDY: The aim of this study is to explore the ability of the carotenoids (CARs) to offer protection against acute cardiotoxicity and hepatotoxicity induced by doxorubicin (DOX) (25 mg/kg) in tumor bearing Swiss albino mice. MATERIALS AND METHODS: Tumor bearing Swiss albino mice administered with DOX (25 mg/kg, i.p) and two doses of CARs (50 and 100 MUg/kg). 24 h after administration of the drugs, histopathological evaluation of tumor, liver and heart tissues carried out. Furthermore, various antioxidant parameters in these tissues were investigated. Serum marker enzymes for tissue injury were examined. RESULTS: Administration of CARs prevented the depletion of antioxidants in the heart and liver, thereby protecting the tissue damage and release of marker enzymes. However, similar antioxidant depletion was not observed in the tumor tissue. CARs prevented DOX induced variation in tissue architecture in heart and liver tissues. However, CARs did not influence DOX induced alterations in the tumor. CONCLUSION: Administration of CARs could prevent DOX induced acute toxicity to heart and liver. PMID- 24762489 TI - Comparison of nucleostemin gene expression in CD133+ and CD133- cell population in colon cancer cell line HT29. AB - BACKGROUND: Nucleostemin has been shown to be essential for proliferation and survival of colon cancer cells. In this study, we evaluate and comparing nucleostemin expression in CD133+ and CD133- colon cancer cell line HT29. MATERIALS AND METHODS: After preparation and culturing of HT29 cell line, isolation was performed using magnetic cell separation system by CD133 MicroBeads and phycoerythrin conjugated to monoclonal anti-human CD133 monoclonal antibody and analyzed with flow cytometry. For quantitative expression of nucleostemin in HT29, CD133+ and CD133- cells used specific nucleostemin primer and glyceraldehyde 3-phosphate dehydrogenase primer as endogenous control. RESULTS: The results showed the percentage of CD133+ cells in HT29 colon cancer cell line ranged from 36.5% to 41.5%, whereas the percentage of CD133- cell ranged from 58.5% to 63.5%. The expression rate of nucleostemin in HT29, CD133+ and CD133- cells were 1.44 +/- 0.78, 1.60 +/- 0.70 and 1.00 +/- 0.18 (respectively). The comparison of expression rate represents no significant difference in nucleostemin expression in CD133+, CD133- and HT29 colon cancer cells. CONCLUSION: It is concluded that nucleostemin expression could not be specific in a certain type of cells in colon cancer cell line HT29 and controlling strategies in colon cancer must not be focused on one certain type of colon cancer cells as main expressing nucleostemin gene. PMID- 24762490 TI - Clinical and pathological features of patients with resected synovial sarcoma: a multicenter retrospective analysis of the Anatolian Society of Medical Oncology. AB - BACKGROUND: Synovial sarcoma (SS) is a rare disease and compared with other soft tissue sarcomas has a relatively high mortality rate. The optimal management of this disease and prognostic factors associated with patient outcome remains controversial. AIMS: We aimed to evaluate the factors affecting the outcomes of SS patients in the adjuvant setting. PATIENTS AND METHODS: In this Turkish multicenter study, we assessed the data of 69 SS patients regarding prognostic factors for SS patients retrospectively. RESULTS: Our study included 69 localized SS patients (38 males and 31 females) with a median age of 34.5 years (minimum maximum: 14-68 years). Overall survival (OS) and disease free survival (DFS) rates for 5 years were 64% and 25%, respectively. All patients under went surgical treatment; 64 patients were treated with a wide excision and 5 patients had an amputation. According to the univariate analysis, adverse prognostic factors for OS were male sex, higher mitotic activity, high Ki-67 levels, trunk localization and inadequate surgical margins. In multivariate analysis, none of these factors had independent significant association with OS. Prognostic factors for DFS; in the univariate analysis were higher mitotic activity, high Ki-67 levels and inadequate surgical margins. Only higher mitotic activity (>=10 high power field) was significantly associated with worse DFS in the multivariate analysis (hazard ratio: 0.30, % confidence interval: 0.11-0.80, P = 0.017). CONCLUSION: Our study confirms that high mitotic activity is significantly associated with decreased DFS. The question of whether the chemotherapy provides a survival advantage in patients having adverse prognostic factors requires confirmation in randomized trials. PMID- 24762491 TI - Surgery in cerebral metastases: are numbers so important? AB - BACKGROUND: The prognosis of cerebral metastases (MTS) is linked to progression of both systemic and local disease. The importance of MTS resection has been already pointed out. The observation of a high mortality for not-neurological causes confirms that the modern treatments allow a significant control of the disease within the nervous system. Nevertheless, management difficulties increase with multiple lesions and in these cases the role of surgery has still to be defined. MATERIALS AND METHODS: We collected the clinical data of patients operated in two centers for cerebral MTS from lung carcinoma during 8 years. Patient selection for surgery followed definite criteria; the limit for multiple MTS was three. We analyzed the functional and survival outcomes of the cohort. RESULTS AND CONCLUSIONS: Our series included 242 patients: 105 had multiple MTS. Statistical analysis did not show significant differences in mean survival and outcomes between patients with single and multiple lesions. The decease occurred for neurological causes in 15.7% of cases. The selection of candidates for surgery requires several considerations and entails the success rate of this treatment. In patients with the multiple lesions who fulfilled the selection criteria we observed a nevertheless satisfying success after the operation. Our results imply that surgery may be applied also in selected patients with more diffuse intracranial disease. A pre-operative accurate patient selection is related to acceptable quality-of-life following the operation even in cases of multiple MTS. PMID- 24762492 TI - Validation of a high-performance liquid chromatographic ultraviolet detection method for the quantification of vandetanib in rat plasma and its application to pharmacokinetic studies. AB - AIM: To develop a simple and sensitive high-performance liquid chromatography (HPLC) assay with ultraviolet detection method of vandetanib in rat plasma. MATERIALS AND METHODS: Samples were extracted with methanol and acetonitrile, evaporated, and then the residue was reconstituted in mobile phase. Vandetanib and the internal standard (I.S.) trazodone hydrochloride were separated with gradient elution (on a C18 Atlantis column using a mobile phase of acetonitrile/0.5% triethylamine, pH 3.0, with a flow rate of 1.0 ml/min), then detected at 341 nm. RESULTS: A linear curve over the concentration range of 80 4000 ng/ml (R2 = 0.9998) was obtained. Intra- and inter-assay accuracy ranged from 98.80% to 103.08% and 95.32% to 98.40%, with high precision (R.S.D. % <5%), respectively. The mean absolute recovery was 96.65%. CONCLUSION: A simple and sensitive HPLC assay with ultraviolet detection method was developed for the determination of vandetanib in rat plasma. This method is sufficient for pharmacokinetic studies of vandetanib in small animals and may be applied to human pharmacokinetic studies. PMID- 24762493 TI - Proteomic analysis reveals novel proteins associated with progression and differentiation of colorectal carcinoma. AB - AIM: The objective of this study is to characterize differential proteomic expression among well-differentiation and poor-differentiation colorectal carcinoma tissues and normal mucous epithelium. MATERIALS AND METHODS: The study is based on quantitative 2-dimensional gel electrophoresis and analyzed by PDquest. RESULTS: Excluding redundancies due to proteolysis and posttranslational modified isoforms of over 600 protein spots, 11 proteins were revealed as regulated with statistical variance being within the 95th confidence level and were identified by peptide mass fingerprinting in matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Progression-associated proteins belong to the functional complexes of tumorigenesis, proliferation, differentiation, metabolism, and the regulation of major histocompatibility complex processing and other functions. Partial but significant overlap was revealed with previous proteomics and transcriptomics studies in CRC. Among various differentiation stage of CRC tissues, we identified calreticulin precursor, MHC class I antigen (human leukocyte antigen A ), glutathione S transferase pi1, keratin 8, heat shock protein 27, tubulin beta chain, triosephosphate, fatty acid-binding protein, hemoglobin (deoxy) mutant with val b 1 replaced by met (HBB), and zinc finger protein 312 (FEZF2). CONCLUSIONS: Their functional networks were analyzed by Ingenuity systems Ingenuity Pathways Analysis and revealed the potential roles as novel biomarkers for progression in various differentiation stages of CRC. PMID- 24762494 TI - Fractionated stereotactic radiosurgery with volumetric modulated arc therapy (Rapid Arc) for reradiation in recurrent high grade gliomas. AB - BACKGROUND: To evaluate 'Rapid Arc (RA)' technique for delivering fractionated stereotactic radiosurgery (FSRS) in patients with recurrent high grade gliomas (HGGs) for minimizing the dose to previously radiated high dose brain volume. MATERIALS AND METHODS: Between April 2010 and February 2011, 16 consecutive patients with recurrent HGGs and previously treated with intensity modulated radiation therapy (IMRT) and Temozolamide received FSRS. The median time between IMRT and FSRS was 10.72 months. FSRS to a dose of 30 Gy in a median of 5 fractions was delivered to the recurrent tumor (gross tumor volume [GTV]). Brain volume around the GTV and previously treated to a mean dose >50 Gy was delineated as "Avoidance Volume (AV)." Patients were planned with both RA and Dynamic Conformal Arc (DCA) to achieve minimum dose to AV. Dose received by GTV, AV, rest of the normal brain (brain minus PTV) and conformity index (CI) and heterogenecity index (HI) were compared by the two techniques. RESULTS: At a median follow up of 7.33 months, median progression free and overall survival was 6.4 and 9.3 months, respectively. Mean dose to AV was significantly lower with RA as compared with DCA (10.8 Gy vs. 15.5 Gy, P - 0.0001) with no significant difference in the dose delivered to GTV. No patient developed radiation necrosis. CONCLUSION: As compared with DCA, RA delivered significantly less dose to previously radiated high dose brain volume. It may contribute to minimizing the risk of radionecrosis with stereotactic radiosurgery (SRS) in patients with recurrent HGG. PMID- 24762495 TI - Immunohistochemical expression of syndecan-1 in oral dysplastic epithelium. AB - BACKGROUND: In stratified squamous epithelia, syndecan-1 is proposed to function as a cellto cell adhesion molecule, and plays an important role in regulation of cell growth and differentiation during the developmental process. Oral cancer is a disease with complex etiology, so biological behavior in carcinomas preceded by dysplastic states is difficult to assess and predict its prognosis. Hence, syndecan-1, a recently recognized tumor marker has been proved to be an eminent diagnostic and prognostic tool in assessing biological behavior of various potentially premalignant andmalignant lesions. MATERIALS AND METHODS: The study group consisted of 40 specimens of premalignant stateand 10 specimens of normal mucosa.Thesections were stained withhematoxylin and eosin, andimmunohistochemicallyusing syndecan-1 a primary antibody and was observed under light microscope. RESULTS: Expression decreased with the decreasing grades of dysplasia. CONCLUSION: Syndecan-1 can be efficiently used in early detection and diagnosis of oral carcinoma. PMID- 24762496 TI - The investigation of changes in proteins expression (Apolipoprotein A1 and albumin) in malignant astrocytoma brain tumor. AB - OBJECTIVE: Angiogenesis performs a critical role in the development of cancer. Angiogenesis research is a cutting-edge field in cancer research. Proteomics is a powerful tool in identifying multiple proteins that are altered following a neuropharacological intervention in a disease of the central nervous system. Diagnostic oncoproteomics is the application of proteomic techniques for the diagnosis of malignancies. MATERIALS AND METHODS: We extracted proteins of tumor and normal brain tissues and then evaluated the protein purity by Bradford test and spectrophotometery method. In this study, we separated proteins by two dimensional (2D) gel electrophoresis method and the spots were then analyzed and compared using statistical data and specific software, after providing three dimensional images of spots alteration. Spots were identified by pH isoelectric, molecular weights, and data banks. RESULTS: Simple statistical test were used to establish a putative hierarchy in which the change in protein level were ranked according a cutoff point with P < 0.05. Apolipoprotein A1 (apo A1) protein and albumin were consistently upregulated in astrocytoma brain tumors. CONCLUSION: The vascular microenvironment of glioma play a major role in determining the pathophysiological character is tics of the tumor. apo A1 and albumin are very significant due to their functional consequences in glioma tumor growth, migration and angiogenesis. PMID- 24762497 TI - Preclinical evaluation of [111 In]-DOTA-trastuzumab for clinical trials. AB - CONTEXT: Herceptin and its fragments have been radiolabeled and used in the imaging of human epidermal growth factor receptor 2 (HER2)/neu-positive tumors and development of diagnostic kits is of great importance in radiopharmacy. AIMS: In this study, 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid trastuzumab (111 In-DOTA-trastuzumab) was successively prepared and evaluated for ultimate use in the HER2 antigen imaging in oncology. SETTINGS AND DESIGN: The conjugate was prepared, labeled and evaluated using in vitro (radioimmunoassay [RIA], enzyme-linked immunosorbent assay (ELISA), stability, binding, internalization)/in vivo (bio-distribution, single-photon emission computed tomography [SPECT]) experiments. MATERIALS AND METHODS: 111 In-DOTA-trastuzumab was prepared followed by determination of radiochemical purity (RCP), integrity of protein, immunoreactivity of radiolabeled antibody with HER2/neu antigen (by SkBr3 cell line binding and RIA methods) were determined followed by stability tests, internalization studies and the tissue bio-distribution determination in wild-type rats as well as SPECT imaging in SkBr3-bearing mice. STATISTICAL ANALYSIS USED: All values were expressed as mean +/- standard deviation (mean +/- SD) and the data were compared using Student's t-test. Statistical significance was defined as P < 0.05. RESULTS: 111 In-DOTA-trastuzumab was prepared (RCP >95 +/- 0.5%, S.A. 5.3 MUCi/MUg) with the average number of chelators per antibody of 6:1 showing significant immune-reactivity retention using ELISA. In vitro stability was >90% in phosphate buffered saline and 80 +/- 0.5% in serum over 48 h. Cell binding was significant (>0.79). In vitro internalization reached up to %12-13 in 10 h. Significant tumor uptake was observed. CONCLUSIONS: In vitro and in vivo/SPECT imaging in SkBr3-bearing mice demonstrated that 111 In-DOTA trastuzumab is a potential compound for molecular imaging of SPECT for diagnosis and follow-up of HER2 expression in oncology. PMID- 24762498 TI - PET-CT changes the management and improves outcome in patients with recurrent colorectal cancer. AB - BACKGROUND: The present study aims to analyze the impact of positron emission tomography/computed tomography (PET/CT) on management change in patients with suspected or proven colorectal cancer recurrence, and to assess the effect of this management change on progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS: We retrospectively evaluated 122 patients with suspected potentially resectable recurrent colorectal cancer who underwent PET/CT scan. We determined management plans for these patients before and after the PET/CT examination. RESULTS: While previous conventional imaging studies had revealed solitary metastases, additional sites of disease were determined by PET/CT scan in 52/122 (42%) patients. PET/CT examination results changed the treatment plan to curative intent in 35 (37%) patients. While the median PFS was 22 months (95% CI, 11.2-32.6 months) among the patients planned to receive curative treatment after the PET/CT scan, it was 11 months (95% CI, 8.1-13.9 months) in patients planned to receive curative treatment before the PET/CT examination, and the difference between median PFS durations was statistically significant (HR, 0.51 [95% CI, 0.32 - 0.88], P = 0.004). Furthermore, OS was significantly longer in patients planned to receive curative treatment after the PET/CT scan (27 months [95% CI, 22.1-31.9]) compared with those who received curative treatment before the PET/CT scan (21 months [95% CI, 15.6 - 26.4]), and the difference was statistically significant (HR, 0.63 [95% CI, 0.42 - 0.89], P = 0.045). CONCLUSION: The present study demonstrates the significant impact of PET/CT on the management and outcome in patients with recurrent colorectal cancer. PMID- 24762500 TI - How prostate-specific membrane antigen level may be correlated with stemness in prostate cancer stem cell-like cell populations? AB - BACKGROUND: Prostate-specific membrane antigen (PSMA) is a widely used targeted molecule in prostate patients. The present research, attempts to support the hypothesis that PSMA expression in prostate cancer stem cell-like (CSC) cell populations may be correlated with nanog and other transcription factors in different stages of prostate carcinomas. MATERIALS AND METHODS: To provide more accurate evidence of the above, a population of prostate CSCs was isolated and analyzed using different protocols. The first method was based in the ability of CSCs to form spherical colonies in semi-suspension of a culture. A qPCRbased protocol and a flow cytometric analysis protocol were chosen to test the presence of stemness markers and PSMA in the selected populations. RESULTS: The formation of micro-sphere in semi-suspension has been pointed out. In the other panels of the test, the linear correlation between PSMA and nanog in gene and protein level was shown. However, the statistical analysis including the coefficient of variationand standard deviation's values) has proved that there were differences in PSMA expression between cancer cells and CSCs. CONCLUSION: The previous analysis has pointed out that PSMA expression may be correlated with nanog's expression as well as with other confounders in a population of prostate CSCs. PMID- 24762499 TI - Alteration of radiation-sensitive processes associated with cancer and longevity by dietary 2-mercaptoethanol. AB - BACKGROUND: Previous results demonstrated dietary 2-mercaptoethanol (2-ME) delayed appearance of cancer in certain murine strains. In addition, it had a benefit not found with other organosulfurs, in that it completely prevented spontaneous development of cancer in BXSB-Yaa + over an entire lifespan. AIMS: These benefits raise the question: What, if any, alteration of radiation-induced tumorigenesis would 2-ME impart that may differ from that of other sulfur antioxidants? This is relevant based on the extensive use of radiation in diagnoses and therapy and 2-ME's superior in vitro and in situ immune enhancement properties. MATERIALS AND METHODS: This was addressed by exposing long-lived, B10.A (4R) mice to sublethal, 5.5 Gy ionizing gamma-rays and then tumor development monitored over a lifetime. STATISTICAL ANALYSIS: Two-tailed P-values were determined using the Fischer's Exact Test. RESULTS: The only tumors detected were mammary and only in animals that were both exposed to radiation and not treated with 2-ME. The 43% incidence differed significantly from the absence of tumors in non-irradiated mice that were or were not exposed to 2-ME and in those irradiated and treated daily with 2-ME, irrespective of whether treatment was started prior to or post irradiation. However, quite unexpectedly, radiation shortened longevity 29% from undefined causes, including cancer, in animals pretreated with 2-ME; longevity was not altered in those not pretreated or if treatment was started post-irradiation. CONCLUSIONS: The findings have relevance for cancer prevention and the controversy relative to ''long term survival/safety'' of currently used antioxidants as free radical scavengers in humans undergoing radiotherapy. PMID- 24762501 TI - A novel role of the tumor size in pancreatic cancer as an ancillary factor for predicting resectability. AB - BACKGROUND: Pancreatic adenocarcinoma (PCA) is a devastating disease. Only surgery can provide effective treatment. The resectability of pancreatic cancer is mainly determined by image studies. However, half of the patients deemed as operable, radiologically, are found to be inoperable during surgery. Previously, we have showed that both CA 19-9 and tumor size could predict PCA resectability, independently. Here, we aimed to determine the cut-off value for tumor size permitting PCA resectability by receiver operating characteristic (ROC) curve analysis. MATERIALS AND METHODS: We retrospectively reviewed 372 patients undergoing surgery for histopathologically proven PCA. We compared tumor sizes of patients in resectable and unresectable groups and analyzed them by the ROC curve. RESULTS: The tumor size in unresectable groups is significantly larger than that in the resectable group. The area under the ROC curve was 0.73 (95% confidence interval [CI], 0.665-0.789), which represented a good correlation between the tumor size and pancreatic cancer resectability. The PCA patients with a tumor diameter of > 4.8 cm had a 5.043-fold higher chance of unresectability than did those with a tumor diameter < 4.8 cm (odds ratio, 5.043; 95% CI, 3.221 7.894). CONCLUSIONS: A tumor diameter > 4.8 cm is a potential ancillary parameter for determining the resectability of PCA in addition to traditional image studies. Diagnosis laparoscopy may be indicated for radiologically resectable PCA patients with tumor size > 4.8 cm to prevent unnecessary laparotomy. PMID- 24762502 TI - Influence of the intravenous contrast media on treatment planning dose calculations of lower esophageal and rectal cancers. AB - BACKGROUND: The impact of intravenous (IV) contrast media (CM) on radiation dose calculations must be taken into account in treatment planning. PURPOSE: The aim of this study is to evaluate the effect of an intravenous contrast media on dose calculations in three-dimensional conformal radiation therapy (3D-CRT) for lower esophageal and rectal cancers. MATERIALS AND METHODS: Seventeen patients with lower esophageal tumors and 12 patients with rectal cancers were analyzed. At the outset, all patients were planned for 3D-CRT based on the computed tomography (CT) scans with IV contrast media. Subsequently, all the plans were copied and replaced on the scans without intravenous CM. The radiation doses calculated from the two sets of CTs were compared. RESULTS: The dose differences between the planning image set using intravenous contrast and the image set without contrast showed an average increase in Monitor Units (MUs) in the lower esophageal region that was 1.28 and 0.75% for 6 and 15 MV photon beams, respectively. CONCLUSION: There was no statistical significant difference in the rectal region between the two sets of scans in the 3D-CRT plans. The results showed that the dose differences between the plans for the CT scans with and without CM were small and clinically tolerable. However, the differences in the lower esophageal region were significant in the statistical analysis. PMID- 24762503 TI - Dosimetric comparison of vaginal vault ovoid brachytherapy versus intensity modulated radiation therapy plans in postoperative patients of cervical carcinoma following whole pelvic radiotherapy. AB - INTRODUCTION: Dosimetric study to compare high dose rate (HDR) vaginal vault ovoid brachytherapy plan versus intensity-modulated radiation therapy (IMRT) boost plan for doses delivered to target volume and organs at risk (OAR) in postoperative patients of cervical carcinoma following whole pelvic radiotherapy (WPRT). MATERIALS AND METHODS: Fifteen postoperative patients of cervical carcinoma suitable for vaginal ovoid brachytherapy following WPRT of 46 Gy/23 fractions/4.5 weeks were included. All were treated with brachytherapy (two sessions of 8.5 Gy each). The equivalent dose for IMRT was calculated by computing biologically effective dose of brachytherapy by linear quadratic model. Dose of brachytherapy (two sessions of 8.5 Gy) was equivalent to IMRT dose of 26 Gy/13 fractions. Doses to target volume and OAR were compared between HDR and IMRT plans. RESULTS: Target volume was well covered with both HDR and IMRT plans, but dose with brachytherapy was much higher (P < 0.05). Mean doses, doses to 0.1, 1, 2, and 5cc, 1/3 (rd) , 1/2, and 2/3 (rd) volume of bladder and rectum were significantly lower with HDR plans. CONCLUSION: In postoperative patients of cervical carcinoma, HDR brachytherapy following WPRT appears to be better than IMRT for tumor coverage and reducing dose to critical organs. PMID- 24762504 TI - Adipose derived stem cells isolated from omentum: a novel source of chemokines for ovarian cancer growth. AB - BACKGROUND: The main site of ovarian cancer metastasis is the omentum. Omental adipose tissue is known for contribution to the tumor growth and metastasis through different mechanisms. AIMS: In the present study, adipose derived stem cells (ASCs) were isolated from the omentum of patients with ovarian cancer and those with ovarian cysts and the expression of chemokines, chemokine receptors and cytokines were analyzed. MATERIALS AND METHODS: ASCs were isolated from omental adipose tissues obtained of 10 ovarian cancer and 25 ovarian benign cyst patients. Our investigations were done by quantitative real time-polymerase chain reaction, flowcytometry, western blot and also enzyme-linked immunosorbent assay. RESULT: Expression of CXCL-10 and CCR5 showed statistically significant difference between omentum derived ASCs of ovarian cancer patients compared with those with benign cysts (P < 0.05). Expression of interleukin-10 also detected in the supernatant of cultured malignant ASCs. CONCLUSION: Omental adipose tissue may play crucial roles for tumor promotion through the expression of tumor promoting chemokines. Accordingly, tumor surrounding adipose tissue may be a novel target for immunotherapy of cancer. PMID- 24762505 TI - Assessment of cytogenic damage in the form of micronuclei in oral epithelial cells in patients using smokeless and smoked form of tobacco and non-tobacco users and its relevance for oral cancer. AB - CONTEXT: Early detection of cytological damages may help in reduction of morbidity and mortality in patients with oral cancer. AIMS: (1) The primary aim of this study is to assess the cytogenic damage in the form of micronuclei (MN) in patients with smokeless and smoked tobacco using habit. (2) The secondary aim of this study is to compare the MN score in patients using tobacco and patients with no tobacco habit. (3) To find out incidence of MN according to duration and frequency of tobacco usage. SETTINGS AND DESIGN: This is a clinical study. MATERIALS AND METHODS: A total of 100 patients each with the habit of smokeless tobacco (SLT) chewing, smoked tobacco usage and with no habit were included in the study. Epithelial cell smears were prepared and slides were stained with Papanicolaou stain. Scoring of at least 1000 cells was done and a MN frequency score was assigned for exfoliated oral mucosal cells. STATISTICAL ANALYSIS: Analysis of variance and post hoc tests were used. RESULTS: The difference between the total number of cells with MN was not appreciable between the smokeless and smoked tobacco groups, though the total number of MN was higher in subjects using SLT. Total number of cells with MN and the total number of MN were significantly lower in non-tobacco users when compared with tobacco users. There was very weak positive correlation between the total number of MN as per the duration and frequency of the tobacco habit. CONCLUSION: The use of smokeless and smoked tobacco are associated with cytotoxic and genotoxic effects. SLT seems to cause more damaging effects than the smoked form. PMID- 24762506 TI - Risk factors, lipid profile, and histopathological study of oral cancers in Kolar district: a case-control study. AB - AIMS: To estimate serum lipid profile in oral squamous cell carcinoma and correlate the risk factors and lipid profile with oral squamous cell carcinoma. MATERIALS AND METHODS: Lipid profile was done in agriculturists/laborers in the age group of 30-70 years; 56 subjects (cases = 28, control = 28) were included. Study was carried out for a duration of four months; statistical analyses applied were mean, standard deviation, and independent 't' test. P < 0.05 was considered statistically significant. RESULTS: Eleven cases had buccal mucosa cancer, nine had tongue carcinoma, and eight had gingivobuccal sulcus carcinoma. Lipid profile such as total cholesterol, triglycerides, LDL cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, and very-low-density lipoprotein (VLDL) were marginally and slightly elevated in cases compared to controls. HDL was grossly decreased in cases compared to controls. CONCLUSIONS: There was a significant association between HDL and squamous cell carcinoma; maximum number of SCC had a history of smoking in the range of 10-19 years, irrespective of other lipid parameters, constrained to the fact that lipids are genetically determined, have geographical variation, and are highly skewed. PMID- 24762507 TI - Absence of correlation between serum CRP levels and mitochondrial D-loop DNA mutations in gastro-oesophageal adenocarcinoma. AB - INTRODUCTION: Both inflammation and mitochondrial DNA (mtDNA) mutation are thought to play a role in the many human cancers. The aim of this study was to evaluate the relationship between inflammation and accumulation of mitochondrial DNA (mtDNA) mutations in the D-loop region in carcinogenesis of gastro oesophageal adenocarcinomas. MATERIALS AND METHODS: Blood samples of 20 patients with gastro-oesophageal adenocarcinoma were taken for measurement of serum C reactive protein (CRP) concentration. Direct sequencing of mtDNA in the D-loop region was done in the 20 adenocarcinoma samples and their corresponding surrounding non-cancerous tissue. Sequences were compared with existing mtDNA databases to identify mutations. RESULTS: mtDNA mutations in the D-loop region occur commonly with almost identical frequency in both non-cancerous tissue (3.0 +/- 1.6) and adenocarcinoma (3.1 +/- 1.9) (P = 0.916, paired t-test). CRP levels are not predictive of the number of D-loop mutations in both adenocarcinoma (beta: -0.131; 95% CI: -2.354-1.364; P = 0.583) and non-cancerous tissue samples (beta: 0.130; 95% CI: -1.125-1.933; P = 0.586). Five new mutations were identified that were not recorded previously in mtDNA databases. CONCLUSION: D loop mtDNA mutations are common in both gastro-oesophageal adenocarcinoma and surrounding non-cancerous tissue. However, the accumulation of such mutations appears to occur independent of systemic inflammation. The frequency of D-loop mutations is likely not useful as a marker for carcinogenesis in gastro oesophageal adenocarcinoma. PMID- 24762508 TI - Effects of clinical pathways used in surgery for uterine fibroids: a meta analysis. AB - BACKGROUND: Whether clinical pathways (CPWs) used in surgery for uterine fibroids have positive effects or not remains unclear. AIMS: To assess the implementation effectsof CPW sin surgery for uterine fibroids. MATERIALS AND METHODS: Eight databases were searched comprehensively from inception to November 2012, which including the Cochrane Library, PubMed, EMBASE, Web of Science, Chinese Biomedical Literature Database, etc. Two reviewers selected studies, assessed risk of bias, and extracted data of included studies independently. Jadad methodological approach was applied to assess the quality of included studies and meta-analysis was conducted by RevMan 5.1 software. RESULTS: Ten studies involving 775 patients were included. The aggregate overall results showed that a shorter average length of stay (mean difference (MD) = -1.61; 95% CI (-1.91, 1.31); P < 0.00001) and days of waiting for surgery (MD = -0.75; 95% CI (-1.06, 0.44); P < 0.00001) were associated with CPWs. A reduction in inpatient expenditures was observed in CPWs compared with usual care (MD = -1197.69; 95% CI (-1582.04, -813.35); P < 0.00001). A higher score of patient satisfaction was also found in CPWs. CONCLUSION: CPWs could significantly improve the quality of care in patients undergoing uterine fibroids surgery, which were associated with a significant reduction in average length of stay and days of waiting for surgery, a decrease in inpatient expenditures and an improvement in patient satisfaction. Formulating evidence based CPWs and variation control in CPWs should be focused in the future. PMID- 24762509 TI - A near tetraploid clone in acute myeloid leukemia with CD56 expression. AB - Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by specific morphology, immunophenotype and genetic rearrangements. Multiple recurrent chromosomal aberrations have been identified by conventional cytogenetic analysis, which are now widely recognized as one of the most important diagnostic and prognostic determinants in AML. Here, we present a case with unusual cytogenetics, which has been described in very few patients. PMID- 24762510 TI - Lambda light chain myeloma presenting as nodular hepatic lesion: a clinical rarity. AB - We report a case of a 63-year-old lady presenting with pain in the right hypochondrium, jaundice, anorexia, and firm tender hepatomegaly with remarkably high serum alkaline phosphatase. Abdominal ultrasonography revealed a hypoechoic solid space-occupying lesion in right lobe of liver which was cytologically diagnosed as hepatic plasmacytoma. Serum and urine immunofixation electrophoresis, serum free light chain ratio, and bone marrow examination further confirmed the presence of lambda light chain multiple myeloma in the background. The patient achieved complete remission after four cycles of induction therapy with thalidomide and dexamethasone protocol and consolidated with further four cycles of the same regimen. PMID- 24762511 TI - Calcifying epithelial odontogenic tumor: a clinico-radio-pathological dilemma. AB - The calcifying epithelial odontogenic tumor (CEOT) is a rare benign neoplasm of mandible in adults. The presentation of this entity is varied and often confused with a variety of mucosal and jaw lesions and clinical, radiological, and pathological feature of CEOT often-mimic malignancy. The objective of this report is to highlight the clinical features and radiological findings which should arouse suspicion of a benign lesion and importance of providing adequate clinical information to the pathologist to attain accurate diagnosis.We discussed two cases with tumors located in the maxilla. Both presented as expansile lesions with one biopsy proven squamous cell carcinoma. Both were pursued with clinico radiological suspicion of benign lesions and confirmed with pathological correlation of histology and immunohistochemistry as CEOT. Therefore a High index of suspicion and clinico-radiological information are the key feature for diagnosis of this rare tumor. PMID- 24762512 TI - Impact of hypothyroidism on primary anal malignant melanoma: a rare entity. AB - Primary melanoma of the anal canal is rare and highly malignant condition, which is 1% of all invasive tumors in this site. This condition is often mistaken for benign conditions as either hemorrhoids or rectal polyp. Thyroid-stimulating hormone stimulation causes high proliferation of malignant melanoma. The association of hypothyroidism with primary malignant melanoma of anal canal is very rare. We are reporting such a very rare case. PMID- 24762513 TI - Primary intracranial benign fibrous histiocytoma: report of an unusual case. AB - Benign fibrous histiocytomas (BFH) are neoplasms of the soft tissue and bone composed of fibroblastic and histiocytic components without any nuclear pleomorphism or histological anapalsia. Primary intracranial fibrous histiocytomas are rare entities. In comparison with the malignant counterpart, BFH are more uncommon. We describe a case of a 54-year-old woman, who presented with complaints of headache, giddiness, and gait instability of six months' duration. Magnetic resonance imaging (MRI) studies revealed an extra-axial lesion in the inferior aspect of the left temporal lobe suggestive of en-plaque meningioma. Subsequent histopathological examination of the biopsy sample revealed a benign fibrous histiocytoma, with involvement of the overlying temporal bone. Immunohistochemical analysis showed positivity for vimentin and CD68, with MIB-1 labeling index (MIB-1LI) of 2%, confirming the diagnosis. PMID- 24762514 TI - Postradiation hypertrichosis: a paradox. AB - Alopecia due to radiation has remained a widely accepted aspect of radiotherapy. We present an unexpected clinical scenario, where a patient with left lung stage IIIB nonsmall cell adenocarcinoma, treated with radiochemotherapy achieved a complete response and developed an obscure late effect in terms of paradoxical hypertrichosis in the radiation portals. The paper presents plausible hypothesis for this unusual phenomenon. PMID- 24762515 TI - Pathological features of primary mediastinal neuroendocrine carcinoma. PMID- 24762516 TI - Psychosomatic complaint during S1 cancer therapy: a case study. PMID- 24762517 TI - Breast mass as a clinical feature of B-cell chronic lymphocytic leukemia. PMID- 24762518 TI - A rare case of xanthogranulomatous oopharitis. PMID- 24762519 TI - Papanicolaou (pap) test screening-Need of the hour. PMID- 24762520 TI - Clarifications concerning the case report on "extra-skeletal ewings sarcoma of the sinonasal tract". PMID- 24762521 TI - Bilateral sudden hearing loss following ABVD protocol. PMID- 24762522 TI - Curious case of a primary intranodal kaposi sarcoma, confirmed by immunohistochemistry, in an HIV-positive African male. PMID- 24762523 TI - Thymoma: Clinical experience from a tertiary care institute from North India. PMID- 24762524 TI - Metastatic soft tissue squamous cell carcinoma: unusual presentation of lung cancer. PMID- 24762525 TI - Use of a new availability index to evaluate the effect of policy changes to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) on the food environment in New Orleans. AB - OBJECTIVE: Changes to the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) occurred in 2009 when supplemental foods offered through the programme were updated to align with current dietary recommendations. The present study reports on a new index developed to monitor the retail environment's adoption of these new food supply requirements in New Orleans. DESIGN: A 100-point WIC Availability Index (WIC-AI) was derived from new minimum state stocking requirements for WIC vendors. A sample of supermarkets, medium and small food stores was assessed in 2009 before changes were implemented and in 2010 after revisions had gone into effect. WIC-AI scores were utilized to compare differences in meeting requirements by store type, WIC vendor status and year of measurement. SETTING: Supermarkets, medium and small WIC and non-WIC food stores in New Orleans, Louisiana, USA. RESULTS: At baseline supermarkets had the highest median WIC-AI score (93.3) followed by medium (69.8) and small food stores (48.0). Small WIC stores had a higher median WIC-AI score at baseline than small non-WIC stores (66.9 v. 38.0). Both medium and small WIC stores significantly increased their median WIC-AI scores between 2009 and 2010 (P<0.01). The increased median WIC-AI score in small food stores was largely attributed to increased availability of cereals and grains, juices and fruit, and infant fruit and vegetables. CONCLUSIONS: The WIC-AI is a simple tool useful in summarizing complex food store environment data and may be adapted for use in other states or a national level to inform food policy decisions and direction. PMID- 24762526 TI - TV Watching, but Not Physical Activity, Is Associated With Change in Kidney Function in Older Adults. AB - BACKGROUND: Physical activity (PA) may play a role in preserving kidney health. The purpose of this study was to determine if PA and sedentary behavior are associated with incident chronic kidney disease (CKD) and change in kidney function in older adults. METHODS: The Health, Aging, and Body Composition study is a prospective cohort of 3075 well-functioning older adults. PA and television watching was measured by self-report, and serum cystatin C was used to estimate glomerular filtration rate (eGFR). CKD was defined as an eGFR <60 ml/min/1.73 m(2). Rapid kidney function decline was defined as an annual loss in eGFR of >3 ml/min/1.73 m(2). Discrete survival analysis was used to determine if baseline PA and television watching were related to 10-year cumulative incidence of CKD and rapid decline in kidney function. RESULTS: Individuals who reported watching television >3 hours/day had a higher risk of incident CKD (HR 1.34; 95% CI, 1.09 1.65) and experiencing a rapid decline in kidney function (HR 1.26; 95% CI, 1.05 1.52) compared with individuals who watched television <2 hours/day. PA was not related to either outcome. CONCLUSIONS: High levels of television watching are associated with declining kidney function; the mechanisms that underlie this association need further study. PMID- 24762527 TI - Optimized conditions for phytoremediation of diesel by Scirpus grossus in horizontal subsurface flow constructed wetlands (HSFCWs) using response surface methodology. AB - This study investigated the optimum conditions for total petroleum hydrocarbon (TPH) removal from diesel-contaminated water using phytoremediation treatment with Scirpus grossus. In addition, TPH removal from sand was adopted as a second response. The optimum conditions for maximum TPH removal were determined through a Box-Behnken Design. Three operational variables, i.e. diesel concentration (0.1, 0.175, 0.25% Vdiesel/Vwater), aeration rate (0, 1 and 2 L/min) and retention time (14, 43 and 72 days), were investigated by setting TPH removal and diesel concentration as the maximum, retention time within the given range, and aeration rate as the minimum. The optimum conditions were found to be a diesel concentration of 0.25% (Vdiesel/Vwater), a retention time of 63 days and no aeration with an estimated maximum TPH removal from water and sand of 76.3 and 56.5%, respectively. From a validation test of the optimum conditions, it was found that the maximum TPH removal from contaminated water and sand was 72.5 and 59%, respectively, which was a 5 and 4.4% deviation from the values given by the Box-Behnken Design, providing evidence that S. grossus is a Malaysian native plant that can be used to remediate wastewater containing hydrocarbons. PMID- 24762528 TI - An approach to assessing multicity implementation of healthful food access policy, systems, and environmental changes. AB - Local governments play an increasingly important role in improving residents' access to healthful food and beverages to reduce obesity and chronic disease. Cities can use multiple strategies to improve community health through, for example, land use and zoning policies, city contracting and procurement practices, sponsorship of farmers markets and community gardens, and vending and concession practices in parks and recreation facilities. With 41 cities in the Hennepin County Human Services and Public Health Department jurisdiction, the county undertook to measure the extent to which cities were engaged in making policy, systems, and environmental (PSE) changes to increase residents' access to healthful food. The results revealed that some cities, particularly those with higher resident demand for healthful food, are making nationally recommended PSE changes, such as sponsoring farmers markets and community gardens. Cities have moved more slowly to make changes in areas with perceived negative cost consequences or lesser public demand, such as parks and recreation vending and concessions. This article describes the assessment process, survey tools, findings, and implications for other health departments seeking to undertake a similar assessment. PMID- 24762529 TI - Consumption of sugar-sweetened beverages among US adults in 6 states: Behavioral Risk Factor Surveillance System, 2011. AB - INTRODUCTION: Sugar-sweetened beverage (SSB) intake is linked to weight gain. Our objective was to examine state-specific SSB intake and behavioral characteristics associated with SSB intake. METHODS: We used data from the 2011 Behavioral Risk Factor Surveillance System for 38,978 adults aged 18 years or older from 6 states: Delaware, Hawaii, Iowa, Minnesota, New Jersey, and Wisconsin. Multivariate logistic regression was used to estimate adjusted odds ratios for characteristics associated with SSB intake from regular soda and fruit drinks. RESULTS: Overall, 23.9% of adults drank SSBs at least once a day. Odds of drinking SSBs 1 or more times per day were significantly greater among younger adults; males; non-Hispanic blacks; adults with lower education; low-income adults or adults with missing income data; adults living in Delaware, Iowa, and Wisconsin versus those living in Minnesota; adults with fruit intake of less than 1 time a day versus 1 or more times a day; adults who were physically inactive versus highly active adults; and current smokers versus nonsmokers. Odds for drinking SSBs 1 or more times per day were significantly lower among adults with 100% fruit juice intake of less than 1 time per day versus 1 or more times per day and among adults who drank alcohol versus those who did not drink alcohol. CONCLUSION: SSB intake varied by states and certain sociodemographic and behavioral characteristics. States can use findings from this study to tailor efforts to decrease SSB intake and to encourage consumption of more healthful beverages (eg, water) among their high-risk populations. PMID- 24762530 TI - The relationship between state policies for competitive foods and school nutrition practices in the United States. AB - INTRODUCTION: Most students in grades kindergarten through 12 have access to foods and beverages during the school day outside the federal school meal programs, which are called competitive foods. At the time of this study, competitive foods were subject to minimal federal nutrition standards, but states could implement additional standards. Our analysis examined the association between school nutrition practices and alignment of state policies with Institute of Medicine recommendations (IOM Standards). METHODS: For this analysis we used data from the Centers for Disease Control and Prevention's (CDC's) report, Competitive Foods and Beverages in US Schools: A State Policy Analysis and CDC's 2010 School Health Profiles (Profiles) survey to examine descriptive associations between state policies for competitive foods and school nutrition practices. RESULTS: Access to chocolate candy, soda pop, sports drinks, and caffeinated foods or beverages was lower in schools in states with policies more closely aligned with IOM Standards. No association was found for access to fruits or nonfried vegetables. CONCLUSION: Schools in states with policies more closely aligned with the IOM Standards reported reduced access to less healthful competitive foods. Encouraging more schools to follow these standards will help create healthier school environments and may help promote healthy eating among US children. PMID- 24762532 TI - Using concept mapping to develop a conceptual framework for creating virtual communities of practice to translate cancer research into practice. AB - INTRODUCTION: Translating government-funded cancer research into clinical practice can be accomplished via virtual communities of practice that include key players in the process: researchers, health care practitioners, and intermediaries. This study, conducted from November 2012 through January 2013, examined issues that key stakeholders believed should be addressed to create and sustain government-sponsored virtual communities of practice to integrate cancer control research, practice, and policy and demonstrates how concept mapping can be used to present relevant issues. METHODS: Key stakeholders brainstormed statements describing what is needed to create and sustain virtual communities of practice for moving cancer control research into practice. Participants rated them on importance and feasibility, selected most relevant statements, and sorted them into clusters. I used concept mapping to examine the issues identified and multidimensional scaling analyses to create a 2-dimensional conceptual map of the statement clusters. RESULTS: Participants selected 70 statements and sorted them into 9 major clusters related to creating and sustaining virtual communities of practice: 1) standardization of best practices, 2) external validity, 3) funding and resources, 4) social learning and collaboration, 5) cooperation, 6) partnerships, 7) inclusiveness, 8) social determinants and cultural competency, and 9) preparing the environment. Researchers, health care practitioners, and intermediaries were in relative agreement regarding issues of importance for creating these communities. CONCLUSION: Virtual communities of practice can be created to address the needs of researchers, health care practitioners, and intermediaries by using input from these key stakeholders. Increasing linkages between these subgroups can improve the translation of research into practice. Similarities and differences between groups can provide valuable information to assist the government in developing virtual communities of practice. PMID- 24762531 TI - Adaptation of a cervical cancer education program for African Americans in the faith-based community, Atlanta, Georgia, 2012. AB - BACKGROUND: From 1999 through 2009, African American women in the United States had the second highest incidence rates of cervical cancer and were more likely to die from cervical cancer than women of other races. Con Amor Aprendemos (CAA) is an intervention created to educate the Latino community to reduce their risk for cervical cancer and diseases related to human papilloma virus (HPV). CAA was adapted to With Love We Learn (WLWL) to prevent cervical cancer and HPV in African American communities. COMMUNITY CONTEXT: Health ministries of 2 churches in the Atlanta area partnered with the Spirit Foundation Inc to adapt CAA to WLWL by tailoring the curriculum to the African American faith-based community. METHODS: The National Cancer Institute's Research to Reality (R2R) mentorship program pair collaborated with program staff on an adaptation summary form, a tool to document and assist with adapting the program curriculum with fidelity. Trainers, faith leaders, and participants adapted the program in 4 phases: 1) review of the CAA curriculum, 2) a focus group discussion to determine changes for the WLWL curriculum, 3) train-the-trainer sessions on program delivery, and 4) a pilot intervention and follow-up focus group to evaluate the new curriculum. OUTCOMES: The CAA/WLWL curriculum was adapted and piloted in a faith-based setting. Adaptations to the CAA program included pictures, games, statistics on cervical cancer, dialogues, and delivery of curriculum. INTERPRETATION: Community engagement in the adaptation of WLWL through various methods was critical to tailoring an evidence-based program to a new population and setting. PMID- 24762533 TI - Patient and practice perspectives on strategies for controlling blood pressure, North Carolina, 2010-2012. AB - INTRODUCTION: Patient and practice perspectives can inform development of team based approaches to improving blood pressure control in primary care. We used a community-based participatory research approach to assess patient and practice perceptions regarding the value of team-based strategies for controlling blood pressure in a rural North Carolina population from 2010 through 2012. METHODS: In depth interviews were conducted with 41 adults with hypertension, purposely sampled to include diversity of sex, race, literacy, and blood pressure control, and with key office staff at 5 rural primary care practices in the southeastern US "stroke belt." Interviews explored barriers to controlling blood pressure, the practice's role in controlling blood pressure, and opinions on the use of team care delivery. RESULTS: Patients reported that provider strategies to optimize blood pressure control should include regular visits, medication adjustment, side effect discussion, and behavioral counseling. When discussing team-based approaches to hypertension care, patients valued verbal encouragement, calls from the doctor's office, and the opportunity to ask questions. However, they voiced concerns about the effect of having too many people involved in their care. Practice staff focused on multiple, broad methods to control blood pressure including counseling, regular office visits, media to improve awareness, and support groups. An explicit focus of delivering care as teams was a newer concept. CONCLUSION: When developing a team approach to hypertension treatment, patients value high-quality communication and not losing their primary relationship with their provider. Practice staff members were open to a team based approach but had limited knowledge of what such an approach would entail. PMID- 24762534 TI - Preparation of few-layer bismuth selenide by liquid-phase-exfoliation and its optical absorption properties. AB - Bismuth selenide (Bi2Se3), a new topological insulator, has attracted much attention in recent years owing to its relatively simple band structure and large bulk band gap. Compared to bulk, few-layer Bi2Se3 is recently considered as a highly promising material. Here, we use a liquid-phase exfoliation method to prepare few-layer Bi2Se3 in N-methyl-2-pyrrolidone or chitosan acetic solution. The resulted few-layer Bi2Se3 dispersion demonstrates an interesting absorption in the visible light region, which is different from bulk Bi2Se3 without any absorption in this region. The absorption spectrum of few-layer Bi2Se3 depends on its size and layer number. At the same time, the nonlinear and saturable absorption of few-layer Bi2Se3 thin film in near infrared is also characterized well and further exploited to generate laser pulses by a passive Q-switching technique. Stable Q-switched operation is achieved with a lower pump threshold of 9.3 mW at 974 nm, pulse energy of 39.8 nJ and a wide range of pulse-repetition rate from 6.2 to 40.1 kHz. Therefore, the few-layer Bi2Se3 may excite a potential applications in laser photonics and optoelectronic devices. PMID- 24762535 TI - Mechanisms of reef coral resistance to future climate change. AB - Reef corals are highly sensitive to heat, yet populations resistant to climate change have recently been identified. To determine the mechanisms of temperature tolerance, we reciprocally transplanted corals between reef sites experiencing distinct temperature regimes and tested subsequent physiological and gene expression profiles. Local acclimatization and fixed effects, such as adaptation, contributed about equally to heat tolerance and are reflected in patterns of gene expression. In less than 2 years, acclimatization achieves the same heat tolerance that we would expect from strong natural selection over many generations for these long-lived organisms. Our results show both short-term acclimatory and longer-term adaptive acquisition of climate resistance. Adding these adaptive abilities to ecosystem models is likely to slow predictions of demise for coral reef ecosystems. PMID- 24762536 TI - Genomic diversity and admixture differs for Stone-Age Scandinavian foragers and farmers. AB - Prehistoric population structure associated with the transition to an agricultural lifestyle in Europe remains a contentious idea. Population-genomic data from 11 Scandinavian Stone Age human remains suggest that hunter-gatherers had lower genetic diversity than that of farmers. Despite their close geographical proximity, the genetic differentiation between the two Stone Age groups was greater than that observed among extant European populations. Additionally, the Scandinavian Neolithic farmers exhibited a greater degree of hunter-gatherer-related admixture than that of the Tyrolean Iceman, who also originated from a farming context. In contrast, Scandinavian hunter-gatherers displayed no significant evidence of introgression from farmers. Our findings suggest that Stone Age foraging groups were historically in low numbers, likely owing to oscillating living conditions or restricted carrying capacity, and that they were partially incorporated into expanding farming groups. PMID- 24762537 TI - The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal. AB - Tissue-resident macrophages are heterogeneous as a consequence of anatomical niche-specific functions. Many populations self-renew independently of bone marrow in the adult, but the molecular mechanisms of this are poorly understood. We determined a transcriptional profile for the major self-renewing population of peritoneal macrophages in mice. These cells specifically expressed the transcription factor Gata6. Selective deficiency of Gata6 in myeloid cells caused substantial alterations in the transcriptome of peritoneal macrophages. Gata6 deficiency also resulted in dysregulated peritoneal macrophage proliferative renewal during homeostasis and in response to inflammation, which was associated with delays in the resolution of inflammation. Our investigations reveal that the tissue macrophage phenotype is under discrete tissue-selective transcriptional control and that this is fundamentally linked to the regulation of their proliferation renewal. PMID- 24762538 TI - Faster decomposition under increased atmospheric CO2 limits soil carbon storage. AB - Soils contain the largest pool of terrestrial organic carbon (C) and are a major source of atmospheric carbon dioxide (CO2). Thus, they may play a key role in modulating climate change. Rising atmospheric CO2 is expected to stimulate plant growth and soil C input but may also alter microbial decomposition. The combined effect of these responses on long-term C storage is unclear. Combining meta analysis with data assimilation, we show that atmospheric CO2 enrichment stimulates both the input (+19.8%) and the turnover of C in soil (+16.5%). The increase in soil C turnover with rising CO2 leads to lower equilibrium soil C stocks than expected from the rise in soil C input alone, indicating that it is a general mechanism limiting C accumulation in soil. PMID- 24762539 TI - Palliative sedation for cancer patients included in a home care program: a retrospective study. AB - OBJECTIVE: Palliative sedation is a common treatment in palliative care. The home is a difficult environment for research, and there are few studies about sedation at home. Our aim was to analyze this practice in a home setting. METHOD: We conducted a retrospective cross-sectional descriptive study in a home cohort during 2011. The inclusion criteria were as follows: 18 years or older and enrolled in the Palliative Home Care Program (PHCP) with advanced cancer. The variables employed were: sex, age, primary tumor location, and place of death. We also registered indication, type, drug and dose, awareness of diagnosis and prognosis, consent, survival, presence or absence of rales, painful mouth, and ulcers in patients sedated at home. We also collected the opinions of family members and professionals about the suffering of sedated patients. RESULTS: A total of 446 patients (56% at home) of the 617 admitted to the PHCP between January and December of 2011 passed away. The typical patient in our population was a 70-year-old man with a lung tumor. Some 35 (14%) home patients required sedation, compared to 93 (49%) at the hospital. The most frequent indication was delirium (70%), with midazolam the most common drug (mean dose, 40 mg). Survival was around three days. Rales were frequent (57%) as well as awareness of diagnosis and prognosis (77 and 71%, respectively). Perception of suffering after sedation was rare among relatives (17%) and professionals (8%). In most cases, the decision was made jointly by professionals and family members. SIGNIFICANCE OF RESULTS: Our study confirmed the role of palliative sedation as an appropriate therapeutic tool in the home environment. PMID- 24762540 TI - Interaction of vanadium (IV) solvates (L) with second-generation fluoroquinolone antibacterial drug ciprofloxacin: spectroscopic, structure, thermal analyses, kinetics and biological evaluation (L=An, DMF, Py and Et3N). AB - The preparation and characterization of the new solid complexes [VO(CIP)2L]SO4?nH2O, where L=aniline (An), dimethylformamide (DMF), pyridine (Py) and triethylamine (Et3N) in the reaction of ciprofloxacin (CIP) with VO(SO4)2.2H2O in ethanol. The isolated complexes have been characterized with their melting points, elemental analysis, IR spectroscopy, magnetic properties, conductance measurements, UV-Vis. and (1)H NMR spectroscopic methods and thermal analyses. The results supported the formation of the complexes and indicated that ciprofloxacin reacts as a bidentate ligand bound to the vanadium ion through the pyridone oxygen and one carboxylato oxygen. The activation energies, E(*); entropies, DeltaS(*); enthalpies, DeltaH(*); Gibbs free energies, DeltaG(*), of the thermal decomposition reactions have been derived from thermo gravimetric (TGA) and differential thermo gravimetric (DTG) curves, using Coats-Redfern and Horowitz-Metzeger methods. The lowest energy model structure of each complex has been proposed by using the density functional theory (DFT) at the B3LYP/CEP-31G level of theory. The ligand and their metal complexes were also evaluated for their antibacterial activity against several bacterial species, such as Bacillus Subtilis (B. Subtilis), Staphylococcus aureus (S. aureus), Nesseria Gonorrhoeae (N. Gonorrhoeae), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli). PMID- 24762541 TI - Green synthesis of silver nanoparticles from the extract of the inflorescence of Cocos nucifera (Family: Arecaceae) for enhanced antibacterial activity. AB - Green synthesis of nanoparticles using plant source has been given much importance. In the present study, silver nanoparticles (AgNPs) were synthesized using the ethyl acetate and methanol (EA: M 40:60) extracts of the inflorescence of the tree Cocous nucifera. The synthesized nanoparticles were characterized by UV-visible spectroscope, FTIR and TEM analysis. The particle size of the synthesized AgNPs was 22nm as confirmed by TEM. The qualitative assessment of reducing potential of the extracts of inflorescence indicated the presence of reducing agents. Synthesized AgNPs exhibited significant antimicrobial activity against human bacterial pathogens viz., Klebsiella pneumoniae, Bacillus subtilis, Pseudomonas aeruginosa and Salmonella paratyphi. PMID- 24762542 TI - Prognostic significance of lymphatic invasion in lymph node-positive breast carcinoma: findings from a large case series with long-term follow-up using immunohistochemical endothelial marker. AB - The poor prognostic significance of lymphatic invasion (LI) in breast carcinoma (BC) as a whole and in lymph node (LN)-negative patients in particular has been recognized in several studies; however, its prognostic role in LN-positive patients is still questionable. Aim of the current study was to assess prognostic role of LI in LN-positive BC specimens. Sections from non-selected 557 LN positive BC specimens were stained with antibody to podoplanin/D2-40. LI was identified and correlated with clinicopathological features and patients' outcome. Twenty-year overall survival (OS), disease-free interval (DFI), and development of distant metastasis (DM) or recurrence were known for all patients. LI was detected in 262/557 (47%) of specimens ranging from 1 to 350 lesion per tumor section. Its presence was associated with higher grade tumors (P<0.0001), negative hormonal receptors (P<0.0001), high HER-2 expression (P=0.006), and with increased number of positive LNs (P=0.019). In the whole LN-positive BC, presence of LI was a poor prognostic factor for OS, DFI, and development of DM both in univariate and in multivariate analysis. In further stratification of patients, LI was associated with poorer prognosis in patients with single positive LN and not in patients with >1 positive LN. In T1N1 stage, LI was highly associated with poor OS (P=0.002), DFI (P<0.0001), and DM (P<0.0001). In T2N1 patients, LI was associated only with poorer DFI (P=0.037) but not with death or DM. In the two former patient groups, LI lost significance in multivariate analysis. In conclusion, LI is a poor prognostic factor in LN-positive BC particularly for patients having single positive LN. LI therefore would add further prognostic significance when considered in treatment in those patients. We recommend incorporation of LI in breast carcinoma staging and in prognostic indices. PMID- 24762543 TI - High concordance in grading reticulin fibrosis and cellularity in patients with myeloproliferative neoplasms. AB - The myeloproliferative neoplasms primary myelofibrosis, polycythemia vera, and, rarely, essential thrombocythemia are characterized by variable degrees of bone marrow fibrosis, either at presentation or upon progression. The increasing use of emerging therapies that may alter disease biology and morphology demands accurate and reproducible assessment of fibrosis grade. To assess concordance of hematopoietic cellularity and fibrosis grading, three hematopathologists independently evaluated a total of 728 bone marrow biopsies from 261 patients with myeloproliferative neoplasms on three clinical trials using fedratinib (SAR302503), a JAK2 inhibitor, including 249 taken at baseline and 479 on therapy. Concordance between the pathologists was evaluated by Pearson correlation coefficient (cellularity) and unweighted kappa statistic (fibrosis grade). There was high correlation of cellularity assessment (r=0.92) and fibrosis grading (kappa=0.83) between the three pathologists. Concordance with World Health Organization (WHO) grade 3 samples was higher compared with grades 0, 1, and 2. Concordance of fibrosis grading in pretreatment samples was superior to that of post-treatment samples (kappa=0.83 and 0.79, respectively, P=0.023). Our analysis suggests that the updated 2008 WHO reticulin fibrosis grading system is highly reproducible, even in patients undergoing JAK2 inhibitor therapy. This system is practically applicable to establish baseline fibrosis grade as well as changes in fibrosis in subsequent samples on therapy. PMID- 24762544 TI - Prevalence, morphology, and natural history of FGFR1-amplified lung cancer, including squamous cell carcinoma, detected by FISH and SISH. AB - The aim of this study was to investigate the prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification by fluorescence in situ hybridization (FISH) in a lung cancer patient cohort and to correlate results with morphology, silver in situ hybridization (SISH), and patient outcome. FGFR1 FISH and SISH were performed in 406 and 385 lung cancer cases, respectively, and the results were compared. High-level FGFR1 amplification was defined as the ratio of FGFR1/centromere 8 >=2, or tumor cell percentage with >=15 signals >=10%, or average number of signals/tumor cell nucleus >=6. Low-level amplification was defined as tumor cell percentage with >=5 signals >=50%. Of 406 tumors tested, there were 191 squamous cell carcinomas, 28 carcinomas with focal squamous morphology, 24 large cell carcinomas with squamous immunoprofile, 115 adenocarcinomas, 17 neuroendocrine tumors, and 31 carcinomas without squamous morphology or immunoprofile. FGFR1 FISH was assessable in 368 tumors, with FGFR1 amplification identified in 50, including 48 tumors with either squamous morphology or immunoprofile (48 of 225, 21.3%), and two 'marker-null' tumors without squamous or glandular morphology or immunoprofile (2 of 143, 1.4%; P<0.0001). FGFR1 SISH was assessable in 347 tumors. All 46 FGFR1 FISH-amplified tumors with tumor available for testing showed amplification with SISH, while all other tumors were negative. There was no relationship between FGFR1 amplification status and disease-free (P=0.88, HR=1.04, 95% confidence interval (CI)=0.67-1.60) or overall survival (P=0.97, HR=1.01, 95% CI=0.65-1.58) in surgically radically treated patients with tumors with any squamous morphology or immunoprofile. FGFR1 amplification is a common abnormality in tumors with any squamous morphology or immunoprofile, but it is also present in 'marker-null' tumors. The results of FGFR1 SISH showed 1:1 correlation with the results of FGFR1 FISH, indicating that SISH may be an alternative method to detect FGFR1 amplification. No relationship was detected between patient outcome and FGFR1 amplification. PMID- 24762545 TI - High specificity but low sensitivity of mutation-specific antibodies against EGFR mutations in non-small-cell lung cancer. AB - Determination of epidermal growth factor receptor (EGFR) mutations has a pivotal impact on treatment of non-small-cell lung cancer (NSCLC). A standardized test has not yet been approved. So far, Sanger DNA sequencing has been widely used. Its rather low sensitivity has led to the development of more sensitive methods including real-time PCR (RT-PCR). Immunohistochemistry with mutation-specific antibodies might be a promising detection method. We evaluated 210 samples with NSCLC from an unselected Caucasian population. Extracted DNA was analyzed for EGFR mutations by RT-PCR (Therascreen EGFR PCR kit, Qiagen, UK; reference method). For immunohistochemistry, antibodies against exon19 deletions (clone 6B6), exon21 mutations (clone 43B2) from Cell Signaling Technology (Boston, USA) and EGFR variantIII (clone 218C9) from Dako (Copenhagen, DK) were applied. Protein expression was evaluated, and staining score (multipum of intensity (graded 0-3) and percentages (0-100%) of stained tumor cells) was calculated. Positivity was defined as staining score >0. Specificity of exon19 antibody was 98.8% (95% confidence interval=95.9-99.9%) and of exon21 antibody 97.8% (95% confidence interval=94.4-99.4%). Sensitivity of exon19 antibody was 63.2% (95% confidence interval=38.4-83.7%) and of exon21 antibody was 80.0% (95% confidence interval=44.4-97.5%). Seven exon19 and four exon21 mutations were false negatives (immunohistochemistry negative, RT-PCR positive). Two exon19 and three exon21 mutations were false positive (immunohistochemistry positive, RT-PCR negative). One false positive exon21 mutation had staining score 300. The EGFR variantIII antibody showed no correlation to EGFR mutation status determined by RT-PCR or to EGFR immunohistochemistry. High specificity of the mutation-specific antibodies was demonstrated. However, sensitivity was low, especially for exon19 deletions, and thus these antibodies cannot yet be used as screening method for EGFR mutations in NSCLC. Refinement of sensitivity for the mutation-specific antibodies is warranted to improve molecular diagnosis using EGFR immunohistochemistry. PMID- 24762546 TI - Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer. AB - TMPRSS2:ERG fusions, in combination with deletion of the phosphatase and tensin homolog (PTEN) tumor suppressor, have been suggested to cooperatively drive tumor progression in prostate cancer. We utilized a novel heterogeneity tissue microarray containing samples from 10 different tumor blocks of 189 prostatectomy specimens to study heterogeneity of genomic PTEN alterations in individual foci. PTEN alterations were found in 48/123 (39%) analyzable individual tumor foci, including 40 foci with deletions, 7 with deletion and rearrangement, and 1 focus with rearrangement only. PTEN was homogeneously aberrant in only 4 (8%) and heterogeneously in 44 (92%) of the foci. We found a specific sequence of molecular events from PTEN breakage followed by deletion of DNA sequences flanking the breakpoint, resulting in homozygous deletion. The observation that 16 of 19 foci with homogeneous ERG positivity had focal PTEN alterations but none of 10 foci with PTEN alterations had focal ERG positivity (P<0.0001) suggests that PTEN alterations typically develop subsequent to ERG fusions. We demonstrate a high level of intratumoral heterogeneity of PTEN alterations with deletions and rearrangements that challenges potential PTEN routine diagnosis testing in biopsies. The observation that PTEN alterations develop subsequent to ERG fusion strongly suggests that ERG expression may directly drive development of PTEN aberrations. PMID- 24762547 TI - In vivo intratumoral Epstein-Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications. AB - Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell differentiation and XBP1 activation with prognostic implications. Both latency III and lytic EBV infection are related to aggressive and early-onset post transplant lymphoproliferative disorder. These results suggest that immunohistochemical study of latent and lytic EBV genes in the clinical practice may help to select higher-risk patients to new therapies including antiviral treatments. PMID- 24762548 TI - HPV prevalence and genotypes in different histological subtypes of cervical adenocarcinoma, a worldwide analysis of 760 cases. AB - The goal of our study was to provide comprehensive data on the worldwide human papillomavirus (HPV) genotype distribution in patients with invasive cervical adenocarcinoma in correlation with histologic tumor subtypes, geographical location, patients' age, and duration of sample storage. Paraffin-embedded samples of 760 cervical adenocarcinoma cases were collected worldwide. A three level pathology review of cases was performed to obtain consensus histologic diagnoses and 682 cases were determined to be eligible for further analysis. HPV DNA detection and genotyping was performed using SPF-10/DEIA/LiPA(25) system (version 1). Classic cervical adenocarcinoma accounted for 83.1% of cases, while rare histological variants accounted for a few percent of cases individually. HPV positivity varied significantly between the different histologic tumor subtypes. Classic cervical adenocarcinoma showed high HPV positivity (71.8%), while other adenocarcinoma types had significantly lower HPV prevalence (endometrioid 27.3%, serous 25%, clear cell 20%, not otherwise specified 13.9%, and minimal deviation 8.3%). In all, 91.8% of HPV-positive tumors showed the presence of a single viral type and in 7% of cases multiple viral types were detected. Three HPV genotypes, HPV 16, 18, and 45, dominated in all adenocarcinomas and together accounted for 94.1% of HPV-positive tumors. HPV16 was the most common and found in 50.9% of HPV positive cases, followed by HPV18 (31.6%) and HPV45 (11.6%). HPV prevalence varied depending on geographical region, patient age, and sample storage time. Tumors from older patients and tumor samples with longer storage time showed lower HPV prevalence. Our results indicate that HPV vaccines may prevent up to 82.5% (HPV16/18) and up to 95.3% (9-valent vaccine) of HPV-positive cervical adenocarcinomas, mostly the classic type. HPV testing and vaccination will not provide full coverage for a very small subset of classical adenocarcinomas and most of the rare tumor variants such as clear cell, serous, endometrioid, and minimal deviation. PMID- 24762550 TI - Inhibition of anaerobic wastewater treatment after long-term exposure to low levels of CuO nanoparticles. AB - CuO nanoparticles (NPs) are released into wastewater due to the widespread use and generation as by-product in various applications (e.g. semiconductor manufacturing). However, information on the behavior and impact of CuO NPs on wastewater treatment processes is very limited. The objective of this study was to evaluate the fate and long-term effect of CuO NPs (average size = 37 nm) on high-rate anaerobic bioreactors. A laboratory-scale upflow anaerobic sludge blanket reactor was operated with a synthetic wastewater containing low concentrations of CuO NPs (1.4 mg Cu L(-1)) and a mixture of volatile fatty acids for 107 days. CuO NPs were largely removed during anaerobic treatment and on the average only 20-32% of the NPs fed to the reactor escaped with the effluent. Scanning electron microscopy and chemical analysis confirmed that CuO NPs were partitioned into the anaerobic sludge. While short-term exposure to CuO NPs (1.4 mg Cu L(-1)) only caused minor inhibition to methanogenesis, extended exposure caused severe toxicity and reduced the acetoclastic methanogenic activity by more than 85%. Moreover, the reactor performance was completely disrupted and the methane production decreased by more than 50%. The study is the first to demonstrate a significant long-term effect of low levels of CuO NPs on methanogenesis. PMID- 24762549 TI - Tumor budding is associated with an increased risk of lymph node metastasis and poor prognosis in superficial esophageal adenocarcinoma. AB - The treatment approach for superficial (stage T1) esophageal adenocarcinoma critically depends on the pre-operative assessment of metastatic risk. Part of that assessment involves evaluation of the primary tumor for pathologic characteristics known to predict nodal metastasis: depth of invasion (intramucosal vs submucosal), angiolymphatic invasion, tumor grade, and tumor size. Tumor budding is a histologic pattern that is associated with poor prognosis in early-stage colorectal adenocarcinoma and a predictor of nodal metastasis in T1 colorectal adenocarcinoma. In a retrospective study, we used a semi-quantitative histologic scoring system to categorize 210 surgically resected, superficial (stage T1) esophageal adenocarcinomas according to the extent of tumor budding (none, focal, and extensive) and also evaluated other known risk factors for nodal metastasis, including depth of invasion, angiolymphatic invasion, tumor grade, and tumor size. We assessed the risk of nodal metastasis associated with tumor budding in univariate analyses and controlled for other risk factors in a multivariate logistic regression model. In all, 41% (24 out of 59) of tumors with extensive tumor budding (tumor budding in >=3 20X microscopic fields) were metastatic to regional lymph nodes, compared with 10% (12 out of 117) of tumors with no tumor budding, and 15% (5 out of 34) of tumors with focal tumor budding (P<0.001). When controlling for all pathologic risk factors in a multivariate analysis, extensive tumor budding remains an independent risk factor for lymph node metastasis in superficial esophageal adenocarcinoma associated with a 2.5-fold increase (95% CI=1.1-6.3, P=0.039) in the risk of nodal metastasis. Extensive tumor budding is also a poor prognostic factor with respect to overall survival and time to recurrence in univariate and multivariate analyses. As an independent risk factor for nodal metastasis and poor prognosis after esophagectomy, tumor budding should be evaluated in superficial (T1) esophageal adenocarcinoma as a part of a comprehensive pathologic risk assessment. PMID- 24762551 TI - Forward osmosis for application in wastewater treatment: a review. AB - Research in the field of Forward Osmosis (FO) membrane technology has grown significantly over the last 10 years, but its application in the scope of wastewater treatment has been slower. Drinking water is becoming an increasingly marginal resource. Substituting drinking water for alternate water sources, specifically for use in industrial processes, may alleviate the global water stress. FO has the potential to sustainably treat wastewater sources and produce high quality water. FO relies on the osmotic pressure difference across the membrane to extract clean water from the feed, however the FO step is still mostly perceived as a "pre-treatment" process. To prompt FO-wastewater feasibility, the focus lies with new membrane developments, draw solutions to enhance wastewater treatment and energy recovery, and operating conditions. Optimisation of these parameters are essential to mitigate fouling, decrease concentration polarisation and increase FO performance; issues all closely related to one another. This review attempts to define the steps still required for FO to reach full-scale potential in wastewater treatment and water reclamation by discussing current novelties, bottlenecks and future perspectives of FO technology in the wastewater sector. PMID- 24762552 TI - Photodegradation kinetics of iopamidol by UV irradiation and enhanced formation of iodinated disinfection by-products in sequential oxidation processes. AB - The photochemical degradation of iopamidol with low-pressure UV lamps and the formation of iodinated disinfection by-products (I-DBPs) during sequential oxidation processes including chlorine, monochloramine and chlorine dioxide were investigated in this study. Iopamidol can be effectively decomposed by UV irradiation with pseudo-first order reaction kinetics. The evaluated quantum yield was found to be 0.03318 mol einstein(-1). Results showed that iopamidol degradation rate was significantly increased by higher UV intensity and lower initial iopamidol concentration. However, the effect of solution pH was negligible. Degradation of iopamidol by UV photolysis was subjected to deiodination and hydroxylation mechanisms. The main degradation products including -OH substitutes and iodide were identified by UPLC-ESI-MS and UPLC-UV, respectively. Increasing the intensity of UV irradiation promoted the release of iodide. Destruction pathways of iopamidol photolysis were proposed. Enhanced formation of I-DBPs were observed after iopamidol photolysis followed by disinfection processes including chlorine, monochloramine and chlorine dioxide. With the increase of UV fluence, I-DBPs formation were significantly promoted. PMID- 24762553 TI - Optimal design and operation of booster chlorination stations layout in water distribution systems. AB - This study describes a new methodology for the disinfection booster design, placement, and operation problem in water distribution systems. Disinfectant residuals, which are in most cases chlorine residuals, are assumed to be sufficient to prevent growth of pathogenic bacteria, yet low enough to avoid taste and odor problems. Commonly, large quantities of disinfectants are released at the sources outlets for preserving minimum residual disinfectant concentrations throughout the network. Such an approach can cause taste and odor problems near the disinfectant injection locations, but more important hazardous excessive disinfectant by-product formations (DBPs) at the far network ends, of which some may be carcinogenic. To cope with these deficiencies booster chlorination stations were suggested to be placed at the distribution system itself and not just at the sources, motivating considerable research in recent years on placement, design, and operation of booster chlorination stations in water distribution systems. The model formulated and solved herein is aimed at setting the required chlorination dose of the boosters for delivering water at acceptable residual chlorine and TTHM concentrations for minimizing the overall cost of booster placement, construction, and operation under extended period hydraulic simulation conditions through utilizing a multi-species approach. The developed methodology links a genetic algorithm with EPANET-MSX, and is demonstrated through base runs and sensitivity analyses on a network example application. Two approaches are suggested for dealing with water quality initial conditions and species periodicity: (1) repetitive cyclical simulation (RCS), and (2) cyclical constrained species (CCS). RCS was found to be more robust but with longer computational time. PMID- 24762554 TI - The Academy of Physicians in Wound Healing (APWH). PMID- 24762555 TI - Negative pressure wound therapy with Bio-Dome dressing technology in the treatment of complex wounds: a case series. AB - The treatment of complex wounds is difficult and not always effective. Various treatment options are used with varying degrees of success. Negative pressure wound therapy (NPWT) is a cost-efficient and effective way to help treat these wounds. The use of a vacuum device applies the negative pressure to the site of the wound and promotes waste removal and increases circulation and tissue formation. While various NPWT systems are currently on the market, we utilised the ConvaTec Engenex(r) system with Bio-DomeTM technology; however, our case study is not intended to advocate the specific use of this system, but instead focuses on the use of NPWT as a viable option for wound healing. Each of the following case study patients presented with difficult-to-heal wounds that failed traditional therapeutic approaches. Through the use of NPWT, our patients saw major wound size reductions. Each patient exhibited at least a 94% reduction in wound area, wound volume or both. PMID- 24762556 TI - Taurolidine specifically inhibits growth of neuroblastoma cell lines in vitro. AB - BACKGROUND: Neuroblastoma is a common pediatric solid tumor with poor outcome for metastatic disease. Thus, novel therapeutic options are of main interest. The anti-neoplastic properties of taurolidine have been demonstrated on a variety of human cancer cells. However, data on neuroblastoma is lacking. Therefore, our aim was to evaluate the effect of taurolidine on growth of neuroblastoma cell lines. MATERIALS AND METHODS: Neuroblastoma SK-N-BE(2)-M17 and SK-N-SH cells and nonmalignant human umbilical vein endothelial cells as controls were incubated with increasing concentrations of taurolidine (100, 250, 500 uM). Cell growth was examined after 12, 24, and 48 hours of exposure. RESULTS: Inhibition of cell growth by taurolidine was seen in both malignant cell lines. When compared with human umbilical vein endothelial cells, the neuroblastoma cell lines were significantly more responsive to taurolidine. CONCLUSIONS: The observed negative impact on cell growth, highly distinctive in SK-N-BE(2)-M17 and SK-N-SH, implies a taurolidine-specific mode of action that appears dependent on differences on cellular and molecular level. Further investigations are warranted to evaluate its mechanism and probable clinical use. PMID- 24762557 TI - CDW fluctuations and the pseudogap in the single-particle conductivity of quasi 1D Peierls CDW systems: II. AB - The current-dipole Kubo formula for the dynamical conductivity of interacting multiband electronic systems derived in Kupcic et al (2013 J. Phys.: Condens. Matter 25 145602) is illustrated on the Peierls model for quasi-one-dimensional systems with the charge-density-wave (CDW) instability. Using the microscopic representation of the Peierls model, it is shown in which way the scattering of conduction electrons by CDW fluctuations affects the dynamical conductivity at temperatures above and well below the CDW transition temperature. The generalized Drude formula for the intraband conductivity is derived in the ordered CDW state well below the transition temperature. The natural extension of this formula to the case where the intraband memory function is dependent on frequency and wave vectors is also presented. It is shown that the main adventage of such a memory function conductivity model is that it can be easily extended to study the dynamical conductivity and the electronic Raman scattering in more complicated multiband electronic systems in a way consistent with the law of conservation of energy. The incoherent interband conductivity in the CDW pseudogap state is briefly discussed as well. PMID- 24762558 TI - Fos-dependent induction of Chk1 protects osteoblasts from replication stress. AB - Stable Fos expression in the osteoblast lineage results in the development of osteosarcomas (OS) in mice, yet the underlying mechanisms are poorly understood. Using a genetic system in which Fos expression can be induced in osteoblasts in a doxycycline-dependent manner and through subsequent RNA sequencing and gene set enrichment analysis, we were able to identify novel transcriptional targets of Fos in osteoblasts. These included a distinct activation of cellular response toward replication stress (RS), exemplified by a Fos-dependent induction of the RS-suppressing Chk1 kinase. Importantly, Fos expression protects osteoblasts from RS and DNA damage likely through upregulation of Chk1 and facilitates transformation by Ras/E1A oncogenes. These data reveal a novel function of Fos in safeguarding genome stability during replication, which is particularly relevant in conditions of oncogene-induced S-phase entry. PMID- 24762559 TI - A prospective study of plasma Selenoprotein P and lung cancer risk among low income adults. AB - BACKGROUND: Epidemiologic studies have shown increased risks of lung cancer among adults with low blood levels of selenium, although evidence is inconsistent. In the United States, the incidence of lung cancer is higher and mean serum selenium levels lower among Blacks than Whites, but prior studies have not assessed the selenium-lung cancer association among Blacks. METHODS: From the prospective Southern Community Cohort Study, we identified 372 participants who provided blood samples and subsequently developed lung cancer. Selenoprotein P (SEPP1), the most abundant selenoprotein in plasma and a biomarker of selenium nutriture, was measured in the plasma from these individuals and from 716 matched controls. RESULTS: Mean SEPP1 levels were significantly (P < 0.0001) lower among Blacks than Whites. Conditional logistic regression models accounting for smoking revealed a significant trend of increasing OR of lung cancer with decreasing SEPP1 tertiles among Blacks (P = 0.0006) but not Whites (P = 0.69; Pinteraction = 0.10). The ORs and corresponding 95% confidence intervals of lung cancer risk among those with lowest versus highest tertile levels of SEPP1 were 2.4 (1.5-3.0) among Blacks and 1.1 (0.6-2.1) among Whites. CONCLUSIONS: Among a mostly low income population in the southeastern United States, lower levels of SEPP1 were associated with an increasing risk of lung cancer among Blacks but not Whites. IMPACT: The combined findings of higher prevalence of low selenium status and higher lung cancer risk associated with low status raise the possibility that selenium deficiency may contribute to observed racial disparities in lung cancer incidence. PMID- 24762560 TI - A randomized, controlled trial to increase discussion of breast cancer in primary care. AB - BACKGROUND: Assessment and discussion of individual risk for breast cancer within the primary care setting are crucial to discussion of risk reduction and timely referral. METHODS: We conducted a randomized controlled trial of a multiethnic, multilingual sample of women ages 40 to 74 years from two primary care practices (one academic, one safety net) to test a breast cancer risk assessment and education intervention. Patients were randomly assigned to control or intervention group. All patients completed a baseline telephone survey and risk assessment (via telephone for controls, via tablet computer in clinic waiting room before visit for intervention). Intervention (BreastCARE) patients and their physicians received an individualized risk report to discuss during the visit. One-week follow-up telephone surveys with all patients assessed patient-physician discussion of family cancer history, personal breast cancer risk, high-risk clinics, and genetic counseling/testing. RESULTS: A total of 655 control and 580 intervention women completed the risk assessment and follow-up interview; 25% were high-risk by family history, Gail, or Breast Cancer Surveillance Consortium risk models. BreastCARE increased discussions of family cancer history [OR, 1.54; 95% confidence interval (CI), 1.25-1.91], personal breast cancer risk (OR, 4.15; 95% CI, 3.02-5.70), high-risk clinics (OR, 3.84; 95% CI, 2.13-6.95), and genetic counseling/testing (OR, 2.22; 95% CI, 1.34-3.68). Among high-risk women, all intervention effects were stronger. CONCLUSIONS: An intervention combining an easy-to-use, quick risk assessment tool with patient-centered risk reports at the point of care can successfully promote discussion of breast cancer risk reduction between patients and primary care physicians, particularly for high-risk women. IMPACT: Next steps include scaling and dissemination of BreastCARE with integration into electronic medical record systems. PMID- 24762562 TI - Transcriptomic analysis of fiber strength in upland cotton chromosome introgression lines carrying different Gossypium barbadense chromosomal segments. AB - Fiber strength is the key trait that determines fiber quality in cotton, and it is closely related to secondary cell wall synthesis. To understand the mechanism underlying fiber strength, we compared fiber transcriptomes from different G. barbadense chromosome introgression lines (CSILs) that had higher fiber strengths than their recipient, G. hirsutum acc. TM-1. A total of 18,288 differentially expressed genes (DEGs) were detected between CSIL-35431 and CSIL-31010, two CSILs with stronger fiber and TM-1 during secondary cell wall synthesis. Functional classification and enrichment analysis revealed that these DEGs were enriched for secondary cell wall biogenesis, glucuronoxylan biosynthesis, cellulose biosynthesis, sugar-mediated signaling pathways, and fatty acid biosynthesis. Pathway analysis showed that these DEGs participated in starch and sucrose metabolism (328 genes), glycolysis/gluconeogenesis (122 genes), phenylpropanoid biosynthesis (101 genes), and oxidative phosphorylation (87 genes), etc. Moreover, the expression of MYB- and NAC-type transcription factor genes were also dramatically different between the CSILs and TM-1. Being different to those of CSIL-31134, CSIL-35431 and CSIL-31010, there were many genes for fatty acid degradation and biosynthesis, and also for carbohydrate metabolism that were down regulated in CSIL-35368. Metabolic pathway analysis in the CSILs showed that different pathways were changed, and some changes at the same developmental stage in some pathways. Our results extended our understanding that carbonhydrate metabolic pathway and secondary cell wall biosynthesis can affect the fiber strength and suggested more genes and/or pathways be related to complex fiber strength formation process. PMID- 24762563 TI - Pediatric delirium: evaluating the gold standard. AB - OBJECTIVE: Our aim was to evaluate interrater reliability for the diagnosis of pediatric delirium by child psychiatrists. METHOD: Critically ill patients (N = 17), 0-21 years old, including 7 infants, 5 children with developmental delay, and 7 intubated children, were assessed for delirium using the Diagnostic and Statistical Manual-IV (DSM-IV) (comparable to DSM-V) criteria. Delirium assessments were completed by two psychiatrists, each blinded to the other's diagnosis, and interrater reliability was measured using Cohen's kappa coefficient along with its 95% confidence interval. RESULTS: Interrater reliability for the psychiatric assessment was high (Cohen's kappa = 0.94, CI [0.83, 1.00]). Delirium diagnosis showed excellent interrater reliability regardless of age, developmental delay, or intubation status (Cohen's kappa range 0.81-1.00). SIGNIFICANCE OF RESULTS: In our study cohort, the psychiatric interview and exam, long considered the "gold standard" in the diagnosis of delirium, was highly reliable, even in extremely young, critically ill, and developmentally delayed children. A developmental approach to diagnosing delirium in this challenging population is recommended. PMID- 24762564 TI - Childhood adversities and socioeconomic position as predictors of leisure-time physical inactivity in early adulthood. AB - BACKGROUND: Limited knowledge exists on how childhood social, health-related and economic circumstances predict adult physical inactivity. Our aim was a) to examine how various childhood adversities and living conditions predict leisure time physical inactivity in early adulthood and b) to find out whether these associations are mediated through the respondent's own education. METHODS: Young adults aged 18-29 were used from the Health 2000 Study of the Finnish. The cross sectional data were based on interviews and questionnaires including retrospective information on childhood circumstances. The analyses were carried out on 68% of the original sample (N = 1894). The outcome measure was leisure time physical inactivity. RESULTS: Only a few of the 11 childhood adversities were related with physical activity in early adulthood. Having been bullied at school was associated with physical inactivity independently of the other childhood circumstances and the respondent's own education. Low parental education predicted leisure-time physical inactivity in men and the association was mediated by the respondent's own education. Respondents with only primary or vocational education were more likely to be physically inactive during leisure time compared with those with secondary or higher education. CONCLUSIONS: There is some evidence that few specific childhood adversities, especially bullying at school, have long-lasting effects on physical activity levels. PMID- 24762566 TI - Micelle-templated composite quantum dots for super-resolution imaging. AB - Quantum dots (QDs) have tremendous potential for biomedical imaging, including super-resolution techniques that permit imaging below the diffraction limit. However, most QDs are produced via organic methods, and hence require surface treatment to render them water-soluble for biological applications. Previously, we reported a micelle-templating method that yields nanocomposites containing multiple core/shell ZnS-CdSe QDs within the same nanocarrier, increasing overall particle brightness and virtually eliminating QD blinking. Here, this technique is extended to the encapsulation of Mn-doped ZnSe QDs (Mn-ZnSe QDs), which have potential applications in super-resolution imaging as a result of the introduction of Mn(2+) dopant energy levels. The size, shape and fluorescence characteristics of these doped QD-micelles were compared to those of micelles created using core/shell ZnS-CdSe QDs (ZnS-CdSe QD-micelles). Additionally, the stability of both types of particles to photo-oxidation was investigated. Compared to commercial QDs, micelle-templated QDs demonstrated superior fluorescence intensity, higher signal-to-noise ratios, and greater stability against photo-oxidization,while reducing blinking. Additionally, the fluorescence of doped QD-micelles could be modulated from a bright 'on' state to a dark 'off' state, with a modulation depth of up to 76%, suggesting the potential of doped QD micelles for applications in super-resolution imaging. PMID- 24762565 TI - The iodized salt programme in Bangalore, India provides adequate iodine intakes in pregnant women and more-than-adequate iodine intakes in their children. AB - OBJECTIVE: To compare the iodine status of pregnant women and their children who were sharing all meals in Bangalore, India. DESIGN: A cross-sectional study evaluating demographic characteristics, household salt iodine concentration and salt usage patterns, urinary iodine concentrations (UIC) in women and children, and maternal thyroid volume (ultrasound). SETTING: Antenatal clinic of an urban tertiary-care hospital, which serves a low-income population. SUBJECTS: Healthy pregnant women in all trimesters, aged 18-35 years, who had healthy children aged 3-15 years. RESULTS: Median (range) iodine concentrations of household powdered and crystal salt were 55.9 (17.2-65.9) ppm and 18.9 (2.2-68.2) ppm, respectively. The contribution of iodine-containing supplements and multi-micronutrient powders to iodine intake in the families was negligible. Adequately iodized salt, together with small amounts of iodine in local foods, were providing adequate iodine during pregnancy: (i) the overall median (range) UIC in women was 172 (5 1024) ug/l; (ii) the median UIC was >150 ug/l in all trimesters; and (iii) thyroid size was not significantly different across trimesters. At the same time, the median (range) UIC in children was 220 (10-782) ug/l, indicating more-than adequate iodine intake at this age. Median UIC was significantly higher in children than in their mothers (P=0.008). CONCLUSIONS: In this selected urban population of southern India, the iodized salt programme provides adequate iodine to women throughout pregnancy, at the expense of higher iodine intake in their children. Thus we suggest that the current cut-off for median UIC in children indicating more-than-adequate intake, recommended by the WHO/UNICEF/International Council for the Control of Iodine Deficiency Disorders may, need to be reconsidered. PMID- 24762567 TI - Applying carbon dioxide, plant growth-promoting rhizobacterium and EDTA can enhance the phytoremediation efficiency of ryegrass in a soil polluted with zinc, arsenic, cadmium and lead. AB - This study was conducted to investigate the use of elevated carbon dioxide (CO2), plant growth-promoting rhizobacterium Burkholderia sp. D54 (PGPR) and ethylenediaminetetraacetic acid (EDTA) to enhance the phytoextraction efficiency of ryegrass in response to multiple heavy metal (or metalloid)-polluted soil containing zinc (Zn), arsenic (As), cadmium (Cd) and lead (Pb). All of the single or combined CO2, PGPR and EDTA treatments promoted ryegrass growth. The stimulation of ryegrass growth by CO2 and PGPR could primarily be attributed to the regulation of photosynthesis rather than decreased levels of Zn, As and Cd in the shoots. Most treatments seemed to reduce the Zn, As and Cd contents in the shoots, which might be associated with enhanced shoot biomass, thus causing a "dilution effect" regarding their levels. The combined treatments seemed to perform better than single treatments in removing Zn, As, Cd and Pb from soil, judging from the larger biomass and relatively higher total amounts (TAs) of Zn, As, Cd and Pb in both the shoots and roots. Therefore, we suggest that the CO2 plus PGPR treatment will be suitable for removing Zn, As, Cd and Pb from heavy metal (or metalloid)-polluted soils using ryegrass as a phytoremediation material. PMID- 24762568 TI - Co-treatment of landfill leachate and domestic wastewater using a submerged aerobic biofilter. AB - This study used a pilot-scale submerged aerobic biofilter (SAB) to evaluate the co-treatment of domestic wastewater and landfill leachate that was pre-treated by air stripping. The leachate tested volumetric ratios were 0, 2, and 5%. At a hydraulic retention time of 24 h, the SAB was best operated with a volumetric ratio of 2% and removed 98% of the biochemical oxygen demand (BOD), 80% of the chemical oxygen demand (COD) and dissolved organic carbon (DOC), and 90% of the total suspended solids (TSS). A proposed method, which we called the "equivalent in humic acid" (Eq.HA) approach, indicated that the hardly biodegradable organic matter in leachate was removed by partial degradation (71% of DOC Eq.HA removal). Adding leachate at a volumetric ratio of 5%, the concentration of the hardly biodegradable organic matter was decreased primarily as a result of dilution rather than biodegradation, which was confirmed by Fourier transform infrared (FTIR) spectroscopy. The total ammoniacal nitrogen (TAN) was mostly removed (90%) by nitrification, and the SAB performances at the volumetric ratios of 0 and 2% were equal. For the three tested volumetric ratios of leachate (0, 2, and 5%), the concentrations of heavy metals in the treated samples were below the local limits. PMID- 24762570 TI - 57Fe Mossbauer spectroscopy and electron paramagnetic resonance studies of human liver ferritin, Ferrum Lek and Maltofer(r). AB - A human liver ferritin, commercial Ferrum Lek and Maltofer(r) samples were studied using Mossbauer spectroscopy and electron paramagnetic resonance. Two Mossbauer spectrometers have been used: (i) a high velocity resolution (4096 channels) at 90 and 295K, (ii) and a low velocity resolution (250 channels) at 20 and 40 K. It is shown that the three studied materials have different superparamagnetic features at various temperatures. This may be caused by different magnetic anisotropy energy barriers, sizes (volume), structures and compositions of the iron cores. The electron paramagnetic resonance spectra of the ferritin, Ferrum Lek and Maltofer(r) were decomposed into multiple spectral components demonstrating the presence of minor ferro- or ferrimagnetic phases along with revealing marked differences among the studied substances. Mossbauer spectroscopy provides evidences on several components in the measured spectra which could be related to different regions, layers, nanocrystallites, etc. in the iron cores that coincides with heterogeneous and multiphase models for the ferritin iron cores. PMID- 24762569 TI - A coarse-grained elastic network atom contact model and its use in the simulation of protein dynamics and the prediction of the effect of mutations. AB - Normal mode analysis (NMA) methods are widely used to study dynamic aspects of protein structures. Two critical components of NMA methods are coarse-graining in the level of simplification used to represent protein structures and the choice of potential energy functional form. There is a trade-off between speed and accuracy in different choices. In one extreme one finds accurate but slow molecular-dynamics based methods with all-atom representations and detailed atom potentials. On the other extreme, fast elastic network model (ENM) methods with Calpha-only representations and simplified potentials that based on geometry alone, thus oblivious to protein sequence. Here we present ENCoM, an Elastic Network Contact Model that employs a potential energy function that includes a pairwise atom-type non-bonded interaction term and thus makes it possible to consider the effect of the specific nature of amino-acids on dynamics within the context of NMA. ENCoM is as fast as existing ENM methods and outperforms such methods in the generation of conformational ensembles. Here we introduce a new application for NMA methods with the use of ENCoM in the prediction of the effect of mutations on protein stability. While existing methods are based on machine learning or enthalpic considerations, the use of ENCoM, based on vibrational normal modes, is based on entropic considerations. This represents a novel area of application for NMA methods and a novel approach for the prediction of the effect of mutations. We compare ENCoM to a large number of methods in terms of accuracy and self-consistency. We show that the accuracy of ENCoM is comparable to that of the best existing methods. We show that existing methods are biased towards the prediction of destabilizing mutations and that ENCoM is less biased at predicting stabilizing mutations. PMID- 24762571 TI - NIR and CT luminescence spectra of [Yb(TFN)(S-BINAPO)] and [Yb(HFA)(S-BINAPO)] complexes. AB - The complexes [Yb(TFN)3(S-BINAPO)](TFN=4,4,4-trifluoro-1(2-napthyl)-1,3 butanedione) (complex 1) and [Yb(HFA)3(S-BINAPO)](HFA=hexafluoroacetylacetonate) (complex 2) were synthesized, characterized. The absorption as well as PL spectra have been studied. The complex [Yb(TFN)3(S-BINAPO)] showed narrowed emission peak (half width ~6 nm) at around 981 nm in addition to several emission peaks in NIR (near infrared) region. The complex [Yb(HFA)3(S-BINAPO)] showed strong emission peak at around 985 nm. The charge transfer luminescence of [Yb(TFN)3(S-BINAPO)] was also observed at 412-463 nm. PMID- 24762572 TI - Experimental and theoretical (FT-IR, FT-Raman, UV-vis, NMR) spectroscopic analysis and first order hyperpolarizability studies of non-linear optical material: (2E)-3-[4-(methylsulfanyl) phenyl]-1-(4-nitrophenyl) prop-2-en-1-one using density functional theory. AB - A combined experimental and theoretical investigation on FT-IR, FT-Raman, NMR, UV vis spectra of a chalcone derivative (2E)-3-[4-(methylsulfanyl) phenyl]-1-(4 nitrophenyl) prop-2-en-1-one (4N4MSP) has been reported. 4N4MSP has two planar rings connected through conjugated double bond and it provides a necessary configuration to show non-linear optical (NLO) response. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands are interpreted with the aid of structure optimizations and normal coordinate force field calculations based on density functional theory (DFT) with B3LYP functional and 6-311++G(d,p) basis set combination. The analysis of the fundamental modes was made with the help of potential energy distribution (PED). Molecular electrostatic potential (MEP) surface was plotted over the geometry primarily for predicting sites and relative reactivities towards electrophilic and nucleophilic attack. The delocalization of electron density of various constituents of the molecule has been discussed with the aid of NBO analysis. The electronic properties, such as excitation energies, oscillator strength, wavelengths, HOMO and LUMO energies, were calculated by time-dependent density functional theory (TD-DFT) and the results complement the experimental findings. The recorded and calculated 1H chemical shifts in gas phase and MeOD solution are gathered for reliable calculations of magnetic properties. Thermodynamic properties like heat capacity (C degrees p,m), entropy (S degrees m), enthalpy (H degrees m) have been calculated for the molecule at the different temperatures. Based on the finite field approach, the non-linear optical (NLO) parameters such as dipole moment, mean polarizability, anisotropy of polarizability and first order hyperpolarizability of 4N4MSP molecule are calculated. The predicted first hyperpolarizability shows that the molecule has a reasonably good nonlinear optical (NLO) behavior. PMID- 24762573 TI - Preparation of gold nanoparticles using Salicornia brachiata plant extract and evaluation of catalytic and antibacterial activity. AB - The current study deals with the synthesis of gold nanoparticles (AuNPs) using Salicornia brachiata (Sb) and evaluation of their antibacterial and catalytic activity. The SbAuNPs showed purple color with a characteristic surface plasmon resonance peak at 532 nm. Scanning electron microscopy and transmission electron microscopy revealed polydispersed AuNPs with the size range from 22 to 35 nm. Energy dispersive X-ray and thin layer X-ray diffraction analysis clearly shows that SbAuNPs was pure and crystalline in nature. As prepared gold nanoparticles was used as a catalyst for the sodium borohydride reduction of 4-nitro phenol to 4-amino phenol and methylene blue to leucomethylene blue. The green synthesized nanoparticles exhibited potent antibacterial activity against the pathogenic bacteria, as evidenced by their zone of inhibition. In addition, we showed that the SbAuNPs in combination with the regular antibiotic, ofloxacin, exhibit superior antibacterial activity than the individual. PMID- 24762574 TI - Spectroscopic notes of Methyl Red (MR) dye. AB - In the present work, a combined experimental and theoretical study on molecular structure and vibrational frequencies of MR were reported. The FT-IR spectrum of MR is recorded in the solid phase. The equilibrium geometries, harmonic vibrational frequencies, thermo-chemical parameters, total dipole moment and HOMO LUMO energies are calculated by DFT/B3LYP utilizing 6-311G(d,p) basis set. Results showed that MR is highly recommended to be a promising structure for many applications in optoelectronic devices due to its high calculated dipole moment value (7.2 Debye) and lower HOMO-LUMO energy gap of 3.5 eV. PMID- 24762575 TI - Green synthesis of pullulan stabilized gold nanoparticles for cancer targeted drug delivery. AB - The aim of this study was to synthesize green chemistry based gold nanoparticles using liver specific biopolymer and to develop a liver cancer targeted drug delivery system with enhanced efficacy and minimal side effects. Pullulan stabilized gold nanoparticles (PAuNPs) were coupled with 5-Fluorouracil (5-Fu) and folic acid (Fa) which could be used as a tool for targeted drug delivery and imaging of cancer. The toxicity of 5-Fu, 5-Fu adsorbed gold nanoparticles (5 Fu@AuNPs), Fa-coupled 5-Fu adsorbed gold nanoparticles (5-Fu@AuNPs-Fa), was studied using zebrafish embryo as an in vivo model. The in vitro cytotoxicity of free 5-Fu, 5-Fu@AuNPs, 5-Fu@AuNPs-Fa against HepG2 cells was studied and found that the amount of 5-Fu required to achieve 50% of growth of inhibition (Ic50) was much lower in 5-Fu@AuNP-Fa than in free 5-Fu, 5-Fu@AuNPs. The in vivo biodistribution of PAuNPs showed that higher amount of gold had been accumulated in liver (54.42+/-5.96 MUg) than in other organs. PMID- 24762576 TI - Recent advances in genome-based polyketide discovery. AB - Polyketides are extraordinarily diverse secondary metabolites of great pharmacological value and with interesting ecological functions. The post genomics era has led to fundamental changes in natural product research by inverting the workflow of secondary metabolite discovery. As opposed to traditional bioactivity-guided screenings, genome mining is an in silico method to screen and analyze sequenced genomes for natural product biosynthetic gene clusters. Since genes for known compounds can be recognized at the early computational stage, genome mining presents an opportunity for dereplication. This review highlights recent progress in bioinformatics, pathway engineering and chemical analytics to extract the biosynthetic secrets hidden in the genome of both well-known natural product sources as well as previously neglected bacteria. PMID- 24762577 TI - Ophthalmology: potential future developments in China and worldwide. PMID- 24762578 TI - Age-related macular degeneration: vision challenge of old age. PMID- 24762579 TI - Neovascular glaucoma: challenges we have to face. PMID- 24762580 TI - MicroRNA 145 may play an important role in uveal melanoma cell growth by potentially targeting insulin receptor substrate-1. AB - BACKGROUND: MicroRNAs (miRNAs) contribute to tumorigenesis by acting as either oncogenes or tumor suppressor genes. In this study, we investigated the role of miR-145 in the pathogenesis of uveal melanoma. METHODS: Expression profiles of miRNAs in uveal melanoma were performed using Agilent miRNA array. Quantitative real-time polymerase chain reaction was used to screen the expression levels of miR-145 in normal uveal tissue, uveal melanoma tissue, and uveal melanoma cell lines. Lenti-virus expression system was used to construct MUM-2B and OCM-1 cell lines with stable overexpression of miR-145. Cell proliferation, cell cycle, and cell apoptosis of these miR-145 overexpression cell lines were examined by MTT assay and flow cytometry respectively. The target genes of miR-145 were predicted by bioinformatics and confirmed using a luciferase reporter assay. The expression of insulin-like growth factor-1 receptor (IGF-1R), insulin receptor substrate-1 (IRS-1) proteins was determined by Western blotting analysis. IRS-1 was knocked down in OCM-1 cells. TUNEL, BrdU, and flow cytometry assay were performed in IRS 1 knocked down OCM-1 cell lines to analyze its function. RESULTS: Forty-seven miRNAs were up regulated in uveal melanoma and 61 were down regulated. miR-145 expression was significantly lower in uveal melanoma sample and the cell lines were compared with normal uveal sample. Overexpression of miR-145 suppressed cell proliferation by blocking the G1 phase entering S phase in uveal melanoma cells, and promoted uveal melanoma cell apoptosis. IRS-1 was identified as a potential target of miR-145 by dual luciferase reporter assay. Knocking down of IRS-1 had similar effect as overexpression of miR-145. CONCLUSION: miR-145 might act as a tumor suppressor in uveal melanoma, and downregulation of the target IRS-1 might be a potential mechanism. PMID- 24762581 TI - A prospective comparative study on neovascular glaucoma and non-neovascular refractory glaucoma following Ahmed glaucoma valve implantation. AB - BACKGROUND: Neovascular glaucoma is a refractory disease, and difficult to manage. The aim of this study was to evaluate the clinical outcomes of Ahmed glaucoma valve implantation (AGVI) in neovascular glaucoma (NVG) and non-NVG patients. METHODS: This prospective, non-randomized study included 55 eyes of 55 patients with refractory glaucoma; 27 had NVG (NVG group) and 28 had non-NVG (non NVG group). All of the patients underwent AGVI. The NVG group was adjunctively injected with intravitreal ranibizumab/bevacizumab (IVR/IVB) before AGVI. Intraocular pressure (IOP) was the primary outcome measure in this study. Surgical success rate, number of antiglaucoma medications used, best corrected visual acuity (BCVA), and postoperative complications were analyzed between the groups. RESULTS: All of the patients completed the study (follow-up of 12 months). Kaplan-Meier survival curve analysis indicated that the qualified success rates in the NVG and non-NVG groups at 12 months were 70.5% and 92.9%, respectively; this difference was significant (P = 0.036). The complete success rates in the NVG and non-NVG groups at 12 months were 66.7% and 89.3%, respectively (P = 0.049). Compared with preoperative examinations, the postoperative mean IOP and use of medications were significantly lower at all follow-up time points in both groups (all P < 0.05). There were significant differences in BCVA between the two groups at the 12-month follow-up (chi(2) = 9.86, P = 0.020). Cox proportional hazards regression showed NVG as a risk factor for surgical failure (RR = 15.08, P = 0.033). Postoperative complications were similar between the two groups. CONCLUSIONS: AGVI is a safe and effective procedure in refractory glaucoma, but the success rate of surgery was related to the type of refractory glaucoma. The complete and qualified success rates of NVG patient adjunctive anti-vascular endothelial growth factor treatment are still lower than those of non-NVG patients. PMID- 24762582 TI - Fundus autofluorescence characteristics in patients with diabetic macular edema. AB - BACKGROUND: Diabetic macular edema (DME) is one of the major causes of visual impairment in patients with diabetes mellitus. DME shows a variety of clinical characteristics with unpredictable results to treatment. The purpose of this study was to investigate the characteristics of fundus autofluorescence (FAF) in DME, which is a rapid, noninvasive technique for fundus diseases. METHODS: A total of 18 patients (30 eyes) with clinically significant macular edema (CSME) were enrolled. FAF imaging was performed with a confocal scanning laser ophthalmoscope. Other ophthalmic examinations included best corrected visual acuity (BCVA), MP-1 microperimetry, and spectral-domain optical coherence tomography (SD-OCT). Main outcome measurements included BCVA, macular sensitivity (MS), central retinal thickness (CRT), central retinal volume (CRV), the integrity of the inner segment-outer segment junction (IS/OS), and the integrity of the external limiting membrane (ELM). RESULTS: Among the 30 eyes, four eyes (13.3%) had normal foveal FAF and 26 eyes (86.7%) had abnormal FAF. Abnormal FAF was mainly divided into three types: cystoid increased FAF (iFAF) 16 eyes (53.3%), spot iFAF six eyes (20%), irregular decreased FAF (dFAF) four eyes (13.3%). According to the FAF morphology, patients were categorized into four groups: normal, cystoid iFAF, spot iFAF, and irregular dFAF. There was a significant difference in BCVA (P < 0.001) and MS (P < 0.05) among the four groups. The visual function of patients with spot iFAF and irregular dFAF was relatively poor. However, there was no difference in CRT (P = 0.186) and CRV (P = 0.191) among the four groups. In the normal FAF group, the photoreceptor layers were mostly intact. Regarding the cystoid iFAF group, the photoreceptor layers were relatively intact, while in the other two groups, IS/OS and ELM were disrupted in most patients. No one had intact IS/OS or ELM layer. CONCLUSIONS: FAF might reflect the damage of the retina and had a relationship with visual function as well as photoreceptor integrity, which gives new insight into the evaluation of DME. Dynamic FAF monitoring helps to better evaluate the disease progression of DME as well as visual function. PMID- 24762583 TI - Profile of pediatric glaucoma patients in Shanghai Eye, Ear, Nose and Throat Hospital. AB - BACKGROUND: The extent of our knowledge of the epidemiology of pediatric glaucoma in China is limited. To better characterize the epidemiology of pediatric glaucoma in eastern China, we report the clinical profile, etiologies, and treatment modalities in patients <18 years of age in Shanghai Eye, Ear, Nose and Throat Hospital. METHODS: The medical records of patients presenting glaucoma between January 2003 and December 2010 were retrospectively reviewed. The demographic characteristics, the proportion of different glaucoma subtypes and surgical precedures were collected and analyzed. RESULTS: A total of 1 142 eyes of 734 pediatric patients (500 males) were included. Congenital glaucoma was the leading subtype, accounting for 47.55% of all patients. The ratio of boys to girls was 2.5:1. Patients with congenital glaucoma affecting both eyes accounted for 72.5% of all patients examined. Patients with primary juvenile glaucoma were the second most common group (n = 125, 17.03%). Traumatic glaucoma was the third most common subtype (n = 81, 11.03%). The type of surgery was related to the subtype of glaucoma. CONCLUSIONS: Congenital glaucoma, primary juvenile glaucoma, and traumatic glaucoma are the most prevalent subtypes in pediatric glaucoma patients in Shanghai Eye, Ear, Nose and Throat Hospital. The characteristics of congenital glaucoma in China are similar to those in Western countries. PMID- 24762584 TI - Fundus artery occlusion caused by cosmetic facial injections. AB - BACKGROUND: With the increasing popularity of cosmetic facial filler injections in recent years, more and more associated complications have been reported. However, the causative surgical procedures and preventative measures have not been studied well up to now. The aim of this stady was to investigate the clinical characteristics and visual prognosis of fundus artery occlusion resulting from cosmetic facial filler injections. METHODS: Thirteen consecutive patients with fundus artery occlusion caused by facial filler injections were included. Main outcome measures were filler materials, injection sites, best corrected visual acuity (BCVA), fundus fluorescein angiography, and associated ocular and systemic manifestations. RESULTS: Eleven patients had ophthalmic artery occlusion (OAO) and one patient each had central retinal artery occlusion (CRAO) and anterior ischemic optic neuropathy (AION). Injected materials included autologous fat (seven cases), hyaluronic acid (five cases), and bone collagen (one case). Injection sites were the frontal area (five cases), periocular area (two cases), temple area (two cases), and nose area and nasal area (4 cases). Injected autologous fat was associated with worse final BCVA than hyaluronic acid. The BCVA of seven patients with autologous fat injection in frontal area and temple area was no light perception. Most of the patients with OAO had ocular pain, headache, ptosis, ophthalmoplegia, and no improvement in final BCVA. CONCLUSIONS: Cosmetic facial injections can cause fundus artery occlusion. Autologous fat injection tends to be associated with painful blindness, ptosis, ophthalmoplegia, and poor visual outcomes. The prognosis is much worse with autologous fat injection than hyaluronic acid injection. PMID- 24762585 TI - Anti-inflammatory effects of a synthetic peptide derived from pigment epithelium derived factor on H2O2-induced corneal injury in vitro. AB - BACKGROUND: The common pathological characteristics of corneal injury include inflammatory factors activation, vascular endothelial cells or inflammatory cells infiltration into lesions, corneal edema, corneal neovascularization (CNV), and scar formation. PEDF-34 is the functional fragment of pigment epithelium-derived factor (PEDF) that has anti-angiogenic and anti-inflammatory properties and contains an N-terminal 34-amino acid peptide. This study was to investigate the anti-inflammatory effects of PEDF-34 on H2O2-induced corneal injury in vitro. METHODS: After cultured in H2O2 (0.1 mmol/L) for 2 hours, human corneal fibroblasts (HCFs) and human umbilical vein endothelial cells (HUVECs) were treated with PEDF-34-nanoparticles (NPs) at different concentrations (0.1, 0.5, 1.0, 2.0 ug/ml) or 2.0 ug/ml control-NPs for 24 hours. The viable cells were quantified using the MTT assay. Western blotting or ELISA analysis was performed for measuring the human vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) expression of both HCFs and HUVECs. VEGF and nuclear factor kappaB (NF-kappaB) mRNA levels of HCFs were semi quantified by RT-PCR. RESULTS: The survival rates of HCFs or HUVECs stimulated by H2O2 did not decrease significantly (P > 0.05) compared to those in the normal conditions. As compared to control-NP group, PEDF-34-NPs had dose-dependent inhibitive effect on HUVECs with the MTT assay, but not HCFs. Western blotting analysis showed that the VEGF and ICAM-1 levels in the HCFs and HUVECs stimulated by H2O2 were significantly higher than those in the normal conditions, which were decreased dramatically in those treated with PEDF-34-NPs. RT-PCR analysis revealed that the VEGF mRNA and NF-kappaB mRNA levels increased in H2O2 stimulated HCFs, while both of them decreased in PEDF-34-NP groups dose dependently. CONCLUSIONS: PEDF-34-NPs may play an important role in regulating the NF-kappaB pathway, inhibiting inflammatory activity. PEDF-34-NPs may be a potential new drug for treating corneal injury in the future. PMID- 24762586 TI - Validation of quantitative computed tomography-derived areal bone mineral density with dual energy X-ray absorptiometry in an elderly Chinese population. AB - BACKGROUND: The performance of computed tomography X-ray absorptiometry (CTXA) against the dual energy X-ray absorptiometry (DXA) as standard has not been studied in Chinese population. The aim of this study was to evaluate the precision of this measurement and validate the value of quantitative computed tomography (QCT) by comparing CTXA results with DXA results in an elderly Chinese population. METHODS: One hundred and three females of 46 to 76 years old and 49 males of 52 to 76 years old were recruited from the Prospective Urban Rural Epidemiology study. All subjects underwent hip scans by both QCT and DXA on the same day. For precision determination, 30 subjects had duplicate DXA hip scans. The hip QCT data of a subset of 27 subjects were separately analyzed by two observers and reanalyzed by one observer at a different time. The inter- and intra-observer variations of CTXA measurement were assessed, and the difference and correlation between CTXA and DXA results were analyzed. RESULTS: The inter- and intra-observer variations of CTXA were 0.070 and 0.024 g/cm(2) in the femoral neck (FN), and 0.030 and 0.012 g/cm(2) in the total hip (TH), which were comparable to the DXA inter-scan variations (0.013 g/cm(2) for FN and 0.014 g/cm(2) for TH). The results of CTXA bone mineral density (BMD) were highly correlated with those of DXA (R(2) = 0.810 for FN and R(2) = 0.878 for TH). The BMD values of CTXA in FN and TH were lower than those of DXA by 21.0% and 17.8% (P < 0.05), respectively. However, after appropriate transformation, the difference was eliminated and a comparable T score could be obtained. CONCLUSIONS: CTXA shows good agreement with DXA for the measurement of BMD in the proximal femur, which makes QCT suitable for the quantification of bone mineral content in the hip and helpful for the diagnosis of osteoporosis. PMID- 24762587 TI - Efficacy of sunitinib in patients with metastatic renal cell carcinoma: initial experience in two Chinese centers. AB - BACKGROUND: The advent of targeted therapy has proved a milestone in the history of metastatic renal cell carcinoma treatment, and several guidelines now recommend sunitinib as first- or second-line treatment. But little is known about its efficacy in Asian patients. The aim of this article was to evaluate the efficacy of sunitinib monotherapy in patients with metastatic renal cell carcinoma treated at two Chinese centers. METHODS: One hundred and forty-one patients with metastatic renal cell carcinoma were included in the study. Of them, 119 patients received single-agent sunitinib as first-line therapy and the remaining 22 patients received it as second-line therapy. One hundred and twenty patients received sunitinib in a dosage of 50 mg orally once daily on a 4-2 schedule (4 weeks on treatment, 2 weeks off), while 21 patients received 37.5 mg/day continuously until either disease progression or unacceptable toxicity occurred. The overall response rate, survival outcomes, and safety were evaluated. RESULTS: Over a median follow-up time of 23 months (16 cycles; range 2 45 months), complete responses, partial responses, and stable disease lasting two cycles or longer were achieved in 2.8%, 24.1%, and 60.3% of patients respectively (objective response rate 26.9%; overall benefit 87.2%). The median progression free survival was 14.2 months (range 3-39 months). During the study, 53 patients died and the median survival time was 13.5 months (range 7-25 months). Dose modification or treatment interruption due to adverse events was required in 36.9% of the patients. The most common adverse events were hand-foot syndrome (71.4%), thrombocytopenia (68.8%), hypertension (47.1%), and fatigue (46.3%). CONCLUSION: Sunitinib had a favorable efficacy/tolerability profile in Chinese patients with metastatic renal cell carcinoma. PMID- 24762588 TI - Relationship of Helicobacter pylori eradication with gastric cancer and gastric mucosal histological changes: a 10-year follow-up study. AB - BACKGROUND: Helicobacter pylori (Hp) is a common and potentially curable cause of gastric mucosa lesion. This study investigated the relationship of Hp infection with histological changes in gastric mucosa and gastric cancer in Hp-positive patients compared with Hp-eradication patients followed up for ten years. METHODS: From an initial group of 1 006 adults, 552 Hp-positive subjects were randomly assigned to a treatment group (T; n = 276) or a placebo group (P; n = 276). In the randomized, double-blind, placebo-controlled, parallel trial, T group subjects received oral doses of omeprazole, amoxicillin and clarithromycin for 1 week; those in the P group received a placebo. One month after treatment ended, a 13C urea breath test was performed, and Hp was undetectable in 88.89% of the T group. All subjects were followed at 1, 5, 8, and 10 years after treatment, with endoscopy and biopsies for histological examination. RESULTS: Gastric mucosa inflammation was significantly milder in the T group than that in the P group one year after Hp eradication and this persisted for 10 years. Glandular atrophy and intestinal metaplasia (IM) had deteriorated in both groups during ten years. However, the increased score of glandular atrophy at both the gastric antrum and corpus, and IM only at the gastric antrum, in the P group was more obvious than that in the T group. During the 10 years, 9 patients were diagnosed with gastric cancer (2 in the T group; 7 in the P group; P = 0.176). When mucosal atrophy was absent at the gastric antrum and corpus when entering the study, the incidence of gastric cancer in the P group (n = 6) was much higher than that in the T group (n = 0, P = 0.013). CONCLUSIONS: Hp eradication may significantly diminish and help halt progression of gastric mucosal inflammation and delay the development of IM and atrophy gastritis. Hp eradication is helpful for reducing the risk for gastric cancer, especially in the early stage of Hp infection. PMID- 24762589 TI - Clinical implications and prognostic value of single and combined biomarkers in endometrial carcinoma. AB - BACKGROUND: Endometrial carcinoma is one of the most common gynecological cancers and the incidence has been increasing. This study was to identify the relationship of estrogen receptor (ER), progestrone receptor (PR), P53 protein, Ki-67 and phosphatase and tensin homolog deleted on chromosome ten (PTEN) with endometrial carcinoma, the assessment of these biomarkers and their association with clinicopathological parameters was performed. METHODS: A total of 198 cases of primary endometrial carcinoma were investigated for ER, PR, Ki-67, P53, and PTEN antigens by immunohistochemical methods. The association of these markers with age, menopause status, histological type, FIGO stage, grading, depth of invasion, lymph node involvement and serum tumor marker was examined. RESULTS: The percentages of Ki-67- and P53-negative endometrial tumors were significantly higher in ER-positive compared with ER-negative tumors (both P = 0.000). The same trend was evident with PR status. The percentage of PTEN-positive tumors was significantly higher in PR-positive compared with PR-negative tumors (P = 0.021), but was no difference in tumors with different ER status. There was no clear association between PTEN positivity and clinicopathological parameters except more relevance with endometrioid histotype (P = 0.013). There was a statistically significant difference in the distribution of the different combined biological factors examined in disease-free survival. CONCLUSIONS: ER and PR status were significant predictors with staging, grading and recurrence. P53 and Ki-67 expression were inversely correlated with both ER and PR expression and have more aggressive clinicopathological features. PTEN expression was inversely correlated with PR expression but not with ER expression. The combined type of ER+PR+P53 PTEN+ was in the majority in endometrial cancer and seemed to be related to better clinical outcome. The combination of ER-PR-P53+PTEN- represented the worst disease-free survival and was strongly associated with poorest survival rate. PMID- 24762590 TI - Gene expression profiles of ERCC1, TYMS, RRM1, TUBB3 and EGFR in tumor tissue from non-small cell lung cancer patients. AB - BACKGROUND: Personalized medicine becomes essential in lung cancer treatment, however lung-cancer-related gene expression profiles in Chinese patients remain unknown. In this study, the correlation of gene expression profiles and clinical characteristics in non-small-cell lung cancer (NSCLC) was investigated. METHODS: Seventy-six Chinese patients with NSCLC were enrolled in the study to investigate mRNA expression profiles of excision repair cross complement group 1 (ERCC1), thymidylate synthetase (TYMS), ribonucleotide reductase (RRM1), class III beta tubulin (TUBB3), and epidermal growth factor receptor (EGFR) genes and their correlation with patient clinical characteristics. A novel liquidchip technology was used to detect mRNA expression levels in formalin fixed paraffin embedded tumor pathology samples. The relationships between gene expression and clinical characteristics were assessed using the Mann-Whitney test. RESULTS: ERCC1 mRNA levels were higher in tumors from patients with metastatic disease than patients with non-metastatic disease (P = 0.021), and higher in adenocarcinomas than squamous cell carcinomas (P = 0.006). Increased TUBB3 mRNA expression levels were found in patients with performance status (PS) 1 in comparison with PS 0 (P = 0.049), with poorly differentiated tumors in comparison with tumors that were moderately and well differentiated (P <= 0.000 1), and with advanced stage in comparison with early stage disease (P <= 0.000 1). CONCLUSIONS: ERCC1 mRNA levels were higher in metastatic adenocarcinoma NSCLC; TUBB3 mRNA levels were significantly higher in poorly differentiated tumors and in advanced stage NSCLC, which indicates the poor prognosis. PMID- 24762591 TI - Changes in dendritic cells and dendritic cell subpopulations in peripheral blood of recipients during acute rejection after kidney transplantation. AB - BACKGROUND: Advances in transplantation immunology show that the balance between dendritic cells (DCs) and their subsets can maintain stable immune status in the induction of tolerance after transplantation. The aim of this study was to investigate if DCs and DC subpopulations in recipient peripheral blood are effective diagnostic indicators of acute rejection following kidney transplantation. METHODS: Immunofluorescent flow cytometry was used to classify white blood cells (WBCs), the levels of mononuclear cells and DCs (including the dominant subpopulations, plasmacytoid DC (pDC) and myeloid DC (mDC)) in peripheral blood at 0, 1, 7, and 28 days and 1 year after kidney transplantation in 33 patients. In addition, the blood levels of interleukin-10 (IL-10) and IL-12 were monitored before and after surgery. Fifteen healthy volunteers served as normal controls. Patients were undertaking hemodialysis owing to uremia before surgery. RESULTS: The total number of DCs, pDC, and mDC in peripheral blood and the pDC/mDC ratio were significantly lower in patients than controls (P < 0.05). Peripheral DCs suddenly decreased at the end of day 1, then gradually increased through day 28 but remained below normal levels. After 1 year, levels were higher than before surgery but lower than normal. The mDC levels were higher in patients with acute rejection before and 1 day after surgery (P < 0.005). There was no significant difference in IL-10 and IL-12 levels between patients with and without acute rejection. CONCLUSION: The changes in DCs and DC subpopulations during the acute rejection period may serve as effective markers and referral indices for monitoring the immune state, and predicting rejection and reasonably adjusting immunosuppressants. PMID- 24762592 TI - Evaluation of CD24 as a marker to rapidly define the mesenchymal stem cell phenotype and its differentiation in human nucleus pulposus. AB - BACKGROUND: Recent studies have indicated that human nucleus pulposus contain mesenchymal stem cells (NP-MSCs). However, the immunophenotypic variation of NP MSCs in vitro was unclear. The present study was conducted to address the immunophenotypic variation of mesenchymal stem cells in nucleus pulposus under continuous proliferation in vitro and show the difference between mesenchymal stem cells and nucleus pulposus cell. METHODS: Tissue samples were obtained from thoracolumbar burst fracture patients and degenerative disc disease patients who underwent discectomy and fusion procedures. Flow cytometric and laser scanning confocal microscope (LSCM) were used to detect the variation of mesenchymal stem cells in nucleus pulposus which were expressing CD105 and CD24 in condition with or without transforming growth factor beta1 (TGF-beta1). RESULTS: More than 90% of the analyzed primary cells of mesenchymal stem cells in nucleus pulposus fulfilled the general immunophenotyping criteria for MSCs, such as CD44, CD105 and CD29, but the marker of mature NP cells characterized as CD24 was negative. In continuous cultures, the proportion of mesenchymal stem cells which were expressing CD44, CD105 and CD29 in nucleus pulposus gradually decreased. The mesenchymal stem cells in nucleus pulposus cells were positive for CD105 and CD29, with slight positivity for CD44. The CD24 expression gradually increased in proliferation. Biparametric flow cytometry and laser scanning confocal microscopy confirmed the presence of cells which were expressing CD105 and CD24 independently, and only a small part of cells expressed both CD105 and CD24 simultaneously. TGF-beta1 could stimulate mesenchymal stem cells in nucleus pulposus to express CD24. CONCLUSIONS: Non-degenerative and degenerative NP contains mesechymal stem cells. The variation of CD24 can be used as a marker to identify the NP-MSCs differentiation into NP-like cells. PMID- 24762593 TI - Clinical characteristics of patients with congenital long QT syndrome and bigenic mutations. AB - BACKGROUND: Congenital long QT syndrome (LQTS) is an ion channelopathy associated with genetic mutations. It is well known that most LQTS patients (91%) have a single mutation. The purpose of this study was to investigate the clinical characteristics of congenital LQTS patients with bigenic mutations in Taiwan, China. METHODS: Congenital LQTS patients were recruited consecutively at Taiwan University Hospital in Taiwan from 2003 to 2009. The diagnosis of LQTS was defined by an LQTS Schwartz score greater than 4. Mutation screening in KCNQ1, KCNH2, KCNE1, and SCN5A was performed using direct sequencing. RESULTS: Three of 16 LQTS patients (18.7%) were identified with bigenic mutations. One patient had missense mutations in KCNQ1 and KCNH2, the second in KCNQ1 and KCNE1, and the third in KCNH2 and SCN5A. The mean age at onset of LQTS for patients with bigenic mutations was (17 +/- 3) years, and all of these patients were female. Two of them experienced seizure and one presented with syncope, although one of them had a family history of syncope. The mean QTc interval was (515 +/- 17) ms, similar to those with single mutation or SNPs ((536 +/- 74) ms, P = 0.63). Compared to those LQTS patients with single mutation or SNPs, a significantly higher percentage of LQTS patients with bigenic mutations presented with seizure and were younger at onset of the first index event (P = 0.03 and 0.001, respectively), but lower percentage of them presented with sudden cardiac death (P = 0.03). CONCLUSIONS: Although the percentage of bigenic mutations in LQTS is less than 10% in Caucasian populations, we identified 3 of 16 LQTS patients (18.7%, 95% confidence interval: 0.04-0.46) with bigenic mutations in Taiwan. However, the severity of their clinical presentations was not higher than those patients with single mutation or SNPs. PMID- 24762594 TI - Emergence of truncated PB1-F2 protein of H3N2 influenza virus during its epidemic period in Jiangsu Province, China. AB - BACKGROUND: PB1-F2 protein has been proven to increase the pathogenicity of influenza A virus (IAV) strains in primary infection and in secondary bacterial infection. It can also regulate the activity of viral polymerase. However, it was shown in another retrospective study that a portion of IAVs do not express full length PB1-F2 protein during virus development; different kinds of stop codons cause exits in the open reading frames and form PB1-F2 gene products with the corresponding genotypes. Truncated PB1-F2 in human H3N2 IAVs has long been detected in North America but its evolution in China is still unclear. METHODS: Influenza-like illnesses (ILIs) from the whole of Jiangsu Province were collected and inspected to determine the type and subtype of the viruses. A portion of isolates collected in the epidemic period were selected as samples for later whole-genome sequencing, and the exact sequences were determined and analyzed. RESULTS: H3N2 influenza virus was one of the epidemical strains which had been prevalent during 2009-2010, in Jiangsu. Five H3N2 isolates with truncated PB1-F2 protein (25aa) were detected in influenza samples from Nanjing and Xuzhou, while seven similar H3N2 isolates were also reported in Niigata, Japan. CONCLUSION: This emergence indicates the possibility that there has been transmission of the H3N2 virus between the two countries. PMID- 24762595 TI - Kyphoplasty versus vertebroplasty for the treatment of malignant vertebral compression fractures caused by metastases: a retrospective study. AB - BACKGROUND: There are few comparative studies regarding kyphoplasty (KP) and vertebroplasty (VP) for the treatment of painful vertebral compression fractures (VCF) in patients with cancer. The purpose of this study is to retrospectively compare KP with VP in pain improvement, cement leakage incidence, and the cost of treatment of malignant VCF. METHODS: We performed a retrospective study of clinical data for 80 patients with multiple spinal metastases, treated with KP in 42 cases and VP in 38. Visual analog scale (VAS) scores were collected pre operatively, post-operatively, at 1 month, 6 months, and 1 year after treatment. Cement leakage was identified using fluoroscopy and CT scan. Total cost per patient was also collected. RESULTS: There was a significant difference between the pre- and post-operative VAS scores (7.4 +/- 2.0 to 3.8 +/- 1.6, P < 0.001 in the KP group; 6.7 +/- 2.4 to 3.7 +/- 1.4, P < 0.001 in the VP group), and was maintained at 1-year follow-up (3.2 +/- 1.4 in the KP group, 3.1 +/- 1.3 in the VP group). However, the difference in VAS score between these two groups was insignificant at baseline and every follow-up assessment post-operatively (P > 0.05). The incidence of cement leakage in the KP group was lower than that of the VP group (16.9% (14/83) vs 30.3% (23/76), P < 0.05). However, none of the patients developed any symptoms. The length of postoperative hospital stay in the VP group was shorter than that of the KP group ((2.4 +/- 1.3) vs (5.3 +/- 1.9) days, P < 0.05). Total hospital cost in the KP group was much higher than that of the VP group (RMB Yuan 8 492 +/- 3 332 vs RMB Yuan 3 173 +/- 1 341, P < 0.01). CONCLUSIONS: VP and KP are both effective in providing pain relief for patients with cancer-related VCF. KP provides no greater degree of pain improvement. KP is associated with a lower rate of cement leakage compared with VP. VP is associated with lower cost and shorter postoperative hospital stay in China. PMID- 24762596 TI - Clinical outcome of ileal pouch-anal anastomosis for chronic ulcerative colitis in China. AB - BACKGROUND: The incidence of chronic ulcerative colitis (CUC) in China is remarkably increasing, while little information on surgical treatment has been reported. This study aimed to completely describe and analyze the clinical outcome of restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) for CUC in China. METHODS: Ninety-five consecutive patients, who suffered CUC and had surgical indications, were carefully selected. All patients underwent IPAA. Data on patient characteristics, surgical indications, surgical details, postoperative complications, functional outcome, and quality of life were collected. RESULTS: The mean patient age at the time of the operation was 32 years. Twenty-nine (31%) patients underwent an emergency operation, and 66 (69%) underwent elective procedures. Four patients with severe dysplasia underwent operations, but no carcinoma was histologically confirmed. A two-stage operation was performed in 87 (92%) patients, and a hand-sewn technique was applied in 88 (93%) patients. Sixteen patients (17.0%) experienced early complications, and there was a significant difference between the emergency surgery group and the elective group (31.0% vs. 10.6%, respectively; P < 0.01). Five (5.3%) patients developed pouchitis as a late complication. The mean stool frequency after the operation was 4.6 (2-11) during the first 24 hours and 1.5 (0-4) overnight. According to the Kirwan grading scale, 87 (91.8%) patients showed satisfactory anal continence function. The quality of life improved significantly from a preoperative mean value of 0.28-0.61 before ileostomy closure to 0.78 after ileostomy closure (P < 0.01) according to the Cleveland Global Quality of Life index. CONCLUSIONS: IPAA is an effective and safe surgical procedure for patients with CUC in China. However, some characteristics, such as the low incidence of pouchitis, require further study. PMID- 24762597 TI - Spontaneous brain activity in chronic smokers revealed by fractional amplitude of low frequency fluctuation analysis: a resting state functional magnetic resonance imaging study. AB - BACKGROUND: Nicotine is primarily rsponsible for the highly addictive properties of cigarettes. Similar to other substances, nicotine dependence is related to many important brain regions, particular in mesolimbic reward circuit. This study was to further reveal the alteration of brain function activity during resting state in chronic smokers by fractional amplitude of low frequency fluctuation (fALFF) based on functional magnetic resonance imaging (fMRI), in order to provide the evidence of neurobiological mechanism of smoking. METHODS: This case control study involved twenty healthy smokers and nineteen healthy nonsmokers recruited by advertisement. Sociodemographic, smoking related characteristics and fMRI images were collected and the data analyzed. RESULTS: Compared with nonsmokers, smokers showed fALFF increased significantly in the left middle occipital gyrus, left limbic lobe and left cerebellum posterior lobe but decreases in the right middle frontal gyrus, right superior temporal gyrus, right extra nuclear, left postcentral gyrus and left cerebellum anterior lobe (cluster size >100 voxels). Compared with light smokers (pack years <= 20), heavy smokers (pack years >20) showed fALFF increased significantly in the right superior temporal gyrus, right precentral gyrus, and right occipital lobe/cuneus but decreased in the right/left limbic lobe/cingulate gyrus, right/left frontal lobe/sub gyral, right/left cerebellum posterior lobe (cluster size >50 voxels). Compared with nonsevere nicotine dependent smokers (Fagerstrom test for nicotine dependence, score <= 6), severe nicotine dependent smokers (score >6) showed fALFF increased significantly in the right/left middle frontal gyrus, right superior frontal gyrus and left inferior parietal lobule but decreased in the left limbic lobe/cingulate gyrus (cluster size >25 voxels). CONCLUSIONS: In smokers during rest, the activity of addiction related regions were increased and the activity of smoking feeling, memory, related regions were also changed. The resting state activity changes in many regions were associated with the cumulative amount of nicotine intake and the severity of nicotine dependence. PMID- 24762598 TI - An anatomical comparison of two minimally invasive pelvic reconstructive surgeries using fresh female cadavers. AB - BACKGROUND: During the past decade, graft materials have been widespread used in the vagina in order to correct pelvic organ prolapse. The aim of this study was to describe and compare the exact anatomical position of the puncture devices and their relations to the relevant anatomical structures in the Prolift(TM) and a modified pelvic reconstructive surgery with mesh. METHODS: Twelve fresh cadavers were allocated randomly to either the Prolift(TM) or the modified pelvic reconstructive surgery group. Each group had six fresh cadavers. Relevant distances between the puncture devices and anatomical structures were recorded in both minimally invasive puncture surgeries. RESULTS: The mean distances from the posterior puncture points of the obturator membrane to the posterior branch of obturator arteries were shorter ((0.60 +/- 0.36) cm and (0.78 +/- 0.10) cm) when compared with the distances to the anterior branch of obturator arteries ((1.53 +/- 0.46) cm and (1.86 +/- 0.51) cm) for the reconstruction of the anterior compartment in both surgeries (all P < 0.05). The distance from the puncture points of the pelvic floor through the ischiorectal fossa to the coccygeal and inferior gluteal arteries in the Prolift(TM) technique ((0.88 +/- 0.10) cm) and ((1.59 +/- 0.36) cm)) were much shorter than that in the modified pelvic reconstructive surgery ((2.95 +/- 0.09) cm) and ((3.40 +/- 0.36) cm)) for the reconstruction of the middle and posterior compartments (all P < 0.05). CONCLUSIONS: Compared with the Prolift(TM) technique, the modified pelvic reconstructive surgery with mesh would be safer not to cause great damage to the inferior gluteal arteries and the coccygeal arteries. The posterior branch of obturator arteries would be easier to be injured than the anterior branch of obturator arteries during anterior compartment reconstruction in both surgeries. PMID- 24762600 TI - Metformin ameliorates insulin resistance in L6 rat skeletal muscle cells through upregulation of SIRT3. AB - BACKGROUND: SIRT3 is an important regulator in cell metabolism, and recent studies have shown that it may be involved in the pharmacological effects of metformin. However, the molecular mechanisms underlying this process are unclear. METHODS: The effects of SIRT3 on the regulation of oxidative stress and insulin resistance in skeletal muscle were evaluated in vitro. Differentiated L6 skeletal muscle cells were treated with 750 umol/L palmitic acid to induce insulin resistance. SIRT3 was knocked down and overexpressed in L6 cells. SIRT3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) p65, c-Jun N terminal kinase 1 (JNK1), and superoxide dismutase 2 (SOD2) were evaluated by Western blotting. RESULTS: Over expression of SIRT3 increased glucose uptake and decreased ROS production in L6-IR cells as well as in L6 cells. Knock-down of SIRT3 induced increased production of ROS while decreased glucose uptake in both L6 and L6-IR cells, and these effects were reversed by N-acetyl-L-cysteine (NAC). Metformin increased the expression of SIRT3 (1.5-fold) and SOD2 (2-fold) while down regulating NF-kappaB p65 (1.5-fold) and JNK1 (1.5-fold). Knockdown of SIRT3 (P < 0.05) reversed the metformin-induced decreases in NF-kappaB p65 and JNK1 and the metformin-induced increase in SOD2 (P < 0.05). CONCLUSIONS: Upregulated SIRT3 is involved in the pharmacological mechanism by which metformin promotes glucose uptake. Additionally, SIRT3 may function as an important regulator of oxidative stress and a new alternative approach for targeting insulin resistance-related diseases. PMID- 24762599 TI - Effect of interleukin-33 on Th1/Th2 cytokine ratio in peripheral lymphocytes in asthmatic mice. AB - BACKGROUND: Allergic asthma is a chronic airway inflammatory disease partly characterised by high concentration of T help 2 (Th2) cytokines in bronchoalveolar lavage fluid (BALF). There is no report on the relation of peripherally circulating blood lymphocytes and asthma. We explored the balance of Th2/Th1 cytokines in asthmatic mice. Exogenous recombinant interleukin (IL) 33 acted on murine peripheral circulating blood lymphocytes, IL-5 cytokine was selected for assessing Th2 cytokines and interferon-gamma (IFN-gamma) for Th1 cytokines. METHODS: Female specific pathogen free BABL/c mice were sensitised by intraperitoneal injection of 20 ug of ovalbumin emulsified in 1 mg of aluminium hydroxide gel in a total volume of 200 ul, and challenged for 30 minutes in 7 consecutive days with an aerosol of 2 g ovalbumin in 100 ml of PBS. Then we collected BALF and isolated lymphocytes from the peripheral blood. The lymphocytes were divided into two groups: asthmatic group and normal group. Th1/Th2 cytokines was detected by enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: In the asthma group, we found numerous eosinophils and lymphocytes on the glass slides. We then confirmed that the optimal concentration of IL-33 was 10 ng/ml and time of IL-33 stimulating lymphocytes was 24 hours. In the asthma group, the production of IL-5 was significantly increased over normal group after stimulation with IL-33 (P < 0.05) and the production of IFNgamma was supressed from IL-33 stimulated lymphocytes (P < 0.05). CONCLUSION: IL-33 acts on lymphocytes of peripheral blood increasing secretion of Th2 cytokines and inhibiting secretion of Th1 cytokines. PMID- 24762601 TI - Matrix metalloproteinase-8 inhibitors mitigate sepsis-induced myocardial injury in rats. AB - BACKGROUND: Sepsis-induced myocardial injury (SIMI) is caused by a variety of mechanisms. The aim of the study is to investigate the effects of metalloproteinase-8 (MMP-8) on SIMI and its mechanisms in rats. METHODS: Forty male Sprague Dawley rats were randomly divided into four groups: MMP-8 inhibitor (M8I), dexamethasone (DEX), sepsis, and sham groups. The sepsis model was established by cecal ligation and puncture (CLP). Rats in the M8I group immediately received an intraperitoneal injection of M8I (0.1 mg/kg) after CLP. Rats in the DEX group immediately received an intraperitoneal (IP) injection of DEX (2 mg/kg). Rats in the sepsis and sham groups received intraperitoneal injections of normal saline. Rats were sacrificed 12 hours after CLP. Paraffin sections were stained with hematoxylin and eosin to observe the myocardium. The myocardial ultrastructure was observed with transmission electron microscopy. MMP 8, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta) were detected by immunohistochemistry. The expression of MMP-8 was measured by Western blotting. TNF-alpha and IL-1beta levels in serum and myocardial tissue were determined by enzyme-linked immunosorbent assay. RESULTS: Compared with the sham group, the myocardium in the sepsis group was seriously injured. MMP-8, TNF-alpha and IL-1beta expression was higher in the sepsis group than in the sham group. Treatment with M8I or DEX, however, attenuated sepsis induced histopathological changes in the heart, and was associated with significant reductions in serum and myocardial levels of TNF-alpha and IL-1beta (P < 0.05). M8I significantly inhibited MMP-8 expression in myocardial tissue (P < 0.05). In addition, treatment with DEX was not associated with a change in myocardial levels of MMP-8 (P > 0.05). CONCLUSION: MMP-8 inhibitor attenuated myocardial injury in septic rats, which might be related to reduced expression of TNF-alpha and IL-1beta. PMID- 24762602 TI - Myelin protein zero and its antibody in serum as biomarkers of n-hexane-induced peripheral neuropathy and neurotoxicity effects. AB - BACKGROUND: Chronic exposure to n-hexane can lead to peripheral neuropathy that no effective treatment regimen could be applied presently. This study investigated whether myelin protein zero (P0) protein and its antibody could be used to distinguish n-hexane intoxication and protect workers from peripheral neuropathy. METHODS: We compared P0 protein and its antibody among three levels of n-hexane-exposed groups, which included 18 patients with n-hexane-induced peripheral neuropathy as case group, 120 n-hexane-exposed workers as n hexaneexposed control group, and 147 non-hexane-exposed participants used as control group. ELISA method was applied to detect P0 protein and its antibody. RESULTS: P0 protein in serum was significantly higher in the case group and n hexane-exposed control group in comparison with the control group (P < 0.01). Compared with the n-hexane-exposed control group, the case group also had significant increase of P0 protein (P < 0.01). After 6 months therapy, P0 protein was observed to decrease significantly in the case group (P < 0.01). The P0 antibody in serum was significantly higher in the n-hexane-exposed control group than in the control group (P < 0.01), but not significantly different between cases and controls. CONCLUSIONS: P0 antibodies in serum may be a short-term effect biomarker for n-hexane exposure. P0 protein in serum may be an early effective biomarker for peripheral nerve neuropathy and its biological limit value needs investigation in the future study. PMID- 24762603 TI - A novel, minimally invasive rat model of normothermic cardiopulmonary bypass model without blood priming. AB - BACKGROUND: Cardiopulmonary bypass (CPB) has been shown to be associated with systemic inflammatory response leading to postoperative organ dysfunction. Elucidating the underlying mechanisms and developing protective strategies for the pathophysiological consequences of CPB have been hampered due to the absence of a satisfactory recovery animal model. The purpose of this study was to establish a novel, minimally invasive rat model of normothermic CPB model without blood priming. METHODS: Twenty adult male Sprague-Dawley rats weighing 450-560 g were randomly divided into CPB group (n = 10) and control group (n = 10). All rats were anaesthetized and mechanically ventilated. The carotid artery and jugular vein were cannulated. The blood was drained from the right atrium via the right jugular and further transferred by a miniaturized roller pump to a hollow fiber oxygenator and back to the rat via the left carotid artery. The volume of the priming solution, composed of 6% HES 130/0.4 and 125 IU heparin, was less than 12 ml. The surface of the hollow fiber oxygenator was 0.075 m(2). CPB was conducted for 60 minutes at a flow rat of 100-120 ml * kg (-1)* min(-1) in CPB group. Oxygen flow/perfusion flow was 0.8 to 1.0, and the mean arterial pressure remained 60-80 mmHg. RESULTS: All CPB processes were successfully achieved. Blood gas analysis and hemodynamic parameters of each time point were in accordance with normal ranges. The vital signs of all rats were stable. CONCLUSIONS: The establishment of CPB without blood priming in rats can be achieved successfully. The nontransthoracic model should facilitate the investigation of pathophysiological processes concerning CPB-related multiple organ dysfunction and possible protective interventions. This novel, recovery, and reproducible minimally invasive CPB model may open the field for various studies on the pathophysiological process of CPB and systemic ischemia-reperfusion injury in vivo. PMID- 24762604 TI - Theanine improves the function of dendritic cells via the downregulation of cyclooxygenase-2 expression. AB - BACKGROUND: Tumor cells can reduce the number of dendritic cells (DCs) in the tumor environment and cause DC dysfunction through autocrine or paracrine pathways. We sought to measure cyclooxygenase-2 (COX-2) expression in bombesin inhibited DCs treated with theanine in vitro and to explore the protection and activation effects of theanine on DCs. METHODS: Enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting were used to analyze the effects of theanine on COX-2 expression and interleukin (IL)-12/IL-10 secretion of bombesin-treated DCs. RESULTS: DCs acquired an impaired phenotype as a result of bombesin treatment. Theanine increased the expression of mature DC surface molecules. The number of cell apoptosis with the treatment of bombesin and theanine significantly decreased, accounting for 15.9%, compared with 26.1% of cell apoptosis with bombesin. COX-2 expression in bombesin-treated DCs was inhibited by theanine in a dose-dependent manner. Theanine promoted DC secretion of IL-12. IL-12 levels reached (137.4 +/- 4.9) pg/ml with theanine at 200 umol/L. However, theanine inhibited the secretion of IL-10 in a dose-dependent manner. IL-10 levels were only (58.4 +/- 6.9) pg/ml with theanine at 200 umol/L. CONCLUSION: Theanine inhibits the transcription and translation of COX-2 and regulates the balance of IL-10/IL-12 secretion in bombesin-inhibited DCs, leading to the recovery of a state of activation in DCs. PMID- 24762605 TI - Progress of anti-vascular endothelial growth factor therapy for ocular neovascular disease: benefits and challenges. AB - OBJECTIVE: This review aims to summarize the progress of current clinical studies in ocular angiogenesis treated with anti-vascular endothelial growth factor (VEGF) therapy and to discuss the benefits and challenges of the treatment. DATA SOURCES: Pubmed, Embase and the Cochrane Library were searched with no limitations of language and year of publication. STUDY SELECTION: Clinical trials and case studies presented at medical conferences and published in peer-reviewed literature in the past decade were reviewed. RESULTS: Anti-VEGF agents have manifested great potential and promising outcomes in treating ocular neovascularization, though some of them are still used as off-label drugs. Intravitreal injection of anti-VEGF agents could be accompanied by devastating ocular or systemic complications, and intimate monitoring in both adult and pediatric population are warranted. Future directions should be focused on carrying out more well-designed large-scale controlled trials, promoting sustained duration of action, developing safer and more efficient generation of anti-VEGF agents. CONCLUSIONS: Anti-VEGF treatment has proved to be beneficial in treating both anterior and posterior neovascular ocular diseases. However, more safer and affordable antiangiogenic agencies and regimens are warranted to be explored. PMID- 24762606 TI - New techniques to improve classical corneal collagen cross-linking treatment. AB - OBJECTIVE: The aim of this review is to comprehensively and unbiasedly summarize the improvements in the techniques for classical corneal collagen cross-linking (CXL) by covering the reasons for this improvement, measure, and effect to approach the future direction of the CXL. DATA SOURCES: All articles used in this review were mainly retrieved from the PubMed database. STUDY SELECTION: Original articles and reviews were selected if they were related to the improvement in the technique of classical CXL. Data were mainly extracted from 94 articles, which are listed in the reference section of this review. RESULTS: This innovative research involves every step such as instrument preparation, epithelial management, riboflavin instillation, and UVA irradiation. These clinical and experimental results seem promising. CONCLUSIONS: CXL treatment is the only recent promising method for preventing the progress of keratoconus. The limitations and potential complications that accompany classical CXL such as corneal thickness limitations, ultraviolet-A (UVA) light injury, and the impact of de-epithelialization encourage people to research new improvements in techniques. While this research needs to be further investigated, we hope our review can help related researchers and patients. PMID- 24762607 TI - Vitreomacular traction syndrome. AB - OBJECTIVE: This study aimed to review the available literature on vitreomacular traction (VMT) syndrome and propose the future study prospect in this field. DATA SOURCES: The data used in this review were mainly obtained from articles listed in Medline and Pubmed (1970-2013). The search terms were "vitreomacular traction", "optical coherence tomography", "vitrectomy", and "ocriplasmin". STUDY SELECTION: Articles regarding the pathophysiology, diagnosis, and treatments of VMT were selected and reviewed. RESULTS: VMT syndrome is a persistent attachment of vitreous to the macula in eyes with an incomplete posterior vitreous detachment and considered to be an uncommon status which correlated with some other macular disorders. Optical coherence tomography (OCT) can support a new way to examine and classify VMT. Nonoperative and operative intervenes on this disease have been developed recently, especially the intravitreal medical therapy. CONCLUSIONS: VMT syndrome may be associated with various disorders in the macular region, depending in part on the size and strength of the residual vitreomacular adhesion. Regular OCT monitoring is recommended to detect it. Patients with asymptomatic VMT should be observed for at least 2-3 months; nonoperative treatment with ocriplasmin should be considered when disorders persist; surgery is recommended if VMT-related disease is significant. PMID- 24762608 TI - Role of matrix metalloproteinases in chronic wound healing: diagnostic and therapeutic implications. PMID- 24762609 TI - Metabolic evaluation in stone formation with hyperuricemia. PMID- 24762610 TI - Diagnosis and therapy of primary undifferentiated embryonal sarcoma of the liver. PMID- 24762611 TI - Relationship between heart rate and failure of biological valve: slowing the heart rate could delay the failure of biological valve? PMID- 24762612 TI - Three-dimensional and two-dimensional morphological features of patent foramen ovale revealed by transesophageal echocardiography. PMID- 24762613 TI - Encased heart and aorta by the thymic carcinoma. PMID- 24762614 TI - Endogenous Klebsiella pneumoniae endophthalmitis associated with intravenous drug abuse. PMID- 24762615 TI - Merkel cell carcinoma of the earlobe in a diabetes mellitus patient. PMID- 24762616 TI - Adult multisystem Langerhans cell histiocytosis involving parathyroid glands and pancreas. PMID- 24762617 TI - Primary squamous cell carcinoma of the fallopian tube. PMID- 24762618 TI - Upper limb embolism as the first manifestation of atrial fibrillation. PMID- 24762619 TI - Severe acute interstitial lung disease induced by crizotinib therapy in a patient with c-Met amplification non-small cell lung cancer. PMID- 24762621 TI - Beyond network structure: How heterogeneous susceptibility modulates the spread of epidemics. AB - The compartmental models used to study epidemic spreading often assume the same susceptibility for all individuals, and are therefore, agnostic about the effects that differences in susceptibility can have on epidemic spreading. Here we show that-for the SIS model-differential susceptibility can make networks more vulnerable to the spread of diseases when the correlation between a node's degree and susceptibility are positive, and less vulnerable when this correlation is negative. Moreover, we show that networks become more likely to contain a pocket of infection when individuals are more likely to connect with others that have similar susceptibility (the network is segregated). These results show that the failure to include differential susceptibility to epidemic models can lead to a systematic over/under estimation of fundamental epidemic parameters when the structure of the networks is not independent from the susceptibility of the nodes or when there are correlations between the susceptibility of connected individuals. PMID- 24762620 TI - Constitutional promoter methylation and risk of familial melanoma. AB - Constitutional epigenetic changes detected in blood or non-disease involving tissues have been associated with disease susceptibility. We measured promoter methylation of CDKN2A (p16 and p14ARF) and 13 melanoma-related genes using bisulfite pyrosequencing of blood DNA from 114 cases and 122 controls in 64 melanoma-prone families (26 segregating CDKN2A germline mutations). We also obtained gene expression data for these genes using microarrays from the same blood samples. We observed that CDKN2A epimutation is rare in melanoma families, and therefore is unlikely to cause major susceptibility in families without CDKN2A mutations. Although methylation levels for most gene promoters were very low (<5%), we observed a significantly reduced promoter methylation (odds ratio = 0.63, 95% confidence interval = 0.50, 0.80, P<0.001) and increased expression (fold change = 1.27, P = 0.048) for TNFRSF10C in melanoma cases. Future research in large prospective studies using both normal and melanoma tissues is required to assess the significance of TNFRSF10C methylation and expression changes in melanoma susceptibility. PMID- 24762622 TI - Potential Pediatric Applications of PET/MR. AB - Medical imaging with multimodality and whole-body technologies has continuously improved in recent years. The advent of combined modalities such as PET/CT and PET/MR offers new tools with an exact fusion of molecular imaging and high resolution anatomic imaging. For noninvasive pediatric diagnostics, molecular imaging and whole-body MR have become important, especially in pediatric oncology. Because it has a lower radiation exposure than PET/CT, combined PET/MR is expected to be of special use in pediatric diagnostics. This review focuses on possible pediatric applications of PET/MR hybrid imaging, particularly pediatric oncology and neurology but also the diagnosis of infectious or inflammatory diseases. PMID- 24762623 TI - Reply: Al18F Labeling of Affibody Molecules. PMID- 24762624 TI - Transient Ischemic Dilation of the Left Ventricle on SPECT: Correlation with Findings at Coronary CT Angiography. AB - Transient ischemic dilation (TID) in the setting of abnormal stress-rest cardiac SPECT myocardial perfusion imaging (MPI) has been linked with increased cardiovascular risk. However, the significance of TID in the setting of an otherwise normal SPECT MPI study has not been clearly established. In this study, cardiac CT was used to evaluate the prevalence of atherosclerotic lesions and the severity of coronary artery stenosis in patients with TID of the left ventricle with or without associated myocardial perfusion defects on SPECT MPI. METHODS: The study population consisted of 1,553 consecutive patients who had undergone both cardiac CT and SPECT MPI within 1 mo between January 1, 2006, and September 1, 2011. Patients included in the study group had a pathologic TID value defined as >=1.18 for men and >=1.22 for women. Coronary CT angiography was used to evaluate each coronary segment for the presence and composition of atherosclerotic plaque and the degree of coronary stenosis. TID-positive patients were compared with a 2:1 risk-factor-matched-pair control cohort without TID. RESULTS: TID was identified in 30 patients who were compared with TID-negative risk-factor-matched controls (n = 60). When compared with the TID-negative control cohort, TID-positive patients had no significant differences in the presence and extent of atherosclerosis, the degree of coronary artery stenosis, or the calcium score at cardiac CT. Similarly, there were no significant differences in these CT measures in TID-positive patients with a normal perfusion study (n = 20) when compared with TID-negative patients with a normal perfusion study (n = 48). In addition, there was no significant difference in the incidence of major adverse cardiac events when comparing both the TID-positive patients and the TID-negative control cohort and when comparing patients who were TID-positive with normal perfusion with patients who were TID-negative with normal perfusion. CONCLUSION: The presence of TID with an otherwise normal SPECT MPI study does not translate into a greater extent of coronary artery disease as assessed by cardiac CT or increased risk for future major adverse cardiac events. PMID- 24762625 TI - Al18F Labeling of Affibody Molecules. PMID- 24762626 TI - Potential Applications of PET/MR Imaging in Cardiology. AB - Recent advances in hybrid PET/MR imaging have opened new perspectives for cardiovascular applications. Although cardiac MR imaging has gained wider adoption for routine clinical applications, PET images remain the reference in many applications for which objective analysis of metabolic and physiologic parameters is needed. In particular, in cardiovascular diseases-more specifically, coronary artery disease-the use of quantitative and measurable parameters in a reproducible way is essential for the management of therapeutic decisions and patient follow-up. Functional MR images and dynamic assessment of myocardial perfusion from transit of intravascular contrast medium can provide useful criteria for identifying areas of decreased myocardial perfusion or for assessing tissue viability from late contrast enhancement of scar tissue. PET images, however, will provide more quantitative data on true tissue perfusion and metabolism. Quantitative myocardial flow can also lead to accurate assessment of coronary flow reserve. The combination of both modalities will therefore provide complementary data that can be expected to improve the accuracy and reproducibility of diagnostic procedures. But the true potential of hybrid PET/MR imaging may reside in applications beyond the domain of coronary artery disease. The combination of both modalities in assessment of other cardiac diseases such as inflammation and of other systemic diseases can also be envisioned. It is also predicted that the 2 modalities combined could help characterize atherosclerotic plaques and differentiate plaques with a high risk of rupture from stable plaques. In the future, the development of new tracers will also open new perspectives in evaluating myocardial remodeling and in assessing the kinetics of stem cell therapy in myocardial infarction. New tracers will also provide new means for evaluating alterations in cardiac innervation, angiogenesis, and even the assessment of reporter gene technologies. The fusion of 2 potentially competing modalities can certainly offer the best of each modality in a single procedure. The impact of such advanced technology in routine clinical practice will still need to be demonstrated. Beyond the expected improvement in patient management and the potential impact on patient outcome, PET/MR imaging will also need to establish its medicoeconomic justification in an era of health-care economic restrictions. PMID- 24762627 TI - VIP-expressing dendritic cells protect against spontaneous autoimmune peripheral polyneuropathy. AB - The spontaneous autoimmune peripheral polyneuropathy (SAPP) model in B7-2 knockout nonobese diabetic mice mimics a progressive and unremitting course of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this study, bone marrow-derived dendritic cells (DCs) were transduced to express vasoactive intestinal polypeptide (VIP) using a lentiviral vector (LV-VIP). These transduced DCs (LV-VIP-DCs) were then injected intravenously (i.v.) into 16-week-old (before disease onset) and 21-week-old (after disease onset) SAPP mice in order to prevent or attenuate the disease. Outcome measures included behavioral tests, clinical and histological scoring, electrophysiology, real-time PCR, flow cytometry analyses, and enzyme-linked immunosorbent assay. LV-VIP-DCs were recruited to the inflamed sciatic nerve and reduced the expression of inflammatory cytokines. A single injection of LV-VIP-DC delayed the onset of disease, stabilized, and attenuated clinical signs correlating with ameliorated behavioral functions, reduced nerve demyelination, and improved nerve conduction. This proof-of-principle study is an important step potentially leading to a clinical translational study using DCs expressing VIP in cases of CIDP refractory to standard immunosuppressive therapy. PMID- 24762628 TI - Drosophila embryogenesis scales uniformly across temperature in developmentally diverse species. AB - Temperature affects both the timing and outcome of animal development, but the detailed effects of temperature on the progress of early development have been poorly characterized. To determine the impact of temperature on the order and timing of events during Drosophila melanogaster embryogenesis, we used time-lapse imaging to track the progress of embryos from shortly after egg laying through hatching at seven precisely maintained temperatures between 17.5 degrees C and 32.5 degrees C. We employed a combination of automated and manual annotation to determine when 36 milestones occurred in each embryo. D. melanogaster embryogenesis takes [Formula: see text]33 hours at 17.5 degrees C, and accelerates with increasing temperature to a low of 16 hours at 27.5 degrees C, above which embryogenesis slows slightly. Remarkably, while the total time of embryogenesis varies over two fold, the relative timing of events from cellularization through hatching is constant across temperatures. To further explore the relationship between temperature and embryogenesis, we expanded our analysis to cover ten additional Drosophila species of varying climatic origins. Six of these species, like D. melanogaster, are of tropical origin, and embryogenesis time at different temperatures was similar for them all. D. mojavensis, a sub-tropical fly, develops slower than the tropical species at lower temperatures, while D. virilis, a temperate fly, exhibits slower development at all temperatures. The alpine sister species D. persimilis and D. pseudoobscura develop as rapidly as tropical flies at cooler temperatures, but exhibit diminished acceleration above 22.5 degrees C and have drastically slowed development by 30 degrees C. Despite ranging from 13 hours for D. erecta at 30 degrees C to 46 hours for D. virilis at 17.5 degrees C, the relative timing of events from cellularization through hatching is constant across all species and temperatures examined here, suggesting the existence of a previously unrecognized timer controlling the progress of embryogenesis that has been tuned by natural selection as each species diverges. PMID- 24762629 TI - Immunohistochemical monitoring of wound healing in antibiotic treated Buruli ulcer patients. AB - BACKGROUND: While traditionally surgery has dominated the clinical management of Buruli ulcer (BU), the introduction of the combination chemotherapy with oral rifampicin and intramuscular streptomycin greatly improved treatment and reduced recurrence rates. However management of the often extensive lesions after successful specific therapy has remained a challenge, in particular in rural areas of the African countries which carry the highest burden of disease. For reasons not fully understood, wound healing is delayed in a proportion of antibiotic treated BU patients. Therefore, we have performed immunohistochemical investigations to identify markers which may be suitable to monitor wound healing progression. METHODOLOGY/PRINCIPAL FINDINGS: Tissue specimens from eight BU patients with plaque lesions collected before, during and after chemotherapy were analyzed by immunohistochemistry for the presence of a set of markers associated with connective tissue neo-formation, tissue remodeling and epidermal activation. Several target proteins turned out to be suitable to monitor wound healing. While alpha-smooth muscle actin positive myofibroblasts were not found in untreated lesions, they emerged during the healing process. These cells produced abundant extracellular matrix proteins, such as pro-collagen 1 and tenascin and were found in fibronectin rich areas. After antibiotic treatment many cells, including myofibroblasts, revealed an activated phenotype as they showed ribosomal protein S6 phosphorylation, a marker for translation initiation. In addition, healing wounds revealed dermal tissue remodeling by apoptosis, and showed increased cytokeratin 16 expression in the epidermis. CONCLUSION/SIGNIFICANCE: We have identified a set of markers that allow monitoring wound healing in antibiotic treated BU lesions by immunohistochemistry. Studies with this marker panel may help to better understand disturbances responsible for wound healing delays observed in some BU patients. PMID- 24762630 TI - Preventive behaviors and knowledge of tick-borne illnesses: results of a survey from an endemic area. AB - CONTEXT: Lyme disease (LD) is the most commonly reported vector-borne illness in the United States. With physically and economically burdensome effects, it is a concern of public health officials. OBJECTIVES: To assess knowledge and preventive behaviors of individuals in the endemic area of Martha's Vineyard, Massachusetts, to better understand how sociodemographic data and knowledge correlate with preventive behaviors, and to update previous island studies. DESIGN: A 30-item paper-based anonymous survey in either English or Portuguese based on language preference. SETTING: The island of Martha's Vineyard and the ferry between island and mainland. PARTICIPANTS: A total of 946 participants were recruited at 1 of 4 island locations. The majority of participants were traveling by ferry to and from Martha's Vineyard. To reach 2 populations potentially at high risk, that is, youths and outdoor workers, 3 additional venues included the island high school, an English-as-a-Second-Language class, and a local Brazilian church. OUTCOME MEASURES: Four specific preventive behaviors as well as an overall composite prevention score. RESULTS: Participants' knowledge of tick borne illnesses was poor, and the frequency of practicing preventive behaviors was low; the most commonly reported behavior was checking one's skin for ticks (45%). Approximately one-third of respondents (37%) stated that they did not know the late symptoms of untreated LD, nor did they know early LD treatment options (49%). The 2 high-risk groups reported little participation in preventive measures. In multivariate analyses, only 4 characteristics-older age, confidence in telling deer tick from wood tick, seeing tick-borne illness as a serious threat, and certainty in ability to identify LD symptoms-attained significance associated with preventive behavior as an overall composite score. CONCLUSIONS: Public health interventions focusing on accurately communicating risk, improving knowledge both of LD symptoms and of ticks that carry the disease, as well as teaching preventive behaviors may help reduce tick-borne illness rates. PMID- 24762631 TI - Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. AB - BACKGROUND: Recurrent Clostridium difficile infection (CDI) with poor response to standard antimicrobial therapy is a growing medical concern. We aimed to investigate the outcomes of fecal microbiota transplant (FMT) for relapsing CDI using a frozen suspension from unrelated donors, comparing colonoscopic and nasogastric tube (NGT) administration. METHODS: Healthy volunteer donors were screened and a frozen fecal suspension was generated. Patients with relapsing/refractory CDI were randomized to receive an infusion of donor stools by colonoscopy or NGT. The primary endpoint was clinical resolution of diarrhea without relapse after 8 weeks. The secondary endpoint was self-reported health score using standardized questionnaires. RESULTS: A total of 20 patients were enrolled, 10 in each treatment arm. Patients had a median of 4 (range, 2-16) relapses prior to study enrollment, with 5 (range, 3-15) antibiotic treatment failures. Resolution of diarrhea was achieved in 14 patients (70%) after a single FMT (8 of 10 in the colonoscopy group and 6 of 10 in the NGT group). Five patients were retreated, with 4 obtaining cure, resulting in an overall cure rate of 90%. Daily number of bowel movements changed from a median of 7 (interquartile range [IQR], 5-10) the day prior to FMT to 2 (IQR, 1-2) after the infusion. Self ranked health score improved significantly, from a median of 4 (IQR, 2-6) before transplant to 8 (IQR, 5-9) after transplant. No serious or unexpected adverse events occurred. CONCLUSIONS: In our initial feasibility study, FMT using a frozen inoculum from unrelated donors is effective in treating relapsing CDI. NGT administration appears to be as effective as colonoscopic administration. CLINICAL TRIALS REGISTRATION: NCT01704937. PMID- 24762632 TI - STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b. AB - The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted through mutation or epigenetic events, STAT3 becomes highly active and drives elevated expression of genes underlying these phenotypes, leading to malignant cellular behavior. However, even in the presence of activated STAT3, other cellular modulators can have a major impact on the biological properties of a cancer cell, which is reflected in the clinical behavior of a tumor. Recent evidence has suggested that two such key modulators are the activation status of other STAT family members, particularly STAT5, and the expression of STAT3 regulated genes that are part of negative feedback circuits, including microRNAs such as miR-146b. With attention to these newly emerging areas, we will gain greater insight into the consequence of STAT3 activation in the biology of human cancers. In addition, understanding these subtleties of STAT3 signaling in cancer pathogenesis will allow the development of more rational molecular approaches to cancer therapy. PMID- 24762633 TI - Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial Derived Cancers. AB - Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin(r)) and rituximab (Rituxan(r))) and the first approved cancer vaccine, Provenge(r) (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response. PMID- 24762634 TI - Heat shock response associated with hepatocarcinogenesis in a murine model of hereditary tyrosinemia type I. AB - Hereditary Tyrosinemia type 1 (HT1) is a metabolic liver disease caused by genetic defects of fumarylacetoacetate hydrolase (FAH), an enzyme necessary to complete the breakdown of tyrosine. The severe hepatic dysfunction caused by the lack of this enzyme is prevented by the therapeutic use of NTBC (2-[2-nitro-4 (trifluoromethyl)benzoyl] cyclohexane-1,3-dione). However despite the treatment, chronic hepatopathy and development of hepatocellular carcinoma (HCC) are still observed in some HT1 patients. Growing evidence show the important role of heat shock proteins (HSPs) in many cellular processes and their involvement in pathological diseases including cancer. Their survival-promoting effect by modulation of the apoptotic machinery is often correlated with poor prognosis and resistance to therapy in a number of cancers. Here, we sought to gain insight into the pathophysiological mechanisms associated with liver dysfunction and tumor development in a murine model of HT1. Differential gene expression patterns in livers of mice under HT1 stress, induced by drug retrieval, have shown deregulation of stress and cell death resistance genes. Among them, genes coding for HSPB and HSPA members, and for anti-apoptotic BCL-2 related mitochondrial proteins were associated with the hepatocarcinogenetic process. Our data highlight the variation of stress pathways related to HT1 hepatocarcinogenesis suggesting the role of HSPs in rendering tyrosinemia-affected liver susceptible to the development of HCC. PMID- 24762636 TI - Effect of contraction force and knee joint angle on the spatial representation of soleus activity using high-density surface EMG. AB - The meaningful use of surface electromyographic signals (sEMG) is to find an electrode position and orientation in which the sEMG signals can be detected reliably. This becomes more challenging when muscles with pinnate fiber architecture are investigated. In this study, the effects of contraction force and knee inclination on the spatial representation of the soleus muscle activity on the skin surface have been investigated by using two-dimensional electrode grids. Four differently oriented bipolar leads have been calculated to identify not only a proper electrode location but also an adequate orientation of the bipolar lead. Relative measures have been introduced to compare changes in the spatial RMS distribution. It has been shown that in the case of the soleus muscle, bipolar electrodes should be placed on the lateral side. Additionally, the location of the electrodes should be rather proximal than distal, and the orientation of the bipolar lead should be 45 degrees to the lateral side with respect to a line connecting the insertion of the Achilles tendon and the junction between both gastrocnemius heads. Our results have been used to identify adequate electrode locations and orientations in a muscle with such a complex architecture like the soleus muscle. Additionally, new parameters have been introduced, helping to analyze the resulting information about the spatial activation pattern in the soleus muscle. PMID- 24762635 TI - Eprosartan improves cardiac function in swine working heart model of ischemia reperfusion injury. AB - BACKGROUND: Eprosartan is an angiotensin II receptor antagonist used as an antihypertensive. We sought to evaluate the regional effect of Eprosartan on postinfarct ventricular remodeling and myocardial function in an isolated swine working heart model of ischemia-reperfusion injury. MATERIAL AND METHODS: 22 swine hearts were perfused with the Langendorff perfusion apparatus under standard experimental conditions. Myocardial ischemia was induced by a 10-min left anterior descending artery ligation. Hearts were reperfused with either saline (control group, n=11), or Eprosartan (treatment group, n=11). Left ventricular pressure (LVP) and regional heart parameters such as intramyocardial pressure (IMP), wall thickening rate (WTh), and pressure-length-loops (PLL) were measured at baseline and after 30 min of reperfusion. RESULTS: Measured parameters were statistically similar between the 2 groups at baseline. The administration of Eprosartan led to a significantly better recovery of IMP and WTh: 44.4+/-2.5 mmHg vs. 51.2+/-3.3 mmHg, p<0.001 and 3.8+/-0.4 um vs. 4.4+/-0.3 um, p=0.001, respectively. PLL were also significantly higher in the treatment group following reperfusion (21694+/-3259 units vs. 31267+/-3429 units, p<0.01). There was no difference in the LVP response to Eprosartan versus controls (63.6+/ 3.0 mmHg vs. 62.5+/-3.1 mmHg, p=0.400). CONCLUSIONS: Pre-treatment with Eprosartan is associated with a significant improvement in regional cardiac function under ischemic conditions. Pharmacological treatment with eprosartan may exert a direct cardioprotective effect on ischemic myocardium. PMID- 24762637 TI - A simple method for vital staining of elastin in arterial tissue. AB - Highly diluted solutions of Gentian Violet and Evans Blue were used to visualize the elastin network in viable porcine right common carotid artery (RCCA) preparations. The two simple, alternative methods of staining were applied to proximal, intermediate, and distal sections of RCCA under various experimental conditions. These included the state of the vessel wall soon after excision, under relaxed smooth muscle condition after preconditioning, and during vasoconstriction. Micrographs of arterial rings, sectors, and axial strips show that the RCCA is an artery of the elastic type at the proximal end and of the muscular type at the distal end. While in sections of freshly dissected or KCl constricted arteries the elastic lamellae show the well-known waviness, those in sections from arteries with relaxed smooth muscle and after preconditioning appear nearly straight. It is hoped that the inexpensive staining tools will contribute to solve conflicting interpretations existing on elastin structures in the arterial wall. PMID- 24762638 TI - To precribe or not to prescribe antibiotics. PMID- 24762639 TI - Heavy Internet use and its associations with health risk and health-promoting behaviours among Thai university students. AB - The Internet provides significant benefits for learning about the world, but excessive Internet use can lead to negative outcomes. The aim of this study was to determine the associations between heavy Internet use and health-promoting behaviour, health risk behaviour and health outcomes among university students. The sample included 860 undergraduate university students chosen at random from Mae Fah Luang University in Thailand. Of the participants, 27.3% were male and and 72.7% were female in the age range of 18-25 years (M age=20.1 years, SD=1.3). Overall, students spent on average 5.3 h (SD=2.6) per day on the internet, and 35.3% engaged in heavy internet use (6 or more hours per day). In multivariate logistic regression adjusting for sociodemographics, lack of dental check-ups, three health risk behaviours (sedentary lifestyle, illicit drug use and gambling) and three health outcomes [being underweight, overweight or obese and having screened positive for post-traumatic stress disorder (PTSD)] were found to be associated with heavy Internet use. The results from this study may support the importance of developing early protective and preventive actions against problematic Internet use to promote university student health. PMID- 24762640 TI - University students and the risk of HIV and other sexually transmitted infections in Uganda: the Crane survey. AB - Adolescents and young adults are at high risk of human immunodeficiency virus (HIV) infection in sub-Saharan Africa. Previous reports have found that university students in Africa comprise a sexually active population, although the prevalence of HIV or sexually transmitted infections (STI) has not been measured. We conducted a cross-sectional survey of students from five large universities in Kampala, Uganda, using respondent-driven sampling. We asked students to complete behavioral questionnaires and provide biological samples to test for HIV, Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, Trichomonas vaginalis, and bacterial vaginosis. We enrolled 649 students and obtained interpretable data from 640. Around 50% of the respondents were male, and the mean age was 22 years. An estimated 0.8% (95% CI 0.0-2.0) of male students had Chlamydia infection, approximately 4.3% (95% CI 2.0-7.0) had syphilis, 0.4% (95% CI 0.0-0.9) had HIV, and none had gonorrhea. An estimated 32.6% (95% CI 22.4 40.8) of women had bacterial vaginosis, 2.5% (95% CI 0.7-6.3) had Chlamydia infection, 1.7% (95% CI 0.5-3.6) had syphilis, 1.0% (95% CI 0.0-2.4) had gonorrhea, 0.9% (95% CI 0.0-4.2) had trichomoniasis, and 0.9% (95% CI 0.0-1.8) had HIV. We found no significant risk factors for HIV or other STI among males. We also found that not using a condom during the latest sexual intercourse was significantly associated with HIV infection, other STI, or bacterial vaginosis (OR 2.16; 95% 1.26-3.78) among females. We conclude that while university students are sexually active and there is substantial risk for syphilis, there is little evidence of substantially increased HIV risk among them. PMID- 24762641 TI - Prehypertension and associated factors among university students in the Philippines. AB - BACKGROUND: Prehypertension is a new category of blood pressure, and is considered a cardiovascular risk factor. The aim of this study was to estimate the prevalence of prehypertension and its associated factors in young adults in the Philippines. METHODS: Undergraduate university students from all areas of study in the University of the Philippines-Visayas were invited to participate. Prehypertension was defined as systolic blood pressure between 120 and 139 mm Hg and/or diastolic blood pressure between 80 and 89 mm Hg. Blood pressure, anthropometric, health behavior, and psychosocial stress variables were measured. RESULTS: A total of 754 university students were included in the analysis (mean age, 18.3 +/- 1.4 years, 74.3% women). Prehypertension prevalence was 13.9% (36.1% in men, 6.8% in women), and hypertension prevalence was 2.4% (6.6% in men, 1.1% in women). The condition of prehypertension was associated with body mass index obesity (OR: 5.14, CI: 2.70 to 9.79), male gender (OR: 9.41, CI: 5.41 to 16.36), living off campus on their own (OR: 3.18, CI: 1.35 to 7.48), living with parents or guardians (OR: 2.83, CI: 1.20 to 6.60), and 19 years of age (OR: 2.81, CI: 1.55 to 5.11). CONCLUSION: One out of every 7 young adults presented with prehypertension. This condition is associated with established risk factors. PMID- 24762642 TI - Treatment of refractory substance-induced psychosis in adolescent males with a genetic predisposition to mental illness. AB - This article presents two cases of adolescent males who were admitted to our inpatient psychiatric unit with a psychotic, disorganized presentation. Both males had a genetic vulnerability to mental illness and reported significant substance use. Their symptoms were refractory to treatment and required the use of clozapine. Both patients experienced significant side effects, which limited the maximum daily dose of clozapine. However, they responded to a dose that was much lower than that typically used in adults. There is significant evidence in the literature about cannabis use triggering psychotic breaks in vulnerable individuals. We speculate that substance use (including synthetic cannabinoids) triggers treatment-resistant psychosis that requires the use of clozapine. Further, lower doses of clozapine may be sufficient to treat the substance induced psychotic symptoms than those typically used in adult schizophrenia. PMID- 24762644 TI - LC-MS candidate reference methods for the harmonisation of parathyroid hormone (PTH) measurement: a review of recent developments and future considerations. AB - The analysis of intact parathyroid hormone (PTH) (PTH1-84) is useful in the diagnosis of hyper- and hypocalcaemia, hyperparathyroidism, and in the prevention of bone mineral disorders in renal patients. The analysis is complicated by the presence of PTH fragments, which may accumulate in renal failure and cross-react in immunoassays, including the most recent third-generation immunoassays. Large variability exists between different commercially available assays. This article reviews the current literature on PTH testing, with emphasis on the use of mass spectrometry-based methods, and considers the important sources of variation which still need to be addressed prior to the development of much needed candidate reference methods for PTH analysis. Recently, mass spectrometric methods have been developed for the quantitation of PTH1-84 using surrogate tryptic peptides, but even these methods are subject to significant interferences due to the presence of newly observed modified PTH species, such as oxidised and phosphorylated PTH variants, which can accumulate in patient samples. Further work, including: 1) the use of high-resolution mass spectrometry; and 2) the analysis of PTH without prior protease digestion, is required before these approaches can be considered as reference methods against which other methods should be harmonised. PMID- 24762646 TI - Indoor metallic pollution and children exposure in a mining city. AB - Mining industries are known for causing strong environmental contamination. In most developing countries, the management of mining wastes is not adequate, usually contaminating soil, water and air. This situation is a source of concern for human settlements located near mining centers, especially for vulnerable populations such as children. The aim of this study was to assess the correlations of the metallic concentrations between household dust and children hair, comparing these associations in two different contamination contexts: a mining district and a suburban non-mining area. We collected 113 hair samples from children between 7 and 12 years of age in elementary schools in the mining city of Oruro, Bolivia. We collected 97 indoor dust samples from their households, as well as information about the children's behavior. Analyses of hair and dust samples were conducted to measure As, Cd, Pb, Sb, Sn, Cu and Zn contents. In the mining district, there were significant correlations between non essential metallic elements (As, Cd, Pb, Sb and Sn) in dust and hair, but not for essential elements (Cu and Zn), which remained after adjusting for children habits. Children who played with dirt had higher dust-hair correlations for Pb, Sb, and Cu (P=0.006; 0.022 and 0.001 respectively) and children who put hands or toys in their mouths had higher dust-hair correlations of Cd (P=0.011). On the contrary, in the suburban area, no significant correlations were found between metallic elements in dust and children hair and neither children behavior nor gender modified this lack of associations. Our results suggest that, in a context of high metallic contamination, indoor dust becomes an important exposure pathway for children, modulated by their playing behavior. PMID- 24762647 TI - In vitro bioassays for detecting dioxin-like activity--application potentials and limits of detection, a review. AB - Use of in vitro assays as screening tool to characterize contamination of a variety of environmental matrices has become an increasingly popular and powerful toolbox in the field of environmental toxicology. While bioassays cannot entirely substitute analytical methods such as gas chromatography-mass spectrometry (GC MS), the increasing improvement of cell lines and standardization of bioassay procedures enhance their utility as bioanalytical pre-screening tests prior to more targeted chemical analytical investigations. Dioxin-receptor-based assays provide a holistic characterization of exposure to dioxin-like compounds (DLCs) by integrating their overall toxic potential, including potentials of unknown DLCs not detectable via e.g. GC-MS. Hence, they provide important additional information with respect to environmental risk assessment of DLCs. This review summarizes different in vitro bioassay applications for detection of DLCs and considers the comparability of bioassay and chemical analytically derived toxicity equivalents (TEQs) of different approaches and various matrices. These range from complex samples such as sediments through single reference to compound mixtures. A summary of bioassay derived detection limits (LODs) showed a number of current bioassays to be equally sensitive as chemical methodologies, but moreover revealed that most of the bioanalytical studies conducted to date did not report their LODs, which represents a limitation with regard to low potency samples. PMID- 24762648 TI - On my knees, 1988. PMID- 24762650 TI - Anthropometric parameters in relation to glycaemic status and lipid profile in a multi-ethnic sample in Italy. AB - OBJECTIVE: To examine the health status of ethnic minorities in Italy. Furthermore, we aimed to assess the association between anthropometric and blood parameters connected with health status. DESIGN: A cross-sectional study. Anthropometric data were collected by direct measurements and blood glucose, total cholesterol and TAG were analysed. SETTING: Bologna, northern Italy. SUBJECTS: A multi-ethnic sample of adult immigrants and Roma. RESULTS: Significant correlations between anthropometric and blood parameters were found. Among the ethnic groups, Roma males had the highest values of glucose, total cholesterol and TAG. In the females the situation was more balanced among ethnic groups. CONCLUSIONS: The data from this survey indicate that poor health status is a very common problem among ethnic groups living in Italy, especially the Roma. The use of anthropometric parameters as rapid indicators of health status in screenings of a large number of subjects could be an effective and cheap method to provide preliminary indications on individuals or ethnic groups at greater risk of poor health. PMID- 24762653 TI - Axon and dendritic trafficking. AB - Neuronal trafficking is crucial to the formation and dynamics of presynaptic and postsynaptic structures and the development and maintenance of axonal and dendritic processes. The mechanism for delivering specific organelles and synaptic molecules in axons and dendrites primarily depends on molecular motor proteins that move along the cytoskeleton. Adaptor proteins, regulatory molecules and local signaling pathways provide additional layers of specificity and control over bidirectional movement, polarized transport and cargo delivery. Here we review recent advances and emerging concepts related to the transport machinery of crucial neuronal components, such as mitochondria and presynaptic cargoes, and the mechanisms that modulate their polarized axo-dendritic sorting and synaptic delivery. PMID- 24762652 TI - Shared mechanisms between Drosophila peripheral nervous system development and human neurodegenerative diseases. AB - Signaling pathways and cellular processes that regulate neural development are used post-developmentally for proper function and maintenance of the nervous system. Genes that have been studied in the context of the development of Drosophila peripheral nervous system (PNS) and neuromuscular junction (NMJ) have been identified as players in the pathogenesis of human neurodegenerative diseases, including spinocerebellar ataxia, amyotrophic lateral sclerosis, and spinal muscular atrophy. Hence, by unraveling the molecular mechanisms that underlie proneural induction, cell fate determination, axonal targeting, dendritic branching, and synapse formation in Drosophila, novel features related to these disorders have been revealed. In this review, we summarize and discuss how studies of Drosophila PNS and NMJ development have provided guidance in experimental approaches for these diseases. PMID- 24762651 TI - Proteomic analysis of cattle tick Rhipicephalus (Boophilus) microplus saliva: a comparison between partially and fully engorged females. AB - The cattle tick Rhipicephalus (Boophilus) microplus is one of the most harmful parasites affecting bovines. Similarly to other hematophagous ectoparasites, R. microplus saliva contains a collection of bioactive compounds that inhibit host defenses against tick feeding activity. Thus, the study of tick salivary components offers opportunities for the development of immunological based tick control methods and medicinal applications. So far, only a few proteins have been identified in cattle tick saliva. The aim of this work was to identify proteins present in R. microplus female tick saliva at different feeding stages. Proteomic analysis of R. microplus saliva allowed identifying peptides corresponding to 187 and 68 tick and bovine proteins, respectively. Our data confirm that (i) R. microplus saliva is complex, and (ii) that there are remarkable differences in saliva composition between partially engorged and fully engorged female ticks. R. microplus saliva is rich mainly in (i) hemelipoproteins and other transporter proteins, (ii) secreted cross-tick species conserved proteins, (iii) lipocalins, (iv) peptidase inhibitors, (v) antimicrobial peptides, (vii) glycine-rich proteins, (viii) housekeeping proteins and (ix) host proteins. This investigation represents the first proteomic study about R. microplus saliva, and reports the most comprehensive Ixodidae tick saliva proteome published to date. Our results improve the understanding of tick salivary modulators of host defense to tick feeding, and provide novel information on the tick-host relationship. PMID- 24762655 TI - Introduction to special section on working memory. PMID- 24762654 TI - Contributions of chondroitin sulfate proteoglycans to neurodevelopment, injury, and cancer. AB - Chondroitin sulfate proteoglycans (CSPGs) are a diverse family of extracellular matrix (ECM) molecules that make significant contributions to the patterning and routing of migrating neural cells and extending axons. Three distinct modes of migration mediation result from the relative abundance and positioning of expressed CSPGs, the profile of CSPG receptors expressed by the motile cell types, and the overall way in which the CSPGs integrate into and stabilize the neural ECM. Here we discuss recent findings that help to clarify the molecular mechanisms that underlie these distinct migration-regulating properties as they pertain to neural development, CNS injury, and gliomagenesis. PMID- 24762657 TI - Dynamic competition between spin-density wave order and superconductivity in underdoped Ba(1-x)K(x)Fe2As2. AB - An intriguing aspect of unconventional superconductivity is that it always appears in the vicinity of other competing phases, whose suppression brings the full emergence of superconductivity. In the iron pnictides, these competing phases are marked by a tetragonal-to-orthorhombic structural transition and a collinear spin-density wave (SDW) transition. There has been macroscopic evidence for competition between these phases and superconductivity as the magnitude of both the orthorhombicity and magnetic moment are suppressed in the superconducting state. Here, using angle-resolved photoemission spectroscopy on detwinned underdoped Ba(1-x)K(x)Fe2As2, we observe a coexistence of both the SDW gap and superconducting gap in the same electronic structure. Furthermore, our data reveal that following the onset of superconductivity, the SDW gap decreases in magnitude and shifts in a direction consistent with a reduction of the orbital anisotropy. This observation provides direct spectroscopic evidence for the dynamic competition between superconductivity and both SDW and electronic nematic orders in these materials. PMID- 24762656 TI - S-nitrosylation of FLICE inhibitory protein determines its interaction with RIP1 and activation of NF-kappaB. AB - Death receptor (DR) ligation can lead to divergent signaling pathways causing either caspase-mediated cell death or cell proliferation and inflammation. These variations in cellular fate are determined by adaptor proteins that are recruited to the DR signaling complex. FLICE inhibitory protein (FLIP) is an established inhibitor of caspase-8-mediated apoptosis, and it is also involved in NF-kappaB activation. However, the molecular mechanism that regulates FLIP within this complex is unknown. In this study, we provide new evidence for the regulation of NF-kappaB by FLIP through S-nitrosylation, which involves covalent modification of the protein's cysteine thiol by nitric oxide to form S-nitrosothiol. Point mutations of FLIP at cysteine residues 254 and 259 prevent FLIP S-nitrosylation and its ability to activate NF-kappaB. The mechanism by which FLIP nitrosylation regulates NF-kappaB activity involves RIP1 binding and redistribution, whereas TRAF2 binding and distribution are unaffected. We further show that FLIP processing and cleavage is dependent on its nitrosylation status. Collectively, our study reveals a novel pathway for FLIP regulation of NF-kappaB through protein S-nitrosylation, which is a key posttranslational mechanism controlling DR-mediated cell death and survival. Since increased expression of FLIP and nitric oxide are frequently observed in chemotherapy-resistant tumors, S nitrosylation of FLIP could be a key mechanism of chemoresistance and tumor growth. PMID- 24762658 TI - Correlation effects and phonon modes softening with doping in Ba1-xKxBiO3. AB - The monoclinic crystal structure of the undoped BaBiO3 can be described as a cubic perovskite which is distorted by the frozen breathing and tilting phonon modes of the BiO6 octahedra. The phonon mode softening is experimentally observed (Braden et al 1996 Europhys. Lett. 34 531) in Ba1-xKxBiO3 through potassium doping followed by a transition into an ideal cubic perovskite structure at x = 0.37, close to the emergence of superconductivity. In our previous paper (Korotin et al 2012 J. Phys.: Condens. Matter 24 415603) we demonstrated that it is necessary to take into account correlation effects using the DFT+U method in Wannier functions as a basis to obtain a good agreement between the calculated and experimental values of crystal structure distortion and the energy gap in BaBiO3. In the present work, using the same method, we calculated the breathing mode phonon frequencies as a function of the potassium doping level in Ba1 xKxBiO3. The obtained frequencies are in good agreement with experimental values and the breathing mode softening with doping is reproduced, contrary to calculations made without consideration of correlation effects. We show that the cubic crystal structure becomes stable at x = 0.30 in agreement with the experimental transition to cubic perovskite at x = 0.37. The possible connections between the correlation effects, phonon mode softening and superconductivity in Ba1-xKxBiO3 are discussed. PMID- 24762659 TI - Higher order vortex gyrotropic modes in circular ferromagnetic nanodots. AB - Magnetic vortex that consists of an in-plane curling magnetization configuration and a needle-like core region with out-of-plane magnetization is known to be the ground state of geometrically confined submicron soft magnetic elements. Here magnetodynamics of relatively thick (50-100 nm) circular Ni80Fe20 dots were probed by broadband ferromagnetic resonance in the absence of external magnetic field. Spin excitation modes related to the thickness dependent vortex core gyrotropic dynamics were detected experimentally in the gigahertz frequency range. Both analytical theory and micromagnetic simulations revealed that these exchange dominated modes are flexure oscillations of the vortex core string with n = 0,1,2 nodes along the dot thickness. The intensity of the mode with n = 1 depends significantly on both dot thickness and diameter and in some cases is higher than the one of the uniform mode with n = 0. This opens promising perspectives in the area of spin transfer torque oscillators. PMID- 24762660 TI - Transmission electron microscopy analysis for the process of crystallization of Cu2ZnSnS4 film from sputtered Zn/CuSn precursor. AB - The mechanism of crystallization of Cu2ZnSnS4 (CZTS) made by the sulfurization of a sputtered Zn/CuSn stack was studied by transmission electron microscopy. At 250 degrees C, the Zn buried at the bottom of the metallic stack was found to be driven to the upper layer by alloying with Cu and reacting with S to form ZnS. At 500 degrees C, CZTS was found to be formed and elemental Sn was observed in the vicinity of the back contact region, while large quantities of Cu2S and ZnS were segregated at the film surface. At 575 degrees C, Cu2SnS3 was found, while all the elemental Sn had vanished. Upon extending the duration of the annealing to 10 min, at 575 degrees C, all the secondary phases except ZnS were consumed and the CZTS formation was completed, while around 200 nm of MoS2 was formed between the CZTS layer and Mo back contact. The finished solar cell exhibits an efficiency of 2.66%, an open-circuit voltage of 666.9 mV and a short-circuit current density of 9.14 mA cm-2. The solar cell performance is possibly limited by the thick MoS2 layer and the large density of voids in the back contact region due to the Sn loss at high sulfurization temperatures. PMID- 24762661 TI - Renalase, a new secretory enzyme: Its role in hypertensive-ischemic cardiovascular diseases. AB - Abstract Renalase, a novel amine oxidase, is mainly expressed in the kidney, heart, and skeletal muscle. It has been known to degrade circulating catecholamines and plays a crucial role in human diseases. Recent studies have demonstrated its structure, unique bioactivities, function, and the gene polymorphisms in human diseases. In this review, we summarize the effects of renalase on hypertension, myocardial ischemia, acute kidney injury (AKI), ischemic stroke, cardiac dysfunction, organ transplantation, and diabetes mellitus reported in numerous studies. PMID- 24762662 TI - Ongoing hepatitis A outbreak in Europe 2013 to 2014: imported berry mix cake suspected to be the source of infection in Norway. AB - On 7 March 2014, an increase in hepatitis A virus (HAV) infections was identified in Norway. As of 12 April, 19 cases of HAV infection with a virus strain identical to an ongoing European outbreak have been identified. Six probable cases are currently under investigation. On 11 April, a frozen berry mix cake imported from another European country was found as the likely source of the outbreak; the importer has withdrawn the product in Norway. PMID- 24762663 TI - Infectious diseases prioritisation for event-based surveillance at the European Union level for the 2012 Olympic and Paralympic Games. AB - In 2012, London hosted the Olympic and Paralympic Games (the Games), with events occurring throughout the United Kingdom (UK) between 27 July and 9 September 2012. Public health surveillance was performed by the Health Protection Agency (HPA). Collaboration between the HPA and the European Centre for Disease Prevention and Control (ECDC) was established for the detection and assessment of significant infectious disease events (SIDEs) occurring outside the UK during the time of the Games. Additionally, ECDC undertook an internal prioritisation exercise to facilitate ECDC's decisions on which SIDEs should have preferentially enhanced monitoring through epidemic intelligence activities for detection and reporting in daily surveillance in the European Union (EU). A team of ECDC experts evaluated potential public health risks to the Games, selecting and prioritising SIDEs for event-based surveillance with regard to their potential for importation to the Games, occurrence during the Games or export to the EU/European Economic Area from the Games. The team opted for a multilevel approach including comprehensive disease selection, development and use of a qualitative matrix scoring system and a Delphi method for disease prioritisation. The experts selected 71 infectious diseases to enter the prioritisation exercise of which 27 were considered as priority for epidemic intelligence activities by ECDC for the EU for the Games. PMID- 24762664 TI - Comparison of diagnostic clinical samples and environmental sampling for enterovirus and parechovirus surveillance in Scotland, 2010 to 2012. AB - Human enteroviruses (EV) and parechoviruses (HPeV) within the family Picornaviridae are the most common causes of viral central nervous system (CNS) associated infections including meningitis and neonatal sepsis-like disease. The frequencies of EV and HPeV types identified in clinical specimens collected in Scotland over an eight-year period were compared to those identified in sewage surveillance established in Edinburgh. Of the 35 different EV types belonging to four EV species (A to D) and the four HPeV types detected in this study, HPeV3 was identified as the most prevalent picornavirus in cerebrospinal fluid samples, followed by species B EV. Interestingly, over half of EV and all HPeV CNS associated infections were observed in young infants (younger than three months). Detection of species A EV including coxsackievirus A6 and EV71 in clinical samples and sewage indicates that these viruses are already widely circulating in Scotland. Furthermore, species C EV were frequently identified EV in sewage screening but they were not present in any of 606 EV-positive clinical samples studied, indicating their likely lower pathogenicity. Picornavirus surveillance is important not only for monitoring the changing epidemiology of these infections but also for the rapid identification of spread of emerging EV and/or HPeV types. PMID- 24762665 TI - Measles on a cruise ship: links with the outbreak in the Philippines. PMID- 24762666 TI - Author's reply: measles on a cruise ship--links with the outbreak in the Philippines. PMID- 24762669 TI - Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer. AB - Our understanding of breast cancer heterogeneity at the protein level is limited despite proteins being the ultimate effectors of cellular functions. We investigated the heterogeneity of breast cancer (41 primary tumors and 15 breast cancer cell lines) at the protein and phosphoprotein levels to identify activated oncogenic pathways and developing targeted therapeutic strategies. Heterogeneity was observed not only across histological subtypes, but also within subtypes. Tumors of the Triple negative breast cancer (TNBC) subtype distributed across four different clusters where one cluster (cluster ii) showed high deregulation of many proteins and phosphoproteins. The majority of TNBC cell lines, particularly mesenchymal lines, resembled the cluster ii TNBC tumors. Indeed, TNBC cell lines were more sensitive than non-TNBC cell lines when treated with targeted inhibitors selected based on upregulated pathways in cluster ii. In line with the enrichment of the upregulated pathways with onco-clients of Hsp90, we found synergy in combining Hsp90 inhibitors with several kinase inhibitors, particularly Erk5 inhibitors. The combination of Erk5 and Hsp90 inhibitors was effective in vitro and in vivo against TNBC leading to upregulation of pro apoptotic effectors. Our studies contribute to proteomic profiling and improve our understanding of TNBC heterogeneity to provide therapeutic opportunities for this disease. PMID- 24762668 TI - Genotypic and functional impact of HIV-1 adaptation to its host population during the North American epidemic. AB - HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979-1989) and 382 modern (2000-2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences. The reconstructed epidemic ancestral (founder) HIV sequence was essentially identical to the North American subtype B consensus. Consistent with gradual diversification of a "consensus-like" founder virus, the median "background" frequencies of individual HLA-associated polymorphisms in HIV (in individuals lacking the restricting HLA[s]) were ~ 2-fold higher in modern versus historic HIV sequences, though these remained notably low overall (e.g. in Gag, medians were 3.7% in the 2000s versus 2.0% in the 1980s). HIV polymorphisms exhibiting the greatest relative spread were those restricted by protective HLAs. Despite these increases, when HIV sequences were analyzed as a whole, their total average burden of polymorphisms that were "pre-adapted" to the average host HLA profile was only ~ 2% greater in modern versus historic eras. Furthermore, HLA-associated polymorphisms identified in historic HIV sequences were consistent with those detectable today, with none identified that could explain the few HIV codons where the inferred epidemic ancestor differed from the modern consensus. Results are therefore consistent with slow HIV adaptation to HLA, but at a rate unlikely to yield imminent negative implications for cellular immunity, at least in North America. Intriguingly, temporal changes in protein activity of patient-derived Nef (though not Gag) sequences were observed, suggesting functional implications of population-level HIV evolution on certain viral proteins. PMID- 24762670 TI - Non-Hodgkin lymphoma and occupational exposure to agricultural pesticide chemical groups and active ingredients: a systematic review and meta-analysis. AB - This paper describes results from a systematic review and a series of meta analyses of nearly three decades worth of epidemiologic research on the relationship between non-Hodgkin lymphoma (NHL) and occupational exposure to agricultural pesticide active ingredients and chemical groups. Estimates of associations of NHL with 21 pesticide chemical groups and 80 active ingredients were extracted from 44 papers, all of which reported results from analyses of studies conducted in high-income countries. Random effects meta-analyses showed that phenoxy herbicides, carbamate insecticides, organophosphorus insecticides and the active ingredient lindane, an organochlorine insecticide, were positively associated with NHL. In a handful of papers, associations between pesticides and NHL subtypes were reported; B cell lymphoma was positively associated with phenoxy herbicides and the organophosphorus herbicide glyphosate. Diffuse large B cell lymphoma was positively associated with phenoxy herbicide exposure. Despite compelling evidence that NHL is associated with certain chemicals, this review indicates the need for investigations of a larger variety of pesticides in more geographic areas, especially in low- and middle-income countries, which, despite producing a large portion of the world's agriculture, were missing in the literature that were reviewed. PMID- 24762671 TI - A cross-site intervention in Chinese rural migrants enhances HIV/AIDS knowledge, attitude and behavior. AB - BACKGROUND: With the influx of rural migrants into urban areas, the spread of HIV has increased significantly in Shaanxi Province (China). Migrant workers are at high risk of HIV infection due to social conditions and hardships (isolation, separation, marginalization, barriers to services, etc.). OBJECTIVE: We explored the efficacy of a HIV/AIDS prevention and control program for rural migrants in Shaanxi Province, administered at both rural and urban sites. METHODS: Guidance concerning HIV/AIDS prevention was given to the experimental group (266 migrants) for 1 year by the center of disease control, community health agencies and family planning department. The intervention was conducted according to the HIV/AIDS Prevention Management Manual for Rural Migrants. A control group of migrants only received general population intervention. The impact of the intervention was evaluated by administering HIV/AIDS knowledge, attitudes and sexual behavior (KAB) questionnaires after 6 and 12 months. RESULTS: In the experimental group; 6 months of intervention achieved improvements in HIV/AIDS related knowledge. After 12 months; HIV/AIDS-related knowledge reached near maximal scores. Attitude and most behaviors scores were significantly improved. Moreover; the experimental group showed significant differences in HIV-AIDS knowledge; attitude and most behavior compared with the control group. CONCLUSIONS: The systematic long-term cross-site HIV/AIDS prevention in both rural and urban areas is a highly effective method to improve HIV/AIDS KAB among rural migrants. PMID- 24762672 TI - Associations of lipoprotein lipase gene rs326 with changes of lipid profiles after a high-carbohydrate and low-fat diet in healthy Chinese Han youth. AB - To investigate the effects of a high-carbohydrate and low-fat (HC/LF) diet on plasma lipids and apolipoproteins (Apos) of healthy Chinese Han youth with different genotypes of lipoprotein lipase gene (LPL) rs326, 56 subjects were given a washout diet of 30.1% fat and 54.1% carbohydrate for seven days, followed by the HC/LF diet of 13.8% fat and 70.1% carbohydrate for six days, with no total energy restriction. Plasma glucose, triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), Apo B-100 and Apo A-I were analyzed at baseline and before and after the HC/LF diet. The results show that, when compared with before the HC/LF diet, only the male G carriers experienced increased HDL-C (p = 0.008) and Apo A-I (p = 0.005) after the HC/LF diet. Decreased TC in both males and females and increased TG in females were found regardless of the genotype after the HC/LF diet. LDL-C decreased in all the subjects although the decrease was not significant in the female G carriers. These results demonstrate that the G allele of LPL rs326 associates with the elevated levels of HDL-C and Apo A-I after the HC/LF diet in males of the healthy Chinese Han Youth. PMID- 24762673 TI - Meanings and experiential outcomes of bodily care in a specialist palliative context. AB - OBJECTIVE: The objective of this study was to enhance the depth of existing knowledge about meanings and experiential outcomes of bodily care in the context of an inpatient specialist palliative setting. METHOD: Interpretative phenomenology was chosen as the study sought to explore individuals' lived experiences related to bodily care. Nine participants (five women, four men) of various ages and with various metastasized cancers and bodily-care needs, all from one specialist palliative care ward, participated. Data were collected with repeated narrative interviews and supplementary participating observations. Analysis was informed by van Manen's approach. RESULTS: The following meanings and experiential outcomes of bodily care were revealed by our study: maintaining and losing body capability, breaching borders of bodily integrity, being comforted and relieved in bodily-care situations, and being left in distress with unmet needs. These meanings overlap and shape the nature of each other and involve comforting and distressing experiences related to what can be described as conditional dimensions: the particular situation, one's own experiences of the body, and healthcare professionals' approaches. SIGNIFICANCE OF RESULTS: The results, based on specialist palliative care patients' experiences, outline the meanings and outcomes that relate to the quintessence and complexity of palliative care, deriving from dying persons' blend of both basic and symptom oriented bodily-care needs. Moreover, the results outline how these two dimensions of care equally influence whether comfort and well-being are facilitated or not. Considering this, specialist palliative care may consider how to best integrate and acknowledge the value of skilled basic nursing care as part of and complementary to expertise in symptom relief during the trajectories of illness and dying. PMID- 24762674 TI - Genome-wide analysis of histone modifications in latently HIV-1 infected T cells. AB - OBJECTIVES: The transcriptional silencing of HIV type 1 (HIV-1) provirus in latently infected cells is a major hurdle on the pathway to HIV-1 elimination. The epigenetic mechanisms established by histone modifications may affect the transcriptional silencing of HIV-1 and viral latency. A systematic epigenome profiling could be applicable to develop new epigenetic diagnostic markers for detecting HIV-1 latency. DESIGN: The HIV-1 latency cell lines (NCHA1, NCHA2 and ACH2] were compared with CD4+ T-cell line (A3.01). METHODS: The histone modification profiles obtained from chromatin immunoprecipiation followed by sequencing (ChIP-Seq) for histone H3K4me3 and H3K9ac were systematically examined and differential gene expression patterns along with levels of histone modifications were used for network analysis. RESULTS: The HIV-1 latency gave rise to downregulation of histone H3K4me3 and H3K9ac levels in 387 and 493 regions and upregulation in 451 and 962 sites, respectively. By network analysis, five gene clusters were associated with downregulated histone modifications and six gene clusters came up with upregulated histone modifications. Integration of gene expression with epigenetic information revealed that the cell cycle regulatory genes such as CDKN1A (p21) and cyclin D2 (CCND2) identified by differentially modified histones might play an important role in maintaining the HIV-1 latency. CONCLUSION: The transcriptional regulation by epigenetic memory should play a key role in the evolution and maintenance of HIV-1 latency accompanied by modulation of signalling molecules in the host cells. PMID- 24762675 TI - Contribution of network connectivity in determining the relationship between gene expression and metabolite concentration changes. AB - One of the primary mechanisms through which a cell exerts control over its metabolic state is by modulating expression levels of its enzyme-coding genes. However, the changes at the level of enzyme expression allow only indirect control over metabolite levels, for two main reasons. First, at the level of individual reactions, metabolite levels are non-linearly dependent on enzyme abundances as per the reaction kinetics mechanisms. Secondly, specific metabolite pools are tightly interlinked with the rest of the metabolic network through their production and consumption reactions. While the role of reaction kinetics in metabolite concentration control is well studied at the level of individual reactions, the contribution of network connectivity has remained relatively unclear. Here we report a modeling framework that integrates both reaction kinetics and network connectivity constraints for describing the interplay between metabolite concentrations and mRNA levels. We used this framework to investigate correlations between the gene expression and the metabolite concentration changes in Saccharomyces cerevisiae during its metabolic cycle, as well as in response to three fundamentally different biological perturbations, namely gene knockout, nutrient shock and nutrient change. While the kinetic constraints applied at the level of individual reactions were found to be poor descriptors of the mRNA-metabolite relationship, their use in the context of the network enabled us to correlate changes in the expression of enzyme-coding genes to the alterations in metabolite levels. Our results highlight the key contribution of metabolic network connectivity in mediating cellular control over metabolite levels, and have implications towards bridging the gap between genotype and metabolic phenotype. PMID- 24762677 TI - High-energy spin and charge excitations in electron-doped copper oxide superconductors. AB - The evolution of electronic (spin and charge) excitations upon carrier doping is an extremely important issue in superconducting layered cuprates and the knowledge of its asymmetry between electron- and hole-dopings is still fragmentary. Here we combine X-ray and neutron inelastic scattering measurements to track the doping dependence of both spin and charge excitations in electron doped materials. Copper L3 resonant inelastic X-ray scattering spectra show that magnetic excitations shift to higher energy upon doping. Their dispersion becomes steeper near the magnetic zone centre and they deeply mix with charge excitations, indicating that electrons acquire a highly itinerant character in the doped metallic state. Moreover, above the magnetic excitations, an additional dispersing feature is observed near the Gamma-point, and we ascribe it to particle-hole charge excitations. These properties are in stark contrast with the more localized spin excitations (paramagnons) recently observed in hole-doped compounds even at high doping levels. PMID- 24762676 TI - Model-based investigations of different vector-related intervention strategies to eliminate visceral leishmaniasis on the Indian subcontinent. AB - The elimination of infectious diseases requires reducing transmission below a certain threshold. The Visceral Leishmaniasis (VL) Elimination Initiative in Southeast Asia aims to reduce the annual VL incidence rate below 1 case per 10,000 inhabitants in endemic areas by 2015 via a combination of case management and vector control. Using a previously developed VL transmission model, we investigated transmission thresholds dependent on measures reducing the sand fly density either by killing sand flies (e.g., indoor residual spraying and long lasting insecticidal nets) or by destroying breeding sites (e.g., environmental management). Model simulations suggest that elimination of VL is possible if the sand fly density can be reduced by 67% through killing sand flies, or if the number of breeding sites can be reduced by more than 79% through measures of environmental management. These results were compared to data from two recent cluster randomised controlled trials conducted in India, Nepal and Bangladesh showing a 72% reduction in sand fly density after indoor residual spraying, a 44% and 25% reduction through the use of long-lasting insecticidal nets and a 42% reduction after environmental management. Based on model predictions, we identified the parameters within the transmission cycle of VL that predominantly determine the prospects of intervention success. We suggest further research to refine model-based predictions into the elimination of VL. PMID- 24762678 TI - Atherosclerotic plaque component segmentation in combined carotid MRI and CTA data incorporating class label uncertainty. AB - Atherosclerotic plaque composition can indicate plaque vulnerability. We segment atherosclerotic plaque components from the carotid artery on a combination of in vivo MRI and CT-angiography (CTA) data using supervised voxelwise classification. In contrast to previous studies the ground truth for training is directly obtained from 3D registration with histology for fibrous and lipid-rich necrotic tissue, and with MUCT for calcification. This registration does, however, not provide accurate voxelwise correspondence. We therefore evaluate three approaches that incorporate uncertainty in the ground truth used for training: I) soft labels are created by Gaussian blurring of the original binary histology segmentations to reduce weights at the boundaries between components, and are weighted by the estimated registration accuracy of the histology and in vivo imaging data (measured by overlap), II) samples are weighted by the local contour distance of the lumen and outer wall between histology and in vivo data, and III) 10% of each class is rejected by Gaussian outlier rejection. Classification was evaluated on the relative volumes (% of tissue type in the vessel wall) for calcified, fibrous and lipid-rich necrotic tissue, using linear discriminant (LDC) and support vector machine (SVM) classification. In addition, the combination of MRI and CTA data was compared to using only one imaging modality. Best results were obtained by LDC and outlier rejection: the volume error per vessel was 0.9+/-1.0% for calcification, 12.7+/-7.6% for fibrous and 12.1+/-8.1% for necrotic tissue, with Spearman rank correlation coefficients of 0.91 (calcification), 0.80 (fibrous) and 0.81 (necrotic). While segmentation using only MRI features yielded low accuracy for calcification, and segmentation using only CTA features yielded low accuracy for necrotic tissue, the combination of features from MRI and CTA gave good results for all studied components. PMID- 24762680 TI - [Mutation detection could guide the eradication treatment of antibiotic-resistant patients with Helicobacter pylori]. PMID- 24762679 TI - Proper actin ring formation and septum constriction requires coordinated regulation of SIN and MOR pathways through the germinal centre kinase MST-1. AB - Nuclear DBF2p-related (NDR) kinases constitute a functionally conserved protein family of eukaryotic regulators that control cell division and polarity. In fungi, they function as effector kinases of the morphogenesis (MOR) and septation initiation (SIN) networks and are activated by pathway-specific germinal centre (GC) kinases. We characterized a third GC kinase, MST-1, that connects both kinase cascades. Genetic and biochemical interactions with SIN components and life cell imaging identify MST-1 as SIN-associated kinase that functions in parallel with the GC kinase SID-1 to activate the SIN-effector kinase DBF-2. SID 1 and MST-1 are both regulated by the upstream SIN kinase CDC-7, yet in an opposite manner. Aberrant cortical actomyosin rings are formed in Deltamst-1, which resulted in mis-positioned septa and irregular spirals, indicating that MST 1-dependent regulation of the SIN is required for proper formation and constriction of the septal actomyosin ring. However, MST-1 also interacts with several components of the MOR network and modulates MOR activity at multiple levels. MST-1 functions as promiscuous enzyme and also activates the MOR effector kinase COT-1 through hydrophobic motif phosphorylation. In addition, MST-1 physically interacts with the MOR kinase POD-6, and dimerization of both proteins inactivates the GC kinase hetero-complex. These data specify an antagonistic relationship between the SIN and MOR during septum formation in the filamentous ascomycete model Neurospora crassa that is, at least in part, coordinated through the GC kinase MST-1. The similarity of the SIN and MOR pathways to the animal Hippo and Ndr pathways, respectively, suggests that intensive cross-communication between distinct NDR kinase modules may also be relevant for the homologous NDR kinases of higher eukaryotes. PMID- 24762681 TI - [Antibiotic resistance of Helicobacter pylori in children and macrolide-resistant genotypes in Helicobacter pylori]. AB - OBJECTIVE: To explore the antibiotic resistance of Helicobacter pylori (H.pylori ) in children and identify 23 S rRNA gene mutations in macrolide-resistant strains. METHODS: From December 2008 to December 2010, a total of 73 H.pylori strains were isolated from 120 gastric mucosa specimens obtained from children of gastrointestinal symptoms with a diagnosis of gastritis or peptic ulcer underwent gastroscopy. The antibiotic resistance to 9 antibiotics of 73 H.pylori strains isolated from gastric biopsies was detected by E-test method. Mutations in 23 S rRNA gene of macrolide-resistant of isolated H.pylori strains were examined by polymerase chain reaction (PCR). RESULTS: Seventy-three H.pylori strains (60.8%) were isolated from gastric biopsies.Seventy were drug resistance strains and only 3 sensitive strains.No resistance to amoxicillin, gentamicin and tetracycline was observed. The resistance rate to azithromycin, clarithromycin, metronidazole, rifampicin, levofloxacin and moxifloxacin was 79.5% (58/73), 80.8% (59/73), 58.9% (43/73), 6.8% (5/73), 12.3% (9/73) and 13.7% (10/73) respectively. The dual, triple and quadruple antibacterial resistant percentage was 47.9% (35/73), 8.2% (6/73) and 1.4% (1/73) respectively. And the multi-drug resistance rate to clarithromycin, azithromycin and metronidazole was 43.8% (32/73). The gene mutation rate of A2142C,A2142G, and A2143G in 23 S rRNA gene was 1.6% (1/64), 6.3% (4/64) and 85.9% (55/64) respectively. CONCLUSIONS: There is a high rate of multi-drug resistance to clarithromycin, azithromycin and metronidazole in H.pylori strains isolated from children at our hospital. Therefore amoxicillin and rifampicin sensitive to H.pylori strains should be considered for H.pylori eradication. A2143G is the most populated mutation in macrolide-resistant strains. PMID- 24762682 TI - [Efficacy and safety of 14-day amoxicillin and furazolidone-based quadruple rescue regimen for eradication of Helicobacter pylori: a retrospective study]. AB - OBJECTIVE: To evaluate the efficacy, compliance and adverse effects of 14-day amoxicillin and furazolidone-based quadruple regimen as rescue treatment for Helicobacter pylori (H.pylori) infection. METHODS: A total of 228 patients positive for H.pylori with previous failed treatment at least once were enrolled into this retrospective study. There were 71 males and 157 females, aged (50 +/- 13) years. A 14-day quadruple regimen was administered along with furazolidone, amoxicillin and bismuth citrate in combination with proton pump inhibitors. Adverse effects were recorded at the end of treatment.H.pylori status was assessed by (13)C-urea breath test at 4 weeks after treatment. RESULTS: Among them, 206 patients completed treatment. The H.pylori eradication rates were 91.96% (206/224) and 90.35% (206/228) according to per-protocol (PP) and intention-to-treat (ITT) analyses respectively. Mild and moderate adverse effects such as dizziness, nausea and diarrhea occurred in 43 patients (18.86%). Four of them had to terminate their treatment due to rash, dizziness and headache respectively. CONCLUSIONS: The 14-day quadruple therapy with furazolidone, amoxicillin, bismuth citrate and proton pump inhibitors may be an effective regimen for rescue treatment because of its relatively high eradication rate (>90%). The patients should be watched closely during the treatment since the adverse effects of this regimen happen frequently. Treatment is stopped in events of skin rash, fever or other serious adverse effects.Vitamins B1 and B6 can relieve some discomforts. PMID- 24762683 TI - [Efficacy of triple versus quadruple furazolidone-based eradication regimens for Helicobacter pylori infection]. AB - OBJECTIVE: To explore the eradication efficacies of triple versus quadruple furazolidone-based regimens for Helicobacter pylori (H. pylori) infection. METHODS: A total of 357 outpatients with H. pylori infection were enrolled from June to December 2010. There were 200 males and 157 females with an average age of (42 +/- 12) years. A diagnosis of duodenal ulcer was made according to their endoscopic examination results. They were randomly assigned into 4 treatment groups: 7-day triple (n = 89) and 10-day triple (n = 91), rabeprazole 10 mg, amoxicillin 1 000 mg and furazolidone 100 mg twice daily for 7 and 10 days respectively. 7-day quadruple (n = 88) and 10-day quadruple (n = 89), rabeprazole 10 mg, bismuth 220 mg, amoxicillin 1 000 mg and furazolidone 100 mg twice daily for 7 and 10 days respectively.H. pylori status was re-assessed with (14)C-urea breath test after 4-week therapy. RESULTS: Among them, 323 cases completed the study. According to the analysis of intention-to-treat (ITT), the H. pylori eradication rates were 71.91% (64/89) in 7-day triple, 81.32% (74/91) in 10-day triple, 78.41% (69/88) in 7-day quadruple and 83.15% (74/89) in 10-day quadruple groups. No significant deviation existed among all groups (P > 0.05). According the per-protocol (PP) analysis, H. pylori eradication rates were 78.05% (64/82) in 7-day triple, 88.10% (74/84) in 10-day triple, 87.34% (69/79) in 7-day quadruple and 94.87% (74/78) in 10-day quadruple groups. Significant deviation existed among all groups (P = 0.017). The H. pylori eradication rate in 10-day quadruple group was significantly higher than that in 7-day triple group (P = 0.002). The total adverse reaction rate was 7.00% (25/357). No significant difference existed among all groups (P > 0.05). CONCLUSIONS: Quadruple treatments provide higher H. pylori eradication rates than triple therapies. A 10-day treatment may improve H. pylori eradication rate. And 10-day quadruple regimen with furazolidone and bismuth may be effective for H. pylori infection. PMID- 24762684 TI - [Non-bismuth quadruple therapy versus standard triple therapy for Helicobacter pylori eradication: a randomized controlled study]. AB - OBJECTIVE: To compare the efficacies of non-bismuth quadruple therapy for 7 days versus standard triple therapy for 7 or 10 days in initial treatment of Helicobacter pylori (H.pylori) . METHODS: A randomized, open-labeled, controlled trial comparing non-bismuth quadruple therapy with standard triple therapy was performed at Peking University First Hospital from August 2010 to July 2012. A total of 246 patients with a diagnosis of H.pylori infection by (13)C-urea breath test and receiving no eradication therapy were randomly divided into non-bismuth quadruple therapy and standard triple therapy for 7 or 10 days. There were 110 males and 136 females with an age range of 18-75 years. Among them, 81 patients received non-bismuth quadruple therapy (esomeprazole 20 mg, amoxicillin 1 000 mg, clarithromycin 500 mg and tinidazole 500 mg given twice daily for 7 days); 82 standard triple therapy (esomeprazole 20 mg, amoxicillin 1 000 mg and clarithromycin 500 mg given twice daily) for 7 days and 83 standard triple therapy for 10 days. The efficacies were examined at Week 4 post-therapy by (13)C urea breath test. The incidence of adverse drug reactions was recorded. RESULTS: Among them, 242 patients completed the follow-up. The eradication rates for non bismuth quadruple therapy and standard triple therapy for 7 or 10 days were 91.4% (74/81), 79.3% (65/82) and 79.5% (66/83) as determined by intention-to-treat analysis (ITT). The eradication rates were 92.5% (74/80), 81.3% (65/80) and 80.5% (66/82) respectively as determined by per-protocol analysis (PP).Non-bismuth quadruple therapy was superior to standard triple therapy for 7 days (ITT analysis P = 0.029, PP analysis P = 0.035) and 10 days (ITT analysis P = 0.032, PP analysis P = 0.026). The differences for the eradication rates between standard triple therapy for 7 days and for 10 days were insignificant (ITT analysis P = 0.968, PP analysis P = 0.902): Adverse reaction rates for non bismuth quadruple therapy (8.8%, 7/80) and standard triple therapy for 7 days (7.5%, 6/80) and 10 days (9.8%, 8/82) were not significantly different (P = 0.872). CONCLUSION: Non-bismuth quadruple therapy for 7 days is both effective and safe for the first-line eradication of H.pylori. PMID- 24762685 TI - [Efficacies and toxicities of different platinum-based combination chemotherapies for patients with advanced non-small cell lung cancer]. AB - OBJECTIVE: To explore the efficacies and toxicities of different platinum-based combination chemotherapeutic regiments for patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 239 advanced NSCLC from January 2011 to December 2012 were reviewed in Xinqiao Hospital. The chemotherapeutic efficacies and adverse effects in the first-line treatment of advanced NSCLC by paclitaxel plus platinum (paclitaxel group, n = 113), gemcitabine plus platinum (gemcitabine group, n = 72) and docetaxel plus platinum (docetaxel group, n = 54) regiments were retrospectively analyzed and compared. Their efficacies and toxicities were analyzed by Chi-square test. And survival was estimated with Kaplan-Meier method. RESULTS: The objective response rate (ORR) of three groups were 42.5%, 43.1% and 35.2% respectively (P = 0.612). The disease control rate (DCR) were 84.1%, 75.0% and 74.1% respectively (P = 0.198). The median progression-free survival was 5.6, 5.8 and 3.2 months respectively (P = 0.000). The major adverse effects were myelosuppression, gastrointestinal reaction, alopecia and neurotoxicity, etc. The incidence rate of neurotoxicity among three groups were 34.5% (39/113), 11.1% (8/72) and 18.5% (10/54) respectively (P = 0.001).No significant inter-group difference of adverse effects existed (all P > 0.05), except for neurotoxicity. CONCLUSIONS: Three platinum-based combination chemotherapeutic regiments produce excellent efficacies with acceptable adverse effects. Their ORR and DCR were similar. And the median progression-free survival of paclitaxel and gemcitabine groups is significantly longer than that of docetaxel group. PMID- 24762686 TI - [Efficacies of neoadjuvant chemotherapy plus nutritional support in advanced gastric cancer complicated with pylori obstruction]. AB - OBJECTIVE: To explore the efficacies of neoadjuvant chemotherapy plus nutritional supports for gastric cancer complicated with pyloric obstruction. METHODS: Retrospective analyses were performed for a total of 116 patients of gastric cancer complicated with pyloric obstruction undergoing exploratory laparotomy from January 2004 to June 2013. RESULTS: Sixty-two patients (group A) received neoadjuvant chemotherapy (regimen of FOLFOX) plus preoperative nutritional support. And parenteral (PN, n = 30) and enteral (EN, n = 32) nutritional supports were provided. Another 54 patients (group B) underwent exploratory laparotomy alone. The serum level of albumin and score of quality of life in group A at the last preoperative day improved significantly. And EN was better than PN. The rate of excision/radical excision of group A (85.5%, 45.2%) was much higher than group B (64.8%, 18.5%) (both P < 0.05). CONCLUSION: Nutritional support, especially EN, can improve the nutritional status and quality of life in patients with gastric cancer complicated with pyloric obstruction. And nutritional support plus neoadjuvant chemotherapy increase the rate of tumor excision. PMID- 24762687 TI - [Etiologies of 1 173 hospitalized cases with adrenal incidentaloma]. AB - OBJECTIVE: To summarize the characteristics of etiological distribution of adrenal incidentaloma during the past 20 years. METHODS: All the relevant data of adrenal incidentaloma patients admitted into Chinese PLA General Hospital between January 1993 and January 2013 were collected. Their gender ratio, visiting ages and final diagnoses were retrospectively analyzed. RESULTS: There were 1 173 patients were collected, of which, 629 (53.62%) males and 544 (46.38%) females with a mean age of (50.84 +/- 12.13) years. There were 669 (57.03%) hypertensive cases and 622 cases undergone adrenalectomy. Routine medical checkup and abdominal discomfort led to the discovery of adrenal incidentalomas. As to the etiologies, there were non-functional tumors (n = 809, 68.97%), pheochromocytoma (n = 137, 11.68%), primary aldosteronism (n = 84, 7.16%) and adrenal Cushing syndrome (n = 65, 5.54%). The proportions of adrenal cortical carcinomas and metastases were 1.70% (n = 20) and 1.36% (n = 16) respectively. Compared with normotension group, the proportion of non-functional lesions in hypertension group was significant lower (73.81% vs 65.32%, P < 0.05) while the proportions of primary aldosteronism and adrenal Cushing syndrome were higher (11.96% vs 0.79%, 5.83% vs 5.18%, both P < 0.05). CONCLUSION: Adrenal incidentaloma patients with concurrent hypertension is quite common. In respect of etiologies, non-functional tumor is the most common and followed by pheochromocytoma and primary aldosteronism Cushing syndrome. PMID- 24762688 TI - [Relationship between metabolic diseases and all-cause and cardiovascular disease death in elderly male diabetics during a 10-year follow-up]. AB - OBJECTIVE: To explore the relationship between metabolic diseases and death from all causes and cardiovascular diseases (CVD) in elderly male diabetics. METHODS: A total of 681 elderly male diabetics were recruited from June 1997 to June 1999 and followed up for 10 years. All underwent regular check-ups in PLA General Hospital each year. The Cox proportional hazards model was applied to the multivariate survival analysis for all-cause and CVD mortality. And the cumulative survival rates were calculated by Kaplan-Meier method and log-rank test was used to compare the survival rates. RESULTS: During a 10-year follow-up, 208 subjects died, including 70 deaths from CVD. Multivariate Cox regression analysis showed that age [relative risk (RR) = 1.099, 95% confidence interval (CI)1.076-1.123], pulse pressure (RR = 1.009, 95%CI 1.001-1.017) , elevated postprandial glucose level (RR = 1.115, 95%CI 1.075-1.157) and lower triglyceride (RR = 0.683, 95%CI 0.539-0.865) and high-density lipoprotein cholesterol (RR = 0.444, 95%CI 0.257-0.766) increased the risks of all-cause mortality while age (RR = 1.112, 95%CI 1.070-1.155) , elevated postprandial glucose level (RR = 1.278, 95%CI 1.170-1.396) and systolic blood pressure (RR = 1.013, 95%CI 1.002 1.024) increased the risks of CVD mortality. The cumulative survival rates from CVD mortality in diabetics with metabolic syndrome were significantly lower compared with those with diabetes only (P < 0.01) . CONCLUSION: CVD remains a main cause of death for Chinese elderly male diabetics. Advanced age and elevated postprandial glucose level are risk factors of all-cause and CVD mortality. Diabetes mellitus with concurrent hypertension or metabolic syndrome is associated with an increased risk of CVD death. PMID- 24762689 TI - [Protein expressions of HDAC1 and DNMT1 in non-small-cell lung cancer and its clinical significance]. AB - OBJECTIVE: To detect the serum protein expressions of histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) in patients with non-small-cell lung cancer and explore the correlation between their expressions and clinicopathological features. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to measure the protein expressions of HDAC1 and DNMT1 in 136 lung cancer patients hospitalized at Department of Respiratory Diseases, First Affiliated Hospital,Zhengzhou University from September 2012 to June 2013 (cancer group). And 147 healthy physical examination subjects from Sixth People's Hospital of Zhengzhou were selected as controls and their clinicopathological features analyzed. RESULTS: The protein expressions of HDAC1 and DNMT1 in patients with lung cancer (145 +/- 53, 50 +/- 11) were higher than those in control group (78 +/- 56, 27 +/- 6). And there was statistical significance (t = 596.16, 152.64, both P = 0.000) . The protein expressions of HDAC1 and DNMT1 were correlated with gender, smoking history and age (among P < 0.05). There was a positive association between the protein expressions of HDAC1 and DNMT1 in non-small-cell lung cancer (r = 0.525, P = 0.000). Statistical significance existed between the protein expressions of HDAC1 and DNMT1 and histological types or different stages (all P < 0.01). CONCLUSION: The higher protein expressions of HDAC1 and DNMT1 may play an important role in the early process of lung cancer. PMID- 24762690 TI - [Blastic plasmacytoid dendritic cell neoplasm: a clinicopathologic study of 7 cases]. AB - OBJECTIVE: To improve the clinicopathological understanding of blastic plasmacytoid dendritic cell neoplasm (BPDCN). METHODS: A total of 7 BPDCN patients were recruited from 2009 to 2013. And their clinicopathological and immunohistological features, treatment and prognosis were retrospectively analyzed. RESULTS: There were 6 males and 1 female. The median age range was 60 (6-72) years at the time of diagnosis. The skin lesion at the time of diagnosis presented as generalized (n = 6) or solitary (n = 1) plaques or nodules. Histologic examination showed a diffuse or nodular infiltrate composed of intermediate-sized cells in dermis sparing epidermis area. The tumor cells contained round to ovoid nucleus, finely dispersed chromatin and 1 or 2 small sized nucleoli. Most neoplastic cells were positive for CD4, CD56 and CD123 while negative for CD3, CD20, CD30, CD34, CD79a, MPO and EBER. Two patients received chemotherapy.One had no response while another relapsed rapidly. Two patients had a spontaneous regression of skin lesions and one died 2 years later. And no systematic infiltration was detected at diagnosis. CONCLUSIONS: BPDCN is a rare hematopoietic malignancy with specific immunophenotypes.It primarily affects elderly males and frequently presents initially as cutaneous involvement.It may be easily misdiagnosed and has a rapid course and a poor prognosis. PMID- 24762691 TI - [Clinical and experimental studies of adult hereditary spherocytosis]. AB - OBJECTIVE: To explore the clinical characteristic of adult hereditary spherocytosis (HS) and the efficacies of splenectomy. METHODS: Six cases with adult HS were collected from July 2006 to July 2012. And their clinical features, laboratory profile and treatment were retrospectively analyzed. RESULTS: There were 2 males and 4 females with a diagnostic age of 21-67 years. Their chief complaints were symptoms of upper gastrointestinal tract. The characteristic tetralogy was anemia, hemolysis, splenomegaly and gallstone.Familial inheritance pattern was found in 2 patients. The laboratory examination results demonstrated anemia, reticulocyte and elevated indirect bilirubin in 6 patients. Three patients had positive urobilinogen. The osmotic fragility (OF) test were 2 positive and 4 negative ones. And 2 negatives turned positive after incubation. The acidified glycerol lysis test (AGLT50) was positive in all. Ultrasonography showed splenomegaly and gallstone. There were 3 abnormal types red cells in peripheral blood, densely-dyed red cells (35%-89%) , microspherocytes (14%-20%) and irregular-shaped red cells.Scanning electron microscope showed single or many acanthocytes or spikes in red cell surface.Red cell body was irregular dish or flower-shaped. Biconcave disc shape disappearance. Three patients had short bands 3, 4.1 or 4.2. The age of onset was late and clinical symptoms was lighter.Spectrin-ankyrin was deficient for another 2 patients. The age of onset was early and clinical sign serious.Splenectomy and cholecystectomy were performed in 3 patients. Their postoperative hemoglobin was normal during follow ups. Clinical relief was achieved. CONCLUSIONS: Combined experiments can enhance the diagnostic rate of adult HS so as to avoid misdiagnosis. And the efficacies of splenectomy are definite. PMID- 24762692 TI - [Serotypic distribution of Chlamydia trachomatis infection of genital tract in males]. AB - OBJECTIVE: To explore the serotypic distribution and ompA gene variations of Chlamydia trachomatis (C.trachomatis) of male reproductive tract at our hospital. METHODS: A total of 399 samples of reproductive tract secretion were collected from urinary outpatient with suspected C.trachomatis infection of genital tract from December 2011 to March 2013 and screened by C.trachomatis detection kit. Amplificated by nested PCR and sequenced of C.trachomatis ompA gene after screening positive samples.Sequencing products were typed by BLAST of PubMed and MegAlign program of DNAstar software to compare the clinical isolates of C.trachomatis ompA gene with the standard sequence. And various serotypes of C.trachomatis ompA gene mutation were analyzed. RESULTS: C.trachomatis was detected with a positive rate of 14.8% (59/399). All ompA genes of 59 C.trachomatis positive specimens were successfully amplified and serotyped. The types were E (n = 17, 28.8%), F (n = 16, 27.1%), D (n = 13, 22.0%),G (n = 5, 8.5%), H (n = 3, 5.1%), K (n = 3, 5.1%) and J (n = 2, 3.4%). The most mutations of ompA gene of C.trachomatis in clinical specimens were serotype D (n = 9) , followed by serotype G(n = 5). CONCLUSIONS: The distribution of serotypes in male patients is serotypes E, F, D-type dominant. The serotype D of C.trachomatis is variation up. PMID- 24762693 TI - [Impact of insertion timing of iodophor cotton ball on the control of infection complications after transrectal ultrasound guided prostate biopsy]. AB - OBJECTIVE: To explore the impact of insertion timing of iodophor cotton ball on the control of infection complications after transrectal ultrasound (TRUS) guided prostate biopsy. METHODS: A total of 197 patients undergoing TRUS-guided prostate biopsy from March 2012 to January 2013 were randomly divided into post-discharge, pre-discharge and pre-discharge plus post-discharge groups. A prospective study was made on the symptoms of infections, signs and relevant laboratory examinations in all three groups. RESULTS: Infections occurred in 6/66 patients in the post-discharge group and 2 patients in the other two groups. The prevalence rates were 7.58%, 3.08% and 3.03% respectively. Statistically significant difference existed in the prevalence rate between pre-discharge and post-discharge groups (P < 0.05). Yet no statistically significant difference existed between pre-discharge and pre-discharge plus post-discharge groups (P > 0.05). CONCLUSION: During the TRUS guided prostate biopsy, inserting an iodophor cotton ball before placing an ultrasonic probe to the rectum can control the infection and reduce its prevalence rate. PMID- 24762694 TI - [Effects of autophagy on 5-fluorouracil cytotoxicity for gallbladder carcinoma GBC-SD cell]. AB - OBJECTIVE: To explore the effects of autophagy on 5-fluorouracil (5-FU) cytotoxicity for gallbladder carcinoma GBC-SD cell and discuss a novel and promising strategy of autophagy inhibitor for increasing the clinical efficacy of 5-FU in the treatment of gallbladder carcinoma. METHODS: After a pre-treatment of autophagy inhibitors, such as chloroquine (CQ) and 3-methyladenine (3-MA), or silencing the autophagy-related genes (autophagy-related gene 5, autophagy related gene 7), the inhibition of 5-FU to proliferation and the viability of GBC SD cell were measured. And the apoptotic rate and cell cycle of GBC-SD cell were analyzed. RESULTS: Blocking of autophagy by pharmacological (CQ, 3-MA) or genetic (siRNA) means induced cell death in GBC-SD cell pre-treated with 5 FU.Furthermore, 5-FU treatment resulted in a general increase of apoptotic rate and G0/G1 arrest of GBC cells. And such an effect was potentiated by a pre treatment of CQ. CONCLUSION: Autophagy in GBC-SD cell is induced by DNA damaging agent 5-fluorouracil.While in combination with CQ pre-treatment, the cytotoxicity of 5-fluorouracil becomes potentiated. PMID- 24762695 TI - [Therapeutic effects of Bacille Calmette-Guerin vaccine on asthma airway remodeling in rats and its mechanism]. AB - OBJECTIVE: To explore the therapeutic effects and mechanism of Bacillus Calmette Guerin (BCG) vaccine on airway remodeling in rats. METHODS: Forty male Wistar rats were randomly divided into 5 groups of control, asthma,BCG vaccine, dexamethasone and BCG vaccine plus dexamethasone (n = 8 each). The animals were then sensitized and challenged by ovalbum in to establish the asthmatic model. A subcutaneous injection of BCG vaccine 0.025 mg was administered for the BCG vaccine group and an intraperitoneal injection of dexamethasone 0.5 mg/kg for the dexamethasone group.In BCG vaccine plus dexamethasone group, the rats received a subcutaneous injection of BCG vaccine (0.025 mg) plus an intraperitoneal injection of dexamethasone (0.25 mg/kg). All treatments were offered at half an hour pre-atomization. The control rats received an aerosol inhalation of normal saline instead of ovalbum. The parameters of airway morphological changes and the degree of airway remodeling were analyzed with computer graphics. The levels of transforming growth factor beta 1 (TGF-beta1) in bronchoalveolar lavage fluid (BALF) and the expressions of E-cadherin, alpha-smooth muscle actin (alpha-SMA) and fibronectin in lung tissue and sera were detected. RESULTS: In asthmatic rats, the thickness of airway wall and smooth muscle were more significant than those of the control group ((95.01 +/- 0.48), (43.86 +/- 0.51) vs (25.96 +/- 0.42), (15.14 +/- 0.18) um). Compared with the control group, the levels of TGF beta1 in BALF and sera were significantly higher ((10.05 +/- 0.26), (75.67 +/- 1.17) vs (1.53 +/- 0.18), (22.24 +/- 0.35) ug/L), the expression of E-cadherin significantly decreased (0.26 +/- 0.03 vs 0.45 +/- 0.04), while alpha-SMA and fibronectin significantly increased (0.54 +/- 0.06,0.56 +/- 0.06 vs 0.32 +/- 0.04, 0.35 +/- 0.06) (all P < 0.01); Notably, compared with the asthmatic group, the thickness of airway wall and smooth muscle ((58.46 +/- 2.43),(49.51 +/- 1.44), (49.63 +/- 1.42) and (25.84 +/- 0.54), (25.44 +/- 0.40), (25.62 +/- 1.17) um) significantly decreased by the treatments of BCG vaccine, dexamethasone or BCG vaccine plus dexamethasone, the levels of TGF-beta1 in BALF and sera ((3.42 +/- 0.18), (3.27 +/- 0.34), (3.39 +/- 0.26) and (37.61 +/- 0.22), (35.65 +/- 0.49), (36.22 +/- 0.71) ug/L) significantly decreased, the expressions of E cadherin (0.29 +/- 0.04, 0.32 +/- 0.04, 0.31 +/- 0.03) significantly increased and alpha-SMA and fibronectin (0.40 +/- 0.06, 0.35 +/- 0.06, 0.40 +/- 0.05 and 0.47 +/- 0.03, 0.43 +/- 0.06, 0.47 +/- 0.04) significantly declined (all P < 0.01). Western blot showed the similar results. CONCLUSIONS: BCG vaccine alleviates airway epithelial cell injury and epithelial mesenchymal transition induced by TGF-beta1 through immunoregulation. It also reduces asthmatic airway remodeling with a combination of dexamethasone. PMID- 24762696 TI - Enhanced bioremediation of hydrocarbon-contaminated soil using pilot-scale bioelectrochemical systems. AB - Two column-type bioelectrochemical system (BES) modules were installed into a 50 L pilot scale reactor packed with diesel-contaminated soils to investigate the enhancement of passive biodegradation of petroleum compounds. By using low cost electrodes such as biochar and graphite granule as non-exhaustible solid-state electron acceptors, the results show that 82.1-89.7% of the total petroleum hydrocarbon (TPH) was degraded after 120 days across 1-34 cm radius of influence (ROI) from the modules. This represents a maximum of 241% increase of biodegradation compared to a baseline control reactor. The current production in the BESs correlated with the TPH removal, reaching the maximum output of 70.4 +/- 0.2 mA/m(2). The maximum ROI of the BES, deducting influence from the baseline natural attenuation, was estimated to be more than 90 cm beyond the edge of the reactor (34 cm), and exceed 300 cm should a non-degradation baseline be used. The ratio of the projected ROI to the radius of BES (ROB) module was 11-12. The results suggest that this BES can serve as an innovative and sustainable technology for enhanced in situ bioremediation of petroleum hydrocarbons in large field scale, with additional benefits of electricity production and being integrated into existing field infrastructures. PMID- 24762697 TI - Riboflavin-mediated RDX transformation in the presence of Shewanella putrefaciens CN32 and lepidocrocite. AB - The potential of riboflavin for the reductive degradation of a cyclic nitramine, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), was investigated in the presence of lepidocrocite and/or Shewanella putrefaciens CN32. RDX reduction by CN32 alone or CN32 with lepidocrocite was insignificant, while 110 MUM RDX was completely reduced by CN32 with riboflavin in 78 h. The transformation products identified included nitroso metabolites, formaldehyde, and ammonium, indicating the ring cleavage of RDX. UV and visible light analysis revealed that riboflavin was microbially reduced by CN32, and that the reduced riboflavin was linked to the complete degradation of RDX. In the presence of both CN32 and lepidocrocite (gamma-FeOOH), 100 MUM-riboflavin increased the rate and extent of Fe(II) production as well as RDX reduction. An abiotic study also showed that Fe(II) riboflavin complex, and Fe(II) adsorbed on lepidocrocite, reduced RDX by 48% and 21%, respectively. The findings in this study suggest that riboflavin-mediated RDX degradation pathways in subsurface environments are diverse and complex. However, riboflavin, either from bacteria or exogenous sources, can significantly increase RDX degradation. This will provide a sustainable clean-up option for explosive-contaminated subsurface environments. PMID- 24762698 TI - Aqueous hydrodechlorination of 4-chlorophenol over an Rh/reduced graphene oxide synthesized by a facile one-pot solvothermal process under mild conditions. AB - Reduced graphene oxide (RGO) supported rhodium nanoparticles (Rh-NPs/RGO) was synthesized through one-pot polyol co-reduction of graphene oxide (GO) and rhodium chloride. The catalytic property of Rh-NPs/RGO was investigated for the aqueous phase hydrodechlorination (HDC) of 4-chlorophenol (4-CP). A complete conversion of 4-CP into high valued products of cyclohexanone (selectivity: 23.2%) and cyclohexanol (selectivity: 76.8%) was successfully achieved at 303K and balloon hydrogen pressure in a short reaction time of 50 min when 1.5 g/L of 4-CP was introduced. By comparing with Rh-NPs deposited on the other supports, Rh NPs/RGO delivered the highest initial rate (111.4 mmol/gRh min) for 4-CP HDC reaction under the identical conditions. The substantial catalytic activity of Rh NPs/RGO can be ascribed to the small and uniform particle size of Rh (average particle size was 1.7 +/- 0.14 nm) on the surface of the RGO sheets and an electron-deficient state of Rh in the catalyst as a result of the strong interaction between the active sites and the surface function groups of RGO. PMID- 24762699 TI - The treatment of radioactive wastewater by ultrasonic standing wave method. AB - The radiation hazards of radionuclide arising from the storage of nuclear weapons cannot be ignored to the operators. Ultrasonic standing wave methods can be considered as the green cleaning separation techniques with high efficiency. The application of ultrasonic standing wave methods for liquid radioactive wastes treatment requires solving many problems connected with the proper selection of the frequency and power of ultrasonic transducers, and the processing time, etc. Based on the model of one single suspended radioactive particle subjected to in the field of ultrasonic standing wave, the principle of the treatment of low level radioactive wastewater by ultrasound was analyzed. The theoretical and simulation results show that under the action of ultrasonic standing wave, the particle will move toward the wave node plane, and the time of particle reaching the plane become shorter when the radius of particle and the frequency and power of ultrasound was enlarged. The experimental results show that the radioactive concentration of wastewater could be reduced from 400 Bq L(-1) to 9.3 Bq L(-1) and the decontamination efficiency was 97.68%. The decontamination efficiency could not be obviously improved by further increasing the treating time. PMID- 24762700 TI - Characteristics of cesium ion sorption from aqueous solution on bentonite- and carbon nanotube-based composites. AB - The technology development of Cs(+) capture from aqueous solution is crucial for the disposal of nuclear waste and still remains a significant challenge. Previous researches have been proven that ion exchanges with the cations and hydroxyl exchange are the main sorption mechanisms for Cs(+). Therefore, how important are the cation exchange and the hydroxyl exchange mechanisms to Cs(+) sorption? And whether can we improve the sorption capacity of the material by increasing the amount of hydroxyl groups? With these in mind, we herein designed the chitosan grafted carbon nanotubes (CS-g-CNTs) and the chitosan-grafted bentonite (CS-g bentonite) by plasma-induced grafting method. The interactions of Cs(+) with CNTs, bentonite, CS-g-CNTs and CS-g-bentonite composites were investigated. The sorption of Cs(+) is mainly dominated by strong cation exchange in monovalent Group I and divalent Group II. And the cation-exchange mechanism is much more effective than the hydroxyl group exchange. The effect of hydroxyl groups is dependent on the property of the matrix. We cannot improve the Cs adsorption capacity of material for Cs(+) only by increasing the amount of hydroxyl groups in any case. The spatial structure and the cation-exchange capacity of the material are important factors for choosing the sorbent for Cs(+) removal from radioactive waste water. PMID- 24762701 TI - Performance of a haloalkaliphilic bioreactor and bacterial community shifts under different COD/SO42- ratios and hydraulic retention times. AB - Sulfur dioxide from flue gas was converted into sulfate after the absorption of alkaline solutions. Haloalkaliphilic microorganisms have been used in reducing sulfate to decrease expenses and avoid sulfide inhibition. The effects of different COD/SO4(2-) ratios and hydraulic retention times (HRTs) on the sulfate removal efficiency and bacterial community were investigated in model experiments. Ethanol showed better performance as an electron donor than lactate. The optimum COD/SO4(2-) ratio and HRT were 4.0 and 18 h, respectively, with respective sulfate removal efficiency and rate of 97.8 +/- 1.11% and 6.26 +/- 0.0710 g/Ld. Sulfide concentrations reached 1,603 +/- 3.38 mg/L. Based on denaturing gradient gel electrophoresis analysis of 16S rDNA, the major sulfate reducing bacterium (SRB) was Desulfonatronovibrio sp., which was only detected at a COD/SO4(2-) ratio of 4.0 using ethanol as an electron donor. Different HRTs had no significant effect on the band corresponding to this species. PCR results show that methane-producing archaea (MPA) were from the acetoclastic methanogenic family Methanosarcinaceae. Quantitative real-time PCR did not demonstrate any significant competition between SRB and MPA. The findings of this study indicate that sulfate reduction, nitrate reduction, and sulfide oxidization may occur in the same bioreactor. PMID- 24762702 TI - VIM proteins regulate transcription exclusively through the MET1 cytosine methylation pathway. AB - In Arabidopsis, variant in methylation (VIM) proteins are required for the maintenance of DNA methylation in the CpG dinucleotide context. VIM1 acts as a cofactor of DNA methyltransferase 1 (MET1), although the mechanism for this co regulation remains unclear. In this study, we used RNA-seq analysis to profile the transcriptomes of vim1, vim1 vim2 vim3, and met1 null mutants. Consistent with previous studies indicating functional redundancy between these VIM proteins, we found no transcripts that were significantly misregulated in vim1 mutants. However, we identified a large set of VIM protein regulatory targets through analysis of vim1 vim2 vim3 mutants, and we observed that this set is essentially identical to that regulated by MET1. Log 2 fold changes in gene expression relative to wild type are strongly correlated between vim1 vim2 vim3 and met1 mutants. While the largest subset of these transcripts is upregulated and enriched with transposable elements, we also found small subsets of downregulated genes in each mutant, which are enriched with protein-coding genes. Together, these results expand on previous studies that profiled cytosine methylation in the vim1 vim2 vim3 mutant, and show that VIM proteins function in transcriptional regulation via their roles in the MET1 DNA methylation pathway. PMID- 24762703 TI - High-resolution angioscopic imaging during endovascular neurosurgery. AB - BACKGROUND: Endoluminal optical imaging, or angioscopy, has not seen widespread application during neurointerventional procedures, largely as a result of the poor imaging resolution of existing angioscopes. Scanning fiber endoscopes (SFEs) are a novel endoscopic platform that allows high-resolution video imaging in an ultraminiature form factor that is compatible with currently used distal access endoluminal catheters. OBJECTIVE: To test the feasibility and potential utility of high-resolution angioscopy with an SFE during common endovascular neurosurgical procedures. METHODS: A 3.7-French SFE was used in a porcine model system to image endothelial disruption, ischemic stroke and mechanical thrombectomy, aneurysm coiling, and flow-diverting stent placement. RESULTS: High resolution, video-rate imaging was shown to be possible during all of the common procedures tested and provided information that was complementary to standard fluoroscopic imaging. SFE angioscopy was able to assess novel factors such as aneurysm base coverage fraction and side branch patency, which have previously not been possible to determine with conventional angiography. CONCLUSION: Endovascular imaging with an SFE provides important information on factors that cannot be assessed fluoroscopically and is a novel platform on which future neurointerventional techniques may be based because it allows for periprocedural inspection of the integrity of the vascular system and the deployed devices. In addition, it may be of diagnostic use for inspecting the vascular wall and postprocedure device evaluation. PMID- 24762704 TI - The far lateral transpontomedullary sulcus approach to pontine cavernous malformations: technical report and surgical results. AB - BACKGROUND: Pontine cavernous malformations (CMs) located on a peripheral pontine surface or the fourth ventricular floor are resectable lesions, but those deep within the pons away from a pial surface are typically observed. However, the anterior bulge of the pons formed by the brachium pontis creates a unique entry point for access to deep pontine lesions from below, working upward through the pontomedullary sulcus. OBJECTIVE: We developed a transpontomedullary sulcus (TPMS) approach to these lesions. METHODS: The TPMS approach used the far lateral craniotomy and upper vagoaccessory triangle to define the surgical corridor. The entry point was above the olive, lateral to the pyramidal tracts and cranial nerve (CN) VI, above the preolivary sulcus and CN XII, and medial to CNs VII and VIII and CNs IX through XI. RESULTS: Four patients underwent this approach. All presented with hemorrhage and CN VI palsies. All pontine CMs were resected completely. Three patients were improved or unchanged, with good outcomes (modified Rankin Scale score <=2) in all patients. CONCLUSION: The central pons remains difficult territory to access, and new surgical corridors are needed. The bulging underbelly of the pons allows access to pontine lesions deep to the pial surface from below. The far lateral TPMS approach is a novel and more direct alternative to the retrosigmoid transmiddle cerebellar peduncle approach. Unlike the retrosigmoid approach, the TPMS approach requires minimal parenchymal transgression and uses a brainstem entry point medial to most lower CNs. Favorable results demonstrate the feasibility of resecting pontine CMs that might have been previously deemed unresectable. PMID- 24762705 TI - Management of pediatric delirium in critical illness: a practical update. AB - Pediatric delirium (PD) is an acute state of brain dysfunction and is often seen in the pediatric intensive care unit (PICU). There is a growing awareness of its clinical interdisciplinary importance. The aim of this article was to describe the three clinical presentations, to evaluate the differential diagnosis and to give a concise and practical update for the pharmacological and non pharmacological treatment of PD at the PICU, based on recent literature and expert opinions. We discuss an interdisciplinary flow chart which helps the reader dealing with the diagnosis and management of any acute emotional and or behavioral disturbance, of which PD is a special case. PMID- 24762706 TI - Extended versus bolus infusion of meropenem and piperacillin: a pharmacokinetic analysis. AB - BACKGROUND: Extended infusion of beta-lactam antibiotics has been advocated as a method for optimizing antibiotic exposure in critically ill patients. The objective of this study was to compare the pharmacokinetics/pharmacodynamics of extended infusion versus bolus infusion of piperacillin and meropenem in critically ill patients with normal renal function. METHODS: A prospective study of 3 hours extended infusion of meropenem and piperacillin in critically ill patients without renal dysfunction. Results from the extended infusion cohort were compared to previously published bolus infusion data in critically ill patients. RESULTS: Twenty extended infusion patients (15 piperacillin, 5 meropenem) were compared with 13 bolus infusion patients (8 piperacillin, 5 meropenem). The demographic and clinical characteristics between both groups were not statistically different. Significant pharmacokinetic differences were observed in median (interquartile range) Cmax for both meropenem (extended infusion 17 [12.6-21.9] vs. bolus 85.2 [66.7-140.3]; P=0.01) and piperacillin (extended infusion 76.2 [57.7-92.6] vs. bolus 240.2 [168.5-275.4]; P=0.001). Considerable pharmacokinetic variability existed in each group for both drugs. Compared to bolus infusion, fT>MIC using extended infusion was higher for both drugs: 96% (IQR 71-100%) compared to 77% (IQR 41-93%) for piperacillin (P=0.05) and 82% (IQR 63-89%) compared to 51% (IQR 48-63%) for meropenem (P=0.095); assuming a MIC of 16 mg/L and 2 mg/L respectively. CONCLUSION: This study confirms that extended infusion in critically ill patients result in advantageous pharmacokinetic profiles by increasing the fT>MIC for piperacillin and meropenem. In a significant subpopulation of critically ill patients with normal renal function, a 100% fT>MIC target is not reached, even with 3-hour extended infusions. PMID- 24762707 TI - Care and the luxury of trauma: A South African story. PMID- 24762708 TI - Obstructive sleep apnea and fatigue in head and neck cancer patients. AB - There is a systematic relationship between fatigue, sleep, and decreased quality of life in cancer patients, with notably poor sleep quality among many head and neck cancer patients during and after treatment. An often overlooked cause of sleep disturbance in this patient population is obstructive sleep apnea (OSA). This review explores the current literature on the prevalence and clinical correlates of OSA, management outcomes, and data on cytokine-mediated fatigue in OSA. OSA appears to be prevalent in head and neck cancer patients, both at baseline and after treatment, especially with multimodality therapy including radiation therapy. Predictors of developing OSA include larger tumor size and hypopharynx or larynx primary site. There is evidence that the level of fatigue seen in these patients is not necessarily correlated with the severity of their OSA. Current research highlights the role of proinflammatory cytokines, which can also be synergistically activated by radiation therapy, as mediators of fatigue. Primary management of OSA consists of continuous positive airway pressure. Although continuous positive airway pressure has been shown to improve clinical symptoms, compliance with its use remains a problem and will be an area of future research. PMID- 24762709 TI - 'How many calories are in my burrito?' Improving consumers' understanding of energy (calorie) range information. AB - OBJECTIVE: Energy (calorie) ranges currently appear on menu boards for customized menu items and will likely appear throughout the USA when menu-labelling legislation is implemented. Consumer welfare advocates have questioned whether energy ranges enable accurate energy estimates. In four studies, we examined: (i) whether energy range information improves energy estimation accuracy; (ii) whether misestimates persist because consumers misinterpret the meaning of the energy range end points; and (iii) whether energy estimates can be made more accurate by providing explicit information about the contents of items at the end points. DESIGN: Four studies were conducted, all randomized experiments. SETTING: Study 1 took place outside a Chipotle restaurant. Studies 2 to 4 took place online. SUBJECTS: Participants in study 1 were customers exiting a Chipotle restaurant (n 306). Participants in studies 2 (n 205), 3 (n 290) and 4 (n 874) were from an online panel. RESULTS: Energy ranges reduced energy misestimation across different menu items (studies 1-4). One cause of remaining misestimation was misinterpretation of the low end point's meaning (study 2). Providing explicit information about the contents of menu items associated with energy range end points further reduced energy misestimation (study 3) across different menu items (study 4). CONCLUSIONS: Energy range information improved energy estimation accuracy and defining the meaning of the end points further improved accuracy. We suggest that when restaurants present energy range information to consumers, they should explicitly define the meaning of the end points. PMID- 24762710 TI - ACTH as a treatment for acute crystal-induced arthritis: update on clinical evidence and mechanisms of action. AB - BACKGROUND: ACTH, a member of the melanocortin group of proteins, has long been used in the treatment of gout and is considered as an alternative therapeutic option, especially in difficult-to-treat patients. METHODS: We performed a systematic electronic search (Medline and ScienceDirect) using the keywords gout, treatment, ACTH, adrenocorticotropic hormone, and pseudogout. We identified 5 studies assessing the efficacy of ACTH in acute crystal-induced arthritis. RESULTS: In the studies for acute gout, a total of 266 patients have been treated with ACTH; treatment was highly efficacious with a response rate of 77.9-100%. Only few side effects, such as hyperglycemia, hypokalemia, and edema, were reported, all of which were mild. The available evidence for acute CPP crystal arthritis is limited. A total of 19 patients have been assessed in retrospective studies; the response rate was 90-100%, whereas no significant side effects were recorded. The mechanism of action of ACTH in acute crystal-induced arthritis is not entirely known but seems to extend beyond stimulation of steroid release from the adrenal glands; ACTH is able to stimulate melanocortin receptors on macrophages and downregulate gouty inflammation. CONCLUSIONS: Data suggests that ACTH is effective in acute crystal-induced arthritis and may be a first-line therapy in patients with multiple medical problems. We propose that further evaluation of ACTH should be performed, with a large-scale, randomized controlled study focusing on safety issues in patients with multiple comorbidities. PMID- 24762711 TI - "The Red Dress or the Blue?": How Do Staff Perceive That They Support Decision Making for People With Dementia Living in Residential Aged Care Facilities? AB - Respect for a person's right to make choices and participate in decision making is generally seen as central to quality of life and well-being. When a person moves into a residential aged care facility (RACF), however, decision making becomes more complicated, particularly if the person has a diagnosis of dementia. Little is known about how staff in RACFs perceive that they support decision making for people with dementia within their everyday practice, and this article seeks to address this knowledge gap. The article reports on the findings of a qualitative study conducted in the states of Victoria and Queensland, Australia with 80 direct care staff members. Findings revealed that the participants utilized a number of strategies in their intention to support decision making for people with dementia, and had an overall perception that "a little effort goes a long way." PMID- 24762712 TI - Facile synthesis of Pt/Pd nanodendrites for the direct oxidation of methanol. AB - The demand for clean and energy-efficient fuel cell systems requires electrocatalysts with greater activity and stability. Here, we report a facile wet-chemical approach for the synthesis of high-quality three-dimensional (3D) Pt/Pd bimetallic nanodendrites. The simple and unique process developed here used oleylamine as a reducing agent, and hydrogen gas to control the morphology. The as-prepared Pt/Pd nanodendrites were characterized by transmission electron microscopy, x-ray diffraction and energy dispersive x-ray spectroscopy, cyclic voltammetry, linear sweep voltammetry and chronoamperometry. The nanodendrites showed superior electrocatalytic activity (609.565 mA mg(-1) Pt) for the oxidation of methanol compared with Pt nanoparticle electrocatalysts. This method could provide a general approach for the morphology-controlled synthesis of bimetallic Pt-based nanocatalysts, which are promising materials for applications in fuel cells. PMID- 24762713 TI - Nitrogen concentration driving the hardness of rhenium nitrides. AB - The structures and properties of rhenium nitrides are studied with density function based first principle method. New candidate ground states or high pressure phases at Re:N ratios of 3:2, 1:3, and 1:4 are identified via a series of evolutionary structure searches. We find that the 3D polyhedral stacking with strong covalent N-N and Re-N bonding could stabilize Re nitrides to form nitrogen rich phases, meanwhile, remarkably improve the mechanical performance than that of sub-nitrides, as Re3N, Re2N, and Re3N2. By evaluating the trends of the crystal configuration, electronic structure, elastic properties, and hardness as a function of the N concentration, we proves that the N content is the key factor affecting the metallicity and hardness of Re nitrides. PMID- 24762719 TI - Investigating the development of spurious magnetism in single crystalline BaTi0.95Fe0.05O3-delta with high delta by local structural probes. AB - BaTi0.95Fe0.05O3-delta has been suggested to be an intrinsic dilute magnetic oxide with a clear dependence of magnetism on oxygen vacancy concentration. However, it has also been shown that the dopant Fe ions distribute themselves rather inhomogeneously within the lattice, though without disrupting the crystal phase of the parent BaTiO3. With the help of x-ray absorption spectroscopy (XAS), here we find that the incorporation of a larger amount of anion vacancy pushes this inhomogeneity to the extreme, leading to the precipitation of Fe metal clusters. It is also observed that the residual solid, without the Fe-metal cluster, undergoes massive structural and compositional reorganization. PMID- 24762718 TI - More than a rhythm of life: breathing as a binder of orofacial sensation. AB - When rodents engage in the exploration of novel stimuli, breathing occurs at an accelerated rate that is synchronous with whisking. We review the recently observed relationships between breathing and the sensations of smell and vibrissa based touch. We consider the hypothesis that the breathing rhythm serves not only as a motor drive signal, but also as a common clock that binds these two senses into a common percept. This possibility may be extended to include taste through the coordination of licking with breathing. Here we evaluate the status of experimental evidence that pertains to this hypothesis. PMID- 24762720 TI - [Living medicine: the patient, tie and cock]. PMID- 24762721 TI - Chronic kidney disease and the aging population. PMID- 24762722 TI - Paroxysmal nocturnal hemoglobinuria in Mexico: a 30-year, single institution experience. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) stems from chronic, complement-mediated, intravascular hemolysis, which results in anemia, hemoglobinuria, fatigue, and other hemolysis-related disabling symptoms. Novel diagnostic methods have led into an increased identification of the disease. AIMS: To analyze the salient features of patients with PNH identified in a single institution in Mexico, in a 30-year period. MATERIAL AND METHODS: The records of 31 patients with PNH identified between 1984 and 2013 were reviewed; 20 females. Median age was 39 years, range 5 to 88. Patients were followed for periods of 0.5 to 221 months, median 46 months. RESULTS: Most patients (97%) presented peripheral blood cytopenias, 11 (35%) presented a thrombotic episode, whereas 4 (13%) showed hemolytic anemia. No thrombotic episode was fatal. In the cytopenic group, 4 patients with hemolysis were included and in the patients with the hemolytic variant the red blood cell destruction process was continuous while not paroxysmal. Anemia was recorded in 30 individuals; median hemoglobin levels were 8.5 g/dL, range 3.7 to 12.8. Leukopenia was present in 18 individuals; median white blood cell count was 3.3 x 109/L, range 1.6 to 10.8, whereas thrombocytopenia was present in 18 subjects; median platelet count was 67 x 109/L, range 6 to 546. Pancytopenia was present in 15 patients. Hemoglobinuria was recorded in 12 patients and low free haptoglobin levels coupled with increased lactic dehydrogenase levels, consonant with hemolysis in 4 patients. CONCLUSIONS: In Mexico the cytopenic variants are considerably more common than either the hemolytic or the thrombotic variants of the disease, this being particularly relevant since only the hemolytic variants of PNH are the ones which show a good response to the complement-blocking therapy employed nowadays in the treatment of the disease. PMID- 24762723 TI - [Waist-to-height ratio as a predictor of blood pressure in Mexican children. Follow-up study]. AB - OBJECTIVE: To assess the effect of increased waist-to-height ratio (WHtR) on the development of high blood pressure or hypertension in Mexican children. MATERIAL AND METHODS: 313 preschoolers followed for one year. We measured height and waist circumference (WC) and calculated the WHtR (cm WC/cm height). Blood pressure was obtained with a mercury sphygmomanometer. Children were classified with high blood pressure according to the fourth report of diagnosis, evaluation and treatment of high blood pressure in children and adolescents. We assessed longitudinally the impact of body mass indicators (body mass index, WC and total fat) and WHtR on the development of high pressure in separate models. Longitudinal analysis was performed with random effects using Husman test for assessing the adequacy of the model. RESULTS: WHtR 1.75 unit increased the risk of hypertension. CONCLUSION: The WHtR is a better predictor of hypertension compared to BMI and WC in preschool children followed over time. PMID- 24762724 TI - [Drowning risk factors into cistern for children 1 to 4 years old]. AB - OBJECTIVE: Analyze risk factors for drowning deaths in tanks, from home, for children between one and four years, residents of the metropolitan area of Guadalajara and the neighboring municipalities in the period 2009-2011. MATERIAL AND METHODS: Case-control study, 28 children (cases) between one and four years old, whose cause of death was drowning in the well of your home, from 2009-2011, in the metropolitan zone of Guadalajara and the neighboring municipalities, and 113 children (controls) of the same age, if neighbors whose homes had cistern. Deaths were classified with W73 and W74 codes from International Statistical Classification of Diseases and Related Health Problems (ICD 10th). A questionnaire for variables: age and sex of child; age, marital status, occupation and education of the household head and mother; housing conditions; and location, type and segurity cistern lid, and forms the removal of water therefrom. RESULTS: The rate of drowning deaths, age-specific, was 2.7 deaths per 100,000 children between one and four years of age during the study period. The ages of two and three years had the greatest risk of drowning. Sex had a predominance of children, two girls one over. The heads of families and mothers of cases were younger (< 29 years), with maximum secondary schooling. Most of the houses had not finished complete. The characteristics of de well, as metal lid,foil or plastic, the lack of assurance of the tank and the location of the cover, crossing sites, showed association with death by drowning. The absence of a pump to draw water in cases the proved statistically more significant with p = 0.002. CONCLUSION: The results of our study show the presence of drowning deaths in children between one and four years associated with the type of cistern cover, the locking mechanism, a way of extracting the water and the location of the well, and thus the need to implement preventive measures in education and engineering, to reduce or avoid the risk of death by suffocation in the study group. PMID- 24762725 TI - Metabolic and nutritional profile differences among Mexican, Mexican-American and Non-Hispanic White children. AB - OBJECTIVE: To compare somatometric variables, lipid profile, diet, and physical activity between Mexican children living in Mexico (MEX), and Mexican-American (MXA) and Non-Hispanic White (NHW) children from the United States (US) to examine the possible influence of ethnicity and residency on these factors. MATERIAL AND METHODS: Six to twelve years old children data from a study from central Mexico and the US National Health and Nutrition Examination Survey was compared. Data were categorized to examine the effect of residency (MEX vs. MXA and NHW) and ethnicity (MEX vs. MXA and NHW) on the variables of interest. RESULTS: Living in the US was associated with higher cholesterol levels in younger boys and older girls (p < 0.05), and high saturated fat intake in all groups (p < 0.0001). Living in Mexico increased the likelihood of abnormal HDL (p < 0.001), systolic (p < 0.001), and diastolic blood pressure (p < 0.0001). Caucasian young girls were more likely to have high cholesterol intake (p < 0.02) than their Mexican counterparts. CONCLUSIONS: These findings suggest that residency is linked to impaired lipid profile and blood pressure in children, whereas ethnicity seems to have an impact on dietary choices. PMID- 24762726 TI - [Prevalence and factors associated with intimate partner abuse in female users of public health services in Mexico: a comparative analyses]. AB - OBJECTIVE: To analyze the evolution of the prevalence in intimate partner violence during the years 2003 and 2006 in Mexico, identifying factors associated with its severity, comparing our results with findings from 2003. MATERIAL AND METHODS: Data from the Encuesta Nacional de Violencia contra las Mujeres (ENVIM 2006) was used; it has urban-rural national representation of female users of Mexican public health services. A total of 22,318 women above 14 years of age were interviewed. A multinomial logistic regression model was adjusted. The dependent variable was the Index of Intimate Partner Abuse. RESULTS: Intimate partner abuse increased 17% in comparison to the year 2003. Women's personal history of childhood abuse (ORA= 5.12, 95% CI4.15-6.30) and rape (ORA = 3.5, 95% CI = 2.66-4.62) were the most important women's factors that were found associated with severe violence. Male partner's daily alcohol consumption increased eleven fold the possibility of severe violence; higher disagreement with traditional female gender roles and higher education of both partners were protective factors. Factors associated with violence and their severities were consistent with findings reported in 2003. CONCLUISIONS: Intimate partner violence is a highly prevalent social problem which requires comprehensive strategies supporting empowerment of women through higher education, early detection and care of those battered, as well as structured interventions to prevent violence in future generations. PMID- 24762727 TI - Legality and age influence end of life decisions in Mexican physicians. AB - PURPOSE: To test in two groups of physicians-in-training a simplified questionnaire exploring their acceptance of Physician Assisted Death (PAD), Therapy Withdrawal upon family request (WD), and Personalized PAD (PPAD) on whether the participant would seek PAD for him/herself. MATERIAL AND METHODS: A 4 item questionnaire was answered by 212 residents in different stages of training and grouped as beginners (1st and 3d year internal medicine residents, n = 76) and advanced (5th to 8th year residents of different internal medicine or oncology subspecialties, n = 136). The response options to the PAD and WD questions included a conditioned yes (CYes) dealing with legalization of PAD or the existence of a patient's previous written agreement to WD. RESULTS: Beginners had significantly more Yes plus C-Yes answers than advanced for questions regarding PAD (82 vs. 55%), WD (95 vs. 75%) and PPAD (76 vs. 56%). The importance of legal aspects implied in the conditioned answers can be seen in two findings: a) A sizable 29% of participants conditioned their Yes answers for both questions whereas only 9% gave an unconditioned Yes to both. b) A cross-classification of the PAD and WD answers showed that 13% of participants reversed their No in PAD to C-Yes in WD. CONCLUSIONS: Our simplified questionnaire operated well and was able to confirm the increase in acceptance of PAD and WD by young Mexican physicians, and the need of legislation regarding end of life decisions in our country. PMID- 24762728 TI - [Pulmonary arterial hypertension, a rare entity]. AB - Pulmonary arterial hypertension (PAH) is a rare disease. It is characterized by the progressive remodeling of the small pulmonary arteries that lead to an elevation of the pulmonary vascular resistance and right ventricular dysfunction. Early diagnosis and prompt treatment avoid the deterioration of the patient's quality of life. Statistics show that there are 15 cases per million people worldwide, the majority comprised of young women, with an age at diagnosis of 30 to 40 years. At present, the exact processes that initiate the pathophysiologic changes observed in PAH are unknown; it is thought to be multifactorial. Diagnosis in PAH must be done in a step by step manner. Under the suspicion of pulmonary hypertension (PH), the first thing to do is confirm the diagnosis. The second step is to identify the specific etiology and lastly evaluate the severity by echocardiography, hemodynamic parameters, biomarkers and exercise capacity. PH treatment, particularly PAH, has evolved over the last 2 decades due to the advance in disease knowledge and the availability of agents that act on different pathways. Concerning surgical treatment, it is indicated in PAH when there is not an adequate response to medical treatment. In conclusion, PAH is recognized worldwide as a rare or infrequent disease. The countries that have a registry for the diagnostics, treatment, follow-up and prevalence of PH are mainly in Europe. With the exception of the United States and Canada, there are no registries in America. Recent years have shown an important advance in Latin America. PMID- 24762729 TI - [From hunter-gatherers to the global village: implications for health]. PMID- 24762730 TI - [Brief history of lead poisoning: from Egyptian civilization to the Renaissance]. AB - The exposition to lead in the Antiquity is one of the first environmental health risks in the history of the mankind. In the ancient cultures of Egypt, Crete and Sumer there was no reports of an important exposition to this metal. The first clinical data is described in the Corpus Hipocraticcus, however was Nicandrus of Colophon the first to make a thorough description of the clinical manifestations of this disease. There was an increase in the exposition to this metal in times of the Roman empire and even some researchers propose that Julius Cesar and Octavio had clinical manifestations associated with lead poisoning. Paul of Aegina in the 7th century (a.C.) describes the first epidemic associated with lead intoxication, however in the Middle Ages the use of lead decrease until the Renaissance period in which lead poisoning affects mostly painters, metal smithers and miners. Some studies done in the ice-layers of Greenland showed that the environmental pollution by lead during the Roman empire and the Renaissance was important. PMID- 24762731 TI - [In memoriam: Dr. Luis Guevara Gonzalez (1929-2014)]. PMID- 24762732 TI - [Science and confidence: the need to be clear]. PMID- 24762733 TI - [Science and confidence: the need to be clear-reply]. PMID- 24762734 TI - [Science and confidence: the need to be clear-reply]. PMID- 24762735 TI - [Science and confidence: the need to be clear- reply]. PMID- 24762736 TI - Circulating CD14brightCD16+ 'intermediate' monocytes exhibit enhanced parasite pattern recognition in human helminth infection. AB - Circulating monocyte sub-sets have recently emerged as mediators of divergent immune functions during infectious disease but their role in helminth infection has not been investigated. In this study we evaluated whether 'classical' (CD14brightCD16-), 'intermediate' (CD14brightCD16+), and 'non-classical' (CD14dimCD16+) monocyte sub-sets from peripheral blood mononuclear cells varied in both abundance and ability to bind antigenic material amongst individuals living in a region of Northern Senegal which is co-endemic for Schistosoma mansoni and S. haematobium. Monocyte recognition of excretory/secretory (E/S) products released by skin-invasive cercariae, or eggs, of S. mansoni was assessed by flow cytometry and compared between S. mansoni mono-infected, S. mansoni and S. haematobium co-infected, and uninfected participants. Each of the three monocyte sub-sets in the different infection groups bound schistosome E/S material. However, 'intermediate' CD14brightCD16+ monocytes had a significantly enhanced ability to bind cercarial and egg E/S. Moreover, this elevation of ligand binding was particularly evident in co-infected participants. This is the first demonstration of modulated parasite pattern recognition in CD14brightCD16+ intermediate monocytes during helminth infection, which may have functional consequences for the ability of infected individuals to respond immunologically to infection. PMID- 24762737 TI - Constraint-based modeling of carbon fixation and the energetics of electron transfer in Geobacter metallireducens. AB - Geobacter species are of great interest for environmental and biotechnology applications as they can carry out direct electron transfer to insoluble metals or other microorganisms and have the ability to assimilate inorganic carbon. Here, we report on the capability and key enabling metabolic machinery of Geobacter metallireducens GS-15 to carry out CO2 fixation and direct electron transfer to iron. An updated metabolic reconstruction was generated, growth screens on targeted conditions of interest were performed, and constraint-based analysis was utilized to characterize and evaluate critical pathways and reactions in G. metallireducens. The novel capability of G. metallireducens to grow autotrophically with formate and Fe(III) was predicted and subsequently validated in vivo. Additionally, the energetic cost of transferring electrons to an external electron acceptor was determined through analysis of growth experiments carried out using three different electron acceptors (Fe(III), nitrate, and fumarate) by systematically isolating and examining different parts of the electron transport chain. The updated reconstruction will serve as a knowledgebase for understanding and engineering Geobacter and similar species. PMID- 24762739 TI - Concocting cholinergy. PMID- 24762740 TI - A thrombomodulin mutation that impairs active protein C generation is detrimental in severe pneumonia-derived gram-negative sepsis (melioidosis). AB - BACKGROUND: During severe (pneumo)sepsis inflammatory and coagulation pathways become activated as part of the host immune response. Thrombomodulin (TM) is involved in a range of host defense mechanisms during infection and plays a pivotal role in activation of protein C (PC) into active protein C (APC). APC has both anticoagulant and anti-inflammatory properties. In this study we investigated the effects of impaired TM-mediated APC generation during melioidosis, a common form of community-acquired Gram-negative (pneumo)sepsis in South-East Asia caused by Burkholderia (B.) pseudomallei. METHODOLOGY/PRINCIPAL FINDINGS: (WT) mice and mice with an impaired capacity to activate protein C due to a point mutation in their Thbd gene (TMpro/pro mice) were intranasally infected with B. pseudomallei and sacrificed after 24, 48 or 72 hours for analyses. Additionally, survival studies were performed. When compared to WT mice, TMpro/pro mice displayed a worse survival upon infection with B. pseudomallei, accompanied by increased coagulation activation, enhanced lung neutrophil influx and bronchoalveolar inflammation at late time points, together with increased hepatocellular injury. The TMpro/pro mutation had limited if any impact on bacterial growth and dissemination. CONCLUSION/SIGNIFICANCE: TM mediated protein C activation contributes to protective immunity after infection with B. pseudomallei. These results add to a better understanding of the regulation of the inflammatory and procoagulant response during severe Gram negative (pneumo)sepsis. PMID- 24762741 TI - The challenges of mitochondrial replacement. PMID- 24762742 TI - The periplasmic enzyme, AnsB, of Shigella flexneri modulates bacterial adherence to host epithelial cells. AB - S. flexneri strains, most frequently linked with endemic outbreaks of shigellosis, invade the colonic and rectal epithelium of their host and cause severe tissue damage. Here we have attempted to elucidate the contribution of the periplasmic enzyme, L-asparaginase (AnsB) to the pathogenesis of S. flexneri. Using a reverse genetic approach we found that ansB mutants showed reduced adherence to epithelial cells in vitro and attenuation in two in vivo models of shigellosis, the Caenorhabditis elegans and the murine pulmonary model. To investigate how AnsB affects bacterial adherence, we compared the proteomes of the ansB mutant with its wild type parental strain using two dimensional differential in-gel electrophoresis and identified the outer membrane protein, OmpA as up-regulated in ansB mutant cells. Bacterial OmpA, is a prominent outer membrane protein whose activity has been found to be required for bacterial pathogenesis. Overexpression of OmpA in wild type S. flexneri serotype 3b resulted in decreasing the adherence of this virulent strain, suggesting that the up-regulation of OmpA in ansB mutants contributes to the reduced adherence of this mutant strain. The data presented here is the first report that links the metabolic enzyme AnsB to S. flexneri pathogenesis. PMID- 24762744 TI - Antigen-specific memory B-cell responses to enterotoxigenic Escherichia coli infection in Bangladeshi adults. AB - BACKGROUND: Multiple infections with diverse enterotoxigenic E. coli (ETEC) strains lead to broad spectrum protection against ETEC diarrhea. However, the precise mechanism of protection against ETEC infection is still unknown. Therefore, memory B cell responses and affinity maturation of antibodies to the specific ETEC antigens might be important to understand the mechanism of protection. METHODOLOGY: In this study, we investigated the heat labile toxin B subunit (LTB) and colonization factor antigens (CFA/I and CS6) specific IgA and IgG memory B cell responses in Bangladeshi adults (n = 52) who were infected with ETEC. We also investigated the avidity of IgA and IgG antibodies that developed after infection to these antigens. PRINCIPAL FINDINGS: Patients infected with ETEC expressing LT or LT+heat stable toxin (ST) and CFA/I group or CS6 colonization factors developed LTB, CFA/I or CS6 specific memory B cell responses at day 30 after infection. Similarly, these patients developed high avidity IgA and IgG antibodies to LTB, CFA/I or CS6 at day 7 that remained significantly elevated at day 30 when compared to the avidity of these specific antibodies at the acute stage of infection (day 2). The memory B cell responses, antibody avidity and other immune responses to CFA/I not only developed in patients infected with ETEC expressing CFA/I but also in those infected with ETEC expressing CFA/I cross-reacting epitopes. We also detected a significant positive correlation of LTB, CFA/I and CS6 specific memory B cell responses with the corresponding increase in antibody avidity. CONCLUSION: This study demonstrates that natural infection with ETEC induces memory B cells and high avidity antibodies to LTB and colonization factor CFA/I and CS6 antigens that could mediate anamnestic responses on re-exposure to ETEC and may help in understanding the requirements to design an effective vaccination strategies. PMID- 24762743 TI - Naturally acquired microchimerism: implications for transplantation outcome and novel methodologies for detection. AB - Microchimerism represents a condition where one individual harbors genetically distinct cell populations, and the chimeric population constitutes <1% of the total number of cells. The most common natural source of microchimerism is pregnancy. The reciprocal cell exchange between a mother and her child often leads to the stable engraftment of hematopoietic and non-hematopoietic stem cells in both parties. Interaction between cells from the mother and those from the child may result in maternal immune cells becoming sensitized to inherited paternal alloantigens of the child, which are not expressed by the mother herself. Vice versa, immune cells of the child may become sensitized toward the non-inherited maternal alloantigens of the mother. The extent of microchimerism, its anatomical location, and the sensitivity of the techniques used for detecting its presence collectively determine whether microchimerism can be detected in an individual. In this review, we focus on the clinical consequences of microchimerism in solid organ and hematopoietic stem cell transplantation, and propose concepts derived from data of epidemiologic studies. Next, we elaborate on the latest molecular methodology, including digital PCR, for determining in a reliable and sensitive way the extent of microchimerism. For the first time, tools have become available to isolate viable chimeric cells from a host background, so that the challenges of establishing the biologic mechanisms and function of these cells may finally be tackled. PMID- 24762745 TI - Systematic evaluation of methods for integration of transcriptomic data into constraint-based models of metabolism. AB - Constraint-based models of metabolism are a widely used framework for predicting flux distributions in genome-scale biochemical networks. The number of published methods for integration of transcriptomic data into constraint-based models has been rapidly increasing. So far the predictive capability of these methods has not been critically evaluated and compared. This work presents a survey of recently published methods that use transcript levels to try to improve metabolic flux predictions either by generating flux distributions or by creating context specific models. A subset of these methods is then systematically evaluated using published data from three different case studies in E. coli and S. cerevisiae. The flux predictions made by different methods using transcriptomic data are compared against experimentally determined extracellular and intracellular fluxes (from 13C-labeling data). The sensitivity of the results to method-specific parameters is also evaluated, as well as their robustness to noise in the data. The results show that none of the methods outperforms the others for all cases. Also, it is observed that for many conditions, the predictions obtained by simple flux balance analysis using growth maximization and parsimony criteria are as good or better than those obtained using methods that incorporate transcriptomic data. We further discuss the differences in the mathematical formulation of the methods, and their relation to the results we have obtained, as well as the connection to the underlying biological principles of metabolic regulation. PMID- 24762746 TI - New genetic biomarkers predicting azathioprine blood concentrations in combination therapy with 5-aminosalicylic acid. AB - BACKGROUND AND AIMS: Azathioprine (AZA) is widely used for the treatment of inflammatory bowel disease (IBD) patients. AZA is catabolized by thiopurine S methyltransferase (TPMT), which exhibits genetic polymorphisms. It has also been reported that 5-aminosalicylic acid (5-ASA) inhibits TPMT activity, and that increased 6-thioguanine nucleotide (6-TGN, a metabolite of AZA) blood concentrations result in an increased number of ADRs. In this study, single nucleotide polymorphisms (SNPs) related to differential gene expression affecting AZA drug metabolism in combination therapy with 5-ASA were examined. METHODS: To identify genetic biomarkers for the prediction of 6-TGN blood concentration, ExpressGenotyping analysis was used. ExpressGenotyping analysis is able to detect critical pharmacogenetic SNPs by analyzing drug-induced expression allelic imbalance (EAI) of premature RNA in HapMap lymphocytes. We collected blood samples on 38 patients with inflammatory bowel disease treated with AZA and corroboration of the obtained SNPs was attempted in clinical samples. RESULTS: A large number of SNPs with AZA/5-ASA-induced EAI within the investigated HapMap lymphocytes was identified by ExpressGenotyping analysis. The respective SNPs were analyzed in IBD patients' blood samples. Among these SNPs, several that have not yet been described to be induced by AZA/5-ASA were found. SNPs within SLC38A9 showed a particular correlation with patients' 6-TGN blood concentrations. CONCLUSIONS: Based on these results, ExpressGenotyping analysis and genotyping of patients appears to be a useful way to identify inter-individual differences in drug responses and ADRs to AZA/5-ASA. This study provides helpful information on genetic biomarkers for optimized AZA/5-ASA treatment of IBD patients. PMID- 24762747 TI - Empiric weight-based vancomycin in intensive care unit patients with methicillin resistant Staphylococcus aureus bacteremia. AB - BACKGROUND: Previous studies were conducted in all hospitalized patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia to determine safety and effectiveness of guideline-recommended, weight-based dosing of vancomycin. In these studies, it was observed that severely ill patients (Pitt bacteremia score >=4 or intensive care unit [ICU] patients) were at an increased risk of mortality and/or nephrotoxicity. Therefore, a subanalysis of the effect of guideline recommended vancomycin dosing on in-hospital mortality and nephrotoxicity in ICU patients with MRSA bacteremia was conducted. METHODS: This multicenter, retrospective, cohort study was conducted in a subset of ICU patients from a previous MRSA bacteremia study. Patients were >=18 years old and received >=48 hours of empiric vancomycin from July 1, 2002, to June 30, 2008. The incidence of nephrotoxicity and in-hospital mortality was compared in patients who received guideline-recommended dosing (at least 15 mg/kg per dose) to patients who received non-guideline-recommended dosing of vancomycin. Multivariable generalized linear mixed-effects models were constructed to determine independent risk factors for in-hospital mortality and nephrotoxicity. RESULTS: Guideline recommended dosing was received by 34% of patients (n = 137). Nephrotoxicity occurred in 35% of patients receiving guideline-recommended dosing and 39% receiving non-guideline-recommended dosing (P = 0.67). In-hospital mortality rate was 24% among patients who received guideline-recommended dosing compared with 31% for non-guideline-recommended dosing (P = 0.40). Guideline-recommended dosing was not associated with nephrotoxicity (odds ratio: 1.10; 95% confidence interval: 0.43-2.79) or in-hospital mortality (odds ratio: 0.54; 95% confidence interval: 0.22-1.36) in the multivariable analysis. CONCLUSIONS: Guideline recommended dosing of vancomycin in ICU patients with MRSA bacteremia is not significantly associated with nephrotoxicity or in-hospital mortality. However, the 7% absolute difference for in-hospital mortality suggests that larger studies are needed. PMID- 24762748 TI - Risk factors for frailty in a large prevalent cohort of hemodialysis patients. AB - BACKGROUND: Although individuals with kidney disease, including those dependent on dialysis, often present clinically with signs and symptoms consistent with frailty, there is limited information about sociodemographic and clinical risk factors that may be associated. METHODS: Seven hundred forty-five patients undergoing hemodialysisbetween 2009 and 2011 in 7 Atlanta dialysis clinics and 7 San Francisco bay area dialysis clinics were assessed using the validated Fried frailty index (recent unintentional weight loss, reported exhaustion, low grip strength, slow walk speed, low physical activity) that defines frailty as the presence of 3 or more criteria. Study coordinators interviewed participants; measured grip strength, walk speed, and body composition; and reviewed records for clinical and laboratory parameters. Logistic regression models were used to estimate the association of patient characteristics with frailty. RESULTS: In adjusted analyses, peripheral vascular disease and cardiac diseases, including dysrhythmia, atrial fibrillation, tachycardia, pericarditis, and cardiac arrest, were associated with higher odds for frailty, whereas black race and higher serum albumin concentration were associated with lower odds for frailty. CONCLUSIONS: In multivariable analyses, the risk for frailty in patients undergoing hemodialysis, as assessed by the presence of 3 or more criteria that comprise the Fried frailty index, was increased in association with peripheral vascular disease and cardiac conditions, such as dysrhythmia and atrial fibrillation, and was decreased for those with higher serum albumin concentration and for blacks compared with whites. Among patients who met the Fried definition of frailty, 78% scored as frail on walk speed and 56% scored as frail on grip strength, the 2 physical performance measures. PMID- 24762749 TI - Dynamic use of B-type natriuretic peptide-guided acute coronary syndrome therapy. AB - BACKGROUND: Very few studies have evaluated the potential of using B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT proBNP) as surrogate markers to guide clinical interventional or conservative therapy decisions. AIM: : The aim of the current study was to evaluate the potential of using BNP and NT-proBNP as surrogate markers to guide clinical interventional or conservative therapy decisions. METHODS: We identified randomized controlled trials that randomized patients with acute coronary syndrome (ACS) of unstable angina and myocardial infarction without ST-segment elevation ACS to early invasive therapy versus a more conservative approach by systematic search of articles and databases. RESULTS: Five randomized controlled trials with a total of 8125 patients and with a mean duration of 11.2 months were included in the meta-analysis. At a mean follow-up of 11.2 months, the incidence of all-cause mortality was 5.9% in the early invasive group, compared with 6.8% in the conservative group (risk ratio = 0.74; 95% confidence interval, 0.59-0.86; P = 0.001). CONCLUSIONS: In summary, BNP/NT-proBNP-guided management of ACS is significantly improved by early invasive therapy by improving long-term survival and reducing nonfatal myocardial infarction for unstable angina. However, there does not seem to be a clear benefit of using such a strategy over existing clinical recommendations. PMID- 24762750 TI - Metachronous Metastatic Renal Cell Carcinoma of the Gall Bladder. PMID- 24762751 TI - Left atrial appendage aneurysm. PMID- 24762752 TI - Hampton's hump. PMID- 24762754 TI - Cardiopulmonary resuscitation in the hospitalized patient: impact of system-based variables on outcomes in cardiac arrest. AB - BACKGROUND: A better understanding of the factors affecting the outcome of inpatient cardiopulmonary resuscitation (CPR) is crucial in making key clinical decisions. We aim to study the impact of various patient-related and hospital related variables in a community-based teaching setup that could affect the prognosis of in-hospital cardiac arrests. METHODS: We analyzed the data on all patients who experienced cardiac arrest while hospitalized at a community teaching hospital in Youngstown, Ohio. A multivariable logistic regression was performed to identify patient- and system-based variables associated with mortality in inpatient cardiac arrest. RESULTS: A total of 417 in-hospital cardiopulmonary arrests were recorded during the study period. We analyzed 299 events in our final sample. One hundred sixty-four patients (54.8%) achieved return of spontaneous circulation and 137 (48.5%) survived the cardiopulmonary arrest for at least 24 hours. The duration of CPR, age, initial rhythm, witnessed events and sex were strongly associated with mortality in our univariate analysis. After adjustment for age, location and whether the code was witnessed, the timing of the week, initial rhythm, the duration of CPR and the sex of the patient retained prognostic significance in predicting the mortality. CONCLUSIONS: In our study, we report a 17.4% survival to hospital discharge after an in-hospital cardiopulmonary arrest and subsequent CPR, similar to rates reported in larger multicenter studies. Prolonged duration of CPR (>10 minutes) and male sex were found to be associated with worse outcomes. We report the impact of system-based variables such as physician and nursing staffing during different days of the week, on survival in these patients. PMID- 24762753 TI - Sex and race (black-white) differences in the relationship of childhood risk factors to adulthood arterial stiffness: the Bogalusa Heart Study. AB - BACKGROUND: Cardiovascular risk factors in childhood are predictive of adulthood arterial stiffness. However, it is unknown whether this relationship varies by race or sex. METHODS: Six hundred and eighty adults aged 24 to 43 had been followed for an average of 26.3 years, from the Bogalusa Heart Study. Brachial to ankle pulse wave velocity (baPWV) measured by an automatic oscillometric technique was used as the outcome variable for arterial stiffness during adulthood. Body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, and systolic blood pressure (SBP), all measured in childhood, were used as predictors. The average values of childhood measurements at multiple time points were used, standardized to age, race, and sex-specific z-scores. RESULTS: In the total sample, childhood SBP was the only significant predictor (P < 0.001) for adult baPWV. Significant interactions between sex and BMI (P = 0.001), between sex and LDL-C (P = 0.035), and between race and HDL-C (P = 0.002) on adult baPWV were identified. Childhood predictors of adult baPWV were BMI (30.9 cm/s reduction in baPWV per standard deviation increase, 95% confidence interval [CI]: -55.0, -6.9 cm/s), LDL-C (30.8 cm/s increase, 95% CI: 2.9, 59.5 cm/s), and HDL-C (46.8 cm/s reduction, 95% CI: 76.2, -17.4 cm/s) in white males; SBP (38.2 cm/s increase, 95% CI: 11.0, 65.4 cm/s) in white females; BMI (71.3 cm/s reduction, 95% CI: -119.9, -22.7 cm/s) in black males; and none in black females. CONCLUSIONS: The associations of childhood cardiovascular risk factors with adult arterial stiffness varied by race and sex. PMID- 24762755 TI - Factors influencing pleural adenosine deaminase level in patients with tuberculous pleurisy. AB - BACKGROUND: Adenosine deaminase (ADA) activity is useful for diagnosing tuberculous (TB) pleurisy in regions with a high prevalence of tuberculosis. However, some cases of TB pleural effusion show decreased ADA activity. Therefore, we evaluated factors influencing pleural ADA levels in patients with TB pleurisy. METHODS: We retrospectively evaluated 182 patients with TB pleural effusion who were admitted to Gyeongsang National University Hospital from January 2004 to September 2008. Patients were dichotomized into 2 groups: a low ADA (<40 IU/L) group (n = 22) and a high-ADA (>=40 IU/L) group (n = 160). Age, sex, ADA level of pleural effusion, smoking status, history of tuberculosis and comorbid diseases were evaluated in each group. RESULTS: The median age of the patients was 50.5 years, with a male to female ratio of 1.72:1. Patients with a low-ADA level were significantly older than those with a high ADA level (66.9 +/- 12.0 versus 49.4 +/- 21.2 years, P < 0.001). A history of tuberculosis and hypertension was more common in the low-ADA group than in the high-ADA group (31.8% versus 15.0%, P = 0.049 and 36.4% versus 16.9%, P = 0.03, respectively). A multivariate analysis revealed that older age and current smoking were predictive of TB pleurisy with a low ADA level (odds ratios, 1.053 and 4.848; P = 0.002 and 0.028, respectively). CONCLUSIONS: Physicians should be careful when interpreting pleural ADA levels in elderly patients and/or current smokers for the diagnosis of TB pleurisy. PMID- 24762756 TI - Destructive squamous cell carcinoma of the penis. PMID- 24762757 TI - Ectopic tumoral calcinosis in systemic sclerosis. PMID- 24762758 TI - Bladder Paraganglioma. PMID- 24762759 TI - The shift of microbial community under the adjustment of initial and processing pH during bioleaching of chalcopyrite concentrate by moderate thermophiles. AB - The shift of microbial community under the adjustment of different pH was analyzed by denaturing gradient gel electrophoresis (DGGE). The results indicated, at initial pH 1.0, 2.0 and 3.0, the copper extraction in 22 days amounted to 84.6%, 88.2% and 77.5%, respectively; however, when the initial pH was 2.0, processing pH was adjusted to 1.0 and 3.0 on day 16, the copper extraction in 32 days was 85% and 62.6%, respectively. DGGE analysis showed Acidithiobacillus caldus, Leptospirillum ferriphilum, Sulfobacillus thermosulfidooxidans and Ferroplasma thermophilum existed in bioleaching systems. At initial pH 1.0 and 3.0, S. thermosulfidooxidans and A. caldus were main microorganisms. While at initial pH 2.0, L. ferriphilum, A. caldus and S. thermosulfidooxidans were always detected. At processing pH 1.0 and 3.0, the adjustment of pH greatly inhibited the growth of L. ferriphilum; it was also found microbial community would recover gradually only if pH stimulation did not fatally affect microorganisms. PMID- 24762760 TI - Risk analysis of pyrolyzed biochar made from paper mill effluent treatment plant sludge for bioavailability and eco-toxicity of heavy metals. AB - The risk analysis was performed to study the bioavailability and eco-toxicity of heavy metals in biochar obtained from pyrolysis of sludge of pulp and paper mill effluent treatment plant. The sludge was pyrolyzed at different temperatures (200 700 degrees C) and the resultant biochar were analyzed for fractionation of heavy metals by sequential extraction procedure. It was observed that all the heavy metals get enriched in biochar matrix after pyrolysis, but the bioavailability and eco-toxicity of the heavy metals in biochar were significantly reduced as the mobile and bioavailable heavy metal fractions were transformed into the relatively stable fractions. Moreover, it was observed that the leaching potential of heavy metals decreased after pyrolysis and the best results were obtained for biochar pyrolyzed at 700 degrees C. PMID- 24762761 TI - Advanced nitrogen removal with simultaneous Anammox and denitrification in sequencing batch reactor. AB - In this study, a sequencing batch reactor (SBR) was used to achieve advanced nitrogen removal by simultaneous Anammox and denitrification processes. During the entire experiment, the Anammox microorganisms aggregated in the reactor as wall growth. Nitrogen removal was improved due to the reduction of nitrate, and the maximum total nitrogen (TN, including ammonia, nitrite and nitrate nitrogen) removal efficiency of 97.47% was obtained at C/N of 2. However, the sequentially increased organic matter resulted in a poor TN removal performance due to the suppression of Anammox. Fortunately, the Anammox activity completely resumed quickly after stopping dosing organic matter. PCR analysis results revealed that the Anammox bacteria gene copy number was not significantly reduced during the inhibition, which might explain the quick recover. PMID- 24762762 TI - Design of experiments to assess pre-treatment and co-digestion strategies that optimize biogas production from macroalgae Gracilaria vermiculophylla. AB - A design of experiments was applied to evaluate different strategies to enhance the methane yield of macroalgae Gracilaria vermiculophylla. Biochemical Methane Potential (BMP) of G. vermiculophylla after physical pre-treatment (washing and maceration) reached 481+/-9 L CH4 kg(-1) VS, corresponding to a methane yield of 79+/-2%. No significant effects were achieved in the BMP after thermochemical pre treatment, although the seaweeds solubilisation increased up to 44%. Co-digestion with glycerol or sewage sludge has proved to be effective for increasing the methane production. Addition of 2% glycerol (w:w) increased the BMP by 18%, achieving almost complete methanation of the substrate (96+/-3%). Co-digestion of seaweed and secondary sludge (15:85%, TS/TS) increased the BMP by 25% (605+/-4 L CH4 kg(-1) VS) compared to the seaweed individual digestion. PMID- 24762763 TI - LIM mineralization protein-1 inhibits the malignant phenotypes of human osteosarcoma cells. AB - Osteosarcoma (OS), also known as osteogenic sarcoma, is the most common primary malignancy of bone tumor in children and adolescents. However, its underlying molecular pathogenesis is still only vaguely understood. Recently, LIM mineralization protein-1 (LMP-1) was reported to be an essential positive regulator of osteoblast differentiation. In the present study, we found that the expression of LMP-1 is downregulated in OS tissues compared with adjacent normal tissues. Moreover, we restored the expression of LMP-1 through a recombinant adenovirus. Overexpression of LMP-1 inhibited cell proliferation and invasion, arrested cell cycle progression, and induced apoptosis in vitro. Finally, ectopic LMP-1 expression suppressed the expression of Runx2 and BMP-2 in OS cells. These data demonstrate that LMP-1 is an essential tumor suppressor in the OS pathological process, which will provide a new opportunity for discovering and identifying novel effective treatment strategies. PMID- 24762764 TI - In vitro organogenesis from pluripotent stem cells. AB - Pluripotent stem cells (PSCs) have the ability to spontaneously generate structured tissues in vitro reminiscent of embryonic tissue development. Recently, complex organoids such as cortical tissues, cerebral brain organoids, optical cups, intestinal tissues, and liver buds have been generated from PSCs derived from healthy individuals and patients with genetic diseases, providing powerful tools to understand morphogenesis and disease pathology. This article highlights recent advances in the state-of-art generation of organoids from PSCs, possible signaling pathways and mechanisms involved in organogenesis, and the understanding of extracellular microenvironment. Challenges involved in the organoid generation such as increasing organoid size, enhancing the tissue complexity, and improving functional maturation are also discussed. PMID- 24762766 TI - [Nurses for EXPO]. PMID- 24762765 TI - Rad51-Rad52 mediated maintenance of centromeric chromatin in Candida albicans. AB - Specification of the centromere location in most eukaryotes is not solely dependent on the DNA sequence. However, the non-genetic determinants of centromere identity are not clearly defined. While multiple mechanisms, individually or in concert, may specify centromeres epigenetically, most studies in this area are focused on a universal factor, a centromere-specific histone H3 variant CENP-A, often considered as the epigenetic determinant of centromere identity. In spite of variable timing of its loading at centromeres across species, a replication coupled early S phase deposition of CENP-A is found in most yeast centromeres. Centromeres are the earliest replicating chromosomal regions in a pathogenic budding yeast Candida albicans. Using a 2-dimensional agarose gel electrophoresis assay, we identify replication origins (ORI7-LI and ORI7-RI) proximal to an early replicating centromere (CEN7) in C. albicans. We show that the replication forks stall at CEN7 in a kinetochore dependent manner and fork stalling is reduced in the absence of the homologous recombination (HR) proteins Rad51 and Rad52. Deletion of ORI7-RI causes a significant reduction in the stalled fork signal and an increased loss rate of the altered chromosome 7. The HR proteins, Rad51 and Rad52, have been shown to play a role in fork restart. Confocal microscopy shows declustered kinetochores in rad51 and rad52 mutants, which are evidence of kinetochore disintegrity. CENP-ACaCse4 levels at centromeres, as determined by chromatin immunoprecipitation (ChIP) experiments, are reduced in absence of Rad51/Rad52 resulting in disruption of the kinetochore structure. Moreover, western blot analysis reveals that delocalized CENP-A molecules in HR mutants degrade in a similar fashion as in other kinetochore mutants described before. Finally, co-immunoprecipitation assays indicate that Rad51 and Rad52 physically interact with CENP-ACaCse4 in vivo. Thus, the HR proteins Rad51 and Rad52 epigenetically maintain centromere functioning by regulating CENP-ACaCse4 levels at the programmed stall sites of early replicating centromeres. PMID- 24762767 TI - [Alzheimer's disease and caregivers experience in home care]. AB - The aim of this study is to investigate the experience of primary caregivers (men and women) of Alzheimer Disease dementia, in order to tailor program and project to avoid care giving burden. A qualitative phenomenological method was used and the sample was defined by data saturation. Interviews were carried out and recorded in a day care Centre, transcribed verbatim. The analysis was conducted coding common themes and phrases. Six main themes emerged. Our results are similar to those existing in literature, showing care givers as individual in great danger physically and mentally. In the light of the study it is possible to tailor a nursing model in order to improve quality of life and decrease the burden of caregivers, this model should be implemented and analyzed. PMID- 24762768 TI - [Assessing the effectiveness of Gelclair(r) in the prevention and therapy of stomatitis in patients undergoing hematopoietic stem-cell transplantation: a randomized trial]. AB - INTRODUCTION: Chemotherapy-induced stomatitis is a major side effect of the treatment. Numerous approaches are described in the literature for the prevention and treatment of this complication. OBJECTIVE: the aim was assess the effectiveness of Gelclair(r) in patients undergoing hematopoietic stem-cell transplantation in terms of reducing the incidence of stomatitis, stomatitis-pain and the severity of stomatitis INTERVENTIONS/METHODS: Fifty-seven patients (28 control group and 29 experimental group) used a mouthwash 3 times a day and were evaluated by means of a specially-tailored form containing the following assessment items:stomatitis evaluation scale (WHO), VAS for pain and Likert-Scale for agreement. RESULTS: 61% of patients presented with stomatitis. No difference was observed between the two groups with regard to stomatitis grade throughout the observation period. Painful symptoms were observed in 54% subjects. No differences were observed in terms of average pain perception before the use of mouthwashes throughout the period of observation p=0.06. RESULTS showed a pain relieving effect in the experimental group after using the mouthwash p=0.04. CONCLUSIONS: Although Gelclair(r) had no influence on the onset and severity of stomatitis in transplanted patients, a significant benefit was observed in terms of pain control. Our study suggest the possibility to implementation the use of Gelclair(r) in clinical practice. However, further multicenter trials are needed to provide stronger evidence on the real usefulness of this product. PMID- 24762769 TI - [What, how and why people fall in hospital? Study in a Northern Italian Hospital]. AB - INTRODUCTION: According to the World Health Organization (WHO), falls and falls related-injuries are a main issue for health and social systems in Europe and all over the world, particularly considering that life is lengthening. OBJECTIVE: To describe incidence, causes and falls modalities in a Northern Italian Hospital following the organizational changes set up in 2008. METHODS: The survey consists of two steps: 1. definition of expected situation according to the literature and other similar contexts; 2. examination of the fall report forms between July 1, 2010 and June 30, 2011. RESULTS: In this period the incidence of falls has been 0.8% and in 69% of cases patients' intrinsic factors have been identified to be the cause, followed by extrinsic factors (7.4%), organizational factors (5.4%) and inter-professional communication difficulties (3.1%). CONCLUSION: Falls have a multi-factorial etiology, therefore the most effective approach should be multidimensional. A simultaneous action on three levels, organizational, staff/communication and patient, would be needed. PMID- 24762770 TI - [Empathy in the nurse practitioners of medical area]. AB - INTRODUCTION: There are very few studies that investigate the capacity for empathy in nursing population. The aim of this study is to analyze the capacity for empathy of nurses serving in the surgical area in relation to gender, age, education and length of service. MATERIALS AND METHODS: The study is descriptive observational, on a sample of 60 nurses. The instrument used for the assessment of empathy is the rating scale JSPE (HP version) consists of 20 items, where respondents indicate their agreement or disagreement with a 7-point Likert scale. The range of possible values is from 20 to 140: the higher score corresponds to a greater capacity for empathy The questionnaire has demonstrated the validity and reliability of the Italian version of JSPE with a Cronbach's alpha coefficient of 0.85.The level of statistical significance accepted is equal to P <= 0.05. RESULTS: The average capacity for empathy professionals surveyed was found to be 104/140. From the data analyzed, it is clear that with increasing years of service to the profession there is a decrease of empathy as well as continuing in the same department causes a decrease in empathy. Also showed a greater empathy of nurses compared to the general practice of neurology. CONCLUSIONS: The study shows that professionals would need to increase the capacity for empathy especially with the passing of the years of service to the profession. Probably as a defense mechanism, the practitioner tends to protect themselves from emotional involvement, supporting activities of a more technical gestures, rather than relational. PMID- 24762771 TI - [Surgical site infections in breast surgery: a descriptive study]. AB - BACKGROUND: The incidence of postoperative surgical site infections (SSIs) in breast surgery is 3.1%. The risk to develop SSIs seems correlated to the level of glycemia. MATERIALS AND METHODS: The aim is to test a correlation between glycemic values and SSIs in breast surgery with a longitudinal perspective study. The data were collected in a Surgical Department of a University Hospital of north-east Italy; the study is in the context of the Regional Surveillance Program of Health Agency. RESULTS: We have observed 100 patients. The incidence of the SSIs has been 5.7%. The patients that have developed the SSIs were in ordinary recovery, with a glycemic value taller then the patients without SSIs both in preoperative (92.6 vses 88.5) that in postoperative period (104 vses 91.8 and 108.3 vses 94). CONCLUSIONS: We cannot test a correlation between SSIs and glycemic value nevertheless for the clinical practice we have important guideline. PMID- 24762772 TI - [Nursing students' satisfaction and perception of their first clinical placement: observational study]. AB - BACKGROUND: Clinical learning environments are defined as an interactive network of forces within the clinical context that influence students' learning outcomes. Nursing students' satisfaction could be strictly related to their learning outcomes. Aim. To analyze the first year nursing students' clinical learning experience and to identify the main determinants of students' satisfaction. METHODS: The observational study was carried out in five Italian nursing degree courses. 420 students filled out the validated Italian version of the "Clinical Learning Environment and Supervision plus Nurse Teacher (CLES+T) scale" after the conclusion of their first clinical placement. RESULTS: The mean values of the main sub-dimensions of CLES+T varied from 4.02 (pedagogical atmosphere) to 3.30 (supervisory relationship). Students were mainly satisfied with their clinical placement, however the findings showed statistical significantly differences among the five nursing courses. DISCUSSION: The main determinants of the overall students' satisfaction are the nurse manager's leadership style and the integration between theoretical knowledge and everyday practice of nursing through the relationship among students, clinical tutors and nurse teacher. CONCLUSION: Our results may contribute to better understand nursing students' perception of their first clinical placement. However, further research are needed to evaluate which organizational factors and clinical training models may enhance the clinical learning experience. PMID- 24762773 TI - [The nursing image in Italy: an analysis of the historic archive of national newspaper]. AB - PURPOSE: The main aim is to describe the nursing profession image as it appears in one of the main national newspaper. METHOD: A retrospective study has been conducted through the analysis of 2017 articles published between 1906 and 2005 on the national newspaper "La Stampa". RESULTS: 11 thematic clusters emerged from the analysis. The articles published with a higher frequency were those concerning "news and chronicle", with a relevant increase after the second half of the '80s, followed by "working conditions" with a maximum spread during the '90s. Instead the articles that rarely appeared on the newspaper were those concerning, "aesthetic" and "contests". More than half of the articles concerning "staff shortage" reported consequent disruptions. Almost all the articles concerning "malpractice" highlighted the inadequate care delivered from nurses and they have been published with constant trend starting from the a '50s. The articles concerning "staff shortage", "innovation", and "education", showed their maximum spread starting from the '90s. CONCLUSIONS: The analysis of the articles published in the newspaper "La Stampa" allowed to read the nursing profession story as troubled, made of professional achievements obtained from struggles, claims and countless educational and organizational changes though many of the analyzed articles did not contributed to show, and consequently to appreciate, the nursing profession for its real content and contributions to the population's health. PMID- 24762774 TI - The undergraduate nursing student evaluation of clinical learning environment: an Italian survey. AB - BACKGROUND: Nursing students have to deal with many different clinical and practical aspects of knowledge to become skilled professionals. Student perception may be considered an indicator of teaching quality, since positive perception of students is strictly related to their effective professional learning. The Clinical Learning Environment and Supervision plus Nurse Teacher (CLES+T) scale is considered the gold standard psychometric instrument to evaluate both the quality and the climate of clinical learning environment. AIMS: To evaluate the quality of nurse teaching by means of CLES+T scale and to highlight significant correlations between CLES+T scale and selected characteristics of both students and clinical environments. METHODS: On 4 March 2013, a cross-sectional survey was conducted at University of Modena: CLES+T scale was administered during a plenary convocation to 242 nursing students who attended the second and third years of Nursing Degree. All 34 items of the scale were statistically analysed using the median test. RESULTS: The median values were uniformly represented by "4" level (on the Likert scale). The final marks of clinical learning experience were the only variable statistically significantly related to the scale scores. The paediatrics and emergency areas obtained the highest scale scores. CONCLUSIONS: The nursing student evaluations were uniformly positive and related to their positive final marks. A positive ward atmosphere was identified as especially important in this study. These data indicate that a non-hostile and hospitable environment can favour the best clinical learning. We conclude that CLES+T scale can be a useful instrument to explore the clinical climate in all hospital areas and to highlight critical clinical situations. PMID- 24762775 TI - Dicer-2-dependent activation of Culex Vago occurs via the TRAF-Rel2 signaling pathway. AB - Despite their importance as vectors of human and livestock diseases, relatively little is known about innate antiviral immune pathways in mosquitoes and other insects. Previous work has shown that Culex Vago (CxVago), which is induced and secreted from West Nile virus (WNV)-infected mosquito cells, acts as a functional homolog of interferon, by activating Jak-STAT pathway and limiting virus replication in neighbouring cells. Here we describe the Dicer-2-dependent pathway leading to WNV-induced CxVago activation. Using a luciferase reporter assay, we show that a NF-kappaB-like binding site in CxVago promoter region is conserved in mosquito species and is responsible for induction of CxVago expression following WNV infection. Using dsRNA-based gene knockdown, we show that the NF-kappaB ortholog, Rel2, plays significant role in the signaling pathway that activates CxVago in mosquito cells in vitro and in vivo. Using similar approaches, we also show that TRAF, but not TRAF-3, is involved in activation of Rel2 after viral infection. Overall the study shows that a conserved signaling pathway, which is similar to mammalian interferon activation pathway, is responsible for the induction and antiviral activity of CxVago. PMID- 24762777 TI - A model for MU-biomimetic thermal infrared sensors based on the infrared receptors of Melanophila acuminata. AB - Beetles of the genus Melanophila acuminata detect forest fires from distances as far as 130 km with infrared-sensing organs. Inspired by this extremely sensitive biological device, we are developing an IR sensor that operates at ambient temperature using MEMS technology. The sensor consists of two liquid-filled chambers that are connected by a micro-fluidic system. Absorption of IR radiation by one of these chambers leads to heating and expansion of a liquid. The increasing pressure deflects a membrane covered by one electrode of a plate capacitor. The micro-fluidic system and the second chamber represent a fluidic low-pass filter, preventing slow, but large pressure changes. However, the strong frequency dependence of the filter demands a precise characterization of its properties. Here, we present a theoretical model that describes the frequency dependent response of the sensor based on material properties and geometrical dimensions. Our model is divided into four distinct parts that address different aspects of the sensor. The model describes the frequency-dependent behaviour of the fluidic filter and a thermal low-pass filter as well as saturation effects at low frequencies. This model allows the calculation of optimal design parameters, and thereby provides the foundation for the development of such a sensor. PMID- 24762776 TI - Joint evolution of kin recognition and cooperation in spatially structured rhizobium populations. AB - In the face of costs, cooperative interactions maintained over evolutionary time present a central question in biology. What forces maintain this cooperation? Two potential ways to explain this problem are spatially structured environments (kin selection) and kin-recognition (directed benefits). In a two-locus population genetic model, we investigated the relative roles of spatial structure and kin recognition in the maintenance of cooperation among rhizobia within the rhizobia legume mutualism. In the case where the cooperative and kin recognition loci are independently inherited, spatial structure alone maintains cooperation, while kin recognition decreases the equilibrium frequency of cooperators. In the case of co inheritance, spatial structure remains a stronger force, but kin recognition can transiently increase the frequency of cooperators. Our results suggest that spatial structure can be a dominant force in maintaining cooperation in rhizobium populations, providing a mechanism for maintaining the mutualistic nodulation trait. Further, our model generates unique and testable predictions that could be evaluated empirically within the legume-rhizobium mutualism. PMID- 24762778 TI - An evidence-based approach to organization evaluation and change in human service organizations evaluation and program planning. AB - The work described in this article focuses primarily on how human service organizations can use an evidence-based, self-assessment approach to organization evaluation to facilitate continuous quality improvement and organization change. Real-life examples are presented, strengths and challenges discussed, and future conceptual and measurement issues identified. PMID- 24762779 TI - Does dissociation moderate treatment outcomes of narrative exposure therapy for PTSD? A secondary analysis from a randomized controlled clinical trial. AB - Dissociative symptoms, especially depersonalisation and derealisation, are often perceived as a contraindication for exposure-based treatments of posttraumatic stress disorder (PTSD) despite limited empirical evidence. The present paper examines whether derealisation and depersonalisation influence the treatment outcomes of narrative exposure therapy (NET) and treatment as usual (TaU) among severely traumatised asylum seekers and refugees. We performed a secondary analysis of a recently published randomized controlled multicentre trial comparing NET and TaU for the treatment of PTSD in asylum seekers and refugees. In order to investigate whether depersonalisation and derealisation moderate treatment outcomes, a number of moderated multiple, blockwise regression analyses were conducted. Missing data were handled with multiple imputation. The main finding from intention-to-treat analyses is that derealisation and depersonalisation overall do not moderate the treatment outcomes of either NET or TaU. The treatment condition was the most stable predictor of residual gain scores across outcome measures, with NET being associated with lower residual gain scores indicating better treatment outcomes. The present study substantiates and extends previous research indicating that dissociative symptoms such as derealisation and depersonalisation do not moderate the treatment outcome of exposure-based treatments for PTSD. CLINICALTRIALSGOV IDENTIFIER: NCT00218959. PMID- 24762780 TI - Comparison of filtering methods for the modeling and retrospective forecasting of influenza epidemics. AB - A variety of filtering methods enable the recursive estimation of system state variables and inference of model parameters. These methods have found application in a range of disciplines and settings, including engineering design and forecasting, and, over the last two decades, have been applied to infectious disease epidemiology. For any system of interest, the ideal filter depends on the nonlinearity and complexity of the model to which it is applied, the quality and abundance of observations being entrained, and the ultimate application (e.g. forecast, parameter estimation, etc.). Here, we compare the performance of six state-of-the-art filter methods when used to model and forecast influenza activity. Three particle filters--a basic particle filter (PF) with resampling and regularization, maximum likelihood estimation via iterated filtering (MIF), and particle Markov chain Monte Carlo (pMCMC)--and three ensemble filters--the ensemble Kalman filter (EnKF), the ensemble adjustment Kalman filter (EAKF), and the rank histogram filter (RHF)--were used in conjunction with a humidity-forced susceptible-infectious-recovered-susceptible (SIRS) model and weekly estimates of influenza incidence. The modeling frameworks, first validated with synthetic influenza epidemic data, were then applied to fit and retrospectively forecast the historical incidence time series of seven influenza epidemics during 2003 2012, for 115 cities in the United States. Results suggest that when using the SIRS model the ensemble filters and the basic PF are more capable of faithfully recreating historical influenza incidence time series, while the MIF and pMCMC do not perform as well for multimodal outbreaks. For forecast of the week with the highest influenza activity, the accuracies of the six model-filter frameworks are comparable; the three particle filters perform slightly better predicting peaks 1 5 weeks in the future; the ensemble filters are more accurate predicting peaks in the past. PMID- 24762781 TI - Effects of indoor swimming pools on the nasal cytology of pool workers. AB - OBJECTIVE: We aimed to evaluate the relationship between swimming pool pollutants and allergic rhinitis in swimming pool workers. MATERIALS AND METHODS: Twenty seven indoor pool workers (group 1) and 49 control subjects (group 2) were enrolled in the study. A skin prick test was performed and a nasal smear was obtained from each subject to evaluate rhinitis. RESULTS: When the groups were compared in terms of epithelial cells, group 1 had significantly more epithelial cells than group 2. When the groups were compared with regard to eosinophils, group 1 had significantly more eosinophils than group 2. The skin prick test results for both groups were not significantly different. CONCLUSION: Indoor pool workers showed severe symptoms of rhinitis and eosinophilic nasal cytology, likely due to chlorine. Nasal cytology is an easy-to-administer diagnostic test and can be used to follow up rhinitis in indoor pool workers, along with nasal endoscopy, a detailed clinical history and a skin prick test. PMID- 24762782 TI - Estimating the impact of vitamin A-fortified vegetable oil in Bangladesh in the absence of dietary assessment data. AB - OBJECTIVE: Vitamin A deficiency is a serious health problem in Bangladesh. The 2011-12 Bangladesh Micronutrient Survey found 76.8% of children of pre-school age were vitamin A deficient. In the absence of nationally representative, individual dietary assessment data, we use an alternative--household income and expenditure survey data--to estimate the potential impact of the introduction of vitamin A fortified vegetable oil in Bangladesh. DESIGN: Items in the household income and expenditure survey were matched to food composition tables to estimate households' usual vitamin A intakes. Then, assuming (i) the intra-household distribution of food is in direct proportion to household members' share of the household's total adult male consumption equivalents, (ii) all vegetable oil that is made from other-than mustard seed and that is purchased is fortifiable and (iii) oil fortification standards are implemented, we modelled the additional vitamin A intake due to the new fortification initiative. SETTING: Nationwide in Bangladesh. SUBJECTS: A weighted sample of 12,240 households comprised of 55,580 individuals. RESULTS: Ninety-nine per cent of the Bangladesh population consumes vegetable oil. The quantities consumed are sufficiently large and, varying little by socio-economic status, are able to provide an important, large-scale impact. At full implementation, vegetable oil fortification will reduce the number of persons with inadequate vitamin A intake from 115 million to 86 million and decrease the prevalence of inadequate vitamin A intake from 80% to 60%. CONCLUSIONS: Vegetable oil is an ideal fortification vehicle in Bangladesh. Its fortification with vitamin A is an important public health intervention. PMID- 24762783 TI - In vivo introduction of transgenes into mouse sciatic nerve cells in situ using viral vectors. AB - The myelin sheath is essential for the rapid and efficient propagation of action potentials. However, our understanding of the basic molecular mechanisms that regulate myelination, demyelination and remyelination is limited. Schwann cells produce myelin in the peripheral nervous system and remain associated with the axons of peripheral neurons throughout axonal migration to the target. Owing to the intimate relationship between these cell types it is difficult to fully reproduce their function in vitro. For this reason, we developed an approach based on the injection of an engineered virus into the sciatic nerve of mice to locally transduce peripheral nerve cells. This approach can be used as an alternative to germline transgenesis to facilitate the investigation of peripheral nerve biology in vivo. The detailed protocol, described here, requires 3 weeks to complete. In comparison with genetic modification strategies, this protocol is a fast, reproducible and straightforward method for introducing exogenous factors into myelinating Schwann cells and myelinated axons in vivo to investigate specific molecular mechanisms. PMID- 24762784 TI - Microinjection of membrane-impermeable molecules into single neural stem cells in brain tissue. AB - This microinjection protocol allows the manipulation and tracking of neural stem and progenitor cells in tissue at single-cell resolution. We demonstrate how to apply microinjection to organotypic brain slices obtained from mice and ferrets; however, our technique is not limited to mouse and ferret embryos, but provides a means of introducing a wide variety of membrane-impermeable molecules (e.g., nucleic acids, proteins, hydrophilic compounds) into neural stem and progenitor cells of any developing mammalian brain. Microinjection experiments are conducted by using a phase-contrast microscope equipped with epifluorescence, a transjector and a micromanipulator. The procedure normally takes ~2 h for an experienced researcher, and the entire protocol, including tissue processing, can be performed within 1 week. Thus, microinjection is a unique and versatile method for changing and tracking the fate of a cell in organotypic slice culture. PMID- 24762785 TI - Scalable and chromatography-free synthesis of 2-(2-formylalkyl)arenecarboxylic acid derivatives through the supramolecularly controlled hydroformylation of vinylarene-2-carboxylic acids. AB - This protocol describes how to prepare 2-(2-formylalkyl)-arenecarboxylic acid derivatives, common building blocks for the synthesis of various valuable chemicals (e.g., anti-obesity and Alzheimer's disease treatment pharmaceuticals), by using the fully regioselective hydroformylation of vinyl arene derivatives. This catalytic reaction proceeds cleanly with 100% regioselectivity and chemoselectivity. The procedure is reliably scalable and can be efficiently conducted on a multigram scale. The analytically pure product is easily isolated with a nearly quantitative yield by using a simple acid-base extraction workup and avoids any tedious chromatography. This protocol details the synthesis of a bisphosphite ligand (L1) that is a pivotal element of the catalytic system used, Rh(acac)(CO)2 with ligand L1, starting from commercial building blocks. The protocol also describes a general procedure for the preparative hydroformylation of vinylarene-2-carboxylic acid derivatives to 2-formylalkylarene products, providing a representative example for the hydroformylation of 2-vinylbenzoic acid (1a) to 2-(3-oxopropane)-benzoic acid (2a). The synthesis of L1 (six chemical reactions) uses 2-nitrophenylhydrazine, 4-benzyloxybenzoylchloride and (S)-binol, and takes 5-7 working days. The actual hydroformylation reaction of each vinyl arene derivative takes ~4 h of active effort over a period of 1-3 d. PMID- 24762787 TI - Calcium involved in the poly(gamma-glutamic acid)-mediated promotion of Chinese cabbage nitrogen metabolism. AB - Plant growth can reportedly be promoted by poly(gamma-glutamic acid) (gamma-PGA). However, the underlying mechanism is unknown. To reveal the mechanism of gamma PGA, we designed an experiment that investigated the effect of gamma-PGA on the nitrogen metabolism of Chinese cabbage hydroponic cultured at different calcium (Ca) levels and varied exogenous Ca(2+) inhibitors. The results showed that nitrate reductase (NR), glutamine synthetase (GS), glutamate synthase, and glutamate dehydrogenase activities in leaves and roots were obviously enhanced by gamma-PGA at the normal Ca(2+) level (4.0 mM). Meanwhile, gamma-PGA increased the content of total nitrogen, soluble protein, and soluble amino acids in leaves. However, the promotional effect of gamma-PGA on fresh weight weakened when Ca(2+) was inadequate. Moreover, gamma-PGA not only induced the influx of extracellular Ca(2+) and Ca(2+) in organelles into cytoplasm, but also increased the Ca(2+) ATPase level to modify Ca(2+) homeostasis in plant cells. In addition, exogenous Ca(2+) inhibitors significantly suppressed the gamma-PGA-mediated promotion of cytoplasmic free Ca(2+) level, calmodulin (CaM) content, GS and glutamate dehydrogenase activities. In summary, gamma-PGA accelerated the nitrogen metabolism of plants through the Ca(2+)/CaM signaling pathway, thereby improving the growth of the plant. PMID- 24762788 TI - SnRK1 is differentially regulated in the cotyledon and embryo axe of bean (Phaseolus vulgaris L) seeds. AB - SnRK1 activity is developmentally regulated in bean seeds and exhibits a transient increase with the highest value at 20 days after anthesis (DAA), which coincides with the beginning of protein and starch accumulation. The catalytic subunit of SnRK1 shows a consistent decrease throughout the seed development period. However, by 15 DAA a significant proportion of the catalytic subunit appears phosphorylated. The increase in activity and phosphorylation of the catalytic subunit coincides with a decrease in hexoses. However, SnRK1 activity is differentially regulated in the cotyledon and embryo axe, where a larger proportion of the catalytic subunit is phosphorylated. SnRK1 obtained from endosperm extract is inhibited by T6P and to a lesser extent by ADPG and UDPG, whereas the enzyme isolated from embryo is virtually insensitive to T6P but exhibits some inhibition by ADPG and UDPG. In cotyledon extracts, the effects of T6P and ADPG on SnRK1 activity are additive, whereas in embryo extract, T6P inhibits the enzyme only when ADPG is present. After fractionation on Sephacryl S300, SnRK1 activity obtained from cotyledon extracts is detected as a single peak associated with a molecular weight of 250 kDa whereas that obtained form embryo axe extracts detected as 2 peaks associated with molecular weight of 250 and 180 kDa. In both cases, the catalytic subunit exhibits a wide distribution but is concentrated in the fractions with the highest activity. To analyse the composition of the complex, cotyledon and embryo extracts were treated with a reversible crosslinker (DSP). DSP induced the formation of complexes with molecular weights of 97 and 180 kDa in the cotyledon and embryo extracts, respectively. Since all the phosphorylated catalytic subunit is present in the complexes induced by DSP, it appears that the phosphorylation favors its interaction with other proteins. PMID- 24762790 TI - Nurse's cap: taking a walk on the white side. PMID- 24762789 TI - Induction of associative olfactory memory by targeted activation of single olfactory neurons in Drosophila larvae. AB - It has been postulated that associative memory is formed by at least two sets of external stimuli, CS and US, that are transmitted to the memory centers by distinctive conversing pathways. However, whether associative memory can be induced by the activation of only the olfactory CS and a biogenic amine-mediated US pathways remains to be elucidated. In this study, we substituted the reward signals with dTrpA1-mediated thermogenetic activation of octopaminergic neurons and the odor signals by ChR2-mediated optical activation of a specific class of olfactory neurons. We show that targeted activation of the olfactory receptor and the octopaminergic neurons is indeed sufficient for the formation of associative olfactory memory in the larval brain. We also show that targeted stimulation of only a single type of olfactory receptor neurons is sufficient to induce olfactory memory that is indistinguishable from natural memory induced by the activation of multiple olfactory receptor neurons. PMID- 24762791 TI - Time is of the essence: retain your older nurses. PMID- 24762792 TI - Resolving conflict by setting ground rules. PMID- 24762793 TI - When in doubt, don't! PMID- 24762794 TI - Risk management revisited. PMID- 24762796 TI - Risk for compromised human dignity: the nursing challenge. PMID- 24762797 TI - Building nurse leader relationships. PMID- 24762799 TI - Reeling in RNs with a residency program. PMID- 24762800 TI - Leadership Q&A. Measuring your culture of patient safety. PMID- 24762801 TI - On-farm evaluation of methods to assess welfare of gestating sows. AB - The objectives were to evaluate quantitative animal-based measures of sow welfare (lameness, oral stereotypies and reactivity to humans) under commercial farm conditions, and to estimate the influence of housing, sow parity and stage of gestation on the outcome of these measures. Across 10 farms, 311 sows were used. Farms differed in terms of housing design (pen v. stall), space allowance, floor type in stalls (partially v. fully slatted), and feeding system in pens (floor v. trough). Lameness was assessed in terms of gait score, walking speed, stride length, stepping behaviour, response to a stand-up test and latency to lie down after feeding. The presence of oral stereotypies and saliva foam were recorded. Reactivity to humans was assessed by approach (attempt to touch the sow between the ears) and handling tests (exit of the stall for stall-housed sows, or isolation of the animal for pen-housed sows). Only stride length and walking speed were associated with lameness in stall-housed sows (P<0.05 and P<0.01). In stalls, the probability that a sow was lame when it presented a short stride length (<83 cm) or a low speed (<1 m/s) was high (69% and 72%, respectively), suggesting that these variables were good indicators of lameness, but were not sufficient to detect every lame sow in a herd (sensitivity of 0.39 and 0.71, respectively). The stage of gestation and parity also influenced measures of stride length and walking speed (P<0.05). Saliva foam around the mouth was associated with the presence of sham chewing and fixture biting (P<0.05). The probability that a sow presents sham chewing behaviour when saliva foam around her mouth was observed was moderate (63%) but was not sufficient to detect all sows with stereotypies (41%). A high discrimination index was obtained for behavioural measures (aggressions, escapes) and vocalisations during the approach test (stalls: 78.0 and 64.0; pens: 71.9 and 75.0, respectively), the number of interventions needed to make the sow exit the stall during the handling test for stall-housed sows (74.9), and attempts to escape during the handling test for pen housed sows (96.9). These results suggest that these measures have a good power to discriminate between sows with low and high reactivity to humans. Finally, the outcome of several measures of lameness, stereotypies and reactivity to humans were influenced by the housing characteristics, sow parity and stage of gestation. Therefore, these factors should be considered to avoid misinterpretations of these measures in terms of welfare. PMID- 24762786 TI - Quality control and conduct of genome-wide association meta-analyses. AB - Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete. PMID- 24762802 TI - Magnetocrystalline anisotropy energy for adatoms and monolayers on non-magnetic substrates: where does it come from? AB - The substrate contribution to the magnetic anisotropy energy (MAE) of supported nanostructures can be assessed by a site-selective manipulation of the spin-orbit coupling (SOC) and of the effective exchange field Bex. A systematic study of Co adatoms and Co monolayers on the (1 1 1) surfaces of Cu, Ag, Au, Pd and Pt is performed to study common trends in this class of materials. It is found that for adatoms, the influence of the substrate SOC and Bex is relatively small (10-30% of the MAE) while for monolayers, this influence can be substantial. The influence of the substrate SOC is much more important than the influence of the substrate Bex, except for highly polarizable substrates with a strong SOC (such as Pt). The substrate always promotes the tendency to an out-of-plane orientation of the easy magnetic axis for all the investigated systems. PMID- 24762803 TI - Aquaporins are critical for provision of water during lactation and intrauterine progeny hydration to maintain tsetse fly reproductive success. AB - Tsetse flies undergo drastic fluctuations in their water content throughout their adult life history due to events such as blood feeding, dehydration and lactation, an essential feature of the viviparous reproductive biology of tsetse. Aquaporins (AQPs) are transmembrane proteins that allow water and other solutes to permeate through cellular membranes. Here we identify tsetse aquaporin (AQP) genes, examine their expression patterns under different physiological conditions (blood feeding, lactation and stress response) and perform functional analysis of three specific genes utilizing RNA interference (RNAi) gene silencing. Ten putative aquaporins were identified in the Glossina morsitans morsitans (Gmm) genome, two more than has been previously documented in any other insect. All organs, tissues, and body parts examined had distinct AQP expression patterns. Two AQP genes, gmmdripa and gmmdripb ( = gmmaqp1a and gmmaqp1b) are highly expressed in the milk gland/fat body tissues. The whole-body transcript levels of these two genes vary over the course of pregnancy. A set of three AQPs (gmmaqp5, gmmaqp2a, and gmmaqp4b) are expressed highly in the Malpighian tubules. Knockdown of gmmdripa and gmmdripb reduced the efficiency of water loss following a blood meal, increased dehydration tolerance and reduced heat tolerance of adult females. Knockdown of gmmdripa extended pregnancy length, and gmmdripb knockdown resulted in extended pregnancy duration and reduced progeny production. We found that knockdown of AQPs increased tsetse milk osmolality and reduced the water content in developing larva. Combined knockdown of gmmdripa, gmmdripb and gmmaqp5 extended pregnancy by 4-6 d, reduced pupal production by nearly 50%, increased milk osmolality by 20-25% and led to dehydration of feeding larvae. Based on these results, we conclude that gmmDripA and gmmDripB are critical for diuresis, stress tolerance and intrauterine lactation through the regulation of water and/or other uncharged solutes. PMID- 24762804 TI - The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds. AB - BACKGROUND: The ARTISTIC (A Randomised Trial In Screening To Improve Cytology) trial originally reported after two rounds of primary cervical screening with human papillomavirus (HPV). Extended follow-up of the randomised trial cohort through a third round could provide valuable insight into the duration of protection of a negative HPV test, which could allow extended screening intervals. If HPV primary screening is to be considered in the national programme, then determining its cost-effectiveness is key, and a detailed economic analysis using ARTISTIC data is needed. AIMS/OBJECTIVES: (1) To determine the round 3 and cumulative rates of cervical intraepithelial neoplasia (CIN) grade 2 or worse (2+) and CIN grade 3 or worse (CIN3+) between the revealed and concealed arms of ARTISTIC after three screening rounds over 6 years. (2) To compare the cumulative incidence of CIN2+ over three screening rounds following negative screening cytology with that following negative baseline HPV. (3) To determine whether or not HPV screening could safely extend the screening interval from 3 to 6 years. (4) To study the potential clinical utility of an increased cut-off of 2 relative light unit/mean control (RLU/Co) for Hybrid Capture 2 (HC2) and HPV genotyping in primary cervical screening. (5) To determine the potential impact of HPV vaccination with CervarixTM in terms of preventing abnormal cytology and CIN2+. (6) To determine the cost-effectiveness of HPV primary screening compared with current practice using cervical cytology in England. DESIGN: The ARTISTIC study cohort was recalled for a third round of screening 3 years after round 2 and 6 years following their enrolment to the study. Both arms of the original trial used a single protocol during round 3. SETTING: ARTISTIC study cohort undergoing cervical screening in primary care in Greater Manchester, UK. PARTICIPANTS: Between July 2007 and September 2009, 8873 women participated in round 3; 6337 had been screened in round 2 and 2536 had not been screened since round 1. INTERVENTIONS: All women underwent liquid-based cytology and HPV testing and genotyping. Colposcopy was offered to women with moderate dyskaryosis or worse and with HPV-positive mild dyskaryosis/borderline changes. Women with negative cytology or HPV-negative mild dyskaryosis/borderline changes were returned to routine recall. MAIN OUTCOME MEASURES: Principal outcomes were cumulative rates of CIN2+ over three screening rounds by cytology and HPV status at entry; HPV type specific rates of CIN2+; effect of age on outcomes correlated with cytology and HPV status; comparison of HC2 cut-off RLU/Co of both 1 and 2; and cost-effectiveness of HPV primary screening. RESULTS: The median duration of follow-up was 72.7 months in round 3. Over the three screening rounds, there was no significant difference in CIN2+ [odds ratio (OR): 1.06, 95% confidence interval (CI) 0.89 to 1.26, p = 0.5)] or CIN3+ (OR: 0.90, 95% CI 0.72 to 1.14, p = 0.4) rates between the trial arms (revealed vs. concealed). Overall, 16% of women were HC2 positive at entry, decreasing from 40% in women aged 20-24 years to around 7% in women aged over 50 years. Abnormal cytology rates at entry were 13% for borderline+ and 2% for moderate+ cytology. Following positive cytology at entry, the cumulative rate of CIN2+ was 20.5%, and was 20.1% following a HPV positive result at baseline. The cumulative CIN2+ rate for women who were HPV negative at baseline was only 0.87% (95% CI 0.70% to 1.06%) after three rounds of screening, significantly lower than that for women with negative cytology, which was 1.41% (95% CI 1.19% to 1.65%). Women who were HPV negative at baseline had similar protection from CIN2+ after 6 years as women who were cytology negative at baseline after 3 years. Women who were HPV positive/cytology negative at baseline had a cumulative CIN2+ rate at 6 years of 7.7%, significantly higher than that for women who were cytology positive/HPV negative (3.2%). Women who were HPV type 16 positive at baseline had a cumulative CIN2+ rate over three rounds of 43.6% compared with 20.1% for any HPV-positive test. Using a HC2 cut off of RLU/Co >= 2 would maintain acceptable sensitivity and result in 16% fewer HPV-positive results. Typing data suggested that around 55-60% of high-grade cytology and CIN2+, but less than 25% of low-grade cytology, would be prevented by HPV vaccine given current rates of coverage in the UK national programme. For the cost-effectiveness analysis, most of the primary HPV strategies examined where HPV was used as the sole primary test were cost saving in both unvaccinated and vaccinated cohorts under baseline cost assumptions, with a 7-18% reduction in annual screening-associated costs in unvaccinated cohorts and a 9-22% reduction for vaccinated cohorts. Utilising partial genotyping at the primary screening stage to identify women with HPV 16/18 and referring them to colposcopy was the most effective strategy (barring co-testing, which is significantly more costly than any other strategies considered), resulting in 83 additional life-years per 100,000 women for unvaccinated women when compared with current practice, and similar life-years saved compared with current practice for vaccinated women. In unvaccinated cohorts, however, this genotyping strategy is predicted to result in a 20% increase in the number of colposcopies performed in England, although in vaccinated cohorts the number of colposcopy referrals was predicted to be lower than in current practice. For all strategies in which HPV is used as the sole primary screening test, decreasing the follow-up interval for intermediate-risk women from 24 to 12 months increased the overall effectiveness of primary HPV screening. In exploratory analysis, strategies for which cytology screening was retained until either age 30 or 35 years, and for which HPV testing was used at older ages, were predicted to be of higher costs and intermediate effectiveness than those associated with full implementation of primary HPV screening from age 25 years. However, this finding should be interpreted with caution as it depends on assumptions made about screening behaviour and compliance with recommendations at the 'switch over' point. CONCLUSIONS: HPV testing as an initial screen was significantly more protective over three rounds (6 years) than the current practice of cytology and the use of primary HPV screening could allow a safe lengthening of the screening interval. A substantial decrease in high-grade cytology and CIN2+ can be expected as a consequence of the HPV vaccination programme. A HC2 cut-off of 2RLU/Co instead of the manufacturer's recommended cut off of 1 would be clinically beneficial in terms of an optimal balance between sensitivity and specificity. Modelled analysis predicts that primary HPV screening would be both more effective and cost saving compared with current practice with cervical cytology for a number of potential strategies in both unvaccinated and vaccinated cohorts. Compliance with surveillance and optimal management of HPV-positive/cytology-negative women after primary HPV screening is of key importance. Limitations of the economic investigation included the need to make assumptions around compliance with screening attendance and follow-up for longer screening intervals in the future, assumptions regarding maintenance of current uptake vaccination in the future, and assumptions regarding the stability of cost of HPV and cytology tests in the future. Detailed sensitivity analysis across a range of possible assumptions was conducted to address these issues. This study and the economic evaluation lend support to convert from cytology to HPV-based screening. Future work should include researching (i) the attitudes of women who test HPV positive/cytology negative, (ii) the value of complementary biomarkers and (iii) activities relevant to primary HPV screening in unvaccinated and vaccinated populations from the point of view of QALY assessment. STUDY REGISTRATION: Current Controlled Trials ISRCTN25417821. PMID- 24762805 TI - Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. AB - BACKGROUND: Sick sinus syndrome (SSS) is a common arrhythmia often associated with aging or organic heart diseases but may also occur in a familial form with a variable mode of inheritance. Despite the identification of causative genes, including cardiac Na channel (SCN5A), the pathogenesis and molecular epidemiology of familial SSS remain undetermined primarily because of its rarity. METHODS AND RESULTS: We genetically screened 48 members of 15 SSS families for mutations in several candidate genes and determined the functional properties of mutant Na channels using whole-cell patch clamping. We identified 6 SCN5A mutations including a compound heterozygous mutation. Heterologously expressed mutant Na channels showed loss-of-function properties of reduced or no Na current density in conjunction with gating modulations. Among 19 family members with SCN5A mutations, QT prolongation and Brugada syndrome were associated in 4 and 2 individuals, respectively. Age of onset in probands carrying SCN5A mutations was significantly less (mean+/-SE, 12.4+/-4.6 years; n=5) than in SCN5A-negative probands (47.0+/-4.6 years; n=10; P<0.001) or nonfamilial SSS (74.3+/-0.4 years; n=538; P<0.001). Meta-analysis of SSS probands carrying SCN5A mutations (n=29) indicated profound male predominance (79.3%) resembling Brugada syndrome but with a considerably earlier age of onset (20.9+/-3.4 years). CONCLUSIONS: The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations. PMID- 24762806 TI - Number needed to entrain: a new criterion for entrainment mapping in patients with intra-atrial reentrant tachycardia. AB - BACKGROUND: Measuring postpacing intervals (PPIs) is the standard maneuver for localizing reentrant tachycardia circuits. However, changes or termination of the tachycardia during entrainment pacing, or difficulties in defining the correct local activity, limit the use of PPIs. METHODS AND RESULTS: We hypothesized that the number of pacing stimuli needed to entrain (NNE) was useful for mapping intra atrial reentrant tachycardias. First, 10 patients with typical atrial flutter were studied to characterize the NNE. Next, 317 entrainment attempts in 30 patients with 76 intra-atrial reentrant tachycardias were analyzed to determine the efficacy of the NNE. The NNE was small at sites within the reentrant circuit (median 2) and large at remote sites during typical atrial flutter. The NNE depended on the pacing cycle length and coupling interval of the initial paced beat, where the NNE became smaller at shorter pacing cycle lengths and coupling intervals. The NNE highly correlated with the difference between the PPI and tachycardia cycle length (r = 0.906; P<0.001). When the pacing cycle length and coupling interval were 16 to 30 ms below the tachycardia cycle length, a NNE <=2 and >3 predicted a PPI-tachycardia cycle length <=20 and >20 ms, respectively, with 100% accuracy. Thirty-six (11%) entrainment attempts changed or terminated intra-atrial reentrant tachycardia. Importantly, the NNE remained valid in those cases. Furthermore, the NNE provided additional information in cases with some difficulties with PPI measurements. CONCLUSIONS: The NNE is a simple and reliable criterion, which facilitates mapping intra-atrial reentrant tachycardia. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT001747. PMID- 24762807 TI - Inter-relationship between electrocardiographic left ventricular hypertrophy and QT prolongation as predictors of increased risk of mortality in the general population. AB - BACKGROUND: Prolonged-QT commonly coexists in the ECG with left ventricular hypertrophy (ECG-LVH). However, it is unclear whether to what extent QT prolongation coexisting with ECG-LVH can explain the prognostic significance of ECG-LVH, and whether prolonged-QT coexisting with ECG-LVH should be considered as an innocent consequence of ECG-LVH. METHODS AND RESULTS: The study population consisted of 7506 participants (mean age, 59.4+/-13.3 years; 49% whites; and 47% men) from the US Third National Health and Nutrition Examination Survey. ECG-LVH was defined by Cornell voltage criteria. Prolonged heart-rate-adjusted QT (prolonged-QTa) was defined as QTa>=460 ms in women or 450 ms in men. Cox proportional hazards analysis was used to calculate the hazard ratios with 95% confidence intervals for the risk of all-cause mortality for various combinations of ECG-LVH and prolonged-QTa. ECG-LVH was present in 4.2% (N=312) of the participants, of whom 16.4% had prolonged-QTa. In a multivariable-adjusted model and compared with the group without ECG-LVH or prolonged-QTa, mortality risk was highest in the group with concomitant ECG-LVH and prolonged-QTa (hazard ratio, 1.63; 95% confidence interval, 1.12-2.36), followed by isolated ECG-LVH (1.48; 1.24-1.77), and then isolated prolonged-QTa (1.27; 1.12-1.46). In models with similar adjustment where ECG-LVH and prolonged-QTa were entered as 2 separate variables and subsequently additionally adjusted for each other, the mortality risk was essentially unchanged for both variables. CONCLUSIONS: Although prolonged-QT commonly coexists with LVH, both are independent markers of poor prognosis. Concomitant presence of prolonged-QT and ECG-LVH carries a higher risk than either predictor alone. PMID- 24762808 TI - Assessment of the vasodepressor reflex in carotid sinus syndrome. AB - BACKGROUND: Assessment of the vasodepressor reflex in carotid sinus syndrome is influenced by the method of execution of the carotid sinus massage and the coexistence of the cardioinhibitory reflex. METHODS AND RESULTS: Carotid sinus massage reproduced spontaneous symptoms in 164 patients in the presence of hypotension or bradycardia (method of symptoms). When an asystolic pause was induced, the vasodepressor reflex was reassessed after suppression of the asystolic reflex by means of 0.02 mg/kg IV atropine. An isolated vasodepressor form was found in 32 (20%) patients, who had lowest systolic blood pressure (SBP) of 65+/-15 mm Hg. Of these, only 21 (66%) patients had an SBP fall >=50 mm Hg, which is the universally accepted cut-off value for the diagnosis of the vasodepressor form. Conversely, a lowest SBP value of <=85 mm Hg (corresponding to the fifth percentile) detected 97% of vasodepressor patients, but was also present in 84% of the 132 patients with an asystolic reflex. These latter patients had both asystole >=3 s (mean 7.6+/-2.2 s) and SBP fall to 63+/-22 mm Hg: in 46 (28%) patients, symptoms persisted after atropine (mixed form), in the remaining 86 (52%) patients, symptoms did not (cardioinhibitory form) persist. CONCLUSIONS: The current definition of >=50 mm Hg SBP fall failed to identify one third of patients with isolated vasodepressor form. A cut-off value of symptomatic SBP of <=85 mm Hg seems more appropriate, but it is unable to identify cardioinhibitory forms. In asystolic forms, atropine testing is able to distinguish a cardioinhibitory form from a mixed form. PMID- 24762809 TI - Global hypomethylation and promoter methylation in small intestinal neuroendocrine tumors: an in vivo and in vitro study. AB - Aberrant DNA methylation is a feature of human cancer affecting gene expression and tumor phenotype. Here, we quantified promoter methylation of candidate genes and global methylation in 44 small intestinal-neuroendocrine tumors (SI-NETs) from 33 patients by pyrosequencing. Findings were compared with gene expression, patient outcome and known tumor copy number alterations. Promoter methylation was observed for WIF1, RASSF1A, CTNNB1, CXCL14, NKX2-3, P16, LAMA1, and CDH1. By contrast APC, CDH3, HIC1, P14, SMAD2, and SMAD4 only had low levels of methylation. WIF1 methylation was significantly increased (P = 0.001) and WIF1 expression was reduced in SI-NETs vs. normal references (P = 0.003). WIF1, NKX2 3, and CXCL14 expression was reduced in metastases vs. primary tumors (P<0.02). Low expression of RASSF1A and P16 were associated with poor overall survival (P = 0.045 and P = 0.011, respectively). Global methylation determined by pyrosequencing of LINE1 repeats was reduced in tumors vs. normal references, and was associated with loss in chromosome 18. The tumors fell into three clusters with enrichment of WIF1 methylation and LINE1 hypomethylation in Cluster I and RASSF1A and CTNNB1 methylation and loss in 16q in Cluster II. In Cluster III, these alterations were low-abundant and NKX2-3 methylation was low. Similar analyses in the SI-NET cell lines HC45 and CNDT2 showed methylation for CDH1 and WIF1 and/or P16, CXCL14, NKX2-3, LAMA1, and CTNNB1. Treatment with the demethylating agent 5-azacytidine reduced DNA methylation and increased expression of these genes in vitro. In conclusion, promoter methylation of tumor suppressor genes is associated with suppressed gene expression and DNA copy number alterations in SI-NETs, and may be restored in vitro. PMID- 24762811 TI - A crucial role for DOK1 in PDGF-BB-stimulated glioma cell invasion through p130Cas and Rap1 signalling. AB - DOK1 regulates platelet-derived growth factor (PDGF)-BB-stimulated glioma cell motility. Mechanisms regulating tumour cell motility are essential for invasion and metastasis. We report here that PDGF-BB-mediated glioma cell invasion and migration are dependent on the adaptor protein downstream of kinase 1 (DOK1). DOK1 is expressed in several glioma cell lines and in tumour biopsies from high grade gliomas. DOK1 becomes tyrosine phosphorylated upon PDGF-BB stimulation of human glioma cells. Knockdown of DOK1 or expression of a DOK1 mutant (DOK1FF) containing Phe in place of Tyr at residues 362 and 398, resulted in inhibition of both the PDGF-BB-induced tyrosine phosphorylation of p130Cas (also known as BCAR1) and the activation of Rap1. DOK1 colocalises with tyrosine phosphorylated p130Cas at the cell membrane of PDGF-BB-treated cells. Expression of a non tyrosine-phosphorylatable substrate domain mutant of p130Cas (p130Cas15F) inhibited PDGF-BB-mediated Rap1 activation. Knockdown of DOK1 and Rap1 inhibited PDGF-BB-induced chemotactic cell migration, and knockdown of DOK1 and Rap1 and expression of DOK1FF inhibited PDGF-mediated three-dimensional (3D) spheroid invasion. These data show a crucial role for DOK1 in the regulation of PDGF-BB mediated tumour cell motility through a p130Cas-Rap1 signalling pathway. [Corrected] PMID- 24762810 TI - Nutrient-driven O-GlcNAc cycling - think globally but act locally. AB - Proper cellular functioning requires that cellular machinery behave in a spatiotemporally regulated manner in response to global changes in nutrient availability. Mounting evidence suggests that one way this is achieved is through the establishment of physically defined gradients of O-GlcNAcylation (O-linked addition of N-acetylglucosamine to serine and threonine residues) and O-GlcNAc turnover. Because O-GlcNAcylation levels are dependent on the nutrient-responsive hexosamine signaling pathway, this modification is uniquely poised to inform upon the nutritive state of an organism. The enzymes responsible for O-GlcNAc addition and removal are encoded by a single pair of genes: both the O-GlcNAc transferase (OGT) and the O-GlcNAcase (OGA, also known as MGEA5) genes are alternatively spliced, producing protein variants that are targeted to discrete cellular locations where they must selectively recognize hundreds of protein substrates. Recent reports suggest that in addition to their catalytic functions, OGT and OGA use their multifunctional domains to anchor O-GlcNAc cycling to discrete intracellular sites, thus allowing them to establish gradients of deacetylase, kinase and phosphatase signaling activities. The localized signaling gradients established by targeted O-GlcNAc cycling influence many important cellular processes, including lipid droplet remodeling, mitochondrial functioning, epigenetic control of gene expression and proteostasis. As such, the tethering of the enzymes of O-GlcNAc cycling appears to play a role in ensuring proper spatiotemporal responses to global alterations in nutrient supply. PMID- 24762812 TI - RILP regulates vacuolar ATPase through interaction with the V1G1 subunit. AB - Rab-interacting lysosomal protein (RILP) is a downstream effector of the Rab7 GTPase. GTP-bound Rab7 recruits RILP to endosomal membranes and, together, they control late endocytic traffic, phagosome and autophagosome maturation and are responsible for signaling receptor degradation. We have identified, using different approaches, the V1G1 (officially known as ATP6V1G1) subunit of the vacuolar ATPase (V-ATPase) as a RILP-interacting protein. V1G1 is a component of the peripheral stalk and is fundamental for correct V-ATPase assembly. We show here that RILP regulates the recruitment of V1G1 to late endosomal and lysosomal membranes but also controls V1G1 stability. Indeed, we demonstrate that V1G1 can be ubiquitylated and that RILP is responsible for proteasomal degradation of V1G1. Furthermore, we demonstrate that alterations in V1G1 expression levels impair V-ATPase activity. Thus, our data demonstrate for the first time that RILP regulates the activity of the V-ATPase through its interaction with V1G1. Given the importance of V-ATPase in several cellular processes and human diseases, these data suggest that modulation of RILP activity could be used to control V ATPase function. PMID- 24762813 TI - A genome-scale in vivo RNAi analysis of epithelial development in Drosophila identifies new proliferation domains outside of the stem cell niche. AB - The Drosophila oogenesis system provides an excellent model to study the development of epithelial tissues. Here, we report the first genome-scale in vivo RNA interference (RNAi) screen for genes controlling epithelial development. By directly analysing cell and tissue architecture we identified 1125 genes, which we assigned to seven different functions in epithelial formation and homeostasis. We validated the significance of our screen by generating mutants for Vps60, a component of the endosomal sorting complexes required for transport (ESCRT) machinery. This analysis provided new insights into spatiotemporal control of cell proliferation in the follicular epithelium. Previous studies have identified signals controlling divisions in the follicle stem cell niche. However, 99% of cell divisions occur outside of the niche and it is unclear how these divisions are controlled. Our data distinguish two new domains outside of the stem cell niche where there are differing controls on proliferation. One domain abuts the niche and is characterised by ESCRT, Notch and JAK/STAT-mediated control of proliferation. Adjacent to this domain, another domain is defined by loss of the impact of ESCRT on cell division. Thus, during development epithelial cells pass through a variety of microenvironments that exert different modes of proliferation control. The switch between these modes might reflect a decrease in the 'stemness' of epithelial cells over time. PMID- 24762814 TI - Bcl-2 binds to and inhibits ryanodine receptors. AB - The anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein not only counteracts apoptosis at the mitochondria by scaffolding pro-apoptotic Bcl-2-family members, but also acts at the endoplasmic reticulum, thereby controlling intracellular Ca(2+) dynamics. Bcl-2 inhibits Ca(2+) release by targeting the inositol 1,4,5 trisphosphate receptor (IP3R). Sequence analysis has revealed that the Bcl-2 binding site on the IP3R displays strong similarity with a conserved sequence present in all three ryanodine receptor (RyR) isoforms. We now report that Bcl-2 co-immunoprecipitated with RyRs in ectopic expression systems and in native rat hippocampi, indicating that endogenous RyR-Bcl-2 complexes exist. Purified RyR domains containing the putative Bcl-2-binding site bound full-length Bcl-2 in pulldown experiments and interacted with the BH4 domain of Bcl-2 in surface plasmon resonance (SPR) experiments, suggesting a direct interaction. Exogenous expression of full-length Bcl-2 or electroporation loading of the BH4 domain of Bcl-2 dampened RyR-mediated Ca(2+) release in HEK293 cell models. Finally, introducing the BH4-domain peptide into hippocampal neurons through a patch pipette decreased RyR-mediated Ca(2+) release. In conclusion, this study identifies Bcl-2 as a new inhibitor of RyR-based intracellular Ca(2+)-release channels. PMID- 24762815 TI - The tumor suppressor APC differentially regulates multiple beta-catenins through the function of axin and CKIalpha during C. elegans asymmetric stem cell divisions. AB - The APC tumor suppressor regulates diverse stem cell processes including gene regulation through Wnt-beta-catenin signaling and chromosome stability through microtubule interactions, but how the disparate functions of APC are controlled is not well understood. Acting as part of a Wnt-beta-catenin pathway that controls asymmetric cell division, Caenorhabditis elegans APC, APR-1, promotes asymmetric nuclear export of the beta-catenin WRM-1 by asymmetrically stabilizing microtubules. Wnt function also depends on a second beta-catenin, SYS-1, which binds to the C. elegans TCF POP-1 to activate gene expression. Here, we show that APR-1 regulates SYS-1 levels in asymmetric stem cell division, in addition to its known role in lowering nuclear levels of WRM-1. We demonstrate that SYS-1 is also negatively regulated by the C. elegans homolog of casein kinase 1alpha (CKIalpha), KIN-19. We show that KIN-19 restricts APR-1 localization, thereby regulating nuclear WRM-1. Finally, the polarity of APR-1 cortical localization is controlled by PRY-1 (C. elegans Axin), such that PRY-1 controls the polarity of both SYS-1 and WRM-1 asymmetries. We propose a model whereby Wnt signaling, through CKIalpha, regulates the function of two distinct pools of APC - one APC pool negatively regulates SYS-1, whereas the second pool stabilizes microtubules and promotes WRM-1 nuclear export. PMID- 24762816 TI - Reproductive status of Onchocerca volvulus after ivermectin treatment in an ivermectin-naive and a frequently treated population from Cameroon. AB - BACKGROUND: For two decades, onchocerciasis control has been based on mass treatment with ivermectin (IVM), repeated annually or six-monthly. This drug kills Onchocerca volvulus microfilariae (mf) present in the skin and the eyes (microfilaricidal effect) and prevents for 3-4 months the release of new mf by adult female worms (embryostatic effect). In some Ghanaian communities, the long term use of IVM was associated with a more rapid than expected skin repopulation by mf after treatment. Here, we assessed whether the embryostatic effect of IVM on O. volvulus has been altered following frequent treatment in Cameroonian patients. METHODOLOGY: Onchocercal nodules were surgically removed just before (D0) and 80 days (D80) after a standard dose of IVM in two cohorts with different treatment histories: a group who had received repeated doses of IVM over 13 years, and a control group with no history of large-scale treatments. Excised nodules were digested with collagenase to isolate adult worms. Embryograms were prepared with females for the evaluation of their reproductive capacities. PRINCIPAL FINDINGS: Oocyte production was not affected by IVM. The mean number of intermediate embryos (morulae and coiled mf) decreased similarly in the two groups between D0 and D80. In contrast, an accumulation of stretched mf, either viable or degenerating, was observed at D80. However, it was observed that the increase in number of degenerating mf between D0 and D80 was much lower in the frequently treated group than in the control one (Incidence Rate Ratio: 0.25; 95% CI: 0.10-0.63; p = 0.003), which may indicate a reduced sequestration of mf in the worms from the frequently treated group. CONCLUSION/SIGNIFICANCE: IVM still had an embryostatic effect on O. volvulus, but the effect was reduced in the frequently treated cohort compared with the control population. PMID- 24762818 TI - Adherence to the Spanish dietary guidelines and its association with obesity in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Granada study. AB - OBJECTIVE: Dietary guidelines are intended to prevent chronic diseases and obesity. The aim of the present study was to develop a diet quality index based on the Spanish Food Pyramid (SFP) and to further explore its association with obesity in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Granada study. DESIGN: Cross-sectional study. The SFP score considered recommendations given for twelve food groups, and for physical activity and alcohol consumption. Obesity was defined as BMI over 30 kg/m2 and abdominal obesity as waist circumference larger than 102 cm (men) and 88 cm (women). Logistic regression was conducted to estimate odds ratios of obesity by quintiles and by 10-point increment in adherence to the score, controlling for potential confounders. SETTING: EPIC-Granada study. SUBJECTS: Participants (n 6717) aged 35 69 years (77 % women). RESULTS: A 10-point increase in adherence to the SFP score was associated with a 14 % (OR=0.86; 95 % CI 0.79, 0.94) lower odds of obesity in men (P interaction by sex=0.02). The odds of abdominal obesity decreased globally by 12 % (OR=0.88; 95 % CI 0.84, 0.93) per 10-point increase in adherence to this score. The effect of higher adherence to the score on abdominal obesity was stronger in physically inactive men and women (ORper 10-point increase=0.79; 95 % CI 0.68, 0.92 and ORper 10-point increase=0.89; 95 % CI 0.84, 0.95, respectively). CONCLUSIONS: These findings support that the Spanish dietary guidelines might be an effective tool for obesity prevention. However, prospective studies investigating this association are warranted. PMID- 24762817 TI - Emerging role of the calcium-activated, small conductance, SK3 K+ channel in distal tubule function: regulation by TRPV4. AB - The Ca2+-activated, maxi-K (BK) K+ channel, with low Ca2+-binding affinity, is expressed in the distal tubule of the nephron and contributes to flow-dependent K+ secretion. In the present study we demonstrate that the Ca2+-activated, SK3 (KCa2.3) K+ channel, with high Ca2+-binding affinity, is also expressed in the mouse kidney (RT-PCR, immunoblots). Immunohistochemical evaluations using tubule specific markers demonstrate significant expression of SK3 in the distal tubule and the entire collecting duct system, including the connecting tubule (CNT) and cortical collecting duct (CCD). In CNT and CCD, main sites for K+ secretion, the highest levels of expression were along the apical (luminal) cell membranes, including for both principal cells (PCs) and intercalated cells (ICs), posturing the channel for Ca2+-dependent K+ secretion. Fluorescent assessment of cell membrane potential in native, split-opened CCD, demonstrated that selective activation of the Ca2+-permeable TRPV4 channel, thereby inducing Ca2+ influx and elevating intracellular Ca2+ levels, activated both the SK3 channel and the BK channel leading to hyperpolarization of the cell membrane. The hyperpolarization response was decreased to a similar extent by either inhibition of SK3 channel with the selective SK antagonist, apamin, or by inhibition of the BK channel with the selective antagonist, iberiotoxin (IbTX). Addition of both inhibitors produced a further depolarization, indicating cooperative effects of the two channels on Vm. It is concluded that SK3 is functionally expressed in the distal nephron and collecting ducts where induction of TRPV4-mediated Ca2+ influx, leading to elevated intracellular Ca2+ levels, activates this high Ca2+-affinity K+ channel. Further, with sites of expression localized to the apical cell membrane, especially in the CNT and CCD, SK3 is poised to be a key pathway for Ca2+-dependent regulation of membrane potential and K+ secretion. PMID- 24762819 TI - Microvascular dysfunction: genetic polymorphisms suggest sex-specific differences in disease phenotype. PMID- 24762820 TI - Revascularization choices for complex coronary artery disease: all is not what it seems. PMID- 24762821 TI - [Validation of emotional stress stimuli in 50-to-80-year-old French-Quebecers]. AB - Few batteries of prosodic stimuli testing have been validated for Quebec-French people. Such validation is necessary to develop auditory-verbal tasks in this population. The objective of this study was to validate a battery of emotional prosodic stimuli for French-Quebec aging subjects. The battery of 195 stimuli, which was elaborated by Maurage et al. (2007), is composed of 195 prosodic stimuli and was administrated to 50 healthy Quebecers aged 50-to-80 years. The percentages of good responses were calculated for each stimulus. For each emotion, Cronbach's alphas were calculated to evaluate the internal consistency of the stimuli. Results showed that among the 195 stimuli, 40 were correctly recognized by at least 80 per cent of the subjects. Anger was the emotion that was most correctly identified by the participants, while recognition of disgust was the least recognised. Overall, this study provides data that will guide the selection of prosodic stimuli in evaluating French-Quebecois. PMID- 24762825 TI - Innate immunity: skin fibroblasts shield mast cells. PMID- 24762828 TI - Reply to - IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. PMID- 24762827 TI - Innate immunity to influenza virus infection. AB - Influenza viruses are a major pathogen of both humans and animals. Recent studies using gene-knockout mice have led to an in-depth understanding of the innate sensors that detect influenza virus infection in a variety of cell types. Signalling downstream of these sensors induces distinct sets of effector mechanisms that block virus replication and promote viral clearance by inducing innate and adaptive immune responses. In this Review, we discuss the various ways in which the innate immune system uses pattern recognition receptors to detect and respond to influenza virus infection. We consider whether the outcome of innate sensor stimulation promotes antiviral resistance or disease tolerance, and propose rational treatment strategies for the acute respiratory disease that is caused by influenza virus infection. PMID- 24762829 TI - IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. PMID- 24762830 TI - Systems thinking applied to safety during manual handling tasks in the transport and storage industry. AB - Injuries resulting from manual handling tasks represent an on-going problem for the transport and storage industry. This article describes an application of a systems theory-based approach, Rasmussen's (1997. Safety Science 27, 183), risk management framework, to the analysis of the factors influencing safety during manual handling activities in a freight handling organisation. Observations of manual handling activities, cognitive decision method interviews with workers (n=27) and interviews with managers (n=35) were used to gather information about three manual handling activities. Hierarchical task analysis and thematic analysis were used to identify potential risk factors and performance shaping factors across the levels of Rasmussen's framework. These different data sources were then integrated using Rasmussen's Accimap technique to provide an overall analysis of the factors influencing safety during manual handling activities in this context. The findings demonstrate how a systems theory-based approach can be applied to this domain, and suggest that policy-orientated, rather than worker orientated, changes are required to prevent future manual handling injuries. PMID- 24762831 TI - Tactile surgical navigation system for complex acetabular fracture surgery. AB - The authors describe a tactile surgical navigation system using custom 3 dimensional (3D) models of the bony pelvis for complex acetabular fracture surgery. The bone area of interest was extracted from the Digital Imaging and Communications in Medicine (DICOM) data of computed tomography scans. A standard triangulated language file was used to create 3D models of the bony pelvis by layered manufacturing using a 3D printer and non-cytotoxic, sterilizable, acrylic based photopolymers. No infections and no toxic or other adverse events were observed. The models were useful for preoperative assessment, planning, and simulation; intraoperative assessment; obtaining informed consent; and education. PMID- 24762832 TI - Percutaneous femoral derotational osteotomy for excessive femoral torsion. AB - Femoral derotational osteotomy is an acceptable treatment for excessive femoral torsion. The described procedure is a minimally invasive single-incision technique based on an intramedullary saw that enables an inside-out osteotomy, preserving the periosteum and biological activity in the local bone and soft tissue. After the osteotomy is complete and correction is achieved, an expandable intramedullary nail is used to achieve immediate stability, without the need for locking screws. Indications, tips, and pitfalls related to this novel osteotomy technique are discussed. PMID- 24762833 TI - Infection after primary total hip arthroplasty. AB - The number of primary total hip arthroplasties (THAs) performed in the United States each year continues to climb, as does the incidence of infectious complications. The changing profile of antibiotic-resistant bacteria has made preventing and treating primary THA infections increasingly complex. The goal of this review was to summarize (1) the published data concerning the risk of surgical site infection (SSI) after primary THA by type of bacteria and (2) the effect of potentially modifying factors. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, EMBASE, Web of Science, and PubMed were searched. Studies dated between 2001 and 2011 examining primary THA in adults were included. Meta analysis of the collected data was performed. The pooled SSI rate was 2.5% (95% confidence interval [Cl], 1.4%-4.4%; P<.001; n=28,883). The pooled deep prosthetic joint infection (PJI) rate was 0.9% (95% Cl, 0.4%-2.2%; P<.001; n=28,883). The pooled rate of methicillin-resistant Staphylococcus aureus SSI was 0.5% (95% Cl, 0.2%-1.5%; P<.001; n=26,703). This is approximately 20% of all SSI cases. The pooled rate of intraoperative bacterial wound contamination was 16.9% (95% Cl, 6.6%-36.8%; P=.003; n=2180). All these results had significant heterogeneity. The postoperative risk of SSI was significantly associated with intraoperative bacterial surgical wound contamination (pooled rate ratio, 2.5; 95% Cl, 1.4%-4.6%; P=.001; n=19,049). PMID- 24762834 TI - Effect of chondral defect size, shape, and location on MRI diagnostic performance in the porcine knee. AB - The purpose of this study was to determine the sensitivity and positive predictive value of magnetic resonance imaging (MRI) in the identification of full-thickness articular cartilage defects in the porcine knee. Seventy-two full thickness chondral defects (small or large; circular, oval, or triangular) were created in 12 porcine knees. The authors used 3.0-T MRI with 3-dimensional gradient echo water-selective/fluid (WATSf) sequences acquired in axial, coronal, and sagittal planes. Sensitivity and positive predictive value parameters were calculated for 2 readers. Magnetic resonance imaging was highly sensitive for detection of full-thickness defects in the knee (85%). The highest sensitivity was observed at the medial femoral condyle (93%), while the lowest was observed at the medial patella (71%). The sensitivities for detecting different shapes were unique to each shape, with oval lesions identified with greatest sensitivity (93%). Small lesions (86%) were detected at a similar sensitivity as large lesions (83%). The positive predictive values for accurate true-positive reads were low for all lesion shapes (18%-57%) and moderate for small (69%) and large (59%) sizes, with significant differences observed between the 2 readers. Magnetic resonance imaging has a high sensitivity in the detection of full thickness articular cartilage defects in the porcine knee. Variability in defect shape and intra-articular location affects MRI sensitivity, while size does not. Magnetic resonance imaging was not effective in describing lesion shape or size. Further, there was subjectivity in reading defect shape and size between 2 radiologists. PMID- 24762835 TI - Intraoperative CT in the assessment of posterior wall acetabular fracture stability. AB - Posterior wall acetabular fractures that involve 10% to 40% of the posterior wall may or may not require an open reduction and internal fixation. Dynamic stress examination of the acetabular fracture under fluoroscopy has been used as an intraoperative method to assess joint stability. The aim of this study was to demonstrate the value of intraoperative ISO computed tomography (CT) examination using the Siemens ISO-C imaging system (Siemens Corp, Malvern, Pennsylvania) in the assessment of posterior wall acetabular fracture stability during stress examination under anesthesia. In 5 posterior wall acetabular fractures, standard fluoroscopic images (including anteroposterior pelvis and Judet radiographs) with dynamic stress examinations were compared with the ISO-C CT imaging system to assess posterior wall fracture stability during stress examination. After review of standard intraoperative fluoroscopic images under dynamic stress examination, all 5 cases appeared to demonstrate posterior wall stability; however, when the intraoperative images from the ISO-C CT imaging system demonstrated that 1 case showed fracture instability of the posterior wall segment during stress examination, open reduction and internal fixation was performed. The use of intraoperative ISO CT imaging has shown an initial improvement in the surgeon's ability to assess the intraoperative stability of posterior wall acetabular fractures during stress examination when compared with standard fluoroscopic images. PMID- 24762836 TI - A meta-analysis of reamed versus unreamed intramedullary nailing for the treatment of closed tibial fractures. AB - Controversy exists regarding the clinical outcomes of reamed vs unreamed intramedullary nailing in the treatment of closed tibial fractures. This study assessed the effects of reamed vs unreamed intramedullary nailing for closed tibial fractures. The authors searched PubMed, EMBASE, BIOSIS, and the Cochrane Controlled Trials Register for randomized and quasi-randomized controlled clinical trials from January 1980 to June 2012 comparing reamed with unreamed intramedullary nailing for closed tibial fracture in adults. Primary outcomes were nonunion, delayed union, malunion, secondary procedure, failure of implants, compartment syndrome, infection, and knee pain. Eight randomized and 1 quasi randomized clinical trials (1229 fractures) were included. No statistically significant differences were found between reamed and unreamed nailing groups in delayed union (P=.20), malunion (P=.28), infection (P=.36), compartment syndrome (P=.36), and knee pain (P=.93). The unreamed group had a higher rate of fracture nonunion than the reamed group (P=.02). The subgroup analysis of implant failures (broken screws vs broken nails) indicated that reamed nailing significantly reduced the risk of screw breakage (P<.001); however, there was no significant difference between reamed and unreamed intramedullary nailing in nail breakage (P=.94). The subgroup analysis of a secondary procedure showed that the reamed intramedullary nailing resulted in significantly lower risks of implant exchange (P=.01) and dynamization (P=.04); however, there was no significant difference in bone grafting rate (P=.73). Evidence comparing reamed with unreamed intramedullary nailing for closed tibial fractures indicates that reamed intramedullary nailing may lead to significantly lower risks of nonunion, screw failure, implant exchange, and dynamization without increasing operative complications. PMID- 24762837 TI - Microbial surface contamination after standard operating room cleaning practices following surgical treatment of infection. AB - At the authors' institution, some joint arthroplasty surgeons require the operating room to be terminally cleaned before using the room after infected cases, in theory to decrease exposure to excessive microbial contamination for the subsequent patient. The authors found no guidance in the literature to support this practice. To test this theory, the authors measured microbial surface contamination from 9 surfaces in operating rooms after standard operating room turnover following 14 infected cases vs 16 noninfected cases. A check was made for an association between organisms isolated intraoperatively from infected surgical patients immediately preceding standard cleaning and organisms isolated from common operating room surfaces. Colony counts were made at 24 and 48 hours, and organisms were identified. No significant difference was noted in colony counts between infected and noninfected cases, and no relationship was found between organisms isolated from infected cases and those from operating room surfaces. Furthermore, the largest colony count from both groups (0.08 cfu/cm(2)) was an order of magnitude less than the recently proposed 5 cfu/cm(2) threshold for surface hygiene in hospitals. This finding indicates that standard operating room turnover results in minimal surface contamination, regardless of the previous case's infection status, and that there is no need for a more extensive terminal cleaning after an infected case. PMID- 24762838 TI - Proximally coated cementless bipolar hemiarthroplasty in Dorr type C bone. AB - The current study was conducted to examine the clinical and radiographic outcomes of cementless bipolar arthroplasty in patients who had type C bone at the time of the procedure. A total of 87 patients (105 hips) who had type C femora and had undergone cementless bipolar hemiarthroplasty with a proximally coated cementless prosthesis for the treatment of displaced femoral neck fractures at a single institution were reviewed. Patients included 83 women and 4 men who had a mean age of 84 years (range, 72-100 years) and were followed for a mean of 6 years (range, 2-11 years). Outcomes evaluated included aseptic implant survivorship, surgical complications, Harris Hip scores, and radiographic findings. At final follow-up, there were no revisions for aseptic implant loosening. The overall aseptic implant survivorship was 95%, with 5 patients undergoing revision surgery for aseptic reasons. Three revisions were because of periprosthetic fractures after falls, 1 revision was because of intractable groin pain, and 1 revision was because of recurrent dislocations. The surgical complication rate was 8.5%, which included 3 septic revisions, 2 avulsion fractures of the greater trochanter after falls, 2 superficial wound infections, 1 recurrent dislocation, and 1 wound hematoma. The mean Harris Hip score had improved to 80 points (range, 30-97 points) at final follow-up. Despite generally poor bone quality and medical comorbidities, elderly patients with displaced femoral neck fractures achieved excellent clinical outcomes, with few perioperative complications, through the use of proximally coated cementless bipolar hemiarthroplasty. PMID- 24762839 TI - Mediolateral subchondral tibial bone mineral density difference does not predict osteoarthritis progression. AB - Data on the relationship between osteoporosis and osteoarthritis are conflicting. Most studies report "snapshot" prevalences, and there are few studies evaluating localized knee bone mineral density (BMD) measurements with respect to subsequent osteoarthritis progression. The authors hypothesize that increased mediolateral difference of the proximal tibial BMD may predict progression of knee osteoarthritis. In this study, 246 female volunteers were followed up prospectively over 2 years. Baseline BMD measurements of bilateral proximal (subchondral) tibiae were performed, and the mediolateral BMD ratio was calculated. Precision studies were performed on healthy volunteers to validate the technique. The patients were divided into osteoarthritis progressors and non progressors based on Kellgren-Lawrence radiographic criteria at 2-year follow-up. Patients who were taking bisphosphonates or who had a history of inflammatory, infectious, or metabolic bone disease and previous hip and knee surgery were excluded. Demographic data, calcium supplementation, physical activity, baseline knee radiographs, and radiographs at 2-year follow-up were obtained. The study was adequately powered to detect an effect size of 0.4. There were 121 progressors and 125 non-progressors. Mean mediolateral BMD ratio was 1.02 among the progressors and 1.01 among the non-progressors (t=0.632, P=.528). Potential confounders were equally distributed among both groups. The data suggest that there is no link between proximal tibial BMD ratio and progression of knee osteoarthritis. PMID- 24762840 TI - Free vascularized fibular grafting for patients receiving postoperative corticosteroids. AB - Free vascularized fibular grafting (FVFG) is an effective method to treat corticosteroid-induced osteonecrosis of the femoral head (ONFH). Some patients continued to receive maintenance doses of corticosteroids to treat the primary disease postoperatively. This study was performed to evaluate outcomes of FVFG for corticosteroid-induced ONFH in patients who continued to receive corticosteroids postoperatively. The authors retrospectively reviewed the records of 44 patients (78 hips) who had received corticosteroid treatment for their primary disease after FVFG. They were followed up for at least 2 years (mean, 5.6 years). Demographic details, Harris Hip scores, the Medical Outcomes Study 36 Item Short-Form Health Survey (SF-36), and radiographic data were collected and analyzed. The mean Harris Hip score for all hips was 70.9+/-9.9 points before surgery and increased to 84+/-12.1 points at the latest follow-up. There were also significant increases (P<.05) in physical component summary score and mental component summary score. According to the latest radiographic evaluation, 49 hips (62.8%) appeared improved, 10 hips (12.8%) appeared unchanged, and only 19 hips (24.4%) appeared worse. Seven hips (9%) underwent total hip arthroplasty during the follow-up period. Therefore, the results showed that FVFG was a viable method of treating corticosteroid-induced ONFH in patients who receive maintenance doses of corticosteroids postoperatively. PMID- 24762841 TI - Spinal epidural lipomatosis in lumbar magnetic resonance imaging scans. AB - The goal of this study was to quantify the frequency of advanced spinal epidural lipomatosis (SEL) detected on lumbar magnetic resonance imaging (MRI) scans performed at the authors' hospital and to compare the frequency, cause, and progression of SEL in these cases with that reported in the literature. The total number of MRI examinations of the lumbar spine performed at this hospital over 45 months was 1498 (705 men and 793 women; mean age, 60.3 years). After the MRI data were reduced (T1- and T2-weighted sagittal and axial images) on the basis of the exclusion criteria, the anterior and posterior diameters of the dural sac and spinal canal were measured, as well as the thickness of the epidural fat. On the basis of these parameters, the severity of SEL was classified as grade 0 to grade III. Five cases of grade III SEL were diagnosed. The frequency of grade III SEL noted in this study was 0.33% (5/1498). Obesity (body mass index greater than 27.5) was noted in 3 cases, and the use of exogenous corticosteroids was noted in 3 cases. Exogenous steroid usage associated with advanced SEL in this study was greater than that reported in the literature. Most symptoms of SEL progress slowly, and early diagnosis allows for a dose reduction of the prescribed steroids. Thus, lumbar MRI examinations should be conducted aggressively in patients with exogenous steroid use and presenting with low back pain or buttock pain. PMID- 24762842 TI - Tibial tubercle osteotomy with screw fixation for total knee arthroplasty. AB - This study investigated the efficacy of tibial tubercle osteotomy (TTO) with screw fixation as part of the surgical treatment of primary complicated total knee arthroplasty (TKA) and revision TKA. From January 2000 to April 2011, 15 patients (15 knees) underwent revision TKA and 20 patients (21 knees) underwent primary TKA. The average patient age was 68.7+/-8.7 years. Patients underwent follow-up at the authors' institution for an average of 60.6+/-32.9 months. Comparison of preoperative and postoperative Knee Society Scores and Knee Society Functional Scores showed significant postoperative improvement (P<.05). Moreover, postoperative range of motion of the knee improved from 88.5 degrees +/-33.8 degrees to 104.3 degrees +/-18.2 degrees (P<.05). Radiographic assessment showed that the average period to bone union was 10.8+/-5 weeks (range, 5-28 weeks), the average length of the bone fragment was 59.4+/-5.9 mm, the average width at the proximal end was 18.9+/-2.9 mm, and the average thickness at the proximal end of the osteotomy was 10.3+/-1.2 mm. Tibial tubercle osteotomy provided wide exposure for TKA while protecting the extensor mechanism. Solid bone-to-bone fixation was achieved using TTO with 2 screws, and although the overall complication rate was 8.3%, none of the complications were associated with TTO itself. It is recommended that the bone fragment be 60 mm long, 20 mm wide, and 10 mm thick at the proximal end. Appropriate size of the osteotomized bone and solid screw fixation are essential to prevent complications during this procedure. PMID- 24762843 TI - Functional outcomes after fixation of "terrible triad" elbow fracture dislocations. AB - Historically, the published literature on "terrible triad" injuries has shown a high rate of unacceptable results. The use of systematic treatment protocols may improve functional outcome. The authors performed a retrospective study of all patients aged 18 years or older who underwent surgical treatment for "terrible triad" elbow fracture dislocation at their institution over a period 7 years. Surgical treatment involved fixation or replacement of the radial head, repair of the anterior capsule or coronoid fracture in most cases, and repair of the lateral collateral ligament. Outcomes included grip strength, range of motion, Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire score, and a visual analog score for pain as well as radiographic assessment of arthritis, maintenance of reduction, and development of heterotopic ossification. Eighteen patients were identified and 11 enrolled. Seven patients had suture fixation of the coronoid fragment and anterior capsule, 2 had screw fixation, and 2 had no repair of the coronoid. The radial head was replaced in 9 patients and repaired in 1, and a fracture fragment was excised in another. The average follow-up was 38 months. The average arc of motion of the injured elbow was 112 degrees and that of the contralateral elbow was 142 degrees . The average DASH score was 19.7 (scale, 0-100). The average visual analog score for pain was 2.2 (scale, 0-10). No patients had recurrent elbow instability. Three patients underwent further surgical procedures, all for loss of motion. The authors concluded that a systematic approach to the fixation of "terrible triad" elbow fracture dislocations can provide predictable elbow stability and functional range of motion in the medium term. PMID- 24762844 TI - Complications and technical pitfalls of titanium elastic nail fixation for midclavicular fractures. AB - Intramedullary titanium elastic nails have been reported to fix displaced midclavicular fractures with excellent functional outcomes and minor complications. This study reports and analyzes the complications and technical pitfalls associated with titanium elastic nail fixation of displaced midclavicular fractures and describes how to prevent these problems. The authors operated on 27 patients (17 men, 10 women; mean age, 45.8 years; range, 16.5-66.9 years) with marked displaced midclavicular fractures using intramedullary titanium elastic nail fixation. The mean Constant score and Disability of the Arm, Shoulder, and Hand score were 93.58 (range, 66.5-100) and 6.22 (range, 0 35), respectively. The mean length difference compared with the contralateral clavicle was a shortening of 0.3 cm (range, -1.5 to 1 cm). Eight patients (30%) had different levels of difficulty at the medial entry point. Clavicular length shortening of more than 1 cm occurred in 5 patients (19%), and all of these patients experienced medial nail tip prominence/protrusion. One patient had 1-cm lengthening of the injured clavicle caused by distraction of the fracture site during titanium elastic nail insertion. Iatrogenic perforation of the posterolateral cortex occurred in 3 patients. Initial misplaced nail insertion occurred in 1 woman who underwent revision with the mini-open method. In 2 patients it was impossible to remove the full nail under general anesthesia. In conclusion, high patient satisfaction and functional outcomes were achieved after titanium elastic nail fixation of displaced midclavicular fractures. However, some complications and technical pitfalls must be considered before titanium elastic nails are used to fix displaced midclavicular fractures. PMID- 24762845 TI - Human beta-defensin-3 for the diagnosis of periprosthetic joint infection and loosening. AB - In this study, the difference in expression of human beta-defensin-3 in periprosthetic tissue and cancellous bone was observed in the periprosthetic tissue and cancellous bone of patients in the periprosthetic joint infection group, the aseptic loosening group, and the spacer treatment group as well as the synovial membrane and ilium of the normal control group. Hematoxylin and eosin staining of the synovial tissue showed different levels of neutrophil infiltration in all groups except for the normal control group. Immunofluorescence staining of periprosthetic tissue and cancellous bone showed the most positive cells expressing human beta-defensin-3 and the largest mean optical density in the periprosthetic joint infection group, followed by the aseptic loosening group, the spacer treatment group, and the normal control group, with a significant difference in comparison between the periprosthetic joint infection group and the other 3 groups (P<.01). White blood cell count, erythrocyte sedimentation rate, and C-reactive protein level were highest in the periprosthetic joint infection group, whereas no difference was found between the other 3 groups. Taken together, high levels of human beta-defensin-3 protein expression were found in the periprosthetic tissue and cancellous bone of patients with periprosthetic joint infection and aseptic loosening, but there are differential expressions of human beta-defensin-3, and this may provide a new marker for the differential diagnosis of infection and loosening of the artificial joint. PMID- 24762846 TI - Smoking synthetic marijuana leads to self-mutilation requiring bilateral amputations. AB - Synthetic cannabinoids have become a worldwide epidemic because they provide a sometimes legal, easily accessible, and presumably safe alternative to marijuana. Recently published reports have linked acute psychosis, myocardial infarctions, convulsions, self-harm, and even terrorist organizations to these designer substances. This case report outlines the first reported case of Black Diamond, a synthetic cannabis, leading to a self-inflicted burn to the bilateral upper extremities requiring a transradial amputation of the right arm and a toe transfer procedure of the left hand after loss of all digits. The patient presented to the emergency department with self-inflicted fourth-degree burns to the bilateral hands and forearms with second-degree burns of the face, for a total body surface area of 14.5%. The patient was found by firefighters with his hands aflame on his kitchen stove. With no previous medical or psychiatric history and collateral information to confirm the patient's mental status prior to use of Black Diamond, the patient's acute psychotic episode was attributed to Black Diamond. After multiple procedures and a lengthy recovery, the patient completed his post-graduate education and entered the professional world. As orthopedic surgeons, we should be involved in educating the public on the harm of these designer drugs, including self-mutilation. The popularity of synthetic drugs in the United States will continue to present a major challenge to all health care providers. Orthopedists are on the front lines of this epidemic because these drugs push patients into risky, traumatic behavior. PMID- 24762847 TI - Early intraprosthetic dislocation in a revision dual-mobility hip prosthesis. AB - This article presents a case of early intraprosthetic dislocation of a dual mobility hip prosthesis after revision total hip arthroplasty for instability. A 70-year-old woman was revised to a dual-mobility cup for multiple hip dislocations. She dislocated the dual-mobility construct twice, which was closed reduced. Postreduction radiographs after the second closed reduction showed that the femoral head was eccentrically positioned within the acetabular shell, raising suspicion for intraprosthetic dislocation or disassociation between the femoral head and the mobile polyethylene liner. After closed reduction, the patient reported a mobile, golf ball-size mass deep to the posterior lateral incision and new onset of crepitus. Magnetic resonance imaging verified complete intraprosthetic dissociation between the femoral head and mobile polyethylene liner, which was located between the gluteus medius and minimus. The dual mobility cup was revised to a constrained socket with retention of the femoral stem. The patient recovered uneventfully without further instability. PMID- 24762848 TI - Hip flexion contracture caused by an intraspinal osteochondroma of the lumbar spine. AB - Osteochondroma (or osteocartilaginous exostosis) is the most common bone tumor of childhood, with an incidence ranging from 1 to 1.4 per 1,000,000. In the lumbar spine, osteochondromata usually arise from the posterior column at the secondary ossification center and grow away from the spinal canal without causing neurologic deficits. This article reports a rare intraspinal lumbar osteochondroma that compressed the thecal sac, resulting in a hip flexion contracture in an 11-year-old boy. This lumbar, intraspinal, extradural exostosis was confluent with the L3 inferior articular process and compressed the L3 nerve root and thecal sac severely. The patient underwent an en bloc resection of the tumor with a right-sided hemilaminectomy of L3 and L4, a right-sided partial facetectomy at L3 to L4, and an extended resection from the pars intra articularis of the L2 to the L5 vertebrae. The tumor specimen measured 4.8*3.7*2.5 cm with clear margins. Instrumented posterolateral fusion was completed from L2 to L5 due to iatrogenic instability from the resection. The patient had an uneventful recovery and returned to his normal activities of daily living, including sports. He remains asymptomatic at 54-month follow-up. A solitary lumbar osteochondroma that compresses the spinal cord, resulting in a motor neurological deficit, has not been reported in a pediatric patient. Orthopedic surgeons should be aware of potential intraspinal presentation of osteochondromas. Magnetic resonance imaging is the modality of choice in diagnosing and screening for spinal osteochondromas. These cases can be treated with resection surgery. PMID- 24762849 TI - Ewing sarcoma superimposed on a previous osteochondroma in multiple osteochondromatosis. AB - It has been reported that patients with hereditary multiple exostoses (called multiple osteochondromatosis by the World Health Organization) are at increased risk for malignant transformation of osteochondromas to secondary chondrosarcomas. A review of the literature found 14 cases showing transformation of osteochondromas into osteosarcomas; however, Ewing sarcoma has never been reported superimposed on an osteochondroma. This article presents the case of a boy who underwent biopsy of a previously existent osteochondroma for which the pathology report showed cytologic and immunohistochemical properties consistent with Ewing sarcoma. A 13-year-old boy with hereditary multiple exostoses (multiple osteochondromatosis) presented to an orthopedic clinic because of waxing and waning pain superficial to a previous osteochondroma on the lateral aspect of the right leg, below the knee, of 1 month's duration. On examination, inflammation was noted over a bony mass associated with tenderness to palpation of the affected area. There was no evidence of penetrating injury or trauma, and the patient reported no constitutional symptoms, including fever. Radiographs showed marked osteolysis and signs of periosteal reaction. Magnetic resonance imaging showed evidence of cortical bone erosion and extension of the mass into soft tissue. Malignant transformation was suspected, and the patient underwent biopsy. The pathology findings were consistent with Ewing sarcoma. The highly uncommon presentation of this malignancy must serve as a red flag to other physicians who treat patients with hereditary multiple exostoses. Ewing sarcoma tends to be of higher grade and have a worse prognosis than other malignancies that are more commonly seen in these patients. PMID- 24762850 TI - Total hip arthroplasty with acetabular fixation: an unexpected complication. AB - The incidence of vascular injuries associated with total hip arthroplasty (THA) is low. However, several vascular structures are at risk of injury within the pelvis. These include the external iliac, femoral, and obturator vessels. Both reaming of the acetabulum and drilling of the acetabular screw holes may place these structures at risk. If left untreated, injuries to these vessels may be associated with severe morbidity and mortality. In this report, an acute vascular complication that had an unusual presentation is highlighted. A 72-year-old woman presented to the emergency department following a road traffic accident in which she sustained a combined fracture of the right acetabulum and femoral head. Her treatment involved a combination of THA and pelvic open reduction and internal fixation. The immediate perioperative recovery period was uncomplicated. However, the patient developed a deep venous thrombus in her right calf 7 days after surgery. Further investigation revealed a second thrombus, occluding the right common femoral vein. Surgical exploration revealed that a screw placed during the initial surgery was pressing against the vessel and occluding it. The discrepancy in incidence between the development of deep venous thrombosis and vascular compression or injury means that the association between the 2 events is unlikely to be made. The author highlights this unusual presentation to improve early recognition and prompt management of similar cases. The importance of adequate preoperative planning and intraoperative imaging with a C-arm is also stressed. PMID- 24762851 TI - Bayesian analysis for inference of an emerging epidemic: citrus canker in urban landscapes. AB - Outbreaks of infectious diseases require a rapid response from policy makers. The choice of an adequate level of response relies upon available knowledge of the spatial and temporal parameters governing pathogen spread, affecting, amongst others, the predicted severity of the epidemic. Yet, when a new pathogen is introduced into an alien environment, such information is often lacking or of no use, and epidemiological parameters must be estimated from the first observations of the epidemic. This poses a challenge to epidemiologists: how quickly can the parameters of an emerging disease be estimated? How soon can the future progress of the epidemic be reliably predicted? We investigate these issues using a unique, spatially and temporally resolved dataset for the invasion of a plant disease, Asiatic citrus canker in urban Miami. We use epidemiological models, Bayesian Markov-chain Monte Carlo, and advanced spatial statistical methods to analyse rates and extent of spread of the disease. A rich and complex epidemic behaviour is revealed. The spatial scale of spread is approximately constant over time and can be estimated rapidly with great precision (although the evidence for long-range transmission is inconclusive). In contrast, the rate of infection is characterised by strong monthly fluctuations that we associate with extreme weather events. Uninformed predictions from the early stages of the epidemic, assuming complete ignorance of the future environmental drivers, fail because of the unpredictable variability of the infection rate. Conversely, predictions improve dramatically if we assume prior knowledge of either the main environmental trend, or the main environmental events. A contrast emerges between the high detail attained by modelling in the spatiotemporal description of the epidemic and the bottleneck imposed on epidemic prediction by the limits of meteorological predictability. We argue that identifying such bottlenecks will be a fundamental step in future modelling of weather-driven epidemics. PMID- 24762852 TI - The frequent shift to intermediate flora in preterm delivery cases after abnormal vaginal flora screening. AB - The effect of screening and treatment for abnormal vaginal flora on the reduction of preterm deliveries remains controversial. We evaluated whether this screening and treatment reduces the preterm delivery rate for general-population pregnant women. Pregnant women of the Intervention group (n = 574) underwent the screening test and the treatment of vaginal metronidazole during the early second trimester, and those of the Control group (n = 1,161) did not. We compared the preterm delivery rate between these two groups. We also compared the profiles of vaginal flora of the preterm delivery cases with those of the pregnant women with a normal course. There was no significant difference in the preterm delivery rate between these two groups. However, in the preterm delivery cases, a frequent shift to intermediate flora was observed not before but after the screening in the Intervention group. This shift may explain why most of the previous studies failed in regard to the prevention of preterm deliveries. PMID- 24762853 TI - Neonatal piglet survival: impact of sow nutrition around parturition on fetal glycogen deposition and production and composition of colostrum and transient milk. AB - Piglet survival is a major problem, especially during the first 3 days after birth. Piglets are born deficient of energy, but at the same time they have a very high energy requirement because of high physical activity, high need for thermoregulation (because of their lean body with low insulation) and high heat production in muscle tissues. To be able to survive, newborn piglets may rely upon three different sources of energy, namely, glycogen, colostrum and transient milk, which orchestrate to cover their energy requirements. Piglets are born with limited amounts of energy in glycogen depots in the liver and muscle tissues and these depots are sufficient for normal activity for ~16 h. Intake and oxidation of fat and lactose from colostrum must supply sufficient amount of energy to cover at least another 18 h until transient milk becomes available in the sow udder ~34 h after the first piglet is born. Selection for large litters during the last two decades has challenged piglets even further during the critical neonatal phase because the selection programs indirectly decreased birth weight of piglets and because increased litter size has increased the competition between littermates. Different attempts have been made to increase the short-term survival of piglets, that is, survival until day 3 of lactation, by focusing on improving transfer of vital maternal energy to the offspring, either in utero or via mammary secretions. Thus, the present review addresses how sow nutrition in late gestation may favor survival of newborn piglets by increasing glycogen depots, improving colostrum yield or colostrum composition, or by increasing production of transient milk. PMID- 24762855 TI - Spin dynamics of the giant polyoxometalate molecule {Mn40W224} studied by NMR. AB - (7)Li nuclear magnetic resonance (NMR) studies have been performed to investigate magnetic properties and spin dynamics of Mn(3+) (S = 2) spins in the giant polyoxometalate molecule {Mn40W224}. The (7)Li-NMR line width is proportional to the external magnetic field H as expected in a paramagnetic state above 3 K. Below this temperature the line width shows a sudden increase and is almost independent of H, which indicates freezing of the local Mn(3+) spins. The temperature dependence of T1 for both (1)H and (7)Li reveals slow spin dynamics at low temperatures, consistent with spin freezing. The slow spin dynamics is also evidenced by the observation of a peak of 1/T2 around 3 K, where the fluctuation frequency of spins is of the order of ~200 kHz. An explicit form of the temperature dependence of the fluctuation frequency of Mn(3+) spins is derived from the nuclear relaxation data. PMID- 24762856 TI - Load-bearing capacity and the recommended thickness of dental monolithic zirconia single crowns. AB - PURPOSE: The aim of this study was to evaluate the load bearing capacity and a reasonable thicknesss of dental monolithic zirconia crowns. MATERIALS AND METHODS: Polymethyl methacrylate (PMMA) abutment tooth specimens were made by CAD/CAM technic. Monolithic zirconia crowns (MZC), monolithic lithium disilicate crowns (MLC), layered zirconia crowns (LZC) and metal ceramic crowns(MCC), of which the occlusal thickness was 1.5mm were thereafter fabricated and cemented on the abutment tooth specimens. MCC with occlusal thicknesses of 0.6mm, 0.8mm, 1.00mm, 1.2mm were also made. All specimens underwent load-to-fracture test. Weibull parameters (sigma0) and (m) were calculated. Fracture modes were also evaluated. RESULTS: The mean fracture load was 1863.16+/-116.81 for MLC, 2284.77+/-355.60 for MCC, 2308.0+/-510.94 for LZC, 4109.93+/-610.18 for MZC (1.5mm), 3068.31+/-233.88 for MZC (1.2mm), 2429.88+/-315.03 for MZC (1.0mm), 1814.60+/-68.21 for MZC (0.8mm) and 1308.38+/-111.38 for MZC (0.6mm). The fracture load of MZC was significantly higher than MCC, LZC and MLC (P<0.05). The fracture loads for MCC with different thickness were significantly different (P<0.05). Similar trend was observed for the characteristic strength (sigma0) and Weibull modulus (m). For MZC and MLC, the fracture mode was catastrophic failure. The predominant fracture mode for LZC was catastrophic fracture. The fracture loads of MZC(1.0mm) and MCC were not statistically different (P>0.05). CONCLUSIONS: Monolithic zirconia crowns exhibit higher fracture loads than monolithic lithium disilicate crowns, layered zirconia crowns and metal ceramic crowns. The fracture resistance of monolithic zirconia crowns with a thickness of 1.0mm can be equal to metal ceramic crowns. Doubling the monolithic zirconia core from 0.6mm to 1.5mm increases the fracture resistance of this restorative system threefold. PMID- 24762857 TI - Short- and long-term effects of vertebroplastic bone cement on cancellous bone. AB - Vertebroplasty using poly(methyl methacrylate) (PMMA) bone cement is the most common method to treat osteoporotic vertebral fractures. However, several questions of interest remain to be clarified, including how does PMMA affect the cement-bone interface area and surrounding bone tissue, can damaged bone tissues be repaired, how will PMMA change the bone interface over the long-term, and what happens to PMMA itself? The purpose of this study is to investigate these concerns and provide a basis for clinical evaluation. We made bone defects in the lumbar vertebrae of New Zealand rabbits as a model of osteoporosis and injected them with bone cement. A mechanical testing machine was used to perform axial compression, three-point bending, and twisting resistance tests to observe and investigate the short- and long-term biomechanical properties of PMMA after implantation. Optical, fluorescence, scanning electron microscopy, and nanoindentation were used to observe the changes in the interface microstructure. PMMA can rapidly establish the strong support with stable function in the near future. Biomechanical experiments showed that biomechanical property of bone cement group was significantly higher than those in the other two groups (P<0.05) biomechanical property of bone cement group may decline with the time, but it's still better than that of OP in the control group (P<0.05). Histomorphological observation result shows that under osteoporosis state the bone grows slower, also bone's rebuilding time extended. And in the later period, main bone's continuous osteoporosis has some impact on the interface. Nano-indentation testing shows that the young modulus and stiffness of the interface among bone, material and interface were significantly differences (P<0.05). Bone cement had gave the best nano indentation hardness, then was interface and bone tissue. PMMA bone cement was able to quickly support and stabilize the defect in the short term, and bone growth restarted at the bone interface and was tightly integrated. However, over the long-term, fluorescent signal was weakened, osteoclasts appeared, the mechanical indicators for both the interface and the whole vertebra decreased, and bone resorption was eventually greater than bone formation, resulting in bone loss. Therefore, vertebroplasty is not the end of treatment, and we need to further study ways to improve the bone cement material, which is crucial for long-term vertebroplasty efficacy, to better treat osteoporosis. PMID- 24762858 TI - Influence of physical and mechanical properties of amphiphilic biosynthetic hydrogels on long-term cell viability. AB - Maintaining the mechanical properties of biofunctional hydrogels of natural resources for tissue engineering and biomedical applications for an intended period of duration is a challenge. Though anionic polysaccharide alginate has been hailed for its excellent biomimetic characters for tissue engineering, it usually fails in load bearing and other dynamic mechanical environment. In this paper this issue was addressed by copolymerizing alginate with the biocompatible and mechanically robust synthetic biodegradable polyester and crosslinking with polyethylene glycol diacrylate (PEGDA) and vinyl co-monomers, 2-hydroxy ethyl methacrylate (HEMA), methyl methacrylate (MMA) and N N' methylene bis acrylamide (NMBA) to form three hydrogels. All three hydrogels were amphiphilic, hemocompatible and non-cytotoxic. These hydrogels exhibited appreciable water holding capacity. Comparatively, hydrogel prepared with PEGDA-NMBA crosslinkers displayed larger pore size, increased crosslinking, higher tensile strength and controlled degradation. With appreciable swelling and EWC, this hydrogel elicited better biological responses with long-term cell viability for cardiac tissue engineering. PMID- 24762859 TI - Human African trypanosomiasis research gets a boost: unraveling the tsetse genome. PMID- 24762861 TI - Role of P-glycoprotein in refractoriness of seizures to antiepileptic drugs in Lennox-Gastaut syndrome. AB - Mechanism of seizure refractoriness to antiepileptic drugs in children with Lennox-Gastaut syndrome is not known. Efflux of antiepileptic drugs due to increased expression/function of P-glycoprotein, a multidrug efflux transporter protein on the cell surface is a proposed mechanism. The authors studied the expression/function of P-glycoprotein on peripheral blood mononuclear cells of 29 children with Lennox-Gastaut syndrome, 23 children with other epilepsies, and 19 healthy children. The authors found a higher P-glycoprotein expression/function in Lennox-Gastaut syndrome, a higher percent positive cells as compared to children with other epilepsy (P < 0.001) and to healthy controls (P = 0.012), higher P-glycoprotein expression as compared to healthy controls (P = 0.003), a higher total P-glycoprotein expression (relative florescence intensity * percent positive cells) as compared to children with other epilepsies (P < 0.001) and healthy controls (P < 0.001), and a higher P-glycoprotein function as compared to children with other epilepsies (P = 0.001) and healthy controls (P = 0.002). These findings may explain seizure refractoriness to anti-epileptic drugs in Lennox-Gastaut syndome. PMID- 24762860 TI - Cytochrome p450 gene variants, race, and mortality among clopidogrel-treated patients after acute myocardial infarction. AB - BACKGROUND: Clopidogrel is recommended after acute myocardial infarction but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after acute myocardial infarction remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in black patients. METHODS AND RESULTS: Subjects (2732: 2062 whites; 670 blacks) hospitalized with acute myocardial infarction enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of whites (79%) and blacks (64.4%) were discharged on clopidogrel. Among whites, carriers of the loss-of-function CYP2C19*2 allele had significantly increased 1-year mortality (adjusted hazards ratio [HR]: 1.70; confidence interval [CI]: 1.01-2.86; P=0.046) and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI: 0.95-4.63; P=0.066). Among blacks, increased 1-year mortality was associated with the gain of-function CYP2C19*17 allele (adjusted HR for *1/*17 versus *1/*1: 2.02; CI: 0.92-4.44; *17/*17 versus *1/*1: 8.97; CI: 3.34-24.10; P<0.0001) and the CYP1A2*1C allele (adjusted HR for *1/*1C versus *1/*1: 1.89; CI: 0.85-4.22; *1C/*1C versus *1/*1: 4.96; CI: 1.69-14.56; P=0.014). Bleeding events were significantly more common among black carriers of CYP2C19*17 or CYP1A2*1C. CONCLUSIONS: Both loss-of-function and gain-of-function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel-treated patients after acute myocardial infarction; the specific polymorphism and the putative mechanism vary according to race. PMID- 24762862 TI - Strong correlation between the 6-minute walk test and accelerometry functional outcomes in boys with Duchenne muscular dystrophy. AB - Accelerometry provides information on habitual physical capability that may be of value in the assessment of function in Duchenne muscular dystrophy. This preliminary investigation describes the relationship between community ambulation measured by the StepWatch activity monitor and the current standard of functional assessment, the 6-minute walk test, in ambulatory boys with Duchenne muscular dystrophy (n = 16) and healthy controls (n = 13). All participants completed a 6 minute walk test and wore the StepWatchTM monitor for 5 consecutive days. Both the 6-minute walk test and StepWatch accelerometry identified a decreased capacity for ambulation in boys with Duchenne compared to healthy controls. There were strong, significant correlations between 6-minute walk distance and all StepWatch parameters in affected boys only (r = 0.701-0.804). These data proffer intriguing observations that warrant further exploration. Specifically, accelerometry outcomes may compliment the 6-minute walk test in assessment of therapeutic interventions for Duchenne muscular dystrophy. PMID- 24762863 TI - Di-(2-ethylhexyl) phthalate exposure is negatively correlated with trait anxiety in girls but not with trait anxiety in boys or anxiety-like behavior in male mice. AB - The authors aimed to study the effects of postnatal exposure to phthalate on anxiety-like behavior in mice and anxiety proneness in children. Male Imprinting Control Region (ICR) mice aged 4 weeks were administered 20 to 540 mg/kg of di-(2 ethylhexyl) phthalate (DEHP) or vehicle and assessed in the Open Field Test. A group of 277 children aged 8-11 years (150 males) was recruited from South Korea. A cross-sectional examination of urinary DEHP and dibutylphthalate metabolite concentrations was conducted, and the children were scored on the Trait Anxiety Inventory for Children (TAIC). DEHP metabolite concentrations in the urine were significantly and negatively correlated with TAIC scores in the female population but not in the male population. There were no significant group differences in the percentage of distance moved or time spent in the central area in male mice treated with DEHP or vehicle. Our results suggest a sex-dependent effect of DEHP on anxiety proneness in childhood. PMID- 24762864 TI - Clival encephalocele and 5q15 deletion: a case report. AB - A preterm neonate presenting with respiratory distress after birth was found to have a clival encephalocele, which is a variant of a basal encephalocele, and hypoplasia of the cerebellum. Genetic studies revealed a small deletion of the long arm of chromosome 5: 5q15 deletion. We report a rare variant of a basal encephalocele with a cerebellar malformation and 5q15 deletion. PMID- 24762865 TI - Hyperbaric oxygen suppresses hypoxic-ischemic brain damage in newborn rats. AB - The optimal therapeutic time-window and protective mechanism of hyperbaric oxygen in hypoxic-ischemic brain damage remain unclear. This study aimed to determine the neuroprotective effects of hyperbaric oxygen. Following hypoxic-ischemic brain damage modeling in neonatal rats, hyperbaric oxygen was administered at 6, 24, 48, and 72 hours and 1 week after hypoxia, respectively, once daily for 1 week. Fourteen days after hypoxic-ischemic brain damage, cell density and apoptosis rate, number of Fas-L+, caspase-8+, and caspase-3+ neuronal cells, levels of nitric oxide, malondialdehyde, and superoxide dismutase in hippocampus were examined. Morris water maze test was conducted 28 days after insult. Significant improvements were found in cell density, rate of apoptosis, oxidative stress markers, FasL, and caspases in rats treated with hyperbaric oxygen within 72 hours compared to hypoxic-ischemic injury. Similarly, time-dependent behavioral amelioration was observed in pups treated with hyperbaric oxygen. Our findings suggest that hyperbaric oxygen protects against hypoxic-ischemic brain damage by inhibiting oxidative stress and FasL-induced apoptosis, and optimal therapeutic time window is within 72 hours after hypoxic-ischemic brain damage. PMID- 24762866 TI - Trigger points and pressure pain hypersensitivity in people with postmeniscectomy pain. AB - OBJECTIVES: The objectives of this study are (1) to assess the presence of myofascial trigger points (TrPs) and widespread pressure hyperalgesia; and (2) to assess the relationship between the presence of active TrPs, pain intensity, and widespread pressure hypersensitivity in individuals with postmeniscectomy pain. METHODS: Thirty-three patients with postmeniscectomy pain, 46 to 60 years of age, and 33 matched controls participated. TrPs were explored bilaterally within the tensor fasciae latae, rectus femoris, vastus lateralis, vastus medialis, adductor magnus, adductor longus, semitendinosus, biceps femoris, and gastrocnemius muscles in a blinded manner. TrPs were considered active if the referred pain reproduced knee symptoms. Pressure pain thresholds (PPT) were also assessed bilaterally over the vastus medialis, vastus lateralis, patellar tendon, second metacarpal, and tibialis anterior. Pain was collected with a numerical pain rate scale (0 to 10). RESULTS: Patients with postmeniscectomy pain showed a greater (P<0.001) number of active TrPs (mean: 2+/-1) and a similar number (P=0.611) of latent TrPs (mean: 4+/-4) than pain-free controls (mean latent TrP: 4+/-1). A greater number of active TrPs was associated with higher pain intensity (r=0.352; P=0.045). Patients also exhibited reduced PPT over the affected vastus medialis and patellar tendon (P<0.05) and bilaterally over the tibialis anterior muscle (P=0.001). A greater the number of active muscle TrPs was also associated with widespread pressure pain hyperalgesia. CONCLUSIONS: The referred pain elicited by active TrPs reproduced knee symptoms in patients with postmeniscectomy pain. Patients also showed localized reduction of PPT. The number of TrPs was associated with the intensity of pain and pressure hyperalgesia. Our findings suggest the presence of peripheral sensitization in patients with postmeniscectomy pain could be associated with the presence of active TrPs. PMID- 24762867 TI - Modeling the predictive value of pain intensity on costs and resources utilization in patients with peripheral neuropathic pain. AB - OBJECTIVE: The aim of the present analysis was to model the association and predictive value of pain intensity on cost and resource utilization in patients with chronic peripheral neuropathic pain (PNP) treated in routine clinical practice settings in Spain. METHODS: We performed a secondary economic analysis based on data from a multicenter, observational, and prospective cost-of-illness study in patients with chronic PNP that is refractory to prior treatment. Pain intensity was measured using the Short-Form McGill Pain Questionnaire. Univariate and multivariate linear regression models were fitted to identify independent predictors of cost and health care/non-health care resource utilization. RESULTS: A total of 1703 patients were included in the current analysis. Pain intensity was an independent predictor of total costs ([total costs]=35.6 [pain intensity]+214.5; coefficient of determination [R(2)]=0.19, P<0.001), direct costs ([direct costs]=10.8 [pain intensity]+257.7; R=0.06, P<0.001), and indirect costs ([indirect costs]=24.8 [pain intensity]-43.4; R(2)=0.20, P<0.001) related to chronic PNP in the univariate analysis. Pain intensity remains significantly associated with total costs, direct costs, and indirect costs after adjustment by other covariates in the multivariate analysis (P<0.001). None of the other variables considered in the multivariate analysis were predictors of resource utilization. DISCUSSION: Pain intensity predicts the health care and non-health care resource utilization, and costs related to chronic PNP. Management of patients with drugs associated with a higher reduction of pain intensity may have a greater impact on the economic burden of that condition. PMID- 24762869 TI - Defining that moment. PMID- 24762870 TI - Dentist suicides: Professional investigations. PMID- 24762871 TI - Periodontics: BPE scores. PMID- 24762872 TI - Volunteering: Lights, lamps and burs. PMID- 24762873 TI - We live longer than politicians. PMID- 24762874 TI - Defluoridating water. PMID- 24762875 TI - Fact or fiction: Horse-chestnut toothpaste. PMID- 24762878 TI - Calculus is a long-term reservoir of disease. PMID- 24762883 TI - A dentist's life: Never treat a stranger. PMID- 24762891 TI - Viking teeth offer insight into cultural status. PMID- 24762892 TI - Could beer dregs help fight dental diseases? PMID- 24762894 TI - Dental education - shaping the future. AB - Education is key to shaping the future of the dental profession and careful thought must be given to the direction dental education is heading and whether it still allows for the necessary development and innovation that will lead the profession forth and raise it up. PMID- 24762895 TI - Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth, a Cochrane systematic review. AB - This paper compares the beneficial and harmful effects of paracetamol, ibuprofen and the novel combination of both in a single tablet for pain relief following the surgical removal of lower wisdom teeth. In this systematic review only randomised controlled double-blinded clinical trials were included. We calculated the proportion of patients with at least 50% pain relief at 2 and 6 hours post dosing, along with the proportion of participants using rescue medication at 6 and 8 hours. Adverse events were also analysed. Data was meta-analysed where possible. Seven studies were included with a total of 2,241 participants enrolled. Ibuprofen 400 mg is superior to 1,000 mg paracetamol with a risk ratio for at least 50% pain relief at 6 hours of 1.47 (95% confidence interval [CI] 1.28 to 1.69). For the combined drug, the risk ratio for at least 50% maximum pain relief over 6 hours is 1.77 (95% CI 1.32 to 2.39) based on total pain relief (TOTPAR) data. There is high quality evidence that ibuprofen is superior to paracetamol. The novel combination drug shows encouraging results when compared to the single drugs (based on two trials). PMID- 24762896 TI - A clinical guide to periodontology: pathology of periodontal disease. AB - An appreciation of dental plaque and the host response provides an essential basis from which to understand the disease process and treatment rationale. This information will help the reader to understand not only the way that plaque may have an impact on oral tissues but also why regular effective cleaning may improve periodontal health and why some individuals appear to have a greater susceptibility to periodontitis than others, either intrinsically or in relation to various systemic factors. PMID- 24762897 TI - Minimal intervention dentistry: part 5. Ultra-conservative approach to the treatment of erosive and abrasive lesions. AB - The therapeutic management of tooth wear lesions does not require the removal of diseased tissue. Nevertheless, diverse etiological factors may be associated with the condition and they could be difficult to eliminate; this has to be considered when planning therapy. Interceptive procedures should be reserved for such situations while regular monitoring is recommended for other cases, in accordance with advice provided for using the Basic Erosive Wear Examination (BEWE). Direct and indirect adhesive procedures with composite resins allow treatment of most clinical situations, including even extensive restorations. The possibility of managing subsequent interventions should be considered when planning the initial therapeutic approach. PMID- 24762901 TI - Summary of: 'I felt weird and wobbly.' Child-reported impacts associated with a dental general anaesthetic. PMID- 24762902 TI - Summary of: a review of a child population dental preventive programme in Halton and St Helens. PMID- 24762903 TI - The use of anterior gold basket crowns among remote Amazonian communities. AB - Anterior gold basket crowns are a type of restoration worn among remote Amazonian communities, primarily placed for cosmetic and social reasons. There is very minimal literature reporting the use of these restorations in present day communities. This form of dental modification is outlined in the following article, as well as documenting various cases that show the biological implications that these unconventional restorations can have on healthy teeth. PMID- 24762920 TI - 'I felt weird and wobbly.' Child-reported impacts associated with a dental general anaesthetic. AB - AIM: This qualitative study sought to obtain children's accounts of having dental extractions under general anaesthesia (GA). The aim was to gain greater understanding of the physical and psychological impacts from a child's perspective. METHOD: Ten children, aged 6-11 years, maintained a video diary to document their feelings and experiences before, and following their hospital admission. Two semi-structured home interviews supplemented the video diary data and analysis was guided by narrative approaches. RESULTS: This research revealed new insights into children's experiences of having teeth removed under GA. Several of the post-operative impacts correlated with those previously reported by parents/carers. These were notably nausea, bleeding and tiredness, although children used different terminology. However, additional physical and psychological outcomes, both positive and negative, emerged from the children's narratives. Negative aspects included hunger, disturbed eating, being scared/worried and experiencing discomfort from the IV cannula. Interestingly, pain was not a strong theme. Positive outcomes were also reported, such as satisfaction with the resolution of their dental problem and receipt of rewards and attention from family members. CONCLUSION: These accounts have implications for improving patient experiences and outcomes throughout the dental GA care pathway. A review of pre-operative fasting protocols should be a priority. PMID- 24762921 TI - A review of a child population dental preventive programme in Halton and St Helens. AB - INTRODUCTION: An evaluation was undertaken to measure the dental health of five cohorts of 5-year-old children living in Halton and St Helens, each cohort having had a different length of time they were exposed to a population dental prevention programme before their fifth birthday. METHOD: The dental health of each of five consecutive cohorts of 5-year-old children was measured epidemiologically using standardised methods. RESULTS: The mean level of active decay (dt) in the cohort that had the greatest exposure to the preventive intervention (cohort 5, 2011/12) was 0.83, whereas the mean level of active decay in the cohort with no exposure to the preventive programme (cohort 1, 2007/8) was 1.07. This represents a reduction of 22% in the mean level of active decay in 5 year-olds. There was also a 5.9% absolute increase in the number of 5-year-old children free from decay experience between cohorts 5 and 1. Children living in Halton and St Helens with postcodes in the more socially deprived index of multiple deprivation (IMD) tertiles gained the most from the programme. Comparing cohort 5 and cohort 1, the increase in the proportion of children free from decay was greatest in IMD tertiles 1 and 2 and least in IMD tertile 3 (least socially disadvantaged). CONCLUSION: Following a four-year population dental preventive programme the dental health of 5-year-old children living in Halton and St Helens has improved and dental health inequalities have reduced. As there was no control group, the effects seen are associative and cannot be assumed to be causative. PMID- 24762922 TI - In the attraction, compromise, and similarity effects, alternatives are repeatedly compared in pairs on single dimensions. AB - In multi-alternative choice, the attraction, compromise, and similarity effects demonstrate that the value of an alternative is not independent of the other alternatives in the choice-set. Rather, these effects suggest that a choice is reached through the comparison of alternatives. We investigated exactly how alternatives are compared against each other using eye-movement data. The results indicate that a series of comparisons is made in each choice, with a pair of alternatives compared on a single attribute dimension in each comparison. We conclude that psychological models of choice should be based on these single attribute pairwise comparisons. PMID- 24762923 TI - Rhesus monkeys (Macaca mulatta) map number onto space. AB - Humans map number onto space. However, the origins of this association, and particularly the degree to which it depends upon cultural experience, are not fully understood. Here we provide the first demonstration of a number-space mapping in a non-human primate. We trained four adult male rhesus macaques (Macaca mulatta) to select the fourth position from the bottom of a five-element vertical array. Monkeys maintained a preference to choose the fourth position through changes in the appearance, location, and spacing of the vertical array. We next asked whether monkeys show a spatially-oriented number mapping by testing their responses to the same five-element stimulus array rotated ninety degrees into a horizontal line. In these horizontal probe trials, monkeys preferentially selected the fourth position from the left, but not the fourth position from the right. Our results indicate that rhesus macaques map number onto space, suggesting that the association between number and space in human cognition is not purely a result of cultural experience and instead has deep evolutionary roots. PMID- 24762924 TI - Simulating the N400 ERP component as semantic network error: insights from a feature-based connectionist attractor model of word meaning. AB - The N400 ERP component is widely used in research on language and semantic memory. Although the component's relation to semantic processing is well established, the computational mechanisms underlying N400 generation are currently unclear (Kutas & Federmeier, 2011). We explored the mechanisms underlying the N400 by examining how a connectionist model's performance measures covary with N400 amplitudes. We simulated seven N400 effects obtained in human empirical research. Network error was consistently in the same direction as N400 amplitudes, namely larger for low frequency words, larger for words with many features, larger for words with many orthographic neighbors, and smaller for semantically related target words as well as repeated words. Furthermore, the repetition-induced decrease was stronger for low frequency words, and for words with many semantic features. In contrast, semantic activation corresponded less well with the N400. Our results suggest an interesting relation between N400 amplitudes and semantic network error. In psychological terms, error values in connectionist models have been conceptualized as implicit prediction error, and we interpret our results as support for the idea that N400 amplitudes reflect implicit prediction error in semantic memory (McClelland, 1994). PMID- 24762925 TI - Human brucellosis among pyrexia of unknown origin cases and occupationally exposed individuals in Goa Region, India. AB - BACKGROUND: Brucellosis is a widespread zoonotic infection. This disease is endemic in many parts of Asia, including India. Brucellosis is a major cause of pyrexia of unknown origin (PUO). Persons exposed to infected animals or contaminated animal products are at high risk. Seropositivity among animal handlers, veterinarians and dairy workers has been documented in India. Thus, the present study was aimed to determine prevalence of brucellosis among PUO cases and occupationally exposed individuals. METHODS: In this study, serum samples (n=282) from cases of pyrexia of unknown origin (PUO) (n=243), and occupationally exposed individuals (n=39) were collected and tested for brucellosis by Rose Bengal plate test (RBPT), serum agglutination test (SAT), indirect ELISA, IgG and IgM ELISA. Blood culture for isolation of Brucella was performed for 10 serologically positive patients using BACTEC 9050 automated blood culture system. Biochemical tests and PCR techniques were used for confirmation of the isolates. RESULTS: Of the samples tested, 4.25%, 3.54%, 6.02% and 4.96% samples were positive by RBPT, SAT, indirect ELISA and IgG ELISA, respectively. None of the sample was positive for IgM ELISA. Of the 10 blood samples cultured bacteriologically, one Brucella isolate was recovered. The isolate was confirmed as Brucella abortus. Amplification of the bcsp31 and IS711 genes was also observed. CONCLUSION: Seropositivity for brucellosis was observed among PUO cases, animal handlers and dairy workers in Goa, India. The serological tests showed variable results. One Brucella isolate was obtained by performing blood culture. Confirmation of the case was done rapidly using molecular tools. General awareness about clinical symptoms should be increased which will improve proper diagnosis within short time frame. PMID- 24762926 TI - Contribution to the development of a food guide in Benin: linear programming for the optimization of local diets. AB - OBJECTIVE: Food guides are important tools for nutrition education. While developing a food guide in Benin, the objective was to determine the daily number of servings per food group and the portion sizes of common foods to be recommended. DESIGN: Linear programming (LP) was used to determine, for each predefined food group, the optimal number and size of servings of commonly consumed foods. Two types of constraints were introduced into the LP models: (i) WHO/FAO Recommended Nutrient Intakes and dietary guidelines for the prevention of chronic diseases; and (ii) dietary patterns based on local food consumption data recently collected in southern Benin in 541 adults. Dietary intakes of the upper tertile of participants for diet quality based on prevention and micronutrient adequacy scores were used in the LP algorithms. SETTING: Southern area of the Republic of Benin. SUBJECTS: Local key-players in nutrition (n 30) from the government, academic institutions, international organizations and civil society were partners in the development of the food guide directed at the population. RESULTS: The number of servings per food group and the portion size for eight age sex groups were determined. For four limiting micronutrients (Fe, Ca, folate and Zn), local diets could be optimized to meet only 70 % of the Recommended Nutrient Intakes, not 100 %. CONCLUSIONS: It was possible to determine the daily number of servings and the portion sizes of common foods that can be recommended in Benin with the help of LP to optimize local diets, although Recommended Nutrient Intakes were not fully met for a few critical micronutrients. PMID- 24762928 TI - Use of laboratory reports as predictors of West Nile virus disease cases, Texas, 2008-2012. AB - We evaluated laboratory reports as early indicators of West Nile virus (WNV) disease cases in Texas. We compared WNV laboratory results in the National Electronic Disease Surveillance System Base System (NBS) to WNV disease cases reported to the state health department from 2008 to 2012. We calculated sensitivity and positive predictive value (PPV) of NBS reports, estimated the number of disease cases expected per laboratory report, and determined lead and lag times. The sensitivity and PPV of NBS laboratory reports were 86% and 77%, respectively. For every 10 positive laboratory reports, we expect 9.0 (95% confidence interval 8.9-9.2) reported disease cases. Laboratory reports preceded case reports with a lead time of 7 days. Electronic laboratory reports provided longer lead times than manually entered reports (P < 0.01). NBS laboratory reports are useful estimates of future reported WNV disease cases and may provide timely information for planning public health interventions. PMID- 24762927 TI - Use of a synthetic biosensor for neutralizing activity-biased selection of monoclonal antibodies against atroxlysin-I, an hemorrhagic metalloproteinase from Bothrops atrox snake venom. AB - BACKGROUND: The snake Bothrops atrox is responsible for the majority of envenomings in the northern region of South America. Severe local effects, including hemorrhage, which are mainly caused by snake venom metalloproteinases (SVMPs), are not fully neutralized by conventional serum therapy. Little is known about the immunochemistry of the P-I SVMPs since few monoclonal antibodies (mAbs) against these molecules have been obtained. In addition, producing toxin neutralizing mAbs remains very challenging. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report on the set-up of a functional screening based on a synthetic peptide used as a biosensor to select neutralizing mAbs against SVMPs and the successful production of neutralizing mAbs against Atroxlysin-I (Atr-I), a P-I SVMP from B. atrox. Hybridomas producing supernatants with inhibitory effect against the proteolytic activity of Atr-I towards the FRET peptide Abz-LVEALYQ-EDDnp were selected. Six IgG1 Mabs were obtained (named mAbatr1 to mAbatr6) and also two IgM. mAbatrs1, 2, 3 and 6 were purified. All showed a high specific reactivity, recognizing only Atr-I and B. atrox venom in ELISA and a high affinity, showing equilibrium constants in the nM range for Atr-I. These mAbatrs were not able to bind to Atr-I overlapping peptides, suggesting that they recognize conformational epitopes. CONCLUSIONS/SIGNIFICANCE: For the first time a functional screening based on a synthetic biosensor was successfully used for the selection of neutralizing mAbs against SVMPs. PMID- 24762929 TI - Old lineages in a new ecosystem: diversification of arcellinid amoebae (Amoebozoa) and peatland mosses. AB - Arcellinid testate amoebae (Amoebozoa) form a group of free-living microbial eukaryotes with one of the oldest fossil records known, yet several aspects of their evolutionary history remain poorly understood. Arcellinids occur in a range of terrestrial, freshwater and even brackish habitats; however, many arcellinid morphospecies such as Hyalosphenia papilio are particularly abundant in Sphagnum dominated peatlands, a relatively new ecosystem that appeared during the diversification of Sphagnum species in the Miocene (5-20 Myr ago). Here, we reconstruct divergence times in arcellinid testate amoebae after selecting several fossils for clock calibrations and then infer whether or not arcellinids followed a pattern of diversification that parallels the pattern described for Sphagnum. We found that the diversification of core arcellinids occurred during the Phanerozoic, which is congruent with most arcellinid fossils but not with the oldest known amoebozoan fossil (i.e. at ca. 662 or ca. 750 Myr). Overall, Sphagnum and the Hyalospheniidae exhibit different patterns of diversification. However, an extensive molecular phylogenetic analysis of distinct clades within H. papilio species complex demonstrated a correlation between the recent diversification of H. papilio, the recent diversification of Sphagnum mosses, and the establishment of peatlands. PMID- 24762930 TI - Sensory transduction: Merkel cells bring a delicate touch. PMID- 24762931 TI - Genome Sequences of Eight Salmonella enterica subsp. enterica Serovars Isolated from a Single Dairy Farm. AB - Here, we report draft genome sequences of 26 isolates of Salmonella enterica subsp. enterica, representing eight serotypes, which were isolated from cows in a Pennsylvania dairy herd, the farm on which they were reared, and the associated off-site heifer-raising facility over an 8-year sampling period. PMID- 24762932 TI - Draft Genome Sequence of Trueperella pyogenes, Isolated from the Infected Uterus of a Postpartum Cow with Metritis. AB - Trueperella pyogenes is a common commensal bacterium and an opportunistic pathogen associated with chronic purulent disease, particularly in ruminants. We report here the genome sequence of a T. pyogenes isolate from a severe case of bovine metritis. This is the first full record of a T. pyogenes genome. PMID- 24762933 TI - Genome Sequence of Lactobacillus plantarum 19L3, a Strain Proposed as a Starter Culture for Slovenska Bryndza Ovine Cheese. AB - The genome sequence of Lactobacillus plantarum isolated from ovine cheese is presented here. This bacterium is proposed as a starter strain, named 19L3, for Slovenska bryndza cheese, a traditional Slovak cheese fulfilling European Food Safety Authority (EFSA) requirements. PMID- 24762934 TI - Draft Genome Sequence of Deinococcus phoenicis, a Novel Strain Isolated during the Phoenix Lander Spacecraft Assembly. AB - Deinococcus phoenicis strain 1P10ME(T) is a radiation- and desiccation-resistant bacterium isolated from a cleanroom facility where the Phoenix Lander spacecraft was assembled. In order to facilitate investigations of the nature of the extreme resistance of D. phoenicis to bactericidal factors, a draft genome sequence of D. phoenicis was determined. PMID- 24762935 TI - Complete Genome Sequence of a Mixed-Subtype (H5N1 and H6N6) Avian Influenza Virus Isolated from a Duck in Hunan Province, China. AB - We isolated an avian influenza virus, A/duck/Hunan/747/2011(mixed), which included the H5N1 and H6N6 subtypes, from a duck in China. Phylogenetic analysis indicates that the H5 hemagglutinin (HA) gene belongs to clade 2.3.2.1, the H6 HA gene belongs to the group II lineage, and the other internal genes show different recombination events. PMID- 24762936 TI - Full-Genome Sequence of the Plant Growth-Promoting Bacterium Pseudomonas protegens CHA0. AB - We report the complete genome sequence of the free-living bacterium Pseudomonas protegens (formerly Pseudomonas fluorescens) CHA0, a model organism used in plant microbe interactions, biological control of phytopathogens, and bacterial genetics. PMID- 24762937 TI - Draft Genome Sequence of Lysobacter capsici AZ78, a Bacterium Antagonistic to Plant-Pathogenic Oomycetes. AB - Lysobacter capsici AZ78, isolated from tobacco rhizosphere, effectively controls Phytophthora infestans and Plasmopara viticola on tomato and grapevine plants, respectively. We report the first draft genome sequence of the L. capsici species. PMID- 24762938 TI - Complete Genome Sequences of 16 Canadian Strains of Salmonella enterica subsp. enterica Serovar Enteritidis. AB - Salmonella enterica subsp. enterica serovar Enteritidis is an important zoonotic food-borne pathogen causing serious human illnesses frequently linked to poultry products. Here, we report fully assembled genome sequences of 16 S. Enteritidis strains with common pulsed-field gel electrophoresis (PFGE) and phage types (8, 13, 13a, and 14b) that predominate in North America. PMID- 24762939 TI - Complete genome sequence of a newcastle disease virus isolate from an outbreak in northern India. AB - The complete genome sequence was determined for a Newcastle disease virus strain from vaccinated chicken farms in India during outbreaks in 2010. The genome is 15,192 nucleotides (nt) in length and is classified as genotype VII in class II. Compared to the available vaccine strains, the Indian strain contains a previously described 6-nt insertion in the untranslated region of the nucleoprotein gene. PMID- 24762940 TI - Draft Genome Sequence of Tatumella sp. Strain UCD-D_suzukii (Phylum Proteobacteria) Isolated from Drosophila suzukii Larvae. AB - Here we present the draft genome of Tatumella sp. strain UCD-D_suzukii, the first member of this genus to be sequenced. The genome contains 3,602,931 bp in 72 scaffolds. This strain was isolated from Drosophila suzukii larvae as part of a larger project to study the microbiota of D. suzukii. PMID- 24762941 TI - Complete Genome Sequence of Phage-Like Plasmid pECOH89, Encoding CTX-M-15. AB - A nonconjugative and nontypable plasmid of a clinical Escherichia coli isolate expressing resistance to extended-spectrum cephalosporins (ESCs) was isolated and sequenced. The plasmid pECOH89 contains a CTX-M-15 resistance cassette and comprises 111,741 bp, with strong homology to bacteriophage-like plasmids and to the Salmonella-specific bacteriophage SSU5. PMID- 24762942 TI - Draft Genome Sequence of Umbilicaria muehlenbergii KoLRILF000956, a Lichen Forming Fungus Amenable to Genetic Manipulation. AB - Umbilicaria muehlenbergii strain KoLRILF000956 is amenable to Agrobacterium tumefaciens-mediated transformation (ATMT), making it the only known genetically tractable lichen-forming fungus to date. We report another advancement in lichen genetics, a draft genome assembly for U. muehlenbergii with a size of 34,812,353 bp and a GC content of 47.12%, consisting of seven scaffolds. PMID- 24762943 TI - Action potentials in retinal ganglion cells are initiated at the site of maximal curvature of the extracellular potential. AB - OBJECTIVE: The initiation of an action potential by extracellular stimulation occurs after local depolarization of the neuronal membrane above threshold. Although the technique shows remarkable clinical success, the site of action and the relevant stimulation parameters are not completely understood. APPROACH: Here we identify the site of action potential initiation in rabbit retinal ganglion cells (RGCs) interfaced to an array of extracellular capacitive stimulation electrodes. We determine which feature of the extracellular potential governs action potential initiation by simultaneous stimulation and recording RGCs interfaced in epiretinal configuration. Stimulation electrodes were combined to areas of different size and were presented at different positions with respect to the RGC. MAIN RESULTS: Based on stimulation by electrodes beneath the RGC soma and simultaneous sub-millisecond latency measurement we infer axonal initiation at the site of maximal curvature of the extracellular potential. Stimulation by electrodes at different positions along the axon reveals a nearly constant threshold current density except for a narrow region close to the cell soma. These findings are explained by the concept of the activating function modified to consider a region of lower excitability close to the cell soma. SIGNIFICANCE: We present a framework how to estimate the site of action potential initiation and the stimulus required to cross threshold in neurons tightly interfaced to capacitive stimulation electrodes. Our results underscore the necessity of rigorous electrical characterization of the stimulation electrodes and of the interfaced neural tissue. PMID- 24762944 TI - Lyme neuroborreliosis and dementia. AB - INTRODUCTION: Descriptions of Lyme disease and dementia are rare. OBJECTIVE: To describe patients with dementia and a positive "intrathecal anti-Borrelia antibody index" (AI), specific for neuroborreliosis. METHODS: Among 1,594 patients seen for dementia, we prospectively identified and studied 20 patients (1.25%) with dementia and a positive AI. Patients underwent a battery of neuropsychological tests brain, MRI, FDG-PET, and cerebrospinal fluid (CSF) analysis. An etiological diagnosis of the dementia was made at the end of the follow-up of 5.0 +/- 2.9 years. RESULTS: We found two groups of patients with dementia, the first (n = 7, 0.44%) with certain neuroborreliosis and stability or mild improvement of dementia after treatment by antibiotics and the second (n = 13, 0.81%) with progressive worsening of dementia, despite the antibiotics. In the second group, the final diagnoses were Alzheimer's disease (AD) (n = 4), AD and Lewy body disease (LBD) (n = 3), LBD (n = 1), FTLD (n = 3), hippocampal sclerosis (n = 1), and vascular dementia (n = 1). We did not observe any differences in cognitive test between the two patient groups at baseline. Brain MRI showed more focal atrophy and FDG-PET showed more frontal hypometabolism in the second group. Tau, p-tau, and Abeta42 concentrations in the CSF were normal in the neuroborreliosis group, and coherent with diagnosis in the second. CONCLUSION: Pure Lyme dementia exists and has a good outcome after antibiotics. It is advisable to do Lyme serology in demented patients, and if serology is positive, to do CSF analysis with AI. Neurodegenerative dementia associated with positive AI also exists, which may have been revealed by the involvement of Borrelia in the CNS. PMID- 24762946 TI - Initial memory deficit profiles in patients with a cerebrospinal fluid Alzheimer's disease signature. AB - BACKGROUND: Alzheimer's disease (AD) clinical onset is usually characterized by a memory complaint and a progressive memory deficit. The proportion of typical medial-temporal amnesia revealing AD remains unknown. OBJECTIVE: The present study explores the episodic memory impairment profiles by the Free and Cued Selective Recall Reminding Test (FCSRT) in patients with initial memory complaint and a cerebrospinal fluid (CSF) biomarker signature of AD. METHODS: Seventy-three patients referred for memory complaint to the Centers for Memory, Resource and Research of Lyon and Montpellier (France) were included consecutively. All patients underwent an extensive neuropsychological examination and had a Mini Mental State Examination (MMSE) score >=20 and a positive CSF AD signature. The patients were classified as having mild dementia or prodromal AD. Verbal episodic memory was assessed using the French version of the FCSRT exploring encoding, storage/consolidation, and cued delayed retrieval phases of memorization. Three different memory profiles were identified according to the results of FCSRT. RESULTS: The median age was 72 year-old [interquartiles: 65-76]. The median MMSE score was 23 [interquartiles: 21-25]. 88% of the patients (n = 64) presented with a medial temporal amnesia profile. The dysexecutive amnesia and normal verbal episodic memory profiles represented respectively 5% (n = 4) and 7% (n = 5). There were no significant differences in term of age, gender, and MMSE score between the three profile groups. CONCLUSION: In a population initially presenting with memory complaints and depicting a CSF AD signature, a high proportion of medial temporal amnesia is disclosed as expected, but also a proportion of dysexecutive amnesia and normal FCSRT. PMID- 24762945 TI - Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. AB - Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese. PMID- 24762947 TI - Design of multi-target compounds as AChE, BACE1, and amyloid-beta(1-42) oligomerization inhibitors: in silico and in vitro studies. AB - Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-beta (Abeta) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Abeta, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, beta-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Abeta monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 MUM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Abeta oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models. PMID- 24762948 TI - Hidden risk genes with high-order intragenic epistasis in Alzheimer's disease. AB - Meta-analysis of data from genome-wide association studies (GWAS) of Alzheimer's disease (AD) has confirmed the high risk of APOE and identified twenty other risk genes/loci with moderate effect size. However, many more risk genes/loci remain to be discovered to account for the missing heritability. The contributions from individual singe-nucleotide polymorphisms (SNPs) have been thoroughly examined in traditional GWAS data analysis, while SNP-SNP interactions can be explored by a variety of alternative approaches. Here we applied generalized multifactor dimensionality reduction to the re-analysis of four publicly available GWAS datasets for AD. When considering 4-order intragenic SNP interactions, we observed high consistency of discovered potential risk genes among the four independent GWAS datasets. Ten potential risk genes were observed across all four datasets, including PDE1A, RYR3, TEK, SLC25A21, LOC729852, KIRREL3, PTPN5, FSHR, PARK2, and NR3C2. These potential risk genes discovered by generalized multifactor dimensionality reduction are highly relevant to AD pathogenesis based on multiple layers of evidence. The genetic contributions of these genes warrant further confirmation in other independent GWAS datasets for AD. PMID- 24762949 TI - Propagation mechanism of polymer optical fiber fuse. AB - A fiber fuse phenomenon in polymer optical fibers (POFs) has recently been observed, and its unique properties such as slow propagation, low threshold power density, and the formation of a black oscillatory damage curve, have been reported. However, its characterization is still insufficient to well understand the mechanism and to avoid the destruction of POFs. Here, we present detailed experimental and theoretical analyses of the POF fuse propagation. First, we clarify that the bright spot is not a plasma but an optical discharge, the temperature of which is ~3600 K. We then elucidate the reasons for the oscillation of the damage curve along with the formation of newly-observed gas bubbles as well as for the low threshold power density. We also present the idea that the POF fuse can potentially be exploited to offer a long photoelectric interaction length. PMID- 24762950 TI - Higher order image structure enables boundary segmentation in the absence of luminance or contrast cues. AB - Lower order image statistics, which can be described by an image's Fourier energy content, enable segmentation when they are different on either side of a boundary. We have previously demonstrated that the spatial distribution of the energy in an image (described by its higher order statistics or structure) could influence segmentation thresholds for contrast- and orientation-defined boundaries, even though it was the same on either side of the boundary and thus task irrelevant (Zavitz & Baker, 2013). Here we examined whether higher order statistics can also enable segmentation when boundaries are defined by differences in structure or density of texture elements. We used micropattern based naturalistic synthetic textures to manipulate the sparseness, global phase alignment, and local phase alignment of carrier textures and measured segmentation thresholds based on forced-choice judgments of boundary orientation. We found that both global phase structure and sparseness, but not local phase alignment, enable segmentation and that local structure also has a small effect on segmentation thresholds in both cases. Simulations of a two-stage filter model with a compressive intermediate nonlinearity can reproduce the major features of the experimental data, segmenting boundaries defined by higher order statistics alone while capturing the influence of global image structure on segmentation thresholds. PMID- 24762951 TI - Boundary segmentation from dynamic occlusion-based motion parallax. AB - Active observer movement results in retinal image motion that is highly dependent on the scene layout. This retinal motion, often called motion parallax, can yield significant information about the boundaries between objects and their relative depth differences. Previously we examined segmentation from shear-based motion parallax, which consists of only relative motion information. Here, we examine segmentation from dynamic occlusion-based motion parallax, which contains both relative motion and accretion-deletion. We utilized random dots whose motion was modulated with vertical low spatial frequency envelopes and synchronized to head movements (Head Sync), or recreated using previously recorded head movement data for the same stationary observer (Playback). Observers judged the orientation of a boundary between regions of oppositely moving dots in a 2AFC task. The results demonstrate that observers perform poorer when the stimulus motion is synchronized to head movement, particularly at smaller relative depths, even though that head movement provides significant information about depth. Both expansion-compression and accretion-deletion in isolation could support segmentation, albeit with reduced performance. Therefore, unlike our previous results for depth ordering, expansion-compression and accretion-deletion contribute similarly to segmentation. Furthermore, human observers do not appear to utilize depth information to improve segmentation performance. PMID- 24762952 TI - Optic nerve glioma: case series with review of clinical, radiologic, molecular, and histopathologic characteristics. AB - PURPOSE: This study was designed to better understand the biologic nature of optic nerve gliomas (ONGs) and to investigate staining techniques that might improve the pathologic interpretation of surgical margins. METHODS: In this retrospective case series, clinical data on patient presentation, MRI, surgical visualization, and initial pathologic interpretation were gathered. Specimens were then reexamined using analysis of p53, isocitrate dehydrogenase 1 (IDH1), MIB-1, and B-rapidly accelerated fibrosarcoma (BRAF) duplication. RESULTS: Six patients were studied. All were diagnosed with World Health Organization grade 1 ONGs on original pathology. On reexamination, BRAF tandem duplication was found in 2 patients with neurofibromatosis Type 1 association. P53 immunoreactivity was noted in a third case. No cases had IDH1 immunoreactivity. Focal elevations of MIB-1 up to 7.5% were noted in 2 cases. CONCLUSIONS: ONGs are neoplasms with variable degrees of aggressiveness. As more is understood regarding their varied genetic underpinnings, improved pathologic classification and individualized treatment regimens may be achieved. The authors hope that this study helps guide the oculoplastic community toward a multi-institutional, prospective study of ONG genomic sequencing. PMID- 24762953 TI - Emergence of spin spiral magnetic order in Mn based inverse Heusler alloys. AB - In this article we demonstrate, by first principles density functional calculations, the emergence of spin-spiral magnetic order in Mn2NiX(X=Al,Ga,In,Sn) inverse Heusler alloys with the application of pressure. This noncollinearity originates from the features in the band structures and the nesting of fermi surfaces of collinear spin bands. The calculated interatomic magnetic exchange parameters suggest that the frustrations in the Mn sublattice with octahedral symmetry are responsible for the stabilization of a noncollinear state. We propose that the pressure induced stabilization of spin-spiral magnetic order is a general feature of magnetic alloys crystallizing in inverse Heusler structures. PMID- 24762955 TI - Management of anesthetic emergencies and complications outside the operating room. AB - PURPOSE OF REVIEW: Anesthesia outside the operating room is commonly uncomfortable and risky. In this setting, anesthetic emergencies or complications may occur. This review aims to report the most recent updates regarding the management of prehospital anesthesia, anesthesia in the trauma and emergency rooms, and anesthesia for endoscopy and interventional radiology. RECENT FINDINGS: After tracheal intubation failure, airway control of outpatients could be achieved by pharmacologically assisted laryngeal mask insertion. Management of traumatic injured patients is best guided in the frame of checklists. Monitoring sedation in this setting is challenging notably because of the threat of haemodynamic instability. Unfortunately, BIS monitoring cannot be recommended to guide sedation in this setting. Ketamine can be used to prevent hypotension during prehospital anesthesia or procedural sedation, especially as its neuroprotective effects have been recently best understood. Target-controlled infusion propofol administration with small concentration increments is adapted to prevent hypotension and hypoxaemia during sedation for gastrointestinal endoscopy and interventional radiology. Target-controlled infusion remifentanil administration is also adapted to many procedures. SUMMARY: Anesthesia outside the operating room requires careful monitoring to avoid side-effects and education of nonanaesthetists when they are involved. A useful tool is to continuously improve the protocols and checklists to make anesthesia in this setting safer. PMID- 24762954 TI - Role of novel drugs in sedation outside the operating room: dexmedetomidine, ketamine and remifentanil. AB - PURPOSE OF REVIEW: Progress in medical technology, diagnostic procedures and imaging techniques results in a growing demand for well tolerated sedation regimens, devoid of respiratory and haemodynamic complications. Moreover, rapid turnover time dictates the need for rapid onset of effect and rapid recovery. Recent literature regarding the use of dexmedetomidine, ketamine and remifentanil for sedation outside the operating room is reviewed. As procedural sedation is often performed by nonanaesthesiologists, articles from journals other than anaesthesiology journals are also included. RECENT FINDINGS: Dexmedetomidine seems an attractive choice for sedation, because of the lack of respiratory depression. It has been studied as a sole sedation agent or in combination with benzodiazepines or opioids. As premedication, it can be administered intranasally. Disadvantages are a rather slow onset and recovery. Bradycardia and hypotension are common. Ketamine got renewed attention mainly by nonanaesthesiologists performing procedural sedation. Psychogenic adverse effects and slow recovery limit its use. Psychiatrists are interested in its antidepressive effect. Ketamine has a potential role in lowering the risk of chronification of pain, modified by analgesic and anti-inflammatory effects. Remifentanil as an ultra-short-acting agent is less well studied outside the operating room. Its unique pharmacology permits its use in patient-controlled analgesia and sedation, in target-controlled infusion or in a combined technique. SUMMARY: Recent literature is reviewed regarding dexmedetomidine, ketamine and remifentanil for its use outside the operating room. Sedationists have to keep in mind the pharmacokinetics and pharmacodynamics of the currently used agents in adults and children. PMID- 24762956 TI - Estimating breast cancer mortality reduction and overdiagnosis due to screening for different strategies in the United Kingdom. AB - BACKGROUND: The benefits and harms of population-wide mammography screening have been long debated. This study evaluated the impact of screening frequency and age range on breast cancer mortality reduction and overdiagnosis. METHODS: We developed a Markov simulation model for the evaluation of mammography screening in a cohort of British women born in 1935-40. RESULTS: For triennial screening in women aged 47-73, breast cancer mortality reduction and overdiagnosis was 18.1% (95% confidence interval: 17.3%, 19.0%) and 5.6% (5.1%, 6.1%), of all breast cancer deaths and diagnoses, respectively, from age 40 to 85 years. For annual screening in the same age range, estimates for both outcomes increased considerably to 35.0% (34.2%, 35.7%) and 7.6% (7.1%, 8.1%), respectively. For the age extension of triennial screening from 50-70 to 47-73, we estimated 5 (3, 7) incremental breast cancer deaths avoided and 14 (9, 19) incremental cases overdiagnosed per 10 000 women invited for screening. CONCLUSIONS: Estimates of mortality reduction and overdiagnosis were highly dependent on screening frequency, age range, and uptake, which may explain differences between some previous estimates obtained from randomised trials and from service screening. PMID- 24762957 TI - Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer. AB - BACKGROUND: Amino-acid transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type amino acid transporter 1 (LAT1), system ASC amino-acid transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino-acid transporters in tongue cancer. METHODS: Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53. RESULTS: L-type amino-acid transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC amino-acid transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis. CONCLUSIONS: L-type amino-acid transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer. PMID- 24762958 TI - Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial. AB - BACKGROUND: The SHIVA trial is a multicentric randomised proof-of-concept phase II trial comparing molecularly targeted therapy based on tumour molecular profiling vs conventional therapy in patients with any type of refractory cancer. RESULTS of the feasibility study on the first 100 enrolled patients are presented. METHODS: Adult patients with any type of metastatic cancer who failed standard therapy were eligible for the study. The molecular profile was performed on a mandatory biopsy, and included mutations and gene copy number alteration analyses using high-throughput technologies, as well as the determination of oestrogen, progesterone, and androgen receptors by immunohistochemistry (IHC). RESULTS: Biopsy was safely performed in 95 of the first 100 included patients. Median time between the biopsy and the therapeutic decision taken during a weekly molecular biology board was 26 days. Mutations, gene copy number alterations, and IHC analyses were successful in 63 (66%), 65 (68%), and 87 (92%) patients, respectively. A druggable molecular abnormality was present in 38 patients (40%). CONCLUSIONS: The establishment of a comprehensive tumour molecular profile was safe, feasible, and compatible with clinical practice in refractory cancer patients. PMID- 24762959 TI - Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. AB - BACKGROUND: Mesothelioma is a notoriously chemotherapy-resistant neoplasm, as is evident in the dismal overall survival for patients with those of asbestos associated disease. We previously demonstrated co-activation of multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET, and AXL in mesothelioma cell lines, suggesting that these kinases could serve as novel therapeutic targets. Although clinical trials have not shown activity for EGFR inhibitors in mesothelioma, concurrent inhibition of various activated RTKs has pro-apoptotic and anti-proliferative effects in mesothelioma cell lines. Thus, we hypothesised that a coordinated network of multi-RTK activation contributes to mesothelioma tumorigenesis. METHODS: Activation of PI3K/AKT/mTOR, Raf/MAPK, and co-activation of RTKs were evaluated in mesotheliomas. Effects of RTK and downstream inhibitors/shRNAs were assessed by measuring mesothelioma cell viability/growth, apoptosis, activation of signalling intermediates, expression of cell-cycle checkpoints, and cell-cycle alterations. RESULTS: We demonstrate activation of the PI3K/AKT/p70S6K and RAF/MEK/MAPK pathways in mesothelioma, but not in non-neoplastic mesothelial cells. The AKT activation, but not MAPK activation, was dependent on coordinated activation of RTKs EGFR, MET, and AXL. In addition, PI3K/AKT/mTOR pathway inhibition recapitulated the anti proliferative effects of concurrent inhibition of EGFR, MET, and AXL. Dual targeting of PI3K/mTOR by BEZ235 or a combination of RAD001 and AKT knockdown had a greater effect on mesothelioma proliferation and viability than inhibition of individual activated RTKs or downstream signalling intermediates. Inhibition of PI3K/AKT was also associated with MDM2-p53 cell-cycle regulation. CONCLUSIONS: These findings show that PI3K/AKT/mTOR is a crucial survival pathway downstream of multiple activated RTKs in mesothelioma, underscoring that PI3K/mTOR is a compelling target for therapeutic intervention. PMID- 24762960 TI - Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis. AB - BACKGROUND: Accumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear. METHODS: ALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression. RESULTS: In comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated. CONCLUSIONS: We report here the association of ALDH3A1 with PC progression. PMID- 24762961 TI - A benzoic acid derivative and flavokawains from Piper species as schistosomiasis vector controls. AB - The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic acid derivative and three flavokawains from Piper diospyrifolium, P. cumanense and P. gaudichaudianum displayed significant activities against Biomphalaria glabrata snails. Additionally, "in silico" studies were performed using docking assays and Molecular Interaction Fields to evaluate the physical chemical differences among the compounds in order to characterize the observed activities of the test compounds against Biomphalaria glabrata snails. PMID- 24762962 TI - Bioactivity of a family of chiral nonracemic aminobenzylnaphthols towards Candida albicans. AB - Chiral nonracemic aminobenzylnaphthols were obtained by a Betti multi-component reaction between 2-naphthol, aryl aldehydes and enantiopure arylethylamine. Moreover, some new aminobenzylnaphthols were synthesized by a similar reaction between 2-naphthol, aryl aldehydes and prolinol. These aminobenzylnaphthols, synthesized from different components and thus having different structural features, were tested as anti-yeast agents inhibiting Candida albicans. The effect towards the test strain was studied with a microdilution approach and three different concentrations (150, 300 and 450 ug/mL) were tested. The best results were found for the aminobenzylnaphthols obtained from 1 naphthylethylamine and from natural prolinol. The use of the two-way ANOVA highlighted the better performances of the prolinol derivative among the differently structured aminobenzylnaphthols that were screened. The activity towards C. albicans of this prolinol derivative resulted to be interesting and could represent a promising alternative to overcome the problem of the strains resistant to the traditional antifungals. PMID- 24762963 TI - The intramolecular Diels-Alder reaction of diarylheptanoids--quantum chemical calculation of structural features favoring the formation of phenylphenalenones. AB - Diarylheptanoids have been reported as biosynthetic precursors of phenylphenalenones in plants. Quantum chemical calculations of molecular geometry and orbitals were used to elaborate which structural features are required to determine if diarylheptanoids can undergo an intramolecular Diel-Alder reaction to form phenylphenalenones. The computational data showed that an ortho-quinone- or a hydoxyketone-bearing ring A, containing the dienophile moiety, and a heptadiene chain with conjugated cisoid double bonds at C-4/C-6 and a saturated segment consisting of two sp3-carbon atoms, are required. Only four diarylheptanoids out of eighteen studied compounds proved to be suitable candidates. Among them are two 3,5-dideoxy compounds and two other compounds oxygenated only at C-3, suggesting that lachnanthocarpone, a representative of the 6-oxygenated phenylphenalenones, and anigorufone, a representative of the 6 deoxy phenylphenalenones, are not connected via a precursor-product relationship ("late reduction at C-6") but formed through partially separate pathways. PMID- 24762964 TI - Integrated computational tools for identification of CCR5 antagonists as potential HIV-1 entry inhibitors: homology modeling, virtual screening, molecular dynamics simulations and 3D QSAR analysis. AB - Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed that novel leads demonstrated better binding affinities with CCR5 compared to maraviroc, an FDA-approved HIV-1 entry inhibitor and in clinical use. Per-residue interaction energy decomposition analysis on the averaged MD structure showed that hydrophobic active residues Trp86, Tyr89 and Tyr108 contributed the most to inhibitor binding. The validated 3D-QSAR model showed a high cross-validated rcv2 value of 0.84 using three principal components and non-cross-validated r2 value of 0.941. It was also revealed that almost all compounds in the test set and training set yielded a good predicted value. Information gained from this study could shed light on the activity of a new series of lead compounds as potential HIV entry inhibitors and serve as a powerful tool in the drug design and development machinery. PMID- 24762965 TI - Immunostimulatory effects of polysaccharides isolated from Makgeolli (traditional Korean rice wine). AB - Makgeolli is a traditional Korean rice wine, reported to have various biological functions. In this study, the immunostimulatory activity of a polysaccharide from makgeolli (PSM) was investigated. The polysaccharide fraction was isolated from makgeolli by hot water extraction, ethanol precipitation, dialysis, and lyophilization. The major constituents in PSM were neutral sugars (87.3%). PSM was composed of five different sugars, glucose, mannose, galactose, xylose, and arabinose. In normal mice, PSM treatment increased the spleen index (p<0.05) as well as splenocyte proliferation (p<0.05) in combination with concanavalin A or lipopolysaccharide. The immunostimulatory activities of PSM were also examined in cyclophosphamide (CY)-induced immunosuppressed mice. Mice treated with PSM exhibited increased splenocyte proliferation (p<0.05), natural killer cell activity, and white blood cell counts (p<0.01) compared with immunosuppressed mice. These results indicate that PSM can enhance immune function in normal mice and CY-induced immunosuppressed mice. PMID- 24762966 TI - Thermodynamics and kinetics of guest-induced switching between "basket handle" porphyrin isomers. AB - The synthesis and switching properties of two "basket handle" porphyrin isomers is described. The cis-oriented meso-phenyl groups of these porphyrins are linked at their ortho-positons via benzocrown-ether-based spacers, which as a result of slow atropisomerization are located either on the same side of the porphyrin plane (cis), or on opposite sides (trans). In solution, the cis-linked isomer slowly isomerizes in the direction of the thermodynamically more stable trans isomer. In the presence of viologen (N,N'-dialkyl-4,4'-bipyridinium) derivatives, which have different affinities for the two isomers, the isomerization equilibrium could be significantly influenced. In addition, the presence of these guests was found to enhance the rate of the switching process, which was suggested to be caused by favorable interactions between the positively charged guest and the crown ethers of the receptor, stabilizing the transition state energies of the isomerization reaction between the two isomers. PMID- 24762967 TI - Identifying stereoisomers by ab-initio calculation of secondary isotope shifts on NMR chemical shieldings. AB - We present ab-initio calculations of secondary isotope effects on NMR chemical shieldings. The change of the NMR chemical shift of a certain nucleus that is observed if another nucleus is replaced by a different isotope can be calculated by computing vibrational corrections on the NMR parameters using electronic structure methods. We demonstrate that the accuracy of the computational results is sufficient to even distinguish different conformers. For this purpose, benchmark calculations for fluoro(2-2H)ethane in gauche and antiperiplanar conformation are carried out at the HF, MP2 and CCSD(T) level of theory using basis sets ranging from double- to quadruple-zeta quality. The methodology is applied to the secondary isotope shifts for 2-fluoronorbornane in order to resolve an ambiguity in the literature on the assignment of endo- and exo-2 fluoronorbornanes with deuterium substituents in endo-3 and exo-3 positions, also yielding insight into mechanistic details of the corresponding synthesis. PMID- 24762968 TI - Synthesis, crystal structure, spectra and quantum chemical study on 1-phenyl-3-(4 nitrophenyl)-5-(2-thienyl)-2-pyrazoline. AB - 1-Phenyl-3-(4-nitrophenyl)-5-(2-thienyl)-2-pyrazoline was synthesized and characterized by elemental analysis, IR and X-ray single crystal diffraction. UV Vis spectra and fluorescence spectra were measured. Density functional theory calculations on the structure of the title compound were performed at the B3LYP/6 311G** level of theory. NPA atomic charge distributions indicate that, although the S atom in the thienyl ring loses coordination capacity, the title compound still may be used as a potential multi-dentate ligand to coordinate with metallic ions. The calculation of the second order optical nonlinearity was carried out. Natural bond orbital analyses indicate that the electronic absorption bands are mainly derived from the contribution of n->pi* and pi->pi* transitions. Fluorescence spectra determination shows that the title compound is a potential orange-light emitting material. PMID- 24762969 TI - Rice bran feruloylated oligosaccharides activate dendritic cells via Toll-like receptor 2 and 4 signaling. AB - This work presents the effects of feruloylated oligosaccharides (FOs) of rice bran on murine bone marrow-derived dendritic cells (BMDCs) and the potential pathway through which the effects are mediated. We found that FOs induced phenotypic maturation of DCs, as shown by the increased expression of CD40, CD80/CD86 and MHC-I/II molecules. FOs efficiently induced maturation of DCs generated from C3H/HeN or C57BL/6 mice with normal toll-like receptor 4 (TLR-4) or TLR-2 but not DCs from mice with mutated TLR4 or TLR2. The mechanism of action of FOs may be mediated by increased phosphorylation of ERK, p38 and JNK mitogen activated protein kinase (MAPKs) and increased NF-kB activity, which are important signaling molecules downstream of TLR-4 and TLR-2. These data suggest that FOs induce DCs maturation through TLR-4 and/or TLR-2 and that FOs might have potential efficacy against tumor or virus infection or represent a candidate adjuvant approach for application in immunotherapy and vaccination. PMID- 24762970 TI - The legacies of Eugene Jamot and La Jamotique. PMID- 24762971 TI - Knowledge-based fragment binding prediction. AB - Target-based drug discovery must assess many drug-like compounds for potential activity. Focusing on low-molecular-weight compounds (fragments) can dramatically reduce the chemical search space. However, approaches for determining protein fragment interactions have limitations. Experimental assays are time-consuming, expensive, and not always applicable. At the same time, computational approaches using physics-based methods have limited accuracy. With increasing high resolution structural data for protein-ligand complexes, there is now an opportunity for data-driven approaches to fragment binding prediction. We present FragFEATURE, a machine learning approach to predict small molecule fragments preferred by a target protein structure. We first create a knowledge base of protein structural environments annotated with the small molecule substructures they bind. These substructures have low-molecular weight and serve as a proxy for fragments. FragFEATURE then compares the structural environments within a target protein to those in the knowledge base to retrieve statistically preferred fragments. It merges information across diverse ligands with shared substructures to generate predictions. Our results demonstrate FragFEATURE's ability to rediscover fragments corresponding to the ligand bound with 74% precision and 82% recall on average. For many protein targets, it identifies high scoring fragments that are substructures of known inhibitors. FragFEATURE thus predicts fragments that can serve as inputs to fragment-based drug design or serve as refinement criteria for creating target-specific compound libraries for experimental or computational screening. PMID- 24762973 TI - Is recursion language-specific? Evidence of recursive mechanisms in the structure of intentional action. AB - In their 2002 seminal paper Hauser, Chomsky and Fitch hypothesize that recursion is the only human-specific and language-specific mechanism of the faculty of language. While debate focused primarily on the meaning of recursion in the hypothesis and on the human-specific and syntax-specific character of recursion, the present work focuses on the claim that recursion is language-specific. We argue that there are recursive structures in the domain of motor intentionality by way of extending John R. Searle's analysis of intentional action. We then discuss evidence from cognitive science and neuroscience supporting the claim that motor-intentional recursion is language-independent and suggest some explanatory hypotheses: (1) linguistic recursion is embodied in sensory-motor processing; (2) linguistic and motor-intentional recursions are distinct and mutually independent mechanisms. Finally, we propose some reflections about the epistemic status of HCF as presenting an empirically falsifiable hypothesis, and on the possibility of testing recursion in different cognitive domains. PMID- 24762972 TI - Metabolomic analysis of pressure-overloaded and infarcted mouse hearts. AB - BACKGROUND: Cardiac hypertrophy and heart failure are associated with metabolic dysregulation and a state of chronic energy deficiency. Although several disparate changes in individual metabolic pathways have been described, there has been no global assessment of metabolomic changes in hypertrophic and failing hearts in vivo. Hence, we investigated the impact of pressure overload and infarction on myocardial metabolism. METHODS AND RESULTS: Male C57BL/6J mice were subjected to transverse aortic constriction or permanent coronary occlusion (myocardial infarction [MI]). A combination of LC/MS/MS and GC/MS techniques was used to measure 288 metabolites in these hearts. Both transverse aortic constriction and MI were associated with profound changes in myocardial metabolism affecting up to 40% of all metabolites measured. Prominent changes in branched-chain amino acids were observed after 1 week of transverse aortic constriction and 5 days after MI. Changes in branched-chain amino acids after MI were associated with myocardial insulin resistance. Longer duration of transverse aortic constriction and MI led to a decrease in purines, acylcarnitines, fatty acids, and several lysolipid and sphingolipid species but a marked increase in pyrimidines as well as ascorbate, heme, and other indices of oxidative stress. Cardiac remodeling and contractile dysfunction in hypertrophied hearts were associated with large increases in myocardial, but not plasma, levels of the polyamines putrescine and spermidine as well as the collagen breakdown product prolylhydroxyproline. CONCLUSIONS: These findings reveal extensive metabolic remodeling common to both hypertrophic and failing hearts that are indicative of extracellular matrix remodeling, insulin resistance and perturbations in amino acid, and lipid and nucleotide metabolism. PMID- 24762974 TI - Attentional load and the consciousness of one's own name. AB - We investigated how the location of one's own name in a visual display influences its conscious awareness using recall and recognition tests in an inattentional blindness paradigm. The participant's own name or another person's name appeared unexpectedly in the center or the periphery of the display during a critical trial under low- or high-attentional search load. The results showed that the majority of participants detected their names under low load regardless of location and test method. Under high load, the majority of the participants could recognize or recall their names presented in the center of the display. When the person's name was in the periphery, most of the participants did not recall their names, and approximately half recognized their names. In contrast, conscious awareness of another person's name was low in all conditions. A person's own name is processed with high priority, even under a high-attentional load. PMID- 24762975 TI - Conflict tasks and the diffusion framework: Insight in model constraints based on psychological laws. AB - Formal models of decision-making have traditionally focused on simple, two-choice perceptual decisions. To date, one of the most influential account of this process is Ratcliff's drift diffusion model (DDM). However, the extension of the model to more complex decisions is not straightforward. In particular, conflicting situations, such as the Eriksen, Stroop, or Simon tasks, require control mechanisms that shield the cognitive system against distracting information. We adopted a novel strategy to constrain response time (RT) models by concurrently investigating two well-known empirical laws in conflict tasks, both at experimental and modeling levels. The two laws, predicted by the DDM, describe the relationship between mean RT and (i) target intensity (Pieron's law), (ii) standard deviation of RT (Wagenmakers-Brown's law). Pioneering work has shown that Pieron's law holds in the Stroop task, and has highlighted an additive relationship between target intensity and compatibility. We found similar results in both Eriksen and Simon tasks. Compatibility also violated Wagenmakers-Brown's law in a very similar and particular fashion in the two tasks, suggesting a common model framework. To investigate the nature of this commonality, predictions of two recent extensions of the DDM that incorporate selective attention mechanisms were simulated and compared to the experimental results. Both models predict Pieron's law and the violation of Wagenmakers Brown's law by compatibility. Fits of the models to the RT distributions and accuracy data allowed us to further reveal their relative strengths and deficiencies. Combining experimental and computational results, this study sets the groundwork for a unified model of decision-making in conflicting environments. PMID- 24762976 TI - Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy. AB - Food allergy is mediated by a combination of genetic and environmental risk factors, potentially mediated by epigenetic mechanisms. CD4+ T-cells are key drivers of the allergic response, and may therefore harbor epigenetic variation in association with the disease phenotype. Here we retrospectively examined genome-wide DNA methylation profiles (~450,000 CpGs) from CD4+ T-cells on a birth cohort of 12 children with IgE-mediated food allergy diagnosed at 12-months, and 12 non-allergic controls. DNA samples were available at two time points, birth and 12-months. CASE: control comparisons of CD4+ methylation profiles identified 179 differentially methylated probes (DMP) at 12-months and 136 DMP at birth (FDR adjusted P value<0.05, delta beta>0.1). Approximately 30% of DMPs were coincident with previously annotated SNPs. A total of 92 [corrected] allergy-associated non SNP DMPs were present at birth when individuals were initially disease-free, potentially implicating these loci in the causal pathway. Pathway analysis of differentially methylated genes identified several MAP kinase signaling molecules. Mass spectrometry was used to validate 15 CpG sites at 3 candidate genes. Combined analysis of differential methylation with gene expression profiles revealed gene expression differences at some but not all allergy associated differentially methylated genes. Thus, dysregulation of DNA methylation at MAPK signaling-associated genes during early CD4+ T-cell development may contribute to suboptimal T-lymphocyte responses in early childhood associated with the development of food allergy. PMID- 24762977 TI - Membrane ectopeptidases targeted by human coronaviruses. AB - Six coronaviruses, including the recently identified Middle East respiratory syndrome coronavirus, are known to target the human respiratory tract causing mild to severe disease. Their interaction with receptors expressed on cells located in the respiratory tract is an essential first step in the infection. Thus far three membrane ectopeptidases, dipeptidyl peptidase 4 (DPP4), angiotensin-converting enzyme 2 (ACE2) and aminopeptidase N (APN), have been identified as entry receptors for four human-infecting coronaviruses. Although the catalytic activity of the ACE2, APN, and DPP4 peptidases is not required for virus entry, co-expression of other host proteases allows efficient viral entry. In addition, evolutionary conservation of these receptors may permit interspecies transmissions. Because of the physiological function of these peptidase systems, pathogenic host responses may be potentially amplified and cause acute respiratory distress. PMID- 24762978 TI - The epidemiology of bacteriuria and candiduria in critically ill patients. AB - An observational study was conducted to describe the epidemiology of bacteriuria and candiduria in the intensive care unit (ICU), and the occurrence of blood stream infection (BSI) associated with ICU-acquired positive urine culture. Between 2006 and 2011, 444 episodes of either bacteriuria or candiduria defined by positive urine culture (microorganisms ?105 c.f.u./ml) occurred in 406 patients. Three hundred and seventy-seven (85%) were hospital-acquired including 221 which were ICU-acquired (6.4 +/- 0.8 episodes/1000 ICU days). Escherichia coli was the most common bacteria of both community- and ICU-acquired bacteriuria/candiduria (49.2% and 29%, respectively). Candida spp. represented 55% (129/236) of pathogens responsible for ICU-acquired positive urine cultures. Patients with ICU-acquired candiduria had greater illness severity at ICU admission than those with ICU-acquired bacteriuria (APACHE III score 79 +/- 25 vs. 66 +/- 31, P = 0.0015). BSI associated with ICU-acquired positive urine culture occurred in 0.15/1000 ICU days and was more often due to Candida. In this study, Candida was the most common pathogen responsible for ICU-acquired positive urine cultures and illness severity was a risk factor for candiduria in the study population. PMID- 24762980 TI - Mothers' behaviour contributes to suboptimal iodine status of family members: findings from an iodine-sufficient area. AB - OBJECTIVE: Iodine deficiency still remains a major public health concern worldwide despite global progress in its elimination. The aims of the present study were to evaluate dietary iodine status in the mother and one adult member of each family and the association between mothers' knowledge, attitude and behaviour and the dietary iodine status of adult family members in Tehran. DESIGN: In this cross-sectional study, 24 h urinary iodine and Na concentrations and the iodine content of household salt were measured. Mothers' knowledge, attitude and behaviour were assessed using a questionnaire administered in face to-face interviews. SETTING: Health-care centres from four distinct areas of Tehran. SUBJECTS: Mother-adult family member pairs aged >= 19 years (n 290), enrolled through randomized cluster sampling. RESULTS: In mothers and adult family members, median 24 h urinary iodine concentration was 73 (interquartile range (IQR) 36-141) ug/l and 70 (IQR 34-131) ug/l, dietary iodine intake was 143 (IQR 28-249) ug/d and 130 (IQR 26-250) ug/d and dietary salt intake was 8.0 (IQR 5.9-10.2) g/d and 7.5 (IQR 5.3-10.0) g/d, respectively. Significant correlations were observed between mothers' attitude and behaviour and the 24 h urinary iodine concentration, dietary iodine intake and iodine content of salt of adult family members. In multiple analysis, lower quartiles of salt iodine content and salt intake and inappropriate behaviour scores in mothers increased the risk of urinary iodine concentration <100 ug/l in adult family members. CONCLUSIONS: The present study showed that mothers' behaviour, but not knowledge and attitude, was among major contributors to the suboptimal dietary iodine status observed in adult family members. PMID- 24762979 TI - Leishmania aethiopica field isolates bearing an endosymbiontic dsRNA virus induce pro-inflammatory cytokine response. AB - BACKGROUND: Infection with Leishmania parasites causes mainly cutaneous lesions at the site of the sand fly bite. Inflammatory metastatic forms have been reported with Leishmania species such as L. braziliensis, guyanensis and aethiopica. Little is known about the factors underlying such exacerbated clinical presentations. Leishmania RNA virus (LRV) is mainly found within South American Leishmania braziliensis and guyanensis. In a mouse model of L. guyanensis infection, its presence is responsible for an hyper-inflammatory response driven by the recognition of the viral dsRNA genome by the host Toll like Receptor 3 leading to an exacerbation of the disease. In one instance, LRV was reported outside of South America, namely in the L. major ASKH strain from Turkmenistan, suggesting that LRV appeared before the divergence of Leishmania subgenera. LRV presence inside Leishmania parasites could be one of the factors implicated in disease severity, providing rationale for LRV screening in L. aethiopica. METHODOLOGY/PRINCIPAL FINDINGS: A new LRV member was identified in four L. aethiopica strains (LRV-Lae). Three LRV-Lae genomes were sequenced and compared to L. guyanensis LRV1 and L. major LRV2. LRV-Lae more closely resembled LRV2. Despite their similar genomic organization, a notable difference was observed in the region where the capsid protein and viral polymerase open reading frames overlap, with a unique -1 situation in LRV-Lae. In vitro infection of murine macrophages showed that LRV-Lae induced a TLR3-dependent inflammatory response as previously observed for LRV1. CONCLUSIONS/SIGNIFICANCE: In this study, we report the presence of an immunogenic dsRNA virus in L. aethiopica human isolates. This is the first observation of LRV in Africa, and together with the unique description of LRV2 in Turkmenistan, it confirmed that LRV was present before the divergence of the L. (Leishmania) and (Viannia) subgenera. The potential implication of LRV-Lae on disease severity due to L. aethiopica infections is discussed. PMID- 24762981 TI - Chronic recruitment of primary afferent neurons by microstimulation in the feline dorsal root ganglia. AB - OBJECTIVE: This study describes results of primary afferent neural microstimulation experiments using microelectrode arrays implanted chronically in the lumbar dorsal root ganglia (DRG) of four cats. The goal was to test the stability and selectivity of these microelectrode arrays as a potential interface for restoration of somatosensory feedback after damage to the nervous system such as amputation. APPROACH: A five-contact nerve-cuff electrode implanted on the sciatic nerve was used to record the antidromic compound action potential response to DRG microstimulation (2-15 uA biphasic pulses, 200 us cathodal pulse width), and the threshold for eliciting a response was tracked over time. Recorded responses were segregated based on conduction velocity to determine thresholds for recruiting Group I and Group II/Abeta primary afferent fibers. MAIN RESULTS: Thresholds were initially low (5.1 +/- 2.3 uA for Group I and 6.3 +/- 2.0 uA for Group II/Abeta) and increased over time. Additionally the number of electrodes with thresholds less than or equal to 15 uA decreased over time. Approximately 12% of tested electrodes continued to elicit responses at 15 uA up to 26 weeks after implantation. Higher stimulation intensities (up to 30 uA) were tested in one cat at 23 weeks post-implantation yielding responses on over 20 additional electrodes. Within the first six weeks after implantation, approximately equal numbers of electrodes elicited only Group I or Group II/Abeta responses at threshold, but the relative proportion of Group II/Abeta responses decreased over time. SIGNIFICANCE: These results suggest that it is possible to activate Group I or Group II/Abeta primary afferent fibers in isolation with penetrating microelectrode arrays implanted in the DRG, and that those responses can be elicited up to 26 weeks after implantation, although it may be difficult to achieve a consistent response day-to-day with currently available electrode technology. The DRG are compelling targets for sensory neuroprostheses with potential to achieve recruitment of a range of sensory fiber types over multiple months after implantation. PMID- 24762982 TI - How have ART treatment programmes changed the patterns of excess mortality in people living with HIV? Estimates from four countries in East and Southern Africa. AB - BACKGROUND: Substantial falls in the mortality of people living with HIV (PLWH) have been observed since the introduction of antiretroviral therapy (ART) in sub Saharan Africa. However, access and uptake of ART have been variable in many countries. We report the excess deaths observed in PLWH before and after the introduction of ART. We use data from five longitudinal studies in Malawi, South Africa, Tanzania, and Uganda, members of the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA). METHODS: Individual data from five demographic surveillance sites that conduct HIV testing were used to estimate mortality attributable to HIV, calculated as the difference between the mortality rates in PLWH and HIV-negative people. Excess deaths in PLWH were standardized for age and sex differences and summarized over periods before and after ART became generally available. An exponential regression model was used to explore differences in the impact of ART over the different sites. RESULTS: 127,585 adults across the five sites contributed a total of 487,242 person years. Before the introduction of ART, HIV-attributable mortality ranged from 45 to 88 deaths per 1,000 person years. Following ART availability, this reduced to 14-46 deaths per 1,000 person years. Exponential regression modeling showed a reduction of more than 50% (HR =0.43, 95% CI: 0.32-0.58), compared to the period before ART was available, in mortality at ages 15-54 across all five sites. DISCUSSION: Excess mortality in adults living with HIV has reduced by over 50% in five communities in sub-Saharan Africa since the advent of ART. However, mortality rates in adults living with HIV are still 10 times higher than in HIV-negative people, indicating that substantial improvements can be made to reduce mortality further. This analysis shows differences in the impact across the sites, and contrasts with developed countries where mortality among PLWH on ART can be similar to that of the general population. Further research is urgently needed to establish why the different impacts on mortality were observed and how the care and treatment programmes in these countries can be more effective in reducing mortality further. PMID- 24762983 TI - 'In general, how do you feel today?'--self-rated health in the context of aging in India. AB - This thesis is centered on self-rated health (SRH) as an outcome measure, as a predictor, and as a marker. The thesis uses primary data from the WHO Study on global AGEing and adult health (SAGE) implemented in India in 2007. The structural equation modeling approach is employed to understand the pathways through which the social environment, disability, disease, and sociodemographic characteristics influence SRH among older adults aged 50 years and above. Cox proportional hazard model is used to explore the role of SRH as a predictor for mortality and the role of disability in modifying this effect. The hierarchical ordered probit modeling approach, which combines information from anchoring vignettes with SRH, was used to address the long overlooked methodological concern of interpersonal incomparability. Finally, multilevel model-based small area estimation techniques were used to demonstrate the use of large national surveys and census information to derive precise SRH prevalence estimates at the district and sub-district level. The thesis advocates the use of such a simple measure to identify vulnerable communities for targeted health interventions, to plan and prioritize resource allocation, and to evaluate health interventions in resource-scarce settings. The thesis provides the basis and impetus to generate and integrate similar and harmonized adult health and aging data platforms within demographic surveillance systems in different regions of India and elsewhere. PMID- 24762988 TI - Effects of Rashba and Dresselhaus spin-orbit interactions on the ground state of two-dimensional localized spins. AB - Starting with the indirect exchange model influenced by the Rashba and the Dresselhaus spin-orbit interactions, we derive the Dzyaloshinskii-Moriya interaction of localized spins. The strength of the Dzyaloshinskii-Moriya interaction is compared with that of the Heisenberg exchange term as a function of atomic distance. Using the calculated interaction strengths, we discuss the formation of various atomic ground states as a function of temperature and external magnetic field. By plotting the magnetic field-temperature phase diagram, we present approximate phase boundaries between the spiral, Skyrmion and ferromagnetic states of the two-dimensional weak ferromagnetic system. PMID- 24762986 TI - Cancer and involuntary weight loss: failure to validate a prediction score. AB - BACKGROUND: Many patients who have involuntary weight loss have cancer. The Hernandez prediction rule includes 5 variables (elevated levels of alkaline phosphatase and lactate dehydrogenase, low albumin, high white blood cell count, and age >80 years). The purpose of this study was to evaluate the validity of the prediction rule. METHODS: We prospectively evaluated 290 consecutive inpatients and outpatients who had involuntary weight loss. Clinical, hematologic, and biochemical parameters were determined. There were 259 patients who had follow-up at 6 months to determine the cause of involuntary weight loss, and 31 other patients were lost to follow-up. The 5 variables were introduced into a regression logistic model with cancer as a dependent variable. RESULTS: Cancer was diagnosed in 72 of the 290 patients (25%) who had involuntary weight loss. Bivariate analysis showed that serum albumin, C-reactive protein, erythrocyte sedimentation rate, alkaline phosphatase, iron, lactate dehydrogenase, white blood cell count, hemoglobin, and ferritin levels were associated with cancer (range of area under the receiver operating characteristic curve, 0.589 to 0.688). Multivariate analysis showed that albumin, erythrocyte sedimentation rate, iron, white blood cell count, and lactate dehydrogenase levels were associated with cancer. When dichotomized, only low albumin (odds ratio, 2.6, CI [1.3-5.2]) and high alkaline phosphatase (odds ratio, 2.3, CI [1.7-4.7]) were associated with cancer. The area under the receiver operating characteristic curve of the 5-variable prediction rule was only 0.70 (95% confidence interval, 0.61-0.78). The negative predictive value of this model with 3 variables (age >60 y, alkaline phosphatase, and albumin level) increased from 85% to 95% when all tests were negative. CONCLUSIONS: In patients who had involuntary weight loss, those who have cancer are likely to have >=1 abnormal laboratory test. The 5 variable prediction rule had a significantly lower accuracy than originally reported. Further evaluation of the 3-variable modification of the prediction rule may be useful. PMID- 24762989 TI - [Associations of HLA gene with leukemia in 1186 cases]. AB - The purpose of this study was to evaluate the potential associations between HLA A, B, DRB1 gene and leukemia. A total of 1186 leukemic patients, including 326 patients with acute lymphoblastic leukemia (ALL), 545 patients with acute myeloid leukemia (AML), 315 patients with chronic myeloid leukemia (CML), and 1234 healthy unrelated donors were typed and were compared in a single centre by using same technique, then the Bonferroni correction method was used to correct the Type I error. The results indicated that as compared with the control,the frequency of HLA-DRB1(*)09 in ALL group significantly decreased (10.87% versus 16.08%; Pc = 0.014, OR = 0.637, 95% CI = 0.487-0.834), while in comparison with control, the frequency of HLA-B(*)18 in CML group was significantly higher (1.28% vs 0.20%; Pc = 0.039, OR = 6.336, 95% CI = 2.066-19.434). The positive and negative relation may exist between certain HLA molecules and leukemia. The negative relation between HLA-DRB1(*)09 and ALL indicated that DRB1*09 might play an important role by a restricted T-cell immune response in the early leukemogenic events, whereas the positive relation between HLA-B(*)18 and CML suggests that the B(*)18 molecules may not actively present leukemia-specific antigens resulting in immune escape. It is concluded that these findings can contribute to developing more appropriate method in leukemic immunotherapy. PMID- 24762990 TI - [Establishment of methylation-specific quantitative PCR system for ID4 gene in acute leukemia cells and its specificity and sensitivity]. AB - DNA methylation of ID4 gene promoter occurred frequently in patients with acute leukemia and was found to be highly related to the tumor progression. Due to lack of the appropriate methylation detection methods, the relation between the quantification of ID4 methylation and the states of acute leukemia is still unclear. This study purposed to set up a methylation-specific quantitative PCR system for ID4 and investigate the specificity and sensitivity of this methylation detection. The plasmids combined with target gene as well as with internal reference were constructed, and the standard curves were set up by using above mentioned plasmids. The specificity of this detection system in cell lines was verified through techniques of MSP and quantitative MSP. The sensitivity of this detection system was verified by mixing methylation-positive and negative cell lines in varying proportions and through amplification of qualitative MSP. The results showed that the standard curves were establish successfully. The results of quantitative MS-PCR in cell lines were consistent with those of MS PCR, and as low as 1: 10(-5) of ID4 methylation positive cells could be detected by the new methylation detection assay. In newly diagnosed acute leukemia patients, the positive rate of quantitative MSP was higher. It is concluded that a complete quantitative MSP system for ID4 methylation detection has been established and this quantitative MSP method has good specificity and high sensitivity. PMID- 24762991 TI - [Expression of NANOG gene in acute lymphoblastic leukemia cells and construction of lentiviral vector carrying NANOG specific shRNA]. AB - The aim of this study was to detect the expression of NANOG gene in acute lymphoblastic leukemia (ALL) cells, and to construct the lentiviral vector carrying NANOG specific shRNA. The expression of NANOG was detected by RT-PCR and Western blot in MOLT-4, CCRF-HSB2, Jurkat cells and bone marrow cells from 15 patients with ALL in our hospital. The lentiviral vector carrying NANOG specific shRNA was constructed. After infection of MOLT-4 cells with the lentivirus constructs, GFP (+) cells were harvested by flow cytometry. The efficiency of RNA interference was detected by real-time quantitative PCR and Western blot. The results showed that the expression of NANOG mRNA and protein was detected in MOLT 4, CCRF-HSB2 cells and 33.3% samples of bone marrow from patients with ALL. The sequencing results demonstrated that the mRNAs amplified from these leukemic cells showed higher homology to NANOGP8 than NANOG1. The lentiviral vector pLB shNANOG-1, pLB-shNANOG-2 and pLB-shcontrol were constructed. The viral particles were harvested and concentrated by ultracentrifugation. The virus titers were (1.83-3.12) *10(8) IU/ml. After infection of MOLT-4 cells with the lentivirus, flow cytometry detection indicated that the GFP(+) cells were harvested by real time quantitative PCR and Western blot, the assays showed that the 2 designed shRNA could significantly down-regulate expression of NANOG gene and protein. It is concluded that NANOGP8 is expressed in various types of ALL cells and in 33.3% of marrow cell samples obtained from ALL patients. After infection with the lentivirus constructs, MOLT-4 cells which stably down-regulate the expression of NANOG mRNA are obtained. PMID- 24762992 TI - [Genetic characteristics of human acute lymphoblastic leukemia cell line Molt-4]. AB - This study was aimed to investigate the genetic characteristics of human acute lymphoblastic leukemia cell line Molt-4, and evaluate its application in measuring telomere length by Flow-FISH. Molt-4 cell line was cultured in suspension and subcultured regularly. Eight different passages of Molt-4 cells in exponential stage were selected.The growth curves were drawn by cell counting method, meanwhile calculating the population doubling times of cells,DNA ploidies were determined by flow cytometry,karyotypes were analyzed by G-banding and telomere lengths were measured by Southern blot. The results showed that the population doubling time of Molt-4 cell line was (1.315 +/- 0.062) d, DNA ploidy index was (2.085 +/- 0.0093) , and the telomere length was (32.05 +/- 5.27) kb. There were no significant difference among different passages (P = 0.931,0.888 and 0.935 separately). The karyotypes showed that the chromosome numbers of Molt 4 cell line were from 91 to 99 in different metaphases, and the majority of them were hypertetraploid, and stable and recurrent structural abnormalities of chromosomes could be kept. It is concluded that the stable genetic characteristics and the longer telomere length of Molt-4 cell line makes it be a feasible control cells in measurement of telomere length by Flow-FISH. PMID- 24762993 TI - [Comparison of the efficacy of two chemotherapy protocols for children with TEL AML1[STBZ] fusion gene positive acute lymphoblastic leukemia]. AB - This study was aimed to compare the curative effect of BCH - 2003 protocol and CCLG - 2008 protocol for children with TEL-AML1 fusion gene positive childhood acute lymphoblastic leukemia (ALL) and to investigate the more suitable protocol for this subtype of childhood leukemia. The clinical data for children with TEL AML1 fusion gene positive ALL admitted from January 2003 to October 2010 in Hematology Center of Beijing Children's Hospital were collected. The common clinical characteristics including prednisone response at day 8, minimal residual disease (MRD) at the end of induction of remission (day 33), event free survival (EFS), relapse free survival (RFS) were compared. The results showed that out of 204 children with TEL-AML1 fusion gene positive ALL, 134 and 70 patients were treated by BCH-2003 protocol and CCLG-2008 protocol respectively. There were no statistical difference in age, white blood cell count in peripheral blood at presentation, prednisone response and CNS involvement. However, there were more boys in CCLG-2008 group (P = 0.025). The negative rate of MRD at day 33 in BCH 2003 group was lower than that in CCLG-2008 group (P = 0.013). After re stratifying the patients in CCLG-2008 group according to the stratification criteria of BCH-2003 protocol, the negative rate of MRD at day 33 of patients with intermediate risk remained higher in BCH-2003 group than that in CCLG-2008 group (P = 0.014) . However, no significant difference in the patients with standard risk was found. There were also no significant statistical differences in the incidence of severe infection, EFS and RFS, (P = 1.000, P = 0.327,P = 0.251 respectively) during chemotherapy. It is concluded that for children with TEL-AML1 fusion gene positive ALL, the induction of remission of BCH - 2003 protocol can decrease leukemic load more quickly than that of CCLG - 2008 protocol. However, the outcome of the patients treated by the two protocols is similar. PMID- 24762994 TI - [Correlation analysis of FPGS rs10760502G>a polymorphism with prognosis and MTX related toxicity in pediatric B-cell acute lymphoblastic leukemia]. AB - This study was aimed to explore the relation between folylpolyglutamate synthetase (FPGS) rs10760502 polymorphism and prognosis and methotrexate (MTX) related toxicities in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Sequenom MassARRAY was used to genotype rs10760502. The chi(2) test, Kaplan-Meier method and Cox regression models were used to analyze the data. The results indicated that A allele carriers (GA+AA) had poor relapse free survival (RFS, log rank: P = 0.004) and event free survival (EFS, log-rank: P = 0.022) compared with the GG genotype carriers. Multivariate Cox-regression analysis results showed that A allele is an independent prognosis factor for poor RFS [hazard ratio (HR), 20.173; 95% CI, 2.535-160.545; P = 0.005] and EFS (HR, 8.133; 95% CI, 1.718 38.512; P = 0.008). No relationship was found between any MTX toxicity and rs10760502 polymorphism. It is concluded that FPGS rs10760502G>A polymorphism may affect the treatment outcome of B-ALL patients. PMID- 24762996 TI - [Efficacy and safety analysis of interferon combined with imatinib in treating chronic myeloid leukemia]. AB - Imatinib has been recognized as the frontline therapy drug in chronic myeloid leukemia (CML), however, only limited patients could achieve complete molecular remission (CMR). Recent clinical and basic proofs indicated an improved treatment outcome by the combination of interferon and Imatinib. This study was purposed to evaluated systematically the efficacy and safety of interferon plus Imatinib in patients with CML. Data from relative clinical trials were from clinical trial of gov and Cochrane Collaboration. A comprehensive literature search was performed from data bases such as pubMed and EM. The results indicated that 7 clinical trials and 12 research papers met the criteria enrolled in study, included 697 cases in total. The combination group had higher complete cytogenetic remission (CCgR) rate than imatinib alone at 6 months (58% vs 42%; P = 0.0001) and 12 months (74% vs 68%; P = 0.004). The major molecular remission (MMR) rate was also higher in the combination group at 6 months (58% vs 34%; P = 0.0001) and 12 months (66% vs 47%; P < 0.0001). Furthermore, compared with single drug, the combination group had superior CMR rate at 6 months (13% vs 2%; P = 0.0002) and 12 months (14% vs 5%; P = 0.0009). The major adverse effects of combination therapy were rash, asthenia, edema and musculoskeletal events, and combination therapy was more prone to inducing neutropenia, thrombocytopenia and mild anemia. It is concluded that compared with Imatinib alone, the combination of interferon and Imatinib has better clinical efficacy in treating CML with earlier cytogenetic and molecular remission. It is also a safe therapy in spite of slightly weaker tolerance than single drug therapy. PMID- 24762995 TI - [Evaluation of early response to treatment and its prognostic value in childhood acute lymphoblastic leukemia]. AB - This study was purposed to investigate the prognostic value of early response to treatment in childhood acute lymphoblastic leukemia (ALL). Four indexes were used to assess early response to treatment including response to prednisone on day 8 (D8-PR), percentage of lymphoblast in bone marrow on day 22 (D22-BM) and day 33 (D33-BM), the level of minimal residual disease (MRD) on day 33 (D33-MRD) by morphological and molecular biological method in 426 children with ALL. Prognostic impact of early response to treatment was analyzed, and multivariate analysis of the predictive value was performed by Cox-regression analysis. All patients were followed up until October 31, 2013, with a median follow-up time of 80 months (0.5 to 106 months). The results showed that there were significant differences between event free survivals (EFS) of the sub-groups divided according to the four indexes. The 8 years-EFS in patients with prednisone good response (PGR) was significantly higher than that in patients with prednisone poor response (PPR);patients with M1 in bone marrow on day 22 or day 33 had the better outcomes than that of patients with M2/M3;patients with high level of MRD ( >= 10(-4)) had the worse outcomes as compared with patients with low level of MRD (<10(-4)) (P < 0.001). Cox proportional hazard model analysis showed that BCR/ABL fusion gene positive, D8-PR, D33-BM and D33-MRD were the independent prognostic factors for childhood ALL, and the hazard ratio of D33-MRD >= 10(-2) was highest (HR:11.886, P < 0.001). It is concluded that early response to treatment is an independent prognostic factor with important prognostic values, and it has important clinical guiding instructive significance for risk stratification in the treatment of children ALL. PMID- 24762997 TI - [Inducing effects of ursolic acid on Jurkat cell apoptosis and its mechanisms]. AB - The study was aimed to investigate the inducing effect of ursolic acid (UA) on the apoptosis of human T-cell leukemia/lymphoma (Jurkat), and whether the regulation of PTEN involved in the effect of UA on Jurkat cells. The Jurkat cells were treated with different concentrations of UA for different time. The cell proliferation was analyzed with cytotoxicity test (CCK8 method). Cell apoptosis was detected by fluorescence microscopy and flow cytometry. The expression of PTEN mRNA was detected by real-time quantitative PCR. The results indicated that UA could significantly inhibited the viability of Jurkat cells treated with 10-80 umol/L and in dose- and time-dependent manner. UA could induce Jurkat cell apoptosis in a dose-dependent manner, which was statistical different from the control at the same time (P < 0.05). PTEN mRNA expression was up-regulated by UA, which was statistical different from the control (P < 0.05). It is concluded that UA may induce Jurkat cell apoptosis by up-regulating the PTEN mRNA expression. PMID- 24762998 TI - [Analysis of empirical treatment for newly diagnosed acute promyelocytic leukemia combined with disseminated intravascular coagulation]. AB - This study was aimed to explore the clinical characteristics and optimal therapeutic methods for newly diagnosed acute promyelocytic leukemia (APL) combined with disseminated intravascular coagulation (DIC) so as to guide the clinical therapy. The clinical date and therapeutic outcome of 25 cases of APL combined with DIC treated from January 2008 to March 2013 in our department were analysed retrospectively. The 25 patients were given ATRA 20 mg orally twice a day and arsenic trioxide (ATO) 10 mg intravenously once a day to induce differentiation therapy, the chemotherapy was added after degranulation of promyelocytes. At the same time the platelets, fresh frozen plasma, fibrinogen, cryoprecipitate,prothrombin complex and amino methylbenzoic acid, low molecular weight heparin were given to treat DIC. According to the laboratorial examination of coagulation and fibrinolysis, the medication was adjusted.The white blood cell count, platelet level, prothrombin time (PT), partial thromboplastin time of plasma (APTT), fibrinogen level were detected, and the relation of those factors and age with bleeding severity was analyzed by multivariate manner. The results showed that among 25 patients with APL (low-risk 5 cases, intermediate risk 13 cases and high risk 7 cases), 22 cases combined with DIC, incidence of DIC was 88%. Out of 22 patients with DIC 21 patients (95.5%) were corrected, except 1 case death. After the first course of treatment, 23 cases (92%) gained complete remission (CR) with average CR time 31.8 +/- 7.2 days. During the induction of CR, the average platelet transfusion level was 75.68 +/- 55.88 U, the RBC level was 8.90 +/- 5.69 U, the average level of fresh frozen plasma transfusion of APL patients with DIC was 21.92 +/- 19.32 U. The recovery time of platelet level to normal was 29.3 +/- 9.3 days, the recovery time of PT, APTT, FDP and fibrinogen to normal were 12.7 +/- 9.5 days, 11.6 +/- 8.6 days, 16.0 +/- 9.3 days and 125.3 +/- 85.3 days respectively. The multivariate analysis showed that WBC count at onset was >10 * 10(9)/L and APTT was prolonged. These two factors were main reasons resulting in severe bleeding. It is concluded that the newly diagnosed APL always combined with DIC, therefore in the early phase of disease active transfusion of blood products, application of anti-coagulation and anti fibrinolytic drugs as well as heparin should be performed; the coagulation function should be as soon as recovered to normal so as to early correct DIC. These measures can significantly decrease the mortality of APL patients resulting from DIC. The hyperleukocytosis and prolonged APTT are the main factors for severe bleeding. PMID- 24762999 TI - [Effect of arsenic trioxide and 5-aza-2'-deoxycytidine on SHP-1, JAK3, TYK2 gene expression in K562 cells]. AB - This study was purposed to explore the effects of a methylation inhibitor arsenic trioxide (As2O3, ATO) and 5-Aza-2'-deoxycytidine (5-aza-CdR) on the expression of JAK-STAT signal transduction pathway in family members JAK3, TYK2 and hematopoietic cell phosphatase SHP-1 in chronic myeloid leukemia cell line K562 and their roles in pathogenesis of leukemia. The K562 cells were divided into 3 groups:single drug-treated group, combined 2 drugs-treated group, group without drug treatment as control. The concentration of 5-aza-CdR were 0.5, 1, 2 umol/L; the concentration of ATO was 1, 2.5, 5 umol/L; the concentration of combined drugs was ATO 1 umol/L + 5-aza-CdR 0.5 umol/L, ATO 2.5 umol/L + 5-aza-CdR 1 umol/L, and ATO 5 umol/L + 5-aza-CdR 2 umol/L. The K562 cells were treated with above-mentioned concentration of drugs for 24, 48 and 72 hours, then the total RNA of cells was extracted, the JAK3, TYK2 and SHP-1 expressions were detected by real-time quantitative-PCR. The results showed that after the K562 cells were treated with ATO and 5-aza-CdR alone and their combination, the expression of SHP 1 mRNA increased, the expressions of JAK3 mRNA and TYK2 mRNA decreased along with increasing of concentration and prolonging of time, displaying the concentration and time-dependency. The SHP-1 negatively related with JAK3 and TYK2. The effect of SHP-1 on JAK3 was significantly higher than that on TYK2. It is concluded that when the K562 cells are treated with ATO and 5-aza-CdR alone and their combination, the expression of SHP-1 is up-regulated and the expressions of JAK3, TYK2 are down-regulated in concentration-and time-dependent manners, moreover the ATO and 5-aza-CdR show synergies demethylation effect. The SHP-1 gene exert effect possibly through inhibiting the JAK/STAT pathway, the JAK3 is affected more than TYK2, the JAK3 may exert more important role in TAK/STAT pathway. PMID- 24763000 TI - [Analysis of scatter plots and alarm information in 288 cases of newly diagnosed hematologic malignancies]. AB - This study was aimed to explore the role of full-automatic blood analyzer Sysmex XE-2100 in early screening and diagnosing the hematologic malignancies. A total of 288 samples of the patients with hematologic malignancies was examined. Then, the scatter plots, alarm information and blood smears were analyzed. The results indicated that 76% of these samples showed abnormal scatter plots. CMML and AML M3 patients had their own characteristic scatter plots, while others hadnt's. The coincident rate of CMML and AML-M3 determined by scatter plots with practical diseases was 100%; the coincident rate of ALL determined by scatter plots with practical disease was 67%. The coincident rate of alarm information of blast cells was 92.5%, the coincident rate of immature granulocytes was 77.1%, the coincident rate of nucleated red blood cells was 33.3%, the coincident rate of atypical lymphocytes was 31.3%. It is concluded that the abnormal scatter plots and alarm information are very important for finding the patients with hematologic malignancies and determining the disease type. The alarm information has high reliability for blast cells and immature granulocytes, but has only mirror value for nucleated red blood cells and atypical lymphocytes. PMID- 24763001 TI - [Long-term follow-up for 39 newly diagnosed diffused large B-cell lymphoma patients treated by (R)-EPOCH]. AB - The purpose of this study was to evaluate the efficacy and safety of (R)-EPOCH protocol on patients with diffuse large B-cell lymphoma(DLBCL). From February 2004 to April 2009, a total of 39 patients who suffered from DLBCL and received (R)-EPOCH protocol were enrolled in the study. The median age of patients was 52 years old. 24 patients were on stage I/II, and 15 cases were on stage III/IV. Patients with stage I/II were administered with 4-6 cycles of (R)-EPOCH, while other patients with stage III/IV received 6-8 cycles of (R)-EPOCH. DLBCL patients with bulky disease received radiotherapy after completion of chemotherapy. 39 patients received a total of 209 cycles of chemotherapy and the median chemotherapy cycles was 6 (range, 2-8 cycles). The results showed that the overall response rate of 39 assessable patients was 87.2%, including 28 patients (71.8%) in complete remission (CR) and 6 patients (15.4%) in partial remission(PR). With a median follow-up of 57.7 months, the 1-year overall survival rate was 81.8%, while 70.9% for 3-year and 58.8% for 5-year. The major toxicity of (R)-EPOCH protocol was hematologic toxicity and the incidence of grade III-IV neutropenia and anemia were 29.2% and 14.4%, respectively. Other toxicities were mild, no treatment-related deaths occurred. At the end of follow up,no secondary tumors occurred. It is concluded that (R)-EPOCH protocol is a effective and safe protocol for the patients with DLBCL. PMID- 24763002 TI - [Expression and clinical significance of miR-21 in diffuse large B cell lymphoma]. AB - This study was aimed to investigate the expression of microRNA-21 and its correlation with PTEN in diffuse large B cell lymphoma (DLBCL) paraffin-embedded tissues, and evaluate its potential relevance with clinical characteristics. The expression levels of miR-21 in 26 primary DLBCL and 10 normal lymph node tissue specimens were examined by real-time polymerase chain reaction. The expression of PTEN was detected by immunohistochemical staining. The results indicated that the expression of miR-21 was significantly higher in tumor tissues [6.586(1.10,38.22)] than that in normal tissues [0.791 (0.35,2.87)] (P < 0.05). Among 26 patients with DLBCL the expression of PTEN protein was positive in 6 patients (23%), and was negative in 20 patients (77%). In patients with DLBCL, the expression level of miR-21 was negatively correlated with the level of PTEN protein. The high expression of miR-21 was positively correlated with the level of serum LDH. The expression level of miR-21 in patients with Ann Arbor III-IV stage was obviously higher than that of patients with Ann Arbor I-II stage, but did not correlate with the subtype of patients in clinic (P > 0.05). It is concluded that the expression of miR-21 is high in DLBCL and its overexpression may be related with poor prognosis of DLCBL. These findings suggest that PTEN is possibly one of the targets of miR-21 in DLBCL. PMID- 24763003 TI - Effect of G-CSF on induction of ENA-78 and IL-8 in the patients with malignant lymphoma. AB - Granulocyte colony stimulating factor (G-CSF) restores neutrophil count in patients with chemotherapy-induced neutropenia. G-CSF can also induce production of epithelial neutrophil activating protein-78 (ENA-78) and interleukin-8 (IL-8), chemotactic factors from neutrophils in vitro. This study was purposed to investigate whether this effect is also observed in vivo. 10 lymphoma patients were selected who received chemotherapy and G-CSF (nartograstim) administration. Blood was obtained before chemotherapy [Time Point 1 (TP1)], at neutropenic phase before G-CSF administration (TP2), and at neutrophil recovery phase after G-CSF (TP3). ENA-78 and IL-8 mRNA in neutrophils were quantified by real-time PCR. Phagocytosis and reactive oxygen species (ROS) generation were examined by flow cytometry. The results showed that ENA-78 and IL-8 mRNA expression at TP2 increased in 5 and 8 patients, respectively. The ENA-78 mRNA expression at TP3 was increased in 3 and decreased in 6 patients, and IL-8 mRNA expression at TP3 decreased in 7 patients. G-CSF did not affect phagocytosis and normalized ROS generation in all of the patient. It is concluded that increase of ENA-78 and IL 8 expression in neutrophils is common in chemotherapy-induced neutropenic patients. G-CSF administration does not significantly increase ENA-78 and IL-8 expression. PMID- 24763004 TI - [Identification of splenic marginal zone lymphoma from B lymphoproliferative disorders by flow cytometry]. AB - The splenic marginal zone lymphoma (SMZL) is a relatively rare chronic B lymphoproliferative disease, which primarily manifest increase of peripheral blood lymphocyte count and/or scale, and splenomegaly, while the peripheral superficial lymph nodes are often not swollen. Therefore, the splenectomy are usually needed to confirm the diagnosis, but the majority of patients could not accept such management, resulting in early difficult diagnosis. This study was purposed to explore the more prior way for diagnosis based flow cytometry (FCM). Six patients with suspected diagnosis of SMZL were used as research objects, 10 healthy bone marrow donors and 10 cases of chronic lymphocytic leukemia (CLL), 3 cases of hairy cell leukemia (HCL), 3 cases of lymphatic plasma cell lymphoma/Waldenstro's macroglobulinemia (LPL/WM) were selected as control. The immunophenotype of bone marrow cells were analyzed and compared by FCM using a panel of antibodies including CD45, CD5, CD10, CD19, CD20, CD22, CD23, CD25, CD103, CD11c, CD123, kappa,lambda, Cyclin D1, and combined with bone marrow cell morphology. The results indicated that 6 cases of suspected SMZL showed a large increase of lymphocytes and splenomegaly. Because absence of peripheral lymphadenopathy, 6 patients did not suffer from lymph node biopsy, only 1 patient underwent diagnostic splenectomy. The immunophenotypes of bone marrow in patients and controls were analyzed by FCM, as a result, except for the healthy donors, varying degrees of abnormal mature B cell clones were found in bone marrow of all patients, and the further differentiation from other B-cell tumors was performed through CD5, CD10 expression and combination with other B-cell phenotype. All 6 cases of SMZL patients expressed CD19(+) and CD20(+), but CD10 expression was negative, 4 patients expressed CD5(-), 2 patients expressed CD5(+). The expressions of CD23, CD38, ZAP-70, CD11c, CD103, CD123, Cyclin D1 were negative. The morphological examination of bone marrow cells showed velutinous abnormal lymphocytes. Combined with clinical characteristics, 6 patients were diagnosed as SMZL, 1 patient suffered from splenectomy because of concurrent hypersplenism, and this postoperative pathologic examination confirmed the patient with SMZL. Ten cases of CLL mainly expressed CD5, CD23; 3 cases of HCL had more typical morphology of "hair like" in addition to CD11c, CD103 and CD123 positive; 3 cases of LPL/WM had significantly increased light chain restriction expression, IgM, plasmacytoid lymphocytes. It is concluded that the FCM immunophenotype analysis can be used as a powerful tools for clinical diagnosis of SMZL. PMID- 24763005 TI - Effect of 5-aza-2'-deoxycytidine combined with trichostatin A on RPMI-8226 cell proliferation, apoptosis and DLC-1 gene expression. AB - This study was aimed to investigate the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR) and histone deacetylase inhibitor trichostatin A (TSA) on DLC-1 gene transcription regulation and molecular biological behaviours in the human multiple myeloma RPMI-8226 cells. The cells were treated respectively with 5-Aza-CdR and TSA alone, or the both combination; the cell proliferation and apoptosis, DLC-1 expression, the protein expression of Ras homolog family member A (RhoA) and Ras-related C3 botulinum toxin substrate 1 (Rac1) were examined by CCK-8 method, RT-PCR and ELISA, respectively. The results showed that the 5-Aza-CdR and TSA had cell growth inhibitory and apoptosis inducing effects in dose-dependent manner (P < 0.05). Compared with a single drug (5-Aza-CdR or TSA alone), the effects were significantly enhanced after treatment with the combination of 5-Aza-CdR and TSA (P < 0.05). DLC-1 was weakly expressed in the control group; the treatment with 5-Aza-CdR alone enhanced its re expression dose-dependently (P < 0.05). Compared with 5-Aza-CdR alone, 5-Aza-CdR plus TSA enhanced DLC-1 re-expression significantly.Compared with the control, 5 Aza-CdR and TSA significantly decreased RhoA and Rac1 protein expression (P < 0.05). It is concluded that 5-Aza-CdR and TSA can effectively reverse DLC-1 expression of RPMI-8226 cells; TSA has a synergistic effect on its re-expression. 5-Aza-CdR and TSA have significant cell growth inhibitory and apoptosis-inducing effects on RPMI-8226 cells. These effects may be related to the inhibition of Rho/Rho kinase signalling pathway. PMID- 24763006 TI - [Mechanism concerning antitumor effect of oridonin on multiple myeloma cell line U266]. AB - This study was purposed to investigate the antitumor effect of oridonin on human multiple myeloma cell line U266 and its possible mechanism. The CCK-8 test was used to determine the inhibitory effect of oridonin on proliferation of U266 cells. The morphological changes of U266 cells were observed under optical microscope. The apoptosis rate of U266 cells was detected by flow cytometry. The mRNA levels of FGFR3, BCL2, CCND1 and MYC genes were quantified by using real time quantitative PCR method, and the protein levels of BCL2, MYC, CCND1, FGFR3 and P53 were detected by Western blot. The results showed that the oridonin obviously inhibited the growth of U266 cell in dose-and time-dependent manners. As for morphological changes, characteristic apoptotic cells presented in U266 cells treated with 10 umol/L oridonin for 24 hours. The apoptotic rate of U266 cells increased in dose and time dependent manners; after treatment of U266 cells with oridonin the mRNA levels of FGFR3, BCL2, CCND1 and MYC as well as the their protein levels decreased. Occasionally, the oridonin up-regulated the protein levels of P53 in the same manner. It is concluded that the oridonin can exert its anti-tumor effect by inhibiting proliferation and inducing apoptosis of U266 cell in dose dependent and time dependent manners, that maybe give the clues about new program of target therapy for multiple myeloma. PMID- 24763007 TI - [Expression of WT1 and PRAME gene in bone marrow and peripheral blood samples of patients with myelodysplastic syndrome]. AB - This study was aimed to explore the transcription level of WT1 and PRAME two genes in bone marrow and peripheral blood samples of patients with myelodysplastic syndrome(MDS) and their relationship with bone marrow dysplasia and karyotype. The quantitative expression of WT1 and PRAME transcripts detected by RQ-PCR in the bone marrow samples of 203 MDS patients and 19 aplastic anemia(AA), 6 other benign anemia(BA), 4 paroxysmal nocturnal hemoglobinuria(PNH) patients from July 2009 to June 2012 and 14 healthy donors, and in 92 peripheral blood samples. The results showed that WT1 and PRAME expression levels in both BM and PB samples of MDS group were higher than those in normal controls, AA, and BA patients (BM: WT1:P = 0.000, 0.000, 0.000, PRAME: P = 0.048, 0.000, 0.064; PB: WT1:P = 0.012, 0.000, 0.011, PRAME: P = 0.020, 0.004, 0.003). What is more, this expression in high risk MDS group (RAEB1, RAEB2, MDS-AML) were higher than those in low risk group (RCUD, RCMD, MDS-U) and AA and BA. The WT1 and PRAME mRNA expression levels in PB and BM were well correlated (WT1:r = 0.6028, P = 0.001; PRAME: r = 0.7628, P = 0.000), as well as the WT1 expression levels in BM samples with the Karyotype (P = 0.049). In addition, the same positive rate of WT1 or PRAME expression existed in BM and PB samples of MDS patients. It is concluded that the WT1 and PRAME gene expression levels in both BM and PB samples of MDS patients are higher than those in healthy controls, AA and other benign anemia patients, and increase with the progression of the disease. The WT1 and PRAME transcripts constitute good molecular markers for the clinical diagnosis and prognosis and monitoring minimal residual disease after treatment of MDS. What is more, when bone marrow is not so convenient to get, the transcript levels of PB samples can be detected. PMID- 24763008 TI - [Peripheral blood lymphocyte subsets and their relation with early response to treatment in patients with low or intermediate risk myelodysplastic syndrome (IPSS score <= 1.0) and chronic aplastic anemia]. AB - The purpose of this study was retrospectively to analyze the peripheral blood lymphocyte subset distribution in patients with low or intermediate risk myelodysplastic syndromes (IPSS <= 1.0) and chronic aplastic anemia (CAA), and their hematological changes of peripheral blood after treatment, so as to understand differences and their relation with early treatment response. The lymphocyte subsets in peripheral blood of 67 patient with low or intermediate risk MDS (IPSS <= 1.0), 54 patients with CAA and 73 healthy individuals were analyzed by flow cytometry. The results showed that Th cells, Th/Ts ratio in peripheral blood of low or intermediate risk MDS were 42.94% +/- 10.80% and 1.80% +/- 0.99% respectively, and were significantly higher than those in control group; the CD16(+) CD56(+) cell ratio was 11.22% +/- 7.97%, and was significantly lower than that in control group, the difference was statistically significant (P < 0.05); Ts cells and CD19(+) cell ratio in peripheral blood of CAA patients were 30.87% +/- 9.11% and 16.98% +/- 7.40% respectively, and were significantly higher than those in control group; CD16(+) CD56(+) cell ratio was 9.81% +/- 7.00%, and was significantly lower than that in normal control group, and the difference was statistically significant (P < 0.05); while the Th cells and Th/Ts ratio in low or intermediate risk MDS group were significantly higher than those in CAA group, and the difference was statistically significant (P < 0.05). After treatment for 6 mouths, the HI-E and HI-N rates in CD19(+) cell normal group of low or intermediate risk MDS patients were 18.2% (4/22) and 13.6% (3/22), and were significantly lower than that in the increased group and decreased group. In Ts cell increased group HI-N rate was 15.4% (2/13), and was significantly lower than that in normal group and decreased group. In Th/Ts ratio decreased group HI-N rate was 14.3% (2/14), and was significantly lower than that in the increase group and normal group, the difference was statistically significant (P < 0.05). After treatment of CAA for 6 months, the effective rate for CD3(+) cells, Th cells, Th/Ts ratio in decreased group was 71.4% (5/7), 56.3% (9/16), 50.0% (10/20), and were significantly higher than those in increased and normal group, and the difference was statistically significant (P < 0.05). It is concluded that the peripheral blood lymphocyte subsets of low or intermediate risk MDS(IPSS score <= 1.0) and CAA are abnormal, and these lymphocyte subsets are related with hematologic changes after early response to treatment. PMID- 24763009 TI - [Changes of CD34(+) and CD71(+)CD45(-) cell levels in bone marrow of MDS and AA patients]. AB - This study was aimed to investigate the changes of CD34(+) and CD71(+)CD45(-) cell levels in MDS and AA patients. A total of 25 cases MDS and 43 cases of AA (18 cases SAA and 25 cases of NSAA) from January 2010 to October 2013 in the Department of Hematology, affiliated hospital of Hebei United University were enrolled in this study. The complete blood count, bone marrow smears, bone marrow biopsy, karyotype analysis and bone marrow blood cell immune genotyping (mainly the proportion of CD34(+) cells, CD71(+)CD45(-) cells in nucleated cells) were carried out for all patients; the changes of CD34(+) and CD71(+)CD45(-) cell levels in patients with MDS and AA (SAA NSAA) were compared; the differences of white blood cell count, platelet count and hemoglobin concentration in patients with count of CD71(+)CD45(-) >= 15% or <15% were analyzed. The results showed that the count of CD34(+) in MDS group was higher than that in AA (NSAA and SAA) group (P < 0.05). The count of CD71(+)CD45(-) cells in MDS group was higher than that in SAA (P < 0.05), there was no significant difference between NSAA group and MDS group. In MDS group with CD71(+)CD45(-) >= 15%, the platelet count was significantly higher than that in NSAA group (P < 0.05); and there was no statistical difference for leukocyte, platelet count and hemoglobin level between MDS and NSAA group with CD71(+)CD45(-) <15% (P > 0.05). It is concluded that the count of CD34(+) cells in MDS patients is significantly higher than that in AA and SAA patients. The count of CD71(+)CD45(-) cells in MDS group is significantly higher than that of SAA group. The platelet count in MDS patients with CD71(+)CD45(-) cells >= 15% is significantly higher than that of the NSAA group. PMID- 24763011 TI - [Clinical analysis of recombinant humanized thrombopoietin for treating 25 children with severe immune thrombocytopenia]. AB - This study was aimed to evaluate the efficacy and safety of recombinant humanized thrombopoietin (rhTPO) for treating children with severe immune thrombocytopenia (ITP). A total of 25 patients with severe ITP who accepted rhTPO treatment for 14 days between December, 2009 and November, 2012 in Beijing Children's Hospital was retrospectively analyzed. The results showed that the median platelet counts of all 25 patients increased from the lowest level 4.0*10(9)/L (0*10(9)/L 10*10(9)/L) to the highest level 71*10(9)/L (14*10(9)/L-439*10(9)/L) on median 11 days (range from 3 days to 15 days). After rhTPO discontinuation, the platelet counts of patients gradually decreased. Complete response rate was 44% (11/25), response rate was 32% (8/25), non-response rate was 24% (6/25) and total response rate was 76% (19/25). The platelet count in the patients who showed complete response to rhTPO therapy reached the highest 112*10(9)/L (43*10(9)/L 439*10(9)/L) on median 12 days(range from 7 days to 15 days). The patients showed response to rhTPO treatment on median 4 days (range from 1 days to 11 days). The platelet count decreased gradually after the discontinuation of rhTPO administration but still significantly higher on 28 days than the level before the treatment (P < 0.05). 12 patients who did not respond to gamma-globulin before rhTPO treatment showed response to gamma-globulin after the discontinuation of rhTPO therapy. 2 patients showed mild clinical adverse reaction. It is concluded that rhTPO is an effective and safe treatment method for children with severe ITP. It will help the patient smoothly through the dangerous period of severe bleeding, but the platelet count decreases gradually after rhTPO discontinuation. Maintenance treatment is needed to consolidate the curative efficacy. PMID- 24763010 TI - [Comparison of chromosome karyotype between myelodysplastic syndrome and acute leukemia patients confirmed at the same period]. AB - This study was purposed to compare and analyze the relationship between the abnormality of chromosome karyotypes and diagnosis, prognosis of MDS and AML patients, as well as to explore the characteristics of chromosome prognostic stratification in MDS and AML patients of different ages. The cytogenetic karyotype analysis was performed in 134 cases of MDS and 123 cases of AML by using bone marrow short-term culture and R-banding technique. The results indicated that the detected rates of chromosome abnormal karyotypes in MDS and AML patients were 41% and 61% respectively. The abnormal karyotype analysis of MDS and AML group showed that the abnormal karyotype in MDS group displayed number abnormality as the dominate (mainly the +8), while the abnormal karyotype in AML group displayed structure abnormality as the dominant [mainly, t(15;17) and t(8;21)]. The detected abnormal karyotype are mainly for the +8 which has ambiguous correlation with FAB subtype; the detection rates of complex karyotype abnormalities, favourable prognosis karyotype as well as poor prognosis karyotype in the MDS group obviously higher than that of AML group. Among patients with MDS transformed into AML, 12 cases had chromosome abnormal karyotype. There were 3 cases of chromosome abnormal karyotype in AML group which were transformed by MDS. The analysis of age stratification between two groups showed that the detected rate of abnormal karyotype was enhanced with the increase of age in MDS group, and detected rate in >= 60 years old group was obviously higher than that in patients with <= 30 age group.The detected rate of complex karyotype abnormalities in three age groups of MDS did not show statistical difference; the detected rate of abnormal karyotype in AML group decreased with the increase of age, the detected rate in <= 30 years old group was obviously higher than that in >= 60 age group,while the detection rate of complex karyotype abnormalities showed that the detected rate in patients >= 60 years old group was obviously higher than that in patients with <= 30 years old group; Analysis of karyotype prognosis revealed that the detected rate of poor prognosis karyotype increased along with the age growth both in MDS and AML groups, and detected rate in >= 60 years old group was obviously higher than that in <= 30 years old group; while analysis of favourable prognosis karyotype in MDS and AML group showed that the detected rate in <= 30 years old group was obviously higher than that in >= 60 years old group. It is concluded that the patients with MDS and AML have higher chromosomal abnormalities,which have important reference value for the diagnosis, treatment and prognosis, meanwhile, the analysis of chromosome karyotype provides an important basis for prognostic stratification. PMID- 24763012 TI - [Detection, diagnosis and analysis of the first case of neonatal alloimmune thrombocytopenia purpura associated with anti-HPA-5b in China]. AB - This study was aimed to investigate the detection and diagnosis of the neonatal alloimmune thrombocytopenia purpura (NAITP) caused by anti-HPA-5b antibody. The platelet count and clinical manifestation in the newborn were examined. The HPA-1 21bw genotypes of the newborn and her parents were detected by multiple-PCR and DNA sequencing. The HPA-specific antibody in the sera of newborn and her mother were detected and identified by flow cytometry (FCM) and monoclonal antibody specific immobilization of platelet antigens (MAIPA). The results indicated that the clinical manifestations of the newborn were lighter. The HPA genotyping showed that the genotype of the newborn was HPA-5ab, while that of her mother and father were HPA-5aa and HPA-5ab, respectively. The antibody against the platelet of newborn's father existed in the newborn's mother sera. The HPA antibody of the mother was identified as anti-HPA-5b. It is concluded that the newborn with neonatal alloimmune thrombocytopenia purpura was caused by the antibody against HPA-5b. PMID- 24763013 TI - [Significance of regulatory B cells in nosogenesis of immune thrombocytopenia]. AB - This study was aimed to investigate the role of regulatory B cells (Breg) in pathogenesis of immune thrombocytopenia (ITP) and its clinical significance. A total of 35 ITP patients and 20 normal controls were enrolled in this study. The expression of CD19(+)CD24(hi)CD38(hi) B cells was detected by flow cytometry and the expression of IL-10 mRNA and TGF-beta1 mRNA was assayed by RT-PCR. The results indicated that the expression level of CD19(+)CD24(hi)CD38(hi) B cells in peripheral blood of newly diagnosed ITP patients was obviously lower than that in normal controls (P < 0.05); the expression level of CD19(+)CD24(hi)CD38(hi) B cells in ITP patients with increased platelet count after treatment was higher than that before treatment (P < 0.05); the expression level of IL-10 mRNA in newly diagnosed ITP patients was significantly lower than that the in normal controls (P < 0.05), the expression level of TGF-beta1 mRNA in newly diagnosed ITP patients increases as compared with normal controls (P < 0.05), after treatment with DXM the expression of IL-10 mRNA was enhanced, the expression of TGF-beta1 mRNA was reduced as compared with expression level before treatment (P < 0.05). It is concluded that the Breg cells may play an important role in the pathogenesis of ITP via humoral immunity and its regulation of T lymphocytes. PMID- 24763014 TI - [Clinical analysis of 14 patients with thrombotic thrombocytopenic purpura]. AB - In order to enhance the understanding of thrombotic thrombocytopenic purpura (TTP), the clinical features, laboratory characteristics, treatment and outcome of 14 patients with TTP were retrospectively analyzed and investigated. The results showed that 7 out of 14 patients with TTP had predisposing factors, such as pregnancy in 4 cases, infection in 3 cases, systemic lupus erythematosus (SLE) in 1 case and hematopoietic stem cell transplantation (HSCT) in 1 case. Fourteen patients all had neuropsychological symptoms, hemolytic anemia with negative Coombs test, and decreased platelet counts. Eight patients had irregular fever with different degree. There were 8 patients with kidney damage including proteinuria in 8 cases and renal function abnormalities in 4 cases. The von Willebrand factor-cleaving protease (VWF-CP, ADAMTS13) activity of 13 cases out of 14 patients significantly decreased (less than 10%). At same time, plasma ADAMTS13 inhibitors were detected in 12 cases out of these 13 patients with decreased ADAMTS13 activity. After treatment with plasma exchange, glucocorticoid and rituximab so on, 12 cases achieved complete remission, in which 8 cases relapsed in two years. Two patients died at last, in which one case was secondary to HSCT. It is concluded that TTP is a kind of thrombotic microangiopathy due to platelet microthrombosis involved in multiple systems and multiple organs dysfunction with dangerous clinical process. The mortality of TTP patients is very high. Early diagnosis and early treatment with plasma exchange as the main means can greatly improve the prognosis of patients with TTP. PMID- 24763015 TI - [Knockdown of Puma protects cord blood CD34(+) cells against gamma- irradiation]. AB - Puma (P53 upregulated modulator of apoptosis) is a BCL-2 homology 3 (BH3)-only BCL-1 family member and a critical mediator of P53-dependent and -independent apoptosis. Puma plays an essential role in the apoptosis of hematopoietic stem cells exposed to irradiation without an increased risk of malignancies. This study was purposed to develop an effective lentiviral vector to target Puma in human hematopoietic cells and to investigate the effect of Puma gene knockdown on the biological function of human cord blood CD34(+) cells. SF-LV-shPuma-EGFP and control vectors were constructed, and packaged with the pSPAX2/pMD2.G packaging plasmids via 293T cells to produce pseudo-type lentiviruses. SF-LV-shPuma-EGFP or control lentiviruses were harvested within 72 hours after transfection and then were used to transduce human cord blood CD34(+) cells. GFP(+) transduced cells were sorted by flow cytometry (FCM) for subsequent studies. Semi-quantitative real time RT PCR, Western blot, FCM with Annexin V-PE/7-AAD double staining, Ki67 staining, colony forming cell assay (CFC), CCK-8 assay and BrdU incorporation were performed to determine the expression of Puma and its effect on the cord blood CD34(+) cells. The results showed that Puma was significantly knocked down in cord blood CD34(+) cells and the low expression of Puma conferred a radio protective effect on the cord blood CD34(+) cells. This effect was achieved through reduced apoptosis and sustained quiescence after irradiation due to Puma knockdown. It is concluded that knockdown of puma gene in CD34(+) hematopoietic stem cells of human cord blood possesses the radioprotective effect, maintains the cells in silence targeting Puma in human hematopoietic cells may have a similar effect with that on mouse hematopoietic cells as previously shown, and our lentiviral targeting system for Puma provides a valuable tool for future translational studies with human cells. PMID- 24763016 TI - [Effects of D-methionine on the hematopoietic system injury in irradiated mice]. AB - The aim of this study was to investigate the effects of D-methionine (D-met) on the hematopoietic system injury in irradiated mice. C57BL/6 mice were divided into control group, irradiated group, 300 mg/kg D-met plus irradiation group and 1000 mg/kg D-met plus irradiation group. The control mice received sham irradiation, and the mice in remainder groups were exposed to 7.5 Gy; 1,4,8 Gy and 1 Gy of (137)Cs gamma-ray respectively, were used to detect the survival rate, survival rate of bone marrow cells, WBC and its differential counts as well the colony formation ability in irradiated mice, respectively. The D-met was intraperitoneally injected to mice at 30 min before irradiation. The results showed that 300 and 1000 mg/kd D-met did not obviously enhance the survival rate of mice exposed to 7.5 Gy; the 10(-2),10(-3),10(-4) mol/L D-met significantly increased the survival rate of bone marrow cells in mice exposed to 1,4,8 Gy; 300 and 1000 mg/kg D-met even so increased the WBC count of peripheral blood in mice exposed to 1 Gy, but there was no statistical difference as compared with irradiated alone mice, moreover 300 and 1000 mg/kg D-met could obviously promote the colony formation ability of bone marrow cells in irradiated mice, the CFU-GM count was higher than that in 1 Gy irradiated mice (P < 0.05). It is concluded that the D-met can effectively mitigate the marrow cell injury resulted from irradiation, enhance the survival rate of bone marrow cells in irradiated mice, promote the recovery of hematopoietic function from radiation injury in mice. PMID- 24763017 TI - [Clinical analysis of 15 patients with primary granulocytic sarcoma]. AB - This study was purposed to analyze the clinical feature,diagnosis and treatment efficacy of primary granulocytic sarcoma (PGS). A total of 15 patients with PGS from January 2008 to March 2013 was evaluated retrospectively, among 15 patients 8 patients were treated with chemotherapy (chemotherapy alone,chemotherapy combined with local irradiation,chemotherapy combined with surgical resection or bone marrow transplantation), 7 patients were treated without chemotherapy, but were treated with surgical resection or surgical resection plus local irradiation.The chemotherapy method for PGS patients was similar as treatment of acute myeloid leukemia. The results indicated that the proportion of disease progression into bone marrow abnormality in patients treated with chemotherapy and in patients treated without chemotherapy was 25% and 85.7% respectively, suggesting that the chemotherapy can reduce the incidence of progression into bone marrow abnormality (P < 0.05). The average survival time of PGS patients treated with chemotherapy or without chemotherapy was 26.063 +/- 14.97 and 12.214 +/- 6.83 months (P < 0.05),suggesting prolonging of survival time of patients treated with chemotherapy, moreover 2 patients who were treated using chemotherapy combined with bone marrow transplantation still alive now,and their living times were 39 months and 45 months respectively. It is concluded that intensive chemotherapy similar as treatment of AML can decrease the probability of disease progressing into bone marrow abnormality, and if chemotherapy combines with bone marrow transplantation, the survival time of PGS patients can be longer. In this aspect, the efficacy of treatment and survival time at home and abroad are similar. PMID- 24763018 TI - [Outcome and prognosis in acute myeloid leukemia patients treated with related peripheral blood hematopoietic stem cell transplantation]. AB - This study was purposed to evaluate the outcome of acute myeloid leukemia patients treated with related peripheral blood hematopoietic stem cell transplantation (PBHSCT) and analyse the potential prognostic factors. A total of 64 acute myeloid leukemia patients treated with related peripheral allo-HSCT from march 2008 to august 2012 in our hospital were enrolled in the analysis. All the patients received either HLA-matched related or mismatched related donor mobilized peripheral blood stem cells. All the patients were followed up and evaluated for overall survival (OS), leukemia-free survival (LFS) and relapse rate (RR) , and the potential prognostic factors well analyzed. The results showed that the 3 year OS , LFS and RR were 61.9%, 52% and 39.1% respectively. Univarite analysis demonstrated that the disease status before transplantation (P < 0.01) , donor type (P < 0.01), white blood cell count at initial diagnosis (P < 0.05) are related with outcome, and severe aGVHD has some influence on the outcome (P > 0.05) . Multivariate analysis indicated the status of disease before transplantation, donor type, severe aGVHD are the most important prognostic factors. It is concluded that the related PBHSCT is effective treatment method for AML patients, recurrence is the main reason for the failure after transplantation, disease status before transplantation, donor type, and severe aGVHD are independent prognostic factors. PMID- 24763019 TI - [Therapeutic efficacy of mixed hematopoietic stem cell transplantation for pediatric hematologic diseases]. AB - This study was purposed to explore the effectiveness of mixed transplantation of HLA mismatched bone marrow hematopoietic stem cells(HSC), peripheral blood HSC and umbilical cord blood HSC for treatment of pediatric blood diseases. From August 2012 to December 2012, five children with refractory hematological diseases in our hospital received allogeneic hematopoietic stem cell transplantation. The mixed grafts consisting of HLA-mismatched bone marrow HSC, peripheral blood HSC and umbilical cord blood HSC were used to observe the effects of umbilical cord blood HSC on the time of hematopoietic reconstruction of bone marrow, STR chimeric degrees, incidence of GVHD. and early transplant associated complications. The results showed that all 5 children patients were grafted successfully with the median grafted time of 11 d for ANC>0.5*10(9)/L and 10 d for Plt>20*10(9)/L, respectively. On day 30, the STR-PCR test of peripheral blood showed a stable complete chimera. Five cases suffered from mild to moderate symptoms of GVHD, showing with I-II grade of skin GVHD and in which two cases suffered from diarrhea, showing I-II grade of intestinal GVHD. All the 5 patients had no liver function damage. One patient died of severe hemorrhagic cystitis and multi-site infection, and the remaining four cases survived so far on the current median follow-up time of 137 d (130 d-250 d). It is concluded that transplantation of the mixed HLA mismatched bone marrow HSC, peripheral blood HSC, with third-party cord blood HSC can increase the survival rate for pediatric patients with blood disease. PMID- 24763020 TI - [Comparative analysis of early reconstitution of T-lymphocyte subsets and T-cell receptor excision cycles in patients after myeloablative unrelated cord blood and sibling donor transplantation]. AB - This study was purposed to comparatively analyze the early T-lymphocyte subsets and T-cell receptor excision cycles (TREC) reconstruction in recipients with hematologic malignancies after myeloablative unrelated cord blood transplantation (UCBT) and sibling donor bone marrow and/or peripheral blood stem cell transplantation (BMT/PBSCT). The peripheral blood T lymphocyte subsets were detected using flow cytometry and TREC were detected using real-time quantitative PCR for 40 patients with hematologic malignancies in the first six months after myeloablative allogenic hematopoietic stem cell transplantation. The results showed that in the first month after transplantation, the absolute counts of CD3(+), CD3(+) CD4(+), CD3(+) CD8(+) cells were lower significantly in the UCBT group than those in the BMT/PBSCT group. And later the absolute counts of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+) cells were not different between two groups. The ratio of CD3(+)T subset in the peripheral blood lymphocytes of the UCBT recipients was lower, but the difference was not statistically significant within 2 months after transplantation. The ratio of CD3(+)CD4(+) cells in the patients received the UCBT and BMT/PBSCT decreased obviously since engraftment happened. The CD3(+)CD4(+) cells on the 2 months after transplantation fell to the lowest level, then gradually increased, but did not reach to the normal level until 6 months after transplantation. CD3(+)CD8(+)cells were well reconstituted, rising to normal at the engraftment after transplantation, with a low CD4(+): [KG-*2] CD8(+) ratio over the first 6 months after transplantation. Compared with the BMT/ PBSCT group, the naive T cells (CD3(+)CD4(+)CD45RA(+)CD62L(+)) were more in the first month after transplantation and the terminally differentiated effector memory T cells (CD3(+)CD4(+)CD45RA(+)CD62L(-)) were more at the 3 month after transplantation in the UCBT group, and those were significantly more than the normal control group. TREC were lower and did not recovered until 6 months after transplantation in the recipients of the two groups. It is concluded that compared with sibling donor's BMT/PBSCT, early T cell reconstitution significantly delayed after UCBT, but the terminally differentiated effector memory T cells are higher after transplantation, and thus play a anti-infective or anti-leukemia role. PMID- 24763021 TI - [Effect of autologous peripheral blood stem cell transplantation in 13 patients with AML1/ETO (+) acute myeloid leukemia]. AB - This study was purposed to analyse the clinical efficacy of autologous peripheral blood stem cell transplantation (APBSCT) in 13 Patients with AML1/ETO (+) acute myeloid leukemia, and to evaluate the role of quantitative detecting the AML1/ETO gene in treatment of AML patients. A total of 13 patients with AML1/ETO (+) acute myeloid leukemia treated with APBSCT from August 2007 to November 2012 were retrospectively analyzed. The median follow-up time was 26 (7.8-75.8)months. Kaplan-Meier analysis was used to calculate the overall survival (OS), leukemia free survival (LFS) and cumulative relapse rate (RR). Log rank method was used to perform univariate analysis. The results showed that the 3 year-OS, LFS, and RR were (70.5 +/- 15.3)%, (51.3 +/- 16.7)%, 48.7%, respectively. The AML1/ETO expression level in 4 cases out of 5 relapsed patients was quantified during and after therapy, and the result showed that AML1/ETO expression level significantly increased before morphological relapse. In univariate analysis, there was no statistic significance in terms of age, sex, count of white blood cells at diagnosis, interval from diagnosis to transplantation, count of MNC for infusion. It is concluded that APBSCT has good therapeutic effect on AML1/ETO (+) AML, and regular quantitative monitoring of AML1/ETO expression level can predict early recurrence. Allogeneic hematopoietic stem cell transplantation after relapse may contribute to obtain opportunity to achieve the long-term survival for intermediate and high risk patients. PMID- 24763022 TI - [Relation of Treg and iNKT cell reconstruction with aGVHD after allogeneic hematopoietic stem cell transplantation in children]. AB - This study was aimed to explore the relation of Treg and invariant natural killer T (iNKT) cell reconstruction with acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. According to the occurrence or absence of aGVHD, 29 pediatric patients who underwent allo-HSCT were firstly divided into two groups non-aGVHD and aGVHD group,then those patients with aGVHD were divided into steroid effective group and steroid resistant group according to their reaction to the steroid treatment. Flow cytometry was used to detect the frequency of Treg cells and iNKT cells in the peripheral blood of the recipients at different time after allo-HSCT(d 15, d 30, d 60, d 90, the time of aGVHD onset and two weeks after steroid treatment). The result showed that the frequencies of Treg cells and the iNKT/T ratio on day 15 in non-aGVHD group were significantly higher than those in the aGVHD group (P < 0.05). It is concluded that a combined monitoring strategy of Treg and iNKT cell reconstruction early after allo-HSCT may facilitate the diagnosis and treatment of aGVHD in children. PMID- 24763023 TI - [Risk factors analysis of cytomegalovirus infection after nonmyeloablative allogeneic peripheral blood stem cell transplantation]. AB - The aim of this study was to analyze the risk factors of cytomegalovirus (CMV) infection and CMV disease after nonmyeloablative allogeneic hematopoietic stem cell transplantation(NST) and develop a rational strategy for the diagnosis, monitoring and preemptive treatment of CMV infection. The Clinical data of 80 patients undergoing NST from November 2009 to November 2012 in the hospital 307 were retrospectively analyzed. The cytomegalovirus load in peripheral blood of patients was detected by using RT-PCR. The results indicated that the incidence of CMV infection was 77.5% (62/80), and the median time for the positive CMV-DNA firstly detected by RT-PCR was day 35 (17-133) after NST. The total of 100-day cumulative incidence of CMV disease was 11.3%(9/80) after early preemptive therapy. Both univariate and multivariate analysis showed thymoglobulin (ATG) used in preconditioning regimen, other herpesvirus infection and fungal infection in medical history before NST were the risk factors of CMV infection after NST.Univariate analysis revealed that CMV viremia and ATG used in preconditioning regimen were the risk factors for CMV disease, while the same result was not found in the multivariate analysis.The incidence of CMV infection in patients with II-IV grade of aGVHD was 91.3%,while the incidence of CMV infection in patients with 0-1 grade of aGVHD was 71.9% (P = 0.06), it seems that II-IV grade of aGVHD was not the risk factor of CMV infection for NST. It is concluded that the ATG used in preconditioning regimen may increase the incidence of both CMV infection and CMV disease after NST. CMV infection easily accompanies by other herpesvirus infection and fungal infection.Therefore other herpesvirus infection and fungal infection should be attentively monitored and prevented after trans plantation. PMID- 24763024 TI - [Effects of CD4(+)CD25(+) regulatory T cells on allogeneic hematopoietic stem cell transplantation in sensitized mice]. AB - The aim of this study was to investigate the effects of CD4(+)CD25(+) regulatory T cells (Treg) on allogeneic hematopoietic stem cell transplantation (HSCT) in sensitized mice so as to provide experimental evidence for clinical treatment of allogeneic HSCT rejection in sensitized recipients. The BALB/c mice were divided into 5 groups: group A - mice were sensitized with injection of splenocytes; group B - mice were sensitized with splenocytes and treated with >5*10(5) Treg on day 7 before transplantation; group C - mice were sensitized with splenocytes and treated with 5*10(5) Treg on day 13 and 7 before transplantation; group D - mice were not sensitized, but treated with equal volume of PBS as control; group E - blank control. Each group had 15 mice. On day 0 of transplantation, mice in each group were irradiated lethally with 8 Gy by linear accelerator, and the bone marrow cells of C57BL/6 labeled by fluorescence staining were intravenously injected via the tail vein. The fluorescent cells in peripheral blood and organ tissue were detected by flow cytometry on different time points for homing assessment. Survival rates and hematopoietic reconstitution were also recorded and monitored. The results showed that on 12 and 24 hours after transplantation, as compared with the sensitized group, the number of fluorescence homing cells in different tissue of the applied Treg groups increased significantly and the differences were statistically significant (P < 0.05). The mice in sensitized group and blank control group all died on the 6-13 day, whereas the median survival time of mice in applied Treg once and twice were 15 days and 16 days respectively. Comparing with sensitized group, the difference was statistically significant (P < 0.001), but there was no significant difference between these two groups applied regulatory T cell (P > 0.05). It is concluded that applying Treg can induce immune tolerance of sensitized recipient to allogeneic HSCT and inhibit immune destruction and prolong the survival time, but can not induce full immune tolerance and at last sensitized mice died of rejection of hematopoietic stem cells. PMID- 24763025 TI - [Effects of rhG-CSF mobilization on the polarization and migration of donor's CD4(+)T lymphocytes]. AB - The polarization and migration of T lymphocytes involves the adhesive interaction of lymphocyte function-associated antigen 1(LFA-1) with its ligand intercellular adhesion molecule 1 (ICAM-1). This study was aimed to investigate the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) mobilization on the polarization and migration of donor's CD4(+) T cells in peripheral blood. The peripheral blood mononuclear cells were collected from 10 healthy volunteers and 10 donors on the fifth day of mobilization with rhG-CSF. And the CD4(+)T cells were purified by miniMACS. The polarization and migration of CD4(+) T cells activated by stroma cell-derived factor -1alpha (SDF-1alpha) and ICAM-1 were detected by using inverted and confocal microscopes respectively. The results showed that the percentage of polarized CD4(+)T cells from donors(32.42 +/- 4.91)% was lower than that from healthy controls(56.55 +/- 5.35)% (P < 0.01), the migration velocity of CD4(+)T cells from donors (7.06 +/- 1.44 um/min) was also lower than that of healthy controls(9.05 +/- 1.91 um/min)(P < 0.01). It is concluded that the polarization and migration of CD4(+)T lymphocytes is impaired after rhG-CSF mobilization. PMID- 24763026 TI - [Effect of GW003 on the granulocyte macrophage colony formation ability of bone marrow cells in vitro]. AB - The aim of this study was to investigate the effect of GW003 on the ability of granulocyte colony forming in vitro of bone marrow cells. The bone marrow samples was collected from normal rhesus, the patients with leukemia in stages of remission and chemotherapy respectively, and the nucleated cells were separated and cultured for 12 days after addition of different concentrations of GW003 or rhG-CSF, or G-CSF mutant. Then the amount of colony-forming unit-granulocyte macrophage was counted. The results indicated that GW003 could enhance the ability of bone marrow nucleated cells of rhesus to forming CFU-GM in vitro, and its effect was much better than that of rhG-CSF or G-CSF mutant at the same concentration((r)). The GW003 showed dose-response relationship to CFU-GM level (r = R(2) = 0.965, P = 0.003, in a certain concentration), the GW003 also could enhance CFU-GM formation of marrow nucleated cells in leukemic patients, especially for patients receiving chemotherapy. The GW003 could relieve the marrow suppression caused by chemotherapy significantly. It is concluded that the GW003 can significantly improve the ability of bone marrow cells to form granulocyte colony in vitro as well as effectively alleviate bone marrow suppression. PMID- 24763027 TI - [Effect of intercellular adhesion molecule-1 on the migration in vitro of murine mesenchymal stem cells and its related mechanism]. AB - This study was aimed to investigate the effect of intercellular adhesion molecule 1 (ICAM-1) on the migration in vitro of the murine mesenchymal stem cells (MSC) and its related mechanisms. The migration ability of murine MSC (C3H10T1/2), ICAM 1 transfected MSC (C3H10T1/2-MIGR1-ICAM-1) and empty vector-transfected MSC (C3H10T 1/2-MIGR1) were assayed in vitro by using the transwell system. Briefly, the cells were seeded on the membrane with 8 um aperture and the fetal bovine serum was used as the chemotactic agent to induce MSC migration. The transmigrated cells were stained by crystal purple as well as DAPI for 8 h and 12 h respectively. The absolute cell numbers were counted and the migration rates of MSC were evaluated in each group. To explore the potential mechanisms which control the migration of MSC, the specific chemical inhibitors of MAPK pathway (SB203580, PD98059 and JNK inhibitor II) were added to the transwell system and the alteration of the MSC migration ability were evaluated at 12 h. The results showed that the migration ability at 8 h and 12 h of the ICAM-1-transfected MSC increased. Both absolute cell number and migration rate of MSC were significantly up-regulated by ICAM-1. Furthermore, the promoting effect of ICAM-1 on migration was partially suppressed by the inhibition of JNK/SAPK pathway. The transmigrated cell numbers and the migration rate decreased with the addition of JNK inhibitor II. However, the ICAM-1 promoting migration of MSC was not suppressed by the inhibitors for ERK/MAPK and p38/MAPK pathway did not work in the present study. It is concluded that ICAM-1 can induce mouse MSC migration in vitro, and the promoting effect is partially dependent on the activation of JNK/SAPK pathway. PMID- 24763028 TI - [Promoting effect of thrombin on proliferation of bone marrow-derived mesenchymal stem cells and its mechanisms]. AB - This study was aimed to investigate the growth-promoting activity of thrombin on mesenchymal stem cells (MSC) and its mechanisms. Human bone marrow MSC were cultured in serum-free medium supplemented with graded concentrations of thrombin, and the proliferation status of MSC was detected by MTT test. The expression levels of protease-activated receptors (PAR) and c-MYC gene were detected by PCR. Activated Akt signaling pathway was revealed by Western blot, and specific inhibitors of the signaling pathways were used to confirm the effects. The results showed that thrombin stimulated MSC proliferation in a dose dependent manner; the minimal concentration of thrombin for stimulating MSC growth was 0.5 U/ml, and the promoting effect reached its maximum when thrombin at a dose of 8 U/ml was employed. PCR results showed that MSC expressed the two types of PAR1 and PAR2. After PAR1 was blocked with a specific inhibitor SCH79797, the growth-promoting effect of thrombin was inhibited, while this phenomenon was not observed when MSC were exposed to FSLLRY-NH2, a specific inhibitor for PAR2. Further experiments showed that after exposure to thrombin, the AKT signaling pathway in MSC was promptly activated, and c-MYC expression was greatly up-regulated. Meanwhile, when LY294002, a specific AKT inhibitor, was added into the culture medium, the up-regulation of c-MYC expression was reduced, accompanied by the low rate of MSC growth. It is concluded that thrombin can stimulate MSC proliferation by eliciting PAR1-mediated AKT activation and subsequent up-regulation of c-MYC expression. PMID- 24763029 TI - [Exploration of conditions for releasing microvesicle from human bone marrow mesenchymal stem cells]. AB - The release of microvesicles(MV) is one of the critical mechanisms underlying the angiogenesis-promoting activity of mesenchymal stem cells(MSC). This study was aimed to explore the appropriate condition under which MSC releases MV. Bone marrow samples from 5 healthy adults were collected, and MSC were isolated, culture-expanded and identified. MSC at passage 5 were suspended in medium without or medium with 10% fetal(FCS) calf serum and seeded into culture dishes. The culture was separately maintained in hypoxia (1% oxygen) or normoxia (around 20% oxygen), and 20 dishes of cells (2*10(6)/dish) were used for each group. The supernatants were collected for MV harvesting. The cell number was counted with trypan blue exclusion test and the protein contents in the MV were determined. MV were identified by observation under an electron microscope. The surface markers on MV were analyzed by flow cytometry. MTT test was performed to observe the pro proliferative activity of MV that were added into the culture of human umbilical cord vein endothelial cells at a concentration of 10 ug/ml. The results showed that the majority of MV released by MSC were with diameters of less than 100 nm, and MV took the featured membrane-like structure with a hypodense center. They expressed CD29, CD44, CD73 and CD105, while they were negative for CD31 and CD45. The increase multiples of the adherent trypan blue-resistant cells cultured in normoxia with serum, in normoxia without serum, in hypoxia with serum and hypoxia in the absence of serum were 4.05 +/- 0.73, 1.77 +/- 0.48, 5.80 +/- 0.65 and 3.69 +/- 0.85 respectively, and the estimated protein contents per 10(8) cells were 463.48 +/- 138.74 ug, 1604.07 +/- 445.28 ug, 2389.64 +/- 476.75 ug and 3141.18 +/ 353.01 ug. MTT test showed that MV collected from MSC in hypoxia seemed to promote the growth of endothelial cells more efficiently than those from cells in normoxia. It is concluded that hypoxia can enhance the release of microvesicles from MSC, and cultivation of MSC in hypoxia and medium without serum may provide an appropriate condition for MV harvesting. PMID- 24763030 TI - [Modified method for whole bone marrow adherent culture of human bone marrow mesenchymal stem cells]. AB - This study was aimed to investigate a more convenient and efficient method to cultivate the human bone marrow mesenchymal stem cells by means of natural erythrocyte sedimentation principle, based on the whole bone marrow adherent method. The bone marrow was cultured with a six-well plate instead of the flasks.Firstly, the bone marrow specimen was cultivated with the MSC complete medium for 48 h, then the upper RBC-free supernatant layer was drawn and placed into the new wells to isolate MSC. Inverted microscope was used to observe the cell morphology and to record the adherent time of first cell passage, first passaging time. The traditional whole bone marrow adherent method was used as the control. The cell cycle and cell surface markers were detected by flow cytometry,and the differentiative capacity of MSC into osteocyte and adipocyte was identified by alkaline phosphatase kit and oil red O, respectively. Besides, the proliferative curve of P1,P3,P5 of BMSC was depicted by counting method. The results showed that MSC cultured by the modified method highly expressed CD90, CD105, CD13, CD44 and lowly expressed CD14, CD45, CD34. Concerning the cell cycle feature, it was found that most of the cells were in G0/G1 phase (88.76%) , followed by G2/M phase (3.04%) and S phase (8.2%), which was in accordance with stem cell cycle characteristics. The proliferative curve showed a typical "S" type, and both the oil red O and alkaline phosphatase staining of MSC were positive. Compared with the traditional method, the modified method had the advantage of high adherence rate (P = 0.0001) and shorter passaging time for the first passage (P = 0.001), with the statistically significant difference. It is concluded that there is a large number of adherent, active and suspended MSC in the RBC-free supernatant layer after the culture of bone marrow for 48 h. Isolating MSC by the modified method is more convenient and efficient than the traditional whole bone marrow adherent method. PMID- 24763031 TI - [Preparation of tranexamic acid-loaded porous starch and evaluation of its hemostatic ability]. AB - This study was aimed to develop a new generation of ideal hemostatic powder which can be safely, effectively and easily used mainly to first aid anterior to hospital by the synergistic effect of physical and chemical hemostatic mechanisms. The tranexamic acid(TA)-loaded porous starch(PS) (TAPS) was prepared by using PS as carrier and TA as loaded drug component. The absorption property of TAPS was evaluated by water absorption; the hemostatic ability of TAPS was evaluated by test in vitro and in vivo, the blood coagulation time of TAPS was detected by using Lee-white method. The experiment was divided into 3 groups: blank control group, Yunnan Baiyao group and TAPS group, each group with 10 blood samples in vitro test; the 27 SD rats were used to test in vivo, and randomly were divided into 3 groups: PS,Yunnan Baiyao and TAPS, each group consisted of 9 rats for establishing the animal model of liver trauma and detecting the complete hemostasis time. The results showed that the water absorption of PS did not be affected by TA when dose of TA loaded in PS was <0.02 g/g PS. There was no statistic difference in blood coagulation time between TAPS and PS groups(P > 0.05). The complete hemostatic time of TAPS for trauma of left lobe liver was 236.67 +/- 55.00 seconds, which was shorter than that of Yunnan Baiyao (340.00 +/ 73.48 seconds) and PS (396.67 +/- 68.37 seconds) (P < 0.05 and P < 0.01, respectively). It is concluded that PS can load TA and play the hemostatic effect through releasing TA; the TA loading <0.02 g/g PS did not affect the water absorption and pro-coagulation properties. The TA can enhance the hemostatic efficacy of PS, the hemostatic property of TAPS is derived from synergism of physical and chemical hemostatic mechanisms. PMID- 24763032 TI - [Identification of a novel HLA allele, HLA-DRB1*03:80, by sequencing-based typing]. AB - This study was aimed to identify a novel HLA-DRB1 allele from a Chinese potential hemopoietic stem cell donor of Northeast China. A rare HLA-DRB1 allele was initially detected by Luminex PCR-SSO typing, then the sample was sequenced by sequence-based typing (SBT) and the alignments of sample's alleles was identified by single allele-specific sequencing strategy. The results revealed the existence of a new allele which differs from the closest matching allele DRB1*03:06 by a single nucleotide substitution at position 239, where C->G in exon 2, resulting in an amino acid exchange from Thr to Arg at codon 51. It is concluded that a novel allele has been confirmed and its name DRB1*03:80 is officially assigned by the WHO Nomenclature Committee in February 2012. PMID- 24763034 TI - [Family investigation of a RHD 845A/1227A genotype individual]. AB - This study was aimed to investigate 1 case of rare RHD845A/1227A genotype pedigree and analyse their characters. The D antigen was determined by saline method and indirect anti-globulin test (IAT), the RHD1227A, RHD845A alleles and RHD zygosity were detected by PCR-SSP assay, the RHD coding region was analysed by gene sequencing. The results showed that the serological result of RH(D) antigen was found to be negative in one sample by saline assay, but positive by IAT. The analysis of RHD gene sequence indicated that RHD genes in the 845th and 1227th location were G/A base heterozygosis, it was speculated that the individual genotype may be RHD845A/1227A. Family investigation demonstrated the proband's father was RhD negative, his mother was RhD positive, the results of PCR-SSP assay showed that his father carried the RHD1227A alleles, whose genotype was RHD1227A/RHD(-), however, his mother carried RHD845A alleles, her genotype was RHD845A/RHD(+), which proved that the proband's genotype was RHD845A/1227A, inheriting the RHD1227A and RHD845A alleles from his father and mother respectively. It is concluded that 1 case of rare RHD845A/1227A genotype is found, further study proved that this rare heterozygosis come from the hereditary of RHD845A and RHD1227A alleles, rather than the formation of individual gene mutation. PMID- 24763033 TI - [Discrimination of alleles in HLA-C*04:01:01G groups]. AB - The aim of this study was to investigate the relatively frequencies of alleles in the HLA-C*04:01:01G group and to analyze their relations with HLA-A and -B loci. DNA samples previously typed as HLA-C*04:01:01G were sequentially selected. The sequences for exon 2 to 7 of the HLA-C locus were analyzed by polymerase chain reaction sequence-based typing(PCR-SBT). The HLA-A, -B, -DRB1 and -DQB1 loci were genotyped using PCR-SBT method. The results showed that 178 samples (94.2%) and 11 samples (5.8%) were assigned as HLA-C*04:01:01 and HLA-C*04:82 respectively among 189 samples previously typed as HLA-C*04:01:01G. 72 haplotypes associated with HLA-C*04:01:01 and C*04:82 were found, in which the frequencies of 26 haplotypes were over 0.0050. HLA-C*04:01:01 was strongly related with A*02:03, A*02:07, A*11:01, A*33:03, B*13:01, B*15:01, B*15:05, B*15:27, B*40:01, B*54:01 alleles, while HLA-C*04:82 was related with B*40:01. It is concluded that HLA C*04:01:01 and HLA-C*04:82 alleles were confirmed in the HLA-C*04:01:01G group, which should be discriminated by the routine HLA genotyping. PMID- 24763035 TI - [Qualitative analysis of platelet rich plasma prepared by acute plateletpheresis in patients undergoing heart surgery]. AB - This study was aimed to evaluate the efficiency and effectiveness of platelet rich plasma(PRP) prepared by acute plateletpheresis in patients undergoing open heart surgery, and to analyze the quality of prepared platelet-rich plasma. Whole blood from 20 patients with ASAII-III was collected and PRP was harvested by machine after induction of anesthesia. Platelet count (Plt), mean platelet volume (MPV), platelet distribution width (PDW), plasma pH, plasma lactic acid (LA) concentration, and lactic dehydrogenase (LDH) concentration, germiculture result, CD62p and PAC-1 positive rate of inactivated and activated platelets by ADP in the whole blood before plateletpheresis (T1) , in the PRP after plateletpheresis (T2) and PRP before back-transfusion (T3) were determinated. The results showed that as compared with whole blood the platelet count in the PRP at T2 was (783 +/ 184) *10(9)/L, MPV, PDW and pH significantly decreased (P < 0.01) , while the plasma LDH, LA concentration, CD62p and PAC-1 positive rate of inactivated platelets were not significantly different from the whole blood at T1. In the PRP at T3, the platelet count, MPV, PDW and pH significantly decreased (P < 0.01) , while plasma LDH concentration, CD62p and PAC-1 positive rate of inactivated platelet significantly increased (P < 0.05 or P < 0.01) compared with the whole blood at T1. There were no significant difference among the CD62p and PAC-1 positive rate of activated platelets in the whole blood and PRP. It is concluded that PRP can be efficiently obtained from the patients undergoing open heart surgery by acute plateletpheresis, and the platelets in PRP are not activated during the preparing process. Some platelets in PRP are activated during the preserving process, but the whole activating function of platelets keeps normal. PMID- 24763036 TI - [Myeloid/natural killer cell precursor and myeloid/natural killer cell acute leukemia]. AB - With the popularity of flow cytometry, the classification of leukemia become more detailed. Myeloid/natural killer cell precursor acute leukemia and myeloid/natural killer cell acute leukemias are generally recognized as two kinds of rare leukemias and have poor prognosis. The cells expressed both myeloid and lymphatic antigens in these two leukemia and can not be diagnosed by morphology. The only basis to make a definite diagnosis is their unique Immunophenotyping. The role of CD7 and CD56 in these two leukemia are compelling, in the other hand, as the progress of cell differentiation research, there are many new awareness of NK cell differentiation. In this article, the biological origin, clinical manifestation, diagnosis, treatment and the role of CD7 and CD56 in these two leukemia are briefly summarized. PMID- 24763037 TI - [CAL-101,a novel agent of targeted therapy in hematological malignancies]. AB - CAL-101 is a selective inhibitor of the phosphatidylinositol-3 kinase (PI3K), it inhibits the survival, proliferation and migration of tumor cells by directly inducing apoptosis and inhibiting micro-environmental interactions. It has been determined that the P110delta isoforms of PI3K expressed primarily in cells of hematopoietic lineage, such as B and T cells. This review focuses on the target, mechanism of action, the use and prospect of CAL-101 in tumors of blood and lymph systems. PMID- 24763038 TI - [In vivo migration of mesenchymal stem cells]. AB - Mesenchymal stem cells (MSC) have the capacities of low immunogenicity, multiple differentiation, hematopoietic supporting and immunoregulation. And due to their relative ease of availability and ex vivo expansion, the applications of MSC in the prevention and treatment of clinical disease have been rapidly expanded in the recent years. However, increasing investigations indicate that intravenously infused MSC widely distribute to various organs of the recipients. The two intended clinical goals of adoptive cellular therapy reached to the greatest efficiency. Therefore, the ideal candidate cells showed to have the capacity of site-specific relocation in vivo. In this review, the distribution characteristics of infused MSC and the recent research advances on the strategies to enhance targeted migration of MSCs are summarized. PMID- 24763039 TI - [Recent advances on diagnosis and therapy of lymphoproliferative disorders after allo-HSCT]. AB - Post-transplant lymphoproliferative disorders(PTLD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are a group of rare, but are grievous complications. The occurrence of these diseases are most associated with EBV infection. The clinical manifestations usually include recurrent fever, lymph node enlargement, progressive decline of three lineage cells of hemogram, EB viremia and response failure to formal broad-spectrum antibiotics therapy, then the disease rapidly deteriorated in the short term, which result in high mortality. Therefore, early diagnosis and timely effective treatment such as rituximab, donor lymphocyte infusion and/or EB virus-specific cytotoxic T lymphocytes are needed to improve the prognosis. This review briefly summarized the diagnosis and therapy advance on the lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation. PMID- 24763040 TI - [Novel strategy and latest research progress on treatment of acute graft versus host disease]. AB - Acute graft-versus-host disease (aGVHD) is the major complication associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the major cause of morbidity and mortality following allo-HSCT. Diagnosis of aGVHD is typically based on clinical symptoms and confirmed by biopsy. Once aGVHD has occurrence, the steroids should be the first choice of treatment. However, if the treatment with steroids failed, the prognosis would be poor. In recent years, the novel strategies for the treatment of aGVHD have been developed. In this article, the clinical features, pathogenesis and novel strategies, including mAb treatment, physical and cell therapies are briefly summarized. PMID- 24763041 TI - [Latest research progress on pathogenesis of chronic graft versus host disease and its related problems]. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method for the treating of malignant diseases of hematopoietic system or non malignant proliferative diseases, but the occurrence of graft-versus-host disease (GVHD) limits the success rate of hematopoietic stem cell transplantation. Moreover, chronic graft-versus-host disease (cGVHD) is the main factor affecting the long-term survival rate and life quality of recipient after hematopoietic stem cell transplantation. In this article, the latest research progress of the pathogenesis of cGVHD and related problems are reviewed from the thymus, cytokines, T lymphocyte subsets, B lymphocytes and its secreted antibody. PMID- 24763042 TI - [Research progress on human acute leukemia xenograft mouse models]. AB - The methods for modeling human acute leukemia in mice include xenotransplantation of human leukemia cells, retroviral transduction/transplantation, transgenesis, chemical mutagenesis and insertional mutagenesis. Establishing human acute leukemia mouse models through xenograft is an important way to study acute leukemia. This review focuses on the newest progress of studies on human acute leukemia xenograft mouse models in the regards of the immunodeficiency mouse, preconditioning, cytokines, cell transplantation, the evaluation and application of model. PMID- 24763043 TI - [HMGB1-a as potential target for therapy of hematological malignancies]. AB - HMGB1 is a widely existing DNA-binding nuclear protein, participating in gene transcription, damage repair, recombination and stabilizing nucleosome construction. Under injury, infection and chemotherapy, HMGB1 can be released by nature immunocyte and necrosis cells as a DAMP, exerting pleiotropic biological effects by binding to RAGE, TLR and CXCL12, which lead to activation of CDC42, mitogen-activated protein kinases (MAPKs), c-IAP and NF-kappaB, thereby promoting angiogenesis, unlimited replicative potential, tissue invasion and metastasis. And it also involves in immune response by regulating immunocyte function as a immunocyte warning signal. Scholars have detected that HMGB1 is over expressed and released following chemotherapy and radiation therapy in cells of hematological malignancies, promoting malignant cell replication, decreasing therapeutic effect. Recently, endogenous HMGB1 has been implied to be an intrinsic modulator of autophagy and referenced to resistant to apoptosis in malignant hematosis cells. In contrast, through suppression of HMGB1 expression, tumor cell apoptosis and chemotherapeutic drug sensitivity were increased, which will be a new strategy for the treatment of hematological malignancies. In this article, the basic characteristics of HMGB1, including structure and biological features, and HMGB1 and tumors such as lymphoma, myeloproliferative neoplasms and acute myeloid leukemia are reviewed. PMID- 24763044 TI - [Application of lenalidomide in chronic lymphocytic leukemia]. AB - In recent years, the incidence of chronic lymphocytic leukemia (CLL) is increasing. Microenvironment and immune system play a key role in the pathogenesis of CLL. The immune system is aggravated by the use of chemotherapeutic agents, such as fludarabine and cyclophosphamide with rituximab(FCR) which are the current standards in frontline therapy. This leads to an increase of infection incidence in patients, resulting in a poor prognosis. The present situation was changed by lenalidomide. Recent studies indicated that lenalidomide monotherapy in treatment of refractory or relapsed CLL patients, the overall response rate(ORR) reached about 32%-47%, CR roughly was 7%-13%; when lenalidomide and rituximab were combined for treatment of refractory or relapsed CLL patients, the ORR reached about 53%-66%, CR about 12%-13%. Moreover, when lenalidomide and ofatumumab were combined, the efficacy is improved significantly and the adverse reactions are greatly reduced. The adverse reactions are neutrophilic granulocytopenia, thrombocytopenia, anemia, tumor lysis syndrome(TLS), tumor flare reaction(TFR) and venous thromboembolism(VTE). This review focuses on the related studies and the latest progress about lenalidomide in CLL. PMID- 24763045 TI - [Role of CD8(+)T cells and their secreted cytokines in the pathogenesis of aplastic anemia]. AB - Aplastic anemia(AA) is mostly considered as an immune-mediated bone marrow failure syndrome, characterized by pancytopenia and bone marrow hypoplasia. The pathogenesis of AA is complicated, until now it is not fully understood. Further study on the pathological mechanism will be helpful for the diagnosis and treatment of AA. CD8(+) T cells and their secreted cytokines play important roles in the abnormal immunity during the process of AA. Thus, this review focuses on the role of CD8(+) T cells and their secreted cytokines in the pathogenesis of AA. PMID- 24763046 TI - Adiponectin deficiency exacerbates age-related hearing impairment. AB - Obesity-related disorders are closely associated with the development of age related hearing impairment (ARHI). Adiponectin (APN) exerts protective effects against obesity-related conditions including endothelial dysfunction and atherosclerosis. Here, we investigated the impact of APN on ARHI. APN-knockout (APN-KO) mice developed exacerbation of hearing impairment, particularly in the high frequency range, compared with wild-type (WT) mice. Supplementation with APN prevented the hearing impairment in APN-KO mice. At 2 months of age, the cochlear blood flow and capillary density of the stria vascularis (SV) were significantly reduced in APN-KO mice as compared with WT mice. APN-KO mice also showed a significant increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells in the organ of Corti in the cochlea at 2 months of age. At the age of 6 months, hair cells were lost at the organ of Corti in APN-KO mice. In cultured auditory HEI-OC1 cells, APN reduced apoptotic activity under hypoxic conditions. Clinically, plasma APN levels were significantly lower in humans with ARHI. Multiple logistic regression analysis identified APN as a significant and independent predictor of ARHI. Our observations indicate that APN has an important role in preventing ARHI. PMID- 24763047 TI - Anticancer compound Oplopantriol A kills cancer cells through inducing ER stress and BH3 proteins Bim and Noxa. AB - Oplopantriol-A (OPT) is a natural polyyne from Oplopanax horridus. We show here that OPT preferentially kills cancer cells and inhibits tumor growth. We demonstrate that OPT-induced cancer cell death is mediated by excessive endoplasmic reticulum (ER) stress. Decreasing the level of ER stress either by inactivating components of the unfolded protein response (UPR) pathway or by expression of ER chaperone protein glucose-regulated protein 78 (GRP78) decreases OPT-induced cell death. We show that OPT induces the accumulation of ubiquitinated proteins and the stabilization of unstable proteins, suggesting that OPT functions, at least in part, through interfering with the ubiquitin/proteasome pathway. In support of this, inhibition of protein synthesis significantly decreased the accumulation of ubiquitinated proteins, which is correlated with significantly decreased OPT-induced ER stress and cell death. Finally, we show that OPT treatment significantly induced the expression of BH3 only proteins, Noxa and Bim. Knockdown of both Noxa and Bim significantly blocked OPT-induced cell death. Taken together, our results suggest that OPT is a potential new anticancer agent that induces cancer cell death through inducing ER stress and BH3 proteins Noxa and Bim. PMID- 24763048 TI - Enhancement of auranofin-induced lung cancer cell apoptosis by selenocystine, a natural inhibitor of TrxR1 in vitro and in vivo. AB - Thioredoxin reductase (TrxR) is overexpressed in many human tumors and has a key role in regulating intracellular redox balance. Recently, thioredoxin system has emerged as a valuable target for anticancer drug development. Herein we demonstrate that selenocystine (SeC) could enhance auranofin (AF)-induced A549 human lung adenocarcinoma cell apoptosis in vitro and in vivo through synergetic inhibition of TrxR1. SeC pretreatment significantly enhanced AF-induced loss of mitochondrial membrane potential (Deltapsim) by regulating Bcl-2 family proteins. The combined treatment with SeC and AF also resulted in enhanced intracellular reactive oxygen species (ROS) accumulation, DNA damage, and inactivation of ERK and AKT. Inhibitors of ERK and AKT effectively enhanced combined treatment induced apoptotic cell death. However, inhibition of ROS reversed the apoptosis induced by SeC and AF, and recovered the inactivation of ERK and AKT, which revealed the importance of ROS in cell apoptosis and regulation of ERK and AKT pathways. Moreover, xenograft lung tumor growth in nude mice was more effectively inhibited by combined treatment with SeC and AF by induction of apoptosis through targeting TrxR1 in vivo. Taken together, our results suggest the strategy to use SeC and AF in combination could be a highly efficient way to achieve anticancer synergism by targeting TrxR1. PMID- 24763049 TI - Mesenchymal stem cells infected with Mycoplasma arginini secrete complement C3 to regulate immunoglobulin production in B lymphocytes. AB - Mesenchymal stem cells (MSCs) have immunomodulatory functions such as the suppression of T and B cells. MSCs suppress immunoglobulin (Ig) production by B cells via cell-cell contact as well as via secretion of soluble factors. Our study showed that the conditioned medium (CM) of MSCs infected with a mycoplasma strain, Mycoplasma arginini, has marked inhibitory effects on Ig production by lipopolysaccharide/interleukin-4-induced B cells compared with mycoplasma-free MSC-CM. We analyzed mycoplasma-infected MSC-CM by fast protein liquid chromatography and liquid chromatography to screen the molecules responsible for Ig inhibition. Complement C3 (C3) was the most critical molecule among the candidates identified. C3 was shown to be involved in the suppression of the Ig production of B cells. C3 was secreted by mycoplasma-infected MSCs, but not by mycoplasma-free MSCs or B cells. It was able to directly inhibit Ig production by B cells. In the presence of a C3 inhibitor, Ig inhibition by MSC-CM was abrogated. This inhibitory effect was concomitant with the downregulation of B cell-induced maturation protein-1, which is a regulator of the differentiation of antibody-secreting plasma cells. These results suggest that C3 secreted from mycoplasma-infected MSCs has an important role in the immunomodulatory functions of MSCs. However, its role in vivo needs to be explored. PMID- 24763050 TI - Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death. AB - The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the 'two-in-one' compound that stimulates autophagosome formation (by downregulating Akt/mammalian target of rapamycin (mTOR) pathway) and inhibits their degradation (by acting like a lysosomotropic agent and increasing lysosomal pH). We show that ML-9 as a monotherapy effectively induces prostate cancer cell death associated with the accumulation of autophagic vacuoles. Further, ML-9 enhances the anticancer activity of docetaxel, suggesting its potential application as an adjuvant to existing anticancer chemotherapy. Altogether, our results revealed the complex effect of ML-9 on autophagy and indentified ML-9 as an attractive tool for targeting autophagy in cancer therapy through dual inhibition of both the Akt pathway and the autophagy. PMID- 24763051 TI - A gain-of-function mutant p53-HSF1 feed forward circuit governs adaptation of cancer cells to proteotoxic stress. AB - To overcome proteotoxic stress inherent to malignant transformation, cancer cells induce a range of adaptive mechanisms, with the master transcription factor heat shock factor 1 (HSF1)-orchestrated response taking center stage. Here we define a novel gain-of-function of mutant p53 (mutp53), whereby mutp53-overexpressing cancer cells acquire superior tolerance to proteotoxic stress. mutp53 via constitutive stimulation of EGFR and ErbB2 signaling hyperactivates the MAPK and PI3K cascades, which induce stabilization and phosphoactivation of HSF1 on Ser326. Moreover, mutp53 protein via direct interaction with activated p-Ser326 HSF1 facilitates HSF1 recruitment to its specific DNA-binding elements and stimulates transcription of heat-shock proteins including Hsp90. In turn, induced Hsp90 stabilizes its oncogenic clients including EGFR, ErbB2 and mutp53, thereby further reinforcing oncogenic signaling. Thus, mutp53 initiates a feed forward loop that renders cancer cells more resistant to adverse conditions, providing a strong survival advantage. PMID- 24763052 TI - The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response. AB - The epigenetic sensor BRD4 (bromodomain protein 4) is a potent target for anti cancer therapies. To study the transcriptional impact of BRD4 in cancer, we generated an expression signature of BRD4 knockdown cells and found oxidative stress response genes significantly enriched. We integrated the RNA-Seq results with DNA-binding sites of BRD4 generated by chromatin immunoprecipitations, correlated these with gene expressions from human prostate cancers and identified 21 top BRD4 candidate genes among which the oxidative stress pathway genes KEAP1, SESN3 and HDAC6 are represented. Knock down of BRD4 or treatment with the BRD4 inhibitor JQ1 resulted in decreased reactive oxygen species (ROS) production and increased cell viability under H2O2 exposure. Consistently, a deregulation of BRD4 diminished the KEAP1/NRF2 axis and led to a disturbed regulation of the inducible heme oxygenase 1 (HMOX1). Without exogenous stress induction, we also found BRD4 directly targeting the HMOX1 promoter over the SP1-binding sites. Our findings provide insight into the transcriptional regulatory network of BRD4 and highlight BRD4 as signal transducer of the cellular response to oxidative stress. PMID- 24763053 TI - The histone methyltransferase ESET is required for the survival of spermatogonial stem/progenitor cells in mice. AB - Self-renewal and differentiation of spermatogonial stem cells (SSCs) are the foundation of spermatogenesis throughout a male's life. SSC transplantation will be a valuable solution for young male patients to preserve their fertility. As SSCs in the collected testis tissue from the patients are very limited, it is necessary to expansion the SSCs in vitro. Previous studies suggested that histone methyltransferase ERG-associated protein with SET domain (ESET) represses gene expression and is essential for the maintenance of the pool of embryonic stem cells and neurons. The objective of this study was to determine the role of ESET in SSCs using in vitro cell culture and germ cell transplantation. Cell transplantation assay showed that knockdown of ESET reduced the number of seminiferous tubules with spermatogenesis when compared with that of the control. Knockdown of ESET also upregulated the expression of apoptosis-associated genes (such as P53, Caspase9, Apaf1), whereas inhibited the expression of apoptosis suppressing genes (such as Bcl2l1, X-linked inhibitor of apoptosis protein). In addition, suppression of ESET led to increase in expression of Caspase9 and activation of Caspase3 (P17) as well as cleavage of poly (ADP-ribose) polymerase. Among the five ESET-targeting genes (Cox4i2, spermatogenesis and oogenesis Specific Basic Helix-Loop-Helix 2, Nobox, Foxn1 and Dazl) examined by ChIP assay, Cox4i2 was found to regulate SSC apoptosis by the rescue experiment. BSP analyses further showed that DNA methylation in the promoter loci of Cox4i2 was influenced by ESET, indicating that ESET also regulated gene expression through DNA methylation in addition to histone methylation. In conclusion, we found that ESET regulated SSC apoptosis by suppressing of Cox4i2 expression through histone H3 lysine 9 tri-methylation and DNA methylation. The results obtained will provide unique insights that would broaden the research on SSC biology and contribute to the treatment of male infertility. PMID- 24763054 TI - MicroRNA-185 regulates chemotherapeutic sensitivity in gastric cancer by targeting apoptosis repressor with caspase recruitment domain. AB - Gastric cancer remains the second leading cause of cancer deaths worldwide. Resistance to chemotherapy is a significant barrier for effective cancer treatment. Here, we identified miR-185 to be a contributor to chemosensitivity in gastric cancer. We observed low levels of miR-185 in gastric cancer cell lines and clinical tissues, compared with gastric epithelium cell line and noncancerous tissues. Furthermore, enforced expression of miR-185 increased the sensitivity of gastric cancer cells to low-dose chemotherapeutic agents, which alone cannot trigger significant apoptosis. Conversely, knockdown of endogenous miR-185 prevented high-dose chemotherapy-induced apoptosis. In elucidating the molecular mechanism by which miR-185 participated in the regulation of chemosensitivity in gastric cancer, we discovered that apoptosis repressor with caspase recruitment domain (ARC) is a direct target of miR-185. The role of miR-185 was confirmed in gastric tumor xenograft model. The growth of established tumors was suppressed by a combination therapy using enforced miR-185 expression and a low dose of anticancer drugs. Finally, we found that RUNX3 (Runt-related transcription factor) was involved in the activation of miR-185 at the transcriptional level. Taken together, our results reveal that RUNX3, miR-185 and ARC regulate the sensitivity of gastric cancer cells to chemotherapy. PMID- 24763055 TI - Therapeutic ROS targeting of GADD45gamma in the induction of G2/M arrest in primary human colorectal cancer cell lines by cucurbitacin E. AB - Cucurbitacin E (CuE) or alpha-elaterin is a natural compound previously shown to be an antifeedant as well as a potent chemopreventive agent against several types of cancer. The present study investigated the anticancer effects of CuE on colorectal cancer (CRC) using primary cell lines isolated from five CRC patients in Taiwan, Specifically, we explored the anti-proliferation and cell cycle G2/M arrest induced by CuE in CRC cells. MPM-2 flow cytometry tests show that CuE treated cells accumulated in metaphase (CuE 2.5-7.5 MUM). Results further indicate that CuE produced G2/M arrest as well as the downregulation of CDC2 and cyclin B1 expression and dissociation. Both effects increased proportionally with the dose of CuE; however, the inhibition of proliferation, arrest of mitosis, production of reactive oxygen species (ROS), and loss of mitochondrial membrane potential (DeltaPsim) were found to be dependent on the quantity of CuE used to treat the cancer cells. In addition, cell cycle arrest in treated cells coincided with the activation of the gene GADD45(alpha, beta, gamma). Incubation with CuE resulted in the binding of GADD45gamma to CDC2, which suggests that the delay in CuE-induced mitosis is regulated by the overexpression of GADD45gamma. Our findings suggest that, in addition to the known effects on cancer prevention, CuE may have antitumor activities in established CRC. PMID- 24763056 TI - APPL proteins modulate DNA repair and radiation survival of pancreatic carcinoma cells by regulating ATM. AB - Despite intensive multimodal therapies, the overall survival rate of patients with ductal adenocarcinoma of the pancreas is still poor. The chemo- and radioresistance mechanisms of this tumor entity remain to be determined in order to develop novel treatment strategies. In cancer, endocytosis and membrane trafficking proteins are known to be utilized and they also critically regulate essential cell functions like survival and proliferation. On the basis of these data, we evaluated the role of the endosomal proteins adaptor proteins containing pleckstrin homology domain, phosphotyrosine binding domain and a leucine zipper motif (APPL)1 and 2 for the radioresistance of pancreatic carcinoma cells. Here, we show that APPL2 expression in pancreatic cancer cells is upregulated after irradiation and that depletion of APPL proteins by small interfering RNA (siRNA) significantly reduced radiation survival in parallel to impairing DNA double strand break (DSB) repair. In addition, APPL knockdown diminished radiogenic hyperphosphorylation of ataxia telangiectasia mutated (ATM). Activated ATM and APPL1 were also shown to interact after irradiation, suggesting that APPL has a more direct role in the phosphorylation of ATM. Double targeting of APPL proteins and ATM caused similar radiosensitization and concomitant DSB repair perturbation to that observed after depletion of single proteins, indicating that ATM is the central modulator of APPL-mediated effects on radiosensitivity and DNA repair. These data strongly suggest that endosomal APPL proteins contribute to the DNA damage response. Whether targeting of APPL proteins is beneficial for the survival of patients with pancreatic adenocarcinoma remains to be elucidated. PMID- 24763057 TI - Attenuation of noise-induced hearing loss using methylene blue. AB - The overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been known to contribute to the pathogenesis of noise-induced hearing loss. In this study, we discovered that in BALB/c mice pretreatment with methylene blue (MB) for 4 consecutive days significantly protected against cochlear injury by intense broad-band noise for 3 h. It decreased both compound threshold shift and permanent threshold shift and, further, reduced outer hair cell death in the cochlea. MB also reduced ROS and RNS formation after noise exposure. Furthermore, it protected against rotenone- and antimycin A-induced cell death and also reversed ATP generation in the in vitro UB-OC1 cell system. Likewise, MB effectively attenuated the noise-induced impairment of complex IV activity in the cochlea. In addition, it increased the neurotrophin-3 (NT-3) level, which could affect the synaptic connections between hair cells and spiral ganglion neurons in the noise-exposed cochlea, and also promoted the conservation of both efferent and afferent nerve terminals on the outer and inner hair cells. These findings suggest that the amelioration of impaired mitochondrial electron transport and the potentiation of NT-3 expression by treatment with MB have a significant therapeutic value in preventing ROS-mediated sensorineural hearing loss. PMID- 24763061 TI - The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. AB - A high proportion of peripheral human B cells produce polyreactive or autoreactive antibodies, which indicates that they have escaped the elimination of self-reactive B cells in the bone marrow. CD22 and Siglec-G are two inhibitory receptors of the sialic-acid-binding immunoglobulin-like lectin (Siglec) family that inhibit the B-cell antigen receptor (BCR) signal. The ability of these two receptors to bind sialic acids is crucial for regulating inhibition and inducing tolerance to self-antigens. Sialylated glycans are usually absent on microbes (although several pathogenic microorganisms have evolved strategies to mimic self by decorating their surfaces with sialic acids) but abundant in higher vertebrates and might, therefore, provide an important tolerogenic signal. Combined Siglec-G deficiency and CD22 deficiency leads to spontaneous autoimmunity in mice, and mutations in an enzyme that modifies Siglec ligands are directly linked to several autoimmune diseases in humans. New data show that high affinity ligands for CD22 and Siglec-G can be used to induce antigen-specific B cell tolerance, which might be one strategy for the treatment of autoimmune diseases in the future. PMID- 24763062 TI - California Nino/Nina. AB - The present study shows the existence of intrinsic coastal air-sea coupled phenomenon in the coastal ocean off Baja California and California in boreal summer for the first time. It contributes significantly to the interannual sea surface temperature (SST) anomalies there. An initial decrease/increase in the equatorward alongshore surface winds weakens/strengthens the coastal upwelling and raises/lowers the coastal SSTs through oceanic mixed-layer processes. The resultant coastal warming/cooling, in turn, heats/cools the overlying atmosphere anomalously, decreases/increases the atmospheric pressure in the lower troposphere, generates an anomalous cross-shore pressure gradient, and thus reinforces or maintains the alongshore surface wind anomalies. The regional air sea coupled phenomenon seems to be analogous to the well-known El Nino/Southern Oscillation (ENSO) in the tropical Pacific but with much smaller time and space scales, and may be referred to as California Nino/Nina in its intrinsic sense. PMID- 24763063 TI - Viral microRNA genomics and target validation. AB - A subset of viruses express their own microRNAs (miRNAs) and one way to understand the functions of these microRNAs is to identify the targets of these miRNAs. Sequence analysis and mRNA expression profiling were some of the first techniques to identify targets of viral miRNAs. More recently, proteomics and sequencing of RNA by crosslinking and immunoprecipitation (CLIP) methods have been insightful and discovered many miRNA targets that may be missed using other methods. We are now at a point where numerous validated miRNA targets have been described and integration of these genomic datasets will provide a richer understanding of miRNA targeting and viral infection, persistence, and pathogenesis. PMID- 24763064 TI - Dietary carbohydrates and intestinal lipoprotein production. AB - PURPOSE OF REVIEW: To review new evidence that dietary monosaccharides enhance intestinal chylomicron secretion. RECENT FINDINGS: There is abundant evidence linking diets that are high in carbohydrate content with hypertriglyceridemia. In addition, epidemiological studies reveal that the increase in dietary sugars and refined carbohydrates are associated with the rising prevalence of the metabolic syndrome and type 2 diabetes. Association studies, however, cannot prove causation. Mechanistic studies to date have focused on the link between carbohydrate ingestion and hepatic very low-density lipoprotein metabolism, with very little appreciation that dietary carbohydrates may also regulate intestinal lipid absorption and chylomicron secretion. We have recently studied this phenomenon in healthy humans and have shown that both glucose and fructose, infused concomitantly with a lipid emulsion directly into the duodenum and under conditions of a pancreatic clamp, stimulate chylomicron particle secretion. There are a paucity of data regarding the cellular and molecular mechanisms of this effect, which remains largely unknown and a matter of speculation. SUMMARY: Sugar in the diet enhances dietary fat absorption and chylomicron secretion. Whether this phenomenon contributes quantitatively to the well described hypertriglyceridemia that occurs with diets high in carbohydrate and low in fat requires further investigation, as does the underlying cellular mechanism. A thorough understanding of this phenomenon could provide useful information to optimize dietary guidelines. PMID- 24763065 TI - Functional roles of the sweet taste receptor in oral and extraoral tissues. AB - PURPOSE OF REVIEW: This review summarizes and discusses the current knowledge about the physiological roles of the sweet taste receptor in oral and extraoral tissues. RECENT FINDINGS: The expression of a functional sweet taste receptor has been reported in numerous extragustatory tissues, including the gut, pancreas, bladder, brain and, more recently, bone and adipose tissues. In the gut, this receptor has been suggested to be involved in luminal glucose sensing, the release of some satiety hormones, the expression of glucose transporters, and the maintenance of glucose homeostasis. More recently, the sweet taste receptor was proposed to regulate adipogenesis and bone biology. SUMMARY: The perception of sweet taste is mediated by the T1R2/T1R3 receptor, which is expressed in the oral cavity, wherein it provides input on the caloric and macronutrient contents of ingested food. This receptor recognizes all the chemically diverse compounds perceived as sweet by human beings, including natural sugars and sweeteners. Importantly, the expression of a functional sweet taste receptor has been reported in numerous extragustatory tissues, wherein it has been proposed to regulate metabolic processes. This newly recognized role of the sweet taste receptor makes this receptor a potential novel therapeutic target for the treatment of obesity and related metabolic dysfunctions, such as diabetes and hyperlipidemia. PMID- 24763067 TI - P300 speller BCI with a mobile EEG system: comparison to a traditional amplifier. AB - OBJECTIVE: In a previous study, we presented a low-cost, small and wireless EEG system enabling the recording of single-trial P300 amplitudes in a truly mobile, outdoor walking condition (Debener et al (2012 Psychophysiology 49 1449-53)). Small and wireless mobile EEG systems have substantial practical advantages as they allow for brain activity recordings in natural environments, but these systems may compromise the EEG signal quality. In this study, we aim to evaluate the EEG signal quality that can be obtained with the mobile system. APPROACH: We compared our mobile 14-channel EEG system with a state-of-the-art wired laboratory EEG system in a popular brain-computer interface (BCI) application. N = 13 individuals repeatedly performed a 6 * 6 matrix P300 spelling task. Between conditions, only the amplifier was changed, while electrode placement and electrode preparation, recording conditions, experimental stimulation and signal processing were identical. MAIN RESULTS: Analysis of training and testing accuracies and information transfer rate (ITR) revealed that the wireless mobile EEG amplifier performed as good as the wired laboratory EEG system. A very high correlation for testing ITR between both amplifiers was evident (r = 0.92). Moreover the P300 topographies and amplitudes were very similar for both devices, as reflected by high degrees of association (r > = 0.77). SIGNIFICANCE: We conclude that efficient P300 spelling with a small, lightweight and quick to set up mobile EEG amplifier is possible. This technology facilitates the transfer of BCI applications from the laboratory to natural daily life environments, one of the key challenges in current BCI research. PMID- 24763066 TI - The biological actions of 11,12-epoxyeicosatrienoic acid in endothelial cells are specific to the R/S-enantiomer and require the G(s) protein. AB - Cytochrome P450-derived epoxides of arachidonic acid [i.e., the epoxyeicosatrienoic acids (EETs)] are important lipid signaling molecules involved in the regulation of vascular tone and angiogenesis. Because many actions of 11,12-cis-epoxyeicosatrienoic acid (EET) are dependent on the activation of protein kinase A (PKA), the existence of a cell-surface G(s) coupled receptor has been postulated. To assess whether the responses of endothelial cells to 11,12-EET are enantiomer specific and linked to a potential G protein-coupled receptor, we assessed 11,12-EET-induced, PKA-dependent translocation of transient receptor potential (TRP) C6 channels, as well as angiogenesis. In primary cultures of human endothelial cells, (+/-)-11,12-EET led to the rapid (30 seconds) translocation a TRPC6-V5 fusion protein, an effect reproduced by 11(R),12(S)-EET, but not by 11(S),12(R)-EET or (+/-)-14,15-EET. Similarly, endothelial cell migration and tube formation were stimulated by (+/-) 11,12-EET and 11(R),12(S)-EET, whereas 11(S),12(R)-EET and 11,12 dihydroxyeicosatrienoic acid were without effect. The effects of (+/-)-11,12-EET on TRP channel translocation and angiogenesis were sensitive to EET antagonists, and TRP channel trafficking was also prevented by a PKA inhibitor. The small interfering RNA-mediated downregulation of G(s) in endothelial cells had no significant effect on responses stimulated by vascular endothelial growth or a PKA activator but abolished responses to (+/-)-11,12-EET. The downregulation of G(q)/11 failed to prevent 11,12-EET-induced TRPC6 channel translocation or the formation of capillary-like structures. Taken together, our results suggest that a G(s)-coupled receptor in the endothelial cell membrane responds to 11(R),12(S) EET and mediates the PKA-dependent translocation and activation of TRPC6 channels, as well as angiogenesis. PMID- 24763068 TI - Significance of subjective memory complaints in the clinical setting. AB - OBJECTIVE: The clinical significance of subjective memory complaints in the elderly participants, particularly regarding liability of subsequent progression to dementia, has been controversial. In the present study, we tested the hypothesis that severity or type of subjective memory complaints reported by patients in a clinical setting may predict future conversion to dementia. METHODS: A cohort of nondemented patients with cognitive complaints, followed up for at least 2 years or until conversion to dementia, underwent a neuropsychological evaluation and detailed assessment of memory difficulties with the Subjective Memory Complaints (SMC) Scale. RESULTS: At baseline, patients who converted to dementia (36.8%) had less years of formal education and generally a worse performance in the neuropsychological assessment. There were no differences in the total SMC score between nonconverters (9.5 +/- 4.2) and converters (8.9 +/ 4.0, a nonsignificant difference), but nonconverters scored higher in several items of the scale. CONCLUSION: For patients with cognitive complaints observed in a memory clinic setting, the severity of subjective memory complaints is not useful to predict future conversion to dementia. PMID- 24763069 TI - Validity and reliability of the neuropsychiatric inventory questionnaire version in patients with stroke or transient ischemic attack having cognitive impairment. AB - This study examined the validity and reliability of the Neuropsychiatric Inventory Questionnaire version (NPI-Q), a proxy-reported format of the interview based NPI, in assessing neuropsychiatric symptoms in 173 patients with stroke or transient ischemic attack (TIA) having cognitive impairment. The NPI-Q was validated against the NPI as a gold standard. Informants took approximately 7 minutes to complete the NPI-Q. Bland-Altman analysis revealed a bias of 0.7 points, with 95% limits of agreement between -8.6 and 10.0 between the total symptom scores of the NPI and NPI-Q. The NPI-Q correlated significantly with the NPI in individual and total symptom scores and caregiver distress scores. In predicting presence of symptoms on the NPI, the NPI-Q yielded, on average, sensitivity of 74.1% and specificity of 79.5%. On the NPI-Q, informants tended to overreport symptoms in patients with less severe symptoms but underreport with increasing symptom severity. Internal consistency of the NPI-Q was acceptable (Cronbach's alpha = 0.756). One-week test-retest reliability of the NPI-Q was excellent (intraclass correlation coefficient = .990). The NPI-Q is a valid and reliable instrument for screening neuropsychiatric symptoms in patients with stroke and TIA. PMID- 24763070 TI - Functional impairment in mild cognitive impairment evidenced using performance based measurement. AB - Older adults (OAs) with mild cognitive impairment (MCI) are traditionally thought to have preservation of activities of daily living (ADLs). However, recent evidence suggests OAs with MCI may have difficulty completing ADLs and specifically instrumental ADLs (IADLs). The ADLs are frequently evaluated through self- or collateral report questionnaires, while performance-based measures are infrequently utilized, despite the decreased bias and increased accuracy and sensitivity associated with these instruments. This investigation compared ADLs between community-dwelling OAs with (n = 20) and without MCI (n = 30) using a self-report questionnaire (Older American Resources and Services Activities of Daily Living Scale; OARS), a collateral report questionnaire (OARS), and a performance-based measure (the Direct Assessment of Functional Status-Revised). Consistent with our hypothesis, OAs with MCI had decreased ADLs and IADLs on the performance-based measure compared to cognitively intact OAs, while there were no differences in ADLs or IADLs on self-report questionnaires or collateral report questionnaires. Our results suggest OAs with MCI have decreased ability to complete IADLs. However, this investigation suggests these deficits may not be detected by questionnaires and are more likely to be found with performance-based testing. PMID- 24763071 TI - Functional disability in Alzheimer disease: a validation study of the Turkish version of the disability assessment for dementia scale. AB - This study aimed to determine the reliability and validity of the Turkish version of Disability Assessment for Dementia (DAD) scale in the Turkish elderly population with Alzheimer disease (AD). The DAD scale was administered to the primary caregivers of 157 patients (age 77.7 +/- 6.8 years) with AD. The Turkish version of the DAD scale showed high internal consistency (Cronbach alpha = .942), excellent test-retest, and interrater reliability (intraclass correlation coefficient [ICC] = 0.996 and ICC = 0.994, respectively). The DAD scale was significantly correlated with activities of daily living (ADL; Modified Older Americans Research Survey ADL) and instrumental activities of daily living (IADL; Lawton and Brody IADL) scales (r = .89, P < .001 and r = .90, P < .001). Disability Assessment for Dementia had a high negative correlation with the Global Deterioration Scale (GDS; r = -.880, P < .001). Post hoc comparisons with Tukey test showed significant differences in the mean DAD scores in different GDS stages. Construct validity was estimated using total score correlation analyses between the standardized Mini-Mental State Examination (MMSE) and the DAD scale. Results revealed high and significant correlation between MMSE score and DAD scale (r = .812, P < .001). The results of multivariate analysis showed that DAD score was not correlated with gender, education, and age. The DAD total score was affected mostly by GDS, MMSE, and duration of the disease. Turkish version of the DAD scale was found to be a reliable and valid instrument to assess functional disability in Turkish elderly patients with AD. This scale assists caregivers and physicians to decide for proper interventions. PMID- 24763073 TI - 13C-mixed triglyceride breath test for evaluation of pancreatic exocrine function in diabetes mellitus. AB - OBJECTIVE: The clinical relevance of pancreatic exocrine insufficiency (PEI) in diabetic patients is unclear mostly because established function tests are invasive and expensive or lack sensitivity and specificity. A modified version of the noninvasive 13C-mixed triglyceride breath test (13C-MTGT) has recently been shown to detect moderate PEI reliably in patients with chronic pancreatitis. Its sensitivity and specificity in other patient groups are unknown. We therefore aimed to clarify the significance of this test for patients with diabetes mellitus (DM). METHODS: A secretin cerulein test and a modified 13C-MTGT were performed in 14 patients with DM (10 patients with type 1 DM) and 10 healthy volunteers. RESULTS: Secretin cerulein test showed significantly lower outputs of amylase, trypsin, and lipase in DM compared with healthy volunteers (P < 0.05). Likewise, 13C-MTGT showed significantly lower maximal and cumulative 13C exhalation in DM (P < 0.005). Stimulated lipase output correlated with cumulative 13C-exhalation (P < 0.05). However, when compared with normal values, only 2 patients with diabetes had abnormally low lipase output, whereas cumulative 13C exhalation was pathologically decreased in 8 patients, including those with decreased lipase output. CONCLUSIONS: The noninvasive 13C-MTGT can detect mild to moderate PEI in DM. However, the specificity of the 13C-MTGT is low in these patients probably because nonpancreatic mechanisms contribute to decreased intestinal lipolysis. PMID- 24763072 TI - Limited brain metabolism changes differentiate between the progression and clearance of rabies virus. AB - Central nervous system (CNS) metabolic profiles were examined from rabies virus (RABV)-infected mice that were either mock-treated or received post-exposure treatment (PET) with a single dose of the live recombinant RABV vaccine TriGAS. CNS tissue harvested from mock-treated mice at middle and late stage infection revealed numerous changes in energy metabolites, neurotransmitters and stress hormones that correlated with replication levels of viral RNA. Although the large majority of these metabolic changes were completely absent in the brains of TriGAS-treated mice most likely due to the strong reduction in virus spread, TriGAS treatment resulted in the up-regulation of the expression of carnitine and several acylcarnitines, suggesting that these compounds are neuroprotective. The most striking change seen in mock-treated RABV-infected mice was a dramatic increase in brain and serum corticosterone levels, with the later becoming elevated before clinical signs or loss of body weight occurred. We speculate that the rise in corticosterone is part of a strategy of RABV to block the induction of immune responses that would otherwise interfere with its spread. In support of this concept, we show that pharmacological intervention to inhibit corticosterone biosynthesis, in the absence of vaccine treatment, significantly reduces the pathogenicity of RABV. Our results suggest that widespread metabolic changes, including hypothalamic-pituitary-adrenal axis activation, contribute to the pathogenesis of RABV and that preventing these alterations early in infection with PET or pharmacological blockade helps protect brain homeostasis, thereby reducing disease mortality. PMID- 24763074 TI - The inhibition of SRC family kinase suppresses pancreatic cancer cell proliferation, migration, and invasion. AB - OBJECTIVES: Src is considered a rising therapeutic target for the treatment of solid tumors, and Src family kinases (SFKs) participate in cancer cell proliferation and survival. The role of SFK suppression was investigated in the proliferation, migration, and invasion of pancreatic cancer cells. METHODS: Knockdown of the SFKs in pancreatic cancer cells was achieved by transfecting small interfering RNAs, and its effects were investigated using proliferation, wound, and invasion assays. RESULTS: The SFK inhibitors suppressed proliferation and induced cell cycle arrest in pancreatic cancer cells. The SFK messenger RNA profiles showed that Yes1, Lyn, Fyn, Frk, Hck, and Src were expressed. Specific small interfering RNA transfection suppressed the messenger RNA expressions of Yes1, Lyn, Fyn, Frk, and Src, and the knockdown suppressed cell proliferation by 16.7% to 47.3% in PANC-1 cells. Knockdown of any of these 5 SFKs suppressed proliferation in other pancreatic cancer cell lines by 3.0% to 40.5%. The knockdowns significantly reduced pancreatic cancer cell migration by 24.9% to 66.7% and completely inhibited invasion. CONCLUSIONS: These results suggest that the knockdown of Yes1, Lyn, Fyn, Frk, or Src reduce human pancreatic cancer cell proliferation, migration, and invasion, and that SFKs should be viewed as critical therapeutic targets of pancreatic cancer. PMID- 24763075 TI - Pulmonary embolism: specific risk factor after pancreas resection? AB - OBJECTIVE: Pulmonary embolism (PE) after major abdominal surgery is a serious and potentially lethal complication. The purpose of the present study was to identify risk factors for postoperative PE after pancreas resection. METHODS: Our prospective database for pancreatic surgery was retrospectively analyzed for patients treated between January 2006 and August 2012 in a tertiary care Swiss hospital. Risk factors for PE were identified in univariate and multivariate analyses that included preoperative, intraoperative, and postoperative variables. RESULTS: Among 251 patients, 187 underwent pancreato-duodenectomy (PD), 62 underwent distal pancreatectomy, and 2 underwent other types of pancreas resections. PE was diagnosed in 13 patients (7.0%) after PD and none after other procedures. Compared with the non-PE group, the PE group had higher body mass indices (>=25 kg/m, P = 0.04), longer median operation times (P = 0.009), higher rates of severe abdominal complications (P < 0.001), longer median intensive care unit stays (P = 0.003), and longer hospital stays (P = 0.01). Multivariate analyses identified the following independent predictors for PE: a history of thromboembolic events (odds ratio [OR], 22.3), prolonged operation time (OR, 5.76), and major abdominal complications (OR, 10.8). CONCLUSIONS: Prolonged operation times and major postoperative abdominal complications were strong risk factors for PE after PD, in both univariate and multivariate analyses. PMID- 24763076 TI - The current state of pancreatic cancer in Canada: incidence, mortality, and surgical therapy. AB - OBJECTIVE: This study aimed to evaluate the trends in the incidence, survival, and surgical therapy for Canadian patients affected by pancreatic cancer (PC). METHODS: The incidence, mortality, number of resections, and outcomes of patients with PC stratified by year, sex, and province were extracted from Canadian cancer databases. RESULTS: In 2012, PC was diagnosed in 4600 Canadians and it was responsible for 4300 deaths. The age-standardized incidence was 9 to 10 new cases per 100,000 individuals. The mortality rate remained the highest among all the solid tumors with a case-to-fatality ratio of 0.93. The age-standardized 5-year relative survival was 9.1% (95% confidence interval [CI], 8.3-10). There were geographic variations among provinces with the highest survival registered in Ontario (10.9%; 95% CI, 9.9-12) and the lowest survival reported in Nova Scotia (4.7%; 95% CI, 2.8-7.2). The percentage of patients who underwent surgery decreased from 19% (2006-2007) to 17% (2009-2010). Pancreatic resections were performed in high-volume centers in 74% of cases. In-hospital mortality was 5%, 93% of patients were discharged home, and 36% of patients required home support after discharge. CONCLUSIONS: Long-term outcomes of Canadian patients affected by PC remain unsatisfactory, with only 9% of the patients surviving at 5 years. Surgical therapy was performed only in 17% to 19% of patients. PMID- 24763077 TI - Perceptions of HIV-related health services in Zambia for people with disabilities who are HIV-positive. AB - INTRODUCTION: Despite the emerging body of literature on increased vulnerability to HIV among people with disabilities (PWDs), there is a dearth of evidence related to experiences of PWDs who have become HIV-positive. This priority was identified by a disability advocacy organization in Lusaka, Zambia, where the prevalence of HIV and of disability is each approximately 15%. The purpose of this study was to explore perceptions and experiences of HIV-related health services for PWDs who are also living with HIV in Lusaka, Zambia. METHODS: This qualitative, interpretive study involved in-depth, semi-structured, one-on-one interviews with two groups of participants in Lusaka, Zambia: 21 PWDs who had become HIV-positive, and 11 people working in HIV and/or disability. PWDs had physical, hearing, visual and/or intellectual impairments. Interviews were conducted in English, Nyanja, Bemba or Zambian sign language. Descriptive and thematic analyses were conducted by a multidisciplinary, international research team. RESULTS: Participants described their experiences with HIV-related health services in terms of the challenges they faced. In particular, they encountered three main challenges while seeking care and treatment: (1) disability-related discrimination heightened when seeking HIV services, (2) communication barriers and related concerns with confidentiality, and (3) movement and mobility challenges related to seeking care and collecting antiretroviral therapy. These experiences were further shaped by participants' profound concerns about poverty and unmet basic needs. DISCUSSION: This study demonstrates how PWDs who are HIV positive have the same HIV care, treatment and support needs as able-bodied counterparts, but face avoidable barriers to care. Many challenges mirror concerns identified with HIV prevention, suggesting that efforts to promote inclusion and reduce stigma could have widespread benefits. CONCLUSIONS: Despite the growing body of literature on increased risk of exposure to HIV among HIV negative PWDs, this is the first published study to examine perceptions of testing, treatment and other HIV services for PWDs who have become HIV-positive. Findings reveal far-reaching opportunities for improving the quality of care for this population. PMID- 24763079 TI - A hybrid of ant colony optimization and minimization of metabolic adjustment to improve the production of succinic acid in Escherichia coli. AB - This paper presents a study on gene knockout strategies to identify candidate genes to be knocked out for improving the production of succinic acid in Escherichia coli. Succinic acid is widely used as a precursor for many chemicals, for example production of antibiotics, therapeutic proteins and food. However, the chemical syntheses of succinic acid using the traditional methods usually result in the production that is far below their theoretical maximums. In silico gene knockout strategies are commonly implemented to delete the gene in E. coli to overcome this problem. In this paper, a hybrid of Ant Colony Optimization (ACO) and Minimization of Metabolic Adjustment (MoMA) is proposed to identify gene knockout strategies to improve the production of succinic acid in E. coli. As a result, the hybrid algorithm generated a list of knockout genes, succinic acid production rate and growth rate for E. coli after gene knockout. The results of the hybrid algorithm were compared with the previous methods, OptKnock and MOMAKnock. It was found that the hybrid algorithm performed better than OptKnock and MOMAKnock in terms of the production rate. The information from the results produced from the hybrid algorithm can be used in wet laboratory experiments to increase the production of succinic acid in E. coli. PMID- 24763080 TI - A nutrient combination that can affect synapse formation. AB - Brain neurons form synapses throughout the life span. This process is initiated by neuronal depolarization, however the numbers of synapses thus formed depend on brain levels of three key nutrients-uridine, the omega-3 fatty acid DHA, and choline. Given together, these nutrients accelerate formation of synaptic membrane, the major component of synapses. In infants, when synaptogenesis is maximal, relatively large amounts of all three nutrients are provided in bioavailable forms (e.g., uridine in the UMP of mothers' milk and infant formulas). However, in adults the uridine in foods, mostly present at RNA, is not bioavailable, and no food has ever been compelling demonstrated to elevate plasma uridine levels. Moreover, the quantities of DHA and choline in regular foods can be insufficient for raising their blood levels enough to promote optimal synaptogenesis. In Alzheimer's disease (AD) the need for extra quantities of the three nutrients is enhanced, both because their basal plasma levels may be subnormal (reflecting impaired hepatic synthesis), and because especially high brain levels are needed for correcting the disease-related deficiencies in synaptic membrane and synapses. PMID- 24763081 TI - Long-lasting alterations in 5-HT2A receptor after a binge regimen of methamphetamine in mice. AB - The repeated administration of methamphetamine (MA) to animals in a single-day 'binge' dosing regimen produces damage to dopamine and serotonin terminals and psychosis-like behaviours similar to those observed in MA abusers. The present study aimed to examine the effects of MA binge exposure on 5-HT2A receptors, the subtype of serotonin receptors putatively involved in psychosis. ICR male mice were treated with MA (4 * 5 mg/kg) or saline at 2 h intervals. Recognition memory and social behaviours were sequentially evaluated by a novel location recognition test, a novel object recognition test, a social interaction and a nest-building test to confirm the persistent cognitive and behavioural impairments after this dosing regimen. Subsequently, a hallucinogenic 5-HT2A/2C receptor agonist 2,5 dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch, molecular and electrophysiological responses were monitored. Finally, the levels of 5-HT2C, 5 HT1A, 5-HT2A and mGlu2 receptors in the medial prefrontal cortex were determined. MA binge exposure produced recognition memory impairment, reduced social behaviours, and increased DOI-induced head-twitch response, c-Fos and Egr-2 expression and field potentials in the medial prefrontal cortex. Furthermore, MA binge exposure increased 5-HT2A and decreased mGlu2 receptor expression in the medial frontal cortex, whereas 5-HT2C and 5-HT1A receptors were unaffected. These data reveal that the increased behavioural, molecular and electrophysiological responses to DOI might be associated with an up-regulation of 5-HT2A receptors in the medial prefrontal cortex after MA binge exposure. Identifying the biochemical alterations that parallel the behavioural changes in a mouse model of MA binge exposure may facilitate targeting therapies for treatment of MA-related psychiatric disorders. PMID- 24763083 TI - Changing patterns and widening of antibiotic resistance in Shigella spp. over a decade (2000-2011), Andaman Islands, India. AB - This study is a part of the surveillance study on childhood diarrhoea in the Andaman and Nicobar Islands; here we report the drug resistance pattern of recent isolates of Shigella spp. (2006-2011) obtained as part of that study and compare it with that of Shigella isolates obtained earlier during 2000-2005. During 2006 2011, stool samples from paediatric diarrhoea patients were collected and processed for isolation and identification of Shigella spp. Susceptibility to 22 antimicrobial drugs was tested and minimum inhibitory concentrations were determined for third-generation cephalosporins, quinolones, amoxicillin clavulanic acid combinations and gentamicin. A wide spectrum of antibiotic resistance was observed in the Shigella strains obtained during 2006-2011. The proportions of resistant strains showed an increase from 2000-2005 to 2006-2011 in 20/22 antibiotics tested. The number of drug resistance patterns increased from 13 in 2000-2005 to 43 in 2006-2011. Resistance to newer generation fluoroquinolones, third-generation cephalosporins and augmentin, which was not observed during 2000-2005, appeared during 2006-2011. The frequency of resistance in Shigella isolates has increased substantially between 2000-2006 and 2006-2011, with a wide spectrum of resistance. At present, the option for antimicrobial therapy in shigellosis in Andaman is limited to a small number of drugs. PMID- 24763082 TI - The homeodomain protein ladybird late regulates synthesis of milk proteins during pregnancy in the tsetse fly (Glossina morsitans). AB - Regulation of tissue and development specific gene expression patterns underlies the functional specialization of organs in multi-cellular organisms. In the viviparous tsetse fly (Glossina), the female accessory gland is specialized to generate nutrients in the form of a milk-like secretion to support growth of intrauterine larva. Multiple milk protein genes are expressed specifically in the female accessory gland and are tightly linked with larval development. Disruption of milk protein synthesis deprives developing larvae of nutrients and results in extended larval development and/or in abortion. The ability to cause such a disruption could be utilized as a tsetse control strategy. Here we identify and delineate the regulatory sequence of a major milk protein gene (milk gland protein 1:mgp1) by utilizing a combination of molecular techniques in tsetse, Drosophila transgenics, transcriptomics and in silico sequence analyses. The function of this promoter is conserved between tsetse and Drosophila. In transgenic Drosophila the mgp1 promoter directs reporter gene expression in a tissue and stage specific manner orthologous to that of Glossina. Analysis of the minimal required regulatory region of mgp1, and the regulatory regions of other Glossina milk proteins identified putative homeodomain protein binding sites as the sole common feature. Annotation and expression analysis of Glossina homeodomain proteins identified ladybird late (lbl) as being accessory gland/fat body specific and differentially expressed between lactating/non-lactating flies. Knockdown of lbl in tsetse resulted in a significant reduction in transcript abundance of multiple milk protein genes and in a significant loss of fecundity. The role of Lbl in adult reproductive physiology is previously unknown. These results suggest that Lbl is part of a conserved reproductive regulatory system that could have implications beyond tsetse to other vector insects such as mosquitoes. This system is critical for tsetse fecundity and provides a potential target for development of a reproductive inhibitor. PMID- 24763085 TI - Predictive factors for improvement of gait by low-frequency stimulation in Parkinson's disease. AB - BACKGROUND: After several years duration of Parkinson's disease, with or without deep brain stimulation, axial signs (such as postural instability, freezing of gait) may worsen. High-voltage, low-frequency stimulation has been shown to improve severe gait disorders in some patients. OBJECTIVE: To identify predictive factors for the efficacy of low-frequency stimulation. METHODS: We assessed the respective effects of low- and high-frequency stimulation using an acute stand walk- sit test, and on motor performance in 22 patients with longstanding, bilateral sub-thalamic nucleus stimulation. We calculated the difference in the number of steps (delta steps) between high and low -frequency stimulation during the stand-walk-sit test. Our aim was to establish a profile for low-frequency responders, which was defined by a positive value for delta steps. RESULTS: Low frequency responders presented higher age, a severe axial phenotype five years after surgery and a lower L-dopa responsiveness of (i) the Unified Parkinson's Disease Rating Scale part III score and its akinesia subscore before surgery and (ii) the axial subscore one year after surgery. CONCLUSION: Here we defined a specific and severe axial profile of minority of patients who could benefit from low frequency stimulation parameters. Our findings challenge the conventional treatment approach (i.e. high-frequency stimulation) in patients who develop gait disorders after several years of stimulation. PMID- 24763086 TI - Pigment epithelium-derived factor 34-mer peptide prevents liver fibrosis and hepatic stellate cell activation through down-regulation of the PDGF receptor. AB - Pigment epithelium-derived factor (PEDF) has been shown previously to prevent liver fibrosis and hepatic stellate cell (HSC) activation. By investigating the functional domains in PEDF, we identified a 34-mer peptide (residues Asp44-Asn77) that harbors the same function as the full-length PEDF protein. Not only did the 34-mer suppress the development of fibrosis in carbon tetrachloride (CCl4) treated mouse liver but it also upregulated peroxisome proliferator-activated receptor-gamma (PPARgamma) expression in HSCs in vivo. Platelet-derived growth factor (PDGF) plays a crucial role on the process of HSC activation in response to liver damage. The 34-mer suppressed PDGF-induced cell proliferation and expression of myofibroblastic marker proteins in primary rat HSC culture, increased the levels of PPARgamma mRNA and protein in a dose-dependent manner and markedly reduced the level of active beta-catenin protein, an HSC activating factor, in HSC-T6 cells. Similarly, IWR-1, an inhibitor of the Wnt response, displayed the same effect as the 34-mer in preventing HSC-T6 activation. The Wnt signaling-mediated PPARgamma suppression was abolished by both the IWR-1 inhibitor and a small interfering RNA (siRNA) targeting beta-catenin and the Wnt coreceptor, LRP6. Both PEDF and the 34-mer down-regulated PDGF receptor alpha/beta expression and blocked the PDGF-induced phosphorylation of Akt and ERK. Moreover, the inhibitory effect on PDGF receptor expression was abolished by PPARgamma antagonists and PPARgamma siRNA. Our observations indicate that the PEDF-derived 34-mer peptide can mimic PEDF in attenuating HSC activation. Investigation of this 34-mer peptide led to the identification of a signaling mechanism involving PPARgamma induction, suppression of Wnt/beta-catenin signaling and down-regulation of the PDGF receptor-alpha/beta. PMID- 24763078 TI - Reasons for hospitalization in HIV-infected children in West Africa. AB - INTRODUCTION: Current knowledge on morbidity and mortality in HIV-infected children comes from data collected in specific research programmes, which may offer a different standard of care compared to routine care. We described hospitalization data within a large observational cohort of HIV-infected children in West Africa (IeDEA West Africa collaboration). METHODS: We performed a six month prospective multicentre survey from April to October 2010 in five HIV specialized paediatric hospital wards in Ouagadougou, Accra, Cotonou, Dakar and Bamako. Baseline and follow-up data during hospitalization were recorded using a standardized clinical form, and extracted from hospitalization files and local databases. Event validation committees reviewed diagnoses within each centre. HIV related events were defined according to the WHO definitions. RESULTS: From April to October 2010, 155 HIV-infected children were hospitalized; median age was 3 years [1-8]. Among them, 90 (58%) were confirmed for HIV infection during their stay; 138 (89%) were already receiving cotrimoxazole prophylaxis and 64 children (40%) had initiated antiretroviral therapy (ART). The median length of stay was 13 days (IQR: 7-23); 25 children (16%) died during hospitalization and four (3%) were transferred out. The leading causes of hospitalization were WHO stage 3 opportunistic infections (37%), non-AIDS-defining events (28%), cachexia and other WHO stage 4 events (25%). CONCLUSIONS: Overall, most causes of hospitalizations were HIV related but one hospitalization in three was caused by a non-AIDS-defining event, mostly in children on ART. HIV-related fatality is also high despite the scaling-up of access to ART in resource-limited settings. PMID- 24763088 TI - Quenching ilmenite with a high-temperature and high-pressure phase using super high-energy ball milling. AB - The mass production of highly dense oxides with high-temperature and high pressure phases allows us to discover functional properties that have never been developed. To date, the quenching of highly dense materials at the gramme-level at ambient atmosphere has never been achieved. Here, we provide evidence of the formation of orthorhombic Fe2TiO4 from trigonal FeTiO3 as a result of the high temperature (>1250 K) and high-pressure (>23 GPa) condition induced by the high collision energy of 150 gravity generated between steel balls. Ilmenite was steeply quenched by the surrounding atmosphere, when iron-rich ilmenite (Fe2TiO4) with a high-temperature and high-pressure phase was formed by planetary collisions and was released from the collision points between the balls. Our finding allows us to infer that such intense planetary collisions induced by high energy ball milling contribute to the mass production of a high-temperature and high-pressure phase. PMID- 24763089 TI - High-density lipoproteins: taking the good with the bad. PMID- 24763087 TI - Glutamate-bound NMDARs arising from in vivo-like network activity extend spatio temporal integration in a L5 cortical pyramidal cell model. AB - In vivo, cortical pyramidal cells are bombarded by asynchronous synaptic input arising from ongoing network activity. However, little is known about how such 'background' synaptic input interacts with nonlinear dendritic mechanisms. We have modified an existing model of a layer 5 (L5) pyramidal cell to explore how dendritic integration in the apical dendritic tuft could be altered by the levels of network activity observed in vivo. Here we show that asynchronous background excitatory input increases neuronal gain and extends both temporal and spatial integration of stimulus-evoked synaptic input onto the dendritic tuft. Addition of fast and slow inhibitory synaptic conductances, with properties similar to those from dendritic targeting interneurons, that provided a 'balanced' background configuration, partially counteracted these effects, suggesting that inhibition can tune spatio-temporal integration in the tuft. Excitatory background input lowered the threshold for NMDA receptor-mediated dendritic spikes, extended their duration and increased the probability of additional regenerative events occurring in neighbouring branches. These effects were also observed in a passive model where all the non-synaptic voltage-gated conductances were removed. Our results show that glutamate-bound NMDA receptors arising from ongoing network activity can provide a powerful spatially distributed nonlinear dendritic conductance. This may enable L5 pyramidal cells to change their integrative properties as a function of local network activity, potentially allowing both clustered and spatially distributed synaptic inputs to be integrated over extended timescales. PMID- 24763090 TI - Quality over quantity: buffer strips can be improved with select native plant species. AB - Native plants attractive to beneficial insects may improve the value of buffer strips by increasing biodiversity and enhancing the delivery of insect-derived ecosystem services. In a 2-yr field experiment, we measured the response of insect communities across nine buffers that varied in plant diversity. We constructed buffers with plants commonly found in buffers of USDA-certified organic farms in Iowa (typically a single species), recommended for prairie reconstruction, or recommended for attracting beneficial insects. We hypothesized that the diversity and abundance of beneficial insects will be 1) greatest in buffers composed of diverse plant communities with continuous availability of floral resources, 2) intermediate in buffers with reduced species richness and availability of floral resources, and 3) lowest in buffers composed of a single species. We observed a significant positive relationship between the diversity and abundance of beneficial insects with plant community diversity and the number of flowers. More beneficial insects were collected in buffers composed of species selected for their attractiveness to beneficial insects than a community recommended for prairie restoration. These differences suggest 1) plant communities that dominate existing buffers are not optimal for attracting beneficial insects, 2) adding flowering perennial species could improve buffers as habitat for beneficial insects, 3) buffers can be optimized by intentionally combining the most attractive native species even at modest levels of plant diversity, and 4) plant communities recommended for prairie reconstruction may not contain the optimal species or density of the most attractive species necessary to support beneficial insects from multiple guilds. PMID- 24763091 TI - Facilitation among saproxylic insects inhabiting tree hollows in a Mediterranean forest: the case of cetonids (Coleoptera: Cetoniidae) and syrphids (Diptera: Syrphidae). AB - Tree hollows offer an ideal niche for saproxylic insects in mature Mediterranean forests, where Diptera and Coleoptera are the richest groups. Co-occurrence is frequently observed among many species of both groups in these microhabitats, and some of these species have been considered to facilitate the presence of other species by acting as ecosystem engineers. One of the systems that is found in Mediterranean tree hollows is formed by cetonid (Coleoptera: Cetoniidae) and syrphid (Diptera: Syrphidae) larvae. Here, cetonid larvae feed on wood and litter and produce a substrate that is easier to decompose. To assess the possible role of these larvae as facilitating agents for the saproxylic guild, we studied whether the presence of saprophagous Syrphidae inside tree hollows is associated with the activity of cetonid larvae. Furthermore, in laboratory conditions, we tested whether cetonid larvae activity can improve the development and fitness of the saprophagous syrphid species. Our results show that "cetonid activity" was the variable that best explained the presence of saprophagous syrphid species in natural conditions. Myathropa florea (L., 1758) was one of the species most influenced by this activity. The laboratory experiment gave similar results, demonstrating that an enriched substrate with Cetonia aurataeformis Curti, 1913 larval feces improves syrphid larval growth rate and fitness of adults (measured as longer wing length) of M. florea. PMID- 24763092 TI - Characteristics, phenotype, and transmission of Wolbachia in the sweet potato whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae), and its parasitoid Eretmocerus sp. nr. emiratus (Hymenoptera: Aphelinidae). AB - Wolbachia is a common intracellular bacterial endosymbiont of insects, causing a variety of effects including reproductive manipulations such as cytoplasmic incompatibility (CI). In this study, we characterized Wolbachia in the whitefly Bemisia tabaci and in the whitefly parasitoid Eretmocerus sp. nr. emiratus. We also tested for horizontal transmission of Wolbachia between and within trophic levels, and we determined the phenotype of Wolbachia in E. sp. nr. emiratus. Using multilocus sequence typing and phylogenetic analyses, we found that B. tabaci and E. sp. nr. emiratus each harbor a different and unique strain of Wolbachia. Both strains belong to the phylogenetic supergroup B. No evidence for horizontal transmission of Wolbachia between and within trophic levels was found in our study system. Finally, crossing results were consistent with a CI phenotype; when Wolbachia-infected E. sp. nr. emiratus males mate with uninfected females, wasp progeny survival dropped significantly, and the number of females was halved. This is the first description of CI caused by Wolbachia in the economically important genus Eretmocerus. Our study underscores the expectation that horizontal transmission events occur rarely in the dynamics of secondary symbionts such as Wolbachia, and highlights the importance of understanding the effects of symbionts on the biology of natural enemies. PMID- 24763093 TI - Spatial density and movement of the Lygus spp. parasitoid Peristenus relictus (Hymenoptera: Braconidae) in organic strawberries with alfalfa trap crops. AB - Alfalfa trap crops are currently used to manage Lygus spp. in organic strawberry fields on the California Central Coast. The retention of Lygus spp. in alfalfa creates aggregated distributions that provide improved opportunities for biological control by the introduced parasitoid Peristenus relictus (Ruthe). The abundance and distribution of P. relictus between two trap crops separated by 50 strawberry rows were analyzed in 2008 and 2010. Parasitism of Lygus spp. nymphs by P. relictus (measured by larval abundance and % parasitism) was greatest in alfalfa trap crops compared with strawberry rows. A significantly positive correlation between host nymphs and P. relictus larvae in and between trap crops was found. Movement of P. relictus adults from a marked alfalfa trap crop into adjacent strawberry rows or trap crops was also studied in 2008 and 2009 using a chicken egg-albumin enzyme-linked immunosorbent assay mark-capture technique. In 2008 and 2009, 85 and 49% of protein-marked wasps were captured from central trap crops, respectively, indicating that alfalfa trap crops act as a concentrated "host-density anchor" in organic strawberry fields. PMID- 24763094 TI - Milkweed (Gentianales: Apocynaceae): a farmscape resource for increasing parasitism of stink bugs (Hemiptera: Pentatomidae) and providing nectar to insect pollinators and monarch butterflies. AB - In peanut-cotton farmscapes in Georgia, the stink bugs Nezara viridula (L.) and Chinavia hilaris (Say) (Hemiptera: Pentatomidae) and the leaffooted bug, Leptoglossus phyllopus (L.) (Hemiptera: Coreidae), disperse at crop-to-crop interfaces to feed on bolls in cotton. The main objective of this study was to determine whether insecticide-free tropical milkweed (Asclepias curassavica L.), a nectar-producing plant, can increase parasitism of these bugs by Trichopoda pennipes (F.) (Diptera: Tachinidae) and provide nectar to monarch butterflies and insect pollinators in these farmscapes. Peanut-cotton plots with and without flowering milkweed plants were established in 2009 and 2010. Adult T. pennipes, monarch butterflies, honey bees, and native insect pollinators readily fed on floral nectar of milkweed. Monarch larvae feeding on milkweed vegetation successfully developed into pupae. In 2009, N. viridula was the primary host of T. pennipes in cotton, and parasitism of this pest by the parasitoid was significantly higher in milkweed cotton (61.6%) than in control cotton (13.3%). In 2010, parasitism of N. viridula, C. hilaris, and L. phyllopus by T. pennipes was significantly higher in milkweed cotton (24.0%) than in control cotton (1.1%). For both years of the study, these treatment differences were not owing to a response by the parasitoid to differences in host density, because density of hosts was not significantly different between treatments. In conclusion, incorporation of milkweed in peanut-cotton plots increased stink bug parasitism in cotton and provided nectar to insect pollinators and monarch butterflies. PMID- 24763095 TI - Effect of Telenomus podisi, Trissolcus urichi, and Trissolcus basalis (Hymenoptera: Platygastridae) age on attack of Piezodorus guildinii (Hemiptera: Pentatomidae) eggs. AB - Parasitoid's performance is subject to parasitism decisions influenced by host quality and parasitoid's age. We evaluated parasitism, emergence, and the progeny sex ratio proportions of Telenomus podisi (Ashmead), Trissolcus urichi (Crawford), and Trissolcus basalis (Wollaston) (Hymenoptera: Platygastridae) females of different age attacking Piezodorus guildinii (Westwood) (Hemiptera: Pentatomidae), an important soybean pest. Eggs were offered to females of T. podisi 1-10 d old, T. urichi 1, 3, 4, or 6 d old, or T. basalis 1-6 or 8 d old. Average egg parasitism proportions were 0.71 and 0.79 to T. podisi and T. urichi, respectively; and preimaginal survivorship was >97% for both species. Trissolcus basalis females 1, 2, and 3 d old did not parasitize P. guildinii eggs, and high parasitism proportions were recorded from older females, but only 0.5 of females attacked host eggs. A greater proportion of males were produced in the progeny of T. podisi and T. urichi as maternal age increased, but no differences were found in the progeny of T. basalis wasps of different ages. The results from this study indicate that performance of T. podisi and T. urichi would not be affected by the age of the females. However, aging would induce T. basalis females to attack P. guildinii, although it is known that their main host is Nezara viridula (L.) (Hemiptera: Pentatomidae). Under certain circumstances, such as shortage of preferred host availability, high egg load, and short life expectancy, this wasp may include P. guildinii as a host. PMID- 24763096 TI - Colony-level variation in pollen collection and foraging preferences among wild caught bumble bees (Hymenoptera: Apidae). AB - Given that many pollinators have exhibited dramatic declines related to habitat destruction, an improved understanding of pollinator resource collection across human-altered landscapes is essential to conservation efforts. Despite the importance of bumble bees (Bombus spp.) as global pollinators, little is known regarding how pollen collection patterns vary between individuals, colonies, and landscapes. In this study, Vosnesensky bumble bees (Bombus vosnesenskii Radoszkowski) were collected from a range of human-altered and natural landscapes in northern California. Extensive vegetation surveys and Geographic Information System (GIS)-based habitat classifications were conducted at each site, bees were genotyped to identify colony mates, and pollen loads were examined to identify visited plants. In contrast to predictions based on strong competitive interactions, pollen load composition was significantly more similar for bees captured in a shared study region compared with bees throughout the research area but was not significantly more similar for colony mates. Preference analyses revealed that pollen loads were not composed of the most abundant plant species per study region. The majority of ranked pollen preference lists were significantly correlated for pairwise comparisons of colony mates and individuals within a study region, whereas the majority of pairwise comparisons of ranked pollen preference lists between individuals located at separate study regions were uncorrelated. Results suggest that pollen load composition and foraging preferences are similar for bees throughout a shared landscape regardless of colony membership. The importance of native plant species in pollen collection is illustrated through preference analyses, and we suggest prioritization of specific rare native plant species for enhanced bumble bee pollen collection. PMID- 24763097 TI - The influence of maturity and variety of potato plants on oviposition and probing of Bactericera cockerelli (Hemiptera: Triozidae). AB - The ecological theory on host plant choice by herbivores suggests that mothers should choose plants that will maximize their offspring's success. In annual host plants, physiology (and therefore host suitability) is sometimes influenced by maturity and growth stage, which may influence female choice. Potato plants were grown under greenhouse conditions and used in choice and no-choice bioassays to determine the effect of plant maturity and variety on oviposition and number of stylet sheaths (which approximate stylet insertions) by tomato/potato psyllids. No-choice bioassays suggested that maturity (time since planting) did not influence oviposition behavior, but oviposition varied significantly among potato plant varieties. There was a significant effect of both maturity and variety on the number of stylet sheaths, which peak toward the middle of the growing season. We also examined tomato/potato psyllid responses to plants grown in a commercial field and again found no effect on oviposition but differences in stylet sheaths. The results suggest that differential susceptibility to zebra chip disease may be associated with unequal feeding rates. Future studies should examine whether the maturity of plants influences larval fitness. Finally, potato variety has an influence on both oviposition and "probing," and has implications for management strategies and the development of resistant potato varieties. PMID- 24763098 TI - Attractiveness of fermentation and related products to spotted wing Drosophila (Diptera: drosophilidae). AB - Laboratory screening bioassays and field trapping experiments of spotted wing drosophila flies, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae), were conducted to determine the attractiveness of 17 compounds as well as to compare attractant efficiency during peak fruit ripeness and postharvest captures late in the season. Compounds structurally related to each of the fermentation products acetic acid, ethanol, ethyl acetate, and 2-phenethyl alcohol were screened for attractiveness compared with a soap water control in greenhouse cage bioassays. The compounds determined to be attractive in the greenhouse bioassay (methanol, ethanol, propanol, formic acid, acetic acid, ethyl acetate, propyl acetate, phenethyl acetate, phenethyl propionate, and phenethyl butyrate) were individually tested in the field added to apple cider vinegar (ACV). The acids were also tested individually in neutralized ACV (NACV; pH ?7). Combinations of the compounds were tested in NACV. The capture numbers in ACV traps were not significantly increased by the addition of any of the compounds tested, although significant deterrent effects of some of the compounds allowed differences between treatments to be observed. Compounds that are most prevalent in wine and vinegar (methanol, ethanol, acetic acid, and ethyl acetate) as well as phenethyl propionate and phenethyl butyrate were less deterrent than the other compounds tested in the field. Captures during peak fruit ripeness were compared with the postharvest period when fruit hosts were not available or were overripe. Although the total number of flies captured late in the season was lower, the trends in treatment performance were similar, indicating a consistent performance of these baits from peak fruit ripeness through postharvest. PMID- 24763099 TI - Seasonal phenology of Amphorophora agathonica (Hemiptera: Aphididae) and spread of viruses in red raspberry in Washington. AB - Amphorophora agathonica (Hottes) is the primary vector of aphid-transmitted viruses in red raspberry in the Pacific Northwest region of the United States. To better understand the biology of the aphid, we estimated the lower developmental threshold and studied the seasonal activity of A. agathonica in commercial fields in northern Washington state. In addition, we monitored the spread of raspberry viruses (raspberry latent virus and raspberry leaf mottle virus, RLMV) to determine how rapidly fields became infected and whether there was a relationship between aphid presence and infection. The lower developmental threshold of A. agathonica was estimated to be 2.7 degrees C. In the field, apterous and alate aphid populations began rapidly increasing at ?800 growing degree-days and peaked at 1,050 growing degree-days. RLMV spread rapidly, with 30-60% of plants in four different commercial fields testing positive after three growing seasons. There was no discernible relationship between the presence or abundance of aphids based on 10 leaves sampled per plant location, and the odds of that plant becoming infected with RLMV. PMID- 24763100 TI - Heat-dependent fecundity enhancement observed in Nilaparvata lugens (Hemiptera: Delphacidae) after treatment with triazophos. AB - The brown planthopper Nilaparvata lugens (Stal) (Hemiptera: Delphacidae) is a serious pest of rice crops in the temperate and tropical regions of Asia and Australia, and it is also a classic example of an insecticide-induced resurgent pest. Brown planthopper outbreaks have been reported to be closely associated with pesticide application. Previous studies have shown that the insecticide triazophos enhances thermal tolerance and fecundity in brown planthopper. However, the effects of triazophos and high temperature on reproductive capacity have not been studied in high temperature-conditioned reciprocal pairs of adult males and females. The present experiments showed that triazophos enhanced the reproductive capacity of brown planthopper under high temperature (34 degrees C). The number of eggs laid by females treated with 40 ppm triazophos at 34 degrees C approximately doubled compared with untreated insects. Furthermore, the triazophos-induced fecundity enhancement at 34 degrees C was significantly greater than that at 26 degrees C, and the number of eggs laid for mating pair of adult males at 34 degrees C with adult females under 34 degrees C (?(34) * ?(34)) were significantly greater than that of adult males at 26 degrees C (?(26) * ?3(4)), suggesting that this insecticide enhances the resistance of brown planthopper to high-temperature stress. Insecticide-induced enhancement of reproductive capacity in brown planthopper under high temperatures should be of great concern, and it has important implications for forecasting future brown planthopper outbreaks as well as the pesticide-selection process. PMID- 24763101 TI - Weather factors influencing the population dynamics of Culex pipiens (Diptera: Culicidae) in the Po Plain Valley, Italy (1997-2011). AB - The impact of weather variables on Culex pipiens L. (Diptera: Culicidae) population dynamics in the Po Valley, Northern Italy, a densely populated region containing the largest industrial and agricultural areas in Italy, was investigated. Monitoring of mosquitoes was carried out by using CO(2)-baited traps without light, collecting data weekly from 1700 to 0900 hours during the period May-September, from 1997 to 2011. Daily minimum, average, and maximum relative humidity; daily minimum, maximum, and average temperature; rainfall; and hydroclimatic balance (rainfall-potential evapotranspiration) were obtained from three weather stations within the surveillance zone. The average population dynamic trend over the 15-yr period showed a bell-shaped curve with a major peak in June and a secondary peak at the end of August in the rural areas, whereas bimodality was not evidenced in the urban areas. The correlation analyses showed that the mosquito seasonal population and the population in the period of maximum West Nile virus circulation (August-September) was mostly affected by the relative humidity registered from March to July, particularly in May, and, to a lower extent, also by hydroclimatic balance registered in April-July, and by the rainfall occurred in June-July. In addition, the rate of increase of the population during the spring months influenced the development of the mosquito population of the following months. PMID- 24763102 TI - Effect of temperature on the occurrence and distribution of colorado potato beetle (Coleoptera: Chrysomelidae) in China. AB - Colorado potato beetle, Leptinotarsa decemlineata (Say), is the most destructive pest of potato in many countries of the world. It first invaded China from Kazakhstan in 1990s and now is a major pest of potato in many areas of Xinjiang Uygur Autonomous Region (Xinjiang). The objective of this study was to determine the effect of temperature on the spread of Colorado potato beetle in China after its invasion. Cold temperature in winter (December) and high temperature in summer (July) were analyzed in accordance with the absence and presence of Colorado potato beetle in Xinjiang. The boundary between the absence and presence of Colorado potato beetle in Xinjiang nearly coincided with the -8 degrees C isotherm of monthly mean minimum temperature in winter. The stress of the low temperature in winter for Colorado potato beetle basically disappeared in the southeastern Hexi Corridor in Gansu Province of China, suggesting that the Hexi Corridor is the best channel to prevent any long-distance invasions of Colorado potato beetle into the Central Plains region. However, in Turpan City in northeastern Xinjiang, the extremely hot weather in the summer prevents the local colonization of Colorado potato beetle. Furthermore, according to our monitoring, high temperature in summer also limited Colorado potato beetle to diffuse eastward through Turpan. Results of this study suggest that it is essential to strengthen inspection and quarantine measures to prevent any artificial transmissions of Colorado potato beetle spreading eastward and thus to ensure the sustainable production of potato and other Solanaceae crops in northwest regions of China. PMID- 24763103 TI - Measuring local genetic variability in populations of codling moth (Lepidoptera: Tortricidae) across an unmanaged and commercial orchard interface. AB - The genetic structure of adult codling moth, Cydia pomonella (L.), populations was characterized both inside a managed apple, Malus domestica Borkdhausen, orchard and in surrounding unmanaged hosts and nonhost trees in central Chile during 2006-2007. Adult males were collected using an array of sex pheromone baited traps. Five microsatellite genetic markers were used to study the population genetic structure across both spatial (1-100 ha) and temporal (generations within a season) gradients. Analysis of molecular variance (AMOVA) found a significant, but weak, association in both the spatial and temporal genetic structures. Discriminant analysis also found significant differentiation between the first and second generation for traps located either inside or outside the managed orchard. The Bayesian assignment test detected three genetic clusters during each of the two generations, which corresponded to different areas within the unmanaged and managed apple orchard interface. The lack of a strong spatial structure at a local scale was hypothesized to be because of active adult movement between the managed and unmanaged hosts and the asymmetry in the insecticide selection pressure inside and outside the managed habitats. These data highlight the importance of developing area-wide management programs that incorporate management tactics effective at the landscape level for successful codling moth control. PMID- 24763105 TI - Prevalence of physically active and sedentary adolescents in 10 Eastern Mediterranean countries and its relation with age, sex, and body mass index. AB - BACKGROUND: A cross-country profile of physical activity and sedentary behavior is lacking within Eastern Mediterranean region (EMR) counties. The objectives were to examine prevalence of physical activity and sedentary behavior among adolescents of 10 EMR countries, and to describe potential differences in the 2 factors by sex, age, and BMI. METHODS: A total of 23,562 adolescents were included from 10 EMR counties based on completeness of data (physical activity, sedentary behavior, age, sex, weight and height) from the Global school-based student health survey (GSHS). RESULTS: Overall prevalence of physical activity (19%) is low and sedentary behavior is high (29%), with significant differences among counties. Oman had the highest (26%) and Egypt had the lowest (9%) prevalence of active students. Prevalence of sedentary behavior was the highest in United Arab Emirates (40%) and lowest in Pakistan (8%). Physical activity was lower and sedentary behavior was higher among female adolescents. A linear trend was observed between BMI and both physical activity and sedentary behavior; a similar pattern was seen with age. CONCLUSIONS: There is a need for interventions to increase the prevalence of adolescents meeting physical activity recommendations in the 10 countries. More investigation is required to understand the cultural context of sex and BMI influence on activity patterns. PMID- 24763104 TI - Evaluation of neonatal jaundice in the Makkah region. AB - The aims of this study were to detect the frequency at which the different types of neonatal jaundice occur in Makkah and to estimate the malondialdehyde (MDA) levels. This study included 239 neonates with neonatal jaundice, 20 anemic neonates and 21 healthy neonates. ABO incompatibility was observed in 31.6% of neonates with indirect hyperbilirubinemia, in 14.3% of those with early onset jaundice, in 9.5% of those with persistent jaundice, in 8.5% of those with physiological jaundice, in 5% of anemic neonates and in 12% of all neonates. glucose-6-phosphate dehydrogenase (G6PD) deficiency was observed in 10.5% of neonates with indirect hyperbilirubinemia, in 3.9% of those with physiological jaundice, in 11.1% of those with direct hyperbilirubinemia, in 12% of those with persistent jaundice, in 10% of anemic neonates and in 6.6% of all neonates. Rh incompatibility and polycythemia were found in 2.6% of neonates with indirect hyperbilirubinemia and in 0.4% of all neonates. In comparison to control group, MDA was significantly higher in all groups except for the anemic group. In conclusion, ABO incompatibility and G6PD deficiency frequently result in neonatal jaundice in Makkah, whereas Rh incompatibility and polycythemia are rare. The MDA level may serve as an indicator of oxidative stress. PMID- 24763106 TI - Anxiolytic-like effects of YL-IPA08, a potent ligand for the translocator protein (18 kDa) in animal models of post-traumatic stress disorder. AB - Recently, the translocator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor (PBR) and both the starting point and an important rate limiting step in neurosteroidogenesis, has received increased attention in the pathophysiology of post-traumatic stress disorder (PTSD) because it affects the production of neurosteroids, reinforcing the hypothesis that selective TSPO ligands could potentially be used as anti-PTSD drugs. As expected, we showed that chronic treatment with YL-IPA08 [N-ethyl-N-(2-pyridinylmethyl)-2-(3,4 ichlorophenyl)-7-methylimidazo [1,2-a] pyridine-3-acetamide hydrochloride], a potent and selective TSPO ligand synthesized by our institute, caused significant suppression of enhanced anxiety and contextual fear induced in the inescapable electric foot-shock-induced mouse model of PTSD and the time-dependent sensitization (TDS) procedure. These effects were completely blocked by the TSPO antagonist PK11195. Furthermore, YL-IPA08 could increase the level of allopregnanolone in the prefrontal cortex and serum of post-TDS rats, and these effects were antagonized by PK11195. In summary, the findings from the current study showed that YL-IPA08, a potent and selective TSPO ligand, had a clear anti PTSD-like effect, which might be partially mediated by binding to TSPO and the subsequent synthesis of allopregnanolone. PMID- 24763107 TI - Absolute proteome and phosphoproteome dynamics during the cell cycle of Schizosaccharomyces pombe (Fission Yeast). AB - To quantify cell cycle-dependent fluctuations on a proteome-wide scale, we performed integrative analysis of the proteome and phosphoproteome during the four major phases of the cell cycle in Schizosaccharomyces pombe. In highly synchronized cells, we identified 3753 proteins and 3682 phosphorylation events and relatively quantified 65% of the data across all phases. Quantitative changes during the cell cycle were infrequent and weak in the proteome but prominent in the phosphoproteome. Protein phosphorylation peaked in mitosis, where the median phosphorylation site occupancy was 44%, about 2-fold higher than in other phases. We measured copy numbers of 3178 proteins, which together with phosphorylation site stoichiometry enabled us to estimate the absolute amount of protein-bound phosphate, as well as its change across the cell cycle. Our results indicate that 23% of the average intracellular ATP is utilized by protein kinases to phosphorylate their substrates to drive regulatory processes during cell division. Accordingly, we observe that phosphate transporters and phosphate metabolizing enzymes are phosphorylated and therefore likely to be regulated in mitosis. PMID- 24763108 TI - Structures and mechanism for the design of highly potent glucocorticoids. AB - The evolution of glucocorticoid drugs was driven by the demand of lowering the unwanted side effects, while keeping the beneficial anti-inflammatory effects. Potency is an important aspect of this evolution as many undesirable side effects are associated with use of high-dose glucocorticoids. The side effects can be minimized by highly potent glucocorticoids that achieve the same treatment effects at lower doses. This demand propelled the continuous development of synthetic glucocorticoids with increased potencies, but the structural basis of their potencies is poorly understood. To determine the mechanisms underlying potency, we solved the X-ray structures of the glucocorticoid receptor (GR) ligand-binding domain (LBD) bound to its endogenous ligand, cortisol, which has relatively low potency, and a highly potent synthetic glucocorticoid, mometasone furoate (MF). The cortisol-bound GR LBD revealed that the flexibility of the C1 C2 single bond in the steroid A ring is primarily responsible for the low affinity of cortisol to GR. In contrast, we demonstrate that the very high potency of MF is achieved by its C-17alpha furoate group completely filling the ligand-binding pocket, thus providing additional anchor contacts for high affinity binding. A single amino acid in the ligand-binding pocket, Q642, plays a discriminating role in ligand potency between MF and cortisol. Structure-based design led to synthesis of several novel glucocorticoids with much improved potency and efficacy. Together, these results reveal key structural mechanisms of glucocorticoid potency and provide a rational basis for developing novel highly potent glucocorticoids. PMID- 24763109 TI - Selected activities of Citrus maxima Merr. fruits on human endothelial cells: enhancing cell migration and delaying cellular aging. AB - Endothelial injury and damage as well as accumulated reactive oxygen species (ROS) in aging play a significant role in the development of cardiovascular disease (CVD). Recent studies show an association of high citrus fruit intake with a lower risk of CVD and stroke but the mechanisms involved are not fully understood. This study investigated the effects of pummelo (Citrus maxima Merr. var. Tubtim Siam, CM) fruit extract on human umbilical vein endothelial cell (HUVECs) migration and aging. The freeze-dried powder of fruit extract was characterized for antioxidant capacity (FRAP assay) and certain natural antioxidants, including ascorbic acid, gallic acid, hesperidin, and naringin (HPLC). Short-term (48 h) co-cultivation of HUVECs with CM enhanced cell migration as evaluated by a scratch wound assay and Boyden chamber assay. A long term treatment with CM for 35 days significantly increased HUVEC proliferation capability as indicated by population doubling level (PDL). CM also delayed the onset of aging phenotype shown by senescence-associated beta-galactosidase (SA beta-gal) staining. Furthermore, CM was able to attenuate increased ROS levels in aged cells when determined by 2',7'-dichlorodihydrofluorescein diacetate (DCDHF) while eNOS mRNA expression was increased but the eNOS protein level was not changed. Thus, further in vivo and clinical studies are warranted to support the use of pummelo as a functional fruit for endothelial health and CVD risk reduction. PMID- 24763110 TI - Intake of Tibetan hull-less barley is associated with a reduced risk of metabolic related syndrome in rats fed high-fat-sucrose diets. AB - The objective of this study was to assess the effects of whole grain Tibetan hull less barley on metabolic related syndrome induced by high-fat-sucrose diets in rats. The diets were designed to reflect the dietary patterns of Chinese individuals (>30% energy fat) with refined wheat flour (HFS-W) or Tibetan hull less barley (HFS-THB) as the main carbohydrate sources. Rats fed HFS-W had increased body weight, abdominal fat deposition, liver weight, liver fat deposition, triglyceride (TG), fasting blood glucose (FBG), serum fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR) scores, and decreased low-density lipoprotein cholesterol (LDL-C) levels compared to rats fed a basal diet (BD). However, rats fed HFS-THB had reduced body weight gain, dyslipidemia, and insulin resistance. These findings indicate that whole Tibetan hull-less barley is a functional food that can reduce the prevalence of metabolic related syndrome induced by high-fat-sucrose diets. PMID- 24763111 TI - High plasma homocysteine increases risk of metabolic syndrome in 6 to 8 year old children in rural Nepal. AB - Little attention has been given to the association of plasma homocysteine (Hcy) and metabolic syndrome (MetS) in children. We have evaluated the risk of MetS with plasma Hcy in a cohort of 6 to 8 year old rural Nepalese children, born to mothers who had participated in an antenatal micronutrient supplementation trial. We assessed Hcy in plasma from a random selection of n = 1000 children and determined the relationship of elevated Hcy (>12.0 MUmol/L) to MetS (defined as the presence of any three of the following: abdominal adiposity (waist circumference >= 85th percentile of the study population), high plasma glucose (>= 85th percentile), high systolic or diastolic blood pressure (>= 90th percentile of reference population), triglyceride >= 1.7 mmol/L and high density lipoprotein < 0.9 mmol/L.) and its components. There was an increased risk of low high-density lipoproteins (HDL), [odds ratios (OR) = 1.77, 95% confidence intervals (CI) = 1.08-2.88; p = 0.020], high blood pressure [OR = 1.60, 95% CI = 1.10-2.46; p = 0.015] and high body mass index (BMI) [OR = 1.98, 95% CI = 1.33 2.96; p = 0.001] with elevated Hcy. We observed an increased risk of MetS (OR = 1.75, 95% CI = 1.06-2.90; p = 0.029) with elevated Hcy in age and gender-adjusted logistic regression models. High plasma Hcy is associated with increased risk of MetS and may have implications for chronic disease later in life. PMID- 24763112 TI - Weight status and psychological distress in a Mediterranean Spanish population: a symmetric U-shaped relationship. AB - Psychological disorders in people with extreme weight (low weight or obesity) should be taken into consideration by health professionals in order to practice an effective treatment to these patients. This study evaluates the association between body mass index (BMI) and psychological distress in 563 inhabitants of Malaga (South of Spain). Participants were classified in four categories of BMI: Underweight (BMI <18.5 Kg/m2), Normal weight (BMI 18.5-24.99 Kg/m2), Overweight (BMI 25.0-29.99 Kg/m2) and Obesity (BMI >30 Kg/m2). Psychological distress was measured with the Spanish version of the Derogatis' Symptoms Checklist Revised (SCL-90-R). We observed a symmetric U-shaped relationship between weight status and psychological distress in all SCL-90-R dimensions (p for quadratic trend <0.001) for both men and women. Participants with extreme weight showed the worst psychological status, and participants with normal weight exhibited the best. We found no statistically significant differences between underweight and obese participants in 9 of the 10 SCL-90-R dimensions analyzed among men, and in 8 of the 10 dimensions among women. Underweight and obese participants showed no gender differences in psychological distress levels. Psychological treatment of Mediterranean people with extreme weight, should consider underweight and obese patients at the same level of psychological distress. PMID- 24763113 TI - Caffeine intake may modulate inflammation markers in trained rats. AB - Caffeine is presented in many commercial products and has been proven to induce ergogenic effects in exercise, mainly related to redox status homeostasis, inflammation and oxidative stress-related adaptation mechanisms. However, most studies have mainly focused on muscle adaptations, and the role of caffeine in different tissues during exercise training has not been fully described. The aim of this study was therefore, to analyze the effects of chronic caffeine intake and exercise training on liver mitochondria functioning and plasma inflammation markers. Rats were divided into control, control/caffeine, exercise, and exercise/caffeine groups. Exercise groups underwent four weeks of swimming training and caffeine groups were supplemented with 6 mg/kg/day. Liver mitochondrial swelling and complex I activity, and plasma myeloperoxidase (MPO) and acetylcholinesterase (AChE) activities were measured. An anti-inflammatory effect of exercise was evidenced by reduced plasma MPO activity. Additionally, caffeine intake alone and combined with exercise decreased the plasma AChE and MPO activities. The per se anti-inflammatory effect of caffeine intake should be highlighted considering its widespread use as an ergogenic aid. Therefore, caffeine seems to interfere on exercise-induced adaptations and could also be used in different exercise-related health treatments. PMID- 24763114 TI - Epigenetic effects of human breast milk. AB - A current aim of nutrigenetics is to personalize nutritional practices according to genetic variations that influence the way of digestion and metabolism of nutrients introduced with the diet. Nutritional epigenetics concerns knowledge about the effects of nutrients on gene expression. Nutrition in early life or in critical periods of development, may have a role in modulating gene expression, and, therefore, have later effects on health. Human breast milk is well-known for its ability in preventing several acute and chronic diseases. Indeed, breastfed children may have lower risk of neonatal necrotizing enterocolitis, infectious diseases, and also of non-communicable diseases, such as obesity and related disorders. Beneficial effects of human breast milk on health may be associated in part with its peculiar components, possible also via epigenetic processes. This paper discusses about presumed epigenetic effects of human breast milk and components. While evidence suggests that a direct relationship may exist of some components of human breast milk with epigenetic changes, the mechanisms involved are still unclear. Studies have to be conducted to clarify the actual role of human breast milk on genetic expression, in particular when linked to the risk of non-communicable diseases, to potentially benefit the infant's health and his later life. PMID- 24763115 TI - Obesity and lifespan health--importance of the fetal environment. AB - A marked increase in the frequency of obesity at the population level has resulted in an increasing number of obese women entering pregnancy. The increasing realization of the importance of the fetal environment in relation to chronic disease across the lifespan has focused attention on the role of maternal obesity in fetal development. Previous studies have demonstrated that obesity during adolescence and adulthood can be traced back to fetal and early childhood exposures. This review focuses on factors that contribute to early developmental events, such as epigenetic modifications, the potential for an increase in inflammatory burden, early developmental programming changes such as the variable development of white versus brown adipose tissue, and alterations in organ ontogeny. We hypothesize that these mechanisms promote an unfavorable fetal environment and can have a long-standing impact, with early manifestations of chronic disease that can result in an increased demand for future health care. In order to identify appropriate preventive measures, attention needs to be placed both on reducing maternal obesity as well as understanding the molecular, cellular, and epigenetic mechanisms that may be responsible for the prenatal onset of chronic disease. PMID- 24763116 TI - In vitro anti-osteoporosis properties of diverse Korean Drynariae rhizoma phenolic extracts. AB - Drynariae rhizoma has been used to prevent bone loss that occurs with increasing age. However, the chemical compounds in extracts that act on bone metabolism in herbal medicine are poorly understood. This study aimed to investigate and compare the extraction efficacy of polyphenolic compounds, antioxidant activity, and in vitro anti-osteoporosis properties of water extract (DR-DW) and ethanol extract (DR-EtOH) from D. rhizoma. Total phenolics and flavonoids were better extracted with 70% EtOH, and this extraction method also resulted in higher antioxidant activity and in vitro anti-osteoporosis properties in these extracts. In particular, the contents of phloroglucinol, protocatechuic acid ethyl ester, 2 amino-3,4-dimethyl-benzoic acid, 3-(3,5-dimethyl-pyrazol-1-yl)-benzoic acid, chlorogenic acid, syringic acid, trans-ferulic acid, (-)-epigallocatechin, epigallocatechin gallate, quercetin dehydrate, luteolin and emodin in DR-EtOH were higher than those in DR-DW. These results indicated that DR-EtOH could be a good source of natural herbs with anti-osteoporosis properties. PMID- 24763118 TI - Daytime Versus Nighttime Extubations: A Comparison of Reintubation, Length of Stay, and Mortality. AB - PURPOSE: Despite studies regarding outcomes of day versus night medical care, consequences of nighttime extubations are unknown. It may be favorable to extubate patients off-hours, as soon as weaning parameters are met, since this could decrease complications and shorten length of stay (LOS). Conversely, nighttime extubation could be deleterious, as staffing varies during this time. We hypothesized that patients have similar reintubation rates, irrespective of extubation time. METHODS: A retrospective cohort study performed at 2 hospitals within a tertiary academic medical center included all adult intensive care unit (ICU) patients extubated between July 01, 2009 and May 31, 2011. Those extubated due to withdrawal of support were excluded. The nighttime group included patients extubated between 7:00 pm and 6:59 am and the daytime group included patients extubated between 7:00 am and 6:59 pm. RESULTS: Of 2240 extubated patients, 1555 were extubated during the day and 685 were extubated at night. Of these, 119 (7.7%) and 26 (3.8%), respectively, were reintubated in 24 hours with likelihood of reintubation significantly lower for nighttime than daytime after multivariable adjustment (odds ratio [OR] = 0.5, 95% confidence interval [CI] 0.3 0.9, P = .01), with a similar trend for reintubation within 72 hours (OR = 0.7, 95% CI = 0.5-1.0, P = .07). There was a trend toward decreased mortality for patients extubated at night (OR = 0.6, 95% CI = 0.3-1.0, P = .06). There was also a significantly lower LOS for patients extubated at night (P = .002). In a confirmatory frequency-matched analysis, there was no significant difference in reintubation proportion or mortality, but LOS was significantly less in those extubated at night. CONCLUSIONS: Intensive care unit extubations at night did not have higher likelihood of reintubation, LOS, or mortality compared to those during the day. Since patients should be extubated as soon as they meet parameters in order to potentially decrease complications of mechanical ventilation, these data provide no support for delaying extubation until daytime. PMID- 24763117 TI - Ascorbic acid and the brain: rationale for the use against cognitive decline. AB - This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer's disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration. PMID- 24763120 TI - "Pleats fold" technique of amniotic membrane transplantation for management of corneal perforations. AB - PURPOSE: The aim of this study was to examine the efficacy and surgical success rates of amniotic membrane (AM) transplantation performed for corneal perforation closure using a novel technique. METHODS: This study included 6 eyes from 6 patients with corneal perforation who had received AM transplantation between May 2011 and April 2012. The AM was collected from human placenta shortly after cesarean section. In surgery, the AM was folded into pleats and used to plug the wound using 10-0 nylon suture. The wound was then covered with an AM seal. After reepithelialization and AM scarring, sutures were removed. RESULTS: All 6 patients had successful wound closure with 1 surgery. One patient underwent optical keratoplasty later, and 1 patient required combined preserved sclera transplantation. The absolute value of astigmatism decreased to <3.50 diopters (D) 3 months after surgery and to <3.00 D 6 months after surgery in patients with peripheral AM transplants. The visual acuity gradually improved over the first 3 months after surgery, and visual acuity gains were maintained at the 6-month postoperative mark. CONCLUSIONS: The AM transplantation procedure may be an effective option for treating corneal perforations when the wound is circular or irregular, except for incised wounds. Our "Pleats Fold" AM transplantation technique can achieve definite closure and effectively repair wounds of various sizes. Postoperative astigmatic values were acceptable. Therefore, we recommend this procedure for repairing lesions <3 mm in diameter that do not involve the central cornea and that are infection free. PMID- 24763119 TI - Amelioration of reproduction-associated oxidative stress in a viviparous insect is critical to prevent reproductive senescence. AB - Impact of reproductive processes upon female health has yielded conflicting results; particularly in relation to the role of reproduction-associated stress. We used the viviparous tsetse fly to determine if lactation, birth and involution lead to damage from oxidative stress (OS) that impairs subsequent reproductive cycles. Tsetse females carry an intrauterine larva to full term at each pregnancy cycle, and lactate to nourish them with milk secretions produced by the accessory gland ( = milk gland) organ. Unlike most K-strategists, tsetse females lack an apparent period of reproductive senescence allowing the production of 8-10 progeny over their entire life span. In a lactating female, over 47% of the maternal transcriptome is associated with the generation of milk proteins. The resulting single larval offspring weighs as much as the mother at birth. In studying this process we noted an increase in specific antioxidant enzyme (AOE) transcripts and enzymatic activity at critical times during lactation, birth and involution in the milk gland/fat body organ and the uterus. Suppression of superoxide dismutase (sod) decreased fecundity in subsequent reproductive cycles in young mothers and nearly abolished fecundity in geriatric females. Loss of fecundity was in part due to the inability of the mother to produce adequate milk to support larval growth. Longevity was also impaired after sod knockdown. Generation of OS in virgin females through exogenous treatment with hydrogen peroxide at times corresponding to pregnancy intervals reduced survival, which was exacerbated by sod knockdown. AOE expression may prevent oxidative damage associated with the generation of nutrients by the milk gland, parturition and milk gland breakdown. Our results indicate that prevention of OS is essential for females to meet the growing nutritional demands of juveniles during pregnancy and to repair the damage that occurs at birth. This process is particularly important for females to remain fecund during the latter portion of their lifetime. PMID- 24763121 TI - Clinical features of ocular herpetic infection in an italian referral center. AB - PURPOSE: The aim of this study was to describe clinical manifestations of herpetic ocular infection caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV) in a referral center in Northern Italy. METHODS: This retrospective study included 241 patients with herpetic ocular infection referred to the tertiary-care Ocular Immunology and Uveitis Service, at the San Raffaele Scientific Institute in Milan, from January 2006 to August 2013. The main clinical parameters evaluated were etiology, clinical features, ocular complications, and recurrences of the infection. RESULTS: Two hundred forty-one patients (144 female and 97 male) were followed for a mean time of 24.9 +/- 18.2 months (range, 12-72). One hundred eighty-nine (78.4%) patients had HSV, 45 (18.7%) had VZV, and 7 (2.9%) had CMV infection. In the HSV and VZV groups, the most frequent manifestation was keratitis (41.3% and 31.1%, respectively), followed by anterior uveitis (33.3% and 28.9%, respectively). The most common CMV presentation was retinitis (71.4%). The main complications observed were glaucoma (38.1% in HSV group, 40% in the VZV group, and 28.6% in the CMV group) and cataract (27.5% in HSV group, 26.7% in VZV group, and 28.6% in CMV group), whereas retinal detachment frequently occurred in patients with retinitis (50%, 42.9%, and 40% among HSV, VZV, and CMV patients, respectively). Recurrences were observed in 65.1%, 51.1%, and 28.6% of patients with HSV, VZV, and CMV, respectively. CONCLUSIONS: Manifestations of herpetic ocular disease in our patients are comparable with other published series. However, the rate of ocular complications and recurrences during follow-up were higher compared with other series. PMID- 24763122 TI - Comparison of central corneal thickness, thinnest corneal thickness, anterior chamber depth, and simulated keratometry using galilei, Pentacam, and Sirius devices. AB - PURPOSE: The aim was to evaluate the agreement in the central corneal thickness (CCT), thinnest corneal thickness (TCT), anterior chamber depth (ACD), and mean simulated keratometry (simK) measurements using Pentacam, Galilei, and Sirius Scheimpflug systems in normal eyes. METHODS: Anterior segment measurements were performed with Pentacam, Galilei, and Sirius devices in 32 healthy subjects. The right eye of each participant was selected. Measurements obtained with the 3 systems were compared using repeated-measures analysis of variance and Bonferroni multiple comparisons test. RESULTS: Analysis of variance determined a significant difference in the anterior segment measurements of CCT, TCT, ACD, and simK between the 3 devices (P < 0.001). Pairwise comparisons of CCT and TCT measurements were significantly different except for the comparison between Pentacam and Sirius. All pairwise comparisons for ACD were statistically significant. The pairwise comparison results for simK values showed that the Galilei and Sirius systems demonstrated better agreement with each other than with Pentacam. CONCLUSIONS: The results of this study suggest that the Pentacam, Galilei, and Sirius Scheimpflug systems should not be accepted as interchangeable for CCT, TCT, ACD, and simK in healthy subjects. PMID- 24763123 TI - Simple, inexpensive, and effective injector for descemet membrane endothelial keratoplasty. AB - PURPOSE: We describe an inexpensive, simple, and effective endothelium-Descemet membrane (EDM) graft injector assembled from regular operating room supplies in Descemet membrane endothelial keratoplasty (DMEK). METHODS: To assemble the injector, standard intravenous tubing was cut approximately 2 inches from the Luer lock end, leaving a steep bevel. The cut end of the tubing was firmly wedged bevel up and advanced into the back of an Alcon IOL B cartridge. The Luer lock end of the tubing was then attached to a 5- or 10-mL syringe filled with BSS Plus. The EDM graft was then placed into a Petri dish filled with BSS. After the graft was sucked into an injector with bevel-side up under the surgical microscope, the graft was then inserted into the anterior chamber with the injector through the main incision in the superotemporal quadrant. RESULTS: In seven eyes of seven patients with Fuchs endothelial corneal dystrophy treated with DMEK using our injector, clear attached grafts and improved visual acuity were achieved. CONCLUSIONS: This simple, inexpensive, and effective injector is a safe and viable device to facilitate this part of DMEK surgery. PMID- 24763124 TI - What happens to the corneal transplant endothelium after penetrating keratoplasty? AB - PURPOSE: The aim of this study was to examine the human corneal endothelium of the transplant donor, wound, and adjacent host to determine the fate of the endothelial cells after penetrating keratoplasty. METHODS: We performed dissecting microscopic overviews and light and scanning electron microscopy on clear corneal transplant specimens obtained 1 month to 47 years after transplantation. The indications for the primary keratoplasty were keratoconus (11), Fuchs endothelial dystrophy (7), bullous keratopathy (6), others (5), and 8 cases without clinical data. RESULTS: We were able to visualize the wound and perform relative endothelial cell counts in 17 of 37 specimens. The wounds were of 4 shapes: smooth, anterior and/or posterior gaping, and anterior or posterior overriding. Any combination could be seen in the same specimen. Cells migrated from the center of the donor across the donor-host wound toward the host, but in all cases, the cells spread out, enlarged, and were ultimately lost. One case of Fuchs endothelial dystrophy may have had cell migration from the host across the wound to the donor. CONCLUSIONS: We confirmed that donor cells migrate from higher density to lower density across the transplant wound over time. Wound configuration, donor cell health, recipient endothelial health, and probable cell to-cell contact inhibition are involved in this process. PMID- 24763125 TI - Combined anterior chamber washout, amniotic membrane transplantation, and topical use of corticosteroids for severe peripheral ulcerative keratitis. AB - PURPOSE: The aim of this study was to evaluate the efficacy of anterior chamber washout, amniotic membrane transplantation, and topical use of corticosteroids in the treatment of severe peripheral ulcerative keratitis with membranous endothelial exudation. METHODS: Twelve patients (12 eyes) with severe corneal ulceration were included. All ulcers were located at the corneal periphery, accompanied by central corneal epithelial defects and stromal edema. Membranous endothelial exudates were observed by anterior segment optical coherence tomography. The duration of the ulcers was 1 to 10 months (mean, 3.0 +/- 2.9 months) before the patients visited our institution. Corneal inflammation and ulceration could not be controlled after 2 weeks of topical antiinflammation treatment. Bacterial, fungal, and Acanthamoeba infections were not detected. Surgical treatment was performed. After the necrotic corneal tissue was cut, exudation clinging to the endothelium was removed. Then, amniotic membrane was placed on the corneal lesion. Postoperatively, corticosteroid eye drops and topical and systemic antiinflammation medication were given. Healing of corneal ulcers and improvement of stromal edema were detected by slit-lamp microscopy. All patients were followed up for 3 to 15 months (mean, 6.5 +/- 3.7 months). RESULTS: All corneal ulcers healed by 1 to 2 weeks after surgery. The corneal stromal edema subsided within 1 month. All patients achieved a stable ocular surface. There was no recurrence during the follow-up. CONCLUSIONS: Anterior chamber washout and amniotic membrane transplantation combined with topical corticosteroids seems to be effective for the treatment of severe peripheral ulcerative keratitis with endothelial exudates. PMID- 24763126 TI - Conceptualizing neuropsychiatric diseases with multimodal data-driven meta analyses - the case of behavioral variant frontotemporal dementia. AB - INTRODUCTION: Uniform coordinate systems in neuroimaging research have enabled comprehensive systematic and quantitative meta-analyses. Such approaches are particularly relevant for neuropsychiatric diseases, the understanding of their symptoms, prediction and treatment. Behavioral variant frontotemporal dementia (bvFTD), a common neurodegenerative syndrome, is characterized by deep alterations in behavior and personality. Investigating this 'nexopathy' elucidates the healthy social and emotional brain. METHODS: Here, we combine three multimodal meta-analyses approaches - anatomical and activation likelihood estimates and behavioral domain profiles - to identify neural correlates of bvFTD in 417 patients and 406 control subjects and to extract mental functions associated with this disease by meta-analyzing functional activation studies in the comprehensive probabilistic functional brain atlas of the BrainMap database. RESULTS: The analyses identify the frontomedian cortex, basal ganglia, anterior insulae and thalamus as most relevant hubs, with a regional dissociation between atrophy and hypometabolism. Neural networks affected by bvFTD were associated with emotion and reward processing, empathy and executive functions (mainly inhibition), suggesting these functions as core domains affected by the disease and finally leading to its clinical symptoms. In contrast, changes in theory of mind or mentalizing abilities seem to be secondary phenomena of executive dysfunctions. CONCLUSIONS: The study creates a novel conceptual framework to understand neuropsychiatric diseases by powerful data-driven meta-analytic approaches that shall be extended to the whole neuropsychiatric spectrum in the future. PMID- 24763128 TI - The origin of bacteria responsible for bioerosion to the internal bone microstructure: Results from experimentally-deposited pig carcasses. AB - It is unclear whether the principal forms of bioerosion that are often found within the internal microstructure of human bone are produced by intrinsic gut microbiota or exogenous bacteria from the soil. The aim of this study was to attempt to resolve this issue through the histological analysis of bone sampled from experimentally-deposited domestic pig (Sus scrofa) carcasses. Confirmation of either scenario will dictate how patterns of bone bioerosion can be used in reconstructions of taphonomic events. The results should also reveal the post mortem processes that promote the survival of bone biomolecules as well as the histomorphological structures that can be used in forensic identifications of human remains. Twelve pig carcasses were differentially buried and sub-aerially exposed for one year at Riseholme, Lincolnshire, U.K. Their femora were examined after one year using thin section light microscopy to investigate the patterns of microscopic bioerosion. The distribution and extent of degradation observed within the microstructures of the pig femora were consistent with bacterial bioerosion. The early occurrence of bioerosion within the Riseholme samples suggested that enteric putrefactive bacteria are primarily responsible for characteristic internal bone bioerosion. The distribution of bioerosion amongst the buried/unburied and stillborn/juvenile pig remains also supported an endogenous model. Bone from stillborn neonatal carcasses always demonstrated immaculate histological preservation due to the intrinsic sterility of newborn infant intestinal tracts. Bioerosion within the internal microstructure of mature bone will reflect the extent to which the skeletal element was exposed to putrefaction. Bone histology should be useful in reconstructing early taphonomic events. There is likely to be a relationship between post mortem processes that deny enteric gut bacteria access to internal bone microstructures and the survival of biomolecules. PMID- 24763127 TI - Frontal and parietal cortex contributions to action modification. AB - Successful achievement of task goals depends critically on the ability to adjust ongoing actions in response to environmental changes. The neural substrates underlying action modification have been a topic of great controversy: both, posterior parietal cortex and frontal regions, particularly prefrontal cortex have been previously identified as crucial in this regard, with most studies arguing in favor of one or the other. We aimed to address this controversy and understand whether frontal and parietal regions might play distinct roles during action modification. We tested ipsilesional arm performance of 27 stroke patients with focal lesions to frontal or parietal regions of the left or right cerebral hemisphere, and left or right arm performance of 18 healthy subjects on the classic double-step task in which a target is unpredictably displaced to a new location, requiring modification of the ongoing action. Only right hemisphere frontal lesions adversely impacted the timing of initiation of the modified response, while only left hemisphere parietal lesions impaired the accuracy of the modified action. Patients with right frontal lesions tended to complete the ongoing action to the initially displayed baseline target and initiated the new movement after a significant delay. In contrast, patients with left parietal damage did not accurately reach the new target location, but compared to the other groups, initiated the new action during an earlier phase of motion, before their baseline action was complete. Our findings thus suggest distinct, hemisphere specific contributions of frontal and parietal regions to action modification, and bring together, for the first time, disparate sets of prior findings about its underlying neural substrates. PMID- 24763129 TI - High-mobility group box-1 protein determination in postmortem samples. AB - The aims of this study were to assess whether high-mobility group box-1 protein can be determined in biological fluids collected during autopsy and evaluate the diagnostic potential of high-mobility group box-1 protein in identifying sepsis related deaths. High-mobility group box-1 protein was measured in serum collected during hospitalization as well as in undiluted and diluted postmortem serum and pericardial fluid collected during autopsy in a group of sepsis-related deaths and control cases with noninfectious causes of death. Inclusion criteria consisted of full biological sample availability and postmortem interval not exceeding 6h. The preliminary results indicate that high-mobility group box-1 protein levels markedly increase after death. Concentrations beyond the upper limit of the calibration curve were obtained in undiluted postmortem serum in septic and traumatic control cases. In pericardial fluid, concentrations beyond the upper limit of the calibration curve were found in all cases. These findings suggest that the diagnostic potential of high-mobility group box-1 protein in the postmortem setting is extremely limited due to molecule release into the bloodstream after death, rendering antemortem levels difficult or impossible to estimate even after sample dilution. PMID- 24763131 TI - Authors' response: Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. PMID- 24763130 TI - Still a hard-to-reach population? Using social media to recruit Latino gay couples for an HIV intervention adaptation study. AB - BACKGROUND: Online social networking use has increased rapidly among African American and Latino men who have sex with men (MSM), making it important to understand how these technologies can be used to reach, retain, and maintain individuals in care and promote health wellness. In particular, the Internet is increasingly recognized as a platform for health communication and education. However, little is known about how primarily Spanish-speaking populations use and engage with each other through social media platforms. OBJECTIVE: We aimed to recruit eligible couples for a study to adapt "Connect 'n Unite" (an HIV prevention intervention initially created for black gay couples) for Spanish speaking Latino gay couples living in New York City. METHODS: In order to successfully design and implement an effective social media recruitment campaign to reach Spanish-speaking Latino gay couples for our ongoing "Latinos en Pareja" study, our community stakeholders and research team used McGuire's communication/persuasion matrix. The matrix guided our research, specifically each marketing "channel", targeted "message", and target population or "receiver". We developed a social media recruitment protocol and trained our research staff and stakeholders to conduct social media recruitment. RESULTS: As a result, in just 1 month, we recruited all of our subjects (N=14 couples, that is, N=28 participants) and reached more than 35,658 participants through different channels. One of the major successes of our social media recruitment campaign was to build a strong stakeholder base that became involved early on in all aspects of the research process-from pilot study writing and development to recruitment and retention. In addition, the variety of "messages" used across different social media platforms (including Facebook, the "Latinos en Pareja" study website, Craigslist, and various smartphone applications such as Grindr, SCRUFF, and Jack'd) helped recruit Latino gay couples. We also relied on a wide range of community-based organizations across New York City to promote the study and build in the social media components. CONCLUSIONS: Our findings highlight the importance of incorporating communication technologies into the recruitment and engagement of participants in HIV interventions. Particularly, the success of our social media recruitment strategy with Spanish-speaking Latino MSM shows that this population is not particularly "hard to reach", as it is often characterized within public health literature. PMID- 24763132 TI - Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers. AB - BACKGROUND AND OBJECTIVE: Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis. METHODS: 251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case-control study, which included 184 patients with biopsy-proven liver fibrosis stages. RESULTS: In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant >=45% compared to <45% in the longitudinal cohort; this finding was validated by the case-control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67). CONCLUSIONS: A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection. PMID- 24763133 TI - Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results. AB - OBJECTIVE: The alpha4beta7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated. DESIGN: In this randomised, double-blind, placebo-controlled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre >=10 IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point. RESULTS: A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs. 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs. 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. CONCLUSIONS: Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action. TRIAL REGISTRATION NUMBER: NCT Number: 01981616; EudraCT Number: 2011-001874-24. PMID- 24763134 TI - Enterohaemorrhagic Escherichia coli O157: a survey of dairy cattle in Tripoli, Libya. PMID- 24763135 TI - Seroepidemiology of Toxoplasma gondii infection in free-range chickens (Gallus domesticus) of Central Ethiopia. AB - We performed a seroepidemiological study of Toxoplasma gondii infection in free range chickens from October 2012 to May 2013. We used cross-sectional two-stage cluster sampling to collect blood samples from wing veins of 601 chickens from central Ethiopia. T. gondii-specific antibodies were assayed by modified agglutination test (MAT). We collected information about risk factors by questionnaire and used univariable and multivariable logistic regression to assess risk factors. An overall seroprevalence of 30.5% [95% confidence interval (CI) 26.27-34.14] and 54.2% (95% CI 47.06-61.36) was found at animal- and flock level, respectively. The MAT end titre of seropositive chickens (n = 183) were 1 : 60 in 46, 1 : 180 in 28, 1 : 540 in 29, ?1 : 1620 in 48, 1 : 6000 in 22, 1 : 18,000 in five, 1 : 54,000 in one, and ?1 : 162,000 in four. Animal-level risk factors identified using multivariable logistic regression model were: midland altitude [odds ratio (OR) 2.53, 95% CI 1.12-5.72], cross and exotic breeds (OR 3.17, 95% CI 1.39-7.23), increased age of chickens (OR 2.32, 95% CI 1.19-4.49), extensive management (OR 6.92, 95% CI 1.34-35.86) and the presence of cats (OR 2.08, 95% CI 1.20-3.61). Similarly, flock-level risk factors were midland altitude (OR 3.62, 95% CI 1.31-9.99) and the presence of cats (OR 1.19-4.94). The knowledge of the local people about the health risk of cats to humans and animals is poor. Housing and management of cats and chickens are also poor. The widespread presence of T. gondii infection in free-range chickens of Central Ethiopia provides suggestive evidence for the high level of contamination of the living environment of people with T. gondii oocysts. Meat from free-range chickens might be an important source of infection for humans. Altitude, breed, age, management and presence of cats are independent predictors of seropositivity. Education of farmers about toxoplasmosis and further studies to elucidate the burden of toxoplasmosis in animals and humans warrants consideration. PMID- 24763136 TI - Pneumococcal conjugate vaccines for adults: reasons for optimism and for caution. PMID- 24763137 TI - Brazilian community health agents and qualitative primary healthcare information. AB - AIM: The aim of this study was to explore female community health agents' views about the value of recording qualitative information on contextual health issues they observe during home visits, data that are not officially required to be documented for the Brazilian System of Primary Healthcare Information. BACKGROUND: The study was conducted in community primary healthcare centres located in the cities of Aracatuba and Coroados (state of Sao Paulo) and Rio de Janeiro (state of Rio de Janeiro), Brazil. METHODS: The design was a qualitative, exploratory study. The purposeful sampling criteria were being female, with a minimum of three years of continuous service in the same location. Data collection with 62 participants was conducted via 11 focus groups (in 2007 and 2008). Audio files were transcribed and submitted to the method of thematic analysis. Four themes guided the analysis: working with qualitative information and undocumented observation; reflecting on qualitative information; integrating/analysing quantitative and qualitative information; and information sharing with agents and family health teams. In 2010, 25 community health agents verified the final interpretation of the findings. FINDINGS: Participants valued the recording of qualitative, contextual information to expand understanding of primary healthcare issues and as an indicator of clients' improved health behaviour and health literacy. While participants initiated the recording of additional health information, they generally did not inform the family health team about these findings. They perceived that team members devalued this type of information by considering it a reflection of the clientele's social conditions or problems beyond the scope of medical concerns. Documentation of qualitative evidence can account for the effectiveness of health education in two ways: by improving preventative care, and by amplifying the voices of underprivileged clients who live in poverty to ensure the most appropriate and best quality primary healthcare for them. PMID- 24763138 TI - Genomic analysis of the blood attributed to Louis XVI (1754-1793), king of France. AB - A pyrographically decorated gourd, dated to the French Revolution period, has been alleged to contain a handkerchief dipped into the blood of the French king Louis XVI (1754-1793) after his beheading but recent analyses of living males from two Bourbon branches cast doubts on its authenticity. We sequenced the complete genome of the DNA contained in the gourd at low coverage (~2.5*) with coding sequences enriched at a higher ~7.3* coverage. We found that the ancestry of the gourd's genome does not seem compatible with Louis XVI's known ancestry. From a functional perspective, we did not find an excess of alleles contributing to height despite being described as the tallest person in Court. In addition, the eye colour prediction supported brown eyes, while Louis XVI had blue eyes. This is the first draft genome generated from a person who lived in a recent historical period; however, our results suggest that this sample may not correspond to the alleged king. PMID- 24763139 TI - Cerebral malaria retinopathy predictors of persisting neurocognitive outcomes in Malawian children. AB - BACKGROUND: Neuropsychological sequelae from pediatric cerebral malaria (CM) have been well-documented. Although malaria-specific retinopathy during acute illness has become a defining criterion for CM, its relationship to neurocognitive sequelae has not been documented. This relationship is important if malaria specific retinopathy reflects the possible brain neuropathogenesis leading to long-term neurocognitive deficits. METHODS: From 2008 to 2012, 49 Malawian children 4.5-12 years of age surviving retinopathy-positive CM (CM-R) were tested 1-6 yrs after illness with the Kaufman Assessment Battery for Children, 2 edition, the tests of variables of attention and the Achenbach Child Behavior Checklist. In an observational study of a cohort of cerebral malaria survivors, these neurocognitive and behavioral outcomes were statistically related to types and severity of retinopathy measures, while controlling for age, sex, body mass index, socioeconomic status and time interval between illness and testing. RESULTS: Worse scores for hemorrhages, papilledema, optic disk hyperemia, retinal whitening of macula and foveal annulus were associated with poorer Kaufman Assessment Battery for Children, 2 edition mental processing index and global scale scores. Disk hyperemia was also predictive of tests of variables of attention D prime overall attention performance (inattention) and commission errors (impulsivity). Few associations were found between retinopathy scores and Achenbach Child Behavior Checklist (emotional and behavioral) outcomes. CONCLUSIONS: We are the first to report the relationship between severity of malaria-specific retinopathy during acute illness in CM survivors and persisting neurocognitive problems. These findings support earlier studies documenting that severity of retinopathy during acute illness is medically prognostic in CM survivors. We extend these findings to include long-term neurocognitive outcomes. PMID- 24763141 TI - Ecological consistency of SSU rRNA-based operational taxonomic units at a global scale. AB - Operational Taxonomic Units (OTUs), usually defined as clusters of similar 16S/18S rRNA sequences, are the most widely used basic diversity units in large scale characterizations of microbial communities. However, it remains unclear how well the various proposed OTU clustering algorithms approximate 'true' microbial taxa. Here, we explore the ecological consistency of OTUs--based on the assumption that, like true microbial taxa, they should show measurable habitat preferences (niche conservatism). In a global and comprehensive survey of available microbial sequence data, we systematically parse sequence annotations to obtain broad ecological descriptions of sampling sites. Based on these, we observe that sequence-based microbial OTUs generally show high levels of ecological consistency. However, different OTU clustering methods result in marked differences in the strength of this signal. Assuming that ecological consistency can serve as an objective external benchmark for cluster quality, we conclude that hierarchical complete linkage clustering, which provided the most ecologically consistent partitions, should be the default choice for OTU clustering. To our knowledge, this is the first approach to assess cluster quality using an external, biologically meaningful parameter as a benchmark, on a global scale. PMID- 24763140 TI - Insights into the trypanosome-host interactions revealed through transcriptomic analysis of parasitized tsetse fly salivary glands. AB - The agents of sleeping sickness disease, Trypanosoma brucei complex parasites, are transmitted to mammalian hosts through the bite of an infected tsetse. Information on tsetse-trypanosome interactions in the salivary gland (SG) tissue, and on mammalian infective metacyclic (MC) parasites present in the SG, is sparse. We performed RNA-seq analyses from uninfected and T. b. brucei infected SGs of Glossina morsitans morsitans. Comparison of the SG transcriptomes to a whole body fly transcriptome revealed that only 2.7% of the contigs are differentially expressed during SG infection, and that only 263 contigs (0.6%) are preferentially expressed in the SGs (SG-enriched). The expression of only 37 contigs (0.08%) and 27 SG-enriched contigs (10%) were suppressed in infected SG. These suppressed contigs accounted for over 55% of the SG transcriptome, and included the most abundant putative secreted proteins with anti-hemostatic functions present in saliva. In contrast, expression of putative host proteins associated with immunity, stress, cell division and tissue remodeling were enriched in infected SG suggesting that parasite infections induce host immune and stress response(s) that likely results in tissue renewal. We also performed RNA-seq analysis from mouse blood infected with the same parasite strain, and compared the transcriptome of bloodstream form (BSF) cells with that of parasites obtained from the infected SG. Over 30% of parasite transcripts are differentially regulated between the two stages, and reflect parasite adaptations to varying host nutritional and immune ecology. These differences are associated with the switch from an amino acid based metabolism in the SG to one based on glucose utilization in the blood, and with surface coat modifications that enable parasite survival in the different hosts. This study provides a foundation on the molecular aspects of the trypanosome dialogue with its tsetse and mammalian hosts, necessary for future functional investigations. PMID- 24763142 TI - Physical activity-related and weather-related practices of child care centers from 2 states. AB - BACKGROUND: Young children's physical activity (PA) is influenced by their child care environment. This study assessed PA practices in centers from Massachusetts (MA) and Rhode Island (RI), compared them to best practice recommendations, and assessed differences between states and center profit status. We also assessed weather-related practices. METHODS: Sixty percent of MA and 54% of RI directors returned a survey, for a total of 254. Recommendations were 1) daily outdoor play, 2) providing outdoor play area, 3) limiting fixed play structures, 4) variety of portable play equipment, and 5) providing indoor play area. We fit multivariable linear regression models to examine adjusted associations between state, profit status, PA, and weather-related practices. RESULTS: MA did not differ from RI in meeting PA recommendations (beta = 0.03; 0.15, 0.21; P = .72), but MA centers scored higher on weather-related practices (beta = 0.47; 0.16, 0.79; P = .004). For-profit centers had lower PA scores compared with nonprofits (beta = -0.20; 95% CI: -0.38, -0.02; P = .03), but they did not differ for weather (beta = 0.12; -0.19, 0.44; P = .44). CONCLUSIONS: More MA centers allowed children outside in light rain or snow. For-profit centers had more equipment both fixed and portable. Results from this study may help inform interventions to increase PA in children. PMID- 24763143 TI - Intersegmental eye-head-body interactions during complex whole body movements. AB - Using state-of-the-art technology, interactions of eye, head and intersegmental body movements were analyzed for the first time during multiple twisting somersaults of high-level gymnasts. With this aim, we used a unique combination of a 16-channel infrared kinemetric system; a three-dimensional video kinemetric system; wireless electromyography; and a specialized wireless sport-video oculography system, which was able to capture and calculate precise oculomotor data under conditions of rapid multiaxial acceleration. All data were synchronized and integrated in a multimodal software tool for three-dimensional analysis. During specific phases of the recorded movements, a previously unknown eye-head-body interaction was observed. The phenomenon was marked by a prolonged and complete suppression of gaze-stabilizing eye movements, in favor of a tight coupling with the head, spine and joint movements of the gymnasts. Potential reasons for these observations are discussed with regard to earlier findings and integrated within a functional model. PMID- 24763151 TI - Position statement on mesh midurethral slings for stress urinary incontinence. PMID- 24763152 TI - Long-term follow-up of treatment for synthetic mesh complications. AB - OBJECTIVES: The objectives of this study are (1) to describe the presenting symptoms, findings, and treatment and (2) to describe the self-reported improvement and function at least 6 months after presentation in women presenting to 1 urogynecology division for complications associated with synthetic vaginal mesh. METHODS: Women evaluated between 2006 and 2011 were identified by diagnostic codes. We abstracted information from the medical record and attempted to contact all women to complete a follow-up telephone survey questionnaire consisting of several validated instruments. RESULTS: A total of 111 women were evaluated for complications associated with synthetic vaginal mesh. The mean interval from index surgery was 2.4 years. Of these, 84% were referred from outside hospitals. Index surgeries included vaginal mesh kits/vaginally placed mesh (47%), midurethral mesh slings (37%), abdominally placed vaginal mesh (11%), and vaginal mesh kit with concomitantly placed mesh sling (5%). The most common complications were extrusion (65%), contraction (17%), and chronic pelvic pain (16%). A total of 98 women underwent some type of treatment (85 surgical) by urogynecologists, pelvic pain specialists, or physical therapists. Eighty-four (76%) provided follow-up information at mean interval since presentation of 2.3 years. At follow-up, the mean (SD) Pelvic Floor Distress Inventory score was 98 (67), the mean (SD) EQ-5D index score was 0.69 (0.23), and 22% reported vaginal discharge, 15% vaginal bleeding or spotting, and 45% sexual abstinence due to problems related to mesh. A total of 71% reported being overall better, whereas 29% were the same or worse. CONCLUSIONS: Two years after tertiary care level multidisciplinary treatment of vaginal mesh complications, many women still report symptoms that negatively impact their quality of life. PMID- 24763153 TI - Changed women: the long-term impact of vaginal mesh complications. AB - OBJECTIVES: The aim of this study was to describe how women experience vaginal mesh complications after optimized tertiary care level treatment. METHODS: We conducted telephone interviews in 2012 with women at least 6 months after presentation to our tertiary care clinic between 2006 and 2011 for complications related to vaginal mesh and transcribed verbatim responses to 2 open-ended questions about their experiences surrounding vaginal mesh complications. We analyzed data using qualitative description with low-inference interpretation in a team-based setting followed by consensus meetings to arrive at descriptive trajectories of their experiences. RESULTS: Of 111 women, we successfully contacted 88, and 84 agreed to the interview. The mean duration from index mesh surgery to interview was 4.5 years, and the mean duration from presentation to our clinic for complications to the interview was 2.3 years. The effects of mesh complications caused both physical and emotional pain, in addition to the discomfort of the original pelvic floor dysfunction. The women's experiences followed 1 of 3 recovery trajectories. In "cascading health problems," the women experienced a spiral of health problems, anxiety, and desperation. In "settling for a new normal," the women who once considered themselves healthy now believed that they are unhealthy and worked to adjust to their degraded health status. In "returning to health," the women described a return to health. The women still symptomatic discharged from tertiary care clinic expressed hopelessness and abandonment. CONCLUSIONS: Concomitant with ongoing research to improve the safety of vaginal mesh procedures, there must be dedicated efforts to develop and study a range of therapies for holistically treating women with mesh complications. PMID- 24763154 TI - The fate of abstracts presented at annual meetings of the american urogynecologic society from 2007 to 2008. AB - OBJECTIVES: The purpose of this study was to determine the publication rate of full-text articles after the presentation of abstracts at consecutive annual meetings of the American Urogynecologic Society (AUGS) over a 2-year period. METHODS: Using abstract books published by the Journal of Pelvic Medicine and Surgery, we obtained the text of all abstracts presented at the 2007 and 2008 AUGS annual meetings. A literature search was performed in the US National Library of Medicine to identify the peer-reviewed publications arising from each of those abstracts and to calculate the full-text publication rate and the mean duration from presentation to publication. RESULTS: The overall full-text publication rate was 56% (239/438 publications). The mean time from presentation to publication was 15.7 months. The published articles appeared in 49 peer reviewed journals, with notable distribution in the International Urogynecology Journal (27%), American Journal of Obstetrics and Gynecology (26%), and Obstetrics and Gynecology (10%). Oral presentations (85%) were more likely than posters (71%) to have first authors with university affiliations (P = 0.002). The greater the number of abstract authors, the more likely that the article was to be published (P = 0.0059). The odds of an oral presentation being published were 7 times the odds of a poster being published (odds ratio, 6.99; P < 0.001). CONCLUSIONS: Because not all presentations are published, it is questionable whether it is acceptable to cite AUGS abstracts that have not passed a journal's peer review process and to implement their results in clinical practice. PMID- 24763155 TI - Comparison of mindfulness-based stress reduction versus yoga on urinary urge incontinence: a randomized pilot study. with 6-month and 1-year follow-up visits. AB - OBJECTIVES: The objective of this study is to compare the effects of mindfulness based stress reduction (MBSR) versus yoga on urinary urge incontinence (UI) at 8 weeks, 6 months, and 1 year after beginning an 8-week program. MATERIALS AND METHODS: Participants in this prospective randomized single-masked pilot study were women aged 18 years or older with urge-predominant incontinence, 5 or more UI episodes (UIEs) on a 3-day voiding diary, and no recent anticholinergic use. Women were randomized to MBSR or yoga. The primary outcome was the percent change of UIE. RESULTS: Of 30 enrollees (15 in MBSR, 15 in yoga), 24 completed at least 5 of 8 sessions (13 in MBSR and 11 in yoga). Twenty and 21 women completed the 6 month and 12-month follow-up visits, respectively. At 8 weeks, 6 months, and 12 months, the median percent change from the baseline in UIE on the intention-to treat analysis was greater for the MBSR group (-55.6, -71.4, and -66.7, respectively) compared with that for the yoga group (-33.3, -11.8, and -16.7, respectively), with P values ranging from 0.01 to 0.08. On intention-to-treat analysis, the median percent change in the Overactive Bladder Symptom and Quality of Life-Short Form and the Health-Related Quality of Life was greater at each time point for MBSR than for yoga but was statistically significant only at 8 weeks (P = 0.003 and 0.02, respectively). As per protocol analysis, at 8 weeks, 6/13 and 0/11 women in MBSR and yoga, respectively, reported they were very much or much better (P = 0.02), whereas at 1 year, 6/12 and 1/9 women in MBSR and yoga, respectively, did so (P = 0.16). DISCUSSION: These results support larger scale trials to evaluate MBSR, which seems to be a promising treatment of UI. PMID- 24763157 TI - A preliminary evaluation of the TOPAS system for the treatment of fecal incontinence in women. AB - OBJECTIVES: The TOPAS AMS pelvic floor repair system is a self-fixating polypropylene mesh intended for use to reinforce soft tissues where weakness exists in the gynecological and gastroenterological anatomy. It is not available commercially in any country. This was a preliminary study conducted to obtain initial clinical experience with the TOPAS system for the treatment of fecal incontinence (FI) in women. METHODS: This was a prospective study conducted at 5 centers in the United States. Women with FI who failed 1 or more conservative therapies were candidates for the study. Fecal incontinence was assessed with a bowel diary, Cleveland Clinic incontinence scores (CCISs), and Fecal Incontinence Quality of Life (FIQOL) questionnaires, and patients were followed prospectively up to 24 months. Treatment success was defined as a reduction in number of FI episodes of 50% or more compared with baseline. RESULTS: A total of 29 women (mean age, 60.6 years) were implanted with the TOPAS system. Mean number of FI episodes per 14 days decreased from 6.9 at baseline to 3.5 at 24 months of follow up, and the reduction was significant for the entire follow-up period compared with baseline (P < 0.001). A total of 55.6% of the subjects reported treatment success. The CCIS and FIQOL scores for all domains were significantly improved during the overall follow-up period compared with baseline (P < 0.001). The most common procedure and/or device-related adverse events were de novo urinary incontinence, including bladder spasms (n = 6), worsening FI (n = 2), and constipation (n = 2). No device-related erosions or extrusions were reported. CONCLUSIONS: Initial experience of the TOPAS system demonstrated a significant improvement in FI episodes, CCIS and FIQOL scores, and a benign safety profile. These results indicate that the TOPAS system has potential as a new therapeutic option for FI, but it needs to be confirmed in a larger study. PMID- 24763156 TI - A group-based yoga therapy intervention for urinary incontinence in women: a pilot randomized trial. AB - OBJECTIVE: The aim of this study is to examine the feasibility, efficacy, and safety of a group-based yoga therapy intervention for middle-aged and older women with urinary incontinence. METHODS: We conducted a pilot randomized trial of ambulatory women aged 40 years and older with stress, urgency, or mixed-type incontinence. Women were randomized to a 6-week yoga therapy program (n = 10) consisting of twice weekly group classes and once weekly home practice or a wait list control group (n = 9). All participants also received written pamphlets about standard behavioral self-management strategies for incontinence. Changes in incontinence were assessed with 7-day voiding diaries. RESULTS: The mean (SD) age was 61.4 (8.2) years, and the mean baseline frequency of incontinence was 2.5 (1.3) episodes/d. After 6 weeks, the total incontinence frequency decreased by 70% (1.8 [0.9] fewer episodes/d) in the yoga therapy versus 13% (0.3 [1.7] fewer episodes/d) in the control group (P = 0.049). Participants in the yoga therapy group also reported an average of 71% decrease in stress incontinence frequency (0.7 [0.8] fewer episodes/d) compared with a 25% increase in controls (0.2 [1.1] more episodes/d) (P = 0.039). No significant differences in reduction in urgency incontinence were detected between the yoga therapy versus control groups (1.0 [1.0] versus 0.5 [0.5] fewer episodes/d; P = 0.20). All women starting the yoga therapy program completed at least 90% of the group classes and practice sessions. Two participants in each group reported adverse events unrelated to the intervention. CONCLUSIONS: Findings provide preliminary evidence to support the feasibility, efficacy, and safety of a group-based yoga therapy intervention to improve urinary incontinence in women. PMID- 24763158 TI - Perioperative anticholinergic medications and risk of catheterization after urogynecologic surgery. AB - OBJECTIVE: This study aimed to examine how anticholinergic medication exposure affects the risk of failed postoperative void trial (VT) in women undergoing urogynecologic surgery. METHODS: We conducted a retrospective cohort study of women undergoing outpatient prolapse or incontinence surgery. We evaluated perioperative anticholinergic exposure via the validated anticholinergic risk scale (ARS). Total ARS score was calculated by summing the individual ARS for each medication used during the following periods: at home before surgery, in preoperative holding, intraoperatively, and in postoperative recovery. The "low anticholinergic exposure" cohort (total ARS, <=7) was compared to the "high anticholinergic exposure" cohort (total ARS, >=8) to assess our primary outcome: failed postoperative VT on day of surgery. RESULTS: Of 125 women in the study, 98 (78%) had low anticholinergic exposure and 27 (22%) had high anticholinergic exposure. Overall, 28 (22%) patients failed the postoperative VT. Women in the high anticholinergic group had a significantly higher risk of a failed VT (41% vs 17%, P = 0.01 for high vs low anticholinergic groups, respectively). In logistic regression analysis, adjusting for age, body mass index, diabetes, midurethral sling and anterior repair, high anticholinergic exposure (AOR, 4.15; 95% confidence interval, 1.49-11.57), and anterior repair (AOR, 3.15; 95% CI, 1.15 8.61) remained significantly associated with failed postoperative VT. CONCLUSIONS: Higher exposure to perioperative anticholinergic medications increases the risk of a failed postoperative VT after outpatient urogynecologic surgery. PMID- 24763159 TI - Cost-utility of routine endometrial evaluation before le fort colpocleisis. AB - INTRODUCTION: Routine preoperative evaluation of the endometrium before Le Fort colpocleisis is often recommended. There are no data, however, to support this practice. In select patients, it may not be a necessary addition to the preoperative evaluation of Le Fort colpocleisis. METHODS: A decision analysis model was created to compare uterine evaluation, by either endometrial (EM) biopsy or transvaginal ultrasound, to no evaluation for a hypothetical cohort of women undergoing Le Fort colpocleisis. We assumed the absence of risk factors for EM cancer. Probabilities and health outcome utilities were obtained from literature review. Medicare charges were used to estimate cost in 2012 US dollars. Cost-utility analysis was performed using US recommendations from a health plan perspective. RESULTS: At willingness-to-pay thresholds of $50,000 and $100,000, no evaluation is superior to both biopsy and ultrasound. At a 64% probability of cancer, biopsy is more cost-effective than no evaluation and ultrasound. CONCLUSIONS: Compared to biopsy and ultrasound, in low-risk women, no EM evaluation before Le Fort colpocleisis demonstrates superior cost-utility. PMID- 24763160 TI - Perineal abscess three years after a transobturator sling. AB - OBJECTIVE: This study aimed to report a unique perineal abscess after placement of a transobturator sling, involving the thighs and obturator regions bilaterally without involving mesh exposure. CASE REPORT: A 66-year-old woman treated for stress urinary incontinence with a transobturator sling developed a late bilateral obturator infection 30 months after surgery. This complication appeared 6 months after chemotherapy for breast cancer. Sling removal through vaginal and bilateral inguinal incisions was performed. The patient evolved well, without recurrence of the infection or incontinence. DISCUSSION: This case presents a unique scenario of muscle and skin infection after sling placement without any mesh exposure or vaginal involvement. The occurrence of the infection only after chemotherapy may indicate that immunosuppression had participation on its development. Care should be taken when exposing this mesh in contaminated perineal areas. PMID- 24763161 TI - Cystolith formation complicating single-incision sling. AB - Single-incision slings are the newest midurethral slings developed for the surgical treatment of stress urinary incontinence. We report the case of a patient who underwent single-incision sling placement who presented with recurrent stress incontinence 3 years after the procedure. She was found to have a 1.7-cm bladder stone that formed around the single-incision sling polypropylene barb. PMID- 24763162 TI - Vesicosacrofistulization after robotically assisted laparoscopic sacrocolpopexy. AB - Diskitis after sacrocolpopexy for pelvic organ prolapse has been increasingly reported in the literature. We present a case of vesicosacrofistulization resulting in diskitis and osteomyelitis after robotically assisted laparoscopic sacrocolpopexy performed at an outside institution. A 70-year-old woman with uterovaginal prolapse and stress urinary incontinence underwent robotic supracervical hysterectomy with sacrocolpopexy and transobturator sling placement at an outside hospital. Postoperatively, she had recurrent urinary tract infections; by 3 months postoperatively, fevers and leg and back pain had developed. She was given a diagnosis of L5-S1 spondylodiskitis. After 3.5 weeks of intravenous antibiotic therapy failed, further evaluation revealed a fistulous tract to the sacrum. She was transferred to our institution and underwent sacrocolpopexy mesh removal, L5-S1 debridement, antibiotic treatment, and physical therapy. One year after this repair surgery, she has returned to her usual activities with no current symptoms of infection, prolapse, urinary incontinence, or back pain. Vesicosacrofistulization is a serious complication of sacrocolpopexy that can result in diskitis and osteomyelitis. Prevention involves avoiding placing mesh on the bladder and at the L5-S1 disk space during open or minimally invasive sacrocolpopexy. A high index of suspicion for diskitis, even several months after surgery, should be maintained to expedite evaluation. If fistulization of pelvic structures to the sacrum is suspected, a multidisciplinary evaluation and treatment approach should be considered to optimize patient care. PMID- 24763163 TI - Systematic review highlights difficulty in clearly identifying dental neglect in children. PMID- 24763164 TI - Limited evidence suggests standard fluoride toothpaste reduces caries potential in preschool children. AB - DATA SOURCES: CENTRAL, Medline, Embase, Web of Science, LILACS and BBO databases, the Brazilian database of thesis and dissertations (Banco de Teses CAPES), a Brazilian register of ethically approved projects involving human beings (SISNEP) and two registers of ongoing trials (Current Controlled Trials and Clinical Trials.gov). Reference lists were also scanned for relevant papers. Study authors were contacted for additional information. STUDY SELECTION: Individual or cluster randomised or quasi-randomised controlled trials conducted in children under seven were included. DATA EXTRACTION AND SYNTHESIS: Study selection and data abstraction were conducted by two reviewers independently. Risk of bias assessment was undertaken using the Cochrane Collaboration tool. Meta-analyses of prevented fractions (PF) were performed to assess the effect of fluoride toothpaste on the dmft and dmfs. Meta-analyses were also performed to obtain a pooled relative risk (RR) to assess the effect of fluoride toothpastes on the proportion of children developing caries. RESULTS: Eight studies were included. When standard F toothpastes were compared to placebo or no intervention, significant caries reduction at surface (PF = 31%; 95% CI 18-43; 2644 participants in five studies), tooth (PF = 16%; 95% CI 8-25; 2555 participants in one study) and individual (RR = 0.86; 95% CI 0.81-0.93; 2806 participants in two studies) level were observed. Low F toothpastes were effective only at surface level (PF = 40%; 95% CI 5-75; 561 participants in two studies). CONCLUSIONS: Standard F toothpastes are effective in reducing dental caries in the primary teeth of preschool children and thus their use should be recommended to this age group. PMID- 24763165 TI - Triclosan produces statistically significant reduction in plaque, gingivitis and caries but not clinically important benefit. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and the US National Institutes of Health Trials Register. STUDY SELECTION: Randomised controlled trials (RCTs) of parallel or crossover design, (with a sufficient wash out period) of at least six months duration, and irrespective of language or publication status. DATA EXTRACTION AND SYNTHESIS: Study assessment and data extraction were carried out independently by at least two reviewers. Meta analysis was conducted using random-effects models when there were at least four studies (fixed-effect models when fewer than four studies), reporting mean differences (MD) for continuous data and risk ratios (RR) for dichotomous data. RESULTS: Thirty studies involving 14,835 patients were included. Ten studies were considered to be a low risk of bias, nine at high risk and the remaining 11 were assessed as at unclear risk. After six to seven months use of triclosan/copolymer toothpaste there was a statistically significant reduction in plaque in favour of triclosan/copolymer of 22% (20 studies, 2675 patients, moderate-quality evidence).There was also a statistically significant reduction in plaque severity of 41% (13 studies, 1850 patients, moderate-quality evidence). Triclosan/copolymer toothpaste also reduced gingival inflammation statistically significantly by 22% after six to nine months of use (20 studies, 2743 patients, moderate-quality evidence). After 36 months of use there was no evidence of a difference between triclosan/copolymer toothpaste and control in the development of periodontitis (attachment loss) (RR 0.92, 95% CI 0.67 to 1.27, one study, 480 patients, low-quality evidence). After 24 to 36 months of use, triclosan/copolymer toothpaste slightly reduced coronal caries by about 5% (four studies, 9692 patients, high-quality evidence). One study (1357 patients, moderate-quality evidence) suggested that after 36 months of use triclosan/copolymer toothpaste probably reduced root caries.After six months of use triclosan/copolymer toothpaste may have reduced the mean total calculus by about 15%. There were no data available for meta-analysis regarding adverse effects, but 22 studies (73%) reported that there were no adverse effects caused by either the experimental or control toothpaste.There was considerable heterogeneity present in the meta-analyses for plaque, gingivitis and calculus. Plaque and gingivitis showed such consistent results that it did not affect our conclusions, but the reader may wish to interpret the results with more caution. CONCLUSIONS: There was moderate-quality evidence showing that toothpastes containing triclosan/copolymer, in addition to fluoride, reduced plaque, gingival inflammation and gingival bleeding when compared with fluoride toothpastes without triclosan/copolymer. These reductions may or may not be clinically important, and are evident regardless of initial plaque and gingivitis levels, or whether a baseline oral prophylaxis had taken place or not.High-quality evidence showed that triclosan/copolymer toothpastes led to a small reduction in coronal caries. There was weaker evidence to show that triclosan/copolymer toothpastes may have reduced root caries and calculus, but insufficient evidence to show whether or not they prevented periodontitis. There do not appear to be any serious safety concerns regarding the use of triclosan/copolymer toothpastes in studies up to three years in duration. PMID- 24763166 TI - Some beneficial effect on root caries from use of higher concentration fluoride toothpaste (5000 ppm F). AB - DESIGN: Single-blind, multi-centre, parallel, randomised controlled trial. Intervention Adult patients (18-75 years) with 10 or more natural teeth, and one or more root caries lesion in a tooth not crowned or compromised were included. Patients were randomised to receive a high fluoride toothpaste, 1.1% sodium fluoride (5000 ppm F) or a regular toothpaste (1350 ppm F). Packaging was identical and standard brushes were also provided. Patients were strictly instructed to refrain from using toothpastes or toothbrushes other than the ones provided and restricted from using mouth rinses. OUTCOME MEASURE: The primary outcome measure was changes in the surface structure of the root caries lesions after the intervention. This was graded using a surface hardness score (HS) scale: Level 1: hard; Level 2: hard to leathery; Level 3: leathery; Level 4: leathery with local softening; Level 5: soft. Scores were recorded at baseline, three and six months. Examiners were masked to the group assignment. RESULTS: One hundred and thirty-five patients (test group: n = 67; control group: n = 68) with 318 identified root caries lesions were randomised. Five patients were lost to follow up, three in the test group and two in the control. The groups were similar at baseline. Overall there was no difference between the two groups for the overall HS (test group: HS = 3.4 +/- 0.61; control group: HS = 3.4 +/- 0.66; P = 0.8757, unpaired t-test). However the ANOVA revealed significantly better HS for the test group than for the control groups (T1: test group: HS = 2.9 +/- 0.67; control group: HS = 3.1 +/- 0.75; T2: test group: HS = 2.4 +/- 0.81; control group: HS = 2.8 +/- 0.79; P < 0.0001). CONCLUSIONS: The application of a high-fluoride containing dentifrice (5000 ppm F) in adults, twice daily, significantly improves the surface hardness of otherwise untreated root caries lesions when compared with the use of regular fluoride containing (1350 ppm F) toothpastes. ACKNOWLEDGEMENTS: The authors' institutions received per capita remunerations and the products used in this clinical trial, from Colgate Palmolive Company. Roger P. Ellwood and Michael Warncke are employees of the Colgate-Palmolive Company. PMID- 24763168 TI - Value of prophylactic antibiotics for invasive dental procedures unclear. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, the US National Institutes of Health Trials Register and the metaRegister of Controlled Trials. STUDY SELECTION: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) would be included where available. Due to the low incidence of bacterial endocarditis it was anticipated that few such trials would be found. Cohort and case-control studies were included where suitably matched control or comparison groups had been studied. DATA EXTRACTION AND SYNTHESIS: Two review authors independently selected studies for inclusion then assessed risk of bias and extracted data from the included study. RESULTS: Only one case controlled study met the inclusion criteria. It collected all the cases of endocarditis in the Netherlands over two years, finding a total of 24 people who developed endocarditis within 180 days of an invasive dental procedure, definitely requiring prophylaxis according to current guidelines, and who were at increased risk of endocarditis due to a pre-existing cardiac problem. This study included participants who died because of the endocarditis (using proxies). Controls attended local cardiology outpatient clinics for similar cardiac problems, had undergone an invasive dental procedure within the past 180 days, and were matched by age with the cases. No significant effect of penicillin prophylaxis on the incidence of endocarditis could be seen. No data were found on other outcomes. CONCLUSIONS: There remains no evidence that antibiotic prophylaxis is either effective or ineffective against bacterial endocarditis in people considered at risk who are about to undergo an invasive dental procedure. It is not clear whether the potential harms and costs of penicillin administration outweigh any beneficial effect. Ethically, practitioners need to discuss the potential benefits and harms of antibiotic prophylaxis with their patients before a decision is made about administration. PMID- 24763167 TI - Insufficient evidence to assess the effectiveness of antibiotics for irreversible pulpitis. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and the US National Institutes of Health Trials Register. STUDY SELECTION: Randomised controlled trials (RCTs) which compared pain relief with systemic antibiotics and analgesics, against placebo and analgesics in the acute preoperative phase of irreversible pulpitis. DATA EXTRACTION AND SYNTHESIS: Study selection, risk of bias assessment and data extraction were carried out independently by two reviewers. Pooling of data was not possible and a descriptive summary is presented. RESULTS: One trial assessed at low risk of bias, involving 40 participants, was included in this update of the review. The quality of the body of evidence was rated low for the different outcomes. There was a close parallel distribution of the pain ratings in both the intervention and placebo groups over the seven-day study period.There was insufficient evidence to claim or refute a benefit for penicillin for pain intensity. There was no significant difference in the mean total number of ibuprofen tablets taken over the study period: 9.2 (standard deviation (SD) 6.02) in the penicillin group versus 9.6 (SD 6.34) in the placebo group; mean difference -0.40 (95% confidence interval (CI) -4.23 to 3.43; P value = 0.84). This applied equally for the mean total number of Tylenol tablets: 6.9 (SD 6.87) used in the penicillin group versus 4.45 (SD 4.82) in the placebo group; mean difference 2.45 (95% CI -1.23 to 6.13; P value = 0.19). Our secondary outcome on reporting of adverse events was not addressed in this study. CONCLUSIONS: This systematic, review which was based on one low-powered small sample trial assessed as a low risk of bias, illustrates that there is insufficient evidence to determine whether antibiotics reduce pain or not compared to not having antibiotics. The results of this review confirm the necessity for further larger sample and methodologically sound trials that can provide additional evidence as to whether antibiotics, prescribed in the preoperative phase, can affect treatment outcomes for irreversible pulpitis. PMID- 24763169 TI - Barriers to providing dental care for older people. AB - DATA SOURCES: The Medline, Embase and CINAHL databases were searched together with the reference lists of selected publications. STUDY SELECTION: Studies published since January 1990 and published in English that looked at barriers, experienced by dentists, to delivering oral health care to people over the age of 65 were included. Study quality was assessed independently using criteria developed by the Dutch Cochrane Centre. DATA EXTRACTION AND SYNTHESIS: Study assessment and data extraction were carried out independently by two reviewers and a qualitative summary presented. RESULTS: Seven cross-sectional studies were included. The focus was primarily on dentists delivering oral health care to older people in care homes with only one focused on barriers experienced by dentists working in their own practice and delivering oral health care to community-dwelling older people. The most common barriers to delivering oral health care to older people were identified respectively as: the lack of adequate equipment in a care home and no area for treatment available (n = 4) and the lack of adequate reimbursement for working in a care home (n = 5). In addition, the inadequate training and experience in delivering oral health care to older care home residents (n = 2) were mentioned. Four publications indicated the loss of time from private practice as a barrier to delivering oral health care in a care home. CONCLUSIONS: Most articles retrieved described barriers experienced by dentists delivering oral health in care homes: much less is known about oral health care for community-dwelling older people. Therefore, we suggest that additional research should be initiated to investigate in more detail the barriers dentists experience in delivering oral health care to older people in their own dental practices. PMID- 24763170 TI - Limited evidence for main reason for failure of partially excavated and restored teeth. AB - DATA SOURCES: Medline, PubMed, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched between Jan 1967 and Dec 2012. No grey literature searches were carried out. STUDY SELECTION: Randomised and non randomised, controlled and uncontrolled, pro- and retrospective clinical studies (in English or German) that investigated one- or two-step incomplete dentinal caries removal (where caries was >1/2 dentine thickness) were eligible. Studies had to have teeth that were clinically and/or radiologically vital, primary or permanent teeth requiring a restoration but with no pulp exposure.The main outcomes were; clinical or radiological failure based on reported re-treatment. Failures were classified where possible into pulpal (pain, clinical or radiographic signs of pathology) and non-pulpal (tooth or restoration fracture, restoration loss or breach in integrity, secondary or progressing residual caries or non-pulpal failures). DATA EXTRACTION AND SYNTHESIS: Two authors independently reviewed the title and abstract of the articles (without blinding to authors or journals) and both extracted data, with discrepancies resolved through discussion or consultation with a third reviewer. Risk of bias was carried out using Cochrane collaboration guidelines and studies were assessed using GRADE criteria.Failure was calculated per year and annual failure rates weighted according to the number of teeth. Weighted annual failure rates were then used as the effect estimate for frequency and type of failure. Subgroup analyses were carried out, for factors influencing failure, in studies that compared teeth within one or more of the following groups: primary or permanent teeth; pulpal symptoms prior to treatment; single or multi-surface cavities; one- or two-step incomplete excavation; lining material; and restorative material. RESULTS: Twenty nine articles reporting 19 trials (12 randomised controlled trials, two controlled trials, five case series & retrospective studies), with a median follow up of 24 months (IQR; 12 to 48), were included. In 11 studies pulpal complications were the main reason for failure and only two studies found more non-pulpal than pulpal failures. Median annual failure rate was 3.8 (IQR; 1.4 to 4.4)From the sub-group analyses, there was significantly lower risk of failure for teeth with one- compared to those with two-step excavation (OR=0.21, 95%CI [0.08 to 0.55]) and for those with single compared with multi-surface lesions (OR=0.33, 95%CI [0.16 to 0.67]. Risk of bias scores varied widely and the quality of the studies was very low. CONCLUSIONS: Following incomplete removal of deep caries, pulpal failure (pain, clinical or radiographic signs of pathology) was the most common failure type. One-step incomplete excavation for deep caries lesions reduced the risk of failure compared to two-step removal and multi surface lesions had a higher risk of failure than single surface lesions. PMID- 24763171 TI - Early orthodontic treatment reduced incisal trauma in children with class II malocclusions. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase. STUDY SELECTION: Randomised controlled trials (RCTs) of orthodontic treatments (either one- or two-phase) with any type of orthodontic braces (removable, fixed, functional) or head-braces compared with late treatment with any type of orthodontic braces or head-braces; or, on any type of orthodontic braces or head braces compared with no treatment or another type of orthodontic brace or appliance to correct prominent upper front teeth. DATA EXTRACTION AND SYNTHESIS: Study selection, risk of bias assessment and data extraction were carried out independently by at least two reviewers. The primary measure of effect was over jet measured in millimetres or by any index of malocclusion. Odds ratios (ORs) and 95% confidence intervals (CIs) were used for dichotomous outcomes, mean differences (MDs) and 95% CIs for continuous outcomes and a fixed- effect model for meta-analyses as there were fewer than four studies. RESULTS: Seventeen studies involving 791 patients were included. The overall quality of the evidence was low with only two of the 17 studies being assessed as at low risk of bias. Three trials (n = 343) compared early (two-phase) treatment (7-11 years of age) with a functional appliance with adolescent (one-phase) treatment.Statistically significant differences in over jet, ANB and PAR scores were found in favour of functional appliance when the first phase of early treatment was compared with observation in the children due to receive treatment in adolescence. However, there was no evidence of a difference in the over jet between the groups at the end of treatment. A statistically significant reduction in the incidence of incisal trauma (OR 0.59, 95% CI 0.35 to 0.99, P = 0.04) in favour of two-phase treatment with functional appliance was seen. The incidence of incisal trauma was clinically significant with 29% (54/185) of patients reporting new trauma incidence in the adolescent (one-phase) treatment group compared to only 20% (34/172) of patients receiving early (two-phase) treatment.Two trials (n = 285) compared early (two-phase) treatment using headgear, with adolescent (one-phase) treatment. Statistically significant differences in over jet and ANB were found in favour of headgear when the first phase of early treatment was compared with observation in the children due to receive treatment in adolescence. However, there was no evidence of a difference in the over jet between the groups at the end of treatment. The incidence of incisal trauma was, however, statistically significantly reduced in the two-phase treatment group, the adolescent treatment group having twice the incidence of incisal trauma (47/120) compared to the young children group (27/117).Two trials (n = 282) compared different types of appliances (headgear and functional appliance) for early (two-phase) treatment. At the end of the first phase of treatment statistically significant differences, in favour of functional appliances, were shown with respect to final over jet only. At the end of phase two, there was no evidence of a difference between appliances with regard to over jet, PAR score or the incidence of incisal trauma.Late orthodontic treatment for adolescents with functional appliances showed a statistically significant reduction in over jet of -5.22 mm (95% CI 6.51 to -3.93, P < 0.00001) and ANB of -2.37 degrees (95% CI -3.01 to -1.74, P < 0.00001) when compared to no treatment (very low quality evidence).There was no evidence of a difference in over jet when Twin Block was compared to other appliances. However, a statistically significant reduction in ANB (-0.63 degrees , 95% CI -1.17 to -0.08, P = 0.02) was shown in favour of Twin Block. There was no evidence of a difference in any reported outcome when Twin Block was compared with modifications of Twin Block. CONCLUSIONS: The evidence suggests that providing early orthodontic treatment for children with prominent upper front teeth is more effective in reducing the incidence of incisal trauma than providing one course of orthodontic treatment when the child is in early adolescence. There appear to be no other advantages for providing treatment early when compared to treatment in adolescence. PMID- 24763172 TI - Weak evidence supports the short-term benefits of orthopaedic treatment for Class III malocclusion in children. AB - DATA SOURCES: Data sources The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase. STUDY SELECTION: Randomised controlled trials (RCTs) of orthodontic treatment to correct prominent lower front teeth were included. DATA EXTRACTION AND SYNTHESIS: Study screening, risk of bias assessment and data extraction were carried out independently by two reviewers. The mean differences with 95% confidence intervals were calculated for continuous data. Meta-analysis was undertaken when studies of similar comparisons reported comparable outcome measures. A fixed effect model was used. The l(2) statistic was used as a measure of statistical heterogeneity. RESULTS: Seven RCTs (339 patients) were included in this review. One study was assessed as at low risk of bias, three at high risk of bias and three at unclear risk. Four studies reported on the use of a facemask, two on the chin cup, one on the tandem traction bow appliance and one on mandibular headgear.One study reported on both the chin cup and mandibular headgear appliances. One study (n = 73, low quality evidence), comparing a facemask to no treatment, reported a mean difference (MD) in overjet of 4.10 mm (95% confidence interval (CI) 3.04 to 5.16; P value < 0.0001) favouring the facemask treatment.Three studies (n = 155, low quality evidence) reported ANB differences immediately after treatment with a facemask when compared to an untreated control. The pooled data showed a statistically significant MD in ANB in favour of the facemask of 3.93 degrees (95% CI 3.46 to 4.39; P value < 0.0001). There was significant heterogeneity between these studies (I2 = 82%). This is likely to have been caused by the different populations studied and the different ages at the time of treatment.One study (n = 73, low quality evidence) reported outcomes of the use of the facemask compared to an untreated control at three years follow up. This study showed that improvements in overjet and ANB were still present three years post-treatment. In this study, adverse effects were reported, but due to the low prevalence of temporomandibular (TMJ) signs and symptoms no analysis was undertaken.Two studies (n = 90, low quality evidence) compared the chin cup with an untreated control. Both studies found a statistically significant improvement in ANB, and one study also found an improvement in the Wits appraisal. Data from these two studies were not suitable for pooling.A single study of the tandem traction bow appliance compared to untreated control (n = 30, very low quality evidence) showed a statistically significant difference in both overjet and ANB favouring the intervention group. The remaining two studies did not report the primary outcome of this review. CONCLUSIONS: There is some evidence that the use of a facemask to correct prominent lower front teeth in children is effective when compared to no treatment on a short-term basis. However, in view of the general poor quality of the included studies, these results should be viewed with caution. Further randomised controlled trials with long follow-up are required. PMID- 24763173 TI - Limited evidence on treatments for distalising upper first molars in children and adolescents. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline and Embase. STUDY SELECTION: Randomised clinical trials (RCTs) involving the use of removable or fixed orthodontic appliances intended to distalise upper first molars in children and adolescents. DATA EXTRACTION AND SYNTHESIS: Study selection, risk of bias assessment and data extraction were carried out independently by at least two reviewers. For dichotomous outcomes the measure of treatment effect was the risk ratio; for continuous outcomes the measure of treatment effect was the mean difference. Data analysis followed Cochrane protocols. RESULTS: Results Ten studies (involving 354 patients) were included in this review. Study quality was generally poor; seven studies were assessed to be at high risk of bias and three of unclear risk of bias. Meta-analyses were conducted where appropriate. Four studies (159 patients) compared a distalising appliance to an untreated control. The degree and direction of molar movement and loss of anterior anchorage varied with the type of appliance. Four studies involving (150 patients) compared a distalising appliance versus headgear. The mean molar movement for intraoral distalising appliances was -2.20 mm and -1.04 mm for headgear.There was a statistically significant difference in mean distal molar movement (mean difference (MD) -1.45 mm; 95% confidence interval (CI) -2.74 to -0.15) favouring intraoral appliances compared to headgear. However, a statistically significant difference in mean mesial upper incisor movement (MD 1.82 mm; 95% CI 1.39 to 2.24) and overjet (fixed-effect: MD 1.64 mm; 95% CI 1.26 to 2.02; two studies, unclear risk of bias, 70 participants analysed) favoured headgear, ie there was less loss of anterior anchorage with headgear. Owing to variation in interventions, direct comparisons of intraoral appliances from three studies (93 patients), high or unclear risk of bias was reported narratively. All appliances were reported to provide some degree of distal movement, and loss of anterior anchorage varied with the type of appliance. No included studies reported on the incidence of adverse effects (harm, injury), number of attendances or rate of non compliance. CONCLUSIONS: It is suggested that intraoral appliances are more effective than headgear in distalising upper first molars. However, this effect is counteracted by loss of anterior anchorage, which was not found to occur with headgear when compared with intraoral distalising appliance in a small number of studies. The number of trials assessing the effects of orthodontic treatment for distilisation is low, and the current evidence is of low or very low quality. PMID- 24763174 TI - Limited evidence for non-pharmacological interventions for the relief of dry mouth. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, AMED, CINAHL and CANCERLIT databases were searched. The metaRegister of Controlled Clinical Trials and ClinicalTrials.gov were also searched to identify ongoing and completed trials. Reference lists of included studies and relevant reviews were also searched. There were no restrictions on the language of publication or publication status. STUDY SELECTION: Randomised controlled trials of non pharmacological treatments for patients with dry mouth at baseline. DATA EXTRACTION AND SYNTHESIS: Study assessment and data extraction were carried out independently by at least two reviewers. Mean difference (MD) and standardised mean differences (SMD) together with 95% CIs were calculated where appropriate. RESULTS: Nine studies (366 participants) were included in this review, eight were assessed at high risk of bias and one at unclear risk of bias. Five small studies (153 participants), with dry mouth following radiotherapy treatment compared acupuncture with placebo. Four were at high risk and one at unclear risk of bias. Two trials reported outcome data for dry mouth in a form suitable for meta- analysis. The pooled estimate of these two trials (70 participants, low quality evidence) showed no difference between acupuncture and control in dry mouth symptoms (SMD -0.34, 95% CI -0.81 to 0.14, P value 0.17, I2 = 39%) with the confidence intervals including both a possible reduction or a possible increase in dry mouth symptoms.Acupuncture was associated with more adverse effects (tiny bruises and tiredness which were mild and temporary). There was a very small increase in unstimulated whole saliva (UWS) at the end of four to six weeks of treatment (three trials, 71 participants, low quality evidence) (MD 0.02 ml/minute, 95% CI 0 to 0.04, P value 0.04, I2 = 57%), and this benefit persisted at the 12-month follow-up evaluation (two trials, 54 participants, low quality evidence) (UWS, MD 0.06 ml/minute, 95% CI 0.01 to 0.11, P value 0.03, I2 = 10%). For the outcome of stimulated whole saliva (SWS, three trials, 71 participants, low quality evidence) there was a benefit favouring acupuncture (MD 0.19 ml/minute, 95% CI 0.07 to 0.31, P value 0.002, I2 = 1%) an effect which also persisted at the 12-month follow-up evaluation (SWS MD 0.28 ml/minute, 95% CI 0.09 to 0.47, P value 0.004, I2 = 0%) (two trials, 54 participants, low quality evidence).Two small studies, both at high risk of bias, compared the use of an electrostimulation device with a placebo device in participants with Sjogren's Syndrome (total 101 participants). A further study, also at high risk of bias, compared acupuncture-like electrostimulation. None of these studies reported the outcome of dry mouth.A single study at high risk of bias compared the stimulatory effect of powered versus manual toothbrushing and found no difference for the outcomes of UWS or SWS. CONCLUSIONS: There is low quality evidence that acupuncture is no different from placebo acupuncture with regard to dry mouth symptoms, which is the most important outcome. This may be because there were insufficient participants included in the two trials to show a possible effect or it may be that there was some benefit due to 'placebo' acupuncture, which could have biased the effect to the null. There is insufficient evidence to determine the effects of electrostimulation devices on dry mouth symptoms. It is well known that dry mouth symptoms may be problematic even when saliva production is increased, yet only two of the trials that evaluated acupuncture reported dry mouth symptoms, a worrying reporting bias. There is some low quality evidence that acupuncture results in a small increase in saliva production in patients with dry mouth following radiotherapy.There is insufficient evidence to determine the effects of electrostimulation devices on dry mouth symptoms or saliva production in patients with Sjogren's Syndrome. Reported adverse effects of acupuncture are mild and of short duration, and there were no reported adverse effects from electrostimulation. PMID- 24763175 TI - Radiotherapy associated with higher rates of dental implant loss. AB - DATA SOURCES: Cochrane Oral Health Group's Trials Register, CENTRAL, Medline via PubMed and EMBASE; no restrictions on language, published before February 1st 2013. STUDY SELECTION: Observational studies reporting outcomes from irradiated and non-irradiated patients were eligible for inclusion as were randomised controlled trials (RCTs) and controlled clinical trials (CCTs) assessing irradiated patients submitted to different implant-based treatment protocols. DATA EXTRACTION AND SYNTHESIS: Screening of titles, abstracts and full texts was by two reviewers, with disagreements resolved through discussion, consensus, or failing this by consultation with a third reviewer. Data extraction was in duplicate and attempts were made to contact authors for missing data. Risk of bias was assessed using adapted versions of the Cochrane Collaboration's tool (for RCTs and CCTs) and the Newcastle-Ottawa scale for observational studies. RESULTS: Fifteen trials with 10,150 implants were included with 1,689 (14.3%) placed in irradiated mouths. There were 13 case series and two RCTs. three of the studies were on hyperbaric oxygen (HBO) therapy. Neither of the RCTs was rated as low risk of bias. Mean survival rates ranged from 46.3% to 98% with pooled estimates showing that implant failure was statistically significantly higher in irradiated patients compared to patients who had not undergone radiotherapy (an increase of 174%) with a risk ratio of 2.74 (95% confidence interval {CI}: 1.86, 4.05; p<0.00001). In maxillary sites, the risk ratio was 5.96 (95% CI:2.71, 13.12;p<0.00001) with the risk of loss increasing to 496%. Hyperbaric oxygen therapy did not reduce the risk of implant failure showing a risk ratio of 1.28 (95% CI:0.19, 8.82). CONCLUSIONS: Irradiation of the head was linked to increased failure rate of implants compared to failure rates in patients who had not undergone radiotherapy. The failure rate was higher in the maxilla and HBO therapy did not improve implant survival. PMID- 24763181 TI - Chip-based ingroove microplasma with orthogonal signal collection: new approach for carbon-containing species detection through open air reaction for performance enhancement. AB - A novel microplasma generator based on ceramic chips has been developed and coupled with optical emission spectrometry through orthogonal detection. Stable microplasma was generated between two electrodes in the ingroove discharge chamber and the optical fiber was set in perpendicular to the gas outlet to collect emitted light. The emission signal of CN is surprisingly enhanced by reacting carbon-containing species with back-diffusion nitrogen from open air, and the enhanced CN signal is successfully applied to sensitively detect organic compounds for the first time. This article focuses to study the structural characteristic and the signal enhancement mechanism through back-diffusion reaction. Several organic compounds were detected directly with the limits of detection down to ppb level. Besides, the advantages of low energy consumption and the chip-based discharge chamber show great potential to be applied in portable devices. This development may lead to a new way for the sensitive detection of organic compounds. PMID- 24763182 TI - Serum activin A and follistatin levels in gestational diabetes and the association of the Activin A-Follistatin system with anthropometric parameters in offspring. AB - CONTEXT: The Activin A-Follistatin system has emerged as an important regulator of lipid and glucose metabolism with possible repercussions on fetal growth. OBJECTIVE: To analyze circulating activin A, follistatin and follistatin-like-3 (FSTL3) levels and their relationship with glucose metabolism in pregnant women and their influence on fetal growth and neonatal adiposity. DESIGN AND METHODS: A prospective cohort was studied comprising 207 pregnant women, 129 with normal glucose tolerance (NGT) and 78 with gestational diabetes mellitus (GDM) and their offspring. Activin A, follistatin and FSTL3 levels were measured in maternal serum collected in the early third trimester of pregnancy. Serial fetal ultrasounds were performed during the third trimester to evaluate fetal growth. Neonatal anthropometry was measured to assess neonatal adiposity. RESULTS: Serum follistatin levels were significantly lower in GDM than in NGT pregnant women (8.21+/-2.32 ng/mL vs 9.22+/-3.41, P = 0.012) whereas serum FSTL3 and activin A levels were comparable between the two groups. Serum follistatin concentrations were negatively correlated with HOMA-IR and positively with ultrasound growth parameters such as fractional thigh volume estimation in the middle of the third trimester and percent fat mass at birth. Also, in the stepwise multiple linear regression analysis serum follistatin levels were negatively associated with HOMA IR (beta = -0.199, P = 0.008) and the diagnosis of gestational diabetes (beta = 0.138, P = 0.049). Likewise, fractional thigh volume estimation in the middle of third trimester and percent fat mass at birth were positively determined by serum follistatin levels (beta = 0.214, P = 0.005 and beta = 0.231, P = 0.002, respectively). CONCLUSIONS: Circulating follistatin levels are reduced in GDM compared with NGT pregnant women and they are positively associated with fetal growth and neonatal adiposity. These data suggest a role of the Activin Follistatin system in maternal and fetal metabolism during pregnancy. PMID- 24763183 TI - Catechol-O-methyltransferase Val158-Met polymorphism and a response of hyperactive-impulsive symptoms to methylphenidate: A replication study from South Korea. AB - We investigated the association between the catechol-O-methyltransferase (COMT) Val(158)-Met (rs4680) genotype and both subjective and objective treatment responses to methylphenidate in Korean children with attention deficit/hyperactivity disorder (ADHD). We enrolled 120 medication-naive children with ADHD in an open-label, 8-week trial of methylphenidate. The participants were genotyped and evaluated using the Clinical Global Impression Scale and the ADHD Rating Scale-IV (ADHD-RS), and completed the Continuous Performance Test (CPT) before and after treatment. We found a significant association between the COMT Val/Val genotype and a good response, in terms of hyperactive-impulsive scores on the ADHD-RS (odds ratio (OR) = 2.61; p = 0.044) and response-time variability on the CPT (OR = 2.66; p = 0.028). The association of the COMT Val/Val genotype with a good response, in terms of response time variability, was significant in both the sub-sample of combined-type (OR = 3.45; p = 0.026) and sub-sample of inattentive-type (OR = 5.52; p = 0.029); but the association with a good response in terms of hyperactive-impulsive scores was not significant in sub sample analyses. Although the reported nominally significant associations did not stay significant after correcting for multiple testing, our results support previous findings about the possible involvement of the COMT (Val(158)-Met) polymorphism in the treatment response to methylphenidate in children with ADHD. PMID- 24763186 TI - Description of a teaching method for research education for palliative care healthcare professionals. AB - OBJECTIVE: Despite the rapidly growing availability of palliative care services, there is still much to be done in order to better support clinicians who are starting research programs. Among the barriers identified in the literature, methodological issues and lack of research training programs are often reported. Our aim was to describe an educational research method for healthcare professionals working in palliative care and to report the result of a survey conducted among a three-year sample of students. METHOD: The course was provided for a multidisciplinary group and was open to all healthcare professionals involved in palliative care. It took place over a single session during a full day. We used a 20-question e-survey to assess student outcomes (e.g., satisfaction, current status of their project). RESULTS: We received answers from 83 of the 119 students (70%) who took the course. The majority were physicians (n = 62, 75%), followed by nurses (n = 17, 21%). During the class, students assessed the role of the teacher as an information provider (n = 51, 61%), role model (n = 36, 43%), and facilitator (n = 33, 40%), and considered all of these roles as suitable, with a score of 3.9-4.7 out of 5. Participants reported a high level of support from the teacher, with a mean score of 8.2 (SD, 1.7) out of 10, and good overall satisfaction with a mean score of 7.6 (1.8). Finally, 51 participants (77%) were able to start their research project after the class, 27 (41%) to complete it, and 8 (12%) to submit their research to a journal or conference. SIGNIFICANCE OF RESULTS: Our results suggest that newer teaching methods such as roleplay, group work, and target acquisition are feasible and effective in a palliative research curriculum. Additional studies are needed to confirm the objective outputs of educational interventions, including research outputs. PMID- 24763184 TI - Effects of 7.5% carbon dioxide inhalation on anxiety and mood in cigarette smokers. AB - Cigarette smoking is associated with elevated risk of anxiety and mood disorder. Using the 7.5% carbon dioxide (CO2) inhalation model of anxiety induction, we examined the effects of smoking status and abstinence from smoking on anxiety responses. Physiological and subjective responses to CO2 and medical air were compared in smokers and non-smokers (Experiment One) and in overnight abstinent and non-abstinent smokers (Experiment Two). CO2 induced greater increases in blood pressure in non-smokers compared with smokers (ps < 0.043), and greater increases in anxiety (p = 0.005) and negative affect (p = 0.054) in non-abstinent compared with abstinent smokers. CO2 increased physiological and subjective indices of anxiety. There were differences across smoking groups indicating that the CO2 inhalation model is a useful tool for examining the relationship between smoking and anxiety. The findings suggested that both acute smoking and acute abstinence may protect against anxious responding. Further investigation is needed in long-term heavy smokers. PMID- 24763185 TI - Community-associated methicillin-resistant Staphylococcus aureus transmission in households of infected cases: a pooled analysis of primary data from three studies across international settings. AB - Diverse strain types of methicillin-resistant Staphylococcus aureus (MRSA) cause infections in community settings worldwide. To examine heterogeneity of spread within households and to identify common risk factors for household transmission across settings, primary data from studies conducted in New York (USA), Breda (The Netherlands), and Melbourne (Australia) were pooled. Following MRSA infection of the index patient, household members completed questionnaires and provided nasal swabs. Swabs positive for S. aureus were genotyped by spa sequencing. Poisson regression with robust error variance was used to estimate prevalence odds ratios for transmission of the clinical isolate to non-index household members. Great diversity of strain types existed across studies. Despite differences between studies, the index patient being colonized with the clinical isolate at the home visit (P < 0.01) and the percent of household members aged <18 years (P < 0.01) were independently associated with transmission. Targeted decolonization strategies could be used across geographical settings to limit household MRSA transmission. PMID- 24763187 TI - Reproducibility of the Veterans Physical Activity Questionnaire in an elderly population. AB - BACKGROUND: Quantifying lifetime physical activity using self-reported measures is challenging due to reliance on recall, especially in older populations. The purpose of this study was to determine the 1-year reproducibility of the Veterans Physical Activity Questionnaire (VAPAQ) in a cohort of patients with documented abdominal aortic aneurysm disease (AAA). METHODS: Subjects included men (n = 52) and women (n = 3) enrolled in AAA STOP, a randomized trial designed to test the ability of supervised exercise training to modify AAA biology and early disease progression. RESULTS: The overall correlation coefficient for lifetime recreational energy expenditure between the 2 examinations was 0.93 (P < .001), with an overall difference of 26 kcal/week, a typical error (standard deviation of the differences) of 171 kcals/week, and a coefficient of variation (CV) of 15.5%. CONCLUSIONS: The VAPAQ is a reproducible tool to quantify lifetime energy expenditure in older adults with documented vascular disease. PMID- 24763188 TI - Exon 11 skipping of SCN10A coding for voltage-gated sodium channels in dorsal root ganglia. AB - The voltage-gated sodium channel Na(V)1.8 (encoded by SCN10A) is predominantly expressed in dorsal root ganglia(DRG) and plays a critical role in pain perception. We analyzed SCN10A transcripts isolated from human DRGs using deep sequencing and found a novel splice variant lacking exon 11, which codes for 98 amino acids of the domain I/II linker. Quantitative PCR analysis revealed an abundance of this variant of up to 5-10% in human, while no such variants were detected in mouse or rat. Since no obvious functional differences between channels with and without the exon-11 sequence were detected, it is suggested that SCN10A exon 11 skipping in humans is a tolerated event. PMID- 24763189 TI - New insights in carbohydrate-deficient transferrin analysis with capillary electrophoresis-mass spectrometry. AB - Capillary zone electrophoresis (CZE) with UV detection has been widely used for the determination of carbohydrate-deficient transferrin (CDT), an indirect marker of the chronic alcohol consumption (>=60-80g/day). A commercially available method (CEofixTM CDT kit), containing a bilayer anionic coating, allows for the analysis of CDT with a high resolution between transferrin (Tf) glycoforms with reduced protein adsorption onto the capillary wall. Although widely used in routine analysis, this procedure presents some limitations in terms of selectivity and sensitivity which may be overcome with mass spectrometry (MS). However, the available method is not MS-compatible due to the non-volatile coating as well as the phosphate and borate buffers present in the background electrolyte (BGE). This study firstly consisted in developing MS-compatible separation conditions, i.e., coating and BGE compositions. Numerous cationic, neutral, and anionic coatings were evaluated in combination with BGEs covering a broad range of pH values. A bilayer coating composed of a cationic layer of 10% polybrene (m/v) and an anionic layer of 10% dextran sulfate (m/v) combined with a BGE composed of 20mM ammonium acetate at pH 8.5 provided the best results in terms of glycoforms' resolution, efficiency, adsorption reduction, migration times' repeatability, and coating stability. The method was then transferred to CZE-MS after investigations of the electrospray ionization (ESI) source, equipped with a sheath-flow interface, and the time-of-flight (TOF/MS) parameters. A successful MS detection of tetrasialo-Tf was obtained during infusion, while the experiments highlighted the challenges and issues encountered with intact glycoprotein analysis by CZE-ESI-MS. PMID- 24763190 TI - Effects of statins-use for patients with aneurysmal subarachnoid hemorrhage: a meta-analysis of randomized controlled trials. AB - Aneurysmal subarachnoid hemorrhage (aSAH)-induced cerebral vasospasm and delayed ischemic neurological deficit (DIND) are the major causes of morbidity and mortality in patients with aSAH. The effects of statins-use for patients with aSAH remain controversial. Here,a total of 249 patients from six randomized controlled trials(RCTs) were subjected to meta-analysis. No significant decrease was found in the incidence of vasospasm(RR, 0.80; 95% CI, 0.54-1.17), with substantial heterogeneity (I(2) = 49%, P = 0.08), which was verified by the further sensitivity analysis and subgroup meta-analysis. Furthermore, no significant difference was presented in the incidence of poor neurological outcome(RR, 0.94; 95% CI, 0.77-1.16), and potential side effects(RR, 2.49; 95% CI, 0.75-8.33). Nevertheless, significant difference was reported in the occurrence of DIND(RR, 0.58; 95% CI, 0.37-0.92) and mortality(RR, 0.30; 95% CI, 0.14-0.64). At present, although statins-use in the patients with aSAH should not be considered standard care at present, statins-use may have the potential effects in the prevention of mortality in patients with aSAH. PMID- 24763191 TI - Odorant and gustatory receptors in the tsetse fly Glossina morsitans morsitans. AB - Tsetse flies use olfactory and gustatory responses, through odorant and gustatory receptors (ORs and GRs), to interact with their environment. Glossina morsitans morsitans genome ORs and GRs were annotated using homologs of these genes in Drosophila melanogaster and an ab initio approach based on OR and GR specific motifs in G. m. morsitans gene models coupled to gene ontology (GO). Phylogenetic relationships among the ORs or GRs and the homologs were determined using Maximum Likelihood estimates. Relative expression levels among the G. m. morsitans ORs or GRs were established using RNA-seq data derived from adult female fly. Overall, 46 and 14 putative G. m. morsitans ORs and GRs respectively were recovered. These were reduced by 12 and 59 ORs and GRs respectively compared to D. melanogaster. Six of the ORs were homologous to a single D. melanogaster OR (DmOr67d) associated with mating deterrence in females. Sweet taste GRs, present in all the other Diptera, were not recovered in G. m. morsitans. The GRs associated with detection of CO2 were conserved in G. m. morsitans relative to D. melanogaster. RNA-sequence data analysis revealed expression of GmmOR15 locus represented over 90% of expression profiles for the ORs. The G. m. morsitans ORs or GRs were phylogenetically closer to those in D. melanogaster than to other insects assessed. We found the chemoreceptor repertoire in G. m. morsitans smaller than other Diptera, and we postulate that this may be related to the restricted diet of blood-meal for both sexes of tsetse flies. However, the clade of some specific receptors has been expanded, indicative of their potential importance in chemoreception in the tsetse. PMID- 24763192 TI - Characteristics of corn stover pretreated with liquid hot water and fed-batch semi-simultaneous saccharification and fermentation for bioethanol production. AB - Corn stover is a promising feedstock for bioethanol production because of its abundant availability in China. To obtain higher ethanol concentration and higher ethanol yield, liquid hot water (LHW) pretreatment and fed-batch semi simultaneous saccharification and fermentation (S-SSF) were used to enhance the enzymatic digestibility of corn stover and improve bioconversion of cellulose to ethanol. The results show that solid residues from LHW pretreatment of corn stover can be effectively converted into ethanol at severity factors ranging from 3.95 to 4.54, and the highest amount of xylan removed was approximately 89%. The ethanol concentrations of 38.4 g/L and 39.4 g/L as well as ethanol yields of 78.6% and 79.7% at severity factors of 3.95 and 4.54, respectively, were obtained by fed-batch S-SSF in an optimum conditions (initial substrate consistency of 10%, and 6.1% solid residues added into system at the prehydrolysis time of 6 h). The changes in surface morphological structure, specific surface area, pore volume and diameter of corn stover subjected to LHW process were also analyzed for interpreting the possible improvement mechanism. PMID- 24763193 TI - Middle East respiratory syndrome coronavirus disease in children. AB - BACKGROUND: In the initial description of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, many affected patients were adults with underlying medical comorbidities. Data on the clinical presentation and outcome of pediatric cases are lacking. We report the clinical presentation and outcome of MERS-CoV infection in 11 pediatric patients. METHODS: The clinical presentation, demographic and laboratory data of pediatric patients with MERS-CoV were analyzed. RESULTS: A total of 11 pediatric cases that tested positive by screening and confirmatory polymerase chain reaction for MERS-CoV were reported from Saudi Arabia. Two patients were symptomatic and the other 9 cases were asymptomatic. The median age of patients was 13 (range 2-16) years. There were 8 females and 3 males (2.7:1 ratio). One symptomatic patient died and the other symptomatic patient recovered. The diagnosis of patients was based on positive nasopharyngeal swabs on 10 patients. CONCLUSIONS: MERS-CoV disease is not limited to adults. Most cases of childhood MERS-CoV infection were asymptomatic and tested positive during contact investigation of older patients. Severe disease can occur in children with underlying conditions. PMID- 24763194 TI - Ferroic properties in bi-component perovskites: artificial superlattices and naturally forming compounds. AB - The use of four different metal cations in a bi-component perovskite ABO3 structure with 50 : 50 substitution at A sublattice as well as B sublattice, opens up the door for materials designing, with the aim to improve ferroic properties. This can be achieved following two different routes; one using the concept of artificially grown superlattices with alternating layers of ABO3 and A'B'O3 perovskites in a periodic set-up and another, through synthesis of naturally grown bulk double perovskites with ordered arrangement of A and A' cations, simultaneously with that of B and B' cations. The tremendous progress in layered deposition techniques as well as advances in solid state chemistry methods, has made both routes equally plausible and an area of much activity. This review summarizes some of the recent progress in this field, with a special emphasis on two computational studies, (i) one on ultra-thin 1-1 superlattices built out of paraelectric and ferroelectric components, showing tunable piezoelectric properties, and (ii) another on CrOs-based double perovskites which show multiferroic behavior, achieved through layered ordering of A and A' cations. PMID- 24763195 TI - Agent-based modeling of oxygen-responsive transcription factors in Escherichia coli. AB - In the presence of oxygen (O2) the model bacterium Escherichia coli is able to conserve energy by aerobic respiration. Two major terminal oxidases are involved in this process - Cyo has a relatively low affinity for O2 but is able to pump protons and hence is energetically efficient; Cyd has a high affinity for O2 but does not pump protons. When E. coli encounters environments with different O2 availabilities, the expression of the genes encoding the alternative terminal oxidases, the cydAB and cyoABCDE operons, are regulated by two O2-responsive transcription factors, ArcA (an indirect O2 sensor) and FNR (a direct O2 sensor). It has been suggested that O2-consumption by the terminal oxidases located at the cytoplasmic membrane significantly affects the activities of ArcA and FNR in the bacterial nucleoid. In this study, an agent-based modeling approach has been taken to spatially simulate the uptake and consumption of O2 by E. coli and the consequent modulation of ArcA and FNR activities based on experimental data obtained from highly controlled chemostat cultures. The molecules of O2, transcription factors and terminal oxidases are treated as individual agents and their behaviors and interactions are imitated in a simulated 3-D E. coli cell. The model implies that there are two barriers that dampen the response of FNR to O2, i.e. consumption of O2 at the membrane by the terminal oxidases and reaction of O2 with cytoplasmic FNR. Analysis of FNR variants suggested that the monomer dimer transition is the key step in FNR-mediated repression of gene expression. PMID- 24763198 TI - Automated high-throughput quantification of mitotic spindle positioning from DIC movies of Caenorhabditis embryos. AB - The mitotic spindle is a microtubule-based structure that elongates to accurately segregate chromosomes during anaphase. Its position within the cell also dictates the future cell cleavage plan, thereby determining daughter cell orientation within a tissue or cell fate adoption for polarized cells. Therefore, the mitotic spindle ensures at the same time proper cell division and developmental precision. Consequently, spindle dynamics is the matter of intensive research. Among the different cellular models that have been explored, the one-cell stage C. elegans embryo has been an essential and powerful system to dissect the molecular and biophysical basis of spindle elongation and positioning. Indeed, in this large and transparent cell, spindle poles (or centrosomes) can be easily detected from simple DIC microscopy by human eyes. To perform quantitative and high-throughput analysis of spindle motion, we developed a computer program ACT for Automated-Centrosome-Tracking from DIC movies of C. elegans embryos. We therefore offer an alternative to the image acquisition and processing of transgenic lines expressing fluorescent spindle markers. Consequently, experiments on large sets of cells can be performed with a simple setup using inexpensive microscopes. Moreover, analysis of any mutant or wild-type backgrounds is accessible because laborious rounds of crosses with transgenic lines become unnecessary. Last, our program allows spindle detection in other nematode species, offering the same quality of DIC images but for which techniques of transgenesis are not accessible. Thus, our program also opens the way towards a quantitative evolutionary approach of spindle dynamics. Overall, our computer program is a unique macro for the image- and movie-processing platform ImageJ. It is user-friendly and freely available under an open-source licence. ACT allows batch-wise analysis of large sets of mitosis events. Within 2 minutes, a single movie is processed and the accuracy of the automated tracking matches the precision of the human eye. PMID- 24763197 TI - Oleuropein prevents the progression of steatohepatitis to hepatic fibrosis induced by a high-fat diet in mice. AB - Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased levels of triglycerides in the liver. The purposes of this study were to establish a mouse model of NASH by feeding mice a 60% high-fat diet (HFD) and to demonstrate the anti-fibrotic effects of oleuropein, which has been shown to have anti-oxidant and anti-inflammatory properties, in this HFD induced mouse model of NASH. C57BL/6 mice were divided into three groups: a regular diet group (Chow), a HFD group and an oleuropein-supplemented HFD group (OSD), which was fed a 0.05% OSD for 6 months. The effects of oleuropein in this model were evaluated using biochemical, histological and molecular markers. The expression levels of alpha-smooth muscle actin (alpha-SMA)and collagen type I in the HFD and OSD groups were evaluated using real-time PCR and western blotting. The body weight, biochemical marker levels, nonalcoholic fatty liver disease activity score, homeostasis model of assessment-insulin resistance (HOMA-IR) and leptin levels observed in the HFD group at 9 and 12 months were higher than those observed in the Chow group. The HOMA-IR and leptin levels in the OSD group were decreased compared with the HFD group. In addition, alpha-SMA and collagen type I expression were decreased by oleuropein treatment. We established a NASH model induced by HFD and demonstrated that this model exhibits the histopathological features of NASH progressing to fibrosis. Our results suggest that oleuropein may be pharmacologically useful in preventing the progression of steatohepatitis and fibrosis and may be a promising agent for the treatment of NASH in humans. PMID- 24763199 TI - A study of dietary habits and eating-out behavior of college students in Cheongju area. AB - To find out the effects of the general characteristic on dietary habits and eating out behavior of college students in Cheongju area. The ratios of major were 50.3% (80/159) for food and nutrition and 49.7% (79/159) for the others. The most of respondents missed breakfast and the most reason for skipping meal was no time. Older and younger group were different significantly in skipping meal, reason of meal skip, place of lunch, cost of lunch, and preferred lunch menu (P< 0.05, P< 0.01). Continuous instructions should be made on the problems of dietary habits or eating-out behaviors in the results of this study through education, and by seeking for alternatives from different angles such as various nutrition education and nutrition improvement programs. PMID- 24763200 TI - Perceptual effects of Yangsaeng on middle aged Koreans. AB - This study was conducted on Korean middle age adults during a stage of their physical, psychological, and social transition in society. The primary objective of this research is to ascertain participants' Yangsaeng levels, as well as determining the effects of factors related to health perceptions. In addition, this empirical research study provides basic data to develop and diffuse how the Yangsaeng program can be applied to a method of health care management. The questionnaire was distributed to Korean middle aged men and women between the ages of 40-65 years old. In the end, a total of 465 participants were analyzed using SPSS/WIN 19.0. The majority of the participants' responses identified four major influential factors on health perception; 'morality Yangsaeng', 'exercise Yangsaeng', 'diet Yangsaeng' and 'sexual life Yangsaeng'. Notably, in consideration of the effects that Yangsaeng has upon the lifestyle of health perception, there is no influential factor in the fashion seeking ('diet Yangsaeng') group. Nevertheless, there is evidence of influential factors affecting 'exercise Yangsaeng' and 'sexual life Yangsaeng' in the health inclination group, as well as additional influential factors affecting 'morality Yangsaeng' and 'sexual Yangsaeng' in the societal group. PMID- 24763201 TI - Comparative study on the attitudes of female seniors and female university students toward seniors. AB - This study compared the relating factors on the attitude for elderly between elderly women group and female university student group. The elderly woman group had higher scores in perceived health status, self integrity, self-efficacy, social support, attitude for elderly than female university students group. These differences were statistically significant. The relating factor on the attitude for elderly was self integrity in elderly women group significantly. Variables that significantly affected the attitude towards seniors were not found in the female university student group. PMID- 24763202 TI - 2nd dimensional GC-MS analysis of sweat volatile organic compounds prepared by solid phase micro-extraction. AB - The characteristics of an individual's odor from sweat, breath and skin provide important information for criminal tracking in field of forensic science. Solid phase micro-extraction gas chromatography/mass spectrometry (SPME-GC/MS) was used to determine human sweat volatile organic compounds (VOCs) profiles. The mass spectrometric analysis (with electron impact mode) followed by 2nd dimensional separation with two different GC columns (one polar and one relatively nonpolar) connected in parallel were used to identify the 574 compounds from sweat samples. The components included alcohols, aldehydes, aliphatics/aromatics, carboxylic acids, esters, ketones, and other organic compounds (amides/amines, thio/thioesters, oxide, sulfides, nitro compounds). Of these compounds, 1 tridecanol, 1,3-bis(1,1-dimethyl ethyl)-benzene, 4,4'-(1-methylethylidene) bis phenol and 7-acetyl-6-ethyl-1,1,4,4,-tetramethyl-tetraline were common components in all donor's sweat volatile samples. Age-related specific compounds were also detected. The results suggest that characteristic volatile profiles of human sweat emanations could provide the valuable information to forensic scientists. PMID- 24763203 TI - Percutaneous cementation: a case of a failed treatment of a loose revision total knee arthroplasty. AB - BACKGROUND: Total joint replacements provide many benefits to patients but expose them to a variety of possible complications. Revision surgery is demanding and associated to a greater number of risks and possible complications than primary joint replacement. OBJECTIVE: We describe the unsuccessful technique of percutaneous cementing in a loosened revision total knee arthroplasty. METHODS: We report on a 66-year old male patient, admitted to our clinic with a painful left knee, four months after percutaneous cementation without implant exchange of the loosened rotating hinge implant was performed. RESULTS: Although less demanding, for the surgeon and the patient, it resulted in a delayed revision surgery. This attempt at avoiding revision surgery could have led to even further complications. CONCLUSIONS: This case emphasizes the need to avoid novel techniques on patients, with no previous studies and to refer these patients to specialized joint replacement centers for revision surgery. PMID- 24763204 TI - Factors influencing clinical cancer stage in women patients with rectal cancer. AB - Rectal cancer is the most frequent cancer in Korea. Until effective systemic therapy is available for rectal cancer, development of new treatment strategies depends on knowledge of the end results achieved for carefully staged groups of patients in the rectal cancer population. This study was performed to identify the factors influencing on clinical cancer stage in women patients with rectal cancer. The subjects of this study were 227 patients who had been visited a general hospital which located in the area of Metropolitan. Data collect was surveyed using questionnaires from January 21, 2013 to February 21, 2013. Major findings are as followings. First, according to this result, a strong positive correlation was shown between women's age at first marriage and education (r=0.45, p< 0.01). Second, in multiple regression, women's age, previous cancer screening, stress, and age of menopause were significant predictors of rectal cancer stage. The explanatory of R^{2} on rectal cancer stage accounted for 36.2% of these correlation. Based on the results obtained by the study, it needs to develop more systemical program and consistent policies of individual and organization for rectal cancer prevention. PMID- 24763205 TI - Nonlinearities in personalization-privacy paradox in mHealth adoption: the mediating role of perceived usefulness and attitude. AB - BACKGROUND AND OBJECTIVE: Personalization in healthcare refers to individualizing services and products based on patients' health conditions and interests. In order to deliver highly personalized offerings, mHealth providers need to use patients' health information, which provokes patients' concerns over personal health information leakage. So the personalization-privacy paradox is an important issue in the mHealth context. To gain a better understanding of this paradox, we take the personalization and privacy paradox factors as independent variables, incorporating the nonlinear relationships between personalization and privacy, and take attitude and perceived usefulness as middle variables to study mHealth adoption. METHODS: The hypothesized model is tested through an empirical research of a 489-respondent sample in China. PLS is used for data analysis. KEY FINDINGS: (1) Personalization and privacy are found to influence mHealth adoption intention via attitude and perceived usefulness; (2) there is a substitution relationship, also called negative synergy between personalization and privacy in mHealth contexts; (3) attitude mediates the effect of perceived usefulness on intention, indicating a significant role of attitude. PMID- 24763206 TI - Inertia in health care organizations: A case study of peritoneal dialysis services. AB - BACKGROUND: Change is difficult for health care organizations where adoption of new practices is notoriously slow. Inertial behavior may reflect organizations' rational, strategic nonresponse to its environment or latent, institutionalizing preservation of dominant organizational routines and norms. Such strategic and selective influences of organizational inertia have different implications on the efficacy of policy to induce intended change. PURPOSE: The aim of this study was to examine whether strategic and selective factors were associated with the provision of peritoneal dialysis (PD) services in outpatient dialysis facilities in the United States between 1995 and 2003. APPROACH: We conducted a longitudinal retrospective study of all outpatient end-stage renal disease dialysis facilities, using 1995-2003 administrative data from the U.S. Renal Data System. FINDINGS: Less than half of U.S. dialysis facilities offered PD, and this pattern was stable despite substantial growth of dialysis facilities entering the market. We found little support for strategic influences and some evidence that selective factors were predictive of dialysis facilities' PD provision. PRACTICE IMPLICATIONS: Although the design of many policy and health care reform efforts widely accepts the strategic perspective of altering incentives and the environment to induce change, the presence of selective inertial influences raises concerns about the efficacy of policy intervention in the face of institutionalized organizational behavior that may be less amenable to policy intervention. Incentives recently introduced by Medicare to increase facility provision of PD may be less effective than might be expected. PMID- 24763207 TI - Active Transportation to and on Campus is Associated With Objectively Measured Fitness Outcomes Among College Students. AB - BACKGROUND: Active transportation (AT) has been associated with positive health outcomes, yet limited research has addressed this with college students, a population at-risk for inactivity. The purpose of this study was to examine the relationship between AT behavior and objectively measured fitness outcomes. METHODS: A volunteer, convenience sample (n = 299) of college students from a large northeastern university completed a survey about their AT habits to and on campus and psychosocial constructs related to AT and participated in a laboratory based fitness assessment (cardiovascular endurance, muscular strength and endurance, flexibility, body composition).Off-campus students were dichotomized as nonactive (0-1 AT trips/day) or active travelers (> 1 AT trips/day) to campus; t-tests compared nonactive and active travelers for psychosocial and fitness variables. RESULTS: Students were 56.3% male, 79.2% non-Hispanic White, and primarily living off-campus (87%). Most students (n = 177, 59.2%) reported active travel between classes. Off-campus students were primarily active travelers (76.1%). Active travelers to campus had greater cardiovascular fitness (P = .005), were more flexible (P = .006) and had lower systolic blood pressure (P = .05) compared with nonactive travelers. CONCLUSION: This study documents a relationship between AT behavior and objectively measured fitness among college students and provides a rationale for targeting this behavior as a method for improving health outcomes. PMID- 24763208 TI - Electrically robust metal nanowire network formation by in-situ interconnection with single-walled carbon nanotubes. AB - Modulation of the junction resistance between metallic nanowires is a crucial factor for high performance of the network-structured conducting film. Here, we show that under current flow, silver nanowire (AgNW) network films can be stabilised by minimizing the Joule heating at the NW-NW junction assisted by in situ interconnection with a small amount (less than 3 wt%) of single-walled carbon nanotubes (SWCNTs). This was achieved by direct deposition of AgNW suspension containing SWCNTs functionalised with quadruple hydrogen bonding moieties excluding dispersant molecules. The electrical stabilisation mechanism of AgNW networks involves the modulation of the electrical transportation pathway by the SWCNTs through the SWCNT-AgNW junctions, which results in a relatively lower junction resistance than the NW-NW junction in the network film. In addition, we propose that good contact and Fermi level matching between AgNWs and modified SWCNTs lead to the modulation of the current pathway. The SWCNT-induced stabilisation of the AgNW networks was also demonstrated by irradiating the film with microwaves. The development of the high-throughput fabrication technology provides a robust and scalable strategy for realizing high-performance flexible transparent conductor films. PMID- 24763209 TI - Experience in evaluating AAL solutions in living labs. AB - Ambient assisted living (AAL) is a complex field, where different technologies are integrated to offer solutions for the benefit of different stakeholders. Several evaluation techniques are commonly applied that tackle specific aspects of AAL; however, holistic evaluation approaches are lacking when addressing the needs of both developers and end-users. Living labs have been often used as real life test and experimentation environments for co-designing AAL technologies and validating them with relevant stakeholders. During the last five years, we have been evaluating AAL systems and services in the framework of various research projects. This paper presents the lessons learned in this experience and proposes a set of harmonized guidelines to conduct evaluations in living labs. PMID- 24763210 TI - Quantitative damage detection and sparse sensor array optimization of carbon fiber reinforced resin composite laminates for wind turbine blade structural health monitoring. AB - The active structural health monitoring (SHM) approach for the complex composite laminate structures of wind turbine blades (WTBs), addresses the important and complicated problem of signal noise. After illustrating the wind energy industry's development perspectives and its crucial requirement for SHM, an improved redundant second generation wavelet transform (IRSGWT) pre-processing algorithm based on neighboring coefficients is introduced for feeble signal denoising. The method can avoid the drawbacks of conventional wavelet methods that lose information in transforms and the shortcomings of redundant second generation wavelet (RSGWT) denoising that can lead to error propagation. For large scale WTB composites, how to minimize the number of sensors while ensuring accuracy is also a key issue. A sparse sensor array optimization of composites for WTB applications is proposed that can reduce the number of transducers that must be used. Compared to a full sixteen transducer array, the optimized eight transducer configuration displays better accuracy in identifying the correct position of simulated damage (mass of load) on composite laminates with anisotropic characteristics than a non-optimized array. It can help to guarantee more flexible and qualified monitoring of the areas that more frequently suffer damage. The proposed methods are verified experimentally on specimens of carbon fiber reinforced resin composite laminates. PMID- 24763211 TI - Optical sensor based on a single CdS nanobelt. AB - In this paper, an optical sensor based on a cadmium sulfide (CdS) nanobelt has been developed. The CdS nanobelt was synthesized by the vapor phase transportation (VPT) method. X-Ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) results revealed that the nanobelt had a hexagonal wurtzite structure of CdS and presented good crystal quality. A single nanobelt Schottky contact optical sensor was fabricated by the electron beam lithography (EBL) technique, and the device current-voltage results showed back-to-back Schottky diode characteristics. The photosensitivity, dark current and the decay time of the sensor were 4 * 104, 31 ms and 0.2 pA, respectively. The high photosensitivity and the short decay time were because of the exponential dependence of photocurrent on the number of the surface charges and the configuration of the back to back Schottky junctions. PMID- 24763212 TI - Using massive vehicle positioning data to improve control and planning of public road transport. AB - This study describes a system for the automatic recording of positioning data for public transport vehicles used on roads. With the data provided by this system, transportation-regulatory authorities can control, verify and improve the routes that vehicles use, while also providing new data to improve the representation of the transportation network and providing new services in the context of intelligent metropolitan areas. The system is executed autonomously in the vehicles, by recording their massive positioning data and transferring them to remote data banks for subsequent processing. To illustrate the utility of the system, we present a case of application that consists of identifying the points at which vehicles stop systematically, which may be points of scheduled stops or points at which traffic signals or road topology force the vehicle to stop. This identification is performed using pattern recognition techniques. The system has been applied under real operating conditions, providing the results discussed in the present study. PMID- 24763213 TI - Development of a sweetness sensor for aspartame, a positively charged high potency sweetener. AB - Taste evaluation technology has been developed by several methods, such as sensory tests, electronic tongues and a taste sensor based on lipid/polymer membranes. In particular, the taste sensor can individually quantify five basic tastes without multivariate analysis. However, it has proven difficult to develop a sweetness sensor, because sweeteners are classified into three types according to the electric charges in an aqueous solution; that is, no charge, negative charge and positive charge. Using membrane potential measurements, the taste sensing system needs three types of sensor membrane for each electric charge type of sweetener. Since the commercially available sweetness sensor was only intended for uncharged sweeteners, a sweetness sensor for positively charged high-potency sweeteners such as aspartame was developed in this study. Using a lipid and plasticizers, we fabricated various lipid/polymer membranes for the sweetness sensor to identify the suitable components of the sensor membranes. As a result, one of the developed sensors showed responses of more than 20 mV to 10 mM aspartame and less than 5 mV to any other taste. The responses of the sensor depended on the concentration of aspartame. These results suggested that the developed sweetness sensor had high sensitivity to and high selectivity for aspartame. PMID- 24763214 TI - An accurate and computationally efficient model for membrane-type circular symmetric micro-hotplates. AB - Ideally, the design of high-performance micro-hotplates would require a large number of simulations because of the existence of many important design parameters as well as the possibly crucial effects of both spread and drift. However, the computational cost of FEM simulations, which are the only available tool for accurately predicting the temperature in micro-hotplates, is very high. As a result, micro-hotplate designers generally have no effective simulation tools for the optimization. In order to circumvent these issues, here, we propose a model for practical circular-symmetric micro-hot-plates which takes advantage of modified Bessel functions, computationally efficient matrix-approach for considering the relevant boundary conditions, Taylor linearization for modeling the Joule heating and radiation losses, and external-region-segmentation strategy in order to accurately take into account radiation losses in the entire micro hotplate. The proposed model is almost as accurate as FEM simulations and two to three orders of magnitude more computationally efficient (e.g., 45 s versus more than 8 h). The residual errors, which are mainly associated to the undesired heating in the electrical contacts, are small (e.g., few degrees Celsius for an 800 degrees C operating temperature) and, for important analyses, almost constant. Therefore, we also introduce a computationally-easy single-FEM compensation strategy in order to reduce the residual errors to about 1 degrees C. As illustrative examples of the power of our approach, we report the systematic investigation of a spread in the membrane thermal conductivity and of combined variations of both ambient and bulk temperatures. Our model enables a much faster characterization of micro-hotplates and, thus, a much more effective optimization prior to fabrication. PMID- 24763215 TI - Fiber Bragg grating sensors toward structural health monitoring in composite materials: challenges and solutions. AB - Nowadays, smart composite materials embed miniaturized sensors for structural health monitoring (SHM) in order to mitigate the risk of failure due to an overload or to unwanted inhomogeneity resulting from the fabrication process. Optical fiber sensors, and more particularly fiber Bragg grating (FBG) sensors, outperform traditional sensor technologies, as they are lightweight, small in size and offer convenient multiplexing capabilities with remote operation. They have thus been extensively associated to composite materials to study their behavior for further SHM purposes. This paper reviews the main challenges arising from the use of FBGs in composite materials. The focus will be made on issues related to temperature-strain discrimination, demodulation of the amplitude spectrum during and after the curing process as well as connection between the embedded optical fibers and the surroundings. The main strategies developed in each of these three topics will be summarized and compared, demonstrating the large progress that has been made in this field in the past few years. PMID- 24763216 TI - Calibration-free pulse oximetry based on two wavelengths in the infrared - a preliminary study. AB - The assessment of oxygen saturation in arterial blood by pulse oximetry (SpO2) is based on the different light absorption spectra for oxygenated and deoxygenated hemoglobin and the analysis of photoplethysmographic (PPG) signals acquired at two wavelengths. Commercial pulse oximeters use two wavelengths in the red and infrared regions which have different pathlengths and the relationship between the PPG-derived parameters and oxygen saturation in arterial blood is determined by means of an empirical calibration. This calibration results in an inherent error, and pulse oximetry thus has an error of about 4%, which is too high for some clinical problems. We present calibration-free pulse oximetry for measurement of SpO2, based on PPG pulses of two nearby wavelengths in the infrared. By neglecting the difference between the path-lengths of the two nearby wavelengths, SpO2 can be derived from the PPG parameters with no need for calibration. In the current study we used three laser diodes of wavelengths 780, 785 and 808 nm, with narrow spectral line-width. SaO2 was calculated by using each pair of PPG signals selected from the three wavelengths. In measurements on healthy subjects, SpO2 values, obtained by the 780-808 nm wavelength pair were found to be in the normal range. The measurement of SpO2 by two nearby wavelengths in the infrared with narrow line-width enables the assessment of SpO2 without calibration. PMID- 24763217 TI - First-principles surface stress calculations and multiscale deformation analysis of a self-assembled monolayer adsorbed on a micro-cantilever. AB - Micro-cantilever sensors are widely used to detect biomolecules, chemical gases, and ionic species. However, the theoretical descriptions and predictive modeling of these devices are not well developed, and lag behind advances in fabrication and applications. In this paper, we present a novel multiscale simulation framework for nanomechanical sensors. This framework, combining density functional theory (DFT) calculations and finite element method (FEM) analysis, is capable of analyzing molecular adsorption-induced deformation and stress fields in the sensors from the molecular scale to the device scale. Adsorption of alkanethiolate self-assembled monolayer (SAM) on the Au(111) surface of the micro cantilever sensor is studied in detail to demonstrate the applicability of this framework. DFT calculations are employed to investigate the molecular adsorption induced surface stress upon the gold surface. The 3D shell elements with initial stresses obtained from the DFT calculations serve as SAM domains in the adsorption layer, while FEM is employed to analyze the deformation and stress of the sensor devices. We find that the micro-cantilever tip deflection has a linear relationship with the coverage of the SAM domains. With full coverage, the tip deflection decreases as the molecular chain length increases. The multiscale simulation framework provides a quantitative analysis of the displacement and stress fields, and can be used to predict the response of nanomechanical sensors subjected to complex molecular adsorption. PMID- 24763218 TI - Fiddling with memory. PMID- 24763219 TI - Balancing obligations: should written information about life-sustaining treatment be neutral? AB - Parents who are facing decisions about life-sustaining treatment for their seriously ill or dying child are supported by their child's doctors and nurses. They also frequently seek other information sources to help them deal with the medical and ethical questions that arise. This might include written or web-based information. As part of a project involving the development of such a resource to support parents facing difficult decisions, some ethical questions emerged. Should this information be presented in a strictly neutral fashion? Is it problematic if narratives, arguments or perspectives appear to favour stopping over continuing life-sustaining treatment? Similar questions might arise with written materials about decisions for adults, or for other ethically contentious decisions. This paper explores the meaning of 'balance' in information provision, focusing particularly on written information about life-sustaining treatment for children. We contrast the norm of non-directiveness in genetic counselling with the shared decision-making model often endorsed in end-of-life care. We review evidence that parents do not find neutrality from medical professionals helpful in discussions. We argue that balance in written information must be understood in the light of the aim of the document, the most common situation in which it will be used, and any existing biases. We conclude with four important strategies for ensuring that non-neutral information is nevertheless ethically appropriate. PMID- 24763220 TI - Why religion deserves a place in secular medicine. AB - As a science and practice transcending metaphysical and ethical disagreements, 'secular' medicine should not exist. 'Secularity' should be understood in an Augustinian sense, not a secularist one: not as a space that is universally rational because it is religion-free, but as a forum for the negotiation of rival reasonings. Religion deserves a place here, because it is not simply or uniquely irrational. However, in assuming his rightful place, the religious believer commits himself to eschewing sheer appeals to religious authorities, and to adopting reasonable means of persuasion. This can come quite naturally. For example, Christianity (theo)logically obliges liberal manners in negotiating ethical controversies in medicine. It also offers reasoned views of human being and ethics that bear upon medicine and are not universally held-for example, a humanist view of human dignity, the bounding of individual autonomy by social obligation, and a special concern for the weak. PMID- 24763221 TI - Minimizing harm via psychological intervention: response to Glannon. AB - In a recent discussion, Walter Glannon discusses a number of ways we might try to minimise harm to patients who experience intraoperative awareness. In this response, I direct attention to a possibility that deserves further attention. It might be that a kind of psychological intervention--namely, informing patients of the possibility of intraoperative awareness and of what to expect in such a case- would constitute a unique way to respect patient autonomy, as well as minimise the harm that typically follows intraoperative awareness events. PMID- 24763222 TI - Understanding, interests and informed consent: a reply to Sreenivasan. AB - It is widely agreed that the view of informed consent found in the regulations and guidelines struggles to keep pace with the ever-advancing enterprise of human subjects research. Over the last 10 years, there have been serious attempts to rethink informed consent so that it conforms to our considered judgments about cases where we are confident valid consent has been given. These arguments are influenced by an argument from Gopal Sreenivasan, which apparently shows that a potential participant's consent to research participation can be perfectly valid even if she fails to understand the risk-benefit profile of the study. I argue that Sreenivasan's argument fails. The set of clinical trials that is supposed to be ethical in the face of this kind of ignorance is empty. However, I argue that his argument is nonetheless instructive in allowing us to identify three important but neglected areas for future conceptual research on informed consent. I close by arguing that research on these identified questions promises to yield a defensible view of consent, lessen the burden of ambiguity on researchers attempting to obtain consent to research participation, and facilitate socially valuable research. PMID- 24763223 TI - Feedback signals in myelodysplastic syndromes: increased self-renewal of the malignant clone suppresses normal hematopoiesis. AB - Myelodysplastic syndromes (MDS) are triggered by an aberrant hematopoietic stem cell (HSC). It is, however, unclear how this clone interferes with physiologic blood formation. In this study, we followed the hypothesis that the MDS clone impinges on feedback signals for self-renewal and differentiation and thereby suppresses normal hematopoiesis. Based on the theory that the MDS clone affects feedback signals for self-renewal and differentiation and hence suppresses normal hematopoiesis, we have developed a mathematical model to simulate different modifications in MDS-initiating cells and systemic feedback signals during disease development. These simulations revealed that the disease initiating cells must have higher self-renewal rates than normal HSCs to outcompete normal hematopoiesis. We assumed that self-renewal is the default pathway of stem and progenitor cells which is down-regulated by an increasing number of primitive cells in the bone marrow niche--including the premature MDS cells. Furthermore, the proliferative signal is up-regulated by cytopenia. Overall, our model is compatible with clinically observed MDS development, even though a single mutation scenario is unlikely for real disease progression which is usually associated with complex clonal hierarchy. For experimental validation of systemic feedback signals, we analyzed the impact of MDS patient derived serum on hematopoietic progenitor cells in vitro: in fact, MDS serum slightly increased proliferation, whereas maintenance of primitive phenotype was reduced. However, MDS serum did not significantly affect colony forming unit (CFU) frequencies indicating that regulation of self-renewal may involve local signals from the niche. Taken together, we suggest that initial mutations in MDS particularly favor aberrant high self-renewal rates. Accumulation of primitive MDS cells in the bone marrow then interferes with feedback signals for normal hematopoiesis- which then results in cytopenia. PMID- 24763225 TI - Gut microbiomes of Indian children of varying nutritional status. AB - BACKGROUND: Malnutrition is a global health problem affecting more than 300 million pre-school children worldwide. It is one of the major health concerns in India since around 50% of children below the age of two suffer from various forms of malnutrition. The gut microbiome plays an important role in nutrient pre processing, assimilation and energy harvest from food. Consequently, dysbiosis of the gut microbiota has been implicated in malnutrition. METHODOLOGY/PRINCIPAL FINDINGS: Metagenomics approach was adopted to investigate the gut microbiome sampled from 20 rural Indian children with varying nutritional status. The changes in the abundances of various taxonomic and functional groups were investigated across these gut microbiomes. A core set of 23 genera were observed across samples, with some showing differential abundances with varying nutritional status. One of the findings of the current study is the positive/negative associations of specific taxonomic and functional groups with the nutritional status of the children. Notable alterations in the architecture of the inter-microbial co-occurrence networks were also observed with changes in nutritional status. A key example is the clustering of potentially pathogenic groups into a distinct hub in severely malnourished gut. Our data does not demonstrate causality with the microbiome patterns that we observed, rather a description of some interesting patterns, whose underlying mechanism remains to be uncovered. CONCLUSIONS: The present study envisioned interrelationships between the pattern of gut microbiome and the nutritional status of children. The cause of this pattern needs to be explored. However, insights obtained from the present study form the basis for further metagenomic investigations on larger population of children. Results of such studies will be useful in identifying the key microbial groups that can be utilized for targeted therapeutic interventions for managing severe acute malnutrition. PMID- 24763226 TI - Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis. AB - Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China and Southeast Asia, with the highest metastasis rate among head and neck cancers. The mechanisms underlying NPC progression remain poorly understood. Genome-wide expression profiling on 18 NPC vs. 18 noncancerous nasopharyngeal tissues together with GeneGo pathway analysis and expression verification in NPC cells and tissues revealed a potential role of urokinase-type plasminogen activator receptor (uPAR) in NPC progression, which has not been investigated in NPC. We then observed that uPAR expression is increased in poorly differentiated, highly metastatic NPC cells compared with lowly metastatic cells or differentiated NPC cells. In vitro studies demonstrated that uPAR regulates NPC cell growth, colony formation, migration, and invasion and promotes the epithelial-mesenchymal transition (EMT). Additional tumor xenograft and spontaneous metastasis experiments revealed that uPAR promotes NPC cell growth and metastasis in vivo. The JAK-STAT pathway is involved in uPAR-regulated signaling in NPC cells as determined by immunoblotting. Moreover, uPAR-mediated growth and motility is partially abolished upon treatment with the Jak1/Jak2 inhibitor INCB018424. We suppressed uPA expression in uPAR-overexpressing NPC cells and found that uPAR-mediated cellular growth and motility is not exclusively dependent on uPA. In summary, uPAR is a significant regulator of NPC progression and could serve as a promising therapeutic target. PMID- 24763227 TI - In trans complementation of lethal factor reveal roles in colonization and dissemination in a murine mouse model. AB - Lethal factor (LF) is a component of the B. anthracis exotoxin and critical for pathogenesis. The roles of LF in early anthrax pathogenesis, such as colonization and dissemination from the initial site of infection, are poorly understood. In mice models of infection, LF-deficient strains either have altered dissemination patterns or do not colonize, precluding analysis of the role of LF in colonization and dissemination from the portal of entry. Previous reports indicate rabbit and guinea pig models infected with LF-deficient strains have decreased virulence, yet the inability to use bioluminescent imaging techniques to track B. anthracis growth and dissemination in these hosts makes analysis of early pathogenesis challenging. In this study, the roles of LF early in infection were analyzed using bioluminescent signature tagged libraries of B. anthracis with varying ratios of LF-producing and LF-deficient clones. Populations where all clones produced LF and populations where only 40% of clones produce LF were equally virulent. The 40% LF-producing clones trans complimented the LF mutants and permitted them to colonize and disseminate. Decreases of the LF producing strains to 10% or 0.3% of the population led to increased host survival and decreased trans complementation of the LF mutants. A library with 10% LF producing clones could replicate and disseminate, but fewer clones disseminated and the mutant clones were less competitive than wild type. The inoculum with 0.3% LF producing clones could not colonize the host. This strongly suggests that between 10% and 0.3% of the population must produce LF in order to colonize. In total, these findings suggest that a threshold of LF must be produced in order for colonization and dissemination to occur in vivo. These observations suggest that LF has a major role in the early stages of colonization and dissemination. PMID- 24763228 TI - Adaptive cluster synchronization of directed complex networks with time delays. AB - This paper studied the cluster synchronization of directed complex networks with time delays. It is different from undirected networks, the coupling configuration matrix of directed networks cannot be assumed as symmetric or irreducible. In order to achieve cluster synchronization, this paper uses an adaptive controller on each node and an adaptive feedback strategy on the nodes which in-degree is zero. Numerical example is provided to show the effectiveness of main theory. This method is also effective when the number of clusters is unknown. Thus, it can be used in the community recognizing of directed complex networks. PMID- 24763229 TI - The Malaysian Journal of Pathology - moving forward. PMID- 24763230 TI - Molecular profiling of breast cancer in Nigerian women identifies an altered p53 pathway as a major mechanism underlying its poor prognosis compared with British counterpart. AB - BACKGROUND: Advances in breast cancer (BC) research have demonstrated differences between black and white women with regarding tumour behaviour, patient outcome and response to treatment which can be explained by underlying genetic changes. The tumour suppressor gene p53 has been speculated to be involved in tumour biology of triple negative and/or basal -like BC and more commonly observed in black than caucasian women. MATERIALS AND METHODS: In this study, the protein expression of p53 was investigated in tissue samples from a series of 308 Nigerian women, prepared as a tissue microarray (TMA), using immunohistochemistry. Clinicopathological parameters, biomarkers of functional significance in BC and patient outcome of tumours expressing p53 in Nigerian women were correlated with UK grade matched series. RESULTS: A significantly large proportion of BC from Nigerian women showed high p53 expression compared with UK women (p<0.001). In those tumours showing positive p53 in the Nigerian series, a significant proportion were premenopausal, diagnosed before 50 years, larger in size, with evidence of metastasis into lymphatic vessels ( all p<0.001). In addition, p53 positive expression was also significantly correlated with negative expression of ER and PgR (p<0.001, p<0.03 respectively), BRCA1, MDM2 (all p<0.001), p21 (p=0.006) and E-cadherin (p=0.001) and positively associated with P-cadherin (p=0.001), triple negative phenotype, basal cytokeratin (CK) 5/6 expression (p<0.04) and basal phenotype compared with the UK series (p<0.001). Survival analyses showed Nigerian women with BC were significantly associated with poor BC specific survival (p<0.001, but no significant association with disease free interval was observed. CONCLUSION: In this study, protein expressions of p53 pathways are different between Nigerian and UK BC women and this may also contribute to differences in tumour biology. Therefore, targeting these p53 pathways for therapeutic usage might improve the poor outcome observed in Black Nigerian women. PMID- 24763231 TI - Serum soluble FMS-like tyrosine kinase 1 and placental growth factor concentration as predictors of preeclampsia in high risk pregnant women. AB - Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) contribute in the development of preeclampsia and are suggested as prediction markers in healthy pregnant women but limited data is available in women with major preeclampsia risk factors. This study aimed to determine the role of sFlt-1 and PlGF in predicting preeclampsia among high risk pregnant women. This was a prospective study and samples were collected for a period of ten months. Blood samples were obtained from 84 pregnant women who had at least one risk factor for preeclampsia at 25 to 28 weeks and at 29 to 36 weeks of gestation. SFlt-1 and PlGF concentrations were determined by immunoassay method. There were significantly higher median sFlt-1 and sFlt-1:PlGF ratio at gestational interval 25 to 28 weeks and sFlt-1:PlGF ratio at 29 to 36 weeks in high risk women who developed preeclampsia. Significant lower median serum PlGF levels at 25 to 28 weeks and 29 to 36 weeks were observed in this group of women. In conclusion, the concentrations of these markers were altered in high risk preeclamptic women, a similar pattern seen in low risk preeclamptic women. However the predictive value of these markers could not be established clearly. PMID- 24763232 TI - Molecular characteristic of alpha thalassaemia among patients diagnosed in UKM Medical Centre. AB - Alpha (Alpha) thalassaemia is the most common inherited disorder in Malaysia. The clinical severity is dependant on the number of Alpha genes involved. Full blood count (FBC) and haemoglobin (Hb) analysis using either gel electrophoresis, high performance liquid chromatography (HPLC) or capillary zone electrophoresis (CE) are unable to detect definitively alpha thalassaemia carriers. Definitive diagnosis of Alpha-thalassaemias requires molecular analysis and methods of detecting both common deletional and non-deletional molecular abnormailities are easily performed in any laboratory involved in molecular diagnostics. We carried out a retrospective analysis of 1623 cases referred to our laboratory in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) for the diagnosis of Alpha thalassaemia during the period October 2001 to December 2012. We examined the frequency of different types of alpha gene abnormalities and their haematologic features. Molecular diagnosis was made using a combination of multiplex polymerase reaction (PCR) and real time PCR to detect deletional and non deletional alpha genes relevant to southeast Asian population. Genetic analysis confirmed the diagnosis of Alpha-thalassaemias in 736 cases. Majority of the cases were Chinese (53.1%) followed by Malays (44.2%), and Indians (2.7%). The most common gene abnormality was AlphaAlpha/--(SEA) (64.0%) followed by AlphaAlpha/-Alpha(3.7) (19.8%), -Alpha(3.7) /--(SEA) (6.9%), AlphaAlpha/AlphaAlphaCS (3.0%), --(SEA)/--(SEA) (1.2%), -Alpha(3.7)/-Alpha(3.7) (1.1%), AlphaAlpha/-Alpha(4.2) (0.7%), -Alpha(4.2)/--(SEA (0.7%), -Alpha(3.7)/ Alpha(4.2) (0.5%), AlphaAlpha(CS)/-- SEA) (0.4%), AlphaAlpha(CS)/AlphaAlpha(Cd59) (0.4%), AlphaAlpha(CS)/AlphaAlpha(CS) (0.4%), -Alpha(3.7)/AlphaAlpha(Cd59) (0.3%), AlphaAlpha/AlphaAlpha(Cd59) (0.1%), AlphaAlpha(Cd59)/ AlphaAlpha(IVS I-1) (0.1%), -Alpha(3.7)/AlphaAlpha(CS) (0.1%) and --(SEA) /AlphaAlpha(Cd59) (0.1%). This data indicates that the molecular abnormalities of Alpha-thalassaemia in the Malaysian population is heterogenous. Although Alpha-gene deletion is the most common cause, non-deletional Alpha-gene abnormalities are not uncommon and at least 3 different mutations exist. Establishment of rapid and easy molecular techniques is important for definitive diagnosis of alpha thalassaemia, an important prerequisite for genetic counselling to prevent its deleterious complications. PMID- 24763233 TI - Blunt force trauma to skull with various instruments. AB - Deaths due to blunt force trauma to the head as a result of assault are some of the most common cases encountered by the practicing forensic pathologist. Previous studies have shown inflicting injury to the head region is one of the most effective methods of murder. The important factors that determine severity of trauma include the type of weapon used, type and site of skull fracture, intracranial haemorrhage and severity of brain injury. The aim of this study was to determine the characteristics of blunt force trauma to the skull produced by different instruments. Nine adult monkeys (Macaca fascicularis) skulls were used as models. Commonly found blunt objects comprising of Warrington hammer, hockey stick and open face helmet were used in this study. A machine calibrated force generator was used to hold the blunt object in place and to hit the skulls at forces of 12.5N and 25N. Resultant traumatic effects and fractures (linear, depressed, basilar, comminuted, and distastic) were analyzed according to type of blunt object used; surface area of contact and absolute force (N/cm(2)) delivered. Results showed that all investigated instruments were capable of producing similar injuries. The severity of trauma was not related to the surface area of contact with the blunt objects. However, only high absolute forces produced comminuted fractures. These findings were observational, as the samples were too small for statistical conclusions. PMID- 24763234 TI - Psychological traits underlying different killing methods among Malaysian male murderers. AB - Murder is the most notorious crime that violates religious, social and cultural norms. Examining the types and number of different killing methods that used are pivotal in a murder case. However, the psychological traits underlying specific and multiple killing methods are still understudied. The present study attempts to fill this gap in knowledge by identifying the underlying psychological traits of different killing methods among Malaysian murderers. The study adapted an observational cross-sectional methodology using a guided self-administered questionnaire for data collection. The sampling frame consisted of 71 Malaysian male murderers from 11 Malaysian prisons who were selected using purposive sampling method. The participants were also asked to provide the types and number of different killing methods used to kill their respective victims. An independent sample t-test was performed to establish the mean score difference of psychological traits between the murderers who used single and multiple types of killing methods. Kruskal-Wallis tests were carried out to ascertain the psychological trait differences between specific types of killing methods. The results suggest that specific psychological traits underlie the type and number of different killing methods used during murder. The majority (88.7%) of murderers used a single method of killing. Multiple methods of killing was evident in 'premeditated' murder compared to 'passion' murder, and revenge was a common motive. Examples of multiple methods are combinations of stabbing and strangulation or slashing and physical force. An exception was premeditated murder committed with shooting, when it was usually a single method, attributed to the high lethality of firearms. Shooting was also notable when the motive was financial gain or related to drug dealing. Murderers who used multiple killing methods were more aggressive and sadistic than those who used a single killing method. Those who used multiple methods or slashing also displayed a higher level of minimisation traits. Despite its limitations, this study has provided some light on the underlying psychological traits of different killing methods which is useful in the field of criminology. PMID- 24763235 TI - Myoepithelial carcinoma of the parotid gland. AB - Myoepithelial carcinomas exhibit a wide spectrum of cytomorphologic features and diverse clinical outcomes. As a result of their morphologic heterogeneity, they can be confused easily with many tumours. Herein we report the morphological features of myoepithelial carcinoma in a 74-year-old female clinically presenting with a parotid mass. FNAB revealed hypercellular, three-dimensional clusters with considerable overlapping and crowding of pleomorphic neoplastic cells which consisted predominantly of spindle cells, with oval to elongated to spindle shaped nuclei showing considerable variation in size. The excised tumour was solid, with cells arranged in trabeculae, nests and cords. Tumour cells were mixed epithelioid and spindle with eosinophilic or clear cytoplasm, with eccentric nuclei and prominent nuclei. Neoplastic cells were found in blood vessels, in the skin and facial nerve. Tumour cells were immunopositive for PAS, PAS-D, S-100 protein, GFAP, P63, CK5/ CK6, CK7, and CK14. This case illustrates that cytological features in FNAB generally reflect the histology. FNAB was able to confirm the diagnosis and guide patient management. PMID- 24763236 TI - Unilateral ovarian fibrothecoma with menorrhagia. AB - Ovarian fibrothecoma is a relatively new term that is used to describe an ovarian sex cord stromal tumour that has mixed features of both fibroma and thecoma. The prevalence of ovarian fibrothecoma tumours is very rare and is reported to be about 1.2% of all ovarian tumours. We report a case of a 32-year-old woman who presented with acute menorrhagia with no previous medical, surgical or gynecological history. She was amenorrhic for four years after the insertion of a levonorgestrelreleasing intrauterine system (LNG-IUS) for contraception. The efficacy and location of LNG-IUS was reflected due to the sudden onset of menorrhagia. On pelvic examination and ultrasound the LNG-IUS could not be visualized and a uterine fibroid was noted. A diagnostic laparoscopy was done to identify the LNG-IUS, which revealed an incidental large ovarian mass on the left ovary. CA-125 level was elevated to 45 kU/L (Normal range <35 kU/L). Total abdominal hysterectomy, left salpingo-oopherectomy and cystectomy were performed. On histopathology, the mass was proven to be an ovarian fibrothecoma. No signs of malignancy were noted on peritoneal fluid cytology. The LNG-IUS was found inside the uterus. Our case is reported on the basis of the rare incidence of ovarian fibrothecoma and the possible effect it may have on the efficacy of LNG-IUS causing menorrhagia. PMID- 24763237 TI - Fibrolipomatous hamartoma of sural nerve: a new site of an unusual lesion. AB - Neural fibrolipomatous hamartoma is a rare benign tumour commonly involving the median nerve. Other less frequently involved nerves include the ulnar, radial, brachial plexus, superficial peroneal nerve, inferior calcaneal nerve and median plantar nerve. Involvement of sural nerve has not been reported in the available literature so far. A three-year-old female child presented with a painless swelling over the posterolateral aspect of left leg with no associated motor or sensory deficits. Radiological investigations revealed a fat density lesion with interspersed neural element in the subcutaneous plane of the left leg. Histopathological examination of the excised specimen showed features of a fibrolipomatous hamartoma of the nerve. This report describes the occurrence of fibrolipomatous hamartoma in the sural nerve for the first time in the literature. This rare tumour should be considered in the differential diagnosis of such lesions. PMID- 24763238 TI - Epithelioid hemangioma of distal femoral epiphysis in a patient with congenital talipes equinovarus. AB - BACKGROUND: Epithelioid hemangioma (EH) is a rare benign vascular lesion of soft tissue and bone, characterized by endothelial cells with epithelioid or histiocytoid appearance. Though tubular bones, flat bones, vertebra and short bones are common sites for this lesion, the epiphyseal involvement is extremely rare. We present an unusual case of EH of the distal femur in a young boy. CASE REPORT: A 12-year-old boy who had congenital talipes equinovarus of the right foot presented with progressively increasing pain in the right lower thigh for six months. Physical examination revealed muscular atrophy of the right lower limb and a moderately tender swelling in the medial aspect of the right knee without restriction of knee movement. An X-ray revealed an osteolytic lesion, which appeared iso- and hypointense on T1W and hyperintense on T2W MRI images in the distal epiphysis and adjacent metaphysis of the right femur. A radiological diagnosis of chondroblastoma was entertained. The patient was treated with curettage and bone grafting. Histopathology showed a tumor composed of thin walled arteriolar capillaries lined by large, polyhedral epithelioid endothelial cells with vesicular nuclei, finely distributed nuclear chromatin, and moderate amount of eosinophilic cytoplasm. The endothelial cells were strongly immunopositive for CD34. Mitotic activity was low and the Ki-67 proliferative rate was <2%. A diagnosis of EH was made. EH is a benign lesion and it should be differentiated from its histologically similar malignant counterparts such as epithelioid hemangioendothelioma and epithelioid angiosarcoma as the lesion can be successfully treated with curettage or resection. PMID- 24763239 TI - Post mortem changes and clothing. PMID- 24763240 TI - Response: post mortem changes and clothing. PMID- 24763241 TI - Intravitreal bevacizumab in the successful management of choroidal metastases secondary to lung and breast cancer unresponsive to systemic therapy: a case series. AB - PURPOSE: Management of choroidal metastases is commonly with systemic chemotherapy; however, if tumours are refractory to treatment and vision is endangered, local therapy modalities are feasible. A novel option is the use of intravitreal bevacizumab. This report presents three cases of choroidal metastatic tumours secondary to lung and breast cancer treated with intravitreal bevazizumab. PATIENTS AND METHODS: Three patients with choroidal metastases secondary to lung and breast tumours were treated at the Ophthalmology Unit, University of Rome 'Sapienza', S.Andrea Hospital from January 2009 to August 2012. All patients developed vision loss with diagnosis of chorioidal metastasis during systemic chemotherapy. Off label intravitreal bevacizumab treatment was performed with two 1.25 mg injections in two patients and four injections in one patient at 30-day intervals. RESULTS: Vision improved, subretinal fluid resolved, and choroidal tumour regression was obtained in all cases. Follow-up was 6, 9, and 12 months and there were no complications related to treatment. CONCLUSIONS: Intravitreal bevacizumab administration represented an efficacious therapeutic option with rapid effect in the treatment of choroidal metastatic tumours unresponsive to systemic therapy. It can have a role in the management of these tumours by preventing vision loss and improving the quality of life of patients. PMID- 24763242 TI - The effect of erythropoietin on the severity of retinopathy of prematurity. AB - AIMS: Exogenous human erythropoietin (EPO) artificially synthesised through recombinant DNA technology (rHuEPO) is currently used as a substitute for blood transfusion in preterm and low birth weight neonates. The objective of this study is to determine whether the use of rHuEPO is associated with an increased severity of retinopathy of prematurity (ROP) in preterm neonates. METHOD: This retrospective review studies neonates who were admitted to a tertiary perinatal unit and screened for ROP during the 10-year period from January 2003 to December 2012. RESULTS: : During the 10-year period, 688 preterm neonates underwent ROP screening, with 198 identified as having ROP. The incidence of stage 1 ROP was 51.5% (102/198), followed by 35.9% (71/198) for stage 2, and 12.6% (25/198) for stage 3 and greater. Plus disease was seen in 14 neonates (7.1%). Treatment (laser photocoagulation) was administered in 64% of neonates (16/25) with stage 3 of the disease and above because of progression to threshold ROP. Twenty-six (13%) of the neonates received rHuEPO treatment. There were no statistically significant differences in birth weight (910.4 vs 885 g; P=0.71), gestational age (26.5 vs 25.8 weeks; P=0.09), and duration of ventilation (512 vs 501.4 h; P=0.92) between neonates who did not receive rHuEPO compared with those who were treated with rHuEPO. Multivariate regression analysis showed that the use of EPO was associated with increased severity of ROP. CONCLUSIONS: EPO therapy appears to increase the risk of development and worsening of ROP. PMID- 24763243 TI - A case of accidental retinal injury by cosmetic laser. PMID- 24763244 TI - Multifocal chorioretinitis caused by Bartonella henselae: imaging findings of spectral domain optical coherence tomography during treatment with trimethoprim sulfamethoxazole. PMID- 24763245 TI - Molecular dynamics simulations of mutated Mycobacterium tuberculosis L-alanine dehydrogenase to illuminate the role of key residues. AB - L-Alanine dehydrogenase from Mycobacterium tuberculosis (L-MtAlaDH) catalyzes the NADH-dependent interconversion of l-alanine and pyruvate, and it is considered to be a potential target for the treatment of tuberculosis. The experiment has verified that amino acid replacement of the conserved active-site residues which have strong stability and no great changes in biological evolutionary process, such as His96 and Asp270, could lead to inactive mutants [Agren et al., J. Mol. Biol. 377 (2008) 1161-1173]. However, the role of these conserved residues in catalytic reaction still remains unclear. Based on the crystal structures, a series of mutant structures were constructed to investigate the role of the conserved residues in enzymatic reaction by using molecular dynamics simulations. The results show that whatever the conserved residues were mutated, the protein can still convert its conformation from open state to closed state as long as NADH is present in active site. Asp270 maintains the stability of nicotinamide ring and ribose of NADH through hydrogen bond interactions, and His96 is helpful to convert the protein conformation by interactions with Gln271, whereas, they would lead to the structural rearrangement in active site and lose the catalytic activity when they were mutated. Additionally, we deduce that Met301 plays a major role in catalytic reaction due to fixing the nicotinamide ring of NADH to prevent its rotation, and we propose that Met301 would be mutated to the hydrophobic residue with large steric hindrance in side chain to test the activity of the protein in future experiment. PMID- 24763246 TI - Health care satisfaction among foreign residents in Taiwan--an assessment and improvement. AB - BACKGROUND: In 2012, almost half-million foreigners (2.3% of the total population) from 160 countries were estimated to live in Taiwan. In 2010, approximately eighty-seven percent of the population expressed high satisfaction in the national health care system of Taiwan. However, satisfaction level among foreign residents towards the Taiwanese health care system has not been clearly documented in the literature. OBJECTIVE: In this study, we assessed satisfaction level among foreign residents for receiving healthcare facility in Taiwanese hospital. In addition, the study came out with some potential solutions to improve health care received by them. METHODS: Human-Centered Design (HCD) approach was deployed, which included three phases: observation, pattern recognition, and ideation and delivery. Each phase involved various steps. Techniques, such as ethnography, interview, discussion, and survey were used in accomplishing various steps within each phase. Four participants and two facilitators from Taiwan took part in the study. RESULTS: The study revealed various stories, insights, and themes about the health care received by the foreigners in Taiwan. In addition, some potential solutions and immediate available opportunities were recommended to improve their health care. CONCLUSIONS: The results provided a deeper understanding into the satisfaction level among foreign residents in Taiwan. For instance, this study pointed out the need to improve English proficiency of hospital's administrative staffs because a lack of English language proficiencies was found to be a major barrier in delivering quality health care to foreign residents. Therefore, adoption of various training modalities, such as English training using mobile device based games, role-play, and hospital's workflow depiction using English posters were recommended. PMID- 24763247 TI - Structure-related antibacterial activity of a titanium nanostructured surface fabricated by glancing angle sputter deposition. AB - The aim of this study was to reproduce the physico-mechanical antibacterial effect of the nanocolumnar cicada wing surface for metallic biomaterials by fabrication of titanium (Ti) nanocolumnar surfaces using glancing angle sputter deposition (GLAD). Nanocolumnar Ti thin films were fabricated by GLAD on silicon substrates. S. aureus as well as E. coli were incubated with nanostructured or reference dense Ti thin film test samples for one or three hours at 37 degrees C. Bacterial adherence, morphology, and viability were analyzed by fluorescence staining and scanning electron microscopy and compared to human mesenchymal stem cells (hMSCs).Bacterial adherence was not significantly different after short (1 h) incubation on the dense or the nanostructured Ti surface. In contrast to S. aureus the viability of E. coli was significantly decreased after 3 h on the nanostructured film compared to the dense film and was accompanied by an irregular morphology and a cell wall deformation. Cell adherence, spreading and viability of hMSCs were not altered on the nanostructured surface. The results show that the selective antibacterial effect of the cicada wing could be transferred to a nanostructured metallic biomaterial by mimicking the natural nanocolumnar topography. PMID- 24763248 TI - Ultrasmooth, extremely deformable and shape recoverable Ag nanowire embedded transparent electrode. AB - Transparent electrodes have been widely used in electronic devices such as solar cells, displays, and touch screens. Highly flexible transparent electrodes are especially desired for the development of next generation flexible electronic devices. Although indium tin oxide (ITO) is the most commonly used material for the fabrication of transparent electrodes, its brittleness and growing cost limit its utility for flexible electronic devices. Therefore, the need for new transparent conductive materials with superior mechanical properties is clear and urgent. Ag nanowire (AgNW) has been attracting increasing attention because of its effective combination of electrical and optical properties. However, it still suffers from several drawbacks, including large surface roughness, instability against oxidation and moisture, and poor adhesion to substrates. These issues need to be addressed before wide spread use of metallic NW as transparent electrodes can be realized. In this study, we demonstrated the fabrication of a flexible transparent electrode with superior mechanical, electrical and optical properties by embedding a AgNW film into a transparent polymer matrix. This technique can produce electrodes with an ultrasmooth and extremely deformable transparent electrode that have sheet resistance and transmittance comparable to those of an ITO electrode. PMID- 24763249 TI - The early innate response of chickens to Salmonella enterica is dependent on the presence of O-antigen but not on serovar classification. AB - Salmonella vaccines used in poultry in the EU are based on attenuated strains of either Salmonella serovar Enteritidis or Typhimurium which results in a decrease in S. Enteritidis and S. Typhimurium but may allow other Salmonella serovars to fill an empty ecological niche. In this study we were therefore interested in the early interactions of chicken immune system with S. Infantis compared to S. Enteritidis and S. Typhimurium, and a role of O-antigen in these interactions. To reach this aim, we orally infected newly hatched chickens with 7 wild type strains of Salmonella serovars Enteritidis, Typhimurium and Infantis as well as with their rfaL mutants and characterized the early Salmonella-chicken interactions. Inflammation was characterized in the cecum 4 days post-infection by measuring expression of 43 different genes. All wild type strains stimulated a greater inflammatory response than any of the rfaL mutants. However, there were large differences in chicken responses to different wild type strains not reflecting their serovar classification. The initial interaction between newly hatched chickens and Salmonella was found to be dependent on the presence of O antigen but not on its structure, i.e. not on serovar classification. In addition, we observed that the expression of calbindin or aquaporin 8 in the cecum did not change if inflammatory gene expression remained within a 10 fold fluctuation, indicating the buffering capacity of the cecum, preserving normal gut functions even in the presence of minor inflammatory stimuli. PMID- 24763250 TI - Chronology of Fabry-Perot interferometer fiber-optic sensors and their applications: a review. AB - Optical fibers have been involved in the area of sensing applications for more than four decades. Moreover, interferometric optical fiber sensors have attracted broad interest for their prospective applications in sensing temperature, refractive index, strain measurement, pressure, acoustic wave, vibration, magnetic field, and voltage. During this time, numerous types of interferometers have been developed such as Fabry-Perot, Michelson, Mach-Zehnder, Sagnac Fiber, and Common-path interferometers. Fabry-Perot interferometer (FPI) fiber-optic sensors have been extensively investigated for their exceedingly effective, simple fabrication as well as low cost aspects. In this study, a wide variety of FPI sensors are reviewed in terms of fabrication methods, principle of operation and their sensing applications. The chronology of the development of FPI sensors and their implementation in various applications are discussed. PMID- 24763251 TI - Non-destructive quality evaluation of pepper (Capsicum annuum L.) seeds using LED induced hyperspectral reflectance imaging. AB - In this study, we developed a viability evaluation method for pepper (Capsicum annuum L.) seeds based on hyperspectral reflectance imaging. The reflectance spectra of pepper seeds in the 400-700 nm range are collected from hyperspectral reflectance images obtained using blue, green, and red LED illumination. A partial least squares-discriminant analysis (PLS-DA) model is developed to classify viable and non-viable seeds. Four spectral ranges generated with four types of LEDs (blue, green, red, and RGB), which were pretreated using various methods, are investigated to develop the classification models. The optimal PLS DA model based on the standard normal variate for RGB LED illumination (400-700 nm) yields discrimination accuracies of 96.7% and 99.4% for viable seeds and nonviable seeds, respectively. The use of images based on the PLS-DA model with the first-order derivative of a 31.5-nm gap for red LED illumination (600-700 nm) yields 100% discrimination accuracy for both viable and nonviable seeds. The results indicate that a hyperspectral imaging technique based on LED light can be potentially applied to high-quality pepper seed sorting. PMID- 24763252 TI - Model parameter adaption-based multi-model algorithm for extended object tracking using a random matrix. AB - Traditional object tracking technology usually regards the target as a point source object. However, this approximation is no longer appropriate for tracking extended objects such as large targets and closely spaced group objects. Bayesian extended object tracking (EOT) using a random symmetrical positive definite (SPD) matrix is a very effective method to jointly estimate the kinematic state and physical extension of the target. The key issue in the application of this random matrix-based EOT approach is to model the physical extension and measurement noise accurately. Model parameter adaptive approaches for both extension dynamic and measurement noise are proposed in this study based on the properties of the SPD matrix to improve the performance of extension estimation. An interacting multi-model algorithm based on model parameter adaptive filter using random matrix is also presented. Simulation results demonstrate the effectiveness of the proposed adaptive approaches and multi-model algorithm. The estimation performance of physical extension is better than the other algorithms, especially when the target maneuvers. The kinematic state estimation error is lower than the others as well. PMID- 24763253 TI - Floor sensing system using laser reflectivity for localizing everyday objects and robot. AB - This paper describes a new method of measuring the position of everyday objects and a robot on the floor using distance and reflectance acquired by laser range finder (LRF). The information obtained by this method is important for a service robot working in a human daily life environment. Our method uses only one LRF together with a mirror installed on the wall. Moreover, since the area of sensing is limited to a LRF scanning plane parallel to the floor and just a few centimeters above the floor, the scanning covers the whole room with minimal invasion of privacy of a resident, and occlusion problem is mitigated by using mirror. We use the reflection intensity and position information obtained from the target surface. Although it is not possible to identify all objects by additionally using reflection values, it would be easier to identify unknown objects if we can eliminate easily identifiable objects by reflectance. In addition, we propose a method for measuring the robot's pose using the tag which has the encoded reflection pattern optically identified by the LRF. Our experimental results validate the effectiveness of the proposed method. PMID- 24763254 TI - The enhanced locating performance of an integrated cross-correlation and genetic algorithm for radio monitoring systems. AB - The rapid development of wireless broadband communication technology has affected the location accuracy of worldwide radio monitoring stations that employ time difference-of-arrival (TDOA) location technology. In this study, TDOA-based location technology was implemented in Taiwan for the first time according to International Telecommunications Union Radiocommunication (ITU-R) recommendations regarding monitoring and location applications. To improve location accuracy, various scenarios, such as a three-dimensional environment (considering an unequal locating antenna configuration), were investigated. Subsequently, the proposed integrated cross-correlation and genetic algorithm was evaluated in the metropolitan area of Tainan. The results indicated that the location accuracy at a circular error probability of 50% was less than 60 m when a multipath effect was present in the area. Moreover, compared with hyperbolic algorithms that have been applied in conventional TDOA-based location systems, the proposed algorithm yielded 17-fold and 19-fold improvements in the mean difference when the location position of the interference station was favorable and unfavorable, respectively. Hence, the various forms of radio interference, such as low transmission power, burst and weak signals, and metropolitan interference, was proved to be easily identified, located, and removed. PMID- 24763255 TI - A multi-resolution approach for an automated fusion of different low-cost 3D sensors. AB - The 3D acquisition of object structures has become a common technique in many fields of work, e.g., industrial quality management, cultural heritage or crime scene documentation. The requirements on the measuring devices are versatile, because spacious scenes have to be imaged with a high level of detail for selected objects. Thus, the used measuring systems are expensive and require an experienced operator. With the rise of low-cost 3D imaging systems, their integration into the digital documentation process is possible. However, common low-cost sensors have the limitation of a trade-off between range and accuracy, providing either a low resolution of single objects or a limited imaging field. Therefore, the use of multiple sensors is desirable. We show the combined use of two low-cost sensors, the Microsoft Kinect and the David laserscanning system, to achieve low-resolved scans of the whole scene and a high level of detail for selected objects, respectively. Afterwards, the high-resolved David objects are automatically assigned to their corresponding Kinect object by the use of surface feature histograms and SVM-classification. The corresponding objects are fitted using an ICP-implementation to produce a multi-resolution map. The applicability is shown for a fictional crime scene and the reconstruction of a ballistic trajectory. PMID- 24763257 TI - Cloning and expression analysis of litchi (Litchi Chinensis Sonn.) polyphenol oxidase gene and relationship with postharvest pericarp browning. AB - Polyphenol oxidase (PPO) plays a key role in the postharvest pericarp browning of litchi fruit, but its underlying mechanism remains unclear. In this study, we cloned the litchi PPO gene (LcPPO, JF926153), and described its expression patterns. The LcPPO cDNA sequence was 2120 bps in length with an open reading frame (ORF) of 1800 bps. The ORF encoded a polypeptide with 599 amino acid residues, sharing high similarities with other plant PPO. The DNA sequence of the ORF contained a 215-bp intron. After carrying out quantitative RT-PCR, we proved that the LcPPO expression was tissue-specific, exhibiting the highest level in the flower and leaf. In the pericarp of newly-harvested litchi fruits, the LcPPO expression level was relatively high compared with developing fruits. Regardless of the litchi cultivar and treatment conditions, the LcPPO expression level and the PPO activity in pericarp of postharvest fruits exhibited the similar variations. When the fruits were stored at room temperature without packaging, all the pericarp browning index, PPO activity and the LcPPO expression level of litchi pericarps were reaching the highest in Nandaowuhe (the most rapid browning cultivar), but the lowest in Ziniangxi (the slowest browning cultivar) within 2 d postharvest. Preserving the fruits of Feizixiao in 0.2-MUm plastic bag at room temperature would decrease the rate of pericarp water loss, delay the pericarp browning, and also cause the reduction of the pericarp PPO activity and LcPPO expression level within 3 d postharvest. In addition, postharvest storage of Feizixiao fruit stored at 4 degrees C delayed the pericarp browning while decreasing the pericarp PPO activity and LcPPO expression level within 2 d after harvest. Thus, we concluded that the up-regulation of LcPPO expression in pericarp at early stage of postharvest storage likely enhanced the PPO activity and further accelerated the postharvest pericarp browning of litchi fruit. PMID- 24763258 TI - Scanning gate imaging of a disordered quantum point contact. AB - Scanning gate microscopy (SGM) is a novel technique that has been used to image characteristic features related to the coherent electron flow in mesoscopic structures. For instance, SGM has successfully been applied to study peculiar electron transport properties that arise due to small levels of disorder in a system. The particular case of an InGaAs quantum well layer in a heterostructure, which is dominated by a quasi-ballistic regime, was analyzed. A quantum point contact fabricated onto this material exhibits conduction fluctuations that are not expected in typical high-mobility heterostructures such as AlGaAs/GaAs. SGM revealed not only interference patterns corresponding to specific conductance fluctuations but also mode-dependent resistance peaks corresponding to the first and second quantum levels of conductance (2e(2)/h) at zero magnetic field. On the other hand, clear conductance plateaus originating from the integer quantum Hall effect were observed at high magnetic fields. The physical size of incompressible edge channels was estimated from cross-sectional analysis of these images. PMID- 24763256 TI - An investigation into the protein composition of the teneral Glossina morsitans morsitans peritrophic matrix. AB - BACKGROUND: Tsetse flies serve as biological vectors for several species of African trypanosomes. In order to survive, proliferate and establish a midgut infection, trypanosomes must cross the tsetse fly peritrophic matrix (PM), which is an acellular gut lining surrounding the blood meal. Crossing of this multi layered structure occurs at least twice during parasite migration and development, but the mechanism of how trypanosomes do so is not understood. In order to better comprehend the molecular events surrounding trypanosome penetration of the tsetse PM, a mass spectrometry-based approach was applied to investigate the PM protein composition using Glossina morsitans morsitans as a model organism. METHODS: PMs from male teneral (young, unfed) flies were dissected, solubilised in urea/SDS buffer and the proteins precipitated with cold acetone/TCA. The PM proteins were either subjected to an in-solution tryptic digestion or fractionated on 1D SDS-PAGE, and the resulting bands digested using trypsin. The tryptic fragments from both preparations were purified and analysed by LC-MS/MS. RESULTS: Overall, nearly 300 proteins were identified from both analyses, several of those containing signature Chitin Binding Domains (CBD), including novel peritrophins and peritrophin-like glycoproteins, which are essential in maintaining PM architecture and may act as trypanosome adhesins. Furthermore, 27 proteins from the tsetse secondary endosymbiont, Sodalis glossinidius, were also identified, suggesting this bacterium is probably in close association with the tsetse PM. CONCLUSION: To our knowledge this is the first report on the protein composition of teneral G. m. morsitans, an important vector of African trypanosomes. Further functional analyses of these proteins will lead to a better understanding of the tsetse physiology and may help identify potential molecular targets to block trypanosome development within the tsetse. PMID- 24763260 TI - Combined effects of connective tissue growth factor-modified bone marrow-derived mesenchymal stem cells and NaOH-treated PLGA scaffolds on the repair of articular cartilage defect in rabbits. AB - In cartilage tissue engineering using stem cells, it is important to stimulate proliferation and control the differentiation of stem cells to specific lineages. Here we reported a combined technique for articular cartilage repair, consisting of bone marrow mesenchymal stem cells (BMMSCs) transfected with connective tissue growth factor (CTGF) gene and NaOH-treated poly(lactic-co-glycolic) acid (PLGA) scaffolds. In the present study, BMMSCs or CTGF-modified BMMSCs seeded on PLGA or NaOH-treated PLGA scaffolds were incubated in vitro and NaOH-treated PLGA significantly stimulated proliferation of BMMSCs, while CTGF gene transfer promoted chondrogenic differentiation. The effects of the composite on the repair of cartilage defects were evaluated in rabbit knee joints in vivo. Full-thickness cartilage defects (diameter: 5 mm; depth: 3 mm) were created unilaterally in the patellar groove. Defects were either left empty (n = 18) or implanted with BMMSCs/PLGA (n = 18), BMMSCs/NaOH-treated PLGA (n = 18), or CTGF-modified BMMSCs/NaOH-treated PLGA (n = 18). The defect area was examined grossly, histologically, and mechanically at 6, 12, and 24 weeks postoperatively. Implanted cells were tracked using adeno-LacZ labeling at 6 weeks after implantation. Overall, the CTGF-modified BMMSCs/NaOH-treated PLGA group showed successful hyaline-like cartilage regeneration similar to normal cartilage, which was superior to the other groups using gross examination, qualitative and quantitative histology, and mechanical assessment. The in vivo viability of the implanted cells was demonstrated by their retention for 6 weeks after implantation. These findings suggested that a combination of CTGF-modified BMMSCs and NaOH-treated PLGA may be an alternative treatment for large osteochondral defects in high-loading sites. PMID- 24763261 TI - Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening. AB - Rapid Overlay of Chemical Structures (ROCS), which can rapidly identify potentially active compounds by shape comparison, is recognized as a powerful virtual screening tool. By ROCS, a class of novel Hsp90 inhibitors was identified. The calculated binding mode of the most potent hit 36 guided us to design and synthesize a series of analogs (57a-57h). Over 100-fold improvement was achieved in the target-based assay. The most potent compound 57h inhibited Hsp90 with IC50 0.10 +/- 0.01 MUM. It also showed much improved cell potency and ligand efficiency. Our study showed that ROCS is efficient in the identification of novel cores of Hsp90 inhibitors. 57h can be ideal leads for further optimization. PMID- 24763262 TI - 4-Oxo-1,4-dihydro-quinoline-3-carboxamides as BACE-1 inhibitors: synthesis, biological evaluation and docking studies. AB - In this work, we report a series of new 4-oxo-1,4-dihydro-quinoline-3-carboxamide derivatives as beta-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. The studies revealed that the most potent analog 14e (IC50 = 1.89 MUM) with low cellular cytotoxicity and high predicted blood brain barrier permeability, could serve as a good structure for further modification. PMID- 24763263 TI - Synthesis and biological evaluation of some novel pyrido[1,2-a]pyrimidin-4-ones as antimalarial agents. AB - Novel pyrido[1,2-a]pyrimidin-4-ones have been synthesized and evaluated for their antimalarial activity by SYBR Green I assay against erythrocytic stages of chloroquine (CQ) sensitive Pf 3D7 strain. The antimalarial screening of 42 different compounds revealed that 3-Fluorobenzyl(4-oxo-4H-pyrido [1,2-a]pyrimidin 3-yl)carbamate (21, IC50 value 33 MUM) and 4-Oxo-N-[4-(trifluoromethyl)benzyl]-4H pyrido[1,2-a]pyrimidine-3-carboxamide (37, IC50 value 37 MUM) showed moderate antimalarial activity. Cytotoxicity study was performed against mammalian cell line (Huh-7) by using the MTT assay for the moderately active compounds. Structural activity relationship (SAR) studies displayed that B-ring unsubstituted pyrido[1,2-a]pyrimidine scaffold is responsible for the antimalarial activities of the evaluated derivatives. This SAR based antimalarial screening supported that pyrido[1,2-a]pyrimidin-4-one can be considered as a lead heterocyclic structure for further development of more potent derivatives for antimalarial activity. PMID- 24763264 TI - Synthesis and biological evaluation of novel (123)I-labeled 4-(4 iodophenyl)butanoyl-L-prolyl-(2S)-pyrrolidines for imaging prolyl oligopeptidase in vivo. AB - Prolyl oligopeptidase (POP) may be associated with neuromodulation and development of neurodegenerative diseases and it was recently shown to participate in the inflammatory cascade along with matrix metalloproteinases. Radiotracers, which can be used for non-invasive imaging, are needed for investigating the role of POP in normal physiology and in pathophysiological conditions in vivo. We synthesized two novel POP-specific (123)I-radiolabeled 4 phenylbutanoyl-L-prolyl-pyrrolidines of which 4-(4-[(123)I]iodophenyl)butanoyl-L prolyl-2(S)-cyanopyrrolidine ([(123)I]2f, Ki = 4.2 nM) was selected. The selected compound has an electrophilic cyano group that is known to increase the dissociation time of POP inhibitors. [(123)I]2f was synthesized in high radiochemical yield and purity (87 +/- 4%, >99%, respectively) and with a specific activity of 456 +/- 98 GBq/MUmol. [(123)I]2f was evaluated in healthy mice (C57Bl/6JRccHsd) by ex vivo biodistribution studies and SPECT imaging. Pretreatment with the known inhibitor 4-phenylbutanoyl-L-prolyl-(2S) cyanopyrrolidine (KYP-2047, 2d, Ki = 0.023 nM) showed that binding of [(123)I]2f was POP specific. In addition, [(123)I]2f was evaluated in models of neuroinflammation and acute localized inflammation. A minor increase in binding of [(123)I]2f was observed in the inflamed region in the acute localized inflammation model. Similar increase in binding was not observed in the neuroinflammation model. PMID- 24763265 TI - Design, synthesis and biological evaluation of some novel substituted quinazolines as antitumor agents. AB - A novel series of 6-chloro-2-p-tolylquinazolinone and substituted-(4 methylbenzamido)benzamide (1-20) were designed, synthesized and evaluated for their in-vitro antitumor activity. Compounds 3, 14 and 16 possessed remarkable broad-spectrum antitumor activity. Compound 16 was found to be a particularly active growth inhibitor of the renal cancer (GI50 = 4.07 MUM), CNS cancer (GI50 = 7.41 MUM), ovarian cancer (GI50 = 7.41 MUM) and non-small cell lung cancer (GI50 = 7.94 MUM). Compound 16 ranks as nearly 1.5-fold more potent (mean GI50 = 15.8 MUM) compared to 5-FU (mean GI50 = 22.6 MUM). PMID- 24763266 TI - Pharmacokinetic properties of arsenic species after oral administration of Sargassum pallidum extract in rats using an HPLC-HG-AFS method. AB - Sargassum pallidum is one of the Traditional Chinese Medicine widely used for phlegm elimination and detumescence. Arsenic is present in high concentration in seaweed belonging to the genus Sargassum. Therefore, the consumption of S. pallidum is a route of exposure to arsenic. Since the toxicity of arsenic is highly dependent on its chemical speciation, the determination of total arsenic is not adequate to assess the risks. Here, a high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) was developed for determination of the common arsenic species including arsenite [As(III)], dimethylarsinate (DMA), methylarsonate (MMA) and arsenate [As(V)] simultaneously. This method was applied to study the pharmacokinetic profile of these arsenic species in rats after oral administration of S. pallidum extract at different doses. The described assay was validated for limit of quantification, linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability according to the FDA validation guidelines. As(III) or MMA was not detected in any samples collected at all time points using the present HPLC-HG AFS method. As(V) and DMA in the S. pallidum could be readily absorbed and eliminated in rats. A trend of dose-dependence was shown for DMA and As(V) in the drug concentration-time profiles. This study would be helpful for the apprehension of the action mechanism and clinical application of medicinal seaweeds. PMID- 24763267 TI - Evidence into practice: a look at epic 3 in IV therapy nursing. PMID- 24763268 TI - Paediatric ICU nurses: preventing central venous device infections. PMID- 24763269 TI - The One Million Global Catheters PIVC worldwide prevalence study. PMID- 24763270 TI - Long-term central IV access in patients with mitochondrial disease. AB - Mitochondrial disease results from alteration in genes that control mitochondrial function. Patients with this disease present with multisystem organ involvement that may include gastrointestinal (GI) tract dysfunction, including obstruction, pseudo obstruction, bowel infarction and malabsorption syndromes. For this reason, care of this population may require long-term central intravenous (IV) access for administration of hyperalimentation, fluid, medications and blood products. Additionally, these patients may be immunosuppressed and at risk of sepsis. With vulnerability across many organ systems, symptom exacerbation can result from any physiological, psychological, or environmental stressor. There is no cure for mitochondrial disease, and quality-of-life goals are paramount. If GI tract dysfunction develops, treatment may require high-acuity level home care that includes the use of a central IV access device. This article presents an overview of this challenging population, and a plan for safe and effective central IV access care. PMID- 24763271 TI - An exploration of the past, present and future of catheter securement. PMID- 24763273 TI - Community and congress: communicate and collaborate. PMID- 24763272 TI - Blood transfusion sampling and a greater role for error recovery. AB - INTRODUCTION: Patient identification errors in pre-transfusion blood sampling ('wrong blood in tube') are a persistent area of risk. These errors can potentially result in life-threatening complications. Current measures to address root causes of incidents and near misses have not resolved this problem and there is a need to look afresh at this issue. PROJECT PURPOSE: This narrative review of the literature is part of a wider system-improvement project designed to explore and seek a better understanding of the factors that contribute to transfusion sampling error as a prerequisite to examining current and potential approaches to error reduction. SEARCH STRATEGY: A broad search of the literature was undertaken to identify themes relating to this phenomenon. KEY DISCOVERIES: Two key themes emerged from the literature. Firstly, despite multi-faceted causes of error, the consistent element is the ever-present potential for human error. Secondly, current focus on error prevention could potentially be augmented with greater attention to error recovery. CONCLUSIONS: Exploring ways in which clinical staff taking samples might learn how to better identify their own errors is proposed to add to current safety initiatives. PMID- 24763274 TI - Novice research: central venous access device care infections. AB - This article describes a literature review of published evidence on infection prevention and control in central venous access device (CVAD) care conducted by a novice researcher (lead author) under the supervision of her lecturer (second author). It includes details of the search as well as of the analysis which led to the selection and critical appraisal of a selected article identified and, importantly, discussion of the limitations and lessons learned by the novice researcher with her experimental approach. Infection control is paramount within nursing practice as a result of the number of healthcare-associated infections, which are preventable if evidence-based practice is followed and when trust protocols are informed by evidence. The question posed by the author prior to undertaking the literature search related to whether the use of sterile gloves for CVADs reduces infections in the oncology patient population compared with the use of non-sterile gloves. The question was formulated using the PICO (Population, Intervention, Comparison, Outcome) process and relevant literature was located using CINAHL and MEDLINE databases. The results of the review demonstrated no significant difference in infection rates using sterile or non sterile gloves when handling CVADs but further research in this area is needed to validate the findings. PMID- 24763275 TI - Nurse-led line insertion and management in renal access. PMID- 24763276 TI - NICE CG 174: intravenous fluid therapy in adults in hospital. PMID- 24763278 TI - Dimerization interface of 3-hydroxyacyl-CoA dehydrogenase tunes the formation of its catalytic intermediate. AB - 3-Hydroxyacyl-CoA dehydrogenase (HAD, EC 1.1.1.35) is a homodimeric enzyme localized in the mitochondrial matrix, which catalyzes the third step in fatty acid beta-oxidation. The crystal structures of human HAD and subsequent complexes with cofactor/substrate enabled better understanding of HAD catalytic mechanism. However, numerous human diseases were found related to mutations at HAD dimerization interface that is away from the catalytic pocket. The role of HAD dimerization in its catalytic activity needs to be elucidated. Here, we solved the crystal structure of Caenorhabditis elegans HAD (cHAD) that is highly conserved to human HAD. Even though the cHAD mutants (R204A, Y209A and R204A/Y209A) with attenuated interactions on the dimerization interface still maintain a dimerization form, their enzymatic activities significantly decrease compared to that of the wild type. Such reduced activities are in consistency with the reduced ratios of the catalytic intermediate formation. Further molecular dynamics simulations results reveal that the alteration of the dimerization interface will increase the fluctuation of a distal region (a.a. 60 80) that plays an important role in the substrate binding. The increased fluctuation decreases the stability of the catalytic intermediate formation, and therefore the enzymatic activity is attenuated. Our study reveals the molecular mechanism about the essential role of the HAD dimerization interface in its catalytic activity via allosteric effects. PMID- 24763277 TI - A novel highly divergent protein family identified from a viviparous insect by RNA-seq analysis: a potential target for tsetse fly-specific abortifacients. AB - In tsetse flies, nutrients for intrauterine larval development are synthesized by the modified accessory gland (milk gland) and provided in mother's milk during lactation. Interference with at least two milk proteins has been shown to extend larval development and reduce fecundity. The goal of this study was to perform a comprehensive characterization of tsetse milk proteins using lactation-specific transcriptome/milk proteome analyses and to define functional role(s) for the milk proteins during lactation. Differential analysis of RNA-seq data from lactating and dry (non-lactating) females revealed enrichment of transcripts coding for protein synthesis machinery, lipid metabolism and secretory proteins during lactation. Among the genes induced during lactation were those encoding the previously identified milk proteins (milk gland proteins 1-3, transferrin and acid sphingomyelinase 1) and seven new genes (mgp4-10). The genes encoding mgp2 10 are organized on a 40 kb syntenic block in the tsetse genome, have similar exon-intron arrangements, and share regions of amino acid sequence similarity. Expression of mgp2-10 is female-specific and high during milk secretion. While knockdown of a single mgp failed to reduce fecundity, simultaneous knockdown of multiple variants reduced milk protein levels and lowered fecundity. The genomic localization, gene structure similarities, and functional redundancy of MGP2-10 suggest that they constitute a novel highly divergent protein family. Our data indicates that MGP2-10 function both as the primary amino acid resource for the developing larva and in the maintenance of milk homeostasis, similar to the function of the mammalian casein family of milk proteins. This study underscores the dynamic nature of the lactation cycle and identifies a novel family of lactation-specific proteins, unique to Glossina sp., that are essential to larval development. The specificity of MGP2-10 to tsetse and their critical role during lactation suggests that these proteins may be an excellent target for tsetse specific population control approaches. PMID- 24763279 TI - Dietary flavanols modulate the transcription of genes associated with cardiovascular pathology without changes in their DNA methylation state. AB - BACKGROUND: In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation. METHODOLOGY/PRINCIPAL FINDINGS: Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-alpha-stimulated endothelial cells. Nuclear factor kappa B (NF-kappaB) reporter gene assays confirmed that MOF decrease the activity of NF-kappaB. Strong inter-individual variability in the leukocytes' DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found. CONCLUSION: Our study revealed that an 8 week daily supplementation with 200 mg MOF modulates the expression of genes associated with cardiovascular disease pathways without major changes of their DNA methylation state. However, strong inter-individual variation in leukocyte DNA methylation may obscure the subtle epigenetic response to dietary flavanols. Despite the lack of significant changes in DNA methylation, the modulation of gene expression appears to contribute to the observed vascular health effect of MOF in humans. PMID- 24763280 TI - Widespread occurrence of expressed fungal secretory peroxidases in forest soils. AB - Fungal secretory peroxidases mediate fundamental ecological functions in the conversion and degradation of plant biomass. Many of these enzymes have strong oxidizing activities towards aromatic compounds and are involved in the degradation of plant cell wall (lignin) and humus. They comprise three major groups: class II peroxidases (including lignin peroxidase, manganese peroxidase, versatile peroxidase and generic peroxidase), dye-decolorizing peroxidases, and heme-thiolate peroxidases (e.g. unspecific/aromatic peroxygenase, chloroperoxidase). Here, we have repeatedly observed a widespread expression of all major peroxidase groups in leaf and needle litter across a range of forest ecosystems (e.g. Fagus, Picea, Acer, Quercus, and Populus spp.), which are widespread in Europe and North America. Manganese peroxidases and unspecific peroxygenases were found expressed in all nine investigated forest sites, and dye decolorizing peroxidases were observed in five of the nine sites, thereby indicating biological significance of these enzymes for fungal physiology and ecosystem processes. Transcripts of selected secretory peroxidase genes were also analyzed in pure cultures of several litter-decomposing species and other fungi. Using this information, we were able to match, in environmental litter samples, two manganese peroxidase sequences to Mycena galopus and Mycena epipterygia and one unspecific peroxygenase transcript to Mycena galopus, suggesting an important role of this litter- and coarse woody debris-dwelling genus in the disintegration and transformation of litter aromatics and organic matter formation. PMID- 24763282 TI - FRA2A is a CGG repeat expansion associated with silencing of AFF3. AB - Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship. PMID- 24763284 TI - Prognostic significance of the pN classification supplemented by vascular invasion for esophageal squamous cell carcinoma. AB - BACKGROUND: The biological behavior and clinical outcome of esophageal squamous cell carcinoma (ESCC) are difficult to predict. METHODOLOGY/PRINCIPAL FINDINGS: We investigate the prognostic impact of vascular invasion to establish a risk stratification model to predict recurrence and overall survival. We retrospectively evaluated the vascular invasion of 433 patients with ESCC treated with surgery between 2000 and 2007 at a single academic center. Those patients were assigned to a testing cohort and a validation cohort by random number generated in computer. The presence of vascular invasion was observed in 113 of 216 (52.3%) and 96 of 217 (44.2%) of ESCC in the training and validation cohorts, respectively. Further correlation analysis demonstrated that vascular invasion in ESCC was significantly correlated with more advanced pN classification and stage in both cohorts (P<0.05). Additionally, presence of vascular invasion in ESCC patients was associated closely with poor overall and recurrence-free survival as evidenced by univariate and multivariate analysis in both cohorts (P<0.05). In the subset of ESCC patients without lymph node metastasis, vascular invasion was evaluated as a prognostic predictor as well (P<0.05). More importantly, the combined prognostic model with pN classification supplemented by vascular invasion can significantly stratify the risk (low, intermediate and high) for overall survival and recurrence-free survival in both cohorts (P<0.05). The C index to the combined model showed improved predictive ability when compared to the pN classification (0.785 vs 0.739 and 0.689 vs 0.650 for the training and validation cohorts, respectively; P<0.05). CONCLUSIONS/SIGNIFICANCE: The examination of vascular invasion could be used as an additional effective instrument in identifying those ESCC patients at increased risk of tumor progression. The proposed new prognostic model with the pN classification supplemented by vascular invasion might improve the ability to discriminate ESCC patients' outcome. PMID- 24763285 TI - Alternative splicing contributes to the coordinated regulation of ferritin subunit levels in Bactrocera dorsalis (Hendel). AB - A constant ratio of ferritin heavy chain homolog (HCH) and light chain homolog (LCH) subunits seems to be required to compose the ferritin heteropolymer protein in insects. However, the mechanism by which insect LCH genes regulate protein levels remains unclear. We report that alternative promoters and alternative splicing contribute to maintaining a constant ratio of the two subunits, BdFer1HCH and BdFer2LCH (ferritin 1 HCH and ferritin 2 LCH), in Bactrocera dorsalis, a notorious quarantine pest. The genes BdFer1HCH and BdFer2LCH were identified with a series of potential transcription factor binding sites and were shown to be clustered within the genome in a "head to head" fashion. Thus, we unearthed a potential post-transcriptional mechanism to regulate the levels of LCH subunits, and confirmed that the expressions of BdFer1HCH and BdFer2LCH were induced by 20-hydroecdysone, iron overload, and immune challenge. PMID- 24763283 TI - Presence of extensive Wolbachia symbiont insertions discovered in the genome of its host Glossina morsitans morsitans. AB - Tsetse flies (Glossina spp.) are the cyclical vectors of Trypanosoma spp., which are unicellular parasites responsible for multiple diseases, including nagana in livestock and sleeping sickness in humans in Africa. Glossina species, including Glossina morsitans morsitans (Gmm), for which the Whole Genome Sequence (WGS) is now available, have established symbiotic associations with three endosymbionts: Wigglesworthia glossinidia, Sodalis glossinidius and Wolbachia pipientis (Wolbachia). The presence of Wolbachia in both natural and laboratory populations of Glossina species, including the presence of horizontal gene transfer (HGT) events in a laboratory colony of Gmm, has already been shown. We herein report on the draft genome sequence of the cytoplasmic Wolbachia endosymbiont (cytWol) associated with Gmm. By in silico and molecular and cytogenetic analysis, we discovered and validated the presence of multiple insertions of Wolbachia (chrWol) in the host Gmm genome. We identified at least two large insertions of chrWol, 527,507 and 484,123 bp in size, from Gmm WGS data. Southern hybridizations confirmed the presence of Wolbachia insertions in Gmm genome, and FISH revealed multiple insertions located on the two sex chromosomes (X and Y), as well as on the supernumerary B-chromosomes. We compare the chrWol insertions to the cytWol draft genome in an attempt to clarify the evolutionary history of the HGT events. We discuss our findings in light of the evolution of Wolbachia infections in the tsetse fly and their potential impacts on the control of tsetse populations and trypanosomiasis. PMID- 24763286 TI - Molecular diagnosis of putative Stargardt disease by capture next generation sequencing. AB - Stargardt Disease (STGD) is the commonest genetic form of juvenile or early adult onset macular degeneration, which is a genetically heterogeneous disease. Molecular diagnosis of STGD remains a challenge in a significant proportion of cases. To address this, seven patients from five putative STGD families were recruited. We performed capture next generation sequencing (CNGS) of the probands and searched for potentially disease-causing genetic variants in previously identified retinal or macular dystrophy genes. Seven disease-causing mutations in ABCA4 and two in PROM1 were identified by CNGS, which provides a confident genetic diagnosis in these five families. We also provided a genetic basis to explain the differences among putative STGD due to various mutations in different genes. Meanwhile, we show for the first time that compound heterozygous mutations in PROM1 gene could cause cone-rod dystrophy. Our findings support the enormous potential of CNGS in putative STGD molecular diagnosis. PMID- 24763287 TI - Framework for development of physician competencies in genomic medicine: report of the Competencies Working Group of the Inter-Society Coordinating Committee for Physician Education in Genomics. AB - Completion of the Human Genome Project, in conjunction with dramatic reductions in the cost of DNA sequencing and advances in translational research, is gradually ushering genomic discoveries and technologies into the practice of medicine. The rapid pace of these advances is opening up a gap between the knowledge available about the clinical relevance of genomic information and the ability of clinicians to include such information in their medical practices. This educational gap threatens to be rate limiting to the clinical adoption of genomics in medicine. Solutions will require not only a better understanding of the clinical implications of genetic discoveries but also training in genomics at all levels of professional development, including for individuals in formal training and others who long ago completed such training. The National Human Genome Research Institute has convened the Inter-Society Coordinating Committee for Physician Education in Genomics (ISCC) to develop and share best practices in the use of genomics in medicine. The ISCC has developed a framework for development of genomics practice competencies that may serve as a starting point for formulation of competencies for physicians in various medical disciplines. PMID- 24763288 TI - Underutilization of specimens in biobanks: an ethical as well as a practical concern? PMID- 24763289 TI - Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. AB - PURPOSE: The aim of this study was to determine the clinical and molecular characteristics of 2,079 patients who underwent hereditary cancer multigene panel testing. METHODS: Panels included comprehensive analysis of 14-22 cancer susceptibility genes (BRCA1 and BRCA2 not included), depending on the panel ordered (BreastNext, OvaNext, ColoNext, or CancerNext). Next-generation sequencing and deletion/duplication analyses were performed for all genes except EPCAM (deletion/duplication analysis only). Clinical histories of ColoNext patients harboring mutations in genes with well-established diagnostic criteria were assessed to determine whether diagnostic/testing criteria were met. RESULTS: Positive rates were defined as the proportion of patients with a pathogenic mutation/likely pathogenic variant(s) and were as follows: 7.4% for BreastNext, 7.2% for OvaNext, 9.2% for ColoNext, and 9.6% for CancerNext. Inconclusive results were found in 19.8% of BreastNext, 25.6% of OvaNext, 15.1% of ColoNext, and 23.5% of CancerNext tests. Based on information submitted by clinicians, 30% of ColoNext patients with mutations in genes with well-established diagnostic criteria did not meet corresponding criteria. CONCLUSION: Our data point to an important role for targeted multigene panels in diagnosing hereditary cancer predisposition, particularly for patients with clinical histories spanning several possible diagnoses and for patients with suspicious clinical histories not meeting diagnostic criteria for a specific hereditary cancer syndrome. PMID- 24763290 TI - Genetic legacy and the genomic future. PMID- 24763291 TI - A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis. AB - PURPOSE: Schwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease. METHODS: We performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family. RESULTS: We identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells. CONCLUSION: Although the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792. PMID- 24763293 TI - The NMC's top table: where have all the nurses gone? PMID- 24763292 TI - Unaffected family members report improvements in daily routine sun protection 2 years following melanoma genetic testing. AB - PURPOSE: Reducing ultraviolet radiation exposure may decrease melanoma risk in the hereditary melanoma setting. It is unknown whether genetic counseling and test reporting of CDKN2A/p16 mutation status promote long-term compliance with photoprotection recommendations, especially in unaffected mutation carriers. METHODS: This study evaluated changes 2 years following melanoma genetic testing in self-reported practice of sun protection (sunscreen, photoprotective clothing, and ultraviolet radiation avoidance) among 37 members of two CDKN2A/p16 kindreds (10 unaffected carriers, 11 affected carriers, and 16 unaffected noncarriers; response rate = 64.9% of eligible participants). RESULTS: Multivariate profile analysis indicated that all three participant groups reported increased daily routine practice of sun protection 2 years following melanoma genetic testing (P < 0.02), with 96.9% reporting that at least one sun protection behavior was part of their daily routine, up from 78.1% at baseline (P < 0.015). Unaffected carriers (P < 0.024) and unaffected noncarriers (P < 0.027) reported significantly more frequent use of photoprotective clothing. Affected carriers maintained adherence to all sun protection behaviors. Reported sunburns in the past 6 months decreased significantly (P < 0.018). CONCLUSION: Members of high risk families reported increased daily routine sun protection and decreased sunburns 2 years following melanoma genetic testing, with no net decline in sun protection following negative test results. Thus, genetic testing and counseling may motivate sustained improvements in prevention behaviors. PMID- 24763294 TI - BJN Awards 2014: Lifetime Achievement winner. PMID- 24763295 TI - Nurses' role in clinical commissioning. PMID- 24763296 TI - Why don't nurses consistently take patient respiratory rates? AB - This is an investigation into nurses' practice of when they would not take and record a patient's respiratory rate. It reports results of qualitative, descriptive research involving interviews with ten ward nurses from three hospitals in New Zealand. Results affirm that, despite it being the most sensitive vital sign for managing patients, nurses acknowledged circumstances in which respiratory rate taking was missed. Reasons were complex and, contrary to expectations, not always associated with the introduction of technology to record other vital signs. Time pressures, work interruptions and rationalised judgements made by experienced nurses all contributed to incidences of missed respiratory rate taking. It is concluded that patient respiratory rate measures do not seem to be highly valued, calling into questions nurses' level of understanding of respiratory physiology, as well as the extent to which intuitive nursing practice is supported by critical analysis. PMID- 24763297 TI - Effects and impacts of Productive Ward from a nursing perspective. AB - The Productive Ward: releasing time to care (PW) initiative is predominantly a nurse-led quality improvement (QI) offering, designed to streamline ward work processes and clinical environments in an attempt to 'release time to care'. It has been implemented widely in the UK, recently attracting international interest. This paper systematically reviews the literature relating to the PW initiative, highlights and ranks the reported effects and impacts from a nursing perspective. Nine themes emerged from our content analysis. This paper examines the three most reported themes-empowerment, leadership and engagement-exploring how they may influence the opportunities for implementing and sustaining the initiative. This study brings some experience, learning and insight from the PW initiative to those currently involved in implementation. It also highlights some elements of change not being delivered by PW. The comprehensive list of reported impacts and effects, from a nursing perspective, adds value to senior nurses attempting to cultivate a culture of QI. PMID- 24763298 TI - Management of menopausal symptoms for breast cancer patients. AB - BACKGROUND: Menopausal symptoms are commonly experienced in women treated for breast cancer. This project aimed to identify the types and prevalence of menopausal symptoms women experience and assess how well such symptoms are managed by means of a clinical audit. The authors also wanted to identify whether patients and health professionals require further education in this area to enhance patients' quality of life. METHOD: A pilot audit was initially undertaken. Twenty women were recruited from medical and clinical oncology clinics spanning a 2-week period. The main audit was conducted over a 3-week period (19 March 2012 to 6 April 2012). A total of 215 patients were surveyed from 11 consultant-led and 1 nurse-led clinic per week. A menopause rating scale (MRS) developed by Heinemann et al (2003) was used to assess the types and severity of symptoms. RESULTS: Findings from the main audit provided preliminary evidence that certain breast cancer treatments can cause either the early onset of menopausal symptoms in pre-menopausal women or the return or aggravation of menopausal symptoms in peri-menopausal or post-menopausal women. This indicated that, for many women, symptoms are inadequately managed and supported. DISCUSSION: A more detailed exploratory study of the management of menopausal symptoms is needed. Health professionals should consider discussing such symptoms when patients start treatment and assess these symptoms at follow-up appointments to identify potential interventions. PMID- 24763299 TI - The use of deprivation of liberty safeguards in hospitals to increase. AB - The UK Supreme Court has delivered its long-awaited judgment on the factors to be considered when determining whether the care and treatment of a person amounts to a deprivation of liberty (Cheshire West and Chester Council v P [2014]). In this article the author discusses the impact of the Supreme Court's ruling on the use of the Mental Capacity Act's Deprivation of Liberty Safeguards in hospitals (Mental Capacity Act 2005, sections 4A&4B). PMID- 24763300 TI - Putting the patient's interests first in the NHS. PMID- 24763301 TI - Reducing the inappropriate use of restrictive interventions. PMID- 24763302 TI - Reflection: from staff nurse to nurse consultant. Part 6: reflective teaching. PMID- 24763303 TI - Advanced practice in nursing. PMID- 24763304 TI - Mammalian cells contain two functionally distinct PBAF complexes incorporating different isoforms of PHF10 signature subunit. AB - The PBAF subtype of the mammalian chromatin remodeling SWI/SNF complex has wide and diverse functions in transcription regulation and development, being both transcription activator and repressor. However, a mechanism accounting for such functional diversity remains unclear. Human PHF10/BAF45a subunit of the PBAF complex plays an important role in brain development but has not been studied sufficiently. We have shown that the PHF10 gene encodes 2 types of evolutionarily conserved, ubiquitously expressed isoforms that are incorporated into the PBAF complex in a mutually exclusive manner. One isoform contains C-terminal tandem PHD fingers, which in the other isoform are replaced by the consensus sequence for phosphorylation-dependent SUMO 1 conjugation (PDSM). PBAF complexes containing different PHF10 isoforms can bind to the promoters of the same genes but produce different effects on the recruitment of Pol II to the promoter and on the level of gene transcription. In addition, it is only the PBAF with PHD containing isoform that activates proliferation. Our study demonstrates the existence of functionally different PBAF complexes in mammalian cell. It also provides an insight into the molecular structure and role of human PHF10/BAF45a and characterizes it as an essential PBAF subunit. PMID- 24763305 TI - Association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma: a meta-analysis. AB - OBJECTIVES: To comprehensively evaluate the association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma. METHODS: Potential studies were searched and selected through the Pubmed/MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI) platforms, WanFang and VIP database up to June 2013. Two investigators independently reviewed full text and included studies met inclusion criteria. Combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in a fixed-effects model or a random-effects model according to results of heterogeneity test. All analyses were performed by Revman 5.2 and Stata 10.0 software. RESULTS: A total of 10 studies were included in our meta analysis, including 3,580 glioma patients and 4,728 controls. Overall, ERCC1 C8092A polymorphism was associated with the risk of glioma (AA vs. CC: OR = 1.29, 95%CI: 1.07-1.55, P = 0.01; recessive model: OR = 1.29; 95% CI: 1.07-1.55, P = 0.01). When stratified by ethnicity, significant association was only observed in the Chinese population (AA vs. CC: OR = 1.37, 95%CI: 1.03-1.81, P = 0.03; recessive model: OR = 1.34; 95% CI: 1.02-1.75, P = 0.04). For ERCC2 Lys751Gln polymorphism, no significant association was found between ERCC2 Lys751Gln polymorphism and the risk of glioma in different genetic models. A significant association of ERCC2 Lys751Gln polymorphism with the risk of glioma was identified in the Caucasian population under recessive model (OR = 0.87; 95% CI: 0.78-0.98, P = 0.02), but not in the Chinese population. CONCLUSION: This meta analysis suggested that the AA genotype of ERCC1 C8092A polymorphism might increase the susceptibility of glioma in the Chinese population. And the TT genotype of ERCC2 Lys751Gln polymorphism may decrease the risk of glioma in the Caucasian population. But the small number of studies and moderate methodological quality require cautious interpretation of the study results. PMID- 24763308 TI - Longer telomere length in COPD patients with alpha1-antitrypsin deficiency independent of lung function. AB - Oxidative stress is involved in the pathogenesis of airway obstruction in alpha1 antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in alpha1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 alpha1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in alpha1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1*10(-29)). Telomere length was not related to lung function in alpha1 antitrypsin deficient patients (p = 0.3122) or in COPD controls (p = 0.1430). Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078), telomere length was correlated between the two tissue types (p = 0.0122). Our results indicate that telomere length is better preserved in alpha1-antitrypsin deficient COPD patients than in non deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung. PMID- 24763309 TI - Sleeping sickness epidemics and colonial responses in East and Central Africa, 1900-1940. PMID- 24763310 TI - Computational biology and bioinformatics in Nigeria. AB - Over the past few decades, major advances in the field of molecular biology, coupled with advances in genomic technologies, have led to an explosive growth in the biological data generated by the scientific community. The critical need to process and analyze such a deluge of data and turn it into useful knowledge has caused bioinformatics to gain prominence and importance. Bioinformatics is an interdisciplinary research area that applies techniques, methodologies, and tools in computer and information science to solve biological problems. In Nigeria, bioinformatics has recently played a vital role in the advancement of biological sciences. As a developing country, the importance of bioinformatics is rapidly gaining acceptance, and bioinformatics groups comprised of biologists, computer scientists, and computer engineers are being constituted at Nigerian universities and research institutes. In this article, we present an overview of bioinformatics education and research in Nigeria. We also discuss professional societies and academic and research institutions that play central roles in advancing the discipline in Nigeria. Finally, we propose strategies that can bolster bioinformatics education and support from policy makers in Nigeria, with potential positive implications for other developing countries. PMID- 24763311 TI - Galactodendritic phthalocyanine targets carbohydrate-binding proteins enhancing photodynamic therapy. AB - Photosensitizers (PSs) are of crucial importance in the effectiveness of photodynamic therapy (PDT) for cancer. Due to their high reactive oxygen species production and strong absorption in the wavelength range between 650 and 850 nm, where tissue light penetration is rather high, phthalocyanines (Pcs) have been studied as PSs of excellence. In this work, we report the evaluation of a phthalocyanine surrounded by a carbohydrate shell of sixteen galactose units distributed in a dendritic manner (PcGal16) as a new and efficient third generation PSs for PDT against two bladder cancer cell lines, HT-1376 and UM-UC 3. Here, we define the role of galacto-dendritic units in promoting the uptake of a Pc through interaction with GLUT1 and galectin-1. The photoactivation of PcGal16 induces cell death by generating oxidative stress. Although PDT with PcGal16 induces an increase on the activity of antioxidant enzymes immediately after PDT, bladder cancer cells are unable to recover from the PDT-induced damage effects for at least 72 h after treatment. PcGal16 co-localization with galectin 1 and GLUT1 and/or generation of oxidative stress after PcGal16 photoactivation induces changes in the levels of these proteins. Knockdown of galectin-1 and GLUT1, via small interfering RNA (siRNA), in bladder cancer cells decreases intracellular uptake and phototoxicity of PcGal16. The results reported herein show PcGal16 as a promising therapeutic agent for the treatment of bladder cancer, which is the fifth most common type of cancer with the highest rate of recurrence of any cancer. PMID- 24763312 TI - A systematic comparison of supervised classifiers. AB - Pattern recognition has been employed in a myriad of industrial, commercial and academic applications. Many techniques have been devised to tackle such a diversity of applications. Despite the long tradition of pattern recognition research, there is no technique that yields the best classification in all scenarios. Therefore, as many techniques as possible should be considered in high accuracy applications. Typical related works either focus on the performance of a given algorithm or compare various classification methods. In many occasions, however, researchers who are not experts in the field of machine learning have to deal with practical classification tasks without an in-depth knowledge about the underlying parameters. Actually, the adequate choice of classifiers and parameters in such practical circumstances constitutes a long-standing problem and is one of the subjects of the current paper. We carried out a performance study of nine well-known classifiers implemented in the Weka framework and compared the influence of the parameter configurations on the accuracy. The default configuration of parameters in Weka was found to provide near optimal performance for most cases, not including methods such as the support vector machine (SVM). In addition, the k-nearest neighbor method frequently allowed the best accuracy. In certain conditions, it was possible to improve the quality of SVM by more than 20% with respect to their default parameter configuration. PMID- 24763306 TI - Almost all antipsychotics result in weight gain: a meta-analysis. AB - INTRODUCTION: Antipsychotics (AP) induce weight gain. However, reviews and meta analyses generally are restricted to second generation antipsychotics (SGA) and do not stratify for duration of AP use. It is hypothesised that patients gain more weight if duration of AP use is longer. METHOD: A meta-analysis was conducted of clinical trials of AP that reported weight change. Outcome measures were body weight change, change in BMI and clinically relevant weight change (7% weight gain or loss). Duration of AP-use was stratified as follows: <=6 weeks, 6 16 weeks, 16-38 weeks and >38 weeks. Forest plots stratified by AP as well as by duration of use were generated and results were summarised in figures. RESULTS: 307 articles met inclusion criteria. The majority were AP switch studies. Almost all AP showed a degree of weight gain after prolonged use, except for amisulpride, aripiprazole and ziprasidone, for which prolonged exposure resulted in negligible weight change. The level of weight gain per AP varied from discrete to severe. Contrary to expectations, switch of AP did not result in weight loss for amisulpride, aripiprazole or ziprasidone. In AP-naive patients, weight gain was much more pronounced for all AP. CONCLUSION: Given prolonged exposure, virtually all AP are associated with weight gain. The rational of switching AP to achieve weight reduction may be overrated. In AP-naive patients, weight gain is more pronounced. PMID- 24763314 TI - Proteomics based identification of cell migration related proteins in HBV expressing HepG2 cells. AB - Proteomics study was performed to investigate the specific protein expression profiles of HepG2 cells transfected with mutant HBV compared with wildtype HBV genome, aiming to identify the specific functions of SH3 binding domain (proline rich region) located in HBx. In addition to the cell movement and kinetics changes due to the expression of HBV genome we have observed previously, here we further targeted to explore the specific changes of cellular proteins and potential intracellular protein interactions, which might provide more information of the potential cellular mechanism of the differentiated cell movements. Specific changes of a number of proteins were shown in global protein profiling in HepG2 cells expressing wildtype HBV, including cell migration related proteins, and interestingly the changes were found recovered by SH3 binding domain mutated HBV. The distinctive expressions of proteins were validated by Western blot analysis. PMID- 24763315 TI - Phylogeny and patterns of diversity of goat mtDNA haplogroup A revealed by resequencing complete mitogenomes. AB - We sequenced to near completion the entire mtDNA of 28 Sardinian goats, selected to represent the widest possible diversity of the most widespread mitochondrial evolutionary lineage, haplogroup (Hg) A. These specimens were reporters of the diversity in the island but also elsewhere, as inferred from their affiliation to each of 11 clades defined by D-loop variation. Two reference sequences completed the dataset. Overall, 206 variations were found in the full set of 30 sequences, of which 23 were protein-coding non-synonymous single nucleotide substitutions. Many polymorphic sites within Hg A were informative for the reconstruction of its internal phylogeny. Bayesian and network clustering revealed a general similarity over the entire molecule of sequences previously assigned to the same D-loop clade, indicating evolutionarily meaningful lineages. Two major sister groupings emerged within Hg A, which parallel distinct geographical distributions of D-loop clades in extant stocks. The pattern of variation in protein-coding genes revealed an overwhelming role of purifying selection, with the quota of surviving variants approaching neutrality. However, a simple model of relaxation of selection for the bulk of variants here reported should be rejected. Non synonymous diversity of Hg's A, B and C denoted that a proportion of variants not greater than that allowed in the wild was given the opportunity to spread into domesticated stocks. Our results also confirmed that a remarkable proportion of pre-existing Hg A diversity became incorporated into domestic stocks. Our results confirm clade A11 as a well differentiated and ancient lineage peculiar of Sardinia. PMID- 24763316 TI - Single-electron transport in a three-ion magnetic molecule modulated by a transverse field. AB - We study single-electron transport in a three-ion molecule with strong uniaxial anisotropy and in the presence of a transverse magnetic field. Two magnetic ions are connected to each other through a third, nonmagnetic ion. The magnetic ions are coupled to ideal metallic leads and a back gate voltage is applied to the molecule, forming a field-effect transistor. The microscopic Hamiltonian describing this system includes inter-ion hopping, on-site repulsions and magnetic anisotropies. For a range of values of the parameters of the Hamiltonian, we obtain an energy spectrum similar to that of single-molecule magnets in the giant spin approximation where the two states with maximum spin projection along the uniaxial anisotropy axis are well separated from other states. In addition, upon applying an external in-plane magnetic field, the energy gap between the ground and first excited states of the molecule oscillates, going to zero at certain special values of the field, analogous to the diabolical points resulting from Berry phase interference in the giant spin model. Thus, our microscopic model provides the same phenomenological behavior expected from the giant spin model of a single-molecule magnet but with direct access to the internal structure of the molecule, thus making it more appropriate for realistic electronic transport studies. To illustrate this point, the nonlinear electronic transport in the sequential tunneling regime is evaluated for values of the field near these degeneracy points. We show that the existence of these points has a clear signature in the I-V characteristics of the molecule, most notably the modulation of excitation lines in the differential conductance. PMID- 24763319 TI - Assessment of Acropora palmata in the Mesoamerican Reef System. AB - The once-dominant shallow reef-building coral Acropora palmata has suffered drastic geographical declines in the wider Caribbean from a disease epidemic that began in the late 1970s. At present there is a lack of quantitative data to determine whether this species is recovering over large spatial scales. Here, we use quantitative surveys conducted in 107 shallow-water reef sites between 2010 and 2012 to investigate the current distribution and abundance of A. palmata along the Mesoamerican Reef System (MRS). Using historical data we also explored how the distribution and abundance of this species has changed in the northern portion of the MRS between 1985 and 2010-2012. A. palmata was recorded in only a fifth of the surveyed reef sites in 2010-2012. In the majority of these reef sites the presence of A. palmata was patchy and rare. Only one site (Limones reef), in the northernmost portion of the MRS, presented considerably high A. palmata cover (mean: 34.7%, SD: 24.5%). At this site, the size-frequency distribution of A. palmata colonies was skewed towards small colony sizes; 84% of the colonies were healthy, however disease prevalence increased with colony size. A comparison with historical data showed that in the northern portion of the MRS, in 1985, A. palmata occurred in 74% of the 31 surveyed sites and had a mean cover of 7.7% (SD = 9.0), whereas in 2010-2012 this species was recorded in 48% of the sites with a mean cover of 2.9% (SD = 7.5). A. palmata populations along the MRS are failing to recover the distribution and abundance they had prior to the 1980s. Investigating the biological (e.g., population genetics) and environmental conditions (e.g., sources of stress) of the few standing reefs with relatively high A. palmata cover is crucial for the development of informed restoration models for this species. PMID- 24763317 TI - Fast protein loop sampling and structure prediction using distance-guided sequential chain-growth Monte Carlo method. AB - Loops in proteins are flexible regions connecting regular secondary structures. They are often involved in protein functions through interacting with other molecules. The irregularity and flexibility of loops make their structures difficult to determine experimentally and challenging to model computationally. Conformation sampling and energy evaluation are the two key components in loop modeling. We have developed a new method for loop conformation sampling and prediction based on a chain growth sequential Monte Carlo sampling strategy, called Distance-guided Sequential chain-Growth Monte Carlo (DISGRO). With an energy function designed specifically for loops, our method can efficiently generate high quality loop conformations with low energy that are enriched with near-native loop structures. The average minimum global backbone RMSD for 1,000 conformations of 12-residue loops is 1:53 A degrees , with a lowest energy RMSD of 2:99 A degrees , and an average ensembleRMSD of 5:23 A degrees . A novel geometric criterion is applied to speed up calculations. The computational cost of generating 1,000 conformations for each of the x loops in a benchmark dataset is only about 10 cpu minutes for 12-residue loops, compared to ca 180 cpu minutes using the FALCm method. Test results on benchmark datasets show that DISGRO performs comparably or better than previous successful methods, while requiring far less computing time. DISGRO is especially effective in modeling longer loops (10-17 residues). PMID- 24763321 TI - Charitable funding: the need for transparency and accountability. PMID- 24763320 TI - Modeling to predict cases of hantavirus pulmonary syndrome in Chile. AB - BACKGROUND: Hantavirus pulmonary syndrome (HPS) is a life threatening disease transmitted by the rodent Oligoryzomys longicaudatus in Chile. Hantavirus outbreaks are typically small and geographically confined. Several studies have estimated risk based on spatial and temporal distribution of cases in relation to climate and environmental variables, but few have considered climatological modeling of HPS incidence for monitoring and forecasting purposes. METHODOLOGY: Monthly counts of confirmed HPS cases were obtained from the Chilean Ministry of Health for 2001-2012. There were an estimated 667 confirmed HPS cases. The data suggested a seasonal trend, which appeared to correlate with changes in climatological variables such as temperature, precipitation, and humidity. We considered several Auto Regressive Integrated Moving Average (ARIMA) time-series models and regression models with ARIMA errors with one or a combination of these climate variables as covariates. We adopted an information-theoretic approach to model ranking and selection. Data from 2001-2009 were used in fitting and data from January 2010 to December 2012 were used for one-step-ahead predictions. RESULTS: We focused on six models. In a baseline model, future HPS cases were forecasted from previous incidence; the other models included climate variables as covariates. The baseline model had a Corrected Akaike Information Criterion (AICc) of 444.98, and the top ranked model, which included precipitation, had an AICc of 437.62. Although the AICc of the top ranked model only provided a 1.65% improvement to the baseline AICc, the empirical support was 39 times stronger relative to the baseline model. CONCLUSIONS: Instead of choosing a single model, we present a set of candidate models that can be used in modeling and forecasting confirmed HPS cases in Chile. The models can be improved by using data at the regional level and easily extended to other countries with seasonal incidence of HPS. PMID- 24763322 TI - Palliative care nursing in the virtual realm. PMID- 24763318 TI - Folliculin regulates ampk-dependent autophagy and metabolic stress survival. AB - Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dube renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function. PMID- 24763323 TI - Palliative care: a patient's perspective. PMID- 24763324 TI - Sharing the care: the key-working experiences of professionals and the parents of life-limited children. AB - AIMS: To explore the lived experience of caring and care planning for a child with a life-limiting condition (LLC). METHOD: Using van Manen's conceptualisation of hermeneutic phenomenology, three focus groups were conducted with 21 paediatric palliative care professionals, and interviews were conducted with 20 parents of children with LLCs. FINDINGS: Parents' expectations for support were raised by the diagnosis, but the reality could disappoint, which put pressures on professionals. Current service designs with respect to key working did not always coincide with family preferences. Both parents and professionals found that the care journey required them to shift personas to respond to different contexts. CONCLUSIONS: The findings are limited by the sample characteristics, but they provide insight for current policy and practice initiatives. The key worker needs to be mindful of historical care arrangements and be prepared to step into the family 'team' arrangements. PMID- 24763325 TI - Bereavement support used by mothers in Ireland following the death of their child from a life-limiting condition. AB - BACKGROUND: Children's palliative care is a rapidly developing specialism internationally. Bereavement support is an integral component of children's palliative care but to date little research has investigated the bereavement support that mothers in Ireland use following the death of their child. OBJECTIVE: The aim of this study was to explore mothers' experiences of bereavement support in Ireland following the death of their child from a life limiting condition. METHOD: A descriptive qualitative design was used. The study sample was ten mothers who had been bereaved in the previous 5 years. All mothers were recruited to the study by a gatekeeper from a voluntary organisation. Data were obtained through unstructured single interviews and analysed using conventional content analysis. RESULTS: The findings indicate that the mothers relied on a combination of informal and formal bereavement support. In addition to depending on others to provide support, the mothers described their ability to self-support. CONCLUSIONS: The findings show that mothers in Ireland use a variety of sources of support following the death of their child from a life limiting condition. Health professionals involved in caring for families and children with a life-limiting condition should have an understanding of these sources. PMID- 24763326 TI - The lived experiences of the Sikh population of South East England when caring for a dying relative at home. AB - BACKGROUND: Few ethnic minorities access specialist palliative care (SPC) services when caring for a dying relative at home. OBJECTIVE: This project aimed to explore and understand the experiences of the Sikh population of south east England when caring for a dying relative at home without support from SPC. METHODS: Six semi-structured interviews were conducted with carers in Punjabi or English and the transcripts were analysed using interpretative phenomenology. RESULTS: Five super-ordinate themes were identified: factors leading to the caring role, emotional effects of caring on the carer, impact of caring on the wider family, influence of health-care services, and religious and cultural influence. The most common emergent theme was lack of support from health professionals, which emerged from a lack of awareness of services. A sense of duty and hard work was apparent throughout, and appeared to sustain the family. There seemed to be a sense of duty to care for the relative at home. Financial concerns were expressed frequently. The decision to adopt the caring role appeared to be made by the entire family. The Sikh faith seemed to give strength to carers. There appeared to be heightened awareness of what other community members think of carers' actions. CONCLUSIONS: There is a need for health professionals to reach out to this population to increase awareness of and trust in the services that are available to support care at the end of life. However, an unwillingness to accept assistance may persist in some cases. PMID- 24763327 TI - Improving dementia care in nursing homes: experiences with a palliative care symptom-assessment tool (MIDOS). AB - BACKGROUND: In the past decade, the palliative care approach has been used in the care of frail older people living with debilitating chronic conditions, including dementia. AIM: To describe health professionals' experiences of assessing the symptoms of people with dementia using a cancer-patient-oriented symptom assessment tool from a palliative care context. METHOD: This was a qualitative study that used semi-structured interviews (n=13) with clinical staff in three nursing homes prior to and following the implementation of the Minimal Documentation system for Palliative care (MIDOS) tool for assessing symptoms over a period of 6 weeks. RESULTS: Baseline interviews showed specific concerns about symptom assessment, such as uncertainty about underlying symptoms in residents who appeared to be in distress. After the implementation of the MIDOS tool, participants reported that daily use of the tool was perceived as helpful in evaluating symptoms other than pain and improved internal communication between staff regarding clinical decision making. CONCLUSION: The MIDOS tool was perceived as a helpful and valuable complement to existing tools. Participants expressed some concerns regarding the subjective nature of perceiving symptoms and clinical decision making. The use of tools such as the MIDOS tool has the potential to enhance the quality of palliative care in dementia care. PMID- 24763328 TI - Swedish nursing students' reasoning about emotionally demanding issues in caring for dying patients. AB - AIM: To describe nursing students' reasoning about emotionally demanding questions concerning the care of dying patients. METHODS: The Frommelt Attitude Toward Care of the Dying (FATCOD) Scale was completed by students at the beginning of their education, and there was great variation in the responses to five items. At a follow-up measurement in the second year, an open-ended question, 'How did you reason when completing this question?', was added to each of the these five items. Qualitative content analysis was used to analyse the responses. RESULTS: Of 140 students who completed the FATCOD, 111 provided free text responses. The analysis of these responses revealed three themes: death perceptions, the students' understanding of their current situation, and the nurse's responsibility. CONCLUSION: This study provides useful information on students' reasoning about emotionally demanding questions relating to the care of dying patients. Such knowledge is valuable in helping students to overcome their fear and fulfil their expectations concerning their future proficiency. PMID- 24763331 TI - Politics and palliative care: Paraguay. PMID- 24763332 TI - Potentially inappropriate prescribing in older primary care patients. AB - OBJECTIVES: The aim of the study was to determine the rate of Potentially Inappropriate Medicines (PIM) and Potential Prescription Omissions (PPO) according to Screening Tool of Older Person's potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment (STOPP/START) criteria. STUDY DESIGN: A cross-sectional survey in community pharmacy. METHOD: A prospective cross-sectional study was performed, during March May 2012, in five community pharmacies. Patients aged >=65 years, who collected one or more prescribed medications, were asked to participate in the study, and an interview was scheduled. Patients were asked to provide their complete medical and biochemical record from their general practitioner. RESULTS: 509 patients, mean age 74.8+/-6.5 years, 57.4% female, participated in the study. 164 PIM were identified in 139 patients (27.3%). The most common were: long-term use of long acting benzodiazepines (20.7%), use of non-steroidal antiinflammatory drugs (NSAID) in patients with moderate-severe hypertension (20.1%), use of theophylline as monotherapy for chronic obstructive pulmonary disease (COPD, 15.9%) and use of aspirin without appropriate indication (15.2%). Patients with more than four prescpritions had a higher risk for PIM (OR 2.85, 95% CI 1.97 4.14, p<0.001). There were 439 PPO, identified in 257, (50.5%) patients. Predictors for PPO were older age, presence of diabetes, myocardial infarction, osteoporosis, stroke, COPD and/or angina pectoris. CONCLUSION: STOPP/START criteria may be useful in identifying inappropriate prescribing and improving the current prescribing practices. Pharmacists should focus more on patients with more than four medications and/or patients with gout or pain accompanied with arterial hypertension because those patient may be at higher risk of PIM. Additionlly, patients older than 74 years with diabetes, osteoporosis, myocardial infarction, stroke, angina pectoris and/or COPD may have an increased risk of PPO. PMID- 24763333 TI - The use of recently developed histochemical markers for localizing neurotoxicant induced regional brain pathologies. AB - Neuronal and vascular brain components are interrelated morphologically, physiologically and developmentally. Due to this close interrelationship, it is often difficult to understand the cause and effect relationship between neuronal vs. vascular dysfunction and pathology. This review will discuss four of the more promising recent developments for detecting vascular pathology, and will compare them with the labeling pattern seen with markers of glial and neuronal pathology; following exposure to well characterized neurotoxicants. To detect the vascular dysfunction in the brain, we recently developed a Fluoro-Turquoise gelatin conjugate (FT-gel), a fluorescent probe that helps to delineate between healthy vs. sclerotic vessels. Similarly, we have investigated the potential for Fluoro Gold to label in vivo all the endothelial cells in the brain as they co-localize with RECA, an endothelial cell marker. We have also developed Amylo-Glo, a fluorescent tracer that can detect neurotoxic A-beta aggregates in the brain. In this article, we will discuss the potential use of these novel histochemical markers to study the neurotoxicant induced brain. We will also discuss neurovascular strategies that may offer novel therapeutic opportunities for neurodegenerative disorders. PMID- 24763335 TI - The strengths of r- and K-selection shape diversity-disturbance relationships. AB - Disturbance is a key factor shaping species abundance and diversity in plant communities. Here, we use a mechanistic model of vegetation diversity to show that different strengths of r- and K-selection result in different disturbance diversity relationships. R- and K-selection constrain the range of viable species through the colonization-competition tradeoff, with strong r-selection favoring colonizers and strong K-selection favoring competitors, but the level of disturbance also affects the success of species. This interplay among r- and K selection and disturbance results in different shapes of disturbance-diversity relationships, with little variation of diversity with no r- and no K-selection, a decrease in diversity with r-selection with disturbance rate, an increase in diversity with K-selection, and a peak at intermediate values with strong r- and K-selection. We conclude that different disturbance-diversity relationships found in observations may reflect different intensities of r- and K-selection within communities, which should be inferable from broader observations of community composition and their ecophysiological trait ranges. PMID- 24763336 TI - miR393 is required for production of proper auxin signalling outputs. AB - Auxins are crucial for plant growth and development. Auxin signalling primarily depends on four partially redundant F-box proteins of the TIR1/AFB2 Auxin Receptor (TAAR) clade to trigger the degradation of AUX/IAA transcriptional repressors. Auxin signalling is a balanced system which involves complex feedback regulations. miR393 regulation of TAAR genes is important for different developmental programs and for responses to environment. However, so far, the relevance of the two MIR393 genes for Arabidopsis leaf development and their significance for auxin signalling homeostasis have not been evaluated. First, our analyses of mir393a-1 and mir393b-1 mutants and of mir393ab double mutant show that the two genes have only partially redundant functions for leaf development. Expression analyses of typical auxin-induced reporter genes have shown that the loss of miR393 lead to several unanticipated changes in auxin signalling. The expression of DR5pro:GUS is decreased, the expression of primary AUX/IAA auxin responsive genes is slightly increased and the degradation of the AXR3-NT:GUS reporter protein is delayed in mir393ab mutants. Additional analyses using synthetic auxin and auxin antagonists indicated that miR393 deficient mutants have higher levels of endogenous AUX/IAA proteins, which in turn create a competition for degradation. We propose that the counter-intuitive changes in the expression of AUX/IAA genes and in the accumulation of AUX/IAA proteins are explained by the intrinsic nature of AUX/IAA genes which are feedback regulated by the AUX/IAA proteins which they produce. Altogether our experiments provide an additional highlight of the complexity of auxin signaling homeostasis and show that miR393 is an important component of this homeostasis. PMID- 24763337 TI - Epigenome rejuvenation: HP1beta mobility as a measure of pluripotent and senescent chromatin ground states. AB - We measured the dynamics of an essential epigenetic modifier, HP1beta, in human cells at different stages of differentiation using Fluorescence Recovery After Photobleaching (FRAP). We found that HP1beta mobility is similar in human embryonic stem cells (hES) and iPS cells where it is more mobile compared to fibroblasts; HP1beta is less mobile in senescent fibroblasts than in young (dividing) fibroblasts. Introduction of "reprogramming factors", Oct4, Sox2, Klf4, cMyc and Lin28, into senescent fibroblasts and measuring the changes in HP1beta mobility as reprogramming proceeds shows that the mobility of HP1beta in senescent cells increases and by day 9 is the same as that found in young fibroblasts. Thus the dynamics of a key epigenetic modifier can be rejuvenated without de-differentiation through an embryonic stage. Future work will test whether other aspects of cellular physiology that age can be so rejuvenated without de-differentiation. PMID- 24763338 TI - A New Approach to Rigid Body Minimization with Application to Molecular Docking. AB - Our work is motivated by energy minimization in the space of rigid affine transformations of macromolecules, an essential step in computational protein protein docking. We introduce a novel representation of rigid body motion that leads to a natural formulation of the energy minimization problem as an optimization on the [Formula: see text] manifold, rather than the commonly used SE(3). The new representation avoids the complications associated with optimization on the SE(3) manifold and provides additional flexibilities for optimization not available in that formulation. The approach is applicable to general rigid body minimization problems. Our computational results for a local optimization algorithm developed based on the new approach show that it is about an order of magnitude faster than a state of art local minimization algorithms for computational protein-protein docking. PMID- 24763340 TI - Ten simple rules for the care and feeding of scientific data. PMID- 24763341 TI - What are individuals with serious mental illness (SMI) dealing with in a competitive labor market? Two case studies. AB - Understanding individual experiences is crucial for consumer-centered practice and policy. However, limited literature has thoroughly explored individual employment experiences outside of rehabilitation programs. The purpose of this study is to demonstrate the challenges that two individuals with severe mental illness (SMI) had experienced in competitive employment settings. Through in depth interviews followed by an inductive qualitative analysis, the barriers that restrained them from obtaining and keeping a job were identified. Even though the two cases had dissimilar backgrounds and diagnoses, they had both been struggling with multiple problems including psychiatric symptoms, medications, and social stigma. The findings indicate that a flexible work schedule and a supportive work environment are important to their work participation. However, many competitive employment settings did not allow them to have a flexible schedule for frequent medical leaves. The stigma toward mental illness was also prevalent in various workplaces they worked at. The implications for policy and practice are discussed. PMID- 24763339 TI - Isl1 directly controls a cholinergic neuronal identity in the developing forebrain and spinal cord by forming cell type-specific complexes. AB - The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebrate development. Here, we investigated the gene regulatory networks that specify the cholinergic neuronal fates in the spinal cord and forebrain, specifically, spinal motor neurons (MNs) and forebrain cholinergic neurons (FCNs). Conditional inactivation of Isl1, a LIM homeodomain factor expressed in both differentiating MNs and FCNs, led to a drastic loss of cholinergic neurons in the developing spinal cord and forebrain. We found that Isl1 forms two related, but distinct types of complexes, the Isl1-Lhx3-hexamer in MNs and the Isl1-Lhx8-hexamer in FCNs. Interestingly, our genome-wide ChIP-seq analysis revealed that the Isl1-Lhx3-hexamer binds to a suite of cholinergic pathway genes encoding the core constituents of the cholinergic neurotransmission system, such as acetylcholine synthesizing enzymes and transporters. Consistently, the Isl1 Lhx3-hexamer directly coordinated upregulation of cholinergic pathways genes in embryonic spinal cord. Similarly, in the developing forebrain, the Isl1-Lhx8 hexamer was recruited to the cholinergic gene battery and promoted cholinergic gene expression. Furthermore, the expression of the Isl1-Lhx8-complex enabled the acquisition of cholinergic fate in embryonic stem cell-derived neurons. Together, our studies show a shared molecular mechanism that determines the cholinergic neuronal fate in the spinal cord and forebrain, and uncover an important gene regulatory mechanism that directs a specific neurotransmitter identity in vertebrate CNS development. PMID- 24763342 TI - Telework research and practice: impacts on people with disabilities. PMID- 24763345 TI - Influence of occupational safety management on the incidence rate of occupational accidents in the Spanish industrial and ornamental stone mining. AB - BACKGROUND: Mines are hazardous and workers can suffer many types of accidents caused by fire, flood, explosion or collapse. Injury incidence rates in mining are considerably higher than those registered by other economic sectors. One of the main reasons for this high-level incidence rate is the existence of a large number of dangerous workplaces. OBJECTIVE: This work analyzes the influence that occupational safety management had on the accidents that took place in Spanish mining of industrial and ornamental stone during the period 2007-2008. METHODS: Primary data sources are: (a) Results from a statistical study of the occupational health and safety management practices of 71 quarries defined by a questionnaire of 41 items; and (b) Occupational accidents registered in the Spanish industrial and ornamental stone mining throughout the period 2007-2008. RESULTS: The obtained results indicate that workplaces with a low average score in the analysis of occupational safety management have a higher incidence rate of accidents. CONCLUSIONS: Studies on mining workplaces are very important to help detect occupational safety concerns. Results from this study help raise awareness and will encourage the adoption of appropriate measures to improve safety. PMID- 24763343 TI - Predictors of low back pain in a longitudinal study of Iranian nurses and office workers. AB - BACKGROUND: A previous survey had indicated high rates of low back pain (LBP) in Iranian nurses and office workers. OBJECTIVE: To explore possible risk factors, we carried out a longitudinal study of the same subjects. METHODS: Baseline information about risk factors and recent history of LBP was collected by self administered questionnaire from 246 nurses and 182 office workers. Approximately 12 months later, 385 (90%) answered a second questionnaire about LBP in the past month. Predictors of LBP at follow-up were assessed by Poisson regression and summarised by prevalence rate ratios (PRRs) with 95% confidence intervals (CIs). RESULTS: In a regression model that included all risk factors, the strongest predictor of LBP at follow-up was report of recent LBP at baseline. In addition, LBP was associated with older age, adverse beliefs about the work-relatedness of LBP (PRR 1.3, 95%CI 1.0-1.5), and incentives from piecework or bonuses (PRR 1.4, 95%CI 1.1-1.6). When baseline report of LBP was omitted from the model, associations were also observed with tendency to somatise, poor mental health and time pressures at work. CONCLUSIONS: Our findings support the importance of psychosocial risk factors for LBP, including adverse health beliefs and working conditions that encourage higher output. PMID- 24763344 TI - Comparison of the lumbar flexion angle and repositioning error during lumbar flexion-extension in young computer workers in Korea with differing back pain. AB - BACKGROUND: Differences in LBP symptoms are particularly important with regard to the controversy over repositioning error because there can be considerable variation in the pattern of LBP symptoms in a heterogeneous LBP group. For this reason, several researchers have suggested that a study of subdivided LBP types is needed. Indeed, some recent studies have attempted to differentiate LBP subgroups. OBJECTIVE: This study used a comparative cross-sectional design to compare the lumbar flexion angle and repositioning error between people with and without LBP during a lumbar flexion-extension task. METHODS: The subjects were divided into three groups: a control group of 13 asymptomatic subjects, 13 LBP subjects with L4-5 pain associated with lumbar flexion, and 13 LBP subjects with L4-5 pain associated with lumbar extension. The subjects performed a lumbar flexion-extension task. Joint kinematics on the lumbar flexion angle and lumbar spine repositioning error were measured using a 3-D motion capture system. RESULTS: The lumbar flexion angle of the LBP group with flexion pain was significantly greater than that of the asymptomatic group and the LBP group with extension pain. The difference in lumbar repositioning error was significantly greater in the LBP group with lumbar flexion pain than in the asymptomatic group. CONCLUSIONS: This study suggests that lumbar hyper-mobility occurred and proprioception of the lumbar segment was decreased in people with LBP associated with lumbar flexion compared with people with LBP associated with lumbar extension. We also suggest that a lumbar repositioning error measurement using the lumbar flexion-extension test may be a more effective evaluation method in people with LBP associated with lumbar flexion than in those with LBP associated with lumbar extension. PMID- 24763346 TI - The reproducibility of two task-specific functional capacity evaluation protocols for household waste collectors. AB - OBJECTIVE: The aim of this study was to assess the reproducibility (i.e., agreement and inter-rater reliability) of two task-specific functional capacity evaluation protocols meant to simulate the daily workload of collectors using either two-wheeled waste containers or bags. METHODS: A within-subjects design was used to assess reproducibility in terms of agreement and reliability. Twenty one household waste collectors were assessed twice with both task-specific protocols with a time interval of seven days. Agreement was assessed using the Standard Error of Measurement (SEM), and inter-rater reliability was assessed using the Intra-Class Correlation Coefficient (ICC). RESULTS: For the task specific protocol for waste collection using two-wheeled containers, agreement was excellent (SEM=0.9 points; 0-340 scale; mean score 339), but inter-rater reliability was poor (ICC=0.22). For the task-specific protocol for bag collection, agreement was acceptable (SEM=53 s; continuous scale; mean time 779 s), and inter-rater reliability was good (ICC=0.79). CONCLUSIONS: Reproducibility of the task-specific protocol for bag collection is acceptable to good, while the task-specific protocol for waste collection using two-wheeled containers has an excellent agreement but a poor reliability. Although face and content validity have been covered within the development of both protocols, further studies should evaluate the construct and criterion-related validity of both task specific protocols. PMID- 24763347 TI - Self-employment as a solution for attitudinal barriers: a case study. AB - This paper uses a case study to examine attitudinal barriers to employment and underemployment. We follow the career path of PR, a woman with multiple physical impairments, as she seeks financial independence through several employment strategies. In these, she faced attitudinal barriers and employment situations without opportunity for advancement. Eventually, PR opens her own business, turning to an alternative loan program to acquire the funds necessary to purchase a ready-made vehicle that matches her needs for accessible transportation. Use of this vehicle to provide delivery services for her business has more than doubled her income. PMID- 24763348 TI - Successful collaboration between occupational health service providers and client companies: Key factors. AB - BACKGROUND: Occupational health services (OHS) are often described as an important resource to reduce work-related diseases and improve the workplace. OBJECTIVE: This paper identifies key factors for successful collaboration between Swedish OHS providers and their client companies. METHODS: Interviews were carried out with representatives of 15 companies and their OHS providers. The interviews were transcribed and their content analyzed. RESULTS: The results revealed that successful collaboration was highly correlated with six factors. First, the collaboration depends on both parties; ''it takes two to tango''. Second, the company and the OHS provider have a joint commitment to a long-term collaboration. Third, the collaboration is built on frequent contact at different organizational levels. Fourth, the company has a well-structured work environment for occupational health and safety management. Fifth, the OHS provider uses a consultative approach in its prevention and promotion activities. Finally, OHS providers seek to treat the company, not the individual. CONCLUSIONS: Our research indicates that a successful collaboration requires both occupational health and safety management (OHSM) within the company and the assistance of a competent OHS provider. A change toward more promotion and prevention services benefits the company, since the occupational health services are better tailored to the company's needs. PMID- 24763349 TI - Ergonomic risk factors in bicycle repairing units at Jabalpur. AB - BACKGROUND: Bicycle repairing at Jabalpur in the Madhya Pradesh state of India employs a large number of local youths. In this sector occupational ergonomic issues of Work Related Musculoskeletal Disorders (WMSDs) are a big problem and a threat to this profession. OBJECTIVE: The objective of this study was to identify the different ergonomic risk factors for Work Related Musculoskeletal Disorders (WMSDs) in the job of bicycle repairing. METHODS: Still photography and video photography was used to record different activities. Different types of non invasive tools like Rapid Entire Body Assessment (REBA), Rapid Upper Limb Assessment (RULA), and Occupational Repetitive Action Index (OCRA) were used. Psychophysical measures were investigated by rated perceived exertion scale and visual analogue scale. RESULTS: OVAKO scores (4), REBA scores (13/13), RULA scores (8/8) were extremely high, indicating immediate intervention. CONCLUSION: The results indicate that the different tasks in this profession are in the high risk category and demands immediate ergonomic intervention in the form of re design of the tools used and work station or/and the design of the work process. PMID- 24763350 TI - Musculoskeletal symptoms associated with posterior load carriage: An assessment of manual material handling workers in Indonesia. AB - BACKGROUND: Concerns have been raised regarding the high prevalence of musculoskeletal symptoms (MSS) among manual material handling (MMH) workers. However, limited investigations have been undertaken among one large group of workers using a particular MMH method called posterior load carriage (PLC). This is typically done without the use of a backpack in developing countries, and involves exposure to known risk factors for MSS such as heavy loads, non-neutral postures, and high levels of repetition. OBJECTIVES: To 1) determine the types and prevalence of MSS among PLC workers and the impacts of these MSS on workers, 2) explore job demands potentially contributing to MSS, and (3) obtain input from workers regarding possible improvements to facilitate future interventions. METHODS: Structured interview applied to 108 workers to assess PLC worker characteristics and job demands in eight cities in Indonesia. RESULTS: MSS were reported in all anatomical regions evaluated, with symptoms most commonly reported at the lower back (72.2%), feet (69.4%), knees (64%), shoulders (47.2%), and neck (41.7%). Logistic regression indicated that MSS in the lower back were associated with longer work hours/day, MSS in the hands were associated with load mass, and MSS in the ankles/feet were associated with stature and load carriage frequency. MSS were reported to interfere with daily activity, but only few workers sought medical treatment. Possible improvements included the use of a belt, hook, or backpack/frame, and changes in the carriage method. CONCLUSIONS: The study suggests that PLC workers incur a relatively high MSS burden. Future studies are needed to develop and evaluate practical interventions and specific guidelines to improve working conditions and occupational health and safety for PLC workers. PMID- 24763351 TI - "Home is at work and work is at home": telework and individuals who use augmentative and alternative communication. AB - BACKGROUND: Telework, the use of distance communication technologies to participate in the workforce, has been suggested as a promising employment strategy for individuals with disabilities. OBJECTIVE: The goal of this study was to obtain a better understanding of the benefits and negative impacts of telework, as well as the supports and challenges to telework activities, for persons who use augmentative and alternative communication (AAC). METHODS: This study used a series of focus group discussions, conducted on the internet, to examine the employment experiences of nine individuals with disabilities who used AAC and who held jobs that involved the use of telework. RESULTS: Four major themes emerged from the discussion: (a) benefits of telework, (b) negative impacts of telework, (c) strategies for addressing negative impacts of telework, and (d) recommendations for improving employment outcomes for individuals who use AAC. CONCLUSIONS: In summary, while participants identified the elimination of travel time and flexible work schedules as key strengths of telework, concerns were expressed regarding feelings of isolation and the difficulty in separating home and work environments. The participants also emphasized the important role of educational programs in supporting the acquisition of literacy and self advocacy skills, and the need for post-secondary programs to support the school to-workplace transition. PMID- 24763352 TI - When more is less: An examination of the relationship between hours in telework and role overload. AB - BACKGROUND: Proponents of telework arrangements assert that those who telework have more control over their work and family domains than their counterparts who are not permitted to work from home. OBJECTIVE: Using Karasek's theory we hypothesized that the relationship between demands (hours in work per week; hours in childcare per week) and strain (work role overload; family role overload) would be moderated by the number of hours the employee spent per week teleworking (control). METHODS: To determine how the number of telework hours relates to work role overload and family role overload, we follow the test for moderation and mediation using hierarchical multiple regression analysis as outlined by Frazier et al. [50] We used survey data collected from 1,806 male and female professional employees who spent at least one hour per week working from home during regular hours (i.e. teleworking). RESULTS: As hypothesized, the number of hours in telework per week negatively moderated the relation between work demands (total hours in paid employment per week) and work strain (work role overload). Contrary to our hypothesis, the number of hours in telework per week only partially mediated the relation between family demands (hours a week in childcare) and family role overload (strain). CONCLUSIONS: The findings from this study support the idea that the control offered by telework is domain specific (helps employees meet demands at work but not at home). PMID- 24763353 TI - The relationship between work arrangements and work-family conflict. AB - BACKGROUND: A review of the literature determined that our understanding of the efficacy of flexible work arrangements (FWA) in reducing work-family conflict remains inconclusive. OBJECTIVE: To shed light on this issue by examining the relationship between work-to-family conflict, in which work interferes with family (WFC), family-to-work conflict, in which family interferes with work (FWC), and four work arrangements: the traditional 9-5 schedule, compressed work weeks (CWWs) flextime, and telework. METHODS: Hypotheses were tested on a sample of 16,145 employees with dependent care responsibilities. MANCOVA analysis was used with work arrangement as the independent variable and work interferes with family (WFC) and family interferes with work (FWC) as dependent variables. Work demands, non-work demands, income, job type and gender were entered into the analysis as covariates. RESULTS: The more flexible work arrangements such as flextime and telework were associated with higher levels of WFC than were fixed 9 to 5 and CWW schedules. Employees who teleworked reported higher FWC than their counterparts working a traditional 9-to-5 schedule particularly when work demands were high. CONCLUSIONS: The removal of both temporal and physical boundaries separating work and family domains results in higher levels of work-family interference in both directions. The results from this study suggest that policy makers and practitioners who are interested in improving employee well-being can reduce work-family conflict, and by extension improve employee mental health, by focusing on the effective use of traditional and CWW schedules rather than by implementing flextime and telework arrangements. PMID- 24763354 TI - Development and validation of an arrhythmia-specific scale in tachycardia and arrhythmia with focus on health-related quality of life. AB - BACKGROUND: Arrhythmias can cause a profoundly negative impact on a person's daily life, leading to impaired health-related quality of life (HRQOL). Assessment of HRQOL can provide valuable information before, during, and after healthcare interventions for arrhythmias. OBJECTIVE: The aim was to develop and validate a disease-specific scale evaluating HRQOL in patients with different forms of arrhythmia. METHODS: The Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA HRQOL) was developed from a literature review, patient interviews, and expert panel evaluations. This version was then psychometrically evaluated in patients treated with radiofrequency catheter ablation because of different forms of arrhythmias and patients who sought emergency care because of atrial fibrillation. Construct validity was evaluated with item-total correlations, confirmatory factor analyses, and convergent and discriminant validity. Internal consistency was evaluated using Cronbach's alpha. RESULTS: All items reached the expected level of item-total correlations of greater than 0.3 for the total scale. The content validity index was sufficient for all items, as was the total scale (0.86-1.0). The 2-factor confirmatory factor analysis model that included the physical and mental factors showed a better fit between model and data than the 1-factor model did (P < .001). Convergent and discriminant validities were evaluated in the correlation analyses between the ASTA HRQOL subscales and SF-36 physical and mental dimensions. A strong correlation was found between the hypothesized physical and mental scales. Internal consistency was satisfactory with a lower bound confidence interval (95%) for Cronbach's alpha .70 or greater for all the ASTA HRQOL scales. CONCLUSIONS: The ASTA HRQOL questionnaire can be a valuable contribution to HRQOL assessments in patients with different forms of arrhythmia. Until there is more evidence regarding validity and reliability, using both the total and subscale scores is recommended. PMID- 24763355 TI - Robotic mitral valve repair. AB - BACKGROUND: Mitral valve repair is the standard therapy for patients with severe mitral regurgitation. Currently, robotic mitral valve repair is the least invasive surgical approach and an alternative to the traditional sternotomy. Recent studies and newer guidelines on mitral valve repair advocate for earlier referral to surgery, resulting in better long-term outcomes of valve function and decreased left ventricular remodeling. PURPOSE: Robotic mitral valve repair outcomes were compared with nonrobotic mitral repair outcomes through analysis of 4 recent studies, one of which was the Food and Drug Administration trial that granted approval of robotic cardiac surgery. Two studies included their own nonrobotic groups for comparison, with one comparing the robotic approach with complete sternotomy, partial sternotomy, and mini-anterolateral thoracotomy to assess all currently available techniques. CONCLUSIONS: All 4 studies showed positive outcomes including decreased need for postoperative mechanical ventilation, intensive care unit length of stay, and hospital length of stay. The studies also showed that postrepair mitral regurgitation was equivalent to that of traditional open repairs at multiple different periods after surgery. CLINICAL IMPLICATIONS: Patients should be given the option for minimally invasive robotic mitral valve repair if they have no other risk factors such as peripheral vascular disease that prevent femoral cannulation for cardiopulmonary bypass or the need for concomitant cardiac surgery such as coronary artery bypass. With the equality of robotic outcomes compared with full sternotomy valve surgery comes the need for more research into what kind of complex valve repairs can be done, which methods of repair work best with robotic techniques, whether the learning curve for robotic surgery can be shortened with more widespread use, and what outcomes can be improved upon from this standpoint. Healthcare professionals need to be aware of all choices for patients who need surgical intervention for their mitral regurgitation. PMID- 24763356 TI - Experiences and actions during the decision making process among men with a first acute myocardial infarction. AB - BACKGROUND: Previous studies have shown that people hesitate to seek medical attention when experiencing the initial symptoms of acute myocardial infarction (AMI), but the reasons why and the events underpinning the decision-making process are unclear. The aim of this study was to describe the actions and experiences involved in the process of seeking medical attention in men with a first AMI. METHODS: We studied 21 men, aged 39-73 years, hospitalized with a first AMI between May 2011 and March 2013. All were interviewed in the coronary unit before discharge, with one exception. Data collection and analysis were carried out simultaneously in accordance with grounded theory methodology. RESULTS: Men diagnosed with a first AMI experienced a spectrum of insidious and vague symptoms, which they did not associate with an AMI. This caused uncertainty in how to interpret symptom severity and contributed to a reluctance to seek medical care. Participants also had difficulty interpreting online information when seeking to explain their symptoms. Weighing up and comparing the various experiences during the early stages of AMI proved to be the trigger that changed the men's perspectives and made them aware of the abnormality, the severity of their illness, and the need for action. CONCLUSION: Healthcare professionals should be aware that men experience a range of insidious and vague symptoms during their first AMI and must give greater emphasis to their narratives, particularly when objective clinical signs are limited or absent. Consideration should be given to the ways laypeople interpret online information when designing healthcare resources for the Internet. PMID- 24763357 TI - Depression and anxiety as predictors of recurrent cardiac events 12 months after percutaneous coronary interventions. AB - BACKGROUND: Anxiety and depression are associated with recurrent cardiac events after percutaneous coronary interventions (PCIs). However, few investigators have evaluated the impact of depression and anxiety on recurrent cardiac events in Korea. OBJECTIVE: The aim of this study was to examine the relationship among depression, anxiety, and recurrent cardiac events in Korean patients with coronary artery disease (CAD) after PCI. METHODS: A prospective longitudinal study was undertaken with a sample of 133 CAD patients with PCI. Data were collected between August 2009 and September 2010, and patients were followed after discharge through 2011 with self-report questionnaires on anxiety and depression using the Hospital Anxiety and Depression Scale and with patient medical records on sociodemographic and clinical characteristics. Recurrent cardiac events were collected for 12 months after discharge and were assessed by patient interviews and medical records. RESULTS: There were 18 recurrent cardiac events (13.5%) among the 133 participants. After adjustment for sociodemographic and clinical characteristics, a hierarchical Cox proportional hazards regression model found that a moderate or severe level of anxiety (hazard ratio, 6.21; 95% confidence interval, 1.64-23.54) and a moderate or severe level of depression (hazard ratio, 4.32; 95% confidence interval, 1.35-13.88) were independent predictors of recurrent cardiac events. CONCLUSIONS: Patients with CAD who have a high level of anxiety and depression are at increased risk for recurrent cardiac events after PCI. Screening should be focused on patients who experience anxious and depressive feelings in addition to traditional risk factors. Furthermore, psychoeducational support interventions to reduce anxiety and depression after PCI may improve health outcomes. PMID- 24763358 TI - Cognitive behavioral therapy in depressed cardiac surgery patients: role of ejection fraction. AB - AIMS: The aim of this study was to evaluate the relationship of ejection fraction (EF) and depressive symptoms in cardiac surgery patients assigned to nurse-guided cognitive behavioral therapy (CBT) or usual care (UC). METHODS: Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Seventy-seven patients (31% women; mean [SD] age, 63.6 [9.8] years) received 8 weeks of either CBT or UC. Using repeated-measures analysis of variance, changes in depressive symptoms over time were evaluated. RESULTS: There was a significant interaction among time, treatment group, and EF status (p = 0.019). In the patients with preserved EF (>=40%), mean BDI scores in the UC group worsened by 1.9%, whereas those in the CBT group improved by 31.0%. In the patients with low EF (<40%), mean BDI scores worsened by 26.8% and improved by 75.3% in the UC and CBT groups, respectively. CONCLUSIONS: Nurse-guided CBT is effective in reducing depressive symptoms after cardiac surgery, particularly in patients with low EF. PMID- 24763359 TI - Synthesis, cytotoxicity for mimics of catalase: inhibitors of lactate dehydrogenase and hypoxia inducible factor. AB - Lactate dehydrogenase A (LDH-A) is a potentially important metabolic target for the inhibition of the highly activated glycolysis pathway in cancer cells. Two Mn(II) complexes with ligand containing di(pyridylmethyl) amine and pyrrol-ketone were used to attenuate the activity of LDH-A. The inhibition of the manganese(II) complexes on the proliferation of HepG-2 cells is related to their ability to disproportionate H2O2. Importantly, the synthesized mimic of catalase can decrease the expression of hypoxia inducible factor (HIF-1alpha) in HepG-2 cells. So we envision that the multifunctional mimics of catalase could attenuate the activity of LDH-A signaling the cancer cells to death through HIF-1alpha involved path. PMID- 24763360 TI - Towards the development of 5-HT7 ligands combining serotonin-like and arylpiperazine moieties. AB - Many known 5-HT7 ligands contain either a serotonin-like or an arylpiperazine structure that, in published SAR studies, are generally supposed to bind the same receptor pocket. Conversely, we explored the hypothesis that two such moieties can co-exist in the same ligand, binding to different pockets. We thus designed and synthesized a set of compounds including both a 5-hydroxyindol-3-ylethyl and a 1-arylpiperazine moieties connected by a short linker. The compounds were tested for their affinity for human 5-HT7 serotonin receptor. We further prepared a novel series of 5-HT7 ligands, where the 5-hydroxyindol-3-ylethyl moiety was bioisosterically replaced by a 3-hydroxyanilinoalkyl one. Among the newly synthesized compounds, potent ligands at the 5-HT7 receptor, behaving as antagonists in functional tests, were identified, even if they showed limited subtype selectivity. Docking studies within a model of the 5-HT7 receptor showed that the binding site can actually accommodate both moieties, with the serotonin like one in the putative orthosteric site and the arylpiperazine one occupying an accessory pocket. The present results demonstrate that it is possible to devise and develop new 5-HT7 ligands merging two privileged structures in the same molecule. PMID- 24763361 TI - Influence of the alkylsulfonylamino substituent located at the 6-position of 2,2 dimethylchromans structurally related to cromakalim: from potassium channel openers to calcium entry blockers? AB - The present study described the synthesis of original R/S-6-alkylsulfonylamino 3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans bearing a 3- or 4-substituted phenylthiourea or phenylurea moiety at the 4-position. Their biological effects were evaluated both on insulin-secreting and smooth muscle cells and were compared to those of reference KATP channel activators such as (+/-)-cromakalim, diazoxide and previously synthesized cromakalim analogues. The study aimed at exploring the influence of the introduction of an alkylsulfonylamino substituent at the 6-position of 2,2-dimethylchromans in order to improve biological activity, tissue selectivity but also hydrophilicity of dihydrobenzopyran derivatives. Several compounds were found to be equipotent or even more potent than (+/-)-cromakalim and diazoxide at inhibiting the insulin releasing process. Most of the newly synthesized and more hydrophilic dihydrobenzopyrans also exhibited a marked vasorelaxant activity although they were less potent than (+/ )-cromakalim. Additional pharmacological and radioisotopic investigations suggested that R/S-N-3-chlorophenyl-N'-(3,4-dihydro-6-methylsulfonylamino-2,2 dimethyl-2H-1-benzopyran-4-yl)thiourea (21) did not act as a potassium channel opener but rather as a Ca(2+) entry blocker. PMID- 24763362 TI - Synthesis, biological evaluation, molecular docking and theoretical evaluation of ADMET properties of nepodin and chrysophanol derivatives as potential cyclooxygenase (COX-1, COX-2) inhibitors. AB - Nepodin and chrysophanol, isolated from Rumex nepalensis roots, showed significant cyclooxygenase (COX) inhibitory activity. To further optimize these lead molecules and study structure activity relationship (SAR), eighteen derivatives of nepodin and nine derivatives of chrysophanol were synthesized and evaluated for COX-1 and COX-2 inhibitory potential. Among the synthesized compounds, four nepodin (1f, 1g, 1h and 1i) and three chrysophanol (2e, 2f and 2h) derivatives displayed more pronounced COX-2 inhibition than their respective lead molecule. Further, compounds 1f, 1g, 2e and 2h exhibited better anti inflammatory activity than ibuprofen in carrageenan-induced rat paw edema assay. Taking into account the in vitro and in vivo results, molecular docking and in silico prediction of ADMET properties of compounds were carried out respectively. PMID- 24763363 TI - DNA fastening and ripping actions of novel Knoevenagel condensed dicarboxylic acid complexes in antitumor journey. AB - Few novel Cu(II) and Zn(II) oxali-platin type complexes of stoichiometry [ML(ox)] where, L is a Knoevenagel ligand and ox is oxalic acid, have been explored. They are well characterized by spectroanalytical methods. The binding and cleavage propensity of these complexes on DNA and their cytotoxic effect in tumor cells have been investigated. They bind to DNA preferentially by intercalation and cleave the strands under mild reaction conditions even in the absence of external cofactors. However, in H2O2 medium they exhibit better efficacy in the nuclease reaction process by initiating DNA cleavage in an oxidative pattern. Complex 1 shows higher in vitro cytotoxic property against HeLa/EAC cells comparing to other complexes and the standards (cisplatin/5-FU). Moreover, the in vivo antitumor efficacy of copper complexes against EAC tumor model reveals that they are non-toxic to normal cells (lymphocytes). Among the copper complexes, complex 1 reveals excellent antitumor activity. PMID- 24763364 TI - Semisynthesis and in vitro cytotoxic evaluation of new analogues of 1-O acetylbritannilactone, a sesquiterpene from Inula britannica. AB - Semisynthetic analogues of the natural product 1-O-acetylbritannilactone (ABL), a sesquiterpene isolated from the medicinal plant Inula britannica, have been prepared and exhibited significant in vitro cytotoxic activities against four cell lines including three human cancer cell lines (HCT116, HEp-2 and HeLa) and one normal hamster cell line (CHO). Structure-activity relationships indicate that esterification of 6-OH (enhanced lipophilicity) and alpha-methylene-gamma lactone functionalities play important roles in conferring cytotoxicity. Among the tested compounds, 14 bearing a lauroyl group (12C) at the 6-OH position displayed most potent in vitro cytotoxic activity, with IC50 values between 2.91 and 6.78 MUM, comparable to the positive control etoposide (VP-16, IC50 values between 2.13 and 4.79 MUM). Moreover, the compound 14 triggered remarkable apoptosis at a low concentration, and induced cell cycle arrest in G2/M phase in HCT116 cells. The biological assays conducted with normal cells (CHO) revealed that all the synthetic compounds are no selective against cancer cell lines tested. PMID- 24763365 TI - Model of a realistic InP surface quantum dot extrapolated from atomic force microscopy results. AB - We report on numerical simulations of a zincblende InP surface quantum dot (QD) on In0.48Ga0.52 buffer. Our model is strictly based on experimental structures, since we extrapolated a three-dimensional dot directly by atomic force microscopy results. Continuum electromechanical, [Formula: see text] bandstructure and optical calculations are presented for this realistic structure, together with benchmark calculations for a lens-shape QD with the same radius and height of the extrapolated dot. Interesting similarities and differences are shown by comparing the results obtained with the two different structures, leading to the conclusion that the use of a more realistic structure can provide significant improvements in the modeling of QDs fact, the remarkable splitting for the electron p-like levels of the extrapolated dot seems to prove that a realistic experimental structure can reproduce the right symmetry and a correct splitting usually given by atomistic calculations even within the multiband [Formula: see text] approach. Moreover, the energy levels and the symmetry of the holes are strongly dependent on the shape of the dot. In particular, as far as we know, their wave function symmetries do not seem to resemble to any results previously obtained with simulations of zincblende ideal structures, such as lenses or truncated pyramids. The magnitude of the oscillator strengths is also strongly dependent on the shape of the dot, showing a lower intensity for the extrapolated dot, especially for the transition between the electrons and holes ground state, as a result of a relevant reduction of the wave functions overlap. We also compare an experimental photoluminescence spectrum measured on an homogeneous sample containing about 60 dots with a numerical ensemble average derived from single dot calculations. The broader energy range of the numerical spectrum motivated us to perform further verifications, which have clarified some aspects of the experimental results and helped us to develop a suitable model for the spectrum, by assuming a not equiprobable weight from each dot, a model which is extremely consistent with the experimental data. PMID- 24763366 TI - Impact of forest harvesting on trophic structure of eastern Canadian Boreal Shield lakes: insights from stable isotope analyses. AB - Perturbations on ecosystems can have profound immediate effects and can, accordingly, greatly alter the natural community. Land-use such as forestry activities in the Canadian Boreal region have increased in the last decades, raising concerns about their potential impact on aquatic ecosystems. The objective of this study was to evaluate the impact of forest harvesting on trophic structure in eastern Canadian Boreal Shield lakes. We measured carbon and nitrogen stable isotopes values for aquatic primary producers, terrestrial detritus, benthic macroinvertebrates, zooplankton and brook trout (Salvelinus fontinalis) over a three-year period in eight eastern Boreal Shield lakes. Four lakes were studied before, one and two years after forest harvesting (perturbed lakes) and compared with four undisturbed reference lakes (unperturbed lakes) sampled at the same time. Stable isotope mixing models showed leaf-litter to be the main food source for benthic primary consumers in both perturbed and unperturbed lakes, suggesting no logging impact on allochthonous subsidies to the littoral food web. Brook trout derived their food mainly from benthic predatory macroinvertebrates in unperturbed lakes. However, in perturbed lakes one year after harvesting, zooplankton appeared to be the main contributor to brook trout diet. This change in brook trout diet was mitigated two years after harvesting. Size-related diet shift were also observed for brook trout, indicating a diet shift related to size. Our study suggests that carbon from terrestrial habitat may be a significant contribution to the food web of oligotrophic Canadian Boreal Shield lakes. Forest harvesting did not have an impact on the diet of benthic primary consumers. On the other hand, brook trout diet composition was affected by logging with greater zooplankton contribution in perturbed lakes, possibly induced by darker-colored environment in these lakes one year after logging. PMID- 24763368 TI - Anaerobic oxidation of long-chain n-alkanes by the hyperthermophilic sulfate reducing archaeon, Archaeoglobus fulgidus. AB - The thermophilic sulfate-reducing archaeon Archaeoglobus fulgidus strain VC-16 (DSM 4304), which is known to oxidize fatty acids and n-alkenes, was shown to oxidize saturated hydrocarbons (n-alkanes in the range C10-C21) with thiosulfate or sulfate as a terminal electron acceptor. The amount of n-hexadecane degradation observed was in stoichiometric agreement with the theoretically expected amount of thiosulfate reduction. One of the pathways used by anaerobic microorganisms to activate alkanes is addition to fumarate that involves alkylsuccinate synthase as a key enzyme. A search for genes encoding homologous enzymes in A. fulgidus identified the pflD gene (locus-tag AF1449) that was previously annotated as a pyruvate formate lyase. A phylogenetic analysis revealed that this gene is of bacterial origin and was likely acquired by A. fulgidus from a bacterial donor through a horizontal gene transfer. Based on three-dimensional modeling of the corresponding protein and molecular dynamic simulations, we hypothesize an alkylsuccinate synthase activity for this gene product. The pflD gene expression was upregulated during the growth of A. fulgidus on an n-alkane (C16) compared with growth on a fatty acid. Our results suggest that anaerobic alkane degradation in A. fulgidus may involve the gene pflD in alkane activation through addition to fumarate. These findings highlight the possible importance of hydrocarbon oxidation at high temperatures by A. fulgidus in hydrothermal vents and the deep biosphere. PMID- 24763369 TI - Variation in gut microbial communities and its association with pathogen infection in wild bumble bees (Bombus). AB - Bacterial gut symbiont communities are critical for the health of many insect species. However, little is known about how microbial communities vary among host species or how they respond to anthropogenic disturbances. Bacterial communities that differ in richness or composition may vary in their ability to provide nutrients or defenses. We used deep sequencing to investigate gut microbiota of three species in the genus Bombus (bumble bees). Bombus are among the most economically and ecologically important non-managed pollinators. Some species have experienced dramatic declines, probably due to pathogens and land-use change. We examined variation within and across bee species and between semi natural and conventional agricultural habitats. We categorized as 'core bacteria' any operational taxonomic units (OTUs) with closest hits to sequences previously found exclusively or primarily in the guts of honey bees and bumble bees (genera Apis and Bombus). Microbial community composition differed among bee species. Richness, defined as number of bacterial OTUs, was highest for B. bimaculatus and B. impatiens. For B. bimaculatus, this was due to high richness of non-core bacteria. We found little effect of habitat on microbial communities. Richness of non-core bacteria was negatively associated with bacterial abundance in individual bees, possibly due to deeper sampling of non-core bacteria in bees with low populations of core bacteria. Infection by the gut parasite Crithidia was negatively associated with abundance of the core bacterium Gilliamella and positively associated with richness of non-core bacteria. Our results indicate that Bombus species have distinctive gut communities, and community-level variation is associated with pathogen infection. PMID- 24763370 TI - Impact of diet and individual variation on intestinal microbiota composition and fermentation products in obese men. AB - There is growing interest in understanding how diet affects the intestinal microbiota, including its possible associations with systemic diseases such as metabolic syndrome. Here we report a comprehensive and deep microbiota analysis of 14 obese males consuming fully controlled diets supplemented with resistant starch (RS) or non-starch polysaccharides (NSPs) and a weight-loss (WL) diet. We analyzed the composition, diversity and dynamics of the fecal microbiota on each dietary regime by phylogenetic microarray and quantitative PCR (qPCR) analysis. In addition, we analyzed fecal short chain fatty acids (SCFAs) as a proxy of colonic fermentation, and indices of insulin sensitivity from blood samples. The diet explained around 10% of the total variance in microbiota composition, which was substantially less than the inter-individual variance. Yet, each of the study diets induced clear and distinct changes in the microbiota. Multiple Ruminococcaceae phylotypes increased on the RS diet, whereas mostly Lachnospiraceae phylotypes increased on the NSP diet. Bifidobacteria decreased significantly on the WL diet. The RS diet decreased the diversity of the microbiota significantly. The total 16S ribosomal RNA gene signal estimated by qPCR correlated positively with the three major SCFAs, while the amount of propionate specifically correlated with the Bacteroidetes. The dietary responsiveness of the individual's microbiota varied substantially and associated inversely with its diversity, suggesting that individuals can be stratified into responders and non-responders based on the features of their intestinal microbiota. PMID- 24763371 TI - Composition and enzymatic function of particle-associated and free-living bacteria: a coastal/offshore comparison. AB - We compared the function and composition of free-living and particle-associated microbial communities at an inshore site in coastal North Carolina and across a depth profile on the Blake Ridge (offshore). Hydrolysis rates of six different polysaccharide substrates were compared for particle-associated (>3 MUm) and free living (<3 to 0.2 MUm) microbial communities. The 16S rRNA- and rDNA-based clone libraries were produced from the same filters used to measure hydrolysis rates. Particle-associated and free-living communities resembled one another; they also showed similar enzymatic hydrolysis rates and substrate preferences. All six polysaccharides were hydrolyzed inshore. Offshore, only a subset was hydrolyzed in surface water and at depths of 146 and 505 m; just three polysaccharides were hydrolyzed at 505 m. The spectrum of bacterial taxa changed more subtly between inshore and offshore surface waters, but changed greatly with depth offshore. None of the OTUs occurred at all sites: 27 out of the 28 major OTUs defined in this study were found either exclusively in a surface or in a mid-depth/bottom water sample. This distinction was evident with both 16S rRNA and rDNA analyses. At the offshore site, despite the low community overlap, bacterial communities maintained a degree of functional redundancy on the whole bacterial community level with respect to hydrolysis of high-molecular-weight substrates. PMID- 24763372 TI - Efficient CO2 fixation by surface Prochlorococcus in the Atlantic Ocean. AB - Nearly half of the Earth's surface is covered by the ocean populated by the most abundant photosynthetic organisms on the planet--Prochlorococcus cyanobacteria. However, in the oligotrophic open ocean, the majority of their cells in the top half of the photic layer have levels of photosynthetic pigmentation barely detectable by flow cytometry, suggesting low efficiency of CO2 fixation compared with other phytoplankton living in the same waters. To test the latter assumption, CO2 fixation rates of flow cytometrically sorted (14)C-labelled phytoplankton cells were directly compared in surface waters of the open Atlantic Ocean (30 degrees S to 30 degrees N). CO2 fixation rates of Prochlorococcus are at least 1.5-2.0 times higher than CO2 fixation rates of the smallest plastidic protists and Synechococcus cyanobacteria when normalised to photosynthetic pigmentation assessed using cellular red autofluorescence. Therefore, our data indicate that in oligotrophic oceanic surface waters, pigment minimisation allows Prochlorococcus cells to harvest plentiful sunlight more effectively than other phytoplankton. PMID- 24763374 TI - All-round robustness of the Mn19 coordination cluster system: experimental validation of a theoretical prediction. AB - Experimental and theoretical studies indicate that achieving the maximum possible ground spin state of ST = 83/2 for the mixed-valent Mn19 coordination cluster is insensitive to replacement of its eight MU3-N3 ligands by MU3-Cl, MU3-Br, MU3-OH or MU3-OMe, substantiating that the ferromagnetic interactions are indeed mediated mainly by the internal (MU4-O) ligands. The robustness of the inorganic {Mn(III)12Mn(II)7(MU4-O)8} core is clear from the molecular structure and ESI-MS studies have shown that the structure of the Mn19 aggregate, and also of its Mn18Y analogue, are stable beyond the solid state. PMID- 24763373 TI - Expanded HIV testing in low-prevalence, high-income countries: a cost effectiveness analysis for the United Kingdom. AB - OBJECTIVE: In many high-income countries with low HIV prevalence, significant numbers of persons living with HIV (PLHIV) remain undiagnosed. Identification of PLHIV via HIV testing offers timely access to lifesaving antiretroviral therapy (ART) and decreases HIV transmission. We estimated the effectiveness and cost effectiveness of HIV testing in the United Kingdom (UK), where 25% of PLHIV are estimated to be undiagnosed. DESIGN: We developed a dynamic compartmental model to analyze strategies to expand HIV testing and treatment in the UK, with particular focus on men who have sex with men (MSM), people who inject drugs (PWID), and individuals from HIV-endemic countries. METHODS: We estimated HIV prevalence, incidence, quality-adjusted life years (QALYs), and health care costs over 10 years, and cost-effectiveness. RESULTS: Annual HIV testing of all adults could avert 5% of new infections, even with no behavior change following HIV diagnosis because of earlier ART initiation, or up to 18% if risky behavior is halved. This strategy costs L67,000-L106,000/QALY gained. Providing annual testing only to MSM, PWID, and people from HIV-endemic countries, and one-time testing for all other adults, prevents 4-15% of infections, requires one-fourth as many tests to diagnose each PLHIV, and costs L17,500/QALY gained. Augmenting this program with increased ART access could add 145,000 QALYs to the population over 10 years, at L26,800/QALY gained. CONCLUSIONS: Annual HIV testing of key populations in the UK is very cost-effective. Additional one-time testing of all other adults could identify the majority of undiagnosed PLHIV. These findings are potentially relevant to other low-prevalence, high-income countries. PMID- 24763375 TI - Gait strategy in genetically obese patients: a 7-year follow up. AB - The aim of this study was to quantitatively evaluate the change in gait and body weight in the long term in patients with Prader-Willi Syndrome (PWS). Eight adults with PWS were evaluated at baseline and after 7 years. During this period patient participated an in- and out-patient rehabilitation programs including nutritional and adapted physical activity interventions. Two different control groups were included: the first group included 14 non-genetically obese patients (OCG: obese control group) and the second group included 10 age-matched healthy individuals (HCG: healthy control group). All groups were quantitatively assessed during walking with 3D-GA. The results at the 7-year follow-up revealed significant weight loss in the PWS group and spatial-temporal changes in gait parameters (velocity, step length and cadence). With regard to the hip joint, there were significant changes in terms of hip position, which is less flexed. Knee flexion-extension showed a reduction of flexion in swing phase and of its excursion. No changes of the ankle position were evident. As for ankle kinetics, we observed in the second session higher values for the peak of ankle power in terminal stance in comparison to the first session. No changes were found in terms of ankle kinetics. The findings demonstrated improvements associated to long-term weight loss, especially in terms of spatial-temporal parameters and at hip level. Our results back the call for early weight loss interventions during childhood, which would allow the development of motor patterns under normal body weight conditions. PMID- 24763376 TI - A systematic review on the effect of exercise interventions on challenging behavior for people with intellectual disabilities. AB - BACKGROUND: Challenging behavior, such as aggressive or self-injurious behavior, is a major concern for the health and well-being of people with intellectual disabilities (ID) and for their relatives, friends, and caregivers. The most common contemporary treatments have drawbacks, such as the adverse side effects of antipsychotics. Exercise interventions could be a good alternative, but little is known about its beneficial effects on challenging behavior in people with ID yet. METHOD: A systematic review of the literature was done and methodological quality of the selected studies has been judged on four points. With one-way Analysis of Variance (ANOVA), the effect of exercise interventions on challenging behavior was studied. The effect of low versus high intensity exercise interventions was studied with independent samples T-test using mean improvement scores. RESULTS: Twenty studies studying the effects of exercise interventions on challenging behavior in people with ID have been found. A quantitative evaluation of the results showed a significant decrease in challenging behavior after participating in an exercise intervention (M=30.9%, 95% CI: 25.0, 36.8). Furthermore, no significant difference was found between high (M=32.2%) and low (M=22.9%) intensity exercise interventions. CONCLUSIONS: The found decrease in challenging behavior shows that exercise seems to be recommendable as an effective treatment for people with challenging behavior and ID. However, most studies were of low methodological quality and more research is needed to optimize recommendations about the exact intensity, duration, frequency, and mode (group or individual) of exercise interventions for this group of people. PMID- 24763377 TI - The Democritos Movement Screening Tool for Preschool Children (DEMOST-PRE(c)): development and factorial validity. AB - The aim of this study was (a) to develop an assessment tool (the Democritos Movement Screening Tool for Preschool Children - DEMOST-PRE), designed to provide preschool educators, clinicians and researchers with information about assessment and screening of the motor proficiency of children aged 4-6 years, as well as the development and control of movement programmes and (b) to assess its factorial validity. First, tool's content and face validity were established and its final structure was determined. Then, the DEMOST-PRE was administered to 435 children (197 girls) aged 48-71 months (M=60.48 months, SD=6.98). The factor analysis conducted revealed two distinct components. Present evidence combined with the DEMOST-PRE administrative traits make it promising for preschool aged children's assessment. PMID- 24763379 TI - Simple approach to reinforce hydrogels with cellulose nanocrystals. AB - The physical crosslinking of colloidal nanoparticles via dynamic and directional non-covalent interactions has led to significant advances in composite hydrogels. In this paper, we report a simple approach to fabricate tough, stretchable and hysteretic isotropic nanocomposite hydrogels, where rod-like cellulose nanocrystals (CNCs) are encapsulated by flexible polymer chains of poly(N,N dimethylacrylamide) (PDMA). The CNC-PDMA colloidal clusters build a homogeneously cross-linked network and lead to significant reinforcing effect of the composites. Hierarchically structured CNC-PDMA clusters, from isolated particles to an interpenetrated network, are observed by transmission electron microscopy measurements. Dynamic shear oscillation measurements are applied to demystify the differences in network rheological behaviors, which were compared with network behaviors of chemically cross-linked PDMA counterparts. Tensile tests indicate that the hybrid hydrogels possess higher mechanical properties and a more efficient energy dissipation mechanism. In particular, with only 0.8 wt% of CNC loading, a 4.8-fold increase in Young's modulus, 9.2-fold increase in tensile strength, and 5.8-fold increase in fracture strain are achieved, which is ascribed to a combination of CNC reinforcement in the soft matrix and CNC-PDMA colloidal cluster conformational rearrangement under stretching. Physical interactions within networks serve as reversible sacrificial bonds that dissociate upon deformation, exhibiting large hysteresis as an energy dissipation mechanism via cluster mobility. This result contrasts with the case of chemically cross-linked PDMA counterparts where the stress relaxation is slow due to the permanent cross-links and low resistance against crack propagation within the covalent network. PMID- 24763378 TI - Psychometric validation of the Family Outcome Survey-Revised in Singapore. AB - This study sought to examine the construct validity of the Family Outcomes Survey Revised (FOS-R) in Singapore, describe the extent to which family outcomes of early childhood intervention (ECI) are attained, and obtain caregivers' perception on the extent to which ECI has served their needs. The FOS-R was translated into Chinese (simplified) and Malay for use in Singapore. Bilingual (i.e., English-Chinese and English-Malay) versions of the instrument were distributed to caregivers of young children with disabilities receiving ECI in four centers in Singapore. A total of 291 surveys were available for analyses (response rate of 43.1%). Confirmatory factor analyses indicated that there was a fit between the current data set and the FOS-R structure proposed by the developers. Overall, the participants reported moderately high attainment of family outcomes. They also reported that the ECI programs were mostly helpful. Other aspects of the cross-cultural application of instruments were considered and implications for local service provision as well as directions for future research were discussed. PMID- 24763380 TI - Early mortality syndrome outbreaks: a microbial management issue in shrimp farming? PMID- 24763381 TI - Mutations in conserved residues of the C. elegans microRNA Argonaute ALG-1 identify separable functions in ALG-1 miRISC loading and target repression. AB - microRNAs function in diverse developmental and physiological processes by regulating target gene expression at the post-transcriptional level. ALG-1 is one of two Caenorhabditis elegans Argonautes (ALG-1 and ALG-2) that together are essential for microRNA biogenesis and function. Here, we report the identification of novel antimorphic (anti) alleles of ALG-1 as suppressors of lin 28(lf) precocious developmental phenotypes. The alg-1(anti) mutations broadly impair the function of many microRNAs and cause dosage-dependent phenotypes that are more severe than the complete loss of ALG-1. ALG-1(anti) mutant proteins are competent for promoting Dicer cleavage of microRNA precursors and for associating with and stabilizing microRNAs. However, our results suggest that ALG-1(anti) proteins may sequester microRNAs in immature and functionally deficient microRNA Induced Silencing Complexes (miRISCs), and hence compete with ALG-2 for access to functional microRNAs. Immunoprecipitation experiments show that ALG-1(anti) proteins display an increased association with Dicer and a decreased association with AIN-1/GW182. These findings suggest that alg-1(anti) mutations impair the ability of ALG-1 miRISC to execute a transition from Dicer-associated microRNA processing to AIN-1/GW182 associated effector function, and indicate an active role for ALG/Argonaute in mediating this transition. PMID- 24763382 TI - Mechanisms of zero-lag synchronization in cortical motifs. AB - Zero-lag synchronization between distant cortical areas has been observed in a diversity of experimental data sets and between many different regions of the brain. Several computational mechanisms have been proposed to account for such isochronous synchronization in the presence of long conduction delays: Of these, the phenomenon of "dynamical relaying"--a mechanism that relies on a specific network motif--has proven to be the most robust with respect to parameter mismatch and system noise. Surprisingly, despite a contrary belief in the community, the common driving motif is an unreliable means of establishing zero lag synchrony. Although dynamical relaying has been validated in empirical and computational studies, the deeper dynamical mechanisms and comparison to dynamics on other motifs is lacking. By systematically comparing synchronization on a variety of small motifs, we establish that the presence of a single reciprocally connected pair--a "resonance pair"--plays a crucial role in disambiguating those motifs that foster zero-lag synchrony in the presence of conduction delays (such as dynamical relaying) from those that do not (such as the common driving triad). Remarkably, minor structural changes to the common driving motif that incorporate a reciprocal pair recover robust zero-lag synchrony. The findings are observed in computational models of spiking neurons, populations of spiking neurons and neural mass models, and arise whether the oscillatory systems are periodic, chaotic, noise-free or driven by stochastic inputs. The influence of the resonance pair is also robust to parameter mismatch and asymmetrical time delays amongst the elements of the motif. We call this manner of facilitating zero-lag synchrony resonance-induced synchronization, outline the conditions for its occurrence, and propose that it may be a general mechanism to promote zero-lag synchrony in the brain. PMID- 24763383 TI - Phosphatidylinositol-4,5-bisphosphate enhances anionic lipid demixing by the C2 domain of PKCalpha. AB - The C2 domain of PKCalpha (C2alpha) induces fluorescence self-quenching of NBD-PS in the presence of Ca2+, which is interpreted as the demixing of phosphatidylserine from a mixture of this phospholipid with phosphatidylcholine. Self-quenching of NBD-PS was considerably increased when phosphatidylinositol-4,5 bisphosphate (PIP2) was present in the membrane. When PIP2 was the labeled phospholipid, in the form of TopFluor-PIP2, fluorescence self-quenching induced by the C2 domain was also observed, but this was dependent on the presence of phosphatidylserine. An independent indication of the phospholipid demixing effect given by the C2alpha domain was obtained by using 2H-NMR, since a shift of the transition temperature of deuterated phosphatidylcholine was observed as a consequence of the addition of the C2alpha domain, but only in the presence of PIP2. The demixing induced by the C2alpha domain may have a physiological significance since it means that the binding of PKCalpha to membranes is accompanied by the formation of domains enriched in activating lipids, like phosphatidylserine and PIP2. The formation of these domains may enhance the activation of the enzyme when it binds to membranes containing phosphatidylserine and PIP2. PMID- 24763384 TI - Selfish play increases during high-stakes NBA games and is rewarded with more lucrative contracts. AB - High-stakes team competitions can present a social dilemma in which participants must choose between concentrating on their personal performance and assisting teammates as a means of achieving group objectives. We find that despite the seemingly strong group incentive to win the NBA title, cooperative play actually diminishes during playoff games, negatively affecting team performance. Thus team cooperation decreases in the very high stakes contexts in which it is most important to perform well together. Highlighting the mixed incentives that underlie selfish play, personal scoring is rewarded with more lucrative future contracts, whereas assisting teammates to score is associated with reduced pay due to lost opportunities for personal scoring. A combination of misaligned incentives and psychological biases in performance evaluation bring out the "I" in "team" when cooperation is most critical. PMID- 24763385 TI - Nanoscale mechanical contacts mapped by ultrashort time-scale electron transport. AB - Mechanical contacts are crucial to systems in engineering, electronics and biology. The microscopic nature of the contacting surfaces determines how they mesh on the nanoscale. There is thus much interest in methods that can map the actual area of two surfaces in contact--the real contact area--during the loading or unloading phases. We address this problem using an ultrafast optical technique to generate non-equilibrium electrons that diffuse across a nanoscale mechanical contact between two thin gold films deposited on sapphire. We image this process in the contact and near-contact regions to micron resolution in situ using transient optical reflectivity changes on femtosecond time scales. By use of a model of the ultrashort-time electron dynamics, we account for an up to ~40% drop in the transient optical reflectivity change on contact. We thereby show how the real contact area of a nanoscale contact can be mapped. Applications include the probing of microelectronic mechanical devices. PMID- 24763386 TI - Sequential exercise in triathletes: variations in GH and water loss. AB - Growth hormone (GH) may stimulate water loss during exercise by activating sweating. This study investigated GH secretion and water loss during sequential cycling and running, taking postural changes into account. The two exercise segments had similar durations and were performed at the same relative intensity to determine their respective contributions to water loss and the plasma volume variation noted in such trials. Eight elite triathletes first performed an incremental cycle test to assess maximal oxygen consumption. Then, the triathletes performed one of two trials in randomized order: constant submaximal cycling followed by treadmill running (C1-R2) or an inversed succession of running followed by cycling (R1-C2). Each segment of both trials was performed for 20 minutes at ~75% of maximal oxygen consumption. The second trial, reversing the segment order of the first trial, took place two weeks later. During cycling, the triathletes used their own bicycles equipped with a profiled handlebar. Blood sampling (for GH concentrations, plasma viscosity and plasma volume variation) was conducted at rest and after each segment while water loss was estimated from the post- and pre-measures. GH increases were significantly lower in R2 than C2 (72.2+/-50.1 vs. 164.0+/-157 ng x ml(-1) x min(-1), respectively; P<0.05). Water loss was significantly lower after C1-R2 than R1-C2 (1105+/-163 and 1235+/-153 ml, respectively; P<0.05). Plasma volume variation was significantly negative in C1 and R1 (-6.15+/-2.0 and -3.16+/-5.0%, respectively; P<0.05), not significant in C2, and significantly positive for seven subjects in R2 (4.05+/-3.1%). We concluded that the lower GH increases in R2 may have contributed to the smaller reduction in plasma volume by reducing sweating. Moreover, this lower GH response could be explained by the postural change during the transition from cycling to running. We recommend to pay particular attention to their hydration status during R1 which could limit a potential dehydration during C2. PMID- 24763387 TI - An overview of respiratory syncytial virus. PMID- 24763388 TI - A biomechanical comparison of unilateral and bilateral String-of-PearlsTM locking plates in a canine distal humeral metaphyseal gap model. AB - OBJECTIVE: To compare the in vitro biomechanical performance of two String-of Pearls (SOP) plate constructs in a canine distal humeral metaphyseal gap model. METHODS: Seven pairs of canine cadaveric humeri, including the elbow joints, were prepared. One group consisted of a unilateral medially placed SOP plate with bicortical screws (UNI). The second group consisted of bilateral caudo-medial and caudo-lateral SOP plates applied with monocortical screws (BI). A 2 cm ostectomy was performed immediately proximal to the supratrochlear foramen. Constructs were tested in torsion and axial compression. RESULTS: The UNI constructs had significantly lower stiffness in torsion and axial compression than the BI group. However, UNI constructs had a significantly higher ultimate strength than BI constructs. All UNI constructs failed by bending of the transcondylar screw and SOP plate. All BI constructs failed by axial pullout of the distal most screws. CLINICAL SIGNIFICANCE: In stabilizing canine supracondylar humeral fractures as modeled here, both the UNI model and the BI model demonstrated biomechanical advantages. The incorporation of a transcondylar screw through the medial plate appears to be beneficial to construct strength. PMID- 24763390 TI - Sentence imitation as a marker of SLI in Czech: disproportionate impairment of verbs and clitics. AB - PURPOSE: The authors examined sentence imitation as a potential clinical marker of specific language impairment (SLI) in Czech and its use to identify grammatical markers of SLI. METHOD: Children with SLI and the age- and language matched control groups (total N = 57) were presented with a sentence imitation task, a receptive vocabulary task, and digit span and nonword repetition tasks. Sentence imitations were scored for accuracy and error types. A separate count of inaccuracies for individual part-of-speech categories was performed. RESULTS: Children with SLI had substantially more inaccurate imitations than the control groups. The differences in the memory measures could not account for the differences between children with SLI and the control groups in imitation accuracy, even though they accounted for the differences between the language matched and age-matched control groups. The proportion of grammatical errors was larger in children with SLI than in the control groups. The categories that were most affected in imitations of children with SLI were verbs and clitics. CONCLUSION: Sentence imitation is a sensitive marker of SLI. Verbs and clitics are the most vulnerable categories in Czech SLI. The pattern of errors suggests that impaired syntactic representations are the most likely source of difficulties in children with SLI. PMID- 24763391 TI - Lead isotopic compositions of ash sourced from Australian bushfires. AB - This study identifies natural and industrial lead remobilized in ash deposits from three bushfires in relatively pristine areas of Australia in 2011 using lead isotopic compositions ((208)Pb/(207)Pb; (206)Pb/(207)Pb). Lead concentrations in the ash ranged from 1 to 36 mg/kg, bracketing the range of lead (4-23 mg/kg) in surface soils (0-2 cm), subsurface (40-50 cm) soils and rocks. The lead isotopic compositions of ash and surface soil samples were compared to subsurface soils and local bedrock samples. The data show that many of the ash and surface soil lead isotopic compositions were a mixture of natural lead and legacy industrial lead depositions (such as leaded petrol combustion). However, some of the ash samples at each of the sites had lead isotopic compositions that did not fit a simple two end-member mixing model, indicating other, unidentified sources. PMID- 24763392 TI - High intensity induced photocurrent polarity switching in lead sulfide nanowire field effect transistors. AB - We report an optoelectronic investigation of lead sulfide nanowires (NWs) by scanning photocurrent microscopy. The photocurrent in p-type lead sulfide NW field effect transistors has demonstrated unusually nonlinear dependence on the intensity of local excitation. Surprisingly, the photocurrent polarity can be reversed under high illumination intensity on the order of 100 W cm(-2). The origin of this photocurrent polarity switching is that the photo-injected carriers flip the direction of the electric field near the contact. These observations shed light on the nonlinear optoelectronic characteristics in semiconductor nanostructures and may provide an innovative method for optically tailoring local band structures. PMID- 24763393 TI - WebDoctor: Your Online Guide to Health Care and Wellness. PMID- 24763394 TI - Bullous eruption in a 36-year-old man with polycystic kidney disease. PMID- 24763395 TI - The yeast kinetochore - structural insights from optical microscopy. AB - In eukaryotic organisms each chromosome is captured by spindle microtubules. This interaction is mediated by an evolutionarily conserved, multi-protein complex called kinetochore. The main function of the kinetochore is to maintain correct chromosome segregation during cell division by transporting each sister chromatid to the spindle pole bodies localized at the opposite sites of the yeast nucleus. The kinetochore of budding yeast (Saccharomyces cerevisiae) is often used as a model system due to its simple composition compared to higher eukaryotes. This review highlights results obtained using optical imaging that revealed relative positions and stoichiometry of the major components of the budding yeast kinetochore. PMID- 24763397 TI - Photophysical properties of open-framework germanates templated by nickel complexes. AB - Open-framework germanates are a group of germanium oxides with a well-defined porous structure, suitable for ion-exchange and gas adsorption applications. Recently, Ni incorporation into the porous structure by establishing Ge-O-Ni bonds with the molecular complexes [Ni(H2N(CH2)2NH2)2] was realized. We investigate the optical and electronic features of these systems (SUT-1 and SUT 2) from first principles. To describe the photophysical behavior, we analyze the bonding between the Ni and nearest-neighboring atoms and simulate the absorption spectra. Because of their optical characteristics, germania-based nanomaterials are expected to be essential components of future optical and electronic devices. We discuss to what extent molecular transition-metal complexes embedded into porous germanium oxide can modify the optical response to potentially expand the area of applications. PMID- 24763400 TI - Risk adapted high-dose and dose-dense therapies modulate the impact of biological classification in diffuse large B-cell lymphoma prognosis. PMID- 24763401 TI - The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01. AB - The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed AML2001/01 trial. Both day 15 and day 28 status was classified as good (<=20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of <=5%, 6-10%, 11-20% and >20% had 4-year probabilities of survival of 52%+/-3% versus 36%+/-10% versus 21%+/-9% versus 14%+/-4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or >=12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677. PMID- 24763399 TI - Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. AB - Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 * 10(9)/L. PMID- 24763402 TI - Bortezomib cumulative dose, efficacy, and tolerability with three different bortezomib-melphalan-prednisone regimens in previously untreated myeloma patients ineligible for high-dose therapy. AB - Substantial efficacy has been demonstrated with bortezomib-melphalan-prednisone in phase III studies in transplant-ineligible myeloma patients using various twice-weekly and once-weekly bortezomib dosing schedules. In VISTA, the regimen comprised four 6-week twice-weekly cycles, plus five 6-week once-weekly cycles. In the GIMEMA MM-03-05 study, the bortezomib-melphalan-prednisone regimen was either per VISTA ('GIMEMA twice-weekly'), or comprised nine 5-week once-weekly cycles ('GIMEMA once-weekly'). In the GEM2005MAS65 study, the regimen comprised one 6-week twice-weekly cycle, plus five 5-week once-weekly cycles. We evaluated the cumulative bortezomib dose administered during bortezomib-melphalan prednisone, as well as efficacy and tolerability, using patient-level study data. Over all bortezomib-melphalan-prednisone cycles (nine in VISTA/GIMEMA; six in GEM2005MAS65), the median cumulative bortezomib dose administered was 38.5, 42.1, 40.3, and 32.9 mg/m(2) in VISTA, GIMEMA twice-weekly, GIMEMA once-weekly, and GEM2005MAS65, respectively, and the respective proportions of planned bortezomib dose actually delivered were 57.0%, 62.3%, 86.1%, and 90.4%. Response rates following bortezomib-melphalan-prednisone were 74-87% and appeared generally similar between studies. Three-year survival rates were 67.9-75.7% across studies. Grade 3/4 peripheral neuropathy rates were 13% in VISTA and 14% in GIMEMA twice-weekly, but were lower at 2% in GIMEMA once-weekly and 7% in GEM2005MAS65. Discontinuations and bortezomib dose reductions due to peripheral neuropathy were reduced in GIMEMA once-weekly versus VISTA and GIMEMA twice weekly. Exclusive or predominant use of once-weekly bortezomib dosing in GIMEMA once-weekly and GEM2005MAS65 resulted in high efficacy, comparable with that demonstrated in VISTA, and similar cumulative bortezomib dose with reduced toxicity. Trials are registered with ClinicalTrials.gov: VISTA (Identifier:00111319), GIMEMA MM-03-05 (Identifier:01063179), and GEM2005MAS65 (Identifier:00443235). PMID- 24763403 TI - Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis. AB - Class I histone deacetylases are critical regulators of gene transcription by erasing lysine acetylation. Targeting histone deacetylases using relative non specific small molecule inhibitors is of major interest in the treatment of cancer, neurological disorders and acquired immune deficiency syndrome. Harnessing the therapeutic potential of histone deacetylase inhibitors requires full knowledge of individual histone deacetylases in vivo. As hematologic malignancies show increased sensitivity towards histone deacetylase inhibitors we targeted deletion of class I Hdac1 and Hdac2 to hematopoietic cell lineages. Here, we show that Hdac1 and Hdac2 together control hematopoietic stem cell homeostasis, in a cell-autonomous fashion. Simultaneous loss of Hdac1 and Hdac2 resulted in loss of hematopoietic stem cells and consequently bone marrow failure. Bone-marrow-specific deletion of Sin3a, a major Hdac1/2 co-repressor, phenocopied loss of Hdac1 and Hdac2 indicating that Sin3a-associated HDAC1/2 activity is essential for hematopoietic stem cell homeostasis. Although Hdac1 and Hdac2 show compensatory and overlapping functions in hematopoiesis, mice expressing mono-allelic Hdac1 or Hdac2 revealed that Hdac1 and Hdac2 contribute differently to the development of specific hematopoietic lineages. PMID- 24763404 TI - Targeted resequencing of 52 bone marrow failure genes in patients with aplastic anemia reveals an increased frequency of novel variants of unknown significance only in SLX4. PMID- 24763405 TI - Younger age is associated with lower reactive hyperemic index but not lower flow mediated dilation among children and adolescents. AB - BACKGROUND: The use of digital reactive hyperemia as a measure of endothelial function among children and adolescents is becoming increasingly common. However, unexpected observations of low reactive hyperemic index values in younger children in our laboratory led us to conduct a study evaluating the influence of age, sex, height, weight, blood pressure, body mass index (BMI), and finger volume on RHI values. METHODS: Endothelial function, measured by digital reactive hyperemia (reactive hyperemic index: RHI) was assessed in 113 children and adolescents (mean age 12.4 +/- 3.8 years; 64 males), with 102 also assessed for brachial artery flow-mediated dilation (FMD) using ultrasound imaging. Associations with age, sex, height, weight, systolic and diastolic blood pressure (SBP, DBP), BMI, and finger volume were evaluated. RESULTS: Using GLM regression, age (beta = 0.03, P = 0.014) and SBP (beta = 0.015, P = 0.004) were significantly associated with RHI. No measures were associated with FMD. In the subset of individuals with measured finger volume, age (beta = 0.025, P = 0.037) was the only measure significantly associated with log RHI. Similarly, no measures were associated with FMD. CONCLUSION: Younger age is associated with lower RHI but not lower FMD among children and adolescents. These findings call into question the validity and usefulness of digital reactive hyperemia as a method to quantify endothelial function among younger children. PMID- 24763406 TI - Paraoxonase-1 activity and oxidative stress in patients with anterior ST elevation myocardial infarction undergoing primary percutaneous coronary intervention with and without no-reflow. AB - BACKGROUND: Reperfusion and ischemic injuries are pathogenetic mechanisms of no reflow. Oxidative stress plays a critical role during ischemia as well as during the reperfusion phase following ST elevation myocardial infarction (STEMI). We sought to investigate the relationship between no-reflow with paraoxonase-1 (PON 1) activity and oxidative stress markers (total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), lipid hydro-peroxide (LOOH)) in patients with anterior STEMI undergoing primary percutaneous coronary intervention (PCI). METHODS: In this study, 319 consecutive anterior STEMI patients undergoing primary PCI were prospectively included (mean age 56.5 +/- 12.5 years). The patients were divided into two groups as normal flow (n = 231) and no-reflow (n = 88) groups. Serum PON-1 activity was measured spectrophotometrically. TAC and TOS levels were determined by using an automated measurement method. LOOH levels were measured by ferrous oxidation with xylenol orange assay. RESULTS: PON-1 activity and TAC levels were significantly lower and TOS, OSI and LOOH levels were significantly higher in patients with no-reflow compared to normal flow group (p < 0.05, for all). On multivariate logistic regression analysis, PON-1 activity (beta = 0.976, 95% CI = 0.962-0.990, p = 0.001) and OSI (beta = 1.094, 95% CI = 1.042-1.148, p < 0.001) as well as diabetes, infarction time, thrombus score and initial SYNTAX score were independently associated with no-reflow. CONCLUSION: In patients with no-reflow compared with normal flow, oxidants are increased, while serum PON-1 activity and antioxidants are decreased. This result shows that increased oxidative stress has a role in the pathogenesis of no-reflow. PMID- 24763407 TI - Low serum bilirubin concentration is a predictor of chronic kidney disease. AB - OBJECTIVE: Chronic kidney disease (CKD) is a worldwide public health problem. It is very important to identify the factors that affect CKD. Previous studies have reported that serum bilirubin concentration was positively correlated with renal function in a cross-sectional study. The aim of this study was to investigate the relationship between serum bilirubin concentration and the progression of CKD. METHODS: A cohort study was performed on a consecutive series of 2784 subjects without CKD, defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), at baseline. We analyzed the relationship between serum total bilirubin concentration at baseline and new-onset CKD in the general population. RESULTS: We followed the subjects for a median period of 7.7 years. There were 1157 females and 1627 males, and 231 females and 370 males developed CKD during this period. Multiple Cox regression analyses revealed that serum total bilirubin concentration (hazard ratio (HR) per 1.0 MUmol/L increase 0.97 (95% CI 0.95 0.99), P = 0.0084) in addition to age, gamma-glutamyl transpeptidase (GGT), uric acid (UA), creatinine and medication for hypertension in men and serum total bilirubin concentration (HR per 1.0 MUmol/L increase 0.96 (95% CI 0.93-1.00), P = 0.0309) in addition to age, GGT, alanine aminotransferase, UA, creatinine and medication for dyslipidemia in women were independent predictors of new-onset CKD, after adjusting for confounders. CONCLUSION: Our study demonstrated that serum total bilirubin concentration could be a novel risk factor for the progression of CKD, defined as eGFR <60 ml/min/1.73 m(2), in the general population. PMID- 24763410 TI - Unfolding the crucial role of a nucleophile in Ziegler-Natta type Ir catalyzed polyaminoborane formation. AB - formation through dehydropolymerization of ammonia-borane by Brookhart's iridium pincer catalyst has been under intense scrutiny but a sound molecular level understanding has remained elusive. Herein, using DFT the mechanism outlined by us for IrH2POCOP catalyzed formation underscores the importance of generation of nucleophiles, in particular that of the metal bound NH2BH2 moiety armed with a nitrogen lone pair for chain initiation and chain propagation steps. PMID- 24763409 TI - Predicting impacts of climate change on the aboveground carbon sequestration rate of a temperate forest in northeastern China. AB - The aboveground carbon sequestration rate (ACSR) reflects the influence of climate change on forest dynamics. To reveal the long-term effects of climate change on forest succession and carbon sequestration, a forest landscape succession and disturbance model (LANDIS Pro7.0) was used to simulate the ACSR of a temperate forest at the community and species levels in northeastern China based on both current and predicted climatic data. On the community level, the ACSR of mixed Korean pine hardwood forests and mixed larch hardwood forests, fluctuated during the entire simulation, while a large decline of ACSR emerged in interim of simulation in spruce-fir forest and aspen-white birch forests, respectively. On the species level, the ACSR of all conifers declined greatly around 2070s except for Korean pine. The ACSR of dominant hardwoods in the Lesser Khingan Mountains area, such as Manchurian ash, Amur cork, black elm, and ribbed birch fluctuated with broad ranges, respectively. Pioneer species experienced a sharp decline around 2080s, and they would finally disappear in the simulation. The differences of the ACSR among various climates were mainly identified in mixed Korean pine hardwood forests, in all conifers, and in a few hardwoods in the last quarter of simulation. These results indicate that climate warming can influence the ACSR in the Lesser Khingan Mountains area, and the largest impact commonly emerged in the A2 scenario. The ACSR of coniferous species experienced higher impact by climate change than that of deciduous species. PMID- 24763408 TI - Molecular recognition of CCR5 by an HIV-1 gp120 V3 loop. AB - The binding of protein HIV-1 gp120 to coreceptors CCR5 or CXCR4 is a key step of the HIV-1 entry to the host cell, and is predominantly mediated through the V3 loop fragment of HIV-1 gp120. In the present work, we delineate the molecular recognition of chemokine receptor CCR5 by a dual tropic HIV-1 gp120 V3 loop, using a comprehensive set of computational tools predominantly based on molecular dynamics simulations and free energy calculations. We report, what is to our knowledge, the first complete HIV-1 gp120 V3 loop : CCR5 complex structure, which includes the whole V3 loop and the N-terminus of CCR5, and exhibits exceptional agreement with previous experimental findings. The computationally derived structure sheds light into the functional role of HIV-1 gp120 V3 loop and CCR5 residues associated with the HIV-1 coreceptor activity, and provides insights into the HIV-1 coreceptor selectivity and the blocking mechanism of HIV-1 gp120 by maraviroc. By comparing the binding of the specific dual tropic HIV-1 gp120 V3 loop with CCR5 and CXCR4, we observe that the HIV-1 gp120 V3 loop residues 13-21, which include the tip, share nearly identical structural and energetic properties in complex with both coreceptors. This result paves the way for the design of dual CCR5/CXCR4 targeted peptides as novel potential anti-AIDS therapeutics. PMID- 24763411 TI - Toward improving fidelity of computational fluid dynamics simulations: boundary conditions matter. PMID- 24763412 TI - Conventional and functional MR imaging of peripheral nerve sheath tumors: initial experience. AB - BACKGROUND AND PURPOSE: Differentiating benign from malignant peripheral nerve sheath tumors can be very challenging using conventional MR imaging. Our aim was to test the hypothesis that conventional and functional MR imaging can accurately diagnose malignancy in patients with indeterminate peripheral nerve sheath tumors. MATERIALS AND METHODS: This institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study retrospectively reviewed 61 consecutive patients with 80 indeterminate peripheral nerve sheath tumors. Of these, 31 histologically proved peripheral nerve sheath tumors imaged with conventional (unenhanced T1, fluid-sensitive, contrast-enhanced T1-weighted sequences) and functional MR imaging (DWI/apparent diffusion coefficient mapping, dynamic contrast-enhanced MR imaging) were included. Two observers independently assessed anatomic (size, morphology, signal) and functional (ADC values, early arterial enhancement by dynamic contrast-enhanced MR) features to determine interobserver agreement. The accuracy of MR imaging for differentiating malignant from benign was also determined by receiver operating characteristic analysis. RESULTS: Of 31 peripheral nerve sheath tumors, there were 9 malignant (9%) and 22 benign ones (81%). With anatomic sequences, average tumor diameter (6.3 +/- 1.8 versus 3.9 +/- 2.3 mm, P = .009), ill-defined/infiltrative margins (77% versus 32%; P = .04), and the presence of peritumoral edema (66% versus 23%, P = .01) were different for malignant peripheral nerve sheath tumors and benign peripheral nerve sheath tumors. With functional sequences, minimum ADC (0.47 +/- 0.32 * 10( 3) mm(2)/s versus 1.08 +/- 0.26 * 10(-3) mm(2)/s; P < .0001) and the presence of early arterial enhancement (50% versus 11%; P = .03) were different for malignant peripheral nerve sheath tumors and benign peripheral nerve sheath tumors. The minimum ADC (area under receiver operating characteristic curve was 0.89; 95% confidence interval, 0.73-0.97) and the average tumor diameter (area under the curve = 0.8; 95% CI, 0.66-0.94) were accurate in differentiating malignant peripheral nerve sheath tumors from benign peripheral nerve sheath tumors. With threshold values for minimum ADC <= 1.0 * 10(-3) mm(2)/s and an average diameter of >=4.2 cm, malignancy could be diagnosed with 100% sensitivity (95% CI, 66.4% 100%). CONCLUSIONS: Average tumor diameter and minimum ADC values are potentially important parameters that may be used to distinguish malignant peripheral nerve sheath tumors from benign peripheral nerve sheath tumors. PMID- 24763414 TI - Enhanced aneurysmal flow diversion using a dynamic push-pull technique: an experimental and modeling study. AB - BACKGROUND AND PURPOSE: Neurovascular flow diverters are flexible, braided stent meshes for intracranial aneurysm treatment. We applied the dynamic push-pull technique to manipulate the flow-diverter mesh density at the aneurysm orifice to maximize flow diversion. This study investigated the hemodynamic impact of the dynamic push-pull technique on patient-specific aneurysms by using the developed high-fidelity virtual-stenting computational modeling technique combined with computational fluid dynamics. MATERIALS AND METHODS: We deployed 2 Pipeline Embolization Devices into 2 identical sidewall anterior cerebral artery aneurysm phantoms by using the dynamic push-pull technique with different delivery-wire advancements. We then numerically simulated these deployment processes and validated the simulated mesh geometry. Computational fluid dynamics analysis was performed to evaluate detailed hemodynamic changes by deployed flow diverters in the sidewall aneurysm and a fusiform basilar trunk aneurysm (deployments implemented previously). Images of manipulated flow diverter mesh from sample clinical cases were also evaluated. RESULTS: The flow diverters deployed in silico accurately replicated in vitro geometries. Increased delivery wire advancement (21 versus 11 mm) by using a dynamic push-pull technique produced a higher mesh compaction at the aneurysm orifice (50% metal coverage versus 36%), which led to more effective aneurysmal inflow reduction (62% versus 50% in the sidewall aneurysm; 57% versus 36% in the fusiform aneurysm). The dynamic push pull technique also caused relatively lower metal coverage along the parent vessel due to elongation of the flow diverter. High and low mesh compactions were also achieved for 2 real patients by using the dynamic push-pull technique. CONCLUSIONS: The described dynamic push-pull technique increases metal coverage of pure braided flow diverters over the aneurysm orifice, thereby enhancing the intended flow diversion, while reducing metal coverage along the parent vessel to prevent flow reduction in nearby perforators. PMID- 24763415 TI - Reliability of the STIR sequence for acute type II odontoid fractures. AB - BACKGROUND AND PURPOSE: The STIR sequence is routinely used to assess acute traumatic osseous injury. Because the composition of the odontoid in older individuals may be altered with osteopenia and decreased vascularity, the STIR sequence may not accurately depict the acuity of an odontoid fracture. The purpose of this study was to evaluate the reliability of the STIR sequence to differentiate acute-versus-chronic type II odontoid fractures in older patients, particularly those with osteopenia. MATERIALS AND METHODS: A retrospective review was performed for patients with type II odontoid fractures during a 10-year period with both CT and MR imaging performed within 24 hours of injury. Patients were paired with controls of similar ages and were grouped by age. The STIR images were evaluated in a blinded fashion for the presence of hyperintensity in the odontoid. Demographic and clinical characteristics were also recorded. RESULTS: Seventy-five patients with type II odontoid fracture and 75 healthy controls (mean and median age of 57 years) were identified. The sensitivity of STIR to detect fracture in the age group 57 years and older was significantly worse than that in the age group younger than 57 years (54% and 82%, respectively; P = .018). CONCLUSIONS: Older patients, particularly those with osteopenia, may have acute odontoid injuries without corresponding STIR hyperintensity. Additionally, interobserver agreement in STIR interpretation decreases with increasing patient age. As such, in this patient population, in which the presence of bone marrow edema as an indicator of fracture acuity may impact therapeutic decisions, correlation with CT findings and clinical history is crucial. PMID- 24763416 TI - Midbrain-hindbrain involvement in septo-optic dysplasia. AB - BACKGROUND AND PURPOSE: Midbrain-hindbrain involvement in septo-optic dysplasia has not been well described, despite reported mutations of genes regulating brain stem patterning. We aimed to describe midbrain-hindbrain involvement in patients with septo-optic dysplasia and to identify possible clinical-neuroimaging correlations. MATERIALS AND METHODS: Using MR imaging, we categorized 38 patients (21 males) based on the presence (group A, 21 patients) or absence (group B, 17 patients) of visible brain stem anomalies. We measured height and anteroposterior diameter of midbrain, pons, and medulla, anteroposterior midbrain/pons diameter (M/P ratio), vermian height, and tegmento-vermian angle, and compared the results with 114 healthy age-matched controls. Furthermore, patients were subdivided based on the type of midline anomalies. The associations between clinical and neuroradiological features were investigated. Post hoc tests were corrected according to Bonferroni adjustment (pB). RESULTS: Patients with brain stem abnormalities had smaller anteroposterior pons diameter than controls (pB < .0001) and group B (pB = .012), higher M/P ratio than controls (pB < .0001) and group B (pB < .0001), and smaller anteroposterior medulla diameter (pB = .001), pontine height (pB = .00072), and vermian height (pB = .0009) than controls. Six of 21 patients in group A had thickened quadrigeminal plate, aqueductal stenosis, and hydrocephalus; 3 also had agenesis of the epithalamus. One patient had a short midbrain with long pons and large superior vermis. There was a statistically significant association between brain stem abnormalities and callosal dysgenesis (P = .011) and developmental delay (P = .035), respectively. CONCLUSION: Midbrain-hindbrain abnormalities are a significant, albeit underrecognized, component of the septo-optic dysplasia spectrum, and are significantly associated with developmental delay in affected patients. PMID- 24763418 TI - Imaging appearance of the lateral rectus-superior rectus band in 100 consecutive patients without strabismus. AB - BACKGROUND AND PURPOSE: The lateral rectus-superior rectus band is an orbital connective tissue structure that has been implicated in a form of strabismus termed sagging eye syndrome. Our purpose was to define the normal MR imaging and CT appearance of this band in patients without strabismus. MATERIALS AND METHODS: Orbital MR imaging and CT examinations in 100 consecutive patients without strabismus were evaluated. Readers graded the visibility of the lateral rectus superior rectus band on coronal T1WI, coronal STIR, and coronal CT images. Readers determined whether the band demonstrated superotemporal bowing or any discontinuities and whether a distinct lateral levator aponeurosis was seen. Reader agreement was assessed by kappa coefficients. Association between imaging metrics and patient age/sex was calculated by using the Fisher exact test. RESULTS: The lateral rectus-superior rectus band was visible in 95% of coronal T1WI, 68% of coronal STIR sequences, and 70% of coronal CT scans. Ninety-five percent of these bands were seen as a continuous, arc-like structure extending from the superior rectus/levator palpebrae muscle complex to the lateral rectus muscle; 24% demonstrated superotemporal bowing; and in 82% of orbits, a distinct lateral levator aponeurosis was visible. Increasing patient age was negatively associated with lateral rectus-superior rectus band visibility (P=.03), positively associated with lateral rectus-superior rectus band superotemporal bowing (P=.03), and positively associated with lateral levator aponeurosis visibility (P=.01). CONCLUSIONS: The lateral rectus-superior rectus band is visible in most patients without strabismus on coronal T1WI. The age effect with respect to its visibility and superotemporal bowing could represent age-related connective tissue degeneration. PMID- 24763417 TI - Diffusion-weighted imaging with dual-echo echo-planar imaging for better sensitivity to acute stroke. AB - BACKGROUND AND PURPOSE: Parallel imaging facilitates the acquisition of echo planar images with a reduced TE, enabling the incorporation of an additional image at a later TE. Here we investigated the use of a parallel imaging-enhanced dual-echo EPI sequence to improve lesion conspicuity in diffusion-weighted imaging. MATERIALS AND METHODS: Parallel imaging-enhanced dual-echo DWI data were acquired in 50 consecutive patients suspected of stroke at 1.5T. The dual-echo acquisition included 2 EPI for 1 diffusion-preparation period (echo 1 [TE = 48 ms] and echo 2 [TE = 105 ms]). Three neuroradiologists independently reviewed the 2 echoes by using the routine DWI of our institution as a reference. Images were graded on lesion conspicuity, diagnostic confidence, and image quality. The apparent diffusion coefficient map from echo 1 was used to validate the presence of acute infarction. Relaxivity maps calculated from the 2 echoes were evaluated for potential complementary information. RESULTS: Echo 1 and 2 DWIs were rated as better than the reference DWI. While echo 1 had better image quality overall, echo 2 was unanimously favored over both echo 1 and the reference DWI for its high sensitivity in detecting acute infarcts. CONCLUSIONS: Parallel imaging enhanced dual-echo diffusion-weighted EPI is a useful method for evaluating lesions with reduced diffusivity. The long TE of echo 2 produced DWIs that exhibited superior lesion conspicuity compared with images acquired at a shorter TE. Echo 1 provided higher SNR ADC maps for specificity to acute infarction. The relaxivity maps may serve to complement information regarding blood products and mineralization. PMID- 24763419 TI - An in vivo, MRI-integrated real-time model of active contrast extravasation in acute intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: The "spot sign" or contrast extravasation is strongly associated with hematoma formation and growth. An animal model of contrast extravasation is important to test existing and novel therapeutic interventions to inform present and future clinical studies. The purpose of this study was to create an animal model of contrast extravasation in acute intracerebral hemorrhage. MATERIALS AND METHODS: Twenty-eight hemispheres of Yorkshire male swine were insonated with an MR imaging-guided focused sonography system following lipid microsphere infusion and mean arterial pressure elevation. The rate of contrast leakage was quantified by using dynamic contrast-enhanced MR imaging and was classified as contrast extravasation or postcontrast leakage by using postcontrast T1. Hematoma volume was measured on gradient recalled-echo MR imaging performed 2 hours postprocedure. Following this procedure, sacrificed brain was subjected to histopathologic examination. Power level, burst length, and blood pressure elevation were correlated with leakage rate, hematoma size, and vessel abnormality extent. RESULTS: Median (intracerebral hemorrhage) contrast extravasation leakage was higher than postcontrast leakage (11.3; 6.3 23.2 versus 2.4; 1.1-3.1 mL/min/100 g; P<.001). Increasing burst length, gradient recalled-echo hematoma (rho=0.54; 95% CI, 0.2-0.8; P=.007), and permeability were correlated (rho=0.55; 95% CI, 0.1-0.8; P=.02). Median permeability (P=.02), gradient recalled-echo hematoma (P=.02), and dynamic contrast-enhanced volumes (P=.02) were greater at 1000 ms than at 10 ms. Within each burst-length subgroup, incremental contrast leakage was seen with mean arterial pressure elevation (rho=0.2-0.8). CONCLUSIONS: We describe a novel MR imaging-integrated real-time swine intracerebral hemorrhage model of acute hematoma growth and contrast extravasation. PMID- 24763420 TI - Are we effectively informing patients? A quantitative analysis of on-line patient education resources from the American Society of Neuroradiology. AB - BACKGROUND AND PURPOSE: The ubiquitous use of the Internet by the public in an attempt to better understand their health care requires the on-line resources written at an appropriate level to maximize comprehension for the average user. The National Institutes of Health and the American Medical Association recommend on-line patient education resources written at a third-to-seventh grade level. We evaluated the readability of the patient education resources provided on the Web site of the American Society of Neuroradiology (http://www.asnr.org/patientinfo/). MATERIALS AND METHODS: All patient education material from the ASNR Web site and the Society of Neurointerventional Surgery Web site were downloaded and evaluated with the computer software, Readability Studio Professional Edition, by using 10 quantitative readability scales: the Flesch Reading Ease, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook, Coleman-Liau Index, Gunning Fog Index, New Dale-Chall, FORCAST Formula, Fry Graph, Raygor Reading Estimate, and New Fog Count. An unpaired t test was used to compare the readability level of resources available on the American Society of Neuroradiology and the Society of Neurointerventional Surgery Web sites. RESULTS: The 20 individual patient education articles were written at a 13.9 +/- 1.4 grade level with only 5% written at <11th grade level. There was no statistical difference between the level of readability of the resources on the American Society of Neuroradiology and Society of Neurointerventional Surgery Web sites. CONCLUSIONS: The patient education resources on these Web sites fail to meet the guidelines of the National Institutes of Health and American Medical Association. Members of the public may fail to fully understand these resources and would benefit from revisions that result in more comprehensible information cast in simpler language. PMID- 24763422 TI - Comparison of radiographic measurements of the patellar tendon-tibial plateau angle with anatomical measurements in dogs. Validity of the common tangent and tibial plateau methods. AB - OBJECTIVE: To evaluate the validity of the common tangent and conventional tibial plateau angle methods for measuring the patellar tendon angle (PTA) in dogs. METHODS: Radiographs of cadaveric stifles (n = 20) placed at 135 degrees in true lateral position were obtained to measure the PTA with both methods. A Kirschner wire was inserted perpendicularly to the patellar tendon at its insertion on the tibia and the stifle was dissected. Two Kirschner wires were then used to identify the anatomical landmarks of the tibial plateau. A digital image was obtained of the proximal tibia in true lateral position. Six blinded observers measured each PTA digitally while the anatomical PTA was determined by an independent blinded observer from the angle between the line representing the tibial plateau and the Kirschner wire representing the perpendicular to the patellar tendon. The agreement between the methods was determined statistically from an intraclass correlation coefficient (ICC). RESULTS: The global ICC for the common tangent method (0.44) and for the conventional method (0.4) indicated that their overall validity is poor. The measurements obtained by common tangentmethod and conventional method were respectively below and above the anatomical measurements. The reproducibility of the PTA measurements based on images of the dissected stifles was very good. CLINICAL SIGNIFICANCE: Both the common tangent and conventional methods show poor concordance with the anatomical measurement of PTA. Further studies are needed to determine if errors in measurements affect the clinical outcome. PMID- 24763423 TI - Autoregulation of the Kluyveromyces lactis pyruvate decarboxylase gene KlPDC1 involves the regulatory gene RAG3. AB - In the yeast Kluyveromyces lactis, the pyruvate decarboxylase gene KlPDC1 is strongly regulated at the transcription level by different environmental factors. Sugars and hypoxia act as inducers of transcription, while ethanol acts as a repressor. Their effects are mediated by gene products, some of which have been characterized. KlPDC1 transcription is also strongly repressed by its product- KlPdc1--through a mechanism called autoregulation. We performed a genetic screen that allowed us to select and identify the regulatory gene RAG3 as a major factor in the transcriptional activity of the KlPDC1 promoter in the absence of the KlPdc1 protein, i.e. in the autoregulatory mechanism. We also showed that the two proteins Rag3 and KlPdc1 interact, co-localize in the cell and that KlPdc1 may control Rag3 nuclear localization. PMID- 24763425 TI - Multiple personalities of the RNA polymerase active centre. AB - Transcription in all living organisms is accomplished by highly conserved multi subunit RNA polymerases (RNAPs). Our understanding of the functioning of the active centre of RNAPs has transformed recently with the finding that a conserved flexible domain near the active centre, the trigger loop (TL), participates directly in the catalysis of RNA synthesis and serves as a major determinant for fidelity of transcription. It also appears that the TL is involved in the unique ability of RNAPs to exchange catalytic activities of the active centre. In this phenomenon the TL is replaced by a transcription factor which changes the amino acid content and, as a result, the catalytic properties of the active centre. The existence of a number of transcription factors that act through substitution of the TL suggests that the RNAP has several different active centres to choose from in response to external or internal signals. A video of this Prize Lecture, presented at the Society for General Microbiology Annual Conference 2014, can be viewed via this link: https://www.youtube.com/watch?v=79Z7iXVEPo4. PMID- 24763424 TI - Sky1 regulates the expression of sulfur metabolism genes in response to cisplatin. AB - Cisplatin is commonly used in cancer therapy and yeast cells are also sensitive to this compound. We present a transcriptome analysis discriminating between RNA changes induced by cisplatin treatment, which are dependent on or independent of SKY1 function--a gene whose deletion increases resistance to the drug. Gene expression changes produced by addition of cisplatin to W303 and W303-Deltasky1 cells were recorded using DNA microarrays. The data, validated by quantitative PCR, revealed 122 differentially expressed genes: 69 upregulated and 53 downregulated. Among the upregulated genes, those related to sulfur metabolism were over-represented and partially dependent on Sky1. Deletions of MET4 or other genes encoding co-regulators of the expression of sulfur-metabolism-related genes, with the exception of MET28, did not modify the cisplatin sensitivity of yeast cells. One of the genes with the highest cisplatin-induced upregulation was SEO1, encoding a putative permease of sulfur compounds. We also measured the platinum, sulfur and glutathione content in W303, W303-Deltasky1 and W303 Deltaseo1 cells after cisplatin treatment, and integration of the data suggested that these transcriptional changes might represent a cellular response that allowed chelation of cisplatin with sulfur-containing amino acids and also helped DNA repair by stimulating purine biosynthesis. The transcription pattern of stimulation of sulfur-containing amino acids and purine synthesis decreased, or even disappeared, in the W303-Deltasky1 strain. PMID- 24763426 TI - Calcineurin phosphatase and phospholipase C are required for developmental and pathological functions in the citrus fungal pathogen Alternaria alternata. AB - Excessive Ca(2+) or compounds interfering with phosphoinositide cycling have been found to inhibit the growth of the tangerine pathotype of Alternaria alternata, suggesting a crucial role of Ca(2+) homeostasis in this pathotype. The roles of PLC1, a phospholipase C-coding gene and CAL1, a calcineurin phosphatase-coding gene were investigated. Targeted gene disruption showed that both PLC1 and CAL1 were required for vegetative growth, conidial formation and pathogenesis in citrus. Fungal strains lacking PLC1 or CAL1 exhibited extremely slow growth and induced small lesions on calamondin leaves. Deltaplc1 mutants produced fewer conidia, which germinated at slower rates than wild-type. Deltacal1 mutants produced abnormal hyphae and failed to produce any mature conidia, but instead produced highly melanized bulbous hyphae with distinct septae. Fluorescence microscopy using Fluo-3 dye as a Ca(2+) indicator revealed that the Deltaplc1 mutant hyphae emitted stronger cytosolic fluorescence, and the Deltacal1 mutant hyphae emitted less cytosolic fluorescence, than those of wild-type. Infection assessed on detached calamondin leaves revealed that application of CaCl2 or neomycin 24 h prior to inoculation provided protection against Alt. alternata. These data indicate that a dynamic equilibrium of cellular Ca(2+) is critical for developmental and pathological processes of Alt. alternata. PMID- 24763429 TI - Textbook of dermatologic surgery. PMID- 24763427 TI - Nanoscale characterization of effect of L-arginine on Streptococcus mutans biofilm adhesion by atomic force microscopy. AB - A major aetiological factor of dental caries is the pathology of the dental plaque biofilms. The amino acid L-arginine (Arg) is found naturally in saliva as a free molecule or as a part of salivary peptides and proteins. Plaque bacteria metabolize Arg to produce alkali and neutralize glycolytic acids, promoting a less cariogenous oral microbiome. Here, we explored an alternative and complementary mechanism of action of Arg using atomic force microscopy. The nanomechanical properties of Streptococcus mutans biofilm extracellular matrix were characterized under physiological buffer conditions. We report the effect of Arg on the adhesive behaviour and structural properties of extracellular polysaccharides in S. mutans biofilms. High-resolution imaging of biofilm surfaces can reveal additional structural information on bacterial cells embedded within the surrounding extracellular matrix. A dense extracellular matrix was observed in biofilms without Arg compared to those grown in the presence of Arg. S. mutans biofilms grown in the presence of Arg could influence the production and/or composition of extracellular membrane glucans and thereby affect their adhesion properties. Our results suggest that the presence of Arg in the oral cavity could influence the adhesion properties of S. mutans to the tooth surface. PMID- 24763430 TI - The absorption properties of "physical" sunscreens. PMID- 24763431 TI - An erythematous nodule on the vulva. PMID- 24763433 TI - Synthesis of homochiral tris-indanyl molecular rods. AB - Homochiral tris-indanyl molecular rods designed for supramolecular surface self assembly were synthesized. The chiral indanol moiety was constructed via a Ti mediated alkyne trimerization. Further manipulations resulted in a homochiral indanol monomer. This was employed as the precursor for successive Sonogashira and Ohira-Bestman reactions towards the homochiral tris-indanyl molecular rods. The molecular rods will be applied for scanning tunnelling microscopy studies of their surface self-assembly and chirality. PMID- 24763432 TI - Role of calmodulin-calmodulin kinase II, cAMP/protein kinase A and ERK 1/2 on Aeromonas hydrophila-induced apoptosis of head kidney macrophages. AB - The role of calcium (Ca2+) and its dependent protease calpain in Aeromonas hydrophila-induced head kidney macrophage (HKM) apoptosis has been reported. Here, we report the pro-apoptotic involvement of calmodulin (CaM) and calmodulin kinase II gamma (CaMKIIg) in the process. We observed significant increase in CaM levels in A. hydrophila-infected HKM and the inhibitory role of BAPTA/AM, EGTA, nifedipine and verapamil suggested CaM elevation to be Ca2+-dependent. Our studies with CaM-specific siRNA and the CaM inhibitor calmidazolium chloride demonstrated CaM to be pro-apoptotic that initiated the downstream expression of CaMKIIg. Using the CaMKIIg-targeted siRNA, specific inhibitor KN-93 and its inactive structural analogue KN-92 we report CaM-CaMKIIg signalling to be critical for apoptosis of A. hydrophila-infected HKM. Inhibitor studies further suggested the role of calpain-2 in CaMKIIg expression. CaMK Kinase (CaMKK), the other CaM dependent kinase exhibited no role in A. hydrophila-induced HKM apoptosis. We report increased production of intracellular cAMP in infected HKM and our results with KN-93 or KN-92 implicate the role of CaMKIIg in cAMP production. Using siRNA to PKACA, the catalytic subunit of PKA, anti-PKACA antibody and H-89, the specific inhibitor for PKA we prove the pro-apoptotic involvement of cAMP/PKA pathway in the pathogenicity of A. hydrophila. Our inhibitor studies coupled with siRNA approach further implicated the role of cAMP/PKA in activation of extracellular signal-regulated kinase 1 and 2 (ERK 1/2). We conclude that the alteration in intracellular Ca2+ levels initiated by A. hydrophila activates CaM and calpain-2; both pathways converge on CaMKIIg which in turn induces cAMP/PKA mediated ERK 1/2 phosphorylation leading to caspase-3 mediated apoptosis of infected HKM. PMID- 24763434 TI - Rapamycin inhibition of polyposis and progression to dysplasia in a mouse model. AB - Familial adenomatous polyposis (FAP) is often due to adenomatous polyposis coli (APC) gene germline mutations. Somatic APC defects are found in about 80% of colorectal cancers (CRCs) and adenomas. Rapamycin inhibits mammalian target of rapamycin (mTOR) protein, which is often expressed in human adenomas and CRCs. We sought to assess the effects of rapamycin in a mouse polyposis model in which both Apc alleles were conditionally inactivated in colon epithelium. Two days after inactivating Apc, mice were given rapamycin or vehicle in cycles of two weeks on and two weeks off. Polyps were scored endoscopically. Mice were euthanized at time points or when moribund, and tissue analyses were performed. In other studies, mice with demonstrable Apc-defective colon polyps were given rapamycin, followed by analysis of their colon tissues. The median survival of mice receiving rapamycin treatment cycles was 21.5 versus 6.5 weeks in control mice (p = 0.03), and rapamycin-treated mice had a significantly lower percentage of their colon covered with polyps (4.3+/- 2 vs 56.5+/- 10.8 percent, p = 0.001). Mice with Apc-deficient colon tissues that developed high grade dysplasia treated with rapamycin underwent treatment for significantly longer than mice treated with vehicle (15.8 vs 5.1 weeks, p = 0.003). In Apc-defective colon tissues, rapamycin treatment was linked to decreased levels of beta-catenin and Sox9 at 7 weeks. Other effects of rapamycin in Apc-defectivecolon tissues included decreased proliferation and increased numbers of differentiated goblet cells at 7 weeks. Rapamycin did not affect beta-catenin-regulated gene expression in cultured intestinal epithelial cells. Rapamycin has potent inhibitory effects in a mouse colon polyposis model, and mTOR inhibition is linked to decreased proliferation and increased expression of differentiation markers in Apc-mutant colon epithelium and delays development of dysplasia. Our findings highlight the possibility that mTOR inhibitors may have relevance for polyposis inhibition approaches in FAP patients. PMID- 24763436 TI - Massive fistulization into the left ventricle of a transplanted heart. PMID- 24763435 TI - Stimulus-response mappings shape inhibition processes: a combined EEG-fMRI study of contextual stopping. AB - Humans are rarely faced with one simple task, but are typically confronted with complex stimulus constellations and varying stimulus-relevance in a given situation. Through modifying the prototypical stop-signal task and by combined recording and analysis of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), we studied the effects of stimulus relevance for the generation of a response or its inhibition. Stimulus response mappings were modified by contextual cues, indicating which of two different stimuli following a go stimulus was relevant for stopping. Overall, response inhibition, that is comparing successful stopping to a stop-signal against go-signal related processes, was associated with increased activity in right inferior and left midfrontal regions, as well as increased EEG delta and theta power; however, stimulus-response conditions in which the most infrequent stop-signal was relevant for inhibition, were associated with decreased activity in regions typically involved in response inhibition, as well as decreased activity in the delta and theta bands as compared to conditions wherein the relevant stop-signal frequency was higher. Behaviorally, this (aforementioned) condition, which demanded inhibition only from the most infrequent stimulus, was also associated with reduced reaction times and lower error rates. This pattern of results does not align with typical stimulus frequency-driven findings and suggests interplay between task relevance and stimulus frequency of the stop-signal. Moreover, with a multimodal EEG-fMRI analysis, we demonstrated significant parameterization for response inhibition with delta, theta and beta time-frequency values, which may be interpreted as reflecting conflict monitoring, evaluative and/or motor processes as suggested by previous work (Huster et al., 2013; Aron, 2011). Further multimodal results suggest a possible neurophysiological and behavioral benefit under conditions whereby the most infrequent stimulus demanded inhibition, indicating that the frequency of the stop-signal interacts with the current stimulus-response contingency. These results demonstrate that response inhibition is prone to influence from other cognitive functions, making it difficult to dissociate real inhibitory capabilities from the influence of moderating mechanisms. PMID- 24763437 TI - The UV absorption spectrum of the simplest Criegee intermediate CH2OO. AB - SO2 scavenging and self-reaction of CH2OO were utilized for the decay of CH2OO to extract the absorption spectrum of CH2OO under bulk conditions. Absolute absorption cross sections of CH2OO at 308.4 and 351.8 nm were obtained from laser depletion measurements in a jet-cooled molecular beam. The peak cross section is (1.23 +/- 0.18) * 10(-17) cm(2) at 340 nm. PMID- 24763438 TI - Highly transparent and conductive Al-doped ZnO nanoparticulate thin films using direct write processing. AB - Solution processable Al-doped ZnO (AZO) thin films are attractive candidates for low cost transparent electrodes. We demonstrate here an optimized nanoparticulate ink for the fabrication of AZO thin films using scalable, low-cost direct write processing (ultrasonic spray deposition) in air at atmospheric pressure. The thin films were made via thermal processing of as-deposited films. AZO films deposited using the proposed nanoparticulate ink with further reducing in vacuum and rf plasma of forming gas exhibited optical transparency greater than 95% across the visible spectrum, and electrical resistivity of 0.5 Omega cm and it drops down to 7.0 * 10(-2) Omega cm after illuminating with UV light, which is comparable to commercially available tin doped indium oxide colloidal coatings. Various structural analyses were performed to investigate the influence of ink chemistry, deposition parameters, and annealing temperatures on the structural, optical, and electrical characteristics of the spray deposited AZO thin films. Optical micrographs confirmed the presence of surface defects and cracks using the AZO NPs ink without any additives. After adding N-(2-Aminoethyl)-3 aminopropylmethyldimethoxy silane to the ink, AZO films exhibited an optical transparency which was virtually identical to that of the plain glass substrate. PMID- 24763439 TI - Statins and weight gain. PMID- 24763441 TI - Disclosure of adverse events and errors in surgical care: challenges and strategies for improvement. AB - The disclosure of adverse events to patients, including those caused by medical errors, is a critical part of patient-centered healthcare and a fundamental component of patient safety and quality improvement. Disclosure benefits patients, providers, and healthcare institutions. However, the act of disclosure can be difficult for physicians. Surgeons struggle with disclosure in unique ways compared with other specialties, and disclosure in the surgical setting has specific challenges. The frequency of surgical adverse events along with a dysfunctional tort system, the team structure of surgical staff, and obstacles created inadvertently by existing surgical patient safety initiatives may contribute to an environment not conducive to disclosure. Fortunately, there are multiple strategies to address these barriers. Participation in communication and resolution programs, integration of Just Culture principles, surgical team disclosure planning, refinement of informed consent and morbidity and mortality processes, surgery-specific professional standards, and understanding the complexities of disclosing other clinicians' errors all have the potential to help surgeons provide patients with complete, satisfactory disclosures. Improvement in the regularity and quality of disclosures after surgical adverse events and errors will be key as the field of patient safety continues to advance. PMID- 24763440 TI - Withanolides are potent novel targeted therapeutic agents against adrenocortical carcinomas. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with poor prognosis, as a majority of patients present with advanced disease. Current adjuvant strategies for metastatic patients include mitotane or other cytotoxic agents and carry a significant morbidity as well as a low (<10 %) 5 year survival. Withanolides, including withaferin A, are novel chemotherapeutic agents with potent targeted effects in medullary thyroid cancer and a number of solid malignancies with low toxicity in vivo. We hypothesize that novel naturally derived withanolides will have potent targeted anti-cancer activity against ACCs. METHODS: In vitro cell viability of ACC cell lines (Y1 and SW13) was measured using MTS cell proliferation assay. Cell cycle and apoptotic analysis studied using annexin V/propidium iodide staining on flow cytometry (FC) and targeted molecular mechanisms of withanolide cytotoxicity were assessed using standard Western blot analysis. RESULTS: All the withanolides potently reduced ACC cell viability on MTS assay with 7- to 185-fold higher selectivity than normal fibroblasts. Cell cycle analysis demonstrated a shift in cell cycle arrest from G1/G0 to G2/M with induction of apoptosis at nanomolar concentrations of withanolides. Unlike current ACC therapeutics, withanolides modulated expression of several key oncogenic pathway proteins in ACCs by Western blot, including Jagged 1, MAPK, and Akt/mTOR pathway proteins in a dose-dependent manner after 24 h drug treatment of SW13 cells. CONCLUSION: These results demonstrate the first evidence of the anticancer efficacy of withanolides in ACC cells and provide support for future translational evaluation of these compounds as novel therapeutic agents for ACC patients. PMID- 24763442 TI - History and evolution of surgical ethics: John Gregory to the twenty-first century. AB - As surgery grew to become a respected medical profession in the eighteenth century, medical ethics emerged as a response to the growing need to protect patients and maintain the public's trust in physicians. The early influences of John Gregory and Thomas Percival were instrumental in the formulation of patient centered medical ethics. In the late nineteenth century, the modern surgical advances of anesthesia and antisepsis created the need for a discipline of ethics specific to surgery in order to confront new and evolving ethical issues. One of the founding initiatives of the American College of Surgeons in 1913 was to eliminate unethical practices such as fee-splitting and itinerant surgery. As surgery continued to advance in the era of solid organ transplantation and minimally invasive surgery in the latter half of the twentieth century, surgical innovation and conflict of interest have emerged as important ethical issues moving forward into the twenty-first century. Surgical ethics has evolved into a distinct branch of medical ethics, and the core of surgical ethics is the surgeon patient relationship and the surgeon's responsibility to advance and protect the well-being of the patient. PMID- 24763443 TI - Feeding health: problems, opportunities, goals. AB - Food security is when all people at all times have access to sufficient, safe, nutritious food to maintain a healthy and active life. On the one hand, the European Union Commission proposes new laws to achieve the highest possible levels of protection for human health and consumer interests in relation to food, plants and biodiversity. On the other hand, International Agencies (WHO, FAO, EU) pay attention to malnutrition and its consequences for health; poor people are usually the ones that suffer the consequences of underfeeding or dietary excess. In Italy, the mission of Food and Nutrition Services (Public Health National Service) is to promote food safety and good nutrition for the population; furthermore, they must pay attention to social equity. Suppressing or reducing their activity would be detrimental for public health and the national economy. PMID- 24763444 TI - Anxiety and dysthymia: local prevalence estimates based on drug prescriptions by general practitioners in Turin (Italy). AB - BACKGROUND: The aim of the study was to obtain local estimates of the prevalence of anxiety and dysthymic disorders among attendees of primary care at local level, useful to pursue a better management of the health care services. METHODS: The study was conducted in the Health District no. 2 of Turin (industrial town in northwest Italy). The criteria for identification of cases were based on the drugs prescriptions made by general practitioners (GPs), selected in order to assure high specificity. The study involved 86 physicians (with 87,885 attendees). RESULTS: As expected, the crude and standardized prevalences were higher in women (anxiety: 2.9% vs 1.3% in men; dysthymia: 3.8% vs 1.7% in men), with a peak in women aged over 75 yrs (anxiety: 4.8%; dysthymia: 6.2%). In comparison to male GPs, female GPs had an higher prevalence of patients with anxious disorders, whereas the prevalences of dysthymia were similar. CONCLUSIONS: Despite the discussed limitations, the used methodology allows to obtain sufficiently reliable estimates of prevalence of common mental disorders at local level, providing informations useful for organizing the primary care in the Health district. PMID- 24763445 TI - Evidence Based Design and healthcare: an unconventional approach to hospital design. AB - Evidence Based Design (EBD) is a scientific analysis methodology that emphasises the use of data acquired in order to influence the design process in hospitals. It measures the physical and psychological effects of the built environment on its users. EBD uses formularization of hypothesis, testing/analyzing and outcome gathering as a framework. The design practice, in general, has always been based on a combination of legal, technical/ functional/ and aesthetical knowledge. This generalization has been shifted to another level after the implementation of EBD. In the last 30 years many case studies were collected which demonstrate the built environment's impact on users. EBD methodology can be applied to any type of building, but it is particularly used to analyze the efficiency of healthcare facilities. The Goal of this paper is to demonstrate various applications of EBD principles in healthcare buildings through case studies concerning: - reduction of infections - reduction of stress on medical staff - improved patient healing In addition to the analysis of case studies, we will also focus on official EBD researches developed by healthcare designers and professionals as "alternative solutions". These alternative "ad hoc" solutions are developed in order to answer EBD research results. The solutions that are developed from the results can answer the real needs of each hospital and improve best technological practice to reduce infection, stress and improve patient comfort. Abroad the EBD research results are studied and used by many contemporary hospital architects to develop new solutions to meet the specific requirements of any hospital project they are currently designing. This procedure demonstrates that for each outcome and key finding, there is always at least one alternative solution and, therefore, the achievement of a new hypothesis, case studies to test/measure and outcome to gather occurs. This repetitive attitude leads to a "virtuous circle" where the development of new samples produces a double- positive effect in both EBD research (in terms of new case studies to analyze) and in EBD lessons for implementation in various hospitals. Through this paper the authors state that the combined effort is needed by EBD practitioners, healthcare architects and hospital managers for the improvement and diffusion of EBD in healthcare, especially in Italy where this methodology is not widely used. PMID- 24763447 TI - Liver damage in automotive and industrial workers of the glass. AB - OBJECTIVE: High doses of organic solvents can cause hepatic disease. We investigated whether exposure to low doses of solvents in automotive and industrial workers may lead to changes in liver tests. METHODS: We studied the liver parameters (glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), gamma-glutamyl-traspeptidasi (gamma-GT), alkaline phosphatase (PHA), total (TB) and direct bilirubin (DB) of 24 workers exposed to organic solvents and of 30 unexposed controls. RESULTS: A significant increase of GOT, GPT and gamma-GT was found in exposed workers compared to unexposed controls workers. The ratio GPT/GOT was significantly higher among the exposed compared to controls. CONCLUSIONS: The results confirmed the hypothesis that exposure to low doses of solvents may determine a liver damage. PMID- 24763448 TI - Geographical and epidemiological analysis of oncological mortality in a Municipality of North-Western Italy Vercelli years 2000-2009. AB - BACKGROUND: We performed a geographic analysis study on mortality in the town of Vercelli, in order to respond to the concerns of the population and some local administrators. Main reason to carry out a detailed and sophisticated study for a city of medium-small size was represented by the presence of various sources of environmental and industrial pressure (i.e. old-generation incinerator for solid urban waste, industrial site for chemicals production, intense agricultural activity of rice production...). METHODS: The study analyzed census, ISTAT death cards, both from the epidemiological point of view with admirers that SMR standardized spatial analysis using Bayesian models. RESULTS: Overall, both approaches highlighted major risks for the area south of the capital for major cancers such as colorectal and lung and increases worthy of investigation for the young-adult age groups in both genders. And being processed a similar study that considers the incidence oncology. CONCLUSIONS: The imminent elaboration of the cartography by oncological incidence will allow us to confirm, or less, the areas in excess for the death data, and in the meanwhile observe any excesses for low mortality pathologies (e.g., thyroid) or neoplasies whose present therapies allowed complete recovery and/or very long survivals (e.g. leukaemia, lymphomas and testicle). PMID- 24763449 TI - Thyroid hormones in male workers exposed to urban stressors. AB - BACKGROUND: The occupational exposure to urban pollution may induce adverse effects on the human health. METHODS: Plasma levels of thyrotropin stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) of 50 outdoor workers and 50 indoor workers were compared. RESULTS: In the outdoor workers the TSH levels were significantly higher than in the control subjects (p =0.02) while the average of FT3 and FT4 values, was not significantly different compared to the controls (p > 0.05). CONCLUSIONS: The differences found for TSH levels between outdoor and indoor workers, though not high, suggest that, due to greater exposure to environmental pollutants, the outdoor workers are more susceptible to the development of function abnormalities of the thyroid gland compared to indoor workers. PMID- 24763450 TI - Action against vaccine-preventable infectious diseases and tuberculosis in Nomad Camps: the experience of a Local Health Unit in Rome. AB - In Italy the highest incidence of Tuberculosis (TB) cases is in young adult migrants. In 2011, the sanitarystaff of the Local Health Unit (ASL) Roma A promoted a vaccination campaign conducting several public health interventions in Nomad Camps. After notification of a case of TB in the Camp of Via Salaria, out of 357 Mantoux skin tests performed, 93 were positive (26%); subsequently, 5 subjects with radiographic positivity were hospitalized. The vaccination campaign was carried out to prevent the spread of infectious diseases in immigrant communities at high risk of contagion and to avoid the consequent transmission in the host country. As a result, vaccinations coverage among the residents of the Camps increased: 367 vaccinated subjects (30% more than previous year) and 612 administered vaccinations. PMID- 24763451 TI - Pilot study on the antibacterial activity of hydrogen peroxide and silver ions in the hospital environment. AB - BACKGROUND: Nosocomial environmental contamination plays an important role in the transmission of several health care-associated pathogens. Control of surfaces contamination can reduce the risk of cross-infection in hospitals. The aim of our study is to evaluate the disinfectant effectiveness of hydrogen peroxide and silver ions, against nosocomial multidrug-resistant strains, when it's used directly on surfaces. METHODS: Staphylococcus aureus ATCC 6538, Pseudomonas aeruginosa ATCC 15442 and the same multidrug-resistant clinical isolates were selected to study the effectiveness of the disinfectant used in suspension or on the clean and dirty surface. RESULTS: Regarding the suspension activity test, the hydrogen peroxide and silver ions resulted effective after 5 min for ATCC strains and after 10 min for multidrug-resistant isolates; about the surface activity test, its action resulted after 10 min for ATCC strains and after 15 min for multidrug-resistant isolates. Moreover, it was more effective when used in the absence or in presence of a low concentration of biological materials. CONCLUSIONS: In a complex environment such as hospital wards, to have a disinfectant notoriously effective but more easy and quick to use would be an useful solution to treat small surfaces occasionally contaminated by biological materials. PMID- 24763452 TI - Indoor particulate matter and secondhand smoke: simulation of an exposure scenario. AB - BACKGROUND: To evaluate secondhand smoke (SHS) contribution on indoor Particulate Matter (PM) concentrations due to a single smoked cigarette in a real exposure scenario. METHODS: Total Suspended Particles (TSP) and sizes <=10 (PM(10)), <=4 (PM(4)), <=2.5 (PM(2.5)), and <=1 MUm (PM(1)) levels were measured before, during and after smoking in an enclosed smoke-free environment. The measurement was stopped 30 minutes after extinguishing the cigarette, to focus the monitoring just on SHS. RESULTS: PM(1) concentrations dramatically increased during and 30 minutes after smoking (mean values: 21.1, 1544.0 and 279.0 MUg/m3 before, during and after, respectively), while the other PM fractions remained almost unchanged. CONCLUSIONS: This experiment implies that smoking even one cigarette produces important indoor air pollution which may considerably increase individual exposure to ultrafine particles, and, consequently, pose a serious threat to health. PMID- 24763453 TI - New members of layered oxychloride perovskites with square planar coordination: Sr2MO2Cl2 (M = Mn, Ni) and Ba2PdO2Cl2. AB - New members of Ruddlesden-Popper type layered oxychloride compounds, Sr2MO2Cl2 (M = Mn, Ni) and Ba2PdO2Cl2, were synthesized under high-pressure conditions. Synchrotron XRD analysis revealed that all the phases adopt the tetragonal space group I4/mmm, where two-dimensional sheets composed of corner-sharing MO4/PdO4 squares were separated by rock-salt SrCl/BaCl layers. PMID- 24763454 TI - Psoriasis: third edition, revised and expanded. PMID- 24763455 TI - An erythematous noduloplaque on the trunk. PMID- 24763456 TI - Emergence of blind areas in information spreading. AB - Recently, contagion-based (disease, information, etc.) spreading on social networks has been extensively studied. In this paper, other than traditional full interaction, we propose a partial interaction based spreading model, considering that the informed individuals would transmit information to only a certain fraction of their neighbors due to the transmission ability in real-world social networks. Simulation results on three representative networks (BA, ER, WS) indicate that the spreading efficiency is highly correlated with the network heterogeneity. In addition, a special phenomenon, namely Information Blind Areas where the network is separated by several information-unreachable clusters, will emerge from the spreading process. Furthermore, we also find that the size distribution of such information blind areas obeys power-law-like distribution, which has very similar exponent with that of site percolation. Detailed analyses show that the critical value is decreasing along with the network heterogeneity for the spreading process, which is complete the contrary to that of random selection. Moreover, the critical value in the latter process is also larger than that of the former for the same network. Those findings might shed some lights in in-depth understanding the effect of network properties on information spreading. PMID- 24763458 TI - Menage a Trois: intimate relationship among a microRNA, long noncoding RNA, and mRNA. PMID- 24763459 TI - LINCing MALAT1 and angiogenesis. PMID- 24763460 TI - Cardiac alternans and ventricular fibrillation: a bad case of ryanodine receptors reneging on their duty. PMID- 24763461 TI - Inherited dysfunctional nitric oxide signaling and the pathobiology of atherothrombotic disease. PMID- 24763462 TI - Steven Houser: the beat goes on. PMID- 24763463 TI - Atrial fibrillation compendium: historical context and detailed translational perspective on an important clinical problem. PMID- 24763464 TI - The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. AB - Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%-26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca(2+) handling abnormalities, (3) structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure, myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca(2+)-handling abnormalities that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease. Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to develop improved methods for AF prevention and management. PMID- 24763466 TI - Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. AB - Atrial fibrillation (AF) is the most common clinically relevant arrhythmia and is associated with increased morbidity and mortality. The incidence of AF is expected to continue to rise with the aging of the population. AF is generally considered to be a progressive condition, occurring first in a paroxysmal form, then in persistent, and then long-standing persistent (chronic or permanent) forms. However, not all patients go through every phase, and the time spent in each can vary widely. Research over the past decades has identified a multitude of pathophysiological processes contributing to the initiation, maintenance, and progression of AF. However, many aspects of AF pathophysiology remain incompletely understood. In this review, we discuss the cellular and molecular electrophysiology of AF initiation, maintenance, and progression, predominantly based on recent data obtained in human tissue and animal models. The central role of Ca(2+)-handling abnormalities in both focal ectopic activity and AF substrate progression is discussed, along with the underlying molecular basis. We also deal with the ionic determinants that govern AF initiation and maintenance, as well as the structural remodeling that stabilizes AF-maintaining re-entrant mechanisms and finally makes the arrhythmia refractory to therapy. In addition, we highlight important gaps in our current understanding, particularly with respect to the translation of these concepts to the clinical setting. Ultimately, a comprehensive understanding of AF pathophysiology is expected to foster the development of improved pharmacological and nonpharmacological therapeutic approaches and to greatly improve clinical management. PMID- 24763465 TI - Emerging directions in the genetics of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity. As the population ages and the prevalence of AF continues to rise, the socioeconomic consequences of AF will become increasingly burdensome. Although there are well-defined clinical risk factors for AF, a significant heritable component is also recognized. To identify the molecular basis for the heritability of AF, investigators have used a combination of classical Mendelian genetics, candidate gene screening, and genome-wide association studies. However, these avenues have, as yet, failed to define the majority of the heritability of AF. The goal of this review is to describe the results from both candidate gene and genome-wide studies, as well as to outline potential future avenues for creating a more complete understanding of AF genetics. Ultimately, a more comprehensive view of the genetic underpinnings for AF will lead to the identification of novel molecular pathways and improved risk prediction of this complex arrhythmia. PMID- 24763467 TI - Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy. AB - Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future. PMID- 24763468 TI - Mathematical approaches to understanding and imaging atrial fibrillation: significance for mechanisms and management. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia in humans. The mechanisms that govern AF initiation and persistence are highly complex, of dynamic nature, and involve interactions across multiple temporal and spatial scales in the atria. This article aims to review the mathematical modeling and computer simulation approaches to understanding AF mechanisms and aiding in its management. Various atrial modeling approaches are presented, with descriptions of the methodological basis and advancements in both lower-dimensional and realistic geometry models. A review of the most significant mechanistic insights made by atrial simulations is provided. The article showcases the contributions that atrial modeling and simulation have made not only to our understanding of the pathophysiology of atrial arrhythmias, but also to the development of AF management approaches. A summary of the future developments envisioned for the field of atrial simulation and modeling is also presented. The review contends that computational models of the atria assembled with data from clinical imaging modalities that incorporate electrophysiological and structural remodeling could become a first line of screening for new AF therapies and approaches, new diagnostic developments, and new methods for arrhythmia prevention. PMID- 24763471 TI - Structure-property relationships in a series of diglycerol tetraether model lipids and their lyotropic assemblies: the effect of branching topology and chirality. AB - Three novel diglycerol tetraether lipids with one membrane-spanning chain have been synthesized. These lipids contain only two or four racemic methyl branches at selected positions of the hydrophobic chains in contrast to natural lipids from archaebacterial membranes with an isoprenoid substitution pattern. The insertion of the methyl moieties was realized starting from either (RS) citronellyl bromide or the inexpensive methyl malonic acid ethyl ester. For chain elongation the Cu-catalysed Grignard coupling reaction was used. The preparation of diglycerol tetraethers was either performed by condensing suitable blocked monoglycerol diethers by Grubbs metathesis or by reaction of the transmembrane C32-chain with blocked glycerols followed by further alkylation steps. Finally, we could show that the resulting lipids can form closed lipid vesicles comparable to the optically pure counterparts. Therefore, these much simpler lipids compared to the natural lipids from archaebacterial membranes are also suitable for preparation of stable tailored liposomes. PMID- 24763469 TI - Atrial fibrillation therapy now and in the future: drugs, biologicals, and ablation. AB - Atrial fibrillation (AF) is a complex disease with multiple inter-relating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is rapidly changing and improving. The purpose of this review is to summarize current state-of-the-art diagnostic and therapeutic modalities for treatment of AF. The review focuses on reviewing treatment as it relates to the pathophysiological basis of disease and reviews preclinical and clinical evidence for potential new diagnostic and therapeutic modalities, including imaging, biomarkers, pharmacological therapy, and ablative strategies for AF. Current ablation and drug therapy approaches to treating AF are largely based on treating the arrhythmia once the substrate occurs and is more effective in paroxysmal AF rather than persistent or permanent AF. However, there is much research aimed at prevention strategies, targeting AF substrate, so-called upstream therapy. Improved diagnostics, using imaging, genetics, and biomarkers, are needed to better identify subtypes of AF based on underlying substrate/mechanism to allow more directed therapeutic approaches. In addition, novel antiarrhythmics with more atrial specific effects may reduce limiting proarrhythmic side effects. Advances in ablation therapy are aimed at improving technology to reduce procedure time and in mechanism-targeted approaches. PMID- 24763470 TI - Rapid response to selection, competitive release and increased transmission potential of artesunate-selected Plasmodium chabaudi malaria parasites. AB - The evolution of drug resistance, a key challenge for our ability to treat and control infections, depends on two processes: de-novo resistance mutations, and the selection for and spread of resistant mutants within a population. Understanding the factors influencing the rates of these two processes is essential for maximizing the useful lifespan of drugs and, therefore, effective disease control. For malaria parasites, artemisinin-based drugs are the frontline weapons in the fight against disease, but reports from the field of slower parasite clearance rates during drug treatment are generating concern that the useful lifespan of these drugs may be limited. Whether slower clearance rates represent true resistance, and how this provides a selective advantage for parasites is uncertain. Here, we show that Plasmodium chabaudi malaria parasites selected for resistance to artesunate (an artemisinin derivative) through a step wise increase in drug dose evolved slower clearance rates extremely rapidly. In single infections, these slower clearance rates, similar to those seen in the field, provided fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. In mixed infections, removal of susceptible parasites by drug treatment led to substantial increases in the densities and transmission potential of resistant parasites (competitive release). Our results demonstrate the double-edged sword for resistance management: in our initial selection experiments, no parasites survived aggressive chemotherapy, but after selection, the fitness advantage for resistant parasites was greatest at high drug doses. Aggressive treatment of mixed infections resulted in resistant parasites dominating the pool of gametocytes, without providing additional health benefits to hosts. Slower clearance rates can evolve rapidly and can provide a strong fitness advantage during drug treatment in both single and mixed strain infections. PMID- 24763472 TI - Optical coherence tomography combined with videokeratography to differentiate mild keratoconus subtypes. AB - PURPOSE: To develop parameters using a combination of optical coherence tomography (OCT) and videokeratography to detect early keratoconus. METHODS: Videokeratography, wavefront analysis, and measured OCT indices were performed on 180 normal eyes, 46 eyes with moderate keratoconus, 54 eyes with early keratoconus, 7 eyes with forme fruste keratoconus, and 16 eyes with keratoconus "suspect" to determine the most sensitive parameters for separating these groups. RESULTS: A combination of videokeratography and OCT indices (inferior-superior [I S] value and minimum pachymetry) was statistically the most significant in separating the keratoconus groups from normal eyes (P < .001). Using a newly derived index, the minimum pachymetry divided by the I-S value (pachymetry/asymmetry [PA]/I-S index) with a cut-off of 100, 100% of early and forme fruste keratoconus could be identified as being abnormal with 7 normals misclassified (misclassification rate 2.7%). By adding keratoconus "suspect" to the analysis and an I-S value of 1.2 as a cut-off point, 5 "suspects" were classified as normal and 11 normals as abnormal (misclassification rate 7.8%). The PA/I-S index, with a cut-off point of 100, reduced this misclassification rate to 4.4%. CONCLUSIONS: These results suggest that OCT combined with videokeratography may be more useful for differentiating mild forms of keratoconus than videokeratography alone. PMID- 24763473 TI - Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (the Athens Protocol). AB - PURPOSE: To investigate refractive, topometric, pachymetric, and visual rehabilitation changes induced by anterior surface normalization for keratoconus by partial topography-guided excimer laser ablation in conjunction with accelerated, high-fluence cross-linking. METHODS: Two hundred thirty-one keratoconic cases subjected to the Athens Protocol procedure were studied for visual acuity, keratometry, pachymetry, and anterior surface irregularity indices up to 3 years postoperatively by Scheimpflug imaging (Oculus Optikgerate GmbH, Wetzlar, Germany). RESULTS: Mean visual acuity changes at 3 years postoperatively were +0.38 +/- 0.31 (range: -0.34 to +1.10) for uncorrected distance visual acuity and +0.20 +/- 0.21 (range: -0.32 to +0.90) for corrected distance visual acuity. Mean K1 (flat meridian) keratometric values were 46.56 +/- 3.83 diopters (D) (range: 39.75 to 58.30 D) preoperatively, 44.44 +/- 3.97 D (range: 36.10 to 55.50 D) 1 month postoperatively, and 43.22 +/- 3.80 D (range: 36.00 to 53.70 D) up to 3 years postoperatively. The average Index of Surface Variance was 98.48 +/ 43.47 (range: 17 to 208) pre-operatively and 76.80 +/- 38.41 (range: 7 to 190) up to 3 years postoperatively. The average Index of Height Decentration was 0.091 +/- 0.053 MUm (range: 0.006 to 0.275 MUm) preoperatively and 0.057 +/- 0.040 MUm (range: 0.001 to 0.208 MUm) up to 3 years postoperatively. Mean thinnest corneal thickness was 451.91 +/- 40.02 MUm (range: 297 to 547 MUm) preoperatively, 353.95 +/- 53.90 MUm (range: 196 to 480 MUm) 1 month postoperatively, and 370.52 +/- 58.21 MUm (range: 218 to 500 MUm) up to 3 years postoperatively. CONCLUSIONS: The Athens Protocol to arrest keratectasia progression and improve corneal regularity demonstrates safe and effective results as a keratoconus management option. Progressive potential for long-term flattening validates using caution in the surface normalization to avoid overcorrection. PMID- 24763474 TI - Comparison of corneal sensation between small incision lenticule extraction (SMILE) and femtosecond laser-assisted LASIK for myopia. AB - PURPOSE: To compare the impact on corneal sensation after small incision lenticule extraction (SMILE) and femtosecond laser-assisted LASIK (femto-LASIK) in patients with myopia. METHODS: In this prospective, nonrandomized comparative study, 71 subjects were enrolled. Thirty-eight eyes of 38 patients underwent SMILE and 33 eyes of 33 patients underwent femto-LASIK. Corneal sensation was tested with Cochet-Bonnet esthesiometry in five corneal areas preoperatively and at 1 week and 1, 3, and 6 months postoperatively. Comparison of corneal sensation was performed for the SMILE and femto-LASIK groups. Additionally, the correlations were evaluated between the postoperative corneal sensation, preoperative spherical equivalent, and ablation depth. RESULTS: All tested areas within the cap or flap demonstrated corneal hypoesthesia immediately after both surgeries. SMILE-treated eyes showed less compromised corneal sensation than femto-LASIK-treated eyes at all postoperative visits in the central, inferior, nasal, and temporal areas at the 1-week and 1-month visits. In the SMILE group, the inferior, nasal, and temporal quadrants recovered faster than other areas. In the femto-LASIK group, the sensation over the flap did not recover to preoperative levels by postoperative 6 months. There was no correlation between postoperative corneal sensation, preoperative spherical equivalent, and ablation depth in both groups. CONCLUSIONS: The impairment of corneal sensation was less significant in the SMILE group than in the femto-LASIK group and was independent of preoperative spherical equivalent or ablation depth. PMID- 24763475 TI - Central corneal sublayer pachymetry and biomechanical properties after refractive femtosecond lenticule extraction. AB - PURPOSE: To compare central corneal sublayer pachymetry and biomechanical properties after femtosecond lenticule extraction (FLEX) and small-incision lenticule extraction (SMILE). METHODS: A prospective, randomized, single-masked clinical trial of 35 patients treated for moderate to high myopia with FLEX in one eye and SMILE in the other. Anterior segment optical coherence tomography imaging (Heidelberg Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany) was used to measure central corneal thickness (CCT) and epithelial, flap/cap, and residual stromal bed thickness centrally. The Ocular Response Analyzer (Reichert Ophthalmic Instruments, Buffalo, NY) was used to assess corneal hysteresis (CH) and corneal resistance factor (CRF). Patients were examined before and 6 months after surgery. RESULTS: Mean decrease in CCT was 105 MUm in FLEX-treated eyes and 106 MUm in SMILE-treated eyes (P = .70), which is equivalent to approximately 14 MUm/diopters corrected. Mean central epithelial thickness increased 7 +/- 6 MUm in FLEX-treated eyes and 6 +/- 5 MUm in SMILE-treated eyes (P = .64). Achieved mean flap/cap thickness was 4 +/- 6 MUm from the expected thickness in FLEX treated eyes and 4 +/- 9 MUm in SMILE-treated eyes (P = .37). CH was reduced 2.7 +/- 1.3 mm Hg in FLEX-treated eyes and 3.3 +/- 1.2 mm Hg in SMILE-treated eyes (P = .08). CRF was reduced 4.5 +/- 1.2 mm Hg in FLEX-treated eyes and 4.6 +/- 1.2 mm Hg in SMILE-treated eyes (P = .71). CH and CRF were highly correlated with CCT, but not patient age. CONCLUSIONS: In this paired-eye study, the flap-based FLEX and cap-based SMILE resulted in almost identical changes in central corneal sublayer pachymetry and biomechanical properties for moderate to high myopia 6 months after treatment. PMID- 24763476 TI - Outcomes of small aperture corneal inlay implantation in patients with pseudophakia. AB - PURPOSE: To evaluate the improvement in near visual acuity after KAMRA corneal inlay (AcuFocus, Inc., Irvine, CA) implantation in patients with pseudophakia. METHODS: A retrospective study analysis of patients with pseudophakia undergoing monocular corneal inlay implantation in the non-dominant eye was performed. The inlay was implanted monocularly in the non-dominant eye of patients. Manifest refractive spherical equivalent, uncorrected distance visual acuity, corrected distance visual acuity, uncorrected near visual acuity, and corrected near visual acuity were evaluated. The follow-up period was 3 months. RESULTS: Thirteen eyes from 13 patients were evaluated. Four patients underwent LASIK for improved distance acuity at the time of inlay implantation. Mean uncorrected near visual acuity improved five lines (from J10 to J4) postoperatively. Mean uncorrected distance visual acuity, corrected distance visual acuity, and corrected near visual acuity remained stable and were 20/20, 20/16, and J1, respectively, before and after KAMRA implantation. Three eyes lost two lines and 1 eye lost one line of uncorrected distance visual acuity. Two eyes lost two lines and 1 eye lost 1 line of corrected distance visual acuity. Mean manifest refractive spherical equivalent changed before and after KAMRA implantation from -0.01 +/- 1.07 diopters (D) (range: 2.25 to -1.88 D) to -1.12 +/- 0.87 D (range: 0.25 to -2.75 D), respectively. CONCLUSIONS: Implantation of a small aperture corneal inlay improved uncorrected near visual acuity while maintaining uncorrected and corrected distance visual acuity in monofocal patients with pseudophakia. PMID- 24763477 TI - Refractive surgery for accommodative esotropia: 5-year follow-up. AB - PURPOSE: To assess the long-term effectiveness and safety of refractive surgery with LASIK or photorefractive keratectomy (PRK) for treating accommodative esotropia in adults. METHODS: All patients with accommodative esotropia treated with LASIK or PRK until December 2007 and with a minimum follow-up of 5 years were retrospectively included. RESULTS: LASIK was performed on 44 eyes of 22 patients (12 women, 10 men; mean age: 22.7 +/- 2.9 years). Mean postoperative follow-up was 62.1 +/- 3.2 months. PRK was performed on 16 eyes of 8 patients (4 women, 4 men; mean age: 23.7 +/- 1.7 years). Mean postoperative follow-up was 61.3 +/- 2.8 months. At the 5-year follow-up, the mean cycloplegic refraction was more hyperopic in the PRK group (0.3 +/- 0.8 vs 0.06 +/- 0.3 diopters, P = .01). Correction of esotropia to esophoria or orthotropia was present in 21 patients (95.4%) treated with LASIK and in all patients treated with PRK. CONCLUSIONS: Both LASIK and PRK were effective in the long-term reduction of accommodative esotropia. PMID- 24763478 TI - Epithelial and stromal remodeling after corneal collagen cross-linking evaluated by spectral-domain OCT. AB - PURPOSE: To evaluate changes in corneal epithelial and stromal thickness after corneal collagen cross-linking (CXL) in eyes with keratoconus and postoperative corneal ectasia using spectral-domain optical coherence tomography (SD-OCT). METHODS: Anterior segment SD-OCT (RTVue-100; Optovue, Inc., Fremont, CA) was used to compare regional corneal epithelial and stromal thickness in eyes with keratoconus and ectasia before CXL and 1 and 3 months after CXL. The anterior surface of the cornea, epithelium-Bowman's layer interface, and posterior reflective surface were used as anatomical landmarks to measure epithelial and stromal thickness, respectively. Regional thickness was assessed centrally and at 21 points 0.5 mm apart across the central 6 mm of the corneal vertex in the horizontal and vertical meridians. RESULTS: Thirty-one eyes from 30 patients were evaluated, including 17 eyes (17 patients) with keratoconus and 14 eyes (13 patients) with ectasia. Preoperatively, a highly irregular epithelial thickness profile and distribution was observed in both groups. After CXL, epithelial thickness was significantly thinner 2.5 and 2 mm below and 1.5 mm above the corneal apex (49.26 +/- 5.69 MUm; range: 43 to 62 MUm), and 2.5 and 1 mm nasal and 2 mm temporal to the corneal apex (46.66 +/- 4.53 MUm; range: 39 to 57 MUm) compared to preoperative values (P < .05 for all measurements). Epithelial thickness standard deviations were significantly lower (by 3 to 6 MUm) 3 months after CXL, compared to ranges before CXL in both the vertical and horizontal meridians for keratoconus and ectasia (P = .048). No significant differences were found between epithelial remodeling in keratoconus and corneal ectasia (P = .98). No significant or consistent stromal changes were found for either group. CONCLUSIONS: Significant epithelial remodeling occurs after CXL in eyes with keratoconus and corneal ectasia, creating a similar, more regularized thickness profile in all meridians in the early postoperative period. This pattern of remodeling may facilitate interpretation of corneal curvature and thickness changes after CXL and may be related to visual acuity after CXL. PMID- 24763479 TI - Primary posterior laser-assisted capsulotomy. AB - PURPOSE: To describe new techniques for performing primary posterior laser assisted capsulotomy (PLC) to prevent posterior capsule opacification after cataract surgery. METHODS: After lens and cortex removal, three different techniques were used to cut the posterior capsule with an image-guided (optical coherence tomography [OCT]) femtosecond laser. Technique 1: Prior to intra-ocular lens (IOL) implantation, the posterior capsule was carefully opened and elevated with ophthalmic viscosurgical device (OVD) whereas the anterior hyaloid surface remains intact. After sterile re-docking, the posterior capsule was cut and removed and followed by IOL implantation. Techniques 2 and 3: After IOL implantation, a thin layer of OVD was injected between the IOL optic and the posterior capsule. After sterile re-docking, Berger's space and the posterior capsule were identified using OCT and the capsule was cut by the laser. The posterior capsule is located close to the anterior hyaloid membrane in Technique 2 and the posterior capsule is located between the posterior optic surface of the IOL and the anterior hyaloid in Technique 3. RESULTS: Technique 1 was performed in 50 PLC cases. All capsulotomies were easy to remove and no complications were observed. Techniques 2 and 3 were performed in 53 of 55 PLC cases. In 45 of these cases (82%), the posterior capsule was localized with open space between the IOL and Berger's space. In all treated PLC cases, a 360 degrees cut was successfully accomplished. CONCLUSION: The described techniques for PLC have the potential to prevent and solve posterior capsule opacification in routine cases. PMID- 24763480 TI - Nerve growth factor expression and nerve regeneration in monkey corneas after LASIK. AB - PURPOSE: To determine whether changes in cornea nerve growth factor (NGF) protein and gene expression correlate with corneal nerve regeneration after LASIK in rhesus monkeys. METHODS: Ten rhesus monkeys underwent randomly assigned LASIK procedures to correct -8.0 diopters of myopia in both eyes and two additional monkeys (with no surgery) served as controls. The central corneas of the experimental animals were excised 3 and 7 days and 1, 3, and 6 months after the surgery. Nerve regeneration, NGF mRNA, and protein expression were analyzed by gold chloride staining, real-time polymerase chain reaction, and enzyme-linked immune sorbent assay analysis, respectively. RESULTS: Compared to controls, the LASIK-treated animals had a significantly diminished nerve plexus in the sub basal region of the cornea at all times after the surgery (P < .001). NGF protein levels decreased significantly on days 3 and 7 after LASIK (P < .001), but returned to control levels 1 month later. NGF mRNA levels increased 5.4-fold on day 3 after the surgery (P < .001), then reduced to two-fold (P < .05) above control levels on day 7 and were back to normal at 3 months and beyond. After LASIK, the changes of early NGF protein and NGF mRNA levels correlated with the density of the corneal nerve plexuses. CONCLUSIONS: The results showed that the LASIK procedure in non-human primates was associated with changes in NGF protein and mRNA levels in the cornea. Such changes may be related to the initiation of nerve regeneration and the final recovery of nerve plexuses in the cornea. PMID- 24763481 TI - In memory of Robert L. Spilker. PMID- 24763484 TI - Local nanotip arrays sculptured by atomic force microscopy to enhance the light output efficiency of GaN-based light-emitting diode structures. AB - In this work, local nanotip arrays on GaN-based light-emitting (LED) structures were fabricated through nano-oxidation using an atomic force microscope (AFM). The photoluminescence (PL) intensity of the InGaN/GaN multiple quantum wells (MQWs) active layer and the light extraction efficiency of the LED structure were enhanced by forming this nanotips structure to serve as a graded-refractive index layer, which is further validated by the finite-difference time-domain analysis. The PL emission peak of the MQWs active layer has a blue-shift phenomenon that is caused by a partial reduction of the strain on the InGaN well. It is expected that our approach opens a promising route for simultaneously enhancing both the internal quantum efficiency and the light extraction efficiency of GaN-based LEDs. The proposed AFM-based method will be of importance for local patterning the light emitting components for optoelectronic applications. PMID- 24763485 TI - Patient Outcomes in Magnet-Based Implantable Auditory Assist Devices. AB - IMPORTANCE: Magnet-based implantable auditory assist devices (MIAADs) are a recent development in bone-anchored hearing devices. This report increases the number of children studied with specific outcome criteria and provides detailed solutions to avoid device use difficulties in other centers considering this device. OBJECTIVE: To assess hearing thresholds, use rates, and complications in children implanted with a MIAAD for conductive hearing loss. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of children implanted with an MIAAD at an ambulatory care quaternary referral center since the Food and Drug Administration approved the Sophono device (Sophono Inc) for use in the United States (May 2011 through January 2013). Ten pediatric patients were implanted for conductive hearing loss (14 ears; mean age at implantation, 9 years [range, 3.8-17.2 years]). Diagnoses included aural atresia (n = 7) and chronic ear disease and cholesteatoma (n = 3). INTERVENTIONS: Implantation of MIAAD and management of skin complications. MAIN OUTCOMES AND MEASURES: Demographics, hearing thresholds, use rates, and complications were assessed. RESULTS: After fitting with the magnetic baseplate and sound processor, the mean (SD) aided pure-tone average was 20.2 (6.0) dB hearing level (HL), with a mean (SD) functional gain of 39.9 (12.4) dB HL. There were no surgical complications. Negative outcomes were assessed following fitting of the sound processor. The skin complication rate was 35.7%, including skin breakdown (n = 2) and pain and erythema (n = 5), which resulted in decreased use of the device for these patients. Intervention included decreasing the magnet strength, graduated wearing schedule, antibiotic ointment, barrier protection, and reoperation for well widening with Alloderm (LifeCell Corporation) placement. Patients without skin complications are consistent users of their device, with an average daily use of 8 to 10 hours. CONCLUSIONS AND RELEVANCE: The MIAAD device has equivalent levels of hearing restoration to other previously described methods of intervention for children with conductive hearing loss. This early report indicates high rates of skin difficulties and a need for improved methods of implantation, magnetic baseplate fitting, and device use. We suggest decreased magnet strength at the initial fitting, a graduated wearing schedule, caution with patients who have a history of skin issues from a bone anchored hearing aid or multiple surgical procedures, and parent counseling regarding potential skin irritation. PMID- 24763487 TI - Different time trends of caloric and fat intake between statin users and nonusers among US adults: gluttony in the time of statins? AB - IMPORTANCE: Both dietary modification and use of statins can lower blood cholesterol. The increase in caloric intake among the general population is reported to have plateaued in the last decade, but no study has examined the relationship between the time trends of caloric intake and statin use. OBJECTIVE: To examine the difference in the temporal trends of caloric and fat intake between statin users and nonusers among US adults. DESIGN, SETTING, AND PARTICIPANTS: A repeated cross-sectional study in a nationally representative sample of 27,886 US adults, 20 years or older, from the National Health and Nutrition Examination Survey, 1999 through 2010. EXPOSURES: Statin use. MAIN OUTCOMES AND MEASURES: Caloric and fat intake measured through 24-hour dietary recall. Generalized linear models with interaction term between survey cycle and statin use were constructed to investigate the time trends of dietary intake for statin users and nonusers after adjustment for possible confounders. We calculated model-adjusted caloric and fat intake using these models and examined if the time trends differed by statin use. Body mass index (BMI) changes were also compared between statin users and nonusers. RESULTS: In the 1999-2000 period, the caloric intake was significantly less for statin users compared with nonusers (2000 vs 2179 kcal/d; P = .007). The difference between the groups became smaller as time went by, and there was no statistical difference after the 2005-2006 period. Among statin users, caloric intake in the 2009-2010 period was 9.6% higher (95% CI, 1.8-18.1; P = .02) than that in the 1999-2000 period. In contrast, no significant change was observed among nonusers during the same study period. Statin users also consumed significantly less fat in the 1999-2000 period (71.7 vs 81.2 g/d; P = .003). Fat intake increased 14.4% among statin users (95% CI, 3.8-26.1; P = .007) while not changing significantly among nonusers. Also, BMI increased more among statin users (+1.3) than among nonusers (+0.4) in the adjusted model (P = .02). CONCLUSIONS AND RELEVANCE: Caloric and fat intake have increased among statin users over time, which was not true for nonusers. The increase in BMI was faster for statin users than for nonusers. Efforts aimed at dietary control among statin users may be becoming less intensive. The importance of dietary composition may need to be reemphasized for statin users. PMID- 24763488 TI - Loop-mediated isothermal amplification of specific endoglucanase gene sequence for detection of the bacterial wilt pathogen Ralstonia solanacearum. AB - The increased globalization of crops production and processing industries also promotes the side-effects of more rapid and efficient spread of plant pathogens. To prevent the associated economic losses, and particularly those related to bacterial diseases where their management relies on removal of the infected material from production, simple, easy-to-perform, rapid and cost-effective tests are needed. Loop-mediated isothermal amplification (LAMP) assays that target 16S rRNA, fliC and egl genes were compared and evaluated as on-site applications. The assay with the best performance was that targeted to the egl gene, which shows high analytical specificity for diverse strains of the betaproteobacterium Ralstonia solanacearum, including its non-European and non-race 3 biovar 2 strains. The additional melting curve analysis provides confirmation of the test results. According to our extensive assessment, the egl LAMP assay requires minimum sample preparation (a few minutes of boiling) for the identification of pure cultures and ooze from symptomatic material, and it can also be used in a high-throughput format in the laboratory. This provides sensitive and reliable detection of R. solanacearum strains of different phylotypes. PMID- 24763490 TI - Additional diagnostic value of first-pass myocardial perfusion imaging without stress when combined with 64-row detector coronary CT angiography in patients with coronary artery disease. AB - OBJECTIVE: Multi-detector coronary CT angiography (CCTA) can detect coronary stenosis, but it has a limited ability to evaluate myocardial perfusion. We evaluated the usefulness of first-pass CT-myocardial perfusion imaging (MPI) in combination with CCTA for diagnosing coronary artery disease (CAD). METHODS: A total of 145 patients with suspected CAD were enrolled. We used 64-row multi detector CT (Definition Flash, Siemens). The same coronary CCTA data were used for first-pass CT-MPI without drug loading. Images were reconstructed by examining the signal densities at diastole as colour maps. Diagnostic accuracy was assessed by comparison with invasive coronary angiography. RESULTS: First pass CT-MPI in combination with CCTA significantly improved diagnostic performance compared with CCTA alone. With per-vessel analysis, the sensitivity, specificity, positive predictive value and negative predictive value increased from 81% to 85%, 87% to 94%, 63% to 79% and 95% to 96%, respectively. The area under the receiver operating characteristic curve for detecting CAD also increased from 0.84 to 0.89 (p=0.02). First-pass CT-MPI was particularly useful for assessing segments that could not be directly evaluated due to severe calcification and motion artefacts. CONCLUSIONS: First-pass CT-MPI has an additional diagnostic value for detecting coronary stenosis, in particular in patients with severe calcification. PMID- 24763493 TI - The one-electron reduction of dithiolate and diselenolate ligands. AB - Herein we present an assessment to determine which of nine well-established DFT functionals best describes the reduction of C2H2Se2(-). In addition, we have also studied the effects of changing the substituents bound to the alkene functional group of dithiolene and diselenolene ligands. Such ligands are important due to their unique electrochemical and physical properties when ligated to metals. The M06-L functional shows best agreement with the QCISD/cc-pVTZ value of -2.45 V for the reduction potential of the (C2H2Se2(-)/C2H2Se2(-2)) redox couple. At the M06 L/6-311+G(d,p) level of theory the calculated reduction potential for the (C2H2Se2(-)/C2H2Se2(-2)) redox couple is only 0.09 V in error. However, as a result of the nature of the oxidized species for the respective ligands the absolute reduction potential of the (C2H2Se2(-)/C2H2Se2(-2)) redox couple is 0.57 V more oxidizing than the (C2H2S2(-)/C2H2S2(-2)) redox couple. This is due to the radical electron in C2H2S2(-) being delocalized within the alkene backbone, whereas in C2H2Se2(-) the electron is largely localized on the Se atoms. The relative reducing power of the S- and Se-containing redox couples is shown to vary depending on the choice of substituents. In particular the reduction potential of the various S-containing redox couples range from being 0.34 V more reducing to 0.28 V more oxidizing than the analogous Se-containing redox couples. This difference in the relative reducing power appears to be a result of the nature of the oxidized ligand. Thus, depending on the choice of moiety very different chemistry is seen between the analogous dithiolate and diselenolate ligands. PMID- 24763491 TI - Resuscitated cardiac arrest and prognosis following myocardial infarction. AB - OBJECTIVES: To determine whether resuscitated cardiac arrest (CA) complicating ST elevation myocardial infarction (STEMI) impacts outcome, particularly in patients surviving to discharge. BACKGROUND: Resuscitated CA complicating STEMI is associated with increased inpatient mortality. The impact on later prognosis is unclear. METHODS: We analysed data from the UK Myocardial Ischaemia National Audit Project for STEMI patients admitted during January 2008-March 2010. We used survival analyses to assess the independent impact of resuscitated CA during the index episode on inhospital, 30 days, 1 year and medium term all-cause mortality. RESULTS: Of 48 749 STEMI patients, 5308 (10.9%) were recorded as having a CA. Of these, 1557 (29.3%) died on the day of CA. In survivors, after covariate adjustment, resuscitated CA was associated with increased risk of death during the index admission (HR 4.05 (3.69 to 4.45) p<0.001). In patients surviving to discharge, a history of resuscitated CA was associated with increased risk of death to 30 days (HR 1.53 (1.18 to 2.00), p<0.001). However, beyond 30 days, resuscitated CA was not associated with increased mortality risk (1-year HR 0.95 (0.79 to 1.14, p=0.596); 3.5 years HR 0.90 (0.78 to 1.04), p=0.144). The influence of resuscitated CA on inhospital or 30-day mortality was similar whether CA occurred before or after hospital admission. Where the resuscitated CA rhythm was asystole, inhospital mortality was higher compared with ventricular arrhythmia (p<0.001) or pulseless electrical activity (p=0.011). Late resuscitated CA (occurring after the day of index STEMI) was associated with higher 30-day postdischarge mortality compared with early resuscitated CA (p=0.023). CONCLUSIONS: STEMI complicated by resuscitated CA merits careful monitoring in the early period postevent. In contemporary practice, there is no impact of resuscitated CA on longer-term prognosis. PMID- 24763494 TI - Editor's Note. PMID- 24763492 TI - Cardiac steatosis in patients with dilated cardiomyopathy. AB - OBJECTIVE: Ectopic fat accumulation within and around the heart has been related to increased risk of heart disease. Limited data exist on cardiac adiposity in subjects with dilated cardiomyopathy (DCM). The aim of the study was to examine the components of cardiac steatosis and their relationship to LV structure and function in non-diabetic DCM patients. METHODS: Myocardial and hepatic triglyceride (TG) contents were measured with 1.5 T magnetic resonance spectroscopy (MRS), and LV function, visceral adipose (VAT) and abdominal subcutaneous tissue (SAT), epicardial and pericardial fat by MRI in 10 non diabetic men with DCM and in 20 controls. RESULTS: In face of comparable intra abdominal fat depots, myocardial TG [0.41% (0.21-2.19) vs. 0.86% (0.31-2.24), p=0.038] was markedly lower and epicardial (895 mm2+/-110 vs. 664 mm2+/-180, p=0.002) and pericardial fat [2173 mm2 (616-3673) vs 1168 mm2 (266-2319), p=0.039] depots were larger in patients with DCM compared with controls. In subjects with DCM, the LV global function index was decreased to a greater extent than the LV EF [21%+/-6 vs. 34% (16-40)]. CONCLUSIONS: Myocardial TG content decreased and epicardial and pericardial fat depots increased in non-diabetic subjects with DCM. Although recognised as a site of ectopic fat accumulation, the derangement of myocardial TG seems to play a specific role in the myocardial energy metabolism in congestive heart failure. PMID- 24763495 TI - Chronic actinic dermatitis is not a viable concept. PMID- 24763496 TI - Hypopigmented papules of the cheeks, neck, and shoulders. PMID- 24763497 TI - Identification of novel regulatory genes in development of the avian reproductive tracts. AB - The chicken reproductive system is unique in maintaining its functions including production of eggs or sperm, fertilization of the egg by sperm maintained in sperm nests, production of hormones regulating its growth, development and function, and reproduction. Development of the reproductive organs is a highly regulated process that results in differentiation and proliferation of germ cells in response to predominant regulatory factors such as hormones and transcription factors. However, only a few genes are known to determine morphogenesis of the chicken reproductive tract and their mechanisms are unknown. Therefore, in the present study, we investigated the expression patterns of four genes including SNCA, TOM1L1, TTR and ZEB1 in the gonads at embryonic days 14 and 18, and in immature (12-week-old) and mature (50-week-old) chickens, as well as the reproductive tract including ovary, oviduct and testes of the respective sexes by qRT-PCR, in situ hybridization and immunofluorescence analyses. The expression of SNCA, TOM1L1 and ZEB1 genes was higher in immature and mature female reproductive tracts than expression of TTR. In addition, different temporal and spatial patterns of expression of the four genes were observed during maturation of testis in chickens. Specifically, SNCA, TOM1L1 and TTR were highly expressed in testes of 12-week-old chickens. Moreover, several chicken specific microRNAs (miRs) were demonstrated to affect expression of target gene mRNAs by directly binding to the 3'-UTR of their target genes through actions at the post transcriptional level as follows: miR-153 and miR-1643 for SNCA; miR-1680* for TTR; and miR-200b and miR-1786 for ZEB1. These results suggest that four-selected genes play an important role in development of the male and female reproductive tract in chickens and expression of most candidate genes is regulated at the post transcriptional level through specific microRNAs. PMID- 24763498 TI - A three-dimensional in vitro model of tumor cell intravasation. AB - Metastasis is the cause of over 90% of all human cancer deaths. Early steps in the metastatic process include: the formation of new blood vessels, the initiation of epithelial-mesenchymal transition (EMT), and the mobilization of tumor cells into the circulation. There are ongoing efforts to replicate the physiological landscape of human tumor tissue using three-dimensional in vitro culture models; however, few systems are able to capture the full range of authentic, complex in vivo events such as neovascularization and intravasation. Here we introduce the Prevascularized Tumor (PVT) model to investigate early events of solid tumor progression. PVT spheroids are composed of endothelial and tumor cells, and are embedded in a fibrin matrix containing fibroblasts. The PVT model facilitates two mechanisms of vessel formation: robust sprouting angiogenesis into the matrix, and contiguous vascularization within the spheroid. Furthermore, the PVT model enables the intravasation of tumor cells that is enhanced under low oxygen conditions and is also dependent on the key EMT transcription factor Slug. The PVT model provides a significant advance in the mimicry of human tumors in vitro, and may improve investigation and targeting of events in the metastatic process. PMID- 24763499 TI - Discrete molecular dynamics can predict helical prestructured motifs in disordered proteins. AB - Intrinsically disordered proteins (IDPs) lack a stable tertiary structure, but their short binding regions termed Pre-Structured Motifs (PreSMo) can form transient secondary structure elements in solution. Although disordered proteins are crucial in many biological processes and designing strategies to modulate their function is highly important, both experimental and computational tools to describe their conformational ensembles and the initial steps of folding are sparse. Here we report that discrete molecular dynamics (DMD) simulations combined with replica exchange (RX) method efficiently samples the conformational space and detects regions populating alpha-helical conformational states in disordered protein regions. While the available computational methods predict secondary structural propensities in IDPs based on the observation of protein protein interactions, our ab initio method rests on physical principles of protein folding and dynamics. We show that RX-DMD predicts alpha-PreSMos with high confidence confirmed by comparison to experimental NMR data. Moreover, the method also can dissect alpha-PreSMos in close vicinity to each other and indicate helix stability. Importantly, simulations with disordered regions forming helices in X-ray structures of complexes indicate that a preformed helix is frequently the binding element itself, while in other cases it may have a role in initiating the binding process. Our results indicate that RX-DMD provides a breakthrough in the structural and dynamical characterization of disordered proteins by generating the structural ensembles of IDPs even when experimental data are not available. PMID- 24763501 TI - Mining herbaria for plant pathogen genomes: back to the future. PMID- 24763503 TI - Skin surgery: a practical guide. PMID- 24763502 TI - Characterization of genomic vitamin D receptor binding sites through chromatin looping and opening. AB - The vitamin D receptor (VDR) is a transcription factor that mediates the genomic effects of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). Genome-wide there are several thousand binding sites and hundreds of primary 1,25(OH)2D3 target genes, but their functional relation is largely elusive. In this study, we used ChIA-PET data of the transcription factor CTCF in combination with VDR ChIP-seq data, in order to map chromatin domains containing VDR binding sites. In total, we found 1,599 such VDR containing chromatin domains and studied in THP-1 human monocytic leukemia cells four representatives of them. Our combined ChIP-seq and FAIRE-seq time course data showed that each of these four domains contained a master VDR binding site, where an increase of VDR binding pairs with 1,25(OH)2D3-promoted chromatin opening and the presence of a highly significant DR3-type sequence below the peak summit. These sites differed in their relative VDR binding but not in their kinetics, while other loci either had a weaker and delayed VDR association or could not be confirmed at all. All studied chromatin domains contained at least one primary 1,25(OH)2D3 target gene demonstrating a characteristic slope of mRNA increase, while neighboring genes responded delayed, if at all. In conclusion, the observation of ligand-inducible VDR binding and chromatin opening combined with a DR3-type sequence highlighted genome-wide 160 VDR loci that have within their chromatin domain a more than 4-fold increased likelihood to identify a primary 1,25(OH)2D3 target gene than in the vicinity of other genomic VDR binding sites. PMID- 24763504 TI - Careful evaluation needed of "alternative" claims. PMID- 24763505 TI - Recurrent oral blood blisters. PMID- 24763506 TI - Assessing sleep disturbance in low back pain: the validity of portable instruments. AB - Although portable instruments have been used in the assessment of sleep disturbance for patients with low back pain (LBP), the accuracy of the instruments in detecting sleep/wake episodes for this population is unknown. This study investigated the criterion validity of two portable instruments (Armband and Actiwatch) for assessing sleep disturbance in patients with LBP. 50 patients with LBP performed simultaneous overnight sleep recordings in a university sleep laboratory. All 50 participants were assessed by Polysomnography (PSG) and the Armband and a subgroup of 33 participants wore an Actiwatch. Criterion validity was determined by calculating epoch-by-epoch agreement, sensitivity, specificity and prevalence and bias- adjusted kappa (PABAK) for sleep versus wake between each instrument and PSG. The relationship between PSG and the two instruments was assessed using intraclass correlation coefficients (ICC 2, 1). The study participants showed symptoms of sub-threshold insomnia (mean ISI = 13.2, 95% CI = 6.36) and poor sleep quality (mean PSQI = 9.20, 95% CI = 4.27). Observed agreement with PSG was 85% and 88% for the Armband and Actiwatch. Sensitivity was 0.90 for both instruments and specificity was 0.54 and 0.67 and PABAK of 0.69 and 0.77 for the Armband and Actiwatch respectively. The ICC (95%CI) was 0.76 (0.61 to 0.86) and 0.80 (0.46 to 0.92) for total sleep time, 0.52 (0.29 to 0.70) and 0.55 (0.14 to 0.77) for sleep efficiency, 0.64 (0.45 to 0.78) and 0.52 (0.23 to 0.73) for wake after sleep onset and 0.13 (-0.15 to 0.39) and 0.33 (-0.05 to 0.63) for sleep onset latency, for the Armband and Actiwatch, respectively. The findings showed that both instruments have varied criterion validity across the sleep parameters from excellent validity for measures of total sleep time, good validity for measures of sleep efficiency and wake after onset to poor validity for sleep onset latency. PMID- 24763507 TI - Cap analogs containing 6-thioguanosine--reagents for the synthesis of mRNAs selectively photo-crosslinkable with cap-binding biomolecules. AB - Numerous biomolecules recognize the 7-methylguanosine cap structure present at the 5' ends of eukaryotic mRNAs. Photo-crosslinking is a valuable technique to study these interactions. We report three anti-reverse cap analogs containing a photo-activable nucleoside, 6-thioguanosine ((6S)G), that enable the synthesis of capped RNAs with (6S)G positioned exclusively as the first transcribed nucleotide. The effect of the 6-thioguanosine moiety on binding to the translation factor eIF4E and the efficiency of mRNA translation was determined. The utility of mRNAs with a (6S)G-modified cap in crosslinking experiments is shown by mapping the histone H4 cap-binding pocket. PMID- 24763508 TI - Multimodal brain connectivity analysis in unmedicated late-life depression. AB - Late-life depression (LLD) is a common disorder associated with emotional distress, cognitive impairment and somatic complains. Structural abnormalities have been suggested as one of the main neurobiological correlates in LLD. However the relationship between these structural abnormalities and altered functional brain networks in LLD remains poorly understood. 15 healthy elderly comparison subjects from the community and 10 unmedicated and symptomatic subjects with geriatric depression were selected for this study. For each subject, 87 regions of interest (ROI) were generated from whole brain anatomical parcellation of resting state fMRI data. Whole-brain ROI-wise correlations were calculated and compared between groups. Group differences were assessed using an analysis of covariance after controlling for age, sex and education with multiple comparison correction using the false discovery rate. Structural connectivity was assessed by tract-based spatial statistics (TBSS). LLD subjects had significantly decreased connectivity between the right accumbens area (rA) and the right medial orbitofrontal cortex (rmOFC) as well as between the right rostral anterior cingulate cortex (rrACC) and bilateral superior frontal gyrus (bsSFG). Altered connectivity of rrACC with the bsSFG was significantly correlated with depression severity in depressed subjects. TBSS analysis showed a 20% reduction in fractional anisotropy (FA) in the right Forceps Minor (rFM) in depressed subjects. rFM FA values were positively correlated with rA-rmOFC and rrACC-bsFG functional connectivity values in our total study sample. Coordinated structural and functional impairment in circuits involved in emotion regulation and reward pathways play an important role in the pathophysiology of LLD. PMID- 24763509 TI - The adrenal psoas sign: surgical outcomes following a simple technique to maximize removal of extracortical adrenal tissue during bilateral laparoscopic adrenalectomy. AB - BACKGROUND: Bilateral laparoscopic adrenalectomy (BLA) is an effective therapy for the management of persistent hypercortisolism in patients after failed transphenoidal pituitary tumor resection for Cushing's disease. Extracortical adrenal tissue has been identified as a source of persistent hypercortisolism and, if not resected along with both adrenal glands, may lead to treatment failure. We report a reliable and reproducible technique called the "psoas sign" for BLA in patients with Cushing's disease which reduces the likelihood of retained extra-adrenal cortical rests and may reduce intraoperative complications. METHODS: A 16-year retrospective review of all consecutive patients who underwent transabdominal BLA at a single tertiary care center was performed. All patients underwent BLA utilizing the psoas sign technique and all procedures were performed replicating these predetermined surgical steps: (1) Identification of the inferior pole of the gland. (2) Identification of the inferior aspect of the adreno-caval groove on the right or the adrenal vein/renal vein confluence on the left. (3) Division of the adrenal vein. (4) Dissection and removal of the adrenal gland with clearance of all retroperitoneal fat overlying the psoas muscle. RESULTS: Between October 1996 and December 2012, 92 patients underwent BLA for refractory Cushing's disease. Patients were predominantly female (90 %) with a median age of 40 years (17-71). There were 3 intraoperative complications (3.2 %), 2 conversions (2.2 %), and 1 death (1.09 %). Four patients were identified as having extracortical rests of adrenal tissue within the retroperitoneal fat (4.3 %). Mean operative time was 272 min (+/-79.25, n = 68) and median estimated blood loss was 50 mL (10-800 mL). CONCLUSIONS: The psoas sign technique provides a clear view of the adrenal fossa and facilitates careful dissection of the anatomic planes around the adrenal gland. This technique is feasible, reproducible and in our experience allows for safe removal of both adrenal glands and all surrounding extracortical adrenal tissue. PMID- 24763512 TI - Computational study of the Rayleigh light scattering properties of atmospheric pre-nucleation clusters. AB - The Rayleigh and hyper Rayleigh scattering properties of the binary (H2SO4)(H2O)n and ternary (H2SO4)(NH3)(H2O)n clusters are investigated using a quantum mechanical response theory approach. The molecular Rayleigh scattering intensities are expressed using the dipole polarizability alpha and hyperpolarizability beta tensors. Using density functional theory, we elucidate the effect of cluster morphology on the scattering properties using a combinatorial sampling approach. We find that the Rayleigh scattering intensity depends quadratically on the number of water molecules in the cluster and that a single ammonia molecule is able to induce a high anisotropy, which further increases the scattering intensity. The hyper Rayleigh scattering activities are found to be extremely low. This study presents the first attempt to map the scattering of atmospheric molecular clusters using a bottom-up approach. PMID- 24763510 TI - Hybrid endoscopic thymectomy: combined transesophageal and transthoracic approach in a survival porcine model with cadaver assessment. AB - BACKGROUND: Video-assisted thoracoscopic surgery thymectomy has been used in the treatment of Myastenia Gravis and thymomas (coexisting or not). In natural orifice transluminal endoscopic surgery, new approaches to the thorax are emerging as alternatives to the classic transthoracic endoscopic surgery. The aim of this study was to assess the feasibility and reliability of hybrid endoscopic thymectomy (HET) using a combined transthoracic and transesophageal approach. METHODS: Twelve consecutive in vivo experiments were undertaken in the porcine model (4 acute and 8 survival). The same procedure was assessed in a human cadaver afterward. For HET, an 11-mm trocar was inserted in the 2nd intercostal space in the left anterior axillary line. A 0 degrees 10-mm thoracoscope with a 5-mm working channel was introduced. Transesophageal access was created through a submucosal tunnel using a flexible gastroscope with a single working channel introduced through the mouth. Using both flexible (gastroscope) and rigid (thoracoscope) instruments, the mediastinum was opened; the thymus was dissected, and the vessels were ligated using electrocautery alone. RESULTS: Submucosal tunnel creation and esophagotomy were performed safely without incidents in all animals. Complete thymectomy was achieved in all experiments. All animals in the survival group lived for 14 days. Thoracoscopic and postmortem examination revealed pleural adhesions on site of the surgical procedure with no signs of infection. Histological analysis of the proximal third of the esophagus revealed complete cicatrization of both mucosal defect and myotomy site. In the human cadaver, we were able to replicate all the procedure even though we were not able to identify the thymus. CONCLUSIONS: Hybrid endoscopic thymectomy is feasible and reliable. HET could be regarded as a possible alternative to classic thoracoscopic approach for patients requiring thymectomy. PMID- 24763513 TI - Mantle cell lymphoma epidemiology: a population-based study in France. AB - Only limited population-based data are available on mantle cell lymphoma (MCL), a relatively rare and aggressive mature B cell non-Hodgkin lymphoma (NHL) entity. We conducted an epidemiological study based on the three French registries devoted to haematological malignancies over the period 2002-2006. Main clinical features and management characteristics were collected. Incidence and survival rates were estimated, and independent prognostic factors were analysed. MCL was diagnosed in 135 patients between 2002 and 2006. Seventy-four percent of patients were men. Age-standardised incidence rate of MCL (per 100,000) was 1.1 in men and 0.26 in women. Median age at diagnosis was 72 years (range 30-92). Advanced-stage (III or IV) disease was diagnosed in 81.5 % of patients, and 55 % of them were identified as high risk according to MCL International Prognostic Index (MIPI). Median net survival time was 41 months (95 % confidence interval (CI), 38-62). Main independent prognostic factors were age at diagnosis, performance status and use of rituximab in first-line treatment. Median overall survival was 36 months (95 % CI, 27-40) for high MIPI and 60 months (95 % CI, 35-74) for low/intermediate MIPI patients (p = 0.02). This study confirms that MCL remains an aggressive NHL with a median overall survival less than 4 years and demonstrates that the use of rituximab has modified overall survival duration. PMID- 24763514 TI - FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia. AB - FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1 retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL 3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia. PMID- 24763515 TI - HSCARG negatively regulates the cellular antiviral RIG-I like receptor signaling pathway by inhibiting TRAF3 ubiquitination via recruiting OTUB1. AB - RIG-I like receptors (RLRs) recognize cytosolic viral RNA and initiate innate immunity; they increase the production of type I interferon (IFN) and the transcription of a series of antiviral genes to protect the host organism. Accurate regulation of the RLR pathway is important for avoiding tissue injury induced by excessive immune response. HSCARG is a newly reported negative regulator of NF-kappaB. Here we demonstrated that HSCARG participates in innate immunity. HSCARG inhibited the cellular antiviral response in an NF-kappaB independent manner, whereas deficiency of HSCARG had an opposite effect. After viral infection, HSCARG interacted with tumor necrosis receptor-associated factor 3 (TRAF3) and inhibited its ubiquitination by promoting the recruitment of OTUB1 to TRAF3. Knockout of HSCARG attenuated the de-ubiquitination of TRAF3 by OTUB1, and knockdown of OTUB1 abolished the effect of HSCARG. HSCARG also interacted with Ikappa-B kinase epsilon (IKKepsilon) after viral infection and impaired the association between TRAF3 and IKKepsilon, which further decreased the phosphorylation of IKKepsilon and interferon response factor 3 (IRF3), thus suppressed the dimerization and nuclear translocation of IRF3. Moreover, knockdown of TRAF3 dampened the inhibitory effect of IFN-beta transcription by HSCARG, suggesting that TRAF3 is necessary for HSCARG to down-regulate RLR pathway. This study demonstrated that HSCARG is a negative regulator that enables balanced antiviral innate immunity. PMID- 24763516 TI - Diagnosis and treatment of fetal cardiac disease: a scientific statement from the American Heart Association. AB - BACKGROUND: The goal of this statement is to review available literature and to put forth a scientific statement on the current practice of fetal cardiac medicine, including the diagnosis and management of fetal cardiovascular disease. METHODS AND RESULTS: A writing group appointed by the American Heart Association reviewed the available literature pertaining to topics relevant to fetal cardiac medicine, including the diagnosis of congenital heart disease and arrhythmias, assessment of cardiac function and the cardiovascular system, and available treatment options. The American College of Cardiology/American Heart Association classification of recommendations and level of evidence for practice guidelines were applied to the current practice of fetal cardiac medicine. Recommendations relating to the specifics of fetal diagnosis, including the timing of referral for study, indications for referral, and experience suggested for performance and interpretation of studies, are presented. The components of a fetal echocardiogram are described in detail, including descriptions of the assessment of cardiac anatomy, cardiac function, and rhythm. Complementary modalities for fetal cardiac assessment are reviewed, including the use of advanced ultrasound techniques, fetal magnetic resonance imaging, and fetal magnetocardiography and electrocardiography for rhythm assessment. Models for parental counseling and a discussion of parental stress and depression assessments are reviewed. Available fetal therapies, including medical management for arrhythmias or heart failure and closed or open intervention for diseases affecting the cardiovascular system such as twin-twin transfusion syndrome, lung masses, and vascular tumors, are highlighted. Catheter-based intervention strategies to prevent the progression of disease in utero are also discussed. Recommendations for delivery planning strategies for fetuses with congenital heart disease including models based on classification of disease severity and delivery room treatment will be highlighted. Outcome assessment is reviewed to show the benefit of prenatal diagnosis and management as they affect outcome for babies with congenital heart disease. CONCLUSIONS: Fetal cardiac medicine has evolved considerably over the past 2 decades, predominantly in response to advances in imaging technology and innovations in therapies. The diagnosis of cardiac disease in the fetus is mostly made with ultrasound; however, new technologies, including 3- and 4-dimensional echocardiography, magnetic resonance imaging, and fetal electrocardiography and magnetocardiography, are available. Medical and interventional treatments for select diseases and strategies for delivery room care enable stabilization of high-risk fetuses and contribute to improved outcomes. This statement highlights what is currently known and recommended on the basis of evidence and experience in the rapidly advancing and highly specialized field of fetal cardiac care. PMID- 24763517 TI - Acoustic actuated fluorescence activated sorting of microparticles. AB - In this paper, we present a fluorescence activated sorter realized in a continuous flow microfluidic chip. Sorting is achieved by deflecting a focused particle stream with short acoustic bursts (2.5 ms), in a fluorescence activated configuration. The system utilizes two-dimensional acoustic pre-focusing, using a single actuation frequency, to position all particles in the same fluid velocity regime at flow rates up to 1.7 mL min(-1). Particles were sorted based on their fluorescence intensities at throughputs up to 150 particles s(-1). The highest purity reached was 80% when sorting at an average rate of 50 particles s(-1). The average recovery of a sort was 93.2 +/- 2.6%. The presented system enables fluorescence activated cell sorting in a continuous flow microfluidic format that allows aseptic integration of downstream microfluidic functionalities, opening for medical and clinical applications. PMID- 24763519 TI - Clinical dermatology illustrated: a regional approach, third edition. PMID- 24763518 TI - Bilateral Vestibular Deficiency: Quality of Life and Economic Implications. AB - IMPORTANCE: Bilateral vestibular deficiency (BVD) causes chronic imbalance and unsteady vision and greatly increases the risk of falls; however, its effects on quality of life and economic impact are not well defined. OBJECTIVE: To quantify disease-specific and health-related quality of life, health care utilization, and economic impact on individuals with BVD in comparison with those with unilateral vestibular deficiency (UVD). DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional survey study of patients with BVD or UVD and healthy controls at an academic medical center. Vestibular dysfunction was diagnosed by means of caloric nystagmography. INTERVENTIONS: Survey questionnaire. MAIN OUTCOMES AND MEASURES: Health status was measured using the Dizziness Handicap Index (DHI) and Health Utility Index Mark 3 (HUI3). Economic burden was estimated using participant responses to questions on disease-specific health care utilization and lost productivity. RESULTS: Fifteen patients with BVD, 22 with UVD, and 23 healthy controls participated. In comparison with patients with UVD and controls, patients with BVD had significantly worse DHI (P < .001) and HUI3 scores. Statistically significant between-group differences were observed for overall HUI3 score (P < .001) and for specific attributes including vision, hearing, ambulation, emotion, and pain (P < .001 for all). Generalized linear model analysis of clinical variables associated with HUI3 scores after adjustment for other variables (including sex, race, education, age, and frequency of dizziness related outpatient clinic visits) showed that the presence of UVD (P < .001) or BVD (P < .001), increased dizziness-related emergency room visits (P = .002), and increased dizziness-related missed work days (P < .001) were independently associated with worse HUI3 scores. Patients with BVD and UVD incurred estimated mean (range) annual economic burdens of $13,019 ($0-$48,830) and $3531 ($0 $48,442) per patient, respectively. CONCLUSIONS AND RELEVANCE: Bilateral vestibular deficiency significantly decreases quality of life and imposes substantial economic burdens on individuals and society. These results underscore the limits of adaptation and compensation in BVD. Furthermore, they quantify the potential benefits of prosthetic restoration of vestibular function both to these individuals and to society. PMID- 24763520 TI - Prognostic factors in leukocytoclastic vasculitis: what is the role of antineutrophil cytoplasmic antibody? PMID- 24763521 TI - Red eroded nodule on the foot. PMID- 24763522 TI - A bromine-radical mediated three-component reaction comprising allenes, electron deficient alkenes and allyl bromides: facile synthesis of 2-bromo-1,7-dienes. AB - A bromine-radical mediated three-component coupling reaction was effectively achieved by the use of allenes, electron-deficient alkenes, and allyl bromides and led to the synthesis of 2-bromo-1,7-dienes in good to high yields. This protocol was extended to the three-component process using alkylidenecyclopropane, which gave 2-bromo-1,8-diene along with alkylidenecyclopentane. PMID- 24763523 TI - A porphyrin/beta-cyclodextrin conjugated nano-system having a pan-lid molecular structure for smart drug carrier applications. AB - In this study, 5,10,15-tri[p(9-methoxy-triethyleneoxy)phenyl]-20-[p phenylisophthalate-beta-cyclodextrin]porphyrin, a compound containing a porphyrin and a beta-cyclodextrin unit covalently linked by means of an isophthalic bridge, was synthesized and characterized by NMR, MALDI-TOF mass spectrometry and UV-vis and circular dichroism spectroscopies. This porphyrin/beta-cyclodextrin system, with the porphyrin unit connected to the lower rim (OH-2) of the cyclodextrin structure, is water-soluble and no evidence of a self-assembly arrangement between the porphyrin and cyclodextrin units appears. In this way, the beta cyclodextrin cavities remain free, retaining their potential ability of drug delivery, with the spectroscopic advantage induced by the high absorbance of the porphyrin unit. Furthermore, the porphyrin unit, interacting with the guest and acting as a lid, could have a role in the controlled release process of the drug. PMID- 24763524 TI - The synthesis and characterization of nonperipherally tetra terminal alkynyl substituted phthalocyanines and glycoconjugation via the click reaction. AB - In order to obtain nonperipherally tetra terminal alkynyl substituted phthalocyanines (Pcs), new 3-pent-4-ynyloxy phthalonitrile (3) was prepared by the nucleophilic displacement reaction of 3-nitrophthalonitrile (1) and 4-pentyn 1-ol (2) and then cyclotetramerization was attained in the presence of zinc acetate, cobalt acetate, and/or DBU in n-pentanol without protection/deprotection. For the first time, the glycoconjugation of the nonperipherally tetra terminal alkynyl substituted zinc phthalocyanine (ZnPc) (6) can be easily achieved via the click reaction in a high yield. The electronic absorption spectrum of the glucopyranosyl substituted ZnPc (10) derivative showed a red-shifted Q band at 751 nm in dichloromethane due to the protonation of the meso nitrogens of the Pc macrocycle. Deacylation yielded ZnPc (11) bearing glucose substituents at nonperipheral positions with an improved water-solubility and non-aggregation in DMSO. The chemical structures of the new compounds were characterized by (1)H NMR, (13)C NMR, FT-IR, UV-Vis, mass spectrometry and elemental analysis. Moreover, the phthalonitrile compound was characterized using X-ray. PMID- 24763525 TI - [Pulmonary complications in liver diseases]. AB - Pulmonary-hepatic vascular disorders are frequent complications in patients with portal hypertension and cirrhosis. Hepatopulmonary syndrome (HPS), portopulmonary hypertension (POPH), and hepatic hydrothorax are relevant disease entities in these patients. HPS occurs in up to 30 % of patients with cirrhosis and is associated with a more than 2-fold increased mortality. The diagnosis of HPS should be established early by arterial blood gas analysis and contrast-enhanced echocardiography, whereas POPH is diagnosed by the presence of pulmonary arterial hypertension evaluated via right heart catheterization and the presence of portal hypertension. Therapeutic options include initiation of long-term oxygen therapy and liver transplantation in patients with severe HPS. Patients with POPH should receive targeted medical therapies with endothelin receptor antagonists, phosphodiesterase-5 inhibitors and/or prostanoids. In contrast, beta-blockers should be avoided. This review summarizes current knowledge regarding pulmonary hepatic vascular disorders, with a focus on HPS. PMID- 24763527 TI - [Acute muscle loss in critically ill patients]. PMID- 24763526 TI - [Renal insufficiency in patients with hepatic insufficiency]. AB - BACKGROUND: Renal dysfunction is a common complication of cirrhosis, occurring in approximately 20 % of all hospitalized patients with cirrhosis and associated with increased mortality. In about two thirds of the patients, renal dysfunction is caused by prerenal disorders (e.g. gastrointestinal bleeding, diuretics, bacterial infection); one third is caused by intrarenal diseases (e.g. hepatitis associated glomerulonephritis). In most patients, prerenal failure can be successfully handled by volume therapy. In one third, volume replacement is not effective any more to improve kidney function. This kind of prerenal failure is called hepatorenal syndrome (HRS). PATHOPHYSIOLOGY: The pathophysiology is based on an increased splanchic vasodilation, which cannot be compensated any more by an increased cardiac output. Therefore, patients with cardiac insufficiency are more at risk of developing HRS. The decompensation leads to a stimulation of the baroreceptors with consecutive activation of the sympathetic nerve system, the renin-angiotensin-aldosteron system (RAAS), and nonosmotic release of vasopressin. This results in renal vasoconstriction, which is strengthened by the activation of hepatorenal reflex secondary to an increase in intrahepatic pressure and/or decrease in sinusoidal blood flow. THERAPY: Several studies have shown that the vasopressin analogue terlipressin combined with albumin can reverse HRS in up to 50 % of patients. Long-term survival can only be achieved by liver transplantation. Improving kidney function before transplantation improves outcome after transplantation. PMID- 24763529 TI - 20-Hydroxyeicosatetraenoic acid impairs endothelial insulin signaling by inducing phosphorylation of the insulin receptor substrate-1 at Ser616. AB - 20-Hydroxyeicosatetraenoic acid (20-HETE) induces endothelial dysfunction and is correlated with diabetes. This study was designed to investigate the effects of 20-HETE on endothelial insulin signaling.Human umbilical vein endothelial cells (HUVECs) or C57BL/6J mice were treated with 20-HETE in the presence or absence of insulin, and p-ERK1/2, p-JNK, IRS-1/PI3K/AKT/eNOS pathway, were examined in endothelial cells and aortas by immunoblotting. eNOS activity and nitric oxide production were measured. 20-HETE increased ERK1/2 phosphorylation and IRS-1 phosphorylation at Ser616; these effects were reversed by ERK1/2 inhibition. We further observed that 20-HETE treatment resulted in impaired insulin-stimulated IRS-1 phosphorylation at Tyr632 and subsequent PI3-kinase/Akt activation. Furthermore, 20-HETE treatment blocked insulin-stimulated phosphorylation of eNOS at the stimulatory Ser1177 site, eNOS activation and NO production; these effects were reversed by inhibiting ERK1/2. Treatment of C57BL/6J mice with 20-HETE resulted in ERK1/2 activation and impaired insulin-dependent activation of the IRS-1/PI3K/Akt/eNOS pathway in the aorta. Our data suggest that the 20-HETE activation of IRS-1 phosphorylation at Ser616 is dependent on ERK1/2 and leads to impaired insulin-stimulated vasodilator effects that are mediated by the IRS 1/PI3K/AKT/eNOS pathway. PMID- 24763530 TI - Nrf2 negatively regulates melanogenesis by modulating PI3K/Akt signaling. AB - Nrf2 plays a role in protection of cells against oxidative stress and xenobiotic damage by regulating cytoprotective genes. In this study, we investigated the effect of Nrf2 on melanogenesis in normal human melanocytes (NHMCs). When NHMCs were transduced with a recombinant adenovirus expressing Nrf2, melanin synthesis was significantly decreased. Consistent with this result, overexpression of Nrf2 decreased the expression of tyrosinase and tyrosinase-related protein 1. The inhibitory effect of Nrf2 was reversed by overexpression of Keap1, an intracellular regulator of Nrf2. Interestingly, Nrf2 overexpression resulted in marked activation of PI3K/Akt signaling. Conversely, inhibition of PI3K activity by treatment with wortmannin reversed the depigmentary effects of Nrf2. Taken together, these results strongly suggest that Nrf2 negatively regulates melanogenesis by modulating the PI3K/Akt signaling pathway. PMID- 24763531 TI - The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. A characteristic feature of SLE is the presence of autoantibodies against double-stranded (ds)DNA, histones and nucleosomes, and other chromatin components. SLE is a prototype type III hypersensitivity reaction. Local deposition of anti-nuclear antibodies in complex with released chromatin induces serious inflammatory conditions by activation of the complement system. The severe renal manifestation, lupus nephritis, is classified based on histological findings in renal biopsies. Apoptotic debris, including chromatin, is present in the extracellular matrix and circulation of patients with SLE. This may be due to an aberrant process of apoptosis and/or insufficient clearance of apoptotic cells/chromatin. The non-cleared apoptotic debris may lead to activation of both the innate and adaptive immune systems. In addition, an aberrant presentation of peptides by antigen-presenting cells, disturbed selection processes for lymphocytes, and deregulated lymphocyte responses may be involved in the development of autoimmunity. In the present review, we briefly will summarize current knowledge on the pathogenesis of SLE. We will also critically discuss and challenge central issues that need to be addressed in order to fully understand the pathogenic mechanisms involved in the development of SLE and in order to have an improved diagnosis for SLE. Disappointingly, in our opinion, there are still more questions than answers for the pathogenesis, diagnosis, and treatment of SLE. PMID- 24763532 TI - The pathogenic potential of autoreactive antibodies in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease affecting ~1 % of the population. Although major advances have been made in the treatment of RA, relatively little is known about disease pathogenesis. Autoantibodies, present in approximately 60 % of the patients with early disease, might provide indications for immunological mechanisms underlying RA. Among the RA-associated autoantibodies, especially anti-citrullinated protein antibodies (ACPAs) have been studied intensively in the last decade. The discovery of ACPAs resulted into novel insight in RA pathogenesis and allowed division of the heterogeneous entity of RA into an ACPA-positive and ACPA-negative subset of disease. Other autoantibodies discovered in the serum of RA patients, including rheumatoid factors (RFs) targeting human IgG and anti-peptidylarginine deiminase (PAD)3/4 antibodies reactive against and activating the enzyme involved in citrullination, might contribute in collaboration with ACPAs to a feed-forward loop to aggravate erosive outcome of disease. Recently, a novel autoantibody system associated with RA was identified. These autoantibodies recognize carbamylated proteins (anti CarP antibodies) and are detected in approximately 20 % of ACPA-negative patients, suggesting another parameter to sub-classify RA. In this review, the implication of autoantibodies in RA pathogenesis, diagnosis, prognosis and as biomarker for personalized medicine is discussed. PMID- 24763534 TI - Epigenetics and the microbiome: developing areas in the understanding of the aetiology of lupus. PMID- 24763533 TI - Rationale for B cell targeting in SLE. AB - B cells are central pathogenic players in systemic lupus erythematosus and multiple other autoimmune diseases through antibody production as well as antibody independent function. At the same time, B cells are known to play important regulatory functions that may protect against autoimmune manifestations. Yet, the functional role of different B cell populations and their contribution to disease remain to be understood. The advent of agents that specifically target B cells, in particular anti-CD20 and ant-BLyS antibodies, have demonstrated the efficacy of this approach for the treatment of human autoimmunity. The analysis of patients treated with these and other B cell agents provides a unique opportunity to understand the correlates of clinical response and the significance of different B cell subsets. Here, we discuss this information and how it could be used to better understand SLE and improve the rational design of B cell-directed therapies in this disease. PMID- 24763535 TI - The effects of lupus and antiphospholipid antibody syndrome on foetal outcomes. AB - Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that primarily affects women of childbearing-age. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder defined by the occurrence of venous and arterial thrombosis, often multiple, and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Recently, the long-term outcome of children born to patients with lupus and APS has become a major topic of interest both to patients and physicians. One of the major problems related to maternal disease is preterm delivery with all the consequences that this condition may bring. Prematurity may also be due to the presence of aPL; however, aPL do not generally display any thrombotic potential on neonates. Another complication may be neonatal lupus (NL), mediated by the presence of maternal antibodies (anti-Ro/SSA and anti-La/SSB). In addition, behaviour and neuropsychological outcomes have also been a matter of interest, but there are currently few data available. Beyond the biological influence of both maternal disease and autoimmune background, it is important to focus on the possible influence of maternal chronic illness on the neuropsychological development of her children. Whether aPL exposure could have a direct effect on brain development is still being debated. In children of mothers with APS, language delays have been noted and learning disabilities were described with a higher rate than the general age school population. Several studies were performed on children born to lupus mothers: even if maternal lupus does not seem to impair intelligence levels, it may increase the occurrence of learning disabilities and particularly dyslexia in male children. To the best of our knowledge, no studies are available on the long term outcome of children born to mothers with lupus or APS and particularly regarding the development of autoimmune diseases. Nevertheless, common experience of experts in the field is that these children do not show a significantly increased risk of displaying the same autoimmune disease as their mothers. The purpose of this paper is to answer the frequently asked questions of patients with lupus and APS who desire to become mothers, based on the little information available. PMID- 24763536 TI - Diet, microbiota and autoimmune diseases. AB - There is growing evidence that the commensal bacteria in the gastrointestinal tract (the gut microbiota) influence the development of autoimmunity in rodent models. Since humans have co-evolved with commensals for millennia, it is likely that people, who are genetically predisposed to autoimmunity, harbor gut microbial communities that similarly influence the onset and/or severity of disease. Beyond the current efforts to identify such disease-promoting or preventing commensals ("pathobionts" or "symbionts"), it will be important to determine what factors modulate them. Dietary changes are known to affect both the composition and function of the gut microbial communities, which in turn can alter the innate and adaptive immune system. In this review, we focus on the relationships between diet, microbiota, and autoimmune diseases. We hypothesize that the beneficial and life-prolonging effects of caloric restriction on a variety of autoimmune models including lupus might partly be mediated by its effects on the gut microbiome and associated virome, the collection of all viruses in the gut. We give recent examples of the immunomodulatory potential of select gut commensals and their products or diet-derived metabolites in murine models of arthritis, multiple sclerosis, and type 1 diabetes. Lastly, we summarize the published phenotypes of germ-free mouse models of lupus and speculate on any role of the diet-sensitive microbiome and virome in systemic lupus and the related antiphospholipid syndrome. PMID- 24763538 TI - Cigarette smoking, alcohol consumption and risk of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis is thought to involve both genetic and environmental factors. It is possible that common environmental exposures, such as cigarette smoking and alcohol consumption, might modify risk of disease development in certain individuals. Here we aim to review the epidemiologic evidence related to the association of cigarette smoking, alcohol consumption and the risk of developing SLE. A growing body of evidence suggests that cigarette smoking confers a short term increased risk of SLE in genetically susceptible individuals. On the other hand, alcohol consumption in moderate doses may have a protective effect against the development of SLE, although this is still debated. We also have reviewed proposed mechanistic explanations underlying the role of cigarette smoking and alcohol consumption in SLE pathogenesis. PMID- 24763537 TI - Pesticides, chemical and industrial exposures in relation to systemic lupus erythematosus. AB - Growing evidence suggests exposure to chemicals and industrial pollutants may increase risk of systemic lupus erythematosus (SLE). Here we review research on SLE associations with occupational and industrial exposures, primarily drawing on studies in human populations and summarizing epidemiologic research published in the past decade. The association of occupational silica exposure with SLE is well established, but key questions remain, including the required dose and susceptibility factors, and SLE risk due to other silicate exposures. Research on SLE and other exposures is less well developed, though several potential associations merit further consideration because of the consistency of preliminary human findings, experimental animal research, and biologic plausibility. These include pesticides and solvents, for which experimental findings also support investigation of specific agents, including organochlorines and trichloroethylene. Experimental findings and biologic plausibility suggest research on SLE and occupational exposure to hydrocarbons (i.e. mineral oils) is warranted, especially given the widespread exposures in the population. Experimental and limited human findings support further investigation of SLE related to mercury exposure, especially in dental occupations. Research on environmental risk factors in risk-enriched cohorts (family-based) is recommended, as is further investigation of exposures in relation to intermediate markers of effect (e.g. antinuclear antibodies), clinical features (e.g. nephritis), and outcomes. PMID- 24763539 TI - Immune thrombocytopaenic purpura: an autoimmune cross-link between infections and vaccines. AB - Immune thrombocytopaenic purpura (ITP) is an autoimmune systemic disease detectable by the presence of low blood platelets count (<10(5)/ul) and the production of autoantibodies against glycoproteins expressed on the platelet surface. The clinical course is often acute, and life-threatening events may occur especially in children, with 52% of paediatric patients recovering either spontaneously or after treatment. A chronic ITP evolution is observed in 64% of adults, of whom 12% will develop an overlapping autoimmune disease. Several microbial agents such as CagA-positive Helicobacter pylori or Candida albicans and a number of viruses including CMV, EBV or HIV can potentially trigger ITP through molecular mimicry. Moreover, ITP improves after treatment of the underlying infection. Similarly, vaccines such as MMR may prompt ITP (IRR 5.48, 1.61-18.64, p < 0.006). Early recognition of the underlying microbial trigger and the removal of modifiable aetiopathogenetic factors should be integrated as a complementary treatment strategy in all patients who do not readily improve with standard ITP care. PMID- 24763541 TI - Immunomodulation in human and experimental arthritis: including vitamin D, helminths and heat-shock proteins. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that is mainly directed to the joints, affecting the synovial membrane, the cartilage and also the bone. This disease affects 1% to 2% of the world population and is associated with significant morbidity and increased mortality. RA experimental models have allowed a great deal of information to be translated to the corresponding human disease. This review summarizes some of the most relevant findings targeting immunomodulation in arthritis. Some general guidelines to choose an adequate experimental model and also our experience with arthritis are supplied. PMID- 24763540 TI - Environmental exposures, epigenetic changes and the risk of lupus. AB - A dose-dependent combination of environmental exposures, estrogenic hormones and genetic predisposition is thought to be required for lupus to develop and flare, but how the environment modifies the immune system in genetically predisposed people is unclear. Current evidence indicates that environmental agents that inhibit DNA methylation can convert normal antigen-specific CD4+ T lymphocytes into autoreactive, cytotoxic, pro-inflammatory cells that are sufficient to cause lupus-like autoimmunity in animal models, and that the same changes in DNA methylation characterize CD4+ T cells from patients with active lupus. Environmental agents implicated in inhibiting T-cell DNA methylation include the lupus-inducing drugs procainamide and hydralazine, as well as diet, and agents causing oxidative stress, such as smoking, UV light exposure, and infections, which have been associated with lupus onset or disease activity. Other studies demonstrate that demethylated T cells cause only anti-DNA antibodies in mice lacking a genetic predisposition to lupus, but are sufficient to cause lupus-like autoimmunity in genetically predisposed mice and likely people, and that estrogens augment the disease. Collectively, these studies suggest that environmental agents that inhibit DNA methylation, together with lupus genes and estrogens or endocrine disruptors, combine in a dose-dependent fashion to cause lupus flares. PMID- 24763542 TI - Ultraviolet radiation and systemic lupus erythematosus. AB - Exposure to ultraviolet (UV) radiation is among the environmental factors that have been proposed and studied in association with systemic lupus erythematosus (SLE). While it is known that UV radiation exposure may exacerbate pre-existing lupus, it remains unclear whether UV exposure is a risk factor for the development of SLE. Experimental studies show a significant immunomodulatory role for UV radiation, but strong epidemiologic data regarding its role in triggering SLE onset are lacking. Further studies are needed to assess the role of UV radiation in relation to development of incident SLE, yet they are challenging to design due to difficulties in accurate exposure assessment, the heterogeneous nature of SLE, and the challenge of assessing photosensitivity, a feature of SLE, which often precedes its diagnosis. PMID- 24763543 TI - Viruses as potential pathogenic agents in systemic lupus erythematosus. AB - Genetic and environmental factors appear to contribute to the pathogenesis of systemic lupus erythematosus (SLE). Viral infections have been reported to be associated with the disease. A number of exogenous viruses have been linked to the pathogenesis of SLE, of which Epstein-Barr virus (EBV) has the most evidence of an aetiological candidate. In addition, human endogenous retroviruses (HERV), HRES-1, ERV-3, HERV-E 4-1, HERV-K10 and HERV-K18 have also been implicated in SLE. HERVs are incorporated into human DNA, and thus can be inherited. HERVs may trigger an autoimmune reaction through molecular mimicry, since homology of amino acid sequences between HERV proteins and SLE autoantigens has been demonstrated. These viruses can also be influenced by oestrogen, DNA hypomethylation, and ultraviolet light (UVB) exposure which have been shown to enhance HERV activation or expression. Viral infection, or other environmental factors, could induce defective apoptosis, resulting in loss of immune tolerance. Further studies in SLE and other autoimmune diseases are needed to elucidate the contribution of both exogenous and endogenous viruses in the development of autoimmunity. If key peptide sequences could be identified as molecular mimics between viruses and autoantigens, then this might offer the possibility of the development of blocking peptides or antibodies as therapeutic agents in SLE and other autoimmune conditions. PMID- 24763544 TI - Therapeutic drug monitoring in pediatric renal transplantation. AB - Finding the balance between clinical efficacy and toxicity of immunosuppressive drugs is a challenge in renal transplantation (RTx), but especially in pediatric RTx patients. Due to the expected longer life-span of pediatric transplant patients and the long-term consequences of drug-induced infectious, malignant and cardiovascular adverse effects, protocols which minimize immunosuppressive therapy make conceptual sense. In this context, therapeutic drug monitoring is a tool which provides support for the individualization of therapy. It has, however, limitations, and specific data in the pediatric cohort are comparatively sparse. There is large heterogeneity among the studies conducted to date in terms of methods, follow-up, endpoints, immunosuppressive regimens and patients. In addition, data from adult studies are not readily transferrable to the pediatric situation. This educational review gives a concise overview on aspects of therapeutic drug monitoring in pediatric RTx. PMID- 24763545 TI - Detection of circulating tumor cells in hepatocellular carcinoma using antibodies against asialoglycoprotein receptor, carbamoyl phosphate synthetase 1 and pan cytokeratin. AB - BACKGROUND: Asialoglycoprotein receptor (ASGPR)-ligand-based separation combined with identification with Hep Par 1 or pan-cytokeratin (P-CK) antibody have been demonstrated to detect circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC). The aim of this study was to develop an improved enrichment and identification system that allows the detection of all types of HCC CTCs. METHODS: The specificity of the prepared anti-ASGPR monoclonal antibody was characterized. HCC cells were bound by ASGPR antibody and subsequently magnetically isolated by second antibody-coated magnetic beads. Isolated HCC cells were identified by immunofluorescence staining using a combination of anti P-CK and anti-carbamoyl phosphate synthetase 1 (CPS1) antibodies. Blood samples spiked with HepG2 cells were used to determine recovery and sensitivity. CTCs were detected in blood samples from HCC patients and other patients. RESULTS: ASGPR was exclusively expressed in human hepatoma cell line, normal hepatocytes and HCC cells in tissue specimens detected by the ASGPR antibody staining. More HCC cells could be identified by the antibody cocktail for CPS1 and P-CK compared with a single antibody. The current approach obtained a higher recovery rate of HepG2 cells and more CTC detection from HCC patients than the previous method. Using the current method CTCs were detected in 89% of HCC patients and no CTCs were found in the other test subjects. CONCLUSIONS: Our anti-ASGPR antibody could be used for specific and efficient HCC CTC enrichment, and anti-P-CK combined with anti-CPS1 antibodies is superior to identification with one antibody alone in the sensitivity for HCC CTC detection. PMID- 24763547 TI - Multiplexing of miniaturized planar antibody arrays for serum protein profiling- a biomarker discovery in SLE nephritis. AB - In the quest to decipher disease-associated biomarkers, miniaturized and multiplexed antibody arrays may play a central role in generating protein expression profiles, or protein maps, of crude serum samples. In this conceptual study, we explored a novel, 4-times larger pen design, enabling us to, in a unique manner, simultaneously print 48 different reagents (antibodies) as individual 78.5 MUm(2) (10 MUm in diameter) sized spots at a density of 38,000 spots cm(-2) using dip-pen nanolithography technology. The antibody array set-up was interfaced with a high-resolution fluorescent-based scanner for sensitive sensing. The performance and applicability of this novel 48-plex recombinant antibody array platform design was demonstrated in a first clinical application targeting SLE nephritis, a severe chronic autoimmune connective tissue disorder, as the model disease. To this end, crude, directly biotinylated serum samples were targeted. The results showed that the miniaturized and multiplexed array platform displayed adequate performance, and that SLE-associated serum biomarker panels reflecting the disease process could be deciphered, outlining the use of miniaturized antibody arrays for disease proteomics and biomarker discovery. PMID- 24763546 TI - Finite element model of the knee for investigation of injury mechanisms: development and validation. AB - Multiple computational models have been developed to study knee biomechanics. However, the majority of these models are mainly validated against a limited range of loading conditions and/or do not include sufficient details of the critical anatomical structures within the joint. Due to the multifactorial dynamic nature of knee injuries, anatomic finite element (FE) models validated against multiple factors under a broad range of loading conditions are necessary. This study presents a validated FE model of the lower extremity with an anatomically accurate representation of the knee joint. The model was validated against tibiofemoral kinematics, ligaments strain/force, and articular cartilage pressure data measured directly from static, quasi-static, and dynamic cadaveric experiments. Strong correlations were observed between model predictions and experimental data (r > 0.8 and p < 0.0005 for all comparisons). FE predictions showed low deviations (root-mean-square (RMS) error) from average experimental data under all modes of static and quasi-static loading, falling within 2.5 deg of tibiofemoral rotation, 1% of anterior cruciate ligament (ACL) and medial collateral ligament (MCL) strains, 17 N of ACL load, and 1 mm of tibiofemoral center of pressure. Similarly, the FE model was able to accurately predict tibiofemoral kinematics and ACL and MCL strains during simulated bipedal landings (dynamic loading). In addition to minimal deviation from direct cadaveric measurements, all model predictions fell within 95% confidence intervals of the average experimental data. Agreement between model predictions and experimental data demonstrates the ability of the developed model to predict the kinematics of the human knee joint as well as the complex, nonuniform stress and strain fields that occur in biological soft tissue. Such a model will facilitate the in-depth understanding of a multitude of potential knee injury mechanisms with special emphasis on ACL injury. PMID- 24763548 TI - Impact of age on 30-day postoperative outcome of surgery for ruptured and unruptured intracranial aneurysms. AB - OBJECTIVE: To assess in a retrospective analysis of a prospectively collected database, the impact of increased age on 30-day postoperative outcomes of surgery for intracranial aneurysms (ICAs). METHODS: 721 adult patients who underwent surgery for ICA were identified in the 2006-2012 American College of Surgeons' National Surgical Quality Improvement Program. Baseline characteristics and 30 day outcomes were stratified by age: <50 years (n=221), 50-60 years (n=221), and >60 years (n=266). Patients <50 and 50-60 years old were propensity score-matched to those aged >60 years. Logistic regression was used to examine the relationship between increased age and surgical outcome. RESULTS: In unadjusted analyses, age <50 years was associated with fewer postoperative complications (OR=0.5, 95% CI 0.3 to 0.7) and lower mortality (OR=0.4, 95% CI 0.2 to 0.9) compared with those aged >60 years. Patients aged between 50 and 60 years were less likely to have complications (OR=0.6, 95% CI 0.4 to 0.8) in unadjusted analyses. Upon propensity score matching, covariate balance was achieved for all age strata. In adjusted analyses, patients <50 years (OR=0.4, 95% CI 0.2 to 0.7) and 50-60 years (OR=0.5, 95% CI 0.3 to 0.8) of age continued to have fewer complications than those aged >60. CONCLUSIONS: Age >60 is independently associated with 30-day postoperative morbidity in patients undergoing surgery for ICA. The results of this study suggest age >60 should be considered an a priori risk factor in surgical management of ICA, regardless of associated comorbidities often associated with increased age. PMID- 24763549 TI - Rare presentation of intracranial vascular blowout after tumor resection and radiation therapy. AB - A middle-aged patient presented with a rapidly growing right dural-based extra axial posterior clinoid mass extending to the right cavernous sinus that was surgically resected. Histological examination showed solid growth of primitive neuroectodermal tumor arising from the third nerve. Following surgical resection, the patient was further managed by radiation and chemotherapy. Two years later the patient developed new intracranial hemorrhage in the area adjacent to the previous surgical cavity. A cerebral angiogram showed contrast extravasation at the junction of the posterior communicating artery (Pcom) and the right posterior cerebral artery (PCA), with an expanding pseudoaneurysm. This was managed with N butyl cyanoacrylate embolization. Autopsy showed microscopic recurrence of tumor into the PCA/PCom region with invasion of the wall of the Pcom. This case report illustrates the concept of vascular blowout in intracranial cerebral vasculature. It appears that, in the presence of risk factors that contribute to weakening of vessel walls (surgery, radiation, tumor recurrence), a blowout can occur intracranially. PMID- 24763550 TI - Physician and Patient and Caregiver Health Attitudes and Their Effect on Medicare Resource Allocation for Patients With Advanced Cancer. AB - IMPORTANCE: Physicians must participate in end-of-life discussions, but they understand poorly their patients' end-of-life values and preferences. A better understanding of these preferences and the effect of baseline attitudes will improve end-of-life discussions. OBJECTIVE: To determine how baseline attitudes toward quality vs quantity of life affect end-of-life resource allocation. DESIGN, SETTING, AND PARTICIPANTS: Otolaryngology-head and neck surgery (OHNS) physicians were recruited to use a validated online tool to create a Medicare health plan for advanced cancer patients. During the exercise, participants allocated a limited pool of resources among 15 benefit categories. These data were compared with preliminary data from patients with cancer and their caregivers obtained from a separate study using the same tool. Attitudes toward quality vs quantity of life were assessed for both physicians and patients and caregivers. INTERVENTIONS: Participation in online assessment exercise. MAIN OUTCOMES AND MEASURES: Medicare resource allocation. RESULTS: Of 9120 OHNS physicians e-mailed, 767 participated. Data collected from this group were compared with data collected from 146 patients and 114 caregivers. Compared with patients and caregivers, OHNS physician allocations differed significantly in all 15 benefit categories except home care. When stratified by answers to 3 questions about baseline attitudes toward quality vs quantity of life, there were 3 categories in which allocations of patients and caregivers differed significantly from the group with the opposite attitude for at least 2 questions: other medical care (question 1, P < .001; question 2, P = .005), palliative care (question 1, P = .008; question 2, P = .006; question 3, P = .009), and treatment for cancer (questions 1 and 2, P < .001). In contrast, physician preferences showed significant differences in only 1, nonmatching category for each attitude question: cash (question 1, P = .02), drugs (question 2, P = .03), and home care (question 3, P = .048). CONCLUSIONS AND RELEVANCE: Patients with cancer and their caregivers have different preferences from physicians. These preferences are, for these patients and their caregivers, affected by their baseline health attitudes, but physician preferences are not. Understanding the effect of baseline attitudes is important for effective end-of-life discussions. PMID- 24763551 TI - Expression of heat shock proteins 27 and 72 correlates with specific commensal microbes in different regions of porcine gastrointestinal tract. AB - The gastrointestinal (GI) tract of mammals is inhabited by trillions of microorganisms, resulting in exceedingly complex networking. The interaction between distinct bacterial species and the host immune system is essential in maintaining homeostasis in the gut ecosystem. For instance, the gut commensal microbiota dictates intestinal mucosa maturation and its abundant immune components, such as cytoprotective heat shock proteins (HSP). Here we examined physiological expression of HSP in the normal porcine GI tract and found it to be gut region- and cell type-specific in response to dietary components, microbes, and microbial metabolites to which the mucosa surface is exposed. Correlations between HSP72 expression and ileal Lactobacillus spp. and colonic clostridia species, and between HSP27 expression and uronic acid ingestion, were important interplays identified here. Thus this study provides novel insights into host microbe interactions shaping the immune system that are modifiable by dietary regime. PMID- 24763552 TI - RNA sequencing shows transcriptomic changes in rectosigmoid mucosa in patients with irritable bowel syndrome-diarrhea: a pilot case-control study. AB - Our aim was to conduct a pilot case-control study of RNA expression profile using RNA sequencing of rectosigmoid mucosa of nine females with -diarrhea-predominant irritable bowel syndrome (IBS-D) with accelerated colonic transit and nine female healthy controls. Mucosal total RNA was isolated and purified, and next generation pair-end sequencing was performed using Illumina TruSeq. Analysis was carried out using a targeted approach toward 12 genes previously associated with IBS and a hypothesis-generating approach. Of the 12 targeted genes tested, patients with IBS-D had decreased mRNA expression of TNFSF15 (fold change controls to IBS-D: 1.53, P = 0.01). Overall, up- and downregulated mRNA expressions of 21 genes (P = 10(-5) to 10(-8); P values with false detection rates are shown) were potentially relevant to IBS-D including the following: neurotransmitters [P2RY4 (P = 0.001), vasoactive intestinal peptide (VIP, P = 0.02)]; cytokines [CCL20 (P = 0.019)]; immune function [C4BPA complement cascade (P = 0.0187)]; interferon-related [IFIT3 (P = 0.016)]; mucosal repair and cell adhesion [trefoil protein (TFF1, P = 0.012)], retinol binding protein [RBP2 (P = 0.017)]; fibronectin (FN1, P = 0.009); and ion channel functions [guanylate cyclase (GUCA2B, P = 0.017), PDZ domain-containing protein 3 (PDZD3, P = 0.029)]. Ten genes associated with functions related to pathobiology of IBS-D were validated by RT-PCR. There was significant correlation in fold changes of the selected genes (Rs = 0.73, P = 0.013). Up- or downregulation of P2RY4, GUC2AB, RBP2, FNI, and C4BPA genes were confirmed on RT-PCR, which also revealed upregulation of farnesoid X receptor (FXR) and apical sodium-coupled bile acid transporter (IBAT/ASBT). RNA-Seq and RT-PCR analysis of rectosigmoid mucosa in IBS-D show transcriptome changes that provide the rationale for validation studies to explore the role of mucosal factors in the pathobiology of IBS-D. PMID- 24763553 TI - CD55 limits sensitivity to complement-dependent cytolysis triggered by heterologous expression of alpha-gal xenoantigen in colon tumor cells. AB - Engineering cancer cells to express heterologous antigen alpha-gal and induce the destruction of tumor cells depending on the complement cascade may be a promising strategy of tumor therapy. However, the feasibility and effect of using alpha-gal to induce colorectal adenocarcinoma cell line cytolysis is not yet known. In this study, we evaluated alpha-gal expression's ability to sensitize human colorectal adenocarcinoma cell lines to complement attack in cell lines LoVo, SW620, and Ls 174T. Nearly all alpha-gal-expressing LoVo and SW620 cells were killed by normal human serum (NHS), but alpha-gal-expressing Ls-174T cells showed no significant lysis. We analyzed the expression levels of membrane-bound complement regulatory proteins (mCRPs) on the three cell lines, and their protective role in alpha-gal mediated activation of the complement. LoVo showed no expression of any of the three proteins. CD59 was strongly expressed by SW620 and Ls-174T. CD46 and CD55 varied between the two cell lines. CD46 on SW620 was only half the intensity of CD46 on Ls-174T. Ls-174T showed a notable expression of CD55, while expression of CD55 on SW620 was not detected. The sensitivity of Ls-174T expressing alpha-gal to NHS greatly increased following the downregulation of CD46 and CD55 with short hairpin RNA (shRNA). However, there is no increase in cell killing when CD59 expression was diminished. Our findings suggest that the use of alpha-gal as antigen to induce tumor cell killing may be a potential therapeutic strategy in colon cancer and that CD55 plays a primary role in conferring resistance to lysis. PMID- 24763554 TI - Metabolic profiling reveals that PNPLA3 induces widespread effects on metabolism beyond triacylglycerol remodeling in Huh-7 hepatoma cells. AB - PNPLA3 was recently associated with the susceptibility to nonalcoholic fatty liver disease, a common cause of chronic liver disease characterized by abnormal triglyceride accumulation. Although it is established that PNPLA3 has both triacylglycerol lipase and acylglycerol O-acyltransferase activities, is still unknown whether the gene has any additional role in the modulation of the human liver metabolome. To uncover the functional role of PNPLA3 on liver metabolism, we performed high-throughput metabolic profiling of PNPLA3 siRNA-silencing and overexpression of wild-type and mutant Ile148Met variants (isoleucine/methionine substitution at codon 148) in Huh-7 cells. Metabolomic analysis was performed by using GC/MS and LC/MS platforms. Silencing of PNPLA3 was associated with a global perturbation of Huh-7 hepatoma cells that resembled a catabolic response associated with protein breakdown. A significant decrease in amino- and gamma glutamyl-amino acids and dipeptides and a significant increase in cysteine sulfinic acid, myo-inositol, lysolipids, sphingolipids, and polyunsaturated fatty acids were observed. Overexpression of the PNPLA3 Met148 variant mirrored many of the metabolic changes observed during gene silencing, but in the opposite direction. These findings were replicated by the exploration of canonical pathways associated with PNPLA3 silencing and Met148 overexpression. Overexpression of the PNPLA3 Met148 variant was associated with a 1.75-fold increase in lactic acid, suggesting a shift to anaerobic metabolism and mitochondrial dysfunction. Together, these results suggest a critical role of PNPLA3 in the modulation of liver metabolism beyond its classical participation in triacylglycerol remodeling. PMID- 24763556 TI - Dietary flaxseed intake exacerbates acute colonic mucosal injury and inflammation induced by dextran sodium sulfate. AB - Flaxseed (FS), a dietary oilseed, contains a variety of anti-inflammatory bioactives, including fermentable fiber, phenolic compounds (lignans), and the n 3 polyunsaturated fatty acid (PUFA) alpha-linolenic acid. The objective of this study was to determine the effects of FS and its n-3 PUFA-rich kernel or lignan- and soluble fiber-rich hull on colitis severity in a mouse model of acute colonic inflammation. C57BL/6 male mice were fed a basal diet (negative control) or a basal diet supplemented with 10% FS, 6% kernel, or 4% hull for 3 wk prior to and during colitis induction via 5 days of 2% (wt/vol) dextran sodium sulfate (DSS) in their drinking water (n = 12/group). An increase in anti-inflammatory metabolites (hepatic n-3 PUFAs, serum mammalian lignans, and cecal short-chain fatty acids) was associated with consumption of all FS-based diets, but not with anti-inflammatory effects in DSS-exposed mice. Dietary FS exacerbated DSS-induced acute colitis, as indicated by a heightened disease activity index and an increase in colonic injury and inflammatory biomarkers [histological damage, apoptosis, myeloperoxidase, inflammatory cytokines (IL-6 and IL-1beta), and NF kappaB signaling-related genes (Nfkb1, Ccl5, Bcl2a1a, Egfr, Relb, Birc3, and Atf1)]. Additionally, the adverse effect of the FS diet was extended systemically, as serum cytokines (IL-6, IFNgamma, and IL-1beta) and hepatic cholesterol levels were increased. The adverse effects of FS were not associated with alterations in fecal microbial load or systemic bacterial translocation (endotoxemia). Collectively, this study demonstrates that although consumption of a 10% FS diet enhanced the levels of n-3 PUFAs, short-chain polyunsaturated fatty acids, and lignans in mice, it exacerbated DSS-induced colonic injury and inflammation. PMID- 24763557 TI - Addressing vaccine hesitancy. PMID- 24763562 TI - Climate science. Climate outsider finds missing global warming. PMID- 24763555 TI - Animal models of gastrointestinal and liver diseases. Animal models of necrotizing enterocolitis: pathophysiology, translational relevance, and challenges. AB - Necrotizing enterocolitis is the leading cause of morbidity and mortality from gastrointestinal disease in premature infants and is characterized by initial feeding intolerance and abdominal distention followed by the rapid progression to coagulation necrosis of the intestine and death in many cases. Although the risk factors for NEC development remain well accepted, namely premature birth and formula feeding, the underlying mechanisms remain incompletely understood. Current thinking indicates that NEC develops in response to an abnormal interaction between the mucosal immune system of the premature host and an abnormal indigenous microflora, leading to an exaggerated mucosal inflammatory response and impaired mesenteric perfusion. In seeking to understand the molecular and cellular events leading to NEC, various animal models have been developed. However, the large number and variability between the available animal models and the unique characteristics of each has raised important questions regarding the validity of particular models for NEC research. In an attempt to provide some guidance to the growing community of NEC researchers, we now seek to review the key features of the major NEC models that have been developed in mammalian and nonmammalian species and to assess the advantages, disadvantage, challenges and major scientific discoveries yielded by each. A strategy for model validation is proposed, the principal models are compared, and future directions and challenges within the field of NEC research are explored. PMID- 24763563 TI - Genomics. Genome yields clues to tsetse fly's strange and deadly ways. PMID- 24763564 TI - Biomedical funding. At NIH, two strikes policy is out. PMID- 24763566 TI - Tanks for the batteries. PMID- 24763565 TI - Neurodegeneration. Potential Alzheimer's drug spurs protein recycling. PMID- 24763567 TI - After the deluge. PMID- 24763568 TI - The cyclone addict. PMID- 24763569 TI - Protecting lemurs: Madagascar's forests. PMID- 24763570 TI - Protecting lemurs: ecotourism. PMID- 24763571 TI - Protecting lemurs--response. PMID- 24763572 TI - Comment on "A complete skull from Dmanisi, Georgia, and the evolutionary biology of early Homo". AB - Lordkipanidze et al. (Research Article, 18 October 2013, p. 326) conclude, from gross morphological comparisons and geometric-morphometric analysis of general shape, that the five hominid crania from Dmanisi in Georgia represent a single regional variant of Homo erectus. However, dental, mandibular, and cranial morphologies all suggest taxic diversity and, in particular, validate the previously named H. georgicus. PMID- 24763573 TI - Response to comment on "A complete skull from Dmanisi, Georgia, and the evolutionary biology of early Homo". AB - Schwartz et al. hold that variation among the Dmanisi skulls reflects taxic diversity. The morphological observations to support their hypothesis, however, are partly incorrect, and not calibrated against intraspecific variation in living taxa. After proper adjustment, Schwartz et al.'s data are fully compatible with the hypothesis of a single paleodeme of early Homo at Dmanisi. PMID- 24763575 TI - Land use. Cracking Brazil's Forest Code. PMID- 24763576 TI - Planetary science. Analyzing Moon rocks. PMID- 24763577 TI - Genetics. Being selective in the Prochlorococcus collective. PMID- 24763578 TI - Chemistry. A two-catalyst photochemistry route to homochiral rings. PMID- 24763579 TI - Biophysics. Silencing neurons with light. PMID- 24763580 TI - Structural biology. The 30-nm fiber redux. PMID- 24763581 TI - Neuroscience. Mapping neural activation onto behavior in an entire animal. PMID- 24763582 TI - Geochemistry. Carbon storage in basalt. PMID- 24763583 TI - Cryo-EM study of the chromatin fiber reveals a double helix twisted by tetranucleosomal units. AB - The hierarchical packaging of eukaryotic chromatin plays a central role in transcriptional regulation and other DNA-related biological processes. Here, we report the 11-angstrom-resolution cryogenic electron microscopy (cryo-EM) structures of 30-nanometer chromatin fibers reconstituted in the presence of linker histone H1 and with different nucleosome repeat lengths. The structures show a histone H1-dependent left-handed twist of the repeating tetranucleosomal structural units, within which the four nucleosomes zigzag back and forth with a straight linker DNA. The asymmetric binding and the location of histone H1 in chromatin play a role in the formation of the 30-nanometer fiber. Our results provide mechanistic insights into how nucleosomes compact into higher-order chromatin fibers. PMID- 24763585 TI - A dual-catalysis approach to enantioselective [2 + 2] photocycloadditions using visible light. AB - In contrast to the wealth of catalytic systems that are available to control the stereochemistry of thermally promoted cycloadditions, few similarly effective methods exist for the stereocontrol of photochemical cycloadditions. A major unsolved challenge in the design of enantioselective catalytic photocycloaddition reactions has been the difficulty of controlling racemic background reactions that occur by direct photoexcitation of substrates while unbound to catalyst. Here, we describe a strategy for eliminating the racemic background reaction in asymmetric [2 + 2] photocycloadditions of alpha,beta-unsaturated ketones to the corresponding cyclobutanes by using a dual-catalyst system consisting of a visible light-absorbing transition-metal photocatalyst and a stereocontrolling Lewis acid cocatalyst. The independence of these two catalysts enables broader scope, greater stereochemical flexibility, and better efficiency than previously reported methods for enantioselective photochemical cycloadditions. PMID- 24763586 TI - Detection of the gravitational lens magnifying a type Ia supernova. AB - Objects of known brightness, like type Ia supernovae (SNIa), can be used to measure distances. If a massive object warps spacetime to form multiple images of a background SNIa, a direct test of cosmic expansion is also possible. However, these lensing events must first be distinguished from other rare phenomena. Recently, a supernova was found to shine much brighter than normal for its distance, which resulted in a debate: Was it a new type of superluminous supernova or a normal SNIa magnified by a hidden gravitational lens? Here, we report that a spectrum obtained after the supernova faded away shows the presence of a foreground galaxy-the first found to strongly magnify a SNIa. We discuss how more lensed SNIa can be found than previously predicted. PMID- 24763587 TI - Preservation of a preglacial landscape under the center of the Greenland Ice Sheet. AB - Continental ice sheets typically sculpt landscapes via erosion; under certain conditions, ancient landscapes can be preserved beneath ice and can survive extensive and repeated glaciation. We used concentrations of atmospherically produced cosmogenic beryllium-10, carbon, and nitrogen to show that ancient soil has been preserved in basal ice for millions of years at the center of the ice sheet at Summit, Greenland. This finding suggests ice sheet stability through the Pleistocene (i.e., the past 2.7 million years). The preservation of this soil implies that the ice has been nonerosive and frozen to the bed for much of that time, that there was no substantial exposure of central Greenland once the ice sheet became fully established, and that preglacial landscapes can remain preserved for long periods under continental ice sheets. PMID- 24763588 TI - Organic matter stoichiometry, flux, and oxygen control nitrogen loss in the ocean. AB - Biologically available nitrogen limits photosynthesis in much of the world ocean. Organic matter (OM) stoichiometry had been thought to control the balance between the two major nitrogen removal pathways-denitrification and anammox-but the expected proportion of 30% anammox derived from mean oceanic OM is rarely observed in the environment. With incubations designed to directly test the effects of stoichiometry, however, we showed that the ratio of anammox to denitrification depends on the stoichiometry of OM supply, as predicted. Furthermore, observed rates of nitrogen loss increase with the magnitude of OM supply. The variable ratios between denitrification and anammox previously observed in the ocean are thus attributable to localized variations in OM quality and quantity and do not necessitate a revision to the global nitrogen cycle. PMID- 24763584 TI - Genome sequence of the tsetse fly (Glossina morsitans): vector of African trypanosomiasis. AB - Tsetse flies are the sole vectors of human African trypanosomiasis throughout sub Saharan Africa. Both sexes of adult tsetse feed exclusively on blood and contribute to disease transmission. Notable differences between tsetse and other disease vectors include obligate microbial symbioses, viviparous reproduction, and lactation. Here, we describe the sequence and annotation of the 366-megabase Glossina morsitans morsitans genome. Analysis of the genome and the 12,308 predicted protein-encoding genes led to multiple discoveries, including chromosomal integrations of bacterial (Wolbachia) genome sequences, a family of lactation-specific proteins, reduced complement of host pathogen recognition proteins, and reduced olfaction/chemosensory associated genes. These genome data provide a foundation for research into trypanosomiasis prevention and yield important insights with broad implications for multiple aspects of tsetse biology. PMID- 24763589 TI - High-resolution genomic analysis of human mitochondrial RNA sequence variation. AB - Mutations in the mitochondrial genome are associated with multiple diseases and biological processes; however, little is known about the extent of sequence variation in the mitochondrial transcriptome. By ultra-deeply sequencing mitochondrial RNA (>6000*) from the whole blood of ~1000 individuals from the CARTaGENE project, we identified remarkable levels of sequence variation within and across individuals, as well as sites that show consistent patterns of posttranscriptional modification. Using a genome-wide association study, we find that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 that explains ~22% of the variance. These results reveal a major nuclear genetic determinant of posttranscriptional modification in mitochondria and suggest that tRNA posttranscriptional modification may affect cellular energy production. PMID- 24763592 TI - Neural mechanisms of object-based attention. AB - How we attend to objects and their features that cannot be separated by location is not understood. We presented two temporally and spatially overlapping streams of objects, faces versus houses, and used magnetoencephalography and functional magnetic resonance imaging to separate neuronal responses to attended and unattended objects. Attention to faces versus houses enhanced the sensory responses in the fusiform face area (FFA) and parahippocampal place area (PPA), respectively. The increases in sensory responses were accompanied by induced gamma synchrony between the inferior frontal junction, IFJ, and either FFA or PPA, depending on which object was attended. The IFJ appeared to be the driver of the synchrony, as gamma phases were advanced by 20 ms in IFJ compared to FFA or PPA. Thus, the IFJ may direct the flow of visual processing during object-based attention, at least in part through coupled oscillations with specialized areas such as FFA and PPA. PMID- 24763591 TI - Structure-guided transformation of channelrhodopsin into a light-activated chloride channel. AB - Using light to silence electrical activity in targeted cells is a major goal of optogenetics. Available optogenetic proteins that directly move ions to achieve silencing are inefficient, pumping only a single ion per photon across the cell membrane rather than allowing many ions per photon to flow through a channel pore. Building on high-resolution crystal-structure analysis, pore vestibule modeling, and structure-guided protein engineering, we designed and characterized a class of channelrhodopsins (originally cation-conducting) converted into chloride-conducting anion channels. These tools enable fast optical inhibition of action potentials and can be engineered to display step-function kinetics for stable inhibition, outlasting light pulses and for orders-of-magnitude-greater light sensitivity of inhibited cells. The resulting family of proteins defines an approach to more physiological, efficient, and sensitive optogenetic inhibition. PMID- 24763593 TI - A chloroplast retrograde signal regulates nuclear alternative splicing. AB - Light is a source of energy and also a regulator of plant physiological adaptations. We show here that light/dark conditions affect alternative splicing of a subset of Arabidopsis genes preferentially encoding proteins involved in RNA processing. The effect requires functional chloroplasts and is also observed in roots when the communication with the photosynthetic tissues is not interrupted, suggesting that a signaling molecule travels through the plant. Using photosynthetic electron transfer inhibitors with different mechanisms of action, we deduce that the reduced pool of plastoquinones initiates a chloroplast retrograde signaling that regulates nuclear alternative splicing and is necessary for proper plant responses to varying light conditions. PMID- 24763595 TI - Trichology: diseases of the pilosebaceus follicles. PMID- 24763596 TI - The ethical dispensing of nonprescription skin care medications is useful as we approach the new millennium. PMID- 24763594 TI - Concerted spatio-temporal dynamics of imported DNA and ComE DNA uptake protein during gonococcal transformation. AB - Competence for transformation is widespread among bacterial species. In the case of Gram-negative systems, a key step to transformation is the import of DNA across the outer membrane. Although multiple factors are known to affect DNA transport, little is known about the dynamics of DNA import. Here, we characterized the spatio-temporal dynamics of DNA import into the periplasm of Neisseria gonorrhoeae. DNA was imported into the periplasm at random locations around the cell contour. Subsequently, it was recruited at the septum of diplococci at a time scale that increased with DNA length. We found using fluorescent DNA that the periplasm was saturable within minutes with ~40 kbp DNA. The DNA-binding protein ComE quantitatively governed the carrying capacity of the periplasm in a gene-dosage-dependent fashion. As seen using a fluorescent-tagged derivative protein, ComE was homogeneously distributed in the periplasm in the absence of external DNA. Upon addition of external DNA, ComE was relocalized to form discrete foci colocalized with imported DNA. We conclude that the periplasm can act as a considerable reservoir for imported DNA with ComE governing the amount of DNA stored potentially for transport through the inner membrane. PMID- 24763598 TI - The cleveland clinic foundation dermatopathology self-assessment workshop. PMID- 24763597 TI - National registry for ichthyosis and related disorders. PMID- 24763590 TI - Single-cell genomics reveals hundreds of coexisting subpopulations in wild Prochlorococcus. AB - Extensive genomic diversity within coexisting members of a microbial species has been revealed through selected cultured isolates and metagenomic assemblies. Yet, the cell-by-cell genomic composition of wild uncultured populations of co occurring cells is largely unknown. In this work, we applied large-scale single cell genomics to study populations of the globally abundant marine cyanobacterium Prochlorococcus. We show that they are composed of hundreds of subpopulations with distinct "genomic backbones," each backbone consisting of a different set of core gene alleles linked to a small distinctive set of flexible genes. These subpopulations are estimated to have diverged at least a few million years ago, suggesting ancient, stable niche partitioning. Such a large set of coexisting subpopulations may be a general feature of free-living bacterial species with huge populations in highly mixed habitats. PMID- 24763599 TI - Palmar ulceration. PMID- 24763600 TI - An easy arylation of 2-substituted 1,2,3-triazoles. AB - A selective, efficient and catalytic ligand-free method for the direct arylation of 2-aryl-1,2,3-triazoles via Pd-catalyzed C-H bond activation is described. The process smoothly proceeds in moderate to excellent yields. PMID- 24763601 TI - Acetobacter sicerae sp. nov., isolated from cider and kefir, and identification of species of the genus Acetobacter by dnaK, groEL and rpoB sequence analysis. AB - Five acetic acid bacteria isolates, awK9_3, awK9_4 ( = LMG 27543), awK9_5 ( = LMG 28092), awK9_6 and awK9_9, obtained during a study of micro-organisms present in traditionally produced kefir, were grouped on the basis of their MALDI-TOF MS profile with LMG 1530 and LMG 1531(T), two strains currently classified as members of the genus Acetobacter. Phylogenetic analysis based on nearly complete 16S rRNA gene sequences as well as on concatenated partial sequences of the housekeeping genes dnaK, groEL and rpoB indicated that these isolates were representatives of a single novel species together with LMG 1530 and LMG 1531(T) in the genus Acetobacter, with Acetobacter aceti, Acetobacter nitrogenifigens, Acetobacter oeni and Acetobacter estunensis as nearest phylogenetic neighbours. Pairwise similarity of 16S rRNA gene sequences between LMG 1531(T) and the type strains of the above-mentioned species were 99.7%, 99.1%, 98.4% and 98.2%, respectively. DNA-DNA hybridizations confirmed that status, while amplified fragment length polymorphism (AFLP) and random amplified polymorphic DNA (RAPD) data indicated that LMG 1531(T), LMG 1530, LMG 27543 and LMG 28092 represent at least two different strains of the novel species. The major fatty acid of LMG 1531(T) and LMG 27543 was C18 : 1omega7c. The major ubiquinone present was Q-9 and the DNA G+C contents of LMG 1531(T) and LMG 27543 were 58.3 and 56.7 mol%, respectively. The strains were able to grow on D-fructose and D-sorbitol as a single carbon source. They were also able to grow on yeast extract with 30% D glucose and on standard medium with pH 3.6 or containing 1% NaCl. They had a weak ability to produce acid from d-arabinose. These features enabled their differentiation from their nearest phylogenetic neighbours. The name Acetobacter sicerae sp. nov. is proposed with LMG 1531(T) ( = NCIMB 8941(T)) as the type strain. PMID- 24763602 TI - Hanseniaspora nectarophila sp. nov., a yeast species isolated from ephemeral flowers. AB - Seven apiculate yeast strains that were isolated from the flowers of Syphocampylus corymbiferus Pohl in Brazil are genetically, morphologically and phenotypically distinct from recognized species of the genera Hanseniaspora and Kloeckera. Genetic discontinuities between the novel strains and their closest relatives were found using a networking approach based on the concatenated sequences of the rRNA gene (internal transcribed spacer and D1/D2 of the LSU), and the protein-coding genes for actin and translation elongation factor-1alpha. Phylogenetic analysis based on the rRNA and the actin gene placed the novel species represented by the strains in close relationship to Hanseniaspora meyeri and Hanseniaspora clermontiae. PCR fingerprinting with microsatellite primers confirmed the genetic heterogeneity of the novel species. The name Hanseniaspora nectarophila sp. nov. is proposed, with UFMG POG a.1(T) ( = ZIM 2311(T) = CBS 13383(T)) as the type strain; MycoBank no. MB807210. As the current description of the genus does not allow the presence of multilateral budding, an emended diagnosis of the genus Hanseniaspora Zikes is proposed. PMID- 24763603 TI - Pedobacter huanghensis sp. nov. and Pedobacter glacialis sp. nov., isolated from Arctic glacier foreland. AB - Two psychrotolerant, Gram-stain-negative, rod-shaped bacterial strains, designed M1-27(T) and 8-24(T), were subjected to polyphasic taxonomic studies. Strain M1 27(T) was isolated from the foreland of the Midtre Lovenbreen glacier, whereas strain 8-24(T) was isolated from the foreland of the Austre Lovenbreen glacier. Both were Arctic glacier forelands, near Ny-Alesund, Svalbard Archipelago, Norway. Strains M1-27(T) and 8-24(T) exhibited 16S rRNA gene sequence similarities of 91.0-96.0% and 92.3-96.7%, respectively, to type strains of recognized species of the genus Pedobacter. Phylogenetic analysis based on 16S rRNA gene sequences showed that the two strains were grouped with members of the genus Pedobacter, but represented distinct taxa. Both strains contained MK-7 as the predominant menaquinone. The DNA G+C contents of strains M1-27(T) and 8-24(T) were 43.8% and 39.4%, respectively. The phenotypic characteristics, biochemical properties and polygenetic analysis, clearly indicated that strains M1-27(T) ( = CCTCC AB 2012936(T) = LMG 28205(T)) and 8-24(T) ( = CCTCC AB 2012941(T) = NRRL B 59993(T)) represent two novel species of the genus Pedobacter, for which the names Pedobacter huanghensis sp. nov. and Pedobacter glacialis sp. nov., respectively, are proposed. PMID- 24763604 TI - Agaribacter marinus gen. nov., sp. nov., an agar-degrading bacterium from surface seawater. AB - A Gram-stain-negative, motile, mesophilic, aerobic, rod-shaped bacterium, strain 8-8(T), was isolated from surface seawater at Muroto, Kochi, Japan. The strain exhibited agar-degrading activity. Phylogenetic analyses based on 16S rRNA gene sequences showed that the strain fell within the family Alteromonadaceae and clustered distantly with members of the genus Glaciecola (<= 94.0% similarity). The DNA G+C content was 41.8 mol%. The major fatty acids were C16 : 1omega7c and/or iso-C15 : 0 2-OH, C16 : 0 and C18 : 1omega7c and the major hydroxy fatty acid was C12 : 0 3-OH. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and an unidentified polar lipid; lysophosphatidylethanolamine and unidentified polar lipids were found as minor components. The major quinone was Q-8. On the basis of phenotypic, genotypic and chemotaxonomic data, strain 8-8(T) represents a novel species of a new genus, for which the name Agaribacter marinus gen. nov., sp. nov. is proposed. The type strain of Agaribacter marinus is 8-8(T) ( = NBRC 110023(T) = LMG 28167(T)). PMID- 24763605 TI - New modular manganese(I) tricarbonyl complexes as PhotoCORMs: in vitro detection of photoinduced carbon monoxide release using COP-1 as a fluorogenic switch-on probe. AB - Five manganese(i) tricarbonyl complexes of the general formulae [Mn(bpea(N=CHC6H4R))(CO)3]PF6 and [Mn(bpea(NHCH2C6H4R))(CO)3]PF6 based on the tridentate bis(pyrazolyl)ethylamine (bpea) ligand, each containing a pendant 4 substituted phenyl group with R = H, I, and C=C-H, were synthesized and fully characterized, including X-ray structure analysis for three compounds. All complexes are stable in the dark in aqueous buffer for an extended period of time. However, CO-release could be triggered by illumination at 365 nm, establishing these compounds as novel photoactivatable CO-releasing molecules (PhotoCORMs). The influence of the imine vs. amine group in the ligands on the electronic structure and the photophysical behavior was investigated with the aid of DFT and TDDFT calculations. Solution IR studies on selected compounds allowed identification of intermediates resulting from the photoreaction. Finally, light induced CO release from a model compound was demonstrated both in PBS buffer and in vitro in human umbilical vein endothelial cells (HUVECs) using COP-1 as a fluorescent switch-on probe. PMID- 24763607 TI - Genotypic variation in partitioning of dry matter and manganese between source and sink organs of rice under manganese stress. AB - KEY MESSAGE: Genetic variability in dry matter and manganese partitioning between source and sink organs was the key mechanism for Mn efficient rice genotypes to cope with Mn stress. Considerable differences exist among cereal genotypes to cope manganese (Mn) deficiency, but the underlying mechanisms are poorly understood. Minimal information regarding partitioning and/or remobilization of dry matter and Mn between source and sink organs exists in rice genotypes differing in Mn efficiency. The present study was aimed to assess the growth dynamics in terms of dry matter and Mn remobilization in the whole plant (leaves and tillers as source and panicles and grains as sink) during the grain development in diverse rice genotypes. The efficient genotypes accumulated higher dry matter than inefficient genotypes under low Mn level. The translocation index i.e., uptake in grain/total uptake was 0.11 in efficient genotype (PR 116) and 0.04 in inefficient genotypes (PR 111). The efficient genotype had higher grain Mn utilization efficiency of 0.71 in comparison to 0.48 of inefficient genotype indicating that in efficient genotype, Mn in grain produces more dry matter than inefficient genotypes. The efficient genotypes also had higher flag leaf area and nitrate reductase activity. The source of efficient genotypes contributed to a greater extent to developing sink but further mobilization to grain was hindered by panicle. The panicle of inefficient genotypes had higher per cent of Mn uptake than efficient genotypes indicating that Mn was least mobilized from panicle to grain in inefficient genotypes. The lower per cent uptake of Mn in efficient genotypes indicated that Mn was mobilized from panicle to developing grain and this led to higher Mn translocation index in grain of efficient genotypes. The uptake partitioning revealed that source of all genotypes mobilized the Mn towards the sink to almost same extent but it was the panicle where highest per cent uptake per plant was in inefficient genotypes and lowest in efficient genotypes. The lowest per cent uptake in panicle of efficient genotypes revealed that it supported developing grain to have highest translocation index. PMID- 24763608 TI - GmSGT1 is differently required for soybean Rps genes-mediated and basal resistance to Phytophthora sojae. AB - KEY MESSAGE: Using RNAi approach, we demonstrate that GmSGT1 is an essential component in soybean against Phytophthora sojae, but not required for Rps 2 or Rps 3a-mediated resistance. Utilization of disease resistance in soybean is a major approach to combat root and stem rot disease, which is caused by Phytophthora sojae and poses a growing threat to soybean safety production. The SGT1 protein is essential for disease resistance in many plant species. Here, we analyzed and characterized functions of GmSGT1 gene family in R protein-mediated resistance and basal defense in this important crop. Five candidate genes of GmSGT1 were identified and they were grouped into three clades. Transcriptional levels of all the tested genes were highly induced upon P. sojae infection in four soybean cultivars that confer different resistant levels. Using a gene silencing system in soybean cotyledons, we demonstrated that silencing GmSGT1 genes comprised race-specific resistance in soybean lines carrying genes at the following loci for race-specific resistance to P. sojae: Rps1a, Rps1c, Rps1d, Rps1k, and Rps8. In contrast, the resistance mediated by Rps2 or Rps3a was not affected. Silencing GmSGT1 genes in cotyledons also reduced resistance to this pathogen in a moderately partial resistant cultivar. We further showed that transient overexpression of GmSGT1-1 in Nicotiana benthamiana could enhance the resistance to P. capsici. These results suggest that GmSGT1 is an essential component for soybean in resisting the pathogen and pathways of Rps-mediated disease resistance are diverse in soybean. PMID- 24763609 TI - [Expert testimony in post-traumatic stress disorder with pain as the main symptom]. AB - Post-traumatic stress disorder (PTSD) is one of the most relevant disorders of patients with chronic pain, but is often underdiagnosed. This also applies to expert testimony. Further complicating the assessment are the different definitions of PTSD in ICD-10 and DSM-IV; the new DSM-5 has added a further definition. The present review aims to provide guidance for making a valid diagnosis. This forms the basis for a differentiated expert testimony in the different fields of law (e.g., criminal law, statutory or private accident insurance or social security benefits), in which different requirements must be taken into consideration by the expert. The recognition of malingering is described at length, which plays a major role in PTSD expert testimony in all fields of law. PMID- 24763610 TI - Global patterns in ecological indicators of marine food webs: a modelling approach. AB - BACKGROUND: Ecological attributes estimated from food web models have the potential to be indicators of good environmental status given their capabilities to describe redundancy, food web changes, and sensitivity to fishing. They can be used as a baseline to show how they might be modified in the future with human impacts such as climate change, acidification, eutrophication, or overfishing. METHODOLOGY: In this study ecological network analysis indicators of 105 marine food web models were tested for variation with traits such as ecosystem type, latitude, ocean basin, depth, size, time period, and exploitation state, whilst also considering structural properties of the models such as number of linkages, number of living functional groups or total number of functional groups as covariate factors. PRINCIPAL FINDINGS: Eight indicators were robust to model construction: relative ascendency; relative overhead; redundancy; total systems throughput (TST); primary production/TST; consumption/TST; export/TST; and total biomass of the community. Large-scale differences were seen in the ecosystems of the Atlantic and Pacific Oceans, with the Western Atlantic being more complex with an increased ability to mitigate impacts, while the Eastern Atlantic showed lower internal complexity. In addition, the Eastern Pacific was less organised than the Eastern Atlantic although both of these systems had increased primary production as eastern boundary current systems. Differences by ecosystem type highlighted coral reefs as having the largest energy flow and total biomass per unit of surface, while lagoons, estuaries, and bays had lower transfer efficiencies and higher recycling. These differences prevailed over time, although some traits changed with fishing intensity. Keystone groups were mainly higher trophic level species with mostly top-down effects, while structural/dominant groups were mainly lower trophic level groups (benthic primary producers such as seagrass and macroalgae, and invertebrates). Keystone groups were prevalent in estuarine or small/shallow systems, and in systems with reduced fishing pressure. Changes to the abundance of key functional groups might have significant implications for the functioning of ecosystems and should be avoided through management. CONCLUSION/SIGNIFICANCE: Our results provide additional understanding of patterns of structural and functional indicators in different ecosystems. Ecosystem traits such as type, size, depth, and location need to be accounted for when setting reference levels as these affect absolute values of ecological indicators. Therefore, establishing absolute reference values for ecosystem indicators may not be suitable to the ecosystem-based, precautionary approach. Reference levels for ecosystem indicators should be developed for individual ecosystems or ecosystems with the same typologies (similar location, ecosystem type, etc.) and not benchmarked against all other ecosystems. PMID- 24763611 TI - Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. AB - PURPOSE: Regorafenib, a multikinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer. However, the mechanisms of action of regorafenib in colorectal cancer cells have been unclear. We investigated how regorafenib suppresses colorectal cancer cell growth and potentiates effects of other chemotherapeutic drugs. EXPERIMENTAL DESIGN: We determined whether and how regorafenib induces the expression of PUMA, a p53 target and a critical mediator of apoptosis in colorectal cancer cells. We also investigated whether PUMA is necessary for the killing and chemosensitization effects of regorafenib in colorectal cancer cells. Furthermore, xenograft tumors were used to test if PUMA mediates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib. RESULTS: We found that regorafenib treatment induces PUMA in colorectal cancer cells irrespective of p53 status through the NF-kappaB pathway following ERK inhibition and glycogen synthase kinase 3beta activation. Upregulation of PUMA is correlated with apoptosis induction in different colorectal cancer cell lines. PUMA is necessary for regorafenib-induced apoptosis in colorectal cancer cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib. CONCLUSIONS: Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in colorectal cancer cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs. PMID- 24763612 TI - Genome-wide study of hypomethylated and induced genes in patients with liver cancer unravels novel anticancer targets. AB - PURPOSE: We utilized whole-genome mapping of promoters that are activated by DNA hypomethylation in hepatocellular carcinoma (HCC) clinical samples to shortlist novel targets for anticancer therapeutics. We provide a proof of principle of this approach by testing six genes short-listed in our screen for their essential role in cancer growth and invasiveness. EXPERIMENTAL DESIGN: We used siRNA- or shRNA-mediated depletion to determine whether inhibition of these genes would reduce human tumor xenograft growth in mice as well as cell viability, anchorage independent growth, invasive capacities, and state of activity of nodal signaling pathways in liver, breast, and bladder cancer cell lines. RESULTS: Depletion of EXOSC4, RNMT, SENP6, WBSCR22, RASAL2, and NENF effectively and specifically inhibits cancer cell growth and cell invasive capacities in different types of cancer, but, remarkably, there is no effect on normal cell growth, suggesting a ubiquitous causal role for these genes in driving cancer growth and metastasis. Depletion of RASAL2 and NENF in vitro reduces their growth as explants in vivo in mice. RASAL2 and NENF depletion interferes with AKT, WNT, and MAPK signaling pathways as well as regulation of epigenetic proteins that were previously demonstrated to drive cancer growth and metastasis. CONCLUSION: Our results prove that genes that are hypomethylated and induced in tumors are candidate targets for anticancer therapeutics in multiple cancer cell types. Because these genes are particularly activated in cancer, they constitute a group of targets for specific pharmacologic inhibitors of cancer and cancer metastasis. Clin Cancer Res; 20(12); 3118-32. (c)2014 AACR. PMID- 24763613 TI - Combined PET/MRI improves diagnostic accuracy in patients with prostate cancer: a prospective diagnostic trial. AB - PURPOSE: The pretherapeutic assessment of prostate cancer is challenging and still holds the risk of over- or undertreatment. This prospective trial investigates positron emission tomography (PET) with [(18)F]fluoroethylcholine (FEC) combined with endorectal magnetic resonance imaging (MRI) for the assessment of primary prostate cancer. EXPERIMENTAL DESIGN: Patients with prostate cancer based on needle biopsy findings, scheduled for radical prostatectomy, were assessed by FEC-PET and MRI in identical positioning. After prostatectomy, imaging results were compared with histologic whole-mount sections, and the PET/MRI lesion-based semiquantitative FEC uptake was compared with biopsy Gleason scores and postoperative histology. RESULTS: PET/MRI showed a patient-based sensitivity of 95% (36/38; 95% confidence interval (CI), 82%-99%). The analysis of 128 prostate lesions demonstrated a sensitivity/specificity/positive predictive value/negative predictive value/accuracy of 67%/35%/59%/44%/54% (P = 0.8295) for MRI and 85%/45%/68%/69%/68% (P = 0.0021) for PET, which increased to 84%/80%/85%/78%/82% (P < 0.0001) by combined FEC-PET/MRI in lesions >5 mm (n = 98). For lesions in patients with Gleason >6 tumors (n = 43), MRI and PET achieved 73%/31%/71%/33%/60% (P = 1.0000) and 90%/62%/84%/73%/81% (P = 0.0010), which were improved to 87%/92%/96%/75%/88% (P < 0.0001) by combined PET/MRI. Applying semiquantitative PET analysis, carcinomas with Gleason scores >6 were distinguished from those with Gleason <= 6 with a specificity of 90% and a positive predictive value of 83% (P = 0.0011; needle biopsy 71%/60%, P = 0.1071). CONCLUSIONS: In a prospective diagnostic trial setting, combined FEC-PET/MRI achieved very high sensitivity in the detection of the dominant malignant lesion of the prostate, and markedly improved upon PET or MRI alone. Noninvasive Gleason score assessment was more precise than needle biopsy in this patient cohort. Hence, FEC-PET/MRI merits further investigation in trials of randomized, multiarm design. PMID- 24763614 TI - Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. AB - PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive collagen-rich stroma. T cells that infiltrate pancreatic cancers frequently become trapped in the stroma and do not contact tumor cells. Here, we aimed to analyze how chemokines and extracellular matrix (ECM) collagen interact in mediating T-cell infiltration in PDAC. EXPERIMENTAL DESIGN: T-cell distribution and ECM structure within tumors were analyzed. Chemokine concentrations in human PDAC were compared with the levels of immune cell infiltration. We assessed the influences of selected chemokines and collagen on directed and random T-cell movement using in vitro migration systems. RESULTS: PDAC overproduced several T cell-active chemokines, but their levels were not correlated with intratumoral T cell infiltration. In the absence of collagen, directed migration of activated T cells was induced by chemokines. Interestingly, collagen itself promoted high migratory activity of T cells, but completely abolished chemokine-guided movement. This effect was not altered by a beta1-integrin blocking antibody. Activated T cells actively migrated in low-density collagen matrices, but migration was inhibited in dense collagen. Accordingly, T cells were heterogeneously distributed in the pancreatic cancer stroma, with the majority residing in areas of low-density collagen far from tumor clusters. CONCLUSION: The excessive desmoplasia in PDAC promotes T-cell migration by contact guidance, which abrogates tumor cell-directed movement. Furthermore, dense collagen networks represent a physical barrier, additionally rearranging T-cell distribution to favor tumor stroma. These mechanisms are mainly responsible for intrastromal T-cell trapping in pancreatic cancer and may hinder the development of T-cell-based immunotherapies. PMID- 24763615 TI - Influence of hyperthermia on efficacy and uptake of carbon nanohorn-cisplatin conjugates. AB - Single-walled carbon nanohorns (SWNHs) have significant potential for use in photothermal therapies due to their capability to absorb near infrared light and deposit heat. Additionally, their extensive relative surface area and volume makes them ideal drug delivery vehicles. Novel multimodal treatments are envisioned in which laser excitation can be utilized in combination with chemotherapeutic-SWNH conjugates to thermally enhance the therapeutic efficacy of the transported drug. Although mild hyperthermia (41-43 degrees C) has been shown to increase cellular uptake of drugs such as cisplatin (CDDP) leading to thermal enhancement, studies on the effects of hyperthermia on cisplatin loaded nanoparticles are currently limited. After using a carbodiimide chemical reaction to attach CDDP to the exterior surface of SWNHs and nitric acid to incorporate CDDP in the interior volume, we determined the effects of mild hyperthermia on the efficacy of the CDDP-SWNH conjugates. Rat bladder transitional carcinoma cells were exposed to free CDDP or one of two CDDP-SWNH conjugates in vitro at 37 degrees C and 42 degrees C with the half maximal inhibitory concentration (IC50) for each treatment. The in vitro results demonstrate that unlike free CDDP, CDDP-SWNH conjugates do not exhibit thermal enhancement at 42 degrees C. An increase in viability of 16% and 7% was measured when cells were exposed at 42 deg compared to 37 deg for the surface attached and volume loaded CDDP-SWNH conjugates, respectively. Flow cytometry and confocal microscopy showed a decreased uptake of CDDP-SWNH conjugates at 42 degrees C compared to 37 degrees C, revealing the importance of nanoparticle uptake on the CDDP-SWNH conjugate's efficacy, particularly when hyperthermia is used as an adjuvant, and demonstrates the effect of particle size on uptake during mild hyperthermia. The uptake and drug release studies elucidated the difference in viability seen in the drug efficacy studies at different temperatures. We speculate that the disparity in thermal enhancement efficacy observed for free drug compared to the drug SWNH conjugates is due to their intrinsic size differences and, therefore, their mode of cellular uptake: diffusion or endocytosis. These experiments indicate the importance of tuning properties of nanoparticle-drug conjugates to maximize cellular uptake to ensure thermal enhancement in nanoparticle mediated photothermal-chemotherapy treatments. PMID- 24763616 TI - Pathological changes in pulmonary circulation in carbon tetrachloride (CCl4) induced cirrhotic mice. AB - RATIONALE: Lack of an experimental model of portopulmonary hypertension (POPH) has been a major obstacle in understanding of pathophysiological mechanisms underlying the disease. OBJECTIVE: We investigated the effects of CCl4-mediated cirrhosis on the pulmonary vasculature, as an initial step towards an improved understanding of POPH. METHODS AND RESULTS: Male C57BL/6 mice received intraperitoneal injection of either sterile olive oil or CCl4 3 times/week for 12 weeks. Cirrhosis and portal hypertension were confirmed by evidence of bridging fibrosis and nodule formation in CCl4-treated liver determined by trichrome/picrosirius red staining and an increase in spleen weight/body weight ratio, respectively. Staining for the oxidative stress marker, 4-hydroxynonenal (4-HNE), was strong in the liver but was absent in the lung, suggesting that CCl4 did not directly induce oxidative injury in the lung. Pulmonary acceleration time (PAT) and the ratio of PAT/pulmonary ejection time (PET) measured by echocardiography were significantly decreased in cirrhotic mice. Increase in right ventricle (RV) weight/body weight as well as in the weight ratio of RV/(left ventricle + septum) further demonstrated the presence of pathological changes in the pulmonary circulation in these mice. Histological examination revealed that lungs of cirrhotic mice have excessive accumulation of perivascular collagen and thickening of the media of the pulmonary artery. CONCLUSION: Collectively, our data demonstrate that chronic CCl4 treatment induces pathological changes in pulmonary circulation in cirrhotic mice. We propose that this murine cirrhotic model provides an exceptional tool for future studies of the molecular mechanisms mediating pulmonary vascular diseases associated with cirrhosis and for evaluation of novel therapeutic interventions. PMID- 24763618 TI - The structural analysis of MARK4 and the exploration of specific inhibitors for the MARK family: a computational approach to obstruct the role of MARK4 in prostate cancer progression. AB - Prostate cancer, the second most common form of cancer in adult males is generally treated using hormone therapy but the emergence of hormone refractory prostate cancer poses serious challenges to the existing therapeutic strategies. However, protein kinases are now currently identified as potent targets for treating cancer, and MARK4L, a Ser/Thr kinase in the Par-1 family, is one such kinase that is expressed primarily in the testis and is involved in the regulation of spermatid polarity during spermatogenesis. It is also associated with Wnt-induced prostate carcinogenesis, making it a promising target for the development of anti-cancer therapeutics as part of alternative therapies to counter prostate cancer. In the present work, we predicted the three dimensional structure for the kinase domain of MARK4 and analyzed its structural properties. The results illuminate the presence of the unusual DFG Asp-in/alphaC helix-out conformation along with the absence of an additional hydrophobic pocket adjacent to the ATP binding site in its inactive state. These structural features accentuate the need for new specific therapeutics against MARK4. Hence, a robust ligand-based pharmacophore model AARRR.9 was developed based on the three dimensional chemical features of 9-oxo-9H-acridin-10-yl derivatives which possess a high specificity towards MARK kinases. A pharmacophore based search identified six potent compounds with a better specificity and binding efficiency to MARK4 bearing stable interactions with key residues K88, A138, D199 and E106, thereby making them tough ATP competitors. The closure of the catalytic cleft observed in the ligand bound complexes and its independency to the movement of the T-loop makes them promising candidates in hampering the role of MARK4 in prostate cancer. PMID- 24763617 TI - Profile of the HIV epidemic in Cape Verde: molecular epidemiology and drug resistance mutations among HIV-1 and HIV-2 infected patients from distinct islands of the archipelago. AB - HIV-1 and HIV-2 have been detected in Cape Verde since 1987, but little is known regarding the genetic diversity of these viruses in this archipelago, located near the West African coast. In this study, we characterized the molecular epidemiology of HIV-1 and HIV-2 and described the occurrence of drug resistance mutations (DRM) among antiretroviral therapy naive (ARTn) patients and patients under treatment (ARTexp) from different Cape Verde islands. Blood samples, socio demographic and clinical-laboratory data were obtained from 221 HIV-positive individuals during 2010-2011. Phylogenetic and bootscan analyses of the pol region (1300 bp) were performed for viral subtyping. HIV-1 and HIV-2 DRM were evaluated for ARTn and ARTexp patients using the Stanford HIV Database and HIV GRADE e.V. Algorithm Homepage, respectively. Among the 221 patients (169 [76.5%] HIV-1, 43 [19.5%] HIV-2 and 9 [4.1%] HIV-1/HIV-2 co-infections), 67% were female. The median ages were 34 (IQR = 1-75) and 47 (IQR = 12-84) for HIV-1 and HIV-2, respectively. HIV-1 infections were due to subtypes G (36.6%), CRF02_AG (30.6%), F1 (9.7%), URFs (10.4%), B (5.2%), CRF05_DF (3.0%), C (2.2%), CRF06_cpx (0.7%), CRF25_cpx (0.7%) and CRF49_cpx (0.7%), whereas all HIV-2 infections belonged to group A. Transmitted DRM (TDRM) was observed in 3.4% (2/58) of ARTn HIV-1 infected patients (1.7% NRTI, 1.7% NNRTI), but not among those with HIV-2. Among ARTexp patients, DRM was observed in 47.8% (33/69) of HIV-1 (37.7% NRTI, 37.7% NNRTI, 7.4% PI, 33.3% for two classes) and 17.6% (3/17) of HIV-2-infections (17.6% NRTI, 11.8% PI, 11.8% both). This study indicates that Cape Verde has a complex and unique HIV-1 molecular epidemiological scenario dominated by HIV-1 subtypes G, CRF02_AG and F1 and HIV-2 subtype A. The occurrence of TDRM and the relatively high level of DRM among treated patients are of concern. Continuous monitoring of patients on ART, including genotyping, are public policies to be implemented. PMID- 24763619 TI - 7-5 by '05. PMID- 24763620 TI - Symmetrical hemorrhagic bullae in an immunocompromised host. PMID- 24763621 TI - Abnormal Fetal Cystic Left Neck Mass. PMID- 24763623 TI - Rounded cutting edge model for the prediction of bone sawing forces. AB - A new analytical model to predict bone sawing forces is presented. Development of the model was based on the concept of a single tooth sawing at a depth of cut less than the cutting edge radius. A variable friction model was incorporated as well as elastic Hertzian contact stress to determine a lower bound for the integration limits. A new high speed linear apparatus was developed to simulate cutting edge speeds encountered with sagittal and reciprocating bone saws. Orthogonal cutting experiments in bovine cortical bone were conducted for comparison to the model. A design of the experiment's approach was utilized with linear cutting speeds between 2600 and 6200 mm/s for depths of cut between 2.5 and 10 MUm. Resultant forces from the design of experiments were in the range of 8 to 11 N, with higher forces at greater depths of cut. Model predictions for resultant force magnitude were generally within one standard deviation of the measured force. However, the model consistently predicted a thrust to cutting force ratio that was greater than measured. Consequently, resultant force angles predicted by the model were generally 20 deg higher than calculated from experimental thrust and cutting force measurements. PMID- 24763624 TI - The biomechanical function of arterial elastin in solutes. AB - Elastin is essential to accommodate physiological deformation and provide elastic support for blood vessels. As a long-lived extracellular matrix protein, elastin can suffer from cumulative effects of exposure to chemical damage, which greatly compromises the mechanical function of elastin. The mechanical properties of elastin are closely related to its microstructure and the external chemical environments. The purpose of this study is to investigate the changes in the macroscopic elastic and viscoelastic properties of isolated porcine aortic elastin under the effects of nonenzymatic mediated in vitro elastin-lipid interactions and glycation. Sodium dodecyl sulfate (SDS) was used for elastin lipid interaction, while glucose was used for glycation of elastin. Elastin samples were incubated in SDS (20 mM) or glucose (2 M) solutions and were allowed to equilibrate for 48 h at room temperature. Control experiments were performed in 1 * Phosphate buffered saline (PBS). Biaxial tensile and stress relaxation experiments were performed to study the mechanical behavior of elastin with solute effects. Experimental results reveal that both the elastic and viscoelastic behaviors of elastin change in different biochemical solvents environments. The tangent stiffness of SDS treated elastin decreases to 63.57 +/- 4.7% of the control condition in circumference and to 58.43 +/- 2.65% in the longitude. Glucose treated elastin exhibits an increase in stiffness to 145.06 +/ 1.48% of the control condition in the longitude but remains similar mechanical response in the circumferential direction. During stress relaxation experiments with a holding period of half an hour, elastin treated with SDS or glucose shows more prominent stress relaxation than the untreated ones. PMID- 24763622 TI - Functionally redundant RXLR effectors from Phytophthora infestans act at different steps to suppress early flg22-triggered immunity. AB - Genome sequences of several economically important phytopathogenic oomycetes have revealed the presence of large families of so-called RXLR effectors. Functional screens have identified RXLR effector repertoires that either compromise or induce plant defense responses. However, limited information is available about the molecular mechanisms underlying the modes of action of these effectors in planta. The perception of highly conserved pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), such as flg22, triggers converging signaling pathways recruiting MAP kinase cascades and inducing transcriptional re programming, yielding a generic anti-microbial response. We used a highly synchronizable, pathogen-free protoplast-based assay to identify a set of RXLR effectors from Phytophthora infestans (PiRXLRs), the causal agent of potato and tomato light blight that manipulate early stages of flg22-triggered signaling. Of thirty-three tested PiRXLR effector candidates, eight, called Suppressor of early Flg22-induced Immune response (SFI), significantly suppressed flg22-dependent activation of a reporter gene under control of a typical MAMP-inducible promoter (pFRK1-Luc) in tomato protoplasts. We extended our analysis to Arabidopsis thaliana, a non-host plant species of P. infestans. From the aforementioned eight SFI effectors, three appeared to share similar functions in both Arabidopsis and tomato by suppressing transcriptional activation of flg22-induced marker genes downstream of post-translational MAP kinase activation. A further three effectors interfere with MAMP signaling at, or upstream of, the MAP kinase cascade in tomato, but not in Arabidopsis. Transient expression of the SFI effectors in Nicotiana benthamiana enhances susceptibility to P. infestans and, for the most potent effector, SFI1, nuclear localization is required for both suppression of MAMP signaling and virulence function. The present study provides a framework to decipher the molecular mechanisms underlying the manipulation of host MAMP triggered immunity (MTI) by P. infestans and to understand the basis of host versus non-host resistance in plants towards P. infestans. PMID- 24763625 TI - A mean-field model of ventricular muscle tissue. AB - A theoretical model of the cross-linking topology of ventricular muscle tissue is developed. Using parameter estimation the terms of the theoretical model are estimated for normal and pathological conditions. The model represents the anisotropic structure of the tissue, reproduces published experimental data and characterizes the role of different tissue components in the observed macroscopic behavior. Changes in the material parameters are consistent with expected structural changes and the model is extended to reproduce force-Calcium relationships. Model results are invoked to argue that semisoft behavior and the material axis anisotropy arise from the constraints on the extracellular matrix cross-linking topology. PMID- 24763626 TI - Physics-based seated posture prediction for pregnant women and validation considering ground and seat pan contacts. AB - An understanding of human seated posture is important across many fields of scientific research. Certain demographics, such as pregnant women, have special postural limitations that need to be considered. Physics-based posture prediction is a tool in which seated postures can be quickly and thoroughly analyzed, as long the predicted postures are realistic. This paper proposes and validates an optimization formulation to predict seated posture for pregnant women considering ground and seat pan contacts. For the optimization formulation, the design variables are joint angles (posture); the cost function is dependent on joint torques. Constraints include joint limits, joint torque limits, the distances from the end-effectors to target points, and self-collision avoidance constraints. Three different joint torque cost functions have been investigated to account for the special postural characteristics of pregnant women and consider the support reaction forces (SRFs) associated with seated posture. Postures are predicted for three different reaching tasks in common reaching directions using each of the objective function formulations. The predicted postures are validated against experimental postures obtained using motion capture. A linear regression analysis was used to evaluate the validity of the predicted postures and was the criteria for comparison between the different objective functions. A 56 degree of freedom model was used for the posture prediction. Use of the objective function minimizing the maximum normalized joint torque provided an R2 value of 0.828, proving superior to either of two alternative functions. PMID- 24763627 TI - Investigation of the effects of dynamic change in curvature and torsion on pulsatile flow in a helical tube. AB - Cardiovascular diseases are the number one cause of death in the world, making the understanding of hemodynamics and the development of treatment options imperative. The effect of motion of the coronary artery due to the motion of the myocardium is not extensively studied. In this work, we focus our investigation on the localized hemodynamic effects of dynamic changes in curvature and torsion. It is our objective to understand and reveal the mechanism by which changes in curvature and torsion contribute towards the observed wall shear stress distribution. Such adverse hemodynamic conditions could have an effect on circumferential intimal thickening. Three-dimensional spatiotemporally resolved computational fluid dynamics (CFD) simulations of pulsatile flow with moving wall boundaries were carried out for a simplified coronary artery with physiologically relevant flow parameters. A model with stationary walls is used as the baseline control case. In order to study the effect of curvature and torsion variation on local hemodynamics, this baseline model is compared to models where the curvature, torsion, and both curvature and torsion change. The simulations provided detailed information regarding the secondary flow dynamics. The results suggest that changes in curvature and torsion cause critical changes in local hemodynamics, namely, altering the local pressure and velocity gradients and secondary flow patterns. The wall shear stress (WSS) varies by a maximum of 22% when the curvature changes, by 3% when the torsion changes, and by 26% when both the curvature and torsion change. The oscillatory shear stress (OSI) varies by a maximum of 24% when the curvature changes, by 4% when the torsion changes, and by 28% when both the curvature and torsion change. We demonstrate that these changes are attributed to the physical mechanism associating the secondary flow patterns to the production of vorticity (vorticity flux) due to the wall movement. The secondary flow patterns and augmented vorticity flux affect the wall shear stresses. As a result, this work reveals how changes in curvature and torsion act to modify the near wall hemodynamics of arteries. PMID- 24763628 TI - Three-dimensional flow patterns in the upper human airways. AB - Flow dynamics are studied for different ventilation conditions at a three dimensional model of the human lung airways. The model is based on Horsfield and Weibel data and bifurcates down to the sixth generation. The flow is analyzed numerically and compared to experimental data received from exactly the same model. Numerical and experimental results agree well. Based on this agreement, flow behavior for conventional mechanical ventilation (CMV) as well as for high frequency oscillatory ventilation (HFOV) conditions can be analyzed. Velocity profiles as well as secondary flow structures are investigated during different phases of the unsteady flow. It is shown that the velocity profiles at peak inspiration and expiration are very similar for CMV and HFOV, probably due to too short branch lengths for the development of a frequency-dependent velocity profile. At the flow reversal times, characteristic zones of bidirectional mass flow emerge with increasing amplitude at higher frequencies. Furthermore, secondary flow structures are analyzed. This investigation reveals that the structures only depend on the local curvature and branch orientation, but are not influenced much by the nearby upper or lower branching generations. PMID- 24763629 TI - Performance of self-expanding nitinol stent in a curved artery: impact of stent length and deployment orientation. AB - The primary aim of this work was to investigate the performance of self-expanding Nitinol stents in a curved artery through finite element analysis. The interaction between a PROTEGETM GPSTM self-expanding Nitinol stent and a stenosed artery, as well as a sheath, was characterized in terms of acute lumen gain, stent underexpansion, incomplete stent apposition, and tissue prolapse. The clinical implications of these parameters were discussed. The impact of stent deployment orientation and the stent length on the arterial wall stress distribution were evaluated. It was found that the maximum principal stress increased by 17.46%, when the deployment orientation of stent was varied at a 5 deg angle. A longer stent led to an increased contact pressure between stent and underlying tissue, which might alleviate the stent migration. However, it also caused a severe hinge effect and arterial stress concentration correspondingly, which might aggravate neointimal hyperplasia. The fundamental understanding of the behavior of a self-expanding stent and its clinical implications will facilitate a better device design. PMID- 24763630 TI - Comparative analysis of thrust production for distinct arm-pull styles in competitive swimming. AB - A computational fluid dynamics (CFD) based analysis of the propulsive forces generated by two distinct styles of arm-pulls in front-crawl as well as backstroke is presented in this Technical Brief. Realistic models of the arm pulling through water are created by combining underwater video footage and laser scans of an arm with computer animation. The contributions of drag and lift forces on the arm to thrust are computed from CFD, and it is found that lift forces provide a dominant contribution to thrust for all the arm-pull styles examined. However, contrary to accepted notions in swimming, pronounced sculling (lateral motion) not only does not increase the contribution of lift forces on the hand to overall thrust, it decreases the contribution of drag forces to thrust. Consequently, pronounced sculling seems to reduce the effectiveness of the arm-pull. PMID- 24763631 TI - Blood oxygenation level-dependent MR imaging as a predictor of therapeutic response to concurrent chemoradiotherapy in cervical cancer: a preliminary experience. AB - OBJECTIVES: To investigate the value of blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) as a predictor of therapeutic response in cervical cancer patients undergoing concurrent chemoradiotherapy (CCRT). METHODS: Thirty consecutive patients with biopsy-proven cervical cancer were examined by BOLD MRI before (preTx) and after CCRT (postTx). The R2* value (s(-1)) was calculated in the tumour and normal myometrium for preTx and postTx studies. Final tumour responses, as determined by changes of tumour size or volume on MRI, were correlated with tumour R2* values at preTx. RESULTS: The mean R2* values of tumours at preTx (21.1) were significantly lower than those at postTx (39.4 s( 1)) (p < 0.001), while those of normal myometrium were similar between preTx and postTx (p = 0.363). At preTx, tumour R2* values showed significantly negative correlation with final tumour size response (p = 0.022, Spearman's coefficient = 0.415). However, tumour R2* values at preTx were not associated with final tumour volume response (p = 0.069). CONCLUSIONS: BOLD MRI at 3 T, as an imaging biomarker, may have the potential to evaluate therapeutic response in cervical cancers. The association between BOLD MRI findings and CCRT responses warrants further validation. KEY POINTS: * Hypoxia in cervical cancer is an independent risk factor * BOLD MRI reflect oxygenation status of tissue adjacent to perfused microvessels * Pretreatment tumour R2* reveal negative correlation with final tumour size response * Accurate oxygenation assessment in cervical cancer may help clinical decision making. PMID- 24763633 TI - Polarization control of an X-ray free-electron laser with a diamond phase retarder. AB - A diamond phase retarder was applied to control the polarization states of a hard X-ray free-electron laser (XFEL) in the photon energy range 5-20 keV. The horizontal polarization of the XFEL beam generated from the planar undulators of the SPring-8 Angstrom Compact Free-Electron Laser (SACLA) was converted into vertical or circular polarization of either helicity by adjusting the angular offset of the diamond crystal from the exact Bragg condition. Using a 1.5 mm thick crystal, a high degree of circular polarization, 97%, was obtained for 11.56 keV monochromatic X-rays, whereas the degree of vertical polarization was 67%, both of which agreed with the estimations including the energy bandwidth of the Si 111 beamline monochromator. PMID- 24763632 TI - A new sensor for measurement of dynamic contact stress in the hip. AB - Various techniques exist for quantifying articular contact stress distributions, an important class of measurements in the field of orthopaedic biomechanics. In situations where the need for dynamic recording has been paramount, the approach of preference has involved thin-sheet multiplexed grid-array transducers. To date, these sensors have been used to study contact stresses in the knee, shoulder, ankle, wrist, and spinal facet joints. Until now, however, no such sensor had been available for the human hip joint due to difficulties posed by the deep, bi-curvilinear geometry of the acetabulum. We report here the design and development of a novel sensor capable of measuring dynamic contact stress in human cadaveric hip joints (maximum contact stress of 20 MPa and maximum sampling rate 100 readings/s). Particular emphasis is placed on issues concerning calibration, and on the effect of joint curvature on the sensor's performance. The active pressure-sensing regions of the sensors have the shape of a segment of an annulus with a 150-deg circumferential span, and employ a polar/circumferential "ring-and-spoke" sensel grid layout. There are two sensor sizes, having outside radii of 44 and 48 mm, respectively. The new design was evaluated in human cadaver hip joints using two methods. The stress magnitudes and spatial distribution measured by the sensor were compared to contact stresses measured by pressure sensitive film during static loading conditions that simulated heel strike during walking and stair climbing. Additionally, the forces obtained by spatial integration of the sensor contact stresses were compared to the forces measured by load cells during the static simulations and for loading applied by a dynamic hip simulator. Stress magnitudes and spatial distribution patterns obtained from the sensor versus from pressure sensitive film exhibited good agreement. The joint forces obtained during both static and dynamic loading were within +/-10% and +/-26%, respectively, of the forces measured by the load cells. These results provide confidence in the measurements obtained by the sensor. The new sensor's real-time output and dynamic measurement capabilities hold significant advantages over static measurements from pressure sensitive film. PMID- 24763634 TI - Performance of a collimating L-shaped laterally graded multilayer mirror for the IXS analyzer system at NSLS-II. AB - The L-shaped laterally graded multilayer mirror is a vital part of the ultrahigh energy and momentum-resolution inelastic X-ray scattering spectrometer at the National Synchrotron Light Source II. This mirror was designed and implemented as a two-dimensional collimating optic for the analyzer system. Its performance was characterized using a secondary large-divergence source at the 30-ID beamline of the Advanced Photon Source, which yielded an integrated reflectivity of 47% and a collimated beam divergence of 78 urad with a source size of 10 um. Numerical simulations of the mirror performance in tandem with the analyzer crystal optics provided details on the acceptance sample volume in forward scattering and defined the technical requirements on the mirror stability and positioning precision. It was shown that the mirror spatial and angular stability must be in the range <8.4 um and <21.4 urad, respectively, for reliable operation of the analyzer. PMID- 24763635 TI - Development of a bent Laue beam-expanding double-crystal monochromator for biomedical X-ray imaging. AB - The Biomedical Imaging and Therapy (BMIT) beamline at the Canadian Light Source has produced some excellent biological imaging data. However, the disadvantage of a small vertical beam limits its usability in some applications. Micro-computed tomography (micro-CT) imaging requires multiple scans to produce a full projection, and certain dynamic imaging experiments are not possible. A larger vertical beam is desirable. It was cost-prohibitive to build a longer beamline that would have produced a large vertical beam. Instead, it was proposed to develop a beam expander that would create a beam appearing to originate at a source much farther away. This was accomplished using a bent Laue double-crystal monochromator in a non-dispersive divergent geometry. The design and implementation of this beam expander is presented along with results from the micro-CT and dynamic imaging tests conducted with this beam. Flux (photons per unit area per unit time) has been measured and found to be comparable with the existing flat Bragg double-crystal monochromator in use at BMIT. This increase in overall photon count is due to the enhanced bandwidth of the bent Laue configuration. Whilst the expanded beam quality is suitable for dynamic imaging and micro-CT, further work is required to improve its phase and coherence properties. PMID- 24763636 TI - X-ray harmonics rejection on third-generation synchrotron sources using compound refractive lenses. AB - A new method of harmonics rejection based on X-ray refractive optics has been proposed. Taking into account the fact that the focal distance of the refractive lens is energy-dependent, the use of an off-axis illumination of the lens immediately leads to spatial separation of the energy spectrum by focusing the fundamental harmonic at the focal point and suppressing the unfocused high-energy radiation with a screen absorber or slit. The experiment was performed at the ESRF ID06 beamline in the in-line geometry using an X-ray transfocator with compound refractive lenses. Using this technique the presence of the third harmonic has been reduced to 10(-3). In total, our method enabled suppression of all higher-order harmonics to five orders of magnitude using monochromator detuning. The method is well suited to third-generation synchrotron radiation sources and is very promising for the future ultimate storage rings. PMID- 24763637 TI - Microfocusing options for the inelastic X-ray scattering beamline at sector 3 of the Advanced Photon Source. AB - Synchrotron radiation from third-generation high-brilliance storage rings is an ideal source for X-ray microbeams. The aim of this paper is to describe a microfocusing scheme that combines both a toroidal mirror and Kirkpatrick-Baez (KB) mirrors for upgrading the existing optical system for inelastic X-ray scattering experiments at sector 3 of the Advanced Photon Source. SHADOW ray tracing simulations without considering slope errors of both the toroidal mirror and KB mirrors show that this combination can provide a beam size of 4.5 um (H) * 0.6 um (V) (FWHM) at the end of the existing D-station (66 m from the source) with use of full beam transmission of up to 59%, and a beam size of 3.7 um (H) * 0.46 um (V) (FWHM) at the front-end of the proposed E-station (68 m from the source) with a transmission of up to 52%. A beam size of about 5 um (H) * 1 um (V) can be obtained, which is close to the ideal case, by using high-quality mirrors (with slope errors of less than 0.5 urad r.m.s.). Considering the slope errors of the existing toroidal and KB mirrors (5 and 2.9 urad r.m.s., respectively), the beam size grows to about 13.5 um (H) * 6.3 um (V) at the end of the D-station and to 12.0 um (H) * 6.0 um (V) at the front-end of the proposed E-station. The simulations presented here are compared with the experimental measurements that are significantly larger than the theoretical values even when slope error is included in the simulations. This is because of the experimental set-up that could not yet be optimized. PMID- 24763638 TI - High-efficiency zone-plate optics for multi-keV X-ray focusing. AB - High-efficiency nanofocusing of hard X-rays using stacked multilevel Fresnel zone plates with a smallest zone width of 200 nm is demonstrated. The approach is to approximate the ideal parabolic lens profile with two-, three-, four- and six level zone plates. By stacking binary and three-level zone plates with an additional binary zone plate, the number of levels in the optical transmission function was doubled, resulting in four- and six-level profiles, respectively. Efficiencies up to 53.7% focusing were experimentally obtained with 6.5 keV photons using a compact alignment apparatus based on piezoelectric actuators. The measurements have also been compared with numerical simulations to study the misalignment of the two zone plates. PMID- 24763639 TI - Fast continuous energy scan with dynamic coupling of the monochromator and undulator at the DEIMOS beamline. AB - In order to improve the efficiency of X-ray absorption data recording, a fast scan method, the Turboscan, has been developed on the DEIMOS beamline at Synchrotron SOLEIL, consisting of a software-synchronized continuous motion of the monochromator and undulator motors. This process suppresses the time loss when waiting for the motors to reach their target positions, as well as software dead-time, while preserving excellent beam characteristics. PMID- 24763640 TI - Anisotropic elasticity of silicon and its application to the modelling of X-ray optics. AB - The crystal lattice of single-crystal silicon gives rise to anisotropic elasticity. The stiffness and compliance coefficient matrix depend on crystal orientation and, consequently, Young's modulus, the shear modulus and Poisson's ratio as well. Computer codes (in Matlab and Python) have been developed to calculate these anisotropic elasticity parameters for a silicon crystal in any orientation. These codes facilitate the evaluation of these anisotropy effects in silicon for applications such as microelectronics, microelectromechanical systems and X-ray optics. For mechanically bent X-ray optics, it is shown that the silicon crystal orientation is an important factor which may significantly influence the optics design and manufacturing phase. Choosing the appropriate crystal orientation can both lead to improved performance whilst lowering mechanical bending stresses. The thermal deformation of the crystal depends on Poisson's ratio. For an isotropic constant Poisson's ratio, nu, the thermal deformation (RMS slope) is proportional to (1 + nu). For a cubic anisotropic material, the thermal deformation of the X-ray optics can be approximately simulated by using the average of nu12 and nu13 as an effective isotropic Poisson's ratio, where the direction 1 is normal to the optic surface, and the directions 2 and 3 are two normal orthogonal directions parallel to the optical surface. This average is independent of the direction in the optical surface (the crystal plane) for Si(100), Si(110) and Si(111). Using the effective isotropic Poisson's ratio for these orientations leads to an error in thermal deformation smaller than 5.5%. PMID- 24763641 TI - Benchmarking and validation of a Geant4-SHADOW Monte Carlo simulation for dose calculations in microbeam radiation therapy. AB - Microbeam radiation therapy (MRT) is a synchrotron-based radiotherapy modality that uses high-intensity beams of spatially fractionated radiation to treat tumours. The rapid evolution of MRT towards clinical trials demands accurate treatment planning systems (TPS), as well as independent tools for the verification of TPS calculated dose distributions in order to ensure patient safety and treatment efficacy. Monte Carlo computer simulation represents the most accurate method of dose calculation in patient geometries and is best suited for the purpose of TPS verification. A Monte Carlo model of the ID17 biomedical beamline at the European Synchrotron Radiation Facility has been developed, including recent modifications, using the Geant4 Monte Carlo toolkit interfaced with the SHADOW X-ray optics and ray-tracing libraries. The code was benchmarked by simulating dose profiles in water-equivalent phantoms subject to irradiation by broad-beam (without spatial fractionation) and microbeam (with spatial fractionation) fields, and comparing against those calculated with a previous model of the beamline developed using the PENELOPE code. Validation against additional experimental dose profiles in water-equivalent phantoms subject to broad-beam irradiation was also performed. Good agreement between codes was observed, with the exception of out-of-field doses and toward the field edge for larger field sizes. Microbeam results showed good agreement between both codes and experimental results within uncertainties. Results of the experimental validation showed agreement for different beamline configurations. The asymmetry in the out-of-field dose profiles due to polarization effects was also investigated, yielding important information for the treatment planning process in MRT. This work represents an important step in the development of a Monte Carlo-based independent verification tool for treatment planning in MRT. PMID- 24763642 TI - Characterization of an in-vacuum PILATUS 1M detector. AB - A dedicated in-vacuum X-ray detector based on the hybrid pixel PILATUS 1M detector has been installed at the four-crystal monochromator beamline of the PTB at the electron storage ring BESSY II in Berlin, Germany. Owing to its windowless operation, the detector can be used in the entire photon energy range of the beamline from 10 keV down to 1.75 keV for small-angle X-ray scattering (SAXS) experiments and anomalous SAXS at absorption edges of light elements. The radiometric and geometric properties of the detector such as quantum efficiency, pixel pitch and module alignment have been determined with low uncertainties. The first grazing-incidence SAXS results demonstrate the superior resolution in momentum transfer achievable at low photon energies. PMID- 24763643 TI - Matching X-ray beam and detector properties to protein crystals of different perfection. AB - An analysis is given of the effect of different beam and detector parameters on the sharpness of recorded diffraction features for macromolecular crystals of different quality. The crystal quality parameters include crystal strain, crystal or mosaic block size and mosaic block misorientation. Calculations are given for instrument parameters such as angular resolution of the detector, beam divergence and wavelength bandpass to be matched to the intrinsic diffraction properties from these crystals with the aim of obtaining the best possible data out of each crystal. Examples are given using typical crystal imperfections obtained from the literature for both room-temperature and cryo-cooled crystals. Possible implications for the choice of X-ray source, beamline design, detector specifications, instrument set-up and data processing are discussed, together with the limitations of the approach. PMID- 24763644 TI - Investigation of surface topology of printed nanoparticle layers using wide-angle low-Q scattering. AB - A new small-angle scattering technique in reflection geometry is described which enables a topological study of rough surfaces. This is achieved by using long wavelength soft X-rays which are scattered at wide angles but in the low-Q range normally associated with small-angle scattering. The use of nanometre-wavelength radiation restricts the penetration to a thin surface layer which follows the topology of the surface, while moving the scattered beam to wider angles preventing shadowing by the surface features. The technique is, however, only applicable to rough surfaces for which there is no specular reflection, so that only the scattered beam was detected by the detector. As an example, a study of the surfaces of rough layers of silicon produced by the deposition of nanoparticles by blade-coating is presented. The surfaces of the blade-coated layers have rough features of the order of several micrometers. Using 2 nm and 13 nm X-rays scattered at angular ranges of 5 degrees <= theta <= 51 degrees and 5 degrees <= theta <= 45 degrees , respectively, a combined range of scattering vector of 0.00842 A(-1) <= Q <= 0.4883 A(-1) was obtained. Comparison with previous transmission SAXS and USAXS studies of the same materials indicates that the new method does probe the surface topology rather than the internal microstructure. PMID- 24763645 TI - Application of singular value decomposition analysis to time-dependent powder diffraction data of an in-situ photodimerization reaction. AB - Singular value decomposition (SVD) analysis has important applications for time dependent crystallographic data, extracting significant information. Herein, a successful application of SVD analysis of time-resolved powder diffraction data over the course of an in-situ photodimerization reaction of anthracene derivatives is introduced. SVD revealed significant results in the case of 9 methylanthracene and 1-chloroanthracene. The results support the formation of the 9-methylanthracene stable dimer phase and suggest the existence of an excimer state. PMID- 24763646 TI - Correction method for the self-absorption effects in fluorescence extended X-ray absorption fine structure on multilayer samples. AB - A novel correction method for self-absorption effects is proposed for extended X ray absorption fine structure (EXAFS) detected in the fluorescence mode on multilayer samples. The effects of refraction and multiple reflection at the interfaces are fully considered in this correction method. The correction is performed in k-space before any further data analysis, and it can be applied to single-layer or multilayer samples with flat surfaces and without thickness limit when the model parameters for the samples are known. The validity of this method is verified by the fluorescence EXAFS data collected for a Cr/C multilayer sample measured at different experimental geometries. PMID- 24763647 TI - Unsupervised cell identification on multidimensional X-ray fluorescence datasets. AB - A novel approach to locate, identify and refine positions and whole areas of cell structures based on elemental contents measured by X-ray fluorescence microscopy is introduced. It is shown that, by initializing with only a handful of prototypical cell regions, this approach can obtain consistent identification of whole cells, even when cells are overlapping, without training by explicit annotation. It is robust both to different measurements on the same sample and to different initializations. This effort provides a versatile framework to identify targeted cellular structures from datasets too complex for manual analysis, like most X-ray fluorescence microscopy data. Possible future extensions are also discussed. PMID- 24763648 TI - Synchrotron far-infrared spectroscopy of corroded steel surfaces using a variable angle of incidence. AB - Far-infrared spectroscopy, using a synchrotron source, has been used to study carbon steel corroded in CO2-saturated brine in the presence and absence of the corrosion inhibitor 2-mercaptopyrimidine (MPY), which allowed the steel surface roughness to be modified. The effect of the angle of incidence (thetai, 30-80 degrees ) on the band intensity and observed bands of the spectra from these surfaces has been determined. For the MPY-treated steel (low surface roughness) the highest band intensity is observed at high thetai (80 degrees ) and different bands were observed at different thetai. In contrast, for the MPY-free steel (high surface roughness) the highest band intensity is observed at low thetai (30 degrees ) and spectral content changes were not observed. The results are explained in terms of the roughness of the MPY-treated and MPY-free steels, and their effect on the level of diffusely reflected light of the incident infrared beam. PMID- 24763649 TI - A synchrotron-based local computed tomography combined with data-constrained modelling approach for quantitative analysis of anthracite coal microstructure. AB - Quantifying three-dimensional spatial distributions of pores and material compositions in samples is a key materials characterization challenge, particularly in samples where compositions are distributed across a range of length scales, and where such compositions have similar X-ray absorption properties, such as in coal. Consequently, obtaining detailed information within sub-regions of a multi-length-scale sample by conventional approaches may not provide the resolution and level of detail one might desire. Herein, an approach for quantitative high-definition determination of material compositions from X ray local computed tomography combined with a data-constrained modelling method is proposed. The approach is capable of dramatically improving the spatial resolution and enabling finer details within a region of interest of a sample larger than the field of view to be revealed than by using conventional techniques. A coal sample containing distributions of porosity and several mineral compositions is employed to demonstrate the approach. The optimal experimental parameters are pre-analyzed. The quantitative results demonstrated that the approach can reveal significantly finer details of compositional distributions in the sample region of interest. The elevated spatial resolution is crucial for coal-bed methane reservoir evaluation and understanding the transformation of the minerals during coal processing. The method is generic and can be applied for three-dimensional compositional characterization of other materials. PMID- 24763650 TI - Three-dimensional coherent diffractive imaging on non-periodic specimens at the ESRF beamline ID10. AB - The progress of tomographic coherent diffractive imaging with hard X-rays at the ID10 beamline of the European Synchrotron Radiation Facility is presented. The performance of the instrument is demonstrated by imaging a cluster of Fe2P magnetic nanorods at 59 nm 3D resolution by phasing a diffraction volume measured at 8 keV photon energy. The result obtained shows progress in three-dimensional imaging of non-crystalline samples in air with hard X-rays. PMID- 24763651 TI - Data processing software suite SITENNO for coherent X-ray diffraction imaging using the X-ray free-electron laser SACLA. AB - Coherent X-ray diffraction imaging is a promising technique for visualizing the structures of non-crystalline particles with dimensions of micrometers to sub micrometers. Recently, X-ray free-electron laser sources have enabled efficient experiments in the 'diffraction before destruction' scheme. Diffraction experiments have been conducted at SPring-8 Angstrom Compact free-electron LAser (SACLA) using the custom-made diffraction apparatus KOTOBUKI-1 and two multiport CCD detectors. In the experiments, ten thousands of single-shot diffraction patterns can be collected within several hours. Then, diffraction patterns with significant levels of intensity suitable for structural analysis must be found, direct-beam positions in diffraction patterns determined, diffraction patterns from the two CCD detectors merged, and phase-retrieval calculations for structural analyses performed. A software suite named SITENNO has been developed to semi-automatically apply the four-step processing to a huge number of diffraction data. Here, details of the algorithm used in the suite are described and the performance for approximately 9000 diffraction patterns collected from cuboid-shaped copper oxide particles reported. Using the SITENNO suite, it is possible to conduct experiments with data processing immediately after the data collection, and to characterize the size distribution and internal structures of the non-crystalline particles. PMID- 24763652 TI - Combining Monte Carlo methods with coherent wave optics for the simulation of phase-sensitive X-ray imaging. AB - Phase-sensitive X-ray imaging shows a high sensitivity towards electron density variations, making it well suited for imaging of soft tissue matter. However, there are still open questions about the details of the image formation process. Here, a framework for numerical simulations of phase-sensitive X-ray imaging is presented, which takes both particle- and wave-like properties of X-rays into consideration. A split approach is presented where we combine a Monte Carlo method (MC) based sample part with a wave optics simulation based propagation part, leading to a framework that takes both particle- and wave-like properties into account. The framework can be adapted to different phase-sensitive imaging methods and has been validated through comparisons with experiments for grating interferometry and propagation-based imaging. The validation of the framework shows that the combination of wave optics and MC has been successfully implemented and yields good agreement between measurements and simulations. This demonstrates that the physical processes relevant for developing a deeper understanding of scattering in the context of phase-sensitive imaging are modelled in a sufficiently accurate manner. The framework can be used for the simulation of phase-sensitive X-ray imaging, for instance for the simulation of grating interferometry or propagation-based imaging. PMID- 24763653 TI - Sample thickness and quantitative concentration measurements in Br K-edge XANES spectroscopy of organic materials. AB - While XANES spectroscopy is an established tool for quantitative information on chemical structure and speciation, elemental concentrations are generally quantified by other methods. The edge step in XANES spectra represents the absolute amount of the measured element in the sample, but matrix effects and sample thickness complicate the extraction of accurate concentrations from XANES measurements, particularly at hard X-ray energies where the X-ray beam penetrates deeply into the sample. The present study demonstrates a method of quantifying concentration with a detection limit approaching 1 mg kg(-1) using information routinely collected in the course of a hard X-ray XANES experiment. The XANES normalization procedure unambiguously separates the signal of the absorber from any source of background. The effects of sample thickness on edge steps at the bromine K-edge were assessed and an empirical correction factor for use with samples of variable mass developed. PMID- 24763655 TI - 08B1-1: an automated beamline for macromolecular crystallography experiments at the Canadian Light Source. AB - Beamline 08B1-1 is a recently commissioned bending-magnet beamline at the Canadian Light Source. The beamline is designed for automation and remote access. Together with the undulator-based beamline 08ID-1, they constitute the Canadian Macromolecular Crystallography Facility. This paper describes the design, specifications, hardware and software of beamline 08B1-1. A few scientific results using data obtained at the beamline will be highlighted. PMID- 24763654 TI - Macromolecular crystallography beamline X25 at the NSLS. AB - Beamline X25 at the NSLS is one of the five beamlines dedicated to macromolecular crystallography operated by the Brookhaven National Laboratory Macromolecular Crystallography Research Resource group. This mini-gap insertion-device beamline has seen constant upgrades for the last seven years in order to achieve mini-beam capability down to 20 um * 20 um. All major components beginning with the radiation source, and continuing along the beamline and its experimental hutch, have changed to produce a state-of-the-art facility for the scientific community. PMID- 24763656 TI - The benefit of the European User Community from transnational access to national radiation facilities. AB - Transnational access (TNA) to national radiation sources is presently provided via programmes of the European Commission by BIOSTRUCT-X and CALIPSO with a major benefit for scientists from European countries. Entirely based on scientific merit, TNA allows all European scientists to realise synchrotron radiation experiments for addressing the Societal Challenges promoted in HORIZON2020. In addition, by TNA all European users directly take part in the development of the research infrastructure of facilities. The mutual interconnection of users and facilities is a strong prerequisite for future development of the research infrastructure of photon science. Taking into account the present programme structure of HORIZON2020, the European Synchrotron User Organization (ESUO) sees considerable dangers for the continuation of this successful collaboration in the future. PMID- 24763659 TI - The role of climatic variables in winter cereal yields: a retrospective analysis. AB - This study examined the effects of observed climate including [CO2] on winter cereal [winter wheat (Triticum aestivum), barley (Hordeum vulgare) and oat (Avena sativa)] yields by adopting robust statistical analysis/modelling approaches (i.e. autoregressive fractionally integrated moving average, generalised addition model) based on long time series of historical climate data and cereal yield data at three locations (Moree, Dubbo and Wagga Wagga) in New South Wales, Australia. Research results show that (1) growing season rainfall was significantly, positively and non-linearly correlated with crop yield at all locations considered; (2) [CO2] was significantly, positively and non-linearly correlated with crop yields in all cases except wheat and barley yields at Wagga Wagga; (3) growing season maximum temperature was significantly, negatively and non-linearly correlated with crop yields at Dubbo and Moree (except for barley); and (4) radiation was only significantly correlated with oat yield at Wagga Wagga. This information will help to identify appropriate management adaptation options in dealing with the risk and in taking the opportunities of climate change. PMID- 24763662 TI - Secondary metabolomics: the impact of mass spectrometry-based approaches on the discovery and characterization of microbial natural products. AB - Covering: up to the end of 2013 The in-depth analysis of secondary metabolomes of many microbes offers tremendous opportunities for the discovery of novel natural products which often exhibit promising biological activities. However, over the last years the increasing availability of whole-genome information has led to raised expectations, as bioinformatic analysis revealed that traditional strategies to discover novel secondary metabolites apparently have so far only scratched the surface of the real microbial "secondary metabolome landscape". Metabolomics-based approaches using modern mass spectrometry techniques can help to bridge the gap between genome-encoded potential for the production of secondary metabolites and the usually contradictory low numbers of compounds known from a specific producer. In this article recent studies are highlighted in which metabolomics-driven analysis played a crucial role for the discovery of novel secondary metabolites from microbial sources. We also exemplify how the implementation of metabolomics techniques facilitates the structural characterization of novel metabolites and contributes to the in-depth investigation of underlying biosynthetic pathways. Furthermore, the constantly increasing role of secondary metabolomics for the identification of novel natural products in a drug discovery context is discussed. PMID- 24763664 TI - The creation and implementation of the newly implemented Korean Health Education Specialist certification. AB - Professional competencies, standards, and professional preparation of public health professionals, which includes health education and health promotion competencies, is documented in Australia, Europe, Japan, and the United States. Preparing a competent public health education workforce is a newly established priority of the South Korean Ministry of Health and Welfare. In 2010, the first ever Health Education Specialist credential was implemented in South Korea. This commentary describes the creation and implementation of the Health Education Specialist credential and initial workforce preparation outcomes of the new credential. PMID- 24763663 TI - MRI-detected skull-base invasion: prognostic value and therapeutic implication in intensity-modulated radiotherapy treatment for nasopharyngeal carcinoma. AB - PURPOSE: With advances in imaging and radiotherapy, the prognostic value of skull base invasion in nasopharyngeal carcinoma (NPC) needs to be reassessed. We aimed to define a classification system and evaluate the prognostic value of the classification of magnetic resonance imaging (MRI)-detected skull-base invasion in NPC treated with intensity-modulated radiotherapy (IMRT). PATIENTS AND MATERIALS: We retrospectively reviewed 749 patients who underwent MRI and were subsequently histologically diagnosed with nondisseminated NPC and treated with IMRT. RESULTS: MRI-detected skull-base invasion was not found to be an independent prognostic factor for overall survival (OS), distant metastasis-free survival (DMFS), local relapse-free survival (LRFS), or disease-free survival (DFS; p > 0.05 for all). Skull-base invasion was classified according to the incidence of each site (type I sites inside pharyngobasilar fascia and clivus vs. type II sites outside pharyngobasilar fascia). The 5-year OS, DMFS, LRFS, and DFS rates in the classification of skull-base invasion in NPC were 83 vs. 67 %, 85 vs.75 %, 95 vs. 88 %, and 76 vs. 62 %, respectively (p < 0.05 for all). Multivariate analysis indicated the classification of skull-base invasion was an independent prognostic factor. CONCLUSION: MRI-detected skull-base invasion is not an independent prognostic factor in patients with NPC treated with IMRT. However, classification according to the site of invasion has prognostic value. Therefore, patients with various subclassifications of stage T3 disease may receive treatment with different intensities; however, further studies are warranted to prove this. PMID- 24763666 TI - Atlas of infections of the skin. PMID- 24763665 TI - Training tomorrow's global health leaders: applying a transtheoretical model to identify behavior change stages within an intervention for health leadership development. AB - Training health professionals in leadership and management skills is a key component of health systems strengthening in low-resource settings. The importance of evaluating the effectiveness of these programs has received increased attention over the past several years, although such evaluations continue to pose significant challenges. This article presents evaluation data from the pilot year of the Afya Bora Fellowship, an African-based training program to increase the leadership capacity of health professionals. Firstly, we describe the goals of the Afya Bora Fellowship. Then, we present an adaptation of the transtheoretical model for behavior change called the Health Leadership Development Model, as an analytical lens to identify and describe evidence of individual leadership behavior change among training participants during and shortly after the pilot year of the program. The Health Leadership Development Model includes the following: pre-contemplation (status quo), contemplation (testing and internalizing leadership), preparation - (moving toward leadership), action (leadership in action), and maintenance (effecting organizational change). We used data from surveys, in-depth interviews, journal entries and course evaluations as data points to populate the Health Leadership Development Model. In the short term, fellows demonstrated increased leadership development during and shortly after the intervention and reflected the contemplation, preparation and action stages of the Health Leadership Development Model. However, expanded interventions and/or additional time may be needed to support behavior change toward the maintenance stages. We conclude that the Health Leadership Development Model is useful for informing health leadership training design and evaluation to contribute to sustainable health organizational change. PMID- 24763667 TI - Initial Evaluation of Melanoma: Don't Stop Getting That Chest X-ray . . . Yet. PMID- 24763668 TI - Erythematous nodule on the nail bed. PMID- 24763669 TI - Comparison of microtia reconstruction outcomes using rib cartilage vs porous polyethylene implant. AB - IMPORTANCE: Auricular reconstruction is a unique blend of cosmesis and functionality. The choice of the optimal framework material to use is an important decision for the patient with microtia. OBJECTIVE: To evaluate and compare the outcomes of reconstruction of microtia using porous polyethylene implants and rib cartilage grafts. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review from January 1, 2001, through December 31, 2012, at a tertiary academic institution. Thirty-five patients (36 ears) undergoing microtia repair were divided into groups using high-density porous polyethylene (17 ears), rib cartilage (17 ears), and both materials (2 ears). Only patients with completed repair were included in the analysis. EXPOSURES: Reconstructive surgery for microtia. MAIN OUTCOME AND MEASURES: We compared groups in terms of mean number of operations, age at treatment initiation, and complications (infection, extrusion, cartilage exposure, and pneumothorax). Photographs were graded by blinded observers to give each patient a score on protrusion, definition, shape, size, location, and color match. RESULTS: The cartilage group was older than the polyethylene group (mean age, 8.0 vs 6.9 years; P = .23). The mean number of operations was 4.88 for the cartilage group vs 3.35 for the polyethylene group (P = .004). Two patients in the polyethylene group had postoperative infections and implant extrusion and underwent subsequent reconstruction with cartilage grafts. Patients in the cartilage group had no infection or extrusion; 1 had a minor cartilage exposure. No patient had pneumothorax. Patients in the polyethylene group had significantly better grades for ear definition and size match, whereas those in the cartilage group had a significantly better color match. Patients in the cartilage group had better protrusion and location outcomes, although the difference was not significant. CONCLUSIONS AND RELEVANCE: Comparison of reconstruction with porous polyethylene implants and rib cartilage grafts showed neither material to be clearly superior. Polyethylene implants may achieve a better cosmetic outcome in the categories of ear definition, shape, and size with a higher risk for infection and extrusion. Patients in the cartilage group were older and underwent significantly more surgical procedures, which should factor into the decision on which technique to choose. LEVEL OF EVIDENCE: 3. PMID- 24763670 TI - A study of the optical properties of metal-doped polyoxotitanium cages and the relationship to metal-doped titania. AB - To what extent the presence of transition metal ions can affect the optical properties of structurally well-defined, metal-doped polyoxotitanium (POT) cages is a key question in respect to how closely these species model technologically important metal-doped TiO2. This also has direct implications to the potential applications of these organically-soluble inorganic cages as photocatalytic redox systems in chemical transformations. Measurement of the band gaps of the series of closely related polyoxotitanium cages [MnTi14(OEt)28O14(OH)2] (1), [FeTi14(OEt)28O14(OH)2] (2) and [GaTi14(OEt)28O15(OH)] (3), containing interstitial Mn(II), Fe(II) and Ga(III) dopant ions, shows that transition metal doping alone does not lower the band gaps below that of TiO2 or the corresponding metal-doped TiO2. Instead, the band gaps of these cages are within the range of values found previously for transition metal-doped TiO2 nanoparticles. The low band gaps previously reported for 1 and for a recently reported related Mn-doped POT cage appear to be the result of low band gap impurities (most likely amorphous Mn-doped TiO2). PMID- 24763671 TI - Alkylglycerols modulate the proliferation and differentiation of non-specific agonist and specific antigen-stimulated splenic lymphocytes. AB - Alkylglycerols (AKGs) are ether-linked glycerols derived from shark liver oil and found in small amounts in human milk. Previous studies showed that oral AKGs administration significantly increased the immune response in mice. The aim of the present study was to investigate the in vitro immunomodulatory effect of AKGs on stimulating splenic lymphocyte responses. C57BL/6 mice were immunized with hepatitis B surface antigen (HBsAg). Splenic B cells were purified and stimulated with anti-BCR and anti-CD38. Meanwhile, splenic CD4+ T cells were purified and stimulated with anti-CD3 and anti-CD28. For antigen specific stimulation, the purified CD4+ T cells were cocultured with HBsAg -pulsed dendritic cells. The stimulated lymphocytes were treated with different concentrations of AKGs. The cell proliferation was assessed by [3H]-thymidine incorporation assay. The maturation of B cells was assessed by examining the germline (GL) transcription of IgG (gamma1) mRNA expression, and the surface expressions of CD80/CD86 markers were examined by flow cytometry analysis. Th1/Th2 polarity was assessed by T-BET (Th1)/GATA-3 (Th2) flow cytometry assay and by characteristic cytokines ELISA assay (TNF-alpha and IFN-gamma for Th1; IL-4 and IL-10 for Th2). It was found that AKGs significantly increased the BCR/CD38 -stimulated B cell proliferation. The T cell proliferation in response to CD3/CD28 or specific antigen stimulation was also increased by AKGs. The transcriptional level of IgG (gamma1) and the expressions of CD80/CD86 molecules were markedly increased by AKGs in BCR/CD38 stimulated B cells. Meanwhile, the results showed that AKGs increased the expression of T-BET transcriptional factor and the production of Th1 cytokines (TNF-alpha and IFN-gamma) upon CD3/CD28 stimulation; whereas, levels of Th2 cytokines (IL-4 and IL-10) were decreased by AKGs. Our study demonstrated that AKGs can modulate immune responses by boosting the proliferation and maturation of murine lymphocytes in vitro. PMID- 24763673 TI - Switching an O2 sensitive glucose oxidase bioelectrode into an almost insensitive one by cofactor redesign. AB - In the 5-8 mM glucose concentration range, of particular interest for diabetes management, glucose oxidase bioelectrodes are O2 dependent, which decrease their efficiencies. By replacing the natural cofactor of glucose oxidase, we succeeded in turning an O2 sensitive bioelectrode into an almost insensitive one. PMID- 24763672 TI - Expression of organic anion transporting polypeptide 1c1 and monocarboxylate transporter 8 in the rat placental barrier and the compensatory response to thyroid dysfunction. AB - Thyroid hormones (THs) must pass from mother to fetus for normal fetal development and require the expression of placental TH transporters. We investigate the compensatory effect of placental organic anion transporting polypeptide 1c1 (Oatp1c1) and monocarboxylate transporter 8 (Mct8) on maternal thyroid dysfunction. We describe the expressions of these two transporters in placental barriers and trophoblastic cell populations in euthyroidism and thyroid dysfunction resulting from differential iodine nutrition at gestation day (GD) 16 and 20, that is, before and after the onset of fetal thyroid function. Immunohistochemistry revealed that in the blood-placenta barrier, these two TH transporters were strongly expressed in the villous interstitial substance and were weakly expressed in trophoblast cells. Levels of Oatp1c1 protein obviously increased in the placental fetal portion during maternal thyroid deficiency at GD16. Under maternal thyroid deficiency after the production of endogenous fetal TH, quantitative PCR analysis revealed down-regulation of Oatp1c1 occurred along with up-regulation of Mct8 in trophoblast cell populations isolated by laser capture microdissection (LCM); this was consistent with the protein levels in the fetal portion of the placenta. In addition, decreased D3 mRNA at GD16 and increased D2 mRNA on two gestational days were observed in trophoblast cells with thyroid dysfunction. However, levels of Oatp1c1 mRNA at GD16 and D3 mRNA at GD20 were too low to be detectable in trophoblast cells. In conclusion, placental Oatp1c1 plays an essential compensatory role when the transplacental passage of maternal THs is insufficient at the stage before the fetal TH production. In addition, the coordinated effects of Oatp1c1, Mct8, D2 and D3 in the placental barrier may regulate both transplacental TH passage and the development of trophoblast cells during thyroid dysfunction throughout the pregnancy. PMID- 24763674 TI - Continuous flow chemistry: a discovery tool for new chemical reactivity patterns. AB - Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up. PMID- 24763675 TI - Delayed phenotypic expression of growth hormone transgenesis during early ontogeny in Atlantic salmon (Salmo salar)? AB - Should growth hormone (GH) transgenic Atlantic salmon escape, there may be the potential for ecological and genetic impacts on wild populations. This study compared the developmental rate and respiratory metabolism of GH transgenic and non-transgenic full sibling Atlantic salmon during early ontogeny; a life history period of intense selection that may provide critical insight into the fitness consequences of escaped transgenics. Transgenesis did not affect the routine oxygen consumption of eyed embryos, newly hatched larvae or first-feeding juveniles. Moreover, the timing of early life history events was similar, with transgenic fish hatching less than one day earlier, on average, than their non transgenic siblings. As the start of exogenous feeding neared, however, transgenic fish were somewhat developmentally behind, having more unused yolk and being slightly smaller than their non-transgenic siblings. Although such differences were found between transgenic and non-transgenic siblings, family differences were more important in explaining phenotypic variation. These findings suggest that biologically significant differences in fitness-related traits between GH transgenic and non-transgenic Atlantic salmon were less than family differences during the earliest life stages. The implications of these results are discussed in light of the ecological risk assessment of genetically modified animals. PMID- 24763676 TI - A risk-based regulatory framework for health IT: recommendations of the FDASIA working group. AB - The Secretary of Health and Human Services (HHS) acting through the Food and Drug Administration (FDA), and in collaboration with the Federal Communications Commission (FCC) and Office of the National Coordinator for Health IT (ONC) was tasked with delivering a report on an appropriate, risk-based regulatory framework for health information technology (IT). An expert stakeholder group was established under the auspices of the Health IT Policy Committee to help provide input into the development of this framework, including how healthcare IT systems could be stratified in terms of risk and recommendations about how the regulatory requirements currently in place should be adapted. In this paper, we summarize the public deliberations and final public report of the expert stakeholder group, and conclude with key suggestions intended to address the charge to recommend the features of a risk-based regulatory framework that promote innovation, protect patient safety, and avoid regulatory duplication. PMID- 24763677 TI - Implementation and evaluation of an efficient secure computation system using 'R' for healthcare statistics. AB - BACKGROUND AND OBJECTIVE: While the secondary use of medical data has gained attention, its adoption has been constrained due to protection of patient privacy. Making medical data secure by de-identification can be problematic, especially when the data concerns rare diseases. We require rigorous security management measures. MATERIALS AND METHODS: Using secure computation, an approach from cryptography, our system can compute various statistics over encrypted medical records without decrypting them. An issue of secure computation is that the amount of processing time required is immense. We implemented a system that securely computes healthcare statistics from the statistical computing software 'R' by effectively combining secret-sharing-based secure computation with original computation. RESULTS: Testing confirmed that our system could correctly complete computation of average and unbiased variance of approximately 50,000 records of dummy insurance claim data in a little over a second. Computation including conditional expressions and/or comparison of values, for example, t test and median, could also be correctly completed in several tens of seconds to a few minutes. DISCUSSION: If medical records are simply encrypted, the risk of leaks exists because decryption is usually required during statistical analysis. Our system possesses high-level security because medical records remain in encrypted state even during statistical analysis. Also, our system can securely compute some basic statistics with conditional expressions using 'R' that works interactively while secure computation protocols generally require a significant amount of processing time. CONCLUSIONS: We propose a secure statistical analysis system using 'R' for medical data that effectively integrates secret-sharing based secure computation and original computation. PMID- 24763678 TI - Autogenous transplantation of a third molar using a two-stage technique. PMID- 24763679 TI - Volumetric evaluation of root resorption during orthodontic treatment. PMID- 24763680 TI - The orthodontics of bobsledding. PMID- 24763681 TI - Early class III facemask treatment with the hybrid hyrax and Alt-RAMEC protocol. PMID- 24763682 TI - The hot seat: temporary anchorage devices. PMID- 24763683 TI - The iTero intraoral scanner in Invisalign treatment: a two-year report. PMID- 24763684 TI - Concise review: unraveling stem cell cocultures in regenerative medicine: which cell interactions steer cartilage regeneration and how? AB - Cartilage damage and osteoarthritis (OA) impose an important burden on society, leaving both young, active patients and older patients disabled and affecting quality of life. In particular, cartilage injury not only imparts acute loss of function but also predisposes to OA. The increase in knowledge of the consequences of these diseases and the exponential growth in research of regenerative medicine have given rise to different treatment types. Of these, cell-based treatments are increasingly applied because they have the potential to regenerate cartilage, treat symptoms, and ultimately prevent or delay OA. Although these approaches give promising results, they require a costly in vitro cell culture procedure. The answer may lie in single-stage procedures that, by using cell combinations, render in vitro expansion redundant. In the last two decades, cocultures of cartilage cells and a variety of (mesenchymal) stem cells have shown promising results as different studies report cartilage regeneration in vitro and in vivo. However, there is considerable debate regarding the mechanisms and cellular interactions that lead to chondrogenesis in these models. This review, which included 52 papers, provides a systematic overview of the data presented in the literature and tries to elucidate the mechanisms that lead to chondrogenesis in stem cell cocultures with cartilage cells. It could serve as a basis for research groups and clinicians aiming at designing and implementing combined cellular technologies for single-stage cartilage repair and treatment or prevention of OA. PMID- 24763685 TI - Differentiation of mouse induced pluripotent stem cells into alveolar epithelial cells in vitro for use in vivo. AB - Alveolar epithelial cells (AECs) differentiated from induced pluripotent stem cells (iPSCs) represent new opportunities in lung tissue engineering and cell therapy. In this study, we modified a two-step protocol for embryonic stem cells that resulted in a yield of ~9% surfactant protein C (SPC)(+) alveolar epithelial type II (AEC II) cells from mouse iPSCs in a 12-day period. The differentiated iPSCs showed morphological characteristics similar to those of AEC II cells. When differentiated iPSCs were seeded and cultured in a decellularized mouse lung scaffold, the cells reformed an alveolar structure and expressed SPC or T1alpha protein (markers of AEC II or AEC I cells, respectively). Finally, the differentiated iPSCs were instilled intratracheally into a bleomycin-induced mouse acute lung injury model. The transplanted cells integrated into the lung alveolar structure and expressed SPC and T1alpha. Significantly reduced lung inflammation and decreased collagen deposition were observed following differentiated iPSC transplantation. In conclusion, we report a simple and rapid protocol for in vitro differentiation of mouse iPSCs into AECs. Differentiated iPSCs show potential for regenerating three-dimensional alveolar lung structure and can be used to abrogate lung injury. PMID- 24763686 TI - Increased genomic integrity of an improved protein-based mouse induced pluripotent stem cell method compared with current viral-induced strategies. AB - It has recently been shown that genomic integrity (with respect to copy number variants [CNVs]) is compromised in human induced pluripotent stem cells (iPSCs) generated by viral-based ectopic expression of specific transcription factors (e.g., Oct4, Sox2, Klf4, and c-Myc). However, it is unclear how different methods for iPSC generation compare with one another with respect to CNV formation. Because array-based methods remain the gold standard for detecting unbalanced structural variants (i.e., CNVs), we have used this approach to comprehensively identify CNVs in iPSC as a proxy for determining whether our modified protein based method minimizes genomic instability compared with retro- and lentiviral methods. In this study, we established an improved method for protein reprogramming by using partially purified reprogramming proteins, resulting in more efficient generation of iPSCs from C57/BL6J mouse hepatocytes than using protein extracts. We also developed a robust and unbiased 1 M custom array CGH platform to identify novel CNVs and previously described hot spots for CNV formation, allowing us to detect CNVs down to the size of 1.9 kb. The genomic integrity of these protein-based mouse iPSCs (p-miPSCs) was compared with miPSCs developed from viral-based strategies (i.e., retroviral: retro-miPSCs or lentiviral: lenti-miPSCs). We identified an increased CNV content in lenti-miPSCs and retro-miPSCs (29~53 CNVs) compared with p-miPSCs (9~10 CNVs), indicating that our improved protein-based reprogramming method maintains genomic integrity better than current viral reprogramming methods. Thus, our study, for the first time to our knowledge, demonstrates that reprogramming methods significantly influence the genomic integrity of resulting iPSCs. PMID- 24763688 TI - A model for the generation and transmission of variations in evolution. AB - The inheritance of characteristics induced by the environment has often been opposed to the theory of evolution by natural selection. However, although evolution by natural selection requires new heritable traits to be produced and transmitted, it does not prescribe, per se, the mechanisms by which this is operated. The mechanisms of inheritance are not, however, unconstrained, because they are themselves subject to natural selection. We introduce a schematic, analytically solvable mathematical model to compare the adaptive value of different schemes of inheritance. Our model allows for variations to be inherited, randomly produced, or environmentally induced, and, irrespectively, to be either transmitted or not during reproduction. The adaptation of the different schemes for processing variations is quantified for a range of fluctuating environments, following an approach that links quantitative genetics with stochastic control theory. PMID- 24763689 TI - [Standardized Descemet membrane endothelial keratoplasty (DMEK): technique and latest results]. AB - BACKGROUND: The procedure of posterior lamellar keratoplasty has now become established as first choice therapy for the treatment of corneal endothelial diseases, with Descemet membrane endothelial keratoplasty (DMEK) as the most recent refinement of endothelial keratoplasty techniques. In this study the outcome of 400 consecutive cases after standardized no-touch DMEK was evaluated. METHODS: This was a non-randomized retrospective clinical study of 400 consecutive eyes in 321 patients who underwent standard DMEK. Outcome measures included best corrected visual acuity (BCVA) preoperatively and postoperatively at 1, 3 and 6 months, endothelial cell density (ECD), pachymetry and complications within the first 6 months. In addition two subgroups were analyzed (subgroup I cases 1-200 and subgroup II cases 201-400). RESULTS: At 6 months postoperatively 80 % of all eyes had a BCVA of >= 20/25 (>= 0.8), 44 % of >= 20/20 (>= 1.0) and 14 % of >= 20/18 (>= 1.2). There were no significant differences between the two subgroups. The mean ECD preoperatively was 2,542 (+/- 217) cells/mm(2) and 6 months postoperatively 1,622 (+/- 500) cells/mm(2). The mean ECD decrease was 36 % 6 months after DMEK. No difference between the subgroups was noted. In 5 % a re-operation was needed of which 75 % were performed in subgroup I. CONCLUSION: With the standardized no-touch DMEK technique a rapid and nearly complete visual rehabilitation as well as ECD values similar to earlier endothelial keratoplasty techniques can be achieved. Therefore DMEK may become the preferred treatment for corneal endothelial disorders. PMID- 24763687 TI - Peroxisome proliferator-activated receptor delta promotes colonic inflammation and tumor growth. AB - Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator activated receptor delta (PPARdelta) attenuates colonic inflammation and colitis associated adenoma formation/growth. Importantly, PPARdelta is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E2 (PGE2), in vivo. We further show that activation of PPARdelta induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARdelta promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages. PMID- 24763690 TI - [Management of suicidal orbital gunshot wounds to the temple]. AB - BACKGROUND: Orbital gunshot wounds are rarely found after suicide. A gunshot fired at point blank range into the temple has devastating effects on all intraorbital and neighboring structures. CASE REPORTS: This article reports on two cases of gunshot wounds to the lateral orbit in attempted suicides with different weapons from 2012 and 2013 and treated at the Ruhr University Eye Hospital in Bochum. In both cases treatment was carried out in cooperation with the department of oral and maxillofacial surgery, Ruhr University Hospital, Bochum. In the first case a 7.65 mm gun was used. The patient presented with a double penetration of both orbits with total destruction of both globes and a reconstruction was not possible. The second patient presented with multiple shots to the head from a small caliber gun (5.6 mm) where one bullet entered the right orbit behind the globe. The bullet could be localized using computed tomography (CT) and surgically removed with preservation of the globe and with a postoperative visual acuity of 20/60. CONCLUSION: The preservation of visual function after orbital gunshot wounds depends on both the projectile channel and the characteristics of the gun and bullet. Close collaboration in surgical management between ophthalmologists, maxillofacial surgeons and neurosurgeons in specialized centers is necessary because patients often present with multiple trauma and prompt interdisciplinary treatment is needed. PMID- 24763691 TI - Bilateral diffuse uveal melanocytic proliferation with multiple iris cysts. AB - IMPORTANCE: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic syndrome with characteristic findings, including exudative retinal detachment, rapid cataract formation, and uveal melanocytic tumors. We report a case notable for bilateral iris and ciliary body cysts--a rare presentation of the disease. OBSERVATIONS: A woman in her 50s presented with bilateral decreased vision. Her medical history was significant for clear cell adenocarcinoma of the endometrium. Slitlamp examination revealed a contiguous ring of pigmented translucent iris cysts at the pupillary margin of each eye, confirmed with ultrasound biomicroscopy. Ophthalmoscopic examination of the left eye showed a geographic patch of subretinal fluid temporal to the macula that was associated with orange polygonal pigment. The patient underwent periocular injection of triamcinolone acetonide, with resolution of the subretinal fluid. Recurrent fluid was treated successfully with a second injection of triamcinolone. CONCLUSIONS AND RELEVANCE: Our case of BDUMP appears to be the first to demonstrate multiple iris and ciliary body cysts with high-quality color photography and ultrasound biomicroscopy. Involvement of the anterior uveal tract may be more common than reported in the literature because of its occult nature. Ultrasound biomicroscopy and anterior segment optical coherence tomography may be useful in patients with suspected BDUMP to identify anterior uveal tract involvement. PMID- 24763693 TI - A universal fluorescence sensing strategy based on biocompatible graphene quantum dots and graphene oxide for the detection of DNA. AB - A novel and efficient fluorescence sensing platform based on biocompatible graphene quantum dots and graphene oxide was established. It showed high selectivity and sensitivity for DNA detection. PMID- 24763695 TI - [Interdisciplinary treatment of soft tissue sarcoma of the extremities]. AB - Soft tissue sarcomas are a rare and heterogeneous group of tumors. Surgery clearly remains the standard therapy of non-metastatic soft tissue sarcoma. A pretreatment biopsy is necessary to determine the histology and grade of soft tissue sarcomas and to diagnose entities that can be treated by targeted therapies, such as dermatofibrosarcoma protuberans or alveolar soft tissue sarcoma once they are in a metastatic stage. Nevertheless, locally advanced disease requires multimodal treatment and interdisciplinary treatment decisions. Limb sarcoma of borderline resectability (encasement of vessels, invasion of joints or close proximity to motor nerves) may profit from isolated limb perfusion with recombinant tumor necrosis factor and melphalan. Preoperative chemotherapy may be applied in locally advanced high grade tumors when clear resection margins are difficult to achieve. Deep wave hyperthermia has proven to be a useful addition to systemic chemotherapy in such a neoadjuvant setting. Also preoperative radiation therapy has proven to be effective in controlling locally advanced sarcoma despite higher perioperative morbidity which pays off in the long run by better limb function. Postoperative adjuvant external beam irradiation therapy with the best available technique is recommended for any tumor larger than 5 cm with (FNLCC) grades 2 and 3 (American Joint Committee on Cancer stage IIb/III). Given all these therapeutic options, it is absolutely crucial that interdisciplinary decision-making starts early in the therapeutic process. Patients are often seen first by the surgeon. For an optimal treatment surgeons need to know the efficacy and toxicity of the multimodal treatment options described. PMID- 24763694 TI - Cationic antimicrobial peptides promote microbial mutagenesis and pathoadaptation in chronic infections. AB - Acquisition of adaptive mutations is essential for microbial persistence during chronic infections. This is particularly evident during chronic Pseudomonas aeruginosa lung infections in cystic fibrosis (CF) patients. Thus far, mutagenesis has been attributed to the generation of reactive species by polymorphonucleocytes (PMN) and antibiotic treatment. However, our current studies of mutagenesis leading to P. aeruginosa mucoid conversion have revealed a potential new mutagen. Our findings confirmed the current view that reactive oxygen species can promote mucoidy in vitro, but revealed PMNs are proficient at inducing mucoid conversion in the absence of an oxidative burst. This led to the discovery that cationic antimicrobial peptides can be mutagenic and promote mucoidy. Of specific interest was the human cathelicidin LL-37, canonically known to disrupt bacterial membranes leading to cell death. An alternative role was revealed at sub-inhibitory concentrations, where LL-37 was found to induce mutations within the mucA gene encoding a negative regulator of mucoidy and to promote rifampin resistance in both P. aeruginosa and Escherichia coli. The mechanism of mutagenesis was found to be dependent upon sub-inhibitory concentrations of LL-37 entering the bacterial cytosol and binding to DNA. LL 37/DNA interactions then promote translesion DNA synthesis by the polymerase DinB, whose error-prone replication potentiates the mutations. A model of LL-37 bound to DNA was generated, which reveals amino termini alpha-helices of dimerized LL-37 bind the major groove of DNA, with numerous DNA contacts made by LL-37 basic residues. This demonstrates a mutagenic role for antimicrobials previously thought to be insusceptible to resistance by mutation, highlighting a need to further investigate their role in evolution and pathoadaptation in chronic infections. PMID- 24763696 TI - Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: possible role of the Akt/GSK3beta signaling pathway. AB - BACKGROUNDS: Early brain injury (EBI) plays a key role in the pathogenesis of subarachnoid hemorrhage (SAH). Neuronal apoptosis is involved in the pathological process of EBI. Hydrogen can inhibit neuronal apoptosis and attenuate EBI following SAH. However, the molecular mechanism underlying hydrogen-mediated anti apoptotic effects in SAH has not been elucidated. In the present study, we aimed to evaluate whether hydrogen alleviates EBI after SAH, specifically neuronal apoptosis, partially via the Akt/GSK3beta signaling pathway. METHODS: Sprague Dawley rats (n = 85) were randomly divided into the following groups: sham group (n = 17), SAH group (n = 17), SAH + saline group (n = 17), SAH + hydrogen-rich saline (HS) group (n = 17) and SAH + HS + Ly294002 (n = 17) group. HS or an equal volume of physiological saline was administered immediately after surgery and repeated 8 hours later. The PI3K inhibitor, Ly294002, was applied to manipulate the proposed pathway. Neurological score and SAH grade were assessed at 24 hours after SAH. Western blot was used for the quantification of Akt, pAkt, GSK3beta, pGSK3beta, Bcl-2, Bax and cleaved caspase-3 proteins. Neuronal apoptosis was identified by double staining of terminal deoxynucleotidyl transferase mediated nick end labeling (TUNEL) staining and NeuN, and quantified by apoptosis index. Immunohistochemistry and immunofluorescent double-labeling staining was performed to clarify the relationships between neuronal apoptosis and pAkt or pGSK3beta. RESULTS: HS significantly reduced neuronal apoptosis and improved neurological function at 24 hours after SAH. The levels of pAkt and pGSK3beta, mainly expressed in neurons, were markedly up-regulated. Additionally, Bcl-2 was significantly increased while Bax and cleaved caspase-3 was decreased by HS treatment. Double staining of pAkt and TUNEL showed few colocalization of pAkt positive cells and TUNEL-positive cells. The inhibitor of PI3K, Ly294002, suppressed the beneficial effects of HS. CONCLUSIONS: HS could attenuate neuronal apoptosis in EBI and improve the neurofunctional outcome after SAH, partially via the Akt/GSK3beta pathway. PMID- 24763697 TI - Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. AB - Exogenous interleukin 6 (IL-6), synthesized at the initiation of the acute phase response, is considered responsible for signaling hepatocytes to produce acute phase proteins. It is widely posited that IL-6 is either delivered to the liver in an endocrine fashion from immune cells at the site of injury, or alternatively, in a paracrine manner by hepatic immune cells within the liver. A recent publication showed there was a muted IL-6 response in lipopolysaccharide (LPS)-injured mice when nuclear NFkappaB was specifically inactivated in the hepatocytes. This indicates hepatocellular signaling is also involved in regulating the acute phase production of IL-6. Herein, we present extensive in vitro and in vivo evidence that normal hepatocytes are directly induced to synthesize IL-6 mRNAs and protein by challenge with LPS, a bacterial hepatotoxin, and by HGF, an important regulator of hepatic homeostasis. As the IL-6 receptor is found on the hepatocyte, these results reveal that induction of the acute phase response can be regulated in an autocrine as well as endocrine/paracrine fashion. Further, herein we provide data indicating that following partial hepatectomy (PHx), HGF differentially regulates IL-6 production in hepatocytes (induces) versus immune cells (suppresses), signifying disparate regulation of the cell sources involved in IL-6 production is a biologically relevant mechanism that has previously been overlooked. These findings have wide ranging ramifications regarding how we currently interpret a variety of in vivo and in vitro biological models involving elements of IL-6 signaling and the hepatic acute phase response. PMID- 24763698 TI - Mapping amyloid-beta(16-22) nucleation pathways using fluorescence lifetime imaging microscopy. AB - The cross-beta peptide architecture is associated with numerous functional biomaterials and deleterious disease related aggregates. While these diverse and ubiquitous paracrystalline assemblies have been widely studied, a fundamental understanding of the nucleation and aggregation pathways to these structures remains elusive. Here we highlight a novel application of fluorescence lifetime imaging microscopy in characterising the critical stages of peptide aggregation. Using the central nucleating core of the amyloid-beta (Abeta), Abeta(16-22), as a model cross-beta system, and utilising a small fraction of rhodamine labelled peptide (Rh110-Abeta(17-22)), we map out a folding pathway from monomer to paracrystalline nanotube. Using this intrinsic fluorescence reporter, we demonstrate the effects of interfaces and evaporation on the nucleation of sub critical concentration solutions, providing access to previously uncharacterised intermediate morphologies. Using fluorescence lifetime we follow the local peptide environment through the stages of nucleation and hydrophobic collapse, ending in a stable final structure. This work provides a metric for future implementations of measuring fluorescence lifetimes of intrinsic fluorescence reporters during the very dynamic processes relating to peptide nucleation and maturation. PMID- 24763699 TI - Rational development of iron catalysts for asymmetric transfer hydrogenation. AB - The asymmetric reduction of ketones and imines by transfer of hydrogen from isopropanol as the solvent catalyzed by metal complexes is a very useful method for preparing valuable enantioenriched alcohols and amines. Described here is the development of three generations of progressively more active iron catalysts for this transformation. Key features of this process of discovery involved the realization that one carbonyl ligand was needed (as in hydrogenases), the synthesis of modular ligands templated by iron, the elucidation of the mechanisms of catalyst activation and action, as well as the rational synthesis of precursors that lead directly and easily to the species in the catalytic cycle. The discovery that iron, an abundant element that is essential to life, can form catalysts of these hydrogenation reactions is a contribution to green chemistry. PMID- 24763700 TI - New variants including ARG1 polymorphisms associated with C-reactive protein levels identified by genome-wide association and pathway analysis. AB - C-reactive protein (CRP) is a general marker of systemic inflammation and cardiovascular disease (CVD). The genetic contribution to differences in CRP levels remains to be explained, especially in non-European populations. Thus, the aim of this study was to identify genetic loci associated with CRP levels in Korean population. We performed genome-wide association studies (GWAS) using SNPs from 8,529 Korean individuals (7,626 for stage 1 and 903 for stage 2). We also performed pathway analysis. We identified a new genetic locus associated with CRP levels upstream of ARG1 gene (top significant SNP: rs9375813, Pmeta = 2.85*10( 8)), which encodes a key enzyme of the urea cycle counteract the effects of nitric oxide, in addition to known CRP (rs7553007, Pmeta = 1.72*10(-16)) and HNF1A loci (rs2259816, Pmeta = 2.90*10(-10)). When we evaluated the associations between the CRP-related SNPs with cardiovascular disease phenotypes, rs9375813 (ARG1) showed a marginal association with hypertension (P = 0.0440). To identify more variants and pathways, we performed pathway analysis and identified six candidate pathways comprised of genes related to inflammatory processes and CVDs (CRP, HNF1A, PCSK6, CD36, and ABCA1). In addition to the previously reported loci (CRP, HNF1A, and IL6) in diverse ethnic groups, we identified novel variants in the ARG1 locus associated with CRP levels in Korean population and a number of interesting genes related to inflammatory processes and CVD through pathway analysis. PMID- 24763702 TI - In the clinic. Multiple sclerosis. PMID- 24763701 TI - Morpho-histology and genotype dependence of in vitro morphogenesis in mature embryo cultures of wheat. AB - Cellular totipotency is one of the basic principles of plant biotechnology. Currently, the success of the procedure used to produce transgenic plants is directly proportional to the successful insertion of foreign DNA into the genome of suitable target tissue/cells that are able to regenerate plants. The mature embryo (ME) is increasingly recognized as a valuable explant for developing regenerable cell lines in wheat biotechnology. We have previously developed a regeneration procedure based on fragmented ME in vitro culture. Before we can use this regeneration system as a model for molecular studies of the morphogenic pathway induced in vitro and investigate the functional links between regenerative capacity and transformation receptiveness, some questions need to be answered. Plant regeneration from cultured tissues is genetically controlled. Factors such as age/degree of differentiation and physiological conditions affect the response of explants to culture conditions. Plant regeneration in culture can be achieved through embryogenesis or organogenesis. In this paper, the suitability of ME tissues for tissue culture and the chronological series of morphological data observed at the macroscopic level are documented. Genetic variability at each step of the regeneration process was evaluated through a varietal comparison of several elite wheat cultivars. A detailed histological analysis of the chronological sequence of morphological events during ontogeny was conducted. Compared with cultures of immature zygotic embryos, we found that the embryogenic pathway occurs slightly earlier and is of a different origin in our model. Cytological, physiological, and some biochemical aspects of somatic embryo formation in wheat ME culture are discussed. PMID- 24763703 TI - Inadvertent corneal intrastromal intraocular lens implantation during phacoemulsification. PMID- 24763704 TI - A radical thia-Brook rearrangement. AB - Geminal mercapto trialkyl- and trialkoxy-silanes undergo an efficient radical chain rearrangement, whereby the silyl group migrates from carbon to sulfur; the starting materials are readily obtained by exploiting the peroxide initiated radical addition of dithiocarbonates (xanthates) to trialkyl- or trialkoxy vinylsilanes. PMID- 24763705 TI - An intervention to improve nursing teamwork using virtual simulation. AB - The purpose of this study was to test the use of virtual simulation to improve teamwork among nursing staff. Using a quasi-experimental design, nursing staff (n = 43) from one patient care unit participated in a 1-hr session, which focused on common nursing teamwork problems. The overall mean teamwork scores improved from pre- (M = 3.25, SD = 0.58) to post-intervention (M = 3.49, SD = 0.67, p < .012). The intervention also had large (0.60 <= d <= 0.97) and significant effects on the measures of three teamwork subscales (i.e., trust, team orientation, and backup). PMID- 24763706 TI - Left atrial wall thickness and outcomes of catheter ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy. AB - PURPOSE: Catheter ablation of atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) is still challenging, and it is unclear whether the difficulty is caused by the hypertrophy of left atrial (LA) myocardial wall thickness. The objective of the study was to compare the LA wall thickness and AF ablation outcomes between patients with HCM and those without structural heart disease. METHODS: The present study enrolled 17 consecutive HCM patients (63 +/- 12 years) with drug-refractory AF and 34 control patients without any detectable heart disease, whose age, gender, type of AF, and LA dimension were matched to the HCM patients. The myocardial wall thickness of 11 distinct LA locations, measured using 64-slice computed tomography images, and AF ablation outcomes were compared between the two groups. RESULTS: The LA wall thickness did not differ at 9 of the 11 locations and was significantly thinner in the HCM patients than in the control patients at the mid-posterior wall (1.44 +/- 0.17 vs. 1.58 +/- 0.22, p = 0.04) and infero-posterior wall (1.62 +/- 0.16 vs. 1.74 +/- 0.18, p = 0.03). Although antiarrhythmic drugs were used more frequently in the HCM patients (p = 0.008), the rate of maintaining sinus rhythm during the follow-up did not differ between the HCM and control patients (53 vs. 56% after the initial ablation [log rank p = 0.78] and 82 and 88% after the repeat procedure [log-rank p = 0.35]). CONCLUSIONS: The LA wall in the HCM patients with AF was not thicker than that of the matched patients without structural heart disease. Catheter ablation of AF showed favorable outcomes in both patient groups. PMID- 24763707 TI - Adipose tissue depot specific promoter methylation of TMEM18. AB - Epigenetic processes such as dynamic promoter methylation may play a role in obesity, fat distribution and its accompanied metabolic alterations. TMEM18 is a candidate gene for body mass index (BMI) comprising the second largest effect size among all loci identified so far via GWAS. We hypothesized that differential TMEM18 gene expression in visceral (VAT) and subcutaneous adipose tissue (SAT) may be a consequence of depot specific differential methylation at the TMEM18 promoter region. Differential methylation levels may confer fat depot specific correlations with measures of obesity and fat distribution. Here, we measured TMEM18 mRNA expression in VAT and SAT from 500 subjects. A total of 146 Caucasian individuals were investigated for differential methylation levels in VAT vs. SAT at three CpG sites. Subsequently, we tested for potential correlation of methylation levels with anthropometric and metabolic parameters. (1) In 500 individuals, we observed significantly decreased mRNA expression in SAT (paired t test, P < 0.0001) compared to VAT with strongest effects in obese subjects. (2) We identified significantly higher methylation levels for the entire CpG locus in SAT (paired t-test, P = 0.00015). In 146 individuals, we detected positive correlations between CpG methylation levels in SAT with parameters of obesity and fat distribution (e.g., BMI, r = 0.173; P = 0.036; visceral fat area, r = 0.246; P = 0.004) and with metabolic traits (P <= 0.05). However, these correlations did not withstand adjustment for covariates. Our data suggest an adipose tissue depot specific TMEM18 promoter methylation that may mediate inter-depot specific variance in TMEM18 mRNA expression. KEY MESSAGES: Higher mean methylation across the entire CpG locus in SAT compared to VAT. Lower TMEM18 mRNA expression levels in SAT compared to VAT. TMEM18 mRNA expression levels are related to phenotypes of obesity and glucose metabolism. PMID- 24763709 TI - Evaluation of bioaccumulation and toxic effects of copper on hepatocellular structure in mice. AB - The present study was to evaluate the hepatotoxicity effects in mice exposed to copper (Cu) used as dietary supplements for 95 days. Cu-treated mice showed increased body weight, and no toxic symptoms were observed at the beginning, but the tendency gradually changed with progress of experiment. In the liver, beneficial metals [Cu, iron (Fe), zinc (Zn), manganese (Mn), and molybdenum (Mo)] were analyzed by flame atomic absorption spectrometry. The content of Cu maintained at the same level during the experiments, but not resulting in the imbalance of Fe, Zn, Mn, and Mo being distributed. The activities of alkaline phosphatase (AKP) and super oxidation dismutase (SOD) showed significantly improvement during the first 30 days in Cu-supplemented group (P<0.01) but declined rapidly from 30th to 60th days, and later, they stabilized and were not statistically significant compared with control (P>0.05). No statistically significant correlation of ceruloplasmin (CPL) activity was appreciated during the experiment. The histopathological and ultrastructural abnormalities changes were observed in the liver of mice including vacuolar degeneration, necrosis, karyorrhexis, and endolysis. Many hepatocytes showed increased collagenic fibers, appearance of triglyceride droplets, and swollen mitochondria due to oral route of copper, which may lead to lipid peroxidation and free radicals. In conclusion, our study showed that exposure to copper influenced behavioral pattern and body weight, affected several enzymatic activities, and led to the physiological and considerable structural changes in the liver of mice. The public should pay more attention to avoid being exposed to copper. PMID- 24763710 TI - Assessment of essential elements and heavy metals content on Mytilus galloprovincialis from river Tagus estuary. AB - Trace elemental content was analysed in edible tissues of Mytilus galloprovincialis collected in five different sampling areas near the mouth of river Tagus estuary in Lisbon. The concentrations of essential elements (S, K, Ca, Fe, Cu, Zn, As, Br and Sr) were determined by energy-dispersive X-ray fluorescence (EDXRF) spectrometry, while toxic elements (Cr, Cd, Hg, Se and Pb) were measured by inductively coupled plasma-atomic emission spectrometry (ICP AES). The results show that the essential elements K and S are present at the highest concentrations in all the studied samples reaching 2,920 and 4,520 MUg g( 1) (fresh weight), respectively. The highest levels of heavy metals found were in two areas close to the city for Pb and Cd, but below the maximum allowed values. PMID- 24763711 TI - Metal levels in the liver, muscle, gill, intestine, and gonad of Lake Van fish (Chalcalburnus tarichi) with abnormal gonad. AB - Recently, an increasing number of studies have shown that Lake Van--the biggest soda lake in the world--is polluted due to an increasing population. Studies have shown abnormalities in the Lake Van fish (Chalcalburnus tarichi), the sole fish species that inhabits the lake. Unlike the vitellogenic and mature oocytes in normal gonads, abnormal gonads show large amounts of connective tissue and young oocytes. In this study, metal levels (nickel [Ni], copper [Cu], cobalt [Co], iron [Fe], zinc [Zn], cadmium [Cd], lead [Pb], and manganese [Mn]) in the muscle, liver, gill, intestine, and gonad of Lake Van fish with normal and abnormal gonads were assessed. Further, the metal contents in the wastewater from the wastewater treatment facility situated near Lake Van in Van City were assessed. All the metal levels, except that of Zn, were high in the Lake Van environment (P<0.05). The highest metal content in the tissues was for Fe, while the lowest level was for Co. The Pb level was found to be very high in both fish groups. Cd was not found in the tissues of both fish groups. The levels of Fe, Cu, Pb, and Mn were not significant in the tissues of both normal and abnormal fish groups. Zn level was significantly high in the livers and gonads of fish with abnormal gonads, and Co level was significantly high only in the livers (P<0.05). Consequently, high levels of Zn in the liver and gonads and high levels of Co in the liver may be factors causing the abnormal gonads in the Lake Van fish. PMID- 24763712 TI - Comparison of serum and tissue levels of trace elements in different models of cervical cancer. AB - Cervical cancer is a leading cause of death by cancer among women worldwide. It is necessary to develop and refine cervical cancer models to more accurately reflect human tumor type. The relevance of cervical cancer to trace element was studied in this paper. By means of quantitative trace element analysis in models and patients with cervical cancer, the tissue and serum levels of trace elements in papillomaviruses-induced cancer models were more similar to that of patients than the levels in models induced by HeLa cell and methylcholanthrene. The results reflect papillomaviruses model most accurately mimic in vivo carcinogenesis of patients with cervical cancer. It will have a superior predictive value over HeLa cell and methylcholanthrene models in pre-clinical trials. The papillomaviruses-induced cervical cancer can provide more reliable models for testing the efficacy of drugs in treating human cancers. PMID- 24763713 TI - Surgical treatment of primary gynecomastia in children and adolescents. AB - PURPOSE: Idiopathic gynecomastia is a common diagnosis in children and adolescents. Though medical treatments reveal potentially harmful side effects, surgical interventions are performable in numerous techniques. In children and adolescents, only minimal evidence exists. This retrospective study presents our experiences with two common surgical techniques, namely subcutaneous mastectomy and combination with liposuction. PATIENTS AND METHODS: This retrospective study included all patients <18 years who underwent surgery due to idiopathic gynecomastia. Height, weight and grade of gynecomastia according to Simon's classification before surgery were reviewed in all patients' files. Additionally, duration of surgery, inpatient stay and postoperative complications were documented. Follow-up examinations were performed with assessment of scar formation, numbness and retraction of the nipple region. Furthermore, patients were asked to report on general satisfaction with surgery (satisfactory/not satisfactory) and esthetic outcome on a numeric scale (1 = good, 6 = bad). RESULTS: 37 patients underwent surgery for verified idiopathic gynecomastia. Grade of gynecomastia was I degrees in 13.5% (n = 5), II degrees in 40.5% (n = 15) and III degrees in 46% (n = 17) of cases. Subcutaneous mastectomy was applied in 11 patients (group I, 30%) and both subcutaneous mastectomy and liposuction in 26 patients (group II, 70.3%). Postoperative complications occurred in two patients. Long-term follow-up was performed in 32 patients after a median of 34 months (range 6-96 months). Hypertrophic scar formation was seen in one patient (3%) and nipple retraction in two patients (5%). Recurrence of gynecomastia occurred in two patients (5%). Patient rating was satisfactory in 9% of cases and esthetic outcome was received with a median of 2.0 (1-5). In comparing both surgical techniques, combination of mastectomy and liposuction revealed better results in every measure except for surgical duration (median 73 vs. 90 min). CONCLUSION: Surgical correction of gynecomastia remains a purely elective intervention. In contrast to adults, skin in children and adolescents provides high retractability. Therefore, open reduction combined with minimally invasive liposuction was proven useful. PMID- 24763714 TI - Microwave-assisted one-pot synthesis and anti-biofilm activity of 2-amino-1H imidazole/triazole conjugates. AB - A microwave-assisted protocol was developed for the construction of 2-amino-1H imidazole/triazole conjugates starting from the previously described 2-hydroxy 2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium salts. The process involves a one pot hydrazinolysis/Dimroth-rearrangement of these salts followed by a ligand-free copper nanoparticle-catalyzed azide-alkyne Huisgen cycloaddition. The 2-amino-1H imidazole/triazole conjugates showed moderate to high preventive activity against biofilms of S. Typhimurium, E. coli, P. aeruginosa and S. aureus. The most active compounds had BIC50 values between 1.3 and 8 MUM. A remarkable finding was that introduction of the triazole moiety into the side chain of 2-aminoimidazoles with a long (C8-C13) 2N-alkyl chain did drastically improve their activity. Conclusively, the 2-amino-1H-imidazole/triazole scaffold provides a lead structure for further design and development of novel biofilm inhibitors. PMID- 24763715 TI - Activation of the C-N bond of N-heterocyclic carbenes by inorganic elements. AB - N-heterocyclic carbenes (NHCs) are generally considered to be extremely robust, ideal spectator ligands. However, in the past two years there have been several reports of the activation of the endocyclic C-N bond with subsequent insertion into element-hydrogen and element-carbon bonds. The new reaction pathway casts the reactivity of the NHC heterocyclic ring into a new light, especially in the context of potential catalyst decomposition. The synthetic reports and theoretical studies in this rapidly developing area are summarized here. PMID- 24763716 TI - The effect of primary care fellowship training on career satisfaction, happiness and perceived stress. AB - PURPOSE: This study was designed to measure the impact of primary care fellowship training on the subsequent happiness, career satisfaction and perceived stress levels of fellowship-trained physicians as compared to a general population of Family Medicine physicians in North Carolina. METHODS: A written survey instrument was completed by fellowship graduates of the Brody School of Medicine (n=53) and general population of Family Medicine physicians in North Carolina (n=203) in 2011. The survey included general demographic and practice variables, and validated psychological scales on subjective happiness, satisfaction with life, and perceived stress. RESULTS: Fellowship graduates (n=50), and non fellowship graduates (n=203), exhibited similar levels of satisfaction with life (fellows=27.36 SD 5.45, FM physicians=26.91, SD 5.99 on a 5-35 scale), statistically higher levels of perceived stress (fellows=5.92, SD 3.03, FM physicians=4.98, SD 2.70 on a 0-16 scale), and significantly higher levels of subjective happiness (fellows=5.61SD 83, FM physician=4.75 SD 1.00 on a 1-7 scale). Female fellow response was significantly higher on the Satisfaction with Life and Subjective Happiness Scores, and lower on the Perceived Stress Scale. Male fellowship graduates presented with a reverse relationship, with higher perceived stress and lower satisfaction with life and subjective happiness. CONCLUSIONS: Fellowship training exhibited a positive psychological effect on the graduate respondents versus the general physician population. Scores on various well-being scales were higher than the general Family Medicine physician population as a whole, although stress levels were also higher. Female physicians seem to garner a much larger gain in satisfaction than male fellowship graduates, who score slightly worse than the general family medicine population on the satisfaction with life and Perceived Stress Scales. PMID- 24763717 TI - Clinical outcomes of Carbomedics Top Hat valve with a robust follow-up system. AB - AIM: Late failure of bioprosthetic valves may limit their use in patients < 60 years. The superior hemodynamic performance offered by the Carbomedics Top Hat supraannular valve enables greater effective orifice areas to be achieved. The aim of this study was to assess the clinical outcomes of this valve, using a robust follow-up system. METHODS: Patients who underwent aortic valve replacement with or without coronary artery bypass grafting between July 1997 and January 2010 with Carbomedics supraannular Top Hat valves were identified. Details of readmissions and late deaths were obtained from the National Hospital Episodes Statistics data and the Office of National Statistics, tracked by the Quality and Outcomes Research Unit. Late complications associated with this prosthesis were evaluated. RESULTS: Of 253 patients identified, 181 underwent isolated aortic valve replacement and 72 had aortic valve replacement with coronary artery bypass grafting. The 30-day mortality was 1.6%, and 5- and 10-year survival rates were 91.4% and 80.5%, respectively. Detailed readmission data were available after 2001 (n = 170). Two (1.2%) patients required reoperation for endocarditis and pannus formation. Of the 17 late deaths in this subset, 4 were attributable to cardiac causes. One patient was treated for heart failure, and 2 developed bleeding complications. CONCLUSIONS: Implantation of the Carbomedics Top Hat supraannular valve in our unit resulted in satisfactory in-hospital and midterm survival with low incidences of endocarditis and late heart failure. PMID- 24763719 TI - The effect of femtosecond laser capsulotomy on the development of posterior capsule opacification. AB - PURPOSE: To evaluate and compare the effects of femtosecond laser-assisted anterior capsulotomy and manual anterior capsulorhexis on posterior capsule opacification (PCO) development. METHODS: Femtosecond laser-assisted anterior capsulotomy was performed in 40 eyes of 40 patients (FS group) and manual anterior capsulorhexis was performed in 39 eyes of 39 patients (CCC group). An AcrySof one-piece hydrophobic acrylic intraocular lens (Alcon Laboratories, Inc., Fort Worth, TX) was implanted in all eyes. The PCO level was measured using Open Access Systematic Capsule Assessment (OSCA) software 18 to 26 months after surgery. Postoperative intraocular lens position (ie, tilt and decentration) was measured using Scheimpflug images (Pentacam; Oculus Optikgerate GmbH, Wetzlar, Germany). RESULTS: There was no statistically significant difference in age, axial length, and follow-up time between the two groups (P > .05). Vertical tilt, horizontal and total decentration of intraocular lenses, and PCO proved to be significantly higher in the CCC group (P = .03, .04, .03, and .01, respectively). After adjusting for axial length and follow-up time, manual anterior capsulorhexis was found to be a significant predictor of higher PCO scores in the multivariable regression model (beta: 0.33; 95% CI: 0.01 to 0.65; P = .04). Vertical tilt affected PCO scores after adjusting for axial length and follow-up time (beta: 0.07; 95% CI: 0.01 to 0.12; P = .02). No capsulotomies were performed during follow-up in either group. CONCLUSIONS: Femtosecond laser-assisted anterior capsulotomy proved to be a safe procedure for postoperative PCO rates. Due to better intraocular lens position, femtosecond laser-assisted anterior capsulotomy resulted in slightly decreased PCO scores; however, evaluating its clinical significance requires further studies. PMID- 24763720 TI - The role of the mesopic pupil on patient-reported outcomes in young patients with myopia 1 month after wavefront-guided LASIK. AB - PURPOSE: To determine the relationship between low-light pupil size and patient reported outcomes 1 month after wavefront-guided LASIK in young patients with myopia. METHODS: Retrospective case series of 10,944 eyes of 5,563 young patients with myopia who underwent wavefront-guided LASIK (6.0-mm optical zone). Preoperative pupil size was measured under low-light conditions with an infrared pupillometer. Visual and refractive outcomes were evaluated at 1 month postoperatively. A questionnaire was administered to assess patient-reported outcomes including satisfaction with the procedure, night driving, and glare and halo visual symptoms. RESULTS: The average patient age was 29.8 years (range: 18 to 40 years). The mean preoperative manifest spherical equivalent of -3.49 diopters (D) (range: -0.50 to -11.75 D) was reduced to -0.04 +/- 0.29 D at 1 month, with 94% of eyes achieving an uncorrected distance visual acuity of 20/20 or better. The mean low-light pupil diameter was 6.6 mm (range: 4 to 9 mm) and 1,514 patients (27.2%) had a diameter of 8 mm or larger. No correlation between pupil diameter and patient-reported outcomes was found (r range: -0.02 to 0.07). Logistic regression analysis identified postoperative uncorrected distance visual acuity and postoperative manifest refraction as significant predictors of night halo complaints after wavefront-guided LASIK (P < .01). CONCLUSIONS: In this large series of young patients with myopia treated with wavefront-guided LASIK, low-light pupil diameter was not predictive of surgery satisfaction, ability to perform activities, or visual symptoms at 1 month postoperatively. PMID- 24763718 TI - JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants. AB - JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7*10(-15)) and controls (OR = 0.53, p = 2*10(-5)). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1*10(-5)). The German dataset confirmed these findings (OR = 0.54, p = 1*10(-4) and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention. PMID- 24763721 TI - Confocal microscopy evaluation of the corneal response following AcuFocus KAMRA inlay implantation. AB - PURPOSE: To describe the corneal appearance on confocal microscopy after AcuFocus KAMRA Inlay (AcuFocus, Inc., Irvine, CA) implantation and evaluate the visual acuity compared to the confocal microscopy data. METHODS: Twelve eyes of 12 patients implanted with one of three models of the AcuFocus KAMRA Inlay (ACI 7000, 7000T, and 7000PDT) were prospectively evaluated by confocal microscopy 6 months after implantation. Additionally, 4 eyes of 4 patients explanted during the follow-up period were evaluated. RESULTS: Among the eyes implanted, mean epithelial thickness was 54.6 +/- 22 MUm. The subbasal nerve plexus was detected in 10 patients. The corneal nerves per unit area were 2.73 +/- 2.1 sprouts/mm(2). The branch pattern was found in 8 patients. The mean keratocyte density value was 540 +/- 210 cells/mm(2). A low grade of keratocyte activation was found in all patients. Among the eyes explanted, the mean wound healing opacity was 1,092.75 +/- 1,877.35 MUm/pixel. CONCLUSIONS: The corneal tolerance to the KAMRA Inlay appeared to be good. The inlay modified the normal structure of the corneal layer, but it was not associated with severe complications of the eye. Keratocyte activation was the finding most associated with a negative visual outcome. Confocal microscopy can be useful to evaluate the long-term evolution of the corneal layer changes following KAMRA Inlay implantation. PMID- 24763722 TI - AcuTarget measurements: repeatability and comparison to OPD-Scan III. AB - PURPOSE: To evaluate repeatability of the AcuTarget (SensoMotoric Instruments, Teltow, Germany) measurements and compare them to those obtained with the OPD Scan III (NIDEK, Inc., Fremont, CA). METHODS: Measurements were taken with the AcuTarget and OPD-Scan III in 62 eyes of 31 patients. Results were compared using paired Student's t tests, Pearson correlation coefficients, and 95% limits of agreement. RESULTS: Repeatability of the AcuTarget was good with intraclass correlation coefficients of 0.773, 0.777, and 0.780 for Purkinje-versus-pupil along the x-axis, y-axis, and chord length measurements, respectively. No statistically significant difference was observed between the AcuTarget and OPD Scan III for Purkinje-versus-pupil measurement along the x-axis (P = .061) and chord length (P = .950). Conversely, a statistically significant difference was observed between the two systems for measurements along the y-axis (P < .001). No statistical difference was found between the mean of the first three acquisitions and the best acquisition obtained with the AcuTarget. CONCLUSIONS: Measurements provided by the AcuTarget have good repeatability and are close to those obtained with the OPD-Scan III. Although controversies remain on where to best center refractive procedures, this may help in analyzing the importance of refractive surgery centration in relation to visual acuity and visual symptoms. PMID- 24763723 TI - Dry eye after small incision lenticule extraction and LASIK for myopia. AB - PURPOSE: To compare the effects of small incision lenticule extraction (SMILE) and LASIK with either femtosecond laser or mechanical microkeratome on dry eye. METHODS: A total of 176 patients (338 eyes) who underwent refractive procedures for myopia were observed in this nonrandomized, interventional, prospective study. To evaluate dry eye, the Schirmer secretion test without anesthesia, tear break-up time, and the McMonnies questionnaire were used preoperatively and at 1, 3, and 6 months postoperatively. RESULTS: In all groups, there was no significant decrease in the results from the Schirmer secretion test without anesthesia after surgery. The value in the LASIK group was significantly lower than any other group at 3 and 6 months postoperatively. In all groups, the tear break-up time decreased significantly after surgery and did not return to preoperative levels within 6 months; the SMILE group time lasted significantly longer than the LASIK group at 1 month. The McMonnies score increased significantly in all groups after surgery. The preoperative levels returned within 6 months in all groups except the LASIK group. The mean McMonnies score in the SMILE group was better than other groups. CONCLUSIONS: Dry eye after corneal refractive surgery usually occurs transiently. The SMILE procedure had better dry eye parameters and relatively fewer subjective symptoms than LASIK. PMID- 24763724 TI - Age-related changes in anterior, posterior, and total corneal astigmatism. AB - PURPOSE: To evaluate age-related changes in anterior, posterior, and total corneal astigmatism by comparing simulated keratometric astigmatism to total corneal astigmatism. METHODS: Corneal topography of the anterior and posterior surfaces was evaluated using three-dimensional optical coherence tomography in 419 patients with normal eyes (218 men and 201 women) with ages ranging from 8 to 93 years (mean +/- standard deviation: 49.5 +/- 23.1 years). Keratometric astigmatism was calculated using the keratometric index (1.3375) and radius of the anterior corneal curvature; anterior and posterior corneal curvature measurements were used to calculate total corneal astigmatism. RESULTS: The keratometric and total astigmatism were 1.08 +/- 0.71 diopters (D) and 1.03 +/- 0.69 D, respectively. Vector analysis revealed a mean difference between keratometric and total astigmatism of 0.24 +/- 0.09 D, which showed a significant correlation to age (P < .0001). In eyes with with-the-rule astigmatism, keratometric astigmatism overestimated total astigmatism. In eyes with against the-rule astigmatism, keratometric astigmatism underestimated total astigmatism. CONCLUSIONS: The anterior corneal surface shifts from with-the-rule to against the-rule astigmatism with aging, whereas the posterior corneal surface remains as against-the-rule astigmatism in most cases. The variation in the anterior astigmatism is the most important factor contributing to this change. Total corneal astigmatism is a better predictor than keratometric astigmatism for selecting toric intraocular lenses. PMID- 24763725 TI - Intraocular lens fixated in the anterior capsulotomy created in the line of sight by a femtosecond laser. AB - PURPOSE: To describe a new surgical technique and a new generation of foldable, hydrophilic acrylate intraocular lenses available for femtosecond laser-assisted capsulotomy. METHODS: After femtosecond laser-assisted capsulotomy (diameter: 5.2 mm) and lens fragmentation, the new intraocular lens (90F; Morcher GmbH, Stuttgart, Germany) was implanted in the capsular bag. Three-dimensional spectral domain optical coherence tomography scanned the anterior and posterior capsules to create the position of the anterior capsulotomy. The anterior capsulotomy rim was positioned in the flank of the intraocular lens optic. Distance visual acuity, refractive outcome, and anterior chamber depth were measured at 1 week and 1 month postoperatively. RESULTS: No complications were observed at the 1 month follow-up in 6 eyes of 6 patients. No statistically significant changes in anterior chamber depth and refraction were observed at 1 week and 1 month postoperatively. CONCLUSIONS: Image-guided femtosecond lasers can perform a capsulotomy with a predictable size and position according to the line of sight. After implanting the 90F intraocular lens, the final effective lens position can be achieved sooner and may allow more predictable refractive outcomes. PMID- 24763726 TI - Corneal curvature gradient map: a new corneal topography map to predict the corneal healing process. AB - PURPOSE: To evaluate a new curvature gradient topography map to predict postoperative corneal remodeling. METHODS: In this retrospective study, 32 eyes of 16 patients with myopia underwent excimer ablation surgery with a postoperative high curvature gradient. The new curvature gradient map (acquired immediately postoperatively) shows the difference between the curvatures of two points over the distance between them; it was compared to the tangential curvature difference map between 1 and 12 months postoperatively to determine their relationship. Corneas were divided into 12 regions for analysis: four 90 degrees -wide sectors centered on 0 degrees , 90 degrees , 180 degrees , and 270 degrees . There were three subdivisions in each sector: central (radius: 0 to 2.75 mm), paracentral (radius: 2.75 to 3.25 mm), and peripheral (radius: 3.25 to 4.5 mm). Linear regression analysis was performed by region. RESULTS: The following regions had significant relationships between the initial curvature gradient and curvature difference between 1 and 12 months postoperatively: the paracentral zone of the 90 degrees sector (P = .0145; R(2) = 0.1832) and both the central (P = .0034; R(2) = 0.2522) and paracentral (P = .0452; R(2) = 0.1271) zones of the 270 degrees sector. The greatest average initial tangential curvature was in the 270 degrees sector. CONCLUSIONS: The initial curvature gradient after surgery predicted change in tangential curvature over the subsequent 12 months in areas where initial tangential curvature was greatest. When the curvature gradient was high, the surface curvature modification remained in progress months after surgery. PMID- 24763727 TI - Air puff induced corneal vibrations: theoretical simulations and clinical observations. AB - PURPOSE: To investigate air puff induced corneal vibrations and their relationship to the intraocular pressure (IOP), viscoelasticity, mass, and elasticity of the cornea based on theoretical simulations and preliminary clinical observations. METHODS: To simulate the corneal movement during air puff deformation, a kinematic viscoelastic corneal model was developed involving the factors of corneal mass, damping coefficient, elasticity, and IOP. Different parameter values were taken to investigate how factors would affect the corneal movements. Two clinical ocular instruments, CorVis ST (Oculus Optikgerate GmbH, Wetzlar, Germany) and the Ocular Response Analyzer (ORA; Reichert, Inc., Buffalo, NY), were employed to observe the corneal dynamical behaviors. RESULTS: Numerical results showed that during the air puff deformation, there would be vibrations along with the corneal deformation, and the damping viscoelastic response of the cornea had the potential to reduce the vibration amplitude. With consistent IOP, the overall vibration amplitude and inward motion depths were smaller with a stiffer cornea. CONCLUSIONS: A kinematic viscoelastic model of the cornea is presented to illustrate how the vibrations are associated with factors such as corneal mass, viscoelasticity, and IOP. Also, the predicted corneal vibrations during air puff deformation were confirmed by clinical observation. PMID- 24763728 TI - Efficacy and safety of eldecalcitol, a new active vitamin D3 analog, in the bone metabolism of postmenopausal women receiving maintenance hemodialysis. AB - Eldecalcitol (ELD), a new active vitamin D3 analog developed in Japan, has attracted attention as an effective osteoporotic therapeutic drug. However, because ELD leads to greater calcium absorption than does conventional active vitamin D3, it has yet to be used in patients with renal insufficiency. Therefore, we evaluated the efficacy and safety of ELD treatment in 27 postmenopausal women receiving maintenance dialysis in our institution and underwent ELD treatment (starting at 0.5 MUg/day) for 6 months. The mean serum albumin-corrected calcium (Caalb) level was significantly increased following treatment (9.01 +/- 0.60 before versus 9.56 +/- 0.55 after treatment, mean +/- SD). Severe hypercalcemia was prevented through cessation or adjustment of the dosage of calcium-containing phosphate binders or existing active vitamin D. The mean serum phosphorus and intact parathyroid hormone levels were well-controlled throughout. The median levels of bone turnover markers, bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase-5b were significantly decreased. The mean lumbar spine bone mineral density (BMD) was increased, a significant difference being observed in age-matched Z-scores (-0.60 +/- 1.6 versus -0.36 +/- 1.5, p = 0.018). The average change in lumbar spine BMD after ELD treatment was 3.10%, and in patients with a T-score of <-4.0, it was 5.63%. There was no effect on forearm BMD. Although this study is based on short-term observation in a single institution, our results suggest that ELD could be used to increase bone density in dialysis patients. PMID- 24763730 TI - Inhibition of breast cancer metastasis suppressor 1 promotes a mesenchymal phenotype in lung epithelial cells that express oncogenic K-RasV12 and loss of p53. AB - Expression of the breast cancer metastasis suppressor 1 (BRMS1) protein is dramatically reduced in non-small cell lung cancer (NSCLC) cells and in primary human tumors. Although BRMS1 is a known suppressor of metastasis, the mechanisms through which BRMS1 functions to regulate cell migration and invasion in response to specific NSCLC driver mutations are poorly understood. To experimentally address this, we utilized immortalized human bronchial epithelial cells in which p53 was knocked down in the presence of oncogenic K-RasV12 (HBEC3-p53KD-K RasV12). These genetic alterations are commonly found in NSCLC and are associated with a poor prognosis. To determine the importance of BRMS1 for cytoskeletal function, cell migration and invasion in our model system we stably knocked down BRMS1. Here, we report that loss of BRMS1 in HBEC3-p53KD-K-RasV12 cells results in a dramatic increase in cell migration and invasion compared to controls that expressed BRMS1. Moreover, the loss of BRMS1 resulted in additional morphological changes including F-actin re-distribution, paxillin accumulation at the leading edge of the lamellapodium, and cellular shape changes resembling mesenchymal phenotypes. Importantly, re-expression of BRMS1 restores, in part, cell migration and invasion; however it does not fully reestablish the epithelial phenotype. These finding suggests that loss of BRMS1 results in a permanent, largely irreversible, mesenchymal phenotype associated with increased cell migration and invasion. Collectively, in NSCLC cells without p53 and expression of oncogenic K Ras our study identifies BRMS1 as a key regulator required to maintain a cellular morphology and cytoskeletal architecture consistent with an epithelial phenotype. PMID- 24763731 TI - Behaviour of whey protein emulsion gel during oral and gastric digestion: effect of droplet size. AB - A set of whey protein stabilized-emulsion gels with different droplet size distributions (D4,3 = ~1, 6 and 12 MUm) was produced, and the mechanical properties of the gels in the linear viscoelastic region and at large deformation were measured, along with the physicochemical and structural changes of the gels during oral mastication and gastric digestion. The gels containing 1 MUm oil droplets had an aggregated particle structure with proteins coating at oil droplets whereas the gels containing 12 MUm oil droplets had a particle-filled structure with spatially continuous matrix. During oral processing, the release of oil droplets from the gels increased as the droplet size increased, with coalescence being seen in gels containing oil droplets of 6 and 12 MUm diameter. Under gastric digestion, high degrees of coalescence and phase separation of oil droplets occurred in the gels containing 6 and 12 MUm oil droplets because of oil droplet release from the gel matrix; this led to slow gastric emptying. The gels were finally broken down into peptide aggregates and oil droplets (or free oil). The gels, containing 1 MUm oil droplets disintegrated into various particles of several to several tens of microns with a low degree of oil droplet release and coalescence. Protein breakdown was slower in these gels, suggesting that the protein structures of the gel matrices were affected by the sizes of the incorporated oil droplets. PMID- 24763732 TI - Melvin L. Rubin, MD (1932-2014). PMID- 24763733 TI - Correlating Fischer-Tropsch activity to Ru nanoparticle surface structure as probed by high-energy X-ray diffraction. AB - Synchrotron X-ray diffraction coupled to atomic pair distribution function analysis and Reverse Monte Carlo simulations is used to determine the atomic scale structure of Ru nanoparticle catalysts for the Fischer-Tropsch reaction. The rate of CO hydrogenation strongly correlates with the abundance of surface atoms with coordination numbers of 10 and 11. DFT calculations confirm that CO dissociation proceeds with a low barrier on these Ru surface atom ensembles. PMID- 24763735 TI - On the poisson's ratio of the nucleus pulposus. AB - Existing experimental data on the Poisson's ratio of nucleus pulposus (NP) tissue is limited. This study aims to determine whether the Poisson's ratio of NP tissue is strain-dependent, strain-rate-dependent, or varies with axial location in the disk. Thirty-two cylindrical plugs of bovine tail NP tissue were subjected to ramp-hold unconfined compression to 20% axial strain in 5% increments, at either 30 MUm/s or 0.3 MUm/s ramp speeds and the radial displacement determined using biaxial video extensometry. Following radial recoil, the true Poisson's ratio of the solid phase of NP tissue increased linearly with increasing strain and demonstrated strain-rate dependency. The latter finding suggests that the solid matrix undergoes stress relaxation during the test. For small strains, we suggest a Poisson's ratio of 0.125 to be used in biphasic models of the intervertebral disk. PMID- 24763734 TI - Finding and characterizing the complexes of drug like molecules with quadruplex DNA: combined use of an enhanced hydroxyl radical cleavage protocol and NMR. AB - Structural information on the complexes of drug like molecules with quadruplex DNAs can aid the development of therapeutics and research tools that selectively target specific quadruplex DNAs. Screening can identify candidate molecules that require additional evaluation. An enhanced hydroxyl radical cleavage protocol is demonstrated that can efficiently provide structural information on the complexes of the candidate molecules with quadruplex DNA. NMR methods have been used to offer additional structural information about the complexes as well as validate the results of the hydroxyl radical approach. This multi-step protocol has been demonstrated on complexes of the chair type quadruplex formed by the thrombin binding aptamer, d(GGTTGGTGTGGTTGG). The hydroxyl radical results indicate that NSC 176319, Cain's quinolinium that was found by screening, exhibits selective binding to the two TT loops. The NMR results are consistent with selective disruption of the hydrogen bonding between T4 and T13 as well as unstacking of these residues from the bottom quartet. Thus, the combination of screening, hydroxyl radical footprinting and NMR can find new molecules that selectively bind to quadruplex DNAs as well as provide structural information about their complexes. PMID- 24763736 TI - Noncanonical role for the host Vps4 AAA+ ATPase ESCRT protein in the formation of Tomato bushy stunt virus replicase. AB - Assembling of the membrane-bound viral replicase complexes (VRCs) consisting of viral- and host-encoded proteins is a key step during the replication of positive stranded RNA viruses in the infected cells. Previous genome-wide screens with Tomato bushy stunt tombusvirus (TBSV) in a yeast model host have revealed the involvement of eleven cellular ESCRT (endosomal sorting complexes required for transport) proteins in viral replication. The ESCRT proteins are involved in endosomal sorting of cellular membrane proteins by forming multiprotein complexes, deforming membranes away from the cytosol and, ultimately, pinching off vesicles into the lumen of the endosomes. In this paper, we show an unexpected key role for the conserved Vps4p AAA+ ATPase, whose canonical function is to disassemble the ESCRT complexes and recycle them from the membranes back to the cytosol. We find that the tombusvirus p33 replication protein interacts with Vps4p and three ESCRT-III proteins. Interestingly, Vps4p is recruited to become a permanent component of the VRCs as shown by co-purification assays and immuno-EM. Vps4p is co-localized with the viral dsRNA and contacts the viral (+)RNA in the intracellular membrane. Deletion of Vps4p in yeast leads to the formation of crescent-like membrane structures instead of the characteristic spherule and vesicle-like structures. The in vitro assembled tombusvirus replicase based on cell-free extracts (CFE) from vps4Delta yeast is highly nuclease sensitive, in contrast with the nuclease insensitive replicase in wt CFE. These data suggest that the role of Vps4p and the ESCRT machinery is to aid building the membrane bound VRCs, which become nuclease-insensitive to avoid the recognition by the host antiviral surveillance system and the destruction of the viral RNA. Other (+)RNA viruses of plants and animals might also subvert Vps4p and the ESCRT machinery for formation of VRCs, which require membrane deformation and spherule formation. PMID- 24763737 TI - Never in mitosis gene A related kinase-6 attenuates pressure overload-induced activation of the protein kinase B pathway and cardiac hypertrophy. AB - Cardiac hypertrophy appears to be a specialized form of cellular growth that involves the proliferation control and cell cycle regulation. NIMA (never in mitosis, gene A)-related kinase-6 (Nek6) is a cell cycle regulatory gene that could induce centriole duplication, and control cell proliferation and survival. However, the exact effect of Nek6 on cardiac hypertrophy has not yet been reported. In the present study, the loss- and gain-of-function experiments were performed in Nek6 gene-deficient (Nek6-/-) mice and Nek6 overexpressing H9c2 cells to clarify whether Nek6 which promotes the cell cycle also mediates cardiac hypertrophy. Cardiac hypertrophy was induced by transthoracic aorta constriction (TAC) and then evaluated by echocardiography, pathological and molecular analyses in vivo. We got novel findings that the absence of Nek6 promoted cardiac hypertrophy, fibrosis and cardiac dysfunction, which were accompanied by a significant activation of the protein kinase B (Akt) signaling in an experimental model of TAC. Consistent with this, the overexpression of Nek6 prevented hypertrophy in H9c2 cells induced by angiotonin II and inhibited Akt signaling in vitro. In conclusion, our results demonstrate that the cell cycle regulatory gene Nek6 is also a critical signaling molecule that helps prevent cardiac hypertrophy and inhibits the Akt signaling pathway. PMID- 24763738 TI - A comparison of multivariate genome-wide association methods. AB - Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three quantitative traits and one bi-allelic quantitative trait locus (QTL), and varied the number of traits associated with the QTL (explained variance 0.1%), minor allele frequency of the QTL, residual correlation between the traits, and the sign of the correlation induced by the QTL relative to the residual correlation. We compared the power of the methods using empirically fixed significance thresholds (alpha = 0.05). Our results showed that the multivariate methods implemented in PLINK, SNPTEST, MultiPhen and BIMBAM performed best for the majority of the tested scenarios, with a notable increase in power for scenarios with an opposite sign of genetic and residual correlation. All multivariate analyses resulted in a higher power than univariate analyses, even when only one of the traits was associated with the QTL. Hence, use of multivariate GWAS methods can be recommended, even when genetic correlations between traits are weak. PMID- 24763740 TI - Characterization of Staphylococcus aureus from distinct geographic locations in China: an increasing prevalence of spa-t030 and SCCmec type III. AB - Staphylococcus aureus belongs to one of the most common bacteria causing healthcare and community associated infections in China, but their molecular characterization has not been well studied. From May 2011 to June 2012, a total of 322 non-duplicate S. aureus isolates were consecutively collected from seven tertiary care hospitals in seven cities with distinct geographical locations in China, including 171 methicillin sensitive S. aureus (MSSA) and 151 MRSA isolates. All isolates were characterized by spa typing. The presence of virulence genes was tested by PCR. MRSA were further characterized by SCCmec typing. Seventy four and 16 spa types were identified among 168 MSSA and 150 MRSA, respectively. One spa type t030 accounted for 80.1% of all MRSA isolates, which was higher than previously reported, while spa-t037 accounted for only 4.0% of all MRSA isolates. The first six spa types (t309, t189, t034, t377, t078 and t091) accounted for about one third of all MSSA isolates. 121 of 151 MRSA isolates (80.1%) were identified as SCCmec type III. pvl gene was found in 32 MSSA (18.7%) and 5 MRSA (3.3%) isolates, with ST22-MSSA-t309 as the most commonly identified strain. Compared with non-epidemic MRSA clones, epidemic MRSA clones (corresponding to ST239) exhibited a lower susceptibility to rifampin, ciprofloxacin, gentamicin and trimethoprim-sulfamethoxazole, a higher prevalence of sea gene and a lower prevalence of seb, sec, seg, sei and tst genes. The increasing prevalence of multidrug resistant spa-t030 MRSA represents a major public health problem in China. PMID- 24763744 TI - First report of fossil "keratose" demosponges in Phanerozoic carbonates: preservation and 3-D reconstruction. AB - Fossil record of Phanerozoic non-spicular sponges, beside of being important with respect to the lineage evolution per se, could provide valuable references for the investigation of Precambrian ancestral animal fossils. However, although modern phylogenomic studies resolve non-spicular demosponges as the sister group of the remaining spiculate demosponges, the fossil record of the former is extremely sparse or unexplored compared to that of the latter; the Middle Cambrian Vauxiidae Walcott 1920, is the only confirmed fossil taxon of non spicular demosponges. Here, we describe carbonate materials from Devonian (Upper Givetian to Lower Frasnian) bioherms of northern France and Triassic (Anisian) microbialites of Poland that most likely represent fossil remnants of keratose demosponges. These putative fossils of keratose demosponges are preserved as automicritic clumps. They are morphologically distinguishable from microbial fabrics but similar to other spiculate sponge fossils, except that the skeletal elements consist of fibrous networks instead of assembled spicules. Consistent with the immunological behavior of sponges, these fibrous skeletons often form a rim at the edge of the automicritic aggregate, separating the inner part of the aggregate from foreign objects. To confirm the architecture of these fibrous networks, two fossil specimens and a modern thorectid sponge for comparison were processed for three-dimensional (3-D) reconstruction using serial grinding tomography. The resulting fossil reconstructions are three-dimensionally anastomosing, like modern keratose demosponges, but their irregular and nonhierarchical meshes indicate a likely verongid affinity, although a precise taxonomic conclusion cannot be made based on the skeletal architecture alone. This study is a preliminary effort, but an important start to identify fossil non spicular demosponges in carbonates and to re-evaluate their fossilization potential. PMID- 24763745 TI - Role of c-Jun N-terminal kinase (JNK) activation in micturition reflexes in cyclophosphamide (CYP)-induced cystitis in female rats. AB - c-Jun N-terminal kinase (JNK) is member of the mitogen-activated protein kinase (MAPK) family, activated through phosphorylation following cytokine exposure and stress. In this study, phosphorylation of JNK was examined in the urinary bladder with cyclophosphamide (CYP)-induced cystitis and the effects of SP600125, a selective inhibitor of phosphorylation of JNK, on urinary bladder function were assessed using conscious, open outlet, cystometry with continuous instillation of intravesical saline. We induced bladder inflammation in adult female Wistar rats by injecting CYP intraperitoneally to produce acute (150 mg/kg; 4 h), intermediate (150 mg/kg; 48 h), and chronic (75 mg/kg; every third day for 10 days) treatments. Western blotting of urinary bladder demonstrated a significant (p <= 0.01) increase (i.e., phosphorylation) in JNK activation with 4- and 48-h CYP-induced cystitis. Immunohistochemistry and image analyses demonstrated a significant (p <= 0.01) increase in JNK activation in the urothelium with 4- and 48-h CYP-induced cystitis. Blockade of JNK phosphorylation significantly (p <= 0.01) increased bladder capacity and intercontraction void intervals in CYP treated rats (4 and 48 h). Furthermore, blockade of JNK phosphorylation reduced (p <= 0.01) neuropeptide (substance P, calcitonin gene-related peptide) expression in the urinary bladder with CYP-induced cystitis (4 and 48 h). In contrast, blockade of JNK phosphorylation was without effect on bladder function or neuropeptide expression in urinary bladder in control (no inflammation) rats. Blockade of JNK phosphorylation may represent a novel target for improving urinary bladder function with CYP-induced cystitis. PMID- 24763746 TI - Stress fiber response to mechanics: a free energy dependent statistical model. AB - An experimental observation has been puzzling scientists for years: cells tend to align perpendicular to cyclic uniaxial strain, but parallel to external static strain. Recent experimental results demonstrate that both the magnitude of the external strain and the cell contractility manipulate the cells' orientation under cyclic uniaxial strain. In light of these reports, we introduce a minimum free energy model to explain the different orientation tendencies of cells subjected to external strain, and elucidate the significant role of cell contractility in this issue. With the present model, we successfully explain a series of well-documented phenomena: (1) cells orient nearly parallel to static uniaxial strain; (2) cell alignment depends on the magnitude of the cyclic uniaxial strain; (3) under cyclic uniaxial stretch, a tensioned contractility results in a strengthened perpendicular alignment of the cells, whereas a contractility relaxation results in a nearly parallel alignment. In addition, this model also successfully describes the functional relationship between cell contractility and substrate stiffness. PMID- 24763747 TI - Abortive T follicular helper development is associated with a defective humoral response in Leishmania infantum-infected macaques. AB - Leishmania infantum causes a chronic infectious disease named visceral leishmaniasis (VL). We employed a non-human primate model to monitor immune parameters over time and gain new insights into the disease. Rhesus macaques were infected with L. infantum and the T helper and B cell immunological profiles characterized during acute and chronic phases of infection. Parasite detection in visceral compartments during the acute phase was associated with differentiation of effector memory CD4 T cells and increased levels of Th1 transcripts. At the chronic phase, parasites colonized novel lymphoid niches concomitant with increased expression of IL10. Despite the occurrence of hypergammaglobulinemia, the production of parasite-specific IgG was poor, being confined to the acute phase and positively correlated with the frequency of an activated memory splenic B cell population. We noticed the expansion of a splenic CD4 T cell population expressing CXCR5 and Bcl-6 during acute infection that was associated with the differentiation of the activated memory B cell population. Moreover, the number of splenic germinal centers peaked at one month after infection, hence paralleling the production of specific IgG. However, at chronic infection these populations contracted impacting the production of parasite-specific IgG. Our study provides new insights into the immune events taking place in a physiologically relevant host and a mechanistic basis for the inefficient humoral response during VL. PMID- 24763748 TI - Guidelines disconcordance in acute bipolar depression: data from the national Bipolar Mania Pathway Survey (BIPAS) in mainland China. AB - With the recent attention to the importance of evidence-based medicine in psychiatry, a number of treatment guidelines have been published. This survey investigated prescribing pattern and predictors for guideline disconcordance in the acute treatment of bipolar depression across mainland China. Pharmacological treatments of 1078 patients with bipolar depression were examined. Guidelines disconcordance was determined by comparing the medication(s) patients were prescribed with the recommendation(s) in the guidelines of the Canadian Network for Mood and Anxiety Treatments. Predictors for guidelines discordance were analyzed with logistic regression. Of the 1078 patients, 50.2% patients were treated against treatment guidelines recommendations. The patients who were treated in general hospitals (OR = 1.53, 95% CI 1.18-1.97), with a depressive episode (OR = 1.67, 95% CI 1.27-2.19) and an older age at first onset (OR = 1.62, 95% CI 1.15-2.28) were more likely to receive guideline-disconcordant treatment than their counterparts. In contrast, the patients with current mental comorbidity, an older age at study entry, a longer duration of disease, and more frequent episodes in past year were less likely to receive guideline disconcordant treatments than their counterparts with an OR of 0.43 (95% CI 0.24 0.77), 0.52 (95CI% 0.36-0.75), 0.48 (95% CI 0.36-0.65), and 0.50 (95% CI 0.38 0.64), respectively. Our finding suggested the disconcordance with treatment guidelines in patients with an acute bipolar depression is common under naturalistic conditions in mainland China, and the predicting factors correlated with guidelines disconcordance include both psychiatrist-specific (clinicians from general hospitals) and patient-specific features (a depressive episode at first onset, no current co-morbidity with mental disorders, a younger age at study entry, an older age at first onset, shorter duration of disease, and non frequent episodes in past year). PMID- 24763751 TI - Bilateral dexamethasone intravitreal implant in a young patient with Vogt Koyanagi-Harada disease and refractory uveitis. AB - Vogt-Koyanagi-Harada disease (VKHD) is a multisystemic disorder characterized by granulomatous panuveitis with exudative retinal detachments, often associated with neurologic and cutaneous manifestations. Therapy relies mainly on the use of corticosteroids, administrated as oral or intravenous high-dose pulses, and immunosuppressants. However, since macular edema and retinal detachment can often be refractory to systemic therapies, intravitreal triamcinolone acetate has been used successfully. Herein, we report the first case of refractory bilateral panuveitis in a young patient with VKHD successfully treated with dexamethasone intravitreal implant. PMID- 24763753 TI - Inter/intramolecular Cherenkov radiation energy transfer (CRET) from a fluorophore with a built-in radionuclide. AB - The Cherenkov radiation (CR) from [(18)F]-FDG, [(177)Lu]-LuCl3 and [(90)Y]-YCl3 was detected and CR energy transfer (CRET) to several fluorophores was examined. Subsequent fluorescence emission was found to be a function of the position of absorption bands with respect to the CR peak, energy of emitted particles, radionuclide/fluorophore loading, and fluorophore brightness. A variant of the best fluorophore with a built-in radionuclide was synthesized to achieve inter- and intra-molecular CRET. PMID- 24763752 TI - Coffee or tea consumption and the risk of rheumatoid arthritis: a meta-analysis. AB - Meta-analysis of the cohort studies revealed a trend of an association between total coffee intake and RA incidence (RR of the highest vs. the lowest group = 1.309, 95 % confidence interval [CI] = 0.967-1.771, p = 0.085). Meta-analysis of case-control studies showed a significant association between total coffee intake and RA incidence (RR = 1.201, 95 % CI =1.058-1.361, p = 0.005). There were differences in the reference groups (all categories of coffee) between the case control meta-analysis that showed a significant association and the cohort studies where meta-analysis results were non-significant. In addition, the highest category of coffee intake varied between Heliovaara et al. cohort study from Finland where the highest category included drinking up to 13 cups per day, compared to US studies where it was very unusual to have > 4 cups coffee intake per day. Combining the data of the cohort and case-control studies showed a significant association between total coffee intake and RA incidence (RR = 1.217, 95 % CI = 1.083-1.368,p = 0.001). Meta-analysis stratified by seropositivity indicated a significant association between coffee consumption and seropositive RA risk (RR=1.309, 95 % CI=1.142-1.499, p=1.1x10-5), but not seronegative RA risk (RR=1.097, 95 % CI=0.886-1.357, p=0.396). There was no significant association between decaffeinated coffee consumption and RA incidence (RR=1.709, 95 % CI 0.786-3.715), or between caffeinated coffee consumption and RA incidence (RR=1.055, 95 % CI 0.782-1.421). [corrected]. PMID- 24763754 TI - Skeletal muscle characterization of Japanese quail line selectively bred for lower body weight as an avian model of delayed muscle growth with hypoplasia. AB - This study was designed to extensively characterize the skeletal muscle development in the low weight (LW) quail selected from random bred control (RBC) Japanese quail in order to provide a new avian model of impaired and delayed growth in physically normal animals. The LW line had smaller embryo and body weights than the RBC line in all age groups (P<0.05). During 3 to 42 d post hatch, the LW line exhibited approximately 60% smaller weight of pectoralis major muscle (PM), mainly resulting from lower fiber numbers compared to the RBC line (P<0.05). During early post-hatch period when myotubes are still actively forming, the LW line showed impaired PM growth with prolonged expression of Pax7 and lower expression levels of MyoD, Myf-5, and myogenin (P<0.05), likely leading to impairment of myogenic differentiation and consequently, reduced muscle fiber formation. Additionally, the LW line had delayed transition of neonatal to adult myosin heavy chain isoform, suggesting delayed muscle maturation. This is further supported by the finding that the LW line continued to grow unlike the RBC line; difference in the percentages of PMW to body weights between both quail lines diminished with increasing age from 42 to 75 d post-hatch. This delayed muscle growth in the LW line is accompanied by higher levels of myogenin expression at 42 d (P<0.05), higher percentage of centered nuclei at 42 d (P<0.01), and greater rate of increase in fiber size between 42 and 75 d post-hatch (P<0.001) compared to the RBC line. Analysis of physiological, morphological, and developmental parameters during muscle development of the LW quail line provided a well characterized avian model for future identification of the responsible genes and for studying mechanisms of hypoplasia and delayed muscle growth. PMID- 24763755 TI - Early addition of topical corticosteroids in the treatment of bacterial keratitis. AB - IMPORTANCE: Scarring from bacterial keratitis remains a leading cause of visual loss. OBJECTIVE: To determine whether topical corticosteroids are beneficial as an adjunctive therapy for bacterial keratitis if given early in the course of infection. DESIGN, SETTING, AND PARTICIPANTS: The Steroids for Corneal Ulcers Trial (SCUT) was a randomized, double-masked, placebo-controlled trial that overall found no effect of adding topical corticosteroids to topical moxifloxacin hydrochloride in bacterial keratitis. Here, we assess the timing of administration of corticosteroids in a subgroup analysis of the SCUT. We define earlier administration of corticosteroids (vs placebo) as addition after 2 to 3 days of topical antibiotics and later as addition after 4 or more days of topical antibiotics. MAIN OUTCOMES AND MEASURES: We assess the effect of topical corticosteroids (vs placebo) on 3-month best spectacle-corrected visual acuity in patients who received corticosteroids or placebo earlier vs later. Further analyses were performed for subgroups of patients with non-Nocardia keratitis and those with no topical antibiotic use before enrollment. RESULTS: Patients treated with topical corticosteroids as adjunctive therapy within 2 to 3 days of antibiotic therapy had approximately 1-line better visual acuity at 3 months than did those given placebo (-0.11 logMAR; 95% CI, -0.20 to -0.02 logMAR; P = .01). In patients who had 4 or more days of antibiotic therapy before corticosteroid treatment, the effect was not significant; patients given corticosteroids had 1 line worse visual acuity at 3 months compared with those in the placebo group (0.10 logMAR; 95% CI, -0.02 to 0.23 logMAR; P = .14). Patients with non-Nocardia keratitis and those having no topical antibiotic use before the SCUT enrollment showed significant improvement in best spectacle-corrected visual acuity at 3 months if corticosteroids were administered earlier rather than later. CONCLUSIONS AND RELEVANCE: There may be a benefit with adjunctive topical corticosteroids if application occurs earlier in the course of bacterial corneal ulcers. PMID- 24763756 TI - Blue dye injection does not induce dissemination of epithelial cells during SLN procedure in colon cancer patients. AB - INTRODUCTION: The sentinel lymph node (SLN) procedure for colon cancer patients has been increasingly performed over the past decade and has shown advantages regarding lymph node staging. However, there are concerns that the manipulation of the colon, particularly the blue dye injection, results in isolated tumor cell dissemination to lymph nodes. Therefore, the objective of the present study was to evaluate whether the blue dye injection during the SLN procedure for colon cancer induces epithelial cell dissemination to the regional lymph nodes using a fake SLN procedure as a model. METHODS: One hundred seventy-four colon cancer patients underwent open oncologic colon resection and SLN procedure according to a standardized protocol. For the fake SLN procedure, blue dye was injected ex vivo, into the subserosa of a nontumor-bearing segment of the resected colon in 37 unselected patients. Three levels of each SLN were stained with H&E and with the pancytokeratin marker AE1/AE3 and were analyzed for the presence of cytokeratin positive cells. RESULTS: Identification of fake SLN was successful in 32 of the 37 patients (86 %). Seventy fake SLN were histologically confirmed. The median number of fake SLN was 2 per patient (range 1-8). None of the fake SLN showed any disseminated epithelial cells. CONCLUSIONS: The present prospective study provides compelling evidence that blue dye injection during sentinel lymph node procedure for colon cancer does not induce epithelial cell dissemination to the sentinel lymph nodes. Therefore, isolated tumor cells in sentinel lymph nodes result from a true metastatic process. PMID- 24763760 TI - Long-term neuropsychological safety of subgenual cingulate gyrus deep brain stimulation for treatment-resistant depression. AB - Deep brain stimulation (DBS) of the subgenual cingulate gyrus (SCG) is a promising investigational intervention for treatment-resistant depression (TRD), but long-term outcome data are limited. Serial neuropsychological evaluations, using a comprehensive battery, were conducted on four subjects with TRD prior to surgery, and up to 42 months post-operatively. Reliable change methodology suggested general stability and/or select statistically reliable improvement in cognitive abilities over time. This is the first known set of multi-year neuropsychological follow-up data for SCG DBS for TRD. Observed improvements are likely attributable to reduced depressive symptomatology, recovery of functional capacities, and/or specific practice effects of repeated assessment. PMID- 24763759 TI - Systematic review of neuroimaging correlates of executive functioning: converging evidence from different clinical populations. AB - Executive functioning (EF) is an important cognitive domain that is negatively affected in a number of neuropsychiatric conditions. Neuroimaging methods have led to insights into the anatomical and functional nature of EF. The authors conducted a systematic review of the recent cognitive and neuroimaging literature to investigate how the neuroimaging correlates of EF compare between different diagnostic groups. The authors found that the frontal, parietal, and cerebellar lobes were most frequently associated with EF when comparing results from different clinical populations; the occipital lobe was not correlated with EF in any group. These findings suggest that individual disease processes affect circuits within an identifiable distributed network rather than isolated regions. PMID- 24763762 TI - A link between perianal strep and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). AB - Perianal streptococcal dermatitis is an infection caused by group A streptococcus (GAS). Children with a pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) phenotype may have tics or obsessive compulsive symptoms secondary to a systemic immune activation by GAS infecting perianal areas. In this retrospective case series, the authors describe three children with symptoms consistent with PANDAS and a confirmed perianal streptococcal dermatitis as the likely infectious trigger. Concomitant perianal dermatitis and new-onset obsessive-compulsive symptoms and/or tics are strong indications for perianal culture and rapid antigen detection test in young children. PMID- 24763757 TI - Risk of obstructive sleep apnea with daytime sleepiness is associated with liver damage in non-morbidly obese patients with nonalcoholic fatty liver disease. AB - BACKGROUND: A high prevalence of obstructive sleep apnea syndrome (OSAS) has been reported in severely obese patients with nonalcoholic fatty liver disease (NAFLD), but few studies have evaluated OSAS in non-morbidly obese NAFLD patients. AIMS: To determine the prevalence of risk for OSAS with or without daytime sleepiness in non-morbidly obese patients with NAFLD and evaluate the association with the severity of liver damage. METHODS: We considered 159 consecutive patients with histological NAFLD and body mass index (BMI) <35 Kg/m2, and 80 controls without ultrasonographic steatosis matched for age, sex, and BMI. OSAS risk was determined by positivity for Berlin questionnaire (BQ), and daytime sleepiness by the Sleepness Epworth Scale (ESS). Liver damage was evaluated according to the NAFLD activity score. RESULTS: In NAFLD patients, BQ alone was positive in 39 (25%), ESS in 8 (5%), and both in 13 (8%, OSAS with sleepines); p = ns vs. controls without steatosis. In NAFLD patients at risk for OSAS with (but not in those without) sleepiness, we observed a higher prevalence of nonalcoholic steatohepatitis (NASH; 11/13, 85% vs. 72/146, 49%; p = 0.018), and of clinically significant fibrosis (stage>1; 9/13, 69% vs. 39/146, 27%; p = 0.003). At multivariate logistic regression analysis, OSAS with sleepiness was strongly associated with NASH and fibrosis>1 independently of known clinical risk factors such as age, gender, BMI, diabetes, and ALT levels (OR 7.1, 95% c.i. 1.7-51, p = 0.005 and OR 14.0, 95% c.i. 3.5-70, p = 0.0002, respectively). CONCLUSIONS: A proportion of NAFLD patients without severe obesity is at risk for OSAS with daytime sleepiness, which is associated with the severity of liver damage independently of body mass and other cofactors. PMID- 24763763 TI - Psychiatric manifestations associated with mega cisterna magna. AB - The Dandy-Walker variant is a milder form of the Dandy-Walker complex and is characterized by normal-sized posterior fossa, mild vermian hypoplasia, and a cystic lesion that communicates with the fourth ventricle. This syndrome has been described in association with schizophrenia, obsessive-compulsive disorder, manic episode, psychosis (delusional type), and recurrent catatonia. The authors present two cases of mega cisterna magna associated with mania and catatonic schizophrenia. PMID- 24763764 TI - Treatment of depression in a former smoker with varenicline? A case report and discussion. AB - The U.S. Food and Drug Administration has warned that patients being treated for smoking cessation with varenicline may develop depression. A case of successful treatment for depression with varenicline is described. The patient's depression recurred several times with inadvertent varenicline discontinuation, then remitted again after resuming varenicline. The literature supporting the potential use of varenicline for depression is reviewed. PMID- 24763765 TI - Inefficacy of antipsychotics in treatment of delirium and agitation in two cases of bickerstaff brainstem encephalitis. AB - The authors report two unusual cases of Bickerstaff encephalitis that presented with encephalopathy and severe agitation. Management with neuroleptics typically used for management of delirium was not effective and worsened agitation. Valproic acid was effective in treatment of agitation and well tolerated. PMID- 24763767 TI - Delirium after transdermal scopolamine patch in two children. PMID- 24763768 TI - Cerebral blood flow changes after transcranial direct current stimulation for a patient with schizophrenia: a case report. PMID- 24763769 TI - Psychiatric symptoms accompanying multiple sclerosis onset: a case report. PMID- 24763770 TI - The relationship between telephone-administered cognitive-behavioral therapy for depression and neuropsychological functioning in Parkinson's disease. PMID- 24763771 TI - A case of an elderly woman with progressive supranuclear palsy associated with depression. PMID- 24763772 TI - Blonanserin improved dystonia induced by risperidone or olanzapine in two patients with schizophrenia. PMID- 24763773 TI - Punding as a cause of death in a patient with Parkinson's disease. PMID- 24763774 TI - Cerebral trauma, Campylobacter jejuni infection, and monosialotetrahexosylganglioside sodium mediated Guillain-Barre syndrome in a Chinese patient: a rare case event. PMID- 24763775 TI - Bupropion-related sexual dysfunction and possible management in a fresh patient with major depressive disorder. PMID- 24763776 TI - Worsening of psychosis with aripiprazole. PMID- 24763777 TI - Post-ECT hyperthermia and rapid mood improvements: a case report. PMID- 24763778 TI - Bilateral shoe deterioration as a result of complex motor tics in tourette syndrome. PMID- 24763779 TI - Olanzapine-induced tardive dystonia: a case report. PMID- 24763780 TI - Possession trance, epilepsy, and primary psychosis: the challenges in diagnosis and management. PMID- 24763781 TI - Treatment of pathological crying in patient with schizophrenia after stroke. PMID- 24763782 TI - From metabolism to psychiatric symptoms: psychosis as a manifestation of acute intermittent porphyria. PMID- 24763783 TI - Mania secondary to traumatic brain injury: a case report. PMID- 24763784 TI - Metacognition training for schizophrenia: a French pilot study. PMID- 24763785 TI - The effectiveness of high-dosage amisulpride combined with moderate-dosage sodium valproate treatment for an overweight patient with psychotic bipolar disorder. PMID- 24763786 TI - Lower risk for body weight gain and better control of appetite after switching risperidone to paliperidone in a schizoaffective patient. PMID- 24763787 TI - Iatrogenic zolpidem dependence. PMID- 24763788 TI - Normal pressure hydrocephalus in a professional athlete: a model of brain functional reserve. PMID- 24763789 TI - Low-dose caffeine may exacerbate psychotic symptoms in people with schizophrenia. PMID- 24763790 TI - Repetitive transcranial magnetic stimulation for the treatment of catatonia: an alternative treatment to electroconvulsive therapy? PMID- 24763791 TI - Rapid responses of high-dose combined therapy of escitalopram and aripiprazole in a case of severe obsessive compulsive disorder with delusion. PMID- 24763792 TI - Electroconvulsive therapy induced hyperammonemia and delirium: a case report. PMID- 24763793 TI - Organic catatonia with small vessel vascular lesions involving Basal Ganglia. PMID- 24763794 TI - GAD65 autoantibodies in Kleine-Levin syndrome. PMID- 24763795 TI - Bupropion-related weight gain in a fresh depression patient. PMID- 24763796 TI - Primary antiphospholipid syndrome mimicking demyelinating disorders. PMID- 24763797 TI - Sertraline-induced acneiform eruption. PMID- 24763798 TI - Pathologic laughing as a presenting feature in a patient with neuromyelitis optica. PMID- 24763799 TI - First manic episode due to discontinuation of valproic acid in a patient with epilepsy. PMID- 24763800 TI - Citalopram in agitated and delusional demented patients who failed treatment with antipsychotic agents. PMID- 24763801 TI - Mild depressive symptoms are associated with enhanced affective theory of mind in nonclinical adult women. PMID- 24763802 TI - Post-traumatic epilepsy: review of risks, pathophysiology, and potential biomarkers. PMID- 24763810 TI - [Treatment after first seizure? Against]. PMID- 24763809 TI - Mast cells expedite control of pulmonary murine cytomegalovirus infection by enhancing the recruitment of protective CD8 T cells to the lungs. AB - The lungs are a noted predilection site of acute, latent, and reactivated cytomegalovirus (CMV) infections. Interstitial pneumonia is the most dreaded manifestation of CMV disease in the immunocompromised host, whereas in the immunocompetent host lung-infiltrating CD8 T cells confine the infection in nodular inflammatory foci and prevent viral pathology. By using murine CMV infection as a model, we provide evidence for a critical role of mast cells (MC) in the recruitment of protective CD8 T cells to the lungs. Systemic infection triggered degranulation selectively in infected MC. The viral activation of MC was associated with a wave of CC chemokine ligand 5 (CCL5) in the serum of C57BL/6 mice that was MC-derived as verified by infection of MC-deficient Kit(W sh/W-sh) "sash" mutants. In these mutants, CD8 T cells were recruited less efficiently to the lungs, correlating with enhanced viral replication and delayed virus clearance. A causative role for MC was verified by MC reconstitution of "sash" mice restoring both, efficient CD8 T-cell recruitment and infection control. These results reveal a novel crosstalk axis between innate and adaptive immune defense against CMV, and identify MC as a hitherto unconsidered player in the immune surveillance at a relevant site of CMV disease. PMID- 24763811 TI - [Mild neurocognitive disorder - a disease? Against]. PMID- 24763812 TI - Mindfulness-based interventions for people diagnosed with a current episode of an anxiety or depressive disorder: a meta-analysis of randomised controlled trials. AB - OBJECTIVE: Mindfulness-based interventions (MBIs) can reduce risk of depressive relapse for people with a history of recurrent depression who are currently well. However, the cognitive, affective and motivational features of depression and anxiety might render MBIs ineffective for people experiencing current symptoms. This paper presents a meta-analysis of randomised controlled trials (RCTs) of MBIs where participants met diagnostic criteria for a current episode of an anxiety or depressive disorder. METHOD: Post-intervention between-group Hedges g effect sizes were calculated using a random effects model. Moderator analyses of primary diagnosis, intervention type and control condition were conducted and publication bias was assessed. RESULTS: Twelve studies met inclusion criteria (n = 578). There were significant post-intervention between-group benefits of MBIs relative to control conditions on primary symptom severity (Hedges g = -0.59, 95% CI = -0.12 to -1.06). Effects were demonstrated for depressive symptom severity (Hedges g = -0.73, 95% CI = -0.09 to -1.36), but not for anxiety symptom severity (Hedges g = -0.55, 95% CI = 0.09 to -1.18), for RCTs with an inactive control (Hedges g = -1.03, 95% CI = -0.40 to -1.66), but not where there was an active control (Hedges g = 0.03, 95% CI = 0.54 to -0.48) and effects were found for MBCT (Hedges g = -0.39, 95% CI = -0.15 to -0.63) but not for MBSR (Hedges g = -0.75, 95% CI = 0.31 to -1.81). CONCLUSIONS: This is the first meta-analysis of RCTs of MBIs where all studies included only participants who were diagnosed with a current episode of a depressive or anxiety disorder. Effects of MBIs on primary symptom severity were found for people with a current depressive disorder and it is recommended that MBIs might be considered as an intervention for this population. PMID- 24763813 TI - The unforeseen toll of birth defects and their economic burden at a tertiary care public institute in Mumbai. AB - OBJECTIVES: To determine the proportion of patients with birth defects receiving indoor medical care and the economic burden incurred by the Institution in terms of cost of hospitalization. METHODS: This single center, prospective, observational study recruited children>28 d and <12 y of age with birth defect(s) not attributable to an acquired disease. Demographic data, maternal and antenatal data, nature of the defect and information about current and past hospitalization were recorded. Economic burden was estimated by computing bed charges and daily costs incurred by the Institution. RESULTS: Ninety-eight children (mean age was 3.18 y, M : F ratio was 2.4:1) with 268 birth defects represented 13% of indoor admissions. The cardiovascular system was involved in 42.9%. The defect was isolated in 58.2% of cases and 41.8% (9.2% having Down syndrome) had multiple defects. Mean duration of hospital stay (11.23 d) of the birth defect cohort was significantly more (p value=0.0005) than other children (7.81 d). Average cost of stay for those with birth defects (18.3% of the total cost) and other indoor patients was INR 23,481 and INR 16,328 respectively. CONCLUSIONS: Birth defects are an emerging burden in referral centers, incurring one-fifth of the hospital expenditure, partly due to increased length of stay. The figure is an underestimate as the expenses are highly subsidized in a Public health facility. PMID- 24763814 TI - Prevention of Kernicterus in South Asia: role of neonatal G6PD deficiency and its identification. AB - Extreme hyperbilirubinemia (EHB) caused by neonatal glucose-6-phosphate dehydrogenase (G6PD) deficiency is strongly associated with mortality and long term neurodevelopmental impairment, yet there are limited national strategies to reduce this burden in South Asia. Current known and predicted prevalence of G6PD deficiency in Afghanistan, Bangladesh, Bhutan, India, Nepal, and Pakistan ranges from 3.8 to 15 %, with regional "hot spots" exceeding 22 %. Annually, 3.14 million infants are born at risk for this condition. In 2010, South Asian countries reported 37 million (27 %) of world-wide livebirths >= 32 wk gestational-age and G6PD deficiency accounted for > 33 % of the global EHB burden, in contrast to 2.2 % for those born in high-income nations. Traditional national approach includes universal newborn screening in malaria-endemic countries or those with prevalence >3.5 %. However, screening implementation should be best optimized using timely quantitative enzyme assay and identification of at-risk female newborns. Furthermore, economic and social constraints, in context of sub-regional variances, call for flexible problem solving methods in anticipation of changing community demographics. Thus, incremental and need-based newborn screening programs could be the most optimal approach. A human-centered design (HCD) approach, as an alternate pathway, could build the evidence to translate the complex biology of G6PD deficiency and the biodesign of affordable technologies, allowing facilitation of access to knowledge and services, in order to deliver on a long-term public health mandate. Key steps would encompass the initiation of local inquiry of both quantitative and qualitative data to identify at-risk communities and to prospectively design for local innovative solutions. PMID- 24763815 TI - Neonatal severe hyperparathyroidism due to compound heterozygous mutation of calcium sensing receptor (CaSR) gene presenting as encephalopathy. AB - The authors report a 14-d-old neonate who presented with lethargy, polyuria and dehydration and was found to have severe hypercalcemia with hyperparathyroidism. This neonate was treated with saline hydration, diuresis and injection pamidronate. Genetic analysis revealed a compound heterozygous mutation of CaSR. PMID- 24763817 TI - Construction of novel chloroplast expression vector and development of an efficient transformation system for the diatom Phaeodactylum tricornutum. AB - Plastids are ideal subcellular hosts for the expression of transgenes and have been successfully used for the production of different biopolymers, therapeutic proteins and industrial enzymes. Phaeodactylum tricornutum is a widely used aquatic feed species. In this study, we focused on developing a high-efficiency plastid expression system for P. tricornutum. In the plastid transformation vector, the site selected for integration was the transcriptionally active intergenic region present between the trnI and trnA genes, located in the IR (inverted repeat) regions of the plastid genome. Initially, a CAT reporter gene (encoding chloramphenicol acetyltransferase) was integrated at this site in the plastid genome. The expression of CAT in the transformed microalgae conferred resistance to the antibiotic chloramphenicol, which enabled growth in the selection media. Overall, the plastid transformation efficiency was found to be approximately one transplastomic colony per 1,000 microalgae cells. Subsequently, a heterologous gene expression cassette for high-level expression of the target gene was created and cloned between the homologous recombination elements. A TA cloning strategy based on the designed XcmI-XcmI sites could conveniently clone the heterologous gene. An eGFP (green fluorescent protein) reporter gene was used to test the expression level in the plastid system. The relatively high-level expression of eGFP without codon optimisation in stably transformed microalgae was determined to account for 0.12 % of the total soluble protein. Thus, this study presents the first and convenient plastid gene expression system for diatoms and represents an interesting tool to study diatom plastids. PMID- 24763818 TI - Rapid fluorescent detection of Escherichia coli K88 based on DNA aptamer library as direct and specific reporter combined with immuno-magnetic separation. AB - Nucleic acid aptamers have long demonstrated the capacity to bind cells with high affinity so that they have been utilized to diagnose various important pathogens. In this study, a DNA aptamer library was on initial efforts developed to act as a specific reporter for rapid detection of enter toxigenic Escherichia coli (ETEC) K88 combined with immuno-magnetic separation (IMS). During a Whole-cell Systematic Evolution of Ligands by Exponential Enrichment (CELL-SELEX) procedure, the last selection pool against ETEC K88, which is named "DNA aptamer library" here, was selected and subsequently identified by flow cytometric analysis and confocal imaging. A K88 monoclonal antibody (mAb) with high affinity (K(aff): 1.616 +/- 0.033 * 10(8) M(-1)) against K88 fimbrial protein was prepared, biotinylated and conjugated to streptavidin-coated magnetic beads (MBs). After the bacteria were effectively captured and enriched from the complex sample by immuno-magnetic beads (IMBs), 5'-FITC modified aptamer library was directly bound to target cells as a specific reporter for its detection. The detection system showed clearly high specificity and sensitivity with the detection limit of 1.1 * 10(3) CFU/ml in pure culture and 2.2 * 10(3) CFU/g in artificially contaminated fecal sample. The results also indicated that fluorophore-lablled DNA aptamer library as specific reporter could generate more reliable signals than individual aptamer with best affinity against target cells and implied it would have great applied potential in directly reporting bacteria from complex samples combined with IMS technology. PMID- 24763820 TI - A label-free fluorescence detection strategy for lysozyme assay using CuInS2 quantum dots. AB - We have developed a simple and efficient fluorescence detection system for lysozyme utilizing I-III-VI type Cu-In-S ternary quantum dots (CuInS2 QDs) as the probe. Water-soluble near-infrared CuInS2 QDs capped with 3-mercaptopropionic acid were directly synthesized by using a hydrothermal method. Poly(dimethyl diallyl ammonium chloride), as a cationic polyelectrolyte, could bind to 3 mercaptopropionic acid-capped CuInS2 QDs via electrostatic interactions that would lead to fluorescence quenching of CuInS2 QDs. And the addition of a lysozyme aptamer could effectively turn on the quenched fluorescence due to the stronger interaction between the cationic polyelectrolyte and negatively charged aptamer. The addition of lysozyme would result in fluorescence quenching of CuInS2 QDs again due to the specific binding between lysozyme and the lysozyme aptamer. Therefore, this label-free fluorescence system could be applied to selectively detect lysozyme. PMID- 24763821 TI - Catalytic liquid marbles: Ag nanowire-based miniature reactors for highly efficient degradation of methylene blue. AB - Ag nanowire-based catalytic liquid marbles are fabricated as miniature reactors, which demonstrate highly efficient, support-free and rate-controllable heterogeneous degradation of methylene blue, with catalytic efficiency close to 100%. Our miniature catalytic liquid marbles are essential for reactions involving highly toxic/hazardous or costly reactants, where small volume preliminary reactions are preferred. PMID- 24763822 TI - Loss of function of endothelin-2 leads to reduced ovulation and CL formation. AB - Endothelin-2 (EDN2), a potent vasoconstrictive peptide, is transiently produced by periovulatory follicles at the time of ovulation when corpus luteum (CL) formation begins. EDN2 induces contraction of ovarian smooth muscles ex vivo via an endothelin receptor A-mediated pathway. In this study, we aimed to determine if EDN2 is required for normal ovulation and subsequent CL formation in?vivo. In the ovaries of a mouse model that globally lacks the Edn2 gene (Edn2 knockout mouse; Edn2KO), histology showed that post-pubertal Edn2KO mice possess follicles of all developmental stages, but no corpora lutea. When exogenous gonadotropins were injected to induce super-ovulation, Edn2KO mice exhibited significantly impaired ovulation and CL formation compared to control littermates. Edn2KO ovaries that did ovulate in response to gonadotropins did not contain histologically and functionally identifiable CL. Intra-ovarian injection of EDN2 peptide results suggest partial induction of ovulation in Edn2KO mice. Endothelin receptor antagonism in wild type mice similarly disrupted ovulation, CL formation, and progesterone secretion. Overall, this study suggests that EDN2 is necessary for normal ovulation and CL formation. PMID- 24763823 TI - Implication of K-ras and p53 in colorectal cancer carcinogenesis in Tunisian population cohort. AB - According to the multistep route of genetic alterations in the colorectal adenoma carcinoma sequence, the complex K-ras/p53 mutation is one of the first alterations to occur and represent an important genetic event in colorectal cancer (CRC). An evaluation of the mutation spectra in K-ras and p53 gene was effected in 167 Tunisian patients with sporadic CRC to determine whether our populations have similar pattern of genetic alteration as in Maghrebin's population. Mutation patterns of codon 12-13 of K-ras and exon 5-8 of p53 were analyzed by immunohistochemistry and PCR-SSCP and confirmed by sequencing. Mutations in the K-ras gene were detected in 31.13 % and affect the women more than the men (p = 0.008). Immunostaining showed that expression of p21 ras was correlated with the advanced age (p = 0.004), whereas loss of signal was associated with mucinous histotype (p = 0.003). Kaplan-Meier survival curve found that patients with the K-ras mutation had a shorter survival compared with patients without mutation (p = 0.005). Alteration in p53 was seen in 17.4 % of patients and affects three hot spot codons such as 175, 245, and 248. Overexpression of p53 was seen in 34.1 % and correlated with tumor node metastasis (TNM) advanced stage (p = 0.037) and mucinous histotype (p = 0.001). A high concordance between p53 expression and alteration (p<0.005) was shown. Concomitant mutations in K-ras and p53 gene were detected in only 4 % of tumors. K-ras and p53 undergo separate pathways in colorectal tumorogenesis. Interestingly, mutations in the K-ras gene might be considered a valuable prognostic factor correlated to poor outcome. p53 gene alterations were rather low in our set, and methylation pattern of p53 is required to elucidate the molecular basis of this protein in CRC. PMID- 24763824 TI - Restoring TGFbeta1 pathway-related microRNAs: possible impact in metastatic prostate cancer development. AB - In developed countries, prostate cancer (PC) is the neoplasia more frequently diagnosed in men. The signaling pathway induced by the transforming growth factor beta1 (TGFbeta1) has an important role in cell growth, differentiation, and development, the downregulation of this pathway being associated with cancer development. In PC, the activation of this signaling pathway is lost, resulting in favoring of tumor growth, proliferation, and evasion of apoptosis. Several studies have shown that microRNAs (miRNAs), small non-coding RNA, are closely associated with the development, invasion, and metastasis, suggesting that they have a critical role in cancer development. Recently, Smad proteins, the signal transducers of the TGFbeta1 signaling pathway, were found to regulate miRNA expression, through both transcriptional and posttranscriptional mechanisms. In this review, we summarize the mechanisms underlying Smad-mediated regulation of miRNA biogenesis and the effects on cancer development, particularly in PC. We identify that TGFbeta1-related miR-143, miR-145, miR-146a, and miR-199a may have a key role in the development of prostate cancer metastasis and the restoration of their expression may be a promising therapeutic strategy for PC treatment. PMID- 24763825 TI - Incidence of Bcr-Abl kinase domain mutations in imatinib refractory chronic myeloid leukemia patients from South India. AB - Mutations in the Bcr-Abl kinase domain (KD) are a major cause for acquired resistance to imatinib (IM) treatment and have been associated with progression and poor prognosis in chronic myeloid leukemia patients. The present study includes 63 patients resistant to standard imatinib dose of 400 mg according to ELN guidelines. Direct sequencing method is used for mutational analysis. The present study revealed 15 exonic mutations in 46.03 % of patients; among them, seven cases (24.13 %) had multiple mutations. Mutations were found to be higher in sokal high- (45.0 %) and intermediate- (68.42 %) compared to low-risk (29.16 %) group. Mutations were observed in 38.09 % of patients with EUTOS (European Treatment and Outcome Study) high risk and in 50.0 % with low risk. The frequency of mutations was 50.0 % in advanced phase, 47.36 % in late chronic-phase, and 43.33 % in chronic-phase patients. 42.10 % of patients with primary resistance and 52.0 % with secondary resistance had mutations. P-loop and T315I mutations were associated with poor survival in advanced phase patients (85.71 %) (P = 0.03). No significant variation was observed with Bcr-Abl transcript levels between the patients with the presence or absence of mutations (P = 0.73). Bcr Abl levels were found to be significantly elevated in P-loop and T315I mutation carriers (P = 0.001) and also in T315I mutation-positive patients (P = 0.01). P loop mutations and T315I are frequent in advanced phases and strongly associated with poor prognosis and survival. Hence, the identification of mutations in IM resistant CML patients will help in treatment optimization with 2nd- or 3rd generation tyrosine kinase inhibitors (TKIs). PMID- 24763826 TI - Examining Nek2 as a better proliferation marker in non-small cell lung cancer prognosis. AB - The purpose of this study is to identify a better potential biomarker for the prognosis of patients with non-small cell lung cancer (NSCLC). The expressions of Nek2, MCM7, and Ki-67 were evaluated in 270 NSCLC tissues using immunohistochemical and immunofluorescence techniques. Associations between protein expression and clinical pathologic characters were assessed, and the impact on overall survival was analyzed. We detected high levels of Nek2, MCM7, and Ki-67 expression in 25.9, 35.2, and 24.4 % of NSCLC tissues, respectively. Overexpressions of Nek2 were detected more frequently in high T-stage and N-stage cases (P = 0.000, 0.011). The expressions of Nek2, MCM7, and Ki-67 were correlated with each other. Kaplan-Meier curves indicated that patients with overexpression of Nek2, MCM7, and Ki-67 had a poorer overall survival rate compared to those with low expression for all stages (P = 0.000). In particular, the patients with Nek2 overexpression had the most negative prognosis. Multivariate Cox regression analysis showed that Nek2, MCM7, and Ki-67 are independent prognostic indicators for NSCLC. Our data suggest that among Nek2 kinase, MCM7, and Ki-67, it is Nek2 kinase that is the more effective tumor proliferation marker of poor prognosis for NSCLC patients. Thus, Nek2 may represent a new potential target for NSCLC therapeutic intervention. PMID- 24763827 TI - Association between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer: a meta-analysis. AB - Several previous studies have investigated the association between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer in various populations. However, these results remain inconsistent. Therefore, we performed this meta analysis to evaluate the relationship between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer. An extensive literature search was performed to identify all eligible studies regarding this association. The odds ratios (ORs) with 95 % confidence intervals (CIs) were used to estimate the strength of risk under fixed and random effects models. We identified and included eight case control studies including 2,036 cases and 2,273 controls. No significant association was found between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer under the dominant model; however, those with the SULT1A1 Arg/Arg genotype had a significantly increased risk (OR = 1.218, 95 % CI = 1.067-1.392, P = 0.0044) under the recessive model. In the subgroup analysis of ethnicity, a significant association was observed in Caucasians under the recessive model (OR = 1.269, 95 % CI = 1.069-1.506, P = 0.007). Furthermore, an increased risk of bladder cancer was observed between the Arg213His polymorphism and never smokers in the recessive model (OR = 1.428, 95 % CI = 1.079-1.890, P = 0.013). The results of this meta-analysis indicate that the SULT1A1 Arg213His polymorphism is associated with the risk bladder cancer under a recessive model; however, a possibly higher risk for Caucasians with the Arg/Arg genotype and never smokers needs further investigation. PMID- 24763828 TI - Concomitant upregulation of nucleostemin and downregulation of Sox2 and Klf4 in gastric adenocarcinoma. AB - Nucleostemin (NS) is a nucleolar protein involved in stem cell (SC) self-renewal by controlling cell cycle progression. In addition to SCs, NS is also expressed in some highly proliferating cells including several adult stem cells and cancer cell lines. NS knock-down in different cell lines demonstrated its cell type dependent function in arresting cell cycle in either G1 or G2/M phases. Here, we have evaluated the expression of NS and iPS genes in 36 gastric cancer and their matched marginal nontumor tissues by means of real-time polymerase chain reaction (RT-PCR). We have also examined a potential causative role of NS in gastric tumorigenesis by suppressing its expression in a gastric cancer cell line, AGS. Our data revealed that NS expression level is much higher in tumor tissues (p = 0.046), especially in high-grade ones (p < 0.001), whereas the expression of Klf4 and Sox2 is downregulated in tumor tissues compared to marginal nontumor samples (p < 0.001). Furthermore, NS suppression in the AGS cell line caused some morphological alterations, a cell cycle arrest at G1 phase, and an upregulation of iPS genes: Nanog, Sox2, and Klf4. Based on our results, NS overexpression seems to have a causative role in gastric tumorigenesis and/or progression, and it could be considered as a potential tumor marker for diagnosis, molecular classification, and molecular therapy of gastric adenocarcinoma. PMID- 24763829 TI - The transcriptional activator LdtR from 'Candidatus Liberibacter asiaticus' mediates osmotic stress tolerance. AB - The causal agent of Huanglongbing disease, 'Candidatus Liberibacter asiaticus', is a non-culturable, gram negative, phloem-limited alpha-proteobacterium. Current methods to control the spread of this disease are still limited to the removal and destruction of infected trees. In this study, we identified and characterized a regulon from 'Ca. L. asiaticus' involved in cell wall remodeling, that contains a member of the MarR family of transcriptional regulators (ldtR), and a predicted L,D-transpeptidase (ldtP). In Sinorhizobium meliloti, mutation of ldtR resulted in morphological changes (shortened rod-type phenotype) and reduced tolerance to osmotic stress. A biochemical approach was taken to identify small molecules that modulate LdtR activity. The LdtR ligands identified by thermal shift assays were validated using DNA binding methods. The biological impact of LdtR inactivation by the small molecules was then examined in Sinorhizobium meliloti and Liberibacter crescens, where a shortened-rod phenotype was induced by growth in presence of the ligands. A new method was also developed to examine the effects of small molecules on the viability of 'Ca. Liberibacter asiaticus', using shoots from HLB-infected orange trees. Decreased expression of ldtRLas and ldtPLas was observed in samples taken from HLB-infected shoots after 6 h of incubation with the LdtR ligands. These results provide strong proof of concept for the use of small molecules that target LdtR, as a potential treatment option for Huanglongbing disease. PMID- 24763830 TI - Descemet stripping automated endothelial keratoplasty after failed penetrating keratoplasty: survival, rejection risk, and visual outcome. AB - IMPORTANCE: Descemet stripping automated endothelial keratoplasty (DSAEK) for isolated endothelial dysfunction has become the preferred surgical option for many corneal surgeons. However, there are limited large-scale reports on DSAEK survival and clinical variables affecting the risk of rejection and failure after failed penetrating keratoplasty (PK). OBJECTIVE: To report the survival, risk factors for graft rejection and failure, and visual outcome of DSAEK after failed PK. DESIGN, SETTING, AND PARTICIPANTS: A multicenter retrospective interventional case series included patients recruited from 6 tertiary referral surgical centers: 3 in the United States, 2 in Europe, and 1 in Asia. A total of 246 consecutive eyes (246 patients) that underwent DSAEK after failed PK, with a minimum follow-up period of 1 month, was included. Data comprising demographic details, preoperative and postoperative risk factors, time to rejection, time to failure, and corrected distance visual acuity were collected. MAIN OUTCOMES AND MEASURES: Cumulative probability of graft survival, hazard ratio estimates for survival, and corrected distance visual acuity were determined. RESULTS: The mean (SD) recipient age was 63.2 (16.6) years and the median follow-up period was 17 months (interquartile range, 6-30 months). One-third of the grafts (n = 82) had follow-up data for more than 2 years; 18.3% had more than 1 failed PK before DSAEK. In total, 19.1% (47 of 246) of DSAEK grafts failed. The cumulative probability of DSAEK survival after a failed PK was 0.89 (95% CI, 0.84-0.92), 0.74 (95% CI, 0.64-0.81), and 0.47 (95% CI, 0.29-0.61) at 1 year, 3 years, and 5 years, respectively. Based on multivariate analysis, significant preoperative risk factors for failure were young recipient age (hazard ratio [HR], 5.18 [95% CI, 1.57-17.18]), previous tube filtration surgery (HR, 5.23 [95% CI, 1.47 7.33]), and rejection episodes before PK failure (HR, 3.28 [95% CI, 1.47-7.33]); single-surgeon centers had a protective effect. Any rejection episode prior to PK failure was a significant predictor of post-DSAEK rejection, which in turn was a significant predictor of DSAEK failure. After a median follow-up of 17 months, 33.3% of the grafts achieved 0.3 or greater logMAR (20/40) corrected distance visual acuity. CONCLUSIONS AND RELEVANCE: Descemet stripping automated endothelial keratoplasty after failed PK combines greater wound stability and reduced suture-related complications, with visual outcomes and graft survival rates comparable to those of a second PK. PMID- 24763831 TI - Antonio Egas Moniz (1874-1955): Lobotomy pioneer and Nobel laureate. PMID- 24763832 TI - Post-thyroidectomy neck ultrasonography in patients with thyroid cancer and a review of the literature. AB - The importance of routine neck ultrasonography for the detection of unsuspected local or nodal recurrence of thyroid cancer following thyroidectomy (with or without neck dissection) is well documented in many journal articles and international guidelines. Herein, we present a pictorial summary of the sonographic features of benign and malignant central neck compartment nodules and cervical lymph nodes via a series of high-quality ultrasonographic images, with a review of the literature. PMID- 24763833 TI - Managing the 'picky eater' dilemma. AB - Picky eating is a common cause of concern for parents of young children. Paediatricians and family physicians are in a key position to help parents learn ways to feed their children effectively. Despite the high prevalence of picky eating, the growth of the majority of picky eaters does not suffer adversely. In the absence of worrying signs and symptoms, reassurance of the child's normal growth would help allay parental anxieties. Reinforcement of basic feeding principles and providing healthy dietary advice are important strategies to help parents manage children who are picky eaters. PMID- 24763834 TI - Inguinal hernia repair: are the results from a general hospital comparable to those from dedicated hernia centres? AB - INTRODUCTION: We aimed to report the outcomes of inguinal hernia repair performed at Tan Tock Seng Hospital and compare them with those performed at dedicated hernia centres. METHODS: We retrospectively analysed the medical records and telephone interviews of 520 patients who underwent inguinal hernia repair in 2010. RESULTS: The majority of the patients were male (498 [95.8%] men vs. 22 [4.2%] women). The mean age was 59.9 +/- 15.7 years. Most patients (n = 445, 85.6%) had unilateral hernias (25.8% direct, 64.3% indirect, 9.9% pantaloon). The overall recurrence rate was 3.8%, with a mean time to recurrence of 12.0 +/- 8.6 months. Risk factors for recurrence included contaminated wounds (odds ratio [OR] 50.325; p = 0.004), female gender (OR 8.757; p = 0.003) and pantaloon hernias (OR 5.059; p = 0.013). Complication rates were as follows: chronic pain syndrome (1.2%), hypoaesthesia (5.2%), wound dehiscence (0.4%), infection (0.6%), haematoma/seroma (4.8%), urinary retention (1.3%) and intraoperative visceral injury (0.6%). Most procedures were open repairs (67.7%), and laparoscopic repair constituted 32.3% of all the inguinal hernia repairs. Open repairs resulted in longer operating times than laparoscopic repairs (86.6 mins vs. 71.6 mins; p < 0.001), longer hospital stays (2.7 days vs. 0.7 days; p = 0.020) and a higher incidence of post-repair hypoaesthesia (6.8% vs. 1.8%; p = 0.018). However, there were no significant differences in recurrence or other complications between open and laparoscopic repair. CONCLUSION: A general hospital with strict protocols and teaching methodologies can achieve inguinal hernia repair outcomes comparable to those of dedicated hernia centres. PMID- 24763835 TI - Incidence and radiological characteristics of fabellae in an Asian population. AB - INTRODUCTION: The fabella, a sesamoid bone sometimes found in the lateral head of the gastrocnemius muscle, often articulates directly with the lateral femoral condyle. This study aimed to determine the incidence of fabellae in an Asian population and to characterise the radiological features of the fabella. METHODS: Electronic radiographs and magnetic resonance imaging films of 80 consecutive patients who underwent knee arthroscopy between May 2005 and October 2009 were reviewed to determine the presence and characteristics of the fabella. RESULTS: The incidence of fabellae was 31.25% in our study cohort. The median length, thickness, width and distance of the fabella from the lateral femoral condyle were 7.06 mm, 4.89 mm, 6.12 mm and 33.19 mm, respectively. The fabella was consistently bony and located in the lateral head of the gastrocnemius, with 52% of the fabellae having an articulating facet. Fabellae in men were found to be larger than in women, although the difference was not statistically significant. The presence of an articulating groove was associated with increased size of the fabella, but not with the distance between the fabella and its insertion onto the lateral head of the gastrocnemius. CONCLUSION: The incidence of fabellae in our population was lower than that in regional studies. They were consistently bony and not all had articulating grooves on the lateral femoral condyle. We found that the larger the fabella, the higher the chances of it having an articulating groove. By defining the radiological characteristics of the fabella, we provide objective parameters to help differentiate the fabella from other loose bodies or calcifications in the knee. PMID- 24763836 TI - Association between urinary 8-OHdG and pulse wave velocity in hypertensive patients with type 2 diabetes mellitus. AB - INTRODUCTION: Oxidative stress, assessed using 8-hydroxy-2'-deoxyguanosine (8 OHdG), can be associated with arterial stiffness in patients with type 2 diabetes mellitus (T2DM) and/or hypertension (HT). We investigated the correlation between urinary 8-OHdG and pulse wave velocity (PWV) in hypertensive and non-hypertensive T2DM patients with fair glycaemic control to determine the clinical significance of HT as a comorbidity in the diabetic state. METHODS: Clinical data, including traditional cardiovascular risk factors, diabetic complications, prescribed agents, urinary 8-OHdG level and brachial-ankle PWV, was collected from T2DM patients with and without HT. RESULTS: There were 76 patients (45 men, 31 women; mean age 61 years; mean haemoglobin A1c level 6.5%) in the study cohort. T2DM patients with HT had significantly higher mean PWV than patients without HT (1,597 cm/s vs 1,442 cm/s; p < 0.05). Patients with HT showed no significant difference in 8-OHdG levels relative to those without HT (median 7.9 ng/mg creatinine vs 8.8 ng/mg creatinine; p > 0.05). Simple linear correlation and stepwise multiple linear regression analyses revealed that 8-OHdG levels correlated independently, significantly and positively with PWV among T2DM patients with HT (r = 0.33, p < 0.05; beta= 0.23, p < 0.05). No significant correlation was observed between 8-OHdG levels and PWV among T2DM patients without HT. CONCLUSION: In the hypertensive state, oxidative stress can be responsible for the development of arterial stiffness, even in patients with fairly well controlled T2DM. Oxidative stress management may be necessary for the prevention of cardiovascular disease in this population. PMID- 24763837 TI - The association of cardiovascular disease with impaired health-related quality of life among patients with type 2 diabetes mellitus. AB - INTRODUCTION: The aim of this study was to evaluate the health-related quality of life (HRQoL) of Malaysian patients with type 2 diabetes mellitus (T2DM) who have cardiovascular disease (CVD), as well as identify the determinants of HRQoL among this cohort of patients. METHODS: This study was an analytical cross-sectional study involving 313 patients aged 30-78 years (150 men, 163 women; mean age 55.7 +/- 9.2 years) who were diagnosed with T2DM (mean duration of T2DM 10.1 +/- 8.1 years) at two tertiary Malaysian government hospitals. The patients' sociodemographic, lifestyle, clinical and laboratory data were collected prospectively from medical records and via face-to-face interviews. HRQoL was assessed using the 15D instrument - a generic, 15-dimensional and standardised measure of HRQoL that can be used as both a profile and a single index score measure. RESULTS: T2DM patients with CVD were found to have significantly lower 15D HRQoL scores than their nonCVD counterparts (p < 0.001). The HRQoL of T2DM patients with CVD was significantly lower than those without CVD (p < 0.05) in all of the 15 dimensions of the 15D instrument. Multinomial logistic regression analysis using backward stepwise method revealed a significant association between CVD and impaired HRQoL (odds ratio [OR] 11.746, 95% confidence interval [CI] 4.898-28.167). Age (OR 1.095, 95% CI 1.054-1.137), duration of T2DM (OR 1.085, 95% CI 1.032-1.140), ethnicity (OR 0.411, 95% CI 0.187-0.903), body mass index (OR 1.074, 95% CI 1.006-1.148), and physical activity level (OR 3.506, 95% CI 1.415-8.689) were also significant predictors of HRQoL. CONCLUSION: In T2DM patients, the presence of CVD was significantly associated with a lower HRQoL. Therefore, the importance of tertiary prevention to minimise the potential deterioration of the HRQoL of T2DM patients with CVD should be highly emphasised. PMID- 24763838 TI - Clinical characteristics and treatment outcomes of patients with Brugada syndrome in northeastern Thailand. AB - INTRODUCTION: Brugada syndrome (BrS) is a common genetic cause of sudden cardiac arrest (SCA) due to polymorphic ventricular tachycardia and ventricular fibrillation. The current recommended therapy for high-risk BrS patients is the use of an implantable cardioverter defibrillator (ICD). The present study aimed to report the clinical characteristics and treatment outcomes of BrS patients in northeastern Thailand. METHODS: Patients who were diagnosed with BrS or had a Brugada electrocardiogram (ECG) between 2005 and 2012 at Khon Kaen University's hospitals were enrolled in the present study. Patients' clinical characteristics, ECG type, laboratory results and treatment were reviewed. RESULTS: A total of 90 eligible patients were enrolled. Of these, 79 (87.8%) patients were symptomatic- 65 (82.3%) had documented SCA and 14 (17.7%) had unexplained syncope. The remaining 11 (12.2%) patients were asymptomatic with Brugada ECG. A majority of the patients enrolled were born in northeastern Thailand. The mean age of the symptomatic patients was 44.49 +/- 8.55 years. Among the symptomatic patients, a majority were male (n = 77, 97.5%) and 23 (29.1%) patients had a family history of SCA. Almost all BrS patients who were symptomatic (96.2%) received ICD treatment for secondary prevention. The number of patients who received appropriate ICD therapy was 4.2 times of those who received inappropriate shocks. Only 3 (3.8%) symptomatic BrS patients refused ICD treatment. CONCLUSION: Clinical characteristics did not distinguish between symptomatic BrS patients and asymptomatic patients with Brugada ECGs. The clinical characteristics and treatment outcomes for the symptomatic BrS patients with SCA and unexplained syncope were similar. Among the BrS patients implanted with secondary prevention ICD in Northeastern Thailand, nearly one-third had received appropriate ICD therapy, far exceeding the incidence of device-related complications and inappropriate therapy. PMID- 24763839 TI - Age- and gender-related differences in drug utilisation and adverse drug reaction patterns among patients in a coronary care unit. AB - INTRODUCTION: This study aimed to examine age- and gender-related differences in the comorbidities, drug utilisation and adverse drug reaction (ADR) patterns of patients admitted to a coronary care unit (CCU). METHODS: The present study was a retrospective cohort study. Two trained physicians independently reviewed the case records of CCU patients over a period of one year (Jan-Dec 2008). The demographic, clinical, and drug prescription data of the patients were analysed according to age group (18-59 years vs >= 60 years) and gender. RESULTS: A total of 574 patients were admitted to the CCU during the study period. Of these 574 patients, 65.2% were male, and 48.4% were >= 60 years old. No significant gender based differences were found for the prescription of cardiovascular and non cardiovascular drugs, and ADR patterns (p > 0.05). Male patients aged >= 60 years were found to have a higher rate of polypharmacy than those aged 18-59 years (p = 0.001). The duration of hospital stay was longer in male than female patients (p = 0.008), and the duration of CCU stay was longer for male patients aged >= 60 years than males aged 18-59 years (p = 0.013). Compared to patients aged 18-59 years, a greater number of patients aged >= 60 years were prescribed cardiovascular (p = 0.006) and non-cardiovascular drugs (p = 0.015). Patients aged >= 60 years also had a higher rate of polypharmacy (p = 0.001) and ADRs (p = 0.013), and a longer duration of CCU stay (p = 0.013). Renal (p = 0.047) and cutaneous (p = 0.003) ADRs were found to be more common in patients aged >= 60 years. CONCLUSION: No major gender-related differences were observed in the prescription, drug utilisation and ADR patterns of our study cohort. Higher drug utilisation, ADR rates, and longer duration of CCU stay were noted in patients aged >= 60 years. PMID- 24763840 TI - Addition of clonidine or lignocaine to ropivacaine for supraclavicular brachial plexus block: a comparative study. AB - INTRODUCTION: Clonidine is used with local anaesthetics to improve analgesia. However, the improvement conferred when clonidine is used together with ropivacaine is controversial. Thus, the present study aimed to evaluate the improvement in analgesia when clonidine is used together with ropivacaine for supraclavicular brachial plexus block. METHODS: This was a prospective, randomised, double-blind controlled study. A total of 75 patients who were scheduled to undergo supraclavicular block were randomly assigned into three groups (i.e. clonidine, lignocaine and control groups) of 25. Patients in all three groups received 20 mL of 0.75% ropivacaine. In addition to that, patients in the clonidine group received 1 mL of clonidine (150 MUg) plus 9 mL of saline, patients in the lignocaine group received 10 mL of 2% lignocaine with adrenaline (1:200,000), and patients in the control group received 10 mL of saline. The characteristics of anaesthesia and analgesia for these three groups were assessed. RESULTS: The addition of 2% lignocaine with adrenaline to ropivacaine led to earlier onset of the sensory block (by 4.88 mins), but no increase in the duration of analgesia when compared to analgesia using ropivacaine alone. The addition of clonidine to ropivacaine led to earlier onset of sensory and motor blocks (by 2.88 mins and 3.28 mins, respectively), as well as an increased duration of sensory and motor blocks (by 222.64 mins and 192.92 mins, respectively) when compared to analgesia using ropivacaine alone. The total duration of analgesia was increased by 208.24 mins with clonidine when compared to analgesia using ropivacaine alone. There were no significant differences in sedation score and no side effects in all three groups. CONCLUSION: When compared to the use of ropivacaine alone, the addition of 150 MUg clonidine to ropivacaine for brachial plexus block achieved earlier analgesic onset and improved duration of analgesia, without unwanted side effects. PMID- 24763842 TI - From divination to madness: features of acute intoxication with Salvia use. AB - Salvia divinorum is a psychoactive botanical plant that is increasingly used for the 'legal' highs that it can produce. It is readily available for purchase on the Internet, and most abusers are unaware of the toxicity and abuse potential associated with its use. As the use of novel compounds among abusers is not uncommon, physicians need to increase their awareness and recognition of these new substances. Herein, we report a case of an acute presentation of Salvia intoxication. PMID- 24763843 TI - Melorheostosis of the hand affecting the c6 sclerotome and presenting with carpal tunnel syndrome. AB - Melorheostosis is a rare, progressive bone disease accompanied by hyperostosis and soft tissue fibrosis. While affected adults present with contracture and pain, children present with limb length discrepancy and deformity. We report the case of a 20-year-old woman with melorheostosis since childhood who presented with right hand deformity and numbness. Radiographs showed not only a combination of dense sclerosis and opacities, but also the classic 'flowing candle wax' appearance. Radiography can be used to identify melorheostosis, thus preventing unnecessary bone biopsies. Carpal tunnel release revealed the presence of a thickened flexor retinaculum and a degenerated median nerve distal to the retinaculum, but did not show hyperostosis. This case highlights the role of nerve decompression in melorheostosis and the importance of early identification of the disease to prevent unnecessary bone biopsies. PMID- 24763844 TI - Myoclonic seizures in a preterm baby: is this a presentation of venlafaxine withdrawal? AB - Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, is increasingly used in pregnant women with pre-existing depression who require continued treatment. However, its in uteroeffects on the developing fetus are not clear. Herein, we report the unusual presentation of venlafaxine withdrawal in a female preterm baby of 29 weeks gestation, who presented with myoclonic seizures on her second day of life. The seizures were confirmed using amplitude-integrated electroencephalography, and other possible causes of neonatal seizures were excluded. The baby responded to treatment with phenobarbitone and phenytoin. Magnetic resonance imaging of her brain was unremarkable at corrected gestational age of 39 weeks and 2 days. On follow-up at the corrected age of five months, she was well and developing normally with no further seizures. To the best of our knowledge, this is the first report of seizures in a preterm baby resulting from maternal venlafaxine use. PMID- 24763845 TI - Ostraceous and inverse psoriasis with psoriatic arthritis as the presenting features of advanced HIV infection. AB - Knowledge of both the common and atypical presentations of human immunodeficiency virus (HIV)-associated dermatoses may be helpful in arousing suspicion of HIV, especially in patients with no reported risk factors. Herein, we report the case of an otherwise healthy, nonpromiscuous 29-year-old man who presented to our institution with an eight-week history of plaques with oyster shell-like scales on the trunk, extremities and genital area. The plaques were associated with fever, and intermittent knee pain and swelling. Initial diagnostic tests were suggestive of drug hypersensitivity syndrome, and the patient's condition improved with treatment using oral prednisone. However, the lesions recurred when the dose of prednisone was tapered, even after the culprit drug had long been discontinued. Repeat skin punch biopsy and arthrocentesis revealed a diagnosis of psoriasis vulgaris with psoriatic arthritis. Due to the atypical presentation of psoriasis, the patient was counselled to undergo HIV testing, which came back positive. Clinicians should be attuned to the skin signs heralding HIV/acquired immunodeficiency syndrome, in order to facilitate early diagnosis and treatment. PMID- 24763846 TI - Subcutaneous abscess due to Pyrenochaeta romeroi in a renal transplant recipient. AB - An infective aetiology, including fungal infection, should be considered in the differential diagnosis of immunocompromised patients presenting with skin lesions. Dematiaceous fungi are recognised as pathogens in organ transplant recipients. Herein, we describe a rare case of a chronic necrotising granulomatous skin lesion caused by Pyrenochaeta romeroi in a renal transplant recipient, and review the existing literature on the topic. To the best of our knowledge, this is the first report of such a case in Singapore. Recognition of infections caused by dematiaceous fungi is important because some strains are difficult to identify and require special molecular diagnostic techniques. Treatment involves surgical excision and long-term antifungal therapy. Data on the optimal antifungal regimen in such a diagnosis is limited. PMID- 24763848 TI - Expression of Raf Kinase Inhibitor Protein (RKIP) is a predictor of uveal melanoma metastasis. AB - Melanoma arising from melanocytes within the choroid is the most frequent primary intraocular neoplasm in adults. It is biologically distinct from cutaneous melanoma by a very strong propensity to metastasize the liver. Raf kinase inhibitor protein is a member of an evolutionarily conserved group of proteins called phosphatidylethanolamine-binding proteins. It is an interacting partner of Raf-1 and a negative regulator of the mitogen-activated protein kinase cascade initiated by Raf-1. Raf kinase inhibitor protein expression is low in many human cancers and represents an indicator of poor prognosis and/or induction of metastasis. In the present study, we examined the immunohistochemical expression levels of Raf kinase inhibitor protein and phosphorylated Raf kinase inhibitor protein in primary uveal melanoma with and without metastasis, and evaluated their association with other high risk characteristics for metastasis in order to assess whether Raf kinase inhibitor protein and phosphorylated Raf kinase inhibitor protein can be used to predict metastasis. A significant low expression of Raf kinase inhibitor protein was seen in patients with metastasis but not in patients without metastasis. The latter more frequently had a high expression of Raf kinase inhibitor protein. No significant difference was seen in phosphorylated Raf kinase inhibitor protein expression between patients with and without metastasis. Raf kinase inhibitor protein expression is a suitable and easily determinable marker in the primary tumour that could predict the risk of uveal melanoma to metastasize, and hence guide strategies for monitoring and therapy. PMID- 24763850 TI - Calcium and phosphate concentrations and future development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study. AB - AIMS/HYPOTHESIS: Low phosphate and high calcium concentrations have been linked to altered glucose tolerance and reduced insulin sensitivity in non-diabetic individuals. The aim of this study was to examine the relationships of calcium and phosphate levels and the calcium-phosphate product with the development of type 2 diabetes. METHODS: Participants were 863 African-Americans, Hispanics and non-Hispanic whites in the Insulin Resistance Atherosclerosis Study who were free of diabetes at baseline. The mean follow-up period was 5.2 years. The insulin sensitivity index (SI) and acute insulin response (AIR) were directly measured using the frequently sampled IVGTT. RESULTS: Calcium concentration (OR per 1 SD unit increase, 1.26 [95% CI 1.04, 1.53]) and calcium-phosphate product (OR 1.29 [95% CI 1.04, 1.59]) were associated with incident diabetes after adjustment for demographic variables, family history of diabetes, and 2 h glucose. The relationship between phosphate concentration and progression to diabetes was close to statistical significance (OR 1.21 [95% CI 0.98, 1.49]). Calcium concentration (OR 1.37 [95% CI 1.09, 1.72]) and calcium-phosphate product (OR 1.39 [95% CI 1.09, 1.77]) remained associated with incident diabetes after additional adjustment for BMI, plasma glucose, SI, AIR, C-reactive protein, estimated GFR, diuretic drugs and total calcium intake. CONCLUSIONS/INTERPRETATION: Elevated serum calcium and calcium-phosphate product are associated with increased risk of developing type 2 diabetes independently of measured glucose, insulin secretion and insulin resistance. Future studies need to analyse the role of calcium-phosphate homeostasis in the pathophysiology of diabetes. PMID- 24763853 TI - Malignancy-associated hyperamylasaemia. PMID- 24763851 TI - Validation of a model to estimate personalised screening frequency to monitor diabetic retinopathy. AB - AIMS/HYPOTHESIS: Our study aimed to validate a model to determine a personalised screening frequency for diabetic retinopathy. METHODS: A model calculating a personalised screening interval for monitoring retinopathy based on patients' risk profile was validated using the data of 3,319 type 2 diabetic patients in the Diabetes Care System West-Friesland, the Netherlands. Two-field fundus photographs were graded according to the EURODIAB coding system. Sight threatening retinopathy (STR) was considered to be grades 3-5. Validity of the model was assessed using calibration and discrimination measures. We compared model-based time of screening with time of STR diagnosis and calculated the differences in the number of fundus photographs using the model compared with those in annual or biennial screening. RESULTS: During a mean of 53 months of follow-up, 76 patients (2.3%) developed STR. Using the model, the mean screening interval was 31 months, leading to a reduced screening frequency of 61% compared with annual screening and 23% compared with biennial screening. STR incidence occurred after a mean of 26 months after the model-based time of screening in 67 patients (88.2%). In nine patients (11.8%), STR had developed before the model based time of screening. The discriminatory ability of the model was good (C statistic 0.83; 95% CI 0.74, 0.92). Calibration showed that the model overestimated STR risk. CONCLUSIONS/INTERPRETATION: A large reduction in retinopathy screening was achieved using the model in this population of patients with a very low incidence of retinopathy. Considering the number of potentially missed cases of STR, there is room for improvement in the model. Use of the model for personalised screening may eventually help to reduce healthcare use and costs of diabetes care. PMID- 24763854 TI - A simple electronic alert for acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is frequently under-recognized and contributes to poor outcomes. Electronic alerts (e-alerts) to highlight AKI based on changes in serum creatinine may facilitate earlier recognition and treatment, and sophisticated algorithms for AKI detection have been proposed or implemented elsewhere. However, many laboratories currently lack the resources or capability to replicate these systems. METHODS: A real-time automated delta check e-alert flags a 50% increase in creatinine to a concentration of >50 umol/L from the most recent result within a 90-day period and automatically adds the comment '?AKI - creatinine increase >50% from previous' with a link to local AKI guidelines. In addition, creatinine results >300 umol/L are retrospectively reviewed and phoned if AKI is suspected. For each alert over a 12-day period we manually reviewed previous and subsequent creatinine results to determine baseline creatinine and stage AKI according to Acute Kidney Injury Network (AKIN) criteria. RESULTS: From 11,930 creatinine requests, 63 of 90 (70%) delta check e-alerts were due to AKI, identifying 61 episodes of AKI. Thirty four of 54 (63%) creatinine results >300 umol/L were due to AKI, identifying a further 10 episodes of AKI. The positive predictive value (PPV) for AKI of a delta check e-alert was greater when the trigger creatinine was >100 umol/L (PPV 89%) or when the absolute change in creatinine was >50 umol/L (PPV 93%). CONCLUSION: This study demonstrates that a simple automated delta check can detect and flag AKI in real time, continuously, at little extra cost and without manual input. PMID- 24763860 TI - Criteria for sensitivity enhancement by compressed sensing: practical application to anisotropic NAD 2D-NMR spectroscopy. AB - Numerous contributions over the last two decades have proven that non-uniform sampling (NUS) allows significant acceleration of NMR experiments. It has been also shown that relaxation-matched NUS can improve the sensitivity when compared to conventional regularly sampled experiments acquired within the same measurement time. The method of compressed sensing (CS), recently introduced to NMR, constitutes an effective approach to NUS processing. However, the relaxation matched sampling, providing an optimal signal-to-noise ratio, does not optimally fulfill the mathematical criteria of CS reconstruction. In this paper, we show that restricted isometry constants allow prediction of the optimal sampling time constant for exponentially decaying NUS. We also introduce criteria for the choice of the maximal indirect evolution period and we analyze the influence of the maximal indirect evolution period and the sampling time constant on the NUS sensitivity enhancement. As a practical example of application, we have chosen two natural abundance deuterium two dimensional NMR (NAD 2D-NMR) experiments using polypeptide lyotropic chiral liquid crystals (CLCs) as aligning NMR solvents, requiring superior sensitivity and resolution for a wide range of analytical domains (chirality, stereochemistry studies, isotopic fractionation, ...). From an experimental viewpoint, the combination of NUS and CS can be successfully applied both for symmetrical anisotropic NAD Q-COSY Fz 2D experiments and asymmetrical NAD Q-resolved Fz ones. The possibility to boost the sensitivity/resolution of anisotropic NAD 2D-NMR experiments opens up new potentialities for the method. PMID- 24763861 TI - Amyotrophic lateral sclerosis in a patient with a family history of huntington disease: genetic counseling challenges. AB - Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are generally considered to be distinct and easily differentiated neurologic conditions. However, there are case reports of the co-occurrence of ALS with HD. We present a 57-year-old male with a clinical diagnosis of sporadic ALS in the context of a family history of HD. This case adds to the limited literature regarding individuals with a family history of HD who present with features of ALS. There were several genetic counseling challenges in counseling this patient including the diagnostic consideration of two fatal conditions, complex risk information, the personal and familial implications, and the patient's inability to communicate verbally or through writing due to disease progression. DNA banking effectively preserved the right of our patient and his wife not to learn his HD genetic status during a stressful time of disease progression while providing the option for family members to learn this information in the future if desired. We present lessons learned and considerations for other clinical genetics professionals who are presented with similar challenging issues. PMID- 24763862 TI - To err is human: lessons from patient safety research for transplant care. PMID- 24763863 TI - Expression of fibroblast growth factor 23, vitamin D receptor, and sclerostin in bone tissue from hypercalciuric stone formers. AB - BACKGROUND AND OBJECTIVES: Increased bone resorption, low bone formation, and abnormal mineralization have been described in stone formers with idiopathic hypercalciuria. It has been previously shown that the receptor activator of NF kappaB ligand mediates bone resorption in idiopathic hypercalciuria (IH). The present study aimed to determine the expression of fibroblast growth factor 23 (FGF-23), vitamin D receptor (VDR), and sclerostin in bone tissue from IH stone formers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Immunohistochemical analysis was performed in undecalcified bone samples previously obtained for histomorphometry from 30 transiliac bone biopsies of idiopathic hypercalciuria stone-forming patients between 1992 and 2002 and 33 healthy individuals (controls). Serum parameters were obtained from their medical records. RESULTS: Histomorphometry disclosed 21 IH patients with high and 9 IH patients with normal bone resorption. Importantly, eroded surfaces (ES/BS) from IH patients but not controls were significantly correlated with VDR immunostaining in osteoblasts (r=0.51; P=0.004), sclerostin immunostaining in osteocytes (r=0.41; P=0.02), and serum 1,25-dihydroxyvitamin D (r=0.55; P<0.01). Of note, both VDR and sclerostin immunostaining were significantly correlated with serum 1,25-dihydroxyvitamin D in IH patients (r=0.52; P=0.01 and r=0.53; P=0.02, respectively), although VDR and sclerostin expression did not differ between IH and controls. IH patients with high bone resorption exhibited a significantly stronger sclerostin immunostaining than IH patients with normal bone resorption. FGF-23 expression in osteocytes from IH patients did not differ from controls and was not correlated with any histomorphometric parameter. CONCLUSIONS: These findings suggest the contribution of VDR and sclerostin, as well as 1,25-dihydroxyvitamin D, to increase bone resorption in idiopathic hypercalciuria but do not implicate FGF-23 in the bone alterations seen in these patients. PMID- 24763864 TI - A patient with heart failure and worsening kidney function. AB - There is high prevalence of CKD, defined by reduced GFR, in patients with heart failure. Reduced kidney function is associated with increased morbidity and mortality in this patient population. The cardiorenal syndrome (CRS) involves a bidirectional relationship between the heart and kidneys whereby dysfunction in either may exacerbate the function of the other, but this syndrome has been difficult to precisely define because it has many complex physiologic, biochemical, and hormonal abnormalities. The pathophysiology of CRS is not completely understood, but potential mechanisms include reduced kidney perfusion due to decreased forward flow, increased right ventricular and venous pressure, and neurohormonal adaptations. Treatment options include inotropic medications; diuretics; ultrafiltration; and medications, such as beta-blockers, inhibitors of the renin-angiotensin-aldosterone system, and more novel treatments that focus on unique aspects of the pathophysiology. Recent observational studies suggest that treatments that result in a decrease in venous pressure and lead to hemoconcentration may be associated with improved outcomes. Patients with CRS that is not responsive to medical interventions should be considered for ventricular assist devices, heart transplantation, or combined heart and kidney transplantation. PMID- 24763865 TI - Socioeconomic differences in the uptake of home dialysis. AB - BACKGROUND AND OBJECTIVES: Home dialysis creates fewer lifestyle disruptions while providing similar or better outcomes than in-center hemodialysis. Socioeconomically advantaged patients are more likely to commence home dialysis (peritoneal dialysis and home hemodialysis) in many developed countries. This study investigated associations between socioeconomic status and uptake of home dialysis in Australia, a country with universal access to health care and comparatively high rates of home dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study analyzed 23,281 non-Indigenous adult patients who commenced chronic RRT in Australia from 2000 to 2011 according to the Australia and New Zealand Dialysis and Transplant Registry in a retrospective cohort study. This study investigated the proportion of patients who were ever likely to use home dialysis using nonmixture cure models and followed patients until the end of 2011 (median follow-up time=3.0 years, interquartile range=1.3-5.5 years). The main predictor was area socioeconomic status from postcodes grouped into quartiles using standard indices. RESULTS: Patients from the most advantaged quartile of areas were less likely to commence peritoneal dialysis (odds ratio, 0.63; 95% confidence interval, 0.58 to 0.69) and more likely to use in-center hemodialysis than patients from the most disadvantaged areas (odds ratio, 1.19; 95% confidence interval, 1.10 to 1.30). Socioeconomic status was not associated with uptake of home hemodialysis. Rural areas were more disadvantaged and had higher rates of peritoneal dialysis, and privately funded hospitals rarely used home dialysis. Patients from the most advantaged quartile of areas were more likely to use private hospitals than patients from the most disadvantaged quartile (odds ratio, 5.9; 95% confidence interval, 4.6 to 7.5). CONCLUSION: The lower incidence of peritoneal dialysis among patients from advantaged areas seems to be multifactorial. Identifying and addressing barriers to home dialysis in Australia could improve patient quality of life and reduce costs. PMID- 24763866 TI - Clinical and economic outcomes associated with medication errors in kidney transplantation. AB - BACKGROUND AND OBJECTIVES: Modern immunosuppressant regimens have significantly decreased acute rejection rates, but may have increased the risk of graft loss driven by adverse drug reactions (ADRs) and medication errors (MEs). The objectives of this study were to determine the incidence and risk factors for MEs and ADRs and determine the association between transplant outcomes and these events. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a post hoc analysis of a prospective, randomized trial that included patients aged>18 years that received a solitary renal transplant at an academic medical center recruited between March 2009 and July 2011. Patients were divided into groups based on developing a clinical significant ME (CSME), defined as a significant ME that contributed to a hospital admission. RESULTS: The mean study follow-up was 2.5 +/ 0.7 years. There were a total of 233 MEs and 327 ADRs in the 200 patients included in the analysis, with 64% of the cohort experiencing at least one ME and 87% experiencing an ADR; 23 patients (12%) experienced a CSME. Patients that experienced CSMEs had a trend toward more post-transplant readmissions (median 1 [interquartile range (IQR), 0-5] versus 0 [0-2]; P=0.06), higher costs for readmissions (median $18,091 [IQR, $3023-$56,268] versus $0 [$0-$15,991]; P<0.01), and overall length of stay (median 5.0 days [IQR, 2.0-14.0] versus 0.0 days [IQR, 0.0-5.5]; P<0.01) after the CSME event. CSME patients were also more likely to experience graft failure (22% versus 10%; P=0.05). CONCLUSIONS: Significant MEs commonly occur in renal transplant recipients and are associated with an increased risk of deleterious clinical outcomes, including subsequent hospital days, costs, and graft loss. PMID- 24763867 TI - Accidental falls and risk of mortality among older adults on chronic peritoneal dialysis. AB - BACKGROUND AND OBJECTIVES: More than 40% of elderly hemodialysis patients experience one or more accidental falls within a 1-year period. Such falls are associated with higher mortality. The objectives of this study were to assess whether falls are also common in elderly patients established on peritoneal dialysis and evaluate if patients with falls have a higher risk of mortality than patients who do not experience a fall. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a prospective cohort study design, patients ages >= 65 years on chronic peritoneal dialysis from April 2002 to April 2003 at the University Health Network were recruited. Patients were followed biweekly, and falls occurring within the first 15 months were recorded. Outcome data were collected until death, study end (July 31, 2012), transplantation, or transfer to another dialysis center. RESULTS: Seventy-four of seventy-six potential patients were recruited, assessed at baseline, and followed biweekly for falls; 40 of 74 (54%) peritoneal dialysis patients experienced 89 falls (adjusted mean fall rate, 1.7 falls per patient-year; 95% confidence interval, 1.0 to 2.7). Patients with falls were more likely to have had previous falls, be more recently initiated onto dialysis, be men, be older, and have higher comorbidity. Twenty-eight patients died during the follow-up period. After adjustment for known risk factors, each successive fall was associated with a 1.62-fold higher mortality (hazard ratio, 1.62; 95% confidence interval, 1.29 to 2.02; P<0.001). CONCLUSIONS: Accidental falls are common in the peritoneal dialysis population and often go unrecognized. Falls were associated with higher mortality risk. Because fall interventions are effective in other populations, screening peritoneal dialysis patients for falls may be a simple measure of clinical importance. PMID- 24763868 TI - Associations of body size and body composition with functional ability and quality of life in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Modifiable factors, such as body size and body composition, could influence physical function and quality of life in patients undergoing maintenance hemodialysis (MHD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From January 2008 to June 2012, in body mass index (BMI), waist circumference (WC), and magnetic resonance imaging measurements of midthigh muscle area (MTMA) and intra-abdominal fat area (IAFA) were obtained at baseline in 105 MHD patients. Six-minute walk distances and physical and mental component scores (PCS and MCS) from the Short Form-12 questionnaire were obtained at baseline and 6 and 12 months. Separate mixed-effects regression models were used to relate baseline BMI, WC, and IAFA with baseline and the average of follow-up 6 minute walk distances and PCS and MCS after adjustment for baseline covariates and MTMA. RESULTS: for baseline covariates and baseline MTMA, each SD increase in baseline BMI was inversely associated with baseline (-31.5 m; 95% confidence interval [95% CI], -53.0 to -10.0 m) and follow-up (-36.9 m; 95% CI, -54.6 to 19.2 m) 6-minute walk distances. Results were similar for WC and IAFA. In each of these models, each SD increase in MTMA had a strong positive association with 6 minute walk distance. Adiposity measures were not associated with baseline or follow-up PCS and MCS. After adjustment for baseline BMI, each SD increase in baseline MTMA was associated with higher baseline PCS score (3.78; 95% CI, 0.73 to 6.82) and MCS (3.75; 95% CI, 0.44 to 7.05) but had weaker associations with follow-up PCS and MCS. CONCLUSIONS: Body size and composition are significantly associated with physical functioning and quality of life. Interventions that improve muscle mass and decrease obesity might improve these measures in patients undergoing MHD. PMID- 24763869 TI - Do socioeconomic factors affect dialysis modality selection? PMID- 24763870 TI - Superior rectus transposition vs medial rectus recession for treatment of esotropic Duane syndrome. AB - IMPORTANCE: Superior rectus transposition (SRT) with or without medial rectus recession (MRc) has been introduced as an alternative to MRc alone for treatment of esotropic Duane syndrome; however, the effectiveness of these procedures has not been compared previously. OBJECTIVE: To compare the safety and efficacy of MRc and SRT in treatment of Duane syndrome. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of all patients with esotropic Duane syndrome who underwent surgical treatment from January 1, 2006, through December 31, 2012, in a multispecialty, hospital-based pediatric ophthalmology/adult strabismus practice at Boston Children's Hospital. Patients in the SRT group underwent SRT with or without MRc; those in the non-SRT group underwent unilateral or bilateral MRc. EXPOSURES: Surgical treatment of esotropic Duane syndrome. MAIN OUTCOMES AND MEASURES: Binocular alignment, ocular ductions, head position, stereopsis, and fundus torsion were recorded before surgery and at the 2-month and final postoperative visits. We also evaluated postoperative drift. RESULTS: The medical record review identified 36 patients who underwent 37 procedures, including 19 in the SRT group (13 SRT + MRc and 6 SRT alone) and 18 in the non-SRT group (11 unilateral MRc and 7 bilateral medial rectus resession). Mean MRc was smaller when performed with SRT (3.3 vs 5.3 mm; P = .004). Although the initial deviation was larger in the SRT group, both groups had a similar improvement in esotropia and head turn. Abduction improved by at least 1 unit in 15 of 19 patients in the SRT group (79%) vs 5 of 18 in the non-SRT group (28%). In 24 patients followed up for more than 6 months, mean esotropia decreased from 8.2 to 6.1 prism diopters (Delta) in the SRT group (n = 12) but increased from 7.2 to 10.9Delta in the non SRT group (n = 12). CONCLUSIONS AND RELEVANCE: The combination of SRT and MRc was more effective than MRc or bilateral medial rectus resession at improving abduction while allowing for a smaller recession to align the eyes and eliminate a compensatory head posture. Although any surgery on the vertical rectus muscles should in theory increase the risk for vertical or torsional complications, to date this theory has not been borne out in our patients. Patients treated with SRT appear to have a reduced likelihood of long-term undercorrection. We therefore recommend SRT with adjustable MRc for treatment of Duane syndrome in patients with larger amounts of esotropia. PMID- 24763871 TI - Effect of intermittent hypoxia on rat INS-1 cells and the protective effect of melatonin. AB - OBJECTIVES: This study aimed to observe the influence of intermittent hypoxia on rat INS-1 cells and the protective effect of melatonin (MT). MATERIALS AND METHODS: Intermittent hypoxia condition was induced in rat INS-1 cells. The supernatants were used to detect oxidative stress indicators, and the cells were used to detect JNK1 mRNA and JNK1/2 protein. After different dose-dependent interventions of MT, the cells were harvested to observe corresponding oxidative stress indicators and JNK1/2 protein change. RESULTS: With prolonged exposure time, malondialdehyde (MDA) increased in cultured supernatants whereas superoxide dismutase (SOD) activity decreased. Cells with intermittent hypoxia showed significantly increased JNK1 mRNA expression, whereas phosphorylated JNK1 was highly expressed on the third day. With increased MT dose, MDA in cultured supernatants decreased whereas SOD activity increased. In the group dosed with 100 uM MT, phosphorylated JNK1 protein expression significantly decreased. CONCLUSIONS: Intermittent hypoxia can cause oxidative damage to INS-1 cells possibly by increasing the JNK1 transcription level and protein activation. A high dose of MT (100 uM) can protect INS-1 cells from oxidative damage induced by intermittent hypoxia. PMID- 24763872 TI - Cytoprotective effect of beta-lapachone by inducing heme oxygenase-1 expression and AMP-activated protein kinase activation in human endothelial cells. AB - OBJECTIVES: AMP-activated protein kinase (AMPK) is suggested to exert cytoprotective and anti-inflammatory effects in endothelial cells, but the precise mechanisms are not fully understood. It has been reported that pharmacological activation of AMPK induces endothelial heme oxygenase-1 (HO-1) expression. beta-Lapachone (BL), a well-known substrate of NAD(P)H: quinone oxidoreductase (NQO1), stimulates AMPK activation via NQO1 activation. Here we examined whether AMPK activation by BL would be linked to HO-1 expression in ECV304 endothelial cells and whether HO-1 expression could mediate the cytoprotective effect of BL. MATERIALS AND METHODS: Endothelial cells were pre incubated for 6 h with BL or 5-aminoimidazole-4-carboxamide-1-beta-D ribofuranoside (AICAR) in the absence or presence of dicoumarol (DC), compound C (CC), or tin protoporphyrin-IX (SnPP), and then challenged with tumor necrosis factor-alpha (TNF-alpha) for 24 h. Cell viability was evaluated by 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. AMPK phosphorylation and HO-1 expression were detected by Western blot analysis. RESULTS: At non-cytotoxic concentrations, BL induced AMPK phosphorylation and HO 1 expression. AICAR, an AMPK activator, also induced HO-1 expression. In contrast, CC, an inhibitor of AMPK activation, and DC, an inhibitor of NQO1, prevented the increase in BL-induced HO-1 expression. Pretreatment with BL or AICAR reduced TNF-alpha-induced endothelial cell death. Cytoprotection by BL was almost completely abolished by CC and DC and partly by SnPP, a competitive inhibitor of HO-1. CONCLUSIONS: Our results suggest that BL induces cytoprotective HO-1 expression in endothelial cells via AMPK activation, providing one of possible mechanisms by which BL can exert beneficial effects. PMID- 24763873 TI - Effects of fasudil on hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats. AB - AIM: The aim of this study was to investigate the effects of Rho kinase inhibitor Fasudil on hypoxic pulmonary hypertension (HPH) and pulmonary vascular remodeling in rats. MATERIALS AND METHODS: A total of 24 Sprague Dawley rats were evenly randomized into control, model and Fasudil intervention groups. Light and transmission electron microscopy were utilized to observe pulmonary vascular remodeling as well as ultrastructural changes in pulmonary arteriole endothelial cells. RESULTS: The model group showed apparent pulmonary vascular remodeling, pulmonary arteriole endothelial cell injury, the proliferation and swelling of smooth muscle cells around, and the proliferation of collagen fibers. Fasudil intervention improved pulmonary vascular remodeling as well as relieved pulmonary arteriole endothelial cell injury and the proliferation of smooth muscle cells and collagen fibers. CONCLUSIONS: Fasudil has preventive and reverse effects on HPH, pulmonary vascular remodeling, and pulmonary arteriole endothelial cell injury. PMID- 24763874 TI - Microbiological and molecular detection of VIM-1 metallo beta lactamase-producing Acinetobacter baumannii. AB - BACKGROUND: Acinetobacter resistant to carbapenems, is one of the most frequently isolated pathogens in the hospital settings and presents a challenge to the clinician. AIM: to detect metallo-beta-lactamase in A. baumannii by E-test and VIM-1 genes by PCR. MATERIALS AND METHODS: A four-month prospective study was done on Forty eight carbapenem resistant A. baumannii strains that isolated from patients with different types of infection either admitted or attending to the Outpatient Clinics at King Fahd Hospital in Al-Madinah Al-Monawarah. For all collected specimens, microbiological analysis, antimicrobial susceptibility testing using disk diffusion method, metallo Beta-lactamases (MBLs) detection by E-test (Epsilometer test) and VIM-1 metallo b-lactamase detection by PCR (polymerase chain reaction) were performed. RESULTS: Among the 48 carbapenem resistant A. baumannii isolates, 13 strains had MBL detected by E-test and among them VIM-1 gene was detected by PCR in 8 isolates but among the 35 A. baumannii isolates that did not produce MBL by E-test, VIM-1 gene was detected in 5 isolates. CONCLUSIONS: The study revealed that specificity of the E-test is low, thus overestimating the number of MBL-positive isolates while, reduction of blaVIM-1 gene expression, revealing hidden MBL phenotypes. So, all carbapenem resistant isolates should be tested by PCR regardless of whether the conventional MBL testing is performed. PMID- 24763875 TI - Antidepressant and antihemolytic activities of Vicia sojakii. AB - OBJECTIVES: Many pharmacological activities have been reported in Vicia (V.) genus. The aim of present study was to investigate antidepressant and antihemolytic activities of aerial parts of V. sojakii. MATERIALS AND METHODS: Antidepressant activity of methanolic extract was evaluated by forced swimming test (FST) and tail suspension tests (TST) in male Swiss albino mice. Antihemolytic effect of extract was also determined. RESULTS: Extract showed good antidepressant activity in both FST and TST. It shortened remarkably the immobility period in FST and TST and exhibited a dose dependent activity. Extract in 125 mg kg(-1) showed significant activity as compared to control (p < 0.05) in both test. Extract at 1500 mg kg(-1) showed the same activity of imipramine 15 mg kg(-1) (p > 0.05) in FST. Extract show good antihemolytic activity against H2O2 induced hemolysis. CONCLUSIONS: Our report indicated the V. sojakii aerial parts extract was safe and showed remarkable antidepressant activity in FST and TST in mice. It also exhibited good antihemolytic activity. These results introduced V. sojakii as an easily accessible source of natural antidepressant. PMID- 24763876 TI - Post-EVAR aortic neck elongation: is a real phenomenon or a conformational change during the cardiac cycle? AB - BACKGROUND: Stent-graft migration is a late-term complication of endovascular abdominal aortic aneurysm repair (EVAR). A recent published study suggests that stent graft migration could be explained only by aortic neck elongation, mimicking the appearance of distal stent graft migration. Several studies about the use of dynamic CT Angiography (CTA) in the evaluation of aortic conformation changes during the cardiac cycle demonstrate that axial aortic pulsatility exists. No studies have been carried out to evaluate if a longitudinal aortic pulsatility also exists, that could justify the aortic neck elongation previously reported. AIM: To assess variations in length of proximal neck and infrarenal abdominal aorta in patients selected to undergo EVAR; to assess if longitudinal aortic pulsatility could modify EVAR planning. PATIENTS AND METHODS: 40 patients with Abdominal Aortic Aneurysm (AAA) underwent both static and dynamic ECG-gated 64-CTA (0.625 mm-slice-collimation; 1.25 mm-reconstruction increment). Manual measurements of aortic neck length and infrarenal abdominal aorta were performed on modified coronal images to determine dynamic conformational changes. RESULTS: Significant longitudinal pulsatility was demonstrated within aneurysm neck (19.1 +/- 8.6%) and infrarenal abdominal aorta (6.6 +/- 1.6%). When compared to dynamic measurements, the endograft previously selected according to static images in terms of fixation, would be potentially changed in 6/40 patients (15%) whereas 4/40 (10%) patients were not eligible for EVAR. CONCLUSIONS: Dynamic ECG-gated CTA may provide information regarding longitudinal pulsatile motion that could change the EVAR planning based on static imaging. Reported post-EVAR elongation of infrarenal aortic neck could be an unreal phenomenon only due to a conformational change during cardiac cycle. PMID- 24763877 TI - Prophylactic accessory-pathway ablation in asymptomatic patients with a Wolff Parkinson-White electrocardiographic pattern. AB - OBJECTIVES: The optimal approach is controversial in asymptomatic patients who are coincidentally found to have evidence of an accessory pathway (AP) on an ECG. The risk of sudden cardiac death (SCD) is low, and the risk of developing symptoms also appears to be low, although a wide range of incidences have been reported. In our trial, we tested the hypothesis that if prophylactic accessory pathway ablation performed at the time of the initial electrophysiological testing would improve the long-term outcome in asymptomatic patients with a Wolff Parkinson-White electrocardiographic pattern. PATIENTS AND METHODS: Recruitment of patients began on February 1, 2004, and ended on February 5, 2009. All 110 asymptomatic patients were hospitalized and underwent electrophysiological testing the same day to assess the inducibility of atrioventricular reciprocating tachycardia. The anterograde effective refractory period of the accessory pathway was defined as the longest coupling interval at which anterograde block in the bypass tract was observed. For the statistical analysis, the statistical software SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). RESULTS: Of 110 asymptomatic patients with a Wolff-Parkinson-White electrocardiographic pattern, 80 patients were ablated. Ablation group consisted of these patients. Control group consisted of remaining 30 and were divided into two groups according to the anterograde effective refractory period of the accessory pathway. There was no significant difference between three groups in terms of arrhythmic events (p: 0.58). CONCLUSIONS: Asymptomatic patients with the Wolff-Parkinson-White syndrome do not require prophylactic ablation, since they remain asymptomatic for many years. PMID- 24763878 TI - Angiotensin-(1-7) upregulates (ATP-binding cassette transporter A1) ABCA1 expression through cyclic AMP signaling pathway in RAW 264.7 macrophages. AB - OBJECTIVES: ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in reverse cholesterol transport and anti-atherosclerosis. Cyclic AMP (cAMP) could increase the ABCA1 expression. Angiotensin (Ang)-(1-7) can protect endothelial cells, inhibit smooth muscle cell growth, ameliorate inflammation and exert anti atherosclerotic effects. In this study, we attempted to clarify the effect of Ang (1-7) on expression of ABCA1, and explored the role of cAMP in the regulation of ABCA1 in RAW 264.7 macrophages. MATERIALS AND METHODS: RAW 264.7 macrophages were cultured. Then the macro-phages were incubated with different concentration Ang (1-7) or 10 mM MDL respectively, or 10 mM adenylate cyclase inhibitor MDL-12330A (MDL) plus 1000 nM Ang-(1-7) for 24 h. The expression of ABCA1 was examined by real-time quantitative PCR and western blot analyses. cAMP expression was measured by Enzyme-Linked Immuno Sorbent Assay. Cellar cholesterol efflux from RAW 264.7 macrophages was analyzed using liquid scintillation counting assays. The cellular total cholesterol and free cholesterol were performed to determine by High Performance Liquid Chromatography assays. RESULTS: Our results showed that Ang-(1-7) increased ABCA1 expression at both the mRNA and protein levels in a dose-dependent manner. Consequently, the increase in cholesterol efflux was consistent with an ABCA1 expression increase. The cAMP expression was up regulated by Ang-(1-7). When being treated with MDL and Ang-(1-7), the ABCA1 expression, cellular cholesterol efflux and cholesterol content were partially reversed by MDL. CONCLUSIONS: Ang-(1-7) could increase ABCA1 expression partially due to the cAMP pathway. PMID- 24763879 TI - The effects of mobile phones on apoptosis in cerebral tissue: an experimental study on rats. AB - INTRODUCTION: The concern about mobile phone effects is increasing as the number of users increasing too. Different studies have different results, so this topic is still open to discussion. Aim of this report was to investigate the effects of the mobile phones on the Bcl-2 gene and p53 proteins in rat brains. MATERIALS AND METHODS: In the study group of 10 rats; mobile phones that spread EMW at a frequency between 1900-2100 MHz and Specific Absorption Rate range between 0.005 W/kg and 0.288 W/kg (Dialing mode), 0.004 W/kg and 0.029 W/kg (Calling mode) were attached to rat ears for simulating usage in daily life for 7 times a day during 5 minutes (3 seconds dialing mode, 4 minutes and 47 seconds of calling mode) for a four week period. Sham group (n=10) rats were only immobilized without EMW exposure. Another group of rats (n=10) were counted as control without any application. immunohistopathological examination was performed for p53 and Bcl-2 expression. RESULTS: Immunohistopathological examinations revealed that the samples in the study group had more p53 and Bcl-2 positive stained cells and they were stained denser. In both evaluations, these differences between the study and control group were found statistically significant (p < 0.003); In Bcl-2 evaluation statistically significant difference was found between study and sham group to (p < 0.005); however, the p53 evaluation between the study and the sham group did not show any statistically significant difference (p > 0.005). CONCLUSIONS: Our results showed that the electro-magnetic waves emitted by the mobile phones may have effect on apoptosis. Besides, obtained data revealed that more realistic application of mobile phones during experiments is more important as expected. PMID- 24763880 TI - Behavioural, psychological, and temperamental predictors of risk suicide trend after brief psychodynamic psychotherapy. AB - BACKGROUND: Evidence has shown that psychotherapy is effective for depression, whereas the outcome for suicide risk is unclear. AIM: It was to investigate whether possible pre-treatment predictors of suicide risk (SR) decrease after a brief psychodynamic psychotherapy treatment and at follow-up. PATIENTS AND METHODS: Forty-one patients were assessed at: baseline (T0) for clinical history, clinical family history, physical diseases, type of suffered abuse; after the treatment (T1); and, at six-month follow-up (T2) for mood ratings, temperamental features, and SR levels. RESULTS: The levels of depression and cyclothymia decreased at T1 and T2 compared to T0; however, the distribution of the patients with high SR level was similar between T0 and T1, and at T2 it increased. T1-T0 SR (Delta1SR) was correlated with suicidality in the last month and with depression levels at T0; T2-T0 SR (Delta2SR) was correlated with many historical, clinical, and temperamental variables; T2-T1 SR (Delta3SR) was correlated with the presence of previous psychotherapy, abuse, and anxiety. Linear regression models revealed that Delta1SR was predicted by the suicidality in the last month; Delta2SR was not significantly predicted by any variable; and, Delta3SR was predicted by anxiety. CONCLUSIONS: The treatment was able to decrease the depression but not the SR. Findings confirm the difficulty of affecting SR and the importance of carefully considering the anxiety and the previous experiences of abuse in order to manage the interruption of the psychotherapy. PMID- 24763881 TI - Uricemia and homocysteinemia: nontraditional risk factors in the early stages of chronic kidney disease--preliminary data. AB - BACKGROUND: Patients with chronic kidney disease (CKD) show a risk of cardiovascular death, which is 10-100 times higher than that in the general population. This increase is not completely explained by the traditional cardiovascular risk factors. Hyperuricemia and hyperhomocysteinemia are highly prevalent in CKD. Patients suffering from these complications present accelerated atherosclerosis, determined mainly from the endothelial dysfunction that carries out a central role in the pathogenesis of cardiovascular diseases. AIM: The hypothesis was that brachial artery flow mediated dilation (FMD) and carotid intima-media thickness (cIMT) evaluation can be considered as early and systemic markers of atherosclerosis and that nontraditional risk factors, such as hyperhomocysteinemia and hyperuricemia, are associated with early endothelial dysfunction and vascular damage in patients suffering from first- and second stage CKD. PATIENTS AND METHODS: The study comprised 50 patients, 10 for each CKD stage, and 15 age- and sex-matched healthy controls. We compared the traditional and nontraditional factors for cardiovascular diseases with alterations of vascular reactivity, such as cIMT, and brachial artery FMD, in patients affected by CKD with those in the control group. RESULTS: In our study, hyperuricemia was significantly and independently associated with brachial artery FMD reduction (p = 0.007), while hyperhomocysteinemia was significantly and independently associated with carotid intima-media thickening (p = 0.021) in patients at Stage I and II KDOQI (Kidney Disease Outcomes Quality Initiative). CONCLUSIONS: In our study, we found a progressive increase in the inflammatory indices and endothelial dysfunction at the early stages of CKD. Hyperuricemia and hyperhomocysteinemia were associated with IMT and FMD at Stage I-III KDOQI, and can be used as markers of subclinical atherosclerosis, especially in nephropathic patients with high cardiovascular risk. PMID- 24763882 TI - Clinical effectiveness of multimodality treatment on advanced pediatric hepatoblastoma. AB - OBJECTIVES: To investigate the effect of multimodality treatment of advanced paediatric hepatoblastoma and the factors affecting the prognosis. PATIENTS AND METHODS: 35 childhood patients were treated with multimodality treatments consisting of chemotherapy, surgery, interventional therapy, and autologous peripheral blood stem cell transplantation. Patients were followed up every month. RESULTS: 33 patients completed the follow-up, of which 17 were in complete remission, 5 were in partial remission, 1 case got worse, and 10 died. The remission rate was 66.7% (22/33), and the overall survival rate was 69.7% (23/33). 1 patient with advanced hepatoblastoma got high-dose chemotherapy combined with autologous peripheral blood stem cell transplantation (APBSCT) treatment, and a primary lesion by 18 x 15 x 9 cm reduced to 10 x 8 x 4 cm. Remote metastases significantly alleviated, and partial remission reached six months. The overall survival was 9 months after transplantation. Patients with the mixed phenotype of hepatoblastoma had a worse prognosis than with the epithelial phenotype (p < 0.001), and patients in stage IV had a lower survival rate than in stage III (p < 0.001). CONCLUSIONS: Multimodality treatment can effectively improve remission rate and prolong the survival of children with the advanced hepatoblastoma. In addition, alpha-fetoprotein (AFP), hepatoblastoma pathological classification and staging are of great use in prediction of prognosis. PMID- 24763883 TI - Down-regulation of microRNA-205 promotes gastric cancer cell proliferation. AB - OBJECTIVE: Increasing evidence indicates that MicroRNAs, a class of small RNA molecules, play crucial roles in tumorigenesis, through affecting cell proliferation, apoptosis and metastasis. The present study aimed to investigate the effect of miR-205 on gastric cancer cell proliferation. MATERIALS AND METHODS: The expression of miR-205 was examined in the gastric cancer tissues and cell lines. BrdU incorporation assay was used to measure the cell proliferation. Western blot was performed to determine the protein expression. RESULTS: miR-205 is significantly down-regulated in gastric cancer tissues, compared with adjacent normal tissues. Besides, miR-205 expression is associated with clinical and pathological characteristics of patients. In vitro studies further found that inhibition of miR-205 significantly promoted gastric cancer cell proliferation via cell-cycle progression. Further analyses indicated that miR-205 was able to repress oncoprotein Yin Yang 1 expression, through targeting its 3'-untranlated region. CONCLUSIONS: Our data suggest that down-regulation of miR-205 may represent an important mechanism for the development of gastric cancer. PMID- 24763884 TI - Identified differently expressed genes in renal cell carcinoma by using multiple microarray datasets running head: differently expressed genes in renal cell carcinoma. AB - OBJECTIVE: The purpose of this study was to identify differentially expressed genes and analysis biological processes related to renal cell carcinoma. METHODS: A meta-analysis was performed using the Rank Product package of Gene Expression Omnibus datasets of renal cell carcinoma. Then Gene Ontology enrichment analyses and pathway analysis were performed based on Gene Ontology website and Kyoto Encyclopedia of Genes and Genomes. Protein-protein interaction network was constructed used Cytoscape software. RESULTS: We identified a total of 1992 differentially expressed genes Rank Product package of renal cell carcinoma, 840 of them were not involved in individual DEGs. Gene Ontology enrichment analyses showed that those 840 genes enriched in terms such as response to hormone stimulus, endogenous stimulus, biological adhesion, and cell proliferation. Pathway analysis showed that significant pathways included pyruvate metabolism, glycerolipid metabolism, complement and coagulation cascades and so on. Protein protein interaction network indicated that MT2A, MYC, CENPF and NEK2 has high degree which participated many interactions. CONCLUSIONS: Our study displayed genes that were consistently differentially expressed in renal cell carcinoma, and the biological pathways, protein-protein interaction network associated with those genes. PMID- 24763885 TI - Effect of a high monounsaturated vs high polyunsaturated fat hypocaloric diets in nonalcoholic fatty liver disease. AB - OBJECTIVE: Hyperaminotransferasemia is an important problem in obese patients. We decide to examine the changes in hyperaminotransferasemia after weight reduction in obese patients with and without NAFLD secondary to a high monounsaturated fat vs. a high polyunsaturated fat hypocaloric diets. PATIENTS AND METHODS: A population of 306 obese patients was randomly allocated to two groups: Diet M (high monounsaturated fat hypocaloric diet) and Diet P (high polyunsaturated fat hypocaloric diet). Patients were classified as group I (obese subjects; n=262) when serum ALT activity was normal or group II (NAFLD patients; n=44) when serum ALT activity was (>= 43 UI/L). RESULTS: In NAFLD group with diet M, BMI, weight, fat mass, waist circumference, systolic blood pressure, total cholesterol, LDL cholesterol), insulin and HOMA-R decreased. In NAFLD group with diet P, BMI, weight, fat mass, waist circumference, systolic blood pressure, total cholesterol, LDL cholesterol), insulin and HOMA-R decreased, too. In NAFLD group, alanine aminotransferase [(diet M) -20.3+/-19.2 UI/L vs. (diet P) -14.2+/-20.1 UI/L], aspartate aminotransferase [(diet M) -11.3+/-12.2 UI/L vs. (diet P) 11.1+/-10.1 UI/L], and gammaglutamyl transferase [(diet M) -18.1+/-12.2 UI/L vs. (diet P) -10.9+/-20.1 UI/L] improved with both diets. CONCLUSIONS: We showed that weight reduction secondary to two hypocaloric diets was associated with improvement in hypertransaminasemia and insulin resistance in NAFLD patients. PMID- 24763886 TI - Prevalence of erectile dysfunction among Saudi type 2 diabetic patients. AB - OBJECTIVES: The present study aimed to determine the prevalence and etiology of erectile dysfunction in Saudi type 2 diabetic patients. PATIENTS AND METHODS: 429 Saudi type 2 diabetic male patients aged more than 30 years were recruited. Total and bio-available serum testosterone, sex hormone binding globulin and free testosterone levels were measured by ELISA-IBL GMBH Germany. RESULTS: 47 (12.6%) subjects had hypogonadism with total testosterone < 8 nmol/l and 109 (29.3%) had possible hypogonadism with a total testosterone between 8 and 12 nmol/l. Similarly, using bioavailable levels, 30 (8%) men had overt hypogonadism with bioavailable testosterone < 2.5 nmol/l and 89 (33.9%) men had possible hypogonadism with bioavailable testosterone between 2.5-4 nmol/l; while 266 (71.6%) patients with free testosterone < 0.255 nmol/l had hypogonadism. BMI and waist circumference were both significantly negatively correlated with testosterone levels in Saudi type 2 diabetic men. CONCLUSIONS: Testosterone levels are frequently low in Saudi men with type 2 diabetes and majority of these patients have symptoms of hypogonadism. The prevalence of erectile dysfunction (ED) was 86.7% in diabetic men with low testosterone level of 8-12 nmol/L. Obesity is an associated factor with low testosterone levels and ED in Saudi type 2 diabetic patients. PMID- 24763887 TI - Meta-analysis of protective effect of sevoflurane on myocardium during cardiac surgery. AB - BACKGROUND: This study aims to evaluate the effect of sevoflurane anesthesia on myocardium in cardiac surgery and provide evidence for clinical anesthesia practice. MATERIALS AND METHODS: Literature about the protective effect of sevoflurane anesthesia on myocardium in cardiac surgery published before March, 2012 was retrieved from the database of PubMed and EMBASE. The quality of inclusive randomized controlled trials was evaluated and screened according to the Jadad scale. Finally, meta-analysis was performed by using the RevMan5.0 software. RESULTS: In this research, there were totally 17 articles in accordance with the inclusive criteria and all of them were in English with the study sites being abroad. Each article was more than 3 points in Jadad scale. Compared with total intravenous anesthesia group, postoperative 12h CO and CI of patients have been significantly improved in the sevoflurane anesthesia group; and concentration of postoperative 24 h cTnI in the sevoflurane anesthesia group has been reduced, as well as assisted respiratory time and ICU stay after operation. There is no significant difference in hospitalization stay between both groups; postoperative usage of vasoactive drugs in sevoflurane anesthesia group is less than in total intravenous anesthesia group. There is no significant difference in postoperative appearance of atrial fibrillation, recurrence rate of angina pectoris and mortality of patients after operation between both groups. CONCLUSIONS: Sevoflurane can better protect myocardium in the cardiac surgery. PMID- 24763888 TI - Comparison of unilateral spinal anesthesia and L1 paravertebral block combined with psoas compartment and sciatic nerve block in patients to undergo partial hip prosthesis. AB - OBJECTIVES: Just as hip prosthesis, most of the patients undergoing orthopedic lower extremity surgery (OLES) belong to the advanced age group. Sciatic nerve block combined with psoas compartment block is used as a technique alternative to central neuraxial block and GA. In geriatric patients that will undergo partial hip prosthesis, the effects of the methods of unilateral spinal anesthesia (SA) and L1 paravertebral block combined with psoas compartment block (PCB) and sciatic nerve block (PCSL) on peroperative hemodynamic parameters and the duration of need for postoperative analgesia were studied. PATIENTS AND METHODS: Fifty patients from the ASA III-IV group were randomly divided into two groups. Group SA was administered spinal anesthesia with hyperbaric bupivacaine (2 ml, 0.5%) from the selected intervertebral distance (L4-L5 or L3-L4) in lateral position. Group PCSL was administered L1 paravertebral block combined with PCB and sciatic nerve block with bupivacaine hydrochloride (total 35 ml). Hemodynamic parameters (HR: heart rate and MAP: mean artery pressure) were recorded in pre- and post-intervention 5-minute intervals. The initial time of the need for analgesia of patients were evaluated postoperatively. RESULTS: Any failure in methods implemented on patients in either group was not observed. Times of anesthesia and surgical preparation of patients were observed to have significantly prolonged in the PCSL compared to Group SA (p < 0.005). Hundred and 5th and 110th min. mean arterial pressures of patients was found to be significantly higher in Group SA compared to Group PCSL (p < 0.05). The initial time of the need for analgesia was observed to be significantly prolonged in Group PCSL (432.80 +/- 236.77 min) compared to Group SA (185.40 +/- 171.40 min) (p < 0.001). CONCLUSIONS: Unilateral SA conducted with bupivacaine hydrochloride and PCSL block technique provided a hemodynamically similar activity in the perioperative period in patients that underwent partial hip operation. However, PCSL block implementation extended the initial time of the need for analgesia in postoperative period. PCSL method could be selected in cases belonging to such group of patients. PCSL block can be a alternative anesthetic tecniques in patients that underwent partial hip operation. PMID- 24763889 TI - Association of colon adenomas and skin tags: coincidence or coexistence? AB - OBJECTIVES: Skin tag (STs) are benign connective tissue tumors of the dermis. Some researchers have argued that there is a relationship between skin tag and colon polyps, although the physiopathological mechanisms underlying this relation were not well elucidated. In this study we aimed to investigate the co-existence of colonic adenomatous polyps and ST, additionally to shed light on the physiopathological mechanisms underlying this coincidence. PATIENTS AND METHODS: A total of 45 patients aged between 18 and 60 diagnosed with adenomatous colonic polyps and 45 sex, age, and socio-demographically matched subjects, had no polyps, were enrolled as the control group. Routine blood analysis of all participants, including serum glucose, total cholesterol, low-density lipoprotein cholesterol (LDL-C), (high-density lipoprotein cholesterol (HDL-C), triglyceride, insulin, IGF-1, and EGF, were performed. The chi-square and independent sample t or Mann Whitney U test were used to determine differences between groups. RESULTS: The number of participants with ST was significantly higher in the patient group (OR 7.067, p < 0.01). Serum levels of IGF-1 and EGF were statistically similar between the groups. In the subgroup analyses, no difference was found in serum levels of insulin, IGF-1, or EGF between patients with and without ST. However, higher serum levels of insulin and EGF were found in control subjects with ST (p < 0.01 and p < 0.01, respectively). For the entire study group, 67 participants had ST and 23 patients did not. Serum insulin, and IGF-1 were similar, while serum EGF levels were higher in patients with ST (p < 0.01). CONCLUSIONS: Findings of the present study may show a co-existence of colonic polyps and ST. Although previous studies have indicated that insulin resistance may play a role in the pathogenesis of both lesions in diabetic and obese patients, we found no indication of a relationship in nondiabetic and nonobese patients with increased levels of EGF in patients with ST, suggesting an alternative pathogenesis in this patient group. PMID- 24763890 TI - Effects of Aloe vera cream on chronic anal fissure pain, wound healing and hemorrhaging upon defection: a prospective double blind clinical trial. AB - Aloe vera is a medicinal plant that promotes wound healing in burn injuries. A prospective clinical trial was conducted to evaluate the effects of a topical cream containing 0.5% Aloe vera juice powder in the treatment of chronic anal fissures. The aloe cream was applied by the patients to the wound site 3 times per day for 6 weeks following the instructions of a physician. Pain was assessed with a visual analog scale before treatment and at the end of each week of treatment. Wound healing and the amount and severity of bleeding were examined and evaluated before and at the end of each week of treatment. There were statistically significant differences in chronic anal fissure pain, hemorrhaging upon defection and wound healing before and at the end of the first week of treatment also in comparison with control group (p < 0.0001). In this study, a topical cream containing aloe vera juice was an effective treatment for chronic anal fissures. This is a promising result indicating that further comparative studies are justified. PMID- 24763891 TI - Topical application of a new monoclonal antibody against fibroblast growth factor 10 (FGF 10) mitigates propranolol-induced psoriasis-like lesions in guinea pigs. AB - OBJECTIVES: Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation of keratinocytes. Fibroblast growth factor 10 (FGF10) acts as a growth factor for keratinocyte proliferation. The aim of this study is to investigate whether FGF10 blockage, a new monoclonal antibody against FGF10 we generated, could mitigate topical propranolol-induced psoriasis-like lesions in guinea pigs. MATERIALS AND METHODS: The monoclonal anti-FGF10 was generated by a routine method and purified by affinity chromatography. The effect of FGF10 and anti-FGF10 on human keratinocyte HaCaT cell proliferation was determined by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The back of the ears of individual guinea pigs was topically exposed to 5% propranolol emulsion to induce psoriasis-like lesions and randomly treated topically with phosphate buffered saline (PBS), hydrocortisone butyrate, or different doses of anti-FGF10. The pathologic changes and the degrees of inflammation in the auricular areas of individual animals were examined histologically. RESULTS: Characterization revealed that anti-FGF10 had a purity of 90% and a titer of 1:12800. We found that FGF10 stimulated HaCaT cell proliferation while treatment with different doses of anti-FGF10 inhibited FGF10-induced cell proliferation in a dose dependent manner (100, 200 ng/ml, p < 0.05 vs. control; 400, 800, 1600 ng/ml, p < 0.01 vs. control). Compared to PBS-treated psoriatic animals, treatment with anti FGF10, like hydrocortisone butyrate, greatly inhibited the severity of psoriasis like lesions by reducing the Baker's scores, the thickness of epidermis, and the numbers of monocyte infiltrates in the dermis of animals. CONCLUSIONS: The newly generated anti-FGF10 monoclonal antibody inhibited the proliferation of human keratinocytes in vitro and mitigated inflammation and pathogenic changes in propranolol-induced psoriasis-like lesions in animals. Therefore, these findings may provide a proof of principle that blockage of FGF-10 may inhibit psoriasis related inflammation. PMID- 24763892 TI - The outcomes of surgical treatment modalities to decrease "near miss" maternal morbidity caused by peripartum hemorrhage. AB - BACKGROUND: The treatment of patients with peripartum hemorrhage is unfortunately characterized by inadequate treatment that does not adhere to standard therapeutic measures. AIM: Assessment of different management strategies among patients with severe hemorrhage, particularly the ones with "near-miss" maternal morbidity and mortality to establish clinically useful guidelines for the prevention and management of peripartum hemorrhage. PATIENTS AND METHODS: In this study, the medical records of 458 patients who have experienced peripartum hemorrhage between March 2009 and March 2012 in a tertiary perinatal center were retrospectively reviewed. Specific surgical treatment modalities utilized to 61 patients with severe peripartum hemorrhage with respect to the procedure timing and effectivity were compared according to the outcomes and efficiency. RESULTS: Sixty-one patients who have been diagnosed as severe peripartum hemorrhage have been included to the study. Six (75%) of the 8 patients who were treated with B Lynch brace suture for uterine atony and 9 (60%) of the 15 patients who were treated with the Bakri balloon tamponade system for uterine atony or placenta accreta required hysterectomy following the initial therapeutic measures. The patients who have been treated with bilateral hypogastric artery ligation and B Lynch brace suture or Bakri balloon uterine tamponade system were less likely to need a complementary hysterectomy for definitive treatment of peripartum hemorrhage when compared with patients treated with either B-Lynch brace suture or Bakri uterine tamponade balloon system alone. CONCLUSIONS: The efficiency of B Lynch compression brace sutures and the Bakri balloon uterine tamponade system is unpredictable in terms of the need for hysterectomy for peripartum hemorrhage patients diagnosed as either uterine atony or placenta previa. Regardless of the initial diagnosis, these modalities seem to be more effective in alleviating peripartum hemorrhage when accompanied by hypogastric artery ligation. PMID- 24763893 TI - Cauda equina syndrome: evaluation of the clinical outcome. AB - AIM: Cauda equina syndrome is a rare but highly impairing syndrome involving lower limbs as well as urinary, defecatory and sexual function. In the literature the most investigated sphincter dysfunction is the urinary. Bowel and sexual function are often overlooked since they become more relevant after the acute phase. PATIENTS AND METHODS: Eight consecutive male patients affected by cauda equina syndrome with sphincter dysfunction due to herniated disc disease of lumbar spine were treated between 2007 and 2009. Five patients were followed-up for at least two years. Sexual function was evaluated by IIEF-5 questionnaire; bowel function was investigated by means of clinical and instrumental investigation and manometry. RESULTS: Although little clinical improved, patients still complained severe symptoms at first year follow-up while all but one improved significantly in the following year. At two years follow-up only the patient whose cauda equina syndrome was misdiagnosed and surgically treated late respect to the onset of the syndrome, complained a persistent severe sexual and bowel dysfunction. CONCLUSIONS: Our results show that a long-term follow-up is mandatory to evaluate the real outcome of surgical managed cauda equine syndrome because short-term evaluation could be misleading about the residual capacity of late neurologic improving. Despite the relatively low number of cases evaluated, our results confirm that early diagnosing and treating the syndrome are relevant for the final outcome. PMID- 24763894 TI - Centipede bite. PMID- 24763895 TI - Retrospective platelet values measurement. Is it acceptable to discuss? PMID- 24763896 TI - Epicardial adipose tissue thickness may be related diastolic dysfunction in obese adolescents. PMID- 24763897 TI - Cardiomyopathies with an unclear etiology: fundamental diagnostic role of cardiac magnetic resonance imaging. PMID- 24763898 TI - Recurrence of Tako-Tsubo syndrome, idiopathic dilated cardiomyopathy, and iterative ventricular tachycardia: just a fortuitous coincidence or a pathophysiological link? PMID- 24763899 TI - Overview of pleiotropic effects of platelet P2Y12 receptor inhibitors. AB - Dual antiplatelet therapy consisting of one of the P2Y12 receptor inhibitors in conjunction with aspirin is the mainstay of treatment for patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary interventions (PCI). In recent years, multiple extra-platelet features of P2Y12 receptor antagonists have been reported in numerous clinical trials. The aim of this review is to summarise reported pleiotropic effects of clopidogrel, prasugrel, ticagrelor and other P2Y12 receptor blockers. We included observations made both in human and in animal models, together with proposed mechanisms of action for described features. If confirmed in randomised studies and properly applied to everyday practice, the observed extra-platelet actions could enable us to improve efficacy of ACS and post-PCI treatment, as well as to confine mortality and occurrence rate of cardiovascular events. PMID- 24763900 TI - Self-employment in joinery: an occupational risk facor? AB - OBJECTIVES: Only a few studies have analyzed the health of self-employed workers. This cross-sectional study is the first to compare health status among craftsmen joiners and paid joiners. MATERIAL AND METHODS: Clinical and paraclinical data for self-employed craftsmen and employees were collected by occupational health doctors according to a standardized protocol and compared. Health data and professional status relationships were analyzed by logistic regression. RESULTS: A total of 171 craftsmen and 196 paid workers were included. Craftsmen had more dermatologic pathologies (odds ratio (OR) = 2.67, p < 0.05), ear/nose/throat symptoms (OR = 3.38, p < 0.001), pulmonary symptoms (OR = 2.46, p < 0.05), musculoskeletal symptoms (OR = 3.09, p < 0.001), and abnormal audiogram (OR = 3.50, p < 0.001). The FEV1 was significantly lower among craftsmen (p < 0.01), independently of tobacco smoke exposure. CONCLUSIONS: This survey high-lights a high morbidity rate among self-employed craftsmen, suggesting that among woodworkers, professional status can be a risk factor for health. The preventive medical system for craftsmen has to be rethought to guarantee better safety for this population. PMID- 24763901 TI - IL-20 and IL-20R1 antibodies protect against liver fibrosis. AB - Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis, atherosclerosis, stroke, and osteoporosis. However, the pathophysiological roles of IL-20 in liver injury have not been extensively studied. We explored the involvement of IL-20 in liver injury and the therapeutic potential of IL-20 antagonists for treating liver fibrosis. Compared with normal liver tissue from healthy individuals, the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis, cirrhosis, and hepatocellular carcinoma. Carbon tetrachloride (CCl4) treatment induced IL-20 that further up-regulated the expression of transforming growth factor (TGF)-beta1 and p21(WAF1) and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line. IL-20 activated quiescent rat hepatic stellate cells (HSCs) and up-regulated TGF-beta1 expression. IL-20 also increased TGF-beta1, tumor necrosis factor (TNF)-alpha, and type I collagen (Col I) expression, and promoted the proliferation and migration of activated HSCs. Serum IL-20 was significantly elevated in mice with short-term and long-term CCl4 -induced liver injury. In mice with short-term liver injury, anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl4, TGF-beta1, and chemokine production. In mice with long-term liver injury, 7E and 51D inhibited CCl4 induced cell damage, TGF-beta1 production, liver fibrosis, HSC activation, and extracellular matrix accumulation, which was caused by the reduced expression of tissue inhibitors of metalloproteinases as well as increased metalloproteinase expression and Col-I production. IL-20R1-deficient mice were protected from short term and long-term liver injury. CONCLUSION: We identified a pivotal role of IL 20 in liver injury and showed that 7E and 51D may be therapeutic for liver fibrosis. PMID- 24763902 TI - Neuromuscular electrical stimulation cycling exercise for persons with advanced multiple sclerosis. AB - OBJECTIVE: To investigate the feasibility of neuromuscular electrical stimulation cycling modified to suit persons with advanced multiple sclerosis. SUBJECTS: Eight women with secondary progressive multiple sclerosis. METHODS: Subjects participated in an 18-session (40 min) neuromuscular electrical stimulation cycling program. A pedaling cadence of 10 rev*min-1 was employed and stimulation intensity was not modulated to control cadence, but increased gradually throughout each session. The outcomes included the stimulation intensity tolerated, thigh circumference changes, and power output and cardiorespiratory response during cycling. Participants were interviewed about perceived benefits of the treatment including changes in transfer ability. RESULTS: Seven participants (Expanded Disability Status Scale 6.5-8.5) (mean 7.4 (standard deviation 0.7)) completed the training program over an average of 10 weeks. Greater stimulation intensities were tolerated than previously reported for persons with multiple sclerosis. Increases were found in thigh volume. Perceived benefits included improvements in transfer ability, leg circulation, spasticity and strength. CONCLUSION: Modifying neuromuscular electrical stimulation cycling allowed persons with advanced multiple sclerosis to tolerate greater stimulation intensities and exercise their muscles more intensely than previous studies. The benefits reported, which were solely due to neuromuscular electrical stimulation cycling, demonstrate that persons with preserved sensation and muscle paralysis/paresis might benefit from neuromuscular electrical stimulation exercise when it is adjusted appropriately. PMID- 24763907 TI - Investigation of putative arene-C-H...pi(quasi-chelate ring) interactions in copper(I) crystal structures. AB - Evidence for C-H...pi(CuCl...HNCS) interactions, i.e. C-H...pi(quasi-chelate ring) where a six-membered quasi-chelate ring is closed by an N-H...Cl hydrogen bond, is presented based on crystal structure analyses of (Ph3P)2Cu[ROC(=S)N(H)Ph]Cl. Similar intramolecular interactions are identified in related literature structures. Calculations suggest that the energy of attraction provided by such interactions approximates 3.5 kcal mol(-1). PMID- 24763908 TI - [Diagnosis and management of gout in Austria. Survey of current practice considering the EULAR recommendations]. AB - BACKGROUND AND OBJECTIVES: Gout shows an increasing incidence and has become a major health problem in the Western world. Despite effective treatment options, neither diagnosis nor therapeutic efforts can be regarded sufficient to date. It was of interest to investigate current handling of gout among Austrian rheumatologists. MATERIAL AND METHODS: In 2012, a survey of Austrian rheumatologists concerning diagnosis and management of hyperuricemia and gout was performed. With the consent of the Austrian Society of Rheumatology, 574 society members (343 via electronic mail, 23 via mail) were sent a questionnaire consisting of 17 questions. This is the first survey assessing the management of gout among Austrian rheumatologists. RESULTS: The overall response rate was 22.1 %. Of all the contacted members (email and mail), 19.9 % answered the questionnaire electronically and only 5.6 % by mail. The adherence to the EULAR recommendations for gout ranged between 69 and 95 % (median 84 %). CONCLUSION: Among Austrian rheumatologists, the knowledge about gout, its diagnostic and imaging procedures, management and therapeutic goals is good and mainly in line with current international recommendations. To improve the management of patients with gout and hyperuricemia, a more frequent referral to rheumatologists could be beneficial. PMID- 24763909 TI - Distribution pattern of Sjogren's syndrome: a sialographical study. AB - BACKGROUND/OBJECTIVES: The present controlled sialographical study was conducted to learn more from the horizontal and vertical symmetry of the ductal lesions of the major salivary glands in primary (pSS) and secondary (sSS) forms of the disease. MATERIALS AND METHODS: A total of 98 patients (38 pSS patients, 38 sSS patients, 22 control subjects) were included in the study. Contrast radiography of both parotid and submandibular glands was performed within the same session. A 6-point scoring system allowed summary indexes for each of the glands to be calculated. RESULTS: Pansialography was accomplished within 30 min each. The sparsity of the branching pattern of the ducts was the most frequent pathological finding. In pSS, horizontal symmetry was more pronounced in the parotid glands, whereas in sSS it was more pronounced in the submandibular glands. The most discriminating features were the width of the peripheral ducts in the parotid and the number of acinar dilatations in the submandibular glands. The most advanced lesions were found in the left parotid gland. CONCLUSION: The peripheral ducts are more affected by SS than the main excretory duct. There is a tendency for asymmetric involvement of the parotid glands in pSS and of the submandibular glands in sSS. Parotid glands are globally more involved than submandibular glands. Differential diagnosis between pSS and sSS cannot be accomplished by means of pansialography alone. Left parotid sialography is recommended for routine use. PMID- 24763910 TI - Opposing neural effects of naltrexone on food reward and aversion: implications for the treatment of obesity. AB - RATIONALE: Opioid antagonism reduces the consumption of palatable foods in humans but the neural substrates implicated in these effects are less well understood. OBJECTIVES: The aim of the present study was to examine the effects of the opioid antagonist, naltrexone, on neural response to rewarding and aversive sight and taste stimuli. METHODS: We used functional magnetic resonance imaging (fMRI) to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 20 healthy volunteers who received a single oral dose of naltrexone (50 mg) and placebo in a double-blind, repeated measures cross-over, design. RESULTS: Relative to placebo, naltrexone decreased reward activation to chocolate in the dorsal anterior cingulate cortex and caudate, and increased aversive-related activation to unpleasant strawberry in the amygdala and anterior insula. CONCLUSIONS: These findings suggest that modulation of key brain areas involved in reward processing, cognitive control and habit formation such as the dorsal anterior cingulate cortex (dACC) and caudate might underlie reduction in food intake with opioid antagonism. Furthermore we show for the first time that naltrexone can increase activations related to aversive food stimuli. These results support further investigation of opioid treatments in obesity. PMID- 24763911 TI - Insulin reverses anxiety-like behavior evoked by streptozotocin-induced diabetes in mice. AB - Clinical and preclinical data suggest that diabetes is often associated with anxiety. Insulin, a peptide hormone has been reported to have key functions in the brain and in alleviating several psychological impairments, occur as a consequence of diabetes. However, its effects in diabetes-induced anxiety are scanty. The present study examined whether; insulin can reverse the anxiety-like behavior in streptozotocin (STZ)-induced diabetes in mice. After 8-weeks of diabetes induced by STZ (200 mg/kg, intraperitoneally (i.p.)), mice were given insulin (1-2 IU/kg/day, i.p.)/ diazepam (1 mg/kg/day, i.p.)/ vehicle for 14 days and evaluated for behavioral effects in three validated models of anxiety viz. elevated plus maze (EPM), light-dark (L/D) and hole board (HB) tests. STZ-induced diabetic mice elicited significant behavioral effects which include, decreased percentage open arm entries and time in EPM, reduced latency and time spent in light chamber in L/D, decreased number of head dips, squares crossed and rearings in HB tests respectively. Insulin treatment attenuated the behavioral effects evoked by STZ-induced diabetes in mice as indicated by increased open arms activity in EPM, decreased aversion in light chamber during L/D test and increased exploratory behavior in HB test. In conclusion, this study revealed that insulin can reverse anxiety-like behavior in STZ-induced diabetes in mice. PMID- 24763913 TI - Using audio script fading and multiple-exemplar training to increase vocal interactions in children with autism. AB - Script-fading procedures have been shown to be effective for teaching children with autism to initiate and participate in social interactions without vocal prompts from adults. In previous script and script-fading research, however, there has been no demonstration of a generalized repertoire of vocal interactions under the control of naturally occurring relevant stimuli. In this study, 4 boys with autism were taught to initiate a conversation in the presence of toys through the use of a script and script-fading procedure. Training with multiple categories and exemplars of toys was used to increase the likelihood of generalization of vocal interactions across novel toys. A multiple-probe design across participants was used to assess the effects of these procedures. The intervention successfully brought interactions by children with autism under the control of relevant stimuli in the environment. Future research pertaining to the specific implementation of these procedures (e.g., fading, script placement, participant characteristics) is discussed. PMID- 24763914 TI - Prognostic value of clinical and pathologic T stages defined by the American Joint Committee on Cancer for eyelid sebaceous carcinoma in Korea. AB - PURPOSE: To investigate whether the clinical and pathologic T category classification, as defined by the American Joint Committee on Cancer (AJCC), is associated with lymph nodes (LN) or distant metastasis in patients with eyelid sebaceous carcinoma. METHODS: Forty patients treated for eyelid sebaceous carcinoma at Seoul National University Hospital between March 1999 and December 2011 were retrospectively staged according to the AJCC 7th edition criteria. Three different primary tumor classifications-(1) clinical tumor size at presentation; (2) clinical AJCC T stage (cT) at presentation based not only on size, but also on the extent of involvement and (3) pathologic AJCC T stage (pT) based on histopathological examination-were compared and evaluated with regard to their association with LN or distant metastasis. RESULTS: In univariate analysis, the AJCC cT (p = 0.005) and pT (p = 0.029) categories were significantly associated with metastasis, but clinical tumor size alone did not correlate with metastasis (p = 0.093). Clinical and pathologic AJCC stage T2b or higher tumors were significantly associated with metastasis compared to stage T1 or T2a tumors [odds ratio cT, 8.00 (p = 0.025); pT, 6.91 (p = 0.028)]. CONCLUSIONS: The clinical and pathologic AJCC T category has predictive value for LN or distant metastasis in eyelid sebaceous carcinoma. However, the clinically assessed largest tumor dimension alone is not an effective predictive factor. Clinicians should be aware of the increased risk of metastasis in patients with tumors of stage T2b or higher at initial presentation. PMID- 24763917 TI - Enantio-differentiation of O-heterocycles using a binol-derived disulfonimide as a chiral solvating agent. AB - The disulfonimide (R)-1 enables enantio-differentiation of a large scope of chiral O-heterocycles, thanks to the formation of diastereomeric adducts. The underlying H-bond has been investigated by NMR. (R)-1 has been used as a chiral solvating agent (CSA) to determine the stereochemical purity of D/L lactide by (1)H NMR. PMID- 24763918 TI - PLIC: protein-ligand interaction clusters. AB - Most of the biological processes are governed through specific protein-ligand interactions. Discerning different components that contribute toward a favorable protein- ligand interaction could contribute significantly toward better understanding protein function, rationalizing drug design and obtaining design principles for protein engineering. The Protein Data Bank (PDB) currently hosts the structure of ~68 000 protein-ligand complexes. Although several databases exist that classify proteins according to sequence and structure, a mere handful of them annotate and classify protein-ligand interactions and provide information on different attributes of molecular recognition. In this study, an exhaustive comparison of all the biologically relevant ligand-binding sites (84 846 sites) has been conducted using PocketMatch: a rapid, parallel, in-house algorithm. PocketMatch quantifies the similarity between binding sites based on structural descriptors and residue attributes. A similarity network was constructed using binding sites whose PocketMatch scores exceeded a high similarity threshold (0.80). The binding site similarity network was clustered into discrete sets of similar sites using the Markov clustering (MCL) algorithm. Furthermore, various computational tools have been used to study different attributes of interactions within the individual clusters. The attributes can be roughly divided into (i) binding site characteristics including pocket shape, nature of residues and interaction profiles with different kinds of atomic probes, (ii) atomic contacts consisting of various types of polar, hydrophobic and aromatic contacts along with binding site water molecules that could play crucial roles in protein-ligand interactions and (iii) binding energetics involved in interactions derived from scoring functions developed for docking. For each ligand-binding site in each protein in the PDB, site similarity information, clusters they belong to and description of site attributes are provided as a relational database-protein ligand interaction clusters (PLIC). Database URL: http://proline.biochem.iisc.ernet.in/PLIC. PMID- 24763919 TI - Small-worldness and gender differences of large scale brain metabolic covariance networks in young adults: a FDG PET study of 400 subjects. AB - BACKGROUND: Many studies have demonstrated the small-worldness of the human brain, and have revealed a sexual dimorphism in brain network properties. However, little is known about the gender effects on the topological organization of the brain metabolic covariance networks. PURPOSE: To investigate the small worldness and the gender differences in the topological architectures of human brain metabolic networks. MATERIAL AND METHODS: FDG-PET data of 400 healthy right handed subjects (200 women and 200 age-matched men) were involved in the present study. Metabolic networks of each gender were constructed by calculating the covariance of regional cerebral glucose metabolism (rCMglc) across subjects on the basis of AAL parcellation. Gender differences of network and nodal properties were investigated by using the graph theoretical approaches. Moreover, the gender related difference of rCMglc in each brain region was tested for investigating the relationships between the hub regions and the brain regions showing significant gender-related differences in rCMglc. RESULTS: We found prominent small-world properties in the domain of metabolic networks in each gender. No significant gender difference in the global characteristics was found. Gender differences of nodal characteristic were observed in a few brain regions. We also found bilateral and lateralized distributions of network hubs in the females and males. Furthermore, we first reported that some hubs of a gender located in the brain regions showing weaker rCMglc in this gender than the other gender. CONCLUSION: The present study demonstrated that small-worldness was existed in metabolic networks, and revealed gender differences of organizational patterns in metabolic network. These results maybe provided insights into the understanding of the metabolic substrates underlying individual differences in cognition and behaviors. PMID- 24763920 TI - Ocular adnexal follicular lymphoma: a multicenter international study. AB - IMPORTANCE: The clinical features of the follicular subtype of ocular adnexal lymphoma (OAL) have not been previously evaluated in a large cohort. OBJECTIVE: To characterize the clinical features of follicular OAL. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective multicenter study that involved 6 eye cancer centers from January 1, 1980, through December 31, 2010. A total of 105 patients with follicular OAL were identified, of which 7 patients were excluded because of missing clinical data. The median follow-up time was 52 months (range, 13-118 months). MAIN OUTCOMES AND MEASURES: Overall survival, disease-specific, and progression-free survivals were the primary end points. RESULTS: Ninety-eight eligible patients with follicular OAL were included; 60 (61%) were women. The median patient age was 63 years (range, 32-96 years). Sixty-nine patients (70%) had primary OAL, 19 (19%) had OAL in conjunction with a concurrent systemic lymphoma, and 10 (10%) presented with an ocular adnexal relapse. The lacrimal gland (28%), conjunctiva (28%), and orbit (28%) were the most frequently involved sites. Of the 69 patients with primary follicular lymphoma, 38 (55%) presented with Ann Arbor stage IE lymphoma, and 31 (45%) had stage IIE lymphoma. Patients with disseminated lymphoma had stage IIIE (9 of 19 [47%]) and stage IV (10 of 19 [53%]) disease, whereas patients with a relapse of systemic lymphoma presented with stage IE (8 of 10 [80%]), stage IIE (1 of 10 [10%]), and stage IIIE (1 of 10 [10%]) disease. Patients with primary follicular lymphoma (n = 69) and those with isolated ocular relapse (n = 9) were treated with external beam radiation therapy (EBRT) (35 of 78 [45%]) or EBRT plus chemotherapy (22 of 78 [28%]). Patients presenting with stage IIIE-IV follicular lymphoma (n = 20) most frequently received chemotherapy (9 of 20 [45%]) or EBRT plus chemotherapy (4 of 20 [20%]). The 10-year overall survival for the entire study cohort was 60%. Primary patients treated with EBRT had a better disease-specific survival compared with patients receiving ERBT plus chemotherapy (10-year disease-specific survival, 94% vs 40%; P = .02 by log-rank test). CONCLUSIONS AND RELEVANCE: Follicular OAL was more commonly found in elderly female patients. These tumors were equally noted to involve the conjunctiva, lacrimal gland, and orbit. Patients with ocular adnexal follicular lymphoma primarily treated with EBRT had a more favorable long term disease-specific survival. PMID- 24763921 TI - EEG theta phase coupling during executive control of visual working memory investigated in individuals with schizophrenia and in healthy controls. AB - In healthy humans, it has been shown that executive functions are associated with increased frontal-midline EEG theta activity and theta phase coupling between frontal and posterior brain regions. In individuals with schizophrenia, central executive functions are supposed to be heavily impaired. Given that theta phase coupling is causally involved in central executive functions, one would expect that patients with an executive function deficit should display abnormal EEG theta synchronization. We therefore investigated executive functioning in 21 healthy controls and 21 individuals with schizophrenia while they performed a visuospatial delayed match to sample task. The task required either high executive demands (manipulation of content in working memory [WM]) or low executive demands (retention of WM content). In addition, WM load (one vs. three items) was varied. Results indicated higher frontal theta activity for manipulation processes than for retention processes in patients with schizophrenia, as compared with healthy controls, independently of WM load. Furthermore, individuals with schizophrenia revealed a reduction in theta phase coupling during early stages of the delay period for retention, as well as for manipulation processes at high-WM loads. Deviations in theta phase coupling in individuals with schizophrenia were mainly characterized by aberrant fronto posterior connections, but also by attenuated posterior connections during manipulation of high-WM load. To conclude, fronto-parietal theta coupling seems to be substantially involved in executive control, whereas frontal theta activity seems to reflect general task demands, such as deployment of attentional resources during WM. PMID- 24763922 TI - Face-sex categorization is better above fixation than below: Evidence from the reach-to-touch paradigm. AB - The masked congruence effect (MCE) elicited by nonconsciously presented faces in a sex-categorization task has recently been shown to be sensitive to the effects of attention. Here we investigated how spatial location along the vertical meridian modulates the MCE for face-sex categorization. Participants made left and right reaching movements to classify the sex of a target face that appeared either immediately above or below central fixation. The target was preceded by a masked prime face that was either congruent (i.e., same sex) or incongruent (i.e., opposite sex) with the target. In the reach-to-touch paradigm, participants typically classify targets more efficiently (i.e., their finger heads in the correct direction earlier and faster) on congruent than on incongruent trials. We observed an upper-hemifield advantage in the time course of this MCE, such that primes affected target classification sooner when they were presented in the upper visual field (UVF) rather than the lower visual field (LVF). Moreover, we observed a differential benefit of attention between the vertical hemifields, in that the MCE was dependent on the appropriate allocation of spatial attention in the LVF, but not the UVF. Taken together, these behavioral findings suggest that the processing of faces qua faces (e.g., sex categorization) is more robust in upper-hemifield locations. PMID- 24763923 TI - Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamic effect. PMID- 24763925 TI - Cognitive and emotional problems in patients after cerebral meningioma surgery. AB - OBJECTIVES: To determine long-term cognitive complaints and symptoms of depression or anxiety in patients following surgery for a cerebral meningioma, and to examine factors associated with these outcomes. DESIGN: Cross-sectional study. PATIENTS: Patients operated on for a cerebral meningioma in the University Medical Center Utrecht, The Netherlands, between 2007 and 2009. METHODS: Clinical data were retrieved from medical files. Patients completed a postal questionnaire. Cognitive complaints were measured with the Cognitive Failures Questionnaire. A score above 43.5 was defined as presence of cognitive complaints. Anxiety and depressive symptoms were measured with the Hospital Anxiety and Depression Scale, and were considered present if the scale score was >= 8. RESULTS: The response rate was 76% (n = 136). Mean time after operation was 32.6 months (standard deviation 10.6 months). Overall, 40% of patients experienced cognitive and/or emotional problems. Thirty-one patients (23%) experienced cognitive complaints, 39 (29%) showed anxiety, and 31 (23%) showed depressive symptoms. Country of birth and previous depression/burn-out were the most important factors. Scores on all outcome measures were related to each other. CONCLUSION: Forty percent of patients experienced cognitive or emotional problems following surgery for a cerebral meningioma. Screening for these problems is therefore important in order to provide patients with the care they require as soon as possible. PMID- 24763926 TI - Marketplace analysis demonstrates quality control standards needed for black raspberry dietary supplements. AB - There is currently no standard for the minimum anthocyanin concentration a black raspberry dietary supplement must contain for legal sale in the US. All consumer available black raspberry products (n = 19), packaged as dietary supplements or otherwise prepared (freeze-dried whole and pre-ground powders), were purchased and analyzed for their anthocyanin composition and concentration. Seven of the 19 samples contained no anthocyanins from black raspberry fruit, while three of those seven (without black raspberry fruit) had no anthocyanins of any kind. There was a wide range of anthocyanin concentration within the remaining products (18.1-2,904.8 mg/100 g; n = 12). When expressed as per capsule or per ~1 teaspoon, concentration ranged from 0.1 to 145.2 mg (average 28 mg; n = 12). Until US dietary supplement labeling comes under regulatory oversight similar to food guidelines, foods are a more dependable source for dietary phenolics than supplements. PMID- 24763928 TI - Epidermal growth factor and erythropoietin infusion accelerate functional recovery in combination with rehabilitation. AB - BACKGROUND AND PURPOSE: Rehabilitation is the only treatment option for chronic stroke deficits, but unfortunately, it often provides incomplete recovery. In this study, a novel combination of growth factor administration and rehabilitation therapy was used to facilitate functional recovery in a rat model of cortical stroke. METHODS: Ischemia was induced via injection of endothelin-1 into the sensorimotor cortex. This was followed by either a 2-week infusion of epidermal growth factor and erythropoietin or artificial cerebrospinal fluid into the ipsilateral lateral ventricle. Two weeks after ischemia, animals began an 8 week enriched rehabilitation program. Functional recovery was assessed after ischemia using the Montoya staircase-reaching task, beam-traversing, and cylinder test of forelimb asymmetry. RESULTS: The combination of growth factor infusion and rehabilitation led to a significant acceleration in recovery in the staircase task. When compared with controls, animals receiving the combination treatment attained significant recovery of function at 4 weeks after stroke, whereas those receiving rehabilitation alone did not recover until 10 weeks. Significant recovery was also observed on the beam-traversing and cylinder tasks. CONCLUSIONS: Combining behavioral rehabilitation with growth factor infusion accelerates motor recovery. These data suggest a promising new avenue of combination therapies that may have the potential to reduce the rehabilitation time necessary to recover from sensorimotor deficits arising from stroke. PMID- 24763929 TI - Virtual reality exercise improves mobility after stroke: an inpatient randomized controlled trial. AB - BACKGROUND AND PURPOSE: Exercise using virtual reality (VR) has improved balance in adults with traumatic brain injury and community-dwelling older adults. Rigorous randomized studies regarding its efficacy, safety, and applicability with individuals after stroke are lacking. The purpose of this study was to determine whether an adjunct VR therapy improves balance, mobility, and gait in stroke rehabilitation inpatients. METHODS: A blinded randomized controlled trial studying 59 stroke survivors on an inpatient stroke rehabilitation unit was performed. The treatment group (n=30) received standard stroke rehabilitation therapy plus a program of VR exercises that challenged balance (eg, soccer goaltending, snowboarding) performed while standing. The control group (n=29) received standard stroke rehabilitation therapy plus exposure to identical VR environments but whose games did not challenge balance (performed in sitting). VR training consisted of 10 to 12 thirty-minute daily sessions for a 3-week period. Objective outcome measures of balance and mobility were assessed before, immediately after, and 1 month after training. RESULTS: Confidence intervals and effect sizes favored the treatment group on the Timed Up and Go and the Two Minute Walk Test, with both groups meeting minimal clinical important differences after training. More individuals in the treatment group than in the control group showed reduced impairment in the lower extremity as measured by the Chedoke McMaster Leg domain (P=0.04) immediately after training. CONCLUSIONS: This VR exercise intervention for inpatient stroke rehabilitation improved mobility related outcomes. Future studies could include nonambulatory participants as well as the implementation strategies for the clinical use of VR. CLINICAL TRIAL REGISTRATION URL: http://www.ANZCTR.org.au/. Unique identifier: ACTRN12613000710729. PMID- 24763931 TI - Effect of telestroke on emergent stroke care and stroke outcomes. PMID- 24763930 TI - Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. AB - BACKGROUND AND PURPOSE: In Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants. METHODS: Baseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed. RESULTS: A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 30-49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non-East Asians (interaction P=0.666). Relative event rates for the major or nonmajor clinically relevant bleeding in patients treated with rivaroxaban and warfarin were consistent among East Asians and non-East Asians (interaction P=0.867). CONCLUSIONS: Observed relative efficacy and safety of rivaroxaban versus warfarin were similar among patients within and outside East Asia. Rivaroxaban, 20 mg once daily, is an alternative to warfarin for stroke prevention in East Asians with nonvalvular atrial fibrillation. PMID- 24763932 TI - Stroke prevention in Asian patients with atrial fibrillation. PMID- 24763933 TI - The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3 mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity. AB - c-Cbl-associated protein (CAP), also called Sorbs1 or ponsin, has been described as an essential adapter protein in the insulin-signalling pathway. Here, we describe for the first time a unique protective role for CAP in viral myocarditis. Mortality and heart failure development were increased in CAP(-/-) mice compared to CAP(+/+) littermates after Coxsackievirus (CVB3) infection. Mechanistically, CAP protected from tissue apoptosis because of reduced CD8(+) T and natural killer cell cytotoxicity. Despite reduced cytotoxic elimination of CVB3-infected cells in CAP(+/+) hearts, however, CAP enhanced interferon regulatory factor 3 (IRF3)-dependent antiviral type I interferon production and decreased viral proliferation in vitro by binding to the cytoplasmic RIG-I-like receptor melanoma differentiation-associated protein 5 (MDA5). Taken together, these findings reveal a novel modulatory role for CAP in the heart as a key protein stabilizing antiviral type I interferon production, while protecting from excessive cytotoxic responses. Our study will help to define future strategies to develop treatments to limit detrimental responses during viral heart inflammation. PMID- 24763935 TI - Sensitizing questions: a method to facilitate analyzing the meaning of an utterance. AB - Much social science research entails interpreting the meaning of utterances, that is, phrases spoken, written or gestured. But how should researchers interpret the meaning of such utterances? A recent surge of research, informed by dialogism, emphasizes the contextual, social and unfinished nature of meaning. The present article operationalizes dialogism theory into six 'sensitizing questions' which can guide analysis. The questions are: (1) What is the context? (2) What is the speaker doing? (3) Who is being addressed? (4) Who is doing the talking? (5) What future is constituted? (6) What are the responses? Each question (and 16 sub questions) is illustrated by analyzing the potential meanings of a single utterance. The article is a contribution to the development of new forms of 'method' for interpretative qualitative research. These methods aid the 'human instrument' to become a sensitive, theoretically-informed, and accountable analyst. PMID- 24763934 TI - Impact of CYP3A5 polymorphism on platelet reactivity at percutaneous coronary intervention and after 9 months of aspirin and clopidogrel therapy in Japanese patients with coronary artery disease. AB - BACKGROUND: High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy. METHODS: We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively. RESULTS: The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/*1), 46 % in intermediate metabolizers (IM; *1/*2, *1/*3), and 25 % in poor metabolizers (PM; *2/*2, *2/*3, *3/*3). Platelet reactivity levels in during the early and late phases were 3,793 +/- 1,476 and 2,960 +/- 1,410, respectively, in EM, 4,706 +/- 1,417 and 3,239 +/- 1,479, respectively, in IM, and 5,402 +/- 776 and 4,736 +/- 1,356 aggregation units (AU)*min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963 +/- 1,436 and 5,100 +/- 1,190 AU*min in Expressor and Non-expressor, respectively (P < 0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM. CONCLUSIONS: Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19. PMID- 24763940 TI - Highly ordered macro-mesoporous carbon nitride film for selective detection of acidic/basic molecules. AB - Well-ordered meso-macroporous carbon nitride film fabricated via a simple and flexible template replication method by using the P123 block copolymer and polystyrene spheres as dual templates shows selective sensing performance for acetic acid but after treating the surface of the film with UV light and oxygen, the selectivity of sensing can be tuned for basic molecules. PMID- 24763943 TI - Norms and reading times for acronyms in French. AB - We collected subjective frequency, age-of-acquisition, and imageability norms for 319 acronyms from French adults. Objective printed frequency, bigram frequency, and lengths in letters, phonemes, and syllables, as well as orthographic neighbors, were computed. The time taken to read acronyms aloud was also recorded. Correlational analyses indicated that the relations between the psycholinguistic variables were similar to those usually found for common words (e.g., highly imageable acronyms were more frequent and learned earlier in life than less imageable acronyms), but were generally weaker in the former than in the latter. Linear mixed-model analyses performed on the reading latencies revealed that the main determinants were the voicing feature of initial phonemes, the type of pronunciation of the acronyms (ambiguous vs. unambiguous, typical vs. atypical characteristics), length (number of letters and number of syllables), together with bigram frequency, printed frequency, and imageability. Both objective frequency and imageability interacted reliably with the ambiguous typical and ambiguous atypical properties. Accuracy was predicted by the number of letters and by imageability factors: More errors occurred on longer than on shorter acronyms, and also more errors on less imageable than on more imageable acronyms. The theoretical and methodological implications of the findings for the understanding of acronym reading are discussed. The entire set of norms and the acronym reading times (and accuracy scores), together with the acronym definitions, are provided as supplemental materials. PMID- 24763942 TI - The association of weight with the detection of airflow obstruction and inhaled treatment among patients with a clinical diagnosis of COPD. AB - BACKGROUND: Most patients with a clinical diagnosis of COPD have not had spirometry to confirm airflow obstruction (AFO). Overweight and obese patients report more dyspnea than normal weight patients, which may be falsely attributed to AFO. We sought to determine whether overweight and obese patients who received a clinical diagnosis of COPD were more likely to receive a misdiagnosis (ie, lack of AFO on spirometry) and be subsequently treated with inhaled medications. METHODS: The cohort comprised US veterans with COPD (International Classification of Diseases, 9th Revision, code; inhaled medication use; or both) and spirometry measurements from one of three Pacific Northwest Veterans Administration Medical Centers. The measured exposures were overweight and obesity (defined by BMI categories). Outcomes were (1) AFO on spirometry and (2) escalation or deescalation of inhaled therapies from 3 months before spirometry to 9 to 12 months after spirometry. We used multivariable logistic regression with calculation of adjusted proportions for all analyses. RESULTS: Fifty-two percent of 5,493 veterans who had received a clinical diagnosis of COPD had AFO. The adjusted proportion of patients with AFO decreased as BMI increased (P < .01 for trend). Among patients without AFO, those who were overweight and obese were less likely to remain off medications or to have therapy deescalated (adjusted proportions: normal weight, 0.69 [95% CI, 0.64-0.73]; overweight, 0.62 [95% CI, 0.58-0.65; P = .014]; obese, 0.60 [95% CI, 0.57-0.63; P = .001]). CONCLUSIONS: Overweight and obese patients are more likely to be given a misdiagnosis of COPD and not have their inhaled medications deescalated after spirometry demonstrated no AFO. Providers may be missing potential opportunities to recognize and treat other causes of dyspnea in these patients. PMID- 24763944 TI - Association between lumbopelvic pain, disability and sick leave during pregnancy a comparison of three Scandinavian cohorts. AB - OBJECTIVE: To explore the association between disability and sick leave due to lumbopelvic pain in pregnant women in 3 cohorts in Sweden and Norway and to explore possible factors of importance to sick leave. A further aim was to compare the prevalence of sick leave due to lumbopelvic pain. DESIGN/SUBJECTS: Pregnant women (n = 898) from two cohorts in Sweden and one in Norway answered to questionnaires in gestational weeks 10-24; two of the cohorts additionally in weeks 28-38. METHODS: Logistic regression models were performed with sick leave due to lumbopelvic pain as dependent factor. Disability, pain, age, parity, cohort, civilian status, and occupational classification were independents factors. RESULTS: In gestational weeks 10-24 the regression model included 895 cases; 38 on sick leave due to lumbopelvic pain. Disability, pain and cohort affiliation were associated with sick leave. In weeks 28-38, disability, pain and occupation classification were the significant factors. The prevalence of lumbopelvic pain was higher in Norway than in Sweden (65%, vs 58% and 44%; p < 0.001). CONCLUSION: Disability, pain intensity and occupation were associated to sick leave due to lumbopelvic pain. Yet, there were significant variations between associated factors among the cohorts, suggesting that other factors than workability and the social security system are also of importance. PMID- 24763945 TI - Avian influenza from an ecohealth perspective. AB - To understand and better control AI outbreaks, not only is it necessary to understand the biology of influenza viruses but also the natural history of the hosts in which these viruses multiply and the different environments in which the hosts and viruses interact. This includes the anthropogenic factors that have influenced where, whether and how avian influenza (AI) viruses can replicate and transmit between wild birds and poultry, and between poultry and mammals, including factors influencing uptake and application of appropriate control and preventive measures for AI. This disease represents one of the best examples of the need for a 'One Health' approach to understand and tackle disease with an increasing need to comprehend and unravel the environmental and ecology drivers that affect the virus host interactions. This forum piece seeks to bring together these aspects through a review of recent outbreaks and how a deeper understanding of all three aspects, the virus, the host and the environment, can help us better manage future outbreaks. PMID- 24763946 TI - The psychosocial impact of the environmental damage caused by the MT Merapi eruption on survivors in Indonesia. AB - The eruption of Indonesia's Mount Merapi volcano in 2010 caused extensive environmental degradation. Settlements and hundreds of hectares of farmlands were buried under volcanic ash. Until now, there has been no research on the psychosocial impact of living in an environment damaged by a volcanic eruption. We studied and compared the psychosocial impact of environmental damage on volcano survivors from two subdistricts-Cangkringan and Pakem. Cangkringan survivors affected by the 2010 eruption continue to live in a damaged environment. The Pakem subdistrict was damaged by eruptions of Mt Merapi in the 1990s but there is no recent damage to their environment. The Indonesian Environmental Distress Scale (I-EDS), a translated revision of the original Environmental Distress Scale (EDS), was used to collect data. Exploratory statistical methods and multivariate linear regression analyses were performed to examine the relative contributions of demographic variables on the psychosocial impact of living in an environment damaged by volcanic eruption. A total of 348 survivors of the Mt Merapi eruption participated in the survey. The mean I-EDS score for Cangkringan district was 15.8 (SD 1.6; range 11.8-19.8) compared to 14.6 (SD 1.3; range 11.8-18.3) for Pakem district (P < 0.001). This result was confirmed by multiple linear regression analysis showing further that older respondents (P < 0.001), unemployed and retired respondents (P = 0.007), and respondents with no formal school education (P = 0.037) had lower I-EDS scores compared to the respective reference groups. Survivors of the Mt Merapi eruption who continue to live in the environment damaged by the 2010 volcanic eruption experience environmental distress. Relevant interventions should target those from low sosioeconomic groups to deal with the distress. PMID- 24763965 TI - Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin. AB - Aspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, in vivo thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB2 was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5-10 mg, 20-40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB2 (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB2 [OR=2.95 (0.1.57-5.50, p=0.0007); OR=2.25 (1.24-4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB2 was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB2 may be a useful method to optimise statin dosing in order to reduce thrombotic risk. PMID- 24763964 TI - Centromere identity from the DNA point of view. AB - The centromere is a chromosomal locus responsible for the faithful segregation of genetic material during cell division. It has become evident that centromeres can be established literally on any DNA sequence, and the possible synergy between DNA sequences and the most prominent centromere identifiers, protein components, and epigenetic marks remains uncertain. However, some evolutionary preferences seem to exist, and long-term established centromeres are frequently formed on long arrays of satellite DNAs and/or transposable elements. Recent progress in understanding functional centromere sequences is based largely on the high resolution DNA mapping of sequences that interact with the centromere-specific histone H3 variant, the most reliable marker of active centromeres. In addition, sequence assembly and mapping of large repetitive centromeric regions, as well as comparative genome analyses offer insight into their complex organization and evolution. The rapidly advancing field of transcription in centromere regions highlights the functional importance of centromeric transcripts. Here, we comprehensively review the current state of knowledge on the composition and functionality of DNA sequences underlying active centromeres and discuss their contribution to the functioning of different centromere types in higher eukaryotes. PMID- 24763966 TI - 3D printed microfluidic devices with integrated versatile and reusable electrodes. AB - We report two 3D printed devices that can be used for electrochemical detection. In both cases, the electrode is housed in commercially available, polymer-based fittings so that the various electrode materials (platinum, platinum black, carbon, gold, silver) can be easily added to a threaded receiving port printed on the device; this enables a module-like approach to the experimental design, where the electrodes are removable and can be easily repolished for reuse after exposure to biological samples. The first printed device represents a microfluidic platform with a 500 * 500 MUm channel and a threaded receiving port to allow integration of either polyetheretherketone (PEEK) nut-encased glassy carbon or platinum black (Pt-black) electrodes for dopamine and nitric oxide (NO) detection, respectively. The embedded 1 mm glassy carbon electrode had a limit of detection (LOD) of 500 nM for dopamine and a linear response (R(2) = 0.99) for concentrations between 25-500 MUM. When the glassy carbon electrode was coated with 0.05% Nafion, significant exclusion of nitrite was observed when compared to signal obtained from equimolar injections of dopamine. When using flow injection analysis with a Pt/Pt-black electrode and standards derived from NO gas, a linear correlation (R(2) = 0.99) over a wide range of concentrations (7.6-190 MUM) was obtained, with the LOD for NO being 1 MUM. The second application showcases a 3D printed fluidic device that allows collection of the biologically relevant analyte adenosine triphosphate (ATP) while simultaneously measuring the release stimulus (reduced oxygen concentration). The hypoxic sample (4.8 +/- 0.5 ppm oxygen) released 2.4 +/- 0.4 times more ATP than the normoxic sample (8.4 +/- 0.6 ppm oxygen). Importantly, the results reported here verify the reproducible and transferable nature of using 3D printing as a fabrication technique, as devices and electrodes were moved between labs multiple times during completion of the study. PMID- 24763967 TI - Tissue Border Enhancement by inversion recovery MRI at 7.0 Tesla. AB - INTRODUCTION: This contribution presents a magnetic resonance imaging (MRI) acquisition technique named Tissue Border Enhancement (TBE), whose purpose is to produce images with enhanced visualization of borders between two tissues of interest without any post-processing. METHODS: The technique is based on an inversion recovery sequence that employs an appropriate inversion time to produce images where the interface between two tissues of interest is hypo-intense; therefore, tissue borders are clearly represented by dark lines. This effect is achieved by setting imaging parameters such that two neighboring tissues of interest have magnetization with equal magnitude but opposite sign; therefore, the voxels containing a mixture of each tissue (that is, the tissue interface) possess minimal net signal. The technique was implemented on a 7.0 T MRI system. RESULTS: This approach can assist the definition of tissue borders, such as that between cortical gray matter and white matter; therefore, it could facilitate segmentation procedures, which are often challenging on ultra-high-field systems due to inhomogeneous radiofrequency distribution. TBE allows delineating the contours of structural abnormalities, and its capabilities were demonstrated with patients with focal cortical dysplasia, gray matter heterotopia, and polymicrogyria. CONCLUSION: This technique provides a new type of image contrast and has several possible applications in basic neuroscience, neurogenetic research, and clinical practice, as it could improve the detection power of MRI in the characterization of cortical malformations, enhance the contour of small anatomical structures of interest, and facilitate cortical segmentation. PMID- 24763968 TI - Solvent free selective dehydrogenation of indolic and carbazolic molecules with an iridium pincer catalyst. AB - A previously known iridium POCOP pincer catalyst was found to selectively dehydrogenate the heterocyclic portion of several indolic and carbazolic molecules. These molecules were found to have an "activity window" (172-178 degrees C) upon which only the heterocyclic ring underwent dehydrogenation. All reactions were run solvent free, yields for selected substrates were excellent, and the products were isolated by either distillation or alumina plug filtration. PMID- 24763969 TI - Discrepancy between parents and children in reporting of distress and impairment: Association with critical symptoms. AB - BACKGROUND: We examined discrepant parent-child reports of subjective distress and psychosocial impairment. METHOD: Parent-child pairs (N = 112 pairs) completed the Health Dynamics Inventory at intake for outpatient therapy. RESULTS: Average parent scores were significantly higher than average child scores on distress, impairment, and externalizing symptoms, but not internalizing symptoms. There were significant associations between parent-child discrepancy (i.e. children who reported greater distress or impairment than parents or vice versa) and child endorsement of several notable symptoms (rapid mood swings, panic, nightmares, and suicidal ideation). CONCLUSION: Parents tended to report more externalizing symptoms, distress, and impairment than children reported; however, when children report more distress and impairment than parents, this may indicate serious psychological problems. PMID- 24763970 TI - Lack of adenosine A3 receptors causes defects in mouse peripheral blood parameters. AB - The role of the adenosine A3 receptor in hematopoiesis was studied using adenosine A3 receptor knockout (A3AR KO) mice. Hematological parameters of peripheral blood and femoral bone marrow of irradiated and untreated A3AR KO mice and their wild-type (WT) counterparts were investigated. Irradiation of the mice served as a defined hematopoiesis-damaging means enabling us to evaluate contingent differences in the pattern of experimentally induced hematopoietic suppression between the A3AR KO mice and WT mice. Defects were observed in the counts and/or functional parameters of blood cells in the A3AR KO mice. These defects include statistically significantly lower values of blood neutrophil and monocyte counts, as well as those of mean erythrocyte volume, mean erythrocyte hemoglobin, blood platelet counts, mean platelet volume, and plateletcrit, and can be considered to bear evidence of the lack of a positive role played by the adenosine A3 receptor in the hematopoietic system. Statistically significantly increased values of the bone marrow parameters studied in A3AR KO mice (femoral bone marrow cellularity, granulocyte/macrophage progenitor cells, and erythrocyte progenitor cells) can probably be explained by compensatory mechanisms attempting to offset the disorders in the function of blood elements in these mice. The pattern of the radiation-induced hematopoietic suppression was very similar in A3AR KO mice and their WT counterparts. PMID- 24763971 TI - Measurement scale influences in the evaluation of sight-word reading interventions. AB - Working with elementary students with disabilities, we used alternating treatment designs to evaluate and compare the effects of 2 computer-based flash card sight word reading interventions, 1 with 1-s response intervals and another with 5-s response intervals. In Study 1, we held instructional time constant, applying both interventions for 3 min. Although students completed 6 learning trials per word during each 1-s session and 2 trials per word during each 5-s session, results showed similar acquisition rates for 1-s and 5-s words. During Study 2, we held learning trials constant (3 per word) and allowed instructional time to vary. When we measured learning using cumulative instructional sessions, the interventions appeared to cause similar increases in acquisition rates. When the same learning data were measured and plotted using cumulative instructional seconds, all participants showed greater learning rates under the 1-s intervention. Discussion focuses on how measurement scales can influence comparative effectiveness studies. PMID- 24763973 TI - Capturing eating behavior where the action takes place: a comment on McKee et al. PMID- 24763972 TI - Home telehealth uptake and continued use among heart failure and chronic obstructive pulmonary disease patients: a systematic review. AB - BACKGROUND: Home telehealth has the potential to benefit heart failure (HF) and chronic obstructive pulmonary disease (COPD) patients, however large-scale deployment is yet to be achieved. PURPOSE: The aim of this review was to assess levels of uptake of home telehealth by patients with HF and COPD and the factors that determine whether patients do or do not accept and continue to use telehealth. METHODS: This research performs a narrative synthesis of the results from included studies. RESULTS: Thirty-seven studies met the inclusion criteria. Studies that reported rates of refusal and/or withdrawal found that almost one third of patients who were offered telehealth refused and one fifth of participants who did accept later abandoned telehealth. Seven barriers to, and nine facilitators of, home telehealth use were identified. CONCLUSIONS: Research reports need to provide more details regarding telehealth refusal and abandonment, in order to understand the reasons why patients decide not to use telehealth. PMID- 24763974 TI - Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B. AB - BACKGROUND: The occurrence of factor inhibitory antibodies, or inhibitors, is a significant complication in the care of individuals with congenital haemophilia A or B. Currently, immune tolerance induction is the only known intervention to successfully eradicate inhibitors. However, ideal dosing regimens, and the comparative safety and efficacy of different immune tolerance induction regimens have not yet been established. OBJECTIVES: The objective of this review was to assess the effects of immune tolerance induction (different protocols of this therapy versus each other, or versus only bypassing agents) for treating inhibitors in people with congenital haemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched: MEDLINE (from 1946 to 15 July 2013); Embase (from 1980 to 15 July 2013) via the OVID platform; CINAHL (from conception to 15 July 2013); and ClinicalTrials.gov (most recent search: 15 July 2013). We also searched the reference lists of relevant articles and reviews. SELECTION CRITERIA: Randomised controlled trials comparing either different immune tolerance induction regimens or immune tolerance induction versus only bypassing therapy for the eradication of factor inhibitory antibodies in patients with congenital haemophilia A or B. DATA COLLECTION AND ANALYSIS: Two review authors independently completed data collection, extraction and assessment of the risk of bias of trials. MAIN RESULTS: One methodologically sound randomised controlled trial met the inclusion criteria and was included in the review. One further randomised controlled trial has been recently stopped, but it has not yet been reported.The included multinational trial randomised 115 paediatric participants with severe haemophilia A and high-responding inhibitors, for whom this was the first attempt at immune tolerance induction, to receive either a low dose (50 IU/kg of factor VIII concentrate three times per week) or a high dose (200 IU/kg of factor VIII daily). Although, there was no statistically significant difference in the success of immune tolerance induction between treatment arms, the confidence intervals were too wide to infer no effect: 24 out of 58 participants (46.6%) in the low-dose group and 22 out of 57 (38.6%) in the high-dose group experiencing full tolerance, risk ratio 1.07 (95% CI 0.68 to 1.68) (moderate quality evidence). The rate of infection was not statistically different between groups, but again confidence intervals were too wide. Of those patients who had a central venous catheter device, 19 out of 47 participants (40.4%) in the low-dose arm had 69 infections, and 22 out of 52 participants (42.3%) in the high-dose arm had 55 infections, risk ratio 0.96 (95% CI 0.60 to 1.53) (moderate quality evidence). However, participants in the low-dose immune tolerance induction group experienced significantly more bleeding episodes (50 out of 58 participants (86.2%) experienced one or more bleeding events) than those in the high-dose group (36 out of 57 participants (63.1%) experienced one or more bleeding events), risk ratio 1.36 (95% CI 1.09 to 1.71) (low quality evidence). One factor VIII reaction, one incidence of trauma and 13 incidences of needing to insert or remove the catheter were reported as trial-related serious adverse events; however, the treatment group where these events occurred was not specified. No incidence of nephrotic syndrome was reported. AUTHORS' CONCLUSIONS: We did not find any randomised controlled trial-based comparison of immune tolerance induction with alternate treatment schemes (i.e. bypassing agents for bleeding only). In a single randomised trial, there were no significant differences in the immune tolerance induction success rate between different dosing regimens, which may have been due to imprecision of the estimate. There is low-quality evidence to suggest that high-dose immune tolerance induction may induce tolerance more quickly which is associated with fewer bleeding complications. The choice of immune tolerance induction regimen should be considered individually for each case, until further research provides additional evidence. PMID- 24763975 TI - Ready or not: responding to measles in the postelimination era. PMID- 24763976 TI - Nutrition and foraging strategies of the black howler monkey (Alouatta pigra) in Palenque National Park, Mexico. AB - Food resources consumed by primates vary markedly in nutritional content. As a result, foragers must develop a feeding strategy to select resources that balance energy and macronutrient intake and reduce the consumption of fiber and toxins. In this study, we collected data on dietary patterns, rates of food consumption, and weight of food items consumed and combined them with published values of the nutritional content of Neotropical foods to estimate energy and nutrient intake during a 10-month period in two groups (N=16 individuals) of black howler monkeys (Alouatta pigra) inhabiting Palenque National Park, Mexico. Although howler monkeys are generally assumed to exploit a leaf-dominated diet and be energy limited, our results indicated that black howlers met their estimated energy requirements, consuming an average of 0.58 MJ of overall energy per metabolic body mass per day. The howlers also surpassed protein requirements by consuming an average of 8.2 g of protein per metabolic body mass per day. The amount of time they spent resting was not correlated with the amount of leaves or fruit in the diet or with overall energy intake. Therefore, despite consuming a leaf-heavy diet during some months of the year, black howlers do not appear to be energy limited. Additionally, the howlers maintained a relatively consistent level of average daily protein energy intake regardless of diet composition, while non protein energy intake varied in response to the amount of ripe fruits consumed. Although our use of published nutritional data introduces error, these findings suggest that black howler feeding ecology is more similar to other fruit-eating atelines than previously suspected, and several common assumptions regarding howler behavior and feeding ecology need to be reexamined. PMID- 24763977 TI - A gold-catalysed fully intermolecular oxidation and sulfur-ylide formation sequence on ynamides. AB - An efficient C-O, C-S and C-C bond-forming sequence leads to functionalised compounds bearing sulfur-substituted quaternary carbons. Ynamides are employed as diazo-equivalents to access the [2,3]-sigmatropic rearrangements of allyl sulfonium ylides by a three-component chemoselective oxidation and intermolecular ylide formation. PMID- 24763978 TI - A diagnosis of dismobility--giving mobility clinical visibility: a Mobility Working Group recommendation. PMID- 24763979 TI - Accuracy of biovolume formulas for CMEIAS computer-assisted microscopy and body size analysis of morphologically diverse microbial populations and communities. AB - Cell biovolume is a commonly used metric of microbial abundance analyzed by computer-assisted microscopy, but the accuracies of most biovolume formulas have not been validated by ground truth data. We examined the accuracy of 17 biovolume formulas by comparing the computed volumes of 3D models representing 11 microbial morphotypes (cocci, spirals, curved rods, U-shaped rods, regular straight rods, unbranched filaments, ellipsoids, clubs, prosthecates, rudimentary branched rods, and branched filaments) to the volume displacement of the same objects as ground truth. As anticipated, formula accuracy was significantly influenced by the morphotype examined. A few formulas performed very accurately (> 95 %), especially those that adapted to the cell's shape, whereas others were consistently inaccurate or only accurate for one or two morphotypes. As an example of application, indices of morphological diversity in a freshwater biofilm assemblage were shown to be significantly different when microbial abundance among morphotype classes was measured as biovolume body mass rather than cell counts. Spatial analysis of biovolume body mass can also provide insights on the in situ ecophysiological attributes among individuals in microbial populations and communities, including their spatially autocorrelated allometric scaling interrelationships between body size, metabolic activity, resource apportionment and use, food web dynamics, and various cell-cell interactions affecting their growth and colonization behavior within spatially structured biofilm landscapes. This improved computing technology of biovolume algorithms with proven accuracy identifies which formula(s) should be used to compute microbial biovolumes in 2D images of morphologically diverse communities acquired by conventional phase-contrast light microscopy at single-cell resolution. PMID- 24763980 TI - Integrating space with place in health research: a multilevel spatial investigation using child mortality in 1880 Newark, New Jersey. AB - Research on neighborhoods and health increasingly acknowledges the need to conceptualize, measure, and model spatial features of social and physical environments. When ignoring underlying spatial dynamics, we run the risk of biased statistical inference and misleading results. In this article, we propose an integrated multilevel spatial approach for Poisson models of discrete responses. In an empirical example of child mortality in 1880 Newark, New Jersey, we compare this multilevel spatial approach with the more typical aspatial multilevel approach. Results indicate that spatially defined egocentric neighborhoods, or distance-based measures, outperform administrative areal units, such as census units. In addition, although results do not vary by specific definitions of egocentric neighborhoods, they are sensitive to geographic scale and modeling strategy. Overall, our findings confirm that adopting a spatial multilevel approach enhances our ability to disentangle the effect of space from that of place, pointing to the need for more careful spatial thinking in population research on neighborhoods and health. PMID- 24763981 TI - Prognostic impact of primary tumor resection and lymph node dissection in stage IV colorectal cancer with unresectable metastasis: a propensity score analysis in a multicenter retrospective study. AB - BACKGROUND: Retrospective studies have shown that primary tumor resection improves the prognosis of patients with colorectal cancer with unresectable metastasis (mCRC). Prognostic significance of lymph node dissection (LND) in mCRC has not been examined previously. The aim of this study was to investigate the prognostic impact of primary tumor resection and LND in mCRC. METHODS: A total of 1,982 patients with mCRC from January 1997 to December 2007 were retrospectively studied. The impact of primary tumor resection and LND on overall survival (OS) was analyzed using Cox proportional hazards model and propensity score analysis to mitigate the selection bias. Covariates in the models for propensity scores included treatment period, institution, age, sex, carcinoembryonic antigen, tumor location, histology, depth, lymph node metastasis, lymphovascular invasion, and number of metastatic organs. RESULTS: In a multivariate analysis, primary tumor resection and treatment in the latter period were associated with an improved OS, and age over 70 years, female sex, lymph node metastasis, and multiple organ metastasis were associated with a decreased OS. In the propensity-matched cohort, patients treated with primary tumor resection showed a significantly better OS than those without tumor resection (median OS 13.8 vs. 6.3 months; p = 0.0001). Furthermore, among patients treated with primary tumor resection, patients treated with D3 LND showed a significantly better OS than those with less extensive LND (median OS 17.2 vs. 13.7 months; p < 0.0001). CONCLUSIONS: It was suggested that primary tumor resection with D3 LND improves the survival of patients with mCRC. PMID- 24763982 TI - A retrospective review of 126 high-grade neuroendocrine carcinomas of the colon and rectum. AB - BACKGROUND: High-grade neuroendocrine carcinomas (HGNECs) of the colon and rectum are rare, constituting less than 1 % of colorectal cancers. The purpose of this study was to identify the natural history and oncologic outcomes of this disease, describe the use of surgery, and determine the clinical and pathological factors associated with outcomes. METHODS: Following Institutional Review Board approval, patients with HGNEC were identified from our institutional database. Patient charts and pathology reports were analyzed retrospectively for clinical and pathological factors. RESULTS: A total of 126 patients with a median follow-up of 9 months were identified. Median survival was 13.2 months, and 85 (67 %) patients had metastatic disease at diagnosis. Three-year overall survival (OS) was 5 and 18 % for patients with and without metastatic disease, respectively. Factors associated with improved OS on multivariable analysis were absence of metastatic disease and presence of an adenocarcinoma component within the tumor. In patients with metastatic disease, response to chemotherapy was the only factor associated with survival. In patients with localized disease, an adenocarcinoma component within the tumor was the only factor associated with survival. Resection of tumor was not associated with survival in either localized or metastatic disease. CONCLUSION: High-grade colorectal NECs are extremely aggressive tumors with poor prognosis. Patients appear to have a marginally better prognosis if they present without metastatic disease, have an adenocarcinoma component within their tumor, or respond to chemotherapy. Surgery, particularly in the presence of metastatic disease, may not offer a survival benefit for the majority of patients. PMID- 24763983 TI - ERCC1 mRNA expression as a postoperative prognostic marker in extrahepatic bile duct cancer. AB - BACKGROUND: No reliable biomarker for biliary tract cancer has yet been identified because of the varying composition of the cancer type, differences in tumor location, a mixture of curative and non-curative operations, and differences in operative methods. METHODS: Fifty extrahepatic bile duct cancer patients, pathologically diagnosed with papillary or tubular adenocarcinoma who underwent a pancreatoduodenectomy with R0 resection, were included in the study. Messenger RNA (mRNA) expression levels were measured from formalin-fixed, paraffin-embedded samples by real-time reverse-transcription polymerase chain reaction. RESULTS: The preliminary analysis selected ten patients who have survived more than 5 years (LS group) and ten who had a relapse within 2 years (SS group). mRNA expression of seven target genes was examined, but only excision repair cross-complementing 1 (ERCC1) mRNA levels showed a significant difference between the LS and SS groups (median ERCC1: LS 26.5 vs. SS 9.7; p = 0.0073). The median survival time of patients with high ERCC1 levels was significantly longer than in patients with low ERCC1 levels (p = 0.0105). Thirty more patients with identical backgrounds were added to the study, and ERCC1 mRNA levels were measured in all 50 patients. Those with high ERCC1 mRNA levels had a significantly greater overall survival (OS) time compared with those with low ERCC1 levels (MST: 174 vs. 86 M; p = 0.048). Multivariate analysis found that an absence of lymph node metastases and high ERCC1 expression were significantly associated with improved OS. CONCLUSION: ERCC1 mRNA expression appears to be a useful prognostic biomarker for extrahepatic bile duct cancer with R0 resection. PMID- 24763984 TI - Open versus minimally invasive resection of gastric GIST: a multi-institutional analysis of short- and long-term outcomes. AB - BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Overall surgical experience with minimally invasive surgery (MIS) has increased; however, published reports on MIS resection of GIST are limited to small, single-institution experiences. METHODS: A total of 397 patients who underwent open surgery (n = 230) or MIS (n = 167) for a gastric GIST between 1998 and 2012 were identified from a multicenter database. The impact of MIS approach on recurrence and survival was analyzed using propensity-score matching by comparing clinicopathologic factors between patients who underwent MIS versus open resection. RESULTS: There were 19 conversions (10 %) to open; the most common reasons for conversion were tumor more extensive than anticipated (26 %) and unclear anatomy (21 %). On multivariate analysis, smaller tumor size and higher body mass index (BMI) were associated with receipt of MIS. In the propensity-matched cohort (n = 248), MIS resection was associated with decreased length of stay (MIS, 3 days vs open, 8 days) and fewer >= grade 3 complications (MIS, 3 % vs open, 14 %) compared with open surgery. High rates of R0 resection and low rates of tumor rupture were seen in both groups. After propensity-score matching, there was no difference in recurrence-free or overall survival comparing the MIS and the open group (both p > 0.05). CONCLUSIONS: An MIS approach for gastric GIST was associated with low morbidity and a high rate of R0 resection. The long-term oncological outcome following MIS was excellent, and therefore the MIS approach should be considered the preferred approach for gastric GIST in well-selected patients. PMID- 24763985 TI - Ethylene bis-imidazoles are highly potent and selective activators for isozymes VA and VII of carbonic anhydrase, with a potential nootropic effect. AB - A series of ethylene bis-imidazoles was synthesized via a novel microwave mediated synthesis. Biological testing on eight isozymes of carbonic anhydrase (CA) present in the human brain revealed compounds with nanomolar potency against CA VA and CA VII, also displaying excellent selectivity against other CA isozymes present in this organ. PMID- 24763987 TI - Further evaluation of a functional analysis of moderate-to-vigorous physical activity in young children. AB - Inadequate physical activity increases the risks related to several health problems in children; however, increasing physical activity mitigates these risks. In this study, we examined the relations between moderate-to-vigorous physical activity (MVPA) and several environmental conditions (attention, interactive play, alone, escape) with 4 preschool children. We compared the experimental conditions to a control condition and a naturalistic baseline according to a combined multielement and reversal design. Results indicated that all participants were most active in the interactive play condition and that the percentage of MVPA varied across experimental and control conditions. In addition, the frequency and duration of bouts of MVPA were greatest in the interactive play condition. The current study presents a methodology for the identification of environmental contingencies that support increased levels of MVPA in young children, and it holds promise for improving our understanding of the variables related to physical activity. PMID- 24763992 TI - Mitochondrial genome interrogation for forensic casework and research studies. AB - This unit describes methods used in the analysis of mitochondrial DNA (mtDNA) for forensic and research applications. UNIT describes procedures specifically for forensic casework where the DNA from evidentiary material is often degraded or inhibited. In this unit, protocols are described for quantification of mtDNA before amplification; amplification of the entire control region from high quality samples as well as procedures for interrogating the whole mitochondrial genome (mtGenome); quantification of mtDNA post-amplification; and, post-PCR cleanup and sequencing. The protocols for amplification were developed for high throughput databasing applications for forensic DNA testing such as reference samples and population studies. However, these same protocols can be applied to biomedical research such as age-related disease and health disparities research. PMID- 24763993 TI - Using VAAST to Identify Disease-Associated Variants in Next-Generation Sequencing Data. AB - The VAAST pipeline is specifically designed to identify disease-associated alleles in next-generation sequencing data. In the protocols presented in this paper, we outline the best practices for variant prioritization using VAAST. Examples and test data are provided for case-control, small pedigree, and large pedigree analyses. These protocols will teach users the fundamentals of VAAST, VAAST 2.0, and pVAAST analyses. PMID- 24763994 TI - Using XHMM Software to Detect Copy Number Variation in Whole-Exome Sequencing Data. AB - Copy number variation (CNV) has emerged as an important genetic component in human diseases, which are increasingly being studied for large numbers of samples by sequencing the coding regions of the genome, i.e., exome sequencing. Nonetheless, detecting this variation from such targeted sequencing data is a difficult task, involving sorting out signal from noise, for which we have recently developed a set of statistical and computational tools called XHMM. In this unit, we give detailed instructions on how to run XHMM and how to use the resulting CNV calls in biological analyses. PMID- 24763995 TI - Genetic tests: clinical validity and clinical utility. AB - When evaluating the appropriate use of new genetic tests, clinicians and health care policymakers must consider the accuracy with which a test identifies a patient's clinical status (clinical validity) and the risks and benefits resulting from test use (clinical utility). Genetic tests in current use vary in accuracy and potential to improve health outcomes, and these test properties may be influenced by testing technology and the clinical setting in which the test is used. This unit defines clinical validity and clinical utility, provides examples, and considers the implications of these test properties for clinical practice. PMID- 24763996 TI - Use and effects of custom-made therapeutic footwear on lower-extremity-related pain and activity limitations in patients with rheumatoid arthritis: A prospective observational study of a cohort. AB - OBJECTIVES: An estimated 55-90% of patients with rheumatoid arthritis have foot problems. Therapeutic footwear is frequently prescribed as part of usual care, but data on its use and effect is incomplete. This study aimed to investigate the use and effects of therapeutic footwear. METHODS: Patients with rheumatoid arthritis receiving custom-made therapeutic footwear for the first time formed an inception cohort. Patients reported their therapeutic footwear use on 3 consecutive days in activity diaries 14 and 20 weeks after delivery of the footwear. The Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) was used as the primary outcome of lower-extremity-related pain and activity limitations, and the Health Assessment Questionnaire (HAQ) as a secondary outcome measure of activity limitations, both at baseline and 26 weeks after therapeutic footwear delivery. RESULTS: The cohort comprised 114 rheumatoid arthritis patients (median disease duration 10 years). Mean (standard deviation) therapeutic footwear use was 54 (25)% of the time patients were out of bed. The median (interquartile range) WOMAC score improved from 41 (27-59) to 31 (16-45) (p < 0.001). Secondary outcome measures improved significantly. CONCLUSION: Therapeutic footwear was used with moderate intensity by most rheumatoid arthritis patients and was associated with a substantial decrease in pain and activity limitations. Therapeutic footwear is a relevant treatment option for patients with rheumatoid arthritis and foot problems. PMID- 24763997 TI - Confidence intervals around Bayes Cost in multi-state diagnostic settings to estimate optimal performance. AB - A critical feature of diagnostic testing is correctly classifying subjects based upon specified thresholds of some measure. The commonly employed Youden index determines a test's optimal thresholds by maximizing the correct classification rates for a diagnostic scenario. An alternative to the Youden index is the cost function, Bayes Cost (BC). BC determines a test's optimal setting by minimizing the sum of all misclassification rates from the test. Unlike the Youden index, BC can consider a priori costs of all the diagnostic outcomes including class specific misclassifications regardless of the number of classes. Delta method approximate confidence intervals around BC are derived under the assumption of normally distributed classes as a means for quantifying a test's performance and comparing classifiers at their optimal settings in a multi-state diagnostic framework. A simulation study is conducted to demonstrate the performance of the derived confidence intervals that are found to perform well, especially for sample sizes of 50 or larger in each diagnostic class. Finally, the proposed methods are applied to a four-class breast tissue classification problem, where four possible discriminatory features are compared under varying decision cost structures. Using the confidence intervals around BC, the best feature for classification is selected, and the optimal thresholds and their 95% confidence intervals are determined. PMID- 24763998 TI - Surgical repair of thoraco-lumbar vertebral fracture-luxations in eight cats using screws and polymethylmethacrylate fixation. AB - OBJECTIVE: To report our clinical experience in the surgical treatment of feline thoraco-lumbar vertebral fracture-luxations using optimal safe implantation corridors as previously described in vitro. STUDY DESIGN: Retrospective clinical study. MATERIALS AND METHODS: Medical records and radiographs of cats with vertebral fracture-luxations stabilized by screws and polymethylmethacrylate (PMMA) using optimal safe implantation corridors between 2009 and 2011 were reviewed. For each patient the data included: signalment, cause of vertebral fracture-luxations, presence of concurrent injuries, pre- and postoperative neurological grade, surgical treatment, imaging findings, and clinical outcome with short-term (2 weeks) and long-term (12 months) follow-up. RESULTS: Eight cats with vertebral fracture-luxations involving the lumbar (L)(n = 5), the thoracic (T) spinal segments (n = 2), or the thoraco-lumbar junction (n = 1) were included in the study. Screws and PMMA were used bilaterally in five cats and unilaterally in three cats. No surgical intra-operative complications using the defined corridors were recorded. Implant failure followed by spontaneous recovery was recorded in one case. Two cats died in the postoperative period (<= 4 days). The short-term and long-term clinical outcome was excellent in four out of eight cats and satisfactory in two out of eight cats. CONCLUSION AND CLINICAL RELEVANCE: This pilot study demonstrates the clinical applicability of optimal safe implantation corridors for stabilization of feline thoraco-lumbar vertebral fracture-luxations with screws and PMMA. This technique can be used with limited risks of iatrogenic injuries for stabilization of vertebral fracture-luxation localized between T11-L4. PMID- 24763999 TI - Unadulterated BODIPY-dimer nanoparticles with high stability and good biocompatibility for cellular imaging. AB - Purely organic nanoparticles based on a BODIPY dimer, BDY-NPs, have been prepared for the first time using a nanoprecipitation procedure. The fluorescent nanoparticles have high physical homogeneity, good stability in water, and low cytotoxicity, which are suitable for cell imaging. PMID- 24764000 TI - Bidentate cycloimidate palladium complexes with aliphatic and aromatic anagostic bonds. AB - Palladium(II) complexes of bidentate cycloimidate ligand systems with a triarylmethyl moiety exhibit exceptional downfield shifts in proton NMR spectra due to rare anagostic interactions. PMID- 24764001 TI - Studies on arsenic transforming groundwater bacteria and their role in arsenic release from subsurface sediment. AB - Ten different Gram-negative arsenic (As)-resistant and As-transforming bacteria isolated from As-rich groundwater of West Bengal were characterized to assess their role in As mobilization. 16S rRNA gene analysis confirmed the affiliation of these bacteria to genera Achromobacter, Brevundimonas, Rhizobium, Ochrobactrum, and Pseudoxanthomonas. Along with superior As-resistance and As transformation abilities, the isolates showed broad metabolic capacity in terms of utilizing a variety of electron donors and acceptors (including As) under aerobic and anaerobic conditions, respectively. Arsenic transformation studies performed under various conditions indicated highly efficient As(3+) oxidation or As(5+) reduction kinetics. Genes encoding As(3+) oxidase (aioA), cytosolic As(5+) reductase (arsC), and As(3+) efflux pump (arsB and acr3) were detected within the test isolates. Sequence analyses suggested that As homeostasis genes (particularly arsC, arsB, and acr3) were acquired by most of the bacteria through horizontal gene transfer. A strong correlation between As resistance phenotype and the presence of As(3+) transporter genes was observed. Microcosm study showed that bacterial strain having cytosolic As(5+) reductase property could play important role in mobilizing As (as As(3+)) from subsurface sediment. PMID- 24764002 TI - Phytomanagement of Cd-contaminated soils using maize (Zea mays L.) assisted by plant growth-promoting rhizobacteria. AB - Zea mays (L.) is a crop widely cultivated throughout the world and can be considered suitable for phytomanagement due to its metal resistance and energetic value. In this study, the effect of two plant growth-promoting rhizobacteria, Ralstonia eutropha and Chryseobacterium humi, on growth and metal uptake of Z. mays plants in soils contaminated with up to 30 mg Cd kg(-1) was evaluated. Bacterial inoculation increased plant biomass up to 63% and led to a decrease of up to 81% in Cd shoot levels (4-88 mg Cd kg(-1)) and to an increase of up to 186% in accumulation in the roots (52-134 mg Cd kg(-1)). The rhizosphere community structure changed throughout the experiment and varied with different levels of Cd soil contamination, as revealed by molecular biology techniques. Z. mays plants inoculated with either of the tested strains may have potential application in a strategy of soil remediation, in particular short-term phytostabilization, coupled with biomass production for energy purposes. PMID- 24764003 TI - Distribution of PAHs and trace metals in urban stormwater sediments: combination of density fractionation, mineralogy and microanalysis. AB - Sediment management from stormwater infiltration basins represents a real environmental and economic issue for stakeholders due to the pollution load and important tonnages of these by-products. To reduce the sediment volumes to treat, organic and metal micropollutant-bearing phases should be identified. A combination of density fractionation procedure and microanalysis techniques was used to evaluate the distribution of polycyclic aromatic hydrocarbons (PAHs) and trace metals (Cd, Cr, Cu, Ni, Pb, and Zn) within variable density fractions for three urban stormwater basin sediments. The results confirm that PAHs are found in the lightest fractions (d < 1.9, 1.9 < d < 2.3 g cm(-3)) whereas trace metals are equally distributed within the light, intermediary, and highest fractions (d < 1.9, 1.9 < d < 2.3, 2.3 < d < 2.6, and d > 2.8 g cm(-3)) and are mostly in the 2.3 < d < 2.6 g cm(-3) fraction. The characterization of the five fractions by global analyses and microanalysis techniques (XRD and MEB-EDX) allowed us to identify pollutant-bearing phases. PAHs are bound to the organic matter (OM) and trace metals to OM, clays, carbonates and dense particles. Moreover, the microanalysis study underlines that OM is the main constituent responsible for the aggregation, particularly for microaggregation. In terms of sediment management, it was shown that density fractionation is not suitable for trace metals but could be adapted to separate PAH-enriched phases. PMID- 24764004 TI - NAPL migration and ecotoxicity of conventional and renewable fuels in accidental spill scenarios. AB - Fuels derived from non-petroleum renewable resources have raised interest due to their potential in replacing petroleum-based fuels, but information on their fate and effects in the terrestrial and aquatic environments in accidental spill scenario is limited. In this study, migration of four fuels (conventional diesel, conventional gasoline, renewable diesel NExBTL, and ethanol-blended gasoline RE85 containing maximum 85% ethanol) as non-aqueous phase liquids (NAPL) in soil was demonstrated in a laboratory-scale experiment. Ecotoxicity data was produced for the same fuels. There was no significant difference in migration of conventional and renewable diesel, but gasoline migrated 1.5 times deeper and 7-9 times faster in sand than diesel. RE85 spread horizontally wider but not as deep (p < 0.05) as conventional gasoline. Conventional gasoline was the most toxic (lethal concentration [LC50] 20 mg/kg total hydrocarbon content [THC]) among the studied fuels in soil toxicity test with earthworm Eisenia fetida followed by ethanol blended gasoline (LC50 1,643 mg/kg THC) and conventional diesel (LC50 2,432 mg/kg THC), although gasoline evaporated fast from soil. For comparison, the toxicity of the water-accommodated fractions (WAF) of the fuels was tested with water flea Daphnia magna and Vibrio fischeri, also demonstrating groundwater toxicity. The WAF of conventional gasoline and RE85 showed almost similar toxicity to both the aquatic test species. EC50 values of 1:10 (by volume) WAF were 9.9 %WAF (gasoline) and 9.3 %WAF (RE85) to D. magna and 9.3 %WAF (gasoline) and 12.3 %WAF (RE85) to V. fischeri. Low solubility decreased toxicity potential of conventional diesel in aquatic environment, but direct physical effects of oil phase pose a threat to organisms in nature. Renewable diesel NExBTL did not show clear toxicity to any test species. PMID- 24764005 TI - A diagnostic evaluation of modeled mercury wet depositions in Europe using atmospheric speciated high-resolution observations. AB - This study is part of the Global Mercury Observation System (GMOS), a European FP7 project dedicated to the improvement and validation of mercury models to assist in establishing a global monitoring network and to support political decisions. One key question about the global mercury cycle is the efficiency of its removal out of the atmosphere into other environmental compartments. So far, the evaluation of modeled wet deposition of mercury was difficult because of a lack of long-term measurements of oxidized and elemental mercury. The oxidized mercury species gaseous oxidized mercury (GOM) and particle-bound mercury (PBM) which are found in the atmosphere in typical concentrations of a few to a few tens pg/m(3) are the relevant components for the wet deposition of mercury. In this study, the first European long-term dataset of speciated mercury taken at Waldhof/Germany was used to evaluate deposition fields modeled with the chemistry transport model (CTM) Community Multiscale Air Quality (CMAQ) and to analyze the influence of the governing parameters. The influence of the parameters precipitation and atmospheric concentration was evaluated using different input datasets for a variety of CMAQ simulations for the year 2009. It was found that on the basis of daily and weekly measurement data, the bias of modeled depositions could be explained by the bias of precipitation fields and atmospheric concentrations of GOM and PBM. A correction of the modeled wet deposition using observed daily precipitation increased the correlation, on average, from 0.17 to 0.78. An additional correction based on the daily average GOM and PBM concentration lead to a 50% decrease of the model error for all CMAQ scenarios. Monthly deposition measurements were found to have a too low temporal resolution to adequately analyze model deficiencies in wet deposition processes due to the nonlinear nature of the scavenging process. Moreover, the general overestimation of atmospheric GOM by the CTM in combination with an underestimation of low precipitation events in the meteorological models lead to a good agreement of total annual wet deposition besides the large error in weekly deposition estimates. Moreover, it was found that the current speciation profiles for GOM emissions are the main factor for the overestimation of atmospheric GOM concentrations and might need to be revised in the future. The assumption of zero emissions of GOM lead to an improvement of the mean normalized bias for three hourly observations of atmospheric GOM from 9.7 to 0.5, Furthermore, the diurnal correlation between model and observation increased from 0.01 to 0.64. This is a strong indicator that GOM is not directly emitted from primary sources but is mainly created by oxidation of GEM. PMID- 24764006 TI - Modeling of 2-chloronaphthalene interaction with high carbon iron filings (HCIF) in semi-batch and continuous systems. AB - Unrusted high carbon iron filings (HCIF) were contacted sequentially with successive aliquots of aqueous 2-chloronaphthalene (2-CN), i.e., in semi-batch mode, both in well-mixed and poorly-mixed conditions. Aqueous concentration of 2 CN and the dehalogenation by-product naphthalene (N) were monitored at the beginning and end of each 2-CN addition cycle. Experimental data was modeled using the 2-CN dehalogenation and adsorption/desorption rate constants determined from batch experiments involving 2-CN and a similar HCIF sample. Model predictions for the semi-batch experiments matched quite well with the experimental data in both well-mixed and poorly-mixed cases. Further, it was experimentally demonstrated that adsorption and hence accumulation of N on HCIF surface did not substantially hinder either 2-CN adsorption or dehalogenation under the conditions examined in this study. Continuous transport of water containing 0.5 MUmol L(-1) 2-CN through a 1.0-m thick unrusted HCIF layer was simulated at superficial velocities of 0.01 and 0.10 m h(-1). Both simulations indicated nearly complete removal of 2-CN in the HCIF layer. This study suggests that HCIF can be used as a potential reactive material in permeable reactive barriers (PRBs) for in situ remediation of groundwater contaminated with 2-CN. PMID- 24764007 TI - The effect of urban heat island on Izmir's city ecosystem and climate. AB - Depending on the researches done on urban landscapes, it is found that the heat island intensity caused by the activities in any city has some impact on the ecosystem of the region and on the regional climate. Urban areas located in arid and semiarid lands somehow represent heat increase when it is compared with the heat in the surrounding rural areas. Thus, cities located amid forested and temperate climate regions show moderate temperatures. The impervious surfaces let the rainfall leave the city lands faster than undeveloped areas. This effect reduces water's cooling effects on these lands. More significantly, if trees and other vegetations are rare in any region, it means less evapotranspiration-the process by which trees "exhale" water. Trees also contribute to the cooling of urban lands by their shade. Land cover and land use maps can easily be produced by processing of remote sensing satellites' images, like processing of Landsat's images. As a result of this process, urban regions can be distinguished from vegetation. Analyzed GIS data produced and supported by these images can be utilized to determine the impact of urban land on energy, water, and carbon balances at the Earth's surface. Here in this study, it is found that remote sensing technique with thermal images is a liable technique to asses where urban heat islands and hot spots are located in cities. As an application area, in Izmir, it was found that the whole city was in high level of surface temperature as it was over 28 degrees C during the summer times. Beside this, the highest temperature values which go up to 47 degrees C are obtained at industrial regions especially where the iron-steel factories and the related industrial activities are. PMID- 24764008 TI - Analyzing sediment dissolved oxygen based on microprofile modeling. AB - Sediment plays a key role in controlling the oxygen demand of aquatic systems. The reaction rate, penetration depth, and flux across the sediment-water interface (SWI) are important factors in sediment oxygen consumption. However, there were few methods to collect these data until recently. In this study, methods were developed to simulate the oxygen microprofile and calculate the sediment oxygen consumption rate, oxygen penetration depth, and oxygen flux across the SWI. We constructed a sediment oxygen measuring system using an oxygen microelectrode and a control device. The simulation equations were derived from both zero and first-order kinetic models, while the penetration depth and the oxygen flux were calculated from the simulation results. The method was tested on four prepared sediment samples. Decreases in dissolved oxygen in surface sediment were clearly detected by the microelectrode. The modeled data were a good fit for the observed data (R (2) > 0.95), and zero-order kinetics were more suitable than first-order kinetics. The values for penetration depth (1.3-3.9 mm) and oxygen fluxes (0.061-0.114 mg/cm(2)/day) calculated by our methods are comparable with those from other studies. PMID- 24764009 TI - Treatment of a wastewater from a pesticide manufacture by combined coagulation and Fenton oxidation. AB - The treatment of a non-biodegradable agrochemical wastewater has been studied by coupling of preliminary coagulation-flocculation step and further Fenton oxidation. High percentages of chemical oxygen demand (COD) removal (up to 58 %) were achieved in a first step using polyferric chloride as coagulant. This reduced significantly the amount of H2O2 required in the further Fenton oxidation. Using the stoichiometric amount relative to COD around 80 % of the remaining organic load was mineralized. The combined treatment allowed achieving the regional discharge limits of ecotoxicity at a cost substantially lower than the solution used so far where these wastewaters are managed as hazardous wastes. PMID- 24764010 TI - Photolysis of atrazine in aqueous solution: role of process variables and reactive oxygen species. AB - Photochemical advanced oxidation processes have been considered for the treatment of water and wastewater containing the herbicide atrazine (ATZ), a possible human carcinogen and endocrine disruptor. In this study, we investigated the effects of the photon emission rate and initial concentration on ATZ photolysis at 254 nm, an issue not usually detailed in literature. Moreover, the role of reactive oxygen species (ROS) is discussed. Photon emission rates in the range 0.87 * 10(18)-3.6 * 10(18) photons L(-1) s(-1) and [ATZ]0 = 5 and 20 mg L(-1) were used. The results showed more than 65 % of ATZ removal after 30 min. ATZ photolysis followed apparent first-order kinetics with k values and percent removals decreasing with increasing herbicide initial concentration. A fivefold linear increase in specific degradation rate constants with photon emission rate was observed. Also, regardless the presence of persistent degradation products, toxicity was efficiently removed after 60-min exposure to UV radiation. Experiments confirmed a noticeable contribution of singlet oxygen and radical species to atrazine degradation during photolysis. These results may help understand the behavior of atrazine in different UV-driven photochemical degradation treatment processes. PMID- 24764011 TI - Effects of light and temperature fluctuations on the growth of Myriophyllum spicatum in toxicity tests--a model-based analysis. AB - Laboratory toxicity tests are a key component of the aquatic risk assessments of chemicals. Toxicity tests with Myriophyllum spicatum are conducted based on working procedures that provide detailed instructions on how to set up the experiment, e.g., which experimental design is necessary to get reproducible and thus comparable results. Approved working procedures are established by analyzing numerous toxicity tests to find a compromise between practical reasons (e.g., acceptable ranges of ambient conditions as they cannot be kept completely constant) and the ability for detecting growth alterations. However, the benefit of each step of a working procedure, e.g., the random repositioning of test beakers, cannot be exactly quantified, although this information might be useful to evaluate working procedures. In this paper, a growth model of M. spicatum was developed and used to assess the impact of temperature and light fluctuations within the standardized setup. It was analyzed how important it is to randomly reassign the location of each plant during laboratory tests to keep differences between the relative growth rates of individual plants low. Moreover, two examples are presented on how modeling can give insight into toxicity testing. Results showed that randomly repositioning of individual plants during an experiment can compensate for fluctuations of light and temperature. A method is presented on how models can be used to improve experimental designs and to quantify their benefits by predicting growth responses. PMID- 24764013 TI - Evolving concepts in migraine. PMID- 24764014 TI - The psychiatry milestones: new developments and challenges. PMID- 24764012 TI - The fate and importance of organics in drinking water treatment: a review. AB - In the pioneer days, the main driving forces for research of organics in drinking water treatment (DWT) were human health risks and optimisation of technology. The focus was on natural organic matter (NOM) structure, disinfection by-products (DBPs) formation, NOM removal by means of coagulation, adsorption, and oxidation, and development of the most efficient water treatment trains. Surprisingly, after decades of research, rapid development of analytical techniques and progress in risk assessment, the same driving forces are still in the limelight - although the topics have changed slightly. The attention switched from trihalomethanes to a new generation of DBPs. The definition of hydrophilic/hydrophobic NOM depends on the technique used for characterisation. It has become evident that numerous organic compounds can threaten water supply sources. Some of them had been ignored or overlooked in the past, but have recently been detected by advanced analytical tools even in drinking water. Prioritisation becomes priority per se. As far as processes are concerned, mainstream research has been following three lines: fouling mechanisms, application of hybrid processes and interactions between synthetic organic chemicals, other water constituents and materials used in DWT. Significant development has been made in membrane technology. This paper presents a broad overview of the recent organics research. Although the state-of the-art technologies seem to have an answer to each and every question raised, it is still necessary to deal with specific problems on a case-by-case basis mainly due to the unique nature of NOM and different xenobiotics that may appear in various types of waters. In the end, human health risk, which derives from the presence/absence of organics, is only the tip of the iceberg - underneath lies a whole new universe - the socio-economic aspect of water treatment and quality that deserves much more attention. PMID- 24764015 TI - Construction of helper plasmid-mediated dual-display phage for autoantibody screening in serum. AB - M13 filamentous bacteriophage has been used in displaying disease-specific antibodies, biomarkers, and peptides. One of the major drawbacks of using phage in diagnostic assays is the aspecific adsorption of proteins leading to a high background signal and decreasing sensitivity. To deal with this, we developed a genetically pure, exchangeable dual-display phage system in which biomarkers and streptavidin-binding protein (SBP) are displayed at opposite ends of the phage. This approach allows for sample purification, using streptavidin-coated magnetic beads resulting in a higher sensitivity of signal detection assays. Our dual display cassette system approach also allows for easy exchange of both the anchor protein (SBP) and the displayed biomarker. The presented principle is applied for the detection of antibody reactivity against UH-RA.21 which is a good candidate biomarker for rheumatoid arthritis (RA). The applicability of dual-display phage preparation using a helper plasmid system is demonstrated, and its increased sensitivity in phage ELISA assays using patient serum samples is shown. PMID- 24764016 TI - Lactobacillus plantarum IFPL935 impacts colonic metabolism in a simulator of the human gut microbiota during feeding with red wine polyphenols. AB - The colonic microbiota plays an important role in the bioavailibility of dietary polyphenols. This work has evaluated the impact on the gut microbiota of long term feeding with both a red wine polyphenolic extract and the flavan-3-ol metabolizer strain Lactobacillus plantarum IFPL935. The study was conducted in the dynamic Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The feeding of the gut microbiota model with red wine polyphenols caused an initial decrease in the counts of total bacteria in the ascending colon (AC), with Bacteroides, Clostridium coccoides/Eubacterium rectale and Bifidobacterium being the most affected bacterial groups. The bacterial counts recovered to initial numbers faster than the overall microbial fermentation and proteolysis, which seemed to be longer affected by polyphenols. Addition of L. plantarum IFPL935 helped to promptly recover total counts, Lactobacillus and Enterobacteriaceae and led to an increase in lactic acid formation in the AC vessel at the start of the polyphenol treatment as well as butyric acid in the transverse (TC) and descending (DC) vessels after 5 days. Moreover, L. plantarum IFPL935 favoured the conversion in the DC vessel of monomeric flavan-3-ols and their intermediate metabolites into phenylpropionic acids and in particular 3-(3' hydroxyphenyl)propionic acid. The results open the possibilities of using L. plantarum IFPL935 as a food ingredient for helping individuals showing a low polyphenol-fermenting metabotype to increase their colonic microbial capacities of metabolizing dietary polyphenols. PMID- 24764017 TI - Cupriavidus metallidurans biomineralization ability and its application as a bioconsolidation enhancer for ornamental marble stone. AB - Bacterially induced calcium carbonate precipitation of a Cupriavidus metallidurans isolate was investigated to develop an environmentally friendly method for restoration and preservation of ornamental stones. Biomineralization performance was carried out in a growth medium via a Design of Experiments (DoE) approach using, as design factors, the temperature, growth medium concentration, and inoculum concentration. The optimum conditions were determined with the aid of consecutive experiments based on response surface methodology (RSM) and were successfully validated thereafter. Statistical analysis can be utilized as a tool for screening bacterial bioprecipitation as it considerably reduced the experimental time and effort needed for bacterial evaluation. Analytical methods provided an insight to the biomineral characteristics, and sonication tests proved that our isolate could create a solid new layer of vaterite on marble substrate withstanding sonication forces. C. metallidurans ACA-DC 4073 provided a compact vaterite layer on the marble substrate with morphological characteristics that assisted in its differentiation. The latter proved valuable during spraying minimum amount of inoculated media on marble substrate under conditions close to an in situ application. A sufficient and clearly distinguishable layer was identified. PMID- 24764018 TI - Creating Qungasvik (a Yup'ik intervention "toolbox"): case examples from a community-developed and culturally-driven intervention. AB - This paper describes the development of a Yup'ik Alaska Native approach to suicide and alcohol abuse prevention that resulted in the creation of the Qungasvik, a toolbox promoting reasons for life and sobriety among youth. The Qungasvik is made up of thirty-six modules that function as cultural scripts for creating experiences in Yup'ik communities that build strengths and protection against suicide and alcohol abuse. The Qungasvik manual represents the results of a community based participatory research intervention development process grounded in culture and local process, and nurtured through a syncretic blending of Indigenous and Western theories and practices. This paper will provide a description of the collaborative steps taken at the community-level to develop the intervention modules. This process involved university researchers and community members coming together and drawing from multiple sources of data and knowledge to inform the development of prevention activities addressing youth suicide and alcohol abuse. We will present case examples describing the development of three keystone modules; Qasgiq (The Men's House), Yup'ik Kinship Terms, and Surviving Your Feelings. These modules each are representative of the process that the community co-researcher team took to develop and implement protective experiences that: (1) create supportive community, (2) strengthen families, and (3) give individuals tools to be healthy and strong. PMID- 24764020 TI - Pentacoordinate silicon(IV): cationic, anionic and neutral complexes derived from the reaction of NHC->SiCl4 with highly Lewis acidic (C2F5)2SiH2. AB - Addition of NHC->SiCl4 to the highly Lewis acidic bis(pentafluoroethyl)silane ((C2F5)2SiH2) afforded the salt [(NHC)2SiCl2H][(C2F5)2SiCl3] with pentacoordinate silicon in the cation and the anion. The anion represents the first example of a chlorosilicate structurally characterized in the solid state. In this reaction, the long sought pentacoordinate NHC-adduct of silicochloroform was identified as an intermediate and its crystal structure is presented. PMID- 24764019 TI - Partial characterization of a crude cold-active lipase from Rhodococcus cercidiphylli BZ22. AB - Cold-active lipase production by the psychrophilic strain Rhodococcus cercidiphylli BZ22 isolated from hydrocarbon-contaminated alpine soil was investigated. Depending on the medium composition, high cell densities were observed at a temperature range of 1-10 degrees C in Luria-Bertani (LB) broth or 1-30 degrees C in Reasoner's 2A (R2A). Maximum enzyme production was achieved at a cultivation temperature of 1-10 degrees C in LB medium. About 70-80% of the secreted enzyme was bound to the cell and was highly active as a cell-immobilized lipase which exhibited good reusability; more than 60% of the initial lipase activity was retained after five-fold reuse. The properties of the lipase produced by the investigated strain were compared with those of a mesophilic porcine pancreatic lipase (PPL). The thermal stability of the cell-immobilized bacterial lipase was higher than that of the extracellular enzyme. Highest activity was detected at 30 degrees C for the cell-immobilized enzyme and for PPL, while the extracellular enzyme displayed highest activity at 10-20 degrees C. The bacterial lipase hydrolyzed p-nitrophenyl (p-NP) esters with different acyl chain lengths (C2-C18). The highest hydrolytic activity was obtained with p NP-butyrate (C4) as substrate, while the highest substrate affinity was obtained with p-NP-dodecanoate (C12) as substrate, indicating a clear preference of the enzyme for medium acyl chain lengths. PMID- 24764023 TI - Silicon nanoparticles as Raman scattering enhancers. AB - In this communication we demonstrate the large amplification values of the Raman signal of organic molecules attached to silicon nanoparticles (SiNPs). Light induced Mie resonances of high refractive index particles generate strong evanescent electromagnetic (EM) fields, thus boosting the Raman signal of species attached to the nanoparticles. The interest of this process is justified by the wide range of experimental configurations that can be implemented including photonic crystals, the sharp spectral resonances easily tuneable with the particle size, the biocompatibility and biodegradability of silicon, and the possibility of direct analysis of molecules that do not contain functional groups with high affinity for gold and silver. Additionally, silicon nanoparticles present stronger field enhancement due to Mie resonances at larger sizes than gold. PMID- 24764027 TI - In transit recurrence of Merkel cell carcinoma associated with polyarthritis effectively treated with immunocryosurgery. PMID- 24764028 TI - Accuracy of a radiographic stitching technique to measure tibial plateau angle in large and giant breed dogs. AB - OBJECTIVE: To determine if a novel radiographic stitching technique yields accurate tibial plateau angle (TPA) measurements in large and giant breed dogs. METHODS: Three medio-lateral digital radiographic projections (traditional TPLO, stifle-centred, tarsus-centred) were obtained from each of 17 pairs of pelvic limbs from skeletally mature large and giant breed dogs. Eight observers performed image stitching followed by TPA measurements on the stitched (sTPA) and traditional radiographs (tTPA). The TPA was also measured on photographs made of isolated anatomical tibial specimens (aTPA). Measurements were compared between observers and between image type using ANOVA and correlation coefficients. RESULTS: There was no statistically significant difference in TPA between observers for tTPA or sTPA radiographs (p >0.05); both sTPA and tTPA were highly correlated with aTPA and with each other (r = 0.88, 0.89, and 0.97 respectively). CLINICAL RELEVANCE: This novel digital stitching method provides an alternative technique for accurately measuring TPA utilizing a stifle-centred radiograph that may be useful when traditional TPLO radiographs are difficult to obtain. This may be particularly useful in large and giant breed dogs because collimation to include the entire tibial length can preclude proper centring of the radiographic beam over the stifle. PMID- 24764029 TI - Skin Diseases in Clinical Practice, 2nd ed. PMID- 24764030 TI - Zinc in wound repair. PMID- 24764031 TI - Malar rash in a child. PMID- 24764033 TI - Distribution of TRPVs, P2X3, and parvalbumin in the human nodose ganglion. AB - Immunohistochemistry for several neurochemical substances, the transient receptor potential cation channel subfamily V member 1 (TRPV1) and 2 (TRPV2), P2X3 receptor, and parvalbumin (PV), was performed on the nodose ganglion, pharynx, and epiglottis in human cadavers. The nodose ganglion was situated beneath the jugular foramen, and had a spindle shape with the long rostrocaudal axis. The pharyngeal branch (PB) issued from a rostral quarter of the nodose ganglion, whereas the superior laryngeal nerve (SLN) usually originated from a caudal half of the ganglion. In the nodose ganglion, sensory neurons were mostly immunoreactive for TRPV1 (89 %) or P2X3 (93.9 %). About 30 % of nodose neurons contained TRPV2 (35.7 %)-or PV (29.9 %)-immunoreactivity (-IR). These neurons mainly had small to medium-sized cell bodies, and were distributed throughout the ganglion. Neurodegenerative profiles such as shrinkage or pyknosis could not be detected in the examined ganglion. Occasionally, TRPV2-IR nerve fibers surrounded blood vessels in the epiglottis as well as in the nasal and oral parts of the pharynx. Isolated TRPV2-IR nerve fibers were also located beneath the epithelium. TRPV1-, P2X3-, or PV-IR nerve endings could not be detected in the pharynx or epiglottis. In the PB and SLN, however, numerous nerve fibers contained TRPV1-, TRPV2-, P2X3-, and PV-IR. The present study suggests that TRPV1-, TRPV2-, P2X3-, and PV-IR neurons in the human nodose ganglion innervate the pharynx and epiglottis through the PB and SLN. These neurons may respond to chemical, thermal, and mechanical stimuli during respiration and swallowing. PMID- 24764034 TI - Characterizing IgG4-related disease with 18F-FDG PET/CT: a prospective cohort study. AB - PURPOSE: IgG4-related disease (IgG4-RD) is an increasingly recognized clinicopathological disorder with immune-mediated inflammatory lesions mimicking malignancies. A cohort study was prospectively designed to investigate the value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in characterizing IgG4-RD. METHODS: Thirty-five patients diagnosed with IgG4-RD according to the consensus criteria were enrolled with informed consent. All patients underwent baseline (18)F-FDG PET/CT evaluation. Among them, 29 patients underwent a second (18)F-FDG PET/CT scan after 2 to 4 weeks of steroid-based therapy. RESULTS: All 35 patients were found with (18)F FDG-avid hypermetabolic lesion(s); 97.1% (34/35) of these patients showed multi organ involvement. Among the 35 patients, 71.4% (25/35) patients were found with more organ involvement on (18)F-FDG PET/CT than conventional evaluations including physical examination, ultrasonography, and computed tomography (CT). (18)F-FDG PET/CT demonstrated specific image characteristics and pattern of IgG4 RD, including diffusely elevated (18)F-FDG uptake in the pancreas and salivary glands, patchy lesions in the retroperitoneal region and vascular wall, and multi organ involvement that cannot be interpreted as metastasis. Comprehensive understanding of all involvement aided the biopsy-site selection in seven patients and the recanalization of ureteral obstruction in five patients. After 2 to 4 weeks of steroid-based therapy at 40 mg to 50 mg prednisone per day, 72.4% (21/29) of the patients showed complete remission, whereas the others exhibited > 81.8% decrease in (18)F-FDG uptake. CONCLUSION: F-FDG PET/CT is a useful tool for assessing organ involvement, monitoring therapeutic response, and guiding interventional treatment of IgG4-RD. The image pattern is suggested to be updated into the consensus diagnostic criteria for IgG4-RD. PMID- 24764036 TI - Deletion of the carboxyl-terminal residue disrupts the amino-terminal folding, self-association, and thermal stability of an amphipathic antimicrobial peptide. AB - Understanding the complex relationship between amino acid sequence and protein behaviors, such as folding and self-association, is a major goal of protein research. In the present work, we examined the effects of deleting a C-terminal residue on the intrinsic properties of an amphapathic alpha-helix of mastoparan-B (MP-B), an antimicrobial peptide with the sequence LKLKSIVSWAKKVL-NH2. We used circular dichroism and nuclear magnetic resonance to demonstrate that the peptide MP-B([1-13]) displayed significant unwinding at the N-terminal helix compared with the parent peptide of MP-B, as the temperature increased when the residue at position 14 was deleted. Pulsed-field gradient nuclear magnetic resonance data revealed that MP-B forms a larger diffusion unit than MP-B([1-13]) at all experimental temperatures and continuously dissociates as the temperature increases. In contrast, the size of the diffusion unit of MP-B([1-13]) is almost independent of temperature. These findings suggest that deleting the flexible, hydrophobic amino acid from the C-terminus of MP-B is sufficient to change the intrinsic helical thermal stability and self-association. This effect is most likely because of the modulation of enthalpic interactions and conformational freedom that are specified by this residue. Our results implicate terminal residues in the biological function of an antimicrobial peptide. PMID- 24764035 TI - Cost-effectiveness of preoperative SPECT/CT combined with lymphoscintigraphy vs. lymphoscintigraphy for sentinel lymph node excision in patients with cutaneous malignant melanoma. AB - PURPOSE: Malignant melanoma has become a major growing interdisciplinary problem in public health worldwide. Sentinel lymph node excision (SLNE) in conjunction with preoperative SPECT/CT is considered the most sensitive and specific staging test for the detection of micrometastatic melanoma in regional lymph nodes. Among patients with clinically lymph node-negative melanoma, the use of SPECT/CT-aided SLNE compared with SLNE alone has been found to be associated with a higher frequency of metastatic involvement and a higher rate of disease-free survival. The aim of this study was to analyse the cost-effectiveness of SLNE with preoperative SPECT/CT for detecting sentinel lymph nodes versus that of standard SLNE with preoperative lymphoscintigraphy from a single-institution database. METHODS: Cost-effectiveness analysis of two surgical approaches for SLNE for malignant melanoma at the University Hospital Essen, Skin Cancer Center in Essen, Germany. Between March 2003 and April 2011 464 patients eligible for SLNE were identified . Of these patients, 403 with clinically negative lymph nodes who underwent SLNE with or without preoperative SPECT/CT qualified for subsequent analysis. RESULTS: Between March 2003 and October 2008, 254 patients were operated upon with the standard technique. From November 2008, 149 patients underwent the SPECT/CT technique. Cost analysis showed a mean cost saving of 710.50 when SPECT/CT was added to preoperative imaging. This was achieved by a reduction in operative time (median, Q1;Q3, 40 min, 40;50 min, vs. 45 min, 35;60 min; p = 0.002), hospital stay duration (5 days, 3;8 days, vs. 8 days, 4.5;14.5 days; p < 0.001) and more frequent use of local anaesthesia (90.6 % vs. 70.5 %; p < 0.001). The median cost of SLNE using SPECT/CT was 1,619.7 (Q1;Q3 1,317.0;2,603.4) and of SLNE without SPECT/CT was 2,330.2 ( 1,468.3;4,058.1; p < 0.001), a cost saving of 30.5 %. CONCLUSION: In patients with cutaneous melanoma, the use of preoperative SPECT/CT-aided SLNE compared with standard SLNE was associated not only with higher detection of metastatic involvement but also with a significant cost reduction. PMID- 24764037 TI - Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AB - Immunogenicity is a significant concern for biologic drugs as it can affect both safety and efficacy. To date, the descriptions of product immunogenicity have varied not only due to different degrees of understanding of product immunogenicity at the time of licensing but also due to an evolving lexicon that has generated some confusion in the field. In recent years, there has been growing consensus regarding the data needed to assess product immunogenicity. Harmonization of the strategy for the elucidation of product immunogenicity by drug developers, as well as the use of defined common terminology, can benefit medical practitioners, health regulatory agencies, and ultimately the patients. Clearly, understanding the incidence, kinetics and magnitude of anti-drug antibody (ADA), its neutralizing ability, cross-reactivity with endogenous molecules or other marketed biologic drugs, and related clinical impact may enhance clinical management of patients treated with biologic drugs. To that end, the authors present terms and definitions for describing and analyzing clinical immunogenicity data and suggest approaches to data presentation, emphasizing associations of ADA development with pharmacokinetics, efficacy, and safety that are necessary to assess the clinical relevance of immunogenicity. PMID- 24764038 TI - A novel spectral-domain optical coherence tomography model to estimate changes in vitreomacular traction syndrome. AB - PURPOSE: To analyze the course of eyes with vitreomacular traction (VMT), and to find by optical coherence tomography (OCT) possible correlations between vitreomacular interface area changes and the chance of spontaneous VMT resolution. METHODS: Retrospective analysis of all consecutive patients presenting with VMT over a 24-month period. We introduced a novel OCT evaluation model to assess the vitreomacular interface area. Central foveal thickness (CFT) and best-corrected visual acuity (BCVA) were also analyzed throughout follow-up. RESULTS: Twenty-six eyes of 18 symptomatic patients were followed for 12.9 +/- 4.8 months. Eyes were subdivided into groups according to their clinical course. Six eyes (23%) had a spontaneous resolution of the VMT (group A), and the interface area before its occurrence (39565 +/- 26409 MUm(2)) was smaller than at study entry (99434 +/- 38819 MUm(2); p = 0.03). The interface area did not significantly change throughout follow-up in the group that underwent surgery (group B, 11 eyes) and in the group that remained overall stable (group C, 9 eyes). At baseline, the interface area was smaller in group A compared to groups with non-resolved VMT (mean values of group B and C together) (785095 +/- 920721 MUm(2); p = 0.002). CFT and BCVA did not significantly change in any of the studied groups. Vitreomacular interface area of 101002 MUm(2) was identified as the threshold value separating the spontaneous VMT resolution group from the group with non-resolved VMT (p < 0.001). CONCLUSIONS: The more the vitreomacular interface area reduced over time, the higher was the chance of spontaneous VMT resolution. An area below 101002 MUm(2) was the threshold value indicating a higher chance of spontaneous release of VMT. PMID- 24764040 TI - Force and conductance molecular break junctions with time series crosscorrelation. AB - Force and conductance, measured across 4,4'-bipyridine simultaneously, are crosscorrelated using a two dimensional (2D) histogram method. The result is a 2D multivariate statistical analysis superior to current one dimensional histogram techniques for exploring significant conductance and force modulations within SMBJs. This method is sensitive enough to crosscorrelate signal modulations between force and conductance traces associated with contact geometry perturbations predicted in literature such as Au-molecule contact twisting and slipping during junction elongation. PMID- 24764039 TI - Modeling deficits in attention, inhibition, and flexibility in HAND. AB - Nearly half of all HIV-1-positive individuals on combination antiretroviral therapy (cART) are afflicted with HIV-1-associated neurocognitive disorders (HAND). The most prevalent cognitive deficits observed in the cART era are those of attention and executive function. Presently, we sought to model deficits in attention and core components of executive function (inhibition, flexibility, and set-shifting) observed in HAND using the HIV-1 transgenic (Tg) rat, which expresses 7 of the 9 HIV-1 genes. Ovariectomized female Fischer HIV-1 Tg and non transgenic control rats (ns = 39-43) were tested in a series of operant tasks: signal detection, discrimination learning, reversal learning, and extradimensional set-shifting. The HIV-1 Tg animals attained the criterion of three sessions at 70% accuracy at a significantly slower rate than the control animals on all tasks with the exception of the extradimensional set-shifting task. Of the animals that met the criteria, there was no significant difference in percent accuracy in any task. However, the HIV-1 Tg rats showed a lower overall response rate in signal detection and discrimination learning. A discriminant function analysis classified the animals by genotype with 90.4% accuracy based on select measures of their performance. The functional consequences of chronic low-level expression of the HIV-1 proteins on attention, as well as inhibition and flexibility as core components of executive function, are apparent under conditions which resemble the brain proinflammatory immune responses and suppression of infection in HIV-1+ individuals under cART. Deficits in attention and core components of executive function may reflect an underlying impairment in temporal processing in HAND. PMID- 24764044 TI - Survival of bone marrow mesenchymal stem cells labelled with red fluorescent protein in an ovine model of collagenase-induced tendinitis. AB - OBJECTIVE: The aim of this study was to track the survival and efficacy of allogeneic bone marrow mesenchymal stem cells (BM-MSC) marked with red fluorescent protein (BM-MSCRFP) in an ovine model of collagenase-induced tendinopathy. METHODS: Bone marrow was harvested from one donor sheep and BM-MSC were isolated, cultivated and transfected with red fluorescent protein (BM MSCRFP). Collagenase was injected into both Achilles tendons in the remaining nine sheep. After two weeks the left tendon was injected with a solution of 6 x 106 BM-MSCRFP and fibrin glue, while only fibrin glue was administered to the contra-lateral tendon in each sheep. After three, four and six weeks the tendons were harvested and evaluated for morphology, collagen I deposition, presence of CD34+ cells, and fluorescent labelled BM-MSC. RESULTS: We demonstrated that delivery of BM-MSC into tendon lesions had positive effects on the injured tendons. The BM-MSCRFP survived at three, four and six weeks after treatment, leading to better quality healing of tendons as compared to the controls, where no labelled cells were detected. Interestingly, we demonstrated high expression of CD34+ cells in tendons that had been treated with BM-MSCRFP. CLINICAL RELEVANCE: Mesenchymal stem cell allografts have a positive effect on tendon healing and local injection of BM-MSC directly into the tendon allows the homing of BM-MSC for good efficiency of engraftment. PMID- 24764045 TI - Augmented mixed beta regression models for periodontal proportion data. AB - Continuous (clustered) proportion data often arise in various domains of medicine and public health where the response variable of interest is a proportion (or percentage) quantifying disease status for the cluster units, ranging between zero and one. However, because of the presence of relatively disease-free as well as heavily diseased subjects in any study, the proportion values can lie in the interval [0,1]. While beta regression can be adapted to assess covariate effects in these situations, its versatility is often challenged because of the presence/excess of zeros and ones because the beta support lies in the interval (0,1). To circumvent this, we augment the probabilities of zero and one with the beta density, controlling for the clustering effect. Our approach is Bayesian with the ability to borrow information across various stages of the complex model hierarchy and produces a computationally convenient framework amenable to available freeware. The marginal likelihood is tractable and can be used to develop Bayesian case-deletion influence diagnostics based on q-divergence measures. Both simulation studies and application to a real dataset from a clinical periodontology study quantify the gain in model fit and parameter estimation over other ad hoc alternatives and provide quantitative insight into assessing the true covariate effects on the proportion responses. PMID- 24764046 TI - What is the mechanism behind increased permeation rate of a poorly soluble drug from aqueous dispersions of an amorphous solid dispersion? AB - Our aim was to explore the influence of micelles and microparticles emerging in aqueous dispersions of amorphous solid dispersions (ASDs) on molecular/apparent solubility and Caco-2 permeation. The ASD, prepared by hot-melt extrusion, contained the poorly soluble model drug ABT-102, a hydrophilic polymer, and three surfactants. Aqueous dispersions of the ASD were investigated at two concentrations, one above and one close to the critical micelle concentration of the surfactants blend in the extrudate. Micelles were detected at the higher concentration and no micelles at the lower concentration. Apparent solubility of ABT-102 was 20-fold higher in concentrated than in diluted dispersions, because of micelles. In contrast, Caco-2 permeation of ABT-102 was independent of the ASD concentration, but three times faster than that of crystalline suspensions. Molecular solubility of ABT-102 (equilibrium dialysis) was also independent of the ASD concentration, but by a factor 2 higher than crystalline ABT-102. The total amount of ABT-102 accumulated in the acceptor during Caco-2 experiments exceeded the initial amount of molecularly dissolved drug in the donor. This may indicate that dissolution of amorphous microparticles present in aqueous dispersions induces lasting supersaturation maintaining enhanced permeation. The hypothesis is supported by a slower drug permeation when the microparticles were removed. PMID- 24764047 TI - Preparation of new amphiphilic macroporous nonwoven polymeric adsorbents aimed for selective removal of low-density lipoprotein from plasma. AB - In the present work, new amphiphilic macroporous polymeric adsorbent (AMPA) membranes for LDL-apheresis were prepared by (60)Co gamma-ray irradiation-induced grafting copolymerization of polypropylene (PP) nonwoven fabric with acrylic acid, followed by bonding cholesterol through linkers of different length. The new AMPA membranes were characterized by attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscope (SEM), and contact angle microscopy. Static adsorption and hemo-perfusion tests show these new adsorbents could efficiently remove LDL from human plasma. Meanwhile, the AMPA displayed good adsorption capacity for triglyceride (TG) as well. The static adsorption performance of the AMPA membranes depends on the length of linker. In addition, a balance between the amount of bonded cholesterol and remaining carboxyl group was found necessary to reach the optimal adsorption performance. The best result was achieved by the AMPA membrane PA15C6-3, by which 62.8 +/- 3.8 MUg of LDL-C, 16.5 +/- 0.71 MUg of HDL-C, 132.4 +/- 3.0 MUg of TG are removed from human plasma per square centimeter. PMID- 24764048 TI - Stereospecific formal [3+2] dipolar cycloaddition of cyclopropanes with nitrosoarenes: an approach to isoxazolidines. AB - The MgBr2-catalyzed formal [3+2] cycloaddition of donor-acceptor activated cyclopropanes with nitrosoarenes offers a novel approach to various structurally diverse isoxazolidines. The reactions, which are experimentally easy to conduct, occur with complete stereospecificity and perfect control of regioselectivity. Product isoxazolidines can be readily transformed into alpha-amino lactones by reductive or decarboxylative N-O cleavage and subsequent lactonisation, and the N aryl bond cleavage is also possible under oxidative conditions. PMID- 24764049 TI - Electrochemistry of orthosilicate-based lithium battery cathodes: a perspective. AB - Lithium metal orthosilicates are attracting a lot of attention owing to their promising prospects as potential high capacity cathode materials for Li-ion batteries. Currently, great efforts are being made in order to achieve the full theoretical specific capacity of 330 mA h g(-1), but many issues remain unsolved (e.g., poor structural and cycling stability), which limit their practical application. The present perspective highlights the importance of assessing the electrochemical behaviour of Li2(Fe,Mn)SiO4 by combining an arsenal of characterization techniques both spectroscopic and structural, in and ex situ. Here, we review the most recent achievements in the investigation of the electrochemical performance of lithium metal orthosilicate cathodes and, through some of our recent results, we attempt to clarify the relationship between the structure and electrochemistry of these compounds. PMID- 24764050 TI - A biomechanical comparison of fixed angle locking compression plate osteosynthesis and cement augmented screw osteosynthesis in the management of intra articular calcaneal fractures. AB - PURPOSE: The purpose of this study was to investigate whether cement-augmented screw osteosynthesis results in stability comparable to conventional fixed-angle locking plate osteosynthesis using cadaveric bones to model a Sanders type 2B fracture. METHODS: Seven pairs of fresh frozen human calcanei and the corresponding tali were used. The specimens were assigned pairwise to two study groups in a randomised manner. In order to determine the initial quasi-static stiffness of the bone-implant construct, testing commenced with quasi-static compression ramp loading; subsequently, sinusoidal cyclic compression loading at 2 Hz was performed until construct failure occurred. Initial dynamic stiffness (cycle 1), range of motion (ROM), cycles to failure and load to failure were determined from the machine data during the cyclic test. In addition, at 250 cycle intervals, Bohler's angle and the critical angle of Gissane were determined on mediolateral X-rays shot with a triggered C-arm; 5 degrees angle flattening was arbitrarily defined as a failure criterion. RESULTS: Bone mineral density was normally distributed without significant differences between the groups. The augmented screw osteosynthesis resulted in higher stiffness values compared to the fixed-angle locking plate osteosynthesis. The fracture fragment motion in the locking plate group was significantly higher compared to the group with augmented screw osteosynthesis. CONCLUSIONS: The results of this study indicate that in our selected test set-up augmented screw osteosynthesis was significantly superior to the conventional fixed-angle locking plate osteosynthesis with respect to primary stability and ROM during cyclic testing. PMID- 24764051 TI - Power and trust in organizational relations: an empirical study in Turkish public hospitals. AB - Given the salience of the interplay between trust and power relations in organizational settings, this paper examines the perceptions of social power and its effects on trust in supervisors within the context of public hospitals. Following the theoretical background from which the study model is developed, the recent situation of hospitals within Turkish healthcare system is discussed to further elucidate the working conditions of physicians. Sample data were collected employing a structured questionnaire that was distributed to physicians working at seven different public hospitals. The statistical analyses indicate that perceptions of supervisors' social power affect subordinates' trust in supervisors. Although coercive power is found to have the greatest impact on trust in supervisors, the influence of the power base is weak. In addition, the results show that perceptions of social power differ between genders. However, the results do not support any of the hypotheses regarding the relations between trust in supervisors and the examined demographic variables. PMID- 24764052 TI - Comparison of Erbium:YAG and Carbon Dioxide Laser for the Treatment of Facial Rhytides. PMID- 24764053 TI - A generalized papular eruption. PMID- 24764054 TI - Amounts of artificial food dyes and added sugars in foods and sweets commonly consumed by children. AB - Artificial food colors (AFCs) are used to color many beverages, foods, and sweets in the United States and throughout the world. In the United States, the Food and Drug Administration (FDA) limits the AFCs allowed in the diet to 9 different colors. The FDA certifies each batch of manufactured AFCs to guarantee purity and safety. The amount certified has risen from 12 mg/capita/d in 1950 to 62 mg/capita/d in 2010. Previously, we reported the amounts of AFCs in commonly consumed beverages. In this article, the amounts of AFCs in commonly consumed foods and sweets are reported. In addition, the amount of sugars in each product is included. Amounts of AFCs reported here along with the beverage data show that many children could be consuming far more dyes than previously thought. Clinical guidance is given to help caregivers avoid AFCs and reduce the amount of sugars in children's diets. PMID- 24764055 TI - Imported pediatric malaria. PMID- 24764056 TI - Electrically controlled eight-spin-qubit entangled-state generation in a molecular break junction. AB - The generation of spin-based multi-qubit entangled states in the presence of an electric field is one of the most challenging tasks in current quantum-computing research. Such examples are still elusive. By using non-equilibrium Green's function-based quantum-transport calculations in combination with non-collinear spin density functional theory, we report that an eight-spin-qubit entangled state can be generated with the high-spin state of a dinuclear Fe(II) complex when the system is placed in a molecular break junction. The possible gate operation scheme, gating time, and decoherence issues have been carefully addressed. Furthermore, our calculations reveal that the preservation of the high spin state of this complex is possible if the experimentalists keep the electric field strength below 0.78 V nm(-1). In brief, the present study offers a unique way to realize the first example of a multi-qubit entangled state by electrical means only. PMID- 24764057 TI - Are dyslexic children sensitive to the morphological structure of words when they read? The case of dyslexic readers of French. AB - Typically, research has cited a deficient use of word recognition procedures mainly caused by a phonological deficit as the source of dyslexic students' reading difficulties. However, recent studies have shown that morphological processing also plays an important part in reading. In the present study, sensitivity to the morphological structure of words was assessed with a plausibility judgment task, where participants determined which of two pseudo words most resembled a real word in French, and with a decomposition task requiring participants to extract the base forms of morphologically complex words. Dyslexic participants (DYS, n = 26) aged 9-12 years were matched to 26 participants of the same chronological age (CA) and 30 younger participants of the same reading age (RA). Overall, the decomposition task was less successful at demonstrating morphological knowledge than the plausibility judgment task. Results indicate that dyslexic participants demonstrated some morphological sensitivity, particularly on the plausibility task, but were outperformed by both control groups on both tasks. Performance on morphological tasks was significantly correlated to reading comprehension scores. More research needs to be carried out to better comprehend the effects of task characteristics on dyslexic participants' success and before claiming a different or deviant developmental path for morphological knowledge. PMID- 24764058 TI - Morphometric stability of the corneal subbasal nerve plexus in healthy individuals: a 3-year longitudinal study using corneal confocal microscopy. AB - PURPOSE: We examined the age-dependent alterations and longitudinal course of subbasal nerve plexus (SNP) morphology in healthy individuals. METHODS: Laser scanning corneal confocal microscopy, ocular screening, and health and metabolic assessment were performed on 64 healthy participants at baseline and at 12-month intervals for 3 years. At each annual visit, eight central corneal images of the SNP were selected and analyzed using a fully-automated analysis system to quantify corneal nerve fiber length (CNFL). Two linear mixed model approaches were fitted to examine the relationship between age and CNFL, and the longitudinal changes of CNFL over three years. RESULTS: At baseline, mean age was 51.9 +/- 14.7 years. The cohort was sex balanced (chi(2) = 0.56, P = 0.45). Age (t = 1.6, P = 0.12) and CNFL (t = -0.50, P = 0.62) did not differ between sexes. A total of 52 participants completed the 36-month visit and 49 participants completed all visits. Age had a significant effect on CNFL (F[1,33] = 5.67, P = 0.02) with a linear decrease of 0.05 mm/mm(2) in CNFL per one year increase in age. No significant change in CNFL was observed over the 36-month period (F[1,55] = 0.69, P = 0.41). CONCLUSIONS: The CNFL showed a stable course over a 36-month period in healthy individuals, although there was a slight linear reduction in CNFL with age. The findings of this study have implications for understanding the time-course of the effect of pathology and surgical or therapeutic interventions on the morphology of the SNP, and serves to confirm the suitability of CNFL as a screening/monitoring marker for peripheral neuropathies. PMID- 24764059 TI - Correlation between disease severity and presence of ocular autoantibodies in juvenile idiopathic arthritis-associated uveitis. AB - PURPOSE: The pathogenesis of juvenile idiopathic arthritis-associated uveitis (JIAU) is undefined. This study intended to analyze the presence of antiocular autoantibodies in serum and their correlation with disease course. METHODS: Serum samples from children with JIAU (n = 47); JIA without uveitis (n = 67); idiopathic anterior uveitis (IAU; n = 12); and healthy controls (n = 52) were collected. The binding patterns of serum antibodies to ocular cryosections from swine eyes were analyzed by indirect immunohistochemistry, and were correlated to epidemiological, clinical, and laboratory test results. RESULTS: The patient groups differed with respect to their presence of antibody binding to the sections: JIAU (94%), JIA (75%), IAU (75%), and healthy controls (29%) to uveal and/or retinal structures. Serum antibodies of JIAU patients predominantly bound at iris (74%), and ciliary body (79%). Iris/ciliary body positive staining correlated with the presence of uveitis complications (P < 0.005) in JIAU patients, but not with positivity of serum antinuclear antibodies (ANA), rheumatoid factor (RF), or HLA-B27, and was independent from uveitis activity or type of anti-inflammatory therapy. CONCLUSIONS: In JIAU patients, antiocular serum antibodies can be detected more frequently than in control groups. Binding patterns to ocular tissue correlate with complicated uveitis course but not with uveitis activity and anti-inflammatory treatment. Antibody binding is not specific for this uveitis entity, and does not correlate with ANA positivity. PMID- 24764060 TI - Gene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins. AB - PURPOSE: Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness. METHODS: Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays. RESULTS: We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P < 10(-11)). In the Indian cohort CNVs > 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9 fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls. CONCLUSIONS: To our knowledge, our study is the first report on large CNV bias for gene-rich regions in glaucomatous neurodegeneration, implicating its impact across populations of contrasting ethnicities. We identified CNTN4 as a novel candidate gene for POAG. PMID- 24764061 TI - A novel OCT technique to measure in vivo the corneal adhesiveness for sodium carboxymethylcellulose in humans and its validity in the diagnosis of dry eye. AB - PURPOSE: The purpose of this work was to gather preliminary data on tear film stability, and the adhesive properties of the corneal surface in dry eye patients and control group subjects, using a new, minimally invasive optical coherence tomography (OCT) imaging method. METHODS: We screened 85 human subjects for dry eye and classified them in two groups, as dry eye or normal patients. Sodium carboxymethylcellulose (NaCMC) adhesiveness over the central cornea was measured using Fourier domain anterior segment OCT. The corneal adhesiveness for NaCMC was compared between the two groups, correlated with classical tests, and analyzed for diagnostic validity and repeatability. RESULTS: The corneal adhesiveness for NaCMC median and mode values was fair (between 1 and 3 minutes) for dry eye subjects (n = 36) and borderline (between 3 and 5 minutes) for control group subjects (n = 49), and was significantly different between the two groups (P < 0.001). Significant correlations were observed between the corneal adhesiveness measures and dry eye patients' symptoms (P < 0.001), Schirmer I test (P < 0.001), ocular surface staining (P < 0.001), and, particularly, fluorescein break-up time (P < 0.001). The area under the receiver operating characteristic curve was 0.94 (P < 0.001), suggesting reliable sensitivity and specificity of OCT imaging. A statistically significant intraclass correlation (ICC) value of 0.99 was found for measurements of corneal adhesiveness on two subsequent days at the same time (P < 0.001). CONCLUSIONS: This minimally invasive, novel technique of OCT imaging of the corneal surface following NaCMC drop instillation provides a measure of corneal adhesiveness. This technique may improve the clinician's ability in the understanding and diagnosis of the dry eye syndrome. PMID- 24764062 TI - Evaluation of inner retinal layers in eyes with temporal hemianopic visual loss from chiasmal compression using optical coherence tomography. AB - PURPOSE: We measured macular inner retinal layer thicknesses using frequency domain optical coherence tomography (fd-OCT) and correlated these measures with visual field (VF) in eyes with temporal hemianopia from chiasmal compression and band atrophy (BA) of the optic nerve. METHODS: Macular fd-OCT scans and VFs were obtained from 33 eyes of 33 patients with temporal hemianopia and 36 control eyes. The macular retinal nerve fiber layer (mRNFL), combined retinal ganglion cell and inner plexiform layers (RGCL+), and the inner nuclear layer (INL) were segmented. Measurements were averaged for each macula quadrant. Scans were assessed qualitatively for microcysts in the INL. The VF was estimated from the central 16 test points. The two groups were compared. Correlations between VF and OCT measurements were assessed. RESULTS: The mRNFL, RGCL+, and total retinal (TR) macular thickness measurements were significantly smaller in BA eyes than controls. In the nasal quadrants, INL measurements were significantly greater in BA eyes than controls. The mRNFL and RGCL+ measurements had greater discrimination ability than TR measurements in the temporal quadrants. A significant correlation was found between most OCT parameters and their corresponding VF parameters. The strongest association was observed between RNFL and RGCL+ thickness, and VF loss in the corresponding area. The INL microcysts were found in seven eyes with BA, but not in controls. CONCLUSIONS: Band atrophy leads to mRNFL and RGCL+ thinning, and INL thickening, and mRNFL and RGCL+ measurements are correlated strongly with VF loss. Segmented macular thickness measurements may be useful for quantifying neuronal loss in chiasmal compression. PMID- 24764064 TI - Quantitative analysis of iris changes after physiologic and pharmacologic mydriasis in a rural Chinese population. AB - PURPOSE: To estimate and compare the change in iris cross-sectional area (IA) and iris volume (IV) following physiologic and pharmacologic pupil dilation in primary angle closure suspects (PACS) and normal subjects. METHODS: Anterior segment-optical coherence tomography (AS-OCT) measurements in light, dark, and following pharmacologic dilation were obtained on 186 PACS and 224 normal subjects examined during the 5-year follow-up of the Handan Eye Study. Iris cross sectional area, IV, and other biometric parameters calculated using the Zhongshan angle assessment program in the right eyes of all subjects were analyzed. RESULTS: The mean IA and IV decreased in dark compared with light and after pharmacologic dilation in both PACS and normal eyes. This change was statistically significant in normal eyes: light versus pharmacologic dilation for IA (P = 0.038) and for IV, both light versus dark (P = 0.031) and light versus pharmacologic dilation (P = 0.012). A longer axial length (P = 0.028) and a greater change in pupil diameter (PD) (P < 0.001) were associated with a larger decrease of IA for the light to dark comparison. A diagnosis of normal eyes (P = 0.011), larger PD in dark (P = 0.001), and a larger change in PD (P = 0.001) were associated with a larger decrease of IV from light to dark. CONCLUSIONS: The differences in iris behavior between PACS and normal rural Chinese subjects following physiologic or pharmacologic pupillary dilation may help provide insights into the pathogenesis of angle closure. PMID- 24764063 TI - Examination of VLC-PUFA-deficient photoreceptor terminals. AB - PURPOSE: Juvenile-onset autosomal dominant Stargardt-like macular dystrophy (STGD3) is caused by mutations in ELOVL4 (elongation of very long fatty acids-4), an elongase necessary for the biosynthesis of very long chain fatty acids (VLC FAs >= C26). Photoreceptors are enriched with VLC polyunsaturated fatty acids (VLC-PUFAs), which are necessary for long-term survival of rod photoreceptors. The purpose of these studies was to determine the effect of deletion of VLC-PUFAs on rod synaptic function in retinas of mice conditionally depleted (KO) of Elovl4. METHODS: Retina function was assessed in wild-type (WT) and KO by electroretinography. Outer plexiform structure was evaluated by immunofluorescence and transmission electron microscopy. Single-cell recordings measured rod ion channel operation and rod bipolar glutamate signaling. Sucrose gradient centrifugation was used to isolate synaptosomes from bovine retina. Proteins and lipids were analyzed by Western blotting and tandem mass spectroscopy, respectively. RESULTS: Inner retinal responses (b-wave, oscillatory potentials, and scotopic threshold responses) of the ERG were decreased in the KO mice compared to controls. However the rod ion channel operation and bipolar glutamate responses were comparable between groups. Biochemical analysis revealed that conventional and ribbon synapses have VLC-PUFAs. Ultrastructural analysis showed that the outer plexiform layer was disorganized and the diameter of vesicles in rod terminals was smaller in the KO mice. CONCLUSIONS: Very long chain PUFAs affect rod function by contributing to synaptic vesicle size, which may alter the dynamics of synaptic transmission, ultimately resulting in a loss of neuronal connectivity and death of rod photoreceptors. PMID- 24764065 TI - Natural involution of acute retinopathy of prematurity not requiring treatment: factors associated with the time course of involution. AB - PURPOSE: We identified the timing of natural involution of acute retinopathy of prematurity (ROP) not requiring treatment and determined the risk factors associated with delayed involution. METHODS: In this retrospective case series, 82 eyes (the more severe eye) of 82 infants who developed at least one clock hour of acute ROP, stages 1 through 3, but who didn't progress to type 1 ROP, were selected for analysis. The location, extent, and severity of ROP were documented by investigators during serial retinal examinations. The onset and completion of the ROP's involution were determined from a review of these data. Two groups were classified by the involution pattern: Group 1 included infants whose ROP disease involuted before 50 weeks of postmenstrual age, and Group 2 included infants whose ROP disease involuted over 50 weeks (delayed involution). A total of 14 possible risk factors was included in the logistic regression analysis to assess the relationship between each factor and the involution pattern. RESULTS: Acute ROP not requiring treatment began to involute at a mean of 40.4 weeks of postmenstrual age and finished at a mean of 50.6 weeks. Involution began at the same mean postmenstrual age for each zone of disease (P = 0.48) and finished earlier in zone III than in zone II (P < 0.01). An analysis by severity of ROP found that involution began the earliest with the mildest disease (stage 1; mean, 38.1 weeks) and latest with the most serious disease (stage 3; mean, 42.3 weeks; P < 0.01). Zone II disease took longer to finish involution (16.04 +/- 12.35 weeks) than zone III (8.30 +/- 7.3 weeks), and stage 3 (23.88 +/- 10.58 weeks) took longer to finish involution than stage 1 (2.03 +/- 0.96 weeks) and stage 2 disease (7.69 +/- 4.75 weeks, P < 0.01, respectively). No unfavorable outcome was found in our series. Multivariable logistic regression analysis showed that continuous positive airway pressure (CPAP, P < 0.0001), active stage 3 disease (P = 0.006), and anemia (P = 0.03) were significant risk factors associated with delayed involution. CONCLUSIONS: The natural involution of acute ROP not requiring treatment correlated better with severity than with ROP location. Active stage 3 disease, CPAP, and anemia were predictive risk factors for delayed involution of ROP. PMID- 24764066 TI - Comparative study of nJ- and MUJ-energy level femtosecond lasers: evaluation of flap adhesion strength, stromal bed quality, and tissue responses. AB - PURPOSE: To compare flap adhesion strength, stromal bed quality, and tissue responses after flap preparation using nJ- and MUJ-energy level femtosecond lasers. METHODS: All corneal flaps were created by either VisuMax laser (MUJ energy level) or femto-LDV (nJ-energy level). Flap adhesion strength in the rabbits was measured with a tension meter 1 and 2 months postoperatively. To investigate tissue responses to laser delivery, immunofluorescence staining and TUNEL assay were performed 4 and 24 hours postoperatively. To assess flap bed smoothness, human donor corneas were used. Surface irregularities were graded based on scanning electron microscopy results. RESULTS: The flap adhesion strength in the VisuMax group at month 1 and 2 was 16.95 +/- 1.45 kPa and 18.33 +/- 1.81 kPa, respectively; and 12.31 +/- 4.15 kPa and 13.85 +/- 4.78 kPa in the LDV group, respectively. No significant difference was found between the groups. Fibronectin and apoptotic cells were largely absent at the central incision site in the LDV group, but were present in the VisuMax group. The smoothness of flap beds appeared similar for both groups. An observer scored the VisuMax group 8.00 +/- 1.00 and the LDV group 7.33 +/- 0.58 (P = 0.387). CONCLUSIONS: The flap adhesion strength increased over time after treatment with both lasers. The nJ energy pulses produced minimal wound healing reaction and apoptotic cells along the incision plane. The application of an nJ-energy laser, which can incise the cornea without inducing significant damage to cells and wound healing reaction, offers great potential at reducing scarring following incisional laser stromal surgery. PMID- 24764068 TI - Audiovisual perception in adults with amblyopia: a study using the McGurk effect. AB - PURPOSE: The effects on multisensory integration have rarely been examined in amblyopia. The McGurk effect is a well-established audiovisual illusion that is manifested when an auditory phoneme is presented concurrently with an incongruent visual phoneme. Visually healthy viewers will hear a phoneme that does not match the actual auditory stimulus, having been perceptually influenced by the visual phoneme. This study examines audiovisual integration in adults with amblyopia. METHODS: Twenty-two subjects with amblyopia and 25 visually healthy controls participated. Participants viewed videos of combinations of visual and auditory phonemes, and were asked to report what they heard. Some videos had congruent video and audio (control), whereas others had incongruent video and audio (McGurk). The McGurk effect is strongest when the visual phoneme dominates over the audio phoneme, resulting in low auditory accuracy on the task. RESULTS: Adults with amblyopia demonstrated a weaker McGurk effect than visually healthy controls (P = 0.01). The difference was greatest when viewing monocularly with the amblyopic eye, and it was also evident when viewing binocularly or monocularly with the fellow eye. No correlations were found between the strength of the McGurk effect and either visual acuity or stereoacuity in subjects with amblyopia. Subjects with amblyopia and controls showed a similar response pattern to different speakers and syllables, and subjects with amblyopia consistently demonstrated a weaker effect than controls. CONCLUSIONS: Abnormal visual experience early in life can have negative consequences for audiovisual integration that persists into adulthood in people with amblyopia. PMID- 24764067 TI - In vivo assessment of aqueous humor dynamics upon chronic ocular hypertension and hypotensive drug treatment using gadolinium-enhanced MRI. AB - PURPOSE: Although glaucoma treatments alter aqueous humor (AH) dynamics to lower intraocular pressure, the regulatory mechanisms of AH circulation and their contributions to the pathogenesis of ocular hypertension and glaucoma remain unclear. We hypothesized that gadolinium-enhanced magnetic resonance imaging (Gd MRI) can visualize and assess AH dynamics upon sustained intraocular pressure elevation and pharmacologic interventions. METHODS: Gadolinium contrast agent was systemically administered to adult rats to mimic soluble AH components entering the anterior chamber (AC) via blood-aqueous barrier. Dynamic Gd-MRI was applied to examine the signal enhancement in AC and vitreous body upon microbead-induced ocular hypertension and unilateral topical applications of latanoprost, timolol maleate, and brimonidine tartrate to healthy eyes. RESULTS: Gadolinium signal time courses in microbead-induced hypertensive eyes possessed faster initial gadolinium uptake and higher peak signals in AC than control eyes, reflective of reduced gadolinium clearance upon microbead occlusion. Opposite trends were observed in latanoprost- and timolol-treated eyes, indicative of their respective drug actions on increased uveoscleral outflow and reduced AH production. The slowest initial gadolinium uptake but strongest peak signals were found in AC of both brimonidine-treated and untreated fellow eyes. These findings drew attention to the systemic effects of topical hypotensive drug treatment. Gadolinium leaked into the vitreous of microbead-induced hypertensive eyes and brimonidine-treated and untreated fellow eyes, suggestive of a compromise of aqueous-vitreous or blood-ocular barrier integrity. CONCLUSIONS: Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered AH dynamics and ocular tissue permeability for better understanding the physiological mechanisms of ocular hypertension and the efficacy of antiglaucoma drug treatments. PMID- 24764069 TI - Lysyl oxidase-like 2 level and glaucoma surgical outcomes. AB - PURPOSE: To evaluate the levels of TGF-beta and lysyl oxidases in both the aqueous humor and in Tenon's tissue in patients with POAG, and to assess their association with bleb morphological features and outcomes of glaucoma surgery. METHODS: Eighteen POAG patients scheduled to undergo glaucoma surgery and 17 healthy controls were enrolled. At the time of surgery, approximately 0.1 mL aqueous humor through an anterior chamber paracentesis and a 4 * 4-mm sample of Tenon's tissue were obtained. Concentrations of TGF-beta and lysyl oxidases (types 1 and 2) were analyzed by ELISA. The bleb morphologic features based on the Moorfields Bleb Grading System were evaluated by bleb photographs. RESULTS: The TGF-beta in Tenon's tissue and lysyl oxidase-like 2 in aqueous humor and in Tenon's tissue were significantly elevated in POAG patients. When POAG patients were divided by outcome 1 year after surgery, lysyl oxidase-like 2 protein was significantly higher in both aqueous humor and Tenon's tissue of the failure group. The level of lysyl oxidase-like 2 protein was significantly correlated with that of TGF-beta in the Tenon's tissue. Lysyl oxidase-like 2 level in the aqueous humor (r = 0.563, P < 0.001) and Tenon's tissue (r = 0.760, P < 0.001) had significantly negative correlation with bleb area. CONCLUSIONS: The TGF-beta and lysyl oxidase-like 2 levels at the time of surgery were significantly correlated with 1-year outcomes of glaucoma surgery. The level of lysyl oxidase like 2 was significantly correlated with that of TGF-beta, suggesting induction by TGF-beta. Modulation of lysyl oxidase-like 2 levels may have important applications in glaucoma surgery. PMID- 24764071 TI - Relationships between balance and cognition in patients with subjective cognitive impairment, mild cognitive impairment, and Alzheimer disease. AB - BACKGROUND: Balance impairments are common in patients with Alzheimer disease (AD), but which aspects of balance are affected, at which stage of cognitive impairment, and their associations with cognitive domains remain unexplored. OBJECTIVES: The aims of this study were: (1) to explore differences in balance abilities among patients with subjective cognitive impairment (SCI) or mild cognitive impairment (MCI), mild AD, and moderate AD and (2) to examine the relationship between the various aspects of balance and cognitive domains. DESIGN: This was a cross-sectional study. METHODS: Home-dwelling patients with SCI or MCI (n=33), mild AD (n=99), and moderate AD (n=38) participated in this study. The Balance Evaluation Systems Test (BESTest), comprising 6 subscales "Biomechanical Constraints," "Stability Limits/Verticality," "Anticipatory Postural Adjustments," "Postural Responses," "Sensory Orientation," and "Stability in Gait"-was used to assess balance. Cognitive domains were assessed using the following measures: Mini-Mental Status Examination, Word-List Learning Test from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Verbal Fluency Test, Clock Drawing Test, and Trail Making Test, parts A and B (TMT-A and TMT-B, respectively). Two-way between-group analyses of variance, adjusted for age, were used to analyze differences among the groups. Multiple linear regression analysis was used to explore the associations between balance and cognition. RESULTS: Differences were found between the groups on all BESTest subscales; the moderate AD group had the worst scores. The TMT-B (measuring executive function) was associated with all of the BESTest subscales after controlling for demographic factors. LIMITATIONS: The cross-sectional design hampered interpretation of the development of balance impairments. CONCLUSIONS: The study findings indicate that all aspects of balance control deteriorate with increasing severity of cognitive impairment and that executive function plays an important role in balance control. Physical therapists should pay attention to these findings both in clinical practice and in future research. PMID- 24764070 TI - Pain sensitivity subgroups in individuals with spine pain: potential relevance to short-term clinical outcome. AB - BACKGROUND: Cluster analysis can be used to identify individuals similar in profile based on response to multiple pain sensitivity measures. There are limited investigations into how empirically derived pain sensitivity subgroups influence clinical outcomes for individuals with spine pain. OBJECTIVE: The purposes of this study were: (1) to investigate empirically derived subgroups based on pressure and thermal pain sensitivity in individuals with spine pain and (2) to examine subgroup influence on 2-week clinical pain intensity and disability outcomes. DESIGN: A secondary analysis of data from 2 randomized trials was conducted. METHODS: Baseline and 2-week outcome data from 157 participants with low back pain (n=110) and neck pain (n=47) were examined. Participants completed demographic, psychological, and clinical information and were assessed using pain sensitivity protocols, including pressure (suprathreshold pressure pain) and thermal pain sensitivity (thermal heat threshold and tolerance, suprathreshold heat pain, temporal summation). A hierarchical agglomerative cluster analysis was used to create subgroups based on pain sensitivity responses. Differences in data for baseline variables, clinical pain intensity, and disability were examined. RESULTS: Three pain sensitivity cluster groups were derived: low pain sensitivity, high thermal static sensitivity, and high pressure and thermal dynamic sensitivity. There were differences in the proportion of individuals meeting a 30% change in pain intensity, where fewer individuals within the high pressure and thermal dynamic sensitivity group (adjusted odds ratio=0.3; 95% confidence interval=0.1, 0.8) achieved successful outcomes. LIMITATIONS: Only 2-week outcomes are reported. CONCLUSIONS: Distinct pain sensitivity cluster groups for individuals with spine pain were identified, with the high pressure and thermal dynamic sensitivity group showing worse clinical outcome for pain intensity. Future studies should aim to confirm these findings. PMID- 24764072 TI - How do somatosensory deficits in the arm and hand relate to upper limb impairment, activity, and participation problems after stroke? A systematic review. AB - BACKGROUND: The association between somatosensory impairments and outcome after stroke remains unclear. PURPOSE: The aim of this study was to systematically review the available literature on the relationship between somatosensory impairments in the upper limb and outcome after stroke. DATA SOURCES: The electronic databases PubMed, CINAHL, EMBASE, Cochrane Library, PsycINFO, and Web of Science were systematically searched from inception until July 2013. STUDY SELECTION: Studies were included if adult patients with stroke (minimum n=10) were examined with reliable and valid measures of somatosensation in the upper limb to investigate the relationship with upper limb impairment, activity, and participation measures. Exclusion criteria included measures of somatosensation involving an overall score for upper and lower limb outcome and articles including only lower limb outcomes. DATA EXTRACTION: Eligibility assessment, data extraction, and quality evaluation were completed by 2 independent reviewers. A cutoff score of >=65% of the maximal quality score was used for further inclusion in this review. DATA SYNTHESIS: Six articles met all inclusion criteria. Two point discrimination was shown to be predictive for upper limb dexterity, and somatosensory evoked potentials were shown to have predictive value in upper limb motor recovery. Proprioception was significantly correlated with perceived level of physical activity and social isolation and had some predictive value in functional movements of the upper limb. Finally, the combination of light touch and proprioception impairment was shown to be significantly related to upper limb motor recovery as well as handicap situations during activities of daily living. LIMITATIONS: Heterogeneity of the included studies warrants caution when interpreting results. CONCLUSIONS: Large variation in results was found due to heterogeneity of the studies. However, somatosensory deficits were shown to have an important role in upper limb motor and functional performance after stroke. PMID- 24764073 TI - AM-PAC "6-Clicks" functional assessment scores predict acute care hospital discharge destination. AB - BACKGROUND: Physical therapists and occupational therapists practicing in acute care hospitals play a crucial role in discharge planning. A standardized assessment of patients' function could be useful for discharge recommendations. OBJECTIVES: The study objective was to determine the accuracy of "6-Clicks" basic mobility and daily activity measures for predicting discharge from an acute care hospital to a home or institutional setting. DESIGN: The study was retrospective and observational. METHODS: "6-Clicks" scores obtained at initial visits by physical therapists or occupational therapists and patients' discharge destinations were used to develop and validate receiver operating characteristic curves for predicting discharge destination. Positive predictive values (PPV), negative predictive values (NPV), and likelihood ratios were calculated. RESULTS: Areas under the receiver operating characteristic curves for basic mobility scores were 0.857 (95% confidence interval [CI]=0.852, 0.862) and 0.855 (95% CI=0.850, 0.860) in development and validation samples, respectively. Areas under the curves for daily activity scores were 0.846 (95% CI=0.841, 0.851) and 0.845 (95% CI=0.840, 0.850) in development and validation samples, respectively. Cutoff scores providing the best accuracy for determining discharge destination were 42.9 for basic mobility and 39.4 for daily activity. For basic mobility, the PPV was 0.748 and the NPV was 0.801 in both development and validation samples. For daily activity, the PPVs were 0.787 and 0.784 and the NPVs were 0.748 and 0.746 in development and validation samples, respectively. LIMITATIONS: Limitations included lack of information on the rater reliability of "6-Clicks" instruments, use of surrogate data for some discharge designations, and use of a clinical database for research purposes. CONCLUSIONS: This study provides evidence of the accuracy of "6-Clicks" scores for predicting destination after discharge from an acute care hospital. PMID- 24764074 TI - Expression of Eph A4, Eph B2 and Eph B4 receptors in AML. AB - Eph receptors represent the largest subfamily of receptor tyrosine kinases (RTKs). The up- regulation of Eph receptors has been documented in various solid tumors, where it often correlates with poor prognosis. Their significance in hematologic malignancies is still unclear. This study aimed to investigate the expression of Eph A4, Eph B2, and Eph B4 mRNA in non - M3 AML patients and determine their prognostic significance. Bone marrow samples from 101 newly diagnosed non - M3 AML patients and 26 healthy controls for comparison were quantified by real time reverse transcriptase polymerase chain reaction (RT-PCR), and the comparative cycle threshold (Ct) method was used to determine their relative expression levels to GUS control gene. The results showed that expression of all selected Eph receptors was significantly lower in AML patients comparing to controls. It also differed according to FAB subtypes. The decreased expression levels of Eph A4 were associated with higher leukocytes (p = 0.022) and blast cell counts (p = 0.001), and unfavorable FLT3-ITD mutation. Our study revealed significant correlation between lower EphB2 expression levels, and higher complete remission rate (p = 0.009724) and longer overall survival. Additionally, we found that patients with shorter RFS had decreased EphB4 expression (p = 0.00). In conclusion, the results suggest the prognostic impact of decreased expression levels of some Eph receptors in AML patients. PMID- 24764075 TI - The primary cilium calcium channels and their role in flow sensing. AB - The primary cilium has been the focus of intense research since it was discovered that mutations in ciliary/basal body localized proteins give rise to a multitude of disorders. While these studies have revealed the contribution of this sensory organelle to multiple signalling pathways, little is known about how it actually mediates downstream events and why its loss causes disease states. Ciliopathies are linked to defects in either structure or function of cilia and are often associated with kidney cysts. The ciliopathy, autosomal dominant polycystic kidney disease (ADPKD), is caused by mutations to the PKD1 or PKD2 gene. The PKD gene products localize to the primary cilium, where they have been proposed to form a mechanosensory complex, sensitive to flow. Since mouse knockout models of Pkd1 or Pkd2 develop structurally normal cilia, it has been hypothesized that the loss of polycystins may lead to an impairment of flow sensing. Today, technically challenging patch clamp recordings of the primary cilium have become available, and the genetic relationship between polycystins (TRPPs) and the primary cilium has recently been dissected in detail. PMID- 24764076 TI - The Wnt/JNK signaling target gene alcam is required for embryonic kidney development. AB - Proper development of nephrons is essential for kidney function. beta-Catenin independent Wnt signaling through Fzd8, Inversin, Daam1, RhoA and Myosin is required for nephric tubule morphogenesis. Here, we provide a novel mechanism through which non-canonical Wnt signaling contributes to tubular development. Using Xenopus laevis as a model system, we found that the cell-adhesion molecule Alcam is required for proper nephrogenesis and functions downstream of Fzd3 during embryonic kidney development. We found alcam expression to be independent of Fzd8 or Inversin, but to be transcriptionally regulated by the beta-Catenin independent Wnt/JNK pathway involving ATF2 and Pax2 in a direct manner. These novel findings indicate that several branches of Wnt signaling are independently required for proximal tubule development. Moreover, our data indicate that regulation of morphogenesis by non-canonical Wnt ligands also involves direct transcriptional responses in addition to the effects on a post-translational level. PMID- 24764077 TI - Highly efficient targeted mutagenesis in axolotl using Cas9 RNA-guided nuclease. AB - Among tetrapods, only urodele salamanders, such as the axolotl Ambystoma mexicanum, can completely regenerate limbs as adults. The mystery of why salamanders, but not other animals, possess this ability has for generations captivated scientists seeking to induce this phenomenon in other vertebrates. Although many recent advances in molecular biology have allowed limb regeneration and tissue repair in the axolotl to be investigated in increasing detail, the molecular toolkit for the study of this process has been limited. Here, we report that the CRISPR-Cas9 RNA-guided nuclease system can efficiently create mutations at targeted sites within the axolotl genome. We identify individual animals treated with RNA-guided nucleases that have mutation frequencies close to 100% at targeted sites. We employ this technique to completely functionally ablate EGFP expression in transgenic animals and recapitulate developmental phenotypes produced by loss of the conserved gene brachyury. Thus, this advance allows a reverse genetic approach in the axolotl and will undoubtedly provide invaluable insight into the mechanisms of salamanders' unique regenerative ability. PMID- 24764078 TI - A dynamic cell adhesion surface regulates tissue architecture in growth plate cartilage. AB - The architecture and morphogenetic properties of tissues are founded in the tissue-specific regulation of cell behaviors. In endochondral bones, the growth plate cartilage promotes bone elongation via regulated chondrocyte maturation within an ordered, three-dimensional cell array. A key event in the process that generates this cell array is the transformation of disordered resting chondrocytes into clonal columns of discoid proliferative cells aligned with the primary growth vector. Previous analysis showed that column-forming chondrocytes display planar cell divisions, and the resulting daughter cells rearrange by ~90 degrees to align with the lengthening column. However, these previous studies provided limited information about the mechanisms underlying this dynamic process. Here we present new mechanistic insights generated by application of a novel time-lapse confocal microscopy method along with immunofluorescence and electron microscopy. We show that, during cell division, daughter chondrocytes establish a cell-cell adhesion surface enriched in cadherins and beta-catenin. Rearrangement into columns occurs concomitant with expansion of this adhesion surface in a process more similar to cell spreading than to migration. Column formation requires cell-cell adhesion, as reducing cadherin binding via chelation of extracellular calcium inhibits chondrocyte rearrangement. Importantly, physical indicators of cell polarity, such as cell body alignment, are not prerequisites for oriented cell behavior. Our results support a model in which regulation of adhesive surface dynamics and cortical tension by extrinsic signaling modifies the thermodynamic landscape to promote organization of daughter cells in the context of the three-dimensional growth plate tissue. PMID- 24764080 TI - The use of medical leeches for venous congestion. A review and case report. AB - The medicinal leech, Hirudo medicinalis, has been used for hundreds of years in human medicine for a variety of diseases, most recently including venous congestion following reconstructive surgeries (skin flaps and reimplantations), excessive lingual and periorbital swelling, and non-traditional treatments for osteoarthritis, compartment syndrome and sialoadenitis. The treatment of venous congestion in animals using leeches has been mentioned anecdotally, but the only published report pertains to the use of leeches in a cat suffering from polycythemia vera. We report the use of medical grade leeches in a one-year-old male castrated Domestic Shorthaired cat presenting with severe swelling of the paw after sustaining a constrictive injury from a bandage. The limb use had become compromised and the swelling was not responsive to compression bandages so leech therapy was instituted for four days and the swelling dramatically improved. The patient's limb use improved back to normal and the constrictive wound went on to heal without complication. The use of leeches in this case allowed for resolution of severe venous congestion and a full return to function in this patient with no continued skin loss. The mechanism of action of hirudotherapy for venous congestion is to allow for an alternative egress of pooled venous blood leading to a reduction in capillary pressure and increases in arterial reperfusion of capillary beds. The human and veterinary applications, method, and potential complications with hirudotherapy are discussed in this review. PMID- 24764081 TI - Electrodeposited polyethylenedioxythiophene with infiltrated gel electrolyte interface: a close contest of an all-solid-state supercapacitor with its liquid state counterpart. AB - We report the design of an all-solid-state supercapacitor, which has charge storage characteristics closely matching that of its liquid-state counterpart even under extreme temperature and humidity conditions. The prototype is made by electro-depositing polyethylenedioxythiophene (PEDOT) onto the individual carbon fibers of a porous carbon substrate followed by intercalating the matrix with polyvinyl alcohol-sulphuric acid (PVA-H2SO4) gel electrolyte. The electrodeposited layer of PEDOT maintained a flower-like growth pattern along the threads of each carbon fiber. This morphology and the alignment of PEDOT led to an enhanced surface area and electrical conductivity, and the pores in the system enabled effective intercalation of the polymer-gel electrolyte. Thus, the established electrode-electrolyte interface nearly mimics that of its counterpart based on the liquid electrolyte. Consequently, the solid device attained very low internal resistance (1.1 Omega cm(-2)) and a high specific capacitance (181 F g( 1)) for PEDOT at a discharge current density of 0.5 A g(-1). Even with a high areal capacitance of 836 mF cm(-2) and volumetric capacitance of 28 F cm(-3), the solid device retained a mass-specific capacitance of 111 F g(-1) for PEDOT. This is in close agreement with the value displayed by the corresponding liquid-state system (112 F g(-1)), which was fabricated by replacing the gel electrolyte with 0.5 M H2SO4. The device also showed excellent charge-discharge stability for 12 000 cycles at 5 A g(-1). The performance of the device was consistent even under wide-ranging humidity (30-80%) and temperature (-10 to 80 degrees C) conditions. Finally, a device fabricated by increasing the electrode area four times was used to light an LED, which validated the scalability of the process. PMID- 24764079 TI - Co-activation of microRNAs by Zelda is essential for early Drosophila development. AB - Transcription factors and microRNAs (miRNAs) are two important classes of trans regulators in differential gene expression. Transcription factors occupy cis regulatory motifs in DNA to activate or repress gene transcription, whereas miRNAs specifically pair with seed sites in target mRNAs to trigger mRNA decay or inhibit translation. Dynamic spatiotemporal expression patterns of transcription factors and miRNAs during development point to their stage- and tissue-specific functions. Recent studies have focused on miRNA functions during development; however, much remains to explore regarding how the expression of miRNAs is initiated and how dynamic miRNA expression patterns are achieved by transcriptional regulatory networks at different developmental stages. Here, we focused on the identification, regulation and function of miRNAs during the earliest stage of Drosophila development, when the maternal-to-zygotic transition (MZT) takes place. Eleven miRNA clusters comprise the first set of miRNAs activated in the blastoderm embryo. The transcriptional activator Zelda is required for their proper activation and regulation, and Zelda binding observed in genome-wide binding profiles is predictive of enhancer activity. In addition, other blastoderm transcription factors, comprising both activators and repressors, the activities of which are potentiated and coordinated by Zelda, contribute to the accurate temporal and spatial expression of these miRNAs, which are known to function in diverse developmental processes. Although previous genetic studies showed no early phenotypes upon loss of individual miRNAs, our analysis of the miR-1; miR-9a double mutant revealed defects in gastrulation, demonstrating the importance of co-activation of miRNAs by Zelda during the MZT. PMID- 24764082 TI - Dual-pore mesoporous carbon@silica composite core-shell nanospheres for multidrug delivery. AB - Monodispersed mesoporous phenolic polymer nanospheres with uniform diameters were prepared and used as the core for the further growth of core-shell mesoporous nanorattles. The hierarchical mesoporous nanospheres have a uniform diameter of 200 nm and dual-ordered mesopores of 3.1 and 5.8 nm. The hierarchical mesostructure and amphiphilicity of the hydrophobic carbon cores and hydrophilic silica shells lead to distinct benefits in multidrug combination therapy with cisplatin and paclitaxel for the treatment of human ovarian cancer, even drug resistant strains. PMID- 24764084 TI - The dynamics of growing islets and transmission of schistosomiasis japonica in the Yangtze River. AB - We formulate and analyze a system of ordinary differential equations for the transmission of schistosomiasis japonica on the islets in the Yangtze River, China. The impact of growing islets on the spread of schistosomiasis is investigated by the bifurcation analysis. Using the projection technique developed by Hassard, Kazarinoff and Wan, the normal form of the cusp bifurcation of codimension 2 is derived to overcome the technical difficulties in studying the existence, stability, and bifurcation of the multiple endemic equilibria in high-dimensional phase space. We show that the model can also undergo transcritical bifurcations, saddle-node bifurcations, a pitchfork bifurcation, and Hopf bifurcations. The bifurcation diagrams and epidemiological interpretations are given. We conclude that when the islet reaches a critical size, the transmission cycle of the schistosomiasis japonica between wild rats Rattus norvegicus and snails Oncomelania hupensis could be established, which serves as a possible source of schistosomiasis transmission along the Yangtze River. PMID- 24764083 TI - Impact of electrode design and surgical approach on scalar location and cochlear implant outcomes. AB - OBJECTIVES/HYPOTHESIS: Three surgical approaches: cochleostomy (C), round window (RW), and extended round window (ERW); and two electrodes types: lateral wall (LW) and perimodiolar (PM), account for the vast majority of cochlear implantations. The goal of this study was to analyze the relationship between surgical approach and electrode type with final intracochlear position of the electrode array and subsequent hearing outcomes. STUDY DESIGN: Comparative longitudinal study. METHODS: One hundred postlingually implanted adult patients were enrolled in the study. From the postoperative scan, intracochlear electrode location was determined and using rigid registration, transformed back to the preoperative computed tomography which had intracochlear anatomy (scala tympani and scala vestibuli) specified using a statistical shape model based on 10 microCT scans of human cadaveric cochleae. Likelihood ratio chi-square statistics were used to evaluate for differences in electrode placement with respect to surgical approach (C, RW, ERW) and type of electrode (LW, PM). RESULTS: Electrode placement completely within the scala tympani (ST) was more common for LW than were PM designs (89% vs. 58%; P < 0.001). RW and ERW approaches were associated with lower rates of electrode placement outside the ST than was the cochleostomy approach (9%, 16%, and 63%, respectively; P < 0.001). This pattern held true regardless of whether the implant was LW or PM. When examining electrode placement and hearing outcome, those with electrode residing completely within the ST had better consonant-nucleus-consonant word scores than did patients with any number of electrodes located outside the ST (P = 0.045). CONCLUSION: These data suggest that RW and ERW approaches and LW electrodes are associated with an increased likelihood of successful ST placement. Furthermore, electrode position entirely within the ST confers superior audiological outcomes. LEVEL OF EVIDENCE: 2b. PMID- 24764085 TI - Structure and general properties of flavins. AB - Flavins are a family of yellow-colored compounds with the basic structure of 7,8 dimethyl-10-alkylisoalloxazine. Riboflavin, commonly known as vitamin B2, is an essential component of living organisms and is the precursor of all biologically important flavins. In this chapter, the redox properties of flavins are described, with special emphasis in their ability to participate in both one electron and two-electron transfer processes; hence, flavins are indispensable mediators between two-electron and one-electron processes in biological systems. The photophysical and photochemical properties of flavins are also discussed. All oxidized flavins exhibit strong absorption in the ultraviolet and visible regions and an intense yellow-green fluorescence (in their neutral oxidized form). Flavins are thermostable compounds; however, they are photosensitive. In the absence of an external reductant, the isoalloxazine ring system undergoes intramolecular photoreduction. Some flavins are efficient photosensitizers; they can induce photomodifications of compounds that are not directly modified by visible light. PMID- 24764086 TI - Recent advances in riboflavin biosynthesis. AB - Riboflavin is biosynthesized from GTP and ribulose 5-phosphate. Whereas the early reactions conducing to 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione 5' phosphate show significant taxonomic variation, the subsequent reaction steps are universal in all taxonomic kingdoms. With the exception of a hitherto elusive phosphatase, all enzymes of the pathway have been characterized in some detail at the structural and mechanistic level. Some of the pathway enzymes (GTP cycloyhdrolase II, 3,4-dihydroxy-2-butanone 4-phosphate synthase, riboflavin synthase) have exceptionally complex reaction mechanisms. The commercial production of the vitamin is now entirely based on highly productive fermentation processes. Due to their absence in animals, the pathway enzymes are potential targets for the development of novel anti-infective drugs. PMID- 24764087 TI - Natural riboflavin analogs. AB - Riboflavin analogs have a good potential to serve as basic structures for the development of novel anti-infectives. Riboflavin analogs have multiple cellular targets, since riboflavin (as a precursor to flavin cofactors) is active at more than one site in the cell. As a result, the frequency of developing resistance to antimicrobials based on riboflavin analogs is expected to be significantly lower. The only known natural riboflavin analog with antibiotic function is roseoflavin from the bacterium Streptomyces davawensis. This antibiotic negatively affects flavoenzymes and FMN riboswitches. Another roseoflavin producer, Streptomyces cinnabarinus, was recently identified. Possibly, flavin analogs with antibiotic activity are more widespread than anticipated. The same could be true for flavin analogs yet to be discovered, which could constitute tools for cellular chemistry, thus allowing a further extension of the catalytic spectrum of flavoenzymes. PMID- 24764088 TI - A roadmap to the isotopolog space of flavocoenzymes. AB - Flavocoenzymes with selective or universal stable isotope labeling are important tools for the investigation of flavoproteins using a variety of spectroscopic methods. Numerous selectively labeled flavin isotopologs can be generated by the combined application of chemical synthesis and in vitro biotransformation using commercially available enzymes and/or recombinant riboflavin biosynthesis enzymes. Notably, the complex reaction sequences can be rapidly carried out using enzyme-assisted one-pot reaction strategies. PMID- 24764089 TI - Electron transferases. AB - The flavin isoalloxazine ring in electron transferases functions in a redox capacity, being able to take up electrons from a donor to subsequently deliver them to an acceptor. The main characteristics of these flavoproteins, including their unique ability to mediate obligatory processes of two-electron transfers with those involving single-electron transfer, are here described. To illustrate the versatility of these proteins, the acquired knowledge of the function of the two electron transferases involved in the cyanobacterial photosynthetic electron transfer from photosystem I to NADP(+) is presented. Many aspects of their biochemistry and biophysics have been extensively characterized using site directed mutagenesis, steady-state and transient kinetics, spectroscopy, calorimetry, X-ray crystallography, electron paramagnetic resonance, and computational methods. PMID- 24764090 TI - Aldonolactone oxidoreductases. AB - Vitamin C is a widely used vitamin. Here we review the occurrence and properties of aldonolactone oxidoreductases, an important group of flavoenzymes responsible for the ultimate production of vitamin C and its analogs in animals, plants, and single-cell organisms. PMID- 24764091 TI - Flavins and flavoproteins: applications in medicine. AB - The potential of flavoproteins as targets of pharmacological treatments is immense. In this review we present an overview of the current research progress on medical interventions based on flavoproteins with a special emphasis on cancer, infectious diseases, and neurological disorders. PMID- 24764092 TI - Practical aspects on the use of kinetic isotope effects as probes of flavoprotein enzyme mechanisms. AB - The measurement of kinetic isotope effects (KIEs) has proved useful in many mechanistic studies of enzyme activity, most notably in enzyme-catalyzed hydrogen transfer reactions. Primary KIEs (1 degrees KIE) greater than unity indicate that transfer of the hydrogen species of interest is partially or fully rate limiting, and studies of the magnitude of the temperature and pressure dependence of these KIEs can inform on the mechanism of transfer. For example, KIE measurements have proved crucial in understanding the role of quantum mechanical tunneling in enzyme systems. The measurement of secondary KIEs (2 degrees KIEs) is also informative and can be used to infer a significant tunneling contribution and details of transition state geometry. Here the deuterium label is introduced next to that of the transferred hydrogen. Measurements of 1 degrees and 2 degrees KIEs are being used increasingly in studies of H-transfer in flavoprotein enzymes and this requires the preparation of high purity and stereospecific labeled isotopologues. Strategies for the synthesis of labeled substrates are dependent on the enzyme system being studied. However, the nicotinamide coenzymes are often used in studies of flavoprotein enzyme mechanisms. Here, we provide practical details for the enzymatic synthesis of high purity deuterated isotopologues of the common biological coenzymes NADH and NADPH as well as the corresponding nonreactive mimics, tetrahydroNAD(P)H. Both forms of the coenzyme have proven useful in the study of mechanisms, particularly in relation to the involvement of quantum mechanical tunneling and dynamics in enzymatic H-transfer chemistry. The focus here is on practical considerations in the synthesis of these compounds. We also provide an abbreviated description of how measurements of KIEs can inform on flavoprotein mechanisms. The aim of this contribution is not to give a detailed description of the underlying theory (which has been reviewed extensively in the literature), but to provide a basic introduction and practical considerations for nonexpert readers who wish to incorporate such measurements in studies of enzyme mechanisms. PMID- 24764093 TI - On the in vivo redox state of flavin-containing photosensory receptor proteins. AB - Measured values of the redox midpoint potential of flavin-containing photoreceptor proteins range from physiologically very negative values, i.e., < 300 mV (compared to the calomel electrode) for some LOV domains, to slightly positive values for some cryptochromes. The actual intracellular redox potential of several key physiological electron-transfer intermediates, like the nicotinamide dinucleotides, particularly in chemoheterotrophic bacteria, may be varying beyond these two values, and are subject to physiological- and environmental regulation. The photochemical activity of photoreceptor proteins containing their flavin chromophore in the reduced, and in the fully oxidized form, is very different. We therefore have addressed the question whether or not the functioning of these flavin-containing photosensory receptors in vivo is subject to redox regulation. Here we (1) provide further evidence for the overlap of the ranges of the redox midpoint potential of the flavin in a specific photoreceptor protein and the redox potential of key intracellular redox-active metabolites, and (2) demonstrate that the redox state and photochemical activity of LOV domains can be recorded in vivo in Escherichia coli. Significantly, so far in vivo reduction of LOV domains under physiological conditions could not be detected. The implications of these observations are discussed. PMID- 24764094 TI - Computational spectroscopy, dynamics, and photochemistry of photosensory flavoproteins. AB - Extensive interest in photosensory proteins stimulated computational studies of flavins and flavoproteins in the past decade. This review is dedicated to the three central topics of these studies: calculations of flavin UV-visible and IR spectra, simulated dynamics of photoreceptor proteins, and flavin photochemistry. Accordingly, this chapter is divided into three parts; each part describes corresponding computational protocols, summarizes computational results, and discusses the emerging mechanistic picture. PMID- 24764095 TI - NMR spectroscopy on flavins and flavoproteins. AB - (1)H-, (11)B-, (13)C-, (15)N-, (17)O-, (19)F-, and (31)P-NMR chemical shifts of flavocoenzymes and derivatives of it, as well as of alloxazines and isoalloxazinium salts, from NMR experiments performed under various experimental conditions (e.g., dependence of the chemical shifts on temperature, concentration, solvent polarity, and pH) are reported. Also solid-state (13)C- and (15)N-NMR experiments are described revealing the anisotropic values of corresponding chemical shifts. These data, in combination with a number of coupling constants, led to a detailed description of the electronic structure of oxidized and reduced flavins. The data also demonstrate that the structure of oxidized flavin can assume a configuration deviating from coplanarity, depending on substitutions in the isoalloxazine ring, while that of reduced flavin exhibits several configurations, from almost planar to quite bended. The complexes formed between oxidized flavin and metal ions or organic molecules revealed three coordination sites with metal ions (depending on the chemical nature of the ion), and specific interactions between the pyrimidine moiety of flavin and organic molecules, mimicking specific interactions between apoflavoproteins and their coenzymes. Most NMR studies on flavoproteins were performed using (13)C- and (15)N-substituted coenzymes, either specifically enriched in the pterin moiety of flavin or uniformly labeled flavins. The chemical shifts of free flavins are used as a guide in the interpretation of the chemical shifts observed in flavoproteins. Although the hydrogen-bonding pattern in oxidized and reduced flavoproteins varies considerably, no correlation is obvious between these patterns and the corresponding redox potentials. In all reduced flavoproteins the N(1)H group of the flavocoenzyme is deprotonated, an exception is thioredoxin reductase. Three-dimensional structures of only a few flavoproteins, mostly belonging to the family of flavodoxins, have been solved. Also the kinetics of unfolding and refolding of flavodoxins has been investigated by NMR techniques. In addition, (31)P-NMR data of all so far studied flavoproteins and some (19)F NMR spectra are discussed. PMID- 24764096 TI - Solid-state NMR of flavins and flavoproteins. AB - Why apply solid-state NMR (SSNMR) to flavins and flavoproteins? NMR provides information on an atom-specific basis about chemical functionality, structure, proximity to other groups, and dynamics of the system. Thus, it has become indispensable to the study of chemicals, materials, catalysts, and biomolecules. It is no surprise then that NMR has a great deal to offer in the study of flavins and flavoenzymes. In general, their catalytic or electron-transfer activity resides essentially in the flavin, a molecule eminently accessible by NMR. However, the specific reactivity displayed depends on a host of subtle interactions whereby the protein biases and reshapes the flavin's propensities to activate it for one reaction while suppressing other aspects of this cofactor's prodigious repertoire (Massey et al., J Biol Chem 244:3999-4006, 1969; Muller, Z Naturforsch 27B:1023-1026, 1972; Joosten and van Berkel, Curr Opin Struct Biol 11:195-202, 2007). Thus, we are fascinated to learn about how the flavin cofactor of one enzyme is, and is not, like the flavin cofactor of another. In what follows, we describe how the capabilities of SSNMR can help and are beginning to bear fruit in this exciting endeavor. PMID- 24764097 TI - EPR on Flavoproteins. AB - Flavoproteins often employ radical mechanisms in their enzymatic reactions. This involves paramagnetic species, which can ideally be investigated with electron paramagnetic resonance (EPR) spectroscopy. In this chapter we focus on the example of flavin-based photoreceptors and discuss, how different EPR methods have been used to extract information about the flavin radical's electronic state, its binding pocket, electron-transfer pathways, and about the protein's tertiary and quaternary structure. PMID- 24764098 TI - FTIR spectroscopy of flavin-binding photoreceptors. AB - Light-induced difference Fourier transform infrared (FTIR) spectroscopy is a powerful, sensitive, and informative method to study structure-function relationships in photoreceptive proteins. Strong absorption of water in the IR region is always problematic in this method, but if water content in the sample is controlled during measurements, this method can provide useful information on a single protein-bound water molecule. We established three kinds of sample preparations: hydrated film, redissolved sample, and concentrated solution. Hydrated films were used for the measurements of LOV and BLUF domains, where accurate difference FTIR spectra were obtained in the whole mid-IR region (4,000 800 cm(-1)). Vibrations of S-H stretch of cysteine, O-H stretch of water, and O-H stretch of tyrosine provide important information on hydrogen bonds in these proteins. Redissolved samples were used for the measurements of (6-4) photolyase, in which enzymatic turnover takes place. From the illumination time-dependence of excess amount of substrate, it is possible to isolate the signal originating from the binding of enzyme to substrate. If proteins are less tolerant to drying, as for example cryptochromes of the DASH type, concentrated solution is used. Detailed methodological aspects in light-induced difference FTIR spectroscopy are reviewed by mainly focusing on our results. PMID- 24764099 TI - Resonance Raman spectroscopy. AB - Flavin is a general name given to molecules having the heteroaromatic ring system of 7,8-dimethylisoalloxazine but practically means riboflavin (Rfl), flavin adenine dinucleotide (FAD), and flavin mononucleotide (FMN) in biological systems, whose structures are illustrated in Fig. 1, together with the atomic numbering scheme and ring numbering of the isoalloxazine moiety. As the isoalloxazine skeleton cannot be synthesized in human cells, it is obtained from diet as Rfl (vitamin B2). FAD and FMN can act as cofactors in flavoenzymes but Rfl does not. Most flavoenzymes catalyze redox reactions of substrates (Miura, Chem Rec 1:183-194, 2001). When O2 serves as the oxidant in the oxidation half cycle of an enzymic reaction, the enzyme is called "flavo-oxidase" but when others do, the enzyme is called "flavo-dehydrogenase." The difference between the two types of oxidative catalysis arises from delicate differences in the pi electron distributions in the isoalloxazine ring, which can be revealed by Raman spectroscopy (Miura, Chem Rec 1:183-194, 2001). Since a flavin is an extremely versatile molecule, the scientific field including chemistry, biochemistry, and enzymology is collectively called "flavonology." It was found recently, however, that the flavin also acts as a chromophore to initiate light-induced DNA repair and signal transductions (Sancar, Chem Rev 103:2203-2237, 2003). PMID- 24764100 TI - Photoactivation mechanisms of flavin-binding photoreceptors revealed through ultrafast spectroscopy and global analysis methods. AB - Flavin-binding photoreceptor proteins use the isoalloxazine moiety of flavin cofactors to absorb light in the blue/UV-A wavelength region and subsequently translate it into biological information. The underlying photochemical reactions and protein structural dynamics are delicately tuned by the protein environment and represent fundamental reactions in biology and chemistry. Due to their photo switchable nature, these proteins can be studied efficiently with laser-flash induced transient absorption and emission spectroscopy with temporal precision down to the femtosecond time domain. Here, we describe the application of both visible and mid-IR ultrafast transient absorption and time-resolved fluorescence methods in combination with sophisticated global analysis procedures to elucidate the photochemistry and signal transduction of BLUF (Blue light receptors using FAD) and LOV (Light oxygen voltage) photoreceptor domains. PMID- 24764101 TI - A "how-to" guide to the stark spectroscopy of flavins and flavoproteins. AB - Flavins and flavoproteins have been studied by a plethora of spectroscopic techniques. Beginning with the characterization of DNA photolyases and the discovery of the diversity of roles played by excited-state flavins in photobiology, the characterization of the electronic excited state of flavins has become increasingly important. In this protocol, we provide a guide to using Stark spectroscopy in obtaining the degree of electronic charge redistribution in simple flavins and in flavoproteins. Stark spectroscopy is technically simpler than more common approaches used to explore the structure of the excited state, considerably cheaper to implement, and yet very powerful in its scope. At the end of this guide, we present data taken on non-photobiological flavoproteins, glutathione reductase and lipoamide dehydrogenase, that suggest that Stark spectroscopy is a unique way to elucidate the electrostatic environment that the flavin cofactor experiences bound inside the protein. PMID- 24764102 TI - Run, jump, and be merry: how much exercise is needed for building young bones? PMID- 24764103 TI - Prominent Howell-Jolly bodies when megaloblastic anemia develops in a hyposplenic patient. PMID- 24764105 TI - Breast implant capsule flaps and grafts: a review of the literature. AB - BACKGROUND: A breast implant capsule forms as a physiological response to the foreign material. Over the past decades, authors started to consider the breast implant capsule as a new source of tissue, thus describing several capsular flaps and grafts. The aim of this article is to provide an overview of the applications and indications for the use of capsular tissue flaps and grafts in reconstructive and aesthetic surgery. METHODS: A review of the literature on breast implant capsule grafts and flaps was conducted. The reported surgical techniques were described and compared for indications and complications. The studies were evaluated and compared for number of patients and follow-up. RESULTS: The search yielded a total of 21 citations. Patient population was reported in 11 studies for capsular flaps and 2 articles for capsular grafts. Between 1997 and 2012, a total of 74 patients underwent surgery with the use of capsular tissue. Among these, 60 patients had a capsular flap (81 %) and 14 (19 %) had a capsular graft. Complications were experienced in 5 patients (6.7 %). CONCLUSIONS: Capsular flaps and grafts are indicated mainly to address breast implant-related problems. The breast implant capsule represents a versatile and reliable source of tissue for both aesthetic and reconstructive surgery. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266. PMID- 24764106 TI - Autologous fat graft in postmastectomy pain syndrome following breast conservative surgery and radiotherapy. AB - BACKGROUND: Breast cancer is the most common cancer in women worldwide, affecting one in eight women. Breast-conserving surgery (BCS) has become a well-established alternative to mastectomy in the treatment of breast cancer, providing a less invasive treatment. Just as life expectancy after breast cancer has improved, so has morbidity increased. One of the most relevant and debilitating consequences of oncological breast surgery is postmastectomy pain syndrome (PMPS). Our results published in 2011 on the treatment of PMPS in patients who had undergone mastectomy and radiotherapy and our experience in scar treatment with fat grafts were the theoretical bases for this prospective study. METHODS: From April 2011 to April 2012 a total of 96 patients, who had undergone lumpectomy and radiation therapy, with the diagnosis of PMPS were considered for fat grafts. We performed autologous fat grafting in 59 patients (study group), whereas 37 patients did not receive any further surgical procedure (control group). Pain assessment was performed using the visual analog scale (VAS) before and after treatment in the treated group and in the control group at the first visit and the control visit, with a mean follow-up of 10 months. Results were analyzed using the Wilcoxon rank sum test. RESULTS: Four patients were lost to follow-up (two patients in the control group and two patients in the treated group). A significant VAS pain decrease was detected in patients treated with autologous fat grafting (3.1 point reduction, p <= 0.005). CONCLUSION: Because of the safety, efficacy, and optimal tolerability of the procedure, we believe that fat grafting can be considered useful in treating PMPS in patients who have undergone BCS and radiotherapy. LEVEL OF EVIDENCE III: For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24764107 TI - Chronic wound healing: clinical measurement and basic science. PMID- 24764104 TI - The effect of tumour necrosis factor-alpha and insulin on equine digital blood vessel function in vitro. AB - OBJECTIVE AND DESIGN: Insulin and inflammatory cytokines may be involved in equine laminitis, which might be associated with digital vascular dysfunction. This study determined the effects of TNF-alpha and insulin on the endothelial dependent relaxant responses of equine digital blood vessels and on equine digital vein endothelial cell (EDVEC) cGMP production. MATERIAL: Isolated rings of equine digital arteries (EDAs) and veins (EDVs) were obtained and EDVECs were cultured from horses euthanized at an abattoir. METHODS: The effect of incubation with TNF-alpha (10 ng/ml) and/or insulin (1,000 MUIU/ml) for 1.5 h or overnight under hyperoxic and hypoxic conditions on carbachol (endothelium-dependent) induced relaxation was assessed. The time course and concentration dependency of the effect of TNF-alpha and the effect of insulin (1,000 MUIU/ml) on EDVEC cGMP production was determined. RESULTS: Incubation of EDAs overnight with TNF-alpha under hypoxic conditions resulted in endothelial-dependent vascular dysfunction. EDVs produced a more variable response. TNF-alpha increased EDVEC cGMP formation in a time- and concentration-dependent manner. Insulin had no significant effects. CONCLUSIONS: There is a mismatch between the results obtained from isolated vessel rings and cultured endothelial cells suggesting TNF-alpha may reduce the biological effect of NO by reducing its bioavailability rather than its formation, leading to endothelial cell dysregulation. PMID- 24764108 TI - IgE Level and the Validation of the Diagnostic Criteria for Atopic Dermatitis. PMID- 24764109 TI - Nodule on the cheek of an 81-year-old woman. PMID- 24764110 TI - Disruptive chemical doping in a ferritin-based iron oxide nanoparticle to decrease r2 and enhance detection with T1-weighted MRI. AB - Inorganic doping was used to create flexible, paramagnetic nanoparticle contrast agents for in vivo molecular magnetic resonance imaging (MRI) with low transverse relaxivity (r2). Most nanoparticle contrast agents formed from superparamagnetic metal oxides are developed with high r2. While sensitive, they can have limited in vivo detection due to a number of constraints with T2 or T2*-weighted imaging. T1-weighted imaging is often preferred for molecular MRI, but most T1-shortening agents are small chelates with low metal payload or are nanoparticles that also shorten T2 and limit the range of concentrations detectable with T1-weighting. Here we used tungsten and iron deposition to form doped iron oxide crystals inside the apoferritin cavity to form a WFe nanoparticle with a disordered crystal and un-coupled atomic magnetic moments. The atomic magnetic moments were thus localized, resulting in a principally paramagnetic nanoparticle. The WFe nanoparticles had no coercivity or saturation magnetization at 5 K and sweeping up to +/- 20,000 Oe, while native ferritin had a coercivity of 3000 Oe and saturation at +/- 20,000 Oe. This tungsten-iron crystal paramagnetism resulted in an increased WFe particle longitudinal relaxivity (r1) of 4870 mm(-1) s(-1) and a reduced transverse relaxivity (r2) of 9076 mm(-1) s(-1) compared with native ferritin. The accumulation of the particles was detected with T1-weighted MRI in concentrations from 20 to 400 nm in vivo, both injected in the rat brain and targeted to the rat kidney glomerulus. The WFe apoferritin nanoparticles were not cytotoxic up to 700 nm particle concentrations, making them potentially important for targeted molecular MRI. PMID- 24764111 TI - Insight into the effect of boron doping on sulfur/carbon cathode in lithium sulfur batteries. AB - To exploit the high energy density of lithium-sulfur batteries, porous carbon materials have been widely used as the host materials of the S cathode. Current studies about carbon hosts are more frequently focused on the design of carbon structures rather than modification of its properties. In this study, we use boron-doped porous carbon materials as the host material of the S cathode to get an insightful investigation of the effect of B dopant on the S/C cathode. Powder electronic conductivity shows that the B-doped carbon materials exhibit higher conductivity than the pure analogous porous carbon. Moreover, by X-ray photoelectron spectroscopy, we prove that doping with B leads to a positively polarized surface of carbon substrates and allows chemisorption of S and its polysulfides. Thus, the B-doped carbons can ensure a more stable S/C cathode with satisfactory conductivity, which is demonstrated by the electrochemical performance evaluation. The S/B-doped carbon cathode was found to deliver much higher initial capacity (1300 mA h g(-1) at 0.25 C), improved cyclic stability, and rate capability when compared with the cathode based on pure porous carbon. Electrochemical impedance spectra also indicate the low resistance of the S/B doped C cathode and the chemisorption of polysulfide anions because of the presence of B. These features of B doping can play the positive role in the electrochemical performance of S cathodes and help to build better Li-S batteries. PMID- 24764112 TI - Fever, thoracic pain, skin lesions and Hampton hump. PMID- 24764113 TI - The first reference equations for the 6-minute walk distance over a 10 m course. AB - RATIONALE: As primary care practice space is mostly limited to 10 m, the 6-minute walk test (6MWT) over a 10 m course is a frequently used alternative to evaluate patients' performance in COPD. Considering that course length significantly affects distance walked in 6 minutes (6MWD), this study aims to develop appropriate reference equations for the 10 m 6MWT. METHODS: 181 healthy subjects, aged 40-90 years, performed two standardised 6MWTs over a straight 10 m course in a cross-sectional study. RESULTS: Average distance achieved was 578+/-108 m and differed between males and females (p<0.001). Resulting sex-specific reference equations from multiple regression analysis included age, body mass index and change in heart rate, explaining 62% of the variance in 6MWD for males and 71% for females. CONCLUSIONS: The presented reference equations are the first to evaluate 6MWD over a 10 m course and expand the usefulness of the 6MWT. PMID- 24764114 TI - Don't let radiation scare trump patient care: 10 ways you can harm your patients by fear of radiation-induced cancer from diagnostic imaging. PMID- 24764115 TI - Investigating and managing suspected pulmonary embolism in an outpatient setting: the Leicester experience. AB - Having established an ambulatory service for patients with suspected and proven PE, we reviewed our outcomes. All patients referred from June 2010 to May 2012 were analysed. Of 971 patients referred, 905 underwent complete assessment (66 admitted as ineligible). 754 (77.7%) patients were discharged and required no follow-up. 96 (10.6%) patients had PE confirmed of whom 70 (72.9%) were managed as outpatients. 14 (1.6%) patients have died since attending the clinic; no death was related to PE. This audit shows that ambulatory investigation and management of selected low risk patients with suspected PE is safe and reduces hospital admissions. PMID- 24764116 TI - A Belgian consensus-statement on growing-up milks for children 12-36 months old. AB - Growing-up milks (GUM) are milk-based drinks with low protein and added minerals and vitamins intended for children 12-36 months. Since the advantages of GUM are heavily debated, we reviewed the literature. A literature search was done using the classic databases (Pubmed, Embase, Cochrane) on the use of GUM in 12- to 36 month-old young children. Only limited data are available. GUM have a highly variable composition as their marketing is not regulated. Nevertheless, all papers conclude that GUM help to cover nutritional requirements of 12- to 36 month-old infants. CONCLUSION: Appropriate intakes of macro- and micronutrients in 1- to 3-year-old children have long-term health benefits. Present diets offered to toddlers do in general not meet the requirements. Supplemented foods are therefore helpful, of which GUM is a possibility. PMID- 24764117 TI - RTP801 regulates maneb- and mancozeb-induced cytotoxicity via NF-kappaB. AB - Environmental factors have been implicated in the pathogenesis of neurodegenerative diseases. Maneb (MB) and mancozeb (MZ) have been extensively used as pesticides. Exposure to MB lowers the threshold for dopaminergic damage triggered by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. MB and MZ potentiate 1 methyl-4-phenylpyridium (MPP(+))-induced cytotoxicity in rat pheochromocytoma (PC12) cells partially via nuclear factor kappa B (NF-kappaB) activation. RTP801 dramatically increased by oxidative stresses and DNA damage is the possible mechanism of neurotoxins-induced cell death in many studies. This study demonstrated that MB and MZ induced DNA damage as seen in comet assay. The expressions of RTP801 protein and mRNA were elevated after MB and MZ exposures. By knocking down RTP801 using shRNA, we demonstrated that NF-kappaB activation by MB and MZ was regulated by RTP801 and cell death triggered by MB and MZ was associated with RTP801 elevation. This revealed that the toxic mechanisms of dithiocarbamates are via the cross talk between RTP801 and NF-kappaB. PMID- 24764118 TI - Maternal age as a potential explanation of the role of the L allele of the serotonin transporter gene in anxiety and depression in Asians. PMID- 24764119 TI - Authors' response to "Maternal age as a potential explanation of the role of the L allele of the serotonin transporter gene in anxiety and depression in Asians". PMID- 24764120 TI - Is the Eichenholtz classification still valid for the diabetic Charcot foot? AB - In his 1966 monograph "Charcot joints", Sidney N. Eichenholtz (1909-2000) described "three well defined stages ... in the course and development of a Charcot joint", based on plain X-rays of 68 patients. Since then, medical imaging has advanced very much: computed tomography and magnetic resonance imaging (MRI) scans exceed plain X-ray by far in detecting foot fractures and other injuries. The earliest, nondeforming, X-ray-negative inflammatory stage of the acute Charcot joint of the diabetic foot can be visualised only by use of MRI. This stage, which Eichenholtz evidently failed to recognise, will heal without significant arthropathy, if treated in time. By contrast, the stages considered by Eichenholtz inevitably result in major arthropathy and foot deformity. Hence, superseding the Eichenholtz classification is overdue. We propose an MRI-based classification comprising two severity grades (0 and 1, according to absence/presence of cortical fractures) and two stages (active/inactive, according to presence/absence of skeletal inflammation). PMID- 24764121 TI - Influence of aromatase inhibition on the bone-protective effects of testosterone. AB - The influence of the aromatase enzyme in androgen-induced bone maintenance after skeletal maturity remains somewhat unclear. Our purpose was to determine whether aromatase activity is essential to androgen-induced bone maintenance. Ten-month old male Fisher 344 rats (n = 73) were randomly assigned to receive Sham surgery, orchiectomy (ORX), ORX + anastrozole (AN; aromatase inhibitor), ORX + testosterone-enanthate (TE, 7.0 mg/wk), ORX + TE + AN, ORX + trenbolone-enanthate (TREN; nonaromatizable, nonestrogenic testosterone analogue; 1.0 mg/wk), or ORX + TREN + AN. ORX animals exhibited histomorphometric indices of high-turnover osteopenia and reduced cancellous bone volume compared with Shams. Both TE and TREN administration suppressed cancellous bone turnover similarly and fully prevented ORX-induced cancellous bone loss. TE- and TREN-treated animals also exhibited greater femoral neck shear strength than ORX animals. AN co administration slightly inhibited the suppression of bone resorption in TE treated animals but did not alter TE-induced suppression of bone formation or the osteogenic effects of this androgen. In TREN-treated animals, AN co administration produced no discernible effects on cancellous bone turnover or bone volume. ORX animals also exhibited reduced levator ani/bulbocavernosus (LABC) muscle mass and elevated visceral adiposity. In contrast, TE and TREN produced potent myotrophic effects in the LABC muscle and maintained fat mass at the level of Shams. AN co-administration did not alter androgen-induced effects on muscle or fat. In conclusion, androgens are able to induce direct effects on musculoskeletal and adipose tissue, independent of aromatase activity. PMID- 24764122 TI - Why plant trichomes might be better than we think for predatory insects. PMID- 24764123 TI - Evaluation of a novel blood pressure scoring method and its association with clinical response in cancer patients treated with anti-vascular endothelial growth factor therapy. AB - BACKGROUND: The purposes of this study were to establish a novel blood pressure (BP) scoring method and to correlate it with clinical response in advanced cancer patients treated with anti-vascular endothelial growth factor (VEGF) therapies. METHODS: We retrospectively analyzed data for 368 patients from 23 clinical trials that included at least one anti-VEGF agent. We determined BP scores using the traditional Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and our novel method that considers both BP readings and number of anti hypertensive medications the patient received. BP scores were categorized at baseline and four months. Logistic regression analysis correlated elevated scores with clinical response. Agreement between the CTCAE and the new method was assessed. RESULTS: Under the new BP scoring method, partial response rates were 20 % in patients with an elevated score at four months versus 6 % in patients without elevated score (P < 0.001). When adjusted for tumor type, age, sex, history of anti-VEGF treatment, and number of anti-VEGF treatments, elevated BP under the new scoring method had an odds ratio of 3.8 (95 % confidence interval [CI]: 1.8, 8.2; P < 0.001). The kappa statistic for agreement between the CTCAE and new scoring methods was 0.57 (95 % CI: 0.47, 0.67; P < 0.001), indicating significant concordance. CONCLUSION: Using the novel scoring method, an increase in BP scores was a marker for favorable clinical response in patients who received anti-VEGF treatment. This new method ultimately provides information with regard to clinical tumor response over and above that provided by the CTCAE scoring method. PMID- 24764125 TI - Engineering the stereochemistry of cephalosporin for specific detection of pathogenic carbapenemase-expressing bacteria. AB - Reported herein is the design of fluorogenic probes specific for carbapenem resistant Enterobacteriaceae (CRE) and they were designed based on stereochemically modified cephalosporin having a 6,7-trans configuration. Through experiments using recombinant beta-lactamase enzymes and live bacterial species, these probes demonstrate the potential for use in the specific detection of carbapenemases, including metallo-beta-lactamases in active bacterial pathogens. PMID- 24764124 TI - Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. AB - Androgen receptor-mediated transcription is directly coupled with the induction of DNA damage, and castration-resistant tumor cells exhibit increased activity of poly (ADP-ribose) polymerase (PARP)-1, a DNA repair enzyme. This study assessed the efficacy and safety of low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide (TMZ) in docetaxel-pretreated patients with metastatic castration resistant prostate cancer (mCRPC) in a single-arm, open-label, pilot study. Patients with mCRPC progressing on at least one docetaxel-based therapy and prostate specific antigen (PSA) >= 2 ng/mL were treated with veliparib 40 mg twice daily on days 1-7 and TMZ once daily (150 mg/m(2)/day cycle 1; if well tolerated then 200 mg/m(2)/day cycle 2 onwards) on days 1-5 q28 days. Patients received 2 (median) treatment cycles (range, 1-9). The primary endpoint was confirmed PSA response rate (decline >= 30 %). Twenty-six eligible patients were enrolled, 25 evaluable for PSA response. Median baseline PSA was 170 ng/mL. Two patients had a confirmed PSA response (8.0 %; 95 % CI: 1.0-26.0), 13 stable PSA, and 10 PSA progression. The median progression-free survival was 9 weeks (95 % CI: 7.9-17) and median overall survival 39.6 weeks (95 % CI: 26.6-not estimable). The most frequent treatment-emergent adverse events (AEs) were thrombocytopenia (77 %), anemia (69 %), fatigue (50 %), neutropenia (42 %), nausea (38 %), and constipation (23 %). Grade 3/4 AEs occurring in > 10 % of patients were thrombocytopenia (23 %) and anemia (15 %). Veliparib and TMZ combination was well tolerated but with modest activity. Biomarker analysis supported the proof of concept that this combination has some antitumor activity in mCRPC. PMID- 24764126 TI - Overexpression of cyclin dependent kinase inhibitor P27/Kip1 increases oligodendrocyte differentiation from induced pluripotent stem cells. AB - Cell transplantation therapy with oligodendrocyte precursor cells (OPCs) is a promising and effective treatment for diseases involving demyelination in the central nervous system (CNS). In previous studies, we succeeded in producing O4(+) oligodendrocytes (OLs) from mouse- and human-induced pluripotent stem cells (iPSCs) in vitro; however, the efficiency of differentiation into OLs was lower for iPSCs than that for embryonic stem cells (ESCs). To clarify the cause of this difference, we compared the expression of proteins that contribute to OL differentiation in mouse iPSC-derived cells and in mouse ESC-derived cells. The results showed that the expression levels of cyclin dependent kinase inhibitor P27/Kip1, mitogen-activated protein kinase (MAPK) JNK3, and transcription factor Mash1 were lower in iPSC-derived cells. In contrast, the expression levels of MAPK P38alpha, P38gamma, and thyroid hormone receptor beta1 were higher in iPSC derived cells. We attempted to compensate for the expression changes in P27/Kip1 protein and Mash1 protein in iPSC-derived cells through retrovirus vector mediated gene expression. Although the overexpression of Mash1 had no effect, the overexpression of P27/Kip1 increased the differentiation efficiency of iPSC derived cells into O4(+) OLs. PMID- 24764127 TI - Does surgery for obstructive sleep apnea improve depression and sleepiness? AB - OBJECTIVES/HYPOTHESIS: To determine if surgical intervention for OSA (obstructive sleep apnea), particularly multilevel surgery, decreases depression and sleepiness. STUDY DESIGN: Prospective cohort study. METHODS: Chart and prospective outcome database review of patients who underwent surgery from August 2008 through November 2012. Patients were evaluated before and after surgery using the Epworth Sleepiness Scale (ESS), the Beck Depression Index (BDI), and overnight polysomnography. RESULTS: Forty-four patients (12 females; 32 males) met inclusion criteria. Mean age of participants was 44.0 years (SD, 10.2); mean body mass index was 31.9 (SD, 9.3). The mean preoperative obstructive respiratory disturbance index (RDI) was 35.8 events/hour (SD, 21.9; range, 6.6-94.2), which decreased to 17.1 (SD, 19.5; range, 0.8-78.1; P < 0.0001). Mean ESS improved from 10.8 (SD, 4.7) to 6.3 (SD, 3.7; P = 0.0001); whereas BDI scores improved from 8.4 (SD, 8.2) to 4.9 (SD, 6.0; P = 0.0051). There were 22 (50.0%) patients with excessive daytime sleepiness and 12 (27.3%) patients with depression before surgery. Surgery was associated with resolution of sleepiness in 17 patients (77.3%) and depression in 9 patients (75.0%). In multivariable regression analysis, only change in ESS (P = 0.003) and baseline BDI (P < 0.001) were associated with improvement in depression. RDI was not significant (P = 0.15). CONCLUSIONS: Surgical treatment of OSA, especially multilevel surgery, resulted in significantly reduced depression, with resolution in 75% of patients. Similarly, surgery resulted in significantly reduced sleepiness, with resolution in 77% of patients. Reduction in sleepiness scores, but not OSA severity, was predictive of improvement in depression scores. Further evaluation with a larger sample size and a control group is warranted. LEVEL OF EVIDENCE: 4. PMID- 24764128 TI - IV iron in pregnancy: an unmet clinical need. PMID- 24764129 TI - Acute and late side effects to salivary glands and oral mucosa after head and neck radiotherapy in children and adolescents. Results of the "Registry for the evaluation of side effects after radiotherapy in childhood and adolescence". AB - BACKGROUND: The registry for the evaluation of side effects after radiotherapy in childhood and adolescence (RiSK) was established to prospectively characterize radiation-associated side effects. The purpose of this analysis was to characterize side effects after radiotherapy to the head and neck in children and adolescents. METHODS: Radiation doses have been collected across Germany since 2001. Acute and late side effects were characterized. RESULTS: Until January 2010, 133 patients (median age, 12.7 years) were recruited who had received radiotherapy to the salivary glands. Toxicity evaluation was available for 114 patients (median follow-up, 2.9 years). Acute and late toxicity significantly depended on the maximum radiation dose to the salivary glands. An increase of the mean value of maximum dose of 1 Gray (Gy) to the submandibular glands resulted in an odds ratio of 1.04 (range, 1.00-1.08; p = .039) for acute toxicities of the salivary glands and 1.08 (range, 1.03-1.13; p = .001) for acute mucosal toxicities. CONCLUSION: These data can be used for an individual risk assessment in pediatric head and neck radiotherapy. PMID- 24764130 TI - Minimization of self-quenching fluorescence on dyes conjugated to biomolecules with multiple labeling sites via asymmetrically charged NIR fluorophores. AB - Self-aggregation of dyes even at low concentrations poses a considerable challenge in preparing sufficiently bright molecular probes for in vivo imaging, particularly in the conjugation of near infrared cyanine dyes to polypeptides with multiple labeling sites. Such self-aggregation leads to a significant energy transfer between the dyes, resulting in severe quenching and low brightness of the targeted probe. To address this problem, we designed a novel type of dye with an asymmetrical distribution of charge. Asymmetrical distribution prevents the chromophores from pi-stacking thus minimizing the energy transfer and fluorescence quenching. The conjugation of the dye to polypeptides showed only a small presence of an H-aggregate band in the absorption spectra and, hence, a relatively high quantum efficiency. PMID- 24764132 TI - Cardiac Tissue Vascularization: From Angiogenesis to Microfluidic Blood Vessels. AB - Myocardial infarction results from a blockage of a major coronary artery that shuts the delivery of oxygen and nutrients to a region of the myocardium, leading to massive cardiomyocytes death and regression of microvasculature. Growth factor and cell delivery methods have been attempted to revascularize the ischemic myocardium and prevent further cell death. Implantable cardiac tissue patches were engineered to directly revascularize as well as remuscularize the affected muscle. However, inadequate vascularization in vitro and in vivo limits the efficacy of these new treatment options. Breakthroughs in cardiac tissue vascularization will profoundly impact ischemic heart therapies. In this review, we discuss the full spectrum of vascularization approaches ranging from biological angiogenesis to microfluidic blood vessels as related to cardiac tissue engineering. PMID- 24764131 TI - Somatic Cell Reprogramming into Cardiovascular Lineages. AB - Ischemic cardiac disease is the leading cause of death in the developed world. The inability of the adult mammalian heart to adequately repair itself has motivated stem cell researchers to explore various strategies to regenerate cardiomyocytes after myocardial infarction. Over the past century, progressive gains in our knowledge about the cellular mechanisms governing fate determination have led to recent advances in cellular reprogramming. The identification of specific factors capable of inducing pluripotent phenotype in somatic cells as well as factors that can directly reprogram somatic cells into cardiomyocytes suggests the potential for these approaches to translate into clinical therapies in the future. Although conceptually appealing, the field of cell lineage reprogramming is in its infancy, and further research will be needed to improve the efficiency of the reprogramming process and the fidelity of the reprogrammed cells to their in vivo counterpart. PMID- 24764133 TI - Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans. AB - Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19-30 yr, 70-84 yr), 15 postmenopausal women (51-62 yr, 70-84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 +/- 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA. PMID- 24764134 TI - Rat lungs show a biphasic formation of new alveoli during postnatal development. AB - Roughly 90% of the gas-exchange surface is formed by alveolarization of the lungs. To the best of our knowledge, the formation of new alveoli has been followed in rats only by means of morphological description or interpretation of semiquantitative data until now. Therefore, we estimated the number of alveoli in rat lungs between postnatal days 4 and 60 by unambiguously counting the alveolar openings. We observed a bulk formation of new alveoli between days 4 and 21 (17.4 times increase from 0.8 to 14.3 millions) and a second phase of continued alveolarization between days 21 and 60 (1.3 times increase to 19.3 million). The (number weighted) mean volume of the alveoli decreases during the phase of bulk alveolarization from ~593,000 MUm(3) at day 4 to ~141,000 MUm(3) at day 21, but increases again to ~298,000 MUm(3) at day 60. We conclude that the "bulk alveolarization" correlates with the mechanism of classical alveolarization (alveolarization before the microvascular maturation is completed) and that the "continued alveolarization" follows three proposed mechanisms of late alveolarization (alveolarization after microvascular maturation). The biphasic pattern is more evident for the increase in alveolar number than for the formation of new alveolar septa (estimated as the length of the free septal edge). Furthermore, a striking negative correlation between the estimated alveolar size and published data on retention of nanoparticles was detected. PMID- 24764135 TI - Clinician perspectives on considering radiation exposure to patients when ordering imaging tests: a qualitative study. AB - BACKGROUND AND OBJECTIVES: Increased computer tomography (CT) scan use has contributed to a rise in medically-associated radiation exposure. The extent to which clinicians consider radiation exposure when ordering imaging tests is unknown. We examined (1) outpatient clinician attitudes towards considering radiation exposure when ordering CT scans; and (2) clinician reactions to displaying radiation exposure information for CT scans at clinician electronic order entry. METHODS: We conducted nine focus groups with primary care clinicians and subspecialty physicians (nephrology, pulmonary and neurology) (n=50) who deliver outpatient care across 12 hospital-based clinics and community health centres in an urban safety-net health system, which use a common electronic order entry system. We analysed focus group transcripts using an inductive framework to identify emergent themes and illustrative quotations. FINDINGS: Clinicians felt they had limited knowledge of the clinical implications of radiation exposure. Many believed clinically relevant information such as the increased risk of malignancy from CT scans would be useful to inform decision-making and patient clinician discussions. Clinicians noted that patient vulnerability and long wait times for tests with less radiation exposure (such as MRI or ultrasound) often acted as barriers to minimise patient radiation exposure from CT scans. Clinicians suggested providing patients' cumulative radiation exposure or formal decision aids to improve the usefulness of the radiation exposure information. CONCLUSIONS: Displaying clinically relevant radiation exposure information at order entry may improve clinician knowledge and inform patient-clinician discussions regarding risks and benefits of imaging. However, limited access to tests with lower radiation exposure in safety-net settings may trump efforts to minimise patient radiation exposure. PMID- 24764136 TI - Safety measurement and monitoring in healthcare: a framework to guide clinical teams and healthcare organisations in maintaining safety. AB - Patients, clinicians and managers all want to be reassured that their healthcare organisation is safe. But there is no consensus about what we mean when we ask whether a healthcare organisation is safe or how this is achieved. In the UK, the measurement of harm, so important in the evolution of patient safety, has been neglected in favour of incident reporting. The use of softer intelligence for monitoring and anticipation of problems receives little mention in official policy. The Francis Inquiry report into patient treatment at the Mid Staffordshire NHS Foundation Trust set out 29 recommendations on measurement, more than on any other topic, and set the measurement of safety an absolute priority for healthcare organisations. The Berwick review found that most healthcare organisations at present have very little capacity to analyse, monitor or learn from safety and quality information. This paper summarises the findings of a more extensive report and proposes a framework which can guide clinical teams and healthcare organisations in the measurement and monitoring of safety and in reviewing progress against safety objectives. The framework has been used so far to promote self-reflection at both board and clinical team level, to stimulate an organisational check or analysis in the gaps of information and to promote discussion of 'what could we do differently'. PMID- 24764137 TI - Nitric-oxide-mediated cell death is triggered by chitosan in Fusarium eumartii spores. AB - BACKGROUND: The genus Fusarium comprises a heterogeneous group of fungi important for agriculture. Fusarium solani f. sp. eumartii (F. eumartii), historically considered to be a fungal pathogen of potato, has also been associated with tomato disease. Currently, chitosan and its derivatives have been receiving more attention as environmentally friendly antimicrobial compounds in sustainable practices. The aim of the present work was to characterize downstream events associated with the mode of action of chitosan, including nitrosative reactive species, in order to identify new biomarkers of its cytotoxic action. RESULTS: Data indicated that chitosan-mediated nitric oxide (NO) production might lead to conidial death, concomitant with the strong reduction in fungal pathogenicity in tomato plants. Following chitosan applications, a notably dose-dependent reduction in conidial viability was demonstrated in F. eumartii. Thereafter, the infectivity of chitosan-treated spores was tested by a bioassay using tomato seedlings. CONCLUSION: All these data highlight NO valuable properties as a quantitative and qualitative biomarker of cytotoxic action of chitosan in conidial cells. In addition, these findings place the chitosan assayed here as a fungicide with a high potential of application in sustainable horticultural practices. PMID- 24764138 TI - Thalassemia bone disease: a 19-year longitudinal analysis. AB - Thalassemia is an inherited disorder of alpha or beta globin chain synthesis leading to ineffective erythropoiesis requiring chronic transfusion therapy in its most severe form. This leads to iron overload, marrow expansion, and hormonal complications, which are implicated in bone deformity and loss of bone mineral density (BMD). In this 19-year retrospective longitudinal study, the relationships between BMD (determined by dual-energy X-ray absorptiometry) and risk factors for osteoporosis in 277 subjects with transfusion-dependent thalassemia were examined. The mean age at first review was 23.2 +/- 11.9 years and 43.7% were male. Hypogonadism was present in 28.9%. Fractures were confirmed in 11.6% of subjects and were more frequent in males (16.5%) compared with females (7.7%). Lumbar spine (LS), femoral neck (FN), and total body (TB) Z scores were derived. Patients with transfusion-dependent thalassemia had a significant longitudinal decline in BMD at the FN and TB. In the linear mixed model analysis of BMD and risk factors for bone loss, FN Z-score was more significantly associated with risk factors compared with the LS and TB. The rate of decline at the FN was 0.02 Z-score per year and was 3.85-fold greater in males. The decline in FN Z-score over the last 5 years (years 15 to 19) was 2.5 fold that of the previous 7 years (years 8 to 14) and coincided with a change in iron chelator therapy from desferrioxamine to deferasirox. Hemoglobin (Hb) levels positively correlated with higher TB and LS Z-scores. In conclusion, the FN is the preferred site for follow-up of BMD. Male patients with beta-thalassemia experienced a greater loss of BMD and had a higher prevalence of fractures compared with females. Transfusing patients (particularly males) to a higher Hb target may reduce the decline in BMD. Whether deferasirox is implicated in bone loss warrants further study. PMID- 24764139 TI - Introduction to Volume 6, Issue 2 of topiCS. PMID- 24764140 TI - Decision theory with resource-bounded agents. AB - There have been two major lines of research aimed at capturing resource-bounded players in game theory. The first, initiated by Rubinstein (), charges an agent for doing costly computation; the second, initiated by Neyman (), does not charge for computation, but limits the computation that agents can do, typically by modeling agents as finite automata. We review recent work on applying both approaches in the context of decision theory. For the first approach, we take the objects of choice in a decision problem to be Turing machines, and charge players for the "complexity" of the Turing machine chosen (e.g., its running time). This approach can be used to explain well-known phenomena like first-impression matters biases (i.e., people tend to put more weight on evidence they hear early on) and belief polarization (two people with different prior beliefs, hearing the same evidence, can end up with diametrically opposed conclusions) as the outcomes of quite rational decisions. For the second approach, we model people as finite automata, and provide a simple algorithm that, on a problem that captures a number of settings of interest, provably performs optimally as the number of states in the automaton increases. PMID- 24764141 TI - Commentary on utility and bounds. PMID- 24764142 TI - The influence of heterocyclic compound-PAMAM dendrimer complexes on evoked electrical responses in slices of hypoxic brain tissue. AB - We used complexes between a fourth generation polyamidoamine (PAMAM) dendrimer and one of two heterocyclic compounds - 1-(6-hydroxyhexyl)-3-(5-phenyl-isoxazole 3-yl)-urea or 5-phenyl-isoxazole-3-carboxylic acid - to reduce oxygen consumption in transverse slices of the hippocampus taken from 4-week old male rats. In vitro electrophysiological experiments revealed that the inhibitory effect of the hypoxic state on the evoked responses was enhanced in the presence of the complexes. The data were analyzed in terms of the potential antitumor effects of these complexes. PMID- 24764143 TI - CA-125 of fetal origin can act as a ligand for dendritic cell-specific ICAM-3 grabbing non-integrin. AB - CA-125 (coelomic epithelium-related antigen) forms the extracellular portion of transmembrane mucin 16 (MUC16). It is shed after proteolytic degradation. Due to structural heterogeneity, CA-125 ligand capacity and biological roles are not yet understood. In this study, we assessed CA-125 as a ligand for dendritic cell specific ICAM-3-grabbing non-integrin (DC-SIGN), which is a C-type lectin showing specificity for mannosylated and fucosylated structures. It plays a role as a pattern recognition molecule for viral and bacterial glycans or as an adhesion receptor. We probed a human DC-SIGN-Fc chimera with CA-125 of fetal or cancer origin using solid- or fluid-phase binding and inhibition assays. The results showed that DC-SIGN binds to CA-125 of fetal origin and that this interaction is carbohydrate-dependent. By contrast, cancer-derived CA-125 displayed negligible binding. Inhibition assays indicated differences in the potency of CA-125 to interfere with DC-SIGN binding to pathogen-related glycoconjugates, such as mannan and Helicobacter pylori antigens. The differences in ligand properties between CA-125 of fetal and cancer origin may be due to specificities of glycosylation. This might influence various functions of dendritic cells based on their subset diversity and maturation-related functional capacity. PMID- 24764144 TI - Monitoring of membrane phospholipid scrambling in human erythrocytes and K562 cells with FM1-43 - a comparison with annexin V-FITC. AB - The styryl dye FM1-43 becomes highly fluorescent upon binding to cell membranes. The breakdown of membrane phospholipid asymmetry in ionophore-stimulated T lymphocytes further increases this fluorescence [Zweifach, 2000]. In this study, the capacity of FM1-43 to monitor membrane phospholipid scrambling was explored using flow cytometry in human erythrocytes and human erythrocyte progenitor K562 cells. The Ca(2+)-dependent phosphatidylserine-specific probe annexin V-FITC was used for comparison. The presented data show that the loss of phospholipid asymmetry that could be induced in human erythrocytes by elevated intracellular Ca(2+) or by structurally different membrane intercalated amphiphilic compounds increases the FM1-43 fluorescence two- to fivefold. The profile of FM1-43 fluorescence for various treatments resembles that of phosphatidylserine exposure reported by annexin V-FITC. FM1-43 detected the onset of scrambling more efficiently than annexin V-FITC. The amphiphile-induced scrambling was shown to be a Ca(2+)-independent process. Monitoring of scrambling in K562 cells caused by NEM-induced Ca(2+)-release from intracellular stores and by Ca(2+) and ionophore A23187 treatment showed that the increase in FM1-43 fluorescence correlated well with the number of annexin V-FITC-detected phosphatidylserine-positive cells. The results presented here show the usefulness of FM1-43 as a Ca(2+)-independent marker of dissipation in asymmetric membrane phospholipid distribution induced by various stimuli in both nucleated and non-nucleated cells. PMID- 24764145 TI - More than skin-deep: the many dimensions of the psoriatic disease. AB - Psoriasis is among the most common skin diseases, exhibiting a wide spectrum of clinical manifestations. Joint involvement in the form of psoriatic arthritis is readily recognised, but both frequency and severity of this manifestation have long been underestimated. More recently, additional important diseases have been found to be associated with psoriasis, including the metabolic syndrome (or components thereof), cardiovascular diseases, lymphoma, and anxiety/depression. In the past, psoriasis treatment aimed at suppressing acute rashes. Current concepts regard psoriasis as a chronic systemic inflammatory condition and cardiovascular risk factor. In the light of this concept, long-term disease control through systemic maintenance therapy is increasingly recommended by experts. This approach became feasible with the approval of numerous biologics for the treatment of psoriasis. But to really address all medical needs of psoriasis patients, a truly interdisciplinary, comprehensive management approach is needed. Several national societies have already published algorithms to ensure that this need will be implemented in the daily practice of dermatologists and nondermatologists alike. PMID- 24764146 TI - Risk factors for adult-onset recurrent respiratory papillomatosis. AB - OBJECTIVES/HYPOTHESIS: To evaluate risk factors strongly associated with adult onset recurrent respiratory papillomatosis (AO-RRP). STUDY DESIGN: Prospective, age- and sex-matched, case control. METHODS: Patients with AO-RRP and controls completed a computer-based, 89-item questionnaire across three academic institutions. RESULTS: Forty-eight AO-RRP patients were compared to 73 controls; 43 of the 48 AO-RRP patients were male (89.5%). The difference in the median number of lifetime sexual partners between AO-RRP (15) and controls (10) was significant (P = 0.0387). Additionally, an increased number of lifetime sexual partners (>= 26) was associated with AO-RRP. No significant difference for the number of lifetime oral sex partners was observed between groups. Increased comorbidity, as quantified by the Charlson Comorbidity Index, was observed in patients with AO-RRP. AO-RRP and control groups were similar across many other variables, including birth history, smoking history, alcohol use, drug use, education, income, and the Short Form Health Survey scores. CONCLUSIONS: AO-RRP was not associated with previously proposed risk factors for juvenile-onset RRP and may be associated with an increased number of lifetime sexual partners. PMID- 24764147 TI - Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics. AB - As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, six-sequence, three-period crossover study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75-g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following coadministration with pantoprazole and rabeprazole, respectively. The maximum plasma metformin concentrations (Cmax) also increased by 15% and 22%, respectively, compared with when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole [geometric mean ratio: 0.96 (90% confidence interval: 0.92-0.99) and 0.77 (0.63-0.93), respectively]. There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered. PMID- 24764148 TI - Evaluation of the HC-04 cell line as an in vitro model for mechanistic assessment of changes in hepatic cytochrome P450 3A during adenovirus infection. AB - HC-04 cells were evaluated as an in vitro model for mechanistic study of changes in the function of hepatic CYP3A during virus infection. Similar to in vivo observations, infection with a first generation recombinant adenovirus significantly inhibited CYP3A4 catalytic activity in an isoform-specific manner. Virus (MOI 100) significantly reduced expression of the retinoid X receptor (RXR) by 30% 96 hours after infection. Cytoplasmic concentrations of the pregnane X receptor (PXR) were reduced by 50%, whereas the amount of the constitutive androstane receptor (CAR) in the nuclear fraction doubled with respect to uninfected controls. Hepatocyte nuclear factor 4alpha (HNF-4alpha) and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) were also reduced by ~70% during infection. Virus suppressed CYP3A4 activity in the presence of the PXR agonist rifampicin and did not affect CYP3A4 activity in the presence of the CAR agonist CITCO [6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole 5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime], suggesting that virus-induced modification of PXR may be responsible for observed changes in hepatic CYP3A4. The HC-04 cell line is easy to maintain, and CYP3A4 in these cells was responsive to known inducers and suppressors. Dexamethasone (200 MUM) and phenobarbital (500 MUM) increased activity by 230 and 124%, whereas ketoconazole (10 MUM) and lipopolysaccharide (LPS) (10 MUg/ml) reduced activity by 90 and 92%, respectively. This suggests that HC-04 cells can be a valuable tool for mechanistic study of drug metabolism during infection and for routine toxicological screening of novel compounds prior to use in the clinic. PMID- 24764150 TI - Accelerating diffusion-ordered NMR spectroscopy by joint sparse sampling of diffusion and time dimensions. AB - Diffusion-ordered multidimensional NMR spectroscopy is a valuable technique for the analysis of complex chemical mixtures. However, this method is very time consuming because of the costly sampling of a multidimensional signal. Various sparse sampling techniques have been proposed to accelerate such measurements, but they have always been limited to frequency dimensions of NMR spectra. It is now revealed how sparse sampling can be extended to diffusion dimensions. PMID- 24764149 TI - Glucuronidation of drugs and drug-induced toxicity in humanized UDP glucuronosyltransferase 1 mice. AB - UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and drug-induced toxicity in humans. PMID- 24764151 TI - Three-dimensional imaging of the mouse heart and vasculature using micro-CT and whole-body perfusion of iodine or phosphotungstic acid. AB - Recent studies have investigated histological staining compounds as micro computed tomography (micro-CT) contrast agents, delivered by soaking tissue specimens in stain and relying on passive diffusion for agent uptake. This study describes a perfusion approach using iodine or phosphotungstic acid (PTA) stains, delivered to an intact mouse, to capitalize on the microvasculature as a delivery conduit for parenchymal staining and direct contact for staining artery walls. Twelve C57BL/6 mice, arterially perfused with either 25% Lugol's solution or 5% PTA solution were scanned intact and reconstructed with 26 um isotropic voxels. The animals were fixed and the heart and surrounding vessels were excised, embedded and scanned; isolated heart images were reconstructed with 13 um isotropic voxels. Myocardial enhancement and artery diameters were measured. Both stains successfully enhanced the myocardium and vessel walls. Interestingly, Lugol's solution provided a significantly higher enhancement of the myocardium than PTA [2502 +/- 437 vs 656 +/- 178 Hounsfield units (HU); p < 0.0001], delineating myofiber architecture and orientation. There was no significant difference in vessel wall enhancement (Lugol's, 1036 +/- 635 HU; PTA, 738 +/- 124 HU; p = 0.29), but coronary arteries were more effectively segmented from the PTA stained hearts, enabling segmented imaging of fifth- order coronary artery branches. The combination of whole mouse perfusion delivery and use of heavy metal-containing stains affords high-resolution imaging of the mouse heart and vasculature by micro-CT. The differential imaging patterns of Lugol's- and PTA stained tissues reveals new opportunities for micro-analyses of cardiac and vascular tissues. PMID- 24764153 TI - [The Ogilvie syndrome in elderly patients with multimorbidity]. AB - Two patients presented with the Ogilvie syndrome which is an acute colonic pseudo obstruction without any mechanical obstruction. Both patients suffered from multiple medical conditions such as infections, electrolyte disturbances and functional decline.The Ogilvie syndrome is particularly seen in patients with multimorbidity who stay in the hospital or nursing home. The incidence of the Ogilvie syndrome will probably increase because of ageing of our population and will be most prevalent in the frail elderly. The precise mechanism of this disease is still unclear, but there is evidence in the literature that the aetiology is multifactorial and runs via autonomic dysregulation of the colon.Early recognition and appropriate treatment may reduce the risk of complications and limit mortality, also depending on the related comorbidity. PMID- 24764152 TI - Phase II clinical study of erlotinib for treatment of myelodysplastic syndromes. AB - Outcome in patients with myelodysplastic syndrome (MDS) after azanucleoside failure is poor with unmet need for active novel agents. Preclinical data have suggested that erlotinib has in vivo and in vitro off epidermal growth factor receptor (EGFR)-target activity in MDS. We conducted a phase II study with single agent erlotinib 150 mg/day orally in MDS patients following azanucleoside failure. All intermediate-2 or high-risk MDS patients by International Prognostic Scoring System and only those low/intermediate-1 patients with transfusion dependent anemia or platelet counts <50 * 10(9) /L or a significant clinical hemorrhage requiring platelet transfusion or ANC <1 * 10(9) /L were eligible, with most of our patients being at high risk. In 35 eligible patients, overall best response was 14% (3 patients having marrow complete response and 2 hematological improvement). Four deaths occurred on study (sepsis, intracranial hemorrhage, sudden death, and acute myeloid leukemia (AML)). The most common observed grade 3/4 toxicities according to CTCAE v3 were diarrhea (17.1%), rash (17.1%), and infection (11.6%), accompanied by fatigue, thrombocytopenia, and anorexia at 5.7% each. Median overall survival was 6.8 months (95% CI 4.9-13.2), and leukemia-free survival was 5 months (95% CI 3.4-7.3). Erlotinib was generally well tolerated, with modest single-agent activity. Given these results and preclinical data suggesting synergistic effect with azanucleosides, the combination should be further explored. PMID- 24764154 TI - Identification of the first glyphosate-resistant wild radish (Raphanus raphanistrum L.) populations. AB - BACKGROUND: In Australia, glyphosate has been used routinely to control wild radish (Raphanus raphanistrum L.) for the past 40 years. This study focuses on two field-evolved glyphosate-resistant populations of wild radish collected from the grainbelt of Western Australia. RESULTS: Two wild radish biotypes were confirmed to be glyphosate resistant by comparing R/S of two suspected populations. Based on R/S from dose-response curves, the R1 and R2 populations were 2.3 and 3.2 times more resistant to glyphosate respectively. Dose response on glyphosate-selected progeny (>1080 g ha(-1)) demonstrated that the glyphosate resistance mechanism was heritable. When compared with the pooled mortality results of three known susceptible populations (S1, S2 and S3), the R1 and R2 subpopulations were 3.4-fold and 4.5-fold more resistant at the LD50 level respectively. Both populations were found to have multiple resistance to the phytoene desaturase inhibitor; diflufenican, the synthetic auxin; 2,4-D and the ALS inhibitors; chlorsulfuron, sulfometuron-methyl, imazethapyr and metosulam. CONCLUSIONS: This is the first report confirming glyphosate resistance evolution in wild radish and serves to re-emphasise the importance of diverse weed control strategies. Proactive and integrated measures for resistance management need to be developed to diversify control measures away from glyphosate and advance the use of non-herbicidal techniques. PMID- 24764155 TI - Nodal metastasis and survival in oral cancer: Association with protein expression of SLPI, not with LCN2, TACSTD2, or THBS2. AB - BACKGROUND: Gene expression profiling revealed a strong signature predicting lymph node metastases in oral squamous cell carcinoma (OSCC). Four of the most predictive genes are secretory leukocyte protease inhibitor (SLPI), lipocalin-2 (LCN2), thrombospondin-2 (THBS2), and tumor-associated calcium signal transducer 2 (TACSTD2). This study correlates their protein expression with lymph node metastases, overall survival (OS), and disease-specific survival (DSS). METHODS: Two hundred twelve patients with OSCC were included for protein expression analysis by immunohistochemistry. RESULTS: SLPI expression correlates with lymph node metastases in the whole cohort, not in a subgroup of cT1 to 2N0. SLPI expression correlates with OS (hazard ratio [HR] = 0.61) and DSS (HR = 0.47) in multivariate analysis. LCN2, THBS2, and TACSTD2 show no correlation with lymph node metastases, OS, or DSS. CONCLUSION: Although SLPI expression correlates with lymph node metastases, it has no additional value in determining lymph node metastases in early oral cancer. However, it is an independent predictor for both OS and DSS and therefore a relevant prognostic biomarker in OSCC. PMID- 24764156 TI - Systematic review of power mobility outcomes for infants, children and adolescents with mobility limitations. AB - OBJECTIVE: To summarize and critically appraise the evidence related to power mobility use in children (18 years or younger) with mobility limitations. DATA SOURCES: Searches were performed in 12 electronic databases along with hand searching for articles published in English to September 2012 and updated February 2014. REVIEW METHODS: The search was restricted to quantitative studies including at least one child with a mobility limitation and measuring an outcome related to power mobility device use. Articles were appraised using American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) criteria for group and single-subject designs. The PRISMA statement was followed with inclusion criteria set a priori. Two reviewers independently screened titles, abstracts and full-text articles. AACPDM quality ratings were completed for levels I-III studies. RESULTS: Of 259 titles, 29 articles met inclusion criteria, describing 28 primary research studies. One study, rated as strong level II evidence, supported positive impact of power mobility on overall development as well as independent mobility. Another study, rated as moderate level III evidence, supported positive impact on self-initiated movement. Remaining studies, rated evidence levels IV and V, provided support for a positive impact on a broad range of outcomes from to International Classification of Functioning (ICF) components of body structure and function, activity and participation. Some studies suggest that environmental factors may be influential in successful power mobility use and skill development. CONCLUSION: The body of evidence supporting outcomes for children using power mobility is primarily descriptive rather than experimental in nature, suggesting research in this area is in its infancy. PMID- 24764157 TI - Controversies in the mammography screening programme in Switzerland. PMID- 24764159 TI - Immunogenicity and antigenicity of Plasmodium vivax merozoite surface protein 10. AB - Among the proteins involved in the invasion by merozoite, the glycosylphosphatidylinositol-anchored proteins (GPI-APs) are suggested as potential vaccine candidates because of their localization to apical organelles and the surface; these candidates are predicted to play essential roles during invasion. As a GPI-AP, Plasmodium vivax merozoite surface protein 10 (PvMSP-10) induces high antibody titers. However, such high antibody titers have shown no protective efficacy for animals challenged with P. vivax parasites in a previous study. To adequately evaluate the immunogenicity and further characterize PvMSP 10 in order to understand its vaccine potential, we assessed its immunogenicity by immunizing BALB/c mice with cell-free expressed recombinant PvMSP-10 protein. The antigenicity of MSP-10 was analyzed, and we found 42% sensitivity and 95% specificity using serum samples from P. vivax-infected Korean patients. The IgG1 and IgG3 were the predominant immunoreactive antibodies against PvMSP-10 in vivax patient sera, and IgG1 and IgG3 and Th1-type cytokines were predominantly secreted in PvMSP-10-immunized mice. We conclude that the immunogenicity and antigenicity of MSP-10 may serve as a potential vaccine against vivax malaria. PMID- 24764160 TI - Platysma synkinesis in facial palsy and botulinum toxin type A. AB - OBJECTIVES/HYPOTHESIS: Facial synkinesis is a well-known disabling occurrence following severe facial palsy. Platysma muscle, innervated by the facial nerve, can be involved in synkinesis as well, but thus far has been little investigated. The aim of our study is to evaluate the presence of platysma synkinesis and its clinical evolution after onabotulinumtoxinA (BoNT-A) (Botox((r)) ; Allergan Pharmaceuticals, Irvine, CA) injections. STUDY DESIGN: Retrospective study. METHODS: Sixty-nine patients were treated for synkinesis following facial palsy. Of those, 45 were affected by platysma synkinesis and thus were injected in the platysma muscle. The total number of sessions was 124. The Sunnybrook Facial Grading System (SFGS) and a specific platysmal evaluation for the presence and severity of synkinesis and local symptoms were performed before and after BoNT-A treatments. RESULTS: Platysma synkinesis was present in 65.2% of the sample and was associated with subjective complaints in 85.5% of the cases. The facial expressions more related to platysma synkinesis were snarl, followed by open mouth smile and lip pucker. After each BoNT-A treatment, there was an improvement in facial symmetry at rest and during voluntary movements, a global reduction of synkinesis, and a specific reduction of synkinesis and symptoms related to the platysma. No adverse reaction to BoNT-A occurred. CONCLUSION: Platysma involvement represents a recurring and symptomatic problem in patients affected by synkinetic recovery following facial palsy. After BoNT-A injections, there is a reduction in platysma synkinesis and related symptoms. LEVEL OF EVIDENCE: 4. PMID- 24764158 TI - Constitutive expression of Gsalpha(R201C) in mice produces a heritable, direct replica of human fibrous dysplasia bone pathology and demonstrates its natural history. AB - Fibrous dysplasia of bone (FD) is a crippling skeletal disease associated with postzygotic mutations (R201C, R201H) of the gene encoding the alpha subunit of the stimulatory G protein, Gs. By causing a characteristic structural subversion of bone and bone marrow, the disease results in deformity, hypomineralization, and fracture of the affected bones, with severe morbidity arising in childhood or adolescence. Lack of inheritance of the disease in humans is thought to reflect embryonic lethality of germline-transmitted activating Gsalpha mutations, which would only survive through somatic mosaicism. We have generated multiple lines of mice that express Gsalpha(R201C) constitutively and develop an inherited, histopathologically exact replica of human FD. Robust transgene expression in neonatal and embryonic tissues and embryonic stem (ES) cells were associated with normal development of skeletal tissues and differentiation of skeletal cells. As in humans, FD lesions in mice developed only in the postnatal life; a defined spatial and temporal pattern characterized the onset and progression of lesions across the skeleton. In individual bones, lesions developed through a sequence of three distinct histopathological stages: a primary modeling phase defined by endosteal/medullary excess bone formation and normal resorption; a secondary phase, with excess, inappropriate remodeling; and a tertiary fibrous dysplastic phase, which reproduced a full-blown replica of the human bone pathology in mice of age >=1 year. Gsalpha mutations are sufficient to cause FD, and are per se compatible with germline transmission and normal embryonic development in mice. Our novel murine lines constitute the first model of FD. PMID- 24764161 TI - [18F]DPA-C5yne, a novel fluorine-18-labelled analogue of DPA-714: radiosynthesis and preliminary evaluation as a radiotracer for imaging neuroinflammation with PET. AB - DPA-C5yne, the lead compound of a novel series of DPA-714 derivatives in which the fluoroethoxy chain linked to the phenylpyrazolopyrimidine scaffold has been replaced by a fluoroalkyn-1-yl moiety, is a high affinity (Ki : 0.35 nM) and selective ligand targeting the translocator protein 18 kDa. In the present work, DPA-C5yne was labelled with no-carrier-added [(18)F]fluoride based on a one-step tosyloxy-for-fluorine nucleophilic substitution reaction, purified by cartridge and HPLC, and formulated as an i.v. injectable solution using a TRACERLab FX N Pro synthesizer. Typically, 4.3-5.2 GBq of [(18)F]DPA-C5yne, ready-to-use, chemically and radiochemically pure (> 95%), was obtained with specific radioactivities ranging from 55 to 110 GBq/umol within 50-60 min, starting from a 30 GBq [(18)F]fluoride batch (14-17%). LogP and LogD of [(18)F]DPA-C5yne were measured using the shake-flask method and values of 2.39 and 2.51 were found, respectively. Autoradiography studies performed on slices of ((R,S)-alpha-amino-3 hydroxy-5-methyl-4-isoxazolopropionique (AMPA)-lesioned rat brains showed a high target-to-background ratio (1.9 +/- 0.3). Selectivity and specificity of the binding for the translocator protein was demonstrated using DPA-C5yne (unlabelled), PK11195 and Flumazenil (central benzodiazepine receptor ligand) as competitors. Furthermore, DPA-C5yne proved to be stable in plasma at 37 degrees C for at least 90 min. PMID- 24764163 TI - Response: blood culture for suspected disseminated tuberculosis. PMID- 24764162 TI - Targeting human prostate cancer with 111In-labeled D2B IgG, F(ab')2 and Fab fragments in nude mice with PSMA-expressing xenografts. AB - D2B is a new monoclonal antibody directed against an extracellular domain of prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer. The potential of D2B IgG, and F(ab')2 and Fab fragments of this antibody for targeting prostate cancer was determined in mice bearing subcutaneous prostate cancer xenografts. The optimal time point for imaging was determined in biodistribution and microSPECT imaging studies with (111)In-D2B IgG, (111)In capromab pendetide, (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments in mice with PSMA-expressing LNCaP and PSMA-negative PC3 tumors at several time points after injection. All (111)In-labeled antibody formats specifically accumulated in the LNCaP tumors, with highest uptake of (111)In-D2B IgG and (111)In-capromab pendetide at 168 h p.i. (94.8 +/- 19.2% injected dose per gram (ID/g) and 16.7 +/ 2.2% ID/g, respectively), whereas uptake of (111)In-D2B F(ab')2 and (111)In-D2B Fab fragments peaked at 24 h p.i. (12.1 +/- 3.0% ID/g and 15.1 +/- 2.9% ID/g, respectively). Maximum LNCaP tumor-to-blood ratios were 13.0 +/- 2.3 (168 h p.i.), 6.2 +/- 0.7 (24 h p.i.), 23.0 +/- 4.0 (24 h p.i.) and 4.5 +/- 0.6 (168 h p.i.) for (111)In-D2B IgG, (111)In-F(ab')2, (111)In-Fab and (111)In-capromab pendetide, respectively. LNCaP tumors were clearly visualized with microSPECT with all antibody formats. This study demonstrates the feasibility of D2B IgG, F(ab')2 and Fab fragments for targeting PSMA-expressing prostate cancer xenografts. PMID- 24764165 TI - Laboratory real-time and in situ monitoring of mechanochemical milling reactions by Raman spectroscopy. AB - Mechanistic understanding of mechanochemical reactions is sparse and has been acquired mostly by stepwise ex situ analysis. We describe herein an unprecedented laboratory technique to monitor the course of mechanochemical transformations at the molecular level in situ and in real time by using Raman spectroscopy. The technique, in which translucent milling vessels are used that enable the collection of a Raman scattering signal from the sample as it is being milled, was validated on mechanochemical reactions to form coordination polymers and organic cocrystals. The technique enabled the assessment of the reaction dynamics and course under different reaction conditions as well as, for the first time, direct insight into the behavior of liquid additives during liquid-assisted grinding. PMID- 24764164 TI - Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region. AB - BACKGROUND: Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients. METHODS: Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls. RESULTS: New duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24-1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes. CONCLUSION: Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation. PMID- 24764166 TI - Reversible click reactions with boronic acids to build supramolecular architectures in water. AB - The interaction of boronic acids with various bifunctional reagents offers great potential for the preparation of responsive supramolecular architectures. Boronic acids react with 1,2-diols yielding cyclic boronate esters that are stable at pH>7.4 but can be hydrolyzed at pH<5.0. The phenylboronic acid (PBA) salicylhydroxamic acid (SHA) system offers ultra-fast reaction kinetics and high binding affinities. This Focus Review summarizes the current advances in exploiting the bioorthogonal interaction of boronic acids to build pH-responsive supramolecular architectures in water. PMID- 24764167 TI - Pigmented villonodular synovitis of the temporomandibular joint with intracranial extension: A case series and systematic review. AB - BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare proliferative disorder of the synovial membrane. PVNS generally affects large joints but occasionally involves the temporomandibular joint (TMJ), with occasional extension into the middle cranial fossa. The purpose of this study was to report our experience with PVNS along with a focused literature review. METHODS: Patients with PVNS of the TMJ treated at the University of California - San Francisco from 2007 to 2013 were reviewed. A PubMed search was performed to identify additional cases. RESULTS: Five patients underwent surgical resection, with 1 recurrence at 61 months. A literature review identified 58 patients, 19 of which had intracranial involvement. Interestingly, intracranial extension was more common in men. Intracranial extension was not associated with an increased rate of recurrence. CONCLUSION: PVNS of the TMJ is a rare entity associated with excellent outcomes, even with intracranial extension. Management should consist of maximal resection, with radiotherapy reserved for extensive or recurrent lesions. PMID- 24764171 TI - Normalising the good doctor ... and other health services personnel: commentary on Deborah Oyer's review of The Good Doctor. PMID- 24764170 TI - [Posterior uveitis. Part 2: specific disorders]. PMID- 24764172 TI - Factors influencing the introduction of physical activity interventions in primary health care: a qualitative study. AB - BACKGROUND: The introduction of efficacious physical activity (PA) interventions in routine primary health care (PHC) is a complex process. Understanding factors influencing the process can enhance the development of successful introduction strategies. PURPOSE: The aim of this qualitative study was to explore stakeholders' perceptions on factors influencing the introduction, i.e., adoption, implementation, and continuation, of PA interventions in PHC. METHOD: Twenty-eight semistructured interviews were held with intervention managers, PHC advisors, intervention providers, and referring general practitioners of five PA interventions delivered in PHC. A theoretical framework on the introduction of innovations in health care was used to guide the data collection. Influencing factors were identified using thematic analysis. RESULTS: Stakeholders reported preconditions for the introduction of PA interventions in PHC (e.g., support, resources, and networks and collaborations), in addition to characteristics of PA interventions (e.g., compatibility, flexibility, and intervention materials) and characteristics of PHC professionals (e.g., knowledge, positive attitudes, and beliefs about capabilities) perceived to enhance the introduction process. Furthermore, they proposed strategies for the development of PA interventions (e.g., involvement of future stakeholders, full development, and refinement) and strategies to introduce PA interventions in PHC (e.g., training, assistance, and reinforcement). The majority of the influencing factors were discussed specifically in relation to one or two stages. CONCLUSION: This study presents an overview of factors that are perceived to influence the introduction of PA interventions in PHC. It underscores the importance of taking these factors into account when designing introduction strategies and of giving special attention to the distinct stages of the process. PMID- 24764173 TI - Effect of AST on age-associated changes of vocal folds in a rat model. AB - OBJECTIVES/HYPOTHESIS: Reactive oxygen species (ROS) are associated with aging. Astaxanthin (AST) is a strong antioxidant and has been reported to prevent various ROS-induced diseases. In the current study, we investigated the effect of AST on age-associated histological and mRNA changes of vocal folds. STUDY DESIGN: Prospective animal experiment with control. METHODS: Six-month-old Sprague-Dawley rats were fed on a normal powder diet with 0.01% (w/w) AST (aged AST-treated group) or without AST (aged sham-treated group). After 12 months of feeding, the larynges were harvested for histology, immunohistochemical detection of 4-hydroxy 2-nonenal (4-HNE), and quantitative real-time polymerase chain reaction for basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF). Thirteen-week old rats were used as a young control group (young group). RESULTS: The expression of 4-HNE, an oxidative stress marker, significantly increased in the two aged groups compared with the young group. Histological examination showed that the deposition of hyaluronic acid in the lamina propria (LP) was significantly reduced in the aged sham-treated group compared with the young group, but no significant difference was observed between the aged AST-treated group and the young group. There were no significant differences in the mRNA expression of bFGF and HGF between the aged AST-treated group and the young group, although the expression of these genes was significantly reduced in the aged sham-treated group as compared with the young group. CONCLUSIONS: These results suggest that AST has the potential to attenuate age-associated changes of vocal folds. PMID- 24764174 TI - In vivo quantification of SPIO nanoparticles for cell labeling based on MR phase gradient images. AB - Along with the development of modern imaging technologies, contrast agents play increasingly important roles in both clinical applications and scientific research. Super-paramagnetic iron oxide (SPIO) nanoparticles, a negative contrast agent, have been extensively used in magnetic resonance imaging (MRI), such as in vivo labeling and tracking of cells. However, there still remain many challenges, such as in vivo quantification of SPIO nanoparticles. In this work, an MR phase gradient-based method was proposed to quantify the SPIO nanoparticles. As a calibration, a phantom experiment using known concentrations (10, 25, 50, 100, 150 and 250 ug/ml) of SPIO was first conducted to verify the proposed quantification method. In a following in vivo experiment, C6 glioma cells labeled with SPIO nanoparticles were implanted into flanks of four mice, which were scanned 1-3 days post-injection for in vivo quantification of SPIO concentration. The results showed that the concentration of SPIO nanoparticles could be determined in both phantom and in vivo experiments using the developed MR phase gradients approach. PMID- 24764176 TI - Comment on "Fluorine in shark teeth: its direct atomic-resolution imaging and strengthening function". PMID- 24764175 TI - PAHs, nitro-PAHs, hopanes, and steranes in lake trout from Lake Michigan. AB - The present study examines concentrations and risks of polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs (NPAHs), steranes, and hopanes in lake trout collected in Lake Michigan. A total of 74 fish were collected in 2 seasons at 3 offshore sites. The total PAH concentration (Sigma9 PAH) in whole fish ranged from 223 pg/g to 1704 pg/g wet weight, and PAH concentrations and profiles were similar across season, site, and sex. The total NPAH (Sigma9 NPAH) concentrations ranged from 0.2 pg/g to 31 pg/g wet weight, and carcinogenic compounds, including 1-nitropyrene and 6-nitrochrysene, were detected. In the fall, NPAH concentrations were low at the Illinois site (0.2-0.5 pg/g wet wt), and site profiles differed considerably; in the spring, concentrations and profiles were similar across sites, possibly reflecting changes in fish behavior. In the fall, the total sterane (Sigma5 Sterane) and total hopane (Sigma2 Hopane) levels reached 808 pg/g and 141 pg/g wet weight, respectively, but concentrations in the spring were 10 times lower. Concentrations in eggs (fall only) were on the same order of magnitude as those in whole fish. These results demonstrate the presence of target semivolatile organic compounds in a top predator fish, and are consistent with PAH biodilution observed previously. Using the available toxicity information for PAHs and NPAHs, the expected cancer risk from consumption of lake trout sampled are low. However, NPAHs contributed a significant portion of the toxic equivalencies in some samples. The present study provides the first measurements of NPAHs in freshwater fish, and results suggest that additional assessment is warranted. PMID- 24764177 TI - Controlled release of BMP-2 using a heparin-conjugated carrier system reduces in vivo adipose tissue formation. AB - There is growing concern about unwanted effects associated with the clinical use of recombinant human bone morphogenetic protein-2 (rhBMP-2) at high concentrations, including cyst-like bone formation and excessive fatty marrow formation. We, therefore, evaluated the induction of mineralized/adipose tissue formation and the bone-healing pattern associated with the controlled release of E. coli-derived rhBMP-2 (ErhBMP-2) by a heparin-conjugated fibrin (HCF) system using ectopic and orthotopic in vivo models, respectively. In the ectopic transplantation model, mineralized tissue formed at the most superficial layer of the transplanted area and on the surfaces of grafted materials, and most of the interstitial space within the transplanted area was filled with excessive adipose tissue specifically at sites that received ErhBMP-2. However, sites that received ErhBMP-2 and HCF showed significantly increased mineralized tissue formation and decreased adipose tissue formation compared to the normal fibrin system with ErhBMP-2. In the orthotopic (calvarial defect) model, controlled release of ErhBMP-2 induced by HCF significantly reduced adipose tissue formation within the defect area compared to the clinically approved absorbable collagen sponge. From these results, it can be concluded that the use of a HCF system loaded with ErhBMP-2 may reduce adipose tissue formation and enhance mineralized tissue formation. PMID- 24764178 TI - Strong influence of the humidity on the electrical properties of InGaAs surface quantum dots. AB - The impact of the environment on the electrical properties of uncapped In0.5Ga0.5As nanostructures is studied as a function of different atmospheres for sensing applications. Electrical response from surface quantum dots (QD) shows a strong dependence on the atmosphere, in contrast to the response of 2D nanostructures. The sheet resistance drops by 99% from vacuum to air, and decreases more than one order of magnitude when relative humidity changes from 0 to 70%. The adsorption of water molecules onto the QD surface improves the conductivity likely by reducing the density of surface states acting as carrier traps, which enhances electron transport. PMID- 24764179 TI - Synthesis, crystal packing, and ambipolar carrier transport property of twisted dibenzo[g,p]chrysenes. AB - A versatile method for the synthesis of dibenzo[g,p]chrysene (DBC) derivatives based on regio- and stereoselective stannyllithiation to diarylacetylenes is described. This method affords a variety of DBCs possessing both electron donating and electron-withdrawing functional groups. These twisted molecules take brickwork packing structures in single crystals. Thus, ambipolar carrier transport properties with mobility values of up to 10(-3) cm(2) V(-1) s(-1) in the amorphous state were achieved. Functional groups on DBC frameworks are considered to increase carrier mobility through the enhancement of intermolecular interactions in the brickwork packing structures. PMID- 24764180 TI - Optimizing carbon storage and biodiversity protection in tropical agricultural landscapes. AB - With the rapidly expanding ecological footprint of agriculture, the design of farmed landscapes will play an increasingly important role for both carbon storage and biodiversity protection. Carbon and biodiversity can be enhanced by integrating natural habitats into agricultural lands, but a key question is whether benefits are maximized by including many small features throughout the landscape ('land-sharing' agriculture) or a few large contiguous blocks alongside intensive farmland ('land-sparing' agriculture). In this study, we are the first to integrate carbon storage alongside multi-taxa biodiversity assessments to compare land-sparing and land-sharing frameworks. We do so by sampling carbon stocks and biodiversity (birds and dung beetles) in landscapes containing agriculture and forest within the Colombian Choco-Andes, a zone of high global conservation priority. We show that woodland fragments embedded within a matrix of cattle pasture hold less carbon per unit area than contiguous primary or advanced secondary forests (>15 years). Farmland sites also support less diverse bird and dung beetle communities than contiguous forests, even when farmland retains high levels of woodland habitat cover. Landscape simulations based on these data suggest that land-sparing strategies would be more beneficial for both carbon storage and biodiversity than land-sharing strategies across a range of production levels. Biodiversity benefits of land-sparing are predicted to be similar whether spared lands protect primary or advanced secondary forests, owing to the close similarity of bird and dung beetle communities between the two forest classes. Land-sparing schemes that encourage the protection and regeneration of natural forest blocks thus provide a synergy between carbon and biodiversity conservation, and represent a promising strategy for reducing the negative impacts of agriculture on tropical ecosystems. However, further studies examining a wider range of ecosystem services will be necessary to fully understand the links between land-allocation strategies and long-term ecosystem service provision. PMID- 24764181 TI - Endothelial dysfunction: its clinical value and methods of assessment. AB - Endothelial dysfunction (ED) is a systemic disorder characterized by reduced production of nitric oxide. This pathologic condition, which impairs vascular homeostasis, leads to the loss of protective properties of endothelial cells and is related to the pathogenesis of cardiovascular diseases. ED may affect every vascular bed, accounting for several clinical implications, particularly when the coronary bed is affected. Although the reliability of ED as a cardiovascular disease surrogate is still debated, many methods for its assessment have been proposed. In this review, we underline the clinical value of ED in the cardiovascular field and summarize the principal methods currently available for its assessment. PMID- 24764182 TI - Multivalency by self-assembly: binding of concanavalin A to metallosupramolecular architectures decorated with multiple carbohydrate groups. AB - Multiplication of functional units through self-assembly is a powerful way to new properties and functions. In particular, self-organization of components decorated with recognition groups leads to multivalent entities, amenable to strong and selective binding with multivalent targets, such as protein receptors. Here we describe an efficient, supramolecular, one-pot valency multiplication process proceeding through self-organization of monovalent components into well defined, grid-shaped [2*2] tetranuclear complexes bearing eight sugar residues for multivalent interaction with the tetrameric lectin, concanavalin A (Con A). The grids are stable in water under physiological pH at a relatively high concentration, but dissociate readily at slightly more acidic pH or upon dilution below a certain threshold, in a type of on-off behavior. The carbohydrate decorated grids interact strongly and selectively with Con A forming triply supramolecular bio-hybrid polymeric networks, which lead to a highly specific phase-separation and quasi-quantitative precipitation of Con A out of solution. Dramatic effects of valency number on agglutination properties were demonstrated by comparison of grids with divalent carbohydrates of covalent and non-covalent (L-shaped, mononuclear zinc complex) scaffolds. The results presented here provide prototypical illustration of the power of multivalency generation by self assembly leading to defined arrays of functional groups and binding patterns. PMID- 24764183 TI - Measuring the impact of simulation: from utopia to reality. PMID- 24764184 TI - Use of tracheal palpation to assure correct placement of an endotracheal tube: Letter One. PMID- 24764185 TI - Use of tracheal palpation to assure correct placement of an endotracheal tube: Letter Two. PMID- 24764186 TI - Transversus abdominis plane block does not improve early or late pain outcomes after Cesarean delivery: a randomized controlled trial. AB - OBJECTIVES: Cesarean delivery is a common surgical procedure with anticipated substantial postoperative pain. The addition of a transversus abdominis plane block (TAPB) to a multimodal analgesic regimen that includes intrathecal morphine may provide improved early pain outcomes and decrease the risk of chronic post surgical pain. The purpose of this research was to assess the ability of an ultrasound-guided TAPB with low-dose ropivacaine to decrease early postoperative pain, opioid consumption, and risk of developing persistent pain when compared with a placebo block. METHODS: Eighty-three women were randomly assigned to either a treatment (0.25% ropivacaine) or control group (0.9% saline) in this double-blind trial, and 74 women were included in the final analysis. Ultrasound guided TAPBs were performed with an injection of 20 mL of study solution per side. The primary outcome measures of this study were: pain at rest and pain after movement measured with a numeric rating scale, results of the Quality of Recovery-40 (QoR-40) questionnaire, and opioid consumption at 24 hr. These were used with an a priori sample size calculation to detect a 30% reduction in pain scores, a 10% improvement in QoR-40 score, and a 50% reduction in opioid consumption. Health quality and physical functioning were assessed using the Short Form 36 (SF-36(r)) Health Survey at 30 days and six months. RESULTS: Assessment at 24 hr after Cesarean delivery revealed no clinically important differences between groups in postoperative pain, QoR-40, or opioid consumption. There were no clinically important differences between groups regarding measures of nausea, pruritus, vomiting, urine retention (2, 24, and 48 hr postoperatively), 24-hr QoR-40 sub-dimensions, or the SF-36 Health Survey (30 days and six months postoperatively). CONCLUSIONS: Ultrasound-guided TAPB did not improve postoperative pain, quality of recovery, or opioid consumption 24 hr following surgery. Similar health and functioning (SF-36) at 30 days and six months were reported by both groups. This trial was registered at ClinicalTrials.gov number: NCT01261637. PMID- 24764187 TI - Sensitivity to volatile anesthetics in patients with dementia: a case-control analysis. AB - BACKGROUND: Patients with dementia are thought to be more sensitive to anesthesia, although volatile anesthetic requirement has not specifically been evaluated in this population. We tested the hypothesis that patients with dementia having non-cardiac surgery have a lower ratio of bispectral index (BIS) to minimal alveolar concentration (MAC) during the five minutes immediately preceding incision, thus exhibiting deeper hypnotic levels at a given MAC fraction. METHODS: We obtained records from our database registry on patients who had volatile general anesthesia during their most recent operation. We excluded patients premedicated with midazolam. Patients with dementia were identified and their diagnosis was confirmed by chart review. Each patient with dementia was successfully matched with a maximum of five patients without dementia using a multivariate nearest-neighbor distance-matching algorithm restricted to the following criteria: American Society of Anesthesiologists physical status, age, five-minute pre-incision time-weighted average (TWA) estimated effect-site concentration of propofol and fentanyl, and use of remifentanil. Our primary outcome was the TWA BIS-to-MAC ratio during the five minutes immediately preceding incision. RESULTS: We analyzed 31 patients with dementia matched with 151 patients without dementia. Median [quartiles] TWA BIS-to-MAC ratios for the matched patients were 85 [73, 100] for the patients with dementia and 78 [73, 84] for the patients without dementia. The percent difference in mean BIS-to-MAC ratios between patients with dementia and patients without dementia was 9% (95% confidence interval: -9% to 29%) (P = 0.35, Wald test). CONCLUSIONS: Our results do not support the hypothesis that patients with dementia are more sensitive to volatile anesthetics than patients without dementia. PMID- 24764188 TI - Recurrence of cutaneous melanoma of the head and neck after negative sentinel lymph node biopsy. AB - BACKGROUND: Sentinel lymph node biopsy remains controversial for cutaneous melanoma of the head and neck (CMHN). Incidence and factors associated with recurrence after negative sentinel lymph node biopsy have not been well delineated. METHODS: Characteristics of 204 patients with head and neck melanoma who had a negative sentinel lymph node biopsy were studied. Main outcomes were overall survival and disease-free survival. RESULTS: Recurrence developed in 45 patients (22%) with a median time to recurrence of 20.1 months. Five-year overall survival was 91.8% for patients without recurrence and 57.0% for those with recurrence. The overall regional recurrence rate was 8.8% (n = 18) and was associated with Breslow thickness >2 mm and scalp location of the primary tumor. The false omission rate was 3.4%. CONCLUSION: For CMHN, regional recurrence after negative sentinel lymph node biopsy occurs at acceptably low rates relative to other sites, although it is associated with adverse survival. PMID- 24764189 TI - Relaxivity enhancement of aquated Tris(beta-diketonate)gadolinium(III) chelates by confinement within ultrashort single-walled carbon nanotubes. AB - Ultrashort single-walled carbon nanotubes loaded with gadolinium ions (gadonanotubes) have been previously shown to exhibit extremely high T1 -weighted relaxivities (>100 mm(-1) s(-1) ). To further examine the effect of nanoconfinement on the relaxivity of gadolinium-based contrast agents for magnetic resonance imaging, a series of ultrashort single-walled carbon nanotube (US-tube) materials internally loaded with gadolinium chelates have been prepared and studied. US-tubes were loaded with Gd(acac)3 . 2H2 O, Gd(hfac)3 . 2H2 O, and Gd(thd)3 (acac = acetylacetone, hfac = hexafluoroacetylacetone, thd = tetramethylheptanedione). The longitudinal relaxivities of the prepared materials determined at 25 degrees C in a 1.5 T field were 103 mm(-1) s(-1) for Gd(acac)3 . 2H2 O@US-tubes, 105 mm(-1) s(-1) for Gd(hfac)3 . 2H2 O@US-tubes and 26 mm(-1) s(-1) for Gd(thd)3 @US-tubes. Compared with the relaxivities obtained for the unloaded chelates (<10 mm(-1) s(-1) ) as well as accounting for the T1 reduction observed for the empty US-tubes, the boost in relaxivity for chelate-loaded US tubes is attributed to confinement within the nanotube and depends on the number of coordinated water molecules. PMID- 24764190 TI - Contribution of neural cell death to depressive phenotypes of streptozotocin induced diabetic mice. AB - Major depression disorder (MDD) or depression is highly prevalent in individuals with diabetes, and the depressive symptoms are more severe and less responsive to antidepressant therapies in these patients. The underlying mechanism is little understood. We hypothesized that the pathophysiology of comorbid depression was more complex than that proposed for MDD and that neural cell death played a role in the disease severity. To test this hypothesis, we generated streptozotocin (STZ)-induced diabetic mice. These mice had blood glucose levels threefold above controls and exhibited depressive phenotypes as judged by a battery of behavioral tests, thus confirming the comorbidity in mice. Immunohistological studies showed markedly increased TUNEL-positive cells in the frontal cortex and hippocampus of the comorbid mice, indicating apoptosis. This finding was supported by increased caspase-3 and decreased Bcl-2 proteins in these brain regions. In addition, the serum brain-derived neurotrophic factor (BDNF) level of comorbid mice was reduced compared with controls, further supporting the neurodegenerative change. Mechanistic analyses showed an increased expression of mitochondrial fission genes fission protein 1 (Fis1) and dynamin-related protein 1 (Drp1), and a decreased expression of mitochondrial fusion genes mitofusin 1 (Mfn1), mitofusin 2 (Mfn2) and optical atrophy 1 (Opa1). Representative assessment of the proteins Drp1 and Mfn2 mirrored the mRNA changes. The data demonstrated that neural cell death was associated with the depressive phenotype of comorbid mice and that a fission-dominant expression of genes and proteins mediating mitochondrial dynamics played a role in the hyperglycemia-induced cell death. The study provides new insight into the disease mechanism and could aid the development of novel therapeutics aimed at providing neuroprotection by modulating mitochondrial dynamics to treat comorbid depression with diabetes. PMID- 24764191 TI - Role of insulin signaling impairment, adiponectin and dyslipidemia in peripheral and central neuropathy in mice. AB - One of the tissues or organs affected by diabetes is the nervous system, predominantly the peripheral system (peripheral polyneuropathy and/or painful peripheral neuropathy) but also the central system with impaired learning, memory and mental flexibility. The aim of this study was to test the hypothesis that the pre-diabetic or diabetic condition caused by a high-fat diet (HFD) can damage both the peripheral and central nervous systems. Groups of C57BL6 and Swiss Webster mice were fed a diet containing 60% fat for 8 months and compared to control and streptozotocin (STZ)-induced diabetic groups that were fed a standard diet containing 10% fat. Aspects of peripheral nerve function (conduction velocity, thermal sensitivity) and central nervous system function (learning ability, memory) were measured at assorted times during the study. Both strains of mice on HFD developed impaired glucose tolerance, indicative of insulin resistance, but only the C57BL6 mice showed statistically significant hyperglycemia. STZ-diabetic C57BL6 mice developed learning deficits in the Barnes maze after 8 weeks of diabetes, whereas neither C57BL6 nor Swiss Webster mice fed a HFD showed signs of defects at that time point. By 6 months on HFD, Swiss Webster mice developed learning and memory deficits in the Barnes maze test, whereas their peripheral nervous system remained normal. In contrast, C57BL6 mice fed the HFD developed peripheral nerve dysfunction, as indicated by nerve conduction slowing and thermal hyperalgesia, but showed normal learning and memory functions. Our data indicate that STZ-induced diabetes or a HFD can damage both peripheral and central nervous systems, but learning deficits develop more rapidly in insulin-deficient than in insulin-resistant conditions and only in Swiss Webster mice. In addition to insulin impairment, dyslipidemia or adiponectinemia might determine the neuropathy phenotype. PMID- 24764193 TI - Polybrominated diphenyl ethers, dechlorane plus, and polychlorinated biphenyls in tree bark near the upper Yellow River, China. AB - Willow tree bark samples from urban and rural sites in Inner Mongolia, Ningxia Province, and Gansu Province, in the Yellow River basin, were analyzed for polybrominated diphenyl ethers (PBDEs), dechlorane plus (DP), and dioxin-like polychlorinated biphenyls (DL-PCBs) to compare their relative levels in air in these areas (i.e., treating bark as a passive air sampler). No difference was found between the pollutant concentrations in Salix matsudana and Salix babylonica bark samples. The mean concentrations of the total PBDEs, DP, and total DL-PCBs were 13000 +/- 6400, 46 +/- 44, and 26 +/- 17 pg/g dry weight, respectively, with urban samples containing much higher concentrations (19000 +/- 5700 pg/g, 51 +/- 27 pg/g, and 37 +/- 29 pg/g dry wt in PBDEs, DP, and DL-PCBs, respectively) than rural samples (10000 +/- 5200 pg/g, 45 +/- 53 pg/g, 22 +/- 9 pg/g dry wt). A strong positive correlation between PBDEs and DP was found in all of the samples (r=0.712, p=0.006), but correlations between PCBs and the other pollutants were only found in the rural samples. The total DL-PCB concentration in the tree bark correlated with population density. PMID- 24764192 TI - A novel mouse model of Warburg Micro syndrome reveals roles for RAB18 in eye development and organisation of the neuronal cytoskeleton. AB - Mutations in RAB18 have been shown to cause the heterogeneous autosomal recessive disorder Warburg Micro syndrome (WARBM). Individuals with WARBM present with a range of clinical symptoms, including ocular and neurological abnormalities. However, the underlying cellular and molecular pathogenesis of the disorder remains unclear, largely owing to the lack of any robust animal models that phenocopy both the ocular and neurological features of the disease. We report here the generation and characterisation of a novel Rab18-mutant mouse model of WARBM. Rab18-mutant mice are viable and fertile. They present with congenital nuclear cataracts and atonic pupils, recapitulating the characteristic ocular features that are associated with WARBM. Additionally, Rab18-mutant cells exhibit an increase in lipid droplet size following treatment with oleic acid. Lipid droplet abnormalities are a characteristic feature of cells taken from WARBM individuals, as well as cells taken from individuals with other neurodegenerative conditions. Neurological dysfunction is also apparent in Rab18-mutant mice, including progressive weakness of the hind limbs. We show that the neurological defects are, most likely, not caused by gross perturbations in synaptic vesicle recycling in the central or peripheral nervous system. Rather, loss of Rab18 is associated with widespread disruption of the neuronal cytoskeleton, including abnormal accumulations of neurofilament and microtubule proteins in synaptic terminals, and gross disorganisation of the cytoskeleton in peripheral nerves. Global proteomic profiling of peripheral nerves in Rab18-mutant mice reveals significant alterations in several core molecular pathways that regulate cytoskeletal dynamics in neurons. The apparent similarities between the WARBM phenotype and the phenotype that we describe here indicate that the Rab18-mutant mouse provides an important platform for investigation of the disease pathogenesis and therapeutic interventions. PMID- 24764194 TI - Mild nasal clefting may be predictive for ALX4 heterozygotes. AB - Heterozygous loss-of-function mutations in ALX4 are responsible for enlarged parietal foramina, whereas patients with biallelic ALX4 mutations display a phenotypic spectrum of clinical findings, from mild to severe alopecia, cranium bifidum, hypertelorism, microphthalmia, with alar clefting being the pivotal sign in all affecteds. We report on four affected individuals in a three-generation family, displaying a phenotypic spectrum ranging from mild nasal clefting and broad columella to subtle changes in nasal configuration in addition to parietal foramina, caused by a novel ALX4 mutation (c.646C>G, p.Arg216Gly). This is the second report of a family showing vertical transmission of a dominant ALX4 mutation with facial involvement in addition to parietal foramina, mimicking mild recessive ALX4 phenotype. We discuss possible pathological mechanisms that may have lead to phenotypic variation in the family and challenges in genetic counseling. PMID- 24764195 TI - anti-Markovnikov hydroamination of alkenes catalyzed by a two-component organic photoredox system: direct access to phenethylamine derivatives. AB - Disclosed herein is a general catalytic system for the intermolecular anti Markovnikov hydroamination of alkenes. By using an organocatalytic photoredox system, alpha- and beta-substituted styrenes as well as aliphatic alkenes undergo anti-Markovnikov hydroamination. Heterocyclic amines were also successfully employed as nitrogen nucleophiles, thus providing a direct route to heterocyclic motifs common in medicinal agents. PMID- 24764196 TI - Solid-state perovskite-sensitized p-type mesoporous nickel oxide solar cells. AB - Perovskite has been adopted as photosensitizer to develop solid state p-type mesoporous nickel oxide (NiO) dye-sensitized solar cells (DSCs) employing PCBM as electron conductor. The optimal device achieved an efficiency of 1.5% with an impressive open circuit voltage of more than 800 mV, which is the record of solar cell based on p-type mesoporous NiO electrode. This result shows the potential for building highly efficient p-type NiO solar cells as stand-alone device. PMID- 24764198 TI - Ibuprofen dependence: a case report. AB - Ibuprofen is currently widely prescribed and has not been reported to produce dependence. We report the case of a 17-year old patient who presented many positive psychic symptoms related to a pharmacological dependence. During the treatment, she adjusted herself posology as she developed withdrawal symptoms. Pharmacological evidences (effect on COX-1 and COX-2, FAAH and PPARs) allow us to formulate hypotheses explaining this effect. PMID- 24764197 TI - Traditional herbal medicine use among hypertensive patients in sub-Saharan Africa: a systematic review. AB - Hypertension is increasingly common in sub-Saharan Africa, and rates of hypertension control are low. Use of traditional herbal medicines (THM) is common among adults in sub-Saharan Africa and may affect hypertension therapy. We searched Ovid MEDLINE, Ovid EMBASE, and Web of Knowledge in June 2013 to find studies about THM use among hypertensive patients living in sub-Saharan Africa. Two independent reviewers evaluated titles and abstracts. Qualifying references were reviewed in full text. Data were extracted using a standardized questionnaire. Four hundred and eighty-one references were retrieved, and four articles from two countries met criteria for inclusion. The prevalence of THM use was 25-65% (average 38.6%). THM was the most common type of complementary and alternative medicines used by patients (86.7-96.6%). Among THM users, 47.5% concomitantly used both allopathic medicine and THM. Increased age (p<0.001), male sex (RR 2.58), belief in a supernatural cause of hypertension (RR 2.11), and family history of hypertension (OR 1.78) were positively associated with THM use, while belief that hypertension is preventable was negatively associated with THM use (OR 0.57). More than one-third of adults with hypertension in sub-Saharan Africa use THM. Half of these patients use THM concurrently with allopathic medicine. Healthcare workers in sub-Saharan Africa must discuss THM use with their hypertensive patients. More research is urgently needed to define the impact of THM use on hypertension control and outcomes in sub-Saharan Africa. PMID- 24764199 TI - Can valproic acid be an inducer of clozapine metabolism? AB - INTRODUCTION: Prior clozapine studies indicated no effects, mild inhibition or induction of valproic acid (VPA) on clozapine metabolism. The hypotheses that (i) VPA is a net inducer of clozapine metabolism, and (ii) smoking modifies this inductive effect were tested in a therapeutic drug monitoring study. METHODS: After excluding strong inhibitors and inducers, 353 steady-state total clozapine (clozapine plus norclozapine) concentrations provided by 151 patients were analyzed using a random intercept linear model. RESULTS: VPA appeared to be an inducer of clozapine metabolism since total plasma clozapine concentrations in subjects taking VPA were significantly lower (27% lower; 95% confidence interval, 14-39%) after controlling for confounding variables including smoking (35% lower, 28-56%). DISCUSSION: Prospective studies are needed to definitively establish that VPA may (i) be an inducer of clozapine metabolism when induction prevails over competitive inhibition, and (ii) be an inducer even in smokers who are under the influence of smoking inductive effects on clozapine metabolism. PMID- 24764200 TI - Effects of escitalopram on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in Japanese patients. AB - INTRODUCTION: The effects of escitalopram (10 mg/d) coadministration on plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, were studied in 13 Japanese psychiatric patients and compared with those of paroxetine (10 mg/d) coadministration. METHODS: The patients had received 6-24 mg/d of aripiprazole for at least 2 weeks. Patients were randomly allocated to one of 2 treatment sequences: paroxetine-escitalopram (n=6) or escitalopram paroxetine (n=7). Each sequence consisted of two 2-week phases. Plasma concentrations of aripiprazole and dehydroaripiprazole were measured using liquid chromatography with mass spectrometric detection. RESULTS: Plasma concentrations of aripiprazole and the sum of aripiprazole and dehydroaripiprazole during paroxetine coadministration were 1.7-fold (95% confidence intervals [CI], 1.3 2.1, p<0.001) and 1.5-fold (95% CI 1.2-1.9, p<0.01) higher than those values before the coadministration. These values were not influenced by escitalopram coadministration (1.3-fold, 95% CI 1.1-1.5 and 1.3-fold, 95% CI 1.0-1.5). Plasma dehydroaripiprazole concentrations remained constant during the study. CONCLUSION: The present study suggests that low doses of escitalopram can be safely coadministered with aripiprazole, at least from a pharmacokinetic point of view. PMID- 24764202 TI - UV-assisted removal of inactive peroxide species for sustained epoxidation of cyclooctene on anatase TiO2. AB - Epoxidation of olefins with H2O2 is one of the most important reactions in organic synthesis. We found that anatase TiO2 can be a good catalyst for the epoxidation of cyclooctene with H2O2 at room temperature. However, the catalyst deactivated quickly in the presence of excess amount of H2O2 because of the formation of inactive side-on Ti-eta(2)-peroxide species on the surface of TiO2, the presence of which was confirmed by isotope-labelled resonance UV Raman spectroscopy and kinetics studies. Interestingly, the epoxidation reaction could be dramatically accelerated under irradiation of UV light with lambda>=350 nm. This phenomenon is attributed to the photo-assisted removal of the inactive peroxide species, through which the active sites on the surface of anatase TiO2 are regenerated and the catalytic epoxidation of cyclooctene with H2O2 is resumed. This finding provides an alternative for sustained epoxidation reactions on TiO2 at room temperature. Moreover, it also has significant implications on the deactivation pathway and possible solutions in Ti-based heterogeneous catalysis or photocatalysis. PMID- 24764201 TI - 2-methoxyestradiol and disorders of female reproductive tissues. AB - 2-Methoxyestradiol (2ME) is an endogenous metabolite of 17beta-estradiol. Once thought of as a mere degradation product, 2ME has gained attention as an important component of reproductive physiology and as a therapeutic agent in reproductive pathologies such as preeclampsia, endometriosis, infertility, and cancer. In this review, we discuss the involvement of 2ME in reproductive pathophysiology and summarize its known mechanisms of action: microtubule disruption, inhibition of angiogenesis and stimulation of apoptosis. Currently, the clinical uses of 2ME as a single agent are limited due to its poor water solubility and thus low bioavailability; however, 2ME analogs and derivatives have been recently developed and tested as cancer treatments. Despite some isolated success stories and ongoing research, 2ME derivatives have not yet provided the expected results. The adjuvant use of 2ME derivatives with chemotherapeutic agents is hindered by their intrinsic toxicity confounding the unwanted secondary effects of chemotherapy. However, due to the well-tested tolerance of the body to high doses of native 2ME, it may the combination of native 2ME with conventional treatments that will offer novel clinically relevant regimens for cancer and other reproductive disorders. PMID- 24764203 TI - Nicotinamide treatment ameliorates the course of experimental colitis mediated by enhanced neutrophil-specific antibacterial clearance. AB - SCOPE: In previous studies, we could show that the B vitamin nicotinamide (NAM) enhanced antimicrobial activity of neutrophils. Here, we assessed the effects of NAM in two models of experimental colitis. METHODS AND RESULTS: Colitis was induced in C57BL/6 mice either by oral infection with Citrobacter rodentium or by DSS (dextran sodium sulphate) administration, and animals were systemically treated with NAM. Ex vivo bacterial clearance was assessed in murine and human whole blood, as well as isolated human neutrophils. In C. rodentium-induced colitis, NAM treatment resulted in markedly decreased systemic bacterial invasion, histological damage and increased fecal clearance of C. rodentium by up to 600-fold. In contrast, NAM had no effect when administered to neutrophil depleted mice. Ex vivo stimulation of isolated human neutrophils, as well as murine and human whole blood with NAM led to increased clearance of C. rodentium and enhanced expression of antimicrobial peptides in neutrophils. Moreover, NAM treatment significantly ameliorated the course of DSS colitis, as assessed by body weight, histological damage and myeloperoxidase activity. CONCLUSION: Pharmacological application of NAM mediates beneficial effects in bacterial and chemically induced colitis. Future studies are needed to explore the clinical potential of NAM in the context of intestinal bacterial infections and human inflammatory bowel disease (IBD). PMID- 24764204 TI - Salvage endoscopic nasopharyngectomy and intensity-modulated radiotherapy versus conventional radiotherapy in treating locally recurrent nasopharyngeal carcinoma. AB - BACKGROUND: Although endoscopic nasopharyngectomy and intensity-modulated radiotherapy (IMRT) have been reported to be useful in treating isolated local recurrent nasopharyngeal carcinoma (NPC), their efficacy needs to be revaluated with comparison to 2D conventional radiotherapy (RT). METHODS: Four hundred ten patients with recurrent NPC were retrospectively analyzed, among whom the patients underwent IMRT, endoscopic nasopharyngectomy, and 2D conventional RT. RESULTS: The 5-year overall survival (OS) and distant metastasis-free survival were significantly higher in endoscopic nasopharyngectomy and IMRT groups than in 2D conventional RT group both in the entire series and in the subgroup of patients with recurrent T1 to 2 NPC (p < .05), except in the subgroup of recurrent T3 to 4 stratifications (IMRT vs 2D conventional RT; 28.8% vs 16.8%; p = .351). Furthermore, endoscopic nasopharyngectomy was associated with better OS than IMRT in the recurrent T1 to 2 subgroup (79.2% vs 62.1%; p = .007). Multivariate analysis indicated therapeutic modality was an independent predictor of OS and distant metastasis-free survival (p < .001). CONCLUSION: Endoscopic nasopharyngectomy and IMRT are associated with an improved OS and distant metastasis-free survival of patients with recurrent NPC compared to 2D conventional RT in early recurrent disease. PMID- 24764205 TI - The effects of variable-time versus contingent reinforcement delivery on problem behavior maintained by escape. AB - Results of previous research indicate that the delivery of positive reinforcement (e.g., food) for an appropriate, alternative target response (e.g., compliance) or delivery of food on a time-based schedule can decrease problem behavior reinforced by escape, even when problem behavior continues to produce negative reinforcement (e.g., Lalli et al., ; Lomas, Fisher, & Kelley, ). In this study, we compared the levels of both compliance and problem behavior when food and praise were delivered either contingent on compliance or on a time-based schedule. Results for 3 of the 4 participants showed that contingent delivery of preferred edible items and praise was more effective in both reducing problem behavior and increasing compliance compared to variable-time delivery of these same items. These findings are discussed in the context of motivating operations and competition between positive and negative reinforcement. PMID- 24764206 TI - Using ordination and clustering techniques to assess multimetric fish health response following a coal ash spill. AB - The effect of coal ash exposure on fish health in freshwater communities is largely unknown. Given the large number of possible pathways of effects (e.g., toxicological effect of exposure to multiple metals, physical effects from ash exposure, and food web effects), measurement of only a few health metrics is not likely to give a complete picture. The authors measured a suite of 20 health metrics from 1100+ fish collected from 5 sites (3 affected and 2 reference) near a coal ash spill in east Tennessee over a 4.5-yr period. The metrics represented a wide range of physiological and energetic responses and were evaluated simultaneously using 2 multivariate techniques. Results from both hierarchical clustering and canonical discriminant analyses suggested that for most species * season combinations, the suite of fish health indicators varied more among years than between spill and reference sites within a year. In a few cases, spill sites from early years in the investigation stood alone or clustered together separate from reference sites and later year spill sites. Outlier groups of fish with relatively unique health profiles were most often from spill sites, suggesting that some response to the ash exposure may have occurred. Results from the 2 multivariate methods suggest that any change in the health status of fish at the spill sites was small and appears to have diminished since the first 2 to 3 yr after the spill. PMID- 24764207 TI - A novel mutation in the EDAR gene causes severe autosomal recessive hypohidrotic ectodermal dysplasia. AB - We report on a 2-year-old girl presenting with a severe form of hypohidrotic ectodermal dysplasia (HED). The patient presented with hypotrichosis, anodontia, hypohidrosis, frontal bossing, prominent lips and ears, dry, pale skin, and dermatitis. The patient had chronic rhinitis with malodorous nasal discharge. The girl was the second born child of first-cousin immigrants from Northern Iraq. A novel homozygous mutation (c.84delC) in the EDAR gene was identified. This mutation most likely causes a frameshift in the protein product (p.S29fs*74). This results in abolition of all ectodysplasin-mediated NF-kB signalling. This complete loss-of-function mutation likely accounts for the severe clinical abnormalities in ectodermal structures in the described patient. PMID- 24764208 TI - Predicting factors for unresectability in patients with pancreatic ductal adenocarcinoma. AB - BACKGROUND: The aim of the present study was to identify the predicting factors for unresectability and to clarify who should receive precise evaluations for distant metastasis and locally advanced unresectability in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: A total of 200 consecutive patients with PDAC who presented to the outpatient clinic between June 2009 and October 2012 were analyzed retrospectively. Clinical factors and the serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, DUPAN-2 (pancreatic cancer-associated antigen) and CA 125 were analyzed. RESULTS: Of the 200 patients who were investigated for PDAC, 60 (30%) were initially considered unresectable (15 patients with locally advanced tumors, 45 patients with distant metastases). Of the 136 (68%) patients who were surgically explored, 19 (9.5%) were detected to have minute metastases on laparotomy. A multivariate analysis revealed that tumor size (>=30 mm) and abnormalities in the levels of DUPAN-2 and CA 125 were independent predictors of unresectability (P = 0.002, 0.014, < 0.001, respectively). The patients with triple positive findings presented with the highest sensitivity (78.8%) for unresectability. CONCLUSIONS: Patients with triple positive findings for a tumor size >=30 mm, abnormalities in the levels of DUPAN-2 and CA 125 should receive precise evaluations for unresectability. PMID- 24764209 TI - Silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids in aqueous emulsion. AB - A silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary carboxylic acids under mild conditions tolerates a wide range of functional groups. The reaction was dramatically accelerated by its performance in an aqueous emulsion, which was formed by the addition of sodium dodecyl sulfate to water. It was proposed that the radical, which was generated from the silver-catalyzed decarboxylation in the "oil-in-water" droplets, could easily react with the trifluoromethylthiolating reagent to form the product. PMID- 24764210 TI - White paper: clinical studies in radiology. PMID- 24764211 TI - High-resolution ultrasonography of peripheral nerves: measurements on 14 nerve segments in 56 healthy subjects and reliability assessments. AB - PURPOSE: The aim of this study was to assess different aspects of reliability in high-resolution ultrasonography (HRUS) of the peripheral nerves and to establish reference values for the most frequently examined nerve segments. MATERIALS AND METHODS: A nerve size parameter, the cross-sectional area (CSA) of the C5, C6 and C7 cervical roots, the median, ulnar, radial, superficial radial, peroneal, tibial, and the sural nerves was measured using HRUS at a total of 14 predefined anatomical sites in two different cohorts of healthy subjects (n = 56), and the inter-rater, intra-rater and inter-equipment reliability of measurements was assessed. RESULTS: The mean CSA of the 14 nerve segments ranged from 2 to 10 mm(2). The intra-rater, inter-rater and inter-equipment reliability was high with intraclass correlation coefficients of 0.93, 0.98, and 0.86, respectively. The CSA values showed no consistent correlation with age, height, and body weight, but males had significantly larger values than females for nerve segments on the arm after correcting for age, weight and height in multivariate analysis. CSA values did not differ when two independent cohorts were compared. CONCLUSION: Peripheral nerve ultrasonography is a reliable and reproducible diagnostic method in the hands of experienced examiners. Normal values for several upper and lower extremity nerves are provided by our study. PMID- 24764212 TI - Comparison of Cancer Yields and Diagnostic Performance of Screening Mammography vs. Supplemental Screening Ultrasound in 4394 Women with Average Risk for Breast Cancer. AB - PURPOSE: The effectiveness of supplemental screening ultrasound (US) was investigated in women >= 40 years at average risk for breast cancer regardless of breast parenchymal density. A total of 4394 women at average risk and having previously undergone screening mammography were classified as the mammography group. MATERIALS AND METHODS: Of 4394 women, 2005 underwent screening US after a final assessment of category 1 or 2 on screening mammography, and were categorized as the US group. Category 0, 4, and 5 on mammography and 3, 4, and 5 on US were defined as positive. The cancer yields per 1000 women and diagnostic performance of two groups were compared. RESULTS: The total cancer and invasive cancer yields for the mammography group were 3.0 (95 % confidence interval 1.6, 5.1) and 2.0 (95 % CI, 0.9, 3.9) per 1000 women, higher than the US values of 2.0 (0.5, 5.1) and 1.0 (0.1, 3.6), not statistically significant. The specificity, accuracy, and positive predictive value (PPV) for mammography were 88.90 % (87.93, 89.81), 88.85 % (87.88, 89.76), and 2.61 % (1.39, 4.41), significantly higher than the US values of 69.07 % (66.99, 71.09), 69.13 % (67.05, 71.15), and 0.64 % (0.18, 1.64). The short-term follow-up rate of mammography was 5.51 % (4.85, 6.22), significantly lower than the rate of 26.58 (24.66, 28.58) for US. CONCLUSION: Supplemental screening US in mammographically negative breasts can find additional carcinomas in women at average risk but is not as effective as screening mammography because of the lower cancer yield, invasive cancer yield, specificity, accuracy, PPV and a high short-term follow-up rate. PMID- 24764213 TI - [Sonographic criteria for diagnosing sentinel node metastases in melanoma patients]. AB - PURPOSE: Ultrasound-guided fine needle aspiration cytology (US-FNAC) prior to surgical excision of a sentinel lymph node (SLN) is a new microinvasive approach for detecting micrometastases in melanoma patients. The aim of the current prospective study was to determine the sensitivity and specificity of the method and to define new diagnostic generally applicable ultrasound criteria. MATERIALS AND METHODS: In 800 consecutive patients suffering from malignant melanoma of stage I/II, the SNs were examined sonographically after lymphoscintigraphy. US FNAC was performed in all suspicious lesions in 302 patients. All patients underwent surgical removal of the SLN. The final histopathology and sonographic findings were correlated. RESULTS: After a follow-up of 37 months and a given median tumor thickness of 1.6 mm in our cohort, 21 % of the patients had a positive SLN in the histologic examination. We calculated a sensitivity and specificity of US-FNAC of 56 % and 99 %, respectively. The positive and negative predictive values were 92 % and 89 %, respectively. The highest positive predictive values were achieved using the ultrasound criterion of peripheral perfusion in power mode. The sensitivity of US-FNAC increased in parallel with an increasing pT stage of the primary tumor and increasing size of the largest diameter of the involved SN nest. CONCLUSION: Our prospective study shows the impact of ultrasound-guided FNAC in the staging of the SN prior to a planned SLNB. It proved to be an additional, cost-effective diagnostic tool that enhances the discriminatory power for the indication to perform SLNB and spares both the patient and the surgeon a second surgical procedure. Among the tested ultrasound criteria, peripheral perfusion (PP) showed the highest sensitivity for detecting early SN. PMID- 24764214 TI - [Combined first trimester screening and cell-free fetal DNA - "next generation screening"]. AB - In the last decades, prenatal screening for aneuploidy has become increasingly effective. While first trimester combined screening is considered to be the current gold standard, the use of cell-free fetal DNA (cffDNA), which is also called noninvasive prenatal testing (NIPT), will result in a change of paradigm. Respective studies indicate that in screening for trisomy 21, the detection and false-positive rates are 99 % and 0.1 %, respectively. For trisomies 18 and 13, there is less evidence but recent studies report detection rates of 98 % and 86 %. Despite the excellent results in screening for trisomy 21, NIPT should not be considered as a diagnostic test. Due to the costs of NIPT, it is unlikely that NIPT will be applied in the near future in population-based screening for trisomy. In addition, the scope of the current approach in first trimester screening exceeds the screening for aneuploidy as it is possible to assess the risk for various pregnancy complications. Therefore, a combination of both NIPT and first trimester combined screening seems reasonable. Both examinations could be applied in a contingent model where the latter is offered to everyone and NIPT is restricted to women with an intermediate risk after first trimester combined screening. Such a policy would result in a detection rate of about 97 % for a false-positive rate of about 1 %. While NIPT currently focuses on screening for trisomy 21, 18, 13 and sex chromosomal abnormalities, the scope of NIPT will soon become broader. In this respect, some study groups have managed to examine the whole fetal genome within the course of the pregnancy. However, moral and ethical considerations need to be taken into account. PMID- 24764215 TI - Transcranial sonography (TCS) of brain parenchyma in movement disorders: quality standards, diagnostic applications and novel technologies. AB - Transcranial B-mode sonography (TCS) of brain parenchyma is being increasingly used as a diagnostic tool in movement disorders. Compared to other neuroimaging modalities such as magnetic resonance imaging (MRI) and computed tomography, TCS can be performed today with portable machines and has the advantages of noninvasiveness and high resistance to movement artifacts. In distinct brain disorders TCS detects abnormalities that cannot be visualized or can only be visualized with significant effort with other imaging methods. In the field of movement disorders, TCS has been established mainly as a tool for the early and differential diagnosis of Parkinson's disease. The postoperative position control of deep brain stimulation electrodes, especially in the subthalamic nucleus, can reliably and safely be performed with TCS. The present update review summarizes the current methodological standards and defines quality criteria of adequate TCS imaging and assessment of diagnostically relevant deep brain structures such as substantia nigra, brainstem raphe, basal ganglia and ventricles. Finally, an overview is given on recent technological advances including TCS-MRI fusion imaging and upcoming technologies of digitized image analysis aiming at a more investigator-independent assessment of deep brain structures on TCS. PMID- 24764216 TI - Nonenzymatic rubylation and ubiquitination of proteins for structural and functional studies. AB - Uncovering the mechanisms that allow conjugates of ubiquitin (Ub) and/or Ub-like (UBL) proteins such as Rub1 to serve as distinct molecular signals requires the ability to make them with native connectivity and defined length and linkage composition. A novel, effective, and affordable strategy for controlled chemical assembly of fully natural UBL-Ub, Ub-UBL, and UBL-UBL conjugates from recombinant monomers is presented. Rubylation of Ub and Rub1 and ubiquitination of Rub1 was achieved without E2/E3 enzymes. New residue-specific information was obtained on the interdomain contacts in naturally-occurring K48-linked Rub1-Ub and Ub-Rub1, and K29-linked Rub1-Ub heterodimers, and their recognition by a K48-linkage specific Ub receptor. The disassembly of these heterodimers by major deubiquitinating enzymes was examined and it was discovered that some deubiquitinases also possess derubylase activity. This unexpected result suggests possible crosstalk between Ub and Rub1/Nedd8 signaling pathways. PMID- 24764217 TI - Nitrogen and phosphorus additions impact arbuscular mycorrhizal abundance and molecular diversity in a tropical montane forest. AB - Increased nitrogen (N) depositions expected in the future endanger the diversity and stability of ecosystems primarily limited by N, but also often co-limited by other nutrients like phosphorus (P). In this context a nutrient manipulation experiment (NUMEX) was set up in a tropical montane rainforest in southern Ecuador, an area identified as biodiversity hotspot. We examined impacts of elevated N and P availability on arbuscular mycorrhizal fungi (AMF), a group of obligate biotrophic plant symbionts with an important role in soil nutrient cycles. We tested the hypothesis that increased nutrient availability will reduce AMF abundance, reduce species richness and shift the AMF community toward lineages previously shown to be favored by fertilized conditions. NUMEX was designed as a full factorial randomized block design. Soil cores were taken after 2 years of nutrient additions in plots located at 2000 m above sea level. Roots were extracted and intraradical AMF abundance determined microscopically; the AMF community was analyzed by 454-pyrosequencing targeting the large subunit rDNA. We identified 74 operational taxonomic units (OTUs) with a large proportion of Diversisporales. N additions provoked a significant decrease in intraradical abundance, whereas AMF richness was reduced significantly by N and P additions, with the strongest effect in the combined treatment (39% fewer OTUs), mainly influencing rare species. We identified a differential effect on phylogenetic groups, with Diversisporales richness mainly reduced by N additions in contrast to Glomerales highly significantly affected solely by P. Regarding AMF community structure, we observed a compositional shift when analyzing presence/absence data following P additions. In conclusion, N and P additions in this ecosystem affect AMF abundance, but especially AMF species richness; these changes might influence plant community composition and productivity and by that various ecosystem processes. PMID- 24764218 TI - Intracerebral hemorrhage: a multimodality approach to improving outcome. PMID- 24764219 TI - Theoretical investigations on C60 -ionic liquid interactions and their impacts on C60 dispersion behavior. AB - Increased use and production of carbon nanomaterials (e.g., fullerene C60 ) and ionic liquids (ILs) may result in their concomitant releases into the environment. Inevitably there will be interactions between carbon nanoparticles (CNPs) and ILs. However, experimental data on the interaction of CNPs with ILs are not readily available, and the mechanism behind the interactions is still elusive. To contribute to an understanding of the molecular interactions established between CNPs and ILs, theoretical investigations at multiple levels were performed to determine the interactions of C60 with 6 different imidazolium based ILs. The results indicate that C60 mainly interacts with the IL molecules through the van der Waals, pi-cation, and hydrophobic interactions. Mulliken population analysis suggests that charge transfer occurs from the IL to C60 during the C60 -IL interaction. The self-diffusion coefficient (D) of C60 in [C60 + IL] systems reaches the maximum in the case of moderate C60 -IL interaction (interaction energy, EINT ), implying that in this case a good dispersion of an agglomerate species of C60 is obtained. The D value of C60 in [C60 + IL +water] systems increases with an increase of the EINT , implying that the presence of ILs can play an important role in the aqueous dispersion of the C60 agglomerate. PMID- 24764220 TI - N-diazo-bridged nitroazoles: catenated nitrogen-atom chains compatible with nitro functionalities. AB - N-diazo-bridged azoles were synthesized based on oxidative coupling of N aminoazoles. Incorporation of extended catenated nitrogen-atom chains with nitro groups led to compounds with favorable functional compatibilities. This combination gives rise to a series of high-density energetic materials (HEDMs) with high heats of formation, enhanced densities, positive oxygen balances, and good detonation properties while retaining excellent thermal stabilities and relatively low impact sensitivities. Calculated and experimental studies showed the delicate balance between the length of the nitrogen atom chain, energetic performance, and inherent stability, thus, providing a promising strategy for designing advanced energetic materials. PMID- 24764221 TI - Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)--10-year follow-up of patients who previously participated in an MPS VI Survey Study. AB - Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylgalactosamine 4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4-7-year-old baseline age group and by 16.8 cm in the 8-12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those >=13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 ug/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the >=13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naive patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10-0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival. PMID- 24764223 TI - The influence of the extent of enzymatic hydrolysis on antioxidative properties and ACE-inhibitory activities of protein hydrolysates from goby (Zosterisessor ophiocephalus) muscle. AB - Antioxidant properties and angiotensin-converting enzyme (ACE) inhibitory activities of protein hydrolysates from goby (Zosterisessor ophiocephalus) muscle, with different degrees of hydrolysis (DH) from 5 to 25%, prepared by treatment with crude proteases extract from smooth hound intestines, were investigated. Goby protein hydrolysates (GPHs) are rich in Gly and Thr, which accounted for 14.1-15% and 11.6-13.2% of the total amino acids, respectively. The antioxidant activities of GPHs were investigated by using several in vitro assay systems. All GPHs exhibited significant metal chelating activity and DPPH free radical-scavenging activity, and inhibited linoleic acid peroxidation. For the ACE-inhibitory activity, as the DH increased, the activity of GPHs increased. The obtained results revealed that antioxidant and ACE-inhibitory activities of GPHs were influenced by the degree of hydrolysis. A medium degree of enzymatic hydrolysis was appropriate to obtain GPHs with good antioxidant activity, while small peptides were essential to obtain high ACE inhibitory activity. PMID- 24764222 TI - Synergistic induction of early stage of bone formation by combination of recombinant human bone morphogenetic protein-2 and epidermal growth factor. AB - This study evaluates whether the combination of the rhBMP-2 and various types of growth factors including EGF, FGF, PDGF and VEGF increases osteoinductivity compared to the single use of rhBMP-2 through in vitro and in vivo study. Cultured human MSCs were treated with rhBMP-2 only or in combination with growth factors. For in vivo evaluation, rhBMP-2 only or with growth factors was implanted into the calvarial defect made on SD rats. Both EGF and PDGF significantly increased both ALP activity and expression level in hMSCs when treated in combination with rhBMP-2 at 3 and 7 days of differentiation and significantly raised the accumulation of the calcium at day 14. Furthermore, micro-CT scanning revealed that the EGF an FGF groups show significantly increased new bone surface ratio compared to the rhBMP-2 only group and, the EGF treatment significantly up regulated percent bone volume and trabecular number at two weeks after the surgery. VEGF treatment also significantly raised trabecular number and FGF treatment significantly increased the trabecular thickness. Histological examination revealed that the EGF combination group showed enhanced bone regeneration than the rhBMP-2 only group two weeks after the implantation. Even though the treatment of rhBMP-2 with PDGF and FGF failed to show enhanced osteogenesis in vitro and in vivo simultaneously, these results suggest that the positive effect of the combination of EGF and rhBMP-2 is expected to induce the bone formation earlier compared to the single use of rhBMP-2 in vitro and in vivo. PMID- 24764225 TI - Establishing fire safety skills using behavioral skills training. AB - The use of behavioral skills training (BST) to educate 3 adolescent boys on the risks of lighters and fire setting was evaluated using in situ assessment in a school setting. Two participants had a history of fire setting. After training, all participants adhered to established rules: (a) avoid a deactivated lighter, (b) leave the training area, and (c) report the lighter to an adult. The response sequence was maintained for both participants after training. The use of in situ assessment to evoke and observe infrequent behavior is discussed. PMID- 24764226 TI - Different exosome cargo from plasma/bronchoalveolar lavage in non-small-cell lung cancer. AB - Tumor-derived exosomes mediate tumorigenesis by facilitating tumor growth, metastasis, development of drug resistance, and immunosuppression. However, little is known about the exosomes isolated from bronchoalveolar lavage (BAL) in patients with lung neoplasm. Exosomes isolated in plasma and BAL from 30 and 75 patients with tumor and nontumor pathology were quantified by acetylcholinesterase activity and characterized by Western Blot, Electron Microscopy, and Nanoparticle Tracking Analysis. Differences in exosome cargo were analyzed by miRNA quantitative PCR in pooled samples and validated in a second series of patients. More exosomes were detected in plasma than in BAL in both groups (P < 0.001). The most miRNAs evaluated by PCR array were detected in tumor plasma, tumor BAL, and nontumor BAL pools, but only 56% were detected in the nontumor plasma pool. Comparing the top miRNAs with the highest levels detected in each pool, we found close homology only between the BAL samples of the two pathologies. In tumor plasma, we found a higher percentage of miRNAs with increased levels than in tumor BAL or in nontumor plasma. The data reveal differences between BAL and plasma exosome amount and miRNA content. PMID- 24764227 TI - Large-field-of-view wide-spectrum artificial reflecting superposition compound eyes. AB - In nature, reflecting superposition compound eyes (RSCEs) found in shrimps, lobsters and some other decapods are extraordinary imaging systems with numerous optical features such as minimum chromatic aberration, wide-angle field of view (FOV), high sensitivity to light and superb acuity to motion. Here, we present life-sized, large-FOV, wide-spectrum artificial RSCEs as optical imaging devices inspired by the unique designs of their natural counterparts. Our devices can form real, clear images based on reflection rather than refraction, hence avoiding chromatic aberration due to dispersion by the optical materials. Compared to imaging at visible wavelengths using conventional refractive lenses of comparable size, our artificial RSCEs demonstrate minimum chromatic aberration, exceptional FOV up to 165 degrees without distortion, modest aberrations and comparable imaging quality without any post-image processing. Together with an augmenting cruciform pattern surrounding each focused image, our large-FOV, wide-spectrum artificial RSCEs possess enhanced motion-tracking capability ideal for diverse applications in military, security, medical imaging and astronomy. PMID- 24764228 TI - Barbed sutures in total knee arthroplasty: are these safe, efficacious, and cost effective? AB - The use of barbed sutures has become increasingly popular; however, their efficacy and safety continues to be debated. We review the records of 333 primary total knee arthroplasties (TKAs) to determine the difference in wound closure and total operative time between patients closed with a barbed versus standard sutures. We also evaluated complication rates and cost differences between the two groups. Overall, we saw no significant difference in either wound closure time (31 vs. 30 minutes) or total operative time (115 vs. 114 minutes). No significant differences were observed in the complication rate. Material costs were lower overall in the barbed suture group ($66.78 vs. 82.59). Further studies will be required to determine the role of barbed sutures in TKA. PMID- 24764229 TI - Outcomes following microfracture of full-thickness articular cartilage lesions of the knee in adolescent patients. AB - The purpose of this study was to document outcomes following microfracture for full-thickness cartilage defects of the knee in adolescents. Our hypothesis was that patients aged 18 years or less would have excellent outcomes and function following microfracture of full-thickness knee articular cartilage defects. This study was approved by the Institutional Review Board. Patients < 19 years old with full-thickness knee articular cartilage defects treated with microfracture between January 1992 and June 2008 were identified. Surgical, demographic data, Lysholm score, Tegner activity scale, and patient satisfaction were collected prospectively. A total of 26 patients (14 females, 12 males) met inclusion criteria. Average age was 16.6 years (range: 12-18.9 years). Ninety-six percent of lesions were patellar (37%) or femoral condyle defects (medial 26%, lateral 33%). Minimum 2-year follow-up was obtained in 22/26 patients (85%) with average follow-up of 5.8 years (range: 2.0-13.3 years). Average postoperative Lysholm score was 90 (range: 50-100). Median Tegner scale was 6 (range: 2-10). Median patient satisfaction with outcome was 10 (range: 1-10). Lysholm correlated with Tegner scale (rho = 0.586; p = 0.011) and patient satisfaction (rho = 0.70; p = 0.001). Average postoperative Lysholm score in males was 93 and 86 in females (p = 0.22). One patient underwent revision microfracture. This study showed that adolescent patients who underwent microfracture for treatment of full-thickness knee chondral defects demonstrated increased activity levels and excellent function following surgery. PMID- 24764230 TI - Emerging technologies in arthroplasty: additive manufacturing. AB - Additive manufacturing is an industrial technology whereby three-dimensional visual computer models are fabricated into physical components by selectively curing, depositing, or consolidating various materials in consecutive layers. Although initially developed for production of simulated models, the technology has undergone vast improvements and is currently increasingly being used for the production of end-use components in various aerospace, automotive, and biomedical specialties. The ability of this technology to be used for the manufacture of solid-mesh-foam monolithic and coated components of complex geometries previously considered unmanufacturable has attracted the attention of implant manufacturers, bioengineers, and orthopedic surgeons. Currently, there is a paucity of reports describing this fabrication method in the orthopedic literature. Therefore, we aimed to briefly describe this technology, some of the applications in other orthopedic subspecialties, its present use in hip and knee arthroplasty, and concerns with the present form of the technology. As there are few reports of clinical trials presently available, the true benefits of this technology can only be realized when studies evaluating the clinical and radiographic outcomes of cementless implants manufactured with additive manufacturing report durable fixation, less stress shielding, and better implant survivorship. Nevertheless, the authors believe that this technology holds great promise and may potentially change the conventional methods of casting, machining, and tooling for implant manufacturing in the future. PMID- 24764231 TI - Cementless total knee arthroplasty: a review. AB - There is ongoing debate over the use of cementless fixation in total knee arthroplasty (TKA). Previous generation prostheses resulted in less than optimal outcomes which was somewhat attributed to design issues. As the demand for TKA is continuously increasing and the current U.S. age population is getting younger, cemented fixation may not provide adequate long-term outcomes due to failure of fixation. Thus, there has been a reemergence of the development and use of cementless TKA. Recent short-term trials have demonstrated that modern cementless TKA has comparable survivorship and functional outcomes as cemented prostheses. However, more prospective, randomized trials are needed to clearly delineate any differences between these two fixation options. PMID- 24764232 TI - Bicruciate-retaining total knee arthroplasty: a review. AB - Total knee arthroplasty (TKA) has been shown to have excellent long-term outcomes and survivorship in numerous studies, however, with changes in patient demographics, questions have arisen about the use of conventional arthroplasties and their functionality in highly active, young patients. The recent interest in bicruciate-retaining prostheses is aimed to address the need for an implant that can mimic a natural knee during high activity levels. Although there are currently few of these prostheses which are being utilized, results from prior studies have demonstrated similar results to that of anterior cruciate ligament sacrificing TKA in terms of function and survivorship. In this review, we will describe the history, kinematics, clinical outcomes, concerns, and future outlook of bicruciate-retaining arthroplasty. PMID- 24764233 TI - Does the use of navigation in total knee arthroplasty affect outcomes? AB - Numerous studies have demonstrated that deviation from the mechanical axis of more than 3 degrees can lead to increased complications and decreased patient satisfaction. The stimulus for navigation of total knee arthroplasty (TKA) was born out of the need for more precise and reliable component alignment. Proponents believe that navigated TKA has the theoretical benefits of improved implant survivorship, better functional outcomes, and greater patient satisfaction. Several studies have shown that intraoperative use of navigation results in superior component positioning when compared with conventional TKA. However, because of concerns about higher institutional costs, intraoperative difficulties, steep learning curves, and potential tracker pin complications, navigation TKA has not gained wide popularity. Moreover, to fully evaluate the use of navigation in TKA, we believe that larger prospective randomized studies are required to clearly define outcomes, as well as economic implications. PMID- 24764234 TI - Patient-specific instrumentation in total knee arthroplasty. AB - Patient-specific instrumentation (PSI) is a technology that allows the surgeon to perform a total knee arthroplasty (TKA) potentially more easily with preformed cutting blocks and jigs, which are developed from preoperative computed tomographic or magnetic resonance image scans of the knee. It was introduced with the goal of reducing surgical time, minimizing costs, improving alignment, and reducing radiographic outliers when performing a TKA. Although multiple reports have demonstrated that PSI can reduce the amount of trays and instrumentation required, operative time, and turnover rates, this has not been extrapolated to an overall cost reduction. This is potentially related to the costs of preoperative imaging and the intrinsic costs of production of the patient specific guides. With the present technology, it is also controversial whether improvements in alignment can be achieved. In addition, it remains to be seen whether this will lead to a reduction in costs and improvements in clinical, radiographic, and functional outcomes. As PSI is relatively new, there is a paucity of long-term studies, which makes it difficult to predict whether long term improvements in implant survivorship will lead to substantial improvements in patient function, overall outcomes, or cost benefits. PMID- 24764235 TI - Direct umpolung of glycals and related 2,3-unsaturated N-acetylneuraminic acid derivatives using samarium diiodide. AB - The umpolung of glycals with samarium diiodide offers a simple route to novel carbohydrate-derived nucleophilic reagents in a single step using a readily available reductant. The corresponding allyl samarium reagent that arises from the hexose series reacts with ketones at the C3 position with high stereoselectivity; carbon-carbon bond formation takes place only anti to the substituent at the C4 position of the dihydropyran ring. For the sialic acid series, the completely regio- and stereoselective coupling process of the samarium reagent occurs at the anomeric carbon atom and provides a new approach to the alpha-C-glycosides of N-acetyl neuraminic acid. PMID- 24764236 TI - Patterns of morphological variation of extant sloth skulls and their implication for future conservation efforts. AB - Several studies have shown an increased morphological variability of sloths from mammalian norms, affecting varied phenotypic traits from skeletal parts to soft tissues. We present here the first descriptive comparison of the whole skull morphology within the two extant sloth genera, combining geometric morphometric approaches with comparative anatomy. We used these methods to explore the patterns of the intra- and interspecific morphological variation of the skull with regard to several factors such as phylogeny, geography, allometry, or sexual dimorphism. Our study first revealed strong phylogenetic and geographical imprints on the cranial and mandibular morphological traits. This result demonstrates the importance of accurate knowledge of species and their geographical distributions; here we show from an example pertaining to Bradypus variegatus populations the implications this has on conservation management. Moreover, in order to control the amount of this detected variation, we tentatively compared sloths to a wide range of mammalian species. Our analysis found no significant increase in the average deviation of skull shape within each investigated sloth species compared to other mammals. This suggests that the intraspecific cranial variation in sloths does not depart significantly from the variation observed in other mammals. This result has positive implications for the demarcation of anatomical regions that maintain high levels of morphological variation in sloths. PMID- 24764237 TI - pH-controlled multiple chiral inversion that induces molecular dimerization in a gold(I)-cobalt(III) coordination system with L-cysteinate. AB - Herein, a unique coordination system that exhibits multiple chiral inversions and molecular dimerization in response to a subtle pH change is reported. Treatment of (Delta)2-H3[Au3Co2(L-cys)6] (H3[1 a]) with [Co3(aet)6](NO3)3 (aet=2 aminoethanethiolate) in water at pH 7 gave a 1:1 complex salt of [Co3(aet)6](3+) and [1 a](3-), retaining the Au(I)3Co(III)2 structure and chiral configurations of [1 a](3-). Similar treatment at pH 9 led to not only the inversion of all of the chiral Co(III) and S centers but also the dimerization of [1 a](3-), giving a 2:1 complex salt of [Co3(aet)6](3+) and (Lambda)4(R)12-[Au6Co4(L-cys)12](6-) ([2](6-)). When dissociated from [Co3(aet)6](3+) in solution, [2](6-) was converted to (Lambda)2(R)6-[Au3Co2(L-cys)6](3-) ([1 b](3-)) with retention of the chiral configurations. PMID- 24764238 TI - Tumor genetics and survival of thymic neuroendocrine neoplasms: a multi institutional clinicopathologic study. AB - Thymic neuroendocrine tumors (TNET) are rare primary epithelial neoplasms of the thymus. This study aimed to determine clinically relevant parameters for their classification and for therapeutic decisions. We performed a comprehensive histological, clinical, and genetic study of 73 TNET cases (13 thymic typical carcinoids [TTC], 40 thymic atypical carcinoids [TAC], and 20 high-grade neuroendocrine carcinomas [HGNEC] of the thymus), contributed by multiple institutions. The mean number of chromosomal imbalances per tumor was 0.8 in TTC (31% aberrant cases) versus 1.1 in TAC (44% aberrant cases) versus 4.7 in HGNEC (75% aberrant cases). Gains of 8q24 (MYC gene locus) were the most frequent alteration and one of the overlapping features between carcinoids and HGNEC. The 5-year survival rates for TTC, TAC, and HGNEC were 100, 60, and 30%. The 10-year survival rates for TTC and TAC were 50 and 30% (P = 0.002). Predictive mitotic cut-off values for TTC versus TAC were 2.5 per 10 high-power fields (HPF; indicating a higher death rate, P = 0.062) and 15 per 10 HPF (indicating higher risk of recurrence, P = 0.036) for separating HGNEC from TAC. We conclude that the current histopathologic classifications of TNET reflect tumor biology and provide important information for therapeutic management. PMID- 24764239 TI - Advances of human bone marrow-derived mesenchymal stem cells in the treatment of cartilage defects: a systematic review. AB - Mesenchymal stem cell (MSC)-based therapies represent a new option for treating damaged cartilage. However, the outcomes following its clinical application have seldom been previously compared. The present paper presents the systematic review of current literatures on MSC-based therapy for cartilage repair in clinical applications. Ovid, Scopus, PubMed, ISI Web of Knowledge and Google Scholar online databases were searched using several keywords, which include "cartilage" and "stem cells". Only studies using bone marrow-derived MSC (BM-MSC) to treat cartilage defects clinically were included in this review. The clinical outcomes were compared, and the quality of the tissue repair was analysed where possible. Of the 996 articles, only six (n = 6) clinical studies have described the use of BM-MSC in clinical applications. Two studies were cohort observational trials, three were case series, and one was a case report. In the two comparative trials, BM-MSCs produced superior repair to cartilage treatment without cells and have comparable outcomes to autologous chondrocyte implantation. The case series and case-control studies have demonstrated that use of BM-MSCs resulted in better short- to long-term clinical outcomes with minimal complications. In addition, histological analyses in two studies have resulted in good repair tissue formation at the damaged site, composed mainly of hyaline-like cartilage. Although results of the respective studies are highly indicative that BM-MSC based therapy is superior, due to the differences in methods and selection criteria used, it was not possible to make direct comparison between the studies. In conclusion, published studies do suggest that BM-MSCs could provide superior cartilage repair. However, due to limited number of reports, more robust studies might be required before a definitive conclusion can be drawn. PMID- 24764240 TI - Expression of histone variant, H2A.1 is associated with the undifferentiated state of hepatocyte. AB - Recent studies suggest the incorporation of histone variants into the chromatin regulate cellular proliferation, differentiation, and de-differentiation. We have earlier reported the increase of H2A.1 variant during sequential de differentiation of hepatocyte to hepato-cellular carcinoma. Here, we decipher the alterations in expression of H2A.1 and H2A.2 variants during rat liver embryogenesis and regeneration. The expression of H2A.1 and H2A.2, at protein and mRNA level, does not alter in normal cellular proliferation associated with regeneration of liver post PH. In contrast, gradual decrease of H2A.1 with increase of H2A.2 is observed during differentiation of embryonic to adult liver. Furthermore, the accumulation of H2A.1 is higher in embryonic stem cells compared to normal adult liver. Collectively, these data support a strong correlation of H2A.1 expression with undifferentiated cells and overall epigenetic reprogramming in dedifferentiation and maturation of undifferentiated cells, rather than with normal cellular proliferation. PMID- 24764242 TI - Hypermethylation-mediated transcriptional repression of TMPRSS2 in androgen receptor-negative prostate cancer cells. AB - Prostate cancer is the most common type of cancer for men in the developed world. Androgen receptor (AR) is very important in prostate cancer progression. TMPRSS2 is an AR signaling downstream gene and closely related to prostate carcinogenesis. DNA methylation is a key mechanism to influence gene expression. Though previous reports have shown that AR signaling plays a critical role in the regulation of TMPRSS2 in prostate cancer, hardly any studies have examined whether the DNA methylation has been involved in the regulation of TMPRSS2. In the present study, we demonstrated that AR-negative prostate cancer (PCa) cells showed low expression levels and hypermethylation of TMPRSS2. In contrast, AR positive PCa cells displayed high levels and hypomethylation of TMPRSS2. Treatment with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine reversed the low expression levels of TMPRSS2 in the AR-negative PCa cells. Additionally, we found that the level of DNA methyltransferases 1 (DNMT1) was high in AR-negative PCa cells, in which hypermethylation of TMPRSS2 and low expression level of TMPRSS2 were observed. Collectively, these data suggest that the high level of DNMT1 might be the mechanism for the hypermethylation-mediated transcriptional repression of TMPRSS2 in AR-negative PCa cells. PMID- 24764244 TI - Retraction notice. PMID- 24764243 TI - Molecular genetics and antisocial behavior: where do we stand? AB - Over the last two decades, it has become increasingly evident that control of aggressive behavior is modulated by the individual genetic profile as well. Several candidate genes have been proposed to play a role in the risk to develop antisocial behavior, and distinct brain imaging studies have shown that specific cortical areas may be functionally and/or structurally impaired in impulsive violent subjects on the basis of their genotypes. In this paper, we review the findings regarding four polymorphisms-MAOA (Monoamine oxidase A) uVNTR, SLC6A4 (solute carrier family 6 (neurotransmitter transporter), member 4) 5HTTLPR, COMT (Catechol-O-methyltransferase) Val158Met and DRD4 (dopamine D4 receptor) VNTR 1 11-that all have been found to be associated with an increased vulnerability for antisocial and impulsive behavior in response to aversive environmental conditions. These results, however, have not been replicated by other studies, likely because of crucial methodological discrepancies, including variability in the criteria used to define antisocial behavior and assessment of environmental factors. Finally, it has been recently proposed that these genetic variants may actually increase the individual susceptibility not merely to the negative environmental factors, but to the positive ones as well. In this view, such alleles would play a wider modulatory role, by acting as "plasticity" rather than "vulnerability" genes. Overall, these findings have potential important implications that span well outside of neuroscience and psychiatry, to embrace ethics, philosophy, and the law itself, as they pose new challenges to the very notion of Free Will. Novel properly controlled studies that examine multi-allelic genetic profiles, rather than focusing on distinct single variants, will make it possible to achieve a clearer understanding of the molecular underpinnings of the nature by nurture interaction. PMID- 24764241 TI - In vitro platforms for evaluating liver toxicity. AB - The liver is a heterogeneous organ with many vital functions, including metabolism of pharmaceutical drugs and is highly susceptible to injury from these substances. The etiology of drug-induced liver disease is still debated although generally regarded as a continuum between an activated immune response and hepatocyte metabolic dysfunction, most often resulting from an intermediate reactive metabolite. This debate stems from the fact that current animal and in vitro models provide limited physiologically relevant information, and their shortcomings have resulted in "silent" hepatotoxic drugs being introduced into clinical trials, garnering huge financial losses for drug companies through withdrawals and late stage clinical failures. As we advance our understanding into the molecular processes leading to liver injury, it is increasingly clear that (a) the pathologic lesion is not only due to liver parenchyma but is also due to the interactions between the hepatocytes and the resident liver immune cells, stellate cells, and endothelial cells; and (b) animal models do not reflect the human cell interactions. Therefore, a predictive human, in vitro model must address the interactions between the major human liver cell types and measure key determinants of injury such as the dosage and metabolism of the drug, the stress response, cholestatic effect, and the immune and fibrotic response. In this mini-review, we first discuss the current state of macro-scale in vitro liver culture systems with examples that have been commercialized. We then introduce the paradigm of microfluidic culture systems that aim to mimic the liver with physiologically relevant dimensions, cellular structure, perfusion, and mass transport by taking advantage of micro and nanofabrication technologies. We review the most prominent liver-on-a-chip platforms in terms of their physiological relevance and drug response. We conclude with a commentary on other critical advances such as the deployment of fluorescence-based biosensors to identify relevant toxicity pathways, as well as computational models to create a predictive tool. PMID- 24764245 TI - The inhibitory effect of iridoid glycoside extracted from Fructus Gardeniae on intracellular acidification and extracellular Ca2+ influx induced by influenza A virus. AB - Influenza is a serious public health problem that causes severe illnesses and deaths for higher risk populations. Iridoid glycoside is one of the main active components from Fructus Gardeniae with antivirus and anti-inflammatory characteristics. The present study was designed to investigate the inhibitory effect of iridoid glycoside extracted from Fructus Gardeniae (IGE) on influenza and explore the potential mechanism of the action. In vitro, IGE exhibited highest activity against influenza virus A/FM1/47 induced visible cytopathic effect (CPE), with half maximal inhibitory concentration and therapeutic index values of 3.15 mg/mL and 11.37, respectively, and the replication of influenza virus A/FM1/47 was inhibited markedly by IGE at the concentrations of 25, 12.5 and 6.25 mg/mL. In vivo, treatment of mice with IGE decreased pulmonary index, viral titers and M2 protein expression in a dose-dependent manner. IGE increased the declining pHi induced by influenza virus significantly at the concentrations of 25 and 12.5 mg/mL 0.5 or 1 h post-infection, respectively. IGE treatment inhibited elevation of [Ca2+]i significantly at the concentrations of 25 and 12.5 mg/mL 0.5, 1 or 24 h post-infection, respectively. In addition, IGE reduced the rate of early-apoptotic cells at the concentrations of 25, 12.5 and 6.25 mg/mL, but showed no apparent effect on the rate of late-apoptotic cells. Our study demonstrates that IGE possesses antiviral activity against influenza A virus, and the antiviral action might be related to the inhibition of intracellular acidification and Ca2+ influx during fusion and uncoating of influenza replication cycle. PMID- 24764246 TI - Toxicity of biosolids-derived triclosan and triclocarban to six crop species. AB - Biosolids are an important source of nutrients and organic matter, which are necessary for the productive cultivation of crop plants. Biosolids have been found to contain the personal care products triclosan and triclocarban at high concentrations relative to other pharmaceuticals and personal care products. The present study investigates whether exposure of 6 plant species (radish, carrot, soybean, lettuce, spring wheat, and corn) to triclosan or triclocarban derived from biosolids has an adverse effect on seed emergence and/or plant growth parameters. Plants were grown in soil amended with biosolids at a realistic agronomic rate. Biosolids were spiked with triclosan or triclocarban to produce increasing environmentally relevant exposures. The concentration of triclosan and triclocarban in biosolids-amended soil declined by up to 97% and 57%, respectively, over the course of the experiments. Amendment with biosolids had a positive effect on the majority of growth parameters in radish, carrot, soybean, lettuce, and wheat plants. No consistent triclosan- or triclocarban-dependent trends in seed emergence and plant growth parameters were observed in 5 of 6 plant species. A significant negative trend in shoot mass was observed for lettuce plants exposed to increasing concentrations of triclocarban (p<0.001). If best management practices are followed for biosolids amendment, triclosan and triclocarban pose a negligible risk to seed emergence and growth of crop plants. PMID- 24764247 TI - Brain magnetic resonance in the routine management of Rubinstein-Taybi syndrome (RTS) can prevent life-threatening events and neurological deficits. PMID- 24764248 TI - Prenatal diagnosis of congenital femoral deficiency and fibular hemimelia. AB - OBJECTIVES: Routine ultrasonography can detect congenital femoral deficiency (CFD) and fibular hemimelia (FH), but prenatal detection rate and its relation to deformity severity have never been reported. Whether mothers prefer prenatal diagnosis is also unknown. We aimed to determine whether mothers prefer prenatal diagnosis, to report detection rates for CFD and/or FH, and to correlate detection rates to severity of limb shortening. METHODS: Surveys were mailed to 171 mothers who gave birth to children with CFD/FH between 2000 and 2008. Bilateral femoral and tibial lengths were measured on postnatal radiographs. We calculated corresponding femoral/tibial lengths at gestational weeks 20 and 30. RESULTS: Sixty-five surveys were returned, and 56 radiographs were reviewed. Most mothers (63%) preferred prenatal diagnosis as it enables prenatal counseling. Congenital limb shortening was detected in 24 cases (37%) and was not detected in 41 cases (63%). Detection rate was 52% (12 of 23) in CFD cases, 23% (three of 13) in FH cases, and 30% (six of 20) in combined cases. CFD cases with severe shortening had a higher detection rate. CONCLUSIONS: Ultrasonographers should measure both femoral and tibial lengths. Unilateral shortening should result in pediatric orthopedic consultation to estimate limb-length discrepancy at maturity and discuss treatment. PMID- 24764249 TI - An evaluation of interrupted and uninterrupted measurement of vocal stereotypy on perceived treatment outcomes. AB - The type of procedure used to measure a target behavior may directly influence the perceived treatment outcomes. In the present study, we examined the influence of different data-analysis procedures on the outcomes of two commonly used treatments on the vocal stereotypy of 2 children with an autism spectrum disorder. In Study 1, we compared an interrupted and uninterrupted data-analysis procedure to measure vocal stereotypy during the implementation of response interruption and redirection (RIRD). The results showed that the interrupted data analysis procedure overestimated the effectiveness of RIRD. In Study 2, we examined the influence of different data-analysis procedures on the interpretation of the relative effects of 2 different treatments for vocal stereotypy. Specifically, we compared interrupted and uninterrupted data-analysis procedures during the implementation of RIRD and noncontingent reinforcement (NCR) as a treatment for vocal stereotypy. The results showed that, as in Study 1, the interrupted data-analysis procedure overestimated the effectiveness of RIRD; however, this effect was not apparent with NCR. These findings suggest that different types of data analysis can influence the perceived success of a treatment. PMID- 24764250 TI - Pain worlds: towards the integration of a sociocultural perspective of pain in clinical physical therapy. AB - The World Health Organization's International Classification of Functioning, Disability and Health (WHO-ICF) model has been advocated as a model of function to conceptualize physical therapist practice. Among its advances, the WHO-ICF model explicitly recognizes the existence of social factors that may influence patients' and clients' understanding of pain. However, understandings of the historical, social and cultural processes that shape the individual and collective experiences of pain and the therapeutic relationship remain limited. We call for a more intentional and sustained dialogue between clinical practice and sociology to help elucidate the nature, characteristics, complexities and clinical implications of one specific element of the WHO-ICF model, environmental factors. The purpose of this review is to advocate for the continued adoption of a sociological lens to help physical therapists better understand the broader networks of people, ideologies and practices in which people 'in pain' are enmeshed and the historical, geographical and cultural spaces in which they operate. In this review, we discuss existing empirical findings in sociology to introduce the concept of 'pain worlds', which can be applied by physical therapists to help characterize the sociocultural factors identified in the WHO ICF model. Pain worlds is designed to complement the WHO-ICF model and assist in developing interdisciplinary research agendas that illuminate and examine the role, significance and clinical implications of sociocultural and environmental dimensions of pain. We conclude with a brief set of recommendations for the development of such translational research agendas and call for the integration of pain worlds in clinical practice. PMID- 24764251 TI - Effects of rolipram and zaprinast on learning and memory in the Morris water maze and radial arm maze tests in naive mice. AB - Inhibition of phosphodiesterase 5 (PDE) improved recognition memory and counteracted spatial learning impairment induced by nitric oxide synthase (NOS) inhibition in recent studies. Aim of this study was to investigate effects of rolipram, a PDE4 inhibitor and zaprinast, a PDE5 inhibitor, on learning and memory in Morris water maze (MWM) and radial arm maze (RAM) tests in naive mice. Male Balb-c mice were treated subchronically with zaprinast (3 and 10 mg/kg) and rolipram (0.05 and 0.1 mg/kg) for 6 days in the MWM test and acutely before the retention trial of radial arm maze test. Rolipram (0.05 and 0.1 mg/kg) significantly decreased escape latency between 2(nd) and 5(th) sessions, while zaprinast (10 mg/kg) significantly decreased escape latency only in 2(nd) session. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly increased time spent in escape platform's quadrant in probe trial of MWM test; only rolipram decreased mean distance to platform, while zaprinast had no effect on mean distance to platform. Zaprinast (3 and 10 mg/kg) significantly decreased number of errors compared to control group, while rolipram (0.05 and 0.1mg/kg) had no effect on number of errors in retention trial of RAM test. Rolipram (0.05 and 0.1 mg/kg) and zaprinast (10 mg/kg) significantly decreased time spent to complete retention trial (latency) compared to control group. Our study revealed that both zaprinast and rolipram enhanced spatial memory in MWM, while zaprinast seems to have more memory enhancing effects compared to rolipram in radial arm maze test. PMID- 24764252 TI - Pharmacokinetics and pharmacodynamics of two vitamin K1 formulations in rats. AB - PURPOSE: Severe allergic reactions associated with the commercially available formulation of vitamin K1 injection (VKI) could be a result of polysorbate that was added to solubilize vitamin K1 (VK1). Hence, we sought to develop vitamin K1 lipid emulsion (VKLE) devoid of polysorbate, in order to reduce the clinical risk of severe allergic reactions. This study aims to evaluate the pharmacokinetics and pharmacodynamics of VKLE in comparison to VKI in rats. METHODS: Plasma concentration-time profiles of VK1 were investigated in rats after dosing VKLE or VKI at the range of 1-4 mg/kg. Tissue distribution of VKLE and VKI were investigated in rats at the dose of 2 mg/kg. The pharmacodynamics of VKLE and VKI were also studied by comparing their effects on coagulation factors (II/VII/IX/X) and prothrombin time in hypoprothrombinemic rats. RESULTS: VKI demonstrated over proportional increase in AUC at the dosage range of 1.0-4.0 mg/kg, whereas VKLE demonstrated a linear kinetics trend in general. Compared to VKI, VKLE could selectively deliver VK1 to the liver, spleen and heart. VKLE and VKI produced comparable maximal responses, in terms of coagulation factors and prothrombin time. CONCLUSIONS: VKLE and VKI demonstrated different pharmacokinetics but comparable pharmacodynamics in rats. PMID- 24764253 TI - The inhibition of acetylcholinesterase by dantrolene and ondansetron. AB - PURPOSE: A virtual screening study has suggested that the skeletal muscle relaxant, dantrolene, and the antiemetic drug, ondansetron, may act as inhibitors of the enzyme acetylcholinesterase (AChE). Based on this proposal, the current study examines the AChE inhibitory properties of these drugs. METHODS AND FINDINGS: Using AChE from human erythrocytes as enzyme source, it is shown that dantrolene and ondansetron inhibit AChE with IC(50) values of 12.8 uM and 37.1 uM, respectively. For comparison, the reference AChE inhibitors, tacrine and ranitidine, exhibit IC(50) values of 0.144 uM and 3.37 uM, respectively. By measuring the recoveries of enzyme activities after dilution of enzyme-inhibitor mixtures, it is further shown that dantrolene and ondansetron act as reversible AChE inhibitors. CONCLUSIONS: By considering the typical plasma concentrations of dantrolene and ondansetron in humans at therapeutic doses, the pharmacological relevance of the AChE inhibitory potencies of these drugs is discussed. At typical plasma concentrations, ondansetron is unlikely to inhibit AChE under physiological conditions. The inhibition of AChE by ondansetron is therefore not of clinical relevance in humans. In contrast, after intravenous administration of dantrolene to humans, the typical plasma concentrations reached are similar to the recorded IC(50) value for the inhibition of AChE, and dantrolene may thus produce pharmacological significant inhibition of AChE. Further investigation is necessary to clarify the pharmacological relevance of the AChE inhibitory effect of dantrolene. PMID- 24764254 TI - Pharmacokinetics of metronidazole, tetracycline and bismuth in healthy volunteers after oral administration of compound tablets containing a combination of metronidazole, tetracycline hydrochloride and bismuth oxide. AB - BACKGROUND: To eradicate Helicobacter pylori in human pylorus and to heal duodenal ulcers, recently, a new formulation of combination tablets containing metronidazole 125 mg, tetracycline hydrochloride 125 mg and bismuth oxide 40 mg has been developed. OBJECTIVE: To investigate the pharmacokinetics of metronidazole, tetracycline and bismuth in healthy Chinese volunteers after oral administration of the test formulation. METHODS: A one-sequence, 3-period study was conducted in 12 Chinese healthy volunteers (6 male, 6 female). Volunteers each received single low dose (1 tablet) under fed condition in period 1, single high dose (3 tablets) under fasted condition in period 2, and single high dose (3 tablets) and multiple doses (3 tablets at once, 4 times daily for 7 consecutive days) under fed condition in period 3. Blood samples were collected and determined over 48 h in every period. RESULTS AND CONCLUSION: After single high dose administration under fed condition, the C max of metronidazole, tetracycline and bismuth were 6.833 +/- 0.742 MUg/mL, 0.8513 +/- 0.1253 MUg/mL and 3.32 +/- 1.89 ng/mL, respectively. The C max and AUC 0-48 of metronidazole increased in proportion to the doses within the tested dose range, but tetracycline and bismuth did not. Food caused 10% and 80% decrease of the C max for metronidazole and bismuth, respectively, but did not affect tetracycline. No gender effect was found on the pharmacokinetics of the 3 ingredients. In the steady state, the C av of metronidazole, tetracycline and bismuth were 20.75 +/- 3.52 MUg/mL, 1.900 +/- 0.243 MUg/mL and 5.61 +/- 1.34 ng/mL, respectively. PMID- 24764255 TI - Intramolecular metal-free oxidative aryl-aryl coupling: an unusual hypervalent iodine-mediated rearrangement of 2-substituted N-phenylbenzamides. AB - Hypervalent-iodine-mediated oxidative coupling of the two aryl groups in either 2 acylamino-N-phenyl-benzamides or 2-hydroxy-N-phenylbenzamides, with concomitant insertion of the ortho-substituted N or O atom into the tether, has been described for the first time. This unusual metal-free rearrangement reaction involves an oxidative C(sp(2))-C(sp(2)) aryl-aryl bond formation, cleavage of a C(sp(2))-C(O) bond, and a lactamization/lactonization. Furthermore, unsymmetrical diaryl compounds can be easily obtained by removing the tether within the cyclized product. PMID- 24764257 TI - First-trimester maternal factors and biomarker screening for preeclampsia. AB - Preeclampsia (PE), which affects about 2% of pregnancies, is a major cause of maternal and perinatal morbidity and mortality. PE can be subdivided into early onset PE with delivery <34 weeks' gestation and late onset PE with delivery >=34 weeks. Early onset PE is associated with a higher incidence of adverse outcome. This review illustrates that effective screening for the development of early onset PE can be provided in the first-trimester of pregnancy. Screening by a combination of maternal risk factors, mean arterial pressure, uterine artery Doppler, maternal serum pregnancy-associated plasma protein-A and placental growth factor can identify about 95% of cases of early onset PE for a false positive rate of 10%. PMID- 24764256 TI - Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer model in vivo as monitored by (31) P MRS. AB - Abnormal choline phospholipid metabolism is an emerging hallmark of cancer, which is implicated in carcinogenesis and tumor progression. The malignant metabolic phenotype is characterized by high levels of phosphocholine (PC) and relatively low levels of glycerophosphocholine (GPC) in aggressive breast cancer cells. Phosphorus ((31) P) MRS is able to non-invasively detect these water-soluble metabolites of choline as well as ethanolamine phospholipid metabolism. Here we have investigated the effects of stably silencing glycerophosphoester diesterase domain containing 5 (GDPD5), which is an enzyme with glycerophosphocholine phosphodiesterase activity, in MDA-MB-231 breast cancer cells and orthotopic tumor xenografts. Tumors in which GDPD5 was stably silenced with GDPD5-specific shRNA contained increased levels of GPC and phosphoethanolamine (PE) compared with control tumors. PMID- 24764258 TI - An evaluation of methods to determine the porosity of calcium phosphate cements. AB - The porosity of a material can be determined using a diversity of methods; however, the results from these methods have so far not been compared and analyzed for calcium phosphate cements (CPCs). The aim of this study was to compare a fast and easy method for porosity measurements with some commonly used porosity methods for CPCs. The investigated method is based on the assumption that when a wet cement sample is dried, the volume of the evaporated water is equal to the volume of pores within the cement. Moreover, different methods of drying the cements were evaluated for acidic CPCs. The results showed that drying at room temperature (22 +/- 1 degrees C) is preferable, since a phase transformation was observed at higher temperatures. The results also showed that drying for 24 h in vacuum was sufficient to achieve water-free cements. The porosity measured was found to vary between the porosity methods evaluated herein, and to get a complete picture of a cement's porosity more than one method is recommended. Water evaporation, is, however, a fast and easy method to estimate the porosity of CPCs and could simplify porosity measurements in the future. PMID- 24764259 TI - Interferon-alpha is not elevated in idiopathic thrombotic thrombocytopenic purpura patients. AB - Idiopathic thrombotic thrombocytopenic purpura (TTP) patients have ADAMTS13 deficiency, which is usually caused by ADAMTS13 autoantibodies. However, the triggering factors for the autoantibody production remain unclear. Interferon alpha (IFN-alpha) is a cytokine involved with many autoimmune processes such as inducing the activation of peripheral dendritic cells and stimulating T cells and B cells. It also plays an important role in some autoimmune diseases. Elevated IFN-alpha levels have been observed in some TTP patients and previous case reports have shown the occurrence of TTP after IFN-alpha treatment. Thus, we hypothesized that high levels of IFN-alpha would correlate with presence of ADAMTS13 autoantibodies. However, we did not observe elevated IFN-alpha levels in 36 TTP patients (mean 5.29 pg/ml, standard deviation (SD) 26.56 pg/ml) compared to healthy controls (mean 0 pg/ml, SD 0 pg/ml), P = 0.59. IFN-alpha levels of most patients (94%) were undetectable. Only two patients had increased IFN-alpha levels and ADAMTS13 autoantibodies were detected in these two patients. Interestingly, both the patients had an underlying autoimmune disease. Although there have been cases of secondary TTP following IFN-alpha treatment, no evidence supports a role of IFN-alpha in the development of idiopathic TTP in our patient population. PMID- 24764260 TI - Pullulan encapsulation of labile biomolecules to give stable bioassay tablets. AB - A simple and inexpensive method is reported for the long-term stabilization of enzymes and other unstable reagents in premeasured quantities in water-soluble tablets (cast, not compressed) made with pullulan, a nonionic polysaccharide that forms an oxygen impermeable solid upon drying. The pullulan tablets dissolve in aqueous solutions in seconds, thereby facilitating the easy execution of bioassays at remote sites with no need for special reagent handling and liquid pipetting. This approach is modular in nature, thus allowing the creation of individual tablets for enzymes and their substrates. Proof-of-principle demonstrations include a Taq polymerase tablet for DNA amplification through PCR and a pesticide assay kit consisting of separate tablets for acetylcholinesterase and its chromogenic substrate, indoxyl acetate, both of which are highly unstable. The encapsulated reagents remain stable at room temperature for months, thus enabling the room-temperature shipping and storage of bioassay components. PMID- 24764261 TI - Comparison of simple and complex auditory-visual conditional discrimination training. AB - We investigated the relative effects of simple and complex auditory-visual discrimination training using an adapted alternating treatments design to establish derived stimulus relations in 2 children who had been diagnosed with autism and 1 typically developing peer. Emergence of untrained conditional relations was observed after training in both conditions, with a possible advantage of simple-sample training for 1 participant. Results of generalization and follow-up probes were mixed. PMID- 24764262 TI - Alginate-coated magnetic nanoparticles for noninvasive MRI of extracellular calcium. AB - Nanoparticles (NPs) have great potential to increase the diagnostic capacity of many imaging modalities. MRI is currently regarded as the method of choice for the imaging of deep tissues, and metal ions, such as calcium ions (Ca(2+)), are essential ingredients for life. Despite the tremendous importance of Ca(2+) for the well-being of living systems, the noninvasive determination of the changes in Ca(2+) levels in general, and extracellular Ca(2+) levels in particular, in deep tissues remains a challenge. Here, we describe the preparation and contrast mechanism of a flexible easy to prepare and selective superparamagnetic iron oxide (SPIO) NPs for the noninvasive determination of changes in extracellular Ca(2+) levels using conventional MRI. We show that SPIO NPs coated with monodisperse and purified alginate, having a specific molecular weight, provide a tool to selectively determine Ca(2+) concentrations in the range of 250 um to 2.5 mm, even in the presence of competitive ions. The alginate-coated magnetic NPs (MNPs) aggregate in the presence of Ca(2+) , which, in turn, affects the T2 relaxation of the water protons in their vicinity. The new alginate-coated SPIO NP formulations, which have no effect on cell viability for 24 h, allow the detection of Ca(2+) levels secreted from ischemic cell cultures and the qualitative examination of the change in extracellular Ca(2+) levels in vivo. These results demonstrate that alginate-coated MNPs can be used, at least qualitatively, as a platform for the noninvasive MRI determination of extracellular Ca(2+) levels in myriad in vitro and in vivo biomedical applications. PMID- 24764263 TI - Secreted frizzled-related protein 5 suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes through down-regulation of c Jun N-terminal kinase. AB - OBJECTIVE: This study was performed to investigate the effect of secreted frizzled-related protein 5 (Sfrp5), a novel anti-inflammatory adipokine that competes with the frizzled proteins for Wnt binding, on inflammatory response and the c-Jun N-terminal kinase (JNK) signalling pathway in RA. METHODS: Expression of Sfrp5 mRNA in peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLSs) from patients with RA and OA was determined using real-time quantitative PCR (qPCR). Sfrp5 RNA interference (RNAi) plasmids were transfected to abrogate Sfrp5 expression in RA FLSs, and adenovirus containing the Sfrp5 transcript was delivered into RA FLSs to strengthen Sfrp5 expression. Levels of pro-inflammatory genes and their protein products were determined using real-time qPCR and ELISA in RA FLSs. Production of mitogen-activated protein kinase kinase 7 (MKK-7), JNK and c-Jun were assessed by Western blot analysis. RESULTS: Expression of Sfrp5 mRNA was decreased in PMBCs and FLSs from patients with RA compared with patients with OA. Gene expression and production of IL-1beta, IL-6, chemokine ligand 2 (CCL-2), CCL-7, cyclooxygenase 2 and MMP-9 were markedly increased in Sfrp5 RNAi plasmid-transfected RA FLSs, while transfection with adenoviral vectors encoding Sfrp5 induced reductions in those levels. Phosphorylated forms of MKK-7, JNK and c-Jun were increased by Sfrp5 RNAi plasmids and were decreased by adenoviral vectors encoding Sfrp5. CONCLUSION: Sfrp5 suppressed the inflammatory response and down-regulated JNK signalling in RA FLSs. These findings provide evidence for the anti-inflammatory effect of Sfrp5 in RA. PMID- 24764264 TI - Prevalence and clinical prediction of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis. AB - OBJECTIVE: Osteoporosis has previously been reported to be twice as common in patients with RA as in controls, but these studies predate the introduction of aggressive management of RA. The aim of this study was to evaluate the prevalence and clinical predictors of osteoporosis in RA in a contemporary cohort and to develop a clinical tool for the identification of patients at risk. METHODS: The prevalence of osteoporosis was related to clinical and demographic variables in 304 consecutive RA patients undergoing DXA at a single centre between 2009 and 2010 and compared with the frequency of osteoporosis in a population-based cohort of 903 subjects. RESULTS: The RA cohort was predominantly female (81.9%), with an average age of 63.5 years (s.d. 11.8) and a disease duration of 9.6 years (s.d. 10.2). Osteoporosis was present in 91 (29.9%) patients at either the spine or total hip compared with 157/903 (17.4%) of age- and gender-matched controls. In RA patients, osteoporosis was associated with female gender (P = 0.002), age (P < 0.001), time since menopause (P < 0.001), BMI (P < 0.001), ESR (P = 0.006), Larsen score (P = 0.011) and co-morbidities (P = 0.020), but logistic regression analysis showed that only age and BMI were independent predictors. A predictive tool based on age and BMI was developed that had 91.4% sensitivity for the detection of osteoporosis in an independent RA population. CONCLUSION: The prevalence of osteoporosis in RA remains high in the modern era despite aggressive management and the use of biologic therapy. Most RA patients with osteoporosis can be identified by a simple algorithm taking age and BMI into account. PMID- 24764265 TI - Can colchicine response be predicted in familial Mediterranean fever patients? AB - OBJECTIVES: The aims of this study were to explore whether the demographic and clinical features of paediatric familial Mediterranean fever (FMF) patients with different colchicine response vary or not and to determine whether colchicine response can be predicted in FMF patients. METHODS: Files of patients who have been on colchicine therapy for at least 6 months were retrospectively evaluated. Patients were divided into two groups: group I included patients with no attacks after colchicine and group II comprised patients with ongoing attacks. Thereafter group II was further divided into two groups according to the reduction rate of attack frequency: group IIA (>50%) and group IIB (<=50%). RESULTS: The study group comprised 221 FMF patients (116 females, 105 males). There were 131 patients in group I and 90 patients in group II (54 in group IIA and 36 in group IIB). Leg pain and M694V homozygosity were more frequent in group II (P < 0.05). Final colchicine doses, disease severity scores and number of patients with elevated acute phase reactant levels (attack-free period) were significantly higher and colchicine compliance was lower in group II when compared with group I (P < 0.05). Erysipelas-like erythema (ELE), leg pain and protracted arthritis/protracted febrile myalgia/vasculitis were more frequently detected in group IIB (P < 0.05). CONCLUSION: Colchicine response is excellent in the majority of FMF patients, however, colchicine unresponsiveness cannot be predicted easily at onset. More rarely encountered clinical findings such as ELE, leg pain and protracted complaints and M694V homozygosity may be a clue for less colchicine response. PMID- 24764266 TI - The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis. AB - OBJECTIVE: Interstitial lung diseases (ILDs) complicated with PM or DM are frequently aggressive and refractory to treatment. Recently some reports have suggested the potential benefit of tacrolimus for severe ILD complicated with PM/DM. However, little evidence has yet shown the efficacy of tacrolimus in these settings. The aim of this study was to evaluate the efficacy of tacrolimus as a treatment for PM-/DM-related ILD. METHODS: This retrospective study comprised 49 previously untreated patients diagnosed as PM-/DM-related ILD admitted to Hokkaido University Hospital from January 2000 to July 2013. These patients were treated with tacrolimus plus conventional therapy or only with conventional therapy (prednisolone, i.v. CYC and/or ciclosporin). The primary endpoint was defined as the time to relapse or death of respiratory cause or a serious adverse event. The secondary endpoint was defined as the time from the initiation of immunosuppressive treatment to relapse or death of respiratory cause. Endpoints were compared by adjusted Cox regression model by using inverse probability of treatment weighting in order to reduce the impact of these selection biases and potential confounding factors. RESULTS: After adjustment, the tacrolimus group (n = 25) had significantly longer event-free survival as compared with the conventional therapy group (n = 24). The weighted hazard ratio (HR) was 0.32 (95% CI 0.14, 0.75, P = 0.008). In addition, the tacrolimus group had significantly longer disease-free survival as compared with the conventional therapy group. The weighted HR was 0.25 (95% CI 0.10, 0.66, P = 0.005). CONCLUSION: The addition of tacrolimus to conventional therapy significantly improved the prognosis of patients with PM-/DM-related ILD. PMID- 24764267 TI - High expression levels of the B cell chemoattractant CXCL13 in rheumatoid synovium are a marker of severe disease. AB - OBJECTIVE: The B cell chemoattractant chemokine ligand 13 (CXCL13) is emerging as a new biochemical marker in RA. This study was undertaken to dissect the relationship between CXCL13 expression levels in the synovium and clinico pathological variables relevant to RA pathogenesis and outcome. METHODS: Synovial tissues from 71 RA patients were evaluated by immunohistochemistry. Thirty paired samples were used for comparative gene expression analysis by quantitative real time PCR. CXCL13 levels were analysed in relation to cellular, molecular and clinical features of inflammation, lymphocyte activation and joint damage. RESULTS: In patients with early disease (<12 months duration), CXCL13 expression correlated significantly with synovial markers of local disease activity and systemic inflammation. Such correlation was less evident in established RA. Notably, the association with lymphocyte infiltration and with expression of B/T cell-related activation and proliferation genes, such as activation-induced cytidine deaminase, IFN-gamma and IL-2, remained highly significant independent of disease duration and local disease activity. Patients featuring the highest levels of CXCL13 were more frequently ACPA positive and IgG ACPA titres were increased in the high CXCL13 expression group. Furthermore, the frequency of erosive disease on radiographs was significantly higher in the upper tertile of CXCL13 expression (P = 0.01 with adjustment for disease duration and ACPA). Accordingly, synovial CXCL13 and the local receptor activator of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) ratio significantly co-varied (rho = 0.52, P < 0.01), independent of the level of local inflammation. CONCLUSION: Synovial CXCL13 appears to be a marker of a more severe pattern of RA disease, characterized by increased lymphocyte activation and bone remodelling beyond the level of conventional markers of inflammation. PMID- 24764268 TI - Evaluation of tarsal navicular stress fracture fixation using intraoperative O arm computed tomography. AB - Stress fractures of the tarsal navicular are high-risk injuries that can result in displacement, avascular necrosis, malunion, and nonunion. Delayed diagnosis and improper treatment can lead to long-term functional impairments and poor clinical outcomes. Increased shear stress and decreased vascularity in the central third of the navicular can complicate bony healing with often unpredictable return times to activity using conservative management in a non weight-bearing cast. There recently has been increasing debate regarding the effectiveness of treatment options with a trend toward surgical management to anatomically reduce and stabilize navicular stress fractures in athletes. However, anatomic reduction and fixation of the navicular can be difficult despite direct visualization and intraoperative fluoroscopy. We report a case of a chronic navicular stress fracture in a high-level teenage athlete treated with open reduction internal fixation (ORIF) and calcaneus autograft using intraoperative computed tomography (CT) (O-arm(r), Medtronic, Minneapolis, MN) for real-time evaluation of fracture reduction and fixation. Intraoperative CT was fast, reliable, and allowed for confirmation of guide wire orientation, alignment, and length across the fracture site. Anatomic fixation of navicular stress fractures can be challenging, and it is important for surgeons to be aware of the potential advantages of using intraoperative CT when treating these injuries. LEVELS OF EVIDENCE: Therapeutic, Level IV: Case Report. PMID- 24764269 TI - Noninvasive electrical impedance sensor for in vivo tissue discrimination at radio frequencies. AB - Compared to traditional open surgery, minimally invasive surgery (MIS) allows for a more rapid and less painful recovery. However, the lack of significant haptic feedback in MIS can make tissue discrimination difficult. This paper tests a noninvasive electrical impedance sensor for in vivo discrimination of tissue types in MIS. The sensor consists of two stainless steel spherical electrodes used to measure the impedance spectra over the frequency range of 200 kHz to 5 MHz. The sensor helps ensure free movement on an organ surface and prevents soft tissues from being injured during impedance measurement. Since the recorded electrical impedance is correlated with the force pressed on the electrode and the mechanical property of the tissue, the electrode-tissue contact impedance is calculated theoretically. We show that the standard deviation of the impedance ratio at each frequency point is sufficient to distinguish different tissue types. Both in vitro experiment in a pig kidney and in vivo experiment in rabbit organs were performed to demonstrate the feasibility of the electrical impedance sensor. The experimental results indicated that the sensor, used with the proposed data-processing method, provides accurate and reliable biological tissue discrimination. PMID- 24764270 TI - Advanced lytic lesion is a poor mobilization factor in peripheral blood stem cell collection in patients with multiple myeloma. AB - This study examined the incidence and predictors of peripheral blood stem cell (PBSC) mobilization failure in patients with multiple myeloma (MM). Retrospective data for 104 patients who received granulocyte colony-stimulating factor (G-CSF) alone or with cyclophosphamide as mobilization regimens were analyzed. The rates of mobilization failure using two definitions of failure (< 2 * 10(6) and < 4 * 10(6) CD34(+) cells/kg) following the first collection attempt were 16.3 and 33.7%, respectively. Predictors of mobilization failure were evaluated using logistic regression analysis which included age, advanced osteolytic lesions, bone marrow cellularity before mobilization, platelet count, body mass index before mobilization, and mobilization method. Lytic bone lesions were assessed using a conventional skeletal survey, and advanced osteolytic lesions were defined as lytic lesions in more than three skeletal sites regardless of the number of lytic lesions. On multivariate analysis, advanced osteolytic lesions [hazard ratio (HR) = 10.95, P = 0.001] and age >=60 years (HR = 5.45, P = 0.016) were associated with a PBSC yield < 2 * 10(6) CD34(+) cells/kg, and advanced osteolytic lesions (HR = 5.08, P = 0.006), white blood cell count <=4,000/uL before mobilization (HR = 4.72, P = 0.005), and G-CSF only mobilization (HR 10.52, P < 0.001) were associated with PBSC yield < 4 * 10(6) CD34(+) cells/kg. The data suggest that an advanced osteolytic lesion is a significant predictor of mobilization failure in MM patients. PMID- 24764271 TI - alpha-Tricalcium phosphate cements modified with beta-dicalcium silicate and tricalcium aluminate: physicochemical characterization, in vitro bioactivity and cytotoxicity. AB - Biocompatibility, injectability and in situ self-setting are characteristics of calcium phosphate cements which make them promising materials for a wide range of clinical applications in traumatology and maxillo-facial surgery. One of the main disadvantages is their relatively low strength which restricts their use to nonload-bearing applications. alpha-Tricalcium phosphate (alpha-C3P) cement sets into calcium-deficient hydroxyapatite (CDHA), which is biocompatible and plays an essential role in the formation, growth and maintenance of tissue-biomaterial interface. beta-Dicalcium silicate (beta-C2S) and tricalcium aluminate (C3A) are Portland cement components, these compounds react with water to form hydrated phases that enhance mechanical strength of the end products. In this study, setting time, compressive strength (CS) and in vitro bioactivity and biocompatibility were evaluated to determine the influence of addition of beta C2S and C3A to alpha-C3P-based cement. X-ray diffraction and scanning electron microscopy were used to investigate phase composition and morphological changes in cement samples. Addition of C3A resulted in cements having suitable setting times, but low CS, only partial conversion into CDHA and cytotoxicity. However, addition of beta-C2S delayed the setting times but promoted total conversion into CDHA by soaking in simulated body fluid and strengthened the set cement over the limit strength of cancellous bone. The best properties were obtained for cement added with 10 wt % of beta-C2S, which showed in vitro bioactivity and cytocompatibility, making it a suitable candidate as bone substitute. PMID- 24764272 TI - RNA aminoacylation mediated by sequential action of two ribozymes and a nonactivated amino acid. AB - In the transition from the RNA world to the modern DNA/protein world, RNA catalyzed aminoacylation might have been a key step towards early translation. A number of ribozymes capable of aminoacylating their own 3' termini have been developed by in vitro selection. However, all of those catalysts require a previously activated amino acid-typically an aminoacyl-AMP-as substrate. Here we present two ribozymes connected by intermolecular base pairing and carrying out the two steps of aminoacylation: ribozyme 1 loads nonactivated phenylalanine onto its phosphorylated 5' terminus, thereby forming a high-energy mixed anhydride. Thereafter, a complex of ribozymes 1 and 2 is formed by intermolecular base pairing, and the "activated" phenylalanine is transferred from the 5' terminus of ribozyme 1 to the 3' terminus of ribozyme 2. This kind of simple RNA aminoacylase complex was engineered from previously selected ribozymes possessing the two required activities. RNA aminoacylation with a nonactivated amino acid as described here is advantageous to RNA world scenarios because initial amino acid activation by an additional reagent (in most cases, ATP) and an additional ribozyme would not be necessary. PMID- 24764273 TI - Confinement and deformation of single cells and their nuclei inside size-adapted microtubes. PMID- 24764277 TI - Pulsed electromagnetic field treatment enhances healing callus biomechanical properties in an animal model of osteoporotic fracture. AB - Delayed bone healing has been noted in osteoporosis patients and in the ovariectomized (OVX) rat model of estrogen-depletion osteopenia. Pulsed electromagnetic field (PEMF) devices are clinically approved as an adjunct to cervical fusion surgery in patients at high risk for non-fusion and for the treatment of fracture non-unions. These bone growth stimulating devices also accelerate the healing of fresh fracture repair in skeletally mature normal rats but have not been tested for efficacy to accelerate and/or enhance the delayed bone repair process in OVX rats. The current study tested the hypothesis that daily PEMF treatments would improve the fracture healing response in skeletally mature OVX rats. By 6 weeks of healing, PEMF treatments resulted in improved hard callus elastic modulus across fibula fractures normalizing the healing process in OVX rats with respect to this mechanical property. Radiographic evidence showed an improved hard callus bridging across fibula fractures in OVX rats treated with PEMF as compared to sham treatments. These findings provide a scientific rationale for investigating whether PEMF might improve bone-healing responses in at-risk osteoporotic patients. PMID- 24764278 TI - Prostate MR elastography with transperineal electromagnetic actuation and a fast fractionally encoded steady-state gradient echo sequence. AB - Our aim is to develop a clinically viable, fast-acquisition, prostate MR elastography (MRE) system with transperineal excitation. We developed a new actively shielded electromagnetic transducer, designed to enable quick deployment and positioning within the scanner. The shielding of the transducer was optimized using simulations. We also employed a new rapid pulse sequence that encodes the three-dimensional displacement field in the prostate gland using a fractionally encoded steady-state gradient echo sequence, thereby shortening the acquisition time to a clinically acceptable 8-10 min. The methods were tested in two phantoms and seven human subjects (six volunteers and one patient with prostate cancer). The MRE acquisition time for 24 slices, with an isotropic resolution of 2 mm and eight phase offsets, was 8 min, and the total scan, including positioning and set up, was performed in 15-20 min. The phantom study demonstrated that the transducer does not interfere with the acquisition process and that it generates displacement amplitudes that exceed 100 um even at frequencies as high as 300 Hz. In the in vivo human study, average wave amplitudes of 30 um (46 um at the apex) were routinely achieved within the prostate gland at 70 Hz. No pain or discomfort was reported. Results in a single patient suggest that MRE can identify cancer tumors, although this result is preliminary. The proposed methods allow the integration of prostate MRE with other multiparametric MRI methods. The results of this study clearly motivate the clinical evaluation of transperineal MRE in patients. PMID- 24764279 TI - Hemocompatible polyethersulfone/polyurethane composite membrane for high performance antifouling and antithrombotic dialyzer. AB - Researches on blood purification membranes are fuelled by diverse clinical needs, such as hemodialysis, hemodiafiltration, hemofiltration, plasmapheresis, and plasma collection. To approach high-performance dialyzer, the integrated antifouling and antithrombotic properties are highly necessary for the design/modification of advanced artificial membranes. In this study, we propose and demonstrate that the physical blend of triblock polyurethane (PU) and polyethersulfone (PES) may advance the performance of hemodialysis membranes with greatly enhanced blood compatibility. It was found that the triblock PU could be blended with PES at high ratio owing to their excellent miscibility. The surfaces of the PES/PU composite membranes were characterized using attenuated total reflectance-Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, water contact angle measurement, and surface zeta-potentials. The results indicated that the membrane surfaces were assembled with hydrophilic segregation layer owing to the migration of amphiphilic PU segments during membrane preparation, which might confer the composite membranes with superior hemocompatibility. The cross-section scanning electron microscopy images of the composite membranes exhibited structure transformation from finger-like structure to sponge-like structure, which indicated that the composite membrane had tunable porosity and permeability. The further ultrafiltration experiments indicated that the composite membranes showed increased permeability and excellent antifouling ability. The blood compatibility observation indicated that PES/PU composite membranes owned decreased protein adsorption, suppressed platelet adhesion, and prolonged plasma recalcification time. These results indicated that the PES/PU composite membranes exhibited enhanced antifouling and antithrombotic properties than the pristine PES membrane. The strategy may forward the fabrication of blood compatible composite membranes for clinical blood dialysis by using the various functional miscible polymers. PMID- 24764280 TI - An expanded set of fluorogenic sulfatase activity probes. AB - Fluorogenic probes that are activated by an enzymatic transformation are ideally suited for profiling enzyme activities in biological systems. Here, we describe two fluorogenic enzyme probes, 3-O-methylfluorescein-sulfate and resorufin sulfate, that can be used to detect sulfatases in mycobacterial lysates. Both probes were validated with a set of commercial sulfatases and used to reveal species-specific sulfatase banding patterns in a gel-resolved assay of mycobacterial lysates. The fluorogenic probes described here are suitable for various assays and provide a starting point for creating new sulfatase probes with improved selectivity for mycobacterial sulfatases. PMID- 24764281 TI - Attenuation of allograft rejection by intragraft inhibition of class II transcativator in high responder rat liver transplantation. AB - Major histocompatibility complex-II (MHC-II) plays an important role in graft rejection and class II transactivator (CIITA) is the key regulator for MHC-II expression. The aim of this study was to determine the efficacy of intragraft inhibition of CIITA in attenuating liver transplant rejection. Three plasmids containing small hairpin RNA (shRNA) against rat CIITA (pCIITA-shRNA) and one control plasmid of pHK-shRNA were constructed. In vitro dendritic cell (DC) transfection and liver transfection via portal vein in donor rats (n = 8) by shRNA plasmids were performed to confirm the inhibitory effect of pCIITA-shRNA on CIITA expression. It showed that expressions of CIITA and MHC-II were significantly inhibited by pCIITA-shRNA in both DC in vitro and liver of donor rats in vivo (p < 0.05 vs. control pHK-shRNA treatment). pCIITA1-shRNA was proved to be the best inhibitor among three pCIITA-shRNAs and then used in high responder rat liver transplantation model (DA donors-to-Lewis recipients). Transplant groups (n = 16/group) include untreated recipients transplanted with donor liver graft pretreated with either saline, or pHK-shRNA, or pCIITA1-shRNA. Cyclosporine-treated (10 mg/kg, im, day 0-7) recipients transplanted with unmodified liver grafts were used as no rejection control. The results showed that the recipient rats survived significantly longer in pCIITA1-shRNA-treated group with markedly attenuated liver graft rejection (p < 0.05 vs. saline and pHK shRNA-treated groups). Furthermore, significantly decreased intragraft expressions of CIITA, MHC-II, IL-2, and IFN-gamma were found in pCIITA1-shRNA treated group (p < 0.05 vs. saline and pHK-shRNA-treated groups). This study suggests that intragraft inhibition of CIITA could be a novel strategy for attenuating graft rejection in liver transplantation. PMID- 24764282 TI - Whispering-gallery-mode microlaser based on self-assembled organic single crystalline hexagonal microdisks. AB - Whispering-gallery-mode (WGM) resonators of semiconductor microdisks have been applied for achieving low-threshold and narrow-linewidth microlasers, but require sophisticated top-down processing technology. Organic single-crystalline hexagonal microdisks (HMDs) of p-distyrylbenzene (DSB) self-assembled from solution can function as WGM microresonators with a cavity quality factor (Q) of 210. Both multiple- and single-mode lasing had been achieved using DSB HMDs with an edge length of 4.3 and 1.2 MUm, respectively. These organic microdisks fabricated by bottom-up self-assembly approach may offer potential applications as low-threshold microlaser sources for photonic circuit integration. PMID- 24764283 TI - Proteinuria testing among patients with diabetes mellitus is associated with bladder cancer diagnosis: potential for unmeasured confounding in studies of pioglitazone and bladder cancer. AB - BACKGROUND: The observed association between pioglitazone and bladder cancer could be causal or because of bias in the design of prior studies. We hypothesize that proteinuria testing may lead to detection bias if routine test results for proteinuria lead to a full urinalysis. METHODS: We reanalyzed patients with diabetes mellitus within Kaiser Permanente Northern California. Logistic and Cox regression adjusted for age, sex, race, and smoking were used to assess the association of proteinuria testing with pioglitazone use, subsequent full urinalysis, and diagnosis with bladder cancer. RESULTS: Patients treated with pioglitazone were more likely than others with diabetes to undergo testing for proteinuria (p < 0.001). The odds of positive tests for proteinuria were higher among pioglitazone-treated patients (OR = 1.41, 95%CI 1.36-1.46). A positive proteinuria test was associated with increased odds of completing a urinalysis in the following 6 months (OR = 1.78, 95%CI 1.73-1.85). Negative and positive proteinuria test results were inversely (hazard ratio (HR) 0.63, 95%CI 0.52-0.75) and positively associated (HR 2.45, 95%CI 2.12-2.82) with bladder cancer risk, respectively. Adjustment for negative and positive proteinuria testing reduced the magnitude of association between pioglitazone and bladder cancer by only 5 to 10% (ever-exposed HR: from 1.06 to 1.01 and >4 years exposure HR: from 1.38 to 1.28). CONCLUSIONS: Proteinuria testing may be a confounder in studies of pioglitazone and bladder cancer but does not fully explain the association between pioglitazone and bladder cancer in this cohort. Optimal adjustment for proteinuria testing likely requires knowledge of the test result. PMID- 24764284 TI - Polymeric-gold nanohybrids for combined imaging and cancer therapy. AB - Here, the use of folic acid (FA)-functionalized, doxorubicin (DOXO)/superparamagnetic iron oxide nanoparticles (SPION)-loaded poly(lactic-co glycolic acid) (PLGA)-Au porous shell nanoparticles (NPs) as potential nanoplatforms is reported for targeted multimodal chemo- and photothermal therapy combined with optical and magnetic resonance imaging in cancer. These polymeric gold nanohybrids (PGNH) are produced by a seeded-growth method using chitosan as an electrostatic "glue" to attach Au seeds to DOXO/SPION-PLGA NPs. In order to determine their potential as theranostic nanoplatforms, their physicochemical properties, cellular uptake, and photothermal and chemotherapeutic efficiencies are tested in vitro using a human cervical cancer (HeLa) cell line. The present NPs show a near-infrared (NIR)-light-triggered release of cargo molecules under illumination and a great capacity to induce localized cell death in a well focused region. The functionalization of the PGNH NPs with the targeting ligand FA improves their internalization efficiency and specificity. Furthermore, the possibility to guide the PGNH NPs to cancer cells by an external magnetic field is also proven in vitro, which additionally increases the cellular uptake and therapeutic efficiency. PMID- 24764285 TI - Stressful life events and depressive symptoms among symptomatic long QT syndrome patients. AB - We examined whether long QT syndrome status moderates the association between stressful life events and depressive symptoms. Participants were 562 (n= 246 symptomatic) long QT syndrome mutation carriers. Depressive symptoms were measured with a modified version of the Beck's Depression Inventory. There was an interaction between long QT syndrome status and stressful life events on depressive symptoms. In the symptomatic long QT syndrome patients, stressful life events were associated with depressive symptoms (B= 0.24, p< 0.001). In the asymptomatic long QT syndrome mutation carriers, this association was 62.5 percent weaker (B= 0.09, p= 0.057). Compared to asymptomatic long QT syndrome mutation carriers, symptomatic long QT syndrome patients are more sensitive to the depressive effects of stressful life events. PMID- 24764286 TI - Depression and disease progression in amyotrophic lateral sclerosis: A comprehensive meta-regression analysis. AB - Depression in people with amyotrophic lateral sclerosis, a fatal and progressive neurodegenerative disorder, is a serious issue with important clinical consequences. However, physical impairment may confound the diagnosis when using generic questionnaires. We conducted a comprehensive review of literature. Mean scores from depression questionnaires were meta-regressed on study-level mean time since onset of symptoms. Data from 103 studies (3190 subjects) indicate that the Beck Depression Inventory and, to a lesser degree, the Hospital Anxiety and Depression Scale are influenced by the time since symptom onset, strongly related to physical impairment. Our results suggest that widely used depression scales overestimate depression due to confounding with physical symptoms. PMID- 24764287 TI - Basic study of soft tissue augmentation by adipose-inductive biomaterial. AB - Reconstructive surgery for tumor resection, trauma, and congenital anomaly involves volume augmentation with autologous tissue transfer. However, a healthy region is damaged as a donor site, and the autologous tissue is transferred like a patchwork to the recipient site. We have attempted to induce adipogenesis activity in artificial biomaterial that is injectable with an injection needle for soft tissue augmentation. First of all, the optimal dose of pioglitazone hydrochloride was examined with adipo-precursor cells in terms of the proliferator-activated receptor-gamma mRNA expression levels affected by reagent in vitro. Then, salmon collagen with pioglitazone was adjusted in terms of the dose and the salmon collagen was injected into mouse back using an injection needle in vivo. At 4 weeks after implantation, the pioglitazone collagen gel was substituted by mature adipocytes in comparison with the case for control collagen gel without pioglitazone. These results are indicative of the possibility of promoting adipogenesis using collagen with pioglitazone as an adipose-inductive substance. PMID- 24764288 TI - Quantification of zinc atoms in a surface alloy on copper in an industrial-type methanol synthesis catalyst. AB - Methanol has recently attracted renewed interest because of its potential importance as a solar fuel. Methanol is also an important bulk chemical that is most efficiently formed over the industrial Cu/ZnO/Al2O3 catalyst. The identity of the active site and, in particular, the role of ZnO as a promoter for this type of catalyst is still under intense debate. Structural changes that are strongly dependent on the pretreatment method have now been observed for an industrial-type methanol synthesis catalyst. A combination of chemisorption, reaction, and spectroscopic techniques provides a consistent picture of surface alloying between copper and zinc. This analysis enables a reinterpretation of the methods that have been used for the determination of the Cu surface area and provides an opportunity to independently quantify the specific Cu and Zn areas. This method may also be applied to other systems where metal-support interactions are important, and this work generally addresses the role of the carrier and the nature of the interactions between carrier and metal in heterogeneous catalysts. PMID- 24764289 TI - Modulating the pKa of a tyrosine in KlenTaq DNA polymerase that is crucial for abasic site bypass by in vivo incorporation of a non-canonical amino acid. AB - It is estimated that about 10,000 abasic sites are formed per day per cell. Abasic sites impose a significant challenge for bypass synthesis by DNA polymerases. Recently, a tyrosine in KlenTaq DNA polymerase has been highlighted as being crucial for nucleotide selection opposite abasic sites. Structural data indicated a hydrogen bond between the tyrosine's hydroxy group and the N3 of an incoming ddATP opposite the abasic site. In order to further investigate abasic site bypass, we incorporated the unnatural amino acid 2,3,5-trifluorotyrosine at the position of the crucial tyrosine of KlenTaq DNA polymerase. Fluorine substitution at the tyrosine decreased the pka value of the tyrosine's hydroxy group and allowed its protonation state to be modulated. Single-nucleotide incorporation experiments revealed reduced activity for the KlenTaq mutant compared to the wild-type when bypassing an abasic site analogue. The finding stresses the involvement of this tyrosine and its hydrogen bonding in abasic site bypass. PMID- 24764290 TI - A cadherin-like protein from the beet armyworm Spodoptera exigua (Lepidoptera: Noctuidae) is a putative Cry1Ac receptor. AB - In S. exigua, ingestion of Cry1Ac reduces larval growth, shortens lifespan, and decreases copulation and oviposition of the adults. Cadherin-like protein SeCad1b in S. exigua has recently been published. Here, we tested whether SeCad1b mediates the negative effects of Cry1Ac. We identified three potential Cry toxin binding regions in SeCad1b, i.e., (879) EIAIQITDTNN(889) , (1357) SLLTVTI(1363) , and (1436) GVISLNFQ(1443) . We expressed and purified a truncated cadherin, rSeCad1bp, and its interspecific homologue, rHaBtRp, from H. armigera that contain the putative toxin binding regions. Using a toxin overlay assay, we found that rSeCad1bp specifically binds to biotinylated Cry1Ac in a dose-dependent manner. We also discovered that an addition of rSeCad1bp and rHaBtRp enhances the suppression of larval growth by Cry1Ac, although rSeCad1bp is less suppressive than rHaBtRp. Finally, RNA interference-mediated knockdown of SeCad1b reduced approximately 80% of the target gene and significantly alleviated the negative effect of CrylAc on larval growth. We infer that the S. exigua SeCad1b is a functional receptor of Cry1Ac. PMID- 24764291 TI - The impact of prostate cancer on partners: a qualitative exploration. AB - OBJECTIVE: Prostate cancer and its treatment can result in numerous physical and psychological morbidities for the patient as well as his partner. This qualitative study aimed to explore the experiences of intimate spouses or partners of men diagnosed and/or treated for prostate cancer to better understand the personal impact of prostate cancer on the partner. METHODS: Twenty-seven partners participated in this study. Six focus groups were convened, and one in depth interview was undertaken to explore the practical impact of prostate cancer on the intimate spouse/partner. All discussions were audio-recorded and transcribed and then coded using a thematic approach. RESULTS: Six themes emerged: (a) The influence of the man's response to prostate cancer on the partner, (b) The need to be involved in treatment and medical decision making, (c) Supporting a man who is experiencing a loss of masculinity, (d) Degree of congruence between each partner's coping responses, (e) Constrained communication, and (f) Changed roles and increased practical management. CONCLUSIONS: It is clear that prostate cancer impacts substantially on many areas of partner well-being. An effective intervention provided to this population seems warranted and may lead to improvements in partner well-being, assist the couple in lessening the impact of prostate cancer and its treatment on their relationship, and assist in the man's recovery. PMID- 24764292 TI - The RUNX2 cistrome in osteoblasts: characterization, down-regulation following differentiation, and relationship to gene expression. AB - RUNX2 is a transcription factor that is first expressed in early osteoblast lineage cells and represents a primary determinant of osteoblastogenesis. While numerous target genes are regulated by RUNX2, little is known of sites on the genome occupied by RUNX2 or of the gene networks that are controlled by these sites. To explore this, we conducted a genome-wide analysis of the RUNX2 cistrome in both pre-osteoblastic MC3T3-E1 cells (POB) and their mature osteoblast progeny (OB), characterized the two cistromes and assessed their relationship to changes in gene expression. We found that although RUNX2 was widely bound to the genome in POB cells, this binding profile was reduced upon differentiation to OBs. Numerous sites were lost upon differentiation, new sites were also gained; many sites remained common to both cell states. Additional features were identified as well including location relative to potential target genes, abundance with respect to single genes, the frequent presence of a consensus TGTGGT RUNX2 binding motif, co-occupancy by C/EBPbeta and the presence of a typical epigenetic histone enhancer signature. This signature was changed quantitatively following differentiation. While RUNX2 binding sites were associated extensively with adjacent genes, the distal nature of the majority of these sites prevented assessment of whether they represented direct targets of RUNX2 action. Changes in gene expression, however, revealed an abundance of genes that contained RUNX2 binding sites and were regulated in concert. These studies establish a basis for further analysis of the role of RUNX2 activity and its function during osteoblast lineage maturation. PMID- 24764293 TI - Dominant negative effects of tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) receptor 4 on TRAIL receptor 1 signaling by formation of heteromeric complexes. AB - The cytokine TNF-related apoptosis-inducing ligand (TRAIL) and its cell membrane receptors constitute an elaborate signaling system fulfilling important functions in immune regulation and tumor surveillance. Activation of the death receptors TRAILR1 and TRAILR2 can lead to apoptosis, whereas TRAILR3 and TRAILR4 are generally referred to as decoy receptors, which have been shown to inhibit TRAIL induced apoptosis. The underlying molecular mechanisms, however, remain unclear. Alike other members of the TNF receptor superfamily, TRAIL receptors contain a pre-ligand binding assembly domain (PLAD) mediating receptor oligomerization. Still, the stoichiometry of TRAIL receptor oligomers as well as the issue of whether the PLAD mediates only homotypic or also heterotypic interactions remained inconclusive until now. Performing acceptor-photobleaching FRET studies with receptors 1, 2, and 4, we demonstrate interactions in all possible combinations. Formation of dimers was shown by chemical cross-linking experiments for interactions of TRAILR2 and heterophilic interactions between the two death receptors or between either of the death receptors and TRAILR4. Implications of the demonstrated receptor-receptor interactions on signaling were investigated in suitable cellular models. Both apoptosis induction and activation of the transcription factor NFkappaB were significantly reduced in the presence of TRAILR4. Our experimental data combined with mathematical modeling show that the inhibitory capacity of TRAILR4 is attributable to signaling-independent mechanisms, strongly suggesting a reduction of signaling competent death receptors through formation heteromeric receptor complexes. In summary, we propose a model of TRAIL receptor interference driven by PLAD-mediated formation of receptor heterodimers on the cell membrane. PMID- 24764294 TI - Endothelial nitric-oxide synthase (eNOS) is activated through G-protein-coupled receptor kinase-interacting protein 1 (GIT1) tyrosine phosphorylation and Src protein. AB - Nitric oxide (NO) is a critical regulator of vascular tone and plays an especially prominent role in liver by controlling portal blood flow and pressure within liver sinusoids. Synthesis of NO in sinusoidal endothelial cells by endothelial nitric-oxide synthase (eNOS) is regulated in response to activation of endothelial cells by vasoactive signals such as endothelins. The endothelin B (ETB) receptor is a G-protein-coupled receptor, but the mechanisms by which it regulates eNOS activity in sinusoidal endothelial cells are not well understood. In this study, we built on two previous strands of work, the first showing that G protein betagamma subunits mediated activation of phosphatidylinositol 3-kinase and Akt to regulate eNOS and the second showing that eNOS directly bound to the G protein-coupled receptor kinase-interacting protein 1 (GIT1) scaffold protein, and this association stimulated NO production. Here we investigated the mechanisms by which the GIT1-eNOS complex is formed and regulated. GIT1 was phosphorylated on tyrosine by Src, and Y293F and Y554F mutations reduced GIT1 phosphorylation as well as the ability of GIT1 to bind to and activate eNOS. Akt phosphorylation activated eNOS (at Ser(1177)), and Akt also regulated the ability of Src to phosphorylate GIT1 as well as GIT1-eNOS association. These pathways were activated by endothelin-1 through the ETB receptor; inhibiting receptor activated G-protein betagamma subunits blocked activation of Akt, GIT1 tyrosine phosphorylation, and ET-1-stimulated GIT1-eNOS association but did not affect Src activation. These data suggest a model in which Src and Akt cooperate to regulate association of eNOS with the GIT1 scaffold to facilitate NO production. PMID- 24764295 TI - Non-repair pathways for minimizing protein isoaspartyl damage in the yeast Saccharomyces cerevisiae. AB - The spontaneous degradation of asparaginyl and aspartyl residues to isoaspartyl residues is a common type of protein damage in aging organisms. Although the protein-l-isoaspartyl (d-aspartyl) O-methyltransferase (EC 2.1.1.77) can initiate the repair of l-isoaspartyl residues to l-aspartyl residues in most organisms, no gene homolog or enzymatic activity is present in the budding yeast Saccharomyces cerevisiae. Therefore, we used biochemical approaches to elucidate how proteins containing isoaspartyl residues are metabolized in this organism. Surprisingly, the level of isoaspartyl residues in yeast proteins (50-300 pmol of isoaspartyl residues/mg of protein extract) is comparable with organisms with protein-l isoaspartyl (d-aspartyl) O-methyltransferase, suggesting a novel regulatory pathway. Interfering with common protein quality control mechanisms by mutating and inhibiting the proteasomal and autophagic pathways in vivo did not increase isoaspartyl residue levels compared with wild type or uninhibited cells. However, the inhibition of metalloproteases in in vitro aging experiments by EDTA resulted in an ~3-fold increase in the level of isoaspartyl-containing peptides. Characterization by mass spectrometry of these peptides identified several proteins involved in metabolism as targets of isoaspartyl damage. Further analysis of these peptides revealed that many have an N-terminal isoaspartyl site and originate from proteins with short half-lives. These results suggest that one or more metalloproteases participate in limiting isoaspartyl formation by robust proteolysis. PMID- 24764296 TI - Phosphorylation at threonine 288 by cell cycle checkpoint kinase 2 (CHK2) controls human monopolar spindle 1 (Mps1) kinetochore localization. AB - Human Mps1 (hMps1) is a mitotic checkpoint kinase responsible for sensing the unattached and tensionless kinetochore. Despite its importance in safeguarding proper chromosome segregation, how hMps1 is recruited to the kinetochore remains incompletely understood. Here, we demonstrate that phosphorylation at Thr-288 by the cell cycle checkpoint kinase CHK2 is involved in this process. We discovered that the phosphorylation-deficient T288A mutant has an impaired ability to localize to the kinetochore and cannot reestablish the mitotic checkpoint in hMps1-depleted cells. In support, we found that nocodazole induced hMps1 phosphorylation at the previously identified CHK2 site Thr-288 and that this could be detected at the kinetochore in a CHK2-dependent manner. Mechanistically, phosphorylation at Thr-288 promoted the interaction with the KMN (KNL1-Mis12 Ndc80 network) protein HEC1. Forced kinetochore localization corrected the defects associated with the T288A mutant. Our results provide evidence of a newly identified hMps1 phosphorylation site that is involved in the mitotic checkpoint and that CHK2 contributes to chromosomal stability through hMps1. PMID- 24764297 TI - The crystal structure of the active domain of Anopheles anti-platelet protein, a powerful anti-coagulant, in complex with an antibody. AB - Blood clotting is a vitally important process that must be carefully regulated to prevent blood loss on one hand and thrombosis on the other. Severe injury and hemophilia may be treated with pro-coagulants, whereas risk of obstructive clotting or embolism may be reduced with anti-coagulants. Anti-coagulants are an extremely important class of drug, one of the most widely used types of medication, but there remains a pressing need for novel treatments, however, as present drugs such as warfarin have significant drawbacks. Nature provides a number of examples of anti-coagulant proteins produced by blood-sucking animals, which may provide templates for the development of new small molecules with similar physiological effects. We have, therefore, studied an Anopheles anti platelet protein from a malaria vector mosquito and report its crystal structure in complex with an antibody. Overall the protein is extremely sensitive to proteolysis, but the crystal structure reveals a stable domain built from two helices and a turn, which corresponds to the functional region. The antibody raised against Anopheles anti-platelet protein prevents it from binding collagen. Our work, therefore, opens new avenues to the development of both novel small molecule anti-clotting agents and anti-malarials. PMID- 24764298 TI - Enhanced arginine methylation of programmed cell death 4 protein during nutrient deprivation promotes tumor cell viability. AB - The role of programmed cell death 4 (PDCD4) in tumor biology is context dependent. PDCD4 is described as a tumor suppressor, but its coexpression with protein arginine methyltransferase 5 (PRMT5) promotes accelerated tumor growth. Here, we report that PDCD4 is methylated during nutrient deprivation. Methylation occurs because of increased stability of PDCD4 protein as well as increased activity of PRMT5 toward PDCD4. During nutrient deprivation, levels of methylated PDCD4 promote cell viability, which is dependent on an enhanced interaction with eIF4A. Upon recovery from nutrient deprivation, levels of methylated PDCD4 are regulated by phosphorylation, which controls both the localization and stability of methylated PDCD4. This study reveals that, in response to particular environmental cues, the role of PDCD4 is up-regulated and is advantageous for cell viability. These findings suggest that the methylated form of PDCD4 promotes tumor viability during nutrient deprivation, ultimately allowing the tumor to grow more aggressively. PMID- 24764299 TI - Multifunctional activity of a small tellurium redox immunomodulator compound, AS101, on dextran sodium sulfate-induced murine colitis. AB - Inflammatory bowel diseases (IBDs) are a group of idiopathic, chronic immune mediated diseases characterized by an aberrant immune response, including imbalances of inflammatory cytokine production and activated innate and adaptive immunity. Selective blockade of leukocyte migration into the gut is a promising strategy for the treatment of IBD. This study explored the effect of the immunomodulating tellurium compound ammonium trichloro (dioxoethylene-o,o') tellurate (AS101) on dextran sodium sulfate (DSS)-induced murine colitis. Both oral and intraperitoneal administration of AS101 significantly reduced clinical manifestations of IBD. Colonic inflammatory cytokine levels (IL-17 and IL-1beta) were significantly down-regulated by AS101 treatment, whereas IFN-gamma was not affected. Neutrophil and alpha4beta7(+) macrophage migration into the tissue was inhibited by AS101 treatment. Adhesion of mesenteric lymph node cells to mucosal addressin cell adhesion molecule (MAdCAM-1), the ligand for alpha4beta7 integrin, was blocked by AS101 treatment both in vitro and in vivo. DSS-induced destruction of colonic epithelial barrier/integrity was prevented by AS101, via up-regulation of colonic glial-derived neurotrophic factor, which was found previously to regulate the intestinal epithelial barrier through activation of the PI3K/AKT pathway. Indeed, the up-regulation of glial-derived neurotrophic factor by AS101 was associated with increased levels of colonic pAKT and BCL-2 and decreased levels of BAX. Furthermore, AS101 treatment reduced colonic permeability to Evans blue and decreased colonic TUNEL(+) cells. Our data revealed multifunctional activities of AS101 in the DSS-induced colitis model via anti-inflammatory and anti-apoptotic properties. We suggest that treatment with the small, nontoxic molecule AS101 may be an effective early therapeutic approach for controlling human IBD. PMID- 24764300 TI - A novel intracellular peptide derived from g1/s cyclin d2 induces cell death. AB - Intracellular peptides are constantly produced by the ubiquitin-proteasome system, and many are probably functional. Here, the peptide WELVVLGKL (pep5) from G1/S-specific cyclin D2 showed a 2-fold increase during the S phase of HeLa cell cycle. pep5 (25-100 MUm) induced cell death in several tumor cells only when it was fused to a cell-penetrating peptide (pep5-cpp), suggesting its intracellular function. In vivo, pep5-cpp reduced the volume of the rat C6 glioblastoma by almost 50%. The tryptophan at the N terminus of pep5 is essential for its cell death activity, and N terminus acetylation reduced the potency of pep5-cpp. WELVVL is the minimal active sequence of pep5, whereas Leu-Ala substitutions totally abolished pep5 cell death activity. Findings from the initial characterization of the cell death/signaling mechanism of pep5 include caspase 3/7 and 9 activation, inhibition of Akt2 phosphorylation, activation of p38alpha and -gamma, and inhibition of proteasome activity. Further pharmacological analyses suggest that pep5 can trigger cell death by distinctive pathways, which can be blocked by IM-54 or a combination of necrostatin-1 and q-VD-OPh. These data further support the biological and pharmacological potential of intracellular peptides. PMID- 24764301 TI - Dissection of the neonatal Fc receptor (FcRn)-albumin interface using mutagenesis and anti-FcRn albumin-blocking antibodies. AB - Albumin is the most abundant protein in blood and plays a pivotal role as a multitransporter of a wide range of molecules such as fatty acids, metabolites, hormones, and toxins. In addition, it binds a variety of drugs. Its role as distributor is supported by its extraordinary serum half-life of 3 weeks. This is related to its size and binding to the cellular receptor FcRn, which rescues albumin from intracellular degradation. Furthermore, the long half-life has fostered a great and increasing interest in utilization of albumin as a carrier of protein therapeutics and chemical drugs. However, to fully understand how FcRn acts as a regulator of albumin homeostasis and to take advantage of the FcRn albumin interaction in drug design, the interaction interface needs to be dissected. Here, we used a panel of monoclonal antibodies directed towards human FcRn in combination with site-directed mutagenesis and structural modeling to unmask the binding sites for albumin blocking antibodies and albumin on the receptor, which revealed that the interaction is not only strictly pH-dependent, but predominantly hydrophobic in nature. Specifically, we provide mechanistic evidence for a crucial role of a cluster of conserved tryptophan residues that expose a pH-sensitive loop of FcRn, and identify structural differences in proximity to these hot spot residues that explain divergent cross-species binding properties of FcRn. Our findings expand our knowledge of how FcRn is controlling albumin homeostasis at a molecular level, which will guide design and engineering of novel albumin variants with altered transport properties. PMID- 24764302 TI - High-throughput assays for superoxide and hydrogen peroxide: design of a screening workflow to identify inhibitors of NADPH oxidases. AB - Recent progress characterizing the reaction mechanism(s) of fluorescent probes with reactive oxygen species has made it possible to rigorously analyze these reactive species in biological systems. We have developed rapid high throughput compatible assays for monitoring cellular production of superoxide radical anion and hydrogen peroxide using hydropropidine and coumarin boronic acid probes, respectively. Coupling plate reader-based fluorescence measurements with HPLC based simultaneous monitoring of superoxide radical anion and hydrogen peroxide provides the basis for the screening protocol for NADPH oxidase (Nox) inhibitors. Using this newly developed approach along with the medium-throughput plate reader based oximetry and EPR spin trapping as confirmatory assays, it is now eminently feasible to rapidly and reliably identify Nox enzyme inhibitors with a markedly lower rate of false positives. These methodological advances provide an opportunity to discover selective inhibitors of Nox isozymes, through enhanced conceptual understanding of their basic mechanisms of action. PMID- 24764303 TI - Structural basis for calcium and magnesium regulation of a large conductance calcium-activated potassium channel with beta1 subunits. AB - Large conductance Ca(2+)- and voltage-activated potassium (BK) channels, composed of pore-forming alpha subunits and auxiliary beta subunits, play important roles in diverse physiological activities. The beta1 is predominately expressed in smooth muscle cells, where it greatly enhances the Ca(2+) sensitivity of BK channels for proper regulation of smooth muscle tone. However, the structural basis underlying dynamic interaction between BK mSlo1 alpha and beta1 remains elusive. Using macroscopic ionic current recordings in various Ca(2+) and Mg(2+) concentrations, we identified two binding sites on the cytosolic N terminus of beta1, namely the electrostatic enhancing site (mSlo1(K392,R393)-beta1(E13,T14)), increasing the calcium sensitivity of BK channels, and the hydrophobic site (mSlo1(L906,L908)-beta1(L5,V6,M7)), passing the physical force from the Ca(2+) bowl onto the enhancing site and S6 C-linker. Dynamic binding of these sites affects the interaction between the cytosolic domain and voltage-sensing domain, leading to the reduction of Mg(2+) sensitivity. A comprehensive structural model of the BK(mSlo1 alpha-beta1) complex was reconstructed based on these functional studies, which provides structural and mechanistic insights for understanding BK gating. PMID- 24764304 TI - Vipp1 is essential for the biogenesis of Photosystem I but not thylakoid membranes in Synechococcus sp. PCC 7002. AB - The biogenesis of thylakoid membranes in cyanobacteria is presently not well understood, but the vipp1 gene product has been suggested to play an important role in this process. Previous studies in Synechocystis sp. PCC 6803 reported that vipp1 (sll0617) was essential. By constructing a fully segregated null mutant in vipp1 (SynPCC7002_A0294) in Synechococcus sp. PCC 7002, we show that Vipp1 is not essential. Spectroscopic studies revealed that Photosystem I (PS I) was below detection limits in the vipp1 mutant, but Photosystem II (PS II) was still assembled and was active. Thylakoid membranes were still observed in vipp1 mutant cells and resembled those in a psaAB mutant that completely lacks PS I. When the vipp1 mutation was complemented with the orthologous vipp1 gene from Synechocystis sp. PCC 6803 that was expressed from the strong P(cpcBA) promoter, PS I content and activities were restored to normal levels, and cells again produced thylakoids that were indistinguishable from those of wild type. Transcription profiling showed that psaAB transcripts were lower in abundance in the vipp1 mutant. However, when the yfp gene was expressed from the P(psaAB) promoter in the presence and the absence of Vipp1, no difference in YFP expression was observed, which shows that Vipp1 is not a transcription factor for the psaAB genes. This study shows that thylakoids are still produced in the absence of Vipp1 and that normal thylakoid biogenesis in Synechococcus sp. PCC 7002 requires expression and biogenesis of PS I, which in turn requires Vipp1. PMID- 24764306 TI - Sphere of Lorentz and demagnetization factors in white matter. PMID- 24764305 TI - TMTC1 and TMTC2 are novel endoplasmic reticulum tetratricopeptide repeat containing adapter proteins involved in calcium homeostasis. AB - The endoplasmic reticulum (ER) is organized in part by adapter proteins that nucleate the formation of large protein complexes. Tetratricopeptide repeats (TPR) are well studied protein structural motifs that support intermolecular protein-protein interactions. TMTC1 and TMTC2 were identified by an in silico search as TPR-containing proteins possessing N-terminal ER targeting signal sequences and multiple hydrophobic segments, suggestive of polytopic membrane proteins that are targeted to the secretory pathway. A variety of cell biological and biochemical assays was employed to demonstrate that TMTC1 and TMTC2 are both ER resident integral membrane proteins with multiple clusters of TPR domains oriented within the ER lumen. Proteomic analysis followed by co immunoprecipitation verification found that both proteins associated with the ER calcium uptake pump SERCA2B, and TMTC2 also bound to the carbohydrate-binding chaperone calnexin. Live cell calcium measurements revealed that overexpression of either TMTC1 or TMTC2 caused a reduction of calcium released from the ER following stimulation, whereas the knockdown of TMTC1 or TMTC2 increased the stimulated calcium released. Together, these results implicate TMTC1 and TMTC2 as ER proteins involved in ER calcium homeostasis. PMID- 24764307 TI - On-top pi-stacking of quasiplanar molecules in hole-transporting materials: inducing anisotropic carrier mobility in amorphous films. AB - Dimers of partially oxygen-bridged triarylamines were designed and synthesized as hole-transporting materials. X-ray structural analyses revealed that these compounds form on-top pi-stacking aggregates in the crystalline state. TRMC measurements showed that high levels of anisotropic charge transport were induced in the direction of the pi-stacking. Surprisingly, even in vacuum-deposited amorphous films, these compounds retained some of the face-on pi-stacking, thus facilitating an out-of-plane carrier mobility. PMID- 24764308 TI - In-body tissue-engineered aortic valve (Biovalve type VII) architecture based on 3D printer molding. AB - In-body tissue architecture--a novel and practical regeneration medicine technology--can be used to prepare a completely autologous heart valve, based on the shape of a mold. In this study, a three-dimensional (3D) printer was used to produce the molds. A 3D printer can easily reproduce the 3D-shape and size of native heart valves within several processing hours. For a tri-leaflet, valved conduit with a sinus of Valsalva (Biovalve type VII), the mold was assembled using two conduit parts and three sinus parts produced by the 3D printer. Biovalves were generated from completely autologous connective tissue, containing collagen and fibroblasts, within 2 months following the subcutaneous embedding of the molds (success rate, 27/30). In vitro evaluation, using a pulsatile circulation circuit, showed excellent valvular function with a durability of at least 10 days. Interposed between two expanded polytetrafluoroethylene grafts, the Biovalves (N = 3) were implanted in goats through an apico-aortic bypass procedure. Postoperative echocardiography showed smooth movement of the leaflets with minimal regurgitation under systemic circulation. After 1 month of implantation, smooth white leaflets were observed with minimal thrombus formation. Functional, autologous, 3D-shaped heart valves with clinical application potential were formed following in-body embedding of specially designed molds that were created within several hours by 3D printer. PMID- 24764309 TI - The Process of Seeking Psychotherapy and Its Impact on Therapy Expectations and Experiences. AB - Seeking psychotherapy can be conceptualized as having three stages: deciding that therapy might help, deciding to seek therapy and contacting a therapist. The present study examined the duration and difficulty of clients' decisions to seek psychotherapy and whether these experiences were predictive of expected difficulty and commitment to the therapy process. One-hundred and fifty-five adults seeking individual psychological services from a university training clinic were assessed before intake; 107 of these participants also completed measures between the third and fourth therapy sessions and at post-therapy. Deciding that therapy might help was reported to be the most difficult step and took the longest, with each subsequent step becoming easier and briefer. At each step, the more difficult the decision, the more time participants took to make it. Higher distress was associated with more difficulty in deciding that therapy might help and deciding to seek therapy. Duration and difficulty of decisions to seek therapy were positively correlated with expectations of difficulty in therapy as measured prior to treatment and following the third session but were not associated with participants' commitment to therapy. The implications of these results for clinicians and mental health services are discussed. KEY PRACTITIONER MESSAGE: The most difficult and time-consuming step for those who seek mental health services is recognizing that their distressing experiences are connected to mental health; clinicians may aid this challenge by providing information on the nature of mental disorders and common symptoms of emotional distress on websites or through other means (e.g., physicians' waiting rooms and advertising campaigns). The next most difficult and time-consuming step for those who seek mental health services is deciding that psychotherapy may help; by providing easily accessible information (e.g., on websites) about what psychotherapy entails, including clinicians' expectations of clients and the benefits/challenges of therapy, potential clients may be able to progress through this step more rapidly and with less difficulty. Clients' expectations of the value of psychotherapy and their commitment to engage in therapy do not appear to be affected by how long it took, or how difficult it was, to obtain psychotherapy. Factors such as forming a strong therapeutic alliance and providing support and guidance during the initial sessions of therapy may be more important in helping potential clients commit to therapy than what they experienced in their efforts to receive psychotherapy. PMID- 24764310 TI - Combined mutagenesis and kinetics characterization of the bilin-binding GAF domain of the protein Slr1393 from the Cyanobacterium Synechocystis PCC6803. AB - The gene slr1393 from Synechocystis sp. PCC6803 encodes a protein composed of three GAF domains, a PAS domain, and a histidine kinase domain. GAF3 is the sole domain able to bind phycocyanobilin (PCB) as chromophore and to accomplish photochemistry: switching between a red-absorbing parental and a green-absorbing photoproduct state (lambdamax =649 and 536 nm, respectively). Conversions in both directions were followed by time-resolved absorption spectroscopy with the separately expressed GAF3 domain of Slr1393. Global fit analysis of the recorded absorbance changes yielded three lifetimes (3.2 MUs, 390 MUs, and 1.5 ms) for the red-to-green conversion, and 1.2 MUs, 340 MUs, and 1 ms for the green-to-red conversion. In addition to the wild-type (WT) protein, 24 mutated proteins were studied spectroscopically. The design of these site-directed mutations was based on sequence alignments with related proteins and by employing the crystal structure of AnPixJg2 (PDB ID: 3W2Z), a Slr1393 orthologous from Anabaena sp. PCC7120. The structure of AnPixJg2 was also used as template for model building, thus confirming the strong structural similarity between the proteins, and for identifying amino acids to target for mutagenesis. Only amino acids in close proximity to the chromophore were exchanged, as these were considered likely to have an impact on the spectral and dynamic properties. Three groups of mutants were found: some showed absorption features similar to the WT protein, a second group showed modified absorbance properties, and the third group had lost the ability to bind the chromophore. The most unexpected result was obtained for the exchange at residue 532 (N532Y). In vivo assembly yielded a red-absorbing, WT like protein. Irradiation, however, not only converted it into the green absorbing form, but also produced a 660 nm, further-red-shifted absorbance band. This photoproduct was fully reversible to the parental form upon green light irradiation. PMID- 24764311 TI - Fluorescence resonance energy transfer studies of DNA polymerase beta: the critical role of fingers domain movements and a novel non-covalent step during nucleotide selection. AB - During DNA repair, DNA polymerase beta (Pol beta) is a highly dynamic enzyme that is able to select the correct nucleotide opposite a templating base from a pool of four different deoxynucleoside triphosphates (dNTPs). To gain insight into nucleotide selection, we use a fluorescence resonance energy transfer (FRET) based system to monitor movement of the Pol beta fingers domain during catalysis in the presence of either correct or incorrect dNTPs. By labeling the fingers domain with ((((2-iodoacetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid (IAEDANS) and the DNA substrate with Dabcyl, we are able to observe rapid fingers closing in the presence of correct dNTPs as the IAEDANS comes into contact with a Dabcyl-labeled, one-base gapped DNA. Our findings show that not only do the fingers close after binding to the correct dNTP, but that there is a second conformational change associated with a non-covalent step not previously reported for Pol beta. Further analyses suggest that this conformational change corresponds to the binding of the catalytic metal into the polymerase active site. FRET studies with incorrect dNTP result in no changes in fluorescence, indicating that the fingers do not close in the presence of incorrect dNTP. Together, our results show that nucleotide selection initially occurs in an open fingers conformation and that the catalytic pathways of correct and incorrect dNTPs differ from each other. Overall, this study provides new insight into the mechanism of substrate choice by a polymerase that plays a critical role in maintaining genome stability. PMID- 24764312 TI - In situ synthesis of alkenyl tetrazines for highly fluorogenic bioorthogonal live cell imaging probes. AB - In spite of the wide application potential of 1,2,4,5-tetrazines, particularly in live-cell and in vivo imaging, a major limitation has been the lack of practical synthetic methods. Here we report the in situ synthesis of (E)-3-substituted 6 alkenyl-1,2,4,5-tetrazine derivatives through an elimination-Heck cascade reaction. By using this strategy, we provide 24 examples of pi-conjugated tetrazine derivatives that can be conveniently prepared from tetrazine building blocks and related halides. These include tetrazine analogs of biological small molecules, highly conjugated buta-1,3-diene-substituted tetrazines, and a diverse array of fluorescent probes suitable for live-cell imaging. These highly conjugated probes show very strong fluorescence turn-on (up to 400-fold) when reacted with dienophiles such as cyclopropenes and trans-cyclooctenes, and we demonstrate their application for live-cell imaging. This work provides an efficient and practical synthetic methodology for tetrazine derivatives and will facilitate the application of conjugated tetrazines, particularly as fluorogenic probes for live-cell imaging. PMID- 24764313 TI - Regulation of endothelial progenitor cell differentiation and function by dimethylarginine dimethylaminohydrolase 2 in an asymmetric dimethylarginine independent manner. AB - Endothelial progenitor cells (EPCs) are involved in the repair of vessels and angiogenesis and are useful in the treatment of ischemic diseases. The dimethylarginine dimethylaminohydrolase (DDAH)/asymmetric dimethylarginine (ADMA) pathway is regulated by silent information regulator 1 (SIRT1), leading to the senescence of endothelial cells (ECs). Here, we demonstrated that peripheral blood EPCs predominantly expressed DDAH2 that increased with EPC differentiation. EPC senescence and dysfunction were induced on interruption of DDAH2 expression, whereas the mRNA expression of vascular endothelial growth factor (VEGF) and kinase-domain insert containing receptor (KDR) were downregulated. Moreover, SIRT1 expression increased with EPC differentiation. Interruption of SIRT1 inhibited DDAH2, VEGF, and KDR expression, but had no effect on the level of ADMA. From our data, we concluded that DDAH2 is involved in the differentiation of EPCs and regulates the senescence and function of EPCs through the VEGF/KDR pathway by activation of SIRT1. PMID- 24764314 TI - Influence of cassette design on three-dimensional perfusion culture of artificial bone. AB - Media perfusion is often required to maintain cell viability within topographically complex 3-dimensional scaffold cultures. Osteoblast-seeded scaffolds for bone regeneration require robust cell proliferation and survival both within the scaffold and over the exterior for optimal osteogenic capacity. Conventional press-fitting cassettes ensure internal fluid flow through the scaffold but may restrict external flow around the scaffold, resulting in a barren (cell-free) external scaffold surface. In this study, we aimed to solve this problem by modifying the cassette structure to enhance external flow in an oscillatory perfusion culture system. Mouse osteoblast-like MC 3T3-E1 cells were seeded in porous ceramic scaffolds and incubated for 3 days either under static culture conditions or in an oscillatory perfusion bioreactor. Scaffolds were held in the bioreactor with either conventional press-fitting cassettes or cassettes with rings to separate the scaffold exterior from the internal cassette wall. The external surfaces of scaffolds maintained under static conditions were well seeded, but cells failed to grow deeply into the core, reflecting poor internal chemotransport. Alternatively, scaffolds cultured by perfusion with press-fitting cassettes had poor cell viability at the cassette-external scaffold surface interface, but cells were widely distributed within the scaffold core. Scaffolds cultured using the modified cassettes with 1 or 2 rings exhibited uniformly distributed living cells throughout the internal pores and over the entire external surface, possibly because of the improved medium flow over the scaffold surface. This modified oscillatory perfusion culture system may facilitate the production of engineered bone with superior osteogenic capacity for grafting. PMID- 24764315 TI - Selective DNA-binding by designed bisbenzamidine-homeodomain chimeras. AB - We report the construction of conjugates between three variants of the helix 3 region of a Q50K engrailed homeodomain and bisbenzamidine minor-groove DNA binders. The hybrid featuring the sequence of the native protein failed to bind to DNA; however, modifications that increased the alpha-helical folding propensity of the peptide allowed specific DNA binding by a bipartite (major/minor groove) interaction. PMID- 24764316 TI - Synapse reorganization-a new partnership revealed. PMID- 24764317 TI - Enhanced anticancer efficacy by ATP-mediated liposomal drug delivery. AB - A liposome-based co-delivery system composed of a fusogenic liposome encapsulating ATP-responsive elements with chemotherapeutics and a liposome containing ATP was developed for ATP-mediated drug release triggered by liposomal fusion. The fusogenic liposome had a protein-DNA complex core containing an ATP responsive DNA scaffold with doxorubicin (DOX) and could release DOX through a conformational change from the duplex to the aptamer/ATP complex in the presence of ATP. A cell-penetrating peptide-modified fusogenic liposomal membrane was coated on the core, which had an acid-triggered fusogenic potential with the ATP loaded liposomes or endosomes/lysosomes. Directly delivering extrinsic liposomal ATP promoted the drug release from the fusogenic liposome in the acidic intracellular compartments upon a pH-sensitive membrane fusion and anticancer efficacy was enhanced both in vitro and in vivo. PMID- 24764318 TI - 8-cyclopropyl-2'-deoxyguanosine: a hole trap for DNA-mediated charge transport. AB - DNA duplexes containing 8-cyclopropyl-2'-deoxyguanosine ((8CP) G) were synthesized to investigate the effect of the C8-modified deoxyguanosine as a kinetic trap for transient hole occupancy on guanines during DNA-mediated hole transport (HT). Thermal denaturation and CD spectra show that DNA duplexes containing (8CP) G are able to form stable B-form duplexes. Photoirradiation of terminal tethered anthraquinone can induce oxidative decomposition of (8CP) G through DNA HT along adenine tracts with lengths of up to 4.8 nm. Shallow and periodic distance dependence was observed in a long adenine tract with intervening guanines. The efficient charge transport indicates that (8CP) G can electronically couple well with a DNA bridge and form HT-active conformational domains to facilitate transient hole delocalization over an adenine tract. PMID- 24764319 TI - A new bioassay identifies proliferation ratios of fibroblasts and myofibroblasts. AB - Myofibroblasts are resident cells of wound healing, contractures and fibroses; these tissues are often referred to as fibroproliferative. Whether myofibroblasts themselves proliferate is of interest. Since many in vitro cultures are heterogeneous, staining in situ is required to identify the myofibroblast. We have tested a newly available fluorescent staining kit using ethynyl deoxyuridine (EdU) and click chemistry to identify EdU incorporation into the replicated DNA of proliferative cells. The proliferation stain was combined with the definitive myofibroblast immunostain for alpha smooth muscle actin (alpha-sma). Fibroblasts were grown on coverslips and within attached collagen lattices. Cultures were pulsed with EdU 4 h prior to fixation. Different standard methods of fixation and permeabilization were used to test the effects of these variables on EdU and alpha-sma labeling. Images of the stained samples were quantified as the total percentage of proliferative cells, as well as the proportion of fibroblasts and myofibroblasts that were proliferating. Proliferative myofibroblasts were identified in both culture conditions and with all preparation methods tested. Proliferation within the fibroblast population was greater than within the myofibroblast population in both culture conditions. Fixation and permeabilization had little effect on EdU or alpha-sma labeling. This method of identifying proliferative myofibroblasts will be useful in future studies of myofibroblast proliferation within heterogeneous populations. PMID- 24764320 TI - Intracordal auricular cartilage injection for unilateral vocal fold paralysis. AB - We evaluated the efficacy and outcome of intracordal auricular cartilage injection in patients with unilateral vocal fold paralysis. Our interest developed from findings of a canine model study that reported that histologic characteristics of cartilage were preserved 2 and 3 years after intracordal autologous cartilage injection. Between May 2002 and July 2010, 29 patients with breathy dysphonia caused by unilateral vocal fold paralysis underwent intracordal auricular cartilage injection. Each subject underwent preoperative and postoperative perceptual assessments, acoustical voice analysis, and videostroboscopy. Fourteen patients were male, and the mean age was 52-years old. Patients were tracked for a mean duration of 257 days. Injections were performed through a transoral approach under general anesthesia. Perceptual assessments by GRBAS scale, acoustic parameters of jitter, shimmer, noise-to-harmonic ratio, and maximum phonation time significantly improved at 3, 6, and 12 months after cartilage injection (p < 0.005). No major complications were observed after injection. Initial clinical results with intracordal auricular cartilage injection are promising for patients with unilateral vocal fold paralysis. Autologous auricular cartilage can be a safe, effective, and alternative material for vocal fold medialization, and can be a long lasting one. PMID- 24764322 TI - Expression of cyclin D1 after treatment with doxorubicin in the HL-60 cell line. AB - Increased levels of cyclin D1 and amplification of CCND1 gene occur in many types of cancers. We have followed the expression of cyclin D1 after treatment with doxorubicin with reference to cell death and other possible therapeutic implications. The effect of the treatment on the cell cycle, survival, intracellular level (flow cytometry), and intracellular localization of cyclin D1 (fluorescence microscopy) and expression of CCND1 (real-time RT-PCR) was investigated in HL-60 cells. An increase in the fluorescence intensity of cyclin D1 occurred after treatment with 0.15 and 0.3 MUM doxorubicin. This tendency was confirmed by real-time RT-PCR. Expression of CCND1 in relation to the reference gene PBGD was increased in cells exposed to 0.15 MUM doxorubicin. Concomitantly, some alterations in the regulation of the G0/G1, S, and G2/M checkpoints occurred, accompanied by changes in the polyploid fraction of the population. This was particularly evident at 0.3 MUM doxorubicin, at which concentration the rate of cell death was also clearly higher. In conclusion, depending on the concentration used, alterations in cell death and the number of S, G2/M, and polyploid cells may correspond with cyclin D1 levels. This, in turn, may reflect an important role of the protein as one of the possible survival/point-of-no return regulators dependent on its concentration, which seems especially plausible in the context of more prominent cell death in the above-mentioned fractions of cells. PMID- 24764321 TI - Genome-wide screen identifies signaling pathways that regulate autophagy during Caenorhabditis elegans development. AB - The mechanisms that coordinate the regulation of autophagy with developmental signaling during multicellular organism development remain largely unknown. Here, we show that impaired function of ribosomal protein RPL-43 causes an accumulation of SQST-1 aggregates in the larval intestine, which are removed upon autophagy induction. Using this model to screen for autophagy regulators, we identify 139 genes that promote autophagy activity upon inactivation. Various signaling pathways, including Sma/Mab TGF-beta signaling, lin-35/Rb signaling, the XBP-1 mediated ER stress response, and the ATFS-1-mediated mitochondrial stress response, regulate the expression of autophagy genes independently of the TFEB homolog HLH-30. Our study thus provides a framework for understanding the role of signaling pathways in regulating autophagy under physiological conditions. PMID- 24764323 TI - Wernicke encephalopathy in subjects undergoing restrictive weight loss surgery: a systematic review of literature data. AB - The use of weight loss surgery is progressively increasing, and in recent years, restrictive bariatric surgery procedures have been more often used. Although thought to be associated with a lower incidence of post-operative side effects than malabsorpitive surgery, some cases of micronutrients deficiency have been reported because of an acquired thiamine deficiency; in this clinical setting, some cases of Wernicke encephalopathy (WE) have been described. Major determinants and predictors of this major neurological complication are currently unknown. The aim of this systematic review was to analyse literature data in order to address this issue. The main result of our systematic review was that persistent vomiting is the major determinant of WE in patients undergoing restrictive weight loss surgery. In addition, early thiamine supplementation can rapidly improve the clinical conditions, avoiding permanent deficiencies. On the other hand, given the wide variability of clinical and demographic characteristics, definite prognostic factors of WE occurrence and of clinical outcome cannot be identified. In conclusion, although our results are suggestive, further ad hoc prospective studies evaluating changes in micronutrients levels according to different types of surgery are needed. PMID- 24764325 TI - Synchronous splenic and bone marrow haemangiolymphangioma: a novel entity. PMID- 24764326 TI - Histopathologists' approach to keratoacanthoma: a multisite survey of regional variation in Great Britain and Ireland. AB - INTRODUCTION: This survey examines regional variation in the diagnosis of keratoacanthoma (KA). METHODS: Twenty-three departments from Great Britain and Ireland were invited. The number of cases coded as KA or cutaneous SCC in the previous 12 months was retrieved. An SCC: KA ratio was calculated. Participants also provided free text responses. RESULTS: Seventeen departments replied. A total of 11,718 cases were included with a breakdown of 998 KA and 10,720 SCC. The mean SCC:KA ratio was 10.7:1, range (2.5:1 to 139:1). Free text responses are presented. DISCUSSIONS: An extreme variation in approach is highlighted by this survey. We believe a multidisciplinary team approach to the diagnosis of KA is essential. There seems to be a need for a carefully considered clinicopathological study, backed up by molecular studies, to better understand the natural biology of this diagnosis. PMID- 24764327 TI - Training in molecular pathology during residency: the experience of a Brazilian hospital. PMID- 24764328 TI - Antitumor Activities of Rauwolfia vomitoria Extract and Potentiation of Gemcitabine Effects Against Pancreatic Cancer. AB - Pancreatic cancer is one of the most lethal malignancies with very limited treatment option. In the effort of enhancing the effect of the conventional chemotherapeutic drug gemcitabine against pancreatic cancer, we investigatedin vitroandin vivothe anticancer effect of a beta-carboline-enriched extract from the plantRauwolfia vomitoria(Rau), either alone or in combination with gemcitabine, in preclinical pancreatic cancer models. Rau induced apoptosis in pancreatic cancer cells in a concentration-dependent manner, and completely inhibited colony formation of PANC-1 cells in soft agar. The combination of Rau and gemcitabine had synergistic effect in inhibiting cell growth with dose reduction effect for gemcitabine. In an orthotopic pancreatic cancer mouse model, PANC-1 tumor growth was significantly suppressed by Rau treatment. Metastasis was inhibited by Rau. Adding Rau to gemcitabine treatment reduced tumor burden and metastatic potential in the gemcitabine non-responsive tumor. These data suggest that Rau possesses anti-pancreatic cancer activity and could improve effect of gemcitabine. PMID- 24764330 TI - Prediction of postnatal outcomes in fetuses with isolated congenital diaphragmatic hernias using different lung-to-head ratio measurements. AB - OBJECTIVES: The purpose of this study was to compare different methods for measuring the fetal lung area-to-head circumference ratio and to investigate their prediction of postpartum survival and the need for neonatal extracorporeal membrane oxygenation (ECMO) therapy in fetuses with isolated congenital diaphragmatic hernias. METHODS: This prospective study included 118 fetuses of at least 20 weeks' gestation with isolated left-sided congenital diaphragmatic hernias. The lung-to-head ratio was measured with 3 different methods (longest diameter, anteroposterior diameter, and tracing). To eliminate the influence of gestational age, the observed-to-expected lung-to-head ratio was calculated. Receiver operating characteristic (ROC) curves were calculated for the statistical prediction of survival and need for ECMO therapy by the observed-to expected lung-to-head ratio measured with the different methods. RESULTS: For survival and ECMO necessity 118 and 102 cases (16 neonates were not eligible for ECMO) were assessed, respectively. For prediction of postpartum survival and ECMO necessity, the areas under the ROC curves and 95% confidence intervals showed very similar results for the 3 methods for prediction of survival (tracing, 0.8445 [0.7553-0.9336]; longest diameter, 0.8248 [0.7360-0.9136]; and anteroposterior diameter, 0.8002 [0.7075-0.8928]) and for ECMO necessity (tracing, 0.7344 [0.6297-0.8391]; longest diameter, 0.7128 [0.6027-0.8228]; and anteroposterior diameter, 0.7212 [0.6142-0.8281]). Comparisons between the areas under the ROC curves showed that the tracing method was superior to the anteroposterior diameter method in predicting postpartum survival (P = .0300). CONCLUSIONS: Lung-to-head ratio and observed-to-expected lung-to-head ratio measurements were shown to accurately predict postnatal survival and the need for ECMO therapy in fetuses with left-sided congenital diaphragmatic hernias. Tracing the limits of the lungs seems to be the favorable method for calculating the fetal lung area. PMID- 24764329 TI - Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging Workshop. AB - Given that practice variation exists in the frequency and performance of ultrasound and magnetic resonance imaging (MRI) in pregnancy, the Eunice Kennedy Shriver National Institute of Child Health and Human Development hosted a workshop to address indications for ultrasound and MRI in pregnancy, to discuss when and how often these studies should be performed, to consider recommendations for optimizing yield and cost effectiveness, and to identify research opportunities. This article is the executive summary of the workshop. PMID- 24764331 TI - Inter-rater reliability and measurement error of sonographic muscle architecture assessments. AB - OBJECTIVES: Sonography of muscle architecture provides physicians and researchers with information about muscle function and muscle-related disorders. Inter-rater reliability is a crucial parameter in daily clinical routines. The aim of this study was to assess the inter-rater reliability of sonographic muscle architecture assessments and quantification of errors that arise from inconsistent probe positioning and image interpretation. METHODS: The medial gastrocnemius muscle of 15 healthy participants was measured with sagittal B-mode ultrasound scans. The muscle thickness, fascicle length, superior pennation angle, and inferior pennation angle were assessed. The participants were examined by 2 investigators. A custom-made foam cast was used for standardized positioning of the probe. To analyze inter-rater reliability, the examinations of both raters were compared. The impact of probe positioning was assessed by comparison of foam cast and freehand scans. Error arising from picture interpretation was assessed by comparing the investigators' analyses of foam cast scans independently. Reliability was expressed as the intraclass correlation coefficient (ICC), inter rater variability (IRV), Bland-Altman analysis (bias +/- limits of agreement [LoA]), and standard error of measurement (SEM). RESULTS: Inter-rater reliability was good overall (ICC, 0.77-0.90; IRV, 9.0%-13.4%; bias +/- LoA, 0.2 +/- 0.2-1.7 +/- 3.0). Superior and inferior pennation angles showed high systematic bias and LoA in all setups, ranging from 2.0 degrees +/- 2.2 degrees to 3.4 degrees +/- 4.1 degrees . The highest IRV was found for muscle thickness (13.4%). When the probe position was standardized, the SEM for muscle thickness decreased from 0.1 to 0.05 cm. CONCLUSIONS: Sonographic examination of muscle architecture of the medial gastrocnemius has good to high reliability. In contrast to pennation angle measurements, length measurements can be improved by standardization of the probe position. PMID- 24764332 TI - Prediction of postoperative pancreatic fistulas after pancreatectomy: assessment with acoustic radiation force impulse elastography. AB - OBJECTIVES: The purpose of this prospective study was to investigate the usefulness of acoustic radiation force impulse (ARFI) elastography of the pancreas for predicting postoperative pancreatic fistula occurrence after pancreatic resection. METHODS: Twenty-five patients underwent ARFI elastography of the pancreas before pancreatic resection (11 men and 14 women; mean age, 59.1 years; range, 28-76 years). In each patient, 3 valid ARFI measurements (meters per second) were performed at the head of the pancreas, and the median values were calculated. Patients underwent pancreaticoduodenectomy (n = 18) or distal pancreatectomy (n = 7). Clinically relevant fistulas (grade B or higher) were determined according to the standard criteria used by the International Study Group on Pancreatic Fistula. Preoperative ARFI values were compared between the fistula and nonfistula groups (Mann-Whitney test). RESULTS: Clinically relevant fistulas (grade B or higher) were observed in 8 patients (32%; fistula group), including 5 of 18 patients with pancreaticoduodenectomy (28%) and 3 of 7 patients with distal pancreatectomy (43%). The ARFI values in the fistula group (median, 1.45 m/s; range, 0.80-1.98 m/s) were lower than in the nonfistula group (median, 1.54 m/s; range, 0.98-3.40 m/s), but there was no statistical significance (P = .1374). When confining the results to only patients with pancreaticoduodenectomy, the ARFI values were significantly lower in the patients with fistulas (median, 0.98 m/s; range, 0.80-1.94 m/s) than in those without fistulas (median, 1.60 m/s; range, 1.08-3.40 m/s; P = .0460). CONCLUSIONS: This preliminary study showed the potential feasibility of a clinical application of ARFI elastography in preoperatively predicting postoperative pancreatic fistulas after pancreaticoduodenectomy. Investigation of this method in larger studies is needed. PMID- 24764333 TI - Value of virtual touch tissue quantification in stages of diabetic kidney disease. AB - OBJECTIVES: The purpose of this study was to evaluate Virtual Touch tissue quantification (VTQ; Siemens AG, Erlangen, Germany) in stages of diabetic kidney disease. METHODS: A total of 120 patients with type 2 diabetes mellitus were divided into 3 groups according to their urinary albumin-to-creatinine ratio (ACR): normoalbuminuria (ACR <30 mg/g of creatinine), microalbuminuria (ACR 30 300 mg/g), and macroalbuminuria (ACR >= 300 mg/g and estimated glomerular filtration rate >=30 mL/min/1.73 m(2)). Thirty volunteers served as controls. Virtual Touch tissue quantification was performed in the 4 groups to determine the shear wave velocity (SWV) of the renal cortex, and changes in the SWV were compared between the groups. Correlation analysis was performed between the SWV and ACR in the type 2 diabetes groups. RESULTS: When SWVs were compared, there was no significant difference between the normoalbuminuria and control group (P = .40), but there was a significant difference between the microalbuminuria and macroalbuminuria groups and the control group (P < .05). There was also a significant difference between each pair of type 2 diabetes groups (P < .05). The correlation coefficient for the SWV and log(ACR) in type 2 diabetes was 0.773 (P < .05). Receiver operating characteristic curve analysis showed that the area under the curve for SWV diagnosis of diabetes complicated by renal injury was 0.93; the best cutoff point, sensitivity, and specificity were 2.43 m/s, 85.7%, and 84.5%, respectively. CONCLUSIONS: It is feasible to use VTQ to determine the renal cortical SWV for judging renal injury in type 2 diabetes mellitus. The SWV increases as the renal injury progresses and thus plays an important role in diabetic kidney disease stages. PMID- 24764334 TI - Acoustic radiation force impulse elastography of the kidneys: is shear wave velocity affected by tissue fibrosis or renal blood flow? AB - OBJECTIVES: The aim of this study was to identify the main influencing factor of the shear wave velocity (SWV) of the kidneys measured by acoustic radiation force impulse elastography. METHODS: The SWV was measured in the kidneys of 14 healthy volunteers and 319 patients with chronic kidney disease. The estimated glomerular filtration rate was calculated by the serum creatinine concentration and age. As an indicator of arteriosclerosis of large vessels, the brachial-ankle pulse wave velocity was measured in 183 patients. RESULTS: Compared to the degree of interobserver and intraobserver deviation, a large variance of SWV values was observed in the kidneys of the patients with chronic kidney disease. Shear wave velocity values in the right and left kidneys of each patient correlated well, with high correlation coefficients (r = 0.580-0.732). The SWV decreased concurrently with a decline in the estimated glomerular filtration rate. A low SWV was obtained in patients with a high brachial-ankle pulse wave velocity. Despite progression of renal fibrosis in the advanced stages of chronic kidney disease, these results were in contrast to findings for chronic liver disease, in which progression of hepatic fibrosis results in an increase in the SWV. Considering that a high brachial-ankle pulse wave velocity represents the progression of arteriosclerosis in the large vessels, the reduction of elasticity succeeding diminution of blood flow was suspected to be the main influencing factor of the SWV in the kidneys. CONCLUSIONS: This study indicates that diminution of blood flow may affect SWV values in the kidneys more than the progression of tissue fibrosis. Future studies for reducing data variance are needed for effective use of acoustic radiation force impulse elastography in patients with chronic kidney disease. PMID- 24764335 TI - Changes in the diameter and valve closure time of leg veins across the menstrual cycle. AB - OBJECTIVES: The purpose of this study was to determine the changes (if any) in the diameter and valve closure time of the lower limb veins in healthy young nulliparous women at different phases of the menstrual cycle. METHODS: Fifty three young nulliparous women were asked to undergo clinical evaluations and duplex ultrasound examinations of both lower limb veins to monitor changes in the vein diameter and valve closure time at different phases of their menstrual cycles. The vein diameter on B-mode imaging and valve closure time on pulsed Doppler tracing were calculated at days 1 to 4, 14 to 16, and 25 to 28 of the menstrual cycle. Freidman and related samples Wilcoxon signed rank tests were used to determine time-related changes in venous function. RESULTS: The volunteers' mean age +/- SD was 20.60 +/- 1.90 years, and their mean body mass index was 23.90 +/- 4.90 kg/m(2). There was a gradual increase in the vein diameter and valve closure time at the specified phases of the menstrual cycle. Friedman and related samples Wilcoxon signed rank tests for venous segment diameter and valve closure time changes between the different phases of the menstrual cycle were performed and showed statistical significance for each venous segment within each limb (P = .003-.025). Also, when adjusted for body mass index, statistical significance existed for the same venous segments in the same limbs (P =.001-.049). There was no statistical significance for the same venous segments at the same phase of the menstrual cycle between limbs (related samples Wilcoxon signed rank test: P =.079-.97). CONCLUSIONS: During the menstrual cycle, the lower limb veins show an increase in their diameter and valve closure time. These changes are probably mediated by the female sex hormones. PMID- 24764336 TI - Evaluation of vertebral artery involvement by Doppler sonography in patients with Behcet disease. AB - OBJECTIVES: Neurologic lesions in Behcet disease are most frequently observed in areas supplied by the vertebrobasilar system. We aimed to evaluate possible vertebral artery involvement by Doppler sonography in patients with Behcet disease. METHODS: Forty-five patients with Behcet disease and 29 healthy volunteers had Doppler sonography of the vertebral arteries. Patients were grouped according to neurologic examination and magnetic resonance imaging findings as follows: group 1, Behcet disease without neurologic involvement; group 2, neuro-Behcet disease; and group 3, control. Results were assessed with a 95% confidence interval. RESULTS: The main findings of our study were as follows: (1) total vertebral artery volume flow was significantly lower in the patient groups than the control group (P< .05); (2) total volume flow was lower in group 2 than group 1, although the difference was not statistically significant; (3) peak systolic and end-diastolic velocity values were significantly lower in the patient groups than the control group; (4) right and left mean volume values were lower in group 2; and (5) resistive and pulsatility index values for the left vertebral artery were significantly higher in group 2, but no statistically significant differences were found in the resistive and pulsatility index values for the right vertebral artery. CONCLUSIONS: Doppler sonography of the vertebral arteries in Behcet disease shows alterations that may aid in the diagnosis and treatment of this condition. PMID- 24764337 TI - Preoperative assessment of extrathyroidal extension of papillary thyroid carcinoma: comparison of 2- and 3-dimensional sonography. AB - OBJECTIVES: The purpose of this study was to evaluate the diagnostic performance and interobserver agreement of 2-dimensional (2D) and 3-dimensional (3D) sonography for evaluating extrathyroidal extension of papillary thyroid carcinoma. METHODS: A total of 79 papillary thyroid carcinomas in 79 patients who underwent both 2D and 3D sonography for preoperative staging of papillary thyroid carcinoma were included. When the lesion was abutting on the thyroid capsule on 2D sonography, 3D sonography was performed. Three radiologists reviewed 3 data sets: 2D sonography, 3D sonography, and a combined set of both for tumor staging. The diagnostic performance, including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, for extrathyroidal extension was analyzed. Interobserver agreement of the 3 radiologists was assessed with kappa values. RESULTS: The overall accuracy rates for 2D sonography, 3D sonography, and the combined set in predicting extrathyroidal extension were 60.8%, 66.2%, and 67.9%, respectively. The accuracy of the combined set was significantly higher than that of 2D sonography (P = .016). The interobserver agreement of the 3 reviewers was fair (kappa = 0.33) for 2D sonography and moderate for 3D sonography (kappa = 0.46) and the combined set (kappa = 0.49). CONCLUSIONS: Adding 3D sonography to 2D sonography could improve the accuracy and interobserver agreement for predicting extrathyroidal extension of papillary thyroid carcinoma. PMID- 24764338 TI - Diagnostic accuracy of sonography versus magnetic resonance imaging for primary nasopharyngeal carcinoma. AB - OBJECTIVES: The purpose of this study was to prospectively assess the accuracy of sonography versus magnetic resonance imaging (MRI) for a diagnosis of primary nasopharyngeal carcinoma. METHODS: A total of 150 patients suspected of having nasopharyngeal carcinoma underwent sonography and MRI. A diagnosis was obtained from an endoscopic biopsy that was collected from the suspected tumor or a normal nasopharynx. The diagnostic performance of sonography and MRI for nasopharyngeal carcinoma was evaluated by receiver operating characteristic curve analysis. The sensitivity and specificity of the two imaging methods were compared by the McNemar test. RESULTS: Nasopharyngeal carcinoma was present in 71 of 150 patients (47.3%) and absent in 79 (52.7%). The sensitivity, specificity, and accuracy of sonography versus MRI for these cases were 90.1%, 84.8%, and 87.3% for sonography and 97.2%, 89.9%, and 93.3% for MRI, respectively. Both sonography and MRI had good diagnostic performance for nasopharyngeal carcinoma, with area under the curve values of 0.958 and 0.987, respectively. There was no significant difference in the rate of tumor detectability between sonography and MRI (P = .12), and the specificities of sonography and MRI were similar (P = .22). CONCLUSIONS: Both sonography and MRI are useful tools for clinical screening of nasopharyngeal carcinoma. However, sonography is less expensive and easier to perform. The results of this study also suggest that nasopharyngeal sonography could be used for the initial investigation of primary cancer in patients suspected of having nasopharyngeal carcinoma. PMID- 24764339 TI - Three-dimensional contrast-enhanced sonography in the assessment of breast tumor angiogenesis: correlation with microvessel density and vascular endothelial growth factor expression. AB - OBJECTIVES: The purpose of this study was to differentiate perfusion and vascular characteristics between benign and malignant breast lesions by 3-dimensional contrast-enhanced sonography and evaluate their correlation with microvessel density and vascular endothelial growth factor (VEGF) expression for further clinical exploration. METHODS: Three-dimensional contrast-enhanced sonography was performed in 183 patients with breast lesions, and sonographic characteristics were carefully observed for further analysis. The mean microvessel density and VEGF expression were measured by immunohistochemical analysis. RESULTS: Pathologic results showed 35 benign and 148 malignant cases. Malignancy and benignity differed significantly in peripheral vessel characteristics (number, distribution, course, degree of dilatation, and penetrating vessels), rim perfusion and coarseness degree, intratumoral perfusion type, and intratumoral vessel dilatation (P< .05) but not the presence of peripheral and intratumoral vessels and intratumoral perfusion (P > .05). The specificity of penetrating vessels was 88.6% for diagnosing malignancy. The sensitivity, specificity, and accuracy of rim perfusion coarseness were 90.2%, 70.4%, and 85.3% respectively. The sensitivity of the intratumoral perfusion type was 77.8%, whereas the specificity of intratumoral vessel dilatation was 88.9%. Microvessel density and VEGF expression were significantly correlated with perfusion and vascular characteristics (P < .05), except the presence of peripheral vessels, rim perfusion, and intratumoral perfusion (P> .05). The presence of intratumoral vessels was related to VEGF (P< .05) but not microvessel density (P > .05). CONCLUSIONS: Three-dimensional contrast-enhanced sonographic characteristics were statistically different between benign and malignant breast lesions. Some of them also correlated significantly with microvessel density and VEGF expression and therefore have potential for objective evaluation of tumor angiogenesis. PMID- 24764340 TI - Three-dimensional Doppler sonography in asymptomatic and symptomatic women after medical termination of pregnancy. AB - OBJECTIVES: To characterize the 3D Doppler sonographic appearance of the uterine cavity in asymptomatic and symptomatic women after administration of mifepristone and misoprostol for medical termination of pregnancy. METHODS: A prospective observational study was performed. Women admitted for medical termination of pregnancy underwent transvaginal sonography 15 days after the procedure. Volumes were acquired, and offline analyses of the 3D vascularization indices were performed. Outcomes were collected at the follow-up scan and by telephone after the termination. Women were subclassified as asymptomatic or symptomatic according to the presence/absence of fever, vaginal bleeding, abdominal/pelvic pain, and infections. Spotting was defined as any episodic vaginal bleeding that was less than an expected menstruation and not regarded as a symptom. RESULTS: A total of 104 women who underwent medical termination of pregnancy between 6 and 9 weeks' gestation were enrolled in the study. The termination procedure was successful in 98% of cases; among them, 9 women (8.6%) were symptomatic due to bleeding. Two asymptomatic women required surgery; 1 had sonographic evidence of suspected retained products of conception (endometrial thickness >= 15 mm or power Doppler vascularization presence). Fifty-seven women (55%) presented with retained products of conception. All the women with suspected retained products regained normal menses; of these, 3 symptomatic women with retained products (2.9%) underwent a 1-month sonographic follow-up. The symptomatic status was not associated with endometrial thickness, 3D intrauterine mass volume, or 2 dimensional (2D) and 3D power Doppler appearances. CONCLUSIONS: The necessity of surgery after medical termination of pregnancy cannot be predicted by sonography. In cases with sonographic evidence of suspected retained products of conception, endometrial thickness, 2D Doppler findings, and the 3D vascularization indices correlated poorly with bleeding symptoms. Long-term follow-up should be considered in symptomatic women, and it can avoid any unnecessary surgical intervention. PMID- 24764341 TI - Transient elastography and sonography for prediction of liver fibrosis in infants with biliary atresia. AB - OBJECTIVES: The purpose of this study was to assess the diagnostic performance of transient elastography and sonography for noninvasive evaluation of liver fibrosis in infants with biliary atresia. METHODS: Forty-seven infants with biliary atresia who underwent both transient elastography and sonography before surgery were included in this study. Two types of transient elastographic probes were used: an M probe, which is used for the general adult population; and an S probe, which is specific to children. Transient elastographic measurements and sonographic findings such as triangular cord thickness and hepatic artery and portal vein diameters were compared with the METAVIR histopathologic fibrosis scoring system. RESULTS: Only transient elastography (rho = 0.63; P < .001) was significantly correlated with METAVIR fibrosis stages. The areas under the receiver operating characteristic curves for transient elastography were 0.86 and 0.96 for diagnosis of severe fibrosis and cirrhosis, respectively. The cutoff value of transient elastography for diagnosis of severe fibrosis was greater than 9.6 kPa, with sensitivity of 89.5% and specificity of 75%. The cutoff value of transient elastography for diagnosis of cirrhosis was greater than 18.1 kPa, with sensitivity of 100% and specificity of 90.5%. The success rate for the S probe (100%) was significantly higher than that for the M probe (77%; P < .001). CONCLUSIONS: Transient elastography may be a useful noninvasive method for diagnosis of severe fibrosis and cirrhosis and may help predict outcomes before surgery or invasive liver biopsy in infants with biliary atresia. The success rate of transient elastography in infants was improved by using the S probe. PMID- 24764342 TI - Low-intensity pulsed ultrasound induces osteogenic differentiation of human periodontal ligament cells through activation of bone morphogenetic protein-smad signaling. AB - OBJECTIVES: Low-intensity pulsed ultrasound (US) can accelerate fracture healing and osteogenic differentiation. The aim of this study was to investigate the osteogenic effect of low-intensity pulsed US on human periodontal ligament cells and to determine whether bone morphogenetic protein (BMP)-Smad signaling was involved. METHODS: Human periodontal ligament cells were exposed to low-intensity pulsed US at a frequency of 1.5 MHz and intensity of 90 mW/cm(2) for 20 min/d. Osteogenic differentiation was determined by assaying alkaline phosphatase (ALP) and calcium deposition. Expression of BMP-2, BMP-6, and BMP-9 was detected by real-time polymerase chain reaction analysis. Phosphorylated Smad was detected by western blotting; Smad in the cells was labeled by an immunofluorescent antibody and observed by laser-scanning confocal microscopy. RESULTS: The optical density of ALP stimulated by US at 1.5 MHz and 90 mW/cm(2) for 20 min/d was significantly higher than in other groups (P < .01); therefore, this dosage was considered optimal for promoting osteogenic differentiation. After 13 days of US exposure, ALP increased gradually after 5 days, peaked at 11 days, and decreased at 13 days, with a significant difference compared with the control group (P < .05). Osteocalcin production increased from 9 to 13 days and peaked at 15 days, with a significant difference compared with the control group (P < .05). BMP-2 and BMP-6 increased dynamically after exposure for 13 days. BMP-2 increased 6.07-fold at 3 days, 6.39-fold at 11 days, and 5.97-fold at 13 days. BMP-6 expression increased 6.82-fold at 1 day and 51.5-fold at 3 days and decreased thereafter. BMP-9 was not expressed. Phospho-Smad1/5/8 expression was significantly increased after exposure (P< .05) and transferred from the cytoplasm into the nuclei. CONCLUSIONS: Low-intensity pulsed US effectively induced osteogenic differentiation of human periodontal ligament cells, and the BMP-Smad signaling pathway was involved in the mechanism. PMID- 24764343 TI - Assessment of left ventricular myocardial systolic acceleration in diabetic rats using velocity vector imaging. AB - OBJECTIVES: The purpose of this study was to investigate how the myocardial acceleration during isovolumic contraction changed in rats with diabetic cardiomyopathy and a normal left ventricular ejection fraction (LVEF) by using velocity vector imaging. METHODS: Velocity vector imaging was performed in 12 control rats and 15 rats with streptozotocin-induced diabetic cardiomyopathy 12 weeks after streptozotocin injection. The segmental radial displacement, velocity, acceleration, and percent wall thickening were measured at the mid-left ventricular (LV) level. RESULTS: Compared to control rats, rats with cardiomyopathy had a significant decrease in the peak radial acceleration during isovolumic contraction in most segments of the LV wall (including the anterior, anterolateral, inferolateral, and inferior segments; P < .05) but a similar LVEF, fractional shortening, and segmental displacement. Rats with cardiomyopathy also had a significant increase in LV end-diastolic and end-systolic diameters when corrected for body mass (P < .001; P = .003, respectively) and a significant decrease in the radial peak systolic velocities of the inferolateral and inferior wall segments (P < .05). In addition, rats with cardiomyopathy had a significant decrease in the peak radial diastolic acceleration in most segments of the LV wall (except for the anterolateral one; P< .05) but similar peak radial diastolic velocities in all LV wall segments compared to controls. Pathologic examination in rats with cardiomyopathy revealed ultrastructural impairment of the capillary and cardiocyte without any atherosclerotic lesion in the coronary artery compared to control rats. CONCLUSIONS: Myocardial acceleration during isovolumic contraction decreases in rats with diabetic cardiomyopathy and a preserved LVEF, suggesting the presence of regional LV systolic dysfunction. PMID- 24764344 TI - Meaning of free intraperitoneal fluid in small-bowel obstruction: preliminary results using high-frequency microsonography in a rat model. AB - OBJECTIVES: The aim of this study was to detect the onset, evolution, and meaning of extraluminal free fluid in a rat model of small-bowel obstruction using high frequency microsonography. METHODS: Small-bowel obstruction was surgically created in 8 rats divided into 2 groups of 4 rats each. All rats were examined by high-frequency microsonography to monitor the evolution of small-bowel obstruction and the abdominal sonographic findings. In group 2 rats, the obstruction was resolved 2 hours after surgery. RESULTS: In all rats, free peritoneal fluid was detected just near the obstructed loop after 1 hour and in the hepatorenal recess after 2 hours. These features progressively increased in the following hours in group 1 rats. In group 2, the amount of free fluid decreased shortly after removing the obstruction. CONCLUSIONS: Free fluid is an early finding in small-bowel obstruction, and the increase or decrease of its amount is correlated with the worsening or resolution of the obstruction. PMID- 24764345 TI - Imaging and differential diagnosis of suprarenal masses in the fetus. AB - Prenatal sonography and magnetic resonance imaging of suprarenal fetal masses is presented, along with clinical information and follow-up. Imaging pearls and differential considerations for each diagnosis will be discussed. Fetal suprarenal mass diagnoses include neuroblastoma, extralobar pulmonary sequestration, congenital adrenal hyperplasia, partial multicystic dysplastic kidney, renal duplication, urinoma, gastric duplication cyst, and splenic cyst. Recognizing the range of malignant and benign suprarenal fetal masses that can present on prenatal imaging can help guide patient counseling and management. PMID- 24764346 TI - Application of echogenic technology for catheters used in ultrasound-guided continuous peripheral nerve blocks. AB - Limited data exist regarding the echogenicity of perineural catheters, but visualization is crucial to ensure accurate placement and efficacy of the subsequent local anesthetic infusion. The objective of this study was to determine the comparative echogenicity of various regional anesthesia catheters. In an in vitro porcine-bovine model, we compared the echogenic qualities of 3 commercially available regional anesthesia catheters and 1 catheter under development to optimize echogenicity. Outcomes included visual echogenicity ranking, image quality, and scanning time, as assessed by 2 blinded investigators. The experimental catheter was found to be more echogenic than 2 of the 3 comparators. PMID- 24764347 TI - Sonographic findings of tuberculous vasitis. AB - The purpose of this series was to describe the sonographic findings of tuberculous vasitis. We conducted a retrospective analysis of 3 cases of tuberculous vasitis. The following grayscale and color Doppler sonographic features were analyzed: location, echogenicity of the lesion, epididymal or testicular involvement, presence of hydrocele, and blood flow within the lesion. All 3 patients had focal (n = 2) or multifocal (n = 1) involvement of the scrotal segment of the vas deferens. The sonographic findings for tuberculous vasitis were heterogeneously hypoechoic in all of the cases. On color Doppler sonography, no blood flow was identified within the lesions of the vas deferens. All 3 patients had tuberculous epididymitis in addition to tuberculous vasitis. Tuberculous vasitis presents with infection along with tuberculous epididymitis, and it appears as a heterogeneously hypoechoic lesion in the scrotal segment of the vas deferens adjacent to the epididymal tail. PMID- 24764348 TI - Transvaginal sonographic monitoring of cervical length in uterus didelphys. PMID- 24764349 TI - Huge fetal cervicomediastinal thymic cyst: successful antenatal intervention for vaginal delivery. PMID- 24764350 TI - Maternal hydration therapy improves the quantity of amniotic fluid and the pregnancy outcome in third-trimester isolated oligohydramnios. PMID- 24764351 TI - Reply: To PMID 22298867. PMID- 24764352 TI - Adverse experiences in childhood, adulthood neighbourhood disadvantage and health behaviours. AB - BACKGROUND: Early life adversities may play a role in the associations observed between neighbourhood contextual factors and health behaviours. METHODS: We examined whether self-reported adverse experiences in childhood (parental divorce, long-term financial difficulties, serious conflicts, serious/chronic illness or alcohol problem in the family, and frequent fear of a family member) explain the association between adulthood neighbourhood disadvantage and co occurrence of behavioural risk factors (smoking, moderate/heavy alcohol use, physical inactivity). Study population consisted of 31 271 public sector employees from Finland. The cross-sectional associations were analysed using two level cumulative logistic regression models. RESULTS: Childhood adverse experiences were associated with the sum of risk factors (cumulative OR 1.32 (95% CI 1.25 to 1.40) among those reporting 3-6 vs 0 adversities). Adverse experiences did not attenuate the association between neighbourhood disadvantage and risk factors; this cumulative OR was 1.52 (95% CI 1.43 to 1.62) in the highest versus lowest quartile of neighbourhood disadvantage when not including adversities, and 1.50 (95% CI 1.40 to 1.60) when adjusted for childhood adversities. In adversity stratified analyses those reporting 3-6 adversities had 1.60-fold (95% CI 1.42 to 1.80) likelihood of risk factors if living in the neighbourhood of the highest disadvantage, while in those with fewer adversities this likelihood was 1.09-1.34 fold (95% CI 0.98 to 1.53) (p interaction 0.07). CONCLUSIONS: Childhood adverse experiences and adulthood neighbourhood disadvantage were associated with behavioural risk factors. Childhood experiences did not explain associations between neighbourhood disadvantage and the risk factors. However, those with more adverse experiences may be susceptible for the socioeconomic conditions of neighbourhoods. PMID- 24764353 TI - Individual and spousal education, mortality and life expectancy in Switzerland: a national cohort study. AB - BACKGROUND: Household measures of socioeconomic position may better account for the shared nature of material resources, lifestyle, and social position of cohabiting persons, but household measures of education are rarely used. We aimed to evaluate the association of combined educational attainment of married couples on mortality and life expectancy in Switzerland. METHODS: The study included 3,496,163 ever-married persons aged >=30 years. The 2000 census was linked to mortality records through 2008. Mortality by combined educational attainment was assessed by gender-age-specific HRs, with 95% CIs from adjusted models, life expectancy was derived using abridged life tables. RESULTS: Having a less educated partner was associated with increased mortality. For example, the HR comparing men aged 50-64 years with tertiary education married to women with tertiary education to men with compulsory education married to women with compulsory education was 2.05 (1.92-2.18). The estimated remaining life expectancy in tertiary educated men aged 30 years married to women with tertiary education was 4.6 years longer than in men with compulsory education married to women with compulsory education. The gradient based on individual education was less steep: the HR comparing men aged 50-64 years with tertiary education with men with compulsory education was 1.74 (1.67-1.81). CONCLUSIONS: Using individual educational attainment of married persons is common in epidemiological research, but may underestimate the combined effect of education on mortality and life expectancy. These findings are relevant to epidemiologic studies examining socio demographic characteristics or aiming to adjust results for these characteristics. PMID- 24764354 TI - Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair. AB - BACKGROUND: Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70*10(-8) mutations per base per generation. However, contribution of early postzygotic mutations to the overall human de novo SNV rate is unknown. METHODS: We performed deep whole-genome sequencing (more than 30-fold coverage per individual) of the whole-blood-derived DNA samples of a healthy monozygotic twin pair and their parents. We examined the genotypes of each individual simultaneously for each of the SNVs and discovered de novo SNVs regarding the timing of mutagenesis. Putative de novo SNVs were validated using Sanger-based capillary sequencing. RESULTS: We conservatively characterised 23 de novo SNVs shared by the twin pair, 8 de novo SNVs specific to twin I and 1 de novo SNV specific to twin II. Based on the number of de novo SNVs validated by Sanger sequencing and the number of callable bases of each twin, we calculated the overall de novo SNV rate of 1.31*10(-8) and 1.01*10(-8) for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34*10(-8) for twin I and 0.04*10(-8) for twin II. CONCLUSIONS: Early postzygotic mutations constitute a substantial proportion of de novo mutations in humans. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of diseases. PMID- 24764355 TI - Age-related diagnostic utility of rheumatoid factor, anticyclic citrullinated peptide and antikeratin antibodies in Chinese patients with rheumatoid arthritis. AB - OBJECTIVES: Retrospective study to evaluate the diagnostic utility of rheumatoid factor (RF), anticyclic citrullinated peptide antibodies (ACPA) and antikeratin antibodies (AKA) in a broad age range of patients with rheumatoid arthritis (RA). METHODS: Clinical and serological data from patients with RA were collected and analysed. Patients were stratified according to age (<16 years [juvenile idiopathic arthritis; JIA], 16-40 years; 41-60 years and >60 years) and sex. RESULTS: The study included 3725 patients. There were no significant sex-related differences in rates of RF, ACPA or AKA positivity. RF, ACPA and AKA positivity were significantly less common in patients aged <16 years than those aged >= 16 years. There were no other significant differences between age groups. CONCLUSIONS: RF, ACPA and AKA have better diagnostic value for RA in adult patients than in patients with JIA. A combination of RF, ACPA and AKA serological testing may be a useful diagnostic tool for RA in Chinese adults. PMID- 24764356 TI - The impact of leucoaraiosis on neurological function recovery in elderly patients with acute cerebral infarction: Clinical study involving 279 Chinese patients. AB - OBJECTIVE: To explore the link between leucoaraiosis and recovery of neurological function in elderly patients with acute cerebral infarction. METHODS: The study included elderly patients, hospitalized with acute cerebral infarction. Magnetic resonance imaging examinations were performed before or within 5 days after admission; T1-weighted, T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted imaging sequence data were collected. Using the Fazekas scale, leucoaraiosis (white matter hyperintensity [WMH]) was graded as 0 (absent), 1 (mild), 2 (moderate) or 3 (severe) for all participants. RESULTS: The study included 279 patients. WMH grades of 0, 1, 2 and 3 were seen in 27 (9.67%), 90 (32.26%), 104 (37.28%) and 58 cases (20.79%) respectively. Improvement on the National Institutes of Health Stroke Scale for neurological impairment was negatively associated with WMH grade. Patients with severe leucoaraiosis at hospital admission had worse neurological functional recovery and a higher rate of self-care incapability compared with those with mild or no leucoaraiosis. CONCLUSIONS: The results suggest that severe leucoaraiosis in elderly patients with acute cerebral infarction is associated with poor prognosis and poor recovery of neurological function. PMID- 24764357 TI - An alternative to the adenovirus inverted terminal repeat sequence increases the viral genome replication rate and provides a selective advantage in vitro. AB - During the development of human adenovirus 35-derived replication-incompetent (rAd35) vaccine vectors for prevention of infectious diseases, we detected mutations in the terminal 8 nt of the inverted terminal repeats (ITRs) of rAd35. The switch from the plasmid-encoded sequence 5'-CATCATCA-3' to the alternative sequence 5'-CTATCTAT-3' in the ITRs was found to be a general in vitro propagation phenomenon, as shown for several vectors carrying different transgenes or being derived from different adenovirus serotypes. In each tested case, the plasmid-encoded ITR sequence changed to exactly the same alternative ITR sequence, 5'-CTATCTAT-3'. The outgrowth of this alternative ITR version should result from a growth advantage conferred by the alternative ITR sequence. Indeed, replication kinetics studies of rAd35 harbouring either the original or alternative ITR sequence confirmed an increase in replication speed for rAd35 vectors with the alternative ITR sequence. These findings can be applied to generate recombinant adenoviral vectors harbouring the alternative ITR sequence, which will facilitate the generation of genetically homogeneous seed virus batches. Moreover, vector production may be accelerated by taking advantage of the observed improved replication kinetics associated with the alternative ITR sequence. PMID- 24764358 TI - Trimeric knob protein specifically distinguishes neutralizing antibodies to different human adenovirus species: potential application for adenovirus seroepidemiology. AB - Adenoviruses (Ads) are non-enveloped DNA viruses that have been extensively studied and used as vectors for gene therapy and several potential vaccines. There are 57 Ad serotypes in seven species (A-G), and Ad neutralizing antibody (NAb) titres can vary by serotype and geographical location. Until now serotype- and species-specific antibodies have been detected by neutralization or haemagglutination inhibition assays. These expensive and cumbersome methods of adenovirus typing have mainly been used in epidemiological studies. Our prior work demonstrated that NAbs against the fiber protein are commonly generated during natural Ad infection in humans and the trimeric knob is preferentially recognized by fiber-induced NAbs. In this study, we expressed nine trimeric knob proteins from representative Ad serotypes of human Ad (HAdV)-A-F in Escherichia coli and found no cross-reactivity of these recombinant proteins with rabbit hyperimmune sera (among HAdV-A-F or within HAdV-C). Results of the ELISA based on Ad2 and Ad5 (both HAdV-C) knob proteins were consistent with those of neutralization assays, indicating that the trimeric knob protein would be a good candidate antigen for detecting Ad serotype-specific NAbs in sera from naturally infected subjects. We also demonstrated the primary seroepidemiology of nine Ad serotypes in 274 children using the knob-based ELISA. These results have potential implications for epidemiology of Ad serotypes and future development of Ad-based vaccines and gene therapy. PMID- 24764359 TI - Abstracts of the IMPAKT Breast Cancer Conference, 8-10 May 2014, Brussels, Belgium. PMID- 24764449 TI - Response to: 'Overweight/obesity and vitamin D deficiency contribute to the global burden of low back pain' by Professor Grant. PMID- 24764450 TI - The issue of bioavailability of oral low dose methotrexate: should we choose only 10 mg of MTX a week in conjunction with anti-TNF therapy? PMID- 24764451 TI - Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants. AB - OBJECTIVES: Bruton's tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA). MATERIALS AND METHODS: Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays. RESULTS: Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants. CONCLUSIONS: Btk is expressed equivalently in RA and PsA synovial tissue, primarily in macrophages. Btk activity is needed to drive macrophage activation in response to multiple agonists relevant to inflammatory arthritis, and promotes RA synovial tissue cytokine and MMP production. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA and other inflammatory diseases. PMID- 24764452 TI - Genetic dissection of tie pathway in mouse lymphatic maturation and valve development. AB - OBJECTIVE: The genetic program underlying lymphatic development is still incompletely understood. This study aims to dissect the role of receptor tyrosine kinase with immunoglobulin-like and EGF (epidermal growth factor)-like domains 1 (Tie1) and Tie2 in lymphatic formation using genetically modified mouse models. APPROACH AND RESULTS: We generated conditional knockout mouse models targeting Tie1, Tie2, and angiopoietin-2 in this study. Tie1(DeltaICD/DeltaICD) mice, with its intracellular domain targeted, appeared normal at E10.5 but displayed subcutaneous edema by E13.5. Lymph sac formation occurred in Tie1(DeltaICD/DeltaICD) mice, but they had defects with the remodeling of primary lymphatic network to form collecting vessels and valvulogenesis. Consistently, induced deletion of Tie1-ICD postnatally using a ubiquitous Cre deleter led to abnormal lymphangiogenesis and valve formation in Tie1-ICD(iUCKO/-) mice. In comparison with the lymphatic phenotype of Tie1 mutants, we found that the diameter of lymphatic capillaries was significantly less in mice deficient of angiopoietin-2, besides the disruption of collecting lymphatic vessel formation as previously reported. There was also no lymphedema observed in Ang2(-/-) mice during embryonic development, which differs from that of Tie1(DeltaICD/DeltaICD) mice. We further investigated whether Tie1 exerted its function via Tie2 during lymphatic development. To our surprise, genetic deletion of Tie2 (Tie2(iUCKO/-)) in neonate mice did not affect lymphatic vessel growth and maturation. CONCLUSIONS: In contrast to the important role of Tie2 in the regulation of blood vascular development, Tie1 is crucial in the process of lymphatic remodeling and maturation, which is independent of Tie2. PMID- 24764453 TI - Tissue plasminogen activator promotes postischemic neutrophil recruitment via its proteolytic and nonproteolytic properties. AB - OBJECTIVE: Neutrophil infiltration of the postischemic tissue considerably contributes to organ dysfunction on ischemia/reperfusion injury. Beyond its established role in fibrinolysis, tissue-type plasminogen activator (tPA) has recently been implicated in nonfibrinolytic processes. The role of this serine protease in the recruitment process of neutrophils remains largely obscure. APPROACH AND RESULTS: Using in vivo microscopy on the postischemic cremaster muscle, neutrophil recruitment and microvascular leakage, but not fibrinogen deposition at the vessel wall, were significantly diminished in tPA(-/-) mice. Using cell transfer techniques, leukocyte and nonleukocyte tPA were found to mediate ischemia/reperfusion-elicited neutrophil responses. Intrascrotal but not intra-arterial application of recombinant tPA induced a dose-dependent increase in the recruitment of neutrophils, which was significantly higher compared with stimulation with a tPA mutant lacking catalytic activity. Whereas tPA-dependent transmigration of neutrophils was selectively reduced on the inhibition of plasmin or gelatinases, neutrophil intravascular adherence was significantly diminished on the blockade of mast cell activation or lipid mediator synthesis. Moreover, stimulation with tPA caused a significant elevation in the leakage of fluorescein isothiocyanate dextran to the perivascular tissue, which was completely abolished on neutrophil depletion. In vitro, tPA-elicited macromolecular leakage of endothelial cell layers was abrogated on the inhibition of its proteolytic activity. CONCLUSIONS: Endogenously released tPA promotes neutrophil transmigration to reperfused tissue via proteolytic activation of plasmin and gelatinases. As a consequence, tPA on transmigrating neutrophils disrupts endothelial junctions allowing circulating tPA to extravasate to the perivascular tissue, which, in turn, amplifies neutrophil recruitment through the activation of mast cells and release of lipid mediators. PMID- 24764454 TI - Is carotid intima-media thickness as predictive as other noninvasive techniques for the detection of coronary artery disease? AB - Carotid intima-media thickness (CIMT) measured by B-mode ultrasound is the most widely used noninvasive imaging method to assess atherosclerosis and cardiovascular risk. CIMT has been consistently associated with coronary artery disease and stroke; however, recent meta-analyses and systematic reviews suggest that its clinical usefulness may be limited because the addition of CIMT to traditional risk factors has not improved the risk prediction of cardiovascular events in the general population. Characterizing the carotid wall by MRI may have greater clinical utility compared with CIMT measurements by ultrasound. Unlike CIMT, MRI measurements of wall thickness include the adventitia and may be sensitive to adventitial thickening that results from vasa vasorum proliferation as a sign of early plaque development. MRI also has the ability to image the entire circumference of the carotid wall, including the outer wall of the carotid bulb where plaque forms in its earliest stage, and identify plaque components such as the lipid core, fibrous cap, and intraplaque hemorrhage that are closely related to plaque vulnerability and cardiovascular risk. Additional research is needed to assess the added prognostic value of MRI measurements of wall and plaque features in risk prediction beyond traditional risk factors. PMID- 24764455 TI - The H2.0-like homeobox transcription factor modulates yolk sac vascular remodeling in mouse embryos. AB - OBJECTIVE: The H2.0-like homeobox transcription factor (HLX) plays an essential role in visceral organogenesis in mice and has been shown to regulate angiogenic sprouting in vitro and in zebrafish embryos. We therefore examined the role of HLX in vascular development in mouse and avian embryos. APPROACH AND RESULTS: In situ hybridization showed that Hlx is expressed in a subset of sprouting blood vessels in postnatal mouse retinas and embryos. Hlx expression was conserved in quail embryos and upregulated in blood vessels at the onset of circulation. In vitro assays showed that Hlx is dynamically regulated by growth factors and shear stress alterations. Proangiogenic vascular endothelial growth factor induces Hlx expression in cultured endothelial cells, whereas signals that induce stalk cell identity lead to a reduction in Hlx expression. HLX was also downregulated in embryos in which flow was ablated, whereas injection of a starch solution, which increases blood viscosity and therefore shear stress, causes an upregulation in HLX. HLX knockdown in vitro resulted in a reduction in tip cell marker expression and in reduced angiogenic sprouting, but Hlx(-/-) embryos showed no defect in vascular sprouting at E8.5, E9.5, or E11.5 in vivo. Vascular remodeling of the capillary plexus was altered in Hlx(-/-) embryos, with a modestly enlarged venous plexus and reduction of the arterial plexus. CONCLUSIONS: Our findings indicate not only that Hlx regulates sprouting in vitro, but that its role in sprouting is nonessential in vivo. We find HLX is regulated by shear stress and a subtle defect in vascular remodeling is present in knockout embryos. PMID- 24764456 TI - Antiatherogenic properties of high-density lipoprotein-enriched microRNAs. PMID- 24764458 TI - Tailoring the microstructure of sol-gel derived hydroxyapatite/zirconia nanocrystalline composites. AB - In this study, we tailor the microstructure of hydroxyapatite/zirconia nanocrystalline composites by optimizing processing parameters, namely, introducing an atmosphere of water vapor during sintering in order to control the thermal stability of hydroxyapatite, and a modified sol-gel process that yields to an excellent intergranular distribution of zirconia phase dispersed intergranularly within the hydroxyapatite matrix. In terms of mechanical behavior, SEM images of fissure deflection and the presence of monoclinic ZrO2 content on cracked surface indicate that both toughening mechanisms, stress induced tetragonal to monoclinic phase transformation and deflection, are active for toughness enhancement. PMID- 24764457 TI - Prenatal exposure to lipopolysaccharide results in myocardial remodelling in adult murine offspring. AB - BACKGROUND: The epigenetic plasticity hypothesis indicates that pregnancy exposure may result in adult-onset diseases, including hypertension, diabetes and cardiovascular disease, in offspring. In a previous study, we discovered that prenatal exposure to inflammatory stimulants, such as lipopolysaccharides (LPS), could lead to hypertension in adult rat offspring. In the present study, we further demonstrate that maternal inflammation induces cardiac hypertrophy and dysfunction via ectopic over-expression of nuclear transcription factor kappaB (NF- kappaB), and pyrrolidine dithiocarbamate (PDTC) can protect cardiac function by reducing maternal inflammation. METHODS: Pregnant SD rats were randomly divided into three groups and intraperitoneally injected with a vehicle, LPS (0.79 mg/kg), or LPS (0.79 mg/kg) plus PDTC (100 mg/kg) at 8 to 12 days of gestation. The offspring were raised until 4 and 8 months old, at which point an echocardiographic study was performed. The left ventricular (LV) mass index and apoptosis were examined. RESULTS: At 4 months of age, the LPS offspring exhibited augmented posterior wall thickness. These rats displayed left ventricle (LV) hypertrophy and LV diastolic dysfunction as well as a higher apoptotic index, a higher level of Bax and a lower level of Bcl-2 at 8 months of age. The protein levels of NF-kappaB (p65) in the myocardium of the offspring were measured at this time. NF-kappaB protein levels were higher in the myocardium of LPS offspring. The offspring that were prenatally treated with PDTC displayed improved signs of blood pressure (BP) and LV hypertrophy. CONCLUSIONS: Maternal inflammation can induce cardiac hypertrophy in offspring during aging accompanied with hypertension emergence and can be rescued by the maternal administration of PDTC (the inhibitor of NF-kappaB). PMID- 24764459 TI - kdetrees: Non-parametric estimation of phylogenetic tree distributions. AB - MOTIVATION: Although the majority of gene histories found in a clade of organisms are expected to be generated by a common process (e.g. the coalescent process), it is well known that numerous other coexisting processes (e.g. horizontal gene transfers, gene duplication and subsequent neofunctionalization) will cause some genes to exhibit a history distinct from those of the majority of genes. Such 'outlying' gene trees are considered to be biologically interesting, and identifying these genes has become an important problem in phylogenetics. RESULTS: We propose and implement kdetrees, a non-parametric method for estimating distributions of phylogenetic trees, with the goal of identifying trees that are significantly different from the rest of the trees in the sample. Our method compares favorably with a similar recently published method, featuring an improvement of one polynomial order of computational complexity (to quadratic in the number of trees analyzed), with simulation studies suggesting only a small penalty to classification accuracy. Application of kdetrees to a set of Apicomplexa genes identified several unreliable sequence alignments that had escaped previous detection, as well as a gene independently reported as a possible case of horizontal gene transfer. We also analyze a set of Epichloe genes, fungi symbiotic with grasses, successfully identifying a contrived instance of paralogy. AVAILABILITY AND IMPLEMENTATION: Our method for estimating tree distributions and identifying outlying trees is implemented as the R package kdetrees and is available for download from CRAN. PMID- 24764460 TI - Circular RNAs are depleted of polymorphisms at microRNA binding sites. AB - MOTIVATION: Circular RNAs (circRNAs) are an abundant class of highly stable RNAs that can affect gene regulation by binding and preventing microRNAs (miRNAs) from regulating their messenger RNA (mRNA) targets. Mammals have thousands of circRNAs with predicted miRNA binding sites, but only two circRNAs have been verified as being actual miRNA sponges. As it is unclear whether these thousands of predicted miRNA binding sites are functional, we investigated whether miRNA seed sites within human circRNAs are under selective pressure. RESULTS: Using SNP data from the 1000 Genomes Project, we found a significant decrease in SNP density at miRNA seed sites compared with flanking sequences and random sites. This decrease was similar to that of miRNA seed sites in 3' untranslated regions, suggesting that many of the predicted miRNA binding sites in circRNAs are functional and under similar selective pressure as miRNA binding sites in mRNAs. PMID- 24764461 TI - relax: the analysis of biomolecular kinetics and thermodynamics using NMR relaxation dispersion data. AB - Nuclear magnetic resonance (NMR) is a powerful tool for observing the motion of biomolecules at the atomic level. One technique, the analysis of relaxation dispersion phenomenon, is highly suited for studying the kinetics and thermodynamics of biological processes. Built on top of the relax computational environment for NMR dynamics is a new dispersion analysis designed to be comprehensive, accurate and easy-to-use. The software supports more models, both numeric and analytic, than current solutions. An automated protocol, available for scripting and driving the graphical user interface (GUI), is designed to simplify the analysis of dispersion data for NMR spectroscopists. Decreases in optimization time are granted by parallelization for running on computer clusters and by skipping an initial grid search by using parameters from one solution as the starting point for another -using analytic model results for the numeric models, taking advantage of model nesting, and using averaged non-clustered results for the clustered analysis. AVAILABILITY AND IMPLEMENTATION: The software relax is written in Python with C modules and is released under the GPLv3+ license. Source code and precompiled binaries for all major operating systems are available from http://www.nmr-relax.com. CONTACT: edward@nmr-relax.com. PMID- 24764464 TI - Fishy food for thought. PMID- 24764462 TI - On non-detects in qPCR data. AB - MOTIVATION: Quantitative real-time PCR (qPCR) is one of the most widely used methods to measure gene expression. Despite extensive research in qPCR laboratory protocols, normalization and statistical analysis, little attention has been given to qPCR non-detects-those reactions failing to produce a minimum amount of signal. RESULTS: We show that the common methods of handling qPCR non-detects lead to biased inference. Furthermore, we show that non-detects do not represent data missing completely at random and likely represent missing data occurring not at random. We propose a model of the missing data mechanism and develop a method to directly model non-detects as missing data. Finally, we show that our approach results in a sizeable reduction in bias when estimating both absolute and differential gene expression. AVAILABILITY AND IMPLEMENTATION: The proposed algorithm is implemented in the R package, nondetects. This package also contains the raw data for the three example datasets used in this manuscript. The package is freely available at http://mnmccall.com/software and as part of the Bioconductor project. PMID- 24764463 TI - GenCLiP 2.0: a web server for functional clustering of genes and construction of molecular networks based on free terms. AB - Identifying biological functions and molecular networks in a gene list and how the genes may relate to various topics is of considerable value to biomedical researchers. Here, we present a web-based text-mining server, GenCLiP 2.0, which can analyze human genes with enriched keywords and molecular interactions. Compared with other similar tools, GenCLiP 2.0 offers two unique features: (i) analysis of gene functions with free terms (i.e. any terms in the literature) generated by literature mining or provided by the user and (ii) accurate identification and integration of comprehensive molecular interactions from Medline abstracts, to construct molecular networks and subnetworks related to the free terms. AVAILABILITY AND IMPLEMENTATION: http://ci.smu.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24764465 TI - In-vitro immunomodulatory and anti-cancerous activities of biotransformed products of Dianabol through Azadirachta indica and its molecular docking studies. AB - BACKGROUND: Plant Biotransformation is one of the tools for structural modifications of the organic substrate of low, moderate or high biological value utilizing plant cultured cells, these modifications of organic structures may lead to biologically augmented products and which may be ultimately substantial in cure or improvement of various morbidities and diseases. RESULTS: Azadirachta indica A. Juss. suspension culture was employed for the biotransformation of dianabol (1) for the first time, and two metabolites, 17beta-hydroxy-17alpha methyl-5alpha-androst-1-en-3-one (2), and 17beta-hydroxy-17alpha-methyl-5alpha androstan-3-one (3) were obtained. CONCLUSIONS: Most important aspect of this work was the evaluation of metabolite 2, which strongly and differentially suppressed [not affecting whole blood and human polymorphonuclear cells (PMN)] the phytohemagglutinin (PHA)-activated T-cell proliferation (IC50: <10.33 MUM), and also found to inhibit IL-2 production (IC50: 16.89 +/- 1.32) unlike metabolite 3 and compound 1. Compound 2 also exhibited anticancer activity against lung cancer cell line; NCI-H460, it moderately inhibited the growth of cancer cells (22.5 +/- 4.15 MUM). Furthermore, a good correlation between the predicted binding energies of the compounds acquired by the FlexX program and the experimental affinities were speculated upon interacting with IL-2 protein during molecular docking studies. PMID- 24764466 TI - Modelling acute leukemias in mice: clonal evolution and the emergence of leukemic stem cells. PMID- 24764467 TI - Chemical carcinogenesis - mode of action to inform quantitative human risk. PMID- 24764468 TI - Viral carcinogenesis: virus implicated in cancer. PMID- 24764469 TI - Head and neck cancer. PMID- 24764470 TI - Domestic animals as sentinels for environmental carcinogenic agents. PMID- 24764471 TI - Hereditary cancer syndromes: opportunities and challenges. PMID- 24764472 TI - Structural biology and cancer. PMID- 24764473 TI - Tumors as complex organs: are cancers manageable through the modification of their microenvironment? PMID- 24764474 TI - 3D nuclear organization and genomic instability in cancer. PMID- 24764475 TI - Biomarker analysis in human neoplasias: superior next-generation sequencing on frozen bone marrow cells and on formalin-fixed, paraffin-embedded tumor tissues. PMID- 24764476 TI - INCT in oncogenetics focusing on hereditary breast-colorectal carcinoma syndrome. PMID- 24764477 TI - Hereditary colorectal cancer and Lynch syndrome. PMID- 24764478 TI - Inflammation, immune suppression, and tumor progression. PMID- 24764479 TI - Medical applications of RNA interference (RNAi). PMID- 24764480 TI - Epigenetic field for cancerization: its cause and clinical implications. PMID- 24764481 TI - Prion protein signaling as therapeutic target in human tumors. PMID- 24764482 TI - Modeling squamous cell carcinoma development and malignant progression in mice. PMID- 24764483 TI - Impact of molecular imaging in preclinical cancer research. PMID- 24764484 TI - Comparative oncology - the North American experience. PMID- 24764486 TI - Integrative cancer informatics for the identification of prognostic and predictive biomarkers. PMID- 24764485 TI - Comparative mammary oncology: canine model. PMID- 24764488 TI - Comparative breast cancer research, lessons from companion animals. PMID- 24764487 TI - Evolution of energy metabolism, stem cells and cancer stem cells: how the Warburg and Barker hypothesis might be linked. PMID- 24764489 TI - Where we are now - Monitoring health and disability in older European populations and what harmonisation efforts (CLESA, EPOSA) could tell. PMID- 24764490 TI - World Health Organisation's (WHO) Study on Global Ageing and Adult Health (SAGE). PMID- 24764491 TI - Addressing health and ageing in the German national health monitoring system. PMID- 24764492 TI - Towards an integrated systems-based modelling framework for drug transport and its effect on tumour cells. AB - BACKGROUND: A systematic understanding of chemotherapeutic influence on solid tumours is highly challenging and complex as it encompasses the interplay of phenomena occurring at multiple scales. It is desirable to have a multiscale systems framework capable of disentangling the individual roles of multiple contributing factors, such as transport and extracellular factors, and purely intracellular factors, as well as the interactions among these factors. Based on a recently developed systems-based modelling framework, we have developed a coupled system in order to further elucidate the role of drug transport, and its interplay with cellular signalling by incorporating intra- and extra-vascular drug transport in tumour, dynamic descriptions of intracellular signalling and tumour cell density dynamics. RESULTS: Different aspects of the interaction between transport and cell signalling and the effects of transport parameters have been investigated in silico. Limited drug penetration is found to be a major constraint in inducing drug effect; many aspects of the interaction of transport with cell signalling are independent of the details of cell signalling. A sensitivity analysis indicates that the effect of drug diffusivity depends on the balance between interstitial drug transport and the specific requirement for triggering apoptosis (governed by highly nonlinear signalling networks), suggesting that the effect of drug diffusivity in such cases must be considered in conjunction with descriptions of cellular dynamics. CONCLUSIONS: The modelling framework developed in this study provides qualitative and mechanistic insights into the effect of drug on tumour cells. It provides an in silico experimental platform to investigate the interplay between extracellular factors (e.g. transport) and intracellular factors. Such a platform is essential to understanding the individual and combined effects of transport and cellular factors in solid tumour. PMID- 24764495 TI - Response to 'pervasive sequence patents cover the entire human genome' - authors' reply. AB - An author reply to the Letter to the Editor from Tu et al. regarding Pervasive sequence patents cover the entire human genome by J Rosenfeld and C Mason. Genome Med 2013, 5:27. See related Correspondence by Rosenfeld and Mason, http://genomemedicine.com/content/5/3/27, and related letter by Tu et al., http://genomemedicine.com/content/6/2/14. PMID- 24764496 TI - A controlled trial of Partners in Dementia Care: veteran outcomes after six and twelve months. AB - INTRODUCTION: "Partners in Dementia Care" (PDC) tested the effectiveness of a care-coordination program integrating healthcare and community services and supporting veterans with dementia and their caregivers. Delivered via partnerships between Veterans Affairs medical centers and Alzheimer's Association chapters, PDC targeted both patients and caregivers, distinguishing it from many non-pharmacological interventions. Hypotheses posited PDC would improve five veteran self-reported outcomes: 1) unmet need, 2) embarrassment about memory problems, 3) isolation, 4) relationship strain and 5) depression. Greater impact was expected for more impaired veterans. A unique feature was self-reported research data collected from veterans with dementia. METHODS AND FINDINGS: Five matched communities were study sites. Two randomly selected sites received PDC for 12 months; comparison sites received usual care. Three structured telephone interviews were completed every 6 months with veterans who could participate. RESULTS: Of 508 consenting veterans, 333 (65.6%) completed baseline interviews. Among those who completed baseline interviews, 263 (79.0%) completed 6-month follow-ups and 194 (58.3%) completed 12-month follow-ups. Regression analyses showed PDC veterans had significantly less adverse outcomes than those receiving usual care, particularly for more impaired veterans after 6 months, including reduced relationship strain (B = -0.09; p = 0.05), depression (B = -0.10; p = 0.03), and unmet need (B = -0.28; p = 0.02; and B = -0.52; p = 0.08). PDC veterans also had less embarrassment about memory problems (B = -0.24; p = 0.08). At 12 months, more impaired veterans had further reductions in unmet need (B = 0.96; p < 0.01) and embarrassment (B = -0.05; p = 0.02). Limitations included use of matched comparison sites rather than within-site randomization and lack of consideration for variation within the PDC group in amounts and types of assistance provided. CONCLUSIONS: Partnerships between community and health organizations have the potential to meet the dementia-related needs and improve the psychosocial functioning of persons with dementia. TRIAL REGISTRY: NCT00291161. PMID- 24764497 TI - State of world allergy report 2008 allergy and chronic respiratory diseases. PMID- 24764501 TI - ABA signal in rice under stress conditions. AB - Ever since its discovery, abscisic acid (ABA) has been intensively studied due to its versatile functions in plant developmental and physiological processes. Many signaling details of ABA have been well elucidated and reviewed. The identification of ABA receptors is a great breakthrough in the field of ABA study, whereas the discovery of ABA transporter has changed our concept that ABA is delivered solely by passive transport. The intensity of ABA signaling pathway is well known to be controlled by multi-regulators. Nonetheless, the interaction and coordination among ABA biosynthesis, catabolism, conjugation and transportation are seldom discussed. Here, we summarize the biological functions of ABA in response to different stresses, especially the roles of ABA in plant defense to pathogen attack, and discuss the possible relationships of these determinants in controlling the specificity and intensity of ABA signaling pathway in the rice. PMID- 24764503 TI - Nomenclature report on rice WRKY's - Conflict regarding gene names and its solution. AB - BACKGROUND: Since whole genome sequences of rice were made publically accessible, the number of articles on new rice genes has increased remarkably. The Committee on Gene Symbolization, Nomenclature and Linkage (CGSNL) of the Rice Genetics Cooperative published the gene nomenclature system for rice and encouraged researchers to follow the rules before publishing their results. The CGSNL provides an on-line registration system for newly identified rice genes to prevent conflicts and/or duplication of gene name in journal articles. FINDINGS: Recently, the CGSNL surveyed genes in the rice WRKY family in published journal articles and found several duplicated gene names. CONCLUSIONS: To discuss and resolve inconsistencies in WRKY gene nomenclature, the rice WRKY working group was established and redefined the nomenclature. This report announces the conclusion. PMID- 24764502 TI - Mechanisms for coping with submergence and waterlogging in rice. AB - Rice (Oryza sativa L.), unlike other cereals, can grow well in paddy fields and is highly tolerant of excess water stress, from either submergence (in which part or all of the plant is under water) or waterlogging (in which excess water in soil limits gas diffusion). Rice handles submergence stress by internal aeration and growth controls. A quiescence strategy based on Submergence-1A (SUB1A) or an escape strategy based on SNORKEL1 (SK1) and SNORKEL2 (SK2) is used for the growth controls. On the other hand, rice handles waterlogging stress by forming lysigenous aerenchyma and a barrier to radial O2 loss (ROL) in roots in order to supply O2 to the root tip. In this article, we summarize recent advances in understanding the mechanisms of responding to excess water stresses (i.e., submergence and waterlogging) in rice and other gramineous plants. PMID- 24764504 TI - Small and round seed 5 gene encodes alpha-tubulin regulating seed cell elongation in rice. AB - Seed size is an important trait in determinant of rice seed quality and yield. In this study, we report a novel semi-dominant mutant Small and round seed 5 (Srs5) that encodes alpha-tubulin protein. Lemma cell length was reduced in Srs5 compared with that of the wild-type. Mutants defective in the G-protein alpha subunit (d1-1) and brassinosteroid receptor, BRI1 (d61-2) also exhibited short seed phenotypes, the former due to impaired cell numbers and the latter due to impaired cell length. Seeds of the double mutant of Srs5 and d61-2 were smaller than those of Srs5 or d61-2. Furthermore, SRS5 and BRI1 genes were highly expressed in Srs5 and d61-2 mutants. These data indicate that SRS5 independently regulates cell elongation of the brassinosteroid signal transduction pathway. PMID- 24764505 TI - Cadmium transport and tolerance in rice: perspectives for reducing grain cadmium accumulation. AB - Cadmium (Cd) is a toxic heavy metal which harms human health. In Japan, a major source of human Cd-intake is rice grains and contamination of paddy soils by Cd and accumulation of Cd in rice grains are the serious agricultural issues. There also exist Cd contamination of rice and its toxicity in several populations in countries including China and Thailand. Understanding the Cd transport mechanisms in rice can be a basis for regulating rice Cd transport and accumulation by molecular engineering and marker-assisted breeding. Recently, a number of studies have revealed the behavior of Cd in rice, genetic diversity of Cd accumulation, quantitative trait loci controlling Cd accumulation and transporter molecules regulating Cd accumulation and distribution in rice. In this article, we summarize recent advances in the field and discuss perspectives to reduce grain Cd contents. PMID- 24764507 TI - Translating longevity research into healthspan. PMID- 24764506 TI - Toward understanding transcriptional regulatory networks in abiotic stress responses and tolerance in rice. AB - Abiotic stress causes loss of crop production. Under abiotic stress conditions, expression of many genes is induced, and their products have important roles in stress responses and tolerance. Progress has been made in understanding the biological roles of regulons in abiotic stress responses in rice. A number of transcription factors (TFs) regulate stress-responsive gene expression. OsDREB1s and OsDREB2s were identified as abiotic-stress responsive TFs that belong to the AP2/ERF family. Similar to Arabidopsis, these DREB regulons were most likely not involved in the abscisic acid (ABA) pathway. OsAREBs such as OsAREB1 were identified as key components in ABA-dependent transcriptional networks in rice. OsNAC/SNACs including OsNAC6 were characterized as factors that regulate expression of genes important for abiotic stress responses in rice. Here, we review on the rice abiotic-stress responses mediated by transcriptional networks, with the main focus on TFs that function in abiotic stress responses and confer stress tolerance in rice. PMID- 24764508 TI - Evidence of a metabolic memory to early-life dietary restriction in male C57BL/6 mice. AB - BACKGROUND: Dietary restriction (DR) extends lifespan and induces beneficial metabolic effects in many animals. What is far less clear is whether animals retain a metabolic memory to previous DR exposure, that is, can early-life DR preserve beneficial metabolic effects later in life even after the resumption of ad libitum (AL) feeding. We examined a range of metabolic parameters (body mass, body composition (lean and fat mass), glucose tolerance, fed blood glucose, fasting plasma insulin and insulin-like growth factor 1 (IGF-1), insulin sensitivity) in male C57BL/6 mice dietary switched from DR to AL (DR-AL) at 11 months of age (mid life). The converse switch (AL-DR) was also undertaken at this time. We then compared metabolic parameters of the switched mice to one another and to age-matched mice maintained exclusively on an AL or DR diet from early life (3 months of age) at 1 month, 6 months or 10 months post switch. RESULTS: Male mice dietary switched from AL-DR in mid life adopted the metabolic phenotype of mice exposed to DR from early life, so by the 10-month timepoint the AL-DR mice overlapped significantly with the DR mice in terms of their metabolic phenotype. Those animals switched from DR-AL in mid life showed clear evidence of a glycemic memory, with significantly improved glucose tolerance relative to mice maintained exclusively on AL feeding from early life. This difference in glucose tolerance was still apparent 10 months after the dietary switch, despite body mass, fasting insulin levels and insulin sensitivity all being similar to AL mice at this time. CONCLUSIONS: Male C57BL/6 mice retain a long-term glycemic memory of early-life DR, in that glucose tolerance is enhanced in mice switched from DR AL in mid life, relative to AL mice, even 10 months following the dietary switch. These data therefore indicate that the phenotypic benefits of DR are not completely dissipated following a return to AL feeding. The challenge now is to understand the molecular mechanisms underlying these effects, the time course of these effects and whether similar interventions can confer comparable benefits in humans. PMID- 24764509 TI - Male mice retain a metabolic memory of improved glucose tolerance induced during adult onset, short-term dietary restriction. AB - BACKGROUND: Chronic dietary restriction (DR) has been shown to have beneficial effects on glucose homeostasis and insulin sensitivity. These factors show rapid and robust improvements when rodents were crossed over from an ad libitum (AL) diet to DR in mid life. We aimed to determine whether the beneficial effects induced by short-term exposure to DR can be retained as a 'metabolic memory' when AL feeding is resumed (AL-DR-AL) and vice versa: whether the effects of long-term DR can be reversed by a period of AL feeding (DR-AL-DR). C57BL/6 male and female mice were used to examine sex differences (N = 10/sex/group). Mice were fed AL or DR from 3 until 15 months (baseline) and each dietary crossover lasted approximately 5 months. RESULTS: In females, body and fat mass were proportional to the changes in feeding regime and plasma insulin and glucose tolerance were unaffected by the crossovers. However, in male mice, glucose tolerance and plasma insulin levels were reversed within 6 to 12 weeks. When males returned to AL intake following 5 months DR (AL-DR-AL), body mass was maintained below baseline, proportional to changes in fat mass. Glucose tolerance was also significantly better compared to baseline. CONCLUSIONS: Male mice retained a metabolic memory of 5 months of DR feeding in terms of reduced body mass and improved glucose tolerance. This implies that some of the beneficial effects induced by a period of DR in adult life may be beneficial, even when free feeding is resumed at least in males. However, under continuous DR, lifespan extension was more prominent in females than in males. PMID- 24764510 TI - Thioredoxin, oxidative stress, cancer and aging. AB - The Free Radical or Oxidative Stress Theory of Aging is one of the most popular theories in aging research and has been extensively studied over the past several decades. However, recent evidence using transgenic/knockout mice that overexpress or down-regulate antioxidant enzymes challenge the veracity of this theory since the animals show no increase or decrease in lifespan. These results seriously call into question the role of oxidative damage/stress in the aging process in mammals. Therefore, the theory requires significant modifications if we are to understand the relationship between aging and the regulation of oxidative stress. Our laboratory has been examining the impacts of thioredoxins (Trxs), in the cytosol and mitochondria, on aging and age-related diseases. Our data from mice that are either up-regulating or down-regulating Trx in different cellular compartments, that is, the cytosol or mitochondria, could shed some light on the role of oxidative stress and its pathophysiological effects. The results generated from our lab and others may indicate that: 1) changes in oxidative stress and the redox state in the cytosol, mitochondria or nucleus might play different roles in the aging process; 2) the role of oxidative stress and redox state could have different pathophysiological consequences in different tissues/cells, for example, mitotic vs. post-mitotic; 3) oxidative stress could have different pathophysiological impacts in young and old animals; and 4) the pathophysiological roles of oxidative stress and redox state could be controlled through changes in redox-sensitive signaling, which could have more diverse effects on pathophysiology than the accumulation of oxidative damage to various molecules. To critically test the role of oxidative stress on aging and age related diseases, further study is required using animal models that regulate oxidative stress levels differently in each cellular compartment, each tissue/organ, and/or at different stages of life (young, middle and old) to change redox sensitive signaling pathways. PMID- 24764511 TI - Aging, immunosenescence and membrane rafts: the lipid connection. AB - The decreased efficiency of immune responses in older people is partly a consequence of alterations in T lymphocyte functions caused by modifications in the early events of signal transduction. Several alterations in the signaling pathways of T lymphocytes have been described in older humans and animals. A unifying cause could be modifications in the physicochemical properties of the plasma membrane resulting from changes in its lipid composition and the distribution and function of lipid rafts (LR). The latter serve to assemble the initial components of the signaling cascade. Accumulating data suggest that the function of plasma membrane LR is altered with aging; we hypothesize that this would significantly contribute to immune dysregulation. The role of aging and cholesterol in LR functions in T lymphocytes is reviewed and discussed here. PMID- 24764512 TI - Oxidative stress in the etiology of age-associated decline in glucose metabolism. AB - One of the most common pathologies in aging humans is the development of glucose metabolism dysfunction. The high incidence of metabolic dysfunction, in particular type 2 diabetes mellitus, is a significant health and economic burden on the aging population. However, the mechanisms that regulate this age-related physiological decline, and thus potential preventative treatments, remain elusive. Even after accounting for age-related changes in adiposity, lean mass, blood lipids, etc., aging is an independent factor for reduced glucose tolerance and increased insulin resistance. Oxidative stress has been shown to have significant detrimental impacts on the regulation of glucose homeostasis in vitro and in vivo. Furthermore, oxidative stress has been shown to be modulated by age and diet in several model systems. This review provides an overview of these data and addresses whether increases in oxidative stress with aging may be a primary determinant of age-related metabolic dysfunction. PMID- 24764513 TI - Immunosenescence, inflammation and Alzheimer's disease. AB - Ageing impacts negatively on the development of the immune system and its ability to fight pathogens. Progressive changes in the T-cell and B-cell systems over the lifespan of individuals have a major impact on the capacity to respond to immune challenges. The cumulative age-associated changes in immune competence are termed immunosenescence that is characterized by changes where adaptive immunity deteriorates, while innate immunity is largely conserved or even upregulated with age. On the other hand, ageing is also characterized by "inflamm-ageing", a term coined to explain the inflammation commonly present in many age-associated diseases. It is believed that immune inflammatory processes are relevant in Alzheimer's disease, the most common cause of dementia in older people. In the present paper we review data focusing on changes of some immunoinflammatory parameters observed in patients affected by Alzheimer's disease. PMID- 24764514 TI - Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans. AB - BACKGROUND: The longevity of an organism is influenced by both genetic and environmental factors. With respect to genetic factors, a significant effort is being made to identify pharmacological agents that extend life span by targeting pathways with a defined role in the aging process. On the environmental side, the molecular mechanisms responsible for the positive influence of interventions such as dietary restriction are being explored. The environment experienced by humans in modern societies already contains countless compounds that may influence longevity. Understanding the role played by common compounds that substantially affect the aging process will be critical for predicting and interpreting the outcome of introducing new interventions. Caffeine is the most widely used psychoactive drug worldwide. Prior studies in flies, worms, and mice indicate that caffeine may positively impact age-associated neurodegenerative pathology, such as that observed in Alzheimer's disease. RESULTS: Here we report that caffeine is capable of extending life span and improving healthspan in Caenorhabditis elegans, a finding that is in agreement with a recently published screen looking for FDA-approved compounds capable of extending worm life span. Life span extension using caffeine displays epistatic interaction with two known longevity interventions: dietary restriction and reduced insulin signaling. Caffeine treatment also delays pathology in a nematode model of polyglutamine disease. CONCLUSIONS: The identification of caffeine as a relevant factor in aging and healthspan in worms, combined with prior work in both humans and rodents linking caffeine consumption to reduced risk of age-associated disease, suggests that caffeine may target conserved longevity pathways. Further, it may be important to consider caffeine consumption when developing clinical interventions, particularly those designed to mimic dietary restriction or modulate insulin/IGF-1-like signaling. The positive impact of caffeine on a worm model of polyglutamine disease suggests that chronic caffeine consumption may generally enhance resistance to proteotoxic stress and may be relevant to assessing risk and developing treatments for human diseases like Alzheimer's and Huntington's disease. Future work addressing the relevant targets of caffeine in models of aging and healthspan will help to clarify the underlying mechanisms and potentially identify new molecular targets for disease intervention. PMID- 24764515 TI - Accumulation of prelamin A compromises NF-kappaB-regulated B-lymphopoiesis in a progeria mouse model. AB - BACKGROUND: Alteration in the immune system is one of the most profound aspects of aging. Progressive changes in the number of B lymphocyte progenitors during aging have been reported but the underlying mechanisms are still elusive. A heterozygous G608G mutation in the LMNA gene leads to a deletion of 50 amino acids in lamin A protein, termed progerin, and is the predominant cause of Hutchinson-Gilford progeria syndrome (HGPS). Lack of Zmpste24, a metalloproteinase responsible for prelamin A processing, leads to progeroid features resembling HGPS. Therefore Zmpste24-deficient mice provide an ideal mouse model to study the impact of lamin A and (premature) aging on the aging related decline of B lymphopoiesis. RESULTS: Analysis of bone marrow (BM) nucleated cells revealed a decline of early B cell progenitors in Zmpste24 (-/-) mice. BM transplantation in a congenic strain completely rescued the defects in B lymphopoiesis, indicating that the decline in B cell progenitors in Zmpste24 (-/ ) mice is attributable to defective BM microenvironments rather than to cell intrinsic defects. Further investigation revealed downregulation of a set of important early B lymphopoiesis factors in Zmpste24 (-/-) bone marrow stromal cells (BMSCs), such as Vcam-1, SDF-1alpha, Flt3L and TSLP, and most of them are under transcriptional control of NF-kappaB signaling. Though TNFalpha stimulates IkappaBalpha degradation and NF-kappaB nuclear translocation in Zmpste24 (-/-) BMSCs, NF-kappaB fails to stimulate IkappaBalpha re-expression, which mediates a negative feedback loop of NF-kappaB signaling in wild-type BMSCs. CONCLUSIONS: Our data demonstrate a cell-extrinsic defect of B cell development in a progeroid mouse model and a critical role for lamin A in the regulation of NF-kappaB signaling and cytokines that are essential for lymphopoiesis. PMID- 24764516 TI - Frostbite: a practical approach to hospital management. AB - Frostbite presentation to hospital is relatively infrequent, and the optimal management of the more severely injured patient requires a multidisciplinary integration of specialist care. Clinicians with an interest in wilderness medicine/freezing cold injury have the awareness of specific potential interventions but may lack the skill or experience to implement the knowledge. The on-call specialist clinician (vascular, general surgery, orthopaedic, plastic surgeon or interventional radiologist), who is likely to receive these patients, may have the skill and knowledge to administer potentially limb-saving intervention but may be unaware of the available treatment options for frostbite. Over the last 10 years, frostbite management has improved with clear guidelines and management protocols available for both the medically trained and winter sports enthusiasts. Many specialist surgeons are unaware that patients with severe frostbite injuries presenting within 24 h of the injury may be good candidates for treatment with either TPA or iloprost. In this review, we aim to give a brief overview of field frostbite care and a practical guide to the hospital management of frostbite with a stepwise approach to thrombolysis and prostacyclin administration for clinicians. PMID- 24764517 TI - Welcome to perioperative medicine. PMID- 24764518 TI - Perioperative fluid management: Consensus statement from the enhanced recovery partnership. PMID- 24764519 TI - The cost-effectiveness of an outpatient anesthesia consultation clinic before surgery: a matched Hong Kong cohort study. AB - BACKGROUND: Outpatient anesthesia clinics are well established in North America, Europe and Australia, but few economic evaluations have been published. The Perioperative Systems in Hong Kong are best described as a hybrid model of the new and old systems of surgical care. In this matched cohort study, we compared the costs and effects of an outpatient anesthesia clinic (OPAC) with the conventional system of admitting patients to the ward a day before surgery for their pre-anesthesia consultation. A second objective of the study was to determine the patient's median Willingness To Pay (WTP) value for an OPAC. METHODS: A total of 352 patients were matched (1:1) on their elective surgical procedure to either the clinic group or to the conventional group. The primary outcome was quality of recovery score and overall perioperative treatment cost (US$). To detect a difference in the joint cost-effect relationship between groups, a cost-effectiveness acceptability curve (CEAC) was drawn. A modified Poisson regression model was used to examine the factors associated with patients willing to pay more than the median WTP value for an OPAC. RESULTS: The quality of recovery scores on the first day after surgery between the clinic and conventional groups were similar (mean difference, -0.1; 95% confidence interval (CI), -0.6 to 0.3; P = 0.57). Although the preoperative costs were less in the clinic group (mean difference, -$463, 95% CI, -$648 to -$278 per patient; P <0.001), the total perioperative cost was similar between groups (mean difference, -$172; 95% CI, -$684 to $340 per patient; P = 0.51). The CEAC showed that we could not be 95% confident that the clinic was cost-effective. Compared to the conventional group, clinic patients were three times more likely to prefer OPAC care (relative risk (RR) 2.75, 95% CI, 2.13 to 3.55; P <0.001) and pay more than the median WTP (US$13) for a clinic consultation (RR 3.27, 95% CI, 2.32 to 4.64; P <0.001). CONCLUSIONS: There is uncertainty about the cost-effectiveness of an OPAC in the Hong Kong setting. Most clinic patients were willing to pay a small amount for an anesthesia clinic consultation. PMID- 24764520 TI - Analgesic efficacy of continuous femoral nerve block commenced prior to operative fixation of fractured neck of femur. AB - BACKGROUND: Peripheral nerve blocks are effective in treating acute pain, thereby minimizing the requirement for opiate analgesics. Fractured neck of femur (FNF) is a common, painful injury. The provision of effective analgesia to this cohort is challenging but an important determinant of their functional outcome. We investigated the analgesic efficacy of continuous femoral nerve block (CFNB) in patients with FNF. METHODS: Following institutional ethical approval and with informed consent, patients awaiting FNF surgery were randomly allocated to receive either standard opiate-based analgesia (Group 1) or a femoral perineural catheter (Group 2). Patients in Group 1 received parenteral morphine as required. Those in Group 2 received a CFNB comprising a bolus of local anaesthetic followed by a continuous infusion of 0.25% bupivacaine. For both Groups, rescue analgesia consisted of intramuscular morphine as required and all patients received paracetamol regularly. Pain was assessed using a visual analogue scale at rest and during passive movement (dynamic pain score) at 30 min following first analgesic intervention and six hourly thereafter for 72 hours. Patient satisfaction with the analgesic regimen received was recorded using verbal rating scores (0-10). The primary outcome measured was dynamic pain score from initial analgesic intervention to 72 hours later. RESULTS: Of 27 recruited, 24 patients successfully completed the study protocol and underwent per protocol analysis. The intervals from recruitment to the study until surgery were similar in both groups [31.4(17.7) vs 27.5(14.2) h, P = 0.57]. The groups were similar in terms of baseline clinical characteristics. For patients in Group 2, pain scores at rest were less than those reported by patients in Group 1 [9.5(9.4) vs 31(28), P = 0.031]. Dynamic pain scores reported by patients in Group 2 were less at each time point from 30 min up to 54 hours [e.g at 6 h 30.7(23.4) vs 67.0(32.0), P = 0.004]. Cumulative morphine consumption over 72 h was less in Group 2. Patient satisfaction scores were greater in Group 2 [9.4(1.1) vs 7.6(1.8), P = 0.014]. CONCLUSIONS: CFNB provides more effective perioperative analgesia than a standard opiate-based regimen for patients undergoing fixation of FNF. It is associated with lesser opiate use and greater patient satisfaction. PMID- 24764521 TI - Strategies to promote reporting of Surgical Care Improvement Project (SCIP) measures: a pilot survey of anesthesia department leaders. AB - BACKGROUND: The Surgical Care Improvement Project (SCIP) is a quality improvement initiative focused on reducing surgical complications. Reporting SCIP performance measures helps determine whether hospitals receive the full payment update from the Centers for Medicare and Medicaid Services. Strategies in use by hospitals to motivate departmental participation in SCIP reporting are poorly understood. METHODS: A 12-item pilot survey exploring strategies to promote reporting of SCIP measures was developed and mailed to department of anesthesiology chairs at 1,426 US hospitals. Descriptive statistics and chi (2) analysis were used to summarize respondent and survey data. RESULTS: In all, 29.5% of the sample responded to the survey, with 96.9% indicating SCIP participation; 62.5% participated primarily for voluntary reasons, and 4.2% reported an incentive from their hospital as the primary reason for participation. CONCLUSIONS: Hospital strategies promoting physician participation in SCIP currently vary. A minority of survey respondents indicated that an incentive was used to encourage adherence to SCIP measures. Further research to optimize such strategies may support future efforts to improve perioperative care. PMID- 24764524 TI - A new era of open access publishing in eating disorders. PMID- 24764523 TI - Protocol-directed insulin infusion sliding scales improve perioperative hyperglycaemia in critical care. AB - Perioperative hyperglycaemia is associated with poor outcomes in patients undergoing cardiac surgery. Frequent postoperative hyperglycaemia in cardiac surgery patients has led to the initiation of an insulin infusion sliding scale for quality improvement. A systematic review was conducted to determine whether a protocol-directed insulin infusion sliding scale is as safe and effective as a conventional practitioner-directed insulin infusion sliding scale, within target blood glucose ranges. A literature survey was conducted to identify reports on the effectiveness and safety of an insulin infusion protocol, using seven electronic databases from 2000 to 2012: MEDLINE, CINAHL, EMBASE, the Cochrane Library, the Joanna Briggs Institute Library and SIGLE. Data were extracted using pre-determined systematic review and meta-analysis criteria. Seven research studies met the inclusion criteria. There was an improvement in overall glycaemic control in five of these studies. The implementation of protocols led to the achievement of blood glucose concentration targets more rapidly and the maintenance of a specified target blood glucose range for a longer time, without any increased frequency of hyperglycaemia. Of the seven studies, four used controls and three had no controls. In terms of the meta-analysis carried out, four studies revealed a failure of patients reaching target blood glucose levels (P < 0.0005) in the control group compared with patients in the protocol group. The risk of hypoglycaemia was significantly reduced (P <0.00001) between studies. It can be concluded that the protocol-directed insulin infusion sliding scale is safe and improves blood glucose control when compared with the conventional practitioner-directed insulin infusion sliding scale. This study supports the adoption of a protocol-directed insulin infusion sliding scale as a standard of care for post-cardiac surgery patients. PMID- 24764525 TI - The role of perfectionism in body dissatisfaction. AB - BACKGROUND: Body dissatisfaction is a robust risk factor for disordered eating and is thought to be especially problematic in the presence of high levels of perfectionism. The aim of the current study was to investigate what types of perfectionism were associated with body dissatisfaction. Participants were 1083 women aged 28 to 40 years, with a mean age of 35 years (SD=2.11). Self-reports on perfectionism (using the Frost Multidimensional Perfectionism Scale), weight, height, desired weight, and current and ideal figural stimuli were analysed for the current study. Two measures of body dissatisfaction were utilised: discrepancy between the current and desired weight, and discrepancy between the current and ideal figural stimuli. RESULTS: Linear regressions controlling for current body mass index (BMI)/current silhouette examined the relationship between desired BMI/silhouette and simultaneous entry of the 6 subscales of the perfectionism measure. A lower desired BMI was associated with higher levels of Concern over Mistakes and Organisation, and a smaller ideal silhouette was associated with higher levels of Concern over Mistakes and Doubt about Actions and Organisation. CONCLUSIONS: These findings confirm the pertinence of different dimensions of perfectionism to body dissatisfaction, and suggest avenues to explore in terms of universal prevention work. PMID- 24764522 TI - Perioperative acute kidney injury. AB - Acute kidney injury (AKI) is a serious complication in the perioperative period, and is consistently associated with increased rates of mortality and morbidity. Two major consensus definitions have been developed in the last decade that allow for easier comparison of trial evidence. Risk factors have been identified in both cardiac and general surgery and there is an evolving role for novel biomarkers. Despite this, there has been no real change in outcomes and the mainstay of treatment remains preventive with no clear evidence supporting any therapeutic intervention as yet. This review focuses on definition, risk factors, the emerging role of biomarkers and subsequent management of AKI in the perioperative period, taking into account new and emerging strategies. PMID- 24764526 TI - Health and health-related quality of life among treatment-seeking overweight and obese adults: associations with internalized weight bias. AB - BACKGROUND: Weight bias is widespread and has numerous harmful consequences. The internalization of weight bias has been associated with significant psychological impairment. Other forms of discrimination, such as racial and anti-gay bias, have been shown to be associated with physical health impairment. However, research has not yet examined whether internalized weight bias is associated with physical as well as psychological impairment in health-related quality of life. METHODS: Participants included 120 treatment-seeking overweight and obese adults (mean body mass index = 35.09; mean age = 48.31; 68% female; 59% mixed or Asian ethnicity). Participants were administered measures of internalized weight bias and physical and mental health-related quality of life, and they were assessed for the presence of chronic medical conditions, use of prescription and non prescription medications, and current exercise. RESULTS: Internalized weight bias was significantly correlated with health impairment in both physical (r = -.25) and mental (r = -.48) domains. In multivariate analyses controlling for body mass index, age, and other physical health indicators, internalized weight bias significantly and independently predicted impairment in both physical (beta = .31) and mental (beta = -.47) health. CONCLUSIONS: Internalized weight bias was associated with greater impairment in both the physical and mental domains of health-related quality of life. Internalized weight bias also contributed significantly to the variance in physical and mental health impairment over and above the contributions of BMI, age, and medical comorbidity. Consistent with the association between prejudice and physical health in other minority groups, these findings suggest a link between the effects of internalized weight-based discrimination and physical health. Research is needed on strategies to prevent weight bias and its internalization on both a societal and individual level. PMID- 24764527 TI - Publications on cross-cultural aspects of eating disorders. AB - BACKGROUND: The prevalence of eating disorders in the non-Western world appears to be increasing and much research into the cross-cultural aspects of eating disorders is needed. This bibliometric study analyses the profile of cross cultural studies into eating disorders published from 1970 through to 2011. RESULTS: 1,417 articles were indexed by Medline and PsychInfo from 1970 to 2011. There has been an exponential increase in publications in this field. Four articles were published in 1970-74 and this increased to 427 in 2004-9. Comparative and empirical studies were the most common types of publications. Of all the ethnic groups studied, Africans and African Americans were subject of the most publications. Pacific Islanders and South Europeans had the fewest publications. CONCLUSION: It is heartening that there has been a large increase in published studies about eating disorders across cultures. This suggests greater awareness and interest in the field. However, the results from one particular ethnic group cannot always be applied directly to another. Some ethnic and cultural groups have been poorly studied and warrant more research attention. As more patients from such backgrounds present for treatment, more research is needed to provide culturally appropriate and acceptable care. PMID- 24764528 TI - Stigmatizing attitudes towards individuals with anorexia nervosa: an investigation of attribution theory. AB - BACKGROUND: Guided by Attribution Theory, this study assessed stigmatizing attitudes towards an individual with anorexia nervosa (AN) compared to obesity and skin cancer, and examined the extent to which manipulating a target individual's level of blameworthiness affects levels of stigmatizing attitudes. One hundred and thirty-five female undergraduate students were randomly assigned to one of three conditions. Before and after receiving blameworthy or non blameworthy information relating to the target's condition, participants completed a series of self-report inventories measuring their emotional reactions, desire for social distance, and causal attributions regarding the target. RESULTS: Participants reported a significantly greater desire for social distance from the target with AN compared to targets with obesity or skin cancer, and yet (contrary to Attribution Theory) attributed less blame to the target with AN. There were significant increases in stigmatization towards targets described as blameworthy relative to targets described as non-blameworthy. CONCLUSION: The findings provide insight into the elevated levels of stigmatizing attitudes held towards individuals with AN, and the role of Attribution Theory in partially accounting for this stigma. PMID- 24764529 TI - I'm not just fat, I'm old: has the study of body image overlooked "old talk"? AB - BACKGROUND: Research indicates that body dissatisfaction is correlated with and often predictive of both physical and mental health problems. "Fat talk," a well studied form of body image talk in adolescents and university-aged women, has been implicated as contributing to body dissatisfaction and mediating the relationship between body dissatisfaction and other mental health problems. Limited research, however, has investigated fat talk across the female lifespan. Further, consistent with most body image research, fat talk research solely focuses on the thin dimension of idealized female attractiveness, even though other dimensions may contribute to body dissatisfaction in women. METHOD: The current study investigated whether or not "old talk," a hereto un-described form of body image talk, appears to be a parallel, but distinct, form of body image talk that taps into the young dimension of the thin-young-ideal standard of female beauty. An international, internet sample of women (aged 18-87, N = 914) completed questionnaires aimed at assessing fat talk, old talk, body image disturbance, and eating disorder pathology. RESULTS: Results indicated that both fat talk and old talk were reported by women across the lifespan, although they evidenced different trajectories of frequency. Like fat talk, old talk was significantly correlated with body image disturbance and eating disorder pathology, albeit at a lower rate than fat talk in the total sample. Old talk was more highly correlated with ageing appearance anxiety than fat talk, and the correlation between old talk and body image disturbance and ED pathology increased with women's ages. CONCLUSION: Results suggest that old talk is a form of body image talk that is related to but distinct from fat talk. Old talk appears to be similarly problematic to fat talk for women whose age increases their deviation from the thin-young-ideal. Further research into the phenomenon of old talk is warranted as is increased attention to fat talk across the full lifespan of women. PMID- 24764530 TI - Measuring eating disorder attitudes and behaviors: a reliability generalization study. AB - BACKGROUND: Although score reliability is a sample-dependent characteristic, researchers often only report reliability estimates from previous studies as justification for employing particular questionnaires in their research. The present study followed reliability generalization procedures to determine the mean score reliability of the Eating Disorder Inventory and its most commonly employed subscales (Drive for Thinness, Bulimia, and Body Dissatisfaction) and the Eating Attitudes Test as a way to better identify those characteristics that might impact score reliability. METHODS: Published studies that used these measures were coded based on their reporting of reliability information and additional study characteristics that might influence score reliability. RESULTS: Score reliability estimates were included in 26.15% of studies using the EDI and 36.28% of studies using the EAT. Mean Cronbach's alphas for the EDI (total score = .91; subscales = .75 to .89), EAT-40 (total score = .81) and EAT-26 (total score = .86; subscales = .56 to .80) suggested variability in estimated internal consistency. Whereas some EDI subscales exhibited higher score reliability in clinical eating disorder samples than in nonclinical samples, other subscales did not exhibit these differences. Score reliability information for the EAT was primarily reported for nonclinical samples, making it difficult to characterize the effect of type of sample on these measures. However, there was a tendency for mean score reliability to be higher in the adult (vs. adolescent) samples and in female (vs. male) samples. CONCLUSIONS: Overall, this study highlights the importance of assessing and reporting internal consistency during every test administration because reliability is affected by characteristics of the participants being examined. PMID- 24764532 TI - Call for an urgent rethink of the 'health at every size' concept. PMID- 24764531 TI - PreDictor Research in Obesity during Medical care - weight Loss in children and adolescents during an INpatient rehabilitation: rationale and design of the DROMLIN study. AB - BACKGROUND: Obesity in adults and children is increasing worldwide at alarming rates. Obese children and adolescents are likely to become obese adults with increased risk of a number of comorbidities. In addition to preventing the development of obesity at young age, it is necessary to individualize the therapy of already obese children and adolescents in order to increase the likelihood of weight loss and maintenance. Therefore, the aim of this study is to identify predictors which play a significant role in successful weight loss and weight loss maintenance in children and adolescents. METHODS/DESIGN: Over a one year period, 60 obese children and adolescents between 9 to 17 years of age shall be recruited at an inpatient children rehabilitation facility in Germany. They will be investigated twice within a few days following admission and prior to discharge. The study will be an integrated component of an established inpatient weight-loss and in part psychosomatic therapy. The collected data can be grouped into four clusters: 1) demographic, sociometric and psychometric data, 2) objective and subjective parameters of body condition, 3) autonomic nervous system regulated functions and 4) objective and subjective parameters for eating behavior. Primary outcome is the change of the body mass index standard deviation score (BMI-SDS). In order to evaluate the data appropriately, all examinations will be also conducted in a normal-weight reference group, matched for age and gender. DISCUSSION: For some of the collected parameters the time span between measures may be too short. Therefore, a 6 months, 1 year and 2 year follow-up will be performed for evaluating the different predictors and their influence in regard to a successful intervention. Further middle- and long-term follow-up studies are planned. TRIAL REGISTRATION: The study protocol was approved by the Ethics Committee of the University Hospital Tubingen, Germany. This study is registered at the German Clinical Trials Register (DRKS) with the clinical trial number DRKS00005122. PMID- 24764533 TI - Presence of antigen-specific somatic allelic mutations and splice variants do not predict for immunological response to genetic vaccination. AB - BACKGROUND: Antigen-specific anti-tumor vaccines have demonstrated clinical efficacy, but immunological and clinical responses appear to be patient dependent. We hypothesized that naturally-occurring differences in amino acid sequence of a host's target antigen might predict for immunological outcome from genetic vaccination by presentation of epitopes different from the vaccine. METHODS: Using peripheral blood cells from 33 patients who had been treated with a DNA vaccine encoding prostatic acid phosphatase (PAP), we sequenced the exons encoding PAP and PSA genes from somatic DNA to identify single nucleotide polymorphisms. In addition, mRNA was collected to detect alternative splice variants of PAP. RESULTS: We detected four synonymous coding mutations of PAP among 33 patients; non-synonymous coding mutations were not identified. Alternative splice variants of PAP were detected in 22/27 patients tested. The presence of detectable splice variants was not predictive of immunological outcome from vaccination. Immune responses to peptides encoded by these splice variants were common (16/27) prior to immunization, but not associated with immune responses elicited with vaccination. CONCLUSIONS: These results suggest that antigen-specific immune responses detectable after treatment with this genetic vaccine are specific for the host-encoded antigen and not due to epitope differences between the vaccine and a particular individual's somatic coding sequence. PMID- 24764534 TI - Essential complicity of perforin-granzyme and FAS-L mechanisms to achieve tumor rejection following treatment with anti-CD137 mAb. AB - BACKGROUND: Treatment with agonist anti-CD137 (4-1BB) immunostimulatory monoclonal antibodies elicits complete tumor regressions in a number of transplanted hematological and solid malignancies in mice. Rejection is mainly dependent on cytotoxic T lymphocytes (CTL) and IFNgamma, although a role for NK cells and dendritic cells has been observed in some tumor models. Rejection of EG7-derived thymomas has been shown to be CTL-dependent but not NK-dependent. FINDINGS: In this therapeutic setting, we show that both the perforin-granzyme and FasL effector systems are readily expressed by CD8(+) T lymphocytes infiltrating the EG7 lymphomas which are undergoing rejection. Using knock-out mice, we demonstrate that both effector cytolytic systems are involved in the execution of complete immune rejections against EG7 established tumors. In accordance, EG7 tumor cells were susceptible in vitro to both killing mechanisms acting in a synergistic fashion. CONCLUSIONS: CD137-elicited rejection of EG7 derived tumors involves the interplay of at least two final effector cytolytic mechanisms that act in cooperation. PMID- 24764535 TI - Regulation of immunotherapeutic products for cancer and FDA's role in product development and clinical evaluation. AB - Immunotherapeutics include drugs and biologics that render therapeutic benefit by harnessing the power of the immune system. The promise of immune-mediated therapies is target specificity with a consequent reduction in off-target side effects. Recent scientific advances have led to clinical trials of both active and passive immunotherapeutic products that have the potential to convert life ending diseases into chronic but manageable conditions. Clinical trials investigating immunotherapeutics are ongoing with some trials at advanced stages of development. However, as with many products involving novel mechanisms of action, major regulatory and scientific issues arising with clinical use of immunotherapeutic products remain to be addressed. In this review, we address issues related to different immunotherapeutics and provide recommendations for the characterization and evaluation of these products during various stages of product and clinical development. PMID- 24764536 TI - Southern Med Review to Journal of Pharmaceutical Policy and Practice: broadening the remit! PMID- 24764537 TI - Assessment of the therapeutic value of new medicines marketed in Australia. AB - BACKGROUND: The belief that all new medicines bring a therapeutic innovation and better health outcomes is widely shared among the public, health professionals and policy makers. OBJECTIVES: To examine the therapeutic value of new medicines marketed in Australia using two classification systems. METHODS: The therapeutic value of new medicines was categorised using the Motola's s and the Ahlqvist Rastad's systems for all approvals made by the Australian Therapeutics Goods Administration (TGA) between 2005 and 2007. Scores were assigned independently by the three authors on the basis of the Public Summary Documents and Prescrire' review articles. RESULTS: Overall, 217 approval recommendations were made including 81 (37.3%) for new indications and 69 (31.8%) for new medicines. In Motola's rating system, 31 (52.5%) of the 59 drugs were rated as pharmacological or technological innovations and 28 (47.5%) were rated as therapeutic innovations. Only seven of the 59 drugs (11.9%) were rated as important innovations. In Ahlqvist-Rastad's system, only a third of the new drugs were rated as "added therapeutic value". CONCLUSION: Only a minority of the new medicines marketed in Australia provide added therapeutic value compared to existing treatments. Stricter regulatory approval criteria would ensure better safety of the public and simplify the reimbursement processes. PMID- 24764538 TI - Evaluating patients' perceptions regarding generic medicines in Jordan. AB - OBJECTIVE: The aim of this study was to explore Jordanian patients' perceptions toward generic medicines and to evaluate their opinions regarding generic substitution. METHOD: A cross-sectional descriptive study involving Jordanian patients was undertaken, using a self-administrated anonymous questionnaire. The response rate was 80% (n=400/500). RESULTS: The study showed that cost of medicines is high according to 83% of the patients. Most patients (92%) preferred to be prescribed the cheapest medicine. Majority of patients (79%) believed that cost should be considered before a drug is prescribed. Most patients (78%) accepted generic substitution and believed that it can provide significant saving. Surveyed patients (78%) agreed that they should have the option of choosing between generic and originator and 74% believed that physicians should give them that choice. These results showed a significant statistical correlation with the monthly income of the patient, percentage cost they pay and number of medicines prescribed (P<0.05). CONCLUSION: The high cost of medicines in Jordan is believed to be the main driver for choosing generic medicines Furthermore; patients have positive attitudes towards generic medicines. The involvement of patients in the treatment decision would result in more adherence and improvement in health. The insights gained from patients in this study will be useful to health organisations and policy makers to design a robust generic policy to use medicines cost-effectively in Jordan. PMID- 24764539 TI - Antimicrobial sensitivity patterns of cerebrospinal fluid (CSF) isolates in Namibia: implications for empirical antibiotic treatment of meningitis. AB - OBJECTIVE: Bacterial meningitis is a medical emergency associated with high mortality rates. Cerebrospinal fluid (CSF) culture is the "gold standard" for diagnosis of meningitis and it is important to establish the susceptibility of the causative microorganism to rationalize treatment. The Namibia Standard Treatment Guidelines (STGs) recommends initiation of empirical antibiotic treatment in patients with signs and symptoms of meningitis after taking a CSF sample for culture and sensitivity. The objective of this study was to assess the antimicrobial sensitivity patterns of microorganisms isolated from CSF to antibiotics commonly used in the empirical treatment of suspected bacterial meningitis in Namibia. METHODS: This was a cross-sectional descriptive study of routinely collected antibiotic susceptibility data from the Namibia Institute of Pathology (NIP) database. Results of CSF culture and sensitivity from January 1, 2009 to May 31, 2012, from 33 state hospitals throughout Namibia were analysed. RESULTS: The most common pathogens isolated were Streptococcus species, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus, and Escherichia coli. The common isolates from CSF showed high resistance (34.3% -73.5%) to penicillin. Over one third (34.3%) of Streptococcus were resistance to penicillin which was higher than 24.8% resistance in the United States. Meningococci were susceptible to several antimicrobial agents including penicillin. The sensitivity to cephalosporins remained high for Streptococcus, Neisseria, E. coli and Haemophilus. The highest percentage of resistance to cephalosporins was seen among ESBL K. pneumoniae (n = 7, 71%-100%), other Klebsiella species (n = 7, 28% 80%), and Staphylococcus (n = 36, 25%-40%). CONCLUSIONS: The common organisms isolated from CSF were Streptococcus Pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Staphylococcus, and E. coli. All common organisms isolated from CSF showed high sensitivity to cephalosporins used in the empirical treatment of meningitis. The resistance of the common isolates to penicillin is high. Most ESBL K. pneumoniae were isolated from CSF samples drawn from neonates and were found to be resistant to the antibiotics recommended in the Namibia STGs. Based on the above findings, it is recommended to use a combination of aminoglycoside and third-generation cephalosporin to treat non-ESBL Klebsiella isolates. Carbapenems (e.g., meropenem) and piperacillin/tazobactam should be considered for treating severely ill patients with suspected ESBL Klebsiella infection. Namibia should have a national antimicrobial resistance surveillance system for early detection of antibiotics that may no longer be effective in treating meningitis and other life-threatening infections due to resistance. PMID- 24764541 TI - Access to antibiotics in New Delhi, India: implications for antibiotic policy. AB - OBJECTIVE: The present survey was conducted to investigate the price and availability of a basket of 24 essential antibiotics and eight high-end antibiotics at various levels of health care in public and private sector in National Capital Territory of Delhi, India using standardized WHO/HAI methodology. METHODS: DATA ON PROCUREMENT PRICE AND AVAILABILITY WAS COLLECTED FROM THREE PUBLIC HEALTHCARE PROVIDERS IN THE STATE: the federal (central) government, state government and Municipal Corporation of Delhi (MCD). Overall a total of 83 public facilities, 68 primary care, 10 secondary cares and 5 tertiary care facilities were surveyed. Data was also collected from private retail (n = 40) and chain pharmacies (n = 40) of a leading corporate house. Prices were compared to an international reference price (expressed as median price ratio MPR). RESULTS: PUBLIC SECTOR: Delhi state government has its essential medicine list (Delhi state EML) and was using Delhi state EML 2007 for procurement; the other two agencies had their own procurement list. All the antibiotics procured including second and third generation antibiotics except for injections were available at primary care facilities. Antibiotic available were on the basis of supply rather than rationality or the Delhi state EML and none was 100% available. There was sub-optimal availability of some essential antibiotics while other non-essential ones were freely available. Availability of antibiotics at tertiary care facilities was also sub-optimal. Private sector: Availability of antibiotics was good. For most of the antibiotics the most expensive and popular trade names were often available. High-end antibiotics, meropenam, gemifloxacin, and moxifloxacin were commonly available. In retail pharmacies some newer generation non-essential antibiotics like gemifloxacin were priced lower than the highest-priced generic of amoxicillin + clavulanic acid, azithromycin, and cefuroxime aexitl. CONCLUSIONS: Inappropriate availability and pricing of newer generation antibiotics, which may currently be bought without prescription, is likely to lead to their over-use and increased resistance. All providers should follow the EML of whichever of the three concerned Delhi public sector agencies that it is under and these EMLs should follow the essential medicine concept. The Indian regulatory authorities need to consider urgently, drug schedules and pricing policies that will curtail inappropriate access to new generation antibiotics. PMID- 24764540 TI - National medicines policies - a review of the evolution and development processes. AB - OBJECTIVES: Continuous provision of appropriate medicines of assured quality, in adequate quantities, and at reasonable prices is a concern for all national governments. A national medicines policy (NMP) developed in a collaborative fashion identifies strategies needed to meet these objectives and provides a comprehensive framework to develop all components of a national pharmaceutical sector. To meet the health needs of the population, there is a general need for medicine policies based on universal principles, but nevertheless adapted to the national situation. This review aims to provide a quantitative and qualitative (describing the historical development) study of the development process and evolution of NMPs. METHODS: The number of NMPs and their current status has been obtained from the results of the assessment of WHO Level I indicators. The policy formulation process is examined in more detail with case studies from four countries: Sri Lanka, Australia, former Yugoslav Republic of Macedonia and South Africa. RESULTS: The number of NMPs worldwide has increased in the last 25 years with the highest proportional increase in the last 5-10 years in high-income countries. Higher income countries seem to have more NMP implementation plans available and have updated their NMP more recently. The four case studies show that the development of a NMP is a complex process that is country specific. In addition, it demonstrates that an appropriate political window is needed for the policy to be passed (for South Africa and the FYR Macedonia, a major political event acted as a trigger for initiating the policy development). Policy-making does not stop with the official adoption of a policy but should create mechanisms for implementation and monitoring. The NMPs of the FYR Macedonia and Australia provide indicators for monitoring. CONCLUSIONS: To date, not all countries have a NMP since political pressure by national experts or non-governmental organizations is generally needed to establish a NMP. Case studies in four countries showed that the policy process is just as important as the policy document since the process must create a mechanism by which all stakeholders are brought together and a sense of collective ownership of the final policy may be achieved. PMID- 24764542 TI - Converting non-metallic printed circuit boards waste into a value added product. AB - The aim of this study was to investigate the feasibility of using nonmetallic printed circuit board (PCB) waste as filler in recycled HDPE (rHDPE) in production of rHDPE/PCB composites. Maleic anhydride modified linear low-density polyethylene (MAPE) was used as compatibilizer. In particular, the effects of nonmetallic PCB and MAPE on mechanical properties of the composites were assessed through tensile, flexural and impact testing. Scanning electron microscope (SEM) was used to study the dispersion of nonmetallic PCB and MAPE in the matrix. Nonmetallic PCB was blended with rHDPE from 0-30 wt% and prepared by counter rotating twin screw extruder followed by molding into test samples via hot press for analysis. A good balance between stiffness, strength and toughness was achieved for the system containing 30 wt% PCB. Thus, this system was chosen in order to investigate the effect of the compatibilizer on the mechanical properties of the composites. The results indicate that MAPE as a compatiblizer can effectively promote the interfacial adhesion between nonmetallic PCB and rHDPE. The addition of 6 phr MAPE increased the flexural strength, tensile strength and impact strength by 71%, 98% and 44% respectively compared to the uncompatibilized composites. PMID- 24764543 TI - Associations between common mental disorders and sexual dissatisfaction in the general population. AB - BACKGROUND: Little is known about the associations between common mental disorders and sexual dissatisfaction in the general population. AIMS: To assess the associations between the presence of 12-month and remitted (lifetime minus 12 month) mood, anxiety and substance use disorders and sexual dissatisfaction in the general population of The Netherlands. METHOD: A total of 6646 participants, aged 18-64, took part in a face-to-face survey using the Composite International Diagnostic Interview 3.0. Childhood trauma, somatic disorders and sexual dissatisfaction were also assessed in an additional questionnaire. Associations were assessed with multivariate regression analyses. RESULTS: In total, 29% reported some sexual dissatisfaction. Controlling for demography, somatic disorders and childhood trauma, significant associations with 12-month mood disorder (B = 0.31), substance use disorder (B = 0.23) and anxiety disorder (B = 0.16) were found. Specifically, relatively strong associations were found for alcohol dependence (B = 0.54), bipolar disorder (B = 0.45) and drug dependence (B = 0.44). The association between remitted disorders and sexual dissatisfaction showed significance for the category substance use disorder. CONCLUSIONS: People with mood, anxiety and substance use disorders show elevated scores on sexual dissatisfaction, even when relevant confounders are controlled for. Sexual satisfaction appears to be reduced most by alcohol and drug dependence and bipolar disorder. Once remitted, substance use disorder shows a persisting association with present sexual dissatisfaction. PMID- 24764544 TI - Impact of depressive episodes on cognitive deficits in early bipolar disorder: data from the Systematic Treatment Optimization Programme for Early Mania (STOP EM). AB - BACKGROUND: Although manic episodes reportedly contribute to cognitive deficits in bipolar I disorder, the contribution of depressive episodes is poorly researched. AIMS: We investigated the impact of depressive episodes on cognitive function early in the course of bipolar I disorder. METHOD: A total of 68 patients and 38 controls from the Systematic Treatment Optimization Programme for Early Mania (STOP-EM) first-episode mania programme were examined. We conducted (a) a cross-sectional analysis of the impact of prior depressive episodes on baseline cognitive function and (b) a prospective analysis assessing the contribution of depression recurrence within 1 year following a first episode of mania on cognitive functioning. RESULTS: The cross-sectional analysis showed no significant differences between patients with past depressive episodes compared with those without, on overall or individual domains of cognitive function (all P>0.09). The prospective analysis failed to reveal a significant group*time interaction for cognitive decline from baseline to 1 year (P = 0.99) in patients with a recurrence of depressive episodes compared with those with no recurrence. However, impaired verbal memory at baseline was associated with a depression recurrence within 1 year. CONCLUSIONS: Although deficits in all domains of cognitive function are seen in patients early in the course of bipolar disorder, depressive episodes do not confer additional burden on cognitive function. However, poorer verbal memory may serve as a marker for increased susceptibility to depression recurrence early in the course of illness. PMID- 24764545 TI - Developmental pathways from childhood conduct problems to early adult depression: findings from the ALSPAC cohort. AB - BACKGROUND: Pathways from early-life conduct problems to young adult depression remain poorly understood. AIMS: To test developmental pathways from early-life conduct problems to depression at age 18. METHOD: Data (n = 3542) came from the Avon Longitudinal Study of Parents and Children (ALSPAC). Previously derived conduct problem trajectories (ages 4-13 years) were used to examine associations with depression from ages 10 to 18 years, and the role of early childhood factors as potential confounders. RESULTS: Over 43% of young adults with depression in the ALSPAC cohort had a history of child or adolescent conduct problems, yielding a population attributable fraction of 0.15 (95% CI 0.08-0.22). The association between conduct problems and depression at age 18 was considerable even after adjusting for prior depression (odds ratio 1.55, 95% CI 1.24-1.94). Early-onset persistent conduct problems carried the highest risk for later depression. Irritability characterised depression for those with a history of conduct problems. CONCLUSIONS: Early-life conduct problems are robustly associated with later depressive disorder and may be useful targets for early intervention. PMID- 24764546 TI - Brain-derived neurotrophic factor levels and bipolar disorder in patients in their first depressive episode: 3-year prospective longitudinal study. AB - BACKGROUND: Early identification of patients with bipolar disorder during their first depressive episode is beneficial to the outcome of the disorder and treatment, but traditionally this has been a great challenge to clinicians. Recently, brain-derived neurotrophic factor (BDNF) has been suggested to be involved in the pathophysiology of bipolar disorder and major depressive disorder (MDD), but it is not clear whether BDNF levels can be used to predict bipolar disorder among patients in their first major depressive episode. AIMS: To explore whether BDNF levels can differentiate between MDD and bipolar disorder in the first depressive episode. METHOD: A total of 203 patients with a first major depressive episode as well as 167 healthy controls were recruited. After 3 years of bi-annual follow-up, 164 patients with a major depressive episode completed the study, and of these, 21 were identified as having bipolar disorder and 143 patients were diagnosed as having MDD. BDNF gene expression and plasma levels at baseline were compared among the bipolar disorder, MDD and healthy control groups. Logistic regression and decision tree methods were applied to determine the best model for predicting bipolar disorder at the first depressive episode. RESULTS: At baseline, patients in the bipolar disorder and MDD groups showed lower BDNF mRNA levels (P<0.001 and P = 0.02 respectively) and plasma levels (P = 0.002 and P = 0.01 respectively) compared with healthy controls. Similarly, BDNF levels in the bipolar disorder group were lower than those in the MDD group. These results showed that the best model for predicting bipolar disorder during a first depressive episode was a combination of BDNF mRNA levels with plasma BDNF levels (receiver operating characteristics (ROC) = 0.80, logistic regression; ROC = 0.84, decision tree). CONCLUSIONS: Our findings suggest that BDNF levels may serve as a potential differential diagnostic biomarker for bipolar disorder in a patient's first depressive episode. PMID- 24764548 TI - The fight against doping is a fight for the protection of the clean athlete, the health of the athlete and the integrity of sport. PMID- 24764547 TI - Designing clinical trials in trauma surgery: overcoming research barriers. AB - The surgical community is plagued with a reputation for both failing to engage and to deliver on clinical research. This is in part due to the absence of a strong research culture, however it is also due to a multitude of barriers encountered in clinical research; particularly those involving surgical interventions. 'Trauma' amplifies these barriers, owing to the unplanned nature of care, unpredictable work patterns, the emergent nature of treatment and complexities in the consent process. This review discusses the barriers to clinical research in surgery, with a particular emphasis on trauma. It considers how barriers may be overcome, with the aim to facilitate future successful clinical research. Cite this article: Bone Joint Res 2014;3:123-9. PMID- 24764549 TI - Drawing the map to implement the 2015 World Anti-Doping Code. PMID- 24764551 TI - Challenges and threats to implementing the fight against doping in sport. AB - Prominent doping cases in certain sports have recently raised public awareness of doping and reinforced the perception that doping is widespread. Efforts to deal with doping in sport have intensified in recent years, yet the general public believes that the 'cheaters' are ahead of the testers. Therefore, there is an urgent need to change the antidoping strategy. For example, the increase in the number of individual drug tests conducted between 2005 and 2012 was approximately 90 000 and equivalent to an increase of about 50%, yet the number of adverse analytical findings remained broadly the same. There is also a strikingly different prevalence of doping substances and methods in sports such as a 0.03% prevalence of anabolic steroids in football compared to 0.4% in the overall WADA statistics. Future efforts in the fight against doping should therefore be more heavily based on preventative strategies such as education and on the analysis of data and forensic intelligence and also on the experiences of relevant stakeholders such as the national antidoping organisations, the laboratories, athletes or team physicians and related biomedical support staff. This strategy is essential to instigate the change needed to more effectively fight doping in sport. PMID- 24764550 TI - Time for change: a roadmap to guide the implementation of the World Anti-Doping Code 2015. AB - A medical and scientific multidisciplinary consensus meeting was held from 29 to 30 November 2013 on Anti-Doping in Sport at the Home of FIFA in Zurich, Switzerland, to create a roadmap for the implementation of the 2015 World Anti Doping Code. The consensus statement and accompanying papers set out the priorities for the antidoping community in research, science and medicine. The participants achieved consensus on a strategy for the implementation of the 2015 World Anti-Doping Code. Key components of this strategy include: (1) sport specific risk assessment, (2) prevalence measurement, (3) sport-specific test distribution plans, (4) storage and reanalysis, (5) analytical challenges, (6) forensic intelligence, (7) psychological approach to optimise the most deterrent effect, (8) the Athlete Biological Passport (ABP) and confounding factors, (9) data management system (Anti-Doping Administration & Management System (ADAMS), (10) education, (11) research needs and necessary advances, (12) inadvertent doping and (13) management and ethics: biological data. True implementation of the 2015 World Anti-Doping Code will depend largely on the ability to align thinking around these core concepts and strategies. FIFA, jointly with all other engaged International Federations of sports (Ifs), the International Olympic Committee (IOC) and World Anti-Doping Agency (WADA), are ideally placed to lead transformational change with the unwavering support of the wider antidoping community. The outcome of the consensus meeting was the creation of the ad hoc Working Group charged with the responsibility of moving this agenda forward. PMID- 24764552 TI - Blood doping: potential of blood and urine sampling to detect autologous transfusion. AB - The collection of blood, its storage as red blood cell (RBC) concentrates and its reinjection is prohibited; until now, the practice cannot be reliably detected. A recent innovation-the haematological module of the athlete's biological passport can provide authorities with indications towards autologous blood transfusion. In situations where a given athlete has been exposed to altitude, heat stress, sickness, etc, additional evidence may be needed to establish beyond any reasonable doubt that a blood transfusion may actually have occurred. Additional evidence may be obtained from at least three different approaches using parameters related to blood and urine matrices.Genomics applied to mRNA or miRNA is one of the most promising analytical tools. Proteomics of changes associated with RBC membranes may reveal the presence of cells stored for some time, as can an abnormal pattern of size distribution of aged cells. In urine, high concentrations of metabolites of plasticisers originating from the blood storing bags strongly suggest a recent blood transfusion. We emphasise the usefulness of simultaneously obtaining and then analysing blood and urine for complementary evidence of autologous blood transfusion ('blood doping'). PMID- 24764555 TI - Deep sequencing blood transcriptomes. PMID- 24764553 TI - Confounding factors and genetic polymorphism in the evaluation of individual steroid profiling. AB - In the fight against doping, steroid profiling is a powerful tool to detect drug misuse with endogenous anabolic androgenic steroids. To establish sensitive and reliable models, the factors influencing profiling should be recognised. We performed an extensive literature review of the multiple factors that could influence the quantitative levels and ratios of endogenous steroids in urine matrix. For a comprehensive and scientific evaluation of the urinary steroid profile, it is necessary to define the target analytes as well as testosterone metabolism. The two main confounding factors, that is, endogenous and exogenous factors, are detailed to show the complex process of quantifying the steroid profile within WADA-accredited laboratories. Technical aspects are also discussed as they could have a significant impact on the steroid profile, and thus the steroid module of the athlete biological passport (ABP). The different factors impacting the major components of the steroid profile must be understood to ensure scientifically sound interpretation through the Bayesian model of the ABP. Not only should the statistical data be considered but also the experts in the field must be consulted for successful implementation of the steroidal module. PMID- 24764556 TI - Dangerous power: mitochondria in CLL cells. PMID- 24764557 TI - Podosomes are disrupted in PAPA syndrome. PMID- 24764558 TI - Eliminate dark side from antiplatelet therapy. PMID- 24764559 TI - Decrypting C2 inhibitors. PMID- 24764560 TI - Rituximab maintenance obviates the poor prognosis associated with circulating lymphoma cells in patients with follicular lymphoma. PMID- 24764561 TI - PLZF staining identifies peripheral T-cell lymphomas derived from innate-like T cells with TRAV1-2-TRAJ33 TCR-alpha rearrangement. PMID- 24764562 TI - Somatic mutations in calreticulin can be found in pedigrees with familial predisposition to myeloproliferative neoplasms. PMID- 24764563 TI - Physical activity limits pulmonary endothelial activation in sickle cell SAD mice. PMID- 24764565 TI - How I treat renal complications in sickle cell disease. AB - Renal disease is one of the most frequent and severe complications experienced by patients with sickle cell disease; its prevalence is likely to increase as the patient population ages. We recommend regular monitoring for early signs of renal involvement and a low threshold for the use of hydroxyurea as preventative measures for end-stage renal disease. Once renal complications are detected, a careful assessment of the patient is required to rule out other causes of renal disease. Proteinuria and hypertension should be managed aggressively and the patient referred to a specialist nephrology center when progressive decline in renal function is noted. For the few patients who develop advanced chronic kidney disease, timely planning for dialysis and transplantation can significantly improve outcome, and we recommend an exchange blood transfusion policy for all patients on the transplant waiting list and for those with a functioning graft. Alongside the invasive treatment regimes, it is important to remember that renal failure in conjunction with sickle cell disease does carry a significant burden of morbidity and that focusing on symptom control has to be central to good patient care. PMID- 24764566 TI - NHS should be exempt from EU-US free trade treaty, campaigners say. PMID- 24764564 TI - Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. AB - Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9-driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts. PMID- 24764567 TI - Deaths from pancreatic cancer in Europe continue to increase while rates for other cancers fall. PMID- 24764568 TI - The safety of incretin based drugs. PMID- 24764570 TI - A man with a palpable abdominal mass and night sweats. PMID- 24764569 TI - Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study. AB - OBJECTIVES: To determine whether the use of incretin based drugs, compared with sulfonylureas, is associated with an increased risk of acute pancreatitis. DESIGN: Population based cohort study. SETTING: 680 general practices in the United Kingdom contributing to the Clinical Practice Research Datalink. PARTICIPANTS: From 1 January 2007 to 31 March 2012, 20 748 new users of incretin based drugs were compared with 51 712 users of sulfonylureas and followed up until 31 March 2013. MAIN OUTCOME MEASURES: Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for acute pancreatitis in users of incretin based drugs compared with users of sulfonylureas. Models were adjusted for tenths of high dimensional propensity score (hdPS). RESULTS: The crude incidence rate for acute pancreatitis was 1.45 per 1000 patients per year (95% confidence interval 0.99 to 2.11) for incretin based drug users and 1.47 (1.23 to 1.76) for sulfonylurea users. The rate of acute pancreatitis associated with the use of incretin based drugs was not increased (hdPS adjusted hazard ratio: 1.00, 95% confidence interval 0.59 to 1.70) relative to sulfonylurea use. CONCLUSIONS: Compared with use of sulfonylureas, the use of incretin based drugs is not associated with an increased risk of acute pancreatitis. While this study is reassuring, it does not preclude a modest increased risk, and thus additional studies are needed to confirm these findings. PMID- 24764571 TI - Cancer care team. PMID- 24764572 TI - FDA chief defends Zohydro approval as US states rebel. PMID- 24764574 TI - Cancer immunology essentials: a preface. PMID- 24764573 TI - Are patients with Parkinson's disease blind to blindsight? AB - In Parkinson's disease, visual dysfunction is prominent. Visual hallucinations can be a major hallmark of late stage disease, but numerous visual deficits also occur in early stage Parkinson's disease. Specific retinopathy, deficits in the primary visual pathway and the secondary ventral and dorsal pathways, as well as dysfunction of the attention pathways have all been posited as causes of hallucinations in Parkinson's disease. We present data from patients with Parkinson's disease that contrast with a known neuro-ophthalmological syndrome, termed 'blindsight'. In this syndrome, there is an absence of conscious object identification, but preserved 'guess' of the location of a stimulus, preserved reflexive saccades and motion perception and preserved autonomical and expressive reactions to negative emotional facial expressions. We propose that patients with Parkinson's disease have the converse of blindsight, being 'blind to blindsight'. As such they preserve conscious vision, but show erroneous 'guess' localization of visual stimuli, poor saccades and motion perception, and poor emotional face perception with blunted autonomic reaction. Although a large data set on these deficits in Parkinson's disease has been accumulated, consolidation into one specific syndrome has not been proposed. Focusing on neuropathological and physiological data from two phylogenetically old and subconscious pathways, the retino-colliculo-thalamo-amygdala and the retino-geniculo-extrastriate pathways, we propose that aberrant function of these systems, including pathologically inhibited superior colliculus activity, deficient corollary discharges to the frontal eye fields, dysfunctional pulvinar, claustrum and amygdaloid subnuclei of the amygdala, the latter progressively burdened with Lewy bodies, underlie this syndrome. These network impairments are further corroborated by the concept of the 'silent amygdala'. Functionally being 'blind to blindsight' may facilitate the highly distinctive 'presence' or 'passage' hallucinations of Parkinson's disease and can help to explain handicaps in driving capacities and dysfunctional 'theory of mind'. We propose this synthesis to prompt refined neuropathological and neuroimaging studies on the pivotal nuclei in these pathways in order to better understand the networks underpinning this newly conceptualized syndrome in Parkinson's disease. PMID- 24764575 TI - The biology and medical implications of interleukin-6. AB - Cytokines are soluble mediators, which aid cell-to-cell communication in immune responses, and interleukin-6 (IL-6) is a prototypical cytokine featuring redundant and pleiotropic activity. The complete elucidation of the IL-6-mediated signal transduction system has provided a molecular basis for the characteristic features of cytokines. When tissue damage or inflammation due to infections or injuries occurs, IL-6 synthesis is promptly induced, contributing to the host defense through the stimulation of acute-phase immune reactions and hematopoiesis. The production of IL-6 is terminated when tissue homeostasis is restored. The synthesis of IL-6 is tightly regulated transcriptionally and posttranscriptionally. However, the dysregulated continual synthesis of IL-6 has been implicated in the development of various diseases, including autoimmune and chronic inflammatory diseases and cancers. Clinical trials using the humanized anti-IL-6 receptor monoclonal antibody tocilizumab have demonstrated the efficacy of IL-6 blockade for the treatment of refractory inflammatory diseases, such as rheumatoid arthritis, systemic juvenile idiopathic arthritis, and Castleman disease. Moreover, favorable results from the off-label use of tocilizumab strongly suggest that it may be applicable for the treatment of other refractory immune-mediated diseases, including cancer. Therefore, the mechanisms for the dysregulated synthesis of IL-6 need to be elucidated to understand the pathogenesis of the resultant diseases and to facilitate the development of effective therapeutic strategies. PMID- 24764576 TI - Oncolytic viruses and their application to cancer immunotherapy. AB - Oncolytic viruses (OV) selectively replicate and kill cancer cells and spread within the tumor, while not harming normal tissue. In addition to this direct oncolytic activity, OVs are also very effective at inducing immune responses to themselves and to the infected tumor cells. OVs encompass a broad diversity of DNA and RNA viruses that are naturally cancer selective or can be genetically engineered. OVs provide a diverse platform for immunotherapy; they act as in situ vaccines and can be armed with immunomodulatory transgenes or combined with other immunotherapies. However, the interactions of OVs with the immune system may affect therapeutic outcomes in opposing fashions: negatively by limiting virus replication and/or spread, or positively by inducing antitumor immune responses. Many aspects of the OV-tumor/host interaction are important in delineating the effectiveness of therapy: (i) innate immune responses and the degree of inflammation induced; (ii) types of virus-induced cell death; (iii) inherent tumor physiology, such as infiltrating and resident immune cells, vascularity/hypoxia, lymphatics, and stromal architecture; and (iv) tumor cell phenotype, including alterations in IFN signaling, oncogenic pathways, cell surface immune markers [MHC, costimulatory, and natural killer (NK) receptors], and the expression of immunosuppressive factors. Recent clinical trials with a variety of OVs, especially those expressing granulocyte macrophage colony stimulating factor (GM-CSF), have demonstrated efficacy and induction of antitumor immune responses in the absence of significant toxicity. Manipulating the balance between antivirus and antitumor responses, often involving overlapping immune pathways, will be critical to the clinical success of OVs. PMID- 24764577 TI - JAK2 expression is associated with tumor-infiltrating lymphocytes and improved breast cancer outcomes: implications for evaluating JAK2 inhibitors. AB - Janus kinase-2 (JAK2) supports breast cancer growth, and clinical trials testing JAK2 inhibitors are under way. In addition to the tumor epithelium, JAK2 is also expressed in other tissues including immune cells; whether the JAK2 mRNA levels in breast tumors correlate with outcomes has not been evaluated. Using a case control design, JAK2 mRNA was measured in 223 archived breast tumors and associations with distant recurrence were evaluated by logistic regression. The frequency of correct pairwise comparisons of patient rankings based on JAK2 levels versus survival outcomes, the concordance index (CI), was evaluated using data from 2,460 patients in three cohorts. In the case-control study, increased JAK2 was associated with a decreasing risk of recurrence (multivariate P = 0.003, n = 223). Similarly, JAK2 was associated with a protective CI (<0.5) in the public cohorts: NETHERLANDS CI = 0.376, n = 295; METABRIC CI = 0.462, n = 1,981; OSLOVAL CI = 0.452, n = 184. Furthermore, JAK2 was strongly correlated with the favorable prognosis LYM metagene signature for infiltrating T cells (r = 0.5; P < 2 * 10(-16); n = 1,981) and with severe lymphocyte infiltration (P = 0.00003, n = 156). Moreover, the JAK1/2 inhibitor ruxolitinib potently inhibited the anti-CD3 dependent production of IFN-gamma, a marker of the differentiation of Th cells along the tumor-inhibitory Th1 pathway. The potential for JAK2 inhibitors to interfere with the antitumor capacities of T cells should be evaluated. PMID- 24764578 TI - Apoptosis-regulated low-avidity cancer-specific CD8(+) T cells can be rescued to eliminate HER2/neu-expressing tumors by costimulatory agonists in tolerized mice. AB - A major barrier to vaccines in cancer treatment is their failure to activate and maintain a complete cancer-specific CD8(+) effector T-cell repertoire. Low avidity T cells are more likely to escape clonal deletion in the thymus when compared with high-avidity T cells, and therefore comprise the major population of effector T cells available for activation in patients with cancer. However, low-avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to high avidity T cells that escape clonal deletion and function in tumor killing. We used high- and low-avidity T-cell receptor transgenic CD8(+) T cells specific for the immunodominant epitope HER2/neu (RNEU420-429) to identify signaling pathways responsible for the inferior activity of the low-avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified the members of apoptosis pathways that are upregulated in low-avidity T cells. The increased expression of proapoptotic proteins by low-avidity T cells promoted their own cell death and also that of other tumor-specific CD8(+) T cells within their local environment. Importantly, we show that this proapoptotic effect can be overcome by using a strong costimulatory signal that prevents the activation induced cell death and enables the low-avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T-cell responses. PMID- 24764579 TI - PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection. AB - Programmed death-1 (PD-1) receptor is an inhibitory receptor on hematopoietic cells that can negatively regulate immune responses, particularly responses to tumors, which often upregulate PD-1 ligands. PD-1/PD-1 ligand blocking antibodies can reverse the inhibition and show significant therapeutic promise in treating renal cell carcinoma (RCC), lung cancer, and melanoma. While PD-1 expression on tumor-infiltrating lymphocytes has been associated with poor outcome in RCC, we sought to define immune cell biomarkers, including PD-1, on peripheral blood mononuclear cells (PBMC) that could predict disease progression of RCC patients before and after nephrectomy. We analyzed expression of numerous immune cell markers on fresh PBMCs from 90 RCC patients preoperatively and 25 age-matched healthy controls by 10-color flow cytometry. Postoperative blood samples were also analyzed from 23 members of the RCC patient cohort. The most striking phenotypic immune biomarker in RCC patients was a significant increase in PD-1 expression on certain PBMCs in a subset of patients. Increased PD-1 expression on CD14(bright) myelomonocytic cells, effector T cells, and natural killer (NK) cells correlated to disease stage, and expression was significantly reduced on all cell types soon after surgical resection of the primary tumor. The results indicate that PD-1 expression on fresh peripheral blood leukocytes may provide a useful indicator of RCC disease progression. Furthermore, measuring PD-1 levels in peripheral blood may assist in identifying patients likely to respond to PD-1 blocking antibodies, and these therapies may be most effective before and immediately after surgical resection of the primary tumor, when PD-1 expression is most prominent. PMID- 24764581 TI - Nonclassical antigen-processing pathways are required for MHC class II-restricted direct tumor recognition by NY-ESO-1-specific CD4(+) T cells. AB - Tumor antigen-specific CD4(+) T cells that directly recognize cancer cells are important for orchestrating antitumor immune responses at the local tumor sites. However, the mechanisms of direct MHC class II (MHC-II) presentation of intracellular tumor antigen by cancer cells are poorly understood. We found that two functionally distinct subsets of CD4(+) T cells were expanded after HLA DPB1*04 (DP04)-binding NY-ESO-1157-170 peptide vaccination in patients with ovarian cancer. Although both subsets recognized exogenous NY-ESO-1 protein pulsed on DP04(+) target cells, only one type recognized target cells with intracellular expression of NY-ESO-1. The tumor-recognizing CD4(+) T cells more efficiently recognized the short 8-9-mer peptides than the non-tumor-recognizing CD4(+) T cells. In addition to endosomal/lysosomal proteases that are typically involved in MHC-II antigen presentation, several pathways in the MHC class I presentation pathways, such as the proteasomal degradation and transporter associated with antigen-processing-mediated peptide transport, were also involved in the presentation of intracellular NY-ESO-1 on MHC-II. The presentation was inhibited significantly by primaquine, a small molecule that inhibits endosomal recycling, consistent with findings that pharmacologic inhibition of new protein synthesis enhances antigen presentation. Together, our data demonstrate that cancer cells selectively present peptides from intracellular tumor antigens on MHC-II by multiple nonclassical antigen-processing pathways. Harnessing the direct tumor-recognizing ability of CD4(+) T cells could be a promising strategy to enhance antitumor immune responses in the immunosuppressive tumor microenvironment. PMID- 24764582 TI - MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells. AB - Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocyte-derived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion. However, no significant decrease in CD4(+) or CD8(+) T-lymphocyte viability was observed following kinase inhibition. MoDC cross presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings. PMID- 24764580 TI - Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome. AB - The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 * 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 * 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19 1.64; P = 5.6 * 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 * 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 * 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. PMID- 24764583 TI - PD-L1 expression in triple-negative breast cancer. AB - Early-phase trials targeting the T-cell inhibitory molecule programmed cell death ligand 1 (PD-L1) have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of PTEN as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n = 120) compared with non-TNBC (n = 716; P < 0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression, which was present in 19% (20 of 105) of TNBC specimens. PD-L1(+) tumors had greater CD8(+) T-cell infiltrate than PD-L1(-) tumors (688 cells/mm vs. 263 cells/mm; P < 0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN short hairpin RNA (shRNA). PTEN knockdown led to significantly higher cell-surface PD L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, phosphoinositide 3-kinase (PI3K) pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Coculture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T-cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBCs, suggesting PD-L1 as a therapeutic target in TNBCs. Because PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses. PMID- 24764584 TI - Tumor subtype-specific cancer-testis antigens as potential biomarkers and immunotherapeutic targets for cancers. AB - Cancer-testis (CT) antigens are potential targets for cancer immunotherapy because of their restricted expression in immune-privileged germ cells and various malignancies. Current application of CT-based immunotherapy has been focused on CT expression-rich tumors such as melanoma and lung cancers. In this study, we surveyed CT expression using The Cancer Genome Atlas (TCGA) datasets for ten common cancer types. We show that CT expression is specific and enriched within certain cancer molecular subtypes. For example, HORMAD1, CXorf61, ACTL8, and PRAME are highly enriched in the basal subtype of breast cancer; MAGE and CSAG are most frequently activated in the magnoid subtype of lung adenocarcinoma; and PRAME is highly upregulated in the ccB subtype of clear cell renal cell carcinoma. Analysis of CT gene expression and DNA methylation indicates that some CTs are regulated epigenetically, whereas others are controlled primarily by tissue- and subtype-specific transcription factors. Our results suggest that although for some CT expression is associated with patient outcome, not many are independent prognostic markers. Thus, CTs with shared expression pattern are heterogeneous molecules with distinct activation modes and functional properties in different cancers and cancer subtypes. These data suggest a cancer subtype orientated application of CT antigen as biomarkers and immunotherapeutic targets. PMID- 24764585 TI - A phase Ib study of the effects of black raspberries on rectal polyps in patients with familial adenomatous polyposis. AB - Familial adenomatous polyposis (FAP) is characterized by the early onset of colonic polyposis and a high risk for colorectal cancer. FAP is treated by colectomy followed by lifelong removal of rectal polyps. This study determined whether black raspberries (BRBs) might regress rectal polyps in patients with FAP. Fourteen patients with FAP were treated with BRBs daily for 9 months. Seven patients received BRB powder orally plus two BRB suppositories inserted into the rectum at bedtime. The other 7 received an oral placebo plus the suppositories. Rectal polyp counts and polyp sizes were obtained at time zero and after 9 months of BRB treatment. Polyps and adjacent normal tissue were collected at both time points. The burden (P = 0.036) but not number (P = 0.069) of rectal polyps was significantly decreased. No benefit was noted with the addition of oral BRBs. Three patients were nonresponders. BRBs significantly decreased cellular proliferation, DNA methylation methyl transferase 1 protein expression, and p16 promoter methylation, but not promoter methylation of the Wnt pathway antagonists, SFRP2 and WIF1, in rectal polyps (adenomas) from responders but not from nonresponders. The MBD-seq assay revealed more demethylated transcription start sites (TSS), including those for miRNAs, in BRB-treated adenomas from the responders. In conclusion, BRB suppositories seem sufficient for regressing rectal polyps in patients with FAP. PMID- 24764586 TI - Second-line and third-line trial for helicobacter pylori infection in patients with duodenal ulcers: A prospective, crossover, controlled study. AB - BACKGROUND: Following standard first-line triple therapies for Helicobacter pylori infection, up to 20% of patients require further eradication. OBJECTIVE: The aim of this study was to assess the effects of second-line triple therapies and third-line quadruple therapies for the eradication of H pylori. METHODS: This 7-week, prospective, crossover, controlled, second- and third-line trial was conducted at the Department of Gastroenterology, Ferencvaros Health Center (Budapest, Hungary). Patients aged 18 to 80 years with duodenal ulcers and an H pylori infection resistant to first-line triple therapy (pantoprazole 40 mg BID + amoxicillin 1000 mg BID + clarithromycin 500 mg BID [PAC] given as tablets) received a different triple therapy regimen (ranitidine bismuth citrate 400 mg BID + metronidazole 500 mg BID + clarithromycin 500 mg BID [RBC-MC]) for 7 days (group 1A), and nonresponders after RBC + 2 antimicrobials received the pantoprazole-based regimen (group 1B). After secondary failure, patients were randomized to receive quadruple therapies: pantoprazole, amoxicillin, tetracycline, and either nitrofurantoin or bismuth subsalicylate (groups 2A and 2B). RESULTS: One hundred thirty-four patients were enrolled in the second-line study (56 men, 78 women; mean [SD] age, 51.1 [12.4] years; group 1A, 68 patients; group 1B, 66 patients). Subsequently, 41 (30.6%) of these patients were randomized to receive quadruple therapies. Using intent-to-treat (ITT) analysis, the eradication rates did not differ significantly (60.3% and 65.2% in groups 1A and 1B, respectively; 61.9% and 55.0% in groups 2A and 2B, respectively). Perprotocol eradication rates did not differ significantly (66.1% and 68.3% in groups 1A and 1B, respectively); however, the rates were significantly different in group 2A (66.7%) versus group 2B (55.5%) (P = 0.03). PMID- 24764587 TI - An observational study of the effect of two thiazolidinediones on blood lipid levels: Rosiglitazone and pioglitazone in routine clinical practice. AB - BACKGROUND: Rosiglitazone maleate and pioglitazone hydrochloride are established antihyperglycemic agents that are effective when used as monotherapy or in combination with other medications. However, the data regarding the effects of these agents on blood lipid levels are contradictory. OBJECTIVE: The aim of this study was to determine whether the use of rosiglitazone and pioglitazone in clinical practice is associated with any changes in blood lipid levels. METHODS: A retrospective chart review using electronic medical record data was conducted of patients with type 2 diabetes mellitus who were newly treated with either rosiglitazone or pioglitazone and had 1 lipid measurement within 6 months prior to and 12 months following initial thiazolidinedione (TZD) therapy. Outcome measures were mean changes in low- and high-density lipoprotein cholesterol (LDL C and HDL-C, respectively). To control for differences in baseline characteristics and/or selection bias, the treatment cohorts were compared using multivariate statistical techniques. RESULTS: A total of 371 patients were included in the study; the pioglitazone cohort comprised 148 patients (82 women, 66 men; mean [SD] age, 64.9 [10.8] years) and the rosiglitazone cohort comprised 223 patients (113 men, 110 women; mean [SD] age, 66.1 [11.9] years). Pioglitazone treated patients had a statistically higher mean baseline LDL-C compared with rosiglitazone-treated patients (125.0 mg/dL vs 116.6 mg/dL; P = 0.04). On average, LDL-C levels decreased over the study period, with no significant differences between the 2 cohorts (9.9 mg/dL vs 4.3 mg/dL for pioglitazone and rosiglitazone, respectively), although changes in both cohorts were statistically significant (P < 0.001). CONCLUSIONS: TZD therapy appears to be associated with a small decrease in LDL-C within the first 6 months after initiation. No differences in changes in LDL-C or HDL-C could be discerned between patients treated with rosiglitazone compared with pioglitazone. PMID- 24764588 TI - Double-masked, randomized, parallel-group study comparing olopatadine 0.1% ophthalmic solution with cromolyn sodium 2% and levocabastine 0.05% ophthalmic preparations in children with seasonal allergic conjunctivitis. AB - BACKGROUND: It is estimated that >50% of medications have not been tested in children. Physicians need pediatric data to guide them in treating children. Olopatadine hydrochloride ophthalmic solution 0.1% is a topical antiallergic agent that is both an antihistamine with high affinity and selectivity for the histamine H1 receptor and a mast cell stabilizer that inhibits the release of histamine and other proinflammatory mediators from human conjunctival mast cells. The efficacy and tolerability of olopatadine has been demonstrated by comparative studies in adults and children with seasonal allergic conjunctivitis (SAC). OBJECTIVE: Pediatric patient data were extracted from 2 clinical trials to assess the efficacy and tolerability of olopatadine hydrochloride ophthalmic solution 0.1% compared with those of cromolyn sodium ophthalmic solution 2% and levocabastine ophthalmic solution 0.05% as treatment for SAC in children. METHODS: In study 1, conducted at 15 centers in 7 countries (Europe and Australia) from October 1995 to December 1997, olopatadine was instilled BID and placebo (vehicle) BID for 6 weeks and compared with cromolyn instilled QID. Study 2, conducted at 17 centers in 8 countries (Europe and Australia) from November 1998 to June 2000, compared olopatadine BID with levocabastine BID. In both studies, children of either sex and any race, aged 4 to 11 years, and having proven grass pollen allergies were assigned to treatment in a double-masked, randomized fashion. Slit-lamp examination, the physician's impression scale, and self-ratings were used to obtain efficacy data. Data analyses were based on pollen concentrations. The tolerability assessments were based on visual acuity, pupil diameter, intraocular pressure, and a dilated fundus examination. RESULTS: Study 1 comprised 30 children (olopatadine [n = 13] and cromolyn sodium [n = 17]; 18 boys, 12 girls; mean age, 7.9 years [range, 4-11 years]). Study 2 comprised 22 children (olopatadine [n = 10] and levocabastine [n = 12]; 12 boys, 10 girls; mean age, 8.6 years [range, 5-11 years]). In study 1, ocular itching (P = 0.010), redness seen on slit-lamp examination (P = 0.003), and eyelid swelling (P = 0.034) were significantly less intense with olopatadine than with cromolyn sodium during the peak pollen period. In study 2, redness seen on slit-lamp examination (P = 0.040) and self-rated ocular redness (P = 0.024) were significantly less intense with olopatadine than levocabastine during the peak pollen period. Olopatadine was well tolerated. CONCLUSION: Olopatadine hydrochloride ophthalmic solution 0.1% was more effective than both cromolyn sodium 2% and levocabastine 0.05% ophthalmic preparations in controlling ocular signs and symptoms of SAC in children and was well tolerated when administered twice daily for 6 weeks. PMID- 24764589 TI - Use of the respiratory fluoroquinolones for the outpatient management of community-acquired pneumonia. AB - BACKGROUND: Approximately 4 million cases of community-acquired pneumonia (CAP) occur in the United States each year, with the majority treated on an outpatient basis. The first fluoroquinolones (eg, ciprofloxacin) were used with caution for respiratory tract infections due to limited in vitro activity against common gram positive pathogens. With the availability of levofloxacin, followed by gatifloxacin and moxifloxacin hydrochloride, which exhibited increased activity against gram-positive organisms, the fluoroquinolones have become a practical choice for the treatment of CAP. OBJECTIVE: The aim of this review was to compare the respiratory fluoroquinolones in the outpatient management of CAP. METHODS: We conducted a search for English-language articles (key terms: fluoroquinolone, levofloxacin, gatifloxacin, moxifloxacin, and pneumonia; years: 1996-2004). Data from published literature were reviewed regarding clinical and microbiologic efficacy and tolerability; pharmacokinetic and pharmacodynamic properties; and drug costs of levofloxacin, gatifloxacin, and moxifloxacin. RESULTS: The 3 fluoroquinolones reviewed showed comparable clinical and microbiologic efficacy for the treatment of CAP. In general, the fluoroquinolones were well tolerated, although some differences have been reported, including higher rates of gastrointestinal and other adverse events for gatifloxacin and moxifloxacin. Gatifloxacin and moxifloxacin exhibited greater in vitro potency than levofloxacin against Streptococcus pneumoniae. However, levofloxacin achieved a higher serum drug concentration than the other agents, allowing similar attainment of pharmacokinetic and pharmacodynamic targets required for effective treatment. CONCLUSIONS: The respiratory fluoroquinolones provided appropriate first line treatment in select patients with CAP on the basis of their microbiologic and clinical efficacy and their safety profiles. PMID- 24764590 TI - Frequency of cardiovascular events in patients treated with anti hypertensive agents: A cohort study based on claims data generated by primary care practice. AB - BACKGROUND: Large-scale clinical trials have shown that antihypertensive drugs reduce the risk for cardiovascular events. However, little is known about the effectiveness of these drugs in the primary care setting. OBJECTIVE: The aim of this study was to investigate the frequency of cardiovascularevents during treatment with either of 2 of the most frequently prescribed antihypertensive drugs. METHODS: This observational, longitudinal, cohort study considered the entirepopulation listed in the administrative databases of the Local Health Authority of Ravenna, Italy (356,000 residents). The demographic registry and the pharmaceutical and nosocomial databases were cross-linked to determine drug treatment, as well as the frequency of cardiovascular events on a patient-by patient basis. Each patient aged >18 years receiving a first prescription for amlodipine or enalapril in the period between January 1, 1996, and December 31, 2000, with >=6 months of continuous treatment with the drug was included. The follow-up period varied from 6 months to 4.5 years. RESULTS: Of the 7500 patients analyzed (4092 women and 3408 men; mean[SD] age, 68.0 [12.4] years), 2231 (29.7%) were given amlodipine and 5269 (70.3%) were given enalapril. The observed rate of cardiovascular events was higher among patients treated with amlodipine (54 per 1000 patient-years vs 46 per 1000 patient-years; P = 0.007), with a hazard ratio 17% higher compared with enalapril (95% Cl, 5.0-24.0; P = 0.007). The result was also confirmed using Cox multivariate regression analysis. The combination of enalapril plus diuretic showed the lowest risk for cardiovascular events (0.73; 95% Cl, -36.0 to -16.0; P < 0.001). CONCLUSION: This analysis showed that treatment with enalapril was associatedwith a significantly lower frequency of cardiovascular events compared with amlodipine. PMID- 24764591 TI - Protective effect of mesalamine against oxidativeinjury in a rat model of radiation rectitis. AB - BACKGROUND: Radiation rectitis is a major problem associated with high doseirradiation used for pelvic malignancies. OBJECTIVE: The aim of this study was to investigate the possible protectiveeffect of mesalamine against irradiation-induced oxidative tissue damage in an experimental model. METHODS: THREE GROUPS OF FEMALE SPRAGUE DAWLEY RATS WERE ASSIGNED TO RECEIVE TREATMENT AS FOLLOWS: mesalamine enema (60 mg/mL) BID + irradiation (IR) was given to the mesalamine + IR group, and isotonic saline enema BID + irradiation to the control group. Treatments were given from the day before irradiation until euthanization (72 hours after the irradiation). Sham control rats received isotonic saline enema BID but no irradiation. On the third day of treatment, all animals were euthanized, and reduced glutathione (GSH) level, malondialdehyde (MDA) level, and myeloperoxidase (MPO) activity were measured in the rectal, intestinal, and hepatic tissue of the rats. RESULTS: The sham group comprised 7 rats; the control and mesalamine + IRgroups, 16 rats each. The median GSH levels of rectal and intestinal specimens were lower in the control group compared with the sham group. The rectal and intestinal MDA levels were higher in the control group compared with the sham group. The rectal and intestinal MPO activities were higher in the control group compared with the sham group. All of these differences were statistically significant (P < 0.001) and indicated oxidative stress. With the topical application of mesalamine, the GSH and MDA levels and MPO activities were similar to those of the sham group. CONCLUSION: The pelvic irradiation of rats caused oxidative rectal, intestinal,and hepatic tissue damage, which was ameliorated with the use of mesalamine. PMID- 24764592 TI - Effects of caffeine on placental total nitrite concentration: A 21-day, vehicle controlled study in rats. AB - BACKGROUND: Nitric oxide (NO) is a potent vasodilator that might have an10 important role in the modulation of maternal and fetal vascular tone during pregnancy. The effects of caffeine intake on maternal and fetal hemodynamic properties during pregnancy have been investigated in several human and animal studies. However, based on a literature search, there has been no study of placental total nitrite (a stable product of NO) concentration (PTNC) in pregnant humans or rats given caffeine. OBJECTIVE: The aim of this study was to assess the effects of caffeine intake 10 on PTNC in rats. METHODS: This 21-day, vehicle controlled study was conducted at the Department10 of Pharmacology, Gaziantep University Hospital, Gaziantep, Turkey. Female Wistar rats were randomly assigned; based on age and weight, to receive 25, 50, or 100 mg/kg QD caffeine or 50 mg/kg QD isotonic saline solution (vehicle; age-matched control group), intraperitoneally for 21 days. After euthanization of the rats and cesarean section, the numbers of fetuses and fetal deaths were counted. The lengths and weights of the fetuses in each study group were noted. PTNC in the rats was determined using the Greiss reaction. RESULTS: This study included 26 rats (7, 7, and 6 rats in the groups receiving10 25, 50, and 100 mg/kg. d caffeine, respectively; 6 rats in the control group). The mean (SD) lengths of the fetuses of the rats given 25, 50, and 100 mg/kg . d caffeine (4.90 [0.15], 4.02 [0.27], and 3.45 [0.17] mm, respectively) were significantly less compared with controls (5.10 [0.18] mm) (all, P < 0.001), as were the mean (SD) weights of the fetuses of rats given caffeine (5.86 [0.24], 4.97 [0.59], and 3.41 [0.23] g, respectively) versus controls (6.18 [0.21] g) (all, P < 0.001). The mean (SD) PTNCs in rats given 25, 50, and 100 mg/kg. d caffeine (19.82 [1.97], 29.39 [2.07], and 45.51 [7.66] nmol/g, respectively) were significantly higher compared with controls (16.10 [2.12] nmol/g) (all, P < 0.001). CONCLUSIONS: The results of this study in rats suggest that caffeine intake 10 might increase NO production in the placenta. In addition, based on our findings and those from previous studies, we suggest that this increase might be an adaptive physiologic response to prevent undesirable effects of caffeine on vascular tone during pregnancy. PMID- 24764593 TI - Combination therapy with pegylated interferon plus ribavirin in the treatment of hepatitis C virus-related thrombocytopenia. AB - BACKGROUND: Isolated thrombocytopenia is a common manifestation of hepatitis C virus (HCV) infection. There is no established treatment modality for this condition. The efficacy of standard interferon (IFN) monotherapy has been reported in some studies. The major disadvantage of this treatment is the high rate of recurrence due to viral breakthrough during the first 12 weeks of treatment. Pegylated IFNs are now the standard regimen for chronic hepatic disease due to HCV infection. However, due to a lack of evidence, pegylated IFNs are not widely used for HCV-related isolated thrombocytopenia. OBJECTIVE: The aim of this report was to present the case of a male patientwith severe symptomatic thrombocytopenia due to HCV infection. METHODS: Thrombocytopenia was treated with pegylated IFN plus ribavirin. RESULTS: Although standard IFN monotherapy failed to achieve virologic and hematologic improvement, therapy with pegylated IFN alfa 2a plus ribavirin was associated with both virologic and hematologic improvement without any significant adverse effects. CONCLUSIONS: Pegylated IFN plus ribavirin was effective in this patient for thetreatment of HCV-related thrombocytopenia. However, further research is needed to define the response rate in different patient populations. PMID- 24764594 TI - Effects of diazepam on diaphragmatic functionand recovery in pentobarbital anesthetized dogs: An open-label, dose-finding, pharmacologic study. AB - BACKGROUND: Diazepam, a highly lipid-soluble benzodiazepine, is commonly used as a sedative agent during and after surgery. Based on a literature search, no published data are available concerning diaphragmatic function (as measured by contractility and electrical activity) during and after the administration of diazepam. OBJECTIVE: The purpose of this study was to assess the effects of diazepam use on diaphragmatic function and recovery in pentobarbital-anesthetized dogs. METHODS: This open-label, dose-finding, pharmacologic study was conductedat the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan. Healthy adult mongrel dogs weighing 10 to 15 kg were assigned to 1 of 3 study groups: low dose (0.2-mg/kg) diazepam, high-dose (0.5 mg/kg) diazepam, or control (no study drug). Each dog was anesthetized with pentobarbital 2 mg/kg . h IV Study drug was administered IV for 1 hour. Diaphragmatic function was assessed before (baseline) and at 0 (immediately after), 1, and 2 hours after the end of study drug administration, using measurement of transdiaphragmatic pressure (Pdi), defined as the difference between gastric and esophageal pressures, and by integrated electrical activity (20- and 100-Hz stimulation) of the crural (Edi-cru) and costal (Edi-cost) parts of the diaphragm. The percentage changes from baseline in Edi-cru (%Edi-cru) and Edi-cost (%Edi-cost) were calculated. RESULTS: Twenty-four mongrel dogs were used in the study; 8 dogs were assigned to each treatment group. During diazepam administration in the low-dose group, significant decreases from baseline in Pdi were found with 20-Hz stimulation (15.6 [1.7] vs 13.3 [1.9] cm H2O; P < 0.05) and 100-Hz stimulation (22.0 [2.1] vs 19.6 [1.8] cm H2O; P < 0.05). In the high-dose group, the decreases in Pdi were significant with 20-Hz stimulation (15.5 [1.8] vs 10.0 [2.0] cm H2O; P < 0.05) and 100-Hz stimulation (22.2 [1.9] vs 16.2 [ 2.0 ] cm H2O; P < 0.05). In the low-dose group at 100-Hz stimulation, mean (SD) %Edi cru and %Edi-cost were significantly lower compared with baseline (88.8% [6.6%] and 88.5% [5.9%], respectively; both, P < 0.05). In the high-dose group at 100-Hz stimulation, mean (SD) %Edi-cru and %Edi-cost were significantly lower compared with baseline (77.5% [4.3%] and 78.0% [5.0%], respectively; both, P < 0.05). The decreases in Pdi, %Edi-cru, and %Edi-cost were significantly greater in the high dose group compared with the low-dose group (all, P < 0.05). CONCLUSION: The results of this experimental study of the effects of diazepamon diaphragmatic function and recovery in pentobarbital-anesthetized dogs suggest that diazepam inhibits diaphragmatic function in a dose-related manner and delays recovery. PMID- 24764595 TI - Psychotropic medication use at a private eating disorders treatment facility: A retrospective chart review and descriptive data analysis. AB - BACKGROUND: The extent of psychotropic medication use in patients with eating disorders worldwide is unknown. OBJECTIVES: THE PURPOSES OF THIS STUDY WERE TO: (1) describe the extent and pattern of psychotropic medication use at a private treatment facility for patients with eating disorders and (2) describe patient characteristics and treatment outcomes at the facility. METHODS: This retrospective chart review included data from a private treatment facility (inpatient or outpatient) for patients with eating disorders in the greater Los Angeles area. Data from all patients of any age who attended the facility between January 1, 2004, and January 1, 2005, and who met the criteria for anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (ED NOS) defined in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision were included. Two investigators used a consistent chart-review method for recording clinical status, including treatment-related adverse effects and discharge status (improved, no change, or decompensated from admission). Improved was defined as meeting 1 or more of the following criteria: achieved ideal body weight, stabilized mood, decreased eating disorder symptoms (binge-purge, restrictive, or ritualistic behavior), eating disorder remission, or decreased suicidal ideation plus another improvement in this list. RESULTS: Data from 60 patients were included (31 with AN, 28 with 13N, and I with ED NOS). Ages ranged from 12 to 47 years, and the mean duration of treatment was 35 days. Fifty-eight (96.7%) patients received a psychotropic agent; 35 (58.3%) patients were prescribed 2 or more agents concomitantly. Selective serotonin reuptake inhibitors (SSRls) were the most commonly prescribed class of psychotropic medication (86.7%), followed by antipsychotics (38.3%). Fluoxetine, escitalopram, and aripiprazole were the most commonly prescribed agents (41.7%, 28.3%, and 23.3%, respectively). A total of 63.3% of patients had a comorbid diagnosis of major depressive disorder, with 96.7% of these patients prescribed an antidepressant. At discharge, 51.6% of the inpatients and 37.9% of the outpatients had improved (AN, 52.6% and 33.3%, respectively; BN, 54.5% and 41.2%, respectively). Of the patients prescribed an SSRI, 40.4% had improved. In the inpatient setting, 35.5% of patients receiving an antipsychotic had improved, versus 6.9% in the outpatient setting. CONCLUSIONS: The results of this retrospective chart review and descriptive analysis of data from patients at a private eating disorders treatment facility in the United States suggest that psychotropics, particularly antidepressants and antipsychotics, were highly utilized, largely to treat comorbid symptoms. Fluoxetine, escitalopram, and aripiprazole were the most commonly prescribed agents. We observed that psychotropic medication selection was based on patient comorbidities and symptom expression and severity. PMID- 24764598 TI - Characterization of grain nutritional quality in wheat. AB - Ten Indian wheat varieties viz. RSP-566, RSP-561, PBW-396, HD-2687, C-306, PBW 175, RSP-81, PBW-550, DBW-17 and WH-542 were characterized for grain nutritional quality parameters viz., macronutrients (viz. starch, protein, protein fractions, sugars, fat), essential elements (calcium, phosphorus, iron and zinc), carotenoids, antioxidant and antinutritional parameters (phytic acid, total phenol, polyphenol oxidase (PPO) and trypsin inhibitor). RSP-561 possessed highest starch content, total protein, albumin, globulin, microelements (iron and zinc) and lowest antinutritional phytic acid and its grain contained second highest values of gluten (gliadin + glutenin), calcium, carotenoids and antioxidant contents and second lowest in antinutritional total phenol, PPO, trypsin inhibitor compositions. HD-2687 showed highest content of albumin, gliadin and total phenol constituents besides highest starch and total protein content. PBW-175 had highest sugar, calcium and carotenoids. However, antinutritional trypsin inhibitor, total phenol and PPO were found lowest in RSP 566, PBW-550 and RSP-81 respectively. The finding of this study concludes that on the basis of overall nutritional status, RSP-561 genotypes can be selected as one of best genotypes. PMID- 24764596 TI - Effects of simvastatin 20 mg/d on serum lipid profiles in Japanese hyperlipidemic patients: A prospective, open-label pilot study. AB - BACKGROUND: Hyperlipidemia is a major risk factor for ischemic heart disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors ("statins") (eg, simvastatin) are considered first-line cholesterol-lowering therapy because they are effective and well tolerated, even at high doses. Based on a literature search, no studies have been published concerning the effects of simvastatin 20 mg/d in Japanese patients who had not previously received lipid-lowering treatment. OBJECTIVE: The aim of this study was to assess the clinical tolerability and effectiveness of simvastatin 20 mg/d in achieving the target lipid concentrations recommended in the 2002 Japan Atherosclerosis Society (JAS) guidelines in Japanese patients with hyperlipidemia. METHODS: This prospective, open-label pilot study was conducted at Kashiwa Hospital, Jikei University School of Medicine, Kashiwa, Japan. Male and postmenopausal female patients aged >=18 to 70 years with hyperlipidemia (total cholesterol [TC], >=220 mg/dL; triglycerides [TG], 150-400 mg/dL) who had not received lipid-lowering medications for at least 6 months before the study were enrolled. Patients received simvastatin 20 mg PO QD for 4 weeks. Effectiveness was assessed using serum concentrations of TC, low density lipoprotein cholesterol (LDL-C), TG, and lipid peroxide, measured at 0 (baseline) and 4 weeks. Target serum TC and LDL-C concentrations as outlined by the JAS were as follows: category A, TC <240 mg/dL and LDL-C <160 mg/dL; category B1 and B2, TC <220 mg/dL and LDL-C <140 mg/dL; and category C, TC <200 mg/dL and LDL-C <120 mg/dL. A subanalysis of the correlation between baseline high-density lipoprotein cholesterol (HDL-C) and target achievement rates was conducted by baseline HDL-C concentration (<50 or >=50 mg/dL). Tolerability was assessed using spontaneous reporting of adverse events and laboratory analysis, including liver function tests. RESULTS: Twenty-two patients participated in the study (16 women, 6 men; mean [SD] age, 56.0 [8.0] years; mean [SD] body mass index, 23.6 [3.4] kg/m(2)). Mean serum TC, LDL-C, TG, and lipid peroxide concentrations significantly decreased from baseline (changes, -28.6%, -40.4%, -24.0%, and 14.5%, respectively; P < 0.001, <0.001, <0.001, and <0.01, respectively). The mean HDL-C concentration significantly increased from baseline (change, 7.2%; P < 0.001); the mean increase was significantly greater in patients with baseline HDL C <50 mg/dL compared with those with baseline HDL-C >=50 mg/dL (changes, 11.3% vs 4.4%; P < 0.05). Target TC and LDL-C concentrations were achieved in 90.9% of patients. No serious adverse events were observed, and liver enzyme and creatine kinase concentrations did not increase to above-normal values. CONCLUSIONS: The results of this study suggest that simvastatin 20 mg/d might be useful in the clinical treatment of hyperlipidemia in Japanese patients. The study drug was well tolerated. PMID- 24764599 TI - Protocol optimization for enhanced production of pigments in Spirulina. AB - Spirulina has attracted special attention due to its importance as human foodstuff and natural colours with specific functional properties. These functional properties have been attributed to phycobilins, carotenoids, phenolics and unsaturated fatty acids. Present study was conducted under controlled phytotron conditions to identify the efficient strains of Spirulina in terms of pigment synthesis and to optimize their enhanced production. Methodology for enhanced production was standardized by varying specific environmental parameters (light intensity, temperature, carbon dioxide concentration, pH and NaCl level). Different strains of Spirulina depicted variability and environmental parameters showed distinct influence on pigments. Growth and pigment production was recorded to be most efficient under optimized conditions of light intensity (70 MUmol m-2 s-1), temperature (30 degrees C), CO2 concentration (550 ppm and 750 ppm), pH (10.5) and NaCl level (2 g L-1). PMID- 24764600 TI - Amelioration of moisture stress effect by CaCl2 pre-treatment in upland rice. AB - Five varieties of rice viz., Subhadra, Ghanteswari, Sidhant, Jogesh and Khandagiri were grown to study the stress alleviating effect of CaCl2 at panicle initiation (PI) stage. CaCl2 (1 %) was given as seed treatment, which ameliorated the adverse effect of drought stress on photosynthesis (Pn), stomatal conductance (Gs), membrane stability index (MSI), leaf moisture retention index (LMRI) and grain weight. Under stress condition Pn, Gs, MSI and LMRI were significantly reduced. All CaCl2 pre-treatments enhanced yield, and the reduction under moisture stress was only 21.9 % as compared to 62 % in untreated stressed plants. Amongst the varieties Shubadra and Ghanteswari possessed better drought adaptive mechanism than Sidhant, Jogesh and Khandagiri. PMID- 24764601 TI - LIPID MAPS-Nature Lipidomics Gateway: An Online Resource for Students and Educators Interested in Lipids. AB - The LIPID MAPS-Nature Lipidomics Gateway is a free, comprehensive online resource providing tutorials and instructional material, experimental data for lipids and genes along with protocols and standards, databases of lipid structures and lipid associated genes or proteins, and a variety of lipidomics tools. PMID- 24764602 TI - Preliminary Development of a DNA Aptamer-Magnetic Bead Capture Electrochemiluminescence Sandwich Assay for Brain Natriuretic Peptide. AB - Fifty-two candidate DNA aptamer sequences were selected for binding to the cardiovascular biomarker B-type or brain natriuretic peptide (BNP). Candidate aptamers were screened to rank their relative affinities against BNP by an aptamer-based ELISA-like aptamer microplate assay (ELASA). The highest affinity aptamers from ELASA screening were also paired in all possible combinations and screened for electrochemiluminescence (ECL) assay potential in capture aptamer magnetic bead and ruthenium trisbipyridine (Ru(bpy)32+)-reporter aptamer sandwich formats. The top ECL sandwich combinations utilized the same aptamer pair in either capture or reporting roles with nanogram to low picogram per mL levels of detection even in 50% human serum. ECL assay sensitivity and linearity even in 50% human serum suggest that the aptamer-based assay is at least comparable to other reported immunoassays for BNP. PMID- 24764603 TI - Intramolecular arylation of benzimidazoles via Pd(II)/Cu(I) catalyzed cross dehydrogenative coupling. AB - Electron poor benzimidazole substrates were arylated via an intramolecular cross dehydrogenative coupling (CDC) reaction. These CDC reactions were catalyzed by a Pd(II)/Cu(I) catalyst system, capable of producing moderate yields on a large library of substrates. The substrate scope consisted of tethered arene benzimidazoles that upon coupling, produced a fused polycyclic motif. PMID- 24764604 TI - ML versus MI for Missing Data with Violation of Distribution Conditions. AB - Normal-distribution-based maximum likelihood (ML) and multiple imputation (MI) are the two major procedures for missing data analysis. This article compares the two procedures with respects to bias and efficiency of parameter estimates. It also compares formula-based standard errors (SEs) for each procedure against the corresponding empirical SEs. The results indicate that parameter estimates by MI tend to be less efficient than those by ML; and the estimates of variance covariance parameters by MI are also more biased. In particular, when the population for the observed variables possesses heavy tails, estimates of variance-covariance parameters by MI may contain severe bias even at relative large sample sizes. Although performing a lot better, ML parameter estimates may also contain substantial bias at smaller sample sizes. The results also indicate that, when the underlying population is close to normally distributed, SEs based on the sandwich-type covariance matrix and those based on the observed information matrix are very comparable to empirical SEs with either ML or MI. When the underlying distribution has heavier tails, SEs based on the sandwich type covariance matrix for ML estimates are more reliable than those based on the observed information matrix. Both empirical results and analysis show that neither SEs based on the observed information matrix nor those based on the sandwich-type covariance matrix can provide consistent SEs in MI. Thus, ML is preferable to MI in practice, although parameter estimates by MI might still be consistent. PMID- 24764605 TI - Solvent-free Fabrication of Tissue Engineering Scaffolds with Immiscible Polymer Blends. AB - A completely organic solvent-free fabrication method is developed for tissue engineering scaffolds by gas foaming of immiscible polylactic acid (PLA) and sucrose blends, followed by water leaching. PLA scaffolds with above 90% porosity and 25-200 MUm pore size were fabricated. The pore size and porosity was controlled with process parameters including extrusion temperature and foaming process parameters. Dynamic mechanical analysis showed that the extrusion temperature could be used to control the scaffold strength. Both unfoamed and foamed scaffolds were used to culture glioblastoma (GBM) cells M059K. The results showed that the cells grew better in the foamed PLA scaffolds. The method presented in the paper is versatile and can be used to fabricate tissue engineering scaffolds without any residual organic solvents. PMID- 24764606 TI - Modeling and Global Optimization of DNA separation. AB - We develop a non-convex non-linear programming problem that determines the minimum run time to resolve different lengths of DNA using a gel-free micelle end labeled free solution electrophoresis separation method. Our optimization framework allows for efficient determination of the utility of different DNA separation platforms and enables the identification of the optimal operating conditions for these DNA separation devices. The non-linear programming problem requires a model for signal spacing and signal width, which is known for many DNA separation methods. As a case study, we show how our approach is used to determine the optimal run conditions for micelle end-labeled free-solution electrophoresis and examine the trade-offs between a single capillary system and a parallel capillary system. Parallel capillaries are shown to only be beneficial for DNA lengths above 230 bases using a polydisperse micelle end-label otherwise single capillaries produce faster separations. PMID- 24764607 TI - A risk index model for predicting eastern equine encephalitis virus transmission to horses in Florida. AB - A GIS-based risk index model was developed to quantify EEEV transmission risk to horses in the State of Florida. EEEV is a highly pathogenic arbovirus that is endemic along the east coast of the United States, and it is generally fatal to both horses and humans. The model evaluates EEEV transmission risk at individual raster cells in map on a continuous scale of 0 to 1. The risk index is derived based on local habitat features and the composition and configuration of surrounding land cover types associated with EEEV transmission. The model was verified and validated using the locations of documented horse cases of EEEV. These results of the verification and validation indicate that the model is able to predict locations of EEEV transmission to horses broadly across the state. The model is relatively robust to regional variation in EEEV transmission and habitat conditions in Florida, and it accurately predicted nearly all verification and validation cases in the Panhandle, North, and Central regions of the state. The model performed less accurately in the South, where relatively few cases are documented. Despite these differences, the model provides a useful way to assess EEEV risk both from a regional perspective and at more localized scales. The resulting predictive maps are designed to guide EEEV surveillance and prevention efforts by county mosquito control districts. PMID- 24764608 TI - Effect of Cane Length on Drop-off Detection Performance. PMID- 24764609 TI - Kernels, Degrees of Freedom, and Power Properties of Quadratic Distance Goodness of-Fit Tests. AB - In this article, we study the power properties of quadratic-distance-based goodness-of-fit tests. First, we introduce the concept of a root kernel and discuss the considerations that enter the selection of this kernel. We derive an easy to use normal approximation to the power of quadratic distance goodness-of fit tests and base the construction of a noncentrality index, an analogue of the traditional noncentrality parameter, on it. This leads to a method akin to the Neyman-Pearson lemma for constructing optimal kernels for specific alternatives. We then introduce a midpower analysis as a device for choosing optimal degrees of freedom for a family of alternatives of interest. Finally, we introduce a new diffusion kernel, called the Pearson-normal kernel, and study the extent to which the normal approximation to the power of tests based on this kernel is valid. Supplementary materials for this article are available online. PMID- 24764610 TI - Addiction as a disorder of belief. AB - Addiction is almost universally held to be characterized by a loss of control over drug-seeking and consuming behavior. But the actions of addicts, even of those who seem to want to abstain from drugs, seem to be guided by reasons. In this paper, I argue that we can explain this fact, consistent with continuing to maintain that addiction involves a loss of control, by understanding addiction as involving an oscillation between conflicting judgments. I argue that the dysfunction of the mesolimbic dopamine system that typifies addictions causes the generation of a mismatch between the top-down model of the world that reflects the judgment that the addict ought to refrain from drugs, and bottom-up input caused by cues predictive of drug availability. This constitutes a powerful pressure toward revising the judgment and thereby attenuating the prediction error. But the new model is not stable, and shifts under the pressure of bottom up inputs in different contexts; hence the oscillation of all-things-considered judgment. Evidence from social psychology is adduced, to suggest that a similar process may be involved in ordinary cases of weakness of will. PMID- 24764611 TI - Creating safe places: an exploratory evaluation of a school-based emotional support service. AB - School-based interventions for young people with emotional/mental health problems are often provided by external practitioners and their relationship with host schools is a key influence on implementation. Poor integration within school systems, schools' tendency to define interventions around pupils' behaviour and teachers' control over access, may undermine therapeutic relationships. This study examines how one school-based intervention-Bounceback-addressed these challenges. Methods comprised interviews with programme staff, school staff and service users. Bounceback sought to develop therapeutic relationships through creating a safe, welcoming place and maximising pupils' choice about how they engaged with it. To ensure Bounceback was delivered as intended, staff developed five conditions which schools were asked to meet: adhering to referral criteria, ensuring that attendance was voluntary, appropriate completion of referral forms, mechanisms for contacting pupils and private accommodation to maintain confidentiality. Pupils reported high levels of acceptability and described relationships of trust with Bounceback staff. Although pupils had choice about most aspects of Bounceback, teachers controlled access to it, partly in order to manage demand. The study highlights the need for external agencies to communicate their aims and needs clearly to schools and the importance of peripatetic practitioners being well integrated within their parent organisations. PMID- 24764612 TI - Emotions, Social Work Practice and Supervision: An Uneasy Alliance? AB - This paper examines the place of emotions within social work practice. The perceived tensions between emotions and rational decision making are explored and it is argued that their relationship is compatible and necessary. A model for the co-creation of emotionally intelligent supervision is developed to support this vision of practice. PMID- 24764613 TI - Influence of taekwondo as security martial arts training on anaerobic threshold, cardiorespiratory fitness, and blood lactate recovery. AB - [Purpose] This study was conducted to determine the influence of Taekwondo as security martial arts training on anaerobic threshold, cardiorespiratory fitness, and blood lactate recovery. [Subjects and Methods] Fourteen healthy university students were recruited and divided into an exercise group and a control group (n = 7 in each group). The subjects who participated in the experiment were subjected to an exercise loading test in which anaerobic threshold, value of ventilation, oxygen uptake, maximal oxygen uptake, heart rate, and maximal values of ventilation / heart rate were measured during the exercise, immediately after maximum exercise loading, and at 1, 3, 5, 10, and 15 min of recovery. [Results] At the anaerobic threshold time point, the exercise group showed a significantly longer time to reach anaerobic threshold. The exercise group showed significantly higher values for the time to reach VO2max, maximal values of ventilation, maximal oxygen uptake and maximal values of ventilation / heart rate. Significant changes were observed in the value of ventilation volumes at the 1- and 5-min recovery time points within the exercise group; oxygen uptake and maximal oxygen uptake were significantly different at the 5- and 10-min time points; heart rate was significantly different at the 1- and 3-min time points; and maximal values of ventilation / heart rate was significantly different at the 5-min time point. The exercise group showed significant decreases in blood lactate levels at the 15 and 30-min recovery time points. [Conclusion] The study results revealed that Taekwondo as a security martial arts training increases the maximal oxygen uptake and anaerobic threshold and accelerates an individual's recovery to the normal state of cardiorespiratory fitness and blood lactate level. These results are expected to contribute to the execution of more effective security services in emergencies in which violence can occur. PMID- 24764614 TI - Influence of pilates mat and apparatus exercises on pain and balance of businesswomen with chronic low back pain. AB - [Purpose] The purpose of this study was to examine the influence of mat Pilates and apparatus Pilates on pain and static balance of businesswomen with chronic back pain. [Subjects and Methods] Participants were randomly allocated to Pilates mat exercises (PME) or Pilates apparatus exercise (PAE), and performed the appropriate Pilates exercises 3 days per week for 8 weeks. In order to measure the improvement in the participants' static balance ability as a result of the exercise, the sway length and sway velocity of the subjects were measured before and after the experiment while the subjects stood on a Balance Performance Monitor (BPM) facing the front wall for 30 seconds with their eyes open. The visual analogue scale (VAS) was used to measure the degree of pain. [Results] The VAS score, sway length, and sway velocity of both groups decreased significantly after the experiment, but the PME group showed a greater decrease than the PAE group. [Conclusion] PME showed greater improvement in pain level and balance compared with PAE in this research. Since the subjects of this study were patients with low back pain, PME is assumed to have been more suitable and effective because it uses body weight to strengthen core muscles rather than heavier apparatuses as in PAE. PMID- 24764615 TI - Immediate effects of rhythmic auditory stimulation with tempo changes on gait in stroke patients. AB - [Purpose] The aim of this study was to investigate the effects of tempo changes in rhythmic auditory stimulation (RAS) on gait in stroke patients. [Subjects] Forty-one chronic stroke patients who had had a stroke with more than 6 months previously were recruited for this study. [Methods] All participants were asked to walk under 5 different conditions in random order: (1) no RAS (baseline); (2) baseline-matched RAS (0%); and (3) -10%, (4) +10%, and (5) +20% of the baseline. A GAITRite system was used to evaluate the spatial and temporal parameters of gait. [Results] Compared with under the RAS 0% conditions, the gait velocity, cadence, and stride length on the affected side were significantly decreased under the RAS -10% conditions. Gait velocity and cadence were significantly improved, but gait symmetry was significantly decreased under the RAS +10% and +20% conditions compared with under the RAS 0% conditions. [Conclusion] A faster RAS tempo significantly improved gait velocity and cadence, and applying RAS significantly improved the gait symmetry of stroke patients. PMID- 24764616 TI - Study on the Usefulness of Sit to Stand Training in Self-directed Treatment of Stroke Patients. AB - [Purpose] This study sought to determine the usefulness of sit to stand training in self-directed treatment of stroke patients. It examined the effect that sit to stand training has on balance and functional movement depending on the form of support surfaces. [Subjects and Methods] Thirty stroke patients were randomly sampled and divided into an unstable support surface group (15) and stable support surface group (15). In order to identify the effect depending on the form of support surfaces, 15 minutes of support surface training plus + 15 minutes of free gait training was performed. [Results] The results of the unstable support surface training showed that the corresponding sample t-test results were significant for the 7-item 3-point Berg balance scale, timed Up and Go test, and 6-minute walking test. The independent samples t-test, showed that there were significant outcomes in step length on the affected side, and step length on the unaffected side. [Conclusion] In conclusion, the sit to stand training on stable support surfaces was not as effective as the training using unstable support surfaces, but it is a simple and stable exercise with less risk of falls during training. It can also be performed alone by the patient in order to increase endurance and dynamic balance ability. Therefore, it is considered a useful exercise that can be performed alone by the patient outside the treatment room. PMID- 24764617 TI - Study of treadmill exercise effect on rats with osteoarthritis using proteomic analysis. AB - [Purpose] To investigate the correlation between the effect treadmill exercise and change in serum proteins in rats with osteoarthritis, a study of proteins was carried out using a mass spectrometer. [Subjects and Methods] Rats were randomly divided into five groups. After 4 weeks of treadmill training, serum from each rat was analyzed by Liquid chromatography-electrospray ionization tandem mass spectrometry. Complementary component 9 (C9) was discovered to be downregulated in the serum of the exercise groups, and this was validated by Western blot. [Results] Seventeen proteins were discovered to be elevated in the monosodium iodoacetate injection osteoarthritis group samples by more than 1.5 fold compared with the control group. One of the proteins upregulated, C9 protein, was validated, and it was found to decrease in the middle-intensity exercise group. [Conclusion] We showed that the serum level of C9, an inflammatory-related protein, decreased after treadmill exercise. Therefore, treadmill exercise with an appropriate intensity might be recommended for OA patients. PMID- 24764618 TI - The effects of stretching and stabilization exercise on the improvement of spastic shoulder function in hemiplegic patients. AB - [Purpose] This study investigated the effects of stretching and joint stabilization exercises applied to spastic shoulder joints on improving shoulder dysfunction in hemiplegic patients. [Subjects and Methods] Hemiplegic patients were classified into three groups: one group received 30 min of traditional exercise therapy for the spastic shoulder joint; one group received 30 min stretching; and one group received 15 min of stretching and 15 min of joint stabilization exercises. The exercises were performed once a day, five times per week for eight weeks. Changes in the pathologic thickness of tendons and recovery of shoulder function were compared among the three groups. Differences among the three groups before the experiment, at four weeks, and at eight weeks were analyzed using repeated measures ANOVA. [Results] The stretching and joint stabilization exercise therapy group showed greater improvement in shoulder function than the traditional exercise therapy group and the stretching only group. This group also showed greater decreases in the pathologic thickness of tendons, than the other groups. [Conclusion] This study demonstrated that an exercise therapy program that combined stretching and joint stabilization exercise was more effective than other exercises for improvement of spastic shoulder joint dysfunction in hemiplegic patients. PMID- 24764619 TI - The effect of mirror therapy integrating functional electrical stimulation on the gait of stroke patients. AB - [Purpose] The aim of the present study was to examine whether mirror therapy in conjunction with FES in stroke patients can improve gait ability. [Subjects] This study was conducted with 30 subjects who were diagnosed with hemiparesis due to stroke. [Methods] Experimental group I contained 10 subjects who received mirror therapy in conjunction with functional electrical stimulation, experimental group II contained 10 subjects who received mirror therapy, and the control group contained 10 subjects who received a sham therapy. A gait analysis was performed using a three-dimensional motion capture system, which was a real-time tracking device that delivers data in an infrared mode via reflective markers using six cameras. [Results] The results showed a significant difference in gait velocity between groups after the experiment, and post hoc analysis revealed significant differences between experimental group I and the control group and between experimental group II and the control group, respectively. There were also significant differences in step length and stride length between the groups after the experiment, and post hoc analysis revealed significant differences between experimental group I and control group. [Conclusion] The present study showed that mirror therapy in conjunction with FES is more effective for improving gait ability than mirror therapy alone. PMID- 24764620 TI - Waveform Analysis of the Brachial-ankle Pulse Wave Velocity in Hemiplegic Stroke Patients and Healthy Volunteers: A Pilot Study. AB - [Purpose] Brachial-ankle pulse wave velocity (BaPWV), which has been reported as an index of arterial stiffness, is very closely related to cardiovascular risk factors. A high BaPWV indicates high cardiovascular risk. However, BaPWV and pressure waveforms after stroke are not fully understood. [Methods] BaPWV was measured in thirty-two subjects (twenty-two healthy volunteers and ten stroke patients) while they were in the supine position. It was measured in their bilateral upper and lower extremities. [Results] BaPWV was significantly increased in the stroke group compared with the healthy volunteers. It was also significantly increased on both the affected and non-affected sides of stroke patients in the stroke group. Furthermore, analysis of the pressure waveforms showed that the peak pressure was significantly increased in the stroke group compared with the control group. The peak pressure on both the affected and non affected sides was also significantly greater than in the control group. However, the rise and decay times were significantly decreased in the stroke group compared with the control group. The rise and decay time on both the affected and non-affected sides were also significantly more decreased than in the control group. [Conclusion] The results demonstrated that increased BaPWV and changed pulse waves are closely associated with the pathologic states of hemiplegic stroke patients. PMID- 24764621 TI - The Immediate Effect of Humerus Anatomical Neck-shaft Rotation on Glenohumeral Joint Contracture. AB - [Purpose] Elderly female patients with glenohumeral joint (GHJ) contracture, forced into prolonged immobility were examined. Range of motion exercises using humerus anatomical neck-shaft rotation were performed, and the immediate effect and adaptation were investigated. [Subjects and Methods] A total of ten individuals with a mean age of 79.4 +/- 11.0 years were included in this study. The controlled intervention involved conventional range of motion exercises, and the experimental intervention involved humerus anatomical neck-shaft rotation. Each exercise was performed 30 times. Shoulder joint flexion and abduction and external rotation of the GHJ range of motion were measured with the scapula fixed. Each change in range of motion was compared using ANOVA; less than 5% was considered significant. [Results] After the experimental intervention, significant increases were seen in shoulder joint flexion, abduction, and external rotation ranges of motion. [Conclusion] Therefore, this method was effective as a means of improving the range of motion of the GHJ. PMID- 24764622 TI - Users' satisfaction with assistive devices in South Korea. AB - [Purpose] The objective of this study was to determine users' satisfaction with assistive devices, and their serviceability and effectiveness. [Methods] A random sample of 138 users participated in this study. The Korean-Quebec User Evaluation of Satisfaction with Assistive Technology 2.0 and an additional questionnaire were used for data collection. Data were analyzed by using descriptive statistics. [Results] Overall client satisfaction was high. Respondents most commonly reported use of their device for "personal activities of daily living" and "mobility", and considered engagement in "activities of daily living", and "social participation" to be most desirable, respectively. [Conclusion] This study will provide rehabilitation professionals with valuable information about client satisfaction with assistive devices. PMID- 24764623 TI - The effects of a balance exercise program for enhancement of gait function on temporal and spatial gait parameters in young people with intellectual disabilities. AB - [Purpose] The aim of the study was to assess the effect of an 8-week balance exercise program for enhancement of gait function on temporal and spatial parameters of school aged children with intellectual disabilities. [Subjects] Forty young people with intellectual disabilities were assigned either to the balance exercise program for enhancement of gait function group (BG group, n=19) or the control group (n=21). [Methods] The BG group attended an 8-week balance exercise program for enhancement of gait function consisting of two sessions a week. Gait was assessed using temporal and spatial parameters. [Results] The balance exercise program resulted in significant improvements in participant performance in temporal and spatial parameters. [Conclusion] A balance exercise program for enhancement of gait function can be an effective intervention for improving functional outcomes and can be recommended as an alternative mode of physical activity programming for improving balance and gait. PMID- 24764624 TI - The effects of stair walking training on the balance ability of chronic stroke patients. AB - [Purpose] The purpose of this study was to evaluate the effects of stair walking training on balance ability of chronic stroke patients. [Subjects and Methods] Forty stroke patients were allocated equally and randomly to an experimental group and a control group. The experimental group undertook 30 minutes of training therapy and 30 minutes of walking exercise on stairs with flat surfaces. The control group undertook 30 minutes went of training therapy and 30 minutes of walking exercise on a flat surface. All the participants had five training sessions each week for four weeks. A Biorescue system was used to measure the weight-bearing footprint, anterior length in the limit of stability, posterior length in the limit of stability, surface area ellipse of Romberg, and length of Romberg before and after the training. [Results] With regard to changes in the weight-bearing footprint, the anterior length in the limit of stability, and the posterior length in the limit of stability, there were significant differences on both the paretic and nonparetic sides, and there were also significant differences in the surface area ellipse of Romberg and length of Romberg after the intervention. [Conclusion] The experiment results showed that walking exercise on stairs is effective in enhancing balance performance. The same exercise can be applied to patients with other types of neurological disorders to improve their balance. PMID- 24764625 TI - The Influence of an Unstable Surface on Trunk and Lower Extremity Muscle Activities during Variable Bridging Exercises. AB - [Purpose] The aim of this study was to investigate the influence of an unstable surface on trunk and lower extremity muscle activities during various types of bridging exercises. [Subjects] Thirty healthy female adults voluntarily participated in this study. [Methods] All subjects were asked to perform 3 different bridging exercises (bridging exercise, single leg lift bridging exercise, single leg cross bridging exercise) with and without an unstable surface. The trunk and lower extremity muscle activities were measured by using surface electromyography during bridging exercise. [Results] During the bridging exercise (BE), single leg lift bridging exercise (LBE), and single leg cross bridging exercise (CBE), the muscle activities of the external oblique muscle (EO), erector spinae (ES), and biceps femoris (BF) were significantly higher on an unstable surface than on a stable surface. The muscle activities of the EO on both sides, contralateral BF, and ipsilateral ES were significantly higher during LBE than during BE and CBE. [Conclusion] Use of an unstable surface increases muscle activity of the trunk and lower extremities, and single leg lift bridging exercise increases the muscle activity of the EO on both sides, ipsilateral ES, and contralateral BF. PMID- 24764626 TI - Effect of Resistance Training Maintaining the Joint Angle-torque Profile Using a Haptic-based Machine on Shoulder Internal and External Rotation. AB - [Purpose] The aim of this study was to present an individualized resistance training method to enable exercise while maintaining an exercise load that is set according to an individual's joint angle-torque using a haptic-based resistance training machine. [Methods] Five participants (machine group) performed individualized shoulder internal and external rotation training with a haptic resistance training machine, while another five participants performed general dumbbell-based shoulder internal and external rotation training for eight weeks. Internal and external rotation powers of subjects were measured using an isokinetic machine before and after training. [Results] The average powers of both shoulder internal and external rotation has been improved after training (25.72%, 13.62%). The improvement in power of external rotation in the machine group was significantly higher than that in the control group. [Conclusion] This study proposes a haptic-based individualized rotator cuff muscle training method. The training protocol maintaining the joint angle-torque profile showed better improvement of shoulder internal/external rotation than dumbbell training. PMID- 24764627 TI - Manual lymph drainage attenuates frontal EEG asymmetry in subjects with psychological stress: a preliminary study. AB - [Purpose] The purpose of this preliminary study was to investigate the effect of manual lymph drainage (MLD) of the neck on frontal electroencephalogram (EEG) asymmetry in subjects with psychological stress. [Subjects] Thirteen subjects with psychological stress participated in the study. [Methods] Subjects received MLD of the neck for 15 min. [Results] Analysis of the frontal asymmetry index showed that the energy shift in the alpha frequency band from the left hemisphere to the right hemisphere after MLD resulted in greater left-side activation (positive asymmetry values), which could be related to the positive emotional state observed particularly in the F7-F8 area. [Conclusion] These preliminary findings suggest that frontal EEG asymmetry was significantly attenuated after MLD. PMID- 24764628 TI - The effect of a complex training program on skating abilities in ice hockey players. AB - [Purpose] Little data exist on systemic training programs to improve skating abilities in ice hockey players. The purpose of this study was to evaluate the effectiveness of a complex training program on skating abilities in ice hockey players. [Methods] Ten male ice hockey players (training group) that engaged in 12 weeks of complex training and skating training and ten male players (control group) that only participated in 12 weeks of skating training completed on-ice skating tests including a 5 time 18 meters shuttle, t-test, Rink dash 5 times, and line drill before, during, and the training. [Results] Significant group-by time interactions were found in all skating ability tests. [Conclusion] The complex training program intervention for 12 weeks improved their skating abilities of the ice hockey players. PMID- 24764629 TI - Can walking ability enhance the effectiveness of breathing exercise in children with spastic cerebral palsy? AB - [Purpose] The purpose of this study was to compare differences in respiratory pressure and pulmonary function and the effectiveness of respiratory feedback training according to walking ability in children with cerebral palsy (CP). [Subjects and Methods] Twenty-three children with spastic CP were enrolled in the final analysis and were divided into an independent walking group (n=12) and non independent walking group. All children received respiratory feedback training for four weeks. Before and after the training, respiratory muscle strength was measured and a pulmonary function test was performed. [Results] Comparison of respiratory pressure and pulmonary function test results between the two revealed that the independent walking group had significantly higher respiratory function than the other group in all variables except peak expiratory flow. In comparison of changes in respiratory function between the two groups, the independent walking group showed significantly higher improvement of respiratory function in terms of maximal inspiratory pressure, maximal expiratory pressure, and forced vital capacity. [Conclusion] These findings showed that children with independent walking ability had better respiratory muscle strength and pulmonary function compared with children without independent walking ability. Understanding respiratory function and the effectiveness of respiratory training according to walking ability will be valuable clinical information for respiratory assessment and therapy in children with CP. PMID- 24764630 TI - The Effects of Visual Field Conditions on Electromyography of the Lower Extremities during Reaching Tasks in Healthy Adults. AB - [Purpose] The purpose of this study was to identify the effects of visual field condition on electromyography of the lower extremities during arm reaching in healthy adults, and to compare differences in electromyography of the lower extremities between young and old adults according to visual fields condition. [Subjects and Methods] Twenty-nine young persons in their 20s and 19 elderly persons in their 60s, a total of 48 persons, participated in this study. Prior to participation in the study, each subject signed an informed consent form to comply with ethics guidelines dictated by the ethics committee for research at Silla University, Korea. We collected the muscle activation data for both of tibialis anterior and gastrocnemius muscle during reaching by subjects using electromyography. Data analysis with SPSS for Window Version 20.0 was performed using repeated one-way analysis of variance according to visual fields and age. [Results] There were no significantly differences between subjects in their 20s and 60s to visual field conditions except for left tibialis anterior muscle activation during left-side reaching. Left tibialis anterior muscle activation in subjects in their 60s was higher than in subjects in their 20s during left-side reaching. [Conclusion] We determined that tibialis anterior muscle activation in subjects in their 60s was higher than in subjects in their 20s. We suggest that visual field conditions are the important factor for physical therapy interventions to improve balance and priority of intervention . PMID- 24764631 TI - The Effects of VR-based Wii Fit Yoga on Physical Function in Middle-aged Female LBP Patients. AB - [Purpose] The purpose of this research was to determine the effects of a virtual reality-based yoga program on middle-aged female low back pain patients. [Subjects and Methods] Thirty middle-aged female patients who suffered from low back pain were assigned to either a physical therapy program or a virtual reality based yoga program for a period of four weeks. Participants could check their posture and weight bearing on a monitor as they shifted their weight or changed their postures on a Wii balance board. There were a total of seven exercise programs. A 30-minute, three times per week, virtual reality-based Wii Fit yoga program or trunk stabilizing exercise was performed, respectively. [Results] Repeated-measures analysis of covariance revealed significant differences in between pre- and post-training VAS, algometer, Oswestry low-back pain disability index (ODI), Roland Morris disability questionnaire (RMDQ), and fear avoidance beliefs questionnaire (FBQ) scores. The VAS, algometer, ODI, RMDQ, and FBQ scores showed significant differences in groups. Regarding the effect of time-by-group interaction, there were significant differences in VAS, ODI, ODI, and FBQ scores. [Conclusion] In conclusion, for middle-aged female patients who have low back pain, a virtual reality-based yoga program was shown to have positive effects on physical improvements, and this program can be employed as a therapeutic medium for prevention and cure of low back pain. PMID- 24764632 TI - Decrease in Talocrural Joint Mobility is Related to Alteration of the Arterial Blood Flow Velocity in the Lower Limb in Diabetic Women. AB - [Purpose] The purpose of this study was to correlate the talocrural range of motion (ROM) and blood flow velocity in the lower limb arteries of diabetic women. [Subjects and Methods] Thirty women were divided into a control group (G1), consisting of 15 sedentary right-handed subjects (41.27 +/- 7.24 years old) who had no history of blood system disorder, and a diabetes group (G2), consisting of 15 sedentary right-handed subjects (57.87 +/- 6.20 years old) who had type 2 diabetes mellitus. Talocrural ROM was measured by using goniometry for dorsiflexion and plantar flexion movements. In addition, blood flow velocity of the dorsalis pedis, posterior tibial, and popliteal arteries was also assessed. [Results] No significant differences were found between the groups by comparing talocrural ROM and arterial blood velocity. However, a significant association was found in G2 only between the following variables: plantar flexion and blood flow velocity of the dorsalis pedis artery (rs = 0.57), plantar flexion and blood flow velocity of the popliteal artery (rs = 0.50), and dorsiflexion and blood flow velocity of the posterior tibial artery (rs = 0.57). [Conclusion] The decrease in talocrural ROM is related to a decrease in the arterial blood flow velocity in diabetic women. PMID- 24764633 TI - Lack of maintenance of shortwave diathermy equipment has a negative impact on power output. AB - Although shortwave diathermy has been widely used by physiotherapists, there are a few studies assessing the performance of the equipment in use. The aim of the present study was to evaluate the procedures adopted by physiotherapists as users of shortwave diathermy continuous (CSWD), as well as to measure the power output and frequency of CSWD equipment. [Subjects and Methods] Twenty-three physical therapists were interviewed and 23 CSWD equipment were evaluated. Admeasurement was carried out by using a standard phantom to simulate the electrode-skin distance, which ranged from 0.5 to 3.0 cm. Data analysis was performed by using descriptive statistics, ANOVA, and a post-hoc Tukey's test or Pearson's correlation coefficient. [Results] The questionnaires showed that 48% of the interviewees use the correct electrode-skin distance, 70% use a single electrical outlet, and 35% use a grounded electrical outlet, and that 48% of the physiotherapy tables and 61% of the plinths were made of wood. However, only 13% of the interviewees perform yearly preventive maintenance. The highest power (95.56 W) was achieved at electrode-skin distances ranging from 1.0 to 1.5 cm, with distances of 2.5 cm and 3.0 cm being null in four and eight equipment, respectively. There was a negative correlation between power output and electrode skin distance as well as between power output and purchase date. [Conclusion] The physiotherapists involved in this study had inadequate knowledge about the correct use of CSWD equipment, which may adversely affect its performance and patient safety. PMID- 24764634 TI - Comparison of Gait Aspects According to FES Stimulation Position Applied to Stroke Patients. AB - [Purpose] This study sought to identify the gait aspects according to the FES stimulation position in stroke patients during gait training. [Subjects and Methods] To perform gait analysis, ten stroke patients were grouped based on 4 types of gait conditions: gait without FES stimulation (non-FES), gait with FES stimulation on the tibialis anterior (Ta), gait with FES stimulation on the tibialis anterior and quadriceps (TaQ), and gait with FES stimulation on the tibialis anterior and gluteus medius (TaGm). [Results] Based on repeated measures analysis of variance of measurements of gait aspects comprised of gait speed, gait cycle, and step length according to the FES stimulation position, the FES stimulation significantly affected gait aspects. [Conclusion] In conclusion, stimulating the tibialis anterior and quadriceps and stimulating the tibialis anterior and gluteus medius are much more effective than stimulating only the tibialis anterior during gait training in stroke patients using FES. PMID- 24764635 TI - Pain, Work-related Characteristics, and Psychosocial Factors among Computer Workers at a University Center. AB - [Purpose] Complaint of pain is common in computer workers, encouraging the investigation of pain-related workplace factors. This study investigated the relationship among work-related characteristics, psychosocial factors, and pain among computer workers from a university center. [Subjects and Methods] Fifteen subjects (median age, 32.0 years; interquartile range, 26.8-34.5 years) were subjected to measurement of bioelectrical impedance; photogrammetry; workplace measurements; and pain complaint, quality of life, and motivation questionnaires. [Results] The low back was the most prevalent region of complaint (76.9%). The number of body regions for which subjects complained of pain was greater in the no rest breaks group, which also presented higher prevalences of neck (62.5%) and low back (100%) pain. There were also observed associations between neck complaint and quality of life; neck complaint and head protrusion; wrist complaint and shoulder angle; and use of a chair back and thoracic pain. [Conclusion] Complaint of pain was associated with no short rest breaks, no use of a chair back, poor quality of life, high head protrusion, and shoulder angle while using the mouse of a computer. PMID- 24764636 TI - Comparison of the Effects on Dynamic Balance Ability of Warming up in Water Versus on the Ground. AB - [Purpose] This research was designed to find out how the so-called "dynamic balance" is affected by doing different types of warm up exercises. In particular, the research is focused on the difference in the effect on dynamic Balance of warming up in water versus on the ground. [Subjects and Methods] Twenty healthy adults were the subjects of this study, with 10 people assigned each to two groups, one warming up in water and another warming up on the ground. The dynamic balance was measured for all subjects before the warming up. The group warming up on the ground conducted active stretching on the ground, and the group warming up in water conducted stretching in water by using water as resistance. [Results] The results indicate that warming up in water has a more powerful effect on a subject's dynamic balance than warming up on the ground. [Conclusion] The group warming up in water, who made use of the viscosity and flow of the water, showed better balance than the group warming up on the ground. Warming up in water, which entails an element of resistance, should be implemented in warm-up routines in the future. PMID- 24764637 TI - Effects of Spinal Stabilization Exercise on the Cross-sectional Areas of the Lumbar Multifidus and Psoas Major Muscles, Pain Intensity, and Lumbar Muscle Strength of Patients with Degenerative Disc Disease. AB - [Purpose] The aim of this study was to evaluate the efficacy of using spinal stabilizing exercise to reduce atrophy of the multifidus and psoas major muscles, reduce the levels of pain and disability, and increase paraspinal muscle strength in patients with degenerative disc disease (DDD). [Subjects and Methods] In 33 patients (Age range: 25-65 years) diagnosed with DDD, spinal stabilization exercise was conducted for 8 weeks. The levels of pain and disability were measured before and after exercise using the visual analogue scale (VAS) and the Oswestry Disability Index (ODI). Paraspinal muscular strength in four directions was evaluated with a CENTAUR 3D Spatial Rotation Device. Cross-sectional areas (CSAs) of both the left and right multifidus and the psoas major at the upper endplate of L4 were measured before and after exercise using computed tomography (CT). [Results] After 8 weeks of spinal stabilization exercise, the pain and lumbar disability in subjects decreased significantly from 6.12+/-1.24 to 2.43+/ 1.14. The ODI score also improved from 20.18+/-7.14 to 8.81+/-5.73. In addition, paraspinal muscle strength increased significantly, while the CSAs of the left and right multifidus and psoas major widened as compared with the pre-exercise size. [Conclusion] Spinal stabilization exercise was effective for reducing pain and disability in DDD patients. It was an effective adjunct to aid rehabilitation in these cases. PMID- 24764638 TI - Physical performance, balance, mobility, and muscle strength decline at different rates in elderly people. AB - [Purpose] The aim of this study was to verify the decline in functionality of elderly people. [Subjects and Methods] The study subjects comprised 152 individuals (96 women; 56 men) divided into 3 groups: G1 (60 to 69 years, n=53); G2 (70 to 79 years, n=65); and G3 (80 years or older, n=34). Physical performance, balance, mobility, and muscle strength were assessed using Short Physical Performance Battery (SPPB), Berg Balance Scale (BERG), Timed Up and Go (TUG) test, and leg press test, respectively. Comparison among age-stratified groups (G1, G2 and G3) and between genders were examined using analysis of variance with Tukey's test as a post hoc test or the Kruskal-Wallis test with Bonferroni correction. [Results] SPPB and BERG scores decreased significantly in comparison between G1 and G3, and between G2 and G3 in women. TUG and leg press scores decreased significantly in comparison between G1 and G3 and between G2 and G3. [Conclusion] People in their 60s and 70s have similar functional characteristics (physical performance, balance, mobility and muscle strength for both genders), and functionality starts to decline when people are in their 80s. PMID- 24764639 TI - Altered Co-contraction of Cervical Muscles in Young Adults with Chronic Neck Pain during Voluntary Neck Motions. AB - [Purpose] Muscle co-contraction is important in stabilizing the spine. The aim of this study was to compare cervical muscle co-contraction in adults with and without chronic neck pain during voluntary movements. [Subjects and Methods] Surface electromyography of three paired cervical muscles was measured in fifteen young healthy subjects and fifteen patients with chronic neck pain. The subjects performed voluntary neck movements in the sagittal and coronal plane at slow speed. The co-contraction ratio was defined as the normalized integration of the antagonistic electromyography activities divided by that of the total muscle activities. [Results] The results showed that the co-contraction ratio of patients was greater during flexion movement, lesser during extension movement, slightly greater during right lateral bending, and slightly lesser during left lateral bending compared with in the controls. [Conclusion] The results suggested that neck pain patients exhibit greater antagonistic muscle activity during flexion and dominate-side bending movements to augment spinal stability, while neuromuscular control provides relatively less protection in the opposite movements. This study helps to specify the changes of the stiffness of the cervical spine in neck pain patients and provides a useful tool and references for clinical assessment of neck disorders. PMID- 24764640 TI - Effect of Different Positions on FVC and FEV1 Measurements of Asthmatic Patients. AB - [Purpose] The purpose of our study was to investigate the effect of different positions on pulmonary function test (PFT) values such as forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) of asthmatic patients .[Subjects and Methods] Thirty subjects with severe asthma aged between 20-39 years were enrolled after they had signed a written consent. Subjects were selected using the inclusion criteria, and PFT were randomly administered. Spirometer measurements (FVC, FEV1) were taken in the supine, side lying on right, side lying on left, sitting and standing positions. Each measurement was taken three times, and the average values were analyzed. [Results] One- way analysis of variance (ANOVA) and Tukey's Test (post hoc) for pair- wise comparison indicated that there was a significant difference in the FEV1 values of the asthmatic patients however a significant difference was obtained between standing and supine positions. There was also a significant difference in the FVC values between the standing and supine lying position in the pair -wise comparison. [Conclusion] This study showed standing is the best position for measuring FEV1 and FVC of asthmatic subjects. The more upright the position, the higher the FEV1 and FVC will be. PMID- 24764641 TI - The comparison of cervical repositioning errors according to smartphone addiction grades. AB - [Purpose] The purpose of this study was to compare cervical repositioning errors according to smartphone addiction grades of adults in their 20s. [Subjects and Methods] A survey of smartphone addiction was conducted of 200 adults. Based on the survey results, 30 subjects were chosen to participate in this study, and they were divided into three groups of 10; a Normal Group, a Moderate Addiction Group, and a Severe Addiction Group. After attaching a C-ROM, we measured the cervical repositioning errors of flexion, extension, right lateral flexion and left lateral flexion. [Results] Significant differences in the cervical repositioning errors of flexion, extension, and right and left lateral flexion were found among the Normal Group, Moderate Addiction Group, and Severe Addiction Group. In particular, the Severe Addiction Group showed the largest errors. [Conclusion] The result indicates that as smartphone addiction becomes more severe, a person is more likely to show impaired proprioception, as well as impaired ability to recognize the right posture. Thus, musculoskeletal problems due to smartphone addiction should be resolved through social cognition and intervention, and physical therapeutic education and intervention to educate people about correct postures. PMID- 24764642 TI - The effects of active scapular protraction on the muscle activation and function of the upper extremity. AB - [Purpose] The purpose of this study was to determine the effects of adjusting the scapula into its ideal position through active scapular protraction on the muscle activation and function of the upper extremity. [Subjects] Twenty female college students aged 19-21 without any physical or functional disability were the subjects of this study. They had no history of injury to their upper extremities or hands. [Methods] After the initial measurements the experimental group was asked to perform active scapular protraction; then, their grip strength and muscle activation were measured again. Every action was maintained for 5 seconds and repeated 3 times. The mean values of the measurements were analyzed. A resting of 1 minute was given between each action. [Results] The results revealed a significant change in the experimental group's grip strength after active scapular protraction had been performed. The surrounding muscles of the scapula, such as the serratus anterior, upper trapezius, flexor carpi ulnaris, flexor carpi radialis and palmaris longus, showed significant changes in muscle activation after active scapular protraction. The muscles of the upper extremity also showed significant changes after active scapular protraction. [Conclusion] The adjustment of scapula into its ideal position through active scapular protraction increased the activations of the muscles surrounding the shoulder joint and improved the function of the upper extremity. PMID- 24764643 TI - The effects of precise contraction of the pelvic floor muscle using visual feedback on the stabilization of the lumbar region. AB - [Purpose] The purpose of this study is to verify whether precise contraction of the pelvic floor muscle (PFM) using visual feedback actually affects the thickness of abdominal muscles. [Subjects] The subjects were 29 healthy adults in their 20s who consented to participate in this study. [Methods] This study provided visual feedback on PFM using one ultrasound device and identified changes in the transversus abdominis (TRA) using another ultrasound device. Abdominal muscle thicknesses were measured by ultrasound under three conditions (rest, PFM contraction, PFM contraction with visual feedback). [Results] There were no statistically significant differences in the external oblique (EO) and internal oblique (IO) muscles between the measurements taken at rest and during the contraction of the PFM, and between those taken at rest and during the contraction of the PFM with visual feedback. There were significant differences in the TRA. In particular, TRA thickness was highest in the order of PFM contraction, PFM contraction with visual feedback, and rest. [Conclusion] Hollowing with visual feedback is not an efficient stabilization exercise method for the PFM. PMID- 24764644 TI - Effects of Exercise Type on Hemodynamic Responses and Cardiac Events in ACS Patients. AB - [Purpose] This study investigated the effects of mid, and high exercise intensities on hemodynamic responses and cardiac events during two exercise types of treadmill exercise (TM) and cycle ergometer exercises (CE) in patients with acute coronary syndrome (ACS). [Subjects] Patients who had percutaneous coronary intervention (PCI) for ACS and were participating in cardiac rehabilitation program were included. [Methods] The patients were assessed for hemodynamic responses, cardiac events, and rate of perceived exertion (RPE) with target heart rates of 60% and 85% heart rate reserve (HRR) during TM and CE. [Results] Maximum systolic blood pressure (SBP), diastolic blood pressure (DBP), RPE, and rate pressure product (RPP) measured during CE were significantly higher than their values in TM at the same exercise intensities. The highest SBP was shown at 85% HRR during CE. SBPmax to SBPmax ratios obtained during the graded exercise test (GXT) showed that all %SBPmax were significantly greater in CE than in TM at the same exercise intensities. Out of 102 patients, cardiac events occurred in 8 at 85% HRR during CE, and 1 at 85% HRR during TM. Patients with cardiac events (CE E) had significantly higher %SBP, %RPP, and RPE at 85% HRR than those without events (CE-NE) during CE. [Conclusion] Prescribing exercise based on the intensity obtained in a treadmill GXT may expose patients to cardiovascular complications such as higher RPP, higher exercise intensity, and cardiac events during CE. PMID- 24764645 TI - The Effects of Virtual Reality-based Balance Training on Balance of the Elderly. AB - [Purpose] The objective of this study was to determine the effects of virtual reality-based balance training on balance of the elderly. [Methods] The subjects were 32 healthy elderly people aged between 65 and 80, who were divided into a VR (virtual reality) training group (n=17) and a control group (n=15). The VR training group engaged in a 30-minute exercise session using Wii Fit three times a week for eight weeks, while the control group received no intervention. The balance of the two groups was measured before and after the intervention. [Results] According to the Romberg Test conducted to examine the effects of the training on balance, both the area covered by the body's center of pressure movement, and movement distances per unit area of the body's center of pressure envelope significantly decreased in the VR training group. Moreover, the two groups showed significant differences in balance. [Conclusion] Virtual reality training is effective at improving the balance of the healthy elderly. Thus, virtual reality training can be proposed as a form of fall prevention exercise for the elderly. PMID- 24764646 TI - The Effect of an Inclined Ankle on the Activation of the Abductor Hallucis Muscle during Short Foot Exercise. AB - [Purpose] The purpose of this study was to identify the effects of an inclined ankle on the activation of the abductor hallucis muscle during short foot exercises. [Subjects] We recruited 14 healthy volunteers who were free of pain, and did not suffer from arthritis or osteomuscular problems related to the foot or ankle. [Methods] The subjects performed short foot exercises and short inclined foot exercises with 30 degrees passive ankle dorsiflexion. [Results] The exercise with an inclined foot showed a significantly larger activation of the abductor hallucis than that shown during the neutral short foot exercises. [Conclusion] These results suggest that passive ankle dorsiflexion during short foot exercise for strengthening the abductor hallucis is a more effective clinical treatment exercise. PMID- 24764647 TI - Relationship between Muscle Fiber Conduction Velocity and the Force-time Curve during Muscle Twitches. AB - [Purpose] The aim of this study was to clarify the relationship between the muscle fiber conduction velocity (MFCV) obtained during muscle twitches from evoked potentials and the dynamic characteristics of muscular tension (muscle dynamic characteristics) by manipulating deep temperature. [Subjects] Subjects were 10 healthy adult men. Their mean age was 23.0 +/- 3.9 years. [Methods] Measurement items were MFCV of the right tibialis anterior muscle and the force time curve of right ankle dorsiflexion (muscle twitch). Measurements were made under conditions of ordinary (room) temperature, hot and cold. The rate of change in maximum torque was calculated from the force-time curve. [Results] In all subjects, MFCV increased significantly with heating and decreased significantly with cooling. A strong correlation was seen between MFCV and deep temperature. A strong correlation was also seen between MFCV and the rate of change in maximum torque. Stronger correlations were seen in the present results than in previous studies that conducted investigations using voluntary contractions. [Conclusion] The present results were not affected by psychological or other such factors, and are valuable as data with high physiological reliability. In conclusion, this study was able to clarify the relationship between MFCV from evoked potentials and muscle dynamic characteristics. PMID- 24764648 TI - The effects of wobble board training on the eyes open and closed static balance ability of adolescents with down syndrome. AB - [Purpose] The aim of the present study was to examine the influence of wobble board training on static balance, with and without vision, of adolescents with Down syndrome (DS). [Subjects] Ten adolescents with DS were recruited for this study. [Methods] Participants performed quiet standing with their eyes open and closed, pre- and post-wobble board training. During quiet standing, the center of pressure (COP) data was recorded using a force plate. To assess the static balance ability of the participants, the 95% confidence ellipse area of COP was calculated. The paired t-test was used to compare the 95% confidence ellipse area of COP between the eyes open and closed conditions, and between pre- and post training. [Results] Although there was no significant difference in the 95% confidence ellipse area of COP between with and without vision, the 95% confidence ellipse area of COP decreased significantly after wobble board training. [Conclusion] These findings suggest that wobble board training is an effective at improving the static balance ability of adolescents with DS. PMID- 24764649 TI - Potential for Polychlorinated Biphenyl Biodegradation in Sediments from Indiana Harbor and Ship Canal. AB - Polychlorinated biphenyls (PCBs) are carcinogenic, persistent, and bioaccumulative contaminants that pose risks to human and environmental health. In this study, we evaluated the PCB biodegradation of sediments from Indiana Harbor and Ship Canal (IHSC), a PCB-contaminated site (average PCB concentration = 12,570 ng/g d.w.). PCB congener profiles and bacterial community structure in a core sediment sample (4.57 m long) were characterized. Analysis of vertical PCB congener profile patterns in sediment and pore water strongly suggest that in situ dechlorination occurred in sediments. However, 16S rRNA genes from putative PCB-dechlorinating Chloroflexi were relatively more abundant in upper 2 m sediments, as were genes indicative of aerobic biodegradation potential (i.e. biphenyl dioxygenase (bphA)). Characterization of the bacterial community by terminal restriction fragment length polymorphism and comparison of these with sediment and pore water PCB congener profiles with the Mantel test revealed a statistical correlation (p<0.001). Sequences classified as Acinetobacter and Acidovorax were highly abundant in deep sediments. Overall, our results suggest that PCB dechlorination has already occurred, and that IHSC sediments have the potential for further aerobic and anaerobic PCB biodegradation. PMID- 24764650 TI - Hepatocellular carcinoma review: current treatment, and evidence-based medicine. AB - Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide. Multiple treatment options are available for HCC including curative resection, liver transplantation, radiofrequency ablation, trans-arterial chemoembolization, radioembolization and systemic targeted agent like sorafenib. The treatment of HCC depends on the tumor stage, patient performance status and liver function reserve and requires a multidisciplinary approach. In the past few years with significant advances in surgical treatments and locoregional therapies, the short term survival of HCC has improved but the recurrent disease remains a big problem. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. For patients with advanced disease, sorafenib is the only approved therapy, but novel systemic molecular targeted agents and their combinations are emerging. This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature. PMID- 24764651 TI - Role of the tissue microenvironment as a therapeutic target in hepatocellular carcinoma. AB - Hepatocellular carcinoma is difficult to treat, primarily because the underlying molecular mechanisms driving clinical outcome are still poorly understood. Growing evidence suggests that the tissue microenvironment has a role in the biological behavior of the tumor. The main clinical issue is to identify the best target for therapeutic approaches. Here, we discuss the hypothesis that the entire tissue microenvironment might be considered as a biological target. However, the tissue microenvironment consists of several cellular and biochemical components, each of which displays a distinct biological activity. We discuss the major components of this environment and consider how they may interact to promote tumor/host crosstalk. PMID- 24764652 TI - Staging systems of hepatocellular carcinoma: a review of literature. AB - Hepatocellular carcinoma (HCC) is a major health problem with a high incidence and mortality all over the world. Natural history of HCC is severe and extremely variable, and prognostic factors influencing outcomes are incompletely defined. Over time, many staging and scoring systems have been proposed for the classification and prognosis of patients with HCC. Currently, the non-ideal predictive performance of existing prognostic systems is secondary to their inherent limitations, as well as to a non-universal reproducibility and transportability of the results in different populations. New serological and histological markers are still under evaluation with promising results, but they require further evaluation and external validation. The aim of this review is to highlight the main tools for assessing the prognosis of HCC and the main concerns, pitfalls and warnings regarding its staging systems currently in use. PMID- 24764653 TI - Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age. AB - The kinase inhibitor sorafenib is the only systemic therapy proven to have a positive effect on survival of patients with advanced hepatocellular carcinoma (HCC). After development of sorafenib and its introduction as a therapeutic agent used in the clinic, several critical questions have been raised. Clinical parameters and biomarkers predicting sorafenib efficacy are the most important issues that need to be elucidated. Although it is difficult to know the responders in advance using conventional characteristics of patients, there are specific serum cytokines and/or gene amplification in tumor tissues that have been reported to predict efficacy of sorafenib. Risk and benefits of continuation of sorafenib beyond radiological progression is another issue to consider because no other standard therapy for advanced HCC as yet exists. In addition, effectiveness of the expanded application of sorafenib is still controversial, although a few studies have shed some light on combinational treatment with sorafenib for intermediate-stage HCC. Recently, over 50 relevant drugs have been developed and are currently under investigation. The efficacy of some of these drugs has been extensively examined, but none have demonstrated any superiority over sorafenib, so far. However, there are several drugs that have shown efficacy for treatment after sorafenib failure, and these are proceeding to further studies. To address these issues and questions, we have done extensive literature review and summarize the most current status of therapeutic application of sorafenib. PMID- 24764654 TI - Therapeutic response assessment of RFA for HCC: contrast-enhanced US, CT and MRI. AB - Radiofrequency ablation (RFA) is commonly applied for the treatment of hepatocellular carcinoma (HCC) because of the facile procedure, and the safety and effectiveness for the treatment of this type of tumor. On the other hand, it is believed that HCC cells should spread predominantly through the blood flow of the portal vein, which could lead to the formation of intrahepatic micrometastases. Therefore, monitoring tumor response after the treatment is quite important and accurate assessment of treatment response is critical to obtain the most favorable outcome after the RFA. Indeed, several reports suggested that even small HCCs of <= 3 cm in diameter might carry intrahepatic micrometastases and/or microvascular invasion. From this point of view, for preventing local recurrences, RFA should be performed ablating a main tumor as well as its surrounding non-tumorous liver tissue where micrometastases and microvascular invasion might exist. Recent advancement of imaging modalities such as contrast-enhanced ultrasonic, computed tomography, and magnetic resonance imaging are playing an important role on assessing the therapeutic effects of RFA. The local recurrence rate tends to be low in HCC patients who were proven to have adequate ablation margin after RFA; namely, not only disappearance of vascular enhancement of main tumor, but also an adequate ablation margin. Therefore, contrast enhancement gives important findings for the diagnosis of recurrent HCCs on each imaging. However, hyperemia of non-tumorous liver surrounding the ablated lesion, which could be attributed to an inflammation after RFA, may well obscure the findings of local recurrence of HCCs after RFA. Therefore, we need to carefully address to these imaging findings given the fact that diagnostic difficulties of local recurrence of HCC. Here, we give an overview of the current status of the imaging assessment of HCC response to RFA. PMID- 24764655 TI - Genetic variations in colorectal cancer risk and clinical outcome. AB - Colorectal cancer (CRC) has an apparent hereditary component, as evidenced by the well-characterized genetic syndromes and family history associated with the increased risk of this disease. However, in a large fraction of CRC cases, no known genetic syndrome or family history can be identified, suggesting the presence of "missing heritability" in CRC etiology. The genome-wide association study (GWAS) platform has led to the identification of multiple replicable common genetic variants associated with CRC risk. These newly discovered genetic variations might account for a portion of the missing heritability. Here, we summarize the recent GWASs related to newly identified genetic variants associated with CRC risk and clinical outcome. The findings from these studies suggest that there is a lack of understanding of the mechanism of many single nucleotide polymorphisms (SNPs) that are associated with CRC. In addition, the utility of SNPs as prognostic markers of CRC in clinical settings remains to be further assessed. Finally, the currently validated SNPs explain only a small fraction of total heritability in complex-trait diseases like CRC. Thus, the "missing heritability" still needs to be explored further. Future epidemiological and functional investigations of these variants will add to our understanding of CRC pathogenesis, and may ultimately lead to individualized strategies for prevention and treatment of CRC. PMID- 24764656 TI - Targeting mTOR network in colorectal cancer therapy. AB - The mechanistic target of rapamycin (mTOR) integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth, proliferation and survival. A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division. Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate. Multiple genetic alterations are involved in colorectal carcinogenesis, including oncogenic Ras activation, phosphatidylinositol 3-kinase pathway hyperactivation, p53 mutation, and dysregulation of wnt pathway. Many oncogenic pathways activate the mTOR pathway. mTOR has emerged as an effective target for colorectal cancer therapy. In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives. However, the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest, especially in advanced metastatic colorectal cancer. Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy, inhibitors of vascular endothelial growth factor, epidermal growth factor receptor and Mitogen-activated protein kinase kinase (MEK) inhibitors are being intensively studied and appear to be promising. Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens. In this paper, oncogenic gene alterations in colorectal cancer, as well as their interaction with the mTOR pathway, are systematically summarized. The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed. New players in mTOR signaling pathway, such as non-steroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here. PMID- 24764657 TI - Hallmarks in colorectal cancer: angiogenesis and cancer stem-like cells. AB - Carcinogenesis is a multistep process that requires the accumulation of various genetic and epigenetic aberrations to drive the progressive malignant transformation of normal human cells. Two major hallmarks of carcinogenesis that have been described are angiogenesis and the stem cell characteristic of limitless replicative potential. These properties have been targeted over the past decade in the development of therapeutic treatments for colorectal cancer (CRC), one of the most commonly diagnosed and lethal cancers worldwide. The treatment of solid tumor cancers such as CRC has been challenging due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells. Furthermore, the same microenvironment that maintains the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia also provides the necessary conditions for proliferative growth of cancer stem-like cells. These cancer stem-like cells are responsible for the resistance to therapy and cancer recurrence, though they represent less than 2.5% of the tumor mass. The stromal environment surrounding the tumor cells, referred to as the tumor niche, also supports angiogenesis, which supplies the oxygen and nutrients needed for tumor development. Anti-angiogenic therapy, such as with bevacizumab, a monoclonal antibody against vascular-endothelial growth factor, significantly prolongs the survival of metastatic CRC patients. However, such treatments are not completely curative, and a large proportion of patient tumors retain chemoresistance or show recurrence. This article reviews the current knowledge regarding the molecular phenotype of CRC cancer cells, as well as discusses the mechanisms contributing to their maintenance. Future personalized therapeutic approaches that are based on the interaction of the carcinogenic hallmarks, namely angiogenic and proliferative attributes, could improve survival and decrease adverse effects induced by unnecessary chemotherapy. PMID- 24764658 TI - Circadian clock circuitry in colorectal cancer. AB - Colorectal cancer is the most prevalent among digestive system cancers. Carcinogenesis relies on disrupted control of cellular processes, such as metabolism, proliferation, DNA damage recognition and repair, and apoptosis. Cell, tissue, organ and body physiology is characterized by periodic fluctuations driven by biological clocks operating through the clock gene machinery. Dysfunction of molecular clockworks and cellular oscillators is involved in tumorigenesis, and altered expression of clock genes has been found in cancer patients. Epidemiological studies have shown that circadian disruption, that is, alteration of bodily temporal organization, is a cancer risk factor, and an increased incidence of colorectal neoplastic disease is reported in shift workers. In this review we describe the involvement of the circadian clock circuitry in colorectal carcinogenesis and the therapeutic strategies addressing temporal deregulation in colorectal cancer. PMID- 24764659 TI - Role of cetuximab in first-line treatment of metastatic colorectal cancer. AB - The treatment of metastatic colorectal cancer (mCRC) has evolved considerably in the last decade, currently allowing most mCRC patients to live more than two years. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor play an important role in the current treatment of these patients. However, only antibodies directed against EGFR have a predictive marker of response, which is the mutation status of v-Ki ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC. The CRYSTAL study showed that adding cetuximab to FOLFIRI (regimen of irinotecan, infusional fluorouracil and leucovorin) significantly improved results in the first-line treatment of KRAS wild-type mCRC. However, results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory. On the other hand, recent advances in the management of colorectal liver metastases have improved survival in these patients. Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients. In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC. PMID- 24764660 TI - Role of stereotactic body radiotherapy for oligometastasis from colorectal cancer. AB - Systemic chemotherapy has enabled prolongation of survival in patients with stage IV colorectal cancer. This has subsequently increased the relative significance of local therapy for patients with oligometastases because they can be cured by removal of oligometastatic lesions. One of the most frequently reported tumor histologies for oligometastases is colorectal cancer. Resection is the standard therapy in most settings of oligometastases. Recently, studies have shown that stereotactic body radiotherapy (SBRT) may become a treatment option that provides high local control with minimal morbidity. Two-year local control rates following SBRT for hepatic and pulmonary oligometastases are almost over 80% and are even higher for patients treated with high-dose regimens. The indications of SBRT for other metastatic sites or conditions include isolated lymph nodes, spinal and adrenal metastasis, and post-surgical pelvic recurrence. Many retrospective studies have indicated that SBRT for various lesions results in good outcomes with low morbidity, both in the curative and palliative setting. However, few reports with a high level of evidence have indicated the efficacy of SBRT compared to standard therapy. Hereafter, the optimal indication of SBRT needs to be prospectively investigated to obtain convincing evidence. PMID- 24764661 TI - Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. AB - Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn's-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels. PMID- 24764662 TI - Multimodal imaging evaluation in staging of rectal cancer. AB - Rectal cancer is a common cancer and a major cause of mortality in Western countries. Accurate staging is essential for determining the optimal treatment strategies and planning appropriate surgical procedures to control rectal cancer. Endorectal ultrasonography (EUS) is suitable for assessing the extent of tumor invasion, particularly in early-stage or superficial rectal cancer cases. In advanced cases with distant metastases, computed tomography (CT) is the primary approach used to evaluate the disease. Magnetic resonance imaging (MRI) is often used to assess preoperative staging and the circumferential resection margin involvement, which assists in evaluating a patient's risk of recurrence and their optimal therapeutic strategy. Positron emission tomography (PET)-CT may be useful in detecting occult synchronous tumors or metastases at the time of initial presentation. Restaging after neoadjuvant chemoradiotherapy (CRT) remains a challenge with all modalities because it is difficult to reliably differentiate between the tumor mass and other radiation-induced changes in the images. EUS does not appear to have a useful role in post-therapeutic response assessments. Although CT is most commonly used to evaluate treatment responses, its utility for identifying and following-up metastatic lesions is limited. Preoperative high resolution MRI in combination with diffusion-weighted imaging, and/or PET-CT could provide valuable prognostic information for rectal cancer patients with locally advanced disease receiving preoperative CRT. Based on these results, we conclude that a combination of multimodal imaging methods should be used to precisely assess the restaging of rectal cancer following CRT. PMID- 24764663 TI - Interval to surgery after neoadjuvant treatment for colorectal cancer. AB - The current standard treatment of low-lying locally advanced rectal cancer consists of chemoradiation followed by radical surgery. The interval between chemoradiation and surgery varied for many years until the 1999 Lyon R90-01 trial which compared the effects of a short (2-wk) and long (6-wk) interval. Results showed a better clinical tumor response (71.7% vs 53.1%) and higher rate of positive and pathologic tumor regression (26% vs 10.3%) after the longer interval. Accordingly, a 6-wk interval between chemoradiation and surgery was set to balance the oncological results with the surgical complexity. However, several recent retrospective studies reported that prolonging the interval beyond 8 or even 12 wk may lead to significantly higher rates of tumor downstaging and pathologic complete response. This in turn, according to some reports, may improve overall and disease-free survival, without increasing the surgical difficulty or complications. This work reviews the data on the effect of different intervals, derived mostly from retrospective analyses using a wide variation of treatment protocols. Prospective randomized trials are currently ongoing. PMID- 24764664 TI - Anti-EGFR and anti-VEGF agents: important targeted therapies of colorectal liver metastases. AB - Colorectal liver metastasis (CLM) is common worldwide. Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. The development and application of anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies represents significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. The Kirsten rat sarcoma viral oncogene (KRAS) has been proven to be a crucial predictor of the success of anti EGFR treatment in CLM. Whereas a recent study summarized several randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Some other studies also reported that the KRAS G13D mutation might not be absolutely predictive of non-responsiveness to anti-EGFR therapy. At the same time, "new" RAS mutations, including mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)4 treatment led to inferior PFS (HR = 1.28, 95%CI: 0.79-2.07) and OS (HR = 1.29, 95%CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2. Then, the update of the PEAK trial and the FIRE-III trial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. In first-line targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII trial. Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. By the update and further analysis of the COIN trial and the NORDIC-VII trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial. In addition, some trials have reported that bevacizumab is not suitable for conversion therapy. The results of the FIRE-III trial showed that cetuximab led to a significant advantage over bevacizumab in response rate (72% vs 63%, P = 0.017) for evaluable population. With the balanced allocation of second-line treatment, the FIRE-III trial was expected to provide evidence for selecting following regimens after first-line progression. There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM, although the combined regimen is often administered based on experience. Combination therapy with more than one targeted agent has been proven to provide no benefit, and even was reported to be harmful as first-line treatment by four large clinical trials. However, recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment. The mechanism of antagonism between different targeted agents deserves further study, and may also provide greater understanding of the development of resistance to targeted agents. PMID- 24764665 TI - Advances in epigenetic biomarker research in colorectal cancer. AB - Colorectal cancer (CRC) causes approximately 600000 deaths annually and is the third leading cause of cancer mortality worldwide. Despite significant advancements in treatment options, CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making. Since there exists a need to find new biomarkers to improve diagnosis of CRC, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. Epigenetic alterations are thought to hold great promise as tumor biomarkers. In this review, we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers, including DNA methylation, microRNA expression and histone modification, in cancer tissue, stool, plasma, serum, cell lines and xenografts. These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening, early diagnosis, prognosis, therapy choice and recurrence surveillance for CRC patients. However, these studies have typically been small in size, and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use. PMID- 24764666 TI - MicroRNAs in colorectal cancer as markers and targets: Recent advances. AB - MicroRNAs are evolutionarily conserved small non-coding RNA molecules encoded by eukaryotic genomic DNA, and function in post-transcriptional regulation of gene expression via base-pairing with complementary sequences in target mRNAs, resulting in translational repression or degradation of target mRNAs. They represent one of the major types of epigenetic modification and play important roles in all aspects of cellular activities. Altered expression of microRNAs has been found in various human diseases including cancer. Many efforts have been made to discover the characteristic microRNA expression profiles, to understand the roles of aberrantly expressed microRNAs and underlying mechanisms in different cancers. With the application of DNA microarray, real-time quantitative polymerase chain reaction and other molecular biology techniques, increasing evidence has been accumulated which reveal that aberrant microRNAs can be detected not only intracellularly within the cancer cells, but also extracellularly in plasma of patients, postulating the potential of aberrant microRNAs as promising diagnostic/prognostic markers and attracting therapeutic targets. This review is intended to provide the most recent advances in microRNA studies in one of the most common cancers, colorectal cancer, especially the identification of those specifically altered microRNAs in colorectal cancer, validation for their relevance to clinical pathological parameters of patients, functional analyses and potential applications of these microRNAs. PMID- 24764668 TI - Non-transmissible Sendai virus vector encoding c-myc suppressor FBP-interacting repressor for cancer therapy. AB - AIM: To investigate a novel therapeutic strategy to target and suppress c-myc in human cancers using far up stream element (FUSE)-binding protein-interacting repressor (FIR). METHODS: Endogenous c-Myc suppression and apoptosis induction by a transient FIR-expressing vector was examined in vivo via a HA-tagged FIR (HA FIR) expression vector. A fusion gene-deficient, non-transmissible, Sendai virus (SeV) vector encoding FIR cDNA, SeV/dF/FIR, was prepared. SeV/dF/FIR was examined for its gene transduction efficiency, viral dose dependency of antitumor effect and apoptosis induction in HeLa (cervical squamous cell carcinoma) cells and SW480 (colon adenocarcinoma) cells. Antitumor efficacy in a mouse xenograft model was also examined. The molecular mechanism of the anti-tumor effect and c-Myc suppression by SeV/dF/FIR was examined using Spliceostatin A (SSA), a SAP155 inhibitor, or SAP155 siRNA which induce c-Myc by increasing FIR?exon2 in HeLa cells. RESULTS: FIR was found to repress c-myc transcription and in turn the overexpression of FIR drove apoptosis through c-myc suppression. Thus, FIR expressing vectors are potentially applicable for cancer therapy. FIR is alternatively spliced by SAP155 in cancer cells lacking the transcriptional repression domain within exon 2 (FIR?exon2), counteracting FIR for c-Myc protein expression. Furthermore, FIR forms a complex with SAP155 and inhibits mutual well established functions. Thus, both the valuable effects and side effects of exogenous FIR stimuli should be tested for future clinical application. SeV/dF/FIR, a cytoplasmic RNA virus, was successfully prepared and showed highly efficient gene transduction in in vivo experiments. Furthermore, in nude mouse tumor xenograft models, SeV/dF/FIR displayed high antitumor efficiency against human cancer cells. SeV/dF/FIR suppressed SSA-activated c-Myc. SAP155 siRNA, potentially produces FIR?exon2, and led to c-Myc overexpression with phosphorylation at Ser62. HA-FIR suppressed endogenous c-Myc expression and induced apoptosis in HeLa and SW480 cells. A c-myc transcriptional suppressor FIR expressing SeV/dF/FIR showed high gene transduction efficiency with significant antitumor effects and apoptosis induction in HeLa and SW480 cells. CONCLUSION: SeV/dF/FIR showed strong tumor growth suppression with no significant side effects in an animal xenograft model, thus SeV/dF/FIR is potentially applicable for future clinical cancer treatment. PMID- 24764667 TI - Invasive and non-invasive diagnosis of cirrhosis and portal hypertension. AB - With advances in the management and treatment of advanced liver disease, including the use of antiviral therapy, a simple, one stage description for advanced fibrotic liver disease has become inadequate. Although refining the diagnosis of cirrhosis to reflect disease heterogeneity is essential, current diagnostic tests have not kept pace with the progression of this new paradigm. Liver biopsy and hepatic venous pressure gradient measurement are the gold standards for the estimation of hepatic fibrosis and portal hypertension (PHT), respectively, and they have diagnostic and prognostic value. However, they are invasive and, as such, cannot be used repeatedly in clinical practice. The ideal noninvasive test should be safe, easy to perform, inexpensive, reproducible as well as to give numerical and accurate results in real time. It should be predictive of long term outcomes related with fibrosis and PHT to allow prognostic stratification. Recently, many types of noninvasive alternative tests have been developed and are under investigation. In particular, imaging and ultrasound based tests, such as transient elastography, have shown promising results. Although most of these noninvasive tests effectively identify severe fibrosis and PHT, the methods available for diagnosing moderate disease status are still insufficient, and further investigation is essential to predict outcomes and individualize therapy in this field. PMID- 24764669 TI - Case-control study of factors that trigger inflammatory bowel disease flares. AB - AIM: To explore the association between inflammatory bowel diseases (IBD) flares and potential triggers. METHODS: Patients evaluated for an acute flare of IBD by a gastroenterologist at the Dallas VA Medical Center were invited to participate, as were a control group of patients with IBD in remission. Patients were systematically queried about nonsteroidal anti-inflammatory drug use, antibiotic use, stressful life events, cigarette smoking, medication adherence, infections, and travel in the preceding 3 mo. Disease activity scores were calculated for each patient at the time of enrollment and each patient's chart was reviewed. Multivariate regression analysis was performed. RESULTS: A total of 134 patients with IBD (63 with Crohn's disease, 70 with ulcerative colitis, and 1 with indeterminate colitis) were enrolled; 66 patients had flares of their IBD and 68 were controls with IBD in remission (for Crohn's patients, average Crohn's disease activity index was 350 for flares vs 69 in the controls; for UC patients, Mayo score was 7.6 for flares vs 1 for controls in those with full Mayo available and 5.4p for flares vs 0.1p for controls in those with partial Mayo score). Only medication non-adherence was significantly more frequent in the flare group than in the control group (48.5% vs 29.4%, P = 0.03) and remained significant on multivariate analysis (OR = 2.86, 95%CI: 1.33-6.18). On multivariate regression analysis, immunomodulator use was found to be associated with significantly lower rates of flare (OR = 0.40, 95%CI: 0.19-0.86). CONCLUSION: In a study of potential triggers for IBD flares, medication non-adherence was significantly associated with flares. These findings are incentive to improve medication adherence. PMID- 24764670 TI - Pediatric non-alcoholic steatohepatitis: the first report on the ultrastructure of hepatocyte mitochondria. AB - AIM: To investigate the ultrastructure of abnormal hepatocyte mitochondria, including their cellular and hepatic zonal distribution, in bioptates in pediatric non-alcoholic steatohepatitis (NASH). METHODS: Ultrastructural investigations were conducted on biopsy liver specimens obtained from 10 children (6 boys and 4 girls) aged 2-14 years with previously clinicopathologically diagnosed NASH. The disease was diagnosed if liver biopsy revealed steatosis, inflammation, ballooned hepatocytes, Mallory hyaline, or focal necrosis, varying degrees of fibrosis in the absence of clinical, serological, or histological findings of infectious liver diseases, autoimmune hepatitis, metabolic liver diseases, or celiac disease. For ultrastructural analysis, fresh small liver blocks (1 mm(3) volume) were fixed in a solution containing 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 mol/L cacodylate buffer. The specimens were postfixed in osmium tetroxide, subsequently dehydrated through a graded series of ethanols and propylene oxide, and embedded in Epon 812. The material was sectioned on a Reichert ultramicrotome to obtain semithin sections, which were stained with methylene blue in sodium borate. Ultrathin sections were contrasted with uranyl acetate and lead citrate, and examined using an Opton EM 900 transmission electron microscope. RESULTS: Ultrastructural analysis of bioptates obtained from children with non-alcoholic steatohepatitis revealed characteristic repetitive mitochondrial abnormalities within hepatocytes; mainly mitochondrial polymorphisms such as megamitochondria, loss of mitochondrial cristae, and the presence of linear crystalline inclusions within the mitochondrial matrix of an increased electron density. The crystalline inclusions were particularly evident within megamitochondria (MMC), which seemed to be distributed randomly both within the hepatic parenchymal cell and the zones of hepatic lobule, without special variations in abundance. The inclusions appeared as bundles viewed longitudinally, or as an evenly spaced matrix in cross section, and frequently caused mitochondrial deformation. The average diameter of these linear structures was 10 nm and the average space between them 20 nm. Sometimes enlarged intramitochondrial granules were seen in their vicinity. Foamy cytoplasm of hepatocytes was found, resulting from the proliferation of smooth endoplasmic reticulum and glycogen accumulation. The perivascular space of Disse was frequently dilated, and contained transitional hepatic stellate cells, as well as mature and/or newly forming collagen fiber bundles. CONCLUSION: Marked ultrastructural abnormalities observed in hepatocyte mitochondria, especially their polymorphism in the form of MMC and loss of mitochondrial cristae, accompanied by foamy cytoplasm, clearly indicate a major role of these organelles in the morphogenesis of pediatric NASH. Our findings seem to prove the high effectiveness of electron microscopy in the diagnosis of the disease. PMID- 24764671 TI - Role of triamcinolone in radiation enteritis management. AB - AIM: To investigate the role of triamcinolone in the management of acute and chronic enteritis caused by pelvic radiotherapy. METHODS: Twenty-eight patients with rectum adenocarcinoma or endometrium adenocarcinoma were studied. We compared the results of 14 patients treated with injected triamcinolone acetonide (TA) with those of 14 patients who were not treated with TA. For the TA group, 40 mg of TA was injected intramuscularly on the 1(st), 11(th) and 21(st) d of radiotherapy; the control group received no injections. All of the study participants had a median age of 65 years, had undergone postoperative radiotherapy and were evaluated weekly using Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer Acute Morbidity Score Criteria, and complete blood counts for every 10 d. RESULTS: Triamcinolone was found to effectively prevent and treat radiation-induced acute gastrointestinal (enteritis) and genitourinary (cystitis) side effects (P = 0.022 and P = 0.023). For the lower GI side effect follow up, 11 patients in the control group had Grade 2 toxicity and 3 patients had Grade 1 toxicity. In the TA group, 5 patients had Grade 2 toxicity and 9 patients had Grade 1 toxicity. For the genitourinary system side effect follow up, 4 patients had Grade 2 toxicity and 6 patients had Grade 1 toxicity. Additionally, 2 patients had Grade 2 toxicity and 2 patients had Grade 1 toxicity. The neutrophil counts did not differ between the TA group and the control group. There was no meaningful difference between age groups and primary cancers. At the 12th mo of follow up, there were no differences between groups for chronic side effects. CONCLUSION: Triamcinolone is a moderately potent steroid, that is inexpensive and has a good safety profile. It would be beneficial for reducing medical expenses related to treatment of radiation induced enteritis. PMID- 24764672 TI - Hepcidin expression in colon during trinitrobenzene sulfonic acid-induced colitis in rats. AB - AIM: To investigate hepcidin expression, interleukin-6 (IL-6) production and iron levels in the rat colon in the presence of trinitrobenzene sulfonic acid (TNBS) induced colitis. METHODS: In rats, we evaluated the severity of colitis induced by repeated TNBS administration using macroscopic and microscopic scoring systems and myeloperoxidase activity measurements. The colonic levels of hepcidin, tumor necrosis factor alpha (TNF-alpha), IL-10 and IL-6 were measured by Enzyme-Linked Immunosorbent Assay, and hepcidin-25 expression and iron deposition were analyzed by immunohistochemistry and the Prussian blue reaction, respectively. Stat-3 phosphorylation was assessed by Western blot analysis. Hematological parameters, iron and transferrin levels, and transferrin saturation were also measured. Additionally, the ability of iron, pathogen-derived molecules and IL-6 to induce hepcidin expression in HT-29 cells was evaluated. RESULTS: Repeated TNBS administration to rats resulted in macroscopically and microscopically detectable colon lesions and elevated colonic myeloperoxidase activity. Hepcidin-25 protein levels were increased in colonic surface epithelia in colitic rats (10.2 +/- 4.0 pg/mg protein vs 71.0 +/- 8.4 pg/mg protein, P < 0.01). Elevated IL-6 levels (8.2 +/- 1.7 pg/mg protein vs 14.7 +/- 0.7 pg/mg protein, P < 0.05), TNF-alpha levels (1.8 +/- 1.2 pg/mg protein vs 7.4 +/- 2.1 pg/mg protein, P < 0.05) and Stat-3 phosphorylation were also observed. Systemic alterations in iron homeostasis, hepcidin levels and anemia were not detected in colitic rats. Iron deposition in the colon was only observed during colitis. Hepcidin gene expression was increased in HT-29 cells after IL-6 and lipopolysaccharide [a toll-like receptor 4 (TLR-4) ligand] treatment. Deferoxamine, ferric citrate and peptidoglycan (a TLR-2 ligand) were unable to alter the in vitro expression of hepcidin in HT-29 cells. CONCLUSION: Colitis increased local hepcidin-25 expression, which was associated with the IL-6/Stat-3 signaling pathway. An increase in local iron sequestration was also observed, but additional studies are needed to determine whether this sequestration is a defensive or pathological response to intestinal inflammation. PMID- 24764673 TI - Risk factors associated with Barrett's epithelial dysplasia. AB - AIM: To elucidate risk factors associated with dysplasia of short-segment Barrett's esophagus (BE). METHODS: A total of 151 BE patients who underwent endoscopic examination from 2004 to 2008 in Aoyama Hospital, Tokyo Women's Medical University, Japan and whose diagnosis was confirmed from biopsy specimens were enrolled in the study. BE was diagnosed based on endoscopic findings of gastric-appearing mucosa or apparent columnar-lined esophagus proximal to the esophagogastric junction. Dysplasia was classified into three grades - mild, moderate and severe - according to the guidelines of the Vienna Classification System for gastrointestinal epithelial neoplasia. Anthropometric and biochemical data were analyzed to identify risk factors for BE dysplasia. The prevalence of Helicobacter pylori (H. pylori) infection and the expression of p53 by immunohistological staining were also investigated. RESULTS: Histological examination classified patients into three types: specialized columnar epithelium (SCE) (n = 65); junctional (n = 38); and gastric fundic (n = 48). The incidence of dysplasia or adenocarcinoma from BE of the SCE type was significantly higher than that of the other two types (P < 0.01). The univariate analysis revealed that sex, H. pylori infection, body weight, p53 overexpression, and low diastolic blood pressure (BP) were associated with BE dysplasia. In contrast, body mass index, waist circumference, metabolic syndrome complications, and variables related to glucose or lipid metabolism were not associated with dysplasia. Multivariate logistic analysis showed that overexpression of p53 [odds ratio (OR) = 13.1, P = 0.004], H. pylori infection (OR = 0.19, P = 0.066), and diastolic BP (OR = 0.87, P = 0.021) were independent risk factors for epithelial dysplasia in BE patients with the SCE type. CONCLUSION: Overexpression of p53 is a risk factor for dysplasia of BE, however, H. pylori infection and diastolic BP inversely associated with BE dysplasia might be protective. PMID- 24764674 TI - Comparative study of esomeprazole and lansoprazole in triple therapy for eradication of Helicobacter pylori in Japan. AB - AIM: To evaluate the efficacy and safety of esomeprazole-based triple therapy compared with lansoprazole therapy as first-line eradication therapy for patients with Helicobacter pylori (H. pylori) in usual post-marketing use in Japan, where the clarithromycin (CAM) resistance rate is 30%. METHODS: For this multicenter, randomized, open-label, non-inferiority trial, we recruited patients (>= 20 years of age) with H. pylori infection from 20 hospitals in Japan. We randomly allocated patients to esomeprazole therapy (esomeprazole 20 mg, CAM 400 mg, amoxicillin (AC) 750 mg for the first 7 d, with all drugs given twice daily) or lansoprazole therapy (lansoprazole 30 mg, CAM 400 mg, AC 750 mg for the first 7 d, with all drugs given twice daily) using a minimization method with age, sex, and institution as adjustment factors. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. H. pylori eradication was confirmed by a urea breath test from 4 to 8 wk after cessation of therapy. RESULTS: ITT analysis revealed the eradication rates of 69.4% (95%CI: 61.2%-76.6%) for esomeprazole therapy and 73.9% (95%CI: 65.9%-80.6%) for lansoprazole therapy (P = 0.4982). PP analysis showed eradication rate of 76.9% (95%CI: 68.6%-83.5%) for esomeprazole therapy and 79.8% (95%CI: 71.9%-86.0%) for lansoprazole therapy (P = 0.6423). There were no differences in adverse effects between the two therapies. CONCLUSION: Esomeprazole showed non-inferiority and safety in a 7 day-triple therapy for eradication of H. pylori compared with lansoprazole. PMID- 24764675 TI - Clinical meaning of BRAF mutation in Korean patients with advanced colorectal cancer. AB - AIM: To evaluate the clinicopathological features of colorectal cancer (CRC) with a v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and its molecular interaction with microsatellite instability (MSI) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in patients with advanced CRCs. METHODS: From October 2009 to December 2011, 141 patients with stage III (n = 51) or IV (n = 90) CRCs who were tested for the BRAF mutation at Severance Hospital were included. Among 141 patients, five were excluded due to follow-up loss. Therefore, 136 patients were included in the study. The clinicopathological data, MSI status, and KRAS/BRAF mutation status were reviewed retrospectively. In addition, to evaluating the value of BRAF mutation status, progression-free survival and overall survival in all patients were collected and compared between the BRAF wild-type group and BRAF mutation group. RESULTS: Of 136 patients, 80 (58.8%) were male and the mean age was 59 years. BRAF and KRAS mutations were detected in 9.6% and 35.3% of patients, respectively. Only 4.3% of patients had MSI-high tumors and there were no MSI-high in tumors with a BRAF mutation. BRAF mutations tended to be more frequent in stage IV than in stage III (11.76% vs 5.88%, P = 0.370). Patients with a BRAF mutation had a lower incidence of KRAS mutation than those without (7.69% vs 38.21%, P = 0.033). Overall survival was significantly shorter in the BRAF mutation group than in the BRAF wild-type group both by univariate analysis (P = 0.041) and multivariate analysis (HR = 2.195; 95%CI: 1.039-4.640; P = 0.039), while progression-free survival was not different according to BRAF mutation status. CONCLUSION: CRCs with a BRAF mutation have distinct molecular features and resulted in a poor prognosis in Korean patients with advanced CRC. PMID- 24764676 TI - Unexpected FDG-PET uptake in the gastrointestinal tract: endoscopic and histopathological correlations. AB - AIM: To investigate the nature and significance of unexpected positron emission tomography with fluorodeoxyglucose (FDG-PET) uptake within the gastrointestinal tract (GIT). METHODS: Patients with unexpected FDG-PET findings in the GIT were evaluated. All patients had a previous confirmed malignancy, either solid or lymphoproliferative. The radiologic reports were performed by experienced radiologists with an exclusive PET expertise. Endoscopy, i.e., esophagogastroduodenoscopy (EGD) and colonoscopy, and histopathological evaluation of all findings was performed in all patients in accordance to the FDG PET results. The findings from each of these modalities were compared to each other. Both clinically significant and insignificant findings were assessed. RESULTS: Seventy-two patients were endoscopically evaluated. Twenty-seven patients (37.5%) had primarily a lymphoproliferative tumor and 45 (62.5%) had solid tumors. In 50 patients (69.4%) the endoscopic examination revealed lesions in the same anatomical areas as the FDG-PET findings. Among these 50 patients, malignant and premalignant lesions i.e., adenomatous polyps were found in 16 (32%) and 9 (18%) patients, respectively. Inflammation was noted in an additional 20 patients (40%). Compared to primary solid tumors, a background of primary lymphoproliferative malignancy was more likely to reveal an additional primary malignancy (15.6% vs 33.3%, respectively, P < 0.01). EGD compared to colonoscopy, revealed altogether 11 (25.6%) new malignancies compared to 5 (17.2%), respectively, P = 0.12. No GIT clinically significant findings were overseen by the FDG-PET. CONCLUSION: Unexpected FDG uptake in the GIT is commonly encountered and may contain significant findings. Endoscopy evaluation is justified in order to detect these additional findings. PMID- 24764678 TI - Living-donor or deceased-donor liver transplantation for hepatic carcinoma: a case-matched comparison. AB - AIM: To compare the surgical outcomes between living-donor and deceased-donor liver transplantation in patients with hepatic carcinoma. METHODS: From January 2007 to December 2010, 257 patients with pathologically confirmed hepatic carcinoma met the eligibility criteria of the study. Forty patients who underwent living-donor liver transplantation (LDLT) constituted the LDLT group, and deceased-donor liver transplantation (DDLT) was performed in 217 patients. Patients in the LDLT group were randomly matched (1:2) to patients who underwent DDLT using a multivariate case-matched method, so 40 patients in the LDLT group and 80 patients in the DDLT group were enrolled into the study. We compared the two groups in terms of clinicopathological characteristics, postoperative complications, long-term cumulative survival and relapse-free survival outcomes. The modified Clavien-Dindo classification system of surgical complications was used to evaluate the severity of perioperative complications. Furthermore, we determined the difference in the overall biliary complication rates in the perioperative and follow-up periods between the LDLT and DDLT groups. RESULTS: The clinicopathological characteristics of the enrolled patients were comparable between the two groups. The duration of operation was significantly longer (553 min vs 445 min, P < 0.001) in the LDLT group than in the DDLT group. Estimated blood loss (1188 mL vs 1035 mL, P = 0.055) and the proportion of patients with intraoperative transfusion (60.0% vs 43.8%, P = 0.093) were slightly but not significantly greater in the LDLT group. In contrast to DDLT, LDLT was associated with a lower rate of perioperative grade II complications (45.0% vs 65.0%, P = 0.036) but a higher risk of overall biliary complications (27.5% vs 7.5%, P = 0.003). Nonetheless, 21 patients (52.5%) in the LDLT group and 46 patients (57.5%) in the DDLT group experienced perioperative complications, and overall perioperative complication rates were similar between the two groups (P = 0.603). No significant difference was observed in 5-year overall survival (74.1% vs 66.6%, P = 0.372) or relapse-free survival (72.9% vs 70.9%, P = 0.749) between the LDLT and DDLT groups. CONCLUSION: Although biliary complications were more common in the LDLT group, this group did not show any inferiority in long-term overall survival or relapse-free survival compared with DDLT. PMID- 24764677 TI - Effect of resistance training on non-alcoholic fatty-liver disease a randomized clinical trial. AB - AIM: To evaluate the effect of resistance training (RT) on non alcoholic liver disease (NAFLD) patients. METHODS: A randomized clinical trial enrolling NAFLD patients without secondary liver disease (e.g., without hepatitis B virus, hepatitis C virus or excessive alcohol consumption). Patients were randomly allocated either to RT, three times weekly, for 3 mo or a control arm consisting of home stretching. The RT included leg press, chest press, seated rowing, latissimus pull down etc. with 8-12 repetitions, 3 sets for each exercise, for a total duration of 40 min. Hepatic ultrasound, fasting blood tests, anthropometrics and body composition by dual energy X-ray absorptiometry were assessed. At baseline and follow-up, patients filled out a detailed semi quantitative food frequency questionnaire reporting their habitual nutritional intake. Steatosis was quantified by the hepatorenal-ultrasound index (HRI) representing the ratio between the brightness level of the liver and the right kidney. The HRI has been previously demonstrated to be highly reproducible and was validated against liver biopsy and proton magnetic resonance spectroscopy. RESULTS: Eighty two patients with primary NAFLD were randomized to receive 3 mo of either RT or stretching. After dropout or exclusion from analysis because of protocol violation (weight change > 3 kg), thirty three patients in the RT arm and 31 in the stretching arm completed the study per protocol. All baseline characteristics were similar for the two treatment groups with respect to demographics, anthropometrics and body composition, blood tests and liver steatosis on imaging. HRI score was reduced significantly in the RT arm as compared to the stretching arm (-0.25 +/- 0.37 vs -0.05 +/- 0.28, P = 0.017). The RT arm had a significantly higher reduction in total, trunk and android fat with increase in lean body mass. There was no correlation between the reduction in HRI in the RT arm and weight change during the study, but it was positively correlated with the change in trunk fat (r = 0.37, P = 0.048). The RT arm had a significant reduction in serum ferritin and total cholesterol. There was no significant difference between arms in dietary changes and these did not correlate with HRI change. CONCLUSION: Three months RT improves hepatic fat content accompanied by favorable changes in body composition and ferritin. RT may serve as a complement to treatment of NAFLD. PMID- 24764679 TI - Clinicopathological features and trend changes of gastric carcinoma in Southern China. AB - AIM: To investigate the clinicopathological features of gastric carcinoma in southern China and disease trends changes over the last 18 years. METHODS: We designed a retrospective study in the Department of Gastrointestinal Surgery, the first affiliated hospital, Sun Yat-sen University. A total of 2100 adult patients with definitely diagnosed, histologically proven gastric carcinomas treated with radical gastrectomy from 1994 to 2013 were examined retrospectively. In all cases patient age, gender, tumor location, Borrmann type, histopathological type and grade, and pTNM stage were identified and recorded. The information was obtained from hospital records. The data were analyzed with Stata12.0 software. RESULTS: In this study, the mean age of patients was 57 years with a range from 19-89 years. A higher incidence was found in patients over 60 years of age. In the study population, 67.38% of patients were male and 32.62% were female. Women had a higher disease incidence than men in patients less than 40 years of age (P < 0.001). No obvious change of patient age and gender was observed in the last 18 years. The rates of disease by location were the following: antrum (44.57%), followed by fundus/ body (24.95%) and cardia/gastroesophageal junction (23.00%). The mean tumor diameter was 5.57 cm, and advanced gross type Borrmann III was most common. Most patients were at advanced stages when first diagnosed, and patients with early stage disease were relatively rare. More early stage patients were detected in recent years, especially after 2000 (P < 0.001). Gastric carcinoma has different features in young and old patients. The young patients had the following features: more frequently female, tumors in the antrum, larger tumor size, poorly differentiated carcinoma, high rate of metastasis to other sites and advanced stages (P < 0.05). CONCLUSION: In southern China, gastric carcinoma was more frequent in old men and young women. Young and old patients should be treated differently for having different features. PMID- 24764680 TI - HBsAg levels in HBeAg-positive chronic hepatitis B patients with different immune conditions. AB - AIM: To investigate hepatitis B surface antigen (HBsAg) levels in patients with HBeAg-positive chronic hepatitis B (CHB) and different immune conditions. METHODS: HBeAg-positive CHB patients with different immune conditions were enrolled in this cross-sectional study. These patients were grouped according to the following criteria: immune-tolerant patients, IT group; patients with a mild immune response in the immune clearance phase, IC-Mild group; and patients with a dramatic immune response in the immune clearance phase and exhibiting acute on chronic liver failure (ACLF), ACLF group. All these patients had not previously received antiviral therapy and were enrolled at a pre-settled ratio of 2:2:1. Serum HBsAg levels and the correlation between serum HBsAg level and serum hepatitis B virus (HBV) DNA level were evaluated in these groups. RESULTS: In total, 180 HBeAg-positive CHB patients [IT group (n = 72), IC-Mild group (n = 72), and ACLF group (n = 36)] were enrolled in this study. The median serum HBsAg levels varied among the groups (P < 0.001): IT, 4.86 log10 IU/mL; IC-Mild, 3.97 log10 IU/mL; and ACLF, 3.57 log10 IU/mL. Serum HBsAg level showed a moderate positive correlation with serum HBV-DNA level in the IC-Mild group (r = 0.60, P < 0.001), but exhibited a weaker correlation in the IT (r = 0.52, P < 0.001) and ACLF groups (r = 0.51, P = 0.001). The ratio of HBsAg/HBV DNA did not differ significantly among the IT, IC-Mild, and ACLF groups (medians: 0.56, 0.55, and 0.56, respectively; P = 0.179). CONCLUSION: Serum HBsAg levels varied significantly in HBeAg-positive patients with different immune conditions. These findings may have important implications for understanding the immune clearance of HBV in HBeAg-positive CHB patients. PMID- 24764681 TI - Caspase-3 expression in metastatic lymph nodes of esophageal squamous cell carcinoma is prognostic of survival. AB - AIM: To assess whether differential expression of caspase-3 in paired metastatic lymph nodes (LNs) is prognostic of survival in patients with resectable esophageal squamous cell carcinoma (ESCC). METHODS: Capases-3 expression was evaluated immunohistochemically in 122 pairs of primary ESCCs and regional metastatic LNs assembled on tissue microarrays. The impact of caspase-3 expression on survival outcomes was analyzed by the Kaplan-Meier method and Cox proportional hazards regression model. RESULTS: The level of caspase-3 expression was significantly higher in LN metastases than in primary tumors (P < 0.001). Caspase-3 expression in the primary tumors was associated with longer median survival (23 mo vs 21 mo, P = 0.033), whereas higher expression in paired metastatic LNs was associated with shorter median survival (20 mo vs 22 mo, P = 0.043). Multivariate analysis showed that both were independent prognostic factors. CONCLUSION: Caspase-3 expression in metastatic LNs may be a potential independent predictor of poorer overall survival in patients with resected ESCC and LN metastasis. Protein expression in metastatic tumors may be a biomarker prognostic of survival. PMID- 24764682 TI - Expression of monocyte chemotactic protein-1/CCL2 in gastric cancer and its relationship with tumor hypoxia. AB - AIM: To investigate the expression and prognostic value of CCL2 in gastric cancer, as well as its relationship with tumor hypoxia. METHODS: Tumor tissues from 68 gastric cancer patients (GC) were analyzed, and the expression of CCL2 and hypoxia-inducible factor 1 alpha (HIF-1alpha) in tumor tissues was detected by immunohistochemistry. Statistical evaluations that were used included univariate log-rank tests of Kaplan-Meier curves and multivariate Cox regression model analysis. RESULTS: CCL2 was highly expressed in 66.2% (45/68) of gastric cancer specimens. The distribution of CCL2 expression in tumor tissue was consistent with that of HIF-1alpha. Patients with high CCL2 expression in GC had a lower overall survival rate [50.6 mo (95%CI: 44.44-56.93) vs 64.6 mo (95%CI: 60.27-68.94), P = 0.013]. CONCLUSION: CCL2 expression correlates closely with HIF 1alpha expression in gastric cancer. CCL2 may be an independent prognostic marker for GC. PMID- 24764683 TI - Preliminary study correlating CX3CL1/CX3CR1 expression with gastric carcinoma and gastric carcinoma perineural invasion. AB - AIM: To study the relationship between the CX3CL1 chemokine, its receptor CX3CR1, and gastric carcinoma/gastric carcinoma perineural invasion (PNI). METHODS: Thirty cases of gastric carcinoma were surgically resected (radical resection or palliative resection) between February 2012 and July 2012. Tumour and tumour adjacent tissues were evaluated for the presence of CX3CL1 (ELISA) and CX3CR1 (immunohistochemistry and Western blotting) in an effort to analyse the relationship between CX3CL1/CX3CR1 and gastric carcinoma/gastric carcinoma PNI. RESULTS: Of these 30 cases, 14 were PNI-positive (46.7%). No significant differences in CX3CL and CX3CR1 expression in tumour-adjacent tissues were found between the PNI positive and negative groups. Expression levels of CX3CL and CX3CR1 in tumour tissues were significantly higher than those in adjacent tissues (P < 0.01), and were significantly higher in tumour tissues from the PNI-positive group compared to the PNI-negative group (P < 0.01). CONCLUSION: CX3CL1/CX3CR1 expression may be associated with the occurrence and development of gastric carcinoma as well as gastric carcinoma PNI. PMID- 24764684 TI - Anatomic resection of liver segments 6-8 for hepatocellular carcinoma. AB - AIM: To report the devised anatomic liver resection of segments 6, 7 and 8 to improve the resection rate for patients with right liver tumors. METHODS: We performed anatomic liver resection of segments 6, 7 and 8 to guarantee the maximum preservation of the remaining normal liver tissue. Segment 5 was determined by two steps of Glissonean pedicle occlusion. And a "??" shaped broken resection line was marked upon the diaphragmatic surface of the liver. Selective right hemihepatic inflow occlusion was used to reduce blood loss during parenchymal transection between segments 6 and 5 and between segments 8 and 5. If needed, total hepatic Glissonean pedicle occlusion was used during parenchymal transection between segment 8 and the left liver. RESULTS: Compared to right hemihepatectomy, the percentage of future liver remnant volume was increased by an average of 13.9% if resection of segments 6, 7 and 8 was performed. Resection of segments 6, 7 and 8 was completed uneventfully. After hepatectomy, the inflow and outflow of segment 5 were maintained. There was no perioperative mortality, postoperative abdominal bleeding or bile leakage in this group. Alpha-fetoprotein (AFP) returned to the normal range within 2 mo after the operation in all the patients. One patient died 383 d postoperatively due to obstructive suppurative cholangitis. One patient suffered from severe liver dysfunction shortly after surgery and had intrahepatic recurrence 4 mo postoperatively. Postoperative lung metastasis was found in one patient. No tumor recurrence was found in the other patients and the parameters including liver function and AFP level were in the normal range. CONCLUSION: Anatomic liver resection of segments 6, 7 and 8 can be a conventional operation to improve the overall resection rate for hepatocellular carcinoma. PMID- 24764686 TI - Comparative study of intestinal tuberculosis and primary small intestinal lymphoma. AB - AIM: To characterize the clinical, radiological, endoscopic and pathological features of intestinal tuberculosis (ITB) and primary small intestinal lymphoma (PSIL). METHODS: This was a retrospective study from February 2005 to October 2012 of patients with a diagnosis of ITB (n = 41) or PSIL (n = 37). All patients with ITB or PSIL underwent computed tomography (CT) and pathological examination. Thirty-five patients with ITB and 32 patients with PSIL underwent endoscopy. These patients were followed for a further 18 mo to ascertain that the diagnosis had not changed. Clinical, endoscopic, CT and pathological features were compared between ITB and PSIL patients. RESULTS: Night sweating, fever, pulmonary TB and ascites were discovered significantly more often in ITB than in PSIL patients (P < 0.05), however, abdominal mass, hematochezia and intestinal perforation were found significantly more frequently in PSIL than in ITB patients (P < 0.05). Ring like and rodent-like ulcers occurred significantly more often in ITB than in PSIL patients (P < 0.05), however, enterorrhagia and raised lesions were significantly more frequent in PSIL than in ITB patients (P < 0.05). The rate of granuloma was significantly higher in ITB than in PSIL patients (87.8% vs 13.5%, chi(2) = 43.050, P < 0.05), and the incidence of confluent granulomas with caseous necrosis was significantly higher in ITB than in PSIL patients (47.2% vs 0.0%, chi(2) = 4.034, P < 0.05). Multi-segmental lesions, mural stratification, mural gas sign, and intestinal stricture were more frequent in ITB than in PSIL patients (P < 0.05), however, a single-layer thickening of bowel wall, single segmental lesions, and intussusception were more common in PSIL than in ITB patients (P < 0.05). Necrotic lymph nodes, comb sign and inflammatory mass were more frequent in ITB than in PSIL patients (P < 0.05). The bowel wall enhancement in ITB patients was greater than that in PSIL patients (P < 0.05), while the thickening and lymph node enlargement in PSIL patients were higher than those in ITB patients (P < 0.05). CONCLUSION: Combined evaluation of clinical, radiological, endoscopic and pathological features is the key to differentiation between ITB and PSIL. PMID- 24764685 TI - Death decoy receptor overexpression and increased malignancy risk in colorectal cancer. AB - AIM: To evaluate human epidermal growth factor receptor 2 (HER2) and death decoy receptor (DcR3) as colorectal cancer prognostic indicators. METHODS: Colorectal carcinoma specimens from 300 patients were analyzed by immunohistochemistry to detect the staining patterns of HER2 and DcR3. Classification of HER2 staining was carried out using the United States Food and Drug Administration semi quantitative scoring system, with scores of 0 or 1+ indicating a tumor-negative (normal expression) status and scores of 2+ and 3+ indicating a tumor-positive (overexpression) status. Classification of DcR3 was carried out by quantitating the percentage of positive cells within the stained section, with < 10% indicating a tumor-negative status and >= 10% indicating a tumor-positive status. Correlation of the HER2 and DcR3 staining status with clinicopathological parameters [age, sex, tumor size, differentiation, and the tumor, node, metastasis (pTNM) classification] and survival was statistically assessed. RESULTS: Tumor-positive status for HER2 and DcR3 was found in 18.33% and 58.33% of the 300 colorectal carcinoma specimens, respectively. HER2 tumor-positive status showed a significant correlation with tumor size (P = 0.003) but not with other clinicopathological parameters. DcR3 tumor-positive status showed a significant correlation with tumor differentiation (P < 0.001), pTNM stage (P < 0.001), and lymph node metastasis (P < 0.001). However, correlation coefficient analysis did not indicate that a statistically significant correlation exists between tumor-positive status for the HER2 and DcR3 overexpression (P = 0.236). Patients with specimens classified as DcR3-overexpressing had a significantly worse overall survival (OS) rate than those without DcR3 overexpression (median OS: 42.11 vs 61.21 mo; HR = 50.27, 95%CI: 44.90-55.64, P < 0.001). HER2 overexpression had no significant impact on median OS (35.10 mo vs 45.25 mo; HR = 44.40, 95%CI: 39.32-49.48, P = 0.344). However, patients with specimens classified as both HER2- and DcR3-overexpressing had a significantly poorer median OS than those with only HER2 overexpression (31.80 mo vs 52.20 mo; HR = 35.10, 95%CI: 22.04-48.16, P = 0.006). CONCLUSION: HER2 overexpression is not an independent prognostic marker of colorectal cancer, but DcR3 overexpression is highly correlated with lymph node metastasis and poor OS. PMID- 24764687 TI - Squamous cell carcinoma after radiofrequency ablation for Barrett's dysplasia. AB - Barrett's oesophagus (BO) is a usually indolent condition that occasionally requires endoscopic therapy. Radiofrequency ablation (RFA) is an effective endoscopic treatment for high grade dysplasia (HGD) and intramucosal cancer in BO. It has a good efficacy, durability and safety profile although complications can occur. Here we describe a case of RFA in a patient with high grade dysplasia. Although the response to treatment was initially very good with the development of neosquamous epithelium, the patient very rapidly developed a squamous cell cancer of the oesophagus confirmed on radiology, histology and immunohistochemistry. Sanger sequencing confirmed that the original HGD and the squamous cell cancer (SCC) were derived from separate clonal origins. The report highlights the fact that SCC of the oesophagus has been noted after endoscopic ablation for BO previously and suggest that ablation of BO may encourage the clonal expansion of cells carrying carcinogenic mutations once a dominant clonal population has been eradicated. PMID- 24764688 TI - Colonic perforation by a transmural and transvalvular migrated retained sponge: multi-detector computed tomography findings. AB - Transmural migrated retained sponges usually impact at the level of the ileo cecal valve leading to a small bowel obstruction. Once passed through the ileo cecal valve, a retained sponge can be propelled forward by peristaltic activity and eliminated with feces. We report the case of a 52-year-old female with a past surgical history and recurrent episodes of abdominal pain and constipation. On physical examination, a generalized resistance was observed with tenderness in the right flank. Contrast-enhanced multi-detector computed tomography findings were consistent with a perforated right colonic diverticulitis with several out pouchings at the level of the ascending colon and evidence of free air in the right parieto-colic gutter along with an air-fluid collection within the mesentery. In addition, a ring-shaped hyperdense intraluminal material was also noted. At surgery, the ascending colon appeared irregularly thickened and folded with a focal wall interruption and a peri-visceral abscess at the level of the hepatic flexure, but no diverticula were found. A right hemi-colectomy was performed and on dissection of the surgical specimen a retained laparotomy sponge was found in the bowel lumen. PMID- 24764689 TI - Failed stapled rectal resection in a constipated patient with rectal aganglionosis. AB - A rare case of a severely constipated patient with rectal aganglionosis is herein reported. The patient, who had no megacolon/megarectum, underwent a STARR, i.e., stapled transanal rectal resection, for obstructed defecation, but her symptoms were not relieved. She started suffering from severe chronic proctalgia possibly due to peri-retained staples fibrosis. Intestinal transit times were normal and no megarectum/megacolon was found at barium enema. A diverting sigmoidostomy was then carried out, which was complicated by an early parastomal hernia, which affected stoma emptying. She also had a severe diverting proctitis, causing rectal bleeding, and still complained of both proctalgia and tenesmus. A deep rectal biopsy under anesthesia showed no ganglia in the rectum, whereas ganglia were present and normal in the sigmoid at the stoma site. As she refused a Duhamel procedure, an intersphincteric rectal resection and a refashioning of the stoma was scheduled. This case report shows that a complete assessment of the potential causes of constipation should be carried out prior to any surgical procedure. PMID- 24764690 TI - Race, Relationships and Trust in Providers among Black Patients with HIV/AIDS. AB - A trustful patient-provider relationship is a strong predictor of positive outcomes, including treatment adherence and viral suppression, among patients with HIV/AIDS. Understanding factors that inform this relationship is especially relevant for Black patients, who bear a disproportionate burden of HIV morbidity and mortality, and may face challenges associated with seeing providers of a racial/ethnic background that is different from their own. Using data collected through the Enhancing Communication and HIV Outcomes (ECHO) study, we build upon extant research by examining patient and provider characteristics that may influence Black patients' trust in their provider. ECHO data were collected from four ambulatory care sites in Baltimore, Detroit, New York and Portland, Oregon (N=435). Regression analysis results indicate that trust in health care institutions and cultural similarity between patient and provider are strongly associated with patients' trust in their provider. Lower perceived social status, being currently employed, and having an older provider were also related to greater patient-provide trust. These findings can inform interventions to improve trust and reduce disparities in HIV care and outcomes that stem from mistrust among Black patients. PMID- 24764691 TI - Measurement error in two-stage analyses, with application to air pollution epidemiology. AB - Public health researchers often estimate health effects of exposures (e.g., pollution, diet, lifestyle) that cannot be directly measured for study subjects. A common strategy in environmental epidemiology is to use a first-stage (exposure) model to estimate the exposure based on covariates and/or spatio temporal proximity and to use predictions from the exposure model as the covariate of interest in the second-stage (health) model. This induces a complex form of measurement error. We propose an analytical framework and methodology that is robust to misspecification of the first-stage model and provides valid inference for the second-stage model parameter of interest. We decompose the measurement error into components analogous to classical and Berkson error and characterize properties of the estimator in the second-stage model if the first stage model predictions are plugged in without correction. Specifically, we derive conditions for compatibility between the first- and second-stage models that guarantee consistency (and have direct and important real-world design implications), and we derive an asymptotic estimate of finite-sample bias when the compatibility conditions are satisfied. We propose a methodology that (1) corrects for finite-sample bias and (2) correctly estimates standard errors. We demonstrate the utility of our methodology in simulations and an example from air pollution epidemiology. PMID- 24764692 TI - Relating Nanoparticle Properties to Biological Outcomes in Exposure Escalation Experiments. AB - A fundamental goal in nano-toxicology is that of identifying particle physical and chemical properties, which are likely to explain biological hazard. The first line of screening for potentially adverse outcomes often consists of exposure escalation experiments, involving the exposure of micro-organisms or cell lines to a library of nanomaterials. We discuss a modeling strategy, that relates the outcome of an exposure escalation experiment to nanoparticle properties. Our approach makes use of a hierarchical decision process, where we jointly identify particles that initiate adverse biological outcomes and explain the probability of this event in terms of the particle physicochemical descriptors. The proposed inferential framework results in summaries that are easily interpretable as simple probability statements. We present the application of the proposed method to a data set on 24 metal oxides nanoparticles, characterized in relation to their electrical, crystal and dissolution properties. PMID- 24764693 TI - Palliative sedation-still a complex clinical issue! PMID- 24764694 TI - A prior diagnosis of breast cancer is a risk factor for breast cancer in BRCA1 and BRCA2 carriers. AB - BACKGROUND: The risk of breast cancer in carriers of BRCA1 and BRCA2 mutations is influenced by factors other than the genetic mutation itself. Modifying factors include a woman's reproductive history and family history of cancer. Risk factors are more likely to be present in women with breast cancer than in women without breast cancer, and therefore the risk of cancer in the two breasts should not be independent. It is not clear to what extent modifying factors influence the risk of a first primary or a contralateral breast cancer in BRCA carriers. METHODS: We conducted a matched case-control study of breast cancer among 3920 BRCA1 or BRCA2 mutation carriers. We asked whether a past history of breast cancer in the contralateral breast was a risk factor for breast cancer. RESULTS: After adjustment for age, country of residence, and cancer treatment, a previous cancer of the right breast was found to be a significant risk factor for cancer of the left breast among BRCA1 or BRCA2 carriers (relative risk: 2.1; 95% confidence interval: 1.4 to 3.0; p < 0.0001). CONCLUSIONS: In a woman with a BRCA1 or BRCA2 mutation who is diagnosed with breast cancer, the risk of cancer in the contralateral breast depends on the first diagnosis. That observation supports the hypothesis that there are important genetic or non-genetic modifiers of cancer risk in BRCA carriers. Discovering risk modifiers might lead to greater personalization of risk assessment and management recommendations for BRCA positive patients. PMID- 24764695 TI - Patient perceptions of a comprehensive cancer navigation service. AB - OBJECTIVE: Our aim was to determine the extent to which comprehensive navigation augments the provincial health system for meeting the needs of newly-diagnosed cancer patients (clients). We also assessed reactions of attending physicians to comprehensive navigation. METHODS: Clients who completed navigation as an employee benefit or through membership in an insurance organization were polled to determine whether they needed help beyond that provided by the provincial health system and the extent to which that help was provided by navigation. Exit interviews were analyzed for perceptions of the clients about reactions by their attending physicians to navigation. RESULTS: Of eligible clients, 72% responded. They reported needing help beyond that which the provincial system could provide in 64%-98% of specified areas. Navigation provided help in more than 90% of those cases. Almost all respondents (98%) appreciated having a designated oncology nurse navigator. Family doctors were perceived to be positive or neutral about navigation in 100% of exit interviews. Oncologists were positive or neutral in 92% (p < 0.001 for difference from family doctors). CONCLUSIONS: In many areas, cancer patients need additional help beyond that which the provincial health system can provide. Comprehensive cancer navigation provides that help to a considerable extent. Clients perceived the reactions of attending physicians to comprehensive navigation to be generally supportive or neutral. PMID- 24764696 TI - Perioperative chemotherapy for gastroesophageal cancer in British Columbia: a multicentre experience. AB - BACKGROUND: In 2006, perioperative epirubicin, cisplatin, and 5-fluorouracil (ecf), compared with surgery alone, demonstrated a significant survival benefit in resectable gastroesophageal cancers. We report the results of our experience with that protocol. METHODS: The BC Cancer Agency (bcca) is a multicentre institution that treats most oncology patients for the province. Characteristics of the 83 bcca patients with localized gastric, gastroesophageal junction, or lower esophageal cancer who initiated perioperative chemotherapy either ecf or epirubicin, cisplatin, and capecitabine (ecx) from 2008 to 2011 were abstracted to an anonymous database and analyzed. RESULTS: Of the 83 patients in the cohort [66 men; median age: 62 years (range: 37-79 years)], 87.9% completed 3 cycles of perioperative chemotherapy, and 93.9% (n = 78) underwent an attempt at surgery (2 patients died of chemotherapy toxicities, 1 refused surgery, and 2 developed disease progression before surgery). In 11 of the surgeries (14.1%), tumours could not be resected because of unresectability (n = 1), liver metastasis (n = 1), and peritoneal carcinomatosis (n = 9). One patient died of surgical complications. The 6 patients (7.2%) who achieved a pathologic complete response are all alive and recurrence-free. Of 46 patients (55.4%) who subsequently began postoperative chemotherapy, 44.5% completed 3 cycles. Estimated median survival was 40.3 months. Weight loss was the only significant prognostic factor for worse overall survival. CONCLUSIONS: Our multicentre experience confirmed the feasibility of the magic protocol in a real-world scenario and showed that ecx is also an adequate regimen in the perioperative setting. Weight loss was the only significant prognostic factor for worse overall survival. All patients who achieved a pathologic complete response are recurrence-free after a median follow up of 40.3 months. PMID- 24764697 TI - Can oncologists predict survival for patients with progressive disease after standard chemotherapies? AB - BACKGROUND: Prediction of prognosis is important for patients so that they can make the most of the rest of their lives. Oncologists could predict survival, but the accuracy of such predictions is unclear. METHODS: In this observational prospective cohort study, 14 oncologists treating 9 major adult solid malignancies were asked to complete questionnaires predicting survival based on performance status, oral intake, and other clinical factors when patients experienced progressive disease after standard chemotherapies. Clinically predicted survival (cps) was calculated by the oncologists from the date of progressive disease to the predicted date of death. Actual survival (as) was compared with cps using Kaplan-Meier survival curves, and factors affecting inaccurate prediction were determined by logistic regression analysis. The prediction of survival time was considered accurate when the cps/as ratio was between 0.67 and 1.33. RESULTS: The study cohort consisted of 75 patients. Median cps was 120 days (interquartile range: 60-180 days), and median as was 121 days (interquartile range: 40-234 days). The participating oncologists accurately predicted as within a 33% range 36% of the time; the survival time was overestimated 36% of time and underestimated 28% of the time. The factors affecting the accuracy of the survival estimate were the experience of the oncologist, patient age, and information given about the palliative care unit. CONCLUSIONS: Prediction of cps was accurate for just slightly more than one third of all patients in this study. Additional investigation of putative prognostic factors with a larger sample size is warranted. PMID- 24764698 TI - Effects of dna-dependent protein kinase inhibition by NU7026 on dna repair and cell survival in irradiated gastric cancer cell line N87. AB - Repair of radiation-induced dna double-strand breaks is a key mechanism in cancer cell radio-resistance. The synthesized compound NU7026 specifically inhibits dna dependent protein kinase (dna-pk) within the non-homologous end-joining repair mechanism. Earlier studies demonstrated increased radiosensitivity in dna-pk deficient cells compared with wild-type cells. In chronic leukemia cells, NU7026 appears to enhance the cytotoxic effect of chlorambucil. The radio-modifying effects of NU7026 on cell survival, cell cycle, apoptosis, and dna double-strand break repair have yet to be studied in gastric cancer cells. METHODS: The gastric cancer cell line N87 was treated with 0 Gy or 4 Gy in the presence of NU7026 at a dose range of 0-20 MUmol/L. Clonogenic assays were used to assess cell survival after treatment. Cell-cycle distribution was analyzed using propidium iodide with fluorescence-activated cell sorting. Apoptosis was detected using annexin-V and propidium iodide with fluorescence-activated cell sorting. The gammaH2AX assay was used to measure dna double-strand breaks. RESULTS: Statistically significant increases in G2/M arrest were observed in N87 cells treated with radiation and NU7026 compared with those treated with radiation alone (p = 0.0004). Combined treatment also led to an increase in apoptosis (p = 0.01). At 24 hours, the gammaH2AX analysis revealed more dna double-strand breaks in N87 cells treated with radiation and NU7026 than in those treated with radiation alone (p = 0.04). Clonogenic assays demonstrated declining cell survival as both the radiation and the NU7026 dose increased. The dose enhancement factor at 0.1 survival fraction was 1.28 when N87 cells were treated with 4 Gy radiation and 5 MUmol/L NU7026. CONCLUSIONS: In gastric cancer cells, NU7026 appears to enhance the cytotoxic effect of irradiation as assessed by clonogenic assays. This increased cytotoxicity might be the result of an increase in dna double-strand breaks resulting in G2/M cell arrest and possibly higher levels of apoptosis. PMID- 24764699 TI - Geographic disparities in surgery for breast and rectal cancer in Canada. PMID- 24764700 TI - Practice and documentation of palliative sedation: a quality improvement initiative. AB - BACKGROUND: Palliative sedation (ps), the continuous use of sedating doses of medication to intentionally reduce consciousness and relieve refractory symptoms at end of life, is ethically acceptable if administered according to standards of best practice. Procedural guidelines outlining the appropriate use of ps and the need for rigorous documentation have been developed. As a quality improvement strategy, we audited the practice and documentation of ps on our palliative care unit (pcu). METHODS: A pharmacy database search of admissions in 2008 identified, for a subsequent chart review, patients who had received either a continuous infusion of midazolam (>=10 mg/24 h), regular parenteral dosing of methotrimeprazine (>=75 mg daily), or regular phenobarbital. Documentation of the decision-making process, consent, and medication use was collected using a data extraction form based on current international ps standards. RESULTS: Interpretation and comparison of data were difficult because of an apparent lack of a consistent operational definition of ps. Patient records had no specific documentation in relation to ps initiation, to clearly identified refractory symptoms, and to informed consent in 60 (64.5%), 43 (46.2%), and 38 (40.9%) charts respectively. Variation in the medications used was marked: 54 patients (58%) were started on a single agent and 39 (42%), on multiple agents. The 40 patients (43%) started on midazolam alone received a mean daily dose of 21.4 mg (standard deviation: 24.6 mg). CONCLUSIONS: The lack of documentation and standardized practice of ps on our pcu has resulted in a quality improvement program to address those gaps. They also highlight the importance of conducting research and developing clinical guidelines in this area. PMID- 24764702 TI - Prospective evaluation of unmet needs of rural and aboriginal cancer survivors in Northern British Columbia. AB - BACKGROUND: The unmet needs of cancer survivors in rural, remote, and aboriginal communities are largely unexplored. We explored potential differences between rural survivors (rss) in 4 general population (gp) and 4 First Nations (fn) communities. METHODS: We approached 4 gp and 4 fn rs communities to participate in a mixed-methods project. Participants completed the Hospital Anxiety and Depression Scale (hads) and the Survivor Unmet Needs Survey (suns) and provided demographic information. Each question on the suns can be scored from 0 to 4, with 0 representing "no unmet need" and 4 representing "very high unmet need." A directed approach to content analysis of focus group and interview data was used to triangulate the hads and suns results. RESULTS: We prospectively accrued 23 fn rss and 56 gp rss for this study. More fn rss had borderline or abnormal anxiety (5% vs. 21%, p = 0.02). Compared with gp rss, fn rss had higher unmet needs scores in all categories: Information (2.29 vs. 0.8, p < 0.001), Work and Financial (1.66 vs. 0.5, p < 0.001), Access and Continuity of Health Care (1.83 vs. 0.44, p < 0.001), Coping and Sharing (2.22 vs. 0.62, p < 0.001), and Emotional (2.12 vs. 0.63, p < 0.001). The qualitative findings provided examples and insight into the unmet needs experienced by rss. CONCLUSIONS: First Nations rss had significantly higher anxiety and unmet needs compared with their gp rs counterparts. In addition, different qualitative themes were identified in the groups. Our findings support the development of tailored approaches to survivorship for these populations. PMID- 24764703 TI - Rasch analysis of the Edmonton Symptom Assessment System and research implications. AB - BACKGROUND: Reliable and valid assessment of the disease burden across all forms of cancer is critical to the evaluation of treatment effectiveness and patient progress. The Edmonton Symptom Assessment System (esas) is used for routine evaluation of people attending for cancer care. In the present study, we used Rasch analysis to explore the measurement properties of the esas and to determine the effect of using Rasch-proposed interval-level esas scoring compared with traditional scoring when evaluating the effects of an exercise program for cancer survivors. METHODS: Polytomous Rasch analysis (Andrich's rating-scale model) was applied to data from 26,645 esas questionnaires completed at the Juravinski Cancer Centre. The fit of the esas to the polytomous Rasch model was investigated, including evaluations of differential item functioning for sex, age, and disease group. The research implication was investigated by comparing the results of an observational research study previously analysed using a traditional approach with the results obtained by Rasch-proposed interval-level esas scoring. RESULTS: The Rasch reliability index was 0.73, falling short of the desired 0.80-0.90 level. However, the esas was found to fit the Rasch model, including the criteria for uni-dimensional data. The analysis suggests that the current esas scoring system of 0-10 could be collapsed to a 6-point scale. Use of the Rasch-proposed interval-level scoring yielded results that were different from those calculated using summarized ordinal-level esas scores. Differential item functioning was not found for sex, age, or diagnosis groups. CONCLUSIONS: The esas is a moderately reliable uni-dimensional measure of cancer disease burden and can provide interval-level scaling with Rasch-based scoring. Further, our study indicates that, compared with the traditional scoring metric, Rasch based scoring could result in substantive changes to conclusions. PMID- 24764704 TI - Surgical process improvement tools: defining quality gaps and priority areas in gastrointestinal cancer surgery. AB - BACKGROUND: Surgery is a cornerstone of cancer treatment, but significant differences in the quality of surgery have been reported. Surgical process improvement tools (spits) modify the processes of care as a means to quality improvement (qi). We were interested in developing spits in the area of gastrointestinal (gi) cancer surgery. We report the recommendations of an expert panel held to define quality gaps and establish priority areas that would benefit from spits. METHODS: The present study used the knowledge-to-action cycle was as a framework. Canadian experts in qi and in gi cancer surgery were assembled in a nominal group workshop. Participants evaluated the merits of spits, described gaps in current knowledge, and identified and ranked processes of care that would benefit from qi. A qualitative analysis of the workshop deliberations using modified grounded theory methods identified major themes. RESULTS: The expert panel consisted of 22 participants. Experts confirmed that spits were an important strategy for qi. The top-rated spits included clinical pathways, electronic information technology, and patient safety tools. The preferred settings for use of spits included preoperative and intraoperative settings and multidisciplinary contexts. Outcomes of interest were cancer-related outcomes, process, and the technical quality of surgery measures. CONCLUSIONS: Surgical process improvement tools were confirmed as an important strategy. Expert panel recommendations will be used to guide future research efforts for spits in gi cancer surgery. PMID- 24764705 TI - Patients' perceptions of gene expression profiling in breast cancer treatment decisions. AB - INTRODUCTION: Determining the likely benefit of adjuvant chemotherapy for early stage breast cancer patients depends on estimating baseline recurrence risk. Gene expression profile (gep) testing of tumours informs risk prediction, but evidence of its clinical utility is limited. We explored patient perceptions of gep testing and the impact of those perceptions on chemotherapy decisions. METHODS: We conducted one focus group (n = 4) and individual interviews (n = 24) with patients who used gep testing, recruited through clinics at two hospitals in Ontario. Data were analyzed using content analysis and constant comparison techniques. RESULTS: Patients' understanding of gep testing was variable, and misapprehensions were common. Patients valued the test because it provided them with certainty amidst confusion, with options and a sense of empowerment, and with personalized, authoritative information. They commonly believed that the test was better and fundamentally different from other clinical tests, attributing to it unique power and truth-value. This kind of "magical thinking" was derived from an amplified perception of the test's validity and patients' need for reassurance about their treatment choices. Despite misperceptions or magical thinking, gep was widely considered to be the deciding factor in treatment decisions. CONCLUSIONS: Patients tend to overestimate the truth-value of gep testing based on misperceptions of its validity. Our results identify a need to better support patient understanding of the test and its limitations. Findings illustrate the deep emotional investment patients make in gep test results and the impact of that investment on their treatment decisions. PMID- 24764707 TI - Toward successful migration to computerized physician order entry for chemotherapy. AB - BACKGROUND: Computerized physician order entry (cpoe) systems allow for medical order management in a clinical setting. Use of a cpoe has been shown to significantly improve chemotherapy safety by reducing the number of prescribing errors. Usability of these systems has been identified as a critical factor in their successful adoption. However, there is a paucity of literature investigating the usability of cpoe for chemotherapy and describing the experiences of cancer care providers in implementing and using a cpoe system. METHODS: A mixed-methods study, including a national survey and a workshop, was conducted to determine the current status of cpoe adoption in Canadian oncology institutions, to identify and prioritize knowledge gaps in cpoe usability and adoption, and to establish a research agenda to bridge those gaps. Survey respondents were representatives of cancer care providers from each Canadian province. The workshop participants were oncology clinicians, human factors engineers, patient safety researchers, policymakers, and hospital administrators from across Canada, with participation from the United States. RESULTS: A variety of issues related to implementing and using a cpoe for chemotherapy were identified. The major issues concerned the need for better understanding of current practices of chemotherapy ordering, preparation, and administration; a lack of system selection and procurement guidance; a lack of implementation and maintenance guidance; poor cpoe usability and workflow support; and other cpoe system design issues. An additional three research themes for addressing the existing challenges and advancing successful adoption of cpoe for chemotherapy were identified: The need to investigate variances in workflows and practices in chemotherapy ordering and administrationThe need to develop best-practice cpoe procurement and implementation guidance specifically for chemotherapyThe need to measure the effects of cpoe implementation in medical oncology. CONCLUSIONS: Addressing the existing challenges in cpoe usability and adoption for chemotherapy, and accelerating successful migration to cpoe by cancer care providers requires future research focusing on workflow variations, chemotherapy specific cpoe procurement needs, and implementation guidance needs. PMID- 24764706 TI - Potential drug interactions in patients with a history of cancer. AB - BACKGROUND: Cancer survivors (css) are frequently exposed to polypharmacy, which might increase their risk of drug interactions. Our study aimed to determine the relative prevalence of potential drug interactions (pdis) among css compared with non-cancer respondents (ncrs). METHODS: Self-reported prescription data from 4975 patients were extracted from the U.S. National Health and Nutrition Examination Survey and screened for pdis using iFacts: Drug Interaction Facts (Facts and Comparisons, St. Louis, MO, U.S.A.). The clinical significance of each pdi was graded on a 5-point scale based on the severity of the interaction and the level of evidence documenting the interaction. Summary statistics and logistic regression models were used to assess the impact of cancer history on the risk of pdis. RESULTS: Of patients eligible for the analyses, the css (n = 302) indicated using 4.4 +/- 0.22 prescriptions on average, and the ncrs (n = 908), 3.8 +/- 0.09. Nearly half of both cohorts (40% of css, 43% of ncrs) had at least 1 pdi. In both cohorts, 12% were at risk for fatal or permanently debilitating effects. In multivariate analyses, css were significantly less likely than ncrs to be at risk for any pdis (odds ratio: 0.65; 95% confidence interval: 0.46 to 0.92; p = 0.02). Advanced age and low household income were associated with pdis among css. Medications most commonly prescribed to css with a pdi included metoprolol (15.6%), levothyroxine (13.6%), and furosemide (11.9%). CONCLUSIONS: Although css appear to be less susceptible than ncrs to pdis, the prevalence of pdis among css remains suboptimal. Specific subgroups of css may be particularly prone to pdis, underscoring the importance of increased vigilance. PMID- 24764708 TI - The use of granulocyte colony-stimulating factors in a Canadian outpatient setting. AB - BACKGROUND: Data on real-life utilization of granulocyte colony-stimulating factors (g-csfs) in Canada are limited. The objective of the present study was to describe the reasons for, and the patterns of, g-csf use in selected outpatient oncology clinics in Ontario and Quebec. METHODS: In a retrospective longitudinal cohort study, a review of medical records from 9 Canadian oncology clinics identified patients being prescribed filgrastim (fil) and pegfilgrastim (peg). Patient characteristics, reasons for g-csf use, and treatment patterns were descriptively analyzed. RESULTS: Medical records of 395 patients initiating g-csf therapy between January 2008 and January 2009 were included. Of this population, 80% were women, and breast cancer was the predominant diagnosis (59%). The most commonly prescribed g-csf was fil (56% in Ontario and 98% in Quebec). The most frequent reason for g-csf use was primary prophylaxis (42% for both fil and peg), followed by secondary prophylaxis (37% fil, 41% peg). Those proportions varied by tumour type and chemotherapy regimen. Delayed g-csf administration (more than 1 day after the end of chemotherapy) was frequently observed for fil, but rarely reported for peg, and that finding was consistent across tumours and concurrent chemotherapy regimens. CONCLUSIONS: The use of g-csf varies with the malignancy type and the provincial health care setting. The most commonly prescribed g-csf agent was fil, and most first g-csf prescriptions were for primary prophylaxis. Delays were frequently observed for patients receiving fil, but were rarely reported for those receiving peg. PMID- 24764709 TI - Patient preferences for stopping tyrosine kinase inhibitors in chronic myeloid leukemia. AB - BACKGROUND: We used an interview-assisted survey of patients with chronic myeloid leukemia (cml) at a single tertiary care centre to explore patient reactions to and preferences for, and the risk-acceptability of, stopping tyrosine kinase inhibitor (tki) treatment. METHODS: The study included patients with confirmed cml currently being treated with a tki. The survey was conducted by structured interview using a standard form. Patient preferences were explored in a case based scenario using 0%-100% visual analog scales and 5-point Likert scales. Data were analyzed using proportions for dichotomous variables and medians and interquartile ranges for continuous variables. RESULTS: Of 63 patients approached, 56 completed the survey. Participant responses suggest that the idea of stopping tki use is appealing to many patients if there is a chance of long term stable disease and a high probability of response upon restarting a tki. Participants were more likely to stop their tki as the risk of relapse decreased. Participants reported loss of disease control and failure of disease to respond to treatment as important concerns if they chose to stop their tki. CONCLUSIONS: Given the current 60% estimated rate of relapse after discontinuation of tki therapy, most patients with cml chose to continue with tki. However, at the lower relapse rates reported with second-generation tkis, participants were more undecided, demonstrating a basic understanding of risk. Contrary to our hypothesis, neither compliance nor occurrence of side effects significantly affected patient willingness to stop their tki. PMID- 24764710 TI - Publication rates of abstracts presented at the 2007 and 2010 Canadian Association of Radiation Oncology meetings. AB - BACKGROUND: We set out to determine the rate, time-trend, and defining factors associated with publication of abstracts presented at two annual scientific meetings of the Canadian Association of Radiation Oncology (caro). METHODS: All abstracts accepted for oral presentation in 2007 and 2010 were obtained from the caro program archives and searched using the PubMed database. Variables in the dataset included the year of presentation at caro and of publication in a scientific journal, time to publication (in months), publishing journal, impact factor of publishing journal, abstract research type (clinical, technical, or basic science) and disease site, country of origin, and university of the first author. RESULTS: Overall, 88 of 172 abstracts from the 2007 (n = 102) and 2010 (n = 70) caro meetings were published in peer-reviewed journals (publication rate: 51.2%). Mean time to publication was 18.5 months. Among research types, clinical research (62.5%) and, among disease sites, prostate cancer (40.4%) were most likely to be published. Of all the abstracts, 50.1% were contributed by only 2 universities, a proportion that resembles the overall abstract publication rate of 51.2%. The conversion rate for those 2 universities (51.1%) is very similar to that for all abstracts presented at the two meetings. CONCLUSIONS: Half the abstracts presented at the 2007 and 2010 caro meetings were ultimately published in journals indexed in PubMed by about 1.5 years after presentation. Half the abstracts and publications came from just 2 universities; more must to be done to close the gap. PMID- 24764711 TI - The road ahead for cervical cancer prevention and control. AB - Since the early 1950s, Papanicolaou ("Pap") cytology screening has dramatically reduced cervical cancer mortality in most high-income settings. Currently, human papillomavirus (hpv) vaccination has the greatest potential to reduce the global burden of cervical cancer and precancerous lesions. However, as the prevalence of precancerous lesions declines, maintaining cytology as the primary screening test in settings with established programs might become less efficient. A reduction in test performance (sensitivity, specificity, and positive predictive value) would lead to an increase in unnecessary colposcopy referrals. Fortunately, hpv dna testing has emerged as a suitable candidate to replace cytology. Compared with the Pap test, hpv testing is less specific but much more sensitive in detecting high-grade precancerous lesions, less prone to human error, and more reproducible across settings. Linkage of hpv vaccination and screening registries could serve the added role of monitoring vaccine efficacy. As a triage test, cytology is expected to perform with sufficient accuracy because most hpv-positive smears would contain relevant abnormalities. This approach and others-for example, hpv testing followed by genotyping-are being evaluated in large population studies and have already been recommended in some settings. Other specific biomarkers that might perform well for screening and triage include hpv E6/E7 messenger rna testing, methylation of host or viral genes, and p16(INK4a) staining. Considering the rapid pace of major discoveries and the anticipated arrival of a nonavalent hpv vaccine (currently in phase iii trials), the evidence base in this field has become an elusive target and will continue to be an obstacle for policymakers. PMID- 24764712 TI - Evidence-based guidelines for the use of tyrosine kinase inhibitors in adults with Philadelphia chromosome-positive or BCR-ABL-positive acute lymphoblastic leukemia: a Canadian consensus. AB - Adult Philadelphia chromosome-positive (Ph+) or BCR-ABL-positive (BCR-ABL+) acute lymphoblastic leukemia (all) is an acute leukemia previously associated with a high relapse rate, short disease-free survival, and poor overall survival. In adults, allogeneic hematopoietic cell transplant in first remission remains the only proven curative strategy for transplant-eligible patients. The introduction of tyrosine kinase inhibitors (tkis) in the treatment of patients with Ph+ or BCR ABL+ all has significantly improved the depth and duration of complete remission, allowing more patients to proceed to transplantation. Although tkis are now considered a standard of care in this setting, few randomized trials have examined the optimal use of tkis in patients with Ph+ all. Questions of major importance remain, including the best way to administer these medications, the choice of tki to administer, and the schedule and the duration to use. We present the results of a systematic review of the literature with consensus recommendations based on the available evidence. PMID- 24764713 TI - Extracorporeal photopheresis in the management of graft-versus-host disease. AB - QUESTION: Is there a benefit associated with the use of extracorporeal photopheresis (ecp) compared with other treatment options for patients who have received allogeneic stem-cell transplantation (sct) and are experiencing graft versus-host disease (gvhd), if response rate, survival, or improvement in symptoms are the outcomes of interest? PERSPECTIVES: After allogeneic sct, gvhd is a common complication historically categorized as either acute (agvhd: onset <=100 days post-transplantation) or chronic (cgvhd: >100 days post transplantation). Graft-versus-host disease occurs when the donor's immune cells recognize the host patient's tissues and organs as foreign and attack them, causing a multitude of problems, often in liver, gastrointestinal system, and skin. Photopheresis is one therapy that has emerged since the early 2000s for the management of steroid-refractory gvhd because of its steroid-sparing ability, low associated toxicity, and efficacy in some clinical settings. The present recommendation report summarizes the available data about photopheresis for the treatment of gvhd and provides recommendations on its use. METHODOLOGY: The medline (Ovid) database was systematically searched for January 1995 to August 2013, and the best available evidence was used to draft recommendations relevant to adult and pediatric patients in Ontario who have received allogeneic sct and are experiencing gvhd. Draft recommendations were first reviewed by clinical and methodology experts before undergoing internal review. Final approval of this practice guideline report was obtained from both the Stem Cell Transplant Steering Committee and the Report Approval Panel of the Program in Evidence-Based Care. RECOMMENDATIONS: These recommendations apply to adult and pediatric patients who have received an allogeneic sct and are experiencing gvhd: ecp is an acceptable therapy for the treatment of steroid-dependent or refractory agvhd in adult and pediatric patients.ecp is an effective therapy for the treatment of steroid-dependent or refractory cgvhd in adult and pediatric patients. QUALIFYING STATEMENT: In Ontario, ecp is currently a covered therapy for patients with steroid-refractory gvhd who meet certain eligibility criteria. PMID- 24764714 TI - Predictors of recurrence after radiotherapy for non-melanoma skin cancer. AB - Predictive factors of recurrence were examined in 448 non-melanoma skin cancers (72% basal cell carcinoma, 28% squamous cell carcinoma) treated with radiotherapy. The overall recurrence rate was 15.8% at a median follow-up of 18.4 months. In multivariate analysis, significant factors for recurrence were age (p = 0.0197), tumour size 2 cm or greater (p = 0.0095), immunosuppression (p = 0.0082), and treatment modality (p = 0.0009). PMID- 24764715 TI - Screening for distress in patients with cancer: methodologic considerations. AB - Distress has been declared the 6th vital sign in Canadian cancer care. Accordingly, health care professionals in Canada are expected to screen for distress in patients with cancer, for which a toolkit has been developed. Identifying patients who may be in need of further resources has the potential to improve quality of care because those patients are more likely to have their existing distress identified and to be referred for appropriate follow-up services. The present article briefly reviews the background literature and the validation of the measures in the toolkit, and highlights future directions for methodologic validation of the toolkit for use according to the protocol. PMID- 24764716 TI - Challenges and outcomes of a randomized study of early nutrition support during autologous stem-cell transplantation. AB - Patients undergoing myeloablative conditioning regimens and autologous stem-cell transplantation (asct) are at high risk of malnutrition. This randomized study aimed to determine if early nutrition support (commenced when oral intake is less than 80% of estimated requirements) compared with usual care (commenced when oral intake is less than 50% of estimated requirements) reduces weight loss in well nourished patients undergoing high-nutritional-risk conditioning chemotherapy and asct. In the 50 well-nourished patients who were randomized, the outcomes evaluated included changes in weight and lean body mass (mid-upper arm circumference), length of stay, time to hemopoietic engraftment, and quality of life (Memorial Symptom Assessment Scale - Short Form). On secondary analysis, after exclusion of a single extreme outlier, both groups demonstrated significant weight loss over time (p = 0.0005). Weight loss was less in the early nutrition support group at time of discharge (mean: -0.4% +/- 2.9% vs. -3.4% +/- 2.6% in the usual care group, p = 0.001). This difference in weight was no longer observed at 6 months after discharge (mean: -1.0% +/- 6.8% vs. 1.4% +/- 6.1%, p = 0.29). In practice, an early start to nutrition support proved difficult because of patient resistance and physician preference, with 8 patients (33%) in the control group and 4 (15%) in the intervention group not commencing nutrition support when stipulated by the study protocol. No significant differences between the groups were found for other outcomes. In well-nourished patients receiving asct, early nutrition support maintained weight during admission, but did not affect other outcomes. Interpretation of results should take into consideration the difficulties encountered with intervention implementation. PMID- 24764717 TI - Metabolic syndrome-related hepatocellular carcinoma treated by volumetric modulated arc therapy. AB - Hepatocellular carcinoma (hcc) is a leading cause of cancer mortality, and its incidence is increasing in developed countries. Risk factors include cirrhosis from viral hepatitis or alcohol abuse. Metabolic syndrome is a newly recognized, but important, risk factor that is likely contributing to the increased incidence of hcc. Surgery is the therapy of choice for hcc, but local therapies are often contraindicated, usually because of advanced disease or comorbid conditions such as cardiac disease (which is associated with metabolic syndrome). Current radiation therapy techniques such as stereotactic body radiotherapy allow for treatment plans that highly conform to the target and provide excellent sparing of normal structures. Radiation therapy is emerging as a viable option in patients not eligible for surgery or other locoregional therapies. Here, we report a case of a large hcc presenting in a patient with metabolic syndrome without significant alcohol history or biochemical liver dysfunction. The patient was not a candidate for locoregional therapies because of cardiac and renal comorbidities typical of patients experiencing the long-term sequelae of metabolic syndrome. Treatment using an arc-based volumetric-modulated arc therapy technique allowed for the highest dose of radiation to be delivered to the tumour while the peripheral radiation dose was minimized. A complete local response was confirmed by computed tomography imaging 21 months after treatment completion. PMID- 24764718 TI - fdg-pet in two cases of neurofibromatosis type 1 and atypical malignancies. AB - Patients with neurofibromatosis type 1 (nf1) are at increased risk for both benign and malignant tumours, and distinguishing the malignant potential of an individual tumour is a common clinical problem in these patients. Here, we review two cases of uncommon malignancies (Hodgkin lymphoma and mediastinal germ-cell tumour) in patients with nf1. Although (18)F-fluorodeoxyglucose positron-emission tomography (fdg-pet) has been used to differentiate benign neurofibromas from malignant peripheral nerve sheath tumours, fdg-pet characteristics for more rare tumours have been poorly described in children with nf1. Here, we report the role of pet imaging in clinical decision-making in each case. In nf1, fdg-pet might be useful in the clinical management of unusual tumour presentations and might help to provide information about the malignant potential of uncommon tumours. PMID- 24764719 TI - Lack of toxicity in a patient with germline TP53 mutation treated with radiotherapy. AB - Li-Fraumeni syndrome is an autosomal dominant disorder characterized by germline TP53 mutation and increased susceptibility to cancer. Despite certain in vitro findings and a theoretical rationale for patients with TP53 mutation to be more radiosensitive and more prone to developing radiotherapy (rt)-induced secondary malignancies, corresponding clinical data remain elusive. Here, we report the case of a woman with TP53 mutation who was treated with adjuvant pelvic rt for stage ib uterine leiomyosarcoma in 2000, with radioactive iodine for papillary thyroid cancer in 2001, and with palliative rt to the humerus in 2010 for metastatic uterine leiomyosarcoma. She has not developed any acute or late rt related toxicity, nor any secondary malignancies, since her first rt treatment. The literature review describes the potential risks and benefits of using irradiation in patients with TP53 mutation. PMID- 24764720 TI - Localized synchronous squamous cell carcinomas of the esophagus and hypopharynx treated with definitive concurrent chemoradiotherapy with a unified radiotherapy plan. AB - Because of common risk factors, synchronous squamous cell carcinomas of the esophagus and head and neck are common, and their concurrent presence can significantly complicate disease eradication and survival. Here, we report the case of a patient with a history of extensive tobacco and alcohol use who was diagnosed with a localized thoracic esophageal squamous cell carcinoma, and in whom positron-emission tomography-computed tomography discovered a nearby asymptomatic localized hypopharyngeal focus that was confirmed by biopsy to also be malignant. He was treated with definitive concurrent chemoradiotherapy in a single unified radiotherapy plan, with surgery reserved for salvage treatment. He currently remains in remission without a need for surgical salvage. However, significant concern remains for both treatment failure and development of another primary because of "field cancerization." PMID- 24764721 TI - Remembrance day. PMID- 24764722 TI - Taking count. PMID- 24764723 TI - Turkish journal of hematology: from "istanbul contribution to clinical science" to "pubmed central". PMID- 24764725 TI - A Polymorphism in the IL-5 Gene is Associated with Inhibitor Development in Severe Hemophilia A Patients. AB - OBJECTIVE: A severe complication in the replacement therapy of hemophilia A (HA) patients is the development of alloantibodies (inhibitors) against factor VIII, which neutralizes the substituted factor. The primary genetic risk factors influencing the development of inhibitors are F8 gene mutations. Interleukins and cytokines that are involved in the regulation of B-lymphocyte development are other possible targets as genetic risk factors. This study assesses the possible involvement of 9 selected single nucleotide gene polymorphisms (SNPs) with interleukins (IL-4, IL-5, and IL-10), transforming growth factor beta 1 (TGF beta1), and interferon gamma (IFN-gamma) in inhibitor development in severely affected HA patients carrying a null mutation in the F8 gene. MATERIALS AND METHODS: A total of 173 HA patients were screened for intron 22 inversion and null mutations (nonsense and deletions). Genotyping of a total of 9 SNPs in genes IL-4, IL-5, IL-10, TGF-beta1, and IFN-gamma in 103 patients and 100 healthy individuals was carried out. RESULTS: An association analysis between 42 inhibitor (+) and 61 inhibitor (-) patients showed a significant association with the T allele of rs2069812 in the IL-5 gene promoter and patients with inhibitors (p=0.0251). The TT genotype was also significantly associated with this group with a p-value of 0.0082, odds ratio of about 7, and confidence interval of over 90%, suggesting that it is the recessive susceptibility allele and that the C allele is the dominant protective allele. CONCLUSION: The lack of other variants in the IL-5 gene of patients and controls suggests that rs2069812 may be a regulatory SNP and may have a role in B-lymphocyte development, constituting a genetic risk factor in antibody development. PMID- 24764724 TI - beta-Thalassemia Intermedia: A Bird's-Eye View. AB - Beta-thalassemia is due to a defect in the synthesis of the beta-globin chains, leading to alpha/beta imbalance, ineffective erythropoiesis, and chronic anemia. The spectrum of thalassemias is wide, with one end comprising thalassemia minor, which consists of a mild hypochromic microcytic anemia with no obvious clinical manifestations, while on the other end is thalassemia major, characterized by patients who present in their first years of life with profound anemia and regular transfusion requirements for survival. Along the spectrum lies thalassemia intermedia, a term developed to describe patients with manifestations that are neither mild enough nor severe enough to be classified in the spectrum's extremes. Over the past decade, our understanding of beta-thalassemia intermedia has increased tremendously with regards to molecular information as well as pathophysiology. It is now clear that beta-thalassemia intermedia has a clinical presentation as well as complications associated with the disease that are different from those of beta-thalassemia major. This review is designed to tackle issues related to beta-thalassemia intermedia from the basic definition of the disease to paramedical issues, namely the quality of life in these patients. Genetics and pathophysiology are revisited, as well as the complications specific to this disease. These complications include effects on several organ systems, including the cardiovascular, hepatic, endocrine, renal, brain, and skeletal systems. Extramedullary hematopoiesis is also discussed in this article. Risk factors are highlighted and cutoffs are identified to minimize morbidities in beta-thalassemia intermedia. Several treatment modalities are considered by shining a light on the pros and cons of each modality, as well as the role of special pharmacological agents in the progress of the disease and its morbidities. Finally, health-related quality of life is discussed in these patients with a direct comparison to the more severe beta-thalassemia major. PMID- 24764726 TI - Evaluation of red cell membrane cytoskeletal disorders using a flow cytometric method in South iran. AB - OBJECTIVE: The diagnosis of hereditary red blood cell (RBC) membrane disorders, and in particular hereditary spherocytosis (HS) and Southeast Asian ovalocytosis (SAO), is based on clinical history, RBC morphology, and other conventional tests such as osmotic fragility. However, there are some milder cases of these disorders that are difficult to diagnose. The application of eosin-5'-maleimide (EMA) was evaluated for screening of RBC membrane defects along with some other anemias. We used EMA dye, which binds mostly to band 3 protein and to a lesser extent some other membrane proteins, for screening of some membrane defects such as HS. MATERIALS AND METHODS: Fresh RBCs from hematologically normal controls and patients with HS, SAO, hereditary elliptocytosis, hereditary spherocytosis with pincered cells, severe iron deficiency, thalassemia minor, and autoimmune hemolytic anemia were stained with EMA dye and analyzed for mean fluorescent intensity (MFI) using a flow cytometer. RESULTS: RBCs from patients with HS and iron deficiency showed a significant reduction in MFI compared to those from normal controls (p<0.0001 and p<0.001, respectively), while macrocytic RBCs showed a significant increase in MFI (p<0.01). A significant correlation was shown between mean corpuscular volume and MFI, with the exceptions of HS and thalassemia minor. CONCLUSION: Our results showed that the flow cytometric method could be a reliable diagnostic method for screening and confirmation, with higher sensitivity and specificity (95% and 93%, respectively) than conventional routine tests for HS patients prior to further specific membrane protein molecular tests. PMID- 24764727 TI - Childhood Immune Thrombocytopenia: Long-term Follow-up Data Evaluated by the Criteria of the International Working Group on Immune Thrombocytopenic Purpura. AB - OBJECTIVE: Immune thrombocytopenia (ITP) is a common bleeding disorder in childhood, characterized by isolated thrombocytopenia. The International Working Group (IWG) on ITP recently published a consensus report about the standardization of terminology, definitions, and outcome criteria in ITP to overcome the difficulties in these areas. MATERIALS AND METHODS: The records of patients were retrospectively collected from January 2000 to December 2009 to evaluate the data of children with ITP by using the new definitions of the IWG. RESULTS: The data of 201 children were included in the study. The median follow up period was 22 months (range: 12-131 months). The median age and platelet count at presentation were 69 months (range: 7-208 months) and 19x10(9)/L (range: 1x10(9)/L to 93x10(9)/L), respectively. We found 2 risk factors for chronic course of ITP: female sex (OR=2.55, CI=1.31-4.95) and age being more than 10 years (OR=3.0, CI=1.5-5.98). Life-threatening bleeding occurred in 5% (n=9) of the patients. Splenectomy was required in 7 (3%) cases. When we excluded 2 splenectomized cases, complete remission at 1 year was achieved in 70% (n=139/199). The disease was resolved in 9 more children between 12 and 90 months. CONCLUSION: Female sex and age above 10 years old significantly influenced chronicity. Therefore, long-term follow-up is necessary in these children. PMID- 24764729 TI - Leukocyte populations and C-reactive protein as predictors of bacterial infections in febrile outpatient children. AB - OBJECTIVE: Infections remain the major cause of unnecessary antibiotic use in pediatric outpatient settings. Complete blood count (CBC) is the essential test in the diagnosis of infections. C-reactive protein (CRP) is also useful for assessment of young children with serious bacterial infections. The purpose of the study was to evaluate leukocyte populations and CRP level to predict bacterial infections in febrile outpatient children. MATERIALS AND METHODS: The values of CBC by Cell-DYN 4000 autoanalyzer and serum CRP levels were evaluated in 120 febrile patients with documented infections (n:74 bacterial, n:46 viral) and 22 healthy controls. RESULTS: The mean CRP, neutrophil and immature granulocyte (IG) values were significantly higher in bacterial infections than in viral infections and controls (p<0.05). C-reactive protein was significantly correlated with neutrophil level in bacterial infections (r: 0.76, p<0.05). Specificity of IG was greatest at 93%, only a modest 56% for neutrophil and mild 18% for CRP, whereas 100% for combination of IG, neutrophil and CRP. CONCLUSION: Acute bacterial infection seems to be very unlikely in children with normal leukocyte populations and CRP values, even if clinically signs and symptoms indicate acute bacterial infections. PMID- 24764728 TI - NPM1 Gene Type A Mutation in Bulgarian Adults with Acute Myeloid Leukemia: A Single-Institution Study. AB - OBJECTIVE: Mutations of the nucleophosmin (NPM1) gene are considered as the most frequent acute myeloid leukemia (AML)-associated genetic lesion, reported with various incidences in different studies, and type A (NPM1-A) is the most frequent type. However, since most series in the literature report on the features of all patients regardless of the type of mutation, NPM1-A(+) cases have not been well characterized yet. Therefore, we evaluated the prevalence of NPM1-A in Bulgarian AML patients and searched for an association with clinical and laboratory features. MATERIALS AND METHODS: One hundred and four adults (51 men, 53 women) were included in the study. NPM1-A status was determined using allele-specific reverse-transcription polymerase chain reaction with co-amplification of NPM1-A and beta-actin and real-time quantitative TaqMan-based polymerase chain reaction. Patients received conventional induction chemotherapy and were followed for 13.2+/-16.4 months. RESULTS: NPM1-A was detected in 26 (24.8%) patients. NPM1-A mutation was detected in all AML categories, including in one patient with RUNX1 RUNX1T1. There were no differences associated with the NPM1-A status with respect to age, sex, hemoglobin, platelet counts, percentage of bone marrow blasts, splenomegaly, complete remission rates, and overall survival. NPM1-A(+) patients, compared to NPM1-A(-) patients, were characterized by higher leukocyte counts [(75.4+/-81.9)x109/L vs. (42.5+/-65.9)x109/L; p=0.049], higher frequency of normal karyotype [14/18 (77.8%) vs. 26/62 (41.9%); p=0.014], higher frequency of FLT3-ITD [11/26 (42.3%) vs. 8/77 (10.4%); p=0.001], and lower incidence of CD34(+) [6/21 (28.8%) vs. 28/45 (62.2%); p=0.017]. Within the FLT3-ITD(-) group, the median overall survival of NPM1-A(-) patients was 14 months, while NPM1-A(+) patients did not reach the median (p=0.10). CONCLUSION: The prevalence of NPM1-A mutation in adult Bulgarian AML patients was similar to that reported in other studies. NPM1-A(+) patients were characterized by higher leukocyte counts, higher frequency of normal karyotypes and FLT3-ITD, and lower incidence of CD34(+), supporting the idea that the specific features of type A mutations might contribute to the general clinical and laboratory profile of NPM1(+) AML patients. PMID- 24764730 TI - FIP1L1-PDGFRA-Positive Chronic Eosinophilic Leukemia: A Low-Burden Disease with Dramatic Response to Imatinib - A Report of 5 Cases from South India. AB - OBJECTIVE: Eosinophilia associated with FIP1L1-PDGFRA rearrangement represents a subset of chronic eosinophilic leukemia and affected patients are sensitive to imatinib treatment. This study was undertaken to learn the prevalence and associated clinicopathologic and genetic features of FIP1L1-PDGFRA rearrangement in a cohort of 26 adult patients presenting with profound eosinophilia (>1.5x10(9)/L). MATERIALS AND METHODS: Reverse-transcriptase polymerase chain reaction and gel electrophoresis were used for the detection of FIP1L1-PDGFRA rearrangement. RESULTS: Five male patients with splenomegaly carried the FIP1L1 PDGFRA gene rearrangement. All patients achieved complete hematological response within 4 weeks of starting imatinib. One patient had previous deep vein thrombosis and 1 patient had cardiomyopathy, which improved with steroids and imatinib. Conventional cytogenetics was normal in all these patients. No primary resistance to imatinib was noted. CONCLUSION: This study indicates the need to do the FIP1L1-PDGFRA assay in patients with hypereosinophilic syndrome. Prompt treatment of this condition with imatinib can lead to complete hematological response and resolution of the organ damage that can be seen in this setting. PMID- 24764731 TI - The impact of obesity and insulin resistance on iron and red blood cell parameters: a single center, cross-sectional study. AB - OBJECTIVE: Obesity and iron deficiency (ID) are the 2 most common nutritional disorders worldwide causing significant public health implications. Obesity is characterized by the presence of low-grade inflammation, which may lead to a number of diseases including insulin resistance (IR) and type 2 diabetes. Increased levels of acute-phase proteins such as C-reactive protein (CRP) have been reported in obesity-related inflammation. The aim of this study was to investigate the impact of obesity/IR on iron and red blood cell related parameters. MATERIALS AND METHODS: A total of 206 patients and 45 control subjects of normal weight were included in this cross-sectional study. Venous blood samples were taken from each patient to measure hemoglobin (Hb), serum iron (Fe), iron-binding capacity (IBC), ferritin, CRP, fasting blood glucose, and fasting insulin. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated for each patient. IR was determined using the HOMA-IR formula. RESULTS: Subjects were divided into 3 groups according to BMI. There were 152 severely obese (BMI: 42.6+/-10.1), 54 mildly obese (BMI: 32.4+/-2.1), and 45 normal-weight (BMI: 24.3+/-1.3) patients. Hb levels in severely obese patients and normal controls were 12.8+/-1.3 g/dL and 13.6+/-1.8 g/dL, respectively. We found decreasing Fe levels with increasing weight (14.9+/-6.9 umol/L, 13.6+/-6.3 umol/L, and 10.9+/-4.6 umol/L for normal controls and mildly and severely obese patients, respectively). Hb levels were slightly lower in patients with higher HOMA-IR values (13.1+/-1.5 g/dL vs. 13.2+/-1.2 g/dL; p=0.36). Serum iron levels were significantly higher in the group with low HOMA-IR values (13.6+/-5.9 umol/L vs. 11.6+/-4.9 umol/L; p=0.008). IBC was found to be similar in both groups (60.2+/-11.4 umol/L vs. 61.9+/-10.7 umol/L; p=0.23). Ferritin was slightly higher in patients with higher HOMA-IR values (156.1+/-209.5 pmol/L vs. 145.3+/-131.5 pmol/L; p=0.62). CONCLUSION: Elevated BMI and IR are associated with lower Fe and hemoglobin levels. These findings may be explained by the chronic inflammation of obesity and may contribute to obesity-related co-morbidities. People with IR may present with ID without anemia. PMID- 24764732 TI - The role of nitric oxide in Doxorubicin-induced cardiotoxicity: experimental study. AB - OBJECTIVE: We evaluated the myocardial damage in rats treated with doxorubicin (DOX) alone and in combination with nitric oxide synthase (NOS) inhibitors. MATERIALS AND METHODS: Twenty-four male Sprague Dawley rats (12 weeks old, weighing 262+/-18 g) were randomly assigned into 4 groups (n=6). Group I was the control group. In Group II, rats were treated with intraperitoneal (ip) injections of 3 mg/kg DOX once a week for 5 weeks. In Group III, rats received weekly ip injections of 30 mg/kg L-NAME (nonspecific NOS inhibitor) 30 min before DOX injections for 5 weeks. In Group IV, rats received weekly ip injections of 3 mg/kg L-NIL (inducible NOS inhibitor) 30 min before DOX injections for 5 weeks. Rats were weighed 2 times a week. At the end of 6 weeks, hearts were excised and then fixed for light and electron microscopy evaluation and tissue lipid peroxidation (malondialdehyde). Blood samples were also obtained for measuring plasma lipid peroxidation. RESULTS: Weight loss was observed in Group II, Group III, and Group IV. Weight loss was statistically significant in the DOX group. Findings of myocardial damage were significantly higher in animals treated with DOX only than in the control group. Histopathological findings of cardiotoxicity in rats treated with DOX in combination with L-NAME and L-NIL were not significantly different compared with the control group. The level of plasma malondialdehyde in the DOX group (9.3+/-3.4 umol/L) was higher than those of all other groups. CONCLUSION: Our results showed that DOX cardiotoxicity was significantly decreased when DOX was given with NO synthase inhibitors. PMID- 24764733 TI - Central nervous system involvement of T-cell prolymphocytic leukemia diagnosed with stereotactic brain biopsy: case report. AB - Prolymphocytic leukemia (PLL) is a generalized malignancy of the lymphoid tissue characterized by the accumulation of monoclonal lymphocytes, usually of B cell type. Involvement of the central nervous system (CNS) is an extremely rare complication of T-cell prolymphocytic leukemia (T-PLL). We describe a case of T PLL presenting with symptomatic infiltration of the brain that was histopathologically proven by stereotactic brain biopsy. We emphasize the importance of rapid diagnosis and immediate treatment for patients presenting with CNS involvement and a history of leukemia or lymphoma. PMID- 24764734 TI - Epstein-barr virus-negative post-transplant lymphoproliferative diseases: three distinct cases from a single center. AB - Three cases of Epstein-Barr virus (EBV)-negative post-transplant lymphoproliferative disease that occurred 6 to 8 years after renal transplantation are reported. The patients respectively had gastric mucosa associated lymphoid tissue lymphoma, gastric diffuse large B-cell lymphoma, and atypical Burkitt lymphoma. Absence of EBV in the tissue samples was demonstrated by both in situ hybridization for EBV early RNA and polymerase chain reaction for EBV DNA. Patients were treated with reduction in immunosuppression and combined chemotherapy plus an anti-CD20 monoclonal antibody, rituximab. Despite the reduction in immunosuppression, patients had stable renal functions without loss of graft functions. The patient with atypical Burkitt lymphoma had an abnormal karyotype, did not respond to treatment completely, and died due to disease progression. The other patients are still alive and in remission 5 and 3 years after diagnosis, respectively. EBV-negative post-transplant lymphoproliferative diseases are usually late-onset and are reported to have poor prognosis. Thus, reduction in immunosuppression is usually not sufficient for treatment and more aggressive approaches like rituximab with combined chemotherapy are required. PMID- 24764735 TI - Serum Level of Lactate Dehydrogenase is a Useful Clinical Marker to Monitor Progressive Multiple Myeloma Diseases: A Case Report. AB - To follow the progression of multiple myeloma (MM) disease, serum lactate dehydrogenase (LDH) levels are as useful markers as beta-2 microglobulin and monoclonal immunoglobulin. With this study, we have presented a case of a patient with a multiple myeloma which was fulminant course, whose LDH levels were normal at the onset of diagnosis increasing as 27 times more than normal as the disease progressed and who showed the development of extramedullary plasmacytomas. The patient, an 80-year-old female, was diagnosed with stage IIIA IgA type multiple myeloma and melphalan-prednisolon (MP) treatment was started. Although the LDH levels were low during the diagnosis and chemotherapy, the LDH levels increased up to 7557 U/L following the progression and occurrence of extramedullary plasmacytomas and the patient died. During the observation of the patient with MM, if the LDH levels are abnormally high, the progression of the disease should be considered after eliminating the other causes. Bone marrow aspiration and biopsy should be examined and the progression or relapse should be shown. On the other hand, the patients with LDH levels are high should be considered to have added plasmacytomas, the whole body should be examined at an early stage before the development of clinical symptoms and early treatment should be started. PMID- 24764736 TI - Isolated Granulocytic Sarcoma of the Breast after Allogeneic Stem Cell Transplantation: A Rare Involvement Also Detected by 18FDG-PET/CT. AB - Granulocytic sarcoma is a tumor consisting of myeloid blasts with or without maturation that occurs at an anatomical site other than bone marrow. Most frequently affected sites are skin, lymph nodes, gastrointestinal tract, bone, soft tissue and testes. AML may manifest as granulocytic sarcoma at diagnosis or relapse. Although it has been considered to be rare relapse as granulocytic sarcoma after stem cell transplantation is being increasingly reported. However it is rare without bone marrow involvement and in AML M6 subtype. Breast is also a rare involvement. We report a 30-year-old woman with AML M6 relapsed 16 months after allogeneic stem cell transplantation as a granulocytic sarcoma in right breast without bone marrow involvement. She was treated with systemic chemotherapy but died of sepsis. 18FDG-PET/CT images were also obtained and detected lesions other than detected by breast ultrasound. The incidence of granulocytic sarcoma may increase if suspected or new diagnostic modalities are performed. PMID- 24764737 TI - Chronic myeloid leukemia as a secondary malignancy following treatment of diffuse large B-cell lymphoma. PMID- 24764738 TI - Acute myocardial infarction after first dose of rituximab infusion. PMID- 24764739 TI - An updated review of abnormal hemoglobins in the Turkish population. PMID- 24764740 TI - Lenalidomide-induced pure red cell aplasia. PMID- 24764741 TI - Early postnatal hemorrhagic shock due to intraabdominal hemorrhage in a newborn with severe hemophilia a. PMID- 24764742 TI - Severe adenovirus infection associated with hemophagocytic lymphohistiocytosis. PMID- 24764743 TI - Cystinosis: diagnostic role of bone marrow examination. PMID- 24764744 TI - Deviation from Normal Values of Leukocyte and Erythroblast Parameters in Complete Blood Count is a Messenger for Platelet Abnormalities. PMID- 24764745 TI - Intrathecal Methotrexate-Induced Posterior Reversible Encephalopathy Syndrome (PRES). PMID- 24764747 TI - 'One of the Best Fathers until He Went Out of His Mind': Paternal Child-Murder, 1864-1900. PMID- 24764746 TI - A Statistical Modeling Framework for Projecting Future Ambient Ozone and its Health Impact due to Climate Change. AB - The adverse health effects of ambient ozone are well established. Given the high sensitivity of ambient ozone concentrations to meteorological conditions, the impacts of future climate change on ozone concentrations and its associated health effects are of concern. We describe a statistical modeling framework for projecting future ozone levels and its health impacts under a changing climate. This is motivated by the continual effort to evaluate projection uncertainties to inform public health risk assessment. The proposed approach was applied to the 20 county Atlanta metropolitan area using regional climate model (RCM) simulations from the North American Regional Climate Change Assessment Program. Future ozone levels and ozone-related excesses in asthma emergency department (ED) visits were examined for the period 2041-2070. The computationally efficient approach allowed us to consider 8 sets of climate model outputs based on different combinations of 4 RCMs and 4 general circulation models. Compared to the historical period of 1999-2004, we found consistent projections across climate models of an average 11.5% higher ozone levels (range: 4.8%, 16.2%), and an average 8.3% (range: -7% to 24%) higher number of ozone exceedance days. Assuming no change in the at-risk population, this corresponds to excess ozone-related ED visits ranging from 267 to 466 visits per year. Health impact projection uncertainty was driven predominantly by uncertainty in the health effect association and climate model variability. Calibrating climate simulations with historical observations reduced differences in projections across climate models. PMID- 24764748 TI - Nursing empire: travel letters from Africa and the Caribbean. AB - This essay analyses colonial nurses' travel letters, written from West Africa and the Caribbean between the turn of the century and 1920, in order to better understand the role of nurses in forming satellite versions of home. Though their primary function was to 'nurse empire' by helping to repair and maintain the bodies needed for imperial labour, nurses also contributed to written discourses supporting Britain's economic interests and political goals. Through careful consideration of primary archival material, this essay analyses the rhetorical modes that may have helped nurses gain professional and personal authority abroad. It considers nurses as moving within several kinds of imperial networks - geographical, institutional and discursive - and traces the shifts in their written self-representation according to these different contexts. In order to reform nursing, in the mid-nineteenth century Florence Nightingale defined the 'New Nurse's' ideal personality as well as her duties. Ever since, the nurse's 'character' has often been essentialised in literature and culture. As Julia Hallam observes in Nursing the Image (2000), the nurse is commonly portrayed as ministering angel, potential seductress, battleaxe or doctor's helpmate. The goal of this essay is to resist simplifying nurses' cultural significance, motivations or experiences by studying the multiple influences to which colonial nurses were subject and the shifting registers in their writing. PMID- 24764749 TI - ELAG - 10 Successful Years. PMID- 24764750 TI - The challenges of organizing an international course in Latin America. AB - The Latin American School of Human and Medical Genetics (ELAG) is the main course of its kind in the genetics field in Latin America. Here we describe the main challenges regarding the organization of such event, including how we obtain funding and how we proceed with student selection. Thus, we aim to share our experience with other groups that intend to follow this format to create similar events in other areas in this region of the world. PMID- 24764752 TI - Genealogical data in population medical genetics: Field guidelines. AB - This is a guide for fieldwork in Population Medical Genetics research projects. Data collection, handling, and analysis from large pedigrees require the use of specific tools and methods not widely familiar to human geneticists, unfortunately leading to ineffective graphic pedigrees. Initially, the objective of the pedigree must be decided, and the available information sources need to be identified and validated. Data collection and recording by the tabulated method is advocated, and the involved techniques are presented. Genealogical and personal information are the two main components of pedigree data. While the latter is unique to each investigation project, the former is solely represented by gametic links between persons. The triad of a given pedigree member and its two parents constitutes the building unit of a genealogy. Likewise, three ID numbers representing those three elements of the triad is the record field required for any pedigree analysis. Pedigree construction, as well as pedigree and population data analysis, varies according to the pre-established objectives, the existing information, and the available resources. PMID- 24764753 TI - From rumors to genetic isolates. AB - Here we propose a registration process for population genetic isolates, usually geographic clusters of genetic disorders, based on the systematic search of rumors, defined as any type of account regardless of its reliability. Systematically ascertained rumors are recorded, and validated through a progressive process of pre-established steps. This paper outlines the conceptual basis for this approach and presents the preliminary results from a rumor-based nationwide registry of genetically isolated populations, named CENISO (Censo Nacional de Isolados), operating in Brazil since 2009. During the first four years of its existence (2009-2013), a total of 191 Rumors were registered and validated, resulting in a prevalence rate of one per million inhabitants of Brazil. When the five statutory geographic regions of Brazil were considered, more Rumors were registered for the Northeast (2.11; 1.74-2.54 per 10(6)) than for the remaining four regions, North, Center-West, Southeast, and South, which did not differ among themselves. About half (86/191) of the recorded rumors were proven to be geographic clusters; of these disorders, 58 were autosomal recessive, 17 autosomal dominant, 5 X-linked, 3 multifactorial, and one environmental (thalidomide embryopathy). PMID- 24764751 TI - Interethnic admixture and the evolution of Latin American populations. AB - A general introduction to the origins and history of Latin American populations is followed by a systematic review of the data from molecular autosomal assessments of the ethnic/continental (European, African, Amerindian) ancestries for 24 Latin American countries or territories. The data surveyed are of varying quality but provide a general picture of the present constitution of these populations. A brief discussion about the applications of these results (admixture mapping) is also provided. Latin American populations can be viewed as natural experiments for the investigation of unique anthropological and epidemiological issues. PMID- 24764754 TI - Human molecular cytogenetics: From cells to nucleotides. AB - The field of cytogenetics has focused on studying the number, structure, function and origin of chromosomal abnormalities and the evolution of chromosomes. The development of fluorescent molecules that either directly or via an intermediate molecule bind to DNA has led to the development of fluorescent in situ hybridization (FISH), a technology linking cytogenetics to molecular genetics. This technique has a wide range of applications that increased the dimension of chromosome analysis. The field of cytogenetics is particularly important for medical diagnostics and research as well as for gene ordering and mapping. Furthermore, the increased application of molecular biology techniques, such as array-based technologies, has led to improved resolution, extending the recognized range of microdeletion/microduplication syndromes and genomic disorders. In adopting these newly expanded methods, cytogeneticists have used a range of technologies to study the association between visible chromosome rearrangements and defects at the single nucleotide level. Overall, molecular cytogenetic techniques offer a remarkable number of potential applications, ranging from physical mapping to clinical and evolutionary studies, making a powerful and informative complement to other molecular and genomic approaches. This manuscript does not present a detailed history of the development of molecular cytogenetics; however, references to historical reviews and experiments have been provided whenever possible. Herein, the basic principles of molecular cytogenetics, the technologies used to identify chromosomal rearrangements and copy number changes, and the applications for cytogenetics in biomedical diagnosis and research are presented and discussed. PMID- 24764755 TI - New microdeletion and microduplication syndromes: A comprehensive review. AB - Several new microdeletion and microduplication syndromes are emerging as disorders that have been proven to cause multisystem pathologies frequently associated with intellectual disability (ID), multiple congenital anomalies (MCA), autistic spectrum disorders (ASD) and other phenotypic findings. In this paper, we review the "new" and emergent microdeletion and microduplication syndromes that have been described and recognized in recent years with the aim of summarizing their main characteristics and chromosomal regions involved. We decided to group them by genomic region and within these groupings have classified them into those that include ID, MCA, ASD or other findings. This review does not intend to be exhaustive but is rather a quick guide to help pediatricians, clinical geneticists, cytogeneticists and/or molecular geneticists. PMID- 24764756 TI - DNA repair diseases: What do they tell us about cancer and aging? AB - The discovery of DNA repair defects in human syndromes, initially in xeroderma pigmentosum (XP) but later in many others, led to striking observations on the association of molecular defects and patients' clinical phenotypes. For example, patients with syndromes resulting from defective nucleotide excision repair (NER) or translesion synthesis (TLS) present high levels of skin cancer in areas exposed to sunlight. However, some defects in NER also lead to more severe symptoms, such as developmental and neurological impairment and signs of premature aging. Skin cancer in XP patients is clearly associated with increased mutagenesis and genomic instability, reflecting the defective repair of DNA lesions. By analogy, more severe symptoms observed in NER-defective patients have also been associated with defective repair, likely involving cell death after transcription blockage of damaged templates. Endogenously induced DNA lesions, particularly through oxidative stress, have been identified as responsible for these severe pathologies. However, this association is not that clear and alternative explanations have been proposed. Despite high levels of exposure to intense sunlight, patients from tropical countries receive little attention or care, which likely also reflects the lack of understanding of how DNA damage causes cancer and premature aging. PMID- 24764757 TI - Prevalence and impact of founder mutations in hereditary breast cancer in Latin America. AB - Approximately 10% of all cancers are considered hereditary and are primarily caused by germline, high penetrance mutations in cancer predisposition genes. Although most cancer predisposition genes are considered molecularly heterogeneous, displaying hundreds of different disease-causing sequence alterations, founder mutations have been identified in certain populations. In some Latin American countries, founder mutations associated with increased risk of breast and other cancers have been described. This is particularly interesting considering that in most of these countries, populations are highly admixed with genetic contributions from native populations and from the in-flux of several distinct populations of immigrants. In this article, we present a review of the scientific literature on the subject and describe current data available on founder mutations described in the most common breast cancer predisposition genes: BRCA1, BRCA2 and TP53. PMID- 24764758 TI - Impact of NGS in the medical sciences: Genetic syndromes with an increased risk of developing cancer as an example of the use of new technologies. AB - The increased speed and decreasing cost of sequencing, along with an understanding of the clinical relevance of emerging information for patient management, has led to an explosion of potential applications in healthcare. Currently, SNP arrays and Next-Generation Sequencing (NGS) technologies are relatively new techniques used to scan genomes for gains and losses, losses of heterozygosity (LOH), SNPs, and indel variants as well as to perform complete sequencing of a panel of candidate genes, the entire exome (whole exome sequencing) or even the whole genome. As a result, these new high-throughput technologies have facilitated progress in the understanding and diagnosis of genetic syndromes and cancers, two disorders traditionally considered to be separate diseases but that can share causal genetic alterations in a group of developmental disorders associated with congenital malformations and cancer risk. The purpose of this work is to review these syndromes as an example of a group of disorders that has been included in a panel of genes for NGS analysis. We also highlight the relationship between development and cancer and underline the connections between these syndromes. PMID- 24764759 TI - Molecular analysis of holoprosencephaly in South America. AB - Holoprosencephaly (HPE) is a spectrum of brain and facial malformations primarily reflecting genetic factors, such as chromosomal abnormalities and gene mutations. Here, we present a clinical and molecular analysis of 195 probands with HPE or microforms; approximately 72% of the patients were derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), and 82% of the patients were newborns. Alobar HPE was the predominant brain defect in almost all facial defect categories, except for patients without oral cleft and median or lateral oral clefts. Ethmocephaly, cebocephaly, and premaxillary agenesis were primarily observed among female patients. Premaxillary agenesis occurred in six of the nine diabetic mothers. Recurrence of HPE or microform was approximately 19%. The frequency of microdeletions, detected using Multiplex Ligation-dependant Probe Amplification (MLPA) was 17% in patients with a normal karyotype. Cytogenetics or QF-PCR analyses revealed chromosomal anomalies in 27% of the probands. Mutational analyses in genes SHH, ZIC2, SIX3 and TGIF were performed in 119 patients, revealing eight mutations in SHH, two mutations in SIX3 and two mutations in ZIC2. Thus, a detailed clinical description of new HPE cases with identified genetic anomalies might establish genotypic and phenotypic correlations and contribute to the development of additional strategies for the analysis of new cases. PMID- 24764760 TI - Genetic counseling and presymptomatic testing programs for Machado-Joseph Disease: lessons from Brazil and Portugal. AB - Machado-Joseph disease (MJD) is an autosomal dominant, late-onset neurological disorder and the most common form of spinocerebellar ataxia (SCA) worldwide. Diagnostic genetic testing is available to detect the disease-causing mutation by direct sizing of the CAG repeat tract in the ataxin 3 gene. Presymptomatic testing (PST) can be used to identify persons at risk of developing the disease. Genetic counseling provides patients with information about the disease, genetic risks, PST, and the decision-making process. In this study, we present the protocol used in PST for MJD and the relevant observations from two centers: Brazil (Porto Alegre) and Portugal (Porto). We provide a case report that illustrates the significant ethical and psychological issues related to PST in late-onset neurological disorders. In both centers, counseling and PST are performed by a multidisciplinary team, and genetic testing is conducted at the same institutions. From 1999 to 2012, 343 individuals sought PST in Porto Alegre; 263 (77%) of these individuals were from families with MJD. In Porto, 1,530 individuals sought PST between 1996 and 2013, but only 66 (4%) individuals were from families with MJD. In Brazil, approximately 50% of the people seeking PST eventually took the test and received their results, whereas 77% took the test in Portugal. In this case report, we highlight several issues that might be raised by the consultand and how the team can extract significant information. Literature about PST testing for MJD and other SCAs is scarce, and we hope this report will encourage similar studies and enable the implementation of PST protocols in other populations, mainly in Latin America. PMID- 24764761 TI - Reprogenetics: Preimplantational genetics diagnosis. AB - Preimplantational Genetics Diagnosis (PGD) is requested by geneticists and reproductive specialists. Usually geneticists ask for PGD because one or both members of the couple have an increased genetic risk for having an affected offspring. On the other hand, reproductive specialists ask for embryo aneuploidy screening (PGS) to assures an euploid embryo transfer, with the purpose to achieve an ongoing pregnancy, although the couple have normal karyotypes. As embryonic aneuploidies are responsible for pre and post implantation abortions, it is logical to considerer that the screening of the embryonic aneuploidies prior to embryo transfer could improve the efficiency of the in vitro fertilization procedures. Nevertheless, it is still premature to affirm this until well-designed clinical trials were done, especially in women of advanced age where the rate of embryos with aneuploidies is much greater. Although the indications of PGD are similar to conventional prenatal diagnosis (PND), PGD has less ethical objections than the PND. As with the PGD/PGS results only unaffected embryos are transferred, both methods can avoid the decision to interrupt the pregnancy due to a genetic problem; this makes an important difference when compared to conventional prenatal diagnosis. PMID- 24764763 TI - A snapshot of gene therapy in Latin America. AB - Gene therapy attempts the insertion and expression of exogenous genetic material in cells for therapeutic purposes. Conceived in the 1960s, gene therapy reached its first clinical trial at the end of the 1980s and by December 2013 around 600 genuine open clinical trials of gene therapy were registered at NIH Clinical Trials Database. Here, we summarize the current efforts towards the development of gene therapy in Latin America. Our survey shows that the number of scientists involved in the development of gene therapy and DNA vaccines in Latin America is still very low. Higher levels of investment in this technology are necessary to boost the advancement of innovation and intellectual property in this field in a way that would ease both the social and financial burden of various medical conditions in Latin America. PMID- 24764764 TI - Genetics and human rights. Two histories: Restoring genetic identity after forced disappearance and identity suppression in Argentina and after compulsory isolation for leprosy in Brazil. AB - Over the past three decades, there has been an accelerated development of genetic technology, leading to its use in human genetic identification for many purposes. Additionally, it has been made explicit that identity is a fundamental human right. A number of historical circumstances have connected these developments. Personal identity is increasingly associated with the preservation and defense of human rights and is a tool to repair the violation of these rights, particularly the right to identity. In this article, we report the use of genetics to support the right to identity in two historical circumstances. First, we report the search, localization, DNA testing and genetic identification of 110 individuals who were appropriated as babies by the Argentine military dictatorship of 1976 1983 in the context of savage repression and egregious violations of human rights, including forced disappearance and suppression of identity. Second, we report on the repair of right-to-identity violations of hundreds of individuals that occurred during the process of compulsory isolation of patients with leprosy in Brazil through the Program "Reencontro", which has led to the genetic identification of 158 pairs of individuals who previously did not have proof that they were siblings. The high value placed on genetic identification by victims of identity suppression did not counter the prevailing view that genetic factors were not more important than other factors (social, emotional, educational, cultural, spiritual) in determining the complex phenomenon of personal identity. The use of genetic identification as a tool to redress and repair human rights violations is a novel application of human genetics for the benefit of mankind. PMID- 24764762 TI - The new world of RNAs. AB - One of the major developments that resulted from the human genome sequencing projects was a better understanding of the role of non-coding RNAs (ncRNAs). NcRNAs are divided into several different categories according to size and function; however, one shared feature is that they are not translated into proteins. In this review, we will discuss relevant aspects of ncRNAs, focusing on two main types: i) microRNAs, which negatively regulate gene expression either by translational repression or target mRNA degradation, and ii) small interfering RNAs (siRNAs), which are involved in the biological process of RNA interference (RNAi). Our knowledge regarding these two types of ncRNAs has increased dramatically over the past decade, and they have a great potential to become therapeutic alternatives for a variety of human conditions. PMID- 24764765 TI - RELAGH - The challenge of having a scientific network in Latin America: An account from the presidents. AB - Latin America and the Caribbean region make up one of the largest areas of the world, and this region is characterized by a complex mixture of ethnic groups sharing Iberian languages. The area is comprised of nations and regions with different levels of social development. This region has experienced historical advances in the last decades to increase the minimal standards of quality of life; however, several factors, such as concentrated populations in large urban centers and isolated and poor communities, still have an important impact on medical services, particularly genetics services. Latin American researchers have greatly contributed to the development of human genetics and historic inter ethnic diversity, and the multiplicity of geographic areas are unique for the study of gene-environment interactions. As a result of regional developments in the fields of human and medical genetics, the Latin American Network of Human Genetics (Red Latinoamericana de Genetica Humana - RELAGH) was created in 2001 to foster the networking of national associations and societies dedicated to these scientific disciplines. RELAGH has developed important educational activities, such as the Latin American School of Human and Medical Genetics (ELAG), and has held three biannual meetings to encourage international research cooperation among the member countries and international organizations. Since its foundation, RELAGH has been admitted as a full regional member to the International Federation of Human Genetics Societies. This article describes the historical aspects, activities, developments, and challenges that are still faced by the Network. PMID- 24764766 TI - A tribute to jose maria ("chema") cantu. AB - Jose Maria ("Chema") Cantu (1938-2007), born in Mexico, was a pioneering, loved and respected leader in medical and human genetics and bioethics in Latin America. He graduated as a physician in Mexico and then trained in medical and human genetics in France and the United States. He was instrumental in developing a first-rate research, training and genetic services program in medical and human genetics in Guadalajara, in northwestern Mexico. He acted forcefully at national, regional and international levels to promote scientific development through collaboration and education in science and humanities, while he simultaneously strived for justice, peace, love and human rights. He attained some of the highest honors a scientist and humanist could aspire to as well as the recognition of the communities he served. Hundreds of disciples throughout Latin America and the world have been inspired by his vision of a better world through the conjunction of science, respect for humankind, ethics and love. PMID- 24764767 TI - Does Sequence Matter in Multi-Mode Surveys: Results from an Experiment. AB - Interest in a multi-mode approach to surveys has grown substantially in recent years, in part due to increased costs of face-to-face interviewing and the emergence of the internet as a survey mode. Yet, there is little systematic evidence of the impact of a multimode approach on survey costs and errors. This paper reports the results of an experiment designed to evaluate whether a mixed mode approach to a large screening survey would produce comparable response rates at a lower cost than a face-to-face screening effort. The experiment was carried out in the Health and Retirement Study (HRS), an ongoing panel study of Americans over age 50. In 2010, HRS conducted a household screening survey to recruit new sample members to supplement the existing sample. The experiment varied the sequence of modes with which the screening interview was delivered. One treatment offered mail first, followed by face-to-face interviewing; the other started with face-to-face and then mail. A control group was offered only face-to-face interviewing. Results suggest that the mixed mode options reduced costs without reducing response rates to the screening interview. There is some evidence, however, that the sequence of modes offered may impact the response rate for a follow-up in-depth interview. PMID- 24764768 TI - A novel high-power dual-band coupled-line Gysel power divider with impedance transforming functions. AB - A novel coupled-line structure is proposed to design dual-band and high-power Gysel power dividers with inherent impedance-transforming functions. Based on traditional even- and odd-mode technique, the analytical design methods in closed form formula are obtained and the accurate electrical parameters analysis is presented. Due to the usage of coupled-line sections, more design-parameter freedom and a wider frequency-ratio operation range for this kind of dual-band Gysel powder divider are obtained. Several numerical examples are designed and calculated to demonstrate flexible dual-band applications with different impedance-transforming functions. A practical microstrip power divider operating at 2 GHz and 3.2 GHz is designed, fabricated, and measured. The good agreement between the calculated and measured results verifies our proposed circuit structure and analytical design approach. PMID- 24764769 TI - Interannual differences for sea turtles bycatch in Spanish longliners from Western Mediterranean Sea. AB - Recent studies showed that regional abundance of loggerhead and leatherback turtles could oscillate interannually according to oceanographic and climatic conditions. The Western Mediterranean is an important fishing area for the Spanish drifting longline fleet, which mainly targets swordfish, bluefin tuna, and albacore. Due to the spatial overlapping in fishing activity and turtle distribution, there is an increasing sea turtle conservation concern. The main goal of this study is to analyse the interannual bycatch of loggerhead and leatherback turtles by the Spanish Mediterranean longline fishery and to test the relationship between the total turtle by-catch of this fishery and the North Atlantic Oscillation (NAO). During the 14 years covered in this study, the number of sea turtle bycatches was 3,940 loggerhead turtles and 8 leatherback turtles, 0.499 loggerhead turtles/1000 hooks and 0.001014 leatherback turtles/1000 hooks. In the case of the loggerhead turtle the positive phase of the NAO favours an increase of loggerhead turtles in the Western Mediterranean Sea. However, in the case of leatherback turtle the negative phase of the NAO favours the presence of leatherback turtle. This contraposition could be related to the different ecophysiological response of both species during their migration cycle. PMID- 24764770 TI - Research on coordination of fresh produce supply chain in big market sales environment. AB - In this paper, we propose two decision models for decentralized and centralized fresh produce supply chains with stochastic supply and demand and controllable transportation time. The optimal order quantity and the optimal transportation time in these two supply chain systems are derived. To improve profits in a decentralized supply chain, based on analyzing the risk taken by each participant in the supply chain, we design a set of contracts which can coordinate this type of fresh produce supply chain with stochastic supply and stochastic demand, and controllable transportation time as well. We also obtain a value range of contract parameters that can increase profits of all participants in the decentralized supply chain. The expected profits of the decentralized setting and the centralized setting are compared with respect to given numerical examples. Furthermore, the sensitivity analyses of the deterioration rate factor and the freshness factor are performed. The results of numerical examples show that the transportation time is shorter, the order quantity is smaller, the total profit of whole supply chain is less, and the possibility of cooperation between supplier and retailer is higher for the fresh produce which is more perishable and its quality decays more quickly. PMID- 24764771 TI - Multiple chaos synchronization system for power quality classification in a power system. AB - This document proposes multiple chaos synchronization (CS) systems for power quality (PQ) disturbances classification in a power system. Chen-Lee based CS systems use multiple detectors to track the dynamic errors between the normal signal and the disturbance signal, including power harmonics, voltage fluctuation phenomena, and voltage interruptions. Multiple detectors are used to monitor the dynamic errors between the master system and the slave system and are used to construct the feature patterns from time-domain signals. The maximum likelihood method (MLM), as a classifier, performs a comparison of the patterns of the features in the database. The proposed method can adapt itself without the need for adjustment of parameters or iterative computation. For a sample power system, the test results showed accurate discrimination, good robustness, and faster processing time for the detection of PQ disturbances. PMID- 24764772 TI - Effects of paliperidone palmitate on coagulation: an experimental study. AB - OBJECTIVE: The aim of the present study was to examine the effects of a new antipsychotic drug paliperidone palmitate on hemogram and coagulation parameters in rats. MATERIALS AND METHODS: Experiments were performed on 22 female albino Wistar rats (8-12 weeks old). Control group was given drinking water as vehicle (0.3 mL). PAL-1 rats were given 1 mg/kg paliperidone palmitate (in 0.3 mL drinking water) by oral gavage once a day for ten days and PAL-3 rats received 3 mg/kg paliperidone palmitate (in 0.3 mL drinking water) by oral gavage for ten days. Blood samples were drawn from the heart 24 hours after the last drug dose, and hemogram and coagulation parameters were measured with automated analyzers. RESULTS: Hemogram did not change in the paliperidone treated groups compared to the controls. Factor VIII levels decreased in the PAL-1 and PAL-3 groups; and this decrease was significantly greater in the PAL-3. Factor IX levels decreased in PAL-3 rats, but its levels also increased in PAL-1 rats compared to the control. DISCUSSION: Paliperidone has led to changes in the serum levels of coagulation factors VIII and IX in rats. As a result, paliperidone may be causing thromboembolism or bleeding in a dose-independent manner. PMID- 24764773 TI - A new approach for clustered MCs classification with sparse features learning and TWSVM. AB - In digital mammograms, an early sign of breast cancer is the existence of microcalcification clusters (MCs), which is very important to the early breast cancer detection. In this paper, a new approach is proposed to classify and detect MCs. We formulate this classification problem as sparse feature learning based classification on behalf of the test samples with a set of training samples, which are also known as a "vocabulary" of visual parts. A visual information-rich vocabulary of training samples is manually built up from a set of samples, which include MCs parts and no-MCs parts. With the prior ground truth of MCs in mammograms, the sparse feature learning is acquired by the l(P) regularized least square approach with the interior-point method. Then we designed the sparse feature learning based MCs classification algorithm using twin support vector machines (TWSVMs). To investigate its performance, the proposed method is applied to DDSM datasets and compared with support vector machines (SVMs) with the same dataset. Experiments have shown that performance of the proposed method is more efficient or better than the state-of-art methods. PMID- 24764774 TI - Asymptotic analysis of SPTA-based algorithms for no-wait flow shop scheduling problem with release dates. AB - We address the scheduling problem for a no-wait flow shop to optimize total completion time with release dates. With the tool of asymptotic analysis, we prove that the objective values of two SPTA-based algorithms converge to the optimal value for sufficiently large-sized problems. To further enhance the performance of the SPTA-based algorithms, an improvement scheme based on local search is provided for moderate scale problems. New lower bound is presented for evaluating the asymptotic optimality of the algorithms. Numerical simulations demonstrate the effectiveness of the proposed algorithms. PMID- 24764776 TI - Letter from the editor. PMID- 24764775 TI - Diffusion-weighted magnetic resonance imaging findings of kidneys with obstructive uropathy: differentiation between benign and malignant etiology. AB - PURPOSE: In this study, we aimed to evaluate the capability of diffusion-weighted magnetic resonance imaging (DWI) in differentiation between benign and malignant etiology of obstructive uropathy. MATERIALS AND METHODS: DWI was performed in 41 patients with hydronephrotic kidneys and 26 healthy volunteers. MR imaging was performed using a 1.5 T whole-body superconducting MR scanner. The signal intensities of the renal parenchyma on DWI and apparent diffusion coefficient (ADC) maps were noted. DWI was performed with the following diffusion gradient b values: 100, 600, and 1000 s/mm(2). A large circular region of interest was placed in the corticomedullary junction of the kidneys. For statistical analysis, the independent-samples t test was used. RESULTS: The mean renal ADC values for b100, b600, and b1000 in hydronephrosis patients with benign and malignant etiology and the healthy volunteers of the control group were analysed. ADC measurements of renal parenchyma in all hydronephrotic kidneys with benign and malignant etiology were found to be statistically low compared to those of normal kidneys (P < 0.05). CONCLUSIONS: There were significant differences in the ADC values of obstructed kidneys compared to those of normal kidneys. Obstructed kidneys with malignant etiology had lower ADC values for b1000 compared to obstructed kidneys with benign etiology, but these alterations were statistically insignificant. PMID- 24764777 TI - Liver disease in women: the influence of gender on epidemiology, natural history, and patient outcomes. AB - Women more commonly present with acute liver failure, autoimmune hepatitis, benign liver lesions, primary biliary cirrhosis, and toxin-mediated hepatotoxicity. Women less commonly have malignant liver tumors, primary sclerosing cholangitis, and viral hepatitis. There is a decreased rate of decompensated cirrhosis in women with hepatitis C virus infection, no survival difference in alcohol-related liver disease, and improved survival from hepatocellular carcinoma. In general, men are 2-fold more likely to die from chronic liver disease and cirrhosis than are women. Liver transplant occurs less commonly in women than in men, with variable disease outcomes based on etiology. This review highlights the epidemiology, natural history, treatment outcomes, and pathophysiology of common liver diseases in women and discusses how gender influences disease incidence, presentation, progression, and outcomes. Pregnancy related liver disease is not covered. PMID- 24764779 TI - Interferon-free regimens and direct-acting antiviral agents. PMID- 24764780 TI - Discontinuation of nucleoside analogues in hepatitis B virus infection. PMID- 24764778 TI - Gastric polyps: a review of clinical, endoscopic, and histopathologic features and management decisions. AB - The increasing use of endoscopy has led to more discernable abnormalities in the stomach, including polyps. Gastric polyps encompass a spectrum of pathologic conditions that can vary in histology, neoplastic potential, and management. Despite their high prevalence, there is a paucity of literature to support management and treatment decisions for endoscopists. The goal of this review is to summarize clinical, endoscopic, and histopathologic features of various polyps, review syndromes associated with such polyps, and provide management recommendations. PMID- 24764782 TI - In the pipeline: updates on promising agents in development for gastroenterology & hepatologys. PMID- 24764781 TI - The Esophageal Sphincter Device for Treatment of GERD. PMID- 24764783 TI - Monitoring and management of toxicities in long-term thiopurine therapy. PMID- 24764784 TI - Difficult colonoscopy. PMID- 24764785 TI - Sofosbuvir plus ribavirin as a treatment alternative for chronic HCV genotype 2 or 3 patients unable to benefit from standard therapy. PMID- 24764787 TI - Letter from the editor. PMID- 24764786 TI - Commentary: sofosbuvir for treatment of hepatitis C virus genotype 2 or 3 infection in patients without treatment options. PMID- 24764790 TI - Gastro-hep news. PMID- 24764788 TI - Environmental influences on the onset and clinical course of Crohn's disease-part 1: an overview of external risk factors. AB - The pathogenesis of Crohn's disease (CD) involves host, genetic, and environmental factors. These factors result in disturbances in the innate and adaptive immune systems and composition of the intestinal microbiota. Epidemiologic and migration studies support an environmental component in the development of CD. Environmental risk factors include childhood hygiene, air pollution, breastfeeding, smoking, diet, stress, exercise, seasonal variation, and appendectomy. This review, part 1 of a 2-part series, provides an overview of these external contributors to the development or exacerbation of CD. Part 2, which will be published in a subsequent issue, will discuss the influences of infections, vaccinations, and medications (including antibiotics, nonsteroidal anti-inflammatory agents, and oral contraceptives) on CD. PMID- 24764791 TI - Reversibility of liver fibrosis. PMID- 24764789 TI - Sleep and inflammatory bowel disease: exploring the relationship between sleep disturbances and inflammation. AB - Sleep disturbances are associated with a greater risk of serious adverse health events, economic consequences, and, most importantly, increased all-cause mortality. Several studies support the associations among sleep, immune function, and inflammation. The relationship between sleep disturbances and inflammatory conditions is complex and not completely understood. Sleep deprivation can lead to increased levels of inflammatory cytokines, including interleukin (IL)-1beta IL-6, tumor necrosis factor-alpha and C-reactive protein, which can lead to further activation of the inflammatory cascade. The relevance of sleep in inflammatory bowel disease (IBD), a chronic immune-mediated inflammatory disease of the gastrointestinal tract, has recently received more attention. Several studies have shown that patients with both inactive and active IBD have self reported sleep disturbances. Here, we present a concise review of sleep and its association with the immune system and the process of inflammation. We discuss the studies that have evaluated sleep in patients with IBD as well as possible treatment options for those patients with sleep disturbances. An algorithm for evaluating sleep disturbances in the IBD population is also proposed. Further research is still needed to better characterize sleep disturbances in the IBD population as well as to assess the effects of various therapeutic interventions to improve sleep quality. It is possible that the diagnosis and treatment of sleep disturbances in this population may provide an opportunity to alter disease outcomes. PMID- 24764792 TI - Inflammatory bowel disease, women, and pregnancy. PMID- 24764793 TI - New topical hemostatic powders in endoscopy. PMID- 24764794 TI - Discontinuation of proton pump inhibitor therapy and the role of esophageal testing. PMID- 24764795 TI - The impact of the affordable care act on the future of endoscopy practice. PMID- 24764796 TI - Isotretinoin, acne, and Crohn's disease: a convergence of bad skin, bad science, and bad litigation creates the perfect storm. PMID- 24764797 TI - Correspondence: cytomegalovirus complicating inflammatory bowel disease: useful remarks. PMID- 24764798 TI - Response. PMID- 24764799 TI - Highlights from ACG 2013. PMID- 24764800 TI - Novel Applications of Laser Doppler Vibration Measurements to Medical Imaging. AB - Laser Doppler Vibrometry (LDV) has been widely used in engineering applications involving non-contact vibration and sound measurements. This technique has also been used in some biomedical applications including hearing research. The detectable frequencies are in the range of near-DC to 1 GHz or higher. This paper reviews applications of LDV in biomedical engineering and proposes new medical imaging applications based on measuring surface vibrations of tissues and organs. Tests were conducted on human skin using single point and scanning laser vibrometers. These tests suggest that skin vibrations due to the forcing excitation from the heart can be used in imaging of blood flow. The results of these tests illustrate the potential of such vibration measurements in a variety of diagnostic medical imaging applications including blood flow/restrictions, real-time monitoring of blood pressure variations, wound healing, muscle movements, etc. The fact that the measurements can be conducted remotely (non contact) is an important benefit that adds to the promise of this approach. PMID- 24764801 TI - What Does Stock Ownership Breadth Measure? AB - Using holdings data on a representative sample of all Shanghai Stock Exchange investors, we show that increases in ownership breadth (the fraction of market participants who own a stock) predict low returns: highest change quintile stocks underperform lowest quintile stocks by 23% per year. Small retail investors drive this result. Retail ownership breadth increases appear to be correlated with overpricing. Among institutional investors, however, the opposite holds: Stocks in the top decile of wealth-weighted institutional breadth change outperform the bottom decile by 8% per year, consistent with prior work that interprets breadth as a measure of short-sales constraints. PMID- 24764802 TI - K9Y3[Si12O32]F2. AB - Single-crystals of the title compound, nona-potassium triyttrium dodeca-silicate difluoride, were obtained from flux synthesis experiments in the system SiO2-Y2O3 KF. The crystal structure belongs to the group of single-layer silicates and is based on silicate sheets parallel to (110). A single layer contains secondary (Q (2)) and tertiary (Q (3)) silicate tetra-hedra in the ratio 1:2 and is build up from six-, eight- and twelve-membered rings. The linkage between neighboring layers is achieved by two crystallographically independent Y(3+) cations, which are coordinated by six oxygen ligands in form of distorted octa-hedra. Charge compensation is accomplished by incorporation of additional F(-) anions and K(+) cations in the structural channels, forming anion-centred [F2K7] groups. Apart from one K(+) and one Y(3+) cation (each with site symmetry -1), the 30 crystallographically independent atoms reside on general positions. PMID- 24764803 TI - Redetermination of beta-Ba(PO3)2. AB - In comparison with the previous structure determination of the beta-modification of barium catena-polyphosphate that was based on Weissenberg film data [Grenier et al. (1967 ?). Bull. Soc. Fr. Mineral. Cristallogr. 90, 24-31], the current CCD data-based redetermination reveals all atoms with anisotropic displacement parameters, standard uncertainties for the atomic coordinates, and the determination of the absolute structure. Moreover, a much higher accuracy in terms of the bond-length distribution for the polyphosphate chain, with two shorter and two longer P-O distances, was achieved. The structure consists of polyphosphate chains extending parallel to [100] with a periodicity of two PO4 tetra-hedra. The Ba(2+) cations are located between the chains and are surrounded by ten O atoms in the form of a distorted coordination polyhedron, with Ba-O distances ranging from 2.765 (3) to 3.143 (3) A, also reflecting the higher precision of the current redetermination. PMID- 24764804 TI - The mixed-metal tris-(di-sulfide) thio-phosphate, KNb1.77Ta0.23PS10. AB - The title compound catena-poly[potassium [tri-MU-disulfido-MU-tetra-thiophos-pha to-di[niobate(IV)/tantalate(IV)(0.885/0.115)]]], has been obtained through the reaction of the elements with KCl. The title compound is isostructural with KNb2PS10, with the Nb sites occupied by statistically disordered Nb (88.5%) and Ta (11.5%) atoms. The structure is composed of anionic infinity (1)[M 2PS10](-) chains along [100] (M = Nb/Ta) and K(+) ions. This chain is built up from distorted bicapped trigonal prisms [MS8] and [PS4] tetra-hedra. There are no inter-chain bonding inter-actions, except for electrostatic and van der Waals forces. The S2 (2-) and S(2-) anionic species and the M (4+)-M (4+) pair [M-M = 2.8939 (3) A] are observed. The classical charge balance is represented by [K(+)][M (4+)]2[PS4 (3-)][S2 (2-)]3. PMID- 24764805 TI - beta-Li0.37Na0.63Fe(MoO4)2. AB - The title compound, lithium/sodium iron(III) bis-[ortho-molyb-date(VI)], was obtained by a solid-state reaction. The main structure units are an FeO6 octa hedron, a distorted MoO6 octa-hedron and an MoO4 tetra-hedron sharing corners. The crystal structure is composed of infinite double MoFeO11 chains along the b axis direction linked by corner-sharing to MoO4 tetra-hedra so as to form Fe2Mo3O19 ribbons. The cohesion between ribbons via mixed Mo-O-Fe bridges leads to layers arranged parallel to the bc plane. Adjacent layers are linked by corners shared between MoO4 tetra-hedra of one layer and FeO6 octa-hedra of the other layer. The Na(+) and Li(+) ions partially occupy the same general position, with a site-occupancy ratio of 0.631 (9):0.369 (1). A comparison is made with AFe(MoO4)2 (A = Li, Na, K and Cs) structures. PMID- 24764806 TI - Di-aqua-{MU2-N,N'-bis-[(cyclo-hexa-nyl-idene)amino]-oxamide}-bis-(tri-phenyl phosphane)silver(I) dinitrate. AB - The dinuclear title compound, [Ag2(C14H22N4O2)(C18H15P)2(H2O)2](NO3)2, lies across an inversion center and consists of two [Ag(H2O)(PPh3)] units bridged by a bis-(cyclo-hexa-none)oxalydihydrazone ligand. The charge-balance is supplied by two nitrate anions. The symmetry-unique Ag(I) ion is in a distorted tetra-hedral geometry coordinated by a P atom from a tri-phenyl-phosphane ligand, an O atom from a water mol-ecule and a bis-(cyclo-hexa-none)oxalydihydrazone ligand bidentate chelating through the O atom and one of N atoms. In the crystal, O-H?O and N-H?O hydrogen bonds link the components, forming chains along the b-axis direction. These chains are connected through weak C-H?O hydrogen bonds, leading to the formation of a two-dimensional supra-molecular network parallel to (001). PMID- 24764807 TI - Poly[tetrakis(MU-1,1,1,3,3,3-hexafluoropropan-2-olato)iron(II)dipotassium]. AB - The title compound, [K2Fe{OCH(CF3)2}4] n , was formed from the reaction of potassium hexa-fluoro-isopropoxide with iron(II) chloride in toluene. The Fe(II) atom has a highly distorted tetra-hedral coordination environment. All four of the non-equivalent hexa-fluoro-isoprop-oxy O atoms link the Fe(II) atoms to one of the K(+) atoms in an alternating chain of Fe-O-K-O fused four-membered rings, with K-Fe distances of 3.715 (2) and 3.717 (2) A. This K(+) atom is also bridged to eight of the F atoms. The other K(+) atom is bonded to only two of the O atoms, but has seven short K?F contacts, one of which links the chains into a three-dimensional arrangement. Weak hydrogen bonding between the lone H atoms on the hexa-fluoro-isoprop-oxy groups and F atoms is also present. The crystal studied was refined as an inversion twin. PMID- 24764808 TI - (5-Methyl-pyrazine-2-carboxyl-ato-kappa(2) N (1),O)bis-[2-(4-methyl-pyridin-2-yl kappaN)-3,5-bis-(tri-fluoro-meth-yl)phenyl-kappaC (1)]iridium(III) chloro-form hemisolvate. AB - In the title complex, [Ir(C14H8F6N)2(C6H5N2O2)].0.5CHCl3, the Ir(III) atom adopts a distorted octa-hedral geometry, being coordinated by three N atoms (arranged meridionally), two C atoms and one O atom of three bidentate ligands. The complex mol-ecules pack with no specific inter-molecular inter-actions between them. The SQUEEZE procedure in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155] was used to model a disordered chloro-form solvent mol-ecule; the calculated unit-cell data allow for the presence of half of this mol-ecule in the asymmetric unit. PMID- 24764809 TI - Bis-(thio-cyanato-kappaN)[tris(pyridin-2-yl-meth-yl)amine-kappa(4) N]-iron(II). AB - In the title complex, [Fe(NCS)2(C18H18N4)], the Fe(II) cation is chelated by a tris-(2-pyridyl-meth-yl)amine ligand and coordin-ated by two thio-cyanate anions in a distorted N6 octa-hedral geometry. In the crystal, weak C-H?S hydrogen bonds and pi-pi stacking inter-actions between parallel pyridine rings of adjacent mol ecules [centroid-centroid distance = 3.653 (3) A] link the mol-ecules into a two dimensional supra-molecular architecture. The structure contains voids of 124 (9) A(3), which are free of solvent molecules. PMID- 24764810 TI - trans-Tetra-carbonyl-bis-(tri-phenyl-phosphane-kappaP)molybdenum(0). AB - The well known title compound, trans-[Mo(C18H15P)2(CO)4], has not been studied previously by X-ray crystallography, unlike its cis isomer. The complex possesses crystallographically imposed inversion symmetry, with the Mo atom residing on an inversion centre (1a Wyckoff position). The two tri-phenyl-phosphane groups are arranged in a staggered orientation. Each of the phenyl groups exhibits significantly different Mo-P-C-C torsion angles ranging from 2.6 (2) to 179.4 (1) degrees , most likely due to steric inter-actions based upon their positions relative to the carbonyl ligands. PMID- 24764811 TI - catena-Poly[[aqua-bis-(4-formyl-benzoato-kappa(2) O (1),O (1'))cadmium]-MU pyrazine-kappa(2) N:N']. AB - The polymeric title compound, [Cd(C8H5O3)2(C4H4N2)(H2O)] n , contains two 4 formyl-benzoate (FB) anions, one pyrazine mol-ecule and one coordinating water mol-ecule; the FB anions act as bidentate ligands. The O atom, the aldehyde H atom and the benzene ring of one of the FB anions are disordered over two positions. The O atoms were freely refined [refined occupancy ratio 0.79 (2):0.21 (2)], while the aldehyde H atoms and the benzene ring atoms were refined with fixed occupancy ratios of 0.8:0.2 and 0.5:0.5, respectively. In the ordered FB anion, the carboxyl-ate group is twisted away from the attached benzene ring (A) by 22.7 (8) degrees . In the disordered FB anion, the corresponding angles are 15.6 (10) and 11.4 (11) degrees for rings B and B', respectively. Benzene rings A and B are oriented at a dihedral angle of 24.2 (7), A and B' at 43.0 (8) degrees . The pyrazine ring makes dihedral angles of 67.5 (4), 89.6 (7) and 86.2 (7) degrees , respectively, with benzene rings A, B and B'. The pyrazine ligands bridge the Cd(II) cations, forming polymeric chains running along the b-axis direction. In the crystal, O-Hwater ? Ocarboxyl-ate hydrogen bonds link adjacent chains into layers parallel to the bc plane. These layers are linked via C Hpyrazine ? Oform-yl hydrogen bonds, forming a three-dimensional network. pi-pi interactions [centroid-centroid distances = 3.870 (11)-3.951 (5) A] further stabilize the crystal structure. There is also a weak C-H?pi inter-action present. PMID- 24764812 TI - MU-1,6,7,12-Tetra-aza-perylene-kappa(4) N (1),N (12):N (6),N (7)-bis-[chlorido (eta(6)-p-cymene)ruthenium(II)] bis-(hexa-fluorido-phosphate) acetone disolvate. AB - In the title compound, [Ru2(C10H14)2Cl2(C16H8N4)](PF6)2.2C3H6O, the binuclear Ru(II) complex dication, [{RuCl(eta(6)-cym)}2(MU-tape)](2+), built up by a planar 1,6,7,12-tetra-aza-perylene (tape) bridge, two eta(6)-bound cymene (cym) ligands and two chloride ligands, includes an inversion center. The Ru(II) atom shows the typical piano-stool motif for arene coordination. The counter-charge is provided by a hexa-fluorido-phosphate anion and the asymmetric unit is completed by an acetone mol-ecule of crystallization. The components of the structure are connected into a three-dimensional architecture by C-H?O/F/Cl inter-actions. PMID- 24764813 TI - [1,4-Bis(di-phenyl-phosphan-yl)butane-kappa(2) P,P']di-bromido-palladium(II). AB - In the title complex, [PdBr2(C28H28P2)], the Pd(II) ion has a distorted cis-Br2P2 square-planar coordination geometry defined by two P atoms from the chelating 1,4 bis-(di-phenyl-phosphan-yl)butane ligand and two Br(-) anions. The four phenyl rings are inclined to the least-squares plane of the PdBr2P2 unit [maximum deviation = 0.1294 (7) A], making dihedral angles of 66.3 (2), 87.2 (2), 68.8 (2) and 86.8 (2) degrees . The butyl-ene chain is in a gauche conformation, with a C C-C-C torsion angle of 57.0 (8) degrees . Inter-molecular C-H?Br hydrogen bonds link the complex mol-ecules into supra-molecular layers in the ab plane. Weak pi pi inter-actions, both intra- and inter-molecular [shortest inter-centroid distance = 4.598 (5) A], are also noted in the three-dimensional architecture. PMID- 24764814 TI - cis-Tri-aqua-[1,1'-(propane-1,3-di-yl)bis-(pyridin-1-ium-4-carboxyl-ato) kappaO]bis-(thio-cyanato-kappaN)manganese(II) dihydrate. AB - In the title compound, [Mn(NCS)2(C15H14N2O4)(H2O)3].2H2O, the metal ion is octa hedrally coordinated by three water mol-ecules, one carboxyl-ate O atom from a 1,1'-(propane-1,3-di-yl)bis-(pyridinium-4-carboxyl-ate) ligand and two N atoms from two thio-cyanate anions in cis positions, forming a mononuclear complex mol ecule. In the crystal, mol-ecules are connected into a three-dimensional architecture through O-H?O hydrogen bonds involving water mol-ecules and carboxyl ate groups. PMID- 24764815 TI - Poly[MU5-{hydrogen bis-[(E)-cinnamato]}-caesium]. AB - In the structure of the title polymeric complex, [Cs(C9H7O2)(C9H8O2)] n , a caesium salt of trans-cinnamic acid, the Cs(+) ions of the two individual irregular CsO8 coordination polyhedra lie on twofold rotation axes and are linked by four bridging carboxyl O-atom donors from two cinnamate ligand species. These two ligand components are inter-linked through a delocalized H atom within a short O?H?O hydrogen bond. Structure extension gives a two-dimensional coordination polymer which lies parallel to (001). The structure was determined from a crystal twinned by non-merohedry, with a twin component ratio of approximately 1:1. PMID- 24764816 TI - Tetra-chloridodi-MU3-oxido-tetra-kis-(MU2-propan-2-olato-kappa(2) O:O)ditin(II)ditin(IV). AB - The centrosymmetric tetranuclear title molecule, [Sn4(C3H7O)4Cl4O2], contains two types of Sn atoms, Sn(II) and Sn(IV). The Sn(II) atom has a trigonal-pyramidal coordination environment and is bonded to two O atoms from two iso-propano-late groups and one MU3-oxide atom. The Sn(IV) atom has an octa-hedral coordination environment, formed by two chloride atoms, two MU3-oxide atoms and two O atoms from iso-propano-late groups. PMID- 24764817 TI - Poly[[di-aqua-deca-MU2-cyanido-kappa(20) C:N-hexa-cyanido-kappa(6) C-bis-(MU2-5 methyl-pyrimidine-kappa(2) N:N')bis-(5-methyl-pyrimidine kappaN)tricopper(II)ditungstate(V)] dihydrate]. AB - In the title complex, {[Cu3[W(CN)8]2(C5H6N2)4(H2O)2].2H2O} n , the coordination polyhedron of the eight-coordinated W(V) atom is a bicapped trigonal prism, in which five CN groups are bridged to Cu(II) ions, and the other three CN groups are terminally bound. Two of the Cu(II) ions lie on a centre of inversion and each of the three independent Cu(II) cations is pseudo-octahedrally coordinated. In the crystal structure, cyanido-bridged-Cu-W-Cu layers are linked by pillars involving the third independent Cu(II) ion, generating a three-dimensional network with non-coordinating water mol-ecules and 5-methyl-pyrimidine mol ecules. O-H?O and O-H?N hydrogen bonds involve the coordinating and non-coordin ating water mol-ecules, the CN groups and the 5-methyl-pyrimidine mol-ecules. PMID- 24764818 TI - Tetra-kis(di-propyl-ammonium) tetra-kis(oxa-lato-kappa(2) O (1),O (2))stannate(IV) mono-hydrate: a complex with an eight-coordinate Sn(IV) atom. AB - In the title salt, [(CH3CH2CH2)2NH2]4[Sn(C2O4)4].H2O, the Sn(IV) atom of the stannate anion is located on a special position with -42m symmetry. It is eight coordinated by four chelating oxalate anions. The di-propyl-ammonium cation possesses mirror symmetry while the lattice water mol-ecule is disordered about a position with -42m symmetry and has an occupancy of 0.25. In the crystal, the anions and cations are linked by N-H?O hydrogen bonds, forming a three dimensional network. This network is futher stabilized by weak O-H?O hydrogen bonds involving the water mol-ecules and oxalate O atoms. The crystal studied was refined as an inversion twin. PMID- 24764819 TI - (1-Methyl-1H-imidazole-kappaN (3))(1-methyl-2-nitroso-benzene-kappaN)(5,10,15,20 tetra-phenyl-porphyrinato-kappa(4) N)iron(II) di-chloro-methane monosolvate. AB - The solvated title compound, [Fe(C44H28N4)(C4H6N2)(C7H7NO)].CH2Cl2, is a porphyrin complex containing an octahedrally coordinated Fe(II) atom with 1 methylimidazole [Fe-N = 2.0651 (17) A] and o-nitro-sotoluene ligands at the axial positions. The o-nitro-sotoluene ligand is N-bound to iron(II) [Fe-N = 1.8406 (18)A and Fe-N-O = 122.54 (14) degrees ]. The axial N-Fe-N linkage is almost linear, with a bond angle of 177.15 (7) degrees . One phenyl group of the porphyrin ligand is disordered over two orientations in a 0.710 (3):0.290 (3) ratio. The di-chloro-methane solvent mol-ecule was severely disordered and its contribution to the scattering was removed with the SQUEEZE routine [van der Sluis & Spek (1990 ?). Acta Cryst. A46, 194-201]. PMID- 24764820 TI - Bis(1,10-phenanthrolin-1-ium) tetra-chlorido-zincate monohydrate. AB - In the crystal structure of the title compound, (C12H9N2)2[ZnCl4].H2O, the two independent 1,10-phenanthrolinium cations are bridged by the water mol-ecule and the tetrahedral tetrachloridozincate anion via N-H?O, O-H?Cl and N-H?Cl hydrogen bonds, forming chains along [100]. The chains are linked via C-H?Cl hydrogen bonds and a number of pi-pi inter-actions [centroid-centroid distances vary from 3.5594 (14) to 3.7057 (13) A], forming a three-dimensional network. In each 1,10 phenanthrolinium cation, there is a short N-H?N inter-action. PMID- 24764821 TI - Tetra-kis(MU3-2-{[1,1-bis-(hy-droxy-meth-yl)-2-oxidoeth-yl]imino-meth-yl}-6-nitro pheno-lato)tetra-copper(II). AB - The title cluster, [Cu4(C11H12N2O6)4], was obtained from the Cu(0)-FeCl2.4H2O-H4 L-Et3N-DMF reaction system (in air), where H4 L is 2-hy-droxy-methyl-2{[(2-hy droxy-3-nitro-phen-yl)methyl-idene]amino}-propane-1,3-diol and DMF is di-methyl formamide. The asymmetric unit consists of one Cu(2+) ion and one dianionic ligand; a -4 symmetry element generates the cluster, which contains a {Cu4O4} cubane-like core. The metal ion has an elongated square-based pyramidal CuNO4 coordination geometry with the N atom in a basal site. An intra-molecular O-H?O hydrogen bond is observed. The solvent mol-ecules were found to be highly disordered and their contribution to the scattering was removed with the SQUEEZE procedure in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155], which indicated a solvent cavity of volume 3131 A(3) containing approximately 749 electrons. These solvent molecules are not considered in the given chemical formula. PMID- 24764822 TI - Di-MU-tricyanido-tetra-cyanidobis[hydro-tris-(pyrazoylborato)]tetra-methanol diiron(III)iron(II) di-methanol disolvate. AB - In the title complex, [Fe(II)Fe(III) 2(C9H10BN6)2(CN)6(CH3OH)4].2CH3OH, two [Fe(III)(Tp)(CN)3](-) anions [Tp is hydro-tris-(pyrazoylborate)] are bridged by an [Fe(II)(MeOH)4](2+) cation, forming a centrosymmetric trinuclear unit. These units are connected via O-H?O and O-H?N hydrogen bonds involving the uncoordinated methanol solvent mol-ecules, forming a three-dimensional network. PMID- 24764823 TI - (Cyanido-kappaC)(2,2-di-phenyl-acetamido-kappa(2) N,O)bis-(eta(5)-penta-methyl cyclo-penta-dien-yl)zirconium(IV). AB - In the title compound, [Zr(C10H15)2(C14H12NO)(CN)], the Zr(IV) atom is coordinated by two penta-methyl-cyclo-penta-dienyl ligands, the amidate ligand via the N and O atoms, and an additional C N ligand. The four-membered metallacycle is nearly planar (r.m.s. deviation = 0.008 A). In the crystal, the mol-ecules are connected into centrosymmetric dimers via pairs of N-H?N hydrogen bonds. PMID- 24764824 TI - Tetra-kis[bis-(pyridin-2-yl)amine-kappaN (2)](nitrato-kappaO)silver(I). AB - In the title complex, [Ag(NO3)(C10H9N3)4], the nitrate ligand is found to be disordered over two sets of positions, with occupancy factors of 0.473 (5) and 0.527 (5). The Ag(I) ion is located in a square-pyramidal coordination environment formed by four N atoms from four bis-(pyridin-2-yl)amine ligands and one O atom from a nitrate ligand. Weak inter-actions between the Ag(I) ions and the nitrate anions acting in a monodentate mode [Ag?O = 2.791 (13) and 2.816 (9) A for the major component of the nitrate ligand, and 2.865 (8) and 2.837 (8) A for the minor component] link the complex mol-ecules into a chain along [001]. N H?O hydrogen bonds are observed. PMID- 24764825 TI - Chlorido[5-meth-oxy-1H-benzimidazole-2(3H)-thione-kappaS]bis-(tri-phenyl-phos phane-kappaP)copper(I) methanol disolvate. AB - In the title complex, [CuCl(C8H8N2OS)(C18H15P)2].2CH3OH, the Cu(I) ion is coordinated by one chloride anion, one S atom from the 5-meth-oxy-1H benzimidazole-2(3H)-thione ligand and two P atoms from two tri-phenyl-phosphine ligands in a distorted tetra-hedral geometry. One of the N-bound H atoms is involved in an intra-molecular N-H?Cl hydrogen bond, while another one inter-acts with the solvent methanol mol-ecule via an N-H?O hydrogen bond. Inter-molecular O H?Cl and O-H?O hydrogen bonds link two further complex mol-ecules and four solvent mol-ecules into a centrosymmetric structural unit. The short distance of 3.624 (4) A between the centroids of the five- and the six-membered rings of two benzimidazole fragments indicates the presence of pi-pi inter-actions. PMID- 24764826 TI - [1H-1,2,4-Triazole-5(4H)-thione-kappaS]bis-(tri-phenyl-phosphane-kappaP)(nitrato kappaO)silver(I) methanol monosolvate. AB - In the title complex, [Ag(NO3)(C2H3N3S)(C18H15P)2].CH3OH, the Ag(I) ion exhibits a distorted tetra-hedral coordination geometry formed by two P atoms from two tri phenyl-phosphine ligands, one S atom from a 1H-1,2,4-triazole-5(4H)-thione ligand and one O atom from a nitrate ion. In the crystal, complex and solvent mol-ecules are linked by O-H?O and N-H?O hydrogen bonds forming a chain along the b-axis direction. The chains are linked by weak C-H?O hydrogen bonds forming a two dimensional supra-molecular architecture parallel to (001). In addition, an intra molecular N-H?O hydrogen bond is observed. PMID- 24764827 TI - Bis(n-do-decyl-ammonium) bis-(chlor-anil-ato)di-ethano-lcuprate(II). AB - In the title compound, (C12H25NH3)2[Cu(C6Cl2O4)2(C2H5OH)2], the Cu(II) atom lies on a crystallographic inversion center and is coordinated in a distorted octa hedral geometry by four O atoms of two chloranilate ligands and two O atoms of two ethanol mol-ecules which are trans to each other in the axial positions. In the crystal, the Cu(II) mononuclear dianions are linked by O-H?O hydrogen bonds into a tape along the a-axis direction. The tapes are linked through N-H?O hydrogen bonds between the dianion and the n-do-decyl-ammonium cation, forming a two-dimensional network parallel to the ab plane. PMID- 24764828 TI - catena-Poly[[di-aqua-bis-(4-formyl-benzo-ato-kappaO (1))nickel(II)]-MU-pyrazine kappa(2) N:N']. AB - In the title polymeric compound, [Ni(C8H5O3)2(C4H4N2)(H2O)2] n , the Ni(II) atom is located on a twofold rotation axis and has a slightly distorted octa-hedral coordination sphere. In the equatorial plane, it is coordinated by two carboxyl ate O atoms of two symmetry-related monodentate formyl-benzoate anions and by two N atoms of the bridging pyrazine ligand, which is bis-ected by the twofold rotation axis. The axial positions are occupied by two O atoms of the coordinating water mol-ecules. In the formyl-benzoate anion, the carboxyl-ate group is twisted away from the attached benzene ring by 7.0 (6) degrees , while the benzene and pyrazine rings are oriented at a dihedral angle of 66.2 (3) degrees . The pyrazine ligands bridge the Ni(II) cations, forming polymeric chains running along the b-axis direction. Intra-molecular O-H?O hydrogen bonds link the water ligands to the carboxyl-ate O atoms. In the crystal, water-water O H?O hydrogen bonds link adjacent chains into layers parallel to the bc plane. Pyrazine-formyl C-H?O hydrogen bonds link the layers, forming a three-dimensional network. There are also weak C-H?pi inter-actions present. The title compound is isotypic with the copper(II) complex [Celik et al. (2014a). Acta Cryst. E70, m4 m5]. PMID- 24764829 TI - Tris(2,6-dibenzoyl-4-methyl-phenolato-kappa(2) O (1),O (2))cobalt(III). AB - In the title compound, [Co(C21H15O3)3], the Co(III) ion is coordinated in a slightly distorted octa-hedral environment by three phenolate O and three benzoyl O atoms from three monoanionic bidentate 2,6-dibenzoyl-4-methyl-phenolate ligands. The dihedral angles between the mean planes of the central phenolate rings and the peripheral phenyl rings are 46.62 (10)/87.06 (9), 60.44 (8)/23.13 (8) and 46.49 (6)/65.29 (6) degrees . The crystal packing is stabilized by weak inter-molecular C-H?O inter-actions. Mol-ecules are further linked by two pi-pi [centroid-centroid distances = 3.8612 (14) and 3.9479 (14) A] and four C-H?pi inter-actions, forming a three-dimensional network. PMID- 24764830 TI - catena-Poly[[(N,N-di-methyl-cyanamide-kappaN)lithium]-MU3-bromido]. AB - The title complex, [LiBr(C3H6N2)] n , is the unexpected product of a reaction beteween (Dipp)N(Li)SiMe3 (Dipp = 2,6-diiso-propyl-phen-yl), Me2NCN and CuBr. The compound is a one-dimensional polymer with a step structure derived from the association of inversion dimers, formed by bromido ligands bridging two Li(+) cations, each of which carries a di-methyl-cyanamide ligand. The planar (LiBr)2 unit of the polymer core has a regular rhombic shape [Li-Br-Li 77.55 (16) degrees and Br-Li-Br 102.45 (16) degrees ]. These (LiBr.NCNMe2)2 dimers represent the repeat unit of a polymer system propagated by additional Br-Li and Li-Br bonds generating an infinite step structure along the a-axis direction. PMID- 24764831 TI - [MU-3,3'-Diisopropyl-1,1'-(propane-1,3-di-yl)bis-(1,3-diazinan-2-yl-idene)]bis [bromido-(eta(4)-cyclo-octa-1,5-diene)rhodium(I)]. AB - The title compound, [Rh2Br2(C8H12)2(C17H32N4)], was obtained by the reaction of 3,3'-(propane-1,3-di-yl)bis-(1-isopropyl-3,4,5,6-tetra-hydro-pyrimidin-1-ium) bromide and [{Rh(cod)Cl}2] (cod is cyclo-octa-1,5-diene) in tetra-hydro-furan. The two Rh(I) atoms each have a distorted square-planar coordination environment, defined by a bidentate cod ligand, a bromide anion and one C atom of the bridging bidentate bis-N-heterocyclcic carbene (NHC) ligand. The average Rh-CNHC distance is 2.038 (7) A, suggesting that the bond has a major sigma contribution with very little back donation. The distances between the cod ligands and the Rh(I) atoms vary between 2.104 (4) and 2.210 (4) A. PMID- 24764832 TI - Hydrido(prolinato-kappa(2) N,O)tris-(tri-methyl-phosphane-kappaP)iridium(III) hexa-fluorido-phosphate. AB - The title complex, [Ir(C5H8NO2)H(C3H9P)3]PF6, has two independent anion-cation pairs in the asymmetric unit. The geometry about each Ir(III) atom is pseudo-octa hedral with a meridional arrangement of the P(CH3)3 ligands, N,O-bidentate coordination of prolinate and a hydride ligand trans to the prolinate N atom. The independent Ir(III) moieties are joined by N-H?O hydrogen bonds and the N-H?O bonding motif continues throughout the structure, creating an extended chain parallel to the c-axis direction. The methyl groups of one P(CH3)3 ligand are rotationally disordered over two sets of sites in a 0.62 (2):0.38 (2) ratio. PMID- 24764833 TI - 1-(4-Hy-droxy-phen-yl)piperazine-1,4-diium tetra-chlorido-cobalt(II) monohydrate. AB - The asymmetric unit of the title inorganic-organic hybrid compound, (C10H16N2O)[CoCl4].H2O, consists of a tetrahedral [CoCl4](2-) anion, together with a [C10H18N2O](2+) cation and a water mol-ecule. Crystal cohesion is achieved through N-H?Cl, O-H?Cl and N-H?O hydrogen bonds between organic cations, inorganic anions and the water mol-ecules, building up a three-dimensional network. PMID- 24764834 TI - MU-Cyanido-kappa(2) C:N-dicyanido-kappa(2) C-bis-(N-ethyl-ethylenedi-amine kappa(2) N,N')copper(II)copper(I). AB - In the title complex, [Cu(I)Cu(II)(CN)3(C4H12N2)2], the Cu(I) and Cu(II) ions and a bridging cyanide group lie on a twofold rotation axis. The Cu(II) ion is in a slightly-distorted square-pyramidal coordination environment, with the N atoms of the two symmetry-related N-ethyl-ethylenedi-amine ligands occupying the basal positions and an N-bonded cyanide group in the apical position. The Cu(I) ion is in a trigonal-planar coordination environment, bonded to the C atom of the bridging cyanide group and to two terminal cyanide groups. In the crystal, N-H?N hydrogen bonds involving two of the symmetry-unique N-H groups of the N-ethyl ethylenedi-amine ligands and the N atoms of the terminal cyanide ligands link the mol-ecules into strands along [010]. PMID- 24764835 TI - N-(3-Chloro-1,4-dioxo-1,4-di-hydro-naph-thalen-2-yl)-N-propionylpropionamide. AB - In the title mol-ecule, C16H14ClNO4, the four essentially planar atoms of the imide group [r.m.s. deviation = 0.0286 (11) A] form a dihedral angle of 77.36 (13) degrees with the naphtho-quinone group [maximun deviation = 0.111 (2) A for the carbonyl O atom in the naphthalene 1-position] and the two imide carbonyl groups are oriented anti with respect to each other. In the crystal, mol-ecules are connected by weak C-H?O hydrogen bonds, as well as pi-pi stacking inter actions [centroid-centroid distance = 3.888 (3) A], forming a three-dimensional network. PMID- 24764836 TI - 8-{1-[(4'-Fluoro-[1,1'-biphen-yl]-4-yl)meth-yl]piperidin-4-yl}-3,4-di-hydro quinolin-2(1H)-one chloro-form 0.25-solvate. AB - In the asymmetric unit of the title compound, C27H27FN2O.0.25CHCl3, there are two independent mol-ecules (A and B) together with a partially disordered chloro-form mol-ecule situated about an inversion center. The conformation of the two mol ecules is very similar. The bridging piperidine rings each have a chair conformation while the piperidin-2-one rings of the quinoline moiety have screw boat conformations. The benzene rings of the biphenyl moiety are inclined to one another by 26.37 (4) and 23.75 (15) degrees in mol-ecules A and B, respectively. The mean plane of the central piperidine ring [r.m.s. deviation = 0.241 (2) A in both mol-ecules A and B] is inclined to the benzene ring of the quinoline moiety by 80.06 (4) in A and 83.75 (15) degrees in B, while it is inclined to the adjacent benzene ring of the biphenyl group by 73.623 (15) in A and 75.65 (14) degrees in B. In the crystal, individual mol-ecules are linked by pairs of N-H?O hydrogen bonds, forming A-A and B-B inversion dimers with R 2 (2)(8) ring motifs. The dimers are stabilized by C-H?O hydrogen bonds and linked via C-H?F and C-H?N hydrogen bonds into a three-dimensional network. Several C-H?pi inter-actions are also present. PMID- 24764837 TI - 1-Carb-oxy-naphthalen-2-yl acetate monohydrate. AB - In the title compound, C13H10O4.H2O, both the carboxylic acid [Car-Car-C-O = 121.1 (2) degrees , where ar = aromatic] and the ester [Car-Car-O-C = -104.4 (3) degrees ] groups lie out of the mean plane of the conjugated aromatic system. In the crystal, the organic mol-ecule is hydrogen bonded to water mol-ecules through the ester and carb-oxy moieties, forming chains along the a-axis direction. The methyl H atoms of the acet-oxy group are disordered over two equally occupied sites. PMID- 24764838 TI - 1-[6-(1H-Indol-1-yl)pyridin-2-yl]-1H-indole-3-carbaldehyde. AB - In the title compound, C22H15N3O, the dihedral angle between the two indole units is 33.72 (3) degrees . The mol-ecular structure features a weak intra-molecular C H?N inter-action. In the crystal, weak C-H?O and C-H?pi inter-actions, forming a two-dimensional network parallel to the bc plane. PMID- 24764839 TI - 1-[(4-Hy-droxy-anilino)methyl-idene]naphthalen-2(1H)-one. AB - The title Schiff base, C17H13NO2, crystallizes in the zwitterionic form and an N H?O hydrogen bond closes an S(6) ring. The dihedral angle between the aromatic ring systems is 15.62 (9) degrees . In the crystal, O-H?O hydrogen bonds link the mol-ecules into C(11) chains propagating in [010]. PMID- 24764840 TI - 2,6-Di-chloro-9-(2',3',5'-tri-O-acetyl-beta-d-ribo-furanos-yl)-9H-purine. AB - The title synthetic analog of purine nucleosides, C16H16Cl2N4O7, has its acetyl ated beta-furan-ose ring in a 3'beta-envelope conformation, with the corresponding C atom deviating by 0.602 (5) A from the rest of the ring. The planar part of the furan-ose ring forms a dihedral angle of 65.0 (1) degrees with the mean plane of the purine bicycle. In the crystal, mol-ecules form a three-dimensional network through multiple C-H?O and C-H?N hydrogen bonds and C H?pi interactions. PMID- 24764841 TI - Dimethyl 5-acetyl-1-hy-droxy-4-methyl-1H-pyrrole-2,3-di-carboxyl-ate, an oxidation-resistant N-hy-droxy-pyrrole. AB - The title compound, C11H13NO6, exhibits an intra-molecular O-H?O=C hydrogen bond between the N-hydroxyl H atom and carbonyl O atom of the neighboring acetyl group. This finding contradicts a previously published model in which the hydrogen bond was postulated to occur with the neighboring carbomethoxy group. This relatively strong hydrogen bond [O-H?O: D = 2.5583 (11) A and theta = 152 degrees ] may underlie the resistance of the title compound to oxidation into the corresponding nitroxide. PMID- 24764842 TI - (E)-2-(4-Benz-yloxy-2-hy-droxy-benzyl-idene)-N-methyl-hydrazinecarbo-thio-amide. AB - The mol-ecule of the title compound, C16H17N3O2S, adopts an E conformation with respect to the azomethine C=N bond. The hydrazinecarbo-thio-amide fragment is close to planar, with a largest deviation from the least-squares plane of 0.079 (2) A for the hydrazide N atom. This fragment forms a dihedral angle of 9.43 (9) degrees with the central benzene ring. The benzene rings are inclined to one another by 67.55 (12) degrees . The mol-ecular conformation is stabilized by an intra-molecular O-H?N hydrogen bond involving the azomethine N atom. In the crystal, mol-ecules are linked through weak N-H?S and N-H?O hydrogen bonds into double ribbons along [010]. The crystal packing also features C-H?pi inter actions. PMID- 24764843 TI - 16-Oxa-penta-cyclo-[6.6.5.0(1,18).0(2,7).0(9,14)]nona-deca-2,4,6,9,11,13,18 heptaen-15-one. AB - In the title compound, C18H12O2, the benzene rings are inclined to one another by 66.79 (7) degrees . The five-membered ring is almost planar with a maximum deviation of 0.014 (1) A. In the crystal, the mol-ecules are linked by pairs of weak C-H?O interactions into centrosymmetric dimers. These dimers are linked by C H?pi interactions, forming a three-dimensional structure. PMID- 24764844 TI - N'-[(1E)-1-(2-Fluoro-phen-yl)ethyl-idene]pyridine-3-carbohydrazide. AB - The title compound, C14H12FN3O, adopts an E conformation with respect to the azomethine double bond whereas the N and methyl C atoms are in a Z conformation with respect to the same bond. The ketonic O and azomethine N atoms are cis to each other. The non-planar mol-ecule [the dihedral angle between the benzene rings is 7.44 (11) degrees ] exists in an amido form with a C=O bond length of 1.221 (2) A. In the crystal, a bifurcated N-H?(O,N) hydrogen bond is formed between the amide H atom and the keto O and imine N atoms of an adjacent mol ecule, leading to the formation of chains propagating along the b-axis direction. Through a 180 degrees rotation of the fluoro-phenyl ring, the F atom is disordered over two sites with an occupancy ratio of 0.632 (4):0.368 (4). PMID- 24764845 TI - Ethyl 2-{5-[(3-oxo-3,4-di-hydro-2H-1,4-benzo-thia-zin-4-yl)meth-yl]-1H-1,2,3 triazol-1-yl}acetate. AB - In the title compound, C15H16N4O3S, the six-membered heterocycle of the benzo thia-zine fragment exhibits a screw boat conformation. The dihedral angle between the planes through the triazole ring and the benzene ring fused to the 1,4-thia zine ring is 62.98 (11) degrees . The mean plane formed by the atoms belonging to the acetate group is nearly perpendicular to the triazole ring [dihedral angle = 74.65 (12) degrees ]. In the crystal, mol-ecules are linked by pairs of C-H?O inter-actions, forming dimeric aggregates. PMID- 24764846 TI - 2,2'-(1,4-Phenyl-ene)bis-(propane-2,2-di-yl) bis-(benzodi-thio-ate). AB - The title compound, C26H26S4, shows a dihedral angle of 76.64 (15) degrees between the central and peripheral benzene rings. An inversion center is located at the centroid of the thio-benzoyl ring. In the crystal, weak C-H?S inter actions form C(5) chains along [001]. There are no classical hydrogen bonds. PMID- 24764847 TI - 1,3,5-Tris(4-meth-oxy-phen-yl)-1,3,5-triazinane-2,4,6-trione. AB - The complete mol-ecule of the title compound, C24H21N3O6, is generated by the application of threefold rotation symmetry about an axis perpendicular to the central ring. The mol-ecule exhibits a propeller-like shape. The dihedral angle between each benzene ring and the heterocyclic ring is 74.0 (1) degrees . The mol ecules pack with no specific inter-molecular inter-actions between them. The SQUEEZE procedure in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155] was used to model disordered solvent mol-ecules, presumed to be acetone; the calculated unit cell data do not take into account the presence of these. PMID- 24764849 TI - (2R,3S,4R,5R)-5-(4-Amino-5-iodo-7H-pyrrolo-[2,3-d]pyrimidin-7-yl)-4-fluoro-2-(hy droxy-meth-yl)tetra-hydro-furan-3-ol. AB - The title compound, C11H12FIN4O3, is composed of a 7-carbapurine moiety connected via an N atom to 2-de-oxy-2-fluoro-beta-d-ribose. The conformation about the N glycosydic bond is -anti with chi = -129.0 (11) degrees . The glycosydic N-C bond length is 1.435 (14) A. The sugar ring adopts an Nconformation with an unsymmetrical twist O-endo-C-exo ((o)T4). The conformation around the C-C bond is +sc, with a torsion angle of 53.0 (12) degrees . In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, forming chains propagating along the a axis. These chains are linked via O-H?I and C-H?O hydrogen bonds, forming layers lying parallel to the c axis. PMID- 24764848 TI - (R)-N-[(R)-2,2-Di-chloro-1-phenyl-2-(phenyl-sulfon-yl)eth-yl]-2-methyl-propane-2 sulfinamide. AB - The title mol-ecule, C18H21Cl2NO3S2, contains one chiral carbon center and the absolute sterochemistry has been confirmed as as R. An intra-molecular N-H?O hydrogen bond occurs and the dihedral angle between the benzene rings is 64.5 (1) degrees . In the crystal, the mol-ecules are linked by weak C-H?O hydrogen bonds, forming a zigzag chain structure extending along the c-axis direction. PMID- 24764850 TI - 2-(3,4-Di-meth-oxy-phen-yl)-4-(thio-phen-2-yl)-2,3-di-hydro-1,5-benzo-thia zepine. AB - In the title compound, C21H19NO2S2, the seven-membered thia-zepine ring adopts a slightly distorted twist boat conformation. The dihedral angle between the benzene rings is 67.4 (2) degrees . The mean plane of the thio-phene ring is twisted by 59.3 (2) and 87.7 (2) degrees from the mean planes of the benezene rings. In the crystal, inversion dimers linked by pairs of C-H?O hydrogen bonds generate R 2 (2)(20) loops. PMID- 24764851 TI - 1,3,5-Tri-p-tolyl-pentane-1,5-diol. AB - In the title compound, C26H30O2, the central benzene ring forms dihedral angles of 14.85 (15) and 28.17 (14) degrees with the terminal benzene rings. The dihedral angle between the terminal benzene rings is 32.14 (13) degrees . The crystal packing exhibits two strong inter-molecular O-H?O hydrogen bonds, forming directed four-membered co-operative rings. A region of disordered electron density, most probably disordered ethyl acetate solvent mol-ecules, occupying voids of ca 519 A(3) for an electron count of 59, was treated using the SQUEEZE routine in PLATON [Spek (2009 ?). Acta Cryst. D65, 148-155]. Their formula mass and unit-cell characteristics were not taken into account during refinement. The structure was refined as an inversion twin [absolute structure parameter = -0.3 (4)]. PMID- 24764852 TI - 1-Fluoro-4-[(E)-2-nitro-vin-yl]benzene. AB - The title compound, C8H6FNO2, is almost planar (r.m.s. deviation for the non-H atoms = 0.019 A) and the conformation across the C=C bond is trans. The C and H atoms of the side chain are disordered over two sets of sites in a 0.56 (3):0.44 (3) ratio. In the crystal, mol-ecules are linked by C-H?O inter-actions, thus forming C(5) chains propagating in [001]. PMID- 24764853 TI - 2-[(E)-2-(3,4-Di-chloro-benzyl-idene)hydrazin-1-yl]quinoxaline. AB - The 21 non-H atoms of the title compound, C15H10Cl2N4, are almost planar (r.m.s. deviation = 0.032 A); the conformation about the N=C bond [1.277 (6) A] is E. In the crystal, zigzag supra-molecular chains along the c axis (glide symmetry) are formed via N-H?N hydrogen bonds. These associate along the b axis by pi-pi inter actions between the fused and terminal benzene rings [inter-centroid distance = 3.602 (3) A] so that layers form in the bc plane. PMID- 24764854 TI - (E)-3-[(Di-methyl-amino)-methyl-idene]-4-phenyl-1H-1,5-benzodiazepin-2(3H)-one. AB - The asymmetric unit of the title compound, C18H17N3O, consists of two independent mol-ecules, each having an E conformation with respect to the C=C bond between the benzodiazepinone and di-methyl-amine groups. In the crystal, the two independent mol-ecules are linked into a dimer by a pair of N-H?O hydrogen bonds. PMID- 24764855 TI - Bis[3-methyl-5-(pyridin-2-yl)-1H-pyrazol-4-yl] selenide methanol hemisolvate. AB - The asymmetric unit of the title compound, C18H16N6Se.0.5CH3OH, contains two independent mol-ecules of bis-[3-methyl-5-(pyridin-2-yl)-1H-pyrazol-4-yl] selenide with similar C-Se-C bond angles [99.30 (14) and 98.26 (13) degrees ], and a methanol molecule of solvation. In one mol-ecule, the dihedral angles between pyrazole and neighbouring pyridine rings are 18.3 (2) and 15.8 (2) degrees , and the corresponding angles in the other mol-ecule are 13.5 (2) and 8.3 (2) degrees . In the crystal, the selenide and solvent mol-ecules are linked by classical O-H?N and N-H?N hydrogen bonds, as well as by weak C-H?O and C-H?pi inter-actions, forming a three-dimensional supra-molecular architecture. PMID- 24764856 TI - Di-ethyl-ammonium di-hydrogen orthophosphate. AB - In the title molecular salt, [NH2(CH2CH3)2][H2PO4], two unique types of cations and anions, which are configurationally very similar, are present in the asymmetric unit. Both ions form sheets approximately parallel to (-1-1) linked by weak hydrogen bonds. The inter-connection within and between the sheets is reinforced by O-H?O and N-H?O hydrogen bonds involving the tetra-hedral H2PO4 anions and the ammonium groups. PMID- 24764857 TI - 2,3-Bis{[2,3-dimethyl-6-(phenyl-vin-yl)phen-yl]imino}-butane. AB - In the title compound, C36H36N2, a product of the condensation reaction of 2,3 dimethyl-6-phenyl-vinyl-benzenamine and 2,3-butane-dione, the complete mol-ecule is generated by the application of an inversion centre. The central C-C bond in the 1,4-di-aza-butadiene fragment is trans-configured and situated about the inversion center. The dihedral angle between the ring attached to N and the 1,4 di-aza-butadiene plane is 78.24 (36) degrees , while the 1,4-di-aza-butadiene plane makes an angle of 30.71 (26) degrees with the phenyl ring. PMID- 24764858 TI - 2-{[2-(2-Hy-droxy-5-meth-oxy-benzyl-idene)hydrazin-1-yl-idene]meth-yl}-4-meth-oxy phenol. AB - The title phenyl-hydrazine derivative, C16H16N2O4, has a crystallographically imposed centre of symmetry. Except for the methyl group, all non-H atoms are almost coplanar (r.m.s. deviation = 0.0095 A). Intra-molecular O-H?N hydrogen bonds are observed, generating S(6) graph-set ring motifs. PMID- 24764859 TI - 4,4'-({[(Pyridine-2,6-di-yl)bis-(methyl-ene)]bis-(-oxy)}bis-(methyl-ene))dibenzo nitrile. AB - The complete title molecule, C23H19N3O2, is generated by a twofold axis passing through the central ring. The two oxymethyl-benzo-nitrile arms are attached at the meta positions of the central pyridine ring. The dihedral angle between the pyridine ring and benzene ring of both arms is 84.55 (6) degrees while the benzene rings make a dihedral angle of 46.07 (7) degrees . In the crystal, weak C H?pi inter-actions link the molecules sheets parallel to the ac plane. PMID- 24764860 TI - 2,3-Diphenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one. AB - The six-membered thia-zine ring in the title compound, C16H15NOS, adopts a half chair conformation, with the S atom forming the back of the chair. The base of the chair has a slight twist reflected in the r.m.s. deviation (0.0756 A) of those five atoms from the plane defined by them. The phenyl substituents are almost perpendicular to each other [dihedral angle 87.06 (9) degrees ]. In the crystal, mol-ecules are linked into chains parallel to the c axis through C-H?O inter-actions. PMID- 24764861 TI - 1,3,4-Tri-O-acetyl-2-N-(tri-fluoro-acetyl)-beta-l-fucose. AB - The title compound, C14H18F3NO8, was produced through conjugation of 1,3,4-tri-O acetyl-2-azidode-oxy-alpha,beta-l-fucose with tri-fluoro-acetyl chloride in the presence of bis-(di-phenyl-phosphino)ethane in tetra-hydro-furan at room temperature. The X-ray crystal structure reveals that the beta-anomer of the product mixture crystallizes from ethyl acetate/hexa-nes. The compound exists in a typical chair conformation with the maximum possible number of substituents, four out of five, located in the sterically preferred equatorial positions. The major directional force facilitating packing of the mol-ecules are N-H?O hydrogen bonds involving the amide moieties of neighboring mol-ecules, which connect mol ecules stacked along the a-axis direction into infinite strands with a C (1) 1(4) graph-set motif. Formation of the strands is assisted by a number of weaker C-H?O inter-actions involving the methine and methyl H atoms. These strands are connected through further C-H?O and C-H?F inter-actions into a three dimensional network. PMID- 24764862 TI - Ethyl 6-(4-cyclo-propyl-1H-1,2,3-triazol-1-yl)pyridine-3-carboxyl-ate. AB - In the title compound, C13H14N4O2, which has approximate mirror symmetry, the dihedral angles between the triazole ring and the cyclo-propane and pyridine rings are 87.1 (2) and 7.60 (9) degrees , respectively. In the crystal, inversion dimers linked by pairs of both C-H?N and C-H?O inter-actions generate R 2 (2)(6) and R 2 (2)(18) loops, respectively. Further C-H?N inter-actions form R 2 (2)(10) loops and link the dimers into [110] chains. PMID- 24764863 TI - 2,6-Bis(4-meth-oxy-phen-yl)-1,4-dithiine. AB - The title mol-ecule, C18H16O2S2, reveals crystallographic twofold rotation symmetry (with both S atoms lying on the axis) and one half-mol-ecule defines an asymmetric unit. The dithiine ring is in a boat conformation. The aromatic ring and the C=C bond are nearly coplanar, with small torsion angles of -171.26 (19) and 8.5 (3) degrees . The two S-C bond lengths [1.7391 (19) and 1.7795 (18) A] are shorter than single C-S bonds and longer than analogous C=S double bonds, which indicates a certain degree of conjugation between the lone pair on the S atom and pi electrons of the C=C bond. The crystal packing only features van der Waals inter-actions. PMID- 24764864 TI - 4-(4-Methyl-phen-yl)-2-(prop-2-yn-1-yl)phthalazin-1(2H)-one. AB - In the title compound, C18H14N2O, the dihedral angle between the methyl-phenyl ring and the phthalazone ring system (r.m.s. deviation = 0.034 A) is 53.93 (9) degrees . In the crystal, mol-ecules are connected by C-H?O hydrogen bonds, forming chains along [101]. The chains are linked by pi-pi inter-actions [centroid-centroid distance 3.6990 (12) A], forming layers parallel to (10-1). PMID- 24764865 TI - 2-Bromo-4-phenyl-1,3-thia-zole. AB - In the title mol-ecule, C9H6BrNS, the planes of the 2-bromo-1,3-thia-zole and phenyl rings are inclined at 7.45 (10) degrees with respect to each other. In the crystal, mol-ecules related by a centre of symmetry are held together via pi pi inter-actions, with a short distance of 3.815 (2) A between the centroids of the five- and six-membered rings. The crystal packing exhibits short inter molecular S?Br contacts of 3.5402 (6) A. PMID- 24764866 TI - (E)-N'-[4-(Di-methyl-amino)-benzyl-idene]-2-(4-methyl-phen-oxy)acetohydrazide. AB - In the title compound, C18H21N3O2, the dihedral angle between the benzene rings is 68.85 (11) degrees . In the crystal, the mol-ecules are linked by C-H?O and N H?O hydrogen bonds, as well as weak C-H?pi contacts, forming a three-dimensional supra-molecular architecture. PMID- 24764867 TI - A second polymorph of (Z)-3-amino-4-(2-phenyl-hydrazinyl-idene)-1H-pyrazol-5(4H) one. AB - The mol-ecule of the title compound, C9H9N5O, is approximately planar (the r.m.s. deviation of all non-H atoms is 0.08 A). The amine substituent is pyramidal at the N atom. An intra-molecular N-Hhydrazine?O=C hydrogen bond is present. In the crystal, mol-ecules are connected via N-H?N and N-H?O hydrogen bonds, forming infinite layers parallel to (010). This polymorph is triclinic, space group P-1, whereas the previously reported form was monoclinic, space group P21/c [Elgemeie et al. (2013 ?). Acta Cryst. E69, o187], with stepped layers and a significantly lower density. PMID- 24764868 TI - 7-Nitro-2-phenyl-imidazo[2,1-b][1,3]benzo-thia-zole. AB - In the title mol-ecule, C15H9N3O2S, the central imidazo[2,1-b][1,3]benzo-thia zole heterotricyclic unit is essentially planar (r.m.s. deviation = 0.021 A). The terminal phenyl ring and nitro group are twisted by 9.06 (1) and 11.02 (4) degrees , respectively, from the mean plane of the heterotricycle. In the crystal, mol-ecules are linked by pi-pi stacking inter-actions into columns along [100]; the inter-planar distance between neighboring imidazo[2,1-b][1,3]benzo thia-zole planes within the columns is 3.370 (2) A. Furthermore, the columns interact with each other by secondary S?O [2.9922 (10) and 3.1988 (11) A] inter actions, forming a three-dimensional framework. PMID- 24764869 TI - 1-Acetyl-5-meth-oxy-4-(phenyl-sulfan-yl)imidazolidin-2-one. AB - The title compound, C12H14N2O3S, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. The five-membered imidazolidin-2-one rings in both mol-ecules are twisted about the C-C bond. In the crystal, the A and B mol-ecules are associated via pairs of N-H?O hydrogen bonds, forming A-B dimers. These dimers are linked via C-H?S hydrogen bonds, forming double dimers, which are in turn linked via C-H?O hydrogen bonds forming two-dimensional networks lying parallel to (001). There are also C-H?pi inter-actions present, which consolide the layers and link them, so forming a three-dimensional structure. PMID- 24764870 TI - 2,5-Di-methyl-phenyl quinoline-2-carboxy-l-ate. AB - In the title compound, C18H15NO2, the dihedral angle between the mean planes of the quinoline ring system and the phenyl ring is 78.8 (1) degrees . The mean plane of the carboxyl-ate group is twisted from the mean planes of the quinoline ring system and phenyl ring by 1.5 (9) and 77.6 (4) degrees , respectively. In the crystal, mol-ecules are linked by weak C-H?O inter-actions, generating C(8) chains along [001]. Weak pi-pi stacking inter-actions are also observed [centroid centroid separation = 3.6238 (12) A]. PMID- 24764871 TI - (E)-1-[2-(2-Nitro-styr-yl)-1-phenyl-sulfonyl-1H-indol-3-yl]propan-1-one. AB - In the title compound, C25H20N2O5S, the phenyl ring makes dihedral angles of 89.88 (8) and 13.98 (8) degrees , respectively, with the indole ring system and the nitro-benzene ring. The dihedral angle between the indole ring system and the nitro-benzene ring is 88.48 (11) degrees . The mol-ecular structure is stabilized by a weak intra-molecular C-H?O inter-action. In the crystal, pi-pi inter actions, with centroid-centroid distances of 3.6741 (18) and 3.8873 (17) A, link the mol-ecules into layers parallel to the ab plane. PMID- 24764872 TI - (E)-2-Bromo-1-[2-(2-nitro-styr-yl)-1-phenyl-sulfonyl-1H-indol-3-yl]ethanone. AB - In the title compound C24H17BrN2O5S, the phenyl ring makes dihedral angles of 85.4 (2) and 8.8 (2) degrees with the indole ring system and the nitro-benzene ring, respectively, while the indole ring system and nitrobenzene ring make a dihedral angle of 80.1 (2) degrees . In the crystal, weak C-H?O inter-actions link the mol-ecules, forming a two-dimensional network parallel to the bc plane. PMID- 24764873 TI - (E)-4-Meth-oxy-N'-(2,4,5-tri-meth-oxy-benzyl-idene)benzohydrazide hemihydrate. AB - The title compound crystallizes as a hemihydrate, C18H20N2O5.0.5H2O. The mol ecule exists in an E conformation with respect to the C=N imine bond. The 4-meth oxy-phenyl unit is disordered over two sets of sites with a refined occupancy ratio of 0.54 (2):0.46 (2). The dihedral angles between the benzene rings are 29.20 (9) and 26.59 (9) degrees , respectively, for the major and minor components of the 4-meth-oxy-substituted ring. All meth-oxy substituents lie close to the plane of the attached benzene rings [the Cmeth-yl-O-C-C torsion angles range from -4.0 (12) to 3.9 (2) degrees ]. In the crystal, the components are linked into chains propagating along [001] via N-H?O and O-H?O hydrogen bonds and weak C-H?O inter-actions. PMID- 24764874 TI - N,N'-(Ethane-1,2-di-yl)bis-(methane-sulfon-amide). AB - The mol-ecular structure of the title compound, C4H12N2O4S2, has crystallographic inversion symmetry. The central N-C-C-N moiety was refined as disordered over two sets of sites with an approximate occupancy ratio of 3:1 [0.742 (15):0.258 (15). In the crystal, N-H?O hydrogen bonds link adjacent mol-ecules into a thick sheet structure parallel to the b-axis direction. PMID- 24764875 TI - rac-2-Phenyl-1-[(2,4,6-triiso-propyl-benzene)-sulfon-yl]aziridine. AB - In the title compound, C23H31NO2S, the geometry of the triiso-propyl-phenyl group is slightly distorted, with elongated C-C bonds at the ipso-C atom, and an S atom which deviates from the benzene ring plane by 0.228 (2) A. This distortion is caused by the bulky substituents and, in comparison, an unbent geometry is observed in N-toluene-sulfonyl-aziridine [Zhu et al. (2006 ?). Acta Cryst. E62, o1507-o1508]. pi-pi inter-actions between adjacent benzene rings [centroid centroid distance = 3.7928 (11) A] and are observed. PMID- 24764876 TI - 1,4-Di-aza-bicyclo-[2.2.2]octane-1,4-diium bis-(3-chloro-benzoate). AB - In the title salt C6H14N2 (2+).2C7H4ClO2 (-), two 3-chloro-benzoate (3CBA) anions are bridged by one diprotonated 1,4-di-aza-bicyclo-[2.2.2]octane-1,4-diium (H2DABCO(2+)) dication through N-H?O hydrogen bonds. In this way, a trimeric unit is generated, in which the mean planes of the two 3CBA anions are twisted with respect to each other by a dihedral angle of 59.87 (9) degrees . The trimeric units are linked into a three-dimensional network via weak C-H?O inter-actions. PMID- 24764877 TI - 1-(6-Chloro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-3-(2-chloro-phen-yl)urea. AB - In the title compound, C14H11Cl2N5O, the plane of the 1H-imidazo[4,5-c]pyridine ring system [r.m.s. deviation = 0.087 (19) A] makes a dihedral angle of 4.87 (10) degrees with the terminal phenyl ring. An intra-molecular N-H?N hydrogen bond stabilizes the mol-ecular conformation. In the crystal, N-H?O hydrogen bonds link the mol-ecules into inversion dimers. These dimers are connected by pi-pi inter actions between imidazole rings [shortest centroid-centroid distance = 3.4443 (14) A]. PMID- 24764878 TI - 2-(1,3-Benzodioxol-5-yl)-1H-benzimid-azole. AB - The asymmetric unit of the title compound, C14H10N2O2, contains two independent mol-ecules. In each mol-ecule, the benzodioxole ring system displays an envelope conformation, with the methyl-ene C atom located at the flap deviating by 0.081 (2) and 0.230 (2) A from the mean plane formed by the other atoms. The dihedral angles between the benzo-imidazole ring system (all atoms) and the benzodioxole benzene ring are 15.35 (6) and 10.99 (7) degrees . In the crystal, mol-ecules are linked by N-H?N hydrogen bonds into chains running along the [101]. PMID- 24764879 TI - 2-(2-Amino-4-nitro-phen-yl)-7-nitro-4H-3,1-benzoxazin-4-one. AB - In the title compound, C14H8N4O6, the benzoxazin-4-one fused-ring system (r.m.s. deviation = 0.018 A) is coplanar with the attached benzene ring [dihedral angle = 0.81 (4) degrees ], there being an intra-molecular N-H?N hydrogen bond between them. Each nitro group is twisted out of the plane of the attached benzene ring [O-N-C-C torsion angles = 167.94 (11) and 170.38 (11) degrees ]. In the crystal, amine-nitro N-H?O hydrogen bonds lead to centrosymmetric dimeric aggregates that are connected into a three-dimensional architecture by oxazin-yl-nitro C-H?O and pi-pi inter-actions [inter-centroid distance between the oxazinyl and terminal benzene rings = 3.5069 (7) A]. PMID- 24764880 TI - 4-[(1-Benzyl-1H-1,2,3-triazol-4-yl)meth-yl]-2H-1,4-benzo-thia-zin-3(4H)-one. AB - In the title compound, C18H16N4OS, the six-membered heterocycle of the benzo-thia zine fragment exhibits a screw-boat conformation. The dihedral angles between the plane through the triazole ring and those through the fused and terminal benzene rings are 76.68 (11) and 71.0 (1) degrees , respectively; the benzene rings are nearly perpendicular [dihedral angle = 79.6 (1) degrees ]. In the crystal, mol ecules are linked by C-H?N and C-H?O inter-actions, forming a three-dimensional network. PMID- 24764881 TI - 5-Imino-3,4-diphenyl-1H-pyrrol-2-one. AB - The title compound, C16H12N2O, exists in the crystalline state as the 5-imino-3,4 di-phenyl--1H-pyrrol-2-one tautomer. The dihedral angles between the pyrrole and phenyl rings are 35.3 (2) and 55.3 (2) degrees . In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate a graph-set motif of R 2 (2)(8) via N-H?N hydrogen bonds. PMID- 24764882 TI - (E)-3-(4-Heptyl-oxyphen-yl)-1-phenyl-prop-2-en-1-one. AB - In the title compound, C22H26O2, the aromatic rings are inclined to one another by 8.39 (9) degrees and the mol-ecule has an E conformation about the C=C bond. In the crystal, mol-ecules stack head-to-tail along the b-axis direction. They are linked by very weak C-H?O contacts, forming C(4) chains along [100]. Two chains are linked by a pair of very weak C-H?O contacts, enclosing inversion dimeric R 2 (2)(8) ring motifs. There are also C-H?pi inter-actions present, which link the double-stranded chains, forming a two-dimensional network. PMID- 24764883 TI - 6,7-Dimeth-oxy-2,4-di-phenyl-quinoline. AB - In the title structure of the title compound, C23H19NO2, two conformationally similar mol-ecules (A and B) comprise the asymmetric unit. The dihedral angle between phenyl rings bridged by the quinoline moiety are 76.25 (8) degrees in mol-ecule A and 70.39 (9) degrees in mol-ecule B. In the crystal, the independent mol-ecules are connected by C-H?O hydrogen bonds and the resulting dimeric aggregates are linked by pi-pi [inter-centroid distance = 3.7370 (8) A] and C-H?pi inter-actions, forming a three-dimensional architecture. PMID- 24764884 TI - Adenin-1-ium hydrogen isophthalate di-methyl-formamide monosolvate. AB - In the title proton-transfer organic salt, C5H6.3N5 (+).C8H4.7O4 (-).C3H7NO, the adeninium moiety is protonated at the N atom in the 1-position of the 6-amino-7H purin-1-ium (adeninium) cation. In the solid state, the second acidic proton of isophthalic acid is partially transferred to the imidazole N atom of the adeninium cation [refined O-H versus N-H ratio = 0.70 (11):0.30 (11)]. Through the partially transferred proton, the adeninium cation is strongly hydrogen bonded (N-H?O/O-H?N) to the isophthalate anion. This strong inter-action is assisted by another N-H?O hydrogen bond originating from the adeninium NH2 group towards the isophthalate keto O atom, with an R (2) 2(8) graph-set motif. This arrangement is linked via N-H?O hydrogen bonds to the O atoms of the carboxyl-ate group of an isophthalate anion. Together, these hydrogen bonds lead to the formation criss-cross zigzag isophthalate?adeninium chains lying parallel to (501) and (50-1). The adeninium cations and the isophthalate anions are arranged in infinite pi stacks that extend along the c-axis direction [inter-planar distance = 3.305 (3) A]. Mol-ecules are inclined with respect to this direction and within the stacks they are offset by ca. half a mol-ecule each. Combination of the N-H?O and O-H?N hydrogen bonds with the pi-pi inter-actions forms infinitely stacked isophthalate?adeninium chains, thus leading to a two dimensional supra-molecular structure with parallel inter-digitating layers formed by the pi stacked isophthalate?adeninium chains. The DMF mol-ecules of crystallization are bonded to the adeninium cations through strong N-H?O hydrogen bonds and project into the lattice space in between the anions and cations. There are also C-H?O hydrogen bonds present which, combined with the other inter actions, form a three-dimensional network. The crystal under investigation was found to be split and was handled as if non-merohedrally twinned. PMID- 24764885 TI - (4S)-3-Methyl-5,6,7,8-tetra-hydro-4H-spiro-[[1,2]oxazolo[5,4-b]quinoline-4,3' indole]-2',5-dione. AB - In the title compound, C18H15N3O3, the dihedral angle between the mean planes of the quinoline and indole ring systems [r.m.s. deviations = 0.189 (2) and 0.027 (2) A, respectively] is 88.65 (5) degrees . The cyclo-hexene ring of the quinoline ring system adopts an envelope conformation with the central -CH2- C atom as the flap. In the crystal, mol-ecules are linked by two pairs of N-H?O hydrogen bonds, forming inversion dimers, and enclosing R 2 (2)(14) ring motifs. This arrangement results in the formation of chains propagating along [100]. PMID- 24764886 TI - (S,Z)-3-Phenyl-2-[(1,1,1-tri-chloro-7-meth-oxy-2,7-dioxohept-3-en-4-yl)amino] propanoic acid monohydrate. AB - In the title compound, C17H18Cl3NO5.H2O, intra-molecular N-H?O and C-H?Cl hydrogen bonds form S(6) and S(5) ring motifs, respectively. The chiral organic mol-ecule is connected to the solvent water mol-ecule by a short O-H?O hydrogen bond. In the crystal, a weak C-H?Cl inter-action connects the organic mol-ecules along [100] while the water mol-ecules act as bridges between the organic mol ecules in both the [100] and [010] directions, generating layers parallel to the ab plane. PMID- 24764887 TI - 1-Ethyl-3-methyl-1H-imidazol-3-ium spiro-penta-borate. AB - In the anion of the title compound, (C6H11N2)[B5O6(OH)4], both six-membered borate rings adopt a flattened boat conformation with the spiro-B atom and its opposite O atom deviating from the remainders of the rings by 0.261 (3)/0.101 (2) and 0.160 (3)/0.109 (2) A, respectively. The imidazolium cation also deviates from planarity due to rotation of the ethyl group (as indicated by the C-N-C-C torsion angle) by 71.4 (2) degrees out of the plane of the heterocycle. In the crystal, the anions are connected in a three-dimensional network through O-H?O hydrogen bonds, forming channels along the a-axis direction. The cations are situated in the channels, forming C-H?O hydrogen bonds with the anions. PMID- 24764888 TI - (4S)-5'-Chloro-3,7,7-trimethyl-5,6,7,8-tetra-hydro-4H-spiro-[1,2-oxazolo[5,4 b]quinoline-4,3'-indole]-2',5-dione. AB - In the title compound, C20H18ClN3O3, the five- and six-membered heterocycles fused through a spiro C atom are inclined to each other at an angle of 87.4 (1) degrees . In the tricyclic ring system, the cyclo-hexene ring adopts an envelope conformation with the spiro atom as the flap. In the crystal, two sets of N-H?O hydrogen bonds link the mol-ecules into columns containing centrosymmetric R 2 (2)(7) ring motifs and propagating along the b-axis direction. PMID- 24764889 TI - Butane-1,4-di-ammonium hexa-fluoro-silicate. AB - The title compound, [NH3(CH2)4NH3](2+).SiF6 (2-), is a hybrid built from an organic butane-1,4-di-ammonium dication linked to a hexa-fluoro-silicate mineral anion. Both ions posses inversion symmetry. In the anion the Si atom is located on an inversion center, while in the cation the center of inversion is situated at the mid-point of the central -CH2-CH2- bond. The Si atom is surrounded by six F atoms, forming a slightly distorted SiF6 (2-) octa-hedron. These octa-hedra are linked to the organic cations through N-H?F hydrogen bonds, forming a three dimensional network. PMID- 24764890 TI - (Z)-N-[(Z)-3-(2,5-Di-methyl-phenyl-imino)-butan-2-yl-idene]-2,5-di-methyl aniline. AB - The asymmetric unit of the title compound, C20H24N2, contains one half-mol-ecule, with the single C-C bond of the 1,4-di-aza-butadiene fragment situated on a centre of symmetry. The benzene rings are inclined to the 1,4-di-aza-butadiene mean plane by 59.5 (1) degrees . PMID- 24764891 TI - 7-Di-ethyl-amino-3-{(E)-4-[(E)-2-(pyridin-4-yl)ethen-yl]styr-yl}-2H-chromen-2 one. AB - In the title coumarin derivative, C28H26N2O2, the coumarin unit is approximately planar, with a maximum deviation of 0.048 (3) A. The central benzene ring is oriented at dihedral angles of 30.15 (14) and 10.51 (11) degrees , respectively, to the pyridine ring and coumarin ring system. In the crystal, weak C-H?O and C H?N hydrogen bonds and weak C-H?pi inter-actions link the mol-ecules into a three dimensional supra-molecular architecture. PMID- 24764892 TI - 2-[(1H-Benzimidazol-1-yl)meth-yl]phenol benzene hemisolvate. AB - In the title solvate, C14H12N2O.0.5C6H6, the complete benzene molecule is generated by a crystallographic inversion centre. The dihedral angle between the planes of the benzimidazole moiety and the phenol substituent is 75.28 (3) degrees . In the crystal, O-H?N hydrogen bonds link the mol-ecules into parallel chains propagating along [100]. The mol-ecules are further connected by C-H?pi inter-actions. PMID- 24764893 TI - 5-Iodo-7-methyl-2-(4-methyl-phen-yl)-3-methyl-sulfinyl-1-benzo-furan. AB - In the title compound, C17H15IO2S, the dihedral angle between the benzofuran group (r.m.s. deviation = 0.009 A) and the 4-methylbenzene ring is 12.69 (5) degrees . In the crystal, mol-ecules are linked via pairs of I?O [I?O = 3.164 (1) A, C-I?O = 166.63 (5) degrees ] contacts into inversion-related dimers. PMID- 24764894 TI - 5-Propyl-6-(p-tolyl-sulfan-yl)pyrimidine-2,4(1H,3H)-dione. AB - In the title pymiridine-2,4-dione derivative, C14H16N2O2S, the dihedral angle between the six-membered rings is 66.69 (10) degrees . The mol-ecule is twisted about the Cp-S (p = pyrimidine) bond, with a C-S-C-N torsion angle of -19.57 (16) degrees . In the crystal, adjacent mol-ecules form inversion dimers through pairs of strong N-H?O hydrogen bonds, generating an R 2 (2)(8) ring motif. The dimers are connected into chains extending along the c-axis direction through additional N-H?O hydrogen bonds. PMID- 24764895 TI - N-(3-Chloro-1-methyl-1H-indazol-5-yl)-4-methylbenzene-sulfonamide. AB - The asymmetric unit of the title compound, C15H14ClN3O2S, contains two independent mol-ecules showing different conformations: in one mol-ecule, the indazole ring system makes a dihedral angle of 51.5 (1) degrees with the benzene ring whereas in the other, the indazole unit is almost perpendicular to the benzene ring [dihedral angle 77.7 (1) degrees ]. In the crystal, the mol-ecules are linked by N-H?N and N-H?O hydrogen bonds, forming a set of four mol-ecules linked in pairs about an inversion centre. PMID- 24764896 TI - (+/-)-trans-6,6'-Dieth-oxy-2,2'-[cyclo-hexane-1,2-diylbis(nitrilo-methanylyl idene)]diphenol monohydrate. AB - In the title hydrate, C24H30N2O4.H2O, the organic mol-ecule adopts an E conformation with respect to the azomethine double bonds. The cyclo-hexane ring is in a chair conformation. The dihedral angle between benzene rings is 79.6 (2) degrees . Two intra-molecular O-H?N hydrogen bonds are present. In the crystal, the components are linked by O-H?O hydrogen bonds and weak C-H?pi inter-actions, generating a three-dimensional supramolecular architecture. PMID- 24764897 TI - 2-(1H-Benzimidazol-2-yl)phenol. AB - The title mol-ecule, C13H10N2O, is essentially planar, the maximum deviation from the plane of the non-H atoms being 0.016 (2) A. The imidazole ring makes a dihedral angle of 0.37 (13) degrees with the attached benzene ring. An intra molecular O-H?N hydrogen bond generates an S(6) ring motif. In the crystal, mol ecules are linked through N-H?O hydrogen bonds, forming chains propagating in [001]. The crystal packing also features four pi-pi stacking inter-actions involving the imidazole ring, fused benzene ring and attached benzene ring system [centroid-centroid distances = 3.6106 (17), 3.6108 (17), 3.6666 (17) and 3.6668 (17) A]. PMID- 24764898 TI - 2,2'-Bi(9,9-di-ethyl-fluorene). AB - The title compound, C34H34, systematic name 9,9,9',9'-tetra-ethyl-2,2'-bi(9H fluorene), crystallized with two crystallographically independent mol-ecules (A and B) in the asymmetric unit. These differ mainly in the orientation of the lateral ethyl chains: in mol-ecule A, they are both on the same side of the mol ecule whereas in mol-ecule B, one di-ethyl-fluorene moiety has undergone a 180 degrees rotation such that the two pairs of ethyl residues appear on opposite sides of the mol-ecule. The fluorene ring systems subtend dihedral angles of 31.37 (4) and 43.18 (3) degrees in mol-ecules A and B, respectively. Hence the two fluorene moieties are tilted slightly toward one another. This may be due to the presence of inter-molecular C-H?pi inter-actions between neighboring mol ecules. The lateral ethyl chains (excluding H atoms) are also almost planar, with each pair almost perpendicular to the plane of the fluorene system to which they are attached with dihedral angles between the ethyl and fluorene planes in the range 86.04 (8)-89.5 (1) degrees . PMID- 24764899 TI - Cytosinium hydrogen selenite. AB - In the crystal structure of the title salt, C4H6N3O(+).HSeO3 (-), systematic name 6-amino-2-methyl-idene-2,3-di-hydro-pyrim-idin-1-ium hydrogen selenite, the hydrogenselenite anions and the cytosinium cations are linked via N-H?O, N-H?Se, O-H?O, O-H..Se and C-H?O hydrogen bonds, forming a three-dimensional framework. PMID- 24764900 TI - 1-(2,4-Di-nitro-phen-yl)-2-[(E)-(3,4,5-tri-meth-oxy-benzyl-idene)]hydrazine. AB - Mol-ecules of the title compound, C16H16N4O7, are not planar with a dihedral angle of 5.50 (11) degrees between the substituted benzene rings. The two meta meth-oxy groups of the 3,4,5-tri-meth-oxy-benzene moiety lie in the plane of the attached ring [Cmeth-yl-O-C-C torsion angles -0.1 (4) degrees and -3.7 (3) degrees ] while the para-meth-oxy substituent lies out of the plane [Cmeth-yl-O-C C, -86.0 (3) degrees ]. An intra-molecular N-H?O hydrogen bond involving the 2 nitro substituent generates an S(6) ring motif. In the crystal structure, mol ecules are linked by weak C-H?O inter-actions into screw chains, that are arranged into a sheet parallel to the bc plane. These sheets are connected by pi pi stacking inter-actions between the nitro and meth-oxy substituted aromatic rings with a centroid-centroid separation of 3.9420 (13) A. C-H?pi contacts further stabilize the two-dimensional network. PMID- 24764901 TI - (E)-3-(9-Ethyl-9H-carbazol-3-yl)-1-(2-meth-oxy-phen-yl)prop-2-en-1-one. AB - In the title mol-ecule, C24H21NO2, the dihedral angle between the carbazole ring system [with a maximum deviation of 0.052 (2) A] and the benzene ring is 38.6 (1) degrees . In the crystal, weak bifurcated (C-H)2?O hydrogen bonds link the mol ecules into chains along [100]. PMID- 24764902 TI - N-(4-Methyl-phenyl-sulfon-yl)-3-nitro-benzamide. AB - In the title compound, C14H12N2O5S, the dihedral angle between the aromatic rings is 86.29 (1) degrees and the conformation between the C=O bond of the amide group and the meta-NO2 group is syn. The C-S-N-C torsion angle is -65.87 (19) degrees and the mol-ecule has an L-shaped conformation. In the crystal, the mol ecules are connected into inversion dimers through pairs of N-H?O hydrogen bonds and C-H?O inter-actions forming R 2 (2)(8) and R 2 (2)(14) loops, respectively. The dimers are connected by further C-H?O inter-actions, thereby forming (100) sheets. PMID- 24764904 TI - N-(4-Meth-oxy-benzo-yl)-2-methyl-benzene-sulfonamide. AB - In the title compound, C15H15NO4S, the dihedral angle between the aromatic rings is 80.81 (1) degrees and the dihedral angle between the planes defined by the S N-C=O fragment and the sulfonyl benzene ring is 86.34 (1) degrees . In the extended structure, dimers related by a crystallographic twofold axis are connected by pairs of both N-H?O hydrogen bonds and C-H?O inter-actions, which generate R 2 (2)(8) and R 2 (2)(14) loops, respectively. A weak aromatic pi-pi stacking inter-action is also observed [centroid-centroid separation = 3.7305 (3) A]. PMID- 24764903 TI - N-(4-Meth-oxy-benzo-yl)benzene-sulfon-amide. AB - In the title compound, C14H13NO4S, the dihedral angle between the aromatic rings is 69.81 (1) degrees ; the dihedral angle between the planes defined by the S-N C=O segment of the central chain and the sulfonyl benzene ring is 74.91 (1) degrees . In the crystal, the mol-ecules are linked by weak N-H?O hydrogen bonds into C(4) chains running along [100]. The mol-ecules in adjacent chains are linked by weak C-H?O inter-actions, generating R 2 (2) (16) dimeric pairs. Weak C H?pi inter-actions connect the double chains into (001) sheets. PMID- 24764905 TI - 3,4-Di-methyl-phenyl benzoate. AB - In the title compound, C15H14O2, the terminal rings form a dihedral angle of 52.39 (4) degrees . The mean plane of the central ester group [r.m.s. deviation = 0.0488 A] is twisted away from the benzene and phenyl rings by 60.10 (4) and 8.67 (9) degrees , respectively. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds, forming C(6) chains which run along [100]. PMID- 24764906 TI - 7-Meth-oxy-2-phenyl-quinoline-3-carbaldehyde. AB - In the title mol-ecule, C17H13NO2, the phenyl ring is inclined to the quinoline ring system by 43.53 (4) degrees . In the crystal, mol-ecules are linked via C H?O hydrogen bonds, forming double-stranded chains propagating along [011]. These chains are linked via pi-pi inter-actions involving inversion-related quinoline rings; the shortest centroid-centroid distance is 3.6596 (17) A. PMID- 24764907 TI - 9-[4-(Azido-meth-yl)phen-yl]-9H-carbazole-3-carbo-nitrile. AB - In the title compound C20H13N5, the dihedral angle between the carbazole ring system (r.m.s. deviation = 0.027 A) and the pendant benzene ring is 55.08 (6) degrees . One of the azide N atoms is disordered over two positions in a 0.65 (2):0.35 (2) ratio. In the crystal, aromatic pi-pi stacking is observed [minimum centroid-centroid separation = 3.6499 (13) A] as well as inversion-dimers connected by pairs of weak C-H?pi inter-actions. PMID- 24764908 TI - 1,1,4,7,7-Penta-methyl-diethylenetri-ammonium trinitrate. AB - In the title compound, C9H26N3 (3+).3NO3 (-), the triprotonated 1,1,4,7,7-penta methyl-diethylenetri-amine mol-ecules are linked to the nitrate anions by multiple bifurcated N-H?(O,O) and weak C-H?O hydrogen bonds. The organic cation is characterized by N-C-C-N torsion angles of -176.2 (2) and 176.6 (2) degrees . PMID- 24764909 TI - 2-Chloro-N-(4-meth-oxy-benzo-yl)-benzene-sulfonamide. AB - In the title compound, C14H12ClNO4S, the dihedral angle between the aromatic rings is 82.07 (1) degrees and the dihedral angle between the planes defined by the S-N-C=O fragment and the sulfonyl benzene ring is 82.46 (3) degrees . In the crystal, the mol-ecules are linked into C(4) chains running along [001] by strong N-H?O hydrogen bonds. A C-H?O intera-ction reinforces the [001] chains: its graph set symbol is C(7). The chains are cross-linked into (100) sheets by further C H?O inter-actions as C(6) chains along [001]. The structure also features weak pi pi stacking inter-actions [centroid-centroid distances = 3.577 (1) and 3.8016 (1) A]. PMID- 24764910 TI - Enrofloxacinium oxalate. AB - The title salt, 2C19H23FN3O3 (+).C2O4 (2-) {systematic name: bis-[4-(3-carb-oxy-1 cyclo-propyl-6-fluoro-4-oxo-1,4-di-hydro-quino-lin-7-yl)-1-ethyl-piperazin-1-ium] oxalate}, crystallizes with two independent monocations (A and B) and an oxalate dianion (C) in the asymmetric unit. The piperazinium ring in both the cations adopts a slightly disordered chair conformation. The dihedral angles between the mean planes of the cyclo-propyl ring and the 10-membered quinoline ring are 50.6 (5) degrees (A) and 62.2 (5) degrees (B). In each of the cations, a single O H?O intra-molecular hydrogen bond is observed. In the crystal, the oxalate anions inter-act with the cations through N-H?O hydrogen bonds and weak C-H?O inter actions, forming R 2 (2)(8) graph-set ring motifs. Weak C-H?F inter-actions along with further C-H?O inter-actions are observed between the cations, forming zigzag chains along [001]. In addition, pi-pi stacking inter-actions are observed with centroid-centroid distances of 3.5089 (13), 3.5583 (13), 3.7900 (13) and 3.7991 (13) A. PMID- 24764911 TI - 2-(4-Chloro-phen-yl)-2,3-di-hydro-quinolin-4(1H)-one. AB - The title mol-ecule, C15H12ClNO, features a di-hydro-quinolin-4(1H)-one moiety attached to a chloro-benzene ring. The heterocyclic ring has a half-chair conformation with the methine C atom lying 0.574 (3) A above the plane of the five remaining atoms (r.m.s. deviation = 0.0240 A). The dihedral angles between the terminal benzene rings is 77.53 (9) degrees , indicating a significant twist in the mol-ecule. In the crystal, supra-molecular zigzag chains along the c-axis direction are sustained by N-H?O hydrogen bonds. These are connected into double chains by C-H?pi inter-actions. PMID- 24764912 TI - 2-Methyl-benzene-1,3-di-ammonium dinitrate. AB - In the crystal structure of the title salt, C7H12N2 (2+).2NO3 (-), the nitrate ions are located in the vicinity of the protonated amine groups, accepting strong N-H?O hydrogen bonds. Each ammonium group is involved in a total of three such inter-actions with neighbouring nitrate ions, generating a three-dimensional network. In addition, there are pi-pi inter-actions between the aromatic rings of centrosymmetrically related di-ammonium moieties, with a centroid-centroid distance of 3.682 (1) A. PMID- 24764913 TI - N-Phenyl-2-(1,2,3,4-tetra-hydro-naph-thalen-1-yl-idene)hydrazinecarbo-thio-amide. AB - The conformation of the title mol-ecule, C17H17N3S, is stabilized by an intra molecular N-H?N hydrogen bond involving the azometinic group. The dihedral angle between the two aromatic rings is 36.49 (06) degrees . The non-aromatic ring of the tetra-lone substituent adopts a sofa conformation. In the crystal, mol-ecules are linked by pairs of N-H?S hydrogen bonds related via centres of symmetry, forming dimers. PMID- 24764914 TI - Flupentixol tartrate. AB - In the title salt, C23H26F3N2OS(+).C4H5O6 (-) [systematic name: 1-(2-hy-droxy-eth yl)-4-[3-(2-(tri-fluoro-meth-yl)thioxanthen-9-yl-idene)prop-yl]piperazin-1-ium 3 carb-oxy-2,3-di-hydroxy-pro-pion-ate], the monoprotonated piperazine ring in the cation adopts a chair conformation, while the thio-pyran ring of the thioxanthene group has a boat conformation. The dihedral angle between the mean planes of the two outer aromatic rings of the thioxanthene groups is 31.6 (2) degrees . In the crystal, the cations and anions are linked via O-H?O, N-H?O, O-H?N and C-H?O hydrogen bonds, forming chains propagating along [100]. In addition, R (2) 2(7), R (2) 2(11), R (2) 2(10) and R (2) 2(12) graph-set ring motifs involving the anions, and R (2) 2(9) graph-set ring motifs involving both the cations and anions are observed. The three F atoms of the tri-fluoro-methyl group are disordered over two sets of sites and the individual atoms were refined with occupancy ratios of 0.54 (6):0.46 (6), 0.72 (2):0.28 (2) and 0.67 (3):0.33 (3). PMID- 24764915 TI - 1-Piperonylpiperazinium picrate. AB - IN THE CATION OF THE TITLE SALT [SYSTEMATIC NAME: 4-(2H-1,3-benzodioxol-5-ylmeth yl)piperazin-1-ium 2,4,6-tri-nitro-phen-o-late], C12H17N2O2 (+).C6H2N3O7 (-), the piperazine ring adopts a slightly disordered chair conformation. The piperonyl ring system and the piperazine ring are twisted with respect to each other with an N-C-C-C torsion angle of 40.7 (2) degrees . In the anion, the dihedral angles between the mean planes of the nitro substituents ortho to the phenolate O atom and the mean plane of the phenyl ring are 28.8 (9) and 32.2 (8) degrees . In contrast, the nitro group in the para position lies much closer to the aromatic ring plane, subtending a dihedral angle of 3.0 (1) degrees . In the crystal, the cations and anions inter-act through N-H?O hydrogen bonds and a weak C-H?O inter action. Weak C-H?O inter-actions are also observed between the anions, forming R 2 (2)(10) graph-set ring motifs. In addition, a weak centroid-centroid pi-pi stacking inter-action between the aromatic rings of the cation and the anion, with an inter-centroid distance of 3.7471 (9) A, contributes to the crystal packing, resulting in a two-dimensional network along (10-1). PMID- 24764916 TI - Methyl 4-(4-bromo-anilino)-2',5-dioxo-5H-spiro-[furan-2,3'-indoline]-3-carboxyl ate. AB - In the title compound, C19H13BrN2O5, the spiro furan ring is almost planar with a maximum deviation of 0.034 (2) A. The indole unit and the furan ring are normal to each other, making a dihedral angle of 87.82 (8) degrees . The mol-ecular structure is stabilized by an intra-molecular N-H?O hydrogen bond, which generates an S(6) ring motif. In the crystal, mol-ecules are linked via pairs of N-H?O hydrogen bonds, forming inversion dimers enclosing R (2) 2(8) ring motifs. PMID- 24764917 TI - 2-(4,5-Di-chloro-2-nitro-phen-yl)-4-meth-oxy-3-methyl-9-phenyl-sulfon-yl-9H carbazole. AB - In the title compound, C26H18Cl2N2O5S, the carbazole ring system is essentially planar with a maximum deviation of 0.0498 (16) A for the N atom. The carbazole ring system is almost orthogonal to the phenyl-sulfonyl and di-chloro-substituted nitro-phenyl rings, making dihedral angles of 84.23 (7) and 85.46 (12) degrees , respectively. The mol-ecular structure features intra-molecular C-H?O inter actions, which generate two S(6) ring motifs. In the crystal, mol-ecules are linked by C-Cl?O halogen bonds [3.016 (3) A, 166.63 (5) degrees ], which generate infinite C(8) chains running parallel to [010]. PMID- 24764918 TI - 2-p-Tolyl-2,3-di-hydro-quinolin-4(1H)-one. AB - In the title mol-ecule, C16H15NO, the tetra-hydro-pyridine ring is in a sofa conformation with the methine C atom forming the flap. The dihedral angle between the benzene rings is 80.85 (8) degrees . In the crystal, mol-ecules are arranged in alternating double layers parallel to (100) and are connected along [001] by N H?O hydrogen bonds. In addition, weak C-H?pi inter-actions are observed. PMID- 24764919 TI - N (1),N (2)-Di-methyl-ethane-1,2-diaminium dichloride. AB - The cation of the title salt, C4H14N2 (2+).2Cl(-), is located on a crystallographic inversion center and is bis-ected by a mirror plane, with one quarter of the C4H14N2 (2+).2Cl(-) formula unit being crystallographically unique. he chloride ions also sit on a mirror plane. The conformation of the cation is a regular straight-chain conformation with all non-H atoms in anti positions. In the crystal, hydrogen bonding between N-H groups and chloride anions yields a zigzag ladder-type structure along [010]. PMID- 24764920 TI - 1-Aza-niumyl-cyclo-butane-1-carboxyl-ate monohydrate. AB - In the title compound, C5H9NO2.H2O, the amino acid is in the usual zwitterionic form involving the alpha-carboxyl-ate group. The cyclo-butane backbone of the amino acid is disordered over two conformations, with occupancies of 0.882 (7) and 0.118 (7). In the crystal, N-H?O and O-H?O hydrogen bonds link the zwitterions [with the water molecule involved as both acceptor (with the NH3 (+)) and donor (through a single carboxylate O from two different aminocyclobutane carb-oxylate moities)], resulting in a two-dimensional layered structure lying parallel to (100). PMID- 24764921 TI - Ethyl (4-{[(di-ethyl-carbamo-thio-yl)sulfan-yl]meth-yl}-2-oxo-2H-chromen-7 yl)carbamate. AB - In the title compound, C18H22N2O4S2, the 2H-chromene ring system is essentially planar (r.m.s. deviation = 0.012 A). The mol-ecular conformation is stabilized by a C-H?O hydrogen bond. In the crystal, N-H?S and C-H?O hydrogen bonds occur, the former enclosing an R (2) 2(22) ring motif, and lead to the formation of a two dimensional slab-like network lying parallel to (10-1). pi-pi inter-actions are observed between inversion-related aromatic rings [shortest centroid-centroid distance = 3.6300 (11) A]. PMID- 24764922 TI - 5-Amino-1H-pyrazol-2-ium hydrogen succinate. AB - In the cation of the title salt, C3H6N3 (+).C4H5O4 (-), the protonated pyrazolium ring is planar (r.m.s. deviation = 0.012 A). An intra-molecular C-H?O hydrogen bond occurs in the anion. In the crystal, N-H?O hydrogen bonds and a weak C-H?O inter-action between the cations and anions form two sets of R 2 (2)(8) graph-set ring motifs. Inter-molecular O-H?O hydrogen bonds between these lead to a criss cross pattern along the b axis. In addition to the classical hydrogen bonds, a weak C-H?pi(pyrazolium) inter-action is observed and contributes to crystal packing. All of these inter-actions link the mol-ecules into a two-dimensional supra-molecular framework parallel to (10-1). PMID- 24764923 TI - N-Ethyl-2,2-dimethyl-N-(3-methyl-phen-yl)propanamide. AB - In the title compound, C14H21NO, the conformation across the N-C(O) bond is syn periplanar, the C-N-C-C torsion being -5.9 (5) degrees . The atoms of the ethyl group attached to the N atom are disordered over two sets of sites with occupancy ratios of 0.65 (2):0.35 (2) (CH2) and 0.689 (14):0.311 (14) (CH3)are linked by very weak C-H?O inter-actions forming C(8) chains along [001]. C-H?pi inter actions link the mol-ecules along the c-axis direction. PMID- 24764924 TI - 1-[2-(Di-methyl-aza-nium-yl)eth-yl]-1H-1,2,3,4-tetra-zole-5-thiol-ate. AB - In the crystal structure of the title zwitterion, C5H11N5S, mol-ecules are linked via N-H?N hydrogen bonds, forming zigzag chains propagating along [010]. The chains are linked by C-H?S hydrogen bonds, forming two dimensional networks lying parallel to (001). PMID- 24764925 TI - 1-[(E)-2-(5-tert-Butyl-2-hy-droxy-phen-yl)diazen-1-yl]naphthalen-2-ol. AB - The non-H atoms of the title compound, C20H20N2O2, is located on a mirror plane except two methyl groups of the tert-butyl group. Intra-molecular N-H?O hydrogen bonds exist between the hy-droxy and diazenyl groups. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds into supra-molecular chains running along the a-axis direction. PMID- 24764926 TI - 3-[2-(4-Fluoro-phen-yl)-2-oxoeth-yl]-5,5-di-phenyl-imidazolidine-2,4-dione. AB - The title compound, C23H17FN2O3, crystallizes with two independent mol-ecules in the asymmetric unit. The mol-ecules are connected by pairs of N-H?O hydrogen bonds and have slightly different conformations, as indicated by the dihedral angles between the central imidazolidine-2,4-dione ring and its three substituents. In one mol-ecule, these are 60.56 (1) and 82.66 (9) degrees to the phenyl rings and 84.35 (16) degrees to the 2-(4-fluoro-phen-yl)-2-oxoethyl side chain. In the other mol-ecule, the corresponding angles are 66.35 (10), 84.94 (9) and 86.31 (16) degrees . In the crystal, weak C-H?O inter-actions leading to a three-dimensional supramolecular architecture. PMID- 24764927 TI - 2-Meth-oxy-4,6-di-phenyl-nicotino-nitrile. AB - In the title compound, C19H14N2O, the phenyl rings form dihedral angles of 10.90 (10) and 42.14 (6) degrees with pyridine ring and an angle of 35.7 (2) degrees with each other. The orientation of the meth-oxy group is defined by the C-O-C-N torsion angle of 4.9 (2) degrees . PMID- 24764928 TI - 1-Do-decyl-indoline-2,3-dione. AB - The structure of the title compound, C20H29NO2, is isotypic to that of its homologue 1-octylindoline-2,3-dione. The indoline ring and the two carbonyl-group O atoms are approximately coplanar, the largest deviation from the mean plane being 0.0760 (10) A. The mean plane through the fused-ring system is nearly perpendicular to the mean plane passing through the 1-dodecyl chain [dihedral angle = 77.69 (5) degrees ]. All C atoms of the dodecyl group are in an anti periplanar arrangement. In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming a three-dimensional network. PMID- 24764929 TI - 2-(4-Chloro-2-nitro-phen-yl)-4-meth-oxy-9-phenyl-sulfonyl-9H-carbazole-3 carbaldehyde. AB - In the sterically hindered title compound, C26H17ClN2O6S, the carbazole ring has a maximum deviation from planarity of 0.067 (4) A for the C atom connected to the aldehyde group. The carbazole moiety forms a dihedral angle of 72.8 (1) degrees with the nitro-substituted benzene ring. The O atom of the meth-oxy group deviates by 0.186 (1) A from the adjacent carbazole moiety. The phenyl-sulfonyl group forms intra-molecular C-H?O bonds between sulfone O atoms and the carbazole moiety, resulting in two S(6) rings. In the crystal, the nitrated benzene rings are linked via C-H?O inter-actions forming infinite C(7) chains along [100]. The crystal packing is also characterized by C-H?pi inter-actions, which result in inversion dimers. PMID- 24764930 TI - [2-(3,4-Di-meth-oxy-phen-yl)eth-yl](3-{N-[2-(3,4-di-meth-oxy-phen-yl)eth yl]carbamo-yl}prop-yl)aza-nium chloride dihydrate. AB - The asymmetric unit of the title hydrated salt, C24H35N2O5 (+).Cl(-).2H2O, contains one organic cation that has its protonation site at the amine function, one chloride anion and two lattice water mol-ecules. In the crystal, one pair of lattice water mol-ecules and two chloride anions form a four-membered centrosymmetric hydrogen-bond cycle. In addition, O-H?O, N-H?O and N-H?Cl hydrogen bonds involving the N-H groups, the water mol-ecules and the C=O group are observed. As a result, a hydrogen-bonded layer parallel to (100) is formed. The thickness of such a layer corresponds to the length of the a axis [21.977 (3) A]. PMID- 24764931 TI - Twinned caesium cerium(IV) penta-fluoride. AB - Single-crystals of CsCeF5 were synthesized hydro-thermally. The crystal under investigation was twinned by pseudo-merohedry with a twofold rotation around the c axis as an additional twinning operation. The crystal structure is built of layers of distorted edge- and corner-sharing CeF8 square-anti-prisms. The Cs(+) cations are located between the layers and exhibit coordination numbers of nine. Upon compression, CsCeF5 undergoes an irreversible phase transition at about 1 GPa. PMID- 24764932 TI - Rb2Lu[Si4O10]F, a tubular chain silicate. AB - Single crystals of Rb2Lu[Si4O10]F (dirubidium lutetium tetra-silicate fluoride) were obtained in flux-synthesis experiments in the system SiO2-Lu2O3-RbF. The compound belongs to the group of tubular chain silicates, i.e. it is based on multiple chains of condensed [SiO4] tetra-hedra forming closed columns. The periodicity of the unbranched multiple chains is four and corresponds to the length of the b axis. Adjacent columns are connected by Lu(3+) cations, which are coordinated by four oxide and two fluoride anions in the form of slightly distorted octa-hedra. By sharing common fluoride corners, the single octa-hedra are linked into chains running parallel to the silicate tubes. Electroneutrality is achieved by the incorporation of additional Rb(+) cations. All four symmetrically independent rubidium ions, four out of twelve oxide as well as the two fluoride anions are located on mirror planes. The remaining atoms reside on general positions. PMID- 24764933 TI - Cd4As2Br3. AB - Single crystals of Cd4As2Br3 (tetra-cadmium biarsenide tri-bromide) were grown by a chemical transport reaction. The structure is isotypic with the members of the cadmium and mercury pnictidohalides family with general formula M 4 A 2 X 3 (M = Cd, Hg; A = P, As, Sb; X = Cl, Br, I) and contains two independent As atoms on special positions with site symmetry -3 and two independent Cd atoms, of which one is on a special position with site symmetry -3. The Cd4As2Br3 structure consists of AsCd4 tetra-hedra sharing vertices with isolated As2Cd6 octa-hedra that contain As-As dumbbells in the centre of the octahedron. The Br atoms are located in the voids of this three-dimensional arrangement and bridge the different polyhedra through Cd?Br contacts. PMID- 24764934 TI - Calcioferrite with composition (Ca3.94Sr0.06)Mg1.01(Fe2.93Al1.07)(PO4)6(OH)4.12H2O. AB - Calcioferrite, ideally Ca4MgFe(3+) 4(PO4)6(OH)4.12H2O (tetra-calcium magnesium tetrairon(III) hexakis-phosphate tetra-hydroxide dodeca-hydrate), is a member of the calcioferrite group of hydrated calcium phosphate minerals with the general formula Ca4 AB 4(PO4)6(OH)4.12H2O, where A = Mg, Fe(2+), Mn(2+) and B = Al, Fe(3+). Calcioferrite and the other three known members of the group, montgomeryite (A = Mg, B = Al), kingsmountite (A = Fe(2+), B = Al), and zodacite (A = Mn(2+), B = Fe(3+)), usually occur as very small crystals, making their structure refinements by conventional single-crystal X-ray diffraction challenging. This study presents the first structure determination of calcioferrite with composition (Ca3.94Sr0.06)Mg1.01(Fe2.93Al1.07)(PO4)6(OH)4.12H2O based on single-crystal X-ray diffraction data collected from a natural sample from the Moculta quarry in Angaston, Australia. Calcioferrite is isostructural with montgomeryite, the only member of the group with a reported structure. The calcioferrite structure is characterized by (Fe/Al)O6 octa-hedra (site symmetries 2 and -1) sharing corners (OH) to form chains running parallel to [101]. These chains are linked together by PO4 tetra-hedra (site symmetries 2 and 1), forming [(Fe/Al)3(PO4)3(OH)2] layers stacking along [010], which are connected by (Ca/Sr)(2+) cations (site symmetry 2) and Mg(2+) cations (site symmetry 2; half-occupation). Hydrogen bonding inter-actions involving the water mol-ecules (one of which is equally disordered over two positions) and OH function are also present between these layers. The relatively weaker bonds between the layers account for the cleavage of the mineral parallel to (010). PMID- 24764935 TI - Bis[(2-methyl-benz-yl)bis-(pyridin-2-ylmethyl-kappaN)amine-kappaN]manganese(II) bis-(perchlorate). AB - In the title complex, [Mn(C20H21N3)2](ClO4)2, two tridentate (2-methyl-benz yl)bis-(pyridin-2-ylmeth-yl)amine (L) ligands form the Mn(II) complex [MnL 2](ClO4)2. The Mn(II) ion lies on a twofold axis and the complex cation is significantly distorted from regular octa-hedral geometry. The packing is stabilized by weak C-H?O inter-actions between the cations and anions, which link them into a zigzag ribbon along [101]. The perchlorate anion is disordered and was constrained to be tetra-hedral with two orientations having occupancies of 0.768 (4) and 0.232 (4). The 2-methylbenzyl moiety is also disordered over two sets of sites, with occupancies of 0.508 (15) and 0.492 (15). PMID- 24764936 TI - [N,N'-Bis(2,6-diethyl-4-phenyl-phen-yl)butane-2,3-di-imine-kappa(2) N,N']di bromido-nickel(II). AB - The complex molecule in the title compound, [NiBr2(C36H40N2)], has mirror symmetry. The Ni(II) atom and two Br atoms are located on the mirror plane. The Ni(II) atom is four-coordinated by the two Br atoms and two N atoms from an N,N' bis(2,6-diethyl-4-phenyl-phen-yl)butane-2,3-di-imine ligand in a distorted tetra hedral geometry. The dihedral angle formed between the two adjacent benzene rings is 47.1 (1) degrees . PMID- 24764937 TI - Tri-methyl-phospho-nium trans-tetra-chlorido-bis-(tri-methyl-phosphane kappaP)iridate(III). AB - The title compound, [HP(CH3)3][IrCl4{(H3C)3P}2], consists of a tri-methyl-phospho nium cation and a tetra-chlorido-bis-(tri-methyl-phosphane)iridate(III) anion. The anion has an octa-hedral arrangement of ligands, with the tri-methyl phosphane groups occupying trans positions. The Ir(III) atom sits on an inversion center with one P(CH3)3 ligand and two chloride ligands in the asymmetric unit. The tri-methyl-phospho-nium cation is disordered about a twofold rotation axis. The title compound is the first structurally characterized tetra-chlorido-bis (phosphane)iridate complex. PMID- 24764938 TI - A one-dimensional polymeric cobalt(III)-potassium complex with 18-crown-6, cyanide and porphyrinate ligands. AB - The reaction of Co(II)(TpivPP) {TpivPP is the dianion of 5,10,15,20-tetra-kis-[2 (2,2-di-methyl-propanamido)-phen-yl]por-ph-yrin} with an excess of KCN salts and an excess of the 18-crown-6 in chloro-benzene leads to the polymeric title compound catena-poly[[dicyanido-2kappa(2) C-(1,4,7,10,13,16-hexa-oxa-cyclo-octa decane-1kappa(6) O){MU3-(2alpha,2beta)-5,10,15,20-tetra-kis-[2-(2,2-di-methyl propanamido)-phen-yl]porphyrinato-1kappaO (5):2kappa(4) N,N',N'',N''':1'kappaO (15)}cobalt(III)potassium] dihydrate], {[CoK(CN)2(C12H24O6)(C64H64N8O4].2H2O} n . The Co(III) ion lies on an inversion center, and the asymmetric unit contains one half of a [Co(III)(2alpha,2beta-TpivPP)(CN)2](-) ion complex and one half of a [K(18-C-6](+) counter-ion (18-C-6 is 1,4,7,10,13,16-hexa-oxa-cyclo-octa-deca-ne), where the K(I) ion lies on an inversion center. The Co(III) ion is hexa coordinated by two C-bonded axial cyanide ligands and the four pyrrole N atoms of the porphyrin ligand. The K(I) ion is chelated by the six O atoms of the 18-crown 6 mol-ecule and is further coordinated by two O atoms of pivalamido groups of the porphyrin ligands, leading to the formation of polymeric chains running along [011]. In the crystal, the polymeric chains and the lattice water mol-ecules are linked by N-H?O and O-H?N hydrogen bonds, as well as weak C-H?O, O-H?pi and C H?pi inter-actions into a three-dimensional supra-molecular architecture. PMID- 24764939 TI - Di-aqua-bis-(cinnamato-kappa(2) O,O')cadmium. AB - The title complex, [Cd(C9H7O2)2(H2O)2], was obtained as an unintended product of the reaction of cadmium nitrate with hexa-methyl-ene-tetra-mine and cinnamic acid. The Cd(II) ion lies on a twofold rotation axis and is coordinated in a slightly distorted trigonal-prismatic environment. In the crystal, the V-shaped mol-ecules are arranged in an inter-locking fashion along [010] and O-H?O hydrogen bonds link the mol-ecules, forming a two-dimensional network parallel to (001). PMID- 24764940 TI - (E)-1-Ferrocenyl-3-(2-meth-oxy-phen-yl)prop-2-en-1-one. AB - The structure of the title compound, [Fe(C5H5)(C15H13O2)], consists of a ferrocenyl moiety and a 2-meth-oxy-phenyl group linked through a prop-2-en-1-one spacer in an E conformation. In the ferrocene unit, the substituted cyclo-penta dienyl (Cps) ring and the unsubstituted cyclo-penta-dienyl ring (Cp) are almost parallel to one another [dihedral angle = 1.78 (14) degrees ], and the Cp and Cps rings are in a gauche conformation. The benzene ring is twisted by 10.02 (14) and 11.38 (11) degrees with respect to the Cp and Cps rings, respectively. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds into supra-molecular chains running along the b-axis direction. PMID- 24764941 TI - trans-Chloridobis-(ethane-1,2-di-amine-kappa(2) N,N')(thio-cyanato kappaN)cobalt(III) diammine-tetra-kis-(thio-cyanato-kappaN)cromate(III). AB - The title ionic complex [CoCl(NCS)(C2H8N2)2][Cr(NCS)4(NH3)2], which crystallizes as a non-merohedral twin, is build up of a complex cation [CoCl(NCS)(en)2](+) (en is ethane-1,2-di-amine) and the Reinecke's salt anion [Cr(NCS)4(NH3)2](-) as complex counter-ion. A network of N-H?S and N-H?Cl hydrogen bonds, as well as short S?S contacts [3.538 (2) and 3.489 (3) A], between the NCS groups of the complex anions link the mol-ecules into a three-dimentional supra-molecular network. Intensity statistic indicated twinning by non-mero-hedry with refined weighs of twin components are 0.5662:0.4338. PMID- 24764942 TI - Poly[(MU3-3,5-di-nitro-benzoato-kappa(3) O (1):O (1'):O (3))(MU2-hydroxido kappa(2) O:O)copper(II)]. AB - The title complex, [Cu{MU3-O2CC6H3(NO2)2-3,5}(MU-OH)] n , features zigzag chains in which successive pairs of Cu(II) atoms are connected by OH bridges and bidentate carboxyl-ate ligands, leading to six-membered Cu(O)(OCO)Cu rings. The zigzag chains are connected into a three-dimensional architecture by Cu-O(nitro) bonds. The coordination geometry of the Cu(II) atom is square-pyramidal, with the axial position occupied by the nitro O atom, which forms the longer Cu-O bond. Bifurcated hy-droxy-nitro O-H?O hydrogen bonds contribute to the stability of the crystal structure. PMID- 24764943 TI - trans-Di-aqua-bis-(pyridazine-3-carboxyl-ato-kappa(2) N (2),O)copper(II). AB - In the title compound, [Cu(C5H3N2O2)2(H2O)2], the Cu(II) ion, located on an inversion center, exhibits an octa-hedral coordination geometry. The equatorial plane is defined by two trans-related N,O-bidentate pyridazine-3-carboxyl-ate ligands and the axial positions are occupied by two water mol-ecules. In the crystal, mol-ecules are connected by O-H?O hydrogen bonds between the water mol ecules and the noncoordinating carboxyl-ate O atoms, forming layers parallel to the bc plane. The layers are stacked along the a axis by further O-H?O hydrogen bonds between the water mol-ecules and the coordinating carboxyl-ate O atoms. Weak C-H?O hydrogen bonds are also observed between the pyridazine rings and the water mol-ecules and between the pyridazine rings and the non-coordinating carboxyl-ate O atoms. PMID- 24764944 TI - Bis(acetato-kappaO)bis-(thio-urea-kappaS)cobalt(II). AB - The title compound, [Co(CH3COO)2(CH4N2S)2], is isotypic with the corresponding Zn(II) complex. The metal atom is in a distorted tetra-hedral coordination environment with the two S atoms from two thio-urea ligands and two O atoms from two acetate anions as the coordinating atoms. All H atoms of the thio-urea ligands are involved in N-H?O and N-H?S hydrogen bonds, leading to a three dimensional network. PMID- 24764945 TI - Bis[5-(pyridin-2-yl-kappaN)tetra-zolido-kappaN (1)]copper(II). AB - In the title complex, [Cu(C6H4N5)2], the Cu(II) ion lies on an inversion center and is coordinated by two chelating 5-(pyridin-2-yl)tetra-zolide ligands in a slightly distorted square-planar coordination geometry. In the crystal, pi-pi stacking inter-actions, with centroid-centroid distances in the range 3.4301 (14) 3.4387 (13) A, link the complex mol-ecules along [101]. PMID- 24764946 TI - Di-aqua-bis-[5-(2-pyrazin-2-yl)tetra-zolato]copper(II)-pyrazine-2-carbo-nitrile (1/2). AB - The title compound, [Cu(C5H3N6)2(H2O)2].2C5H3N3, is a 1:2 co-crystal between the mononuclear complex di-aqua-bis-[5-(pyrazin-2-yl)tetra-zolato]copper(II) and the reagent pyrazine-2-carbo-nitrile which was used in the synthesis. The Cu(II) atom is located on an inversion centre and has a distorted octa-hedral [4 + 2] coordination environment formed by four N atoms of two chelating bidentate 5 (pyrazin-2-yl)tetra-zolate ligands at shorter distances and two water O atoms at longer distances. The Cu(II) complex molecules are held together by O-H?N hydrogen bonds and pi-pi stacking inter-actions [centroid-centroid distance 3.6139 (8) A], forming layers parallel to (100). These layers alternate with layers of pyrazine-2-car-bo-nitrile mol-ecules and both are held together via C H?N hydrogen bonds and further pi-pi stacking inter-actions. PMID- 24764947 TI - mer-Hydridotris(tri-methyl-phosphane-kappaP)(d-valinato-kappa(2) N,O)iridium hexa fluorido-phosphate di-chloro-methane 0.675-solvate. AB - The title compound, [Ir(C5H10NO2)H(C3H9P)3]PF6.0.675CH2Cl2, an iridium compound with a meridional arrangement of PMe3 groups, O,N-bidentate coordination of d valine and with a hydride ligand trans to the N atom is compared with the l valine complex reported previously. As expected, the complexes from the corresponding l and d isomers of valine crystallize in enanti-omorphic space groups (P43 and P41, respectively). In the crystal, N-H?O and N-H?F hydrogen bonding is observed, the N-H to carbonyl oxygen hydrogen bond producing a helical motif that proceeds along the 41 screw of the c axis. PMID- 24764948 TI - Di-chlorido-dimethyl-bis-(thio-urea-kappaS)tin(IV). AB - The title compound, [Sn(CH3)2Cl2(CH4N2S)2], crystallizes with two half-mol-ecules in the asymmetric unit. Both mol-ecules are completed by inversion symmetry with the two Sn(IV) atoms located on inversion centers. The metal atoms have distorted octa-hedral coordination environments defined by two Cl atoms, two C atoms of methyl groups and two thio-urea S atoms. In the crystal, mol-ecules are linked via N-H?Cl and N-H?S hydrogen bonds, forming a three-dimensional structure. PMID- 24764949 TI - Propane-1,2-di-ammonium chromate(VI). AB - In the title mol-ecular salt, (C3H12N2)[CrO4], each chromate anion accepts six N H?O and C-H?O hydrogen bonds from nearby propane-1,2-di-ammonium cations. Three of the four O atoms of the chromate anion accept these bonds; the remaining Cr-O bond length is notably shorter than the others. In the crystal, the anions and cations stack in layers lying parallel to (100): the hydrogen-bonding pattern leads to a three-dimensional network. PMID- 24764950 TI - Bis(2,6-di-methyl-anilinium) di-aqua-bis-(di-hydrogen diphosphato-kappa(2) O,O')cobaltate(II). AB - In the title compound, (C8H12N)2[Co(H2P2O7)2(H2O)2], the Co(2+) ion lies on a crystallographic inversion centre and adopts a slightly distorted octa-hedral CoO6 coordination geometry arising from two chelating diphosphate [H2P2O7](2-) ligands and two trans water mol-ecules. In the crystal, the components are linked by O-H?O, N-H?O and C-H?O hydrogen bonds and weak aromatic pi-pi stacking [shortest centroid-centroid separation = 3.778 (2) A] inter-actions. (001) layers of alternating organic cations and complex inorganic anions are apparent. PMID- 24764951 TI - Bis(eta(5)-penta-methyl-cyclo-penta-dien-yl)aluminium tetra-bromido-aluminate. AB - The title compound, [Al(C10H15)2][AlBr4], was formed during the reduction of a mixture of Cp*AlBr2 and AlBr3. The Al(III) atoms of the two crystallographically independent cations each lie on an inversion center, and the [AlBr4](-) anions are on general positions. At 123 K, the structure exhibits disorder in two of the Br atoms of the [AlBr4](-) ion, with a ratio occupancy of 0.733 (6): 0.267 (3). In the crystal, there is possible weak hydrogen bonding between some methyl groups and Br atoms. The interactions link the moieties in a three-dimensional array. PMID- 24764952 TI - catena-Poly[[bis-(ethanol-kappaO)mangan-ese(II)]-MU-2,5-di-chloro-3,6-di-oxo cyclo-hexa-1,4-diene-1,4-bis-(olato)-kappa(4) O (1),O (6):O (3),O (4)]. AB - In the title coordination polymer, [Mn(C6Cl2O4)(C2H5OH)2] n , the Mn(II) atom and the chloranilate [systematic name: 2,5-di-chloro-3,6-dioxo-cyclo-hexa-1,4-diene 1,4-bis-(olate)] ion lie on crystallographic inversion centers. The geometry around the Mn(II) atom is a distorted octa-hedron involving four O atoms of two chloranilate ions and two O atoms from two ethanol mol-ecules. The chloranilate ion serves as a bridging ligand between the Mn(II) ions, leading to an infinite linear chain along the b-axis direction. The chains are linked by O-H?O hydrogen bonds between the apically coordinating ethanol mol-ecule and the chloranilate ion, affording a two-dimensional layer expanding parallel to the ab plane. PMID- 24764953 TI - trans-Chlorido-(4-fluoro-benzene-thiol-ato-kappaS)bis-(tri-phenyl-phosphane kappaP)palladium(II) methanol hemisolvate. AB - The title compound, [Pd(SC6H4F-p)Cl(PPh3)2].0.5CH3OH, features a Pd(II) complex with two tri-phenyl-phosphane (PPh3) ligands arranged in a trans conformation, with one chloride and one 4-fluoro-benzene-thiol-ate ligand completing the coordination sphere, giving rise to a slightly distorted square-planar geometry of the Pd(II) ion. The methanol solvent mol-ecule is disordered about an inversion centre with an occupancy of 0.25 for each molecule. In the crystal, weak C-H?Cl hydrogen-bonding inter-actions between the complex mol-ecules generate chain frameworks parallel to [010]. PMID- 24764954 TI - Bis(1-benzyl-1H-benzimidazole-kappaN (3))di-chlorido-zinc. AB - In the title compound, [ZnCl2(C14H12N2)2], the Zn(II) atom exhibits a distorted tetra-hedral coordination geometry involving two chloride anions and two N-atom donors from 1-benzyl-1H-benzimidazole ligands. In both ligands, the benzyl and benzimidazole rings are nearly perpendicular [dihedral angles = 81.7 (2) and 81.5 (2) degrees ]. The two benzimidazole systems are essentially planar [maximum deviations = 0.015 (3) and 0.020 (2) A] and form a dihedral angle of 78.09 (8) degrees . In the crystal, centrosymmetrically related mol-ecules are linked by pairs of C-H?Cl hydrogen bonds into chains parallel to the a axis. PMID- 24764955 TI - Bis[tetra-kis-(pyridin-2-yl)methane-kappa(3) N,N',N'']cobalt(II) tetra-kis-(thio cyanato-kappaN)cobaltate(II) methanol monosolvate. AB - The title complex, [Co(C21H16N4)2][Co(NCS)4].CH3OH, consists of one [Co{C(py)4}2](2+) complex cation [C(py)4 = tetra-kis-(pyridin-2-yl)methane], one [Co(NCS)4](2-) complex anion and a methanol solvent mol-ecule. In the cation, the Co(II) atom is coordinated by six N atoms of two C(py)4 ligands in a distorted octa-hedral geometry. In the anion, the Co(II) atom is coordinated by the N atoms of four NCS(-) ligands in a distorted tetra-hedral geometry. The methanol mol ecule is disordered and was modelled over three orientations (occupancies 0.8:0.1:0.1). There are two weak hydrogen-bond-like inter-actions between the methanol solvent mol-ecule and NCS(-) ligands of the anion [O?S = 3.283 (3) and 3.170 (2) A]. PMID- 24764956 TI - Di-aqua-bis-[N-(2-fluoro-benz-yl)-N-nitroso-hydroxy-laminato-kappa(2) O,O']nickel(II). AB - In the centrosymmetric title compound, [Ni(C7H6FN2O2)2(H2O)2], the Ni(II) cation is in a slightly distorted octa-hedral environment and is surrounded by four O atoms from the N-O groups of the organic ligands [Ni-O = 2.0179 (13) and 2.0283 (12) A], and two water mol-ecules [Ni-O = 2.0967 (14) A]. The N-(2-fluoro-benz yl)-N-nitroso-hydroxy-laminate monoanions act as bidentate chelating ligands. In the crystal, the Ni cations in the columns are shifted in such a way that the coordinated water mol-ecules are involved in the formation of hydrogen bonds with the O atoms of the organic species of neighbouring mol-ecules. Thus, a two dimensional network parallel to (100) is built up by hydrogen-bonded molecules. PMID- 24764957 TI - 3-Anilino-5,5-di-methyl-cyclo-hex-2-enone. AB - In the title mol-ecule, C14H17NO, the 5,5-di-methyl-cyclo-hex-2-enone moiety is attached to an aniline group, the dihedral angle subtended [54.43 (3) degrees ] indicating a significant twist. The hexaneone ring has a half-chair conformation with the C atom bearing two methyl groups lying 0.6384 (8) A above the plane of the five remaining atoms (r.m.s. deviation = 0.0107 A). The crystal packing can be described as alternating layers parallel to (-101), which are consolidated by N-H?O hydrogen bonds and C-H?pi inter-actions. PMID- 24764958 TI - 2-[(E)-(4-Bromo-phenyl)imino-methyl]-4-chloro-phenol. AB - In the title compound, C13H9BrClNO, the dihedral angle between the substituted benzene rings is 44.25 (11) degrees . There are strong intra-molecular O-H?N hydrogen bonds, which generate S(6) rings, and also inter-molecular Cl?Cl [3.431 (3) A] and Br? Br [3.846 (1) A] contacts. The crystal packing a C-H?O and C-H?pi inter-actions. PMID- 24764959 TI - Bis(di-cyclo-hexyl-ammonium) sulfate dihydrate. AB - In the title dihydrate salt, 2C12H24N(+).SO4 (2-).2H2O, the cation possesses twofold rotational symmetry, with the N atom situated on the twofold axis. The sulfate anion has fourfold roto-inversion symmetry, with the S atom located on the -4 axis. In the crystal, the components are linked via ammonium-sulfate N-H?O and water-sulfate O-H?O hydrogen bonds, forming a three-dimensional network. PMID- 24764960 TI - 4-Methyl-N-(4-methyl-phenyl-sulfon-yl)-N-phenyl-benzene-sulfonamide. AB - The whole mol-ecule of the title compound, C20H19NO4S2, is generated by twofold rotational symmetry. The N atom is located on the twofold rotation axis and has a trigonal-planar geometry. It is bonded by two S atoms of two symmetry-related 4 methyl-phenyl-sulfonyl groups and by the C atom of the phenyl ring, which is bis ected by the twofold rotation axis. The benzene and phenyl rings are oriented at a dihedral angle of 51.48 (5) degrees while the pendant benzene rings are inclined to one another by 87.76 (9) degrees . In the crystal, weak C-H?O hydrogen bonds link the mol-ecules, forming a three-dimensional network. PMID- 24764961 TI - Ethyl 4,9-dimethyl-9H-carbazole-3-carboxyl-ate. AB - In the title compound, C17H17NO2, the carbazole skeleton includes an eth-oxy carbonyl group at the 3-position. The indole three-ring system is almost planar [maximum deviation = 0.065 (2) A], and the ethyl ester group is inclined to its mean plane by 15.48 (2) degrees . In the crystal, there are pi-pi stacking inter actions between parallel benzene rings and between parallel benzene and pyrrole rings of adjacent mol-ecules [centroid-centroid distances = 3.9473 (8) and 3.7758 (8) A, respectively]. Weak C-H?pi inter-actions are also present. PMID- 24764962 TI - N-(5-Benzyl-sulfanyl-1,3,4-thia-diazol-2-yl)-2-(piperidin-1-yl)acetamide. AB - The title compound, C16H20N4OS2, was synthesized by the reaction of 2-benzyl sulfanyl-5-chloro-acetamido-1,3,4-thia-diazole and piperidine in a 1:2 ratio. The planes of the acetamide and 1,3,4-thia-diazole units are twisted by 10.8 (4) degrees . The thia-diazole S atom and the acetamide O atom are syn-oriented due to a hypervalent S?O inter-action of 2.628 (4) A. In the crystal, mol-ecules form centrosymmetric dimers via N-H?N hydrogen bonds. These dimers are further connected by C-H?O inter-actions into (100) layers. PMID- 24764963 TI - N'-[(E)-Furan-2-ylmethyl-idene]-4-hydroxy-benzohydrazide. AB - The title compound, C12H10N2O3, exists in the E conformation. The five-membered ring and the phenyl rings form dihedral angles of 36.73 (10) and 12.22 (10) degrees , respectively, with the central C(=O)N2C unit. The crystal packing is dominated by strong N-H?O and O-H?N hydrogen bonds. Together with weaker C-H?O inter-actions, these establish a three-dimensional supra-molecular network. PMID- 24764964 TI - 6,6'-Dimethyl-2,2'-[imidazolidine-1,3-diyl-bis(methyl-ene)]diphenol. AB - In the title compound, C19H24N2O2, a di-Mannich base derived from 2-methyl-phenol and 1,3,6,8-tetra-aza-tri-cyclo-[4.4.1.1(3,8)]dodecane, the imidazolidine ring adopts a twist conformation, with a twist about the ring N-C bond [C-N-C-C torsion angle = -44.34 (14) degrees ]. The two 2-hy-droxy-3-methyl-benzyl groups are located in trans positions with respect to the imidazolidine fragment. The structure displays two intra-molecular O-H?N hydrogen bonds, which each form an S(6) ring motif. In the crystal, the mol-ecules are linked by weak C-H?O inter actions with a bifurcated acceptor, forming a three-dimensional network. PMID- 24764965 TI - 4-Cyano-3-fluoro-phenyl 4-(hexa-dec-yl-oxy)benzoate. AB - In the title compound, C30H40FNO3, the dihedral angle between the benzene rings is 57.76 (7) degrees . The alkyl chain adopts an all-trans conformation. In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds, forming inversion dimers. PMID- 24764966 TI - 4-(2-Meth-oxy-phen-yl)piperazin-1-ium 6-chloro-5-isopropyl-2,4-dioxopyrimidin-1 ide. AB - In the cation of the title salt, C11H17N2O(+).C7H8ClN2O2 (-), the piperazine ring adopts a distorted chair conformation and contains a positively charged N atom with quaternary character. Its mean plane makes a dihedral angle of 42.36 (8) degrees with the phenyl ring of its 2-meth-oxy-phenyl substituent. The 2,4 dioxopyrimidin-1-ide anion is generated by deprotonation of the N atom at the 1 position of the pyrimidine-dione ring. Intra-molecular C-H?O hydrogen bonds generate S(6) ring motifs in both the cation and the anion. In the crystal, N H?O, N-H?N and C-H?O hydrogen bonds are also observed, resulting in a two dimensional network parallel to the ab plane. The crystal stability is further consolidated by weak C-H?pi inter-actions. PMID- 24764967 TI - 3-(4-Hexyl-oxyphen-yl)-1,2,4-triazolo[3,4-b]benzo-thia-zole. AB - The title compound, C20H21N3OS, was prepared by Huisgen reaction of 5-(4-hexyl oxyphen-yl)tetra-zole and chloro-benzo-thia-zole. The essentially planar benzo thia-zolotriazole framework [maximum deviation from the mean plane of 0.077 (1) A for the bridgehead N atom] and the phenyl ring form a dihedral angle of 53.34 (5) degrees . The hex-yloxy chain adopts a gauche-all-anti conformation. The intra centroid separation of 3.7258 (8) A between the triazole and benzene rings is the closest contact between individual mol-ecules in the crystal. PMID- 24764968 TI - N-(12-Amino-9,10-di-hydro-9,10-ethano-anthracen-11-yl)-4-methyl-benzene sulfonamide. AB - The title compound, C23H22N2O2S, crystallizes with the 4-methyl-benzene sulfonamide entity oriented towards the center of the bridgehead C atoms with a C N-S-C torsion angle of -61.3 (2) degrees . The mol-ecule features an intra molecular N-H?N hydrogen bond. Weak C-H?O and C-H?pi inter-actions aid in forming the three-dimensional supra-molecular structure. PMID- 24764969 TI - Methyl 3-phenyl-isoxazole-5-carboxyl-ate. AB - In the title compound, C11H9NO3, the dihedral angle between the isoxazole and phenyl rings is 19.79 (12), while the ester group is inclined to the isoxazole group by 12.14 (6) degrees . In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, forming layers lying parallel to (010). PMID- 24764970 TI - (E)-13-(2-Bromo-phen-yl)micheliolide. AB - The title compound, C21H23BrO3 [systematic name: (3E,3aS,6Z,9R,9aS,9bS)-3-(2 bromo-benzyl-idene)-9-hy-droxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octa-hydro azuleno[4,5-b]furan-2(9bH)-one] was prepared by the reaction of 1-bromo-2-iodo benzene with micheliolide [systematic name: (3aS,R,9aS,9bS,Z)-9-hy-droxy-6,9 dimethyl-3-methyl-ene-3,3a,4,5,7,8,9,9a-octa-hydro-azuleno[4,5-b]furan-2(9bH) one] under Heck reaction conditions. The title compound exhibits intra-molecular O-H?O hydrogen bonding between the hy-droxy group and the lactone ring O atom, forming a ring of graph-set motif S(6). The 2-bromo-phenyl group is trans to the lactone ring, indicating that this is the E isomer (geometry of the exocyclic C=C bond). The dihedral angle between the benzene ring of the 2-bromo-phenyl moiety and the mean plane of the lactone ring is 51.68 (7) degrees . PMID- 24764971 TI - Cyclo-hexyl-ammonium nitrate. AB - In the title salt, C6H14N(+).NO3 (-), the cyclo-hexyl ring adopts a chair conformation. The ammonium group occupies an equatorial position and the crystal struture is stabilized by inter-molecular N-H?O hydrogen-bonding inter-actions, resulting in a three-dimensional network. PMID- 24764972 TI - (3R,4S)-3-Methyl-4-phenyl-2-[(R)-1-phenyl-eth-yl]-3,4-di-hydro-isoquinolin-2-ium tetra-fluorido-borate. AB - The title salt, C24H24N(+).BF4 (-), is one of two possible dias-tereoisomers having a different configuration of the asymmetric centre in the alpha-phenyl ethyl substituent, whose absolute configuration was established to be R. The two phenyl substituents of the cation have a cofacial orientation, albeit with a long centroid-centroid separation of 4.129 (3) A. The crystal structure exhibits numerous C-H?F contacts between counter-ions, with the tetra-fluorido-borate anion surrounded by five iminium cations. PMID- 24764973 TI - Bis(6-nitro-1,10-phenanthrolin-1-ium) 2,5-di-carb-oxy-terephthalate. AB - In the structure of the title 2:1 proton-transfer compound, 2C12H8N3O2 (+).C10H4O8 (2-), the 6-nitro-1,10-phenanthroline mol-ecules act as proton sponges, accepting protons from pyromellitic acid. The -NO2 group of one of the 6 nitro-1,10-phenanthrolin-1-ium cations is disordered and was refined with a site occupancy ratio of 0.624 (15):0.376 (15). Two -COOH(-COO(-)) groups of the 2,5-di carb-oxy-terephthalate dianion are disordered and were refined with site occupancy ratios of 0.769 (4):0.231 (4) and 0.766 (5):0.234 (5). The -NO2 group of the second cation is also disordered about a pseudo-twofold rotation axis and was refined with a site-occupancy ratio of 0.903 (3):0.097 (3). There is an intra molecular O-H?O hydrogen bond in the anion. The phenanthroline rings of the two cations are inclined to one another by 31.3 (1) degrees . In the anions, considering the major components only, the carb-oxy-lic acid groups (-COOH) are inclined to the benzene ring by 17.3 (2) and 22.3 (3) degrees . The carboxyl-ate groups (-COO(-)) are twisted by 9.3 (2) and 13.6 (6) degrees with respect to the benzene ring. In the crystal, adjacent 2,5-di-carb-oxy-terephthalate anions are linked via O-H?O hydrogen bonds, forming chains propagating along [010]. The cations are attached to the chain of anions by N-H?O hydrogen bonds. PMID- 24764974 TI - 5-(4-Fluoro-phen-yl)-2-(4-methyl-phen-yl)-3-methyl-sulfanyl-1-benzo-furan. AB - The asymmetric unit of the title compound, C22H17FOS, contains two independent mol-ecules (A and B). The dihedral angles between the benzo-furan ring systems [r.m.s. deviations of 0.026 (1), 0.004 (1) and 0.003 (1) A, respectively, for mol ecule A, and 0.002 (1), 0.004 (1) and 0.005 (1) A for B] and the pendant 4-fluoro phenyl and 4-methyl-phenyl rings are 39.48 (4) and 30.86 (5) degrees , respectively, for mol-ecule A, and 33.34 (6) and 20.99 (8) degrees for B. In the crystal, mol-ecules are linked by weak C-H?F and C-H?pi inter-actions, resulting in a three-dimensional network. PMID- 24764975 TI - 2-(4-Chloro-phen-yl)-4-oxo-4-phenyl-butane-nitrile. AB - The title mol-ecule, C16H12ClNO, has a V-shaped conformation and the dihedral angle between the planes of the phenyl and benzene rings of 64.6 (1) degrees . No directional intermolecular interactions could be identified in the crystal. PMID- 24764976 TI - 2,3-Di-phenyl-male-imide 1-methyl-pyrrol-idin-2-one monosolvate. AB - In the title compound, C16H11NO2.C5H9NO, the dihedral angles between the male imide and phenyl rings are 34.7 (2) and 64.8 (2) degrees . In the crystal, the 2,3-di-phenyl-male-imide and 1-methyl-pyrrolidin-2-one mol-ecules form centrosymmetrical dimers via pairs of strong N-H?O hydrogen bonds and pi-pi stacking inter-actions between the two neighboring male-imide rings [centroid centroid distance = 3.495 (2) A]. The dimers are further linked by weak C-H?O and C-H?pi hydrogen bonds into a three-dimensional framework. PMID- 24764977 TI - 4-(Thio-phen-2-yl)-2-[4-(tri-fluoro-meth-yl)phen-yl]-2,3-di-hydro-1,5-benzo-thia zepine. AB - In the title compound, C20H14F3NS2, the seven-membered thia-zepine ring adopts a slightly distorted twist-boat conformation. The mean plane of the five-membered thio-phene ring fused to the thia-zepine ring is twisted by 32.3 (3) and 55.6 (4) degrees from the benzene and phenyl rings, respectively. In the crystal, inversion dimers linked by pairs of weak C-H?N inter-actions are observed. PMID- 24764978 TI - 3-Amino-5,5-di-phenyl-imidazolidine-2,4-dione. AB - The title compound, C15H13N3O2, crystallizes with two independent mol-ecules in the asymmetric unit, which differ considerably in the dihedral angles made between the phenyl groups and the five-membered rings [47.19 (8) and 61.16 (9) degrees in one mol-ecule and 55.04 (10) and 55.00 (8) degrees in the other]. In the crystal, N-H?O hydrogen bonds generate columnar units having approximate fourfold rotational symmetry about axes parallel to b. PMID- 24764979 TI - (E)-Benz-yl(4-{[1-(prop-2-en-1-yl)-1H-1,2,3-triazol-4-yl]meth-oxy}benzyl idene)amine. AB - The triazole ring of the title compound, C20H20N4O, is normal to the central benzene ring, making a dihedral angle of 90.0 (3) degrees , and forms a dihedral angle of 69.2 (3) degrees with the terminal phenyl ring. The dihedral angle between the phenyl and benzene rings is 88.2 (3) degrees . The atoms of the terminal propenyl group are disordered over two sets of sites, with a site occupancy ratio of 0.663 (13):0.337 (13). In the crystal, C-H?N contacts lead to the formation of a layer structure extending parallel to (011). Two weak C-H?pi inter-actions are also observed. PMID- 24764980 TI - Fluoren-9-one oxime. AB - In the title mol-ecule, C13H9NO, the fluorene system and the oxime group non-H atoms are essentially coplanar, with a maximum deviation from the fluorene mean plane of 0.079 (2) A for the oxime O atom. A short intra-molecular C-H?O generates an S(6) ring. In the crystal, mol-ecules related by a twofold screw axis are connected by O-H?N hydrogen bonds, forming [100] chains Within these chains, mol-ecules related by a unit translation along [100] show pi-pi stacking inter-actions between their fluorene ring systems with an inter-planar distance of 3.347 (2) A. The dihedral angle between the fluorene units of adjacent mol ecules along the helix is 88.40 (2) degrees . There is a short C-H?pi contact between the fluorene groups belonging to neighbouring chains. PMID- 24764981 TI - Redetermination of 1,3,6,8-tetra-aza-tri-cyclo-[4.4.1.1(3,8)]dodeca-ne. AB - The structure of the title compound, C8H16N4, which consists of four fused seven membered rings, has been redetermined at 173 K. This redetermination corrects the orientation of two H atoms, which were located at unrealistic positions in the original room-temperature study [Murray-Rust (1974 ?). J. Chem. Soc. Perkin Trans. 2, pp. 1136-1141]. The complete mol-ecule is generated by -42m symmetry, with one quarter of a mol-ecule [one N atom (site symmetry m), two C atoms (one with site symmetry m and the other with site symmetry 2) and two H atoms] in the asymmetric unit. No directional inter-actions beyond van der Waals contacts are apparent in the crystal structure. PMID- 24764982 TI - Santal monohydrate, an isoflavone isolated from Wye-thia mollis. AB - THE TITLE COMPOUND [SYSTEMATIC NAME: 3-(3,4-di-hydroxy-phen-yl)-5-hy-droxy-7-meth oxy-4H-chromen-4-one monohydrate], C16H12O6.H2O, is a monohydrate of a natural product santal isolated from Wye-thia mollis. In the santal mol-ecule, the dihedral angle between the benzo-quinone and di-hydroxy-phenyl fragments is 53.9 (1) degrees and an intra-molecular O-H?O hydrogen bond occurs. In the crystal, O H?O hydrogen bonds link the components into corrugated layers parallel to the ac plane. The short distance of 3.474 (5) A between the centroids of the benzene rings in neighbouring santal mol-ecules reveals then existence of pi-pi inter actions within the layers. PMID- 24764983 TI - 4-Formyl-2-nitro-phenyl benzoate. AB - In the title nitroaryl benzoate derivative, C14H9NO5, the aromatic rings form a dihedral angle of 46.37 (8) degrees . The central ester moiety, -C-(C=O)-O-, is essentially planar (r.m.s. deviation for all non-H atoms = 0.0283 A) and forms a dihedral angle of 54.06 (9) degrees with the 4-formyl-2-nitro-phenyl ring and 7.99 (19) degrees with the benzoate ring. In the crystal, mol-ecules are inter twined by weak C-H?O inter-actions, forming helical chains along [100]. PMID- 24764984 TI - Bis[5-meth-oxy-2-(meth-oxy-carbon-yl)phen-yl] methyl-phospho-nate. AB - In the title phospho-nate, C19H21O9P, the dihedral angle between the benzene rings is 63.33 (3) degrees , and the P atom has a distorted tetra-hedral geometry, with angles in the range 101.30 (6)-120.38 (6) degrees . No significant inter-molecular inter-actions are observed in the crystal structure, and pi-pi inter-actions between symmetry-related benzene rings are beyond 4 A. PMID- 24764985 TI - 1-Piperonylpiperazinium 4-nitro-benzoate monohydrate. AB - IN THE TITLE HYDRATED SALT [SYSTEMATIC NAME: 1-(1,3-benzodioxol-5-ylmeth yl)piperazin-1-ium 4-nitro-benzoate monohydrate], C12H17N2O2 (+).C7H4NO4 (-).H2O, the piperazinium ring of the cation adopts a slightly distorted chair conformation. The piperonyl and piperazine rings are rotated with respect to each other with an N-C-C-C torsion angle of 45.6 (2) degrees . In the anion, the nitro group is almost coplanar with the adjacent benzene ring, forming a dihedral angle of only 3.9 (4) degrees . In the crystal, the cations, anions and water mol ecules are linked through N-H?O and O-H?O hydrogen bonds into chains along the a axis. In addition, weaker inter-molecular C-H?O inter-actions are also observed within the chains. The anions form centrosymmetric couples through pi-stacking inter-actions, with an inter-centroid distance of 3.681 (4) A between the benzene rings. PMID- 24764986 TI - Methyl 3'-benzyl-4'-(2,4-di-chloro-phen-yl)-1'-methyl-2-oxo-1-propyl-spiro [indoline-3,2'-pyrrolidine]-3'-carboxy-l-ate. AB - In the title compound, C30H30Cl2N2O3, the indole ring system is roughly planar, with a maximum deviation of 0.1039 (18) A for the carbonyl C atom, and makes a dihedral angle of 86.61 (9) degrees with the mean plane of the pyrrolidine ring. This spiro pyrrolidine ring adopts an envelope conformation with the N atom at the flap position. The pyrrole ring of the indole ring system adopts a twisted conformation on the C-C(=O) bond. The mol-ecular structure is stabilized by an intra-molecular C-H?O hydrogen bond, which generates an S(6) ring motif, and a pi pi inter-action [centroid-centroid distance = 3.6577 (12) A] involving the 2,4-di chloro-phenyl ring and the benzyl ring. In the crystal, mol-ecules are linked via C-H?O hydrogen bonds, forming C(9) chains running parallel to [10-1]. PMID- 24764987 TI - 2-(4-Fluoro-2-nitro-phen-yl)-4-hy-droxy-9-phenyl-sulfonyl-9H-carbazole-3 carbaldehyde. AB - In the title compound, C25H15FN2O6S, the carbazole ring system is essentially planar, with a maximum deviation of 0.1534 (16) A for the C atom connected to the 4-fluoro-2-nitro-phenyl ring. It is almost orthogonal to the phenyl-sulfonyl and nitro-phenyl rings, making dihedral angles of 88.45 (8) and 79.26 (7) degrees , respectively. The mol-ecular structure is stabilized by O-H?O and C-H?O hydrogen bonds, which generate three S(6) ring motifs. In the crystal, mol-ecules are linked by two C-H?O hydrogen bonds, which generate C(6) and C(9) chains running in the [100] and [010] directions, respectively, so forming a two-dimensional network lying parallel to (001). There are also supra-molecular R 4 (3)(28) graph set ring motifs enclosed within these networks. PMID- 24764988 TI - N,N'-[(2E,3E)-Butane-2,3-diylidene]bis[4-fluoro-2-(1-phenyl-eth-yl)aniline]. AB - The title mol-ecule, C32H30F2N2, a product of the condensation reaction of butane 2,3-dione and 4-fluoro-2-(1-phenyl-eth-yl)aniline, is located about an inversion centre. In the asymmetric unit, the dihedral angle between the planes of the benzene and phenyl rings is 84.27 (5) degrees . Neither hydrogen bonding nor aromatic stacking is observed in the crystal structure. PMID- 24764989 TI - 9-(2,4-Di-fluoro-phen-yl)-3,3,6,6-tetra-methyl-3,4,5,6,7,9-hexa-hydro-2H-xanthene 1,8-dione. AB - In the title compound, C23H24F2O3, the central pyran ring has a flat-boat conformation, whereas the two fused cyclo-hexenone rings adopt envelope conformations, with the C atom bearing the dimethyl substituent being the flap atom in each case. The pyran ring mean plane and the di-fluoro-phenyl ring are almost normal to each other, making a dihedral angle of 87.55 (4) degrees . In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. The F atom at position 2 on the di-fluoro-phenyl ring is disordered over the 2- and 6-positions, and has a refined occupancy ratio of 0.932 (3):0.068 (3). PMID- 24764990 TI - 4-Hy-droxy-3-meth-oxy-benzaldehyde 4-phenyl-thio-semicarbazone. AB - In the title compound, C15H15N3O2S, the central C-N-N-C unit has an anti conformation [torsion angle = -170.17 (15) degrees ]. The phenyl substituent is oriented perpendicular to this unit [dihedral angle of 89.2 (1) degrees ], whereas the substituted ring is rotated out of this plane by only 18.86 (17) degrees . In the crystal, mol-ecules are linked by pairs of N-H?S hydrogen bonds into inversion dimers that are further connected via N-H?O and O-H?S hydrogen bonds into a three-dimensional network. PMID- 24764991 TI - (3aR*,8bR*)-3a,8b-Dihy-droxy-1-(4-methyl-phen-yl)-2-methyl-sulfanyl-3-nitro-1,8b di-hydro-indeno-[1,2-b]pyrrol-4(3aH)-one. AB - The asymmetric unit of the title compound, C19H16N2O5S, contains four independent mol-ecules (A, B, C and D), with two mol-ecules (B and D) displaying disorder in their methyl-sulfanyl groups [occupancy ratios of 0.797 (11):0.203 (11) and 0.85 (2):0.15 (2)]. The nitro groups are twisted slightly out of the planes of the 2 pyrroline rings to which they are bonded with dihedral angles of 10.17 (1), 8.01 (1), 9.44 (1) and 8.87 (1) degrees in mol-ecules A, B, C and D, respectively. The 2-pyrroline rings are almost orthogonal to the attached tolyl rings, forming dihedral angles of 73.44 (1), 81.21 (1), 88.18 (8) and 73.94 (1) degrees for mol ecules A, B, C and D, respectively. A weak intra-molecular O-H?O inter-action is observed in mol-ecules B and C. The two hy-droxy groups in each mol-ecule are involved in inter-molecular O-H?O hydrogen bonding. In the crystal, mol-ecules are connected via O-H?O and C-H?O hydrogen bonds, forming a complex three dimensional network. PMID- 24764992 TI - Methyl 1-phenyl-3-p-tolyl-1,9b-di-hydro-3H-chromeno[4,3-c]isoxazole-3a(4H) carboxyl-ate. AB - In the title compound, C25H23NO4, the pyran ring of the chroman moiety has an envelope conformation with the methyl-ene C atom as the flap. The isoxazole ring has a twist conformation on the O-C bond. The dihedral angle between their mean planes is 57.87 (9) degrees . The attached phenyl and benzene rings are twisted away from its mean plane by 56.19 (10) and 50.57 (10) degrees , respectively. These two rings are normal to each other, subtending a dihedral angle of 89.2 (1) degrees . In the crystal, there are no classical hydrogen bonds; the mol-ecules are linked via C-H?pi inter-actions, forming a two-dimensional network lying parallel to (10-1). PMID- 24764993 TI - 1-Piperonylpiperazinium 4-chloro-benzoate. AB - In the title salt {systematic name: 1-[(1,3-benzodioxol-5-yl)meth-yl]piperazin-1 ium 4-chloro-benzoate}, C12H17N2O2 (+).C7H4ClO2 (-), the piperazine ring adopts a slightly disordered chair conformation. The dioxole ring is in a flattened envelope conformation with the methyl-ene C atom forming the flap. The relative orientation of the piperonyl ring system and the piperazine rings is reflected in the N-C-C C torsion angle of 132.3 (1) degrees . In the anion, the mean plane of the carboxyl-ate group is twisted from that of the benzene ring by 14.8 (9) degrees . In the crystal, the components are linked by N-H?O and weak C-H?O hydrogen bonds, forming chains along [010]. PMID- 24764994 TI - 5-Phenyl-1,2,5-di-thia-zepane. AB - In the title compound, C10H13NS2, the seven-membered ring adopts a chair conformation. The S-S bond length is 2.0406 (5) A and the C-S-S-C torsion angle is -83.89 (7) degrees . The amine group is sp (2)-hybridized. In the crystal, mol ecules are linked into chains along [001] by weak inter-molecular S?S contacts of 3.5246 (5) A. PMID- 24764995 TI - (4-Fluoro-phen-yl)(2-hy-droxy-5-methyl-phen-yl)methanone. AB - In the title compound, C14H11FO2, the dihedral angles beteen the central C3O ketone residue and the fluoro- and hy-droxy-substituted benzene rings are 50.44 (9) and 12.63 (10) degrees , respectively. The planes of the benzene rings subtend a dihedral angle of 58.88 (9) degrees and an intra-molecular O-H?O hydrogen bond closes an S(6) ring. No directional inter-actions beyond van der Waals packing contacts were identified in the crystal structure. PMID- 24764996 TI - 2-[2-(4-Methyl-piperazin-1-yl)eth-yl]iso-indoline-1,3-dione. AB - In the title compound, C15H19N3O2, the piperazine ring adopts a chair conformation, with its N-C bonds in pseudo-equatorial orientations. The dihedral angle between the C atoms of the piperazine ring and the phthalamide ring system (r.m.s. deviaiton = 0.008 A) is 89.30 (8) degrees . In the crystal, mol-ecules are linked by C-H?O hydrogen bonds, generating a three-dimensional network and aromatic pi-pi inter-actions also occur [centroid-centroid distances = 3.556 (1) 3.716 (1) A]. PMID- 24764997 TI - 9-Benzyl-6-benzyl-sulfanyl-9H-purin-2-amine. AB - In the title compound, C19H17N5S, the dihedral angles between the purine ring system (r.m.s. deviation = 0.009 A) and the S-bound and methyl-ene-bound phenyl rings are 74.67 (8) and 71.28 (7) degrees , respectively. In the crystal, inversion dimers linked by pairs of N-H?N hydrogen bonds generate R 2 (2)(8) loops. C-H?N inter-actions link the dimers into (100) sheets. PMID- 24764998 TI - (E)-N-(4-{[1-(Prop-2-en-1-yl)-1H-1,2,3-triazol-4-yl]meth-oxy}benzyl idene)morpholin-4-amine. AB - The asymmetric unit of the title compound, C17H21N5O2, contains two crystallographically independent mol-ecules, which are linked by a C-H?N hydrogen bond. The morpholine rings of both mol-ecules adopt distorted chair conformations. The dihedral angles between the triazole and benzene rings are 12.8 (3) degrees in the first independent molecule in which the -N=C- group between the morpholine and benzene rings is disordered [site-occupancy ratio = 0.576 (7):0.424 (7)] and 88.1 (2) degrees in the second independent mol-ecule. In the crystal, mol-ecules are linked by C-H?N hydrogen bonds along the [100] direction. In addition, one weak C-H?pi inter-action and two weak pi-pi stacking inter-actions [centroid-centroid distances = 3.840 (3) and 3.823 (2) A] between the triazole rings of adjacent mol-ecules are observed. The atoms of the terminal propenyl groups in both mol-ecules are disordered over two sets of sites [site occupancy ratios = 0.691 (10):0.309 (10) and 0.705 (15):0.295 (15)]. PMID- 24764999 TI - 4-[(1,3-Dioxoisoindolin-2-yl)meth-yl]benzene-sulfonamide. AB - The title compound, C15H12N2O4S, is V-shaped with the isoindoline ring system (r.m.s. deviation = 0.006 A) inclined to the benzene ring by 84.27 (13) degrees . In the crystal, inversion dimers are formed via pairwise N-H?O hydrogen bonds. These dimers associate further into corrugated ribbons, via pairwise N-H?O and C H?O hydrogen bonds, propagating along the a-axis direction and lying parallel to (001). PMID- 24765000 TI - 4-Nitro-phthalamide. AB - In the title compound, C8H7N3O4 (systematic name: 4-nitro-benzene-1,2 dicarboxamide), each of the substituents is twisted out of the plane of the benzene ring to which it is attached [dihedral angles of 11.36 (2) degrees for the nitro group, and 60.89 (6) and 34.39 (6) degrees for the amide groups]. The amide groups are orientated to either side of the least-squares plane through the benzene ring with the amine groups being directed furthest apart. In the crystal, a three-dimensional architecture is established by a network of N-H?O hydrogen bonds. PMID- 24765001 TI - 1-(2-Methyl-5-nitro-1H-imidazol-1-yl)propan-2-yl acetate. AB - In the title compound, C9H13N3O4, an ester of the anti-infection drug secnidazole, the dihedral angle between the nitro-imidazole mean plane (r.m.s. deviation = 0.028 A) and the pendant acetate group is 43.17 (11) degrees . In the crystal, inversion dimers linked by pairs of C-H?O inter-actions generate R 2 (2)(10) loops and further C-H?O hydrogen bonds link the dimers into [100] chains. Weak aromatic pi-pi stacking inter-actions with a centroid-centroid distance of 3.7623 (11) A are also observed. PMID- 24765002 TI - 2-Bromo-1-(1-phenyl-sulfonyl-1H-indol-3-yl)propan-1-one. AB - In the title compound, C17H14BrNO3S, the phenyl ring makes a dihedral angle of 89.78 (16) degrees with the plane of the indole ring system. The terminal Br atom and the methyl group are disordered over two sets of sites, with site occupancies of 0.860 (2) and 0.140 (2). In the crystal, mol-ecules are linked into a chain along the b-axis direction by weak C-H?O hydrogen bonds. The chains are further linked by C-H?pi inter-actions, forming layers parallel to the bc plane. PMID- 24765003 TI - 4-Hy-droxy-5-meth-oxy-N,1-dimethyl-2-oxo-N-[4-(tri-fluoro-meth-yl)phen-yl]-1,2-di hydro-quinoline-3-carboxamide. AB - The title compound, C20H17F3N2O4, named tasquinimod, is a second-generation oral quinoline-3-carboxamide analogue, which is currently in phase III clinical trials for the treatment of metastatic prostate cancer. The quinoline unit is almost planar (r.m.s. deviation of fitted atoms = 0.0075 A). The carboxamide side chain, substituted at position 3, is tilted by 88.07 (7) degrees to the quinoline plane. Both the methyl and carbonyl groups of this carboxamide side chain are in a syn conformation. The 4-(tri-fluoro-meth-yl)phenyl plane is inclined at 50.62 (17) degrees to the plane of the carboxamide side chain, and at 87.14 (4) degrees to the plane of the quinoline ring system. The 4-hy-droxy H atom acts as a double proton donor in an intra-molecular hydrogen bond to the 5-position meth oxy O atom and in an inter-molecular contact to the 2-oxo group, generating a chain along [010] in the crystal structure. PMID- 24765004 TI - Methyl 4'-(3-bromo-phen-yl)-3'-(2,5-di-methyl-benz-yl)-1'-methyl-2-oxo-spiro [indo-line-3,2'-pyrrolidine]-3'-carboxyl-ate. AB - In the title compound, C29H29BrN2O3, the indole ring system is essentially planar (r.m.s. deviation = 0.079 A) and makes a dihedral angle of 85.23 (10) degrees with the mean plane of the 4-methyl-pyrrolidine ring. This ring adopts an envelope conformation with the N atom at the flap. The pyrrolidine ring of the indole ring system adopts a twisted conformation on the C-C(=O) bond. The mol ecular structure is stabilized by an intra-molecular C-H?O hydrogen bond, which generates an S(6) ring motif. In the crystal, mol-ecules are linked via pairs of C-H?O hydrogen bonds, forming inversion dimers with an R 2 (2)(14) ring motif. These dimers are further linked by N-H?O and C-H?O hydrogen bonds, forming two dimensional networks lying parallel to (10-1). PMID- 24765005 TI - N-Methyl-2-(1,2,3,4-tetra-hydro-naph-thalen-1-yl-idene)hydrazinecarbo-thio-amide. AB - There are two independent mol-ecules in the asymmetric unit of the title compound, C12H15N3S, both of which display disorder of several C atoms in the N bound ring (occupancy ratios of 0.75:0.25 in the first independent mol-ecule and 0.50:0.50 in the second) with the methyl H atoms also being disordered in the first mol-ecule (occupancy ratio of 0.70:0.30). The planes of the benzene ring and the N-N-C-N fragment make dihedral angles of 12.92 (14) degrees in the first independent mol-ecule and 7.60 (13) degrees in the second. In the crystal, mol ecules are linked by weak N-H?S hydrogen bonds into chains along the a-axis direction. The crystal packing ressembles a herringbone arrangement. PMID- 24765006 TI - N (1),N (4)-Diphenyl-3,6-bis-(phenyl-imino)-cyclo-hexa-1,4-diene-1,4-di-amine. AB - In the title compound, C30H24N4, the central benzo-quinonedi-imine moiety is approximately planar, with a maximum deviation of 0.044 (14) A. The four terminal phenyl rings are twisted by 44.95 (11), 54.90 (10), 44.98 (10) and 50.68 (11) degrees with respect to the mean plane the benzo-quinonedi-imine unit. In the crystal, mol-ecules are linked by weak C-H?pi inter-actions into supra-molecular chains running along the b-axis direction. PMID- 24765007 TI - Dimethyl 2,2'-di-nitro-biphenyl-4,4'-di-carboxyl-ate. AB - The title compound, C16H12N2O8, exhibits two near-planar aromatic ester groups with ar-yl-ester dihedral angles of 2.1 (2) and 4.2 (3) degrees . The dihedral angle between the aromatic rings is 58.0 (1) degrees . The two nitro groups are tilted slightly from the plane of the aromatic rings, making dihedral angles of 14.1 (1) and 8.2 (2) degrees . In the crystal, mol-ecules are connected by weak C H?O inter-actions, forming a three-dimensional network. PMID- 24765008 TI - Methyl 4-(4-hy-droxy-phen-yl)-6-methyl-2-sulfanyl-idene-1,2,3,4-tetra-hydro pyrimidine-5-carboxyl-ate. AB - In the title mol-ecule, C13H14N2O3S, the di-hydro-pyrimidine ring is in a flattened sofa conformation, with the methine C atom forming the flap. The dihedral angle between the mean plane of the five essentially planar atoms of the di-hydro-pyrimidine ring [maximum deviation = 0.056 (4) A] and the benzene ring is 89.4 (2) degrees . The O atom of the carbonyl group is in a trans conformation with respect to the C=C bond of the di-hydro-pyrimidine ring. In the crystal, N H?O and O-H?S hydrogen bonds connect mol-ecules, forming a two-dimensional network parallel to (001). PMID- 24765009 TI - Ethyl 3-[7-(N-acetyl-4-meth-oxy-benzene-sulfonamido)-3-chloro-2H-indazol-2 yl]propionate. AB - In the title compound, C21H22ClN3O6S, the fused five- and six-membered ring rings are almost perpendicular to the planes through the atoms forming the acetyl and the propionic ester groups, as indicated by the dihedral angles of 80.3 (2) and 88.3 (7) degrees , respectively. The dihedral angle between the indazole system and the 4-meth-oxy-benzene-sulfonyl group is 13.76 (6) degrees . The carbonyl O atom is split over two positions in a 0.60 (5):0.40 (5) ratio. In the crystal, mol-ecules are linked by C-H?O and C-H?N inter-actions into a three-dimensional network. PMID- 24765010 TI - 3-(3-Bromo-phenyl-sulfin-yl)-5-cyclo-hexyl-2-methyl-1-benzo-furan. AB - In the title compound, C21H21BrO2S, the cyclo-hexyl ring adopts a chair conformation. The dihedral angle between the mean plane [r.m.s. deviation = 0.178 (2) A] of the benzo-furan ring system and the mean plane of the 3-bromo-phenyl ring is 86.52 (6) degrees . In the crystal, mol-ecules are linked by weak C-H?O and C-H?pi hydrogen bonds, and by a slipped pi-pi inter-action between the furan rings of neighbouring mol-ecules [centroid-centroid distance = 3.518 (3) A, inter planar distance = 3.471 (3) A and slippage = 0.573 (3) A], resulting in a three dimensional network. PMID- 24765011 TI - 5-Bromo-3-cyclo-hexyl-sulfinyl-2,4,6-trimethyl-1-benzo-furan. AB - In the title compound, C17H21BrO2S, the cyclo-hexyl ring adopts a chair conformation and the aryl-sulfinyl unit is positioned equatorially relative to the cyclo-hexyl group. The benzo-furan unit is essentially planar, with an r.m.s. deviation of 0.016 (2) A. In the crystal, mol-ecules are linked by weak C-H?O, C H?pi and Br?pi [3.663 (2) A] inter-actions, resulting in a three-dimensional network. A Br?Br [3.6838 (6) A] contact is observed. The O atom of the sulfinyl group is disordered over two orientations with an occupancy ratio of 0.863 (5):0.137 (5). PMID- 24765012 TI - r-1,t-3-Bis[4-(di-methyl-amino)-phen-yl]-c-2,t-4-bis-(pyridin-4-yl)cyclo-butane. AB - The title compound, C30H32N4, was synthesized by the photodimerization of trans-4 {2-[4-(di-methyl-amino)-phen-yl]ethen-yl}pyridine in benzene upon irradiation with UV light. This photodimer has a puckered cyclo-butane ring with the four aryl substituents in an r-1,t-2,c-3,t conformation. The puckering angle of the cyclo-butane ring is 32.22 (7) degrees , which is the largest among reported tetra-aryl-substituted cyclo-butanes. In the crystal, the mol-ecules form a hollow, one-dimensional structure extending parallel to the c axis via two different pairs of C-H?pi inter-actions. PMID- 24765013 TI - (Di-methyl-phosphor-yl)methanaminium hydrogen oxalate-oxalic acid (2/1). AB - The reaction of (di-methyl-phosphor-yl)methanamine (dpma) with oxalic acid in ethanol yielded the title solvated salt, C3H11NOP(+).C2HO4 (-).0.5C2H2O4. Its asymmetric unit consists of one dpmaH(+) cation, one hydrogen oxalate anion and a half-mol-ecule of oxalic acid located around a twofold rotation axis. The H atom of the hydrogen oxalate anion is statistically disordered over two positions that are trans to each other. The hydrogen oxalate monoanion is not planar (bend angle ~16 degrees ) whereas the oxalic acid molecule shows a significantly smaller bend angle (~7 degrees ). In the crystal, the components are connected by strong O-H?O and much weaker N-H?O hydrogen bonds, leading to the formation of layers extending parallel to (001). The structure was refined from a racemically twinned crystal with twin components in an approximate 1:1 ratio. PMID- 24765014 TI - 2-((E)-{4-[Bis(4-eth-oxy-phen-yl)amino]-phen-yl}imino-meth-yl)phenol. AB - In the title Schiff base mol-ecule, C29H28N2O3, the three terminal benzene rings are twisted by 73.84 (15), 81.25 (16) and 12.1 (2) degrees with respect to the central benzene ring. An intra-molecular O-H?N hydrogen bond occurs. In the crystal, mol-ecules are linked via weak C-H?pi inter-actions into a three dimensional supra-molecular architecture. PMID- 24765015 TI - 2-{(E)-[4-(Di-phenyl-amino)-phen-yl]imino-meth-yl}phenol. AB - The asymmetric unit of the title Schiff base molecule, C25H20N2O, contains two independent mol-ecules. In each mol-ecule, the C=N bond is in an E conformation. The most significant difference between the two mol-ecules is seen for the dihedral angles between the meth-oxy-substituted benzene ring and the two phenyl rings, which are 85.5 (1) and 82.3 (1) degrees in the first mol-ecule, and 49.0 (1) and 40.4 (1) degrees in the second. This conformational difference is reflected in the central C=N-C C torsion angle, which is 28.7 (2) degrees in the first mol-ecule and -29.8 (3) degrees in the other. In each mol-ecule, there is an intra-molecular O-H?N hydrogen bond. PMID- 24765016 TI - Ethyl 3-(9-chloro-10-oxo-9,10-di-hydro-anthracen-9-yl)-5-methyl-isoxazole-4 carboxyl-ate. AB - The asymmetric unit of the title compound, C21H16ClNO4, contains two independent mol-ecules (A and B), each adopting a conformation wherein the isoxazole ring is roughly orthogonal to the anthrone ring. The dihedral angle between the mean plane of the isoxazole (all atoms) and the mean plane of the anthrone (all atoms) is 88.48 (3) degrees in one mol-ecule and 89.92 (4) degrees in the other. The ester is almost coplanar with the isoxazole ring, with mean-plane dihedral angles of 2.48 (15) and 8.62 (5) degrees . In both mol-ecules, the distance between the ester carbonyl O atom and the anthrone ketone C atom is about 3.3 A. The anthrone ring is virtually planar (r.m.s. deviations of 0.070 and 0.065 A) and adopts a shallow boat conformation in each mol-ecule, as evidenced by the sum of the six intra-B-ring torsion angles [41.43 (15) and 34.38 (15) degrees for molecules A and B, respectively]. The closest separation between the benzene moieties of anthrones A and B is 5.1162 (7) A, with an angle of 57.98 (5) degrees , consistent with an edge-to-face pi-stacking inter-action. In the crystal, weak C H?O and C-H?N inter-actions link the mol-ecules, forming a three-dimensional network. PMID- 24765017 TI - (4bS,8aS)-1-Isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octa-hydro-phenan-thren 2-yl acetate. AB - The hemisynthesis of the title compound, C22H32O2, was carried out through direct acetyl-ation reaction of the naturally occurring diterpene totarol [systematic name: (4bS,8aS)-4b,8,8-trimethyl-1-propan-2-yl-5,6,7,8a,9,10-hexa-hydro-phen-an thren-2-ol]. The mol-ecule is built up from three fused six membered rings, one saturated and two unsaturated. The central unsaturated ring has a half-chair conformation, whereas the other unsaturated ring displays a chair conformation. The absolute configuration is deduced from the chemical pathway. The value of the Hooft parameter [-0.10 (6)] allowed this absolute configuration to be confirmed. PMID- 24765018 TI - 3-(1H-Imidazol-1-yl)propanaminium 2-carb-oxy-4,6-di-nitro-phenolate. AB - In the title salt, C6H12N3 (+).C7H3N2O7 (-), the imidazole ring is planar, with a maximum deviation of 0.0013 (14) A for the N attached to the propanaminium group. In the anion, a single intra-molecular O-H?O hydrogen bond is observed. The mean planes of the nitro groups in the anion are twisted from the benzene ring mean plane making dihedral angles of 24.7 (9) and 3.9 (6) degrees . In the crystal, the ammonium H atoms form N-H?N and N-H?O hydrogen bonds, resulting in an infinite chain along [111]. In addition to the classical hydrogen bonds, weak C H?O and pi-pi [centroid-centroid distance = 3.7124 (9) A] inter-actions are also observed, which lead to the formation a three-dimensional supramolecular structure that links the chains into layers along the bc plane. PMID- 24765019 TI - 5-Bromo-2-methyl-3-(3-methyl-phenyl-sulfin-yl)-1-benzo-furan. AB - In the title compound, C16H13BrO2S, the dihedral angle between the mean plane [r.m.s. deviation = 0.012 (1) A] of the benzo-furan ring system and the 3-methyl phenyl ring is 84.83 (4) degrees . In the crystal, mol-ecules are linked via pairs of Br?O [3.240 (1) A] contacts, forming inversion dimers. These dimers are linked by C-H?pi inter-actions, forming a three-dimensional network. PMID- 24765020 TI - 2,9-Bis(5-sulfanylidene-4,5-di-hydro-1,3,4-oxa-diazol-2-yl)-1,10-phenanthroline dimethyl sulfoxide disolvate. AB - In the title compound, C16H8N6O2S2.2C2H6OS, the phenanthroline mol-ecule resides on a twofold axis, and the asymmetric unit also contains a slightly disordered [occupancy ratio for S atom of 0.95 (3):0.047 (3)] mol-ecule of dimethyl sulfoxide. The O atoms of the solvent mol-ecule accept hydrogen bonds from the N H groups of the five-membered 2,3-di-hydro-1,3,4-oxa-diazole-2-thione ring. This ring is nearly coplanar with the phenanthroline ring, with a dihedral angle between their least-squares planes of 8.86 (6) degrees . In the crystal, the mol ecules are linked by C-H?O inter-actions. PMID- 24765021 TI - 4-Nitro-phthalo-nitrile. AB - In the title compound, C8H3N3O2 (systematic name: 4-nitro-benzene-1,2-dicarbo nitrile), the nitro group is twisted out of the plane of the benzene ring to which it is attached [O-N-Cring-Cring torsion angle = 9.80 (13) degrees ]. In the crystal packing, supra-molecular layers with a zigzag topology in the ac plane are sustained by C-H?N inter-actions. PMID- 24765022 TI - 3-(2-Bromo-phenyl-sulfon-yl)-5-cyclo-hexyl-2-methyl-1-benzo-furan. AB - In the title compound, C21H21BrO3S, the cyclo-hexyl ring adopts a chair conformation. The dihedral angle between the mean planes of the benzo-furan and 2 bromo-phenyl fragments is 82.47 (5) degrees . In the crystal, mol-ecules related by inversion are paired into dimers via C-H?pi and pi-pi inter-actions, the latter are indicated by the short distance of 3.607 (3) A between the centroids of the furan rings. Inter-molecular C-H?O hydrogen bonds and short Br?O [3.280 (1) A] contacts further consolidate the crystal packing. PMID- 24765023 TI - 3-Methyl-4,5-di-hydro-oxazolium tetra-phenyl-borate. AB - In the cation of the title salt, C4H8NO(+).C24H20B(-), the C-N bond lengths are 1.272 (2), 1.4557 (19) and 1.4638 (19) A, indicating double- and single-bond character, respectively. The C-O bond length of 1.3098 (19) A shows that double bond character and charge delocalization occurs within the NCO plane of the cation. In the crystal, a C-H?pi inter-action is present between the methyl-ene H atom of the cation and one phenyl ring of the tetra-phenyl-borate ion. The latter forms an aromatic pocket in which the cation is embedded. PMID- 24765024 TI - 1-Methyl-piperazine-1,4-dium bis-(hydrogen oxalate). AB - In the crystal structure of the title compound, C5H14N2 (2+).2HC2O4 (-), the two crystallographically independent hydrogen oxalate anions are linked by strong inter-molecular O-H?O hydrogen bonds, forming two independent corrugated chains parallel to the b axis. These chains are further connected by N-H?O and C-H?O hydrogen bonds originating from the organic cations, forming a three-dimensional network. The diprotonated piperazine ring adopts a chair conformation, with the methyl group occupying an equatorial position. PMID- 24765025 TI - 2-((1E)-1-{2-[(2Z)-4-(4-Bromo-phen-yl)-3-phenyl-2,3-di-hydro-1,3-thia-zol-2-yl idene]hydrazin-1-yl-idene}eth-yl)pyridin-1-ium bromide monohydrate. AB - In the title hydrated molecular salt, C22H18BrN4S(+).Br(-).H2O, the aromatic rings make dihedral angles of 14.20 (12), 34.29 (10) and 68.75 (11) degrees with the thia-zole ring. In the crystal, mol-ecules are linked into chains running parallel to the a axis by association of the bromide ions and the water mol ecules of crystallization with the cations via N-H?O, O-H?Br, C-H?N and C-H?Br hydrogen-bonding inter-actions. C-H?pi and C-Br?pi [3.7426 (11) A, 161.73 (7) degrees ] inter-actions are also observed, forming infinite chains extending along the b-axis direction. PMID- 24765026 TI - 9-(4-Bromo-phen-yl)-9H-carbazole. AB - In the title mol-ecule, C18H12BrN, the 4-bromo-phenyl ring is inclined to the mean plane of the carbazole moiety (r.m.s. devation = 0.027 A) by 49.87 (5) degrees . In the crystal, molecules stack along [001] and are linked by C-H?pi interactions forming a corrugated two-dimensional network lying parallel to (100). PMID- 24765027 TI - N-[2-(9H-Carbazol-9-yl)eth-yl]-4-(methyl-sulfon-yl)aniline. AB - In the title mol-ecule, C21H20N2O2S, the dihedral angle between the mean plane of the carbazole ring system [maximum deviation = 0.021 (4) A] and the benzene ring is 80.15 (6) degrees . In the crystal, mol-ecules are linked by N-H?O and weak C H?O hydrogen bonds into a C(8) chain along [001]. PMID- 24765028 TI - (Meth-oxy-methyl-idene)di-methyl-aza-nium tetra-phenyl-borate aceto-nitrile monosolvate. AB - In the cation of the title salt, C4H10NO(+).C24H20B(-).C2H3N, the C-N bond lengths are 1.2864 (16), 1.4651 (17) and 1.4686 (16) A, indicating double- and single-bond character, respectively. The C-O bond length of 1.2978 (15) A shows double-bond character, pointing towards charge delocalization within the NCO plane of the iminium ion. C-H?pi inter-actions are present between the methine H atom and two of the phenyl rings of the tetra-phenyl-borate ion. The latter forms an aromatic pocket in which the cation is embedded. The iminium ion is further connected through a C-H?N hydrogen bond to the aceto-nitrile mol-ecule. This leads to the formation of a two-dimensional supramolecular pattern along the bc plane. PMID- 24765029 TI - 1-Methyl-3-phenyl-imidazolidine-2-thione. AB - The asymmetric unit of the title cyclic thio-urea derivative, C10H12N2S, comprises two mol-ecules, each of which has a twist about the CH2-CH2 bond within the five-membered ring. The major difference between the independent mol-ecules is manifested in the relative orientations of the five- and six-membered rings [dihedral angles between the least-squares planes = 28.03 (11) and 41.54 (11) degrees ]. A network of C-H?pi inter-actions consolidates the three-dimensional crystal packing. PMID- 24765030 TI - Methyl 3'-benzyl-4'-(2,4-di-chloro-phen-yl)-1'-methyl-2-oxo-spiro-[indoline-3,2' pyrrolidine]-3'-carboxyl-ate. AB - In the title compound, C27H24Cl2N2O3, the indole ring system is essentially planar, with a maximum deviation of 0.082 (2) A for the carbonyl C atom. It makes a dihedral angle of 88.53 (6) degrees with the mean plane of the 4-methyl pyrrolidine ring, which adopts an envelope conformation with the N atom at the flap position. The mol-ecular structure is stabilized by intra-molecular C-H?O hydrogen bonds, which generate S(6) and S(7) ring motifs, and an intra-molecular pi-pi inter-action involving the benzyl and di-chloro-substituted benzene rings [centroid-centroid distance = 3.6291 (11) A]. In the crystal, mol-ecules are linked via N-H?O hydrogen bonds, forming C(7) chains running parallel to [10-1]. PMID- 24765031 TI - 2-(4,5-Dimeth-oxy-2-nitro-phen-yl)-4-meth-oxy-3-methyl-9-phenyl-sulfonyl-9H carbazole. AB - In the title compound, C28H24N2O7S, the carbazole system is essentially planar, with a maximum deviation of 0.0644 (19) A for the C atom connected to the 4,5 dimeth-oxy-2-nitro-phenyl group. The dihedral angle between the carbazole moiety and the dimethoxy-substituted nitrophenyl ring is 58.55 (7) degrees . The sulfonyl group forms two intra-molecular C-H?O bonds with the adjacent carbazole system, forming two cyclic S(6) motifs. In the crystal, mol-ecules are linked along the a axis in bands consisting of cyclic R 3 (3)(15) motifs through two further C-H?O hydrogen bonds. PMID- 24765032 TI - Methyl 1-benzyl-5-methyl-2,4-diphenyl-1H-pyrrole-3-carboxyl-ate. AB - In the title compound, C26H23NO2, the dihedral angles between the pyrrole ring and the two phenyl rings are 58.1 (6) and 71.5 (5) degrees . The mean planes of the 5-methyl-benzene ring and the carboxyl group are twisted by 89.5 (3) and 22.1 (9) degrees , respectively, from the pyrrole ring. In the crystal, weak C-H?O inter-actions lead to supra-molecular layers in the ab plane. PMID- 24765033 TI - 4-Thio-carbamoylpyridin-1-ium iodide. AB - The title salt, C6H7N2S(+).I(-), crystallizes with two independent cations and two anions in the asymmetric unit. In one of the cations, the dihedral angle between the pyridinium ring and the thioamide group is 28.9 (2) degrees ; in the other it is 33.5 (2) degrees . In the crystal, N-H?S and C-H?S hydrogen bonds link the independent cations into pairs. These pairs form a three-dimensional network through additional N-H?I and C-H?I hydrogen bonds to the anions. PMID- 24765034 TI - Tetra-kis(2-amino-5-chloro-pyridinium) di-hydrogen cyclo-hexa-phosphate. AB - In the crystal structure of the title compound, 4C5H6ClN2 (+).H2P6O18 (4-), the [H2P6O18](4-) anions are interconnected by O-H?O hydrogen bonds, leading to the formation of infinite ribbons extending along the a-axis direction. These ribbons are linked to the organic cations, via N-H?O and C-H?O hydrogen bonds, into a three-dimensional network. The six P atoms of the [H2P6O18](4-) anion form a chair conformation. The complete cyclohexaphosphate anion is generated by inversion symmetry. PMID- 24765035 TI - 4-Bromo-N-(2-nitro-phen-yl)benzamide. AB - The title nitro-phenyl benzamide, C13H9BrN2O3, with two mol-ecules in the asymmetric unit, has dihedral angles of 16.78 (15) and 18.87 (14) degrees between the benzene rings. An intra-molecular N-H?O hydrogen bond is observed in each mol-ecule. In the crystal, the molecules are linked by weak C-H?O inter actions; halogen-halogen inter-actions are also observed [Br?Br = 3.4976 (7) A]. These inter-actions form R (2) 2(10), R (2) 2(15) and R (6) 6(32) edge-fused rings along [010]. PMID- 24765036 TI - 2,5-Bis{[(-)-(S)-1-(4-bromo-phen-yl)eth-yl]imino-meth-yl}thio-phene. AB - The title compound, C22H20Br2N2S, was synthesized under solvent-free conditions. The mol-ecule shows crystallographic C 2 symmetry, with the S atom of the central thio-phene ring lying on a twofold rotation axis. Furthermore, as a consequence of the (S,S) stereochemistry, the mol-ecule has a twisted conformation. The dihedral angle between the thio-phene and benzene rings is 72.7 (2) degrees and that between the two benzene rings is 55.9 (2) degrees . In the crystal, mol ecules are arranged in a chevron-like pattern, without any significant inter molecular inter-actions. PMID- 24765037 TI - (4,9-Dimethyl-9H-carbazol-3-yl)meth-anol. AB - In the title compound, C15H15NO, the carbazole skeleton includes a methanol group at the 3-position. The indole ring system is almost planar [maximum deviation = 0.045 (2) A]. In the crystal, O-H?O hydrogen bonds link the mol-ecules into zigzag chains along the b-axis direction. There are weak C-H?pi inter-actions within the chains and linking neighbouring chains forming sheets lying parallel to (001). PMID- 24765038 TI - Bis(2-amino-5-benzyl-3-eth-oxy-carbonyl-4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin 5-ium) bis-(4-meth-oxy-phen-yl)di-phos-phon-ate. AB - The asymmetric unit of the title salt, 2C17H21N2O2S(+).C14H14O7P2 (2-), contains half of a centrosymmetric bis-(4-meth-oxy-phen-yl)di-phospho-nate anion and one 2 amino-5-benzyl-3-eth-oxy-carbonyl-4,5,6,7-tetra-hydro-thieno[3,2-c]pyri-din-5-ium cation. In the anion, the O atoms of the di-phospho-nate group are disordered over two positions with equal occupancies. In the cation, the ethyl group is disordered over two orientations with a refined occupancy ratio of 0.753 (5):0.247 (5), and the tetra-hydro-pyridinium ring adopts a distorted half-chair conformation. In the crystal, the ions are linked by C-H?O, N-H?O and C-H?S hydrogen bonds into a three-dimensional network. PMID- 24765039 TI - Benzotriazolium 4-methyl-benzene-sulfonate. AB - In the title molecular salt, C6H6N3 (+).C7H7O3S(-), the components are linked by N-H?O hydrogen bonds into zigzag chains along [100]. These chains are further connected by weak C-H?O, C-H?pi and pi-pi (centroid-to-centroid distances = 3.510, 3.701 and 3.754 A) inter-actions into a three-dimensional network. PMID- 24765040 TI - 2,2-Dimethyl-N-(4-methyl-pyridin-2-yl)propanamide. AB - In the title compound, C11H16N2O, the dihedral angle between the mean plane of the 4-methypyridine group and the plane of the amide link is 16.7 (1) degrees , and there is a short intra-molecular C-H?O contact. Hydrogen bonding (N-H?O) between amide groups forms chains parallel to the b axis. Pairs of methyl pyridine groups from mol-ecules in adjacent chains are parallel but there is minimal pi-pi inter-action. PMID- 24765041 TI - Methyl-phospho-nic acid, CH3PO(OH)2. AB - The asymmetric unit of the title compound, CH5O3P, contains two independent mol ecules with nearly identical bond lengths and angles. In the crystal, each of the mol-ecules acts as acceptor (P=O) and donor (P-OH) of four hydrogen bonds to three adjacent mol-ecules, resulting in the formation of two different bilayers (one for each mol-ecule) stacked perpendicular to the a axis in the crystal. PMID- 24765042 TI - [2-Benzyl-3-(naphthalen-1-yl)-2,3-di-hydro-1,2-oxazole-4,5-di-yl]bis-(phenyl methanone). AB - In the title compound, C34H25NO3, the five-membered heterocyclic ring adopts an envelope conformation with the N atom as the flap. The plane through the four basal atoms of this ring makes dihedral angles of 69.78 (13), 53.15 (12) and 86.42 (13) degrees , respectively, with the benzene rings of the benzyl group and the two phenyl-methanone groups at the 4 and 5 positions, and of 78.60 (11) degrees with the naphthalenyl system. In the crystal, the mol-ecules are linked through C-H?O and C-H?pi contacts into layers parallel to (101). PMID- 24765043 TI - N'-[(E)-(Furan-2-yl)methyl-idene]-2-[4-(2-methyl-prop-yl)phen-yl]propano hydrazide. AB - In the title mol-ecule, C18H22N2O2, the furan and benzene rings form a dihedral angle of 70.17 (14) degrees . In the crystal, strong N-H?O and weak C-H?O hydrogen bonds link the mol-ecules into chains running parallel to [010]. PMID- 24765044 TI - 5-((Meth-oxy-imino)-{2-[(2-methyl-phen-oxy)meth-yl]phen-yl}meth-yl)-N-phenyl 1,3,4-oxa-diazol-2-amine. AB - In the title mol-ecule, C24H22N4O3, the plane of the oxa-diazole ring forms a dihedral angle of 32.41 (12) degrees with that of the phenyl ring and dihedral angles of 74.51 (10) and 56.38 (10) degrees with the planes of the benzene rings. In the crystal, pairs of N-H?N hydrogen bonds link molecules into inversion dimers featuring R 2 (2)(8) graph-set motifs. PMID- 24765045 TI - 2-Cyclo-heptyl-idene-N-phenyl-hydrazine-carbo-thio-amide. AB - In the title compound, C14H19N3S, the seven-membered cyclo-heptane ring adopts a chair conformation. An intra-molecular N-H?N hydrogen bond [graph-set motif S(5)] is present in the N-N-C-N chain between the ring systems. An intra-molecular C H?S contact also occurs. In the crystal, pairs of mol-ecules form centrosymmetric dimers through N-H?S hydrogen bonds [graph-set R 2 (2)(8)]. These dimers are connected by C-H?S inter-actions with an R 2 (2)(14) motif. PMID- 24765046 TI - 1-(Prop-2-yn-yl)indoline-2,3-dione. AB - The structure of the title compound, C11H7NO2, is isotypic to that of its homologue, 1-octylindoline-2,3-dione [Qachchachi et al. (2013 ?). Acta Cryst. E69, o1801]. The indoline ring and the two carbonyl O atoms are approximately coplanar, the largest deviation from the mean plane being 0.021 (1) A for one of the O atoms. The mean plane through the fused ring system is nearly perpendicular to the propynyl group, as indicated by the N-C-C-C torsion angle of 77.9 (1) degrees . In the crystal, mol-ecules are linked by C-H?O hydrogen bonds and pi-pi inter-actions between benzene rings [inter-centroid distance = 3.5630 (10) A], forming a three-dimensional structure. PMID- 24765047 TI - 3-(2,3-Dioxoindolin-1-yl)propane-nitrile. AB - The asymmetric unit of the title compound, C11H8N2O2, contains two independent mol-ecules (A and B). Each mol-ecule is build up from fused five- and six membered rings with the former linked to a cyano-ethyl group. The indoline ring and two carbonyl O atoms of each mol-ecule are nearly coplanar, with the largest deviations from the mean planes being 0.0198 (9) (mol-ecule A) and 0.0902 (9) A (mol-ecule B), each by a carbonyl O atom. The fused ring system is nearly perpendicular to the mean plane passing through the cyano-ethyl chains, as indicated by the dihedral angles between them of 69.72 (9) (mol-ecule A) and 69.15 (9) degrees (mol-ecule B). In the crystal, mol-ecules are linked by C-H?O and pi-pi [inter-centroid distance between inversion-related indoline (A) rings = 3.6804 (7) A] inter-actions into a double layer that stacks along the a-axis direction. PMID- 24765048 TI - 4-[(1-Benzyl-1,2,3-triazol-5-yl)meth-yl]-2H-1,4-benzo-thia-zin-3(4H)-one. AB - The asymmetric unit of the title compound, C18H16N4OS, contains two independent mol-ecules of similar conformation, the most relevant difference being the dihedral angle formed by the benzene rings [57.8 (2) and 52.7 (2) degrees ]. The six-membered heterocycle of the benzo-thia-zine fragment exhibits a screw-boat conformation in both mol-ecules. The plane through the triazole ring is nearly perpendicular to those through the fused and terminal benzene rings [dihedral angles of 74.2 (2) and 83.2 (2) degrees in one mol-ecule, and 77.8 (2) and 82.9 (2) degrees in the other]. In the crystal, mol-ecules are linked by C-H?N and C H?O hydrogen bonds into chains parallel to the a-axis direction. The crystal used was a non-merohedral twin, the refined ratio of twin components being 0.85 (10):15 (10). PMID- 24765049 TI - 5,6-Dimethyl-2-(pyridin-2-yl)-1-[(pyri-din-2-yl)meth-yl]-1H-benzimidazole. AB - The title compound, C20H18N4, was obtained via the condensation of 4,5-di-methyl benzene-1,2-di-amine with pyridine-2-carbaldehyde. The plane of the 2-(pyridin-2 yl) substitutent is canted by 2.75 (11) degrees from the plane of the benzimidazole system. The mol-ecule exhibits an S(6) C-H?N intra-molecular hydrogen-bond motif. In the crystal, C-H?N hydrogen bonds link pairs of mol ecules related by a crystallographic inversion center, forming R 2 (2)(20) rings. Additional weak C-H?N hydrogen bonds result in C(9) chains parallel to [001]. PMID- 24765050 TI - Methyl (2Z)-2-{(2Z)-3-[(cyclo-pentyl-idene)amino]-4-oxo-2-phenyl-imino-1,3-thia zol-idin-5-yl-idene}acetate. AB - In the title compound, C17H17N3O3S, the thia-zole ring is nearly planar [maximum deviation = 0.015 (1) A for the ring N atom] and the cyclo-pentane ring has a twist conformation. The mol-ecular conformation is stabilized by a hypervalent inter-action between the S atom and the ester group carbonyl O atom, with an S?O distance of 2.7931 (10) A. In the crystal, C-H?O inter-actions generate chains of mol-ecules propagating along [110] and pi-pi stacking inter-actions [centroid centroid distance = 3.4677 (7) A] between the thia-zole rings organize these chains into (001) layers. PMID- 24765051 TI - 1-(3,4-Di-meth-oxy-phen-yl)-3-phenyl-prop-2-en-1-one. AB - In the title compound, C17H16O3, the dihedral angle between the mean planes of the benzene rings is 57.1 (1) degrees . The mean plane of the ketone group is twisted by 10.0 (5) degrees from that of the di-meth-oxy-phenyl ring. The two di meth-oxy-phenyl groups are twisted slighly from the mean plane of the phenyl ring, with C-O-C-C torsion angles of 6.4 (2) and -7.9 (2) degrees [r.m.s. deviations = 0.15 (3) and 0.18 (3) A for the two methoxy C atoms]. In the crystal, weak centroid-centroid pi-pi stacking inter-actions, with inter-centroid distances of 3.8939 (11) and 3.9430 (10) A are observed. PMID- 24765052 TI - 1-[3-(Morpholin-4-yl)prop-yl]-4-(3-nitro-phen-yl)spiro-[azetidine-3,9'-xanthen]-2 one. AB - The beta-lactam (azetidin-2-one) ring of the title compound, C28H27N3O5, is nearly planar [maximum deviation = 0.010 (1) A] and makes dihedral angles of 75.77 (5), 52.78 (9) and 88.72 (5) degrees , respectively, with the benzene ring, the least-squares plane formed by the four C atoms of the morpholine ring, which adopts a chair conformation, and the xanthene ring system. In the crystal, C-H?O hydrogen-bond contacts connect neighbouring mol-ecules into infinite zigzag chains running parallel to the b axis. PMID- 24765053 TI - Dimethyl 2-nitro-biphenyl-4,4'-di-carboxyl-ate. AB - The title compound, C16H13NO6, exhibits a biphenyl unit with a dihedral angle between the two aryl rings of 56.01 (5) degrees . The two ester groups vary slightly from planarity, with ar-yl-ester dihedral angles of 4.57 (5) and 16.73 (5) degrees . The nitro group is turned from the aromatic unit with an ar-yl nitro dihedral angle of 48.66 (4) degrees . In the crystal, mol-ecules are connected by weak C-H?O inter-actions, forming a three-dimensional network. PMID- 24765054 TI - Monosuccinate ester of melampomagnolide B. AB - THE TITLE MONOSUCCINATE DERIVATIVE OF MELAMPOMAGNOLIDE B [SYSTEMATIC NAME: 4 (((1aR,7aS,10aS,10bS,E)-1a-methyl-8-meth-yl-ene-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b deca-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2-b]furan-5-yl)meth-oxy)-4-oxo-butan oic acid], C19H24O7, was obtained from the reaction of melampomagnolide B with succinic anhydride under nucleophilic addition reaction conditions. The mol-ecule is built up from fused ten-, five- (lactone) and three-membered (epoxide) rings. The inter-nal double bond in the ten-membered ring has the cis geometry (i.e. it is the E isomer). The lactone ring has an envelope-type conformation, with the (chiral) C atom opposite the lactone O atoms as the flap atom. In the crystal, O H?O hydrogen bonds link the mol-ecules into chains parallel to the b-axis direction. PMID- 24765055 TI - Diphen-yl[(phenyl-sulfan-yl)meth-yl]-lambda(5)-phosphane-thione. AB - The title compound, C19H17PS2, results from the direct deprotonation of di-phenyl methyl-phosphine sulfide and subsequent reaction with diphenyl di-sulfide. The C P and C-S bond lengths of 1.8242 (18) and 1.8009 (18) A, respectively, of the central P-C-S linkage are comparable to those found in the sulfonyl analogue, but are considerably longer than those reported for the dimetallated sulfonyl compound. The dihedral angle between the benzene rings of the di-phenyl-methyl moiety is 69.46 (7) degrees . No distinct inter-molecular inter-actions are present in the crystal structure. PMID- 24765056 TI - 6-(4-Fluoro-phen-yl)-3-phenyl-7H-1,2,4-tri-azolo[3,4-b][1,3,4]thia-diazine. AB - In the title compound, C16H11FN4S, the dihedral angles between the triazole ring and the phenyl and fluoro-benzene rings are 23.22 (17) and 18.06 (17) degrees , respectively. The six-membered heterocyclic ring adopts a distorted envelope conformation, with the methyl-ene C atom as the flap. In the crystal, the mol ecules are linked by two C-H?N and C-H?F inter-actions along [010], forming C(5), C(8) and C(13) chains repectively. C-H?pi inter-actions involving the phenyl ring and pi-pi inter-actions [centroid-centroid separation for triazole rings = 3.5660 (18) A] are also observed. PMID- 24765057 TI - Tetra-kis(2,3,5,5-tetra-methyl-hexen-2-yl)silane. AB - In the title compound, C40H76Si, the Si atom is located on a special position of site symmetry -4. Thus, there is just a quarter of a mol-ecule in the asymmetric unit. The C=C double bonds exhibit a trans configuration. The Si atom and the tert-butyl group are located on the same side of the plane formed by the C=C double bond and its four substituents. The crystal packing shows no short contacts between the mol-ecules and despite the low crystal density (0.980 Mg m( 3)), there are no significant voids in the structure. PMID- 24765058 TI - Methyl 3'-(2,5-di-methyl-benz-yl)-1'-methyl-2-oxo-4'-phenyl-spiro-[indoline-3,2' pyrrolidine]-3'-carboxyl-ate chloro-form monosolvate. AB - In the title solvate, C29H30N2O3.CHCl3, the dihedral angle between the indole ring system (r.m.s. deviation = 0.050 A) and the 4-methyl-pyrrolidine ring is 88.88 (8) degrees . The latter ring adopts an envelope conformation with the N atom as the flap. Its mean plane makes dihedral angles of 86.94 (11) and 42.08 (9) degrees with the phenyl and di-methyl-benzene rings, respectively. The mol ecular conformation is stabilized by intra-molecular C-H?O hydrogen bonds, which generate S(6) and S(9) ring motifs. The chloro-form solvent mol-ecule is linked to the organic mol-ecule by a C-H?O hydrogen bond involving the carbonyl O atom of the carboxyl-ate group. In the crystal, mol-ecules are linked via bifurcated N H?(N,O) and C-H?O hydrogen bonds, forming chains propagating along [001]. PMID- 24765059 TI - 5-Chloro-5''-(4-chloro-benzyl-idene)-4'-(4-chloro-phen-yl)-1',1''-dimethyldi spiro-[indoline-3,2'-pyrrolidine-3',3''-piperidine]-2,4''-dione. AB - The racemic title compound, C30H26Cl3N3O2, comprises two spiro links, the first connecting the piperidine and pyrrolidine rings and the other connecting the indole and pyrrolidine rings. The piperidine ring adopts a half-chair conformation, while the pyrrolidine ring has an envelope conformation with the unsubstituted C atom as the flap. The dihedral angles between the two p-Cl substituted benzene rings and the indole ring are 33.13 (14) and 54.11 (14) degrees . In the crystal, mol-ecules form inversion dimers through pairs of N-H?O hydrogen bonds [graph set R 2 (2)(8)]. Aromatic C-H?O hydrogen bonds extend these dimers into a ribbon structure, enclosing R (2) 2(14) ring motifs, along the a axis direction. PMID- 24765061 TI - In vitro catabolism of quercetin by human fecal bacteria and the antioxidant capacity of its catabolites. AB - BACKGROUND: Part of quercetin flows into the colon after escaping the absorption of the small intestine and will be degraded by colonic microbiota. The catabolites in the colon partially determine the physiological activity of quercetin. METHODS: Seven gut bacteria isolated from human feces were utilized to in vitro ferment quercetin. Their catabolites were analyzed with high-performance liquid chromatography and mass spectrometry, and the antioxidant activities of their fermented broths were compared with that of quercetin. RESULTS: One metabolite, 3,4-dihydroxyphenylacetic acid, was produced by both C. perfringens and B. fragilis transforming quercetin. No other metabolites were detected in the other fermented broths. The antioxidant activities of all strains fermenting quercetin reached the highest values at the concentration of 1 mg/mL quercetin in broth; the fermented products of C. perfringens and B. fragilis presented stronger activities than those of other strains at most concentrations of quercetin in broth. Additionally, all of the fermented broths presented a decline of the antioxidant activities compared to quercetin. Therefore, the antioxidant activity of quercetin will be lost when it reaches the human colon because of the gut bacterial fermentation. CONCLUSIONS: This is the first study to report that quercetin can be degraded by C. perfringens and B. fragilis and transformed to the same metabolite, 3,4-dihydroxyphenylacetic acid, and that antioxidant activities decline when quercetin is fermented by seven gut bacteria. PMID- 24765060 TI - A General and Practical Palladium-Catalyzed Direct alpha-Arylation of Amides with Aryl Halides. AB - An efficient system for the direct catalytic intermolecular alpha-arylation of acetamide derivatives with aryl bromides and chlorides is presented. The palladium catalyst is supported by Kwong's indole-based phosphine ligand and provides monoarylated amides in up to 95% yield. Excellent chemoselectivities (>10:1) in the mono- and diarylation with aryl bromides were achieved by careful selection of bases, solvents, and stoichiometry. Under the coupling conditions, the weakly acidic alpha-protons of amides (pKa up to 35) were reversibly depotonated by LiO t Bu, NaO t Bu, or NaN(SiMe3)2. PMID- 24765062 TI - An adaptable neuromorphic model of orientation selectivity based on floating gate dynamics. AB - The biggest challenge that the neuromorphic community faces today is to build systems that can be considered truly cognitive. Adaptation and self-organization are the two basic principles that underlie any cognitive function that the brain performs. If we can replicate this behavior in hardware, we move a step closer to our goal of having cognitive neuromorphic systems. Adaptive feature selectivity is a mechanism by which nature optimizes resources so as to have greater acuity for more abundant features. Developing neuromorphic feature maps can help design generic machines that can emulate this adaptive behavior. Most neuromorphic models that have attempted to build self-organizing systems, follow the approach of modeling abstract theoretical frameworks in hardware. While this is good from a modeling and analysis perspective, it may not lead to the most efficient hardware. On the other hand, exploiting hardware dynamics to build adaptive systems rather than forcing the hardware to behave like mathematical equations, seems to be a more robust methodology when it comes to developing actual hardware for real world applications. In this paper we use a novel time-staggered Winner Take All circuit, that exploits the adaptation dynamics of floating gate transistors, to model an adaptive cortical cell that demonstrates Orientation Selectivity, a well-known biological phenomenon observed in the visual cortex. The cell performs competitive learning, refining its weights in response to input patterns resembling different oriented bars, becoming selective to a particular oriented pattern. Different analysis performed on the cell such as orientation tuning, application of abnormal inputs, response to spatial frequency and periodic patterns reveal close similarity between our cell and its biological counterpart. Embedded in a RC grid, these cells interact diffusively exhibiting cluster formation, making way for adaptively building orientation selective maps in silicon. PMID- 24765063 TI - Social learning in humans and other animals. AB - Decisions made by individuals can be influenced by what others think and do. Social learning includes a wide array of behaviors such as imitation, observational learning of novel foraging techniques, peer or parental influences on individual preferences, as well as outright teaching. These processes are believed to underlie an important part of cultural variation among human populations and may also explain intraspecific variation in behavior between geographically distinct populations of animals. Recent neurobiological studies have begun to uncover the neural basis of social learning. Here we review experimental evidence from the past few decades showing that social learning is a widespread set of skills present in multiple animal species. In mammals, the temporoparietal junction, the dorsomedial, and dorsolateral prefrontal cortex, as well as the anterior cingulate gyrus, appear to play critical roles in social learning. Birds, fish, and insects also learn from others, but the underlying neural mechanisms remain poorly understood. We discuss the evolutionary implications of these findings and highlight the importance of emerging animal models that permit precise modification of neural circuit function for elucidating the neural basis of social learning. PMID- 24765065 TI - Large-scale resting state network correlates of cognitive impairment in Parkinson's disease and related dopaminergic deficits. AB - Cognitive impairment is a common non-motor feature of Parkinson's disease (PD). Understanding the neural mechanisms of this deficit is crucial for the development of efficient methods for treatment monitoring and augmentation of cognitive functions in PD patients. The current study aimed to investigate resting state fMRI correlates of cognitive impairment in PD from a large-scale network perspective, and to assess the impact of dopamine deficiency on these networks. Thirty PD patients with resting state fMRI were included from the Parkinson's Progression Marker Initiative (PPMI) database. Eighteen patients from this sample were also scanned with (123)I-FP-CIT SPECT. A standardized neuropsychological battery was administered, evaluating verbal memory, visuospatial, and executive cognitive domains. Image preprocessing was performed using an SPM8-based workflow, obtaining time-series from 90 regions-of-interest (ROIs) defined from the AAL brain atlas. The Brain Connectivity Toolbox (BCT) was used to extract nodal strength from all ROIs, and modularity of the cognitive circuitry determined using the meta-analytical software Neurosynth. Brain behavior covariance patterns between cognitive functions and nodal strength were estimated using Partial Least Squares. Extracted latent variable (LV) scores were matched with the performances in the three cognitive domains (memory, visuospatial, and executive) and striatal dopamine transporter binding ratios (SBR) using linear modeling. Finally, influence of nigrostriatal dopaminergic deficiency on the modularity of the "cognitive network" was analyzed. For the range of deficits studied, better executive performance was associated with increased dorsal fronto-parietal cortical processing and inhibited subcortical and primary sensory involvement. This profile was also characterized by a relative preservation of nigrostriatal dopaminergic function. The profile associated with better memory performance correlated with increased prefronto limbic processing, and was not associated with presynaptic striatal dopamine uptake. SBR ratios were negatively correlated with modularity of the "cognitive network," suggesting integrative effects of the preserved nigrostriatal dopamine system on this circuitry. PMID- 24765064 TI - Functional craniology and brain evolution: from paleontology to biomedicine. AB - Anatomical systems are organized through a network of structural and functional relationships among their elements. This network of relationships is the result of evolution, it represents the actual target of selection, and it generates the set of rules orienting and constraining the morphogenetic processes. Understanding the relationship among cranial and cerebral components is necessary to investigate the factors that have influenced and characterized our neuroanatomy, and possible drawbacks associated with the evolution of large brains. The study of the spatial relationships between skull and brain in the human genus has direct relevance in cranial surgery. Geometrical modeling can provide functional perspectives in evolution and brain physiology, like in simulations to investigate metabolic heat production and dissipation in the endocranial form. Analysis of the evolutionary constraints between facial and neural blocks can provide new information on visual impairment. The study of brain form variation in fossil humans can supply a different perspective for interpreting the processes behind neurodegeneration and Alzheimer's disease. Following these examples, it is apparent that paleontology and biomedicine can exchange relevant information and contribute at the same time to the development of robust evolutionary hypotheses on brain evolution, while offering more comprehensive biological perspectives with regard to the interpretation of pathological processes. PMID- 24765066 TI - Sleep for cognitive enhancement. AB - Sleep is essential for effective cognitive functioning. Loosing even a few hours of sleep can have detrimental effects on a wide variety of cognitive processes such as attention, language, reasoning, decision making, learning and memory. While sleep is necessary to ensure normal healthy cognitive functioning, it can also enhance performance beyond the boundaries of the normal condition. This article discusses the enhancing potential of sleep, mainly focusing on the domain of learning and memory. Sleep is known to facilitate the consolidation of memories learned before sleep as well as the acquisition of new memories to be learned after sleep. According to a widely held model this beneficial effect of sleep relies on the neuronal reactivation of memories during sleep that is associated with sleep-specific brain oscillations (slow oscillations, spindles, ripples) as well as a characteristic neurotransmitter milieu. Recent research indicates that memory processing during sleep can be boosted by (i) cueing memory reactivation during sleep; (ii) stimulating sleep-specific brain oscillations; and (iii) targeting specific neurotransmitter systems pharmacologically. Olfactory and auditory cues can be used, for example, to increase reactivation of associated memories during post-learning sleep. Intensifying neocortical slow oscillations (the hallmark of slow wave sleep (SWS)) by electrical or auditory stimulation and modulating specific neurotransmitters such as noradrenaline and glutamate likewise facilitates memory processing during sleep. With this evidence in mind, this article concludes by discussing different methodological caveats and ethical issues that should be considered when thinking about using sleep for cognitive enhancement in everyday applications. PMID- 24765067 TI - Risk-taking and pathological gambling behavior in Huntington's disease. AB - Huntington's disease (HD) is a genetic, neurodegenerative disorder, which specifically affects striatal neurons of the indirect pathway, resulting in a progressive decline in muscle coordination and loss of emotional and cognitive control. Interestingly, predisposition to pathological gambling and other addictions involves disturbances in the same cortico-striatal circuits that are affected in HD, and display similar disinhibition-related symptoms, including changed sensitivity to punishments and rewards, impulsivity, and inability to consider long-term advantages over short-term rewards. Both HD patients and pathological gamblers also show similar performance deficits on risky decision making tasks, such as the Iowa Gambling Task (IGT). These similarities suggest that HD patients are a likely risk group for gambling problems. However, such problems have only incidentally been observed in HD patients. In this review, we aim to characterize the risk of pathological gambling in HD, as well as the underlying neurobiological mechanisms. Especially with the current rise of easily accessible Internet gambling opportunities, it is important to understand these risks and provide appropriate patient support accordingly. Based on neuropathological and behavioral findings, we propose that HD patients may not have an increased tendency to seek risks and start gambling, but that they do have an increased chance of developing an addiction once they engage in gambling activities. Therefore, current and future developments of Internet gambling possibilities and related addictions should be regarded with care, especially for vulnerable groups like HD patients. PMID- 24765068 TI - Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype. AB - The transition to motherhood involves CNS changes that modify sociability and affective state. However, these changes also put females at risk for post-partum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for post-partum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Post-partum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated with schizophrenia (5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum (LS) and medial preoptic area (MPOA), enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (Flt1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for post-partum psychosis with aspects of schizophrenia and BPD. PMID- 24765069 TI - Reward and reinforcement activity in the nucleus accumbens during learning. AB - The nucleus accumbens core (NAcc) has been implicated in learning associations between sensory cues and profitable motor responses. However, the precise mechanisms that underlie these functions remain unclear. We recorded single neuron activity from the NAcc of primates trained to perform a visual-motor associative learning task. During learning, we found two distinct classes of NAcc neurons. The first class demonstrated progressive increases in firing rates at the go-cue, feedback/tone and reward epochs of the task, as novel associations were learned. This suggests that these neurons may play a role in the exploitation of rewarding behaviors. In contrast, the second class exhibited attenuated firing rates, but only at the reward epoch of the task. These findings suggest that some NAcc neurons play a role in reward-based reinforcement during learning. PMID- 24765070 TI - The intralaminar thalamus-an expressway linking visual stimuli to circuits determining agency and action selection. AB - Anatomical investigations have revealed connections between the intralaminar thalamic nuclei and areas such as the superior colliculus (SC) that receive short latency input from visual and auditory primary sensory areas. The intralaminar nuclei in turn project to the major input nucleus of the basal ganglia, the striatum, providing this nucleus with a source of subcortical excitatory input. Together with a converging input from the cerebral cortex, and a neuromodulatory dopaminergic input from the midbrain, the components previously found necessary for reinforcement learning in the basal ganglia are present. With this intralaminar sensory input, the basal ganglia are thought to play a primary role in determining what aspect of an organism's own behavior has caused salient environmental changes. Additionally, subcortical loops through thalamic and basal ganglia nuclei are proposed to play a critical role in action selection. In this mini review we will consider the anatomical and physiological evidence underlying the existence of these circuits. We will propose how the circuits interact to modulate basal ganglia output and solve common behavioral learning problems of agency determination and action selection. PMID- 24765072 TI - Thalamo-cortical cross-frequency coupling detected with MEG. PMID- 24765071 TI - The paraventricular nucleus of the thalamus is recruited by both natural rewards and drugs of abuse: recent evidence of a pivotal role for orexin/hypocretin signaling in this thalamic nucleus in drug-seeking behavior. AB - A major challenge for the successful treatment of drug addiction is the long lasting susceptibility to relapse and multiple processes that have been implicated in the compulsion to resume drug intake during abstinence. Recently, the orexin/hypocretin (Orx/Hcrt) system has been shown to play a role in drug seeking behavior. The Orx/Hcrt system regulates a wide range of physiological processes, including feeding, energy metabolism, and arousal. It has also been shown to be recruited by drugs of abuse. Orx/Hcrt neurons are predominantly located in the lateral hypothalamus that projects to the paraventricular nucleus of the thalamus (PVT), a region that has been identified as a "way-station" that processes information and then modulates the mesolimbic reward and extrahypothalamic stress systems. Although not thought to be part of the "drug addiction circuitry", recent evidence indicates that the PVT is involved in the modulation of reward function in general and drug-directed behavior in particular. Evidence indicates a role for Orx/Hcrt transmission in the PVT in the modulation of reward function in general and drug-directed behavior in particular. One hypothesis is that following repeated drug exposure, the Orx/Hcrt system acquires a preferential role in mediating the effects of drugs vs. natural rewards. The present review discusses recent findings that suggest maladaptive recruitment of the PVT by drugs of abuse, specifically Orx/Hcrt-PVT neurotransmission. PMID- 24765073 TI - The neuronal response at extended timescales: a linearized spiking input-output relation. AB - Many biological systems are modulated by unknown slow processes. This can severely hinder analysis - especially in excitable neurons, which are highly non linear and stochastic systems. We show the analysis simplifies considerably if the input matches the sparse "spiky" nature of the output. In this case, a linearized spiking Input-Output (I/O) relation can be derived semi-analytically, relating input spike trains to output spikes based on known biophysical properties. Using this I/O relation we obtain closed-form expressions for all second order statistics (input - internal state - output correlations and spectra), construct optimal linear estimators for the neuronal response and internal state and perform parameter identification. These results are guaranteed to hold, for a general stochastic biophysical neuron model, with only a few assumptions (mainly, timescale separation). We numerically test the resulting expressions for various models, and show that they hold well, even in cases where our assumptions fail to hold. In a companion paper we demonstrate how this approach enables us to fit a biophysical neuron model so it reproduces experimentally observed temporal firing statistics on days-long experiments. PMID- 24765074 TI - Electrostimulation to reduce synaptic scaling driven progression of Alzheimer's disease. AB - Cell death and synapse dysfunction are two likely causes of cognitive decline in AD. As cells die and synapses lose their drive, remaining cells suffer an initial decrease in activity. Neuronal homeostatic synaptic scaling then provides a feedback mechanism to restore activity. This homeostatic mechanism is believed to sense levels of activity-dependent cytosolic calcium within the cell and to adjust neuronal firing activity by increasing the density of AMPA synapses at remaining synapses to achieve balance. The scaling mechanism increases the firing rates of remaining cells in the network to compensate for decreases in network activity. However, this effect can itself become a pathology, as it produces increased imbalance between excitatory and inhibitory circuits, leading to greater susceptibility to further cell loss via calcium-mediated excitotoxicity. Here, we present a mechanistic explanation of how directed brain stimulation might be expected to slow AD progression based on computational simulations in a 470-neuron biomimetic model of a neocortical column. The simulations demonstrate that the addition of low-intensity electrostimulation (neuroprosthesis) to a network undergoing AD-like cell death can raise global activity and break this homeostatic-excitotoxic cascade. The increase in activity within the remaining cells in the column results in lower scaling-driven AMPAR upregulation, reduced imbalances in excitatory and inhibitory circuits, and lower susceptibility to ongoing damage. PMID- 24765075 TI - Induction of ischemic stroke in awake freely moving mice reveals that isoflurane anesthesia can mask the benefits of a neuroprotection therapy. AB - Anesthetics such as isoflurane are commonly used to sedate experimental animals during the induction of stroke. Since these agents are known to modulate synaptic excitability, inflammation and blood flow, they could hinder the development and discovery of new neuroprotection therapies. To address this issue, we developed a protocol for inducing photothrombotic occlusion of cerebral vessels in fully conscious mice and tested two potential neuroprotectant drugs (a GluN2B or alpha4beta2 nicotinic receptor antagonist). Our data show in vehicle treated mice that just 20 min of exposure to isoflurane during stroke induction can significantly reduce ischemic cortical damage relative to mice that were awake during stroke. When comparing potential stroke therapies, none provided any level of neuroprotection if the stroke was induced with anesthesia. However, if mice were fully conscious during stroke, the alpha4beta2 nicotinic receptor antagonist reduced ischemic damage by 23% relative to vehicle treated controls, whereas the GluN2B antagonist had no significant effect. These results suggest that isoflurane anesthesia can occlude the benefits of certain stroke treatments and warrant caution when using anesthetics for pre-clinical testing of neuroprotective agents. PMID- 24765076 TI - A PKA activity sensor for quantitative analysis of endogenous GPCR signaling via 2-photon FRET-FLIM imaging. AB - Neuromodulators have profound effects on behavior, but the dynamics of their intracellular effectors has remained unclear. Most neuromodulators exert their function via G-protein-coupled receptors (GPCRs). One major challenge for understanding neuromodulator action is the lack of dynamic readouts of the biochemical signals produced by GPCR activation. The adenylate cyclase/cyclic AMP/protein kinase A (PKA) module is a central component of such biochemical signaling. This module is regulated by several behaviorally important neuromodulator receptors. Furthermore, PKA activity is necessary for the induction of many forms of synaptic plasticity as well as for the formation of long-term memory. In order to monitor PKA activity in brain tissue, we have developed a 2-photon fluorescence lifetime imaging microscopy (2pFLIM) compatible PKA sensor termed FLIM-AKAR, which is based on the ratiometric FRET sensor AKAR3. FLIM-AKAR shows a large dynamic range and little pH sensitivity. In addition, it is a rapidly diffusible cytoplasmic protein that specifically reports net PKA activity in situ. FLIM-AKAR expresses robustly in various brain regions with multiple transfection methods, can be targeted to genetically identified cell types, and responds to activation of both endogenous GPCRs and spatial-temporally specific delivery of glutamate. Initial experiments reveal differential regulation of PKA activity across subcellular compartments in response to neuromodulator inputs. Therefore, the reporter FLIM-AKAR, coupled with 2pFLIM, enables the study of PKA activity in response to neuromodulator inputs in genetically identified neurons in the brain, and sheds light on the intracellular dynamics of endogenous GPCR activation. PMID- 24765077 TI - Mechanisms of CaMKII Activation in the Heart. AB - Calcium/calmodulin (Ca(2+)/CaM) dependent protein kinase II (CaMKII) has emerged as a key nodal protein in the regulation of cardiac physiology and pathology. Due to the particularly elegant relationship between the structure and function of the kinase, CaMKII is able to translate a diverse set of signaling events into downstream physiological effects. While CaMKII is typically autoinhibited at basal conditions, prolonged rapid Ca(2+) cycling can activate the kinase and allow post-translational modifications that depend critically on the biochemical environment of the heart. These modifications result in sustained, autonomous CaMKII activation and have been associated with pathological cardiac signaling. Indeed, improved understanding of CaMKII activation mechanisms could potentially lead to new clinical therapies for the treatment or prevention of cardiovascular disease. Here we review the known mechanisms of CaMKII activation and discuss some of the pathological signaling pathways in which they play a role. PMID- 24765080 TI - Yoga for Children and Young People's Mental Health and Well-Being: Research Review and Reflections on the Mental Health Potentials of Yoga. AB - This article discusses yoga as a potential tool for children to deal with stress and regulate themselves. Yoga provides training of mind and body to bring emotional balance. We argue that children and young people need such tools to listen inward to their bodies, feelings, and ideas. Yoga may assist them in developing in sound ways, to strengthen themselves, and be contributing social beings. First, we address how children and young people in today's world face numerous expectations and constant stimulation through the Internet and other media and communication technologies. One reason why children experience stress and mental health challenges is that globalization exposes the youth all over the world to various new demands, standards, and options. There is also increased pressure to succeed in school, partly due to increased competition but also a diverse range of options available for young people in contemporary times than in the past. Our argument also partially rests on the fact that modern society offers plenty of distractions and unwelcome attractions, especially linked to new media technologies. The dominant presence of multimedia devices and the time spent on them by children are clear indicators of the shift in lifestyles and priorities of our new generation. While these media technologies are valuable resources in children and young people's lives for communication, learning, and entertainment, they also result in constant competition for youngster's attention. A main concept in our article is that yoga may help children and young people cope with stress and thus, contribute positively to balance in life, well being, and mental health. We present research literature suggesting that yoga improves children's physical and mental well-being. Similarly, yoga in schools helps students improve resilience, mood, and self-regulation skills pertaining to emotions and stress. PMID- 24765078 TI - Magnetic resonance imaging in studying schizophrenia, negative symptoms, and the glutamate system. AB - Schizophrenia is characterized by positive, negative, and cognitive symptoms. While positive symptoms occur periodically during psychotic exacerbations, negative and cognitive symptoms often emerge before the first psychotic episode and persist with low functional outcome and poor prognosis. This review article outlines the importance of modern functional magnetic resonance imaging techniques for developing a stratified therapy of schizophrenic disorders. Functional neuroimaging evidence on the neural correlates of positive and particularly negative symptoms and cognitive deficits in schizophrenic disorders is briefly reviewed. Acute dysregulation of dopaminergic neurotransmission is crucially involved in the occurrence of psychotic symptoms. However, increasing evidence also implicates glutamatergic pathomechanisms, in particular N-methyl-d aspartate (NMDA) receptor dysfunction in the pathogenesis of schizophrenia and in the appearance of negative symptoms and cognitive dysfunctions. In line with this notion, several gene variants affecting the NMDA receptor's pathway have been reported to increase susceptibility for schizophrenia, and have been investigated using the imaging genetics approach. In recent years, several attempts have been made to develop medications modulating the glutamatergic pathway with modest evidences for efficacy. The most successful approaches were those that aimed at influencing this pathway using compounds that enhance NMDA receptor function. More recently, the selective glycine reuptake inhibitor bitopertin has been shown to improve NMDA receptor hypofunction by increasing glycine concentrations in the synaptic cleft. Further research is required to test whether pharmacological agents with effects on the glutamatergic system can help to improve the treatment of negative symptoms in schizophrenic disorders. PMID- 24765079 TI - Restoring cognitive functions using non-invasive brain stimulation techniques in patients with cerebellar disorders. AB - Numerous studies have highlighted the possibility of modulating the excitability of cerebro-cerebellar circuits bi-directionally using transcranial electrical brain stimulation, in a manner akin to that observed using magnetic stimulation protocols. It has been proposed that cerebellar stimulation activates Purkinje cells in the cerebellar cortex, leading to inhibition of the dentate nucleus, which exerts a tonic facilitatory drive onto motor and cognitive regions of cortex through a synaptic relay in the ventral-lateral thalamus. Some cerebellar deficits present with cognitive impairments if damage to non-motor regions of the cerebellum disrupts the coupling with cerebral cortical areas for thinking and reasoning. Indeed, white matter changes in the dentato-rubral tract correlate with cognitive assessments in patients with Friedreich ataxia, suggesting that this pathway is one component of the anatomical substrate supporting a cerebellar contribution to cognition. An understanding of the physiology of the cerebro cerebellar pathway previously helped us to constrain our interpretation of results from two recent studies in which we showed cognitive enhancements in healthy participants during tests of arithmetic after electrical stimulation of the cerebellum, but only when task demands were high. Others studies have also shown how excitation of the prefrontal cortex can enhance performance in a variety of working memory tasks. Thus, future efforts might be guided toward neuro-enhancement in certain patient populations, using what is commonly termed "non-invasive brain stimulation" as a cognitive rehabilitation tool to modulate cerebro-cerebellar circuits, or for stimulation over the cerebral cortex to compensate for decreased cerebellar drive to this region. This article will address these possibilities with a review of the relevant literature covering ataxias and cerebellar cognitive affective disorders, which are characterized by thalamo-cortical disturbances. PMID- 24765081 TI - Expertise and the representation of space. PMID- 24765083 TI - Imageability: now you see it again (albeit in a different form). PMID- 24765082 TI - Short-term plasticity of visuo-haptic object recognition. AB - Functional magnetic resonance imaging (fMRI) studies have provided ample evidence for the involvement of the lateral occipital cortex (LO), fusiform gyrus (FG), and intraparietal sulcus (IPS) in visuo-haptic object integration. Here we applied 30 min of sham (non-effective) or real offline 1 Hz repetitive transcranial magnetic stimulation (rTMS) to perturb neural processing in left LO immediately before subjects performed a visuo-haptic delayed-match-to-sample task during fMRI. In this task, subjects had to match sample (S1) and target (S2) objects presented sequentially within or across vision and/or haptics in both directions (visual-haptic or haptic-visual) and decide whether or not S1 and S2 were the same objects. Real rTMS transiently decreased activity at the site of stimulation and remote regions such as the right LO and bilateral FG during haptic S1 processing. Without affecting behavior, the same stimulation gave rise to relative increases in activation during S2 processing in the right LO, left FG, bilateral IPS, and other regions previously associated with object recognition. Critically, the modality of S2 determined which regions were recruited after rTMS. Relative to sham rTMS, real rTMS induced increased activations during crossmodal congruent matching in the left FG for haptic S2 and the temporal pole for visual S2. In addition, we found stronger activations for incongruent than congruent matching in the right anterior parahippocampus and middle frontal gyrus for crossmodal matching of haptic S2 and in the left FG and bilateral IPS for unimodal matching of visual S2, only after real but not sham rTMS. The results imply that a focal perturbation of the left LO triggers modality-specific interactions between the stimulated left LO and other key regions of object processing possibly to maintain unimpaired object recognition. This suggests that visual and haptic processing engage partially distinct brain networks during visuo-haptic object matching. PMID- 24765084 TI - Free will and paranormal beliefs. AB - Free will is one of the fundamental aspects of human cognition. In the context of cognitive neuroscience, various experiments on time perception, sensorimotor coordination, and agency suggest the possibility that it is a robust illusion (a feeling independent of actual causal relationship with actions) constructed by neural mechanisms. Humans are known to suffer from various cognitive biases and failures, and the sense of free will might be one of them. Here I report a positive correlation between the belief in free will and paranormal beliefs (UFO, reincarnation, astrology, and psi). Web questionnaires involving 2076 subjects (978 males, 1087 females, and 11 other genders) were conducted, which revealed significant positive correlations between belief in free will (theory and practice) and paranormal beliefs. There was no significant correlation between belief in free will and knowledge in paranormal phenomena. Paranormal belief scores for females were significantly higher than those for males, with corresponding significant (albeit weaker) difference in belief in free will. These results are consistent with the view that free will is an illusion which shares common cognitive elements with paranormal beliefs. PMID- 24765085 TI - Reduced thalamic and pontine connectivity in kleine-levin syndrome. AB - The Kleine-Levin syndrome (KLS) is a rare sleep disorder, characterized by exceptionally long sleep episodes. The neuropathology of the syndrome is unknown and treatment is often inadequate. The aim of the study was to improve understanding of the underlying neuropathology, related to cerebral networks, in KLS during sleep episodes. One patient with KLS and congenital nystagmus was investigated by resting state functional magnetic resonance imaging during both asymptomatic and hypersomnic periods. Fourteen healthy subjects were also investigated as control samples. Functional connectivity was assessed from seed regions of interest in the thalamus and the dorsal pons. Thalamic connectivity was normal in the asymptomatic patient whereas the connectivity between the brain stem, including dorsal pons, and the thalamus was diminished during hypersomnia. These results suggest that the patient's nystagmus and hypersomnia might have their pathological origin in adjacent dorsal pontine regions. This finding provides additional knowledge of the cerebral networks involved in the neuropathology of this disabling disorder. Furthermore, these findings regarding a rare syndrome have broad implications, and results could be of interest to researchers and clinicians in the whole field of sleep medicine. PMID- 24765086 TI - Antifungal defensins and their role in plant defense. AB - Since the beginning of the 90s lots of cationic plant, cysteine-rich antimicrobial peptides (AMP) have been studied. However, Broekaert et al. (1995) only coined the term "plant defensin," after comparison of a new class of plant antifungal peptides with known insect defensins. From there, many plant defensins have been reported and studies on this class of peptides encompass its activity toward microorganisms and molecular features of the mechanism of action against bacteria and fungi. Plant defensins also have been tested as biotechnological tools to improve crop production through fungi resistance generation in organisms genetically modified (OGM). Its low effective concentration towards fungi, ranging from 0.1 to 10 MUM and its safety to mammals and birds makes them a better choice, in place of chemicals, to control fungi infection on crop fields. Herein, is a review of the history of plant defensins since their discovery at the beginning of 90s, following the advances on its structure conformation and mechanism of action towards microorganisms is reported. This review also points out some important topics, including: (i) the most studied plant defensins and their fungal targets; (ii) the molecular features of plant defensins and their relation with antifungal activity; (iii) the possibility of using plant defensin(s) genes to generate fungi resistant GM crops and biofungicides; and (iv) a brief discussion about the absence of products in the market containing plant antifungal defensins. PMID- 24765088 TI - Biofilms and lichens on stone monuments: do they damage or protect? PMID- 24765087 TI - Volatile hydrocarbons inhibit methanogenic crude oil degradation. AB - Methanogenic degradation of crude oil in subsurface sediments occurs slowly, but without the need for exogenous electron acceptors, is sustained for long periods and has enormous economic and environmental consequences. Here we show that volatile hydrocarbons are inhibitory to methanogenic oil biodegradation by comparing degradation of an artificially weathered crude oil with volatile hydrocarbons removed, with the same oil that was not weathered. Volatile hydrocarbons (nC5-nC10, methylcyclohexane, benzene, toluene, and xylenes) were quantified in the headspace of microcosms. Aliphatic (n-alkanes nC12-nC34) and aromatic hydrocarbons (4-methylbiphenyl, 3-methylbiphenyl, 2-methylnaphthalene, 1 methylnaphthalene) were quantified in the total hydrocarbon fraction extracted from the microcosms. 16S rRNA genes from key microorganisms known to play an important role in methanogenic alkane degradation (Smithella and Methanomicrobiales) were quantified by quantitative PCR. Methane production from degradation of weathered oil in microcosms was rapid (1.1 +/- 0.1 MUmol CH4/g sediment/day) with stoichiometric yields consistent with degradation of heavier n alkanes (nC12-nC34). For non-weathered oil, degradation rates in microcosms were significantly lower (0.4 +/- 0.3 MUmol CH4/g sediment/day). This indicated that volatile hydrocarbons present in the non-weathered oil inhibit, but do not completely halt, methanogenic alkane biodegradation. These findings are significant with respect to rates of biodegradation of crude oils with abundant volatile hydrocarbons in anoxic, sulphate-depleted subsurface environments, such as contaminated marine sediments which have been entrained below the sulfate reduction zone, as well as crude oil biodegradation in petroleum reservoirs and contaminated aquifers. PMID- 24765089 TI - Surface expression of protein A on magnetosomes and capture of pathogenic bacteria by magnetosome/antibody complexes. AB - Magnetosomes are membrane-enclosed magnetite nanocrystals synthesized by magnetotactic bacteria (MTB). They display chemical purity, narrow size ranges, and species-specific crystal morphologies. Specific transmembrane proteins are sorted to the magnetosome membrane (MM). MamC is the most abundant MM protein of Magnetospirillum gryphiswaldense strain MSR-1. MamF is the second most abundant MM protein of MSR-1 and forms stable oligomers. We expressed staphylococcal protein A (SPA), an immunoglobulin-binding protein from the cell wall of Staphylococcus aureus, on MSR-1 magnetosomes by fusion with MamC or MamF. The resulting recombinant magnetosomes were capable of self-assembly with the Fc region of mammalian antibodies (Abs) and were therefore useful for functionalization of magnetosomes. Recombinant plasmids pBBR-mamC-spa and pBBR mamF-spa were constructed by fusing spa (the gene that encodes SPA) with mamC and mamF, respectively. Recombinant magnetosomes with surface expression of SPA were generated by introduction of these fusion genes into wild-type MSR-1 or a mamF mutant strain. Studies with a Zeta Potential Analyzer showed that the recombinant magnetosomes had hydrated radii significantly smaller than those of WT magnetosomes and zeta potentials less than -30 mV, indicating that the magnetosome colloids were relatively stable. Observed conjugation efficiencies were as high as 71.24 MUg Ab per mg recombinant magnetosomes, and the conjugated Abs retained most of their activity. Numbers of Vibrio parahaemolyticus (a common pathogenic bacterium in seafood) captured by recombinant magnetosome/Ab complexes were measured by real-time fluorescence-based quantitative PCR. One mg of complex was capable of capturing as many as 1.74 * 10(7) Vibrio cells. The surface expression system described here will be useful for design of functionalized magnetosomes from MSR-1 and other MTB. PMID- 24765090 TI - How community ecology can improve our understanding of cholera dynamics. AB - Understanding the seasonal emergence and reemergence of cholera is challenging due to the complex dynamics of different protagonists. The abundance of Vibrio cholerae, the causative agent of cholera and a natural inhabitant of aquatic environments, fluctuates according to abiotic, and biotic factors. Among the biotic factors, the zooplankton community dynamics has been suggested to play a pivotal role in the survival, persistence, and natural competence of V. cholerae. However, factors regulating V. cholerae population structure and seasonal dynamics are still not fully understood. Investigation of the temporal shifts and variability in aquatic community composition in relation to the occurrence or abundance of V. cholerae appears very promising yet remained underexplored. Recent advances in metagenomics, facilitated by high-throughput ultra deep sequencing, have greatly improved our ability for a broader and deeper exploration of microbial communities including an understanding of community structure, function, as well as inter- and intra-specific competitions. Here, we discuss possible areas of research focusing how combination of community ecology and metagenomic approaches could be applied to study the cholera system. PMID- 24765091 TI - Building a better bacillus: the emergence of Mycobacterium tuberculosis. AB - The genus Mycobacterium is comprised of more than 150 species that reside in a wide variety of habitats. Most mycobacteria are environmental organisms that are either not associated with disease or are opportunistic pathogens that cause non transmissible disease in immunocompromised individuals. In contrast, a small number of species, such as the tubercle bacillus, Mycobacterium tuberculosis, are host-adapted pathogens for which there is no known environmental reservoir. In recent years, gene disruption studies using the host-adapted pathogen have uncovered a number of "virulence factors," yet genomic data indicate that many of these elements are present in non-pathogenic mycobacteria. This suggests that much of the genetic make-up that enables virulence in the host-adapted pathogen is already present in environmental members of the genus. In addition to these generic factors, we hypothesize that molecules elaborated exclusively by professional pathogens may be particularly implicated in the ability of M. tuberculosis to infect, persist, and cause transmissible pathology in its host species, Homo sapiens. One approach to identify these molecules is to employ comparative analysis of mycobacterial genomes, to define evolutionary events such as horizontal gene transfer (HGT) that contributed M. tuberculosis-specific genetic elements. Independent studies have now revealed the presence of HGT genes in the M. tuberculosis genome and their role in the pathogenesis of disease is the subject of ongoing investigations. Here we review these studies, focusing on the hypothesized role played by HGT loci in the emergence of M. tuberculosis from a related environmental species into a highly specialized human-adapted pathogen. PMID- 24765092 TI - Balancing Proliferation with Igkappa Recombination during B-lymphopoiesis. AB - The essential events of B-cell development are the stochastic and sequential rearrangement of immunoglobulin heavy (IgMU) and then light chain (Igkappa followed by Iglambda) loci. The counterpoint to recombination is proliferation, which both maintains populations of pro-B cells undergoing IgMU recombination and expands the pool of pre-B cells expressing the IgMU protein available for subsequent Igkappa recombination. Proliferation and recombination must be segregated into distinct and mutually exclusive developmental stages. Failure to do so risks aberrant gene translocation and leukemic transformation. Recent studies have demonstrated that proliferation and recombination are each affected by different and antagonistic receptors. The IL-7 receptor drives proliferation while the pre-B-cell antigen receptor, which contains IgMU and surrogate light chain, enhances Igkappa accessibility and recombination. Remarkably, the principal downstream proliferative effectors of the IL-7R, STAT5 and cyclin D3, directly repress Igkappa accessibility through very divergent yet complementary mechanisms. Conversely, the pre-B-cell receptor represses cyclin D3 leading to cell cycle exit and enhanced Igkappa accessibility. These studies reveal how cell fate decisions can be directed and reinforced at each developmental transition by single receptors. Furthermore, they identify novel mechanisms of Igkappa repression that have implications for gene regulation in general. PMID- 24765093 TI - Human B Cell-Derived Lymphoblastoid Cell Lines Constitutively Produce Fas Ligand and Secrete MHCII(+)FasL(+) Killer Exosomes. AB - Immune suppression mediated by exosomes is an emerging concept with potentially immense utility for immunotherapy in a variety of inflammatory contexts, including allogeneic transplantation. Exosomes containing the apoptosis-inducing molecule Fas ligand (FasL) have demonstrated efficacy in inhibiting antigen specific immune responses upon adoptive transfer in animal models. We report here that a very high frequency of human B cell-derived lymphoblastoid cell lines (LCL) constitutively produce MHCII(+)FasL(+) exosomes that can induce apoptosis in CD4(+) T cells. All LCL tested for this study (>20 independent cell lines) showed robust expression of FasL, but had no detectable FasL on the cell surface. Given this intracellular sequestration, we hypothesized that FasL in LCL was retained in the secretory lysosome and secreted via exosomes. Indeed, we found both MHCII and FasL proteins present in LCL-derived exosomes, and using a bead based exosome capture assay demonstrated the presence of MHCII(+)FasL(+) exosomes among those secreted by LCL. Using two independent experimental approaches, we demonstrated that LCL-derived exosomes were capable of inducing antigen-specific apoptosis in autologous CD4(+) T cells. These results suggest that LCL-derived exosomes may present a realistic source of immunosuppressive exosomes that could reduce or eliminate T cell-mediated responses against donor-derived antigens in transplant recipients. PMID- 24765095 TI - Interactions of IgG1 CH2 and CH3 Domains with FcRn. AB - Antibody fragments are emerging as promising biopharmaceuticals because of their relatively small-size and other unique properties. However, when compared to full size antibodies, most of the current antibody fragments of VH or VL display greatly reduced half-lives. A promising approach to overcome this problem is through the development of novel antibody fragments based on IgG Fc region, which contributes to the long half-life of IgG through its unique pH-dependent association with the neonatal Fc receptor (FcRn). The IgG Fc region comprises two CH2 and two CH3 domains. In this report, we present a comparative study of the FcRn binding capability of the CH2 and CH3 domains. The stability and aggregation resistance of these domains were also investigated and compared. We found that monomeric CH2 and CH3 domains exhibited the pH-dependent FcRn binding while the dimeric forms of CH2 and CH3 domains did not. Although all of these domains had high serum stability, they had aggregation tendencies as measured by dynamic light scattering. By providing a better understanding of the structure-activity relationship of the Fc fragment, these results guide further approaches to generate novel Fc-based small-size antibody fragments that possess pH-dependent FcRn binding capability, desired in vivo half-lives, and other favorable biophysical properties for their druggability. PMID- 24765094 TI - Ly49 receptors: innate and adaptive immune paradigms. AB - The Ly49 receptors are type II C-type lectin-like membrane glycoproteins encoded by a family of highly polymorphic and polygenic genes within the mouse natural killer (NK) gene complex. This gene family is designated Klra, and includes genes that encode both inhibitory and activating Ly49 receptors in mice. Ly49 receptors recognize class I major histocompatibility complex-I (MHC-I) and MHC-I-like proteins on normal as well as altered cells. Their functional homologs in humans are the killer cell immunoglobulin-like receptors, which recognize HLA class I molecules as ligands. Classically, Ly49 receptors are described as being expressed on both the developing and mature NK cells. The inhibitory Ly49 receptors are involved in NK cell education, a process in which NK cells acquire function and tolerance toward cells that express "self-MHC-I." On the other hand, the activating Ly49 receptors recognize altered cells expressing activating ligands. New evidence shows a broader Ly49 expression pattern on both innate and adaptive immune cells. Ly49 receptors have been described on multiple NK cell subsets, such as uterine NK and memory NK cells, as well as NKT cells, dendritic cells, plasmacytoid dendritic cells, macrophages, neutrophils, and cells of the adaptive immune system, such as activated T cells and regulatory CD8(+) T cells. In this review, we discuss the expression pattern and proposed functions of Ly49 receptors on various immune cells and their contribution to immunity. PMID- 24765096 TI - Evaluation of constitutive iron reductase (AtFRO2) expression on mineral accumulation and distribution in soybean (Glycine max. L). AB - Iron is an important micronutrient in human and plant nutrition. Adequate iron nutrition during crop production is central for assuring appropriate iron concentrations in the harvestable organs, for human food or animal feed. The whole-plant movement of iron involves several processes, including the reduction of ferric to ferrous iron at several locations throughout the plant, prior to transmembrane trafficking of ferrous iron. In this study, soybean plants that constitutively expressed the AtFRO2 iron reductase gene were analyzed for leaf iron reductase activity, as well as the effect of this transgene's expression on root, leaf, pod wall, and seed mineral concentrations. High Fe supply, in combination with the constitutive expression of AtFRO2, resulted in significantly higher concentrations of different minerals in roots (K, P, Zn, Ca, Ni, Mg, and Mo), pod walls (Fe, K, P, Cu, and Ni), leaves (Fe, P, Cu, Ca, Ni, and Mg) and seeds (Fe, Zn, Cu, and Ni). Leaf and pod wall iron concentrations increased as much as 500% in transgenic plants, while seed iron concentrations only increased by 10%, suggesting that factors other than leaf and pod wall reductase activity were limiting the translocation of iron to seeds. Protoplasts isolated from transgenic leaves had three-fold higher reductase activity than controls. Expression levels of the iron storage protein, ferritin, were higher in the transgenic leaves than in wild-type, suggesting that the excess iron may be stored as ferritin in the leaves and therefore unavailable for phloem loading and delivery to the seeds. Also, citrate and malate levels in the roots and leaves of transgenic plants were significantly higher than in wild-type, suggesting that organic acid production could be related to the increased accumulation of minerals in roots, leaves, and pod walls, but not in the seeds. All together, these results suggest a more ubiquitous role for the iron reductase in whole plant mineral accumulation and distribution. PMID- 24765097 TI - Functional insights of nucleocytoplasmic transport in plants. AB - Plant nucleocytoplasmic transport beyond the nuclear envelope is important not only for basic cellular functions but also for growth, development, hormonal signaling, and responses to environmental stimuli. Key components of this transport system include nuclear transport receptors and nucleoporins. The functional and physical interactions between receptors and the nuclear pore in the nuclear membrane are indispensable for nucleocytoplasmic transport. Recently, several groups have reported various plant mutants that are deficient in factors involved in nucleocytoplasmic transport. Here, we summarize the current state of knowledge about nucleocytoplasmic transport in plants, and we review the plant specific regulation and roles of this process in plants. PMID- 24765099 TI - Peroxisomal polyamine oxidase and NADPH-oxidase cross-talk for ROS homeostasis which affects respiration rate in Arabidopsis thaliana. AB - Homeostasis of reactive oxygen species (ROS) in the intracellular compartments is of critical importance as ROS have been linked with nearly all cellular processes and more importantly with diseases and aging. PAs are nitrogenous molecules with an evolutionary conserved role in the regulation of metabolic and energetic status of cells. Recent evidence also suggests that polyamines (PA) are major regulators of ROS homeostasis. In Arabidopsis the backconversion of the PAs spermidine (Spd) and spermine to putrescine and Spd, respectively, is catalyzed by two peroxisomal PA oxidases (AtPAO). However, the physiological role of this pathway remains largely elusive. Here we explore the role of peroxisomal PA backconversion and in particular that catalyzed by the highly expressed AtPAO3 in the regulation of ROS homeostasis and mitochondrial respiratory burst. Exogenous PAs exert an NADPH-oxidase dependent stimulation of oxygen consumption, with Spd exerting the strongest effect. This increase is attenuated by treatment with the NADPH-oxidase blocker diphenyleneiodonium iodide (DPI). Loss-of-function of AtPAO3 gene results to increased NADPH-oxidase-dependent production of superoxide anions ([Formula: see text] ), but not H2O2, which activate the mitochondrial alternative oxidase pathway (AOX). On the contrary, overexpression of AtPAO3 results to an increased but balanced production of both H2O2 and [Formula: see text] . These results suggest that the ratio of [Formula: see text] /H2O2 regulates respiratory chain in mitochondria, with PA-dependent production of [Formula: see text] by NADPH-oxidase tilting the balance of electron transfer chain in favor of the AOX pathway. In addition, AtPAO3 seems to be an important component in the regulating module of ROS homeostasis, while a conserved role for PA backconversion and ROS across kingdoms is discussed. PMID- 24765100 TI - Bacterial SET domain proteins and their role in eukaryotic chromatin modification. AB - It has been shown by many researchers that SET-domain containing proteins modify chromatin structure and, as expected, genes coding for SET-domain containing proteins have been found in all eukaryotic genomes sequenced to date. However, during the last years, a great number of bacterial genomes have been sequenced and an important number of putative genes involved in histone post-translational modifications (histone PTMs) have been identified in many bacterial genomes. Here, I aim at presenting an overview of SET domain genes that have been identified in numbers of bacterial genomes based on similarity to SET domains of eukaryotic histone methyltransferases. I will argue in favor of the hypothesis that SET domain genes found in extant bacteria are of bacterial origin. Then, I will focus on the available information on pathogen and symbiont SET-domain containing proteins and their targets in eukaryotic organisms, and how such histone methyltransferases allow a pathogen to inhibit transcriptional activation of host defense genes. PMID- 24765102 TI - A cautionary note on ignoring polygenic background when mapping quantitative trait loci via recombinant congenic strains. AB - In gene mapping, it is common to test for association between the phenotype and the genotype at a large number of loci, i.e., the same response variable is used repeatedly to test a large number of non-independent and non-nested hypotheses. In many of these genetic problems, the underlying model is a mixed model consistent of one or very few major genes concurrently with a genetic background effect, usually thought as of polygenic nature and, consequently, modeled through a random effects term with a well-defined covariance structure dependent upon the kinship between individuals. Either because the interest lies only on the major genes or to simplify the analysis, it is habitual to drop the random effects term and use a simple linear regression model, sometimes complemented with testing via resampling as an attempt to minimize the consequences of this practice. Here, it is shown that dropping the random effects term has not only extreme negative effects on the control of the type I error rate, but it is also unlikely to be fixed by resampling because, whenever the mixed model is correct, this practice does not allow to meet some basic requirements of resampling in a gene mapping context. Furthermore, simulations show that the type I error rates when the random term is ignored can be unacceptably high. As an alternative, this paper introduces a new bootstrap procedure to handle the specific case of mapping by using recombinant congenic strains under a linear mixed model. A simulation study showed that the type I error rates of the proposed procedure are very close to the nominal ones, although they tend to be slightly inflated for larger values of the random effects variance. Overall, this paper illustrates the extent of the adverse consequences of ignoring random effects term due to polygenic factors while testing for genetic linkage and warns us of potential modeling issues whenever simple linear regression for a major gene yields multiple significant linkage peaks. PMID- 24765101 TI - Biosynthesis and functions of sulfur modifications in tRNA. AB - Sulfur is an essential element for a variety of cellular constituents in all living organisms. In tRNA molecules, there are many sulfur-containing nucleosides, such as the derivatives of 2-thiouridine (s(2)U), 4-thiouridine (s(4)U), 2-thiocytidine (s(2)C), and 2-methylthioadenosine (ms(2)A). Earlier studies established the functions of these modifications for accurate and efficient translation, including proper recognition of the codons in mRNA or stabilization of tRNA structure. In many cases, the biosynthesis of these sulfur modifications starts with cysteine desulfurases, which catalyze the generation of persulfide (an activated form of sulfur) from cysteine. Many sulfur-carrier proteins are responsible for delivering this activated sulfur to each biosynthesis pathway. Finally, specific "modification enzymes" activate target tRNAs and then incorporate sulfur atoms. Intriguingly, the biosynthesis of 2 thiouridine in all domains of life is functionally and evolutionarily related to the ubiquitin-like post-translational modification system of cellular proteins in eukaryotes. This review summarizes the recent characterization of the biosynthesis of sulfur modifications in tRNA and the novel roles of this modification in cellular functions in various model organisms, with a special emphasis on 2-thiouridine derivatives. Each biosynthesis pathway of sulfur containing molecules is mutually modulated via sulfur trafficking, and 2 thiouridine and codon usage bias have been proposed to control the translation of specific genes. PMID- 24765103 TI - MicroRNAs in Barrett's esophagus: future prospects. PMID- 24765106 TI - 9th German Conference on Chemoinformatics. PMID- 24765105 TI - Specific Language Impairment Across Languages. AB - Children with specific language impairment (SLI) have a significant and longstanding deficit in spoken language ability that adversely affects their social and academic well-being. Studies of children with SLI in a wide variety of languages reveal diverse symptoms, most of which seem to reflect weaknesses in grammatical computation and phonological short-term memory. The symptoms of the disorder are sensitive to the type of language being acquired, with extraordinary weaknesses seen in those areas of language that are relatively challenging for younger typically developing children. Although these children's deficits warrant clinical and educational attention, their weaknesses might reflect the extreme end of a language aptitude continuum rather than a distinct, separable condition. PMID- 24765107 TI - Putting together the pieces: building a reaction-centric electronic lab notebook for mobile devices. PMID- 24765104 TI - The contribution of epigenetics in Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is a chronic autoimmune epithelitis that combines exocrine gland dysfunctions and lymphocytic infiltrations. While the pathogenesis of SS remains unclear, its etiology is multifunctional and includes a combination of genetic predispositions, environmental factors, and epigenetic factors. Recently, interest has grown in the involvement of epigenetics in autoimmune diseases. Epigenetics is defined as changes in gene expression, that are inheritable and that do not entail changes in the DNA sequence. In SS, several epigenetic mechanisms are defective including DNA demethylation that predominates in epithelial cells, an abnormal expression of microRNAs, and abnormal chromatin positioning-associated with autoantibody production. Last but not least, epigenetic modifications are reversible as observed in minor salivary glands from SS patients after B cell depletion using rituximab. Thus epigenetic findings in SS open new perspectives for therapeutic approaches as well as the possible identification of new biomarkers. PMID- 24765109 TI - Go with the flow and accessorize your drugs. PMID- 24765108 TI - Quantum-mechanics-based molecular interaction fields for 3D-QSAR. PMID- 24765110 TI - Identification of host interactions for phenotypic antimalarial hits. PMID- 24765111 TI - Looking over the rim: algorithms for cheminformatics from computer scientists. PMID- 24765112 TI - Structure-activity relationship analysis on the basis of matched molecular pairs. PMID- 24765113 TI - Combining pharmacophore- and MD-based modelling for phase II metabolism prediction. PMID- 24765114 TI - Analysis and visual summarization of molecular dynamics simulation. PMID- 24765115 TI - Validated scoring of halogen bonding in molecular design. PMID- 24765116 TI - inSARa: intuitive single-target (large-scale) SAR interpretation and multi-target cross-reactivity analysis. PMID- 24765117 TI - Simulating "soft" electronics. PMID- 24765118 TI - Can quantum-chemical NMR chemical shifts be used as criterion for force-field development. PMID- 24765119 TI - New insights on the interface between metal oxide and biosystem. PMID- 24765120 TI - Computational pharmaceutical materials science. PMID- 24765121 TI - Balancing selectivity vs stability using molecular dynamics and umbrella sampling. PMID- 24765122 TI - Membrane simulation analysis using Voronoi tessellation. PMID- 24765123 TI - Use of DEKOIS 2.0 to gain insights for virtual screening. PMID- 24765124 TI - In silico polypharmacology: retrospective recognition vs. rational design. PMID- 24765125 TI - KRIPO - a structure-based pharmacophores approach explains polypharmacological effects. PMID- 24765126 TI - Facing the challenges of computational target prediction. PMID- 24765127 TI - Visualization of chemical space for medicinal chemists. PMID- 24765128 TI - What compound should I make next? Using Matched Molecular Series for prospective medicinal chemistry. PMID- 24765129 TI - Limits to molecular matched-pair analysis: the experimental uncertainty case. PMID- 24765130 TI - An automatic system for the simultaneous translation of lectures. PMID- 24765131 TI - Entropy in specificity and thermodynamics of binding. PMID- 24765132 TI - Development of cannabinoid receptor (CB 2 R) ligands for application in PET studies - where to attach the radiolabel? PMID- 24765133 TI - TRAIL combinations: The new 'trail' for cancer therapy (Review). AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is anticipated to be one of the most effective cancer treatments. However, resistance to TRAIL therapy remains a challenge facing the development of anticancer strategies. To circumvent this problem, TRAIL combinations have been experimented with for over ten years to induce synergism or sensitize resistant cancer cells. By analyzing the signaling pathways triggered by these combinations, this review has defined a set of core targets for novel combinatorial treatments. The review suggests specific pathways to be targeted together with TRAIL for more efficient treatment, including cellular FLICE inhibitory protein and its downstream survival factors, the Bcl-2 family and other prominent targets. The suggested pathways provide new avenues for more effective TRAIL-based cancer therapy. PMID- 24765134 TI - Collapsin response mediator proteins: Potential diagnostic and prognostic biomarkers in cancers (Review). AB - The collapsin response mediator proteins (CRMPs) were originally identified as mediators of semaphorin 3A signaling and neuronal differentiation. The CRMP family consists of five homologous cytosolic proteins, CRMP1-5. Altered expression levels of CRMPs have been observed in several malignant tumors, including lung, breast, colorectal, prostate, pancreatic and neuroendocrine lung cancer. The aim of the current study was to review the recent progress achieved in understanding the association between the different levels of CRMP expression in tumors and their involvement in pathological functions, such as tumor metastasis, disease progression, subtype differentiation and clinical outcome, to address the potential value of CRMPs as biomarkers for the diagnosis and prognosis of cancer patients. PMID- 24765135 TI - Identification of estrogen receptor proteins in breast cancer cells using matrix assisted laser desorption/ionization time of flight mass spectrometry (Review). AB - Estrogen receptors [ERs (subtypes alpha and beta)], classified as a nuclear receptor super family, are intracellular proteins with an important biological role as the transcription factors for estrogen target genes. For ER-induced transcription, an interaction must exist between ligand and coregulators. Coregulators may stimulate (coactivators) or inhibit (corepressors) transcription, following binding with a specific region of the gene, called the estrogen response element. Misbalanced activity of coregulators or higher ligand concentrations may cause increased cell proliferation, resulting in specific types of cancer. These are exhibited as overexpression of ER proteins. Breast cancer currently ranks first in the incidence and second in the mortality of cancer in females worldwide. In addition, 70% of breast tumors are ERalpha positive and the importance of these proteins for diagnostic use is indisputable. Early diagnosis of the tumor and its classification has a large influence on the selection of appropriate therapy, as ER-positive tumors demonstrate a positive response to hormonal therapy. Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI TOF MS) has been hypothesized to have great potential, as it offers reliable, robust and efficient analysis methods for biomarker monitoring and identification. The present review discusses ER protein analysis by MALDI TOF MS, including the crucial step of protein separation. PMID- 24765136 TI - Autophagy: A novel therapeutic target for hepatocarcinoma (Review). AB - Autophagy is a highly conserved intracellular degradation process and plays an important role in hepatocarcinogenesis. Available data show that autophagy is involved in anti-hepatocarcinoma (HCC) therapies. Autophagy regulation involves a novel target for overcoming therapeutic resistance and sensitizing HCC to currently therapeutic methods. This is a systematic review on the interface of autophagy and the development of HCC and outlining the role of autophagy in current anti-HCC approaches. Understanding the significance of autophagy in anti HCC therapy may offer a novel therapeutic target for improving anti-cancer efficacy and prolong survival for HCC patients. PMID- 24765138 TI - Post-translational modifications of proliferating cell nuclear antigen: A key signal integrator for DNA damage response (Review). AB - Previous studies have shown that the post-translational modifications of proliferating cell nuclear antigen (PCNA) may be crucial in influencing the cellular choice between different pathways, such as the cell cycle checkpoint, DNA repair or apoptosis pathways, in order to maintain genomic stability. DNA damage leads to replication stress and the subsequent induction of PCNA modification by small ubiquitin (Ub)-related modifiers and Ub, which has been identified to affect multiple biological processes of genomic DNA. Thus far, much has been learned concerning the behavior of modified PCNA as a key signal integrator in response to DNA damage. In humans and yeast, modified PCNA activates DNA damage bypass via an error-prone or error-free pathway to prevent the breakage of DNA replication forks, which may potentially induce double-strand breaks and subsequent chromosomal rearrangements. However, the exact mechanisms by which these pathways work and by what means the modified PCNA is involved in these processes remain elusive. Thus, the improved understanding of PCNA modification and its implications for DNA damage response may provide us with more insight into the mechanisms by which human cells regulate aberrant recombination events, and cancer initiation and development. The present review focuses on the post-translational modifications of PCNA and its important functions in mediating mammalian cellular response to different types of DNA damage. PMID- 24765137 TI - Molecular mechanisms of chemoresistance in osteosarcoma (Review). AB - Due to the emergence of adjuvant and neoadjuvant chemotherapy, the survival rate has been greatly improved in osteosarcoma (OS) patients with localized disease. However, this survival rate has remained unchanged over the past 30 years, and the long-term survival rate for OS patients with metastatic or recurrent disease remains poor. To a certain extent, the reason behind this may be ascribed to the chemoresistance to anti-OS therapy. Chemoresistance in OS appears to be mediated by numerous mechanisms, which include decreased intracellular drug accumulation, drug inactivation, enhanced DNA repair, perturbations in signal transduction pathways, apoptosis- and autophagy-related chemoresistance, microRNA (miRNA) dysregulation and cancer stem cell (CSC)-mediated drug resistance. In addition, methods employed to circumvent these resistance mechanism have been shown to be effective in the treatment of OS. However, almost all the current studies on the mechanisms of chemoresistance in OS are in their infancy. Further studies are required to focus on the following aspects: i) Improving the delivery of efficacy through novel delivery patterns; ii) improving the understanding of the signal transduction pathways that regulate the proliferation and growth of OS cells; iii) elucidating the signaling pathways of autophagy and its association with apoptosis in OS cells; iv) utilizing high-throughput miRNA expression analysis to identify miRNAs associated with chemoresistance in OS; and v) identifying the role that CSCs play in tumor metastasis and in-depth study of the mechanism of chemoresistance in the CSCs of OS. PMID- 24765140 TI - Inhibition of urokinase-type plasminogen activator expression by dihydroartemisinin in breast cancer cells. AB - The aim of the present study was to investigate the inhibitory effects of dihydroartemisinin (DHA) on the primary tumor growth and metastasis of the human breast cancer cell line, MDA-MB-231, in vitro. The expression levels of urokinase type plasminogen activator (uPA) were detected by immunocytochemistry in two cell lines (MCF-7 and MDA-MB-231). The MDA-MB-231 cell activity was inhibited by various concentration gradients of DHA. The inhibitory rate, cell growth curve and apoptotic morphological observations were obtained using the MTT assay at 0, 24, 48 and 72 h. Cell scratch migration was performed at various time-points to test the cell proliferation and migration capacity. Reverse transcription polymerase chain reaction was used to analyze the effect of DHA on uPA mRNA expression in breast cancer cells. The human breast cancer cell line, MDA-MB-231, possesses higher metastatic potential and relatively higher expression of uPA when compared with the MCF-7 cell line. DHA was found to inhibit the proliferation and migration capacity of the cell line, MDA-MB-231, in vitro. The growth inhibition occurred in a time- and dose-dependent manner, with IC50 values of 117.76+/-0.04, 60.26+/-0.12 and 52.96+/-0.07 MUmol/l following 24, 48 and 72 h, respectively. The inhibition of uPA was observed to decrease breast cancer cell growth and migration. Thus, results of the present study indicate that DHA may be used for further studies with regard to breast cancer therapy. PMID- 24765139 TI - Magnetic fluid hyperthermia inhibits the growth of breast carcinoma and downregulates vascular endothelial growth factor expression. AB - The application of magnetic fluid hyperthermia (MFH) with nanoparticles has been shown to inhibit tumor growth in several animal models. However, the feasibility of using MFH in vivo to treat breast cancer is uncertain, and the mechanism is unclear. In the present study, it was observed that the intratumoral administration of MFH induced hyperthermia significantly in rats with Walker-265 breast carcinomas. The hyperthermia treatment with magnetic nanoparticles inhibited tumor growth in vivo and promoted the survival of the tumor-bearing rats. Furthermore, it was found that MFH treatment downregulated the protein expression of vascular endothelial growth factor (VEGF) in the tumor tissue, as observed by immunohistochemistry. MFH treatment also decreased the gene expression of VEGF and its receptors, VEGF receptor 1 and 2, and inhibited angiogenesis in the tumor tissues. Taken together, these results indicate that the application of MFH with nanoparticles is feasible for the treatment of breast carcinoma. The MFH-induced downregulation of angiogenesis may also contribute to the induction of an anti-tumor effect. PMID- 24765141 TI - Characterization of sonic hedgehog inhibition in gastric carcinoma cells. AB - Aberrant activation of the sonic hedgehog (Shh) signaling pathway plays an important role in gastric cancer. The exact mechanisms defining how the Shh pathway promotes tumorigenesis or regulates its downstream targets remains elusive. In the present study, the effects of inhibiting the Shh signaling pathway in gastric cancer AGS cells was examined. It was identified that the Shh antagonist, cyclopamine, inhibited cancer proliferation, migration and invasion in a dose- and time-dependent manner. Additionally, it was revealed that several key targets that are activated by the Shh signaling pathway, Gli1 and CXCR4, were downregulated at an RNA and protein level by cyclopamine. The results from the present study may be of benefit in facilitating the development of novel therapeutic strategies to treat gastric cancer in human patients. PMID- 24765142 TI - Inhibitory effects of subcutaneous tumors in nude mice mediated by low-frequency ultrasound and microbubbles. AB - The aim of the present study was to investigate the sonication effects of 21-kHz ultrasound (US) with microbubbles (MBs) on the subcutaneous prostate tumors of nude mice. In total, 15 tumor-bearing nude mice were divided into three groups: The control group, the low-frequency US group and the US+MB group. The MBs used were from US contrast agent SonoVue. The parameters of the US were as follows: 21 kHz, 26 mW/cm2 and a 40% duty cycle (2 sec on, 3 sec off) for 3 min, once every other day for 2 weeks. Color Doppler flow imaging, hematoxylin and eosin (HE) staining, immunoblotting and transmission electron microscopy (TEM) were used to evaluate the results. Following 2 weeks of treatment, the blood flow signal disappeared in the US+MB group only, and the tumor size was smaller when compared with the control and US groups. For the immunoblotting, the intensity of cyclooxygenase-2 and vascular endothelial growth factor in the US+MB group was lower compared with the other two groups. Tumor necrosis was present and the nucleus disappeared upon HE staining in the US+MB group. Upon TEM analysis, increased cytoplasmic vacuolation and dilatation of the perinuclear cisternae of the tumor cells were found in the US+MB group. In the control and US groups, the tumors had intact vascular endothelia and vessel lumens. However, lumen occlusion of the vessels was observed in the US+MB group. In conclusion, 21-kHz low intensity US with MBs may result in vessel occlusion and growth inhibitory effects in the subcutaneous tumors of nude mice. PMID- 24765143 TI - Discerning primary tumors from metastases in synchronous nasopharyngeal squamous cell carcinoma and cutaneous squamous cell carcinoma: A case report and review of the literature. AB - Nasopharyngeal carcinoma is one of the most common types of malignant tumor in Southern China and Southeast Asia, and its etiology is closely associated with Epstein-Barr virus (EBV) infection. Non-keratinizing carcinoma accounts for >95% of all nasopharyngeal carcinoma cases. In addition, metastatic nasopharyngeal carcinoma from other locations in the body is extremely rare. This study reports the case of a 53-year-old female who presented with a lesion on the left nasal alar skin that had slowly developed over a five-year period. A biopsy was obtained and the lesion was histologically diagnosed as cutaneous squamous cell carcinoma (SCC). A nasopharyngeal neoplasm was also detected by 18-fluorine-2 fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography and nasopharyngoscopy. A biopsy of the nasopharyngeal neoplasm confirmed a diagnosis of SCC. However, a small EBV-encoded nuclear RNA (EBER) test demonstrated that the nasopharyngeal tumor cells were all negative for EBV. As the majority of nasopharyngeal carcinomas were positive for EBER, it was concluded that the nasopharyngeal carcinoma had metastasized from the cutaneous SCC. A brief review of literature is also presented, in addition to a discussion of the pathogen, epidemiology and diagnosis of cutaneous and nasopharyngeal carcinomas. PMID- 24765144 TI - Significance of semaphorin-3A and MMP-14 protein expression in non-small cell lung cancer. AB - Semaphorin-3A is a chemorepellent guidance protein that is crucial in regulating the tumor microenvironment. MMP-14, a membrane-anchored matrix metalloproteinase, is closely associated with extracellular matrix (ECM) remodeling and cell migration in the progression of cancer metastasis. In the present study, the correlation between the expression levels of semaphorin-3A and MMP-14, and their subsequent prognostic significance in non-small cell lung cancer (NSCLC), was investigated. The expression of semaphorin-3A and MMP-14 protein levels was analyzed in 94 cases of NSCLC tissues and in 80 cases of normal lung tissues, using immunohistochemistry (IHC). Correlation and survival analysis were used to further investigate their association and prognostic value. The results revealed that the NSCLC tissues exhibited a lower expression of semaphorin-3A and a higher expression of MMP-14 than in the control lung tissues. The downregulation of semaphorin-3A and upregulation of MMP-14 may promote pleural invasion, lymph node metastasis, vascular invasion and proliferating cell nuclear antigen expression. The expression of semaphorin-3A was correlated with the maximum diameter of tumor. There was a negative correlation between the protein expression levels of semaphorin-3A and MMP-14 in NSCLC tissues. Furthermore, we identified that the patients with lower expression of semaphorin-3A and a higher expression of MMP-14 had worse disease prognosis. The data suggest that lower expression of semaphorin 3A and a higher expression of MMP-14 may promote occurrence and development in NSCLC and that the combined detection of semaphorin-3A and MMP-14 protein may be a helpful tool in predicting the prognosis of NSCLC. PMID- 24765145 TI - Inhibition of phosphoinositide 3-kinase/Akt pathway decreases hypoxia inducible factor-1alpha expression and increases therapeutic efficacy of paclitaxel in human hypoxic gastric cancer cells. AB - The phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell proliferation, transformation, apoptosis, tumor growth and angiogenesis. Paclitaxel is commonly used to treat multiple human malignancies; however, the underlying mechanisms of paclitaxel in gastric cancer (GC) have not been fully investigated. In the present study, specimens from 45 GC and 36 chronic gastritis patients were collected, and the correlations of PI3K, phosphorylated-Akt (p-Akt) and hypoxia-inducible factor-1alpha (HIF-1alpha) expression with the clinicopathological characteristics of GC were analyzed by immunohistochemistry. The human SGC-7901 GC cells under hypoxic conditions were pretreated with the PI3K inhibitor, LY294002 (40 MUM), and paclitaxel (0.1 MUM). The expression levels of PI3K, p-Akt and HIF-1alpha were detected by quantitative polymerase chain reaction and western blotting. Cell proliferative activity and apoptosis were evaluated by the Cell Counting Kit-8 assay and flow cytometry. As a result, the rates of positive expression of PI3K, p-Akt and HIF-1alpha were significantly higher in GC compared with chronic gastritis patients (each P<0.01), and were positively associated with the tumor-node-metastasis (TNM) staging, lymph node metastases, lymphatic infiltration and vascular infiltration (each P<0.01), but inversely correlated with tumor differentiation (P<0.01) in patients with GC. Under hypoxic conditions, the combined inhibition of the PI3K/Akt pathway with paclitaxel markedly reduced the proliferative activity and induced cell apoptosis in GC cells compared with the single treatment of PI3K inhibitor or paclitaxel (each P<0.01), and was accompanied by a decreased expression of HIF-1alpha. Overall, our findings indicate that the increased expression of the PI3K/Akt/HIF-1alpha pathway was closely correlated with tumor differentiation, TNM staging, lymph node metastases and lymphatic and vascular infiltration. The inhibition of the PI3K/Akt pathway enhanced the therapeutic efficacy of paclitaxel in GC cells under hypoxic conditions, suggesting that the PI3K/Akt/HIF-1alpha pathway may act as an important therapeutic target for paclitaxel treatment of GC. PMID- 24765146 TI - Expression of TSG101 protein and LSF transcription factor in HPV-positive cervical cancer cells. AB - Our previous study demonstrated a decreased expression of tumor susceptibility gene 101 (TSG101) in cervical cancer cells. To identify the mechanism responsible for TSG101 downregulation during cervical cancer development, we analyzed the TSG101 promoter using cis-element cluster finder software. One of the transcription factors whose binding site was detected in the TSG101 promoter was late SV40 factor (LSF). The aim of this study was to analyze the TSG101 protein and LSF expression levels during cervical cancer development. Immunohistochemical analysis confirmed a previously observed decreased expression of TSG101, whereas quantitative polymerase chain reaction (qPCR) and immunohistochemistry analysis revealed high expression of LSF in cervical, precancer and cancer cells compared with human papillomavirus (HPV)-negative non-cancer samples. High expression of LSF in cervical cancer HPV-positive cells suggests that this protein may be important in the regulation of TSG101 expression, as well as in cervical carcinogenesis. The role of LSF as a mediator in cervical cancer development must be confirmed in future studies. PMID- 24765147 TI - Inflammatory pseudotumor of the thymus: A case report and review of the literature. AB - Inflammatory pseudotumors are rare benign tumors consisting of cellular and stromal elements of a localized reactive process. While inflammatory pseudotumors are commonly detected in the lung and occasionally in other organs, only one case of inflammatory pseudotumor of the thymus has been reported in the literature to date. This report presents a 54-year-old male patient with inflammatory pseudotumor of the thymus accompanied by pulmonary inflammation. The patient presented with chest pain and moderate fever for 12 days. Enhanced computed tomography of the thorax revealed an anterior mediastinal solid and cystic mass, which constricted the left brachiocephalic vein accompanied by bilateral lung inflammation and marginal pleural effusion. The patient underwent a median sternotomy for the surgical removal of the mass. Histologically, the resected mass was composed of necrotic and fibrous tissues and inflammatory infiltrates, and the diagnosis was confirmed as an inflammatory pseudotumor of the thymus. The patient's symptoms were resolved following surgery and the patient remained asymptomatic during the six-month follow-up period. In addition, we reviewed the previous literature and discussed the diagnosis and management of our patient. This report provides further insights into the pathogenesis and underlying mechanisms of inflammatory pseudotumors of the thymus to aid in the diagnosis and development of effective therapies. PMID- 24765148 TI - CD30+ extranodal natural killer/T-cell lymphoma mimicking phlegmonous myositis: A case report. AB - The current study presents a case of a 23-year-old male with CD30+ nasal-type extranodal natural killer/T-cell lymphoma (NKTL), with unusual clinical features mimicking phlegmonous myositis. The patient initially presented with swelling and tenderness of the left lower limb, particularly around the left ankle. One month later, pharyngalgia and fever developed and the patient was treated with antibiotics for the phlegmonous inflammation, however, the symptoms were not relieved. A muscle biopsy was performed on the lesion and revealed diffuse infiltration of atypical lymphoid cells with irregular nuclei. Immunohistochemistry showed staining for CD3E(-), CD20(-), CD45(+), CD30(+) and CD56(+) presented with positive staining for certain tumor cells, granzyme B(+), activin receptor-like kinase 1(-), Ki-67(+) and Epstein-Barr virus-encoded small RNA(+), which indicated nasal-type extranodal NKTL. The present case emphasized that extranodal NKTL may be a rare cause of phlegmonous inflammation and fever of undetermined origin. PMID- 24765149 TI - Overexpression of SLC25A38 protein on acute lymphoblastic leukemia cells. AB - SLC25A38 is a recently identified protein that belongs to the mitochondrial solute carrier family, SLC25. Previous studies have shown that it is a pro apoptotic protein, which regulates intrinsic caspase-dependent apoptosis. In order to clarify the effect of SLC25A38 protein expression on acute lymphoblastic leukemia (ALL) cells, we detected the expression of SLC25A38 in various cell lines (RPMI 8226, U266, Molt-4 and Jurkat) by western blot analysis. The results indicate that SLC25A38 is highly expressed in the four cell lines. Among 55 leukemia patients (adult, n=32 and infant, n=23), a high expression of SLC25A38 protein was observed in seven infant (7/23, 30.4%) and 15 adult (15/32, 46.9%) ALL patients. Two adult ALL patients that were positive for SLC25A38 were analyzed and the level of SLC25A38 significantly reduced or disappeared following combined chemotherapy, however, reappeared upon ALL recurrence. The expression level was identified to be associated with the proportion of blast cells in the bone marrow. Additionally, SLC25A38 and Notch1 were co-expressed in the four cell lines and the ALL patient samples. The present results show that expression of SLC25A38 is a common feature of ALL cells and may be a novel biomarker for diagnosis, as well as a potential therapeutic target for ALL. PMID- 24765150 TI - Exophytic gastrointestinal stromal tumor with cystic changes: A case report. AB - Gastrointestinal stromal tumor (GIST) is the most common type of mesenchymal tumor in the gastrointestinal tract. A large tumor size often means a poor prognosis. This report presents a case of a large exophytic GIST with cyst change, for which the outcome of favourable prognosis was unexpected. A 78-year old male presented with abdominal distension and a poor appetite, and was primarily diagnosed with a pancreatic mass. Abdominal ultrasonography, computed tomography and magnetic resonance imaging revealed a tumor in the body of the pancreas, which was closely attached to the gastric wall. Surgery was performed to excise the tumor. The tumor originated from the gastric cells and was ~17*15*16 cm in size. A diagnosis of GIST was confirmed by histomorphological and immunohistochemical findings. According to the postoperative findings, the tumor was classified to be in the high-risk group, for which the suggested treatment is imatinib. However, the patient was not treated with imatinib and, three years following surgery, the patient is alive with no evidence of tumor recurrence. PMID- 24765151 TI - Complex IV subunit 1 defect predicts postoperative survival in hepatocellular carcinoma. AB - Mitochondrial oxidative phosphorylation (OXPHOS) is responsible for adenosine triphosphate synthesis and OXPHOS deficiency plays a significant role in tumorigenesis. The defects of mitochondrial-encoded OXPHOS subunits have been found in normal and cirrhotic liver, however their contributions in hepatocellular carcinoma (HCC) are not clear. The present study aimed to examine these defects in resected HCC tissues. In total, 102 human HCC tissues were collected from patients undergoing curative resection, and immunohistochemical staining was performed to assess tissue expression of complex I subunit 6, complex III subunit 3, complex IV subunit 1 (CIV-1) and complex V subunit 6. Cox proportional hazard model analysis was performed, including all clinicopathological factors, to postoperatively estimate the overall survival rate. The results showed that the majority of HCC tissues contained various degrees of expression defects for OXPHOS subunits. Among these, the major CIV-1 defect (expression defect area of >25% of the examined area) (P<0.001) and early distant metastasis (P<0.001) were independently associated with the overall survival rate. Kaplan-Meier analysis also demonstrated that the major CIV-1 defect was significantly associated with a poor overall survival rate (log-rank, P=0.002). The findings in the present study clearly indicate that the major CIV-1 expression defect may serve as an independent negative prognostic factor in HCC patients following curative resection. PMID- 24765152 TI - Effects of epidermal growth factor on the invasive activity and cytoskeleton of oral squamous cell carcinoma cell lines. AB - Epidermal growth factor (EGF) is present at high concentrations in human saliva and modulates the growth and differentiation of various cancer cells. To elucidate the molecular mechanisms by which EGF affects oral cancer proliferation and invasion, the current study analyzed the Matrigel invasion activity of cultured oral cancer cell lines. Cell proliferation under the influence of EGF was subjected to Matrigel invasion assays, and cell proliferation in the absence of EGF was used as control. Northern blot analyses quantified the invasiveness and tumorigenicity. Chloramphenicol acetyltransferase assay determined the EGF stimulation of matrix metalloproteinase (MMP) 1 expression. EGF increased the number of cells penetrating the Matrigel membrane. Northern blot analysis revealed that MMP1 and cytokeratin 19 expression correlate with EGF. In addition, the morphology of HSC-3 and SAS cells changed following the addition of EGF to the culture medium. A transient transfection assay revealed that EGF increases the promoter activities of MMP1 in HSC-3 cells. These observations suggested that EGF increases the invasive activity of oral cancer cells, partly by increasing MMP1, and morphological changes may be induced by altering the composition of cytoskeletal proteins. PMID- 24765153 TI - Sacral chordoma in an adult showing an aggressive clinical course: A case report. AB - The current report presents a case of a 78-year-old male with sacral chordoma, showing an aggressive clinical course. The patient underwent sacral resection, however, nine months later, multiple metastases were detected by magnetic resonance imaging. The metastases progressed rapidly and 15 months following surgery the patient succumbed to respiratory dysfunction. An autopsy revealed multiple metastases of the lung, liver, heart, kidneys and vertebrae. Pathologically, the tumors did not show proliferation of anaplastic cells or dedifferentiation; however, the metastatic tumor cells were smaller than the primary tumor cells. The Ki-67 labeling indices were <5% in all of the patient's tumors, therefore, the capacity for cellular proliferation of the tumors was considered to be low. Chordoma in adults are generally slow-growing tumors and are associated with a relatively prolonged course and frequent local recurrences. Therefore, it must be recognized that chordoma may grow rapidly and show an aggressive clinical course, even when the Ki-67 labeling index is low. PMID- 24765154 TI - Expression of astrocyte elevated gene-1 closely correlates with the angiogenesis of gastric cancer. AB - Previous studies have demonstrated that astrocyte elevated gene-1 (AEG-1) is overexpressed in several cancer types and that its upregulation may promote cell proliferation, cell transformation and tumor progression. The present study investigated the expression and prognostic value of AEG-1 in primary gastric cancer (GC) as well as its role in angiogenesis. The results obtained from real time reverse transcription polymerase chain reaction and western blotting revealed the upregulation of AEG-1 mRNA (P=0.007) and protein expression (P<0.001) in the majority of cancerous tissues compared with matched adjacent non cancerous gastric tissues. To further investigate the clinicopathological and prognostic roles of AEG-1, immunohistochemical analysis of 216 GC tissue blocks was performed. The results showed that high AEG-1 expression closely correlated with differentiation degree (P<0.001 ), T stage (P<0.001), N stage (P=0.003) and M stage (P=0.013). Consistent with the abovementioned results, AEG-1 upregulation was also found to significantly correlate with poor survival in GC patients (P<0.001). Furthermore, carcinomas with elevated AEG-1 expression demonstrated high vascular endothelial growth factor (VEGF) expression and microvessel density, which was labeled by cluster of differentiation 34. In addition, an AEG 1 siRNA assay in MGC-803 cells showed that the AEG-1 gene may promote VEGF and hypoxia-inducible factor-1alpha protein and mRNA expression. The results of the current study indicated that AEG-1 may serve as a valuable prognostic marker for GC and may be involved in regulating tumor angiogenesis. PMID- 24765155 TI - Complete response of lung metastases from rectal cancer to combination first-line therapy of S-1 and irinotecan plus bevacizumab: A case report and review of the literature. AB - This report presents the case of a 72-year-old male who had undergone abdominoperineal resection following a diagnosis of lower rectal cancer with multiple lung metastases. Pathologically, the resected specimen exhibited advanced rectal cancer with regional lymphoid metastases and was classified as stage IV disease. S-1 and irinotecan (IRIS) plus bevacizumab combination therapy was used to treat the lung metastases following the surgery. S-1 (100 mg/body) was administered orally on days 1-14 of a 28-day cycle, and irinotecan (125 mg/m2) and bevacizumab (7.5 mg/kg) were administered by intravenous infusion on days 1 and 15. Computed tomography revealed a marked decrease in the size of the metastases following three therapeutic courses, and no lung metastases or new lesions were detected following nine therapeutic courses. The response was declared clinically complete. The patient refused additional treatment following nine therapeutic courses, and there was no recurrence 36 months after the final course of therapy. This case demonstrates the efficacy of IRIS plus bevacizumab as a first-line combination therapy against lung metastases of rectal cancer. PMID- 24765156 TI - Malignant transformation of hyperplastic gastric polyps: An immunohistochemical and pathological study of the changes of neoplastic phenotype. AB - In spite of the evidence that the malignant transformation of gastric hyperplastic polyps (HPs) is a rare event, it must always be taken into account during diagnosis. The aim of the current study was to clarify the mechanism of the malignant transformation of gastric hyperplasia polyps, with focus on phenotypic expression, cell proliferation and p53 overexpression. Immunohistochemistry for mucin phenotypic markers, including MUC1, MUC2, MUC5AC, MUC6, tight junction factors (claudin-3, -4 and -18), an intestinal phenotypic marker [caudal type homeobox 2 (Cdx2)], Ki-67 proliferative index and p53 overexpression, was performed on archival specimens of gastric polyps excised from six patients. Histologically, the intermingled components of several lesions were present in these polyps. Furthermore, the cancer components were predominantly differentiated adenocarcinoma. Immunohistochemically, all hyperplastic components expressed MUC5AC, but did not exhibit positivity for MUC2. Additionally, the majority of hyperplastic components were immunonegative for claudin-3, while claudin-3 positivity was observed in the majority of areas of dysplasia and carcinoma. Expression of claudin-4 was also observed in the majority of cases and claudin-18 was preserved in the hyperplastic, dysplastic and adenocarcinomatous lesions of all cases. Nuclear accumulation of Cdx2 was detected in almost all the samples with dysplasia and carcinoma, while nuclear p53 was detected in 24-80% of the dysplastic areas and >85% of the cancer components. The Ki-67 labeling index appeared to correlate with neoplastic progression. The observations provided evidence that the mechanism underlying malignant transformation of gastric HPs may occur by multistep carcinogenesis, such as the hyperplasia-adenoma (dysplasia)-adenocarcinoma sequence, and these neoplastic cells may acquire various phenotypes during this process. PMID- 24765157 TI - Removal of an intra-abdominal desmoplastic small round cell tumor by repetitive debulking surgery: A case report and literature review. AB - In the current study, a case of recurrent desmoplastic small round cell tumor (DSRCT) is presented, which was successfully treated by repetitive debulking surgery. In May 2010, a 39-year-old male, with a history of surgical resection of intra-abdominal DSRCT, visited the Ibaraki Medical Center, Tokyo Medical University Hospital (Ami, Japan) with severe lower abdominal discomfort. Abdominal computed tomography revealed a large tumor in the pouch of Douglas with a small number of nodules in the abdominal cavity. The recurrent DSRCT was diagnosed and removed via lower anterior resection; however, complete resection was impossible due to multiple peritoneal metastases. One year later, the patient developed pain in the right groin due to the growth of metastasized tumor cells in the groin lymph nodes. The affected lymph nodes were removed utilizing an extra-peritoneal approach. At the time of writing, the patient continues to survive without any symptoms 60 months since the initial surgery. In conclusion, surgical debulking is a significant procedure for relieving patient symptoms as well as improving the survival time of patients with metastatic and recurrent DSRCT. PMID- 24765158 TI - Circulating tumor cells as a prognostic factor in patients with small cell lung cancer. AB - The detection of circulating tumor cells (CTCs) in peripheral blood is currently an important field of study. Detection of CTCs by the OBP-401 assay (TelomeScan(r)) has previously been reported to be useful in the diagnosis, prognosis and evaluation of therapeutic efficacy in breast and gastric cancer. The aim of the present study was to evaluate the OBP-401 assay as a novel method of detecting CTCs of small cell lung cancer (SCLC) patients and to evaluate whether CTC count is associated with prognosis. Prospectively, 30 consecutively diagnosed SCLC patients who had commenced chemotherapy or chemoradiotherapy were enrolled as subjects of the current study. Peripheral blood specimens were collected from the SCLC patients prior to and following the initiation of treatment and the viable CTCs were detected in the specimens following incubation with a telomerase-specific, replication-selective, oncolytic adenoviral agent, which was carrying the green fluorescent protein gene. CTCs were detected in 29 patients (96%). The group of 21 patients with a CTC count of <2 cells/7.5 ml prior to treatment (baseline) had a significantly longer median survival time than the group of eight patients with a CTC count of >=2 cells/7.5 ml prior to treatment (14.8 and 3.9 months, respectively; P=0.007). The results of a multivariate analysis showed that the baseline CTC count was an independent prognostic factor for survival time (hazard ratio, 3.91; P=0.026). Among the patients that achieved a partial response to treatment, patients who had a CTC count of <2 cells/7.5 ml following two cycles of chemotherapy tended to have a longer median progression-free survival compared with patients who had a CTC count of >=2 cell/7.5 ml (8.3 and 3.8 months, respectively; P=0.07). Therefore, CTCs may be detected via OBP-401 assay in SCLC patients and the CTC count prior to treatment appears to be a strong prognostic factor. PMID- 24765159 TI - B7-H4 expression and its role in interleukin-2/interferon treatment of clear cell renal cell carcinoma. AB - The immunological mechanism mediated by T cells is the main therapeutic target in the treatment of renal cell carcinoma (RCC) with interleukin (IL)-2 and interferon (IFN)-alpha. The aim of the present study was to evaluate the role of B7-H4 in the IL-2, IFN-alpha and IFN-gamma treatment of clear cell RCC (ccRCC). A total of 154 paraffin-embedded ccRCC tissues were studied using immunohistochemistry, which subsequently indicated that positive B7-H4 expression is associated with adverse clinical features in ccRCC. The effects of IL-2, IFN alpha and IFN-gamma on B7-H4 expression in a ccRCC cell line were evaluated at the mRNA and protein levels. In addition, the effect of B7-H4 on the killing activity of T cells was detected. B7-H4 expression was identified to be upregulated by IL-2, IFN-alpha and IFN-gamma, of which, IFN-gamma was the most capable. Additionally, blocking of B7-H4/B7-H4 ligand interactions may rescue the killing activity of T cells. Altogether, the observations of the current study showed that the immune escape pathway induced by B7-H4 may be one of the most important reasons for the low efficacy of IL-2 and IFN-alpha and the inability to observe the efficacy of IFN-gamma in mRCC. This indicates that B7-H4 may be used as a new molecular biology marker to select treatment options for patients with ccRCC. PMID- 24765160 TI - Damnacanthal is a potent inducer of apoptosis with anticancer activity by stimulating p53 and p21 genes in MCF-7 breast cancer cells. AB - Damnacanthal, an anthraquinone compound, is isolated from the roots of Morinda citrifolia L. (noni), which has been used for traditional therapy in several chronic diseases, including cancer. Although noni has long been consumed in Asian and Polynesian countries, the molecular mechanisms by which it exerts several benefits are starting to emerge. In the present study, the effect of damnacanthal on MCF-7 cell growth regulation was investigated. Treatment of MCF-7 cells with damnacanthal for 72 h indicated an antiproliferative activity. The MTT method confirmed that damnacanthal inhibited the growth of MCF-7 cells at the concentration of 8.2 MUg/ml for 72 h. In addition, the drug was found to induce cell cycle arrest at the G1 checkpoint in MCF-7 cells by cell cycle analysis. Damnacanthal induced apoptosis, determined by Annexin V-fluorescein isothiocyanate/propidium iodide (PI) dual-labeling, acridine-orange/PI dyeing and caspase-7 expression. Furthermore, damnacanthal-mediated apoptosis involves the sustained activation of p21, leading to the transcription of p53 and the Bax gene. Overall, the present study provided significant evidence demonstrating that p53-mediated damnacanthal induced apoptosis through the activation of p21 and caspase-7. PMID- 24765161 TI - Potential enhancement of intravenous nano-hydroxyapatite in high-intensity focused ultrasound ablation for treating hepatocellular carcinoma in a rabbit model. AB - The aim of the present study was to evaluate the safety and efficiency of an intravenously delivered nano-hydroxyapatite (Nano-HA) solution into a rabbit model (Oryctolagus cuniculus) to determine the potential enhancement of high intensity focused ultrasound (HIFU) for the ablation of hepatocellular carcinoma (HCC) in liver tissue. The present study clearly indicated that the intravenous delivery of large quantities of Nano-HA into the body of the rabbit model over relatively short periods of time may be absorbed by the hepatic reticuloendothelial system. Subsequent HIFU treatment for HCC, as well as intravenous Nano-HA, produced a rapid increase in temperature and an enlargement of the coagulated necrotic area during ablation in the in vivo and ex vivo environments. In addition, it was found that the therapeutic doses of Nano-HA produced mild and transient abnormalities in the normal renal function and hepatic enzymes during the first 24 h following administration. The results of the current study indicated that the combination of Nano-HA and HIFU may provide a safe and effective alternative to conventional surgical procedures. PMID- 24765162 TI - Pulmonary sequestration presenting with left upper abdominal bloating and marked elevation of serum carbohydrate antigen 19-9: A case report. AB - Carbohydrate antigen 19-9 (CA19-9) is widely accepted as a tumor marker for cancers of the biliary, pancreatic and gastrointestinal tracts. Occasionally, CA19-9 is markedly elevated in the serum of patients with benign diseases. Pulmonary sequestration is a rare malformation that is characterized by the presence of lung tissue with abnormal or absent communication with the bronchi, to which blood is supplied by the systemic arteries. The current study presents a 48-year-old male who presented with upper left abdominal bloating and marked elevation of serum CA19-9 levels. The patient was referred to the Tongji Hospital (Wuhan, China) with suspected hepato-biliary-pancreatic disease and, following surgery, was diagnosed with intralobar pulmonary sequestration. Immunohistochemistry showed marked positive staining for CA19-9 in the sequestrated lung tissue. The patient's symptoms improved and the CA19-9 levels returned to the normal range following surgery. Therefore, the symptoms of upper left abdominal bloating and marked elevation of serum CA19-9 levels, in this case, may have resulted from the intralobar pulmonary sequestration. PMID- 24765163 TI - Docetaxel extravasation results in significantly delayed and relapsed skin injury: A case report. AB - Chemotherapeutic agents can result in extravasation, which is considered to be a serious complication. The increasing number of exposures to different cytotoxic agents experienced by each patient may enhance the prevalence of this complication. Docetaxel is widely used in the treatment of numerous solid tumors. Thus, the current report presents the case of a breast cancer patient who developed a significantly delayed skin reaction one day after docetaxel extravasation, a rare skin manifestation, and relapsed one week subsequently. This unusual clinical presentation is an indicator that practitioners are required to carefully monitor the patient for further cutaneous reactions in the weeks following extravasation to observe any additional adverse reactions. PMID- 24765164 TI - Long-term administration and efficacy of oxaliplatin with no neurotoxicity in a patient with rectal cancer: Association between neurotoxicity and the GSTP1 polymorphism. AB - Neurotoxicity is one of the most frequent side-effects of oxaliplatin. Oxaliplatin-induced cumulative and dose-limiting neurotoxicity either results in dose reduction or decreases the patients' quality of life. However, the symptoms of neurotoxicity often vary among patients. The current study presents the case of a male with rectal cancer, who was administered a cumulative oxaliplatin dose of >5,000 mg/m2 without developing neurotoxicity or allergic reactions. Consequently, this patient continued therapy with modified 5-fluorouracil, leucovorin and oxaliplatin treatment for four years, with stabilization of the disease. This case indicates that if oxaliplatin-containing chemotherapy shows efficacy with no toxicity, the long-term administration of oxaliplatin would be effective and tolerable. Previously, the analysis of genomic polymorphisms in drug target genes has been important for explaining interindividual variations in the efficacy and toxicity of anti-cancer drugs. In the present patient, the glutathione S-transferase P1 (GSTP1) gene polymorphism, which is involved in the detoxification of platinum drugs, was analyzed. The genotype of the present case has been revealed as wild type (Ile/Ile) genotype. In addition, the associations between oxaliplatin-induced neurotoxicity and the GSTP1 polymorphism were also assessed. Certain studies have demonstrated that oxaliplatin-induced neurotoxicity occurs more frequently in patients with the Ile/Ile genotype, while others have demonstrated that those patients with the Val/Val or Ile/Val genotypes are more likely to develop neurotoxicity. Therefore, correlation between the GSTP1 polymorphism and oxaliplatin-induced neurotoxicity remains controversial. Overall, further development of individualized chemotherapy with an analysis of genomic polymorphisms in the drug target genes is required for the prophylaxis oxaliplatin-induced neurotoxicity. PMID- 24765165 TI - Osteosarcoma of the distal radius treated by en bloc resection and reconstruction with a fibular shaft preserving the radiocarpal joint: A case report. AB - Osteosarcoma is the most common primary malignant bone tumor. The distal radius is a relatively common skeletal site for primary bone tumors, but not for osteosarcoma. It is difficult to treat Osteosarcoma of the distal radius; however, skeletal reconstruction and functional restoration following en bloc resection may be a promising technique. This report presents a 17-year-old male with osteosarcoma of the distal radius that was treated by en bloc resection and reconstruction using a fibular shaft to preserve the radiocarpal joint. After six months, radiographs revealed that the grafted fibular bone had healed well with the host bone. Physical examination demonstrated that active dorsiflexion of the affected wrist was to 90 degrees and palmer flexion was to 45 degrees . Fourteen months after surgery there was no evidence of wrist deformity, instability, metastasis or local recurrence. Therefore, this technique preserved the important structures and the joint surface for wrist stability and effective function. PMID- 24765166 TI - Postoperative spindle cell nodule of the bladder: A case report and review of the literature. AB - Postoperative spindle cell nodule (PSCN) of the bladder is a rare condition. It is a type of benign lesion frequently misdiagnosed as sarcomatoid carcinoma on the basis of similar cell morphology. The present report describes a tumor affecting a 71-year-old male who had undergone three transurethral resections. Pathological results suggested a diagnosis of sarcomatoid carcinoma, and therefore a radical cystectomy was performed. However, the tumor was later identified as a PSCN. In order to prevent such misdiagnosis, this study reviews relevant articles concerning postoperative spindle cell nodules of the bladder and compares PSCN and sarcomatoid carcinomas to identify specific characteristics of PSCN. Finally, the report emphasizes the importance of careful pathological examination in rare cases such as PSCN and sarcomatoid carcinoma. PMID- 24765167 TI - Endothelial progenitor cells contribute to the development of ovarian carcinoma tumor blood vessels. AB - Only a few studies in the literature have reported the contribution of endothelial progenitor cells (EPCs) in ovarian tumors, and with regard to malignant tumors, the data on the pre-existing endothelium insertion rate and the extent to which these cells contribute to tumor angiogenesis is controversial. The present study demonstrated the existence of EPCs and evaluated the expression of two markers, AC133 (also known as cluster of differentiation 133 or prominin) and tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (Tie2), signaling the presence of EPCs in the pre-existing endothelium. In total, 62 female patients who were diagnosed with ovarian tumors were retrospectively selected over a four-year period. Immunohistochemical analyses used Tie2 and AC133 as primary antibodies. In total, 27.4% of ovarian tumor cases expressed AC133 and Tie2 in blood vessel endothelial cells. The expression of these two markers did not correlate with the clinicopathological prognostic parameters, histological type, vascular microdensity or vessel type. The expression of AC133 and Tie2 in blood vessel endothelial cells contributes to angiogenesis progression in cases where the budding process is reduced or absent, as shown by the inverse correlation with the rate of proliferation of the endothelial cells. PMID- 24765168 TI - Unilateral lateral mass fixation of cervical spinal low-grade chondrosarcoma with intralesional resection: A case report. AB - In total, ~10% of chondrosarcomas arise from the mobile spine, and these are prone to local recurrence despite being low-grade malignant tumors. Almost all patients will present with pain and a palpable mass in the area of the lesion. For adequate management of the disease, an early diagnosis and careful surgical staging are important. The present study reports a case of cervical spinal low grade chondrosarcoma in a young female presenting with a slow-growing mass that had not metastasized during a 3-year period. A unilateral lateral mass fixation system of screws and rods was installed following an intralesional resection of the tumor. At present, two years following the surgery, the patient exhibits no neurological deficiency symptoms. Therefore, unilateral fixation presents an effective alternative technique for the treatment of patients with a lesion on the cervical spine. PMID- 24765169 TI - Primary Burkitt's lymphoma of the thyroid without Epstein-Barr virus infection: A case report and literature review. AB - Primary thyroid lymphomas are rare, and the majority are B-cell lymphoma. Primary Burkitt's lymphoma (BL) of the thyroid is much less common than the other types of lymphoma. The current study presents the case of an eight-year-old male with a mass in the right lobe of the thyroid, which was detected by B-ultrasound. The patient was diagnosed with BL by immunohistochemistry, fluorescence in situ hybridization analysis of MYC (8q24) and immunoglobulin rearrangement assays. Furthermore, subsequent positron emission tomography-computed tomography scans revealed no abnormal metabolites in the left lobe of the thyroid or in other parts of the body following surgery. The patient underwent alternate R-B-NHL-BFM 90-A and R-B-NHL-BFM-90-B treatment for four cycles each following the thyroidectomy. The patient is well and remains free of disease recurrence following almost four years follow-up. The present study discusses this rare case of primary BL of the thyroid and presents a review of the literature. This case report provides evidence that the immediate diagnosis and treatment of primary Burkitt's lymphoma of the thyroid is likely to improve patient outcome. PMID- 24765170 TI - Promoter hypermethylation and downregulation of trefoil factor 2 in human gastric cancer. AB - Trefoil factor 2 (TFF2) plays a protective role in gastric mucosa and may be involved in the progression of gastric cancer, but the detailed functions and underlying molecular mechanisms are not clear. The present study used a combination of clinical observations and molecular methods to investigate the correlation between abnormal expression of TFF2 and gastric cancer progression. TFF2 expression was evaluated by reverse transcription polymerase chain reaction (RT-PCR), quantitative PCR (qPCR), and western blot and immunohistochemistry analyses. TFF2 methylation levels were analyzed by genomic bisulfite sequencing method. The results showed that TFF2 mRNA and protein expression were decreased in gastric cancer tissues compared with the matched non-cancerous mucosa, and the decreased level was associated with the differentiation and invasion of gastric cancer. Moreover, the average TFF2 methylation level of CpG sites in the promoter region was 70.4% in three gastric cancer tissues, while the level in associated non-neoplastic tissues was 41.0%. Furthermore, the promoter hypermethylation of TFF2 was also found in gastric cancer cell lines, AGS and N87, and gene expression was significantly increased following treatment with a demethylating agent, 5-Aza-2'-deoxycytidine. In conclusion, TFF2 expression was markedly decreased in gastric cancer and promoter hypermethylation was found to regulate the downregulation of TFF2. TFF2 has been suggested as a tumor suppressor in gastric carcinogenesis and metastasis. PMID- 24765171 TI - KRAS and BRAF genotyping of synchronous colorectal carcinomas. AB - v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genotyping is required prior to anti-epidermal growth factor receptor monoclonal antibody therapy administered in cases of metastatic colorectal carcinoma (CRC). Thus, KRAS mutation screening is required for patient management. The present study reported the experience of KRAS/v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational screening on synchronous CRC pairs from 26 patients, which were defined as index lesions (ILs) and concurrent lesions (CLs) on the basis of tumor grade and dimension and their respective lymph node and distant metastases. Overall, KRAS mutations were present in 38.4% of patients, whereas BRAF mutations were present at a frequency of 11.5%. The genotyping of paired synchronous carcinomas indicated that 11 patients (42.3%) exhibited discordant KRAS mutational statuses in terms of the presence of a mutation in only one lesion of the pair or of two different mutations harbored by each lesion. BRAF mutations were present in the synchronous tumors of two cases, whereas in two other cases, only the IL or CL harbored mutant BRAF. Overall, the mutational statuses of distant and lymph node metastases confirm the genetic heterogeneity of synchronous primary tumors. These results highlighted the fact that adequate sampling and comprehensive testing, when feasible, is likely to optimize the decision-making process for treatment approaches, even in the relatively rare event of multiple synchronous lesions. PMID- 24765172 TI - Overexpression of collagen VI alpha3 in gastric cancer. AB - Collagen VI is significant in the progression of numerous types of cancer. Type VI collagen consists of three alpha-chains and collagen VI alpha3 (COL6A3) encodes the alpha3 chain. The overexpression of COL6A3 has been demonstrated to correlate with high-grade ovarian cancer and contributes to cisplatin resistance; however, its role in human gastric cancer (GC) remains unclear. Using microarray meta-analysis, COL6A3 was observed to be frequently overexpressed in the GC tissues, furthermore, this overexpression was identified in five GC cell lines. A microarray-based co-expression network analysis was conducted and identified a total of 62 genes that were co-expressed with COL6A3, with the majority of the genes being involved in cancer-related processes, such as cell differentiation, migration and adhesion. Network analysis of these 62 genes demonstrated that fibronectin 1, a well-characterized oncogene, was located at the center of the COL6A3 co-expression network. Therefore, COL6A3 may act as an oncogene in human GC and the antagonism of COL6A3 may be an effective therapeutic treatment for GC. PMID- 24765173 TI - Expression and clinical significance of colorectal cancer stem cell marker EpCAMhigh/CD44+ in colorectal cancer. AB - Colorectal cancer stem cells are considered the source of recurrence, metastasis and drug resistance in colorectal tumors. Therefore, the identification and targeting of cancer stem cells facilitates the elimination of tumors. Although epithelial cell adhesion molecule-high (EpCAMhigh)/cluster of differentiation (CD)44+ cells are thought to act as a marker of colorectal cancer stem cells, the clinical significance of these cells in colorectal cancer remains unclear. The aim of the present study was to explore the prevalence and clinical significance of colorectal cancer stem cell marker EpCAMhigh/CD44+ in colorectal cancer. Double immunohistochemical staining was used to detect the expression of EpCAM/CD44 in 80 cases of colorectal cancer and their corresponding liver metastases. The expression of EpCAM/CD44 in colorectal cancer was analyzed, and the correlation of EpCAMhigh/CD44+ with the biological behavior of colorectal cancer was explored. In the 80 cases of colorectal cancer studied, the presence of EpCAMhigh/CD44+ cells had no correlation with gender, patient age or the magnitude of the tumor (P>0.05), but was significantly correlated with degree of differentiation, depth of invasion, clinical stage and metastatic status (P<0.05). In addition, EpCAMhigh/CD44+ cells were detected in the corresponding liver metastases. Thus, the results of this study indicate that EpCAMhigh/CD44+, a marker of colorectal cancer stem cells, is significantly correlated with the invasion and metastases of colorectal cancer. PMID- 24765174 TI - Expression of RECK and MMP-2 in salivary adenoid cystic carcinoma: Correlation with tumor progression and patient prognosis. AB - Reversion-inducing cysteine-rich protein with Kazal motifs (RECK), a glycosylphosphatidylinositol-anchored glycoprotein, inhibits the enzymatic activities of certain matrix metalloproteinases (MMPs). RECK has been studied in numerous human tumors, but the expression of RECK in salivary adenoid cystic carcinoma (SACC), and its correlation with patient prognosis, has never been investigated thus far. In the present study, the expression of RECK and MMP-2 was evaluated in two ACC cell lines and in 83 patients with SACC. The results of quantitative polymerase chain reaction and western blot analysis revealed that the ACC-2 and ACC-M cell lines expressed RECK and MMP-2 mRNA and protein. The immunohistochemical staining in the patients demonstrated that positive expression of RECK and MMP-2 was observed in 21/83 (25.3%) and 69/83 (83.1%) cases, respectively, and that RECK expression was significantly associated with the tumor-node-metastasis stage, histological grade and perineural invasion of patients with SACC (P<0.05). Furthermore, there was a significant association between the positive expression of RECK and that of MMP-2 (P<0.0001). Univariate and multivariate analyses confirmed that a lack of RECK expression was an independent and significant factor for the prediction of a poor prognosis. In conclusion, RECK is a promising prognostic marker and potential therapeutic agent in SACC. PMID- 24765175 TI - Effects of cordycepin on HepG2 and EA.hy926 cells: Potential antiproliferative, antimetastatic and anti-angiogenic effects on hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a hypervascular tumor and accumulating evidence suggests that angiogenesis plays an important role in HCC development. Cordycepin, also known as 3'-deoxyadenosine, is a derivative of adenosine, and numerous cellular enzymes cannot differentiate the two. The aim of the present study was to determine whether cordycepin regulates proliferation, migration and angiogenesis in a human umbilical vein endothelial cell line (EA.hy926) and in a hepatocellular carcinoma cell line (HepG2). MTT was used to assess cell proliferation. Apoptosis was analyzed by flow cytometry (propidium iodide staining). Transwell and wound healing assays were used to analyze the migration and invasion of HepG2 and EA.hy926 cells. Angiogenesis in EA.hy926 cells was assessed using a tube formation assay. Cordycepin strongly suppressed HepG2 and EA.hy926 cell proliferation in a dose- and time-dependent manner. Cordycepin induced EA.hy926 cell apoptosis in a dose-dependent manner (2,000 MUg/ml: 50.20+/ 1.55% vs. 0 MUg/ml: 2.62+/-0.19%; P<0.01). Cordycepin inhibited EA.hy926 cell migration (percentage of wound healing area, 2,000 MUg/ml: 3.45+/-0.29% vs. 0 MUg/ml: 85.48+/-0.84%; P<0.05), as well as tube formation (total length of tubular structure, 1,000 MUg/ml: 107+/-39 MUm vs. 0 MUg/ml: 936+/-56 MUm; P<0.05). Cordycepin also efficiently inhibited HepG2 cell invasion and migration. High-performance liquid chromatography analysis of the cytosol from EA.hy926 cells showed that cordycepin was stable for 3 h. In conclusion, cordycepin not only inhibited human HepG2 cell proliferation and invasion, but also induced apoptosis and inhibited migration and angiogenesis in vascular endothelial cells, suggesting that cordycepin may be used as a novel anti-angiogenic therapy in HCC. PMID- 24765176 TI - Papillary thyroid cancer coexisting with thyroid tuberculosis: A case report. AB - The current study presents the case of a 56-year-old female, with thyroid nodules showing signs of malignancy under B-mode ultrasonography, who was admitted to Shaoxing People's Hospital. A histopathological examination revealed the coexistence of papillary thyroid cancer (PTC) and thyroid tuberculosis (TB). A total thyroidectomy and selective neck dissection (left side, levels III, IV and VI) were performed. This report presents a rare case showing the malignant growth of thyroid nodules and the development of thyroid TB, which implicates the possible role of mycobacterial infection in the tumorigenesis of PTC. PMID- 24765177 TI - Fever of unknown origin as a presentation of colonic inflammatory myofibroblastic tumor in a 36-year-old female: A case report. AB - Inflammatory myofibroblastic tumor is a rare type of lesion that mimics malignancy and has various clinical manifestations. The current study presents a 36-year-old female with a colonic mass, which closely resembled a stromal tumor during imaging. The patient experienced intermittent fever and slight abdominal pain for one month. The fever remained at <=38.5 degrees C until the day of surgery. The patient underwent a right hemicolectomy and the preoperative fever disappeared and did not recur until the patient was discharged. PMID- 24765178 TI - MC3 Mucoepidermoid carcinoma cell line enriched cancer stem-like cells following chemotherapy. AB - Mucoepidermoid carcinoma (MEC) is common in human salivary glands. Surgery is the preferred treatment method for MEC and chemotherapy is often administered following surgery as an adjuvant cancer treatment; however, chemotherapy does not completely prevent tumor recurrence. Emerging evidence has indicated the existence of cancer stem-like (CSL)-cells in tumors. CSL-cells are important in the development, invasion and drug resistance of carcinomas. The present study aimed to investigate whether chemotherapy enriched the CSL-cells in the MEC cell line of MC3 using 5-fluorouracil (5-Fu). The MC3 cells were treated with 5-Fu, which enhanced the spherogenesis and vitality of the cells and upregulated the pluripotency gene, octamer-binding transcription factor 4. Side population analysis demonstrated that the proportion of CSL-cells also increased. These findings showed that compared with other types of cancer cells, chemotherapy was unable to effectively kill the CSL-cells resulting in an enriched CSL-cell subpopulation with a higher resistance to chemotherapy, which may have been key the recurrence of MEC. PMID- 24765179 TI - 786-0 Renal cancer cell line-derived exosomes promote 786-0 cell migration and invasion in vitro. AB - Emerging evidence indicates that cancer-derived exosomes contribute to angiogenesis, tumor immunology and invasion. However, whether cancer cell-derived exosomes regulate the migration and invasion of the cancer cell itself, and the underlying mechanisms are not well understood. In the present study, exosomes derived from the 786-0 human renal cancer cell line were isolated, purified and 100 MUg/ml were co-cultured with 786-0 cells for 24 h. The 786-0 cells were harvested for a cell invasion and migration assay. The expression of chemokine receptor type 4 (CXCR4) and matrix metalloproteinase-9 (MMP-9) in the 786-0 cells was examined by western blot analysis and revealed that the migration and invasion capabilities of the 786-0 cells were increased, however, the cell adhesion abilities were decreased as a result of the 24-h treatment with 786-0 derived exosomes. Furthermore, the expression levels of CXCR4 and MMP-9 in the 786-0 cells were increased. In conclusion, the 786-0 renal cancer cell line derived exosomes increased migration and invasion, however, they decreased the adhesion ability of the 786-0 cells. The exosomes may have increased the CXCR4 and MMP-9 expression levels in the 786-0 cells. These findings indicated that renal tumor-derived exosomes may contribute to renal cancer development and progression. PMID- 24765180 TI - Effect of the LPA-mediated CXCL12-CXCR4 axis in the tumor proliferation, migration and invasion of ovarian cancer cell lines. AB - Ovarian cancer is the most fatal gynecological cancer, with a 5-year survival rate of only 30%. Lysophosphatidic acid (LPA), which possesses growth factor-like functions, is a major regulatory factor in the peritoneal metastasis of ovarian cancer. LPA stimulates the expression of numerous genes that are associated with angiogenesis and metastasis. Ovarian epithelial carcinoma specifically expresses chemotactic factor C-X-C motif chemokine ligand 12 (CXCL12) and its receptor, CXC receptor 4 (CXCR4). The CXCL12-CXCR4 axis directly contributes to ovarian cancer cell proliferation, migration and invasion. The present study investigated the regulation of LPA on the CXCL12-CXCR4 axis and the effect of the LPA-mediated CXCL12-CXCR4 axis on the tumor proliferation, migration and invasion of ovarian cancer cell lines. The CXCR4 proteins expressed in the cell membrane and the cytoplasm of ovarian cancer cells, CAOV3 and SKOV3, were detected by immunocytochemistry. The expression of CXCR4 and CXCL12 was increased in the ovarian cancer cells in a dose- and time-dependent manner when treated with LPA compared with the control groups (P<0.05), as determined by reverse transcription polymerase chain reaction and flow cytometry. LPA (20 MUM) and CXCL12 (100 ng/ml) enhanced the proliferation, migration and invasion of the ovarian cancer cells, CAOV3 and SKOV3, as identified by MTT, Transwell and Matrigel assays following co treatment for 24 h. LPA promoted invasiveness of ovarian cancer by upregulating CXCL12-CXCR4 axis expression. PMID- 24765181 TI - Male breast metastases from nasopharyngeal carcinoma: A case report and literature review. AB - Nasopharyngeal carcinoma (NPC) is known for its high rate of regional lymph node and distant metastasis. However, NPC rarely metastasizes to the breast and, to the best of our knowledge, only four well-documented cases of breast metastasis have previously been reported in the literature, all of which are female. A 49 year-old male was diagnosed with NPC and developed a right breast mass five months later. Breast fine needle aspiration confirmed an abundance of metastatic squamous cells within the thickened tissue. The current study presents the first male case of breast metastases from NPC to broaden the clinical database. PMID- 24765182 TI - Significance of intracellular localization of survivin in cervical squamous cell lesions: Correlation with disease progression. AB - Survivin is a member of the inhibitor of apoptosis protein family. Under normal circumstances, survivin is expressed in embryonic and fetal tissues, but is completely downregulated in normal adult tissues. Notably, this protein has been found to be prominently expressed in a variety of human malignant tumors. The present study was designed to evaluate the possible role of survivin in the tumorigenesis of cervical intraepithelial neoplasia and invasive squamous cell carcinoma (SCC) of the uterine cervix. In addition, it was investigated whether the nuclear or cytoplasmic expression of survivin is associated with tumor progression. In total, 71 samples of cervical squamous tissue were obtained, including 15 normal squamous epithelia, 25 high-grade squamous intraepithelial lesions (HSILs) and 31 SCCs, from cone biopsy and hysterectomy specimens and stained for survivin expression by immunohistochemistry. The intensity of survivin expression tended to increase with tumor progression (60.0% of normal mucosa, 76.0% of HSIL and 80.6% of SCC samples demonstrated high intensity survivin expression), but this correlation was not found to be statistically significant. However, a statistically significant difference was identified in the intracellular localization of survivin among the normal mucosa, HSIL and SCC samples (P<0.001). In total, 72% (18/25) of HSIL and 54.8% (17/31) of SCC cases expressed cytoplasmic staining in contrast to the nuclear staining of the normal mucosa. In addition, 64% (16/25) of HSIL and 42% (13/31) of SCC cases showed coexpression in the nucleus and cytoplasm. An inverse correlation was identified between the decrement of nuclear survivin expression and tumor progression, but was not statistically significant (P=0.08). These results indicated that analysis of the intracellular expression of survivin (particularly cytoplasmic expression) is a marker for predicting disease progression in the uterine cervix. PMID- 24765183 TI - Allogeneic cell-based immunotherapy combined with chemotherapy and targeted therapy in advanced pancreatic cancer with metastases: A case report. AB - Immunotherapy may be an effective and potentially less toxic treatment for cancer in addition to the traditional therapies. The current study presents a case of advanced pancreatic cancer that was treated with cell-based immunotherapy using expanded activated allogeneic lymphocytes (EAAL*) in vitro with cluster of differentiation (CD)3(+) and CD8(+) cytotoxic T lymphocytes, and CD3(-) and CD56(+) natural killer cells as the major effector cells, together with chemotherapy and targeted agents. A 46-year-old female was diagnosed at the Chinese PLA General Hospital (Beijing, China) with stage IV pancreatic cancer with multiple metastases in October 2012. After receiving one cycle of chemotherapy plus nimotuzumab (Nimo), the patient received 14 infusions of EAAL*, which was obtained from a related donor, combined with seven cycles of chemotherapy with gemcitabine plus oxaliplatin and targeted therapy with Nimo. The patient was followed up for eight months. One day prior to the cell infusion, targeted therapy was administered and 48 h following the cell infusion, chemotherapy was administered. Following this treatment, carbohydrate antigen 19 9 levels decreased from 4,136 U/ml to within the normal ranges, along with the significant regression of the lesions. Occasionally mild upset was observed following the EAAL* transfusion. For the entire combined modality, grade II hematological and gastrointestinal toxicities plus grade I liver function damage and skin rash were identified. The present study demonstrated that combining allogeneic cell-based immunotherapy with conventional therapies is effective and safe, even in patients with end-stage pancreatic cancer. Therefore, this strategy is recommended for the treatment of similar cases. PMID- 24765184 TI - Adenoid cystic carcinoma of the breast: A case report and literature review. AB - Adenoid cystic carcinoma (ACC) is a rare malignant tumor of the breast that occurs in <0.1% of all patients diagnosed with breast cancer. The mean patient age at the time of diagnosis is 50-60 years. Typically, the tumor presents as a subareolar mass or as pain in the breast. While the radiological appearances of ACC are generally non-specific, the diagnosis can be made on fine-needle aspiration cytology. In the present study, a 58-year-old female patient was admitted to the Department of Radiation Oncology (Karadeniz Technical University, Faculty of Medicine, Trabzon, Turkey) with complaints of pain in the upper outer quadrant of the right breast. An excision biopsy of a lump in the upper outer quadrant revealed ACC, and perineural invasion was present. Subsequently, the patient underwent breast conservation surgery and sentinel lymph node dissection. Pathology from the second surgery depicted ACC in the form of microscopic foci around the initial surgical cavity, with two reactive sentinel lymph nodes and the closest negative margin at 2 mm. The patient was treated with radiotherapy following the surgery. No recurrence and metastasis were found after 20 months of follow-up. In conclusion, mammary ACC is a rare malignant neoplasm of the breast. Although surgery is the main treatment, the optimal adjuvant treatment of ACC of the breast has not yet been determined due to its low incidence. PMID- 24765185 TI - Langerhans cell histiocytosis misdiagnosed as liver cancer and pituitary tumor in an adult: A case report and brief review of the literature. AB - Langerhans cell histiocytosis (LCH) is a rare proliferative disorder in which pathological Langerhans cells accumulate in a variety of organs. LCH usually affects the bone, skin and lymph nodes of children; however, LCH occasionally affects vital organs, including the liver, spleen and pituitary gland. The present study reports a case of an adult LCH patient with marked liver damage, splenomegaly and pituitary damage treated using a new therapeutic strategy. This case was misdiagnosed as liver cancer and pituitary tumor on the basis of abdominal ultrasound, abdominal magnetic resonance imaging (MRI) and head MRI. The final diagnosis was established by identifying the proliferation of cluster of differentiation 1a-positive LCs in liver tissues. A new regimen of combined 12 week therapy of prednisolone/desmopressin/vincristine and 10 months of maintenance therapy of prednisolone/vinblastine/6-mercaptopurine improved symptoms, liver function and blood cell tests. PMID- 24765186 TI - Primary anorectal malignant melanoma treated with neoadjuvant chemoradiotherapy and sphincter-sparing surgery: A case report. AB - Primary anorectal (PA) malignant melanoma (MM) is a rare disease associated with a high mortality rate. The most appropriate treatment strategy for PAMM remains controversial. A 55-year-old female patient, who was misdiagnosed with locally advanced rectal carcinoma, was treated with preoperative radiotherapy and concurrent oral capecitabine. During the therapy, grade 1 leukopenia occurred, however, there was no interruption to treatment. Following chemoradiotherapy, a computer tomography scan identified that the tumor had shrunk significantly and the original enlarged lymph nodes had disappeared. Eight weeks after completion of chemoradiotherapy, sphincter-sparing surgery was performed on the patient and based on the postoperative pathological result, MM was diagnosed. At the time of writing, the patient has survived disease-free for 15 months and at the most recent follow-up examination the Karnofsky Performance Scale score was 100. The therapeutic regimen of neoadjuvant concurrent chemoradiotherapy together with sphincter-sparing surgery is considered to be an optimal choice for patients with PAMM. However, further studies are required to evaluate the efficacy and clinical utility of this therapeutic regimen. PMID- 24765187 TI - Achievement of three year remission in a case of aggressive glioblastoma using a multidisciplinary treatment strategy: A case report. AB - Glioblastoma (GB) is the most common type of malignant tumor of the central nervous system and, despite extensive research, its prognosis is poor. Although recent advances have been made in the treatment of GB with aggressive resection combined with radiochemotherapy, more than three-quarters of GB patients succumb to the disease within two years. The current study presents a highly aggressive case of small cell GB as diagnosed by histological features and immunohistochemistry for vimentin, glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, isocitrate dehydrogenase 1-R132H and p53. The patient was treated using a multidisciplinary treatment strategy, which included temozolomide, CyberKnife radiotherapy and autologous formalin fixed tumor vaccination. In addition, the patient developed radiation necrosis, which was treated with bevacizumab. In conclusion, three years following the initial diagnosis, the patient continues to experience a successful clinical course, and the observations of the current study demonstrate that a multidisciplinary treatment strategy may be effective for the treatment of aggressive GB. PMID- 24765188 TI - Small bowel adenocarcinoma - terra incognita: A demand for cross-national pooling of data. AB - To date, due to the rarity, tumor biology and carcinogenesis of small bowel adenocarcinoma (SBA), the disease has been explored insufficiently and immunophenotyping and molecular characterization have not been finalized. This knowledge gap consecutively leads to an overt lack of diagnostic and therapeutic recommendations. In the current study, we provide our experience with the treatment of SBA, and demand for cross-national data pooling to enable unlimited information transfer and higher powered study. A comprehensive database of all patients with SBA was established and consecutively reviewed for clinicopathohistological data, information concerning preoperative evaluation, surgical and chemotherapeutical treatment, as well as outcome parameters. Patients underwent curative intended surgery (42.4%; n=14), adjuvant chemotherapy (CTX) following resection (36.4%; n=12) or palliative care (21.2%; n=7). The majority of patients were diagnosed at an advanced disease stage (pT3, 36.4%; pT4, 39.4%) and the duodenum was the most common tumor site (57.1%; n=20). Complete surgical resection was achieved in 88.5% of patients, while postoperative complications occurred in 19.4%. Within a mean follow-up period of 31.4 months, 17 patients succumbed to the disease following a median survival time of 11 months. Mean overall survival (OS) was 47.4, 25.3 and 9.8 months for surgically, surgically and chemotherapeutically and palliatively treated patients, respectively. Early surgical resection remains the mainstay in the treatment of localized SBA, since it is associated with a prolongation of OS. The role of neoadjuvant and adjuvant CTX has not yet been defined. Thus, since no consensus exists on the adequate treatment of these malignancies, we demand an international collaboration and cross-national data pooling to pave the way for the implementation of evidence-based standard care operating procedures. PMID- 24765189 TI - Expression of SDF-1 and CXCR4 transcript variants and CXCR7 in epithelial ovarian cancer. AB - Chemokine stromal cell-derived factor-1 (SDF-1) and its receptors, CXCR4 and CXCR7, have been implicated in epithelial ovarian cancer progression and metastasis. However, limited data are available on the expression levels of SDF-1 and CXCR4 variants and CXCR7 in human epithelial ovarian cancer. The present study aimed to characterize the expression pattern and levels of SDF-1, CXCR4 and CXCR7 in normal human ovaries and epithelial ovarian cancer. The expression of SDF-1 and CXCR4 transcript variants and CXCR7 was determined by quantitative polymerase chain reaction (qPCR). Plasma SDF-1alpha levels were determined by commercially available EIA kits and cancer antigen 125 (CA 125) levels were quantified by automated microparticle enzyme immunosorbent assay. High expression levels of SDF-1 transcript variant 1 were identified in ovarian cancer and control ovaries. By contrast, in both groups the expression levels of SDF-1 transcript variants 3 and 4 were extremely low. Furthermore, SDF-1 variant 1 levels were notably higher in epithelial ovarian cancer than in control ovaries, while data for the remaining transcripts were similar in both groups. CXCR4 transcript variant 2 and CXCR7 expression levels in normal and neoplastic ovaries were similar. In both groups, CXCR4 transcript variant 2 was not detected. Plasma SDF-1alpha levels were notably higher in females with epithelial ovarian cancer than in the control ovaries. Elevated levels of blood SDF-1alpha were found prior to surgery, 6 days after surgery and following completion of the first chemotherapy course. These increases were independent of the type of epithelial ovarian cancer. Our results suggest that the expression of SDF-1 and the genes controlling alternative splicing are elevated in epithelial ovarian cancer, leading to an increased formation of SDF-1 variant 1. Elevated plasma SDF-1alpha levels in epithelial ovarian cancer patients are not associated with the presence of tumors and/or metastases, however reflect a general response to the disease. PMID- 24765190 TI - Casticin inhibits epithelial-mesenchymal transition of liver cancer stem cells of the SMMC-7721 cell line through downregulating Twist. AB - The existence of cancer stem cells (CSCs) is central to the pathogenesis and therapeutic target of human hepatocellular carcinoma. The aim of this study was to investigate the effects of casticin on epithelial-mesenchymal transition (EMT) of liver cancer stem cells (LCSCs) derived from the SMMC-7721 cell line. Our results demonstrated that CD133+ sphere-forming cells (SFCs) sorted from the SMMC 7721 cell line not only possessed a higher capacity to form tumor spheroids in vitro, but also had a greater potential to form tumors when implanted in Balb/c nu mice, indicating that CD133+ SFCs possessed similar traits to LCSCs. Casticin increased the expression levels of E-cadherin and decreased those of N-cadherin in LCSCs. Treatment of LCSCs with casticin for 48 h also decreased the levels of the EMT-associated transcription factor, Twist. Overexpression of Twist attenuated the casticin-induced regulation of E-cadherin and N-cadherin protein expression, as well as the EMT capacity of LCSCs. In conclusion, CD133+ SFCs of the SMMC-7721 cell line may represent a subpopulation of LCSCs with the characteristics of EMT. Furthermore, casticin targeted LCSCs through the inhibition of EMT by downregulating Twist. PMID- 24765191 TI - Inhibition of cell growth by BrMC through inactivation of Akt in HER-2/neu overexpressing breast cancer cells. AB - We previously reported that chrysin (ChR) and its analogs induced cell cycle arrest and apoptosis in human estrogen receptor-positive/-negative breast cancer cells. However, it was unknown whether 8-bromo-7-methoxychrysin (BrMC), a novel synthetic ChR analog, inhibited the cell growth of human epidermal growth factor receptor 2 (HER-2)/neu-overexpressing breast cancers. In the present study, it was demonstrated that BrMC preferentially inhibited the cell viability of HER 2/neu-overexpressing MDA-MB-453 and BT-474 cells. Western blot analysis revealed that HER-2/neu expression and tyrosine phosphorylation were inhibited by BrMC in a concentration-dependent manner; whereas the proteasome inhibitor, MG-132, significantly prevented BrMC-induced HER-2/neu depletion and cell death in MDA-MB 453 cells. This directly indicated that BrMC-induced HER-2/neu depletion and cell growth inhibition was mediated by a proteasomal pathway. BrMC significantly downregulated the expression of cyclin D1, cyclin E and CDK4, followed by the suppression of protein kinase B phosphorylation and downstream effectors, GSK 3beta and beta-catenin. A colony formation assay also confirmed the growth inhibitory effects of BrMC. Thus, these findings clearly demonstrate the anticancer activity of BrMC against human HER-2/neu-overexpressing breast cancer cells. Thus, these findings clearly demonstrate the anticancer activity of BrMC against human HER 2/neu-overexpressing breast cancer cells, and highlight BrMC as a promising candidate for breast cancer therapy. PMID- 24765192 TI - p33ING1b methylation in fecal DNA as a molecular screening tool for colorectal cancer and precancerous lesions. AB - The present study aimed to investigate the feasibility of detecting p33 inhibitor of growth 1b (p33ING1b) gene methylation in fecal DNA as a screening method for colorectal carcinoma (CRC) and precancerous lesions. The methylation of p33ING1b was analyzed in fecal samples from 61 patients with CRCs, 27 patients with precancerous lesions (advanced adenoma) and 20 normal individuals by nested methylation-specific polymerase chain reaction (nMSP) and fecal occult blood test. Methylated p33ING1b was detected in 73.77% of CRC patients and 62.96% of adenoma patients. By contrast, only 5% of normal individuals had methylated p33ING1b. These results indicated 73.77% sensitivity for detecting CRC, 62.96% sensitivity for detecting precancerous lesions and 95% specificity of the assay for detecting CRCs and precancerous lesions. The detection of p33ING1b methylation status by incubation of DNA contained in agarose beads for bisulfite modification, followed by nMSP, is a promising non-invasive screening method for CRCs and precancerous lesions. PMID- 24765193 TI - Expression of neddylation-related proteins in melanoma cell lines and the effect of neddylation on melanoma proliferation. AB - Neddylation promotes the process of ubiquitination, which plays a critical role in the degradation of numerous proteins, including cell cycle and apoptosis regulators. In our previous study, an increase in neddylation was identified in melanoma cell lines. In the present study, the upregulation of neddylation was detected in melanoma tissues which confirmed the results of our previous study on melanoma cell lines. To explore the mechanism by which the process of neddylation was increased, the enzymes that regulate the process were investigated. These neddylation-related regulatory enzymes are potential targets for melanoma therapy. Downregulation of UBA3, a subunit of the E1 enzyme, by RNA interference caused cell cycle arrest at G0/G1 in the M14 cell line. In addition, cyclin D expression declined, whereas p27, p21 and bax expression increased. These findings suggest that interfering with the neddylation pathway may decrease the proliferation of melanoma through the modulation of cell cycle regulators and apoptosis promoters. PMID- 24765194 TI - Antineoplastic activity of rinvanil and phenylacetylrinvanil in leukaemia cell lines. AB - In the search for novel chemotherapeutic agents for cancer treatment, capsaicin has been shown to inhibit proliferation and induce apoptosis in various types of cancer cell line, including leukaemia cell lines. The capsaicin analogues, rinvanil and phenylacetylrinvanil (PhAR), share a binding affinity for vanilloid receptors and may have biological activities similar to capsaicin; however, their anticancer potential has not yet been reported. This study analyses the antineoplastic activities of rinvanil and PhAR in leukaemia versus normal cells. P388, J774 and WEHI-3 leukaemia cell lines, as well as mouse bone marrow mononuclear cells, were cultured with varying concentrations of rinvanil and PhAR. Following this, proliferation and apoptosis were determined by the sulforhodamine B (SRB) assay and DNA ladder. Cultured leukaemia cell lines and mouse bone marrow mononuclear cells demonstrated a dose-dependent inhibition of proliferation, while non-diseased cells were less sensitive to the cytotoxic effect of capsaicin, rinvanil and PhAR. Rinvanil and PhAR also induced apoptosis in leukaemia cell lines but not in bone marrow. Given the lower IC50 values for apoptosis induction in leukaemia cells compared with that of normal cells, PhAR is a promising selective anticancer agent. PMID- 24765195 TI - Colonic interposition between the liver and left diaphragm - management of Chilaiditi syndrome: A case report and literature review. AB - Chilaiditi syndrome refers to a medical condition that is indicated by the presence of Chilaiditi sign, the radiological observation of a colonic interposition between the liver and the diaphragm, and is associated with other clinical symptoms. Chilaiditi syndrome is a rare entity and therefore, is often misdiagnosed in clinical practice, however, it may be accompanied by a series of severe complications, such as bowel obstruction and perforation. The current study describes a 47-year-old male who presented with repeated abdominal pain and acute intestinal obstruction. The patient was diagnosed with Chilaiditi syndrome via radiological observation and was cured by conservative treatment. The clinical data of seven additional patients with Chilaiditi syndrome, which was reported in the Chinese literature between January 1990 and January 2013, were also collected. The pathogenesis, clinical manifestation, diagnosis and treatment of this syndrome have been reviewed and analyzed. The current study may be useful to familiarize clinical practitioners with Chilaiditi syndrome, in order to avoid a misdiagnosis during clinical treatment. PMID- 24765196 TI - Rectal adenocarcinoma resection specimen with an incidental carcinoid in the resection margin. AB - Three cases of incidental carcinoid tumors have been identified in the surgical margin of rectal adenocarcinoma resection specimens. In all cases the rectal carcinoids exhibited low-risk features, such as a tumor size <10 mm, no muscularis propria invasion and no lymph node involvement. No further excision was conducted and the three cases were followed up for 38, 26 and 14 months, respectively. No regional or distant rectal carcinoid recurrence was identified. Occasionally this is inevitable in order to achieve a positive resection margin for the microcarcinoid during the surgical treatment of another malignancy. However, such carcinoids are usually low-risk and behave less aggressively than same-site adenocarcinomas. Thus, it appears reasonable to avoid further excision in patients who are undergoing a rectal adenocarcinoma resection that exhibits a positive margin for low-risk carcinoid tumor. PMID- 24765197 TI - Effects of 14 frequently used drugs on prostate-specific antigen expression in prostate cancer LNCaP cells. AB - Prostate cancer occurs more frequently among older males and such elderly individuals often have chronic underlying disorders for which various drugs are administered for treatment. The levels of prostate-specific antigen (PSA), a widely used prostate cancer marker, are influenced by a number of drugs, such as non-steroidal anti-inflammatory drugs and statins. In the present study, the drugs prescribed to patients on a repeat prescription collected at the pharmacy of the Gifu Pharmaceutical University (Gifu, Japan) were examined for their effects on the levels of PSA expression in prostate cancer LNCaP cells. Among the 14 drugs investigated, betamethasone, an agonist of the glucocorticoid receptor, was found to increase the levels of PSA mRNA expression in the LNCaP cells. This betamethasone-induced expression was mediated, at least in part, through androgen receptor (AR) transcriptional activation. Dexamethasone, a typical agonist of the glucocorticoid receptor, was also found to stimulate the AR transcriptional activity, however, to a lesser extent than betamethasone. Therefore, it would be interesting to examine in future studies whether the serum PSA levels in prostate cancer patients are influenced by betamethasone. PMID- 24765198 TI - Evaluation of hemilaminectomy use in microsurgical resection of intradural extramedullary tumors. AB - The aim of this study was to investigate the microsurgical techniques of hemilaminectomy, used in the excision of intradural extramedullary (IDEM) tumors, and to illustrate its clinical effects. Clinical data obtained from 16 patients (seven males, nine females) with IDEM tumors, which were treated at the China Japan Union Hospital between January 2009 and December 2011, were retrospectively analyzed. The mean age of patients was 49 years, ranging from 34-72 years. The IDEM tumors were located cervically in three patients, thoracically in four patients and at the thoracico-lumbar level in nine patients. Fourteen patients underwent hemilaminectomy, while two patients were treated with laminectomy during surgery. The clinical effect of hemilaminectomy was evaluated based on Frankel grade. The mean bleeding volume was 300 ml (range, 150-500 ml) and the mean duration of surgery was 140 min (range, 90-200 min). The maximum and minimum tumor volumes were 4*1.5*1.5 cm and 1.5*1.0*1.0 cm, respectively. Neurinoma was evident in 11 patients, meningioma in four cases and neurofibroma in one case. Three cases improved from Frankel grade B to C, five cases improved from grade C to D and seven cases improved from grade D to grade E. All patients were followed up for a period of 6-40 months, with a mean follow-up time of 23.7 months. None of the patients exhibited tumor recurrence or spinal instability. The mean bleeding volume of patients that underwent hemilaminectomy and laminectomy was 275 and 475 ml, respectively. The advantages of hemilaminectomy are minor invasion, less bleeding and retention of spinal stability. In general, hemilaminectomy for the excision of IDEM tumors has a satisfactory outcome. PMID- 24765199 TI - PD-0332991 induces G1 arrest of colorectal carcinoma cells through inhibition of the cyclin-dependent kinase-6 and retinoblastoma protein axis. AB - Preclinical and clinical studies have demonstrated the anticancer activity of PD 0332991, a selective cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, in the treatment of various types of cancer in a retinoblastoma protein (RB)-dependent manner. However, it remains unclear whether CDK4, CDK6 or both are required for RB phosphorylation in colorectal carcinoma and thus PD-0332991 can be used to target this CDK-RB axis for the cancer therapy. The aim of this study was to determine whether CDK4, CDK6 and phosphorylated RB proteins were overexpressed in colorectal carcinoma tissues as compared to matched normal colorectal tissues. The results showed that knockdown of CDK6 but not CDK4 reduced RB phosphorylation and inhibited carcinoma cell growth. Thus, CDK6 plays a critical role in RB phosphorylation and cancer growth. PD-0332991 treatment blocked RB phosphorylation and inhibited cell growth through the induction of G1 arrest of colorectal carcinoma cells. The results demonstrated that, by targeting of CDK6 RB axis, PD-0332991 may prove to be a novel therapeutic agent in treating colorectal carcinoma. PMID- 24765200 TI - Intramuscular myxoma of the hyoglossus muscle: A case report and literature review. AB - Intramuscular myxoma (IM) is a benign intramuscular neoplasm composed of fibroblasts and abundant myxoid stroma. IMs most commonly affect larger skeletal muscles, while those affecting the oral and maxillofacial regions are rare, with a small number of documented cases in the available literature. The aim of the present study was to describe a highly rare case of an IM within the hyoglossus muscle of the tongue in a 74-year-old male. The patient presented with a painless mass in the submental space that had been growing slowly for more than five years. A computed tomography scan revealed a hypodense lesion located in the root of the tongue. The mass was easily excised with thin margins, including only a small amount of the adjacent muscle tissue. The pathological diagnosis of the mass was an IM. The patient made an excellent recovery following the surgery and the follow-up three years later revealed no local recurrence. IMs of the hyoglossus muscle are highly rare, however must be considered in the differential diagnosis of swellings in the root of the tongue region. PMID- 24765201 TI - Quantitative analysis of APC promoter methylation in hepatocellular carcinoma and its prognostic implications. AB - The present study aimed to quantitatively determine the aberrant methylation signal of the adenomatous polyposis coli (APC) gene in hepatocellular carcinoma (HCC), and to evaluate whether hypermethylation of the APC promoter could be a prognostic biomarker for HCC. Taqman probe-based quantitative methylation specific polymerase chain reaction was performed to identify the APC promoter methylation levels in 57 HCC and corresponding non-tumorous liver tissues. In the present study, the methylation level of the APC promoter was upregulated by 4.51 fold in the HCC tissues compared with the non-cancerous tissues (P=0.0003). With regard to the clinicopathological data, the methylation level of the APC promoter in the HCC samples was higher in the patients with larger tumors when the cut-off was set at 4 cm (P=0.0008), and in the older patients when the cut-off was set at 60 years old (P=0.0438). However, the methylation status in the HCC samples appeared not to affect the overall patient survival rate (P=0.1684). The findings of the present study showed that APC promoter hypermethylation accumulates during the development of HCC, but that it may not be a promising prognostic biomarker for HCC. PMID- 24765202 TI - Tumor suppressor microRNA-34a inhibits cell proliferation by targeting Notch1 in renal cell carcinoma. AB - MicroRNA-34a (miR-34a) is a tumor suppressive microRNA, which induces G1 arrest, apoptosis and senescence by repressing the expression of multiple oncogenes. This study aimed to investigate the biological function and molecular mechanisms of miR-34a in human renal cell carcinoma (RCC) cells. Quantitative polymerase chain reaction (qPCR) revealed that miR-34a expression was significantly downregulated in eight of the 10 (80%) RCC tissues compared with adjacent normal tissues. In RCC cell lines, several other target genes of miR-34a were dysregulated at the mRNA level when the expression of miR-34a was elevated. In addition, western blot analysis and qPCR revealed that forced expression of miR-34a downregulated the expression of Notch1 at the protein and mRNA level. The Cell Counting Kit-8 identified that transient forced expression of miR-34a inhibited cell growth and resulted in cell cycle arrest, which was evaluated by flow cytometry. Our data demonstrated that miR-34a inhibits cell proliferation by downregulating Notch1 in RCC cell lines. PMID- 24765203 TI - Distribution of endothelial progenitor cells in tissues from patients with gastric cancer. AB - It is accepted that endothelial progenitor cells (EPCs) are recruited into tumor sites and take part in the neovascularization of tumors. However, few articles have discussed the specific distribution of EPCs in vivo in tissues of gastric cancer patients. For this reason, the present study sought to elucidate EPC distribution in vivo in tissues of patients with gastric cancer. Fresh tumor tissues were collected from 26 newly diagnosed patients with histologically confirmed gastric cancer (mean age, 51 years; range, 21-81 years; 7 females, 19 males). All patients were treated surgically with curative intent. One portion of the fresh tissues was prepared for flow cytometric analysis and another was immediately snap frozen in liquid nitrogen and stored at -80 degrees C for later use in quantitative polymerase chain reaction. The analysis was based on two groups of tissues, namely the cancer group and cancer-adjacent group. The presence of CD34/CD133 double-positive cells was determined in cancer-adjacent and cancer tissues by flow cytometry. The analysis revealed that the total number of EPCs in cancer tissue was slightly greater than the number in the cancer adjacent tissue, but not to the point of statistical significance. The number of EPCs in cancer-adjacent and cancer tissues of patients with early-stage gastric cancer was higher than the EPC count in late-stage gastric cancer patients, and significant differences were identified in the number of EPCs in cancer tissue between patients of different tumor stages. Levels of cluster of differentiation (CD)34, CD133 and vascular endothelial growth factor receptor 2 were not significantly different in cancer-adjacent tissue compared with cancer tissue. These results suggest that cancer-adjacent and cancer tissue of gastric cancer patients may be used as a reference index in the clinical and pathological staging of tumors. PMID- 24765204 TI - Bizarre leiomyoma of the scrotum: A case report and review of the literature. AB - Bizarre leiomyomas of the scrotum are rare benign tumors that are often misdiagnosed. In this study, we present a case of bizarre leiomyoma of the scrotum in a 53-year-old male. The patient presented with a painless scrotal mass that was insidious in the right side of the scrotum with no sudden increase in size. Definitive preoperative diagnosis could not be established; however, following surgical resection of the tumor, a diagnosis of bizarre leiomyoma of the scrotum was determined by pathological examination. The patient was followed up six months following resection and no problems were reported. This is the first reported case of bizarre leiomyoma of the scrotum in China. A supplementary review of previously published cases and literature is also presented. PMID- 24765205 TI - Diabetes mellitus and the neutrophil to lymphocyte ratio predict overall survival in non-viral hepatocellular carcinoma treated with transarterial chemoembolization. AB - Diabetes mellitus (DM) and systemic inflammation are closely associated with the development of hepatocellular carcinoma (HCC). However, the prognostic significance of DM on HCC remains controversial. The main purpose of the present study was to evaluate the effects of DM and the systemic inflammation-based neutrophil to lymphocyte ratio (NLR) on the overall survival (OS) rate of non viral HCC patients treated with transarterial chemoembolization (TACE). A retrospective analysis of 138 patients with HCC, who were diagnosed between 2002 and 2012 with non-viral causes and who later underwent TACE, was performed. Among these patients, 34 (24.6%) had pre-existing DM and 46 (33.3%) exhibited an elevated baseline NLR (>=5). The multivariate analysis showed that DM, the NLR and a portal vein tumor thrombus (PVTT) were independent predictors for a poor OS rate (P<0.05). The patients with DM and an elevated NLR exhibited a poorer OS rate when compared with patients without these factors. In addition, there was a significant stepwise improvement in the OS rate of patients with DM and an elevated NLR, and in patients with only one of these factors compared with patients without either (P<0.01). Finally, DM was significantly correlated with PVTT and elevated gamma-glutamyl transpeptidase levels, while the NLR was independently associated with PVTT and tumor multiplicity (P<0.05). The present study revealed that DM, baseline NLR and PVTT are independent indicators of the OS rate in non-viral HCC patients treated with TACE. DM and NLR may affect the OS rate by promoting the malignant progression of HCC. The combination of DM and NLR appears to be a stronger predictor for OS than DM or NLR alone. PMID- 24765206 TI - Casticin induces breast cancer cell apoptosis by inhibiting the expression of forkhead box protein M1. AB - Casticin is an active ingredient derived from Fructus Viticis, a traditional Chinese medicine. This study aimed to investigate the role of forkhead box O3 (FOXO3a) in breast cancer cells and examine the regulatory mechanisms of FOXO3a in response to casticin treatment of the cells by ELISA, flow cytometry, small interfering RNA (siRNA) transfection and western blot analysis. Casticin treatment induced apoptosis and reduced the expression of the transcription factor forkhead box protein M1 (FOXM1). In addition, FOXM1 repression induced by casticin treatment was associated with the activation of FOXO3a via increased dephosphorylation. Notably, silencing FOXO3a expression by siRNA-mediated gene knockdown attenuated casticin-mediated apoptosis. Collectively, these findings suggest that FOXO3a is a critical mediator of the inhibitory effects of casticin on apoptosis in breast cancer cells. PMID- 24765207 TI - Adenomatoid tumors of the testis: A report of two cases and review of the literature. AB - Adenomatoid tumors are rare benign neoplasms that normally occur in the scrotum. The clinical symptoms and routine examinations mean that it is difficult to distinguish adenomatoid tumors from malignant intratesticular solid tumors, which may result in unnecessary orchidectomies. The present report describes two adenomatoid tumor patients treated between 2006 and 2013 at the Peking University Shenzhen Hospital who presented with an asymptomatic mass in the scrotum. Based on thorough analysis of clinical features, blood, radiological images and intra operative findings, limited local excisions were performed, revealing adenomatoid tumors of the testis on pathological examination. The patients were followed up and exhibit no recurrence at the time of writing. The present report also summarizes the morphological and immunohistochemical features of paratesticular tumors and reviews the literature to improve understanding of these rare lesions and assist in accurate diagnosis. PMID- 24765208 TI - Association of interleukin-10 promoter polymorphisms and corresponding plasma levels with susceptibility to laryngeal squamous cell carcinoma. AB - Interleukin (IL)-10 is critically involved in tumorigenesis. In the present study, the association between the IL-10 -1082/-819/-592 promoter polymorphisms, the plasma IL-10 levels and the risk of laryngeal squamous cell carcinoma (LSCC) was investigated in a prospective, case-control study. In total, 146 patients with LSCC, 61 with vocal leukoplakia and 119 healthy controls were genotyped for the IL-10 gene (IL-10 -1082 A/G, -819 T/C and -592 A/C) using pyrosequencing, and their plasma IL-10 levels were analyzed by ELISA. The patients with LSCC had a significantly higher frequency of AC at position -592 and -819 (OR, 1.82 and P=0.024) compared with the control, and a higher frequency of AG at position 1082 (OR, 2.20 and P=0.037). The patients with advanced LSCC had a significantly higher frequency of AG+GG at position -1082 compared with those with early-stage LSCC (OR, 3.13 and P=0.008 vs. OR, 2.06 and P=0.068). The patients with lymph node metastasis had a significantly higher frequency of AG+GG at position -1082 compared with the patients with no lymph node metastasis (OR, 2.97 and P=0.048 vs. OR, 2.23 and P=0.035). In addition, the patients with high frequencies of each genotype polymorphism had high plasma IL-10 concentrations. The present study indicates that the IL-10 -1082/-819/-592 promoter polymorphisms and corresponding high plasma IL-10 concentrations are associated with LSCC, and that variations in genotype distribution and plasma IL-10 concentrations may be associated with the stage and the lymph node metastasis status of LSCC. PMID- 24765209 TI - Laminarin-induced apoptosis in human colon cancer LoVo cells. AB - A number of scientific studies have revealed that laminarin has antitumor effects. Therefore, the aim of the present study was to investigate the apoptosis of LoVo cells and the underlying mechanisms induced by laminarin. LoVo cells were treated with various concentrations of laminarin and fluorescence-inverted microscopy was used to observe the morphology of LoVo cells treated with laminarin. In addition, western blotting was performed to analyze the expression levels of death receptor (DR)4, DR5, TNF-related apoptosis-inducing ligand (TRAIL), Fas-associated protein with death domain (FADD), caspase-8, caspase-3, Bid and tBid. Flow cytometry was conducted to analyze the expressions of Bcl-2 and Bax, and spectrophotometry was performed to quantify the activity of caspases 8, -3, -6 and -7. Following the treatment of LoVo cells with laminarin for 24 h, the expression levels of DR4, DR5, TRAIL, FADD, Bid, tBid and Bax were observed to be upregulated, whereas the expression levels of pro-caspase-8, pro-caspase-3 and Bcl-2 were downregulated. In addition, the activities of casapse-8, -3, -6 and -7 were observed to increase, which was a significant difference when compared with those of the control group. Therefore, laminarin is considered to induce the apoptosis of LoVo cells, which may occur via a DR pathway, suggesting that laminarin may be a potent agent for cancer treatment. PMID- 24765210 TI - BRCA1 regulates insulin-like growth factor 1 receptor levels in ovarian cancer. AB - Breast cancer 1 (BRCA1) and insulin-like growth factor 1 receptor (IGF1R) are critical in ovarian cancer progression. However, the crosstalk between the BRCA1 and IGF1R signaling pathways in ovarian cancer remains largely unknown. The effects of BRCA1 on IGF1R were assessed in 121 serous ovarian cancer patients (BRCA1 mutation, n=30; non-BRCA1 mutation, n=32; hypermethylated BRCA1 promoter, n=28; and non-methylation, n=31). BRCA1 promoter methylation was analyzed via bisulfite sequencing using primers focused on the core promoter region. The expression levels of BRCA1 and IGF1R were assessed by immunohistochemistry and real-time polymerase chain reaction. Knockdown and overexpression of BRCA1 were achieved using a lentiviral vector in 293T and SKOV3 ovarian cancer cells, and primary non-mutated and BRCA1-mutated ovarian cancer cells. The present study demonstrated that IGF1R expression is increased in non-BRCA1-mutated ovarian cancer when compared with adjacent normal tissue. Furthermore, IGF1R levels are additionally significantly elevated in BRCA1 inactivation ovarian cancer (BRCA1 mutation or hypermethylated BRCA1 promoter). In addition, BRCA1 knockdown was found to be an effective method of activating IGF1R expression in non-BRCA1 mutated ovarian cancer cells. The observations of the current study indicate that BRCA1 may be a potential trigger that is involved in the transcriptional regulation of IGF1R in the development of ovarian cancer. PMID- 24765211 TI - Fermentation supernatants of Lactobacillus delbrueckii inhibit growth of human colon cancer cells and induce apoptosis through a caspase 3-dependent pathway. AB - Probiotic bacteria are known to exert a wide range of beneficial effects on their animal hosts. Therefore, the present study explored the effect of the supernatants obtained from Lactobacillus delbrueckii fermentation (LBF) on colon cancer. The results indicated that the proliferation of LBF solution-treated colon cancer SW620 cells was arrested and accumulated in the G1 phase in a concentration-dependent manner. The LBF solution efficiently induced apoptosis through the intrinsic caspase 3-depedent pathway, with a corresponding decreased expression of Bcl-2. The activity of matrix metalloproteinase 9, which is associated with the invasion of colon cancer cells, was also decreased in the LBF treated cells. In conclusion, the results demonstrate the antitumor effect of LBF in vitro and may contribute to the development of novel therapies for the treatment of colon cancer. PMID- 24765213 TI - ? PMID- 24765212 TI - Accelerometry analysis of physical activity and sedentary behavior in older adults: a systematic review and data analysis. AB - Accelerometers objectively monitor physical activity and sedentary patterns and are increasingly used in the research setting. It is important to maintain consistency in data analysis and reporting, therefore, we: (1) systematically identified studies using accelerometry (ActiGraph, Pensacola, FL, USA) to measure moderate-to-vigorous physical activity (MVPA) and sedentary time in older adults, and (2) based on the review findings, we used different cut-points obtained to analyze accelerometry data from a sample of community-dwelling older women. We identified 59 articles with cut-points ranging between 574 and 3,250 counts/min for MVPA and 50 and 500 counts/min for sedentary time. Using these cut-points and data from women (mean age, 70 years), the median MVPA minutes per day ranged between 4 and 80 min while percentage of sedentary time per day ranged between 62 % and 86 %. These data highlight (1) the importance of reporting detailed information on the analysis assumptions and (2) that results can differ greatly depending on analysis parameters. PMID- 24765214 TI - Impacting the Science Community through Teacher Development: Utilizing Virtual Learning. AB - Commitment to the STEM (science, technology, engineering, math) pipeline is slowly declining despite the need for professionals in the medical field. Addressing this, the John A. Burns School of Medicine developed a summer teacher training program with a supplemental technology-learning component to improve science teachers' knowledge and skills of Molecular Biology. Subsequently, students' skills, techniques, and application of molecular biology are impacted. Science teachers require training that will prepare them for educating future professionals and foster interest in the medical field. After participation in the program and full access to the virtual material, twelve high school science teachers completed a final written reflective statement to evaluate their experiences. Using thematic analysis, knowledge and classroom application were investigated in this study. Results were two-fold: teachers identified difference areas of gained knowledge from the teacher-training program and teachers' reporting various benefits in relation to curricula development after participating in the program. It is concluded that participation in the program and access to the virtual material will impact the science community by updating teacher knowledge and positively influencing students' experience with science. PMID- 24765215 TI - Endoscopic ultrasound-guided biliary drainage: a review. AB - Endoscopic retrograde cholangiography (ERCP) is widely used as a first-line therapy for biliary drainage. ERCP occasionally fails owing to anatomical or technical problems, despite high reported success rates. Endoscopic ultrasound guided biliary drainage (EUS-BD) has recently emerged as an effective alternative biliary drainage method after unsuccessful ERCP. EUS-BD can be essentially divided into 3 different techniques-(1) EUS-guided transluminal biliary drainage including choledocoduodenostomy and hepaticogastrostomy, (2) EUS-rendezvous technique, and (3) EUS-antegrade approach. Here, we focus on the current status of EUS-BD in light of these 3 different techniques. PMID- 24765216 TI - A gestural account of the velar fricative in Navajo. AB - Using the framework of Articulatory Phonology, we offer a phonological account of the allophonic variation undergone by the velar fricative phoneme in Navajo, a Southern or Apachean Athabaskan language spoken in Arizona and New Mexico. The Navajo velar fricative strongly coarticulates with the following vowel, varying in both place and manner of articulation. The variation in this velar fricative seems greater than the variation of velars in many well-studied languages. The coronal central fricatives in the inventory, in contrast, are quite phonetically stable. The back fricative of Navajo thus highlights 1) the linguistic use of an extreme form of coarticulation and 2) the mechanism by which languages can control coarticulation. It is argued that the task dynamic model underlying Articulatory Phonology, with the mechanism of gestural blending controlling coarticulation, can account for the multiplicity of linguistically-controlled ways in which velars coarticulate with surrounding vowels without requiring any changes of input specification due to context. The ability of phonological and morphological constraints to restrict the amount of coarticulation argues against strict separation of phonetics and phonology. PMID- 24765218 TI - Role of steroid minimization in the tacrolimus-based immunosuppressive regimen for liver transplant recipients: a systematic review and meta-analysis of prospective randomized controlled trials. AB - To evaluate the efficacy and safety of early steroid withdrawal or steroid avoidance in the tacrolimus (Tac)-based immunosuppressive regimen for liver transplant recipients. According to the requirements of the Cochrane systematic review, a thorough literature search was performed in the PubMed/MEDLINE and Cochrane electronic databases between 1995 and 2011 using the key words "liver transplantation," "Tac," and "steroid free" or "steroid withdrawal," restricting articles to the English language. Data were processed for a meta-analysis by Stata 12 software. Altogether 17 prospective randomized controlled trials containing 1,980 transplanted patients were included in this study. The overall pooled RR estimates of 1-, 2-, 3-, and 5-year patient and graft survival rates were 0.985, 0.998, 0.995, and 1.100 (95 % CI 0.925-1.048, 0.934-1.067, 0.894 1.107, and 0.968-1.250, respectively), as well as 0.998, 0.993, 0.945, and 1.053, respectively (95 % CI 0.928-1.072, 0.902-1.092, 0.833-1.072, and 0.849-1.307, respectively). The other pooled RR estimates of acute rejection and chronic rejection rates for all enrolled studies were 1.077 and 0.311 (95 % CI 0.864 1.343 and 0.003-37.207). As for secondary predictors, the pooled RR estimates such as HCV recurrence, HCC recurrence, diabetes, hypertension, kidney dysfunction, bacterial infection, and CMV were 1.101, 1.403, 1.836, 1.607, 0.842, 1.096, and 2.280, respectively (95 % CI 0.964-1.257, 0.422-4.688, 1.294-2.606, 0.926-1.228, 0.693-1.022, 0.783-1.533, and 1.500-3.465, respectively). There were no differences between the steroid group and steroid-free group for all clinical observational indices except for the incidence of diabetes (p = 0.001) and CMV infection (p < 0.001). In summary, our study indicate that rapid discontinuation of steroid in the Tac-based immunosuppressive regimen may not lead to an increased risk of morbidity and rejection rate. PMID- 24765220 TI - Asymptomatic solitary dermal plaque. PMID- 24765217 TI - Pediatric Sepsis - Part V: Extracellular Heat Shock Proteins: Alarmins for the Host Immune System. AB - Heat shock proteins (HSPs) are molecular chaperones that facilitate the proper folding and assembly of nascent polypeptides and assist in the refolding and stabilization of damaged polypeptides. Through these largely intracellular functions, the HSPs maintain homeostasis and assure cell survival. However, a growing body of literature suggests that HSPs have important effects in the extracellular environment as well. Extracellular HSPs are released from damaged or stressed cells and appear to act as local "danger signals" that activate stress response programs in surrounding cells. Importantly, extracellular HSPs have been shown to activate the host innate and adaptive immune response. With this in mind, extracellular HSPs are commonly included in a growing list of a family of proteins known as danger-associated molecular patterns (DAMPs) or alarmins, which trigger an immune response to tissue injury, such as may occur with trauma, ischemia-reperfusion injury, oxidative stress, etc. Extracellular HSPs, including Hsp72 (HSPA), Hsp27 (HSPB1), Hsp90 (HSPC), Hsp60 (HSPD), and Chaperonin/Hsp10 (HSPE) are especially attractrive candidates for DAMPs or alarmins which may be particularly relevant in the pathophysiology of the sepsis syndrome. PMID- 24765219 TI - FOXP2. AB - The forkhead box P2 gene, designated FOXP2, is the first gene implicated in a speech and language disorder. Since its discovery, many studies have been carried out in an attempt to explain the mechanism by which it influences these characteristically human traits. This review presents the story of the discovery of the FOXP2 gene, including early studies of the phenotypic implications of a disruption in the gene. We then discuss recent investigations into the molecular function of the FOXP2 gene, including functional and gene expression studies. We conclude this review by presenting the fascinating results of recent studies of the FOXP2 ortholog in other species that are capable of vocal communication. WIREs Cogn Sci 2013, 4:547-560. doi: 10.1002/wcs.1247 This article is categorized under: Psychology > Language Neuroscience > Genes, Molecules, and Cells. PMID- 24765221 TI - The role of skin care as an integral component in the management of acne vulgaris: part 1: the importance of cleanser and moisturizer ingredients, design, and product selection. AB - Acne vulgaris is a very common facial skin disorder accounting for approximately 10 percent of all visits to ambulatory dermatology practices across the United States annually. Over time, greater attention has been directed to the roles of multiple epidermal barrier functions in various dermatological disorders, especially the stratum corneum permeability barrier and antimicrobial barrier. As a result, it has become readily apparent that professional direction of skin care is very important in the overall management of acne vulgaris. This article discusses several reasons that support the importance of incorporating specified skin care recommendations and instructions into the overall management plan for acne vulgaris. In addition, the article reviews formulation characteristics and some of the scientific data on two commercially available products that are recommended for use as a skin care regimen in patients with acne-prone and acne affected skin, a foam wash and a moisturizer with a sun protection factor 30 broad spectrum photoprotection rating. The rationale for inclusion of specific ingredients are discussed along with an overview of research results including use in patients with acne vulgaris. PMID- 24765222 TI - The Role of Skin Care as an Integral Component in the Management of Acne Vulgaris: Part 2: Tolerability and Performance of a Designated Skin Care Regimen Using a Foam Wash and Moisturizer SPF 30 in Patients with Acne Vulgaris Undergoing Active Treatment. AB - Proper skin care is considered to be an important component of the total management plan for patients with acne vulgaris. A 28-day, open-label study provided both practical and scientific information on a designated skin care regimen in subjects with acne vulgaris. The cutaneous tolerability overall performance, and assessment of objective parameters evaluating the epidermal permeability barrier were documented with use of a specific foaming skin cleanser and a moisturizer with an SPF 30 broad spectrum rating in actively treated subjects with acne vulgaris. The results were favorable overall with the regimen shown to be nonirritating based on investigator and subject assessments, with high subject satisfaction and cosmetic acceptability ratings reported for both the foaming skin cleanser and the moisturizer with an SPF 30 broad spectrum rating. Objective instrumental testing of transepidermal water loss and epidermal hydration support that this skin care regimen assists in correcting epidermal permeability barrier dysfunctions that are innately present in acne vulgaris, worsened during a flare, and are known to be associated with many medications used to treat acne vulgaris. The recommendation of a specified skin care regimen incorporated into the overall management of acne vulgaris simplifies and standardizes the program for the patient, demonstrates a high level of interest by the clinician, and reduces the risk of the patient self-acquiring facial skin care products that may increase skin irritation. PMID- 24765223 TI - Atopic dermatitis and the stratum corneum: part 3: the immune system in atopic dermatitis. AB - Part 3 of this three-part review of atopic dermatitis and the stratum corneum barrier discerns how immune dysregulation, including upregulation of a TH2 inflammation pattern, augmented allergic sensitization, sustained wound healing inflammation, and impaired innate immunity, plays an integral role in the pathogenesis of atopic dermatitis. An increased understanding of the interdependence, polymorphisms, and dysregulations of epidermal barrier functions, including the stratum corneum permeability barrier, immune defense, and antimicrobial barriers, should provide further knowledge about the pathophysiological mechanisms that are clinically relevant and that contribute to the development of atopic dermatitis. Further understanding of these mechanisms should lead to newer therapies that target specific pathogenic components of atopic dermatitis. PMID- 24765224 TI - The Eraser Challenge Among School-age Children. AB - Skin-related, self-destructive behaviors are being increasingly reported among school-age children. Often disguised as innocuous "challenges," these disturbing actions may have the potential for serious and permanent sequelae. Interest and subsequent participation in these behaviors may also be spread "virally," facilitated by social networking sites that allow participants-regardless of age to share photographs or videos of the activities in question. Consequently, parents and health care providers must learn to recognize signs and symptoms of these disturbing behaviors and make concerted efforts to protect this uniquely vulnerable population of pediatric patients. PMID- 24765225 TI - Myiasis: A Traveler's Dilemma. AB - Myiasis is a tropical infection most often caused by Dermatotobia hominis, also known as the botfly. It is rarely seen in the United States. The infection has a slow evolution and often presents with painful lesions that mimic furunculosis, boils, and infected cysts. The mechanism of infection is based on the deposition of botfly eggs onto an arthropod, which acts as a vector of transmission. The arthropod infects various hosts and botfly eggs are concomitantly deposited on the host. The Dermatobia eggs transform into their larval form and penetrate the skin through adjacent adnexal structures or through the arthropod-based site of inoculation itself. Growth of the organisms within the tissues causes painful cystlike lesions. This article describes cutaneous furuncular myiasis and discusses patterns of recognition and treatment modalities, with a case presentation of an individual diagnosed with the condition attained from a visit to Belize. PMID- 24765226 TI - Safety and Efficacy of Micro-focused Ultrasound Plus Visualization for the Treatment of Axillary Hyperhidrosis. AB - OBJECTIVES: To evaluate the safety, efficacy, and durability of treating axillary hyperhidrosis with high-intensity micro-focused ultrasound plus visualization. DESIGN: Two randomized double-blind, sham-controlled pilot studies. MEASUREMENTS: For Study 1, the primary endpoint was response defined as >=50-percent reduction in baseline sweat production as measured gravimetrically. For Study 2, the primary endpoint was response defined as a reduction of Hyperhidrosis Disease Severity Scale scores from 3 or 4 to 1 or 2. Secondary endpoints included changes in gravimetric and starch-iodine testing and patient satisfaction. RESULTS: In Study 1, >=50 percent of patients achieved a positive treatment response. In Study 2, the response rate at post-treatment Day 60 for micro-focused ultrasound plus visualization- (N=12) and sham-treated (N=8) patients was 67 and zero percent, respectively (p=0.005). Patients evaluated 12 months after treatment (N=11) demonstrated the long-lasting effectiveness of micro-focused ultrasound plus visualization for treating axillary hyperhidrosis. All but one patient in the micro-focused ultrasound plus visualization group were satisfied with their results while all sham group patients were dissatisfied (p=0.0001). Subjective reports of greatest improvement were sweat production (92%) and social embarrassment (83%). Adverse events were found to be mild and were resolved within a short timeframe. CONCLUSION: Micro-focused ultrasound plus visualization appears to be safe, effective, well-tolerated, and a long-lasting means for treating axillary hyperhidrosis. PMID- 24765228 TI - Evaluation of the skin sensitization, photoirritation, and photoallergic potential of ingenol mebutate gel in healthy volunteers. AB - OBJECTIVES: Phase 1 studies were conducted to determine the sensitization (PEP005 005; NCT00357916; http://clinicaltrials.gov/ct2/show/NCT00357916), photoirritation (PEP005-023; NCT00850811; http://clinicaltrials.gov/ct2/show/NCT00850811?term=PEP005-023&rank=1), and photoallergic (photosensitizing) potential (PEP005-024; NCT00850681; http://clinicaltrials.gov/ct2/show/NCT00850681?term=PEP005-024&rank=1) of ingenol mebutate gel 0.01% versus vehicle on normal skin. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Healthy volunteers were enrolled in single-center, randomized, controlled, within-subject comparison trials. PEP005-005 was designed as a repeat insult patch test study. In PEP005-023, treatment areas were examined after irradiation for photoirritation potential; dermal reactions were evaluated. In PEP005-024, irradiation was performed to determine the photoallergic (photosensitizing) potential of the medication. All treatment areas were graded immediately prior to irradiation and 24, 48, and 72 hours following irradiation. In all studies, local tolerability was assessed visually using an ordinal scoring system at set intervals before and after medication application/irradiation. RESULTS: In PEP005-005 (n=238), a significant difference (p<0.001) was seen between ingenol mebutate and vehicle for mean and total cumulative irritation scores. In PEP005-023 (n=34), mild erythema in all irradiated treatment areas was as expected for the ultraviolet dose. There was no clinically significant irritation in response to ingenol mebutate or vehicle, irrespective of irradiation. In PEP005-024 (n=60), there was no significant irritation in response to either ingenol mebutate or vehicle at their irradiated treatment areas. CONCLUSION: RESULTS from three pharmacology studies in healthy volunteers indicate a favorable topical safety profile for ingenol mebutate gel, with no evidence seen of skin sensitization, photoirritation, or photoallergic potential. PMID- 24765229 TI - Video education provides effective wound care instruction pre- or post-mohs micrographic surgery. AB - OBJECTIVE: The objective of this study was to determine if delivery of wound care instruction pre-Mohs micrographic surgery versus the typical, post-Mohs surgery would allow for greater patient retention. DESIGN: A non-blinded, randomized, controlled trial receiving institutional review board exemption from Michigan State University was conducted over a three-month period. Patients scheduled for Mohs surgery on 13 selected days were randomized into pre- versus post-procedure groups to receive wound care education. SETTING: This study was conducted at a dermatology practice in Saint Joseph, Michigan. PARTICIPANTS: Fifty cognitive and literate patients greater than 18 years of age were evaluated in this study. MEASUREMENTS: PARTICIPANTS' ability to recall instructions delivered by a Mohs surgeon in the form of digital media was assessed by a 10-question, multiple choice exam. Additional analyses were conducted on patient's disposition around medical professionals, past experience with Mohs surgery, preference for digital media versus human instruction, and desire for home access. RESULTS: Pre- (n=24; score=77+/-14%) versus post-(n=26; 83+/-11%) procedure education displayed no significant difference (p=0.13) in overall questionnaire performance. Seventy four percent of participants preferred video delivery as opposed to provider instruction. Thirty-four percent reported being intimidated by healthcare workers. Participant performance showed no significant change (p=0.78) with previous exposure (79+/-19%) to Mohs surgery versus a first-time encounter (80+/ 11%). CONCLUSION: Video education prior to or post-Mohs surgery serves as an effective mechanism for patient education and improvement of time management in clinical practice. PMID- 24765227 TI - Updated Physician's Guide to the Off-label Uses of Oral Isotretinoin. AB - While oral isotretinoin is renowned for its ability to treat acne vulgaris, many of its off-label uses continue to go underappreciated. Since the last review on the unapproved indications of isotretinoin, relevant publications have surfaced with new recommendations. This article attempts to provide physicians with the latest information regarding successful and unsuccessful use of isotretinoin as an effective treatment for dermatological conditions, such as rosacea, psoriasis, pityriasis rubra pilaris, condyloma acuminatum, granuloma annulare, Darier's disease, systemic cutaneous lupus erythematosus, nonmelanoma skin cancer, and hidradenitis suppurativa. Variations in dosage regimens and isotretinoin viability as an alternative to other standard treatments are also discussed in relation to these conditions. PMID- 24765230 TI - Itching to learn: school chair allergic contact dermatitis on the posterior thighs. AB - A 10-year-old girl with a history suggestive of nickel allergy presented with pruritic, eczematous plaques on her posterior thighs. Patch testing revealed sensitivities to nickel, cobalt, and chromium. The pattern of her involvement suggested an "outside job," and subsequent investigations confirmed that the exposed metal fasteners on her school chair were the likely source of her focal contact dermatitis. Medical history-taking, clinical observation, and investigative follow-through are essential when trying to identify a specific source of contact dermatitis in the pediatric and adolescent populations. PMID- 24765231 TI - Successful Treatment of a Recalcitrant Mondor's Cord Following Breast Augmentation. AB - Mondor's disease, a superficial thrombophlebitis, is a common complication of thoracoabdominal wall surgeries. While most patients experience disease resolution with expectant management, occasionally the disease may persist. The authors present a case of a 49-year-old woman who had persistent, symptomatic Mondor's disease 15 months status post-breast augmentation. The patient responded rapidly to intralesional triamcinolone injections resulting in complete disease resolution. To the authors' knowledge, this is the first report of intralesional corticosteroids being used to treat this common surgical complication. PMID- 24765232 TI - Getting high on the endocannabinoid system. AB - The endogenous cannabinoid system-named for the plant that led to its discovery is one of the most important physiologic systems involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body's organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease. PMID- 24765233 TI - Migraine and sleep: new connections. AB - "Attack" is often a word associated with migraine, and for good reason. If you suffer from migraine headaches or know someone who does, you are well aware of its crippling nature. This story focuses on new research that has uncovered an important link between migraine and sleep patterns. A better understanding of the relationships among the body's circadian rhythms, the brain's hypothalamus, and a mutated gene holds enormous promise of improved care for the more than 36 million Americans who experience migraine (three times more common in women) and the number of people suffering from familial advanced sleep phase syndrome (FASP). PMID- 24765234 TI - Barriers to Household Risk Management: Evidence from India. AB - Why do many households remain exposed to large exogenous sources of non systematic income risk? We use a series of randomized field experiments in rural India to test the importance of price and non-price factors in the adoption of an innovative rainfall insurance product. Demand is significantly price sensitive, but widespread take-up would not be achieved even if the product offered a payout ratio comparable to U.S. insurance contracts. We present evidence suggesting that lack of trust, liquidity constraints and limited salience are significant non price frictions that constrain demand. We suggest contract design improvements to mitigate these frictions. PMID- 24765235 TI - Quinine, mosquitoes and empire: reassembling malaria in British India, 1890-1910. AB - The drug quinine figured as an object of enforced consumption in British India between the late 1890s and the 1910s, when the corresponding diagnostic category malaria itself was redefined as a mosquito-borne fever disease. This article details an overlapping milieu in which quinine, mosquitoes and malaria emerged as intrinsic components of shared and symbiotic histories. It combines insights from new imperial histories, constructivism in the histories of medicine and literature about non-humans in science studies to examine the ways in which histories of insects, drugs, disease and empire interacted and shaped one another. Firstly, it locates the production of historical intimacies between quinine, malaria and mosquitoes within the exigencies and apparatuses of imperial rule. In so doing, it explores the intersections between the worlds of colonial governance, medical knowledge, vernacular markets and pharmaceutical business. Secondly, it outlines ways to narrate characteristics and enabling properties of non-humans (such as quinines and mosquitoes) while retaining a constructivist critique of scientism and empire. Thirdly, it shows how empire itself was reshaped and reinforced while occasioning the proliferation of categories and entities like malaria, quinine and mosquitoes. PMID- 24765236 TI - Preservation and Modification of Culture in Family Socialization: Development of Parenting Measures for Korean Immigrant Families. AB - This study aims to describe the family socialization beliefs and practices of Korean immigrant parents through testing psychometric properties of several newly developed items and scales to assess the major components of the Korean traditional concept of family socialization, ga-jung-kyo-yuk. These new measures were examined for validity and reliability. The findings show that Korean immigrant parents largely preserve their traditional and core parenting values, while also showing meaningful, yet not very dramatic, signs of adopting new cultural traits. The results also suggest that the acculturative process may not be simply bilinear but may generate a new, unique and blended value and behavior set from the two (or more) cultures involved. Culturally appropriate practice requires not only further validation of existing knowledge with minority groups, but the development of a theoretical framework of family socialization that recognizes the cultural uniqueness of immigrant families. PMID- 24765238 TI - Contrast enhanced ultrasound with quantitative perfusion analysis for objective characterization of pancreatic ductal adenocarcinoma: A feasibility study. AB - The aim of this study was to determine whether contrast enhanced ultrasound (CEUS) quantitative perfusion analysis allows an objective characterization of ductal adenocarcinoma (ADK) of the pancreas. Patients with pancreatic ADK underwent CEUS. All examinations were performed on an Acuson S2000 system (Siemens, Erlangen, Germany) after the iv administration of 2.4 mL contrast agent (SonoVue((r)), Bracco, Milan, Italy). All lesions were pathologically proved. An operator manually drew different regions of interest within the tumor and the adjacent parenchyma to allow the quantitative perfusion analysis. The mean values of peak of enhancement, time to peak and ascending curve were calculated and compared using the Student's t test. The quantitative perfusion analysis was possible in all lesions. The mean values of the peak of enhancement, time to peak and ascending curve were 17.19%, 7.97 s and 159.52% s within the tumor and 33.57%, 8.89 s and 355.29% s within the adjacent parenchyma. The peak of enhancement and the ascending curve values were significantly different within the tumor and the adjacent parenchyma. Thus, CEUS allows the quantitative perfusion analysis of pancreatic ductal adenocarcinoma. PMID- 24765237 TI - New insights into insulin: The anti-inflammatory effect and its clinical relevance. AB - Hyperglycemia, a commonly exhibited metabolic disorder in critically ill patients, activates the body's inflammatory defense mechanism, causing the waterfall release of numerous inflammatory mediators and cytokines, and eventually leads to organ damage. As the only glucose-lowering hormone in the body, insulin not only alleviates the detrimental effects of hyperglycemia through its metabolic regulation, but also directly modulates inflammatory mediators and acts upon immune cells to enhance immunocompetence. In this sense, hyperglycemia is pro-inflammatory whereas insulin is anti-inflammatory. Therefore, during the past 50 years, insulin has not only been used in the treatment of diabetes, but has also been put into practical use in dealing with cardiovascular diseases and critical illnesses. This review summarizes the recent advances regarding the anti-inflammatory effects of insulin in both basic research and clinical trials, with the hope of aiding in the design of further experimental research and promoting effective insulin administration in clinical practice. PMID- 24765241 TI - Adrenal metastasis from differentiated thyroid carcinoma documented on post therapy (131)I scan: A case based discussion. AB - Adrenal metastasis is an unusual site of disease involvement in the natural course of differentiated thyroid carcinoma (DTC). This paper discusses the clinical and imaging features of DTC with adrenal metastasis. An unusual case of unilateral solitary asymptomatic adrenal metastasis in the setting of DTC is described in this report with the imaging features including (131)I scintigraphy and Fluorodeoxyglucose- Positron emission tomography/computed tomography. The adrenal metastasis was associated with other sites of metastatic disease involvement and was unidentified on initial pre-treatment evaluation studies. All such suspicious lesions should be further evaluated with clinicoradiological correlation by other imaging modalities. A post-radioiodine therapy scan revealed radioiodine uptake in the thyroid bed, sternum and a focus of intense radioiodine concentration in the left suprarenal region. Spot oblique images and single photon emission computed tomography of the upper abdomen was undertaken to ascertain the position and better characterization of the lesion. A subsequent whole body PET-CT (non-contrast) was done which revealed a well defined 6.5 cm * 5.0 cm left adrenal lesion with a SUVmax (standardized uptake value-maximum) of 9.5 in addition to a fluorodeoxyglucose avid osteolytic sternal lesion. The serum thyroglobulin level was significantly raised (more than 250 ng/mL) with thyroid stimulating hormone being 4.9 MUIotaU/mL (even following an adequate period of levothyroxine withdrawal), indicating the functioning nature of the metastases. In addition to demonstrating an atypical site of metastatic disease in DTC patients, this case emphasizes the importance of carefully interpreting and correlating a post radio-iodine therapy scan, particularly those with focal abdominal radio-iodine uptake which could aid in detecting metastatic lesions that are not characterized or identified on initial evaluation. The other important feature that can be deciphered from this report is that an adrenal metastasis could be unilateral and solitary, unlike that of renal metastases which are almost always bilateral and multiple at presentation, although both are usually asymptomatic. PMID- 24765239 TI - Imaging pitfalls of pancreatic serous cystic neoplasm and its potential mimickers. AB - The aim of this article is to clarify diagnostic pitfalls of pancreatic serous cystic neoplasm (SCN) that may result in erroneous characterization. Usual and unusual imaging findings of SCN as well as potential SCN mimickers are presented. The diagnostic key of SCN is to look for a cluster of microcysts (honeycomb pattern), which may not be always found in the center. Fibrosis in SCN may be mistaken for a mural nodule of intraductal papillary mucinous neoplasm (IPMN). The absence of cyst wall enhancement may be helpful to distinguish SCN from mucinous cystic neoplasm. However, oligocystic SCN and branch duct type IPMN may morphologically overlap. In addition, solid serous adenoma, an extremely rare variant of SCN, is difficult to distinguish from neuroendocrine tumor. PMID- 24765240 TI - Cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography in tumours other than lung cancer: A systematic review. AB - AIM: To systematically review published data on the cost-effectiveness of Fluorine-18-Fluorodeoxyglucose positron emission tomography (FDG-PET) or PET/computed tomography (PET/CT) in tumours other than lung cancer. METHODS: A comprehensive literature search of studies published in PubMed/MEDLINE, Scopus and Embase databases through the 10(th) of October in 2013 was carried out. A search algorithm based on a combination of the terms: (1) "PET" or " PET/computed tomography (PET/CT)" or "positron emission tomography"; and (2) "cost effectiveness" or "cost-utility" or "cost-efficacy" or "technology assessment" or "health technology assessment" was used. Only cost-effectiveness or cost-utility analyses in English language were included. Exclusion criteria were: (1) articles not within the field of interest of this review; (2) review articles, editorials or letters, conference proceedings; and (3) outcome evaluation studies, cost studies or health technology assessment reports. For each included study, information was collected concerning basic study, type of tumours evaluated, perspective/type of study, results, unit and comparison alternatives. RESULTS: Sixteen studies were included. Head and neck tumours were evaluated in 4 articles, lymphoma in 4, colon-rectum tumours in 3 and breast tumours in 2. Only one article was retrieved for melanoma, oesophagus and ovary tumours. Cost effectiveness results of FDG-PET or PET/CT ranged from dominated to dominant. CONCLUSION: Literature evidence about the cost-effectiveness of FDG-PET or PET/CT in tumours other than lung cancer is still limited. Nevertheless, FDG-PET or PET/CT seems to be cost-effective in selective indications in oncology (staging and restaging of head and neck tumours, staging and treatment evaluation in lymphoma). PMID- 24765242 TI - Attenuation of Candida albicans virulence with focus on disruption of its vacuole functions. AB - The objective of the present review is to discuss if the yeast vacuole can be used as a target for attenuation of Candida albicans virulence. Literature searches were made electronically using predetermined inclusion criteria. The main searches were made through a systematic strategy in PubMed and authoritative journals in microbiology. It appeared that C. albicans virulence may be reduced by inhibiting vacuolar proton-translocating ATPase (V-ATPase) functions and acidification of the yeast vacuole by V-ATPase inhibitors, by seeking the synergistic effect of antifungals and non-antifungals affecting yeast vacuolar functions, and by inhibiting filament production - also regulated by the vacuole. Accordingly, we may impair C. albicans virulence by inhibiting functions of its vacuole, which plays essential roles during colonization and invasion of the host. Except for drugs where indications for clinical use can be redefined, such interventions may be closer to theory than to reality at the moment. But since the yeast is so difficult to eradicate by antifungal treatment, it could be rewarding to seek new strategies for reducing its virulence rather than trying to eradicate it completely from the microbiota, which often turns out to be impossible. PMID- 24765243 TI - Bacterial profiles of saliva in relation to diet, lifestyle factors, and socioeconomic status. AB - BACKGROUND AND OBJECTIVE: The bacterial profile of saliva is composed of bacteria from different oral surfaces. The objective of this study was to determine whether different diet intake, lifestyle, or socioeconomic status is associated with characteristic bacterial saliva profiles. DESIGN: Stimulated saliva samples from 292 participants with low levels of dental caries and periodontitis, enrolled in the Danish Health Examination Survey (DANHES), were analyzed for the presence of approximately 300 bacterial species by means of the Human Oral Microbe Identification Microarray (HOMIM). Using presence and levels (mean HOMIM value) of bacterial probes as endpoints, the influence of diet intake, lifestyle, and socioeconomic status on the bacterial saliva profile was analyzed by Mann Whitney tests with Benjamini-Hochberg's correction for multiple comparisons and principal component analysis. RESULTS: Targets for 131 different probes were identified in 292 samples, with Streptococcus and Veillonella being the most predominant genera identified. Two bacterial taxa (Streptococcus sobrinus and Eubacterium [11][G-3] brachy) were more associated with smokers than non-smokers (adjusted p-value<0.01). Stratification of the group based on extreme ends of the parameters age, gender, alcohol consumption, body mass index (BMI), and diet intake had no statistical influence on the composition of the bacterial profile of saliva. Conversely, differences in socioeconomic status were reflected by the bacterial profiles of saliva. CONCLUSIONS: The bacterial profile of saliva seems independent of diet intake, but influenced by smoking and maybe socioeconomic status. PMID- 24765245 TI - Vacuum-assisted closure versus conventional dressings in the management of diabetic foot ulcers: a prospective case-control study. AB - OBJECTIVE: To compare the effectiveness of vacuum-assisted closure (VAC) versus conventional dressings in the healing of diabetic foot ulcerations (DFUs) in terms of healing rate (time to prepare the wound for closure either spontaneously or by surgery), safety, and patient satisfaction. METHODS: Randomized case control study enrolling 56 patients, divided into two groups. Group A (patients treated with VAC) and Group B (patients treated with conventional dressings), with an equal number of patients in each group. DFUs were treated until wound closure, either spontaneously, surgically, or until completion of the 8-week period. RESULTS: Granulation tissue appeared in 26 (92.85%) patients by the end of Week 2 in Group A, while it appeared in 15 (53.57%) patients by that time in Group B. 100% granulation was achieved in 21 (77.78%) patients by the end of Week 5 in Group A as compared to only 10 (40%) patients by that time in Group B. Patients in Group A had fewer number of positive blood cultures, secondary amputations and were satisfied with treatment as compared to Group B. CONCLUSION: VAC appears to be more effective, safe, and patient satisfactory compared to conventional dressings for the treatment of DFUs. PMID- 24765244 TI - A study of prognostic factors in Chinese patients with diabetic foot ulcers. AB - OBJECTIVE: Few studies have identified factors as predictors of clinical prognosis of patients with diabetic foot ulcers (DFUs), especially of Chinese patients. In this study, we assessed the prognostic factors of Chinese patients with DFUs. METHODS AND MATERIALS: This was a retrospective study (January 2009 January 2011) of 194 DFUs conducted in an inpatient population at PLA 454 Hospital in Nanjing, China, to determine the prognostic influential factors of DFUs in Chinese patients. All of the studied patients were grouped into an amputation group, a non-healing group, and a cured group, according to the clinical prognosis. Patient parameters, including gender, age, smoking habits, education level, family history of diabetes mellitus, medical history, duration of foot lesions and complications, ankle-brachial index (ABI), transcutaneous oxygen pressure (TcPO2), urinary albumin/creatinine ratio (Alb/Cr), fundus oculi, electrocardiogram, DFU characteristics, bacterial nature, and neuropathy, were cross-studied among the three groups. RESULTS: Compared with the other two groups, the amputation group showed a higher number of males, older in age, lower ABI and TcPO2 levels, higher Wagner wound grading and size, and significantly higher urinary Alb/Cr ratio, blood urea nitrogen, serum creatinine, white blood cell count, and erythrocyte sedimentation rate. Compared to the cured group (162 patients), more patients with an older age, smoking, family history of diabetes mellitus, medical history of foot ulcerations, lower ABI and TcPO2 levels, higher urine Alb/Cr ratio, and serum creatinine were found in the non-healing group. Regression analysis was used to study the correlation between various factors and clinical prognosis, and the results were as follows: age, Wagner wound classification, and heel ulcerations were negatively correlated to the DFU prognosis, whereas the female population, ABI, and TcPO2 were positively correlated with DFU prognosis. CONCLUSION: In this retrospective study, we conclude that the DFU prognosis may be related to age, gender, wound location (heel), Wagner wound classification, ABI, and TcPO2 levels in the Chinese population. PMID- 24765246 TI - Risk factors for methicillin-resistant Staphylococcus aureus in diabetic foot infections. AB - OBJECTIVE: The purpose of this study was to evaluate risk factors for methicillin resistant Staphylococcus aureus (MRSA) in patients hospitalized for diabetic foot infections. METHODS: We reviewed hospital admissions for foot infections in patients with diabetes which had nasal swabs, and anaerobic and aerobic tissue cultures at the time of admission. Data collected included patient characteristics and medical history to determine risk factors for developing an MRSA infection in the foot. RESULTS: The prevalence of MRSA in these infections was 29.8%. Risk factors for MRSA diabetic foot infections were history of MRSA foot infection, MRSA nasal colonization, and multidrug-resistant organisms (p<0.05). Positive predictive value (PPV) and negative predictive value (NPV) of nasal colonization with MRSA to identify MRSA diabetic foot infections were 66.7% and 80.0% (sensitivity 41%, specificity 90%). Admission from a nursing home was not a significant risk factor. CONCLUSION: Positive nasal swabs are not predictive of the infecting agent; however, a negative nasal swab rules out MRSA as the infecting agent in foot wounds with 90% accuracy. PMID- 24765247 TI - Feeling psychologically restrained: the effect of social exclusion on tonic immobility. AB - BACKGROUND: A variety of studies have demonstrated posttraumatic stress disorder (PTSD) symptoms in victims of bullying. Because bullying with only relational aggression, such as social exclusion, does not involve physical aggression that could explain PTSD symptoms, it remains unclear why these relational aggression situations are also linked to PTSD symptoms. OBJECTIVE: The aim of the present study was to investigate whether the fear-response tonic immobility (Ti) can occur during social exclusion. Since Ti, as an indicator of peritraumatic dissociation, is an important predictor of PTSD symptoms, we expected that the presence of Ti during social exclusion might contribute to possible explanations of PTSD symptoms in victims of relational aggression. METHOD: Social exclusion was manipulated by a virtual Cyberball game in which participants were excluded and included by virtual confederates. During the game, Ti was measured, both physiologically (heart rate) and psychologically (subjective symptoms). Also, the underlying concepts of Ti, high levels of fear and psychological restraint (threatened sense of control), were measured. RESULTS: Excluded participants experienced higher levels of subjective and physiological Ti symptoms (lower heart rates) in comparison to social inclusion. Also, as expected, social exclusion resulted in higher levels of fear and psychological restraint in comparison to social inclusion. CONCLUSION: Social exclusion can evoke symptoms of Ti, fear, and psychological restraint, which might be important mechanisms to consider in explaining PTSD symptoms after relational forms of bullying in the absence of physical aggression. LIMITATIONS: The sample only contains healthy, female participants. Whether our results translate to bullying victims of relational aggression is therefore not known. Also, the physiological measurement of Ti (average heart rate) was rather limited and could be expanded in future studies. PMID- 24765248 TI - Losing a child: finding meaning in bereavement. AB - BACKGROUND: Confronting the loss of a loved one leads us to the core questions of human existence. Bereaved parents have to deal with the rupture of a widely shared concept of what is perceived to be the natural course of life and are forced into meaning reconstruction. OBJECTIVE: This study aims to expand upon existing work concerning specific themes of meaning reconstruction in a sample of bereaved parents. More specifically, the relationship between meaning reconstruction, complicated grief, and posttraumatic growth was analyzed, with special attention focused on traumatic and unexpected losses. METHOD: In a mixed methods approach, themes of meaning reconstruction (sense-making and benefit finding) were assessed in in-depth interviews with a total of 30 bereaved parents. Posttraumatic growth and complicated grief were assessed using standardized questionnaires, and qualitative and quantitative results were then merged using data transformation methods. RESULTS: In total 42 themes of meaning reconstruction were abstracted from oral material. It was shown that sense-making themes ranged from causal explanations to complex philosophical beliefs about life and death. Benefit-finding themes contained thoughts about personal improvement as well as descriptions about social actions. Significant correlations were found between the extent of sense-making and posttraumatic growth scores (r s=0.54, r s=0.49; p<0.01), especially when the death was traumatic or unexpected (r s=0.67, r s=0.63; p<0.01). However, analysis revealed no significant correlation with complicated grief. Overall results corroborate meaning reconstruction themes and the importance of meaning reconstruction for posttraumatic growth. PMID- 24765249 TI - ESBL-producing Enterobacteriaceae in Africa - a non-systematic literature review of research published 2008-2012. AB - INTRODUCTION: Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBL) has been found all over the world, and risk factors for acquiring these bacteria involve hospital care and antibiotic treatment. Surveillance studies are present in Europe, North America, and Asia, but there is no summarizing research published on the situation in Africa. AIM: This review aims to describe the prevalence of ESBL-producing Enterobacteriaceae in hospital and community settings in Africa and the ESBL genes involved. METHOD: A non-systematic literature search was performed in PubMed. All articles published between 2008 and 2012 were screened and read in full text. Relevant articles were assessed for quality of evidence and included in the review. Articles were divided into regional areas in Africa and tabulated. RESULTS: ESBL-producing Enterobacteriaceae in hospitalized patients and in communities varies largely between countries and specimens but is common in Africa. ESBLs (class A and D) and plasmid-encoded AmpC (pAmpC) were regularly found, but carbapenemases were also present. CONCLUSION: ESBL-producing Enterobacteriaceae in hospital and community settings in Africa is common. Surveillance of antimicrobial resistance needs to be implemented in Africa to tailor interventions targeted at stopping the dissemination of ESBL-producing Enterobacteriaceae. PMID- 24765250 TI - Conditions of the household and peridomicile and severe dengue: a case-control study in Brazil. AB - INTRODUCTION: The potential influence of high-vector-density environments where people are supposedly more exposed to mosquito bites may have a relation to the clinical severity of dengue fever, an association that has been poorly discussed in the literature. OBJECTIVE: This study aimed at analyzing the association between anthropic environmental factors, particularly those related to the conditions of domicile and peridomicile, and the occurrence of severe dengue cases during the 2008 epidemic in the state of Rio de Janeiro. METHODS: We conducted a retrospective case-control study with a sample of 88 severe patients aged 2-18. They were selected through chart review in four children's tertiary care centers. The 367 controls were neighbors of the cases, paired by age. Data were collected through interviews and systematic assessment of house conditions as well as peridomicile area conditions, and they were later analyzed by conditional logistic regression. RESULTS: The presence of three or more high volume capacity containers, which were without a lid or were inadequately sealed (water tanks, wells, cisterns, cement tanks, and pools), was significantly more frequent in households with severe cases when compared with households of controls (OR=1.6; CI 95%=1.36-20.01; p=0.015). DISCUSSION: The presence of such larger reservoirs that could potentially produce more adult forms of the vector is consistent with a situation where people are more exposed to mosquito bites, and consequently are more prone to have multiple infections over a short period of time. CONCLUSION: The emergence of severe dengue cases in a high-transmission context underpins the importance of constant vigilance and interventions in those types of reservoirs, which result from precarious household structures and irregular water supply services. PMID- 24765251 TI - Frequency of resistance to methicillin and other antimicrobial agents among Staphylococcus aureus strains isolated from pigs and their human handlers in Trinidad. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has emerged recently worldwide in production animals, particularly pigs and veal calves, which act as reservoirs for MRSA strains for human infection. The study determined the prevalence of MRSA and other resistant strains of S. aureus isolated from the anterior nares of pigs and human handlers on pig farms in Trinidad. METHODS: Isolation of S. aureus was done by concurrently inoculating Baird-Parker agar (BPA) and Chromagar MRSA (CHROM) with swab samples and isolates were identified using standard methods. Suspect MRSA isolates from Chromagar and BPA were subjected to confirmatory test using Oxoid PBP2 latex agglutination test. The disc diffusion method was used to determine resistance to antimicrobial agents. RESULTS: The frequency of isolation of MRSA was 2.1% (15 of 723) for pigs but 0.0% (0 of 72) for humans. Generally, for isolates of S. aureus from humans there was a high frequency of resistance compared with those from pigs, which had moderate resistance to the following antimicrobials: penicillin G (54.5%, 51.5%), ampicillin (59.1%, 49.5%), and streptomycin (59.1%, 37.1%), respectively. There was moderate resistance to tetracycline (36.4%, 41.2%) and gentamycin (27.2%, 23.7%) for human and pig S. aureus isolates, respectively, and low resistance to sulfamethoxazole-trimethoprim (4.5%, 6.2%) and norfloxacin (9.1%, 12.4%), respectively. The frequency of resistance to oxacillin by the disc method was 36.4 and 34.0% from S. aureus isolates from humans and pigs, respectively. Out of a total of 78 isolates of S. aureus from both human and pig sources that were resistant to oxacillin by the disc diffusion method, only 15 (19.2%) were confirmed as MRSA by the PBP'2 latex test kit. CONCLUSIONS: The detection of MRSA strains in pigs, albeit at a low frequency, coupled with a high frequency of resistance to commonly used antimicrobial agents in pig and humans could have zoonotic and therapeutic implications. Finally, the diagnostic limitation of using CHROMagar and testing for oxacillin resistance by the disc diffusion method alone to determine MRSA strains without performing confirmatory tests cannot be overemphasized because the possibility of overdiagnosis of MRSA infections cannot be ignored. PMID- 24765252 TI - Toward One Health: are public health stakeholders aware of the field of animal health? AB - Motivated by the perception that human and veterinary medicines can cooperate in more ways than just fighting zoonoses, the authors organized a roundtable during the 2013 annual meeting of the International Society for Disease Surveillance (ISDS). Collaborations between human and animal health sectors were reported to often rise in response to zoonotic outbreaks (during crisis time) and be mainly based on personal networks. Ways to maintain and strengthen these links were discussed. PMID- 24765253 TI - An unusual cause of hypoglycemia in a middle-aged female after bariatric surgery. AB - Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a disorder characterized by postprandial hypoglycemia and islet cell hypertrophy. It is an uncommon complication of weight-loss surgery. However, with the rising incidence of gastric bypass surgeries, it is important to be able to recognize the clinical picture of NIPHS and not to incorrectly ascribe the symptoms to late dumping syndrome. PMID- 24765254 TI - Immune thrombocytopenic purpura in ulcerative colitis: a case report and systematic review. AB - Over 100 extraintestinal manifestations are reported in ulcerative colitis (UC). A commonly reported hematological manifestation is autoimmune hemolytic anemia. On rare occasions, immune thrombocytopenic purpura (ITP) has been reported with UC. The presence of thrombocytopenia can complicate the clinical scenario as the number of bloody bowel movements is an important indicator of disease activity in UC. A proposed theory for this association is antigenic mimicry between a platelet surface antigen and bacterial glycoprotein. We are reporting a case of UC and associated ITP managed successfully with anti-TNF therapy. We also performed a systemic review of case reports and a case series reporting this association. PMID- 24765255 TI - Reflex anuria: a rare cause of acute kidney injury. AB - BACKGROUND: Acute Kidney Injury results from pre renal, post renal or intrinsic renal causes. Reflex anuria is a very rare cause of renal impairment which happens due to irritation or trauma to one kidney or ureter, or severely painful stimuli to other nearby organs. CASE PRESENTATION: Here we present a case of acute kidney injury secondary to reflex anuria in a patient who underwent extensive gynecological surgery along with ureteral manipulation which recovered spontaneously. CONCLUSION: Reflex Anuria is a rare and often not considered as cause of acute kidney injury. This case illustrates that this should be kept as a differential in potential cause of acute kidney injury in patient undergoing urogenital or gynecological surgeries. PMID- 24765256 TI - An unusual cause of pancytopenia: Whipple's disease. AB - Whipple's disease is a systemic infectious disease caused by the bacteria Tropheryma whipplei. The most common clinical manifestations of Whipple's disease are weight loss (92%), hypoalbuminemia and steatorrhea (91%, respectively), diarrhea (72%), arthralgia (67%), and abdominal pain (55%). Neurological signs and symptoms from dementia to oculomasticatory myorhythmia or oculofacioskeletal myorhythmia (pathognomonic of Whipple's disease), lymphadenopathy, and fatigue can also be present. Pancytopenia is a rare and less recognized clinical feature in Whipple's disease patients. We are describing a case where a middle-aged Caucasian male diagnosed with Whipple's disease was found to have pancytopenia. Etiology of pancytopenia is postulated to be due to the invasion of bone marrow by T. whipplei. It is important to recognize that bone marrow involvement by the Whipple bacillus is not uncommon. In the presence of lymphadenopathy and pancytopenia, clinicians should think of Whipple's disease as a differential diagnosis apart from lymphoma or other non-specific granulomatous reticuloendothelial disorders. PMID- 24765257 TI - Buprenorphine Outpatient Outcomes Project: can Suboxone be a viable outpatient option for heroin addiction? AB - BACKGROUND: Opioid dependence treatment traditionally involves methadone clinics, for which dispensing schedules can be cumbersome. Buprenorphine, a partial agonist of the mu receptor and antagonist of the kappa receptor, is a potential outpatient alternative to methadone. Funded by a grant from the State of Maryland's Community Health Resources Commission (CHRC), the Buprenorphine Outpatient Outcomes Project (BOOP) evaluates the outcome of Suboxone (buprenorphine/naloxone) treatment on abstinence from heroin use, rates of emergency room visits and hospitalizations, legal issues, and quality of life. METHODS: Active heroin users were recruited between June 2007 and June 2010 and induction therapy with Suboxone was instituted during hospitalization. Once discharged, patients were followed as outpatients for maintenance treatment and counseling. Data were collected from electronic medical records, Maryland state legal records, and SF-36((r)) Health Surveys regarding several parameters and patients were categorized according to duration of treatment with Suboxone into one of three groups: <1 month, 1-3 months, and >3 months. RESULTS: A total of 220 participants were included in the study. The age range of participants was 18-67 years with most being African American males. Eighty-three (38%) remained in the study for at least 1 month, with 37 of the 83 (45%) remaining in treatment for >3 months. Ten of the 37 (27%) never relapsed after their longest period of abstinence from heroin. During the first year after initiating treatment with Suboxone, hospitalization and emergency room visit rates for all 220 participants decreased by 45 and 23%, respectively, as compared to the year prior to starting treatment. The number of legal charges for drug possession decreased from 70 to 62. Anecdotally, the quality of life seemed to improve in those who were treated with Suboxone for longer periods of time and received regular counseling. CONCLUSION: Overall, Suboxone is an effective treatment method for heroin addiction and is a viable outpatient therapy option. Individualized treatment plans and counseling must be implemented for maximum benefits to be seen. Retention of patients for a long duration of therapy was difficult, but for those who did remain, benefits were seen in overall health, abstinence from heroin use, cognition, and quality of life. PMID- 24765258 TI - Use of a standardized code status explanation by residents among hospitalized patients. AB - OBJECTIVES: There is wide variability in the discussion of code status by residents among hospitalized patients. The primary objective of this study was to determine the effect of a scripted code status explanation on patient understanding of choices pertaining to code status and end-of-life care. METHODS: This was a single center, randomized trial in a teaching hospital. Patients were randomized to a control (questionnaire alone) or intervention arm (standardized explanation+ questionnaire). A composite score was generated based on patient responses to assess comprehension. RESULTS: The composite score was 5.27 in the intervention compared to 4.93 in the control arm (p=0.066). The score was lower in older patients (p<0.001), patients with multiple comorbidities (p<=0.001), KATZ score <6 (p=0.008), and those living in an assisted living/nursing home (p=0.005). There were significant differences in patient understanding of the ability to receive chest compressions, intravenous fluids, and tube feeds by code status. CONCLUSION: The scripted code status explanation did not significantly impact the composite score. Age, comorbidities, performance status, and type of residence demonstrated a significant association with patient understanding of code status choices. PRACTICE IMPLICATIONS: Standardized discussion of code status and training in communication of end-of-life care merit further research. PMID- 24765259 TI - Application of ICD guidelines and indications in a community-based academic hospital: a case series-based discussion. AB - BACKGROUND: Implantable cardioverter defibrillators (ICDs) are indeed beneficial in selected patients as evidenced by multiple large randomized controlled trials (RCTs) since 1980. A systematic method for stratification of patients and hospital-wide criteria/guidelines to ascertain appropriate device implantation became necessary. METHODS: Major ICD/CRT (cardiac resynchronization therapy) clinical studies and relevant guidelines were reviewed, and an institution-wide inclusion and exclusion criteria for ICD/CRT was formulated. A retrospective analysis of selected cases was performed to discuss the criteria and special clinical situations. RESULTS: We have translated the evolving ICD/CRT studies into a standard of care at our hospital by formulating a standard, practical, and update-to-date ICD inclusion and exclusion criteria. Thirteen cases were selected to represent major indications and contraindications of ICDs in our practice. These cases cover indications of ICD for secondary prevention of sudden cardiac death (SCD), primary prevention of SCD in patients with CHF resulted from either ischemic or non-ischemic cardiomyopathy, as well as for infiltrative cardiomyopathy and inherited conditions. We discussed the application of CRT in patients with CHF associated with prolonged QRS duration. We then covered the potential benefits of ICD with/without CRT in certain special populations of patients that have not been adequately evaluated by currently available RCTs; these include alcoholic, elderly, female, and ESRD/HD patients. Finally, we addressed risks, complications and contraindications of ICD, as well as application of an external wearable defibrillator in AMI, or status post-CABG patient during the mandatory waiting period for an ICD. CONCLUSIONS: Establishment of the ICD/CRT criteria represents a practical translation of emerging CRTs and helps to standardize patient care in our hospital. It also improves cost-effectiveness as well as appropriate utilization of institute and device resources. PMID- 24765260 TI - Accounting for professionalism: an innovative point system to assess resident professionalism. AB - BACKGROUND: Professionalism is a core competency for residency required by the Accreditation Council of Graduate Medical Education. We sought a means to objectively assess professionalism among internal medicine and transitional year residents. INNOVATION: We established a point system to document unprofessional behaviors demonstrated by internal medicine and transitional year residents along with opportunities to redeem such negative points by deliberate positive professional acts. The intent of the policy is to assist residents in becoming aware of what constitutes unprofessional behavior and to provide opportunities for remediation by accruing positive points. A committee of core faculty and department leadership including the program director and clinic nurse manager determines professionalism points assigned. Negative points might be awarded for tardiness to mandatory or volunteered for events without a valid excuse, late evaluations or other paperwork required by the department, non-attendance at meetings prepaid by the department, and inappropriate use of personal days or leave. Examples of actions through which positive points can be gained to erase negative points include delivery of a mentored pre-conference talk, noon conference, medical student case/shelf review session, or a written reflection. RESULTS: Between 2009 and 2012, 83 residents have trained in our program. Seventeen categorical internal medicine and two transitional year residents have been assigned points. A total of 55 negative points have been assigned and 19 points have been remediated. There appears to be a trend of fewer negative points and more positive points being assigned over each of the past three academic years. CONCLUSION: Commitment to personal professional behavior is a lifelong process that residents must commit to during their training. A professionalism policy, which employs a point system, has been instituted in our programs and may be a novel tool to promote awareness and underscore the merits of the professionalism competency. PMID- 24765261 TI - Professionalism: hard to measure but you know it when you see it. PMID- 24765262 TI - Do medical trainees feel confident communicating with low health literacy patients? AB - BACKGROUND: Medical trainees infrequently use health literacy (HL) skills and overestimate their use of plain language and teach back skills. The aim of this study is to assess if level of training impacts the perception of medical trainees around HL knowledge and skills. METHODS: A structured questionnaire consisting of 5 questions assessing the respondents' perception of their confidence in their HL knowledge, ability to identify and communicate with low HL patients, and use of relevant resources was completed by medical students and residents of 2 community-based internal medicine programs in Pennsylvania and Maryland between July 2012 and January 2013. RESULTS: The response rate was 100% (40) for the PA program and 42% (17) for the MD residency program. All rotating medical students (17) completed the questionnaire. Out of 74 participants, less than 10% were confident of their HL knowledge and ability to identify and communicate with low HL patients. Only 1.4% (1) were confident of their ability to identify appropriate resources. There was no significant difference in communication skills (P=0.305) and ability to identify appropriate resources (P=0.143) across all participants irrespective of their training level. A significant improvement in HL knowledge was observed during the progression from first-year to third-year medical school (P=0.0126) and from internship to second year of residency (P=0.0496). CONCLUSION: Medical trainees perceive that they do not receive adequate training on HL knowledge and skills required to feel confident in identifying and communicating with low HL patients and identifying appropriate resources. There is a need for addressing these deficiencies via medical school and residency curricula. PMID- 24765263 TI - Pure red cell aplasia and associated thymoma. AB - Pure red cell aplasia is a rare cause of anemia, caused by an absence of red blood cell precursors in the bone marrow. It is usually a paraneoplastic syndrome, associated most commonly with large-cell granular lymphocyte leukemia but also thymoma. For patients who present both pure red cell aplasia and thymoma, thymectomy leads to an initial remission of the aplasia in 30% of cases. However, sustained remission may require the addition of medications such as corticosteroids, cyclosporine, or cyclophosphamide. We present a case of pure red cell aplasia associated with a thymoma in an otherwise healthy 80 year-old woman. PMID- 24765264 TI - Supplemental root in a mandibular first molar: a rarity. AB - Anatomic variations are common in human dentition. A clear understanding of these variations is very important for success of endodontic treatment. A dentist should be aware of these anatomic variations as this can affect the treatment outcome. A case of endodontic therapy is presented in which inability to locate an anatomically rare supplemental canal of a three rooted mandibular first molar resulted in treatment failure. A 21-year-old female reported with pain and swelling in relation to lower right first molar. An intra oral periapical radiograph revealed 3 roots; the first canal of the mesial root and a canal of one of the distal roots were found to be treated endodontically, which were infraobturated but the canal of the 2nd distal root had not been treated. The radiograph revealed periapical radiolucency and widening of periodontal space. Prior to starting the endodontic treatment the clinician must be aware of the anatomic variations in tooth pulp morphology and also the importance of preoperative radiographs cannot be underscored. PMID- 24765265 TI - Acute promyelocytic leukemia, hypogranular variant: a rare presentation. AB - Early diagnosis of acute promyelocytic leukemia (APL) is essential because of its associated life threatening coagulopathy and unique response to all trans retinoic acid (ATRA) therapy. The characteristic cell morphology supplemented by cytochemistry offers the most rapid means for diagnosis. Here we describe a rare case of acute promyelocytic leukemia-hypogranular variant that poses particular diagnostic challenge. PMID- 24765266 TI - Completely extruded talus without soft tissue attachments. AB - A completely extruded talus without any remaining soft tissue attachments is extremely rare. The present report describes treatment of a 45-year-old man who sustained a completely extruded talus injury following a rock-climbing fall. Upon admission, the extruded talus was deep-frozen in our bone bank. The open ankle joint underwent massive wound debridement and irrigation for 3 days. Four days later we performed a primary subtalar fusion between the extruded talus and the calcaneus, anticipating revascularization from the calcaneus. However, aseptic loosening and osteolysis developed around the screw and talus. At 12 months post trauma we performed a tibiocalcaneal ankle fusion with a femoral head allograft to fill the talar defect. Follow-up at 24 months post-trauma showed the patient had midfoot motion, tibio-talar-calcaneal fusion, and was able partake in 4-hour physical activity twice per week. PMID- 24765267 TI - Cholestatic hepatitis due to Salmonella typhi. AB - Salmonella infection occurs worldwide and is still an important public health problem in many developing countries. The infection can affect almost all major organs including the liver. Severe hepatic involvement with a clinical feature of acute hepatitis is a rare complication. In this paper, a 39-year-old male with acute cholestatic typhoid hepatitis is presented. The case had a tender hepatomegaly and elevated serum alanine and aspartate transaminase, alkaline phosphatase, and gamma glutamyl transferase levels; these features cannot been distinguished from those of acute viral hepatitis. Serological and viral markers of acute viral hepatitis were negative. No pathology could be determined in abdomen Ultrasonography (USG) or Magnetic Resonance (MR) Cholangiography. As enteric fever is a common infection, the recognition of salmonella hepatitis is of clinical importance. When patients from an endemic or outbreak area present acute febrile hepatitis, typhoid fever should be a consideration. PMID- 24765268 TI - Peritoneal carcinomatosis mimicking a perforated diverticulitis. AB - We report the case of a patient with a pelvic abscess and a malignant pancreatic tumor. The management of this complicated diverticulitis included radiological drainage and surgery. This abscess was due to a peritoneal carcinomatosis originating from the pancreas, which is an extremely rare cause of intestinal perforation. PMID- 24765269 TI - Spontaneous resolution of obstructive hydrocephalus from blood in the cerebral aqueduct. AB - Obstructive hydrocephalus is a neurological emergency that needs to be immediately identified and treated. It very rarely resolves without treatment. We report about an 86-year-old man with right frontal stroke who developed obstructive hydrocephalus caused by blood in the cerebral aqueduct. The patient had sudden and immediate clinical improvement and a repeated head computed tomography (CT) scan showing spontaneous resolution of hydrocephalus. Spontaneous resolution of obstructive hydrocephalus is possible when the cause is minimal blood in the cerebral aqueduct without any blood in the fourth ventricle. PMID- 24765270 TI - An inside story of a thrombosed pile. AB - We report a case of extremely rare variant of ano-rectum malignant tumor. The tumor is often misdiagnosed as either hemorrhoids or rectal polyp, which are benign diseases. On histology also this variant may be confused with other more commonly occurring spindle cell lesions in this area; its recognition is therefore important as it normally has a poor prognosis. PMID- 24765271 TI - Congenital melanocytic nevus of the oral mucosa: report of a rare pigmented lesion and review of the literature. AB - Oral pigmented lesions are uncommon and congenital melanocytic nevi are especially rare. We report a case of a patient with multiple congenital melanocytic nevi including a palatal lesion. This is reported to add to the scant literature that exists on this subject. Prognosis and management are discussed. PMID- 24765272 TI - Recurrent hypothermia and hypoglycemia as the initial presentation of hepatitis C. AB - Hepatitis C most commonly manifests with asymptomatic elevations in transaminase levels or in advanced stages, may present with hepatic encephalopathy or ascites. We report the first case in the literature, in which the initial manifestation of hepatitis C induced chronic liver disease was recurrent hypoglycemia and hypothermia. In our case, the hypoglycemia was induced by glycogen depletion from hepatitis C induced chronic liver disease. In chronic liver disease, glycogen stores are depleted from extensive fibrosis and it has been shown that glycogen depletion may herald hepatic encephalopathy, which later manifested in our patient. PMID- 24765273 TI - Urinary tract infection mimicking acute mesenteric ischaemia in an immunocompromised patient. AB - Bowel infarction due to acute mesenteric ischaemia (AMI) is an abdominal emergency with a high mortality rate. We report a case of exaggerated septic response to a urinary tract infection mimicking AMI in an immunosuppressed diabetic patient. A 56-year-old female was found collapsed at home with a 24 hour history of diarrhoea, a central abdominal pain and a complex past medical history. Examination showed her to be pyrexial, drowsy, profoundly dehydrated with evidence of cardiovascular collapse. She had a tender distended abdomen, raised inflammatory markers, raised lactate of 9.1 u/L and urinalysis was positive for leucocytes and nitrites. An abdominal computed tomography (CT) scan was reported to show small bowel ischaemia. She underwent a negative laparotomy and recovered following management in the intensive therapy unit. The negative laparotomy rate can be reduced by having abdominal CT performed and reported by an experienced radiologist or by the use of diagnostic laparoscopy. PMID- 24765274 TI - Giant epidermoid cyst over the male breast. AB - Epidermoid cyst is commonly known as sebaceous cyst. It is the most commonly encountered cyst of the skin. Epidermoid cyst over the breast is uncommon. Punctum is the hallmark for clinical diagnosis. Local excision with primary closure is the treatment of choice. Biopsy is mandatory in giant cyst to exclude malignancy. PMID- 24765275 TI - Massively dilated right atrium masquerading as a mediastinal tumor. AB - Severe tricuspid valve insufficiency causes right atrial dilatation, venous congestion, and reduced atrial contractility, and may eventually lead to right heart failure. We report a case of a patient with severe tricuspid valve insufficiency, right heart failure, and a massively dilated right atrium. The enormously dilated atrium compressed the right lung, resulting in a radiographic appearance of a mediastinal tumor. Tricuspid valve repair and reduction of the right atrium was performed. Follow up examination revealed improvement of liver function, reduced peripheral edema and improved New York Heart Association (NYHA) class. The reduction of the atrial size and repair of the tricuspid valve resulted in a restoration of the conduit and reservoir function of the right atrium. Given the chronicity of the disease process and the long-standing atrial fibrillation, there is no impact of this operation on right atrial contraction. In combination with the reconstruction of the tricuspid valve, the reduction atrioplasty will reduce the risk of thrombembolic events and preserve the right ventricular function. PMID- 24765276 TI - A rare case of coin impaction in larynx in an adult. AB - Impaction of foreign body in larynx is reported exclusively in paediatric population only. Moreover impaction of coin in larynx has never been reported previously. With this background, we report a rare case of coin impaction in larynx in a healthy adult. PMID- 24765277 TI - It can't be december already: a real life simile to Jeffery Archer's short story. AB - This case reflects the difficulties arising out of the patients autonomy to choose the type, timing, and extent of the medical management even though in some clinical scenarios, like the case presented, the patient was not able to communicate his physiological needs for a safe and protected shelter from the extreme weather, and was unable to follow up with the medical plan offered at the emergency room during each of his prior visits before the catastrophic event of unwitnessed hypoglycemic seizure and severe hypothermia. PMID- 24765278 TI - Resistant thrombocytopenia in an HIV and hepatitis C patient: treatment response with novel agent eltrombopag. AB - HIV-associated thrombocytopenia is a disease which can be recurrent to standard therapy which includes highly active antiretroviral therapy (HAART) therapy, steroids and immunoglobulin. We report a patient with HIV and hepatitis C who presented with resistant thrombocytopenia. Treatment with Eltrombopag - a thrombopoeitin receptor agonist showed initial good response with recurrence of thrombocytopenia. This novel agent could be considered as a treatment option prior to splenectomy and may be useful as a temporizing measure. PMID- 24765279 TI - Sister Mary Joseph's nodule: a rare cytologic presentation. AB - Umbilical metastasis is one of the main characteristic signs of extensive neoplastic disease and is universally referred to as Sister Mary Joseph's nodule. It indicates neoplasm of inner organs mostly located in the gastrointestinal tract or the pelvis. However, in approximately 15-30% the primary tumor remains occult. In most cases, Sister Mary Joseph's nodule appears as an early and sometimes the only symptom of the malignancy. Here we report a rare fine needle aspiration (FNA) cytologic diagnosis of umbilical metastasis of an ovarian carcinoma. PMID- 24765280 TI - Group B streptococcus endocarditis associated with multiple pulmonary septic emboli. AB - Endocarditis is a rare presentation of group B streptococcal infection. Its association with pulmonary septic embolism was only barely studied and limited data is available up to date. Multiple septic emboli is a common complication of bacterial endocarditis, but only a few cases have been documented in relation to group B streptococcus. We present the case of an 87 year old female patient with multiple underlying conditions that predisposed the development of bacterial endocarditis secondary to group B streptococcus and subsequently multiple pulmonary septic emboli. The patient was treated with ceftriaxone and azythromycin with good response and complete recovery without any further complications. In the event of a diagnosed case of group B streptococcus endocarditis, there should be a low threshold for the suspicion of septic pulmonary emboli especially in cases with right valves involvement. PMID- 24765281 TI - Polysubstance abuse related subacute urinary retention and Hutch diverticulum of urinary bladder. AB - The present case highlights the presentation and management of hyperkalemia and acute renal failure secondary to polysubstance abuse related subacute urinary retention due to alpha-adrenergic and MU-receptor activation in a patient with Hutch diverticulum. PMID- 24765282 TI - Incidence of dehydration encephalopathy among patients with disturbed consciousness at a hospital emergency unit. AB - Systemic dehydration and diffuse central nervous system signs without any other illness is referred to as dehydration encephalopathy (DE). However, the incidence of DE at emergency units remains uncertain. We investigated the incidence of DE among persons with disturbed consciousness who visited the emergency unit. We reviewed the medical case records of the emergency unit at our university hospital during a 6-month period. Among them, 132 patients presented with disturbed consciousness as the sole initial manifestation on arrival. They were 75 men, 47 women; mean age 68 years (16-95 years). After carefully excluding other etiologies, the incidence of DE was 2% among all persons in the emergency unit and 4% among persons older than 68 years. In conclusion, the incidence of DE in our emergency unit was not common. Nevertheless, recognition of DE is extremely important in order to avoid unnecessary medication in elderly subjects. PMID- 24765283 TI - Supratherapeutic international normalized ratio: an indicator of chronic malnutrition due to severely debilitating gastrointestinal disease. AB - This case highlights the fact that Supratherapeutic INRs direct the attention of the treating physicians' team to the underlying severely debilitating gastrointestinal diseases. Prolonged fasting or starvation reduces vitamin K levels. Such patients are more sensitive to treatment with Vitamin K antagonist based anticoagulants. Hence, the Supratherapeutic INR can be an objective indicator of chronic loss of appetite with poor nutritional status of the patient and therefore acts as a warning sign for diagnosis of severe debilitating primary gastrointestinal disease. PMID- 24765284 TI - Significant stenoses of twin circumflex arteries accompanied by heart failure: a rare coronary artery anomaly. AB - Although coronary artery anomalies may cause some clinical symptoms, most are incidentally discovered as benign findings on coronary angiograms. A circumflex coronary artery anomalously originating from the right sinus of Valsalva is the most common coronary anomaly. However, a double circumflex coronary artery, both stenotic in their mid portions, resulting in symptomatic heart failure is a rare clinical and angiographic condition. In this case, we present a 71-year-old male patient admitted to our clinic with the diagnosis of acute heart failure. Angiography revealed stenotic double circumflex arteries, arising from the left and right sinus of Valsalva, and the patient was treated by percutaneous coronary intervention. PMID- 24765285 TI - Kawasaki disease: giant aneurysm with a large thrombus of the left coronary artery. AB - We report a six-month-old febrile infant presenting with stridor. Later on, he developed typical Kawasaki disease with giant aneurysm of the coronary artery with thrombosis that resolved with an aggressive anticoagulation therapy. The giant aneurysm still persisted a year later. Respiratory illness with stridor is an unusual presentation of Kawasaki disease. PMID- 24765286 TI - Amyand hernia with appendicitis. AB - The term Amyand hernia refers to presence of appendix within inguinal hernia. The incidence of having a normal appendix within inguinal hernia is about 1%, whereas the finding of appendicitis in the inguinal hernia is only 0.1%. PMID- 24765287 TI - Neuroradiological findings of an adolescent with early treated phenylketonuria: is phenylalanine restriction enough? AB - Phenylketonuria is caused by mutations in the enzyme phenylalanine hydroxylase gene, that can result in abnormal concentrations of phenylalanine on blood, resulting in metabolites that can cause brain damage. The treatment is based on dietary restriction of phenylalanine, and noncompliance with treatment may result in damage of the brain function. Brain abnormalities can be seen on magnetic resonance imaging of these individuals. Studies indicate that the appearance of abnormalities in white matter reflects high levels of phenylalanine on the blood. This case will show the clinical and neuroradiological aspects of a teenager with constant control of phenylalanine levels. Despite the continuous monitoring and early treatment, the magnetic resonance imaging identified impressive abnormalities in the white matter. This leads us to one question: is the restriction of phenylalanine sufficient to prevent changes in the white matter in patients with phenylketonuria? PMID- 24765288 TI - Association of aortic and main left coronary aneurysms with severe aortic insufficiency in Takayasu's arteritis. AB - Takayasu's arteritis is a granulomatous vasculitis of unknown etiology that affects mainly the aorta and its branches. As a result of intimal fibroproliferation, segmental stenosis, occlusion, dilatation, and aneurysmal formation of the involved vessels may develop. It is an uncommon disease and usually affects young Asian female patients during the second and third decades of life. Coronary arteries are exceptionally affected and coronary aneurysm formation is a very rare finding. We describe a case of a previously healthy 26 year-old Caucasian female whose Takayasu's arteritis presented as a previously undescribed association of aortic and main left coronary aneurysms with severe aortic insufficiency. PMID- 24765289 TI - Kala-azar in a Brazilian child. AB - We report the case of a six-year-old Brazilian girl referred for splenomegaly who first presented with fever, asthenia, and weight loss. Geographical location, clinical exam, and blood laboratories suggested kala-azar. Serology confirmed kala-azar diagnosis, but direct evidence of the parasites was not made. A treatment by meglumine antimoniate is given under hospital surveillance for two weeks. Thereupon, the patient is asymptomatic and all tests are normal. PMID- 24765290 TI - Early viral kinetics and response to treatment in a hepatitis C virus genotype 5 infected patient. AB - Genotype 5 hepatitis C has been poorly studied despite its worldwide spread. We have analyzed the early kinetics of genotype 5 hepatitis C virus RNA during pegylated interferon/ribavirin treatment in a 59-year-old man with active liver necroinflammatory changes and advanced liver fibrosis. The patient had a high viral load but a small serum level of hepatitis C core antigen. On combination antiviral treatment with pegylated-interferon alpha 2a, 180 ug/week, and ribavirin, 1200 mg/day, the patient experienced an impressive reduction in serum HCV RNA as early as day 2 of treatment and eventually became a sustained virological responder. Our viral kinetics data support previous clinical studies showing HCV genotype 5 could be as intrinsically sensitive to interferon as HCV genotypes 2 and 3. PMID- 24765291 TI - A case of idiopathic encephalomeningocele. AB - In the present case we report about an encephalomeningocele in an adult female. Since the cause of this medical entity is a congenital fusion defect of the neural tube of the cranial base, most of the encephaloceles occurs in children leading to facial disfigurement. In the rare cases described in adults, rhinorrhea is usually present. Here we present a case of temporobasal encephalomeningocele in a 72-year-old female patient suffering from headaches in the last 4-5 years. No rhinorrhea or other significant neurological symptoms were noticed. No congenital cause was apparent. After diagnostic steps including brain magnetic resonance imaging (MRI), cranial computed tomography (CT) and MR cisternography, an encephalomeningocele was diagnosed. Through a pterional approach this was completely removed. The only symptom the patient complaint about, headache, was eliminated after surgery. PMID- 24765292 TI - Bilateral tuberculate supernumerary teeth. AB - Supernumerary teeth are teeth in excess of the normal series occurring in any region of the dental arch. They are located mostly in the anterior maxillary region and are classified according to their location and morphology. The tuberculate type of supernumerary tooth possesses more than one cusp or tubercle (barrel shaped). It is rare to find bilateral tuberculate supernumerary teeth in the premaxillary region and when found they rarely erupt. This report describes a 13-year-old boy with erupted palatally placed bilateral tuberculate supernumerary teeth. The presence of these supernumerary teeth led to the labial displacement and rotations of the anterior maxillary teeth. The treatment involved extraction of the supernumerary teeth and a referral for orthodontic management of the crowding, displacement and rotations. The occurrence of erupted palatally placed tuberculate anterior teeth in this case is a rare experience. However, the associated orthodontic problems are within familiar spectrum. PMID- 24765293 TI - Primary pineal malignant melanoma. AB - Primary pineal malignant melanoma is a rare entity, with only thirteen cases reported in the world literature to date. We report a case of a 70-year-old man, who consulted with gait disturbance of six months duration, associated in the last month with dizziness, visual abnormalities and diplopia. No other additional melanocytic lesions were found elsewhere. The magnetic resonance showed a 25 mm expansive mass in the pineal gland that was associated with hydrocephaly, ventricular and transependimary oedema. The lesion was partially excised by a supracerebellar infratentorial approach. The histological examination revealed a melanoma. The patient received radiation therapy, but died of disease 16 weeks later. We herein review the literature on this rare tumour and comment on its clinical, radiological and histopathological features and differential diagnosis. PMID- 24765294 TI - Cerebellopontine angle facial schwannoma relapsing towards middle cranial fossa. AB - Facial nerve schwannomas involving posterior and middle fossas are quite rare. Here, we report an unusual case of cerebellopontine angle facial schwannoma that involved the middle cranial fossa, two years after the first operation. A 53-year old woman presented with a 3-year history of a progressive left side hearing loss and 6-month history of a left facial spasm and palsy. Magnetic resonance imaging (MRI) revealed 4.5 cm diameter of left cerebellopontine angle and small middle fossa tumor. The tumor was subtotally removed via a suboccipital retrosigmoid approach. The tumor relapsed towards middle cranial fossa within a two-year period. By subtemporal approach with zygomatic arch osteotomy, the tumor was subtotally removed except that in the petrous bone involving the facial nerve. In both surgical procedures, intraoperative monitoring identified the facial nerve, resulting in preserved facial function. The tumor in the present case arose from broad segment of facial nerve encompassing cerebellopontine angle, meatus, geniculate/labyrinthine and possibly great petrosal nerve, in view of variable symptoms. Preservation of anatomic continuity of the facial nerve should be attempted, and the staged operation via retrosigmoid and middle fossa approaches using intraoperative facial monitoring, may result in preservation of the facial nerve. PMID- 24765295 TI - Fulminating septic shock from Clostridium perfringens in an early breast cancer patient with severe myalgia after docetaxel treatment. AB - Anaerobic bacteraemia could be a life-threatening condition in neutropenic patients receiving chemotherapy. Taxane therapy is associated with necrotising inflammation of the caecum (named also typhlitis) that could be a potential source for bacteraemia. We report the case of a sudden onset of septic shock by Clostridium perfringens in a young patient treated with docetaxel as adjuvant chemotherapy for early breast cancer. A mini-review of the literature has been performed. PMID- 24765296 TI - Coexistence of Behcet's disease with ankylosing spondylitis and familial Mediterranean fever: a rare occurrence. AB - Behcet's disease (BD) and familial Mediterranean fever (FMF), which are two separate diseases sharing some clinical features, may also coexist in the same patient. Further investigations are needed to understand whether this coexistence is due to either chance or geographical distribution patterns of these diseases or to common etiopathogenetic characteristics. Spondylarthritis as part of the clinical picture in these two diseases has been questioned and probably it is not a prominent characteristic of any of them. We report a 35-year-old Tunisian man who had an association of BD, FMF and Human Leukocyte Antigen (HLA) B27 positive ankylosing spondylitis. Although that spondylarthritis is an infrequent joint involvement of FMF and BD, it must be looked for in case of association of these diseases. PMID- 24765297 TI - Acute renal failure, thrombocytopenia, and elevated liver enzymes after concurrent abuse of alcohol and cocaine. AB - Cocaine has been associated with known adverse effects on cardiac, cerebrovascular and pulmonary systems. However, the effect of cocaine on other organs has not been extensively reported. A middle age man presented with abdominal pain and nausea after inhalation of crack cocaine. On admission, he was found to be hypertensive and tachycardic. Physical examination revealed mild abdominal tenderness without rebound. Laboratory investigations were significant for acute kidney failure with elevated serum creatinine (3.72 mg/dL), thrombocytopenia (platelet count 74,000/UL), elevated alanine and aspartate transaminases (ALT 331 U/L; AST 462 U/L) and elevated creatine phosphokinase (CPK 5885 U/L). Urine toxicology screening solely revealed cocaine. A clinical diagnosis of cocaine toxicity was made and patient was admitted to the intensive care unit because of multi organ failure. Despite downward trending of liver enzymes during the hospital course, he continued to have residual renal insufficiency and a low platelet count at the time of discharge. In a patient with history of recent cocaine use presenting with these manifestations, cocaine itself should be considered as a likely cause. PMID- 24765298 TI - Central ossifying fibroma, periapical cemento-osseous dysplasia and complex odon toma occurring in the same jaw. AB - Central ossifying fibroma is a rare, benign fibro-osseous lesion that arises from the periodontal ligament. Periapical cemento-osseous dysplasia is another variant of fibro-osseous lesion which occurs in the anterior region of the mandible of females. Odontoma is a benign odontogenic tumor that contains enamel, dentine cement and pulp tissue. A 46-year-old woman was referred to the Department of Oral Medicine, School of Dentistry, Tehran University of Medical Sciences, with two non-painful swellings on both sides of the mandible, which had been slowly growing over a period of one year. Our differential diagnosis was florid cemento osseous dysplasia, focal cemento-osseous dysplasia for the right side, complex odontoma for the left side and periapical cement-osseous dysplasia for the anterior side. The historical feature revealed ossifying fibroma, complex odontoma and periapical cemento-osseous dysplasia. The occurrence of these three lesions in the same jaw has been rarely reported in the literature. The relationship between the occurrence of these three lesions is not obvious it could be coincidental. It seems that more case reports are needed to establish the relationship between them. PMID- 24765299 TI - Survival post surgery for malignant pericardial effusion. AB - The study reviews the survival of patients with malignant pericardial effusion treated with a subxiphoid pericardial window. The medical records of 60 consecutive patients diagnosed with a malignant pericardial effusion and treated with a subxiphoid pericardial window between 1994 and 2008 were reviewed. 72% had lung cancer. Overall 30-day mortality was 31%. Survival rates at 3 months, 6 months, 1 year, and 2 years were 45%, 28%, 17%, and 9%, respectively. Overall median survival was 2.6 months. Patients with malignant pericardial effusion, especially those with primary lung cancer have poor survival rates. In advanced malignancy, the subxiphoid pericardial window procedure provides only short-term palliation of symptoms, and has no effect on long-term survival. The use of any surgical procedure in patients with malignant advanced pericardial effusion should be considered along with non-surgical options on a case-by-case basis depending on symptoms, general status, and expected survival. PMID- 24765300 TI - Intracameral bevacizumab administered for non-small cell lung cancer metastasis to iris. AB - Ocular iris metastasis from lung cancer is uncommon. We report a patient with metastatic non-small cell lung cancer who was found to have a metastatic lesion to the iris. Local therapy for pain control and vision loss was administered with intracameral bevacizumab. Complete resolution of pain, improvement in vision, and near complete resolution of iris tumor were seen within two months. No ocular toxicity to anterior segment structures was detectable on corneal pachymetry and corneal specular microscopy. This is the first case report demonstrating safety and efficacy of intracameral bevacizumab for iris metastasis from non-small cell lung cancer. PMID- 24765301 TI - Apyretic gastrointestinal disorders due to giardiasis contracted in Morocco. AB - We present the case of a 32-year-old French man who presented with morning nausea, bloating, frequent flatulence, burping, occasional pyrosis, and alternating diarrhea and constipation two weeks after a trip to Morocco. The diagnosis was established by a parasitological stool exam that revealed cysts of Giardia lamblia. He was successfully treated with tinidazole. PMID- 24765302 TI - Diffuse pulmonary infiltrates in an old man with chronic lymphocytic leukemia. AB - An 82-year-old man known case of chronic lymphocytic leukemia (CLL) presented with fever and weakness. He had never received any treatment for his CLL in the past. On admission he was found to be in mild respiratory distress with bilateral crackles and had markedly elevated white blood count (WBC) (137 K/uL with 93% lymphocytes). His respiratory status deteriorated necessitating non-invasive ventilatory support. Chest computed tomography (CT) scan revealed bilateral diffuse ground glass opacities, so broad spectrum antibiotic therapy was initiated. Despite that, he remained febrile and cultures were all negative. Chest x-rays showed progressive worsening of diffuse alveolar opacities. Bronchoalveolar lavage (BAL) was negative for infectious etiologies, however flow cytometry of the fluid was consistent with CLL. Chemotherapy with chlorambucil was started. Although most of the pulmonary infiltrates in CLL patients are due to infectious causes, leukemic cells infiltration should be considered as well in CLL patients with respiratory symptoms who do not respond appropriately to standard antimicrobial regimen. PMID- 24765303 TI - Caecal carcinoma: a review of 3 cases in a private hospital in Lagos. AB - Colorectal tumors are rare in the developing countries but common in the civilized world. With the event of westernization of the diet, the incidence is increasing in the developing countries such as Nigeria. Caecal tumors present late because of the anatomical features of this part of colon. The tumors in the caecum are insidious in onset and often attend large size. Barium enema and colonoscopy have limitation in accessing this region. Computed tomography (CT) scan is expensive and not readily affordable in the developing world. High index of suspicion is therefore necessary to the diagnosed carcinoma of the caecum as it is a curable disease if diagnosed early and treated. We present 3 cases of caecal tumors seen over a 5-year period that were treated with good outcome. PMID- 24765304 TI - Silver nitrate ingestion: report of a case with an uneventful course and review of the literature. AB - Silver nitrate is commonly recognized for the toxic effects followed by the direct contact with the skin and mucosa known as argyria, but there is surprisingly little information about the adverse effects of silver nitrate after ingestion. Since only a few cases were reported in the literature, the aim of this case is to enrich the little experience existent about the possible effects of silver nitrate ingestion. We describe the case of a 15-year-old female who intentionally ingested 15cc of silver nitrate solution in a suicidal attempt. The clinical picture included an excruciating burning sensation in her throat and nostrils followed by vomiting and poor oral intake. The presence of a whitish membrane on the oral and buccal mucosa without bleeding or erosions was the only remarkable finding at physical examination. Unlike the rest of the cases described in the literature the clinical and endoscopic follow up of the patient was benign and without sequela or signs of oesophageal damage. Even though very uncommon, it is very important for physicians to keep in mind the possible toxic effects and appropriate management of silver nitrate ingestion. The outcome is not always devastating as reported, and a good early approach and follow up is important in the anticipation of sequela. PMID- 24765305 TI - Metastasis to the pancreas and the spleen: an increasing diagnostic and therapeutic challenge. AB - We have reviewed the electronic biopsies database files of the Department of Surgical Pathology, Fundacion Jimenez Diaz in Madrid (Spain). In this time period (1998-2010) we have found 3 pancreatic metastasis and 5 splenic metastasis. Two of the pancreatic metastases were originated in clear cell renal cell carcinomas. The last pancreatic metastasis was from a malignant cutaneous melanoma diagnosed and treated 8 years before. As for splenic metastasis, three of them were diagnosed during the abdominal surgery for primary therapy of the tumour (2 ovaries and one endometrium), while the remaining 2 corresponded to metastasis from a lung primary diagnosed 1 year before and a colonic primary diagnosed 6 years before. The patients with splenic metastasis died on the short term with progression of the disease despite resection of the splenic lesions, while the patients with pancreatic metastasis have survived longer. PMID- 24765306 TI - A case report of a patient with Ribbing disease underlines the connections between the skeletal and cardiovascular complications. AB - A 69-year-old woman suffered from Ribbing disease, a hereditary X autosomal dominant disease with multiple sclerosing dysplasias. However, it is less known that the genetic mutation can often induce cardiovascular complications. The patient had a hypertensive cardiopathy and had been treated with percutaneous coronary angioplasty and stenting because of a myocardial infarction. She was seen because of dyspnea and we detected an aneurysm of the ascending thoracic aorta. The patient underwent surgical repair. In Ribbing disease an up-regulation of genes interferes with the production, processing, or formation of collagen type II and XI. These genetic effects are thought to be specific for osteoblasts and are responsible for the skeletal pathology. However, the defective synthesis of collagen can also induce cardiovascular complications which may be similar to those described in patients with type III Ehlers-Danlos syndrome, with type IV Marfan syndrome, and with osteogenesis imperfecta. Rheumatologists who treat patients with Ribbing disease should seek the advice of cardiologists for the occurrence of cardiovascular complications. PMID- 24765307 TI - The immediate effects of a novel auditory and proprioceptive training device on gait after stroke. AB - This case report describes the immediate effects of a new rehabilitation tool on gait in a chronic stroke patient. Specifically, we measured step length symmetry and gait velocity in a 47 year-old male stroke patient who was currently receiving outpatient physical therapy. Objective gait measurements were taken using the GAITRite before, during, and after a 5 minute training session. Step length symmetry improved 26% during the first minute of training, 71% by the fifth minute of training, and 72% after a 5 minute rest period post-training. Gait velocity increased by 5.5% after 5 minutes of training. Clinical research is warranted to validate this new training tool as a useful adjunctive rehabilitation activity for improving spatial and temporal aspects of gait after stroke. PMID- 24765308 TI - Atypical presentations of retroperitoneal giant schwannomas. AB - Schwannomas are usually benign rare tumors that originating from Schwann cells of peripheral nerve sheaths. Presentation is generally varied and changed in a non specific range from abdominal mass, flank pain to incidental findings. Herein we report 2 cases of retroperitoneal giant schwannomas with different clinical presentations, of whom one presented with vague abdominal pain, palpable abdominal mass for 4 years, swelling and bilateral hydronephrosis that caused by giant abdominal mass; the other one presented with right flank pain, rectal hemorrhage and lower extremities edema. Two patients were treated by complete surgical excision of masses. The histological and immunohistochemical diagnosis was reported as benign schwannoma. Both of patients are doing well and had no recurrence in 9 years and 28 months follow-up, respectively. PMID- 24765309 TI - Lymphocitic infundibulo-neurohypophysitis mimicking a pituitary adenoma. AB - A rare case of infundibulo-neurohypophysitis mimicking a pituitary adenoma is presented. A 69-years-old female patient developed polyuria and polydipsia. Laboratory analysis revealed central diabetes insipidus. No hormonal abnormalities. Cranial-magnetic resonance imaging (MRI) showed a left sided mass in the adenohypophysis presuming a pituitary adenoma. The mass had contact to both internal carotids. Admission to our department for neurosurgical treatment followed. Ophthalmologic examination and neurological examination yielded normal findings. A second MRI focussing on the sellar-region showed a left-sided (T2 MRI.hyperintense), distended adenohypophysis, without contrast enhancement in T1. The stalk appeared thickened. T1-weighted sequences of the neurohypophysis showed loss of signal intensity. We diagnosed an infundibulo-neurohypophysitis and abstained from surgical removal. The patient was discharged under treatment with corticosteroids and desmopressin. Hypophysitis is rare and shows special clinical characteristics. Despite defined radiological features to differentiate between hypophysitis and adenoma the possibility of misdiagnosis, and unnecessary surgical procedures, should always kept in mind. PMID- 24765310 TI - Juvenile giant fibroadenoma. AB - Fibroadenomas are benign solid tumor associated with aberration of normal lobular development. Juvenile giant fibroadenoma is usually single and >5 cm in size /or >500 gms in weight. Important differential diagnoses are: phyllodes tumor and juvenile gigantomastia. Simple excision is the treatment of choice. PMID- 24765311 TI - Apocrine carcinoma of the face in a 62-year-old Asian man. AB - Apocrine carcinoma (AC) is a rare tumor with heterogeneous presentation. The disease has a highly morbid course and little is known about it. We present an otherwise healthy, 62-year-old Asian male who originally presented with chronic swelling of his left eyelid associated with excessive tears and diminished vision was diagnosed with AC. AC is often challenging to diagnose, yet it is critical to do so as early diagnosis and treatment can maximize patient survival. PMID- 24765312 TI - Meckel's diverticulitis causing small bowel obstruction by a novel mechanism. AB - Meckel's diverticulum occurs in 2% of the general population and majority of patients remain asymptomatic. Gastrointestinal bleeding is the most common presentation in the paediatric population. While asymptomatic and incidentally found Meckel's diverticulum may be left alone, surgery is essential for treating a symptomatic patient. Despite advances in imaging and technology, pre-operative diagnosis is often difficult. We present a first report of an unusual mechanism of small bowel obstruction due to Meckel's diverticulitis in a paediatric patient. The diagnosis was only apparent at laparotomy. PMID- 24765313 TI - Successful neuroendoscopic treatment of intraventricular brain abscess rupture. AB - Intraventricular rupture of a brain abscess is still associated with a high mortality rate. Here, we report such a case in a patient with normal immunity that was treated successfully using neuroendoscopic approach. A 69-year-old man who had presented with headache and fever developed confusion and restlessness. Magnetic resonance imaging revealed a mass with ring enhancement extending to the right ventricle. Emergency aspiration of cerebrospinal fluid (CSF) from the spinal canal revealed severe purulent meningitis. Bacterial culture of the CSF and blood was negative. Because of prolonged consciousness disturbance, the patient underwent evacuation of the intraventrcular abscess using a neuroendoscope. The pus was centrifuged and collected for bacterial culture, and this revealed Streptococcus intermedius/milleri. After implantation of a ventricular catheter, gentamicin sulfate was administered twice a day for 9 days. Cefotaxime sodium was also administered intravenously for 14 days, followed by oral administration of cefcapene pivoxil hydrochloride for 10 days. The patient made a complete recovery, and was discharged 31 days after admission. After 20 months of follow-up, he is doing well and has returned to his work. In cases of intraventricular rupture of a brain abscess, a neuroendoscopic approach is useful for evacuation of intraventricular debris or septum, and identification of the causative bacterium for selection of antibiotics, possibly reducing the period of hospitalization. PMID- 24765314 TI - Lobar flexible fiberoptic lung lavage: therapeutic benefit in severe respiratory failure in pulmonary alveolar proteinosis and influenza A H1N1 pneumonia. AB - Lobar fiberoptic lung lavage is a well-known procedure used in primary pulmonary alveolar proteinosis (PAP); the use of this procedure has increased in the recent years. This procedure has also been used in other pulmonary diseases such as desquamative interstitial pneumonia with good results. We describe a case of extremely severe respiratory failure due to concurrence of PAP and Influenza A H1N1 virus pneumonia which resolved with the help of this procedure. The patient, a 41-year-old woman, needed less mechanical ventilation after undergoing lobar fiberoptic bronchoscopic lavage. Moreover, a rapid and progressive improvement in the computed tomography of the lungs was observed. Flexibile fiberoptic bronchoscopic lobar lavage is a simple, safe procedure used not only in milder disease, but also in particular severe cases in which the physiological derangement of whole lung lavage would not be tolerated by patient or when extra corporeal membrane oxygenation is not available. PMID- 24765315 TI - Giant cell tumor of soft tissue of hand: simple but rare diagnosis, which is often missed. AB - Giant cell tumor of soft tissue originally described in 1972 in two different series by Salm and Sissons is a rare entity, which is clinically and histopathologically indistinguishable from giant cell tumor of bone. Usually involve thigh, trunk, and lower extremities but rarely involve the hands. GCT-ST is a benign tumor, which can transform into malignant form and also has potential for recurrence and metastasis. We present an otherwise healthy, middle age female who originally presented with swellings on her left finger was diagnosed with giant cell tumor of soft tissue hand. PMID- 24765316 TI - Primary sclerosing cholangitis and pregnancy. AB - Primary sclerosing cholangitis is a progressive disease, and coincidentally in pregnancy it is rare. It is characterized by progressive inflammation and destruction of bile ducts finally resulting in liver failure. A rare case of primary sclerosing cholangitis in pregnancy is presented. The course of the pregnancy was marked by threatened preterm delivery and exacerbation of cholestasis. She was successfully treated with ursodeoxycholic acid (UDCA). Although, primary sclerosing cholangitis has both maternal and fetal effects on pregnancy, the overall outcome is favorable. Only few cases have been reported using high dose ursodeoxycholic acid for primary sclerosing cholangitis in pregnancy, it often improves pruritus but has no protection against stillbirth. Data on the safety to the fetus or neonate and long-term outcome are scarce. PMID- 24765317 TI - Fluctuations in C-reactive protein in a hepatoblastoma patient with thrombocytosis. AB - We observed the changes in serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) in a patient with hepatoblastoma exhibiting thrombocytosis. The concomitant changes of IL-6 and CRP concentrations after the initiation of chemotherapy, in the absence of infection, suggested that the IL-6, which is synthesized in hepatoblastoma cells and induces thrombocytosis, also stimulated CRP production in the present case. IL-6 is thought to play an important role in thrombocytosis in hepatoblastoma. PMID- 24765318 TI - Dexmedetomidine for an awake fiber-optic intubation of a parturient with Klippel Feil syndrome, Type I Arnold Chiari malformation and status post released tethered spinal cord presenting for repeat cesarean section. AB - Patients with Klippel-Feil Syndrome (KFS) have congenital fusion of their cervical vertebrae due to a failure in the normal segmentation of the cervical vertebrae during the early weeks of gestation and also have myriad of other associated anomalies. Because of limited neck mobility, airway management in these patients can be a challenge for the anesthesiologist. We describe a unique case in which a dexmedetomidine infusion was used as sedation for an awake fiber optic intubation in a parturient with Klippel-Feil Syndrome, who presented for elective cesarean delivery. A 36-year-old female, G2P1A0 with KFS (fusion of cervical vertebrae) who had prior cesarean section for breech presentation with difficult airway management was scheduled for repeat cesarean delivery. After obtaining an informed consent, patient was taken in the operating room and non invasive monitors were applied. Dexmedetomidine infusion was started and after adequate sedation, an awake fiber-optic intubation was performed. General anesthetic was administered after intubation and dexmedetomidine infusion was continued on maintenance dose until extubation. Klippel-Feil Syndrome (KFS) is a rare congenital disorder for which the true incidence is unknown, which makes it even rare to see a parturient with this disease. Patients with KFS usually have other congenital abnormalities as well, sometimes including the whole thoraco lumbar spine (Type III) precluding the use of neuraxial anesthesia for these patients. Obstetric patients with KFS can present unique challenges in administering anesthesia and analgesia, primarily as it relates to the airway and dexmedetomidine infusion has shown promising result to manage the airway through awake fiberoptic intubation without any adverse effects on mother and fetus. PMID- 24765319 TI - Cytologic diagnosis of acinic cell carcinoma of minor salivary gland: a distinct rarely described entity. AB - A rare case of acinic cell carcinoma of minor salivary gland with cervical lymph node metastasis in a 50-year-old man is reported and the literature regarding this type of tumor is reviewed. These tumors arise from either an intercalated duct stem cell or the reserve cell of the salivary gland terminal tubule but not from both simultaneously. Rarely these neoplasms arise from more mature acinar cells. It is clear that these tumors behave ominously. The 25 year determinate survival rate is 50%, with a 20% incidence of metastasis. Surgical excision is the treatment of choice. Radiotherapy, especially neutron therapy, has a place in the treatment of this tumor but the role of chemotherapy is not exactly known at this time. PMID- 24765320 TI - Canaliculitis in supernumerary puncta and canaliculi. AB - We report the first case of supernumerary puncta and canaliculi presented with canaliculitis. A-59 year-old gentleman presented with painful swelling of the left lower lid for a week, which was associated with epiphora. The swelling was confined to the nasal aspect of the left lower lid (0.5*0.5 mm) with inflamed overlying skin. Two puncta (0.5 mm apart) were noted. The outer punctum at the normal anatomical position was a cul-de-sac while the inner punctum it the caruncle was patent. We described the embryology leading to supernumerary puncta and canaliculi to explain the paradoxical patency of the abnormally located punctum as well as the pathomechanism leading to canaliculitis. The patient was treated with oral cloxacillin 500 mg, 6 hourly for 5 days; the cellulitis subsided after three days. PMID- 24765321 TI - Melanocytoma of the optic nerve head - a diagnostic dilemma. AB - The clinical features, autofluorescence, B-scan ultrasonography, optical coherence tomography and fluorescein angiography of the lesion were described. Multiple investigation modalities are needed to confirm the benign nature of the lesion. Careful evaluation and follow-up is crucial to avoid misdiagnosis and erroneous management. PMID- 24765322 TI - Post-traumatic extensive knee ganglion cyst. AB - A rare case of a posttraumatic extensive ganglion cyst of the anterolateral thigh with connection to the knee joint is presented. A 54-year-old man presented a palpable mass in the anterolateral region of his right thigh with a 15 months existing sense of fullness and tightness. He had an accident with his bicycle 21 months ago. Magnetic resonance imaging (MRI) was performed showing a cyst inside the quadriceps femoris muscle between vastus lateralis and intermedius with connection to recessus suprapatellaris and knee joint. In addition MRI detected a traumatic lesion in the quadriceps femoris tendon in the near of the knee joint. The ganglion cyst was 18 cm long and was excised completely. Intraoperatively, the knee joint connection was confirmed and excised as well. The ganglion cyst was filled with a gelatinous and viscous fluid. PMID- 24765323 TI - Internal carotid artery pseudo occlusion with embolic cerebral ischemia and low flow in the central retinal artery: a diagnostic challenge. AB - We present a rare case of internal carotid artery pseudoocclusion (ICAPO) in a 60 year-old male Caucasian patient who experienced a reversible sudden loss of vision of the right eye for 10 min followed by recurrent blurring of vision as well as dysarthria and numbness in the left face. The referring ophthalmologist admitted the patient for suspicious occlusion of the internal carotid artery causing anterior ischemic optic neuropathy (AION). PMID- 24765324 TI - Interventricular septal rupture after myocardial infarction despite early percutaneous coronary intervention. AB - Ventricular septal rupture (VSR) complicating acute myocardial infarction (AMI) is a serious clinical problem with high mortality rate due to cardiogenic shock or prolonged hemodynamic compromise. Despite multiple improvements in medical, interventional and surgical techniques, early and long-term prognosis after AMI related VSR still remain unpromising. We report a patient in whom an acute VSR was diagnosed 7 days after an anterior myocardial infarction treated with early primary percutaneous coronary intervention (pPCI). PMID- 24765325 TI - Non-syndromic bilateral dentigerous cysts associated with permanent second premolars. AB - The dentigerous cyst is one of the most common developmental odontogenic cysts in the jaw. Occurrence of the bilateral dentigerous cyst is uncommon, and frequently associated with syndromes like basal cell nevus syndrome or cleidocranial dysplasia. There are few reports on the presence of bilateral dentigerous cyst in nonsyndromic patients, and most of these are associated with first and third molars. The reported case in this paper is bilateral dentigerous cysts associated with mandibular permanent second premolars, in the absence of any signs of syndrome. To our knowledge bilateral dentigerous cysts in these locations have not been previously reported. PMID- 24765326 TI - Delayed diagnosis of hydranencephaly in a nine-month-old child. AB - We present a case of a child suffering of hydranencephaly. The interesting fact in the case is that there were no embryological examinations during pregnancy and therefore could the anomaly, which would have been easily avoided by regular visits to the obstetrician, not be diagnosed timely. Education of mothers is always necessary irrespective on how developed a country is and how good the medical treatment and diagnostic tools are. Every pregnant woman needs to be well educated in matters of pregnancy monitoring. PMID- 24765327 TI - Hydrocephalus, a rare manifestation of sarcoidosis. AB - A 36-week-pregnant woman developed a symptomatic hydrocephalus. Chest imaging showed bihilar lymphadenopathy and histological examination of a mediastinal lymph node revealed non-caseating granulomas. After delivery, her neurologic complaints progressed. Placement of a ventriculoperitoneal drain (VPD) did not reduce the symptoms. However, steroids resulted in rapid disappearance of the hydrocephalus. Hydrocephalus is a very rare manifestation of sarcoidosis. The diagnosis relies on the ability of clinicians to recognize this disorder. This case shows how a difference in opinion of the several specialists involved can lead to a delay in diagnosis and treatment. PMID- 24765328 TI - Neurothekeoma palpebrae in association with multiple superficial angiomyxomas: Tegumental Angiomyxoma-Neurothekeoma syndrome (TAN syndrome). AB - We report a case of 10-year-old Indian girl with history of multiple superficial angiomyxoma, presented with three months history of painless right upper lid swelling. There were no visual dysfunctions. Previously, the patient had multiple superficial angiomyxoma (left pinna, left upper cheek, left upper limb, chest, right axilla, hard palate) and epidermal cyst (chin). The histopathological specimens were negative to S-100 protein antibody. Systemic review and family history was unremarkable. Excision biopsy and upper lid reconstruction were performed. Intraoperatively the tumor was multilobulated, firm, well encapsulated and did not invade the underlying tarsal plate. Histopathological features of the upperlid tumor were consistent with nerves sheath myxoma (neurothekeoma). To the best of the authors' knowledge, this is the first reported case of neurothekeoma in association with multiple superficial angiomyxoma. PMID- 24765329 TI - Testicular atrophy secondary to a large long standing incarcerated inguinal hernia. AB - Testicular atrophy is a rare but distressing complication of inguinal hernia repair. Apart from the postsurgical etiology, ischemic orchitis and subsequent testicular atrophy may occur secondary to compression of the testicular vessels by chronically incarcerated hernias. We present a rare case of testicular atrophy secondary to a large long standing incarcerated inguinal hernia of 2-decade duration in a 79-year-old man. Testicular atrophy should be always considered in long standing incarcerated inguinal hernias and patients should be adequately informed of this possibility during the preoperative work-up. Preoperative scrotal ultrasonography can be used to determine testicular status in this specific group of patients. PMID- 24765330 TI - Celiacomesenteric trunk: a variation that must be known before aortic surgery. AB - The celiac trunk and the mesenteric arteries may present variations with different clinical significance. A celiacomesenteric trunk was discovered in a patient with mesenteric ischemia and a history of aortic bypass without inferior mesenteric artery reimplantation. Despite thrombectomies and digestive resections, the patient died. Anatomic variations like celiacomesenteric trunk must be known before aortic surgery. PMID- 24765331 TI - Pneumomediastinum and bilateral pneumothorax following near drowning in shallow water. AB - We report pneumomediastinum, bilateral pneumothorax and acute respiratory distress syndrome in a victim of near drowning who was intoxicated and did not have thoracic or neck trauma. Chest radiograph revealed the above findings, later confirmed by computed tomography. He was in shock and also had gastrointestinal (GI) bleeding and renal dysfunction. With adequate resuscitative measures including fluids, blood transfusions, intercostal tube drainage and mechanical ventilation he made a complete recovery. Good prognostic indicators in near drowning patients include higher Glasgow Coma Scale, short submersion time and quick resuscitative measures even in the presence of serious cardiorespiratory or hemodynamic compromise. PMID- 24765332 TI - An unusual burn caused by hot argy wormwood leaf water. AB - An unusual burn case caused by hot wormwood leaf water was discussed. A 29-year old woman sustained a 7% second-degree burn on both buttocks and left thigh. This case report highlights a rare cause of a chemical burn that may become more common with increasing use of this Chinese traditional medicine. The prevention measures of this burn injury were also presented. PMID- 24765333 TI - Sinus of Valsalva aneurysm and bicuspid aortic valve: detection and mechanism by cardiac magnetic resonance imaging. AB - Cardiac magnetic resonance imaging (CMR) demonstrated a sinus of Valsalva aneurysm (SVA) with severe dilatation of the right coronary sinus in association with a congenital bicuspid aortic valve (BAV) and sub-aortic membrane. The SVA had not been apparent on echocardiography as the dilatation was outside standard echo image planes. On both CMR and echo, blood flow was eccentrically directed into the right coronary sinus by the domed posterior leaflet of the BAV. The impact of the aortic jet on the wall of the right coronary sinus is probably important in the aetiology of the sinus dilatation. CMR proved valuable in demonstrating the SVA and understanding its aetiology. PMID- 24765334 TI - Unusual case of a graphite foreign body in the anterior chamber. AB - Retained intraocular graphite foreign bodies are uncommon. Although they are generally inert, they have been reported to cause severe inflammatory reaction and progressive damage to intraocular structures. We report a case of a six-year old girl with a retained intraocular graphite pencil lead foreign body in the anterior chamber of the eye and discuss the various considerations in the management of such cases. PMID- 24765335 TI - Forgotten intrauterine device contributing to infertility. AB - The aim of the study is to show that long standing forgotten intrauterine device contributes to infertility, reporting three cases presented at Central Hospital Warri, Nigeria, a government tertiary health center. Three cases of forgotten intrauterine contraceptive device (IUCD) contributing to infertility were seen. Two were inserted for contraceptive reasons while one was inserted while being managed for uterine synechae. Health care providers should ensure proper documentation of all procedures carried out, adequate counseling which should include taking an informed consent and also ensuring both short and long term follow up of their clients. Also all patients being evaluated for infertility and clients with past history of intrauterine device must have a speculum examination and ultrasound scan carried out. PMID- 24765336 TI - Triplane fracture of the distal radius. AB - We report the case of a 14-year-old boy who sustained a displaced triplane fracture of the distal radius. This was treated with closed reduction and application of a cast with good clinical and radiological results. We discuss (for the first time) the reasons for the rarity of this fracture at the distal radius compared to the distal tibia. PMID- 24765337 TI - 64-year-old male with septic arthritis of the pubic symphysis. AB - Septic arthritis of the pubic symphysis is a rare disease. Typical clinical features include fever, pubic or groin pain, pain with hip motion, and painful or waddling gait. Identified predisposing factors to develop an infection in pubic joint include female incontinence surgery or postpartum period; sports, especially soccer; pelvic malignancy; and intravenous drug abuse. The most often identified microorganisms were Staphylococcus aureus and Pseudomonas aeruginosa. Osteomyelitis complicates the majority of cases, and about half of the patients require surgical debridement along with a prolonged antibiotic treatment. We report a case of Streptococcus anginosus septic arthritis of the pubic symphysis. The patient did not have any of the above risk factors. PMID- 24765338 TI - US and MDCT findings in a caudal blind ending bifid ureter with calculi. AB - Herein we present a rare ureteric duplication anomaly; blind ending bifid ureter with calculi which is asymptomatic unless complicated by infection, reflux, calculi or malignancy. The diagnosis is often missed at intravenous urography (IVU) and US because the ipsilateral ureter and kidney are grossly normal. In this case the diagnosis was established with ultrasound (US) and mainly with multidetector computerized tomography (MDCT) imaging using multiplanar reformats and 3-D reconstructions which were unique to this case. MDCT scans not only revealed the exact diagnosis and anatomic relationships but also ruled out other pathologies included in the differential diagnosis as well, such as ureter and bladder diverticula. PMID- 24765339 TI - Severe hypothyroidism associated with the degree of edema in a patient with nephrosis. AB - We report the pleural fluid values of thyroid hormones and their carrier proteins in a patient who suffered from nephrotic syndrome with renal insufficiency and transient hypothyroidism. The pleural effusion was transudate. The concentrations of thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (Alb) were approximately 30-50% of the plasma. The concentrations of total triiodothyronine (TT3), total tetraiodothyronine (TT4), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) were approximately 30 50% of the plasma. Hypothyroidism was associated with the degree of edema. After improving systemic edema, proteinuria remained unchanged but the patient did not require levothyroxine. We speculate that the large amount of transudation of thyroid hormones with their carrier proteins from the blood vessels to the third space (edema and pleural effusion), thereby reducing thyroid hormones in the plasma, was associated with hypothyroidism. PMID- 24765340 TI - CD34(+) stem cells from umbilical cord blood. AB - We describe the relation between umbilical cord clamping time and two different enrichment system of CD34(+) stem cells from umbilical cord blood with the proliferative ability and bone marrow reconstitution of the stem cells obtained. After an obstetrician performed the cord blood collection, the purification of stem cells was performed either with a combination of monoclonal antibodies (negative selections) using the Stem Sep method, or with a positive cells selection based on their surface CD34 antigens using the Mini Macs system. An excellent recovery of haematopoietic progenitors [Burst Forming Unit Erythroids (BFUE); Colony Forming Unit Granulocytes and Macrophages (CFU-GM); and Colony Forming Unit Granulocytes, Erythroids, Monocytes and Macrophages (CFU-GME)], inversely related to the increase in clamping time, was performed with the Mini Macs system (54% of colonies, with 90% purity). With Stem Sep method, haematopoietic progenitor's recovery was 35% (with 80% purity). By applying early clamping of umbilical cord blood we obtained a greater number of CD34(+) cells and their clonogenic activity was increased with enrichment. This is a useful technique considering that the number of CD34(+) stem cells usually contained from a unit of placental blood is enough for the transplant to a child, but not for an adult. Thus, using these methods, we can get a larger number of CD34(+) stem cells which reduces the risk of Graft versus Host Disease also in adult patients, producing survival rates similar to those obtained with transplantation of bone marrow from unrelated donors. PMID- 24765342 TI - Congenital lobar emphysema mimicking as persistent pneumonia in a newborn. AB - Congenital lobar emphysema (CLE) is an uncommon congenital malformation of the lung that can present with respiratory distress in early life. We report a full term female baby who presented with intermittent bluish discoloration of the lips and extremities during crying since birth. An initial diagnosis of left sided collapse-consolidation with right-sided compensatory emphysema was made from chest x-ray. When no improvement was noted after intravenous antibiotic therapy for 7 days, computerized tomographic scan of thorax was done which showed emphysema of the right middle lobe with transherniation and mediastinal shift to the left. Right middle lobectomy was done and postoperative period was uneventful. Histopathological examination of the specimen confirmed the diagnosis of CLE. CLE can mimic more common causes of respiratory distress in neonatal period and needs a high index of suspicion for diagnosis. Early diagnosis and effective surgical treatment is curative. PMID- 24765341 TI - The role of psychological support in cardiac surgery: initial experience. AB - The scientific literature has pointed out several predictors of negative outcome after surgery such as pain and depression, negatively affecting the postoperative outcome in cardiac surgery. From January 2009 until June 2010, 15 patients scheduled for cardiac surgery were enrolled. The patients were assessed by psychological evaluation either in the hospital stay either in the rehabilitation period with the aim of identifying their emotional condition (sentiments about the onset of the disease, support received from family and friends) even by means of preformed tests for anxiety and depression (tests of Stay and Back). Thus, in our preliminary experience, the psychological evaluation failed to detect the occurrence of postoperative complications. Conversely, the psychological evaluation is very effective in detecting a poor emotional state and the psychological support decreases the degree of anxiety and depression with positive effects on postoperative outcome. In conclusion, a standardize test for anxiety and depression should be used for patients at hospital admission to detect who may benefits by psychological support. PMID- 24765343 TI - Endo-biliary stents for benign disease: not always benign after all! AB - This case report describes the presentation, management and treatment of a patient who suffered small bowel perforation due to the migration of his biliary stent which had been inserted for benign disease. PMID- 24765344 TI - Male systemic lupus erythematosus, an overlooked diagnosis. AB - Lupus erythematosus is a chronic autoimmune inflammatory disease of unknown cause that involves multiple systems. Autoimmune diseases that are prevalent in men usually manifest themselves clinically before the age of 50 years old and are characterized by an acute inflammation, whereas autoimmune diseases with predominance among women appear clinically in later stages of life, when chronic diseases, fibrosis and increased number of autoantibodies are present. Lupus erythematosus is more prevalent among women during the reproductive period, but the cause of this predilection is not fully established and little is known about the disease among men. We report a case of systemic lupus erythematosus (SLE) in a male patient whose diagnosis was delayed due to the systemic manifestations and because SLE is considered an uncommon disease in men. PMID- 24765345 TI - A case of delayed cardiac perforation of active ventricular lead. AB - A 65-year-old man was admitted as for one month of repetitive dizziness and one episode of syncope. Electrocardiogram showed sinus bradycardia and his Holter monitoring also showed sinus bradycardia with sinus arrest, sino-atrial block and a longest pause of 4.3 s. Then sick sinus syndrome and Adam-Stokes syndrome were diagnosed. Then a dual chamber pacemaker (Medtronic SDR303) was implanted and the parameters were normal by detection. The patient was discharged 1 week later with suture removed. Then 1.5 month late the patient was presented to hospital once again for sudden onset of chest pain with exacerbation after taking deep breath. Pacemaker programming showed both pacing and sensing abnormality with threshold of > 5.0V and resistance of 1200Omega. Lead perforation was revealed by chest X ray and confirmed by echocardiogram. Considering the fact that there was high risk to remove ventricular lead, spiral tip of previous ventricular lead was withdrew followed by implantation of a new ventricular active lead to the septum. Previous ventricular lead was maintained. As we know that the complications of lead perforation in the clinic was rare. Here we discuss the clinical management and the possible reasons for cardiac perforation of active ventricular lead. PMID- 24765346 TI - Nonpuerperal uterine inversion due to submucous leiomyoma. AB - Uterine inversion is a rare complication of the postpartum period and an even rarer complication of the nonpuerperal period. A 47-year-old woman, gravid 2, para 2, was referred to our hospital with blood-stained leucorrhoea and severe anemia. Magnetic resonance imaging (MRI) scans showed a U-shaped uterine cavity and the pedicles of a tumor attached to the uterine fundi. The patient underwent an abdominal hysterectomy. The diagnosis of uterine inversion was confirmed during the operation. MRI should be performed for the diagnosis of this rare disease. PMID- 24765347 TI - Pemetrexed induced pneumonitis. AB - Pemetrexed is an antifolate chemotherapy agent that is active in malignant mesothelioma and non-small cell lung cancer (NSCLC). Pneumonitis is a rare side effect of Pemetrexed. We report the case of 72-year-old female with metastatic poorly differentiated lung adenocarcinoma. She was placed on maintenance pemetrexed and developed gradual progressive dyspnea after first cycle of maintenance of pemextrexed. The computed tomography (CT) of the chest showed ground glass opacity in both lung fields. Transbronchial lung biopsy showed uniform interstitial widening by a cellular chronic infiltrate with areas of type II pneumocyte and exudation of pale eosinophilic edema fluid; features consistent with acute lung injury. Patient improved both clinically and radiological after stopping pemetrexed and starting prednisone. Although pemetrexed induced lung injury is relatively rare, with the increasing use of peme-trexed in first-line treatment and in maintenance therapy of non-small cell lung cancer, awareness of this potential adverse effects is important. PMID- 24765348 TI - Coronary artery anomalies presenting with ST-segment elevation myocardial infarction. AB - ST-segment elevation MI (STEMI) is a rare presentation in patients with coronary artery anomalies. In these patients, the identification of the culprit lesion and its treatment may be difficult, particularly in the emergency setting of primary percutaneous coronary intervention (PCI). From January 2008 to April 2011, 1015 STEMI patients received coronary artery angiography and primary PCI in our centre. Of these, 5 (0.4%) patients showed a coronary artery anomaly. In this paper we reported two rare cases: i) the first is a single coronary artery originating from right sinus of Valsalva; ii) the second is a separate origin of 3 coronary arteries originating from the right sinus of Valsalva. In conclusion, coronary artery anomalies presenting with STEMI are really uncommon, but often are a challenge. The integration between traditional coronary artery angiography and multidetector computerized tomography is crucial to optimize the interventional and medical management of these patients. PMID- 24765349 TI - Giant mesenteric cyst. AB - Mesenteric cysts are uncommon benign abdominal lesions with no classical clinical features. The preoperative diagnosis requires the common imaging modalities but the final diagnosis is established only during surgery or histological analysis. The treatment of choice is complete surgical excision. We report an 18-year-old female with a non-specific abdominal pain and discomfort since 3 weeks. Her CT scan showed a huge cystic swelling, which necessitated surgical exploration. Preoperatively, a giant cyst was encountered with displacement of bowel loops. The cyst was completely removed and histology report confirmed mesenteric cyst without evidence of malignancy. PMID- 24765350 TI - Intraperitoneal rupture of the bladder after urinary catheterization. AB - Intraperitoneal rupture of the bladder is a rare cause of peritonitis. Intraperitoneal rupture of the bladder was diagnosed during an emergency laparotomy for suspected mesenteric ischemia. The patient had undergone iterative urinary catheterization after a vascular bypass. The perforation was excised and sutured and the patient was catheterized for urinary rest for 15 days. Urinary catheterization is a possible cause of intraperitoneal rupture of the bladder. PMID- 24765351 TI - Posterior-draining dural carotid cavernous fistulae: a possible cause of computed tomographic angiography negative isolated third nerve palsy. AB - Computed tomographic angiography (CTA) is a well-established non-invasive investigation for this neurological presentation to exclude intracranial aneurysms. However, dural arteriovenous fistulae with anterograde venous drainage only can be missed by CTA. Here we reported two patients with painful complete third nerve palsy and dural carotid cavernous fistulae with anterograde venous drainage only missed by CTA. The natural history and management option are discussed. In patients with persistent symptoms or without vasculopathic risk factors, magnetic resonance angiography (MRA) or digital subtraction angiography (DSA) should be considered to exclude the diagnosis. PMID- 24765352 TI - Paroxysmal hemicrania as the clinical presentation of giant cell arteritis. AB - Head pain is the most common complaint in patients with giant cell arteritis but the headache has no distinct diagnostic features. There have been no published reports of giant cell arteritis presenting as a trigeminal autonomic cephalalgia. We describe a patient who developed a new onset headache in her fifties, which fit the diagnostic criteria for paroxysmal hemicrania and was completely responsive to corticosteroids. Removal of the steroid therapy brought a reemergence of her headaches. Giant cell arteritis should be considered in the evaluation of secondary causes of paroxysmal hemicrania; in addition giant cell arteritis needs to be ruled out in patients who are over the age of 50 years with a new onset trigeminal autonomic cephalalgia. PMID- 24765353 TI - Diagnostic dilemma posed by severe pelvic actinomycosis associated with prolonged use of copper intrauterine contraceptive device. AB - Actinomycosis has been recognized to be associated with the use of intrauterine contraceptive device. We are reporting a case where a patient with severe pelvic actinomycosis presented with the clinical picture of an ovarian tumour. A 44-year old lady attended the A&E with progressively worsening lower abdominal pain. A computerized tomography (CT) scan showed the presence of a large pelvic mass, right hydronephrosis and prominent para-aortic lymph nodes and an elevated C reactive proteine (CRP) and white cell count (WCC). When there was no improvement with antibiotic therapy, a laparotomy was performed, where bilateral tubo-ovarian abscess and dense adhesions were found. A subtotal hysterectomy, bilateral salpingoophorectomy and small bowel resection was performed. Histopathology of the specimen confirmed the diagnosis of actinomycosis. The case highlighted the diagnostic dilemma for ascertaining the nature of the pelvic mass in this patient. Due to its invasion of surrounding tissues and the formation of masses severe infection is often confused with an ovarian neoplasm. PMID- 24765354 TI - Simultaneous chickenpox and measles infection among migrant children who stayed in Italy during the second half of June 2011. AB - We are reporting on a household outbreak of measles, in which cases of simultaneous measles and chickenpox infection occured in children of a family who resided in Italy during the incubation period (June 2011). In three children, fever and generalized confluent macular rash were the dominant symptoms. Serology testing revealed simultaneous measles and chickenpox infection in four children. PMID- 24765355 TI - A typical example of cerebral watershed infarct. AB - Watershed infarcts (WI) evolve in hemodynamic risk zones. Clinical picture of WI can be associated to partial epileptic seizures. Diffusion weighted brain magnetic resonance imaging (MRI) allows a clear diagnosis. WI pathogenesis involves either embolic or hemodynamic mechanism. A 69-year old patient presented with sub-acute occurrence of right hemiparesis and partial epileptic seizures of the right arm. Carotid ultrasounds demonstrated occlusion of the right extra cranial internal carotid artery (ICA) and tight stenosis of the contralateral ICA. Brain Diffusion-Weighted magnetic resonance revealed acute ischemic lesions within the watershed area of the left hemisphere. Our case supports the hypothesis of impaired washout of emboli in low-perfusion brain areas as the mechanism underlying cortical WI. PMID- 24765356 TI - A fish bone-related hepatic abscess. AB - We report an unusual case of pyogenic, hepatic abscess caused by fish bone penetration of the duodenum in a 68-year-old woman. The fish bone had migrated into the liver through the duodenal wall. The patient was initially admitted to our emergency room with abdominal pain, fever, and asthenia. A contrastenhanced abdominal coputed tomography (CT) scan showed a hepatic abscess in relation with a straight, foreign body, which had entered through the duodenal wall. Surgery was necessary to remove the foreign body, which was identified as a fish bone. The patient's recovery was uneventful and she was discharged on postoperative day 10. This case is discussed together with the data collected by a medline-based extensive review of the literature. PMID- 24765357 TI - Percutaneous repair of a disrupted left renal artery after rapid stabilization. AB - Fortunately, acute renal artery injuries occur infrequently in blunt trauma patients. Renal salvage in the multi-trauma patient is a daunting task. If after judicious consideration, intervention is warranted, then expeditious repair should follow. Rapid control of exanguinating injuries should be accomplished and the patient stabilized for further intervention - surgical or endovascular. We present the case of a patent who presented with left pneumothorax, multiple bilateral rib, scapula, long bone fractures, hypotension, hemoperitoneum, non perfusion of the left kidney, and a shattered spleen. She underwent emergent splenectomy and stabilization of her pressure. The left renal artery was evaluated and repaired with a covered stent. This approach might be beneficial in highly selected patients with favorable physiologic and anatomical presentations. PMID- 24765358 TI - Primary carcinosarcoma of the parotid gland. AB - Carcinosarcoma is a rare malignant 'mixed' tumour in the head and neck region. We present a case of carcinosarcoma in a long standing parotid lump and share our experience in the management of the disease together with a review of recent English literature on the subject. PMID- 24765359 TI - Osteoblastoma of the jaws: report of a case and review of literature. AB - Benign osteoblastoma (OB) is a rare tumor of bone representing less than 1% of all tumors of the maxillofacial region. Vertebral column, sacrum, long bones, and calvarium are more frequent sites of this tumor. Clinically, patients present with pain and swelling. Histologically, contain a well vascularized, osteoblastic connective tissue stroma and occasionally, osteoclasts along with osteoid and varying degrees of calcification, as well as immature bone may also be noted. The main aim of this report is present a case of OB occurring in the mandible and a brief review of English Medical Literature of this tumor. Many bone-producing lesions possess some overlapping clinical, radiographic or histopathological findings similar to osteoblastoma. Understanding and correlating all features helps in correct diagnosis and adequate management of this rare entity. Hence, osteoblastoma has to be differentiated from other bone lesions for correct diagnosis. PMID- 24765360 TI - Severe gastroenteritis as presentation of a primary cytomegalovirus infection in an immunocompetent woman. AB - In immunocompetent hosts, symptomatic cytomegalovirus (CMV) infection occurs in around 10% and has traditionally been considered to have a benign, self-limiting course. Active CMV infection in immunocompetent subjects is very rare. However, manifestations of CMV infection in immunocompromised hosts have been extensively reported. We present a case of a 58-year-old immunocompetent woman with a primary cytomegalovirus infection which presented as a severe gastroenteritis and hepatitis. PMID- 24765361 TI - Combined spinal epidural anesthesia in achondroplastic dwarf for femur surgery. AB - Achondroplasia is the commonest form of short-limbed dwarfism and occurs in 1:26,000-40,000 live births. This is an autosomal dominant disorder with abnormal endochondral ossification whereas periosteal and intramembranous ossification are normal. The basic abnormality is a disturbance of cartilage formation mainly at the epiphyseal growth plates and at the base of the skull. The anesthetic management of achondroplastic dwarfs is a challenge to the anesthesiologist. Both regional as well as general anesthesia have their individual risks and consequences. We report a case of an achondroplastic dwarf in whom combined spinal epidural anesthesia was used for fixation of a fractured femur. The patient had undergone previous femur surgery under general anesthesia since he had been informed that spinal anesthesia could be very problematic. There was no technical difficulty encountered during the procedure and an adequate level was achieved with low-dose local anesthetics without any problem. Postoperative pain relief was offered for three consecutive postoperative days using epidural tramadol. We discuss the anesthetic issues and highlight the role of combined spinal epidural anesthesia with low-dose local anesthetics in this patient. This approach also helped in early ambulation and postoperative pain relief. PMID- 24765362 TI - Large inclusion cyst complicating female genital mutilation. AB - We report a case of an inclusion cyst, resulting from female genital mutilation (FGM), which enlarged to such a degree that it restricted the patient's movement. This report aims to raise the awareness of the medical community to the dangers that arise from a common remote complication of FGM. PMID- 24765363 TI - High grade leiomyosarcoma of the testes. AB - Testicular leiomyosarcoma is a rare tumor. It may arise secondarily following exposure to radiotherapy, chronic inflammation, or usage of high dose anabolic steroids. However, in absence of risk factors, it is rarely seen. Only 15 cases of Primary Intra testicular leiomyosarcoma have been reported in world literature. We present a case of testicular tumor in an elderly male. Preoperative work up showed raised Lactate Dehydrogenase (LDH) levels. He underwent high orchidectomy. Histopathology and immunohistochemistry confirmed it to be a primary intra testicular leiomyosarcoma. A brief case report with review of literature is presented. PMID- 24765364 TI - Transient loss of consciousness in a patient with a Brugada like ECG. AB - Syncope in a patient with a Brugada syndrome channelopathy carries significant prognostic implications and warrants consideration of implantable cardioverter defibrillator (ICD) implantation. We report a case of a 62-year-old gentleman who presented with a transient loss of consciousness and an electrocardiogram (ECG) suggestive of type 1 Brugada syndrome. Further investigation revealed evidence of a silent myocardial infarction and negative ventricular tachycardia stimulation and Ajmaline testing. Careful review of the ECG's subsequently showed the type 1 pattern was present in only V1. PMID- 24765365 TI - A moderate response to plasmapheresis in nephrogenic systemic fibrosis. AB - Nephrogenic systemic fibrosis (NSF) is a recently identified idiopathic cutaneous fibrosing disorder that occurs in the setting of renal failure. The disease initially called nephrogenic fibrosing dermopathy is closely linked to exposure to gadolinium-based contrast media used during magnetic resonance imaging in patients with renal insufficiency. Although little is known about the pathogenesis of this disease, the increased expression of transforming growth factor-beta has been demonstrated recently. Herein, we present a case of NSF was partially treated due to a moderate and temporary response to plasmapheresis with no recurrence for 6 months, but returned at the end of 6(th) month. PMID- 24765366 TI - Multiple sclerosis in an adrenoleukodystrophy carrier. AB - X-linked adrenoleukodystrophy (X-ALD) is a rare inherited metabolic disorder, in which accumulation of very long chain fatty acids (VLCFAs) results in damage to the central nervous system. As the disease is X-linked, males are affected severely, but female carriers may also present with neurological symptoms. We report the case of a young adult female, who presented with episodic sensorimotor symptoms. Although she was a heterozygous female carrier of X-ALD, subsequent investigations confirmed a diagnosis of multiple sclerosis (MS). To the best of our knowledge, this is the first reported case of a female X-ALD carrier in which the clinical features were more consistent with co-existent MS than ALD-related pathology. The case serves as a reminder that alternative, more common diagnoses should also be considered in carriers of rare neurological syndromes. PMID- 24765367 TI - Partial splenic embolization for refractory thrombocytopenia. AB - When the platelet count falls below 20*10(9)/L, the risk of spontaneous life threatening hemorrhage is concerning for both physician and patient. When medical management fails, splenectomy is often used to manage the severe thrombocytopenia before spontaneous, life-threatening gastrointestinal or intracranial bleeding occurs. We present the non surgical management of such a patient with refractory sever thrombocytopenia who refused surgical intervention. She underwent partial splenic embolic therapy with 500-700MU particles. Her platelet count spontaneous recovered from less than 20*10(9)/L to normal range. Her counts remained in normal range after discharge home. Further study is needed to determine the most appropriate role for embolization in patients who are refractory to medical management and those with chronically low platelet counts requiring frequent plate transfusions for invasive procedures. PMID- 24765368 TI - A case of orbital apex syndrome due to Pseudomonas aeruginosa infection. AB - Orbital apex syndrome is commonly been thought to have a poor prognosis. Many cases of this syndrome have been reported to be caused by paranasal sinus mycosis. We encountered a very rare case (60-year-old woman) of sinusitis with orbital apex syndrome due to Pseudomonas aeruginosa infection. She had received insulin and dialysis for diabtes and diabetic nephropathy, moreover anticoagulants after heart by-pass surgery. She underwent endoscopic sinus operation and was treated with antibiotics, but her loss of left vision did not improve. Recently, sinusitis cases due to Pseudomonas aeruginosa were reported to be a increasing. Therefore, we should consider the possibility of Pseudomonas aeruginosa as well as mycosis as infections of the sinus, especially inpatients who are immunocompromised body. PMID- 24765369 TI - Duodenal lipoma associated with ectopic duodenal glands. AB - Duodenal lipomas are relatively uncommon and are rarely responsible for clinical symptoms. Occasionally, searching for aetiology of gastrointestinal bleeding leads to the final diagnosis of duodenal lipomas. Here, we present the case of a 68-year-old woman who suffered with repeated melena and weight loss. Endoscopy, abdominal computed tomography (CT) and histopathological outcomes are described in this case of duodenal lipoma with ectopic duodenal glands. PMID- 24765370 TI - An omental teratoma in a young girl. AB - Teratoma is the most commonly encountered germ cell tumour among the most common ovarian tumours; however, teratomas of the omentum and mesentery are extremely rare. They are usually asymptomatic or can produce compressive symptoms. The imaging features are suggestive. The present report describes such a case of primary omental teratoma encountered in a young patient, which was managed by surgical resection. The histopathological examination confirmed the diagnosis of mature cystic teratoma. Germ cell tumors are congenital tumors containing derivatives of all the three germinal layers, frequently seen in gonads. But their occurrence in extragonadal sites, such as omental teratoma, is relatively rare. PMID- 24765372 TI - Heterotopic salivary gland presenting as a discharging sinus in the base of the neck. AB - We report a case of congenital heterotopic salivary gland with draining sinus in the lower neck on the right side of a 10-year-old female, which we initially thought to be a branchial fistula. Heterotopic salivary glands are rare lesions in the neck and when present appear very similar to branchial cleft sinus or fistula. This congenital lesion is rare. This is probably the first report from India. It is important to report this case to raise the awareness of this condition. PMID- 24765371 TI - Giant recurrent retroperitoneal liposarcoma presenting as a recurrent inguinal hernia. AB - Retroperitoneal liposarcoma presenting as an inguinal hernia is a rare entity. We present the first case of Giant recurrent liposarcoma presenting as a recurrent inguinal hernia in a 40-year-old male. Physical examination showed an irreducible lump in the right inguinal region and a scar in the right lumbar and right inguinal region. Computed tomography (CT) scan of abdomen revealed it to be a retro peritoneal mass extending into the right inguinal region along and involving the cord structures. Wide local excision of the tumour with right orchidectomy and inguinal hernioplasty was performed. Histo-pathology confirmed it to be a liposarcoma. Patient received postoperative radio therapy. Follow up of two years has shown him to be disease free. Retroperitoneal liposarcoma can grow along cord structures into the inguinal canal and mimic an irreducible indirect inguinal hernia. PMID- 24765373 TI - Upper gastrointestinal bleeding: audit of a single center experience in Western India. AB - Upper gastrointestinal (GI) bleeding is defined as bleeding proximal to the ligament of Treitz. The most important aspect of management of GI bleeding is to locate the site and cause of bleeding. The aim of the study is to find out the common etiology, presentation and management, including the role of upper GI endoscopy. Recent advances have meant that endoscopic hemostatic methods are now associated with a reduced rate of re-bleeding, cost, blood transfusion, length of hospital stay and mortality. A prospective study of 50 cases was carried out between August 2001 and July 2003. Patients with signs and symptoms suggestive of upper GI bleeding (UGIB) such as hematemesis, melena, aspirated blood from nasogastric tubes, profuse hematochezia, etc., were included in the study. The patients were selected randomly. The most common cause of UGIB in the present study was acute erosive gastritis (34%) followed by portal hypertension (24%) and peptic ulcer (22%). All 50 patients underwent upper GI endoscopy, of whom 39 patients were treated conservatively and 11 patients underwent endotherapy to control bleeding. Out of 39 patients treated non-endoscopically, 6 cases required laparotomy to control UGIB. 8 of 50 cases had past history of UGIB, 5 of whom had a previous history of endotherapy. One case was treated with de-vascularization as routine hemostatic methods failed. So, initial method of choice to control the bleeding was endotherapy and surgery was undertaken if an endoscopic method failed. The most common cause of hematemesis in our setting was acute erosive gastritis followed by portal hypertension. Endoscopy is a valuable minimal invasive method to diagnose and treat upper GI bleeding. PMID- 24765374 TI - Unilateral sudden hearing loss due to otosyphilis. AB - The differential diagnosis of sudden hearing loss is very extensive. However, in most patients, no underlying pathology will be found and the patient is consequently diagnosed with idiopathic sudden hearing loss. Nevertheless, it is important that one stays alert in everyday routine practice to less common but potentially treatable pathology. We report a case of a 53-year old patient with sudden unilateral hearing loss and tinnitus caused by otosyphilis. Diagnosis, therapy and the incidence of (oto)syphilis are discussed. Also, as ENT-surgeons, it is important to realise that syphilis is still with us, and that its prevalence might well increase in the near future. PMID- 24765375 TI - Open re-rupture of the Achilles tendon after surgical treatment. AB - The rate of re-rupture of Achilles tendon after surgical treatment were reported to 1.7-5.6% previously. Re-rupture of Achilles tendon generally occurs subcutaneously. We experienced two rare cases of the open re-ruptures of Achilles tendon with a transverse wound perpendicular to the primary surgical incision. Re rupture occurred 4 and 13 weeks after surgical treatment. We suggest that open re rupture correlates more closely with skin scaring and shortening. Another factor may be adhesion between the subcutaneous scar and the suture of the paratenon and Achilles tendon with post-operative immobilization. PMID- 24765376 TI - Extraosseous Ewing's tumor of lateral abdominal wall. AB - Extraosseous Ewings tumor (EES) is a rare entity. Few cases have been reported in literature. There are no specific guidelines for management of this disease. We are reporting a case of EES arising from left lateral abdominal wall. We did wide excision of tumor followed by chemoradiation. Patient is asymptomatic after 8 months of follow up. PMID- 24765377 TI - Odontogenic myxoma of the maxilla. AB - Myxomas are mostly seen in the 2(th) and 3(rd) decades. They rarely occur in childhood and maxillofacial region is rarely involved. The recurrence incidence is high. We report this unusual case occurring in a 9-year-old girl in the maxillofacial region and recurrence four months after initial treatment. PMID- 24765378 TI - Primary solitary fibrous tumor of the retroperitoneum. AB - Solitary fibrous tumor is an uncommon neoplasm affecting adults and typically located in the pleura and can also occur in a large number of other extra thoracic sites. We present the case of a solitary fibrous tumor (SFT) of the retroperitoneum and describe their histopathological and immunohistochemical features. The identification of SFT in the retroperitoneum is of importance because its clinico-pathological behaviour is still unclear. The pathologist plays a fundamental role in establishing both the positive and differential diagnosis. PMID- 24765379 TI - Diagnostic pitfalls in tibial adamantinoma: two cases with a clinicopathological review. AB - Adamantinoma is a rare primary bone tumor that commonly arises in the jaw and has also been described in the appendicular skeleton such as the tibia. We report 2 cases of tibial adamantinomas that were originally misdiagnosed; one as fibrous dysplasia of the tibia and the other as a cutaneous eccrine carcinoma in a groin mass, which was metastatic adamantinoma to the inguinal lymph nodes. Such metastatic adamantinoma to the groin lymph nodes is extremely rare. The clinical and pathological data with a review of the available literature on inguinal lymph node metastases from primary tibial adamantinoma are reported. Increased clinical awareness and accurate recognition of such uncommon patterns of inguinal nodal metastases are imperative for appropriate planning of therapeutic strategies and risk management in these patients. PMID- 24765380 TI - Legg-Calve-Perthes disease in a child with osteopetrosis. AB - Osteopetrosis is a rare inherited disorder of bone causing increased bone density. Legg-Calve-Perthes disease (LCPD), by contrast, is a more common idiopathic condition leading to variable avascular necrosis of the immature femoral head. We present a case of a 5-year-old boy presenting with these co morbidities. We have found only one previous reference suggesting these two conditions can coexist in the literature. We discuss the basic principles of management of this interesting case. PMID- 24765381 TI - Variant insertion of the fibularis tertius muscle is an evidence of the progressive evolutionary adaptation for the bipedal gait. AB - Fibularis tertius (FT) is often considered as part of extensor digitorum longus (EDL) muscle. The muscle is absent in hominoid apes and with the acquisition of the bipedal gait; the muscle emerged as a recent addition in the human foot. From its various modes of insertions, it is evident that the muscles of the sole are in search of its distal attachment, which can best support the relatively weak human midfoot. We describe an unusual insertion of the muscle in support of this hypothesis. PMID- 24765382 TI - Annular pancreas intra operatively discovered: a case report. AB - Annular pancreas is a rare congenital abnormality. This entity can rarely be symptomatic. Patients can present with gastrointestinal obstruction or acute pancreatitis. We report a case with a rich iconography, of an annular pancreas discovered intraoperatively. A 46-year-old woman was operated with the diagnosis of acute cholecystitis with common bile duct stones. At operation, a strip of pancreatic tissue (2 cm) completely encircled the second duodenum. Open cholecytectomy with choledocotomy and stones extractionwas done. Postoperatively, she developed an acute pancreatitis. The post-operative cholangiography showed the annular duct surrounding the second duodenum. Annular pancreas is rare. Symptoms may occur in newborn children. In adults, annular pancreas discovering is radiological or intra operatively. PMID- 24765383 TI - Metoclopramide-induced cardiac arrest. AB - The authors report a case of cardiac arrest in a patient receiving intravenous (IV) metoclopramide and review the pertinent literature. A 62-year-old morbidly obese female admitted for a gastric sleeve procedure, developed cardiac arrest within one minute of receiving metoclopramide 10 mg via slow intravenous (IV) injection. Bradycardia at 4 beats/min immediately appeared, progressing rapidly to asystole. Chest compressions restored vital function. Electrocardiogram (ECG) revealed ST depression indicative of myocardial injury. Following intubation, the patient was transferred to the intensive care unit. Various cardiac dysrrhythmias including supraventricular tachycardia (SVT) associated with hypertension and atrial fibrillation occurred. Following IV esmolol and metoprolol, the patient reverted to normal sinus rhythm. Repeat ECGs revealed ST depression resolution without pre-admission changes. Metoclopramide is a non-specific dopamine receptor antagonist. Seven cases of cardiac arrest and one of sinus arrest with metoclopramide were found in the literature. The metoclopramide prescribing information does not list precautions or adverse drug reactions (ADRs) related to cardiac arrest. The reaction is not dose related but may relate to the IV administration route. Coronary artery disease was the sole risk factor identified. According to Naranjo, the association was possible. Other reports of cardiac arrest, severe bradycardia, and SVT were reviewed. In one case, five separate IV doses of 10 mg metoclopramide were immediately followed by asystole repeatedly. The mechanism(s) underlying metoclopramide's cardiac arrest-inducing effects is unknown. Structural similarities to procainamide may play a role. In view of eight previous cases of cardiac arrest from metoclopramide having been reported, further elucidation of this ADR and patient monitoring is needed. Our report should alert clinicians to monitor patients and remain diligent in surveillance and reporting of bradydysrrhythmias and cardiac arrest in patients receiving metoclopramide. PMID- 24765384 TI - Internal carotid artery thrombosis and its evolution documented by computed tomography angiography. AB - A case of a 79-year-old man, affected by persistent right eye blindness after multiple episodes of transient left hemiparesis and right eye amaurosis. Brain computed tomography (Angio CT) well documented right internal carotid artery (ICA) plaque with a 8-mm thrombus extending from ICA origin to the ophthalmic artery, in progressive lysis in the next days. PMID- 24765385 TI - A fatal combination in a young lady: Long QT syndrome and coronary artery anomaly. AB - Anomalous origin of coronary arteries is also a relatively rare congenital malformation and has been reported as the cause of angina pectoris and arrhythmia. Long QT syndrome (LQTS) is a rare inherited arrythmogenic disease characterized by susceptibility to life-threatening arrhytmias andsudden cardiac death. We present a 36-year-old patient in whom two rare anomalies coexist and treated succesfully with beta-blocker therapy. PMID- 24765386 TI - Management of palatal vascular malformation using absolute ethanol sclerotherapy. AB - Arteriovenous malformation is treated by variety of techniques over the years. Sclerotherapy is considered an effective and conservative technique for the treatment of benign vascular lesions and replaced the traditional role of surgical therapy, especially for the venous lesions that are surgically difficult or at inaccessible areas. Absolute ethanol was adopted as a new sclerosant agent for this complex form of venous defects to improve overall treatment results with acceptable morbidity and recurrence rates. Sclerotherapy has the advantage of no external scaring, low cost, and few complications in comparison to the surgical treatment. PMID- 24765387 TI - Palmar dislocation of scaphoid and lunate. AB - A palmar dislocation of scaphoid and lunate is uncommon. We have found only 19 reported cases in the literature. We reported a simultaneous, divergent dislocation. The closed reduction followed by percutaneous pinning has given a good result without avascular necrosis of any carpal bone. PMID- 24765388 TI - Sigmoid adenocarcinoma with renal metastasis. AB - We report a case of a 75-year-old man submitted to a rectosigmoidectomy and partial cystectomy because of a sigmoid cancer and colovesical fistula. Seven months later and after four cycles of adjuvant chemotherapy, a lesion was detected in the kidney. Histology revealed tubular adenocarcinoma, which meant sigmoid cancer metastasis. Kidney metastases are very rare in colorectal cancer (CRC), but may be generally associated with an unfavorable prognosis. Thus, patients with metastatic CRC and kidney tumors are a diagnostic and therapeutic challenge. PMID- 24765389 TI - Systemic lupus erythematosusmyositis overlap syndrome: report of 6 cases. AB - The incidence of myositis in patients with systemic lupus erythematosus (SLE) is low among different series. Here we attempt to describe the main features of SLE/myositis overlap syndrome. We retrospectively reviewed the medical records of 174 patients with SLE seen over 15-year period. All the patients fulfilled the revised American Rheumatology Association criteria for SLE. Patients who met The Bohan and Peter criteria for definite myositis were included in this study. Among those patients, six patients had an associated myositis (3.4% overall). They were 6 women with a mean age of 29 years (20-41 years). At the initial evaluation, 3 patients (50%) were complained from myalgia, and all patients had symmetrical muscle weakness (proximal muscle weakness in 6 cases with distal muscle weakness in 2 cases). The muscle disease was severe in 1 case. Involvements of muscles of the pharynx and upper esophagus were noted in 4 patients (66.6%). The creatine kinase (CK) levels were elevated in 4 cases with a mean rate of 2153.5 UI/L. The electromyogram (EMG) revealed signs of myositis in 5 cases. Muscle biopsy, performed in 5 patients, revealed an inflammatory myopathy changes in 4 cases. Antinuclear antibodies (ANA) were positive in all cases. All our patients were treated with high doses of corticosteroids with favorable outcome. Relapse of SLE disease had occurred in 2 patients. The association SLE-myositis is rare with heterogeneous presentation. Through our observations and literature data we will specify the characteristics of this association. PMID- 24765390 TI - Tubercular sinus over manubrium sterni: a rare presentation. AB - Isolated sternal involvement in tuberculosis is rare. Very few case reports are available in literature even from the countries where tuberculosis is endemic. We are reporting a case of 32-year-old female who presented to us with a pus discharging sinus over manubrium sterni with no other systemic features of tuberculosis. Sinus tract was excised and biopsy confirmed tuberculosis. Patient received antitubercular therapy for 9 months. PMID- 24765391 TI - Cost awareness among doctors in an Irish university-affiliated teaching hospital. AB - Previous studies in USA and Canada have found that physicians and physicians in training have a limited understanding of medical care costs. In this study, we set out to survey all grades of doctors in the surgical department, emergency department, and anaesthetic department in a university-affiliated, Irish teaching hospital. Open-ended questionnaires on cost of 25 routinely used items in the hospital were sent to each department. The aims of the study were to assess the present knowledge of cost among the various grades of doctors, and to evaluate the level of professional experience on cost awareness and their confidence in their estimates. We had an overall response rate of 56.8% with 68.5% of doctors admitted to have estimated more than 90% of their responses. Ninety three percent of doctors have no confidence in their estimates on cost of listed items. We found that the lack of cost awareness was universal among doctors of all grades (P = 0.236). The doctors in our study population showed a high level of inaccuracy on their estimates of cost of routinely used items with 84% of the items overestimated. Our results were discouraging and demonstrated that considerable educational activity will be necessary if doctors are to be more cost effective in meeting the national health care budget. PMID- 24765392 TI - A case of endocarditis with cerebral embolism successfully treated with daptomycin. AB - A young girl was admitted for fever, headache, paresthesia of the hands, involuntary blinking of the left eye and aphasia. Imaging revealed mycotic cerebral aneurysms and finally infective endocarditis was diagnosed and successfully treated with daptomycin. She had a history of mitral prolapse and she had undergone dental procedures some months before without any antibiotic prophylaxis, according to the 2007 guidelines of the American Heart Association. PMID- 24765393 TI - Clinical response to glycyrrhizinic acid in genital infection due to human papillomavirus and low-grade squamous intraepithelial lesion. AB - Human papilloma virus (HPV) can infect any of the mucosal areas of the body and cause cervical cancer. Until recently, no specific treatments were available for this condition; therefore, any damaged tissue had to be removed or destroyed, which may have presented obstetrical repercussions for some women. Recently, new drugs have been developed that have shown to be effective for the cure of HPV infection. Glycyrrhizinic acid (GA) has shown fewer side effects and its systemic use makes it possible to reach difficult-to-treat lesions. The purpose of this study was to evaluate the clinical outcome of GA to eliminate the epithelial lesion and HPV. We carried out a longitudinal, descriptive study that included women of reproductive age who were diagnosed with HPV associated with low-grade squamous intraepithelial lesion (LSIL). Subjects began treatment based on GA using two routes of administration - systemic (oral) and topical (spray) - with assessments every month to determine the clinical changes of the lesions through colposcopy and Papanicolaou (Pap) smear. Simple statistics were used along with two-tailed Student's t-test; P<0.05 was considered statistically significant before and after treatment. There were 70 eligible patients, of whom 62 fulfilled the inclusion criteria. Age of subjects was 27.8+/-9.5 years. At the time of the study, 100% of the patients had HPV infection, 40% were associated with LSIL, and only 16% used a barrier contraceptive (condom) method. Resolution was achieved in all patients from 4 weeks of treatment initiation and improvement was achieved in the majority of patients at 12 weeks (74%) (P<0.001). However, there was persistence of LSIL in 27.7% of patients and only one patient progressed to cervical intraepithelial neoplasia (CIN) II. The use of GA proved to be effective in resolving clinical HPV lesions. For cervical lesions with epithelial changes (LSIL), treatment may be required for a longer period as with other drugs used for this infection, as well as monitoring for at least 1 year according to the natural evolution of the disease. PMID- 24765394 TI - Lightning strike: a first case of unilateral diaphragmatic paralysis. AB - Lightning injury is the second most common cause of weather-related deaths in the United States. Despite the several neurological complications such as polyneuropathy, myelopathy, spinal cord injury, motor neuron disease due to the lightning-induced injury, there is no documented case of unilateral diaphragmatic paralysis. We describe the case of a patient with a history of lightning strike at childhood period, prior the onset of isolated, diaphragmatic paralysis, unilaterally. Clinical and electrophysiological findings suggest an injury restricted to the phrenic nerve, unilaterally. PMID- 24765396 TI - Denture impacted in the oesophagus for 9 months: successful endoscopic retrieval. AB - This case report describes the presentation and successful endoscopic retrieval of an impacted denture plate from the distal oesophagus where it had been in-situ for nine months. PMID- 24765395 TI - Long-term reversibility of renal dysfunction associated to light chain deposition disease with bortezomib and dexamethasone and high dose therapy and autologous stem cell transplantation. AB - A 63-year-old woman presented with progressive renal insufficiency, until a glomerular filtration rate (GFR) of 12 mL/min. A renal biopsy demonstrated glomerular deposition of immunoglobulin kappalight chain. The presence of a small population of monoclonal plasmacytes producing an only light kappamonoclonal component was demonstrated and Bortezomib and Dexamethasone (BD) was provided as initial therapy. After seven courses of therapy, renal function improved without dialysis requirements up to a GFR 31 mL/min. Under hematological complete response (HCR) the patient underwent high dose of melphalan (HDM) and autologous peripheral blood stem cell transplant. Fifty-four months later the patient remains in HCR and the GFR has progressively improved up to 48 mL/min. This report describes a notably renal function improvement in a patient with Light Chain Deposition Disease after therapy with BD followed by HDM, which can support this treatment as a future option for these patients. PMID- 24765397 TI - Mucoepidermoid carcinoma - unknown primary and late distant metastasis: an unusual course of the disease. AB - The authors report the case to understand this unusual presentation and prognosis of mucoepidermoid carcinoma following treatment. We present a case of mucoepidermoid carcinoma in a 67-year-old man. The cancer was diagnosed in the right side of his neck but the primary tumor remained unknown despite attempts at staging. The neck was treated successfully and followed up for 2 years. Metastasis of the primary lesion to the left triceps was diagnosed following a swelling noticed by the patient during the 2-year follow up period. Mucoepidermoid carcinoma can be a low, intermediate or high-grade malignancy and can metastasize to different parts of the body. However, this is the first case report of a metastasis to the triceps muscle. PMID- 24765398 TI - Iron supplementation reduces the frequency and severity of breath-holding attacks in non-anaemic children. AB - Iron supplementation reduces the frequency and severity of breath-holding attacks (BHAs), particularly in children with iron deficiency. The issue of iron supplementation is less clear for Westernized children with BHAs who present to an outpatient community clinic and are not iron-deficient. This is the first reported case series of iron-replete children with frequent and disabling breath holding attacks who have responded to a course of oral iron supplementation. This intervention is safe, improves quality of life for both child and carer, and is significantly cost-effective in terms of health resource utilization. PMID- 24765399 TI - Systemic sclerosis with hemoptysis and a huge lung cavity. AB - Systemic sclerosis or scleroderma is associated with distal vasculitis, Raynaud's phenomenon, and inflammation of internal organs and the skin. We present on a 58 year-old Thai woman with systemic sclerosis who came to the 10(th) Zonal Tuberculosis and Chest Disease Center, Chiang Mai, Thailand in 2009 and presented with hemoptysis and a solitary huge-lung cavity as the predominant clinical manifestations which spontaneously resoluted 2 months later. This case demonstrates a solitary huge-lung cavity with hemoptysis and looked like from non tuberculous Mycobacterial infections or malignancy with spontaneous resolution of hemoptysis and the lung cavity, which does not need invasive investigations. PMID- 24765400 TI - Mild stroke symptoms as the initial presentation of a patient with underlying subacute bacterial endocarditis. AB - We describe a patient with sub-acute bacterial endocarditis, whose chief presenting feature was mild expressive dysphasia. PMID- 24765401 TI - Ingestion of a foreign body unmasks an asymptomatic small bowel carcinoid tumor. AB - Bowel obstruction is a common surgical admission around the world. On the other hand, small intestinal tumors, such as midgut carcinoid, are uncommon neoplasms and an infrequent cause of intestinal obstruction leading to hospitalization. A foreign body is an extremely rare cause of intestinal obstruction and when ingested, foreign bodies most often lodge in the narrowest portion of the gastrointestinal tract. Narrowing of the small bowel due to a neoplasm can prohibit the passage of an accidentally ingested foreign object and produce an obstruction that neither the neoplasm nor the foreign body could have produced alone. We hereby report a case in which an accidentally ingested piece of foreign material leads to the finding of a small, early stage, asymptomatic, midgut carcinoid cancer in the proximal ileum that would have otherwise eluded detection for several years. PMID- 24765402 TI - Delayed diagnosis of a right-sided traumatic diaphragmatic rupture. AB - Right-sided traumatic diaphragmatic rupture in childhood is a very rare injury. Diaphragmatic rupture often manifests itself later, after an organ progressively herniates into the pleural cavity. When the patient is tubed, the ventilation pressure does not allow herniation of an organ, which occurs when the patient is ex-tubed. We present a patient with a delayed diagnose of right sided diaphragmatic rupture with a complicated post-operation state. PMID- 24765403 TI - Caecal tumour masquerading as an appendicular mass. AB - Appropriate management of appendix mass is based on an accurate diagnosis of the underlying pathology. This is a report of a complex patient presenting with an appendix mass, whose surgery was deferred due to severe co-morbidities and who later died from severe metastatic disease. A 65-year-old lady presented with right iliac fossa pain and a mass. She was treated for an appendix mass initially and when the mass failed to resolve after four weeks, she was thoroughly investigated for the possibility of a tumour. Severe co-morbities had a significant impact on her management as definitive surgery was delayed. She represented 10 months after the initial admission with small bowel obstruction and died of metastatic caecal cancer. Management of appendix mass must entail a careful approach to investigating and treatment with emphasis on early intervention if the mass does not resolve promptly. This will avoid delayed diagnosis, treatment and a detrimental impact on prognosis. PMID- 24765404 TI - A mixed neoplasm of intraosseous hemangioma with an ameloblastoma: a case of collision tumor or a rare variant? AB - Hemangiomas of the head and neck are considered to be benign tumors of infancy that are characterized by a rapid growth phase with endothelial cell proliferation, followed by gradual involution. Central hemangiomas are a rare occurrence and even rarer are the hybrid tumors of central hemangiomas with odontogenic tumors such as ameloblastomas. This paper reports a case of one such hybrid tumor in a middle aged adult clinical presenting as a mandibular swelling with indistinct mixed radiographic presentation and histopathologically comprising of intimately associated hemangiomatous vascular channels and typical ameloblastic areas. To the authors' knowledge this is the sixth case of such a hemangiomatous ameloblastoma which has been reported till date. PMID- 24765405 TI - Acute interstitial nephritis, a rare complication of Giardiasis. AB - Acute interstitial nephritis is a relevant cause of acute renal failure. Drugs are the predominant cause, followed by infections and idiopathic lesions. Acute interstitial nephritis as a form of hypersensitivity reaction is an uncommon manifestation in the setting of human parasitic infections. We present a case of acute interstitial nephritis in association with Giardia infection in a 54-year old woman who developed an impairment of renal function after a prolonged period of slight fever and diarrhea. After an attempt to recover renal impairment by vigorous rehydratation, because of the unclear origin of the persisting renal failure, a percutaneous renal biopsy was performed and a diagnosis of severe acute interstitial nephritis was made. Steroid therapy was started and after six weeks, renal function had completely recovered. In cases of unexplained renal failure in patients affected by parasitic infections, interstitial nephritis should be considered and it is our opinion that a renal biopsy should be always performed. PMID- 24765406 TI - An emerging problem in clinical practice: how to approach acute psychosis. AB - Limbic encephalitis (LE) is rare, presents with memory impairment, seizures and behavioral disorder. We present a 44-year-old female with an agitation-depressive disorder associated with delusions and hallucinations, admitted to our hospital with the diagnosis of psychosis. A computed tomography (CT) scan of the brain and lumbar puncture on admission were normal. Because of clinical deterioration and addition of seizures in the clinical picture, further workup with serum and repeat cerebrospinal fluid studies, magnetic resonance imaging (MRI), and electroencephalogram disclosed a lesion in the left medial temporal lobe consistent with LE. The patient was treated symptomatically with antidepressive, antipsychotic and anticonvulsant drugs. Aggressive diagnostic tests for the presence of an occult cancer were negative. An 8-year follow up has not revealed a tumor to support a paraneoplasmatic origin of LE. This case, initially diagnosed and treated as psychosis, is a case of non-paraneoplasmatic, non infective LE, probably caused by an autoimmune mechanism. PMID- 24765407 TI - Additional biological therapies for attention-deficit hyperactivity disorder: repetitive transcranical magnetic stimulation of 1 Hz helps to reduce methylphenidate. AB - Excessive hyperactivity, impulsiveness and attentional difficulties characterize attention-deficit hyperactivity disorder (ADHD). The aim of this case report is to signal the possible therapeutic effectiveness of the repetitive transcranial magnetic stimulation (rTMS). Low frequency (1Hz, 1200 stim/die for five days) was applied on the impending scalp in the motor additional area of a patient suffering from combined type ADHD who received methylphenidate (MPH). We saw a significant improvement, especially according to criteria associated with hyperactivity. The improvement lasted for at least three weeks and suggested the final reduction in dosage of MPH.to 10 mg. PMID- 24765408 TI - Abdominal wall metastasis in scar after open resection of an adrenocortical carcinoma. AB - A 42-year-old man patient presented with progressively increasing, occasionally painful lump in the left upper and central abdomen. Investigations revealed well defined capsulated left adrenocortical carcinoma. Tumor was resected successfully along with left kidney. Tumor recurred in the abdominal surgical scar 1.5 years after surgery. We are reporting this case because of rarity of metastatic recurrence of an adrenocortical carcinoma in the abdominal surgical scar 1.5 years after resection of primary tumor. PMID- 24765409 TI - Sphenochoanal polyps and the optic nerve. AB - Isolated sphenoid pathology is uncommon. Nasal polyps that originate from the anterior wall of the sphenoid sinus and reach the nasopharynx are called sphenochoanal polyps. The atypical location of sphenochoanal polyps leads to misdiagnosis, and surgery risks injuring the surrounding structures, such as the optic nerve, carotid artery, and brain. For the differential diagnosis of sphenochoanal polyps, nasal endoscopy and computed tomography are very important. We present the clinical and radiological features of a sphenochoanal polyp and review the status of the optic nerve during endoscopic surgery for a sphenochoanal polyp. PMID- 24765410 TI - Hypochondriacal delusion in an elderly woman recovers quickly with electroconvulsive therapy. AB - A 72-year-old woman without any medical and psychiatric history, suffered from nausea, pain in the epigastria and constipation for over a year. She eventually lost 20 kilograms despite nightly drip-feeding. Extensive additional tests did not reveal any clues for her complaints. She remained convinced that her symptoms were a side-effect of anti-fungal medication she used. She was diagnosed with hypochondria. In the course of time her ideas about her somatic symptoms became delusional and she was diagnosed with a hypochondriacal delusion as part of melancholia, without depressed mood or loss of interest or pleasure as prominent features. It is important to recognize melancholia as soon as possible by continually evaluating other symptoms of depression. This may enable to avoid repetitive and exhaustive somatic examinations, which are not indicated, and to start effective treatment. In our patient electroconvulsive therapy resulted in a fast and complete recovery. PMID- 24765411 TI - An under recognized cause of chest pain. AB - Aortic intramural hematoma (IMH) is related to but is pathologically distinct from aortic dissection. In this potentially lethal entity, there is hemorrhage into the aortic media in the absence of an intimal tear. With recent advances in imaging techniques, IMH is now increasingly recognized. The limited data available suggest that the clinical course of IMH mimics that of acute aortic dissection, and mortality rates are similar. Physicians need to be cognizant regarding this entity when they are evaluating chest pain. Here we report a case of IMH, in a 63-year-old female, which was managed conservatively. PMID- 24765412 TI - Awareness about HIV infection among the paramedical staff in a tertiary care hospital in Delhi, India. AB - In India, acquired immunodeficiency syndrome (AIDS) is a growing epidemic involving all sections of the society. Health care personnel are at increased risk of acquiring blood borne diseases like AIDS, hepatitis, etc. We aimed to assess the level of awareness of HIV infection among the paramedical staff working in a tertiary care hospital. A total number of 207 paramedical staff were asked to complete a questionnaire covering the various aspects of HIV and AIDS which was then critically reviewed. We observed that 57.54% of the staff was aware of the different aspects of HIV infection. Our results highlighted that awareness regarding the different facets of HIV varied among the nurses, lab technicians and support staff. Transmission of blood borne infections through needle stick injury is a harsh reality involving health care personnel. There is an urgent need to teach basic knowledge about HIV infection among high-risk populations. PMID- 24765413 TI - Emphysematous pyelonephritis treated with elective nephrectomy in a 75-year-old diabetic patient. AB - We present a case of 75-year-old man with type 2 diabetes and emphysematous pyelonephritis (EPN). The patient presented with abdominal pain, fever of undetermined origin and progressive decrease in urine output. Computerized tomography scan revealed gas formation in the left renal parenchyma and capsule. A left nephrectomy was performed. He made a quick recovery. EPN should be taken into consideration in diabetic patients with symptoms of pyelonephritis who show a poor response to conventional treatment. Elective nephrectomy may be life saving in some patients. PMID- 24765414 TI - Phaeochromocytoma in a 20-year-old Nigerian, resolving the dilemma of benignity or malignancy. AB - Pheochromocytomas are rare tumors that present a diagnostic challenge in developing countries. They occur in the adrenal gland and as paragangliomas along the sympathetic chain. Clinical features are usually those of sustained or paroxysmal hypertension and complications thereof. Surgical extirpation remains the mainstay of treatment and is greatly facilitated by accurate pre-operative tumor localization. Pre-operative medical management with antihypertensive medication has led to significant reductions in peri-operative mortality. Determination of malignancy is difficult in the absence of obvious metastases. We present a case of left adrenal phechromocytoma that was stabilized. Adrenalectomy had a good outcome and the patient has so far been followed up for a year. PMID- 24765415 TI - Neuroendocrine carcinoma arising in a wound of the postoperative maxillary sinus. AB - We report a case of a neuroendocrine carcinoma arising in a wound of the postoperative maxillary sinus that was difficult to distinguish from a postoperative maxillary cyst. The patient was a 65-year-old Japanese woman who complained of left exophthalmos with cheek swelling and eye movement disorders. In past history, she had, 40 years previously undergone operation on the bilateral maxillary sinus by Caldwell-Luc's method. In a preoperative computed tomography, a mass occupied the left maxillary sinus showing irregular densities with destruction of the posterior bone walls and invasion into the left orbital. Both TI and T2 weighted magnetic resonance imaging showed low intensities and unevenness in the mass. We performed a biopsy of the maxillary tumor according to Caldwell-Luc's method. Histological examination diagnosed neuroendocrine carcinoma. Radiation therapy (total 66Gy) resulted in partial response for this tumor. However, sinonasal neuroendocrine carcinoma has been identified as highly aggressive, with a high probability of recurrence and metastasis. PMID- 24765416 TI - Oral alveolar rhabdomyosarcoma: a case report with immunohistochemical analysis. AB - Rhabdomyosarcomas are among the most common soft-tissue tumors in children. These tumors are derived from mesenchymal tissue with a tendency toward myogenic differentiation that probably originates from immature and highly invasive satellite cells associated with the embryogenesis of skeletal muscle. Some of these tumors are associated with high rates of recurrence and metastasis. The diagnosis is made by microscopic analysis and auxiliary techniques such as immunohistochemistry, electron microscopy, cytogenetic analysis, and molecular biology. We report a case of 28-year-old man who presented with a painless progressive swelling of gingiva since 3 months, which was gradually increasing in size without any systemic symptoms or signs of any metastatic spread. An incisional biopsy was done and histopathology reported an alveolar variant of rhabdomyosarcoma. Immunohistochemistry with panel of markers was done which showed positivity for CD99, vimentin and negative for desmin and myogenin. So the characteristic immunohistological expression was negative in present case. Hence we conclude that haematoxylin and eosin morphology and ultrastructure are needed to classify rhabdomyosarcoma and immunohistochemistry act only as an auxiliary. PMID- 24765417 TI - The clinical response of West Nile virus neuroinvasive disease to intravenous immunoglobulin therapy. AB - The aim of the study was to determine whether intravenous gamma globulin (IVIG) treatment is effective in patients with West Nile Virus (WNV) neuroinvasive disease. We contacted hospital based infectious disease experts in Israeli hospitals to identify patients with WNV neuroinvasive disease who were treated with IVIG. The main outcome measure was neurological response after treatment. There were 12 patients who received IVIG and four improved within 48 h. Three patients died, 6 had partial recovery, and 3 recovered completely. Eleven of the 12 patients were infected with Israeli genotypes that are highly homologous to Europe/Africa viruses. The rapid response in some patients suggests that IVIG is effective, and might be used to treat patients with WNV neuroinvasive disease with IVIG. PMID- 24765418 TI - Compartment syndrome obscured by post-operative epidural analgesia. AB - Compartment syndrome is an orthopedic emergency that require early recognition and urgent intervention to avoid catastrophic complications. High index of suspicion is required for early diagnosis based on a constellation of signs and symptoms that include pain out of proportion and worsened by passive stretching, altered sensorium and palpable tenseness. Any event thus, that masks pain, may lead to delay the diagnosis of compartment syndrome. We report here a case of polytrauma where post-operative analgesia was administered using epidural catheter, which obscured pain and lead to delay in recognition of compartment syndrome. Authors wish to share a lesson, learned at the expense of tragedy. PMID- 24765419 TI - Retroperitoneal abscess due to dropped gallstones after laparoscopic cholecystectomy. AB - Complications of dropped gallstones after laparoscopic cholecystectomy are infrequent but retroperitoneal abscess is extremely rare. We present a new case, discuss causes, diagnostic methods, preventive measures and therapeutical options. PMID- 24765420 TI - You can't judge a book by its cover or a tumor by its expression profile. AB - Expression profiling has shown great promise in matching cancers of unknown primary to likely primary tumors of origin based on patterns of mRNA expression. However, it remains uncertain as to whether even well matched tumors will demonstrate the clinical features, such as rate of progression, of their matched counterparts. In this case report, we note that based on histology, immunohistochemistry and expression profile this patient's poorly differentiated neuroendocrine tumor would have been expected to grow very rapidly on no therapy. Instead, this cancer was very indolent, with only very little radiographic progression over several years. We believe this report represents a remarkable case of a tumor where features, including expression profile, would not at all have accurately predicted the clinical course seen. While some series have suggested that matching by expression profiling predicts outcome, this case shows a dramatically different result. PMID- 24765421 TI - Treatment of indolent, nonencapsulated cryptococcal meningitis associated with hydrocephalus. AB - Infection with cryptococcal meningitis is uncommon in immunocompetent patients. The major virulence factor is the polysaccharide capsule, while nonencapsulated mutants are generally considered nonpathogenic. The authors present a case of hydrocephalus caused by meningitis from an indolent, nonencapsulated Cryptococcus sp. requiring placement and multiple revisions of a ventriculoperitoneal shunt (VPS). The patient presented with progressively worsening occipital headaches. Computed tomography and magnetic resonance imaging showed significant hydrocephalus with no apparent cause. Her symptoms initially resolved after placement of a VPS, but returned four months later. Cultures of the shunt tubing and cerebrospinal fluid (CSF) showed no bacterial infection. When the symptoms failed to resolve, CSF fungal culture revealed Cryptococcus-like yeast, although the organisms were nonencapsulated, and the cryptococcal antigen was negative. After antibiotic therapy, the symptoms resolved. The unusual clinical presentation delayed the diagnosis, highlighting the importance of understanding the detection, diagnosis, and treatment of meningeal infections caused by C. neoformans. PMID- 24765422 TI - Undiagnosed xiphopagus twins: a perinatal malady. AB - Conjoined twins are a very rare entity. It is associated with poor survival rate in the presence of vital organ sharing. The entity can be diagnosed as early as the first trimester. A conjoined twin diagnosed late in labor is a malady with high perinatal mortality and maternal morbidity. We present one such case of xiphopagus twins. The management of a case diagnosed late in labor can be very challenging. Such obstetric challenges can be avoided by a meticulous early scan with a high index of suspicion, especially in the absence of separating membrane while scanning multiple pregnancies. PMID- 24765423 TI - Unusual presentation of eosinophilic enteritis as multiple strictures of small intestine. AB - Eosinophilic enteritis is a rare disease of unknown etiology. It is characterized by eosinophilic infiltration of the bowel wall to a variable depth and symptoms associated with gastrointestinal tract depending upon the predominant layer involved. Diagnosis of eosinophilic enteritis requires a high index of suspicion and exclusion of various disorders that are associated with peripheral eosinophilia. We report a case of unusual presentation of eosinophilic enteritis clinically presenting as intestinal obstruction due to multiple strictures of the small bowel in an adult male. PMID- 24765424 TI - Breast metastasis from multiple primary rhabdomyosarcoma in upper extremity. AB - We report a 16-year-old girl with a multiple primary rhabdomyosarcoma of right upper extremity who developed contralateral breast metastasis in her clinical course. She was diagnosed to have multiple primary rhab-domyosarcoma of the right upper extremity with lung metastasis one year prior to finding a mass in her left breast. The excisional biopsy of the breast mass confirmed metastatic rhabdomyosarcoma. Despite aggressive chemotherapy and subcutaneous total mastectomy, she developed a widespread bone and lung metastasis in few months and expired. Metastatic rhabdomyosarcoma of the breast is very rare but it should be considered in adolescent females with primary alveolar rhabdomyosarcoma, specially located on an extremity. PMID- 24765425 TI - Maxillary first molar with two palatal roots located under dental operating microscope. AB - An awareness and understanding of the presence of an additional root and unusual root canal morphology is essential as it determines the successful outcome of endodontic treatment. A thorough knowledge of basic root canal anatomy and its variation is necessary for successful completion of endodontic treatment. This report points to the importance of looking for additional roots and canals with the help of operating microscope. Finding additional roots and canals would enable clinician to successfully treat a case that would otherwise not be successful. PMID- 24765426 TI - Pseudo-tumoral hepatic tuberculosis discovered after surgical resection. AB - Pseudo-tumoral hepatic tuberculosis is rare. It is characterized by non-specific symptoms and radiological polymorphism. Diagnosis is problematic. This article presents three cases, each clinically different from each other, that illustrate how difficult diagnosis can be. The definitive diagnosis of pseudo-tumoral hepatic tuberculosis was reached on the basis of histo-logical examination of surgical samples. Treatment of the disease based on appropriate anti-tubercular therapy generally gives a positive outcome. PMID- 24765427 TI - Mucormycosis of the hard palate masquerading as carcinoma. AB - A growing number of medically compromised patients are encountered by dentists in their practices. Opportunistic fungal infections such as mucormycosis usually occur in immunocompromised patients but can infect healthy individuals as well. Mucormycosis is an acute opportunistic, uncommon, frequently fatal fungal infection, caused by a saprophytic fungus that belongs to the class of phycomycetes. Among the clinical differential diagnosis we can consider squamous cell carcinoma. Such cases present as chronic ulcers with raised margins causing exposure of underlying bone. There is a close histopathological resemblance between mucormycosis and aspergillosis. Microscopically, aspergillosis has septate branching hyphae, which can be distinguished from mucormycotic hyphae by a smaller width and prominent acute angulations of branching hyphae. A definitive diagnosis of mucormycosis can be made by tissue biopsy that identifies the characteristic hyphae, by positive culture or both. The culture of diseased tissue may be negative and histopathologic examination is essential for early diagnosis. Mucormycosis was long regarded as a fatal infection with poor prognosis. However with early medical and surgical management survival rates are now thought to exceed 80%. In the present case, the fungus was identified by hematoxylin and eosin stain and confirmed by Grocott's silver methenamine special staining technique. Removal of the necrotic bone, which acted as a nidus of infection, was done. Post-operatively patient was advised an obturator to prevent oronasal regurgitation. Since mucormycosis occurs infrequently, it may pose a diagnostic and therapeutic dilemma for those who are not familiar with its clinical presentation. PMID- 24765428 TI - A rare case of paratesticular leiomyosarcoma. AB - Soft-tissue sarcomas of the genitourinary tract account for only 1-2% of urological malignancies and 2.1% of soft-tissue sarcomas in general. A 69-year old male complained of a 4 month history of a painless right groin swelling during routine urological review for prostate cancer follow-up. Clinical examination revealed a non-tender, firm right inguinoscrotal mass. There was no discernible cough impulse. Computed tomography of abdomen and pelvis showed a non obstructed right inguinal hernia. During elective hernia repair a solid mass involving the spermatic cord and extending into the proximal scrotum was seen. The mass was widely resected and a right orchidectomy was performed. Pathology revealed a paratesticular sarcoma. He proceeded to receive adjuvant radiotherapy. Only around 110 cases of leiomyosarcoma of the spermatic cord have been described in the literature. They commonly present as painless swellings in the groin. The majority of diagnoses are made on histology. PMID- 24765429 TI - Anterior mandibular ameloblastoma. AB - Ameloblastoma is a benign odontogenic tumor. These are usually asymptomatic until a large size is attained. Ameloblastoma has tendency to spread locally and has a high recurrence rate. Majority of ameloblastomas (80%) arise from the mandible. Ameloblastoma arising from anterior mandibular region (symphysis-menti) is rare. Very few cases of midline anterior ameloblastomas are reported in the literature. They often require wide local excision. Reconstruction of mandible in these cases is challenging. We present a case of mandibular ameloblastoma arising from symphysis-menti. Patient underwent wide surgical excision of the tumor followed by immediate reconstruction using free fibular vascular flap, stabilized with titanium reconstructive plates. A brief case report ands review of literature is presented. PMID- 24765430 TI - Retinal arterial plaques in acquired immunodeficiency syndrome. AB - The authors report the unusual observation discrete plaque like excrescencies along the retinal arterial wall in a young patient with acquired immunodeficiency syndrome. Though bilateral, in the right eye there was severe arteriolar narrowing and so these plaques were less identifiable. Fluorescein angiography did not reveal any arteriolar occlusion or areas of capillary occlusion in both eyes. There were no other signs of HIV associated microangiopathy and the patient did not have any concurrent cardiovascular or hematological abnormality. The cause of these plaques remains unexplained and we conjecture that they could represent macro immune-complex deposition along the arteriolar walls. PMID- 24765432 TI - Dedifferentiated liposarcoma of the retroperitoneum with osteosarcomatous component. AB - Liposarcoma is one of the most common soft-tissue sarcomas and classified as five groups. Dedifferentiated liposarcoma includes multiple elements such as solid tissue, adipose tissue and calcified tissue, which is different from common liposarcoma in tissue constitue. Dedifferentiation to osteosarcoma is rarely described in the literature. We reported the radiological and pathological findings in a case of dedifferentiated liposarcoma with osteo-sarcomatous dedifferentiation in the retroperitoneum and discussed the characteristic features of this specific tumor. Complete surgical resection of the neoplasm is the only curative means, but establishing a prognosis remains a challenge for long-term evaluation. PMID- 24765431 TI - Potassium permanganate ingestion as a suicide attempt. AB - Potassium permanganate is a highly corrosive, water-soluble oxidizing antiseptic. A 68-year-old female patient was admitted to our Emergency Department after ingestion of 3 tablets of 250 mg potassium permanganate as a suicide attempt. The physical exam revealed brown stained lesions in the oropharynx. Emergency endoscopy was performed by the gastroenterologist after the third hour of ingestion. Emergency endoscopy revealed multiple superficial (Grade I-II) lesions on the esophagus and cardia, which were considered secondary to the caustic substance. The mainstay in the treatment of potassium permanganate is supportive and the immediate priority is to secure the airway. Emergency endoscopy is an important tool used to evaluate the location and severity of injury to the esophagus, stomach and duodenum after caustic ingestion. Patients with signs and symptoms of intentional ingestion should undergo endoscopy within 12 to 24 h to define the extent of the disease. PMID- 24765433 TI - Traumatic pseudoaneurysm of the superficial temporal artery. AB - Aneurysms of the superficial temporal artery are relatively rare vascular complications following trauma. Two cases of pseudoaneurysm of the anterior branch of the superficial temporal artery, subjected to blunt maxillofacial trauma are presented here. The first case was treated by surgical resection and the second was cured by application of continuous pressure. The review of the English literature has also been included. An awareness of these vascular injuries, despite their infrequency, is necessary to facilitate early diagnosis, proper investigation and prompt treatment. PMID- 24765434 TI - Intracranial capillary hemangioma mimicking a dissociative disorder. AB - Capillary hemangiomas, hamartomatous proliferation of vascular endothelial cells, are rare in the central nervous system (CNS). Intracranial capillary hemangiomas presenting with reversible behavioral abnormalities and focal neurological deficits have rarely been reported. We report a case of CNS capillary hemangioma presenting with transient focal neurological deficits and behavioral abnormalities mimicking Ganser's syndrome. Patient underwent total excision of the vascular malformation, resulting in complete resolution of his symptoms. PMID- 24765435 TI - Fever of unknown origin in a Swiss-born child: don't miss tuberculosis! AB - Tuberculosis incidence is low in Switzer land. We report here on a Swiss-born toddler. Tuberculosis manifested with a fever of unknown origin, mimicking an inflammatory or autoimmune disorder triggering a high dose of corticosteroid treatment. The disease went unrecognized for several weeks until development of a miliary tuberculosis with advanced central nervous system involvement. This case highlights the difficulties encountered in diagnosing tuberculosis and in identifying the origin of this case. It reminds us that this disease must never be forgotten when facing a child with persistent fever who must be screened for, before starting immunosuppressive therapy. PMID- 24765436 TI - Medulloblastoma: seeding of VP shunt tract and peritoneum. AB - We report on a 5-year-old boy with seeding of the peritoneum and a ventriculoperitoneal shunt tract by anaplastic medulloblastoma. The role of ventriculoperitoneal shunting in the spread of primary central nervous system tumors has been controversial. In the case reported here, the unique distribution of tumor implants on ultrasound and multiplanar computed tomography gives further credence to the argument that ventriculoperitoneal shunting is a pathway for extraneural metastases of primary central nervous system tumors. PMID- 24765437 TI - A rare massive exophytic gingival growth. AB - Oral surgeons ought to be aware of variety of lesions that can present as focal exophytic gingival overgrowths. Most gingival lesions arise due to local irritating factors. The case presented share dramatic clinical pictures and findings of a long-standing fibrous gingival lesion. A massive growth of 6*7 cm in size and 5 years duration from the maxillary left posterior gingival region in a 64-year-old female causing severe facial disfigurement is presented. Lesion was characterized by the central core of woven bone formation. The article discusses on the clinical findings of peripheral ossifying fibroma and stresses on the unrestricted growth potential of this interesting lesion. PMID- 24765438 TI - Hypercalcemia in a patient with autoimmune polyglandular syndrome. AB - Hypercalcemia is a rare condition in patients with autoimmune polyglandular syndrome (APS-1), usually characterized by hypoparathyroidism and hypocalcemia, and it can develop due to simultaneous adrenal insufficiency. We present a case of severe hypercalcemia in a patient with APS-1, found to have adrenal insufficiency secondary to steroid non-compliance. PMID- 24765439 TI - Hemiplegic peripheral neuropathy accompanied with multiple cranial nerve palsy. AB - A 32-year-old man experienced double vision around January, 2010, followed by weakness of his left upper and lower extremities. Articulation disorders and loss of hearing in his left ear developed, and he was admitted to our hospital on February 14, 2010. Physical examination was normal, and neurological examination showed clear consciousness with no impairment of cognitive function, but with articulation disorders. Olfactory sensation was reduced. Left ptosis and left gaze palsy, complete left facial palsy, perceptive deafness of the left ear, and muscle weakness of the left trapezius muscle were observed. Paresis in the left upper and lower extremities was graded 4/5 through manual muscle testing. Sensory system evaluation revealed complete left-side palsy, including the face. Deep tendon reflexes were slightly diminished equally on both sides; no pathologic reflex was seen. No abnormality of the brain parenchyma, cerebral nerves or cervicothoracolumbar region was found on brain magnetic resonance imaging. On electroencephalogram, alpha waves in the main frequency band of 8 to 9 Hz were recorded, indicating normal findings. Brain single photon emission computed tomography (SPECT) scan showed reduced blood flow in the right inner frontal lobe and both occipital lobes. Nerve biopsy (left sural nerve) showed reduction of nerve density by 30%, with demyelination. The patient also showed manifestations of multiple cranial nerve disorder, i.e., of the trigeminal nerve, glossopharyngeal nerve, vagus nerve, and hypoglos-sal nerve. Whole-body examination was negative. Finally, based on ischemic brain SPECT images, spinal fluid findings and nerve biopsy results, peripheral neuropathy accompanied with multiple cranial nerve palsy was diagnosed. PMID- 24765440 TI - Haematuria in association with Lynch syndrome. AB - A 40-year-old Caucasian male presented to the Emergency Department complaining of intermittent painless frank haematuria. Past medical history was significant for Hereditary Non-Polyposis Colon Cancer (HNPCC) and a prophylactic total colectomy. Computed tomography urogram showed thickening in the posterior wall of the bladder. Cystoscopy showed a small bladder mass. Histology showed a papillary urothelial neoplasm of low malignant potential. HNPCC, also known as Lynch Syndrome, is an autosomal dominant disorder responsible for 3-5% of colorectal cancers. There are certain cancers known to be associated with HNPCC; colorectal cancer, endometrial, ovarian, stomach, pancreas, biliary tract, small bowel, brain, renal pelvic and ureteric tumours, sebaceous gland adenomas and keratocanthomas. An association with bladder tumours is not well established. PMID- 24765441 TI - Tuberculous spondylitis presenting as severe chest pain. AB - This case report describes a 32-year-old male who presented to an emergency department with severe chest pain and a history of cough, fever, night sweats, loss of appetite and weight. Chest radiography revealed a left upper lobe consolidation and multiple compression deformities in the thoracic spine. Magnetic resonance imaging demonstrated significant kyphosis and vertebral plana at two thoracic levels. Anterior compression of the spinal cord and adjacent soft tissue masses were also noted. PMID- 24765442 TI - Post-partum anaphylaxis: universal but successful management protocol should not deter appreciation of underlying etio-pathogenesis plethora. AB - Post-partum Anaphylaxis in mothers is extremely rare and has been reported secondary to initiation of the breast-feeding. However, we hereby report the occurrence of post-partum anaphylaxis in a post-partum patient in the absence of the initiated breast-feeding. PMID- 24765443 TI - Primary renal synovial sarcoma. AB - Primary Renal Sarcoma is rare tumor comprising only 1% of all renal tumours. Synovial sarcomas are generally deep-seated tumors arising in the proximity of large joints of adolescents and young adults and account for 5-10% of all soft tissue tumours. Primary synovial sarcoma of kidney is rare and has poor prognosis. It can only be diagnosed by immunohistochemistry. It should be considered as a differential in sarcomatoid and spindle cell tumours. We present a case of 33-year-old female, who underwent left sided radical nephrectomy for renal tumour. Histopathology and genetic analysis diagnosed it to be primary renal synovial sarcoma. Patient underwent radiation therapy and 2 years follow up is uneventful. A brief case report with review of literature is presented. PMID- 24765444 TI - Successful staged management of simultaneous abdominal aortic aneurysm and renal tumor: the novel minimally invasive treatment with endovascular aneurysm repair and retroperitoneal laparoscopic radical nephrectomy in an elderly and high-risk case. AB - The association between abdominal aortic aneurysm (AAA) and renal tumor is becoming more frequent, and the increasing incidence of this synchronous diseases raised questions about the procedures of treatment. In most of the previous cases, open nephrectomy and AAA surgery have been reported, however in high risk and elderly patients, the procedure is life threatening. We present a successful staged treatment of AAA and renal tumor using novel minimally invasive treatment with endovascular aneurysm repair and retroperitoneal laparoscopic radical nephrectomy in an elderly and high-risk case. PMID- 24765445 TI - Ectopic enamel pearl. AB - Enamel pearls are one of a number of different enamel structures that can be found on the roots of deciduous and permanent teeth. They have a distinct predilection for the furcation areas of molar, particularly the maxillary third and second molars. However, they have been found less commonly on the apical portions of the root. This report describes an unusual case of enamel pearl on apical third of mandibular molar teeth. Enamel pearl was confirmed as predisposing factor for the cause of localized periodontitis; it is very important to recognize their radiographic aspect to ensure proper treatment of involved teeth. PMID- 24765446 TI - Colonisation of basal cell carcinoma and actinic keratosis by malignant melanoma in situ in a patient with xeroderma pigmentosum variant. AB - Although malignant melanoma (MM) and both basal cell carcinoma (BCC) and actinic keratosis (AK) are sun-induced lesions, the coexistence of these entities at the same anatomical site (collision tumour) is exceedingly rare. We report the case of a 54-year-old woman with a known history of xeroderma pigmentosum variant (XPV) who presented with 2 separate skin lesions over the middle and upper right forearm, respectively. The clinical impression was that of BCCs or squamous cell lesions. On histological examination, both specimens showed features of melanoma in situ (MIS). In the first lesion, MIS merged with and colonised a superficial and focally invasive BCC. In the second lesion, MIS merged with an AK. No separate invasive nests of malignant melanoma were seen in either specimen. The atypical melanocytes were highlighted by Melan-A and HMB-45 immunostaining, whereas the epithelial cells in both the BCC and AK stained with the pancytokeratin MNF-116. The patient had a previous history of multiple MMs and non-melanomatous skin cancers and finally developed widespread metastatic malignant melanoma, which proved fatal. The rare and interesting phenomenon of collision tumours may pose diagnostic difficulties. To our knowledge, this is the first reported simultaneous presentation of cytologically malignant collision tumours in a patient with XPV. PMID- 24765447 TI - Primary hyperparathyroidism with rare presentation as multiple brown tumours. AB - We present a case of primary hyperparathyroidism with an uncommon presentation as multiple brown tumours, which may easily be mistaken for a primary bone neoplasm. A brief literature review and its clinical and surgical management are also discussed here. PMID- 24765448 TI - Imatinib mesylate treatment for platelet-derived growth factor receptor alfa positive choroid plexus carcinoma. AB - We herein report a female child with choroid plexus carcinoma treated with standard dose of imatinib at disease recurrence. This patient failed initial twice-surgical resections, central nervous system (CNS) irradiation, and adjuvant chemotherapies and high-dose thiotepa and melphalan with auto peripheral blood stem cell rescue. Finally, imatinib treatment was undergone as a palliative setting, however the tumor did not reduce and the patient died of tumor bleedings. We consider that the reasons for the failure are as follows: i) adequate CNS level of imatinib were not obtained because of the blood brain barrier, ii) the lack of platelet-derived growth factor receptor beta expression in our case may have a crucial role. PMID- 24765449 TI - Anaesthetic concerns for large intracranial cyst excision: expect the unexpected! AB - Neurosurgical procedures in infants poses various challenges such as difficulty in venous cannulation, securing invasive vascular lines, difficult airway, controlling intra-cranial tension, managing large fluid shifts to positioning- related issues and temperature maintenance. We hereby present an case of a large intracranial space occupying lesion, suspected to be a hydatid cyst, which later turned out to be an infected ventricular cyst and intraoperative problems. A thorough preparation prior to operation of infected cystic lesion of the brain is required including anticipation of massive blood loss and its management. A slow decompression of the large cystic lesion should be done. PMID- 24765450 TI - The slipping slipper sign: a simple test with high specificity and positive predictive value for peripheral neuropathy among diabetic patients. AB - This study evaluated the ability of the slipping slipper sign (defined as unknowingly losing a slipper while walking) to identify diabetic neuropathy in Jamaican patients. A single question was used to ascertain the presence of the slipping slipper sign (SSS) among 69 patients attending a diabetes clinic. Nurses assessed pain, vibration and pressure perception among the same patients in order to detect diabetic neuropathy. The sensitivity, specificity and positive predictive value for the SSS were calculated. Eight participants (men=5, women=3) reported positive SSS. The SSS had a sensitivity of 28.6%, specificity of 100% and positive predictive value (PPV) 100% for neuropathy on at least one of the three tests. These findings indicate that the SSS has high specificity and PPV for diabetic neuropathy but the sensitivity is low. The sign may be a useful adjuvant to conventional methods of screening for severe neuropathy. PMID- 24765451 TI - A case of retropharyngeal abscess with spondylitis causing tetraplegia. AB - We report a case of retropharyngeal abscess with spondylitis causing tetraplegia. At a previous hospital, administration of antibiotics improved the inflammation findings. However, magnetic resonace imaging showed a remaining retropharyngeal abscess. This patient showed a disturbance of consciousness under this therapy. Therefore, he was admitted to our hospital and underwent a drainage operation. At 1 day after this operation, he recovered from the disturbance of consciousness. PMID- 24765452 TI - Synchronous ovarian carcinoma with colorectal metastases: an unusual presentation. AB - This report describes the case of a 50-year-old female patient who presented with bilateral adnexal lump and dysfunctional uterine bleeding with altered bowel habits. Computed tomography of the abdomen and pelvis revealed a bilateral adnexal lump situated in both the ovaries and a lobular mass of 8 cm in the rectum. Proctoscopy revealed an elevated irregular rectal lesion. The microscopic examination of the ovarian lump revealed a bilateral serous adenocarcinoma with a papillary pattern with psammomatous calcification. A left hemicolectomy with lymphadenectomy was also performed. Immunohistochemical staining was positive for cytokeratin 7 and negative for cytokeratin 20. The use of immunohistochemistry demonstrated the tumor to be of ovarian origin. We report this case of synchronous involvement of the ovary and the colorectum because of its rarity and unusual presentation. PMID- 24765453 TI - Retinal vasculitis in systemic lupus erythematosus: an indication of active disease. AB - A 26-year-old woman with a recent flare-up of systemic lupus erythematosus presented with peripheral retinal hemorrhages at a routine check-up. She is on a tapering dose of immunosuppressive agents. Her visual acuity was good. Fluorescein angiogram revealed vasculitic changes with capillary non-perfusion areas. A few weeks later, she developed cerebral lupus with advanced lupus nephritis. Immunosuppressive therapy was restarted and panretinal photocoagulation was delivered. Her visual acuity remained stable, despite development of a cataract from prednisolone therapy. PMID- 24765454 TI - Post-colonoscopy appendicitis: a rare entity. AB - A 35-year-old woman was admitted to the surgical ward complaining of right-sided lower abdominal pain. She had undergone colonoscopy a week previously. She was diagnosed with acute appendicitis following colonoscopy and laparoscopic appendectomy was performed via the 2-port technique. Post colonoscopy appendicitis is very rare with 14 cases reported since 1988. PMID- 24765455 TI - Treatment of 817 patients with spontaneous supratentorial intracerebral hemorrhage: characteristics, predictive factors and outcome. AB - The aim of this study was to present the data of a large cohort of patients with spontaneous supratentorial intracerebral hemorrhage (ICH), who were treated in our department and give a current overview considering special clinical characteristics, performed therapy and different predictive factors for morbidity and mortality. We reviewed the data of all patients with spontaneous ICH, who were treated in our department in a time span of 11 years through an analysis of our prospective database. Patients with spontaneous supratentorial ICH were included in the study. Patients with hemorrhage associated to vascular malformation or to cerebral ischemic stroke were excluded. The clinical performance at time of admission and discharge were scored using the Glasgow coma scale (GCS) and the Glasgow outcome scale (GOS) respectively. The patients' cohort was divided into surgically and conservatively treated groups. Statistical analysis [Analysis of Variance (ANOVA) and chi(2)-test] was done for various parameters to analyze their impact on morbidity and mortality. In total, we analyzed the data of 817 patients (364 female and 453 male). Two hundred and sixty-nine patients (32%) were treated conservatively and 556 patients (68%) underwent surgical procedures, i.e. cerebrospinal fluid drainage in 110 (19.8%), craniotomy in 338 (60.7%) and application of both methods in 108 patients (19.4%). Total mortality rate was estimated with 23.5%. GCS<8, age over 70 years, intraventricular and basal ganglia hemorrhage, coumadin medication, combination of co-morbidities, hypertensive hemorrhage and postoperative re-bleeding were statistically significant risk factors for worse outcome (GOS 1 and 2) in the operated group. Similar to the observations of the operated group, GCS<8, age over 70 years and coumadin medication were statistically significant for worse outcome in the conservative group. In contrast, lobar plus basal ganglia ICH and multi-lobar hemorrhages were the most significant factors for worse outcome in the conservative group. The results of our study show that ICH remains a multifarious disease and challenges neurosurgeons repeatedly. Selection of the treatment modality and prediction for neurofunc-tional outcome underlies various parameters. Treatment recommendations of ICH remain an unsolved issue. The consideration of the GCS grade at admission is the most important predictive factor. Old age is not an absolute contraindication for surgery, but cumulative multi-morbidity, especially cerebrovascular and cardiovascular diseases and oral anticoagulant therapy should be regarded critically in view of surgical treatment. PMID- 24765456 TI - Acute disseminated intravascular coagulation following surgical resection of a myeloid sarcoma in a 57-year-old male. AB - Myeloid sarcoma is a rare extramedullary tumour consisting of immature myeloid cells. It can arise at any anatomical location and often develops in the bowel. This report describes a case of severe acute disseminated intravascular coagulation (DIC) with multi-organ failure occurring in a 57-year-old man with chronic myelomonocytic leukaemia during bowel resection for newly diagnosed adenocarcinoma of the sigmoid colon. Histopa thology however revealed a differentiating myeloid sarcoma encompassing a well-differentiated adenocarcinoma. This is the first documented case of acute DIC to be triggered following surgical manipulation of myeloid sarcoma. PMID- 24765457 TI - Soft tissue fibrosarcoma of pre maxillary region in an adult: report of a unique pathological entity. AB - Fibrosarcoma of the oral and maxillofacial region is a rare entity with poor prognosis. Most common sites are the extremities, with only one percent of fibrosarcoma arising in the head and neck area. Oral fibrosarcoma are locally infiltrative and destructive, spreads by haematogenous dissemination. The positive immunostaining for vimentin, together with negativity for muscular immunomarkers help to diagnosis the fibrosarcoma. Surgical management of fibrosarcoma in maxillofacial region is far from satisfactory, because of lack of inadequate clearance. This paper describes an unusual case of soft tissue fibrosarcoma of premaxillary region in an adult aged 71 years. PMID- 24765458 TI - Simple bone cyst of mandible mimicking periapical cyst. AB - Simple bone cysts (SBC) are pseudocysts occurring less commonly in the maxillofacial region. The uncertain and unclear etiopathogenesis led to numerous synonyms to refer this particular cyst. These cysts are devoid of an epithelial lining and are usually empty or contain blood or straw-colored fluid. In jaws initially it mimics a periapical cyst and later can lead to cortical bone expansion warranting for radical approach, which is seldom required. SBC is predominantly diagnosed in first two decades of life. Here we report a case of solitary bone cyst mimicking a periapical cyst of a mandibular molar in a 37-year old patient. PMID- 24765459 TI - Factors influencing surgical outcome after anterior stabilization of the cervical spine with heterogeneous material. AB - Intervertebral fusion through an anterior approach with polymethylacrylate is a well-established neurosurgical technique in the treatment of cervical spine degeneration. However, questions still remain concerning the post-surgical outcome. Factors influencing surgical outcome that could help to predict which patients need further post-surgical treatment and what to expect after surgery are the subject of numerous studies. In the present study, we retrospectively collected data from patients who had undergone intervertebral fusion and defined which pre-operative factors could influence the surgical outcome. Between 1993 and 1997, 379 patients were surgically treated with the ventral fusion technique in our hospital. In 2006, we sent a questionnaire to the patients and 164 responses were received. We identified pre-operative presence of severe pain, hypesthesia, palsy and gait disturbance as negative predictive factors, whereas age, body mass index, pre-operative physical strain and the cervical segment involved did not seem to influence prognosis. In conclusion, identifying pre operative factors which influence prognosis after intervetebral fusion will help predict postoperative outcome. PMID- 24765460 TI - A case of carcinoma of the male breast mimicking a mucinous carcinoma of the skin. AB - The authors report a case of mucinous carcinoma of the male breast firstly diagnosed as a mucinous carcinoma of the skin. The immunohistochemical results of this tumor were as follows: cytokeratin7 (-), gross cystic disease fluid protein 15 (-), p63 (-), estrogen receptor (+), and progesterone receptor (+) for the primary nodule; cytokeratin7 (-), thyroid transcription factor-1 (-), gross cystic disease fluid protein 15 (-), p63 (-), cytokeratin8 (+), cytokeratin18 (+), and cytokeratin20 (+) for the recurrent nodule. The tumor cells had cytokeratin7 (-)/ cytokeratin20 (+) phenotype and it was very unusual for mucinous carcinoma of the breast. PMID- 24765461 TI - Sub cuteneous swelling as the first clinical manifestation of small cell carcinoma of lung. AB - Subcutaneous swelling as first clinical presentation of small cell lung carcinoma is uncommon and rarely reported in literature. This case highlights a rare presentation in which subcutaneous swelling was the first clinical manifestation of a small cell carcinoma of lung which also had metastasis to rib bone, muscle and pleural involvement as pleural effusion. We describe the case of a 64-year old male patient who presented with dyspnea, pleuritic pain, loss of weight and nodule on his anterior chest, back and left arm suspicious of lipoma. Biopsies revealed small cell carcinoma of lung. This case demonstrates the meticulous work up of subcutaneous swelling in the clinical scenario of breathlessness, chest pain and loss of weight. PMID- 24765462 TI - Erythroplasia of queyrat. AB - A 58-year-old Caucasian male presented to the urology clinic reporting an approximate one-year history of a persistent irritating, slowly progressive, glans penis redness. Biopsy revealed penile squamous cell carcinoma in situ. He underwent a partial glansectomy with circumcision and skin grafting. At three months follow-up there is no evidence of local disease recurrence. In western countries, primary malignant penile cancer is uncommon, with an incidence of less than 1 per 100,000 males. Squamous cell cancer accounts for more than 95% of cases of penile cancer. Squamous cell carcinoma in situ on the penile mucosa or transitional surfaces is also known as Erythroplasia of Queyrat. In the region, one third of penile squamous cell carcinoma in situ cases progress to invasive squamous cell carcinoma. PMID- 24765463 TI - Successful treatment of HCV/HBV/HDV-coinfection with pegylated interferon and ribavirin. AB - Dual and triple infections with hepatitis virus C (HCV), B (HBV) and D (HDV) frequently lead to severe liver damage. Hereby we describe a 38-year-old Caucasian male coinfected with HCV (genotype 3a), HBV [positive hepatitis B surface antigen (HbsAg) and antibody to hepatitis B core antigen; negative hepatitis B e antigen (HbeAg) and antibody to hepatitis B e antigen (anti-HBe)] and HDV. Laboratory diagnostics revealed increased liver enzymes and histological examination of the liver showed signs of fibrosis with moderate inflammation. On therapy with pegIFN-alpha2b and ribavirin HCV-RNA was undetectable at week 8. After week 24 the antiviral therapy was stopped because of a HBs-seroconversion, the loss of HbeAg and the detection of anti-HBe. Furthermore the HCV-RNA was negative. Six months after successful treatment of the triple-infection, HCV- and HDV-RNA and HbsAg remained negative and the liver enzymes had been completely normalized. In conclusion, pegylated-interferon plus ribavirin may be an effective therapy for HCV, HBV and HDV-coinfected patients. PMID- 24765464 TI - VAC(r) for external fixation of flail chest. AB - A large aterior chest wall defect following tumor resection was reconstructed with a Gore-Tex(r) membrane and a combined musculocutaneous rectus femoris and tensor fasciae latae free flap. Subsequent paradoxical respiration impeded weaning from the ventilator. Appliance of Vacuum Assisted Closure(r) (VAC(r)) resulted in immediate chest wall stability and a decrease in the patient's need for respiratory support. Shortly thereafter, the VAC(r) was discontinued and the patient was discharged from the intensive care unit (ICU). This case report is the first to describe the successful use of VAC(r) as an adjuvant to a one-stage procedure for large thoracic wall reconstruction, allowing sufficient temporary external fixation to eliminate paradoxical respiration and plausibly shorten the stay in the ICU. No adverse effects on flap healing or haemodynamics were recorded. It is likely that external VAC(r) can improve thoracic stability and pulmonary function in a patient with flail chest and decrease the need for mechanical ventilation. PMID- 24765465 TI - Predictors and incidence of posttraumatic seizures in children and adolescents after brain injury. AB - The present study evaluates the incidence of early and late seizures after head injury in patients under 18 years old. Factors correlating with a high risk of developing posttraumatic seizures were identified. Such risk factors were the severity of the head trauma and a Glasgow Coma Scale of 3-8. In contrast to many studies, we observed that the incidence of posttraumatic seizures was significantly higher in patients older than 12 years old (12-16 and 12-18). Most of the late seizures were paroxysmal electroencephalography (EEG) discharges diagnosed on a snapshot-EEG during the follow-up examination of the patients without clinical symptoms. We suppose that EEG-examination in head injured children is important to identify patients with epileptic potentials without clinical symptoms. Epileptic patterns of the EEG could worsen the diagnosis and clinical outcome of the children in accordance to studies performed in the adult population. PMID- 24765466 TI - A case report of meningioma extending to the middle ear. AB - Extracranial meningioma with extension into a middle ear is very uncommon. A 74 year-old female was admitted to our hospital with right ear bleeding when removing earwax. In this case, magnetic resonance imaging, computed tomography, her past history and operative findings would consider as infiltrative growth from the right sphenoid ridge meningioma to the right middle ear via the right petrous pyramid and bilateral optic nerve. She underwent only partial extirpation with decompression for optic nerve, rather than total extirpation including middle ear and temporal bone, due to wide invasion of the middle cranial fossa and caversinus sinus. PMID- 24765467 TI - Asymptomatic T-cell large granular lymphocyte leukemia with an unusual immunophenotype. AB - T-cell large granular lymphocyte (T-LGL) leukemia represents a clonal proliferation of cytotoxic T-cells which etiology has not been entirely elucidated. However, CD4(+), CD4(-), CD8(-), CD4(+), CD8(+) cases have been described. The disease is usually characterized by cytopenias and a modest lymphocytosis. The majority of patients with T-LGL leukemia remains asymptomatic for a long period and will require treatment later during the course of their disease. Hereby we describe a case of T-LGL leukemia diagnosed by flow cytometry, which presented indolent course and required no treatment so far. PMID- 24765468 TI - Small atrial septal defect associated with heart failure in an infant with a marginal left ventricle. AB - Atrial septal defect (ASD) is usually asymptomatic in infancy, unless pulmonary hypertension or severe co-morbidity is present. We report a case of a 4-week-old infant with moderate-sized ASD, small patent ductus arteriosus (PDA), and a borderline sized left ventricle that developed heart failure. Despite the relatively small diameter of the ASD, this defect influenced the mechanism of heart failure significantly. After surgical closure of both PDA and ASD, the signs of pulmonary hypertension resolved and the patient developed a normal sized left ventricle. This report illustrates that the presence of a small ASD in combination with a marginal left ventricle may result in inadequate left ventricular filling, pulmonary hypertension and heart failure. PMID- 24765469 TI - A conservative single visit reattachment of fractured crown fragment. AB - Injury of anterior teeth is a relatively common event that mainly affects children and adolescents. Dentists are confronted with managing dental trauma and restoring fractured teeth on a regular basis. Hence the techniques that speed and simplify the treatment, restore esthetics and improve long term success rate are considered of potential value. If an intact tooth fragment is present after trauma, immediate attachment of the incisal edge is a conservative yet, simple and aesthetic alternative. Fracture reattachment possesses challenging conservative and economically viable procedure within a single visit. The authors wuld report a case of fractured maxillary central incisor using fragment reattachment. PMID- 24765470 TI - Carcino-sarcoma in a case of syringocystadenoma papilliferum: a rare entity. AB - Syringocystadenocarcinoma papilliferum is a rare form of adenocarcinoma of the skin. It is the malignant counterpart of syringocystadenoma papilliferum (SCAP). It usually develops on the scalp in a long-standing lesion identified clinically as SCAP. Twelve cases of syringocystadenocarcinoma papilliferum have been reported in literature, with limited information regarding its clinical and histological characteristics. Sarcomatous change in a case of SCAP has not been reported in literature till date to the best of our knowledge. We present the first case of syringocystadenocarcino-sarcoma papilliferum in a middle-aged female with a satellite lesion over the scalp. PMID- 24765471 TI - A 72-year-old patient with bilateral Maisonneuve fractures. AB - Maisonneuve fractures result from a disruption of the medial ankle structures and a proximal fibular fracture. Patient complaints can be misleading and there is a significant rate of delayed diagnosed injuries. We present a case of bilateral Maisonneuve fractures after a fall due to a syncopal collapse. A precise clinical examination led to this rare diagnosis. The injuries were treated with syndesmotic screw fixation, removal of hardware followed after 6 weeks. The patient was asymptomatic at three-months follow up. Patients with bilateral injuries undergoing standard surgical treatment can gain full recovery, but high suspicion in clinical examination is needed to detect this uncommon bilateral injury. PMID- 24765472 TI - Primary hepatic choriocarcinoma: a rare cause of spontaneous haemoperitoneum in an adult. AB - Choricarcinoma is a beta human chorionic gonadotrophin secreting neoplasm pertinent to uterus and pregnancy mostly. It occurs primarily in gonads but rarely in extragonadal sites. Primary hepatic choriocarcinoma is an extremely rare tumor. Most of the reported cases are seen in infants representing metastasis from an occult placental choriocarcinoma. Till date, only 7 cases of primary hepatic choriocarcinoma in adults have been reported in literature. We present a case of a 40-yearold male presenting as haemoperitoneum due to ruptured hepatic tumor. He underwent emergency left lateral segmentectomy. He died on 10(th) postoperative day. The surgical specimen and autopsy findings confirmed it to be primary hepatic choriocarcinoma. This is the first case report from Indian Subcontinent. A brief case report and review of literature is presented. PMID- 24765473 TI - Use of therapeutic surfactant lavage in a preterm infant with massive pulmonary hemorrhage. AB - We report a case of a premature infant presenting with recurrent pulmonary hemorrhage in which we performed a therapeutic lavage with diluted surfactant after an acute episode of bleeding with severe intractable hypoxemia. Repeated small aliquots of diluted surfactant (10*2 mL) allowed rapid improvement in oxygenation and reduction of required mean airway pressures during high frequency oscillatory ventilation. This observation may suggest that surfactant lavage could be beneficial in massive pulmonary hemorrhage in infants. A randomized controlled trial might be needed to clarify the potential benefit of this therapeutic intervention on outcome of infants suffering from this life threatening complication. PMID- 24765474 TI - Radiological measurements of dimensions of acutely ruptured internal carotid artery aneurysm: a comparative study between computed tomographic angiography and digital subtraction angiography. AB - After aneurysmal subarachnoid hemorrhage, most center practices treatment modality selection based on size and geometry in computed tomographic angiography. However, the validity as compared to digital subtraction angiography (DSA) is not well studied. Twenty patients with ruptured internal carotid artery aneurysm were identified in a two-year period. Mean difference in measurements from 3D computed tomographic angiography (3D-CTA) and 3D-DSA were less than 1 mm and 3D-DSA measurement did not alter the decision to proceed for endovascular embolization. With modern multislice computed tomography technology, good quality 3D-CTA alone would be sufficient to make size and geometry assessment for treatment selection for patients with ruptured internal carotid artery aneurysm. PMID- 24765475 TI - Mortality associated with community-acquired cephalosporin-resistant Escherichia coli in patients admitted to a district hospital in a resource-limited setting. AB - Studies performed in developed countries have shown that infections by third generation cephalosporin resistant Escherichia coli (G3CREC) are associated with increased mortality, but data from developing countries are scarce. In this observational study, we collected clinical and microbiological information of 194 patients admitted to a district hospital in India who had community-acquired isolation of Escherichia coli. The proportion of patients with G3CREC was 79.4%. In a multivariable logistic regression analysis, factors associated with 21-day mortality were isolation from a normally sterile site, HIV infection and isolation of G3CREC. Strains of Escherichia coli isolated from normally sterile sites had lower levels of resistance to quinolones and beta-lactam antibiotics. The proportion of meropenem and ciprofloxacin resistance was 11.1% and 80.9% respectively. The high proportion of G3CREC in the community and the association of G3CREC with 21-day mortality indicate that G3CREC is a major public health problem in developing countries. PMID- 24765476 TI - Spontaneous rupture of kidney: a rare presentation of nephrolithiasis. AB - Spontaneous rupture of kidney is a rare clinical entity. A 35-year-old female presented in emergency with left flank pain and features suggestive of haemorrhagic shock. Investigations showed rupture of kidney with perinephric haematoma. Emergency left nephrectomy was done. Patient was discharged in satisfactory condition. Nephrolithiasis with secondary bacterial infection rarely presents as spontaneous kidney rupture. In presence of haemorrhagic shock management is emergency surgery. PMID- 24765477 TI - Waugh's syndrome in an adult: report of a very rare disease. AB - The authors report a case of Waugh's syndrome in an adult. Waugh's syndrome is rare in adults as most of the cases present in paediatric age group. We have discussed treatment options and it is suggested that the possibility of Waugh's syndrome should always be kept in mind when a case of intussusception is being treated by either operative or non-operative method. PMID- 24765478 TI - Rare, potentially fatal, poorly understood propofol infusion syndrome. AB - We present the case of a 7-year old boy with traumatic brain injury who received propofol during 38 h. Thirty-six hours after cessation of propofol infusion asystole occurred. After immediate mechanical and medical resuscitation, unreactive dilated pupils were observed. The following computed tomography scan revealed a generalized brain edema with transtentorial herniation. Prolonged bradyarrhythmia, rhabdomyolysis, and peracute renal failure were observed. Despite immediate craniectomy, barbiturate treatment, hemofiltration, and recovery of appropriate cardiac function, the patient died four days after discontinuation of propofol. In this case, metabolic acidosis, cardiac failure, rhabdomyolysis, and renal failure are in accordance with the symptoms of propofol infusion syndrome (PRIS), while seizure, brain edema, and transtentorial herniation could be caused by traumatic brain injury. However, it may be assumed that the entire clinical picture was caused by PRIS. This view could be explained by a common loss of function of ryanodine receptors in patients presenting with PRIS. PMID- 24765479 TI - Pseudotumoral autoimmune pancreatitis mimicking a pancreatic cancer: a very difficult disease to diagnose. AB - Autoimmune pancreatitis (AIP) is a rare disorder, although the exact prevalence is still unkown. It is a type of pancreatitis that is presumed to have an autoimmune aetiology, and is currently diagnosed based on a combination of 5 criteria. However, in this day and age, some patients with AIP are likely to be resected for the suspicion of malignancy. The authors report a case of pseudo tumoral autoimmune pancreatitis, reviewing some literature about it and underlining the difficulty in the diagnosis. A 56-year-old patient was referred to our unit for upper abdominal pain. In his past medical history we note mellitus diabetes. The clinical examination was unremarkable. Laboratory data showed no abnormal values. Upper endoscopy showed antral gastritis. Transabdominal ultrasonography showed a hepatic steatosis and 5 angiomas. No computed tomography scan was made. Magnetic resonance imaging (MRI) showed 5 angiomas and a lesion of 20*20 mm of the pancreatic tail with decreased signal intensity on T1-weighted MR images, increased signal intensity on T2-weighted MR images. Due to concerns of pancreatic malignancy, the patient underwent open distal spleno-pancreatectomy. Histolo gical analysis of the resected specimen revealed no malignancy. Postoperatively, immunoglobulin G fraction 4 was slightly above of the upper limit of the normal range. After corticotherapy the patient is getting better. This case underlines the difficulties still encountered in the diagnosis of AIP. It has been frequently misdiagnosed as pancreatic cancer and caused unnecessary resection. In order to avoid unnecessary resections for an otherwise benign and easily treatable condition, it is urgent to refine diagnostic criteria and to reach an international consensus. PMID- 24765480 TI - Optic nerve enlargement in infantile form of Krabbe disease. AB - Krabbe disease (KD) is an autosomal recessive lysosomal storage disorder caused by dysfunctional galactosylceramidase activity. Infantile form is the most common subtype, occurring at about 6-month of age. We present a rare case of infantile KD with magnetic resonance imaging showing white matter, thalamic and basal ganglia lesions rarely associated with an enlargement of the optic nerves bilaterally. PMID- 24765481 TI - Occult ectopic adrenocorticotropic hormone secretion: diagnostic dilemma and infective consequence. AB - A 42-year-old male presented with polyuria, polydipsia and weight loss. His initial physical exam showed a paucity of cushingoid features. Diagnostic work up was consistent with an ectopic adrenocorticotropic hormone (ACTH) secretion. Imaging studies showed a small anterior mediastinal lesion without additional metabolically active tumors. Fine needle aspiration was consistent with a thymic neuroendocrine tumor. Following radical thymectomy, plasma ACTH and cortisol levels remained elevated. Despite medical management, he died within 2 months of presentation of disseminated intracranial aspergillosis. This case underscores the diagnostic dilemma of occult ectopic ACTH-secreting tumors and the fatal consequence of opportunistic infections. PMID- 24765482 TI - Autoimmune hepatitis induced by nitrofurantoin. The importance of the autoantibodies for an early diagnosis of immune disease. AB - Nitrofurantoin has been in use since 1953 as an effective agent for the prevention of recurrent urinary tract infection. It is associated with a wide range of adverse drug reactions. Chronic active hepatitis has increasingly been observed and many cases have been reported with case fatalities. We present a case of nitrofurantoin induced chronic active hepatitis and briefly review the serology and clinico pathological features of 57 similar cases reported in English literature. The consistent presence of antinuclear antibody, anti smooth muscle antibody, elevated immunoglobulin and pathological feature suggests an immunologic mechanism. Complete recovery is possible in most cases if medication is discontinued in time. Steroids may play a role in management if no improvement occurs despite discontinuation of medication. We suggest all patients who are on prolonged nitrofurantoin therapy be followed up with anti nuclear antibody, anti smooth muscle antibody, serum immunoglobulin and hepatic panel every three months. PMID- 24765483 TI - The dilemma of treating vertebrobasilar dolichoectasia. AB - Vertebrobasilar dolichoectasia (VBD) is a common phenomenon among people over 50 years old, and the related clinical expressions are varied. One of our VBD patients presented with brainstem infarction initially, received low molecular weight heparin treatment, and developed rupture of the dolichoectasia segment. Another patient with a similar-sized VBD experienced recurrent brainstem infarction three times over 2 years, despite higher bleeding tendency and long term antiplatelet treatment. The third patient with a smallersized VBD, had left hemiplegia and received intravenous recombinant tissue plasminogen activator within 3 h, totally recovered with no lesions detected on brain Magnetic Resonance Imaging (MRI). The pathophysiology of VBD is unique, its prevalence and risks of ischemic stroke and intracranial hemorrhage both increase as the degree of arterial dolichoectasia extends, making the strategy of management quite a challenge. The best management of VBD is controlling arterial hypertension and following up with image studies regularly to detect the early extension of VBD degree. PMID- 24765484 TI - Foot care and footwear practices among patients attending a specialist diabetes clinic in Jamaica. AB - This study aimed to estimate the proportion of patients at the University Hospital of the West Indies (UHWI) Diabetes Clinic who engage in recommended foot care and footwear practices. Seventy-two participants from the UHWI Diabetes Clinic completed an interviewer-administered questionnaire on foot care practices and types of footwear worn. Participants were a subset of a sex-stratified random sample of clinic attendees and were interviewed in 2010. Data analysis included frequency estimates of the various foot care practices and types of footwear worn. Participants had a mean age of 57.0+/-14.3 years and mean duration of diabetes of 17.0+/-10.3 years. Fifty-three percent of participants reported being taught how to care for their feet, while daily foot inspection was performed by approximately 60% of participants. Most participants (90%) reported daily use of moisturizing lotion on the feet but almost 50% used lotion between the toes. Approximately 85% of participants reported wearing shoes or slippers both indoors and outdoors but over 40% reported walking barefoot at some time. Thirteen percent wore special shoes for diabetes while over 80% wore shoes without socks at some time. Although much larger proportions reported wearing broad round toe shoes (82%) or leather shoes (64%), fairly high proportions reported wearing pointed toe shoes (39%), and 43% of women wore high heel shoes. In conclusion, approximately 60% of patients at the UHWI diabetic clinic engage in daily foot inspection and other recommended practices, but fairly high proportions reported foot care or footwear choices that should be avoided. PMID- 24765485 TI - Oral hygiene status of individuals with cardiovascular diseases and associated risk factors. AB - Dentist and oral health screening may be the latest weapon in identifying persons at risk of cardiovascular disease. Oral infections, specifically periodontitis, may confer independent risks for different systemic conditions. The risk factors associated with cardiovascular diseases also suggest that the relationship between periodontal disease and diabetes works in both ways. The aim of this study was to support and strengthen the association and relationship between oral hygiene status of individuals with cardiovascular diseases and its associated risk factors. A simple random sampling was carried out in 200 inhabitants of Western Utter Pradesh, India. An oral health visit and examination was made for an equal number of males and females of different age groups with cardiovascular diseases. Evaluation of the oral status was made by means of an oral hygiene index, community periodontal index of treatment needs and loss of attachment. Evaluation of oral status in patients with cardiovascular diseases and in the control group has shown a statistically significant low level of oral health in patients with cardiovascular diseases as compared to control. Prevalence of systemic diseases in different age groups significantly correlated with the prevalence of severe periodontal diseases. Treating gum disease may reduce the risk of heart disease and improve health outcomes for patients with periodontal disease and vascular heart problems. PMID- 24765486 TI - Fluoroquinolone toxicity symptoms in a patient presenting with low back pain. AB - Fluoroquinolone medications have been shown to contribute to tendinopathies, cardiotoxicity, and neurotoxicity. Low back pain is a common musculoskeletal condition for which chiropractic treatment is most often sought. This case report details a patient presenting with low back pain and a history of fluoroquinolone toxicity. The patient was initially treated with chiropractic manipulation, which increased her symptoms. She was then referred to an osteopathic physician who treated the patient with intravenous antioxidants and amino acids, an elimination diet, and probiotic supplementation. Within 4 months of therapy, the patient reported a decrease in pain, a resolution of her dizziness, shortness of breath, panic attacks, tachycardia, and blurred vision. After an additional 8 weeks of antioxidant therapy, she reported further reductions in pain and improved disability. People susceptible to fluoroquinolone toxicity may present with common musculoskeletal symptoms. A past medical history and medication history may help to identify this population of patients. People presenting with fluoroquinolone toxicity may have unidentified contributing factors that predispose them to this anomaly. This patient reported improvements in pain and disability following antioxidant amino acid therapy for a total of 6 months. The natural history of fluoroquinolone toxicity is unknown and may account for the observed improvements. PMID- 24765487 TI - Complications of untreated molar-incisor hypomineralization in a 12-year-old boy. AB - Complications arising because of untreated molar-incisor hypomineralization (MIH) have received little mention in the dental literature. However, this can be an area of concern, with severe consequences in rare cases. Hence, early recognition and prompt management of MIH is essential for long-term oral health of affected individuals. This paper describes an untreated case of severe MIH that resulted in infection of facial spaces. PMID- 24765488 TI - The effects of high-frequency transcranial magnetic stimulation combined with transcutaneous electrical stimulation in a severe stroke patient. AB - The case report describes the effects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) combined with transcutaneous electrical stimulation (TES) in a patient with severe stroke. The patient was a 69-year-old male who was affected by a left middle cerebral artery infarction. The patient had no movement in his right hand. To assess the effects, cerebral blood flow and motor function were measured before and after treatment. This treatment delivered rTMS over the affected M1 with TES at the paretic wrist extensor muscles for 10 days. The regional cerebral blood flow (rCBF) in the entire brain was measured by positronemission tomography. To evaluate the motor function, the Fugl-Meyer assessment (FMA) was used. After treatment, the rCBF was increased (except for the stimulated region), and the FMA score was slightly improved. These results suggest the potential therapeutic use of rTMS combined with TES for recovery in severe stroke. PMID- 24765489 TI - Syringomyelia regression after shunting of a trapped fourth ventricle. AB - We describe a case of progressive syringomyelia following post-infectious trapped fourth ventricle (TFV), which resolved after shunting of the fourth ventricle. A 28-year-old female who had previously undergone treatment of intracerebral hemorrhage and meningitis developed a hydrocephalus with TFV. After 3 years she developed disturbance of walking and coordination. Cranial-CT revealed an enlargement of the shunted fourth ventricle as a result of shunt dysfunction. Furthermore a cervical syringomyelia developed. The patient underwent a revision of a failed fourth ventriculo-peritoneal shunt. Postoperatively, syringomyelia resolved within 6 months and the associated neurological deficits improved significantly. An insufficiency of cerebrospinal fluid draining among patients with TFV can be associated with communicating syringomyelia. An early detection and treatment seems important on resolving syringomyelia and avoiding permanent neurological deficits. Ventriculo-peritoneal shunt in trapped fourth ventricles can resolve a secondary syringomyelia. PMID- 24765490 TI - Multiple pancreatic pseudocysts treated with endoscopic transpapillary drainage. AB - Management of a solitary pancreatic pseudocyst with endoscopic transpapillary stent drainage is a well recognized treatment modality. Endoscopic options are however limited in the presence of multiple pancreatic pseudocysts. Conventionally surgery has been the mainstay of treatment in this situation. In this case report, we present a patient with multiple pancreatic pseudocysts who was successfully treated via transpapillary placement of pancreatic duct stent. PMID- 24765491 TI - Invasive pneumococcal infection despite 7-valent conjugated vaccine. AB - Despite good cover with 7-valent vaccination, invasive pneumococcal infections may still be misdiagnosed and may lead to lifethreatening situations or death in young children. New serotypes are emerging and, therefore, clinicians must keep a high level of suspicion in young children regardless of their vaccination status. We report three cases of invasive pneumococcal infection due to new serotypes not covered by the 7-valent conjugated vaccine, two of which led children to death. PMID- 24765492 TI - Air Embolism during Arthrography for Developmental Dysplasia of the Hip. AB - Arthrography is useful method to evaluate obstruct factors and the congruity of the femoral head for developmental dysplasia of the hip. We usually use an air injection to ascertain whether the needle is accurately insert intraarticularly, because leakage of the contrast medium may make it difficult to identify intraarticular structure in the hip joint. We report the experience the case that suspected air embolism by air injection in the arthrogram. An air injection for arthrography must be avoided the case of infants. To confirm that a needle is correctly inserted intraarticularly, it is preferable to inject saline. Alternatively, it may be suitable to use sonography for confirming the position of the needle for arthrography. PMID- 24765493 TI - Retropancreatic Teratoma with Intra-thoracic Extension. AB - Primary retroperitoneal teratoma is a rare entity in adults. We present a case of 23-yearsold female who presented with complaint of abdominal pain in left upper quadrant. Computed tomography scan revealed a retroperitoneal retropancreatic teratoma near celiac axis with intra thoracic extension. Laparotomy with tumor resection was done. The case report is interesting for intra thoracic extension of retropancreatic teratoma. PMID- 24765494 TI - Multiple pulmonary nodules: a complex case of Wegener's granulomatosis. AB - Wegener's granulomatosis is a granulomatous vasculitis that can present with a wide spectrum of clinical manifestations. This disease entity predominantly affects the respiratory tract and the kidneys. Two forms of Wegener's granulomatosis have been recognized: systemic and limited. It has not been established if the two forms represent separate disease entities or different stages of the same condition. In the limited form of Wegener's granulomatosis there is no immediate threat to the function of vital organs and there is no evidence of glomerulonephritis. Environmental factors that could serve as triggers for the activation of Wegener's granulomatosis have not been clearly defined. We report a case of a 78-year old male who was found to have bilateral pulmonary nodules on pre-operative chest X-ray and was diagnosed with the limited form of Wegener's granulomatosis. The patient developed Clostridium difficile infection, and shortly after that active glomerulonephritis, a manifestation of systemic Wegener's granulomatosis. PMID- 24765495 TI - Citrullinemia type I and hypertrophic pyloric stenosis in a 1-month old male infant. AB - Citrullinemia type I (CTLN1) is an inherited urea cycle disorder, now included in most newborn screening panels in the US and Europe. Due to argininosuccinate synthetase deficiency, CTLN1 can lead to recurrent hyperammonemic crisis that may result in permanent neurologic sequelae. Vomiting in patients with urea cycle disorders may either be the result or cause of acute hyperammonemia, particularly if due to an illness that leads to catabolism. Therefore, age-appropriate common etiologies of vomiting must be considered when evaluating these patients. We present a 1-month old male infant with CTLN1 who had a 1-week history of vomiting and was discovered to have hypertrophic pyloric stenosis. This is the first documented case of an infant with CTLN1 who was later diagnosed with hypertrophic pyloric stenosis, and only the second case of concomitant disease. PMID- 24765496 TI - Retroperitoneal approach for recurrent benign multicystic peritoneal mesothelioma. AB - Benign multicystic peritoneal mesothelioma (BMPM) is an uncommon lesion. It presents as a lump in abdomen or a finding seen on imaging modalities. Surgery is the primary modality of treatment. However, it has a high recurrence rate; this results in adhesions and subsequent surgeries difficult. We present a case of recurrent BMPM in a female operated twice earlier in a rural centre. Imaging modalities showed majority of the lesion in paracolic and retroperitoneal region. Hence, retroperitoneal approach for surgery was taken. This avoided previous surgical adhesions. A brief case report on this novel approach and review of literature is presented. PMID- 24765497 TI - Colectomy for Porto-Systemic Encephalopathy: Is it Still Topical? AB - Hepatic encephalopathy (HE) is a common long term complication of porto-systemic shunt. We report herein the case of a 59-year-old man with Child-Pugh A cirrhosis treated successfully 9 years earlier with distal splenorenal shunt for uncontrolled variceal bleeding. In the last year, he developed a severe and persistent hepatic encephalopathy secondary to the shunt, which was resistant to medical therapy. As liver transplantation was not available and obliteration of the shunt was hazardous, we performed subtotal colectomy in order to reduce ammonia production. This therapeutic option proved successful, as the grade of encephalopathy decreased and the patient improved. Our experience indicates that colonic exclusion should be considered as an option in the management of HE refractory to medical treatment in highly selected patients when liver transplantation is not available or even as a bridge given the long waiting time on lists. PMID- 24765498 TI - First Trimester Diagnosis of VACTERL Association. AB - VACTERL association (OMIM 192350) is a non-random combination of multiple congenital malformations including vertebral, anal, cardiac, tracheoesophageal, renal and limb anomalies. The wide spectrum of defects suggests the occurrence of defective development during early embryogenesis. The authors report a case of a complex polymalformative association detected by ultrasound in the first trimester of pregnancy. The ensuing fetal study revealed the presence of vertebral, anorectal, renal and limb anomalies and therefore was considered a case of VACTERL association. This complex association generally entails a poor prognosis. Its early detection allows discussion of management options, including medical termination of pregnancy. PMID- 24765499 TI - Spontaneous transmesenteric hernia: a rare cause of small bowel obstruction in an adult. AB - The authors report a case of spontaneous transmesenteric hernia with strangulation in an adult. Transmesenteric hernia (TMH) is a rare cause of small bowel obstruction and is seldom diagnosed preoperatively, and most TMHs in adults are related to predisposing factors, such as previous surgery, abdominal trauma, and peritonitis. TMH are more likely to develop volvulus and strangulation or ischemia. A brief review of etiology, clinical features, diagnosis, and treatment is discussed. PMID- 24765500 TI - Agenesis of dorsal pancreas with eventration of diaphragm and intrapancreatic pseudocyst: a rare entity. AB - A case of acute pancreatitis in a 43-year-old male patient, which was eventually diagnosed as agenesis of dorsal pancreas with eventration of left hemidiaphragm and intrapancreatic pseudocyst is being reported. PMID- 24765501 TI - Leiomyosarcoma of the inferior vena cava. AB - Vascular leiomyosarcoma (LMS) are unique. The inferior vena cava (IVC) is the most affected organ (about 38% cases). We report the observation of a 50-year old woman who consulted for right upper quadrant pain. Imaging studies revealed a retroperitoneal mass that mimic a LMS of the IVC. The patient was operated. A resection of the IVC along with the tumor was performed without reconstruction. The management of LMS is surgical and depends upon the location and tumor characteristics. PMID- 24765502 TI - Comparative Study of Different Treatment Options of Grade III and IV Diabetic Foot Ulcers to Reduce the Incidence of Amputations. AB - THIS STUDY AIMS TO COMPARE THE EFFICACY OF ANTISEPTIC DRESSINGS, HYPERBARIC OXYGEN THERAPY, AND RECOMBINANT HUMAN PLATELET DERIVED GROWTH FACTOR (RHPDGF) FOR TWO REASONS: i) to reduce the incidence of lower limb amputations in diabetic foot ulcer; ii) to limit the duration of stay in the hospital. A prospective randomized trial was conducted on 60 patients with stage III and IV diabetic foot ulcers (International Association of Enterostomal Therapy classification) and patients were divided randomly in three different therapy groups - antiseptics, hyperbaric oxygen therapy, recombinant platelet derived growth factor, with 20 patients in each group. Patients were managed initially on inpatient and then on outpatient basis till the ulcer healed completely. Results among three groups were compared using unpaired T test and the level of significance was set at P<0.05 using ANOVA. This study compares the efficacy of hyperbaric oxygen therapy, antiseptic dressings, and rhPDGF in grade III and IV diabetic foot ulcers. P value (0.0348) was significant for complete wound contraction while p value healing time (0.6534) and ulcer size (0.0593) in the groups was not significant. PDGF is safe, effective and easy to apply. Results are comparable with hyperbaric oxygen (HBO) therapy and cost of treatment is lower than other therapies. Diabetic foot ulcer management requires multidisciplinary and aggressive approach. PDGF should be recommended for all grade III and IV diabetic foot ulcer at least 8 weeks old. HBO is equally good an option but has limitations and side effects. PMID- 24765503 TI - Acute traumatic tear of latissimus dorsi muscle in an elite track athlete. AB - Soft tissue injuries constitute 30-50% of all sports related injuries; however, injury to the latissimus dorsi muscle is quite rare with only a few cases reported in the literature. Herein, we describe an acute traumatic tear of the latissimus dorsi muscle in an elite track athlete, which has not been reported in the track and field sports before. The injury was caused by forceful resisted arm adduction that took place at hurdling and starting from the block. A pseudotumor appearance in the axillary region was misdiagnosed as a mass. The diagnosis was made by ultrasound alone and the patient was managed conservatively. PMID- 24765504 TI - Disseminated herpes zoster ophthalmicus in an immunocompetent 8-year old boy. AB - Varicella results from a primary infection with the varicella virus while herpes zoster is caused by a reactivation of a latent infection. Dissemination of herpes zoster is uncommon in immunocompetent individuals. Reports of disseminated herpes zoster in children are even less common than in adults. An unusual case of disseminated herpes zoster ophthalmicus in an 8-year old immunocompetent black boy is presented. He had a previous primary Varicella zoster virus infection at three years of age. In the current report, he presented during an on-going chicken pox outbreak and survived with no significant complications. A breakthrough varicella virus re-infection or a reactivation is possible, both of which could present as zoster. This case emphasizes the need for prevention of varicella virus infection through universal childhood immunization and effective infection control strategies in health care settings. PMID- 24765505 TI - Acute steatohepatitis, due to extreme metabolic dysregulation, as the first presentation of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is a slowly progressive chronic disease, with a high prevalence among obese, dyslipidemic or diabetic people, commonly presented as an asymptomatic mild elevation of serum aminotransferases. We report a patient who experienced an acute form of non-alcoholic steatohepatitis, as the first manifestation of NAFLD, due to exacerbation of pre existing metabolic disorders by an extremely unhealthy lifestyle. A 50-year old, obese, diabetic man presented with a one-week history of jaundice and malaise. Analysis revealed elevated liver enzymes, bilirubin, lipids, and glucose. Based on patient's history, physical examination, laboratory results, and imaging findings, acute non-alcoholic steatohepatitis was established as a diagnosis of exclusion. The patient was started on a low-calorie diet free of carbohydrates and fats, in combination with insulin. A dramatic improvement of clinical and laboratory parameters was observed. In the context of extreme metabolic dysregulation, induced by unhealthy diet, NAFLD may present as an acute steatohepatitis. PMID- 24765506 TI - Acinar cell carcinoma: a rare pancreatic malignancy. AB - Acinar cell carcinoma of the pancreas is a rare pancreatic malignancy, constituting only 1-2% of all the pancreatic tumors. A young adult male presented with chronic diarrhea and upper abdominal pain, on investigations was found to have a large pancreatic tumor of size 12*7.5 cm involving the body of the pancreas. Pancreatic body and tail resection with splenectomy was done and final histopathological examination showed acinar cell carcinoma of the pancreas. Prognosis of acinar cell carcinoma is better than adenocarcinoma of the pancreas. PMID- 24765507 TI - Predominantly cystic central mucoepidermoid carcinoma developing from a previously diagnosed dentigerous cyst: case report and review of the literature. AB - Primary intraosseous mucoepidermoid carcinoma of the jawbones is an extremely rare malignant salivary gland tumour constituting 2-4.3% of all the reported mucoepidermoid carcinomas. We report a case of intraosseous mucoepidermoid carcinoma of the mandible in an 80-year old female patient developing from a previously diagnosed dentigerous cyst. An excisional biopsy was performed and the histopathological features confirmed low grade-cystic intraosseous mucoepidermoid carcinoma. The origin of central mucoepidermoid carcinoma could be suggested to be from the epithelial lining of previously diagnosed dentigerous cyst. Thus, emphasizing the need for careful examination of the entire excision specimen to rule out such neoplastic transformation of epithelial lining of odontogenic cyst and provide appropriate and effective treatment. PMID- 24765508 TI - Role of multislice computed tomography in evaluation and management of intestinal obstruction. AB - THE AIMS AND OBJECTIVES OF THIS STUDY WERE: i) to evaluate the efficacy of computed tomography (CT) imaging in diagnosing the presence, level, degree, and cause of intestinal obstruction, and the role of CT in detecting presence of complications; ii) to assess impact of CT in decision making and management (surgical/conservative); iii) to correlate CT findings with intra operative findings whenever possible. A prospective study of 40 patients presented in outpatient/emergency department with features suggestive of intestinal obstruction. Multislice contrast enhanced computed tomography of whole abdomen was done in all patients after preliminary investigations. Whenever indicated, patients were explored. Statistical analysis was performed to determine the efficacy of multidetector computed tomography (MDCT) in diagnosing intestinal obstruction and its complications. Out of 40, 30 patients underwent exploratory laparotomy and it was found that MDCT was 85% sensitive and 70% specific in diagnosing bowel obstruction. Association between MDCT findings suggestive of obstruction and intra-operative findings turn out to be significant (P=0.003). MDCT findings were consistent with intraoperative findings in 22 out of 30 patients (73%). MDCT is sensitive and specific in determining the presence of bowel obstruction and should be recommended for patients with suspected bowel obstruction because it affects outcome in these patients. PMID- 24765509 TI - A rare case of multiple jejunal diverticulosis presenting as intestinal obstruction. AB - Diverticulosis is rare in jejunum and its unusual presentation of mechanical obstruction is difficult to diagnose pre-operatively. We report a case of a 54 year old male patient who had symptoms of general abdominal pain and vomiting off and on for three years. He had been assessed elsewhere and had received a course of anti-tubercular treatment empirically based on features of recurrent intestinal obstruction due to prevalence of tuberculosis in this region. The patient had presented himself with signs and symptoms of dynamic intestinal obstruction. On examination, the abdomen was found to be swollen with a central abdominal distension and hyperactive bowel sounds. The erect abdominal radiograph showed multiple air-fluid levels and dilated jejunal loops. Following this, the patient underwent an emergency exploratory laparotomy. This revealed multiple jejunal diverticulae, multiple bands and adhesions involving jejunum and proximal ileum. The bands and adhesions were removed and the jejunum was resected along with the inflamed diverticulae. PMID- 24765510 TI - Rhabdomyolysis as a presenting manifestation of very long-chain acyl-coenzyme a dehydrogenase deficiency. AB - Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency (MIM 201475) is a rare inherited disorder with three forms of clinical presentation: a severe early-onset form; an intermediate form with childhood onset; and an adult-onset form, of mild severity. During adolescence and adulthood, exercise intolerance, myalgia and recurrent episodes of rhabdomyolysis are the main clinical features. The authors present a case of a 13-year old female, with severe myalgia and dark urine after prolonged exercise. Analytical evaluation showed marked elevation plasma creatine kinase and myoglobin. The increased levels of tetradecenoyl carnitine in patient's dried blood spot suggested a VLCAD deficiency, which was confirmed by molecular study. Family history is remarkable for first grade consanguinity of parents and a 19-year old brother with records of repeated similar episodes after moderate intensity physical efforts which was subsequently also diagnosed with VLCAD deficiency. This is one of the first cases of late onset of disease diagnosed in Portugal. PMID- 24765511 TI - Intrauterine growth restriction associated with excessively long umbilical cord. AB - We present a 37-week female baby, known with intrauterine growth restriction since 25 weeks of pregnancy, born with a placenta with an excessive long umbilical cord (ELUC), without any other abnormalities. ELUC is mostly an incidental finding after delivery, but represents a potentially detectable intrauterine cause of growth restriction. A system that allows ultrasound measurement of the length of the umbilical cord could highly increase antenatal diagnosis of ELUC. PMID- 24765512 TI - Toxic megacolon complicating a first course of Crohn's disease: about two cases. AB - Toxic megacolon is a rare and serious complication of Crohn's disease. Because of the associated high morbidity and mortality, early recognition and management of toxic megacolon is important. Through two cases of toxic megacolon complicating Crohn's disease, we assessed the clinical, radiologic and therapeutic characteristics of this complication. A 35-year-old man presented a first course of Crohn's disease treated with corticosteroid. He exhibited sudden severe abdominal pain and distension with shock. A plain abdominal radiography revealed toxic megacolon. He underwent medical therapy, but symptoms not relieved. The patient underwent subtotal colectomy with ileostomy. The resected specimen confirmed the diagnosis. Recovery of digestive continuity was performed. Endoscopic evaluation six months later did not shown recurrence. A 57-year-old man presented with severe acute colitis inaugurating Crohn's disease, was treated with corticosteroid and antibiotics. He exhibited signs of general peritonitis. Computed tomographic examination revealed toxic megacolon with free perforation, showing prominent dilation of the transverse colon and linear pneumatosis. The patient underwent emergent subtotal colectomy and ileostomy. The final histological patterns were consisting with diagnosis of Crohn's disease associated with cytomegalovirus infection. The patient underwent antiviral therapy during 15 days. Because of the high risk of postoperative recurrence, he underwent immunosuppressive therapy. Recovery of digestive continuity was performed successfully. Toxic megacolon in Crohn's disease is a serious turning of this disease. We underscore the importance of early diagnosis of toxic megacolon and rapid surgical intervention if improvement is not observed on medical therapy. PMID- 24765513 TI - Osseous hamartoma arising from the eustachian tube. AB - A fairly quite rare case of osseous tumor arising from the Eustachian tube (ET) is described. A 56-year-old man presented with a smooth bulky mass in the nasopharynx and secretory otitis media in the right ear. Computed tomography and magnetic resonance imaging indicated a solid tumor-like region occupying the nasopharynx with apparent extension to the right ET. Transnasal endoscopic surgery demonstrated that the tumor had originated from the ET, and the tumor was partially removed in the area where it had expanded into the nasopharynx. The pathological diagnosis was an osseous hamartoma consisting of bony tissue, fat cells and fibroblasts. To our knowledge, this is the first reported case of osseous hamartoma arising from the ET in the world literature. The patient presented symptoms of nasal obstruction and unilateral aural fullness. Reduction surgery and tympanostomy tube insertion were useful for accurate diagnosis and resolution of the symptoms. PMID- 24765514 TI - Alveolar soft part sarcoma: unusual etiology of mediastinal mass in an adolescent. AB - Alveolar soft part sarcoma (ASPS) is a rare malignancy that usually arises in an extremity. Mediastinal involvement is uncommon, with only two reports of primary mediastinal disease and two reports of metastatic mediastinal disease in the literature, all referencing adult patients. To our knowledge, ours is the first report of ASPS presenting with a mediastinal mass in adolescence. Although ASPS is not generally included in the differential for adolescent mediastinal masses, it should be considered when clinical presentation and imaging appearance are characteristic. PMID- 24765515 TI - Adenocarcinoma of an Ileostomy in a Case of Hirschprung's Disease with Retroviral Disease. AB - The number of ileostomies created for benign diseases such as familial adenomatous polyposis and ulcerative colitis is increasing. Long-term ileostomies are prone to develop various complications over time. Ileostomy site carcinoma is a well-established complication in ulcerative colitis and familial adenomatous polyposis that have undergone total colectomy. However, no case of ileostomy site carcinoma has been described in a patient with Hirschprung's disease. We present the first case of adenocarcinoma at an ileostomy site in a patient with Hirschprung's disease with retroviral disease. PMID- 24765516 TI - Evaluation of clinical use of indigenously developed delta plate in management of subcondylar fracture. AB - Condylar fractures account for 25-35% of mandibular fractures and deserve a special consideration apart from rest of the mandible due to their anatomical differences and healing potential. Previous clinical and biomechanical studies have recommended using two miniplates for fixation of condyle fractures. Two miniplates require a certain size of the proximal condyle fragment and thus are applicable mainly in cases involving low fractures. The present study evaluates the clinical use of indigenously developed titanium delta-shaped miniplate in open reduction and internal fixation of subcondylar fracture. PMID- 24765517 TI - Comparison between ivabradine and low-dose digoxin in the therapy of diastolic heart failure with preserved left ventricular systolic function. AB - Multicenter trials have demonstrated that in patients with sinus rhythm ivabradine is effective in the therapy of ischemic heart disease and of impaired left ventricular systolic function. Ivabradine is ineffective in atrial fibrillation. Many patients with symptomatic heart failure have diastolic dysfunction with preserved left ventricular systolic function, and many have asymptomatic paroxysmal atrial fibrillation. Ivabradine is not indicated in these conditions, but it happens that it is erroneously used. Digoxin is now considered an outdated and potentially dangerous drug and while effective in the mentioned conditions, is rarely used. The aim of the study was to compare the therapeutic effects of ivabradine in diastolic heart failure with preserved left ventricular systolic function. Patients were assigned to ivabradine or digoxin according to a randomization cross-over design. Data were single-blind analyzed. The analysis was performed using an intention-to-treat method. Forty-two coronary patients were selected. In spite of maximally tolerated therapy with renin-antagonists, diuretics and beta-blockers, they had congestive diastolic heart failure with preserved systolic function. Both ivabradine and digoxin had positive effects on dyspnea, Nterminal natriuretic peptide, heart rate, duration of 6-min. walk-test and signs of diastolic dysfunction, but digoxin was high-statistically more effective. Side-effects were irrelevant. Data were obtained in a single-center and from 42 patients with ischemic etiology of heart failure. The number of patients is small and does not allow assessing mortality. In coronary patients with symptomatic diastolic heart failure with preserved systolic function low dose digoxin was significantly more effective than ivabradine and is much cheaper. One should be more critical about ivabradine and low-dose digoxin in diastolic heart failure. To avoid possible negative effects on the cardiac function and a severe reduction of the cardiac output the resting heart rate should not be decreased to <65 beats/min. PMID- 24765518 TI - Simple method to reduce the effect of patient positioning variation on three dimensional motion analysis during treadmill gait. AB - Recently, three-dimensional (3D) closed curve trajectories of markers placed at strategic body locations, called cyclograms or Lissajous-like graphs, are used for treadmill gait analysis. A simple method is presented to reduce the effect of patient positioning variation. After breaking down movement into three components (anterior-posterior, medial-lateral and superior-inferior), the time-series data and time-inverted data are serially concatenated. A fast Fourier transform (FFT) is done, and a high-pass filter (except 0 Hz) is applied to the anterior posterior and medial-lateral components. Next an inverse FFT is executed, and the posterior half of the outcome, corresponding to time-inverted data, is deleted. The 3D closed curve is then reconstructed. Results showed that the proposed method was able to reduce the effect of patient positioning variation. Since the adjusted curve is simply a symbolized gait pattern, the method might be useful as an adjunct tool in observational gait analysis. PMID- 24765519 TI - Congenital oligomeganephronia: computed tomography appearance. AB - We report a case of congenital oligomeganephronia unexpectedly imaged with computed tomography (CT). Oligomeganephronia is a form of renal hypoplasia that leads to renal failure in childhood or adolescence. If encountered, its CT features should suggest the diagnosis and prompt renal biopsy. PMID- 24765520 TI - Leiomyoma of the seminal vesicle: a rare case. AB - Leiomyomas though common benign tumors of smooth muscle cells are extremely rare in the male genitourinary tract. We present a case of an elderly male who presented with complaints suggestive of urinary bladder outlet obstruction since 1 year. His evaluation showed it due to a tumour arising from the left seminal vesicle. Excision of the tumor was done which was diagnosed on histopathology as leiomyoma. A brief case report and review of literature is being presented. PMID- 24765521 TI - Selective and Reversible Photochemical Derivatization of Cysteine Residues in Peptides and Proteins. AB - Selective derivatization of solvent-exposed cysteine residues in peptides and proteins is achieved by brief irradiation of an aqueous solution containing 3 (hydroxymethyl)-2-naphthol derivatives (NQMPs) with 350 nm fluorescent lamp. NQMP can be conjugated with various moieties, such as PEG, dyes, carbohydrates, or possess a fragment for further selective derivatization, e.g., biotin, azide, alkyne, etc. Attractive features of this labeling approach include an exceptionally fast rate of the reaction and a requirement for low equivalence of the reagent. The NQMP-thioether linkage is stable under ambient conditions, survives protein digestion and MS analysis. Irradiation of NQMP-labeled protein in a dilute solution (<40 MUM) or in the presence of a vinyl ether results in a traceless release of the substrate. The reversible biotinylation of bovine serum albumin, as well as capture and release of this protein using NeutrAvidin Agarose resin beads has been demonstrated. PMID- 24765522 TI - BIOPHYSICAL PROPERTIES OF NUCLEIC ACIDS AT SURFACES RELEVANT TO MICROARRAY PERFORMANCE. AB - Both clinical and analytical metrics produced by microarray-based assay technology have recognized problems in reproducibility, reliability and analytical sensitivity. These issues are often attributed to poor understanding and control of nucleic acid behaviors and properties at solid-liquid interfaces. Nucleic acid hybridization, central to DNA and RNA microarray formats, depends on the properties and behaviors of single strand (ss) nucleic acids (e.g., probe oligomeric DNA) bound to surfaces. ssDNA's persistence length, radius of gyration, electrostatics, conformations on different surfaces and under various assay conditions, its chain flexibility and curvature, charging effects in ionic solutions, and fluorescent labeling all influence its physical chemistry and hybridization under assay conditions. Nucleic acid (e.g., both RNA and DNA) target interactions with immobilized ssDNA strands are highly impacted by these biophysical states. Furthermore, the kinetics, thermodynamics, and enthalpic and entropic contributions to DNA hybridization reflect global probe/target structures and interaction dynamics. Here we review several biophysical issues relevant to oligomeric nucleic acid molecular behaviors at surfaces and their influences on duplex formation that influence microarray assay performance. Correlation of biophysical aspects of single and double-stranded nucleic acids with their complexes in bulk solution is common. Such analysis at surfaces is not commonly reported, despite its importance to microarray assays. We seek to provide further insight into nucleic acid-surface challenges facing microarray diagnostic formats that have hindered their clinical adoption and compromise their research quality and value as genomics tools. PMID- 24765523 TI - Modelling c-Abl Signalling in Activated Neutrophils: the Anti-inflammatory Effect of Seliciclib. AB - When mammalian tissues are infected by bacteria or fungi, inflammatory cytokines are released that cause circulating neutrophils to invade the infected tissue. The cytosolic tyrosine kinase, c-Abl, in these tissue neutrophils is activated by TNFalpha. c-Abl then phosphorylates STAT transcription factors, which results in production of the antiapoptotic protein Mcl-1. The normally short-lived tissue neutrophils are then unable to enter apoptosis. c-Abl also causes release of reactive oxygen species (ROS) from the mitochondria of the activated neutrophils. These ROS, and ROS generated by NADPH oxidase, are bactericidal agents of the innate immune system. In some inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), the invading neutrophils become permanently activated, and the resulting ROS overproduction causes severe tissue damage. The cyclin dependent kinase inhibitor, seliciclib, blocks transcription through inhibition of cdk9. This results in a relatively rapid decline of antiapoptotic Mcl-1 transcripts in activated neutrophils, an increase in neutrophil apoptosis, and less ROS leakage and oxidative damage. We present here a model of neutrophil kinetics that simulates the principal pathways of c-Abl signalling and use it to explore possible treatment options for inflammatory lung disease. PMID- 24765524 TI - Recognition of Watson-Crick base pairs: constraints and limits due to geometric selection and tautomerism. AB - The natural bases of nucleic acids have a strong preference for one tautomer form, guaranteeing fidelity in their hydrogen bonding potential. However, base pairs observed in recent crystal structures of polymerases and ribosomes are best explained by an alternative base tautomer, leading to the formation of base pairs with Watson-Crick-like geometries. These observations set limits to geometric selection in molecular recognition of complementary Watson-Crick pairs for fidelity in replication and translation processes. PMID- 24765525 TI - New roles for Smad signaling and phosphatidic acid in the regulation of skeletal muscle mass. AB - Skeletal muscle is essential for normal bodily function and the loss of skeletal muscle (i.e. muscle atrophy/wasting) can have a major impact on mobility, whole body metabolism, disease resistance, and quality of life. Thus, there is a clear need for the development of therapies that can prevent the loss, or increase, of skeletal muscle mass. However, in order to develop such therapies, we will first have to develop a thorough understanding of the molecular mechanisms that regulate muscle mass. Fortunately, our knowledge is rapidly advancing, and in this review, we will summarize recent studies that have expanded our understanding of the roles that Smad signaling and the synthesis of phosphatidic acid play in the regulation of skeletal muscle mass. PMID- 24765526 TI - Treatment advances in systemic juvenile idiopathic arthritis. AB - Systemic juvenile idiopathic arthritis (JIA) is an autoinflammatory condition that is distinct from other forms of childhood arthritis. Recently, biologic agents that specifically inhibit the cytokines interleukin (IL)-1 and IL-6 have demonstrated remarkable clinical effectiveness and confirmed the importance of these cytokines in the disease process. Future studies are likely to optimize the care of children with systemic arthritis and further elucidate the disease pathogenesis. PMID- 24765527 TI - Management of atrial fibrillation. AB - Atrial fibrillation (AF) is associated with increases in the risk of mortality, congestive heart failure, and stroke. Medical treatment is aimed at preventing thrombo-embolic complications and reducing symptoms and consequences related to the arrhythmia. In the first section of this review, we discuss the principles of mainstream oral anticoagulant therapy and the possible advantages of the new oral anticoagulants. In the second section, we review the catheter ablation approaches to paroxysmal and persistent/long-standing AF, their results, and the current application of new catheters. PMID- 24765528 TI - Fanconi anemia and the cell cycle: new perspectives on aneuploidy. AB - Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle. This review discusses recent advances in diagnosis and clinical management of Fanconi anemia and presents the new insights into the origins of genomic instability in FA. These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA deficient malignancies in the general population. PMID- 24765529 TI - Polycystic kidney disease - where gene dosage counts. AB - Gene dosage effects have emerged as playing a central role in the pathogenesis of polycystic kidney disease. Yet, how gene dosage can ultimately have an impact on the formation of kidney cysts remains unknown. In this commentary we review the evidence for the role of gene dosage effects versus the "2-hit" mutation model in polycystic kidney disease (PKD), and also discuss how gene networks may potentially make intertwined contributions to PKD. PMID- 24765530 TI - Inhibition of the dorsomedial hypothalamus, but not the medullary raphe pallidus, decreases hyperthermia and mortality from MDMA given in a warm environment. AB - The central mechanisms through which MDMA mediates life-threatening hyperthermia when taken in a warm environment are not well described. It is assumed that MDMA alters normal thermoregulatory circuits resulting in increased heat production through interscapular brown adipose tissue (iBAT) and decreased heat dissipation through cutaneous vasoconstriction. We studied the role of the dorsomedial hypothalamus (DMH) and medullary raphe pallidus (mRPa) in mediating iBAT, tail blood flow, and locomotor effects produced by MDMA. Rats were instrumented with guide cannulas targeting either the DMH or the mRPa-brain regions involved in regulating iBAT and cutaneous vascular beds. In all animals, core temperature and locomotion were recorded with surgically implanted telemetric transmitters; and additionally either iBAT temperature (via telemetric transmitter) or tail artery blood flow (via tail artery Doppler cuff) were also recorded. Animals were placed in an environmental chamber at 32 degrees C and microinjected with either control or the GABA agonist muscimol (80pmol) followed by an intravenous injection of saline or MDMA (7.5 mg kg-1). To prevent undue suffering, a core temperature of 41 degrees C was chosen as the surrogate marker of mortality. Inhibition of the DMH, but not the mRPa, prevented mortality and attenuated hyperthermia and locomotion. Inhibition of either the DMH or the mRPa did not affect iBAT temperature increases or tail blood flow decreases. While MDMA increases iBAT thermogenesis and decreases heat dissipation through cutaneous vasoconstriction, thermoregulatory brain regions known to mediate these effects are not involved. Rather, the finding that inhibiting the DMH decreases both locomotion and body temperature suggests that locomotion may be a key central contributor to MDMA evoked hyperthermia. PMID- 24765531 TI - Imaging of Gastric Cancer Metabolism Using 18 F-FDG PET/CT. AB - Aerobic glycolysis has been the most important hypothesis in cancer metabolism. It seems to be related to increased bioenergetic and biosynthetic needs in rapidly proliferating cancer cells. To this end, F-18 fluorodeoxyglucose (FDG), a glucose analog, became widely popular for the detection of malignancies combined with positron emission tomography/computed tomography (PET/CT). Although the potential roles of FDG PET/CT in primary tumor detection are not fully established, it seems to have a limited sensitivity in detecting early gastric cancer and mainly signet ring or non-solid types of advanced gastric cancer. In evaluating lymph node metastases, the location of lymph nodes and the degree of FDG uptake in primary tumors appear to be important factors affecting the diagnostic accuracy of PET/CT. In spite of the limited sensitivity, the high specificity of PET/CT for lymph node metastases may play an important role in changing the extent of lymphadenectomy or reducing futile laparotomies. For peritoneal metastases, PET/CT seems to have a poorer sensitivity but a better specificity than CT. The roles of PET/CT in the evaluation of other distant metastases are yet to be known. Studies including primary tumors with low FDG uptake or peritoneal recurrence seem suffer from poorer diagnostic performance for the detection of recurrent gastric cancer. There are only a few reports using FDG PET/CT to predict response to neoadjuvant or adjuvant chemotherapy. A complete metabolic response seems to be predictive of more favorable prognosis. PMID- 24765532 TI - Endoscopic Resection for Early Gastric Cancer beyond Absolute Indication with Emphasis on Controversial Issues. AB - Endoscopic resection is the established treatment for early gastric cancer in selected patients with negligible risk of lymph node metastasis ('absolute indication'). Based on clinical observations and large pathological databases, expanding indications for endoscopic resection beyond absolute indication has been tried in Japan and Korea. However, controversies exist regarding the safety of treating early gastric cancer beyond absolute indication in terms of pathological evaluation of the resected specimen, definition of expanded indication, discrepancy between pre-endoscopic resection and post-endoscopic resection diagnoses of gastric neoplasm, and the best strategy for cases with non curative resection. In this brief review, current evidence and clinical experience regarding issues of endoscopic resection beyond absolute indication will be summarized. PMID- 24765533 TI - The impact of esophageal reflux-induced symptoms on quality of life after gastrectomy in patients with gastric cancer. AB - PURPOSE: To evaluate the prevalence of esophageal reflux-induced symptoms after gastrectomy owing to gastric cancer and assess the relationship between esophageal reflux-induced symptoms and quality of life. MATERIALS AND METHODS: From January 2012 to May 2012, 332 patients were enrolled in this cross-sectional study. The patients had a history of curative resection for gastric cancer at least 6 months previously without recurrence, other malignancy, or ongoing chemotherapy. Esophageal reflux-induced symptoms were evaluated with the GerdQ questionnaire. The quality of life was evaluated with the European Organization for Research and Treatment QLQ-C30 and STO22 questionnaires. RESULTS: Of the 332 patients, 275 had undergone subtotal gastrectomy and 57 had undergone total gastrectomy. The number of GerdQ(+) patients was 58 (21.1%) after subtotal gastrectomy, and 7 (12.3%) after total gastrectomy (P=0.127). GerdQ(+) patients showed significantly worse scores compared to those for GerdQ(-) patients in nearly all functional and symptom QLQ-C30 scales, with the difference in the mean score of global health status/quality of life and diarrhea symptoms being higher than in the minimal important difference. Additionally, in the QLQ STO22, GerdQ(+) patients had significantly worse scores in every symptom scale. The GerdQ score was negatively correlated with the global quality of life score (r= 0.170, P=0.002). CONCLUSIONS: Esophageal reflux-induced symptoms may develop at a similar rate or more frequently after subtotal gastrectomy compared to that after total gastrectomy, and decrease quality of life in gastric cancer patients. To improve quality of life after gastrectomy, new strategies are required to prevent or reduce esophageal reflux. PMID- 24765534 TI - Conventional cytology is not beneficial for predicting peritoneal recurrence after curative surgery for gastric cancer: results of a prospective clinical study. AB - PURPOSE: The role of peritoneal washing cytology in determining further treatment strategies after surgery for gastric cancer remains unclear. One reason for this is the fact that optimal procedures to increase the accuracy of predicting peritoneal metastasis have not been established. The aim of this study was to evaluate the efficacy of cytology using samples harvested from two different abdominal cavity sites during gastric cancer surgery. MATERIALS AND METHODS: We prospectively recruited 108 patients who were clinically diagnosed with locally advanced gastric cancer (higher than cT1 stage disease). Peritoneal washing fluids were collected from the pouch of Douglas and the subphrenic area. Patients were prospectively followed up for 2 years to determine the recurrence and survival rates. RESULTS: Thirty-three patients dropped out of the study for various reasons, so 75 patients were included in the final analysis. Seven patients (9.3%) showed positive cytology findings, of whom, three showed peritoneal recurrence. Tumor size was the only factor associated with positive cytology findings (P=0.037). The accuracy and specificity of cytology for predicting peritoneal recurrence were 90.1% and 94.2%, respectively, whereas the sensitivity was 50.0%. The survival rate did not differ between patients with positive cytology findings and those with negative cytology findings (P=0.081). CONCLUSIONS: Peritoneal washing cytology using samples harvested from two different sites in the abdominal cavity was not able to predict peritoneal recurrence or survival in gastric cancer patients. Further studies will be required to determine whether peritoneal washing cytology during gastric cancer surgery is a meaningful procedure. PMID- 24765535 TI - Serial comparisons of quality of life after distal subtotal or total gastrectomy: what are the rational approaches for quality of life management? AB - PURPOSE: The aims of this study were to make serial comparisons of the quality of life (QoL) between patients who underwent total gastrectomy and those who underwent distal subtotal gastrectomy for gastric cancer and to identify the affected scales with consistency. MATERIALS AND METHODS: QoL data of 275 patients who were admitted for surgery between September 2008 and June 2011 and who underwent subtotal gastrectomy or total gastrectomy were obtained preoperatively and postoperatively at 3, 6, 9, 12, 18, and 24 months. The Korean versions of the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the gastric cancer specific module, the EORTC QLQ-STO22, were used to assess QoL. RESULTS: QoL, as assessed by the global health status/QoL and physical functioning, revealed a brief divergence with worse QoL in the total gastrectomy group 3 months postoperatively, followed by rapid convergence. QoL related to restrictive symptoms (nausea/vomiting, dysphagia, reflux, and eating restrictions) and dry mouth was consistently worse in the total gastrectomy group during the first 2 postoperative years. CONCLUSIONS: The general QoL of patients after gastrectomy is highly congruent with subjective physical functioning, and the differences between patients who undergo total gastrectomy and subtotal gastrectomy are no longer valid several months after surgery. In order to further reduce the differences in QoL between patients who underwent total gastrectomy and subtotal gastrectomy, definitive preoperative informing, followed by postoperative symptomatic management, of restrictive symptoms in total gastrectomy patients is the most rational approach. PMID- 24765536 TI - Can perioperative chemotherapy for advanced gastric cancer be recommended on the basis of current research? A critical analysis. AB - PURPOSE: According to current guidelines, perioperative chemotherapy is an integral part of the treatment strategy for advanced gastric cancer. Randomized controlled studies have been conducted in order to determine whether perioperative chemotherapy leads to improved R0 resection rates, fewer recurrences, and prolonged survival. The aim of our project was to critically appraise three major studies to establish whether perioperative chemotherapy for advanced, potentially resectable gastric cancer can be recommended on the basis of their findings. MATERIALS AND METHODS: We analyzed the validity of the three most important studies (MAGIC, ACCORD, and EORTC) using a standardized questionnaire. Each study was evaluated for the study design, patient selection, randomization, changes in protocol, participating clinics, preoperative staging, chemotherapy, homogeneity of subjects, surgical quality, analysis of the results, and recruitment period. RESULTS: All three studies had serious shortcomings with respect to patient selection, homogeneity of subjects, changes in protocol, surgical quality, and analysis of the results. The protocols of the MAGIC and ACCORD-studies were changed during the study period because of insufficient recruitment, such that carcinomas of the lower esophagus and the stomach were examined collectively. In neither the MAGIC study nor the ACCORD study did patients undergo adequate lymphadenectomy, and only about half of the patients in the chemotherapy group could undergo the treatment specified in the protocol. The EORTC study had insufficient statistical power. CONCLUSIONS: We concluded that none of the three studies was sufficiently robust to justify an unrestrained recommendation for perioperative chemotherapy in cases of advanced gastric cancer. PMID- 24765537 TI - Clinical application of electrogastrography in patients with stomach cancer who undergo distal gastrectomy. AB - PURPOSE: Electrogastrography is a method of measuring action potentials of the stomach. The purpose of this study was to investigate early postoperative changes in the electrogastrography and determine the correlation between electrogastrography and quality of life of patients with stomach cancer who underwent distal gastrectomy. MATERIALS AND METHODS: This study analyzed 20 patients with stomach cancer who underwent electrogastrography and quality of life was measured 1, 12, and 24 weeks after the operation. Quality of life-C30 version 3.0 and quality of life-STO22, were used. RESULTS: Fasting and postprandial mean dominant frequency at 1 week after the operation was 2.7 and 2.7 cycles per minute, and 2.8 and 2.7 cycles per minute at 12 weeks, 2.6 and 2.8 cycles per minute at 24 weeks. Fasting and postprandial mean dominant power at 1 week was 36.5 and 36.4 dB, 36.3 and 40.1 dB at 12 weeks and 40.9 and 42.3 dB at 24 weeks. The percentage of tachygastria was increased whereas the percentage of bradygradia was decreased during the postoperative periods (P<0.05). Global health, physical, emotional and social functioning scales were improved, but role and cognitive functioning were not changed. Pain, insomnia, diarrhea and financial difficulties were significantly improved according to the postoperative periods (P<0.05). The correlation between the STO22 and electrogastrography parameters was not significant (P>0.05). CONCLUSIONS: These may suggest that electrogastrography is a simple and noninvasive method and may be applicated for evaluating motility and autonomic functions of the remnant stomach. PMID- 24765538 TI - Gastric carcinoma with bone marrow metastasis: a case series. AB - Gastric cancer is a major cause of cancer-related mortality. At the time of diagnosis, majority of the patients usually have unresectable or metastatic disease. The most common sites of metastases are the liver and the peritoneum, but in the advanced stages, there may be metastases to any region of the body. Bone marrow is an important metastatic site for solid tumors, and the prognosis in such cases is poor. In gastric cancer cases, bone marrow metastasis is usually observed in younger patients and in those with poorly differentiated tumors. Prognosis is worsened owing to the poor histomorphology as well as the occurrence of pancytopenia. The effect of standard chemotherapy is unknown, as survival is limited to a few weeks. This report aimed to evaluate 5 gastric cancer patients with bone marrow metastases to emphasize the importance of this condition. PMID- 24765539 TI - A rare case of primary squamous cell carcinoma of the stomach and a review of the 56 cases reported in Japan. AB - We report an extremely rare case of primary squamous cell carcinoma of the stomach. A 69-year-old man was admitted to our hospital with a 2-month history of dysphagia and tarry stools. Endoscopic examination revealed a cauliflower-shaped protruding mass along the lesser curvature of the gastric cardia. Biopsy of the lesion revealed squamous cell carcinoma of the stomach. Computed tomography revealed a thickened stomach wall and a mass protruding into the gastric lumen. Total gastrectomy with splenectomy, distal pancreatectomy, and Roux-en-Y reconstruction was performed, together with a lower thoracic esophagectomy via a left thoracotomy. Histopathological examination of the specimen revealed well differentiated squamous cell carcinoma of the stomach. Postoperative follow-up was uneventful for the first 18 months. However, multiple liver metastases and para-aortic lymph node metastasis developed subsequently. Despite systemic combination chemotherapy, the patient died because of progression of the recurrent tumors. Here, we review the characteristics of 56 cases of gastric squamous cell carcinoma reported in Japan. PMID- 24765540 TI - Mixed adenoneuroendocrine gastric carcinoma: a case report and review of the literature. AB - We present a rare case of a gastric mixed adenoneuroendocrine tumor and review the related English literature. A 77-year-old Caucasian woman was admitted to our department with nausea, anorexia, weight loss, and anemia. Esophagogastroduodenoscopy showed a large (>7 cm) ulcerative mass in the greater curvature of the stomach. Biopsy showed the presence of an adenocarcinoma with moderate differentiation. The patient underwent D2 subtotal gastrectomy. Histopathological analysis revealed a diagnosis of mixed gastric adenoneuroendocrine carcinoma. The post-operative course was uneventful, and at the 6-month follow-up, the patient was alive without evidence of recurrence. Our review of the English literature suggested that such cases are most often reported from eastern countries. Multimodal treatment should be the aim for these patients because of the neuroendocrine component of the tumor. PMID- 24765541 TI - Yoga and Physical Rehabilitation Medicine: A Research Partnership in Integrative Care. AB - Mind-body interventions, such as yoga, that teach stress management with physical activity may be well suited for investigation in both osteoarthritis and rheumatoid arthritis. In order to be considered as viable care options integrative studies need to offer a comprehensive design and include clinicians familiar with the disease process of the study populations. A review of the literature reveals a dearth of information related to the collaboration between yoga and physical rehabilitation medicine. This article discusses the collaboration with physical rehabilitation medicine to collect relevant pre- and post-intervention measures for an on-going pilot acceptability/feasibility yoga study for minority patients with osteoarthritis or rheumatoid arthritis. An interdisciplinary clinical research team selected psychosocial and physical measures for a community sample of bilingual minority patients, not typically identified as practicing yoga. Sixteen female adults aged 40-63 years (mean =51) completed baseline physical assessments using single leg stance, functional reach test, time up and go test, timed up from the floor test and the Disabilities of the Arm, Shoulder and Hand measures. Baseline values show an average level of functional ability prior to beginning the intervention. Preliminary results indicate some improvement; however, selected measures may not have the sensitivity and specificity needed to identify significant change. In this study, combining interdisciplinary perspectives enhanced the quality of the research study design. The experience of this interdisciplinary clinical research team opens the discussion for future collaborations. PMID- 24765543 TI - Dermatopathology comes to life! PMID- 24765542 TI - Injected Versus Oral Cyclosporine for Human Neural Progenitor Grafting in Rats. AB - BACKGROUND: Neural cell transplantation is a promising therapy for stroke, but rejection of human cells in animal models is an obstacle to furthering this research. Many antirejection strategies have been reported, but few comparison data are available. We asked if human neural cell grafts would have different survival or differentiation with injected or oral cyclosporine regimens. METHODS: Rats received intracerebral grafts of human embryonic stem cell-derived neural progenitors, and 6 rats each were randomized to 4 cyclosporine regimens: 1) daily injections, 2) initial injections followed by oral drug in the drinking water, 3) oral drug only, or 4) no cyclosporine. Histology was performed 14 days after grafting for quantification of markers of human cells, neural cell types, and immune cells. RESULTS: More rats in the injection (6/6) and injection+oral (5/6) groups had surviving graft cells than in the oral (1/6) and control (3/6) groups (p<0.05), with a trend toward a greater number of surviving graft cells as well. All rats with surviving graft cells also had these cells co-label for a neural progenitor marker, and a minority of graft cells co-labeled for a cell division marker and a neuronal marker. Rats with areas of dead graft cell debris were seen in all of the groups. In these areas, cells that labeled for microglial markers also contained the human nuclear marker in their cytoplasm, suggesting phagocytosis of the graft cells. CONCLUSIONS: Human neural cell survival in rat brain tissue differed between cyclosporine regimens, but microglial phagocytosis of graft cells occurred in all the groups. Frequent injection of laboratory animals is undesirable, and a compromise strategy of peritransplant injections followed by drug in the drinking water showed good results in preventing graft cell rejection. Further research is needed to optimize the antirejection approach for this application. PMID- 24765544 TI - Combining in vivo reflectance with fluorescence confocal microscopy provides additive information on skin morphology. AB - BACKGROUND: Within the last decade, confocal microscopy has become a valuable non invasive diagnostic tool in imaging human skin in vivo. Of the two different methods that exist, reflectance confocal microscopy (RCM) displays the backscattering signal of naturally occurring skin components, whereas fluorescence confocal microscopy (FCM) provides contrast by using an exogenously applied fluorescent dye. METHODOLOGY: A newly developed multilaser device, in which both techniques are implemented, has been used to combine both methods and allows to highlight different information in one image. In our study, we applied the fluorophore sodium fluorescein (SFL) intradermally on forearm skin of 10 healthy volunteers followed by fluorescence and reflectance imaging. RESULTS: In fluorescence mode the intercellular distribution of SFL clearly outlines every single cell in the epidermis, whereas in reflectance mode keratin and melanin rich cells and structures provide additional information. The combination of both methods enables a clear delineation between the cell border, the cytoplasm and the nucleus. Imaging immediately, 20, 40 and 60 minutes after SFL injection, represents the dynamic distribution pattern of the dye. CONCLUSION: The synergism of RCM and FCM in one device delivering accurate information on skin architecture and pigmentation will have a great impact on in vivo diagnosis of human skin in the future. PMID- 24765545 TI - Differentiation of pigmented Spitz nevi and Reed nevi by integration of dermatopathologic and dermatoscopic findings. AB - BACKGROUND: It is unclear whether pigmented Spitz and Reed nevi are distinct morphologic entities or part of the spectrum of Spitz nevi. METHODS: In a retrospective observational study we analyzed dermatopathologic slides of 22 cases with clinical and dermatoscopic features indicative of pigmented Spitz or Reed nevus in a blinded fashion according to predefined criteria and subsequently correlated dermatopathologic with clinical and dermatoscopic findings. RESULTS: We differentiated pigmented Spitz and Reed nevus dermatopathologically by their capacity of melanin production and a vertical versus horizontal growth pattern. Based on histopathology 20 nevi (91%) could be reliably diagnosed as Reed nevus (68%, n=15) or as pigmented Spitz nevus (23%, n=5). In two cases (9%, n=2) it was not possible to make a clear distinction from a dermatopathologic point of view. Dermatopathologic-dermatoscopic correlation showed that Reed nevi were characterized by a dermatoscopic pattern of peripheral radial lines or pseudopods (fascicular growth pattern), whereas pigmented Spitz nevi were typified by a pattern consisting of clods (nested growth pattern). "Spitz cells" (large epithelioid melanocytes) were more commonly found in Spitz nevi (100%, n = 5) but were also present in Reed nevi (n=6, 40%). Spindle cells were found in both types of nevi. CONCLUSIONS: Pigmented Spitz and Reed nevi can be reliably distinguished based on their dermatopathologic and dermatoscopic patterns. The specific dermatopathologic patterns of pigmented Spitz and Reed nevi correspond well to their dermatoscopic patterns. The presence of "Spitz cells" or spindle cells should not be regarded as the decisive criterion to differentiate between these two entities. PMID- 24765546 TI - Langerhans cell histiocytosis - a case report. AB - A 17-year-old male presented for dermatologic consultation with slightly elevated reddish papules covered by yellowish scales in the scalp for the last two years and reddish and indurated ulcers in the perineum lasting six months. Additional complaints included polyuria, polydipsia, delay in the development of secondary sexual characteristics and hearing loss of the right ear secondary to a medium otitis. Lesions from scalp and perineum were sampled for histopathologic examination and revealed a dense cellular infiltrate made up of mononuclear cells with conspicuous eosinophilic cytoplasm and large cleaved vesicular nucleus, some of them with shapes resembling the format of a kidney and others reminiscent of coffee beans. Numerous intermingling eosinophils were present. The diagnosis of Langerhans cell histiocytosis was then rendered and confirmed by positive immunostaining of neo-plastic cells for anti-CD1a and anti-S100 protein antibodies. The work-up revealed diabetes insipidus, hypogonadotropic hypogonadism, hiperprolactenemia, growing-hormone deficiency and thickness of the pituitary stalk. The patient was treated with prednisone and vinblastin based chemotherapy regimen for six months with complete remission, but presented recurrence of some lesions in the scalp, which were handled with topical mustard and corticosteroids. After chemotherapy, the endocrinologic disturbances were corrected with hormonal replacement therapy. The patient is currently in good health with a follow-up of five years. PMID- 24765547 TI - Nodules on the right ear. PMID- 24765548 TI - From the dermatologikum hamburg: quiz. PMID- 24765549 TI - Extraocular sebaceous carcinoma: a series of three cases with varied presentation. AB - BACKGROUND: Extraocular sebaceous carcinomas are rare cutaneous malignancies that account for only about 25% of all sebaceous carcinomas. The most common site of occurrence is the head/neck region. They are aggressive neoplasms that possess metastatic potential to regional or distant sites. Wide local excision of the lesion with removal of regional lymph nodes is the usual mode of therapy. METHODS: We present a series of three cases of sebaceous carcinomas occurring in extraocular sites outside the head and neck areas, like the axilla, chest wall, arm and thigh. One of these cases had an associated colonic carcinoma and constituted Muir-Torre syndrome (MTS). Another case presented with a skin nodule and regional nodal metastasis. The third case had a history of recurrent similar lesions at the same site. CONCLUSION: Although rare, extraocular sebaceous carcinomas are seen at varied sites and frequently pose problems in diagnosis. A longterm follow-up of these cases is warranted due to their aggressive behaviour, risks of recurrence, metastasis and the possibility of development of visceral malignancies. PMID- 24765550 TI - Primary adenomyoepithelioma of the skin - a variant of apocrine mixed tumor? AB - Analogous to adenomyoepitheliomas of the breast, cutaneous adenomyoepithelioma is composed of two components, one being myoepithelial, the other ductal epithelial, and it lies in the spectrum of neoplasms having a "pure" myoepithelioma at one end and a mixed apocrine tumor at the other. We present the case of a 53-year-old woman with a 3 cm nodular lesion on her left forearm that had been present for many years. Histopathologic examination revealed a large lobulated neoplasm surrounded by a compressed fibrous pseudocapsule. Most of the cells that constituted the lesion displayed myoepithelial differentiation arranged in solid sheets, cords, and solitary units. Glandular and ductal structures with features of apocrine differentiation composed the second part of the neoplasm. The myoepithelial cellular component of the neoplasm stained for S100 protein and was negative for cytokeratin and carcinoembryonic antigen (CEA). Based on findings by conventional microscopy and immunohistochemistry, the neoplasm was classified as primary adenomyoepithelioma of the skin. PMID- 24765551 TI - Glomangiosarcoma in the shoulder of a 51-year-old man. AB - Glomangiosarcoma is a very rare type of soft tissue neoplasm. Here we report such a case in the shoulder of a 51-year-old man. PMID- 24765552 TI - Dermatoscopy and Skin Imaging: The section to share your morphological observations and scientific insights. PMID- 24765553 TI - Human papillomavirus-induced periungual pigmented Bowen's disease. PMID- 24765554 TI - Pre-emptive diagnosis of a case of scabies by dermatopathology. PMID- 24765555 TI - Medical dramas - the pros and the cons. PMID- 24765556 TI - The cannabis conundrum. PMID- 24765557 TI - The current status of medical marijuana in the United States. AB - Medical marijuana is currently a controversial issue in medicine. There are strong pro and con opinions but relatively little scientific data on which to base medical decisions. The unfortunate scheduling of marijuana in class I has limited research and only serves to fuel the controversy. This article will review the history of laws to regulate drugs in the United States in the 20th century to provide context for the current status of medical marijuana. It will include the rationale for opposing medical marijuana laws and the problem of the Schedule I inclusion of marijuana as well as other drugs. It will examine the problems associated with smoking raw marijuana and review other routes of administration. Finally, it examines the inadvisability of medicine's promotion of smoked marijuana. PMID- 24765558 TI - Therapeutic benefits of cannabis: a patient survey. AB - Clinical research regarding the therapeutic benefits of cannabis ("marijuana") has been almost non-existent in the United States since cannabis was given Schedule I status in the Controlled Substances Act of 1970. In order to discover the benefits and adverse effects perceived by medical cannabis patients, especially with regards to chronic pain, we hand-delivered surveys to one hundred consecutive patients who were returning for yearly re-certification for medical cannabis use in Hawai'i. The response rate was 94%. Mean and median ages were 49.3 and 51 years respectively. Ninety-seven per cent of respondents used cannabis primarily for chronic pain. Average pain improvement on a 0-10 pain scale was 5.0 (from 7.8 to 2.8), which translates to a 64% relative decrease in average pain. Half of all respondents also noted relief from stress/anxiety, and nearly half (45%) reported relief from insomnia. Most patients (71%) reported no adverse effects, while 6% reported a cough or throat irritation and 5% feared arrest even though medical cannabis is legal in Hawai'i. No serious adverse effects were reported. These results suggest that Cannabis is an extremely safe and effective medication for many chronic pain patients. Cannabis appears to alleviate pain, insomnia, and may be helpful in relieving anxiety. Cannabis has shown extreme promise in the treatment of numerous medical problems and deserves to be released from the current Schedule I federal prohibition against research and prescription. PMID- 24765559 TI - Paraneoplastic syndrome in Hawai'i: a case of dermatomyositis associated with endometrial cancer. AB - Dermatomyositis as a paraneoplastic consequence of gynecological malignancy has rarely been reported in literature and never been reported in Honolulu. This case report describes a local Honolulu resident who was diagnosed with endometrial adenocarcinoma upon presenting with acute dermatomyositis symptoms. PMID- 24765561 TI - Medical school hotline: the Pacific Basin Rehabilitation Research and Training Center at the John A. Burns School of Medicine: thirty years of service to Hawai'i and beyond. PMID- 24765560 TI - Mid-ventricular variant takotsubo cardiomyopathy associated with Cannabinoid Hyperemesis Syndrome: a case report. AB - A case of the mid-ventricular variant of takotsubo cardiomyopathy is reported, occurring in a patient with Cannabinoid Hyperemesis Syndrome (CHS), and presented with a review of the relevant literature. The patient is a 32-year-old woman who presented with epigastric pain, nausea and vomiting. Her EKG showed dynamic T wave changes associated with a modest cardiac biomarker elevation. Ventricular wall motion abnormalities suggestive of the mid-ventricular variant of takotsubo cardiomyopathy were demonstrated by echocardiography, ventriculography and cardiac angiography, the latter showing normal coronary arteries. The patient was a previous marijuana user who had recently ingested marijuana after a period of abstinence. Severe epigastric pain, nausea and cyclic vomiting followed this. She had previously experienced similar gastrointestinal symptoms, relieved by compulsive hot water bathing, and resolving after marijuana cessation. Recent resumption of marijuana use was followed by a recurrence of these symptoms, a pattern characteristic of CHS. The association of cardiomyopathy with CHS has been described only once in the literature, and if this is a true relationship, its mechanism is not clearly defined. Animal models have suggested that endocannabinoid receptors are expressed in the myocardium, which could be a pathway for developing cardiac manifestations with cannabinoid use. PMID- 24765562 TI - Insights in public health: perspectives on pain in the low back and neck: global burden, epidemiology, and management. PMID- 24765564 TI - Internet publicity of data problems in the bioscience literature correlates with enhanced corrective action. AB - Several online forums exist to facilitate open and/or anonymous discussion of the peer-reviewed scientific literature. Data integrity is a common discussion topic, and it is widely assumed that publicity surrounding such matters will accelerate correction of the scientific record. This study aimed to test this assumption by examining a collection of 497 papers for which data integrity had been questioned either in public or in private. As such, the papers were divided into two sub sets: a public set of 274 papers discussed online, and the remainder a private set of 223 papers not publicized. The sources of alleged data problems, as well as criteria for defining problem data, and communication of problems to journals and appropriate institutions, were similar between the sets. The number of laboratory groups represented in each set was also similar (75 in public, 62 in private), as was the number of problem papers per laboratory group (3.65 in public, 3.54 in private). Over a study period of 18 months, public papers were retracted 6.5-fold more, and corrected 7.7-fold more, than those in the private set. Parsing the results by laboratory group, 28 laboratory groups in the public set had papers which received corrective action, versus 6 laboratory groups in the private set. For those laboratory groups in the public set with corrected/retracted papers, the fraction of their papers acted on was 62% of those initially flagged, whereas in the private set this fraction was 27%. Such clustering of actions suggests a pattern in which correction/retraction of one paper from a group correlates with more corrections/retractions from the same group, with this pattern being stronger in the public set. It is therefore concluded that online discussion enhances levels of corrective action in the scientific literature. Nevertheless, anecdotal discussion reveals substantial room for improvement in handling of such matters. PMID- 24765566 TI - Bone microstructure and the evolution of growth patterns in Permo-Triassic therocephalians (Amniota, Therapsida) of South Africa. AB - Therocephalians were a speciose clade of nonmammalian therapsids whose ecological diversity and survivorship of the end-Permian mass extinction offer the potential to investigate the evolution of growth patterns across the clade and their underlying influences on post-extinction body size reductions, or 'Lilliput effects'. We present a phylogenetic survey of limb bone histology and growth patterns in therocephalians from the Middle Permian through Middle Triassic of the Karoo Basin, South Africa. Histologic sections were prepared from 80 limb bones representing 11 genera of therocephalians. Histologic indicators of skeletal growth, including cortical vascularity (%CV) and mean primary osteon diameters (POD), were evaluated in a phylogenetic framework and assessed for correlations with other biologically significant variables (e.g., size and robusticity). Changes in %CV and POD correlated strongly with evolutionary changes in body size (i.e., smaller-bodied descendants tended to have lower %CV than their larger-bodied ancestors across the tree). Bone wall thickness tended to be high in early therocephalians and lower in the gracile-limbed baurioids, but showed no general correlation with cross-sectional area or degree of vascularity (and, thus, growth). Clade-level patterns, however, deviated from previously studied within-lineage patterns. For example, Moschorhinus, one of few therapsid genera to have survived the extinction boundary, demonstrated higher %CV in the Triassic than in the Permian despite its smaller size in the extinction aftermath. Results support a synergistic model of size reductions for Triassic therocephalians, influenced both by within-lineage heterochronic shifts in survivor taxa (as reported in Moschorhinus and the dicynodont Lystrosaurus) and phylogenetically inferred survival of small-bodied taxa that had evolved short growth durations (e.g., baurioids). These findings mirror the multi-causal Lilliput patterns described in marine faunas, but contrast with skeletochronologic studies that suggest slow, prolonged shell secretion over several years in marine benthos. Applications of phylogenetic comparative methods to new histologic data will continue to improve our understanding of the evolutionary dynamics of growth and body size shifts during mass extinctions and recoveries. PMID- 24765565 TI - Leishmania amazonensis promastigotes in 3D Collagen I culture: an in vitro physiological environment for the study of extracellular matrix and host cell interactions. AB - Leishmania amazonensis is the causative agent of American cutaneous leishmaniasis, an important neglected tropical disease. Once Leishmania amazonensis is inoculated into the human host, promastigotes are exposed to the extracellular matrix (ECM) of the dermis. However, little is known about the interaction between the ECM and Leishmania promastigotes. In this study we established L. amazonensis promastigote culture in a three-dimensional (3D) environment mainly composed of Collagen I (COL I). This 3D culture recreates in vitro some aspects of the human host infection site, enabling the study of the interaction mechanisms of L. amazonensis with the host ECM. Promastigotes exhibited "freeze and run" migration in the 3D COL I matrix, which is completely different from the conventional in vitro swimming mode of migration. Moreover, L. amazonensis promastigotes were able to invade, migrate inside, and remodel the 3D COL I matrix. Promastigote trans-matrix invasion and the freeze and run migration mode were also observed when macrophages were present in the matrix. At least two classes of proteases, metallo- and cysteine proteases, are involved in the 3D COL I matrix degradation caused by Leishmania. Treatment with a mixture of protease inhibitors significantly reduced promastigote invasion and migration through this matrix. Together our results demonstrate that L. amazonensis promastigotes release proteases and actively remodel their 3D environment, facilitating their migration. This raises the possibility that promastigotes actively interact with their 3D environment during the search for their cellular "home"-macrophages. Supporting this hypothesis, promastigotes migrated faster than macrophages in a novel 3D co-culture model. PMID- 24765568 TI - A cross-ocean comparison of responses to settlement cues in reef-building corals. AB - Caribbean coral reefs have deteriorated substantially over the past 30 years, which is broadly attributable to the effects of global climate change. In the same time, Indo-Pacific reefs maintain higher coral cover and typically recover rapidly after disturbances. This difference in reef resilience is largely due to much higher coral recruitment rates in the Pacific. We hypothesized that the lack of Caribbean recruitment might be explained by diminishing quality of settlement cues and/or impaired sensitivity of Caribbean coral larvae to those cues, relative to the Pacific. To evaluate this hypothesis, we assembled a collection of bulk samples of reef encrusting communities, mostly consisting of crustose coralline algae (CCA), from various reefs around the world and tested them as settlement cues for several coral species originating from different ocean provinces. Cue samples were meta-barcoded to evaluate their taxonomic diversity. We observed no systematic differences either in cue potency or in strength of larval responses depending on the ocean province, and no preference of coral larvae towards cues from the same ocean. Instead, we detected significant differences in cue preferences among coral species, even for corals originating from the same reef. We conclude that the region-wide disruption of the settlement process is unlikely to be the major cause of Caribbean reef loss. However, due to their high sensitivity to the effects of climate change, shifts in the composition of CCA-associated communities, combined with pronounced differences in cue preferences among coral species, could substantially influence future coral community structure. PMID- 24765567 TI - Can resistant coral-Symbiodinium associations enable coral communities to survive climate change? A study of a site exposed to long-term hot water input. AB - Climate change has led to a decline in the health of corals and coral reefs around the world. Studies have shown that, while some corals can cope with natural and anthropogenic stressors either through resistance mechanisms of coral hosts or through sustainable relationships with Symbiodinium clades or types, many coral species cannot. Here, we show that the corals present in a reef in southern Taiwan, and exposed to long-term elevated seawater temperatures due to the presence of a nuclear power plant outlet (NPP OL), are unique in terms of species and associated Symbiodinium types. At shallow depths (<3 m), eleven coral genera elsewhere in Kenting predominantly found with Symbiodinium types C1 and C3 (stress sensitive) were instead hosting Symbiodinium type D1a (stress tolerant) or a mixture of Symbiodinium type C1/C3/C21a/C15 and Symbiodinium type D1a. Of the 16 coral genera that dominate the local reefs, two that are apparently unable to associate with Symbiodinium type D1a are not present at NPP OL at depths of <3 m. Two other genera present at NPP OL and other locations host a specific type of Symbiodinium type C15. These data imply that coral assemblages may have the capacity to maintain their presence at the generic level against long-term disturbances such as elevated seawater temperatures by acclimatization through successful association with a stress-tolerant Symbiodinium over time. However, at the community level it comes at the cost of some coral genera being lost, suggesting that species unable to associate with a stress-tolerant Symbiodinium are likely to become extinct locally and unfavorable shifts in coral communities are likely to occur under the impact of climate change. PMID- 24765569 TI - Comparison of automated nucleic acid extraction methods for the detection of cytomegalovirus DNA in fluids and tissues. AB - Testing for cytomegalovirus (CMV) DNA is increasingly being used for specimen types other than plasma or whole blood. However, few studies have investigated the performance of different nucleic acid extraction protocols in such specimens. In this study, CMV extraction using the Cell-free 1000 and Pathogen Complex 400 protocols on the QIAsymphony Sample Processing (SP) system were compared using bronchoalveolar lavage fluid (BAL), tissue samples, and urine. The QIAsymphonyAssay Set-up (AS) system was used to assemble reactions using artus CMV PCR reagents and amplification was carried out on the Rotor-Gene Q. Samples from 93 patients previously tested for CMV DNA and negative samples spiked with CMV AD-169 were used to evaluate assay performance. The Pathogen Complex 400 protocol yielded the following results: BAL, sensitivity 100% (33/33), specificity 87% (20/23); tissue, sensitivity 100% (25/25), specificity 100% (20/20); urine, sensitivity 100% (21/21), specificity 100% (20/20). Cell-free 1000 extraction gave comparable results for BAL and tissue, however, for urine, the sensitivity was 86% (18/21) and specimen quantitation was inaccurate. Comparative studies of different extraction protocols and DNA detection methods in body fluids and tissues are needed, as assays optimized for blood or plasma will not necessarily perform well on other specimen types. PMID- 24765570 TI - Evaluation of granular anaerobic ammonium oxidation process for the disposal of pre-treated swine manure. AB - With rising environmental concerns on potable water safety and eutrophication, increased media attention and tighter environmental regulations, managing animal waste in an environmentally responsible and economically feasible way can be a challenge. In this study, the possibility of using granular anammox process for ammonia removal from swine waste treatment water was investigated. A rapid decrease of NO2 (-)-N and NH4 (+)-N was observed during incubation with wastewater from an activated sludge deodorization reactor and anaerobic digestion partial oxidation treatment process treating swine manure and its corresponding control artificial wastewaters. Ammonium removal dropped from 98.0 +/- 0.6% to 66.9 +/- 2.7% and nearly absent when the organic load in the feeding increased from 232 mg COD/L to 1160 mg COD/L and 2320 mg COD/L. The presence of organic carbon had limited effect on nitrite and total nitrogen removal. At a COD to N ratio of 0.9, COD inhibitory organic load threshold concentration was 727 mg COD/L. Mass balance indicated that denitrifiers played an important role in nitrite, nitrate and organic carbon removal. These results demonstrated that anammox system had the potential to effectively treat swine manure that can achieve high nitrogen standards at reduced costs. PMID- 24765571 TI - Sense of presence and anxiety during virtual social interactions between a human and virtual humans. AB - Virtual reality exposure therapy (VRET) has been shown to be effective in treatment of anxiety disorders. Yet, there is lack of research on the extent to which interaction between the individual and virtual humans can be successfully implanted to increase levels of anxiety for therapeutic purposes. This proof-of concept pilot study aimed at examining levels of the sense of presence and anxiety during exposure to virtual environments involving social interaction with virtual humans and using different virtual reality displays. A non-clinical sample of 38 participants was randomly assigned to either a head-mounted display (HMD) with motion tracker and sterescopic view condition or a one-screen projection-based virtual reality display condition. Participants in both conditions engaged in free speech dialogues with virtual humans controlled by research assistants. It was hypothesized that exposure to virtual social interactions will elicit moderate levels of sense of presence and anxiety in both groups. Further it was expected that participants in the HMD condition will report higher scores of sense of presence and anxiety than participants in the one-screen projection-based display condition. Results revealed that in both conditions virtual social interactions were associated with moderate levels of sense of presence and anxiety. Additionally, participants in the HMD condition reported significantly higher levels of presence than those in the one-screen projection-based display condition (p = .001). However, contrary to the expectations neither the average level of anxiety nor the highest level of anxiety during exposure to social virtual environments differed between the groups (p = .97 and p = .75, respectively). The findings suggest that virtual social interactions can be successfully applied in VRET to enhance sense of presence and anxiety. Furthermore, our results indicate that one-screen projection-based displays can successfully activate levels of anxiety in social virtual environments. The outcome can prove helpful in using low-cost projection based virtual reality environments for treating individuals with social phobia. PMID- 24765572 TI - Honey bee sting pain index by body location. AB - The Schmidt Sting Pain Index rates the painfulness of 78 Hymenoptera species, using the honey bee as a reference point. However, the question of how sting painfulness varies depending on body location remains unanswered. This study rated the painfulness of honey bee stings over 25 body locations in one subject (the author). Pain was rated on a 1-10 scale, relative to an internal standard, the forearm. In the single subject, pain ratings were consistent over three repetitions. Sting location was a significant predictor of the pain rating in a linear model (p < 0.0001, DF = 25, 94, F = 27.4). The three least painful locations were the skull, middle toe tip, and upper arm (all scoring a 2.3). The three most painful locations were the nostril, upper lip, and penis shaft (9.0, 8.7, and 7.3, respectively). This study provides an index of how the painfulness of a honey bee sting varies depending on body location. PMID- 24765573 TI - In situ effects of simulated overfishing and eutrophication on settlement of benthic coral reef invertebrates in the Central Red Sea. AB - In the Central Red Sea, healthy coral reefs meet intense coastal development, but data on the effects of related stressors for reef functioning are lacking. This in situ study therefore investigated the independent and combined effects of simulated overfishing through predator/grazer exclusion and simulated eutrophication through fertilizer addition on settlement of reef associated invertebrates on light-exposed and -shaded tiles over 4 months. At the end of the study period invertebrates had almost exclusively colonized shaded tiles. Algae were superior settling competitors on light-exposed tiles. On the shaded tiles, simulated overfishing prevented settlement of hard corals, but significantly increased settlement of polychaetes, while simulated eutrophication only significantly decreased hard coral settlement relative to controls. The combined treatment significantly increased settlement of bryozoans and bivalves compared to controls and individual manipulations, but significantly decreased polychaetes compared to simulated overfishing. These results suggest settlement of polychaetes and hard corals as potential bioindicators for overfishing and eutrophication, respectively, and settlement of bivalves and bryozoans for a combination of both. Therefore, if the investigated stressors are not controlled, phase shifts from dominance by hard corals to that by other invertebrates may occur at shaded reef locations in the Central Red Sea. PMID- 24765574 TI - The evolutionary history and diagnostic utility of the CRISPR-Cas system within Salmonella enterica ssp. enterica. AB - Evolutionary studies of clustered regularly interspaced short palindromic repeats (CRISPRs) and their associated (cas) genes can provide insights into host pathogen co-evolutionary dynamics and the frequency at which different genomic events (e.g., horizontal vs. vertical transmission) occur. Within this study, we used whole genome sequence (WGS) data to determine the evolutionary history and genetic diversity of CRISPR loci and cas genes among a diverse set of 427 Salmonella enterica ssp. enterica isolates representing 64 different serovars. We also evaluated the performance of CRISPR loci for typing when compared to whole genome and multilocus sequence typing (MLST) approaches. We found that there was high diversity in array length within both CRISPR1 (median = 22; min = 3; max = 79) and CRISPR2 (median = 27; min = 2; max = 221). There was also much diversity within serovars (e.g., arrays differed by as many as 50 repeat-spacer units among Salmonella ser. Senftenberg isolates). Interestingly, we found that there are two general cas gene profiles that do not track phylogenetic relationships, which suggests that non-vertical transmission events have occurred frequently throughout the evolutionary history of the sampled isolates. There is also considerable variation among the ranges of pairwise distances estimated within each cas gene, which may be indicative of the strength of natural selection acting on those genes. We developed a novel clustering approach based on CRISPR spacer content, but found that typing based on CRISPRs was less accurate than the MLST-based alternative; typing based on WGS data was the most accurate. Notwithstanding cost and accessibility, we anticipate that draft genome sequencing, due to its greater discriminatory power, will eventually become routine for traceback investigations. PMID- 24765575 TI - The challenge of evaluating pain and a pre-incisional local anesthetic block. AB - Background. Our objective was to test the effectiveness of a local anesthetic line block administered before surgery in reducing postoperative pain scores in dogs undergoing ovariohysterectomy (OVHX). Methods. This study is a prospective, randomized, blinded, clinical trial involving 59 healthy female dogs. An algometric pressure-measuring device was used to determine nociceptive threshold, and compared to three subjective pain scales. Group L/B received a line block of lidocaine (4 mg/kg) and bupivacaine (1 mg/kg) subcutaneously in the area of the incision site and saline subcutaneously as premedication; group L/BM (positive control) received a similar block and morphine (0.5 mg/kg) subcutaneously for premedication; and group SS (negative control) received a saline line block and saline premedication. Criteria for rescue analgesia were defined before the study. Dogs were assessed prior to surgery, at extubation (time 0) and at 2, 4, 6, 8 and 24 h post-recovery. The data were analyzed with one-way ANOVA, and a Split Plot Repeated Measures ANOVA with one grouping factor and one repeat factor (time). P < 0.05 was considered statistically significant. Results. Approximately 33% of dogs required rescue analgesia at some point during the study, with no significant difference between groups. There was no significant difference between treatment groups with any assessment method. Conclusions. As there were no statistically significant differences between positive and negative controls, the outcome of this technique cannot be proven. PMID- 24765576 TI - There and back again: putting the vectorial movement planning hypothesis to a critical test. AB - Based on psychophysical evidence about how learning of visuomotor transformation generalizes, it has been suggested that movements are planned on the basis of movement direction and magnitude, i.e., the vector connecting movement origin and targets. This notion is also known under the term "vectorial planning hypothesis". Previous psychophysical studies, however, have included separate areas of the workspace for training movements and testing the learning. This study eliminates this confounding factor by investigating the transfer of learning from forward to backward movements in a center-out-and-back task, in which the workspace for both movements is completely identical. Visual feedback allowed for learning only during movements towards the target (forward movements) and not while moving back to the origin (backward movements). When subjects learned the visuomotor rotation in forward movements, initial directional errors in backward movements also decreased to some degree. This learning effect in backward movements occurred predominantly when backward movements featured the same movement directions as the ones trained in forward movements (i.e., when opposite targets were presented). This suggests that learning was transferred in a direction specific way, supporting the notion that movement direction is the most prominent parameter used for motor planning. PMID- 24765577 TI - Automated electronic medical record sepsis detection in the emergency department. AB - Background. While often first treated in the emergency department (ED), identification of sepsis is difficult. Electronic medical record (EMR) clinical decision tools offer a novel strategy for identifying patients with sepsis. The objective of this study was to test the accuracy of an EMR-based, automated sepsis identification system. Methods. We tested an EMR-based sepsis identification tool at a major academic, urban ED with 64,000 annual visits. The EMR system collected vital sign and laboratory test information on all ED patients, triggering a "sepsis alert" for those with >=2 SIRS (systemic inflammatory response syndrome) criteria (fever, tachycardia, tachypnea, leukocytosis) plus >=1 major organ dysfunction (SBP <= 90 mm Hg, lactic acid >=2.0 mg/dL). We confirmed the presence of sepsis through manual review of physician, nursing, and laboratory records. We also reviewed a random selection of ED cases that did not trigger a sepsis alert. We evaluated the diagnostic accuracy of the sepsis identification tool. Results. From January 1 through March 31, 2012, there were 795 automated sepsis alerts. We randomly selected 300 cases without a sepsis alert from the same period. The true prevalence of sepsis was 355/795 (44.7%) among alerts and 0/300 (0%) among non-alerts. The positive predictive value of the sepsis alert was 44.7% (95% CI [41.2-48.2%]). Pneumonia and respiratory infections (38%) and urinary tract infection (32.7%) were the most common infections among the 355 patients with true sepsis (true positives). Among false-positive sepsis alerts, the most common medical conditions were gastrointestinal (26.1%), traumatic (25.7%), and cardiovascular (20.0%) conditions. Rates of hospital admission were: true-positive sepsis alert 91.0%, false-positive alert 83.0%, no sepsis alert 5.7%. Conclusions. This ED EMR-based automated sepsis identification system was able to detect cases with sepsis. Automated EMR-based detection may provide a viable strategy for identifying sepsis in the ED. PMID- 24765578 TI - Red deer synchronise their activity with close neighbours. AB - Models of collective animal behaviour frequently make assumptions about the effects of neighbours on the behaviour of focal individuals, but these assumptions are rarely tested. One such set of assumptions is that the switch between active and inactive behaviour seen in herding animals is influenced by the activity of close neighbours, where neighbouring animals show a higher degree of behavioural synchrony than would be expected by chance. We tested this assumption by observing the simultaneous behaviour of paired individuals within a herd of red deer Cervus elaphus. Focal individuals were more synchronised with their two closest neighbours than with the third closest or randomly selected individuals from the herd. Our results suggest that the behaviour of individual deer is influenced by immediate neighbours. Even if we assume that there are no social relationships between individuals, this suggests that the assumptions made in models about the influence of neighbours may be appropriate. PMID- 24765579 TI - Peruvians' sleep duration: analysis of a population-based survey on adolescents and adults. AB - Background. Sleep duration, either short or long, has been associated with diseases such as obesity, type-2 diabetes and cardiovascular diseases. Characterizing the prevalence and patterns of sleep duration at the population level, especially in resource-constrained settings, will provide informative evidence on a potentially modifiable risk factor. The aim of this study was to explore the patterns of sleep duration in the Peruvian adult and adolescent population, together with its socio-demographic profile. Material and Methods. A total of 12,424 subjects, mean age 35.8 years (SD +/-17.7), 50.6% males, were included in the analysis. This is a cross-sectional study, secondary analysis of the Use of Time National Survey conducted in 2010. We used weighted means and proportions to describe sleep duration according to socio-demographic variables (area and region; sex; age; education attainment; asset index; martial and job status). We used Poisson regressions, taking into account the multistage sampling design of the survey, to calculate crude and adjusted prevalence ratios (PR) and 95% confidence intervals (95% CI). Main outcomes were short- (<6 h) and long sleep duration (>= 9 h). Results. On average, Peruvians slept 7.7 h (95% CI [7.4 8.0]) on weekdays and 8.0 h (95% CI [7.8-8.1]) during weekends. The proportions of short- and long-sleep, during weekdays, were 4.3% (95% CI [2.9%-6.3%]) and 22.4% (95% CI [14.9%-32.1%]), respectively. Regarding urban and rural areas, a much higher proportion of short-sleep was observed in the former (92.0% vs. 8.0%); both for weekdays and weekends. On the multivariable analysis, compared to regular-sleepers (>= 6 to <9 h), short-sleepers were twice more likely to be older and to have higher educational status, and 50% more likely to be currently employed. Similarly, relative to regular-sleep, long-sleepers were more likely to have a lower socioeconomic status as per educational attainment. Conclusions. In this nationally representative sample, the sociodemographic profile of short sleep contrasts the long-sleep. These scenarios in Peru, as depicted by sleeping duration, differ from patterns reported in other high-income settings and could serve as the basis to inform and to improve sleep habits in the population. Moreover, it seems important to address the higher frequency of short-sleep duration found in urban versus rural settings. PMID- 24765580 TI - Vertebrate blood cell volume increases with temperature: implications for aerobic activity. AB - Aerobic activity levels increase with body temperature across vertebrates. Differences in these levels, from highly active to sedentary, are reflected in their ecology and behavior. Yet, the changes in the cardiovascular system that allow for greater oxygen supply at higher temperatures, and thus greater aerobic activity, remain unclear. Here we show that the total volume of red blood cells in the body increases exponentially with temperature across vertebrates, after controlling for effects of body size and taxonomy. These changes are accompanied by increases in relative heart mass, an indicator of aerobic activity. The results point to one way vertebrates may increase oxygen supply to meet the demands of greater activity at higher temperatures. PMID- 24765581 TI - Fluvial transport potential of shed and root-bearing dinosaur teeth from the late Jurassic Morrison Formation. AB - Shed dinosaur teeth are commonly collected microvertebrate remains that have been used for interpretations of dinosaur feeding behaviors, paleoecology, and population studies. However, such interpretations may be biased by taphonomic processes such as fluvial sorting influenced by tooth shape: shed teeth, removed from the skull during life, and teeth possessing roots, removed from the skull after death. As such, teeth may behave differently in fluvial systems due to their differences in shape. In order to determine the influence of fluvial processes on the preservation and distribution of shed and root-bearing dinosaur teeth, the hydrodynamic behaviors of high-density urethane resin casts of shed and root-bearing Allosaurus and Camarasaurus teeth were experimentally tested for relative transport distances at increasing flow velocities in an artificial fluviatile environment. Results show that tooth cast specimens exhibited comparable patterns of transport at lower velocities, though the shed Camarasaurus teeth transported considerably farther in medium to higher flow velocities. Two-Way ANOVA tests indicate significant differences in the mean transport distances of tooth casts oriented perpendicular to flow (p < 0.05) with varying tooth morphologies and flow velocities. The differences exhibited in the transportability of shed and root-bearing teeth has important implications for taphonomic reconstructions, as well as future studies on dinosaur population dynamics, paleoecology, and feeding behaviors. PMID- 24765582 TI - Re-examining the relationship between invasive lionfish and native grouper in the Caribbean. AB - Biotic resistance is the idea that native species negatively affect the invasion success of introduced species, but whether this can occur at large spatial scales is poorly understood. Here we re-evaluated the hypothesis that native large bodied grouper and other predators are controlling the abundance of exotic lionfish (Pterois volitans/miles) on Caribbean coral reefs. We assessed the relationship between the biomass of lionfish and native predators at 71 reefs in three biogeographic regions while taking into consideration several cofactors that may affect fish abundance, including among others, proxies for fishing pressure and habitat structural complexity. Our results indicate that the abundance of lionfish, large-bodied grouper and other predators were not negatively related. Lionfish abundance was instead controlled by several physical site characteristics, and possibly by culling. Taken together, our results suggest that managers cannot rely on current native grouper populations to control the lionfish invasion. PMID- 24765583 TI - TMEM65 is a mitochondrial inner-membrane protein. AB - It has been reported that the expression of TMEM65 is regulated by steroid receptor RNA activator (SRA). To date, however, the localization and function of TMEM65 remained unknown. We analyzed the intracellular localization of TMEM65. Immunoblot and immunostaining analysis revealed mitochondrial localization of TMEM65. Alkali extraction analysis and digitonin extraction test using isolated mitochondria revealed that TMEM65 is an integral membrane protein that localizes to the inner-membrane of mitochondria. Analysis using deletion mutants of TMEM65 suggested that the N-terminal region (1-20) of this protein is sufficient for mitochondrial targeting and that this mitochondrial targeting signal (MTS) is cleaved between the amino acid positions 35 and 64, which contain a putative recognition site of matrix processing protease (MPP). Together, these results suggest that TMEM65 is imported into the mitochondria, integrated into mitochondrial inner-membrane, and processed into its mature form by an MPP. PMID- 24765584 TI - Diet and kwashiorkor: a prospective study from rural DR Congo. AB - The etiology of kwashiorkor remains enigmatic and longitudinal studies examining potential causes of kwashiorkor are scarce. Using historical, longitudinal study data from the rural area of Bwamanda, Democratic Republic of Congo, we investigated the potential causal association between diet and the development of kwashiorkor in 5 657 preschool children followed 3-monthly during 15 months. We compared dietary risk factors for kwashiorkor with those of marasmus. Kwashiorkor was diagnosed as pitting oedema of the ankles; marasmus as abnormal visibility of skeletal structures and palpable wasting of the gluteus muscle. A 24-h recall was administered 3-monthly to record the consumption of the 41 locally most frequent food items. We specified Hanley-Miettinen smooth-in-time risk models containing potential causal factors, including food items, special meals prepared for the child, breastfeeding, disease status, nutritional status, birth rank, age, season and number of meals. Bayesian Information Criteria identified the most plausible causal model of why some children developed kwashiorkor. In a descriptive analysis of the diet at the last dietary assessment prior to development of kwashiorkor, the diet of children who developed kwashiorkor was characterized by low consumption of sweet potatoes, papaya and "other vegetables" [0.0% , 2.3% (95% CI [0.4, 12.1]) and 2.3% (95% CI [0.4, 12.1])] in comparison with children who did not develop kwashiorkor [6.8% (95% CI [6.4, 7.2]), 15.5% (95% CI [15, 16.1]) and 15.1% (95% CI [14.6, 15.7])] or children who developed marasmus [4.5% (95% CI [2.6, 7.5]) 11.8% (95% CI [8.5, 16.0]) and 17.6% (95% CI [13.7, 22.5])]. Sweet potatoes and papayas have high beta-carotene content and so may some of "the other vegetables". We found that a risk model containing an age function, length/height-for age Z-score, consumption of sweet potatoes, papaya or other vegetables, duration of this consumption and its interaction term, was the most plausible model. Among children aged 10-42 months, the risk of developing kwashiorkor increased with longer non-consumption of these foods. The analysis was repeated with only children who developed marasmus as the reference series, yielding similar results. Our study supports that beta-carotene may play an important role in the protection against kwashiorkor development. PMID- 24765585 TI - Can head louse repellents really work? Field studies of piperonal 2% spray. AB - Background. Many families find regular checking of children's heads for head louse infestation too onerous and would prefer to be able to prevent infestation by use of a topical application that deters lice from infesting the head. Identification in the laboratory of a repellent activity for piperonal provided the basis for developing a spray product to repel lice. Methods. A proof of principle field study in Dhaka, Bangladesh, compared the effect of using 2% piperonal spray with that of a placebo in 105 children and adults from three communities with infestation levels close to 100%. All participants were treated for infestation and subsequent incidence of reinfestation monitored daily by investigators. A second randomised, controlled, double blind, study in North London, UK, evaluated the effect of the product in normal use. One hundred and sixty-three children from schools with a high level (20-25%) of infestation were treated and confirmed louse free and randomly divided between 2% piperonal, a placebo spray, and a control group for up to 22 weeks. Parents applied the spray and monitored for infestation. Regular investigator visits confirmed the parental monitoring and replenished supplies of spray. Results. In Dhaka, over 18 days there were only 4 infestations in the piperonal group and 8 in the placebo group. This difference was not significant (p = 0.312). In North London, there were 41 cases of infestation over the course of the study. Although there were fewer infestations in the piperonal group, analysis of time to first infestation showed a no significant (p = 0.4368) difference between groups. Conclusion. Routine use of 2% piperonal spray in communities with a high prevalence of head louse infestation may provide some protection from infestation. However, the difference between use of the product and no active intervention was sufficiently small that regular checking for presence of lice is likely to be a more practical and cost effective approach to prevention of infestation. PMID- 24765586 TI - Castration modulates singing patterns and electrophysiological properties of RA projection neurons in adult male zebra finches. AB - Castration can change levels of plasma testosterone. Androgens such as testosterone play an important role in stabilizing birdsong. The robust nucleus of the arcopallium (RA) is an important premotor nucleus critical for singing. In this study, we investigated the effect of castration on singing patterns and electrophysiological properties of projection neurons (PNs) in the RA of adult male zebra finches. Adult male zebra finches were castrated and the changes in bird song assessed. We also recorded the electrophysiological changes from RA PNs using patch clamp recording. We found that the plasma levels of testosterone were significantly decreased, song syllable's entropy was increased and the similarity of motif was decreased after castration. Spontaneous and evoked firing rates, membrane time constants, and membrane capacitance of RA PNs in the castration group were lower than those of the control and the sham groups. Afterhyperpolarization AHP time to peak of spontaneous action potential (AP) was prolonged after castration.These findings suggest that castration decreases song stereotypy and excitability of RA PNs in male zebra finches. PMID- 24765587 TI - Culture of equine fibroblast-like synoviocytes on synthetic tissue scaffolds towards meniscal tissue engineering: a preliminary cell-seeding study. AB - Introduction. Tissue engineering is a new methodology for addressing meniscal injury or loss. Synovium may be an ideal source of cells for in vitro meniscal fibrocartilage formation, however, favorable in vitro culture conditions for synovium must be established in order to achieve this goal. The objective of this study was to determine cellularity, cell distribution, and extracellular matrix (ECM) formation of equine fibroblast-like synoviocytes (FLS) cultured on synthetic scaffolds, for potential application in synovium-based meniscal tissue engineering. Scaffolds included open-cell poly-L-lactic acid (OPLA) sponges and polyglycolic acid (PGA) scaffolds cultured in static and dynamic culture conditions, and PGA scaffolds coated in poly-L-lactic (PLLA) in dynamic culture conditions. Materials and Methods. Equine FLS were seeded on OPLA and PGA scaffolds, and cultured in a static environment or in a rotating bioreactor for 12 days. Equine FLS were also seeded on PGA scaffolds coated in 2% or 4% PLLA and cultured in a rotating bioreactor for 14 and 21 days. Three scaffolds from each group were fixed, sectioned and stained with Masson's Trichrome, Safranin-O, and Hematoxylin and Eosin, and cell numbers and distribution were analyzed using computer image analysis. Three PGA and OPLA scaffolds from each culture condition were also analyzed for extracellular matrix (ECM) production via dimethylmethylene blue (sulfated glycosaminoglycan) assay and hydroxyproline (collagen) assay. PLLA coated PGA scaffolds were analyzed using double stranded DNA quantification as areflection of cellularity and confocal laser microscopy in a fluorescent cell viability assay. Results. The highest cellularity occurred in PGA constructs cultured in a rotating bioreactor, which also had a mean sulfated glycosaminoglycan content of 22.3 ug per scaffold. PGA constructs cultured in static conditions had the lowest cellularity. Cells had difficulty adhering to OPLA and the PLLA coating of PGA scaffolds; cellularity was inversely proportional to the concentration of PLLA used. PLLA coating did not prevent dissolution of the PGA scaffolds. All cell scaffold types and culture conditions produced non-uniform cellular distribution. Discussion/Conclusion. FLS-seeding of PGA scaffolds cultured in a rotating bioreactor resulted in the most optimal cell and matrix characteristics seen in this study. Cells grew only in the pores of the OPLA sponge, and could not adhere to the PLLA coating of PGA scaffold, due to the hydrophobic property of PLA. While PGA culture in a bioreactor produced measureable GAG, no culture technique produced visible collagen. For this reason, and due to the dissolution of PGA scaffolds, the culture conditions and scaffolds described here are not recommended for inducing fibrochondrogenesis in equine FLS for meniscal tissue engineering. PMID- 24765588 TI - The spectacular human nose: an amplifier of individual quality? AB - Amplifiers are signals that improve the perception of underlying differences in quality. They are cost free and advantageous to high quality individuals, but disadvantageous to low quality individuals, as poor quality is easier perceived because of the amplifier. For an amplifier to evolve, the average fitness benefit to the high quality individuals should be higher than the average cost for the low quality individuals. The human nose is, compared to the nose of most other primates, extraordinary large, fragile and easily broken-especially in male-male interactions. May it have evolved as an amplifier among high quality individuals, allowing easy assessment of individual quality and influencing the perception of attractiveness? We tested the latter by manipulating the position of the nose tip or, as a control, the mouth in facial pictures and had the pictures rated for attractiveness. Our results show that facial attractiveness failed to be influenced by mouth manipulations. Yet, facial attractiveness increased when the nose tip was artificially centered according to other facial features. Conversely, attractiveness decreased when the nose tip was displaced away from its central position. Our results suggest that our evaluation of attractiveness is clearly sensitive to the centering of the nose tip, possibly because it affects our perception of the face's symmetry and/or averageness. However, whether such centering is related to individual quality remains unclear. PMID- 24765589 TI - Shoulder pain and concomitant hand oedema among stroke patients with pronounced arm paresis. AB - BACKGROUND: The aim of this prospective study was to identify clinical factors associated with the development of shoulder pain in stroke patients with pronounced arm paresis. METHODS: At stroke onset, 485 patients were initially assessed in 2007-2009. Sixty-three patients with pronounced arm paresis completed the study, and 21 of these developed shoulder pain. Clinical findings were recorded fortnightly by the attending physiotherapist during hospital stay. RESULTS: Hand oedema on the paretic side was more common in patients developing shoulder pain compared with those who did not develop shoulder pain. The onset of shoulder pain was associated with concomitant hand oedema. High NIHSS score was associated with developing shoulder pain. Patients with a history of shoulder pain developed pain earlier than those without previous shoulder pain. Patients with haemorrhagic stroke were significantly more prone to developing shoulder pain. CONCLUSIONS: One-third of the stroke patients with pronounced arm paresis developed shoulder pain. Concomitant hand oedema seems to be an additional symptom of shoulder injury. Patients with low general status are more vulnerable to develop post-stroke shoulder pain. PMID- 24765591 TI - Predictive factors for endoscopic hemostasis in patients with upper gastrointestinal bleeding. PMID- 24765592 TI - When is pre-emptive treatment necessary after endoscopic mucosal resection of early esophageal neoplasm? PMID- 24765590 TI - Metabolic Evidence of Diminished Lipid Oxidation in Women With Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS), a common female endocrinopathy, is a complex metabolic syndrome of enhanced weight gain. The goal of this pilot study was to evaluate metabolic differences between normal (n=10) and PCOS (n=10) women via breath carbon isotope ratio, urinary nitrogen and nuclear magnetic resonance (NMR)-determined serum metabolites. Breath carbon stable isotopes measured by cavity ring down spectroscopy (CRDS) indicated diminished (p<0.030) lipid use as a metabolic substrate during overnight fasting in PCOS compared to normal women. Accompanying urinary analyses showed a trending correlation (p<0.057) between overnight total nitrogen and circulating testosterone in PCOS women, alone. Serum analyzed by NMR spectroscopy following overnight, fast and at 2 h following an oral glucose tolerance test showed that a transient elevation in blood glucose levels decreased circulating levels of lipid, glucose and amino acid metabolic intermediates (acetone, 2-oxocaporate, 2-aminobutyrate, pyruvate, formate, and sarcosine) in PCOS women, whereas the 2 h glucose challenge led to increases in the same intermediates in normal women. These pilot data suggest that PCOS related inflexibility in fasting-related switching between lipid and carbohydrate/protein utilization for carbon metabolism may contribute to enhanced weight gain. PMID- 24765593 TI - Endoscopic diagnosis of ampullary tumors using conventional endoscopic ultrasonography and intraductal ultrasonography in the era of endoscopic papillectomy: advantages and limitations. PMID- 24765595 TI - Sedation regimens for gastrointestinal endoscopy. AB - Sedation allows patients to tolerate unpleasant endoscopic procedures by relieving anxiety, discomfort, or pain. It also reduces a patient's risk of physical injury during endoscopic procedures, while providing the endoscopist with an adequate setting for a detailed examination. Sedation is therefore considered by many endoscopists to be an essential component of gastrointestinal endoscopy. Endoscopic sedation by nonanesthesiologists is a worldwide practice and has been proven effective and safe. Moderate sedation/analgesia is generally accepted as an appropriate target for sedation by nonanesthesiologists. This focused review describes the general principles of endoscopic sedation, the detailed pharmacology of sedatives and analgesics (focused on midazolam, propofol, meperidine, and fentanyl), and the multiple regimens available for use in actual practice. PMID- 24765594 TI - Endoscopist-directed propofol: pros and cons. AB - Concerns about the safety of endoscopist-directed propofol (EDP) have been voiced that propofol should be given only by healthcare professionals trained in the administration of general anesthesia. Here we discuss the safety and drawbacks of EDP for routine endoscopic procedures. Currently, both diagnostic and therapeutic endoscopy are well tolerated and accepted by both patients and endoscopists due to the application of sedation in most clinics worldwide. Accordingly, propofol use is increasing in many countries. It is crucial for endoscopists to be very familiar with the use of propofol or a combination of drugs. However, the controversy regarding the administration of sedation by an endoscopist or an anesthesiologist continues. Until now, there have been no randomized control trials comparing sedation induced by propofol administered by an endoscopist or by an anesthesiologist. It might be difficult to perform this kind of study. For the convenience and safety of sedative endoscopy, it would be important that EDP be generally applied to endoscopic procedures, and for more safety, an anesthesiologist may automatically take care of particular patients at high risk of suffering from propofol side effects. PMID- 24765597 TI - Endoscopic sedation: risk assessment and monitoring. AB - Sedation for endoscopic procedures is done to increase patient comfort and endoscopic performance. Drugs used for sedation suppress respiratory and cardiovascular function, and while the degree of suppression may vary, it may be fatal in certain patients. The aim of this article is to provide an overview and brief summary of presedation risk assessment and monitoring during and after sedation in order to maintain patient safety. PMID- 24765596 TI - Endoscopic sedation: from training to performance. AB - Adequate sedation and analgesia are considered essential requirements to relieve patient discomfort and pain and ultimately to improve the outcomes of modern gastrointestinal endoscopic procedures. The willingness of patients to undergo sedation during endoscopy has increased steadily in recent years and standard sedation practices are needed for both patient safety and successful procedural outcomes. Therefore, regular training and education of healthcare providers is warranted. However, training curricula and guidelines for endoscopic sedation may have conflicts according to varying legal frameworks and/or social security systems of each country, and well-recognized endoscopic sedation training systems are not currently available in all endoscopy units. Although European and American curricula for endoscopic sedation have been extensively developed, general curricula and guidelines for each country and institution are also needed. In this review, an overview of recent curricula and guidelines for training and basic performance of endoscopic sedation is presented based on the current literature. PMID- 24765598 TI - Predictors of esophageal stricture formation post endoscopic mucosal resection. AB - BACKGROUND/AIMS: Stricture formation is a common complication after endoscopic mucosal resection. Predictors of stricture formation have not been well studied. METHODS: We conducted a retrospective, observational, descriptive study by using a prospective endoscopic mucosal resection database in a tertiary referral center. For each patient, we extracted the age, sex, lesion size, use of ablative therapy, and detection of esophageal strictures. The primary outcome was the presence of esophageal stricture at follow-up. Multivariate logistic regression was used to analyze the association between the primary outcome and predictors. RESULTS: Of 136 patients, 27% (n=37) had esophageal strictures. Thirty-two percent (n=44) needed endoscopic dilation to relieve dysphagia (median, 2; range, 1 to 8). Multivariate logistic regression analysis showed that the size of the lesion excised is associated with increased odds of having a stricture (odds ratio, 1.6; 95% confidence interval, 1.1 to 2.3; p=0.01), when controlling for age, sex, and ablative modalities. Similarly, the number of lesions removed in the index procedure was associated with increased odds of developing a stricture (odds ratio, 2.3; 95% confidence interval, 1.3 to 4.2; p=0.007). CONCLUSIONS: Stricture formation after esophageal endoscopic mucosal resection is common. Risk factors for stricture formation include large mucosal resections and the resection of multiple lesions on the initial procedure. PMID- 24765599 TI - Predictive factors for intractability to endoscopic hemostasis in the treatment of bleeding gastroduodenal peptic ulcers in Japanese patients. AB - BACKGROUND/AIMS: Despite improvements in endoscopic hemostasis and pharmacological therapies, upper gastrointestinal (UGI) ulcers repeatedly bleed in 10% to 20% of patients, and those without early endoscopic reintervention or definitive surgery might be at a high risk for mortality. This study aimed to identify the risk factors for intractability to initial endoscopic hemostasis. METHODS: We analyzed intractability among 428 patients who underwent emergency endoscopy for bleeding UGI ulcers within 24 hours of arrival at the hospital. RESULTS: Durable hemostasis was achieved in 354 patients by using initial endoscopic procedures. Sixty-nine patients with Forrest types Ia, Ib, IIa, and IIb at the second-look endoscopy were considered intractable to the initial endoscopic hemostasis. Multivariate analysis indicated that age >=70 years (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.07 to 4.03), shock on admission (OR, 5.26; 95% CI, 2.43 to 11.6), hemoglobin <8.0 mg/dL (OR, 2.80; 95% CI, 1.39 to 5.91), serum albumin <3.3 g/dL (OR, 2.23; 95% CI, 1.07 to 4.89), exposed vessels with a diameter of >=2 mm on the bottom of ulcers (OR, 4.38; 95% CI, 1.25 to 7.01), and Forrest type Ia and Ib (OR, 2.21; 95% CI, 1.33 to 3.00) predicted intractable endoscopic hemostasis. CONCLUSIONS: Various factors contribute to intractable endoscopic hemostasis. Careful observation after endoscopic hemostasis is important for patients at a high risk for incomplete hemostasis. PMID- 24765601 TI - Endoscopic Treatment of Various Gastrointestinal Tract Defects with an Over-the Scope Clip: Case Series from a Tertiary Referral Hospital. AB - Recently, increasingly invasive therapeutic endoscopic procedures and more complex gastrointestinal surgeries such as endoscopic mucosal resection, endoscopic submucosal dissection, and novel laparoscopic approaches have resulted in endoscopists being confronted more frequently with perforations, fistulas, and anastomotic leakages, for which nonsurgical closure is desired. In this article, we present our experiences with the use of over-the-scope clip (OTSC) for natural orifice transluminal endoscopic surgery (NOTES) closure, prevention of perforation, anastomotic leakages, and fistula closures. The OTSC is a valuable device for closing intestinal perforations and fistulas, for NOTES closure, and for the prevention of perforation after the excision of a tumor from the proper muscle layer. Furthermore, it seems to be quite safe to perform, even by endoscopists with little experience of the technique. PMID- 24765600 TI - Endosonographic preoperative evaluation for tumors of the ampulla of vater using endoscopic ultrasonography and intraductal ultrasonography. AB - BACKGROUND/AIMS: In recent years, endoscopic snare papillectomy has been performed to treat tumors of the ampulla of Vater. This procedure requires accurate preoperative evaluation. In this study, we diagnosed the focal extension of such tumors by using endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS), and examined the indications for endoscopic snare papillectomy. METHODS: The subjects were 48 patients with a papillary tumor (13 patients, surgical resection; 35 patients, endoscopic snare papillectomy) who were evaluated preoperatively with EUS and IDUS. The tumor-node-metastasis classification was used for the endosonographic evaluation and pathological diagnosis of these tumors. RESULTS: The diagnostic accuracy of EUS was 97% for diagnosing adenomas and pTis tumors, 73% for pT1 tumors, 50% for pT2 tumors, and 50% for pT3-4 tumors, for an overall accuracy of 85% for T-staging. The diagnostic accuracy of IDUS was 94% for adenomas and pTis tumors, 73% for pT1 tumors, 50% for pT2 tumors, and 100% for pT3-4 tumors, for an overall accuracy of 80% for T-staging. CONCLUSIONS: EUS and IDUS are highly capable of evaluating tumors of the ampulla of Vater preoperatively. However, these techniques are not sufficient for evaluating the focal extension of carcinomas preoperatively. Currently, endoscopic snare papillectomy is adequate for treating adenomas and pTis tumors. PMID- 24765602 TI - Endoscopic removal of a migrated coil after embolization of a splenic pseudoaneurysm: a case report. AB - Splenic artery pseudoaneurysms can be caused by pancreatitis, trauma, or operation. Traditionally, the condition has been managed through surgery; however, nowadays, transcatheter arterial embolization is performed safely and effectively. Nevertheless, several complications of pseudoaneurysm embolization have been reported, including coil migration. Herein, we report a case of migration of the coil into the jejunal lumen after transcatheter arterial embolization of a splenic artery pseudoaneurysm. The migrated coil was successfully removed by performing endoscopic intervention. PMID- 24765603 TI - An unusual case of duodenal perforation caused by a lollipop stick: a case report. AB - Most ingested foreign bodies often pass through the gastrointestinal tract uneventfully; however, complications such as perforation do occur. Most cases of perforation are caused by thin, pointed objects such as needles, toothpicks, or fish and chicken bones. Herein, we report an unusual case of duodenal perforation caused by a lollipop stick with blunt ends. A 23-year-old woman was admitted to the emergency department complaining of epigastric and right upper quadrant pain for the last 2 days. Abdominal computed tomography scans confirmed the presence of a foreign body in the duodenum, with signs of duodenal perforation and inflammation. The patient was not aware of ingesting the foreign body. Endoscopy revealed the presence of a lollipop stick in the duodenum, which was removed with forceps. The duodenal perforation was successfully managed by using hemoclips and a detachable snare. PMID- 24765604 TI - A case of mucosa-associated lymphoid tissue lymphoma of the sigmoid colon presenting as a semipedunculated polyp. AB - Mucosa-associated lymphoid tissue (MALT) lymphomas are characterized by lymphoepithelial lesions pathologically. Colonic MALT lymphomas are relatively rarer than lymphomas of the stomach or small intestine. Endoscopically, colonic MALT lymphoma frequently appears as a nonpedunculated protruding polypoid mass and/or an ulceration in the cecum and/or rectum. We report a unique case of a colonic MALT lymphoma presenting as a semipedunculated polyp. A 54-year-old man was found to have a 2-cm semipedunculated polyp in the sigmoid colon during screening colonoscopy. The polyp was removed by endoscopic mucosal resection. Histologic examination of the resected polyp revealed diffuse epithelial infiltration by discrete aggregates of lymphoma cells. We diagnosed the tumor as low-grade B-cell MALT lymphoma by immunohistochemical staining. PMID- 24765605 TI - A case of malignant granular cell tumor in the sigmoid colon. AB - Granular cell tumor (GCT) is an uncommon, usually benign neoplasm; however, a malignant potential has been described. Malignant GCT is an extremely rare neoplasm showing rapid growth and invasion into adjacent muscles, lymph nodes, or vessels, or even distant metastasis. We recently experienced a case of a histologically benign or atypical but clinically malignant GCT, with invasion of the lymph nodes and vessels in the sigmoid colon, diagnosed by segmental colon resection with lymph node dissection. We also performed a review of relevant medical literature. PMID- 24765606 TI - A case of choledocholithiasis and intestinal malrotation in an adolescent with repaired gastroschisis. AB - Most infants with repaired gastroschisis develop normally and remain in good health. About 10% of patients with gastroschisis have other malformations. We report a case of choledocholithiasis and intestinal malrotation in an adolescent with repaired gastroschisis. A 17-year-old girl presented with fever, jaundice, and abdominal pain. She had undergone an operation to repair gastroschisis at birth. Physical examination revealed icteric sclera, a tight abdominal wall, and a longitudinal surgical scar at the midline. An abdominal computed tomography scan revealed a round calcifying lesion near the pancreas and a midline positioned liver and gallbladder. Absence of the retroperitoneal duodenum and the anterior and left-sided position of the superior mesenteric vein compared with the superior mesenteric artery were observed. Results of abarium examination revealed intestinal malrotation. Endoscopic retrograde cholangiopancreatography revealed diffuse dilatation of the biliary trees and a malpositioned gallbladder. A single stone was removed by using a basket. The clinical symptoms improved after the patient underwent endoscopic retrograde cholangiopancreatography. PMID- 24765607 TI - Frameless stereotactic aspiration for spontaneous intracerebral hemorrhage and subsequent fibrinolysis using urokinase. AB - OBJECTIVES: The optimal management of patients with spontaneous intracerebral hemorrhage (ICH) remains controversial. The aim of this study was to evaluate technical results and clinical outcomes of frameless stereotactic aspiration and fibrinolysis using urokinase performed in a single center. MATERIALS AND METHODS: The subjects of this study were 62 consecutive patients with spontaneous ICH who were treated with frameless stereotactic aspiration and subsequent fibrinolysis using urokinase between February 2009 and June 2010 in our hospital. The surgical results, procedure-related complications, and clinical outcomes were evaluated. RESULTS: A total of 62 patients were enrolled in the study. The median age was 54 years (range, 32-86). The mean initial Glasgow coma scale score was 7.7 (range 5 11). The mean initial hemorrhage volume was 43 cm(3) (range 30-70). Seven patients (11.2%) died of respiratory failure (four patients), postoperative edema (two patients), and heart disease (one patient). There were seven cases of procedure-related complications (11.2%), including malpositioning of catheters (two patients), pneumocephalus (one patient), and rebleeding (four patients, 6.4%). At the three-month follow-up, a good outcome (three-month Glasgow outcome scale > 3) was noted in 32 patients (51.6%). CONCLUSIONS: Frameless stereotactic aspiration and subsequent fibrinolytic thearpy using urokinase for spontaneous ICH is a simple and safe procedure with low mortality and rebleeding rate. PMID- 24765608 TI - Arterial stiffness and functional outcome in acute ischemic stroke. AB - OBJECTIVE: Arterial stiffness is a common change associated with aging and can be evaluated by measuring pulse wave velocity (PWV) between sites in the arterial tree, with the stiffer artery having the higher PWV. Arterial stiffness is associated with the risk of stroke in the general population and of fatal stroke in hypertensive patients. This study is to clarify whether PWV value predicts functional outcome of acute ischemic stroke. METHODS: ONE HUNDRED PATIENTS WERE ENROLLED WITH A DIAGNOSIS OF ACUTE ISCHEMIC STROKE AND CATEGORIZED INTO TWO GROUPS: large-artery atherosclerosis (LAAS) or small vessel disease (SVD) subtype of Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Each group was divided into two sub-groups based on the functional outcome of acute ischemic stroke, indicated by modified Rankin Scale (mRS) at discharge. Poor functional outcome group was defined as a mRS >= 3 at discharge. Student's t-test or Mann-Whitney U-test were used to compare maximal brachial-ankle PWV (baPWV) values. RESULTS: Twenty-four patients whose state was inadequate to assess baPWV or mRS were excluded. There were 38 patients with good functional outcome (mRS < 3) and 38 patients with poor functional outcome (mRS >= 3). The baPWV values were significantly higher in patients with poor outcome (2,070.05 +/- 518.37 cm/s) compared with those with good outcome (1,838.63 +/- 436.65) (p = 0.039). In patients with SVD subtype, there was a significant difference of baPWV values between groups (2,163.18 +/- 412.71 vs. 1,789.80 +/- 421.91, p = 0.022), while there was no significant difference of baPWV among patients with LAAS subtype (2,071.76 +/- 618.42 vs. 1,878.00 +/- 365.35, p = 0.579). CONCLUSIONS: Arterial stiffness indicated by baPWV is associated with the functional outcome of acute ischemic stroke. This finding suggests that measurement of baPWV predicts functional outcome in patients with stroke especially those whose TOAST classification was confirmed as SVD subtype. PMID- 24765609 TI - Endovascular treatment for ruptured distal anterior inferior cerebellar artery aneurysm. AB - A 42-year-old woman presented with Hunt and Hess grade (HHG) III subarachnoid hemorrhage (SAH) caused by a ruptured left distal anterior inferior cerebellar artery (AICA) aneurysm. Computed tomography showed a thin SAH on the cerebellopontine angle cistern, and small vermian intracerebral hemorrhage and intraventricular hemorrhage in the fourth ventricle. Digital subtraction angiography revealed the aneurysm on the postmeatal segment of left distal AICA, a branching point of rostrolateral and caudomedial branch of the left distal AICA. Despite thin caliber, tortuous running course and far distal location, the AICA aneurysm was obliterated successfully with endovascular coils without compromising AICA flow. However, the patient developed left side sensorineural hearing loss postoperatively, in spite of definite patency of distal AICA on the final angiogram. She was discharged home without neurologic sequela except hearing loss and tinnitus. Endovascular treatment of distal AICA aneurysm, beyond the meatal loop, is feasible while preserving the AICA flow. However, because the cochlear hair cell is vulnerable to ischemia, unilateral hearing loss can occur, possibly caused by the temporary occlusion of AICA flow by microcatheter during endovascular treatment. PMID- 24765610 TI - Microsurgical strategies following failed endovascular treatment with the pipeline embolization device: case of a giant posterior cerebral artery aneurysm. AB - Treatment of giant posterior circulation aneurysms, via endovascular or microsurgical approaches, carries a high risk of morbidity and mortality. While flow-diverting stents (FDSs) represent a potent therapy for endovascular reconstruction of complex aneurysms, they are also associated with novel complications for which effective salvage techniques are lacking. We present a unique complication from failed treatment with a FDS. A 51 year-old male presented with increasing headaches secondary to a giant, fusiform aneurysm of the left posterior cerebral artery, which was largely thrombosed. Due to progressive enlargement of the aneurysm corresponding to worsening clinical symptoms, the lesion was treated with two Pipeline embolization devices (ev3, Plymouth, MN, United States). Three months after Pipeline embolization device treatment, complete posterior cerebral artery occlusion was observed at the origin of the proximal stent. Despite the lack of arterial inflow, the aneurysm dome continued to grow, resulting in obstructive hydrocephalus. Therefore microsurgical intervention was undertaken to trap and excise the aneurysm. The patient's postoperative course was complicated by multiple venous infarcts, ultimately resulting in death. Successful microsurgical obliteration of aneurysms previously treated with FDSs is extremely difficult. A combination of judicious preoperative planning and meticulous intraoperative surgical technique are requisite for effective management of these complicated cases. PMID- 24765611 TI - Clipping of incidental aneurysm of middle cerebral artery through small temporal craniotomy and linear skin incision. AB - The authors introduced a new approach for clipping of the incidental aneurysm of the middle cerebral artery (MCA) and reported the clinical results. We retrospectively reviewed 26 patients with 27 incidental MCA aneurysms who were treated from January 2010 to December 2012. All clippings were performed through a small temporal craniotomy and linear skin incision. Follow-up imaging showed complete occlusion of 26 aneurysms (96.3%), residual neck in one (3.7%). In one case, residual neck of the aneurysm did not grow on serial follow up. In one of 26 cases (3.8%), approach-related complication was retraction injury of the temporal cortex. Two patients developed postoperative infarction on the MCA territories due to vasospasm and on the cerebellum due to unknown causes. These were not approach-related complications. Operation time was 95 min-250 min (mean 143 min). There were no complications of temporal muscle atrophy, scar deformity, paresthesia, or pain around the scalp incision and frontalis palsy. This approach offers good surgical possibilities and little approach related morbidity in the clipping of incidental MCA aneurysms. PMID- 24765612 TI - Intravenous Versus Intra-arterial Thrombolysis for Acute Ischemic Stroke Secondary to Basilar Artery Occlusion. PMID- 24765613 TI - High-Risk HPVs and Human Carcinomas in the Syrian Population. AB - Human papillomavirus (HPV) infection is the most common sexually transmitted infection; persistent infection with high-risk types of HPV present a major risk factor for the initiation and progression of a variety of human carcinomas including cervical, colorectal, head, and neck (HN) as well as breast carcinomas. A huge number of studies investigated and reported the incidence of high-risk HPVs in these cancers worldwide particularly in the developed countries; therefore, two HPV prophylactic vaccines against the two most frequent high-risk HPV types (16 and 18) have been developed and used worldwide. However, there are very limited studies about the prevalence of HPVs in the developing countries especially in Africa and some states of the Middle East. In this mini review, we outline the presence of high-risk HPVs in human cervical, colorectal, HN as well as breast cancers in the Syrian population, which was recently explored for the first time by a Canadian/Syrian group. PMID- 24765615 TI - Municipal water quantities and health in Nunavut households: an exploratory case study in Coral Harbour, Nunavut, Canada. AB - BACKGROUND: Access to adequate quantities of water has a protective effect on human health and well-being. Despite this, public health research and interventions are frequently focused solely on water quality, and international standards for domestic water supply minimums are often overlooked or unspecified. This trend is evident in Inuit and other Arctic communities even though numerous transmissible diseases and bacterium infections associated with inadequate domestic water quantities are prevalent. OBJECTIVES: Our objective was to explore the pathways by which the trucked water distribution systems being used in remote northern communities are impacting health at the household level, with consideration given to the underlying social and environmental determinants shaping health in the region. METHODS: Using a qualitative case study design, we conducted 37 interviews (28 residents, 9 key informants) and a review of government water documents to investigate water usage practices and perspectives. These data were thematically analysed to understand potential health risks in Arctic communities and households. RESULTS: Each resident receives an average of 110 litres of municipal water per day. Fifteen of 28 households reported experiencing water shortages at least once per month. Of those 15, most were larger households (5 people or more) with standard sized water storage tanks. Water shortages and service interruptions limit the ability of some households to adhere to public health advice. The households most resilient, or able to cope with domestic water supply shortages, were those capable of retrieving their own drinking water directly from lake and river sources. Residents with extended family and neighbours, whom they can rely on during shortages, were also less vulnerable to municipal water delays. CONCLUSIONS: The relatively low in-home water quantities observed in Coral Harbour, Nunavut, appear adequate for some families. Those living in overcrowded households, however, are accessing water in quantities more typically seen in water insecure developing countries. We recommend several practical interventions and revisions to municipal water supply systems. PMID- 24765614 TI - Control of the immune response by pro-angiogenic factors. AB - The progressive conversion of normal cells into cancer cells is characterized by the acquisition of eight hallmarks. Among these criteria, the capability of the cancer cell to avoid the immune destruction has been noted. Thus, tumors develop mechanisms to become invisible to the immune system, such as the induction of immunosuppressive cells, which are able to inhibit the development of an efficient immune response. Molecules produced in the tumor microenvironment are involved in the occurrence of an immunosuppressive microenvironment. Recently, it has been shown that vascular endothelial growth factor A (VEGF-A) exhibits immunosuppressive properties in addition to its pro-angiogenic activities. VEGF-A can induce the accumulation of immature dendritic cells, myeloid-derived suppressor cells, regulatory T cells, and inhibit the migration of T lymphocytes to the tumor. Other pro-angiogenic factors such as placental growth factor (PlGF) could also participate in tumor-induced immunosuppression, but only few works have been performed on this point. Here, we review the impact of pro-angiogenic factors (especially VEGF-A) on immune cells. Anti-angiogenic molecules, which target VEGF-A/VEGFR axis, have been developed in the last decades and are commonly used to treat cancer patients. These drugs have anti-angiogenic properties but can also counteract the tumor-induced immunosuppression. Based on these immunomodulatory properties, anti-angiogenic molecules could be efficiently associated with immunotherapeutic strategies in preclinical models. These combinations are currently under investigation in cancer patients. PMID- 24765616 TI - Safety of early air travel after treatment of traumatic pneumothorax. PMID- 24765619 TI - Intravenous Ketamine for Refractory Bronchospasm Precipitated by H1N1 Infection. AB - Acute severe bronchospasm is an emergency situation and sometimes these children may fail to respond to conventional treatment and deteriorate rapidly to respiratory failure requiring mechanical ventilation. We present a case of 2-year old girl, who presented with severe bronchospasm resulting in respiratory failure not responding to conventional management including mechanical ventilation and was found to be H1N1 positive. She was treated with ketamine infusion, which led to prompt improvement in airway obstruction. PMID- 24765617 TI - Molecular imaging in heart failure patients. AB - This review focuses on molecular imaging using various radioligands for the tissue characterization of patients with heart failure. 123I-labeled metaiodobenzylguanidine (MIBG), as a marker of adrenergic neuron function, plays an important role in risk stratification in heart failure and may be useful for predicting fatal arrhythmias that may require implantable cardioverter defibrillator treatment. MIBG has also been used for monitoring treatment effects under various medications. Various positron emission tomography (PET) radioligands have been introduced for the quantitative assessment of presynaptic and postsynaptic neuronal function in vivo. 11C-hydroxyephedrine, like MIBG, has potential for assessing the severity of heart failure. Our PET study using the beta-receptor antagonist 11C-CGP 12177 in patients with heart failure showed a reduction of beta-receptor density, indicating downregulation, in most of the patients. More studies are needed to confirm the clinical utility of these molecular imaging modalities for the management of heart failure patients. PMID- 24765618 TI - Peptide receptor radionuclide therapy using radiolabeled somatostatin analogs: focus on future developments. AB - Peptide receptor radionuclide therapy (PRRT) has been shown to be an effective treatment for neuroendocrine tumors (NETs) if curative surgery is not an option. A majority of NETs abundantly express somatostatin receptors. Consequently, following administration of somatostatin (SST) analogs labeled with gamma emitting radionuclides, these tumors can be imaged for diagnosis, staging or follow-up purposes. Furthermore, when beta-emitting radionuclides are used, radiolabeled peptides (radiopeptides) can also be used for the treatment for NET patients. Even though excellent results have been achieved with PRRT, complete responses are still rare, which means that there is room for improvement. In this review, we highlight some of the directions currently under investigation in pilot clinical studies or in preclinical development to achieve this goal. Although randomized clinical trials are still lacking, early studies have shown that tumor response might be improved by application of other radionuclides, such as alpha-emitters or radionuclide combinations, or by adjustment of radiopeptide administration routes. Individualized dosimetry and better insight into tumor and normal organ radiation doses may allow adjustment of the amount of administered activity per cycle or the number of treatment cycles, resulting in more personalized treatment schedules. Other options include the application of novel (radiolabeled) SST analogs with improved tumor uptake and radionuclide retention time, or a combination of PRRT with other systemic therapies, such as chemotherapy or treatment with radio sensitizers. Though promising directions appear to bring improvements of PRRT within reach, additional research (including randomized clinical trials) is needed to achieve such improvements. PMID- 24765620 TI - Social cognitive determinants of dietary behavior change in university employes. AB - Many adults have poor dietary habits and few studies have focused on mechanisms underlying these behaviors. This study examined psychosocial determinants of dietary behavior change in university employes across a 5-month period. Participants completed measures of fruit and vegetable consumption (FVC) and low fat food consumption (LFC) and social cognitive constructs. Multiple regression analyses accounted for a unique proportion of variation in dietary change. Outcome expectations significantly predicted FVC and LFC. Self-efficacy significantly predicted LFC. Goals were not associated with dietary behaviors. Further research into implementation strategies may provide insight into how goals work to bring about change. PMID- 24765622 TI - "I am the best!". PMID- 24765621 TI - Inhibition of Rab5 Activation During Insulin Receptor-Mediated Endocytosis. AB - Activation of receptor tyrosine kinases is a key feature in receptor signaling and membrane trafficking processes. In this study, we found that the insulin receptor tyrosine kinase activity is required for fusion between early endosomes. AG1024, a receptor tyrosine kinase inhibitor, blocked the in vitro endosome fusion in a concentration-dependent manner. We observed that Rab5: wild type partially rescued the fusion reaction, whereas Rab5: Q79L mutant fully rescued it. We also observed that treatment of cells with insulin receptor kinase inhibitor HNMPA-(AM)3 blocked the formation of Rab5-positive endosomes as well as the activation of Rab5 upon addition of insulin in intact cells. HNMPA-(AM)3 inhibitor also affected the endosomal co-localization of Rab5 and insulin receptor. However, the formation of Rab5: Q79L mutant-positive endosomes were not affected by the HNMPA-(AM)3 inhibitor. In addition, HNMPA-(AM)3 inhibitor affected the association of Rin1 to membrane upon insulin stimulation. Furthermore, Rin1 did not fully support endosome fusion in the presence of the AG1024 inhibitor. These results constitute the first evidence that, at least in part, the enzymatic activity of insulin receptor is required for the fusion events via the activation of Rab5. PMID- 24765623 TI - Minimally invasive rehabilitation of a patient with amelogenesis imperfecta. AB - This case report describes a minimally invasive step-by-step approach to treat a patient with amelogenesis imperfecta. This is a genetic developmental disorder of the dental enamel, which clinically manifests as white and dark discolorations of the teeth. The clinical examination did not reveal the true depth of the staining. Therefore, a step-wise treatment approach was chosen. The first step consisted of a home bleaching procedure, which led to a slight improvement of the esthetic appearance, but the stains were still clearly visible. The next step was the application of a microabrasion technique. This led to further improvement, but not to a satisfactory result for this patient who had high esthetic expectations. Thus, the third step was undertaken: it was planned to restore the maxillary incisors and canines with ceramic veneers. The dental technician prepared a wax-up, which served as a basis for a clinical mock-up. After discussing the mock-up and the treatment plan with the patient, crown lengthening was performed on teeth 11 and 23 to improve the pink esthetics. Subsequently, the teeth were prepared in a minimally invasive way and a final impression was taken. Following try-in, the six veneers were inserted with resin cement. PMID- 24765624 TI - Wax-up and mock-up. A guide for anterior periodontal and restorative treatments. AB - When starting a case, having the end result in mind is the basis in any kind of treatment, even more so in those where the anterior teeth morphology, size and proportion will be changed. Here is where a good treatment plan based on a diagnostic wax-up that is tried in with a mock-up and approved by the patient becomes crucial. This case report exemplifies how transferring the information from the diagnostic wax up to the patient's mouth is of help not only to the restorative dentist and the laboratory technician, but also to the surgeon when performing the crown lengthening. This treatment plan cannot be seen as a sequence of isolated procedures but as a single workflow. The wax-up/mock-up binomial is a guide even for the periodontist in a novel approach to surgical crown lengthening. PMID- 24765625 TI - Composite shade guides and color matching. AB - Finding reliable systems that can help the clinician match the color of direct composite restorations is often an issue. After reviewing several composite shade guides available on the market and outlining their main characteristics and limits (unrealistic specimen thickness, not made with the same material the clinician will use, only a few allow to overlap enamel tabs on dentin ones), the authors evaluated the reliability of a system designed to produce self-made standardized "tooth-shaped" shade guide specimens. Small changes in composite enamel thickness may determine huge differences in esthetic outcomes. In conclusion, the results showed that all the specimens demonstrated comparable enamel thickness in all the examined areas (cervical, middle, incisal). PMID- 24765626 TI - Superficial roughness on composite surface, composite-enamel and composite-dentin junctions after different finishing and polishing procedures. Part II: roughness with diamond finishing and differences between enamel composite vs body composite. AB - The following study asks three principle questions relative to composite finishing and composite polishing: 1) Will the superficial roughness of different restoration surfaces have different values, utilizing the same polishing system (multistep), after finishing with the tungsten carbide or diamond bur? 2) Under the same conditions of finishing and polishing sequences, will the composite surfaces (C), the composite-enamel (CE) and composite-dentin (CD) interfaces show different roughness values? 3) Will the surface roughness of composites of different translucency in the various phases of finishing and polishing, and on different interfaces, have different results? The null hypothesis is represented by the fact that there are no significant differences on roughness of composite restorations when polishing, after finishing with tungsten carbide or diamond burs. Furthermore, the null hypothesis is that there are no significant differences on roughness between polishing on composite surface, composite-enamel and composite-dentin interfaces, and finally there are no differences on roughness after finishing and polishing of two composite with different translucency. For the study, 56 class V cavities were prepared on extracted teeth. Restorations were done in nanofilled composite Filtek XTE (3M Espe) in a standard fashion, and then finished and polished. The 28 buccal cavities were restored on the surface with composite enamel and the 28 palatals with composite body. Finishing was done with fine toothing burs in tungsten carbide (16 blades) or fine grit diamond burs (46 MUm), and made by the same manufacturer (Komet). The second phase of finishing was done with burs (with the same form as already mentioned) ultrafine toothing tungsten carbide (30 blades) or with extra and ultrafine grit diamond (25 and 8 MUm). The polishing phase for both of the earlier sequences was done with the application of three rubber tips with decreasing abrasiveness and an application with a self-polishing brush. All measurements were taken from surfaces C, and interfaces CE and CD. Statistical analyses were carried out with c2 test (a = 0.05). CONCLUSIONS: 1) There were no relevant differences of surface roughness on the different surfaces if the polishing was done after finishing with tungsten carbide or diamond burs. 2) Keeping the same sequence of finishing and polishing, a difference was noticed between C, CE and CD, where the latter showed greater roughness. 3) Analyzing the data in all the phases of finishing and polishing on every interface, it can be concluded that the composite enamel and the composite body did not show different levels of superficial roughness. The clinical relevance could be resumed as follows: no difference after polishing, which is preceded by tungsten carbide or diamond finishing burs. The less favorable interface to be polished is CD, compared to CE and C. Considering two composites with different translucency, no difference on roughness after finishing and polishing were detected. PMID- 24765627 TI - Extreme masking: achieving predictable outcomes in challenging situations with lithium disilicate bonded restorations. AB - In contemporary dentistry, we have a vast range of materials to choose from, and metal free restorations have become the premier materials for achieving the ultimate in both esthetics and durability. Metal-free restorations are utilized with more conservative preparations to preserve the vital natural dentition, and have proven to be superior alternatives to traditional porcelain-fused-to-metal (PFM) restorations in many cases. There are always "pros and cons" when selecting materials, and to make the best choice it is essential for dental professionals to plan precisely and understand their options in any clinical situation. Selecting suitable materials and techniques involves consideration of the following factors: - Esthetic zone. - Required strength based on the patient's occlusion/dental habits. - Preparation reduction. - Position of the margin. - Type of restoration/preparation. - The treating clinician's philosophy. - Stump shade. Final shade. One of the most significant challenges in the metal-free dentistry is the reproduction of natural dentition without the influence of a "negative stump" - a very dark or metal core showing through the final restorations. There are many factors to be considered when working on such a case, and controlling the opacity of the coping and crown is the key to success. This article presents a unique "outside of the box" technique that provides consistent, predictable and durable restorations, which provide the best possible esthetic outcome. PMID- 24765628 TI - Change of optical properties of contemporary polychromatic resin composites after light curing and finishing. AB - OBJECTIVES: To compare color and translucency changes after light curing and finishing in various shades of five contemporary resin composites. METHODS: Light and dark (A1 & A4 or equivalents), enamel (e) and dentin (d), shades were selected from the resin composites Enamel Plus HRi (Micerium), Miris 2 (Coltene), IPS Empress Direct (Ivoclar), Filtek Supreme (3M ESPE) and TPH Spectum (Densply). Ten disc-shaped samples (depth = 10 mm, thickness = 1 mm) per material and shade were fabricated. Three colorimetric readings, over white and black background, according to the CIELab system were taken before and after light polymerization and after finishing with wet carbide papers. Color (DeltaE) and translucency (DeltaTP) differences were calculated. Results were analyzed by ANOVA, post-hoc Scheffe's test and linear regression analysis. RESULTS: Polymerization provided a wide range of color change, ranging from 1.36 (Hri/UD1) to 8.07 (Miris/WB). Translucency increased in all groups, except Miris/NT. Translucency change varied from -0.4 (Miris/NT) to 8.88 (Hri/UE3). After finishing, DeltaE ranged from 0.58 (Hri/ UD4) to 3.41 (Miris/NT). DeltaE was significantly positively correlated with DeltaL, Deltab after curing and with DeltaL, Deltaa, DeltaTP after finishing. CONCLUSIONS: Polymerization caused remarkable color and translucency changes, which were product and shade dependent. Thirteen out of 18 of the tested resin composites exhibited clinically perceptible (DeltaE>2.6) color change after light curing and 2 out of 18 after finishing. CLINICAL SIGNIFICANCE: Shade matching with non-polymerized resin composite may be erroneous. PMID- 24765630 TI - Periodontics and periodontal prosthesis - editor's and scientific chairman introduction. PMID- 24765629 TI - Influence of mounthrinse solutions on the color stability and microhardness of a composite resin. AB - OBJECTIVE: The aim of the present study was to evaluate three mouth rinse solutions' (Plax, Listerine and Periogard) influence on the microhardness and color stability of a composite resin (Esthet.X, Dentsply). MATERIALS AND METHODS: For this purpose, forty specimens were prepared, being 10 specimens for each solution and 10 for artificial saliva (control group). Initially, specimens were polished and immersed in artificial saliva and following the initial color, an evaluation was made. For 30 days, specimens were immersed in the solutions three times a day for 1 min. After this cycling period, color change was analyzed and Knoop microhardness measures were carried out. A new color measurement was performed after repolishing the specimens. RESULTS: The microhardness and color stability results showed no statistically significant difference among the studied solutions. However, samples immersed in Periogard showed a significant alteration in the composite resin brightness test. CONCLUSION: It can be concluded that mouth rinse can influence the luminosity of composite resin. PMID- 24765631 TI - Periodontal treatment. PMID- 24765632 TI - Nonsurgical periodontal treatment. AB - The primary goal of nonsurgical periodontal therapy is to control microbial periodontal infection by removing bacterial biofilm, calculus, and toxins from periodontally involved root surfaces. A review of the scientific literature indicates that mechanical nonsurgical periodontal treatment predictably reduces the levels of inflammation and probing pocket depths, increases the clinical attachment level and results in an apical shift of the gingival margin. Another parameter to be considered, in spite of the lack of scientific evidence, is the reduction in the degree of tooth mobility, as clinically experienced. It is important to point out that nonsurgical periodontal treatment presents limitations such as the long-term maintainability of deep periodontal pockets, the risk of disease recurrence, and the skill of the operator. A high number of posttreatment residual pockets exhibiting bleeding on probing and > 5 mm deep are related to lower clinical stability. The successful treatment of plaque-induced periodontitis will restore periodontal health, but with reduced periodontium. In such cases, anatomical damage from previous periodontal disease will persist and inverse architecture of soft tissue may impair home plaque removal. The clinician can select one of the following therapeutic options according to the individual patient's needs: - Quadrant/sextant wise instrumentation (conventional staged debridement, CSD). - Instrumentation of all pockets within a 24-hour period with (full mouth disinfection [FMD]) or without (full mouth scaling and root planing [FMSRP]) local antiseptics. Both procedures can be associated with systemic antimicrobials. -CSD or FMD in combination with laser or photodynamic therapy. Patients with aggressive periodontitis constitute a challenge to the clinician. To date there are no established protocols for controlling the disease. However, data from the literature on the application of the FMD protocol combined with amoxicillin-metronidazole systemic administration are promising. A new classification in supra- and subcrestal nonsurgical periodontal therapy will be proposed. The supracrestal therapy includes the treatment of gingivitis, nonsurgical coverage of recession-type defects, treatment of suprabony defects and papilla reconstruction techniques. Within subcrestal periodontal therapy, it is of paramount importance to preserve both marginal tissues and connective fibers inserted in the root cementum at the apical part of the bony defects. PMID- 24765633 TI - Osseous surgery in periodontal treatment. PMID- 24765634 TI - Periodontal prosthesis: control of key factors from surgery to teeth preparation, occlusion and final cementation. PMID- 24765635 TI - Periodontal prosthesis: control of key factors from surgery to teeth preparation and to final cementation. PMID- 24765636 TI - Discussion: periodontics and periodontal prosthesis. PMID- 24765637 TI - Pseudo-capacitive performance of titanate nanotubes as a supercapacitor electrode. AB - Layered titanate H2Ti3O7 nanotubes were synthesized and firstly used as a supercapacitor electrode in a non-aqueous electrolyte. They exhibited the specific capacitances as high as 414 and 306 F g(-1) at 0.5 and 10 A g(-1), respectively, and 82% of the specific capacitance at the 10th cycle can be retained after 1000 cycles. PMID- 24765638 TI - Synthesis and mechanical response of disordered colloidal micropillars. AB - We present a new approach for studying the uniaxial compressive behavior of colloidal micropillars as a function of the initial defect population, pillar and colloid dimension, and particle-particle interaction. Pillars composed of nanometer scale particles develop cracks during drying, while pillars composed of micron scale particles dry crack-free. We subject the free-standing pillars, with diameters of 580 MUm and 900 MUm, to uniaxial compression experiments using a custom-built micromechanical testing apparatus. In pillars with pre-existing cracks, compression activates the macroscopic defects, leading to fracture and stochastic mechanical response as a result of the flaw distribution. Pillars that dry crack-free fail by shear bands that initiate near the punch face. While macroscopically identical, pillar-to-pillar mechanical response varies significantly. We attribute the disparate response to varying structure and environmental conditions. To isolate the effects of environment, we performed controlled experiments over a range of relative humidity levels (<2% to >98% RH). The level of atmospheric humidity affects particle-particle cohesion and friction, resulting in dramatically different mechanical responses. We discuss the results in the context of underlying particle rearrangements leading to mesoscopic shear localization and examine comparisons with atomic disordered systems such as metallic glasses. PMID- 24765639 TI - Computer modeling of the complexes of Chlorin e6 with amphiphilic polymers. AB - Recently it has been shown that Chlorin e6 (Ce6) when complexed with Pluronics (hydrophilic ethylene and propylene oxide block copolymers) and poly(N vinylpyrrolidone) (PVP) exhibits considerably higher phototoxicity towards tumor cells than free Ce6. The present work aimed to model Ce6 interactions with hydrophilic Pluronic F127 and PVP and find out the nature of intermolecular forces stabilizing these complexes. Modeling included 3 steps: (i) application of molecular dynamics to study polymer folding using AMBER 8 program, (ii) evaluation of partial charges in the Ce6 molecule using different quantum mechanical, semi-empirical and topological approaches and (iii) docking analysis of Ce6 interactions with polymer coils using AUTODOCK 4.2. It was found that the folding in regular polymers does not occur stochastically, but involves the formation of "primary" helical structures, which further combined to form hairpin like "secondary" structures. The latter in turn associated to form coils with minimal solvent accessible hydrophobic area. The Ce6 ring lies flat on the surface of the polymer coil at the interface between hydrophobic and hydrophilic regions. Calculations showed higher affinity of Ce6 for PVP in comparison to Pluronic and revealed marginal contribution of Coulomb forces to the stabilization of both complexes, which are mainly stabilized by van der Waals and hydrogen interactions. PMID- 24765640 TI - Mesosilica materials and organic pollutant adsorption: part B removal from aqueous solution. AB - This tutorial review will focus on the removal of organic pollutants from the aqueous phase by mesoporous silica. After a brief discussion about mesosilica formation (MCM-41 and SBA-15) and silica surface modification, the review will focus on the use of mesosilica for the removal of (i) organic compounds, (ii) organic dyes, or (iii) pharmaceuticals from aqueous solutions. PMID- 24765641 TI - Mesosilica materials and organic pollutant adsorption: part A removal from air. AB - This tutorial review focuses on the application of mesoporous silica materials, primarily MCM-41 and SBA-15, for the removal of organic pollutants in the vapour phase. After briefly providing an introduction into the types of mesosilica covered in this review article the information is presented on a topic by topic basis and covers mesosilica and its interaction with vapour phase organic pollutants under the general subject headings of (i) adsorption isotherms and temperature programme desorption, (ii) dynamic adsorption experiments and (iii) gas separations. PMID- 24765642 TI - Ecological and enzymatic responses to petroleum contamination. AB - The changes in microbial ecology interpreted from taxonomic and functional genes and biological functions represented by urease and dehydrogenase activities were monitored in soil contaminated with different petroleum hydrocarbons including crude oil, diesel, n-hexadecane and poly-aromatic hydrocarbons (PAHs). It was shown that the presence of n-hexadecane stimulated the activity of indigenous microorganisms, especially alkane degrading bacteria, and led to over 20% degradation of n-hexadecane within one month. No obvious degradation of the other three types of petroleum hydrocarbons was observed. The stimulation effect was most marked in the soil spiked with a medium concentration (2500 mg kg(-1) dry soil) of n-hexadecane. However, the presence of PAHs completely inhibited the previously-mentioned bioactivities of the soil. The content of PAH degrading bacteria, however, increased more than 10-fold, indicating the selection effect of PAHs on soil bacteria. The impacts of diesel and crude oil on the microbial ecology and biological functions varied significantly with their concentration. The disclosure of the ecological and enzymatic responses could be helpful in soil bioremediation. PMID- 24765643 TI - Treatment of hypercholesterolemia - a revolution. PMID- 24765644 TI - Menopause issues in Nigeria. PMID- 24765645 TI - Metformin treatment and evolution of endometrial cancer. PMID- 24765646 TI - Exercise, breast size and cancer risk. PMID- 24765647 TI - Painless skull mass in a 70-year-old man. C. Lymphoma. PMID- 24765648 TI - Powerful, multifunctional torsional micromuscles activated by phase transition. AB - Micro bimorph coils driven by a metalinsulator phase transition in VO2 function as powerful torsional muscles. Reversible torsional motion over one million cycles without degradation is demonstrated, with a superior rotational speed up to ca. 200,000 rpm, an amplitude of 500 degrees per mm length, and a power density up to ca. 39 kW kg-1. PMID- 24765649 TI - A polymer optoelectronic interface provides visual cues to a blind retina. AB - A polymer bulk heterojunction structure utilized as an active photosensitive platform to evoke neuronal activity in a blind retina. The features of the elicited action potentials correlate with the optoelectronic properties of the polymer/electrolyte interface, and resembles the natural response of the retina to light. The polymer interface can be used as an optoelectronic epiretinal interface for retinal prosthesis with no requirement for external power sources or connection cables. PMID- 24765650 TI - In vivo and ex vivo evaluation of a multi-particulate composite construct for sustained transbuccal delivery of carbamazepine. AB - Carbamazepine (CBZ) is a leading molecule in the management of epilepsy. Surveys have revealed that a sufficient lack of therapeutically efficient CBZ transbuccal formulation exists. Therefore, this investigation was directed toward designing multiparticulate composite construct (MCC) for the transbuccal delivery of CBZ. The MCC was formulated using interphase, coparticulate-cosolvent homogenization technique, and lyophilization. In vitro, ex vivo, and in vivo investigations were performed. The mesoporous (pore width = 80.1233 A) MCC was mechanically stable (?(D) = 0.0290 J, M(F) = 8.5490 N/mm) and resilient (M(R) = 5.5040%). It demonstrated distinctive controlled release (9.9800%/h), permeation enhancing (10.8730%/h), drug loading (90.0541%), and bioadhesive (omega(adh) = 0.0034 J, F(det) = 1.0751 N) capacities. In vivo studies on pigs showed the ability of the MCC to effectively initiate and regulate transbuccal permeation of CBZ as visualized by outcomes of the quantitative and qualitative assessments of isolated plasma samples. Furthermore, comparisons of in vitro and in vivo data of MCC with a conventional product highlighted its capability to attain higher bioavailability and more controlled release trends. Histological and cytological investigations confirmed that the MCC is biocompatible. The mathematical model produced relevant pharmacokinetics and in vitro/in vivo correlation information. PMID- 24765651 TI - Snapshot quiz 14/5. Cutaneous horn in the natal cleft. PMID- 24765652 TI - Direct and real-time quantification of tenofovir release from ph-sensitive microparticles into simulated biological fluids using (1)h nuclear magnetic resonance. AB - In vitro drug release evaluation is a very important step toward the quality control of nano- or micro-particular drug delivery systems. However, most quantitative techniques such as high-performance liquid chromatography requires a dialysis membrane to separate the released free drug from these delivery systems, thus are not capable of direct detection and real-time quantification of the drug release kinetics. This study describes, for the first time, a rapid, specific, and direct method for the real-time quantification of in vitro tenofovir (TNF) release from pH-sensitive microparticles using a Varian 400 MHz (1)H nuclear magnetic resonance ((1)H-NMR) spectrometer. Various analytical performance parameters such as linearity, precision, accuracy, limit of quantification, limit of detection, and robustness were validated according to International Conference on Harmonization (ICH) guidelines. The in vitro release of TNF from microparticles in both simulated vaginal fluid (VFS) and the mixture of VFS and simulated semen fluid was monitored and quantified in real time using (1)H-NMR. The capability of real-time quantification of in vitro drug release from microparticles not only provides a more accurate prediction of its biological behavior in vivo, but is also independent of potential interference from the dialysis membrane. PMID- 24765653 TI - Snapshot quiz 14/6. Caecal diverticular disease with an associated stricture of the ileocaecal valve. PMID- 24765654 TI - The influence of drug physical state on the dissolution enhancement of solid dispersions prepared via hot-melt extrusion: a case study using olanzapine. AB - In this study, we examine the relationship between the physical structure and dissolution behavior of olanzapine (OLZ) prepared via hot-melt extrusion in three polymers [polyvinylpyrrolidone (PVP) K30, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) 6:4, and Soluplus(r) (SLP)]. In particular, we examine whether full amorphicity is necessary to achieve a favorable dissolution profile. Drug-polymer miscibility was estimated using melting point depression and Hansen solubility parameters. Solid dispersions were characterized using differential scanning calorimetry, X-ray powder diffraction, and scanning electron microscopy. All the polymers were found to be miscible with OLZ in a decreasing order of PVP>PVPVA>SLP. At a lower extrusion temperature (160 degrees C), PVP generated fully amorphous dispersions with OLZ, whereas the formulations with PVPVA and SLP contained 14%-16% crystalline OLZ. Increasing the extrusion temperature to 180 degrees C allowed the preparation of fully amorphous systems with PVPVA and SLP. Despite these differences, the dissolution rates of these preparations were comparable, with PVP showing a lower release rate despite being fully amorphous. These findings suggested that, at least in the particular case of OLZ, the absence of crystalline material may not be critical to the dissolution performance. We suggest alternative key factors determining dissolution, particularly the dissolution behavior of the polymers themselves. PMID- 24765655 TI - The influence of feedstock and process variables on the encapsulation of drug suspensions by spray-drying in fast drying regime: the case of novel antitubercular drug-palladium complex containing polymeric microparticles. AB - The purpose of this study was to address the effect of feedstock properties and process variables on the characteristics of antitubercular drug-palladium (Pd) containing poly(lactic) acid (PLA) microparticles (MP) obtained by spray-drying of noncolloidal particle dispersions in fast drying regime. Two different systems were compared: capreomycin-Pd (C-Pd) and ofloxacin-Pd (Ofx-Pd) dispersions in acetonitrile PLA solution. Particle size, dynamic light scattering, differential scanning calorimetry, SEM-energy dispersive X-ray, and spectrophotometric methods were used for MP characterization. C-Pd-loaded MP were optimized preliminarily by experimental design and compared with Ofx-Pd-loaded MP investigated in our previous work. Morphology of feedstock particles had a dominant role in determining MP morphology. The Charlesworth and Marshall theory was used to explain such behavior. The smaller and homogeneous C-Pd microparticulates favored MP inflation and buckling by forming a thick and nonporous shell. A percolation effect was proposed for the larger and irregular Ofx-Pd particles that produced smaller MP with a more porous shell. Increasing feedstock concentration led to higher particle loss. A tentative descriptive scheme of MP formation according to feedstock particle arrangement was proposed. This work suggested that spray drying of drug dispersions should carefully consider the morphology of feedstock particles as a major parameter influencing final MP properties. PMID- 24765656 TI - Yersinia pestis Ail recruitment of C4b-binding protein leads to factor I mediated inactivation of covalently and noncovalently bound C4b. AB - The outer membrane protein Ail of Yersinia pestis mediates several virulence functions, including serum resistance. Here, we demonstrate that Ail binds C4b binding protein (C4BP), the primary fluid-phase regulator of the classical and lectin pathways. Noncovalent binding of C4 and C4b to Ail was also observed. C4BP bound to Ail can act as a cofactor to the serine protease factor I (fI) in the cleavage of fluid-phase C4b. Employing a panel of C4BP alpha-chain mutants, we observed that the absence of complement control protein domain 6 and 8 reduced binding to Ail. Immunoblot analysis of normal human serum (NHS)-treated bacteria revealed minimal C4b alpha'-chain complexes with bacterial outer membrane targets. Addition of the anti-C4BP monoclonal antibody MK104 to NHS restored C4b alpha' chain target complexes, suggesting that C4b binds covalently to targets on the Y. pestis surface. C4b bound to Ail noncovalently was also cleaved in a C4BP and fI-dependent manner, leaving the C4c fragment bound to Ail. MK104 also prevented the cleavage of noncovalently bound C4b. Collectively, these data suggest that when C4BP is bound to Ail, fI can cleave and inactivate C4b that has bound covalently to bacterial surface structures as well as C4b bound noncovalently to Ail. PMID- 24765657 TI - New era dawns for the South African MRC. PMID- 24765658 TI - Tackling violence against health-care workers. PMID- 24765660 TI - [Not Available]. PMID- 24765661 TI - With the president of the ESP- Prof. Carneiro about the 24th European Congress of Pathology in Prague 2012. PMID- 24765659 TI - Hydrocarbon contamination and plant species determine the phylogenetic and functional diversity of endophytic degrading bacteria. AB - Salt marsh sediments are sinks for various anthropogenic contaminants, giving rise to significant environmental concern. The process of salt marsh plant survival in such environment is very intriguing and at the same time poorly understood. The plant-microbe interactions may play a key role in the process of environment and in planta detoxification.In this study, a combination of culture dependent and culture-independent molecular approaches [enrichment cultures, polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGGE), DNA sequencing] were used to investigate the effect of petroleum hydrocarbons (PH) contamination on the structure and function[polycyclic aromatic hydrocarbon (PAH) dioxygenase genes] of endophytic bacterial communities of salt marsh plant species (Halimione portulacoides and Sarcocornia perennis)in the estuarine system Ria de Aveiro (Portugal). Pseudomonads dominated the cultivable fraction of the endophytic communities in the enrichment cultures. In a set of fifty isolates tested, nine were positive for genes encoding for PAH dioxygenases (nahAc)and four were positive for plasmid carrying genes encoding PAH degradation enzymes(nahAc). Interestingly, these plasmids were only detected in isolates from most severely PH-polluted sites. The results revealed site-specific effects on endophytic communities,related to the level of PH contamination in the sediment, and plant-species-specific 'imprints' in community structure and in genes encoding for PAH dioxygenases. These results suggest a potential ecological role of bacterial plant symbiosis in the process of plant colonization in urban estuarine areas exposed to PH contamination. PMID- 24765662 TI - Genetic differentiation among isolates of Teredinibacter turnerae, a widely occurring intracellular endosymbiont of shipworms. AB - Teredinibacter turnerae is a cultivable intracellular endosymbiont of xylotrophic (woodfeeding)bivalves of the Family Teredinidae (shipworms). Although T. turnerae has been isolated from many shipworm taxa collected in many locations, no systematic effort has been made to explore genetic diversity within this symbiont species across the taxonomic and geographical range of its hosts. The mode of symbiont transmission is unknown. Here, we examine sequence diversity in fragments of six genes (16S rRNA, gyrB, sseA, recA, rpoB and celAB) among 25 isolates of T. turnerae cultured from 13 shipworm species collected in 15 locations in the Atlantic, Pacific and Indian Oceans. While 16S rRNA sequences are nearly invariant between all examined isolates (maximum pairwise difference <0.26%), variation between examined protein-coding loci is greater (mean pairwise difference 2.2-5.9%). Phylogenetic analyses based on each protein-coding locus differentiate the 25 isolates into two distinct and well-supported clades. With five exceptions, clade assignments for each isolate were supported by analysis of alleles of each of the five protein-coding loci. These exceptions include (i) putative recombinant alleles of the celAB and gyrB loci in two isolates (PMS 535T.S.1b.3 and T8510), suggesting homologous recombination between members of the two clades; and (ii) evidence for a putative lateral gene transfer event affecting a second locus (recA) in three isolates (T8412, T8503 and T8513). These results demonstrate that T. turnerae isolates do not represent a homogeneous global population. Instead, they indicate the emergence of two lineages that, although distinct, likely experience some level of genetic exchange with each other and with other bacterial species. PMID- 24765663 TI - Autosomal dominant cerebellar ataxias: a systematic review of clinical features. AB - BACKGROUND AND PURPOSE: To assess, through systematic review, distinctive or common clinical signs of autosomal dominant cerebellar ataxias (ADCAs), also referred to as spinocerebellar ataxias (SCAs) in genetic nomenclature. METHODS: This was a structured search of electronic databases up to September 2012 conducted by two independent reviewers. Publications containing proportions or descriptions of ADCA clinical features written in several languages were selected. Gray literature was included and a back-search was conducted of retrieved publication reference lists. Initial selection was based on title and abstract screening, followed by full-text reading of potentially relevant publications. Clinical findings and demographic data from genetically confirmed patients were extracted. Data were analyzed using the chi-squared test and controlled for alpha-error inflation by applying the Holms step-down procedure. RESULTS: In all, 1062 publications reviewing 12 141 patients (52% male) from 30 SCAs were analyzed. Mean age at onset was 35 +/- 11 years. Onset symptoms in 3945 patients revealed gait ataxia as the most frequent sign (68%), whereas overall non-ataxia symptom frequency was 50%. Some ADCAs often presented non-ataxia symptoms at onset, such as SCA7 (visual impairment), SCA14 (myoclonus) and SCA17 (parkinsonism). Therefore a categorization into two groups was established: pure ataxia and mainly non-ataxia forms. During overall disease course, dysarthria (90%) and saccadic eye movement alterations (69%) were the most prevalent non ataxia findings. Some ADCAs were clinically restricted to cerebellar dysfunction, whilst others presented additional features. CONCLUSIONS: Autosomal dominant cerebellar ataxias encompass a broad spectrum of clinical features with high prevalence of non-ataxia symptoms. Certain features distinguish different genetic subtypes. A new algorithm for ADCA classification at disease onset is proposed. PMID- 24765664 TI - Etanercept-induced sarcoidosis presented with scrotal lesion: a rare manifestation in genital area. PMID- 24765665 TI - [Sex and risk]. PMID- 24765666 TI - Nodular melanoma on the hyponychium: clinical and dermoscopic features. PMID- 24765667 TI - Tumor microenvironment and cellular stress: signaling, metabolism, imaging, and therapeutic targets. Preface. PMID- 24765668 TI - Medical genomics: Gather and use genetic data in health care. PMID- 24765670 TI - A question of trust. PMID- 24765669 TI - A toxic legacy. PMID- 24765671 TI - The effects of presenting delays before and after task completion on self-control responding in children with behavior disorders. AB - We examined relations between self-control responding and environmental variables with 3 children with behavior disorders. Differential delays were presented before or after task completion in a single-session reversal design. Delays presented before task completion produced more impulsive responding than those presented after task completion for all participants. PMID- 24765673 TI - Honorary note: Manuel G. Velarde. PMID- 24765672 TI - Take care. PMID- 24765674 TI - Miniaturization of computer elements. Preface. PMID- 24765675 TI - Banting memorial lecture 2013. A life in balance: wandering the pathways of control. AB - 'To keep in equilibrium', one of the Oxford English Dictionary's many definitions of balance, is a desirable target for anylife, but has special meaning for the life of a person with diabetes. Achieving balance-between hypo- and hyperglycaemia; between energy intake and energy consumption; between insulin action and insulin secretion; between attention to diabetes and attention to everything else-remains challenging, but progress has been made over the last three decades, both in our understanding of how nature achieves balance and in the tools we have to try to reproduce the actions of nature in disease states. In particular, the role of the brain in controlling diabetes, from glucose sensing to decision making, has been investigated. Physiological and neuro-imaging studies are finally being translated into patient benefit, with the aim of improving, as Dr Banting put it, the provision of 'energy for the economic burdens of life'. PMID- 24765676 TI - Deficits in cognitive function and hippocampal plasticity in GM2/GD2 synthase knockout mice. AB - In this study, we used GM2/GD2 synthase knockout (GM2/GD2-/-) mice to examine the influence of deficiency in ganglioside "a-pathway" and "b-pathway" on cognitive performances and hippocampal synaptic plasticity. Eight-week-old GM2/GD2-/- male mice showed a longer escape-latency in Morris water maze test and a shorter latency in step-down inhibitory avoidance task than wild-type (WT) mice. Schaffer collateral-CA1 synapses in the hippocampal slices from GM2/GD2-/- mice showed an increase in the slope of EPSPs with reduced paired-pulse facilitation, indicating an enhancement of their presynaptic glutamate release. In GM2/GD2-/- mice, NMDA receptor (NMDAr)-dependent LTP could not be induced by high-frequency (100-200 Hz) tetanus or theta-burst conditioning stimulation (CS), whereas NMDAr independent LTP was induced by medium-frequency CS (20-50 Hz). The application of mono-sialoganglioside GM1 in the slice from GM2/GD2-/- mice, to specifically recover the a-pathway, prevented the increased presynaptic glutamate release and 20 Hz-LTP induction, whereas it could not rescue the impaired NMDAr-dependent LTP. These findings suggest that b-pathway deficiency impairs cognitive function probably through suppression of NMDAr-dependent LTP, while a-pathway deficiency may facilitate NMDAr-independent LTP through enhancing presynaptic glutamate release. As both of the NMDAr-independent LTP and increased presynaptic glutamate release were sensitive to the blockade of L-type voltage-gated Ca2+ channels (L VGCC), a-pathway deficiency may affect presynaptic L-VGCC. PMID- 24765677 TI - Assessment of the efficacy and potential complications of transjugular liver biopsy in canine cadavers. AB - BACKGROUND: Transjugular liver biopsy (TJLB) is used in humans at risk of bleeding. There are no reports of its use in veterinary medicine. OBJECTIVE: To assess the efficacy and potential complications of TJLB in canine cadavers, and compare with samples obtained via needle liver biopsy (NLB) and surgical liver biopsy (SLB). ANIMALS: Twenty-five medium and large breed canine cadavers. METHODS: Prospective study. TJLBs were procured through the right jugular vein. After biopsy, intravenous contrast and gross inspection were used to assess the biopsy site. Minor and major complications were recorded. NLBs and SLBs were then obtained. Histopathology was performed, and TJLB and NLB were compared for number of complete portal tracts (CPTs), length, and fragmentation. Pathologic process and autolysis were assessed in all samples. RESULTS: All TJLBs yielded liver tissue. The proportion of minor complications was 12/25 (48%), and major complications 16/25 (64%); 13/16 (81%) of the major complications were liver capsule perforation. In 21/25 (84%), the histopathology in the SLB was reflected in the TJLBs. For cases with minimal autolysis, median number of CPTs in TJLBs was 7.5, compared with 4 in NLBs (P = .018). Median length of TJLB specimen was 28 mm compared to 22 mm in NLBs (P = .007). Fragmentation rate was median of 1.25 for TJLB compared to 1.50 in NLBs (P = .11). CONCLUSIONS AND CLINICAL IMPORTANCE: TJLB is technically feasible and achieves comparable results to NLB and SLB. The number of complications, in particular liver capsule perforation, was greater than expected. Further studies are indicated before clinical use is recommended. PMID- 24765678 TI - Relationship among insulin resistance, growth hormone, and insulin-like growth factor I concentrations in diestrous Swedish Elkhounds. AB - BACKGROUND: In the dog, the normal estrous cycle includes a prolonged luteal phase. Progesterone stimulates local canine mammary growth hormone (GH) production, which may act systemically and contribute to insulin resistance. Swedish Elkhounds are predisposed to progesterone-related diabetes mellitus, and the relationship among insulin resistance, GH, and insulin-like growth factor I (IGF-I) is of particular interest. OBJECTIVE: To study insulin resistance in relation to GH and IGF-I in nondiabetic Swedish Elkhounds during diestrus. We also assessed whether alterations in these hormones could predict diestrus-linked diseases and all-cause mortality. ANIMALS: Eighty-four privately owned female intact Swedish Elkhounds >4 years of age. METHODS: Blood sampling and clinical examination during luteal phase, with a follow-up questionnaire after 20 months. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). RESULTS: In multivariable regression analysis, GH was positively associated with HOMA-IR (P = .009). An increase in GH of 1 ng/mL was associated with a 12.7% increase in HOMA-IR. Moreover, C-peptide was positively associated with IGF-I (P = .04), and an increase in C-peptide of 0.1 ng/mL was associated with a 6.9% increase in IGF-I. Structural equation modeling supported these results. Twenty three animals were found to have previously unrecognized mammary masses and had higher GH (P < .0001) and IGF-I (P = .007) than dogs without mammary masses (n = 61). There was no association between high GH and IGF-I concentrations at sampling and future mammary masses. CONCLUSION: We showed that GH was strongly associated with insulin resistance in older Swedish Elkhounds during diestrus. PMID- 24765679 TI - Do ureteric stent extraction strings affect stent-related quality of life or complications after ureteroscopy for urolithiasis: a prospective randomised control trial. AB - OBJECTIVE: To determine whether ureteric stent extraction strings affect stent related quality of life (QoL) or increase complications after ureteroscopy (URS) for stone disease. PATIENTS AND METHODS: In all, 68 patients undergoing URS (October 2011 to May 2013) for stone disease were randomised to receive a ureteric stent with or without an extraction string. Patients completed the Ureteric Stent Symptom Questionnaire (USSQ) on postoperative days 1 and 6, and 6 weeks after stent removal. Pain was assessed at stent removal. Adverse events, including early stent removal, stent migration, retained stent, urinary tract infection (UTI), emergency room (ER) visits and postoperative phone calls were monitored. RESULTS: There was no difference in stent-related QoL as measured by the USSQ between those with and without a stent extraction string, pain at stent removal between those who pulled their stent independently vs those who underwent cystoscopy for stent removal, or in the rate of UTIs, ER visits or phone calls between groups. Five patients (four female, one male) removed their stent early by inadvertently pulling the string; none required replacement. Patients without a string had a significantly longer period with the postoperative ureteric stent (10.6 vs 6.3 days, P < 0.001). One patient without a stent string retained her ureteric stent for 6 months, which was removed by cystoscopy without incident. CONCLUSION: Ureteric stent extraction strings may offer several advantages without increasing stent-related urinary symptoms, complications, or postoperative morbidity. PMID- 24765680 TI - Multicentre prospective crossover study of the 'prostatic urethral lift' for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. AB - OBJECTIVE: To assess the clinical effect of the 'prostatic urethral lift' (PUL) on lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) through a crossover design study. PATIENTS AND METHODS: Men aged >= 50 years with an International Prostate Symptom Score of >= 13, a maximum urinary flow rate (Qmax) of <= 12 mL/s, and a prostate of 30-80 mL were enrolled into a crossover study after completing a prospective, randomised, controlled, 'blinded' pivotal study in which they were control subjects receiving a sham procedure. Patients were followed for 1 year after crossover PUL at 19 centres in the USA, Canada and Australia. The sham procedure involved rigid cystoscopy with simulated active treatment sounds. PUL involved placing permanent UroLift(r) (NeoTract, Inc., Pleasanton, CA, USA) implants into the lateral lobes of the prostate to enlarge the urethral lumen. Urinary symptom relief, health-related quality of life (HRQL) impact, urinary flow parameters, sexual function, and adverse events were assessed and compared between the sham and PUL using paired statistical analysis. RESULTS: Symptom, flow, HRQL and sexual function assessments showed response improvements from baseline results, similar to results from other published studies, and most parameters were markedly improved after PUL vs the sham procedure in the same patients. Symptom, flow, and HRQL improvements were durable over the 12 months of the study. Adverse events associated with the procedure were typically transient and mild to moderate; one patient (2%) required re-intervention with transurethral resection of the prostate in the first year. There were no occurrences of de novo, sustained ejaculatory or erectile dysfunction. CONCLUSION: The PUL can be performed under local anaesthesia, causes minimal associated perioperative complications, allows patients to quickly return to normal activity, provides rapid and durable improvement in symptoms, and preserves sexual function. PMID- 24765682 TI - Genomic variants of a temperature-sensitive mutant of Autographa californica nuclear polyhedrosis virus containing specific reiterations of viral DNA. AB - Restriction endonuclease analysis of DNA from isolates of a temperature-sensitive mutant, ts.8, of Autographa californica nuclear polyhedrosis virus revealed the presence of genomic variants. ts8 type A plaque isolate DNA had altered restriction patterns while ts8 type B plaque isolate DNA restriction patterns were similar to wild-type viral DNA. The alterations in ts8 type A included an extra 1.35 kilobase pair (kbp) EcoRI fragment, and a series of extra Hind111 and XhoI restriction fragments present in decreasing molar ratios with increasing molecular weight.Southern blot and DNA-DNA cross-blot analysis indicated that the ts8A extra restriction fragments were homologous to viral sequences from the 90% region of the genome. The t&A extra restriction fragments appeared to result from an insertion of repeated viral DNA sequence at the EcoRI P-B junction. The higher molecular weight ts8A Hind111 and XhoI submolar fragments appeared to have increasing copy numbers of the 1.35 kbp EcoRI-EcoRI repeat-unit flanked by authentic EcoRI fragment P and B sequences. Approximately 57% of the ts8 plaques isolates analyzed were type A and 43% were type B genomic variants. Although type A and type B genomic variants appeared to be stable in high multiplicity of infection passage experiments, lo-20% of plaque isolates in stock homogeneity experiments converted from one type to another. The genomic alterations did not appear to have any observable effect on the temperature-sensitive phenotype of the mutant. PMID- 24765681 TI - How do they do it: working women meeting physical activity recommendations. AB - OBJECTIVE: To identify factors that facilitate adherence to physical activity among employed women. METHODS: Participants were 103 employed women (Mean 44.4 years +/-11.8). Measures included physical activity by accelerometry, location by global positioning systems, and psychosocial constructs, perception of worksite policies and the built environment by questionnaire. RESULTS: Meeting physical activity recommendations was significantly associated with use of the built environment, self-regulation, perception of higher land-use mix diversity, and perception of lower infrastructure and safety for walking. Perception of worksite policies, self-efficacy, and social support were not associated with meeting recommendations. CONCLUSIONS: The findings provide evidence that working women's physical activity behavior is influenced by both psychosocial and environmental factors. PMID- 24765683 TI - Physicians' role in improving adolescent vaccination rates. PMID- 24765684 TI - New developments in metastatic breast cancer: general discussion. PMID- 24765685 TI - [Shortage of anesthesiologists in university hospitals]. PMID- 24765686 TI - International thalassaemia day and present scenario of thalassaemia in West Bengal. PMID- 24765687 TI - Low use of contraceptives among rural women in Maitha, Uttar Pradesh, India. AB - Low contraceptive utilisation and high fertility in rural Uttar Pradesh (UP), India, is a major concern for the world's second most populous country. The association between reasons for low contraceptive utilisation and maternal factors has been inadequately researched. Data from the 'morbidity and performance assessment' study were analysed to explore reasons for low contraceptive utilisation and their association with maternal factors among 308 women in Maitha, rural UP, India. Chi-square, t-test, ANOVA, and logistic regression analyses were conducted. Majority (84.2%) of the rural women in Maitha, UP, India were not using any contraceptives. Upper caste, literate wives, and wives whose husbands were literate were more likely to use contraceptives. About one-third of the women did not want to use a contraceptive because they wanted another child. Large numbers (65.3%) of women wanted to use contraceptives but were unable to do so due to lack of knowledge (38.9%), fear of side-effects (15.5%), husband/family disapproval (15.5%), inconvenience (10.7%), and other reasons (19.1%). Maternal parity, wives' and husband's literacy were significantly associated with the reasons for low contraceptive utilisation (p < 0.05). Contraceptive utilisation can be Improved by taking into consideration such maternal characteristics. All state subsidised contraceptives should be more widely known, understood and made available. PMID- 24765688 TI - Clinicodiagnostic features of tuberculous meningitis and the role of CSF PCR in early diagnosis: a study from north-west India. AB - The objective of this study was to study the clinical features and laboratory profile including acid fast bacillus microscopy, cerebrospinal fluid (CSF) culture and M. tuberculosis polymerase chain reaction (PCR) for an early diagnosis of tuberculous meningitis. Fifty consecutive patients, fulfilling the clinical criteria of tuberculous meningitis, were included in the study. All patients were subjected to detailed clinical and laboratory evaluation and radiological tests. CSF acid fast bacillus microscopy, culture and PCR were carried out in all and results were analysed. Majority of the patients presented with fever, headache, vomiting and signs of meningeal Irritation. Ziehl-Neelsen staining for acid-fast bacillus was positive in 4% cases, culture in 18% cases and CSF PCR for Mycobacterium tuberculosis was positive in 68%. Miliary pattern on chest x-ray was seen in 16% and CNS tuberculomas were seen in 14% cases. The CSF PCR estimation in clinically suspected cases of tuberculous meningitis may be an extremely valuable test for early diagnosis and institution of specific therapy. PMID- 24765689 TI - Study of lymph node lesions with fine needle aspiration cytology and histopathology along with immunohistochemistry. AB - Lymphadenopathy is one of the commonest clinical presentations of the patients attending hospital outdoor. Aetiology varies from Inflammatory process to malignant conditions. Fine needle aspiration cytology has become an integral part of the initial diagnosis. Histology remains the gold standard. But there exists some gray zones both in cytology and histology where immunohistochemistry plays a major role for final diagnosis. In this study, an attempt has been made to evaluate the importance of immunohistochemistry in this field. Fifty cases were studied. Clinical history was noted and examination done. All cases were examined both cytologically and histologically. Immunocytochemistry was done in all the cases by monoclonal antibody against p53 and Ki67. The results were tabulated and analysed according to unpaired 't' test. Reactive hyperplasia was present in maximum number followed by tuberculosis, non-Hodgkin's lymphoma and Hodgkin's lymphoma. All of these lesions showed statistically significant difference in p53 and Ki67 expression both in cytology and in histology. To conclude, fine needle aspiration cytology is an adjuvant to histology for early diagnosis and immunohistochemistry can help us in the gray zones. PMID- 24765690 TI - Establishment of social club for adolescents living in urban slums: a potential tool to impart HIV/AIDS education. AB - An interventional study was carried out under a Government of Madhya Pradesh, India supported project with aims to describe establishment of a social club (a youth club), incorporating strategy of life-skill-based education and its potential as a tool for creating HIV/AIDS awareness among adolescents of age 15 19 years living in slums of Ujjain city. The social club activities included AIDS education by combined methods, vocational training and recreational activities for the adolescents. Establishment of social club was feasible with available local resources. Social club activities were need based, thus received good response from adolescents (94% had attendance above 75% in AIDS awareness sessions). Knowledge and attitude improved and misconceptions reduced significantly by AIDS education. Majority (86%) of the participants contributed as AIDS messengers in the community. The social clubs seem to have potential to improve HIV/AIDS awareness and empower adolescents to adopt healthy lifestyle through combination of teen friendly activities and atmosphere. PMID- 24765691 TI - Insulin resistance and hypothyroidism: a complex relationship in non-alcoholic fatty liver disease. AB - An association of non-alcoholic fatty liver disease with insulin resistant metabolic syndrome and hypothyroidism has been suggested. Aim of the present study was to explore the above association and also to establish the correlation between hypothyroidism and insulin resistance in patients with nonalcoholic fatty liver disease. Study group comprised 40 cases of non-alcoholic fatty liver disease and 30 healthy controls. Serum samples were analysed for fasting glucose, insulin, lipid profile and thyroid hormones. Insulin resistance was assessed by homeostatic model of assessment calculation. Nonalcoholic fatty liver disease patients demonstrated significantly higher insulin resistance, TSH values and significantly lower FT4 values as compared to controls, which illustrates the prevalence of insulin resistance and hypothyroidism in patients. A significant positive correlation between TSH and Insulin resistance (r = 0.87, p < 0.001) and a significant negative correlation between FT4 and insulin resistance (r = -0.14, p < 0.001) were established in the cases. Moreover TSH was significantly related to low density lipoprotein cholesterol, independent of insulin resistance. There have been some doubts over the clinical correlation between insulin resistance and hypothyroidism to delineate increased risk of cardiovascular disease. So earlier detection and treatment of risk factors may have a significant impact on progression of non-alcoholic fatty liver disease. PMID- 24765692 TI - Sociodemographic profile of breast cancer patients diagnosed by FNAC. AB - The study included 431 patients who underwent breast FNAC over a period of five years between 2003 and 2008. The required clinical details were obtained from the requisition forms. The Information about the level of education and occupation were collected by interviewing the subjects. The number of cases of breast carcinoma was significant constituting 14.84% (n = 64). The study showed that the peak age for breast carcinoma was between 41 and 50 years. This correlates with the national figure where most of the cases observed belonged to the reproductive age group. Most of the females were married (93.75%) and were multiparous (92.18%). Maximum number of patients had only received primary education. There was not much difference in the number regarding whether they lived in urban or rural areas. Middle and lower socioeconomic class contributed the bulk of the cases and it were the housewives who were in majority (85.93%). PMID- 24765693 TI - Maternal and neonatal outcomes in gestational diabetes mellitus. AB - To describe maternal complications and neonatal outcomes caused by gestational diabetes mellitus a descriptive observational study was conducted in the department of obstetrics and gynaecology at Ramakrishna Mission Seva Pratisthan and Vivekananda Institute of Medical Sciences, Kolkata, over a period of one year from July 2009 to June 2010. Women diagnosed by oral glucose tolerance test as gestational diabetes mellitus were enrolled as study subjects and were followed regularly at outpatient department. Blood glucose levels controlled by diet or with insulin. Foetal well-being was assessed by ultrasonography, foetal kick count and cardiotocography. Time and mode of delivery were decided on admission depending upon the complications encountered. Intrapartum blood glucose level was monitored and foetal monitoring was done. After delivery all the babies were assessed by the paediatrician. After discharge patients were advised oral glucose tolerance test at 6 weeks postpartum. Out of 644 women delivered, 58 (9%) were diagnosed gestational diabetes mellitus and were studied. Mean age was 30 years and 55.2% were multigravida; 50% were obese (BMI > or = 30 kg/m2); 60.3% required insulin therapy to achieve glycaemic control. Most common maternal and neonatal complications observed were premature prelabour rupture of membrane (10.3%) and jaundice (29.3%) respectively. Caesarean section was done in 60.3% gestational diabetas mellitus mothers. A total of 57 babies (98.2%) were delivered alive. PMID- 24765694 TI - Diagnosis of pulmonary tuberculosis: recent advances. AB - India continues to have the highest number of TB cases in the world, and over 2 million cases are reported in India every year. The private sector in India is an important source of TB care with over 50% of TB patients seeking TB treatment in the private health sector. Early and accurate diagnosis is the first critical step in controlling TB. All persons with cough lasting two weeks or more, or with unexplained chronic fever and/or weight loss should be evaluated for TB. For pulmonary TB, Sputum is the most critical sample for laboratory testing. Although blood is a popular sample in the Indian private sector, there is no accepted, valid blood test for pulmonary TB. There are three accepted, validated sputum tests for active TB: Sputum smear microscopy for acid-fast bacilli; molecular or nucleic acid amplification test (NAAT); and culture. Chest radiography is useful but is not specific for the diagnosis of pulmonary TB. Therefore, chest radiography cannot provide a conclusive diagnosis on its own, and needs to be followed by sputum testing. If sputum smears and NAATs are negative, and TB is still suspected, cultures are the most sensitive tests available for TB. Culture is therefore very useful in diagnosing smear-negative TB; and drug-resistant TB. Blood-based antibody tests (eg, IgG/IgM tests) and Interferon-gamma release assays (eg, TB Gold) are not accurate and should not be used for pulmonary TB diagnosis. In fact, use of serodiagnostic tests for TB is banned by the Government of India. PMID- 24765695 TI - Role of viscosupplementation in osteo-arthritis of knee joint. AB - Osteo-arthritis is the chronic degenerative disease associated with joint pain and loss of joint function. It is caused by 'wear and tear' on a joint. Knee is the most commonly Involved joint. Disease is so crippling that patient is unable to walk independently from bed to bathroom. The major causes of osteo-arthritis are age, gender, obesity, medical condition and hereditary. The signs and symptoms of osteo-arthritis are pain, joint stiffness, joint swelling, and loss of function. No blood tests are helpful in diagnosing osteo-arthritis. Management of osteo-arthritis includes non-pharmacological, pharmacological and surgical. A relatively new procedure is viscosupplementation, in which a preparation of hyaluronic acid is injected into the knee joint. Hyaluronic acid is a naturally occurring substance found in the synovial fluid. It acts as a lubricant to enable bones to move smoothly over each other and a shock absorber for joint loads. The decrease in the elastic and viscous properties of synovial fluid in osteo arthritis results from both a reduced molecular size and a reduced concentration of hyaluronic acid in the synovial fluid. Viscosupplementation may be a therapeutic option for individuals with osteo-arthritis of the knee. Viscosupplementation has been shown to relieve pain in many patients who cannot get relief from non-medicinal measures or analgesic drugs. This article is to know the mechanism of action, patients' selection criteria, rationale and efficacy of viscosupplimentation in the management of osteo-arthritis of knee. PMID- 24765696 TI - Auto-immune hepatitis following delivery. AB - Auto-immune hepatitis first presenting in the early postpartum period is rare. Immunosuppressive effects of pregnancy result in delayed manifestation of auto immune hepatitis, and in established cases, the spontaneous improvements are there. Auto-immune hepatitis should be considered in the differential diagnosis of liver dysfunction first presenting in the early postpartum period. A case of postpartum hepatitis of auto-immune aetiology is being presented here. It is disease of unknown aetiology, characterised by inflammation of liver (as evidenced by raised serum transaminases, presence of interface hepatitis on histological examination), hypergammaglobulinaemia (> 1.5 times normal), presence of auto-antibodies [(antinuclear antibodies (ANA)], smooth muscle antibody (SMA) and antibody to liver-kidney microsome type 1 (LKM1) in the absence of viral markers ie, hepatitis B (HBsAg) and C (AntiHCV) and excellent response to corticosteroid therapy. PMID- 24765697 TI - Acute primary angle closure in a patient with high myopia: a case report. AB - Primary angle closure in a high myopic patient is rare. Here is presented a report of one such patient who presented with acute primary angle closure in one eye. Conservative management followed by laser iridotomy was effective in the treatment of this patient. PMID- 24765698 TI - An unexpected oesophageal web in a case of suspected tracheo-oesophageal fistula in a premature neonate posted for diagnostic broncho-oesophagoscopy. AB - Oesophageal webs are thin (2-3mm) membranes of normal oesophageal tissue consisting of mucosa and submucosa. They can be congenital or acquired. Congenital oesophageal webs are very rare and usually present in adulthood. This report describes an unusual presentation of congenital web in lower oesophagus in a premature neonate with respiratory distress who was posted for diagnostic bronchoscopy and oesophagoscopy under general anaesthesia to rule out tracheo oesophageal fistula or tracheomalacia. Endoscopic dilatation of the web was done and the baby improved after the procedure. PMID- 24765699 TI - Thalassaemia intermedia presenting with compressive myelopathy: a case report. AB - Extramedullary haematopoiesis leading to spinal cord compression is a rare complication of thalassaemia. An interesting case has been reported where a diagnosis of thalassaemia intermedia was made at the age of 35 years in a male patient with no history of blood transfusion, who presented with compressive myelopathy caused by extramedullary haematopoietic tissue in epidural space. The patient recovered after surgical decompression. PMID- 24765700 TI - Hepatopleuropulmonary amoebiasis--a case report. AB - Amoebiasis is a food-borne protozoan infection, caused by Entamoeba histolytica. Here a case of hepatopleuropulmonary amoebiasis, which was detected after fibre optic bronchoscopy is reported. Bronchial aspirate showed trophozoites of Entamoeba histolytica. The patient was treated with tinidazole and responded favourably. PMID- 24765701 TI - Migration of subclavian venous catheter. PMID- 24765703 TI - Why doctors have become the soft targets! PMID- 24765702 TI - Synchronous double primary malignancy: intracystic papillary carcinoma male breast and adenocarcinoma stomach. PMID- 24765704 TI - A randomised study to evaluate the efficacy and safety of placentrex injection in patients suffering from pelvic inflammatory disease. AB - To evaluate the efficacy of placentrex injection along with oral doxycycline against oral doxycycline in pelvic inflammatory diseases, a comparative study was undertaken among two groups of patients comprising 60 in each at Pt BD Sharma Postgraduate Institute of Medical Sciences, Rohtak during the period April 2010 to April 2012. It was observed remission of symptoms and signs was better noticed among the group of patients receiving placentrex + doxycycline than those getting only doxycycline. Placentrex is safe with less side-effects and inexpensive. PMID- 24765705 TI - Validity of the Italian version of the Severity of Dependence Scale (SDS) for nicotine dependence in smokers intending to quit. AB - The objective was to test the psychometric properties of an Italian version of the Severity of Dependence Scale, a five-item measure designed to assess the compulsive dimension of drug dependence. 635 smokers enrolled in a tobacco dependence treatment program served as the participants. The Fagerstrom Test for Nicotine Dependence was used as a comparative measure. Dimensionality of the Severity of Dependence Scale and the Fagerstrom Test for Nicotine Dependence was assessed by factor analysis. Prediction of smoking at one year was evaluated by logistic regression. Factor analysis yielded a two-factor solution; however, the second factor explained very little variance. Factor 1 had a Cronbach's alpha of .66 (overall Scale coefficient = .44). The total Severity of Dependence Score predicted smoking at one year (OR = 1.10). PMID- 24765706 TI - Emotion regulation in male abstinent heroin abusers. AB - The present study examined 25 male prisoners with a history of heroin dependency (M = 35.3 yr., SD = 8.5, range = 21-48) and 25 male prisoners with no history of substance abuse (M = 31.5 yr., SD = 9.8, range = 19-47) who were selected to complete the Emotion Regulation Questionnaire. Results showed that the group with a history of heroin dependency used a cognitive reappraisal strategy less frequently than controls and that there was no difference in the use of expression suppression strategies between the two groups. It was concluded that the negative impact of heroin abuse on an individual's emotion regulation is primarily reflected in the cognitive reappraisal dimension. PMID- 24765707 TI - Voluntary smoking bans at home and in the car and smoking cessation, obesity, and self-control. AB - This study of female former and current smokers assessed the associations between voluntary smoking bans at home and in the car and smoking cessation, obesity, and self-control. Data from self-reported female smokers (N = 194) who were in a community-based random cohort at four points in time, from 1983 to 2009, were analyzed. These female participants (M age = 63.7 yr.) were given self administered questionnaires. Analyses showed that complete smoking bans at home and in the car were positively associated with a greater likelihood of smoking cessation. Complete smoking bans at home and in the car were positively associated with greater self-control. Public health policies should focus on the positive health effects of smoking bans on smoking cessation and greater self control. PMID- 24765708 TI - Transformational leadership in the consumer service workgroup: competing models of job satisfaction, change commitment, and cooperative conflict resolution. AB - This paper discusses the effects of transformational leadership on cooperative conflict resolution (management) by evaluating several alternative models related to the mediating role of job satisfaction and change commitment. Samples of data from customer service personnel in Taiwan were analyzed. Based on the bootstrap sample technique, an empirical study was carried out to yield the best fitting model. The procedure of hierarchical nested model analysis was used, incorporating the methods of bootstrapping mediation, PRODCLIN2, and structural equation modeling (SEM) comparison. The analysis suggests that leadership that promotes integration (change commitment) and provides inspiration and motivation (job satisfaction), in the proper order, creates the means for cooperative conflict resolution. PMID- 24765709 TI - Effects of anger and sadness on attentional patterns in decision making: an eye tracking study. AB - Past research examining the effect of anger and sadness on decision making has associated anger with a relatively more heuristic decision-making approach. However, it is unclear whether angry and sad individuals differ while attending to decision-relevant information. An eye-tracking experiment (N=87) was conducted to examine the role of attention in links between emotion and decision making. Angry individuals looked more and earlier toward heuristic cues while making decisions, whereas sad individuals did not show such bias. Implications for designing persuasive messages and studying motivated visual processing were discussed. PMID- 24765710 TI - Teacher self-efficacy and perceived autonomy: relations with teacher engagement, job satisfaction, and emotional exhaustion. AB - When studied separately, research shows that both teacher self-efficacy and teacher autonomy are associated with adaptive motivational and emotional outcomes. This study tested whether teacher self-efficacy and teacher autonomy are independently associated with engagement, job satisfaction, and emotional exhaustion. 2,569 Norwegian teachers in elementary school and middle school (719 men, 1,850 women; M age = 45.0 yr., SD = 11.5) were administered the Norwegian Teacher Self-Efficacy Scale, the Teacher Autonomy Scale, the Utrecht Work Engagement Scale, the Teacher Job Satisfaction Scale, and the Maslach Burnout Inventory. The analysis revealed that both teacher autonomy and self-efficacy were independent predictors of engagement, job satisfaction, and emotional exhaustion. This study suggests that autonomy or decision latitude works positively but through different processes for teachers with high and low mastery expectations. PMID- 24765711 TI - Discriminant and criterion-related validity of a relative deprivation scale in a merger and acquisition context. AB - This study examined the discriminant and criterion-related validity of the Relative Deprivation Scale. The data were collected from 151 Korean employees who had recently experienced a merger and acquisition. The results of confirmatory factor analysis revealed that the two dimensions of relative deprivation (egoistic and fraternal relative deprivation) are clearly distinguishable from other conceptually related variables, such as negative affectivity, resistance to change, overall job dissatisfaction, and distributive justice. In addition, egoistic relative deprivation made a unique incremental contribution to explaining employee turnover intention beyond the contribution of conceptually related variables, while fraternal relative deprivation did not. PMID- 24765712 TI - Reliability of Autism-Tics, AD/HD, and other Comorbidities (A-TAC) inventory in a test-retest design. AB - The Autism-Tics, AD/HD, and other Comorbidities (A-TAC) inventory is used in epidemiological research to assess neurodevelopmental problems and coexisting conditions. Although the A-TAC has been applied in various populations, data on retest reliability are limited. The objective of the present study was to present additional reliability data. The A-TAC was administered by lay assessors and was completed on two occasions by parents of 400 individual twins, with an average interval of 70 days between test sessions. Intra- and inter-rater reliability were analysed with intraclass correlations and Cohen's kappa. A-TAC showed excellent test-retest intraclass correlations for both autism spectrum disorder and attention deficit hyperactivity disorder (each at .84). Most modules in the A TAC had intra- and inter-rater reliability intraclass correlation coefficients of > or = .60. Cohen's kappa indi- cated acceptable reliability. The current study provides statistical evidence that the A-TAC yields good test-retest reliability in a population-based cohort of children. PMID- 24765713 TI - Effects of the common scale setting in the assessment of differential item functioning. AB - This study compares three methods of detecting differentialitem functioning (DIF), the equal mean difficulty (EMD), all-other-item (AOI), and constant item (CI) methods, in terms of estimation bias and rank order change of ability estimates using a series of simulations and two empirical examples. The CI method generated accurate DIF parameter estimates, whereas the EMD and AOI methods produced biased estimates. Moreover, as the percentage of DIF items in a test increased, the superiority of the CI method over the EMD and AOI methods became more apparent. The superiority of the CI method is independent of the sample size, test length, and item type (dichotomous or polytomous). Two empirical examples, a mathematics test and a hostility questionnaire, demonstrated that these three methods yielded inconsistent DIF detections and produced different ability estimate rankings. PMID- 24765714 TI - Psychometric properties of the feedback orientation scale among South African salespersons. AB - Feedback to employees is an important management tool, and the literature demonstrates that it has a positive effect on learning, motivation, and job performance. This study investigates in a non-U.S. context the psychometric properties of the Feedback Orientation Scale. Data were gathered from a sample of 202 salespersons from a large South African firm within the industrial fuels and lubricants sector. Confirmatory Factor Analysis provided evidence for the intended dimensionality, reliability, and convergent and discriminant validity of the scale. PMID- 24765715 TI - Perceptual frames in frequency estimation. AB - This study is an introductory investigation of cognitive frames, focused on perceptual frames divided into information and formal perceptual frames, which were studied based on sub-additivity of frequency estimations. It was postulated that different presentations of a response scale would result in different percentage estimates of time spent watching TV or using the Internet. The results supported the existence of perceptual frames that influence the perception process and indicated that information perceptual frames had a stronger effect than formal frames. The measures made possible the exploration of the operation of perceptual frames and also outlined the relations between heuristics and cognitive frames. PMID- 24765716 TI - Range of confidence scale and consumer knowledge calibration. AB - The study examined the effect of range of a confidence scale on consumer knowledge calibration, specifically whether a restricted range scale (25%-100%) leads to difference in calibration compared to a full range scale (0%-100%), for multiple-choice questions. A quasi-experimental study using student participants (N = 434) was employed. Data were collected from two samples; in the first sample (N=167) a full range confidence scale was used, and in the second sample (N = 267) a restricted range scale was used. No differences were found between the two scales on knowledge calibration. Results from studies of knowledge calibration employing restricted range and full range confidence scales are thus comparable. PMID- 24765717 TI - Forgiveness and vengeance: the mediating role of gratitude. AB - This study examined the mediating role of gratitude on the relationship between forgiveness and vengeance. Participants were 331 university students (185 women, 146 men; ages 17 to 24 years), who completed a questionnaire package that includes the Vengeance Scale, the Trait Forgiveness Scale, and the Gratitude Questionnaire-Six Item Form. Hierarchical regression analyses showed that gratitude partially mediated the relationship between forgiveness and vengeance. The significance and limitations of the results were discussed. PMID- 24765718 TI - Children's sense of loneliness and social dissatisfaction, after-school care. AB - The study examined the loneliness and social dissatisfaction of elementary school students in relation to type of after-school care. 358 students completed the Loneliness and Social Dissatisfaction Scale and an information form that included age and the students' after-school care arrangements. Results indicated that children who were in self or sibling care had greater loneliness and social dissatisfaction compared to their peers under formal center care. PMID- 24765719 TI - Effectiveness of an enhancement program on Taiwanese university students' self concept'. AB - This study examined the effectiveness of a Self-Concept Enhancement Program (SCEP) on Taiwanese university students. Participants were randomly assigned to an experimental group (n = 30) and a waiting-list control group (n = 30). The experimental group received SCEP psycho-educational treatment for 8 weeks, whereas the control group did not. Results indicated significant improvements on physical, personal, self-identity, and total self-concept in the experimental group, but not in the control group. Participants evaluated the SCEP as useful, beneficial, and powerful in promoting their self-concept. Cultural issues were highlighted and discussed. Implications for research and counseling practice are suggested. PMID- 24765720 TI - Confirmatory factor analysis of DOSPERT scale with Chinese university students. AB - The factor structure of the 30-item Domain Specific Risk Taking Attitude (DOSPERT) scale (Blais & Weber, 2006) was examined with a convenience sample of 205 Chinese undergraduate students from Macao. A comparison of five competing models via confirmatory factor analysis yielded empirical support for the perspective that risk-taking attitude was content-dependent. After removing the items in the Financial subscale of the DOSPERT scale and some post hoc modifications, a reasonably good fit to the four-correlated-factor model was achieved, in concordance with the theoretical framework. However, items in some scales needed further revision to purify their factor structure so that the DOSPERT scale would be a more psychometrically sound measure for investigating one's risk-taking attitudes in different life domains. PMID- 24765721 TI - Diversity effect in category-based inductive reasoning of young children: evidence from two methods. AB - Previous studies have shown that diverse pieces of evidence, rather than similar pieces of evidence, are considered to have greater strength in adults' inductive reasoning. However, this diversity effect is inconsistently recognized by children. Three experiments using the same materials but different tasks examined whether young children consider the diversity principle in their reasoning. Although Experiment 1 applied a data selection task showed five-year-old children in both China and Korea were not sensitive to the diversity of evidence, Experiments 2 and 3 employed an identification task and demonstrated that children as young as five years were sensitive to diverse evidence. These findings indicated that young children, less than nine years of age, may have diversity effect. Methodological and cultural differences were discussed. PMID- 24765722 TI - Media preferences in scenarios involving relationship closeness and information valence: evidence of strategic self-presentation and sex differences. AB - The study investigated strategic self-presentation (relationship closeness, information valence, and sex) on hypothetical choice of media used. 145 participants (73 women, 72 men; M age = 22.3 yr.) were randomly assigned to experimental conditions where they indicated their preference for communicating with either a friend or a stranger using Short Messaging Service (SMS), e-mail, or telephone, compared to face-to-face. Information valence was manipulated as a within-subjects variable by scenarios where information was self-referential and either negative or positive. Preference to mediated channels in the two scenarios was measured as an average of self-reported scores on a scale from 1-5 where 3 indicated face-to-face communication. Relationship closeness and scenario affected media preferences. Participants had higher preference scores for mediated channels when communicating with strangers than with friends and when sharing self-referential and negative information. Only women's preferences appeared to be affected by the manipulation of relationship closeness. PMID- 24765723 TI - Media exposure and romantic relationship quality: a slippery slope? AB - This study examines whether media consumption predicted relationship quality among 188 college students who were involved in romantic relationships. The respondents assessed their commitment to the relationship, their satisfaction from the relationship, and their tendency to engage in conflicts within the relationship. Media consumption was measured by assessing the time dedicated to television viewing in general, watching specific genres, Internet use, and newspaper reading. Hierarchical regression analyses indicated that total TV viewing time statistically predicted lower commitment to the relationship, while viewing of programming focusing on romantic relationships predicted lower satisfaction and stronger tendency to engage in conflicts. Consumption of media other than television and the control factors did not predict any indicator of relationship quality. The pattern of negative associations between TV viewing and relationship quality is discussed with reference to cultivation theory and mood management theory. PMID- 24765724 TI - Relationship between parenting styles and gender role identity in college students. AB - The relationship between perceived parenting styles and gender role identity was examined in college students. 230 undergraduate students (48 men, 182 women; 18 23 years old) responded to the Parental Authority Questionnaire (PAQ) and the Bem Sex-Role Inventory (BSRI). The hypothesis was that parenting styles (authoritarian, authoritative, and permissive for both fathers and mothers) would be significantly associated with gender role identity (undifferentiated, feminine, masculine, and androgynous) of college students, specifically whether authoritative parenting styles associated with androgyny. To account for differences in sex on gender role identity or parenting styles, sex was included as a factor. The pattern of the difference in identity groups was similar for males and females. There were significant differences in parenting styles between gender role groups. Maternal and paternal authoritativeness correlated with participants' femininity, and for both parents, the relationship was observed to be stronger in males than females; paternal authoritativeness was significantly associated with androgyny. Future research based on these results should investigate how the findings relate to children's psychological well-being and behavioral outcomes. PMID- 24765726 TI - College student stressors, depression, and suicidal ideation. AB - This study was designed to explore whether stressors from college-related activities and stressors from general life experiences differed in their power to predict depression and suicidal ideation in college students. In a sample of 165 college undergraduates, depression was predicted by both sources of stress whereas past and current suicidal ideation were predicted only by general life stress. PMID- 24765725 TI - Comparison of the effects of two phonics training programs on L2 word reading. AB - Empirical evidence shows that explicit phonics teaching is beneficial for English word reading. However, there has been controversy as to whether phonics teaching should incorporate meaning-involved decodable text instruction to facilitate children's word reading. This study compares the effects of phonics teaching with and without decodable text instruction on immediate and delayed English word reading in 117 Taiwanese children learning English, assigned to a Phonics-only group (n = 58) and a phonics plus decodable text instruction (Phonics+) group (n = 59). Results showed that although both groups significantly improved in immediate and delayed post-test word reading, the Phonics+ group performed better in both post-tests, but the difference was significant only in the delayed word reading, suggesting a better long-term retention effect produced by Phonics+ teaching. These indicated that incorporated meaning-involved decodable text reading might offer another better facilitative linking route for English word reading even for non-alphabetic child learners of English. The findings were discussed from linguistic, psycholinguistic, and reading perspectives, with implications drawn for second/foreign language teaching and research in reading instruction. PMID- 24765727 TI - Personality, sex of participant, and face-to-face interaction affect reading of informed consent forms. AB - Students (N = 183) participated in a study designed to determine if each student read the informed consent form. Approximately 12% of students in the online condition followed the procedure compared with 38% in the laboratory phase. Participants with higher trait worry and those with lower emotion reappraisal were more likely to follow the procedure, while women were more likely to read the form than men. Across conditions, most students do not read informed consent documents, particularly in online formats. These findings of this research support the idea that women tend to be more information-seeking than men in health and research settings and those with higher trait worry tend to read the consent forms to alleviate uncertainty and trust concerns. PMID- 24765728 TI - Obamacare goes live; challenges result in debate reaching new heat levels. PMID- 24765729 TI - Common embezzlement myths. AB - With published statistics suggesting that embezzlement strikes three in five doctors at some point in their careers, this topic is of interest to every professional owning a medical or dental office, and tackles some of the biggest areas of misunderstanding concerning embezzlement in professional offices. Many readers will be surprised to learn that many of the steps that are frequently advocated to control embezzlement are, in fact, ineffective. This article suggests an approach that is quite different from what is normally recommended, and yet is far easier to implement than conventional embezzlement-control strategies. PMID- 24765730 TI - Can we talk? The search for common ground in the doctor-patient relationship. AB - Communication is an essential component of providing quality care. Proper communication incorporates the use of plain language and culturally sensitive information in oral, written, and nonverbal communication to patients. Plain language explains medical concepts and conditions in understandable terms without "talking down" to patients or coming across as erudite or condescending. Timing and delivery are also important. Patients are less likely to retain information under stressful circumstances. Bad news should be delivered compassionately and disclosed according to the patient's knowledge and understanding of the situation. Physicians need to individualize their communication to patients based on patients' needs and desires. Online communication to patients needs to clearly focus on medical issues, separating personal and professional content. PMID- 24765731 TI - Design a compliance plan for the medical office. AB - The Affordable Care Act has mandated that all physician offices will need to have a compliance plan and compliance point of contact. Although the Office of Inspector General has not yet set the date, now is the time to get ready and design a compliance plan for your medical office. Fraud, waste, and abuse are at an all-time high. The government and taxpayers want to plug the holes where valuable healthcare dollars are being inappropriately used. Be proactive and take the time to design your compliance plan now. Read on to learn how to remove the question of "who, what, and I don't know" from your vocabulary when it comes to the topic of compliance! PMID- 24765732 TI - Guidelines for setting up an ambulatory surgery center. PMID- 24765733 TI - Mirror, mirror: six ways to take an honest look at your practice from your patients' perspective. AB - Unsatisfied patients cost practices thousands of dollars every year in lost revenue through attrition, loss of referrals, and noncompliance, and yet the often unspoken needs and wants of patients are rarely analyzed in relation to the service delivered. This article explains the importance and value of taking an honest look at your healthcare organization from the other side of the check-in counter. It gives six practical steps any practice can take to begin to better understand the patient experience and perspective, including how to garner honest feedback and get your staff onboard with a patient-centric culture. Learn how to gain valuable insight to develop strategies that give your practice a competitive edge and a rock-solid future. PMID- 24765734 TI - How physicians can survive the "perfect storm" developing in healthcare today- and thrive. AB - The healthcare environment post-Affordable Care Act is changing the way that physicians practice and the way that they are compensated for patient care services. With the change from fee-based to value-based reimbursement comes significant stress related to needed change in processes and procedures, as well as the potential for a reemergence of some "traditional risk" categories. Physicians need to be vigilant and refocus efforts in some of these traditional risk areas. There is also a role for innovative health insurers and medical professional liability insurers in supporting physicians during this time of change. Best clinical practices and the patient experience are two key strategies that can also help physicians today. PMID- 24765735 TI - The shared medical appointment: a proposed model of medical appointments. AB - Today's healthcare providers are struggling more than ever with providing high quality care and while controlling the spiraling costs of healthcare. The demands of an aging population, combined with a shrinking pool of medical personnel, have brought challenges to the medical office where doctors are saddled with the need of improving access to medical care. Recruiting new partners, using physician assistants and nurse practitioners, and seeing more patients in a workday are some ways doctors are trying to meet these challenges. For the most part, that does not solve the problems afflicting most physicians and practices. This article will discuss the concept of the shared medical appointment and how it might be applied to most medical practices. PMID- 24765736 TI - Ready ... mindset ... go! PMID- 24765737 TI - Preparing for ICD-10 and conforming your documentation. AB - There are many unknowns right now with the implementation of ICD-10-CM. However, tackling a few obstacles early on along with a keen sense of ICD-10 awareness will put you ahead of the game and able to continue on after October 1, 2014. Waiting until the last minute in hopes of delays will surely hinder the financial stability of your practice. This article will take you through what is needed for ICD-10 implementation and help you jumpstart your efforts. PMID- 24765738 TI - Need versus cost: understanding EHR data migration options. AB - Over 50% of physician offices and group practices are replacing their electronic health record (EHR) systems. Dissatisfaction with first-generation systems, physician practice mergers, and hospital acquisitions are all driving the move from legacy EHRs to newer, more sophisticated software. With this painful decision comes the same challenge experienced with a medical practice's original EHR implementation--getting data into the new system. However, now practices have decades of data, terabytes of information, and multiple vendors to manage. Time and cost requirements to migrate data from one EHR to another must be weighed against the benefits of physician productivity and continuing patient care. Core areas for practices to consider include staff stress, financial risk, and physician productivity. This article helps practice directors navigate new data migration decisions when replacing their EHR system. Key considerations and "must haves" for effective data migration decisions are included. Conversion, vendor neutral archive, and document imaging options are reviewed along with practical best practices for identifying which data should be included in the go-forward EHR. PMID- 24765739 TI - Understanding awareness of pharmacist-led medication therapy management among primary care physicians in New York City, Part II: Findings and implications. AB - Pharmacist scope of practice has evolved over the last few decades. As such, pharmacists are more widely involved in disease management, medication therapy management (MTM), and patient education. As the primary care shortage continues to be of concern for the U.S. healthcare system, pharmacists are well positioned as accessible, trusted, and knowledgeable professionals to help ease physician burden in assisting patients with medication management. Very few studies have been done to understand the perceptions of primary care providers regarding the involvement and role of pharmacists in MTM programs. The New York City Department of Health and Mental Hygiene performed a qualitative study to obtain a better understanding of the perceptions related to pharmacist-led MTM programs among primary care physicians in New York City. Physician education around the role of pharmacists was found to be critical in building collaborative relationships between physicians and pharmacists. Our study rationale, design, and preliminary findings have been discussed previously. This paper provides the detailed report and potential impact of our study findings on building collaborative team-based relationships that will allow for improved patient outcomes. PMID- 24765740 TI - The virtual doctor visit. AB - American healthcare is changing at a rapid pace. No one knows for certain what the impact will be for the Affordable Care Act. What we do know is that changes are going to take place, and the physician of the future needs to be ready to embrace changes in the way healthcare is conducted. One of those changes certain to occur is that patients will have a significant amount of their medical care delivered using the technology of the Internet and not the traditional in-office visit where the doctor and patient are eyeball-to-eyeball. This article will describe the virtual office visit and the benefits to both the patient and physician. PMID- 24765741 TI - What to do when trust has been breached in your practice. AB - We've all experienced gossiping, missed deadlines, someone taking credit for another's work, and little white lies. These and other breaches of trust are commonplace. However, they do more damage in the medical practice than many practice managers realize. This article argues that medical practice employees need to trust their managers, patients, doctors, one another, and even the security of their jobs so they are able to focus on their daily tasks and perform well. It defines trust as both a logical and emotional act and describes common breaches of workplace trust. It defines three characteristics of high-trust organizations and illustrates through examples how practice managers can demonstrate their trustworthiness through their actions, not only through their words. This article also offers seven steps for rebuilding trust that has been breached. It offers readers two instruments: a survey tool practice managers can use to assess the trust in their practices and a self-quiz practice managers can take to assess their own trustworthiness. Finally, this article offers research about the impact of trust on the bottom line and 10 truths about trust that medical practice managers can share with their employees. PMID- 24765742 TI - Public speaking: creating presentations that are awe inspiring not yawn producing. AB - Many physicians want to be good platform speakers; however, few of us have the background and training necessary to be an outstanding public speaker. Yes, we all have slide decks and PowerPoint programs provided to us so that we can turn our backs to the audience and read the verbiage on the slides. But does that technique generate useful information to the audience? Or if speaking to a lay audience, does that kind of talk make the audience members get out their cell phones and call the office to make an appointment in our practice? Probably not. This article will provide suggestions that will enhance your speaking and presentation skills. This, in turn, will make you a darling of the pharma industry and encourage potential patients in your audience to become patients in your practice. PMID- 24765743 TI - Supreme Court same-sex marriage decision and an update on wellness programs. PMID- 24765744 TI - Plans use narrow networks in exchanges; public, politicians predictably perturbed. PMID- 24765745 TI - High-utilizing patients. Where are the savings? PMID- 24765746 TI - A conversation with David B. Nash, MD, MBA. Game changers for population health. PMID- 24765747 TI - Slight pay increases for doctors as contracting system evolves. PMID- 24765748 TI - New generation of anti-obesity pills slow to obtain coverage. PMID- 24765749 TI - Hospitals embrace bundled payment systems. PMID- 24765750 TI - Retrospective cohort study of medication adherence and risk for 30-day hospital readmission in a Medicare Cost Plan. AB - PURPOSE: Reducing hospital readmissions requires deploying appropriate interventions to groups at highest risk for readmission. Long-term medication adherence may indicate one's ability to manage recovery and chronic illness after discharge. If so, medication adherence also may be a predictor of hospital readmission. DESIGN: The objective of this study was to test the association of long-term medication adherence with hospital readmission in a cohort of beneficiaries enrolled in a Medicare Cost Plan. METHODOLOGY: The study employed a retrospective cohort design using administrative pharmacy and health care claims for a sample hospitalized in 2009. Medication adherence was measured with the medication possession ratio (MPR) for the 12 months prior to the first hospitalization in 2009. The likelihood of readmission within 30 days from the first hospitalization in 2009 was estimated using the logistic regression model. RESULTS: Long-term medication adherence was not associated with likelihood of 30 day hospital readmission (odds ratio [OR] = 0.82, P = .71). However, older age (OR = 1.07, P = .003) and longer length of hospital stay (OR = 1.2, P < .001) were associated with higher likelihood of 30-day readmission, while having an office visit within 30 days of discharge (OR = 0.38, P = .03) was associated with lower odds of readmission. CONCLUSION: Except for older age, variables associated with likelihood of readmission are difficult for clinical teams to access during a hospital stay to identify those at risk for readmission. Additional work is needed to identify indicators of readmission risk that can be utilized during hospitalization to identify patients needing post-discharge support to help prevent readmission. PMID- 24765751 TI - New hepatitis C drugs. Major killer disease comes under control. PMID- 24765752 TI - Sovaldi ushers in wave of costly hepatitis C drugs. PMID- 24765753 TI - More physicians expected to enter workforce. PMID- 24765754 TI - Disaster preparedness. PMID- 24765755 TI - It's a plan! A look at the Hospital Incident Command System. PMID- 24765756 TI - Exploring the laws and ethics with disaster nursing. PMID- 24765757 TI - With a huff and a puff, your profession is blown away ... building a solid foundation. PMID- 24765758 TI - Disaster preparedness for the professional nurse. PMID- 24765759 TI - Governor Kasich and the House Health & Aging Committee focuses on opiate addiction. PMID- 24765760 TI - The role of the emergency preparedness nurse. PMID- 24765761 TI - Flood in Lake County, Ohio: will the President sign Declaration of Disaster? PMID- 24765762 TI - Surviving in your car, briefly! PMID- 24765763 TI - Myocardial dynamic contrast-enhanced Mr: vascular diseases and beyond. AB - Contrast-enhanced cardiac magnetic resonance imaging allows the evaluation of both myocardial perfusion and myocardial tissue characteristics. This paper reviews different microvascular and non-vascular conditions that can cause abnormal findings on contrast-enhanced myocardial magnetic resonance imaging. Knowledge of their characteristics can avoid misinterpretation and avoid inappropriate referral for further invasive imaging in patients suspected of myocardial vascular disease. PMID- 24765764 TI - Correlation of MRI T2 mapping sequence with knee pain location in young patients with normal standard MRI. AB - OBJECTIVE: To assess the correlation of T2 mapping abnormalities to knee pain location, in young adults with normal standard knee MRI at 3.0 Tesla. SUBJECTS AND METHODS: Twenty-three consecutive patients were included prospectively from September 2011 to April 2012. Inclusion criteria were age under 50 years old, knee pain without surgical history, and normal knee MRI at 3.0 Tesla (sagittal T1 weighted images, and sagittal, axial and coronal proton-density-weighted images with saturation of fat signal). Ten asymptomatic volunteers were also included as a control group. Patients and controls had a cartilage T2 mapping MRI sequence in addition to the standard MRI protocol. Two musculoskeletal radiologists, blinded to the patient/control condition and pain location, independently reviewed the T2 mapping images. T2 values below 40 ms were considered normal. They rated the number of hyaline cartilage lesions and their grade according to an ICRS-like score (inspired by the International Cartilage Research Society score) in each anatomical compartment (medial and lateral femoro-tibial and anterior patello femoral joints). In addition, the T2 value of the largest lesion was measured. Patient's pain location was classified in the following categories: anterior, lateral, medial and global. T2 mapping findings were compared to pain location, and retrospectively to the initial standard sequences. Sensitivity and specificity were calculated for MRI with T2 mapping according to pain location for each reader. Kappa coefficient was calculated for inter-reader agreement. We used variance analysis in a linear regression to compare T2 values and ICRS-like classification in each compartment. RESULTS: Sensitivity of MRI with T2 mapping, according to the symptomatic compartment, was respectively: 78% and 87% for Reader 1 and Reader 2 and specificity was 70% for both readers. Kappa coefficient for T2 mapping abnormalities location and pain location was good, with a calculated value of 0.64. There was no significant correlation between ICRS-like classification and T2 values of lesions (p = 0.18). CONCLUSION: Our results suggest that T2 mapping is an interesting MRI sequence for the exploration of young patients knee pain in case of normal MRI with a standard protocol, with a good correlation between pain location and focal prolongations of the cartilage T2 relaxation time. PMID- 24765765 TI - Developmental venous anomaly: MR and angiographic features. AB - Developmental venous anomaly (DVA) is probably the most common anomaly of the intracranial vasculature. DVAs consist of multiple, radially oriented dilated medullary veins that converge into a transcerebral vein. We describe the imaging findings of this vascular anomaly in different patients and the role of different imaging modalities. PMID- 24765766 TI - Spinal chondrosarcoma arising from a solitary lumbar osteochondroma. AB - Chondrosarcoma is a primary malignant neoplasm of cartilage-forming cells that rarely involves the axial skeleton, typically affecting skeletally mature patients. It may arise as a primary bone tumour or as a secondary lesion from a pre-existing benign cartilaginous neoplasm such as an osteochondroma or enchondroma. We report the case of a 68-year-old female who presented with a mildly painful paraspinal mass lesion as a result of malignant degeneration of a previously unknown solitary lumbar osteochondroma into a large chondrosarcoma. The characteristic imaging findings on cross-sectional imaging techniques are reviewed and illustrated, along with an outline of relevant clinical and therapeutic aspects. PMID- 24765767 TI - Computed tomography features of small bowel obstruction due to mesodiverticular band. AB - Meckel's diverticulum is the most common congenital anomaly of the small intestine. Common complications related to a Meckel's diverticulum include hemorrhage, intestinal obstruction, and inflammation. Small bowel obstruction due to mesodiverticular band of Meckel's diverticulum is a rare complication. Herein, we report a case of small bowel obstruction occurring due to mesodiverticular band of a Meckel's diverticulum. The important aspect of our case is clear demonstration of the mesodiverticular band adjacent to the Meckel's diverticulum on pre-operative computed tomography (CT). PMID- 24765768 TI - Arteries get confused: an arch variation. AB - We present a case of an arch anomaly in a 54-year-old female who was admitted to our hospital for magnetic resonance angiography (MRA) to evaluate her right-sided numbness. MRA revealed a truncus bicaroticus, right common carotid artery (CCA) originating right vertebral artery, right subclavian artery arising as the final branch of the descending aortic arch and arch originating left vertebral artery. The possible embryologic mechanism and clinical importance of this previously unreported variant are reviewed. PMID- 24765769 TI - Incidentally detected congenital giant left atrial appendage aneurysm in a child: MRI findings. AB - Left atrial appendage aneurysms are usually congenital and are very infrequent anomalies of the heart. They are very rarely diagnosed during childhood, with most cases symptomatic between the 2nd and 4th decades of life. Diagnosis is vitally important due to potential life-threatening complications. Surgical excision is the treatment of choice. Surgery reduces the risks of cardiac arrest, respiratory distress, arrhythmia, heart failure, thromboembolism, or rupture. We report the case of a 3-year-old boy with incidental diagnosis of a giant aneurysm of the left atrial appendage that was confirmed with magnetic resonance imaging and treated with surgery. PMID- 24765770 TI - Ultrasonographic diagnosis of acute pancreatitis caused by ruptured hydatid disease to the biliary system. AB - Acute pancreatitis is a rare complication of hydatic disease which occurs following the rupture of a cyst to the intrahepatic bile ducts. Herein, we report a case of a 34-year-old Turkish man, who presented with upper abdominal pain. In laboratory examination, amylase and lipase levels were elevated. Ultrasound examination showed a cystic hypoechoic mass lesion located in the right lobe of the liver with dilated intrahepatic bile ducts, and germinative membranes were detected originating from the ruptured hydatid cyst to the common bile duct. The pancreas was found to be diffusely hypoechoic, consistent with acute pancreatitis. Contrast enhanced CT and MRI were also performed for further evaluation of the primary lesion and its complications. PMID- 24765771 TI - Ileocolic intussusception due to lipomatosis of the ileum: a common complication of a rare clinical entity. AB - We report a case of intestinal ileal lipomatosis in a 56-year-old Caucasian male complicated with small bowel obstruction due to ileocolic intussusception with a lipoma serving as lead point. This rare disease is often only discovered incidentally as a consequence of mechanical complications and not well reported in the international literature, compared to intussusception due to an isolated lipoma. Computed tomography is the imaging modality of choice to depict complications of this distinct clinicopathological entity. Density measurements can confirm the fatty content and homogeneity analysis of the lesions can guide the radiologist in the differential diagnosis. PMID- 24765772 TI - The case of HNF-1beta mutation with medullary cysts. AB - We describe one case of long-term post-natal follow-up of hyperechoic fetal kidneys related to HNF-1beta mutation with cystic changes over a 9-year period in a female patient. This diagnosis was suspected on the basis of the renal US findings and was confirmed by complementary genetic examination. After birth, cortical cysts were detected and at the age of 4, medullary cysts were found, that disappeared with time. Currently our patient displays hyperechoic kidneys with only cortical cysts. This case report highlights the variability of US appearances in relation with HNF-1beta genetic mutation. PMID- 24765773 TI - A rare case of diffuse alveolar hemorrhage following oral amphetamine intake. AB - Diffuse alveolar hemorrhage (DAH) is a clinical syndrome, which refers to injury to the capillaries, arterioles and venules, leading to red blood cell accumulation in the distal air spaces. It is defined by the clinical triad of hemoptysis, anemia and progressive hypoxemia. Chest radiographs reveal non specific patchy or diffuse bilateral pulmonary consolidation. Multiple conditions are associated with DAH, of which Wegener's granulomatosis is the most frequent, and underlying disease determines the prognosis and treatment. This case describes DAH as a result of oral amphetamine abuse in a young patient of which the diagnosis was established by laboratory, clinical and radiologic findings. The patient experienced a rapid recovery without significant sequelae. PMID- 24765774 TI - Drink responsibly! Rapid regression of fatty liver disease on enhanced CT after alcohol withdrawal. PMID- 24765775 TI - Bilateral elastofibroma dorsi: typical CT and MRI features. PMID- 24765776 TI - Intraparenchymal meningioma in a child. PMID- 24765777 TI - Toothpick perforation of the caecum. PMID- 24765778 TI - Epiphyseal "systemic" osteonecrosis of humeral head. PMID- 24765779 TI - Midwifery and nursing--a shared history. PMID- 24765780 TI - Is New Zealand a bicultural or a multicultural society? PMID- 24765781 TI - DHBs and minister accountable. PMID- 24765783 TI - Positive messages for CEOs. PMID- 24765784 TI - Passionate nurse fails to get job. PMID- 24765785 TI - The kaiwhakahaere comments. PMID- 24765787 TI - 58 per cent of new grads have jobs. PMID- 24765786 TI - End child poverty! Te Henga believes every child should be a wealthy child. PMID- 24765788 TI - Health Minister will leave mixed legacy. PMID- 24765789 TI - Morunga wins her unfair dismissal case. PMID- 24765790 TI - Wanted: a healthy democracy. PMID- 24765791 TI - Training for an emergency Caesar. PMID- 24765792 TI - Staffing woes cut hospital midwives to the core. PMID- 24765793 TI - Seeing high-needs women at home 'a privilege'. PMID- 24765794 TI - Committed leader in midwifery revolution. PMID- 24765795 TI - Promoting wellness in women and whanau. PMID- 24765796 TI - Mother's mental health vital for baby. PMID- 24765797 TI - Enhancing the role of fathers. PMID- 24765798 TI - Meeting the needs of birthing women. PMID- 24765799 TI - Professionally yours. PMID- 24765800 TI - Online organising--the way ahead. PMID- 24765801 TI - Identifying Maori workforce issues. PMID- 24765802 TI - DHBs: Dunedin nurses want action now. PMID- 24765803 TI - Rethinking and reconceptualising work. PMID- 24765804 TI - Cancer education in physician assistant programs. AB - PURPOSE: The purpose of this study was to describe the current state of oncology education provided by physician assistant (PA) programs. METHODS: This is a descriptive, cross-sectional study of PA programs using a web-based survey. RESULTS: The response rate was 22%. All programs reported dedicated curricular hours to address cancer: genetics, prevention/screening, diagnosis, and general treatment and counseling regarding delivering "bad news." The majority of programs provided 2 hours or less of content related to the evaluation and management of acute cancer treatment effects, oncologic emergencies, and symptoms of cancers/palliative care. Most common content areas without any dedicated time were management of patients with long-term sequelae of prior treatment or undergoing cancer surveillance and identification/management of cancer survivors. The most commonly used instructional format is lecture, interaction with preceptors, and direct patient care. Other forms of learning such as case-based learning and team-based learning are less commonly used. Most programs report the most common cancer patient encounters occur during internal medicine/primary care rotations. Although typically available, few students participate in oncology elective rotations. Data regarding faculty perception of cancer education, teaching resources, and barriers to teaching were also collected. CONCLUSION: Cancer prevention and initial diagnosis are the primary foci of instruction by PA schools. Instruction is typically by classroom lecture and clinical encounters during primary care rotations. Given the challenges faced by PA programs to provide a generalist's education for students, novel means of enhancing cancer education during PA school and continuing medical education following primary PA education will be essential to expand PAs' competencies in cancer care. PMID- 24765805 TI - Tales from the trenches: physician assistants' perspectives about precepting students. AB - PURPOSE: A national survey of physician assistants (PAs) found that only 25% of respondents were involved as preceptors for PA students in 2011, and it also identified important barriers and incentives to precept PA students. These findings offer limited information for understanding the nature of this complex phenomenon within its context. The purpose of this study was to further describe key factors that influence the involvement of PAs as preceptors. METHODS: A qualitative study of four focus groups with clinically practicing PAs (N = 29) was conducted at the American Academy of Physician Assistants' annual conference in May 2012. Semistructured interview questions and follow-up probes were used to elicit participants' perspectives about their own and/or witnessed preceptor experiences. The group discussions were audio-recorded, professionally transcribed, and then analyzed line-by-line by four investigators using conceptual and free coding. The independently coded transcripts were merged, and iterative analysis was used to identify recurrent themes until saturation was reached. RESULTS: Four themes emerged: (1) The preceptor role provides an opportunity to "pay back," or contribute to future colleagues' training while advancing the clinician's own knowledge; (2) Student qualities that incentivize precepting are characterized by motivation and self-directed learning, independent of the level of medical knowledge and/or prior experience; (3) Preceptors value feeling connected with the PA program through initial and ongoing communication; (4) Significant competition for clinical rotation sites for various health professional learners limits the access to sites and preceptors. CONCLUSION: PAs identified key areas for potential preceptor recruitment and retention interventions. PMID- 24765806 TI - The relationship between physician assistant program costs and student tuition and fees. AB - PURPOSE: Leaders in medical and physician assistant (PA) education are faced with reduced sources of funding, tuition increases, and enrollment expansion, while students compete for the same pool of federal aid. The amount of research on the cost of education for both PA students and education programs is minimal. METHODS: This retrospective analysis of Physician Assistant Education Association (PAEA) data, 2008-2011, examined the relationship between PA program costs and student tuition and fees. Statistical analyses included descriptive and parametric testing. RESULTS: Analyses suggest that PA programs rely on student tuition and fees as a significant source of program revenue. Statistical significance was found for mean annual comparisons, 2008-2011. CONCLUSION: Based on trends in medical education, the burgeoning debt crisis among medical graduates, and rapid changes in the health care environment, it would benefit the PA community to complete additional research on student debt load, cost of education, and allocation of program revenue. PMID- 24765807 TI - Longitudinal integration of cultural components into a physician assistant program's clinical year may improve cultural competency. AB - PURPOSE: This study assessed the efficacy of longitudinal integration of cultural components into the clinical year of a 2-year master of science in physician assistant studies (MSPAS) program. METHODS: Students submitted cultural reflection papers, gave a medical case/cultural presentation, and participated in cultural awareness discussion groups throughout the clinical year. Students completed the same cultural awareness survey at the conclusion of their clinical year that they had completed at benchmarked intervals during their didactic year. Additionally, cultural competency was assessed during the students' summative objective structured clinical examination (OSCE) using a combination of the program's objectives and established professional standards. RESULTS: Qualitative data suggested that students recognized the importance of cultural competency in providing quality patient care and recognized that remaining culturally competent is an ongoing process. Linear trend analyses revealed significant positive relationships between survey response scores and time in the program. The OSCE's cultural assessment scores indicated cultural competency in broad, general categories, but scores declined as cultural categories narrowed and became more detailed. CONCLUSION: Continued integration of cultural awareness training and assessment throughout the clinical year of a physician assistant (PA) program may have a positive impact on improving cultural competency. PA programs seeking to improve cultural competency in their students should consider continued integration of cultural components throughout the clinical year. PMID- 24765808 TI - Effect of a long-term care geriatrics rotation on physician assistant students' knowledge and attitudes towards the elderly. AB - Physician assistants (PAs) have the opportunity to contribute to the high demand of providing health care to the growing older adult population. It is essential they have the knowledge to meet this need. The purpose of this study was to determine the difference in knowledge of and attitudes towards the elderly among a group of PA students before and after a required four-week geriatric rotation. PA students' knowledge of geriatrics was significantly improved following the long-term care rotation. Attitude did not change following the rotation but reflected a positive attitude at baseline. It is recommended that PA programs incorporate a rotation in geriatrics/long-term care to help increase PA students' geriatrics-specific knowledge and to better prepare them to provide care to their elderly patients. PMID- 24765809 TI - Criminal background checks: their role during the admissions process. PMID- 24765810 TI - Reliability and evidence-based medicine. PMID- 24765811 TI - The time is now for physician assistant leadership in global health. PMID- 24765812 TI - Prepare for landing: a student orientation for international clinical rotations. PMID- 24765813 TI - The case of Jahi McMath: professionalism and knowing one's limitations. PMID- 24765814 TI - A towel less: social norms enhance pro-environmental behavior in hotels. AB - Previous research has shown that normative appeals to engage in environmentally friendly behavior were most effective when they were accompanied by a provincial norm (e.g., when norms matched individuals' immediate situational circumstances). Analyzing hotel guests' towel-use during their stay, the current study tests whether messages employing provincial norms were more effective in reducing towel use than standard environmental messages. In line with previous findings, guests of two hotels used significantly fewer towels when provincial normative appeals- rather than standard environmental messages--were communicated. These findings corroborate to the body of research demonstrating the power of social norms on environmental behavior. PMID- 24765815 TI - The others will help: the presence of multiple video game characters reduces helping after the game is over. AB - The bystander effect refers to the phenomenon that individuals are less likely to help if there are potential other helpers present. For instance, past research revealed that participants were less likely to help computer-controlled characters if there were other computer-controlled characters present. Research has also shown that the bystander effect occurs if the presence of others is merely imagined. The present research examined the idea that the presence of multiple characters within a video game reduces the player's helping behavior even after the video game is over. In fact, participants who played a video game with multiple characters present were less likely to devote time to assisting in a future study than participants who had played the same video game with only a single character present. PMID- 24765816 TI - Gender hierarchy in the space: the role of gender status in shaping the spatial agency bias. AB - According to the Spatial Agency Bias (SAB), more agentic groups (men) are envisioned to the left of less agentic groups (women). This research investigated the role of social status in shaping the spatial representation of gender couples. Participants were presented pairs consisting of one male and one female target who confirmed gender stereotypes. The status of the targets in each pair was systematically varied (high-status vs. low-status job). Participants chose the target order (female/male vs. male/female) they preferred. In line with gender-status expectations (male: high-status, female: low-status), a male in a high-status job led to a spatial arrangement that favored the male/female order, regardless of the status of the female target. The female/male order was favored only when the female had a high-status job and the male a low-status job. No SAB occurred for pairs in which both targets displayed low-status jobs. The implications of status for the SAB are discussed. PMID- 24765817 TI - Within-culture variations of uniqueness: towards an integrative approach based on social status, gender, life contexts, and interpersonal comparison. AB - Research on uniqueness is widely focused on cross-cultural comparisons and tends to postulate a certain form of within-culture homogeneity. Taking the opposite course of this classic posture, we aimed at testing an integrative approach enabling the study of within-culture variations of uniqueness. This approach considered different sources of variation: social status, gender, life contexts, and interpersonal comparison. Four hundred seventy-nine participants completed a measure based on descriptions of "self" and "other." Results showed important variations of uniqueness. An interaction between social status and life contexts revealed the expression of uniqueness in the low-status group. This study highlights the complexity of uniqueness that appears to be related to both cultural ideology and social hierarchy. PMID- 24765818 TI - The mating sociometer and attractive others: a double-edged sword in romantic relationships. AB - Eighty-one participants were recruited to test the sensitivity of the mating sociometer to mate-value feedback in the context of ongoing intimate relationships. Experiences of social rejection/acceptance by attractive opposite sex confederates were manipulated. The effects of this manipulation on self esteem, relationship satisfaction and commitment, perceptions of dating alternatives, and friendship-dedication were assessed. Social rejection/acceptance by members of the opposite sex altered relationship satisfaction and commitment; this causal link was amplified by changes in state self-esteem; and these effects were specific to intimate relationships and did not generalize to friendship-dedication. This research supports a domain-specific conceptualization of sociometer theory, extending the theory in important directions. PMID- 24765819 TI - With a little help from my friends: bystander context and children's attitude toward peer helping. AB - This experimental vignette study examined children's perceptions and evaluations of helping a peer, in the context of friendships and in the presence of by standing peers. A total of 1246 children (8 to 12 years) reported their attitude toward helping when either friends of the helper, friends of the recipient of help, or no bystanders were present. In agreement with the competitive altruism model, children most strongly endorsed helping when friends of the helper were present compared to the other two situations. This indicates that children take reputation concerns into account when evaluating helping situations. However, in contrast to lower prosocial children, the evaluations of higher prosocial children were not influenced by the presence of by-standing peers. These children seemed to base their evaluation on increasing the recipient's welfare and less on reputation concerns of the helper. PMID- 24765820 TI - The "saying is repeating" effect: dyadic communication can generate cultural stereotypes. AB - It has been long established that interpersonal communication underpins the existence of cultural stereotypes. However, research has either examined the formation of new or the maintenance of existing stereotypes. In a series of three studies, the present research bridges the gap between these phases by showing that newly formed stereotypes can spread through repeated dyadic communication with others. The stereotypic representation arose due to the audience tuning in to communication to a first audience. Further transmission to two types of subsequent audiences was simulated: a newcomer and an old-timer with an unknown attitude towards the target. A "saying-is-repeating" effect was obtained: the stereotypic representation was invariably transmitted to the newcomer, regardless of whether communicators personally believed in the bias; perceived group-level consensus moderated its transmission to the old-timer. These findings demonstrate that once a stereotypic representation is formed, it is likely to spread in a community and potentially become a cultural stereotype. PMID- 24765821 TI - [The 35th Report on Survey of the Adverse Reaction to Radiopharmaceuticals (the 38th Survey in 2012)]. AB - This survey was performed in order to investigate the incidence of adverse reactions to radiopharmaceuticals in FY2012 in Japan. It was based on responses to questionnaires sent to nuclear medicine institutions. The reply was obtained from 977 institutions among 1,251 to which the questionnaire had been sent. Eleven cases of adverse reactions were reported. A total of 1,060,526 radiopharmaceutical administrations was reported. The incidence of adverse reactions per 100,000 cases was 1.0. One case of defect products was reported, and the incidence of defect products per 100,000 cases was 0.1. PMID- 24765822 TI - Incidence of multiglandular disease in sporadic primary hyperparathyroidism. AB - OBJECTIVES: Multiple, minimally invasive surgical techniques have been developed over the last few decades for the management of sporadic primary hyperparathyroidism (PHTP). However, in cases with multiglandular disease, bilateral cervical exploration remains the gold standard. Therefore, it is important to have an accurate estimation of the incidence of multiglandular disease in sporadic PHTP. METHODOLOGY: 698 patients were treated for PHTP between 1993 and 2010 at the University Hospitals Leuven, using the bilateral cervical exploration method. After excluding cases of multiple endocrine carcinoma syndrome, the incidences of double adenoma and multiple gland hyperplasia were investigated in these patients. Age, gender, imaging results, serum calcium and parathyroid hormone concentrations were analyzed and compared to the data of 50 randomly-selected, PHTP patients with solitary adenomas. RESULTS: 6.6% and 2.4% of the patients with sporadic PHTP had double adenomas and multiple gland hyperplasia, respectively. The female/male ratio was 4.8 (38/8) and 1.8 (11/6), and the average age was 63 and 52 yrs for patients with double adenomas and multiple gland hyperplasia, respectively. The patients with solitary adenomas had a female/male ratio of 3.5, and an average age of 60 yrs. There were no significant differences in serum calcium or parathyroid hormone concentrations between patients with multiglandular disease and those with solitary adenomas. CONCLUSIONS: Multiglandular disease occurs in 9% of patients with sporadic PHTP, and cannot be excluded before surgery. This incidence must be considered when using minimally invasive techniques for treatment of sporadic PHTP. In cases of multiglandular disease, bilateral cervical exploration is indicated. PMID- 24765823 TI - HPV-related oropharyngeal cancers in Flanders (Belgium): a multicenter study. AB - INTRODUCTION: Human papilloma virus (HPV) was recently reported to play a major role in oropharyngeal carcinoma. Large geographical differences in the disease prevalence have been described. Until now, no data have been reported for Flanders (Belgium). METHODS: A multicenter cooperative study was undertaken at the radiation-oncology departments of Flemish universities. Tumor blocks from patients diagnosed with oropharyngeal carcinoma between 2000 and 2010 were tested for HPV at a single center. Patients' characteristics, treatments, and follow-up data were recorded from medical files. Age standardized incidence rates of oropharyngeal carcinoma were collected from the Belgian Cancer Registry. RESULTS AND CONCLUSIONS: The incidence of oropharyngeal carcinoma has increased in males and females. Tissues were collected from 264 patients and the HPV status could be defined in 249 of them. The prevalence of HPV(+) oropharyngeal carcinoma was 24.78% (19.93-30.36%). In our cohort, HPV(+) tumors occurred in patients with more advanced tumor stages (p < 0.05), who smoked less (p < 0.05), consumed less alcohol (p < 0.05), had a tonsillar/base of tongue sublocalization (p < 0.05), and were older (p < 0.05). After radiotherapy, locoregional control and disease free survival were significantly better for patients with HPV(+) status (p < 0.05) in univariate analysis. HPV status remained a strong predictor of better locoregional control after multivariate analysis. We found that concurrent chemotherapy had an equal benefit for locoregional control in both HPV(+) and HPV(-) patients. PMID- 24765824 TI - Appraisal of the peri-hospital management and evolving microbiology of peritonsillar abscess disease. AB - OBJECTIVES: Peritonsillar abscess (PTA) is a common complication of tonsillitis, yet there is limited consensus regarding its management and epidemiology. Current issues include pre-hospital care provided by general practitioners (GP) in the community (ii) the lack of standardized protocols for in-patient management and (iii) the role of routine microbiology studies in patients with PTA. We performed a retrospective review of confirmed cases of PTA presenting to a west of Ireland tertiary referral center to evaluate the peri-hospital management and role of microbiology studies in such cases. METHODOLOGY: Retrospective chart review of 200 confirmed cases of peritonsillar abscess. RESULTS: The annual incidence of PTA in the west of Ireland population was 14/100,000. Pre-hospital treatment given by Primary Care Physicians (PCP) was often deficient with 84 (42%) patients receiving no treatment prior to hospital referral. Needle aspiration was the most common technique used to drain the PTA 142 (71%). Anaerobes were isolated in 54 (27%) of cases demonstrating an increasing importance of these bacteria in PTA disease. Metronidazole with either benzylpenicillin 72 (36%), or co-amoxiclav 82 (41%), was the most common empiric antibiotics used. Successful treatment of all cases of PTA with the use of empiric antibiotics was achieved before results arising from microbiology became available. CONCLUSION: The epidemiology of PTA is not well described. We have described the epidemiology for PTA disease in the west of Ireland population for the first time. Needle aspiration was the most common drainage technique used. Empiric antibiotic treatment based on clinical response is advised with antibiotics effective against aerobic and anaerobic bacteria recommended. PMID- 24765825 TI - Use of the Berlin Questionnaire to screen at-risk patients for obstructive sleep apnea. AB - OBJECTIVE: To investigate the value of the Berlin Questionnaire (BQ) for screening at-risk patients for obstructive sleep apnea (OSA). MATERIALS AND METHODS: This study included 217 subjects who were referred to a Department of Otolaryngology, Head and Neck Surgery for evaluation of suspected OSA. The subjects were classified as being at high or low risk of OSA according to their BQ score. The apnea hypopnea index (AHI), body mass index (BMI), Epworth sleepiness score, and BQ results were compared in the two risk groups, and the correlation of BQ with AHI was analyzed. The predictive accuracy of risk grouping was assessed for AHI > 5 and AHI > 15. RESULTS: The BQ identified 82.03% of the subjects as being at high risk of sleep apnea and 17.9% as being at low risk. Using a cut-off point of AHI > 5, the sensitivity was 83.4% and the specificity was 22.2%; the positive predictive value was 76.4% and the negative predictive value was 30.8%. Using a cut-off point of AHI > 15, the sensitivity was 89.3% and the specificity was 22.6%; the positive predictive value was 42.1% and the negative predictive value was 76.9%. CONCLUSIONS: These findings indicate that BQ is a poor predictor of OSA in patients who are at high risk of OSA. The BQ does not appear to be an appropriate screening tool for determining the risk of sleep apnea in this population. PMID- 24765826 TI - Platelet-rich fibrin (PRF): an autologous packing material for middle ear microsurgery. AB - OBJECTIVES: To assess the use of PRF prepared using an optimised protocol in middle ear surgery as a substitute for conventional packing products of animal origin such as collagen derived from porcine skin. METHODOLOGY: A retrospective study of 108 patients in whom optimised PRF was used exclusively to pack the external auditory canal or middle ear. The effectiveness or harmlessness of the PRF was evaluated by assessing a range of parameters. A morphological comparison was also made of PRF produced using the Choukroun procedure and our procedure. RESULTS: The success rate of the repair of the tympanic membrane one year after the surgery was 45/48 patients. In 5 of 63 patients in whom a retro-auricular approach and wall-up technique were used, granuloma was observed along the incision in the ear canal. Granuloma was not seen in any of the 23 patients undergoing a procedure with an endaural approach. CONCLUSION: The use of a material prepared from patients themselves and not of animal origin has numerous advantages in terms of biocompatibility and safety, without any adverse effect on the success rate for general middle ear procedures. The protocol is simple and does not prolong the time spent by the patient in the operating theatre. The Choukroun technique should be modified to prevent excessive failure rates in PRF processing. PMID- 24765827 TI - To study the role of antibiotic+steroid irrigation of the middle ear in active chronic otitis media with small perforation and pulsatile discharge. AB - OBJECTIVE: To evaluate the usefulness of antibiotic+steroid irrigation of the middle ear in patients with otitis media with small perforation and pulsatile discharge. METHOD: A prospective, randomised, evaluator-blinded study was carried at a single tertiary care centre over eight years, looking at 100 patients with chronic suppurative otitis media involving small tympanic membrane perforations and pulsatile mucopurulent discharge. The patients were randomised and divided into two groups. In group A, the examination under microscope, with suction cleaning of the external canal, was followed by irrigation of the middle ear with antibiotic+steroid solution for up to one week, while group B was prescribed self administration of the same drops with systemic antibiotics. The patients were followed up daily for 10 days to monitor otorrhoea relief and on a weekly basis subsequently to monitor the healing of the tympanic membrane. RESULTS: Forty-nine patients in group A had a dry ear after 3-7 days of daily suction and the irrigation of middle ear with the antibiotic+steroid solution and 44 had a healed tympanic membrane after an average three months of follow-up. Five patients with dry ear but persistent perforation underwent tympanoplasty, while only one patient with a persistent ear discharge underwent mastoid exploration. In group B, eight patients on oral antibiotics and self-administration of the same drops had dry ear while 34 had dry ear after receiving intravenous antibiotics. Thirty perforations healed spontaneously and 12 required tympanoplasty. In 8 patients, the tympano-mastoid was explored and these patients had dry, hearing ears only after surgery. CONCLUSION: Patients with chronic suppurative otitis media involving small perforations and pulsatile discharge can be managed conservatively with simple suction cleaning + middle ear irrigation with antibiotics + steroid drops. PMID- 24765828 TI - Quality of life in patients with tinnitus and sensorineural hearing loss. AB - The severity of tinnitus often correlates to psychological and general health factors and the risk of depression and insomnia may be higher in patients with tinnitus. METHODS: Three questionnaires about physical and psychological health were mailed to 714 Swedish patients with tinnitus and sensorineural hearing loss. A total of 555 (78%) patients replied and 426 patients (77%) submitted their answers to the questionnaires. RESULTS: Female patients had significantly higher Tinnitus Handicap Inventory scores than male patients. An open question about the experienced quality of the care that the patients obtained at our ENT clinics resulted in 159 comments (37%). The majority of the comments were about the hearing aids and many patients did not identify their hearing aids as a treatment. Patients who did not feel that the treatment they obtained at our ENT clinics was good had a significantly higher pure tone average (PTA). CONCLUSION: The results showed that many patients who did not feel that the treatment they obtained at our ENT clinics was good had no hearing aids (61%) and this level of dissatisfaction was significantly higher than in patients who stated that they had received treatment (45%). The use of hearing aids as the main treatment model in patients suffering from tinnitus and hearing impairment can be recommended in these patients. Further research is required to find an approach that could motivate patients with both tinnitus and hearing impairment to use hearing aids. PMID- 24765829 TI - Ototoxicity screening of patients treated with streptomycin using distortion product otoacoustic emissions. AB - OBJECTIVE: Pure tone audiometry (PTA) is currently widely used to monitor ototoxicity, but this method is time-consuming. Here we validate distortion product otoacoustic emission (DPOAE) as an instrument for early detection of ototoxicity. METHODS: A cohort study was performed on newly diagnosed tuberculosis patients who were treated with streptomycin. The patients underwent hearing assessment using conventional PTA and high-frequency DPOAE (8, 9 and 10 kHz) on days 0, 7, 14, 28 and 56 of streptomycin treatment. Detection of ototoxicity according to the duration of streptomycin treatment was compared between DPOAE and PTA. RESULTS: Of 96 newly diagnosed patients treated with streptomycin, 50 completed the study. During the treatment period, 62.5% of the patients had vertigo, while 37.5% complained of tinnitus. DPOAE detected ototoxicity in 47.7% of the cases at day 7, 66.0% at day 14, 70.0% at day 28 and 77.1% at day 56 of streptomycin treatment. The higher frequencies were affected more by ototoxicity, with significant differences at 8 vs. 9 kHz on all testing days and at 9 vs. 10 kHz except on days 7 and 56 (p < 0.001). Hearing loss was detected by PTA in 2.3% of patients on day 7, in 10.6% on day 14, in 22.0% on day 48 and in 29.2% on day 56. CONCLUSION: DPOAE is a sensitive tool that can detect early changes in the cochlea due to ototoxicity. Use of DPOAE rather than PTA to screen for ototoxicity could reduce screening time and would allow clinical monitoring of more patients. PMID- 24765830 TI - Impact of endoscopic sinus surgery on the quality of life of patients with nasal polyposis. AB - OBJECTIVES: Chronic sinusitis with polyposis (CSWP) is associated with high direct and indirect annual costs. This condition affects several aspects of daily life, and CSWP patients usually suffer from decreased quality of life (QOL). Treatment with functional endoscopic sinus surgery (FESS) is reported to improve the QOL of patients with CS. Here we evaluated the factors that affected QOL improvement in CSWP patients who were candidates for FESS. METHODS: All patients with CSWP who were treated at the Imam Khomeini Hospital Complex in Tehan, Iran that were candidates for FESS were recruited. Patients with systemic or neurologic diseases that could affect their QOL were excluded. Clinical signs were recorded before and after FESS using the sinonasal outcome test (SNOT-22) and QOL questionnaires. The patient's history of allergic rhinitis, aspirin sensitivity, asthma and smoking was recorded. QOL and associations with clinical features were evaluated within twelve months after FESS. RESULTS: The study included 47 patients with a mean age of 39.5 +/- 15.4 years (61.7% women). FESS resulted in significant improvements in QOL based on the SNOT-22 and QOL questionnaires (p = 0.0001 for both). Septal deviation was the only single characteristic that was significantly associated with QOL improvements. CONCLUSION: FESS significantly improved the QOL of patients with CSWP. However, patients with septal deviation benefited the most from FESS. PMID- 24765831 TI - Primary undifferentiated carcinoma of the trachea. AB - BACKGROUND: Primary undifferentiated or lymphoepithelial carcinoma mainly occurs in the nasopharynx. Tracheal localization is exceedingly rare. To the best of our knowledge, only four cases have been reported previously, all in Asian patients. CASE REPORT: A 61-year-old male European patient presented with hemoptysis and cough for several months. The workup revealed a primary tracheal tumor without regional or distant metastasis. The patient was treated with tracheal resection followed by end-to-end reconstruction. Pathologic analysis of the tumor, including immunohistochemistry, confirmed the diagnosis of lymphoepithelioma-like carcinoma. Testing for Epstein-Barr virus by hybridization in situ was massively positive. With a follow-up at 15 months, the patient is alive and free of disease. CONCLUSION: We report the first case of lymphoepithelioma-like carcinoma in the trachea in the European population. Treatment possibilities are discussed. They should be based on each patient's clinical presentation and the results of their preoperative workup. PMID- 24765832 TI - Immature teratoma of the parapharyngeal space presenting with airway obstruction in an infant. AB - Teratoma is the most common germ cell tumour in childhood. Teratoma typically arises in the sacrococcygeal region, gonads and mediastinum. The head and neck region is seldom involved. Teratomas of the neck region represent one of the most unusual causes of respiratory distress during the neonatal period. We present a case of an immature teratoma in the parapharyngeal space presenting with airway obstruction in an infant. Surgeons should consider the possibility of immature teratoma in the head and neck region in the differential diagnosis of respiratory distress in an infant, even if the patient does not have an external deformity. PMID- 24765833 TI - Pseudotumoral allergic fungal sinusitis with skull base involvement. AB - Here we report a case of pseudotumoral recurrence of allergic fungal sinusitis with involvement of the skull base that was successfully treated with systemic corticosteroids and itraconazole without surgery. This report discusses the sometimes misleading radiological and clinical features as well as the diagnostic and therapeutic challenges of a condition that should be recognized by ENT specialists, neurosurgeons, ophtalmologists and radiologists. PMID- 24765834 TI - Endoscopic endonasal surgery for pterygopalatine fossa schwannoma via prelacrimal recess-maxillary sinus. AB - OBJECTIVE: To explore a new approach for treating pterygopalatine fossa (PPF) schwannomas via endoscopic transnasal prelacrimal recess-maxillary sinus (MS). METHODOLOGY: Five patients with PPF schwannomas underwent surgical resection of the tumors using this approach. RESULTS: All patients had adequate exposure and complete tumor resection. No major postoperative complications were observed. No evidence of tumor recurrence was noted after follow-up with magnetic resonance imaging and serial evaluations for 12 to 40 months postoperatively. No patients had epiphora, and the shape of the inferior turbinate (IT) was favorable. CONCLUSIONS: Treatment of PPF schwannoma via endoscopic transnasal prelacrimal recess-MS is safe and effective. Additionally, this approach is minimally invasive not only for the PPF, from which the benign lesions can be completely removed, but also for the MS. This is especially true with lesions of the prelacrimal and alveolar recesses that can be resected. This approach is necessary to prevent structural and functional damage of the nasal cavity, especially the IT and nasolacrimal duct, allowing better healing with decreased morbidity and shorter recovery periods. PMID- 24765835 TI - [What is sustainability science?]. AB - Sustainability is the theme of our time and also the grandest challenge to humanity. Since the 1970s, the term, sustainable development, has frequently appeared in the scientific literature, governmental documents, media promotions for public goods, and commercial advertisements. However, the science that provides the theoretical foundation and practical guidance for sustainable development--sustainability science--only began to emerge in the beginning of the 21st century. Nevertheless, the field has rapidly developed in depth and expanded in scope during the past decade, with its core concepts and research methods coalescing. China, as the most populous country in the world and home to the philosophical root of sustainability science-the unity of man and nature, is obligated to take upon the challenge of our time, to facilitate global sustainability while pursuing the Chinese Dream, and to play a leading role in the development of sustainability science. Toward this grandiose goal, this paper presents the first Chinese introduction to sustainability science, which discusses its basic concepts, research questions, and future directions. Sustainability science is the study of the dynamic relationship between humans and the environment, particularly focusing on the vulnerability, robustness, resilience, and stability of the coupled human-environment system. It is a transdisciplinary science that integrates natural sciences with humanities and social sciences. It hinges on the environment-economy-society nexus, and merges basic and applied research. The key components of sustainability often change with time, place, and culture, and thus sustainability science needs to emphasize multi-scale studies in space and time, with emphasis on landscapes and regions over a horizon of 50 to 100 years. It needs to focus on the relationship between ecosystem services and human well-being, as influenced by biodiversity and ecosystem processes as well as climate change, land use change, and other socioeconomic drivers. Landscape sustainability is at the core of sustainability science, and is expected to be a hot research topic in the next few decades. PMID- 24765836 TI - [Effects of tree species transfer on soil dissolved organic matter pools in a reforested Chinese fir (Cunninghamia lanceolata) woodland]. AB - Based on the comparison between reforested 19-year-old Mytilaria laosensis and Cunninghamia lanceolata plantations on cut-over land of C. lanceolata, effects of tree species transfer on soil dissolved organic matter were investigated. Cold water, hot water and 2 mol x L(-1) KCl solution were used to extract soil dissolved organic carbon (DOC) and dissolved organic nitrogen (DON) from 0-5, 5 10 and 10-20 cm soil layers. In M. laosensis plantaion, the concentrations of soil DOC extracted by cold water, hot water and 2 mol L(-1) KCl solutions were significantly higher than that in C. lanceolata plantation. In the 0-5 and 5-10 cm layers, the concentrations of soil DON extracted by cold water and hot water in M. laosensis plantation were significantly higher than that in C. lanceolata plantation. The extracted efficiencies for DOC and DON were both in order of KCl solution > hot water > cold water. In the 0-5 cm layers, soil microbial biomass carbon (MBC) under M. laosensis was averagely 76.3% greater than under C. lanceolata. Correlation analysis showed that there were significant positive relationships between hot water extractable organic matter and soil MBC. Differences in the sizes of soil DOC and DON pools between the M. laosensis and C. lanceolata forests might be attributed to the quality and quantity of organic matter input. The transfer from C. lanceolata to M. laosensis could improve soil fertility in the plantation. PMID- 24765837 TI - [Spatial heterogeneity of soil organic carbon and total nitrogen in a monsoon evergreen broadleaf forest in Dinghushan, Guangdong, China]. AB - Geostatistical techniques were used to quantify the spatial heterogeneity of soil organic carbon and total nitrogen of one monsoon evergreen broadleaf forest area in Dinghushan, Guangdong, China. The results demonstrated that a significant spatial autocorrelation existed between soil organic carbon and total nitrogen contents in the Dinghushan monsoon evergreen broadleaf forest, such that 93.6% and 53.7% of their total spatial heterogeneity originated from their spatial autocorrelation. This observation agreed with a traditional statistics analysis showing a significant linear correlation between soil organic carbon and total nitrogen, and also their spatial autocorrelation existed at a landscape level. The best fit from an exponential model showed that soil organic carbon had high degree of spatial heterogeneity at a scale of 17.4 m. PMID- 24765838 TI - [Eco-physiological response of Quercus variabilis seedlings to increased atmospheric CO2 and N supply]. AB - The effect of CO2 enhancement, nitrogen deposition and their interaction on the northern boundary (Zhuanghe in Liaoning Province) of Quercus variabilis seedlings was studied by controlling the CO2 concentration (700 micromol x mol(-1); 400 micromol x mol(-1)) and nitrogen level (non nitrogen fertilizer: CK; nitrogen fertilizer: 120 kg N x hm(-2)). The results showed that under elevated CO2 the Q. variabilis seedlings' leaf morphology, photosynthetic pigments and leaf nitrogen content tended to decrease, and the dark respiration rate decreased 63. 3% and soluble sugar increased 2.6%. Nitrogen deposition significantly promoted the Q. variabilis seedlings' leaf morphology and photosynthetic pigments, leading to increased leaf nitrogen content, decreased potassium content, and 26.7% of increase in nitrogen to potassium ratio. CO2 and N interaction played a significant role on promoting the Q. variabilis seedlings' leaf morphology and photosynthetic. The maximum net photosynthetic and light saturation point were 1.4 and 2.6 times of the control, while dark respiration and light compensation point decreased 65.9% and 50.0%, respectively. Elevated CO2 and nitrogen deposition had a positive effect on Q. variabilis seedlings to some degree, which might result in the movement of distribution boundary of Q. variabilis to north. PMID- 24765839 TI - [Germination and seedling growth of Artemisia halodendron under different incubation environments]. AB - Artemisia halodendron is a dominant species in mobile and semi-mobile dunes of Horqin Sand Land. To investigate the germination character and seedling growth under different temperature and light conditions, the germination rate, germination index and growth of radicle and plumule were measured after treatments in laboratory and heating cabinet incubations. In the laboratory the light and temperature were near to nature condition, while in the heating cabinet it was kept at 25 degrees C with varying durations of light supply, including 24 , 12- and 0-hour light per day. Germination rate (66.6%) and germination index (19.1%) under laboratory condition were both significantly lower than in the heating cabinet (P < 0.05). In the heating cabinet, the germination rate under 0 hour light was 70.2%, which was insignificantly lower (P > 0.05) than under 12- and 24-hour light conditions (both 73.4%), and the germination index under 24 hour light was 28.2%, which was significantly (P < 0.05) lower than under 0- and 12-hour light conditions (31.3% and 30.8%, respectively). Radicle and plumule growth responded to light more readily than the seed germination rate and germination index during the process of germination, and the radicle growth was inhibited by darkness while promoted by light, and the plumule lengths under 0- and 12-hour light conditions were 2.81 cm and 1.51 cm, respectively, significantly higher than under 24-hour light (1.21 cm) and natural condition (1.27 cm). It was concluded that temperature was a main factor in seed germination, and seedling growth was mainly influenced by light regime. PMID- 24765840 TI - [Dynamics of unprotected soil organic carbon with the restoration process of Pinus massoniana plantation in red soil erosion area]. AB - By the method of spatiotemporal substitution and taking the bare land and secondary forest as the control, we measured light fraction and particulate organic carbon in the topsoil under the Pinus massoniana woodlands of different ages with similar management histories in a red soil erosion area, to determine their dynamics and evaluate the conversion processes from unprotected to protected organic carbon. The results showed that the content and storage of soil organic carbon increased significantly along with ages in the process of vegetation restoration (P < 0.01). The unprotected soil organic carbon content and distribution proportion to the total soil organic carbon increased significantly (P < 0.05) after 7-11 years' restoration but stabilized after 27 and 30 years of restoration. It suggested that soil organic carbon mostly accumulated in the form of unprotected soil organic carbon during the initial restoration period, and reached a stable level after long-term vegetation restoration. Positive correlations were found between restoration years and the rate constant for C transferring from the unprotected to the protected soil pool (k) in 0-10 cm and 10-20 cm soil layers, which demonstrated that the unprotected soil organic carbon gradually transferred to the protected soil organic carbon in the process of vegetation restoration. PMID- 24765841 TI - [Soil respiration dynamics and its controlling factors of typical vegetation communities on meadow steppes in the western Songnen Plain]. AB - In order to accurately explore the soil respiration dynamics and its controlling factors of typical vegetation types in the western Songnen Plain, soil respiration rates of Chloris virgata, Puccinellia distans, Phragmites australis and Leymus chinensis communities were measured. The results showed that the diurnal curves of soil respiration rates of the four vegetation communities had simple peak values, which appeared at 11:00-15:00, and the valley values occurred at 21:00-1:00 or 3:00-5:00. The seasonal dynamic patterns of their soil respiration rates were similar, with the maximum (3.21-4.84 micromol CO2 x m(-2) x s(-1)) occurring in July and August and the minimum (0.46-1.51 micromol CO2 x m(-2) x s(-1)) in October. The soil respiration rates of the four vegetation communities had significant exponential correlations with ambient air temperature and soil temperature. Soil moisture, however, only played an important role in affecting the soil respiration rate of C. virgata community while air humidity near the soil surface was significantly correlated with the soil respiration rates of P. australis and L. chinensis communities. The soil salt contents seriously constrained the CO2 dioxide emission, and the soil pH, electrical conductivity (EC), exchangeable sodium percentage (ESP) could explain 87%-91% spatial variations of the soil respiration rate. PMID- 24765842 TI - [Effects of coat and sowing depth on seed germination and early seedling growth of Quercus wutaishanica]. AB - Under shade environment in glasshouse, the effects of seed coat and sowing depth (0, 2, 5, 10 or 15 cm) on seed germination and early seedling growth of Quercus wutaishanica were studied. Seed coat had obvious inhibiting effects on the germination of Q. wutaishanica seeds. The germination percentage of uncoated seeds increased significantly, averagely by 19.4% at different sowing depths. The germination index and vigor index were increased significantly and the germination was speeded in the peeling treatment. The germination percentages of uncoated and coated seeds were the highest at the sowing depth of 2 cm with 78.9% and 62.2%, respectively. The germination index and vigor index were the highest at the sowing depth of 2 cm, while the coefficient of rate of germination were the highest at the sowing depth of 5 cm. Leaf area per seedling and dry mass of seedlings increased significantly in the peeling treatment compared with those in the unpeeling treatment, but specific root length decreased significantly. The shoot height in the peeling and unpeeling treatments were the highest at the sowing depth of 5 cm with 13.8 and 14.2 cm, respectively. With the increasing of sowing depth, the basal stem diameter of seedlings increased, but tap-root length, number of lateral root and maximum of lateral root all decreased. Sowing depth had little influence on dry mass of seedlings. PMID- 24765843 TI - [Greenhouse gases fluxes of biological soil crusts and soil ecosystem in the artificial sand-fixing vegetation region in Shapotou area]. AB - Uncertainties still existed for evaluating greenhouse gases fluxes (GHGs), including carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) at the regional scale for desert ecosystem because available GHGs data about biological soil crusts (BSCs) was very scarce. In 2011 and 2012, soil ecosystem covered by various types of BSCs and BSCs at different succession stages in an artificial sand-fixing vegetation region established in various periods at southeast of the Shapotou area in Tengger Desert was selected to measure fluxes of CO2, CH4 and N2O using static chamber and gas chromatography. The results showed that curst type, recovery time and their interactions with sampling date significantly affected CO2 flux. Recovery time and interaction of crust type and sampling date significantly affected CH4 flux. Sampling date significantly affected the fluxes of CO2, CH4 and N2O. The mean annual flux of CO2 for moss crust (105.1 mg x m(-2) x h(-1)) was significantly higher than that of algae crust (37.7 mg x m(-2) x h( 1)) at the same succession stage. Annual mean CH4 and N2O consumption was 19.9 and 3.4 microg x m(-2) x h(-1), respectively. Mean annual consumption of CH4 and N2O for algae crust was slightly higher than that of moss crust, however, significant difference was not found. Ecosystem respiration (Re) of desert soil covered by BSCs increased with the recovery process of desert ecosystem, in contrast, consumption of CH4 and N2O decreased. Re of moss crust was more sensitive to temperature and moisture variation than algae crust and Re sensitivity of temperature and moisture gradually increased with the development and succession of BSCs. Both soil temperature and moisture were not the main factor to determine CH4 and N2O fluxes of BSCs-soil in desert ecosystem. PMID- 24765844 TI - [Diurnal and seasonal variations of energy balance over Horqin meadow]. AB - Based on the measurements of eddy flux and micrometeorological factors, this paper analyzed the diurnal and seasonal variations of energy balance over Horqin meadow. The results showed that annual energy balance ratio (EBR) of the eddy covariance system was 0.77, and EBR was biggest in growing season, middle in bare soil period and smallest in snow-covered period. Diurnal variations of energy components all presented bell-shaped curves. The peak of net radiation appeared around 12:00 and peaks of other components slightly lagged. Seasonal variation of net radiation presented a single-peak curve, and the annual average was 5.71 MJ x m(-2) x d(-1). Seasonal variation of latent heat flux was similar to that of net radiation, and the annual average was 2.84 MJ x m(-2) x d(-1). Seasonal variation of sensible heat flux presented a double-peak curve, and the peaks appeared in April and September, respectively. Annual averaged sensible heat flux was 1.87 MJ x m(-2) x d(-1). Maximum soil heat flux (3.47 MJ x m(-2) x d(-1)) appeared in April, and the soil heat flux became negative after September. Annual budget ratios of energy components presented a decreasing order of latent heat flux, sensible heat flux and soil heat flux, which accounted for 49.8%, 35.8% and 3.1% of net radiation, respectively. Seasonal variation of Bowen ratio (beta) presented a 'U' shape, and the annual average was 1.61. beta was small (0.18) and relatively stable in growing season, while it was large (2.39) and fluctuated severely in non-growing season. PMID- 24765845 TI - [Edge effect of the plant community structure on land-bridge islands in the Thousand Island Lake]. AB - The research was conducted on 29 land-bridge islands in the Thousand Island Lake (TIL), where long-term monitoring plots were set up during 2009-2010. The community attributes including species richness, Shannon index, plant mean height, plant mean diameter at breast height (DBH) and plant density along the edge-interior gradient from edge to interior forest were calculated to investigate the edge effect. The results showed that the species richness and Shannon index were affected through the whole gradient (larger than 50 m), while the range of edge effect was 20-30 m on mean plant height, and 10 m on plant density and mean DBH. Community attributes differed significantly among the edge gradients. The species richness and Shannon index peaked at the intermediate edge gradient. Plant density decreased and plant mean height increased along the edge to interior gradient. All five community attributes were significantly associated with the edge gradient, also different functional groups, evergreen or deciduous species, trees or shrubs, shade tolerant or shade intolerant species, were differentially influenced by the edge effect. It was demonstrated the influence of edge effect on the fragmented forest community varied with community attributes and functional groups. PMID- 24765846 TI - [Distribution of soil carbon storage in different saltmarsh plant communities in Chongming Dongtan wetland]. AB - Abstract: The high productivity of saltmarsh vegetation in coastal wetlands plays an important role on the formation of soil carbon pool. This paper studied the biomass difference, the spatiotemporal dynamics and vertical distribution of soil carbon storage in three dominant saltmarsh plant communities, i. e., Phragmites australis, Spartina alterniflora and Scirpus mariqueter in the Chongming Dongtan wetland, in the Yangtze Estuary. The results indicated that the gross biomass in the three saltmarsh plant communities was in the order of S. alterniflora (5750.7 g x m(-2)) > P. australis (4655.1 g x m(-2)) > S. mariqueter (812.7 g x m(-2)). The aboveground biomass was the highest in summer and autumn, and the underground biomass was the highest in winter. The soil carbon storage (0-50 cm) was the lowest in spring, gradually increased, and was the highest in winter. The annual increment of soil carbon storage decreased from the high tidal zone to the low tidal zone, and was in the order of P. australis community (711. 8 g x m(-2)) > S. alterniflora community (646.2 g x m(-2)) > S. mariqueter community (185.3 g x m(-2)) > bare mudflat (65.6 g x m(-2)). The highest value was in the 25-30 cm, 10 15 cm, 30-35 cm and 30-40 cm soil layers for bare mudflat and the S. mariqueter, S. alterniflora and P. australis communities, respectively. There was a significant linear relationship between the soil carbon storage and the underground biomass in the different saltmarsh communities. PMID- 24765847 TI - [Characteristics of spatial variation of soil nutrients in sloping field in a gorge karst region, southwest China]. AB - Based on a grid (20 m x 20 m) sampling, spatial heterogeneity and pattern of soil nutrients in sloping field in the gorge karst region, southwestern China, were explored by using classical statistics and geostatistics methods. The results showed that soil nutrient contents in slope field in the canyon karst region were more abundant, where pH value had a weak variation and the soil organic matter (SOM) had a moderate degree of variation. All the soil nutrients had moderate or strong variation with an order of available phosphorus (AP) > total potassium (TK) > SOM > alkaline nitrogen (AN) > total nitrogen (TN) > total phosphorus (TP) > available potassium (AK). All of the soil nutrients had a good spatial autocorrelation and the autocorrelation function performed in the same law of developing from positive to negative direction with the inflection point ranged from 80 to 100 m. In addition, the Moran's I was small for TK and AP while large for other nutrients. Characteristics of spatial variation differed among soil nutrients. Exponential model fitted best for TK and AP, in which the ratio of nugget to sill (C0/(C0 + C)) and the range (A) were small and the fractal dimension (D) was high, showed a strong spatial correlation. Spherical model fitted best for other soil nutrients, with C0/(C0 + C) , the range (A) and D showing a moderate autocorrelation. Kriging analysis clearly indicated that pH, SOM, TN, TP and AN were distributed in a concave pattern, while AP and AK had fragmented patch distribution. Therefore, vegetation, topography, human disturbance and strong heterogeneity of microhabitats are main factors leading to the differences in patterns of soil nutrients on the sloping land in the gorge karst region. PMID- 24765848 TI - [Remote sensing analysis of forest resources characteristics in main ecological restoration counties in the Three-gorge area based on the 2nd-class inventory data]. AB - Based on high-resolution SPOT-5 images, combined with topographic (1:10000) calculating terrain-bit index, the distribution characteristics of woodlands in different terrain niches, and the buffer radii of different roads, water bodies and settlements were identified by using ArcGIS space overlay and buffer analysis function. Results showed that woodland resources were abundant, and arbor woodland and shrub land were the main species, which mainly distributed in two mountain areas (Fangdou Mountain, Qiyao Mountain) affected by topographic restriction and woodland natural basis. The woodland terrain niche distribution index showed an overall upward trend with increasing terrain niche gradient, especially for the arbor woodland and shrub land, while the other woodland types presented an opposite trend. The percentage of woodland area occupying the corresponding buffer radius around the roads, waterbodies and settlements had a strong similarity with the woodland terrain niche distribution index. Only around the settlements, bamboo forest, sparse woodland and immature woodland occupied higher percentages of the woodland area of the corresponding buffer radius than that of arbor woodland and shrub land. Woodland distribution was mainly controlled by large landform patterns of mountain features, while the distribution of woodlands in the different terrain niches and the different buffer radii of roads, waterbodies and settlements were driven mainly by duress of human activities under the auspices of the large landform patterns. PMID- 24765849 TI - [Models for biomass estimation of four shrub species planted in urban area of Xi'an city, Northwest China]. AB - Four common greening shrub species (i. e. Ligustrum quihoui, Buxus bodinieri, Berberis xinganensis and Buxus megistophylla) in Xi'an City were selected to develop the highest correlation and best-fit estimation models for the organ (branch, leaf and root) and total biomass against different independent variables. The results indicated that the organ and total biomass optimal models of the four shrubs were power functional model (CAR model) except for the leaf biomass model of B. megistophylla which was logarithmic functional model (VAR model). The independent variables included basal diameter, crown diameter, crown diameter multiplied by height, canopy area and canopy volume. B. megistophylla significantly differed from the other three shrub species in the independent variable selection, which were basal diameter and crown-related factors, respectively. PMID- 24765850 TI - [Assessment for spatial uncertainty of daily minimum temperature by using sequential Gaussian simulation]. AB - Understanding daily minimum temperature is of great importance for assessing low temperature damages to crops and guiding people to take timely remedial measures to ensure food security. Kriging is a widely used technology for mapping the spatial distribution of the near-surface temperature. However, the smoothing effect, commonly found in the Kriging maps, leads to low values to be overestimated and high values to he underestimated. For daily minimum temperature on Hainan Island which was affected by cold air on December 12, 2011, cross validation was adopted to evaluate the prediction accuracy of ordinary Kriging (OK) and Kriging with external drift (KED). The spatial distribution maps of daily minimum temperature on Hainan Island on December 12, 2011 produced by OK and sequential Gaussian simulation (SGS) were compared. Results showed that the prediction accuracy of KED (r = 0.86) was not superior to OK (r = 0.86) significantly. SGS could generate multiple equiprobable simulation realizations, and the distribution and variance function of the original data could be reproduced in the realizations. The simulation realizations generated by SGS overcame the smoothing effect of Kriging and could more truly reflect the spatial distribution of minimum temperature on the day on Hainan Island. In the region where daily minimum temperature was low, and the temperature change was small, the conditional variance of the SGS results was less than the ordinary Kriging variance. Spatial uncertainty of a potential chilling damage area could be quantified by multiple simulation realizations generated by SGS. SGS was a valuable tool for assessing agro-meteorological disasters caused by low temperature. PMID- 24765851 TI - [Characteristics of soil ammonia-oxidation microbial communities in different subtropical forests, China]. AB - To investigate the effects of different forest stands in subtropical China on the communities of soil ammonia-oxidizing microorganisms, we characterized the abundance of ammonia-oxidizing archaea (AOA) and bacteria (AOB), and the community structure of AOA in soils under stands of broad-leaved (BF) , Chinese fir (CF) , Pinus massoniana (PF) and moso bamboo (MB) forests using real-time quantitative PCR and denaturing gradient gel electrophoresis (DGGE). The results showed that the AOA gene copy numbers (1.62 x 10(6)-1.88 x 10(7) per gram of dry soil) were significantly higher than those of AOB genes (2.41 x 10(5)-4.36 x 10(5) per gram of dry soil). Significantly higher soil AOA abundance was detected in the MB than that in the CF (P < 0.05), and the latter was significantly higher than that in the BF and PF soils (P < 0.05). There were no significant differences in the soil AOB abundance among the four forest stands. As indicated by DGGE pattern, soil AOA species varied among the four forest stands. There was a difference in the soil AOA communities between the CF and MB stands. The AOA demonstrated a competitive advantage over the AOB in the soils under these major subtropical forests. Soil pH, concentrations of soil available potassium and organic carbon as well as the forest type were the main factors that influence the variation of AOA community structure and diversity. PMID- 24765852 TI - [Effects of deep plowing and mulch in fallow period on soil water and yield of wheat in dryland]. AB - A field test was carried out in Qiujialing Village, Wenxi, Shanxi from 2009 to 2011 to study the soil water movement of 0-300 cm layer, yield formation and water use efficiency (WUE) of wheat with deep plowing and mulching the whole ground immediately (no mulch as control) 15 days and 45 days after harvest. The results indicated that deep plowing and mulch in fallow period could improve soil water storage of the 100-180 cm layer before sowing, the soil water storage efficiency in fallow period, and soil water storage from pre-wintering stage to booting stage. Compared with deep plowing 15 days after wheat harvest, deep plowing 45 days after wheat harvest did better in improving soil water storage and water use efficiency, as well as ear number and yield, which was more conducive in the year with more precipitation. Generally, deep plowing and mulching after raining during fallow period could benefit the soil water storage and conservation, thus would be helpful to improve wheat yield in dryland. PMID- 24765853 TI - [Resource competition in maize/soybean intercropping system]. AB - The soil water storage, growth development, biomass and yield in maize/soybean intercropping system under different separation methods were measured to analyze the resource competition of the intercropping crops. The treatments included no shoot or root separation (T1), shoot and root separation (T2), only root separation (T3), and only shoot separation (T4). Results indicated that compared to others, the average soil moisture content in the 0-120 cm soil layer decreased by 3.1%-12.9% in maize line, and by 2.8%-12.5% in soybean line for T1. Compared to T1, maize growth stage in T2, T3 and T4 came late, and the plant height, leaf area and cumulative total biomass, yield and yield components all decreased, while the trends found for soybean were the opposite. In summary, the changes of crop growth and yield in the maize/soybean intercropping system were driven by the interactions of above- and below-ground parts, and the below-ground part played a more important role. PMID- 24765854 TI - [Relationship between drought resistance and endogenous hormone content in different citrus species]. AB - Eight plant seedlings of citrus species, Citrus tangerina, C. erythrosa, C. chuana, Poncirus trifoliate, C. sinensis x P. trifoliate, C. grandis, C. sinensis and C. vessucosa were used to investigate the effects of drought stress on plant biomass, drought resistance coefficient and leaf hormone (ABA, GA1+3 , ZR, IAA) changes. The results showed that, on the condition of precipitation less than 1200 mm, the biomass of different citrus species reduced obviously, and drought resistance index and drought resistance showed in order of C. erythrosa > C. tangerina > P. trifoliate > C. chuana > C. sinensis x P. trifoliate > C. grandis > C. sinensis > C. vessucosa. The leaf ABA contents of the eight species increased whereas GA1+3 , ZR and IAA decreased, under the condition of drought stress. The ratios of ABA/GA1+3 and ABA/ZR in the species of C. erythrosa and C. tangerina increased drastically, yet there was no significant correlation between the ratio of ABA/IAA and the drought tolerance. The drought-resistance index was significantly positively related to the relative content of ABA (P < 0.01), while significantly negatively related to the relative content of GA1+3. The function to enhance drought resistance by those endogenous hormones in the citrus species showed in order of ABA > GA1+3, ZR > IAA. PMID- 24765855 TI - [Impacts of climate change on summer maize production and adaptive selection of varieties in Xingtai County, Hebei, China]. AB - Understanding the impacts of climate change on agriculture production and the underlying mechanism in North China Plain is important to take effective adaptations for national food security. Using Hybrid-Maize model, this paper investigated the impacts of climate change on summer maize yield potential and famers' adaptation by changing varieties with longer growth periods from 1981 to 2010 in Xingtai County, Hebei Province. Results showed a significant warming trend with the average temperature increasing by 0.49 degrees C x 10 a(-1) since the 1980s. Both solar radiation and sunshine hours decreased significantly since the 1980s. The sunshine hours decreased by 0.56 h x d(-1) x 10 a(-1) and the solar radiation decreased by 265.1 MJ x m(-2) x 10 a(-1), while the precipitation kept constant with large variation among years since 1981. Yield potentials of both irrigated and rainfed maize were simulated to decrease by 0.63-0.64 Mg x hm( 2) x 10 a(-1) since 1981 if varieties were assumed fixed with the 1980s. This was mainly due to the decrease of solar radiation during the maize growth season and the shortened growth stage by warming, and around 60% of grain yield decrease was attributed to the decreased solar radiation. In practice, by changing varieties with longer growth periods, the growing degree days of varieties adopted by local farmers since the 2000s increased by 19% (280 degrees C) compared to the 1980s, and consequently the yield potential was simulated to increase by 34%-40% (2.73 3.40 Mg x hm(-2)) for both irrigated and rainfed maize. PMID- 24765856 TI - [Compensation effect of cotton growth and development after soil salt content reduction at bud stage]. AB - To elucidate the dynamic characteristics of cotton growth and development after soil salt content reduction (SD) at bud stage and its effect on yield formation, a pot experiment was conducted in which soil salt content was declined from 5 per thousand level to 2 per thousand level at cotton bud stage. The results showed that the plant height, biomass, total fruit branch and fruit node number, boll number, boll mass of cotton plants increased after soil salt content reduction at bud stage. The distribution proportions of biomass in root and boll decreased after soil salt content reduction, however, the distribution proportions of biomass in leaf, main stem and fruit branch were on the rise. The growth rate of cotton plant increased after soil salt content reduction. Plant dry matter accumulation rate of SD cotton exceeded CK cotton at 22 days after soil salt content reduction. The response of different organs of cotton plant were different to soil salt content reduction, the plant height was the earliest, followed by the fruit branch and fruit node formation, and the bud and boll were the latest, which indicated that the compensation effect of cotton growth and development after soil salt content reduction at bud stage firstly appeared on the formation and growth of new leaf, fruit branch and fruit node, and on this basis, gradually brought out yield compensation. PMID- 24765857 TI - [Effects of girdling on growth, yield and water use efficiency of cotton]. AB - An experiment with girdling applied on the main stem and fruit branch during the early or flourishing stage of flowering and boll-setting was conducted to investigate the effects of different girdling treatments on the growth, yield and water use efficiency (WUE) of cotton. The results showed that compared with the control (CK), leaf area index (LAI) of girdling treatments reduced significantly and the maximum LAI of girdled cotton occurred 5-15 days in advance. Girdling reduced the shedding rate of squares and bolls significantly, and the shedding rate of squares and bolls with girdling applied on the main stem at the flourishing stage was 15.8% lower than that of CK. In contrast with CK, the seed cotton yield and WUE increased by 24.4% and 26.7% with girdling applied on the main stem at the flourishing stage, and increased by 13.9% and 16.7% with girdling applied on the fruit branch at the early stage, respectively. However, the girdling on the fruit branch at the flourishing stage improved the seed cotton yield and WUE insignificantly. The seed-cotton yield with girdling on the main stem at the early stage had not significant difference and its WUE reduced slightly compared with CK. It has been concluded that the girdling applied on the main stem at the flourishing stage of flowering and boll-setting could effectively reduce the abscission rate of squares and bolls, improve yield and WUE significantly, and realize the effective unity of high production and water saving. PMID- 24765858 TI - [Role of water-water circulation in excessive light energy dissipation of ginger leaves]. AB - To investigate the photo-protection of water-water circulation in ginger leaves, the effects of different treatments such as natural light + water control (T1), shading 50% + water control (T2), natural light + 10 mmol x L(-1) IA (T3), shading 50% + 10 mmol x L(-1) IA (T4) on leaf chlorophyll fluorescence parameters, Mehler reaction and the activities of SOD, APX of potted ginger were studied. The results showed that the Pn and Fv/Fm of ginger leaves in T3 and T4 reduced constantly, but that of T1 and T2 had no significant change during treatment. For example, at the ninth day after treatment, the Pn of T3 and T4 decreased by 64% and 33.2% respectively, and the Fv/Fm decreased by 16.5% and 10.9% respectively, while Mehler reaction of T3 and T4 increased by 139.4% and 72.6% respectively, the activity of SOD and APX were significantly higher than those of the controls. At the sixth day after treatment, the leaf Pn and Fv/Fm in all treatments reduced significantly at noon, but Mehler reaction and the activities of SOD and APX increased markedly, and the largest amplitude was observed in T3, followed by T4, and then T1 and T2. So, it was clear that Mehler reaction and the activity of reactive-oxygen scavenging enzymes increased when leaf Pn was inhibited by exogenous IA. The results suggested that water-water circulation played an essential role in dissipating excessive light energy of ginger leaves. PMID- 24765859 TI - [Situation of distribution and utilization of crop straw resources in seven western provinces, China]. AB - Based on agricultural statistical and investigating data on farmers, amount, distribution density and amount per capita of crop straw resources of seven western provinces of China were estimated, the trends of amount dynamics from 1997 to 2011 and distribution and utilization of crop straw resources were analyzed, and the constraints of comprehensive utilizing straw resources and possible ways to improve straw utilization were discussed. Results showed that theoretical amount of crop straw resources in seven western provinces was 8.82 x 10(7) t in 2009, in which straw of cereals accounted for 63.1% of the total, and straw nutrients returned back to fields was 1.20 x 10(6) t, accounting for 50.5% of the total. The distribution density of straw resources of the seven western provinces was less than the national mean, while the amount per capita of straw resources was higher. According to the survey, the straw was mainly used as fuel, feed, industrial materials, matrix and returned field directly, accounting for 33.8%, 29.3%, 5.2%, 1.8% and 13.5% of the total amount, respectively. In addition, the amounts of straw burned and abandoned were 11.1% and 5.3% of the total, respectively. PMID- 24765860 TI - [Assessment of eco-economic system sustainable development of Liaoning province based on emergy analysis]. AB - By constructing an evaluation system based on emergy analysis which included emergy flow, source of emergy index, social subsystem evaluation index, economic subsystem evaluation index, natural subsystem evaluation index and composite index, the development and sustainability of the eco-economic system of Liaoning Province between 2000 and 2010 were evaluated. The result showed that from 2000 to 2010, the total used emergy increased from 3440.12 x 10(20) sej to 7636.33 x 10(20) sej, among which the proportion of the nonrenewable emergy in 2010 occupied the most in the total by 68.6% , and the emergy per capita increased from 8.32 x 10(15) sej to 17.96 x 10(15) sej. The emergy self-support ratio in the system was generally higher, while it dropped from 91.1% in 2000 to 79.9% in 2010. The emergy loading ratio increased from 3.22 to 7.80, the emergy sustainable index dropped from 3.47 to 0.64, and the emergy index for sustainable development decreased from 6.73 to 1.56. It suggested the eco-economic system of Liaoning Province presented an unsustainable development trend. The development level of Liaoning in 2010 merely equaled to the level of Japan and America in the 1980s. PMID- 24765861 TI - [Energy flow characteristics of the compound agriculture-fruit farming system in Xipo Village, Shaanxi, Northwest China]. AB - Taking the crop-fruit farming system in Xipo Village in Chunhua, Shaanxi Province as a case, the energy flow path, input and output structure, and the indices of energy cycle for the agriculture, fruit, stockbreeding and human subsystems were compared between 2008 and 2010. Results showed that during the study period the total investment to the agriculture-fruit farming system (CAF) decreased by 1.6%, while the total output increased by 56.7%, which led to a 59.4% increase of the output/input ratio. Energy output/input ratio of the agriculture, fruit, stockbreeding, human subsystems increased by 36.6%, 21.0%, 10.0% and 3.8%, respectively. The Xipo Village still needed to stabilize the agriculture, develop stockbreeding and strengthen fruit to upgrade the compound agriculture-fruit farming system. PMID- 24765862 TI - [Dynamics and combined injuries of main pest species in rice cropping zones of Yunnan, Southwest China]. AB - A series of rice pest injuries (due to pathogens, insects, and weeds) were surveyed in 286 farmers' fields for major rice varieties of three rice cropping zones of Yunnan Province, Southwest China. The composition and dynamics of main pest species were analyzed, and the trend of rice pest succession in Yunnan was discussed based upon landmark publications. The results showed that the three rice cropping zones had different pest characteristics as regard to main species, dynamics and combined injuries. Sheath rot, bacterial leaf blight, rice stripe, leaf hoppers, armyworms and stem borers were serious in the japonica rice zone. Sheath blight and rice stripe were serious in the japonica-indica interlacing zone. Leaf blast, sheath blight, leaf folders and weeds above rice crop canopy were serious in the indica rice zone. False smut, plant hoppers and weeds below rice crop canopy were ubiquitous and serious in the three kinds of rice cropping zones. Many kinds of weed infestation emerged in the whole rice cropping seasons. Echinochloa crusgalli, Sagittaria pygmaea, Potamogeton distinctus and Spirodela polyrhiza were the main species of weeds in the rice cropping zones of Yunnan. Overall, levels of combined injuries due to pests in the japonica rice zone and the indica rice zone were higher than that in the japonica-indica interlacing zone. In terms of the trend of rice pest succession in Yunnan, injuries due to false smut, sheath blight and plant hoppers seemed to be in a worse tendency in all rice cropping zones of Yunnan, while dominants species of weeds in the paddy fields are shifting from the annual weeds to the perennial malignant weeds. PMID- 24765863 TI - [Sustainability of ecological water transfer and rehabilitation project based on participatory survey]. AB - In the arid inland area of Northwest China, the ecological water transfer and rehabilitation project (EWTRP) is an important measure to restore the deteriorated ecosystem. However, the sustainability of the project is affected by many socio-economic factors. This research was based on results of the questionnaire from Ejina County's farmer households, which included the farmer households' attitude, livelihood and the efficiency of the water resource usage. The results showed that although the EWTRP had made great achievements in vegetation restoration, but the sustainability of the project was affected by the following factors: the ecologically-motivated relocated/resettled herdsmen mainly relied on the compensation from the project, causing them a hard living, and increasing the risk of maintaining the current achievement; the project didn't have a positive impact on water-saving agriculture, the efficiency of water usage was relatively low and had not yet reached the final goal; the compensation of the project only considered the loss of agriculture, but neglected the externality and publicity of eco-water. We suggest that developing education, offering job opportunity and training programs, improving the efficiency of water usage and establishing reasonable water resources compensation mechanisms are needed to be considered as main domain of environmental recovery as well as ecological water transfer and rehabilitation. PMID- 24765864 TI - [Intensive utilization of land in Tiexi old industrial district, Shenyang, Northeast China]. AB - Land use types of the Tiexi old industrial district, Shenyang, Northeast China were derived from QUICKBIRD and IKONOS satellite image interpretation to analyze its dynamics and intensive use by geostatistics and convention statistical methods which could reveal regional environment and socio-economic services. The results showed the main land use types were industrial land and residential land in Tiexi old industrial district. Land use changed significantly from 2000-2010, i. e., the industrial land area decreased rapidly and the housing land area, park land, commercial service land, and grassland increased simultaneously. The district environment was improved and the comprehensive livable level was increasing. Also, the regional functional orientation was becoming clear, the living and business function verged to maturity, and the land use efficiency was increasing. From 2002, the intensive land use level in Tiexi old industrial district was evidently improved, however, the potential of intensive land use could still be further exploited. PMID- 24765865 TI - [Assemblage effect of ground arthropod community in desert steppe shrubs with different ages]. AB - Taking the 6-, 15-, 24- and 36-year-old Caragana intermedia shrubs in desert steppe as a subject, an investigation on soil properties and ground arthropod community was carried out under the shrub and in the open to probe into the assemblage effect of ground arthropod community in desert steppe shrubs with different ages. The results were as follows: 1) In the 6-year-old shrubland, significant differences were only found in soil physical properties (soil texture, soil moisture and electrical conductivity) between the microhabitats under shrub and in the open. Beginning from the 15-year-old shrubland, however, soil organic matter and nutrition (N, P) increased significantly. 2) A total of 27 groups were captured in the studied sites which dominated by Carabidae, Tenebrionidae and Formicidae. From 6- to 15-year-old shrubland, the number of dominant groups decreased while that of common groups increased for the ground arthropod community under the shrub. From 15- to 24- and 36-year-old shrubland, the difference between the microhabitats under the shrub and in the open decreased firstly, and then increased. Some special groups appeared under the shrub in the 36-year-old shrubland, and dung beetles became dominant. 3) In the 6 and 24-year-old shrublands, there were no significant differences in group richness, abundance, and diversity index between the microhabitats under the shrub and in the open. As for the 15- and 36-year-old shrublands, however, significant differences were observed. 4) The shrub age had a stronger effect on the distribution of ground arthropods living under the shrubs compared to that in the open. The changes in soil texture, pH and electrical conductivity could significantly influence on the distribution of ground arthropods under the shrub, also in the open to some degree. It was suggested that the development of shrubland had strong impact on assemblage effect of ground arthropods, which was closely correlated with the stand age and would affect the recovery of sandy grassland ecosystems. PMID- 24765866 TI - [Effect of light intensity on the growth and digestive enzyme activity of juvenile sea cucumber Apostichopus japonicas under two kinds of culture methods]. AB - The effects of light intensity (0, 1000, 2000 and 3000 1x) on the growth and digestive enzyme activity of juvenile sea cucumber Apostichopus japonicus under two kinds of culture methods (compound Chinese medicine preparation and microbial preparation) were studied. Results showed that the relative mass gain rate (WGR) and the specific growth rate (SGR) of juvenile sea cucumber were significantly affected by light intensity (P < 0.05) , and the orders of WGR and SGR (form high to low) of juvenile sea cucumber under different light intensities were 2000 1x > 1000 1x > 3000 1x > 0 1x. Under the same light intensity, the growth of juvenile sea cucumber under the two kinds of culture methods were significantly different (P < 0.05), with the WGR and SGR of the Chinese medicine treatment being greater than those of the microbial treatment. The light intensity also significantly affected the digestive enzyme activity of juvenile sea cucumber. The order of amylase and lipase activity was 2000 1x > 1000 1x > 3000 1x > 0 1x, while that of protease activity was 1000 1x > 2000 1x > 0 1x > 3000 1x. Under the same light intensity, the digestive enzyme activities of the Chinese medicine treatment were generally higher than those of the microbial treatment. PMID- 24765867 TI - [Fish assembles in the coastal water of Lusi fishing ground during spring and summer]. AB - Based on data from bottom trawl surveys during spring and summer of 2010, the species composition and community structure of fish community in Lusi fishing ground were investigated and compared with those at different latitudes. A total of 21 were identified in spring and 28 identified in summer. In spring, it was mainly composed of warm-temperate fish (9 species), accounting for 45.2% and 72.9% in the individual density and biomass density, respectively. Warm-temperate species Larimichthys polyactis, Cynoglossus joyneri and Cynoglossus semilaevis were dominant in spring. In summer, warm water species appeared in large numbers by 21, accounting for 75.2% and 71.7% in the individual density and biomass density, respectively. Collichthys lucidus and Coilia mystus were the predominant species in summer. One way-ANOVA indicated that the temperature and salinity between spring and summer in Lusi fishing ground were significantly different, which resulted in the succession of fish community, i. e. the gradual decrease of the warm-temperate, neritic and nearshore species and the concomitant gradual increase of warm-water and estuarine species. PMID- 24765868 TI - [Reasons of drifting floating objects aggregating rainbow runner (Elagatis bipinnulata)]. AB - Many pelagic species tend to aggregate under drifting floating objects. This has led to the development of drifting fish aggregation devices (FADs) to attract the tropical tunas for the tuna purse seine fishery. However, FADs can also attract other non-targeting small pelagic species such as rainbow runner Elagatis bipinnulata, although it is still unclear why those species can be attracted and aggregated under an FAD. Using the fishery biological data collected in the Western and Central Pacific Ocean by the scientific observers on board Chinese tuna purse seine fishing vessels, we evaluated the potential motivations for rainbow runner to aggregate under drifting objects. This study indicated 1) Fork length of rainbow runner ranged from 30.0 to 90.6 cm, with the dominant fork lengths of 60.0 to 80.0 cm, accounting for 76.3% of the total sampled fish, suggesting large rainbow runner dominating around the drifting objects; 2) Size (fork length) of E. bipinnulata at 50% maturity was 65.7 cm, and mature individuals were dominant under the FADs; and 3) Some commonly observed small fish species, such as Decapterus macarellus, Kyphosus cinerascens, Caranx sexfasciatus, Katsuwonus pelamis and the juveniles of Thunnus obesus and Thunnus albacares, were found in the stomach of rainbow runner, which suggested that rainbow runner under FAD preyed on other associated small pelagic species. As an oceanic predator associated with drifting objects, feeding is perhaps one of the most possible motivations for adult E. bipinnulata to aggregate under the FAD. Both the "concentration of food supply" hypothesis and the "comfortability stipulation" hypothesis can be used to explain why E. bipinnulata aggregate under drifting floating objects. PMID- 24765869 TI - [Spatial distribution patterns of adult population of Pseudorobitis gibbus (Coleoptera: Apionidae) in Taixing Garden, Tai'an, Shandong, China]. AB - The vertical and horizontal distributions of Pseudorobitis gibbus adults on Lagerstroemia indica were analyzed by using the aggregation indices and geostatistics. The results from aggregation index methods indicated that its vertical distribution was an aggregated distribution, and the aggregation average (lambda) was above two, showing that the aggregation resulted from its bionomics and behaviors, not from the environmental factors. The results of geostatistic analysis showed that the best fitting models for the five different sampling data in June 4, June 16, June 29, July 25 and August 22 were Gaussian, Gaussian, Linear, Gaussian and Linear models, respectively, but random models in July 12 and August 7. It was concluded that the horizontal distribution of the pest was aggregated on the whole, and there existed a spatial correlation ranging from 1.68 to 9.79 m on the different dates. PMID- 24765870 TI - [Review of dynamic global vegetation models (DGVMs)]. AB - Dynamic global vegetation model (DGVM) is an important and efficient tool for study on the terrestrial carbon circle processes and vegetation dynamics. This paper reviewed the development history of DGVMs, introduced the basic structure of DGVMs, and the outlines of several world-widely used DGVMs, including CLM DGVM, LPJ, IBIS and SEIB. The shortages of the description of dynamic vegetation mechanisms in the current DGVMs were proposed, including plant functional types (PFT) scheme, vegetation competition, disturbance, and phenology. Then the future research directions of DGVMs were pointed out, i. e. improving the PFT scheme, refining the vegetation dynamic mechanism, and implementing a model inter comparison project. PMID- 24765871 TI - [Responses of riverine nitrogen export to net anthropogenic nitrogen inputs: a review]. AB - Nitrogen (N) inputs caused by human activities potentially influences the aquatic environment. However, researches on N pollution in China are mainly discussed from the microscopic point of view, i. e. field experiment. Watershed-scale diagnosis of N pollution has just started, leading to ambiguous identification of ecological problems, pollution issues and pollution potential at watershed scale. In this paper, relationships between net anthropogenic N inputs (NANI) and riverine N flux (RNF) and factors influencing these relationships at watershed scale had been investigated. This would help diagnose ecological and environmental problems at watershed scale, understand the roles of natural climate and human activities in affecting N fluxes, and ultimately provide both theoretical and practical insights into environmental management decisions. PMID- 24765872 TI - [Effects and influence factors of dicyandiamide (DCD) application in agricultural ecosystem]. AB - The low utilization efficiency of nitrogen fertilizer in agricultural ecosystem has caused serious economic and environmental issues. Dicyandiamide (DCD) is a widely used nitrification inhibitor, which can inhibit nitrification via affecting ammonia oxidizing microorganisms with minimal influence on other soil microorganisms, thereby reducing the leaching of nitrate and emission of greenhouse gases. The factors influencing the efficiency of DCD in soil include soil temperature, pH, texture, organic matter, moisture, etc. Recently, the application of molecular methods in agricultural systems has shed new light on the microbial mechanism underlying nitrification inhibition by DCD. In this review, the enzymatic inhibition mechanism, the application effects and their influence factors of DCD were summarized, and the prospects of its application were discussed as well. PMID- 24765873 TI - [Research advances in uptake, translocation, accumulation and detoxification of Pb in plants]. AB - Contamination of soils by lead (Pb) is of widespread occurrence because of the industrialization, urbanization, mining, and many other anthropogenic activities. It is urgent and necessary for scientists to uncover the mechanisms of uptake, translocation, accumulation and detoxification of Pb in plants for the following two reasons. First, it helps target and regulate the key process of Pb uptake by crops and vegetables and minimize the threat of Pb introduction to the food chain. Second, it helps cultivate Pb hyperaccumulating plants that can absorb and sequester excessive amounts from contaminated soils in their biomass without incurring damage to basic metabolic functions. The purpose of this review was to summarize the research advances in uptake, translocation and accumulation of Pb in plants and address the mechanisms by which plants or plant systems detoxify Pb. The further researches on the foliar uptake, the interactions between soil components and plant cell wall, as well as the integrated technologies for phytoremediation of Pb-contaminated soils were prospected. PMID- 24765874 TI - [Role of modern hunting in wildlife management]. AB - Although modern hunting is different from traditional hunting, it remains a controversial topic. A large number of scholars in the world have studied the effects of hunting on wild animals from an ecological, ethological, genetic and economic aspect. This paper reviewed the role of controlled hunting in wildlife production from population dynamics, behavior, genetic and a phenotypic level, and by integrating a large number of domestic and foreign literatures. Many studies have shown that regulated hunting is an efficient approach in managing wildlife populations, which could be beneficial to the recovery and possibly even growth of wildlife populations. Meanwhile, over-exploitation or inappropriate hunting could affect the sex, birth and mortality ratios of wildlife populations, change foraging behavior and socio-spatial behavior and generate artificial selection of their genotype and phenotype. To apply modern hunting properly to wildlife management, China could learn from successful hunting programs implemented in many other countries, which are based on ecological and economic principles to formulate scientifically determined hunting quotas and set up an effective system to regulate and manage the hunting of wildlife populations. PMID- 24765875 TI - The maddening itch: an approach to chronic urticaria. AB - Chronic spontaneous urticaria (CSU) is defined as the presence of urticaria with daily or almost daily symptoms for 6 weeks or more. CSU affects 0.1%-0.8% of the population. Its pathogenesis involves autoimmunity, abnormalities in signal transduction, and the action of histamine on H1 receptors. Investigation of CSU should be guided by a thorough history and physical examination. A concise laboratory evaluation, including the CU index, is recommended. This index can provide useful data on severity and response to therapy. Initial treatment should involve increasing doses of nonsedating antihistamines until the intended effect is achieved. Only when a patient is unresponsive to high-dose nonsedating antihistamines (or sedating antihistamines) can we consider CSU refractory and consider immunomodulatory therapy. The most promising drugs are cyclosporine and, more recently, omalizumab. PMID- 24765876 TI - Genetic defects in B-cell development and their clinical consequences. AB - Expression of selected genes in hematopoietic stem cells has been identified as a regulator of differentiation of B cells in the liver and bone marrow. Moreover, naive B cells expressing surface immunoglobulin need other types of genes for antigen-dependent development in secondary lymphoid organs. Many advanced molecular mechanisms underlying primary antibody deficiencies in humans have been described. We provide an overview of the mutations in genes known to be involved in B-cell development and their clinical consequences. PMID- 24765877 TI - Cypress pollen: an unexpected major sensitizing agent in different regions of Italy. AB - OBJECTIVES: In this multicenter survey, we assessed the impact of sensitization to cypress in atopic patients in Italy and determined whether cypress pollen concentration changed over time. METHODS: Allergists were required to collect the results of 100-200 consecutive skin prick tests (SPTs) performed during 2012. Seasonal symptoms were also recorded, as were airborne cypress pollen concentrations (data from the Italian Aerobiology Association) in 1998-2000 and 2010-2012. RESULTS: We examined 2258 atopic outpatients (56% females; age, 2-84 years) sensitized to at least 1 of the aeroallergens tested (Dermatophagoides species, grass, pellitory, olive, cypress, birch, Alternaria tenuis, and dog and cat dander). We found that 62.9%, 16.1%, and 32.7% of patients living in central, northern, and southern Italy, respectively, were sensitized to cypress (P < .0001). The cypress pollen concentration peak was delayed from February to March in 1998-2000 and 2010-2012 in all 3 regions, with a shift in pollination towards spring. Patients who were monosensitized to cypress reported mainly rhinitis (90.7%-97.6%) and conjunctivitis (38.1%-100%). In polysensitized patients, the prevalence of rhinitis, conjunctivitis, and asthma increased progressively (P < .0001) from southern to northern Italy. The same trend was observed for the prevalence of reported winter symptoms typical of cypress allergy (28%-65%). CONCLUSIONS: Today, cypress pollen is the most frequent sensitizing aeroallergen (assessed by SPT) in several areas of central Italy. Variations in the timing of the cypress pollination period may have favored this increased sensitization. Rhinitis and conjunctivitis are the predominant symptoms. The clinical impact of this allergy was poor in southern Italy and increased in central areas before reaching its peak in northern regions. PMID- 24765878 TI - House dust mite subcutaneous immunotherapy does not induce new sensitization to tropomyosin: does it do the opposite? AB - BACKGROUND: It is still uncertain whether house dust mite (HDM) tropomyosin present in allergen extracts can cross-sensitize patients receiving subcutaneous immunotherapy (SCIT) and thus induce food allergy. OBJECTIVES: Our aim was to assess whether new sensitization to tropomyosin occurred during HDM-SCIT, and, if so, whether it was clinically relevant. PATIENTS AND METHODS: The study sample comprised 56 HDM-allergic patients treated with SCIT using HDM extract. All patients were screened for specific IgE (sIgE) to mite tropomyosin (rDer p 10) before and after SCIT. In patients with a positive result, we also monitored the dynamics of sIgE to rDer p 10 and shrimp tropomyosin (rPen a 1) at several time points. The levels of sIgE were measured using the CAP System fluorescent-enzyme immunoassay. RESULTS: sIgE to tropomyosin was found in only 5 patients, 3 of whom expressed low and clinically irrelevant levels of sIgE to Der p 10, while sIgE to Pen a 1 was not found. The remaining 2 patients expressed sIgE to both tropomyosins. In the first, the initial increase and subsequent decrease resembled the dynamics of the IgE antibodies usually seen in SCIT patients and were never accompanied by seafood-induced symptoms. In the other, a decrease in levels of sIgE to both tropomyosins resulted in the complete loss of his reactivity toward seafood. CONCLUSIONS: Immunotherapy using HDM extracts does not induce clinically relevant sensitization to tropomyosin. In certain cases of combined mite and seafood allergy, treatment may even lead to the improvement of food allergy symptoms. The levels of sIgE to Der p 10 and Pen a 1 may be useful monitoring markers. PMID- 24765879 TI - Serum specific IgE: a biomarker of response to allergen immunotherapy. AB - BACKGROUND: Allergen immunotherapy (AIT) has proven to be effective. However, no biomarkers capable of predicting the clinical response to AIT have been detected. The aim of the present study was to determine a cutoff value for serum specific IgE that could be associated with effective AIT. METHODS: We evaluated 174 allergic patients (83 males) with ages ranging between 6 and 77 years. All patients were monsensitized and received sublingual immunotherapy (SLIT) for at least 3 years with a single allergen extract. Symptom severity was assessed using the visual analog scale (VAS). Drug use was also evaluated. A responder was defined as a patient whose VAS score fell by at least 30% over baseline. RESULTS: The response to SLIT was considered effective in 145 patients (83.3%). The use of allergen-specific IgE levels > 9.74 kU(A)/L as a biomarker of effective SLIT yielded a sensitivity value of 96.4%, specificity of 100%, and an area under the receiver operator characteristic curve of 0.987. CONCLUSIONS: Assessment of serum specific-IgE before AIT could be a useful biomarker for predicting response to AIT. PMID- 24765880 TI - Drug-induced anaphylaxis survey in Portuguese Allergy Departments. AB - BACKGROUND AND OBJECTIVE: Drug-induced anaphylaxis is an unpredictable and potentially fatal adverse drug reaction. The aim of this study was to identify the causes of drug-induced anaphylaxis in Portugal. METHODS: During a 4-year period a nationwide notification system for anaphylaxis was implemented, with voluntary reporting by allergists. Data on 313 patients with drug anaphylaxis were received and reviewed. Statistical analysis included distribution tests and multiple logistic regression analysis to investigate significance, regression coefficients, and marginal effects. RESULTS: The mean (SD) age of the patients was 43.8 (17.4) years, and 8.3% were younger than 18 years. The female to male ratio was 2:1.The main culprits were nonsteroidal anti-inflammatory drugs (NSAIDs) (47.9% of cases), antibiotics (35.5%), and anesthetic agents (6.1%). There was a predominance of mucocutaneous symptoms (92.2%), followed by respiratory symptoms (80.4%) and cardiovascular symptoms (49.0%). Patients with NSAID-induced anaphylaxis showed a tendency towards respiratory and mucocutaneous manifestations. We found no significant associations between age, sex, or atopy and type of drug. Anaphylaxis recurrence was observed in 25.6% of cases, and the risk was higher when NSAIDs were involved. CONCLUSIONS: NSAIDs were the most common cause of anaphylaxis in this study and were also associated with a higher rate of recurrence. We stress the need for better therapeutic management and prevention of recurring episodes of drug-induced anaphylaxis. PMID- 24765881 TI - The effect of inhaled corticosteroids on the concentration of soluble CD163 in induced sputum of allergic asthma patients. AB - BACKGROUND AND OBJECTIVE: CD163 is a monocyte/macrophage-specific molecule whose expression is induced by corticosteroids and IL-10. The aim of this study was to evaluate the concentration of soluble CD163 (sCD163) in the induced sputum of asthmatic patients before and after therapy with inhaled corticosteroids (ICSs). PATIENTS AND METHODS: The study was performed in 24 patients with mild allergic asthma (AAs) and 10 healthy controls (HCs). In 18 AAs, induced sputum and serum samples were obtained before ICS therapy (T0) and 7 days later (T7). In the 6 AAs not treated with ICSs the procedures were performed at To and T7. The concentration of sCD163 in sputum and serum samples was evaluated using ELISA. RESULTS: There was no significant difference in mean (SD) baseline serum sCD163 concentration between AAs (1030 [449] ng/mL) and HCs (930 [334.5] ng/mL, P = .530). However, at To the mean sputum sCD163 concentration was significantly greater in AAs (4.78 [3.34] ng/mL) than in HCs (1.8 [0.41] ng/mL, P =.009). Treatment with ICSs resulted in a significant increase in sCD163 concentration in sputum (P < .0001) but not in serum (P =.679). No change in sputum or serum sCD163 concentration was detected in AAs who were not treated with ICSs. The change in sputum sCD163 concentration inversely correlated with changes in sputum eosinophilia or exhaled nitric oxide concentration. CONCLUSIONS: ICS therapy leads to local upregulation of sCD163 expression, which in turn may participate in the anti-inflammatory effects of ICS therapy. PMID- 24765882 TI - Cross-reactivity between buckwheat and quinoa in a patient with eosinophilic esophagitis caused by wheat. PMID- 24765883 TI - Occupational allergy in a holm oak pruner. PMID- 24765884 TI - Suspicion of a new cross-reaction between carbamazepine and olanzapine. PMID- 24765885 TI - Oral pancreatic enzyme supplements can reduce excretion of ovalbumin in breast milk. PMID- 24765886 TI - A curious case of exercise-induced wheat allergy in adulthood. PMID- 24765887 TI - First case report of acute generalized exanthematous pustulosis due to intravenous iopromide. PMID- 24765888 TI - Eosinophilic bronchitis caused by styrene. PMID- 24765889 TI - Rapid iron desensitization after generalized urticaria and facial angioedema. PMID- 24765890 TI - Clinical and laboratory parameters associated with eclampsia in Thai pregnant women. AB - OBJECTIVE: Determine the risk factors and pregnancy outcomes of eclampsia in our institution. MATERIAL AND METHOD: The authors conducted a case-control study of 80 Thai pregnant women with eclampsia and 240 controls with mild preeclampsia who delivered at King Chulalongkorn Memorial Hospital, Bangkok, Thailand between 1995 and 2011. Information was abstracted on established and hypothesized risk factors for eclampsia documented in the medical records. RESULTS: The risk factors that were significantly associated with eclampsia compared to mild preeclampsia after using multivariate logistic regression analysis were maternal age < 20 years [adjusted odd ratio (aOR) 4.8, 95% confidence interval (CI) 1.7 to 14), antenatal care (ANC) < 4 visits (aOR 3.4, 95% CI 1.2 to 9.1), deep tendon reflex (DTR) > or = 3+ (aOR 15.1, 95% CI 15.3 to 42.7), serum uric acid > or = 6 mg/dL (aOR 8.3, 95% CI 13.5 to 19.8), serum creatinine > or = 0.9 mg/dL (aOR 18, 95% CI 4.8 to 67.5), and serum glutamate oxaloacetate transaminase (SGOT) > or = 44 IU/L (aOR 15.9, 95% CI 5.6 to 45.3). CONCLUSION: The risk factors of the development of eclampsia compared to mild preeclampsia are maternal age < 20 years, ANC < 4 visits, DTR > or = 3+, serum uric acid > or = 6 mg/dL, serum creatinine > or = 0.9 mg/dL, and serum SGOT > or = 44 IU/L. This information may be useful for obstetricians to predict which mild preeclamptic patients are at great risk for eclampsia and to consider administration of magnesium sulfate to prevent convulsion in these patients. PMID- 24765891 TI - Prevalence of endometriosis in women undergoing surgery for benign gynecologic diseases. AB - OBJECTIVE: To determine the prevalence of endometriosis among other benign gynecologic diseases and to identify the characteristics of patients at increased risk of concomitant diagnosis before surgery MATERIAL AND METHOD: A descriptive cross-sectional study of331 women with benign gynecologic diseases who underwent surgery in the Department of Obstetrics and Gynecology, Faculty ofMedicine Siriraj Hospital, Mahidol University, Bangkok, Thailand were included The subjects were interviewed for demographic data, obstetrics, and medical history. Data from medical records were reviewed and collected Operative notes and pathological reports were reviewedfor the diagnosis of endometriosis. The outcome measurement is the prevalence of endometriosis that was diagnosed by the surgeon from operative finding or pathological report and the characteristics of the patients at increased risk of concomitant diagnosis before surgery. RESULTS: Of the 331 women with benign gynecologic diseases, 101 had coexistent endometriosis. Prevalence ofendometriosis in benign gynecologic diseases was 30.5%. Of the 285 women with benign gynecologic diseases that did not have concomitant diagnosis of endometriosis before surgery, endometriosis was found in 55 patients postoperatively. Prevalence of endometriosis in this group was 19.3%. The three most common diseases in women undergoing surgery were uterine leiomyoma, adenomyosis, and benign ovarian cysts, respectively. The coexistence ofendometriosis with uterine leiomyoma, adenomyosis, and benign ovarian cysts were 28%, 43.5%, and 50%, respectively. Women with preexisting endometriosis were significantly younger than those with postoperative diagnosed endometriosis. CONCLUSION: The prevalence of coexistence of endometriosis and benign gynecologic diseases, especially uterine leiomyoma, adenomyosis, and benign ovarian cyst, was high. The diagnosis of concomitant diseases was made intra-operatively and postoperatively in more than half of the cases. Physicians should be concerned about the coexistence of both conditions and put this finding into the preoperative counseling data and definite surgery should be informed in advanced stage of endometriosis. PMID- 24765892 TI - Prevalence of perioperative asymptomatic proximal deep vein thrombosis in Thai gynecologic cancer patients. AB - BACKGROUND: Thromboprophylaxis of deep vein thrombosis in gynecologic cancer surgery in Thai patients is not routinely performed. OBJECTIVE: The prevalence of perioperative asymptomatic proximal deep vein thrombosis of 100 patients with gynecologic cancer was identified. MATERIAL AND METHOD: Duplex ultrasonography of proximal vein of legs was performed in each patient, seven to 14 days, before and after surgery. RESULTS: The prevalence of perioperative asymptomatic proximal deep vein thrombosis was 7%. The prevalence of preoperative asymptomatic proximal deep vein thrombosis of legs was 5% and postoperative incidence of asymptomatic proximal deep vein thrombosis of legs was 2.11%. Acute symptomatic pulmonary embolism was found in only one patient. All patients who developed deep vein thrombosis had adenocarcinoma of ovary or uterus, but not cervical cancer The other risk factors of venous thromboembolism were comparable between deep vein thrombosis and non-deep vein thrombosis group. CONCLUSION: The patients with adenocarcinoma of ovary and uterus seem to be the greatest risk of perioperative deep vein thrombosis. High prevalence of venous thromboembolism in gynecologic cancer surgery of Thai patients should be concerned. PMID- 24765893 TI - The percentages of endometrial hyperplasia and endometrial cancer among polycystic ovary syndrome (PCOS) patients presenting with abnormal menstrual pattern. AB - OBJECTIVE: Assess the occurrence of endometrial hyperplasia and endometrial cancer among PCOS patients having abnormal menstrual pattern. Endometrial thickness and other clinical characteristics associated with endometrial hyperplasia and endometrial cancer were also evaluated MATERIAL AND METHOD: Women with PCOS and abnormal menstrual pattern were enrolled into this cross-sectional study. Endometrial thicknesses were evaluated using transvaginal sonography. Endometrial aspiration was performed with endometrial aspirator and sent for pathology. RESULTS: Out of 52 PCOS patients with abnormal menstrual pattern, nine (17.3%) and one (1.9%) had endometrial hyperplasia and endometrial cancer, respectively. There was no significant difference in mean endometrial thickness between those who had abnormal and normal endometrium (8.19 +/- 2.58 mm and 7.76 +/- 4.03 mm, respectively). However BMI and age of patients with abnormal endometrium were significantly higher and older than those with normal endometrium (p = 0.031 and p = 0.009, respectively). CONCLUSION: Nineteen point two percent (19.2%) of patients with PCOS and abnormal menstrual pattern had endometrial hyperplasia or endometrial cancer Endometrial thickness was not different between those with abnormal and normal endometrium. PMID- 24765894 TI - Acetaminophen Psi Nomogram: a sensitive and specific clinical tool to predict hepatotoxicity secondary to acute acetaminophen overdose. AB - BACKGROUND: Acetaminophen Psi Parameter (APP) is a composite of acetaminophen (paracetamol) level and lag time before N-acetylcysteine (NAC) therapy. The APP is a significant predictor of hepatotoxicity secondary to acute acetaminophen overdose. Acetaminophen Psi Nomogram (APN) was invented as a graphic analog of the APP for use in predicting individual patient's risk of hepatotoxicity. Clinical accuracy of the APN has never been validated OBJECTIVE: The authors are reporting the validity of APN in predicting hepatotoxicity secondary to acute acetaminophen overdose at Siriraj Hospital. MATERIAL AND METHOD: This present study is a retrospective review of medical records of patients with acute acetaminophen overdose at Siriraj Hospital between January 2004 and June 2009. Each case was classified by APN into an appropriate risk group. The outcome of interest was hepatotoxicity. The validity of the APN is reported as sensitivity and specificity. Secondary outcomes include serum acetaminophen concentrations, delay to NAC therapy, and APP for each APN's risk group. RESULTS: One hundred and sixty-one patients were enrolled Higher APN risk classifications are associated with a trend towards higher acetaminophen levels, longer delayed to NAC initiation, and larger APP. Twenty five patients (15.5%) developed hepatotoxicity. The number of patients who were above the APN's risk lines, 1% and 50% were 88 (54.7%) and 17 (10.6%), respectively, with corresponding sensitivities of 100.0% (95% CI 186.6, 100.0) and 40.0% (95% C121.2, 61.3). APN's risk lines 50% had specificity of 94.9% (95% CI 89.7, 97.9). CONCLUSION: Acetaminophen Psi Nomogram is a sensitive and specific tool for prediction of hepatotoxicity secondary to acute acetaminophen overdose. By application of the APN, a significant proportion of patients may not require either further follow up after the completion of NAC therapy or prolongation of NAC therapy. Patients in high APN's risk ranges may be treated and monitored more intensively with confidence. PMID- 24765895 TI - Usefulness of syncope guidelines in risk stratification of syncope in emergency department. AB - BACKGROUND: Management of patients with syncope in the Emergency Department now focuses on identifying patients who will be at future risk of serious morbidity. Among the risk stratification scoring systems being used were the San Francisco Syncope Rule (SFSR) and Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) score. OBJECTIVE: To assess the accuracy of SFSR and OESIL score at predicting short-term serious outcome in Maharaj Nakorn Chiang Mai Hospital. MATERIAL AND METHOD: In a prospective descriptive analysis study, adult patients presenting with syncope or near syncope between October 1, 2009 and April 24, 2010 were enrolled. All patients were followed-up at 7-day and 1-month. Statistical analysis included accuracy, sensitivity, specificity, predictive values, and likelihood ratios. RESULTS: One hundred seventy eight patients were enrolled in the present study. Fifty-three patients had a short-term serious outcome on follow-up. SFSR had 74.7% accuracy, 90.6% sensitivity, 68% specificity, 54.5% PPV 94.4% NPV likelihood ratio positive (LR+) of 2.8, and likelihood ratio negative (LR-) of 0.1, whereas OESIL score had 80.9% accuracy, 79.4% sensitivity, 81.6% specificity, 64.6% PPV 90.3% NPV, LR+ of 4.3, and LR- of 0.2. CONCLUSION: Both scores have good accuracy and sensitivity, but they should not be used as the only device in patient disposition. However, both scores showed a low false negative rate. Therefore, they may help in helping physician discharge low-risk patients. PMID- 24765896 TI - Clinical presentations of bipolar disorder in children and adolescents. AB - OBJECTIVE: To describe clinical presentations of bipolar disorder in children and adolescents when they were diagnosed. MATERIAL AND METHOD: The present study was a retrospective chart review of patients who were diagnosed bipolar disorder when they were under 19 years of age. All subjects, both inpatients and outpatients, received psychiatric treatment at Ramathibodi hospital between January 1998 and May 2008. RESULTS: Forty-nine subjects aged between eight and 18-years-old (mean 15.3 years) were diagnosed as bipolar disorder Thirty-seven percent of patients had cardinal symptoms including elevated mood and/or grandiosity. Being talkative was the most common associated symptom, found in 47% of patients. Psychotic symptoms were found in 39% of patients. Moreover 27% of patients suffered from suicidal idea or had attempted suicide at the time of diagnostic. CONCLUSION: Although there is very limited information about clinical presentations of bipolar disorder in children and adolescents, especially in Thai population, the author found that only 37% of these patients presented with cardinal symptoms at the time of diagnosis. PMID- 24765897 TI - Missed appointment in adolescent clinic; perspective from tertiary care hospital, Thailand. AB - OBJECTIVE: To determine the missed appointment rate and evaluate the factors related to appointment adherence in adolescent patients, based on the patients' characters and services provided. MATERIAL AND METHOD: All medical records in adolescent clinic at Siriraj Hospital between 2004 and 2009 were reviewed Patients that visited the clinic at least twice with the follow-up visit order were recruited. Data analyses were performed by Chi-square test and Fisher's exact test wherever appropriated. RESULTS: One hundred twenty six patients met the inclusion criteria. Patients'mean age were 14.3-year-old (SD = 2.7) and the majority (95%) were students. Seventy one point five percent of principle diagnosis related to behavioral problems while 90% had at least one risky behavior detected Comparing between missed and non-missed appointment, only the acute illness and the history of appointment cancellation were significant different characters between groups (p < 0.001). Of 429 visits, 409 (95.3%) got telephone reminder a few days prior the appointment date, 48 (11.2%) remained non complying and 40 (9.7%) had rescheduled. Only 18 (4.2%) of the visits were the patients themselves made re-appointments, which all complied with the new visit. Having rescheduled after being reminded and having history of a missed previous appointment were the most significant predictors for next appointment adherence (p = 0. 01 and p = 0.02 respectively). CONCLUSION: In adolescents, appointment non-compliance is a challenging issue for clinicians. Predicting factors found in this study might help foster appointment adherence. Interestingly, services provided such as telephone reminder short waiting time, appointment time did not influence adherence in this population. PMID- 24765898 TI - Unclosed fascial defect: is it the risk to develop port-site hernia after laparoscopic cholecystectomy? AB - OBJECTIVE: Port-site hernia (PSH) is one of the complications after laparoscopic cholecystectomy (LC). Closure of the fascial defect has been mentioned to prevent such complication. However, the results are still controversial. The present study was done to clarify whether unclosed fascial defect was actually the risk factor for the development of PSH MATERIAL AND METHOD: Two hundred ninety four patients underwent LC by a single surgeon at Kalasin Hospital between 2007 and 2010. The procedure was done by using a four-port technique without closure of any fascial defects. The male:female ratio was 85:209, and the mean body mass index was 24.38 +/- 3.33 (SD). The mean operative time was 18.71 +/- 3.76 minutes and there was no postoperative wound infection. Patients were regularly followed up and underwent both supine and upright physical examination. The mean duration of follow-up period was 4.94 +/- 1.31 years with the shortest follow-up period of two years. RESULTS: None of the patients in the present study developed PSH in any port sites during the follow-up period. CONCLUSION: Unclosed fascial defect may not have the significant risk factor of developing PSH after LC. PMID- 24765899 TI - Effects of single shot femoral nerve block combined with intrathecal morphine for postoperative analgesia: a randomized, controlled, dose-ranging study after total knee arthroplasty. AB - OBJECTIVE: Pain after total knee arthroplasty (TKA) is severe, thus adequate pain control can be a challenge. Intrathecal morphine (ITM) provides excellent postoperative analgesia for TKA, but may have side effects. Femoral nerve block (FNB) also has been used for postoperative analgesia in TKA. We examined postoperative analgesia efficacy and side effects of ITM combined with single shot femoral nerve block (SSFNB) after TKA, over the dosage range of 0.0 to 0.3 mg. MATERIAL AND METHOD: Sixty patients undergoing elective TKA received SSFNB (0.5% bupivacaine 20 ml) and spinal anesthesia with 15 mg of hyperbaric bupivacaine (0.5% Heavy Marcaine) were included in this study. They were randomized to receive ITM (0, 0.1, 0.2, and 0.3 mg). A patient-controlled analgesia (PCA) device provided additional intravenous morphine. Morphine consumption, pain score, and side effects were recorded at 0, 1, 4, 8, 12, and 24 hour postoperative. Patient satisfaction was rated at the 24-hour postoperative visit. RESULTS: Morphine consumption was significant higher in 0 mg ITM group (control) than other groups, but there was no difference between ITM groups. Pain score was significant lower in 0.3 mg ITM group compared to 0 mg at 1 hour (0.5 vs. 3.5, respectively; p-value = 0.013) and 4 hour (1.5 vs. 4.5, respectively; p value = 0.037) postoperative period Side effects were not different in all groups. CONCLUSION: The present study concluded that, low-dose ITM combination with SSFNB provided good pain relief with low side effects and reduced morphine consumption during the first 24 hours post TKA. PMID- 24765900 TI - Incidence of red blood cell transfusion in mechanically ventilated surgical patients at Siriraj Hospital. AB - BACKGROUND: Anemia is commonly encountering surgical critically ill patients. The incidence of red blood cell (RBC) transfusion and transfusion trigger in this population has not been previously reported in a large tertiary care center in Thailand OBJECTIVE: To describe the incidence of RBC transfusion and transfusion trigger and to determine the factors and outcomes associated with RBC transfusion. MATERIAL AND METHOD: Data of 288 adult surgical patients requiring mechanical ventilation for > 24 hours was retrospectively reviewed Patient characteristic, outcomes, and transfusion data were collected. RESULTS: The incidence ofRBC transfusion was 83.0% (95% confidence interval (CI) 78.0-87.0%). The mean hemoglobin level before RBC transfusion was 8.7 +/- 1.2 g/dL. Patients who received RBC transfusion had significantly higher morbidity and mortality when compared with those who did not. Independent factors associated with RBC transfusion were low body weight, high Sequential Organ Failure Assessment (SOFA) score, and low hemoglobin level on admission (adjusted odds ratio 0.97, 1.19, and 0.60. respectively). CONCLUSION: In critically ill adult surgical patients, the incidence of RBC transfusion and transfusion trigger remained within high threshold Large randomized controlled studies are warranted to confirm potential benefit of RBC transfusion in surgical critically ill patients. PMID- 24765901 TI - Diagnostic accuracy of coronary CT angiography in patients after coronary bypass surgery: evaluation of grafts and native coronary arteries. AB - OBJECTIVE: To evaluate the diagnostic accuracy in the assessment of both grafts and native coronary arteries in patients after coronary artery bypass grafts (CABG) by coronary CT angiography (CCTA) in comparison to invasive conventional coronary angiography (CCA). MATERIAL AND METHOD: CCTA was performed in 54 symptomatic post-CABG patients. Two independent, blinded observers assessed all grafts and native coronary arteries for significant stenosis. CCA served as a reference standard One hundred seventy two graft segments, 156 distal coronary run-offs, 314 grafted coronary segments, and 18 non-grafted coronary segments were analyzed RESULTS: The diagnostic accuracy of CCTA for exclusion or detection of significant stenosis in venous grafts and non-grafted segments of native coronary arteries was 100%. Sensitivity, specificity, and positive and negative predictive values were all 100%. Sensitivity, specificity, and positive and negative predictive values to detect significant stenosis were 100%, 98%, 91%, and 100%, respectively, in arterial grafts, 100%, 99%, 75%, and 100%, respectively, in distal runoffs, and 100%, 87%, 99%, and 100%, respectively, in grafted segments of native coronary arteries. CONCLUSION: Non-invasive coronary CT angiography provides high diagnostic accuracy for evaluation of both bypass grafts and native coronary arteries, although, CCTA is more effective in evaluation of bypass grafts as compared to heavily calcified native coronary arteries. PMID- 24765902 TI - Evaluation of five commercial assays for the detection of anti-dsDNA antibodies: three Crithidia luciliae indirect immunofluorescence test kits and two enzyme immunoassay kits. AB - OBJECTIVE: There are various methods for anti-dsDNA detection. Crithidia luciliae indirect immunofluorescence test (CLIFT) and enzyme immunoassay (EIA) are the most commonly used at present. A number of CLIFT and EIA kits are commercially available. The objective of the present study was to evaluate the diagnostic performance of three commercial CLIFT kits, two commercial EIA kits, and their combinations for anti-dsDNA detection. MATERIAL AND METHOD: One hundred thirty nine sera sent for anti-dsDNA testing were investigated. Three commercial CLIFT kits (kit C1, C2, and C3) and two commercial EIA kits (kit E1 and E2) were evaluated. Sensitivities and specificities were calculated. The gold standard methods were the consensus results of all five kits, together with the clinical diagnosis when the results of five kits were discrepant. RESULTS: Of 139 sera investigated, 94 (67.6%) sera showed concordant results for all five kits and 45 (32.4%) sera showed discordant results. Thirty-five of those 45 patients (77.7%) were diagnosed as SLE. Sensitivities and specificities of the kits were as follows, Cl 82.1% and 94%, C2 46.4% and 100%, C3 78.6% and 98.8%, E1 71.4% and 94%, and E2 75% and 93.8%, respectively. Kit C3 yielded the maximum sum of sensitivity and specificity (177.4%). Sensitivities and specificities of the combinations of CLIFT and EIA kits were as follows, C1 + E1 89.3% and 90.4%, C1 + E2 98.2% and 87.9%, C2 + E1 73.2% and 94%, C2 + E2 82.1% and 92.8%, C3 + E1 85.7% and 94%, and C3 + E2 94.6% and 91.6%, respectively. The combination of kit C3 and E2 yielded the maximum sum of sensitivity and specificity (186.2%). CONCLUSION: Kit C3 was the assay of choice for anti-dsDNA detection. EIA kits yielded lower sensitivities and specificities than two of three CLIFT kits. Therefore, they should not be used as the first assay for anti-dsDNA screening. When CLIFT and EIA assays were combined, sensitivities were increased Kit E2 helped CLIFT kits to detect more SLE cases than E1. PMID- 24765904 TI - Calcium consumption for osteoporosis prevention: knowledge, attitudes and behavior in the northeastern region, Thailand. AB - OBJECTIVE: Identified Thai adults' knowledge and attitudes towards calcium and determined factors predicting calcium consumption. MATERIAL AND METHOD: One thousand four hundred seventy five Thai adults, aged > or = 20 years old were interviewed, using a semi-structured questionnaire. Knowledge about role of calcium and good sources of calcium was measured using 17 questions. Attitudes towards calcium were measured with 10 opinion statements, using 7-point Likert scale (1 = strongly disagree to 7 = strongly agree). Calcium consumption, based on a 24-hour recall, was assessed using food frequency checklists and open-ended questions. RESULTS: The median score for knowledge was 15 (IQR: 12, 16; total possible score: 17). The overall median of attitudinal score was 5.6 (IQR: 4.9, 6.1; cronbach's alpha = 0.80). Approximately 10.9% consumed adequate amounts of calcium (800 mg/day). CONCLUSION: Factors significantly determining the likelihood an adequate intake of calcium were age < 35 years, support from peers and taking calcium-supplements. PMID- 24765905 TI - Major health problems of expressway workers in Thailand: an 8-year cohort study. AB - BACKGROUND AND OBJECTIVE: Workers in the transportation sector may be expose to environmental hazards resulting in adverse health outcomes. The present study aimed to assess environmental-hazard-related morbidity among transportation workers over an eight-year period MATERIAL AND METHOD: Data were extracted from the registry database of a cohort of workers in the Expressway Authority of Thailand between 2004 and 2011. Annual trends and changes in health status were described. Factors associated with major health problems were also evaluated RESULTS: The cohort consisted of 2,000 to 2,700 workers. The trend of abnormal lung function, abnormal hearing, high blood pressure, high cholesterol, and asthma significantly increased over the period. Very few workers had high serum lead levels. CONCLUSION: The present study revealed several major occupation related health problems among transportation workers. In addition to an annual health assessment, other control measures should be instituted to protect workers from occupation-related exposures. PMID- 24765903 TI - Characteristics and determinants of Thailand's declining birth rate in women age 35 to 59 years old: data from the Fourth National Health Examination Survey. AB - OBJECTIVE: To describe characteristics and determinants of Thailand's declining birth rate using national representative survey data. MATERIAL AND METHOD: The Fourth National Health Examination Survey was conducted between 2008 and 2009. Four stages of stratified probability samples, proportionate to size, were used to represent the whole Thai population. Information from women aged 35 to 59 years old was included in the analysis. Curve estimation was used to characterize the correlation between the number of children ever born and the age of married and un-married women. Binary logistic regression analysis was used to identify predictors of having fewer than two children among ever married women. RESULTS: Of all 4120 women, the number of children decreased sharply among the oldest women aged 45 to 59 years old, decreased less sharply for women younger than 45 years of age, reached the lowest level at the age of 37 and 38 years old, and then increased minimally among the younger women surveyed. Among those who were ever married (n = 3,761), the independent predictors of having one or no child instead of having two or more children were aged 45 to 49 compared to 50 to 59 years old (OR = 1.66; 95% CI = 1.37-2.00), age 35 to 44 compared to 50 to 59 years old (OR = 1.39; 95% CI = 1.16-1.68), living in households with wealth index level 3 compared to level 1 (OR = 1.28; 95% CI = 1.01-1.63), urban residence (OR = 1.33; 95% CI = 1.14-1.57), attaining secondary school education (OR = 1.35; 95% CI = 1.11-1.64), and having junior college diploma or higher level of education compared to elementary or no education (OR = 1.81; 95% CI = 1.39-2.34). CONCLUSION: Birth rate of Thai women declined steeply in the past then less steeply, and might have begun to rise minimally in recent years. Younger age, living in an urban area, and having higher socioeconomic status were predictors of having fewer than two children. PMID- 24765906 TI - Single port laparoscopic donor nephrectomy: first case report in Ramathibodi Hospital. AB - The prevalence of patients with end stage renal disease (ESRD) is showing an increasing trend. At the same time, the waiting lists for cadaveric donor kidney transplantation continue to grow. Living donor kidneys may be an alternative for patients to receive kidneys for transplantation. However a wide gap exists between the numbers of living kidney donors and the numbers of recipients on waiting lists. Many considerations are involved in living organ donation, including cosmetic reasons. Laparoscopic living donor nephrectomy has become the technique of choice for kidney transplantation in many centers. The benefits of a laparoscopic technique compared with open surgery include reduced blood loss, less analgesic requirement, a shorter hospital stay, faster return to work, and fewer cosmetic effects. The next step in minimal invasive surgery is laparoendoscopic single port donor nephrectomy Early outcomes show this technique to be safe and cosmetically improved This procedure may be the answer to reduce the gap between numbers of kidney donors and waiting recipients. We report our first experience of single port laparoendoscopic left donor nephrectomy. A 48 year-old healthy Thai man wished to donate his kidney to his 18-year-old son who suffered from IgA nephropathy and ended up with ESRD. The operation took three hours. The estimated blood loss was 50 ml and no blood transfusion was required. The donor was discharged home safely without any complications. PMID- 24765907 TI - [Social media]. PMID- 24765908 TI - [Belgian and Dutch veterinarians are basically the same. "Only the outside is different"]. PMID- 24765909 TI - [Tecar therapy]. PMID- 24765910 TI - [Ludo Hellebrekers: 'veterinarians cannot be without social legitimacy']. PMID- 24765911 TI - [Trends from the GD-monitoring]. PMID- 24765912 TI - ['Koi Sleepy Disease' found for the first time in Koi Carps in the Netherlands]. PMID- 24765913 TI - [The 'body condition score' in horses]. PMID- 24765914 TI - [Vaccination for Q fever in goats effective against shedding]. PMID- 24765915 TI - [Better websites veterinary practice possible!]. PMID- 24765916 TI - [Social media in veterinary practice]. PMID- 24765917 TI - [Flexible education through the internet]. PMID- 24765918 TI - [VetCEE-label for continuing education at a high level]. PMID- 24765920 TI - [As teacher I am a role model]. PMID- 24765919 TI - [Orthomanual veterinary medicine: the long road to recognition]. PMID- 24765921 TI - Carbon- and oxygen-free Cu(InGa)(SSe)2 solar cell with a 4.63% conversion efficiency by electrostatic spray deposition. AB - We have demonstrated the first example of carbon- and oxygen-free Cu(In,Ga)(SSe)2 (CIGSSe) absorber layers prepared by electrospraying a CuInGa (CIG) precursor followed by annealing, sulfurization, and selenization at elevated temperature. X ray diffraction and scanning electron microscopy showed that the amorphous as deposited (CIG) precursor film was converted into polycrystalline CIGSSe with a flat-grained morphology after post-treatment. The optimal post-treatment temperature was 300 degrees C for annealing and 500 degrees C for both sulfurization and selenization, with a ramp rate of 5 degrees C/min. The carbon impurities in the precursor film were removed by air annealing, and oxide that was formed during annealing was removed by sulfurization. The fabricated CIGSSe solar cell showed a conversion efficiency of 4.63% for a 0.44 cm(2) area, with Voc = 0.4 V, Jsc = 21 mA/cm(2), and FF = 0.53. PMID- 24765922 TI - NIR dual luminescence from an extended porphyrin. Spectroscopy, photophysics and theory. AB - Spectroscopic and photophysical properties of an extended Zn porphyrin with fused bis(tetraazaanthracene) arms including a 2,9-diphenyl-1,10-phenanthroline incorporated in a polyether macrocycle are investigated in solvents of different polarity pointing to the presence of two emitting singlet excited states. The absorption and emission features are identified and ascribed, on the basis of solvent polarity dependence, to a pi-pi* and to a charge transfer (CT) state, respectively. Whereas the intraligand pi-pi* transition is assigned to the intense absorption observed at 442-455 nm, the CT states contribute to the bands at 521-525 nm and 472-481 nm. The theoretical analysis of the absorption spectrum confirms the presence of two strong bands centered at 536 and 437 nm corresponding to CT and pi-pi* states, respectively. Weak CT transitions are calculated at 657 and 486 nm. Two emission maxima are observed in toluene at 724 nm from a (1)pi-pi* state and at 800 nm from a (1)CT state, respectively. (1)CT bands shift bathochromically by increasing the solvent polarity whereas the energy of the (1)pi-pi band is less affected. Likewise, the emission yield and lifetime associated with the low energy (1)CT band are strongly affected by solvent polarity. This is rationalized by a (1)pi-pi* -> (1)CT internal conversion driven by solvent polarity, this process being competitive with the (1)pi-pi* to ground state deactivation channel. Time resolved absorption spectra indicate the presence of two triplet states, a short-lived one (nanoseconds range) and a longer lived one (hundreds of microsecond range) ascribed to a (3)pi pi* and a (3)CT, respectively. For them, a conversion mechanism similar to that of the singlet excited states is suggested. PMID- 24765923 TI - Experimental tests of classical and quantum dimensionality. AB - We report on an experimental test of classical and quantum dimension. We have used a dimension witness that can distinguish between quantum and classical systems of dimensions two, three, and four and performed the experiment for all five cases. The witness we have chosen is a base of semi-device-independent cryptographic and randomness expansion protocols. Therefore, the part of the experiment in which qubits were used is a realization of these protocols. In our work we also present an analytic method for finding the maximum quantum value of the witness along with corresponding measurements and preparations. This method is quite general and can be applied to any linear dimension witness. PMID- 24765924 TI - Certifying separability in symmetric mixed states of N qubits, and superradiance. AB - Separability criteria are typically of the necessary, but not sufficient, variety, in that satisfying some separability criterion, such as positivity of eigenvalues under partial transpose, does not strictly imply separability. Certifying separability amounts to proving the existence of a decomposition of a target mixed state into some convex combination of separable states; determining the existence of such a decomposition is "hard." We show that it is effective to ask, instead, if the target mixed state "fits" some preconstructed separable form, in that one can generate a sufficient separability criterion relevant to all target states in some family by ensuring enough degrees of freedom in the preconstructed separable form. We demonstrate this technique by inducing a sufficient criterion for "diagonally symmetric" states of N qubits. A sufficient separability criterion opens the door to study precisely how entanglement is (not) formed; we use ours to prove that, counterintuitively, entanglement is not generated in idealized Dicke model superradiance despite its exemplification of many-body effects. We introduce a quantification of the extent to which a given preconstructed parametrization comprises the set of all separable states; for "diagonally symmetric" states our preconstruction is shown to be fully complete. This implies that our criterion is necessary in addition to sufficient, among other ramifications which we explore. PMID- 24765925 TI - Coherent backscattering in Fock space: a signature of quantum many-body interference in interacting bosonic systems. AB - We predict a generic signature of quantum interference in many-body bosonic systems resulting in a coherent enhancement of the average return probability in Fock space. This enhancement is robust with respect to variations of external parameters even though it represents a dynamical manifestation of the delicate superposition principle in Fock space. It is a genuine quantum many-body effect that lies beyond the reach of any mean-field approach. Using a semiclassical approach based on interfering paths in Fock space, we calculate the magnitude of the backscattering peak and its dependence on gauge fields that break time reversal invariance. We confirm our predictions by comparing them to exact quantum evolution probabilities in Bose-Hubbard models, and discuss their relevance in the context of many-body thermalization. PMID- 24765926 TI - Test of genuine multipartite nonlocality without inequalities. AB - In this Letter we propose a set of conditions on the joint probabilities as a test of genuine multipartite nonlocality without inequality. Our test is failed by all nonsignaling local models in which even nonlocal correlations among some observables (not all) are allowed as long as these correlations respect the nonsignaling principle. A pass of our test by a state therefore indicates that this state cannot be simulated by any nonsignaling local models; i.e., the state exhibits genuine multipartite nonlocality. It turns out that all entangled symmetric n-qubit (n>=3) states pass our test and therefore are n-way nonlocal. Also we construct two Bell-type inequalities from our proposed test whose violations indicate genuine multipartite nonlocal correlations. PMID- 24765927 TI - On-demand dark soliton train manipulation in a spinor polariton condensate. AB - We theoretically demonstrate the generation of dark soliton trains in a one dimensional exciton-polariton condensate within experimentally accessible schemes. In particular, we show that the frequency of the train can be finely tuned fully optically or electrically to provide a stable and efficient output signal modulation. Taking the polarization of the condensate into account, we elucidate the possibility of forming on-demand half-soliton trains. PMID- 24765928 TI - Amplification, redundancy, and quantum Chernoff information. AB - Amplification was regarded, since the early days of quantum theory, as a mysterious ingredient that endows quantum microstates with macroscopic consequences, key to the "collapse of the wave packet," and a way to avoid embarrassing problems exemplified by Schrodinger's cat. Such a bridge between the quantum microworld and the classical world of our experience was postulated ad hoc in the Copenhagen interpretation. Quantum Darwinism views amplification as replication, in many copies, of the information about quantum states. We show that such amplification is a natural consequence of a broad class of models of decoherence, including the photon environment we use to obtain most of our information. This leads to objective reality via the presence of robust and widely accessible records of selected quantum states. The resulting redundancy (the number of copies deposited in the environment) follows from the quantum Chernoff information that quantifies the information transmitted by a typical elementary subsystem of the environment. PMID- 24765929 TI - Certifying the dimension of classical and quantum systems in a prepare-and measure scenario with independent devices. AB - We consider the problem of testing the dimension of uncharacterized classical and quantum systems in a prepare-and-measure setup. Here we assume the preparation and measurement devices to be independent, thereby making the problem nonconvex. We present a simple method for generating nonlinear dimension witnesses for systems of arbitrary dimension. The simplest of our witnesses is highly robust to technical imperfections, and can certify the use of qubits in the presence of arbitrary noise and arbitrarily low detection efficiency. Finally, we show that this witness can be used to certify the presence of randomness, suggesting applications in quantum information processing. PMID- 24765930 TI - Quantum criticality and dynamical instability in the kicked-top model. AB - We investigate precursors of critical behavior in the quasienergy spectrum due to the dynamical instability in the kicked top. Using a semiclassical approach, we analytically obtain a logarithmic divergence in the density of states, which is analogous to a continuous excited state quantum phase transition in undriven systems. We propose a protocol to observe the cusp behavior of the magnetization close to the critical quasienergy. PMID- 24765931 TI - Experimental entanglement activation from discord in a programmable quantum measurement. AB - In quantum mechanics, observing is not a passive act. Consider a system of two quantum particles A and B: if a measurement apparatus M is used to make an observation on B, the overall state of the system AB will typically be altered. When this happens, no matter which local measurement is performed, the two objects A and B are revealed to possess peculiar correlations known as quantum discord. Here, we demonstrate experimentally that the very act of local observation gives rise to an activation protocol which converts discord into distillable entanglement, a stronger and more useful form of quantum correlations, between the apparatus M and the composite system AB. We adopt a flexible two-photon setup to realize a three-qubit system (A, B, M) with programmable degrees of initial correlations, measurement interaction, and characterization processes. Our experiment demonstrates the fundamental mechanism underpinning the ubiquitous act of observing the quantum world and establishes the potential of discord in entanglement generation. PMID- 24765932 TI - How energy conservation limits our measurements. AB - Observations in quantum mechanics are subject to complex restrictions arising from the principle of energy conservation. Determining such restrictions, however, has been so far an elusive task, and only partial results are known. In this Letter, we discuss how constraints on the energy spectrum of a measurement device translate into limitations on the measurements which we can effect on a target system with a nonconstant energy operator. We provide efficient algorithms to characterize such limitations and, in case the target is a two-level quantum system, we quantify them exactly. Our Letter, thus, identifies the boundaries between what is possible or impossible to measure, i.e., between what we can see or not, when energy conservation is at stake. PMID- 24765933 TI - Device-independent certification of high-dimensional quantum systems. AB - An important problem in quantum information processing is the certification of the dimension of quantum systems without making assumptions about the devices used to prepare and measure them, that is, in a device-independent manner. A crucial question is whether such certification is experimentally feasible for high-dimensional quantum systems. Here we experimentally witness in a device independent manner the generation of six-dimensional quantum systems encoded in the orbital angular momentum of single photons and show that the same method can be scaled, at least, up to dimension 13. PMID- 24765934 TI - Asymptotically optimal topological quantum compiling. AB - We address the problem of compiling quantum operations into braid representations for non-Abelian quasiparticles described by the Fibonacci anyon model. We classify the single-qubit unitaries that can be represented exactly by Fibonacci anyon braids and use the classification to develop a probabilistically polynomial algorithm that approximates any given single-qubit unitary to a desired precision by an asymptotically depth-optimal braid pattern. We extend our algorithm in two directions: to produce braids that allow only single-strand movement, called weaves, and to produce depth-optimal approximations of two-qubit gates. Our compiled braid patterns have depths that are 20 to 1000 times shorter than those output by prior state-of-the-art methods, for precisions ranging between 10(-10) and 10(-30). PMID- 24765936 TI - Implementation of a measurement-device-independent entanglement witness. AB - Entanglement, the essential resource in quantum information processing, should be witnessed in many tasks such as quantum computing and quantum communication. The conventional entanglement witness method, relying on an idealized implementation of measurements, could wrongly conclude a separable state to be entangled due to imperfect detections. Inspired by the idea of a time-shift attack, we construct an attack on the conventional entanglement witness process and demonstrate that a separable state can be falsely identified to be entangled. To close such detection loopholes, based on a recently proposed measurement-device-independent entanglement witness method, we design and experimentally demonstrate a measurement-device-independent entanglement witness for a variety of two-qubit states. By the new scheme, we show that an entanglement witness can be realized without detection loopholes. PMID- 24765935 TI - Measurement-based classical computation. AB - Measurement-based quantum computation (MBQC) is a model of quantum computation, in which computation proceeds via adaptive single qubit measurements on a multiqubit quantum state. It is computationally equivalent to the circuit model. Unlike the circuit model, however, its classical analog is little studied. Here we present a classical analog of MBQC whose computational complexity presents a rich structure. To do so, we identify uniform families of quantum computations [refining the circuits introduced by Bremner Proc. R. Soc. A 467, 459 (2010)] whose output is likely hard to exactly simulate (sample) classically. We demonstrate that these circuit families can be efficiently implemented in the MBQC model without adaptive measurement and, thus, can be achieved in a classical analog of MBQC whose resource state is a probability distribution which has been created quantum mechanically. Such states (by definition) violate no Bell inequality, but, if widely held beliefs about computational complexity are true, they, nevertheless, exhibit nonclassicality when used as a computational resource an imprint of their quantum origin. PMID- 24765937 TI - Can communication power of separable correlations exceed that of entanglement resource? AB - The scenario of remote state preparation with a shared correlated quantum state and one bit of forward communication [B. Dakic et al., Nat. Phys. 8, 666 (2012)] is considered. Optimization of the transmission efficiency is extended to include general encoding and decoding strategies. The importance of the use of linear fidelity is recognized. It is shown that separable states cannot exceed the efficiency of entangled states by means of "local operations plus classical communication" actions limited to 1 bit of forward communication. It is proven however that such a surprising phenomena may naturally occur when the decoding agent has limited resources in the sense that either (i) has to use decoding which is insensitive to the change of the coordinate system in the plane in question (which is the natural choice if the receiver does not know the latter) or (ii) is forced to use bistochastic operations which may be imposed by physically inconvenient local thermodynamical conditions. PMID- 24765938 TI - Classical Nernst engine. AB - We introduce a simple model for an engine based on the Nernst effect. In the presence of a magnetic field, a vertical heat current can drive a horizontal particle current against a chemical potential. For a microscopic model invoking classical particle trajectories subject to the Lorentz force, we prove a universal bound 3-2?2?0.172 for the ratio between the maximum efficiency and the Carnot efficiency. This bound, as the slightly lower one 1/6 for efficiency at maximum power, can indeed be saturated for a large magnetic field and small fugacity. PMID- 24765939 TI - Nonequilibrium fluctuation-dissipation theorem and heat production. AB - We use a relationship between response and correlation function in nonequilibrium systems to establish a connection between the heat production and the deviations from the equilibrium fluctuation-dissipation theorem. This scheme extends the Harada-Sasa formulation [Phys. Rev. Lett. 95, 130602 (2005)], obtained for Langevin equations in steady states, as it also holds for transient regimes and for discrete jump processes involving small entropic changes. Moreover, a general formulation includes two times and the new concepts of two-time work, kinetic energy, and of a two-time heat exchange that can be related to a nonequilibrium "effective temperature." Numerical simulations of a chain of anharmonic oscillators and of a model for a molecular motor driven by adenosine triphosphate hydrolysis illustrate these points. PMID- 24765940 TI - Parallelized quantum Monte Carlo algorithm with nonlocal worm updates. AB - Based on the worm algorithm in the path-integral representation, we propose a general quantum Monte Carlo algorithm suitable for parallelizing on a distributed memory computer by domain decomposition. Of particular importance is its application to large lattice systems of bosons and spins. A large number of worms are introduced and its population is controlled by a fictitious transverse field. For a benchmark, we study the size dependence of the Bose-condensation order parameter of the hard-core Bose-Hubbard model with L*L*betat=10240*10240*16, using 3200 computing cores, which shows good parallelization efficiency. PMID- 24765941 TI - Conformal field theories in fractional dimensions. AB - We study the conformal bootstrap in fractional space-time dimensions, obtaining rigorous bounds on operator dimensions. Our results show strong evidence that there is a family of unitary conformal field theories connecting the 2D Ising model, the 3D Ising model, and the free scalar theory in 4D. We give numerical predictions for the leading operator dimensions and central charge in this family at different values of D and compare these to calculations of phi4 theory in the epsilon expansion. PMID- 24765942 TI - Topological response theory of Abelian symmetry-protected topological phases in two dimensions. AB - It has been shown that the symmetry-protected topological (SPT) phases with finite Abelian symmetries can be described by Chern-Simons field theory. We propose a topological response theory to uniquely identify the SPT orders, which allows us to obtain a systematic scheme to classify bosonic SPT phases with any finite Abelian symmetry group. We point out that even for finite Abelian symmetry, there exist bosonic SPT phases beyond the current Chern-Simons theory framework. We also apply the theory to fermionic SPT phases with Zm symmetry and find the classification of SPT phases depends on the parity of m: for even m there are 2m classes, m out of which is intrinsically fermionic SPT phases and cannot be realized in any bosonic system. Finally we propose a classification scheme of fermionic SPT phases for any finite, Abelian symmetry. PMID- 24765943 TI - Pion masses in two-flavor QCD with eta condensation. AB - We investigate some aspects of two-flavor QCD with mu?md at low energy, using the leading order chiral perturbation theory including anomaly effects. While nothing special happens at mu=0 for the fixed md?0, the neutral pion mass becomes zero at two critical values of mu, between which the neutral pion field condenses, leading to a spontaneously CP broken phase, the so-called Dashen phase. We also show that the "topological susceptibility" in the chiral perturbation theory diverges at these two critical points. We briefly discuss a possibility that mu=0 can be defined by the vanishing the "topological susceptibility. We finally analyze the case of mu=md=m with theta=pi, which is equivalent to mu=-md=-m with theta=0 by the chiral rotation. In this case, the eta condensation occurs at small m, violating the CP symmetry spontaneously. Deep in the eta condensation phase, three pions become Nambu-Goldstone bosons, but they show unorthodox behavior at small m that mpi2=O(m2), which, however, is shown to be consistent with the chiral Ward-Takahashi identities. PMID- 24765944 TI - High-precision predictions for the light CP-even Higgs boson mass of the minimal supersymmetric standard model. AB - For the interpretation of the signal discovered in the Higgs searches at the LHC it will be crucial in particular to discriminate between the minimal Higgs sector realized in the standard model (SM) and its most commonly studied extension, the minimal supersymmetric standard model (MSSM). The measured mass value, having already reached the level of a precision observable with an experimental accuracy of about 500 MeV, plays an important role in this context. In the MSSM the mass of the light CP-even Higgs boson, Mh, can directly be predicted from the other parameters of the model. The accuracy of this prediction should at least match the one of the experimental result. The relatively high mass value of about 126 GeV has led to many investigations where the scalar top quarks are in the multi TeV range. We improve the prediction for Mh in the MSSM by combining the existing fixed-order result, comprising the full one-loop and leading and subleading two loop corrections, with a resummation of the leading and subleading logarithmic contributions from the scalar top sector to all orders. In this way for the first time a high-precision prediction for the mass of the light CP-even Higgs boson in the MSSM is possible all the way up to the multi-TeV region of the relevant supersymmetric particles. The results are included in the code FEYNHIGGS. PMID- 24765947 TI - Evolution of collectivity in 72Kr: evidence for rapid shape transition. AB - The transition rates from the yrast 2+ and 4+ states in the self-conjugate 72Kr nucleus were studied via lifetime measurements employing the GRETINA array with a novel application of the recoil-distance method. The large collectivity observed for the 4+->2+ transition suggests a prolate character of the excited states. The reduced collectivity previously reported for the 2+->0+ transition was confirmed. The irregular behavior of collectivity points to the occurrence of a rapid oblate prolate shape transition in 72Kr, providing stringent tests for advanced theories to describe the shape coexistence and its evolution. PMID- 24765948 TI - Neutrino propagation in nuclear medium and neutrinoless double-beta decay. AB - We discuss a novel effect in neutrinoless double-beta (0nubetabeta) decay related with the fact that its underlying mechanisms take place in the nuclear matter environment. We study the neutrino exchange mechanism and demonstrate the possible impact of nuclear medium via lepton-number-violating (LNV) four-fermion interactions of neutrinos with quarks from a decaying nucleus. The net effect of these interactions is the generation of an effective in-medium Majorana neutrino mass matrix. The enhanced rate of the 0nubetabeta decay can lead to the apparent incompatibility of observations of the 0nubetabeta decay with the value of the neutrino mass determined or restricted by the beta-decay and cosmological data. The effective neutrino masses and mixing are calculated for the complete set of the relevant four-fermion neutrino-quark operators. Using experimental data on the 0nubetabeta decay in combination with the beta-decay and cosmological data, we evaluate the characteristic scales of these operators: LambdaLNV>=2.4 TeV. PMID- 24765946 TI - Deformation-driven p-wave halos at the drip line: 31Ne. AB - The halo structure of 31Ne is studied using 1n-removal reactions on C and Pb targets at 230 MeV/nucleon. A combined analysis of the cross sections of these nuclear and Coulomb dominated reactions that feed directly the 30Ne ground-state reveals 31Ne to have a small neutron separation energy, 0.15(-0.10)(+0.16) MeV, and spin-parity 3/2-. Consistency of the data with reaction and large-scale shell model calculations identifies 31Ne as deformed and having a significant p-wave halo component, suggesting that halos are more frequent occurrences at the neutron drip line. PMID- 24765949 TI - Dynamic dimensionality identification for quantum control. AB - The control of quantum systems with shaped laser pulses presents a paradox since the relative ease with which solutions are discovered appears incompatible with the enormous variety of pulse shapes accessible with a standard pulse shaper. Quantum landscape theory indicates that the relevant search dimensionality is not dictated by the number of pulse shaper elements, but rather is related to the number of states participating in the controlled dynamics. The actual dimensionality is encoded within the sensitivity of the observed yield to all of the pulse shaper elements. To investigate this proposition, the Hessian matrix is measured for controlled transitions amongst states of atomic rubidium, and its eigendecomposition reveals a dimensionality consistent with that predicted by landscape theory. Additionally, this methodology furnishes a low-dimensional picture that captures the essence of the light-matter interaction and the ensuing system dynamics. PMID- 24765951 TI - Umklapp superradiance with a collisionless quantum degenerate Fermi gas. AB - The quantum dynamics of the electromagnetic light mode of an optical cavity filled with a coherently driven Fermi gas of ultracold atoms strongly depends on the geometry of the Fermi surface. Superradiant light generation and self organization of the atoms can be achieved at low pumping threshold due to resonant atom-photon umklapp processes, where the fermions are scattered from one side of the Fermi surface to the other by exchanging photon momenta. The cavity spectrum exhibits sidebands that, despite strong atom-light coupling and cavity decay, retain narrow linewidth, due to absorptionless transparency windows outside the atomic particle-hole continuum and the suppression of broadening and thermal fluctuations in the collisionless Fermi gas. PMID- 24765945 TI - Photoproduction of pi0 mesons off neutrons in the nucleon resonance region. AB - Precise angular distributions have been measured for the first time for the photoproduction of pi0 mesons off neutrons bound in the deuteron. The effects from nuclear Fermi motion have been eliminated by a complete kinematic reconstruction of the final state. The influence of final-state-interaction effects has been estimated by a comparison of the reaction cross section for quasifree protons bound in the deuteron to the results for free protons and then applied as a correction to the quasifree neutron data. The experiment was performed at the tagged photon facility of the Mainz Microtron MAMI with the Crystal Ball and TAPS detector setup for incident photon energies between 0.45 and 1.4 GeV. The results are compared to the predictions from reaction models and partial-wave analyses based on data from other isospin channels. The model predictions show large discrepancies among each other and the present data will provide much tighter constraints. This is demonstrated by the results of a new analysis in the framework of the Bonn-Gatchina coupled-channel analysis which included the present data. PMID- 24765950 TI - Fermionic superradiance in a transversely pumped optical cavity. AB - Following the experimental realization of Dicke superradiance in Bose gases coupled to cavity light fields, we investigate the behavior of ultracold fermions in a transversely pumped cavity. We focus on the equilibrium phase diagram of spinless fermions coupled to a single cavity mode and establish a zero temperature transition to a superradiant state. In contrast to the bosonic case, Pauli blocking leads to lattice commensuration effects that influence self organization in the cavity light field. This includes a sequence of discontinuous transitions with increasing atomic density and tricritical superradiance. We discuss the implications for experiment. PMID- 24765952 TI - Superradiance of degenerate Fermi gases in a cavity. AB - In this Letter we consider spinless Fermi gases placed inside a cavity and study the critical strength of a pumping field for driving a superradiance transition. We emphasize that the Fermi surface nesting effect can strongly enhance the superradiance tendency. Around certain fillings, when the Fermi surface is nearly nested with a relevant nesting momentum, the susceptibility of the system toward a checkboard density-wave ordered state is greatly enhanced in comparison with a Bose gas with the same density, because of which a much smaller (sometime even vanishingly small) critical pumping field strength can give rise to superradiance. This effect leads to interesting reentrance behavior and a topologically distinct structure in the phase diagram. Away from these fillings, the Pauli exclusion principle brings about the dominant effect for which the critical pumping strength is lowered in the low-density regime and increased in the high-density regime. These results open the prospect of studying the rich phenomena of degenerate Fermi gases in a cavity. PMID- 24765953 TI - Double photoionization in ring molecules: search of the cooper pair formation. AB - We provide a final state selective experimental study on the direct double photoionization of the valence states of benzene and pyrrole. The experiment is carried out using a magnetic-bottle electron time-of-flight coincidence setup at the incident photon energy region of 25-120 eV. We discuss on the recently discovered phenomenon of so-called Cooper pair formation [R. Wehlitz et al., Phys. Rev. Lett. 109, 193001 (2012)] and show that our experiment provides contradicting evidence on its existence in the proposed form. We confirm the finding of a new two-electron continuum resonance structure observed at about 30 70 eV above the double ionization threshold in benzene, provide further information from it, and suggest an alternative explanation. PMID- 24765954 TI - Ionization of excited atoms by intense single-cycle THz pulses. AB - We have employed intense, single-cycle THz pulses to explore strong-field ionization of low-lying Na Rydberg states in the low-frequency limit. At the largest fields used, F?430 kV/cm, electrons with energies up to 60 eV are created. The field ionization threshold is greater than expected for adiabatic "over-the-barrier" ionization and is found to scale as n-3. In addition, for a given field amplitude, higher energy electrons are produced during the ionization of the most tightly bound states. These observations can be attributed to the suppression of scattering from the nonhydrogenic ion core, the long times required for Rydberg electrons to escape over the barrier in the field-dressed Coulomb potential, and the failure, in the single-cycle limit, of the standard prediction for electron energy transfer in an oscillating field. The latter, in particular, holds important implications for future strong-field experiments involving the interaction of ground-state atoms and molecules with true single cycle laser fields. PMID- 24765955 TI - Bose-Einstein condensates with cavity-mediated spin-orbit coupling. AB - We propose a novel scheme to generate the spin-orbit coupling for a condensate placed inside an optical cavity by using a standing wave and a traveling wave. It is shown that the interplay of the laser lights and the cavity gives rise to rich quantum phases. Our scheme also generates a large synthetic magnetic field for the dressed spin state, which may facilitate the study of the quantum Hall effect in ultracold atomic gases. PMID- 24765956 TI - Alignment of D-state Rydberg molecules. AB - We report on the formation of ultralong-range Rydberg D-state molecules via photoassociation in an ultracold cloud of rubidium atoms. By applying a magnetic offset field on the order of 10 G and high resolution spectroscopy, we are able to resolve individual rovibrational molecular states. A full theory, using a Fermi pseudopotential approach including s- and p-wave scattering terms, reproduces the measured binding energies. The calculated molecular wave functions show that in the experiment we can selectively excite stationary molecular states with an extraordinary degree of alignment or antialignment with respect to the magnetic field axis. PMID- 24765957 TI - Neutral gas sympathetic cooling of an ion in a Paul trap. AB - A single ion immersed in a neutral buffer gas is studied. An analytical model is developed that gives a complete description of the dynamics and steady-state properties of the ions. An extension of this model, using techniques employed in the mathematics of economics and finance, is used to explain the recent observation of non-Maxwellian statistics for these systems. Taken together, these results offer an explanation of the long-standing issues associated with sympathetic cooling of an ion by a neutral buffer gas. PMID- 24765958 TI - Microscopic superfluidity in 4He clusters stirred by a rotating impurity molecule. AB - The effective moment of inertia of a CO impurity molecule in 4HeN and p-(H2)N solvent clusters initially increases with N but then commences a nonclassical decrease at N=4 (4He) or N=6 (p-H2). This suggests molecule-solvent decoupling and a transition to microscopic superfluidity. However, the quantum decoupling mechanism has not been elucidated. To understand the decoupling mechanism, a one dimensional model is introduced in which the 4He atoms are confined to a ring. This model captures the physics and shows that decoupling happens primarily because of bosonic solvent-solvent repulsion. Quantum Monte Carlo and basis set calculations suggest that the system can be modeled as a stirred Tonks-Girardeau gas. This allows the N-particle time-dependent Schrodinger equation to be solved directly. Computations of the integrated particle current reveal a threshold for stirring and current generation, indicative of superfluidity. PMID- 24765959 TI - Quantum control of molecular gas hydrodynamics. AB - We demonstrate that strong impulsive gas heating or heating suppression at standard temperature and pressure can occur from coherent rotational excitation or deexcitation of molecular gases using a sequence of nonionizing laser pulses. For the case of excitation, subsequent collisional decoherence of the ensemble leads to gas heating significantly exceeding that from plasma absorption under the same laser focusing conditions. In both cases, the macroscopic hydrodynamics of the gas can be finely controlled with ~40 fs temporal sensitivity. PMID- 24765960 TI - Heralded single-phonon preparation, storage, and readout in cavity optomechanics. AB - We show how to use the radiation pressure optomechanical coupling between a mechanical oscillator and an optical cavity field to generate in a heralded way a single quantum of mechanical motion (a Fock state). Starting with the oscillator close to its ground state, a laser pumping the upper motional sideband produces correlated photon-phonon pairs via optomechanical parametric down-conversion. Subsequent detection of a single scattered Stokes photon projects the macroscopic oscillator into a single-phonon Fock state. The nonclassical nature of this mechanical state can be demonstrated by applying a readout laser on the lower sideband to map the phononic state to a photonic mode and performing an autocorrelation measurement. Our approach proves the relevance of cavity optomechanics as an enabling quantum technology. PMID- 24765961 TI - Observation of entanglement-dependent two-particle holonomic phase. AB - Holonomic phases--geometric and topological--have long been an intriguing aspect of physics. They are ubiquitous, ranging from observations in particle physics to applications in fault tolerant quantum computing. However, their exploration in particles sharing genuine quantum correlations lacks in observations. Here, we experimentally demonstrate the holonomic phase of two entangled photons evolving locally, which, nevertheless, gives rise to an entanglement-dependent phase. We observe its transition from geometric to topological as the entanglement between the particles is tuned from zero to maximal, and find this phase to behave more resiliently to evolution changes with increasing entanglement. Furthermore, we theoretically show that holonomic phases can directly quantify the amount of quantum correlations between the two particles. Our results open up a new avenue for observations of holonomic phenomena in multiparticle entangled quantum systems. PMID- 24765962 TI - Quantum walks of correlated photon pairs in two-dimensional waveguide arrays. AB - We demonstrate quantum walks of correlated photons in a two-dimensional network of directly laser written waveguides coupled in a "swiss cross" arrangement. The correlated detection events show high-visibility quantum interference and unique composite behavior: strong correlation and independence of the quantum walkers, between and within the planes of the cross. Violations of a classically defined inequality, for photons injected in the same plane and in orthogonal planes, reveal nonclassical behavior in a nonplanar structure. PMID- 24765963 TI - Light transport and localization in two-dimensional correlated disorder. AB - Structural correlations in disordered media are known to affect significantly the propagation of waves. In this Letter, we theoretically investigate the transport and localization of light in 2D photonic structures with short-range correlated disorder. The problem is tackled semianalytically using the Baus-Colot model for the structure factor of correlated media and a modified independent scattering approximation. We find that short-range correlations make it possible to easily tune the transport mean free path by more than a factor of 2 and the related localization length over several orders of magnitude. This trend is confirmed by numerical finite-difference time-domain calculations. This study therefore shows that disorder engineering can offer fine control over light transport and localization in planar geometries, which may open new opportunities in both fundamental and applied photonics research. PMID- 24765964 TI - Macroscopic effects in noncollinear high-order harmonic generation. AB - We study two-color high-order harmonic generation using an intense driving field and its weak second harmonic, crossed under a small angle in the focus. Employing sum- and difference-frequency generation processes, such a noncollinear scheme can be used to measure and control macroscopic phase matching effects by utilizing a geometrical phase mismatch component, which depends on the noncollinear angle. We further show how spatial phase effects in the generation volume are mapped out into the far field allowing a direct analogy with temporal carrier envelope effects in attosecond pulse generation. PMID- 24765965 TI - Experimental demonstration of a coherent perfect absorber with PT phase transition. AB - We report the realization of a coherent perfect absorber, using a pair of passive resonators coupled to a microwave transmission line in the background, which can completely absorb light in its parity-time (PT-)symmetric phase but not in its broken phase. Instead of balancing material gain and loss, we exploit the incident waves in the open system as an effective gain so that ideal PT symmetry can be established by using only passive materials. Such a route will be effective to construct PT-symmetric metamaterials and also tunable PT-symmetric optical elements in general. It also provides a flexible platform for studying exceptional-point physics with both electric and magnetic responses. PMID- 24765966 TI - Laboratory demonstration of spatial-coherence analysis of a blackbody through an up-conversion interferometer. AB - In the field of high resolution imaging in astronomy, we experimentally demonstrate the spatial-coherence analysis of a blackbody using an up-conversion interferometer in the photon counting regime. The infrared radiation of the blackbody is converted to a visible one in both arms of the interferometer thanks to the sum-frequency generation processes achieved in Ti-diffused periodically poled lithium niobate waveguides. The coherence analysis is performed through a dedicated imaging stage which mimics a classical telescope array analyzing an astrophysical source. The validity of these measurements is confirmed by the comparison with spatial-coherence analysis through a reference interferometer working at infrared wavelengths. PMID- 24765967 TI - Chimera states: the existence criteria revisited. AB - Chimera states, representing a spontaneous breakup of a population of identical oscillators that are identically coupled, into subpopulations displaying synchronized and desynchronized behavior, have traditionally been found to exist in weakly coupled systems and with some form of nonlocal coupling between the oscillators. Here we show that neither the weak-coupling approximation nor nonlocal coupling are essential conditions for their existence. We obtain, for the first time, amplitude-mediated chimera states in a system of globally coupled complex Ginzburg-Landau oscillators. We delineate the dynamical origins for the formation of such states from a bifurcation analysis of a reduced model equation and also discuss the practical implications of our discovery of this broader class of chimera states. PMID- 24765968 TI - Universal quantum graphs. AB - For time-reversal invariant graphs we prove the Bohigas-Giannoni-Schmit conjecture in its most general form: For graphs that are mixing in the classical limit, all spectral correlation functions coincide with those of the Gaussian orthogonal ensemble of random matrices. For open graphs, we derive the analogous identities for all S-matrix correlation functions. PMID- 24765970 TI - Negative refraction and energy funneling by hyperbolic materials: an experimental demonstration in acoustics. AB - This Letter reports the design, fabrication, and experimental characterization of hyperbolic materials showing negative refraction and energy funneling of airborne sound. Negative refraction is demonstrated using a stack of five holey Plexiglas plates where their thicknesses, layer separation, hole diameters, and lattice periodicity have been determined to show hyperbolic dispersion around 40 kHz. The resulting hyperbolic material shows a flat band profile in the equifrequency contour allowing the gathering of acoustic energy in a broad range of incident angles and its funneling through the material. Our demonstrations foresee interesting developments based on both phenomena. Acoustic imaging with subwavelength resolution and spot-size converters that harvest and squeeze sound waves irradiating from many directions into a collimated beam are just two possible applications among many. PMID- 24765969 TI - Chimeralike states in an ensemble of globally coupled oscillators. AB - We demonstrate the emergence of a complex state in a homogeneous ensemble of globally coupled identical oscillators, reminiscent of chimera states in nonlocally coupled oscillator lattices. In this regime some part of the ensemble forms a regularly evolving cluster, while all other units irregularly oscillate and remain asynchronous. We argue that the chimera emerges because of effective bistability, which dynamically appears in the originally monostable system due to internal delayed feedback in individual units. Additionally, we present two examples of chimeras in bistable systems with frequency-dependent phase shift in the global coupling. PMID- 24765971 TI - Upscale energy transfer in three-dimensional rapidly rotating turbulent convection. AB - Rotating Rayleigh-Benard convection exhibits, in the limit of rapid rotation, a turbulent state known as geostrophic turbulence. This state is present for sufficiently large Rayleigh numbers representing the thermal forcing of the system, and is characterized by a leading order balance between the Coriolis force and pressure gradient. This turbulent state is itself unstable to the generation of depth-independent or barotropic vortex structures of ever larger scale through a process known as spectral condensation. This process involves an inverse cascade mechanism with a positive feedback loop whereby large-scale barotropic vortices organize small scale convective eddies. In turn, these eddies provide a dynamically evolving energy source for the large-scale barotropic component. Kinetic energy spectra for the barotropic dynamics are consistent with a k-3 downscale enstrophy cascade and an upscale cascade that steepens to k-3 as the box-scale condensate forms. At the same time the flow maintains a baroclinic convective component with an inertial range consistent with a k-5/3 spectrum. The condensation process resembles a similar process in two dimensions but is fully three-dimensional. PMID- 24765972 TI - Recurrent bursts via linear processes in turbulent environments. AB - Large-scale instabilities occurring in the presence of small-scale turbulent fluctuations are frequently observed in geophysical or astrophysical contexts but are difficult to reproduce in the laboratory. Using extensive numerical simulations, we report here on intense recurrent bursts of turbulence in plane Poiseuille flow rotating about a spanwise axis. A simple model based on the linear instability of the mean flow can predict the structure and time scale of the nearly periodic and self-sustained burst cycles. Poiseuille flow is suggested as a prototype for future studies of low-dimensional dynamics embedded in strongly turbulent environments. PMID- 24765973 TI - Surface nanobubbles nucleate microdroplets. AB - When a hydrophobic solid is in contact with water, surface nanobubbles often form at the interface. They have a lifetime many orders of magnitude longer than expected. Here, we show that they even withstand a temperature increase to temperatures close to the boiling point of bulk water; i.e., they do not nucleate larger bubbles ("superstability"). On the contrary, when the vapor-liquid contact line passes a nanobubble, a liquid film remains around it, which, after pinch off, results in a microdroplet in which the nanobubbles continue to exist. Finally, the microdroplet evaporates and the nanobubble consequently bursts. Our results support that pinning plays a crucial role for nanobubble stability. PMID- 24765974 TI - Shock-wave compression and Joule-Thomson expansion. AB - Structurally stable atomistic one-dimensional shock waves have long been simulated by injecting fresh cool particles and extracting old hot particles at opposite ends of a simulation box. The resulting shock profiles demonstrate tensor temperature, Txx?Tyy and Maxwell's delayed response, with stress lagging strain rate and heat flux lagging temperature gradient. Here this same geometry, supplemented by a short-ranged external "plug" field, is used to simulate steady Joule-Kelvin throttling flow of hot dense fluid through a porous plug, producing a dilute and cooler product fluid. PMID- 24765975 TI - Numerical simulation of a self-similar cascade of filament instabilities in the surface quasigeostrophic system. AB - We provide numerical evidence for the existence of a cascade of filament instabilities in the surface quasigeostrophic system for rotating, stratified flow near a horizontal boundary. The cascade involves geometrically shrinking spatial and temporal scales and implies the singular collapse of the filament width to zero in a finite time. The numerical method is both spatially and temporally adaptive, permitting the accurate simulation of the evolution over an unprecedented range of spatial scales spanning over ten orders of magnitude. It provides the first convincing demonstration of the cascade, in which the large separation of scales between subsequent instabilities has made previous numerical simulation difficult. PMID- 24765976 TI - Nonuniformly driven two-plasmon-decay instability in direct-drive implosions. AB - Half-harmonic emission spectra and images taken during directly driven implosions show that the two-plasmon decay (TPD) instability is driven nonuniformly over the target surface and that multibeam effects dominate this instability. The images show a spatially limited extent of the TPD instability. A prominent spectral feature is used to determine the electron temperature in the corona. Near threshold the temperatures agree with one-dimensional hydrodynamic predictions but exceed them by ~10% above the TPD threshold. Two-dimensional hydrodynamic simulations indicate that a significant part (~20%) of the laser intensity must be locally absorbed by the TPD instability (i.e., by collisional damping of the electron plasma waves) to maintain these temperature islands. PMID- 24765977 TI - Cerenkov emission of quasiparallel whistlers by fast electron phase-space holes during magnetic reconnection. AB - Kinetic simulations of magnetotail reconnection have revealed electromagnetic whistlers originating near the exhaust boundary and propagating into the inflow region. The whistler production mechanism is not a linear instability, but rather is Cerenkov emission of almost parallel whistlers from localized moving clumps of charge (finite-size quasiparticles) associated with nonlinear coherent electron phase space holes. Whistlers are strongly excited by holes without ever growing exponentially. In the simulation the whistlers are emitted in the source region from holes that accelerate down the magnetic separatrix towards the x line. The phase velocity of the whistlers vphi in the source region is everywhere well matched to the hole velocity vH as required by the Cerenkov condition. The simulation shows emission is most efficient near the theoretical maximum vphi=half the electron Alfven speed, consistent with the new theoretical prediction that faster holes radiate more efficiently. While transferring energy to whistlers the holes lose coherence and dissipate over a few local ion inertial lengths. The whistlers, however, propagate to the x line and out over many 10's of ion inertial lengths into the inflow region of reconnection. As the whistlers pass near the x line they modulate the rate at which magnetic field lines reconnect. PMID- 24765978 TI - Radiation-reaction trapping of electrons in extreme laser fields. AB - A radiation-reaction trapping (RRT) of electrons is revealed in the near-QED regime of laser-plasma interaction. Electrons quivering in laser pulse experience radiation reaction (RR) recoil force by radiating photons. When the laser field reaches the threshold, the RR force becomes significant enough to compensate for the expelling laser ponderomotive force. Then electrons are trapped inside the laser pulse instead of being scattered off transversely and form a dense plasma bunch. The mechanism is demonstrated both by full three-dimensional particle-in cell simulations using the QED photonic approach and numerical test-particle modeling based on the classical Landau-Lifshitz formula of RR force. Furthermore, the proposed analysis shows that the threshold of laser field amplitude for RRT is approximately the cubic root of laser wavelength over classical electron radius. Because of the pinching effect of the trapped electron bunch, the required laser intensity for RRT can be further reduced. PMID- 24765979 TI - Observations of continuum depression in warm dense matter with x-ray Thomson scattering. AB - Detailed measurements of the electron densities, temperatures, and ionization states of compressed CH shells approaching pressures of 50 Mbar are achieved with spectrally resolved x-ray scattering. Laser-produced 9 keV x-rays probe the plasma during the transient state of three-shock coalescence. High signal-to noise x-ray scattering spectra show direct evidence of continuum depression in highly degenerate warm dense matter states with electron densities ne>1024 cm-3. The measured densities and temperatures agree well with radiation-hydrodynamic modeling when accounting for continuum lowering in calculations that employ detailed configuration accounting. PMID- 24765980 TI - Electron-ion equilibration in ultrafast heated graphite. AB - We have employed fast electrons produced by intense laser illumination to isochorically heat thermal electrons in solid density carbon to temperatures of ~10,000 K. Using time-resolved x-ray diffraction, the temperature evolution of the lattice ions is obtained through the Debye-Waller effect, and this directly relates to the electron-ion equilibration rate. This is shown to be considerably lower than predicted from ideal plasma models. We attribute this to strong ion coupling screening the electron-ion interaction. PMID- 24765981 TI - Direct detection of resonant electron pitch angle scattering by whistler waves in a laboratory plasma. AB - Resonant interactions between energetic electrons and whistler mode waves are an essential ingredient in the space environment, and in particular in controlling the dynamic variability of Earth's natural radiation belts, which is a topic of extreme interest at the moment. Although the theory describing resonant wave particle interaction has been present for several decades, it has not been hitherto tested in a controlled laboratory setting. In the present Letter we report on the first laboratory experiment to directly detect resonant pitch angle scattering of energetic (~keV) electrons due to whistler mode waves. We show that the whistler mode wave deflects energetic electrons at precisely the predicted resonant energy, and that varying both the maximum beam energy, and the wave frequency, alters the energetic electron beam very close to the resonant energy. PMID- 24765982 TI - Ab initio simulations for the ion-ion structure factor of warm dense aluminum. AB - We perform ab initio simulations based on finite-temperature density functional theory in order to determine the static and dynamic ion-ion structure factor in aluminum. We calculate the dynamic structure factor via the intermediate scattering function and extract the dispersion relation for the collective excitations. The results are compared with available experimental x-ray scattering data. Very good agreement is obtained for the liquid metal domain. In addition we perform simulations for warm dense aluminum in order to obtain the ion dynamics in this strongly correlated quantum regime. We determine the sound velocity for both liquid and warm dense aluminum which can be checked experimentally using narrow-bandwidth free electron laser radiation. PMID- 24765983 TI - Optically controlled solid-density transient plasma gratings. AB - A general approach for optically controlled spatial structuring of overdense plasmas generated at the surface of initially plain solid targets is presented. We demonstrate it experimentally by creating sinusoidal plasma gratings of adjustable spatial periodicity and depth, and study the interaction of these transient structures with an ultraintense laser pulse to establish their usability at relativistically high intensities. We then show how these gratings can be used as a "spatial ruler" to determine the source size of the high-order harmonic beams produced at the surface of an overdense plasma. These results open new directions both for the metrology of laser-plasma interactions and the emerging field of ultrahigh intensity plasmonics. PMID- 24765984 TI - Onsager-Kraichnan condensation in decaying two-dimensional quantum turbulence. AB - Despite the prominence of Onsager's point-vortex model as a statistical description of 2D classical turbulence, a first-principles development of the model for a realistic superfluid has remained an open problem. Here we develop a mapping of a system of quantum vortices described by the homogeneous 2D Gross Pitaevskii equation (GPE) to the point-vortex model, enabling Monte Carlo sampling of the vortex microcanonical ensemble. We use this approach to survey the full range of vortex states in a 2D superfluid, from the vortex-dipole gas at positive temperature to negative-temperature states exhibiting both macroscopic vortex clustering and kinetic energy condensation, which we term an Onsager Kraichnan condensate (OKC). Damped GPE simulations reveal that such OKC states can emerge dynamically, via aggregation of small-scale clusters into giant OKC clusters, as the end states of decaying 2D quantum turbulence in a compressible, finite-temperature superfluid. These statistical equilibrium states should be accessible in atomic Bose-Einstein condensate experiments. PMID- 24765985 TI - Finite size analysis of zero-temperature jamming transition under applied shear stress by minimizing a thermodynamic-like potential. AB - By finding local minima of a thermodynamic-like potential, we generate jammed packings of frictionless spheres under constant shear stress sigma and obtain the yield stress sigmay by sampling the potential energy landscape. For three dimensional systems with harmonic repulsion, sigmay satisfies the finite size scaling with the limiting scaling relation sigmay~phi-phic,infinity, where phic,infinity is the critical volume fraction of the jamming transition at sigma=0 in the thermodynamic limit. The finite size scaling implies a length xi~(phi-phic,infinity)-nu with nu=0.81+/-0.05, which turns out to be a robust and universal length scale exhibited as well in the finite size scaling of multiple quantities measured without shear and independent of particle interaction. Moreover, comparison between our new approach and quasistatic shear reveals that quasistatic shear tends to explore low-energy states. PMID- 24765986 TI - Fermi-Pasta-Ulam physics with nanomechanical graphene resonators: intrinsic relaxation and thermalization from flexural mode coupling. AB - Thermalization in nonlinear systems is a central concept in statistical mechanics and has been extensively studied theoretically since the seminal work of Fermi, Pasta, and Ulam. Using molecular dynamics and continuum modeling of a ring-down setup, we show that thermalization due to nonlinear mode coupling intrinsically limits the quality factor of nanomechanical graphene drums and turns them into potential test beds for Fermi-Pasta-Ulam physics. We find the thermalization rate Gamma to be independent of radius and scaling as Gamma~T*/epsilonpre2, where T* and epsilonpre are effective resonator temperature and prestrain. PMID- 24765987 TI - Plasticity initiation and evolution during nanoindentation of an iron-3% silicon crystal. AB - Our investigations confirm that the collective, avalanchelike dislocation nucleation and multiplication is responsible for the pop-in event in a body centered-cubic Fe-3% Si single crystal. Dislocation was not observed prior to pop in but was apparent after the event. We find that a transition from an initial stage dominated by discrete dislocation nucleation to subsequent continuum plasticity occurs just after the pop-in event as elastoplastic deformation ensues. PMID- 24765988 TI - Glass transitions in a monatomic liquid with two glassy states. AB - We perform out-of-equilibrium molecular dynamics simulations of a monatomic liquid that exhibits liquid and glass polymorphism, with two distinct glasses, low- (LDA) and high-density (HDA) amorphous solids. By performing isobaric heating simulations of LDA and HDA at different pressures, we determine (a) the glass transition temperature of LDA and HDA, TgLDA(P) and TgHDA(P), as well as (b) the corresponding glass-glass transformation temperatures, TLDA-HDA(P) and THDA-LDA(P). It is found that TgLDA(P) is anomalous; i.e., it decreases with increasing pressure, while TgHDA(P) increases with increasing pressure. Interestingly, the TgLDA(P) and TLDA-HDA(P) loci, as well as the TgHDA(P) and THDA-LDA(P) loci, constitute smooth single lines in the P-T plane, suggesting that heating-induced glass-glass and glass transitions are related. We discuss the present results in the context of water experiments and simulations. PMID- 24765989 TI - Relationships between atomic diffusion mechanisms and ensemble transport coefficients in crystalline polymorphs. AB - Ionic transport in conventional ionic solids is generally considered to proceed via independent diffusion events or "hops." This assumption leads to well-known Arrhenius expressions for transport coefficients, and is equivalent to assuming diffusion is a Poisson process. Using molecular dynamics simulations of the low temperature B1, B3, and B4 AgI polymorphs, we have compared rates of ion hopping with corresponding Poisson distributions to test the assumption of independent hopping in these common structure types. In all cases diffusion is a non-Poisson process, and hopping is strongly correlated in time. In B1 the diffusion coefficient can be approximated by an Arrhenius expression, though the physical significance of the parameters differs from that commonly assumed. In low temperature B3 and B4, diffusion is characterized by concerted motion of multiple ions in short closed loops. Diffusion coefficients cannot be expressed in a simple Arrhenius form dependent on single-ion free energies, and intrinsic diffusion must be considered a many-body process. PMID- 24765990 TI - Effects of rotational-symmetry breaking on physisorption of ortho- and para-H2 on Ag(111). AB - Quantum-state-selective thermal desorption of H2 weakly physisorbed on Ag(111) demonstrates significantly different desorption features between the nuclear-spin modifications. An energy shift due to the rotational-symmetry breaking induced by an anisotropic interaction affects not only the enthalpy but also the entropy of adsorption. The preexponential factor for desorption of the ortho-H2 is about three times as large as that of the para-H2. The entropy difference indicates a perpendicular orientation preference of anisotropic physisorption potential, which also suggests the importance of partial hybridization interaction for weak physisorption. PMID- 24765991 TI - Wetting of elastic solids on nanopillars. AB - Solids and liquids are both known to exhibit Cassie-Baxter states, where a drop or a solid nanoparticle is maintained on top of pillars due to wetting forces. We point out that due to elastic strain, solid nanocrystals exhibit a behavior different from that of liquids. First, the equilibrium Cassie-Baxter state on a single pillar exhibits a spontaneous symmetry breaking due to elastic effects. The second consequence of elasticity is the existence of stable partially impaled states, resulting from a compromise between wetting forces which favor impalement and elastic strain which resists impalement. Based on kinetic Monte Carlo simulations which include elastic strain, we discuss these effects and we propose a global phase diagram for the stability of nanocrystals on nanopillars. PMID- 24765992 TI - Mechanism for limiting thickness of thin oxide films on aluminum. AB - A first-principles account of the observed limiting thickness of oxide films formed on aluminum during oxidizing conditions is presented. The results uncover enhanced bonding of oxygen to thin alumina films in contact with metallic aluminum that stems from charge transfer between a reconstructed oxide-metal interface and the adsorbed molecules. The first-principles results are compared with the traditional Cabrera-Mott (CM) model, which is a classical continuum model. Within the CM model, charged surface oxygen species and metal ions generate a (Mott) potential that drives oxidation. An apparent limiting thickness is observed as the oxidation rate decreases rapidly with film growth. The present results support experimental estimates of the Mott potential and film thicknesses. In contrast to the CM model, however, the calculations reveal a real limiting thickness that originates from a diminishing oxygen adsorption energy beyond a certain oxide film thickness. PMID- 24765993 TI - First-principles calculation of atomic forces and structural distortions in strongly correlated materials. AB - We introduce a novel computational approach for the investigation of complex correlated electron materials which makes it possible to evaluate interatomic forces and, thereby, determine atomic displacements and structural transformations induced by electronic correlations. It combines ab initio band structure and dynamical mean-field theory and is implemented with the linear response formalism regarding atomic displacements. We apply this new technique to explore structural transitions of prototypical correlated systems such as elemental hydrogen, SrVO3, and KCuF3. PMID- 24765994 TI - Coexistence of spin density waves and superconductivity in (TMTSF)2PF6. AB - We present simultaneous measurements of angular-dependent magnetoresistance and thermopower along all three crystal axes in (TMTSF)2PF6 for pressures to 7.4 kbar and magnetic fields to 35 T. (TMTSF)2PF6 under pressure shows the coexistence of spin density wave and metal-superconducting orders. We suggest that this coexistence results neither in microscopic coexistence nor in a new soliton wall phase, contrary to previous suggestions, but in phase separation into domains of the high-pressure metal and the low-pressure spin density wave phases. Simultaneous measurement of transport along all crystal axes allows us to unambiguously describe the domain structure, whereas the superconducting transition temperature and four independent Fermi surface-sensitive magnetoresistance signatures allow us to unambiguously characterize the coexisting metallic domains. PMID- 24765995 TI - Inducing a Lifshitz transition by extrinsic doping of surface bands in the topological crystalline insulator Pb1-xSnxSe. AB - The narrow gap semiconductor Pb1-xSnxSe was investigated for topologically protected surface states in its rocksalt structural phase for x=0.45, 0.23, 0.15, and 0. Angle-resolved photoelectron spectroscopy of intrinsically p-doped samples showed a clear indication of two Dirac cones, eccentric about the time-reversal invariant point X- of the surface Brillouin zone for all but the x=0 sample. Adsorption of alkalies gradually filled the surface bands with electrons, driving the x>0 topological crystalline insulator systems through Lifshitz transitions, and from a holelike to electronlike Fermi surface. The electron-doped bands in x>0 samples exhibited the full configuration of the Dirac cones, also confirming electron-hole symmetry of the surface bands. PMID- 24765996 TI - Fractal energy spectrum of a polariton gas in a Fibonacci quasiperiodic potential. AB - We report on the study of a polariton gas confined in a quasiperiodic one dimensional cavity, described by a Fibonacci sequence. Imaging the polariton modes both in real and reciprocal space, we observe features characteristic of their fractal energy spectrum such as the opening of minigaps obeying the gap labeling theorem and log-periodic oscillations of the integrated density of states. These observations are accurately reproduced solving an effective 1D Schrodinger equation, illustrating the potential of cavity polaritons as a quantum simulator in complex topological geometries. PMID- 24765997 TI - Time reversal symmetric topological exciton condensate in bilayer HgTe quantum wells. AB - We investigate a bilayer system of critical HgTe quantum wells, each featuring a spin-degenerate pair of massless Dirac fermions. In the presence of an electrostatic interlayer Coulomb coupling, we determine the exciton condensate order parameter of the system self-consistently. Calculating the bulk topological Z2 invariant of the resulting mean-field Hamiltonian, we discover a novel time reversal symmetric topological exciton condensate state, coined the helical topological exciton condensate. We argue that this phase can exist for experimentally relevant parameters. Interestingly, due to its multiband nature, the present bilayer model exhibits a nontrivial interplay between spontaneous symmetry breaking and topology: Depending on which symmetry the condensate order parameter spontaneously picks in combined orbital and spin space, stable minima in the free energy corresponding to both trivial and nontrivial gapped states can be found. PMID- 24765998 TI - Finite-temperature conductivity and magnetoconductivity of topological insulators. AB - The electronic transport experiments on topological insulators exhibit a dilemma. A negative cusp in magnetoconductivity is widely believed as a quantum transport signature of the topological surface states, which are immune from localization and exhibit the weak antilocalization. However, the measured conductivity drops logarithmically when lowering temperature, showing a typical feature of the weak localization as in ordinary disordered metals. Here, we present a conductivity formula for massless and massive Dirac fermions as a function of magnetic field and temperature, by taking into account the electron-electron interaction and quantum interference simultaneously. The formula reconciles the dilemma by explicitly clarifying that the temperature dependence of the conductivity is dominated by the interaction, while the magnetoconductivity is mainly contributed by the quantum interference. The theory paves the road to quantitatively study the transport in topological insulators, and can be extended to other two dimensional Dirac-like systems, such as graphene, transition metal dichalcogenides, and silicene. PMID- 24765999 TI - High-field terahertz bulk photovoltaic effect in lithium niobate. AB - The terahertz (THz) response of the ferroelectric prototype material lithium niobate (LiNbO3) is studied in the nonperturbative regime of light-matter interaction. Applying two-dimensional THz spectroscopy with few-cycle pulses of an amplitude E~100 kV/cm and a center frequency of 2 THz, we dissect the overall nonlinear response into different orders in the electric field. The underlying nonlinear current is of interband character and consists of a strong low frequency shift current (SC) and higher harmonics of the THz fundamental. The SC component originates from the lack of inversion symmetry and the strong interband decoherence for long electron trajectories in k space as shown by theoretical calculations. PMID- 24766000 TI - Floquet theory of electron waiting times in quantum-coherent conductors. AB - We present a Floquet scattering theory of electron waiting time distributions in periodically driven quantum conductors. We employ a second-quantized formulation that allows us to relate the waiting time distribution to the Floquet scattering matrix of the system. As an application we evaluate the electron waiting times for a quantum point contact, modulating either the applied voltage (external driving) or the transmission probability (internal driving) periodically in time. Lorentzian-shaped voltage pulses are of particular interest as they lead to the emission of clean single-particle excitations as recently demonstrated experimentally. The distributions of waiting times provide us with a detailed characterization of the dynamical properties of the quantum-coherent conductor in addition to what can be obtained from the shot noise or the full counting statistics. PMID- 24766001 TI - Green's functions from real-time bold-line Monte Carlo calculations: spectral properties of the nonequilibrium Anderson impurity model. AB - The nonequilibrium spectral properties of the Anderson impurity model with a chemical potential bias are investigated within a numerically exact real-time quantum Monte Carlo formalism. The two-time correlation function is computed in a form suitable for nonequilibrium dynamical mean field calculations. Additionally, the evolution of the model's spectral properties are simulated in an alternative representation, defined by a hypothetical but experimentally realizable weakly coupled auxiliary lead. The voltage splitting of the Kondo peak is confirmed and the dynamics of its formation after a coupling or gate quench are studied. This representation is shown to contain additional information about the dot's population dynamics. Further, we show that the voltage-dependent differential conductance gives a reasonable qualitative estimate of the equilibrium spectral function, but significant qualitative differences are found including incorrect trends and spurious temperature dependent effects. PMID- 24766002 TI - One-dimensional weak antilocalization due to the berry phase in HgTe wires. AB - We study the weak antilocalization (WAL) effect in the magnetoresistance of narrow HgTe wires fabricated in quantum wells with normal and inverted band ordering. Measurements at different gate voltages indicate that the WAL is only weakly affected by Rashba spin-orbit splitting and persists when the Rashba splitting is about zero. The WAL amplitude in wires with normal band ordering is an order of magnitude smaller than for wires with an inverted band structure. These observations are attributed to the Dirac-like dispersion of the energy bands in HgTe quantum wells. From the magnetic-field and temperature dependencies we extract the dephasing lengths and band Berry phases. The weaker WAL for samples with a normal band structure can be explained by a nonuniversal Berry phase which always exceeds pi, the characteristic value for gapless Dirac fermions. PMID- 24766003 TI - Edge physics of the quantum spin Hall insulator from a quantum dot excited by optical absorption. AB - The gapless edge modes of the quantum spin Hall insulator form a helical liquid in which the direction of motion along the edge is determined by the spin orientation of the electrons. In order to probe the Luttinger liquid physics of these edge states and their interaction with a magnetic (Kondo) impurity, we consider a setup where the helical liquid is tunnel coupled to a semiconductor quantum dot that is excited by optical absorption, thereby inducing an effective quantum quench of the tunneling. At low energy, the absorption spectrum is dominated by a power-law singularity. The corresponding exponent is directly related to the interaction strength (Luttinger parameter) and can be computed exactly using boundary conformal field theory thanks to the unique nature of the quantum spin Hall edge. PMID- 24766004 TI - Optical birefringence and dichroism of cuprate superconductors in the THz regime. AB - The presence of optical polarization anisotropies, such as Faraday or Kerr effects, linear birefringence, and magnetoelectric birefringence are evidence for broken symmetry states of matter. The recent discovery of a Kerr effect using near-IR light in the pseudogap phase of the cuprates can be regarded as a strong evidence for a spontaneous symmetry breaking and the existence of an anomalous long-range ordered state. In this work we present a high precision study of the polarimetry properties of the cuprates in the THz regime. While no Faraday effect was found in this frequency range to the limits of our experimental uncertainty (1.3 milli-radian or 0.07 degrees ), a small but significant polarization rotation was detected that derives from an anomalous linear dichroism. In YBa2Cu3Oy the effect has a temperature onset that mirrors the pseudogap temperature T* and is enhanced in magnitude in underdoped samples. In x=1/8 La2 xBaxCuO4, the effect onsets above room temperature, but shows a dramatic enhancement near a temperature scale known to be associated with spin- and charge ordered states. These features are consistent with a loss of both C4 rotation and mirror symmetry in the electronic structure of the CuO2 planes in the pseudogap state. PMID- 24766005 TI - Superconductivity on the brink of spin-charge order in a doped honeycomb bilayer. AB - Using a controlled weak-coupling renormalization group approach, we establish the mechanism of unconventional superconductivity in the vicinity of spin or charge ordered excitonic states for the case of electrons on the Bernal stacked bilayer honeycomb lattice. With one electron per site, this system, physically realized in bilayer graphene, is unstable towards a spontaneous symmetry breaking. Repulsive interactions favor excitonic order, such as a charge nematic and/or a layer antiferromagnet. We find that upon adding charge carriers to the system, the excitonic order is suppressed, and unconventional superconductivity appears in its place, before it is replaced by a Fermi liquid. We focus on firmly establishing this phenomenon using the renormalization group formalism within an idealized model with parabolic touching of conduction and valence bands. PMID- 24766006 TI - Tuning magnetic coupling in Sr2IrO4 thin films with epitaxial strain. AB - We report x-ray resonant magnetic scattering and resonant inelastic x-ray scattering studies of epitaxially strained Sr2IrO4 thin films. The films were grown on SrTiO3 and (LaAlO3)0.3(Sr2AlTaO6)0.7 substrates, under slight tensile and compressive strains, respectively. Although the films develop a magnetic structure reminiscent of bulk Sr2IrO4, the magnetic correlations are extremely anisotropic, with in-plane correlation lengths significantly longer than the out of-plane correlation lengths. In addition, the compressive (tensile) strain serves to suppress (enhance) the magnetic ordering temperature TN, while raising (lowering) the energy of the zone-boundary magnon. Quantum chemical calculations show that the tuning of magnetic energy scales can be understood in terms of strain-induced changes in bond lengths. PMID- 24766007 TI - Lattice-site-specific spin dynamics in double perovskite Sr2CoOsO6. AB - Magnetic properties and spin dynamics have been studied for the structurally ordered double perovskite Sr2CoOsO6. Neutron diffraction, muon-spin relaxation, and ac-susceptibility measurements reveal two antiferromagnetic (AFM) phases on cooling from room temperature down to 2 K. In the first AFM phase, with transition temperature TN1=108 K, cobalt (3d7, S=3/2) and osmium (5d2, S=1) moments fluctuate dynamically, while their average effective moments undergo long range order. In the second AFM phase below TN2=67 K, cobalt moments first become frozen and induce a noncollinear spin-canted AFM state, while dynamically fluctuating osmium moments are later frozen into a randomly canted state at T~5 K. Ab initio calculations indicate that the effective exchange coupling between cobalt and osmium sites is rather weak, so that cobalt and osmium sublattices exhibit different ground states and spin dynamics, making Sr2CoOsO6 distinct from previously reported double-perovskite compounds. PMID- 24766008 TI - Crystals of bound states in the magnetization plateaus of the Shastry-Sutherland model. AB - Using infinite projected entangled-pair states, we show that the Shastry Sutherland model in an external magnetic field has low-magnetization plateaus which, in contrast to previous predictions, correspond to crystals of bound states of triplets, and not to crystals of triplets. The first sizable plateaus appear at magnetization 1/8, 2/15 and 1/6, in agreement with experiments on the orthogonal-dimer antiferromagnet SrCu2(BO3)2, and they can be naturally understood as regular patterns of bound states, including the intriguing 2/15 one. We also show that, even in a confined geometry, two triplets bind into a localized bound state with Sz=2. Finally, we discuss the role of competing domain wall and supersolid phases, as well as that of additional anisotropic interactions. PMID- 24766009 TI - Antiferromagnetic domain wall motion induced by spin waves. AB - Spin waves in antiferromagnets are linearly or circularly polarized. Depending on the polarization, traversing spin waves alter the staggered field in a qualitatively different way. We calculate the drift velocity of a moving domain wall as a result of spin wave-mediated forces and show that the domain wall moves in opposite directions for linearly and circularly polarized waves. The analytical results agree with micromagnetic simulations of an antiferromagnetic domain wall driven by a localized, alternating magnetic field. PMID- 24766010 TI - Femtosecond dynamics of momentum-dependent magnetic excitations from resonant inelastic X-ray scattering in CaCu2O3. AB - Taking spinon excitations in the quantum antiferromagnet CaCu2O3 as an example, we demonstrate that femtosecond dynamics of magnetic electronic excitations can be probed by direct resonant inelastic x-ray scattering (RIXS). To this end, we isolate the contributions of single and double spin-flip excitations in experimental RIXS spectra, identify the physical mechanisms that cause them, and determine their respective time scales. By comparing theory and experiment, we find that double spin flips need a finite amount of time to be generated, rendering them sensitive to the core-hole lifetime, whereas single spin flips are, to a very good approximation, independent of it. This shows that RIXS can grant access to time-domain dynamics of excitations and illustrates how RIXS experiments can distinguish between excitations in correlated electron systems based on their different time dependence. PMID- 24766011 TI - Suris tetrons: possible spectroscopic evidence for four-particle optical excitations of a two-dimensional electron gas. AB - The excitations of a two-dimensional electron gas in quantum wells with intermediate carrier density (ne~1011 cm-2), i.e., between the exciton-trion and the Fermi-sea range, are so far poorly understood. We report on an approach to bridge this gap by a magnetophotoluminescence study of modulation-doped (Cd,Mn)Te quantum well structures. Employing their enhanced spin splitting, we analyzed the characteristic magnetic-field behavior of the individual photoluminescence features. Based on these results and earlier findings by other authors, we present a new approach for understanding the optical transitions at intermediate densities in terms of four-particle excitations, the Suris tetrons, which were up to now only predicted theoretically. All characteristic photoluminescence features are attributed to emission from these quasiparticles when attaining different final states. PMID- 24766012 TI - Laser excitation of lattice-driven anharmonic magnetization dynamics in dielectric FeBO3. AB - Femtosecond laser pulses trigger in dielectric FeBO3 coherent oscillations of the magnetic anisotropy followed by spins. The oscillations are driven by optically excited lattice vibrations strongly coupled to the magnetic system. Unlike the spin resonances, this mode is characterized by a very small damping ratio and can be easily pushed into an anharmonic regime. PMID- 24766013 TI - Long-time correlation in non-Markovian dephasing of an exciton-phonon system in InAs quantum dots. AB - We have observed a time-correlated frequency fluctuation in non-Markovian dephasing of excitons in InAs quantum dots using a six-wave mixing technique. In this measurement, the arrival times of the excitation pulses were controlled to eliminate the influence of Markovian dephasing and to measure the pure non Markovian behavior. The experimental result shows that the time correlation of the frequency fluctuation due to exciton-phonon interactions was maintained in the quantum dots for over 10 ps. This long-time correlation is caused by the modification of the phonon coupling distribution. PMID- 24766014 TI - Ultrafast switching of the electric polarization and magnetic chirality in BiFeO3 by an electric field. AB - Using a first-principles-based effective Hamiltonian within molecular dynamics simulations, we discover that applying an electric field that is opposite to the initial direction of the polarization results in a switching of both the polarization and the magnetic chirality vector of multiferroic BiFeO3 at an ultrafast pace (namely, of the order of picoseconds). We discuss the origin of such a double ultrafast switching, which is found to involve original intermediate magnetic states and may hold promise for designing various devices. PMID- 24766015 TI - Investigation of surface magnetic noise by shallow spins in diamond. AB - We present measurements of spin relaxation times (T1, T1rho, T2) on very shallow (?5 nm) nitrogen-vacancy centers in high-purity diamond single crystals. We find a reduction of spin relaxation times up to 30 times compared to bulk values, indicating the presence of ubiquitous magnetic impurities associated with the surface. Our measurements yield a density of 0.01-0.1MUB/nm2 and a characteristic correlation time of 0.28(3) ns of surface states, with little variation between samples and chemical surface terminations. A low temperature measurement further confirms that fluctuations are thermally activated. The data support the atomistic picture where impurities are associated with the top carbon layers, and not with terminating surface atoms or adsorbate molecules. The low spin density implies that the presence of a single surface impurity is sufficient to cause spin relaxation of a shallow nitrogen-vacancy center. PMID- 24766016 TI - Triplet correlations dominate the transition from simple to tetrahedral liquids. AB - The total, triplet, and pair contributions to the entropy with increasing tetrahedrality are mapped out for the Stillinger-Weber liquids to demonstrate the qualitative and quantitative differences between triplet-dominated, tetrahedral liquids and pair-dominated, simple liquids with regard to supercooling and crystallization. The heat capacity anomaly of tetrahedral liquids originates in local ordering due to both pair and triplet correlations. The results suggest that structural correlations can be directly related to thermodynamic anomalies, phase changes, and self-assembly in other atomic and colloidal fluids. PMID- 24766017 TI - Spontaneous division and motility in active nematic droplets. AB - We investigate the mechanics of an active droplet endowed with internal nematic order and surrounded by an isotropic Newtonian fluid. Using numerical simulations we demonstrate that, due to the interplay between the active stresses and the defective geometry of the nematic director, this system exhibits two of the fundamental functions of living cells: spontaneous division and motility, by means of self-generated hydrodynamic flows. These behaviors can be selectively activated by controlling a single physical parameter, namely, an active variant of the capillary number. PMID- 24766018 TI - High-velocity drag friction in granular media near the jamming point. AB - Drag friction that acts on a disk in a two-dimensional granular medium is studied at high packing fractions. We concentrate on a high-velocity region, in which the dynamic component of the force, obtained as an average of a strongly fluctuating force, clearly scales with velocity squared. We find that the total force composed of dynamic and static components, as well as its fluctuation, diverges with practically the same exponent as the packing fraction approaches the jamming point. To explain the critical behavior, we propose a simple theory equipped with a diverging length scale, which agrees well with the data and elucidates physical pictures for the divergence. PMID- 24766019 TI - Nonmonotonic effects of migration in subdivided populations. AB - The influence of migration on the stochastic dynamics of subdivided populations is still an open issue in various evolutionary models. Here, we develop a self consistent mean-field-like method in order to determine the effects of migration on relevant nonequilibrium properties, such as the mean fixation time. If evolution strongly favors coexistence of species (e.g., balancing selection), the mean fixation time develops an unexpected minimum as a function of the migration rate. Our analysis hinges only on the presence of a separation of time scales between local and global dynamics, and therefore, it carries over to other nonequilibrium processes in physics, biology, ecology, and social sciences. PMID- 24766020 TI - Emergent spatial structures in flocking models: a dynamical system insight. AB - We show that hydrodynamic theories of polar active matter generically possess inhomogeneous traveling solutions. We introduce a unifying dynamical-system framework to establish the shape of these intrinsically nonlinear patterns, and show that they correspond to those hitherto observed in experiments and numerical simulation: periodic density waves, and solitonic bands, or polar-liquid droplets both cruising in isotropic phases. We elucidate their respective multiplicity and mutual relations, as well as their existence domain. PMID- 24766021 TI - Range expansion of heterogeneous populations. AB - Risk spreading in bacterial populations is generally regarded as a strategy to maximize survival. Here, we study its role during range expansion of a genetically diverse population where growth and motility are two alternative traits. We find that during the initial expansion phase fast-growing cells do have a selective advantage. By contrast, asymptotically, generalists balancing motility and reproduction are evolutionarily most successful. These findings are rationalized by a set of coupled Fisher equations complemented by stochastic simulations. PMID- 24766022 TI - Synchronization and liquid crystalline order in soft active fluids. AB - We introduce a phenomenological theory for a new class of soft active fluids with the ability to synchronize. Our theoretical framework describes the macroscopic behavior of a collection of interacting anisotropic elements with cyclic internal dynamics and a periodic phase variable. This system can (i) spontaneously undergo a transition to a state with macroscopic orientational order, with the elements aligned, a liquid crystal, (ii) attain another broken symmetry state characterized by synchronization of their phase variables, or (iii) a combination of both types of order. We derive the equations describing a spatially homogeneous system and also study the hydrodynamic fluctuations of the soft modes in some of the ordered states. We find that synchronization can promote or inhibit the transition to a state with orientational order, and vice versa. We provide an explicit microscopic realization: a suspension of microswimmers driven by cyclic strokes. PMID- 24766023 TI - Dynamics of sheared ellipses and circular disks: effects of particle shape. AB - Much recent effort has focused on glassy and jamming properties of spherical particles. Very little is known about such phenomena for nonspherical particles, and we take a first step by studying ellipses. We find important differences between the dynamical and structural properties of disks and two-dimensional ellipses subject to continuous Couette shear. In particular, ellipses show slow dynamical evolution, without a counterpart in disks, in the mean velocity, local density, orientational order, and local stress. Starting from an unjammed state, ellipses can first jam under shear, and then slowly unjam. The slow unjamming process is understood as a result of gradual changes in their orientations, leading to a denser packing. For disks, the rotation of particles only contributes to the relaxation of frictional forces, and hence, does not significantly cause structural changes. For the shear-jammed states, the global building up and relaxation of stress, which occurs in the form of stress avalanches, is qualitatively different for disks and ellipses, and is manifested by different forms of rate dependence for ellipses versus disks. Unlike the weak rate dependence typical for many granular systems, ellipses show power-law dependence on the shearing rate Omega. PMID- 24766024 TI - Quantum simulation of collective proton tunneling in hexagonal ice crystals. AB - The effect of proton tunneling on many-body correlated proton transfer in hexagonal ice is investigated by quantum simulation. Classical single-particle hopping along individual hydrogen bonds leads to charge defects at high temperature, whereas six protons in ringlike topologies can move concertedly as a delocalized quasiparticle via collective tunneling at low temperature, thus preventing the creation of high-energy topological defects. Our findings rationalize many-body quantum tunneling in hydrogen-bonded networks and suggest that this phenomenon might be more widespread than previously thought. PMID- 24766025 TI - Adsorption and pattern recognition of polymers at complex surfaces with attractive stripelike motifs. AB - We construct the complete structural phase diagram of polymer adsorption at substrates with attractive stripelike patterns in the parameter space spanned by the adsorption affinity of the stripes and temperature. Results were obtained by extensive generalized-ensemble Monte Carlo simulations of a generic model for the hybrid organic-inorganic system. By comparing with adhesion properties at homogeneous substrates, we find substantial differences in the formation of adsorbed polymer structures if translational invariance at the surface is broken by a regular pattern. Beside a more specific understanding of polymer adsorption processes, our results are potentially relevant for the design of macromolecular pattern recognition devices such as sensors. PMID- 24766026 TI - Theory and simulations of electrocatalyst-coated semiconductor electrodes for solar water splitting. AB - We develop a theory of charge transfer at semiconductor-catalyst interfaces to elucidate the current-potential behavior of semiconductor-catalyst-solution systems used for solar water splitting and compare simulations based on this theory to experimental data. Ion-permeable catalysts are found to form semiconductor-catalyst interfaces where the effective barrier height changes under operation yielding higher photovoltages and efficiencies relative to dense catalysts with the same catalytic activity. Such behavior is not captured by current equivalent circuit models, but is central to the study and design of efficient water-splitting systems. PMID- 24766027 TI - Controlling the position of traveling waves in reaction-diffusion systems. AB - We present a method to control the position as a function of time of one dimensional traveling wave solutions to reaction-diffusion systems according to a prespecified protocol of motion. Given this protocol, the control function is found as the solution of a perturbatively derived integral equation. Two cases are considered. First, we derive an analytical expression for the space (x) and time (t) dependent control function f(x,t) that is valid for arbitrary protocols and many reaction-diffusion systems. These results are close to numerically computed optimal controls. Second, for stationary control of traveling waves in one-component systems, the integral equation reduces to a Fredholm integral equation of the first kind. In both cases, the control can be expressed in terms of the uncontrolled wave profile and its propagation velocity, rendering detailed knowledge of the reaction kinetics unnecessary. PMID- 24766028 TI - Slowing down of accelerated structural relaxation in ultrathin polymer films. AB - We demonstrate with molecular simulation that the acceleration of structural relaxation, also known as physical aging, commonly experimentally observed in thin polymer films slows down at extremely small thicknesses. This phenomenon can be attributed to an inversed free volume diffusion process caused by the sliding motion of chain molecules. Our findings provide direct evidence of the relationship between the sliding motion of short chain fragments and the structural relaxation of ultrathin polymer films, and also verify the existence of a new confinement effect at the nanoscale. PMID- 24766029 TI - Resonant acoustic propagation and negative density in liquid foams. AB - We measured the dispersion relation for acoustic longitudinal waves in liquid foams, over a broad frequency range (60-600 kHz). Strong dispersion was found, with two nondispersive behaviors, separated by a negative density regime. A new model, based on the coupled displacements of films, liquid channels, and gas in the foam, rationalizes all the experimental findings. PMID- 24766030 TI - Enhanced flow in small-world networks. AB - The proper addition of shortcuts to a regular substrate can lead to the formation of a complex network with a highly efficient structure for navigation [J. M. Kleinberg, Nature 406, 845 (2000)]. Here we show that enhanced flow properties can also be observed in these small-world topologies. Precisely, our model is a network built from an underlying regular lattice over which long-range connections are randomly added according to the probability, Pij ~ r-alpha ij , where rij is the Manhattan distance between nodes i and j, and the exponent alpha is a controlling parameter. The mean two-point global conductance of the system is computed by considering that each link has a local conductance given by gij ? r-C ij , where C determines the extent of the geographical limitations (costs) on the long-range connections. Our results show that the best flow conditions are obtained for C = 0 with alpha = 0, while for C ? 1 the overall conductance always increases with alpha. For C ~ 1, alpha = d becomes the optimal exponent, where d is the topological dimension of the substrate. Interestingly, this exponent is identical to the one obtained for optimal navigation in small-world networks using decentralized algorithms. PMID- 24766031 TI - The inking brush in Mohs micrographic surgery: a potential source of malignant cell contamination. PMID- 24766033 TI - Follow-up for Bosniak category 2F cystic renal lesions. AB - PURPOSE: To determine percentage of Bosniak category 2F complex cystic renal masses that progress to malignancy based on serial follow-up studies,and to determine if there are demographic and/or imaging features associated with progression. MATERIALS AND METHODS: This retrospective study was institutional review board-approved with waiver of informed consent. Hospital database system was searched from January 1, 1996, to May 1, 2011, for category 2F cysts studied with contrast agent-enhanced computed tomography or magnetic resonance imaging and followed with serial contrast-enhanced imaging. Demographics of patients and imaging features of lesions that progressed were compared with those that did not. The relationship of these features to progression or stability was assessed by using chi(2), Fisher exact, or Cochran Armitage trend tests. RESULTS: Identified in 144 patients (98 men, 46 women; age range, 31-83 years; average, 63 years) were 156 category 2F lesions. Follow-up studies were from 6 months to 13 years (median, 3.6 years; average, 4.2 years). Nineteen of 156 lesions progressed to category 3 or 4 in 6 months to 3.2 years; 17 lesions (89.5% of those that progressed and 10.9% of initial 2F lesions) were malignant and two were benign. To date, no patients had recurrent or metastatic disease. Men had significant risk for progression to malignancy (P = .003). Of 17 category 2F lesions that progressed to malignancy, 12 were endophytic (P = .02). Category 2F lesions with minimally irregular septa (nine of 17; P= .001) or wall (seven of 17; P = .016), and lesions with indistinct parenchymal interface (nine of 17; P < .001) were associated with progression to cancer. A multilobulated border was not associated with progression (P = .999). CONCLUSION: Based on this study, 10.9% (17 of 156) Bosniak category 2F cystic lesions progress to malignancy, and progression occurs within 6 months to 3.2 years. PMID- 24766032 TI - Biodegradable polymeric nanoparticles show high efficacy and specificity at DNA delivery to human glioblastoma in vitro and in vivo. AB - Current glioblastoma therapies are insufficient to prevent tumor recurrence and eventual death. Here, we describe a method to treat malignant glioma by nonviral DNA delivery using biodegradable poly(beta-amino ester)s (PBAEs), with a focus on the brain tumor initiating cells (BTICs), the tumor cell population believed to be responsible for the formation of new tumors and resistance to many conventional therapies. We show transfection efficacy of >60% and low biomaterial mediated cytotoxicity in primary human BTICs in vitro even when the BTICs are grown as 3-D oncospheres. Intriguingly, we find that these polymeric nanoparticles show intrinsic specificity for nonviral transfection of primary human BTICs over primary healthy human neural progenitor cells and that this specificity is not due to differences in cellular growth rate or total cellular uptake of nanoparticles. Moreover, we demonstrate that biodegradable PBAE/DNA nanoparticles can be fabricated, lyophilized, and then stored for at least 2 years without losing efficacy, increasing the translational relevance of this technology. Using lyophilized nanoparticles, we show transgene expression by tumor cells after intratumoral injection into an orthotopic murine model of human glioblastoma. PBAE/DNA nanoparticles were more effective than naked DNA at exogenous gene expression in vivo, and tumor cells were transfected more effectively than noninvaded brain parenchyma in vivo. This work shows the potential of nonviral gene delivery tools to target human brain tumors. PMID- 24766034 TI - Irreversible electroporation of the lumbar vertebrae in a porcine model: is there clinical-pathologic evidence of neural toxicity? AB - PURPOSE: To evaluate the effects of irreversible electroporation (IRE) in the porcine spine. MATERIALS AND METHODS: This study was approved by the institutional animal care and use committee. Twenty computed tomographically guided IRE ablations in either a transpedicular location or directly over the posterior cortex were performed in the lumbar vertebrae of 10 pigs by a single operator. T1- and T2-weighted magnetic resonance (MR) imaging was performed with and without contrast material 2 or 7 days after ablation. Mathematical modeling was performed to estimate the extent of ablation. Clinical, radiologic, pathologic, and simulation findings were analyzed. The Miller low-bias back transformation was used to construct 95% confidence intervals for the mean absolute percentage difference between the maximum length and width of the ablation zone on MR images and pathologic measurements by using square-root transformed data. RESULTS: Bipolar IRE electrode placement and ablation were successful in all cases. The mean distances from the IRE electrode to the posterior wall of the vertebral body or the exiting nerve root were 2.93 mm +/- 0.77 (standard deviation) and 7.87 mm +/- 1.99, respectively. None of the animals had neurologic deficits. Well-delineated areas of necrosis of bone, bone marrow, and skeletal muscle adjacent to the vertebral body were present. Histopathologic changes showed outcomes that matched with simulation-estimated ablation zones. The percentage absolute differences in the ablation measurements between MR imaging and histopathologic examination showed the following average errors: 24.2% for length and 28.8% for width measurements on T2-weighted images, and 26.1% for length and 33.3% for width measurements on T1-weighted contrast material-enhanced images. CONCLUSION: IRE ablation in the porcine spine is feasible and safe and produces localized necrosis with minimal neural toxicity. Signal intensity changes on images acquired with standard MR imaging sequences demonstrate the ablation zone to be larger than that at histopathologic examination. PMID- 24766035 TI - Intralocus sexual conflict and environmental stress. AB - Intralocus sexual conflict (IaSC) occurs when selection at a given locus favors different alleles in males and females, placing a fundamental constraint on adaptation. However, the relative impact of IaSC on adaptation may become reduced in stressful environments that expose conditionally deleterious mutations to selection. The genetic correlation for fitness between males and females (rMF ) provides a quantification of IaSC across the genome. We compared IaSC at a benign (29 degrees C) and a stressful (36 degrees C) temperature by estimating rMF s in two natural populations of the seed beetle Callosobruchus maculatus using isofemale lines. In one population, we found substantial IaSC under benign conditions signified by a negative rMF (-0.51) and, as predicted, a significant reduction of IaSC under stress signified by a reversed and positive rMF (0.21). The other population displayed low IaSC at both temperatures (rMF : 0.38; 0.40). In both populations, isofemale lines harboring alleles beneficial to males but detrimental to females at benign conditions tended to show overall low fitness under stress. These results offer support for low IaSC under stress and suggest that environmentally sensitive and conditionally deleterious alleles that are sexually selected in males mediate changes in IaSC. We discuss implications for adaptive evolution in sexually reproducing populations. PMID- 24766036 TI - A novel approach to identify and map kitten clusters using geographic information systems (GIS): a case study from Tompkins County, NY. AB - A retrospective study using a geographic information system (GIS) was conducted to capture, map, and analyze intake data of caregiver (owner)-surrendered kittens (aged 0-6 months) to the Society for the Prevention of Cruelty to Animals (SPCA) of Tompkins County, NY, from 2009 to 2011. Addresses of caregiver-surrendered kittens during the study period were mapped (n = 1,017). Mapping and analysis of the resultant data set revealed that the distribution of kittens was nonrandom. Seventeen statistically significant (p = .001) clusters were identified, 1 of which was the SPCA of Tompkins County (due to anonymously surrendered nonhuman animals). The remaining 16 clusters were composed of 52 homes; 27.5% (280/1,017) of the kittens in the data set originated from these 52 homes. The majority of kittens within clusters were surrendered from high-density residential and manufactured residential home parks. Analyzing such clusters using GIS is a novel approach for targeting spay/neuter and educational programs to areas contributing disproportionately to shelter populations. This method may prove useful to help shelters more effectively allocate their limited resources, but further evaluation of this and other targeted approaches is needed to assess the long term efficacy of such programs. PMID- 24766037 TI - Prescription of systemic antibiotics during pregnancy in primary care in Friuli Venezia Giulia, Northeastern Italy. AB - OBJECTIVE: To investigate the prescriptions of systemic antibiotics in a population of pregnant women in Italy, to identify socio-demographic factors associated with increased risk of being prescribed potentially unsafe medications, to compare prescriptions before and during pregnancy and to identify the prescribing General Practitioners (GPs). METHODS: A retrospective study based on administrative anonymous databases included all women resident of the Friuli Venezia Giulia Region who delivered babies in 2011 (n=9196). The antibiotic prescription risk was calculated by trimester and overall, and compared with that in the year before. Multivariate logistic regression analyses assessed the role of socio-demographic factors on the risk of being prescribed medications that should not be used as first-line. RESULTS: 6688 women (72.7%) were prescribed medicines (27363 prescriptions) during their pregnancies. Antibiotics were prescribed to 2279 women (24.8%), less commonly during pregnancy than before. Prescriptions were more frequent in the second and third trimesters. 1736 women were prescribed antibiotics other than first-line medicines (of which, seven tetracyclines and 58 quinolones, which are frankly not recommended). Those women were more frequently younger and less educated. The GPs responsible for those prescriptions were identified. CONCLUSIONS: In order to improve the prescription of antibiotics in pregnancy, an audit with the GPs is warranted to understand their motivations, discuss clinical cases and build consensus guidelines on which antibiotics should be preferred for use in pregnancy. PMID- 24766038 TI - Statement of retraction: Guarino A, Wudy A, Basile F, Ruberto E, Buccigrossi V. "Composition and roles of intestinal microbiota in children". PMID- 24766039 TI - Using a student-faculty collaborative learning model to teach grant development in graduate nursing education. AB - Graduate nurses are employed in clinical, research, educational, and policy roles. As leaders, they are expected to develop and sustain projects that support translating research to practice and policy. Funding to support initiatives is tight and requires innovative solutions to cover salaries, benefits, equipment purchases, and other program expenses. In an effort to teach grant writing while developing skilled leaders who are effective and competitive in securing funds, the George Washington University School of Nursing offers a graduate-level grant writing course. In the summer of 2011, a collaborative learning model was developed within the course. The joint approach was foundational to securing an Agency for Healthcare Research and Quality grant to support development and implementation of a patient engagement project by the Nursing Alliance for Quality Care. This article describes the project and offers hints for those seeking to develop a collaborative educational experience that affords new leadership skills for RNs from all backgrounds. PMID- 24766040 TI - The sigma enigma: in vitro/in silico site-directed mutagenesis studies unveil sigma1 receptor ligand binding. AB - The sigma1 receptor is an integral membrane protein that shares no homology with other receptor systems, has no unequivocally identified natural ligands, but appears to play critical roles in a wide variety of cell functions. While the number of reports of the possible functions of the sigma1 receptor is increasing, almost no information about the three-dimensional structure of the receptor and/or possible modes of interaction of the sigma1 protein with its ligands have been described. Here we performed an in vitro/in silico investigation to analyze the molecular interactions of the sigma1 receptor with its prototypical agonist (+)-pentazocine. Accordingly, 23 mutant sigma1 isoforms were generated, and their interactions with (+)-pentazocine were determined experimentally. All direct and/or indirect effects exerted by the mutant residues on the receptor-agonist interactions were reproduced and rationalized in silico, thus shining new light on the three-dimensional structure of the sigma1 receptor and its ligand binding site. PMID- 24766042 TI - Mass envenomation of a mare and foal by bees. AB - CASE REPORT: The clinical course of toxic envenomation of a mare and her foal after an attack by a swarm of bees in the Upper Hunter Valley of New South Wales is described. Early agitation and urticaria were followed by more severe systemic clinical signs within 18 h. There was severe, generalised angioedema, rhabdomyolysis, hypovolaemia, gastrointestinal stasis and renal injury. A particular feature in the mare was almost maniacal behaviour during the first 48 h. Clinical pathological examination showed evidence of haemoconcentration, intravascular haemolysis, thrombocytopenia, azotaemia, rhabdomyolysis and hypoproteinaemia. Symptomatic treatment was initiated using intravenous fluids, anti-inflammatory drugs, histamine antagonists, analgesia and antibiotics. The foal responded within 12 h, but management of the mare was complicated by severe pain, generalised oedema, intrauterine haemorrhage, renal injury and later, recurrent fever. The most severe, acute effects of mass envenomation lasted for 3 4 days. Neither mare nor foal suffered any known lasting systemic effects of envenomation, although localised dermal necrosis resulted in white hairs at some sting sites and deformed ear tips in the foal. CONCLUSION: Early recognition of clinical signs and treatment of toxic envenomation with an understanding of the physiological effects of hymenoptera venom can lead to a favourable outcome in horses receiving a non-lethal dose. Further case reports of the treatment of affected horses are needed to expand knowledge of how best to approach this rare, but serious intoxication. PMID- 24766043 TI - Paul Gotis-Graham: 1967-2014. PMID- 24766044 TI - Canine superficial bacterial pyoderma: evaluation of skin surface sampling methods and antimicrobial susceptibility of causal Staphylococcus isolates. AB - OBJECTIVE: To evaluate three easily performed methods of skin surface sampling for bacterial culture of Staphylococcus isolates obtained from dogs with superficial bacterial pyoderma (SBP) presenting to two veterinary teaching hospitals in Sydney, Australia, and to determine the antimicrobial susceptibility of isolates. DESIGN: Prospective study of 27 dogs with SBP. Cytologically confirmed SBP lesions were sampled for bacterial culture using a dry cotton swab, a saline-moistened cotton swab and a skin surface scraping. Isolates were identified by standard discriminatory phenotypic and biochemical analyses, and confirmed using matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF MS). Susceptibilities to 14 antimicrobials were determined by disk diffusion and by detection of the mecA gene using PCR. Sampling methods were compared according to bacterial yield, antibiograms and bacterial phenotypic analysis. Location of causative bacteria was evaluated via 8 mm punch skin biopsies using haematoxylin and eosin, Gram-Twort and Giemsa staining, and fluorescence in situ hybridisation (FISH). RESULTS: Staphylococcus sp. were isolated from lesions in all dogs, either S. pseudintermedius (24 dogs) or S. schleiferi (3 dogs). Susceptibility was highest to cephalexin (96%) and amoxycillin clavulanate (96%). Methicillin resistance assessed by mecA real-time PCR and phenotypic oxacillin resistance was found in one dog (4.3%). Routine histology and FISH revealed bacteria within superficial stratum corneum. CONCLUSION: Staphylococcal isolates from canine SBP demonstrated high susceptibility to common empirical antimicrobials. Histological techniques confirmed presence of bacteria at superficial sites, likely to be accessed by the sampling techniques. The three techniques afforded similar results and may be equally suitable for obtaining samples for culture. PMID- 24766045 TI - Complications of the angularis oris axial pattern buccal flap for reconstruction of palatine defects in two dogs. AB - CASE REPORT: Complications associated with surgical reconstruction of hard palate defects with a buccal mucosal flap based on the angularis oris artery and vein in two dogs are described. Distal flap necrosis occurred in both cases, but the flaps were successfully salvaged by division of the original flap pedicle and rotation of the flap material into the remaining defect. Postoperative dysphagia was observed in both dogs until flap revision. Salvage of the intact distal portion of the flap following division of the direct artery and vein 14 days postoperatively is discussed. CONCLUSION: The angularis oris axial pattern buccal flap is an option for reconstruction of large defects of the hard palate. Survival of the flap can be improved by removal of teeth likely to cause occlusal trauma to the flap's pedicle. In the event of distal flap necrosis, the repair may be salvaged by rotation of the remaining flap into the defect, following establishment of vascular supply from adjacent tissue. PMID- 24766046 TI - Carbonate apatite nephrolithiasis associated with Corynebacterium urealyticum urinary tract infection in a dog. AB - BACKGROUND: Urinary tract infections caused by Corynebacterium urealyticum are uncommon in veterinary medicine. Encrusted cystitis, encrusted pyelitis and uroliths have been described as complications in humans, but only encrusted cystitis and cystoliths have been reported in dogs so far. Because C. urealyticum is usually resistant to all standard antibacterial drugs, antimicrobial treatment and elimination of this microorganism are challenging. CASE REPORT: An 11-month old female spayed mixed-breed dog was evaluated because of a C. urealyticum urinary tract infection, mineralisation within both renal pelvises and failure of antimicrobial treatment. Physical examination, haematology and biochemistry were unremarkable. Radiographic and ultrasonographic examinations confirmed bilateral nephrolithiasis. Voided uroliths were composed of 100% carbonate apatite. Urinalysis was indicative of bacterial infection. Aerobic culture of the urine and 16S rRNA sequencing identified significant growth of C. urealyticum and susceptibility testing revealed sensitivity to only vancomycin and linezolid. CONCLUSION: Treatment with the oxazolidinone antibacterial, linezolid, in combination with a urine-acidifying diet resulted in elimination of this multiresistant microorganism and complete resolution of nephrolithiasis. PMID- 24766047 TI - Health and production of feedlot cattle following supplementation with urea molasses in starter pens. AB - OBJECTIVE: To determine the effect of providing a urea-molasses supplement to cattle during feedlot introduction on average daily gain, carcase weight and bovine respiratory disease (BRD) morbidity and mortality. METHODS: Commercial mixed sex, mixed breed cattle (387.4 +/- 0.2 kg) were systematically allocated to receive 2.1 L/animal of urea-molasses during feedlot introduction (n = 2307) or remain untreated (n = 2336). Cattle remained in the feedlot for an average of 40 days until reaching slaughter weight. Body weight data was collected prior to feedlot induction and all cases of BRD morbidity and mortality were determined during feeding. Hot standard carcase weight and P8 fat thickness were determined at slaughter. RESULTS: Average daily gain (1.94 +/- 0.06 vs 1.93 +/- 0.06, P = 0.650), BRD incidence (6.46% vs 5.53%, P = 0.183) and BRD mortality (0.17% vs 0.21%, P = 0.752) did not differ between supplemented and unsupplemented cattle. The BRD incidence was higher (P = 0.017) when cattle without permanent incisors were supplemented with urea-molasses (7.26%) compared with unsupplemented cattle (5.26%), and was also higher in steers compared with heifers (12.7% vs 7.8%, P < 0.001) and higher in cattle purchased from saleyards compared with cattle purchased off paddocks (12.4% vs 5.7%, P < 0.001). CONCLUSIONS: Health and production were not significantly improved following supplementation of cattle with urea-molasses during feedlot introduction. BRD incidence was, however, significantly related to cattle sex and source. Further research is required to understand the relationship between feeding high non-protein nitrogen sources and BRD morbidity in young cattle. PMID- 24766049 TI - Validation of ultrasonography in detecting structural disease of the urogenital tract of the koala, Phascolarctos cinereus. AB - A retrospective review of case records of ultrasonography and necropsy outcomes of 62 koalas was used to investigate the accuracy of ultrasonography in assessing koala urogenital tract structural disease at the Port Macquarie Koala Hospital. The results showed high concordance, supporting ultrasonography as an effective tool for evaluating structural disease of the koala urogenital tract, most commonly seen with chlamydiosis. The study also illustrates the advances benefiting animal welfare that can be made by wildlife carer groups through using a scientific, evidence-based approach. PMID- 24766048 TI - Granuloma formation and suspected neuropathic pain in a domestic pigeon (Columba livia) secondary to an oil-based, inactivated Newcastle disease vaccine administered for protection against pigeon paramyxovirus-1. AB - CASE REPORT: A domestic pigeon developed a sterile granuloma following vaccination with an oil-adjuvant, inactivated La Sota strain of Newcastle disease. The aim of vaccination was to provide protection against pigeon paramyxovirus-1 (PPMV-1), a disease previously considered exotic to Australia. Granuloma formation is considered a rare complication of vaccination against PPMV 1 in pigeons. Clinical signs consistent with neuropathic pain became apparent during the extensive management of the granuloma, which included surgical removal of foreign material, control of the pain and inflammation and protection against antimicrobial contamination. CONCLUSION: PPMV-1 is now considered endemic in Australia and protecting pigeons with vaccination is important. Until a product is registered for use, vaccination remains off-label and the risk of adverse reaction, including sterile granuloma, must be considered. PMID- 24766050 TI - Anterior chamber collapse syndrome in a koala. AB - BACKGROUND: Anterior chamber collapse syndrome has been recognised in various species and is associated with early-life ocular disease or trauma. It is important to differentiate this acquired condition from a congenital malformation. CASE REPORT: An adult female koala (Phascolarctos cinereus) was referred for assessment of buphthalmos and severe keratitis of the right eye. The degree of keratitis obstructed examination of intraocular structures. Enucleation of the affected eye was performed and the histopathological diagnosis was anterior chamber collapse syndrome and secondary glaucoma. This case contributes to the limited information available in the literature on anterior chamber collapse syndrome, a disease unique in having secondary glaucoma with minimal or no inflammation. The case also expands the literature available on ocular disease in koalas. More specifically, this is the only reported case of glaucoma, of any aetiology, in the koala. PMID- 24766052 TI - Chronic pulmonary pseudomonal infection in patients with cystic fibrosis: A model for early phase symbiotic evolution. AB - Gain of "antimicrobial resistance" and "adaptive virulence" has been the dominant view of Pseudomonas aeruginosa (Pa) in cystic fibrosis (CF) in the progressively damaged host airway over the course of this chronic infection. However, the pathogenic effects of CF airway-adapted Pa strains are notably reduced. We propose that CF Pa and other bacterial cohabitants undergo host adaptation which resembles the changes found in bacterial symbionts in animal hosts. Development of clonally selected and intraspecific isogenic Pa strains which display divergent colony morphology, growth rate, auxotrophy, and antibiotic susceptibility in vitro suggests an adaptive sequence of infective exploitation parasitism-symbiotic evolution driven by host defenses. Most importantly, the emergence of CF pseudomonal auxotrophy is frequently associated with a few specific amino acids. The selective retention or loss of specific amino acid biosynthesis in CF-adapted Pa reflects bacterium-host symbiosis and coevolution during chronic infection, not nutrient availability. This principle also argues against the long-standing concept of dietary availability leading to evolution of essential amino acid requirements in humans. A novel model of pseudomonal adaptation through multicellular bacterial syntrophy is proposed to explain early events in bacterial gene decay and decreased (not increased) virulence due to symbiotic response to host defense. PMID- 24766054 TI - Correction to Interfacial Structural Role of pH-Shifting Processed Pea Protein in the Oxidative Stability of Oil/Water Emulsions. PMID- 24766053 TI - HIV-related behavioral risk factors among older female sex workers in Guangxi, China. AB - Previous literature suggests a high rate of HIV infections among older female sex workers (FSWs) in China. However, limited data are available regarding HIV- related behavioral risk factors among this population. In the current study, we aim to examine the demographic and behavioral factors that place older FSWs at a high risk of HIV infection. We conducted secondary analysis of the 2010 National Sentinel Surveillance (NSS) data from Guangxi, China. A self-administered, standard behavioral surveillance survey was completed by a total of 12,622 FSWs in Guangxi, China. The Guangxi 2010 NSS sample included 19.4% FSWs aged 35 years or older ("older FSWs"). The overall HIV prevalence was 1.0% for the entire sample with 2.0% among older FSWs and 0.8% among younger ones. Older age was an independent predictor of unprotected sex, injection drug use, and a self-reported history of syphilis infection. Future HIV prevention interventions targeting FSWs should consider older FSWs' vulnerable status. Efforts are needed to address their financial needs and invest in skills for socio-economic empowerment. PMID- 24766055 TI - Janus kinase inhibitors for the treatment of myeloproliferative neoplasms. AB - INTRODUCTION: Disordered signaling through the JAK/STAT pathway is a hallmark of myeloproliferative neoplasms (MPNs). Targeted therapies that inhibit and regulate this pathway are reasonable strategies for disease management. Only one JAK1/JAK2 inhibitor has gained FDA approval for treatment of myelofibrosis. Despite significant reductions in splenomegaly and disease-associated symptoms, additional agents are necessary to manage disease in those that do not respond. AREAS COVERED: A review of the currently available literature and meeting abstracts for JAK inhibitors in myeloproliferative neoplasms identified studies aimed at improving outcomes and establishing alternative therapies in MPNs. Development of specific JAK inhibitors and ongoing trials involving ruxolitinib, CYT387, SAR302503, CEP701, SB 1518, XL-019, LY2784544, BMS-911453, NS-018, AZD1480 and INCB039110 are reviewed. EXPERT OPINION: The identification of JAK2V617F mutation and its link to MPNs has revolutionized treatment options. Resultant research in targeting the JAK/STAT pathway led to the approval of ruxolitinib, a JAK1/JAK2 inhibitor with activity in MPNs. While ruxolitinib produces durable reductions in splenomegaly and improvement of symptoms, and prolongs survival, there is room for new and more specific agents to be developed. Minimizing toxicity and avoiding drug resistance are challenges that lie ahead. Combining agents with different mechanisms seems to be a rational strategy. PMID- 24766056 TI - Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease. AB - BACKGROUND & AIMS: Patients with alcoholic liver disease (ALD) display inflammation of the subcutaneous adipose tissue (SAT) which correlates with liver lesions. We examined macrophage markers and polarization in the SAT of alcoholic patients and adipokine expression according to liver inflammation; we studied the consequences of alcohol withdrawal. PATIENTS AND METHODS: Forty-seven patients with ALD were prospectively included. SAT and blood samples were collected at inclusion and after 1 week of alcohol withdrawal. Pro-inflammatory cytokines/chemokines, inflammasome components and products, adipokine expression levels, macrophage markers and polarization in liver and SAT samples were assessed by RT-PCR arrays. RESULTS: mRNA expression level of chemokines (IL8, semaphorin 7A) correlated with hepatic steatosis in both liver and SAT. Liver expression of inflammasome components (IL1beta, IL18, caspase-1) and SAT IL6 and CCL2 correlated with liver damage. In patients with mild ALD, 1 week of alcohol withdrawal was sufficient to decrease expression level of total macrophage markers in the adipose tissue, to orient adipose tissue macrophages (ATM) towards an anti-inflammatory M2 phenotype and to decrease the mRNA expression of cytokines/chemokines (IL18, CCL2, osteopontin, semaphorin 7A). In patients with severe ALD, 1 week of abstinence was also associated with an increase in CCL18 expression. CONCLUSIONS: In alcoholic patients, upregulation of chemotactic factors in the liver and SAT is an early event that begins as early as the steatosis stage. The inflammasome pathway is upregulated in the liver of patients with ALD. One week of alcohol withdrawal alleviates macrophage infiltration in SAT and orients ATM towards a M2 anti-inflammatory phenotype; this implicates alcohol in adipose tissue inflammation (ClinicalTrials.gov NCT00388323). PMID- 24766057 TI - Climate-driven range shifts explain the distribution of extant gene pools and predict future loss of unique lineages in a marine brown alga. AB - The climate-driven dynamics of species ranges is a critical research question in evolutionary ecology. We ask whether present intraspecific diversity is determined by the imprint of past climate. This is an ongoing debate requiring interdisciplinary examination of population genetic pools and persistence patterns across global ranges. Previously, contrasting inferences and predictions have resulted from distinct genomic coverage and/or geographical information. We aim to describe and explain the causes of geographical contrasts in genetic diversity and their consequences for the future baseline of the global genetic pool, by comparing present geographical distribution of genetic diversity and differentiation with predictive species distribution modelling (SDM) during past extremes, present time and future climate scenarios for a brown alga, Fucus vesiculosus. SDM showed that both atmospheric and oceanic variables shape the global distribution of intertidal species, revealing regions of persistence, extinction and expansion during glacial and postglacial periods. These explained the distribution and structure of present genetic diversity, consisting of differentiated genetic pools with maximal diversity in areas of long-term persistence. Most of the present species range comprises postglacial expansion zones and, in contrast to highly dispersive marine organisms, expansions involved only local fronts, leaving distinct genetic pools at rear edges. Besides unravelling a complex phylogeographical history and showing congruence between genetic diversity and persistent distribution zones, supporting the hypothesis of niche conservatism, range shifts and loss of unique genetic diversity at the rear edge were predicted for future climate scenarios, impoverishing the global gene pool. PMID- 24766058 TI - A systematic review of occupational exposure to synthetic vitreous fibers and mesothelioma. AB - OBJECTIVE: We investigated whether available epidemiological and toxicological data suggest an increased risk of mesothelioma among workers exposed to synthetic vitreous fibers (SVF). METHODS: We conducted a systematic review of epidemiological studies on the risk of mesothelioma among workers exposed to SVF, and toxicological studies on SVF and mesothelioma. RESULTS: Seven cohort studies were conducted among workers employed in production of rock/slag wool, glass wool, or continuous glass filament in the United States, Canada, and Europe. Of the six deaths from mesothelioma identified in these studies, three had exposure to asbestos. A review of death certificates in a study of rock wool production workers identified one additional probable death. A formal comparison with expected deaths is not feasible. Four community-based case-control studies were identified, of which three reported an increased risk among SVF-exposed workers. The number of cases not exposed to asbestos was less, and residual confounding from asbestos exposure misclassification may explain the association in these studies. The toxicology review of SVF suggested that they present a low hazard mostly due to their low biopersistence, typically with a half-life in rat studies of tens of days compared to amphibole asbestos which has a half-life of 400-500 days. CONCLUSIONS: The combined evidence from epidemiology and toxicology provide little evidence that exposure to SVF increases the risk of mesothelioma. PMID- 24766059 TI - Validity of geographically modeled environmental exposure estimates. AB - Geographic modeling is increasingly being used to estimate long-term environmental exposures in epidemiologic studies of chronic disease outcomes. However, without validation against measured environmental concentrations, personal exposure levels, or biologic doses, these models cannot be assumed a priori to be accurate. This article discusses three examples of epidemiologic associations involving exposures estimated using geographic modeling, and identifies important issues that affect geographically modeled exposure assessment in these areas. In air pollution epidemiology, geographic models of fine particulate matter levels have frequently been validated against measured environmental levels, but comparisons between ambient and personal exposure levels have shown only moderate correlations. Estimating exposure to magnetic fields by using geographically modeled distances is problematic because the error is larger at short distances, where field levels can vary substantially. Geographic models of environmental exposure to pesticides, including paraquat, have seldom been validated against environmental or personal levels, and validation studies have yielded inconsistent and typically modest results. In general, the exposure misclassification resulting from geographic models of environmental exposures can be differential and can result in bias away from the null even if non-differential. Therefore, geographic exposure models must be rigorously constructed and validated if they are to be relied upon to produce credible scientific results to inform epidemiologic research. To our knowledge, such models have not yet successfully predicted an association between an environmental exposure and a chronic disease outcome that has eventually been established as causal, and may not be capable of doing so in the absence of thorough validation. PMID- 24766060 TI - The effect of cone beam CT (CBCT) on therapeutic decision-making in endodontics. AB - OBJECTIVES: The aim was to assess to what extent cone beam CT (CBCT) used in accordance with current European Commission guidelines in a normal clinical setting has an impact on therapeutic decisions in a population referred for endodontic problems. METHODS: The study includes data of consecutively examined patients collected from October 2011 to December 2012. From 2 different endodontic specialist clinics, 57 patients were referred for a CBCT examination using criteria in accordance with current European guidelines. The CBCT examinations were performed using similar equipment and standardized among clinics. After a thorough clinical examination, but before CBCT, the examiner made a preliminary therapy plan which was recorded. After the CBCT examination, the same examiner made a new therapy plan. Therapy plans both before and after the CBCT examination were plotted for 53 patients and 81 teeth. As four patients had incomplete protocols, they were not included in the final analysis. RESULTS: 4% of the patients referred to endodontic clinics during the study period were examined with CBCT. The most frequent reason for referral to CBCT examination was to differentiate pathology from normal anatomy, this was the case in 24 patients (45% of the cases). The primary outcome was therapy plan changes that could be attributed to CBCT examination. There were changes in 28 patients (53%). CONCLUSIONS: CBCT has a significant impact on therapeutic decision efficacy in endodontics when used in concordance with the current European Commission guidelines. PMID- 24766061 TI - User involvement in long-term care. Towards a relational care-ethics approach. AB - BACKGROUND: User involvement in long-term care has become official policy in many countries. Procedural and managerial approaches to user involvement have numerous shortcomings in long-term care. What is needed is a different approach that is beneficial and tuned to the needs of clients and professionals. AIM: This article presents a care-ethics approach to involvement. We illustrate this approach and its practical implementation by examining a case example of user involvement in long-term elderly care. METHODOLOGY: This case example is based on an action research project in a residential care home in the Netherlands. Seven female clients participated in the process, as well as diverse groups of professionals from this residential care home. RESULTS: The clients were concerned about meals, and collectively they became empowered and came up with ideas for improving meals. Professionals also shared the clients' experiences with meals, first in homogeneous groups and then in heterogeneous meetings with the client group. This process led to the development of partnership relations between clients and professionals. CONCLUSION: Our findings suggest that a care-ethics approach to user involvement is a means to increase resident empowerment in long-term care. Clients and professionals start sharing their experiences and values through dialogue, and they develop mutual trust and openness while doing so. PMID- 24766062 TI - Diabetes-specific emotional distress in people with Type 2 diabetes: a comparison between primary and secondary care. AB - AIMS: To compare levels of diabetes distress in people with Type 2 diabetes treated in primary and secondary care and to examine demographic and clinical correlates that may explain potential differences in levels of distress between care settings. METHODS: People with Type 2 diabetes from 24 primary care practices (n = 774) and three secondary care clinics (n = 526) completed the Problem Areas In Diabetes questionnaire. Data on HbA1c levels and diabetes complications were derived from medical charts. Hierarchical ordinal regression analysis was used to investigate which correlates could explain the potential differences in level of diabetes distress between care settings. RESULTS: Diabetes distress levels and the prevalence of elevated diabetes distress were considerably lower in the participants treated in primary care (mean (SD) total diabetes distress score 8 (11); 4% of participants with a Problem Areas In Diabetes score >= 40) than in secondary care (mean (SD) total diabetes distress score 23 (21); 19% of participants with a Problem Areas In Diabetes score >= 40, P < 0.001). In addition to care setting, the following variables were also independently related to diabetes distress: younger age, ethnic minority status, using insulin, having a higher HbA1c level, having a higher BMI and the presence of neuropathy. Other diabetes complications were not independently associated with diabetes distress. CONCLUSIONS: In primary care, lower levels of diabetes distress were reported than in secondary care. The difference in diabetes distress between care settings can be largely, but not fully, explained by specific demographic and clinical characteristics. These results need to be interpreted with caution as they are based on two separate studies, but do call into question the need to screen for diabetes distress in people with Type 2 diabetes in primary care. PMID- 24766063 TI - Vertebral osteomyelitis: clinical features and diagnosis. AB - We aimed to describe clinical and diagnostic features of vertebral osteomyelitis for differential diagnosis and treatment. This is a prospective observational study performed between 2002 and 2012 in Ankara Numune Education and Research Hospital in Ankara, Turkey. All the patients with vertebral osteomyelitis were followed for from 6 months to 3 years. In total, 214 patients were included in the study, 113 out of 214 (53%) were female. Out of 214 patients, 96 (45%) had brucellar vertebral osteomyelitis (BVO), 63 (29%) had tuberculous vertebral osteomyelitis (TVO), and 55 (26%) had pyogenic vertebral osteomyelitis (PVO). Mean number of days between onset of symptoms and establishment of diagnosis was greater with the patients with TVO (266 days) than BVO (115 days) or PVO (151 days, p <0.001). In blood cultures, Brucella spp. were isolated from 35 of 96 BVO patients (35%). Among 55 PVO patients, the aetiological agent was isolated in 11 (20%) patients. For tuberculin skin test >15 mm, sensitivity was 0.66, specificity was 0.97, positive predictive value was 0.89, negative predictive value was 0.88, and receiver operating characteristics area was 0.8. Tuberculous and brucellar vertebral osteomyelitis remained the leading causes of vertebral osteomyelitis with delayed diagnosis. In differential diagnosis of vertebral osteomyelitis, consumption of unpasteurized cheese, dealing with husbandry, sweating, arthralgia, hepatomegaly, elevated alanine transaminase, and lumbar involvement in magnetic resonance imaging were found to be predictors of BVO, thoracic involvement in magnetic resonance imaging and tuberculin skin test > 15 mm were found to be predictors of TVO, and history of spinal surgery and leucocytosis were found to be predictors of PVO. PMID- 24766064 TI - "Take your pill": the role and fantasy of pills in modern medicine. AB - The pharmaceutical industry has undergone a vast expansion in the 20th and 21st centuries. This article explores the central role now played by pills in clinical practice, but also in the public imagination. First, this article analyzes four properties that, together, account for many of the promises and perils associated with pills: They are ingestible, potent, reproducible, and miniaturized. This allows them to serve as ideal consumer items for widespread distribution and sale and also as model technological "devices" capable of downloading into the body healing chemicals. As such, they seem to promise a disburdening solution to many of life's ills. In our cultural fantasy, often shared by physician and patient alike, pills can be used not only to treat and prevent disease but also raise energy, lose weight, lessen pain, lift mood, cope with stress, and enhance sexual and athletic performance. This article also explores many adverse effects not only of pills themselves but of this exaggerated cultural fantasy of the pill. It tends to distract us from other, more holistic understandings of the locus of disease and healing. It even fosters misunderstandings of the ways in which pills themselves work, which is to assist bodily processes, and the mind's "meaning response." The intent here is not to demonize all pills-many have great therapeutic potential-but to learn how to better choose and use them wisely. We propose that this process be assisted through recontextualizing the pill as a multidimensional gift. Taken in such a way, with appropriate gratitude and discernment, we may ingest fewer pills, but with greater efficacy. PMID- 24766065 TI - The Sheffield RNAi Screening Facility (SRSF): portfolio growth and technology development. AB - The Sheffield RNAi Screening Facility (SRSF) (www.rnai.group.shef.ac.uk) was established in 2008 with Wellcome Trust and University of Sheffield funding, with the task to provide the first UK RNAi screening resource for academic groups interested in identifying genes required in a diverse range of biological processes using Drosophila cell culture. The SRSF has carried out a wide range of screens varying in sizes from bespoke small-scale libraries, targeting a few hundred genes, to high-throughput, genome-wide studies. The SRSF has grown and improved with a dedicated partnership of its academic customers based mainly in the UK. We are part of the UK Academics Functional Genomics Network, participating in organizing an annual meeting in London and are part of the University of Sheffield's D3N (www.d3n.org.uk), connecting academics, biotech and pharmaceutical companies with a multidisciplinary network in Drug Discovery and Development. Recently, the SRSF has been funded by the Yorkshire Cancer Research Fund to perform genome-wide RNAi screens using human cells as part of a core facility for regional Yorkshire Universities and screens are now underway. Overall the SRSF has carried out more than 40 screens from Drosophila and human cell culture experiments. PMID- 24766066 TI - Clinical instructors' perceptions of structural and psychological empowerment in academic nursing environments. AB - The study purpose was to explore clinical instructors' (CIs') perceptions of empowerment in academic nursing environments. Clinical instructors, often part time faculty, facilitate learning in professional practice environments. However, they also need to function within the academic environment to learn about the curriculum and how students are to be evaluated. The qualitative description method was used to obtain an understanding of CIs' empowerment experiences and to interpret their perceptions within the frameworks of Kanter's structural empowerment and Spreitzer's psychological empowerment theories. Eight CIs from two nursing programs were interviewed for this study. The empowerment components of support and confidence were important, yet insufficient, in CIs' perceptions of their role effectiveness. An implication for CIs was slow development of confidence in their ability to facilitate student learning that was consistent with curriculum goals. Recommendations for CIs and academic faculty are offered to support and retain clinical faculty. PMID- 24766067 TI - D-Penicillamine tripodal derivatives as efficient copper(I) chelators. AB - New tripodal metal-chelating agents derived from nitrilotriacetic acid (NTA) and extended by three unnatural amino acids D-penicillamine (D-Pen) are presented. D Pen is actually the drug most extensively used to treat copper (Cu) overload in Wilson's disease and as such is a very attractive building block for the design of chelating agents. D-Pen is also a bulkier analogue of cysteine, with the beta methylene hydrogen atoms replaced by larger methyl groups. The hindrance of the gem-dimethyl group close to the thiol functions is demonstrated to influence the speciation and stability of the metal complexes. The ligands L(4) (ester) and L(5) (amide) were obtained from NTA and commercial D-Pen synthons in four and five steps with overall yields of 14 and 24%, respectively. Their ability to bind Cu(I), thanks to their three thiolate functions, has been investigated using both spectroscopic and analytical methods. UV, CD, and NMR spectroscopy and mass spectrometry evidence the formation of two Cu(I) complexes with L(5): the mononuclear complex CuL(5) and one cluster (Cu2L(5))2. In contrast, the bulkier ethyl ester derivative L(4) cannot accommodate the mononuclear complex in solution and thus forms exclusively the cluster (Cu2L(4))2. Cu K-edge X-ray absorption spectroscopy (XAS and EXAFS) confirms that Cu(I) is bound in trigonal planar sulfur-only environments in all of these complexes with Cu- - -S distances ranging from 2.22 to 2.23 A. Such C3-symmetric CuS3 cores are coordination modes frequently adopted in Cu(I) proteins such as metallothioneins. These two ligands bind Cu(I) tightly and selectively, which makes them promising chelators for intracellular copper detoxification in vivo. PMID- 24766068 TI - Centering the concept of transitional care: a teaching-learning innovation. AB - Coordination of care, including the provision of safe and effective transitions, is a core professional standard for nurses. However, as currently designed, prelicensure nursing education prepares nurses to function in discrete settings rather than across settings. A teaching-learning innovation focusing on transitional care was implemented as an educational pilot project with 20 senior level baccalaureate students in their leadership course. Students in the educational pilot immersed in the subject of transitional care via concept-based learning activities and performance improvement projects. During the course, students were assigned to designated clinical sites representative of a continuum of care. An integrated clinical postconference offered students the opportunity to discover the role of the nurse in transitional care from a systems perspective and facilitated a deeper understanding of the subject that extended beyond the walls of students' discrete clinical sites. PMID- 24766069 TI - Type 2 diabetes and memory: using neuroimaging to understand the mechanisms. AB - The most robust and frequently reported cognitive deficits in type 2 diabetes (DM2) are those that relate to memory. Behavioural research has identified a number of potential contributory physiological factors, including abnormalities in glucose metabolism, such as hyperglycaemia and hypoglycaemia. The impact of these mechanisms on memory has been further investigated through the use of both structural and functional neuroimaging. Structural brain imaging has indicated that memory impairments in DM2 are associated with global atrophy of the brain. Further data suggest that localised atrophy in the hippocampal area, a brain region critical to memory formation and consolidation, may be primarily responsible for the memory deficits seen in this population. Functional imaging data has corroborates these findings, with functional magnetic resonance imaging (fMRI) suggesting reduced connectivity between the hippocampus and surrounding brain regions, particularly the frontal and temporal gyri. Despite this, little functional neuroimaging research has directly investigated differences in regional brain activity between healthy and DM2 participants whilst memory tasks are being performed. By using neuroimaging techniques to their full potential, we can acquire a fuller, more comprehensive picture of the impact that DM2 has on memory. PMID- 24766070 TI - Exceptional performance of TiNb2O7 anode in all one-dimensional architecture by electrospinning. AB - We report the extraordinary performance of an Li-ion battery (full-cell) constructed from one-dimensional nanostructured materials, i.e. nanofibers as cathode, anode, and separator-cum-electrolyte, by scalable electrospinning. Before constructing such a one-dimensional Li-ion battery, electrospun materials are individually characterized to ensure its performance and balancing the mass loading as well. The insertion type anode TiNb2O7 exhibits the reversible capacity of ~271 mAh g(-1) at current density of 150 mA g(-1) with capacity retention of ~82% after 100 cycles. Under the same current density, electrospun LiMn2O4 cathode delivered the discharge capacity of ~118 mAh g(-1). Gelled electrospun polyvinylidene fluoride-co-hexafluoropropylene (PVdF-HFP) nanofibers membrane is used as the separator-cum-electrolyte in both half-cell and full-cell assembly which exhibit the liquid like conductivity of ~2.9 mS cm(-1) at ambient conditions. Full-cell, LiMn2O4|gelled PVdF-HFP|TiNb2O7 is constructed by optimized mass loading of cathode with respect to anode and tested between 1.95 and 2.75 V at room temperature. The full-cell delivered the reversible capacity of ~116 mAh g(-1) at current density of 150 mA g(-1) with operating potential and energy density of ~2.4 V and ~278 Wh kg(-1), respectively. Further, excellent cyclability is noted for such configuration irrespective of the applied current densities. PMID- 24766071 TI - Vacuum-ultraviolet photolysis of methane at 3 K: synthesis of carbon clusters up to C20. AB - Samples of pure methane and of methane dispersed in solid neon at 3 K subjected to irradiation at wavelengths less than 165 nm with light from a synchrotron yielded varied products that were identified through their infrared absorption spectra, including CH3, C2H2, C2H3, C2H4, C2H6, C4H2, C4H4, C5H2, C8H2, CnH with n = 1-5, and carbon chains Cn with n = 3-20. The efficiency of photolysis of methane and the nature of the photoproducts depended on the concentration of methane and the wavelength selected for irradiation; an addition of H2 into solid neon enhanced the formation of long carbon chains. PMID- 24766072 TI - Fiber-based generator for wearable electronics and mobile medication. AB - Smart garments for monitoring physiological and biomechanical signals of the human body are key sensors for personalized healthcare. However, they typically require bulky battery packs or have to be plugged into an electric plug in order to operate. Thus, a smart shirt that can extract energy from human body motions to run body-worn healthcare sensors is particularly desirable. Here, we demonstrated a metal-free fiber-based generator (FBG) via a simple, cost effective method by using commodity cotton threads, a polytetrafluoroethylene aqueous suspension, and carbon nanotubes as source materials. The FBGs can convert biomechanical motions/vibration energy into electricity utilizing the electrostatic effect with an average output power density of ~0.1 MUW/cm(2) and have been identified as an effective building element for a power shirt to trigger a wireless body temperature sensor system. Furthermore, the FBG was demonstrated as a self-powered active sensor to quantitatively detect human motion. PMID- 24766073 TI - Role of protons in the pump cycle of KdpFABC investigated by time-resolved kinetic experiments. AB - The time-resolved kinetics of the KdpFABC complex solubilized in Aminoxide WS-35 was investigated by ATP concentration jump experiments. ATP was photoreleased from its inactive precursor, caged ATP, and charge movements in the membrane domain of the KdpFABC were detected by the electrochromic dye RH421. At low ATP concentrations, the ATP binding step became rate-limiting with an apparent, pH independent ATP binding affinity of ~70 MUM. At saturating ATP concentrations, the rate-limiting step is the conformational transition (E1-P -> P-E2) with a rate constant of ~1.7 s(-1) at 20 degrees C that was independent of K(+) concentration. This observation together with the detected fluorescence decrease indicates that K(+) (or another positive ion) is bound in the membrane domain after enzyme phosphorylation and the conformational transition to the P-E2 state. pH dependence experiments revealed different roles of H(+) in the transport mechanism. Two different functions of protons for the ion pump must be distinguished. On one hand, there are electrogenically bound "functional" protons, which are not transported but prerequisite for the performance of the ATP-driven half-cycle. On the other hand, protons bind to the transport sites, acting as weak congeners of K(+). There possibly are noncompetitively bound protons, affecting the enzyme activity and/or coupling between KdpA and KdpB subunits. Finally, the recently proposed Post-Albers model for the KdpFABC complex was supplemented with stoichiometry factors of 2 for K(+) and 3 for H(+), and additional inhibitory side reactions controlled by H(+) were introduced, which are relevant at pH <6.5 and/or in the absence of K(+). PMID- 24766074 TI - New RAF kinase inhibitors in cancer therapy. AB - INTRODUCTION: Alterations in some key components of the MAPK pathway, such as BRAF, have been found to be related to the development of several malignancies. A number of BRAF inhibitors have been developed in recent years. Two of these compounds, vemurafenib and dabrafenib, have been licensed for the treatment of BRAF-mutant advanced melanoma. AREAS COVERED: This article reviews the antitumour activity and safety of the BRAF inhibitors, vemurafenib and dabrafenib. Moreover, early clinical data available for the most promising new members of this family of drugs as well as the novel therapeutic strategy of dual RAF-MEK inhibition is reviewed. A perspective of the potential role of MAPK inhibition in the treatment of cancer in forthcoming years is also provided. EXPERT OPINION: Inhibition of BRAF has achieved highly successful results in patients affected by BRAF-mutated melanoma and has revolutionised their care. Its efficacy in other malignancies is currently under evaluation in monotherapy and as combination with other agents. Early clinical results of concomitant inhibition of BRAF and MEK suggest that this therapeutic approach is superior to either BRAF or MEK inhibition alone. Identification of BRAF mutations sensitive to treatment is essential for the success of these drugs. PMID- 24766075 TI - Prenatal control of Hb Bart's hydrops fetalis: a two-year experience at a mainland Chinese hospital. AB - alpha-Thalassemia is a common inherited disease in southern China. The severest form is Hb Bart's hydrops fetalis, in which the affected fetuses almost always die in utero or shortly after birth, and the mothers are at high risk for severe morbidity. Therefore, this condition should be controlled, especially prenatally. In this study, we reported on a two-year experience in prenatal control of Hb Bart's hydrops fetalis at a mainland Chinese hospital. Totally, 573 pregnancies at risk for Hb Bart's hydrops fetalis were referred and different prenatal procedures were offered depending on the gestational age at presentation. One hundred fifty-two affected fetuses were diagnosed prenatally; among these, only half presented in early gestation, and were terminated in time. Although our prenatal program has successfully prevented the birth of children with severe thalassemia, it does not show a satisfactory outcome, considering the gestational age when an affected pregnancy is terminated. PMID- 24766076 TI - Association of young and advanced age of pregnant women with the risk of isolated congenital abnormalities in Hungary - a population-based case-matched control study. AB - OBJECTIVE: To analyze the possible association of maternal age with the risk of all congenital abnormalities (CAs) in a population-based large case-matched control data set. METHODS: The Hungarian Case-Control Surveillance of Congenital Abnormalities included 21,494 cases with isolated CA and their 34,311 matched controls. First the distribution of maternal age groups in 24 CA-groups and their matched controls was compared. In the second step, young (19 years or less) and advanced (35 years or more) age groups were compared. Finally, the subgroups of neural-tube defects, congenital heart defects and abdominal wall's CA were evaluated separately. RESULTS: A higher risk of gastroschisis, congenital heart defects, particularly left-sided obstructive defects, undescended testis and clubfoot was found in the youngest age group (19 years or less) of cases. The higher proportion of pregnant women with advanced age (i.e. 35 years or more) showed only a borderline excess in cases with clubfoot. The so-called U-shaped risk of maternal age distribution was found in cases with clubfoot and in the total group of isolated CAs. CONCLUSIONS: The maternal age is a contributing factor to the origin of some isolated CAs mainly in young pregnant women. PMID- 24766077 TI - Morphological and functional aspects of acute kidney injury after fetal programing in the offspring of diabetic rats. AB - OBJECTIVE: To evaluate the effects of folic acid (FA)-induced renal failure in young offspring of diabetic mothers. METHODS: The offspring of streptozotocin induced diabetic dams were divided into four groups: CC (controls receiving vehicle); DC (diabetics receiving vehicle); CA (controls receiving FA solution, 250 mg/kg) and DA (diabetics receiving FA solution, 250 mg/kg). Renal function tests and morphometry results were analyzed. RESULTS: An increase in creatinine and urea levels was observed in CA and DA groups at two and five months. FA administration caused a significant reduction in the number of glomeruli in the offspring of diabetic dams. The diabetes group treated with FA had fewer glomeruli compared to controls at two and five months. FA caused an increase in the area of the urinary space both in controls and offspring of diabetic dams at two and five months. The number of glomeruli and area of the urinary space at two months were negatively correlated. CONCLUSIONS: Fetal programing promotes remarkable changes in kidney morphology and function in offspring. We suggest that the morphological changes in the kidneys are more pronounced when fetal programing is associated with newly acquired diseases, e.g. renal failure induced by FA. PMID- 24766078 TI - Human insecurity, chronic economic constraints and health in the occupied Palestinian territory. AB - Research on the effects of political conflict has focused predominantly on the association between violence exposure and psychological trauma. This paper expands that focus. We broaden the assessment of health beyond the conventional spotlight on trauma-related stress to include culturally derived measures of health, and we assess the association between a broad array of political and economic conditions and health. Household interviews were conducted in 2011 with a representative sample of 508 30-40 year olds in the occupied Palestinian territory (oPt; response rate = 97%). The four dependent variables were limits on functioning due to health, feeling broken or destroyed (both culturally derived measures of health), feelings of depression and trauma-related stress. Twenty four predictor variables assessed multiple dimensions of political conflict and background characteristics. All four measures of health and suffering were associated with human insecurity and resource adequacy. Exposure to political violence was associated only with trauma-related stress. These findings support the increasing recognition that human insecurity and chronic economic constraints in the oPt broadly threaten health, perhaps more so than direct exposure to violence. Ultimately, a political solution is required, but in the meantime, efforts to reduce insecurity and improve economic conditions may improve health and reduce suffering in the oPt. PMID- 24766080 TI - Direct probing of photoinduced electron transfer in a self-assembled biomimetic [2Fe2S]-hydrogenase complex using ultrafast vibrational spectroscopy. AB - A pyridyl-functionalized diiron dithiolate complex, [MU-(4-pyCH2-NMI-S2)Fe2(CO)6] (3, py = pyridine (ligand), NMI = naphthalene monoimide) was synthesized and fully characterized. In the presence of zinc tetraphenylporphyrin (ZnTPP), a self assembled 3.ZnTPP complex was readily formed in CH2Cl2 by the coordination of the pyridyl nitrogen to the porphyrin zinc center. Ultrafast photoinduced electron transfer from excited ZnTPP to complex 3 in the supramolecular assembly was observed in real time by monitoring the nu(C=O) and nu(C?O)NMI spectral changes with femtosecond time-resolved infrared (TRIR) spectroscopy. We have confirmed that photoinduced charge separation produced the monoreduced species by comparing the time-resolved IR spectra with the conventional IR spectra of 3(*-) generated by reversible electrochemical reduction. The lifetimes for the charge separation and charge recombination processes were found to be tauCS = 40 +/- 3 ps and tauCR = 205 +/- 14 ps, respectively. The charge recombination is much slower than that in an analogous covalent complex, demonstrating the potential of a supramolecular approach to extend the lifetime of the charge-separated state in photocatalytic complexes. The observed vibrational frequency shifts provide a very sensitive probe of the delocalization of the electron-spin density over the different parts of the Fe2S2 complex. The TR and spectro-electrochemical IR spectra, electron paramagnetic resonance spectra, and density functional theory calculations all show that the spin density in 3(*-) is delocalized over the diiron core and the NMI bridge. This delocalization explains why the complex exhibits low catalytic dihydrogen production even though it features a very efficient photoinduced electron transfer. The ultrafast porphyrin-to-NMI-S2-Fe2(CO)6 photoinduced electron transfer is the first reported example of a supramolecular Fe2S2 hydrogenase model studied by femtosecond TRIR spectroscopy. Our results show that TRIR spectroscopy is a powerful tool to investigate photoinduced electron transfer in potential dihydrogen-producing catalytic complexes, and that way to optimize their performance by rational approaches. PMID- 24766079 TI - Dynamic social support networks of younger black men who have sex with men with new HIV infection. AB - Rising rates of HIV infection among younger black men who have sex with men (YBMSM) in the USA have generated a public health emergency. Living with HIV requires deep and persistent social support often available only from close confidants. Enlisting endogenous support network members into the care of HIV infected YBMSM may help shape sustainable supportive environments, leading to long-term improvements in mental and HIV-specific health outcomes. The present study examined trends in support network change over time after new HIV diagnoses among 14 YBMSM. Participants completed a social network survey that utilized sociograms to record support confidants (SCs) preceding HIV diagnosis and at one and nine months postdiagnosis. Reported SCs included family of origin, friends, sex partners, and other associates. Analysis revealed three distinct patterns of change: high gain, high turnover, and stable networks. These patterns offer valuable insights into the social support of YBMSM during the period following diagnosis. This research underscores a growing movement to embrace key support figures in the lives of YBMSM, who may be critical to promoting overall health and adherence to HIV-care. PMID- 24766081 TI - Handling and welfare of bovine livestock at local abattoirs in Bangladesh. AB - The World Organization for Animal Health (OIE) allows rope casting and the tying of legs for nonhuman animal slaughter without stunning. The handling and welfare of bovine livestock (Bos indicus and Bubalus bubalis) were studied in 8 local abattoirs in 5 districts of Bangladesh. A total of 302 animals were evaluated. At the local abattoirs, approximately 1/3 of the cattle and water buffalo were either emaciated or injured/sick. The size and vigor of the animals determined the casting method. Small and weak animals were cast on concrete floors by lifting a foreleg followed by pushing, or simply by twisting the head of the animal and then binding the legs with rope. Vigorous animals such as buffalo were cast using ropes and human force. Bleeding was slow and flaying was sometimes initiated before the animals were unconscious. Pulling and tearing of the trachea and pouring of water into the exposed trachea shortly after cutting were also observed in some cases. The overall animal handling was unnecessarily rough and the OIE standards were not implemented. Animals are subjected to considerable mistreatment, and there is an urgent need for the training and education of the staff in abattoirs concerning humane slaughtering practices as well as a need to build modern slaughtering plants in Bangladesh. PMID- 24766082 TI - Occurrence of Sudan I in paprika fruits caused by agricultural environmental contamination. AB - Current research has demonstrated the presence of sub parts per billion levels of Sudan dye in paprika fruits during the vegetation process, which is difficult to understand on the basis of the conventional concept of cross-contamination or malicious addition. Detailed surveys on Sudan dyes I-IV in paprika fruits, soils, and agronomic materials used from seven fields of Xinjiang (China) were conducted to investigate the natural contamination. Results revealed that Sudan dyes II-IV were never detected and that Sudan I existed in almost all samples except for the mulching film and irrigation water. The higher total amount of Sudan I in soils, pesticides, and fertilizers compared to coated seeds indicated the combination of Sudan I-contaminated soils and application of Sudan I-containing agronomic materials constitutes a major source of 0.18-2.52 MUg/kg levels of Sudan I in fruits during the growth period. The study offers a more reasonable explanation for the previously observed Sudan I in paprika fruits. PMID- 24766083 TI - Preparing for patient-centered care: assessing nursing student knowledge, comfort, and cultural competence toward the Latino population. AB - As the Latino population continues to grow throughout the United States, cultural competence training of nursing students at the baccalaureate level has become a priority. This study aimed to explore undergraduate nursing students' attitudes and beliefs toward Latino patients and their perceived readiness to provide care to Latino patients. A cross-sectional survey was conducted at four major nursing schools in the southeastern United States, which is the region that has seen the highest percentage of growth in the Latino population. Results from multivariable regression suggest that social interaction with Latino individuals and cultural immersion in a Spanish-speaking country predict student knowledge, cultural competence, and comfort with Latino patients. Direct influence by nursing programs, such as clinical experience, coursework, and language proficiency, are positively associated with the designed outcomes, but these relationships are not statistically significant. Our findings suggest that dosage of training matters. Implications for student recruitment, selection, and training are discussed. PMID- 24766084 TI - Role of sex and migration in adaptation to sink environments. AB - Understanding the effects of sex and migration on adaptation to novel environments remains a key problem in evolutionary biology. Using a single-cell alga Chlamydomonas reinhardtii, we investigated how sex and migration affected rates of evolutionary rescue in a sink environment, and subsequent changes in fitness following evolutionary rescue. We show that sex and migration affect both the rate of evolutionary rescue and subsequent adaptation. However, their combined effects change as the populations adapt to a sink habitat. Both sex and migration independently increased rates of evolutionary rescue, but the effect of sex on subsequent fitness improvements, following initial rescue, changed with migration, as sex was beneficial in the absence of migration but constraining adaptation when combined with migration. These results suggest that sex and migration are beneficial during the initial stages of adaptation, but can become detrimental as the population adapts to its environment. PMID- 24766085 TI - Serotype distribution and susceptibility to penicillin and erythromycin among noninvasive or colonization isolates of Streptococcus pneumoniae in northern Japan: a cross-sectional study in the pre-PCV7 routine immunization period. AB - Distribution of serotypes, prevalence of resistance to penicillin and/or erythromycin (EM), and its genetic traits were analyzed for a total of 1,061 noninvasive or colonization isolates of Streptococcus pneumoniae (998 and 61 isolates from children and adults, respectively) in Hokkaido, northern main island of Japan, in the year 2011, the pre-PCV7 routine immunization period. Serotype deduction was performed by sequential multiplex polymerase chain reaction (PCR), employing mutagenic PCR-restriction fragment length polymorphism for discrimination of 6A/C and 6B/D. Unaltered three PBP genes and macrolide resistance genes erm(B) and mef(A/E) were detected by multiplex PCR. Among isolates from children, 25 serotypes, including the prevalent types 6B (17.5%), 19F (15.6%), 23F (12.2%), and 6C (11.6%), were identified, revealing the PCV7 and PCV13 coverage rates as 48.2% and 60.3%, respectively, while serotype 3 was the most frequent (19.0%) among isolates from adults. Most of the pediatric isolates (96.8%) exhibited resistance to EM (minimum inhibitory concentration [MIC], >=1 MUg/ml), with a higher prevalence of erm(B) (67.2%) than mef(A/E) (39.7%). erm(B) was associated with high-level EM resistance (MIC, >=128 MUg/ml) and distributed at high detection rates to major serotypes 23F (85.2%) and 6B (85.1%), as well as minor serotypes 3, 10A, 14, 15B, 15C, 19A, and 23A (>90%). While penicillin resistant S. pneumoniae (PRSP) (penicillin G-MIC, 2-3 MUg/ml) was detected in 7.8% of isolates from children, the most common PBP gene genotype was gPRSP (three altered genes pbp1a, 2x, and 2b; 38.3%), which was detected at higher rates (>60%) in the dominant serotypes 23F, 6B, and 19F, and minor serotypes 6D and 15A. Dominant serotypes in the S. pneumoniae isolates were generally similar to those reported for invasive strains, despite lower coverage rates by PCV7/13. The importance of further surveillance on incidence and drug resistance in the post-PCV7 period was suggested for non-PCV7/13 serotypes 6C, 6D, 10A, 15A, 15B, 15C, 23A, and 35B. PMID- 24766087 TI - Stigma predicts residential treatment length for substance use disorder. AB - BACKGROUND: Stigma has been suggested as a possible contributor to the high rates of treatment attrition in substance-dependent individuals, but no published empirical studies have examined this association. OBJECTIVES: The present paper assessed the relationship between baseline stigma variables and length of treatment stay in a sample of patients in a residential addictions treatment unit. METHODS: The relationship between baseline stigma variables (self-stigma, enacted stigma, and shame) and length of stay for participants (n=103) in a residential addictions treatment unit was examined. RESULTS: Higher self-stigma predicted longer stay in residential addictions treatment, even after controlling for age, marital status, race, overall mental health, social support, enacted stigma, and internalized shame. However, other stigma variables (i.e. internalized shame, stigma-related rejection) did not reliably predict length of treatment stay. CONCLUSION: These results are consistent with other findings suggesting that people with higher self-stigma may have a lowered sense of self efficacy and heightened fear of being stigmatized and therefore retreat into more protected settings such as residential treatment, potentially resulting in higher treatment costs. Specialized clinical interventions may be necessary to help participants cope with reduced self-efficacy and fear of being stigmatized. PMID- 24766088 TI - Gender and racial/ethnic differences in patterns of adolescent alcohol use and associations with adolescent and adult illicit drug use. AB - OBJECTIVES: The study objective was to use latent class analyses (LCAs) to identify gender- and racial/ethnic-specific groups of adolescent alcohol users and associations between alcohol use group and adolescent and adulthood illicit drug use in a nationally-representative US sample. METHODS: We used Wave I (1994 1995, adolescence) of the National Longitudinal Study of Adolescent Health to conduct LCAs by gender and race/ethnicity and measure associations between class membership and Wave I and Wave III (2001-2002, young adulthood) drug use. Participants included white (n=9548), African American (n=4005) and Hispanic (n=3184) participants. LCAs were based on quantity and frequency of adolescent alcohol use; physiological and social consequences of use; and peer use. RESULTS: Males and females were characterized by different alcohol use typologies and consequences. Males in the highest severity class (i.e. drank both heavily and frequently) experienced disproportionate risk of alcohol-related consequences compared with abstainers and other alcohol-using groups. Females who drank heavily when drinking even if only occasionally, experienced high risk of alcohol related consequences. Substantial proportions of males reported diverse alcohol related problems, whereas females most commonly reported alcohol-related problems with dating and sexual experiences. Though levels of alcohol use and report of problems associated with use were higher among white versus minority populations, other racial/ethnic differences in patterns of alcohol use were minimal. Classification in any drinking class was a strong risk factor for adolescent and adulthood illicit drug use, with heavy drinkers at greatest risk of drug use. CONCLUSIONS: Gender-specific adolescent alcohol and substance use prevention programs are warranted. PMID- 24766089 TI - The link between early onset drinking and early onset alcohol-impaired driving in young males. AB - BACKGROUND: Young drivers represent a disproportionate number of the individuals involved in alcohol-impaired driving. Although there is a known association between drinking and alcohol-impaired driving in young drivers, the link between early onset drinking and early onset alcohol-impaired driving has not been explored. OBJECTIVES: The present study aimed to assess this link along with potentially confounding factors. METHODS: The assessment used a proportional hazards model with data collected from the Buffalo Longitudinal Study of Young Men, a population-based sample of 625 males at aged 16-19. RESULTS: Controlling for the effects of potentially relevant confounds, the early onset of drinking was the most influential factor in predicting the early onset of alcohol-impaired driving. Race and the early onset of other forms of delinquency also played a significant role in the early onset of alcohol-impaired driving. CONCLUSION: Preventing an early start of drinking among adolescents may be the most critical factor to address in preventing an early start of alcohol-impaired driving. PMID- 24766090 TI - Ocular Findings in Patients with the Hermansky-Pudlak Syndrome (Types 1 and 3). AB - PURPOSE: To describe and compare ocular findings in patients with Hermansky Pudlak syndrome (HPS) type 1 and 3. METHODS: This is a retrospective case series of 64 patients with HPS from 1999 to 2009 evaluated at an outpatient private ophthalmologic clinic. Patients underwent genetic analysis of selected albinism (Tyrosine and P gene) and HPS genes (HPS-1 and HPS-3) by screening for common mutations and exon sequencing with DNA screening. Descriptive and non-parametric statistical analyses were carried out. RESULTS: Nearly 70% of the patients were homozygous for common Puerto Rican mutations leading to the HPS1 gene (16-BP DUP, 53.6%), while 30% had the 3904-BP DEL HPS3 gene mutation. Best corrected visual acuity (BCVA) was poorer in patients with type 1 HPS than in patients with type 3 HPS (p < 0.001), esotropia was more common among type 1 HPS patients (p < 0.018), while exotropia was more common among patients with type 3 HPS. Total iris transillumination was more common in patients with type 1 HPS and minimal iris transillumination in patients with type 3 HPS (p < 0.001). The maculae were translucent in patients with type 1 HPS, while patients with type 3 HPS had opaque maculae (p < 0.001). CONCLUSIONS: Patients with type 1 HPS had poorer BCVA, increased incidence of esotropia, lighter iris and macular appearance. In contrast, patients with type 3 HPS had more exotropia. In addition, to our knowledge this is the largest series type 3 HPS ever reported. PMID- 24766091 TI - Cirrhosis regression in hepatitis C patients with sustained virological response after antiviral therapy: a meta-analysis. AB - BACKGROUND & AIMS: Chronic hepatitis C may be associated with cirrhosis, liver failure and hepatocellular carcinoma. Studies have demonstrated improved clinical outcome in patients who achieved a sustained viral response (SVR). METHODS: A systematic literature search was performed to identify studies that assessed the association between SVR and cirrhosis regression. The main outcome studied was cirrhosis regression in patients with a SVR as compared with patients without a SVR. Six studies totalling 443 patients were included. Dichotomous outcomes were reported as risk ratios (RR) with 95% confidence intervals (CI). RESULTS: Of the 443 patients with cirrhosis, 137 achieved a SVR. Of these 137 patients who achieved an SVR, 73 (53%) patients had regression of cirrhosis. The risk ratio of cirrhosis regression was 2.69 [Confidence Interval (CI) 1.45-4.97, P < 0.01] in patients who achieved a SVR. The risk of cirrhosis regression was consistently in favour of patients who achieved a SVR regardless of the length of the biopsy or whether the biopsy was reviewed by a single or multiple pathologists. The risk ratio of cirrhosis regression was related to the duration of follow-up between biopsies. The relative risk for regression of cirrhosis in studies in which the mean or median time for the follow-up liver biopsy was greater than 36-month was 4.33 (CI 1.1-17.0, P = 0.04) as compared to a relative risk of 1.79 (CI 1.26 2.29, P < 0.01) in studies with a mean or median time between the follow-up biopsy of less than 36-month. CONCLUSIONS: Our results suggest that the majority of patients with cirrhosis who achieve a SVR develop cirrhosis regression. Time between biopsies appears to be an important determinant of the likelihood of cirrhosis regression. PMID- 24766093 TI - Synchrotron Photoionization Study of Mesitylene Oxidation Initiated by Reaction with Cl(2P) or O(3P) Radicals. AB - This work studies the oxidation of mesitylene (1,3,5-trimethylbenzene) initiated by O(3P) or Cl(2P) atoms. The O(3P) initiated mesitylene oxidation was investigated at room temperature and 823 K, whereas the Cl-initiated reaction was carried out at room temperature only. Products were probed by a multiplexed chemical kinetics photoionization mass spectrometer using the synchrotron radiation produced at the Advanced Light Source (ALS) of Lawrence Berkeley National Laboratory. Reaction products and intermediates are identified on the basis of their time behavior, mass-to-charge ratio, ionization energies, and photoionization spectra. Branching yields are derived for the O-initiated reaction at 823 K and the Cl-initiated reaction at room temperature. Reaction schematics are proposed and presented. PMID- 24766092 TI - Prevalence and risk factors of diabetes and impaired fasting glucose among university applicants in Eastern China: findings from a population-based study. AB - AIMS: To investigate the prevalence and risk factors of diabetes and impaired fasting glucose among urban university applicants in Eastern China. METHOD: The study uses data from the annual health examination among all students finishing high school who applied for university entrance in Changzhou City in 2012. In total, 6716 students aged 17-19 years had fasting blood glucose, alanine transaminase, height, weight and blood pressure measured. Impaired fasting glucose and diabetes were defined as fasting blood glucose >= 5.6 mmol/l (but < 7 mmol/l) and >= 7 mmol/l, respectively. RESULTS: The overall prevalence of impaired fasting glucose and diabetes was 2.40% and 0.13%, respectively (3.67% and 0.09% in boys; 1.09% and 0.18% in girls). In total, 20.9% of boys and 10.6% of girls were overweight/obese. High socio-economic status was associated with an increased risk of diabetes/impaired fasting glucose, but the association was significant only among boys (adjusted odds ratio 1.94, 95% CI 1.26-2.98). Alanine transaminase levels were significantly and positively related to diabetes/impaired fasting glucose risk. Overweight/obesity was significantly associated with increased risk of impaired fasting glucose/diabetes in girls, but not in boys. Moreover, the number of the above-mentioned risk factors (i.e. overweight/obesity, elevated alanine transaminase, pre-hypertension) was significantly and positively related to diabetes/impaired fasting glucose among both boys and girls. CONCLUSIONS: Impaired fasting glucose was prevalent among urban university applicants, in particular boys and those of high socio-economic status in eastern China. Elevated levels of liver function enzyme appear to be the strongest risk factor for diabetes/impaired fasting glucose. PMID- 24766086 TI - Gene expression in closely related species mirrors local adaptation: consequences for responses to a warming world. AB - Local adaptation of populations could preclude or slow range expansions in response to changing climate, particularly when dispersal is limited. To investigate the differential responses of populations to changing climatic conditions, we exposed poleward peripheral and central populations of two Lepidoptera to reciprocal, common-garden climatic conditions and compared their whole-transcriptome expression. We found evidence of simple population differentiation in both species, and in the species with previously identified population structure and phenotypic local adaptation, we found several hundred genes that responded in a synchronized and localized fashion. These genes were primarily involved in energy metabolism and oxidative stress, and expression levels were most divergent between populations in the same environment in which we previously detected divergence for metabolism. We found no localized genes in the species with less population structure and for which no local adaptation was previously detected. These results challenge the assumption that species are functionally similar across their ranges and poleward peripheral populations are preadapted to warmer conditions. Rather, some taxa deserve population-level consideration when predicting the effects of climate change because they respond in genetically based, distinctive ways to changing conditions. PMID- 24766094 TI - An evaluation of inferential procedures for adaptive clinical trial designs with pre-specified rules for modifying the sample size. AB - Many papers have introduced adaptive clinical trial methods that allow modifications to the sample size based on interim estimates of treatment effect. There has been extensive commentary on type I error control and efficiency considerations, but little research on estimation after an adaptive hypothesis test. We evaluate the reliability and precision of different inferential procedures in the presence of an adaptive design with pre-specified rules for modifying the sampling plan. We extend group sequential orderings of the outcome space based on the stage at stopping, likelihood ratio statistic, and sample mean to the adaptive setting in order to compute median-unbiased point estimates, exact confidence intervals, and P-values uniformly distributed under the null hypothesis. The likelihood ratio ordering is found to average shorter confidence intervals and produce higher probabilities of P-values below important thresholds than alternative approaches. The bias adjusted mean demonstrates the lowest mean squared error among candidate point estimates. A conditional error-based approach in the literature has the benefit of being the only method that accommodates unplanned adaptations. We compare the performance of this and other methods in order to quantify the cost of failing to plan ahead in settings where adaptations could realistically be pre-specified at the design stage. We find the cost to be meaningful for all designs and treatment effects considered, and to be substantial for designs frequently proposed in the literature. PMID- 24766096 TI - Electroassisted codeposition of sol-gel derived silica nanocomposite directs the fabrication of coral-like nanostructured porous gold. AB - Herein, we report on a one-step coelectrodeposition method to form gold-silica nanocomposite materials from which high surface area nanostructured gold electrodes can be produced. The as-prepared Au-SiO2 films possess an interconnected three-dimensional porous framework with different silica-gold ratios depending on the deposition solutions and parameters. Chemical etching of the nanocomposite films using hydrofluoric acid resulted in the formation of nanostructured porous gold films with coral-like structures and pores in the nanometer range. The cross-linkage of the gold coral branches resulted in the generation of a porous framework. X-ray photoelectron spectroscopy confirms the complete removal of silica. Well-controlled surface area enhancement, film thickness, and morphology were achieved by manipulating the deposition parameters, such as potential, time, and gold ion and sol-gel monomer concentrations in the deposition solution. An enhancement in the surface area of the electrode up to 57 times relative to the geometric area has been achieved. The thickness of the as-prepared Au-SiO2 nanocomposite films is relatively high and varied from 8 to 15 MUm by varying the applied deposition potential while the thickness of the coral-like nanostructured porous gold films ranged from 0.22 to 2.25 MUm. A critical sol-gel monomer concentration (CSGC) was determined at which the deposited silica around the gold coral was able to stabilize the coral-like gold nanostructures, while below the CSGC, the coral-like gold nanostructures were unstable and the surface area of the nanostructured porous gold electrodes decreased. PMID- 24766097 TI - Carbapenemase genes and genetic platforms in Gram-negative bacilli: Enterobacteriaceae, Pseudomonas and Acinetobacter species. AB - The emergence and rapid spread of carbapenemases in Enterobacteriaceae, Pseudomonas and Acinetobacter (EPA) species is becoming a major public health crisis worldwide, and is responsible for large number of hospital-acquired and nosocomial infections. In this article, we review the current knowledge on the classification, phylogeny and genetic platforms of the main carbapenemases already described in Gram-negative bacteria. PMID- 24766095 TI - Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches. AB - INTRODUCTION: In the era of multidrug-resistant, extensively drug-resistant (XDR) and even pandrug-resistant Gram-negative microorganisms, the medical community is facing the threat of untreatable infections particularly those caused by carbapenemase-producing bacteria, that is, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii. Therefore, all the presently available antibiotics, as well as for the near future compounds, are presented and discussed. AREAS COVERED: Current knowledge concerning mechanisms of action, in vitro activity and interactions, pharmacokinetic/pharmacodynamics, clinical efficacy and toxicity issues for revived and novel antimicrobial agents overcoming current resistance mechanisms, including colistin, tigecycline, fosfomycin, temocillin, carbapenems, and antibiotics still under development for the near future such as plazomicin, eravacycline and carbapenemase inhibitors is discussed. EXPERT OPINION: Colistin is active in vitro and effective in vivo against XDR carbapenemase-producing microorganisms in the critically ill host, whereas tigecycline, with the exception of P. aeruginosa, has a similar spectrum of activity. The efficacy of combination therapy in bacteremias and ventilator associated pneumonia caused by K. pneumoniae carbapenemase producers seems to be obligatory, whereas in cases of P. aeruginosa and A. baumannii its efficacy is questionable. Fosfomycin, which is active against P. aeruginosa and K. pneumoniae, although promising, shares poor experience in XDR infections. The in vivo validity of the newer potent compounds still necessitates the evaluation of Phase III clinical trials particularly in XDR infections. PMID- 24766098 TI - Kinetics and molecular docking studies of the inhibitions of angiotensin converting enzyme and renin activities by hemp seed (Cannabis sativa L.) peptides. AB - Four novel peptide sequences (WVYY, WYT, SVYT, and IPAGV) identified from an enzymatic digest of hemp seed proteins were used for enzyme inhibition kinetics and molecular docking studies. Results showed that WVYY (IC50 = 0.027 mM) was a more potent (p < 0.05) ACE-inhibitory peptide than WYT (IC50 = 0.574 mM). However, WYT (IC50 = 0.054 mM) and SVYT (IC50 = 0.063 mM) had similar renin inhibitory activity, which was significantly better than that of IPAGV (IC50 = 0.093 mM). Kinetics studies showed that WVYY had a lower inhibition constant (Ki) of 0.06 mM and hence greater affinity for ACE when compared to the 1.83 mM obtained for WYT. SVYT had lowest Ki value of 0.89 mM against renin, when compared to the values obtained for WYT and IPAGV. Molecular docking results showed that the higher inhibitory activities of WVYY and SVYT were due to the greater degree of noncovalent bond-based interactions with the enzyme protein, especially formation of higher numbers of hydrogen bonds with active site residues. PMID- 24766099 TI - Biological significance of the importin-beta family-dependent nucleocytoplasmic transport pathways. AB - Importin-beta family proteins (Imp-betas) are nucleocytoplasmic transport receptors (NTRs) that import and export proteins and RNAs through the nuclear pores. The family consists of 14-20 members depending on the biological species, and each member transports a specific group of cargoes. Thus, the Imp-betas mediate multiple, parallel transport pathways that can be regulated separately. In fact, the spatiotemporally differential expressions and the functional regulations of Imp-betas have been reported. Additionally, the biological significance of each pathway has been characterized by linking the function of a member of Imp-betas to a cellular consequence. Connecting these concepts, the regulation of the transport pathways conceivably induces alterations in the cellular physiological states. However, few studies have linked the regulation of an importin-beta family NTR to an induced cellular response and the corresponding cargoes, despite the significance of this linkage in comprehending the biological relevance of the transport pathways. This review of recent reports on the regulation and biological functions of the Imp-betas highlights the significance of the transport pathways in physiological contexts and points out the possibility that the identification of yet unknown specific cargoes will reinforce the importance of transport regulation. PMID- 24766100 TI - Rasch analysis of the Italian version of fear avoidance beliefs questionnaire (FABQ-I). AB - PURPOSE: To perform a Rasch analysis (RA) of the Fear Avoidance Beliefs questionnaire (FABQ-I) in a sample of chronic non-specific low back pain (CLBP) patients. The RA is expected to provide information about the internal construct validity and all the single items consistency of the FABQ-I and then contributing to the knowledge about the questionnaire's clinimetric properties. METHODS: One hundred and fifty subjects with CLBP were enrolled into the study. The FABQ-I have been studied by means of RA. The sample size needed to obtain stable person, item and rating-scale calibrations for use with the Rasch model was based on the level of error expected in the measure. RESULTS: RA did not support the total scale as an unidimensional measure of Fear Avodiance Beliefs. Also the analysis of the Physical Activity (PA) and Word (WO) subscales as well as the attempts of manipulation failed in achieving an acceptable fit to the Rasch model. CONCLUSION: FABQ-I may be considered to reflect a multiple psychological constructs describing scale. The raw score of the FABQ-I and changes in scores must be interpreted with caution because as a general measure of fear avoid beliefs was not supported. PMID- 24766101 TI - Generating political priority for newborn survival in three low-income countries. AB - Deaths to babies in their first 28 days of life now account for more than 40% of global under-5 child mortality. High neonatal mortality poses a significant barrier to achieving the child survival Millennium Development Goal. Surmounting the problem requires national-level political commitment, yet only a few nation states have prioritised this issue. We compare Bolivia, Malawi and Nepal, three low-income countries with high neonatal mortality, with a view to understanding why countries prioritise or neglect the issue. The three have had markedly different trajectories since 2000: attention grew steadily in Nepal, stagnated then grew in Malawi and grew then stagnated in Bolivia. The comparison suggests three implications for proponents seeking to advance attention to neglected health issues in low-income countries: the value of (1) advancing solutions with demonstrated efficacy in low-resource settings, (2) building on existing and emerging national priorities and (3) developing a strong network of domestic and international allies. Such actions help policy communities to weather political storms and take advantage of policy windows. PMID- 24766102 TI - Graphene earphones: entertainment for both humans and animals. AB - The human hearing range is from 20 Hz to 20 kHz. However, many animals can hear much higher sound frequencies. Dolphins, especially, have a hearing range up to 300 kHz. To our knowledge, there is no data of a reported wide-band sound frequency earphone to satisfy both humans and animals. Here, we show that graphene earphones, packaged into commercial earphone casings can play sounds ranging from 100 Hz to 50 kHz. By using a one-step laser scribing technology, wafer-scale flexible graphene earphones can be obtained in 25 min. Compared with a normal commercial earphone, the graphene earphone has a wider frequency response (100 Hz to 50 kHz) and a three times lower fluctuation (+/-10 dB). A nonlinear effect exists in the graphene-generated sound frequency spectrum. This effect could be explained by the DC bias added to the input sine waves which may induce higher harmonics. Our numerical calculations show that the sound frequency emitted by graphene could reach up to 1 MHz. In addition, we have demonstrated that a dog wearing a graphene earphone could also be trained and controlled by 35 kHz sound waves. Our results show that graphene could be widely used to produce earphones for both humans and animals. PMID- 24766103 TI - A novel device for hands-free positioning and adjustment of the surgical microscope. AB - The authors have developed a novel device, which they have named Mari, that allows hands-free utilization of the surgical microscope. The device is attached to the eyepieces of a multifunction counterweight-balanced surgical microscope and consists of a metallic holder with supportive plates that facilitate interaction between the device and surgeon's head. On the holder are installed 1) an electric switch, which allows the surgeon to release the microscope's magnetic clutches, allowing movement of the microscope along the x, y, and z axes as well as the rotational and diagonal ones, and 2) a joystick at the level of the surgeon's mouth for adjustment of focus and zoom. The authors report on the initial experience with the use of the device at the Burdenko Neurosurgery Institute, where the senior author used it in approximately 600 procedures between 2006 and 2012. The surgeries ranged in difficulty and in duration (from 20 minutes to 7 hours, median 2.5 hours). Use of the Mari device resulted in increased accuracy of the surgical manipulations and a reduction in the duration of surgery. PMID- 24766104 TI - Peripheral nerve fibromyxoid sarcoma. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue neoplasm with metastatic potential and needs to be recognized as such, because it can be mistaken for other types of sarcoma due to its unremarkable appearance. This 49 year-old man presented with an approximately 5-cm mass on the anteromedial aspect of his left thigh that slowly increased over 10 years. Clinical symptoms were limited to local discomfort and intermittent distal numbness. Due to the location, imaging findings, and lack of serious symptoms, the initial differential diagnosis favored a schwannoma. An initial biopsy revealed histopathological findings consistent with a perineurioma, although with atypical features. The patient elected to have the mass excised, and the tumor, which arose from a branch of the saphenous nerve, could be separated well from the surrounding soft tissue. Histopathological investigation of the mass displayed characteristic features of a fibromyxoid sarcoma, which was confirmed by subsequent fluorescence in situ hybridization analysis. Due to concerns about infiltration beyond the margins, radical reexcision was advocated and performed, resulting in definite clear surgical margins. At follow-up, the patient had regained full strength with no residual neurological symptoms or any new deficits. He has since been healthy and disease free for a total of 4 years in follow-up. This case documents, to the authors' knowledge, the first observation of an LGFMS associated with a peripheral nerve. It also supports the use of fluorescence in situ hybridization analysis as an essential diagnostic method in establishing the diagnosis of LGFMS. PMID- 24766105 TI - The effect of a calorie-restricted diet on weight gain in short-term psychiatric inpatients receiving atypical antipsychotic medications. AB - This study attempted to evaluate the effect of a calorie-restricted diet on weight change in short-term acute care psychiatric patients receiving atypical antipsychotic medication. A descriptive correlational design utilizing chart review and a convenience sample of 100 participants was used. Fifty charts of patients hospitalized prior to the implementation of the calorie-restricted diet for those receiving atypical antipsychotic agents were compared to 50 charts of patients who received the diet. Weight changes in the two groups were compared relative to age, gender, length of time taking the medication, and the type of medication. The Mann-Whitney U test, Spearman's rank-correlation coefficient, and the two-way analysis of variance were used to conduct the analyses. The calorie restricted diet was not significantly associated with a reduction in weight gain in participants who received any of the atypical antipsychotic agents except for olanzapine; therefore, findings indicate that the calorie-restricted diet may only be effective for patients receiving olanzapine. PMID- 24766106 TI - ADHD Subtype Differences in Reinforcement Sensitivity and Visuospatial Working Memory. AB - Both cognitive and motivational deficits are thought to give rise to the problems in the combined (ADHD-C) and inattentive subtype (ADHD-I) of attention-deficit hyperactivity disorder (ADHD). In both subtypes one of the most prominent cognitive weaknesses appears to be in visuospatial working memory (WM), which is composed of short-term memory (STM) and a central executive (CE). In children with ADHD-C, both STM and the CE seem impaired, and together with motivational impairments, give rise to their deficits in visuospatial WM. In children with ADHD-I, no studies investigated these WM components and their interplay with motivational impairments. Effects of a standard (feedback only) and a high level of reinforcement (feedback + 10 euros) on visuospatial WM-, STM-, and CE performance were examined in 27 children with ADHD-I (restrictive-subtype), 70 children with ADHD-C, and 40 typically developing controls (aged 9-12). In both ADHD-subtypes CE and WM performance was worse than in controls. STM performance of children with ADHD-I was, in contrast to that of children with ADHD-C, not different from controls. STM and WM performance was worse in ADHD-C than in ADHD I, whereas CE-related performance did not differ. High reinforcement improved STM and WM performance in both subtypes but not in controls. This improvement was equally pronounced in both subtypes. High reinforcement did not improve CE related performance. Both subtypes have equally pronounced motivational deficits, which have detrimental effects on their visuospatial STM and WM performance. In contrast to children with ADHD-C, children with ADHD-I seem unimpaired on visuospatial STM; only an impaired CE and motivational impairments give rise to their deficits in visuospatial WM. PMID- 24766107 TI - Competition for hummingbird pollination shapes flower color variation in Andean solanaceae. AB - One classic explanation for the remarkable diversity of flower colors across angiosperms involves evolutionary shifts among different types of pollinators with different color preferences. However, the pollinator shift model fails to account for the many examples of color variation within clades that share the same pollination system. An alternate explanation is the competition model, which suggests that color divergence evolves in response to interspecific competition for pollinators, as a means to decrease interspecific pollinator movements. This model predicts color overdispersion within communities relative to null assemblages. Here, we combine morphometric analyses, field surveys, and models of pollinator vision with a species-level phylogeny to test the competition model in the primarily hummingbird-pollinated clade Iochrominae (Solanaceae). Results show that flower color as perceived by pollinators is significantly overdispersed within sites. This pattern is not simply due to phylogenetic history: phylogenetic community structure does not deviate from random expectations, and flower color lacks phylogenetic signal. Moreover, taxa that occur in sympatry occupy a significantly larger volume of color space than those in allopatry, supporting the hypothesis that competition in sympatry drove the evolution of novel colors. We suggest that competition among close relatives may commonly underlie floral divergence, especially in species-rich habitats where congeners frequently co-occur. PMID- 24766108 TI - Deep healing: ritual healing in the teshuvah movement. AB - Based on an ethnographic analysis of religious healing rituals in Israel, this paper addresses the question of how healer-client relations are structured on these rituals. An examination of what takes place at the rallies held by Rabbi Amnon Yitzhak indicates that, apart from the regular blessings, which can be referred to as ordinary healing, there are some ritual events that can be referred to as 'deep healing'. The current paper demonstrates how deep healing rituals are generally conducted in severe cases through give-and-take between the rabbi and the person upon whom the blessing is bestowed, and that they are linked to relationships between people and the ethic of mutual support. PMID- 24766109 TI - Ethical conditions for transnational gestational surrogacy in Asia. PMID- 24766110 TI - Fostering IRB collaboration for review of international research. AB - This article presents a review of the literature, summarizes current initiatives, and provides a heuristic for assessing the effectiveness of a range of institutional review board (IRB) collaborative strategies that can reduce the regulatory burden of ethics review while ensuring protection of human subjects, with a particular focus on international research. Broad adoption of IRB collaborative strategies will reduce regulatory burdens posed by overlapping oversight mechanisms and has the potential to enhance human subjects protections. PMID- 24766111 TI - Building global inter-IRB trust: A cultural immersion challenge. PMID- 24766112 TI - Streamlining review by accepting equivalence. PMID- 24766113 TI - Existing tools to facilitate international research. PMID- 24766114 TI - One size that could fit all: IRBs joint review collaboration as the key to addressing the challenges of multinational research review involving resource poor countries. PMID- 24766115 TI - "Because it was hard ...": Some lessons developing a joint IRB between Moi University (Kenya) and Indiana University (USA). PMID- 24766116 TI - Glocal bioethics: When international IRB collaboration confronts local politics. PMID- 24766117 TI - Transnational gestational surrogacy: does it have to be exploitative? AB - This article explores the controversial practice of transnational gestational surrogacy and poses a provocative question: Does it have to be exploitative? Various existing models of exploitation are considered and a novel exploitation evaluation heuristic is introduced to assist in the analysis of the potentially exploitative dimensions/elements of complex health-related practices. On the basis of application of the heuristic, I conclude that transnational gestational surrogacy, as currently practiced in low-income country settings (such as rural, western India), is exploitative of surrogate women. Arising out of consideration of the heuristic's exploitation conditions, a set of public education and enabled choice, enhanced protections, and empowerment reforms to transnational gestational surrogacy practice is proposed that, if incorporated into a national regulatory framework and actualized within a low income country, could possibly render such practice nonexploitative. PMID- 24766118 TI - Transnational gestational surrogacy: exploitative or empowering? PMID- 24766119 TI - Maternal-fetal cell transfer in surrogacy: ties that bind. PMID- 24766120 TI - The legacy of patriarchy as context for surrogacy: or why are we quibbling over this? PMID- 24766121 TI - Too blunt a tool: a case for subsuming analyses of exploitation in transnational gestational surrogacy under a justice or human rights framework. PMID- 24766122 TI - Gestational surrogates in rural India: a lot to offer and even more to lose. PMID- 24766123 TI - High-income countries' corresponding obligation not to exploit non-nationals. PMID- 24766124 TI - Cultural influences on transnational gestational surrogacy. PMID- 24766125 TI - Transnational surrogacy and the justice condition of nonexploitation. PMID- 24766126 TI - Context matters! Why terms of transaction as well as autonomy should be analyzed in the context of low-income countries. PMID- 24766127 TI - Engaging with a peer-proposed, additional exploitation condition: response to open peer commentaries on "transnational gestational surrogacy: does it have to be exploitative?". PMID- 24766128 TI - Sulfone-mediated syntheses of crocetin derivatives: regioselectivity of highly functionalized building blocks. AB - New C5 sulfone building blocks containing a masked polar end group have been devised for the efficient synthesis of carotenoids with polar termini. Chemoselectivity or the regiochemical issue of the highly functionalized units has been carefully addressed depending on the soft or hard nature of electrophiles. These building blocks have been successfully applied to the syntheses of crocetin derivatives, crocetin dial and the novel crocetin dinitrile. PMID- 24766129 TI - DNA mimic proteins: functions, structures, and bioinformatic analysis. AB - DNA mimic proteins have DNA-like negative surface charge distributions, and they function by occupying the DNA binding sites of DNA binding proteins to prevent these sites from being accessed by DNA. DNA mimic proteins control the activities of a variety of DNA binding proteins and are involved in a wide range of cellular mechanisms such as chromatin assembly, DNA repair, transcription regulation, and gene recombination. However, the sequences and structures of DNA mimic proteins are diverse, making them difficult to predict by bioinformatic search. To date, only a few DNA mimic proteins have been reported. These DNA mimics were not found by searching for functional motifs in their sequences but were revealed only by structural analysis of their charge distribution. This review highlights the biological roles and structures of 16 reported DNA mimic proteins. We also discuss approaches that might be used to discover new DNA mimic proteins. PMID- 24766130 TI - Neuroactive steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients. AB - Neuroactive steroid family includes molecules synthesized in peripheral glands (i.e., hormonal steroids) and directly in the nervous system (i.e., neurosteroids) which are key regulators of the nervous function. As already reported in clinical and experimental studies, neurodegenerative diseases affect the levels of neuroactive steroids. However, a careful analysis comparing the levels of these molecules in cerebrospinal fluid (CSF) and in plasma of multiple sclerosis (MS) patients is still missing. To this aim, the levels of neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in CSF and plasma of male adults affected by Relapsing-Remitting MS and compared with those collected in control patients. An increase in pregnenolone and isopregnanolone levels associated with a decrease in progesterone metabolites, dihydroprogesterone, and tetrahydroprogesterone was observed in CSF of MS patients. Moreover, an increase of 5alpha-androstane-3alpha,17beta-diol and of 17beta-estradiol levels associated with a decrease of dihydrotestosterone also occurred. In plasma, an increase in pregnenolone, progesterone, and dihydrotestosterone and a decrease in dihydroprogesterone and tetrahydroprogesterone levels were reported. This study shows for the first time that the levels of several neuroactive steroids, and particularly those of progesterone and testosterone metabolites, are deeply affected in CSF of relapsing-remitting MS male patients. We here demonstrated that, the cerebrospinal fluid and plasma levels of several neuroactive steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis. PMID- 24766132 TI - Osstell Resonance Frequency Measurement Values as a Prognostic Factor in Implant Dentistry. AB - Resonance frequency analysis (RFA) using the Osstell device (Osstell AB, Gothenburg, Sweden) has been advocated for quantifying implant stability on a relative scale of implant stability quotients (ISQ). It was the goal of this prospective clinical study to evaluate whether a certain ISQ level, at the time an implant is placed, correlates with successful osseointegration as some have claimed. Four hundred ninety-five implants (Straumann AG, Basel, Switzerland), varying in length and diameter, were placed in a private practice, strictly adhering to the implant manufacturer's surgical protocol. After placement and after healing periods of 42 days in the mandible and 56 days (implant manufacturer's protocol) in the maxilla, implant stability was measured using RFA. After healing, implants were torqued forward at 35 Ncm and allowed to heal further if the patients felt discomfort. Statistical analysis of the data obtained was based on Welch tests and Kolmogorov-Smirnow tests (level of significance alpha = 0.05). Results showed that 432 implants were osseointegrated after the predefined healing periods while 8 implants were lost and, in 55 cases, healing was prolonged. Both at insertion (P = .025) and after healing (P < .001), successful implants showed significantly different ISQ values as compared to implant failures or implants with prolonged healing. However, overlapping ISQ distributions at implant insertion demonstrated that there was no correlation among the data that could be used to predict successful osseointegration. Within the limits of this study, the prognostic value of ISQ values appears to be ambiguous. PMID- 24766133 TI - Heme oxygenase-1 as a target for the design of gene and pharmaceutical therapies for autoimmune diseases. AB - One of the major goals in the research of autoimmune diseases is to develop specific therapies to regulate the expression and function of gene products that could contribute to restoring tolerance to self-constituents and replace conventional systemic immunosuppression, which is associated with important undesired side effects. Although significant progress has been made on the understanding of the pathogenesis of autoimmunity, therapies for these ailments have not seen a change. During the last decade, different strategies such as pharmacologic or gene therapy modulation of heme oxygenase-1 (HO-1) and the administration of its metabolic product, carbon monoxide (CO), have been shown to display beneficial immunoregulatory and cytoprotective properties. In different experimental autoimmune conditions, such as Experimental autoimmune encephalomyelitis, type-1 diabetes and systemic lupus erythematosus, genetic or pharmacological modulation of HO-1, as well as delivery of CO have shown to ameliorate disease progression. Furthermore, it has been demonstrated that dendritic cell and monocyte function can be modulated by HO-1 and/or CO. In this article, recent data related to the immunoregulatory properties of HO-1/CO will be discussed, focusing on their potential therapeutic use to treat autoimmune diseases. PMID- 24766131 TI - Surprising base pairing and structural properties of 2'-trifluoromethylthio modified ribonucleic acids. AB - The chemical synthesis of ribonucleic acids (RNA) with novel chemical modifications is largely driven by the motivation to identify eligible functional probes for the various applications in life sciences. To this end, we have a strong focus on the development of novel fluorinated RNA derivatives that are powerful in NMR spectroscopic analysis of RNA folding and RNA ligand interactions. Here, we report on the synthesis of 2'-SCF3 pyrimidine nucleoside containing oligoribonucleotides and the comprehensive investigation of their structure and base pairing properties. While this modification has a modest impact on thermodynamic stability when it resides in single-stranded regions, it was found to be destabilizing to a surprisingly high extent when located in double helical regions. Our NMR spectroscopic investigations on short single stranded RNA revealed a strong preference for C2'-endo conformation of the 2' SCF3 ribose unit. Together with a recent computational study (L. Li, J. W. Szostak, J. Am. Chem. Soc. 2014, 136, 2858-2865) that estimated the extent of destabilization caused by a single C2'-endo nucleotide within a native RNA duplex to amount to 6 kcal mol(-1) because of disruption of the planar base pair structure, these findings support the notion that the intrinsic preference for C2'-endo conformation of 2'-SCF3 nucleosides is most likely responsible for the pronounced destabilization of double helices. Importantly, we were able to crystallize 2'-SCF3 modified RNAs and solved their X-ray structures at atomic resolution. Interestingly, the 2'-SCF3 containing nucleosides that were engaged in distinct mismatch arrangements, but also in a standard Watson-Crick base pair, adopted the same C3'-endo ribose conformations as observed in the structure of the unmodified RNA. Likely, strong crystal packing interactions account for this observation. In all structures, the fluorine atoms made surprisingly close contacts to the oxygen atoms of the corresponding pyrimidine nucleobase (O2), and the 2'-SCF3 moieties participated in defined water-bridged hydrogen-bonding networks in the minor groove. All these features allow a rationalization of the structural determinants of the 2'-SCF3 nucleoside modification and correlate them to base pairing properties. PMID- 24766134 TI - A suicide gene therapy combining the improvement of cyclophosphamide tumor cytotoxicity and the development of an anti-tumor immune response. AB - Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6/E7 oncoproteins. In mice bearing tumors composed only of TC1 CYP2B6TM-RED cells, four CPA injections (140 mg/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1 CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8(+)T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans. PMID- 24766135 TI - Progress of in vivo electroporation in the rodent brain. AB - In vivo electroporation is one of the most efficient methods for introducing the nucleic acids into the target tissues, and thus plays a pivotal role in gene therapeutic studies. In vivo electroporation in rodent brains is often involved in injection of nucleic acids into the brain ventricle or specific area and then applying appropriate electrical field to the correct area. Better understanding of the progress of electroporation in rodent brain may further facilitate gene therapeutic studies on some brain disorders. For this purpose, we briefly summarized the advantages, the procedures and recent progress of transferring nucleic acids into the rodent brain using in vivo electroporation. PMID- 24766137 TI - Pd nanoparticles in dendrimers immobilized on silica-polyamine composites as catalysts for selective hydrogenation. AB - New heterogeneous hydrogenation catalysts, based on Pd nanoparticles and polypropyleneimine (PPI) dendrimers of the third generation that have been covalently grafted to a silica surface modified with polyallylamine (PAA) have been synthesized. The final products were characterized by TEM, XPS, and solid state NMR spectroscopy. The synthesized materials are effective catalysts for selective hydrogenation of dienes to monoenes and phenyl acetylene to styrene at very high substrate/Pd ratios with turnover rates higher than related Pd nanoparticle catalysts. The synthesized catalysts can be reused without any loss of activity in the case of styrene and isoprene. PMID- 24766136 TI - Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte. AB - The complex spatial and paracrine relationships between the various liver histotypes are essential for proper functioning of the hepatic parenchymal cells. Only within a correct tissue organization, in fact, they stably maintain their identity and differentiated phenotype. The loss of histotype identity, which invariably occurs in the primary hepatocytes in culture, or in vivo in particular pathological conditions (fibrosis and tumours), is mainly because of the phenomenon of epithelial-to-mesenchymal transition (EMT). The EMT process, that occurs in the many epithelial cells, appears to be driven by a number of general, non-tissue-specific, master transcriptional regulators. The reverse process, the mesenchymal-to-epithelial transition (MET), as yet much less characterized at a molecular level, restores specific epithelial identities, and thus must include tissue-specific master elements. In this review, we will summarize the so far unveiled events of EMT/MET occurring in liver cells. In particular, we will focus on hepatocyte and describe the pivotal role in the control of EMT/MET dynamics exerted by a tissue-specific molecular mini-circuitry. Recent evidence, indeed, highlighted as two transcriptional factors, the master gene of EMT Snail, and the master gene of hepatocyte differentiation HNF4alpha, exhorting a direct reciprocal repression, act as pivotal elements in determining opposite cellular outcomes. The different balances between these two master regulators, further integrated by specific microRNAs, in fact, were found responsible for the EMT/METs dynamics as well as for the preservation of both hepatocyte and stem/precursor cells identity and differentiation. Overall, these findings impact the maintenance of stem cells and differentiated cells both in in vivo EMT/MET physio-pathological processes as well as in culture. PMID- 24766138 TI - Role of paraventricular nucleus-projecting norepinephrine/epinephrine neurons in acute and chronic stress. AB - Chronic variable stress (CVS) exposure modifies the paraventricular nucleus of the hypothalamus (PVN) in a manner consistent with enhanced central drive of the hypothalamo-pituitary-adrenocortical (HPA) axis. As previous reports suggest that post-stress enhancement of norepinephrine (NE) action contributes to chronic stress regulation at the level of the PVN, we hypothesised that PVN-projecting NE neurons were necessary for the stress facilitatory effects of CVS. Following intra-PVN injection of saporin toxin conjugated to a dopamine beta-hydroxylase (DBH) antibody (DSAP), in rats PVN DBH immunoreactivity was almost completely eliminated, but immunoreactive afferents to other key regions involved in stress integration were spared (e.g. DBH fiber densities were unaffected in the central nucleus of the amygdala). Reductions in DBH-positive fiber density were associated with reduced numbers of DBH-immunoreactive neurons in the nucleus of the solitary tract and locus coeruleus. Following 2 weeks of CVS, DSAP injection did not alter stress-induced adrenal hypertrophy or attenuation of body weight gain, indicating that PVN-projecting NE [and epinephrine (E)] neurons are not essential for these physiological effects of chronic stress. In response to acute restraint stress, PVN-targeted DSAP injection attenuated peak adrenocorticotrophic hormone (ACTH) and corticosterone in controls, but only attenuated peak ACTH in CVS animals, suggesting that enhanced adrenal sensitivity compensated for reduced excitatory drive of the PVN. Our data suggest that PVN projecting NE/E neurons contribute to the generation of acute stress responses, and are required for HPA axis drive (ACTH release) during chronic stress. However, loss of NE/E drive at the PVN appears to be buffered by compensation at the level of the adrenal. PMID- 24766139 TI - A pathway EM-algorithm for estimating vaccine efficacy with a non-monotone validation set. AB - Here, we consider time-to-event data where individuals can experience two or more types of events that are not distinguishable from one another without further confirmation, perhaps by laboratory test. The event type of primary interest can occur only once. The other types of events can recur. If the type of a portion of the events is identified, this forms a validation set. However, even if a random sample of events are tested, confirmations can be missing nonmonotonically, creating uncertainty about whether an individual is still at risk for the event of interest. For example, in a study to estimate efficacy of an influenza vaccine, an individual may experience a sequence of symptomatic respiratory illnesses caused by various pathogens over the season. Often only a limited number of these episodes are confirmed in the laboratory to be influenza-related or not. We propose two novel methods to estimate covariate effects in this survival setting, and subsequently vaccine efficacy. The first is a pathway expectation-maximization (EM) algorithm that takes into account all pathways of event types in an individual compatible with that individual's test outcomes. The pathway EM iteratively estimates baseline hazards that are used to weight possible event types. The second method is a non-iterative pathway piecewise validation method that does not estimate the baseline hazards. These methods are compared with a previous simpler method. Simulation studies suggest mean squared error is lower in the efficacy estimates when the baseline hazards are estimated, especially at higher hazard rates. We use the pathway EM-algorithm to reevaluate the efficacy of a trivalent live-attenuated influenza vaccine during the 2003 2004 influenza season in Temple-Belton, Texas, and compare our results with a previously published analysis. PMID- 24766142 TI - Adsorption of sub-micron amphiphilic dumbbells to fluid interfaces. AB - We investigate the adsorption of submicrometer bulk-synthesized polymer dumbbells to oil-water interfaces using freeze-fracture, shadow-casting (FreSCa) cryo scanning electron microscopy. We find that the dumbbells are amphiphilic and adsorb to the interface with a preferred orientation. Most particles adsorb in a tilted configuration, with the polar and apolar lobes intersecting the interface and pointing toward the water and oil, respectively. Some particles adsorb with only one lobe attached to the interface. Moreover, we find that each lobe has a preferred angle of contact with the interface, identical in all observed configurations. A simple geometrical calculation using these contact angles accurately predicts the dominant configuration of particles at the interface. This calculation provides insight into how the shape and composition of dumbbells can be tuned to stand upright and pack efficiently on curved interfaces. PMID- 24766143 TI - The psychosocial impact associated with diabetes-related amputation. AB - AIMS: Research has suggested that the additional impact of a diabetes-related amputation is associated with poorer physical functioning, poorer psychosocial outcome and greater body image disturbance. However, no study to date has compared patients with diabetes with and without amputation and adequately controlled for additional medical morbidity often found among individuals with an amputation. The aim of this study was to statistically control for any group differences on medical and demographic variables to examine the isolated psychosocial impact of diabetes-related amputation. METHODS: Individuals with diabetes with an amputation (n = 50) were compared to a control sample (individuals with diabetes without an amputation; n = 240). All participants completed a demographic and medical questionnaire, as well as measures of psychological distress, quality of life and body image. RESULTS: The results indicated that, in univariate analyses, depression, physical quality of life and body image disturbance were all poorer in the amputee group. These differences remained for body image disturbance (P = 0.005), but were no longer significant for depression or physical quality of life in multivariate analyses controlling for important demographic and medical variables. CONCLUSIONS: The present study found that the impact of diabetes-related amputation was significant for body image disturbance. However, it appears that other psychosocial outcomes are better accounted for by medical co-morbidities common in this group rather than the amputation itself. This research certainly highlights that clinicians must assess for and address all potential medical contributors to psychosocial outcomes, rather than assuming that people will experience poorer outcomes following amputation. PMID- 24766140 TI - Incretin-modulated beta cell energetics in intact islets of Langerhans. AB - Incretins such as glucagon-like peptide 1 (GLP-1) are released from the gut and potentiate insulin release in a glucose-dependent manner. Although this action is generally believed to hinge on cAMP and protein kinase A signaling, up-regulated beta cell intermediary metabolism may also play a role in incretin-stimulated insulin secretion. By employing recombinant probes to image ATP dynamically in situ within intact mouse and human islets, we sought to clarify the role of GLP-1 modulated energetics in beta cell function. Using these techniques, we show that GLP-1 engages a metabolically coupled subnetwork of beta cells to increase cytosolic ATP levels, an action independent of prevailing energy status. We further demonstrate that the effects of GLP-1 are accompanied by alterations in the mitochondrial inner membrane potential and, at elevated glucose concentration, depend upon GLP-1 receptor-directed calcium influx through voltage dependent calcium channels. Lastly, and highlighting critical species differences, beta cells within mouse but not human islets respond coordinately to incretin stimulation. Together, these findings suggest that GLP-1 alters beta cell intermediary metabolism to influence ATP dynamics in a species-specific manner, and this may contribute to divergent regulation of the incretin-axis in rodents and man. PMID- 24766141 TI - Minireview: new molecular mediators of glucocorticoid receptor activity in metabolic tissues. AB - The glucocorticoid receptor (GR) was one of the first nuclear hormone receptors cloned and represents one of the most effective drug targets available today for the treatment of severe inflammation. The physiologic consequences of endogenous or exogenous glucocorticoid excess are well established and include hyperglycemia, insulin resistance, fatty liver, obesity, and muscle wasting. However, at the molecular and tissue-specific level, there are still many unknown protein mediators of glucocorticoid response and thus, much remains to be uncovered that will help determine whether activation of the GR can be tailored to improve therapeutic efficacy while minimizing unwanted side effects. This review summarizes recent discoveries of tissue-selective modulators of glucocorticoid signaling that are important in mediating the unwanted side effects of therapeutic glucocorticoid use, emphasizing the downstream molecular effects of GR activation in the liver, adipose tissue, muscle, and pancreas. PMID- 24766144 TI - Digit ratio (2D:4D) as an indicator of body size, testosterone concentration and number of children in human males. AB - OBJECTIVES: The 2nd to 4th digit ratio (2D:4D) is thought to reflect exposure to androgens during foetal development. This study examined the relationship between low (more masculine) and high (more feminine) 2D:4D and body size at different stages of the life course, adult testosterone levels and number of children among males. METHODS: Five hundred and fifty-eight men from rural Poland at the Mogielica Human Ecology Study Site participated in this study. Life history data and anthropometric measurements were collected. Salivary morning and evening testosterone levels among 110 men from the same population were measured. RESULTS: Low 2D:4D was related to higher birth weight (p = 0.04), higher birth length (p = 0.01), higher body mass during childhood and adolescence (p = 0.01), higher BMI (borderline significance, p = 0.06), higher number of children among fathers (p = 0.04) and higher testosterone levels during adulthood (p = 0.04). CONCLUSIONS: This study shows, for the first time in a single population, that digit ratio is related to sub-adult body size at different stages of the life course, adult testosterone levels and number of children. The observed results suggest that digit ratio might be a valuable predictor of male body size and reproductive characteristics. PMID- 24766145 TI - An updated review of antidepressants with marked serotonergic effects in obsessive-compulsive disorder. AB - INTRODUCTION: Since the recognition of the effectiveness of clomipramine in treating obsessive-compulsive disorder (OCD), a number of recent empirical studies have confirmed a key role of the serotonergic (5-HT) system in the pathophysiology of OCD. The current study presents a review of the existing double-blind studies testing 5-HT antidepressants in OCD. AREAS COVERED: A systematic review was performed to identify double-blind, placebo-controlled, randomized clinical trials investigating the efficacy of antidepressants with marked 5-HT effects [clomipramine, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine and vilazodone] in the short-term treatment of OCD. The search provided 29 studies investigating eight different 5-HT antidepressants. While the findings show reliable efficacy of clomipramine and SSRIs in the treatment of OCD symptoms, no double-blind studies were identified investigating the efficacy of desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine or vilazodone. EXPERT OPINION: While our results support the effectiveness of older antidepressants with marked 5-HT effects in OCD, it also suggests that newer agents should be tested more comprehensively. PMID- 24766147 TI - Antioxidant activity and delayed aging effects of hot water extract from Chamaecyparis obtusa var. formosana leaves. AB - The antioxidant activity and delayed aging effects of hot water extracts from leaves of Chamaecyparis obtusa var. formosana were investigated. Free radical, superoxide radical scavenging, and total phenolic content assays were employed to evaluate the in vitro activities of the extracts. In addition, in vivo assays using the nematode Caenorhabditis elegans were also performed in this study. The results showed that among all soluble fractions obtained from the extracts, the ethyl acetate-soluble fraction has the best in vitro and in vivo antioxidant activities. Moreover, it decreased significantly the deposition of lipofuscin (aging pigment) and extended the lifespan of C. elegans. Bioactivity-guided fractionation yielded six potent antioxidant constituents from the ethyl acetate soluble fraction, namely, catechin, quercetin, quercetin-3-O-alpha rhamnoyranoside, myricetin-3-O-alpha-rhamnoyranoside, vanillic acid, and 4 hydroxybenzoic acid. Quercetin-3-O-alpha-rhamnoyranoside pretreatment showed the highest survival of C. elegans upon juglone exposure. Taken together, the results revealed that hot water extracts from C. obtusa var. formosana leaves have the potential to be used as a source for antioxidant or delayed aging health food. PMID- 24766146 TI - Conformational adaptation in the E. coli sigma 32 protein in response to heat shock. AB - E. coli, like other organisms, responds to heat shock by rapidly up-regulating several proteins, including chaperones. The heat-shock sigma factor, sigma 32 (sigma(32)), a transcription factor, plays a pivotal role in this response. The level of sigma(32) is normally kept low through a DnaK/J mediated degradation. Elevated temperature rapidly increases the sigma(32) level and initiates a heat shock response. A plausible way for the up-regulation of free sigma(32) levels would be to destabilize the sigma(32):DnaK:DnaJ complex initiated via a conformational change in sigma(32) structure at elevated temperatures. In this study, we have modeled the E. coli sigma(32) structure by homology modeling and conducted extensive molecular dynamics (MD) simulations at non-heat-shock (30 degrees C) and heat-shock (42 degrees C) temperatures. Substantial structural rearrangements at 42 degrees C were observed around the N-terminus (residues 11 60, which cover the DnaJ binding region) and the region spanning residues 190-210 (covering the DnaK binding site, residues 198-201). At 42 degrees C, a large amount of helix melting and structural destabilization was observed around residues 11-60, while regions 91-101 and 216-221 of sigma(32) undergo conformational change, leading to formation of a lid-like structure over region 198-VLYL-201 resulting in reduced accessibility of the DnaK binding sites. These temperature induced melting and fluctuations observed around the DnaJ and/or DnaK binding regions suggest reduction of DnaK/DnaJ affinity for sigma(32) at 42 degrees C, which is further supported by our molecular docking analysis. Emission maxima of environment sensitive fluorescence probes inserted at several cysteine mutants of sigma(32) protein at 30 and 42 degrees C are also supportive of the structural changes observed in the molecular dynamics study. PMID- 24766148 TI - Unique blood culture for diagnosis of bloodstream infections in emergency departments: a prospective multicentre study. AB - Detection of microorganisms by blood cultures (BCs) is essential in managing patients with bacteraemia. Rather than the number of punctures, the volume of blood drawn is considered paramount in efficient and reliable detection of microorganisms. We performed a 1-year prospective multicentre study in adult emergency departments of three French university hospitals comparing two methods for BCs: a unique blood culture (UBC) collecting a large volume of blood (40 mL) and the standard method of multiple blood cultures (MBC). The performances of both methods for bacterial contamination and efficient microbial detection were compared, each patient serving as his own control. Amongst the 2314 patients included, three hundred were positive for pathogens (n=245) or contaminants (n=55). Out of the 245 patients, 11 were positive for pathogens by UBC but negative by MBC and seven negative by UBC but positive by MBC (p 0.480). In the subgroup of 137 patients with only two BCs, UBC was superior to MBC (p 0.044). Seven and 17 patients had contaminated BCs by UBC and MBC only, respectively (p 0.062). Considering the sums of pathogens missed and contaminants, UBC significantly outperformed MBC (p 0.045). Considering the complete picture of cost savings, efficient detection of microorganisms and decrease in contaminations, UBC offers an interesting alternative to MBC. PMID- 24766149 TI - Women's empowerment and its differential impact on health in low-income communities in Mumbai, India. AB - This paper examines the relationship of empowerment to women's self-reported general health status and women's self-reported health during pregnancy in low income communities in Mumbai. The data on which this paper is based were collected in three study communities located in a marginalised area of Mumbai. We draw on two data sources: in-depth qualitative interviews conducted with 66 married women and a survey sample of 260 married women. Our analysis shows that empowerment functions differently in relation to women's reproductive status. Non pregnant women with higher levels of empowerment experience greater general health problems, while pregnant women with higher levels of empowerment are less likely to experience pregnancy-related health problems. We explain this non intuitive finding and suggest that a globally defined empowerment measure for women may be less useful that one that is contextually and situationally defined. PMID- 24766150 TI - The performance quality rating scale (PQRS): reliability, convergent validity, and internal responsiveness for two scoring systems. AB - PURPOSE: The performance quality rating scale (PQRS) is an observational measure of performance quality of client-selected, personally meaningful activities. It has been used inconsistently with different scoring systems, and there have been no formal publications on its psychometric properties. The purpose of this study was to test and compare the psychometric properties of two PQRS scoring systems in two populations. METHODS: A secondary analysis of video recorded participant selected activities from previous studies involving either adults living with stroke or children diagnosed with developmental coordination disorder (DCD) was conducted. Three pairs of raters scored the video recorded performances with PQRS operational definitions (PQRS-OD) and a generic rating system (PQRS-G). RESULTS: For inter-rater reliability, PQRS-OD ICCs were substantial, ranging from 0.83 to 0.93; while the PQRS-G ICCs were moderate, ranging from 0.71 to 0.77. Test-retest reliability was substantial, >0.80 (ICC), for both rating systems across all rater pairs. Internal responsiveness was high for both rating systems. Convergent validity with the Canadian Occupational Performance Measure (COPM) was inconsistent, with scores ranging from low to moderate. CONCLUSION: Both scoring systems have demonstrated they are reliable and have good internal responsiveness. The PQRS-OD demonstrated greater consistency across raters and is more sensitive to clinically important change than the PQRS-G and should be used when greater accuracy is required. Further exploration of validity with actual rather than perceived performance measures is required. PMID- 24766151 TI - Framing disability among young adults with disabilities and non-disabled young adults: an exploratory study. AB - PURPOSE: To explore how young adults frame disability and to compare the meanings of disability between persons with and without disabilities. METHOD: Snow ball sampling was used to recruit the participants. The sample comprised of 14 young adults from Upstate New York area; nine were non-disabled, five had a physical disability. Data were collected by semi-structured interviews. Qualitative content analysis was used to analyze the data. RESULTS: Five themes emerged from the analysis: disability as a deviation from "the norm", disability as inability, disability as something one needs to overcome, the role of the environment in disability, and disability as a negative phenomenon. The findings suggest that persons with disabilities hold somewhat different meanings of disability compared with non-disabled persons. CONCLUSIONS: While the biomedical frame of disability was somewhat challenged, disability is mainly understood via a biomedical lens. Disability should be framed as form of human diversity, not as a mark of Cain. PMID- 24766152 TI - Comparison of not for resuscitation (NFR) forms across five Victorian health services. AB - BACKGROUND: Within Australian hospitals, cardiac and respiratory arrests result in a resuscitation attempt unless the patient is documented as not for resuscitation. AIM: To examine the consistency of policies and documentation for withholding in-hospital resuscitation across health services. METHOD: An observational, qualitative review of hospital policy and documentation was conducted in June 2013 in three public and two private sector hospitals in metropolitan Melbourne. Not for resuscitation (NFR) forms were evaluated for physical characteristics, content, authorisation and decision-making. Hospital policies were coded for alerts, definition of futility and burden of treatment and management of discussions and dissent. RESULTS: There was a lack of standardisation, with each site using its own unique NFR form and accompanying site-specific policies. Differences were found in who could authorise the decision, what was included on the form, the role of patients and families, and how discussions were managed and dissent resolved. Futility and burden of treatment were not defined independently. These inconsistencies across sites contribute to a lack of clarity regarding the decision to withhold resuscitation, and have implications for staff employed across multiple hospitals. CONCLUSIONS: NFR forms should be reviewed and standardised so as to be clear, uniform and consistent with the legislative framework. We propose a two-stage process of documentation. Stage 1 facilitates discussion of patient-specific goals of care and consideration of limitations of treatment. Stage 2 serves to communicate a NFR order. Decisions to withhold resuscitation are inherently complex but could be aided by separating the decision-making process from the communication of the decision, resulting in improved end-of-life care. PMID- 24766153 TI - Prevalence of 16S rRNA methylase, modifying enzyme, and extended-spectrum beta lactamase genes among Acinetobacter baumannii isolates. AB - Multidrug-resistant Acinetobacter baumannii has become a worldwide problem, and methylation of 16S rRNA has recently emerged as a new mechanism of resistance to aminoglycosides, which is mediated by a newly recognized group of 16S rRNA methylases. 16S rRNA methylase confers a high-level resistance to all 4,6 substituted deoxystreptamine aminoglycosides that are currently used in clinical practice. Some of the A. baumannii isolates have been found to coproduce extended spectrum beta-lactamases (ESBLs), contributing to their multidrug resistance. The aim of this study was to detect the determinants of the 16S rRNA methylase genes armA, rmtA, rmtB, rmtC, rmtD, rmtE, and npmA, the modifying enzyme genes aac(6') Ib, ant(3")-Ia, aph(3')-I, and the extended-spectrum beta-lactamase genes bla(TEM), bla(SHV), and bla(CTX-M-3) among A. baumannii isolates in northeastern Sichuan, China. Minimum inhibitory concentrations (MICs) of 21 different antimicrobial agents against the A. baumannii isolates were determined. The clinical isolates showed a high level of resistance (MIC?256 MUg/ml) to aminoglycosides, which ranged from 50.1 to 83.8%. The resistances to meropenem and imipenem, two of the beta-lactam antibiotics and the most active antibiotics against A. baumannii, were 9.1 and 8.2%, respectively. Among 60 amikacin resistant isolates, only the 16S rRNA methylase gene armA was found to be prevalent (66.7%), but the other 16S rRNA methylase genes rmtA, rmtB, rmtC, rmtD, rmtE, and npmA were not detected. The prevalences of the modifying enzyme genes aac (6')-Ib, ant (3")-Ia, and aph (3')-I were 51.7, 81.7, and 58.3%, respectively, which are different from a previous study in which the occurrences of these genes were 3, 64, and 72%, respectively. Among the 40 isolates that were armA-positive, the prevalences of bla(TEM), bla(SHV), and bla(CTX-M-3) genes were detected for the first time in China, and their occurrences were 45, 65, and 52.5%, respectively. In all, A. baumannii with all the 16S rRNA methylase, modifying enzyme, and ESBL genes is extremely prevalent in northeastern Sichuan, China, posing a serious clinical concern with a major therapeutic threat in the future. PMID- 24766154 TI - Phenotype-environment association of the oxygen transport system in trimorphic European whitefish (Coregonus lavaretus) populations. AB - Replicated adaptive radiation events, typified by phenotypic divergence across resource axes, provide important insight into the eco-evolutionary dynamics that lead to the formation of new species. Here, we show that in trimorphic adaptive radiations of European whitefish (Coregonus lavaretus), divergence of the oxygen transport system has occurred across the pelagic/littoral (shallow)-profundal (deep) resource axis, and at multiple biological scales. Profundal whitefish exhibited significantly larger red blood cells (RBCs), a greater proportion of cathodic hemoglobin protein components, and higher hemoglobin transcript abundance in kidney compared to littoral and pelagic morphs. Hemoglobin transcript abundance in brain and gill, but not kidney, and anodic hemoglobin protein component diversity in blood were also linked to variation at an intronic single nucleotide polymorphism (SNP). As the whitefish morphs differ in population genetic structure at this SNP, hemoglobin transcript and protein divergence between profundal and pelagic/littoral morphs is likely being driven by genetic divergence. Our findings, along with our previous work on lake whitefish, highlight the importance of the oxygen transport system to the postglacial colonization of novel lacustrine environments by whitefish throughout the northern hemisphere. PMID- 24766155 TI - Discredited Assessment and Treatment Methods Used with Children and Adolescents: A Delphi Poll. AB - In the context of intense interest in identifying what works in mental health, we sought to establish a consensus on what doesnot work-discredited psychological assessments and treatments used with children and adolescents. Applying a Delphi methodology, we engaged a panel of 139 experts to participate in a two-stage survey. Participants reported their familiarity with 67 treatments and 35 assessment techniques and rated each on a continuum from not at all discredited to certainly discredited. The composite results suggest considerable convergence in what is considered discredited and offer a first step in identifying discredited procedures in modern mental health practice for children and adolescents. It may prove as useful and easier to identify what does not work for youth as it is to identify what does work-as in evidence-based practice compilations. In either case, we can simultaneously avoid consensually identified discredited practices to eradicate what does not work and use inclusively defined evidence-based practices to promote what does work. PMID- 24766156 TI - Emergence of avian infectious bronchitis in a non-vaccinating country. AB - Infectious bronchitis virus (IBV) is a coronavirus of the chicken. It is a highly contagious pathogen and in addition to causing respiratory and kidney diseases can affect the reproductive organs, resulting in loss of production and poor egg quality. Despite the global distribution of IBV, Finland has been free of clinical cases for almost three decades. Since April 2011, outbreaks involving genotypes QX, D274-like and 4/91-like have occurred in southern Finland. The clinical samples studied were submitted to the Finnish Food Safety Authority Evira from different regions of Finland during 2011 to 2013 and originated from a voluntary health monitoring programme, a national survey for avian influenza and diagnostic specimens from both commercial poultry production and hobby flocks. The sources of the infections are not known, but strains D274 and 4/91 are widely used in vaccines elsewhere. PMID- 24766157 TI - Management of IRVAN syndrome with observation. AB - A 7-year-old girl with IRVAN (idiopathic retinal vasculitis, aneurysms, and neuroretinitis) syndrome was monitored for 9 years. The patient had symmetric multiple aneurysmal dilations, retinal vasculitis, and severe hard exudation in the macula bilaterally. Long-term visual acuity in her untreated right eye was 20/25. In the left eye, treated with laser panretinal photocoagulation and intravitreal vascular endothelial growth factor inhibitor therapy, visual acuity decreased to 20/200 from macular hard exudates and central fibrovascular tissue. Observation is a consideration in IRVAN syndrome if the vision remains good with hard exudation. PMID- 24766158 TI - Loss anxiety: an alternative explanation for the fundamental fears in human beings. AB - In this article, fear of loss as well as fear of death are introduced to explain cultural worldview defence reactions of individuals. Participants were subjected to mortality salience, disability salience and control conditions. Mortality salience and paralysis salience were found to lead to a change in conservatism scores. In a qualitative follow-up study, when reminded about mortality, the participants reported less individual sadness than expected; whereas when the participants were reminded about paralysis, greater individual sadness was reported. Any kind of loss manipulation that is moderately fearful, highly imaginable, and highly self-relevant is suggested to affect cultural worldview defence reactions. PMID- 24766159 TI - Standardization of RNA chemical mapping experiments. AB - Chemical mapping experiments offer powerful information about RNA structure but currently involve ad hoc assumptions in data processing. We show that simple dilutions, referencing standards (GAGUA hairpins), and HiTRACE/MAPseeker analysis allow rigorous overmodification correction, background subtraction, and normalization for electrophoretic data and a ligation bias correction needed for accurate deep sequencing data. Comparisons across six noncoding RNAs stringently test the proposed standardization of dimethyl sulfate (DMS), 2'-OH acylation (SHAPE), and carbodiimide measurements. Identification of new signatures for extrahelical bulges and DMS "hot spot" pockets (including tRNA A58, methylated in vivo) illustrates the utility and necessity of standardization for quantitative RNA mapping. PMID- 24766160 TI - The effect of Cyclin-dependent kinase 5 on voltage-dependent calcium channels in PC12 cells varies according to channel type and cell differentiation state. AB - Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase that plays an important role in the release of neurotransmitter from pre-synaptic terminals triggered by Ca(2+) influx into the pre-synaptic cytoplasm through voltage-dependent Ca(2+) channels (VDCCs). It is reported that Cdk5 regulates L-, P/Q-, or N-type VDCC, but there is conflicting data as to the effect of Cdk5 on VDCC activity. To clarify the mechanisms involved, we examined the role of Cdk5 in regulating the Ca(2+) -channel property of VDCCs, using PC12 cells expressing endogenous, functional L-, P/Q-, and N-type VDCCs. The Ca(2+) influx, induced by membrane depolarization with high K(+) , was monitored with a fluorescent Ca(2+) indicator protein in both undifferentiated and nerve growth factor (NGF)-differentiated PC12 cells. Overall, Ca(2+) influx was increased by expression of Cdk5-p35 in undifferentiated PC12 cells but suppressed in differentiated PC12 cells. Moreover, we found that different VDCCs are distinctly regulated by Cdk5-p35 depending on the differentiation states of PC12 cells. These results indicate that Cdk5-p35 regulates L-, P/Q-, or N-type VDCCs in a cellular context-dependent manner. Calcium (Ca(2+) ) influx through voltage-dependent Ca(2+) channels (VDCCs) triggers neurotransmitter release from pre-synaptic terminal of neurons. The channel activity of VDCCs is regulated by Cdk5-p35, a neuronal Ser/Thr kinase. However, there have been debates about the regulation of VDCCs by Cdk5. Using PC12 cells, we show that Cdk5-p35 regulates VDCCs in a type (L, P/Q, and N) and differentiation-dependent manner. NGF = nerve growth factor. PMID- 24766161 TI - Less Invasive Surgical Procedures Using Narrow-Diameter Implants: A Prospective Study in 20 Consecutive Patients. AB - Narrow-diameter implants (NDIs) are increasingly produced and used in implant dentistry, especially since the introduction of new, more resistant materials. The objective of the present study was to evaluate the clinical performance of NDIs (3.3 mm) placed in thin alveolar crests. Twenty consecutive patients needing implant-supported fixed partial dentures and presenting an alveolar thickness <=6 mm were treated with 1 or several NDIs. The surgical protocol was chosen according to the clinical situation: (1) flapless, (2) mini-cervical flap, (3) wide flap, (4) wide flap + guided bone regeneration (GBR). Implants were immediately loaded if the primary stability was higher than 20 Ncm. Implant survival and success, prosthodontic success rates, and patient-centered outcomes were evaluated after a follow-up period of 1 year. A total of 39 implants were placed in 20 patients, 12 and 27 implants in the anterior regions and in the posterior mandible, respectively. All but 1 implant reached an insertion torque higher than 20 Ncm and were loaded within 48 hours. The implant survival and success rates both reached 94.7%. The need for GBR was avoided in 60% of the implant sites. The mean peri-implant bone remodeling after a follow-up period of 1 year was -0.35 mm at the implant level. Peri-implant bone remodeling was higher in the posterior region, when the alveolar crest was thinner than 4 mm and GBR was required in addition. In conclusion, use of NDIs to restore partial edentation in sites with limited horizontal thickness seems to be an effective treatment option that prevented GBR in the majority of the present cases. Immediate provisionalization of NDIs does not seem to impair the results. PMID- 24766162 TI - Nuclear receptors: how do they position in non-alcoholic fatty liver disease treatment? PMID- 24766163 TI - Piezoelectric paper fabricated via nanostructured barium titanate functionalization of wood cellulose fibers. AB - We have successfully developed hybrid piezoelectric paper through fiber functionalization that involves anchoring nanostructured BaTiO3 into a stable matrix with wood cellulose fibers prior to the process of making paper sheets. This is realized by alternating immersion of wood fibers in a solution of poly(diallyldimethylammonium chloride) PDDA (+), followed by poly(sodium 4 styrenesulfonate) PSS (-), and once again in PDDA (+), resulting in the creation of a positively charged surface on the wood fibers. The treated wood fibers are then immersed in a BaTiO3 suspension, resulting in the attachment of BaTiO3 nanoparticles to the wood fibers due to a strong electrostatic interaction. Zeta potential measurements, X-ray diffraction, and microscopic and spectroscopic analysis imply successful functionalization of wood fibers with BaTiO3 nanoparticles without altering the hydrogen bonding and crystal structure of the wood fibers. The paper has the largest piezoelectric coefficient, d33 = 4.8 +/- 0.4 pC N(-1), at the highest nanoparticle loading of 48 wt % BaTiO3. This newly developed piezoelectric hybrid paper is promising as a low-cost substrate to build sensing devices. PMID- 24766164 TI - Cellular prion protein is present in dopaminergic neurons and modulates the dopaminergic system. AB - Cellular prion protein (PrP(C) ) is widely expressed in the brain. Although the precise role of PrP(C) remains uncertain, it has been proposed to be a pivotal modulator of neuroplasticity events by regulating the glutamatergic and serotonergic systems. Here we report the existence of neurochemical and functional interactions between PrP(C) and the dopaminergic system. PrP(C) was found to co-localize with dopaminergic neurons and in dopaminergic synapses in the striatum. Furthermore, the genetic deletion of PrP(C) down-regulated dopamine D1 receptors and DARPP-32 density in the striatum and decreased dopamine levels in the prefrontal cortex of mice. This indicates that PrP(C) affects the homeostasis of the dopaminergic system by interfering differently in different brain areas with dopamine synthesis, content, receptor density and signaling pathways. This interaction between PrP(C) and the dopaminergic system prompts the hypotheses that the dopaminergic system may be implicated in some pathological features of prion-related diseases and, conversely, that PrP(C) may play a role in dopamine-associated brain disorders. PMID- 24766165 TI - The deepest, darkest secret. PMID- 24766166 TI - A comparison of telephone and texting interventions for persons with schizophrenia spectrum disorders. AB - Problem-solving interventions are not routinely offered to persons with schizophrenia spectrum disorders (SSDs). Telephone calls and text messages are potential avenues to offer problem solving support. This study compared the effect of telephone calls only, text messages only, and both telephone calls and text messages on individuals' symptoms and medication adherence. Thirty outpatient participants with SSDs were randomly assigned to weekly telephone calls, daily text messages, or both for three months. Participants received monthly in-home pill counts and symptom assessments. Repeated measures ANOVA was significant (F (4,26) = 4.2, p = 0.005) for symptom scores. Further work with larger, more diverse, samples is needed. PMID- 24766167 TI - The views of heads of schools of nursing about mental health nursing content in undergraduate programs. AB - Criticisms about the mental health nursing content of Bachelor of Nursing programs have been common since the introduction of comprehensive nursing education in Australia. Most criticism has come from the mental health nursing sector and the views of key stakeholders have not been systematically reported. Heads of Schools of Nursing have considerable influence over the content of nursing programs, and their perspectives must be part of ongoing discussions about the educational preparation of nurses. This article reports the findings of a qualitative exploratory study, involving in-depth interviews with Heads of Schools of Nursing from Queensland, Australia. Thematic data analysis revealed two main themes: Realising the Goal? and Influencing Factors. Overall, participants did not believe current programs were preparing graduates for beginning level practice in mental health settings. In particular, participants believed that the quality of mental health content was influenced by the overcrowded curriculum, the availability of quality clinical placements, the strength of the mental health team, and the degree of consumer focus. The findings suggest the current model of nursing education in Australia does not provide an adequate foundation for mental health nursing practice and alternative approaches should be pursued as a matter of urgency. PMID- 24766168 TI - An educational program for mental health nurses and community health workers from pacific island countries: results from a pilot study. AB - Delivery of mental health care relies upon professionals with the latest evidence upon which to base their care. This research reports on a pre-test/post-test evaluation of a four-week education program delivered to Pacific Island participants (n = 18) to enhance knowledge, skills, and attitudes (KSAs). The education program used a combination of formal lectures, tutorials, clinical visits, simulations, and laboratory sessions. The measure used was the Nurse Self Report (NSR) questionnaire. Results indicate an education intervention can be an effective tool for improving the knowledge, skills, and attitudes of Pacific Island people who care for persons experiencing mental health problems. PMID- 24766169 TI - MAMBRA's impact on IPV symptoms of incarcerated and formerly incarcerated women. AB - This repeated measures, descriptive study investigated the effect of Music and Account-Making for Behavioral-Related Adaptation (MAMBRA), a group psychoeducation music intervention, on symptoms reported by 41 incarcerated and community women survivors of intimate partner violence (IPV). Psychosocial measurements included: the Center for Epidemiologic Studies Depression Scale; Speilberger State Anxiety Inventory; Rosenberg's Self Esteem Scale; the UCLA Loneliness Scale, version 3; and the Index of Spouse Abuse. MAMBRA was administered over four sessions for five groups of women. Through descriptive and univariate statistics, psychosocial measures positively changed across the MAMBRA sessions. These findings suggest MAMBRA impacted IPV symptoms and may be an efficacious intervention. Future longitudinal studies with diverse samples are warranted. PMID- 24766170 TI - Clinical aspects and care production in a Brazilian psychosocial care center of alcohol and other drugs (CAPS AD). AB - The study aimed to analyze the clinical aspects of the treatment of crack cocaine and excessive alcohol users who were seen in a Psychosocial Care Center of Alcohol and Other Drugs (CAPS AD) in Sobral, Ceara, during the years 2010 and 2011. This is an exploratory descriptive and documentary study, with a retrospective quantitative approach. The sample was composed of 567 medical records of drug users, from which 291 were crack cocaine users, and 276 were alcohol users. For data collection, a form was developed based on the Care Script Service, the data from which was then used to populate a database in an EPI INFO 7, a statistics software system. In both groups of users, males were predominant (85%, n = 482), and were between the ages of 20 and 29 years for crack users (50.9%, n = 148), and between 30 and 39 years for alcohol users (31.9%, n = 88). There were significant differences between crack cocaine users and alcohol users in liver disorders (p < 0.01) and withdrawal syndrome (p < 0.05), however, there were similar signs and symptoms between users. Crack users hospitalized less frequently (OR 0.33 [95% CI 0.23 to 0.47 p < 0.01]). Suicidal ideation and suicide attempts were similar in both crack cocaine and alcohol users. Thus, this research will lead to new proposals for health care professionals in order to enhance and improve the care provided to service customers in CAPS AD. PMID- 24766171 TI - Patients subject to high levels of coercion: staff's understanding. AB - Measures to keep staff and patients safe (containment) frequently involve coercion. A small proportion of patients is subject to a large proportion of containment use. To reduce the use of containment, we need a better understanding of the circumstances in which it is used and the understandings of patients and staff. Two sweeps were made of all the wards, spread over four hospital sites, in one large London mental health organization to identify patients who had been subject to high levels of containment in the previous two weeks. Data were then extracted from their case notes about their past history, current problem behaviours, and how they were understood by the patients involved and the staff. Nurses and consultant psychiatrists were interviewed to supplement the information from the case records. Twenty-six heterogeneous patients were identified, with many ages, genders, diagnoses, and psychiatric specialities represented. The main problem behaviours giving rise to containment use were violence and self-harm. The roots of the problem behaviours were to be found in severe psychiatric symptoms, cognitive difficulties, personality traits, and the implementation of the internal structure of the ward by staff. Staff's range and depth of understandings was limited and did not include functional analysis, defence mechanisms, specific cognitive assessment, and other potential frameworks. There is a need for more in-depth assessment and understanding of patients' problems, which may lead to additional ways to reduce containment use. PMID- 24766172 TI - Therapeutic interventions in perinatal and infant mental health services: a mixed methods inquiry. AB - Perinatal mental health disorders potentially have long-term negative sequelae for women, their infants and their families. Multidisciplinary perinatal and infant mental health (PIMH) services are an emerging specialty in mental health designed to improve mother-infant outcomes. This mixed methods study explored the characteristics of women referred to a specialist PIMH service and the therapeutic interventions that PIMH clinicians use. Women referred to the service were identified with multiple and complex risk factors. Perinatal and infant mental health clinicians use a range of interventions, dependent upon their training, such as family of origin work/genograms, non-directive counseling, and strategies to manage anxiety and depression. Clinicians also emphasized the therapeutic relationship and the interventions they use within an attachment based framework, which warrants further research. PMID- 24766173 TI - Mental health status of women in Jordan: a comparative study between attendees of governmental and UN relief and works agency's health care centers. AB - This study aimed at investigating differences in mental health problems between attendees of governmental and United Nations Relief and Works Agency for Palestine Refugees health care centers in Jordan. Further, predictors of mental health problems based on women's demographic profile were investigated. A convenience sample of 620 women attending governmental and United Nations Relief and Works Agency for Palestine Refugees health care centers in Jordan was recruited for this purpose. Independent samples t-tests were used to identify differences in mental health, and multiple linear regression was implemented to identify significant predictors of women's mental health problems. Results indicated an absence of significant differences in mental health problems between attendees of the two types of health care centers. Further, among the demographic indicators that were tested, income, spousal violence, and general health were the predictors of at least three different mental health problems in women. This study highlights opportunities for health professionals to decrease women's propensity for mental health problems by addressing these factors when treating women attending primary care centers in different Jordanian towns, villages, and refugee camps. PMID- 24766174 TI - Contradictions between ideals and reality: Swedish registered nurses' experiences of dialogues with inpatients in psychiatric care. AB - This study explored ten registered nurses' experiences of dialogues with inpatients in psychiatric care. Data were collected through four focus group discussions, and two individual interviews. The nurses described contradictions between their nursing ideals about dialogues and the reality faced in psychiatric inpatient care, resulting in an unsatisfactory work situation and feelings of insufficiency. We conclude that in order to improve quality of care and increase well-being for both patients and health care workers, nursing interventions, such as dialogues and meaningful activities, need to be offered to patients. A management that is visible and present on-site should encourage and facilitate health care workers' participation in clinical supervision. PMID- 24766175 TI - Suicide culture. PMID- 24766176 TI - Contemplating an expatriate health care position? key factors to consider. PMID- 24766178 TI - Cardiovascular event risk dynamics over time in older patients on dialysis: a generalized multiple-index varying coefficient model approach. AB - Among patients on dialysis, cardiovascular disease and infection are leading causes of hospitalization and death. Although recent studies have found that the risk of cardiovascular events is higher after an infection-related hospitalization, studies have not fully elucidated how the risk of cardiovascular events changes over time for patients on dialysis. In this work, we characterize the dynamics of cardiovascular event risk trajectories for patients on dialysis while conditioning on survival status via multiple time indices: (1) time since the start of dialysis, (2) time since the pivotal initial infection-related hospitalization, and (3) the patient's age at the start of dialysis. This is achieved by using a new class of generalized multiple-index varying coefficient (GM-IVC) models. The proposed GM-IVC models utilize a multiplicative structure and one-dimensional varying coefficient functions along each time and age index to capture the cardiovascular risk dynamics before and after the initial infection-related hospitalization among the dynamic cohort of survivors. We develop a two-step estimation procedure for the GM-IVC models based on local maximum likelihood. We report new insights on the dynamics of cardiovascular events risk using the United States Renal Data System database, which collects data on nearly all patients with end-stage renal disease in the United States. Finally, simulation studies assess the performance of the proposed estimation procedures. PMID- 24766179 TI - Effectiveness of a group diabetes education programme in under-served communities in South Africa: a pragmatic cluster randomized controlled trial. AB - AIM: To evaluate the effectiveness of group education, led by health promoters using a guiding style, for people with type 2 diabetes in public sector community health centres in Cape Town. METHODS: This was a pragmatic clustered randomized controlled trial with 17 randomly selected intervention and 17 control sites. A total of 860 patients with type 2 diabetes, regardless of therapy used, were recruited from the control sites and 710 were recruited from the intervention sites. The control sites offered usual care, while the intervention sites offered a total of four monthly sessions of group diabetes education led by a health promoter. Participants were measured at baseline and 12 months later. Primary outcomes were diabetes self-care activities, 5% weight loss and a 1% reduction in HbA(1c) levels. Secondary outcomes were self-efficacy, locus of control, mean blood pressure, mean weight loss, mean waist circumference, mean HbA1c and mean total cholesterol levels and quality of life. RESULTS: A total of 422 (59.4%) participants in the intervention group did not attend any education sessions. No significant improvement was found in any of the primary or secondary outcomes, apart from a significant reduction in mean systolic (-4.65 mmHg, 95% CI 9.18 to 0.12; P = 0.04) and diastolic blood pressure (-3.30 mmHg, 95% CI -5.35 to -1.26; P = 0.002). Process evaluation suggested that there were problems with finding suitable space for group education in these under-resourced settings, with patient attendance and with full adoption of a guiding style by the health promoters. CONCLUSION: The reported effectiveness of group diabetes education offered by more highly trained professionals, in well-resourced settings, was not replicated in the present study, although the reduction in participants' mean blood pressure is likely to be of clinical significance. PMID- 24766180 TI - Palliative radiation therapy outcomes for cats with oral squamous cell carcinoma (1999-2005). AB - Squamous cell carcinoma (SCC) accounts for approximately 10% of all feline tumors. The purpose of this retrospective study was to describe outcomes for a group of cats with oral SCC that were treated with palliative radiation therapy. Fifty-four cats met the inclusion criteria of nonresectable, oral SCC treated with coarse fractionated megavoltage (MeV) radiation therapy. Radiation therapy for all cats was delivered with a 6 MeV linear accelerator. Total radiation doses of 24 Gray to 40 Gray were administered in three to four fractions, once-per-week over 4 to 5 weeks. Concurrent chemotherapy protocols varied and were administered at the discretion of the clinician and client. Forty-nine patients completed the planned treatment protocols. Overall mean and median survival times for cats completing the planned treatment protocols were 127 and 92 days (n = 49). Mean and median survival times of cats receiving palliative radiation therapy alone were 157 and 113 days (n = 12). Mean and median survival times of patients receiving both radiation therapy and chemotherapy were 116 and 80 days (n = 37). Patients with sublingual tumors had a median survival time of 135 days (n = 15), compared to mandibular tumors that had a median survival time of 80 days (n = 26). For the majority of patients that completed the planned treatment protocol (65%), owners reported a subjectively improved quality of life. Findings from this uncontrolled study supported the use of palliative radiation therapy for cats with nonresectable oral squamous cell carcinoma. PMID- 24766181 TI - Liesegang patterns engineered by a chemical reaction assisted by complex formation. AB - Liesegang rings based on a chemical reaction, not a conventional precipitation reaction, have been developed by appropriate design of the nucleation dynamics in a system involving complex formation in a matrix. The periodic and concentric rings consisted of well-dispersed Ag nanoparticles with diameters of a few nanometers. The approach modeled here could be applied to form novel micropatterns out of inorganic salts, metal nanoparticles, organic nanocrystals, or polymeric fibers, and it could also offer a scaffold for novel models of a wide variety of reaction-diffusion phenomena in nature. PMID- 24766182 TI - Management of acute pancreatitis. AB - Acute pancreatitis (AP) is a common medical condition with extensive morbidity and mortality. Approximately 210,000 Americans are hospitalized each year; and 5% of patients with AP will die. It is also an expensive condition, costing 2.6 billion dollars (United States) in 2009 alone. Moreover, the incidence is increasing - the National Hospital Discharge Survey showed hospitalizations increased from 78 per 100,000 in 2007 to 90 per 100,000 just three years later in 2010. There is no proven pharmacologic entity to treat the inflammatory response associated with acute pancreatitis; supportive care with IV fluids, bowel rest and pain control are the mainstays of therapy. Recently, new developments to help increase survival and minimize morbidity with several key interventions have been investigated. This summary highlights new studies and meta-analyses to provide current opinion on treatment of this morbid condition. PMID- 24766183 TI - Gonadoblastoma: an immunohistochemical study and comparison to Sertoli cell nodule with intratubular germ cell neoplasia, with pathogenetic implications. AB - AIMS: To investigate the immunohistochemical properties of the sex cord cells of gonadoblastoma and Sertoli cell nodule with intratubular germ cell neoplasia unclassified (IGCNU) as a means of objective distinction and to provide insight into the pathogenesis. METHODS AND RESULTS: Immunohistochemical stains for SOX9, FoxL2 and SF-1 were performed on 10 gonadoblastomas (all phenotypical females) and 14 Sertoli cell nodules with IGCNU in normal phenotypical males with coexisting germ cell tumours. The sex cord cells of gonadoblastomas showed strong, diffuse FoxL2 and SF-1 positivity and focal weak to moderate SOX9 reactivity, whereas those of Sertoli cell nodules with IGCNU were uniformly, strongly positive for SOX9 and SF-1, while negative for FoxL2. CONCLUSIONS: Coexpression of SOX9 and FoxL2 in the sex cord cells of gonadoblastomas provides evidence that these morphologically ambiguous sex cord cells are incompletely differentiated. The strong, diffuse SOX9 and SF-1 positivity and absence of FoxL2 reactivity in the Sertoli cell nodules with IGNCU support full Sertoli cell differentiation of the sex cord cells and distinguish them from gonadoblastomas. Deficient SOX9 expression in gonadoblastoma supports a current model of pathogenesis where immature germ cells, in the absence of well-formed Sertoli cells, retain a fetal phenotype and susceptibility to malignant transformation. PMID- 24766184 TI - Analysis of phytostanyl fatty acid esters in enriched foods via UHPLC-APCI-MS. AB - A method for the analysis of phytostanyl fatty acid esters, the functional ingredients of cholesterol-lowering enriched foods, was developed. The procedure is based on (i) separation of the intact esters via reversed-phase ultrahigh performance liquid chromatography; (ii) detection by atmospheric pressure chemical ionization-mass spectrometry; and (iii) quantitation using selected ion monitoring (SIM) mode. Employing a C8 column, phytostanyl fatty acid esters sharing the same stanol nucleus could be separated according to the esterified fatty acids while esters with different stanol moieties could be distinguished via SIM based on the formation of an intense fragment ion [M - fatty acid + H](+). The suitability of the approach was demonstrated using different types of enriched foods reflecting the diversity in potential matrices (skimmed milk drinking yogurt, margarine, and soft-cheese-style spread). The developed methodology extends the analytical basis for authenticity and quality assessments of functional foods enriched with phytostanyl fatty acid esters. PMID- 24766185 TI - Tumor-preferential sustained drug release enhances antitumor activity of block copolymer micelles. AB - Nanoparticles are widely used as drug carriers for controlled, tumor-targeted delivery of various anticancer agents that have biopharmaceutical limitations such as water solubility and tissue permeability. Growing evidence suggests that nanoparticles not only reduce toxic side effects of anticancer drugs but also improve the therapeutic efficacy as a function of their drug-release profile. The purpose of this study is to confirm such hypothetical effects of tunable drug release on improving antitumor activity of nanoparticles in vitro and in vivo, using block copolymer micelles as drug carriers. Micelles were prepared from poly(ethylene glycol)-poly(aspartate) block copolymers modified with hydrazide (HYD), aminobenzoate hydrazide (ABZ) and glycine hydrazide (GLY) linkers to achieve a pH-dependent, tunable release of doxorubicin (DOX), a model anticancer drug. Regardless of the drug-release profile, all three micelles showed similar properties in vitro, such as pH-dependent drug release, intracellular drug delivery and cancer cell growth inhibition. However, micelles releasing DOX slowly in vitro showed that the most effective antitumor activity in vivo, compared to the micelles releasing drugs faster. These results demonstrate that tumor-preferential sustained drug release can enhance the antitumor activity of the micelles. PMID- 24766186 TI - Anti-neuropilin 1 antibody Fab' fragment conjugated liposomal docetaxel for active targeting of tumours. AB - Neuropilin-1, a transmembrane receptor entailed in wide range of human tumour cell lines and diverse neoplasms, mediates the effects of VEGF and Semaphorins during the processes of cellular proliferation, survival and migration. In view of this, we had developed and evaluated in vitro and in vivo efficacy of anti neuropilin-1 immunoliposomes against neuropilin-1 receptor expressing tumours. The PEGylated liposomes loaded with docetaxel were prepared using thin film hydration method. Functionalised PEGylated liposomes were prepared using post insertion technique. Anti-neuropilin-1 immunoliposomes were prepared by covalently conjugating Fab' fragments of neuropilin-1 antibody to functionalised PEGylated liposomes via thioether linkage. In vivo evaluation of Taxotere and liposomal formulations was performed using intradermal tumour model to demonstrate anti-angiogenic and tumour regression ability. The modified Fab' fragments and immunoliposomes were found to be immunoreactive against A549 cells. Further, docetaxel loaded PEGylated liposomes and PEGylated immunoliposomes demonstrated higher in vitro cytotoxicity than Taxotere formulation at the same drug concentration and exposure time. The live imaging showed distinctive cellular uptake of functional immunoliposomes. Further, significant decrease in micro-blood vessel density and tumour volumes was observed using bio-engineered liposomes. The results clearly highlight the need to seek neuropilin-1 as one of the prime targets in developing an anti-angiogenic therapy. PMID- 24766187 TI - Association between waist-to-height ratio and chronic kidney disease in the Taiwanese population. AB - BACKGROUND: Obesity, metabolic syndrome (MS) and chronic kidney disease (CKD) are all becoming increasingly prevalent worldwide. Body mass index (BMI) has traditionally been employed to identify overweight or obese individuals, yet multiple studies have yielded conflicting results when BMI was used to evaluate the association between obesity and CKD. AIMS: The purpose of this large, population-based, multicentre study was to evaluate the associations of BMI and waist-to-height ratio (WHtR) with CKD. METHODS: A retrospective study of 41,600 subjects who had physical examinations from January 2010 to December 2011 was performed. Data such as life style and habits were collected by interviews, and systolic and diastolic blood pressure (SBP and DBP), height, body weight, waist circumference, total cholesterol (TC), high-density lipoproteins (HDL), triglycerides (TG), fasting blood glucose and creatinine levels were measured. The association of these factors with CKD was analysed by use of SPSS 15.0 software. RESULTS: The key findings of this study were that WHtR but not BMI was an independent predictor of CKD. Additionally, SBP was a predictor of CKD in males and females, and TG and TC were independent predictors of CKD in females. Such measures are components of MS, which may also be associated with the development of CKD. CONCLUSION: WHtR appears to be a better measure of central obesity than BMI, and is an easy-to-use, noninvasive tool for identifying individuals at risk of developing obesity-related CKD, and potentially also MS related CKD. PMID- 24766189 TI - Bilateral vulvar mass mimicking Bartholin's gland abscess in the postpartum period: Klippel-Trenaunay Syndrome. PMID- 24766188 TI - Barriers to care and service satisfaction following homicide loss: associations with mental health outcomes. AB - Homicide survivors are at increased risk for mental health problems, including depression, posttraumatic stress disorder, and complicated grief. Therefore, improving access to community and mental health resources is critical for this population. The atuhors sought to examine barriers to accessing services and service satisfaction among 47 homicide survivors. Over half of the sample met criteria for a mental disorder, with depression being the most prevalent problem. Frequently endorsed barriers to care included financial barriers, inadequate information, and health-related problems. However, participants who engaged in services were generally satisfied with those services. Only depression was uniquely associated with worse overall service satisfaction. PMID- 24766190 TI - Disentangling the role of phenotypic plasticity and genetic divergence in contemporary ecotype formation during a biological invasion. AB - The occurrence of contemporary ecotype formation through adaptive divergence of populations within the range of an invasive species typically requires standing genetic variation but can be facilitated by phenotypic plasticity. The relative contributions of both of these to adaptive trait differentiation have rarely been simultaneously quantified in recently diverging vertebrate populations. Here we study a case of intraspecific divergence into distinct lake and stream ecotypes of threespine stickleback that evolved in the past 140 years within the invasive range in Switzerland. Using a controlled laboratory experiment with full-sib crosses and treatments mimicking a key feature of ecotypic niche divergence, we test if the phenotypic divergence that we observe in the wild results from phenotypic plasticity or divergent genetic predisposition. Our experimental groups show qualitatively similar phenotypic divergence as those observed among wild adults. The relative contribution of plasticity and divergent genetic predisposition differs among the traits studied, with traits related to the biomechanics of feeding showing a stronger genetic predisposition, whereas traits related to locomotion are mainly plastic. These results implicate that phenotypic plasticity and standing genetic variation interacted during contemporary ecotype formation in this case. PMID- 24766191 TI - Morningness-eveningness interferes with perceived health, physical activity, diet and stress levels in working women: a cross-sectional study. AB - Sleep and health are closely interrelated and sleep quality is a well-known contributor to perceived health. However, effects of sleep-timing preference i.e. morningness-eveningness on health has yet to be revealed. In this study, we explored the relationship between morningness-eveningness and perceived health in a sample of female working professionals (N = 202). Sleep-timing preference was measured using the Composite Scale of Morningness. Perceived health was characterized by Center for Epidemiologic Studies Depression Scale, WHO Well Being Scale-5 and Patient Health Questionnaire-15 scores. We also investigated possible mechanisms, including stress and health-impairing behaviours. In accordance with previous data, we found more depressive mood, lower well-being and poorer perceived health among evening types. To assess health-impairing behaviours we collected data on smoking habits, alcohol consumption, physical activity and diet. Among the possible mechanism variables, greater stress, less frequent physical activity and less healthy diet were associated with eveningness. Furthermore, stress diminished the strength of the association between morningness-eveningness and depressed mood. Physical activity attenuated the strength of the association between morningness-eveningness and well-being. No effects of alcohol consumption could be identified. Our data show that evening preference behaves as a health risk in terms of associating with poor perceived health. Our findings also suggest that this effect might be mediated by health behaviours and stress. PMID- 24766192 TI - Daytime restricted feeding modifies the daily variations of liver gluconeogenesis: adaptations in biochemical and endocrine regulators. AB - Daytime restricted feeding (DRF) promotes circadian adaptations in the metabolic processing of nutrients. We explored the hepatic gluconeogenic response in DRF rats by the temporal profiles of the following: (1) the activity of glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), as well as the periportal and pericentral distribution of PEPCK; (2) conversion of alanine to glucose; (3) glycemia and liver glycogen content; (4) presence of glycogen synthase (GYS) and its phosphorylated form (at Ser641, pGYS); (5) circulating levels of corticosterone, glucagon and insulin; (6) glucose-tolerance test; and (7) sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha). The results showed that DRF promoted: (1) a phase shift in G6Pase activity and an increase in PEPCK activity as well as a change of PEPCK from periportal to pericentral hepatocytes, (2) a net conversion of alanine to circulating glucose, (3) a decrease in glycemic values and a phase shift in the liver glycogen content, (4) a phase shift in GYS and an increase of pGYS, (5) an increase in the daily levels of corticosterone and glucagon, but a reduction in the levels of insulin, (6) normal glucose homeostasis in all groups and (7) an enhanced presence of SIRT1 and PGC-1alpha. It is proposed that the increased gluconeogenic in DRF group promotes synthesis of hepatic glycogen and the production of glucose. These results could be a modulation of the gluconeogenic process due to rheostatic adaptations in the endocrine, metabolic and timing regulation of liver and could be associated with the physiology of the food entrained oscillator. PMID- 24766194 TI - Aspirin inhibits proliferation and induces apoptosis of multiple myeloma cells through regulation of Bcl-2 and Bax and suppression of VEGF. AB - OBJECTIVES: Aspirin (ASA) has been frequently used for thromboprophylaxis in patients with multiple myeloma (MM) when treated with thalidomide or lenalidomide. Despite the well-recognized chemopreventive role of ASA in some solid tumors particularly for colon cancer, whether ASA displays the antimyeloma activity remains unclear. METHODS: MM1.S and RPMI-8226 cell lines harboring K-Ras and N-Ras mutation, respectively, were treated with various concentrations of ASA for different hours. The cell proliferation and apoptosis were performed to explore the effects of ASA on myeloma. Then, the exact mechanisms governing ASA's antimyeloma were explored by qRT-PCR and Western blot. Also, the effect of ASA on tumor growth was observed in NOD/SCID mice bearing myeloma xenografts. RESULTS: ASA of 0-10 mm concentration inhibits proliferation MM1.S and RPMI-8226 cells in time- and dose-dependent manner. The myeloma cells exposed to ASA treatment displayed concentration-dependent apoptosis, which was closely associated with activation of caspases, upregulation of Bax, and downregulation of Bcl-2 and VEGF. Study in vivo revealed that ASA administration retarded the tumor growth accompanying the survival time of mice bearing myeloma xenografts. CONCLUSIONS: ASA exerted antiproliferative and pro-apoptotic action in myeloma cells in vitro and delayed the growth of human myeloma cells in vivo. The underlying mechanisms were ascribed to regulation of Bcl-2 and Bax and suppression of VEGF. PMID- 24766193 TI - Etoposide quinone is a covalent poison of human topoisomerase IIbeta. AB - Etoposide is a topoisomerase II poison that is utilized to treat a broad spectrum of human cancers. Despite its wide clinical use, 2-3% of patients treated with etoposide eventually develop treatment-related acute myeloid leukemias (t-AMLs) characterized by rearrangements of the MLL gene. The molecular basis underlying the development of these t-AMLs is not well understood; however, previous studies have implicated etoposide metabolites (i.e., etoposide quinone) and topoisomerase IIbeta in the leukemogenic process. Although interactions between etoposide quinone and topoisomerase IIalpha have been characterized, the effects of the drug metabolite on the activity of human topoisomerase IIbeta have not been reported. Thus, we examined the ability of etoposide quinone to poison human topoisomerase IIbeta. The quinone induced ~4 times more enzyme-mediated DNA cleavage than did the parent drug. Furthermore, the potency of etoposide quinone was ~2 times greater against topoisomerase IIbeta than it was against topoisomerase IIalpha, and the drug reacted ~2-4 times faster with the beta isoform. Etoposide quinone induced a higher ratio of double- to single-stranded breaks than etoposide, and its activity was less dependent on ATP. Whereas etoposide acts as an interfacial topoisomerase II poison, etoposide quinone displayed all of the hallmarks of a covalent poison: the activity of the metabolite was abolished by reducing agents, and the compound inactivated topoisomerase IIbeta when it was incubated with the enzyme prior to the addition of DNA. These results are consistent with the hypothesis that etoposide quinone contributes to etoposide-related leukemogenesis through an interaction with topoisomerase IIbeta. PMID- 24766195 TI - Role of angiogenic factors/cell adhesion markers in serum of cirrhotic patients with hepatopulmonary syndrome. AB - BACKGROUND & AIMS: Hepatopulmonary syndrome is a complication of chronic liver disease resulting in increased morbidity and mortality. It is caused by intrapulmonary vascular dilations and arteriovenous connections with devastating influence on gas exchange. The pathogenesis is not completely understood but evidence mounts for angiogenesis. Aims of this study were to identify angiogenic factors in serum of patients with hepatopulmonary syndrome and to study the possibility to predict its presence by these factors. METHODS: Multiplex assays were used to measure the concentration of angiogenic factors in patients with (n = 30) and without hepatopulmonary syndrome (n = 30). Diagnosis was based on the presence of gas exchange abnormality and intrapulmonary vasodilations according to published guidelines. RESULTS: Patients with and without hepatopulmonary syndrome had similar MELD scores (median: 11.2 vs. 11.6; P = 0.7), Child-Pugh score (P = 0.7) and PaCO2 values (median: 35 vs. 37; P = 0.06). PaO2 and P(A-a) O2 gradient were significantly different (respectively median of 80 vs. 86, P = 0.02; and 24 vs. 16, P = 0.004). Based on area under the curve (AUC) data and P values, the best predictors were vascular cell adhesion molecule 1 (VCAM1) (AUC = 0.932; P < 0.001) and intercellular adhesion molecule 3 (ICAM3) (AUC = 0.741; P = 0.003). Combining these factors results in an AUC of 0.99 (after cross-validation still 0.99). CONCLUSIONS: VCAM1 and ICAM3 might be promising biomarkers for predicting hepatopulmonary syndrome. Combining these factors results in an AUC of 0.99 and a negative predictive value of 100%. Determining the concentration of these biomarkers might be a screening method to detect hepatopulmonary syndrome. The use of these biomarkers should be validated in larger groups of patients. PMID- 24766196 TI - ZnO nanomulberry and its significant nonenzymatic signal enhancement for protein microarray. AB - It is very challenging to make a highly sensitive protein microarray because of its lack of a universal signal amplification method like PCR used in DNA microarray. The current strategies to improve the sensitivity mainly rely on a unique nanostructured substrate or enzymatically catalyzed signal amplification, of which the former requires a complicated and time-consuming fabrication process while the latter suffers from high cost and poor stability of enzymes as well as downstream biochemical reactions. In this work, an inexpensive ZnO nanomulberry (NMB) decorated glass slide is investigated as a superior substrate to nonenzymatically amplify the signal of protein microarray for sensitive detection, accomplishing a limit of detection (LOD) of 1 pg mL(-1) and a broad dynamic range of 1 pg mL(-1) to 1 MUg mL(-1) to detect an important cancer biomarker, carcinoembryonic antigen (CEA) in 10% human serum. The excellent performance is attributed to ZnO NMB possessing high-density loading of capture antibody and intrinsic enhancement of fluorescence emission. The substrate preparation is simple without using any expensive equipment and complicated technique while offering advantages of low autofluorescence, versatility for various fluorophores, and excellent compatibility with existing microarray fabrication techniques. Thus, a ZnO NMB based protein microarray holds great promise for developing a low cost, sensitive, and high throughput protein assay platform for broad applications in both fundamental research and clinical diagnosis. PMID- 24766197 TI - Effects of Light-Emitting Diode Photobiomodulation Therapy and BioOss as Single and Combined Treatment in an Experimental Model of Bone Defect Healing in Rats. AB - The present study assesses histopathologically and histomorphometrically the effects of light-emitting diode (LED) photobiomodulation therapy (LPT) on bone healing in BioOss-filled femoral defects of rats. It has been reported that LPT modulates cellular metabolic processes, leading to an enhanced regenerative potential for biological tissues. Thirty-six male Wistar rats with femoral bone defects were divided into 4 groups: defect group (empty bone defect, without application of LPT), graft group (bone defect filled with BioOss, without application of LPT), (defect+LPT) group (empty bone defect, with application of LPT), and (graft+LPT) group (bone defect filled with BioOss, with application of LPT). An OsseoPulse LED device (wavelength: 618 nm; output power: 20 mW/cm(2)) was initiated 24 hours postsurgery and performed every 24 hours for 7, 14, and 21 days. The LPT-applied and BioOss-filled defects presented a higher amount of new bone formation with trabeculae formation. These defects showed statistically significant lower values of inflammation severity, and fewer remnants of biomaterial were present. Within the limitations of this study, LPT has positive effects on bone healing histopathologically and histomorphometrically for the defects filled with BioOss 3 weeks after the rats' femora injury. PMID- 24766198 TI - Clinical-pathologic correlation: vitrectomy with epiretinal and internal limiting membrane peel. AB - BACKGROUND AND OBJECTIVE: To correlate clinical and pathologic findings in vitreoretinal surgeries with epiretinal membrane (ERM) and internal limiting membrane (ILM) peels. PATIENTS AND METHODS: A retrospective review of the clinical and pathologic reports for 698 vitrectomy specimens involving ERM and/or ILM peels from 2008 to 2012. RESULTS: Labeling with clear operative clinical diagnoses--ERM, ILM or both--was available for 520 of 698 cases; 492 cases had a corresponding pathology result. Combined ERM-ILM specimens were the dominant clinical and pathologic diagnosis. Over 43% had differing operative and pathologic diagnoses, with 79.6% of cases labeled as ERMs, 75.0% of cases labeled as ILMs, and 22.1% cases labeled as ERM-ILM demonstrating incongruous specimens on pathology. CONCLUSION: It can be difficult to determine the nature of membranes pre- or intraoperatively. Combined ERM-ILM specimens may be more common than previously recognized, implying that the two membranes are not always distinct and surgically separable. PMID- 24766199 TI - Pre-treatment with the synthetic antioxidant T-butyl bisphenol protects cerebral tissues from experimental ischemia reperfusion injury. AB - Treatments to inhibit or repair neuronal cell damage sustained during focal ischemia/reperfusion injury in stroke are largely unavailable. We demonstrate that dietary supplementation with the antioxidant di-tert-butyl-bisphenol (BP) before injury decreases infarction and vascular complications in experimental stroke in an animal model. We confirm that BP, a synthetic polyphenol with superior radical-scavenging activity than vitamin E, crosses the blood-brain barrier and accumulates in rat brain. Supplementation with BP did not affect blood pressure or endogenous vitamin E levels in plasma or cerebral tissue. Pre treatment with BP significantly lowered lipid, protein and thiol oxidation and decreased infarct size in animals subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. This neuroprotective action was accompanied by down-regulation of hypoxia inducible factor-1alpha and glucose transporter-1 mRNA levels, maintenance of neuronal tissue ATP concentration and inhibition of pro-apoptotic factors that together enhanced cerebral tissue viability after injury. That pre-treatment with BP ameliorates oxidative damage and preserves cerebral tissue during focal ischemic insult indicates that oxidative stress plays at least some causal role in promoting tissue damage in experimental stroke. The data strongly suggest that inhibition of oxidative stress through BP scavenging free radicals in vivo contributes significantly to neuroprotection. We demonstrate that pre-treatment with ditert-butyl bisphenol(Di-t-Bu-BP) inhibits lipid, protein, and total thiol oxidation and decreases caspase activation and infarct size in rats subjected to middle cerebral artery occlusion (2 h) and reperfusion (24 h) injury. These data suggest that inhibition of oxidative stress contributes significantly to neuroprotection. PMID- 24766200 TI - The effect of labour on ownership decisions in two cultures: developmental evidence from Japan and the United Kingdom. AB - Creative labour has an effect on children's and adults' ownership decisions in Western cultures. We investigated whether preschoolers and adults from an Eastern culture (Japan) would show a similar bias. In a first-party task (Experiment 1), in which participants created their own objects, Japanese preschoolers but not adults assigned ownership to creators. When participants watched videos of third party conflicts between owners of materials and creators (Experiment 2), Japanese adults, but not preschoolers, transferred ownership to creators. In a British comparison group, both preschoolers and adults showed an effect of creative labour in the third-party task. A bias to attribute ownership on the basis of creative labour is thus not specific to Western culture. PMID- 24766201 TI - Oesophageal function assessed by high-resolution manometry in patients with diabetes and inadequate glycaemic control. AB - AIMS: To describe oesophageal function in people with diabetes and poor glycaemic control using oesophageal high-resolution manometry and to compare the result between control subjects and patients with gastro-oesophageal reflux disease. METHODS: The results of oesophageal high-resolution manometry and a gastric emptying test were reviewed in 20 patients with diabetes. The high-resolution manometry protocol consisted of 5-ml swallows of water and multiple swallows of water. Oesophageal motility disorders were classified according to the Chicago classification system. The occurence of multiphasic contractions and intragastric and intrabolus pressures were measured. High-resolution manometry results were compared between 10 control subjects and 20 patients with gastro-oesophageal reflux disease. Data were expressed as medians and compared using Mann-Whitney and chi-squared tests. RESULTS: Oesophageal motility disorders were similarly distributed between the groups. Multiphasic contractions occurred more frequently in patients with diabetes than in those with gastro-oesophageal reflux disease (60 vs 20% per patient; P<0.01) and were not observed in control subjects. Gastric emptying was delayed in six patients with diabetes and did not correlate with symptoms or oesophageal motility disorders. Intrabolus pressure was higher in patients with diabetes and gastroparesis than in those without (17 vs 10 mmHg; P=0.02) and correlated with intragastric pressure (r=0.46, P<0.01). During multiple swallows of water, oesophageal contractile activity was incompletely inhibited in 83% of patients with diabetes and gastroparesis vs 9% without (P<0.01). Oesophageal function and gastric emptying were not influenced by fasting glycaemia. CONCLUSIONS: Patients with gastroparesis might present with impaired inhibition of contractile activity during multiple swallows of water. Increased intrabolus pressure is suggestive of delayed oesophageal clearance as a consequence of gastroparesis. PMID- 24766202 TI - Optimized canine dental computed tomographic protocol in medium-sized mesaticepahlic dogs. AB - The purpose of this study was to develop an optimized imaging protocol for canine dental imaging using single-detector row CT and multidetector row CT. Two medium sized mesaticephalic cadaver dog heads were scanned using varying slice thickness, sequential vs. helical scanning mode, sequential CT table increment, pitch, image reconstruction algorithm, and an additional moderate edge enhancement filter. For each series, two reviewers scored dental roots as not visible (score: 0), partially visible (score: 1) or completely visible (score: 2). Sharpness of the dento-alveolar margin was scored as blurry (score: 0), sharp (score: 1) or very sharp (score: 2). Consensus reader scores were compared among CT protocols. For single-detector row CT, complete visualization of all tooth roots was only achieved with 1 mm slice thickness and image interval sequential or helical series (pitch of 1 or 2) using a high-frequency image reconstruction algorithm with or without additional edge enhancement. For four-detector row CT, complete visibility of all tooth roots was recorded in all series. For single detector row CT, all medium frequency algorithm series yielded blurry margin scores and all other series yielded sharp margin scores. For four-detector row CT, sequential and helical 0.5 mm thickness images yielded very sharp dento alveolar margin scores, whereas the 1 mm series yielded only sharp margin scores. Authors concluded that the optimal dental imaging protocol was a sequential mode 1 mm slice thickness and interval with a high-frequency image reconstruction algorithm and an additional moderate edge enhancement filter. PMID- 24766203 TI - Short bowel syndrome in infants: the critical role of luminal nutrients in a management program. AB - Short bowel syndrome develops when the remnant mass of functioning enterocytes following massive resections cannot support growth or maintain fluid-electrolyte balance and requires parenteral nutrition. Resection itself stimulates the intestine's inherent ability to adapt morphologically and functionally. The capacity to change is very much related to the high turnover rate of enterocytes and is mediated by several signals; these signals are mediated in large part by enteral nutrition. Early initiation of enteral feeding, close clinical monitoring, and ongoing assessment of intestinal adaptation are key to the prevention of irreversible intestinal failure. The length of the functional small bowel remnant is the most important variable affecting outcome. The major objective of intestinal rehabilitation programs is to achieve early oral nutritional autonomy while maintaining normal growth and nutrition status and minimizing total parenteral nutrition related comorbidities such as chronic progressive liver disease. Remarkable progress has been made in terms of survivability and quality of life, especially in the context of coordinated multidisciplinary programs, but much work remains to be done. PMID- 24766204 TI - Achalasia: advances in treatment. AB - Achalasia is a primary esophageal motility disorder, which shows distinct clinical, manometric, radiologic, and pathologic features. Available treatment strategies are pharmacological, endoscopic or surgical. In the past decades preferred treatment has alternated between surgical myotomy (presently Laparoscopic Heller Myotomy [LHM]) and endoscopic balloon dilation (EBD). While surgical myotomy promises superior long-term results and significantly less retreatment, endoscopic balloon dilation is initially far less invasive and yields comparable results after redilation. Peroral Endoscopic Myotomy (POEM) aims to combine the minimal invasive approach through the mouth with the better long-term results after LHM. Initial findings in the literature point to comparable success-rates after POEM and LHM. In the literature complication rates are similar to those obtained after surgery. This new interventional technique should be subject to randomized controlled trials and compared to EBD and LHM. PMID- 24766205 TI - Encapsulation of essential oils in SiO2 microcapsules and release behaviour of volatile compounds. AB - Natural substances derived from plants such as essential oils (EOs) are used in a variety of applications such as in the release of fragrances or active substances in cosmetics, in food industries to protect sensitive ingredients against oxidative processes and as antimicrobial agents. However, the labile and volatile nature of EOs reduces their activity during application or storage. Here, the microencapsulation of EOs in silica capsules was investigated as a mean to control the fast release of their volatile constituents. The preparation of silica capsules with oil cores was obtained by employing a sol-gel method to oil in-water-in-oil (O/W/O) multiple emulsions. The volatile release from the SiO2 capsules was investigated by comprehensive two-dimensional gas chromatography with time of flight mass spectrometry detection (GC * GC-ToFMS). This research demonstrates that the SiO2 capsules have selectively encapsulated the different volatile species and the corresponding release profiles depend on the chemical properties of each component. PMID- 24766206 TI - Transglutaminase-induced or citric acid-mediated cross-linking of whey proteins to tune the characteristics of subsequently desolvated sub-micron and nano-scaled particles. AB - Whey proteins were inter-connected either by the enzyme transglutaminase or citric acid and then desolvated with ethanol to generate particles. Both samples comprised of sub-micron (>300 nm) and nano-scaled (~100 nm) particles based on the hydrodynamic size measurements. Enzyme-induced cross-linking of proteins yielded more monodisperse particles and decreased the mean size of the major (nano-scaled) fraction of particles. Scanning electron microscopy images revealed a spherical morphology for all samples with mean sizes of <40 nm. Atomic force microscopy indicated a lower height for the particles from enzymatically cross linked proteins. The mediating role of citric acid in bridging the proteins was confirmed by Fourier transform infrared spectroscopy. Differential scanning calorimetry indicated that pre-heating of protein solution before cross-linking and desolvation denatured the proteins entirely. In vitro degradation of whey protein particles in a simulated gastric fluid demonstrated that cross-linking of whey proteins before desolvation stage enhanced significantly the digestion stability of particles. PMID- 24766207 TI - Skin penetration and photoprotection of topical formulations containing benzophenone-3 solid lipid microparticles prepared by the solvent-free spray congealing technique. AB - PURPOSE: Solid-lipid microparticles loaded with high amounts of the sunscreen UV filter benzophenone-3 were prepared by spray congealing with the objective of decreasing its skin penetration and evaluate whether the sunscreen's photoprotection were impaired by the microencapsulation process. METHODS: The microparticles were produced using the natural lipids carnauba wax or bees wax and three different concentrations of benzophenone-3 (30, 50 and 70%) using spray congealing technique. RESULTS: The microparticles presented properties suitable for topical application, such as spherical morphology, high encapsulation efficiency (95.53-102.2%), average particle sizes between 28.5 and 60.0 um with polydispersivities from 1.2 to 2.5. In studies of in vitro skin penetration and preliminary stability, formulations of gel cream containing carnauba wax solid lipid microparticles and 70% benzophenone-3 when compared to the formulation added of bees wax solid-lipid microparticles containing 70% benzophenone-3, was stable considering the several parameters evaluated and were able to decrease the penetration of the UV filter into pig skin. Moreover, the formulations containing solid lipid microparticles with 70% benzophenone-3 increased the photoprotective capacity of benzophenone-3 under UV irradiation. CONCLUSION: The results show that spray-congealed microparticles are interesting solid forms to decrease the penetration solar filters in the skin without compromising their photoprotection. PMID- 24766208 TI - A novel solid dispersion system for natural product-loaded medicine: silymarin loaded solid dispersion with enhanced oral bioavailability and hepatoprotective activity. AB - A surface-attached silymarin-loaded solid dispersion with improved dissolution profile and enhanced oral bioavailability was formulated using silymarin, polyvinylpyrrolidone (PVP) and Tween 80 in water. In this solid dispersion, hydrophilic PVP was adhered onto the surface of crystalline drug rendering silymarin hydrophilic without changing its crystallinity. The drug solubility from the optimised solid dispersion prepared with silymarin/PVP/Tween 80 at the weight ratio of 5/2.5/2.5 increased by almost 650-fold compared to drug powder. The drug was physically and chemically stable in the solid dispersion for at least 6 months. Moreover, the solid dispersion enhanced the oral bioavailability of the drug in rats by almost 3-fold compared to the commercial product. The silymarin-loaded solid dispersion also exhibited advanced hepatoprotective bioactivity against CCl4-induced liver damage compared to silymarin or the commercial product. Thus, this silymarin-loaded solid dispersion would be useful for the enhancement of oral bioavailability and hepatoprotective activity of poorly water-soluble silymarin. PMID- 24766209 TI - Behaviour and ultrastructure of human bone marrow-derived mesenchymal stem cells immobilised in alginate-poly-l-lysine-alginate microcapsules. AB - CONTEXT: Human bone marrow mesenchymal stem cells (hBM-MSCs) show a great promise for the treatment of a variety of diseases. Despite the previous trials to encapsulate hBM-MSCs in alginate-poly-l-lysine-alginate (APA) systems, the various changes that follow immobilisation have not been ascertained yet. OBJECTIVE: Determine the various consequences derived from entrapment on cell behaviour, putting special emphasis on the ultrastructure. METHODS: hBM-MSCs were immobilised in APA microcapsules to further characterise their viability, metabolic activity, proliferation, VEGF-secretability, and morphology. RESULTS: The VEGF produced by monolayer hBM-MSCs increased significantly 1 d post encapsulation, and was maintained for at least 4 weeks. TEM imaging of cells revealed well preserved ultrastructure indicating protein synthesis and high metabolic activity. CONCLUSION: Although APA microencapsulation did not support 100% of fully viable hBM-MSCs for long-term cultures, it was conceived to enhance both VEGF secretion and metabolic activity while not losing their stemness characteristics. PMID- 24766211 TI - Predictive biomarkers of pre-eclampsia and effectiveness of preventative interventions for the disease. AB - INTRODUCTION: Pre-eclampsia (PE) is one of the most common pregnancy complication characterized by placental and maternal vascular dysfunction. It affects about 3 8% of women during the second half of pregnancy and represents one of the major causes of neonatal morbidity and mortality. The etiology of PE largely remains unknown. AREAS COVERED: PE is considered a syndrome with multisystem involvement, so the ideal predictive test for it should utilize a combination of many predictors. Measurement in early pregnancy of a variety of biophysical and biochemical markers implicated in the pathophysiology of PE associated with clinical risk factors has been proposed to predict the development of the syndrome, thereby mitigating an adverse outcome. EXPERT OPINION: The identification of reliable indicators is a clinically relevant issue that could result in early therapeutic intervention and leading to the prevention of maternal and fetal injuries before the manifestation of clinical signs. Many factors complicate the prevention of PE cases. Most are attributed to unknown etiology, the low predictive value of current screening tests and the several presentations of the disease. Although preventative treatments have been studied extensively, an effective intervention to avoid the development of PE has not yet been discovered. PMID- 24766210 TI - Region- and domain-dependent action of nomifensine. AB - The dopamine (DA) terminal fields in the rat dorsal striatum (DS) and nucleus accumbens core (NAcc) are organized as patchworks of domains that exhibit distinct kinetics of DA release and clearance. The present study used fast-scan cyclic voltammetry recordings of electrically evoked DA overflow to test the hypothesis that nomifensine might exhibit domain-dependent actions within the NAcc, as we previously found to be the case within the DS. Within the NAcc, nomifensine preferentially enhanced evoked DA overflow in the slow domains compared with the fast domains. To seek a kinetic explanation for nomifensine's selective actions, we quantified the apparent KM of DA clearance by numerically evaluating the derivative of the descending phase of the DA signal after the end of the stimulus. For comparison, we likewise quantified the apparent KM in the domains of the DS. As expected, because it is a competitive inhibitor, nomifensine significantly increased the apparent KM in both the fast and slow domains of both the NAcc and DS. However, our analysis also led to the novel finding that nomifensine preferentially increases the apparent KM in the NAcc compared with the DS; the apparent KM increased by ~500% in the NAcc and by ~200% in the DS. PMID- 24766212 TI - Integrative analysis of prognosis data on multiple cancer subtypes. AB - In cancer research, profiling studies have been extensively conducted, searching for genes/SNPs associated with prognosis. Cancer is diverse. Examining the similarity and difference in the genetic basis of multiple subtypes of the same cancer can lead to a better understanding of their connections and distinctions. Classic meta-analysis methods analyze each subtype separately and then compare analysis results across subtypes. Integrative analysis methods, in contrast, analyze the raw data on multiple subtypes simultaneously and can outperform meta analysis methods. In this study, prognosis data on multiple subtypes of the same cancer are analyzed. An AFT (accelerated failure time) model is adopted to describe survival. The genetic basis of multiple subtypes is described using the heterogeneity model, which allows a gene/SNP to be associated with prognosis of some subtypes but not others. A compound penalization method is developed to identify genes that contain important SNPs associated with prognosis. The proposed method has an intuitive formulation and is realized using an iterative algorithm. Asymptotic properties are rigorously established. Simulation shows that the proposed method has satisfactory performance and outperforms a penalization-based meta-analysis method and a regularized thresholding method. An NHL (non-Hodgkin lymphoma) prognosis study with SNP measurements is analyzed. Genes associated with the three major subtypes, namely DLBCL, FL, and CLL/SLL, are identified. The proposed method identifies genes that are different from alternatives and have important implications and satisfactory prediction performance. PMID- 24766213 TI - Vascular endothelial growth factor A (VEGFA) expression in mycosis fungoides. AB - AIMS: High levels of vascular endothelial growth factor A (VEGFA) seem to herald a worse prognosis in mycosis fungoides (MF). In this study, we aimed to characterize more clearly VEGFA gene and protein expression in MF. METHODS AND RESULTS: First, we compared VEGFA mRNA levels in MF and in normal T lymphocyte samples; significantly higher VEGFA levels were found in MF. We then studied VEGFA expression in different normal T cell subsets, focusing on CD4(+) , CD8(+) , resting and activated T lymphocytes. We applied the gene signatures of the normal T cell subsets to MF samples and found that activated T lymphocytes represented the closest normal counterpart of the tumour. However, VEGFA mRNA levels were significantly higher in MF than in activated normal T cells, suggesting that VEGFA overexpression in MF represents an attribute acquired during neoplastic transformation: no significant VEGFA expression differences were recorded between early and advanced stages. Gene expression profile results were supported by immunohistochemistry in routine sections from 27 MF cases. CONCLUSIONS: For the first time, we demonstrate VEGFA expression in MF cells, suggesting that the VEGF pathway may be implicated in MF pathogenesis and can represent a novel therapeutic target. PMID- 24766214 TI - Model studies on the oxidation of benzoyl methionine in a carbohydrate degradation system. AB - The stability of benzoyl methionine was analyzed during incubation with carbohydrate compounds such as reducing sugars, dicarbonyl compounds, reductones, and Amadori rearrangement products (ARPs). The reaction products were identified and quantified by HPLC-UV and HPLC-MS. In the presence of ARPs, >40% of benzoyl methionine was oxidized to benzoyl methionine sulfoxide after 48 h at 80 degrees C in acetate-buffered solution (pH 6.0), whereas <10% was oxidized in the presence of mono- and disaccharides. As an important side reaction, peptide bond cleavage through alpha-amidation was verified. The influence of benzoyl methionine on carbohydrate degradation reactions was assessed through analysis of vicinal dicarbonyl compounds by HPLC-UV. Glyoxal, methylglyoxal, diacetyl, and 3 deoxyglucosone were quantified as the most important derivatives. The thioether group of methionine strongly influenced carbohydrate degradation pathways: Less glyoxal was formed from reducing carbohydrates, showing that benzoyl methionine can act as a radical scavenger. However, more diacetyl was formed from ARPs and reductones, indicating that also radical-dependent pathways could be influenced by benzoyl methionine. The degradation of reducing carbohydrates should thus be an important contributor to protein oxidation in food items with low fat content. PMID- 24766215 TI - Codetype-based interpretation of the MMPI-2 in an outpatient psychotherapy sample. AB - In an evaluation of the codetype-based interpretation of the MMPI-2, 48 doctoral student psychotherapists rated their clients' (N = 120) standardized interpretations as more accurate when based on the profile's codetype, in comparison with ratings for interpretations based on alternate codetypes. Effect sizes ranged from nonsignificant to large, depending on the degree of proximity between the profile's codetype and the alternate codetype. There was weak evidence to suggest that well-defined profiles yielded more accurate interpretations than undefined profiles. It appears that codetype-based interpretation of the MMPI-2 is generally valid, but there might be little difference in the accuracy of interpretations based on nearby codetypes. PMID- 24766217 TI - Conserved phenylalanine residues are required for blue-shifting of cyanobacteriochrome photoproducts. AB - Cyanobacteriochromes (CBCRs) are cyanobacterial photosensory proteins distantly related to phytochromes. Both phytochromes and CBCRs reversibly convert between dark-stable and photoproduct states upon photoisomerization of their linear tetrapyrrole (bilin) chromophores. While most phytochromes convert between a red absorbing dark state and a far-red-absorbing photoproduct, CBCRs exhibit spectral responses spanning the entire near-ultraviolet and visible spectrum. For example, red/green CBCRs such as AnPixJ and NpR6012g4 exhibit a red-absorbing dark state similar to that of phytochrome, but photoconversion yields a green-absorbing photoproduct. "Teal-DXCF" CBCRs convert from blue- or green-absorbing dark states to yield photoproducts with very narrow absorption in the teal region of the spectrum (approximately 500 nm). The recent determination of a crystal structure of AnPixJ in its red-absorbing dark state led to the proposal that movement of a Trp residue (the "lid Trp") upon photoconversion would allow solvation of the photoproduct, thereby producing a large blue-shift. We find that substitution of the lid Trp has little effect on the NpR6012g4 photoproduct. Instead, two Phe residues conserved in red/green and teal-DXCF CBCRs are essential for determining photoproduct absorption in both CBCR groups with no significant influence on the dark-adapted state. We propose that these Phe residues constrain chromophore movement after primary photoisomerization. This work supports a trapped-twist mechanism for generating both red/green and teal-DXCF photoproducts. PMID- 24766216 TI - Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma. AB - The nuclear transporter exportin-1 (XPO1) is highly expressed in mantle cell lymphoma (MCL) cells, and is believed to be associated with the pathogenesis of this disease. XPO1-selective inhibitors of nuclear export (SINE) compounds have been shown to induce apoptosis in MCL cells. Given that p53 is a cargo protein of XPO1, we sought to determine the significance of p53 activation through XPO1 inhibition in SINE-induced apoptosis of MCL cells. We investigated the prognostic impact of XPO1 expression in MCL cells using Oncomine analysis. The significance of p53 mutational/functional status on sensitivity to XPO1 inhibition in cell models and primary MCL samples, and the functional role of p53-mediated apoptosis signaling, were also examined. Increased XPO1 expression was associated with poor prognosis in MCL patients. The XPO1 inhibitor KPT-185 induced apoptosis in MCL cells through p53-dependent and -independent mechanisms, and p53 status was a critical determinant of its apoptosis induction. The KPT-185-induced, p53 mediated apoptosis in the MCL cells occurred in a transcription-dependent manner. Exportin-1 appears to influence patient survival in MCL, and the SINE XPO1 antagonist KPT-185 effectively activates p53-mediated transcription and apoptosis, which would provide a novel strategy for the therapy of MCL. PMID- 24766218 TI - Family screening in hypertrophic cardiomyopathy is underperformed, but can be improved by a specialised clinic. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) causes significant morbidity and sudden death. First-degree relatives (FDR) of affected patients are at risk due to autosomal dominant inheritance. Guidelines recommend clinical screening, including echocardiography, for all FDR. AIM: We sought to determine adherence to these guidelines, and whether a specialised HCM clinic improves screening rates. METHOD: This 12-month prospective follow-up study obtained family pedigrees from all patients referred to the HCM Clinic @ The Alfred. The number of living FDR was determined, and whether they had previously been assessed by echocardiography. One year after a coordinated clinic-based family screening approach was instituted, the number of additionally screened FDR was recorded. RESULTS: Three hundred and eight living FDR of 61 HCM patients were identified. Of these, echocardiography had previously been performed in only 80 (26%), yielding 13 (16%) additional cases of HCM. Twelve months after attendance at our clinic, 51 additional FDR were screened (64% improvement) and 8 new cases of HCM were identified. CONCLUSIONS: Recommended family screening for HCM is underperformed, resulting in missed opportunities to detect subclinical HCM. A coordinated approach through a specialised HCM clinic improves screening rates, thus referral to such a service should be considered for all patients with HCM and their families. PMID- 24766219 TI - Glutathione immunosensing platform based on total internal reflection ellipsometry enhanced by functionalized gold nanoparticles. AB - An immunosensor to detect small molecules, such as glutathione (GSH), has been developed by combination of ellipsometry and Kretschmann surface plasmon resonance (SPR). The Au thin film used for surface plasmon polariton (SPP) excitation is functionalized with anti-GSH to specifically bind GSH. At low concentrations, the small refractive index changes caused by the low molecular weight of GSH induced only negligible shifts in the plasmon resonant energy during GSH binding. To improve sensitivity, gold nanoparticles (AuNPs) are functionalized with glutathione acting as amplifiers of the antigen-antibody interaction. Changes induced by the AuNP adsorption are monitored using Psi and Delta ellipsometric functions. After performing competitive assays using solutions containing different concentrations of free GSH and a constant amount of functionalized AuNPs, it was concluded that the resonant energy linearly shifts as the relative concentration of free GSH increases. A detection limit for free GSH in the nanomolar range is found, demonstrating the effectiveness of AuNPs to enhance the sensitivity to immunoreactions in total internal reflection ellipsometry. PMID- 24766220 TI - Effects of mannan oligosaccharide and virginiamycin on the cecal microbial community and intestinal morphology of chickens raised under suboptimal conditions. AB - There is an increasing movement against use of antibiotic growth promoters in animal feed. Prebiotic supplementation is a potential alternative to enhance the host's natural defense through modulation of gut microbiota. In the present study, the effect of mannan oligosaccharide (MOS) and virginiamycin (VIRG) on cecal microbial ecology and intestinal morphology of broiler chickens raised under suboptimal conditions was evaluated. MOS and VIRG induced different bacterial community structures, as revealed by denaturing gradient gel electrophoresis of 16S rDNA. The antibiotic treatment reduced cecal microbial diversity while the community equitability increased. A higher bacterial diversity was observed in the cecum of MOS-supplemented birds. Quantitative polymerase chain reaction results indicated that MOS changed the cecal microbiota in favor of the Firmicutes population but not the Bacteroidetes population. No difference was observed in total bacterial counts among treatments. MOS promoted the growth of Lactobacillus spp. and Bifidobacterium spp. in the cecum and increased villus height and goblet cell numbers in the ileum and jejunum. These results provide a deeper insight into the microbial ecological changes after supplementation of MOS prebiotic in poultry diets. PMID- 24766221 TI - Genetic variants in the P2RX7 gene are associated with risk of multiple myeloma. PMID- 24766222 TI - Protein induced aggregation of conjugated polyelectrolytes probed with fluorescence correlation spectroscopy: application to protein identification. AB - The interaction of a series of water-soluble conjugated polyelectrolytes with varying backbone structure, charge type (cationic and anionic), and charge density with a set of seven different proteins is explored by using fluorescence correlation spectroscopy (FCS). The FCS method affords the diffusion time for a particular CPE/protein pair, and this diffusion time is a reflection of the aggregation state of the polymer/protein in the solution. The diffusion time is larger for oppositely charged CPE/protein combinations, reflecting the tendency toward the formation of CPE/protein aggregates in these systems. However, by careful analysis of the data, other factors emerge, including possible effects of hydrophobic interaction in specific CPE/protein systems. The final diffusion time for each CPE/protein mixture varies and the diffusion time response pattern created by the six-CPE array for a typical protein is unique, and this effect was leveraged to develop a sensor array for protein identification by using linear discriminant analysis (LDA) methods. By application of multimode linear discrimination analysis, the unknown protein samples have been successfully identified with a total accuracy of 93%. PMID- 24766223 TI - Identification and intraspecific genetic diversity of Sarcocystis rileyi from ducks, Anas spp., in Lithuania and Finland. AB - Macroscopic Sarcocystis cysts were detected in the muscles of 28 Mallards ( Anas platyrhynchos ), 1 Eurasian Wigeon ( Anas penelope ), and 1 Common Teal ( Anas crecca ) hunted in Lithuania and Finland. According to the sequences of the 18S rRNA gene, 28S rRNA gene, and ITS-1 region, the macrocysts examined from all 30 ducks belonged to Sarcocystis rileyi. This parasite was found in the Eurasian Wigeon and the Common Teal for the first time. All S. rileyi isolates examined were identical to each other and differed from 2 S. rileyi isolates previously reported from 2 Mallards from the United States only by 1 nucleotide substitution within the ITS-1 region. PMID- 24766224 TI - Pruritus in hemodialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS). AB - Pruritus affects many patients undergoing hemodialysis (HD). In this study, pruritus and its relationship to morbidity, quality of life (QoL), sleep quality, and patient laboratory measures were analyzed in a large sample of Japanese patients undergoing HD. Severity of patient-reported pruritus symptoms experienced during a 4-week period was collected from 6480 Japanese patients undergoing HD in three phases of the Dialysis Outcomes and Practice Patterns Study (DOPPS; 1996-2008; 60-65 study facilities/phase). Adjusted linear and logistic regressions were used to identify associations of pruritus with treatment parameters and QoL outcomes. Adjusted Cox regressions examined the influence of pruritus severity on mortality. Moderate to extreme pruritus was experienced by 44% of prevalent patients undergoing HD in the Japanese Dialysis Outcomes and Practice Patterns Study. Many patient characteristics were significantly associated with pruritus, but this did not explain the large differences in pruritus among facilities (20-70%). Pruritus was slightly less common in patients starting HD than in patients on dialysis >1 year. Patients with moderate to extreme pruritus were more likely to feel drained (adjusted odds ratio = 2.2-5.8, P < 0.0001), have poor sleep quality (adjusted odds ratio = 1.9 3.7, P < 0.0001), and have QoL mental and physical composite scores 2.3-6.7 points lower (P < 0.0001) than patients with no/mild pruritus. Pruritus in patients undergoing HD was associated with a 23% higher mortality risk (P = 0.09). The many poor outcomes associated with pruritus underscore the need for better therapeutic agents to provide relief for the 40-50% of prevalent patients undergoing HD substantially affected by pruritus. Pruritus in new patients with end-stage renal disease likely results from uremia or pre-existing conditions (not HD per se), indicating the need to understand development of pruritus before end-stage renal disease. PMID- 24766225 TI - Magnetic resonance imaging characteristics in four dogs with central nervous system neosporosis. AB - Neosporosis is a polysystemic disease that can affect dogs of any age and can cause inflammation of the central nervous system. Antemortem diagnosis can be challenging, as clinical and conventional laboratory test findings are often nonspecific. A previous report described cerebellar lesions in brain MRI studies of seven dogs and proposed that these may be characteristic for central nervous system Neosporosis. The purpose of this retrospective study was to describe MRI characteristics in another group of dogs with confirmed central nervous system neosporosis and compare them with the previous report. The hospital's database was searched for dogs with confirmed central nervous system neosporosis and four observers recorded findings from each dog's MRI studies. A total of four dogs met inclusion criteria. Neurologic examination was indicative of a forebrain and cerebellar lesion in dog 2 and multifocal central nervous system disease in dogs 1, 3, and 4. Magnetic resonance imaging showed mild bilateral and symmetrical cerebellar atrophy in three of four dogs (dogs 2, 3, 4), intramedullary spinal cord changes in two dogs (dogs 3, 4) and a mesencephalic and metencephalic lesion in one dog (dog 2). Multifocal brain lesions were recognized in two dogs (dogs 1, 4) and were present in the thalamus, lentiform nucleus, centrum semiovale, internal capsule, brainstem and cortical gray matter of the frontal, parietal or temporal lobe. Findings indicated that central nervous system neosporosis may be characterized by multifocal MRI lesions as well as cerebellar involvement in dogs. PMID- 24766227 TI - At least one in three people with Type 2 diabetes mellitus referred to a diabetes centre has symptomatic obstructive sleep apnoea. AB - AIMS: To investigate the prevalence of symptomatic obstructive sleep apnoea in unselected patients with Type 2 diabetes referred to a tertiary diabetes clinic. METHODS: In a cross-sectional design, all newly referred patients were offered a stepwise screening for obstructive sleep apnoea with: (1) The Berlin questionnaire; then, if indicative: (2) overnight home monitoring with the ApneaLinkTM device. Patients with an apnoea-hypopnoea index >= 5/h were offered referral for diagnostic polygraphy and treatment initiation. RESULTS: A total of 200 patients participated (61% men; age 59.6 +/- 10.5 years, diabetes duration 8.3 +/- 6.3 years and BMI 31.7 +/- 6.7 kg/m2). According to the questionnaire, 106 patients showed 'high risk' of obstructive sleep apnoea, and 72 of these were referred to polygraphy based on ApneaLink screening corresponding to a prevalence of symptomatic obstructive sleep apnoea of 39%. Patients with symptomatic obstructive sleep apnoea had significantly higher BMI, poorer glycaemic control and lower plasma HDL cholesterol levels as compared with patients unlikely to have obstructive sleep apnoea. The groups were not different with respect to sex, age, diabetes duration, blood pressure, diabetic complications or medication use. In multiple regression analyses, age, BMI and HDL cholesterol levels were all significant, independent predictors of obstructive sleep apnoea. CONCLUSIONS: At least one third of people with Type 2 diabetes referred to a diabetes clinic in Denmark has symptomatic obstructive sleep apnoea. Our data suggest higher age, a compromised plasma lipid profile and a more obese phenotype in patients with Type 2 diabetes who have obstructive sleep apnoea, highlighting the need to focus on screening and treatment of obstructive sleep apnoea in these patients. PMID- 24766228 TI - S100beta as an early biomarker of excitotoxic damage in spinal cord organotypic cultures. AB - S100beta is a cytoplasmic calcium-binding protein mainly expressed by glia and considered to be a useful biomarker for brain or spinal cord injury. Indeed, clinical studies suggest that the S100beta concentration in serum or cerebrospinal fluid may predict lesion outcome and prognosis. The relation of S100beta levels to damage severity and its timecourse remains, however, unclear. This study used a validated in vitro model of spinal cord injury induced by kainate-mediated excitotoxicity to investigate these issues. After 22 days in vitro, rat organotypic spinal cord slices were subjected to one transient application (1 h) of 1 or 100 MUM kainate followed by washout. While the lower kainate concentration did not evoke neuronal loss or S100beta increase, the larger concentration elicited 40% neuronal death, no change in glial number and a delayed, significant rise in extracellular S100beta that peaked at 24 h. This increase was associated with a stronger expression of the S100beta protein as indicated by western blotting and immunohistochemistry. Application of the microtubule disrupting agent colchicine did not change the rise in S100beta induced by kainate, an effect blocked by the glutamate receptor antagonists CNQX and APV. Our data suggest that excitotoxicity was followed by release of S100beta perhaps from a readily releasable pool through a mechanism independent of microtubule assembly. The raised extracellular level of S100beta appeared to reflect glial reactivity to the kainate-evoked lesion in accordance with the view that this protein may be involved in tissue protection and repair after acute injury. Excitotoxicity is a major mechanism responsible for neuronal death following acute spinal cord injury. The calcium-binding protein S100beta is released by astrocytes into the extracellular compartment during the first 24 h after the initial insult and represents a useful biomarker of lesion progression as its level is related to the occurrence and severity of neuronal loss. PMID- 24766229 TI - Comparative functional analyses of ultrabithorax reveal multiple steps and paths to diversification of legs in the adaptive radiation of semi-aquatic insects. AB - Invasion of new ecological habitats is often associated with lineage diversification, yet the genetic changes underlying invasions and radiations are poorly understood. Over 200 million years ago, the semi-aquatic insects invaded water surface from a common terrestrial ancestor and diversified to exploit a wide array of niches. Here, we uncover the changes in regulation and function of the gene Ultrabithorax associated with both the invasion of water surface and the subsequent diversification of the group. In the common ancestor of the semi aquatic insects, a novel deployment of Ubx protein in the mid-legs increased their length, thereby enhancing their role in water surface walking. In derived lineages that specialize in rowing on the open water, additional changes in the timing of Ubx expression further elongated the mid-legs thereby facilitating their function as oars. In addition, Ubx protein function was selectively reversed to shorten specific rear-leg segments, thereby enabling their function as rudders. These changes in Ubx have generated distinct niche-specialized morphologies that account for the remarkable diversification of the semi-aquatic insects. Therefore, changes in the regulation and function of a key developmental gene may facilitate both the morphological change necessary to transition to novel habitats and fuel subsequent morphological diversification. PMID- 24766230 TI - The role of endoscopic ultrasound in the radiation treatment of pancreatic tumor. AB - Radiotherapy is an established treatment modality for patients with pancreatic cancer. Image-guided radiation therapy (IGRT) allows the delivery of high doses to the tumour, while sparing the sensitive tissues around it, thus reducing side effects. However, the need of precisely contouring and identifying the target lesion is mandatory to be able to perform IGRT. Endoscopic ultrasound has been progressively implemented in the field of radiotherapy as a tool for intra lesional placement of fiducial markers to perform IGRT and for direct placing of sealed radioactive sources in contact with the target lesions. In the current paper we provide an updated review on the role of endoscopic ultrasound in the radiation treatment of pancreatic cancer, highlighting areas of future research. PMID- 24766231 TI - An in vivo study on the photo-enhanced toxicities of S-doped TiO2 nanoparticles to zebrafish embryos (Danio rerio) in terms of malformation, mortality, rheotaxis dysfunction, and DNA damage. AB - The role of light on the acute toxicities of S-doped and Sigma TiO2 nanoparticles in zebrafish was studied. Metrics included mortality for both, and rheotaxis dysfunction and DNA damage for S-doped only. It was found that the acute toxicity of S-TiO2 nanoparticles was enhanced by simulated sunlight (SSL) irradiation (96 h LC50 of 116.56 ppm) and exceeded that of Sigma TiO2, which was essentially non toxic. Behavioral disorder, in terms of rheotaxis, was significantly increased by treatment with S-TiO2 nanoparticles under SSL irradiation. In order to further understand its toxicity mechanism, we investigated hair cells in neuromasts of the posterior lateral line (PLL) using DASPEI staining. Significant hair cell damage was observed in the treated larvae. The Comet assay was employed to investigate the DNA damage, which might be responsible for the loss of hair cells. Production of the superoxide anion ([Formula: see text]), a major ROS generated by TiO2 nanoparticles, was assayed and used to postulate causative factors to account for these damages. Oxidative effects were most severe in the liver, heart, intestine, pancreatic duct, and pancreatic islet - results consistent with our earlier findings in the investigation of embryonic malformation. TEM micrographs, used to further investigate the fate of S-TiO2 nanoparticles at the cellular level, suggested receptor-mediated autophagy and vacuolization. Our findings validate the benefit of using the transparent zebrafish embryo as an in vivo model for evaluating photo-induced nanotoxicity. These results highlight the importance of conducting a systematic risk assessment in connection with the use of doped TiO2 nanoparticles in aquatic ecosystems. PMID- 24766232 TI - Gene therapy for peripheral arterial disease. AB - INTRODUCTION: Gene therapy has emerged as a novel therapy to promote angiogenesis in patients with critical limb ischemia (CLI) caused by peripheral artery disease. Researchers working in this area have focused on pro-angiogenic factors, such as VEGF, fibroblast growth factor (FGF) and hepatocyte growth factor (HGF). Based on the elaborate studies and favorable results of basic research using naked plasmid DNA (pDNA) encoding these growth factors, some clinical Phase I and Phase II trials have been performed. The results of these studies demonstrate the safety of these approaches and their potential for symptomatic improvement in CLI patients. However, the Phase III clinical trials have so far been limited to HGF gene therapy. Because one pitfall of the Phase III trials has been the limited transgene expression achieved using naked pDNA alone, the development of more efficient gene transfer systems, such as ultrasound microbubbles and the needleless injector, as well as the addition of other genes will make these novel therapies more effective and ease the symptoms of CLI. AREAS COVERED: This study reviews the previously published basic research and clinical trials that have studied VEGF, FGF and HGF gene therapies for the treatment of CLI. Adjunctive therapies, such as the addition of prostacyclin synthase genes and the development of more efficient gene transfer techniques for pDNA, are also reviewed. EXPERT OPINION: To date, clinical studies have demonstrated the safety of gene therapy in limb ischemia but the effectiveness of this treatment has not been determined. Larger clinical studies, as well as the development of more effective gene therapy, are needed to achieve and confirm beneficial effects. PMID- 24766233 TI - Reproducibility of near-infrared spectroscopy measurements of oxidative function and postexercise recovery kinetics in the medial gastrocnemius muscle. AB - The purpose of this study was to assess the reproducibility of resting blood flow, resting oxygen consumption, and mitochondrial capacity in skeletal muscle using near-infrared spectroscopy (NIRS). We also determined the influence of 2 exercise modalities (ergometer and rubber exercise bands) on the NIRS measurements. Fifteen young, healthy participants (5 female, 10 male) were tested on 2 nonconsecutive occasions within an 8-day period. The NIRS device was placed on the medial gastrocnemius. Venous and arterial occlusions were performed to obtain blood flow and oxygen consumption. A series of repeated arterial occlusions was used to measure the recovery kinetics of muscle oxygen consumption after ~7-10 s of voluntary plantar flexion exercise. Resting blood flow had mean coefficients of variation (CV) of 42% and 38% for bands and ergometer, respectively, and resting metabolism had mean CVs of 17% and 12% for bands and ergometer, respectively. The recovery time constant of oxygen consumption (day 1 bands and ergometer: 23.2 +/- 3.7 s, 27.6 +/- 6.5 s, respectively; day 2 bands and ergometer: 25.5 +/- 5.4 s, 25.0 +/- 4.9 s, respectively) had mean CVs of 10% and 11% for bands and ergometer, respectively. We conclude that measurements of oxygen consumption and mitochondrial capacity using NIRS can be obtained with good reproducibility. PMID- 24766234 TI - Leptin, vitamin D, and cardiorespiratory fitness as risk factors for insulin resistance in European adolescents: gender differences in the HELENA Study. AB - The purpose of this study was to identify the relevance of a set of risk factors for insulin resistance in adolescents from Europe and to consider their possible gender-specific associations. The Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (HELENA-CSS) was conducted in 1053 European adolescents (mean age, 14.9 years) in a school setting in 9 countries. Three anthropometric markers of body fat and a dietary index were calculated. Total energy intake was estimated from a questionnaire. C-reactive protein, leptin, and vitamin D were assessed, and physical activity, cardiorespiratory fitness, and muscular strength were measured. Center, socioeconomic status, pubertal status, and season were used as potential confounders. The main outcome was the homeostasis model assessment used as a marker of insulin resistance. Correlations, analyses of covariance, and logistic regression models were used. In males, leptin was the only risk factor for insulin resistance after adjusting for confounders including markers of body fat (odds ratios (ORs) from 1.49 to 1.60). In females, leptin, vitamin D, and fitness were the remaining independent risk factors for insulin resistance after adjustments (OR 2.11; 95% confidential interval (CI) 1.29-3.45; OR 0.50, 95% CI 0.31-0.80; and OR 0.54, 95% CI 0.33 0.87, respectively). Our observations suggest a gender dimorphism in the identification of risk factors for high insulin resistance. Preventive strategies should focus on improving modifiable factors such as cardiorespiratory fitness and on ensuring vitamin D sufficiency. Randomized controlled trials focusing on these strategies are necessary to test their efficacy. PMID- 24766235 TI - Effects of different meal compositions after exercise on fat and carbohydrate oxidation in women with different levels of body fat. AB - We investigated the effects of consuming a high-carbohydrate meal (HC), high-fat meal (HF), or no meal (CON) following exercise on fat and carbohydrate oxidation (FAT-OX, CHO-OX) in women with differing levels of body fat. Healthy, physically active females were divided into a Lower Fat (<25% fat, n = 10) or Higher Fat (>25% fat, n = 9) group and tested on 4 occasions. During session 1, body composition and maximal oxygen consumption were determined. During 3 treatment sessions, subjects preformed treadmill exercise at 55% of maximal oxygen consumption until 350 kcal were expended. At 10 min postexercise subjects consumed a liquid meal standardized to provide energy equal to 20% of 24-h energy expenditure plus the 350 kcal of exercise. The HC meal comprised 64% carbohydrate, 21.6% fat, and 14.4% protein. The HF meal comprised 24% carbohydrate, 62% fat, and 14% protein. CON consisted of water equal to the meal volume. During exercise and 2 h postexercise, expired gases were collected to determine FAT-OX and CHO-OX. During exercise CHO-OX was a significantly higher for the Lower Fat group and FAT-OX was significantly higher for the Lower Fat group for each of the meal conditions. A significant difference was observed across meals (p < 0.05) for CHO-OX (first hour) and for CHO-OX and FAT-OX (second hour) postexercise. There were no significant differences (p > 0.05) between the Lower Fat and Higher Fat groups for either recovery period. In physically active females, the macronutrient composition of the postexercise meal affects substrate oxidation, but the level of body fat does not. PMID- 24766236 TI - Weight classification does not influence the short-term endocrine or metabolic effects of high-fructose corn syrup-sweetened beverages. AB - Obesity and high-fructose corn syrup (HFCS)-sweetened beverages are associated with an increased risk of chronic disease, but it is not clear whether obese (Ob) individuals are more susceptible to the detrimental effects of HFCS-sweetened beverages. The purpose of this study was to examine the endocrine and metabolic effects of consuming HFCS-sweetened beverages, and whether weight classification (normal weight (NW) vs. Ob) influences these effects. Ten NW and 10 Ob men and women who habitually consumed <=355 mL per day of sugar-sweetened beverages were included in this study. Initially, the participants underwent a 4-h mixed-meal test after a 12-h overnight fast to assess insulin sensitivity, pancreatic and gut endocrine responses, insulin secretion and clearance, and glucose, triacylglycerol, and cholesterol responses. Next, the participants consumed their normal diet ad libitum, with 1065 mL per day (117 g.day(-1)) of HFCS-sweetened beverages added for 2 weeks. After the intervention, the participants repeated the mixed-meal test. HFCS-sweetened beverages did not significantly alter body weight, insulin sensitivity, insulin secretion or clearance, or endocrine, glucose, lipid, or cholesterol responses in either NW or Ob individuals. Regardless of previous diet, Ob individuals, compared with NW individuals, had ~28% lower physical activity levels, 6%-9% lower insulin sensitivity, 12%-16% lower fasting high-density-lipoprotein cholesterol concentrations, 84%-144% greater postprandial triacylglycerol concentrations, and 46%-79% greater postprandial insulin concentrations. Greater insulin responses were associated with reduced insulin clearance, and there were no differences in insulin secretion. These findings suggest that weight classification does not influence the short-term endocrine and metabolic effects of HFCS-sweetened beverages. PMID- 24766237 TI - Physical fitness, motor skill, and physical activity relationships in grade 4 to 6 children. AB - The present study sought to quantify the relationships among physical activity (PA), health-related fitness, and motor skill in children (grades 4 to 6), and to determine whether specific tests of fitness or motor skill are independently associated with objectively measured PA level. Four hundred and ninety-one students (56.4% female) wore a Digi-Walker pedometer for 7 consecutive days. Standardized protocols were used to assess health-related fitness (body mass index percentile, waist circumference, 20-m shuttle run, plank, handgrip, and trunk flexibility). Motor skill was evaluated using a validated obstacle course. Pearson correlations (with Holm adjustments for multiple comparisons) initially assessed associations among PA, health-related fitness, and motor skill. Multi variable linear regression was used to determine which factors were significantly associated with daily step counts, while adjusting for gender, age, testing season, and socioeconomic status. Step counts were significantly correlated with predicted aerobic power (r = 0.30), obstacle course time (r = -0.27), obstacle course score (r = 0.20), plank isometric torso endurance (r = 0.16), and handgrip strength (r = 0.12), but not with waist circumference (r = -0.10), trunk flexibility (r = 0.10), or overweight status (rho = -0.06). In the multi-variable model, predicted aerobic power, obstacle course time, testing season, gender, and the predicted aerobic power by gender interaction were significantly associated with step counts, explaining 16.4% of the variance. Specifically, the relationship between predicted aerobic power and step counts was stronger in girls. These findings suggest that aerobic fitness and motor skill are independently associated with children's PA. Future longitudinal studies should evaluate whether interventions to enhance aerobic fitness and motor skill could enhance daily PA among children of this age. PMID- 24766238 TI - Changes in salivary hormones, immunoglobulin A, and C-reactive protein in response to ultra-endurance exercises. AB - The aim of the study was to determine the influence of the exercise duration on the changes in salivary stress markers in response to ultra-endurance exercises. The study was developed in 2 ultra-endurance exercise tests: the Ultra-trail Serra de Tramuntana (UTST), a 104 km ultra-marathon competition (n = 64) and the 25 km Cabrera Open Water Race (COWR) (n = 43). Participants in the COWR completed the 25 km at a constant pace of 3 km/h (3K group) or 2.5 km /h (2.5K group). Saliva samples were taken before and after the exercises. Salivary flow rate as well as cortisol, testosterone, C-reactive protein (CRP), and immunoglobulin A (IgA) levels were measured. Salivary flow rate decreased after the UTST but increased after the COWR. The UTST induced significant increases in cortisol and CRP levels and decreases in testosterone and IgA levels. Furthermore, a negative correlation was found between the time the athletes took to complete the exercise and the changes in salivary cortisol. After the COWR, higher increases in salivary cortisol levels were observed in the 3K group than in the 2.5K group. A significant effect of exercise decreasing testosterone and IgA levels was observed in both groups. No changes in the CRP levels were observed during the COWR. In conclusion, shorter times to complete the ultra-endurance exercise were associated with higher increases in cortisol. However, no relationships were found between the time to complete the exercises and the changes in testosterone, CRP, and IgA levels. PMID- 24766239 TI - Exercise training improves aerobic capacity, muscle strength, and quality of life in renal transplant recipients. AB - Renal transplant recipients (RTR) have reduced peak aerobic capacity, muscle strength, arterial function and an unfavorable cardiovascular disease risk (CVD) profile. This study compared the effects of 12 weeks of supervised endurance and strength training (EST, n = 16) versus usual care (UC, n = 15) on peak aerobic capicity, cardiovascular and skeletal muscle function, CVD risk profile, and quality of life (QOL) in RTR (55 +/- 13 years). Peak aerobic capacity and exercise hemodynamics, arterial compliance, 24-h blood pressure, muscle strength, lean body mass, CVD risk score, and QOL were assessed before and after 12 weeks. The change in peak aerobic capacity (EST: 2.6 +/- 3.1 vs. UC: -0.5 +/- 2.5 mL/(kg.min)), cardiac output (EST: 1.7 +/- 2.6 vs. UC: -0.01 +/- 0.8 L/min), leg press (EST: 48.7 +/- 34.1 vs. UC: -10.5 +/- 37.7 kg) and leg extension strength (EST: 9.5 +/- 10.3 vs. UC: 0.65 +/- 5.5 kg) improved significantly after EST compared with UC. The overall change in QOL improved significantly after 12 weeks of EST compared with UC. No significant difference was found between groups for lean body mass, arterial compliance, 24-h blood pressure or CVD risk score. Supervised EST is an effective intervention to improve peak exercise aerobic capacity and cardiac output, muscle strength and QOL in clinically stable RTR. PMID- 24766240 TI - Impact of a smoking cessation lifestyle intervention on vascular mechanics in young women. AB - We tested the hypotheses that smoking-induced changes in vascular mechanics would be detected earlier in the lumped properties of peripheral vascular beds, which include the properties of microvasculature, than in the local properties of central conduits, and that such changes are reversible with lifestyle changes that include smoking cessation and exercise. Vascular measures were made in 53 young (18-40 years) female smokers and 25 age-matched non-smokers. Twenty-two of the smokers were tested before and after a 14-week smoking cessation program and, of these, 13 were tested again after 52 weeks of smoking cessation. Compared with non-smokers, lumped forearm vascular bed compliance (C: mL/mm Hg) was lower, while lumped viscoelasticity (K: mm Hg/(mL.min)) and resistance (R: mm Hg/(mL.min)) were higher in the smoker group. Neither the carotid-to-toe pulse wave velocity nor local carotid artery elasticity indices were different between groups. Compared with non-smokers, brachial artery distensibility was less, and other markers of stiffness higher, in the smoker group. At 14 and 52 weeks of smoking cessation, forearm vascular R was reduced and C was increased while K was unchanged. The changes in C and R occurred while maintaining a constant R*C value, which represents a dynamic time constant. Thus, early changes in K were observed in the forearm vascular bed of smokers, which were not reflected in the local properties of central conduit vessels. Forearm C, but not K, was reversed following smoking cessation, a finding that may represent a persistent effect of smoking on the intercellular matrix of the vessel wall. PMID- 24766241 TI - Discussion of "The efficacy of the self-paced VO2max test to measure maximal oxygen uptake in treadmill running". PMID- 24766242 TI - Reply to "Discussion: Efficacy of the self-paced VO2max test to measure maximal oxygen uptake in treadmill running". PMID- 24766243 TI - Discussion: "The efficacy of the self-paced VO2max test to measure maximal oxygen uptake in treadmill running". PMID- 24766244 TI - Reply to "Discussion: The efficacy of the self-paced VO2max test to measure maximal oxygen uptake in treadmill running". PMID- 24766245 TI - Discussion: The efficacy of the self-paced VO2max test to measure maximal oxygen uptake in treadmill running. PMID- 24766246 TI - Reply to "Discussion: Efficacy of the self-paced VO2max test to measure maximal oxygen uptake in treadmill running". PMID- 24766247 TI - Peripheral resistance artery blood flow in subjects with abnormal glucose tolerance is improved following enhanced external counterpulsation therapy. AB - Enhanced external counterpulsation (EECP) improves resistance artery function in coronary artery disease patients. However, whether EECP elicits similar effects in persons with abnormal glucose tolerance (AGT) is unknown. Here we provide novel evidence that EECP significantly improves resistance arterial function in the forearm of persons with AGT, whereas the calf only approached significance (P <= 0.10). These improvements were coincident with greater glycemic control, providing further insight into the potential mechanisms of EECP-mediated alterations in glycemia. PMID- 24766248 TI - Translating knowledge into dietetic practice: a Functional Foods for Healthy Aging Toolkit. AB - The advance of functional foods has evolved because of research linking functional foods to health, a regulatory environment that allows health claims on foods, and consumer demand for health-promoting food products. Among consumers, the rapidly growing older adult segment is poised to benefit from functional foods because of age-related health issues that are linked to food and health. Registered Dietitians (RDs) are recognized as food and nutrition experts and are well positioned to communicate the benefits of functional foods. The Functional Foods for Healthy Aging Toolkit was developed to provide guidance and resource materials to assist RDs in communicating with older adults about functional foods. The toolkit provides background on functional foods, including definitions, regulations, and case studies of functional food product labels. The role of functional foods in Canada's aging demographic is examined and the relevance to disease risk is discussed. The toolkit is appended with educational resource sheets on common functional food bioactives, including antioxidants, dietary fibre, omega-3 fatty acids, plant sterols, prebiotics, and probiotics. This publicly available toolkit can help RDs and other healthcare professionals in their interactions with older adults to maximize the value and health benefits that dietary inclusion of functional foods can offer. PMID- 24766253 TI - Abstracts of the 54th Annual Scientific Meeting of the British Society for Haematology, 28-30 April 2014, Birmingham, UK. PMID- 24766252 TI - Sequential immunohistochemistry: a promising new tool for the pathology laboratory. AB - AIMS: Current immunohistochemical methods to study the expression of multiple proteins in a single tissue section suffer from several limitations. In this article, we report on sequential immunohistochemistry (S-IHC), a novel, easy method that allows the study of numerous proteins in a single tissue section, while requiring very limited optimization. METHODS AND RESULTS: In S-IHC, a tissue section is stained for multiple antibodies, with intermediate scanning of the section and elution of chromogen and antibodies. Overlays are made of the digital images, allowing assessment of multiple proteins in the same tissue section. We used S-IHC to study nine nodular lymphocyte-predominant Hodgkin lymphomas (NLPHLs) and 10 T-cell-rich and histiocyte-rich diffuse large B-cell lymphomas (T/HRBCLs) for expression of cyclin D1, CD20, and CD68. We observed cyclin D1 expression in single tumour cells in 44% of NLPHLs and 60% of T/HRBCLs. Comparison of S-IHC with classic single immunohistochemical staining revealed discrepancies in eight cases (42%), demonstrating the difficulty of differentiating tumour cells from histiocytes on morphological grounds, and stressing the additional value of S-IHC. CONCLUSIONS: For research and diagnostic purposes, S-IHC is a promising technique that assesses the expression of numerous proteins in single tissue sections with complete architectural information, allowing phenotypic characterization of single cells. PMID- 24766251 TI - Specific molecular signatures of non-tumor liver tissue may predict a risk of hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is one of the most common human cancers and a major cause of cancer-related death worldwide. The bleak outcomes of HCC patients even after curative treatment have been, at least partially, attributed to its multicentric origin. Therefore, it is necessary to examine not only tumor tissue but also non-tumor liver tissue to investigate the molecular mechanisms operating during hepatocarcinogenesis based on the concept of "field cancerization". Several studies previously investigated the association of molecular alterations in non-tumor liver tissue with clinical features and prognosis in HCC patients on a genome-wide scale. In particular, specific alterations of DNA methylation profiles have been confirmed in non-tumor liver tissue. This review focuses on the possible clinical value of array-based comprehensive analyses of molecular alterations, especially aberrant DNA methylation, in non-tumor liver tissue to clarify the risk of hepatocarcinogenesis. Carcinogenetic risk estimation based on specific methylation signatures may be advantageous for close follow-up of patients who are at high risk of HCC development. Furthermore, epigenetic therapies for patients with chronic liver diseases may be helpful to reduce the risk of HCC development because epigenetic alterations are potentially reversible, and thus provide promising molecular targets for therapeutic intervention. PMID- 24766254 TI - Secondary compounds in floral rewards of toxic rangeland plants: impacts on pollinators. AB - The study of plant secondary chemistry has been essential in understanding plant consumption by herbivores. There is growing evidence that secondary compounds also occur in floral rewards, including nectar and pollen. Many pollinators are generalist nectar and pollen foragers and thus are exposed to an array of secondary compounds in their diet. This review documents secondary compounds in the nectar or pollen of poisonous rangeland plants of the western United States and the effects of these compounds on the behavior, performance, and survival of pollinators. Furthermore, the biochemical, physiological, and behavioral mechanisms by which pollinators cope with secondary compound consumption are discussed, drawing parallels between pollinators and herbivores. Finally, three avenues of future research on floral reward chemistry are proposed. Given that the majority of flowering plants require animals for pollination, understanding how floral reward chemistry affects pollinators has implications for plant reproduction in agricultural and rangeland habitats. PMID- 24766256 TI - Coupling paper-based microfluidics and lab on a chip technologies for confirmatory analysis of trinitro aromatic explosives. AB - A new microfluidic paper-based analytical device (MUPAD) in conjunction with confirmation by a lab on chip analysis was developed for detection of three trinitro aromatic explosives. Potassium hydroxide was deposited on the MUPADs (0.5 MUL, 1.5 M), creating a color change reaction when explosives are present, with detection limits of approximately 7.5 +/- 1.0 ng for TNB, 12.5 +/- 2.0 ng for TNT and 15.0 +/- 2.0 ng for tetryl. For confirmatory analysis, positive MUPADs were sampled using a 5 mm hole-punch, followed by extraction of explosives from the punched chad in 30 s using 20 MUL borate/SDS buffer. The extractions had efficiencies of 96.5 +/- 1.7%. The extracted explosives were then analyzed with the Agilent 2100 Bioanalyzer lab on a chip device with minimum detectable amounts of 3.8 +/- 0.1 ng for TNB, 7.0 +/- 0.9 ng for TNT, and 4.7 +/- 0.2 ng for tetryl. A simulated in-field scenario demonstrated the feasibility of coupling the MUPAD technique with the lab on a chip device to detect and identify 1 MUg of explosives distributed on a surface of 100 cm(2). PMID- 24766255 TI - Correlated evolution in parental care in females but not males in response to selection on paternity assurance behaviour. AB - According to classical parental care theory males are expected to provide less parental care when offspring in a brood are less likely to be their own, but empirical evidence in support of this relationship is equivocal. Recent work predicts that social interactions between the sexes can modify co-evolution between traits involved in mating and parental care as a result of costs associated with these social interactions (i.e. sexual conflict). In burying beetles (Nicrophorus vespilloides), we use artificial selection on a paternity assurance trait, and crosses within and between selection lines, to show that selection acting on females, not males, can drive the co-evolution of paternity assurance traits and parental care. Males do not care more in response to selection on mating rate. Instead, patterns of parental care change as an indirect response to costs of mating for females. PMID- 24766257 TI - Should the cut-off values of the lymphocyte to monocyte ratio for prediction of prognosis in diffuse large B-cell lymphoma be changed in elderly patients? AB - OBJECTIVES: A recent study suggested a prognostic role for the peripheral blood absolute lymphocyte/monocyte ratio (LMR) at diagnosis of diffuse large B-cell lymphoma (DLBCL). Here, we investigated the significance of LMR in DLBCL patients in relation to advanced age. METHODS: We examined the prognostic impact of LMR in 603 DLBCL treated with rituximab plus CHOP, using the receiver operating characteristic curve analysis for optimal cut-off values, and performed a subgroup analysis according to age. RESULTS: In elderly groups (age >= 70), absolute monocyte count was significantly increased, whereas LMR was significantly decreased compared to younger groups. Patients under 70 yr of age with LMR < 3.04 had significantly lower overall survival (OS) and progression free survival (PFS) compared to those with LMR >= 3.04 (P < 0.001 for both). However, in elderly patients (age >= 70), there was no significant difference in OS between patients' LMR levels using the 3.04 cut-off value (P = 0.059). Therefore, a new LMR cut-off value of 2.36 was selected in elderly patients, having observed that elderly patients with LMR < 2.36 had significantly lower OS compared to those with LMR >= 2.36 (P = 0.021). In multivariate analysis, LMR remained a significant prognostic factor for OS (P = 0.004) or PFS (P < 0.001). CONCLUSIONS: We suggest the use of a different cut-off value of LMR in elderly patients to distinguish high-risk from low-risk groups. PMID- 24766259 TI - The biology of molecular chaperones--very complex activities for quite simple proteins. PMID- 24766258 TI - Simultaneous alignment and folding of protein sequences. AB - Accurate comparative analysis tools for low-homology proteins remains a difficult challenge in computational biology, especially sequence alignment and consensus folding problems. We present partiFold-Align, the first algorithm for simultaneous alignment and consensus folding of unaligned protein sequences; the algorithm's complexity is polynomial in time and space. Algorithmically, partiFold-Align exploits sparsity in the set of super-secondary structure pairings and alignment candidates to achieve an effectively cubic running time for simultaneous pairwise alignment and folding. We demonstrate the efficacy of these techniques on transmembrane beta-barrel proteins, an important yet difficult class of proteins with few known three-dimensional structures. Testing against structurally derived sequence alignments, partiFold-Align significantly outperforms state-of-the-art pairwise and multiple sequence alignment tools in the most difficult low-sequence homology case. It also improves secondary structure prediction where current approaches fail. Importantly, partiFold-Align requires no prior training. These general techniques are widely applicable to many more protein families (partiFold-Align is available at http://partifold.csail.mit.edu/ ). PMID- 24766260 TI - Polymorphisms of toll-like receptors 2, 3 and 4 in patients that do and do not enter labour spontaneously at term. AB - To assess the association of polymorphisms of toll-like receptors (TLRs) 2, 3 and 4 with the delay in onset of labour at term pregnancies, patients delivering at > 37 weeks and without pre-eclampsia, IUGR or a history of preterm delivery were prospectively evaluated. TLR2 Arg753Gln, TLR3 (c.1377C/T) and TLR4 Asp299Gly and Thr399Ile polymorphisms were genotyped by using PCR-RFLP. Patients labouring spontaneously before the 41st week were compared with those who did not labour spontaneously until this week in terms of baseline characteristics, TLR 2, 3 and 4 polymorphisms. The same comparisons were also performed by using a 40th week cut-off. Chi-square test, two-sample t-test or Mann-Whitney U tests were used for comparisons, as appropriate. In total, 79 patients delivering after 37 weeks were evaluated. All had CC genotype for TLR2 Arg753Gln and TLR4 Thr399Ile. There were no significant differences for TLR4 Asp299Gly GA and TLR3 (c.1377C/T) polymorphisms between patients spontaneously entering or not entering labour until the 41st week; the same was true when the 40th week cut-off was used. Delay in onset of labour at term pregnant women does not seem to be affected by the presence of TLR 2, 3 or 4 polymorphisms. Further studies are needed. PMID- 24766261 TI - New evidence of Entamoeba histolytica infections in pre-Columbian and colonial cemeteries in the Caribbean. AB - ELISA was used to test the presence of the human pathogenic amoeba Entamoeba histolytica in archaeological samples from 2 cemeteries in Guadeloupe, in the Caribbean. Results show that 15.9% of the population was infected during the colonial period, a value comparable to the current rates observed in humans in adjacent countries. This study also confirms the presence of the current strain of E. histolytica in pre-Columbian South America before the European colonization in the 15th century and raises the possibility of an earlier transfer from Europe to the Americas. PMID- 24766262 TI - Survival and other clinical outcomes of maintenance hemodialysis patients in Taiwan: a 5-year multicenter follow-up study. AB - The increasing aging and diabetes mellitus (DM) patients in dialysis population make the quality maintenance of dialysis an imperative issue. Recently, an increasing number of dialysis centers were run by private dialysis providers, many of which apply quality assurance programs and performance management systems to dialysis care. We studied patients in dialysis facilities in Taiwan run by a private chain to see clinical outcomes of centers operating under these systemic strategies. Hemodialysis patients from January 1, 2008 to December 31, 2012 in 25 dialysis facilities in Taiwan, which received the management and consultation from a dialysis service provider, NephroCare (NC), were included. Data pivotal to quality of dialysis were analyzed. During a 5-year interval, 5161 hemodialysis patients were included. For volume control, the proportion of patients with weight gain >=4.5% decreases from 41.7% to 30.2%. Mean Kt/V is 1.74 +/- 0.28. Mean albumin level is 3.92 +/- 0.38 g/dL. Patients with phosphate <5.5 mg/dL is up to 71.8%. The mean hemoglobin level is 10.70 +/- 1.40 g/dL. More than 80% of patients have adequate iron status. Further, 73% of patients use native arteriovenous fistula. Hospitalization-free survival rate was 56% at the fifth year. Patient survival rate at the fifth year was 66.4%. Overall clinical performances were maintained very stable in NC facilities from this temporal data analysis. The hospitalization and survival rate also compare favorably with those reported internationally. These results warrant further studies to justify the application of this kind of quality assurance programs and performance management systems in dialysis care. PMID- 24766263 TI - A fruit fly in the nanoworld: once again Drosophila contributes to environment and human health. AB - Drosophila was the most important model organism used in the fields of medicine and biology over the last century. Recently, Drosophila was successfully used in several studies in the field of nanotoxicology. However, only a part of its potential has been exploited in this field until now. In fact, apart from macroscopic observations of the effect due to the interaction between nanomaterials and living organism (i.e. lifespan, fertility, phenotypic aberrations, etc.), Drosophila has the potential to be a very useful tool to deeply analyze the molecular pathways involved in response to the interactions at nano-bio level. The aim of this editorial is to encourage the use of Drosophila by the different research groups working in the fields of nanotoxicology and nanomedicine, in order to define the effects induced by nanomaterials at molecular level for their subsequent exploitation in the field of nanomedicine. PMID- 24766264 TI - Nonreassuring fetal heart rate decreases heart rate variability in newborn infants. AB - BACKGROUND: Nonreassuring fetal status (NRFS) refers to a compromised fetal condition which implies hypoxia. The influence of intrapartum hypoxia on autonomic nervous system function in early postnatal life is unknown. This study explored the influence of NRFS on the heart rate variability (HRV) of newborn infants. METHODS: Singleton newborn infants delivered through Cesarean delivery (CD) with indications of elective purpose (n = 32), dystocia (n = 29), or NRFS (n = 22), and through vaginal birth (VB) (n = 80) were consecutively collected. HRV parameters including standard deviation of average NN intervals (SDANN), low frequency (LF), high frequency (HF), LF%, HF%, and total power (TP), were obtained for analysis in 3 days postpartum. An independent t-test or one-way ANOVA was used to compare differences in numeric data. RESULTS: SDANN, HF, HF%, and TP of newborn infants in the VB group were significantly higher than those in the CD group. The NRFS group had significantly lower SDANN, HF, and TP than those of the elective group, and significantly lower HF, HF%, and TP than those of the dystocia group. CONCLUSIONS: Newborn infants delivered through Cesarean section had lower HRV, especially those who experienced NRFS during labor. The long-term effects of changes of HRV in neonates require further evaluation. PMID- 24766266 TI - Pharmacological postconditioning of the rabbit heart with non-selective, A1 , A2A and A3 adenosine receptor agonists. AB - OBJECTIVES: We investigated the effects of novel selective and non-selective adenosine receptor agonists (ARs) on cardioprotection. METHODS: Male rabbits divided into six groups were subjected to 30-min heart ischaemia and 3-h reperfusion: (1) control group, (2) postconditioning (PostC) group, (3) group A: treated with the non-selective agonist (S)-PHPNECA, (4) group B: treated with the A1 agonist CCPA, (5) group C: treated with the A2A agonist VT 7 and (6) group D: treated with the A3 agonist AR 170. The infarcted (I) and the areas at risk (R) were estimated as %I/R. In additional rabbits of all groups, heart samples were taken for determination of Akt, eNOS and STAT 3 at the 10th reperfusion minute. KEY FINDINGS: (S)-PHPNECA and CCPA reduced the infarct size (17.2 +/- 2.9% and 17.9 +/- 2.0% vs 46.8 +/- 1.9% in control, P < 0.05), conferring a benefit similar to PostC (26.4 +/- 0.3%). Selective A2A and A3 receptor agonists did not reduce the infarct size (39.5 +/- 0.8% and 38.7 +/- 3.5%, P = NS vs control). Akt, eNOS and STAT 3 were significantly activated after non-selective A1 ARs and PostC. CONCLUSIONS: Non-selective and A1 but not A2A and A3 ARs agonists are essential for triggering cardioprotection. The molecular mechanism involves both RISK and the JAK/STAT pathways. PMID- 24766267 TI - Steps in tailoring a text messaging-based smoking cessation program for young adults. AB - Steps to develop or refine text messaging-based interventions are largely missing from the literature. Here, the authors describe steps in refining Stop My Smoking USA, a text messaging-based smoking cessation program for smokers 18-25 years old. Research activities included the following: needs assessment focus groups (n = 35); a content advisory team to affirm message acceptability (n = 10); and two beta tests to confirm technological feasibility (n = 12 and 28, respectively). Various recruitment strategies were tested to identify the optimal methods to reach young adult smokers ready to quit. Each stage of the refinement process yielded new insights, resulting in improved message content and tone, an effective recruitment strategy, and the identification and subsequent resolution of technology challenges. Findings suggest that young adults prefer messages that provide concrete behavioral strategies to overcome cravings, and which are positive in tone. Craigslist was the most efficient recruitment method and yielded a sample that was racially and economically diverse. Despite a successful beta test of initial technological feasibility, extensive problems were subsequently experienced in a beta test of the technological feasibility of the entire program. Iterative program refinement and adaptation on the basis of user input is necessary to ensure salience, while extensive field testing is required to ensure proper functioning of technology-based programs. PMID- 24766268 TI - The first step in using a robot in brain injury rehabilitation: patients' and health-care professionals' perspective. AB - PURPOSE: To evaluate the usability of a mobile telepresence robot (MTR) in a hospital training apartment (HTA). The MTR was manoeuvred remotely and was used for communication when assessing independent living skills, and for security monitoring of cognitively impaired patients. METHOD: Occupational therapists (OTs) and nurses received training in how to use the MTR. The nurses completed a questionnaire regarding their expectations of using the MTR. OTs and patients staying in the HTA were interviewed about their experiences of the MTR. Interviews and questionnaires were analysed qualitatively. RESULTS: The HTA patients were very satisfied with the MTR. The OTs and nurses reported generally positive experiences. The OT's found that assessment via the MTR was more neutral than being physically present. However, the use of the MTR implied considerable difficulties for health-care professionals. The main obstacle for the nurses was the need for fast and easy access in emergency situations while protecting the patients' integrity. CONCLUSIONS: The results indicate that the MTR could be a useful tool to support daily living skills and safety monitoring of HTA patients. However, when designing technology for multiple users, such as health-care professionals, the needs of all users, their routines and support services involved, should also be considered. Implications for Rehabilitation A mobile telepresence robot (MTR) can be a useful tool for assessments and communication in rehabilitation. The design of the robot has to allow easy use by remote users, particularly in emergency situations. When designing MTRs the needs of ALL users have to be taken into consideration. PMID- 24766269 TI - Special issue technology transfer of hearing aids. Preface. PMID- 24766270 TI - Targeting of injectable drug nanocrystals. AB - "Nano" drug delivery carriers are established technologies for improving the therapeutic index of chemotherapeutic drugs and overcoming formulation challenges of poorly water-soluble compounds. Two important remaining challenges, however, are the need to formulate drugs on a case-by-case basis (due to the specific chemistry of each drug) and the difficulty associated with transporting large amounts of drug specifically to the site of the tumor (in part because of moderate to poor drug loadings). One of the most valuable "nano" opportunities in this field is to address these challenges by creating nanocarriers composed of the drug itself, in the form of so-called nanocrystals. However, "nano" creates both opportunities and challenges for targeted drug delivery, which are critically discussed in both in vitro and in vivo settings in this contribution. PMID- 24766272 TI - Personalized pharmacotherapy in diabetes care using clinical pharmacology data of basal insulin analogues. AB - Advancement in technology led to the development of many insulin analogues in the last three decades. These analogues are characterized by various clinical pharmacology properties that can be utilized in clinical practice to tailor insulin therapy for each patient with diabetes, individually. This paper explores the different aspects of clinical pharmacology data on basal insulin analogues that can influence the choice of basal insulin for a personalized pharmacotherapy. PMID- 24766271 TI - Clinicopathological and prognostic impact of imaging of breast cancer angiogenesis and hypoxia using diffuse optical spectroscopy. AB - Near-infrared diffuse optical spectroscopy (DOS) imaging can non-invasively measure tumor hemoglobin concentration using high contrast to normal tissue, thus providing vascularity and oxygenation status. We assessed the clinical usefulness of DOS imaging in primary breast cancer. In all, 118 women with a histologically confirmed diagnosis of primary malignant tumor were enrolled. All participants underwent testing using time-resolved DOS before treatment initiation. Visual assessment of DOS imaging for detecting tumors was carried out by two readers blinded to the clinical data. Relative total hemoglobin (rtHb) and oxygen saturation (stO2 ) of the tumors was compared with clinicopathological variables and 10-year prognosis was calculated. Sensitivity for detecting a tumor based on the rtHb breast map was 62.7% (74/118). The sensitivity depended on T stage: 100% (7/7) for T3, 78.9% (45/57) for T2, 44.7% (17/38) for T1, and 31.3% (5/16) for Tis . Tumors showed unique features of higher rtHb with a wider range of stO2 than normal breast tissue, depending on histological type. There was a significant correlation of rtHb with tumor size, lymphatic vascular invasion, and histological grade, and of stO2 with age and tumor size. Neither rtHb nor stO2 correlated with intrinsic biomarkers such as estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2; rtHb inversely correlated with 10-year relapse-free survival and overall survival, with statistical significance. Diffuse optical spectroscopy imaging has limited utility for the early detection of breast cancer; nonetheless, the findings suggest that the degree of tumor angiogenesis and hypoxia may be associated with tumor aggressiveness and poor prognosis. PMID- 24766273 TI - Small-size platelet microparticles trigger platelet and monocyte functionality and modulate thrombogenesis via P-selectin. AB - This study aimed to examine the mechanisms of cellular activation by small-size platelet microparticles (sPMP) and to present the performance of high-resolution flow cytometry for the analysis of subcellular entities from different origins. Plasma counts of sPMP were analysed in coronary artery disease patients (n = 40) and healthy controls (n = 40). The effect of sPMP and platelet debris (PD) in pathophysiologically relevant doses on platelet and monocyte activation parameters and thrombogenesis was investigated via flow cytometry and thromboelastometry. New generation flow cytometry identifies differences in size, levels and surface molecules of sPMP derived in the absence of stimulus, thrombin activation and platelet disruption. Addition of sPMP resulted in platelet degranulation and P-selectin redistribution to the membrane (P = 0.019) in a dose and time-dependent manner. Blood clotting time decreased after addition of sPMP (P = 0.005), but was not affected by PD. Blocking P-selectin (CD62P) in sPMP markedly reverted the effect on thrombus kinetics (P = 0.035). Exposure to sPMP stimulated monocyte expression of intercellular adhesion molecule-1 (P < 0.03) and decreased monocyte interleukin-6 receptor density (P < 0.01). These results implicate sPMP as a direct source of downstream platelet and monocyte activation. In pathological coronary artery disease conditions, higher levels of sPMP favour a prothrombotic state, partly through P-selectin expression. PMID- 24766274 TI - Sinecatechins (Polyphenon E) ointment for treatment of external genital warts and possible future indications. AB - INTRODUCTION: Sinecatechins was the first botanical drug licensed for treatment in humans in the US. It is approved for the topical treatment of external genital and perianal warts. Some properties of the polyphenolic components included in sinecatechins suggest additional therapeutic potential for other skin diseases. AREAS COVERED: Studies and articles describing therapeutic application of sinecatechins or green tea polyphenols in viral and proliferative skin diseases or investigating molecular activities relevant for the mode of action were identified by a PubMed search using 'sinecatechins', 'green tea polyphenols', 'polyphenon E' and 'EGCG', each combined with 'skin cancer' and 'genital warts' as search criteria. Although a number of molecular mechanisms of green tea polyphenols were described, the exact mode of action operative in regression of genital warts is not yet clear. It may involve both antiproliferative, pro apoptotic and antiviral activities that probably also account for efficacy against other skin disorders. EXPERT OPINION: In addition to treatment of skin tumors, sinecatchins may also be used to protect against photocarcinogenesis. Considering antioxidative properties of polyphenols and the capability to enhance DNA repair, sinecatechins appears attractive for primary prevention of nonmelanoma skin cancer either as additive in sunscreens or as dietary supplement for oral administration. PMID- 24766275 TI - Biophotonic ring resonator for ultrasensitive detection of DMMP as a simulant for organophosphorus agents. AB - Combining photonic integrated circuits with a biologically based sensing approach has the ability to provide a new generation of portable and low-cost sensor devices with a high specificity and sensitivity for a number of applications in environmental monitoring, defense, and homeland security. We report herein on the specific biosensing under continuous air flow of DMMP, which is commonly used as a simulant and a precursor for the synthesis of Sarin. The proposed technology is based on the selective recognition of the targeted DMMP molecule by specifically modified proteins immobilized on photonic structures. The response of the biophotonic structures shows a high stability and accuracy over 3 months, allowing for the detection in diluted air of DMMP at concentration as low as 35 MUg/m(3) (6.8 ppb) in less than 15 min. The performance of the developed technology satisfies most current homeland and military security requirements. PMID- 24766276 TI - Knowledge-based generalization of metabolic models. AB - Genome-scale metabolic model reconstruction is a complicated process beginning with (semi-)automatic inference of the reactions participating in the organism's metabolism, followed by many iterations of network analysis and improvement. Despite advances in automatic model inference and analysis tools, reconstruction may still miss some reactions or add erroneous ones. Consequently, a human expert's analysis of the model will continue to play an important role in all the iterations of the reconstruction process. This analysis is hampered by the size of the genome-scale models (typically thousands of reactions), which makes it hard for a human to understand them. To aid human experts in curating and analyzing metabolic models, we have developed a method for knowledge-based generalization that provides a higher-level view of a metabolic model, masking its inessential details while presenting its essential structure. The method groups biochemical species in the model into semantically equivalent classes based on the ChEBI ontology, identifies reactions that become equivalent with respect to the generalized species, and factors those reactions into generalized reactions. Generalization allows curators to quickly identify divergences from the expected structure of the model, such as alternative paths or missing reactions, that are the priority targets for further curation. We have applied our method to genome-scale yeast metabolic models and shown that it improves understanding by helping to identify both specificities and potential errors. PMID- 24766277 TI - Experimental predator removal causes rapid salt marsh die-off. AB - Salt marsh habitat loss to vegetation die-offs has accelerated throughout the western Atlantic in the last four decades. Recent studies have suggested that eutrophication, pollution and/or disease may contribute to the loss of marsh habitat. In light of recent evidence that predators are important determinants of marsh health in New England, we performed a total predator exclusion experiment. Here, we provide the first experimental evidence that predator depletion can cause salt marsh die-off by releasing the herbivorous crab Sesarma reticulatum from predator control. Excluding predators from a marsh ecosystem for a single growing season resulted in a >100% increase in herbivory and a >150% increase in unvegetated bare space compared to plots with predators. Our results confirm that marshes in this region face multiple, potentially synergistic threats. PMID- 24766278 TI - 'Neuroendocrine' middle ear adenomas: consistent expression of the transcription factor ISL1 further supports their neuroendocrine derivation. AB - AIMS: Neuroendocrine middle ear adenoma (MEA) is a rare epithelial neoplasm of uncertain histogenesis that frequently shows neuroendocrine features. To date, <120 cases have been reported. The aims of the current study were to describe our experience with neuroendocrine MEA, to assess the frequency of specific neuroendocrine differentiation, and to test these lesions for transcription factors known to be expressed in a variety of other neuroendocrine tumours. METHODS AND RESULTS: We investigated six cases of neuroendocrine MEA, and stained them, for the first time, for the transcription factors CDX2, TTF1, PAX8, and ISL1 (islet-1). The patients were four men and two women (mean age, 39 years; range, 27-53 years). Two of four patients with extended follow-up (4.5-22 years) experienced recurrence at 92 months, and at 9 and 22 years, respectively. One case extending into the external ear coexisted with cholesteatoma. Histological examination showed trabecular, solid, acinar, glandular, cribriform, organoid, nested, diffuse non-cohesive plasmacytoid and pseudoalveolar patterns in varying combinations. Immunohistochemistry showed consistent expression of vimentin (4/4), pancytokeratin (6/6), synaptophysin (6/6), CD56 (4/4), and ISL1 (6/6). A CK7 antibody stained scattered cells in two of five cases. The myoepithelial markers and transcription factors TTF1, CDX2 or PAX8 were not expressed in any of the cases. CONCLUSIONS: Middle ear adenoma is an indolent, locally recurring, but generally non-metastasizing neoplasm with uniform expression of synaptophysin and ISL1, indicating true neuroendocrine differentiation. Because of its highly varied cellular and architectural appearance, MEA should be distinguished from tympanic paraganglioma and a variety of rare benign and malignant lesions at this site. PMID- 24766280 TI - Assessment of the degree of interference of polyphenolic compounds on glucose oxidation/peroxidase assay. AB - The glucose oxidase/peroxidase assay (GOP) is a coupled enzymatic assay commonly used in measuring glucose concentrations in biological sciences and food chemistry, particularly for quantification of alpha-glucosidase activity. However, we found that the GOP assay is prone to interference, especially from reducing substances such as polyphenolic compounds, which are commonly found in botanical materials. To establish the scope and limitation of the assay in measuring alpha-glucosidase inhibition activity, we systematically investigated the structural features of the polyphenolic compounds that can lead to false positives. Utilizing sodium dodecyl sulfate (SDS) as surrogate for the meriquinone intermediate formed during the reaction, we measured the reactivity of this redox active intermediate toward common flavonoids. Our results show that flavonoids with o-dihydroxy groups in the B-ring cause strong interference and that compounds with little DPPH scavenging activity do not have interference. Our results highlight the need for checking the suitability of the GOP assay first before it is applied in measuring alpha-glucosidase inhibition activity. In addition, when the literature data on alpha-glucosidase inhibition activity of botanical extracts or polyphenolic compounds using GOP assay are interpreted, potential false positives due to interference on the assay will need to be taken into consideration. PMID- 24766279 TI - Sulfhydration of p66Shc at cysteine59 mediates the antioxidant effect of hydrogen sulfide. AB - AIMS: Mitochondrion is considered as the major source of intracellular reactive oxygen species (ROS). H2S has been reported to be an antioxidant, but its mechanism remains largely elusive. P66Shc is an upstream activator of mitochondrial redox signaling. The aim of this study was to explore whether the antioxidant effect of H2S is mediated by p66Shc. RESULTS: Application of exogenous H2S with its donor, NaHS, or overexpression of its generating enzyme, cystathionine beta-synthase, induced sulfhydration of p66Shc, but inhibited its phosphorylation caused by H2O2/D-galactose in SH-SY5Y cells or in the mice cortex. H2S also decreased mitochondrial ROS production and protected neuronal cells against stress-induced senescence. PKCbetaII and PP2A are the two key proteins to regulate p66Shc phosphorylation. Although H2S failed to affect the activities of these two proteins, it disrupted their association. Cysteine-59 resides in proximity to serine-36, the phosphorylation site of p66Shc. The C59S mutant attenuated the above-described biological function of H2S. INNOVATION: We revealed a novel mechanism for the antioxidant effect of H2S and its role in oxidative stress-related diseases. CONCLUSION: H2S inhibits mitochondrial ROS production via the sulfhydration of Cys-59 residue, which in turn, prevents the phosphorylation of p66Shc. PMID- 24766282 TI - Host performance as a target of manipulation by parasites: a meta-analysis. AB - The mechanisms underlying parasite-altered host behavior and fitness remain largely unanswered. The purpose of this review is to provide a perspective that has not been fully incorporated into the debate on how parasites manipulate their hosts. We argue that performance capacity is an important target of parasitic manipulation, and we aim to integrate the study of performance with that of parasitic manipulations of host behavior and fitness. We performed a meta analysis from the published literature of 101 measures of the effect of parasites on host performance capacity to address the following questions. (1) Do parasites exert an important effect on host performance capacity? (2) Is that effect routinely to decrease or enhance performance capacity? And, (3) what factors explain variation in the effect sizes that have been quantified? Although negligible-small effect sizes were detected in 40/101 measures, host performance capacity was overall affected by parasitic infection, with a negative direction and medium-large magnitude in 58/101 measures and an increase in performance capacity in 3/101 measures. Host age, type of host performance, the host tissue infected by the parasite, and whether the study was experimental or based on natural infections each explained a significant amount of the variation in effect size. The significance of each factor is briefly discussed in light of the potential adaptive character of host manipulations by parasites. PMID- 24766281 TI - Lineage-dependent skewing of loss of heterozygosity (LOH) of KRAS gene in a case of juvenile myelomonocytic leukemia. AB - Juvenile myelomonocytic leukemia (JMML) is a clonal disease arising from abnormal hematopoietic stem cells, although the involvement of lymphoid lineage differs among reported cases. Here, we present a case of JMML with a KRAS G13D mutation. The mutation was detected in various hematopoietic lineages, including T and B lymphocytes and also in lineage(-) CD34(+) CD38(-) hematopoietic stem cells, showing a different percentage of affected cells in each lineage. Single cell based analysis of hematopoietic cells revealed the loss of wild-type KRAS in a significant proportion of G13D-harboring cells. The percentage of loss of heterozygosity (LOH)/non-LOH cells showed lineage-dependent skewing in hematopoietic cells. The loss of the wild-type KRAS allele may be a common secondary genetic change in KRAS-related JMML and may affect the differentiation behavior of early JMML progenitors. PMID- 24766283 TI - Physical examination of arteriovenous fistula: The influence of professional experience in the detection of complications. AB - Vascular access is one of the leading causes of mobilization of financial resources in health systems for people with chronic kidney disease on hemodialysis. Physical examination of the arteriovenous fistula (AVF) has demonstrated its effectiveness in identifying complications. We decided to evaluate the influence of nurses' professional experience in the detection of complications of the AVF (venous stenosis and steal syndrome). The study took place in eight hemodialysis centers between May and September of 2011 in the north of Portugal. Sample was constituted by registered nurses. The nurses involved in the experiment were divided in two groups: those who had more than 5 years of experience and those who had less than 5 years of experience. Ninety-two nurses participated in the study: 34 nurses had less than 5 years of professional experience and 58 had more than 5 years of professional experience. In the practices considered by nurses in the detection of venous stenosis, there were no differences observed between the groups (P > 0.05). In steal syndrome, there were no differences observed between the groups in the practices of the nurses in the detection of this complication of the AVF (P > 0.05). We concluded that professional experience does not influence the detection of venous stenosis and steal syndrome. PMID- 24766284 TI - Characteristic epithelium with low-grade atypia appears on the surface of gastric cancer after successful Helicobacter pylori eradication therapy. AB - BACKGROUND: The incidence of gastric cancer after successful Helicobacter pylori eradication has been increasing. We previously reported that epithelium with low grade atypia (ELA) appeared on the surface of gastric cancer after H. pylori eradication. Here, we investigate the clinical and biological characteristics of such ELA. METHODS: We studied 27 cases of gastric cancer detected after successful H. pylori eradication therapy. We examined the prevalence of ELA among these cases and its significance for endoscopic discovery after H. pylori eradication. We additionally investigated the mucus, p53 and Ki67 expressions in ELA. RESULTS: Epithelium with low-grade atypia that continuous with the gastric tumor was detected in 22 of 27 cases (81%), a significantly greater percentage than that for controls (p < 0.01). We found that gastric-type mucin was frequently expressed in this epithelium. Neither p53- nor Ki67-positive cells were found in ELA, irrespective of their expression in tumor tissue. The presence of ELA was positively correlated with the clinical interval between H. pylori eradication and gastric cancer detection. CONCLUSIONS: Epithelium with low-grade atypia on gastric cancer tissue, which may develop from gastric cancer cells, is frequently present after successful eradication therapy. This phenomenon could influence the practice of endoscopic diagnosis of gastric cancers. PMID- 24766285 TI - Aminolysis of an N-diazeniumdiolated amidine as an approach to diazeniumdiolated ammonia. AB - Recent theoretical studies have suggested that the parent diazeniumdiolate ion, H2N-N(O)?NO(-) ("diazeniumdiolated ammonia"), might be stable enough to be isolated and that it could potentially serve as a uniquely advantageous prodrug form of bioactive nitroxyl (HNO). Here, we report on an attempt to isolate its O(2)-benzylated derivative by aminolysis of the C?N bond in PhC(NH2)?N-N(O)?NOBn. The reaction proved remarkably sluggish in comparison to aminolysis of unsubstituted benzamidine, and the desired product could not be isolated, apparently because of base sensitivity of the NH2 group. Consistent with this interpretation, O-benzylhydroxylamine and N2O were recovered from the reaction mixture in high yields, along with N,N'-dibutylbenzamidine. Theoretical calculations rationalize the observed slow aminolysis by demonstrating that the diazeniumdiolate group greatly suppresses the electrophilicity of the adjacent C?N carbon center, rendering attack at that position endothermic. The data provide significant insights into the challenges inherent to the pursuit of diazeniumdiolated ammonia. PMID- 24766286 TI - Altered resting functional connectivity of expressive language regions after speed reading training. AB - A goal of interventions designed to increase reading speed is to reduce the practice of articulating words in an individual's thoughts, or subvocalization. This practice may require redundant cognitive resources, slow reading speed, and detract from efficient transfer of written words to semantic understanding. It is unclear, however, whether exercises designed to promote faster reading speed generalize to cognitive function beyond the reading task itself. To investigate this possibility, we measured resting state functional connectivity in classical language regions before and after a course of cognitive exercise designed to increase reading speed in 9 healthy adolescent female volunteers. We found significantly decreased correlation between left Broca area and right Broca homologue and between right Broca homologue and right Wernicke homologue in the resting state after the training period compared to before training. Differences in functional connectivity after training to left Broca area showed a spatial distribution reflecting decreased correlation to memory-associated brain regions and increased correlation to auditory regions, which might be consistent with a hypothesis that such training may decrease subvocalization associated with semantic memory function during the resting state. PMID- 24766287 TI - Accuracy and reproducibility of stem cell side population measurements on clinically relevant products. AB - INTRODUCTION: In 1996, Goodell et al. first described a rare subpopulation of bone marrow stem cells termed the Side Population (SP). SP cells are known to be CD34 negative and to have a high repopulating capability. The SP was identified by ultraviolet excitation based on the efflux of the DNA binding dye, Hoechst 33342 (Ho342). ABCG2, a halftransporter that belongs to the ATP binding cassette transporter superfamily, is the major contributor to the SP phenotype by actively pumping Ho432 selectively from stem cells. To date, very little is known about the identification of the SP in peripheral blood samples, and about its peripheral circulation, enrichment or isolation to evaluate its therapeutic potential. Due to the SP potential role in tissue regeneration, we studied the numbers of the SP in bone marrow and peripheral blood samples in regard to count accuracy and reproducibility. MATERIALS AND METHODS: Bone marrow (BM) and apheresis (AP) specimens were obtained from healthy donors and patients undergoing stem cell transplantation. Bone marrow samples were obtained by aspiration. Peripheral blood cells after granulocyte colony stimulating factor (G CSF) mobilization with or without chemotherapy, were obtained by apheresis. All samples were prepared for identification of SP cells by flow cytometry. RESULTS: SP cells were detected in only 19 of 111 apheretic products, with relative frequency ranging from 0.01 to 4.75% of cells by the Ho342 exclusion method and flow cytometry analysis. Cell preparations used for these measurements consisted of 5 x 10(6) cells. However, no SP cells were detected when aliquots from the same positive specimens, consisting of previously stained 55 x 10(6) cells and fractionated into independent aliquots with 5 x 10(6) cells were used. CONCLUSIONS: In this study, we show that there is great variability in SP cell numbers when aliquots obtained either from leukapheresis or bone marrow products represent about 1% of the total product volume. In contrast, when aliquots represented about 12% of the total product volume SP cells measurements were consistent. The high cell number of some specimens can be a limitation for the accurate identification and isolation of the SP compartment. Aliquots containing a minimum of 55 * 10(6) cells should be used for statistical significance. PMID- 24766288 TI - Cortical bone trajectory for lumbosacral fixation: penetrating S-1 endplate screw technique: technical note. AB - OBJECT: A cortical bone trajectory (CBT) is a new pedicle screw trajectory that maximizes the thread contact with cortical bone surface, providing enhanced screw purchase. Despite the increased use of the CBT in the lumbar spine, little is known about the insertion technique for the sacral CBT. The aim of this study was to introduce a novel sacral pedicle screw trajectory. This trajectory engages with denser bone maximally by the screw penetrating the S-1 superior endplate through a more medial entry point than the traditional technique, and also has safety advantages, with the protrusion of the screw tip into the intervertebral disc space carrying no risk of neurovascular injury. METHODS: In this study, the CT scans of 50 adults were studied for morphometric measurement of the new trajectory. The entry point was supposed to be the junction of the center of the superior articular process of S-1 and approximately 3 mm inferior to the most inferior border of the inferior articular process of L-5. The direction was straight forward in the axial plane without convergence, angulated cranially in the sagittal plane penetrating the middle of the sacral endplate. The cephalad angle to the sacral endplate, length of trajectory, and safety of the trajectory were investigated. Next, the insertional torque of pedicle screws using this technique was measured intraoperatively in 19 patients and compared with the traditional technique. RESULTS: The mean cephalad angle in these 50 patients was 30.7 degrees +/- 5.1 degrees , and the mean length of trajectory was 31.5 +/- 3.5 mm. The CT analysis revealed that the penetrating S-1 endplate technique did not cause any neurovascular injury anteriorly in any case. The new technique demonstrated an average of 141% higher insertional torque than the traditional monocortical technique. CONCLUSIONS: The penetrating S-1 endplate technique through the medial entry point is suitable for the connection of lumbar CBT, has revealed favorable stability for lumbosacral fixation, and has reduced the potential risk of neurovascular injuries. PMID- 24766289 TI - A new type of reconstruction of the hemipelvis after type 3 amputative sacrectomy using pedicled fibula: technical note. AB - This is a technical note of pelvic reconstruction performed by an advanced multidisciplinary team. The authors report a new 3-stage reconstruction of the hemipelvis after Type 3 sacrectomy involving instrumented spinoiliac arthrodesis and pedicled fibula grafting in 2 patients. The anterior stage of the procedure begins with a transabdominal approach to mobilize the viscera and to free up the tumor from the vessels. The posterior divisions of internal iliac vessels, the middle sacral vessels, and the lateral sacral vessels are then ligated. An anterior vertebrectomy is done at the appropriate level, followed by an anterior osteotomy through the lateral planed surgical margin of the sacrum close to the salvaged sacroiliac joint. The second stage includes a major sacral resection with lower-extremity amputation from the pubic symphysis through the intact side of the sacrum, ipsilateral pedicled fibula harvesting, and closure with an ipsilateral pedicled quadriceps flap. The final stage involves reconstruction with lumboiliac instrumentation. The pedicled fibular graft left from the second stage is then placed distally within the previously created iliopectineal docking site and proximally within the L-5 docking site. The authors believe that this is a feasible and reproducible technique with theoretical advantages that have to be proved in the long-term follow-up. PMID- 24766290 TI - Surgical treatment of pathological loss of lumbar lordosis (flatback) in patients with normal sagittal vertical axis achieves similar clinical improvement as surgical treatment of elevated sagittal vertical axis: clinical article. AB - OBJECT: Increased sagittal vertical axis (SVA) correlates strongly with pain and disability for adults with spinal deformity. A subset of patients with sagittal spinopelvic malalignment (SSM) have flatback deformity (pelvic incidence-lumbar lordosis [PI-LL] mismatch > 10 degrees ) but remain sagittally compensated with normal SVA. Few data exist for SSM patients with flatback deformity and normal SVA. The authors' objective was to compare baseline disability and treatment outcomes for patients with compensated (SVA < 5 cm and PI-LL mismatch > 10 degrees ) and decompensated (SVA > 5 cm) SSM. METHODS: The study was a multicenter, prospective analysis of adults with spinal deformity who consecutively underwent surgical treatment for SSM. Inclusion criteria included age older than 18 years, presence of adult spinal deformity with SSM, plan for surgical treatment, and minimum 1-year follow-up data. Patients with SSM were divided into 2 groups: those with compensated SSM (SVA < 5 cm and PI-LL mismatch > 10 degrees ) and those with decompensated SSM (SVA >= 5 cm). Baseline and 1 year follow-up radiographic and health-related quality of life (HRQOL) outcomes included Oswestry Disability Index, Short Form-36 scores, and Scoliosis Research Society-22 scores. Percentages of patients achieving minimal clinically important difference (MCID) were also assessed. RESULTS: A total of 125 patients (27 compensated and 98 decompensated) met inclusion criteria. Compared with patients in the compensated group, patients in the decompensated group were older (62.9 vs. 55.1 years; p = 0.004) and had less scoliosis (43 degrees vs 54 degrees ; p = 0.002), greater SVA (12.0 cm vs. 1.7 cm; p < 0.001), greater PI-LL mismatch (26 degrees vs. 20 degrees ; p = 0.013), and poorer HRQOL scores (Oswestry Disability Index, Short Form-36 physical component score, Scoliosis Research Society-22 total; p <= 0.016). Although these baseline HRQOL differences between the groups reached statistical significance, only the mean difference in Short Form-36 physical component score reached threshold for MCID. Compared with baseline assessment, at 1 year after surgery improvement was noted for patients in both groups for mean SVA (compensated -1.1 cm, decompensated +4.8 cm; p <= 0.009), mean PI-LL mismatch (compensated 6 degrees , decompensated 5 degrees ; p < 0.001), and all HRQOL measures assessed (p <= 0.005). No significant differences were found between the compensated and decompensated groups in the magnitude of HRQOL score improvement or in the percentages of patients achieving MCID for each of the outcome measures assessed. CONCLUSIONS: Decompensated SSM patients with elevated SVA experience significant disability; however, the amount of disability in compensated SSM patients with flatback deformity caused by PI-LL mismatch but normal SVA is underappreciated. Surgical correction of SSM demonstrated similar radiographic and HRQOL score improvements for patients in both groups. Evaluation of SSM should extend beyond measuring SVA. Among patients with concordant pain and disability, PI-LL mismatch must be evaluated for SSM patients and can be considered a primary indication for surgery. PMID- 24766291 TI - Headache in children with Chiari I malformation. AB - BACKGROUND: Headache is the most common symptom of Chiari 1 malformation, a condition characterized by the herniation of cerebellar tonsils through the foramen magnum. However, the headache pattern of cases with Chiari 1 malformations is not well defined in the literature, especially in children. OBJECTIVE: The aim of this retrospective chart review was to evaluate the frequency and the characteristics of headache in children with Chiari 1 malformation at initial evaluation and during follow up. METHODS: Forty-five cases with tonsillar ectopia were selected among 9947 cases under 18 years of age who underwent neuroimaging between 2002 and 2010. A semistructured clinical interview (mean follow-up: 5.2 years) was conducted. Headache was classified according to the second edition of the International Classification of Headache Disorders. RESULTS: Possible associations between clinical picture, in particular headache pattern, but also other signs and symptoms attributable to Chiari 1 malformation, and the extent of tonsillar ectopia were found for 3 different groups: those with borderline (<5 mm, N = 12), mild (5-9 mm, N = 27), and severe tonsillar ectopia (>=10 mm, N = 6), respectively. Twenty-four out of 33 (73%) cases with Chiari 1 malformation complained of headache, and 9/33 (27%) of those patients (5 with mild and 4 with severe tonsillar ectopia) reported headache attributed to Chiari 1 malformation. CONCLUSIONS: In our studied pediatric population, the most common symptom for cases diagnosed with Chiari 1 malformation was headache, and headache attributed to Chiari 1 malformation was the most common headache pattern in patients with Chiari 1 malformation. The presence of headache attributed to Chiari 1 malformation along with 3 other signs or symptoms of Chiari 1 malformation were highly predictive of severe tonsillar ectopia. PMID- 24766292 TI - A United Kingdom national survey of trends in ectopic pregnancy management. AB - Our national survey demonstrates increased use of medical and laparoscopic management of ectopic pregnancy in the UK. In the UK in 2000, 35% of cases were managed by laparoscopy, 63% by laparotomy and 1% with medication. A recent review in the USA revealed increasing rates of medical management and decreasing rates of laparotomy; a trend driven by both cost-effectiveness and patient choice. A total of 119 early pregnancy units were surveyed regarding the nature and management of the three most recent cases of ectopic pregnancy; in addition, feasibility of training residents was also requested. Participants reported on 124 cases with a median of five cases per month per department. A total of 57% of cases were managed laparoscopically, 31% medically, 5% by laparotomy and 6% conservatively. Out of 44 centres, 29 have the facilities for training in both intermediate laparoscopic surgery and early pregnancy ultrasound. PMID- 24766293 TI - Acute pulmonary toxicity following inhalation exposure to aerosolized VX in anesthetized rats. AB - This study evaluated acute toxicity and pulmonary injury in rats at 3, 6 and 24 h after an inhalation exposure to aerosolized O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX). Anesthetized male Sprague-Dawley rats (250-300 g) were incubated with a glass endotracheal tube and exposed to saline or VX (171, 343 and 514 mg*min/m3 or 0.2, 0.5 and 0.8 LCt50, respectively) for 10 min. VX was delivered by a small animal ventilator at a volume of 2.5 ml * 70 breaths/minute. All VX-exposed animals experienced a significant loss in percentage body weight at 3, 6, and 24 h post-exposure. In comparison to controls, animals exposed to 514 mg*min/m3 of VX had significant increases in bronchoalveolar lavage (BAL) protein concentrations at 6 and 24 h post-exposure. Blood acetylcholinesterase (AChE) activity was inhibited dose dependently at each of the times points for all VX-exposed groups. AChE activity in lung homogenates was significantly inhibited in all VX-exposed groups at each time point. All VX-exposed animals assessed at 20 min and 3, 6 and 24 h post-exposure showed increases in lung resistance, which was prominent at 20 min and 3 h post-exposure. Histopathologic evaluation of lung tissue of the 514 mg*min/m3 VX-exposed animals at 3, 6 and 24 h indicated morphological changes, including perivascular inflammation, alveolar exudate and histiocytosis, alveolar septal inflammation and edema, alveolar epithelial necrosis, and bronchiolar inflammatory infiltrates, in comparison to controls. These results suggest that aerosolization of the highly toxic, persistent chemical warfare nerve agent VX results in acute pulmonary toxicity and lung injury in rats. PMID- 24766294 TI - Treatment of hyponatremia: the role of lixivaptan. AB - Hyponatremia is the most common electrolyte disorder and is associated with serious neurologic sequelae and increased mortality. Conventional treatment options for hyponatremia, such as fluid restriction, hypertonic saline, loop diuretics, demeclocycline or urea, are ineffective in the long-term. The present review considers the role of vasopressin receptor inhibitors (vaptans), focusing on lixivaptan, in the treatment of patients with euvolemic or hypervolemic hyponatremia. Lixivaptan is an oral selective V2 receptor inhibitor, which produces a significantly greater increase of serum sodium levels compared with placebo. These effects seem promising, but more trials are needed to examine whether the beneficial effect of lixivaptan on serum sodium concentration translates into clinical benefit in these patient populations. PMID- 24766296 TI - Recurrent GATA1 mutations in Diamond-Blackfan anaemia. PMID- 24766295 TI - Randomized clinical trial: rikkunshito in the treatment of functional dyspepsia- a multicenter, double-blind, randomized, placebo-controlled study. AB - BACKGROUND: Rikkunshito, a standardized Japanese herbal medicine, is thought to accelerate gastric emptying and relieve dyspepsia, although no large-scale, randomized, placebo-controlled trials of rikkunshito have been conducted. This study aimed to determine the efficacy and safety of rikkunshito for treating functional dyspepsia (FD). METHODS: FD patients received 2.5 g rikkunshito or placebo three times a day for 8 weeks in this multicenter, randomized, placebo controlled, parallel-group trial. The primary end point was the proportion of responders at 8 weeks after starting test drug, determined by global patient assessment (GPA). The improvement in four major dyspepsia symptoms severity scale was also evaluated. In addition, plasma ghrelin levels were investigated before and after treatment. KEY RESULTS: Two hundred forty-seven patients were randomly assigned. In the eighth week, the rikkunshito group had more GPA responders (33.6%) than the placebo (23.8%), although this did not reach statistical significance (p = 0.09). Epigastric pain was significantly improved (p = 0.04) and postprandial fullness tended to improve (p = 0.06) in the rikkunshito group at week 8. Rikkunshito was relatively more effective among Helicobacter pylori infected participants (rikkunshito: 40.0% vs placebo: 20.5%, p = 0.07), and seemed less effective among H. pylori-uninfected participants (rikkunshito: 29.3% vs placebo: 25.6%, p = 0.72). Among H. pylori-positive individuals, acyl ghrelin levels were improved just in rikkunshito group. There were no severe adverse events in both groups. CONCLUSIONS & INFERENCES: Administration of rikkunshito for 8 weeks reduced dyspepsia, particularly symptoms of epigastric pain and postprandial fullness. (UMIN Clinical Trials Registry, Number UMIN000003954). PMID- 24766297 TI - It's better to give than to receive: the role of social support, trust, and participation on health-related social networking sites. AB - Nearly 60% of American adults and 80% of Internet users have sought health information online. Moreover, Internet users are no longer solely passive consumers of online health content; they are active producers as well. Social media, such as social networking sites, are increasingly being used as online venues for the exchange of health-related information and advice. However, little is known about how participation on health-related social networking sites affects users. Research has shown that women participate more on social networking sites and social networks are more influential among same-sex members. Therefore, this study examined how participation on a social networking site about pregnancy influenced members' health-related attitudes and behaviors. The authors surveyed 114 pregnant members of 8 popular pregnancy-related sites. Analyses revealed that time spent on the sites was less predictive of health related outcomes than more qualitative assessments such as trust in the sites. Furthermore, providing support was associated with the most outcomes, including seeking more information from additional sources and following recommendations posted on the sites. The implications of these findings, as well as directions for future research, are discussed. PMID- 24766298 TI - Evolving therapies for non-alcoholic steatohepatitis. AB - INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Approved therapies for this disorder, however, are still lacking. In the last decade, pathophysiological insights into this disease have been tremendous. Various aspects, such as insulin resistance, innate immunity, metabolic inflammation and the microbiota, have been characterized as major players. Indeed, at least 1 in 10 sufferers will have the disease escalate toward its inflammatory phenotype, non-alcoholic steatohepatitis (NASH). These pathways currently represent the most attractive treatment targets. Furthermore, interference with insulin resistance has shown some efficacy in the past, although more focused therapies, which also act anti-inflammatory, are needed. AREAS COVERED: In this review, the authors highlight the current most promising treatment strategies in NASH/NAFLD. EXPERT OPINION: Treatment of NAFLD is still in its infancy, although large controlled studies have demonstrated some efficacy for pioglitazone or vitamin E. The natural course of this disease demands long term treatments besides diet and lifestyle changes. Based on the current view of NAFLD pathophysiology, effective therapies have to target metabolic inflammation, glucose and lipid metabolism. The search for agents interfering with all of these pathways has recently generated promising candidates for the treatment of NAFLD such as farnesoid X receptor, peroxisome proliferator-activated receptor alpha/delta agonists or AdipoR small-molecule agonists. PMID- 24766299 TI - Applying trait-based models to achieve functional targets for theory-driven ecological restoration. AB - Manipulating community assemblages to achieve functional targets is a key component of restoring degraded ecosystems. The response-and-effect trait framework provides a conceptual foundation for translating restoration goals into functional trait targets, but a quantitative framework has been lacking for translating trait targets into assemblages of species that practitioners can actually manipulate. This study describes new trait-based models that can be used to generate ranges of species abundances to test theories about which traits, which trait values and which species assemblages are most effective for achieving functional outcomes. These models are generalisable, flexible tools that can be widely applied across many terrestrial ecosystems. Examples illustrate how the framework generates assemblages of indigenous species to (1) achieve desired community responses by applying the theories of environmental filtering, limiting similarity and competitive hierarchies, or (2) achieve desired effects on ecosystem functions by applying the theories of mass ratios and niche complementarity. Experimental applications of this framework will advance our understanding of how to set functional trait targets to achieve the desired restoration goals. A trait-based framework provides restoration ecology with a robust scaffold on which to apply fundamental ecological theory to maintain resilient and functioning ecosystems in a rapidly changing world. PMID- 24766301 TI - Role of N-linked glycans in the interactions of recombinant HCV envelope glycoproteins with cellular receptors. AB - Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and hepatocellular carcinoma. It infects human liver cells through several cellular protein receptors including CD81, SR-BI, claudin-1, and occludin. Previous reports also show that lectin receptors can mediate HCV recognition and entry. The envelope proteins of HCV (E1 and E2) are heavily glycosylated, further indicating the possible roles of lectin receptor-virus interaction in HCV infection. However, there is limited study investigating the relationship of HCV envelope glycoproteins and lectin as well as non-lectin receptors. Here we used surface plasmon resonance to examine the binding affinity of different glycoforms of recombinant HCV envelope protein to receptors and inspected the infectivity and assembly of HCV pseudoparticles composed of different glycoforms of envelope proteins. Our results indicated that DC-SIGN, L-SIGN, and Langerin had higher affinity to recombinant HCV envelope proteins in the presence of calcium ions than non-lectin receptors, and envelope proteins with Man8/9 N-glycans showed approximate 10-fold better binding to lectin receptors than envelope proteins with Man5 and complex type N-glycans. Interestingly, comparing among glycoforms, recombinant envelope proteins with Man5 N-glycans showed the highest binding affinity when interacting with non-lectin receptors. In summary, the glycans on HCV envelope protein play a modulatory role in HCV assembly and infection and direct HCV-receptor interaction, which mediates viral entry in different cells. Receptors with high affinity to HCV envelope proteins may be considered as targets for development of a therapeutic strategy against HCV. PMID- 24766300 TI - Antihelminthic benzimidazoles are novel HIF activators that prevent oxidative neuronal death via binding to tubulin. AB - AIMS: Pharmacological activation of the adaptive response to hypoxia is a therapeutic strategy of growing interest for neurological conditions, including stroke, Huntington's disease, and Parkinson's disease. We screened a drug library with known safety in humans using a hippocampal neuroblast line expressing a reporter of hypoxia-inducible factor (HIF)-dependent transcription. RESULTS: Our screen identified more than 40 compounds with the ability to induce hypoxia response element-driven luciferase activity as well or better than deferoxamine, a canonical activator of hypoxic adaptation. Among the chemical entities identified, the antihelminthic benzimidazoles represented one pharmacophore that appeared multiple times in our screen. Secondary assays confirmed that antihelminthics stabilized the transcriptional activator HIF-1alpha and induced expression of a known HIF target gene, p21(cip1/waf1), in post-mitotic cortical neurons. The on-target effect of these agents in stimulating hypoxic signaling was binding to free tubulin. Moreover, antihelminthic benzimidazoles also abrogated oxidative stress-induced death in vitro, and this on-target effect also involves binding to free tubulin. INNOVATION AND CONCLUSIONS: These studies demonstrate that tubulin-binding drugs can activate a component of the hypoxic adaptive response, specifically the stabilization of HIF-1alpha and its downstream targets. Tubulin-binding drugs, including antihelminthic benzimidazoles, also abrogate oxidative neuronal death in primary neurons. Given their safety in humans and known ability to penetrate into the central nervous system, antihelminthic benzimidazoles may be considered viable candidates for treating diseases associated with oxidative neuronal death, including stroke. PMID- 24766302 TI - External beam radiotherapy +/- chemotherapy in the treatment of anal canal cancer: a single-institute long-term experience on 100 patients. AB - One-hundred patients treated with curative radiotherapy (RT) +/- chemotherapy (CT) for an anal canal carcinoma (T1-4N0-3M0) were retrospectively analyzed. Five and 10-year local control (LC) rates were 73% and 67%, respectively. Acute and late G3-G4 toxicity rates were 32% and 12%, respectively. Two patients underwent a colostomy for a G4 anal toxicity. This study confirms the outcomes of RT +/- CT in the treatment of anal canal cancer. Concomitant CT and LC statistically influenced Overall Survival and Colostomy-Free Survival. CT also statistically reduced the risk of nodal relapse. High rates of acute skin toxicity impose tailored volumes and techniques of irradiation. PMID- 24766303 TI - PLCE1 suppresses p53 expression in esophageal cancer cells. AB - The apoptotic mechanism dysfunction plays a critical role in cancer cell growth and escaping from cancer therapies; the underlying mechanisms are to be further elucidated. This study aims to investigate the role of phospholipase C epsilon 1 (PLCE1) in modulating the apoptosis mechanism in esophageal cancer (Eca) cells. The results showed that Eca cell lines, OE33 and CP-C cells expressed high levels of PLCE1. Knockdown of PLCE1 markedly increased 9.26 folds of the expression of p53 and 13.8 folds of the frequency of apoptotic CP-C cells via modulating the p53 promoter methylation. PMID- 24766304 TI - Recognizing and correcting failures in glioblastoma treatment. AB - While current treatment remains universal for glioblastoma, recent evidence has demonstrated marked heterogeneity in their molecular profiles. Due to the near universal rate of recurrence, attention has focused on individualized treatment and subgroup population differences that may influence the efficacy of adjuvant therapy. Recent studies have implicated chemo-radioresistant GBM stem cells (GSCs) in the propagation of heterogeneous tumor profiles. As a result, there has been a shift to classify and target GSCs in order to increase survival and delay relapse. The overall objective of our editorial is to highlight current failures in GBM treatment and to propose novel personalized methods to correct our shortcomings in GBM treatment. PMID- 24766305 TI - IsoMS: automated processing of LC-MS data generated by a chemical isotope labeling metabolomics platform. AB - A chemical isotope labeling or isotope coded derivatization (ICD) metabolomics platform uses a chemical derivatization method to introduce a mass tag to all of the metabolites having a common functional group (e.g., amine), followed by LC-MS analysis of the labeled metabolites. To apply this platform to metabolomics studies involving quantitative analysis of different groups of samples, automated data processing is required. Herein, we report a data processing method based on the use of a mass spectral feature unique to the chemical labeling approach, i.e., any differential-isotope-labeled metabolites are detected as peak pairs with a fixed mass difference in a mass spectrum. A software tool, IsoMS, has been developed to process the raw data generated from one or multiple LC-MS runs by peak picking, peak pairing, peak-pair filtering, and peak-pair intensity ratio calculation. The same peak pairs detected from multiple samples are then aligned to produce a CSV file that contains the metabolite information and peak ratios relative to a control (e.g., a pooled sample). This file can be readily exported for further data and statistical analysis, which is illustrated in an example of comparing the metabolomes of human urine samples collected before and after drinking coffee. To demonstrate that this method is reliable for data processing, five (13)C2-/(12)C2-dansyl labeled metabolite standards were analyzed by LC-MS. IsoMS was able to detect these metabolites correctly. In addition, in the analysis of a (13)C2-/(12)C2-dansyl labeled human urine, IsoMS detected 2044 peak pairs, and manual inspection of these peak pairs found 90 false peak pairs, representing a false positive rate of 4.4%. IsoMS for Windows running R is freely available for noncommercial use from www.mycompoundid.org/IsoMS. PMID- 24766306 TI - How can we teach them about neurotrauma prevention? Prospective and randomized "Pense Bem-Caxias do Sul" study with multiple interventions in preteens and adolescents. AB - OBJECT.: A previous study published by the authors showed that a single intervention could not change the baseline attitudes toward neurotrauma prevention. The present study was designed to evaluate the effectiveness of multiple interventions in modifying knowledge and attitudes for the prevention of neurotrauma in Brazilian preteens and adolescents. METHODS: In a randomized controlled trial, fifth-year primary school (PS) and second-year high school (HS) students were divided into a control and 2 intervention (single/multiple) groups. The study was conducted in the following 8 stages: T1, questionnaire to measure baseline characteristics; T2, lecture on trauma prevention; T3, reapplying the questionnaire used in T1; T4, Traffic Department intervention; T5, a play about trauma and its consequences; T6, Fire Department intervention; T7, Emergency Medical Service intervention; and T8, reapplying the questionnaire used in T1 and T3. Positive answers were considered those affirming the use of safety devices "always or sometimes" and negative as "never" using safety devices. RESULTS: The sample consisted of 535 students. Regarding attitudes, students in all groups at any stage of measurement showed protective behavior more than 95% of the time about seat belt use. There were only differences between attitudes in PS and HS students on T8 assessment concerning the use of safety equipment on bikes in the multiple-intervention group and concerning the use of safety equipment on skateboards and rollerblades in single- and multiple-intervention groups. These differences were caused mainly by the reduction in positive answers by the HS group, rather than by the increase in positive or protective answers by the PS group. However, there was no difference when the control and intervention groups were compared, independent of the attitudes or the student groups studied. The most important reason for not using protective devices was the belief that they would not get hurt. CONCLUSIONS: Multiple and different types of educational interventions, such as lectures, scenes from plays about trauma and its consequences, traffic and fire department intervention, and medical emergency intervention directed to preteens and adolescents from public and private schools did not modify most students' attitudes toward injury prevention. Clinical trial registration no: U1111-1121-0192 (National System of Ethics and Research in Brazil). PMID- 24766308 TI - Quality measurement in the shunt treatment of hydrocephalus: analysis and risk adjustment of the Revision Quotient. AB - OBJECT.: The Revision Quotient (RQ) has been defined as the ratio of the number of CSF shunt revisions to the number of new shunt insertions for a particular neurosurgical practice in a unit of time. The RQ has been proposed as a quality measure in the treatment of childhood hydrocephalus. The authors examined the construct validity of the RQ and explored the feasibility of risk stratification under this metric. METHODS: The Kids' Inpatient Database for 1997, 2000, 2003, 2006, and 2009 was queried for admissions with diagnostic codes for hydrocephalus and procedural codes for CSF shunt insertion or revision. Revision quotients were calculated for hospitals that performed 12 or more shunt insertions annually. The univariate associations of hospital RQs with a variety of institutional descriptors were analyzed, and a generalized linear model of the RQ was constructed. RESULTS: There were 12,244 admissions (34%) during which new shunts were inserted, and there were 23,349 admissions (66%) for shunt revision. Three hundred thirty-four annual RQs were calculated for 152 different hospitals. Analysis of variance in hospital RQs over the 5 years of study data supports the construct validity of the metric. The following factors were incorporated into a generalized linear model that accounted for 41% of the variance of the measured RQs: degree of pediatric specialization, proportion of initial case mix in the infant age group, and proportion with neoplastic hydrocephalus. CONCLUSIONS: The RQ has construct validity. Risk adjustment is feasible, but the risk factors that were identified relate predominantly to patterns of patient flow through the health care system. Possible advantages of an alternative metric, the Surgical Activity Ratio, are discussed. PMID- 24766307 TI - Choroid plexus coagulation in infants with extreme hydrocephalus or hydranencephaly. AB - OBJECT.: Severe hydrocephalus and hydranencephaly are common congenital conditions in Kenya. In patients with these conditions, ventriculoperitoneal (VP) shunts are associated with appreciable complications and endoscopic third ventriculostomies (ETVs) have limited success. Endoscopic choroid plexus coagulation (CPC) to diminish CSF production is a potential treatment option. The purpose of this study was to evaluate the effect of CPC without ETV in infants with severe hydrocephalus or hydranencephaly. METHODS: Medical records of infants with severe congenital hydrocephalus or hydranencephaly who underwent CPC in Kijabe Hospital from November 2010 to April 2013 were reviewed retrospectively. Thirty-three patients with complete medical records and preoperative radiographic images were identified. After CPC, the infants were followed in the Kijabe Hospital outpatient department, in mobile clinics, or by telephone. Success of the CPC was defined as resolution of preoperative symptoms, stabilization of head size, and avoidance of VP shunt placement. RESULTS: Patients were followed from 30 to 608 days (median of 120 days). Three patients were lost to follow-up. Of the 30 evaluable patients, CPC was considered to be successful in 13 (43.3%), including 8 of 20 patients with severe hydrocephalus and 5 of 10 with hydranencephaly. Failure of CPC was evident from increased head circumference in 14 (82%) of 17 patients and from CSF leakage in 3. Of the 17 failures, 13 occurred within 3 months of surgery. Six patients died: 3 whose CPC procedures were failures, 2 whose CPC was successful, and 1 postoperatively. Of the 17 in whom CPC failed, 10 subsequently underwent VP shunt insertion. CONCLUSIONS: CPC stabilizes macrocephaly in approximately 40% of infants with severe congenital hydrocephalus and hydranencephaly and can be considered as an alternative to VP shunt placement. PMID- 24766309 TI - Stereotactic radiosurgery at a low marginal dose for the treatment of pediatric arteriovenous malformations: obliteration, complications, and functional outcomes. AB - OBJECT.: Stereotactic radiosurgery (SRS) is an established treatment modality for brain arteriovenous malformations (AVMs) in children, but the optimal treatment parameters and associated treatment-related complications are not fully understood. The authors present their single-institution experience of using SRS, at a relatively low marginal dose, to treat AVMs in children for nearly 20 years; they report angiographic outcomes, posttreatment hemorrhage rates, adverse treatment-related events, and functional outcomes. METHODS: The authors conducted a retrospective review of 2 cohorts of children (18 years of age or younger) with AVMs treated from 1991 to 1998 and from 2000 to 2010. RESULTS: A total of 80 patients with follow-up data after SRS were identified. Mean age at SRS was 12.7 years, and 56% of patients had hemorrhage at the time of presentation. Median target volume was 3.1 cm(3) (range 0.09-62.3 cm(3)), and median prescription marginal dose used was 17.5 Gy (range 12-20 Gy). Angiograms acquired 3 years after treatment were available for 47% of patients; AVM obliteration was achieved in 52% of patients who received a dose of 18-20 Gy and in 16% who received less than 18 Gy. At 5 years after SRS, the cumulative incidence of hemorrhage was 25% (95% CI 16%-37%). No permanent neurological deficits occurred in patients who did not experience posttreatment hemorrhage. Overall, good functional outcomes (modified Rankin Scale Scores 0-2) were observed for 78% of patients; for 66% of patients, functional status improved or remained the same as before treatment. CONCLUSIONS: A low marginal dose minimizes SRS-related neurological deficits but leads to low rates of obliteration and high rates of hemorrhage. To maximize AVM obliteration and minimize posttreatment hemorrhage, the authors recommend a prescription marginal dose of 18 Gy or more. In addition, SRS-related symptoms such as headache and seizures should be considered when discussing risks and benefits of SRS for treating AVMs in children. PMID- 24766311 TI - Hemodialysis-related headache. AB - Headache is one of the most frequently encountered neurological symptoms during hemodialysis. According to International Classification of Headache criteria dialysis-related headache was defined as the headache occurring during hemodialysis with no specific characteristic. It resolves spontaneously within 72 hours after the hemodialysis session ends. There are few studies in the literature investigating the clinical features of dialysis headache. The pathophysiology of hemodialysis-related headache is not known, but various triggering factors have been identified, including changes in blood pressure, serum sodium and magnesium levels during hemodialysis sessions, caffeine deprivation and stress. The aim of this article is to evaluate and analyze features of headache in patients undergoing hemodialysis. PMID- 24766310 TI - Prognostic significance of gamma-glutamyltransferase in patients with resectable esophageal squamous cell carcinoma. AB - Gamma-glutamyltransferase (GGT) is a membrane-bound enzyme involved in the glutathione metabolism. Studies suggested that GGT was a marker of apoptotic balance and modulated tumor progression, invasion and drug resistance. Recently, GGT was shown to be associated with the progression of high-grade esophageal epithelial dysplasia to invasive carcinoma. This study was conducted to investigate the value of pre-therapeutic serum GGT levels as prognostic parameter in esophageal squamous cell carcinoma. Six hundred thirty-nine resectable esophageal squamous cell carcinoma patients were recruited in this study and were stratified into two GGT risk groups. The association of pre-therapeutic serum GGT levels and clinical-pathological parameters was examined. Univariate and multivariate survival analyses were performed. GGT serum levels were associated with gender, smoking status, TNM stage and lymph node involvement. Higher pre therapeutic serum GGT was found in males, smoker, advanced TNM stage and lymph node positive patients. Patients assigned to the low-risk group had higher 5-year overall survival rate (53.1% vs. 33.0%, P < 0.01) and disease-free survival rate (45.2% vs. 23.4%, P < 0.01) than the high-risk group. Patients with high-risk group of GGT had 1.568 (95% confidence interval [CI], 1.259 ~ 1.952) times the risk of death and 1.582 (95% CI, 1.286 ~ 1.946) times the risk of disease recurrence contrast with those with low-risk group of GGT. The pre-therapeutic serum GGT is a novel independent prognostic parameter for disease-free survival and overall survival in resectable esophageal squamous cell carcinoma. PMID- 24766312 TI - Impact of risk score calculations in choosing front-line tyrosine kinase inhibitors for patients with newly diagnosed chronic myeloid leukemia in the chronic phase. AB - The approval of multiple tyrosine kinase inhibitors targeting BCR-ABL has broadened the number of available therapeutic options for chronic myeloid leukemia in the chronic phase (CML-CP). This provides an impetus for optimizing prognostic risk score systems that can guide treatment decisions. Presently, three risk scores-the Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) metrics-have been implemented clinically in CML-CP. While these three formulations all endeavor to gauge likely disease course, they differ from one another in several important respects, with potential implications for prognosis and therapy. Here, we review these risk scores and propose how prognostic systems in CML-CP might be refined to direct patients to optimally effective therapies as efficiently and accurately as possible. PMID- 24766313 TI - Improvement of Alcaligenes faecalis nitrilase by gene site saturation mutagenesis and its application in stereospecific biosynthesis of (R)-(-)-mandelic acid. AB - Nitrilases have recently received considerable attention as the biocatalysts for stereospecific production of carboxylic acids. To improve the activity, the nitrilase from Alcaligenes faecalis was selected for further modification by the gene site saturation mutagenesis method (GSSM), based on homology modeling and previous reports about mutations. After mutagenesis, the positive mutants were selected using a convenient two-step high-throughput screening method based on product formation and pH indicator combined with the HPLC method. After three rounds of GSSM, Mut3 (Gln196Ser/Ala284Ile) with the highest activity and ability of tolerance to the substrate was selected. As compared to the wild-type A. faecalis nitrilase, Mut3 showed 154% higher specific activity. Mut3 could retain 91.6% of its residual activity after incubation at pH 6.5 for 6 h. In a fed-batch reaction with 800 mM mandelonitrile as the substrate, the cumulative production of (R)-(-)-mandelic acid after 7.5 h of conversion reached 693 mM with an enantiomeric excess of 99%, and the space-time productivity of Mut3 was 21.50 fold higher than that of wild-type nitrilase. The Km, Vmax, and k(cat) of wild type and Mut3 for mandelonitrile were 20.64 mM, 33.74 MUmol mg(-1) min(-1), 24.45 s(-1), and 9.24 mM, 47.68 MUmol mg(-1) min(-1), and 34.55 s(-1), respectively. A homology modeling and molecular docking study showed that the diameter of the catalytic tunnel of Mut3 became longer and that the tunnel volume was smaller. These structural changes are proposed to improve the hydrolytic activity and pH stability of Mut3. Mut3 has the potential for industrial applications in the upscale production of (R)-(-)-mandelic acid. PMID- 24766314 TI - Stereoselective synthesis of a sulfated tetrasaccharide corresponding to a rare sequence in the galactofucan isolated from Sargassum polycystum. AB - The first chemical synthesis of a highly sulfated tetrasaccharide 1, as the rare sequence in the galactofucan isolated from the brown alga Sargassum polycystum, was achieved in a convergent and stereoselective manner. The key features of the synthetic strategy include construction of multiple contiguous 1,2-cis glycosidic bonds and [2 + 2] assembly based on the rationally developed d-galactose building block 6. The synthesized oligosaccharides were fully characterized using a combination of coupled-HSQC and other 2D NMR techniques. PMID- 24766315 TI - Exploring recollection and familiarity impairments in Parkinson's disease. AB - There is conflicting evidence on whether patients diagnosed with Parkinson's disease (PD) have cognitive deficits associated with episodic memory and particularly with recognition memory. The aim of the present study was to explore whether PD patients exhibit deficits in recollection and familiarity, the two processes involved in recognition. A sample of young healthy participants (22) was tested to verify that the experimental tasks were useful estimators of recognition processes. Two further samples--one of elderly controls (16) and one of PD patients (20)--were the main focus of this research. All participants were exposed to an associative recognition test aimed at estimating recollection followed by a two-alternative forced-choice (2AFC) test designed to estimate familiarity. The analyses showed a deficit in associative recognition in PD patients and no difference between elderly controls and PD patients in the 2AFC test. By contrast, young healthy participants were better than elderly controls and PD patients in both components of recognition. Further analyses of results of the 2AFC test indicated that the measure chosen to estimate conceptual familiarity was adequate. PMID- 24766316 TI - Acute psychosocial stress and children's memory. AB - We investigated whether children's performance on working memory (WM) and delayed retrieval (DR) tasks decreased after stress exposure, and how physiological stress responses related to performance under stress. About 158 children (83 girls; Mage = 10.61 years, SD = 0.52) performed two WM tasks (WM forward and WM backward) and a DR memory task first during a control condition, and 1 week later during a stress challenge. Salivary alpha-amylase (sAA) and cortisol were assessed during the challenge. Only WM backward performance declined over conditions. Correlations between physiological stress responses and performance within the stress challenge were present only for WM forward and DR. For WM forward, higher cortisol responses were related to better performance. For DR, there was an inverted U-shape relation between cortisol responses and performance, as well as a cortisol * sAA interaction, with concurrent high or low responses related to optimal performance. This emphasizes the importance of including curvilinear and interaction effects when relating physiology to memory. PMID- 24766317 TI - Enantioselective insertion of a carbenoid carbon into a C-C bond to expand cyclobutanols to cyclopentanols. AB - When a carbenoid species generated from a tosylhydrazone is reacted with a cyclobutanol in the presence of a chiral rhodium catalyst, a C-C single bond of the cyclobutanol is cleaved, and the carbenoid carbon is inserted therein to furnish a ring-expanded cyclopentanol in an enantioselective manner. PMID- 24766318 TI - How general practitioners treat migraine in children--evaluation of a headache guideline. AB - BACKGROUND: Migraine is a common illness in children associated with a negative impact on the quality of life. In the Netherlands, treatment of migraine is commonly performed by general practitioners (GPs). The migraine guideline of the Dutch College of General Practitioners recommends inactivity and acetaminophen in patients with migraine who are younger than 18 years of age. OBJECTIVE: The aim of our study was to evaluate the pharmacological treatment of migraine in children by GPs before referral to the hospital. Our objective was to answer the following questions. First, are GPs inclined to prescribe medication not listed in the Dutch College of General Practitioners Guideline? Second, which clinical characteristics are associated with the use of medication not listed in this guideline? METHODS: In this retrospective cross-sectional study, prescribed medication and migraine characteristics were investigated in Dutch migraine patients (age <18 years), using hospital records and a paper-and-pencil questionnaire. RESULTS: A total of 223 children were included. Medications not listed in the guideline were used in 41.3% of the patients before referral. In children younger than 12 years, the use of medication not listed in the guideline was associated with an older age, when compared with children who were treated according to the guideline. In the group of patients older than 11 years, the use of medication not listed in the guideline was associated with a longer history of migraine and a longer duration of the migraine attacks. CONCLUSIONS: Medications not listed in the GPs guideline were used in a large portion of the patients younger than 18 years with migraine who were referred to secondary care. PMID- 24766319 TI - Targeting inflammation in cancer-related-fatigue: a rationale for mistletoe therapy as supportive care in colorectal cancer patients. AB - BACKGROUND: Cancer-related fatigue (CRF) affects a majority of patients (pts) with symptoms lasting up to several years after finishing therapy. These symptoms lead to decreased health related quality of life. Fatigue during treatment for colorectal cancer is common, but poorly understood and can affect compliance with post-surgical cancer therapy. We examined the fatigue levels during first-line chemo- or radio-chemotherapy protocols, which were supported by a pharmaceutical mistletoe preparation (Iscador((r))Qu) (181patients). We compared the outcome to a parallel control group (143 patients), which did not receive this supportive care treatment. METHODS: The medical records of 324 patients with non metastasized colorectal cancer (UICC stage I-III), which were obtained from hospitals and resident physicians, were assessed. The documented treatment decision by chemo- or radio-chemotherapy supported by mistletoe interventions was followed for a median treatment period of 8.6 months. During the post-surgical treatment period the patients were diagnosed twice for the presence of fatigue symptoms by structural interviews carried out by physicians. RESULTS: At the end of the median treatment period, 16/181 patients (8.8%) were diagnosed with CRF in the supportive care group and 86/143 (60.1%) in the chemo- or radio-chemotherapy group without supportive mistletoe medication. Multivariable-adjusted ORs provided evidence for a chance to improve CRF by supportive mistletoe medication compared to chemo- or radio-chemotherapy alone over the time of treatment. The OR = 10.651 (95% CI 5.09-22.28; p < 0.001) declined from the first visit to OR = 0.054 (95 CI 0.02-0.13; p < 0.001) at the end of therapy. Furthermore, 14 confounding factors for risk assessment of CRF were compared by means of forest plots. It turned out that the hospital versus office-based treatment and the co morbidity/inflammation represent independent but important determinants for fatigue levels. CONCLUSION: The clinically used mistletoe medication (Iscador((r))Qu) is the first candidate to be included in a supportive care modus into chemo- or chemo-radiotherapy protocols for colorectal patients to improve CRF without discernable toxicities. PMID- 24766320 TI - Adults face increased asthma risk after infant RSV bronchiolitis and reduced respiratory health-related quality of life after RSV pneumonia. AB - AIM: To evaluate the association between hospitalisation for respiratory syncytial virus lower respiratory tract infection (RSV LRTI) in infancy and asthma, respiratory health-related quality of life and lung function at 28-31 years of age. METHODS: In 2010, we carried out a 30-year follow-up on 43 adults admitted to Kuopio University Hospital, Finland, for RSV LRTI, 27 for bronchiolitis and 16 for pneumonia, between 1981 and 1982. Together with 86 population-based controls, they completed the Saint George's Respiratory Questionnaire and underwent prebronchodilator (pre-BD) and post-BD spirometry tests to measure percentage of predicted forced vital capacity (FVC%), percentage of predicted forced expiratory volume in 1 sec (FEV1%) and percentage of predicted FEV1/FVC (FEV1/FVC%). RESULTS: Both the pre-BD and post-BD FEV1% and FEV1/FVC% were significantly lower in former RSV LRTI patients than in the controls. The bronchiolitis patients had more asthma in adulthood than the controls and pneumonia in infancy was associated with lower St George's Respiratory Questionnaire (SGRQ) scores. CONCLUSION: Respiratory tract infection LRTI hospitalisation in infancy was associated with an increased risk of permanent obstructive lung function reduction in adulthood. The asthma risk was higher after hospitalisation for bronchiolitis, than in the controls, and respiratory health-related quality of life was lower after hospitalisation for pneumonia. PMID- 24766321 TI - Improving early cycle economic evaluation of diagnostic technologies. AB - The rapidly increasing range and expense of new diagnostics, compels consideration of a different, more proactive approach to health economic evaluation of diagnostic technologies. Early cycle economic evaluation is a decision analytic approach to evaluate technologies in development so as to increase the return on investment as well as patient and societal impact. This paper describes examples of 'early cycle economic evaluations' as applied to diagnostic technologies and highlights challenges in its real-time application. It shows that especially in the field of diagnostics, with rapid technological developments and a changing regulatory climate, early cycle economic evaluation can have a guiding role to improve the efficiency of the diagnostics innovation process. In the next five years the attention will move beyond the methodological and analytic challenges of early cycle economic evaluation towards the challenge of effectively applying it to improve diagnostic research and development and patient value. Future work in this area should therefore be 'strong on principles and soft on metrics', that is, the metrics that resonate most clearly with the various decision makers in this field. PMID- 24766322 TI - Immunohistochemical analysis of the role of hemocytin in nodule formation in the larvae of the silkworm, Bombyx mori. AB - Hemocytin, a multidomain protein from Bombyx mori L. (Lepidoptera: Bombycidae), is an ortholog of von Willebrand factor and is expected to be a major mediator of hemocyte aggregation. Antiserum was generated against hemocytin, and immune staining of hemocytes, hemolymph, and nodules was performed. Hemocytin was observed in steady-state hemocytes but not in plasma, even after bacterial injection. When hemolymph was smeared on glass slides, hemocytin-containing fibrous structures formed a cellular network mainly consisting of granulocytes and oenocytoids. Hemocytin was stained only in the granules of the granulocytes. When nodule-like aggregates formed 30 sec after bacterial injection, both granulocytes and bacterial cells were observed binding to hemocytin-containing fibrous structures. When nodule sections were stained with antiserum, hemocytin was seen in the matrix of the nodules surrounding the hemocytes. These data suggest that hemocytin plays a major role in nodule formation as a component of the sticky fibrous structure exocytosed from granulocytes. PMID- 24766323 TI - Effect of hypotonic 0.18% sodium hyaluronate eyedrops on inflammation of the ocular surface in experimental dry eye. AB - PURPOSE: To investigate the efficacy of hypotonic 0.18% sodium hyaluronate (SH) eyedrops in a mouse model of experimental dry eye (EDE). METHODS: EDE was induced in C57BL/6 mice by a subcutaneous scopolamine injection and an air draft. The mice were divided into 4 groups according to topical treatment regimens: EDE control, isotonic 0.5% carboxymethycellulose (CMC), isotonic 0.1% SH, and hypotonic 0.18% SH. Tear volume, corneal smoothness, and corneal staining scores were measured at 5 and 10 days of EDE. Multiplex immunobead assay, immunohistochemistry, and flow cytometry for proinflammatory cytokines, chemokines, and inflammatory molecules were performed at 10 days of EDE. RESULTS: The 0.18% SH group had a significantly lower corneal smoothness and staining scores than the 0.5% CMC and 0.1% SH groups at 10 days of EDE (P<0.05). The 0.18% SH group showed significantly low levels of tumor necrosis factor-alpha (TNF alpha), interleukin (IL)-1beta, monokine induced by interferon-gamma, and interferon-gamma-inducible protein 10 compared with the other groups (P<0.05). The mean percentages of CD4(+)CXCR3(+), CD40(+), and CD44(+) cells in the conjunctiva were significantly lower in the 0.18% SH group than in the other groups (P<0.05). In addition, the 0.1% SH group showed lower levels of TNF-alpha and IL-1beta and percentages of CD40(+) and CD44(+) cells than the EDE and 0.5% CMC groups. CONCLUSIONS: Hypotonic 0.18% SH eyedrops are more effective in improving ocular surface irregularity and staining and decreasing inflammatory cytokines, chemokines, and cells on the ocular surface compared with isotonic 0.5% CMC or 0.1% SH eyedrops in the treatment of EDE. PMID- 24766324 TI - Exploring the uncertainties in cancer risk assessment using the integrated probabilistic risk assessment (IPRA) approach. AB - Current methods for cancer risk assessment result in single values, without any quantitative information on the uncertainties in these values. Therefore, single risk values could easily be overinterpreted. In this study, we discuss a full probabilistic cancer risk assessment approach in which all the generally recognized uncertainties in both exposure and hazard assessment are quantitatively characterized and probabilistically evaluated, resulting in a confidence interval for the final risk estimate. The methodology is applied to three example chemicals (aflatoxin, N-nitrosodimethylamine, and methyleugenol). These examples illustrate that the uncertainty in a cancer risk estimate may be huge, making single value estimates of cancer risk meaningless. Further, a risk based on linear extrapolation tends to be lower than the upper 95% confidence limit of a probabilistic risk estimate, and in that sense it is not conservative. Our conceptual analysis showed that there are two possible basic approaches for cancer risk assessment, depending on the interpretation of the dose-incidence data measured in animals. However, it remains unclear which of the two interpretations is the more adequate one, adding an additional uncertainty to the already huge confidence intervals for cancer risk estimates. PMID- 24766325 TI - Stories about life narrated by people with Alzheimer's disease. AB - AIM: To explore how people with Alzheimer's disease present their life story. BACKGROUND: Life story work is a key concept in a person-centred care. An important aspect in understanding the subjective experience and supporting the identity of people with dementia is to listen to their life stories. DESIGN: A narrative design with interviews was used. METHOD: Nine participants with Alzheimer's disease were encouraged to tell about their lives from childhood, adult life, to present life and about their thoughts on the future. The interviews were conducted between September 2010-March 2011 in the participants' homes, with their spouses present and were analysed with a method for analysis of narratives. FINDINGS: Contentment, Connectedness, Self-reliance and Personal growth were identified as core dimensions in the participants' life stories and shown like threads throughout life, from childhood, adult life to present life. All participants expressed an overall contentment with life, and connectedness was related to their relation with significant persons and to be included in the local community. Self-reliance was expressed as a strong confidence in the own ability and an overall curiosity throughout life as a sustained quest for personal growth. CONCLUSIONS: It is important for healthcare professionals, who work with people with dementia, to understand that people with Alzheimer's disease can maintain an overall trusting and hopeful approach to life. It is also important to use life story work to enhance feelings of being connected to the world and thereby support their identity and sense of self. PMID- 24766326 TI - Phylogenetic relatedness and the determinants of competitive outcomes. AB - Recent hypotheses argue that phylogenetic relatedness should predict both the niche differences that stabilise coexistence and the average fitness differences that drive competitive dominance. These still largely untested predictions complicate Darwin's hypothesis that more closely related species less easily coexist, and challenge the use of community phylogenetic patterns to infer competition. We field parameterised models of competitor dynamics with pairs of 18 California annual plant species, and then related species' niche and fitness differences to their phylogenetic distance. Stabilising niche differences were unrelated to phylogenetic distance, while species' average fitness showed phylogenetic structure. This meant that more distant relatives had greater competitive asymmetry, which should favour the coexistence of close relatives. Nonetheless, coexistence proved unrelated to phylogeny, due in part to increasing variance in fitness differences with phylogenetic distance, a previously overlooked property of such relationships. Together, these findings question the expectation that distant relatives should more readily coexist. PMID- 24766327 TI - Antiviral effect of entecavir in nucleos(t)ide analogue-naive and nucleos(t)ide analogue-experienced chronic hepatitis B patients without virological response at week 24 or 48 of therapy. AB - We investigated the antiviral effect of entecavir in nucleos(t)ide analogue (NA) naive and NA-experienced chronic hepatitis B patients without virological response (VR, HBV DNA < 300 copies/mL) at week 24 or 48. A total of 369 NA-naive and 181 NA-experienced patients treated with entecavir monotherapy were analysed. Of the 369 NA-naive patients, 34 did not achieve VR at week 48. Of them, patients with HBV DNA <= 2000 copies/mL at week 48 achieved a higher VR rate than those with HBV DNA >2000 copies/mL (18/23 vs 3/11, P = 0.004). Two naive patients with HBV DNA >2000 copies/mL developed entecavir- or lamivudine-resistant mutants. In 98 lamivudine-experienced patients without ever having lamivudine resistance, most patients with VR (72/72) and partial VR (300-10(4) copies/mL; 20/23) at week 24 or VR at week 48 (89/91) could maintain or achieve VR after prolonged therapy. In 75 patients with prior resistance to lamivudine, prolonged entecavir therapy led to low VR rate in those without VR at week 24 (13/45) or 48 (4/34) and high entecavir-resistance rate in those with or without VR at week 24 (6/30 with and 23/45 without) and 48 (8/41 with and 21/34 without). VR at week 48 was an independent predictor (HR 0.14, 95% CI 0.06-0.33) for entecavir-resistant mutant development among the 75 patients with prior lamivudine-resistant mutants. In conclusion, prolonged entecavir treatment resulted in a poor response in naive patients with HBV DNA >2000 copies/mL at week 48 and patients with prior lamivudine-resistant mutants without VR at week 24 or 48. PMID- 24766328 TI - Supramolecular chemistry at interfaces: host-guest interactions for fabricating multifunctional biointerfaces. AB - CONSPECTUS: Host-guest chemistry can greatly improve the selectivity of biomolecule-ligand binding on account of recognition-directed interactions. In addition, functional structures and the actuation of supramolecular assemblies in molecular systems can be controlled efficiently through various host-guest chemistry. Together, these highly selective, strong yet dynamic interactions can be exploited as an alternative methodology for applications in the field of programmable and controllable engineering of supramolecular soft materials through the reversible binding between complementary components. Many processes in living systems such as biotransformation, transportation of matter, and energy transduction begin with interfacial molecular recognition, which is greatly influenced by various external stimuli at biointerfaces. Detailed investigations about the molecular recognition at interfaces can result in a better understanding of life science, and further guide us in developing new biomaterials and medicines. In order to mimic complicated molecular-recognition systems observed in nature that adapt to changes in their environment, combining host-guest chemistry and surface science is critical for fabricating the next generation of multifunctional biointerfaces with efficient stimuli-responsiveness and good biocompatibility. In this Account, we will summarize some recent progress on multifunctional stimuli-responsive biointerfaces and biosurfaces fabricated by cyclodextrin- or cucurbituril-based host-guest chemistry and highlight their potential applications including drug delivery, bioelectrocatalysis, and reversible adsorption and resistance of peptides, proteins, and cells. In addition, these biointerfaces and biosurfaces demonstrate efficient response toward various external stimuli, such as UV light, pH, redox chemistry, and competitive guests. All of these external stimuli can aid in mimicking the biological stimuli evident in complex biological environments. We begin by reviewing the current state of stimuli-responsive supramolecular assemblies formed by host-guest interactions, discussing how to transfer host guest chemistry from solution onto surfaces required for fabricating multifunctional biosurfaces and biointerfaces. Then, we present different stimuli responsive biosurfaces and biointerfaces, which have been prepared through a combination of cyclodextrin- or cucurbituril-based host-guest chemistry and various surface technologies such as self-assembled monolayers or layer-by-layer assembly. Moreover, we discuss the applications of these biointerfaces and biosurfaces in the fields of drug release, reversible adsorption and release of some organic molecules, peptides, proteins, and cells, and photoswitchable bioelectrocatalysis. In addition, we summarize the merits and current limitations of these methods for fabricating multifunctional stimuli-responsive biointerfaces in a dynamic noncovalent manner. Finally, we present possible strategies for future designs of stimuli-responsive multifunctional biointerfaces and biosurfaces by combining host-guest chemistry with surface science, which will lead to further critical development of supramolecular chemistry at interfaces. PMID- 24766329 TI - The art of attraction: applications of multifunctional magnetic nanomaterials for malignant glioma. AB - INTRODUCTION: Malignant gliomas remain one of medicine's most daunting unsolved clinical problems. The development of new technologies is urgently needed to improve the poor prognosis of patients suffering from these brain tumors. Magnetic nanomaterials are appealing due to unique properties that allow for noninvasive brain tumor diagnostics and therapeutics in one multifunctional platform. AREAS COVERED: We report on the recent advances of magnetic nanomaterials for brain tumor imaging and therapy, with an emphasis on novel approaches and clinical progress. We detail their biomedical applications including brain tumor targeting, MRI contrast enhancement, optical imaging, magnetic hyperthermia, magnetomechanical destruction, drug delivery, gene therapy, as well as tracking of cell-based and viral-based therapies. The clinical cases and obstacles encountered in the use of magnetic nanomaterials for malignant glioma are also examined. EXPERT OPINION: To accelerate the effective translation of these materials to the clinic as theranostics for brain tumors, limitations such as poor intratumoral distribution, targeting efficiency and nonspecific systemic side effects must be addressed. Future innovations should focus on optimizing and combining the unique therapeutic applications of these magnetic nanomaterials as well as improving the selectivity of the system based on the molecular profiling of tumors. PMID- 24766330 TI - PI3K-dependent multiple myeloma cell survival is mediated by the PIK3CA isoform. AB - Constitutive phosphatidylinositide 3-kinase (PI3K) signalling has been implicated in multiple myeloma (MM) pathophysiology and is regarded as an actionable target for pharmacological intervention. Isoform-specific PI3K inhibition may offer the most focused treatment approach and could result in greater clinical efficacy and reduced side effects. We therefore performed isoform-specific knockdown of PIK3CA, PIK3CB, PIK3CD, and PIK3CG to analyse their individual contributions to MM cell survival and downstream signalling. In addition, we tested the effectivity of the novel PI3K isoform-specific inhibitors BYL-719 (PIK3CA), TGX 221 (PIK3CB), CAL-101 (PIK3CD), and CAY10505 (PIK3CG). We found the PIK3CA isoform to be of paramount importance for constitutive Akt activity in MM cells, and - in contrast to inhibition of other class I isoforms - only the blockade of PIK3CA was sufficient to induce cell death in a sizeable subgroup of MM samples. Furthermore, pharmacological PIK3CA inhibition in combination treatments of BYL 719 and established anti-myeloma agents resulted in strongly enhanced MM cell death. Our data thus clearly indicate therapeutic potential of PIK3CA inhibitors and support their clinical evaluation in multiple myeloma. PMID- 24766331 TI - The whales beneath the surface: the muddled story of doing research with poor mothers in a developing country. AB - In this article I attempt to show how research ideals of social change and usefulness can lead to "research paralysis." I also argue that if there is sufficient reflexivity about the research process itself, paralysis is not inevitable, and useful knowledge can indeed be generated. I substantiate this by illustrating how the same interview data can be analyzed on multiple levels, rendering it useful in different ways in different contexts. I thus argue that reflexivity is essential in the Community Psychologist's struggle for usefulness: it is in reflecting on the complexity of the research task (the demands of different contexts and different communities) that the Community Psychologist can engage strategically and productively with the possibilities and the limits of her usefulness. The data that are the focus of this article were generated in a long-term qualitative research project focusing on low-income, Black mothers from a semirural community in South Africa. PMID- 24766332 TI - Clearance of myoglobin by high cutoff continuous veno-venous hemodialysis in a patient with rhabdomyolysis: a case report. AB - Continuous veno-venous hemodialysis using high cutoff filters (HCO-CVVHD) is a promising technique, which may be effective to decrease the extremely high level of circulating myoglobin in patients with rhabdomyolysis (RM). Here, we report a patient with RM caused by heat stroke who was successfully treated by HCO-CVVHD. A male patient received HCO-CVVHD with 4 L/h dialysate for 5 days and then pre dilution continuous veno-venous hemofiltration (CVVH) at a dose of 4 L/h until recovery of renal function. The clearance of myoglobin and albumin at 5 minutes, and at 4, 12, and 24 hours were calculated. The serum myoglobin level decreased from a peak of 25,400 ng/mL on admission to 133 ng/mL at discharge. During HCO CVVHD, the mean clearances of serum myoglobin at four timepoints were 61.3 (range, 61.0-61.6), 52.3 (38.9-65.8), 47.3 (46.8-47.9), and 43.7 (39.5-48.0) mL/min, respectively, and the mean clearances of albumin were 12.4 (range, 11.8 13.1), 3.1 (2.5-3.8), 1.2 (1.0-1.4), and 0.8 (0.6-1.0) mL/min, respectively. During CVVH, the clearance rates of myoglobin at 5 minutes and 24 hours were 17.0 and 3.8 mL/min, respectively, with a negligible clearance of albumin. HCO-CVVHD can effectively decrease serum myoglobin in patients with RM because of much higher clearance of myoglobin than CVVH. However, attention should be paid to albumin loss during HCO-CVVHD. PMID- 24766333 TI - Mesenchymal stem cells reduce cigarette smoke-induced inflammation and airflow obstruction in rats via TGF-beta1 signaling. AB - Cigarette smoke has been shown to cause chronic inflammation of the lungs, eventually leading to chronic obstructive pulmonary disease (COPD). Additionally, recent studies have suggested that mesenchymal stem cells (MSCs) can mediate local inflammatory responses in the lungs. Thus, the aim of the present study was to test the effects of rat MSCs (rMSCs) on inflammation of the lungs and destructive pulmonary function induced by cigarette smoke in rats. Rats were exposed to cigarette smoke for 7 weeks. rMSCs were cultured in vitro and infused intratracheally into cigarette smoke-exposed rats. The total and differential cell counts in the bronchoalveolar lavage fluid (BALF), histological changes, pro inflammatory cytokines, transforming growth factor-beta1 (TGF-beta1) expression, and pulmonary function were evaluated. Additionally, human peripheral blood mononuclear cells and human MSCs were cocultured in vitro to detect cytokines and TGF-beta1 levels. We found that rMSC administration resulted in downregulation of pro-inflammatory cytokines in the lungs while increasing TGF-beta1 expression, reducing total inflammatory cell numbers in the BALF, and improving pulmonary histopathology and airflow obstruction. Coculture revealed that human MSCs mediated an anti-inflammatory effect partly via upregulation of TGF-beta1. These findings suggested that MSCs may have therapeutic potential in cigarette smoke induced inflammation and airflow obstruction, partly via upregulation of TGF beta1. PMID- 24766334 TI - The disappearance of onchocerciasis without intervention in Tigray Region in Northwest Ethiopia. PMID- 24766335 TI - Deepening our understanding of community response to mass health interventions. PMID- 24766336 TI - Gene Xpert MTB/RIF assay confirms its value in the first multicentre, randomised, controlled trial conducted in primary-care settings in Africa. PMID- 24766337 TI - Prevalence and risk factors of acquiring Strongyloides stercoralis infection among patients attending a tertiary hospital in Thailand. AB - OBJECTIVES: We aimed to determine the prevalence and risk factors for Strongyloides stercoralis infection in adult patients attending Siriraj Hospital, a tertiary hospital in Thailand. METHODS: A case-control study was carried out between July 2008 and April 2010. Case and control were identified from 6022 patients for whom results of faecal examination were available. A case was a patient who had S. stercoralis larva detected from faecal examination. Control was randomly selected from patients without S. stercoralis larvae detected in three consecutive faecal examinations. The proportion of control to case was 2 : 1. Demographic and clinical data for the day of diagnosis and retrospectively up to 15 days preceding the date of faecal examination were reviewed from their medical records. RESULTS: Overall, 149 (2.47%) patients had S. stercoralis larvae positive. There were 105 males (70.5%), with the mean (SD) age of 53.9 (17.2) years. A total of 300 controls were selected. Male gender (odds ratio (OR) = 2.79, 95% confidence interval (CI) 1.78-4.27)), human immunodeficiency virus (HIV) infection (OR = 3.23, 95% CI 1.43-7.29), and eosinophilia (OR = 1.81, 95% CI 1.33-2.47) were found to be independent risk factors associated with S. stercoralis infection in this setting. Corticosteroid or other immunosuppressive treatment, and other concomitant illnesses were not associated with increased risk of S. stercoralis infection. CONCLUSION: In this setting, strongyloidiasis was seen more often in male patients with eosinophilia and with HIV infection. Prevention of fatal complication caused by S. stercoralis by regular faecal examination, or serology for early detection and treatment of undiagnosed S. stercoralis infection, is warranted in these high-risk patients. PMID- 24766338 TI - Bacterial load of German cockroach (Blattella germanica) found in hospital environment. AB - BACKGROUND: Cockroaches are among the most common pests in public dwellings and health facilities. Their presence can raise safety concerns, especially as they maybe carriers of pathogenic organisms. METHODS: This study was carried out to isolate and identify the bacterial flora from German cockroaches (Blattella germanica). Cockroaches collected by hand catches from two public hospital environments in Tebessa city (northeast Algeria) were screened for microbial load from their external surfaces and alimentary tract using standard bacterial protocols. RESULTS: A total of 174 bacterial isolates were isolated from 39 German cockroach specimens. The most common and abundant bacterial species belonged to the Pseudomonas group (23.5%) and Serratia (13.2%). Pathogens like Staphylococcus aureus were also isolated, as well as opportunistic pathogens like Klebsiella species and food spoilage bacteria such as Enterobacter and Citrobacter species were isolated from both external surface and digestive tract of the insect. Generalized linear models (GLM) were performed to analyze the variation of abundances and occurrences of bacterial isolates harboured by B. germanica. The GLMs revealed that the main factors affecting variation of bacterial diversity and abundance were sex and hospital (P < 0.001). CONCLUSION: The findings of this study suggest that German cockroach acts as reservoir and potential vector of some bacterial pathogens. PMID- 24766339 TI - An outbreak of West Nile Virus infection in the region of Monastir, Tunisia, 2003. AB - BACKGROUND: A West Nile (WN) fever epidemic occurred in the region of Monastir, Tunisia, between August and October 2003. AIM OF THE STUDY: We attempt to describe the epidemiology, clinical presentation, and outcome of patients with confirmed West Nile virus (WNV) infection. METHODS: Three groups of specimens were prepared. One was made up of serum only (n = 43), the other of cerebrospinal fluid (CSF) only (n = 30), and the third group was made up of both (n = 40). These specimens were obtained from 113 patients. A serological diagnosis and evidence of WNV genome by nested reverse-transcriptase polymerase chain reaction (nRT-PCR) and TaqMan reverse transcription-polymerase chain reaction (RT-PCR) were carried out. RESULTS: Thirty-eight cases (33.6%) were serologically positive. Results of nRT-PCR showed a total of 10 positive cases of WNV (8.8%) detected in group 1 (n = 1/43), group 2 (n = 5/30), and group 3 (n = 4/40) whereas the PCR TaqMan showed 18 positive samples (15.9%) found in group 1 (n = 3/43), group 2 (n = 9/30), and group 3 (n = 6/40). All TaqMan PCR positive cases were nRT-PCR positive. In addition, four serologically probable cases were confirmed by TaqMan PCR. The attempts to isolate WNV by cell culture were unsuccessful. Considering the results of TaqMan assay and the serological diagnosis, WNV infection was confirmed in a total of 42 patients. The main clinical presentations were meningoencephalitis (40%), febrile disease (95%), and meningitis (36%). Eight patients (19%) died. The highest case-fatality rates occurred among patients aged ?55 years. The phylogenetic analysis revealed that isolates of WNV were closely related to the Tunisian strain 1997 (PAH001) and the Israeli one (Is-98). CONCLUSIONS: West Nile virus is a reemerging global pathogen that remains an important public health challenge in the next decade. PMID- 24766340 TI - Gastrointestinal symptoms resembling ulcerative proctitis caused by larvae of the drone fly Eristalis tenax. AB - We report a case of facultative intestinal myiasis due to larvae of the drone fly Eristalis tenax, also named the rat-tailed maggots. The development of larvae in the lower bowel was responsible for non-specific gastrointestinal symptoms that resembled ulcerative proctitis. The diagnosis was established upon the observation of four spontaneously excreted mobile larvae. The definite identification of the E. tenax species was made possible by scanning electron microscopy. The clinical outcome was satisfactory. PMID- 24766341 TI - Intestinal anti-inflammatory effects of oligosaccharides derived from lactulose in the trinitrobenzenesulfonic acid model of rat colitis. AB - Intestinal microbiota modulation is becoming an interesting approach to manage inflammatory bowel disease and can be achieved by the administration of prebiotics. Previous studies showed the intestinal anti-inflammatory effects of the prebiotic lactulose. The aim of the present study was to test the preventative effects of oligosaccharides derived from lactulose with prebiotic properties (OsLu) in the trinitrobenzenesulfonic acid model of rat colitis and compare them with those of lactulose. Both treatments modified bacterial profile in intestinal contents, increasing the bifidobacteria and lactobacilli counts and up-regulating the production of short-chain fatty acids, although OsLu generated a larger amount. OsLu also inhibited to a greater extent different pro inflammatory markers such as interleukins (IL) 1, 6, 12, and 23 and chemokines (MCP-1 and CINC-1). However, both prebiotics equally restored colonic epithelial integrity, evaluated both with a histological score (OsLu, 9.8 +/- 2.2; and lactulose, 12.1 +/- 2.1, vs colitic control, 27.3 +/- 3.3) and by measuring several key proteins of the mucosal barrier (MUC-2, MUC-3, and TTF-3). OsLu effect was also associated with an inhibition of iNOS expression and a reduction of Th17 cell activity in the inflamed tissue that facilitated the intestinal mucosa barrier recovery. In conclusion, OsLu showed a better anti-inflammatory profile than lactulose in this model of experimental colitis. PMID- 24766343 TI - Mapping the fluorescence performance of a photochromic-fluorescent system coupled with gold nanoparticles at the single-molecule-single-particle level. AB - Single-molecule (SM) fluorescence microscopy was used to investigate the photochromic fluorescent system spiropyran-merocyanine (SP <-> MC) interacting with gold nanoparticles (AuNPs). We observe a significant increase in the brightness of the emissive MC form, in the duration of its ON time, and in the total number of emitted photons. The spatial distribution of SMs with improved photophysical performance was obtained with 40 nm precision relative to the nearest AuNP. We demonstrate that even photochromic systems with poor photochemical performance for SM can become suitable for long time monitoring and high performance microscopy by interaction with metallic NP. PMID- 24766342 TI - Statin use reduces the risk of dementia in elderly patients: a nationwide data survey and propensity analysis. AB - OBJECTIVES: The objective of this study was to examine the association between the use of statins and the risk of newly diagnosed dementia in an elderly population. DESIGN, SETTING AND PARTICIPANTS: Random samples of 1,000,000 individuals covered by the National Health Insurance in Taiwan were included in the analysis. All participants were 65 years or older without dementia and either did or did not start treatment with statins from 1 August 1997 to 31 December 2010. Patients with established dementia before the start of treatment were excluded. Baseline characteristics were matched (by propensity score) in those who did and did not receive statins. RESULTS: A total of 57,669 subjects were included in the analysis with approximately 12 years of follow-up. Propensity score matching identified 2003 patients who received statins and another 2003 patients who did not with comparable baseline characteristics. Adjusted hazard ratios (HRs) for dementia were significantly inversely associated with total or daily equivalent statin dosage (total accumulated dose: HRs 0.829, 0.720 and 0.385 from T1 to T3 vs. control, P < 0.001 for trend; mean daily dose: HRs 0.667, 0.798 and 0.503 from T1 to T3 vs. control, P < 0.001). The results remained robust after propensity adjustment. CONCLUSION: Independent of traditional risk factors, there was a decrease in newly diagnosed cases of dementia in elderly patients who had received a high total or daily dose of statins. The more potent statins (e.g. atorvastatin and rosuvastatin) seemed to be particularly effective in the prevention of dementia. PMID- 24766344 TI - Esophageal mucosal mast cell infiltration and changes in segmental smooth muscle contraction in noncardiac chest pain. AB - Mast cells release potent mediators that alter enteric nerve and smooth muscle functions and may contribute to the pathogenesis of functional gastrointestinal disorders. The goal of this study was to determine if mucosal mast cell infiltration was associated with smooth muscle segmental changes in esophageal contraction. All patients with noncardiac chest pain (NCCP) were divided into two groups consisting of patients with non-erosive reflux disease or functional chest pain (FCP) according to the results of ambulatory 24 hours esophageal pH monitoring and high-resolution manometry. Pressure-volume (PV) was calculated by multiplying the length of the esophageal segment, duration of the contraction, and mean pressure over the entire space-time box (P mean). Quantification of mast cells was performed in five consecutive nonoverlapping immunostained sections. Spearman correlation analysis showed that the distal segment PV correlated with the mast cell count in all of the patients combined and in patients with FCP with correlation coefficients of 0.509 and 0.436, respectively (P = 0.004 and P = 0.042). Similar findings were observed for the segmental ratio of distal to proximal smooth muscle PV in all patients and in patients with FCP (correlation coefficients 0.566; P = 0.001 and correlation coefficients 0.525; P = 0.012, respectively). Mucosal mast cell infiltration was associated with distal esophageal contraction as a key pathophysiologic factor of NCCP. PMID- 24766345 TI - Dual oxidase 2 in lung epithelia is essential for hyperoxia-induced acute lung injury in mice. AB - AIMS: Acute lung injury (ALI) induced by excessive hyperoxia has been employed as a model of oxidative stress imitating acute respiratory distress syndrome. Under hyperoxic conditions, overloading quantities of reactive oxygen species (ROS) are generated in both lung epithelial and endothelial cells, leading to ALI. Some NADPH oxidase (NOX) family enzymes are responsible for hyperoxia-induced ROS generation in lung epithelial and endothelial cells. However, the molecular mechanisms of ROS production in type II alveolar epithelial cells (AECs) and ALI induced by hyperoxia are poorly understood. RESULTS: In this study, we show that dual oxidase 2 (DUOX2) is a key NOX enzyme that affects hyperoxia-induced ROS production, particularly in type II AECs, leading to lung injury. In DUOX2 mutant mice (DUOX2(thyd/thyd)) or mice in which DUOX2 expression is knocked down in the lungs, hyperoxia-induced ALI was significantly lower than in wild-type (WT) mice. DUOX2 was mainly expressed in type II AECs, but not endothelial cells, and hyperoxia-induced ROS production was markedly reduced in primary type II AECs isolated from DUOX2(thyd/thyd) mice. Furthermore, DUOX2-generated ROS are responsible for caspase-mediated cell death, inducing ERK and JNK phophorylation in type II AECs. INNOVATION: To date, no role for DUOX2 has been defined in hyperoxia-mediated ALI despite it being a NOX homologue and major ROS source in lung epithelium. CONCLUSION: Here, we present the novel finding that DUOX2 generated ROS induce AEC death, leading to hyperoxia-induced lung injury. PMID- 24766347 TI - Atypical presentation of 'acalculous cholecystitis' with marked isolated hyperbilirubinaemia in patients treated for haematological malignancies. AB - Four patients diagnosed with haematological malignancies developed an isolated hyperbilirubinaemia following cytarabine- and anthracycline-based chemotherapy. The clinical picture was consistent with acalculous cholecystitis, but ultrasonography did not show the typical gallbladder wall thickening. All patients suffered from severe mucositis with neutropenic enterocolitis. We hypothesise that damage of the mucosa of the gallbladder induced by chemotherapy results in hyperpermeability of the mucosal barrier with bile leakage and isolated hyperbilirubinaemia. PMID- 24766346 TI - Multiple redundant medulla projection neurons mediate color vision in Drosophila. AB - The receptor mechanism for color vision has been extensively studied. In contrast, the circuit(s) that transform(s) photoreceptor signals into color percepts to guide behavior remain(s) poorly characterized. Using intersectional genetics to inactivate identified subsets of neurons, we have uncovered the first order interneurons that are functionally required for hue discrimination in Drosophila. We developed a novel aversive operant conditioning assay for intensity-independent color discrimination (true color vision) in Drosophila. Single flying flies are magnetically tethered in an arena surrounded by blue and green LEDs (light-emitting diodes). The flies' optomotor response is used to determine the blue-green isoluminant intensity. Flies are then conditioned to discriminate between equiluminant blue or green stimuli. Wild-type flies are successfully trained in this paradigm when conditioned to avoid either blue or green. Functional color entrainment requires the function of the narrow-spectrum photoreceptors R8 and/or R7, and is within a limited range, intensity independent, suggesting that it is mediated by a color vision system. The medulla projection neurons, Tm5a/b/c and Tm20, receive direct inputs from R7 or R8 photoreceptors and indirect input from the broad-spectrum photoreceptors R1-R6 via the lamina neuron L3. Genetically inactivating these four classes of medulla projection neurons abolished color learning. However, inactivation of subsets of these neurons is insufficient to block color learning, suggesting that true color vision is mediated by multiple redundant pathways. We hypothesize that flies represent color along multiple axes at the first synapse in the fly visual system. The apparent redundancy in learned color discrimination sharply contrasts with innate ultraviolet (UV) spectral preference, which is dominated by a single pathway from the amacrine neuron Dm8 to the Tm5c projection neurons. PMID- 24766349 TI - Medication overuse headache: self-perceived and actual knowledge among pharmacy staff. AB - OBJECTIVE: The aim of this study was to investigate knowledge about medication overuse headache (MOH) among pharmacy staff. BACKGROUND: MOH is a public health problem both in Sweden and in many other countries. Persons with MOH have limited contact with health care, and medications used are to large extent over-the counter (OTC) medications. Therefore, pharmacists have an important role in, eg, advising these individuals about their medication use. Little is, however, known about the actual level of knowledge about MOH among pharmacy staff, which determines the quality of their advice to MOH sufferers. METHODS: A total of 326 questionnaires were distributed to 44 pharmacies in Gothenburg, Sweden. The questionnaire included background questions, questions about advice on headache treatment, source of knowledge about MOH, and questions on self-perceived and actual knowledge on MOH. RESULTS: The response rate was 70%. A majority of the pharmacy staff (90.6%) considered themselves to have knowledge about MOH to some or a greater extent. Almost half had learned about MOH through their university/vocational education. Only 8.6% knew that all 5 headache medications listed in the questionnaire can cause development of MOH, but 40% responded correctly on which treatment advice one can give a person with MOH. Actual knowledge on treatment advice differed significantly between groups of self perceived knowledge. CONCLUSION: The knowledge on MOH is insufficient among pharmacy staff, but with the proper knowledge, pharmacy staff is well positioned to effect both primary and secondary prevention of MOH. We suggest not only increasing educational efforts about MOH within pharmacy programs but also continuing education at the pharmacies for all staff. Further, it is also important to increase knowledge among pharmacy customers. PMID- 24766348 TI - Dual modifications strategy to quantify neutral and sialylated N-glycans simultaneously by MALDI-MS. AB - Differences in ionization efficiency among neutral and sialylated glycans prevent direct quantitative comparison by their respective mass spectrometric signals. To overcome this challenge, we developed an integrated chemical strategy, Dual Reactions for Analytical Glycomics (DRAG), to quantitatively compare neutral and sialylated glycans simultaneously by MALDI-MS. Initially, two glycan samples to be compared undergo reductive amination with 2-aminobenzoic acid and 2-(13)[C6] aminobenzoic acid, respectively. The different isotope-incorporated glycans are then combined and subjected to the methylamidation of the sialic acid residues in one mixture, homogenizing the ionization responses for all neutral and sialylated glycans. By this approach, the expression change of relevant glycans between two samples is proportional to the ratios of doublet signals with a static 6 Da mass difference in MALDI-MS and the change in relative abundance of any glycan within samples can also be determined. The strategy was chemically validated using well characterized N-glycans from bovine fetuin and IgG from human serum. By comparing the N-glycomes from a first morning (AM) versus an afternoon (PM) urine sample obtained from a single donor, we further demonstrated the ability of DRAG strategy to measure subtle quantitative differences in numerous urinary N glycans. PMID- 24766350 TI - Psychometric and biohormonal indices of dental anxiety in children. A prospective cohort study. AB - The stress of dental treatment often elicits negative emotions in children, expressed as dental fear or anxiety. Highly anxious children obstruct treatment and avoid therapy, further amplifying oral health problems. The aim of this study was to examine the neuroendocrine and autonomic nervous system responses to dental treatment and their possible interactions and associations with psychometric indices of anxiety, caries, previous dental experience, anesthesia, age and gender in school children. Upon informed consent, saliva was obtained from 97 children (59% males, mean age +/- SD: 89.73 +/- 15 months) in the Clinic of pediatric dentistry before treatment, immediately post-treatment and at the recall visit to determine cortisol and salivary alpha-amylase (sAA) levels. Dental and general anxiety was assessed through specific questionnaires completed by the children. Compared to pre-treatment, cortisol levels were increased following treatment, while sAA levels were higher at the recall. Pre- and post treatment cortisol and sAA responses were positively correlated. Dental and general anxiety questionnaire scores were also significantly correlated with each other. The integrated autonomic and neuroendocrine responses prior to treatment were correlated with state anxiety and those following treatment with dental anxiety. However, univariable and multivariable linear regression analysis associated post-treatment cortisol, but not sAA, levels with dental anxiety. No associations of cortisol or sAA responses with caries, age, gender, previous dental experience or anesthesia were detected. These data provide some evidence that both sAA and cortisol levels are altered in children in anticipation or during dental treatment, but only cortisol levels are associated to dental anxiety. PMID- 24766351 TI - Metal-free oxidative ipso-carboacylation of alkynes: synthesis of 3 acylspiro[4,5]trienones from N-arylpropiolamides and aldehydes. AB - A general and metal-free radical route to synthesis of 3-acylspiro[4,5]trienones is established that utilizes TBHP (tert-butyl hydrogenperoxide) as an oxidation and a reaction partner to trigger the oxidative ipso-carboacylation of N arylpropiolamides with aldehydes. This method offers a new difunctionalization of alkynes through oxidative cross coupling of the aldehyde C(sp(2))-H bond with an ipso-aromatic carbon. PMID- 24766352 TI - Establishment and characterization of an embryonic cell line from Sarconesiopsis magellanica. AB - Sarconesiopsis magellanica (Le Guillou) (Diptera: Calliphoridae) is a necrophagous fly that is important in both human and veterinary medicines. This insect has been registered in Colombia as a biological indicator in estimating post-mortem interval. Insect cell cultures are an important biotechnological tool for basic and applied studies, and cell cultures derived from S. magellanica embryonic tissues are described in this study. S. magellanica embryonated eggs were taken for tissue explants. These were seeded in L-15, Grace/L-15, Eagle MEM, MM, VP12, MM/VP12, and Schneider culture media. The morphological, cytogenetic, biochemical, and molecular characteristics of the cell cultures were examined. Cell growth was achieved in the L15, Grace/L15, and Schneider culture media, and the confluent monolayers were obtained 8, 10, and 19 days after the embryonated eggs were explanted. However, the Schneider medium was the most efficient to develop the subcultures, and 21 passages have been maintained. The cell morphology of the primary cell cultures was initially heterogeneous, but in the confluent monolayer and in the subcultures there was greater cell morphology uniformity, fibroblastoid types being predominant. Cultured cells had a chromosomal number of 12, and the karyotypic complement consisted of five pairs of somatic chromosomes and one sexual pair. The cell culture isozyme patterns of S. magellanica coincided with adult samples from the same species. The molecular analysis, using RAPD-PCR, demonstrated the authentication of the cell cultures of this fly and their differentiation from other cultures derived from two sand flies species. This cell line is a new in vitro model that will be used in biomedical and biotechnological studies. PMID- 24766353 TI - Are baby hammocks safe for sleeping babies? A randomised controlled trial. AB - AIM: Two reports of infants found dead after sleeping in baby hammocks have raised international concern about the safety of infant hammocks. We therefore tested whether hammock sleep affected oxygenation in infants, when they were at an age of high risk of sudden, unexpected infant death. METHODS: Healthy, full term 4- to 8-week-old infants were randomised to sleep either in a commercially available hammock (n = 14) or a standard bassinet (n = 9), and sleep state, oxygen desaturation (a fall in peripheral haemoglobin oxygen saturation (SpO2 ) >= 4%, for >= 4 sec from baseline to nadir), apnoea and hypopnoea, and mean SpO2 were analysed. RESULTS: There was no significant difference in mean SpO2 (both 98.5%) or rate of oxygen desaturation events between the hammock and the bassinet cot (mean +/- SD, 24 +/- 20 vs. 28 +/- 23 events per hour), but infants slept less in the hammock (59 +/- 31 vs. 81 +/- 34 min, p < 0.02). CONCLUSION: When correctly used, the hammock sleep position did not compromise the upper airway of sleeping infants. The significance of shorter duration of sleep in the hammocks is unclear. These findings should not be applied to all baby hammocks, nor to older babies, particularly once the infant can roll. Given that it is not possible to predict when an infant will be able to roll, we strongly recommend that hammocks should not be used for unsupervised sleep. PMID- 24766354 TI - Aggression and prosocial behaviors in social conflicts mediating the influence of cold social intelligence and affective empathy on children's social preference. AB - This study proposes a model in which aggressive and prosocial behaviors exhibited in social conflicts mediate the influence of empathy and social intelligence to children's social preference by same-sex peers. Data were obtained from kindergarten to the end of the first grade. The sample yielded 117 Spanish children (64 girls and 53 boys) with a mean age of 62.8 months (SD = 3.3) at the beginning of the study. For boys, affective empathy contributed to boys' social preference through a decrease in physical aggression as responses to social conflict. For girls, affective empathy had an indirect effect on girls' preference by increasing assistance to others in their conflicts. No mediating effect in the contribution of social intelligence on girls' social preference was detected. Our results suggest that, only for girls, cold social intelligence can promote both indirect aggression (coercive strategic that do not leave social preference, at least at these ages) and behaviors that lead social preference (such as prosocial behaviors). PMID- 24766355 TI - Middle age, menopause, and opportunity. PMID- 24766357 TI - Identifying barriers to remaining physically active after rehabilitation: differences in perception between physical therapists and older adult patients. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To describe readiness for change and barriers to physical activity in older adults and to contrast perceptions of physical therapists and patients using the Barriers to Being Active Quiz. BACKGROUND: Regular physical activity is vital to recovery after discharge from physical therapy. Physical therapists are positioned to support change in physical activity habits for those transitioning to home care. Understanding of readiness for change and barriers to physical activity could optimize recovery. METHODS: Thirteen physical therapists enrolled in the study and invited patients who met the inclusion criteria to enroll (79 patients enrolled). The physical therapists provided the ICD-9 code, the physical therapist diagnosis, and completed the Barriers to Being Active Quiz as they perceived their patients would. The enrolled patients provided demographics and filled out the Satisfaction With Life Scale, the stages-of-change scale for physical activity, and the Barriers to Being Active Quiz. RESULTS: Patients were predominantly in the early stages of readiness for change. Both patients and physical therapists identified lack of willpower as the primary barrier to physical activity. Patients identified lack of willpower and social influence as critical barriers more often than physical therapists, whereas physical therapists identified fear of injury and lack of time more often than their patients did. Differences between physical therapists and their patients were noted for fear of injury (z = 2.66, P = .008) and lack of time (z = 3.46, P = .001). The stage of change for physical activity impacted perception of social influence (chi2 = 9.64, P<.05), lack of willpower (chi2 = 21.91, P<.01), and lack of skill (chi2 = 12.46, P<.05). Women ranked fear of injury higher than men did (chi2 = 6.76, P<.01). CONCLUSION: Understanding readiness for change in and barriers to physical activity may allow physical therapists to better tailor intervention strategies to impact physical activity behavior change. PMID- 24766356 TI - Ultrasound imaging: intraexaminer and interexaminer reliability for multifidus muscle thickness assessment in adults aged 60 to 85 years versus younger adults. AB - STUDY DESIGN: Intraexaminer and interexaminer, within- and between-day reliability study. OBJECTIVES: To compare the intraexaminer and interexaminer procedural reliability of ultrasound imaging (USI) thickness measurements of the lumbar multifidus muscle at rest and during a contralateral lower-limb lift (CLL) between older (60-85 years of age) and younger (18-40 years of age) adults. BACKGROUND: Among younger adults, USI has been shown to be reliable and valid for assessing multifidus thickness. Older adults present with age-related changes that may impact assessment. To our knowledge, no USI studies have focused on establishing reliability for multifidus thickness assessments in older adults. METHODS: Two examiners performed assessments of lumbar multifidus thickness at rest and during a CLL in 30 older and 31 younger adults. Intraclass correlation coefficient (ICC) with 95% confidence interval, standard error of measurement, 95% minimal detectable change for resting and during the CLL, and percent thickness change were calculated. RESULTS: Within-day interexaminer procedural reliability for multifidus thickness measurements was similar among younger (ICC = 0.90-0.92) and older adults (ICC = 0.86-0.90), as was between-day intraexaminer and interexaminer reliability (younger adults, ICC = 0.84-0.94; older adults, ICC = 0.86-0.93). Throughout, estimates of percent thickness change were inconsistent (ICC = 0.31-0.86), and standard errors of measurement and minimal detectable changes were larger for older adults. CONCLUSION: Ultrasound imaging reliability for measurements of multifidus thickness at rest and during a CLL among older adults is consistent with previously published findings for younger adults. Among older adults, it may be preferable to have a single examiner conduct USI assessments. PMID- 24766358 TI - Effects of physical therapist-guided quadriceps-strengthening exercises for the treatment of patellofemoral pain syndrome: a systematic review. AB - STUDY DESIGN: Systematic literature review. OBJECTIVE: To summarize the evidence for physical therapist-guided quadriceps-strengthening exercises as a treatment for patellofemoral pain syndrome. BACKGROUND: Although quadriceps strengthening is often included in the plan of care for patellofemoral pain syndrome, a systematic review published in 2003 found only limited evidence that exercise was more effective than no exercise for this common condition. METHODS: The PubMed, Embase/MEDLINE, and Cochrane Central Register of Controlled Trials databases, from inception to January 9, 2014, were searched for randomized controlled trials comparing the use of quadriceps-strengthening exercises to interventions consisting of advice/information or a placebo. Outcomes of interest were pain measures and function, as measured with self-report questionnaires. The methodological quality of the randomized controlled trials was assessed with the Physiotherapy Evidence Database scale. Results were summarized using a best evidence synthesis and graphically illustrated using forest plots without meta analysis. RESULTS: Seven studies were included in the literature review. These studies reported strong evidence that isolated quadriceps strengthening is more effective in reducing pain and improving function than advice and information alone. In addition, compared to advice and information or placebo, there was strong evidence that quadriceps-strengthening exercises combined with other interventions may be more effective in reducing pain immediately postintervention and after 12 months, but not in improving function. CONCLUSION: The literature provides strong evidence for the use of quadriceps-strengthening exercises, with or without other interventions, for the treatment of patellofemoral pain syndrome. PMID- 24766359 TI - Abdominal aortic aneurysm in a patient with low back pain. AB - STUDY DESIGN: Resident's case problem. BACKGROUND: The purpose of this report was to describe (1) the clinical reasoning that led a clinician to identify an abdominal aortic aneurysm (AAA) in a patient with low back pain requiring immediate medical referral, and (2) an evidence-based approach to clinical evaluation of patients with suspected AAA. DIAGNOSIS: The patient was unable to identify a specific mechanism of injury for his low back pain, lacked aggravating/easing factors for his symptoms, and complained of night pain and an inability to ease his symptoms with position changes. While the patient's symptoms remained unchanged during physical examination of the lumbar spine and hip, abdominal palpation revealed a strong, nontender pulsation over the midline of the upper and lower abdominal quadrants. Due to concern for an AAA, the patient was immediately referred to his physician. Subsequent computed tomography imaging revealed a prominent AAA, which measured up to 5.5 cm in greatest dimension and extended from below the renal arteries to the bifurcation of the iliac arteries. The patient initially deferred surgical intervention but eventually consented 6 months later, after repeat computed tomography imaging revealed that the AAA had progressed to 6.7 cm in greatest dimension. DISCUSSION: It is essential for physical therapists to be familiar with a diagnostic pathway to help identify AAA in patients presenting with apparent musculoskeletal complaints. Knowledge of the risk factors for AAA, understanding how to screen for nonmusculoskeletal symptoms, and a basic competence in abdominal palpation and how to interpret findings will help with the clinician's clinical decision making. LEVEL OF EVIDENCE: Differential diagnosis, level 4. J Orthop Sports Phys Ther 2014;44(7):500-507. Epub 25 April 2014. doi:10.2519/jospt.2014.4935. PMID- 24766360 TI - Management of a patient with chronic low back pain and multiple health conditions using a pain mechanisms-based classification approach. AB - STUDY DESIGN: Case report. BACKGROUND: Pain can lead to a significant reduction in quality of life. A pain mechanisms-based classification scheme has been outlined to improve management of patients with pain, but studies describing its use are limited. Evidence for physical therapy interventions in those with chronic pain and multiple health conditions is also lacking. This case report describes management of a patient with chronic pain and multiple health conditions. CASE DESCRIPTION: A 29-year-old man presented with a 3-year history of low back pain and 11-month history of lower extremity paresthesia. Current health conditions included left-sided hemiparesis secondary to a stroke, pancreatic kidney transplant, left-sided blindness, and osteoporosis secondary to hyperparathyroidism. Inability to walk to school and sit through class, and pain related sleep disruption were the primary activity and participation restrictions. Outcome measures included the numeric pain rating scale, global rating of change, Oswestry Disability Index, and pain medication usage. A score of 12 on the Leeds assessment of neuropathic symptoms and signs (LANSS) pain scale indicated the presence of neuropathic pain, but other pain mechanisms were also hypothesized to be present. Treatment was designed to improve patient goals considering these pain mechanisms. OUTCOMES: The patient was seen for 20 visits over 6 months. Ten months after the initial evaluation, the patient's Oswestry Disability Index scores improved by more than 50% and the patient achieved all initially stated goals without pain medication. DISCUSSION: A pain mechanisms based approach assisted in the management of a patient with chronic pain and multiple health conditions. Using this approach may enhance clinical decision making when managing individuals with chronic pain. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 24766361 TI - Characterization of the major aroma-active compounds in mango (Mangifera indica L.) cultivars Haden, White Alfonso, Praya Sowoy, Royal Special, and Malindi by application of a comparative aroma extract dilution analysis. AB - The aroma-active compounds present in tree-ripened fruits of the five mango (Mangifera indica L.) cultivars Haden, White Alfonso, Praya Sowoy, Royal Special, and Malindi were isolated by solvent extraction followed by solvent-assisted flavor evaporation (SAFE) and analyzed by gas chromatography-olfactometery (GC O). Application of a comparative aroma extract dilution analysis (cAEDA) afforded 54 aroma-active compounds in the flavor dilution (FD) factor range from 4 to >=2048, 16 of which are reported for the first time in mango. The results of the identification experiments in combination with the FD factors revealed 4-hydroxy 2,5-dimethyl-3(2H)-furanone as an important aroma compound in all cultivars analyzed. Twenty-seven aroma-active compounds were present in at least one mango cultivar at an FD factor >=128. Clear differences in the FD factors of these odorants between each of the mango cultivars suggested that they contributed to the unique sensory profiles of the individual cultivars. PMID- 24766362 TI - Simple hydrazone building blocks for complicated functional materials. AB - CONSPECTUS: The ability to selectively and effectively control various molecular processes via specific stimuli is a hallmark of the complexity of biological systems. The development of synthetic structures that can mimic such processes, even on the fundamental level, is one of the main goals of supramolecular chemistry. Having this in mind, there has been a foray of research in the past two decades aimed at developing molecular architectures, whose properties can be modulated using external inputs. In most cases, reversible conformational, configurational, or translational motions, as well as bond formation or cleavage reactions have been used in such modulations, which are usually initiated using inputs including, irradiation, metalation, or changes in pH. This research activity has led to the development of a diverse array of impressive adaptive systems that have been used in showcasing the potential of molecular switches and machines. That being said, there are still numerous obstacles to be tackled in the field, ranging from difficulties in getting molecular switches to communicate and work together to complications in integrating and interfacing them with surfaces and bulk materials. Addressing these challenges will necessitate the development of creative new approaches in the field, the improvement of the currently available materials, and the discovery of new molecular switches. This Account will describe how our quest to design new molecular switches has led us to the development of structurally simple systems that can be used for complicated functions. Our focus on the modular and tunable hydrazone functional group was instigated by the desire to simplify the structure and design of molecular switches in order to circumvent multistep synthesis. We hypothesized that by avoiding this synthetic bottleneck, which is one of the factors that hinder fast progress in the field, we can expedite the development and deployment of our adaptive materials. It should be noted though that designing structurally simple switches cannot be an end goal by itself! Therefore, we showed that our molecules can be used in applications that are beyond a simple molecular switching event (i.e., the control of the photophysical properties of liquid crystals and multistep switching cascades). While focusing on these switches, we discovered that the hydrazones can be easily transformed, using straightforward one-step reactions, into visible light activated azo switches, and two different families of fluorophores that can be used in sensing applications. These findings demonstrate that our approach of developing simple systems for sophisticated functions is not limited to the field of molecular switches and machines but can also encompass other adaptive materials. PMID- 24766363 TI - Dillenia species: A review of the traditional uses, active constituents and pharmacological properties from pre-clinical studies. AB - CONTEXT: Dillenia (Dilleniaceae) is a genus of about 100 species of flowering plants in tropical and subtropical trees of Southern Asia, Australasia, and the Indian Ocean Islands. Until now, only eight Dillenia species have been reported to be used traditionally in different countries for various medical purposes. Out of eight species, D. pentagyna (Roxb), D. indica (Linn.) and D. suffruticosa (Griffith Ex. Hook. F. & Thomsom Martelli) have been reported to be used to treat cancerous growth. OBJECTIVE: The present review explored and provided information on the therapeutic potential of Dillenia species. METHODS: Comprehensive and relevant literature on the therapeutic potential of Dillenia species was gathered through electronic databases including Google Scholar, Scopus, PubMed, and books, without limiting the dates of publication. RESULTS AND CONCLUSION: The review demonstrated that only a few Dillenia species have been proven scientifically for their therapeutic potential in pre-clinical studies, including D. pentagyna, D. indica, D. papuana (Martelli), D. meliosmifolia (Hook. F. Ex. Thomsom) and D. suffruticosa (Griffith Ex Hook. F. & Thomson). A few species of Dillenia have undergone isolation and characterization of compounds with lupeol and betulinic acids having tremendous pharmacological potential. Dillenia species warrant further studies on their therapeutic potential, which may eventually lead to the development of new drug candidates for treatment of various diseases. PMID- 24766364 TI - Computational analysis of benzofuran-2-carboxlic acids as potent Pim-1 kinase inhibitors. AB - CONTEXT: The three Pim serine/threonine kinases (Pim-1, Pim-2, and Pim-3) belong to a small family of kinases that regulate numerous signaling pathways fundamental to the development of tumors. Pim kinases' overexpression has been reported in numerous solid and hematological tumors and, in particular, prostate cancer (Pim-1). OBJECTIVES: This study investigated the binding modes of benzofuran-2-carboxlic acids against Pim-1 kinase, hence providing useful information for the active inhibition of it. MATERIALS AND METHODS: In present study, molecular docking approach via MOE-Dock program was applied to predict the binding interactions of some known Pim-1 kinase inhibitors. First validation of the docking protocol was carried out by calculating RMSD for the co-crystallized and docked ligands. Using the same protocol, all the compounds were docked into the active site of Pim-1 kinase. RESULTS: All the compounds showed significant interactions and good correlation with the experimental data. The results illustrate that compounds with optimum basicity and relevant distance between the acidic and basic groups showed optimum interactions with the active site residues of Pim-1 kinase. CONCLUSION: We hope that this study will be helpful in designing new, structurally diverse and more potent compounds for the active treatment of prostate cancer and other related diseases caused by deregulation of Pim-1 kinase. PMID- 24766365 TI - Letter-case information and the identification of brand names. AB - A central tenet of most current models of visual-word recognition is that lexical units are activated on the basis of case-invariant abstract letter representations. Here, we examined this assumption by using a unique type of words: brand names. The rationale of the experiments is that brand names are archetypically printed either in lowercase (e.g., adidas) or uppercase (e.g., IKEA). This allows us to present the brand names in their standard or non standard case configuration (e.g., adidas, IKEA vs. ADIDAS, ikea, respectively). We conducted two experiments with a brand-decision task ('is it a brand name?'): a single-presentation experiment and a masked priming experiment. Results in the single-presentation experiment revealed faster identification times of brand names in their standard case configuration than in their non-standard case configuration (i.e., adidas faster than ADIDAS; IKEA faster than ikea). In the masked priming experiment, we found faster identification times of brand names when they were preceded by an identity prime that matched its standard case configuration than when it did not (i.e., faster response times to adidas-adidas than to ADIDAS-adidas). Taken together, the present findings strongly suggest that letter-case information forms part of a brand name's graphemic information, thus posing some limits to current models of visual-word recognition. PMID- 24766366 TI - Remote ester groups switch selectivity: diastereodivergent synthesis of tetracyclic spiroindolines. AB - Stereocontrol in the synthesis of structurally complex molecules, especially those with all-carbon quaternary stereocenters, remains a challenge. Here, we reported the preparation of a class of tetracyclic cyclopenta-fused spiroindoline skeletons through Cu(II)-catalyzed intramolecular [3 + 2] annulation reactions of donor-acceptor cyclopropanes with indoles. Both cis- and trans-diastereomers of tetracyclic spiroindolines are accessed with high selectivities by altering the remote ester groups of cyclopropanes. The origins of this stereocontrol are identified using DFT calculations: attractive interactions between the ester group and arene favor the generation of the trans isomer, while the formation of the cis isomer is preferred when steric repulsions become predominant. PMID- 24766367 TI - Economic challenges associated with tuberculosis diagnostic development. AB - Tuberculosis remains a global health crisis in part due to underdiagnosis. Technological innovations are needed to improve diagnostic test accuracy and reduce the reliance on expensive laboratory infrastructure. However, there are significant economic challenges impeding the development and implementation of new diagnostics. The aim of this piece is to examine the current state of TB diagnostics, outline the unmet needs for new tests, and detail the economic challenges associated with development of new tests from the perspective of developers, policy makers and implementers. PMID- 24766368 TI - Cost-effectiveness of early detection of atrial fibrillation via remote control of implanted devices. AB - RATIONALE, AIMS AND OBJECTIVES: Atrial fibrillation (AF) is an independent risk factor for stroke, and its incidence is high in patients implanted with pacemakers (PMs) and implantable cardioverter defibrillators (ICDs). The aim of our study is to evaluate the potential benefit of remote control (RC) on the incidence of stroke related to AF in patients with new-onset AF implanted with PMs and ICDs and to evaluate the impact of RC on the consumption of medical resources. METHOD: The study consisted of two cohorts of patients: group AMB (patients attending ambulatory care clinics from August to October 2013) and group RC (patients followed remotely). All detected cases of new-onset AF were confirmed by the electrogram stored in the device's memory or by standard electrocardiogram recording. Monte Carlo simulations were performed in order to evaluate the potential risk reduction of stroke related to AF. The costs were estimated from the perspectives of the hospital, the patients and the National Health Service. RESULT: We enrolled 223 patients in group RC and 359 in group AMB. We detected 20 new-onset cases of AF, and the median time to AF detection was 2 days in the RC and 78 days in the ambulatory care clinic control. Management of patients was more efficient with RC, with an average savings in direct costs of ?40.88 per year per patient. Through the use of Monte Carlo simulations, we showed that the early detection of new-onset AF may provide a relative risk reduction of 94.3% for stroke in PM-implanted patients older than 55 years. CONCLUSION: RC potentially provides a risk reduction for stroke because it allows an early detection of new-onset AF. Moreover, it is also a cost-saving means of follow-up. PMID- 24766369 TI - Application of methyl methacrylate copolymers to the development of transdermal or loco-regional drug delivery systems. AB - INTRODUCTION: Methyl methacrylate copolymers (Eudragit(r)) have been exploited to develop transdermal patches, medicated plasters (hereinafter patches) and, more recently, film-forming sprays, microsponges and nanoparticles intended to be applied on the skin. AREAS COVERED: The article reviews the information regarding the application of Eudragits in the design and development of these dosage forms focusing on the impact of formulative variables on the skin drug penetration and the patch adhesive properties. EXPERT OPINION: Eudragits combined with a large amount of plasticizers are used to design the pressure-sensitive adhesives, specialized materials used in the patch development. They have to assure the drug skin penetration and the contact with the skin. Most of the studies mainly deal with the former aspect. The authors used a Eudragit type opportunely plasticized to merely investigate the in vitro or in vivo skin permeability of a loaded drug. However, the summa of these data evidenced that a strict connection between the matrix hydrophilicity and drug penetration probably exists. The criticisms of adhesion are addressed in a limited number of papers reporting data on technological properties, namely tack, shear adhesion and peel adhesion, while the structural data of the Eudragit adhesives, rheology and surface free energy are not described, excepting the case of Eudragit E. Among other applications, micro- and nanosystems exploiting the ionizable nature of some Eudragits can offer novel opportunities to develop pH-sensitive drug delivery systems suitable for triggering its release onto the skin. PMID- 24766370 TI - COPD assessment test: a simple tool to evaluate disease severity and response to treatment. AB - The COPD assessment test (CAT) is a short questionnaire designed to assess the impairment in health status of COPD patients. We aimed to determine the change of the CAT in COPD patients after 1 year of treatment and test the association between the score and clinical and lung function variables. Methods A cohort of 111 newly diagnosed COPD patients in primary care was evaluated at baseline and one year after the implementation of the recommended treatment according to the Global Initiative for the management of COPD (GOLD). Results Most of the patients (82%) were diagnosed with mild to moderate airflow limitation (mean FEV1 72 +/- 21.5% predicted) and the CAT score increased in proportion with the GOLD stage of severity. The CAT significantly correlated with the number of exacerbations, visits to general practitioners and days of hospitalization both at the beginning and at 1 year follow-up. A strong negative correlation between the CAT score and FEV1 predicted was also observed. The CAT was responsive to the application of treatment with a significant improvement in the mean score (95% confidence interval) following 12 months of treatment by -2.4 (-2.9, -1.9) despite the small decline in lung function indices. The number of exacerbations in the preceding year and FEV1 were independent predictors of the CAT score in the general linear model. Conclusion The CAT questionnaire may serve as a simple, measurable tool complementary to spirometry in the assessment of severity and of response to treatment in unselected COPD patients in primary care. PMID- 24766372 TI - Cardiovascular reactivity to a marital conflict version of the Trier social stress test in intimate partner violence perpetrators. AB - Intimate partner violence (IPV) perpetrators have been categorized into two groups based on their heart rate (HR) reactivity to stress following Gottman's studies. Overall, type I perpetrators tend to show autonomic underarousal, whereas type II or reactive perpetrators present a hyper-reactivity in anticipation of stress. In this study, changes in HR, pre-ejection period (PEP), vagal ratio as well as psychological state variables (anxiety and anger) in response to stress were assessed, comparing a group of type II IPV perpetrators (based on violence reports and psychological assessment; n = 17; mean age = 37) with non-violent controls (n = 17; mean age = 35) using modified version of the Trier Social Stress Test. IPV perpetrators had higher HRs and lower vagal ratios than controls, particularly during the recovery period. Moreover, the former presented shorter PEPs than controls. There were no differences between groups in the magnitude of response of the HR, PEP or vagal ratio. High baseline anxiety and anger were associated with an HR increase during the preparation time in IPV perpetrators but not in controls. These findings indicate a different cardiovascular pattern of response to psychosocial stress in IPV perpetrators, especially during recovery. Thus, they contribute to understanding the biological functioning of violence sub-types, supporting the validity of cardiovascular measures as diagnostic indicators for IPV classification. PMID- 24766371 TI - Genetic risk factors for the development of allergic disease identified by genome wide association. AB - An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion, suggesting that the airway epithelium may be particularly important in asthma. Interestingly, concordance/discordance between the genetic factors driving allergic traits such as IgE levels and disease states such as asthma have further supported the accumulating evidence for heterogeneity in these diseases. While GWAS have been useful and continue to identify novel genes for allergic diseases through increased sample sizes and phenotype refinement, future approaches will integrate analyses of rare variants, epigenetic mechanisms and eQTL approaches, leading to greater insight into the genetic basis of these diseases. Gene identification will improve our understanding of disease mechanisms and generate potential therapeutic opportunities. PMID- 24766373 TI - 2D photonic crystal protein hydrogel coulometer for sensing serum albumin ligand binding. AB - Bovine and human serum albumin (BSA and HSA) are globular proteins that function as bloodstream carriers of hydrophobes such as fatty acids and drugs. We fabricated novel photonic crystal protein hydrogels by attaching 2D colloidal arrays onto pure BSA and HSA hydrogels. The wavelengths of the diffracted light sensitively report on the protein hydrogel surface area. The binding of charged species to the protein hydrogel gives rise to Donnan potentials that change the hydrogel volume causing shifts in the diffraction. These photonic crystal protein hydrogels act as sensitive Coulometers that monitor the hydrogel charge state. We find multiple high-affinity BSA and HSA binding sites for salicylate, ibuprofen and picosulfate by using these sensors to monitor binding of charged drugs. We demonstrate proof-of-concept for utilizing protein hydrogel sensors to monitor protein-ionic species binding. PMID- 24766374 TI - Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation. AB - BACKGROUND: Chronic myeloid leukemia (CML) is a hematological disorder that in rare cases, mainly in CML neutrophilic, presents the e19a2 rearrangement. The encoded product is a 230-KDa protein. Despite the remarkable responses to treatment of most patients, a small but significant fraction of them develop clinical resistance to the tyrosine kinase inhibitors (TKIs). The most common mechanism of resistance is point mutations in the ABL1 kinase domain. The recently approved third-generation TKI ponatinib demonstrated remarkable activity in patients with multi-TKI-resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs. METHODS: Qualitative PCR was carried out by multiplex approach. Relative transcripts quantification was performed by one-step real-time PCR, with a specific Taqman probe and primers for the e19a2 rearrangement. We carried out a mutational screening by high-resolution melting, and the mutation was identified by Sanger method. The mutation burden was quantified by quantitative PCR using allele-specific primers. RESULTS: In a patient with CML, we identified a PCR product corresponding to e19a2 rearrangement harboring T315I mutation. At the time of mutational analysis, during dasatinib treatment, the T315I clone was 100% and the quantification of BCR-ABL1 was 18%. After ponatinib therapy, the T315I mutation burden decreased down to undetectable levels and the BCR-ABL1 transcripts showed a very low value (0.011%). CONCLUSIONS: Here, we report the hematological, cytogenetic, and molecular response of a patient with refractory CML in chronic phase with e19a2 transcripts, carrying T315I mutation that was successfully treated with ponatinib. PMID- 24766375 TI - Oxidative protein folding: nature's knotty challenge. AB - Oxidative protein folding (OPF) characterized by intramolecular disulfide bond formation is the most common and likely most ancient post-translational modification. Considering the number of proteins that a cell must fold correctly and the number of possible disulfide structures available to each protein, OPF represents a daunting biochemical permutation problem which is solved by relatively few oxidase and isomerase enzymes. A proper disulfide configuration provides the structural foundation for more nuanced intramolecular folding events that, ultimately, define protein activity. As such, control of OPF is critical to normal cell function and homeostasis. Ironically, when cells are stressed, the very process of OPF can generate reactive oxygen species, contributing to endoplasmic reticulum stress, inefficient protein folding, and initiation of the unfolded protein response-a phenomenon that induces pro-inflammatory signals which can contribute to metabolic and inflammatory diseases, neurodegenerative disease, and cancer. Contributing authors to this Forum of Antioxidants and Redox Signaling review the latest developments in our understanding of the complex and divergent processes that orchestrate OPF. New insights promise to offer improvements in both medicine and industrial biotechnology. PMID- 24766376 TI - Inflammation, high ferritin, and erythropoietin resistance in indigenous maintenance hemodialysis patients from the Top End of Northern Australia. AB - Use of erythropoiesis-stimulating agents (ESAs) has improved the management of anemia in patients on maintenance hemodialysis (MHD). Iron deficiency and inflammation cause ESAs resistance and are both common among indigenous people of Northern Australia. As part of quality assurance in our Renal Anaemia Management program, we observed that there was use of higher doses of ESAs and adjuvant iron therapy in our MHD patients. This study aimed to explore the relationship among iron studies, inflammation, ESA responsiveness, and ESAs and iron requirements in indigenous patients on MHD from the Top End of Northern Australia. We performed a retrospective cohort analysis of anemia management in a cohort of our patients on MHD. We extracted data for 178 indigenous and 19 non-indigenous patients from 1 March 2009 to 28 February 2010 from the Renal Anaemia Management database, which collects data prospectively in MHD patients. Ninety-nine percent of the whole sample had a ferritin level above the international guidelines threshold of >500 ug/L. Indigenous patients had higher ferritin (1534 +/- 245.5 ug/L vs. 1013 +/- 323.3 ug/L, P = 0.002). C-reactive protein (CRP) was high in 56.9% of the total cohort. One hundred percent of those with normal CRP had high ferritin (>500 ug/L). C-reactive protein was higher in indigenous than in non-indigenous patients. Erythropoiesis-stimulating agents hyporesponsiveness was higher in indigenous patients (P < 0.0001). There was no significant difference in ESAs hyporesponsiveness among different levels of CRP (P = 0.116), ferritin (P = 0.408), and transferrin saturation (P = 0.503). Indigenous patients required higher total iron dose (2820.30 [2000-4350] vs. 2336.12 [1912-2900], P = 0.02). There was no significant relationship between the high ferritin and CRP. In indigenous dialysis patients, iron therapy and ESAs use are higher. The high iron use is due to a lack of published evidence to guide the administration of iron in patients with high ferritin. The high ferritin and ESAs resistance could not be fully explained by inflammation and need further evaluation. Further studies are required to determine the safe use of iron and management of ESAs resistance in our hemodialysis population. PMID- 24766377 TI - Drosophila neural stem cells in brain development and tumor formation. AB - Neuroblasts, the neural stem cells in Drosophila, generate the complex neural structure of the central nervous system. Significant progress has been made in understanding the mechanisms regulating the self-renewal, proliferation, and differentiation in Drosophila neuroblast lineages. Deregulation of these mechanisms can lead to severe developmental defects and the formation of malignant brain tumors. Here, the authors review the molecular genetics of Drosophila neuroblasts and discuss some recent advances in stem cell and cancer biology using this model system. PMID- 24766379 TI - One for two: conversion of waste chicken feathers to carbon microspheres and (NH4)HCO3. AB - Pyrolysis of 1 g of waste chicken feathers (quills and barbs) in supercritical carbon dioxide (sc-CO2) system at 600 degrees C for 3 h leads to the formation of 0.25 g well-shaped carbon microspheres with diameters of 1-5 MUm and 0.26 g ammonium bicarbonate ((NH4)HCO3). The products were characterized by powder X-ray diffraction (XRD), Field emission scanning electron microscopy (FE-SEM), Raman spectroscopic, FT-IR spectrum, X-ray electron spectroscopy (XPS), and N2 adsorption/desorption measurements. The obtained carbon microspheres displayed great superhydrophobicity as fabric coatings materials, with the water contact angle of up to 165.2+/-2.5 degrees . The strategy is simple, efficient, does not require any toxic chemicals or catalysts, and generates two valuable materials at the same time. Moreover, other nitrogen-containing materials (such as nylon and amino acids) can also be converted to carbon microspheres and (NH4)HCO3 in the sc CO2 system. This provides a simple strategy to extract the nitrogen content from natural and man-made waste materials and generate (NH4)HCO3 as fertilizer. PMID- 24766380 TI - Reaction of selenoamide dianions with thio- and selenoformamides leading to the formation of 5-aminoselenazoles: photophysical and electrochemical properties. AB - 5-Amino-2-selenazolines were synthesized by reacting selenoamide dianions generated from secondary selenoamides and BuLi with tertiary thio- and selenoformamides followed by treatment with iodine. The resulting 5-amino-2 selenazolines were further oxidized with iodine to give 5-aminoselenazoles in moderate to good yields. The general tendencies in the (77)Se NMR spectra of the starting selenoamides, 5-amino-2-selenazolines, and 5-aminoselenazoles were determined. The chemical shifts of these compounds were highly influenced by the skeletons involving the selenium atom as well as the substituents on the carbon atoms of each skeleton. The molecular structures of 5-aminoselenazoles were clarified by X-ray analyses, and their electronic structures were elucidated by DFT calculations. Finally, UV-vis and fluorescence spectroscopy and cyclic voltammetry (CV) of 5-aminoselenazoles were performed, and their properties are discussed in relation to the substituents on the selenazole rings. PMID- 24766383 TI - Molecular properties and medical applications of peptide nucleic acids. AB - Peptide Nucleic Acids (PNAs) are molecules combining structural features of proteins and nucleic acid. They resemble DNA or RNA by forming helical polyamides containing nitrogen bases attached to the backbone consisting of N-(2-aminoethyl) glycine monomers, which mimics the alternating ribose-phosphodiester-backbone of a nucleic acid. Because PNAs bind exceptionally strong to complementary DNA or RNA sequences obeying Watson-Crick base paring, they became attractive candidates for antisense and antigen therapies. PNAs are also being tested as novel antibiotics, gene-activating agents, and as molecular probes for FISH and imaging or biosensors used in diagnostics. Although PNAs offer many exiting medical applications, improving their cellular uptake and developing specific delivery strategies is crucial for a successful entry in the clinic in the near future. PMID- 24766382 TI - Application of BRET for studying G protein-coupled receptors. AB - G protein-coupled receptors (GPCRs) constitute one of the largest classes of cell surface receptors. GPCR biology has been a subject of widespread interest owing to the functional relevance of these receptors and their potential importance in the development of new drugs. At present, over 30% of all launched drugs target these receptors. GPCRs have been considered for a long time to function as monomeric entities and the idea of GPCR dimerization and oligomerization was initially accepted with disbelief. However, a significant amount of experimental and molecular modeling evidence accumulated during the last several years suggests that the process of GPCRs dimer or oligomer formation is a general phenomenon, in some cases even essential for receptor function. Among the many methods to study GPCR dimerization and oligomerization, modern biophysical techniques such as those based on resonance energy transfer (RET) and particularly bioluminescence resonance energy transfer (BRET) have played a leading role. RET methods are commonly applied as non-destructive indicators of specific protein-protein interactions (PPIs) in living cells. Data from numerous BRET experiments support the idea that the process of GPCR oligomerization may be relevant in many physiological and pathological conditions. The application of BRET to the study of GPCRs is not only limited to the assessment of receptor oligomerization but also expands to the investigation of the interactions of GPCRs with other proteins, including G proteins, G protein-coupled receptor kinases, beta-arrestins or receptor tyrosine kinases, as well as to the characterization of GPCR activation and signaling. In this review, we briefly summarize the fundaments of BRET, discuss new trends in this technology and describe the wide range of applications of BRET to study GPCRs. PMID- 24766381 TI - Osteoporosis prevention, screening, and treatment: a review. AB - Osteoporosis, defined as low bone mass leading to increased fracture risk, is a major health problem that affects approximately 10 million Americans. The aging U.S. population is predicted to contribute to as much as a 50% increase in prevalence by 2025. Although common, osteoporosis can be clinically silent, and without prevention and screening, the costs of osteoporotic fracture-related morbidity and mortality will burden the U.S. healthcare system. This is a particularly relevant concern in the context of diminishing health care resources. Dual-energy X-ray absorptiometry is the most widely used, validated technique for measuring bone mineral density (BMD) and diagnosing osteoporosis. Cost-effectiveness analyses support early detection and treatment of high-risk patients with antiresorptive medications such as bisphosphonates. Moreover, optimization of bone health throughout life can help prevent osteoporosis. Current guidelines recommend screening women by age 65 years, but because no guidelines for screening intervals exist, decisions are made on the basis of clinical judgment alone. Although the recent literature provides some guidance, this review further explores current recommendations in light of newer evidence to provide more clarity on prevention, screening, and management strategies for patients with osteoporosis in the primary care setting. PMID- 24766384 TI - Ascorbic acid: its role in immune system and chronic inflammation diseases. AB - Ascorbic acid (AA), also known as vitamin C, was initially identified as the factor preventing the scurvy disease, and became very popular for its antioxidant properties. It is an important co-substrate of a large class of enzymes, and regulates gene expression by interacting with important transcription factors. AA is important in all stressful conditions that are linked to inflammatory processes and involve immunity. It has been known for decades that the persistence of an inflammatory stimulus is responsible for the onset of many diseases. AA is essential to stimulate the immune system by increasing the strength and protection of the organism. Therefore, its immunostimulant, antinflammatory, antiviral and antibacterial roles are well known, we have summarized its main functions in different types of diseases related to the immune system and chronic inflammation. We can conclude that AA, due to its effects and diversity of regulated pathways, is suitable for use in various fields of medicine including immunology, toxicology, radiobiology and others. AA is not preferable to be used as an isolated mode of treatment, but it can be co applied as an adjuvant to regulate immunity, gene expression and other important physiological processes. However, we propose that future studies will take into consideration the research of new combinations of antioxidant natural substances and drugs. PMID- 24766385 TI - Malaria: hitches and hopes. AB - Malaria, a devastating infectious disease caused by parasites of Plasmodium genera is transmitted from person to person through bites of infected mosquitoes. It generally traps underdeveloped nations with poor infrastructure and high population density. It has attracted considerable attention from academic institutions, pharmaceutical industries and government agencies but the efforts to eradicate this threat face a number of technical, economic, financial and institutional hurdles. In the absence of clinically proven vaccines to combat malaria, chemotherapy continues to be the best available option, although it suffers from a big loophole of resistance. Emergence of resistance is associated with the two phases of Plasmodium's life cycle: asexual in humans and sexual in mosquito, which are intricate to target simultaneously. Consequently, the search for novel antimalarial agents is a never-ending task for scientists and chemists. This review aims at highlighting the currently used antimalarial agents, targets for the therapy and present scenario in the development of new antimalarial drugs to combat this global problem. PMID- 24766386 TI - Latest progress in the identification of novel synthetic ligands for the cannabinoid CB2 receptor. AB - Cannabinoid receptors, belonging to the superfamily of G-protein coupled receptors, play a major role in pathophysiology of a wide range of disparate diseases. Cannabinoid CB2 receptor, which mainly locates in peripheral tissues, represents as a promising drug target for the treatment of pain, osteoporosis, liver disorders, and so on without serious CNS side effects. In the past decades, the identification and optimization of selective ligands for the CB2 receptor has been a major objective in drug discovery. In the present review, we describe recent advances in the development of novel chemotypes of the CB2 receptor selective ligands, and give a simple discussion for the corresponding structure activity relationships of them. PMID- 24766387 TI - Effectiveness of the Healthy Skin Clinic--a randomized clinical trial of nurse led patient counselling in hand eczema. AB - BACKGROUND: Hand eczema is a common disease, and continuous preventive skin protection and skin care must be adopted to prevent a chronic course. Hand eczema is not a uniform disease, and counselling must therefore be individually tailored. OBJECTIVES: To evaluate the effectiveness of a nurse-led counselling programme, the Healthy Skin Clinic, emphasizing the patient's self-management, resources, and risks. PATIENTS AND METHODS: Patients (n = 306) referred for diagnostic work-up and treatment of hand eczema were randomized and allocated either to the programme or to usual care. The primary outcome was clinical disease severity at follow-up. Secondary outcomes were quality of life, burden of disease, skin protective behaviours, and self-reported medication adherence. RESULTS: Patients in the intervention group had greater reductions in clinical severity and reported more beneficial behavioural changes at follow-up than those in the usual-care group. This was especially true of patients who were treated solely with topical corticosteroids and who had a primarily exogenous aetiology of hand eczema. However, the effect was very dependent on baseline disease severity. No differences in quality of life or burden of disease were found between the two groups. CONCLUSION: A tailored nurse-led programme of skin protection counselling may be recommended as an essential part of hand eczema treatment. PMID- 24766388 TI - Chitin microfibers reinforce soy protein gels cross-linked by transglutaminase. AB - To improve the gel strength, we attempt to introduce the microcomposite concept into the food gel system. A stable positively charged chitin microfibers (CMFs) suspension was fabricated by a facile microfluidizer approach without changing its chemical structure. The obtained CMFs bearing width of about 0.5-5 MUm and length of more than 500 MUm were then developed in a transglutaminase cross linked beta-conglycinin (7S) gel. The morphological and rheological characterizations of the 7S-CMF composited gels were done as a function of the protein and CMFs concentrations. Results showed that the presence of the CMFs network improved the gel strength significantly. This effect was CMFs content dependent and was related to the formation of a sponge-like porous microstructure. We inferred that the CMFs provided an initial framework for gel formation and added structural rigidity to the protein gel. The role of protein was to participate in network development as an electrostatic coating and gelation component. PMID- 24766389 TI - Biparental care in insects: paternal care, life history, and the function of the nest. AB - The evolution of parental care is a complex process, and many evolutionary pathways have been hypothesized. Maternal care is common, but paternal care is not. High confidence of paternity should favor the evolution of paternal attendance in caring for young; biparental care is rare because paternity assurance is typically low compared to maternity. Biparental care in insects has evolved several times and has high diversity. To evaluate the conditions for the evolution of biparental care, a comparison across taxa is suitable. In this review, common traits of biparental species are discussed in order to evaluate previous models of biparental care and the life history of insects. It will be shown that nesting is a common feature in biparental insects. Nest structure limits extra-pair copulations, contributing to the evolution of biparental care. PMID- 24766390 TI - Children with Down's syndrome display high rates of hyperuricaemia. AB - AIM: Several studies show that hyperuricaemia, abnormally high levels of uric acid in the blood, frequently occurs in adult Down's syndrome patients, but paediatric research is scarce. We aimed to clarify its prevalence in paediatric Down's syndrome patients and its association with lifestyle-related laboratory variables and nutritional intake, to consider possible effects in later life. METHODS: We compared 52 Down's syndrome patients, from one to 15 years of age, with age-matched controls. Hyperuricaemia was defined using reference values established for children, as uric acid z-scores of more than 2.0. Nutritional intake was estimated using 3-day dietary records. RESULTS: Hyperuricaemia occurred in 17 Down's patients (32.7%) and was significantly higher in Down's patients than the controls. The prevalence was also significantly higher in males. There were no significant differences between hyperuricaemia-positive and hyperuricaemia-negative patients in terms of age, body mass index standard deviation scores, fasting blood glucose, insulin, homeostasis model assessment insulin resistance and triglyceride, and purine body intake was similar. There were differences in high-density lipoprotein cholesterol. CONCLUSION: We found high rates of hyperuricaemia from early childhood in Down's syndrome patients. This suggests careful management of Down's syndrome patients, as hyperuricaemia is an independent risk factor for lifestyle-related diseases in adulthood. PMID- 24766391 TI - Photoinduced single strand breaks and intrastrand cross-links in an oligonucleotide labeled with 5-bromouracil. AB - 5-Bromouracil (BrU) is photoreactive toward near UVB photons and can be introduced into genomic DNA during its biosynthesis in cells. However, PCR seems to be a simpler approach, which can be used to obtain labeled DNA similar to that synthesized within the cell. In the current work, PCR has been employed and optimized in order to substitute all thymines (besides those present in starters) with BrU in the dsDNA fragment of 80 base pairs (bp) in length. The modified oligonucleotide was irradiated with 300 nm photons in a buffered aqueous solution (pH = 7) and digested with a cocktail of enzymes specific to the phosphodiester bond cleavage. Initially, the extent of damage in the intact photolyte was measured with DHPLC. Then, the digested reaction mixture was subjected to HPLC and MS analyses and, in addition to the formation of 5-bromo-2'-deoxuyridine, which proves the occurrence of single strand breaks (SSBs) due to irradiation, U?U and U?C dimers were found, whose molecular structure was confirmed by MS/MS analysis. Although the abundance of such tandem lesions is lower than that of the SSB type, they pose a potent threat to genome integrity. Thus, our findings shed new light on the photosensitizing properties of BrU toward DNA. PMID- 24766392 TI - Fatigue life of bioactive titanium dental implants treated by means of grit blasting and thermo-chemical treatment. AB - OBJECTIVE: This study focuses on the fatigue behavior of titanium dental implants as-received, with a grit-blasted surface and with a new bioactive surface treatment (2Steps). BACKGROUND: The 2Step process consists of (1) an initial grit blasting process to produce a micro-rough surface, followed by (2) a combined thermo-chemical treatment that produces a potentially bioactive surface, that is, that can form an apatitic layer when exposed to biomimetic conditions in vitro. The 2Step treatment produced micro-rough and apatitic coating implants. METHODS: Residual stresses were determined by means of X-ray diffraction. The fatigue tests were carried out at 37 degrees C on 500 dental implants, and the S-N curve was determined. The fatigue-crack nucleation for the different treatments was analyzed. RESULTS: The fatigue tests show that the grit-blasting process improves the fatigue life. This is a consequence of the layer of compressive residual stresses that the treatment generates in titanium surfaces. Dental implants that had its surfaced prepared with the 2Step procedure (grit-blasting and thermo chemical treatment) had its fatigue life decreased by 10% due to the incorporation of oxygen to the surface and the relaxation of the compressive residual stress produced by the heat treatment. CONCLUSIONS: Thermo-chemical treatment is an excellent compromise between the improvement of bioactive and mechanical long-life behaviors. PMID- 24766393 TI - Engineering mammary gland in vitro models for cancer diagnostics and therapy. AB - Breast cancer is a complex disease with many distinct subtypes being recognized on the basis of histological features and molecular signatures. It is difficult to predict how cancers will respond to therapy, which results in many women receiving unnecessary or inappropriate treatment. Advances in materials science and tissue engineering are leading the development of complex in vitro 3D breast tissue models that will increase our understanding of normal development and tumorigenic mechanisms. Ultimately, platforms that support primary tissue culture could readily be adapted to form high-throughput drug screening tools for personalized medicine. This review will summarize the control of mammary gland phenotype within in vitro 3D environments, in the context of a detailed analysis of mammary gland development and stem and progenitor cell controlled tumorigenesis. PMID- 24766394 TI - Metabolomic profiling of anionic metabolites in head and neck cancer cells by capillary ion chromatography with Orbitrap mass spectrometry. AB - A highly sensitive platform coupling capillary ion chromatography (Cap IC) with Q Exactive mass spectrometer has been developed for metabolic profiling of head and neck squamous cell carcinoma (HNSCC) cells. The Cap IC allowed an excellent separation of anionic polar metabolites, and the sensitivities increased by up to 100-fold compared to reversed-phase liquid chromatography and hydrophilic interaction chromatography performed at either high- or capillary-flow rates. The detection limits for a panel of standard metabolites were between 0.04 to 0.5 nmol/L (0.2 to 3.4 fmol) at a signal-to-noise ratio of 3. This platform was applied to an untargeted metabolomic analysis of head and neck cancer cells and stem-like cancer cells. Differential metabolomics analysis identified significant changes in energy metabolism pathways (e.g., glycolysis and tricarboxylic acid cycle). These experiments demonstrate Cap IC/MS as a powerful metabolomics tool by providing enhanced separation and sensitivity of polar metabolites combined with high resolution and accurate mass measurement (HR/AM) capabilities to differentiate isobaric metabolites. PMID- 24766395 TI - Social theory and current affairs: a framework for intellectual engagement. AB - The paper aims to facilitate more adequate critical engagement with current affairs events by journalists, and with current affairs texts by audiences. It draws on social theory to provide the intellectual resources to enable this. The academic ambition is for the framework to be adopted and developed by social thinkers in producing exemplary critical readings of news and current affairs texts. To this end it is offered as a research paradigm. The paper situates its argument in relation to the wider literature in media and cultural studies, acknowledging the subtle skills required to appreciate the relative autonomy of texts. However, it draws attention to the lack of an adequate perspective with which to assess the frames, representations, and judgments within news and current affairs texts. To address this lacuna it proposes the conception of a social-theoretical frame, based on a number of meta-theoretical approaches, designed to provide audiences with a systematic means of addressing the status and adequacy of individual texts. Social theoretical frames can reveal the shortcomings of media framing of the contextual fields within which news and current affairs events take place. Two illustrative case studies are used to indicate the value and potential of the approach: the analysis of a short newspaper report of the return of protesters to Cairo's Tahrir Square in 2011, and a critique of four current affairs reports from various genres on the political turmoil in Thailand leading up to the clashes of May 2010. PMID- 24766397 TI - Drug safety evaluation of naltrexone/bupropion for the treatment of obesity. AB - INTRODUCTION: Obesity is a known health risk for the development of several preventable diseases. Obesity-related metabolic alterations negatively impact different physiological mechanisms, which supports the rationale for the use of combined drug therapy. Naltrexone is an opioid antagonist for the treatment of opioid and alcohol dependency, whereas bupropion is a norepinephrine/dopamine reuptake inhibitor used to treat depression and smoking cessation. Although not effective as individual monotherapies for obesity, naltrexone and bupropion in combination produce weight loss and a metabolic profile beneficial for the potential treatment of obesity. AREAS COVERED: This review examines the safety and antiobesity effects of naltrexone and bupropion alone and in combination. It reviews the results of four Phase III clinical trials of a novel fixed dose of sustained-released naltrexone/bupropion. EXPERT OPINION: Naltrexone/bupropion has a greater weight loss efficacy than two FDA-approved medications, orlistat and lorcaserin. Although the weight loss produced by phentermine/topiramate is superior to naltrexone/bupropion, the safety profile of naltrexone/bupropion has less severe adverse effects. In addition, naltrexone/bupropion is well tolerated, with nausea being the most reported adverse event. Unlike other centrally acting medications, lorcaserin and phentermine/topiramate, naltrexone/bupropion has no abuse potential. PMID- 24766398 TI - A concise colorimetric and fluorimetric probe for sarin related threats designed via the "covalent-assembly" approach. AB - A turn-on signal from zero background allows sensitive detection of a weak signal and is highly desired. The "covalent-assembly" probe design principle is powerful in this regard. Herein, we report an embodiment of this principle (NA570) for detection of Sarin related threats, based on a phenylogous Vilsmeier-Haack reaction. NA570 bears a concise molecular construct, exhibits a colorimetric and a fluorimetric signal, and has potential for real applications. PMID- 24766396 TI - Neuroprotective effects of lithium: implications for the treatment of Alzheimer's disease and related neurodegenerative disorders. AB - Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. More recently, based on findings from translational research, lithium has also been regarded as a neuroprotective agent and a candidate drug for disease-modification in certain neurodegenerative disorders, namely, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and, more recently, Parkinson's disease (PD). The putative neuroprotective effects of lithium rely on the fact that it modulates several homeostatic mechanisms involved in neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Such a wide range of intracellular responses may be secondary to two key effects, that is, the inhibition of glycogen synthase kinase-3 beta (GSK-3beta) and inositol monophosphatase (IMP) by lithium. In the present review, we revisit the neurobiological properties of lithium in light of the available evidence of its neurotrophic and neuroprotective properties, and discuss the rationale for its use in the treatment and prevention of neurodegenerative diseases. PMID- 24766399 TI - The extensive set of accessory Pseudomonas aeruginosa genomic components. AB - Up to 20% of the chromosomal Pseudomonas aeruginosa DNA belong to the so-called accessory genome. Its elements are specific for subgroups or even single strains and are likely acquired by horizontal gene transfer (HGT). Similarities of the accessory genomic elements to DNA from other bacterial species, mainly the DNA of gamma- and beta-proteobacteria, indicate a role of interspecies HGT. In this study, we analysed the expression of the accessory genome in 150 clinical P. aeruginosa isolates as uncovered by transcriptome sequencing and the presence of accessory genes in eleven additional isolates. Remarkably, despite the large number of P. aeruginosa strains that have been sequenced to date, we found new strain-specific compositions of accessory genomic elements and a high portion (10 20%) of genes without P. aeruginosa homologues. Although some genes were detected to be expressed/present in several isolates, individual patterns regarding the genes, their functions and the possible origin of the DNA were widespread among the tested strains. Our results demonstrate the unaltered potential to discover new traits within the P. aeruginosa population and underline that the P. aeruginosa pangenome is likely to increase with increasing sequence information. PMID- 24766400 TI - Blood doping: risks to athletes' health and strategies for detection. AB - Blood doping has been defined as the misuse of substances or certain techniques to optimize oxygen delivery to muscles with the aim to increase performance in sports activities. It includes blood transfusion, administration of erythropoiesis-stimulating agents or blood substitutes, and gene manipulations. The main reasons for the widespread use of blood doping include: its availability for athletes (erythropoiesis-stimulating agents and blood transfusions), its efficiency in improving performance, and its difficult detection. This article reviews and discusses the blood doping substances and methods used for in sports, the adverse effects related to this practice, and current strategies for its detection. PMID- 24766401 TI - Prevalence of the use of anabolic-androgenic steroids in Brazil: a systematic review. AB - The use of anabolic-androgenic steroids (AAS) is increasing among practitioners of recreational physical activity. The aim of this research was to evaluate the prevalence of AAS in practitioners of recreational physical activity in Brazil. After systematic review of four databases, 14 articles were included. The results indicate that the prevalence of AAS varied between 2.1% and 31.6%, according to the region analyzed and the sample characteristics. The study's limitations are noted. PMID- 24766402 TI - The influence of concomitant use of alcohol, tobacco, cocaine, and anabolic steroids on lipid profiles of Brazilian recreational bodybuilders. AB - Anabolic-androgenic steroids (AAS) are used to enhance physical performance and/or appearance. The aim of this study was to evaluate the influence of the concomitant use of alcohol, tobacco, cocaine, and AAS on blood lipid profiles of 145 asymptomatic male bodybuilders from the Northeast region of Brazil. Interviews, clinical exams, and serological evaluations were performed on all participants between 2007 and 2009. All subjects' self-reported use of testosterone or its derivatives, 118 individuals reported alcohol intake, 27 reported cigarette smoking, and 33 confirmed cocaine use. Four subjects were users of all drugs at the same time. Higher levels of total cholesterol and LDL cholesterol were observed among concomitant users of alcohol, tobacco, cocaine, and AAS. The study's limitations are noted. PMID- 24766403 TI - Mudi, a web tool for identifying mutations by bioinformatics analysis of whole genome sequence. AB - In forward genetics, identification of mutations is a time-consuming and laborious process. Modern whole-genome sequencing, coupled with bioinformatics analysis, has enabled fast and cost-effective mutation identification. However, for many experimental researchers, bioinformatics analysis is still a difficult aspect of whole-genome sequencing. To address this issue, we developed a browser accessible and easy-to-use bioinformatics tool called Mutation discovery (Mudi; http://naoii.nig.ac.jp/mudi_top.html), which enables 'one-click' identification of causative mutations from whole-genome sequence data. In this study, we optimized Mudi for pooled-linkage analysis aimed at identifying mutants in yeast model systems. After raw sequencing data are uploaded, Mudi performs sequential analysis, including mapping, detection of variant alleles, filtering and removal of background polymorphisms, prioritization, and annotation. In an example study of suppressor mutants of ptr1-1 in the fission yeast Schizosaccharomyces pombe, pooled-linkage analysis with Mudi identified mip1(+) , a component of Target of Rapamycin Complex 1 (TORC1), as a novel component involved in RNA interference (RNAi)-related cell-cycle control. The accessibility of Mudi will accelerate systematic mutation analysis in forward genetics. PMID- 24766404 TI - Ayurveda--the science of healing. AB - BACKGROUND: Migraine is generally recognized as a complex condition, which is often challenging to treat. Patients are often open to novel approaches to understanding why this pain occurs and how to prevent future attacks. METHODS: Ayurvedic medicine, which is a 5000-year-old healing system, offers additional understanding on this disease by categorizing patients into a unique dosha (mind body) type. Specific herbals, dietary modifications, and lifestyle changes have been utilized for thousands of years to create balance in the system to improve chronic conditions. CONCLUSIONS: Evaluating migraine patients utilizing the Ayurvedic model allows patients and practitioners a further layer of understanding and offers additional treatment options for the patient. PMID- 24766405 TI - Immunological aspects of using plant cells as delivery vehicles for oral vaccines. AB - Genetically engineered plants can be used for the biomanufacture and delivery of oral vaccines. Although a myriad of antigens have been produced using this approach, improving our knowledge of their oral immunogenic properties is a priority as this aspect has not been well researched. Some studies have provided evidence of a higher immunogenic activity for antigens that were orally administered in the form of plant-based vaccines in comparison with conventional pure antigens. The characteristics of the plant-derived vaccines that may influence oral immunogenicity are identified and discussed in this review. Among the hypotheses explaining these immunogenic properties are the following: bioencapsulation favors antigen uptake and displays a resistance to degradation; plant metabolites exert adjuvant activity; plant compounds, such as polysaccharides, exert mucoadhesive properties; differential glycosylation conferred by the plant cell machinery enhances immunogenicity. Perspectives on how these hypotheses may be assessed are examined. PMID- 24766406 TI - Retraction notice: Language abilities of patients with primary progressive multiple sclerosis: a preliminary group and case investigation. PMID- 24766407 TI - Novel apatite-based sorbent for defluoridation: synthesis and sorption characteristics of nano-micro-crystalline hydroxyapatite-coated-limestone. AB - Elevated levels of fluoride (F(-)) in groundwaters of granitic and basaltic terrains pose a major environmental problem and are affecting millions of people all over the world. Hydroxyapatite (HA) has been shown to be a strong sorbent for F(-); however, low permeability of synthetic HA results in poor sorption efficiency. Here we provide a novel method of synthesizing nano- to micrometer sized HA on the surfaces of granular limestone to improve the sorption efficiency of the HA-based filter. Our experiments with granular limestone (38-63, 125-500 MUm) and dissolved PO4(3-) (0.5-5.3 mM) as a function of pH (6-8) and temperature (25-80 degrees C) indicated rapid formation of nano- to micrometer sized HA crystals on granular limestone with the maximum surface coverage at lower pH and in the presence of multiple additions of aqueous PO4(3-). The HA crystal morphology varied with the above variables. The sorption kinetics and magnitude of F(-) sorption by HA-coated-fine limestone are comparable to those of pure HA, and the F(-) levels dropped to below the World Health Organization's drinking water limit of 79 MUM for F(-) concentrations commonly encountered in contaminated potable waters, suggesting that these materials could be used as effective filters. Fluorine XANES spectra of synthetic HA reacted with F(-) suggest that the mode of sorption is through the formation of fluoridated-HA or fluorapatite at low F(-) levels and fluorite at high F(-) loadings. PMID- 24766409 TI - Surgical treatment of primary malignant tumors of the sacrum. AB - OBJECTIVES: The objective of the authors was to provide an up-to-date review about the epidemiology, diagnosis, and surgical management of the malignant primary sacral tumors. METHODS: A PubMed search was conducted using a combination of the following items: (('Spinal Neoplasms'[Mesh]) AND 'Sacrum'[Mesh]) NOT ('Metastasis' OR 'Metastases' OR 'Benign'). The literature review and the author's own surgical experiences were used to assess the current treatment strategies of the malignant sacral tumors. RESULTS: Twenty case series were identified, which studies discuss in detail the surgical strategies, the postoperative complications, the functional and oncologic outcome, and the recurrence-free and disease-specific survival of this rare patient category. DISCUSSION: Sacral tumors are rare pathologies. Their management generates a complex medical problem, as they usually are diagnosed in advanced stages with extended dimensions involving the sacral nerves and surrounding organs. The evaluation and complex treatment of these rare tumors require a multidisciplinary approach, optimally at institutions with comprehensive care and experience. Although conventional oncologic therapeutic methods should be used as neoadjuvant or adjuvant therapies in certain histological types, en bloc resection with wide surgical margins is essential for long-term local oncologic control. This is often technically difficult to achieve, as just a few centers in the world perform sacral tumor surgeries on a regular basis, and have enough wide experience. Therefore international cooperation and organization of multicenter tumor registries are essential to develop evidence based treatment protocols. PMID- 24766408 TI - Adherence to safe handling guidelines by health care workers who administer antineoplastic drugs. AB - The toxicity of antineoplastic drugs is well documented. Many are known or suspected human carcinogens where no safe exposure level exists. Authoritative guidelines developed by professional practice organizations and federal agencies for the safe handling of these hazardous drugs have been available for nearly three decades. As a means of evaluating the extent of use of primary prevention practices such as engineering, administrative and work practice controls, personal protective equipment (PPE), and barriers to using PPE, the National Institute for Safety and Health (NIOSH) conducted a web survey of health care workers in 2011. The study population primarily included members of professional practice organizations representing health care occupations which routinely use or come in contact with selected chemical agents. All respondents who indicated that they administered antineoplastic drugs in the past week were eligible to complete a hazard module addressing self-reported health and safety practices on this topic. Most (98%) of the 2069 respondents of this module were nurses. Working primarily in hospitals, outpatient care centers, and physician offices, respondents reported that they had collectively administered over 90 specific antineoplastic drugs in the past week, with carboplatin, cyclophosphamide, and paclitaxel the most common. Examples of activities which increase exposure risk, expressed as percent of respondents, included: failure to wear nonabsorbent gown with closed front and tight cuffs (42%); intravenous (I.V.) tubing primed with antineoplastic drug by respondent (6%) or by pharmacy (12%); potentially contaminated clothing taken home (12%); spill or leak of antineoplastic drug during administration (12%); failure to wear chemotherapy gloves (12%); and lack of hazard awareness training (4%). The most common reason for not wearing gloves or gowns was "skin exposure was minimal"; 4% of respondents, however, reported skin contact during handling and administration. Despite the longstanding availability of safe handling guidance, recommended practices are not always followed, underscoring the importance of training and education for employers and workers. PMID- 24766410 TI - Surgical resection and reconstruction after resection of tumors involving the sacropelvic region. AB - OBJECTIVES: Surgical management of tumors in the sacropelvic region is a challenging field of spine surgery because of the region's complex local anatomy and biomechanics. Recent developments in anesthesia and intensive care have allowed us to perform extended surgeries focused on the en bloc resection of sacropelvic tumors. Various techniques for the resection and for the reconstruction were published in the last decade. METHODS: Sacropelvic tumor resection techniques and methods for the biomechanical and soft-tissue reconstruction are reviewed in this paper. RESULTS: The literature data is based on case reports and case-series. Several different techniques were developed for the lumbopelvic stabilization after sacropelvic tumor resection according to three different reconstruction principles (spinopelvic fixation (SPF), posterior pelvic ring fixation (PRF), and anterior spinal column fixation (ACF)); however, long-term follow-up data and comparative studies of the different techniques are still missing. Soft-tissue reconstruction can be performed according to an algorithm depending on the surgical approach, but relatively high complication rates are reported with all reconstruction strategies. The clinical outcome of such surgeries should ideally be evaluated in three dimensions; surgical-, oncological-, and functional outcomes. The last and most important step of the presurgical planning procedure is a careful presentation of the surgical goals and risks to the patient, who must provide a fully informed consent before surgery can proceed. DISCUSSION: Sacropelvic tumors are rare conditions. In the last decade, growing evidence was published on resection and reconstruction techniques for these tumors; however, experience at most medical centers is limited due to the low numbers of cases. The formation of international expert groups and the initiation of multicenter studies are strongly encouraged to produce a high level of evidence in this special field of spine surgery. PMID- 24766411 TI - Innovative approach for improved rFVIII concentrate. AB - The development of a new recombinant factor VIII was designed and implemented to answer a number of unmet needs of patients affected by hemophilia A. Turoctocog alfa is bioengineered in a specific Chinese hamster ovary clone to present translational and posttranslational characteristics (sulphation, glycosylation) biosimilar to natural circulating forms of FVIII, with the aim to devoid any minimal change which may impact immunogenicity and antigenicity of recombinant protein. Both producer cell line and media are maintained free of any animal or human plasma derivative. Downstream processes of purification are performed by five steps (immunoaffinity chromatography, ion-exchange chromatography, virus inactivation by means of solvent-detergent treatment and nanofiltration, and to end with gel filtration), to provide the best possible margin of safety from known and unknown infectious agents. Large clinical trials seem to confirm the expectations placed in Turoctocog alfa in terms of high quality and safety of recombinant FVIII toward the goal of overcoming actual and future challenges of hemophilia therapy. PMID- 24766412 TI - Changes in parathyroid proteome in patients with primary hyperparathyroidism due to sporadic parathyroid adenomas. AB - PURPOSE: The pathogenesis of parathyroid tumours is only partially understood. A direct approach using proteomics could be a promising tool to increase our understanding of parathyroid tumorigenesis. The aim of the study was to investigate differentially expressed proteins to explore the underlying molecular basis of the disease and identify potential target proteins responsible for the genesis of adenoma. METHODS: Proteins were extracted from adenomatous and normal parathyroid tissues. Differentially expressed proteins were separated by two dimensional gel electrophoresis (2-D) and identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. Statistical analysis was performed using spss 10.01 software. RESULTS: Comparative analysis of the 2-D profiles of proteins isolated from adenomatous and normal parathyroid tissues showed 15 differentially expressed proteins, of which 11 were overexpressed. The characterized proteins were associated with diverse cellular functions including regulation of cell organization, programmed cell death, transcription and signal transduction. CONCLUSION: The differentially expressed proteins in parathyroid adenomas may potentially serve as new targets to investigate the mechanisms of parathyroid adenoma transformation. PMID- 24766413 TI - Frequency, severity and causes of unexpected allergic reactions to food: a systematic literature review. AB - Food allergic patients have to deal with an avoidance diet. Confusing labelling terms or precautionary labels can result in misinterpretation and risk-taking behaviour. Even those patients that strictly adhere to their diet experience (sometimes severe) unexpected allergic reactions to food. The frequency, severity and causes of such reactions are unknown. The objective of this review was to describe the frequency, severity and causes of unexpected allergic reactions to food in food allergic patients aged > 12 years, in order to develop improved strategies to deal with their allergy. A systematic review was carried out by two researchers, in six electronic databases (CINAHL, Cochrane, EMBASE, Medline, Psychinfo and Scopus). The search was performed with keywords relating to the frequency, severity and causes of unexpected allergic reactions to food. This resulted in 24 studies which met the inclusion criteria; 18 observational and six qualitative studies. This review shows that knowledge about the frequency of unexpected reactions is limited. Peanut, nuts, egg, fruit/vegetables and milk are the main causal foods. Severe reactions and even fatalities occur. Most reactions take place at home, but a significant number also take place when eating at friends' houses or in restaurants. Labelling issues, but also attitude and risky behaviour of patients can attribute to unexpected reactions. We conclude that prospective studies are needed to get more insight in the frequency, severity, quantity of unintended allergen ingested and causes of unexpected allergic reactions to food, to be able to optimize strategies to support patients in dealing with their food allergy. Although the exact frequency is not known, unexpected reactions to food occur in a significant number of patients and can be severe. For clinical practice, this means that patient education and dietary instructions are necessary. PMID- 24766414 TI - Contraceptive counseling by general internal medicine faculty and residents. AB - BACKGROUND: Almost half of US pregnancies are unintended, resulting in many abortions and unwanted or mistimed births. Contraceptive counseling is an effective tool to increase patients' use of contraception. METHODS: Using an online 20-item questionnaire, we evaluated the frequency of contraceptive counseling provided to reproductive-age women during a prevention-focused visit by University of Colorado internal medicine resident and faculty providers. We also evaluated factors hypothesized to affect contraceptive counseling frequency. RESULTS: Although more than 95% of the 146 medicine faculty and resident respondents agreed that contraceptive counseling is important, only one-quarter of providers reported providing contraceptive counseling "routinely" (defined as >=80% of the time) to reproductive-age women during a prevention-focused visit. Providing contraceptive counseling routinely was strongly associated with taking an abbreviated sexual history "often"/"routinely" (odds ratio [OR]=11.6 [3.3 to 40.0]) and with high self-efficacy to provide contraceptive counseling (OR=6.5 [1.5 to 29.0]). However, fewer than two-thirds of providers reported taking an abbreviated sexual history "often"/"routinely." More than 70% of providers reported inadequate knowledge of contraceptive methods as a contraceptive counseling barrier. However, providers' perceived inadequate knowledge was not associated with traditional educational exposures, such as lectures and women's health electives. CONCLUSIONS: In prevention-focused visits with reproductive-age women, a minority of internal medicine faculty and residents reported routine contraceptive counseling. Future efforts to increase contraceptive counseling among internists should include interventions that increase provider contraceptive counseling self-efficacy and ensure that providers obtain an abbreviated sexual history. PMID- 24766415 TI - Single case experimental designs: introduction to a special issue of Neuropsychological Rehabilitation. AB - This paper introduces the Special Issue of Neuropsychological Rehabilitation on Single Case Experimental Design (SCED) methodology. SCED studies have a long history of use in evaluating behavioural and psychological interventions, but in recent years there has been a resurgence of interest in SCED methodology, driven in part by the development of standards for conducting and reporting SCED studies. Although there is consensus on some aspects of SCED methodology, the question of how SCED data should be analysed remains unresolved. This Special Issues includes two papers discussing aspects of conducting SCED studies, five papers illustrating use of SCED methodology in clinical practice, and nine papers that present different methods of SCED data analysis. A final Discussion paper summarises points of agreement, highlights areas where further clarity is needed, and ends with a set of resources that will assist researchers conduct and analyse SCED studies. PMID- 24766417 TI - Extraction of aflatoxins from liquid foodstuff samples with polydopamine-coated superparamagnetic nanoparticles for HPLC-MS/MS analysis. AB - A facile magnetic solid phase extraction (MSPE) of aflatoxins (AFs) from liquid samples was developed using polydopamine-coated magnetic nanoparticles (PD-MNPs) as the adsorbent. PD-MNPs were prepared from amine-terminated MNPs and dopamine via an in situ oxidative self-polymerization approach. Under the selected MSPE conditions, extraction yields ranging from 59.3% for AF G2 to 89.0% for AF B1 were obtained with good repeatability. Coupled with HPLC-MS/MS quantification, the MSPE procedure serves not only for sample cleanup but also for AFs enrichment that is highly desired for trace analysis. The proposed MSPE-HPLC-MS/MS method had a linear calibration curve in the concentration range from 0.00600 to 3.00 ng/mL aflatoxin and limits of detection of 0.0012 ng/mL for AF B1, AF B2, and AF G1, and 0.0031 ng/mL for AF G2. PMID- 24766416 TI - Inhibition of the responses to sex pheromone of the fall armyworm, Spodoptera frugiperda. AB - Trifluoromethyl ketones reversibly inhibit pheromone-degrading esterases in insect olfactory tissues, affecting pheromone detection and behavior of moth males. In this work, (Z)-9-tetradecenyl trifluoromethyl ketone (Z9-14:TFMK), a closely-related analogue of the pheromone of the fall armyworm, Spodoptera frugiperda (Smith) (Lepidoptera: Noctuidae), was prepared and tested in electroantennogram and field tests as possible inhibitors of the pheromone action. The electroantennogram parameters, amplitude, and the repolarization time of the antennal responses of S. frugiperda males were affected by Z9-14:TFMK vapors. Exposure of male antennae to a stream of air passing through 100 MUg of the ketone produced a significant reduction of the amplitude and an increase of 2/3 repolarization time signals to the pheromone. The effect was reversible and dose-dependent. In the field, the analogue significantly decreased the number of males caught when mixed with the pheromone in 10:1 ratio. The results suggest that Z9-14:TFMK is a mating disruptant of S. frugiperda and may be a good candidate to consider in future strategies to control this pest. PMID- 24766418 TI - Anti-inflammatory effects of glutamine on LPS-stimulated human dental pulp cells correlate with activation of MKP-1 and attenuation of the MAPK and NF-kappaB pathways. AB - AIM: To evaluate the anti-inflammatory effects of glutamine and the underlying signal pathway mechanisms in lipopolysaccharide (LPS)-stimulated human dental pulp cells (HDPCs). METHODS: Human dental pulp cells were exposed to 10 MUg mL( 1) LPS and various concentrations of glutamine for 24 h. The production of PGE2 and nitric oxide was determined by enzyme-linked immunosorbent assay (ELISA) and Griess reagent kit, respectively. Cytokines were examined by ELISA, reverse transcriptase-polymerase chain reaction (RT-PCR) and real-time PCR. iNOS and COX protein expression as well as signal pathways were accessed by Western blot. The data were analysed by anova with Bonferroni's test (alpha = 0.05). RESULTS: Glutamine reduced LPS-induced iNOS and COX-2 protein expression as well as production of NO and PGE2 in a dose-dependent fashion. Additionally, glutamine suppressed the production and mRNA expression of inflammatory cytokines including interleukin-1beta (IL-1beta), TNF-alpha, and IL-8. Furthermore, glutamine attenuated phosphorylation of extracellular signal-regulated kinase (ERK), p38, c Jun N-terminal kinase (JNK) and IkappaB-alpha, and nuclear translocation of NF kappaB p65, but enhanced mitogen-activated protein kinase phosphatase-1 (MKP-1) expression in LPS-treated HDPCs. CONCLUSION: Glutamine exerted an anti inflammatory effect via activation of MKP-1 and inhibition of the NF-kappaB and MAPK pathways in LPS-treated HDPCs. PMID- 24766419 TI - Direct electron transfer of glucose oxidase-boron doped diamond interface: a new solution for a classical problem. AB - A planar boron-doped diamond (BDD) electrode was treated with KOH and functionalized with 3-aminopropyltriethoxysilane (APTES) to serve as a biosensing platform for biomolecule immobilization with glucose oxidase (GOx) as a test model. The free amino groups of GOx and APTES were cross-linked by glutaraldehyde (X), a bifunctional chemical to form a stable enzyme layer (GOx-X-APTES) on BDD. Micrographs obtained by scanning electron microscopy revealed that a mesoporous structure uniformly covered the BDD surface. Cyclic voltammetry of GOx immobilized showed a pair of well-defined redox peaks in neutral phosphate buffer solution, corresponding to the direct electron transfer of GOx. The apparent heterogeneous electron transfer rate constant of the immobilized GOx was estimated to be 8.85 +/- 0.47 s(-1), considerably higher than the literature reported values. The determination of glucose was carried out by amperometry at 0.40 V, and the developed biosensor showed good reproducibility and stability with a detection limit of 20 MUM. Both ascorbic and uric acids at normal physiological conditions did not provoke any signals. The dynamic range of glucose detection was further extended by covering the enzyme electrode with a thin Nafion layer. The Nafion/GOx-X-APTES/BDD biosensor showed excellent stability, a detection limit of 30 MUM, a linear range between 35 MUM and 8 mM, and a dynamic range up to 14 mM. Such analytical performances were compared favorably with other complicated sensing schemes using nanomaterials, redox polymers, and nanowires. The APTES-functionalized BDD could be easily extended to immobilize other redox enzymes or proteins of interests. PMID- 24766420 TI - Improved ion-selective detection method using nanopipette with poly(vinyl chloride)-based membrane. AB - Ion-selective electrodes (ISEs) are widely used to detect targeted ions in solution selectively. Application of an ISE to a small area detection system with a nanopipette requires a special measurement method in order to avoid the enhanced background signal problem caused by a cation-rich layer near the charged inner surface of the nanopipette and the selectivity change problem due to relatively fast saturation of the ISE inside the nanopipette. We developed a novel ion-selective detection system using a nanopipette that measures an alternating current (AC) signal mediated by saturated ionophores in a poly(vinyl chloride) (PVC) membrane located at the conical shank of the nanopipette to solve the above problems. Small but reliable K(+) and Na(+) ionic current passing through a PVC membrane containing saturated bis(benzo-15-crown-5) and bis(12 crown-4) ionophore, respectively, could be selectively detected using the AC signal measurement system equipped with a lock-in amplifier. PMID- 24766421 TI - Somatic mosaicism for a FOXG1 mutation: diagnostic implication. PMID- 24766422 TI - A highly sensitive plasmonic DNA assay based on triangular silver nanoprism etching. AB - Specific nucleic acid detection by using simple and low-cost assays is important in clinical diagnostics, mutation detection, and biodefense applications. Most current methods for the quantification of low concentrations of DNA require costly and sophisticated instruments. Here, we have developed a facile DNA detection platform based on a plasmonic triangular silver nanoprism etching process, in which the shape and size of the nanoprisms were altered accompanied by a substantial surface plasmon resonance shift. Through the combination of enzyme-linked hybridization chain reaction amplification and inherent sensitivity of plasmonic silver nanoprims, this assay could detect as low as 6.0 fM target DNA. Considering the high sensitivity and selectivity of this plasmonic DNA assay, it is expected to be of great interest in clinical diagnostics. PMID- 24766423 TI - Recombinant expression and inhibition mechanism analysis of pectin methylesterase from Aspergillus flavus. AB - Phytopathogenic microorganisms can produce pectin methylesterase (PME) to degrade plant cell walls during plant invasion. This enzyme is thought to be a virulence factor of phytopathogens. In this work, PME from Aspergillus flavus (AFPME) was expressed in Pichia pastoris and an in vitro inhibitor study was performed. The purified AFPME with a yield of 52.2% was resolved as one band with a molecular mass of c. 40 kDa by SDS-PAGE. Optimal activity of the enzyme occurred at a temperature of 55 degrees C and a pH of 4.8. Epigallocatechin gallate (EGCG) strongly inhibited the activity of recombinant AFPME. The molecular docking analysis indicated that EGCG could form hydrogen bonds and pi-pi interactions with some amino acid residues in the active site of AFPME. Our studies provide a novel strategy for the control of the plant invasion of A. flavus. PMID- 24766424 TI - Aortic to brachial pulse pressure amplification as functional marker and predictor of renal function loss in chronic kidney disease. AB - Pulse pressure amplification (PPA) reflects large artery function. Its contribution in chronic kidney disease (CKD) remains uncertain. The authors assessed PPA in CKD progression in patients with CKD stage 2 to 4 (n=128) and 89 controls (follow-up: 42 months). PPA was reduced in CKD patients as compared with control patients and associated with decline in renal function. Sixteen renal endpoints, defined by 50% loss of renal function or start of renal replacement therapy, were detected. In Cox regression analysis, PPA, estimated glomerular filtration rate, and proteinuria predicted renal endpoints. Patients with CKD stage 4 and low PPA had the highest risk for developing renal endpoints (unadjusted 8.1; 2.4-27.7 and adjusted for age and proteinuria 5.6; 1.5-21.9, log rank P<.001). Taken together, PPA is reduced in CKD and is associated with declining renal function. In addition, low PPA predicts renal endpoints in severe CKD. Furthermore, this study emphasizes the role of systolic blood pressure as a major determinant of PPA. PMID- 24766426 TI - International resource list of organizations whose mandate is to deal with doping. PMID- 24766425 TI - Socio-economic determinants and inequities in coverage and timeliness of early childhood immunisation in rural Ghana. AB - OBJECTIVES: To assess the extent of socio-economic inequity in coverage and timeliness of key childhood immunisations in Ghana. METHODS: Secondary analysis of vaccination card data collected from babies born between January 2008 and January 2010 who were registered in the surveillance system supporting the ObaapaVita and Newhints Trials was carried out. 20 251 babies had 6 weeks' follow up, 16 652 had 26 weeks' follow-up, and 5568 had 1 year's follow-up. We performed a descriptive analysis of coverage and timeliness of vaccinations by indicators for urban/rural status, wealth and educational attainment. The association of coverage with socio-economic indicators was tested using a chi-square-test and the association with timeliness using Cox regression. RESULTS: Overall coverage at 1 year of age was high (>95%) for Bacillus Calmette-Guerin (BCG), all three pentavalent diphtheria-pertussis-tetanus-haemophilus influenzae B-hepatitis B (DPTHH) doses and all polio doses except polio at birth (63%). Coverage against measles and yellow fever was 85%. Median delay for BCG was 1.7 weeks. For polio at birth, the median delay was 5 days; all other vaccine doses had median delays of 2-4 weeks. We found substantial health inequity across all socio-economic indicators for all vaccines in terms of timeliness, but not coverage at 1 year. For example, for the last DPTHH dose, the proportion of children delayed more than 8 weeks were 27% for urban children and 31% for rural children (P < 0.001), 21% in the wealthiest quintile and 41% in the poorest quintile (P < 0.001), and 9% in the most educated group and 39% in the least educated group (P < 0.001). However, 1-year coverage of the same dose remained above 90% for all levels of all socio-economic indicators. CONCLUSIONS: Ghana has substantial health inequity across urban/rural, socio-economic and educational divides. While overall coverage was high, most vaccines suffered from poor timeliness. We suggest that countries achieving high coverage should include timeliness indicators in their surveillance systems. PMID- 24766427 TI - Suggested readings about doping. PMID- 24766428 TI - Performance optimization and physiological doping. PMID- 24766429 TI - Doping: selected annotated materials. PMID- 24766430 TI - Coeliac disease and socio-economic status. PMID- 24766431 TI - Dendritic assembly of gold nanoparticles during fuel-forming electrocatalysis. AB - We observe the dendritic assembly of alkanethiol-capped gold nanoparticles on a glassy carbon support during electrochemical reduction of protons and CO2. We find that the primary mechanism by which surfactant-ligated gold nanoparticles lose surface area is by taking a random walk along the support, colliding with their neighbors, and fusing to form dendrites, a type of fractal aggregate. A random walk model reproduces the fractal dimensionality of the dendrites observed experimentally. The rate at which the dendrites form is strongly dependent on the solubility of the surfactant in the electrochemical double layer under the conditions of electrolysis. Since alkanethiolate surfactants reductively desorb at potentials close to the onset of CO2 reduction, they do not poison the catalytic activity of the gold nanoparticles. Although catalyst mobility is typically thought to be limited for room-temperature electrochemistry, our results demonstrate that nanoparticle mobility is significant under conditions at which they electrochemically catalyze gas evolution, even in the presence of a high surface area carbon and binder. A careful understanding of the electrolyte- and polarization-dependent nanoparticle aggregation kinetics informs strategies for maintaining catalyst dispersion during fuel-forming electrocatalysis. PMID- 24766433 TI - Multimedia modeling of engineered nanoparticles with SimpleBox4nano: model definition and evaluation. AB - Screening level models for environmental assessment of engineered nanoparticles (ENP) are not generally available. Here, we present SimpleBox4Nano (SB4N) as the first model of this type, assess its validity, and evaluate it by comparisons with a known material flow model. SB4N expresses ENP transport and concentrations in and across air, rain, surface waters, soil, and sediment, accounting for nanospecific processes such as aggregation, attachment, and dissolution. The model solves simultaneous mass balance equations (MBE) using simple matrix algebra. The MBEs link all concentrations and transfer processes using first order rate constants for all processes known to be relevant for ENPs. The first order rate constants are obtained from the literature. The output of SB4N is mass concentrations of ENPs as free dispersive species, heteroaggregates with natural colloids, and larger natural particles in each compartment in time and at steady state. Known scenario studies for Switzerland were used to demonstrate the impact of the transport processes included in SB4N on the prediction of environmental concentrations. We argue that SB4N-predicted environmental concentrations are useful as background concentrations in environmental risk assessment. PMID- 24766432 TI - Current advancements and potential strategies in the development of MERS-CoV vaccines. AB - Middle East respiratory syndrome (MERS) is a newly emerging infectious disease caused by a novel coronavirus, MERS-coronavirus (MERS-CoV), a new member in the lineage C of beta-coronavirus (beta-CoV). The increased human cases and high mortality rate of MERS-CoV infection make it essential to develop safe and effective vaccines. In this review, the current advancements and potential strategies in the development of MERS vaccines, particularly subunit vaccines based on MERS-CoV spike (S) protein and its receptor-binding domain (RBD), are discussed. How to improve the efficacy of subunit vaccines through novel adjuvant formulations and routes of administration as well as currently available animal models for evaluating the in vivo efficacy of MERS-CoV vaccines are also addressed. Overall, these strategies may have important implications for the development of effective and safe vaccines for MERS-CoV in the future. PMID- 24766434 TI - Panitumumab safety for treating colorectal cancer. AB - INTRODUCTION: Panitumumab is a human IgG2 mAb against the EGFR, inhibiting tumor cell proliferation, survival and angiogenesis. It has demonstrated clinical efficacy in metastatic colorectal cancer (CRC) in combination with chemotherapy in first- and second-line settings and as monotherapy in third-line setting. Recently, mutations in the RAS genes have been shown to be predictive of lack of efficacy, panitumumab should be restricted to patients with RAS wild-type (wt) tumors. AREAS COVERED: This review focuses on main efficacy results of panitumumab in metastatic CRC in first-, second- and third-line settings in combination with chemotherapy or as monotherapy. Additionally, we have covered safety aspects of this agent in these indications, especially in K-RAS and all RAS wt patients. These safety aspects refer to the most common toxicities (i.e., acne-like skin rash, diarrhea and hypomagnesaemia). EXPERT OPINION: Panitumumab adds to the armamentarium of effective agents in the treatment of metastatic CRC. Due to its human origin, panitumumab is a well-tolerated agent with low rates of infusional reactions. Skin toxicity is frequent and should be pre-emptively treated. Other common toxicities related to panitumumab treatment, such as diarrhea and hypomagnesaemia, should be closely monitored to ensure early treatment or substitution. PMID- 24766435 TI - Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: current and future perspectives in adult and paediatric disease. AB - Anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma seen in both adults and children. ALCL is associated with a characteristic chromosomal translocation, t(2;5)(p23;35) which fuses the anaplastic lymphoma kinase (ALK) gene on chromosome 2 with the nucleophosmin (NPM) gene on chromosome 5, resulting in a NPM-ALK fusion protein, ALK over-expression and constitutive tyrosine kinase activity. This aggressive lymphoma is more prevalent in males and can present with extranodal involvement (lung, skin and marrow infiltration) and haemophagocytic lymphohistocytosis. The long-term overall survival is approximately 70-90% in children and over 70% in adults. Staging systems and prognostic risk factors are different in both childhood and adult ALCL. Treatment in adults is typically anthracycline-based, with autologous stem cell transplantation (ASCT) salvaging patients in relapsed disease. There is evidence for ALL-like therapy or intensive, pulsed anthracycline-based induction in children. ASCT, allogeneic SCT and vinblastine maintenance are all considered reasonable options in relapsed childhood disease. The anti-CD30 immunoconjugate Brentuximab Vedotin and the specific ALK inhibitor Crizotinib are changing the treatment paradigm in ALCL (ALK-positive or negative) and ALK-positive ALCL respectively. Both agents have shown encouraging responses in relapsed ALCL. It remains to be seen how these novel agents are used, but it is very possible that they may improve overall responses and survival in both children and adults. This review highlights the presentation, histopathological features, prognostic factors, and evidence-based treatment approaches in the first line and relapsed setting in ALK-positive ALCL. The review concludes by discussing the novel approaches using Brentuximab and Crizotinib which are being tested in clinical trials. PMID- 24766436 TI - CAM in the real world: you may practice evidence-based medicine, but your patients don't. AB - BACKGROUND: Complementary and Alternative Medicine (CAM) approaches are widely used among individuals suffering from headache. The medical literature has focused on the evidence base for such use and has largely ignored the fact that these approaches are in wide use despite that evidence base. DISCUSSION: This article focuses on the uses of CAM by patients and suggests strategies for understanding and addressing this use without referring back to the evidence base. The rationale for this discussion pivots on the observation that patients are already using these approaches, and for many there are anecdotal and historical bases for use which patients find persuasive in the absence of scientific evidence. CONCLUSION: Until such time as the body of scientific literature adequately addresses non-conventional approaches, physicians must acknowledge and understand, as best as possible, CAM approaches which are in common use by patients. This is illustrated with a case study and examples from practice. This article does not review the evidence base for various CAM practices as this has been done well elsewhere. PMID- 24766437 TI - Efficiency analysis of the MARS2013 planning strategy. AB - On future human Mars missions, surface sojourn duration and resources will be limited. One possibility to approach a positive cost-benefit ratio of a human Mars mission will be to maximize the scientific research on the martian surface within the operational, environmental, and experimental limitations. Sophisticated mission operations and advanced planning strategies will be a basic requirement for Mars exploration and make operational methods an important research subject during current Mars analog missions conducted by the Austrian Space Forum. The Morocco Mars analog field simulation MARS2013, with a duration of 4 weeks and a simulated time delay of 10 min for communication between field and mission support, was the most advanced Mars analog mission conducted by the Austrian Space Forum so far. Due to these constraints, planning strategies based on real-time adjustments and ground control were not applicable, leading to the development of the "3-days-in-advance" planning strategy. Applying this methodology, 45.7% of the total EVA time was used for scientific experiments that satisfied 75.8% of the planned science goals. Taking into account all activities (donning of the suits included), the fraction of time used for scientific experiments made up only one-third of the total time, whereas it was planned to be above 50%. Here, we present details on the application of the 3-days-in advance planning and on the results of the efficiency analysis of MARS2013. PMID- 24766438 TI - Semi-quantitative HPV viral load in patients with ASC-US cytology: viral load correlates strongly with the presence of CIN but only weakly with its severity. AB - OBJECTIVES: This study was performed to evaluate the prognostic significance of human papillomavirus (HPV) viral load, expressed in relative light units (RLUs), in patients with atypical squamous cells of undetermined significance (ASC-US) cytology. METHODS: A total of 349 ASC-US cases with HPV infection, detected using Hybrid Capture 2, were diagnosed histologically. A colposcopically directed punch biopsy was performed on acetowhite areas. Endocervical curettage biopsy and random cervical punch biopsy in four quadrants were performed in unsatisfactory colposcopy cases. In negative colposcopy cases, random cervical punch biopsy in four quadrants was performed. RESULTS: Case with no cervical intraepithelial neoplasia (CIN), CIN1 and CIN2+ (CIN2/CIN3) accounted for 162, 135 and 52 cases, respectively. The mean age showed no difference among the three groups (P = 0.510). There was a significant correlation between RLU values and the presence of CIN (P < 0.001), but less so with its severity: the median RLU values for negative, CIN1 and CIN2+ cases were 42.68, 146.45 and 156.43, respectively, with widely overlapping confidence intervals. The cut-off values of RLU to detect CIN1+ and CIN2+ were 6.73 and 45.64, respectively. CONCLUSIONS: The HPV viral load in ASC-US cases showed a significant correlation with the presence of CIN and less so with its severity, and showed large overlap of viral loads between grades of CIN. In ASC-US cases, RLU was not an accurate predictor of immediate high-grade CIN. PMID- 24766439 TI - Structural insights into the substrate-binding mechanism for a novel chitosanase. AB - Chitosanase is able to specifically cleave beta-1,4-glycosidic bond linkages in chitosan to produce a chito-oligomer product, which has found a variety of applications in many areas, including functional food and cancer therapy. Although several structures for chitosanase have been determined, the substrate binding mechanism for this enzyme has not been fully elucidated because of the lack of a high-resolution structure of the chitosanase-substrate complex. In the present study we show the crystal structure of a novel chitosanase OU01 from Microbacterium sp. in complex with its substrate hexa-glucosamine (GlcN)6, which belongs to the GH46 (glycoside hydrolyase 46) family in the Carbohydrate Active Enzymes database (http://www.cazy.org/). This structure allows precise determination of the substrate-binding mechanism for the first time. The chitosanase-(GlcN)6 complex structure demonstrates that, from the -2 to +1 position of the (GlcN)6 substrate, the pyranose rings form extensive interactions with the chitosanase-binding cleft. Several residues (Ser27, Tyr37, Arg45, Thr58, Asp60, His203 and Asp235) in the binding cleft are found to form important interactions required to bind the substrate. Site-directed mutagenesis of these residues showed that mutations of Y37F and H203A abolish catalytic activity. In contrast, the mutations T58A and D235A only lead to a moderate loss of catalytic activity, whereas the S27A mutation retains ~80% of the enzymatic activity. In combination with previous mutagenesis studies, these results suggest that the -2, -1 and +1 subsites play a dominant role in substrate binding and catalysis. DSF (differential scanning fluorimetry) assays confirmed that these mutations had no significant effect on protein stability. Taken together, we present the first mechanistic interpretation for the substrate (GlcN)6 binding to chitosanase, which is critical for the design of novel chitosanase used for biomass conversion. PMID- 24766440 TI - A liquid crystal-based passive badge for personal monitoring of exposure to hydrogen sulfide. AB - A new liquid crystal (LC)-based passive dosimeter badge for personal monitoring of exposure to hydrogen sulfide (H2S) gas is reported. When a thin film of LC supported on a surface functionalized with lead perchlorate Pb(ClO4)2 (the LC sensor) is exposed to H2S, the orientation of LC molecules in the film changes from perpendicular to parallel. This reorientation induces a change in the appearance of the LC film when viewed between crossed polarizers. A H2S dosimeter was fabricated by pairing a LC sensor with a glass substrate forming a headspace between the two surfaces, to control diffusion of H2S across the LC film. When the dosimeter is exposed to H2S, a bright front appears as a function of exposure time. An algorithm has been developed to correlate this response length and exposure dose. The dosimeters are functionally stable when subjected to extreme temperature and humidity fluctuations, and are immune to a number of potentially interfering chemicals, except mercaptans. These dosimeters detect H2S at 0.2 ppm TWA (8 hr) with +/-20% overall accuracy. The dosimeters were used to monitor the personal exposure of personnel working in an oil refinery. The TWA concentrations measured by the LC-based dosimeters correlate strongly with the NIOSH 1063 method that uses a sorbent tube and a pump followed by laboratory analysis. Thus, the LC based dosimeters can provide a sensitive tool for on-site assessment of personal exposure to H2S in different environments. PMID- 24766441 TI - Can radioiodine be administered effectively and safely to a patient with severe chronic kidney disease? AB - Chronic kidney disease is an increasingly widespread problem. The progression of renal failure is associated with the development of various hormonal disorders, including those affecting the thyroid gland. The prevalence of multinodular goitre and differentiated thyroid cancer increases significantly in patients with renal failure. However, radioiodine treatment in patients with severe chronic kidney disease gives rise to a number of difficulties. The only conclusions regarding this treatment thus far have been derived from single case studies. It seems that prospective controlled studies can contribute to the creation of standards for radioiodine treatment in patients with various stages of chronic kidney disease, while maintaining the safety of such treatment for both patients and medical staff. This review gives the response to the question how nowadays to treat the patients with severe chronic kidney disease with radioiodine. PMID- 24766442 TI - Scanning electron microscopy of superficial defects in Twisted files and Reciproc nickel-titanium files after use in extracted molars. AB - AIM: To evaluate the usage and superficial defects in size 25, 0.08 taper Twisted files (TF) and R25 Reciproc files after root canal instrumentation. METHODOLOGY: One hundred and twenty mandibular molars with root canal curvature, ranging from 15 degrees to 30 degrees and a 4-5 mm radius, were randomly divided into two groups according to single-file instrumentation: size 25, 0.08 taper TF or R25 files. A total of fifteen files per group were evaluated before and after three, six, nine and 12 uses. The instruments were fixed in custom-made holders and photographed using scanning electron microscopy at *260 to *1200 magnifications. The presence of superficial defects (plastic deformation, microcracks, fracture, craters, disruption of the cutting edges and blunt edges) was scored from the pre and post-usage photographs. Chi-squared test was used to analyse differences after usages in both groups individually. Two-way anova was used to analyse differences between both instruments. The level of significance for all analyses was 5%. RESULTS: Superficial defects were observed after the instrumentation of six root canals in the TF group and after the instrumentation of nine root canals in the R25 group. Plastic deformation and disruption of cutting edges were the prevalent defects observed in the TF group, and craters and blunt edges were observed in R25 files. The presence of defects was significantly increased with successive usages in both groups (P < 0.05), but TF had more superficial defects than R25 files (P < 0.001). Dentine debris was observed on all instruments. No instruments fractured. CONCLUSIONS: Instrumentation was possible for six root canals with TF files and nine root canals with R25 files before the presence of superficial defects appeared. Differences in the prevalence and development of superficial defects were observed between the TF and R25 files. PMID- 24766443 TI - Using single-case experimental design methodology to evaluate the effects of the ABC method for nursing staff on verbal aggressive behaviour after acquired brain injury. AB - The ABC method is a basic and simplified form of behavioural modification therapy for use by nurses. ABC refers to the identification of Antecedent events, target Behaviours, and Consequent events. A single-case experimental AB design was used to evaluate the effects of the ABC method on a woman diagnosed with olivo-ponto cerebellar ataxia. Target behaviour was verbal aggressive behaviour during ADL care, assessed at 9 time points immediately before implementation of the ABC method and at 36 time points after implementation. A randomisation test showed a significant treatment effect between the baseline and intervention phases (t = .58, p = .03; ES [Nonoverlap All Pairs] = .62). Visual analysis, however, showed that the target behaviour was still present after implementation of the method and that on some days the nurses even judged the behaviour to be more severe than at baseline. Although the target behaviour was still present after treatment, the ABC method seems to be a promising tool for decreasing problem behaviour in patients with acquired brain injury. It is worth investigating the effects of this method in future studies. When interpreting single-subject data, both visual inspection and statistical analysis are needed to determine whether treatment is effective and whether the effects lead to clinically desirable results. PMID- 24766444 TI - Correlation between pesticide resistance and enzyme activity in the diamondback moth, Plutella xylostella. AB - The diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), is one of the most important pests that has developed high pesticide resistance. The resistances of five Chinese populations of this moth, four resistant strains (from Beijing, Henan, Fujian, and Guangdong) and one susceptible strain, to five pesticides were determined, and the activities of carboxylesterase, glutathione S transferase, and acetylcholine esterase were tested in all five populations. The correlations between pesticide resistance and enzyme activity were analyzed. The results showed that the resistance status to the five pesticides was different among the five populations. The resistance ratios of the Beijing and Henan populations to spinosad were 5.84 and 8.22, respectively, and those to beta cypermethrin were 4.91 and 4.98, respectively. These ratios were higher than those for the Fujian and Guangdong populations. The Fujian population was more sensitive to abamectin and chlorpyrifos than the susceptible population (the resistance ratios were 0.14 and 0.91, respectively); in fact, the median lethal concentration for P. xylostella was significantly higher for chlorpyrifos than that for any of the other four pesticides. The carboxylesterase activity in P. xylostella showed positive correlations with the resistance to spinosad, beta cypermethrin, chlorpyrifos, and abamectin, but no correlation was observed between the carboxylesterase activity and resistance to emamectin benzoate, between glutathione S-transferase activity and resistance to any of the five pesticides tested, or between acetylcholine esterase activity and any of the pesticides except for emamectin benzoate. PMID- 24766445 TI - Pandemic lineages of extraintestinal pathogenic Escherichia coli. AB - Pathogenic Escherichia coli strains cause a wide variety of intestinal and extraintestinal infections. The widespread geographical clonal dissemination of intestinal pathogenic E. coli strains, such as E. coli O157:H7, is well recognized, and its spread is most often attributed to contaminated food products. On the other hand, the clonal dissemination of extraintestinal pathogenic E. coli (ExPEC) strains is also recognized, but the mechanism of their spread is not well explained. Here, I describe major pandemic clonal lineages of ExPEC based on multilocus sequence typing (MLST), and discuss possible reasons for their global dissemination. These lineages include sequence type (ST)131, ST393, ST69, ST95, and ST73, which are all associated with both community-onset and healthcare-associated infections, in particular urinary tract infections and bloodstream infections. As with many other types of drug-resistant Gram-negative and Gram-positive bacterial infections, drug-resistant ExPEC infections are recognized to be caused by a limited set of clonal lineages. However, reported observations on these major pandemic lineages suggest that the resistance phenotype is not necessarily the determinant of their clonal dissemination. Both epidemiological factors and their intrinsic biological 'fitness' are likely to contribute. An important public health and clinical concern is that pandemicity itself may be a determinant of progressive drug resistance acquisition by clonal lineages. New research is urgently needed to better understand the epidemiological and biological causes of ExPEC pandemicity. PMID- 24766446 TI - 2-Pyridylfuran: a new fluorescent tag for the analysis of carbohydrates. AB - We herein report the use of 1,3-di(2-pyridyl)-1,3-propanedione (DPPD) as a fluorogenic labeling reagent for sugars. Reaction of DPPD with the anomeric carbon affords a fluorescent 2-pyridylfuran (2-PF) moiety that permits the sensitive HPLC-based detection of monosaccharides. 2-PF-labeled monosaccharides can be easily separated and analyzed from mixtures thereof, and the reported protocol compares favorably with established labeling reagents such as 2 aminobenzoic acid (2-AA) and 1-phenyl-3-methyl-5-pyrazolone (PMP), ultimately allowing subfemtomole detection of the galactose-derived product. Furthermore, we demonstrate the application of DPPD in the labeling of monosaccharides in complex biological matrices such as blood and milk samples. We envisage that DPPD will prove to be an excellent choice of labeling reagent in monosaccharide and carbohydrate analysis. PMID- 24766447 TI - Evaluation of three reference genes of Escherichia coli for mRNA expression level normalization in view of salt and organic acid stress exposure in food. AB - Escherichia coli can adapt to various stress conditions encountered in food through induction of stress response genes encoding proteins that counteract the respective stresses. To understand the impact and the induction of these genes under food-associated stresses, changes in the levels of their mRNA expression in response to such stresses can be analysed. Relative quantification of mRNA levels by reverse transcription quantitative real-time polymerase chain reaction (RT qPCR) requires normalization to reference genes with stable expression under the experimental conditions being investigated. We examined the validity of three housekeeping genes (cysG, hcaT and rssA) among E. coli strains exposed to salt and organic acid stress. The rssA gene was shown to be the most stably expressed gene under such stress adaptation experimental models. The cysG gene was the least stable, whereas the hcaT gene showed similar interstrain variability as rssA but lower expression stability in the different stress adaptation models. PMID- 24766448 TI - Raman optical activity of enantiopure cryptophanes. AB - Raman optical activity (ROA) and density functional theory (DFT) calculations were used to determine the absolute configuration of enantiopure cryptophane molecules and to obtain conformational information about their three ethylenedioxy linkers. ROA spectra recorded in chloroform solution for the two resolved enantiomers of cryptophanes derivatives bearing five (2), six (1), nine (3 and 4), and 12 (5) methoxy substituents are presented for the first time. The number of methoxy substituents (cryptophanes 1, 3, and 5) and the arrangement of the three linkers (anti for 3 and syn for 4) are two important parameters that significantly affect the ROA spectra. DFT calculations, at the B3PW91/6-31G** level, for cryptophane bearing six methoxy substituents establish, besides the absolute configuration, the preferential all-trans conformation of the ethylenedioxy linkers of the chloroform-cryptophane complex. This study shows that the ROA/DFT approach exhibits a higher selectivity for the conformation of the linkers than vibrational circular dichroism (VCD) associated with theoretical calculations. PMID- 24766449 TI - Arterial function and cardiorenal damage. PMID- 24766450 TI - Subnormal levels of vitamin D are associated with acute wheeze in young children. AB - AIM: This study evaluated risk factors for acute wheeze in preschool children and investigated whether subnormal levels of vitamin D were associated with increased risk for acute wheeze, atopy or viral/bacterial respiratory infections. METHODS: We recruited 130 children with acute wheeze, aged 6 months to 4 years, from paediatric emergency departments in Stockholm, Sweden, and 101 age-matched controls with no history of wheeze or sensitisation to airborne allergens. Parents answered standardised questionnaires, and blood samples were analysed for specific IgE to airborne and food allergens and levels of 25 hydroxyvitamin D (25(OH)D). Nasopharyngeal virus samples were collected during the emergency department visit in the group of children with wheeze, and a subset were also tested for bacteria. RESULTS: Vitamin D insufficiency (25(OH)D < 75 nmol/L (30 ng/mL)) was associated with an odds ratio of 2.7 (95% confidence interval 1.1 6.2) for acute wheeze. However, no association was found between vitamin D insufficiency and atopy, presence of virus or bacteria or recurrent infections. Children older than 24 months were particularly at risk of subnormal vitamin D levels, irrespective of wheezing history. CONCLUSION: Our findings support the hypothesis that subnormal levels of vitamin D are associated with acute wheeze in young children. PMID- 24766451 TI - Pyrosequencing reveals bacterial communities in unchlorinated drinking water distribution system: an integral study of bulk water, suspended solids, loose deposits, and pipe wall biofilm. AB - The current understanding of drinking water distribution system (DWDS) microbiology is limited to pipe wall biofilm and bulk water; the contributions of particle-associated bacteria (from suspended solids and loose deposits) have long been neglected. Analyzing the composition and correlation of bacterial communities from different phases helped us to locate where most of the bacteria are and understand the interactions among these phases. In the present study, the bacteria from four critical phases of an unchlorinated DWDS, including bulk water, pipe wall biofilm, suspended solids, and loose deposits, were quantified and identified by adenosine triphosphate analysis and pyrosequencing, respectively. The results showed that the bulk water bacteria (including the contribution of suspended solids) contributed less than 2% of the total bacteria. The bacteria associated with loose deposits and pipe wall biofilm that accumulated in the DWDS accounted for over 98% of the total bacteria, and the contributions of bacteria in loose deposits and pipe wall biofilm were comparable. Depending on the amount of loose deposits, its contribution can be 7 fold higher than the pipe wall biofilm. Pyrosequencing revealed relatively stable bacterial communities in bulk water, pipe wall biofilm, and suspended solids throughout the distribution system; however, the communities present in loose deposits were dependent on the amount of loose deposits locally. Bacteria within the phases of suspended solids, loose deposits, and pipe wall biofilm were similar in phylogenetic composition. The bulk water bacteria (dominated by Polaromonas spp.) were clearly different from the bacteria from the other three phases (dominated by Sphingomonas spp.). This study highlighted that the integral DWDS ecology should include contributions from all of the four phases, especially the bacteria harbored by loose deposits. The accumulation of loose deposits and the aging process create variable microenvironments inside loose deposits structures for bacteria to grow. Moreover, loose deposits protect the associated bacteria from disinfectants, and due to their mobility, the associated bacteria reach taps easily. PMID- 24766452 TI - Systems vaccinology for cancer vaccine development. AB - Results of therapeutic vaccines for established chronic infections or cancers are still unsatisfactory. The only therapeutic cancer vaccine approved for clinical use is the sipuleucel-T, for the treatment of metastatic prostate cancer, which induces a limited 4-month improvement in the overall survival of vaccinated patients compared to controls. This represents a remarkable advancement in the cancer immunotherapy field, although the clinical outcome of cancer vaccines needs to be substantially improved. To this aim, a multipronged strategy is required, including the evaluation of mechanisms underlying the effective elicitation of immune responses by cancer vaccines. The recent development of new technologies and computational tools allows the comprehensive and quantitative analysis of the interactions between all of the components of innate and adaptive immunity over time. Here we review the potentiality of systems biology in providing novel insights in the mechanisms of action of vaccines to improve their design and effectiveness. PMID- 24766453 TI - Investigation of blast-induced traumatic brain injury. AB - OBJECTIVE: Many troops deployed in Iraq and Afghanistan have sustained blast related, closed-head injuries from being within non-lethal distance of detonated explosive devices. Little is known, however, about the mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI). This study attempts to identify the precise conditions of focused stress wave energy within the brain, resulting from blast exposure, which will correlate with a threshold for persistent brain injury. METHODS: This study developed and validated a set of modelling tools to simulate blast loading to the human head. Using these tools, the blast-induced, early-time intracranial wave motions that lead to focal brain damage were simulated. RESULTS: The simulations predict the deposition of three distinct wave energy components, two of which can be related to injury-inducing mechanisms, namely cavitation and shear. Furthermore, the results suggest that the spatial distributions of these damaging energy components are independent of blast direction. CONCLUSIONS: The predictions reported herein will simplify efforts to correlate simulation predictions with clinical measures of TBI and aid in the development of protective headwear. PMID- 24766455 TI - Stimulant doping agents used in Brazil: prevalence, detectability, analytical implications, and challenges. AB - This article presents the prevalence of stimulant doping among Brazilian athletes, the analytical approaches used, as well as a general evolution of the detectability of the stimulants being used. Results from the Brazilian accredited doping control laboratory are compared with the global statistics disclosed by the World Anti-Doping Agency. The high prevalence of stimulant doping in Brazil can be attributed to several reasons, including "self-administration," a "body shaping" culture, and the use of nutritional supplements. PMID- 24766454 TI - The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury: a novel mouse model of chronic traumatic encephalopathy. AB - There has been an increased focus on the neurological sequelae of repetitive mild traumatic brain injury (TBI), particularly neurodegenerative syndromes, such as chronic traumatic encephalopathy (CTE); however, no animal model exists that captures the behavioral spectrum of this phenomenon. We sought to develop an animal model of CTE. Our novel model is a modification and fusion of two of the most popular models of TBI and allows for controlled closed-head impacts to unanesthetized mice. Two-hundred and eighty 12-week-old mice were divided into control, single mild TBI (mTBI), and repetitive mTBI groups. Repetitive mTBI mice received six concussive impacts daily for 7 days. Behavior was assessed at various time points. Neurological Severity Score (NSS) was computed and vestibulomotor function tested with the wire grip test (WGT). Cognitive function was assessed with the Morris water maze (MWM), anxiety/risk-taking behavior with the elevated plus maze, and depression-like behavior with the forced swim/tail suspension tests. Sleep electroencephalogram/electromyography studies were performed at 1 month. NSS was elevated, compared to controls, in both TBI groups and improved over time. Repetitive mTBI mice demonstrated transient vestibulomotor deficits on WGT. Repetitive mTBI mice also demonstrated deficits in MWM testing. Both mTBI groups demonstrated increased anxiety at 2 weeks, but repetitive mTBI mice developed increased risk-taking behaviors at 1 month that persist at 6 months. Repetitive mTBI mice exhibit depression-like behavior at 1 month. Both groups demonstrate sleep disturbances. We describe the neurological sequelae of repetitive mTBI in a novel mouse model, which resemble several of the neuropsychiatric behaviors observed clinically in patients sustaining repetitive mild head injury. PMID- 24766456 TI - Ribonuclease PH interacts with an acidic ribonuclease E site through a basic 80 amino acid domain. AB - In this work, we characterize the domains for the in vivo interaction between ribonuclease E (RNase E) and ribonuclease PH (RNase PH). We initially explored the interaction using pull-down assays with full wild-type proteins expressed from a chromosomal monocopy gene. Once the interaction was confirmed, we narrowed down the sites of interaction in each enzyme to an acidic 16-amino acid region in the carboxy-terminal domain of RNase E and a basic 80-amino acid region in RNase PH including an alpha3 helix. Our results suggest two novel functional domains of interaction between ribonucleases. PMID- 24766457 TI - When does postnatal catch-up fat occur in late preterm infants? PMID- 24766458 TI - Weakly coupled biologically relevant Cu(II)2(MU-eta1:eta1-O2) cis-peroxo adduct that binds side-on to additional metal ions. AB - The ability of many copper metalloenzymes to activate O2 and transfer it to organic substrates has motivated extensive attention in the literature. Investigations focusing on synthetic analogues have provided a detailed understanding of the structures of potential intermediates, thereby helping to guide mechanistic studies. We report herein a crystallographically characterized synthetic Cu(II)2(MU-eta(1):eta(1)-O2) complex exhibiting cis-peroxo bonding geometry, known in iron chemistry but previously unobserved for copper. Detailed investigation by UV-vis, resonance Raman, and infrared spectroscopies provides evidence for a significantly diminished copper-oxygen interaction (epsilon ~ 3000 M(-1) cm(-1), nu(Cu-O) = 437 cm(-1), nu(O-O) = 799 cm(-1)) relative to those in known 'coupled' Cu2O2 species, consistent with magnetic measurements which show that the peroxide mediates only weak antiferromagnetic coupling (-2J = 144 cm( 1)). These characteristics are comparable with those of a computationally predicted transition state for O2 binding to type 3 copper centers, providing experimental evidence for the proposed mechanism of O2 activation and supporting the biological relevance of the Cu(II)2(MU-eta(1):eta(1)-O2) cis-species. The peroxide bonding arrangement also allows binding of sodium cations, observed both in the solid state and in solution. Binding induces changes on an electronic level, as monitored by UV-vis spectroscopy (K(a) = 1700 M(-1)), reminiscent of redox-inactive metal binding by iron-oxygen species. The results presented highlight the analogous chemistry these reactive oxygen species undergo, with respect to both their mechanism of formation, and the molecular interactions in which they participate. PMID- 24766460 TI - Targeting IL-6 for the treatment of rheumatoid arthritis: Phase II investigational drugs. AB - INTRODUCTION: IL-6 is a key cytokine in the pathogenesis of rheumatoid arthritis (RA). The clinical efficacy of tocilizumab (TCZ), a humanized anti-IL6-receptor mAb, confirmed the value of IL-6 blockade in this disease. A number of new anti IL-6 biologics are currently in Phase I - III of clinical development for RA. AREAS COVERED: This article reviews the available results from Phase II trials of investigational anti-IL-6 agents in RA. The authors discuss the potential relevance of alternative IL-6-blocking agents, with regard to their specific molecular targets in IL-6 signaling pathways and to the main open questions in the clinical research agenda for anti-IL-6 biologics. EXPERT OPINION: The results of Phase II trials of new anti-IL-6 biologics show promising results in terms of efficacy. The most frequently reported adverse events were not unexpected based on previous experience with TCZ. Further evidence is needed to appraise whether the difference in molecular structure or in the specific target of new anti-IL-6 biologics might result in added therapeutic value over TCZ. New data from Phase III trials that provides a head-to-head comparison against TCZ and anti-TNF agents with or without methotrexate background treatment are expected in the future. PMID- 24766459 TI - Insufficient interleukin-12 signalling favours differentiation of human CD4(+) and CD8(+) T cells into GATA-3(+) and GATA-3(+) T-bet(+) subsets in humanized mice. AB - Differentiation of CD4(+) T cells into type 1 or type 2 subsets is mediated by the expression of the opposing lineage defining transcription factors T-bet and GATA-3. However, the existence of GATA-3(+) T-bet(+) CD4(+) T cells in mice suggests functional plasticity of these subsets. Little is known about type 1 and type 2 plasticity of human T-cell subsets in vivo. Here, we show that in the xenogeneic environment of humanized mice, which lacks a functional immune regulatory network, human CD4(+) and, notably, CD8(+) T cells preferentially differentiate into interleukin (IL)-4(+) GATA-3(+) and IL-4(+) interferon gamma(+) GATA-3(+) T-bet(+) subsets. Treatment with recombinant human IL-12 or expansion of IL-12-producing human dendritic cells in vivo reverted this phenotype and led to the down-regulation of GATA-3 expression. These changes also correlated with improved antiviral immune responses in humanized mice. In conclusion, our study shows the capacity of human CD4(+) and CD8(+) T cells for stable co-expression of GATA-3 and T-bet in humanized mice and reveals a critical role for IL-12 in regulating this phenotype. PMID- 24766461 TI - A potential link among antioxidant enzymes, histopathology and trace elements in canine visceral leishmaniasis. AB - Canine visceral leishmaniasis (CVL) is a severe and fatal systemic chronic inflammatory disease. We investigated the alterations in, and potential associations among, antioxidant enzymes, trace elements and histopathology in CVL. Blood and tissue levels of Cu-Zn superoxide dismutase, catalase and glutathione peroxidase were measured in mixed-breed dogs naturally infected with Leishmania infantum chagasi, symptomatic (n = 19) and asymptomatic (n = 11). Serum levels of copper, iron, zinc, selenium and nitric oxide, and plasma lipid peroxidation were measured. Histological and morphometric analyses were conducted of lesions in liver, spleen and lymph nodes. We found lower blood catalase and glutathione peroxidase activity to be correlated with lower iron and selenium respectively. However, higher activity of Cu-Zn superoxide dismutase was not correlated with the increase in copper and decreased in zinc observed in infected animals compared to controls. Organ tissue was characterized by lower enzyme activity in infected dogs than in controls, but this was not correlated with trace elements. Lipid peroxidation was higher in symptomatic than in asymptomatic and control dogs and was associated with lesions such as chronic inflammatory reaction, congestion, haemosiderin and fibrosis. Systemic iron deposition was observed primarily in the symptomatic dogs showing a higher tissue parasite load. Dogs with symptomatic CVL displayed enhanced LPO and Fe tissue deposition associated with decreased levels of antioxidant enzymes. These results showed new points in the pathology of CVL and might open new treatment perspectives associated with antioxidants and the role of iron in the pathogenesis of CVL. PMID- 24766463 TI - Children's learning of number words in an indigenous farming-foraging group. AB - We show that children in the Tsimane', a farming-foraging group in the Bolivian rain-forest, learn number words along a similar developmental trajectory to children from industrialized countries. Tsimane' children successively acquire the first three or four number words before fully learning how counting works. However, their learning is substantially delayed relative to children from the United States, Russia, and Japan. The presence of a similar developmental trajectory likely indicates that the incremental stages of numerical knowledge - but not their timing - reflect a fundamental property of number concept acquisition which is relatively independent of language, culture, age, and early education. PMID- 24766462 TI - Early and late HIV-1 membrane fusion events are impaired by sphinganine lipidated peptides that target the fusion site. AB - Lipid-conjugated peptides have advanced the understanding of membrane protein functions and the roles of lipids in the membrane milieu. These lipopeptides modulate various biological systems such as viral fusion. A single function has been suggested for the lipid, binding to the membrane and thus elevating the local concentration of the peptide at the target site. In the present paper, we challenged this argument by exploring in-depth the antiviral mechanism of lipopeptides, which comprise sphinganine, the lipid backbone of DHSM (dihydrosphingomyelin), and an HIV-1 envelope-derived peptide. Surprisingly, we discovered a partnership between the lipid and the peptide that impaired early membrane fusion events by reducing CD4 receptor lateral diffusion and HIV-1 fusion peptide-mediated lipid mixing. Moreover, only the joint function of sphinganine and its conjugate peptide disrupted HIV-1 fusion protein assembly and folding at the later fusion steps. Via imaging techniques we revealed for the first time the direct localization of these lipopeptides to the virus-cell and cell-cell contact sites. Overall, the findings of the present study may suggest lipid-protein interactions in various biological systems and may help uncover a role for elevated DHSM in HIV-1 and its target cell membranes. PMID- 24766465 TI - Clonal dominance and clonal evolution in a patient with a "chronic myeloid neoplasm": a challenge in management. PMID- 24766464 TI - Oral hygiene behaviors and caries experience in Northwest PRECEDENT patients. AB - OBJECTIVES: To investigate the association between oral hygiene behaviors (toothbrushing, water rinsing after brushing, interproximal cleaning, and adjunctive use of fluoride products) and recent caries (past 24 months) in a random sample of patients in Northwest PRECEDENT practices. METHODS: Practitioner members of Northwest PRECEDENT, a dental practice-based research network, conducted a longitudinal study on caries risk assessment. At baseline, patients completed a questionnaire on oral self-care, snacking, health, and socio demographics. A dental examination recorded readily visible heavy plaque and decayed, missing, and filled teeth; chart review captured new caries and treatments in the previous 24 months. Bivariate and multiple generalized estimating equations (GEE) log-linear regression models stratified by age-groups were used to relate oral hygiene behaviors to the primary outcome of mean dental caries in the past 24 months on data from 1400 patients in 63 practices. The primary exposure of interest was fluoride toothbrushing frequency. RESULTS: Fluoride toothbrushing once per day or twice or more per day by patients 9-17 was significantly associated with a 50% lower mean caries rate compared with fluoride toothbrushing less than once per day, after adjustment for covariates [rate ratios (RR) = 0.5; 95% confidence intervals (CI) = 0.3-0.8]. After adjustment, for patients 18-64, fluoride toothbrushing two or more times per day was significantly associated with a 40% lower recent mean caries rate (RR = 0.6; 95% CI = 0.4-0.9); in patients 65+, twice a day or more fluoride toothbrushing was not associated with lower caries rates (RR = 1.1; 95% CI = 0.7-1.8). Of the other oral hygiene variables, after adjustment, patients 18-64 who rinsed with water after brushing had a 40% lower mean caries rate compared with no rinsing (RR = 0.6; 95% CI = 0.4-0.9) and the presence of readily visible heavy plaque was significantly associated with an increase in the mean caries rate for patients 18 64 (RR = 1.6; 95% CI = 1.2-2.2) and 65+ (RR = 2.5; 95% CI = 1.8-3.5). CONCLUSIONS: In the present study, the frequency of fluoride toothbrushing and the presence of readily visible heavy plaque were the factors most strongly associated with mean caries rate. In young patients with permanent dentition, the daily application of fluoride toothpaste appears more important than emphasis on thorough plaque removal. While for adults, the protective effect of twice daily fluoride toothbrushing disappears with advancing age and the presence of readily visible heavy plaque becomes increasingly associated with caries risk. PMID- 24766466 TI - Infection in chronic lymphocytic leukemia: parsimony has its limits. PMID- 24766467 TI - Successful management of Rothia aeria pneumonia during the peritransplant period: first reported case in allogeneic hematopoietic stem cell transplant. PMID- 24766468 TI - Bone marrow involvement in nodular lymphocyte predominant Hodgkin lymphoma occurs in tumors with a variant pattern. PMID- 24766469 TI - Emerging therapies for refractory chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) that becomes refractory to chemotherapy is associated with a poor outcome. For these patients, some of the novel substances that are currently in clinical development for CLL seem to offer new hope. These agents include small molecules, new antibodies, immunomodulators, kinase inhibitors, BCL-2 antagonists and chimeric antigen receptor transduced T-cells (CARTs) and combine high efficacy with a good safety profile. To date, allogeneic stem cell transplant remains the only curative treatment option for patients with relapsed, refractory CLL. However, it is possible that new substances will replace allogeneic stem cell transplant in the near future. This review provides an overview of the currently available data and an outlook on future therapies for chemotherapy refractory CLL. PMID- 24766470 TI - Dual inhibition of phosphatidylinositol 3-kinase/mammalian target of rapamycin and mitogen activated protein kinase pathways in non-Hodgkin lymphoma. PMID- 24766471 TI - Ruxolitinib in combination with DNA methyltransferase inhibitors: clinical responses in patients with symptomatic myelofibrosis with cytopenias and elevated blast(s) counts. PMID- 24766472 TI - Sexing live pupae and adults of two wax blooming beetles, Colposcelis microderoides microderoides and Anatolica polita borealis. AB - The wax blooming beetles Colposcelis microderoides microderoides Reitter and Anatolica polita borealis Kaszab (Coleoptera: Tenebrionidae) are small, flightless beetles living in the Guerbantonggut desert in the northwestern region of China. These beetles were recently found to have wax blooms, and their short life cycle and ease of rearing under laboratory conditions make them excellent models for advanced studies on desert adaptation. To date, dissection has been used for sex identification in these species, whereas a nondestructive method is needed for further studies on sexual dimorphism. Microscopic examinations of pupae and adults revealed distinct differences between the sexes in the 8th abdominal sternites, including the presence of a setose cleft in adult males that is not visible in females, in which the 8th sternite forms a single semicircular plate. The female pupae have a pair of tan papillae and a tan genital orifice, which are absent on the male 8th sternite. These two sexual characteristics can be used to sex live adults and pupae. These methods are simple, nondestructive, 100% accurate, and useful for sex differentiation of dead beetles and some other tenebrionid species (including some pests) in both the field and the laboratory. PMID- 24766474 TI - Direct detection and speciation of trace explosives using a nanoporous multifunctional microcantilever. AB - We have developed a highly selective and sensitive nanomechanical infrared (IR) calorimetric spectrometer for use in the direct detection of ultralow concentrations of explosive vapors using a nanoporous TiO2 cantilever. These cantilevers were fabricated using a two-step anodization and photolithography process. By patterning nanoscale wells onto a cantilever, its surface area is increased by 2 orders of magnitude and the surface is converted into a preconcentrator. Resonant excitation of adsorbed molecules using IR radiation causes the cantilever to bend due to temperature changes originating from the nonradiative decay process. The porous structure of the cantilever increases its thermomechanical sensitivity as well as the number of adsorbed molecules. The system performance was demonstrated by detecting binary explosive mixtures under ambient conditions. The TiO2 sensor surface also allows regeneration through the photocatalytic decomposition of adsorbates under UV irradiation. PMID- 24766475 TI - Securing access to effective antibiotics for current and future generations. Whose responsibility? PMID- 24766477 TI - Neisseria meningitidis; clones, carriage, and disease. AB - Neisseria meningitidis, the cause of meningococcal disease, has been the subject of sophisticated molecular epidemiological investigation as a consequence of the significant public health threat posed by this organism. The use of multilocus sequence typing and whole genome sequencing classifies the organism into clonal complexes. Extensive phenotypic, genotypic and epidemiological information is available on the PubMLST website. The human nasopharynx is the sole ecological niche of this species, and carrier isolates show extensive genetic diversity as compared with hyperinvasive lineages. Horizontal gene exchange and recombinant events within the meningococcal genome during residence in the human nasopharynx result in antigenic diversity even within clonal complexes, so that individual clones may express, for example, more than one capsular polysaccharide (serogroup). Successful clones are capable of wide global dissemination, and may be associated with explosive epidemics of invasive disease. PMID- 24766476 TI - Uninterrupted warfarin anticoagulation for atrial fibrillation ablation: too good to be true? PMID- 24766478 TI - Semi-volatile organic compounds in heating, ventilation, and air-conditioning filter dust in retail stores. AB - Retail stores contain a wide range of products that can emit a variety of indoor pollutants. Among these chemicals, phthalate esters and polybrominated diphenyl ethers (PBDEs) are two important categories of semi-volatile organic compounds (SVOCs). Filters in heating, ventilation, and air-conditioning (HVAC) system collect particles from large volumes of air and thus potentially provide spatially and temporally integrated SVOC concentrations. This study measured six phthalate and 14 PBDE compounds in HVAC filter dust in 14 retail stores in Texas and Pennsylvania, United States. Phthalates and PBDEs were widely found in the HVAC filter dust in retail environment, indicating that they are ubiquitous indoor pollutants. The potential co-occurrence of phthalates and PBDEs was not strong, suggesting that their indoor sources are diverse. The levels of phthalates and PBDEs measured in HVAC filter dust are comparable to concentrations found in previous investigations of settled dust in residential buildings. Significant correlations between indoor air and filter dust concentrations were found for diethyl phthalate, di-n-butyl phthalate, and benzyl butyl phthalate. Reasonable agreement between measurements and an equilibrium model to describe SVOC partitioning between dust and gas-phase is achieved. PMID- 24766479 TI - HAGE, the helicase antigen as a biomarker for breast cancer prognosis (WO2013144616). AB - INTRODUCTION: Breast cancer (BC) is the most common cancer in women and it ranks second as a cause of cancer death in women (after lung cancer). The receptor based diagnosis of BC tumors allows application of more individual therapies. Depending on the status of the receptors and other risk markers, like tumor size and lymph node status, patients are assigned to risk classes. Invention of new biomarkers that could improve diagnosis and prognosis of BC patients is thus of an increased need. AREAS COVERED: The invention estimates the possibility of using the amount of expression of helicase antigen (HAGE) in samples of BC tissue as a biomarker for screening and prognosis. A total of 1650 BC patients were tested for HAGE expression and analyzed for well-characterized prognostic and predictive factors. HAGE expression was found to correlate significantly with aggressive clinicopathological features. A total of 443 triple negative patients were analyzed for therapeutic treatment received and survival. The HAGE expression was identified as a predictor of response to anthracycline treatment. The result was confirmed by comparison with an independent validation group. EXPERT OPINION: To identify patients who could be treated, a more detailed analysis taking into account, the full distribution spectrum of HAGE expression is desirable. PMID- 24766480 TI - Vibrational dynamics in dendridic oligoarylamines by Raman spectroscopy and incoherent inelastic neutron scattering. AB - Vibrational dynamics in triarylamine dendrimers was studied in a complementary way by Raman and infrared (IR) spectroscopies and incoherent inelastic neutron scattering (IINS). Three molecules were investigated, namely, unsubstituted triarylamine dendrimer of the first generation and two dendrimers of the first and second generation, substituted in the crown with butyl groups. To facilitate the assignment of the observed IR and Raman modes as well as the IINS peaks, vibrational models, based on the general valence force field method (GVFF), were calculated for all three compounds studied. A perfect consistency between the calculated and experimental results was found. Moreover, an important complementarity of the vibrational spectroscopies and IINS was established for the investigated dendrimers. The IINS peaks originating mainly from the C-H motions were not restricted by particular selection rules and only dependent on the IINS cross section. To the contrary, Raman and IR bands were imposed by the selection rules and the local geometry of the dendrimers yielding mainly C-C and C-N deformation modes with those of C-H nature of much lower intensity. Raman spectroscopy was also applied to the studies of the oxidation of dendrimers to their cationic forms. A strong Raman resonance effect was observed, since the spectra of the studied compounds, registered at different levels of their oxidation, strongly depended on the position of the excitation line with respect to their electronic spectrum. In particular, the blue (458 nm) excitation line turned out to be insensitive toward the cationic forms yielding very limited spectral information. To the contrary, the use of the red (647 nm) and infrared (1064 nm) excitation lines allowed for an unambiguous monitoring of the spectral changes in dendrimers oxidized to nominally monocationic and tricationic states. The analysis of oxidation-induced spectral changes in the tricationic state indicated that the charge storage configuration predominantly involved one spinless dication of the quinoid bond sequence and one radical cation. However, small numbers of dications were also found in a nominally monocationic state, where only radical cations should have been present. This finding was indicative of some inhomogeneity of the oxidation. PMID- 24766481 TI - Authors' Response to Letters to the Editor Re: Interpreting cobalt blood concentrations in hip implant patients. PMID- 24766482 TI - Homogeneous and heterogeneous noncovalent dimers of formaldehyde and thioformaldehyde: structures, energetics, and vibrational frequencies. AB - This work provides the first characterization of five stationary points of the homogeneous thioformaldehyde dimer, (CH2S)2, and seven stationary points of the heterogeneous formaldehyde/thioformaldehyde dimer, CH2O/CH2S, with correlated ab initio electronic structure methods. Full geometry optimizations and corresponding harmonic vibrational frequencies were computed with second-order Moller-Plesset perturbation theory (MP2) and 13 different density functionals in conjunction with triple-zeta basis sets augmented with diffuse and multiple sets of polarization functions. The MP2 results indicate that the three stationary points of (CH2S)2 and four of CH2O/CH2S are minima, in contrast to two stationary points of the formaldehyde dimer, (CH2O)2. Single-point energies were also computed using the explicitly correlated MP2-F12 and CCSD(T)-F12 methods and basis sets as large as heavy-aug-cc-pVTZ. The (CH2O)2 and CH2O/CH2S MP2 and MP2 F12 binding energies deviated from the CCSD(T)-F12 binding energies by no more than 0.2 and 0.4 kcal mol(-1), respectively. The (CH2O)2 and CH2O/CH2S global minimum is the same at every level of theory. However, the MP2 methods overbind (CH2S)2 by as much as 1.1 kcal mol(-1), effectively altering the energetic ordering of the thioformaldehyde dimer minima relative to the CCSD(T)-F12 energies. The CCSD(T)-F12 binding energies of the (CH2O)2 and CH2O/CH2S stationary points are quite similar, with the former ranging from around -2.4 to 4.6 kcal mol(-1) and the latter from about -1.1 to -4.4 kcal mol(-1). Corresponding (CH2S)2 stationary points have appreciably smaller CCSD(T)-F12 binding energies ranging from ca. -1.1 to -3.4 kcal mol(-1). The vibrational frequency shifts upon dimerization are also reported for each minimum on the MP2 potential energy surfaces. PMID- 24766483 TI - Total and methylated mercury in Arctic multiyear sea ice. AB - Mercury is one of the primary contaminants of concern in the Arctic marine ecosystem. While considerable efforts have been directed toward understanding mercury cycling in the Arctic, little is known about mercury dynamics within Arctic multiyear sea ice, which is being rapidly replaced with first-year ice. Here we report the first study on the distribution and potential methylation of mercury in Arctic multiyear sea ice. Based on three multiyear ice cores taken from the eastern Beaufort Sea and McClure Strait, total mercury concentrations ranged from 0.65 to 60.8 pM in bulk ice, with the highest values occurring in the topmost layer (~40 cm) which is attributed to the dynamics of particulate matter. Methylated mercury concentrations ranged from below the method detection limit (<0.1 pM) to as high as 2.64 pM. The ratio of methylated to total mercury peaked, up to ~40%, in the mid to bottom sections of the ice, suggesting the potential occurrence of in situ mercury methylation. The annual fluxes of total and methylated mercury into the Arctic Ocean via melt of multiyear ice are estimated to be 420 and 42 kg yr(-1), respectively, representing an important and changing source of mercury and methylmercury into the Arctic Ocean marine ecosystem. PMID- 24766484 TI - Blood pressure variability in children with primary vs secondary hypertension. AB - Increased blood pressure variability (BPV) is correlated with adverse cardiovascular (CV) events in adults. However, there has been limited research on its effect in the pediatric population. Additionally, BPV differences between primary and secondary hypertension (HTN) are not known. Children with primary and secondary HTN underwent 24-hour ambulatory blood pressure monitoring and echocardiography studies. BPV measures of standard deviation (SD), average real variability (ARV), and range were calculated for the 24-hour, daytime, and nighttime periods. Seventy-four patients (median age, 13.5 years; 74% boys) were examined, 40 of whom had primary HTN. Body mass index z score and age were independent predictors of systolic ARV (R(2) =0.14) and SD (R(2) =0.39). There were no statistically significant differences in overall or wake period BPV measures between secondary or primary HTN groups, but sleep period diastolic SD was significantly greater in the secondary HTN group (9.26+/-3.8 vs 7.1+/-2.8, P=.039). On multiple regression analysis, secondary HTN was associated with increased sleep period diastolic SD (P=.025). No metrics of BPV in the overall, wake, and sleep periods were found to be significantly associated with left ventricular hypertrophy (LVH). The results of this study do not show a strong relationship between overall or wake BPV with primary vs secondary HTN, but the association of secondary HTN with sleep period diastolic BPV deserves further exploration. Contrary to expectation, the findings of this study failed to indicate a relationship between BPV and LVH for all patients as well for primary hypertensive and secondary hypertensive patients. PMID- 24766485 TI - Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice. AB - Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2alpha (eIF2alpha), inositol-requiring enzyme 1alpha (IRE1alpha) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor 4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a 'pathological' response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis. PMID- 24766486 TI - Empowerment programme for parents of extremely premature infants significantly reduced length of stay and readmission rates. AB - AIM: Extremely premature infants experience long hospitalisation and high readmission rates within 30 days of discharge. This quality control investigation retrospectively explored the impact of the Creating Opportunities for Parent Empowerment (COPE(c)) programme on these rates in an all referral, Level-IV small baby intensive care unit setting. METHODS: The parents of 303 extremely premature infants participated in the study. Of those, 135 were admitted before the implementation of COPE(c) and served as baseline historical controls, and the remaining 168 neonates received the intervention. Length of stay and readmission rates were analysed using parametric and nonparametric tests. Additional analyses were used to compare the two groups in terms of gestational age, birthweight and other acuity measures. RESULTS: Neonates who received COPE(c) required significantly reduced lengths of stay than the control neonates (COPE(c) 127.1 +/ 55.8 days vs. control 139.6 +/- 61.9 days, p < 0.05) and significantly lower readmission rates (COPE(c) 23.9% vs. control 13.2%, p = 0.05). CONCLUSION: The COPE(c) programme promoted active parental engagement in the unit and significantly reduced hospital stays and readmission rates. Future interventions should identify the specific components of the programme that support the parents of extremely premature infants during the various phases of hospitalisation. PMID- 24766488 TI - Characterization of tetA-like gene encoding for a major facilitator superfamily efflux pump in Streptococcus thermophilus. AB - Efflux pumps are membrane proteins involved in the active extrusion of a wide range of structurally dissimilar substrates from cells. A multidrug efflux pump named TetA belonging to the major facilitator superfamily (MFS) of transporters was identified in the Streptococcus thermophilus DSM 20617(T) genome. The tetA like gene was found in the genomes of a number of S. thermophilus strains sequenced to date and in Streptococcus macedonicus ACA-DC 198, suggesting a possible horizontal gene transfer event between these two Streptococcus species, which are both adapted to the milk environment. Flow cytometry (single-cell) analysis revealed bistable TetA activity in the S. thermophilus population, and tetA-like gene over-expression resulted in a reduced susceptibility to ethidium bromide, tetracycline, and other toxic compounds even when the efflux pump was over-expressed in a strain naturally lacking tetA-like gene. PMID- 24766490 TI - Regretful liaisons: exploring the role of partner regret in the association between sexual and relationship satisfaction. AB - Regrets over partner selection can negatively influence romantic relationship functioning. It may even undermine stability in otherwise satisfied unions. The present study extends research on partner regret by exploring its several possible links with sexual satisfaction and satisfaction with the relationship as a whole. The authors analyzed data provided by 351 individuals using path analysis. Primary findings indicate that partner regret reduces sexual satisfaction by first depreciating satisfaction with the relationship as a whole. This effect was especially pronounced for parents and women. Implications for assessment and targeted interventions for partner regret are discussed. PMID- 24766487 TI - Wogonin prevents lipopolysaccharide-induced acute lung injury and inflammation in mice via peroxisome proliferator-activated receptor gamma-mediated attenuation of the nuclear factor-kappaB pathway. AB - Acute lung injury (ALI) from a variety of clinical disorders, characterized by diffuse inflammation, is a cause of acute respiratory failure that develops in patients of all ages. Previous studies reported that wogonin, a flavonoid-like chemical compound which was found in Scutellaria baicalensis, has anti inflammatory effects in several inflammation models, but not in ALI. Here, the in vivo protective effect of wogonin in the amelioration of lipopolysaccharide (LPS) -induced lung injury and inflammation was assessed. In addition, the in vitro effects and mechanisms of wogonin were studied in the mouse macrophage cell lines Ana-1 and RAW264.7. In vivo results indicated that wogonin attenuated LPS-induced histological alterations. Peripheral blood leucocytes decreased in the LPS induced group, which was ameliorated by wogonin. In addition, wogonin inhibited the production of several inflammatory cytokines, including tumour necrosis factor-alpha, interleukin-1beta (IL-1beta) and IL-6, in the bronchoalveolar lavage fluid and lung tissues after LPS challenge, while the peroxisome proliferator-activated receptor gamma (PPARgamma) inhibitor GW9662 reversed these effects. In vitro results indicated that wogonin significantly decreased the secretion of IL-6, IL-1beta and tumour necrosis factor-alpha in Ana-1 and RAW264.7 cells, which was suppressed by transfection of PPARgamma small interfering RNA and GW9662 treatment. Moreover, wogonin activated PPARgamma, induced PPARgamma-mediated attenuation of the nuclear translocation and the DNA binding activity of nuclear factor-kappaB in vivo and in vitro. In conclusion, all of these results showed that wogonin may serve as a promising agent for the attenuation of ALI-associated inflammation and pathology by regulating the PPARgamma-involved nuclear factor-kappaB pathway. PMID- 24766491 TI - Childhood acute lymphoblastic leukemia: 12 years of experience, using a Berlin Frankfurt-Munster approach, in a Greek center. PMID- 24766492 TI - CD68-positive tumor-associated macrophages predict unfavorable treatment outcomes in classical Hodgkin lymphoma in correlation with interim fluorodeoxyglucose positron emission tomography assessment. AB - Finding new prognostic factors to identify patients with Hodgkin lymphoma (HL) at risk of treatment resistance or relapse remains challenging in daily practice. We evaluated the relationship between CD68 expression, interim positron emission tomography (iPET) results and outcome in 158 patients with HL diagnosed from February 1995 to July 2011. Immunohistochemistry (anti-CD68) gave two groups: low with <=25% positive cells (121 patients) and high with >25% (37 patients). Five year overall survival was higher in the low group (88.4% vs. 63.2%, p=0.0151), as was progression-free survival (74.5% vs. 40.7%, p=0.0003). In 68 patients evaluable, iPET correlated with CD68: 13/52 patients (25%) in the low group had positive iPET as compared to 11/16 patients (68%) in the high group (p=0.0016). This study confirms the prognostic value of CD68 in HL. We found a correlation between CD68 and iPET suggesting potential for a better stratification. PMID- 24766493 TI - Reproduction of the solenopsis mealybug, Phenacoccus solenopsis: males play an important role. AB - The solenopsis mealybug, Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae), is an aggressive pest threatening crops worldwide. The biology of P. solenopsis has been described in several studies, but detailed information on the reproduction of P. solenopsis has not been investigated. The results of our study showed: 1) no progeny could be produced by virgins; 2) apoptosis of follicle cells, which occurs when the eggs begin to develop, did not happen in virgins; and 3) oosorption occurred in the unfertilized eggs. This suggests that P. solenopsis is an obligate amphimictic species, and resorption of developed eggs fits the "wait to reproduce" oosorption hypothesis. Compared to females that mated when they were two days old, the females that mated 30 days after eclosion had lower reproductive output and longer adult lifespans, but had higher reproductive output and shorter lifespan than those of the unmated females. Such a phenomenon suggests that resources obtained from eggs can be allocated for survival until conditions for reproduction improve. The results of this study provide evidence for a trade-off between survival and future reproduction: delayed reproductive conditions trigger physiological states geared toward survival at the expense of reproduction. The mating history of the males had no effect on progeny production. PMID- 24766494 TI - Random mutagenesis of BoNT/E Hc nanobody to construct a secondary phage-display library. AB - AIMS: To construct secondary mutant phage-display library of recombinant single variable domain (VHH) against botulinum neurotoxin E by error-prone PCR. METHODS AND RESULTS: The gene coding for specific VHH derived from the camel immunized with binding domain of botulinum neurotoxin E (BoNT/E) was amplified by error prone PCR. Several biopanning rounds were used to screen the phage-displaying BoNT/E Hc nanobodies. The final nanobody, SHMR4, with increased affinity recognized BoNT/E toxin with no cross-reactivity with other antigens especially with related BoNT toxins. CONCLUSIONS: The constructed nanobody could be a suitable candidate for VHH-based biosensor production to detect the Clostridium botulinum type E. SIGNIFICANCE AND IMPACT OF THE STUDY: Diagnosis and treatment of botulinum neurotoxins are important. Generation of high-affinity antibodies based on the construction of secondary libraries using affinity maturation step leads to the development of reagents for precise diagnosis and therapy. PMID- 24766496 TI - New Ce3+-activated thiosilicate phosphor for LED lighting-synthesis, luminescence studies, and applications. AB - A new Ce(3+)-activated thiosilicate phosphor, BaLa2Si2S8:Ce(3+), was synthesized by using solid-state methods in a fused silica ampule and found to crystallize in the structure type of La2PbSi2S8. The crystal structure has been characterized by synchrotron X-ray diffraction and refined with Rietveld methods. This novel cyan emitting phosphor can be excited over a broad range from UV to blue light (380 450 nm) and generates a broadband emission peaking at 471 nm with a quantum efficiency of 36%. Nonradiative transitions between Ce(3+) ions in BaLa2Si2S8:Ce(3+) have also been demonstrated to be attributable to dipole-dipole interactions, and the critical distance was calculated to be 17.41 A. When BaLa2Si2S8:Ce(3+) phosphor was utilized to incorporate with yellow-emitting (Sr,Ca)2SiO4:Eu(2+) phosphor and red-emitting CaAlSiN3:Eu(2+) phosphor on a 430 nm blue LED chip, a warm white light LED device with color rendering index of ~96 was obtained. The results indicate that cyan-emitting BaLa2Si2S8:Ce(3+) can serve as a potential phosphor for incorporation in fabrication of solid-state lighting. The preparation, spectroscopic characterization, quantum efficiency, decay lifetime, thermal-quenching behavior, and related LED device data are also presented. PMID- 24766495 TI - Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. AB - AIM: To assess the efficacy and safety of the novel sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin compared with placebo or other antidiabetic agents in patients with type 2 diabetes. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials. We searched Medline, Embase and the Cochrane Library through December 2013 and grey literature. Two reviewers working independently extracted relevant data and carried out risk-of bias assessments. We synthesized results using random-effects models and computed weighted mean differences (WMDs) and odds ratios (ORs). RESULTS: We included 10 studies with 6203 participants. Compared with placebo, mean changes in haemoglobin A1c were -0.62% [95% confidence interval (CI) -0.68 to -0.57%] for empagliflozin 10 mg and -0.66% (-0.76 to -0.57%) for empagliflozin 25 mg. Empagliflozin 25 mg daily had glycaemic efficacy similar to metformin or sitagliptin (WMD -0.11%; 95% CI -0.25 to 0.03%), without increasing risk for hypoglycaemia. It was also associated with body weight loss (WMD -1.84; 95% CI 2.30 to -1.38 kg vs. placebo) and had a favourable effect on blood pressure. Incidence of hypoglycaemia with empagliflozin was similar to placebo (OR 1.10; 95% CI 0.87 to 1.39); nevertheless we noted an increased risk for genital tract infections (OR 3.31; 95% CI 1.55 to 7.09). Findings were similar for the 10-mg dosing regimen. CONCLUSIONS: Empagliflozin effectively lowers blood glucose and provides additional clinical benefits including body weight and blood pressure reduction. Ongoing trials will elucidate the long-term safety and effect of empagliflozin on cardiovascular outcomes. PMID- 24766497 TI - Sport's doping problem: a rational solution--allow drugs. PMID- 24766498 TI - Apparent Failure to Sense during Temporary Pacing with a Permanent Pulse Generator. PMID- 24766499 TI - Chronic consumption of alcohol and sperm parameters: our experience and the main evidences. AB - The present article describes the recent clinical experience and the main clinical and experimental evidences on this topic. In the first part, we present retrospective data collected over the last year on the semen quality and hormonal characteristics of the alcohol consumers evaluated in our centre. In the second part, we describe the mechanisms by which chronic alcohol intoxication impairs the testicular function (evidences for an ethanol-mediated effect at pre testicular/testicular and post-testicular level). In the third part, we present data on ethanol taken a male risk factor of infertility, being present as one among other recreational drugs (also called lifestyle). Finally, is discussed the role of individual susceptibility factors and other variables. PMID- 24766500 TI - Design and biosensing of Mg2+-dependent DNAzyme-triggered ratiometric electrochemiluminescence. AB - A dual-potential ratiometric electrochemiluminescence (ECL) sensing approach based on Mg(2+)-dependent DNAzyme-regulated ECL signals of luminol and CdS quantum dots (QDs) is designed. The system consists of DNAzyme strand functionalized QDs as capture probes and cathode ECL emitters, luminol-reduced gold nanoparticles (Au@luminol) as anode ECL emitters, and a Mg(2+) substrate strand modified with a cyanine dye (Cy5) fluorophore as the quencher. In the absence of Mg(2+) ions, the cathode ECL of the QDs is quenched by electrochemiluminescence resonance energy transfer between CdS QDs and Cy5 molecule, while the anode ECL from Au@luminol is introduced into the system. On the other hand, in the presence of Mg(2+) ions, the DNAzyme cleaves the substrate strand, and then releases the Cy5 and Au@luminol, which results in the recovery of the cathode ECL of the QDs and the decrease of the anode ECL simultaneously. On the basis of the ratio of ECL intensities at two excitation potentials, this approach was demonstrated to yield a linear calibration range from 10 to 10,000 MUM Mg(2+) before it was applied to Mg(2+) detection in Hela cell extract. DNAzyme-triggered ratiometric ECL strategy with potential resolution would provide a reliable and sensitive method in biosensing and clinical diagnosis. PMID- 24766501 TI - Cerebral cyst formation following stereotactic ablative irradiation for non nasopharyngeal head and neck malignancies: imaging findings and relevant dosimetric parameters. AB - OBJECTIVE: To describe the clinical characteristics, imaging findings and relevant dosimetric parameters of cases presenting with cerebral cyst formation (CCF) after single or oligo-fractionated stereotactic radiotherapy (SRT) for non nasopharyngeal head and neck malignancies (HNMs). METHODS: We identified four cases with the follow-up duration of 5.7-9.1 years from SRT. The irradiated sites included the middle ear in one case and the ethmoid sinus in three cases, two of the latter possessed brain invasion. The chronological changes in MR images and the dose-volume histogram of the adjacent brain tissue were evaluated. RESULTS: CCF with or without multiple septi presented with a latency of 29-86 months (median, 45.5 months), which was preceded by either non-specific parenchymal enhancement or typical radiation necrosis. In three cases, CCF adjacent to the frontal base resultantly caused mass effect, and two of these three cases required surgical intervention at 38 and 54 months, respectively, after SRT for alleviation of symptoms. The relation of the irradiated brain volumes to the biological equivalent dose based on the linear-quadratic (LQ) and LQ-cubic models was represented as a threshold. CONCLUSION: When contemplating SRT for HNM cases, caution should be exercised to the dose-volume relation-ship of the adjacent brain tissue, especially the frontal base, as well as other critical structures, and long-term vigilant follow-up is also mandatory. ADVANCES IN KNOWLEDGE: CCF can occur as an unusual consequence of late brain injury with variable but mostly long latency following SRT for non-nasopharyngeal HNMs adjacent to the brain, even superficial parts that were previously irradiated via conventional radiotherapy. PMID- 24766502 TI - Genotyping, local prevalence and international dissemination of beta-lactamase producing Kingella kingae strains. AB - beta-lactamase production has been sporadically reported in the emerging Kingella kingae pathogen but the phenomenon has not been studied in-depth. We investigated the prevalence of beta-lactamase production among K. kingae isolates from different geographical origins and genetically characterized beta-lactamase producing strains. Seven hundred and seventy-eight isolates from Iceland, the USA, France, Israel, Spain and Canada were screened for beta-lactamase production and, if positive, were characterized by PFGE and MLST genotyping, as well as rtxA, por, blaTEM and 16S rRNA sequencing. beta-lactamase was identified in invasive strains from Iceland (n=4/14, 28.6%), the USA (n=3/15, 20.0%) and Israel (n=2/190, 1.1%) and in carriage strains in the USA (n=5/17, 29.4%) and Israel (n=66/429, 15.4%). No French, Spanish or Canadian isolates were beta-lactamase producers. Among beta-lactamase producers, a perfect congruency between the different typing methods was observed. Surprisingly, all US and Icelandic beta lactamase-producing isolates were almost indistinguishable, belonged to the major international invasive PFGE clone K/MLST ST-6, but differed from the four genetically unrelated Israeli beta-lactamase-producing clones. Representative strains of different genotypes produced the TEM-1 enzyme. K. kingae beta lactamase producers exhibit a clear clonal distribution and have dissimilar invasive potential. The presence of the enzyme in isolates belonging to the major worldwide invasive clone K/ST-6 highlights the possible spread of beta-lactam resistance, and emphasizes the importance of routine testing of all K. kingae clinical isolates for beta-lactamase production. PMID- 24766503 TI - Critical size defects for bone regeneration experiments in rabbit calvariae: systematic review and quality evaluation using ARRIVE guidelines. AB - OBJECTIVES: To perform a systematic review of studies that report the healing of critical size defects (CSDs) in rabbit calvaria and to determine the quality of the studies according to ARRIVE guidelines. MATERIALS AND METHODS: An Internet search was made in duplicate between December 2011 and August 2013 using MEDLINE, PubMed and Google Scholar (without restrictions on date of publication) for rabbit studies reporting the healing of CSD in the calvaria. Animal Research Reporting in Vivo Experiment (ARRIVE) guidelines (a list of 20 aspects to score and to ensure comparison between different experimental studies in animals) were used to evaluate the quality of the selected works. RESULTS: Twenty-five manuscripts were evaluated. Case-control studies predominated (92.59%). Animal age was not stated in 70.37% of the studies; weight was not reported in 29.62%; most animals weighed 3.5 kg (26.31%). A CSD dimension of 15 mm was common (51.61%), generally located centrally (51.85%), followed by bilateral locations (48.14%). Circular (66.66%), rectangular (14.81%), square (14.81%) and ovoid (1.48%) geometries were used. Histomorphometric data showed incomplete healing in all CSDs and higher percentages of healing in smaller defects (<10 mm). The longer the healing time allowed, the more bone healing took place, for both smaller and larger defects (>15 mm). Minimum quality grades were assigned to ARRIVE items study design (6), experimental animals (8), housing and husbandry (9), sample size (10), allocation (11), statistics (13), results-baseline data (14), numbers analyzed (15), adverse events (17) and funding (20). CONCLUSIONS: Data on CSDs in rabbit calvariae lack homogeneity. Smaller defects can be considered critical depending on the time of sacrifice. When new diagnostic technologies are used in addition to histomorphometry, these should be applied with caution to facilitate future comparison with other research. The ARRIVE guidelines should be followed in any animal research protocol to improve the homogeneity, comparison and reproducibility between studies. PMID- 24766504 TI - Protein truncating variants of SLC30A8 reduce type 2 diabetes mellitus risk in humans. PMID- 24766505 TI - Mechanism of p-substituted phenol oxidation at a Ti4O7 reactive electrochemical membrane. AB - This research investigated the removal mechanisms of p-nitrophenol, p methoxyphenol, and p-benzoquinone at a porous Ti4O7 reactive electrochemical membrane (REM) under anodic polarization. Cross-flow filtration experiments and density functional theory (DFT) calculations indicated that p-benzoquinone removal was primarily due to reaction with electrochemically formed OH(*), while the dominant removal mechanism of p-nitrophenol and p-methoxyphenol was a function of the anodic potential. At low anodic potentials (1.7-1.8 V/SHE), p nitrophenol and p-methoxyphenol were removed primarily by an electrochemical adsorption/polymerization mechanism on the REM. Increasing anodic potentials (1.9 3.2 V/SHE) resulted in the electroassisted adsorption mechanism contributing far less to p-methoxyphenol removal compared to p-nitrophenol. DFT calculations indicated that an increase in anodic potential resulted in a shift in p methoxyphenol removal from a 1e(-) direct electron transfer (DET) reaction that resulted in radical formation and significant adsorption/polymerization, to a 2e( ) DET reaction that formed nonadsorbing products (i.e., p-benzoquinone). However, the anodic potentials were too low for the 2e(-) DET reaction to be thermodynamically favorable for p-nitrophenol. The decreased COD adsorption for p nitrophenol at higher anodic potentials was attributed to reaction of soluble/adsorbed organics with OH(*). These results provide the first mechanistic explanation for p-substituted phenolic compound removal during advanced electrochemical oxidation processes. PMID- 24766506 TI - Will optometry respond to the growing challenge of providing evidence-based low vision care? PMID- 24766507 TI - Identifying and characterising cerebral visual impairment in children: a review. AB - Cerebral visual impairment (CVI) comprises visual malfunction due to retro chiasmal visual and visual association pathway pathology. This can be isolated or accompany anterior visual pathway dysfunction. It is a major cause of low vision in children in the developed and developing world due to increasing survival in paediatric and neonatal care. CVI can present in many combinations and degrees. There are multiple causes and it is common in children with cerebral palsy. CVI can be identified easily, if a structured approach to history-taking is employed. This review describes the features of CVI and describes practical management strategies aimed at helping affected children. A literature review was undertaken using 'Medline' and 'Pubmed'. Search terms included cerebral visual impairment, cortical visual impairment, dorsal stream dysfunction and visual function in cerebral palsy. PMID- 24766508 TI - Models of low vision care: past, present and future. AB - Over the last 50 years, the concept of a low vision service has changed considerably. It has moved away from just the optometrist or optician dispensing magnifiers, to having a large team working across the health and social/ community care sectors, with voluntary organisations often playing an important role. This paper reviews how low vision rehabilitation services have evolved and what models of low vision care are currently available. It goes on to consider the effectiveness and accessibility of low vision care. Finally it explores what the future might hold for low vision services, to be better prepared for the increase in the number of people with low vision and their evolving needs and what role(s) an optometrist might have within these anticipated developments. PMID- 24766509 TI - Advancing low vision services: a plan for Australian optometry. PMID- 24766510 TI - Re: silicone hydrogel mini-scleral contact lenses in early stage after corneal collagen cross-linking for keratoconus: a retrospective case series. PMID- 24766516 TI - Desmoteplase as a potential treatment for cerebral ischaemia. AB - INTRODUCTION: Desmoteplase is an investigational plasminogen activator found in the saliva of the vampire bat, Desmodus rotundus. It has been of scientific interest for over 25 years as it exhibits pharmacological properties that have led to the hypothesis that desmoteplase may be safer and more effective than recombinant tissue plasminogen activator (rtPA) in arterial thromboembolic disease, and in particular, acute ischaemic stroke (AIS). AREAS COVERED: In this review, the authors cover the pharmacological properties of desmoteplase, focussing on how this translates into a theoretical advantage over rtPA in AIS. The authors further present preclinical studies and clinical data on the use of desmoteplase in AIS. EXPERT OPINION: In contrast to rtPA, and despite a similar structure, desmoteplase has demonstrated high selectivity for fibrin and an absence of neurotoxicity in experimental models. Demonstrating such properties in animal models, one would have expected an ambitious clinical study future. Phase II and Phase III clinical studies in patients with AIS demonstrated an excellent safety profile with low risk of symptomatic intracranial haemorrhage compared to rtPA. However, data on clinical and radiological efficacy end points of desmoteplase in AIS are inconclusive. Further Phase III trials are currently underway and their results are eagerly awaited. PMID- 24766515 TI - Effects of olmesartan-based treatment on masked, white-coat, poorly controlled, and well-controlled hypertension: HONEST study. AB - The authors examined the effects of olmesartan-based treatment on clinic systolic blood pressure (CSBP) and morning home systolic blood pressure (HSBP) in 21,340 patients with masked hypertension (MH), white-coat hypertension (WCH), poorly controlled hypertension (PCH), and well-controlled hypertension (CH) using data from the Home Blood Pressure Measurement With Olmesartan Naive Patients to Establish Standard Target Blood Pressure (HONEST) study. MH, WCH, PCH, and CH were defined using CSBP 140 mm Hg and MHSBP 135 mm Hg as cutoff values at baseline. At 16 weeks, the MH, WCH, PCH, and CH groups had changes in CSBP by 1.0, -15.2, -23.1, and 1.8 mm Hg, and changes in morning HSBP by -12.5, 1.0, 20.3, and 2.0 mm Hg, respectively. In conclusion, in "real-world" clinical practice, olmesartan-based treatment decreased high morning HBP or CBP without excessive decreases in normal morning HBP or CBP according to patients' BP status. PMID- 24766517 TI - Ti(III)-catalyzed cyclizations of ketoepoxypolyprenes: control over the number of rings and unexpected stereoselectivities. AB - We describe a new strategy to control the number of cyclization steps in bioinspired radical (poly)cyclizations involving epoxypolyenes containing keto units positioned along the polyene chain. This approach provides an unprecedentedly straightforward access to natural terpenoids with pendant unsaturated side chains. Additionally, in the case of bi- and tricyclizations, decalins with cis stereochemistry have been obtained as a consequence of the presence of the ketone. The preferential formation of cis-fused adducts was rationalized using DFT calculations. This result is completely unprecedented in biomimetic cyclizations and permits the access to natural terpenoids with this stereochemistry, as well as to non-natural analogues. PMID- 24766518 TI - Emerging therapeutic targets for osteoporosis treatment. AB - INTRODUCTION: To date, osteoporosis still remains a major public health burden especially for the aging populations. Over the last few decades treatments for osteoporosis have largely focused on anti-resorptive agents represented by bisphosphonates and estrogen therapy that dominated the market. Unsatisfactory efficacy, non-specificity and long-term safety of current therapies necessitate the need for new targets effectively preventing and treating of osteoporosis. AREAS COVERED: This review expatiates on the mechanism of osteoporosis occurrence and bone remodeling cycle in detail. New targets of antiresorptive and anabolic agents based on the functions of osteoblasts and osteoclasts as well as associated signaling pathways are outlined. EXPERT OPINION: Advanced understanding in the fields of bone remodeling, functions of osteoblasts, osteoclasts and osteocytes associated with osteoporosis occurrence offers the emerging bone-resorptive or bone-formative targets. Currently, molecules involving RANK-RANKL-OPG system and Wnt/beta-catenin signaling pathway act as the most promising targets. PMID- 24766520 TI - Bilateral Nicolau syndrome after uterine artery embolization for postpartum bleeding. PMID- 24766519 TI - Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll-like receptor-dependent manner. AB - Mycobacterium indicus pranii (MIP) is an atypical mycobacterial species possessing strong immunomodulatory properties. It is a potent vaccine candidate against tuberculosis, promotes Th1 immune response and protects mice from tumours. In previous studies, we demonstrated higher protective efficacy of MIP against experimental tuberculosis as compared with bacillus Calmette-Guerin (BCG). Since macrophages play an important role in the pathology of mycobacterial diseases and cancer, in the present study, we evaluated the MIP in live and killed form for macrophage activation potential, compared it with BCG and investigated the underlying mechanisms. High levels of tumour necrosis factor alpha, interleukin-12p40 (IL-12p40), IL-6 and nitric oxide were produced by MIP stimulated macrophages as compared with BCG-stimulated macrophages. Prominent up regulation of co-stimulatory molecules CD40, CD80 and CD86 was also observed in response to MIP. Loss of response in MyD88-deficient macrophages showed that both MIP and BCG activate the macrophages in a MyD88-dependent manner. MyD88 signalling pathway culminates in nuclear factor-kappaB/activator protein-1 (NF kappaB/AP-1) activation and higher activation of NF-kappaB/AP-1 was observed in response to MIP. With the help of pharmacological inhibitors and Toll-like receptor (TLR) -deficient macrophages, we observed the role of TLR2, TLR4 and intracellular TLRs in MIP-mediated macrophage activation. Stimulation of HEK293 cells expressing TLR2 in homodimeric or heterodimeric form showed that MIP has a distinctly higher level of TLR2 agonist activity compared with BCG. Further experiments suggested that TLR2 ligands are well exposed in MIP whereas they are obscured in BCG. Our findings establish the higher macrophage activation potential of MIP compared with BCG and delineate the underlying mechanism. PMID- 24766521 TI - Poor performance validity predicts clinical characteristics and cognitive test performance of OEF/OIF/OND Veterans in a research setting. AB - This study examined the performance of 198 Veteran research participants deployed during Operation Enduring Freedom, Operation Iraqi Freedom, and/or Operation New Dawn (OEF/OIF/OND) on four measures of performance validity: the Medical Symptom Validity Test (MSVT), California Verbal Learning Test: Forced Choice Recognition (FCR), Reliable Digit Span (RDS), and TOVA Symptom Exaggeration Index (SEI). Failure on these performance validity tests (PVTs) ranged from 4% to 9%. The overall base rate of poor performance validity, as measured by failure of the MSVT in conjunction with an embedded PVT (FCR, RDS, SEI), was 5.6%. Regression analyses revealed that poor performance validity predicted cognitive test performance and self-reported psychological symptom severity. Furthermore, a greater prevalence of traumatic brain injury (TBI), Post-Traumatic Stress Disorder (PTSD), co-morbid TBI/PTSD, and other Axis I diagnoses, was observed among participants with poor effort. Although poor performance validity is relatively uncommon in a research setting, these findings demonstrate that clinicians should be cautious when interpreting psychological symptoms and neuropsychological test performance of Veteran participants who fail effort measures. PMID- 24766523 TI - Insecticidal activity of plant essential oils against the vine mealybug, Planococcus ficus. AB - The vine mealybug, Planococcus ficus (Signoret) (Hemiptera: Pseudococcidae), is a pest in grape vine growing areas worldwide. The essential oils from the following aromatic plants were tested for their insecticidal activity against P. ficus: peppermint, Mentha piperita L. (Lamiales: Lamiaceae), thyme-leaved savory, Satureja thymbra L., lavender, Lavandula angustifolia Mill, and basil, Ocimum basilicum L. Essential oils from peels of the following fruits were also tested: lemon, Citrus limon L. (Sapindales: Rutaceae), and orange, C. sinensis L. The reference product was paraffin oil. Bioassays were conducted in the laboratory by using spray applications on grape leaves bearing clusters of P. ficus of one size class, which mainly represented either 3rd instar nymphs or pre-ovipositing adult females. The LC50 values for each essential oil varied depending on the P. ficus life stage but did not significantly differ between 3(rd) instar nymphs and adult females. The LC50 values of the citrus, peppermint, and thyme-leaved savory essential oils ranged from 2.7 to 8.1 mg/mL, and the LC50 values of lavender and basil oil ranged from 19.8 to 22.5 and 44.1 to 46.8 mg/mL, respectively. The essential oils from citrus, peppermint and thymeleaved savory were more or equally toxic compared to the reference product, whereas the lavender and basil essential oils were less toxic than the paraffin oil. No phytotoxic symptoms were observed on grape leaves treated with the citrus essential oils, and low phytotoxicity was caused by the essential oils of lavender, thyme-leaved savory, and mint, whereas the highest phytotoxicity was observed when basil oil was used. PMID- 24766522 TI - Radioactive 198Au-doped nanostructures with different shapes for in vivo analyses of their biodistribution, tumor uptake, and intratumoral distribution. AB - With Au nanocages as an example, we recently demonstrated that radioactive (198)Au could be incorporated into the crystal lattice of Au nanostructures for simple and reliable quantification of their in vivo biodistribution by measuring the gamma radiation from (198)Au decay and for optical imaging by detecting the Cerenkov radiation. Here we extend the capability of this strategy to synthesize radioactive (198)Au nanostructures with a similar size but different shapes and then compare their biodistribution, tumor uptake, and intratumoral distribution using a murine EMT6 breast cancer model. Specifically, we investigated Au nanospheres, nanodisks, nanorods, and cubic nanocages. After PEGylation, an aqueous suspension of the radioactive Au nanostructures was injected into a tumor bearing mouse intravenously, and their biodistribution was measured from the gamma radiation while their tumor uptake was directly imaged using the Cerenkov radiation. Significantly higher tumor uptake was observed for the Au nanospheres and nanodisks relative to the Au nanorods and nanocages at 24 h postinjection. Furthermore, autoradiographic imaging was performed on thin slices of the tumor after excision to resolve the intratumoral distributions of the nanostructures. While both the Au nanospheres and nanodisks were only observed on the surfaces of the tumors, the Au nanorods and nanocages were distributed throughout the tumors. PMID- 24766524 TI - Melittin triggers apoptosis in Candida albicans through the reactive oxygen species-mediated mitochondria/caspase-dependent pathway. AB - Melittin is one of the best-studied antimicrobial peptides, and many studies have focused on the membrane underlying its membrane-disruptive activity. We previously showed that melittin could cause some hallmarks of apoptosis in Candida albicans. Here, we first report the exact mechanism of melittin-induced fungal apoptosis. We first characterized the reactive oxygen species generated by melittin. The results showed that melittin strongly produced highly reactive hydroxyl radicals (OH), which contribute to cell death. Next, we showed that melittin also disrupted the mitochondrial membrane potential (DeltaPsim) and induced the Ca(2+) release from the endoplasmic reticulum and its remarkable accumulation in mitochondria. Finally, we investigated the role of caspase in the apoptotic pathway. The results showed that melittin activated metacaspase, which was mediated by cytochrome c release. To summarize, melittin is involved in the mitochondria- and caspase-dependent apoptotic pathway in C. albicans. Our findings suggest that melittin possesses a dual antimicrobial mechanism, including membrane-disruptive and apoptotic actions. PMID- 24766525 TI - The effect of face-to-face with telephone-based counseling on sexual satisfaction among reproductive aged women in Iran. AB - This study was designed to investigate and compare the effect of face-to-face with telephone-based counseling on sexual satisfaction in women of reproductive age in Iran. This study was a randomized controlled trial in which 46 married women who got married 1-5 years ago were randomly selected and assigned to 1 of 2 groups (face-to-face and telephone-based counseling). Two groups received counseling by a trained midwife once a week for 4 weeks. The sexual satisfaction (using the Sexual Satisfaction Index) score was calculated in the beginning of the study and after 4 weeks. An independent t test, chi-square test, likelihood ratio test, Fisher's exact test, and linear-by-linear test were used for analyzing data. The mean score of sexual satisfaction in the face-to-face group was 93.6 (SD = 7.1) and improved significantly to 108.08 (SD = 5.44) after intervention (p =.001). The mean score of sexual satisfaction in the telephone based counseling was 93.52 (SD = 5) and increased to 113 (SD = 6.07) after 4 weeks (p =.001). Telephone-based counseling could increase the sexual satisfaction better than face-to-face counseling (mean difference: 20.34 [SD = 7.38] vs. 14.47 [SD = 5.32], p =.003). The telephone-based counseling is an effective and affordable method to solve the sexual problems and could increase the sexual satisfaction. Using this method in public health centers is recommended. PMID- 24766526 TI - Transplant related outcomes in patients with hematopoietic stem cell transplant with Clostridium difficile associated diarrhea. PMID- 24766527 TI - Toxicokinetic of flumethrin in rabbits. AB - In this study, the toxicokinetic of flumethrin after single oral and intravenous applications were studied. For this aim, 14 male New Zealand rabbits were used. The animals were divided into two groups of seven each. While 10 mg/kg.bw of flumethrin was intravenously injected into the first group, the same dose was administered orally with the second group. Serial blood samples were also collected at certain periods. Flumethrin concentrations were measured using a gas chromatography with a micro electron capture detector. The serum flumethrin concentration-time curve was determined to fit a two-compartment open model. Among the parameters calculated following intravenous application of flumethrin, the half-life at beta phase (t1/2beta), mean residence time (MRT) and area under the concentration time curve in 0-infinity (AUC0->infinity) values were respectively found to be 34.0 +/- 4.2 h, 48.0 +/- 5.8 h and 36.1 +/- 5.3. On the other hand, the maximal concentration in serum (Cmax), time needed to reach Cmax (tmax), t1/2beta, MRT and AUC0->infinity values of flumethrin after oral administration were determined to be 0.54 +/- 0.09 MUg/ml, 5.42 +/- 0.97 h, 43.3 +/- 8.6 h, 59.7 +/- 10.5 h and 22.0 +/- 2.0 mg.h/L, respectively. The bioavailability of flumethrin was found to be 60.9%. In conclusion, these results were considered to be important in terms of the toxication risk of flumethrin and its safe use. PMID- 24766528 TI - Directly thiolated modification onto the surface of detonation nanodiamonds. AB - An efficient method for modifying the surface of detonation nanodiamonds (5 and 100 nm) with thiol groups (-SH) by using an organic chemistry strategy is presented herein. Thiolated nanodiamonds were characterized by spectroscopic techniques, and the atomic percentage of sulfur was analyzed by elemental analysis and X-ray photoelectron spectroscopy. The conjugation between thiolated nanodiamonds and gold nanoparticles was elucidated by transmission electron microscopy and UV-vis spectrometry. Moreover, the material did not show significant cytotoxicity to the human lung carcinoma cell line and may prospectively be applied in bioconjugated technology. The new method that we elucidated may significantly improve the approach to surface modification of detonation nanodiamonds and build up a new platform for the application of nanodiamonds. PMID- 24766529 TI - Inhibition of Salmonella typhi growth using extremely low frequency electromagnetic (ELF-EM) waves at resonance frequency. AB - AIMS: Typhoid is a serious disease difficult to be treated with conventional drugs. The aim of this study was to demonstrate a new method for the control of Salmonella typhi growth, through the interference with the bioelectric signals generated from the microbe during cell division by extremely low frequency electromagnetic waves (ELF-EMW-ELF-EM) at resonance frequency. METHODS AND RESULTS: Isolated Salmonella typhi was subjected to square amplitude modulated waves (QAMW) with different modulation frequencies from two generators with constant carrier frequency of 10 MHz, amplitude of 10 Vpp, modulating depth +/- 2 Vpp and constant field strength of 200 V m(-1) at 37 degrees C. Both the control and exposed samples were incubated at the same conditions during the experiment. The results showed that there was highly significant inhibition effect for Salm. typhi exposed to 0.8 Hz QAMW for a single exposure for 75 min. Dielectric relaxation, TEM and DNA results indicated highly significant changes in the molecular structure of the DNA and cellular membrane resulting from the exposure to the inhibiting EM waves. CONCLUSIONS: It was concluded that finding out the inhibiting resonance frequency of ELF-EM waves that deteriorates Salm. typhi growth will be promising method for the treatment of Salm. typhi infection either in vivo or in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: This new non-invasive technique for treatment of bacterial infections is of considerable interest for the use in medical and biotechnological applications. PMID- 24766530 TI - Does the addition of targeted biological agents to first-line chemotherapy for advanced colorectal cancer increase complete response? A systematic review and meta-analysis. AB - AIM: The study assessed whether the addition of monoclonal antibodies (MoAbs) to first-line chemotherapy for advanced colorectal cancer (CRC) increases the complete response (CR) compared with controls. METHOD: PubMed was reviewed for randomized clinical trials (RCTs) with approved MoAbs (bevacizumab, cetuximab and panitumumab) vs non-MoAbs as first-line therapy for patients with advanced CRC. The incidence and ratio of CR events were calculated in patients assigned to MoAbs compared with controls. RESULTS: A total of 3790 patients from nine RCTs were included for analysis. The overall incidence of CR in patients treated with MoAbs was 2.4% (95% CI: 1.7-3.3%) compared with 1.3% (95% CI: 0.8-2.2%) in controls. Comparison of the different types of MoAbs showed that the incidence of CR was higher for bevacizumab (3.1%, 95% CI: 2.1-4.3%) than for cetuximab (0.8%, 95% CI: 0.4-1.8%). The addition of MoAbs to chemotherapy significantly increased the OR of obtaining a CR compared with controls (OR = 1.96; 95% CI: 1.12-3.46; P = 0.02). No significant differences in the OR were observed in any of the subgroups. CONCLUSION: The CR is a rare event in advanced CRC; however, the addition of MoAbs to first-line chemotherapy significantly increases the curative rate of metastatic disease compared with controls. PMID- 24766531 TI - National survey on psychosocial obstetrics and gynecology curriculum in US medical schools. AB - INTRODUCTION: This study sought to identify how psychosocial topics related to women's health are taught and assessed in the obstetrics/gynecology program of American medical schools, and what issues may prevent or promote their instruction. METHODS: A questionnaire was distributed to the ob/gyn clerkship director of every US medical school. Directors were asked whether each of four recommended topics were covered in their curricula. They were also asked about barriers to instructing topics not taught, and the importance of these topics. RESULTS: Out of 136 US medical schools, 57 questionnaires were returned (response rate = 40.4%). In all, 27 schools (48%) include formal training in pregnancy related mood disorders, 33 (58%) include pre-menstrual syndrome/pre-menstrual dysphoric disorder, 29 (51%) include female sexual dysfunction and 45 (79%) include violence against women. Six schools (12%) listed none of these topics as taught. All but three of the clerkship directors agreed that psychosocial topics are important. The most common reason given for lack of instruction was insufficient time allotted. CONCLUSIONS: Despite agreement on their importance, many US medical schools do not teach psychosocial aspects of women's health. Addressing the barriers to teaching these topics would help provide medical students with more opportunities to learn about these issues. PMID- 24766532 TI - A comparative analysis of postpartum maternal mental health in women following spontaneous or ART conception. AB - OBJECTIVE: To determine whether conception following assisted reproductive technology (ART) predisposes women to increased risk of postnatal depression (PND), compared to women who conceived naturally, when controlling for such factors as: multiple birth, previous maternal psychiatric history and sociodemographic status. PARTICIPANTS: A total of 200 women who attended the private antenatal and fertility clinics of a fertility specialist in a large Australian city between January 2009 and December 2011 were contacted via telephone. RESULTS: There was no difference in the rate of PND between the two groups (7.5% versus 7.4%, p = ns). Aside from the slightly older maternal age in the ART group (35.4 versus 33, p < 0.05), baseline socio-demographics were similar. There was a significantly higher rate of previous maternal clinical depression in the ART group compared to the controls (17% versus 5%, p < 0.05); however, other known risk factors for PND, including previous PND (10.6% versus 13.7%, p = ns), multiple births (2.1% versus 4.2%, p = ns) and low infant birth weight (3.3 kg versus 3.4 kg, p = ns), were not different in the two cohorts. Women who conceived naturally were also more likely to breastfeed for a longer duration (78% versus 89%, p < 0.05). CONCLUSION: Our study demonstrates that when accounting for well-known risk and protective factors for postpartum depression, women who conceive using ART are not at an increased risk PND. In addition, the low rate of multiple births in the ART group further validates the practice of single embryo transfer. PMID- 24766533 TI - Association of erosion with timing of detection and selected risk factors in primary dentition: a longitudinal study. AB - OBJECTIVE: The aims of this study were to determine the prevalence of erosion in a birth cohort at 24, 36, and 48 months and to investigate risk factors for erosion. METHODS: One hundred and fifty-four children from a birth cohort were followed at 24, 36, and 48 months of age. RESULTS: Of the 154 children examined, 0% (0/154), 7% (11/154), and 28% (40/154) had erosion detected for the first time at 24, 36, and 48 months, respectively (P < 0.001). A cumulative total of 51 (33%) children and 256 (8%) teeth had erosion by the age of 48 months. There were no significant associations between erosive lesions first detected at 36 months and oral hygiene behaviour, medical conditions, or dietary habits reported at the 24- or 36-month examinations (all P > 0.05). In contrast, erosive lesion first detected at 48 months was positively associated with the use of a feeding bottle reported at the 36-month examination (P = 0.026). CONCLUSIONS: The prevalence of dental erosion in young children increased with age, with clinically detectable lesions forming between 24 and 36 months of age. Erosive lesions first detected at 48 months were positively associated with the use of a feeding bottle reported at 36 months. PMID- 24766534 TI - A 19-year study on pacemaker-related infections: a claim for using postoperative antibiotics. AB - BACKGROUND: Although the incidence of pacemaker-related infection (PMINF) is low, it necessitates removal of the pacing system. There is currently no consensus on antibiotics during implantation. METHODS: A prospective database on patients undergoing pacemaker surgery from 1991 to 2009 was reviewed to determine factors associated with PMINF. Specifically, three eras of antibiotic use were compared to elucidate the effect of antibiotics on PMINF: no antibiotics, perioperative antibiotics, and peri- plus postoperative antibiotics. RESULTS: There were 3,253 procedures with PMINF identified in 46 (1.4%) patients. Over 19 years, PMINF incidence fell from 3.6% (no antibiotics) to 2.9% (perioperative antibiotics), to 0.4% (peri- plus postoperative antibiotics). On univariate analysis, the following were associated with PMINF: nonuse of postoperative antibiotics (3.0% vs 0.4%, P < 0.001), year of implant (P < 0.001), repeat procedures (2.3% vs 1%, P = 0.006), nonuse of perioperative antibiotics (3.6% vs 1.3%, P = 0.027). With postoperative antibiotics, rates were significantly reduced in new implants (1/1,289 = 0.1% vs 22/967 = 2.3%, P < 0.001) and repeat procedures (7/692 = 1.0% vs 16/305 = 5.2%, P < 0.001). On multivariate analysis, the following were significant (standardized coefficients denote relative importance): postoperative antibiotics (0.776), repeat procedures (0.508), year of implant (0.142), perioperative antibiotics (0.088). CONCLUSIONS: The PMINF rate is reduced significantly by perioperative antibiotics with a further significant reduction with postoperative antibiotics. However, the reduction in PMINF rate could be a result of changes in practice in the different time eras. This study suggests consideration of perioperative followed by postoperative antibiotics to minimize pacemaker infections. PMID- 24766535 TI - Surface modification of poly(ether ether ketone) with methacryloyl-functionalized phospholipid polymers via self-initiation graft polymerization. AB - To improve blood compatibility of poly(ether ether ketone) (PEEK), surface modification with methacryloyl-functionalized phospholipid polymers was performed through self-initiation graft polymerization. The copolymers (PMA) of 2 methacryloyloxyethyl phosphorylcholine (MPC) and 2-aminoethyl methacrylate hydrochloride were synthesized by conventional free radical polymerization. The PMA was then immobilized with pentafluorophenyl methacrylate to obtain methacryloyl-functionalized MPC polymers (PMAMA). The degree of substitution of the methacryloyl group into the copolymer was nearly completed. The PMAMA was dissolved in 1-butanol and the solution was dropped on PEEK. UV light (350+/-50 nm) was subsequently irradiated on PEEK for various periods. Elemental analysis of the PEEK surface was performed by X-ray photoelectron spectroscopy and phosphorus and nitrogen signals due to the MPC units on PEEK were observed. The surface wettability of PEEK was also improved by immobilization of PMAMA. Plasma protein adsorption was effectively reduced on the PMAMA-immobilized surface regardless of the type of protein. Furthermore, PMAMA immobilization was also useful in reducing platelet adhesion on PEEK. In conclusion, methacryloyl functionalized MPC polymers could be immobilized on PEEK by simple photo irradiation, resulting in significant improvement in blood compatibility. PMID- 24766536 TI - Gram-negative prosthetic joint infection: outcome of a debridement, antibiotics and implant retention approach. A large multicentre study. AB - We aim to evaluate the epidemiology and outcome of gram-negative prosthetic joint infection (GN-PJI) treated with debridement, antibiotics and implant retention (DAIR), identify factors predictive of failure, and determine the impact of ciprofloxacin use on prognosis. We performed a retrospective, multicentre, observational study of GN-PJI diagnosed from 2003 through to 2010 in 16 Spanish hospitals. We define failure as persistence or reappearance of the inflammatory joint signs during follow-up, leading to unplanned surgery or repeat debridement>30 days from the index surgery related death, or suppressive antimicrobial therapy. Parameters predicting failure were analysed with a Cox regression model. A total of 242 patients (33% men; median age 76 years, interquartile range (IQR) 68-81) with 242 episodes of GN-PJI were studied. The implants included 150 (62%) hip, 85 (35%) knee, five (2%) shoulder and two (1%) elbow prostheses. There were 189 (78%) acute infections. Causative microorganisms were Enterobacteriaceae in 78%, Pseudomonas spp. in 20%, and other gram-negative bacilli in 2%. Overall, 19% of isolates were ciprofloxacin resistant. DAIR was used in 174 (72%) cases, with an overall success rate of 68%, which increased to 79% after a median of 25 months' follow-up in ciprofloxacin-susceptible GN-PJIs treated with ciprofloxacin. Ciprofloxacin treatment exhibited an independent protective effect (adjusted hazard ratio (aHR) 0.23; 95% CI, 0.13-0.40; p<0.001), whereas chronic renal impairment predicted failure (aHR, 2.56; 95% CI, 1.14-5.77; p 0.0232). Our results confirm a 79% success rate in ciprofloxacin-susceptible GN PJI treated with debridement, ciprofloxacin and implant retention. New therapeutic strategies are needed for ciprofloxacin-resistant PJI. PMID- 24766538 TI - Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families. AB - Spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL), type 1 is an autosomal recessive disorder which has been identified in more than 30 affected children in the Afrikaans-speaking community of South Africa. Sequencing of B3GALT6 revealed a specific mutation, c.235A > G, in homozygous form in four families, while three others were compound heterozygotes for this mutation in combination with the c.200C > T mutation. In addition, a proband from one family carried the c.16C > T mutation combined with c.200C > T. In a series of five Iranian persons, mutations in B3GALT6 have been implicated in a syndrome characterised by skeletal abnormalities with intellectual disability, bone and connective tissue fragility. Other mutations in B3GALT6 resulted in the classical SEMD-JL phenotype in seven Japanese families and in a syndrome which has been likened to a progeroid form of Ehlers-Danlos syndrome (EDS). It is evident that there is considerable intragenic heterogeneity in B3GALT6. One of the mutations, c.200C > T, in the affected South Africans was also present in one of the Japanese persons and the respective phenotypes were identical. The multiplicity of allelic mutations and the phenotypic differences in the affected persons supports the concept that a spectrum of connective tissue disorders is programmed by mutations in B3GALT6. PMID- 24766539 TI - Molecular magnets based on homometallic hexanuclear lanthanide(III) complexes. AB - The reaction of lanthanide(III) chloride salts (Gd(III), Dy(III), Tb(III), and Ho(III)) with the hetero donor chelating ligand N'-(2-hydroxy-3 methoxybenzylidene)-6-(hydroxymethyl)picolinohydrazide (LH3) in the presence of triethylamine afforded the hexanuclear Ln(III) complexes [{Ln6(L)2(LH)2}(MU3 OH)4][MeOH]p[H2O]q[Cl]4.xH2O.yCH3OH (1, Ln = Gd(III), p = 4, q = 4, x = 8, y = 2; 2, Ln = Dy(III), p = 2, q = 6, x = 8, y = 4; 3, Ln = Tb(III), p = 2, q = 6, x = 10, y = 4; 4, Ln = Ho(III), p = 2, q = 6, x = 10, y = 2). X-ray diffraction studies revealed that these compounds possess a hexanuclear [Ln6(OH)4](14+) core consisting of four fused [Ln3(OH)](8+) subunits. Both static (dc) and dynamic (ac) magnetic properties of 1-4 have been studied. Single-molecule magnetic behavior has been observed in compound 2 with an effective energy barrier and relaxation time pre-exponential parameters of Delta/kB = 46.2 K and tau0 = 2.85 * 10(-7) s, respectively. PMID- 24766537 TI - Defining the limits: Protein aggregation and toxicity in vivo. AB - Abstract others complementary, to resolve mis-folded proteins when they arise, ranging from refolding through the action of molecular chaperones to elimination through regulated proteolytic mechanisms. These protein quality control pathways are sufficient, under normal conditions, to maintain a functioning proteome, but in response to diverse environmental, genetic and/or stochastic events, protein mis-folding exceeds the corrective capacity of these pathways, leading to the accumulation of aggregates and ultimately toxicity. Particularly devastating examples of these effects include certain neurodegenerative diseases, such as Huntington's Disease, which are associated with the expansion of polyglutamine tracks in proteins. In these cases, protein mis-folding and aggregation are clear contributors to pathogenesis, but uncovering the precise mechanistic links between the two events remains an area of active research. Studies in the yeast Saccharomyces cerevisiae and other model systems have uncovered previously unanticipated complexity in aggregation pathways, the contributions of protein quality control processes to them and the cellular perturbations that result from them. Together these studies suggest that aggregate interactions and localization, rather than their size, are the crucial considerations in understanding the molecular basis of toxicity. PMID- 24766541 TI - New insights into electrocatalysis based on plasmon resonance for the real-time monitoring of catalytic events on single gold nanorods. AB - Gold nanoparticles (GNPs) have been widely applied in industrial catalysis and electrocatalysis. Owing to their wide variety of shapes, sizes, and compositions, a range of different catalytic properties is possible. Thus, it is important to monitor catalytic processes and their mechanisms on single GNP surfaces to avoid averaging effects in bulk systems. Therefore, a novel method based on dark-field scattering spectroscopy was developed to monitor, in real-time, the electrocatalytic oxidation of hydrogen peroxide on a single gold nanoparticle surface. The catalytic mechanism was revealed via the plasmon resonance scattering spectral shift of single gold nanorod with the elimination of bulk effect. Moreover, we found that the presence of chloride ions could block the catalytic activity of nanorods for the oxidation of H2O2. Most importantly, it was discovered that individual nanoparticles have variable properties with different spectra shifts during the catalytic process. The obtained optical signals from individual nanorods not only offer versatile information regarding the reaction but also improve the understanding of electrochemistry and the catalysis mechanism of single nanoparticles. PMID- 24766540 TI - Ethnicity-related variations of left ventricular remodeling in adolescent amateur football players. AB - Adult and adolescent elite black athletes display - as compared with their white counterparts - excessively increased left ventricle (LV) wall thickness (LVWT), mass (LVM), and relative wall thickness (RWT). To investigate such ethnicity related differences in non-professional adolescent athletes, 138 male, amateur football players [age 14.0 +/- 1.7 years, 42 West-African blacks (BA) and 96 Italian whites (WA)] underwent an echocardiographic study of LV diameters, LVWT, maximal wall thickness (MWT), LVM, and RWT as remodeling index. BA vs WA exhibited greater thickness of septum and posterior wall, higher MWT (10.3 +/- 1.7 vs 8.8 +/- 1.1 mm), and higher LVM (117 +/- 27 vs 101 +/- 20 g/m(2)) and RWT (0.44 +/- 0.07 vs 0.35 +/- 0.04). Age, systolic blood pressure, body mass index, and ethnicity predicted MWT and LVM, whereas ethnicity was the sole strong predictor of RWT. The greater MWT, LVWT, and LVM of 14-year-old, amateur-level BA vs WA indicates that ethnicity substantially affects LV structure in adolescent, non-professional athletes. In contrast with MWT and LVM, elevated RWT was predicted by black ethnicity only. We suggest that concentric-type LV remodeling is a peculiar LV phenotype in adolescent African athletes. PMID- 24766542 TI - Agomelatine in treating generalized anxiety disorder. AB - INTRODUCTION: Generalized anxiety disorder (GAD) is a chronic and disabling disorder with a lifetime prevalence of 4.3 - 5.9% in the general population. Many drug and non-drug treatments have been shown to be effective in the treatment of GAD, including benzodiazepines, antidepressants (selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors and tricyclic antidepressants), anticonvulsants, azapirones, antihistamines, atypical antipsychotics, complementary/alternative medicine, psychotherapy and Internet based services. Agomelatine is an antidepressant approved by the European Agency; it is a melatonergic agonist (MT1 and MT2 receptors) and a 5-HT2C antagonist indicated in the treatment of major depressive episodes. AREAS COVERED: The present article looks at the short-term efficacy of Agomelatine assessed in two short-term placebo-controlled studies. It also looks at the long-term efficacy evaluated in one relapse prevention study. EXPERT OPINION: Agomelatine is an effective treatment option for both GAD and somatic anxiety. The trial, which includes an escitalopram arm, shows comparable efficacy in GAD between both antidepressants, whereas the restoration of sleep was significantly better with agomelatine. The low discontinuation rate illustrates the good tolerability and lab results show a low incidence of transient elevations in liver enzymes. Whereas uptitrated patients on a 50 mg dose have a lower chance of reaching the desired outcome than the lower 25 mg dose, those reaching this outcome have a better chance of treatment continuation. PMID- 24766543 TI - Investigation of the association between the outcomes of sperm chromatin condensation and decondensation tests, and assisted reproduction techniques. AB - The main purpose of this prospective study is to examine possible influences of abnormalities of sperm nuclear condensation and chromatin decondensation with sodium dodecyl sulphate (SDS)-EDTA on outcomes of intrauterine insemination (IUI) or intracytoplasmic sperm injection (ICSI) cycles. Semen samples from 122 IUI and 236 ICSI cycles were evaluated. Before semen preparation for IUI or ICSI, basic semen analysis was performed and a small portion from each sample was spared for fixation. The condensation of sperm nuclear chromatin was evaluated with acidic aniline blue, followed by sperm chromatin decondensation by SDS-EDTA and evaluation under light microscope. Ongoing pregnancy rate was 24% and 26.2% in the IUI and ICSI groups respectively. The chromatin condensation rate was significantly higher in the ongoing pregnancy-positive group compared to the negative group, both in IUI (P = 0.042) and ICSI groups (P = 0.027), and it was positively correlated with ongoing pregnancy rate in both IUI and ICSI groups (P = 0.015, r = 0.214 and P = 0.014, r = 0.312 respectively). Chromatin decondensation rates were not significantly different in neither of the groups. These results indicate that IUI and ICSI outcome is influenced by the rate of spermatozoa with abnormal chromatin condensation. Sperm chromatin condensation with aniline blue is useful for selecting assisted reproduction techniques (ART) patients. PMID- 24766544 TI - Late stage benzylic C-H fluorination with [18F]fluoride for PET imaging. AB - We describe the first late-stage (18)F labeling chemistry for aliphatic C-H bonds with no-carrier-added [(18)F]fluoride. The method uses Mn(salen)OTs as an F transfer catalyst and enables the facile labeling of a variety of bioactive molecules and building blocks with radiochemical yields (RCY) ranging from 20% to 72% within 10 min without the need for preactivation of the labeling precursor. Notably, the catalyst itself can directly elute [(18)F]fluoride from an ion exchange cartridge with over 90% efficiency. Using this feature, the conventional and laborious dry-down step prior to reaction is circumvented, greatly simplifying the mechanics of this protocol and shortening the time for automated synthesis. Eight drug molecules, including COX, ACE, MAO, and PDE inhibitors, have been successfully [(18)F]-labeled in this way. PMID- 24766545 TI - Renal nerve ablation for resistant hypertension: the dust has not yet settled. PMID- 24766546 TI - The photosynthetic eukaryote Nannochloris eukaryotum as an intracellular machine to control and expand functionality of human cells. AB - To construct an intracellular machine, we sought a symbiotic relationship between a photosynthetic green alga and human cells. Human cells selectively take up the minimal eukaryote Nannochloris eukaryotum and the resulting symbionts are able to survive and proliferate. Host cells can utilize N. eukaryotum's photosynthetic apparatus for survival, and expression of cellular vascular endothelial growth factor can be controlled with input of photonic energy. This seemingly rare spontaneous association provides an opportunity to fabricate light-controlled, intracellular machines. PMID- 24766547 TI - Sulfur cathodes with hydrogen reduced titanium dioxide inverse opal structure. AB - Sulfur is a cathode material for lithium-ion batteries with a high specific capacity of 1675 mAh/g. The rapid capacity fading, however, presents a significant challenge for the practical application of sulfur cathodes. Two major approaches that have been developed to improve the sulfur cathode performance include (a) fabricating nanostructured conductive matrix to physically encapsulate sulfur and (b) engineering chemical modification to enhance binding with polysulfides and, thus, to reduce their dissolution. Here, we report a three dimensional (3D) electrode structure to achieve both sulfur physical encapsulation and polysulfides binding simultaneously. The electrode is based on hydrogen reduced TiO2 with an inverse opal structure that is highly conductive and robust toward electrochemical cycling. The relatively enclosed 3D structure provides an ideal architecture for sulfur and polysulfides confinement. The openings at the top surface allow sulfur infusion into the inverse opal structure. In addition, chemical tuning of the TiO2 composition through hydrogen reduction was shown to enhance the specific capacity and cyclability of the cathode. With such TiO2 encapsulated sulfur structure, the sulfur cathode could deliver a high specific capacity of ~1100 mAh/g in the beginning, with a reversible capacity of ~890 mAh/g after 200 cycles of charge/discharge at a C/5 rate. The Coulombic efficiency was also maintained at around 99.5% during cycling. The results showed that inverse opal structure of hydrogen reduced TiO2 represents an effective strategy in improving lithium sulfur batteries performance. PMID- 24766548 TI - It is time to introduce ST analysis for fetal monitoring in the labor ward? AB - Five randomized controlled trials have been published on intrapartum fetal heart rate monitoring with ST analysis of the fetal electrocardiogram, but the debate on its usefulness has not yet been ended. We consider ST analysis a useful and cost-effective addition to conventional fetal heart rate monitoring. We will provide support for this opinion by discussing the pathophysiology of ST changes in relation to fetal asphyxia, the results of the randomized controlled trials and numerous meta-analyses of these randomized controlled trials and trends in fetal outcome in hospitals in different countries following the introduction of the ST technology in the labor ward. PMID- 24766549 TI - Consolidated Standards of Reporting Trials (CONSORT): considerations for neuropsychological research. AB - Evidence-based medicine (EBM) is a pillar of clinical medicine (Sackett, Rosenberg, Gray, Haynes, & Richardson, 1996 ), but only recently has this been systematically discussed within the context of clinical neuropsychology (e.g., Chelune, 2010 ). Across the medical sciences, randomized controlled trials (RCTs) are often considered the most important source of evidence for treatment efficacy. To facilitate the conduct, dissemination, and evaluation of research findings, reporting standards have been implemented, including the Consolidated Standards of Reporting Trials (CONSORT) statement. This paper considers the implications of the CONSORT statement for the reporting of clinical trials that include neuropsychological endpoints. Adopting specific guidelines for trials involving neuropsychology endpoints will ultimately serve to strengthen the empirical evidence base by increasing uniformity within the literature, decrease ambiguity in reporting, improving trial design, and fostering methodological transparency. Implementing uniform reporting standards will also facilitate meta analytic review of evidence from published trials, benefiting researchers, clinicians, educators and practitioners, as well as journal editors, reviewers, and ultimately, health care consumers. PMID- 24766551 TI - Validation of classical force fields for the description of thermo-mechanical properties of transition metal materials. AB - It is demonstrated that classical force fields validated through the density functional theory (DFT) calculations of small titanium and nickel clusters can be applied for the description of thermo-mechanical properties of corresponding materials. This has been achieved by means of full-atom molecular dynamics simulations of nanoindentation of amorphous and nanostructured Ti and Ni-Ti materials. The theoretical analysis performed and comparison with experimental data demonstrate that the utilized classical force fields for Ti-Ti, Ni-Ni and Ni Ti interactions describe reasonably well hardness and the Young's modulus of these materials. This observation is of the general nature and can be utilized for similar numerical exploration of thermo-mechanical properties of a broad range of materials. PMID- 24766550 TI - Nod2 and Rip2 contribute to innate immune responses in mouse neutrophils. AB - Nod-like receptors are a family of innate immune receptors that link cytosolic sensing of microbial and danger stimuli to the activation of immune responses. Two Nod-like receptor family members, Nod1 and Nod2, recognize bacterial peptidoglycan and activate immune responses via nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK). The function of Nod1 and Nod2 has been largely studied in macrophages, but the role of these receptors in other innate immune cells remains unclear. In this study, we examined the function of Nod1 and Nod2 in innate immune responses of neutrophils. Mice were injected intraperitoneally with thioglycollate, and then peritoneal neutrophils were isolated 4 hr after injection. Tri-DAP and muramyl-dipeptide (MDP) were used as Nod1 and Nod2 agonists, respectively. The level of cytokines [interleukin-6 (IL 6) and tumour necrosis factor-alpha (TNF-alpha)] and chemokines (CXCL1 and CCL2) was increased by MDP, but not Tri-DAP in wild-type (WT) neutrophils. Increased production of cytokines and chemokines with MDP was abolished in Nod2- and Rip2 deficient neutrophils. MDP also induced the activation of NF-kappaB and MAPK in WT neutrophils, but not in Nod2- and Rip2-deficient cells. Flow cytometry analysis showed that L-selectin shedding was induced by MDP in WT neutrophils, but not in Nod2- and Rip2-deficient cells. MDP and Toll-like receptor (TLR) agonists (Pam3 CSK4 and lipopolysaccharide) exerted synergistic effects on the production of IL-6 and CXCL1 in neutrophils. Moreover, Nod2 and TLR4 cooperated to produce IL-6, TNF-alpha, CXCL1 and CCL2 in neutrophils in response to Gram negative bacteria. Our findings suggest that the Nod2-Rip2 axis may contribute to the innate immune response of neutrophils against bacterial infection. PMID- 24766553 TI - Physicochemical characterization techniques for solid lipid nanoparticles: principles and limitations. AB - Solid lipid nanoparticles (SLNs) are gaining importance due to numerous advantages they offer as a drug delivery system. SLN incorporate poorly soluble drugs, proteins, biologicals, etc. SLN are prepared by techniques like high pressure homogenization, sonication and employs a wide range of lipids and surfactants. Physicochemical characterization techniques include particle size analysis, zeta potential and determination of crystallinity/polymorphism. Furthermore, drug loading and drug entrapment efficiency are common parameters used to test the efficiency of SLN. Most importantly, the functionality assay of SLN is essential to predict the activity and performance in vivo. The review presented discusses the importance of SLN in drug delivery with emphasis on principles and limitations associated with their physicochemical characterization. PMID- 24766552 TI - Sedative load and salivary secretion and xerostomia in community-dwelling older people. AB - OBJECTIVE: The aim was to investigate how sedative load and the total number of drugs used are related to hyposalivation and xerostomia among 75-year-old or older dentate, non-smoking, community-dwelling people. MATERIALS AND METHODS: The study population consisted of 152 older people from the Oral Health GeMS study. The data were collected by interviews and clinical examinations during 2004-2005. Sedative load, which measures the cumulative effect of taking multiple drugs with sedative properties, was calculated using the Sedative Load Model. RESULTS: The results showed that participants with a sedative load of either 1-2 or >=3 had an increased likelihood of having low stimulated salivary flow (<0.7 ml/min; OR: 2.4; CI: 0.6-8.6 and OR: 11; CI: 2.2-59; respectively) and low unstimulated salivary flow (<0.1 ml/min; OR: 2.7, CI: 1.0-7.4 and OR: 4.5, CI: 1.0-20, respectively) compared with participants without a sedative load. Participants with a sedative load >=3 had an increased likelihood of having xerostomia (OR: 2.5, CI: 0.5-12) compared with participants without a sedative load. The results showed that the association between the total number of drugs and hyposalivation was weaker than the association between sedative load and hyposalivation. CONCLUSION: Sedative load is strongly related to hyposalivation and to a lesser extent with xerostomia. The adverse effects of drugs on saliva secretion are specifically related to drugs with sedative properties. PMID- 24766554 TI - Effects of an Obesity Intervention Integrating Physical Activity and Psychological Strategy on BMI, Physical Activity, and Psychological Variables in Male Obese Adolescents. AB - The current study investigated the effect of an obesity intervention incorporating physical activity and behavior-based motivational enhancement intervention on BMI, physical activity levels, and psychological variables toward physical activity in male obese adolescents. Single group study without having a control group was carried out in Korea. Sixty-eight obese male adolescents who had BMI greater than 25 kg/m(2) participated in the 16-week obesity intervention. During this period, the study participants' BMI, physical activity levels, self efficacy, and perceived benefits and barriers were measured at the three time point (baseline, after week 8, and after week 16). Results indicated that obese adolescents' BMI significantly decreased (F = 3.51, p = .03) and physical activity (F = 4.01, p = .02) significantly increased over the 16-week obesity intervention. In addition, Exercise self-efficacy (F = 5.02) and perceived benefits toward physical activity (F = 5.34) significantly increased but perceived barriers of physical activity (F = 5.10) gradually decreased over the intervention. This study suggests that an obesity intervention combining physical activity and behavior-based motivational enhancement intervention significantly contributed to decreased BMI, increased physical activity, and positively changed psychological variables related to physical activity. This first application has resulted in preliminary support for this intervention modality within non-western obese adolescents. PMID- 24766555 TI - Allometric and non-allometric patterns in sexual dimorphism discrimination of wing shape in Ophion intricatus: might two male morphotypes coexist? AB - Bees and wasps could exhibit shape and size sexual dimorphism, and most of their morphological variation could depend on phenotypic responses due to environmental pressure during ontogenetic development. More complex measurement techniques related to size and shape rather than simply to mass and length should be required to analyze such a complex sexual dimorphism. In this study, differences related to wing shape and size of males and females of Ophion intricatus Brulle (Hymenoptera: Ichneumonidae) were evaluated using geometric morphometrics. Right and left wings of specimens were used, and a photographic matrix was constructed in which 18 morphological landmarks based on shape and vein patterns of the wings were digitalized. A multivariate analysis of wing shape showed significant differences between sexes and sites. The geometric variation demonstrated that the points at the intersection of radial and cubital-anal veins might be key characters to differentiate between sexes. This study also showed the presence of two clearly different male morphotypes coexisting in the same study site. However, it should be noted that the results of this study showed that the variation in wing shape is an analytical character in the determination of sexual differences in the family Ichneumonidae. These differences raise the question of whether sexual dimorphism of wing shape may be modulated by natural selection. PMID- 24766556 TI - Fabrication of graphene-encapsulated porous carbon-metal oxide composites as anode materials for lithium-ion batteries. AB - Porous carbons such as CMK-3 are commonly used as matrices to accommodate metal oxides for the improvement of their electrochemical performance. However, the mesostructure of CMK-3 may be destroyed gradually with the increase of metal oxide content and some particles are inevitably formed outside the pores of CMK 3, leading to a gradual decrease in capacity and poor cycling performance. Herein, graphene-encapsulated CMK-3-metal oxides (Fe3O4 and NiO) are synthesized through a stepwise heterocoagulation method and exhibit improved electrochemical performances compared to uncoated CMK-3-metal oxides. The core-shell structure of these novel composites can protect the metal oxide particles on the surface of CMK-3 and avoid the aggregation of porous carbon-metal oxides. Moreover, the introduction of graphene may stabilize the mesostructure of CMK-3 during lithiation and delithiation processes and improve the electronic conductivity of the composite, which are conducive to enhancing electrochemical performances of porous carbon-supported metal oxides. PMID- 24766557 TI - Safety of gastrointestinal endoscopic biopsy in patients taking antithrombotics. AB - BACKGROUND AND AIM: Current Japanese gastrointestinal (GI) endoscopic guidelines permit endoscopic biopsy without cessation of antiplatelet agents and warfarin in patients with a therapeutic range of prothrombin time-international normalized ratio (PT-INR) levels, although the evidence levels are low. We evaluated the safety of endoscopic biopsy in patients currently taking antithrombotics. METHODS: Consecutive patients receiving antithrombotics who underwent GI endoscopy from August 2012 to August 2013 were enrolled. Adverse events and endoscopic hemostasis after biopsy were evaluated. PT-INR level was measured in patients taking warfarin the day before endoscopy. RESULTS: Among 7939 patients undergoing endoscopy, 1034 patients (13.0%, 706 men and 328 women, average age 72.8 years) were receiving antithrombotics. Antithrombotics included aspirin (44.8%), warfarin (34.7%), thienopyridine (16.1%), cilostazol (10.3%), dabigatran (4.8%) etc. PT-INR levels in patients taking warfarin were >3.0 in 13 patients (4.3%), between 2.5 and 3.0 in 18 patients (6.0%), <2.5 in 269 patients (89.7%). Two hundred and six patients received endoscopic biopsy while taking aspirin (51.2%), warfarin (22.8%), and thienopyridine (13.6%). Endoscopic hemostasis was required in three patients after endoscopic biopsy (spraying thrombin in two patients, spraying thrombin and clipping in one patient). There were no major complications. The incidence of endoscopic hemostasis after biopsy in patients without antithrombotic cessation was not significantly different than in the controls not taking antithrombotics (1.5% vs 0.98%, P = 0.51). CONCLUSION: Endoscopic biopsy did not increase the bleeding risk despite not stopping antithrombotics prior to biopsy even among patients taking warfarin whose PT-INR was within the therapeutic range. PMID- 24766558 TI - No increase in colorectal cancer in patients under 50 years of age: a Victorian experience from the last decade. AB - AIM: The study aimed to assess whether there has been an increase in the incidence of colorectal cancer (CRC) among young patients in Victoria and whether such cancers are more advanced at presentation. METHOD: The Victorian Cancer registry database was searched for patients, 18-50 years of age, diagnosed with CRC [young colorectal cancer (YCRC)] between 2000 and 2010. Average annual percentage changes and incidence rate ratios (IRRs) were calculated to characterize trends in CRC rates over time and to make comparisons with patients over 50 years of age with CRC [late colorectal cancer (LCRC)]. RESULTS: Of 37432 CRCs registered during the study period, 2635 (7%) were in YCRC patients (annual increase in incidence = 1.7%; 95% CI: 0.5-2.9), compared with 34797 (93%) in LCRC patients (annual increase in incidence = 1.3%; 95% CI: 0.9-1.6). A small, nonsignificant increase in the incidence of YCRC over time was observed [IRR = 1.004 (95% CI: 0.992-1.016) for YCRC vs. 0.989 (95% CI: 0.986-0.992) for LCRC]. Rectal cancer was more common in YCRC patients than in LCRC patients (42% vs. 34%, respectively; P < 0.0001). The cancer would have been seen on flexible sigmoidoscopy in 63% of YCRC patients compared with 53.6% of LCRC patients (P < 0.0001). YCRC patients were more likely to have node-positive disease (49.3% YCRC patients vs. 40% LCRC patients; P < 0.0001), especially those with colonic cancer (52.7% YCRC patients vs. 41.2% LCRC patients; P < 0.0001). CONCLUSION: There has been an increase in incident cases of YCRC. A small, nonsignificant increase in the incidence of YCRC over time was observed. Young patients are more likely to have rectal cancer and to be node positive. PMID- 24766559 TI - An exploration of Australian hospital pharmacists' attitudes to patient safety. AB - OBJECTIVES: To explore the attitudes of Australian hospital pharmacists towards patient safety in their work settings. METHODS: A safety climate questionnaire was administered to all 2347 active members of the Society of Hospital Pharmacists of Australia in 2010. Part of the survey elicited free-text comments about patient safety, error and incident reporting. The comments were subjected to thematic analysis to determine the attitudes held by respondents in relation to patient safety and its quality management in their work settings. KEY FINDINGS: Two hundred and ten (210) of 643 survey respondents provided comments on safety and quality issues related to their work settings. The responses contained a number of dominant themes including issues of workforce and working conditions, incident reporting systems, the response when errors occur, the presence or absence of a blame culture, hospital management support for safety initiatives, openness about errors and the value of teamwork. A number of pharmacists described the development of a mature patient-safety culture - one that is open about reporting errors and active in reducing their occurrence. Others described work settings in which a culture of blame persists, stifling error reporting and ultimately compromising patient safety. CONCLUSION: Australian hospital pharmacists hold a variety of attitudes that reflect diverse workplace cultures towards patient safety, error and incident reporting. This study has provided an insight into these attitudes and the actions that are needed to improve the patient-safety culture within Australian hospital pharmacy work settings. PMID- 24766560 TI - Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells. AB - A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 MUM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation. PMID- 24766562 TI - Priming word order by thematic roles: no evidence for an additional involvement of phrase structure. AB - Three experiments are reported that studied the priming of word order in German. Experiment 1 demonstrated priming of the order of case-marked verb arguments. However, order of noun phrases and order of thematic roles were confounded. In Experiment 2, we therefore aimed at disentangling the impact of these two possible factors. By using primes that differed from targets in phrase structure but were parallel with regard to the order of thematic roles, we nevertheless found priming demonstrating the critical impact of thematic roles. Experiment 3 replicated the priming effects from Experiments 1 and 2 within participants and revealed no evidence for a modulation of priming by phrase structure. Consequently, our findings suggest that word order priming crucially depends on the structural outline of thematic roles rather than on the linearization of phrases. PMID- 24766561 TI - Frequent and discriminative subnetwork mining for mild cognitive impairment classification. AB - Recent studies on brain networks have suggested that many brain diseases, such as Alzheimer's disease and mild cognitive impairment (MCI), are related to a large scale brain network, rather than individual brain regions. However, it is challenging to find such a network from the whole brain network due to the complexity of brain networks. In this article, the authors propose a novel method to mine the discriminative subnetworks for classifying MCI patients from healthy controls (HC). Specifically, the authors first extract a set of frequent subnetworks from each of the two groups (i.e., MCI and HC), respectively. Then, measure the discriminative ability of those frequent subnetworks using the graph kernel-based classification method and select the most discriminative subnetworks for subsequent classification. The results on the functional connectivity networks of 12 MCI and 25 HC show that this method can obtain competitive results compared with state-of-the-art methods on MCI classification. PMID- 24766563 TI - Impact of ICD artifact burden on late gadolinium enhancement cardiac MR imaging in patients undergoing ventricular tachycardia ablation. AB - BACKGROUND: Cardiac magnetic resonance imaging (CMRI) is the gold standard for myocardial scar evaluation. Although ideal for substrate assessment in ventricular tachycardia (VT), most patients have an implantable cardioverter defibrillator (ICD) at presentation for ablation. This study evaluates the ICD artifact burden during standard late gadolinium enhancement CMRI (LGE-CMRI) evaluation of myocardial scar in VT patients with ICDs. METHODS: Thirty-one patients with ICD and cardiomyopathy underwent LGE-CMRI using 1.5-T magnetic resonance scanner before VT ablation. Using the American Heart Association (AHA) 17-segment model, short-axis LGE series were analyzed for artifact burden localization and assessment. RESULTS: Preablation CMRI was performed in 31 patients with single chamber (n = 13), dual chamber (n = 11), and biventricular (n = 7) ICDs. Pre- and post-MRI ICD parameters were unchanged. All patients had susceptibility artifact and 51.6% (256 of 496) of segments were affected by artifact. The artifact area (178 +/- 136 cm(2) ) resulted in an artifact burden of 54 +/- 21% of the LV myocardial area (327 +/- 15 cm(2) ). The anterior wall was most affected by artifact (89%) compared with 52%, 49%, and 23% in the lateral, septal, and inferior walls, respectively (P < 0.0001). The apical segments had more artifact burden (66%) than the mid (49%) and basal (44%) segments (P = 0.0005). Artifact area correlated with ICD-heart distance on anteroposterior chest radiograph (r = 0.42, P = 0.021) and body mass index (r = 0.48, P = 0.008). CONCLUSIONS: Current clinical LGE-CMRI scar imaging protocols produce ICD artifacts that affect >50% of the LV myocardium and correlate with the ICD-heart distance. This significantly limits the application of CMRI for image-guided VT ablation. PMID- 24766564 TI - Accurate flow cytometric monitoring of Escherichia coli subpopulations on solid food treated with high pressure carbon dioxide. AB - AIMS: Evaluation of flow cytometry coupled with viability markers to monitor the inactivation of Escherichia coli cells spiked on solid food following High Pressure Carbon Dioxide (HPCD), a mild processing technology. METHODS AND RESULTS: Flow cytometry (FCM) coupled with SYBR-Green I and Propidium Iodide was applied to monitor the effect of HPCD treatment on E. coli cells spiked on fresh cut carrots, therefore mimicking contamination of food products by faecal coliforms. FCM allowed to distinguish E. coli cells from carrot debris and natural flora, to evaluate the reduction of total cells, and to quantify viable and dead cells based on their membrane integrity after HPCD treatment. The comparison of FCM results with conventional cultivation methods revealed that HPCD treatments performed at 120 bar, 22 or 35 degrees C for 5 min disrupted 43 and 53% of bacterial cells, respectively, and produced a large percentage of partially permeabilized (96.5 and 98%) cells. CONCLUSIONS: Although treatments at 22 degrees C for 10 min and at 35 degrees C for 7 min were sufficient to inhibit the ability of all E. coli cells to replicate with an inactivation of 8 Log, FCM analysis showed that the inactivation of intact cells was only 2-2.5 Log. A fraction of HPCD-treated cells maintained their metabolic activity and re-growth capacity, indicating that the treatment induces a transitory Viable But Not Cultivable (VNBC) state. SIGNIFICANCE AND IMPACT OF THE STUDY: Under stress conditions many pathogens enter in a VBNC state, thus escaping detection by traditional cultivation methods. We provide the first evaluation of HPCD-mediated bacterial inactivation on fresh food using FCM coupled with viability markers, which should assist in the prevention of food-associated health risks. PMID- 24766565 TI - Environmental variables associated with an increased risk of invasive aspergillosis. AB - Information on the environmental variables that may affect the incidence of invasive aspergillosis (IA) is scarce. We sought to determine the relationship between airborne spore counts, climatic conditions and IA. We also examined whether circulating respiratory viruses predispose patients to IA in a multicentre cohort study of hospitalized adults with IA. Data on environmental mould spores, climatic conditions and circulating respiratory viruses were obtained from the Environmental Department of the Autonomous University of Barcelona, the Meteorological Service of Catalonia and the Acute Respiratory Infection Surveillance Project in Catalonia, respectively. Between 2008 and 2011, 165 patients with IA were identified. Diagnosis was based on one or more of the following: culture (125 cases), galactomannan antigen (98) and histology (34). One hundred and twenty-seven cases (77%) had criteria for probable IA and the remainder for proven IA. Environmental mould spore counts from the period 28-42 days preceding infection presented significant associations with admissions due to IA. None of the climatic conditions were associated with an increased risk of IA, but the presence of circulating respiratory viruses was associated with a higher risk of infection: the most strongly associated viruses were respiratory syncytial virus, influenza A(H1N1)pdm09 and adenovirus. In conclusion, the presence of high numbers of spores in the air increases the risk of admission due to IA. Circulating respiratory viruses appear to be associated with a higher risk of developing IA. Physicians should be aware of this association in order to optimize prevention and diagnosis strategies for IA during viral epidemic periods. PMID- 24766566 TI - Phase identification and structure solution by three-dimensional electron diffraction tomography: Gd-phosphate nanorods. AB - Hydrothermal synthesis of GdPO4 in the presence of poly(methacrylic acid) yields nanorods with a diameter of 15 nm and an aspect ratio of 20. Powder X-ray diffraction patterns showed that the GdPO4 nanorods display peaks characteristics for both monoclinic and hexagonal structures. Three-dimensional electron diffraction tomography (3D EDT) was used to determine the structures ab initio on the basis of reciprocal volume reconstruction of electron diffraction data sets collected from single nanorods. The crystal structure of the monoclinic form was shown to be P21/n, corroborating previous work. We were able to solve the 3D structure of the hexagonal P6222 form, which has not been reported previously. Our work shows that 3D EDT is a powerful method that can be used for solving structures of single nanocrystals. PMID- 24766567 TI - Homolytic cleavage of molecular oxygen by manganese porphyrins supported on Ag(111). AB - Oxygen binding and cleavage are important for both molecular recognition and catalysis. Mn-based porphyrins in particular are used as catalysts for the epoxidation of alkenes, and in this study the homolytic cleavage of O2 by a surface-supported monolayer of Mn porphyrins on Ag(111) is demonstrated by scanning tunneling microscopy, X-ray absorption, and X-ray photoemission. As deposited, {5,10,15,20-tetraphenylporphyrinato}Mn(III)Cl (MnClTPP) adopts a saddle conformation with the average plane of its macrocycle parallel to the substrate and the axial Cl ligand pointing upward, away from the substrate. The adsorption of MnClTPP on Ag(111) is accompanied by a reduction of the Mn oxidation state from Mn(III) to Mn(II) due to charge transfer between the substrate and the molecule. Annealing the Mn(II)ClTPP monolayer up to 510 K causes the chlorine ligands to desorb from the porphyrins while leaving the monolayer intact. The Mn(II)TPP is stabilized by the surface acting as an axial ligand for the metal center. Exposure of the Mn(II)TPP/Ag(111) system to molecular oxygen results in the dissociation of O2 and forms pairs of Mn(III)OTPP molecules on the surface. Annealing at 445 K reduces the Mn(III)OTPP complex back to Mn(II)TPP/Ag(111). The activation energies for Cl and O removal were found to be 0.35 +/- 0.02 eV and 0.26 +/- 0.03 eV, respectively. PMID- 24766568 TI - Treatment of periodontal-endodontic lesions--a systematic review. AB - BACKGROUND: The treatment of periodontal-endodontic lesions is challenging due to the involvement of both periodontal and endodontic tissues. OBJECTIVE: To evaluate the treatment options and outcomes of periodontal-endodontic lesions. MATERIAL AND METHODS: A systematic literature search was performed for articles published by 12 May 2013 using electronic databases and hand search. Two reviewers conducted the study selection, data collection and validity assessment. The PRISMA criteria were applied. From 1087 titles identified by the search strategy, five studies and 18 case reports were included. RESULTS: Clinical studies and case reports were published from the years 1981 to 2012. A pronounced heterogeneity exists among studies regarding applied treatment protocols and quality of reporting. In all clinical studies, comprising 111 teeth, a non surgical root canal treatment (RCT) was performed as initial treatment step. Non surgical and/or a surgical periodontal therapy was applied in some studies without re-evaluation of the endodontic healing. Probing pocket depth reductions were reported in all included studies, comprising the data from 80 teeth at follow-up. CONCLUSIONS: A sequential treatment with root canal treatment as a first treatment step appears to be reasonable. An adequate time for tissue healing is suggested prior to re-evaluation. PMID- 24766569 TI - Medical abortion with mifepristone and home administration of misoprostol up to 63 days' gestation. AB - OBJECTIVE: To evaluate the acceptability and efficacy of medical abortion at home up to 63 days' gestation without limits on travel distance to a registered institution. DESIGN: Observational prospective study. SETTING: Haukeland University Hospital between May 2006 and May 2009. POPULATION: A total of 1018 women requesting abortion before 63 days' gestation who chose medical termination with mifepristone and home administration of misoprostol. METHODS: The women took 200 mg mifepristone under nurse supervision and self-administered 800 MUg misoprostol vaginally 36-48 h later at home. All were contacted by phone for follow-up and assessment of bleeding, pain and acceptability. MAIN OUTCOME MEASURES: Evacuation rate, pain, bleeding, acceptability, influence of distance on treatment. RESULTS: Median gestational age was 50 (range 35-63) days and 70 (7.1%) of the women lived more than 60 min travel from the clinic. The rate of completed abortion was 93.6% and surgical evacuation was performed in 50 (4.9%) cases. Two women requested treatment on the day of misoprostol use. Moderate to strong pain was experienced by 68.4%, and 74.7% reported moderate to heavy bleeding. Parous women experienced less pain than nulliparous women (odds ratio 0.27; 95% confidence interval 0.19-0.34). In all, 95.1% of the women were satisfied with staying at home. Travel distance did not influence treatment outcome variables. CONCLUSIONS: In our experience, home administration of misoprostol is an effective and acceptable method for abortion up to 63 days of gestation and women should be eligible for this treatment option regardless of their travel distance from hospital. PMID- 24766570 TI - Renal sympathetic denervation: early impact on ambulatory resistant hypertension. AB - Although guidelines recommend ambulatory blood pressure (BP) monitoring (ABPM), few data are available regarding the effects of renal denervation (RDN) on 24 hour ABPM values. A total of 44 patients with mean systolic BP >=135 mm Hg on ABPM despite adequate therapy were included. Basal systolic BP (SBP) and diastolic BP (DBP) were 154+/-11 mm Hg and 86+/-12 mm Hg, respectively. At 1 month, SBP and DBP were reduced to 146+/-18 mm Hg (P=.01) and 82+/-14 mm Hg and showed no further decrease up to 6 months. Only 55% of the patients responded to RDN (>=-5 mm Hg SBP), with a mean responder rate drop of 21/11 mm Hg. Neither the number of ablation points nor the amount of impedance drop was predictive of response. Only approximately half of patients with resistant hypertension responded to RDN. However, in these responders, a remarkable reduction of 24-hour BP occurred as early as 1 month after RDN. PMID- 24766571 TI - Emerging therapeutic interventions for idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a devastating and relentlessly progressive lung disorder. Previously, it was thought to be a chronic inflammatory disease; however, it is now considered to be an epithelial fibroblastic disease. In accordance with this paradigm change, efforts toward the development of novel therapeutic targets for IPF have acquired a new direction. Currently available therapies are largely ineffective in reversing the lung damage, and lung transplantation is the only effective treatment for end-stage disease. Limitations in advancement of IPF therapeutics are due to a poor understanding of its pathogenesis, unavailability of reliable animal models and slow disease progression. Recent research on IPF has resulted in the identification of a plethora of novel targets that are in various stages of development and offers hope that in the near future that there will be better therapeutic options available for the treatment of IPF. AREAS COVERED: This review discusses existing therapies and highlights some of the recent, novel therapeutics being explored in the current clinical landscape for the treatment of this chronic, disabling disorder. The review also discusses the pathogenic rationale behind current therapies. EXPERT OPINION: Targeting one fibrotic signaling pathway at a time may not have any significant effect on the control of IPF. It is therefore recommended that future IPF management focuses on targeting multiple pro-fibrotic pathways associated with its complex pathogenesis. PMID- 24766572 TI - Motor development in 3-month-old healthy term-born infants is associated with cognitive and behavioural outcomes at early school age. AB - AIM: To determine whether motor development at 3 months of age is associated with cognitive, motor, and behavioural outcomes in healthy children at early school age. METHOD: In this cohort study, we included 74 term-born, healthy children (44 males, 30 females; median gestational age 40.1 wks, range 38.0-42.6 wks). From video recordings (median 12.9 wks, range 9.3-18.6 wks), we assessed the quality of fidgety movements, and calculated a motor optimality score. At school age (median 5 y 11 mo, range 5 y 8 mo-7 y 6 mo), we performed detailed cognitive, motor, and behavioural assessments. We examined whether aspects of motor development were associated with functional outcomes. RESULTS: An age-adequate motor repertoire, in particular the presence of antigravity, midline leg, and manipulation movements, was related to poorer cognition, whereas variable finger postures was related to better cognition. Children with a monotonous concurrent motor repertoire had better ball skills but experienced more behavioural problems. The presence of antigravity movements tended to be associated with abnormal recognition (odds ratio [OR] 4.4, 95% confidence interval [CI], 0.9-21; R(2) =0.17; p=0.070), where the absence of variable finger postures was associated with borderline and abnormal visual-spatial perception (OR 20, 95% CI, 1.7-238; R(2) =0.39; p=0.018). INTERPRETATION: Detailed aspects of motor development at 3 months of age are associated with cognition and behaviour, but not with motor outcome, in healthy children at early school age. Our findings suggest that early motor development may be the basis for later cognitive and behavioural performance. Since the associations were only moderate, possible environmental influences should be acknowledged. PMID- 24766573 TI - Efficient collection and sensitive detection using conducting magnetic microbeads. AB - Conducting magnetic microbeads were successfully fabricated through a simple procedure that involves coating magnetic microbeads with gold nanoparticles. The formation of a gold layer on the bead enabled the simple introduction of a biotin probe onto the bead, resulting in the binding capacity with streptavidin being 10 times greater than that of commercially available biotin-binding magnetic beads. In addition to the high recovery via magnetic forces and high dispersibility in the sample solution, the accumulation of highly conductive beads on the electrode resulted in the amplification of the electrochemical response of the detection system. This paper reports the efficient collection and highly sensitive detection of target biomolecules using Au-coated magnetic microbeads. PMID- 24766575 TI - Efficient and accurate glycopeptide identification pipeline for high-throughput site-specific N-glycosylation analysis. AB - Study of site-specific N-glycosylation in complex sample remains a huge analytical challenge because protein glycosylation is structurally diverse in post-translational modifications, resulting in an intricacy of N-glycopeptides. Here we have developed a novel approach for high-throughput N-glycopeptide profiling based on a network-centric algorithm for deciphering glycan fragmentation in mass spectrometry. We performed an extensive validation and a high-throughput N-glycosylation study on serum and identified thousands of N glycopeptide spectra with high confidence. The results revealed a similar level of glycan microheterogeneity to that of conventional glycomics approach on individual proteins and provided the unique in-depth site-specific information that could only be studied through glycopeptide profiling. PMID- 24766574 TI - Cognitive correlates of functional abilities in individuals with mild cognitive impairment: comparison of questionnaire, direct observation, and performance based measures. AB - The relationship between, and the cognitive correlates of, several proxy measures of functional status were studied in a population with mild cognitive impairment (MCI). Participants were 51 individuals diagnosed with MCI and 51 cognitively healthy older adults (OA). Participants completed performance-based functional status tests and standardized neuropsychological tests, and performed eight activities of daily living (e.g., watered plants, filled medication dispenser) while under direct observation in a campus apartment. An informant interview about everyday functioning was also conducted. Compared to the OA control group, the MCI group performed more poorly on all proxy measures of everyday functioning. The informant report of instrumental activities of daily living (IADL) did not correlate with the two performance-based measures; however, both the informant-report IADL and the performance-based everyday problem-solving test correlated with the direct observation measure. After controlling for age and education, cognitive predictors did not explain a significant amount of variance in the performance-based measures; however, performance on a delayed memory task was a unique predictor for the informant-report IADL, and processing speed predicted unique variance for the direct observation score. These findings indicate that differing methods for evaluating functional status are not assessing completely overlapping aspects of everyday functioning in the MCI population. PMID- 24766576 TI - Amino acid networks in a (beta/alpha)8 barrel enzyme change during catalytic turnover. AB - Proteins can be viewed as small-world networks of amino acid residues connected through noncovalent interactions. Nuclear magnetic resonance chemical shift covariance analyses were used to identify long-range amino acid networks in the alpha subunit of tryptophan synthase both for the resting state (in the absence of substrate and product) and for the working state (during catalytic turnover). The amino acid networks observed stretch from the surface of the protein into the active site and are different between the resting and working states. Modification of surface residues on the network alters the structural dynamics of active-site residues over 25 A away and leads to changes in catalytic rates. These findings demonstrate that amino acid networks, similar to those studied here, are likely important for coordinating structural changes necessary for enzyme function and regulation. PMID- 24766577 TI - Atmospheric fate of nitramines: an experimental and theoretical study of the OH reactions with CH3NHNO2 and (CH3)2NNO2. AB - The rates of CH3NHNO2 and (CH3)2NNO2 reaction with OH radicals were determined relative to CH3OCH3 and CH3OH at 298 +/- 2 K and 1013 +/- 10 hPa in purified air by long path FTIR spectroscopy, and the rate coefficients were determined to be k(OH+CH3NHNO2) = (9.5 +/- 1.9) * 10(-13) and k(OH+(CH3)2NNO2) = (3.5 +/- 0.7) * 10(-12) (2sigma) cm(3) molecule(-1) s(-1). Ozone was found to react very slowly with the two nitramines, k(O3+nitramine) < 10(-21) cm(3) molecule(-1) s(-1). Product formation in the photo-oxidation of CH3NHNO2 and (CH3)2NNO2 was studied by FTIR, PTR-ToF-MS, and quantum chemistry calculations; the major products in the OH-initiated degradation are the corresponding imines, CH2?NH and CH3N?CH2, and N-nitro amides, CHONHNO2 and CHON(CH3)NO2. Atmospheric degradation mechanisms are presented. PMID- 24766578 TI - Localizing chemical groups while imaging single native proteins by high resolution atomic force microscopy. AB - Simultaneous high-resolution imaging and localization of chemical interaction sites on single native proteins is a pertinent biophysical, biochemical, and nanotechnological challenge. Such structural mapping and characterization of binding sites is of importance in understanding how proteins interact with their environment and in manipulating such interactions in a plethora of biotechnological applications. Thus far, this challenge remains to be tackled. Here, we introduce force-distance curve-based atomic force microscopy (FD-based AFM) for the high-resolution imaging of SAS-6, a protein that self-assembles into cartwheel-like structures. Using functionalized AFM tips bearing Ni(2+)-N nitrilotriacetate groups, we locate specific interaction sites on SAS-6 at nanometer resolution and quantify the binding strength of the Ni(2+)-NTA groups to histidine residues. The FD-based AFM approach can readily be applied to image any other native protein and to locate and structurally map histidine residues. Moreover, the surface chemistry used to functionalize the AFM tip can be modified to map other chemical interaction sites. PMID- 24766579 TI - Where are all the female participants in Sports and Exercise Medicine research? AB - The aim of this study is to estimate the ratio of male and female participants in Sports and Exercise Medicine research. Original research articles published in three major Sports and Exercise Medicine journals (Medicine and Science in Sports and Exercise, British Journal of Sports Medicine and American Journal of Sports Medicine) over a three-year period were examined. Each article was screened to determine the following: total number of participants, the number of female participants and the number of male participants. The percentage of females and males per article in each of the journals was also calculated. Cross tabulations and Chi-square analysis were used to compare the gender representation of participants within each of the journals. Data were extracted from 1382 articles involving a total of 6,076,580 participants. A total of 2,366,968 (39%) participants were female and 3,709,612 (61%) were male. The average percentage of female participants per article across the journals ranged from 35% to 37%. Females were significantly under-represented across all of the journals (chi(2) = 23,566, df = 2, p < 0.00001). In conclusion, Sports and Exercise Medicine practitioners should be cognisant of sexual dimorphism and gender disparity in the current literature. PMID- 24766580 TI - Young women's reasons to seek sexually transmitted infection screening. AB - OBJECTIVES: To describe young women's reasons to seek and not to seek sexually transmitted infection (STI) screening; to explore whether reasons differed by age and STI screening history. DESIGN AND SAMPLE: Cross-sectional, descriptive. Female students (N = 216) at a university in the Midwestern United States. MEASURES: An anonymous online survey was designed based on the Theory of Care Seeking Behavior and literature regarding STI screening among young women. RESULTS: The most common reason to seek STI screening was to start treatment promptly (85%); the most common reason not to seek screening was being asymptomatic (54%). Participants' reasons differed by age and screening history. Women under 25 were more likely than women 25 and older to seek screening because of encouragement from female role models (p < .01). Women who had never been screened were more likely than women who had been screened to avoid screening because of embarrassment (p < .05). Novel findings included seeking STI screening because it "should be done" if sexually active and because of encouragement from female role models. CONCLUSIONS: Health care and public health professionals can use these findings to develop strategies to improve STI screening rates among young women. PMID- 24766581 TI - The effects of riverine physical complexity on anadromy and genetic diversity in steelhead or rainbow trout Oncorhynchus mykiss around the Pacific Rim. AB - This study explored the relationship between riverine physical complexity, as determined from remotely sensed metrics, and anadromy and genetic diversity in steelhead or rainbow trout Oncorhynchus mykiss. The proportion of anadromy (estimated fraction of individuals within a drainage that are anadromous) was correlated with riverine complexity, but this correlation appeared to be driven largely by a confounding negative relationship between drainage area and the proportion of anadromy. Genetic diversity decreased with latitude, was lower in rivers with only non-anadromous individuals and also decreased with an increasing ratio of floodplain area to total drainage area. Anadromy may be less frequent in larger drainages due to the higher cost of migration associated with reaches farther from the ocean, and the negative relationship between genetic diversity and floodplain area may be due to lower effective population size resulting from greater population fluctuations associated with higher rates of habitat turnover. Ultimately, the relationships between riverine physical complexity and migratory life history or genetic diversity probably depend on the spatial scale of analysis. PMID- 24766582 TI - Optimal gating strategy for determining CD4+ recent thymic emigrants in human immunodeficiency virus-1 infected patients. AB - Alterations of the frequencies of recent thymic emigrants (RTEs) in blood have been demonstrated to be associated with human immunodeficiency virus-1 (HIV-1) disease progression and immune reconstitution following antiretroviral therapy. Flow cytometry is a technology that offers many advantages over T-cell receptor excision circles (TRECs) quantification to determine the RTE subset in blood. However, the gating strategies for identifying RTEs by flow cytometry have not been evaluated and compared in much detail. In the present study, we compared the frequencies and the senescence levels of RTEs in 54 HIV-1 seronegative controls (HC) and 70 HIV-1 seropositive (HIV-1+) subjects using two different gating strategies by flow cytometry. Our analysis indicated that the CD4+ RTE population determined by the expressing pattern CD45RO-CD31+ contained the terminal effector memory T-cell population after HIV-1 infection, which could significantly affect the further phenotypic and functional studies. Our data demonstrate the necessity of including an additional marker such as CCR7 to distinguish better CD4+RTE subset in HIV-1+ subjects. PMID- 24766583 TI - Antimicrobial susceptibility testing in biofilm-growing bacteria. AB - Biofilms are organized bacterial communities embedded in an extracellular polymeric matrix attached to living or abiotic surfaces. The development of biofilms is currently recognized as one of the most relevant drivers of persistent infections. Among them, chronic respiratory infection by Pseudomonas aeruginosa in cystic fibrosis patients is probably the most intensively studied. The lack of correlation between conventional susceptibility test results and therapeutic success in chronic infections is probably a consequence of the use of planktonically growing instead of biofilm-growing bacteria. Therefore, several in vitro models to evaluate antimicrobial activity on biofilms have been implemented over the last decade. Microtitre plate-based assays, the Calgary device, substratum suspending reactors and the flow cell system are some of the most used in vitro biofilm models for susceptibility studies. Likewise, new pharmacodynamic parameters, including minimal biofilm inhibitory concentration, minimal biofilm eradication concentration, biofilm bactericidal concentration, and biofilm prevention concentration, have been defined in recent years to quantify antibiotic activity in biofilms. Using these parameters, several studies have shown very significant quantitative and qualitative differences for the effects of most antibiotics when acting on planktonic or biofilm bacteria. Nevertheless, standardization of the procedures, parameters and breakpoints, by official agencies, is needed before they are implemented in clinical microbiology laboratories for routine susceptibility testing. Research efforts should also be directed to obtaining a deeper understanding of biofilm resistance mechanisms, the evaluation of optimal pharmacokinetic/pharmacodynamic models for biofilm growth, and correlation with clinical outcome. PMID- 24766584 TI - Undergraduate physiotherapy students' competencies, attitudes and perceptions after integrated educational pathways in evidence-based practice: a mixed methods study. AB - This mixed methods study aimed to explore perceptions/attitudes, to evaluate knowledge/ skills, to investigate clinical behaviours of undergraduate physiotherapy students exposed to a composite education curriculum on evidence based practice (EBP). Students' knowledge and skills were assessed before and after integrated learning activities, using the Adapted Fresno test, whereas their behaviour in EBP was evaluated by examining their internship documentation. Students' perceptions and attitudes were explored through four focus groups. Sixty-two students agreed to participate in the study. The within group mean differences (A-Fresno test) were 34.2 (95% CI 24.4 to 43.9) in the first year and 35.1 (95% CI 23.2 to 47.1) in the second year; no statistically significant change was observed in the third year. Seventy-six percent of the second year and 88% of the third year students reached the pass score. Internship documentation gave evidence of PICOs and database searches (95-100%), critical appraisal of internal validity (25-75%) but not of external validity (5-15%). The correct application of these items ranged from 30 to 100%. Qualitative analysis of the focus groups indicated students valued EBP, but perceived many barriers, with clinicians being both an obstacle and a model. Key elements for changing students' behaviours seem to be internship environment and possibility of continuous practice and feedback. PMID- 24766585 TI - Pathogenicity of the entomopathogenic fungus Metarhizium anisopliae var. major on different stages of the sunn pest Eurygaster integriceps. AB - The sunn pest, Eurygaster integriceps Puton (Hemiptera: Scutelleridae), is the most important insect pest of wheat and barley. The population management of this pest is of major concern to wheat producers. One of the potential control strategies is to use entomopathogenic fungi. This study evaluates the pathogenicity of the fungus Metarhizium anisopliae var. major (Metchnikoff) Sorokin (Hypocreales: Clavicipitaceae) on the sunn pest, E. integriceps. Five concentrations of the fungus were utilized, ranging from 1*10(4) to 1*10(8) conidia/mL, accompanied by controls. Fifth instar nymphs and adults (a migratory summer population and a diapausing population) previously exposed to fungi were sown to isolate the fungi, and the growth parameters were analyzed. A direct spray technique was used to expose the isolates to the E. integriceps. The experiment was repeated four times, and mortalities of the insects for all treatments were recorded daily. The results showed that the mortality of infected nymphs was significantly higher than the mortality of control nymphs. Also, the longevity of infected adults was lower than the controls. The results also showed that diapausing adults of the sunn pest were much more susceptible to infection than the summer adults. Estimated LC50 values for the M14 isolate were 1.4 * 10(6), 1.4 *10 (5) , and 2.3 * 10(3) spores/mL against the aestivation population, the diapausing population, and 5(th) instar nymphs, respectively. Estimated LT50 values using 10(8) spores/mL of the Mm isolate on the aestivation and diapausing populations were 11.9 and 5.11 days, respectively. The results demonstrated that M. anisoplaie was effective on all of stages of E. integriceps. In addition, the nymphal stage was more susceptible than the adults. PMID- 24766586 TI - Fe3O4/PVIM-Ni2+ magnetic composite microspheres for highly specific separation of histidine-rich proteins. AB - Integration of the advantages of immobilized metal-ion affinity chromatography (IMAC) and magnetic microspheres is considered as an ideal pathway for quick and convenient separation of his-tagged proteins, but rare reports concern the natural histidine-rich proteins. In this article, a novel route was presented to fabricate magnetic microspheres composed of a high-magnetic-response magnetic supraparticle (Fe3O4) core and a Ni(2+)-immobilized cross-linked polyvinyl imidazole (PVIM) shell via reflux-precipitation polymerization. The unique as prepared Fe3O4/PVIM-Ni(2+) microspheres possessed uniform flower-like structure, high magnetic responsiveness, abundant binding sites, and very easy synthesis process. Taking advantage of the pure PVIM-Ni(2+) interface and high Ni(2+) loading amount, the microspheres exhibited remarkable selectivity, excellent sensitivity, large enrichment capacity, and high recyclability in immobilization and separation of his-tagged recombinant proteins. More interestingly, it was found that the Fe3O4/PVIM-Ni(2+) microspheres also showed excellent performance for removal of the natural histidine-rich bovine serum albumin (BSA) from the complex real sample of fetal bovine serum due to the exposed histidine residues. Considering their multiple merits, this new type of Fe3O4/PVIM-Ni(2+) nanomaterial displays great potential in enriching low-abundant his-tagged proteins or removing high-abundant histidine-rich natural proteins for proteomic analysis. PMID- 24766587 TI - Accelerated ketoprofen release from spray-dried polymeric particles: importance of phase transitions and excipient distribution. AB - HPMC-, PVPVA- and PVP-based microparticles loaded with 30% ketoprofen were prepared by spray drying suspensions or solutions in various water:ethanol blends. The inlet temperature, drying gas and feed flow rates were varied. The resulting differences in the ketoprofen release rates in 0.1 M HCl could be explained based on X-ray diffraction, mDSC, SEM and particle size analysis. Importantly, long term stable drug release could be provided, being much faster than: (i) drug release from a commercial reference product, (ii) the respective physical drug:polymer mixtures, as well as (iii) the dissolution of ketoprofen powder as received. In addition, highly supersaturated release media were obtained, which did not show any sign for re-crystallization during the observation period. Surprisingly, spraying suspensions resulted in larger microparticles exhibiting faster drug release compared to spraying solutions, which resulted in smaller particles exhibiting slower drug release. These effects could be explained based on the physico-chemical characteristics of the systems. PMID- 24766588 TI - Mathematical simulation of chlorinated ethene concentration rebound after in situ chemical oxidation. AB - Permanganates have been used for in situ chemical oxidation (ISCO) projects since the 1990s. Unfortunately, there has been very little research performed on the phenomenon of concentration rebound after ISCO. Most research on ISCO has focused on demonstrating effectiveness, estimating kinetics, or quantifying the effects of reaction products. Only one study has demonstrated that a correlation between concentration rebound and hydrogeological parameters exists. Our study uses a numerical solution to an advection-dispersion-reaction equation to quantify a correlation between the rate of concentration rebound and molecular diffusivity in pure water. It accomplishes this by simulating a variety of sites contaminated with chlorinated ethenes that also had an ISCO with permanganate. Each simulation included advection, two-dimensional dispersion, oxidation, concentration rebound, natural oxidant demand, and retardation. Five sites were suitable for simulation and eight cells were delineated within the five sites. These cells allowed for a variety of soils, contaminants, injection methods (i.e. frequency, depth, mass of oxidant, duration, etc...), time scales, spatial scales, and hydrogeological variables to be examined. A robust correlation (R(2) = 0.92) was identified with a regression analysis between the molecular diffusion coefficient in pure water and the rate of concentration rebound. PMID- 24766589 TI - A novel microextractor stick (polyaniline/zinc film/stainless steel) for polycyclic aromatic hydrocarbons in water. AB - A novel microextractor stick (MES) has been developed for the determination of trace amounts of polycyclic aromatic hydrocarbons (PAHs) in water samples. The proposed MES was prepared by electrodepositing a Zn-film onto a stainless steel stick followed by a coating with polyaniline (PANI) sorptive layers. This PANI/Zn film/stainless steel stick produced a large surface area, provided a high extraction efficiency (82.0 +/- 6.2% to 111.0 +/- 7.5% recovery) of spiked chrysene (Chry) and benzo(a)pyrene (BaP). This MES is cost-effective, easy to prepare, robust and provides a good stick-to-stick reproducibility (n = 10) with a relative standard deviation of less than 10%. The effect of various parameters on the efficiency of extraction of PAHs were optimized, including the extraction time, extraction and desorption stirring speeds, volume of desorption solvent and desorption time. Under the optimum conditions, the limit of detection (S/N >= 3) and limit of quantification (S/N >= 10) of both Chry and BaP were 0.05 and 0.12 MUg L(-1), respectively. The developed MES was successfully applied to determine PAHs in real water samples. PMID- 24766590 TI - Kinetic study of acetaminophen degradation by visible light photocatalysis. AB - In this work, a novel photocatalyst K3[Fe(CN)6]/TiO2 synthesized via a simple sol gel method was utilized to degrade acetaminophen (ACT) under visible light with the use of blue and green LED lights. Parameters (medium pH, initial concentration of reactant, catalyst concentration, temperature, and number of blue LED lights) affecting photocatalytic degradation of ACT were also investigated. The experimental result showed that compared to commercially available Degussa P-25 (DP-25) photocatalyst, K3[Fe(CN)6]/TiO2 gave higher degradation efficiency and rate constant (kapp) of ACT. The degradation efficiency or kapp decreased with increasing initial ACT concentration and temperature, but increased with increased number of blue LED lamps. Additionally, kapp increased as initial pH was increased from 5.6 to 6.9, but decreased at a high alkaline condition (pH 8.3). Furthermore, the degradation efficiency and kapp of ACT increased as K3[Fe(CN)6]/TiO2 loading was increased to 1 g L(-1) but decreased and eventually leveled off at photocatalyst loading above this value. Photocatalytic degradation of ACT in K3[Fe(CN)6]/TiO2 catalyst system follows a pseudo-first-order kinetics. The Langmuir-Hinshelwood equation was also satisfactorily used to model the degradation of ACT in K3[Fe(CN)6]/TiO2 catalyst system indicated by a satisfactory linear correlation between 1/kapp and Co, with kini = 6.54 * 10(-4) mM/min and KACT = 17.27 mM(-1). PMID- 24766591 TI - Temporal and spatial variations in PAH concentrations in the sediment from the Nilufer Creek in Bursa, Turkey. AB - The objective of this study was to identify the temporal variations in PAH concentrations in the sediment at different locations on the Nilufer Creek moving along an industrial city. The distribution of various PAH species and their possible sources were determined. Sediment samples were taken from at eight different locations on the Nilufer Creek for a one-year period. Temporal concentration profiles were in the range of 15-9600 ng g(-1) dry matter (dm). PAH concentrations reached their maximum values in the winter (9600 ng g(-1) dm). Molecular diagnostic ratios of PAHs showed that the pollution in the Nilufer Creek in the fall, winter and summer seasons was mostly pyrolytic. It was observed that 3-4 ring species predominated in all seasons in the Nilufer Creek sediment. PMID- 24766592 TI - Adsorption of naphthenic acids on high surface area activated carbons. AB - In oil sands mining extraction, water is an essential component; however, the processed water becomes contaminated through contact with the bitumen at high temperature, and a portion of it cannot be recycled and ends up in tailing ponds. The removal of naphthenic acids (NAs) from tailing pond water is crucial, as they are corrosive and toxic and provide a substrate for microbial activity that can give rise to methane, which is a potent greenhouse gas. In this study, the conversion of sawdust into an activated carbon (AC) that could be used to remove NAs from tailings water was studied. After producing biochar from sawdust by a slow-pyrolysis process, the biochar was physically activated using carbon dioxide (CO2) over a range of temperatures or prior to producing biochar, and the sawdust was chemically activated using phosphoric acid (H3PO4). The physically activated carbon had a lower surface area per gram than the chemically activated carbon. The physically produced ACs had a lower surface area per gram than chemically produced AC. In the adsorption tests with NAs, up to 35 mg of NAs was removed from the water per gram of AC. The chemically treated ACs showed better uptake, which can be attributed to its higher surface area and increased mesopore size when compared with the physically treated AC. Both the chemically produced and physically produced AC provided better uptake than the commercially AC. PMID- 24766593 TI - Removal of boron from oilfield wastewater via adsorption with synthetic layered double hydroxides. AB - Hydrotalcite is a layered double hydroxide (LDH) consisting of brucite-like sheets of metal ions (Mg-Al). In this work, hydrotalcites were synthesized, and boron removal from oilfield wastewater was evaluated. LDHs were synthesized using the co-precipitation method. The calcined products (CLDHs) were obtained by heating at 500 degrees C and characterized using X-ray diffraction, X-ray fluorescence, thermogravimetric analysis and the specific surface area (BET). The affinity of LDHs for borate ions was evaluated for calcined and uncalcined LDHs as a function of contact time, initial pH of the oilfield wastewater (pH ~ 9) and the LDH surface area. The tests were conducted at room temperature (approximately 25oC). The results indicated that 10 min were needed to reach a state of equilibrium during boron removal for calcined LDHs due to the high surface area (202.3 m(2) g(-1)) regardless of the initial pH of the oilfield wastewater, which resulted from the high buffering capacity of the LDHs. The adsorption capacity increased as the adsorbents levels increased for the range studied. After treatment of the oilfield wastewater containing 30 mg L(-1) of boron with Mg-Al CO3-LDHs, the final concentration of boron was within the discharge limit set by current Brazilian environmental legislation, which is 5 mg L(-1). Pseudo-first order and pseudo-second-order kinetic models were tested, and the latter was found to fit the experimental data better. Isotherms for boron adsorption by CLDHs were well described using the Langmuir and Freundlich equations. PMID- 24766594 TI - Online monitoring of Escherichia coli and Bacillus thuringiensis spore inactivation after advanced oxidation treatment. AB - Various studies have shown that advanced oxidation processes (AOPs) such as UV light in combination with hydrogen peroxide is an efficient process for the removal of a large variety of emerging contaminants including microorganisms. The mechanism of destruction in the presence of hydrogen peroxide (H2O2) is the enhanced formation of hydroxyl (.OH) radicals, which have a high oxidation potential. The goal of this study was to utilize in-line advanced oxidation to inactivate microbes, and document the inactivation via an in-line, real-time sensor. Escherichia coli cells and Bacillus thuringiensis spores were exposed to UV/H2O2 treatment in DI water, and the online sensor BioSentry((r)) was evaluated for its potential to monitor inactivation in real-time. B. thuringiensis was selected as a non-pathogenic surrogate for B. anthracis, the causative agent of anthrax and a proven biological weapon. UV radiation and UV/H2O2 exposure resulted in a >6 log10 reduction of the viable culturable counts of E. coli vegetative cells, and a 3 log10 reduction of B. thuringiensis spores. Scanning electron microscopy of the treated samples revealed severe damage on the surface of most E. coli cells, yet there was no significant change observed in the morphology of the B. thuringiensis spores. Following AOP exposure, the BioSentry sensor showed an increase in the categories of unknown, rod and spores counts, but overall, did not correspond well with viable count assays. Data from this study show that advanced oxidation processes effectively inactivate E. coli vegetative cells, but not B. thuringiensis spores, which were more resistant to AOP. Further, the BioSentry in-line sensor was not successful in documenting destruction of the microbial cells in real-time. PMID- 24766595 TI - Removal performance and changes in the microbial communities of SBRs under aerobic and anoxic conditions with trace tetracycline pressure. AB - The reactor performance and microbial community composition of sequencing batch reactor (SBR) under aerobic and anoxic conditions were investigated in this study. The experimental results showed high chemical oxygen demand (COD) removal efficiency. The tetracycline (TC) removal efficiencies were not obviously affected by aerobic and anoxic conditions, and were 64-97 and 60-87%, respectively. Aerobic condition was observed to be more suitable for decreasing tetracycline-resistant bacteria (TRB) than anoxic condition in synthetic and real wastewater. Denaturing gradient gel electrophoresis (DGGE) and clone library analysis revealed that Chlorobaculumthiosulfatiphilum was the dominant species in the tested SBR systems. TC significantly influenced the relative numbers of TRB- and TC-resistant genes, and the microbial community diversity changed with the addition of 250 MUg L(-1) of TC. The genes of tetA and tetC, tetM and tetS, tetA and tetM, tetS and tetA showed significant correlation with each other (P < 0.05). PMID- 24766596 TI - Removal of particles in organic filters in experimental treatment systems for domestic wastewater and black water. AB - This study assesses the total suspended solids (TSS) retention capacity of different organic filter media for two potential applications: (i) a polishing unit for package treatment plants and (ii) a pretreatment for blackwater from low flushing toilets. The results showed that the peat filter media used can be significantly improved in terms of structural stability and TSS removal capacity by mixing it with sawdust. Most of the TSS accumulated in the upper part of the filter material, and filter thickness exceeding 15 cm had no statistically significant effect (P < 0.1) on the TSS treatment performance. The experimental system reached a TSS reduction of 60-70% for blackwater and 80-90% for simulated effluent peaks from a package treatment plant. The main challenge of a full-scale application of an organic filter is the issue of clogging, especially when treating concentrated blackwater. However, this work indicates that a clogged filter media can be regenerated by mixing the uppermost filter layer without significant loss of filter performance regarding TSS. More research is needed to develop an appropriate mechanical unit for automatic filter media regeneration. PMID- 24766597 TI - Electrochemical oxidation of textile industry wastewater by graphite electrodes. AB - In the present article, studies have been performed on the electrochemical (EC) oxidation of actual textile industry wastewater by graphite electrodes. Multi response optimization of four independent parameters namely initial pH (pHo): 4 10, current density (j): 27.78-138.89 A/m(2), NaCl concentration (w): 0-2 g/L and electrolysis time (t): 10-130 min have been performed using Box-Behnken (BB) experimental design. It was aimed to simultaneously maximize the chemical oxygen demand (COD) and color removal efficiencies and minimize specific energy consumption using desirability function approach. Pareto analysis of variance (ANOVA) showed a high coefficient of determination value for COD (R(2) = 0.8418), color (R(2) = 0.7010) and specific energy (R(2) = 0.9125) between the experimental values and the predicted values by a second-order regression model. Maximum COD and color removal and minimum specific energy consumed was 90.78%, 96.27% and 23.58 kWh/kg COD removed, respectively, were observed at optimum conditions. The wastewater, sludge and scum obtained after treatment at optimum condition have been characterized by various techniques. UV-visible study showed that all azo bonds of the dyes present in the wastewater were totally broken and most of the aromatic rings were mineralized during EC oxidation with graphite electrode. Carbon balance showed that out of the total carbon eroded from the graphite electrodes, 27-29.2% goes to the scum, 71.1-73.3% goes into the sludge and rest goes to the treated wastewater. Thermogravimetric analysis showed that the generated sludge and scum can be dried and used as a fuel in the boilers/incinerators. PMID- 24766598 TI - Trace metals in the sponge Ircinia felix and sediments from North-Western Trinidad, West Indies. AB - The purpose of this study was to obtain data for trace metals in the sponge, Ircinia felix, and sediments found in coastal areas of north-western Trinidad, and to determine whether this sponge could be useful as a biomonitor for selected metals. Three sets of sediment and tissue samples were collected from four stations representing a range of anthropogenic input over a 12-month period. Samples were analyzed for Cd, Cr, Cu, Ni, Pb and Zn using flame and graphite furnace atomic absorption spectrometry. Extractable metal concentrations in sediments ranged from 0.01-0.28 MUg g(-1)-cadmium, 0.02-16.2 MUg g(-1)-chromium, 0.19-68.5 MUg g(-1)-copper, <0.05-4.12 MUg g(-1) -nickel, <0.03-37.0 MUg g(-1) lead and 4.08-148 MUg g(-1)-zinc. Total metal concentrations in I. felix tissue (dry weight) ranged from 0.03-1.04 MUg g(-1)-cadmium, 2.51-24.9 MUg g(-1) chromium, 15.2-49.9 MUg g(-1)-copper, 6.30-53.9 MUg g(-1) -nickel, 0.27-35.4 MUg g(-1) -lead and 29.7-127 MUg g(-1)- zinc. The results of the study suggest that I. felix could potentially have use as a biomonitor for Ni, Cd, Cu, and possibly Cr and Zn but may be less useful for monitoring Pb. Further work on temporal trends and intra-species variation of trace metals in the sponge is recommended. PMID- 24766599 TI - Blood concentration of copper, cadmium, zinc and lead in horses and its relation to hematological and biochemical parameters. AB - Environmental pollution results in serious health hazards to animals and blood analysis serves as a good alternative for health status assessment. The target of this study was to analyze the concentration of selected metals in equine blood, to analyze the blood parameters and to find possible correlations. Blood samples were collected from the vena jugularis of healthy adult horses. The highest concentration of all elements was found in whole blood (Cu 3.84 +/- 0.90 mg L( 1); Cd = 0.81 +/- 0.90 mg L(-1); Zn 26.67 +/- 14.12 mg L(-1); Pb 9.33 +/- 5.76 mg L(-1)). Higher concentrations of copper, cadmium, zinc and lead were detected in blood clots compared to blood sera (44.04%). A similar tendency was found for cadmium (50%), zinc (13.08%) and lead (46.02%), which showed generally higher concentrations in blood clots (cells). Correlation analysis proved some relations between analyzed elements. In blood clots there is a strong positive correlation between Cd - Pb (r = 0.93) and Zn - Pb (r = 0.71) was detected. For biochemical and hematological parameters mainly medium correlations were detected. Obtained results prove different correlations of analyzed elements in blood components as well as the effect on parameters of blood biochemical and hematological profiles. PMID- 24766600 TI - Management of severely painful uterine leiomyoma in a pregnant woman with epidural block using a subcutaneous injection port. PMID- 24766601 TI - Nasopharyngeal cancer-specific therapy based on fusion peptide-functionalized lipid nanoparticles. AB - Current treatment of advanced-stage nasopharyngeal carcinoma (NPC) is not satisfactory. Targeted therapies offer hope for extending survival. Here, we developed simple, robust, and NPC-specific therapeutic lipid nanoparticles based on a fusion peptide, alpha-NTP, made up of an amphipathic alpha-helical peptide (alpha-peptide) linked to an NPC-specific therapeutic peptide (NTP). We found that alpha-NTP not only retained the sub-30 nm nanostructure-controlling ability of the alpha-peptide but also displayed the enhanced NPC-targeting ability of the NTP, in which the alpha-peptide accelerated the uptake of the NTP by NPC cells, with a 4.8-fold increase. Following uptake, alpha-NTP-based lipid nanoparticles (alpha-NTP-LNs) exerted coordinated cytotoxicity by inducing cell death via apoptosis and autophagy. In vivo and ex vivo optical imaging data showed that systemically administered alpha-NTP-LNs efficiently accumulated in the NPC xenograft tumor and displayed high contrast between tumor and normal tissues, which was further confirmed by flow cytometry that there had been a 13-fold uptake difference between tumor cells and hepatocytes. More importantly, the therapeutic efficacy of alpha-NTP-LNs was specific to NPC xenograft formed with 5 8F cells but not to fibrosarcoma xenograft formed with HT1080 cells in vivo. The growth of 5-8F tumors was significantly inhibited by alpha-NTP-LNs, with more than 85% inhibition relative to control groups (e.g., alpha-NTP and PBS treatment). In a lung metastasis model of NPC, survival was significantly improved by alpha-NTP-LN treatment. In a word, these excellent properties of alpha-NTP-LNs worked in sync and synergistically, maximizing the therapeutic efficacy of alpha-NTP-LNs against NPC and its metastasis. PMID- 24766602 TI - Risk factors associated with the longevity of multi-rooted teeth. Long-term outcomes after active and supportive periodontal therapy. AB - AIM: To investigate risk factors for the loss of multi-rooted teeth (MRT) in subjects treated for periodontitis and enrolled in supportive periodontal therapy (SPT). MATERIAL AND METHODS: A total of 172 subjects were examined before (T0) and after active periodontal therapy (APT)(T1) and following a mean of 11.5 +/- 5.2 (SD) years of SPT (T2). The association of risk factors with loss of MRT was analysed with multilevel logistic regression. The tooth was the unit of analysis. RESULTS: Furcation involvement (FI) = 1 before APT was not a risk factor for tooth loss compared with FI = 0 (p = 0.37). Between T0 and T2, MRT with FI = 2 (OR: 2.92, 95% CI: 1.68, 5.06, p = 0.0001) and FI = 3 (OR: 6.85, 95% CI: 3.40, 13.83, p < 0.0001) were at a significantly higher risk to be lost compared with those with FI = 0. During SPT, smokers lost significantly more MRT compared with non-smokers (OR: 2.37, 95% CI: 1.05, 5.35, p = 0.04). Non-smoking and compliant subjects with FI = 0/1 at T1 lost significantly less MRT during SPT compared with non-compliant smokers with FI = 2 (OR: 10.11, 95% CI: 2.91, 35.11, p < 0.0001) and FI = 3 (OR: 17.18, 95% CI: 4.98, 59.28, p < 0.0001) respectively. CONCLUSIONS: FI = 1 was not a risk factor for tooth loss compared with FI = 0. FI = 2/3, smoking and lack of compliance with regular SPT represented risk factors for the loss of MRT in subjects treated for periodontitis. PMID- 24766603 TI - Synthesis and characterization of palladium(II) and nickel(II) alcoholate functionalized NHC complexes and of mixed nickel(II)-lithium(I) complexes. AB - The synthesis of Pd(II) and Ni(II) alcohol-functionalized N-heterocyclic carbene (NHC) complexes was explored to examine the possible influence of the functional arm attached to the NHC backbone on their structure and reactivity and, in the case of a Ni(II) complex, on its catalytic properties in ethylene oligomerization. Starting from the alcohol-functionalized imidazolium salt [ImDiPP(C2OH)]Cl (2), the new functionalized NHC palladium(II) complex [PdCl(acac){ImDiPP(C2OH)-CNHC}] (3) was synthesized and fully characterized. Two byproducts, [PdCl{MU-ImDiPP(C2O)-CNHC,O}]2 (4) and trans-[PdCl2{ImDiPP(C2OH) CNHC}2] (5), formed during the synthesis of 3, were also fully characterized. Acids promoted the transformation of 3 into the new CNHC-bound complex [PdCl(MU Cl){ImDiPP(C2OH)-CNHC}]2 (6), unveiling the lability of the acac ligand and the resistance of the Pd-NHC bond to acids. Complex 6 reacted with a base to afford complex 4, in which alkoxide coordination to Pd(II) has occurred to generate a CNHC,O chelate. The stability of 3 was also assessed under basic conditions, and the new complex [Pd(acac){ImDiPP(C2O)-CNHC,O}] (7) was characterized. The new nickel(II) alcoholate-functionalized NHC complex [NiCl{MU-ImDiPP(C2O)-CNHC,O}]2 (8) was synthesized by the reaction of the imidazolium salt 2 with n-BuLi and [NiCl2(dme)]. The reaction of 8 with HCl regenerates the imidazolium and alcohol functions to give [ImDiPP(C2OH)]2[NiCl4] (9). The mixed-metal Ni(II)-Li(I) complexes [Ni2{MU-ImDiPP(C2O)-CNHC,MU-O}4Li]BF4 (10), [Ni2{MU-ImDiPP(C2O)-CNHC,MU O}4Li]Cl (11), and [Ni{ImDiPP(C2O)-CNHC,MU-O}2LiBr] (12) were isolated and characterized. However, it was not possible to synthesize a Ni(II) alcohol functionalized NHC complex in high yield. Small amounts of the square-planar complex [NiCl2{ImDiPP(C2OH)-CNHC}2] (13) could be isolated, and this complex was characterized by single-crystal X-ray diffraction. In 13, only the CNHC atom of the alcohol-functionalized NHC ligand is bound to the metal. The structures of the imidazolium salt 2.2H2O and of the complexes 3, 4, 4-polymorph, 5, 6.CH2Cl2, and 8-13 were established by single-crystal X-ray diffraction. PMID- 24766604 TI - Lead extraction experience with high frequency excimer laser. AB - BACKGROUND: A higher frequency Excimer laser sheath using an 80-Hz pulse repetitive rate was approved by the Food and Drug Administration in April 2012. We reported our initial clinical experience with a high-frequency Excimer laser sheath and compared it with lower-frequency laser sheaths which have been previously used. METHODS: In this single center, retrospective cohort study, we evaluated patients who underwent lead extraction from December 2008 to May 2013. Those who underwent lead removal without using a laser sheath or with approaches other than subclavian were excluded. Primary endpoints included total laser time, number of pulses, and complications. Data on clinical characteristics, lead type, indications, and outcomes were prospectively collected and analyzed. RESULTS: A total of 427 patients were included in the study (72.6% male; age 67.9 +/- 15.23 years). Lower frequency and higher frequency laser sheaths were used in 315 and 112 patients, respectively. A total of 821 leads were removed with 765 leads (93.2%) extracted using the Excimer laser sheath. Lead age was 5.71 +/- 4.96 years. Complete extraction was seen in all patients. A higher-frequency laser sheath was associated with a lower laser time and a lower total number of laser pulses even after adjustments for the number of leads, type of leads, and lead age. In the higher frequency group, mortality rate was 0.9% and minor complication rate was 3.6%. CONCLUSIONS: When compared with the lower-frequency laser sheath, the higher-frequency laser sheath requires less laser times and more efficient amount of pulses for lead extraction with comparable success rate. Due to the rarity of major and minor complications, no statistical significance was found between the two groups. PMID- 24766606 TI - Renal nerve denervation--a hypertension bubble? PMID- 24766607 TI - Intestinal obstruction in von Recklinghausen's disease. AB - AIM: Gastrointestinal manifestations occur in up to 25% of patients with neurofibromatosis type 1. This review reports all published cases of acute intestinal obstruction due to neurofibromatosis type 1 and identifies mechanisms of obstruction, the nature of the tumour and the outcome. METHOD: A systematic review of the literature on acute intestinal obstruction due to neurofibromatosis type 1 was performed by searching the major electronic databases. All relevant references were reviewed for possible inclusion. All the references of the relevant articles were screened for any further articles that were missed in the initial search. RESULTS: We identified 25 articles from 1972 to 2013 reporting 25 patients with von Recklinghausen's disease who underwent laparotomy for acute intestinal obstruction. Three further patients were operated on in our institution. The mean age of the patients was 44.2 years and the male/female ratio 15/13. The mechanisms of obstruction were intrinsic obstruction (16), extrinsic obstruction (8) and intussusception (4). Histology was reported to show neurofibroma (19), gastrointestinal stromal tumour (5) and adenocarcinoma (4). Among patients whose outcome was mentioned (17), 10 were asymptomatic after a mean follow-up of 1.5 years. CONCLUSION: Acute bowel obstruction is a rare manifestation of neurofibromatosis type 1. Surgery is often necessary to treat the complication and to determine the exact nature of the tumour and the prognosis. PMID- 24766605 TI - N-cadherin/catenin complex as a master regulator of intercalated disc function. AB - Intercellular adhesive junctions are essential for maintaining the physical integrity of tissues; this is particularly true for the heart that is under constant mechanical load. The correct functionality of the heart is dependent on the electrical and mechanical coordination of its constituent cardiomyocytes. The intercalated disc (ID) structure located at the termini of the rod-shaped adult cardiomyocyte contains various junctional proteins responsible for the integration of structural information and cell-cell communication. According to the classical description, the ID consists of three distinct junctional complexes: adherens junction (AJ), desmosome (Des), and gap junction (GJ) that work together to mediate mechanical and electrical coupling of cardiomyocytes. However, recent morphological and molecular studies indicate that AJ and Des components are capable of mixing together resulting in a "hybrid adhering junction" or "area composita." This review summarizes recent progress in understanding the in vivo function(s) of AJ components in cardiac homeostasis and disease. PMID- 24766608 TI - Involvement of ligninolytic enzymes in degradation of wheat straw by Trametes trogii. AB - AIMS: Wheat straw is generated in billions of tons around the world every year and has not been fully used. This study sought to evaluate the delignification capacity and enzyme production of Trametes trogii MT strain and to clarify the changes of structure and chemical composition of wheat straw during the decay process. METHODS AND RESULTS: The results obtained revealed that the T. trogii MT strain has the ability to degrade lignin, cellulose as well as hemicellulose of wheat straw simultaneously. The strain can produce high activities of laccase, manganese peroxidase, xylanase, carboxymethylcellulase and feruloyl esterase but no lignin peroxidases during the decay process of a 60-day incubation period on wheat straw. Scanning electron microscopy observation and infrared spectroscopy analysis showed the lignin and carbohydrate of wheat straw were degraded with no obvious different levels. The low molecular mass fractions collected from the culture of the MT strains grown in wheat straw powder liquid medium showed high Fe(3+) chelating, reducing capacity and hydroxyl radical and hydrogen peroxide generation. CONCLUSIONS: Trametes trogii MT has a complex mechanism to degrade lignocellulose, in addition to the extracellular enzymatic systems, and has great potential as an attractive micro-organism used for the biological degradation of waste straws. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed the dynamic changes of the ligninolytic enzymes of T. trogii MT during the degradation of wheat straw, and suggested that the decay patterns of wheat straw by T. trogii MT had some simultaneous type characteristics. PMID- 24766609 TI - Excitation energy transfer in donor-bridge-acceptor systems: a combined quantum mechanical/classical analysis of the role of the bridge and the solvent. AB - The technical application of excitation energy transfer requires a fine control of the geometry of the system. This can be achieved by introducing a chemical bridge between the donor and acceptor moieties that can be tuned in its chemical properties and its length. In such donor-bridge-acceptor systems, however, the role of the bridge in enhancing or depleting the energy transfer efficiency is not easy to predict. Here we propose a computational strategy based on the combination of time-dependent density functional theory, polarizable molecular mechanics and continuum approaches. The resulting three-layer model when applied to the study of the energy transfer process in different porphyrin-based systems, each characterized by a specific donor/acceptor pair and various types of bridges, allows us to dissect the role of through-bond and through-space mechanisms and clarify their dependence on the nature and length of the bridge as well as on the presence of a solvent. PMID- 24766610 TI - Cruise ships and bush medicine: globalization on the Atlantic Coast of Nicaragua and effects on the health of Creole women. AB - OBJECTIVES: Global health research into the relationship between health, economic inequalities, and globalization is necessary to address increasing health disparities in low income countries. Nicaragua has high levels of poverty and extreme poverty when compared with other Central and South American Countries. DESIGN AND SAMPLE: Photovoice and ethnographic research methods were used to explore health experiences of Creole women in Bluefields, Nicaragua and the intersections between culture, socioeconomic status, and gender. Twelve Creole women participants, ages 18-45. MEASURES: After initial focus groups, participants used disposable cameras to document health experiences. Follow-up interviews were conducted about the meaning of each photo. Participants then selected photos to be included in a city-wide photoshow. RESULTS: In initial focus groups, participants described great distress over changes they perceived in Creole culture and how these changes affect the health of the next generation. Participants related most of these changes to the economy and globalization. Photos taken were primarily of aspects of Creole culture, including household practices and traditional remedies from Creole culture. CONCLUSIONS: Findings on the relationships between culture, disease, and community-identified health risks in this minority population can help health care providers and public health policymakers develop and sustain culturally appropriate health interventions. PMID- 24766611 TI - Chiral phosphoric acid-catalyzed asymmetric transfer hydrogenation of quinolin-3 amines. AB - A chiral phosphoric acid catalyzed asymmetric transfer hydrogenation of aromatic amines, quinolin-3-amines, was successfully developed with up to 99% ee. To supplement our previous work on the Ir-catalyzed asymmetric hydrogenation of 2 alkyl substituted quinolin-3-amines, a number of 2-aryl substituted substrates were reduced to provide a series of valuable chiral exocyclic amines with high diastereo- and enantioselectivities. PMID- 24766612 TI - Normalyzer: a tool for rapid evaluation of normalization methods for omics data sets. AB - High-throughput omics data often contain systematic biases introduced during various steps of sample processing and data generation. As the source of these biases is usually unknown, it is difficult to select an optimal normalization method for a given data set. To facilitate this process, we introduce the open source tool "Normalyzer". It normalizes the data with 12 different normalization methods and generates a report with several quantitative and qualitative plots for comparative evaluation of different methods. The usefulness of Normalyzer is demonstrated with three different case studies from quantitative proteomics and transcriptomics. The results from these case studies show that the choice of normalization method strongly influences the outcome of downstream quantitative comparisons. Normalyzer is an R package and can be used locally or through the online implementation at http://quantitativeproteomics.org/normalyzer . PMID- 24766613 TI - The influence of visual and tactile perception on hand control in children with Duchenne muscular dystrophy. AB - AIM: To investigate tactile perception and manual dexterity, with or without visual feedback, in males with Duchenne muscular dystrophy (DMD). METHOD: Forty males with DMD (mean age 9 y 8 mo, SD 2 y 3 mo; range 5-14 y), recruited from the teaching hospital of the School of Medicine of the University of Sao Paulo, with disease severity graded as '1' to '6' on the Vignos Scale and '1' on Brooke's Scale, and 49 healthy males (mean age 8 y 2 mo; range 5-11 y; SD 1 y 11 mo), recruited from a local education center, participated in the study. We assessed tactile perception using two-point discrimination and stereognosis tests, and manual dexterity using the Pick-Up test with the eyes either open or closed. Analysis of variance was used to compare groups; a p value of less than 0.05 was considered statistically significant. RESULTS: Males with DMD exhibited no impairment in tactile perception, as measured by the two-point discrimination test and the number of objects correctly named in the stereognosis test. Manipulation during stereognosis was statistically slower with both hands (p<0.001), and manual dexterity was much worse in males with DMD when there was no visual feedback (p<0.001). INTERPRETATION: Males with DMD exhibited disturbances in manipulation during stereognosis and dexterity tests. Hand control was highly dependent on visual information rather than on tactile perception. Motor dysfunction in males with DMD, therefore, might be related to altered neural control. PMID- 24766614 TI - Findings of a hospital surveillance-based outcome evaluation study for Clostridium difficile-associated colitis. AB - We completed a prospective study of 164 patients involved in a Clostridium difficile surveillance programme, evaluating a range of variables such as disease severity, treatment regimen and known clinical risk factors, for their effect on case lethality. The aim of this study was to determine if there are any additional clinical variables worth considering for inclusion in the therapeutic decision-making process. Beyond common risk factors, secondary immunodeficiencies such as diabetes mellitus, malignancy, autoimmune disease, immunosuppressive therapy and chronic hepatitis were assessed. Overall case lethality was 23%. There was a suggestion that regular proton pump inhibitor use in past medical history might be associated with greater lethality. Immunosuppressive therapy within 1 month before the onset of diarrhoea was associated with a significant four-fold lethality increase. This last finding may have the potential to further improve therapeutic judgement if used as an explicit component of a revised scoring system. In relation to Clostridium difficile-associated colitis, immunosuppressive therapy as a red flag entity, as described here, has not been previously published. PMID- 24766615 TI - Risk factors of depression after prolonged low-dose rate environmental radiation exposure. AB - PURPOSE: More than 10,000 Taiwanese people were exposed to excessive protracted low-dose rate radiation from contaminated reinforcement bars, which were installed in buildings before 1992. This study was conducted to assess the prevalence of depression amongst the exposed and identify related determinants now that more than two decades have passed since this population was informed of their exposure to radiation. MATERIALS AND METHODS: We used the Beck depression inventory (BDI)-1A questionnaire to survey 2143 eligible people during their annual physical examinations between March 2009 and December 2009. In total, 1621 people participated in the survey. We employed multivariate logistic regression models with generalized estimating equations method to identify the determinants of depression. RESULTS: The prevalence of depression (BDI-IA score >= 12) was 18.7%. Those who exhibited higher cumulative exposure [adjusted odds ratio (OR): 1.46, 95% confidence interval (CI): 1.02-2.07] and a previous history of depression (adjusted OR: 2.49, 95% CI: 1.36-4.58) were significantly associated with the risk of depression, whereas education level was inversely related to depression (adjusted OR: 0.71, 95% CI: 0.50-0.99). CONCLUSION: Long-term, low dose rate radiation exposure early in life might cause subsequent psychological stress and an increased risk of depression decades later. PMID- 24766616 TI - Evolutionary hypotheses for a constraint to life-history resilience in depleted Salmo salar populations. AB - Phenotypic plasticity underlies much of the variation in life-history expression in fishes. An understanding of potential constraints on life-history plasticity thus may be critical for assessing the resiliency of populations or species to environmental change. Here, several evolutionary hypotheses are formulated for why a depleted lineage of Canadian Atlantic salmon Salmo salar populations continues to express an apparently maladaptive life history in the face of severe marine mortality. These hypotheses include: (1) reduced genetic variability for expressing plasticity, (2) constraints from genetic architecture, (3) constraints from gene flow, (4) phylogenetic constraints or irreversible evolutionary transitions, (5) environmental constraints to plasticity and (6) a restriction to population rescue from evolutionary-demographic feedbacks. This S. salar lineage is intriguing to consider for understanding resilience or the lack thereof, because it has life-history attributes that should favour resilience (e.g. a high degree of iteroparity, variable age at maturity and the presence of both long- and short-distance migration ecotypes). In particular, the discussion centres on the question of why S. salar females, in contrast to males, do not adopt a non anadromous life history and mature in fresh water, given extremely high marine mortality among anadromous individuals of both sexes. A salient implication, with possibly significant conservation ramifications, is that fishes may exhibit substantial plasticity and potential for adapting to environmental change, but still be incapable of responding to certain environmental changes due to sex specific constraints to life-history plasticity. PMID- 24766617 TI - Shifting contours of boundaries: an exploration of inter-agency integration between hospital and community interprofessional diabetes programs. AB - This article reports on research into the relationships that emerged between hospital-based and community-based interprofessional diabetes programs involved in inter-agency care. Using constructivist grounded theory methodology we interviewed a purposive theoretical sample of 21 clinicians and administrators from both types of programs. Emergent themes were identified through a process of constant comparative analysis. Initial boundaries were constructed based on contrasts in beliefs, practices and expertise. In response to bureaucratic and social pressures, boundaries were redefined in a way that created role uncertainty and disempowered community programs, ultimately preventing collaboration. We illustrate the dynamic and multi-dimensional nature of social and symbolic boundaries in inter-agency diabetes care and the tacit ways in which hospitals can maintain a power position at the expense of other actors in the field. As efforts continue in Canada and elsewhere to move knowledge and resources into community sectors, we highlight the importance of hospitals seeing beyond their own interests and adopting more altruistic models of inter-agency integration. PMID- 24766618 TI - Interprofessional ethics learning between schools of pharmacy and dental medicine. AB - A case-based interprofessional education (IPE) ethics activity between pharmacy and dental students was developed and evaluated. Eighty-two third-year pharmacy and 51 first-year dental students were divided into teams for two sessions. The IPE activity involved the student teams analyzing two cases at each session utilizing an ethical decision-making process followed by debriefing of each case. Assessments included pre-/post-Readiness for Interprofessional Learning Scale (RIPLS), pre-/post-individual ethics knowledge quiz, pre-team ethics knowledge quiz and post-student perception survey. The results indicated no significant differences in RIPLS scores although scores indicated a high readiness for interprofessional learning including teamwork and collaboration among pharmacy and dental students. When comparing pre-/post-ethics knowledge quiz scores a significant difference was found between individual and team scores as well as between professions. Perception survey results were highly favorable toward the value of interprofessional learning activities. The sessions resulted in enhanced knowledge about ethical decision-making. PMID- 24766619 TI - A systematic process for creating and appraising clinical vignettes to illustrate interprofessional shared decision making. AB - Vignettes and written case simulations have been widely used by educators and health services researchers to illustrate plausible situations and measure processes in a wide range of practice settings. We devised a systematic process to create and appraise theory-based vignettes for illustrating an interprofessional approach to shared decision making (IP-SDM) for health professionals. A vignette was developed in six stages: (1) determine IP-SDM content elements; (2) choose true-to-life clinical scenario; (3) draft script; (4) appraise IP-SDM concepts illustrated using two evaluation instruments and an interprofessional concept grid; (5) peer review script for content validity; and (6) retrospective pre-/post-test evaluation of video vignette by health professionals. The vignette contained six scenes demonstrating the asynchronous involvement of five health professionals with an elderly woman and her daughter facing a decision about location of care. The script scored highly on both evaluation scales. Twenty-nine health professionals working in home care watched the vignette during IP-SDM workshops in English or French and rated it as excellent (n = 6), good (n = 20), fair (n = 0) or weak (n = 3). Participants reported higher knowledge of IP-SDM after the workshops compared to before (p < 0.0001). Our video vignette development process resulted in a product that was true-to-life and as part of a multifaceted workshop it appears to improve knowledge among health professionals. This could be used to create and appraise vignettes targeting IP-SDM in other contexts. PMID- 24766620 TI - Does the Golem Feel Pain? Moral Instincts and Ethical Dilemmas Concerning Suffering and the Brain. AB - Pain has variously been used as a means of punishment, extracting information, or testing commitment, as a tool for education and social control, as a commodity for sacrifice, and as a draw for sport and entertainment. Attitudes concerning these uses have undergone major changes in the modern era. Normative convictions on what is right and wrong are generally attributed to religious tradition or to secular-humanist reasoning. Here, we elaborate the perspective that ethical choices concerning pain have much earlier roots that are based on instincts and brain-seated empathetic responses. They are fundamentally a function of brain circuitry shaped by processes of Darwinian evolution. Social convention and other environmental influences, with their idiosyncrasies, are a more recent, ever changing overlay. We close with an example in which details on the neurobiology of pain processing, specifically the question of where in the brain the experience of pain is generated, affect decision making in end-of-life situations. By separating innate biological substrates from culturally imposed attitudes (memes), we may arrive at a more reasoned approach to a morality of pain prevention. PMID- 24766621 TI - Remission of anti-epiligrin cicatricial pemphigoid after excision of cervical adenocarcinoma. PMID- 24766622 TI - Immuno-LipoTRAIL: Targeted delivery of TRAIL-functionalized liposomal nanoparticles. AB - The TNF-related apoptosis-inducing ligand (TRAIL) is a powerful inducer of apoptosis in tumor cells; however, clinical studies with recombinant soluble TRAIL were rather disappointing. Here, we developed TRAIL-functionalized liposomes (LipoTRAIL, LT) to mimic membrane-displayed TRAIL for efficient activation of death receptors DR4 and DR5 and enhanced induction of apoptosis, which were combined with an anti-EGFR single-chain Fv fragment (scFv) for targeted delivery to EGFR-positive tumor cells. These immuno-LipoTRAILs (ILTs) bound specifically to EGFR-expressing cells (Colo205) and exhibited increased cytotoxicity compared with that of nontargeted LTs. Compared to that of the soluble TRAIL, the plasma half-life of the functionalized liposomes was strongly extended, and increased antitumor activity of LT and ILT was demonstrated in a xenograft tumor model. Thus, we established a multifunctional liposomal TRAIL formulation (ILT) with improved pharmacokinetic and pharmacodynamic behavior, characterized by targeted delivery and increased induction of apoptosis due to multivalent TRAIL presentation. PMID- 24766624 TI - Heterogeneity within adult day services: a focus on centers that serve younger adults with intellectual and developmental disabilities. AB - As the population of younger adults with intellectual and developmental disabilities continues to grow, adult day services is positioned to be a key provider of community-based care and support. In this article, researchers examine how adult day centers that serve younger adults with intellectual and developmental disabilities differ from centers that serve older and mixed age groups. One-way analyses of variance and post hoc analyses of 490 adult day services centers (N = 490) revealed significant differences in terms of participant, staffing, and organizational characteristics. These findings have important implications for service providers, researchers, and policy makers. PMID- 24766623 TI - Polymerase chain reaction evaluation of infectious multifocal serpiginoid choroiditis. AB - PURPOSE: To study infectious agents associated with multifocal serpiginoid choroiditis (MSC) based on polymerase chain reaction (PCR) evaluation and specific anti-microbial therapy. METHODS: Retrospective review of medical records. RESULTS: Thirteen patients with MSC were evaluated with PCR for the following organisms: Mycobacterium tuberculosis (MTB), herpes simplex virus 1 (HSV 1), varicella zoster virus (VZV), and cytomegalovirus (CMV). Nine (69.2%) were PCR positive for one or more organisms. Seven (53.8%) were positive for MTB, 3 (23.1%) for CMV (1 positive for both MTB and CMV), and 1 (7.6%) for both HSV 1 and MTB. All 13 patients received anti-TB therapy and corticosteroids. Nine patients completed 6 months follow-up; 6 resolved completely, 2 continued to have active lesions, while 1 CMV PCR-positive patient required additional valgancyclovir therapy. CONCLUSIONS: TB is the most important etiology for MSC in endemic countries. The role of herpes viruses in MSC remains unclear and needs further investigation. PMID- 24766625 TI - Knee extension fatigue attenuates repeated force production of the elbow flexors. AB - Non-local muscle fatigue has been demonstrated with unilateral activities, where fatiguing one limb alters opposite limb forces. Fewer studies have examined if non-local fatigue occurs with unrelated muscles. The purpose of this study was to investigate if knee extensors fatigue alters elbow flexors force and electromyography (EMG) activity. Eighteen males completed a control and fatiguing session (randomised). Blood lactate was initially sampled followed by three maximal voluntary contractions (MVC) with the elbow flexors and two with the knee extensors. Thereafter, subjects either sat (control) or performed five sets of bilateral dynamic knee extensions to exhaustion using a load equal to the dominant limb MVC (1-min rest between sets). Immediately afterwards, subjects were assessed for blood lactate and unilateral knee extensors MVC, and after 1 min performed a single unilateral elbow flexor MVC. Two minutes later, subjects performed 12 unilateral elbow flexor MVCs (5 s contraction/10 s rest) followed by a third blood lactate test. Compared to control, knee extensor force dropped by 35% (p < 0.001; ES = 1.6) and blood lactate increased by 18% (p < 0.001; ES = 2.8). Elbow flexor forces were lower after the fatiguing protocol only during the last five MVCs (p < 0.05; ES = ~ 0.58; ~ 5%). No changes occurred between conditions in EMG. Elbow flexor forces significantly decreased after knee extensors fatigue. The effect was revealed during the later stages of the repeated MVCs protocol, demonstrating that non-local fatigue may have a stronger effect on repeated rather than on single attempts of maximal force production. PMID- 24766626 TI - Synthesis and characterization of (68)Ga-labeled curcumin and curcuminoid complexes as potential radiotracers for imaging of cancer and Alzheimer's disease. AB - Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium 99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, (68)Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic beta-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting (68)Ga(3+) obtained from a (68)Ge/(68)Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent (nat)Ga-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2(+) species formation. Identity of the (68)Ga(L)2(+) complexes was confirmed by coelution with the equivalent (nat)Ga(L)2(+) complexes in ultrahigh-performance liquid chromatography analyses.(68)Ga(CUR)2(+), (68)Ga(DAC)2(+), and (68)Ga(bDHC)2(+) were highly (87 +/- 4, 90 +/- 1%) and moderately (48 +/- 2%), respectively, retained by synthetic beta-amyloid fibrils in vitro. All the Ga-curcuminoid complexes showed an uptake in A549 lung cancer cells, at least equivalent to the respective free curcuminoids, confirming potential applications as cancer-detecting radiotracers. PMID- 24766627 TI - The logistic regression model for gene-environment interactions using both case parent trios and unrelated case-controls. AB - One of the greatest challenges in genetic studies is the determination of gene environment interactions due to underlying complications and inadequate statistical power. With the increased sample size gained by using case-parent trios and unrelated cases and controls, the performance may be much improved. Focusing on a dichotomous trait, a two-stage approach was previously proposed to deal with gene-environment interaction when utilizing mixed study samples. Theoretically, the two-stage association analysis uses likelihood functions such that the computational algorithms may not converge in the maximum likelihood estimation with small study samples. In an effort to avoid such convergence issues, we propose a logistic regression framework model, based on the combined haplotype relative risk (CHRR) method, which intuitively pools the case-parent trios and unrelated subjects in a two by two table. A positive feature of the logistic regression model is the effortless adjustment for either discrete or continuous covariates. According to computer simulations, under the circumstances in which the two-stage test converges in larger sample sizes, we discovered that the performances of the two tests were quite similar; the two-stage test is more powerful under the dominant and additive disease models, but the extended CHRR is more powerful under the recessive disease model. PMID- 24766628 TI - Eliminating the human factor in office blood pressure measurement. PMID- 24766629 TI - Go forth, evolve and prosper: the genetic basis of adaptive evolution in an invasive species. AB - Invasive species stand accused of a familiar litany of offences, including displacing native species, disrupting ecological processes and causing billions of dollars in ecological damage (Cox 1999). Despite these transgressions, invasive species have at least one redeeming virtue--they offer us an unparalleled opportunity to investigate colonization and responses of populations to novel conditions in the invaded habitat (Elton 1958; Sakai et al. 2001). Invasive species are by definition colonists that have arrived and thrived in a new location. How they are able to thrive is of great interest, especially considering a paradox of invasion (Sax & Brown 2000): if many populations are locally adapted (Leimu & Fischer 2008), how could species introduced into new locations become so successful? One possibility is that populations adjust to the new conditions through plasticity--increasing production of allelopathic compounds (novel weapons), or taking advantage of new prey, for example. Alternatively, evolution could play a role, with the populations adapting to the novel conditions of the new habitat. There is increasing evidence, based on phenotypic data, for rapid adaptive evolution in invasive species (Franks et al. 2012; Colautti & Barrett 2013; Sultan et al. 2013). Prior studies have also demonstrated genetic changes in introduced populations using neutral markers, which generally do not provide information on adaptation. Thus, the genetic basis of adaptive evolution in invasive species has largely remained unknown. In this issue of Molecular Ecology, Vandepitte et al. (2014) provide some of the first evidence in invasive populations for molecular genetic changes directly linked to adaptation. PMID- 24766630 TI - Unearthing the impact of human disturbance on a notorious weed. AB - Large-scale anthropogenic changes in the environment are reshaping global biodiversity and the evolutionary trajectory of many species. Evolutionary mechanisms that allow organisms to thrive in this rapidly changing environment are just beginning to be investigated (Hoffmann & Sgro 2011; Colautti & Barrett 2013). Weedy and invasive species represent 'success stories' for how species can cope with human modified environments. As introduced species have spread within recent times, they provide the unique opportunity to track the genetic consequences of rapid range expansion through time and space using historic DNA samples. Using modern collections and herbarium specimens dating back to 1873, Martin et al. (2014) have provided a more complete understanding of the population history of the invasive, agricultural weed, common ragweed (Ambrosia artemisiifolia; Fig. 1) in its native range with surprising results. They find that the recent population explosion of common ragweed in North America coincided with substantial shifts in population genetic structure with implications for invasion. PMID- 24766631 TI - Fitness landscape of sympatric pupfishes a useful tool for visualizing speciation. AB - Arguably the most useful model of evolution emerged from the mind of Sewall Wright when he invented the fitness landscape (Wright 1932). In a recent issue of Molecular Ecology, Martin & Feinstein (2014) investigate the genetics and demographic history of an adaptive radiation of pupfish on San Salvador Island. Since the founder species colonized the island 10,000 years ago, two descendent species have appeared and in several lakes all three species (a durophage, a scale-eater, and the generalist ancestral form) coexist. The three species are thought to occupy three distinct fitness peaks. The durophage and generalists' peaks are close, whereas the scale-eater's peak is predicted to be distant and separated from the other two by a deep valley. Consistent with this view, gene flow between the two species on close fitness peaks is greater than the gene flow between these two species and the third species on a more distant peak. Correspondingly, the inferred fitness landscape predicts progress towards speciation, with more limited separation of species on close peaks, and that speciation is more complete for the scale-eater. The article provides an illustrative example of the power afforded by analysis of large numbers of SNPs for estimating key parameters underlying evolutionary divergence. PMID- 24766632 TI - Assessment of the performance of A1CNow(+) and development of an error grid analysis graph for comparative hemoglobin A1c measurements. AB - BACKGROUND: This study investigated the performance of the A1CNow(+(r)) test (Bayer Diabetes Care, Sunnyvale, CA) in a large population of Chinese patients with diabetes. SUBJECTS AND METHODS: Hemoglobin A1c (HbA1c) levels in 1,618 Chinese patients with diabetes 10-94 years of age were measured with both the A1CNow(+) test, from a fingerstick blood sample, and the high-performance liquid chromatography (HPLC) test, using a venous blood sample, within 24 h. The reportable ranges of the HbA1c values were 4.0-13.0% (A1CNow(+)) and 4.1-16.8% (HPLC). An error grid analysis (EGA) method was developed to quantify the accuracy of the A1CNow(+) results against the HPLC reference results. RESULTS: The A1CNow(+) results were highly correlated with the HPLC reference results (r=0.945, P<0.01). Passing-Bablok regression analysis showed a good linear agreement between the two variables, and the linear regression equation fitted as y=-0.10+1.00x (P=0.21). The Bland-Altman difference plot presented that the mean bias of the A1CNow(+) results minus the HPLC reference results was -0.09% (P<0.001); the 95% confidence intervals for the limits of agreement were -1.28% to 1.09%, with 96.5% of the data points lying within this zone. The results of the EGA showed that 80.2% of the A1CNow(+) results were accurate, 17.7% were acceptable, 1.9% may lead to inappropriate treatment, and 0.3% may lead to severe clinical consequence. CONCLUSIONS: The A1CNow(+) test values demonstrated a slight negative bias from the HPLC values. The majority of A1CNow(+) test values were accurate when compared with results from the reference method. PMID- 24766633 TI - Characteristics of Lactobacillus parafarraginis ZH1 and its role in improving the aerobic stability of silages. AB - AIMS: Lactobacillus parafarraginis ZH1 isolated from silage was characterized, and the effects of inoculating ZH1 and Lact. buchneri (LB) on the aerobic stability of sweet corn stalk (SCS) silage and whole-plant oat (WPO) silage ensiled at 15 and 30 degrees C were studied. METHODS AND RESULTS: After ensiling of SCS or WPO in plastic bottle silo for 45 days, silos were opened, and aerobic stability was studied by monitoring temperature change with thermo recorders in silage for 6 days. SCS silage and WPO silage were well conserved naturally at both storage temperatures. However, silages were prone to aerobic deterioration due to the presence of residual yeasts. ZH1 inoculated silages ensiled at both temperatures, LB inoculated silages ensiled at 30 degrees C had better aerobic stability than the uninoculated silages and the LB-inoculated silage at 15 degrees C. CONCLUSIONS: Strain ZH1 improved the aerobic stability of SCS silage and WPO silage ensiled at both 15 and 30 degrees C, while LB improved the aerobic stability of silage only ensiled at the high temperature of 30 degrees C. SIGNIFICANCE AND IMPACT OF THE STUDY: The new strain ZH1 can be used as an effective inhibitor for aerobic deterioration of silage maintained from 15 to 30 degrees C. PMID- 24766634 TI - Rate of cardiovascular implantable electronic device (CIED) re-extraction after recurrent infection. AB - BACKGROUND: Patients who develop a cardiovascular implantable electronic device (CIED) infection requiring extraction may have risk factors that make them prone to developing another infection of the reimplanted CIED. However, the rate of a second infection requiring repeat extraction in such patients is unknown and may have important clinical implications. METHODS: We retrospectively reviewed all patients at our institution from January 2001 to October 2012 who underwent a CIED extraction for an infection and then required reimplantation. We then reviewed the incidence of a repeat extraction due to a second infection. Clinical and device parameters at the time of the second infection were retrieved. RESULTS: There were 168 patients who underwent a CIED extraction because of infection and were subsequently reimplanted. The median time to reimplantation was 3 [1(st) quartile: 1, 3(rd) quartile: 10] days. After a mean follow-up of 4.4 +/- 2.7 years, nine (5.4%) patients underwent a repeat CIED extraction due to a second infection. Six repeat extractions (67%) occurred in the first year, leading to an event rate of 3.9% within 1 year of reimplantation. Patients with a second infection requiring a repeat CIED extraction were younger (57 +/- 20 vs 68 +/- 16, P = 0.046). Pocket infection was the most common presentation of a second infection, occurring in eight of the nine patients. CONCLUSION: The rate of a second infection leading to a CIED repeat extraction is elevated within the first year after reimplantation. To determine predictors of recurring infection, analysis of a larger multicenter series is warranted. PMID- 24766635 TI - Copper-catalyzed regio- and stereoselective intermolecular three-component oxyarylation of allenes. AB - A copper(II)-catalyzed intermolecular three-component oxyarylation of allenes using arylboronic acids as a carbon source and TEMPO as an oxygen source is described. The reaction proceeded under mild conditions with high regio- and stereoselectivity and functional group tolerance. A plausible reaction mechanism is proposed, involving carbocupration of allenes, homolysis of the intervening allylcopper(II), and a radical TEMPO trap. PMID- 24766636 TI - Gas-phase enthalpies of formation and enthalpies of sublimation of amino acids based on isodesmic reaction calculations. AB - Accurate gas-phase enthalpies of formation (DeltafH298 degrees ) of 20 common alpha-amino acids, seven uncommon amino acids, and three small peptides were calculated by combining G4 theory calculations with an isodesmic reaction approach. The internal consistency over a set of DeltafH298 degrees (g) values was achieved by sequential adjustment of their values through the isodesmic reactions. Four amino acids, alanine, beta-alanine, sarcosine, and glycine, with reliable internally self-consistent experimental data, were chosen as the key reference compounds. These amino acids together with about 100 compounds with reliable experimental data (their accuracy was supported by G4 calculations) were used to estimate the enthalpies of formation of remaining amino acids. All of the amino acids with the previously established enthalpies of formation were later used as the reference species in the isodesmic reactions for the other amino acids. A systematic comparison was made of 14 experimentally determined enthalpies of formation with the results of calculations. The experimental enthalpies of formation for 10 amino acids were reproduced with good accuracy, but the experimental and calculated values for 4 compounds differed by 11-21 kJ/mol. For these species, the theoretical DeltafH298 degrees (g) values were suggested as more reliable than the experimental values. On the basis of theoretical results, the recommended values for the gas-phase enthalpies of formation were also provided for amino acids for which the experimental DeltafH298 degrees (g) were not available. The enthalpies of sublimation were evaluated for all compounds by taking into account the literature data on the solid-phase enthalpies of formation and the DeltafH298 degrees (g) values recommended in our work. A special attention was paid to the accurate prediction of enthalpies of formation of amino acids from the atomization reactions. The problems associated with conformational flexibility of these compounds and harmonic treatment of low frequency torsional modes were discussed. The surprisingly good agreement between the DeltafH298 degrees (g) values calculated from the atomization and isodesmic reactions is largely the result of a fortuitous mutual compensation of various corrections used in the atomization reaction procedure. PMID- 24766637 TI - Mastery motivation as a predictor of occupational performance following upper limb intervention for school-aged children with congenital hemiplegia. AB - AIM: To determine the extent to which children's mastery motivation predicts occupational performance outcomes following upper limb intervention (ULI). METHOD: In this cohort study, participants received 45 hours of ULI, either in an intensive group-based or distributed individualized model. The Dimensions of Mastery Questionnaire (DMQ) measured mastery motivation at baseline. Occupational performance outcomes were assessed at baseline and 13 weeks' post-intervention using the Canadian Occupational Performance Measure (COPM). Multivariable models determined the contribution of mastery motivation to COPM outcome irrespective of group membership. RESULTS: Forty-two children with congenital hemiplegia (29 males, 13 females; mean age 7y 8mo [SD 2y 2mo]; range 5y 1mo-12y 8mo; Manual Ability Classification System [MACS] I=20 and II=22; predominant motor type unilateral spastic n=41) participated in the study. Significant gains were seen in COPM performance and satisfaction scores (p<0.001) post-intervention with no between group differences. Children who had greater persistence with object oriented tasks (p=0.02) and better manual ability (p=0.03) achieved higher COPM performance scores at 13 weeks. Children's persistence on object-oriented tasks was the strongest predictor of COPM satisfaction (p=0.01). INTERPRETATION: Children's persistence with object-oriented tasks as well as manual abilities needs to be considered when undertaking ULI. Predetermining children's motivational predispositions can assist clinicians to tailor therapy sessions individually based on children's strengths, contributing to effective engagement in ULI. PMID- 24766638 TI - Structure of drug delivery DPPA and DPPC liposomes with ligands and their permeability through cells. AB - Dipalmitoylphosphatidylcholine (DPPC) and 1,2-palmitoyl-phosphatidic acid (DPPA) liposomes, prepared by conventional rotary evaporation method, have similar structural organization, though they have significant differences. The similarity is that both types of lipids create standard bilayer liposomes with strong hydrophobic forces between lipids tails and with homogeneous bonds of hydrogen and electrostatic nature between hydrophilic lipids heads. By the calorimetric method, it has been shown that hydrophobic bonds break but liposomes' destruction does not occur by heating till 150 degrees C. As for bonds between lipid heads in liposomes, their cooperative destruction takes place at 41 degrees C for DPPC and 66 degrees C for DPPA liposomes. In the case of thermal distraction of DPPC liposomes, two so-called pre transitions peaks were observed before the main transition peak, which indicates that DPPC liposomes' structure is multilamellar. DPPA liposomes have one cooperative heat absorption peak, which points to a unilamellar structure of such liposomes. Substances of hydrophobic/hydrophilic nature, incorporated into the liposomes, are placed in hydrophobic or hydrophilic parts of liposomes, which lead to a change in calorimetric peak shapes and thermodynamic parameters. It has been shown that gold nanoparticles, incorporated into the DPPC liposomes, are able to enter Caco-2 cells. In contrast, these nanoparticles do not enter red blood cells. PMID- 24766639 TI - Lipid-based capsaicin-loaded nano-colloidal biocompatible topical carriers with enhanced analgesic potential and decreased dermal irritation. AB - Capsaicin (CP), a recent FDA-approved drug for the topical treatment of neuropathic pain, is associated with several side effects like irritation, burning sensation, and erythema, resulting in poor patient compliance. The present study is an attempt to study the effect of CP encasement in nano-lipoidal carriers (NLCs) on skin-transport characteristics, in vivo pharmacological performance, skin compliance, and stability of the finished product. The study also compares two methods of NLC preparation, namely microemulsification and rotary-evaporation for various attributes. The results demonstrated that microemulsion technique produced smaller nanoparticles vis-a-vis the rotary evaporation method. Out of the various studied solid lipids, NLCs from stearic acid offered smallest size and the highest negative zeta potential. The NLC-gel offered higher skin permeation and skin retention of CP across LACA mice skin as compared with the conventional cream. The analgesic effect was observed to be enhanced substantially than that of the conventional cream when tested on a radiant mouse tail-flick model. The most alarming problems of skin-irritation and redness were successfully taken care by NLC-gel while the mice group receiving conventional cream showed marked changes in the skin histopathology. Besides the enhanced efficacy and decreased skin-irritation, the developed CP-NLCs also found to be stable and rheologically accepted formulation for the treatment of pain associated disorders. PMID- 24766640 TI - Evaluation of MYOC, ACAN, HGF, and MET as candidate genes for high myopia in a Han Chinese population. AB - AIM: To investigate the association between high myopia (HM) and single nucleotide polymorphisms (SNPs) in the myocilin (MYOC), hepatocyte growth factor (HGF), hepatocyte growth factor receptor (MET), and aggrecan (ACAN) genes in a Han Chinese population. METHODS: Sixteen SNPs were genotyped by the SNaPshot method in a subject group composed of 1052 HM patients and 1070 controls. Statistical analysis was performed to determine the association between the SNPs and the susceptibility of HM. RESULTS: Two SNPs (rs3784757 and rs1516794) in ACAN were significantly associated with HM (p=0.0334 and 0.0236, odds ratio [OR]=0.83 and 0.79, respectively). The risk haplotype CA and the protective haplotype TT, generated by rs3784757 and rs1516794, showed significant association with HM (p=0.0327 and 0.0304, OR=1.21 and 0.80, respectively). Two SNPs (rs38857 and rs10215153) in MET and one SNP (rs3784757) in ACAN showed significant association with HM (p=0.0064, 0.0113, and 0.0373; OR=4.14, 5.74 and 0.52; respectively) in the recessive model. None of the other SNPs showed significant association with HM. CONCLUSIONS: Our results suggested that genetic variants in ACAN and MET are associated with HM. Functional roles of ACAN and MET in the development of HM need to be further investigated. PMID- 24766641 TI - Mutations in the non-structural protein region contribute to intra-genotypic evolution of enterovirus 71. AB - BACKGROUND: Clinical manifestations of enterovirus 71 (EV71) range from herpangina, hand-foot-and-mouth disease (HFMD), to severe neurological complications. Unlike the situation of switching genotypes seen in EV71 outbreaks during 1998-2008 in Taiwan, genotype B5 was responsible for two large outbreaks in 2008 and 2012, respectively. In China, by contrast, EV71 often persists as a single genotype in the population and causes frequent outbreaks. To investigate genetic changes in viral evolution, complete EV71 genome sequences were used to analyze the intra-genotypic evolution pattern in Taiwan, China, and the Netherlands. RESULTS: Genotype B5 was predominant in Taiwan's 2008 outbreak and was re-emergent in 2012. EV71 strains from both outbreaks were phylogenetically segregated into two lineages containing fourteen non-synonymous substitutions predominantly in the non-structural protein coding region. In China, genotype C4 was first seen in 1998 and caused the latest large outbreak in 2008. Unlike shifting genotypes in Taiwan, genotype C4 persisted with progressive drift through time. A majority of non-synonymous mutations occurred in residues located in the non-structural coding region, showing annual increases. Interestingly, genotype B1/B2 in the Netherlands showed another stepwise evolution with dramatic EV71 activity increase in 1986. Phylogeny of the VP1 coding region in 1971-1986 exhibited similar lineage turnover with genotype C4 in China; however, phylogeny of the 3D-encoding region indicated separate lineage appearing after 1983, suggesting that the 3D-encoding region of genotype B2 was derived from an unidentified ancestor that contributed to intra-genotypic evolution in the Netherlands. CONCLUSIONS: Unlike VP1 coding sequences long used for phylogenetic study of enteroviruses due to expected host immune escape, our study emphasizes a dominant role of non-synonymous mutations in non-structural protein regions that contribute to (re-)emergent genotypes in continuous stepwise evolution. Dozens of amino acid substitutions, especially in non-structural proteins, were identified via genetic changes driven through intra-genotypic evolution worldwide. These identified substitutions appeared to increase viral fitness in the population, affording valuable insights not only for viral evolution but also for prevention, control, and vaccine against EV71 infection. PMID- 24766642 TI - Mental health of carers of children affected by HIV attending community-based programmes in South Africa and Malawi. AB - There is strong evidence that both adults and children infected with and affected by HIV have high levels of mental health burden. Yet there have been few studies investigating carer mental health outcomes in the context of HIV in Malawi and South Africa. The objective of this study was to assess the mental health of carers of children affected by HIV as a part of the Child Community Care study, which aims to generate evidence on the effectiveness of community-based organisation (CBO) services to improve child outcomes. In a cross-sectional study, we interviewed 952 carers of children (aged 4-13 years) attending 28 randomly selected CBOs funded by 11 major donors in South Africa and Malawi. Psychological morbidity was measured using the Shona Symptom Questionnaire and suicidal ideation was measured using an item from the Patient Health Questionnaire. Carers were asked about care-seeking for emotional problems. Overall, 28% of carers scored above the clinical cut-off for current psychological morbidity and 12.2% reported suicidal ideation. We used logistic regression models to test factors associated with poor outcomes. Household unemployment, living with a sick family member and perceived lack of support from the community were associated with both psychological morbidity and suicidal ideation in carers. Reported child food insecurity was also associated with psychological morbidity. In addition, carers living in South Africa were more likely to present with psychological morbidity and suicidal ideation than carers in Malawi. Rates of help-seeking for mental health problems were low. Carers of children affected by HIV are at risk for mental health problems as a result of HIV, socio-economic, care-giving and community factors. We call for increased recognition of the potential role of CBOs in providing mental health care and support for families as a means to improve equity in mental health care. Specifically, we highlight the need for increased training and supervision of staff at CBOs for children affected by HIV, and the inclusion of CBOs in broader efforts to improve population mental health outcomes. PMID- 24766643 TI - HGF induces epithelial-to-mesenchymal transition by modulating the mammalian hippo/MST2 and ISG15 pathways. AB - Epithelial to mesenchymal transition (EMT) is a fundamental cell differentiation/dedifferentiation process which is associated with dramatic morphological changes. Formerly polarized and immobile epithelial cells which form cell junctions and cobblestone-like cell sheets undergo a transition into highly motile, elongated, mesenchymal cells lacking cell-to-cell adhesions. To explore how the proteome is affected during EMT we profiled protein expression and tracked cell biological markers in Madin-Darby kidney epithelial cells undergoing hepatocyte growth factor (HGF) induced EMT. We were able to identify and quantify over 4000 proteins by mass spectrometry. Enrichment analysis of this revealed that expression of proteins associated with the ubiquitination machinery was induced, whereas expression of proteins regulating apoptotic pathways was suppressed. We show that both the mammalian Hippo/MST2 and the ISG15 pathways are regulated at the protein level by ubiquitin ligases. Inhibition of the Hippo pathway by overexpression of either ITCH or A-Raf promotes HGF-induced EMT. Conversely, ISG15 overexpression is sufficient to induce cell scattering and an elongated morphology without external stimuli. Thus, we demonstrate for the first time that the Hippo/MST2 and ISG15 pathways are regulated during growth-factor induced EMT. PMID- 24766644 TI - Diversity of antibiotic resistance genes and staphylococcal cassette chromosome mec elements in faecal isolates of coagulase-negative staphylococci from Nigeria. AB - BACKGROUND: Coagulase-negative staphylococci (CoNS) are opportunistic pathogens found as colonisers of the human gut. This study was carried out to examine the genetic resistance mechanisms in faecal isolates of CoNS. The study investigated 53 non-duplicate CoNS isolates obtained from the fresh stool samples of apparently healthy subjects in the community of Ile-Ife, South-Western Nigeria. Antibiotic susceptibility testing was assessed by the disc diffusion test while antibiotic resistance genes were analysed by PCR. mecA positive isolates were analysed by Staphylococcal Chromosome Cassette mec (SCCmec) and cassette chromosome recombinase (ccr) complex typing methods. RESULTS: Resistance genes were detected only in isolates that showed resistance by phenotypic screening. The aac(6')-aph(2") gene was detected in all the three isolates resistant to gentamicin. Four of the five erythromycin resistant isolates were positive for the ermC gene, the remaining isolate carried the msrA gene. The tetK gene was detected in 6 of the 7 tetracycline resistant isolates while 4 possessed the tetM gene. Three of the isolates (S. haemolyticus, S. xylosus and S. capitis) had both genes. Several SCCmec types were found: SCCmec I- ccrABbeta2-alpha2 (4 isolates: 3 S. epidermidis, 1 S. warneri), SCCmecIVb- ccrABbeta2-alpha3 (1 isolate: S. epidermidis), SCCmecIVd- ccrABbeta2-alpha3 (8 isolates: 3 S. epidermidis, 2 S. xylosus, 1 S. saprophyticus, 1 S. warneri, 1 S. capitis), and untypable (2 isolates: S. epidermidis). CONCLUSION: This genetic background could be a reservoir for interspecies gene transfer among CoNS and S. aureus in the intestinal tract. PMID- 24766645 TI - The contribution of estuary-resident life histories to the return of adult Oncorhynchus kisutch. AB - This study evaluated estuarine habitat use, life-history composition, growth and survival of four successive broods of coho salmon Oncoryhnchus kisutch in Salmon River, Oregon, U.S.A. Subyearling and yearling O. kisutch used restored and natural estuarine wetlands, particularly in the spring and winter. Stream-reared yearling smolts spent an average of 2 weeks in the estuary growing rapidly before entering the ocean. Emergent fry also entered the estuary in the spring, and some resided in a tidal marsh throughout the summer, even as salinities increased to >20. A significant portion of the summer stream-resident population of juvenile O. kisutch migrated out of the catchment in the autumn and winter and used estuary wetlands and adjacent streams as alternative winter-rearing habitats until the spring when they entered the ocean as yearling smolts. Passive integrated transponder (PIT) tag returns and juvenile life-history reconstructions from otoliths of returning adults revealed that four juvenile life-history types contributed to the adult population. Estuarine-associated life history strategies accounted for 20-35% of the adults returning to spawn in the four brood years, indicating that a sizable proportion of the total O. kisutch production is ignored by conventional estimates based on stream habitat capacity. Juvenile O. kisutch responses to the reconnection of previously unavailable estuarine habitats have led to greater life-history diversity in the population and reflect greater phenotypic plasticity of the species in the U.S. Pacific Northwest than previously recognized. PMID- 24766646 TI - Creatine supplementation during pregnancy: summary of experimental studies suggesting a treatment to improve fetal and neonatal morbidity and reduce mortality in high-risk human pregnancy. AB - While the use of creatine in human pregnancy is yet to be fully evaluated, its long-term use in healthy adults appears to be safe, and its well documented neuroprotective properties have recently been extended by demonstrations that creatine improves cognitive function in normal and elderly people, and motor skills in sleep-deprived subjects. Creatine has many actions likely to benefit the fetus and newborn, because pregnancy is a state of heightened metabolic activity, and the placenta is a key source of free radicals of oxygen and nitrogen. The multiple benefits of supplementary creatine arise from the fact that the creatine-phosphocreatine [PCr] system has physiologically important roles that include maintenance of intracellular ATP and acid-base balance, post ischaemic recovery of protein synthesis, cerebral vasodilation, antioxidant actions, and stabilisation of lipid membranes. In the brain, creatine not only reduces lipid peroxidation and improves cerebral perfusion, its interaction with the benzodiazepine site of the GABAA receptor is likely to counteract the effects of glutamate excitotoxicity - actions that may protect the preterm and term fetal brain from the effects of birth hypoxia. In this review we discuss the development of creatine synthesis during fetal life, the transfer of creatine from mother to fetus, and propose that creatine supplementation during pregnancy may have benefits for the fetus and neonate whenever oxidative stress or feto placental hypoxia arise, as in cases of fetal growth restriction, premature birth, or when parturition is delayed or complicated by oxygen deprivation of the newborn. PMID- 24766647 TI - WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells. AB - BACKGROUND: Wnt proteins are important for developmental processes and certain diseases. WNT5A is a non-canonical Wnt protein that previously has been shown to play a role in the progression of malignant melanoma. High expression of WNT5A in melanoma tumors correlates to formation of distant metastasis and poor prognosis. This has partly been described by the findings that WNT5A expression in melanoma cell lines increases migration and invasion. METHODS: Malignant melanoma cell lines were treated with rWNT5A or WNT5A siRNA, and mRNA versus protein levels of soluble mediators were measured using RT-PCR, cytokine bead array and ELISA. The induced signaling pathways were analyzed using inhibitors, Rho-GTPase pull down assays and western blot. Ultracentrifugation and electron microscopy was used to analyze microvesicles. Gene expression microarray data obtained from primary malignant melanomas was used to verify our data. RESULTS: We show that WNT5A signaling induces a Ca2+-dependent release of exosomes containing the immunomodulatory and pro-angiogenic proteins IL-6, VEGF and MMP2 in melanoma cells. The process was independent of the transcriptional machinery and depletion of WNT5A reduced the levels of the exosome-derived proteins. The WNT5A induced exosomal secretion was neither affected by Tetanus toxin nor Brefeldin A, but was blocked by the calcium chelator Bapta, inhibited by a dominant negative version of the small Rho-GTPase Cdc42 and was accompanied by cytoskeletal reorganization. Co-cultures of melanoma/endothelial cells showed that depletion of WNT5A in melanoma cells decreased endothelial cell branching, while stimulation of endothelial cells with isolated rWNT5A-induced melanoma exosomes increased endothelial cell branching in vitro. Finally, gene expression data analysis of primary malignant melanomas revealed a correlation between WNT5A expression and the angiogenesis marker ESAM. CONCLUSIONS: These data indicate that WNT5A has a broader function on tumor progression and metastatic spread than previously known; by inducing exosome-release of immunomodulatory and pro-angiogenic factors that enhance the immunosuppressive and angiogenic capacity of the tumors thus rendering them more aggressive and more prone to metastasize. PMID- 24766648 TI - Acupuncture for acute postoperative pain after back surgery: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: Acupuncture is commonly used as a complimentary treatment for pain management. However, there has been no systematic review summarizing the current evidence concerning the effectiveness of acupuncture for acute postoperative pain after back surgery. This systematic review aimed at evaluating the effectiveness of acupuncture treatment for acute postoperative pain (<=1 week) after back surgery. METHODS: We searched 15 electronic databases without language restrictions. Two reviewers independently assessed studies for eligibility and extracted data, outcomes, and risk of bias. Random effect meta-analyses and subgroup analyses were performed. RESULTS: Five trials, including 3 of high quality, met our inclusion criteria. The meta-analysis showed positive results for acupuncture treatment of pain after surgery in terms of the visual analogue scale (VAS) for pain intensity 24 hours after surgery, when compared to sham acupuncture (standard mean difference -0.67 (-1.04 to -0.31), P = 0.0003), whereas the other meta-analysis did not show a positive effect of acupuncture on 24-hour opiate demands when compared to sham acupuncture (standard mean difference -0.23 (-0.58 to 0.13), P = 0.21). CONCLUSION: Our systematic review finds encouraging but limited evidence for the effectiveness of acupuncture treatment for acute postoperative pain after back surgery. Further rigorously designed clinical trials are required. PMID- 24766651 TI - Successful treatment of macroreentrant atrial tachycardia by radiofrequency ablation targeting channels with continuous activation. AB - BACKGROUND: Macroreentrant atrial tachycardia (MRAT) is frequently unresponsive to antiarrhythmic drugs. The application of three-dimensional (3D) mapping and entrainment pacing contributes to a high success rate for radiofrequency ablation, but programmed electrical pacing may either terminate or transform clinical tachyarrhythmias. On the basis of clinical experiences of the use of ventricular tachycardia ablation, channels with continuous activation are suitable for reentrant circuits, and ablation at these channels can lead to noninducibility of ventricular tachycardias. We reviewed patients referred for symptomatic MRAT with identified channels with continuous activation and evaluated the efficacy of MRAT ablation by targeting these channels. METHODS: Fifteen consecutive patients (10 men, 49 +/- 14 years) with MRAT illustrated by endocardial activation maps using a 3D electroanatomical mapping system (CARTOTM, Biosense Webster, Diamond Bar, CA, USA) were included in this study. Continuous activation was defined as double or continuous potentials without an isoelectric interval, and sites with continuous activation were tagged for measurements of channel properties. Radiofrequency ablation was performed at those targeted sites located within the reentrant circuit. RESULTS: Radiofrequency ablation successfully eliminated MRAT in all patients. The mean cycle length was 283 +/- 60 ms, and the longest activation duration was 112 +/- 38 ms. The minimal and maximal bipolar voltage amplitudes were 0.13 +/- 0.1 mV and 0.7 +/- 0.6 mV, respectively. The targeted ablation length and width were 28.9 +/- 15.3 mm and 9.4 +/- 3.3 mm, respectively. CONCLUSION: Radiofrequency ablation of MRAT targeting channels with continuous activation using a 3D electroanatomical mapping system yields a high success rate. PMID- 24766650 TI - Drug addiction and stress-response genetic variability: association study in African Americans. AB - Stress is a significant risk factor in the development of drug addictions and in addiction relapse susceptibility. This hypothesis-driven study was designed to determine if specific SNPs in genes related to stress response are associated with heroin and/or cocaine addiction in African Americans. The analysis included 27 genes (124 SNPs) and was performed independently for each addiction. The sample consisted of former heroin addicts in methadone maintenance treatment (n = 314), cocaine addicts (n = 281), and controls (n = 208). Fourteen SNPs showed nominally significant association with heroin addiction (p < 0.05), including the African-specific, missense SNP rs5376 (Asn334Ser) in the galanin receptor type 1 gene (GALR1) and the functional FKBP5 intronic SNP rs1360780. Thirteen SNPs showed association with cocaine addiction, including the synonymous SNPs rs237902, in the oxytocin receptor gene (OXTR), and rs5374 in GALR1. No signal remained significant after correction for multiple testing. Four additional SNPs (GALR1 rs2717162, AVP rs2282018, CRHBP rs1875999, and NR3C2 rs1040288) were associated with both addictions and may indicate common liability. The study provides preliminary evidence for novel association of variants in several stress related genes with heroin and/or cocaine addictions and may enhance the understanding of the interaction between stress and addictions. PMID- 24766653 TI - Family-clinician interactions in children's health services: a secondary analysis of occupational therapists' practice descriptions. AB - BACKGROUND: Effective family-clinician interactions are important for good health outcomes. Two types of interactions are consistently recommended: relational (e.g. listening, empathy, and respect) and participatory (e.g. shared decision making, planning and problem-solving), but there is little specific guidance on how to implement these interactions in practice. OBJECTIVE: To identify specific, practice-based examples of relational and participatory family-clinician interactions in children's occupational therapy. DESIGN: A qualitative secondary analysis was used. The data consisted of a list of occupational therapists' self reported practice actions (n = 217) and direct quotes describing their content and context. The practice actions were categorized into a range of relational and participatory family-centred interactions using a modified framework analysis. RESULTS: Of the 217 practice actions, the majority [121 (55.76%)] did not describe examples of therapists implementing family-clinician interactions. Of the remaining practice actions, 19 (8.76%) described 'relational' interactions (e.g. 'Listen to carer', 'Gather perspectives from others'); 47 (21.66%) described 'participatory' interactions (e.g. 'Identify the family's goals and priorities', 'Allow the family to choose'); 2 (0.92%) described both ('Take guidance from carers'); and 28 (12.9%) were excluded from the analysis. DISCUSSION AND CONCLUSIONS: A range of relational and participatory interactions were identified. Descriptions of participatory interactions were more frequent than descriptions of relational interactions, and overall the therapists described their family-clinician interactions less frequently than their other practice actions. The specific, real-life examples of different types of interactions identified in the study can be used as a basis for reflection on practice and developing more specific guidance. PMID- 24766654 TI - Sensory response following knee joint damage in rabbits. AB - BACKGROUND: Altered sensory information arising from damaged knee joint structures has been hypothesized as a contributing factor to persistent muscle dysfunction following injury. METHODS: Composite femoral nerve sensory signal was measured in 24 rabbits randomly allocated (8 per group) to receive surgical anterior cruciate ligament (ACL) transection with or without autograft reconstruction or nothing (control). Two-weeks after the intervention composite afferent signals were recorded from the femoral nerve. Side-to-side ratios (surgical side vs contralateral healthy side) for peak femoral nerve afferent composite signal were used for comparison. RESULTS: Femoral nerve afferent signal ratios were significantly higher in the ACL-R (2.21 +/- 0.74) group when compared to the ACL-T (1.28 +/- 0.61, P=0.02) group and Control group (1.31 +/- 0.78, P=0.03). CONCLUSION: The magnitude of sensory information recorded on the femoral nerve is increased following ACL injury and reconstruction surgery, but not after an isolated ACL injury in rabbits. PMID- 24766655 TI - Comparative study between synthetic and phospholipids of natural origin: effect of phospholipid selection on the behavior of a topical liposomal dosage form incorporating terbinafine. AB - Selection of excipients used is a critical step in the design of a pharmaceutical dosage form as it affects its behavior upon application, as during storage. The purpose of the present study is to evaluate and compare the behavior of six liposomal formulations intended for topical application composed of two widely used phospholipids 1,2-diacyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine with and without incorporation of cholesterol. Liposomal hydrogels made of hydroxyethylcellulose 3% and incorporating the anti fungal agent terbinafine hydrochloride (E)-N-(6,6-dimethyl-2-hepten-4-inyl)-N methyl-1-naphthalene-methanamine (-hydrochloride) were prepared, their viscosity was measured and in vitro drug release was studied. Moreover, physical stability and drug retention during storage at two different temperatures (2-8 degrees C and RT) were examined over time. The results showed differences in the behavior between the two phospholipids while incorporation of cholesterol at the studied concentrations was found to be of minor importance. Drug release was found to be favorable from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomal hydrogels and drug retention was found to be higher at lower storage temperature for all batches. Original physicochemical properties of all batches were found to be retained at least for a week. PMID- 24766656 TI - Intraocular tuberculosis presenting as a large anterior chamber mass. PMID- 24766657 TI - SARS-CoV envelope protein palmitoylation or nucleocapid association is not required for promoting virus-like particle production. AB - BACKGROUND: Coronavirus membrane (M) proteins are capable of interacting with nucleocapsid (N) and envelope (E) proteins. Severe acute respiratory syndrome coronavirus (SARS-CoV) M co-expression with either N or E is sufficient for producing virus-like particles (VLPs), although at a lower level compared to M, N and E co-expression. Whether E can release from cells or E/N interaction exists so as to contribute to enhanced VLP production is unknown. It also remains to be determined whether E palmitoylation or disulfide bond formation plays a role in SARS-CoV virus assembly. RESULTS: SARS-CoV N is released from cells through an association with E protein-containing vesicles. Further analysis suggests that domains involved in E/N interaction are largely located in both carboxyl-terminal regions. Changing all three E cysteine residues to alanines did not exert negative effects on E release, E association with N, or E enhancement of VLP production, suggesting that E palmitoylation modification or disulfide bond formation is not required for SARS-CoV virus assembly. We found that removal of the last E carboxyl-terminal residue markedly affected E release, N association, and VLP incorporation, but did not significantly compromise the contribution of E to efficient VLP production. CONCLUSIONS: The independence of the SARS-CoV E enhancement effect on VLP production from its viral packaging capacity suggests a distinct SARS-CoV E role in virus assembly. PMID- 24766658 TI - Mass spectrometry-based proteomic approach in Oenococcus oeni enological starter. AB - A simple procedure is proposed for selective protein solubilization and trypsin digestion, followed by off-line liquid chromatography-matrix assisted laser desorption ionization mass spectrometry (LC-MALDI MS) analysis of Oenococcus oeni (O. oeni) bacterium. Peptides were identified from tryptic digests using sequencing by tandem mass spectrometry and database searches. Cytoplasmic and membrane related proteins (MRP) were identified in the O. oeni bacterium. MS/MS data analysis points out 13 peptides having one point mutation from 9 proteins. The major microheterogeneity was found for Zn-dependent alcohol dehydrogenase (Zn ADH, Q04GE6) and 60 kDa chaperonin (GroEL, Q04E64) that are involved in methionine catabolism and post-translational protein folding, respectively. MS/MS data processing also leads to the identification of 34 unique phosphorylation sites from 19 phosphoproteins. PMID- 24766659 TI - Attitudes toward, and interest in, the test-and-treat strategy for HIV prevention among Thai men who have sex with men. AB - This study assessed the attitudes toward, and interest in, the test-and-treat strategy, comprising regular HIV testing and immediate antiretroviral treatment (ART) among men who have sex with men (MSM) in Bangkok, Thailand. A total of 363 participants completed the questionnaires before and after learning about their HIV status. Previous HIV testing reported by 69.8% and 34.7% tested at least annually. Before pretest counseling, 83.2% expressed interest in regular HIV testing and 78.8% in immediate ART. MSM who tested HIV-positive at enrollment were less likely than those who tested HIV-negative to have been tested for HIV before (45.7% vs. 60.8%, p < 0.0001). Among MSM who tested HIV-positive (n = 69, 15.9%), the median level of willingness to take ART immediately increased significantly after learning about their positive results (90 vs.100%, p < 0.0001). Interest in regular HIV testing remained high among HIV-negative MSM after becoming aware of their status (70.9% before vs. 71.9% after, p = 0.55). MSM participants have a strong desire and willingness to start ART immediately upon receiving an HIV-positive test result; it is important to provide the necessary information on the health benefits of early ART and education to the community to maintain their health and prevent HIV transmission. PMID- 24766660 TI - Effects of population characteristics and structure on estimates of effective population size in a house sparrow metapopulation. AB - Effective population size (N(e)) is a key parameter to understand evolutionary processes and the viability of endangered populations as it determines the rate of genetic drift and inbreeding. Low Ne can lead to inbreeding depression and reduced population adaptability. In this study, we estimated contemporary N(e) using genetic estimators (LDNE, ONeSAMP, MLNE and CoNe) as well as a demographic estimator in a natural insular house sparrow metapopulation. We investigated whether population characteristics (population size, sex ratio, immigration rate, variance in population size and population growth rate) explained variation within and among populations in the ratio of effective to census population size (N(e)/N(c)). In general, N(e)/N(c) ratios increased with immigration rates. Genetic N(e) was much larger than demographic N(e), probably due to a greater effect of immigration on genetic than demographic processes in local populations. Moreover, although estimates of genetic N(e) seemed to track N(c) quite well, the genetic N(e) -estimates were often larger than Nc within populations. Estimates of genetic N(e) for the metapopulation were however within the expected range ( HCO3(-)+ H(+). These enzymes are involved in many physiologic processes, such as photosynthesis, respiration, CO2 transport, as well as metabolism of xenobiotics. Five different, genetically distinct CA families are known to date: the alpha-, beta-, gamma-, delta- and zeta-CAs. alpha-, beta- and delta-CAs use Zn(II) ions at the active site, the gamma-CAs are probably Fe(II) enzymes (but they are active also with bound Zn(II) or Co(II) ions), whereas the zeta-class uses Cd(II) or Zn(II) to perform the physiologic reaction catalysis. Bacteria encode for enzymes belonging to the alpha-, beta-, and gamma-CA classes. They contain zinc ion (Zn(2+)) in their active site, coordinated by three histidine residues and a water molecule/hydroxide ion (in the alpha and gamma) or by two cysteine and one histidine residues (in the beta class), with the fourth ligand being a water molecule/hydroxide ion. Here we propose that bacterial CAs can be used as markers for understanding the evolution and genetic variability of the Gram-positive and Gram-negative bacteria. We addressed several questions such as: (1) why are alpha CAs present only in the genome of Gram-negative bacteria; (2) why are alpha-CAs not present in all Gram-negative bacteria; (3) why do Bacteria show an intricate pattern of CA gene expression; (4) what are the physiologic roles of such diverse CAs in these prokaryotes. We proposed possible answers to the previous questions. Moreover, we speculated on the evolution of the CA classes (alpha, beta and gamma) identified in the Gram-negative and -positive bacteria. Our main hypothesis is that from the ancestral Ur-CA, the gamma-class arose first, followed by the beta-class; the alpha-class CAs came last it is found only in the Gram-negative bacteria. PMID- 24766662 TI - Catalase, carbonic anhydrase and xanthine oxidase activities in patients with mycosis fungoides. AB - Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. In several studies the relationship between catalase (CAT), human cytosolic carbonic anhydrases (CA; hCA-I and hCA-II) and xanthine oxidase (XO) enzyme activities have been investigated in various types of cancers but carbonic anhydrase, catalase and xanthine oxidase activities in patients with MF have not been previously reported. Therefore, in this preliminary study we aim to investigate CAT, CA and XO activities in patients with MF. This study enrolled 32 patients with MF and 26 healthy controls. According to the results, CA and CAT activities were significantly lower in patients with mycosis fungoides than controls (p < 0.001) (p < 0.001). There was no significant difference in XO activity between patient and control group (p = 0.601). Within these findings, we believe these enzyme activity levels might be a potentially important finding as an additional diagnostic biochemical tool for MF. PMID- 24766663 TI - Screening of Lactobacillus spp. for the prevention of Pseudomonas aeruginosa pulmonary infections. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen that significantly increases morbidity and mortality in nosocomial infections and cystic fibrosis patients. Its pathogenicity especially relies on the production of virulence factors or resistances to many antibiotics. Since multiplication of antibiotic resistance can lead to therapeutic impasses, it becomes necessary to develop new tools for fighting P. aeruginosa infections. The use of probiotics is one of the ways currently being explored. Probiotics are microorganisms that exert a positive effect on the host's health and some of them are known to possess antibacterial activities. Since most of their effects have been shown in the digestive tract, experimental data compatible with the respiratory environment are strongly needed. The main goal of this study was then to test the capacity of lactobacilli to inhibit major virulence factors (elastolytic activity and biofilm formation) associated with P. aeruginosa pathogenicity. RESULTS: Sixty-seven lactobacilli were isolated from the oral cavities of healthy volunteers. These isolates together with 20 lactobacilli isolated from raw milks, were tested for their capacity to decrease biofilm formation and activity of the elastase produced by P. aeruginosa PAO1. Ten isolates, particularly efficient, were accurately identified using a polyphasic approach (API 50 CHL, mass spectrometry and 16S/rpoA/pheS genes sequencing) and typed by pulsed-field gel electrophoresis (PFGE). The 8 remaining strains belonging to the L. fermentum (6), L. zeae (1) and L. paracasei (1) species were sensitive to all antibiotics tested with the exception of the intrinsic resistance to vancomycin. The strains were all able to grow in artificial saliva. CONCLUSION: Eight strains belonging to L. fermentum, L. zeae and L. paracasei species harbouring anti-elastase and anti-biofilm properties are potential probiotics for fighting P. aeruginosa pulmonary infections. However, further studies are needed in order to test their innocuity and their capacity to behave such as an oropharyngeal barrier against Pseudomonas aeruginosa colonisation in vivo. PMID- 24766664 TI - Cancer stem cells and their implication in breast cancer. AB - BACKGROUND: The cancer stem cell (CSC) hypothesis on the origin of cancer has recently gained considerable support. CSCs are tumour cells with the capacity for self-renewal and differentiation that direct the origin and progression of the disease and may be responsible for relapse, metastasis and treatment failures. DESIGN: This article reviews breast CSCs (BCSCs) phenotyping, clinical implications and clinical trials focused on BCSCs in breast cancer. Relevant studies were found through PubMed and Clinicaltrials.gov databases. RESULTS: Cancer stem cells are identified and isolated using membrane and cell activity markers; in the case of BCSCs, these are CD44(+) /CD24(low/-) and show aldehyde dehydrogenase activity, alongside their capacity to grow and form mammospheres. The presence of stem cell properties is associated with a worse outcome. Hence, these cells have important clinical implications, and elucidation of the mechanisms underlying their activity will allow the development of novel effective therapies and diagnostic instruments, improving the prognosis of these patients. CONCLUSIONS: Standard treatments are directed against the tumour mass and do not eliminate CSCs. There is therefore a need for specific anti-CSC therapies, and numerous authors are investigating new targets to this end, as reported in this review. It is also necessary for clinical trials to be undertaken to allow this new knowledge to be applied in the clinical setting. However, there have been few trials on anti-BCSCs therapies to date. PMID- 24766665 TI - Toxoplasma gondii in sympatric wild herbivores and carnivores: epidemiology of infection in the Western Alps. AB - BACKGROUND: Toxoplasma gondii is an apicomplexan parasite that is able to infect almost all warm blooded animals. In Europe, the domestic cat is the main definitive host. Worldwide, 6 billion people are infected with this parasite. The goal of our research is to evaluate the prevalence of T. gondii infection in wild animals from a previously unsampled area in Northern Italy where 0.1% of women seroconvert during pregnancy each year. METHODS: We sampled and tested skeletal muscle and central nervous system tissue of 355 wild animals by PCR (n = 121 roe deer Capreolus capreolus, n = 105 wild boar Sus scrofa, n = 94 red fox Vulpes vulpes, n = 22 alpine chamois Rupicapra rupicapra, n = 13 red deer Cervus elaphus). RESULTS: The overall prevalence of infection with T. gondii was 10.99% (confidence interval (CI) 95% 8.14%-14.67%). A higher rate of infection was recorded in carnivores and omnivores (red fox 20.21%, CI 95% 13.34%-29.43%; wild boar 16.19%, CI 95% 10.36%-24.41%) compared to ruminants (2.48%, CI 95% 0.85% 7.04% in roe deer; 0.00%, CI 95% 0.00%-22.81% in red deer, and 0.00% alpine chamois (CI 95% 0.00%-14.87%) confirming the importance of tissue cysts in transmitting infection. CONCLUSIONS: The relatively high prevalence of T. gondii DNA in highly consumed game species (wild boar and roe deer) gives valuable insights into T. gondii epidemiology and may contribute to improve prevention and control of foodborne toxoplasmosis in humans. PMID- 24766667 TI - Substance abuse/dependence treatment: a European perspective. AB - During the past decade, substantial progress has been made in the field of addiction medicine in Europe, particularly regarding the development of new treatment interventions, resulting in a wide range of therapeutic options for patients with substance use disorders. However, not all interventions are evidence based. Patients with cannabis and cocaine/amphetamine use disorders and special patient populations especially lack evidence-based treatment recommendations. Many patients undergo treatment that has not been scientifically evaluated for quality and efficacy. Moreover, there are large disparities regarding availability and treatment access across Europe, with the new member states of the European Union (EU) reporting long waiting lists and low treatment coverage. Even in Austria, which ranks among the countries with relatively high treatment coverage and good diversification of treatment in opioid maintenance therapy due to the availability of methadone, buprenorphine, and slow-release oral morphine (SROM), a considerable population of untreated or inadequately treated patients exists. Treatment for substance use disorders in Europe still has scope for improvement in terms of treatment availability and access, which is ideally provided by further development and implementation of evidence-based interventions. PMID- 24766666 TI - Associations of nutrient intake with glycemic control in youth with type 1 diabetes: differences by insulin regimen. AB - BACKGROUND: Type 1 diabetes management has evolved from meal plans towards flexible eating with carbohydrate counting. With this shift, youth with type 1 diabetes may consume excess fat and insufficient fiber, which may impact glycemic control. Few studies consider whether insulin regimen influences associations between dietary intake and hemoglobin A1c. PATIENTS AND METHODS: In this cross sectional study, 252 youth (52% male; age, 13.2 +/- 2.8 years; body mass index z score [z-BMI], 0.7 +/- 0.8) with type 1 diabetes completed 3-day food records. Dietary intake was compared with published guidelines. Logistic regression predicted the odds of suboptimal glycemic control (an A1c level of >= 8.5%) related to fat and protein intake or fiber intake according to insulin regimen (pump vs. injection) adjusting for age, sex, diabetes duration, z-BMI, insulin dose, glucose monitoring frequency, and total energy intake (TEI). RESULTS: Youth had a mean TEI of 40.9 +/- 15.4 kcal/kg/day and excess fat and insufficient fiber intake compared against published guidelines. Pump-treated youth consuming the highest quartile of fat intake (as percentage TEI) had 3.6 (95% confidence interval, 1.3-9.7) times the odds of a suboptimal A1c than those in the lowest quartile. No such association was found in injection-treated youth. In the total sample, youth with the lowest quartile of fiber intake had 3.6 (95% confidence interval, 1.4-9.0) times the odds of a suboptimal A1c, but this association did not differ by insulin regimen. There was no association between protein intake and A1c. CONCLUSIONS: Higher fat intake in pump-treated youth and lower fiber intake in all youth were associated with an A1c level of >= 8.5%. Improving dietary quality may help improve A1c. PMID- 24766668 TI - Population pharmacokinetic meta-analysis of vortioxetine in healthy individuals. AB - The objective was to describe the pharmacokinetics of vortioxetine and evaluate the effect of intrinsic and extrinsic factors in the healthy population. Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75 mg (single dose) and 2.5-60 mg (multiple QD doses). The pharmacokinetics of vortioxetine was best characterised by a two-compartment model with first-order absorption, lag-time and linear elimination, with interindividual error terms for absorption rate constant, oral clearance and central volume of distribution. The population mean was 32.7 L/hr for oral clearance and 1.97?10(3) L for the central volume of distribution. The average elimination half-life was 65.8 hr. CYP2D6 inferred metabolic status (ultra, extensive, intermediate or poor metabolisers) and age on oral clearance and height on central volume of distribution were identified as statistically significant covariate-parameter relationships. For CYP2D6 poor metabolisers, CL/F was approximately 50% to that seen in CYP2D6 extensive metabolisers. The impact of height on V2/F and age on CL/F was low and not considered to be clinically relevant. The final model was found to be reliable, stable and predictive. A reliable, stable and predictive pharmacokinetic model was developed to characterise pharmacokinetics of vortioxetine in the healthy population. PMID- 24766669 TI - Physical activity and sedentary behaviour in relation to cardiometabolic risk in children: cross-sectional findings from the Physical Activity and Nutrition in Children (PANIC) Study. AB - BACKGROUND: Lower levels of physical activity (PA) and sedentary behaviour (SB) have been associated with increased cardiometabolic risk among children. However, little is known about the independent and combined associations of PA and SB as well as different types of these behaviours with cardiometabolic risk in children. We therefore investigated these relationships among children. METHODS: The subjects were a population sample of 468 children 6-8 years of age. PA and SB were assessed by a questionnaire administered by parents and validated by a monitor combining heart rate and accelerometry measurements. We assessed body fat percentage, waist circumference, blood glucose, serum insulin, plasma lipids and lipoproteins and blood pressure and calculated a cardiometabolic risk score using population-specific Z-scores and a formula waist circumference + insulin + glucose + triglycerides - HDL cholesterol + mean of systolic and diastolic blood pressure. We analysed data using multivariate linear regression models. RESULTS: Total PA was inversely associated with the cardiometabolic risk score (beta = 0.135, p = 0.004), body fat percentage (beta = -0.155, p < 0.001), insulin (beta = -0.099, p = 0.034), triglycerides (beta = -0.166, p < 0.001), VLDL triglycerides (beta = -0.230, p < 0.001), VLDL cholesterol (beta = -0.168, p = 0.001), LDL cholesterol (beta = -0.094, p = 0.046) and HDL triglycerides (beta = 0.149, p = 0.004) and directly related to HDL cholesterol (beta = 0.144, p = 0.002) adjusted for age and gender. Unstructured PA was inversely associated with the cardiometabolic risk score (beta = -0.123, p = 0.010), body fat percentage (beta = -0.099, p = 0.027), insulin (beta = -0.108, p = 0.021), triglycerides (beta = -0.144, p = 0.002), VLDL triglycerides (beta = -0.233, p < 0.001) and VLDL cholesterol (beta = -0.199, p < 0.001) and directly related to HDL cholesterol (beta = 0.126, p = 0.008). Watching TV and videos was directly related to the cardiometabolic risk score (beta = 0.135, p = 0.003), body fat percentage (beta = 0.090, p = 0.039), waist circumference (beta = 0.097, p = 0.033) and systolic blood pressure (beta = 0.096, p = 0.039). Resting was directly associated with the cardiometabolic risk score (beta = 0.092, p = 0.049), triglycerides (beta = 0.131, p = 0.005), VLDL triglycerides (beta = 0.134, p = 0.009), VLDL cholesterol (beta = 0.147, p = 0.004) and LDL cholesterol (beta = 0.105, p = 0.023). Other types of PA and SB had less consistent associations with cardiometabolic risk factors. CONCLUSIONS: The results of our study emphasise increasing total and unstructured PA and decreasing watching TV and videos and other sedentary behaviours to reduce cardiometabolic risk among children. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01803776. PMID- 24766671 TI - Volunteers in Palliative Care - A Comparison of Seven European Countries: A Descriptive Study. AB - OBJECTIVE: In Europe, volunteers have an important role in the delivery of palliative care. As part of the EU co-funded Europall project, 4 aspects of volunteering in palliative care were studied for 7 European countries (Belgium, England, France, Germany, the Netherlands, Poland, and Spain). These included (1) involvement of volunteers in palliative care, (2) organization of palliative care volunteering, (3) legal regulations concerning volunteering, and (4) education and training of palliative care volunteering. DESIGN/SETTING/METHODS: A literature search combined with an interview study. Information from the scientific literature, and country-specific policy documents were obtained and completed, along with data of consecutive semi-structured interviews with experts in the field of palliative care in the participating countries. RESULTS: In all countries, volunteers appeared to be involved in palliative care, yet their involvement across health care settings differed per country. England, for example, has the highest number of volunteers whereas Spain has the lowest number. Volunteering is embedded in law and regulations in all participating countries except for England and the Netherlands. In all participating countries, training programs are available and volunteers are organized, both on a national and a regional level. CONCLUSION: This study provides a descriptive overview of volunteer work in palliative care in 7 European countries, with a focus on the organizational aspects. Further research should concentrate on the roles and responsibilities of volunteers in the care for the terminally ill in different European health systems. PMID- 24766672 TI - Predictors for the development of temporomandibular disorders in scuba divers. AB - The aim was to determine predictors for the development of complaints of temporomandibular disorders (TMD) in a large sample of Dutch scuba divers who were free of any TMD complaints before they started diving actively. Five-hundred and thirty-six scuba divers (mean +/- SD age = 40.4 +/- 11.9 years; 34.1% women) completed a specifically developed questionnaire, either online or on paper. Stepwise forward logistic regression analysis was performed to predict the presence of TMD pain, with several potential risk factors as predictors. Four hundred and eighty-five of the 536 respondents were free of any TMD pain before they started diving actively. In this sample, TMD pain was present in 214 persons (44.1%). Four predictors contributed significantly to the presence of TMD pain, viz., clenching (OR = 2.466), warm water (OR = 1.685), biting on the mouthpiece (OR = 1.598), and the quality rating of the mouthpiece (OR = 0.887, that is, a higher rating means a smaller odds of having TMD pain). TMD pain is a common complaint among scuba divers who were free of such complaints before they started diving actively. Clenching, biting on the mouthpiece, and a low rating of the mouthpiece are predictors for the presence of TMD pain in scuba divers, while diving in cold water serves as a protective factor for TMD pain. PMID- 24766673 TI - TFAP2B overexpression contributes to tumor growth and a poor prognosis of human lung adenocarcinoma through modulation of ERK and VEGF/PEDF signaling. AB - BACKGROUND: TFAP2B is a member of the AP2 transcription factor family, which orchestrates a variety of cell processes. However, the roles of TFAP2B in regulating carcinogenesis remain largely unknown. Here, we investigated the regulatory effects of TFAP2B on lung adenocarcinomas growth and identified the underlying mechanisms of actions in non-small cell lung cancer (NSCLC) cells. METHODS: We first examined the expression of TFAP2B in lung cancer cell lines and tumor tissues. We also analyzed the prognostic predicting value of TFAP2B in lung adenocarcinomas. Then we investigated the molecular mechanisms by which TFAP2B knockdown or overexpression regulated lung cancer cell growth, angiogenesis and apoptosis, and further confirmed the role of TFAP2B in tumor growth in a lung cancer xenograft mouse model. RESULTS: TFAP2B was highly expressed in NSCLC cell lines and tumor tissues. Strong TFAP2B expression showed a positive correlation with the poor prognoses of patients with lung adenocarcinomas (P < 0.001). TFAP2B knockdown by siRNA significantly inhibited cell growth and induced apoptosis in NSCLC cells in vitro and in a lung cancer subcutaneous xenograft model, whereas TFAP2B overexpression promoted cell growth. The observed regulation of cell growth was accompanied by the TFAP2B-mediated modulation of the ERK/p38, caspase/cytochrome-c and VEGF/PEDF-dependent signaling pathways in NSCLC cells. CONCLUSIONS: These results indicate that TFAP2B plays a critical role in regulating lung adenocarcinomas growth and could serve as a promising therapeutic target for lung cancer treatment. PMID- 24766674 TI - Smoothing out the transition of care between maternity and child and family health services: perspectives of child and family health nurses and midwives'. AB - BACKGROUND: In Australia, women who give birth are transitioned from maternity services to child and health services once their baby is born. This horizontal integration of services is known as Transition of Care (ToC). Little is known of the scope and processes of ToC for new mothers and the most effective way to provide continuity of services. The aim of this paper is to explore and describe the ToC between maternity services to CFH services from the perspective of Australian midwives and child and family health (CFH) nurses. METHOD: This paper reports findings from phase two of a three phase mixed methods study investigating the feasibility of implementing a national approach to CFH services in Australia (the CHoRUS study). Data were collected through a national survey of midwives (n = 655) and CFH nurses (n = 1098). Issues specifically related to ToC between maternity services and CFH services were examined using descriptive statistics and content analysis of qualitative responses. RESULTS: Respondents described the ToC between maternity services and CFH services as problematic. Key problems identified included communication between professionals and services and transfer of client information. Issues related to staff shortages, early maternity discharge, limited interface between private and public health systems and tension around role boundaries were also reported. Midwives and CFH nurses emphasised that these issues were more difficult for families with identified social and emotional health concerns. Strategies identified by respondents to improve ToC included improving electronic transfer of information, regular meetings between maternity and CFH services, and establishment of liaison roles. CONCLUSION: Significant problems exist around the ToC for all families but particularly for families with identified risks. Improved ToC will require substantial changes in information transfer processes and in the professional relationships which currently exist between maternity and CFH services. PMID- 24766675 TI - Being publicly diagnosed: a grounded theory study of Danish patients with tuberculosis. AB - INTRODUCTION: Tuberculosis (TB) is a disease which affects people worldwide, but there is knowledge lacking about patients' experiences in low-prevalence and high income countries. AIM: To provide a theoretical framework for the process of being diagnosed with tuberculosis in a Danish setting. METHOD: A grounded theory design with field studies and qualitative interviews, following the recommendations from Glaser and Strauss. RESULT: A process of being publicly diagnosed was identified, which developed during the patient's trajectory from being on the way to becoming a patient, becoming a patient with TB, and finally being in medical treatment. Before being diagnosed with TB, patients were weighing between biding their time and deciding to undergo an examination. Social pressure and feelings of social responsibility tended to affect the decision. Having undergone the examination(s), the patients were publicly diagnosed. Being publicly diagnosed meant changing social interactions and fighting to regain control. CONCLUSION: Findings offer new insight and an empirically derived basis for developing interventions aimed at reducing the burden of being diagnosed with tuberculosis and increasing the wellbeing of the patients. PMID- 24766676 TI - Are parents of children hospitalized with severe community-acquired pneumonia more satisfied with care when physicians allow them to share decisions on the antibiotic route? AB - CONTEXT AND OBJECTIVE: Despite convincing evidence that oral and injected amoxicillin have equal efficacy in children with severe community-acquired pneumonia (CAP), hospitalized children often receive injected antibiotics. To investigate whether shared decision-making (choosing the antibiotic route) influences parental satisfaction. DESIGN, SETTING AND PARTICIPANTS: In a one-year questionnaire-based study, we enrolled consecutive children hospitalized for CAP. At admission, all children's parents received a leaflet on CAP. Parents arriving during the daytime were assigned to a shared group and could choose the antibiotic route, those admitted at other times were assigned to an unshared group for whom physicians chose the antibiotic route. Shared group parents answered anonymous questionnaire investigating why they chose a specific route. Parents in both groups answered another anonymous questionnaire at discharge assessing perceived satisfaction with care. MAIN OUTCOME MEASURE: Parents' satisfaction with perceived medical information as assessed by data from a questionnaire. RESULTS: Of the 95 children enrolled, more children's parents were assigned to the unshared than the shared group (77 vs. 18). Of the 18 children's parents in the shared group, 14 chose the oral antibiotic route mainly to avoid painful injections. Doctors explanations were considered better in the shared than in the unshared group (P = 0.02). DISCUSSION AND CONCLUSIONS: The larger number of children's parents assigned to the unshared group reflects paediatricians' reluctance to offer shared-decision making. Well-informed parents prefer oral antibiotic therapy for children with severe CAP. Allowing parents choose the antibiotic route respects parents' wishes, reduces children's pain and improves satisfaction. PMID- 24766677 TI - De-novo synthesis of 2-phenylethanol by Enterobacter sp. CGMCC 5087. AB - BACKGROUND: 2-phenylethanl (2-PE) and its derivatives are important chemicals, which are widely used in food materials and fine chemical industries and polymers and it's also a potentially valuable alcohol for next-generation biofuel. However, the biosynthesis of 2-PE are mainly biotransformed from phenylalanine, the price of which barred the production. Therefore, it is necessary to seek more sustainable technologies for 2-PE production. RESULTS: A new strain which produces 2-PE through the phenylpyruvate pathway was isolated and identified as Enterobacter sp. CGMCC 5087. The strain is able to use renewable monosaccharide as the carbon source and NH4Cl as the nitrogen source to produce 2-PE. Two genes of rate-limiting enzymes, chorismate mutase p-prephenate dehydratase (PheA) and 3 deoxy-d-arabino-heptulosonic acid 7-phosphate synthase (DAHP), were cloned from Escherichia coli and overexpressed in E. sp. CGMCC 5087. The engineered E. sp. CGMCC 5087 produces 334.9 mg L-1 2-PE in 12 h, which is 3.26 times as high as the wild strain. CONCLUSIONS: The phenylpyruvate pathway and the substrate specificity of 2-keto-acid decarboxylase towards phenylpyruvate were found in E. sp. CGMCC 5087. Combined with the low-cost monosaccharide as the substrate, the finding provides a novel and potential way for 2-PE production. PMID- 24766678 TI - The role of postoperative radiation therapy for endometrial cancer: Executive summary of an American Society for Radiation Oncology evidence-based guideline. AB - PURPOSE: To present evidence-based guidelines for adjuvant radiation in the treatment of endometrial cancer. METHODS AND MATERIALS: Key clinical questions to be addressed in this evidence-based guideline on endometrial cancer were identified. A comprehensive literature review was performed to identify studies that included no adjuvant therapy, or pelvic radiation or vaginal brachytherapy with or without systemic chemotherapy. Outcomes included local control, survival rates, and overall assessment of quality of life. RESULTS: Patients with grade 1 or 2 cancers with either no invasion or <50% myometrial invasion (MI), especially when no other high risk features are present, can be safely observed after hysterectomy. Vaginal cuff brachytherapy is as effective as pelvic radiation therapy at preventing vaginal recurrence for patients with grade 1 or 2 cancers with >=50% MI or grade 3 tumors with <50% MI. Patients with grade 3 cancer with >=50% MI or cervical stroma invasion may benefit from pelvic radiation to reduce the risk of pelvic recurrence. There is limited evidence for a benefit to vaginal cuff brachytherapy following pelvic radiation. Multimodality treatment is recommended for patients with positive nodes or involved uterine serosa, ovaries or fallopian tubes, vagina, bladder, or rectum. CONCLUSIONS: External beam and vaginal brachytherapy remain integral aspects of adjuvant therapy for endometrial cancer. PMID- 24766679 TI - Postoperative radiation therapy for endometrial cancer: Where do we go from here? PMID- 24766680 TI - Long-term cosmesis and toxicity following 3-dimensional conformal radiation therapy in the delivery of accelerated partial breast irradiation. AB - PURPOSE: To evaluate cosmesis and toxicity in early-stage breast cancer patients treated with adjuvant 3D-CRT who received accelerated partial breast irradiation (APBI). METHODS AND MATERIALS: From November 2003 to June 2006, 60 breasts on 59 patients were treated with 3-dimensional conformal radiation therapy (3D-CRT) APBI. Patients with stage 0, I, or II breast cancer were eligible if a <3-cm tumor was resected with negative surgical margins, and axillary evaluation documented 0-3 positive nodes. The mean age was 58.7 years (range, 31-88 years). Target volume and critical structure definitions, as well as dose delivery guidelines, were consistent across both institutions. Treatment was twice daily for 5 consecutive days with 3.85 Gy per fraction to 38.5 Gy. Clinical follow-up was conducted at regular intervals that included history, physical exam, and mammography. The overall cosmesis was graded using the Harvard scale and toxicity was graded according to the Common Toxicity Criteria (v4.0), including hyperpigmentation, edema, telangiectasia, mastalgia, surgical defect, fibrosis, and fat necrosis. Dose-volume histogram and treatment parameters were collected and analyzed. RESULTS: At a mean follow-up of 44.3 months (range, 2-94 months), there were 4 cases of grade 3-4 toxicity (7%): 1 patient with mastalgia; 1 patient with mastalgia and fat necrosis; 1 patient with telangiectasia; and 1 patient with fibrosis. There was no statistical correlate between dosimetric parameters and cosmetic outcome. Overall cosmetic outcome was good or excellent in 58 breasts (95%) and "fair to poor" in 3 (5%). There were no local-regional failures; 3 patients failed distantly (5%). CONCLUSIONS: Accelerated partial breast irradiation using 3D-CRT is safe and the risk of serious chronic side effect is low and acceptable. PMID- 24766681 TI - Optimization of surgical clip placement for breast-conservation therapy. AB - PURPOSE: The purpose of this study was to determine if seroma cavity visualization could be further improved with placement of gold fiducial markers in each anatomic wall of the seroma cavity compared with placement of surgical titanium clips at the surgeon's discretion. METHODS AND MATERIALS: We identified patients with breast cancer who received breast-conservation surgery. Patients were grouped into 3 categories: patients without clips, patients with titanium clips placed at the discretion of the treating surgeon, and patients with gold fiducial markers directly sutured to each wall of the seroma cavity. Cavity visualization was determined using the cavity visualization score criteria. RESULTS: A total of 262 patients met the criteria for the study; 119 patients did not have surgical clips placed during breast-conservation surgery, 109 patients received surgical titanium clip placement at the surgeon's discretion, and 34 patients received directed placement of gold fiducial markers in each anatomic wall of the seroma cavity. There was improvement in the visualization of the seroma cavity in patients who received directed gold fiducial marker placement in each wall of the seroma cavity compared with titanium clip placement at the surgeon's discretion (P < .05). An association was not identified between the quantity of titanium clips used, the amount of seroma walls with titanium clips present, or the time interval between surgery and radiation therapy planning with cavity visualization when surgical titanium clips were placed at the surgeon's discretion. CONCLUSIONS: The placement of a gold fiducial marker in each of the seroma cavity walls improved visualization of the seroma cavity compared with the placement of titanium clips at the surgeon's discretion. This technique may be utilized in order to assist in planning a seroma boost following whole breast irradiation or in accelerated partial breast irradiation. PMID- 24766682 TI - Simplified strategies to determine the mean respiratory position for liver radiation therapy planning. AB - PURPOSE: Establishing the time-weighted mean respiratory position in the liver is challenging due to poor tumor contrast on 4-dimensional (4D) imaging. The purpose of this study is to validate simplified strategies in determining the mean position of liver tumors for radiation therapy planning, and quantify the potential for planning target volume (PTV) reduction. METHODS AND MATERIALS: Full, 10-phase 4D computed tomography (CT) data sets from 10 liver radiation therapy patients were analyzed to compare 2 techniques. First, a mid-ventilation CT was chosen from the initial reconstruction of the 4DCT. This was based on the minimum displacement of the diaphragm at each phase relative to its mean respiratory position, calculated using rigid registration over all 4DCT phases. Second, the exhale 4DCT was deformed to the inhale 4DCT using biomechanical-based deformable registration. The diaphragm's mean cranio-caudal position in the respiratory cycle (normalized as a percentage relative to exhale) was applied to the exhale-to-inhale deformation map assuming a linear trajectory to reconstruct a mid-position CT. These strategies were compared with the time-weighted mean respiratory position, calculated with deformable registration over all 10 4DCT phases. PTVs incorporating respiratory motion were then compared for 2 planning strategies: exhale 4DCT using the internal target volume (ITV), or mid-position CT using dose-probability margins. RESULTS: Compared with the mean respiratory tumor position, the mid-ventilation CT and mid-position CT had mean (maximum) tumor vector errors of 1.0 +/- 0.5 (2.1) mm and 0.6 +/- 0.3 (1.4) mm, respectively, within the image resolution. Compared with ITV-based PTV, dose probability PTV reduced the irradiated volume by 34% +/- 7% on average, up to 43%. CONCLUSIONS: Simplified strategies to select a mid-ventilation CT or reconstruct a mid-position CT for the liver were validated with respect to the mean respiratory position. These data sets require significantly smaller PTVs, potentially allowing for dose-escalated liver stereotactic body radiation therapy to improve local control. PMID- 24766683 TI - Surgical placement of biologic mesh spacers to displace bowel away from unresectable liver tumors followed by delivery of dose-intense radiation therapy. AB - PURPOSE: Delivery of radiation therapy (RT) to unresectable liver tumors is sometimes limited by proximity of radiosensitive bowel. We sought to determine if biologic mesh spacers (BMS) could be used in this situation. METHODS AND MATERIALS: BMS composed of acellular human dermis were placed via a laparoscopic or open approach to displace bowel away from unresectable liver tumors in patients previously unable to receive radiation therapy (RT) due to risk of bowel toxicity. RESULTS: In 1 year, 14 patients were treated. Median age was 64 years. Diagnoses included intrahepatic cholangiocarcinoma (n = 6), hepatocellular carcinoma (n = 3), and metastases (n = 5). A solitary lesion was present in 8 patients, while 4 patients had 2 lesions and 2 patients had 3 lesions. Median largest tumor size was 6.3 cm (range, 1.6-17.5 cm). Limited extrahepatic disease was present in 5 patients. The surgical approach was laparoscopic in 10 patients and open in 4 patients. Median length of stay was 2.5 days (1-8), and 3 patients developed low-grade complications. Folded, extra thick (2.3-3.3 mm) BMS, with a median area of 384 cm(2) (256-640 cm(2)), were used to displace stomach (n = 9), duodenum (7), colon (6), and small bowel (2). The mean displacement of these organs on postprocedure imaging was 23 mm, 23 mm, 24 mm, and 20 mm, respectively. Two patients did not receive RT due to extrahepatic disease progression. The remaining patients had 3-dimensional conformal proton RT (n = 5), stereotactic body RT (4), or intensity modulated RT (3). Median dose delivered was 54 Gy (40 58.5) in 5-15 fractions with only 1 patient with grade 3-4 toxicity. At short term follow-up of at least 10 months, local disease control was obtained in 11 of 12 patients. CONCLUSIONS: Initial dual institution experience with this novel strategy demonstrates feasibility, allowing previously untreatable liver tumor patients to receive high-dose RT. PMID- 24766684 TI - Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: Impact on normal tissue dose. AB - PURPOSE: Active breathing control (ABC) is emerging as a tool to reduce heart and lung dose for lymphoma patients receiving mediastinal radiation therapy (RT). The objective of this study was to report our early institutional experience with this technique, with emphasis on quantifying the changes in normal tissue dose and exploring factors that could be used to select patients with the greatest benefit. METHODS AND MATERIALS: Patients receiving mediastinal involved-field RT (IFRT) for lymphoma were eligible. The ABC was performed using a moderate deep inspiration breath-hold (mDIBH) technique. All patients were replanned with free breathing (FB) computed tomographic data sets and comparisons of lung, cardiac, and female breast tissue doses were made between mDIBH and FB plans. Logistic regression models were used to identify factors associated with improvement in mean lung and heart dose with mDIBH. RESULTS: Forty-seven patients were analyzed; the majority (87.2%) had Hodgkin lymphoma. Median prescribed dose was 30 Gy (range, 20-36 Gy), with 78.7% of cases being treated with parallel-opposed beams. The use of mDIBH significantly improved average mean lung dose (FB: 11.0 Gy; mDIBH: 9.5 Gy; P < .0001), lung V20 (28% vs 22%; P < .0001), and mean heart dose (14.3 Gy vs 11.8 Gy; P = .003), but increased the mean breast dose (FB: 3.0 Gy; mDIBH 3.6 Gy; P = .0005). The magnitude of diaphragmatic excursion on the inhale scan was significantly associated with dosimetric improvement in both heart and lung dose with mDIBH. CONCLUSIONS: Mediastinal IFRT for lymphoma delivered with mDIBH can significantly reduce lung and heart dose compared with FB, although not for all patients, and may increase breast dose in females. Its implementation is achievable in both adult and pediatric populations. Further work is necessary to better predict which patients benefit from this technique. PMID- 24766685 TI - Evaluating the health-related quality of life of esophageal cancer patients. AB - The current norm of esophageal treatment includes any combination of surgery, chemotherapy and radiation therapy. The effectiveness of medical intervention has been predominantly assessed by morbidity, mortality and disease-free survival in the past. As patients' life expectancies lengthened from advances in treatment modalities, recent movements have shifted to acknowledge patients' health-related quality of life as an important outcome measure. The general trend for the use of multimodal treatments of esophageal cancer indicates an initial degradation of many aspects of HRQoL; however, without postoperative recovery delay related to neoadjuvant treatment. Several recent studies aimed to define aspects of HRQoL as prognostic indicators of esophageal cancer patients that may influence survival. It is imperative for practicing physicians to discuss these concepts with patients as they may cope with treatment complications more favorably if they are informed. PMID- 24766686 TI - Can electronic web-based technology improve quality of life data collection? Analysis of Radiation Therapy Oncology Group 0828. AB - PURPOSE: Missing data are a significant problem in clinical trials, particularly for quality of life (QOL), which cannot be obtained retrospectively. The purpose of this study was to evaluate the feasibility of an electronic web-based strategy for QOL data collection in a cooperative group radiation oncology trial setting. METHODS AND MATERIALS: Radiation Therapy Oncology Group (RTOG) 0828 was a prospective National Cancer Institute cooperative group companion study of RTOG 0415, a randomized study of conventional versus hypofractionated radiation. Forty nine English-speaking patients with favorable risk prostate cancer who enrolled on RTOG-0415 consented to using web-based technology for completing QOL. In RTOG 0415, using paper forms, the 6-month QOL compliance rate was 52%. The purpose of RTOG-0828 was to test the feasibility of a web-based strategy with the goal of increasing the 6-month QOL completion rate by 25% (from 52% to 77%) for a relative improvement of ~50%. The web-based tool used in this study was VisionTree Optimal Care (VTOC; VisionTree Software, Inc, San Diego, CA), a Health Insurance-Portability-Accountability-Act secure, online technology that allows real-time tracking and e-mail reminders. The primary endpoint was the 6-month compliance rate for the validated QOL instrument, Expanded Prostate Index Composite. RESULTS: The QOL completion rate at baseline was 98%. Compared with the prior 52% QOL completion rate at 6 months using paper forms, the QOL web based completion rate at 6 months was 90% (2-sided P value < .001). At 12 months, the EPIC completion rate was 82% (compared with 36% using paper forms). CONCLUSIONS: This RTOG study suggests that a web-based strategy to collect QOL appears to be feasible in the cooperative group radiation oncology trial setting and is associated with an increase in the 6-month QOL compliance rate compared with the prior method of using paper forms. The RTOG plans to further test this strategy in a head-and-neck cancer trial across all participating RTOG sites. PMID- 24766687 TI - The effect of arm position on the dosimetry of thoracic stereotactic ablative radiation therapy using volumetric modulated arc therapy. AB - PURPOSE: Patient comfort and positioning stability may be improved in the arms down (AD) compared with the typical arms up (AU) position in thoracic stereotactic ablative radiation therapy (SABR). We compared plan quality for AD vs AU when using volumetric modulated arc therapy (VMAT), and evaluated the sensitivity of AD plans to arm positioning variability. METHODS AND MATERIALS: We took plans of 14 patients with 17 lung tumors treated with thoracic SABR using VMAT in the AD position and simulated the same treatments in the AU position by re-optimizing after digitally removing the ipsilateral arm. To evaluate the sensitivity of AD plans to arm positioning variability, all plans were recalculated without re-optimization after assigning water density to the ipsilateral arm (AD-W) and then digitally shifting the arm 2.5 cm anterolaterally (AD-WS). RESULTS: Between AD and AU plans, statistically significant but clinically insignificant (all original planning constraints met) differences were found for the following parameters: mean planning target volume maximum dose, difference of 2.3% of prescription dose (P = .049); mean intermediate dose conformity index, difference of 0.27 (P = .012); median percent lung volume receiving a minimum of 10, 20, and 30 Gy (V10, V20, and V30), differences of 0.5%, 0.2%, and 0.1%, respectively (P = .040, .007, and .001); and median spinal cord maximum dose, difference of 33.5 cGy (P = .017). Similarly, between AD-W and AD-WS plans, statistically significant but clinically insignificant differences were found for median lung V20 and V30, difference of 0.0% for both (P = .034 and .016, by matched pair analysis). CONCLUSIONS: Our exploratory planning study suggests that when using VMAT for lung tumor SABR, AD and AU positioning achieve clinically equivalent plan quality, and AD plans are insensitive to relatively large variability in arm position. PMID- 24766688 TI - Lumbosacral spine and marrow cavity modeling of acute hematologic toxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal. AB - PURPOSE: To identify various dosimetric parameters of bone marrow cavity that correlate with acute hematologic toxicity (HT) in patients with anal squamous cell carcinoma treated with definitive chemoradiation therapy (CRT). METHODS AND MATERIALS: We analyzed 32 patients receiving CRT. The whole pelvic bone marrow (PBM) and the lumbosacral spine (LSS) subregion were contoured for each patient. Marrow cavities were contoured using the Hounsfield units (HUs) of 100, 150, 200, and 250 as maximum density threshold levels. The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. The endpoint was grade >=3 HT (HT3+). Normal-tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Maximal likelihood estimate was used to compare the parameter set. Logistic regression was used to test associations between HT and both dosimetric and clinical parameters. RESULTS: Ten patients (31%) experienced HT3+. While dose to both LSS and PBM significantly predicted for HT3+, LSS was superior to PBM by logistic regression and LKB modeling. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.21, n = 1, and TD50 = 32 Gy for LSS. The NTCP fits were better with the whole bone than with marrow cavity using any HU threshold. Mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3+, respectively. Mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3+. CONCLUSIONS: For predicting the risk of HT3+, whole-bone contours were superior to marrow cavity and LSS was superior to PBM by LKB modeling. The results confirm PBM and LSS as parallel organs when predicting hematologic toxicity. Recommended dose constraints to the LSS are V10 <=80%. An LSS mean dose of 23.5 Gy is associated with a 10% risk of HT. PMID- 24766689 TI - Clinical experience with 3-dimensional surface matching-based deep inspiration breath hold for left-sided breast cancer radiation therapy. AB - PURPOSE: Three-dimensional (3D) surface matching is a novel method to administer deep inspiration breath-hold (DIBH) radiation therapy for left-sided breast cancer to reduce cardiac exposure. We analyzed port (x-ray) films to assess patient setup accuracy and treatment times to assess the practical workflow of this system. METHODS AND MATERIALS: The data from 50 left-sided breast cancer patients treated with DIBH were studied. AlignRT (London, UK) was used. The distance between the field edge and the anterior pericardial shadow as seen on the routine port films (dPORT), and the corresponding distance seen on the digitally reconstructed radiographs (DRR) from the planning (dDRR) were compared as a quantitative measure of setup accuracy. Variations of dPORT - dDRR over the treatment course were assessed. In a subset of 21 patients treated with tangential beams alone, the daily treatment durations were analyzed to assess the practical workflow of this system. RESULTS: Considering all 50 patients, the mean absolute systematic uncertainty between dPORT and dDRR was 0.20 cm (range, 0 to 1.22 cm), the mean systematic uncertainty was -0.07 cm (range, -1.22 to 0.67 cm), and their mean random uncertainty was 0.19 cm (range, 0 to 0.84 cm). There was no significant change in dPORT - dDRR during the course of treatment. The mean patient treatment duration for the 21 patients studied was 11 minutes 48 seconds. On intrapatient assessments, 15/21 had nonsignificant trends toward reduced treatment durations during their course of therapy. On interpatient comparisons, the mean treatment times declined as we gained more experience with this technique. CONCLUSIONS: The DIBH patient setup appears to provide a fairly reproducible degree of cardiac sparing with random uncertainties of ~ 0.2 cm. The treatment durations are clinically acceptable and appear not to change significantly over time on an intrapatient basis, and to improve over time on an interpatient basis. PMID- 24766690 TI - Impact of radiation treatment parameters and adjuvant systemic therapy on cosmetic outcomes after accelerated partial breast irradiation using 3 dimensional conformal radiation therapy technique. AB - PURPOSE: There are concerns regarding cosmetic outcomes of 3-dimensional conformal accelerated partial breast radiation therapy (3DCRT APBI). Associations between cosmetic outcomes and treatment parameters or receipt of adjuvant systemic therapy were sought to guide 3DCRT APBI. METHODS AND MATERIALS: An analysis of cosmetic outcomes among patients treated with 3DCRT APBI at Moffitt Cancer Center was performed. Overall cosmesis was evaluated using modified Harvard criteria and toxicity outcomes were graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients were treated to 38.5 Gy in 3.85 Gy twice daily fractions per dose-volume objectives specified in the National Surgical Adjuvant Breast and Bowel B 39/Radiation Therapy Oncology Group 0413 (NSABP B-39/RTOG 0413) trial. RESULTS: At least 1 evaluation was available for 97 treated breasts (94 women) with median follow-up of 17.2 months (range, 1-60 months). Most breasts (90.7%) had grade 1 to 2 (excellent to good) overall cosmesis. Nine breasts (9.3%) had grade 3 to 4 (fair to poor) overall cosmesis, secondary to >25% asymmetry in 5 patients, grade 3 fibrosis in 3 patients, and fat necrosis in 1 patient. Increasing percentage of ipsilateral breast volume receiving more than 50% of the prescription dose (V50%) correlated with less than excellent cosmesis (P < .001), with a threshold V50% of 40%. Telangiectasia formation (6%) correlated with increased evaluation planning target volume (P = .006) and V50% (P = .017). Grade 2+ fibrosis (18%) and grade 1+ induration (83%) were also correlated with increasing V50% (P = .006 and .002, respectively). Smaller ipsilateral breast volume correlated with worsening cosmesis (P = .048) and induration (P = .028). Two of 4 patients receiving chemotherapy developed grade 3 fibrosis (P = .004) and fair/poor cosmesis (P = .04). CONCLUSIONS: The current analysis implies that acceptable cosmetic results are achievable with 3DCRT APBI technique by adhering to optimal radiation therapy dose-volume constraints, particularly ipsilateral breast V50%. PMID- 24766691 TI - Impact of sociodemographic factors on the radiotherapeutic management of lung cancer: Results of a Quality Research in Radiation Oncology survey. AB - PURPOSE: The objective of this study is to describe the impact of sociodemographic (SOC) factors on the management of lung cancer patients treated at radiation therapy facilities participating in the Quality Research in Radiation Oncology survey. METHODS AND MATERIALS: A 2-stage stratified random sample of lung cancer patients treated in 2006 to 2007 at 45 facilities yielded 340 stage I-III non-small cell lung cancer (NSCLC) and 144 limited-stage small cell lung cancer (LS-SCLC) cases. Five SOC variables based on data from the 2000 US Census were analyzed for association with the following clinical factors: patients living in urban versus rural settings (U/R); median household income (AHI); % below poverty level (PPV); % unemployed (PUE); and % with college education (PCE). RESULTS: The 340 NSCLC patients were stage I, 16%; stage II, 11%; stage III, 62%; stage unknown, 11%. Histologic subtypes were adenocarcinoma, 31.8%; squamous cell carcinoma, 35.3%; large cell carcinoma, 3.2%; and NSCLC NOS, 27.7%. The median age was 66 years. Median Karnofsky performance status (KPS) was 80. The 144 LS-SCLC had a median age of 63; 73 were male (50.7%). Median KPS was 80. Stereotactic body radiation therapy (SBRT) and modern imaging utilization was associated with treatment at facilities located in higher SOC regions. SBRT was employed in 46.8% stage I NSCLC patients treated in centers where %PUE was below median versus 14.8% in centers where %PUE was above median (P = .02). Four dimensional computed tomography was utilized in 14.2% of patients treated in centers located in regions with %PPV below median versus 3.7% in centers located in regions with %PPV above median (P < .01). SCLC patients were more likely to receive all of their planned RT when treated at centers located in regions with lower PPV (95.0% vs 79.1%; P = .04). CONCLUSIONS: SOC factors may impact use of modern treatment planning and delivery and multidisciplinary management of NSCLC and SCLC. These results may suggest an impact of these SOC factors on access to health care. PMID- 24766692 TI - Small animal behavioral triage: a guide for practitioners. AB - Behavioral concerns are the principal cause of a weakened human-animal bond and pet relinquishment. Triaging behavioral concerns and providing early intervention may be the difference between a patient remaining in its current home or relinquishment. Prevention and intervention behavior services using a team approach may also improve pet retention through client education and appropriate assistance. Identifying and integrating qualified animal behavior professionals to assist with the hospital's behavior team ensures appropriate support is provided to the client and patient. PMID- 24766693 TI - Common sense behavior modification: a guide for practitioners. AB - Behavior problems are often given as a reason for pet relinquishment to shelters. When presented with any behavior problem, veterinarians should perform a thorough physical examination (including neurologic and orthopedic examination) and a minimum database, including a complete blood cell count, chemistry panel, and total T4 and free T4 by equilibrium dialysis if values are low to rule out any medical contributions. Veterinarians should be a source of information regarding management, safety, and basic behavior modification for common behavior problems. Additionally, various control devices offer pet owners the ability to better manage their pets in difficult situations. PMID- 24766694 TI - Canine and feline enrichment in the home and kennel: a guide for practitioners. AB - As general veterinary practitioners, we have a duty of care that applies not only to the physical health needs of our patients but also to their mental well-being. Advising clients about how to enrich their home and kennel environments is an important part of fulfilling that duty of care and will also enrich the relationship between the veterinary practitioner and client. This article discusses how to optimize welfare for dogs and cats in the home and kenneled environments through appropriate environmental enrichment and understanding of species-typical behavioral requirements. PMID- 24766695 TI - The pet-friendly veterinary practice: a guide for practitioners. AB - Low-stress handling is important for the safety of the veterinary staff and for the welfare of the patient. The commitment to ensuring the emotional well-being of the patient should be equal to that shown toward the physical well-being of the animals under a veterinarian's care. Before handling animals it is essential to assess the environment and the patient's response to it. Taking the time to create a behavior handling plan makes future visits easier and bonds clients to the practice. Understanding how and when to use handling tools is key to making patient visits safer, more humane, and more efficient. PMID- 24766696 TI - Genetics and behavior: a guide for practitioners. AB - Phenotyping behavior is difficult, partly because behavior is almost always influenced by environment. Using objective terms/criteria to evaluate behaviors is best; the more objective the assessment, the more likely underlying genetic patterns will be identified. Behavioral pathologies, and highly desirable behavioral characteristics/traits, are likely complex, meaning that multiple genes are probably involved, and therefore simple genetic tests are less possible. Breeds can be improved using traditional quantitative genetic methods; unfortunately, this also creates the possibility of inadvertently selecting for covarying undesirable behaviors. Patterns of behaviors within families and breed lines are still the best guidelines for genetic counseling in dogs. PMID- 24766697 TI - Recognizing behavioral signs of pain and disease: a guide for practitioners. AB - Disease is always associated with changes in behavior such as disappearance of normal behaviors or appearance of new behaviors. These changes are often considered as abnormal behavior, indicating illness and/or pain. The aim of this article is to illustrate some examples of cases that might present as behavioral disorders but are in fact medical conditions. Subtle behavioral signs of disease are also discussed. PMID- 24766698 TI - Stress--its effects on health and behavior: a guide for practitioners. AB - Stressors impact on all areas of a pet's life, potentially to the detriment of their well-being. In addition, should this lead to behavior change, it is likely to cause strain in the owner-pet relationship with an increased risk of relinquishment. Understanding why events may be perceived as stressful to a given individual is essential in remedying their effect. Clinicians need to be skilled in recognizing and categorizing potential stressors as well as auditing the background stress in the animal's environment as only once this has been accomplished can specific measures be implemented to reduce the effects of the stress load. PMID- 24766699 TI - Abnormal repetitive behaviors in dogs and cats: a guide for practitioners. AB - Abnormal repetitive behaviors (ARBs) represent a diverse group of behaviors whose underlying mechanism is poorly understood. Their neurobiology likely involves several different neurotransmitter systems. These behaviors have been referred to as compulsive disorders, obsessive compulsive disorders and stereotypies. Underlying medical conditions and pain can often cause changes in behavior that are mistaken for ARBs. A complete medical work-up is always indicated prior to reaching a presumptive diagnosis. The frequency of ARBs can be reduced but not always eliminated with the use of selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) in conjunction with behavior modification and environmental enrichment. PMID- 24766700 TI - Intercat aggression: restoring harmony in the home: a guide for practitioners. AB - Intercat aggression is a common problem within multicat households. Diagnosis and treatment requires an understanding of the social structure of free-living cats and of how those interactions are impacted by confinement and household management practices. There are multiple causes of aggression between cats within a home, and treatment plans should be customized to account for the diagnosis and behavior pattern identified. Some cases of intercat aggression can be treated successfully without requiring full separation of the involved cats. In cases where separation is required, treatment includes steps for successful reintroduction and reintegration. Several situational and maintenance medication options can be used to improve the response to treatment. PMID- 24766701 TI - Feline aggression toward family members: a guide for practitioners. AB - Feline aggression toward people is a common and potentially dangerous problem. Proper diagnosis of the underlying cause of the aggression is key in effective treatment. A complete history, including information on the people in the home, other pets, and specific incidents, is necessary to make this diagnosis. A comprehensive treatment plan typically includes management, enhancement of the cat's living environment, techniques for replacing the aggressive behavior with more appropriate behaviors, and, potentially, medication. The treatment plan must reflect the abilities and commitment of the owner. PMID- 24766702 TI - Canine aggression toward people: a guide for practitioners. AB - This article reviews the various causes of human-directed aggression in dogs and provides a step-by-step plan guiding the general practitioner through history taking, behavior observations, diagnosis, consultation, treatment, and follow-up care. Charts summarizing how to obtain behavioral information, the client's management options, treatment recommendations, diagnosis and treatment of human directed aggression, and the clinician's role in preventing human-directed aggression are included. A graphic illustration of canine body language is also provided. PMID- 24766703 TI - Appendix: Drug dosage chart. AB - For many medications, the pharmacokinetics and pharmacodynamics in pets have not been established and even where studies have been done, there is widespread species and individual variation. Practitioners should start with the lower end of the dose range and titrate up to maximum doses where there is insufficient therapeutic effect and no adverse effects or contraindications. Complete blood count, serum chemistry profile, and urinalysis should be performed before initiating the use of any medication, especially with off-label medications. Pharmacologic intervention for the treatment of behavior problems should be considered just one aspect of a comprehensive behavioral management and treatment protocol. PMID- 24766704 TI - Behavior: a guide for practitioners. PMID- 24766705 TI - Monitoring persistence of the entomopathogenic fungus Metarhizium anisopliae under simulated field conditions with the aim of controlling adult Aedes aegypti (Diptera: Culicidae). AB - BACKGROUND: Entomopathogenic fungi are potential candidates for use in integrated vector management, with recent emphasis aimed at developing adult mosquito control methods. Here we investigated the persistence of the fungus Metarhizium anisopliae when tested against female A. aegypti under field conditions. METHODS: Black cotton cloths impregnated with M. anisopliae conidia, formulated in vegetable oil + isoparaffin, were maintained on a covered veranda for up to 30 days. At specific times, pieces of the cloths were removed, placed in Tween 80 and the resuspended conidia were sprayed directly onto mosquitoes. The persistence of conidia impregnated on black cloths using three different carriers was evaluated in test rooms. Fifty mosquitoes were released into each room and after a 5 day period, the surviving insects were captured. Another 50 insects were then released into each room. The capacity of the fungus at reducing mosquito survival was evaluated over a total of 35 days. RESULTS: Conidia extracted from cloths maintained on the veranda for 2 to 18 days remained virulent, with 28 to 60% mosquito survival observed. Mosquito survival following exposure to fungus impregnated cloths showed that fungus + Tween caused similar reductions to that of fungus + vegetable oil. Mosquitoes exposed to the formulation fungus + vegetable oil had survival rates of 36% over the first 5 days of the experiment. Following the release of the second cohort of mosquitoes (6-11days), survival increased to 50%. The survival of the 12-17 day cohort (78%) was statistically equal to that of the controls (84%). Formulation of the fungus in vegetable oil + isoparaffin increased the persistence of the fungus, with the 18-23 day cohort (64% survival) still showing statistical differences to that of the controls (87% survival). CONCLUSIONS: The potential of entomopathogenic fungi for the control of adult A. aegypti was confirmed under field conditions. Vegetable oil + isoparaffin formulations of M. anisopliae significantly increased the effectiveness of the fungus, thus reducing the need for frequent changes of black cloths in residences. Our future aim is to obtain effective control of mosquito populations, with cloths only needing to being replaced once a month. PMID- 24766706 TI - AGE-breaker ALT-711 plus insulin could restore erectile function in streptozocin induced type 1 diabetic rats. AB - INTRODUCTION: The interaction between advanced glycation end-products (AGEs) and its receptors for AGEs (RAGEs) elicits oxidative stress and mediates the development of erectile dysfunction (ED). ALT-711, an AGE cross-link breaker, has the therapeutic potential for ED but has been less intensively investigated. AIM: The aim of this study was to investigate the effects of an AGEs breaker 3 phenacyl-4,5-dimethylthiazolium chloride (ALT-711) plus insulin on erectile function in streptozocin (STZ)-induced type 1 diabetic rats. METHODS: Fifty 8 week-old Sprague-Dawley rats were randomly distributed into five groups: normal control (C), diabetic (D), insulin-treated diabetic (D + I), ALT-711-treated diabetic (D + ALT-711) and insulin plus ALT-711-treated diabetic (D + I + ALT 711) rats. Diabetes was induced by a single intraperitoneal injection of STZ. Eight weeks after induction of diabetes, ALT-711 was administered by intraperitoneal injection. Two to six units of intermediate-acting insulin were utilized to achieve normal levels of glycemic control. After treatment for 6 weeks, erectile function was determined via measurement of intracavernous pressures (ICPs) following electrostimulation of the cavernous nerve. The deposition of AGEs, expression of RAGEs, superoxide dismutase activity, and lipid peroxidation were measured. We also evaluated penile histological changes such as smooth muscle contents, endothelial cells contents, and apoptotic activity. MAIN OUTCOME MEASURES: The main outcome measures were the ratio of ICP/mean arterial pressure (MAP), penile endothelial cells, smooth muscle cells, neuronal nitric oxide synthase, AGE and RAGE expression, malondialdehyde concentration, SOD activity, and apoptosis index. RESULTS: Diabetic rats demonstrated significantly reduced ICP/MAP ratio, penile endothelial cells, smooth muscles cells, increased AGEs and RAGE expression, and increased apoptosis. Insulin and ALT-711 monotherapy partially restored erectile function and histological changes. However, the combination therapy group showed erectile parameters and components similar to those in C. ALT-711-treated group demonstrated less deposition of AGEs and lower expression of RAGE than those in insulin-treated group. CONCLUSION: These results suggest that although insulin can effectively control glycemic levels, it does not completely alter the pathological changes in erectile tissues. Better efficacy could be expected with tight glycemic control plus ALT 711, an AGEs cross-link breaker. The combination therapy might have the potential to eliminate metabolic memory by down-regulating the AGEs-RAGE oxidative stress axis. PMID- 24766707 TI - Mosquitoes rely on their gut microbiota for development. AB - Field studies indicate adult mosquitoes (Culicidae) host low diversity communities of bacteria that vary greatly among individuals and species. In contrast, it remains unclear how adult mosquitoes acquire their microbiome, what influences community structure, and whether the microbiome is important for survival. Here, we used pyrosequencing of 16S rRNA to characterize the bacterial communities of three mosquito species reared under identical conditions. Two of these species, Aedes aegypti and Anopheles gambiae, are anautogenous and must blood-feed to produce eggs, while one, Georgecraigius atropalpus, is autogenous and produces eggs without blood feeding. Each mosquito species contained a low diversity community comprised primarily of aerobic bacteria acquired from the aquatic habitat in which larvae developed. Our results suggested that the communities in Ae. aegypti and An. gambiae larvae share more similarities with one another than with G. atropalpus. Studies with Ae. aegypti also strongly suggested that adults transstadially acquired several members of the larval bacterial community, but only four genera of bacteria present in blood fed females were detected on eggs. Functional assays showed that axenic larvae of each species failed to develop beyond the first instar. Experiments with Ae. aegypti indicated several members of the microbial community and Escherichia coli successfully colonized axenic larvae and rescued development. Overall, our results provide new insights about the acquisition and structure of bacterial communities in mosquitoes. They also indicate that three mosquito species spanning the breadth of the Culicidae depend on their gut microbiome for development. PMID- 24766708 TI - Pattern changes of EEG oscillations and BOLD signals associated with temporal lobe epilepsy as revealed by a working memory task. AB - BACKGROUND: It is known that the abnormal neural activity in epilepsy may be associated to the reorganization of neural circuits and brain plasticity in various ways. On that basis, we hypothesized that changes in neuronal circuitry due to epilepsy could lead to measurable variations in patterns of both EEG and BOLD signals in patients performing some cognitive task as compared to what would be obtained in normal condition. Thus, the aim of this study was to compare the cerebral areas involved in EEG oscillations versus fMRI signal patterns during a working memory (WM) task in normal controls and patients with refractory mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS). The study included six patients with left MTLE-HS (left-HS group) and seven normal controls (control group) matched to the patients by age and educational level, both groups undergoing a blocked design paradigm based on Sternberg test during separated EEG and fMRI sessions. This test consisted of encoding and maintenance of a variable number of consonant letters on WM. RESULTS: EEG analysis for the encoding period revealed the presence of theta and alpha oscillations in the frontal and parietal areas, respectively. Likewise, fMRI showed the co-occurrence of positive and negative BOLD signals in both brain regions. As for the maintenance period, whereas EEG analysis revealed disappearance of theta oscillation, fMRI showed decrease of positive BOLD in frontal area and increase of negative BOLD in the posterior part of the brain. CONCLUSIONS: Generally speaking, these patterns of electrophysiological and hemodynamic signals were observed for both control and left-HS groups. However, the data also revealed remarkable differences between these groups that are consistent with the hypothesis of reorganization of brain circuitry associated with epilepsy. PMID- 24766709 TI - E. coli O157 on Scottish cattle farms: evidence of local spread and persistence using repeat cross-sectional data. AB - BACKGROUND: Escherichia coli (E. coli) O157 is a virulent zoonotic strain of enterohaemorrhagic E. coli. In Scotland (1998-2008) the annual reported rate of human infection is 4.4 per 100,000 population which is consistently higher than other regions of the UK and abroad. Cattle are the primary reservoir. Thus understanding infection dynamics in cattle is paramount to reducing human infections.A large database was created for farms sampled in two cross-sectional surveys carried out in Scotland (1998-2004). A statistical model was generated to identify risk factors for the presence of E. coli O157 on farms. Specific hypotheses were tested regarding the presence of E. coli O157 on local farms and the farms previous status. Pulsed-field gel electrophoresis (PFGE) profiles were further examined to ascertain whether local spread or persistence of strains could be inferred. RESULTS: The presence of an E. coli O157 positive local farm (average distance: 5.96 km) in the Highlands, North East and South West, farm size and the number of cattle moved onto the farm 8 weeks prior to sampling were significant risk factors for the presence of E. coli O157 on farms. Previous status of a farm was not a significant predictor of current status (p = 0.398). Farms within the same sampling cluster were significantly more likely to be the same PFGE type (p < 0.001), implicating spread of strains between local farms. Isolates with identical PFGE types were observed to persist across the two surveys, including 3 that were identified on the same farm, suggesting an environmental reservoir. PFGE types that were persistent were more likely to have been observed in human clinical infections in Scotland (p < 0.001) from the same time frame. CONCLUSIONS: The results of this study demonstrate the spread of E. coli O157 between local farms and highlight the potential link between persistent cattle strains and human clinical infections in Scotland. This novel insight into the epidemiology of Scottish E. coli O157 paves the way for future research into the mechanisms of transmission which should help with the design of control measures to reduce E. coli O157 from livestock-related sources. PMID- 24766710 TI - Perception of built environmental factors and physical activity among adolescents in Nigeria. AB - BACKGROUND: Understanding environmental factors related to adolescents' physical activity can inform intervention for obesity control and prevention, but virtually no study has been conducted in the African region, where adolescents' physical inactivity and chronic diseases rates are rising. This study assessed associations between perceived built environmental variables and adolescents' physical activity (active transportation to school and leisure-time moderate-to- vigorous physical activity), and the moderating effects of neighborhood-level income on association between environmental variables and physical activity among Nigerian boys and girls. METHODS: Participants were 1006 adolescents (12-19 years, 50.4% girls) randomly selected from 11 secondary schools in Maiduguri city, Nigeria. Physical activity and perceptions of environmental characteristics were assessed by validated self-report questionnaires. Separate gender-based, hierarchical multiple moderated linear regression analyses were used to examine the direct associations between the environmental perceptions and physical activity variables (active transportation and leisure-time MVPA; dependent variables), as well as the moderating effects of neighborhood-level income. RESULTS: Only in boys were direct associations and interaction effect of neighborhood-level income found. Access to destinations was positively associated with active transportation to school (beta = 0.18; CI = 0.67, 2.24); while residential density (beta = 0.10; CI = 0.01, 1.74) and availability/quality of infrastructures (beta = 0.14; CI = 0.49, 2.68) were positively associated with leisure-time MVPA. Also, neighborhood-level income moderated the association between perceived safety and leisure-time MVPA, with more perceived safety related to less MVPA (beta = -0.16; CI = -0.01, -0.70) in boys living in high SES neighborhood but marginally related to more MVPA (beta = 0.11; CI = -0.04, 2.88, p = 0.06) in boys living in low SES neighborhood. CONCLUSIONS: Few environmental attributes were associated with adolescents' physical activity in Nigeria. Future studies are needed to determine the multidimensional correlates of physical activity that may be relevant for both adolescents' boys and girls in Nigeria. PMID- 24766711 TI - Intensified hemodialysis in adults, and in children and adolescents. AB - BACKGROUND: There are now almost 70 000 dialysis patients in Germany. Conventional hemodialysis does not adequately compensate for malnutrition, arterial hypertension, renal osteopathy, and diminished performance ability. Various strategies for intensified hemodialysis have been implemented in an attempt to lower the considerable morbidity and mortality of end-stage renal failure. METHOD: We selectively review the literature on intensified dialysis in adults, children, and adolescents. RESULTS: In a randomized, controlled trial (RCT), a group of patients undergoing conventional dialysis was compared to a group undergoing brief, daily dialysis. Daily dialysis significantly improved the combined endpoint of left-ventricular hypertrophy or death (hazard ratio [HR] 0.61). In contrast, another, retrospective study found daily dialysis to be associated with higher mortality (15.6 vs. 10.9 deaths, HR 1.6). A prospective case-control study found nocturnal intermittent hemodialysis to be associated with lower mortality than conventional dialysis (1.77 vs. 6.23 per 100 patient years); this result was confirmed in a further, retrospective study. An RCT on nocturnal dialysis performed every night revealed a significant regression of left-ventricular mass, yet the patients' quality of life improved only in individual domains specifically related to renal function. Small-scale studies of intensified hemodialysis in children and adolescents have found that it leads to a higher growth rate and weight gain. CONCLUSION: Intensified hemodialysis techniques improve arterial blood pressure, uremia-associated variables, and psychosocial variables. They also lower the necessary doses of antihypertensive drugs and phosphate binders. Dietary restrictions need not be as stringent. Further prospective trials are needed for a reliable assessment of the effect of intensified hemodialysis on mortality and quality of life. PMID- 24766712 TI - Sentinel node biopsy and axillary dissection in breast cancer: the evidence and its limits. AB - BACKGROUND: Increasing evidence suggests that surgical removal of the axillary lymph nodes (axillary dissection, ALD) in early breast cancer yields no advantage in terms of either overall or disease-free survival, even in women with involvement of sentinel nodes. The optimal role of sentinel node biopsy (SNB) in neo-adjuvant therapy is currently under discussion. METHOD: This review is based on a selective search in the Medline, EMBASE, Cochrane Library, and G.I.N. (Guidelines International Network) databases for relevant articles on the role of axillary dissection in node-positive breast cancer and the role of SNB in neo adjuvant chemotherapy. RESULTS: Although no single study provides adequate evidence, the available literature increasingly casts doubt on the putative therapeutic benefit of ALD as part of a multimodal treatment strategy for breast cancer. It is currently unclear what group of patients, if any, might benefit from ALD. Nor is any definitive judgment possible, from the available evidence, regarding the optimal role of SNB in neo-adjuvant therapy. The most recent evidence indicates that SNB after neo-adjuvant chemotherapy in ycN0 patients who had suspect lymph nodes before systemic treatment has a low rate of sensitivity. CONCLUSION: Current evidence indicates that the radicality of lymph node surgery in the treatment of breast cancer can be reduced, even if the node status is positive. PMID- 24766713 TI - Reporting guided by competing interests. PMID- 24766714 TI - In reply. PMID- 24766715 TI - Pointers for the examination technique. PMID- 24766716 TI - Consider further differential diagnoses. PMID- 24766717 TI - Laboratory tests are important. PMID- 24766718 TI - Do not administer free glucose solution. PMID- 24766719 TI - Economicalness of outpatient laboratory diagnostics. PMID- 24766720 TI - Additional comments regarding diagnosis and treatment. PMID- 24766721 TI - In reply. PMID- 24766722 TI - Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study. AB - BACKGROUND: Chronic bronchitis (CB) has been related to poor outcomes in Chronic Obstructive Pulmonary Disease (COPD). From a clinical standpoint, we have shown that subjects with CB in a group with moderate to severe airflow obstruction were younger, more likely to be current smokers, male, Caucasian, had worse health related quality of life, more dyspnea, and increased exacerbation history compared to those without CB. We sought to further refine our clinical characterization of chronic bronchitics in a larger cohort and analyze the CT correlates of CB in COPD subjects. We hypothesized that COPD patients with CB would have thicker airways and a greater history of smoking, acute bronchitis, allergic rhinitis, and occupational exposures compared to those without CB. METHODS: We divided 2703 GOLD 1-4 subjects in the Genetic Epidemiology of COPD (COPDGene(r)) Study into two groups based on symptoms: chronic bronchitis (CB+, n = 663, 24.5%) and no chronic bronchitis (CB-, n = 2040, 75.5%). Subjects underwent extensive clinical characterization, and quantitative CT analysis to calculate mean wall area percent (WA%) of 6 segmental airways was performed using VIDA PW2 (http://www.vidadiagnostics.com). Square roots of the wall areas of bronchi with internal perimeters 10 mm and 15 mm (Pi10 and Pi15, respectively), % emphysema, %gas trapping, were calculated using 3D Slicer (http://www.slicer.org). RESULTS: There were no differences in % emphysema (11.4 +/- 12.0 vs. 12.0 +/- 12.6%, p = 0.347) or % gas trapping (35.3 +/- 21.2 vs. 36.3 +/- 20.6%, p = 0.272) between groups. Mean segmental WA% (63.0 +/- 3.2 vs. 62.0 +/- 3.1%, p < 0.0001), Pi10 (3.72 +/- 0.15 vs. 3.69 +/- 0.14 mm, p < 0.0001), and Pi15 (5.24 +/- 0.22 vs. 5.17 +/- 0.20, p < 0.0001) were greater in the CB + group. Greater percentages of gastroesophageal reflux, allergic rhinitis, histories of asthma and acute bronchitis, exposures to dusts and occupational exposures, and current smokers were seen in the CB + group. In multivariate binomial logistic regression, male gender, Caucasian race, a lower FEV1%, allergic rhinitis, history of acute bronchitis, current smoking, and increased airway wall thickness increased odds for having CB. CONCLUSIONS: Histories of asthma, allergic rhinitis, acute bronchitis, current smoking, a lower FEV1%, Caucasian race, male gender, and increased airway wall thickness are associated with CB. These data provide clinical and radiologic correlations to the clinical phenotype of CB. PMID- 24766724 TI - Usefulness of the murine model to study the immune response against Histoplasma capsulatum infection. AB - The present paper is an overview of the primary events that are associated with the histoplasmosis immune response in the murine model. Valuable data that have been recorded in the scientific literature have contributed to an improved understanding of the clinical course of this systemic mycosis, which is caused by the dimorphic fungus Histoplasma capsulatum. Data must be analyzed carefully, given that misinterpretation could be generated because most of the available information is based on experimental host-parasite interactions that used inappropriate proceedings, i.e., the non-natural route of infection with the parasitic and virulent fungal yeast-phase, which is not the usual infective phase of the etiological agent of this mycosis. Thus, due to their versatility, complexity, and similarities with humans, several murine models have played a fundamental role in exploring the host-parasite interaction during H. capsulatum infection. PMID- 24766723 TI - Long-term reduction of T-cell intracellular antigens leads to increased beta actin expression. AB - BACKGROUND: The permanent down-regulated expression of T-cell intracellular antigen (TIA) proteins in HeLa cells improves cytoskeleton-mediated functions such as cell proliferation and tumor growth. METHODS: Making use of human and mouse cells with knocked down/out expression of T-cell intracellular antigen 1 (TIA1) and/or TIA1 related/like (TIAR/TIAL1) proteins and classical RNA (e.g. reverse transcription-quantitative polymerase chain reaction, polysomal profiling analysis using sucrose gradients, immunoblotting, immunoprecipitation, electrophoretic mobility shift assays, ultraviolet light crosslinking and poly (A+) test analysis) and cellular (e.g. immunofluorescence microscopy and quimeric mRNA transfections) biology methods, we have analyzed the regulatory role of TIA proteins in the post-transcriptional modulation of beta-actin (ACTB) mRNA. RESULTS: Our observations show that the acquisition of above cellular capacities is concomitant with increased expression levels of the actin beta subunit (ACTB) protein. Regulating TIA abundance does not modify ACTB mRNA levels, however, an increase of ACTB mRNA translation is observed. This regulatory capacity of TIA proteins is linked to the ACTB mRNA 3'-untranslated region (3'-UTR), where these proteins could function as RNA binding proteins. The expression of GFP from a chimeric reporter containing human AlphaCTauBeta 3'-UTR recapitulates the translational control found by the endogenous ACTB mRNA in the absence of TIA proteins. Additionally, murine embryonic fibroblasts (MEF) knocked out for TIA1 rise mouse ACTB protein expression compared to the controls. Once again steady state levels of mouse ACTB mRNA remained unchanged. CONCLUSIONS: Collectively, these results suggest that TIA proteins can function as long-term regulators of the ACTB mRNA metabolism in mouse and human cells. PMID- 24766725 TI - US emergency department visits for fireworks injuries, 2006-2010. AB - BACKGROUND: Most literature regarding fireworks injuries are from outside the United States, whereas US-based reports focus primarily on children and are based on datasets which cannot provide accurate estimates for subgroups of the US population. METHODS: The 2006-2010 Nationwide Emergency Department Sample was used to identify patients with fireworks injury using International Classification of Diseases, Ninth Revision, Clinical Modification external cause of injury code E923.0. International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes were examined to determine the mechanism, type, and location of injury. Sampling weights were applied during analysis to obtain US population estimates. RESULTS: There were 25,691 emergency department visits for fireworks-related injuries between 2006 and 2010. There was no consistent trend in annual injury rates during the 5-y period. The majority of visits (50.1%) were in patients aged <20 y. Most injuries were among males (76.4%) and were treated in hospitals in the Midwest and South (42.0% and 36.4%, respectively) than in the West and Northeast (13.3% and 8.3%, respectively) census regions. Fireworks-related injuries were most common in July (68.1%), followed by June (8.3%), January (6.6%), December (3.4%), and August (3.1%). The most common injuries (26.7%) were burns of the wrist, hand, and finger, followed by contusion or superficial injuries to the eye (10.3%), open wounds of the wrist, hand, and finger (6.5%), and burns of the eye (4.6%). CONCLUSIONS: Emergency department visits for fireworks injuries are concentrated around major national holidays and are more prevalent in certain parts of the country and among young males. This suggests that targeted interventions may be effective in combating this public health problem. PMID- 24766726 TI - Pediatric histiocytoses in the United States: incidence and outcomes. AB - BACKGROUND: Histiocytoses are rare disorders affecting the pediatric population. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results database was searched for pediatric cases (<20 y old) of histiocytosis diagnosed between 1973 and 2010. Demographics, clinical characteristics, and survival outcomes were analyzed using standard statistical methods. Class I disease (Langerhans cell histiocytosis) and class III (malignant histiocytosis) were included in the data set. RESULTS: A total of 828 cases were identified. Overall incidence was 0.142/100,000 persons per annum. Incidence was highest in younger children and those of Asian or Native American descent. Class III disease had a higher incidence versus class I. Adolescents tended to present with class III, whereas young children presented with class I. Disseminated disease was present in most cases of class III, whereas class I had more localized cases. Surgical excision was more likely to be performed in class I. Overall median survival was 349 mo. Patients 15-19 y old and children<1 y old had the worst outcomes. Class I had higher survival compared with class III, which had a median survival of 33 mo. Cases with hematologic spread carried the worst prognosis. Surgical excision conferred a survival advantage while radiation had no effect. Survival improved over the study period. Gender and race had no association with survival. CONCLUSIONS: Class I disease had localized cases and showed benefit from surgical intervention. Class III disease had a higher incidence and was associated with disseminated disease and lower survival. Radiation therapy did not affect survival. Overall survival increased over the previous 40 y. PMID- 24766727 TI - Combined resection with radiofrequency ablation for bilobar hepatocellular carcinoma: a single-center experience. AB - BACKGROUND: Bilobar hepatocellular carcinoma (HCC) is not rare and curative resection often cannot be achieved. However, the long-term results of nonsurgical treatments remain unsatisfactory. This study investigates the safety, efficacy, and long-term outcome of hepatic resection (HR) and resection combined with radiofrequency ablation (RFA) in treating patients with bilobar HCC. MATERIALS AND METHODS: A retrospective study of 364 patients with bilobar HCC was carried out. Among them, 89 received HR, 114 received resection combined with RFA, and 161 received transarterial chemoembolization (TACE). The clinicopathologic parameters, surgical results, long-term outcomes, and prognostic factors were analyzed. RESULTS: The median follow-up time was 28 mo (range, 3-84 mo). The 1-, 3-, 5-y overall survival rates were better after HR and resection combined with RFA than those of patients after TACE, that is, 78.9%, 49.4%, and 34.4%; 70.7%, 40.7%, and 22.3%; and 47.2%, 17.4%, and 8.6%, respectively (P < 0.001). Overall survival and recurrence-free survival rates were comparable between the two surgical groups. Child-Pugh stage, liver cirrhosis, and tumor number were identified as significant prognostic factors for overall survival by using the multivariate Cox model. CONCLUSIONS: HR combined with RFA provided a chance for cure to patients with bilobar HCC who were traditionally deemed unresectable and yielded better long-term outcomes than TACE in a subset of patients. With preserved liver function, patients can receive aggressive treatment and survival could be prolonged. PMID- 24766728 TI - Formulation of enzyme blends to maximize the hydrolysis of alkaline peroxide pretreated alfalfa hay and barley straw by rumen enzymes and commercial cellulases. AB - BACKGROUND: Efficient conversion of lignocellulosic biomass to fermentable sugars requires the synergistic action of multiple enzymes; consequently enzyme mixtures must be properly formulated for effective hydrolysis. The nature of an optimal enzyme blends depends on the type of pretreatment employed as well the characteristics of the substrate. In this study, statistical experimental design was used to develop mixtures of recombinant glycosyl hydrolases from thermophilic and anaerobic fungi that enhanced the digestion of alkaline peroxide treated alfalfa hay and barley straw by mixed rumen enzymes as well as commercial cellulases (Accelerase 1500, A1500; Accelerase XC, AXC). RESULTS: Combinations of feruloyl and acetyl xylan esterases (FAE1a; AXE16A_ASPNG), endoglucanase GH7 (EGL7A_THITE) and polygalacturonase (PGA28A_ASPNG) with rumen enzymes improved straw digestion. Inclusion of pectinase (PGA28A_ASPNG), endoxylanase (XYN11A_THITE), feruloyl esterase (FAE1a) and beta-glucosidase (E-BGLUC) with A1500 or endoglucanase GH7 (EGL7A_THITE) and beta-xylosidase (E-BXSRB) with AXC increased glucose release from alfalfa hay. Glucose yield from straw was improved when FAE1a and endoglucanase GH7 (EGL7A_THITE) were added to A1500, while FAE1a and AXE16A_ASPNG enhanced the activity of AXC on straw. Xylose release from alfalfa hay was augmented by supplementing A1500 with E-BGLUC, or AXC with EGL7A_THITE and XYN11A_THITE. Adding arabinofuranosidase (ABF54B_ASPNG) and esterases (AXE16A_ASPNG; AXE16B_ASPNG) to A1500, or FAE1a and AXE16A_ASPNG to AXC enhanced xylose release from barley straw, a response confirmed in a scaled up assay. CONCLUSION: The efficacy of commercial enzyme mixtures as well as mixed enzymes from the rumen was improved through formulation with synergetic recombinant enzymes. This approach reliably identified supplemental enzymes that enhanced sugar release from alkaline pretreated alfalfa hay and barley straw. PMID- 24766729 TI - Is formaldehyde the missing link in AD pathology? The differential aggregation of amyloid-beta with APOE isoforms in vitro. AB - Apolipoprotein E (APOE) genetic variation and aging are the two most noted risk factors associated with the development of Alzheimer's disease (AD) related dementia. However, the relationship between these two pathological factors is not understood. Formaldehyde (FA) is an age related factor that has been found to be elevated in AD patients and is known to have protein cross-linking properties. FA forms cross-links with larger arginine, lysine and tryptophan residues but also has thiol reactivity. This study investigated the formation of protein aggregates between amyloid-beta (1-40) peptide (Abeta), the main component of amyloid plaques in AD, with APOE isoforms in vitro. APOE4 protein, the isoform with arginines at residue 112 and 158, was found to form aggregates with more Abeta (P < 0.001) and APOE (P < 0.05) protein content in 10 mM FA than aggregates formed with either APOE3 or APOE2 protein. This aggregation pattern reflected the trend of vulnerability conferred by the APOE genetic variation (APOE4 > APOE3 > APOE2) and suggested that FA may have a role in the differential pattern of amyloid plaque formation in people with differing APOE genetic backgrounds. All told, this finding adds to a growing body of evidence that FA has a role in AD progression as well as provides a novel link between aging and APOE risk factors; the cornerstones of one of the world's largest mental health concerns. PMID- 24766730 TI - Primary tracheal B-cell lymphoma causing recurrent central airway obstruction. PMID- 24766731 TI - Pericardial varices secondary to fibrosing mediastinitis. PMID- 24766732 TI - Randomized phase II study of pemetrexed/cisplatin with or without axitinib for non-squamous non-small-cell lung cancer. AB - BACKGROUND: The efficacy and safety of axitinib, a potent and selective second generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 in combination with pemetrexed and cisplatin was evaluated in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Overall, 170 patients were randomly assigned to receive axitinib at a starting dose of 5-mg twice daily continuously plus pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) on day 1 of up to six 21-day cycles (arm I); axitinib on days 2 through 19 of each cycle plus pemetrexed/cisplatin (arm II); or pemetrexed/cisplatin alone (arm III). The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS was 8.0, 7.9, and 7.1 months in arms I, II, and III, respectively (hazard ratio: arms I vs. III, 0.89 [P = 0.36] and arms II vs. III, 1.02 [P = 0.54]). Median overall survival was 17.0 months (arm I), 14.7 months (arm II), and 15.9 months (arm III). Objective response rates (ORRs) for axitinib-containing arms were 45.5% (arm I) and 39.7% (arm II) compared with 26.3% for pemetrexed/cisplatin alone (arm III). Gastrointestinal disorders and fatigue were frequently reported across all treatment arms. The most common all-causality grade >=3 adverse events were hypertension in axitinib-containing arms (20% and 17%, arms I and II, respectively) and fatigue with pemetrexed/cisplatin alone (16%). CONCLUSION: Axitinib in combination with pemetrexed/cisplatin was generally well tolerated. Axitinib combinations resulted in non-significant differences in PFS and numerically higher ORR compared with chemotherapy alone in advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00768755 (October 7, 2008). PMID- 24766733 TI - Exploring the Relationship of Three Medical Entitlement Beliefs and Psychiatric/Psychological Variables for Acute and Chronic Pain Patients. AB - OBJECTIVES: The belief in medical care entitlement has recently resulted in major changes in the medical system in the United States. The objectives of this study were the following: to compare endorsement of three medical entitlement beliefs (I deserve the best medical care no matter what the cost [BMC], I am entitled to all of the medical care I want at no charge [NC], I shouldn't have to wait to see my doctors [W]) in community nonpatients without pain (CNPWP), acute pain patients (APPs), and chronic pain patients (CPPs) and to develop predictor models for these beliefs in APPs and CPPs. DESIGN: CNPWP, APPs, and CPPs were compared statistically for frequency of endorsement of each belief. All available variables were utilized in logistic regression models to predict each belief in APPs and CPPs. Those affirming/nonaffirming each belief were compared by t-test for affirmation of narcissism, dependency, and antisocial practices on three scales from established inventories. RESULTS: CPPs were significantly more likely than APPs to endorse BMC. No other comparisons were significant. The logistic regression models identified variables that related to narcissism, anger, doctor dissatisfaction, depression, and anxiety, which entered the models for both APPs and CPPs for some beliefs. Those APPs and CPPs who affirmed the beliefs of NC and W were more likely than their counterparts to affirm antisocial practices, but not narcissism or dependency. CONCLUSIONS: Patient medical entitlement beliefs may be related to some psychiatric/psychological issues. PMID- 24766734 TI - Detailed SAR and PCA of the tyrocidines and analogues towards leucocin A sensitive and leucocin A-resistant Listeria monocytogenes. AB - The tyrocidines, antimicrobial cyclic decapeptides from Bacillus aneurinolyticus, have potent activity with drug/disinfectant potential, specifically against Listeria monocytogenes. The tyrocidine activity is dependent on an amphipathic balance. Structure-activity relationship (SAR) analysis combined with principal component analysis showed the best activity correlation with hydropathy and solvent accessible volume (hydrophobicity parameters), Mr and molecular volume (steric/size parameters), coupled with rigid sequence and charge prerequisites. For potent activity against L. monocytogenes strains, there is a prerequisite for a Tyr or Phe in the (W/F)(w/f)NQ(Y/F/W) sequence of the variable pentapeptide and ornithine (Orn, O) as cationic residue in the conserved V(K/O)LfP pentapeptide, particularly with Trp in the aromatic dipeptide moiety of the variable pentapeptide. The roles of Trp and Orn in the tyrocidines were confirmed with most active peptide, tyrocidine B (TrcB) containing Orn and a Trp-D-Phe in the aromatic dipeptide moiety. However, a novel analogue with a trimethylated ornithine and Phe-D-Phe showed an activity rivalling that of TrcB. Our results emphasized that activity is dictated by interplay between the character of the aromatic residues in the variable pentapeptide and the cationic residue. Any residue change resulting in tighter membrane/cell wall interaction is likely to trap tyrocidines and impede their mechanism of action. PMID- 24766736 TI - Distribution of D-3-aminoisobutyrate-pyruvate aminotransferase in the rat brain. AB - BACKGROUND: D-3-aminoisobutyrate, an intermediary product of thymine, is converted to 2-methyl-3-oxopropanoate using pyruvate as an amino acceptor by D-3 aminoisobutyrate-pyruvate aminotransferase (D-AIB AT; EC 2.6.1.40). A large amount of D-AIB AT is distributed in the kidney and liver; however, small amounts are found in the brain. Recently, D-AIB AT was reported to metabolize asymmetric dimethylarginine (ADMA) in vivo and was suggested to be an important enzyme for nitric oxide metabolism because ADMA is a competitive inhibitor for nitric oxide synthase. In this study, we examined the distribution of D-AIB AT in the rat brain further to understand its role. We measured D-AIB AT mRNA and protein expression using quantitative RT-PCR and Western blotting, and monitored its distribution using immunohistochemical staining. RESULTS: D-AIB AT was distributed throughout the brain, with high expression in the cortex and hippocampus. Immunohistochemical staining revealed that D-AIB AT was highly expressed in the retrosplenial cortex and in hippocampal neurons. CONCLUSION: Our results suggest that D-AIB AT is distributed in the examined- just the regions and may play an important role there. PMID- 24766735 TI - Implications of climate change on the distribution of the tick vector Ixodes scapularis and risk for Lyme disease in the Texas-Mexico transboundary region. AB - BACKGROUND: Disease risk maps are important tools that help ascertain the likelihood of exposure to specific infectious agents. Understanding how climate change may affect the suitability of habitats for ticks will improve the accuracy of risk maps of tick-borne pathogen transmission in humans and domestic animal populations. Lyme disease (LD) is the most prevalent arthropod borne disease in the US and Europe. The bacterium Borrelia burgdorferi causes LD and it is transmitted to humans and other mammalian hosts through the bite of infected Ixodes ticks. LD risk maps in the transboundary region between the U.S. and Mexico are lacking. Moreover, none of the published studies that evaluated the effect of climate change in the spatial and temporal distribution of I. scapularis have focused on this region. METHODS: The area of study included Texas and a portion of northeast Mexico. This area is referred herein as the Texas Mexico transboundary region. Tick samples were obtained from various vertebrate hosts in the region under study. Ticks identified as I. scapularis were processed to obtain DNA and to determine if they were infected with B. burgdorferi using PCR. A maximum entropy approach (MAXENT) was used to forecast the present and future (2050) distribution of B. burgdorferi-infected I. scapularis in the Texas Mexico transboundary region by correlating geographic data with climatic variables. RESULTS: Of the 1235 tick samples collected, 109 were identified as I. scapularis. Infection with B. burgdorferi was detected in 45% of the I. scapularis ticks collected. The model presented here indicates a wide distribution for I. scapularis, with higher probability of occurrence along the Gulf of Mexico coast. Results of the modeling approach applied predict that habitat suitable for the distribution of I. scapularis in the Texas-Mexico transboundary region will remain relatively stable until 2050. CONCLUSIONS: The Texas-Mexico transboundary region appears to be part of a continuum in the pathogenic landscape of LD. Forecasting based on climate trends provides a tool to adapt strategies in the near future to mitigate the impact of LD related to its distribution and risk for transmission to human populations in the Mexico-US transboundary region. PMID- 24766737 TI - ShaoYao decoction ameliorates colitis-associated colorectal cancer by downregulating proinflammatory cytokines and promoting epithelial-mesenchymal transition. AB - BACKGROUND: Shaoyao decoction (SYD) is a traditional Chinese medicine prescription formulated by Liu Wan-Su, a master of traditional Chinese medicine in Jin-Yuan Dynasty. SYD is effective in treating ulcerative colitis. Paeonol, a component of SYD, inhibits colorectal cancer (CRC) cell proliferation and induces CRC cell apoptosis. In this study, azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated CRC (caCRC) model and CRC cell lines were used to examine the effects of SYD on CRC in vivo and in vitro. METHODS: A translational medicine strategy based on phytomics quality control was adopted. Liquid chromatography was employed for the chemical characterization and chemical fingerprinting of SYD. Protein expression and macrophage existence were determined by immunohistochemistry and western blot. Serum cytokines were quantified by Luminex assay. RESULTS: AOM/DSS-induced caCRC phenotypically resembled human caCRC. SYD significantly increased the survival rate of the mice, ameliorated the general well-being of the mice, and reduced the incidence and multiplicity of colonic neoplasms. SYD inhibited epithelial-mesenchymal transition (EMT), as indicated by upregulated epithelia cadherin and downregulated neuronal cadherin, fibronectin, vimentin, and transcription factor Snail. SYD reduced the expression levels of serum interleukin 1beta, interleukin 6, tumor necrosis factor alpha, tumor-associated macrophages, and p65. These results showed that SYD can attenuate proinflammatory cytokines and inhibit EMT. CONCLUSIONS: SYD ameliorates caCRC by suppressing inflammation and inhibiting EMT. SYD might be an alternative therapy for caCRC. PMID- 24766739 TI - Typology of perceived family functioning in an American sample of patients with advanced cancer. AB - CONTEXT: Poor family functioning affects psychosocial adjustment and the occurrence of morbidity following bereavement in the context of a family's coping with advanced cancer. Family functioning typologies assist with targeted family centered assessment and intervention to offset these complications in the palliative care setting. OBJECTIVES: Our objective was to identify the number and nature of potential types in an American palliative care patient sample. METHODS: Data from patients with advanced cancer (N = 1809) screened for eligibility for a larger randomized clinical trial were used. Cluster analyses determined whether patients could be classified into clinically meaningful and coherent groups, based on similarities in their perceptions of family functioning across the cohesiveness, expressiveness, and conflict resolution subscales of the Family Relations Index. RESULTS: Patients' reports of perceived family functioning yielded a model containing five meaningful family types. CONCLUSION: Cohesiveness, expressiveness, and conflict resolution appear to be useful dimensions by which to classify patient perceptions of family functioning. "At risk" American families may include those we have called hostile, low communicating, and less-involved. Such families may benefit from adjuvant family centered psychosocial services, such as family therapy. PMID- 24766740 TI - Development and validation of the breakthrough pain assessment tool (BAT) in cancer patients. AB - CONTEXT: The successful management of breakthrough pain depends on a combination of adequate assessment, appropriate (individualized) treatment, and adequate re assessment. Currently, there is no fully validated clinical assessment tool for breakthrough pain in cancer patients. OBJECTIVES: The aim of this project was to develop and validate a breakthrough pain assessment tool (the BAT) for use in the clinical setting. METHODS: The content of the BAT was determined by reviewing the medical literature, conducting a Delphi process with experts in breakthrough pain and/or pain assessment and conducting semi-structured interviews with cancer patients with breakthrough pain. The tool was then subjected to a series of standard psychometric tests to assess its factor structure, validity (i.e., content validity, construct validity), reliability (i.e., internal consistency, test-retest reliability), and responsiveness to change. RESULTS: The BAT comprised two pages with 14 questions. Factor analysis confirmed the presence of two underlying factors. Psychometric testing confirmed that the tool is valid, reliable, and responsive to change. CONCLUSION: This study provides initial evidence for the validity and reliability of the breakthrough pain assessment tool which may be used to facilitate the management of patients with breakthrough cancer pain in the clinical setting. PMID- 24766738 TI - Dyspnea and panic among patients with newly diagnosed non-small cell lung cancer. AB - CONTEXT: Among patients with lung cancer, dyspnea is associated with psychological distress, fatigue, and poor coping. Respiratory symptoms are also a common trigger for panic attacks in the general population. Minimal research has addressed the prevalence of panic disorder or the association of dyspnea with the risk of panic disorder in lung cancer. OBJECTIVES: We explored the frequency of panic disorder symptoms and the association of dyspnea with the risk of panic disorder symptoms among patients with newly diagnosed non-small cell lung cancer. METHODS: During 2006-2010, consecutive patients presenting for initial consultation at a thoracic oncology clinic completed a survey of current symptoms, including dyspnea and panic disorder symptoms. We evaluated the frequency of panic disorder symptoms. Logistic regression was used to test the association of dyspnea with the risk of panic disorder symptoms, adjusting for age, gender, disease stage, performance status, and major depression symptoms. RESULTS: Among 624 patients (mean age=63.7; standard deviation=12.1; 52.6% female), 48.1% reported that breathing was at least somewhat difficult and 11.2% endorsed panic disorder symptoms. Dyspnea was independently associated with higher risk of panic disorder symptoms (odds ratio=2.19, 95% confidence interval=1.11-4.31, P=0.02). Younger age and major depression symptoms also were associated with higher risk (P<0.01). CONCLUSION: Almost half of the patients with newly diagnosed non-small cell lung cancer reported dyspnea, and patients with dyspnea were more than twice as likely to endorse panic disorder symptoms relative to patients without dyspnea. Results highlight the need to differentiate panic disorder symptoms among patients who report dyspnea, particularly those who are younger or experiencing major depression symptoms. PMID- 24766741 TI - Subgroups of cancer patients with unique pain and fatigue experiences during chemotherapy. AB - CONTEXT: Some cancer patients experience pain and fatigue, whereas others experience only one of the two symptoms. Yet, it is not clear who experiences these unique patterns and why. OBJECTIVES: This study aimed to identify subgroups of cancer patients with unique pain and fatigue experiences in two different chemotherapy cycles to examine how selected factors influenced subgroup membership and identify how subgroups differed in concurrently measured functional limitation outcome. METHODS: The sample included 276 patients with diverse cancer types from four U.S. sites. To investigate subgroups, latent profile analyses were performed. Multinomial logistic regression and one-way analysis of variance-type analyses were conducted to examine the influencing variables of subgroup membership and to examine differences among subgroups in patient outcome. RESULTS: The high-pain/high-fatigue (HPHF) and low-pain/low fatigue subgroups were found at both time points. The low-pain/high-fatigue subgroup was present only in the first chemotherapy cycle. Pain and fatigue levels significantly differentiated subgroups at each time point (all P<0.05). Across the two time points, experiencing higher depressed mood increased the risk to be in the HPHF subgroup (all P<0.01). The HPHF subgroup had the most serious limitations in activities (all P<0.01). CONCLUSION: This study confirmed the existence of a unique symptom experience of pain and fatigue. This pattern should be acknowledged for symptom assessment and management. PMID- 24766742 TI - Relationship between symptom burden, distress, and sense of dignity in terminally ill cancer patients. AB - CONTEXT: Maintaining a sense of dignity in terminally ill patients and enabling a dignified dying are important aims of palliative care. OBJECTIVES: To evaluate the impact of symptom burden, distress, overall condition, and individual patient characteristics on self-perceived dignity in terminally ill cancer patients. METHODS: In this cross-sectional study, 61 patients were recruited through a palliative care inpatient ward within 48 hours after admission. Patients completed the Patient Dignity Inventory, a modified version of the Memorial Symptom Assessment Scale, the National Comprehensive Cancer Network Distress Thermometer, and a single-item scale rating subjective of overall condition. Sociodemographic parameters and performance status were taken from the patients' records. RESULTS: Dignity total score correlated highest with lack of energy (P<0.001), anxiety (P<0.001), sadness (P=0.002), pain (P=0.009), shortness of breath (P=0.019), irritability (P=0.023), thirst (P=0.029), and tiredness (P=0.041). Psychological symptoms showed more consistent associations with the different dignity dimensions than physical symptoms except for the dependency dimension. Psychological distress correlated with all dignity dimensions: symptom distress (P<0.001), existential distress (P<0.001), dependency (P=0.020), peace of mind (P<0.001), and social support (P=0.024). Overall condition was significantly associated with existential distress (P=0.013), but not with symptom distress, dependency, peace of mind, or social support. Performance status showed significant association with dependency (P=0.001). CONCLUSION: Self perceived dignity in terminally ill cancer patients is significantly associated with physical as well as psychological symptoms, distress, overall condition, performance status, and comorbidities. Knowledge of these specific interactions is essential for adequate, comprehensive palliative care. PMID- 24766743 TI - Clinical practice guidelines for delirium management: potential application in palliative care. AB - CONTEXT: Delirium occurs in patients across a wide array of health care settings. The extent to which formal management guidelines exist or are adaptable to palliative care is unclear. OBJECTIVES: This review aims to 1) source published delirium management guidelines with potential relevance to palliative care settings, 2) discuss the process of guideline development, 3) appraise their clinical utility, and 4) outline the processes of their implementation and evaluation and make recommendations for future guideline development. METHODS: We searched PubMed (1990-2013), Scopus, U.S. National Guideline Clearinghouse, Google, and relevant reference lists to identify published guidelines for the management of delirium. This was supplemented with multidisciplinary input from delirium researchers and other relevant stakeholders at an international delirium study planning meeting. RESULTS: There is a paucity of high-level evidence for pharmacological and non-pharmacological interventions in the management of delirium in palliative care. However, multiple delirium guidelines for clinical practice have been developed, with recommendations derived from "expert opinion" for areas where research evidence is lacking. In addition to their potential benefits, limitations of clinical guidelines warrant consideration. Guidelines should be appraised and then adapted for use in a particular setting before implementation. Further research is needed on the evaluation of guidelines, as disseminated and implemented in a clinical setting, focusing on measurable outcomes in addition to their impact on quality of care. CONCLUSION: Delirium clinical guidelines are available but the level of evidence is limited. More robust evidence is required for future guideline development. PMID- 24766744 TI - Subcutaneous administration of drugs in palliative care: results of a systematic observational study. AB - CONTEXT: Especially in palliative care, safe and manageable administration of medication is essential. Subcutaneous drug administration is a possible alternative, when oral intake is hampered. However, evidence for this method is rare. OBJECTIVES: This observational study assessed the clinical practice of subcutaneous drug administration, focusing on the evaluation of local reactions or complications to further develop recommendations. METHODS: Over 14 months, patients in a specialized inpatient palliative care unit treated by the subcutaneous route were invited to participate in this clinical study. All subcutaneous medications including dosage and volume of injection, type of needles, and injection site were documented. The injection sites were systematically assessed including the subjective perceptions of patients for analysis of patient tolerability and acceptability. T-tests and Chi-squared tests of these variables were performed to calculate group differences between needles with vs. without complications (P < 0.05). RESULTS: In 120 patients, 3957 applications were administered via 243 needles. The needles were placed in thighs (38.7%) and upper arms (28.8%). Most frequently used medications were hydromorphone (59.0%), haloperidol (12.3%), and midazolam (8.3%). Complications were diagnosed most often on the third or fourth day of the needle in situ and occurred significantly more often in (fully) active patients and patients transferred or discharged at the end of treatment. The mean time of needle in situ was significantly lower (4.1 vs. 5.0 days) in complication cases than in noncomplication cases (t-test: P = 0.027). CONCLUSION: The results of this study acknowledge the clinical practice of subcutaneous administration of medication as a very flexible, broadly feasible, rather safe, and nonburdensome method. Nevertheless, this practice is not free from complications, needs appropriate nursing care, and requires standardized policies and procedures. PMID- 24766745 TI - Practical assessment of delirium in palliative care. AB - CONTEXT: Delirium is a common, distressing neuropsychiatric complication for patients in palliative care settings, where the need to minimize burden yet accurately assess delirium is hugely challenging. OBJECTIVES: This review focused on the optimal clinical and research application of delirium assessment tools and methods in palliative care settings. METHODS: In addition to multidisciplinary input from delirium researchers and other relevant stakeholders at an international meeting, we searched PubMed (1990-2012) and relevant reference lists to identify delirium assessment tools used either exclusively or partly in the context of palliative care. RESULTS: Of the 26 delirium scales identified, we selected six for in-depth review: three screening tools, two severity measures, and one research tool for neuropsychological assessment of delirium. These tools differed regarding intended use, ease of use, training requirements, psychometric properties, and validation in or suitability for palliative care populations. The Nursing Delirium Screening Scale, Single Question in Delirium, or Confusion Assessment Method, ideally with a brief attention test, can effectively screen for delirium. Favoring inclusivity, use of Diagnostic and Statistical Manual of Mental Disorders-IV criteria gives the best results for delirium diagnosis. The Revised Delirium Rating Scale and the Memorial Delirium Assessment Scale are the best available options for monitoring severity, and the Cognitive Test for Delirium provides detailed neuropsychological assessment for research purposes. CONCLUSION: Given the unique characteristics of patients in palliative care settings, further contextually sensitive studies of delirium assessment are required in this population. PMID- 24766746 TI - Oral re-vaccination of Eurasian wild boar with Mycobacterium bovis BCG yields a strong protective response against challenge with a field strain. AB - BACKGROUND: Field vaccination trials with Mycobacterium bovis BCG, an attenuated mutant of M. bovis, are ongoing in Spain, where the Eurasian wild boar (Sus scrofa) is regarded as the main driver of animal tuberculosis (TB). The oral baiting strategy consists in deploying vaccine baits twice each summer, in order to gain access to a high proportion of wild boar piglets. The aim of this study was to assess the response of wild boar to re-vaccination with BCG and to subsequent challenge with an M. bovis field strain. RESULTS: BCG re-vaccinated wild boar showed reductions of 75.8% in lesion score and 66.9% in culture score, as compared to unvaccinated controls. Only one of nine vaccinated wild boar had a culture-confirmed lung infection, as compared to seven of eight controls. Serum antibody levels were highly variable and did not differ significantly between BCG re-vaccinated wild boar and controls. Gamma IFN levels differed significantly between BCG re-vaccinated wild boar and controls. The mRNA levels for IL-1b, C3 and MUT were significantly higher in vaccinated wild boar when compared to controls after vaccination and decreased after mycobacterial challenge. CONCLUSIONS: Oral re-vaccination of wild boar with BCG yields a strong protective response against challenge with a field strain. Moreover, re-vaccination of wild boar with BCG is not counterproductive. These findings are relevant given that re vaccination is likely to happen under real (field) conditions. PMID- 24766748 TI - In memoriam: Remembering Professor Roger Nordmann, May 24, 1926-January 24, 2014. PMID- 24766747 TI - Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)2 D are associated with disease severity. AB - OBJECTIVES: We aimed to explore the association between vitamin D levels and the severity, mortality and microbiological etiology of community-acquired pneumonia. METHODS: Vitamin D levels (both, the reservoir form 25-OH and the activated form 1,25-OH2) of 300 randomly selected patients with community-acquired pneumonia due to pre-specified pathogens included in the German competence network (CAPNETZ) study were measured. Prior to statistical analysis, values of 25-OH and 1,25-OH2 were power-transformed to achieve parametric distribution. All further analyses were performed with seasonally and age adjusted values. RESULTS: There was only a modest (Spearman Coefficient 0.38) positive correlation between 25-OH and 1,25 OH2. For 1,25-OH2 but not 25-OH, the general linear model revealed a significant inverse correlation between serum concentration and CURB score (p = 0.011). Liver and respiratory co-morbidity were associated with significantly lower 25-OH values and renal co-morbidity with significantly lower 1,25-OH2 values. No significant differences of 1,25-OH2 or 25-OH between different pathogens (influenza virus, Legionella spp., Streptococcus pneumoniae) were detected. CONCLUSION: For 1,25-OH2, we found a significant and independent (controlled for age, season and pathogen) negative correlation to pneumonia severity. Therefore, supplementation of non-activated vitamin D to protect from pneumonia may be non sufficient in patients that have a decreased capacity to hydroxylate 25-OH to 1,25-OH2. PMID- 24766749 TI - Alcohol and marijuana use patterns associated with unsafe driving among U.S. high school seniors: high use frequency, concurrent use, and simultaneous use. AB - OBJECTIVE: This article examines noncausal associations between high school seniors' alcohol and marijuana use status and rates of self-reported unsafe driving in the past 12 months. METHOD: Analyses used data from 72,053 students collected through annual surveys of nationally representative cross-sectional samples of U.S. 12th-grade students from 1976 to 2011. Two aspects of past-12 month alcohol and marijuana use were examined: (a) use frequency and (b) status as a nonuser, single substance user, concurrent user, or simultaneous user. Measures of past-12-month unsafe driving included any tickets/warnings or accidents, as well as tickets/warnings or accidents following alcohol or marijuana use. Analyses explored whether an individual's substance use frequency and simultaneous use status had differential associations with their rate of unsafe driving. RESULTS: Higher substance use frequency (primarily alcohol use frequency) was significantly and positively associated with unsafe driving. The rate of engaging in any unsafe driving was also significantly and positively associated with simultaneous use status, with the highest rate associated with simultaneous use, followed by concurrent use, followed by use of alcohol alone. Individuals who reported simultaneous use most or every time they used marijuana had the highest likelihood of reporting unsafe driving following either alcohol or marijuana use. CONCLUSIONS: This article expands the knowledge on individual risk factors associated with unsafe driving among teens. Efforts to educate U.S. high school students (especially substance users), parents, and individuals involved in prevention programming and driver's education about the increased risks associated with various forms of drug use status may be useful. PMID- 24766750 TI - "I will take a shot for every 'like' I get on this status": posting alcohol related Facebook content is linked to drinking outcomes. AB - OBJECTIVE: This study investigated whether self-reports of alcohol-related postings on Facebook by oneself or one's Facebook friends were related to common motives for drinking and were uniquely predictive of self-reported alcohol outcomes (alcohol consumption, problems, and cravings). METHOD: Pacific Northwest undergraduates completed a survey of alcohol outcomes, drinking motives, and alcohol-related Facebook postings. Participants completed the survey online as part of a larger study on alcohol use and cognitive associations. Participants were randomly selected through the university registrar's office and consisted of 1,106 undergraduates (449 men, 654 women, 2 transgender, 1 declined to answer) between the ages of 18 and 25 years (M = 20.40, SD = 1.60) at a large university in the Pacific Northwest. Seven participants were excluded from analyses because of missing or suspect data. RESULTS: Alcohol-related postings on Facebook were significantly correlated with social, enhancement, conformity, and coping motives for drinking (all ps < .001). After drinking motives were controlled for, self alcohol-related postings independently and positively predicted the number of drinks per week, alcohol-related problems, risk of alcohol use disorders, and alcohol cravings (all ps < .001). In contrast, friends' alcohol-related postings only predicted the risk of alcohol use disorders (p < .05) and marginally predicted alcohol-related problems (p = .07). CONCLUSIONS: Posting alcohol related content on social media platforms such as Facebook is associated with common motivations for drinking and is, in itself, a strong predictive indicator of drinking outcomes independent of drinking motives. Moreover, self-related posting activity appears to be more predictive than Facebook friends' activity. These findings suggest that social media platforms may be a useful target for future preventative and intervention efforts. PMID- 24766751 TI - Diary study of sexual risk taking, alcohol use, and strategies for reducing negative affect in female college students. AB - OBJECTIVE: The goal of this study was to examine motivations for engaging in risky sexual behaviors (RSBs) and factors that may increase the likelihood of engaging in RSB. RSB was defined as not using condoms during intercourse and having intercourse with poorly known partners, which were treated separately with regard to analyses. METHOD: Utilizing a weekly diary methodology, the present study examined whether using situation-specific coping strategies (e.g, using alcohol to reduce negative affect and sex to reduce negative affect) and whether subjective reports of intoxication significantly predicted if participants would engage in RSB. Female college students (N = 93) completed a weekly computerized questionnaire for 8 weeks reporting on their sexual behavior, their level of intoxication, and use of strategies (i.e., sex and alcohol) to reduce negative affect at the time of the sexual encounter. RESULTS: Using hierarchical linear modeling, results indicated that level of intoxication was the sole significant main effect related to engaging in RSB; specifically, level of intoxication was positively related to sex with a poorly known partner. CONCLUSIONS: Alcohol use, as opposed to motivation for intercourse, is an important area to focus on with regard to prevention of RSB. PMID- 24766752 TI - Willingness to drink as a function of peer offers and peer norms in early adolescence. AB - OBJECTIVE: The goal of this study was to explore the effect of subjective peer norms on adolescents' willingness to drink and whether this association was moderated by sensitivity to peer approval, prior alcohol use, and gender. METHOD: The sample was 1,023 middle-school students (52% female; 76% White; 12% Hispanic; M(age) = 12.22 years) enrolled in a prospective study of drinking initiation and progression. Using web-based surveys, participants reported on their willingness to drink alcohol if offered by (a) a best friend or (b) a classmate, peer norms for two referent groups (close friends and classmates), history of sipping or consuming a full drink of alcohol, and sensitivity to peer approval (extreme peer orientation). Items were re-assessed at two follow-ups (administered 6 months apart). RESULTS: Multilevel models revealed that measures of peer norms were significantly associated with both willingness outcomes, with the greatest prediction by descriptive norms. The association between norms and willingness was magnified for girls, those with limited prior experience with alcohol, and youths with low sensitivity to peer approval. CONCLUSIONS: Social norms appear to play a key role in substance use decisions and are relevant when considering more reactive behaviors that reflect willingness to drink under conducive circumstances. Prevention programs might target individuals with higher willingness, particularly girls who perceive others to be drinking and youths who have not yet sipped alcohol but report a higher perceived prevalence of alcohol consumption among both friends and peers. PMID- 24766753 TI - Alcohol use trajectories among non-treatment-seeking heavy drinkers. AB - OBJECTIVE: Heavy drinking, often defined as more than five drinks per occasion, is a major public health problem worldwide, yet most individuals who drink heavily never receive treatment. Focusing on those who receive treatment, numerous studies have found that alcohol use following treatment is discontinuous, with periods of abstinence alternating with periods of heavy drinking. In contrast, little is known about changes in alcohol use among the majority of individuals who engage in heavy drinking and never receive treatment. The goal of this study was to examine changes in alcohol consumption (proportion of heavy drinking days) in a sample of non-treatment-seeking heavy drinkers (n = 151). METHOD: The current study focused on three quantitative models--latent growth curve, latent growth mixture, and latent Markov models--to examine changes in the frequency of heavy drinking days (i.e., >= 5/4 drinks per day for men/women) among a sample of heavy drinkers who did not receive any form of treatment or self-help over a 2-year period. RESULTS: Participants significantly reduced their frequency of heavy drinking over a 2-year period, and changes in drinking did not show the discontinuity in trajectories often observed in treatment samples. Alcohol use disorder diagnosis predicted higher initial levels of frequent heavy drinking but did not predict changes in the frequency of heavy drinking over time. CONCLUSIONS: Most individuals, with or without an alcohol use disorder, reported significant reductions in heavy drinking frequency over time. These results have important implications for a public health approach to the problem of heavy drinking. PMID- 24766754 TI - Characteristics and course of dependence in cocaine-dependent individuals who never used alcohol or marijuana or used cocaine first. AB - OBJECTIVE: Cocaine users typically try alcohol or marijuana before cocaine, but this ordering of substance use initiation is not universal. Characterizing cocaine-dependent users who deviate from the typical sequence may be informative for understanding the multiple pathways to cocaine dependence. METHOD: Data were drawn from cocaine-dependent participants (N = 6,333; 41% female) in a multisite study of the genetics of substance dependence who completed in-person structured psychiatric interviews. Participants were categorized with respect to alcohol or marijuana use as (a) never used, (b) used cocaine first, or (c) first used at the same age as or after first cocaine use. The association of a range of demographic, psychiatric, and childhood risk factors with sequences of initiation and the association of those sequences with indicators of dependence course (e.g., severity) were investigated in a series of regression analyses. RESULTS: Women and non-European Americans were overrepresented in the atypical sequence groups. The atypical sequence groups also differed from the typical sequence groups with respect to rates of other substance use disorders. Sequences of substance use initiation were largely unrelated to other psychiatric disorders or childhood risk factors. Individuals who never used marijuana had a lower severity of dependence. CONCLUSIONS: Although only a minority of dependent cocaine users deviate from the typical sequence of substance use initiation, several characteristics distinguish them from those who follow the typical sequence. Findings underscore the diversity in pathways to cocaine dependence. PMID- 24766755 TI - Drinking motives and links to alcohol use in 13 European countries. AB - OBJECTIVE: The purpose of this study was to test the structure and endorsement of drinking motives and their links to alcohol use among 11- to 19-year-olds from 13 European countries. METHOD: Confirmatory factor analysis, latent growth curves, and multiple regression models were conducted, based on a sample of 33,813 alcohol-using students from Belgium, Denmark, Estonia, Finland, Hungary, Ireland, Italy, Poland, Portugal, Scotland, Slovakia, Switzerland, and Wales who completed the Drinking Motives Questionnaire Revised Short Form (DMQ-R SF). RESULTS: The findings confirmed the hypothesized fourdimensional factor structure. Social motives for drinking were most frequently indicated, followed by enhancement, coping, and conformity motives, in that order, in all age groups in all countries except Finland. This rank order was clearest among older adolescents and those from northern European countries. The results confirmed that, across countries, social motives were strongly positively related to drinking frequency, enhancement motives were strongly positively related to frequency of drunkenness, and conformity motives were negatively related to both alcohol outcomes. Against our expectations, social motives were more closely related to drunkenness than were coping motives, particularly among younger adolescents. CONCLUSIONS: The findings reveal striking cross-cultural consistency. Health promotion efforts that are based on, or incorporate, drinking motives are likely to be applicable across Europe. As social motives were particularly closely linked to drunkenness among young adolescents, measures to impede the modeling of alcohol use and skills to resist peer pressure are particularly important in this age group. PMID- 24766756 TI - Predictors of pretreatment commitment to abstinence: results from the COMBINE study. AB - OBJECTIVE: Patients entering treatment for alcohol problems do not have uniform treatment goals, and a pretreatment drinking goal has a significant impact on treatment outcome. The objective of this study was to understand better how an array of individual characteristics, including factors that affect treatment, are related to treatment goals before beginning alcohol treatment in the COMBINE (Combining Medications and Behavioral Interventions) Study. METHOD: Participants were alcohol-dependent individuals (N = 1,156; 357 women) recruited at 11 outpatient academic alcoholism-treatment clinics across the United States to participate in a randomized, double-blind, placebo-controlled trial that combined behavioral intervention with acamprosate and/or naltrexone. Treatment goal was coded as controlled drinking, conditional abstinence, or total abstinence. Multinomial logistic regressions assessed whether there were significant relationships between predictor variables and pretreatment goal selection. RESULTS: Lower levels of alcohol-related consequences, lower readiness to change, higher family income, more daily drinkers in social network, and lack of prior treatment or Alcoholics Anonymous engagement predicted choice of a controlled drinking goal over a total abstinence goal. Fewer alcohol-related consequences, lower readiness to change, and more daily drinkers in-network predicted choice of a conditional abstinence goal over a total abstinence goal. CONCLUSIONS: Higher levels of functioning, lower levels of consequences, no prior involvement in treatment and Alcoholics Anonymous, and a more drinking-saturated social environment are associated with the choice of a non-abstinence goal. PMID- 24766757 TI - The effect of an educational intervention on alcohol consumption, at-risk drinking, and health care utilization in older adults: the Project SHARE study. AB - OBJECTIVE: The purpose of this study was to examine the effectiveness of a patient-provider educational intervention in reducing at-risk drinking among older adults. METHOD: This was a cluster-randomized controlled trial of 31 primary care providers and their patients ages 60 years and older at a community based practice with seven clinics. Recruitment occurred from July 2005 to August 2007. Eligibility was determined by telephone and a baseline mailed survey. A total of 1,186 at-risk drinkers were identified by the Comorbidity Alcohol Risk Evaluation Tool. Follow-up patient surveys were administered at 3, 6, and 12 months after baseline. Study physicians and their patients were randomly assigned to usual care (n = 640 patients) versus the Project SHARE (Senior Health and Alcohol Risk Education) intervention (n = 546 patients), which included personalized reports, educational materials, drinking diaries, physician advice during office visits, and telephone counseling delivered by a health educator. Main outcomes were alcohol consumption, at-risk drinking (overall and by type), alcohol discussions with physicians, health care utilization, and screening and intervention costs. RESULTS: At 12 months, the intervention was significantly associated with an increase in alcohol-related discussions with physicians (23% vs. 13%; p <= .01) and reductions in at-risk drinking (56% vs. 67%; p <= .01), alcohol consumption (-2.19 drinks per week; p <= .01), physician visits (-1.14 visits; p = .03), emergency department visits (16% vs. 25%; p <= .01), and nonprofessional caregiving visits (12% vs. 17%; p <= .01). Average variable costs per patient were $31 for screening and $79 for intervention. CONCLUSIONS: The intervention reduced alcohol consumption and at-risk drinking among older adults. Effects were sustained over a year and may have been associated with lower health care utilization, offsetting screening and intervention costs. PMID- 24766758 TI - A pilot study of two supervision approaches for peer-led alcohol interventions with mandated college students. AB - OBJECTIVE: Despite the increasing need to identify and implement effective interventions to reduce drinking with mandated college students, peer-led brief alcohol interventions have received minimal research attention. The current pilot study tested whether enhanced supervision (evidence-based application approach [EAA; group plus individual]) would improve peer counseling skills beyond those acquired by a common practice approach (CPA; group only). METHOD: Following initial peer counselor skill evaluation, drinking outcomes after intervention were compared between supervision groups with a mandated college student sample (N = 82; 65 men). The relationship between acquired motivational interviewing skills and subsequent drinking behaviors was also assessed. RESULTS: EAA peer counselors showed higher motivational interviewing skill acquisition than CPA peer counselors. Despite differences in counselor skill demonstration, mandated clients in both intervention groups significantly reduced drinking behaviors. Further, higher reflection-to-question ratio and motivational interviewing spirit demonstrated by peer counselors were significantly related to poorer follow-up drinking outcomes. CONCLUSIONS: Findings identify supervision practices that may result in optimal peer counselor learning and brief intervention implementation while also offering initial data about the way in which peer counseling session implementation may relate to drinking outcomes. Future research is needed to identify the within-session processes of peer-led interventions that predict drinking outcomes, which may offer additional direction for training approaches. PMID- 24766759 TI - Dissemination, adoption, and implementation of acamprosate for treating alcohol use disorders. AB - OBJECTIVE: Acamprosate has been available in the United States for treating alcohol use disorders (AUDs) for nearly a decade, yet few studies have examined its use within AUD treatment organizations. In addition to describing dissemination and adoption of acamprosate, this study provides novel data regarding organizational processes that underlie its implementation within adopting programs. METHOD: Data were drawn from interviews with leaders of a nationally representative sample of 307 organizations delivering AUD treatment. Quantitative indicators of organizational characteristics, dissemination, adoption, and implementation of acamprosate, as well as qualitative measures of implementation processes, were measured during face-to-face interviews. RESULTS: Only 18.0% (n = 55) of sampled organizations had adopted acamprosate for treating AUDs, and adoption was positively associated with accreditation, having a physician on staff, receiving information about acamprosate via pharmaceutical representatives, and learning about this medication from other treatment providers. Within adopting programs, an average of 6.0% of AUD patients were currently receiving acamprosate. Numerous implementation challenges were identified, including appropriate patient selection, patient reluctance to be prescribed acamprosate, suboptimal adherence, its costs, and limited counselor training. CONCLUSIONS: The limited adoption and implementation of acamprosate likely limits the potential public health impact of this adjunct to AUD treatment. Research integrating the perspectives of organizational leaders, medical professionals, and patients is needed to determine whether specific strategies can address the implementation challenges identified in the current study and increase use of acamprosate in specialty AUD treatment settings. PMID- 24766760 TI - The transition to medication adoption in publicly funded substance use disorder treatment programs: organizational structure, culture, and resources. AB - OBJECTIVE: Medications for the treatment of substance use disorders (SUDs) are not widely available in publicly funded SUD treatment programs. Few studies have drawn on longitudinal data to examine the organizational characteristics associated with programs transitioning from not delivering any pharmacotherapy to adopting at least one SUD medication. METHOD: Using two waves of panel longitudinal data collected over a 5-year period, we measured the transition to medication adoption in a cohort of 190 publicly funded treatment organizations that offered no SUD medications at baseline. Independent variables included organizational characteristics, medical resources, funding, treatment culture, and detailing activities by pharmaceutical companies. RESULTS: Of 190 programs not offering SUD pharmacotherapy at baseline, 22.6% transitioned to offering at least one SUD medication at follow-up approximately 5 years later. Multivariate logistic regression results indicated that the employment of at least one physician at baseline, having a greater proportion of Medicaid clients, and pharmaceutical detailing were positively associated with medication adoption. CONCLUSIONS: Adoption of pharmacotherapy was more likely in programs that had greater medical resources, Medicaid funding, and contact with pharmaceutical companies. Given the potential expansion of Medicaid under the Affordable Care Act, patients served by publicly funded programs may gain greater access to such treatments, but research is needed to document health reform's impact on this sector of the treatment system. PMID- 24766761 TI - Longitudinal trajectories of readiness to change: alcohol use and help-seeking behavior. AB - OBJECTIVE: Pre-post changes in readiness for change (RC) are commonly assessed in treatment outcome studies, often with contradictory results. Little is known about 12-month RC trajectories among those initiating change or about the association between RC and either within- or between-person alcohol use or time lagged help-seeking behavior. METHOD: This observational longitudinal study measured RC as ambivalence, problem recognition, and taking steps. Participants (N = 253; 66.4% male) diagnosed with alcohol use disorders were recruited from treatment sites, Alcoholics Anonymous (AA) groups, and other community sources when first initiating change and assessed at baseline and 3, 6, 9, and 12 months. RESULTS: Support for significant participant heterogeneity as well as linear and quadratic change in RC trajectories was found, although results differed across the three aspects of RC. Independent associations of both within- and between person percentage of days abstinent were found for ambivalence and taking steps. Lagged, time-specific fluctuations in prior help-seeking behaviors within an individual predicting subsequent RC showed that both AA (B = -1.650, p < .05) and treatment attendance (B = 2.914, p < .01) were associated with subsequent ambivalence. Prior increases in taking steps within individuals were predictive of subsequent AA but not treatment attendance. CONCLUSIONS: Results inform treatment providers about how RC trajectories vary depending on alcohol use, both within and between individuals, and how individuals may mobilize change attitudes and behaviors, especially in relation to AA attendance. Future research should investigate additional predictors of RC trajectories and the causal direction between RC and help seeking. PMID- 24766762 TI - DSM-IV antisocial personality disorder and conduct disorder: evidence for taxonic structures among individuals with and without substance use disorders in the general population. AB - OBJECTIVE: The categorical-dimensional status of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) conduct disorder (CD) and antisocial personality disorder (ASPD) is a source of controversy. This study examined whether the underlying structure of DSM-IV CD and ASPD was dimensional or categorical (taxonic) among individuals with and without substance use disorders. METHOD: Using a national large representative survey of U.S. adults (n = 43,093), taxometric analyses of DSM-IV CD and ASPD diagnostic criteria were conducted on the total sample and among those with and without substance use disorders. RESULTS: Results of three taxometric procedures were consistent in showing that the structures underlying DSM-IV CD and ASPD were clearly taxonic in the total sample and among individuals with and without substance use disorders. Comparison curve fit indices exceeded 0.57 for each model. CONCLUSIONS: Taxonic findings of the present study were in contrast to the dimensional results of prior taxometric research among incarcerated samples with substantial comorbidity of antisocial syndromes and substance use disorders. Results supported the categorical representation and diagnostic thresholds of ASPD and CD as defined in DSM-IV and DSM-5. That the structure of ASPD and CD may be taxonic suggests that further research on these disorders use group comparative designs in which samples with and without these disorders are compared in terms of sociodemographic and clinical correlates, comorbidity, and treatment utilization. The taxonic structure of ASPD and CD may contribute to future research on causal processes through which these antisocial syndromes develop. PMID- 24766763 TI - Linking masculinity to negative drinking consequences: the mediating roles of heavy episodic drinking and alcohol expectancies. AB - OBJECTIVE: This study extends previous research on masculinity and negative drinking consequences among young men by considering mediating effects of heavy episodic drinking (HED) and alcohol expectancies. We hypothesized that masculinity would have a direct relationship with negative consequences from drinking as well as indirect relationships mediated by HED and alcohol expectancies of courage, risk, and aggression. METHOD: A random sample of 1,436 college and university men ages 19-25 years completed an online survey, including conformity to masculine norms, alcohol-related expectancies, HED, and negative drinking consequences. Regression analyses and structural equation modeling were used. RESULTS: Six of seven dimensions of masculinity and the alcohol expectancy scales were significantly associated with both HED and negative consequences. In multivariate regression models predicting HED and negative consequences, the playboy and violence dimensions of masculinity and the risk/aggression alcohol expectancy remained significant. HED and the risk-taking dimension of masculinity were also significant in the model predicting negative consequences. The structural equation model indicated that masculinity was directly associated with HED and negative consequences but also influenced negative consequences indirectly through HED and alcohol expectancies. CONCLUSIONS: The findings suggest that, among young adult male college and university students, masculinity is an important factor related to both HED and drinking consequences, with the latter effect partly mediated by HED and alcohol expectancies. Addressing male norms about masculinity may help to reduce HED and negative consequences from drinking. PMID- 24766764 TI - DSM-IV alcohol dependence and marital dissolution: evidence from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - OBJECTIVE: The purpose of this study was to examine the cross-sectional and longitudinal associations among alcohol use disorder (AUD), stressful life events, and marital dissolution in a probability sample of adults. METHOD: The National Epidemiologic Survey on Alcohol and Related Conditions is a prospective, longitudinal study of a probability sample of 43,083 adults 18 years of age and older living in the United States. The interval between Wave 1 (W1) and Wave 2 (W2) was approximately 3 years. Cross-sectional analyses included 32,359 adults ages 18 and older who were ever married at W1, and longitudinal analyses included 17,192 adults who were currently married at W1 and who completed relevant W2 measures. Participants completed inhome surveys conducted with computer-assisted personal interviewing. RESULTS: Rates of lifetime marital dissolution were significantly higher among those with lifetime AUD (48.3%) than in those with no lifetime AUD (30.1%). The incidence of marital dissolution from W1 to W2 was 15.5% for those with a past-12-month AUD at W1, compared to 4.8% among those with no AUD. Proportional hazards regression analyses showed that past-12-month AUD, tobacco use disorder, other substance use disorder, stressful life events, older age at marriage, being married more than once, and being married to an alcoholic at W1 predicted greater hazards of marital dissolution at W2. These associations were not moderated by gender. CONCLUSIONS: AUD and stressful life events predict subsequent marital dissolution independently of other substance use disorders, mood and anxiety disorders, and personality disorders. Results were discussed within the framework of the Vulnerability-Stress-Adaptation model of marriage. PMID- 24766765 TI - False negatives in the assessment of lifetime alcohol use disorders: a serious but unappreciated problem. AB - OBJECTIVE: Some individuals will not meet criteria for a lifetime alcohol use disorder (AUD) at a baseline assessment but will at a follow-up measurement, but not because the disorder began after the initial evaluation. Despite several research implications, this type of unreliability of lifetime AUD estimates has not been studied extensively. The present study investigated the extent of false negatives in the assessment of lifetime AUDs using longitudinal data. METHOD: A prospective cohort of college freshmen (baseline N = 489) were assessed seven times between ages 18 and 34 years using the Diagnostic Interview Schedule. Individuals were categorized as false negatives at the index assessment using a retrospective (using Diagnostic and Statistical Manual of Mental Disorders, Third Edition [DSM-III], and DSM-IV data), a prospective (using DSM-III data only), and a combined approach (using DSM-III data only). RESULTS: For DSM-IV, of the 29 ostensible new onsets at a follow-up 5 years later (age approximately 34 years), 28 (96%) reported meeting AUD criteria before the index assessment (age approximately 29 years). For DSM-III, of the 25 ostensible new onsets, the retrospective, prospective, and combined approaches categorized 18 (72%) individuals as false negatives at the index assessment. CONCLUSIONS: These findings further demonstrate sensitivity issues with lifetime AUD assessments and call into question the validity of "onset" cases that rely on only two waves of data, especially when the follow-up assessment fails to reassess lifetime fully (i.e., across the entire drinking history). PMID- 24766766 TI - Cholesterol metabolism and serum non-cholesterol sterols: summary of 13 plant stanol ester interventions. AB - BACKGROUND: The efficacy and safety of plant stanols added to food products as serum cholesterol lowering agents have been demonstrated convincingly, but their effects on cholesterol metabolism and on serum non-cholesterol sterols is less evaluated. The aim of this study was to assess the validity of serum non cholesterol sterols and squalene as bioindices of cholesterol synthesis and absorption, and to examine how the individual serum non-cholesterol sterols respond to consumption of plant stanols. METHODS: We collected all randomized, controlled plant stanol ester (STAEST) interventions in which serum cholestanol, plant sterols campesterol and sitosterol, and at least two serum cholesterol precursors had been analysed. According to these criteria, there was a total of 13 studies (total 868 subjects without lipid-lowering medication; plant stanol doses varied from 0.8 to 8.8 g/d added in esterified form; the duration of the studies varied from 4 to 52 weeks). Serum non-cholesterol sterols were assayed with gas-liquid chromatography, cholesterol synthesis with the sterol balance technique, and fractional cholesterol absorption with the dual continuous isotope feeding method. RESULTS: The results demonstrated that during the control and the STAEST periods, the serum plant sterol/cholesterol- and the cholestanol/cholesterol-ratios reflected fractional cholesterol absorption, and the precursor sterol/cholesterol-ratios reflected cholesterol synthesis. Plant sterol levels were dose-dependently reduced by STAEST so that 2 g of plant stanols reduced serum campesterol/cholesterol-ratio on average by 32%. Serum cholestanol/cholesterol-ratio was reduced less frequently than those of the plant sterols by STAEST, and the cholesterol precursor sterol ratios did not change consistently in the individual studies emphasizing the importance of monitoring more than one surrogate serum marker. CONCLUSIONS: Serum non-cholesterol sterols are valid markers of cholesterol absorption and synthesis even during cholesterol absorption inhibition with STAEST. Serum plant sterol concentrations decrease dose-dependently in response to plant stanols suggesting that the higher the plant stanol dose, the more cholesterol absorption is inhibited and the greater the reduction in LDL cholesterol level is that can be achieved. TRIAL REGISTRATION: Clinical Trials Register # NCT00698256 [Eur J Nutr 2010, 49:111 117]. PMID- 24766767 TI - A novel self-assembled oligopeptide amphiphile for biomimetic mineralization of enamel. AB - BACKGROUND: Researchers are looking for biomimetic mineralization of ena/mel to manage dental erosion. This study evaluated biomimetic mineralization of demineralized enamel induced by a synthetic and self-assembled oligopeptide amphiphile (OPA). RESULTS: The results showed that the OPA self-assembled into nano-fibres in the presence of calcium ions and in neutral acidity. The OPA was alternately immersed in calcium chloride and sodium hypophosphate solutions to evaluate its property of mineralization. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) showed nucleation and growth of amorphous calcium phosphate along the self-assembled OPA nano-fibres when it was repetitively exposed to solutions with calcium and phosphate ions. Energy dispersive spectrometry (EDS) confirmed that these nano-particles contained calcium and phosphate. Furthermore, electron diffraction pattern suggested that the nano-particles precipitated on OPA nano-fibres were comparable to amorphous calcium phosphate. Acid-etched human enamel slices were incubated at 37 degrees C in metastable calcium phosphate solution with the OPA for biomimetic mineralization. SEM and X-ray diffraction indicated that the OPA induced the formation of hydroxyapatite crystals in organized bundles on etched enamel. TEM micrographs revealed there were 20-30 nm nano-amorphous calcium phosphate precipitates in the biomimetic mineralizing solution. The particles were found separately bound to the oligopeptide fibres. Biomimetic mineralization with or without the oligopeptide increased demineralized enamel microhardness. CONCLUSIONS: A novel OPA was successfully fabricated, which fostered the biomimetic mineralization of demineralized enamel. It is one of the primary steps towards the design and construction of novel biomaterial for future clinical therapy of dental erosion. PMID- 24766768 TI - MeCP2: the long trip from a chromatin protein to neurological disorders. AB - Since the discovery of its fundamental involvement in Rett syndrome, methyl CpG binding protein 2 (MeCP2) has been the focus of an exhaustive biochemical and functional characterization. It is now becoming apparent that the intrinsic highly disordered nature of MeCP2, which is amenable to a plethora of post translational modifications (PTMs), allows it to recognize a large number of protein interacting partners, including histones. MeCP2 is highly abundant in the brain and it is an important component of neuronal chromatin; nevertheless, the organization and implications of its involvement in terms of DNA methylation binding dependence and effects on transcription are still not well understood. Recent results have shown that MeCP2 plays an important role in brain development, aging, and in neurological disorders. PMID- 24766769 TI - Validation of the Short Form of the Brief Pain Inventory (BPI-SF) in Spanish Patients with Non-Cancer-Related Pain. AB - The Brief Pain Inventory (BPI) is a widely used pain measurement tool. There are 2 versions, the BPI Long Form (BPI-LF) and Short Form (BPI-SF), which share 2 core scales measuring pain severity and pain interference but which use different recall periods (24 hours vs. 1 week). To date, the BPI-SF has not been validated for use in Spain. This study investigated the psychometric properties of the BPI SF Spanish version and compared results on the core scales between BPI-LF and BPI SF. The data came from a 3-month observational study of 3,029 nononcologic patients managed in Spanish pain units. The BPI-SF's reliability, validity, and responsiveness were assessed. The effect of different recall periods was investigated by using intraclass correlation coefficients (ICCs) to determine the strength of correlation between BPI-LF and BPI-SF. The BPI-SF showed good reliability, with Cronbach's alphas of 0.931 for the severity and interference scales, which also discriminated well between patients reporting different levels of quality of life on EuroQol-5D dimensions (between group effect sizes [ESs] over 0.8). Substantial improvements were seen on both subscales after 3 months of treatment (ES of 1.76 for pain severity and 1.51 for pain interference). Recall period did not noticeably affect scores; ICCs (95% CI) between the long and short versions were 0.946 (0.938 to 0.954) and 0.929 (0.919 to 0.939) for the severity and interference subscales, respectively. The Spanish version of the BPI-SF is a valid and reliable instrument to measure pain severity and interference. PMID- 24766770 TI - CC-Chemokine receptor CCR7: a key molecule for lymph node metastasis in esophageal squamous cell carcinoma. AB - BACKGROUND: CC-chemokine receptor 7 (CCR7), a known lymph node homing receptor for immune cells, has been reported as a key molecule in lymph node metastasis. We hypothesized a clinicopathological correlation and functional causality between CCR7 expression and lymph node metastasis in patients with esophageal squamous cell carcinoma (ESCC). METHODS: We performed immunohistochemical analysis of 105 consecutive and 61 exclusive pathological T1 ESCC patients, followed by adhesion assay and in vivo experiment using a newly developed lymph node metastasis mouse model. The adhesive ability in response to CC-chemokine ligand 21/secondary lymphoid-tissue chemokine (CCL21/SLC) was assessed in the presence or absence of lymphatic endothelial cells and anti-CCR7 antibody. We established a heterotopic transplantation mouse model and analyzed lymph node metastasis by quantitative real-time RT-PCR. RESULTS: Positive CCR7 expression in immunohistochemistory was detected in 28 (27%) of 105 consecutive patients and 17 (28%) of 61 T1 patients, which significantly correlated with lymph node metastasis (p = 0.037 and p = 0.040, respectively) and poor five-year survival (p = 0.013 and p = 0.012, respectively). Adhesion assay revealed an enhanced adhesive ability of CCR7-expressing cells in response to CCL21/SLC, in particular, in the presence of lymphatic endothelial cells (p = 0.005). In the mouse model, lymph nodes from mice transplanted with CCR7-expressing cells showed significantly higher DNA levels at 5 weeks (p = 0.019), indicating a high metastatic potential of CCR7-expressing cells. CONCLUSION: These results demonstrated the significant clinicopathological relationship and functional causality between CCR7 expression and lymph node metastasis in ESCC patients. PMID- 24766771 TI - Aporphinoid antagonists of 5-HT2A receptors: further evaluation of ring A substituents and the size of ring C. AB - A series of ring A-modified analogs of nantenine as well as structural variants in ring C were synthesized and evaluated for antagonist activity at 5-HT2A and alpha1A receptors. Halogenation improves 5-HT2A antagonist potency in molecules containing a C1 methoxyl/C2 methoxyl or C1 methoxyl/C2 hydroxyl moiety. Bromination or iodination (but not chlorination) with the latter moiety also significantly increased alpha1A antagonist potency. Homologation or contraction of ring C adversely affected antagonist activity at both receptors, implying that a six-membered ring C motif is beneficial for high antagonist potency at both receptors. Molecular docking studies suggest that the improved antagonist activity (by virtue of improved affinity) of C3-halogenated aporphines in this study is attributable to favorable interactions with the C3 halogen and F339 and/or F340. PMID- 24766772 TI - Development and evaluation of a novel contamination device that targets multiple life-stages of Aedes aegypti. AB - BACKGROUND: The increasing global threat of Dengue demands new and easily applicable vector control methods. Ovitraps provide a low-tech and inexpensive means to combat Dengue vectors. Here we describe the development and optimization process of a novel contamination device that targets multiple life-stages of the Aedes aegypti mosquito. Special focus is directed to the diverse array of control agents deployed in this trap, covering adulticidal, larvicidal and autodissemination impacts. METHODS: Different trap prototypes and their parts are described, including a floater to contaminate alighting gravid mosquitoes. The attractiveness of the trap, different odor lures and floater design were studied using fluorescent powder adhering to mosquito legs and via choice tests. We demonstrate the mosquitocidal impacts of the control agents: a combination of the larvicide pyriproxyfen and the adulticidal fungus Beauveria bassiana. The impact of pyriproxyfen was determined in free-flight dissemination experiments. The effect on larval development inside the trap and in surrounding breeding sites was measured, as well as survival impacts on recaptured adults. RESULTS: The developmental process resulted in a design that consists of a black 3 Liter water filled container with a ring-shaped floater supporting vertically placed gauze dusted with the control agents. On average, 90% of the mosquitoes in the fluorescence experiments made contact with the gauze on the floater. Studies on attractants indicated that a yeast-containing tablet was the most attractive odor lure. Furthermore, the fungus Beauveria bassiana was able to significantly increase mortality of the free-flying adults compared to controls. Dissemination of pyriproxyfen led to >90% larval mortality in alternative breeding sites and 100% larval mortality in the trap itself, against a control mortality of around 5%. CONCLUSION: This ovitrap is a promising new tool in the battle against Dengue. It has proven to be attractive to Aedes aegypti mosquitoes and effective in contaminating these with Beauveria bassiana. Furthermore, we show that the larvicide pyriproxyfen is successfully disseminated to breeding sites close to the trap. Its low production and operating costs enable large scale deployment in Dengue-affected locations. PMID- 24766773 TI - Homologous haplotypes, expression, genetic effects and geographic distribution of the wheat yield gene TaGW2. AB - BACKGROUND: TaGW2-6A, cloned in earlier research, strongly influences wheat grain width and TKW. Here, we mainly analyzed haplotypes of TaGW2-6B and their effects on TKW and interaction with haplotypes at TaGW2-6A. RESULTS: About 2.9 kb of the promoter sequences of TaGW2-6B and TaGW2-6D were cloned in 34 bread wheat cultivars. Eleven SNPs were detected in the promoter region of TaGW2-6B, forming 4 haplotypes, but no divergence was detected in the TaGW2-6D promoter or coding region. Three molecular markers including CAPS, dCAPS and ACAS, were developed to distinguish the TaGW2-6B haplotypes. Haplotype association analysis indicated that TaGW2-6B has a stronger influence than TaGW2-6A on TKW, and Hap-6B-1 was a favored haplotype increasing grain width and weight that had undergone strong positive selection in global wheat breeding. However, clear geographic distribution differences for TaGW2-6A haplotypes were found; Hap-6A-A was favored in Chinese, Australian and Russian cultivars, whereas Hap-6A-G was preferred in European, American and CIMMYT cultivars. This difference might be caused by a flowering and maturity time difference between the two haplotypes. Hap-6A-A is the earlier type. Haplotype interaction analysis between TaGW2-6A and TaGW2-6B showed additive effects between the favored haplotypes. Hap-6A-A/Hap-6B-1 was the best combination to increase TKW. Relative expression analysis of the three TaGW2 homoeologous genes in 22 cultivars revealed that TaGW2-6A underwent the highest expression. TaGW2-6D was the least expressed during grain development and TaGW2 6B was intermediate. Diversity of the three genes was negatively correlated with their effect on TKW. CONCLUSIONS: Genetic effects, expression patterns and historic changes of haplotypes at three homoeologous genes of TaGW2 influencing yield were dissected in wheat cultivars. Strong and constant selection to favored haplotypes has been found in global wheat breeding during the past century. This research also provides a valuable case for understanding interaction of genes that control complex traits in polyploid species. PMID- 24766774 TI - Effects of intra-aortic balloon pump on cerebral blood flow during peripheral venoarterial extracorporeal membrane oxygenation support. AB - BACKGROUND: The addition of an intra-aortic balloon pump (IABP) during peripheral venoarterial extracorporeal membrane oxygenation (VA ECMO) support has been shown to improve coronary bypass graft flows and cardiac function in refractory cardiogenic shock after cardiac surgery. The purpose of this study was to evaluate the impact of additional IABP support on the cerebral blood flow (CBF) in patients with peripheral VA ECMO following cardiac procedures. METHODS: Twelve patients (mean age 60.40+/-9.80 years) received VA ECMO combined with IABP support for postcardiotomy cardiogenic shock after coronary artery bypass grafting. The mean CBF in the bilateral middle cerebral arteries was measured with and without IABP counterpulsation by transcranial Doppler. The patients provided their control values. The mean CBF data were divided into two groups (pulsatile pressure greater than 10 mmHg, P group; pulsatile pressure less than 10 mmHg, N group) based on whether the patients experienced cardiac stun. The mean cerebral blood flow in VA ECMO (IABP turned off) alone and VA ECMO with IABP support were compared using the paired t test. RESULTS: All of the patients were successfully weaned from VA ECMO, and eight patients survived to discharge. The addition of IABP to VA ECMO did not change the mean CBF (251.47+/-79.28 ml/min vs. 251.30+/-79.47 ml/min, P=0.96). The mean CBF was higher in VA ECMO alone than in VA ECMO combined with IABP support in the N group (257.68+/-97.21 ml/min vs. 239.47+/-95.60, P=0.00). The addition of IABP to VA ECMO support increased the mean CBF values significantly compared with VA ECMO alone (261.68+/-82.45 ml/min vs. 244.43+/-45.85 ml/min, P=0.00) in the P group. CONCLUSION: These results demonstrate that an IABP significantly changes the CBF during peripheral VA ECMO, depending on the antegrade blood flow by spontaneous cardiac function. The addition of an IABP to VA ECMO support decreased the CBF during cardiac stun, and it increased CBF without cardiac stun. PMID- 24766775 TI - Effects of glucosamine and risedronate alone or in combination in an experimental rabbit model of osteoarthritis. AB - BACKGROUND: The osteoarthritis (OA) treatment in humans and in animals is a major orthopaedic challenge because there is not an ideal drug for preserving the joint structure and function. The aim of this study was to assess the effects of the treatment with oral glucosamine and risedronate alone or in combination on articular cartilage, synovial membrane and subchondral bone in an experimental rabbit model of OA. Osteoarthritis was surgically induced on one knee of 32 New Zealand White rabbits using the contralateral as healthy controls. Three weeks later treatments were started and lasted 8 weeks. Animal were divided in four groups of oral treatment: the first group received only saline, the second 21.5 mg/kg/day of glucosamine sulfate, the third 0.07 mg/kg/day of risedronate; and the fourth group both drugs simultaneously at the same dosages. Following sacrifice femurs were removed and osteochondral cylinders and synovial membrane were obtained for its histological and micro-CT evaluation. RESULTS: Sample analysis revealed that the model induced osteoarthritic changes in operated knees. OA placebo group showed a significant increase in cartilage thickness respect to the control and inflammatory changes in synovial membrane; whereas subchondral bone structure and volumetric bone mineral density remained unchanged. All the treated animals showed an improvement of the cartilage swelling independent of the drug used. Treatment with glucosamine alone seemed to have no effect in the progression of cartilage pathology while risedronate treatment had better results in superficial fibrillation and in resolving the inflammatory changes of the tissues, as well as modifying the orientation of trabecular lattice. The combination of both compounds seemed to have additive effects showing better results than those treated with only one drug. CONCLUSIONS: The results of this animal study suggested that glucosamine sulfate and risedronate treatment alone or in combination may be able to stop cartilage swelling. The risedronate treatment could partially stop the fibrillation and the inflammation of synovial membrane as well as modify the orientation of trabeculae in healthy and in osteoarthritic knees. PMID- 24766776 TI - Impact of admission triglyceride for early outcome in diabetic patients with stable coronary artery disease. AB - BACKGROUND: The role of triglyceride (TG) in predicting the outcomes in diabetic patients with coronary artery disease (CAD) has not been well investigated. METHODS: A total of 329 cases with stable angina pectoris (SAP) were prospectively enrolled and followed up for an average of 12 months. They were classified into the two groups according to the cut-off values of predicting early outcome of fasting TG level (low group <1.2 mmol/L, n = 103; High group >=1.2 mmol/L, n = 226). The relationship between the TG levels and early outcomes were evaluated. RESULTS: High TG group showed severer lipid profile and elevated inflammatory markers. During an average of 12-month follow-up, 47 out of 329 patients suffered from pre-specified outcomes. Area under the receivers operating characteristic curve suggested that TG, similar to serum Hemoglobin A1C (HbA1C), was a significant predictor of early outcome for diabetic patients with SAP (P = 0.002). In Cox regression models, after adjusted age, gender, body mass index, other lipid parameters, fasting blood glucose, high sensitivity C-reactive protein, neutrophil count and HbA1C, TG remained as an independent predictor of adverse prognosis. CONCLUSIONS: High level of fasting TG (>=1.2 mmol/L) was an independent predictor for early outcome of diabetic patients with SAP as like as HBA1c and number of affected coronary arteries in the era of revascularization and statin therapeutics. PMID- 24766777 TI - ShrinkBayes: a versatile R-package for analysis of count-based sequencing data in complex study designs. AB - BACKGROUND: Complex designs are common in (observational) clinical studies. Sequencing data for such studies are produced more and more often, implying challenges for the analysis, such as excess of zeros, presence of random effects and multi-parameter inference. Moreover, when sample sizes are small, inference is likely to be too liberal when, in a Bayesian setting, applying a non appropriate prior or to lack power when not carefully borrowing information across features. RESULTS: We show on microRNA sequencing data from a clinical cancer study how our software ShrinkBayes tackles the aforementioned challenges. In addition, we illustrate its comparatively good performance on multi-parameter inference for groups using a data-based simulation. Finally, in the small sample size setting, we demonstrate its high power and improved FDR estimation by use of Gaussian mixture priors that include a point mass. CONCLUSION: ShrinkBayes is a versatile software package for the analysis of count-based sequencing data, which is particularly useful for studies with small sample sizes or complex designs. PMID- 24766778 TI - Production of recombinant human annexin V by fed-batch cultivation. AB - BACKGROUND: Annexin V, a 35.8 kDa intracellular protein, is a Ca+2-dependent phospholipid binding protein with high affinity to phosphatidylserine (PS), which is a well-known hallmark of apoptosis. Annexin V is a sensitive probe for PS exposure upon the cell membrane, and used for detection of apoptotic cells both in vivo and in vitro. Large-scale production of recombinant human annexin V is worth optimization, because of its wide use in nuclear medicine, radiolabeled with (99m)Tc, for the evaluation of cancer chemotherapy treatments, and its use in identification of apoptotic cells in histologic studies. Here we describe the high-yield production of a tag-free version of human annexin V recombinant protein by linear fed-batch cultivation in a bioreactor. RESULTS: We cloned the human ANXA5 coding sequence into the pET-30a (+) expression vector and expressed rhANXA5 in batch and fed-batch cultures. Using E. coli BL21 (DE3) in a semi defined medium at 37 degrees C, pH 7 in fed-batch cultures, we obtained a 45-fold increase in biomass production, respective to shaker cultivations. We developed a single-step protocol for rhANXA5 purification using a strong anion-exchange column (MonoQ HR16/10). Using these procedures, we obtained 28.5 mg of homogeneous, nontagged and biologically functional human annexin V recombinant protein from 3 g wet weight of bacterial cells from bioreactor cultures. The identity and molecular mass of rhANXA5 was confirmed by mass spectrometry. Moreover, the purified rhANXA5 protein was functionally evaluated in a FITC annexin V binding experiment and the results demonstrated that rhANXA5 detected apoptotic cells similarly to a commercial kit. CONCLUSIONS: We describe a new fed batch method to produce recombinant human annexin V in large scale, which may expand the commercial utilities for rhANXAV to applications such as in vivo imaging studies. PMID- 24766779 TI - Prognostic significance of tricuspid annular displacement in normotensive patients with acute symptomatic pulmonary embolism. AB - BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) is an emerging prognostic indicator in patients with acute symptomatic pulmonary embolism (PE). METHODS AND RESULTS: We prospectively examined 782 normotensive patients with PE who underwent echocardiography in a multicenter study. As compared with patients with a TAPSE of > 1.6 cm, those with a TAPSE of <= 1.6 cm had increased systolic pulmonary artery pressure (53.7 +/- 16.7 mmHg vs. 40.0 +/- 15.5 mmHg, P < 0.001), right ventricle (RV) end-diastolic diameter (3.5 +/- 0.8 cm vs. 3.0 +/- 0.6 cm, P < 0.001), and RV to left ventricle end-diastolic diameter ratio (1.0 +/- 0.3 vs. 0.8 +/- 0.2, P < 0.001), and a higher prevalence of RV free wall hypokinesis (68% vs. 11%, P < 0.001). Patients with a TAPSE of <= 1.6 cm at the time of PE diagnosis were significantly more likely to die from any cause (hazard ratio [HR] 2.3; 95% confidence interval [CI] 1.2-4.7; P = 0.02) and from PE (HR 4.4; 95% CI 1.3-15.3; P = 0.02) during follow-up. In an external validation cohort of 1326 patients with acute PE enrolled in the international multicenter Registro Informatizado de la Enfermedad TromboEmbolica, a TAPSE of <= 1.6 cm remained a significant predictor of all-cause mortality (HR 2.1; 95% CI 1.3-3.2; P = 0.001) and PE-specific mortality (HR 2.5; 95% CI 1.2-5.2; P = 0.01). CONCLUSIONS: In normotensive patients with PE, TAPSE reflects right ventricular function. For these patients, TAPSE is independently predictive of survival. PMID- 24766780 TI - Combined 1H-NMR and molecular dynamics studies on conformational behavior of a model heptapeptide, GRGDSPC. AB - Among various strategies, the de novo design and in silico approaches are being used to develop the short peptides, models of modified peptides, and mimetics as clinically useful drugs with improved stability and bioavailability. The resulting models will help to isolate the factors behind the folded structure formation and contribute useful information about de novo peptide design. The combined (1)H-NMR spectroscopic and molecular dynamics methods were used to investigate the conformational behavior of an Arg-Gly-Asp (RGD)-containing peptide, GRGDSPC, the cell-binding heptapeptide of extracellular matrix protein, fibronectin. The formation of two fused weak beta-turns of type II (HB, 4->1) and type II' (HB, 7->4) from simulation studies has been consistent with NMR data. The sustainable 'S'-shaped molecular structure (which remained unchanged during the entire simulation) and the conformational transitions due to interconversions between multiple turns initiated at Asp(4), Ser(5), and Cys(7) imply that the peptide is flexible in nature. Thus, the model of 'S'-shaped structure with flexible multiple turns for GRGDSPC peptide may provide the structural rationale for antagonistic properties of this heptapeptide toward the treatment of integrin mediated cellular abnormal behaviors such as thrombosis and metastasis. PMID- 24766781 TI - A role for PAX8 in the tumorigenic phenotype of ovarian cancer cells. AB - BACKGROUND: PAX8 is a member of the paired box (Pax) multigene family of transcription factors, which are involved in the developmental and tissue specific control of the expression of several genes in both vertebrates and invertebrates. Previously, several studies reported that PAX8 is expressed at high levels in specific types of tumors. In particular, PAX8 has been recently reported to be conspicuously expressed in human ovarian cancer, but the functional role of PAX8 in the carcinogenesis of this type of tumor has not been addressed. In this study, we investigated the contribution of PAX8 in ovarian cancer progression. METHODS: Stable PAX8 depleted ovarian cancer cells were generated using short hairpin RNA (shRNA) constructs. PAX8 mRNA and protein were detected by RT-PCR, immunoblot and immunofluorescence. Cell proliferation, motility and invasion potential of PAX8 silenced cells were analyzed by means of growth curves, wound healing and Matrigel assays. In addition, PAX8 knockdown and control cells were injected into nude mice for xenograft tumorigenicity assays. Finally, qPCR was used to detect the expression levels of EMT markers in PAX8 overexpressing and control cells. RESULTS: Here, we show that PAX8 plays a critical role in the migration, invasion and tumorigenic ability of ovarian cancer cells. Our results show that RNA interference-mediated knockdown of PAX8 expression in SKOV-3 ovarian cancer cells produces a significant reduction of cell proliferation, migration ability and invasion activity compared with control parental SKOV-3 cells. Moreover, PAX8 silencing strongly suppresses anchorage independent growth in vitro. Notably, tumorigenesis in vivo in a nude mouse xenograft model is also significantly inhibited. CONCLUSIONS: Overall, our results indicate that PAX8 plays an important role in the tumorigenic phenotype of ovarian cancer cells and identifies PAX8 as a potential new target for the treatment of ovarian cancer. PMID- 24766783 TI - Implementation of surveillance of invasive mosquitoes in Belgium according to the ECDC guidelines. AB - BACKGROUND: In 2012, the new guidelines for the surveillance of IMS in Europe, produced by the European Centre for Disease Prevention and Control (ECDC), were tested in Belgium. This study aimed at (1) testing the usefulness and applicability in the field of the ECDC guidelines for the surveillance of IMS in Europe and (2) surveying IMS throughout Belgium. METHODS: First, the scenarios, which Belgium is facing, were identified according to the ECDC guidelines. Second, the surveillance strategy and the methods were identified based on the guidelines and adjusted to the Belgium context. Two areas colonised by IMS and 20 potential points of entry (PoE) were selected. Mosquito Magnet Liberty Plus (CO2 baited) traps (23) and oviposition traps (147) were set-up, and larval sampling was performed monthly or bi-monthly from July till October 2012. Finally, the costs and workload of the surveillance activities were compared to the estimates provided by the ECDC guidelines. RESULTS: Surveillance at 20 potential PoE (complying with scenario 1) revealed that no new IMS were established in Belgium. Surveillance at two sites colonised by IMS (scenario 2) indicated that although control measures have drastically reduced the Ae. j. japonicus population this species is still present. Furthermore, Ae. koreicus is permanently established. For both scenarios, the problems encountered are discussed and recommendations are given. In addition, the actual workload was lower than the estimated workload, while the actual costs were higher than the estimated ones. CONCLUSIONS: The ECDC guidelines are helpful, applicable and efficient to implement surveillance of IMS in Belgium. Recommendations were customised to the local context (political demands, salary and investment costs, and existing expertise). The workload and costs related to the preparatory phase (i.e., planning, contacts with the PoE, writing a protocol) were found to be missing in the cost evaluation suggested in the guidelines. Updates on the occurrence of IMS in Belgium and the related risk for disease agents they can transmit will only be available once a structured and permanent surveillance system is implemented. PMID- 24766784 TI - Hearing screening using auditory steady state responses obtained by simultaneous air- and bone-conduction stimuli. AB - INTRODUCTION AND OBJECTIVES: Minimising false positives rates is an important goal of universal newborn hearing screening programmes. An adequate way for reaching that goal could be differentiating between transient conductive hearing losses (false positives) and permanent sensorineural hearing impairments (true positives) by means of a methodology that studies electrophysiological responses obtained using both air- and bone-conduction stimuli. Our objective was to evaluate the efficiency of an automated hearing screening test based on auditory steady state responses obtained using simultaneous air- and bone-conduction stimuli. METHODS: A sample of 80 high risk babies lees than 2 months of born were screened using the automatic screening test. A confirmatory clinical and electrophysiological evaluation was used as the gold standard. RESULTS: The estimated diagnostic efficiency of this screening test was equivalent (100% sensitivity and 97.7% specificity) to the efficiency reported for otoacoustic emissions and automated auditory brainstem responses. The introduction of bone conduction in the screening reduced the false positive rate from 13.3% to 2.2%. The test duration was 5.3 (+/- 1.9)min. In 34% of babies only one repetition of the test was needed to raising the result. CONCLUSIONS: The screening test performed quite well in this initial clinical trial, differentiating transient conductive hearing losses from permanent neurosensory impairments and improving the diagnostic efficiency of auditory steady state responses. PMID- 24766785 TI - Case study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate. AB - BACKGROUND: Guanidinoacetate methyltransferase deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. We report a new patient with guanidinoacetate methyltransferase deficiency and her >3-year treatment outcome. PATIENT: This is a 6-year-old girl who was diagnosed with guanidinoacetate methyltransferase deficiency at the age of 28 months. She presented with moderate global developmental delay, one afebrile seizure, and hypotonia between 6 and 18 months of life. She was treated with creatine and ornithine supplementation and a strict arginine-restricted diet for 42 months. RESULTS: Mutation analysis (compound heterozygous mutations, a known c.327G>A and a novel c.58dupT [p.Trp20LeufsX65]) and enzyme studies in primary fibroblasts confirmed the diagnosis. After 33 months of therapy, her cerebrospinal fluid guanidinoacetate level decreased from 47 to 5.3 times the normal level. Brain creatine by proton magnetic resonance spectroscopy increased by >75% but did not normalize in the basal ganglia and white matter after 3 years of therapy. Additional treatment with sodium benzoate for 17 months did not further improve plasma guanidinoacetate levels, which questions the relevance of this therapy. CONCLUSION: Treatment did not improve moderate intellectual disability or normalize guanidinoacetate accumulation in the central nervous system. PMID- 24766786 TI - Carbon and fullerene nanomaterials in plant system. AB - Both the functionalized and non functionalized carbon nanomaterials influence fruit and crop production in edible plants and vegetables. The fullerene, C60 and carbon nanotubes have been shown to increase the water retaining capacity, biomass and fruit yield in plants up to ~118% which is a remarkable achievement of nanotechnology in recent years. The fullerene treated bitter melon seeds also increase the phytomedicine contents such as cucurbitacin-B (74%), lycopene (82%), charantin (20%) and insulin (91%). Since as little as 50 MUg mL-1 of carbon nanotubes increase the tomato production by about 200%, they may be exploited to enhance the agriculture production in future. It has been observed that, in certain cases, non functionalized multi-wall carbon nanotubes are toxic to both plants and animals but the toxicity can be drastically reduced if they are functionalized. PMID- 24766788 TI - Hemiarthroplasty of the elbow: the effect of implant size on kinematics and stability. AB - BACKGROUND: Distal humeral hemiarthroplasty is a treatment option for distal humeral fractures, nonunions, and avascular necrosis. The biomechanical effects, however, have not been reported. The purpose of this in vitro study was to quantify the effects of hemiarthroplasty and implant size on elbow joint kinematics. METHODS: Eight fresh-frozen cadaveric arms were mounted in an in vitro motion simulator. An electromagnetic tracking system quantified elbow kinematics. A custom distal humeral stem was implanted by use of navigation, and 3 humeral articular spools were evaluated: optimally sized, undersized, and oversized. Statistical analysis was performed with repeated-measures analysis of variance. RESULTS: Distal humeral hemiarthroplasty altered elbow kinematics, regardless of implant size. In the valgus position, the optimally sized implant resulted in a mean increase in valgus angulation of 3 degrees +/- 1 degrees (P = .003) as compared with the osteotomy control. In the varus position, the optimal and undersized implants both resulted in significant increases in varus angulation: 3 degrees +/- 1 degrees (P = .01) and 3 degrees +/- 1 degrees (P = .001), respectively. The undersized implant had the greatest alteration in kinematics, whereas the oversized implant best reproduced native elbow kinematics. CONCLUSION: This study showed a small but significant alteration in elbow joint kinematics with placement of a distal humeral hemiarthroplasty implant, regardless of implant size. This could be due to errors in implant positioning and/or differences in the shape of the humeral implant relative to the native elbow. These changes in joint tracking may cause abnormal articular contact and loading, which may result in pain and cartilage degeneration over time. PMID- 24766787 TI - Circulating CD36 and oxLDL levels are associated with cardiovascular risk factors in young subjects. AB - BACKGROUND: Cardiovascular disease (CVD) results from a combination of abnormalities in lipoprotein metabolism, oxidative stress, chronic inflammation, and susceptibility to thrombosis. Atherosclerosis is the major cause of CVD. CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and promote endocytosis of oxidized low-density lipoprotein (oxLDL) and is implicated in the formation of foam cells. The purpose of this research was to evaluate whether there is an association of sCD36 and oxLDL levels with cardiovascular risk factors in young subjects. METHODS: A total of 188 subjects, 18 to 25 years old, 133 normal-weight and 55 obese subjects from the state of Guerrero, Mexico were recruited in the study. The lipid profile and glucose levels were measured by enzymatic colorimetric assays. Enzyme-linked immunosorbant assays (ELISA) for oxLDL and sCD36 were performed. Statistical analyses of data were performed with Wilcoxon- Mann Whitney and chi-square tests as well as with multinomial regression. RESULTS: TC, LDL-C, TG, oxLDL and sCD36 levels were higher in obese subjects than in normal-weight controls, as well as, monocyte and platelet counts (P < 0.05). Obese subjects had 5.8 times higher risk of sCD36 in the third tertil (>97.8 ng/mL) than normal-weight controls (P = 0.014), and 7.4 times higher risk of oxLDL levels in third tertile (>48 U/L) than control group. The subjects with hypercholesterolemia, hypertriglyceridemia, fasting impaired LDL-C had a higher risk of oxLDL levels in the third tertile (>48 U/L) than the control group (P < 0.05). CONCLUSIONS: Circulating CD36 and oxLDL levels are associated with cardiovascular risk factors in young subjects and may be potential early markers for cardiovascular disease (CVD). PMID- 24766789 TI - The anatomy of the coracohumeral ligament and its relation to the subscapularis muscle. AB - BACKGROUND: Only a few reports describe the extension of the coracohumeral ligament to the subscapularis muscle. The purposes of this study were to histo anatomically examine the structure between the ligament and subscapularis and to discuss the function of the ligament. METHODS: Nineteen intact embalmed shoulders were used. In 9 shoulders, the expansion of the ligament was anatomically observed, and in 6 of these 9, the muscular tissue of the supraspinatus and subscapularis was removed to carefully examine the attachments to the tendons of these muscles. Five shoulders were frozen and sagittally sectioned into 3-mm thick slices. After observation, histologic analysis was performed on 3 of these shoulders. In the remaining 5 shoulders, the coracoid process was harvested to investigate the ligament origin. RESULTS: The coracohumeral ligament originated from the horizontal limb and base of the coracoid process and enveloped the cranial part of the subscapularis muscle. The superficial layer of the ligament covered a broad area of the anterior surface of the muscle. Laterally, it protruded between the long head of the biceps tendon and subscapularis and attached to the tendinous floor, which extended from the subscapularis insertion. Histologically, the ligament consisted of irregular and sparse fibers abundant in type III collagen. CONCLUSION: The coracohumeral ligament envelops the whole subscapularis muscle and insertion and seems to function as a kind of holder for the subscapularis and supraspinatus muscles. The ligament is composed of irregular and sparse fibers and contains relatively rich type III collagen, which would suggest flexibility. PMID- 24766790 TI - Chronic Essex-Lopresti injuries: an alternative treatment method. AB - BACKGROUND: Currently, no technique has met general acceptance for the restoration of forearm longitudinal stability in chronic Essex-Lopresti injuries. The purpose of this study is to present an alternative treatment method for chronic Essex-Lopresti lesions by radial head replacement and ulnar shortening osteotomy. METHODS: Seven patients with a mean age of 42.4 years were included in the study. Five patients had a staged approach, and 2 underwent both procedures simultaneously. The pain level was assessed with the use of a visual analog scale. Elbow, forearm, and wrist range of motion was evaluated. The Mayo Elbow Performance Score and Mayo Wrist Score were used to assess the postoperative outcomes. RESULTS: The mean follow-up time was 33 months. The mean pain level was reduced from 8.4 points preoperatively to 3.3 points postoperatively (P < .05). The elbow arc of motion was increased on average from 79 degrees preoperatively to 121 degrees postoperatively (P < .05). Forearm rotation improved from 76 degrees preoperatively to 119 degrees postoperatively (P < .05). The wrist arc of motion improved from 94 degrees preoperatively to 114 degrees postoperatively (P < .05). The mean postoperative Mayo Elbow Performance Score and Mayo Wrist Score were 82 points and 71 points, respectively. The mean ulnar variance was reduced from +8 mm to +3.5 mm postoperatively. CONCLUSION: This study shows that radial head replacement in combination with ulnar shortening osteotomy can be used as an alternative reconstructive procedure in the case of a complex chronic Essex-Lopresti injury. This combination of known procedures yields predictable and satisfactory outcomes and a low complication rate. LEVEL OF EVIDENCE: Level IV, case series, treatment study. PMID- 24766791 TI - Humeral windows and longitudinal splits for component removal in revision shoulder arthroplasty. AB - BACKGROUND: Removal of a humeral component during revision shoulder arthroplasty can be difficult. If the component cannot be extracted from above, an alternative approach may compromise bone integrity. Two potential solutions are a humeral window and a longitudinal split. This review was performed to determine complications and outcomes associated with these osteotomies during revision arthroplasty. METHODS: We reviewed records of 427 patients undergoing revision shoulder arthroplasty, identifying those requiring a window or longitudinal split. Outcomes were intraoperative and postoperative complications, rate of healing, and security of implant fixation. RESULTS: Twenty-six patients underwent creation of a window. Six intraoperative fractures were documented: 5 in greater tuberosity and 1 in humeral shaft. At radiographic follow-up, 23 of 26 windows healed; 2 patients had limited follow-up, and 1 did not have follow-up at our institution. Nineteen patients underwent longitudinal osteotomy. One had intraoperative fracture in greater tuberosity. At radiographic follow-up, 17 of 19 longitudinal splits healed; 1 had limited radiographic follow-up, and 1 did not have follow-up at our institution. Three patients underwent formation of both window and longitudinal osteotomy. At radiographic follow-up, all shoulders healed, and there were no intraoperative or postoperative fractures or malunions. CONCLUSIONS: In both groups, there were no cases of malunion or clinical loosening. These data suggest that windows and longitudinal splits facilitate controlled removal of well-fixed components with high rate of union and low rate of intraoperative or postoperative sequelae. PMID- 24766792 TI - The biomechanical effects of polytetrafluoroethylene suture augmentations in lateral-row rotator cuff repairs in an ovine model. AB - BACKGROUND: This study investigated the biomechanical effects of expanded polytetrafluoroethylene (ePTFE) suture augmentation patches in rotator cuff repair constructs. METHODS: The infraspinatus tendon in 24 cadaveric ovine shoulders was repaired using an inverted horizontal mattress suture with 2 knotless bone anchors (ArthroCare, Austin, TX, USA) in a lateral-row configuration. Four different repair groups (6 per group) were created: (1) standard repair using inverted horizontal mattress sutures, (2) repair with ePTFE suture augmentations on the bursal side of the tendon, (3) repair with ePTFE suture augmentations on the articular side, and, (4) repair with ePTFE suture augmentations on both sides of the tendon. Footprint contact pressure, stiffness, and the load to failure of the repair constructs were measured. RESULTS: Repairs with ePTFE suture augmentations on the bursal side exerted significantly more footprint contact pressure (0.40 +/- 0.01 MPa) than those on the articular side (0.34 +/- 0.02 MPa, P = .04) and those on both sides (0.33 +/- 0.02 MPa, P = .01). At 15 degrees of abduction, ePTFE-augmented repairs on the bursal side had higher footprint contact pressure (0.26 +/- 0.03 MPa) compared with standard repairs (0.15 +/- 0.02 MPa, P = .01) and with ePTFE-augmented repairs on the articular side (0.18 +/- 0.02 MPa, P = .03). The ePTFE-augmented repairs on the bursal side demonstrated significantly higher failure loads (178 +/- 18 N) than standard repairs (120 +/- 17 N, P = .04). CONCLUSIONS: Inverted horizontal mattress sutures augmented with ePTFE patches on the bursal side of the tendon enhanced footprint contact pressures and the ultimate load to failure of lateral row rotator cuff repairs in an ovine model. PMID- 24766793 TI - Diagnostic accuracy of noncontrast MRI for detection of glenohumeral cartilage lesions: a prospective comparison to arthroscopy. AB - BACKGROUND: The purpose of this study was to determine the prevalence of glenohumeral articular cartilage lesions in patients with rotator cuff tendinopathy and to assess the accuracy of noncontrast magnetic resonance imaging (MRI) in detecting these defects compared with the "gold standard" of arthroscopy. METHODS: Noncontrast MRI studies obtained in 84 consecutive patients undergoing shoulder arthroscopy for rotator cuff tendinopathy (mean age, 54.8 years; range, 17-82 years) were prospectively evaluated for glenohumeral cartilage lesions. Two fellowship-trained, experienced musculoskeletal radiologists were blinded from the arthroscopic findings and independently evaluated the glenoid and humeral head cartilage on 2 separate occasions. RESULTS: At arthroscopy, cartilage lesions of the humeral head were detected in 23 patients (frequency, 27.4%), and glenoid cartilage lesions were found in 20 patients (frequency, 23.8%). For detection of a humeral lesion on MRI, the radiologists' combined accuracy was 78%, sensitivity was 43%, and specificity was 91%. The combined accuracy for detection of glenoid lesions on MRI was 84%, sensitivity was 53%, and specificity was 93%. Combining the readers, low-grade lesions (International Cartilage Repair Society grades 1 and 2) of the glenoid and humerus were read as negative on MRI in 63% and 86% of cases, respectively. CONCLUSION: Overall accuracy of noncontrast MRI for detection of glenohumeral articular cartilage lesions is good; however, interpretation is reader dependent, and accuracy is significantly reduced for detection of low-grade lesions. On the basis of these findings, we recommend that patients with rotator cuff tendinopathy undergoing arthroscopy be informed that the presence and severity of cartilage lesions may be underestimated on MRI. PMID- 24766794 TI - Implant survival after total elbow arthroplasty: a retrospective study of 324 procedures performed from 1980 to 2008. AB - BACKGROUND: Total elbow arthroplasty (TEA) is an established treatment for late stage arthritis of the elbow. Indications have expanded to osteoarthritis and nonunion in distal humeral fractures. Information on implant survival and risk factors for revision is still sparse. The aim of this study was to evaluate implant survival and risk factors for revision of TEAs inserted in patients in the eastern part of Denmark in the period from 1980 until 2008. MATERIAL AND METHODS: The Danish National Patient Register provided personal identification numbers for patients who underwent TEA procedures from 1980 until 2008. On the basis of a review of medical reports and linkage to the National Patient Register, we calculated revision rates and evaluated potential risk factors for revision, including, age, sex, period, indication for TEA, and implant design. RESULTS: We evaluated 324 primary TEA procedures in 234 patients at a mean follow up of 8.7 years (range, 0-27 years). The overall 5-year survival was 90% (95% confidence interval [CI], 88%-94%), and 10-year survival was 81% (95% CI, 76% 86%). TEAs performed with the unlinked design had a relative risk of revision of 1.9 (95% CI, 1.1-3.2) compared with the linked design. Fracture sequelae was associated with a relative risk of revision of 1.9 (95% CI, 1.05-3.45). CONCLUSIONS: We found acceptable implant survival rates after 5 and 10 years, with a higher revision rate for the unlinked design and primary TEA due to fracture sequelae. Patient-related outcome measures should be included in future studies for further elaboration of the outcomes after TEA. LEVEL OF EVIDENCE: Level III, Retrospective cohort design, treatment study. PMID- 24766795 TI - A simplified evaluation system of surface-related lung lesions of pigs for official meat inspection under industrial slaughter conditions in Germany. AB - BACKGROUND: European and national administrative legislation require objective evaluation systems for organ lesions at pig slaughter. These results can be used as basis for herd health improvement programs by farmers and their consulting veterinarians. Various studies have shown that the current evaluation and recording of lesions by authorized meat inspectors are not reliable and produce significant inter-rater disagreement especially for lung lesions in pigs. The objectives of this study were to increase the usability of official meat inspection data by a developed and validated scheme and to analyze potential improvements in the reliability of the proposed system under industrialized slaughter conditions. RESULTS: A simplified evaluation scheme for surface-related lung lesions was developed based on morphometric evaluations of unaffected lungs with quantitative relationships of each lobe to the whole lung ("Rule of Tens"). Furthermore, a theoretical as well as a hands-on training program for meat inspectors was developed and applied. Based on 5,183 lungs, the authors established a baseline of the inter-rater reliability of current routine assessments of lung lesions as documented by meat inspectors compared with the assessments of an independent veterinarian using the developed simplified evaluation scheme. Most frequent inter-rater disagreements greater than 75% were found for moderate pneumonia. Sources of the deviations most frequently included misinterpretations of technical artifacts, which were erroneously assessed by the meat inspectors as pneumonic lung lesions. Results of the post-training investigation based on 4,646 lungs showed a significantly improved reliability of lung lesion evaluation and the inter-rater agreement increased in all respects. Especially the disagreement of recording moderate cases of pneumonia decreased in total to 15% deviations from reference. CONCLUSIONS: The presented simplified lung evaluation scheme showed its capability to standardize the evaluation of lung lesions according to administrative legislation under industrialial slaughter conditions. The reliability of official meat inspections can be significantly increased with the help of the presented scheme to assess surface related lung lesions of slaughter pigs. Continuous standardization and optimization can be achieved by personalized training programs in the framework of quality assurance systems for meat inspectors. PMID- 24766796 TI - Scientists' sense making when hypothesizing about disease mechanisms from expression data and their needs for visualization support. AB - A common class of biomedical analysis is to explore expression data from high throughput experiments for the purpose of uncovering functional relationships that can lead to a hypothesis about mechanisms of a disease. We call this analysis expression driven, -omics hypothesizing. In it, scientists use interactive data visualizations and read deeply in the research literature. Little is known, however, about the actual flow of reasoning and behaviors (sense making) that scientists enact in this analysis, end-to-end. Understanding this flow is important because if bioinformatics tools are to be truly useful they must support it. Sense making models of visual analytics in other domains have been developed and used to inform the design of useful and usable tools. We believe they would be helpful in bioinformatics. To characterize the sense making involved in expression-driven, -omics hypothesizing, we conducted an in-depth observational study of one scientist as she engaged in this analysis over six months. From findings, we abstracted a preliminary sense making model. Here we describe its stages and suggest guidelines for developing visualization tools that we derived from this case. A single case cannot be generalized. But we offer our findings, sense making model and case-based tool guidelines as a first step toward increasing interest and further research in the bioinformatics field on scientists' analytical workflows and their implications for tool design. PMID- 24766797 TI - Environmental transmission of violent criminal behavior in siblings: a Swedish national study. AB - BACKGROUND. Violent criminal behaviour (VCB) runs strongly in families partly because of shared environmental factors. Can we clarify the environmental processes that contribute to similarity of risk for VCB in siblings? METHOD: We assessed VCB from the Swedish National Crime Register for the years 1973-2011 in siblings born 1950-1991. We examined by conditional logistic and Cox proportional hazard regression, respectively, whether resemblance for VCB in sibling pairs was influenced by their age difference and whether VCB was more strongly 'transmitted' from older->younger versus younger->older siblings. RESULTS: In our best-fit logistic model, for each year of age difference in full sibling pairs, the risk for VCB in the sibling of a case versus control proband declined by 2.6% [95% confidence interval (CI) 2.2-3.0]. In our best-fit Cox model, the hazard rate for VCB in a sibling when the affected proband was older versus younger was 1.4, 2.1 and 2.9 respectively for a 1-, 5- and 10-year difference in siblings. CONCLUSIONS: Controlling for genetic effects by examining only full siblings, sibling resemblance for risk for VCB was significantly greater in pairs closer versus more distant in age. Older siblings more strongly transmitted risk for VCB to their younger siblings than vice versa. These results strongly support the importance of familial-environmental influences on VCB and provide some insight into the possible mechanisms at work. PMID- 24766798 TI - A novel oxygen carrier "YQ23" suppresses the liver tumor metastasis by decreasing circulating endothelial progenitor cells and regulatory T cells. AB - BACKGROUND: Surgical therapies are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor metastasis after liver surgery remains a severe problem. We aim to investigate the roles and the underlying mechanism of YQ23, stabilized non-polymeric diaspirin cross-linked tetrameric hemoglobin, in liver tumor metastasis after major hepatectomy and partial hepatic ischemia reperfusion (I/R) injury. METHODS: An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Major hepatectomy for tumor-bearing lobe and partial hepatic I/R injury were performed at two weeks after orthotopic liver tumor implantation. YQ23 (0.2 g/kg) was administered at 1 hour before ischemia and immediately after reperfusion. Blood samples were collected at day 0, 1, 7, 14, 21 and 28 for detection of circulating endothelial progenitor cells (EPCs) and regulatory T cells (Tregs). RESULTS: Our results showed that YQ23 treatment effectively inhibited intrahepatic and lung metastases together with less tumor angiogenesis at 4 weeks after major hepatectomy and partial hepatic I/R injury. The levels of circulating EPCs and Tregs were significantly decreased in YQ23 treatment group. Furthermore, YQ23 treatment also increased liver tissue oxygenation during hepatic I/R injury. Up-regulation of HO1 and down-regulation of CXCR3, TNF-alpha and IL6 were detected after YQ23 treatment. CONCLUSIONS: YQ23 treatment suppressed liver tumor metastasis after major hepatectomy and partial hepatic I/R injury in a rat liver tumor model through increasing liver oxygen and reducing the populations of circulating EPCs and Tregs. PMID- 24766799 TI - Connect four with glioblastoma stem cell factors. AB - Hierarchical cell state models, wherein a few stem-like tumor-propagating cells repopulate the tumor after therapy, are often invoked in cancer. Suva et al. demonstrate a plastic developmental hierarchy in glioma cell populations by characterizing the epigenetic states of phenotypically distinct cells and identifying four factors sufficient to reprogram differentiated cells into a tumorigenic stem-like state. PMID- 24766800 TI - Mutant PTEN in Cancer: Worse Than Nothing. AB - Tumor suppressors block the development of cancer and are often lost during tumor development. Papa et al. show that partial loss of normal PTEN tumor suppressor function can be compounded by additional disruption caused by the expression of inactive mutant PTEN protein. This has significant implications for patients with PTEN gene mutations. PMID- 24766801 TI - Protein accounting in the cellular economy. AB - Knowing the copy number of cellular proteins is critical for understanding cell physiology. By being able to measure the absolute synthesis rates of the majority of cellular proteins, Li et al. gain insights into key aspects of translation regulation and fundamental principles of cellular strategies to adjust protein synthesis according to the functional needs. PMID- 24766802 TI - Merkel cells are a touchy subject. AB - How the Merkel cell-neurite complex transduces and encodes touch remains unclear. Ikeda et al. now implicate Merkel cells as the primary sites of tactile transduction and the ion channel Piezo2 as the chief mechanotransducer. Surprisingly, Merkel cells also mediate allodynia, providing a new cellular target for chronic pain treatment. PMID- 24766803 TI - Siri of the cell: what biology could learn from the iPhone. AB - Modern genomics is very efficient at mapping genes and gene networks, but how to transform these maps into predictive models of the cell remains unclear. Recent progress in computer science, embodied by intelligent agents such as Siri, inspires an approach for moving from networks to multiscale models able to predict a range of cellular phenotypes and answer biological questions. PMID- 24766804 TI - Molecular mechanisms underlying bacterial persisters. AB - All bacteria form persisters, cells that are multidrug tolerant and therefore able to survive antibiotic treatment. Due to the low frequencies of persisters in growing bacterial cultures and the complex underlying molecular mechanisms, the phenomenon has been challenging to study. However, recent technological advances in microfluidics and reporter genes have improved this scenario. Here, we summarize recent progress in the field, revealing the ubiquitous bacterial stress alarmone ppGpp as an emerging central regulator of multidrug tolerance and persistence, both in stochastically and environmentally induced persistence. In several different organisms, toxin-antitoxin modules function as effectors of ppGpp-induced persistence. PMID- 24766805 TI - Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. AB - Hematopoietic stem cells (HSCs) sustain blood formation throughout life and are the functional units of bone marrow transplantation. We show that transient expression of six transcription factors Run1t1, Hlf, Lmo2, Prdm5, Pbx1, and Zfp37 imparts multilineage transplantation potential onto otherwise committed lymphoid and myeloid progenitors and myeloid effector cells. Inclusion of Mycn and Meis1 and use of polycistronic viruses increase reprogramming efficacy. The reprogrammed cells, designated induced-HSCs (iHSCs), possess clonal multilineage differentiation potential, reconstitute stem/progenitor compartments, and are serially transplantable. Single-cell analysis revealed that iHSCs derived under optimal conditions exhibit a gene expression profile that is highly similar to endogenous HSCs. These findings demonstrate that expression of a set of defined factors is sufficient to activate the gene networks governing HSC functional identity in committed blood cells. Our results raise the prospect that blood cell reprogramming may be a strategy for derivation of transplantable stem cells for clinical application. PMID- 24766806 TI - The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. AB - The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen rich postnatal environment is the upstream signal that results in cell-cycle arrest of cardiomyocytes. Here, we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of cardiomyocytes, whereas hyperoxemia and ROS generators shorten it. These findings uncover a protective mechanism that mediates cardiomyocyte cell-cycle arrest in exchange for utilization of oxygen-dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be an important component of cardiomyocyte proliferation-based therapeutic approaches. PMID- 24766807 TI - Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. AB - PTEN dysfunction plays a crucial role in the pathogenesis of hereditary and sporadic cancers. Here, we show that PTEN homodimerizes and, in this active conformation, exerts lipid phosphatase activity on PtdIns(3,4,5)P3. We demonstrate that catalytically inactive cancer-associated PTEN mutants heterodimerize with wild-type PTEN and constrain its phosphatase activity in a dominant-negative manner. To study the consequences of homo- and heterodimerization of wild-type and mutant PTEN in vivo, we generated Pten knockin mice harboring two cancer-associated PTEN mutations (PtenC124S and PtenG129E). Heterozygous Pten(C124S/+) and Pten(G129E/+) cells and tissues exhibit increased sensitivity to PI3-K/Akt activation compared to wild-type and Pten(+/-) counterparts, whereas this difference is no longer apparent between Pten(C124S/-) and Pten(-/-) cells. Notably, Pten KI mice are more tumor prone and display features reminiscent of complete Pten loss. Our findings reveal that PTEN loss and PTEN mutations are not synonymous and define a working model for the function and regulation of PTEN. PMID- 24766808 TI - Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources. AB - Quantitative views of cellular functions require precise measures of rates of biomolecule production, especially proteins-the direct effectors of biological processes. Here, we present a genome-wide approach, based on ribosome profiling, for measuring absolute protein synthesis rates. The resultant E. coli data set transforms our understanding of the extent to which protein synthesis is precisely controlled to optimize function and efficiency. Members of multiprotein complexes are made in precise proportion to their stoichiometry, whereas components of functional modules are produced differentially according to their hierarchical role. Estimates of absolute protein abundance also reveal principles for optimizing design. These include how the level of different types of transcription factors is optimized for rapid response and how a metabolic pathway (methionine biosynthesis) balances production cost with activity requirements. Our studies reveal how general principles, important both for understanding natural systems and for synthesizing new ones, emerge from quantitative analyses of protein synthesis. PMID- 24766809 TI - Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. AB - CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis. PMID- 24766810 TI - CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. AB - Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans. PMID- 24766811 TI - Murine pheromone proteins constitute a context-dependent combinatorial code governing multiple social behaviors. AB - During social interactions, an individual's behavior is largely governed by the subset of signals emitted by others. Discrimination of "self" from "other" regulates the territorial urine countermarking behavior of mice. To identify the cues for this social discrimination and understand how they are interpreted, we designed an olfactory-dependent countermarking assay. We find major urinary proteins (MUPs) sufficient to elicit countermarking, and unlike other vomeronasal ligands that are detected by specifically tuned sensory neurons, MUPs are detected by a combinatorial strategy. A chemosensory signature of "self" that modulates behavior is developed via experience through exposure to a repertoire of MUPs. In contrast, aggression can be elicited by MUPs in an experience independent but context-dependent manner. These findings reveal that individually emitted chemical cues can be interpreted based on their combinatorial permutation and relative ratios, and they can transmit both fixed and learned information to promote multiple behaviors. PMID- 24766812 TI - Identification of a circadian output circuit for rest:activity rhythms in Drosophila. AB - Though much is known about the cellular and molecular components of the circadian clock, output pathways that couple clock cells to overt behaviors have not been identified. We conducted a screen for circadian-relevant neurons in the Drosophila brain and report here that cells of the pars intercerebralis (PI), a functional homolog of the mammalian hypothalamus, comprise an important component of the circadian output pathway for rest:activity rhythms. GFP reconstitution across synaptic partners (GRASP) analysis demonstrates that PI cells are connected to the clock through a polysynaptic circuit extending from pacemaker cells to PI neurons. Molecular profiling of relevant PI cells identified the corticotropin-releasing factor (CRF) homolog, DH44, as a circadian output molecule that is specifically expressed by PI neurons and is required for normal rest:activity rhythms. Notably, selective activation or ablation of just six DH44+ PI cells causes arrhythmicity. These findings delineate a circuit through which clock cells can modulate locomotor rhythms. PMID- 24766813 TI - A viral packaging motor varies its DNA rotation and step size to preserve subunit coordination as the capsid fills. AB - Multimeric, ring-shaped molecular motors rely on the coordinated action of their subunits to perform crucial biological functions. During these tasks, motors often change their operation in response to regulatory signals. Here, we investigate a viral packaging machine as it fills the capsid with DNA and encounters increasing internal pressure. We find that the motor rotates the DNA during packaging and that the rotation per base pair increases with filling. This change accompanies a reduction in the motor's step size. We propose that these adjustments preserve motor coordination by allowing one subunit to make periodic, specific, and regulatory contacts with the DNA. At high filling, we also observe the downregulation of the ATP-binding rate and the emergence of long-lived pauses, suggesting a throttling-down mechanism employed by the motor near the completion of packaging. This study illustrates how a biological motor adjusts its operation in response to changing conditions, while remaining highly coordinated. PMID- 24766814 TI - Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. AB - Tissue regeneration is an orchestrated progression of cells from an immature state to a mature one, conventionally represented as distinctive cell subsets. A continuum of transitional cell states exists between these discrete stages. We combine the depth of single-cell mass cytometry and an algorithm developed to leverage this continuum by aligning single cells of a given lineage onto a unified trajectory that accurately predicts the developmental path de novo. Applied to human B cell lymphopoiesis, the algorithm (termed Wanderlust) constructed trajectories spanning from hematopoietic stem cells through to naive B cells. This trajectory revealed nascent fractions of B cell progenitors and aligned them with developmentally cued regulatory signaling including IL-7/STAT5 and cellular events such as immunoglobulin rearrangement, highlighting checkpoints across which regulatory signals are rewired paralleling changes in cellular state. This study provides a comprehensive analysis of human B lymphopoiesis, laying a foundation to apply this approach to other tissues and "corrupted" developmental processes including cancer. PMID- 24766815 TI - Large-scale genetic perturbations reveal regulatory networks and an abundance of gene-specific repressors. AB - To understand regulatory systems, it would be useful to uniformly determine how different components contribute to the expression of all other genes. We therefore monitored mRNA expression genome-wide, for individual deletions of one quarter of yeast genes, focusing on (putative) regulators. The resulting genetic perturbation signatures reflect many different properties. These include the architecture of protein complexes and pathways, identification of expression changes compatible with viability, and the varying responsiveness to genetic perturbation. The data are assembled into a genetic perturbation network that shows different connectivities for different classes of regulators. Four feed forward loop (FFL) types are overrepresented, including incoherent type 2 FFLs that likely represent feedback. Systematic transcription factor classification shows a surprisingly high abundance of gene-specific repressors, suggesting that yeast chromatin is not as generally restrictive to transcription as is often assumed. The data set is useful for studying individual genes and for discovering properties of an entire regulatory system. PMID- 24766817 TI - Warfarin or dabigatran for treatment of atrial fibrillation. AB - BACKGROUND: New antithrombotic drugs for prevention and treatment of thromboembolic disorders in AF that are less demanding on local staff and facilities than warfarin should be welcomed if proved successful. OBJECTIVES: The comparative value and possible dangers of substituting the new drug dabigatran as a replacement remain to be established. Its safety and effectiveness must be reviewed and assessed by further study. METHODS: Clinical results of the European Action on Anticoagulation (EAA) computer-assisted dosage study and the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial have been compared. RESULTS: Clinical events were lower in patients on warfarin in the EAA study compared to patients on both warfarin and dabigatran in the RE-LY study. CONCLUSION: Evaluations should recognize optimum requirements for safe and effective administration of both types of drug. In the warfarin arm improvements in effectiveness and safety recently introduced (i.e. the PT/INR line and variance growth analysis) should be included as they have been shown to be successful in improved prediction of bleeding and further thromboembolism. The incidence of bleeding with dabigatran, for which there is no antidote, will require evaluation. PMID- 24766818 TI - Antibody against N-terminal domain of phospholipid scramblase 1 induces apoptosis in colorectal cancer cells through the intrinsic apoptotic pathway. AB - Phospholipid scramblase 1 involve in biological processes including phospholipid movement, proliferation, and apoptosis. Treatment with an antiphospholipid scramblase 1 antibody (NP1) has been demonstrated to inhibit cell proliferation in colorectal cancer. This study aimed to explore the role of NP1 treatment in the apoptosis of colorectal cancer cells. Results showed that NP1 treatment significantly increases the apoptosis of colorectal cancer cells via the activation of caspase 8, caspase 9, and caspase 3. Moreover, pretreatment with a caspase 8 inhibitor did not fully prevent the apoptotic effects of NP1. Taken together, these data indicate NP1 induces cell apoptosis primary through the intrinsic apoptotic pathway. NP1 may serve as a potential therapeutic agent. PMID- 24766819 TI - Long-term effects of three Tiao-Bu Fei-Shen therapies on NF-kappaB/TGF beta1/smad2 signaling in rats with chronic obstructive pulmonary disease. AB - BACKGROUND: The three Tiao-Bu Fei-Shen (Bufei Jianpi, Bufei Yishen, Yiqi Zishen) granules have been confirmed for their beneficial clinical efficacy in chronic obstructive pulmonary disease (COPD) patients on reducing frequency and duration of acute exacerbation, improving syndromes, pulmonary function and exercise capacity. But the short- or long-term mechanism of them is not fully clear. Nuclear factor (NF)-kappaB/transforming growth factor (TGF)-beta1/smad2 signaling pathway is involved in the progress of inflammation and remodeling in chronic obstructive pulmonary disease COPD. This study aimed to explore the long-term effects mechanism of Tiao-Bu Fei-Shen granules by regulating NF-kappaB/TGF beta/Smads signaling in rats with COPD. METHODS: Sprague Dawley rats were randomized into control, model, Bufei Jianpi, Bufei Yishen, Yiqi Zishen and aminophylline groups. COPD rats, induced by cigarette smoke and bacterial infections exposures, were administrated intragastricly by normal saline, Bufei Jianpi, Bufei Yishen, Yiqi Zishen granules or aminophylline from week 9 through 20, respectively. At week 20 and 32, lung tissues were harvested. Immunohistochemistry was used to detect interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, quantitative real-time polymerase chain reaction (qRT-PCR) was used for TGF-beta1 and Smad2 mRNA analysis, western blotting was used to determine the phosphorylation of NF-kappaB (p-NF-kappaB) and IkappaBalpha (p IkappaBalpha). RESULTS: COPD rats had marked airway injury, such as chronic airway inflammation and remodeling, emphysema, which were improved in the three traditional Chinese medicines (TCM)-treated animals. The levels of IL-1beta, TNF alpha, p-NF-kappaB, p-IkappaBalpha, TGF-beta1 and Smad2 were significantly higher in COPD rats than in controls, while they were dramatically reduced in the three TCM- and aminophylline-treated groups. At the meantime, all these endpoints were significantly lower in three TCM-treated groups than in aminophylline group, especially in Bufei Jianpi and Bufei Yishen groups. Compared to week 20, all endpoints decreased significantly in three TCM groups at week 32. CONCLUSION: The three Tiao-Bu Fei-Shen therapies can reduce pulmonary inflammation and remodeling in COPD and have significant long-term effects. NF-kappaB/TGF-beta1/smad2 signaling might be involved in the mechanism. PMID- 24766820 TI - A nanoliposome delivery system to synergistically trigger TLR4 AND TLR7. AB - BACKGROUND: Recent reports that TLR4 and TLR7 ligands can synergistically trigger Th1 biased immune responses suggest that an adjuvant that contains both ligands would be an excellent candidate for co-administration with vaccine antigens for which heavily Th1 biased responses are desired. Ligands of each of these TLRs generally have disparate biochemical properties, however, and straightforward co formulation may represent an obstacle. RESULTS: We show here that the TLR7 ligand, imiquimod, and the TLR4 ligand, GLA, synergistically trigger responses in human whole blood. We combined these ligands in an anionic liposomal formulation where the TLR7 ligand is in the interior of the liposome and the TLR4 ligand intercalates into the lipid bilayer. The new liposomal formulations are stable for at least a year and have an attractive average particle size of around 140 nm allowing sterile filtration. The synergistic adjuvant biases away from Th2 responses, as seen by significantly reduced IL-5 and enhanced interferon gamma production upon antigen-specific stimulation of cells from immunized mice, than any of the liposomal formulations with only one TLR agonist. Qualitative alterations in antibody responses in mice demonstrate that the adjuvant enhances Th1 adaptive immune responses above any adjuvant containing only a single TLR ligand as well. CONCLUSION: We now have a manufacturable, synergistic TLR4/TLR7 adjuvant that is made with excipients and agonists that are pharmaceutically acceptable and will have a straightforward path into human clinical trials. PMID- 24766821 TI - Antiangiogenic agents and the skin: cutaneous adverse effects of sorafenib, sunitinib, and bevacizumab. AB - As new antiangiogenic therapies have been introduced and added to the therapeutic arsenal against various types of cancer, previously unknown adverse effects have been detected. These effects negatively impact patients' quality of life and can even make it necessary to suspend treatment. Adverse skin reactions occur in 90% of patients treated with angiogenesis inhibitors. In some cases, a correlation has been observed between the severity of reactions and treatment efficacy and tumor response. It is therefore extremely important that dermatologists be able to recognize and manage these reactions. Moreover, in order to avoid the unjustified withdrawal of potentially life-extending treatments, dermatologists must be able to differentiate between non-life-threatening reactions and life threatening reactions that necessitate the suspension of treatment. In this review article, we analyze the main cutaneous adverse effects of the most common antiangiogenic agents. PMID- 24766822 TI - Bat ticks revisited: Ixodes ariadnae sp. nov. and allopatric genotypes of I. vespertilionis in caves of Hungary. AB - BACKGROUND: In Europe two ixodid bat tick species, Ixodes vespertilionis and I. simplex were hitherto known to occur. METHODS: Bat ticks were collected from cave walls and bats in Hungary. Their morphology and genotypes were compared with microscopy and conventional PCR (followed by sequencing), respectively. RESULTS: A year-round activity of I. vespertilionis was observed. Molecular analysis of the cytochrome oxidase subunit I (COI) gene of twenty ticks from different caves showed that the occurrence of the most common genotype was associated with the caves close to each other. A few specimens of a morphologically different tick variant were also found and their COI analysis revealed only 86-88% sequence homology with I. simplex and I. vespertilionis, respectively. CONCLUSIONS: The microenvironment of caves (well separated from each other) appears to support the existence of allopatric I. vespertilionis COI genotypes, most likely related to the distance between caves and to bat migration over-bridging certain caves. The name I. ariadnae sp. nov. is given to the new tick species described here for the first time. PMID- 24766824 TI - "Continuity of care" experiences in midwifery education: perspectives from diverse stakeholders. AB - At least 20 continuity-of-care experiences are compulsory for student midwives in Australia, but little is known about this learning component. This paper presents an analysis of continuity experiences in one Region, incorporating diverse stakeholder perspectives from student midwives, maternity managers and registered midwives, with the aim of better understanding and optimizing experiences. Qualitative methods were utilized, employing mainly focus groups. Participants included 15 student midwives from the Regional University, 14 midwives and six managers, employed at the Regional referral hospital. Four themes were identified in the data; "woman-centred care", "counting the cost", "mutual benefits" and "into the future". The significant benefits of student continuity-of-care experiences were outlined by all three participant groups. Continuity experiences for student midwives facilitated the development of a woman-centred focus in the provision of maternity care. While the experience was challenging for students it was beneficial not only to them, but to registered midwives, the maternity services, and ultimately childbearing women. In order to appropriately prepare midwives for existing and future maternity services, and to continue to meet women's needs in all service delivery models, we require midwives who are well grounded in a woman-centred care philosophy and have had exposure to various care models. PMID- 24766825 TI - Comparison of methods for imputing limited-range variables: a simulation study. AB - BACKGROUND: Multiple imputation (MI) was developed as a method to enable valid inferences to be obtained in the presence of missing data rather than to re create the missing values. Within the applied setting, it remains unclear how important it is that imputed values should be plausible for individual observations. One variable type for which MI may lead to implausible values is a limited-range variable, where imputed values may fall outside the observable range. The aim of this work was to compare methods for imputing limited-range variables, with a focus on those that restrict the range of the imputed values. METHODS: Using data from a study of adolescent health, we consider three variables based on responses to the General Health Questionnaire (GHQ), a tool for detecting minor psychiatric illness. These variables, based on different scoring methods for the GHQ, resulted in three continuous distributions with mild, moderate and severe positive skewness. In an otherwise complete dataset, we set 33% of the GHQ observations to missing completely at random or missing at random; repeating this process to create 1000 datasets with incomplete data for each scenario.For each dataset, we imputed values on the raw scale and following a zero-skewness log transformation using: univariate regression with no rounding; post-imputation rounding; truncated normal regression; and predictive mean matching. We estimated the marginal mean of the GHQ and the association between the GHQ and a fully observed binary outcome, comparing the results with complete data statistics. RESULTS: Imputation with no rounding performed well when applied to data on the raw scale. Post-imputation rounding and imputation using truncated normal regression produced higher marginal means than the complete data estimate when data had a moderate or severe skew, and this was associated with under coverage of the complete data estimate. Predictive mean matching also produced under-coverage of the complete data estimate. For the estimate of association, all methods produced similar estimates to the complete data. CONCLUSIONS: For data with a limited range, multiple imputation using techniques that restrict the range of imputed values can result in biased estimates for the marginal mean when data are highly skewed. PMID- 24766826 TI - Generalized versus partial reflex seizures: a review. AB - In this review we assess our currently available knowledge about reflex seizures with special emphasis on the difference between "generalized" reflex seizures induced by visual stimuli, thinking, praxis and language tasks, and "focal" seizures induced by startle, eating, music, hot water, somatosensory stimuli and orgasm. We discuss in particular evidence from animal, clinical, neurophysiological and neuroimaging studies supporting the concept that "generalized" reflex seizures, usually occurring in the setting of IGE, should be considered as focal seizures with quick secondary generalization. We also review recent advances in genetic and therapeutic approach of reflex seizures. PMID- 24766823 TI - Mast cell plasticity and sphingosine-1-phosphate in immunity, inflammation and cancer. AB - Mast cells (MC) are found in all vascularized tissues at homeostasis and, until recently, were viewed only as effector cells of allergic reactions via degranulation, the canonical process through which MC release mediators, including histamine and pre-formed proteases and cytokines such as TNF. Cross linking of IgE bound to surface high affinity receptors for IgE (FcERI) by a specific antigen (Ag) triggers signaling events leading to degranulation. We and others have reported the concomitant production and export of an influential multifaceted sphingolipid mediator, sphingosine-1-phosphate (S1P) transported outside of MC by ATP-binding cassettes (ABC) transporters, i.e., independently of degranulation. Indeed, the MC horizon expanded by the discovery of their unique ability to selectively release mediators depending upon the stimulus and receptors involved. Aside from degranulation and transporter usage, MC are also endowed with piecemeal degranulation, a slower process during which mediator release occurs with minor morphological changes. The broad spectrum of pro- and anti-inflammatory bioactive substances MC produce and release, their amounts and delivery pace render these cells bona fide fine-tuners of the immune response. In this viewpoint article, MC developmental, phenotypic and functional plasticity, its modulation by microRNAs and its relevance to immunity, inflammation and cancer will be discussed. PMID- 24766827 TI - Comparative analysis of microRNA profiles between adult Ascaris lumbricoides and Ascaris suum. AB - BACKGROUND: The parasitic nematodes Ascaris lumbricoides and A. suum are of great public health and economic significance, and the two taxa were proposed to represent a single species. miRNAs are known with functions of gene regulations at post-transcriptional level. RESULTS: We herein compared the miRNA profiles of A. lumbricoides and A. suum female adults by Solexa deep sequencing combined with bioinformatics analysis and stem-loop real-time PCR. Using the A. suum genome as the reference genome, we obtained 171 and 494 miRNA candidates from A. lumbricoides and A. suum, respectively. Among which, 74 miRNAs were shared between the two taxa, 97 and 420 miRNAs were A. lumbricoides and A. suum specific. Target and function prediction revealed a significant set of targets which are related to ovarian message protein, vitellogenin and chondroitin proteoglycan of the two nematodes. Enrichment analysis revealed that the percentages of most predicted functions of the miRNA targets were similar, with some taxon specific or taxon enhanced functions, such as different target numbers, specific functions (NADH dehydrogenase and electron carrier functions), etc. CONCLUSIONS: This study characterized comparatively the miRNAs of adult A. lumbricoides and A. suum, and the findings provide additional evidence that A. lumbricoides and A. suum represent a single species. Due to the fast evolution nature of miRNAs and the different parasitic living conditions of humans and pigs, the phenomenon above might indicate a fast evolution of miRNAs of Ascaris in humans and pigs. PMID- 24766828 TI - In-vivo T1 cardiovascular magnetic resonance study of diffuse myocardial fibrosis in hypertrophic cardiomyopathy. AB - BACKGROUND: In hypertrophic cardiomyopathy (HCM), autopsy studies revealed both increased focal and diffuse deposition of collagen fibers. Late gadolinium enhancement imaging (LGE) detects focal fibrosis, but is unable to depict interstitial fibrosis. We hypothesized that with T1 mapping, which is employed to determine the myocardial extracellular volume fraction (ECV), can detect diffuse interstitial fibrosis in HCM patients. METHODS: T1 mapping with a modified Look Locker Inversion Recovery (MOLLI) pulse sequence was used to calculate ECV in manifest HCM (n = 16) patients and in healthy controls (n = 14). ECV was determined in areas where focal fibrosis was excluded with LGE. RESULTS: The total group of HCM patients showed no significant changes in mean ECV values with respect to controls (0.26 +/- 0.03 vs 0.26 +/- 0.02, p = 0.83). Besides, ECV in LGE positive HCM patients was comparable with LGE negative HCM patients (0.27 +/- 0.03 vs 0.25 +/- 0.03, p = 0.12). CONCLUSIONS: This study showed that HCM patients have a similar ECV (e.g. interstitial fibrosis) in myocardium without LGE as healthy controls. Therefore, the additional clinical value of T1 mapping in HCM seems limited, but future larger studies are needed to establish the clinical and prognostic potential of this new technique within HCM. PMID- 24766830 TI - Fungal nail infections. PMID- 24766829 TI - H2rs: deducing evolutionary and functionally important residue positions by means of an entropy and similarity based analysis of multiple sequence alignments. AB - BACKGROUND: The identification of functionally important residue positions is an important task of computational biology. Methods of correlation analysis allow for the identification of pairs of residue positions, whose occupancy is mutually dependent due to constraints imposed by protein structure or function. A common measure assessing these dependencies is the mutual information, which is based on Shannon's information theory that utilizes probabilities only. Consequently, such approaches do not consider the similarity of residue pairs, which may degrade the algorithm's performance. One typical algorithm is H2r, which characterizes each individual residue position k by the conn(k)-value, which is the number of significantly correlated pairs it belongs to. RESULTS: To improve specificity of H2r, we developed a revised algorithm, named H2rs, which is based on the von Neumann entropy (vNE). To compute the corresponding mutual information, a matrix A is required, which assesses the similarity of residue pairs. We determined A by deducing substitution frequencies from contacting residue pairs observed in the homologs of 35 809 proteins, whose structure is known. In analogy to H2r, the enhanced algorithm computes a normalized conn(k)-value. Within the framework of H2rs, only statistically significant vNE values were considered. To decide on significance, the algorithm calculates a p-value by performing a randomization test for each individual pair of residue positions. The analysis of a large in silico testbed demonstrated that specificity and precision were higher for H2rs than for H2r and two other methods of correlation analysis. The gain in prediction quality is further confirmed by a detailed assessment of five well studied enzymes. The outcome of H2rs and of a method that predicts contacting residue positions (PSICOV) overlapped only marginally. H2rs can be downloaded from http://www-bioinf.uni-regensburg.de. CONCLUSIONS: Considering substitution frequencies for residue pairs by means of the von Neumann entropy and a p-value improved the success rate in identifying important residue positions. The integration of proven statistical concepts and normalization allows for an easier comparison of results obtained with different proteins. Comparing the outcome of the local method H2rs and of the global method PSICOV indicates that such methods supplement each other and have different scopes of application. PMID- 24766831 TI - Local and regional flaps for hand coverage. AB - Hand surgeons are frequently challenged by the unique requirements of soft tissue coverage of the hand. Whereas many smaller soft tissue defects without involvement of deep structures are amenable to healing by secondary intention or skin grafting, larger lesions and those with exposed tendon, bone, or joint often require vascularized coverage that allows rapid healing without wound contraction. The purpose of this review was to present an overview of local and regional flaps commonly used for soft tissue reconstruction within the hand. PMID- 24766832 TI - Closed soft tissue extensor mechanism injuries (mallet, boutonniere, and sagittal band). AB - The extensor mechanism of the hand is complex and can be disrupted at several different points, from hand trauma. This article summarizes current concepts relating to the presentation and treatment of closed soft tissue injuries of the extensor mechanism in zones I, III, and V, commonly known as mallet finger and boutonniere deformities and sagittal band injuries. PMID- 24766833 TI - Angiomyxoma of the thumb. PMID- 24766834 TI - A simple diagnostic sign for rupture of the flexor digitorum profundus. PMID- 24766835 TI - Wassel type III polydactyly with symphalangism: a rare entity. PMID- 24766836 TI - Synchronous treatment of distant defect sites with bridged vacuum-assisted wound closure technique. PMID- 24766837 TI - Letter regarding "Corticosteroid injection with or without thumb spica cast for de Quervain tenosynovitis". PMID- 24766838 TI - In reply. PMID- 24766839 TI - Regarding "Corticosteroid injection with or without thumb spica cast for de Quervain tenosynovitis". PMID- 24766840 TI - Translational environmental biology: cell biology informing conservation. AB - Typically, findings from cell biology have been beneficial for preventing human disease. However, translational applications from cell biology can also be applied to conservation efforts, such as protecting coral reefs. Recent efforts to understand the cell biological mechanisms maintaining coral health such as innate immunity and acclimatization have prompted new developments in conservation. Similar to biomedicine, we urge that future efforts should focus on better frameworks for biomarker development to protect coral reefs. PMID- 24766841 TI - Hyphema is a risk factor for failure of trabeculectomy in neovascular glaucoma: a retrospective analysis. AB - BACKGROUND: Several retinal ischemic diseases can cause neovascular glaucoma (NVG). Trabeculectomy with mitomycin C (MMC) is a relatively better treatment modality in the management of eyes with NVG than other glaucoma surgeries. The aim of this study was to investigate the factors that may influence the outcome of trabeculectomy with MMC for NVG. METHODS: Forty-nine NVG eyes from 43 patients (26 males and 17 females) underwent primary trabeculectomy with MMC. The mean follow-up period was 16.8 +/- 8.1 months (range, 6 to 34 months). Twenty-one eyes of 21 patients received intravitreal bevacizumab (IVB) 3.6 +/- 1.8 days before trabeculectomy with MMC. A Kaplan-Meier survival-curve analysis was used to summarize the cumulative probability of success. We examined the relationship between the surgical outcome and the following surgical factors: gender, age, history of panretinal photocoagulation, history of cataract surgery, history of vitrectomy, preoperative IVB, NVG in the fellow eye, and postoperative complications (hyphema, choroidal detachment, and formation of fibrin) by multivariate analysis. RESULTS: The survival rate was 83.7% after 6 months, 70.9% after 12 months, and 60.8% after 24 months. The Kaplan-Meier survival curves showed no significant difference in the survival rate between the eyes with preoperative IVB (n = 21) and the eyes without preoperative IVB (n = 28) (p = 0.14). The multiple logistic regression analysis showed that postoperative hyphema (odds ratio, 6.54; 95% confidence interval, 1.41 to 35.97) was significantly associated with the surgical outcome (p = 0.02). CONCLUSIONS: Postoperative hyphema was significantly correlated with the outcome of trabeculectomy for NVG. There was no significant association between preoperative IVB and postoperative hyphema or the results of trabeculectomy. PMID- 24766842 TI - Ready, set, go! How protein kinase C manages dynamic signaling. AB - In this issue of Chemistry & Biology, Antal and colleagues describe how phosphorylation optimizes the signaling range of protein kinase C (PKC) isoforms. Priming of these enzymes regulates intramolecular conformational changes, which reduces access to their diacylglycerol (DAG) binding C1 domains. PMID- 24766843 TI - Cutting through complexity: the proteolytic properties of alternate immunoproteasome complexes. AB - The proteasome core interacts with different activators and incorporates alternate active subunits, thereby generating a diverse pool of subspecies. The enzymatic properties of these different species are not well understood. In this issue of Chemistry & Biology, Raule and colleagues present a comprehensive enzymatic characterization of immunoproteasome complexes associated with the proteasome activator PA28. PMID- 24766844 TI - Targeting mycobacterial proteolytic complexes with natural products. AB - Controlled proteolysis is key to bacterial viability. In this issue of Chemistry & Biology, Gavrish and colleagues characterize a natural product, lassomycin, targeting the Mycobacterium tuberculosis caseinolytic (Clp) protease. Unusually, lassomycin activates ClpC1, inducing ATPase activity and decoupling it from proteolysis. PMID- 24766845 TI - Suppressive drug interactions between antifungals. AB - In this issue of Chemistry & Biology, Cokol and colleagues report a systematic study of drug interactions between antifungal compounds. Suppressive drug interactions occur more frequently than previously realized and come in different flavors with interesting implications. PMID- 24766846 TI - A drug use survey among clients of harm reduction sites across British Columbia, Canada, 2012. AB - BACKGROUND: In British Columbia (BC), understanding of high-risk drug use trends is largely based on survey and cohort study data from two major cities, which may not be representative of persons who use drugs in other regions. Harm reduction stakeholders, representing each of the five geographic health regions in BC, identified a need for data on drug use to inform local and regional harm reduction activities across the province. The aims of this project were to (1) develop a drug use survey that could be feasibly administered at harm reduction (HR) sites across all health regions and (2) assess the data for differences in reported drug use frequencies by region. METHODS: A pilot survey focusing on current drug use was developed with stakeholders and administered among clients at 28 HR supply distribution sites across the province by existing staff and peers. Data were collated and analysed using univariate and bivariate descriptive statistics to assess differences in reported drug use frequencies by geography. A post-survey evaluation was conducted to assess acceptability and feasibility of the survey process for participating sites. RESULTS: Crack cocaine, heroin, and morphine were the most frequently reported drugs with notable regional differences. Polysubstance use was common among respondents (70%) with one region having 81% polysubstance use. Respondents surveyed in or near their region's major centre were more likely to report having used crack cocaine (p < 0.0001) and heroin (p < 0.0001) in the past week as compared to those residing >50 km from the major centre. Participants accessing services >50 km from the regional centre were more likely to have used morphine (p < 0.0001). There was no difference in powder cocaine use by client/site proximity to the regional centre. Participating sites found the survey process acceptable, feasible to administer annually, and useful for responding to client needs. CONCLUSIONS: The survey was a feasible way for harm reduction sites across BC to obtain drug use data from clients who actively use drugs. Drug use frequencies differed substantially by region and community proximity to the regional centre, underlining the need for locally collected data to inform service planning. PMID- 24766847 TI - Theory of mind and its relationship with executive functions and emotion recognition in borderline personality disorder. AB - Impaired social cognition has been claimed to be a mechanism underlying the development and maintenance of borderline personality disorder (BPD). One important aspect of social cognition is the theory of mind (ToM), a complex skill that seems to be influenced by more basic processes, such as executive functions (EF) and emotion recognition. Previous ToM studies in BPD have yielded inconsistent results. This study assessed the performance of BPD adults on ToM, emotion recognition, and EF tasks. We also examined whether EF and emotion recognition could predict the performance on ToM tasks. We evaluated 15 adults with BPD and 15 matched healthy controls using different tasks of EF, emotion recognition, and ToM. The results showed that BPD adults exhibited deficits in the three domains, which seem to be task-dependent. Furthermore, we found that EF and emotion recognition predicted the performance on ToM. Our results suggest that tasks that involve real-life social scenarios and contextual cues are more sensitive to detect ToM and emotion recognition deficits in BPD individuals. Our findings also indicate that (a) ToM variability in BPD is partially explained by individual differences on EF and emotion recognition; and (b) ToM deficits of BPD patients are partially explained by the capacity to integrate cues from face, prosody, gesture, and social context to identify the emotions and others' beliefs. PMID- 24766848 TI - Thoracoscopic lobectomy is associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40% of normal. AB - OBJECTIVE: A predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1%) or diffusing capacity of the lung for carbon monoxide (DLCO%) of <40% has traditionally been considered to convey a high risk of lobectomy owing to elevated postoperative morbidity and mortality. These recommendations, however, were largely derived from the pre-video-assisted thoracoscopic surgical (VATS) era. We hypothesized that VATS lobectomy would be associated with acceptable morbidity and mortality at ppoFEV1% and ppoDLCO% values < 40%. METHODS: PpoFEV1% and ppoDLCO% were calculated for patients undergoing open or VATS lobectomy for lung cancer in the Society of Thoracic Surgeons General Thoracic database from 2009 to 2011. Univariate comparisons, multivariate analyses, and 1:1 propensity matching were performed. RESULTS: A total of 13,376 patients underwent lobectomy (50.9% open, 49.1% VATS). A decreased ppoFEV1% and ppoDLCO% were each independent predictors for both cardiopulmonary complications and mortality in the open group (all P <= .008). In the VATS group, ppoFEV1% was an independent predictor of complications (P = .001) but not mortality (P = .77), and ppoDLCO% was an independent predictor of complications (P = .046) and mortality (P = .008). With decreasing ppoFEV1% or ppoDLCO%, complications and mortality increased at a greater rate in the open lobectomy than in a propensity-matched VATS group (n = 4215 each). For patients with ppoFEV1% < 40%, mortality was greater in the open (4.8%) than in the matched VATS group (0.7%, P = .003). Similar results were seen for ppoDLCO% < 40% (5.2% open, 2.0% VATS, P = .003). The rate of complications was significantly greater at ppoFEV1% < 40% in the open (21.9%) than in the matched VATS (12.8%, P = .005) group and similar results were seen with ppoDLCO% < 40% (14.9% open, 10.4% VATS, P = .016). CONCLUSIONS: VATS lobectomy can be performed with acceptable rates of morbidity and mortality in patients with reduced ppoFEV1% or ppoDLCO%. PMID- 24766850 TI - Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor-induced hypercoagulability in vitro and in vivo. AB - BACKGROUND: Increased hypercoagulability has been reported with low doses of direct thrombin inhibitors but not with direct factor Xa inhibitors. OBJECTIVES: To compare the effects of rivaroxaban with those of melagatran and dabigatran on thrombin generation (TG) and tissue factor-induced hypercoagulability and to explore the possible involvement of the thrombin-thrombomodulin/activated protein C system. METHODS: In normal human plasma and in protein C-deficient plasma, TG was investigated in vitro in the presence and absence of recombinant human soluble thrombomodulin (rhs-TM). TG was determined by calibrated automated thrombography and an ELISA for prothrombin fragments 1+2 (F1+2 ). In an in vivo rat model, hypercoagulability was induced by tissue factor; levels of thrombin antithrombin (TAT) and fibrinogen and the platelet count were determined. RESULTS: Rivaroxaban inhibited TG in a concentration-dependent manner. In the absence of rhs-TM, melagatran and dabigatran also inhibited TG concentration dependently. However, in the presence of rhs-TM, lower concentrations of melagatran (119-474 nmol L(-1) ) and dabigatran (68-545 nmol L(-1) ) enhanced endogenous thrombin potential, peak TG, and F1+2 formation in normal plasma but not in protein C-deficient plasma. In vivo, rivaroxaban dose-dependently inhibited TAT generation, whereas melagatran showed a paradoxical effect, with an increase in TAT and a small decrease in fibrinogen and platelet count at lower doses. CONCLUSION: Low concentrations of the direct thrombin inhibitors melagatran and dabigatran enhanced TG and hypercoagulability, possibly via inhibition of the protein C system. In contrast, rivaroxaban reduced TG and hypercoagulability under all conditions studied, suggesting that it does not suppress this negative-feedback system. PMID- 24766851 TI - Raising the bar for science. PMID- 24766852 TI - Elevating the quality of disability and rehabilitation research: mandatory use of the reporting guidelines. PMID- 24766853 TI - The Convention on the Rights of Persons with Disabilities: what is at stake for physiatrists and the patients we serve. PMID- 24766854 TI - Medical marijuana for failed back surgical syndrome: a viable option for pain control or an uncontrolled narcotic? PMID- 24766855 TI - Robot-assisted laparoscopic ureteral reimplantation: a single surgeon comparison to open surgery. AB - OBJECTIVE: The aim was to report a single surgeon's experience comparing open and robot-assisted laparoscopic extravesical ureteral reimplantation (RALUR) to treat vesicoureteral reflux (VUR). SUBJECTS AND METHODS: We retrospectively reviewed the outcomes of RALUR and open extravesical ureteral reimplantations consecutively performed by a single surgeon between January 2008 and December 2010 using the da Vinci((r)) Surgical System. Both groups of patients were subjected to identical pre- and postoperative care protocols. RESULTS: During the defined study interval, 20 open and 20 RALUR procedures were completed by a single surgeon at our institution. Gender and VUR grade were similar in both cohorts. Operative times were longer in the RALUR group, but postoperative opioid use (morphine equivalents) was significantly lower in the RALUR group (RALUR: 0.14 mg/kg, open: 0.25 mg/kg, p = 0.021). There was no significant difference in estimated blood loss (EBL) or length of hospitalization (LOH). The overall rate of surgical complications was similar; however, the complications in the open group tended to be less severe than those occurring in the RALUR group. On follow up, after a median of 52 months for open surgery and 39 months for RALUR, two children had developed a febrile urinary tract infection in both groups, of which one in the open group had persistent VUR. CONCLUSION: This single-surgeon experience of open and initial experience with RALUR performed with the same surgical technique on consecutive cohorts with identical post-surgical care protocol allows a comparative analysis of outcomes for a surgeon transitioning to RALUR. The RALUR reduces postoperative analgesic requirements while yielding similar clinical outcomes as the open technique. PMID- 24766856 TI - Estimating utility values for vesicoureteral reflux in the general public using an online tool. AB - INTRODUCTION: Cost-utility analyses are useful to study conditions without a widely accepted treatment algorithm; in pediatric urology, one such condition is vesicoureteral reflux (VUR). A necessary component of cost-utility analyses is to accurately calculate the "utility", a numerical surrogate of quality of life, for various health states. Our aims were to determine utility values for representative VUR health states and to verify the feasibility of a novel online platform for utility elicitation in order to reduce the time and expense of such analyses. METHODS: A cross-sectional survey of American adults was conducted using the time-trade-off (TTO) method. Respondents were recruited from an online work interface, Amazon's Mechanical Turk (MTurk). Four annualized VUR health states were assessed: VUR treated with/without continuous antibiotic prophylaxis (CAP) and with/without associated febrile urinary tract infection (UTI). A 6-week post-operative scenario following open ureteroneocystostomy was also assessed. RESULTS: We received 278 survey responses (70% response rate). The respondents were largely between the ages of 25 and 44 (59%), female (60%), and Caucasian (76%). Thirty-seven percent had a college degree, and 44% were parents. Compared with a perfect health state of 1.0, we found mean utilities of 0.87 for VUR, regardless of whether CAP was used or whether UTI was present (p=0.9). The immediate post-operative period following ureteroneocystostomy garnered an annualized utility of 0.94. CONCLUSIONS: Our data suggest that MTurk-based utility assessment is feasible, and that subjects view the VUR health state as only slightly inferior to perfect health. This includes VUR health states incorporating CAP and febrile UTI. PMID- 24766857 TI - Cumulative incidence of outcomes and urologic procedures after augmentation cystoplasty. AB - OBJECTIVE: Augmentation cystoplasty (AC) is a major surgery that can be associated with long-term morbidity. This study aimed to describe the cumulative incidence of outcomes and urologic procedures in a large cohort of children who underwent AC, identify significant sources of morbidity, and to evaluate baseline factors associated with outcomes of interest. METHODS: Children<=18 years who underwent AC in the Pediatric Health Information System from 1999 to 2010 were included. All follow-up encounters up to June 2012 were included. Cumulative incidences for 15 outcomes and urologic procedures were calculated using non informative censoring. Sensitivity analyses were performed to determine effect of censoring assumptions and including hospitals without complete datasets. As an exploratory analysis, baseline patient factors were evaluated for associations with outcomes and urologic procedures of interest using multivariable Cox proportional hazards models adjusted for clustering by hospital. RESULTS: 2831 AC patients were identified. Based on cumulative incidence calculations and sensitivity analyses; the cumulative incidence ranges of outcomes and procedures at 1, 3, 5, and 10 years were calculated. Examples of 10-year cumulative incidence ranges are given for the following outcomes and procedures: bladder rupture (2.9-6.4%), small bowel obstruction (5.2-10.3%), bladder stones (13.3 36.0%), pyelonephritis (16.1-37.1%), cystolithopaxy (13.3-35.1%), and reaugmentation (5.2-13.4%). The development of chronic kidney disease was strongly associated with a diagnosis of lower urinary tract obstruction (HR 13.7; 95% CI 9.4-19.9). Bladder neck surgery and stoma creation at time of AC were associated with an increased hazard of bladder rupture (HR 1.9; 95% CI 1.1-3.3) and bladder stones (HR 1.4; 95% CI 1.1-1.8) respectively. CONCLUSIONS: Outcomes of interest and urologic procedures after AC are common. Results from this large cohort can be used to counsel patients and families about expectations after AC. Pyelonephritis, chronic kidney disease, further reconstructive surgery, and calculus disease appear to cause significant morbidity. Collaborative efforts are needed to further reduce morbidity in this patient population. PMID- 24766858 TI - Research participation effects: a skeleton in the methodological cupboard. AB - OBJECTIVE: There have been concerns about impacts of various aspects of taking part in research studies for a century. The concerns have not, however, been sufficiently well conceptualized to form traditions of study capable of defining and elaborating the nature of these problems. In this article we present a new way of thinking about a set of issues attracting long-standing attention. STUDY DESIGN AND SETTING: We briefly review existing concepts and empirical work on well-known biases in surveys and cohort studies and propose that they are connected. RESULTS: We offer the construct of "research participation effects" (RPE) as a vehicle for advancing multi-disciplinary understanding of biases. Empirical studies are needed to identify conditions in which RPE may be sufficiently large to warrant modifications of study design, analytic methods, or interpretation. We consider the value of adopting a more participant-centred view of the research process as a way of thinking about these issues, which may also have benefits in relation to research methodology more broadly. CONCLUSION: Researchers may too readily overlook the extent to which research studies are unusual contexts, and that people may react in unexpected ways to what we invite them to do, introducing a range of biases. PMID- 24766859 TI - GATA5 and endothelial nitric oxide synthase expression in the ascending aorta is related to aortic size and valve morphology. AB - BACKGROUND: The pathogenesis of aortic dilatation in patients with congenital aortic valve anomalies is poorly understood. Recent studies suggest that alterations of gene expression may be related to ascending aortic aneurysm formation in these patients. Knockout of endothelial nitric oxide synthase (eNOS) and GATA5 is associated with bicuspid aortic valves in mice. To study the role of eNOS and GATA5 in human congenital aortic valve disease and aortic dilatation, we investigated their gene expression in aortic tissue from patients with unicuspid, bicuspid, and tricuspid aortic valves. METHODS: Samples from 84 patients (33 tricuspid, 32 bicuspid, and 19 unicuspid) were harvested intraoperatively from the ascending aorta. GATA5 and eNOS expression was determined by real-time polymerase chain reaction. RESULTS: GATA5 and eNOS expression in the aortic wall from patients with unicuspid aortic valves (GATA5: mean [M], 2.14; standard deviation [SD], 1.72; eNOS: M, 3.40; SD, 3.83) was significantly higher than in tricuspid aortic valves (GATA5: M, 1.12; SD, 0.80; eNOS: M, 1.00; SD, 0.74; each p < 0.05). Patients with bicuspid aortic valves (GATA5: M, 1.29, SD, 1.33; eNOS: M, 1.66; SD, 1.31) had a significantly higher eNOS expression than patients with tricuspid aortic valves (p < 0.05). The expression levels of eNOS and GATA5 correlated positively with each other and negatively with the ascending aortic diameter. CONCLUSIONS: Our data suggest that GATA5, possibly through upregulation of eNOS, plays a role in the development of aortic dilatation in patients with unicuspid and bicuspid aortic valves. The differential gene expression in patients with unicuspid compared with bicuspid aortic valves suggests that the pathogenesis of both aortic valve anomalies may be different. PMID- 24766861 TI - Journal of Optometry in PubMed and PubMed Central. PMID- 24766860 TI - p38alpha MAPK-mediated induction and interaction of FOXO3a and p53 contribute to the inhibited-growth and induced-apoptosis of human lung adenocarcinoma cells by berberine. AB - BACKGROUND: Berberine (BBR), a component from traditional Chinese medicine, has been shown to possess anti-tumor activity against a wide spectrum of cancer cells including human lung cancer, but the detailed mechanism underlining this has not been well elucidated. METHODS: In this study, the effect of berberine on cell growth and apoptosis were assessed by MTT, flow cytometry and Hoechst 33258 staining assays. The phosphorylation of p38 MAPK and ERK1/2, and expressions of p38 MAPK isoforms alpha and beta, total ERK1/2, p53, FOXO3a and p21 protein were evaluated by Western Blot analysis. Silencing of p38 MAPK isoform alpha and beta, p53, FOXO3a and p21 were performed by siRNA methods. Exogenous expression of FOXO3a was carried out by electroporated transfection assays. RESULTS: We showed that BBR significantly inhibited growth and induced cell cycle arrest of non small cell lung cancer (NSCLC) cells in the G0/G1 phase in a dose-dependent manner. Furthermore, we found that BBR increased phosphorylation of p38 MAPK and ERK1/2 in a time-dependent and induced protein expression of tumor suppressor p53 and transcription factor FOXO3a in a dose-dependent fashion. The specific inhibitor of p38 MAPK (SB203580), and silencing of p38alpha MAPK by small interfering RNAs (siRNAs), but not ERK1/2 inhibitor (PD98059) blocked the stimulatory effects of BBR on protein expression of p53 and FOXO3a. Interestingly, inhibition of p53 using one specific inhibitor (Pifithrin-alpha) and silencing of p53 using siRNAs overcome the inhibitory effect of BBR on cell growth. Silencing of FOXO3a appeared to attenuate the effect of BBR on p53 expression, cell proliferation and apoptosis. Furthermore, BBR induces the protein expression of cell cycle inhibitor p21 (CIP1/WAF1), which was not observed in cells silencing of p53 or FOXO3alpha gene. Intriguingly, exogenous expression of FOXO3a enhanced the expression of p21 (CIP1/WAF1) and strengthened BBR-induced apoptosis. CONCLUSION: Our results show that BBR inhibits proliferation and induces apoptosis of NSCLC cells through activation of p38alpha MAPK signaling pathway, followed by induction of the protein expression of p53 and FOXO3a. The latter contribute to the BBR-increased p21 (CIP1/WAF1) protein expression. The exogenous FOXO3a, interaction and mutually exclusive events of p53 and FOXO3a augment the overall response of BBR. PMID- 24766862 TI - Topical timolol in the treatment of monocular oscillopsia secondary to superior oblique myokymia: a review. AB - Some reports have outlined many different treatment strategies for superior oblique myokymia (SOM) that attempt to reduce or eliminate patients' symptoms of monocular oscillopsia and/or diplopia. Most treatment strategies have focused solely on oral medications or invasive surgery. The following is a current and critical review of SOM along with its clinical findings/symptoms, demographics, theories of its pathogenesis, management/treatment options, new observations in SOM, as well as a case report to highlight a relatively novel idea for the treatment of SOM: topical timolol eye drops. It also highlights evidence of a new "localized theory" regarding topical beta-blockers' mechanism of action in SOM compared to the previous systemic hypothesis proposed in 1994. The case report shows a 29-year-old female patient who suffered with SOM symptoms for 8-10 years and then experienced a worsening of her symptoms shortly postpartum. The patient was prescribed topical timolol eye drops by the author in the affected eye based on one case report(12) from 1994, which completely eliminated her symptoms within 1-2 days of starting the treatment with any recurrence with the daily use of the drop at the time of this article. Given the robust effect in this case, topical timolol may be a potentially useful drug in the management of SOM given its affordability and safer side effect profile in comparison to the oral medications traditionally used in SOM. PMID- 24766863 TI - Errors associated with IOLMaster biometry as a function of internal ocular dimensions. AB - PURPOSE: To evaluate the error in the estimation of axial length (AL) with the IOLMaster partial coherence interferometry (PCI) biometer and obtain a correction factor that varies as a function of AL and crystalline lens thickness (LT). METHODS: Optical simulations were produced for theoretical eyes using Zemax-EE software. Thirty-three combinations including eleven different AL (from 20mm to 30mm in 1mm steps) and three different LT (3.6mm, 4.2mm and 4.8mm) were used. Errors were obtained comparing the AL measured for a constant equivalent refractive index of 1.3549 and for the actual combinations of indices and intra ocular dimensions of LT and AL in each model eye. RESULTS: In the range from 20mm to 30mm AL and 3.6-4.8mm LT, the instrument measurements yielded an error between -0.043mm and +0.089mm. Regression analyses for the three LT condition were combined in order to derive a correction factor as a function of the instrument measured AL for each combination of AL and LT in the theoretical eye. CONCLUSIONS: The assumption of a single "average" refractive index in the estimation of AL by the IOLMaster PCI biometer only induces very small errors in a wide range of combinations of ocular dimensions. Even so, the accurate estimation of those errors may help to improve accuracy of intra-ocular lens calculations through exact ray tracing, particularly in longer eyes and eyes with thicker or thinner crystalline lenses. PMID- 24766864 TI - The primary eye care examination: opening the case history and the patient's uninterrupted initial talking time. AB - PURPOSE: The uninterrupted initial talking time (UITT) of optometric patients was measured in response to the clinician's opening question: "Do you have any problems with your eyes or your sight?" METHODS: UITT was measured surreptitiously by the optometrist. Also noted was whether an eye/sight problem was claimed by the patient and whether or not this was subsequently confirmed by the examination. RESULTS: Data were collected from 822 adults, mean age 59.1yrs (SD 17.6), range 16.0-92.0yrs. UITT data were positively skewed; median value 28.87s (IQR 19.81-43.03s) and no statistically significant difference between genders (p=0.9). 53% of patients had completed their opening statement by 30s, and 90% after 1min. 75% of these individuals (age range 26-75yrs) had a median UITT 27.82s; younger patients (16-25yrs) spoke for a significantly shorter time (18.39s: p=0.002) and elderly patients (>=76yrs) a significantly longer time (37.27s: p=0.003) than the majority value. Previously unexamined patients, habitual spectacle wearers, and individuals presenting with an eye/sight problem all recorded a significantly longer UITT (p<=0.006) than their peers. The practitioner's opening question had a sensitivity of 0.54/specificity of 0.95, and a positive predictive value (PV) of 0.78/negative PV of 0.87: with a calculated value of kappa=0.53, the strength of agreement between subjective claim and objective outcome could be regarded as 'moderate'. CONCLUSION: These data suggest that an optometric patient's UITT of <30s is unlikely to prove disruptive to the clinical routine. PMID- 24766865 TI - Clinical comparison of Pulsair non-contact tonometer and Goldmann applanation tonometer in Indian population. AB - INTRODUCTION: Goldmann applanation tonometer (GAT) is the gold standard for Intraocular Pressure (IOP) measurement but has disadvantage of being contact device and problems with portability. The aim of the study was to compare the Keeler's Pulsair noncontact tonometer (NCT) with GAT in Indian Population. MATERIALS AND METHODS: Eighty-one subjects were screened from a Glaucoma clinic of a tertiary care centre in North India. The IOP was measured by Pulsair NCT and GAT after explaining the procedure. Central corneal thickness (CCT) was measured to avoid its bias on IOP readings. The data were analyzed using SPSS software. RESULTS: The mean age of subjects was 49.9+/-8.8 (mean+/-SD) years. The mean IOP as taken by Pulsair NCT was 15.79+/-4.07mmHg and that for GAT was 17.02+/ 4.23mmHg (p=0.062). The mean CCT was 0.536+/-0.019mm. A positive Pearson's correlation coefficient of 0.909 (p=0.0001) was found between the two instruments. Bland and Altmann analysis showed a fair agreement between the two tonometers at lower IOP range. CONCLUSION: Pulsair NCT can be used as a screening tool for community practices but is not reliable in the subjects with higher IOP range. PMID- 24766866 TI - Dynamic contour tonometry over silicone hydrogel contact lens. AB - PURPOSE: This study compared the measurements of intraocular pressure (IOP) and ocular pulse amplitude (OPA) using the Dynamic Contour Tonometry (DCT) over silicone hydrogel contact lenses of different modulus. Corneal biomechanics were also measured using the Ocular Response Analyzer (ORA). METHODS: Forty-seven young (mean age 22.3 years, standard deviation 1.2 years) subjects had IOP, OPA, corneal hysteresis (CH) and corneal resistance factor (CRF) measured without lens and with two brands of silicone hydrogel contact lenses. Each eye wore one brand followed by another, randomly assigned, and then the lenses switched over. Difference and agreement of IOP and OPA with and without silicone hydrogel contact lens were studied. RESULTS: The right and left eyes had similar corneal curvatures, central corneal thicknesses, IOP, OPA and corneal biomechanics at baseline. No significant difference was found in CH and CRF when they were measured over different contact lenses. IOP demonstrated a greater difference (95% limits of agreement: 2.73mmHg) compared with no lens when it was measured over high modulus silicone hydrogel lenses. Agreement improved over low lens modulus silicone hydrogel lenses (95% limits of agreement: 2.2-2.4mmHg). 95% limits of agreement were within 1.0mmHg for OPA. CONCLUSIONS: This study demonstrated the feasibility of DCT over silicone hydrogel lenses. Low lens modulus silicone hydrogel contact lens in situ has no clinical effect on DCT. PMID- 24766867 TI - Residual stereopsis in age-related macular degeneration patients and its impact on vision-related abilities: a pilot study. AB - OBJECTIVE: To determine the effect of residual stereopsis on vision-related abilities of low vision (LV) patients with age-related macular degeneration (AMD). METHODS: Prospective non-randomized observational case series. Inclusion criteria included documented AMD, LV with best corrected visual acuity (BCVA) of 20/50-20/400 in the better eye, and ages between 50 and 90 years. Stereoacuity was measured using the near Frisby Stereotest. Vision related abilities were documented with the VA LV VFQ-48 questionnaire. RESULTS: Twenty-seven subjects with mean age of 84+/-6 years old were recruited, of which 59.3% (16/27) were female. 59.3% (16/27) of the subjects were not able to see any stereoacuity plate, 25.9% (7/27) had stereoacuity of 340s of arc (SOA), 11.1% (3/27) had stereoacuity of 170 SOA and 3.7% (1/27) had stereoacuity of 85 SOA. The mean Overall Functional Visual Abilities (OFVA) score was significantly higher in those with stereopsis (2.25+/-0.99) than those without stereopsis (1.50+/-0.92) (P=0.028). CONCLUSIONS: LV patients with stereopsis have better OFVA than those without. Stereopsis should be considered as a component of LV rehabilitation and considered as an outcome measure in research and clinical practice. PMID- 24766868 TI - Bilateral tonic pupils secondary to Ross syndrome: a case report. PMID- 24766869 TI - Visual performance with changes in eccentricity in PROSE device: a case report. AB - This case report describes the variations in visual performance of a subject with moderate keratoconus with changes in front surface eccentricities (FSEs) of PROSE (Prosthetic Replacement of Ocular Surface Ecosystem). PROSE device of 0.6 FSE provided maximum visual improvement and reduction in Higher Order Aberrations (HOAs) compared to 0, 0.3 and 0.8 FSEs in this clinical condition. PMID- 24766871 TI - Estimating the size of hidden populations from register data. AB - BACKGROUND: Prevalence estimates of drug use, or of its consequences, are considered important in many contexts and may have substantial influence over public policy. However, it is rarely possible to simply count the relevant individuals, in particular when the defining characteristics might be illegal, as in the drug use case. Consequently methods are needed to estimate the size of such partly 'hidden' populations, and many such methods have been developed and used within epidemiology including studies of alcohol and drug use. Here we introduce a method appropriate for estimating the size of human populations given a single source of data, for example entries in a health-care registry. METHODS: The setup is the following: during a fixed time-period, e.g. a year, individuals belonging to the target population have a non-zero probability of being "registered". Each individual might be registered multiple times and the time points of the registrations are recorded. Assuming that the population is closed and that the probability of being registered at least once is constant, we derive a family of maximum likelihood (ML) estimators of total population size. We study the ML estimator using Monte Carlo simulations and delimit the range of cases where it is useful. In particular we investigate the effect of making the population heterogeneous with respect to probability of being registered. RESULTS: The new estimator is asymptotically unbiased and we show that high precision estimates can be obtained for samples covering as little as 25% of the total population size. However, if the total population size is small (say in the order of 500) a larger fraction needs to be sampled to achieve reliable estimates. Further we show that the estimator give reliable estimates even when individuals differ in the probability of being registered. We also compare the ML estimator to an estimator known as Chao's estimator and show that the latter can have a substantial bias when applied to epidemiological data. CONCLUSIONS: The population size estimator suggested herein complements existing methods and is less sensitive to certain types of dependencies typical in epidemiological data. PMID- 24766872 TI - ConSole: using modularity of contact maps to locate solenoid domains in protein structures. AB - BACKGROUND: Periodic proteins, characterized by the presence of multiple repeats of short motifs, form an interesting and seldom-studied group. Due to often extreme divergence in sequence, detection and analysis of such motifs is performed more reliably on the structural level. Yet, few algorithms have been developed for the detection and analysis of structures of periodic proteins. RESULTS: ConSole recognizes modularity in protein contact maps, allowing for precise identification of repeats in solenoid protein structures, an important subgroup of periodic proteins. Tests on benchmarks show that ConSole has higher recognition accuracy as compared to Raphael, the only other publicly available solenoid structure detection tool. As a next step of ConSole analysis, we show how detection of solenoid repeats in structures can be used to improve sequence recognition of these motifs and to detect subtle irregularities of repeat lengths in three solenoid protein families. CONCLUSIONS: The ConSole algorithm provides a fast and accurate tool to recognize solenoid protein structures as a whole and to identify individual solenoid repeat units from a structure. ConSole is available as a web-based, interactive server and is available for download at http://console.sanfordburnham.org. PMID- 24766873 TI - Effects of antioxidant supplements and nutrients on patients with asthma and allergies. AB - Asthma and allergic diseases have become a worldwide public health concern because of their increased prevalence. Despite decades of research on risk factors, the causes of these disorders are poorly understood. They are thought to develop through complex interactions between genetic and environmental factors. Because pulmonary and systemic oxidative stress increase inflammatory responses relevant to asthma and allergy, dietary or vitamin supplementation with antioxidants (a broad and varied category) has been proposed as an approach to reducing asthma incidence or morbidity. Meta-analyses of observational epidemiologic studies of variable methodological quality suggest associations of relatively low dietary intake of antioxidants and higher asthma and allergy prevalence. However, there have been few longitudinal studies of maternal or child dietary or vitamin/supplement antioxidant intake and asthma/allergy development. Moreover, there are no clinical trial data to support the use of dietary antioxidants or supplements to prevent asthma or allergy. A few small clinical trials suggest that specific antioxidants from diet or vitamin supplements might improve asthma control or lung function in asthmatic children or adults. Studies suggest that responses to antioxidants might be modified by life stage, genetic susceptibility, and environmental sources of oxidative stress. Large trials of antioxidant vitamin supplementation to prevent cancer suggest an increase in overall mortality with antioxidant vitamin supplementation, at least in populations with sufficient dietary antioxidant intake. This cautionary experience suggests that future trials to assess whether antioxidants reduce asthma incidence or improve asthma control should focus on supplementation of dietary sources of antioxidants. The potential benefits and risks of trials of vitamin supplements might be considered in special situations in which vulnerable populations have marked deficiency in dietary antioxidants, poor access to dietary antioxidants, and high exposure to environmental sources of oxidants. PMID- 24766870 TI - Clinical variables associated with failure of retinal detachment repair: the European vitreo-retinal society retinal detachment study report number 4. AB - OBJECTIVE: To identify risk factors associated with failure of anatomic reattachment in primary rhegmatogenous retinal detachment repair. DESIGN: Nonrandomized, multicenter, collaborative study. PARTICIPANTS: Primary procedures for 7678 rhegmatogenous retinal detachments reported by 176 surgeons from 48 countries. METHODS: We recorded specific preoperative clinical findings, repair method, and outcome after intervention. We performed univariate, bivariate, and multivariate analyses to identify variables associated with surgical failure. MAIN OUTCOME MEASURES: Final failure of retinal detachment repair (level 1), remaining silicone oil at study conclusion (level 2), and need for additional procedures to repair the detachment (level 3). RESULTS: We analyzed 7678 cases of rhegmatogenous retinal detachment repair. Presence of choroidal detachment or significant hypotony was associated with significantly higher level 1 failure rates when grade 0 or B proliferative vitreoretinopathy (PVR) was present and higher level 2 failure rates, regardless of PVR status (P<0.05). Excluding cases with choroidal detachment or hypotony, increasing PVR was associated with increasing level 1 failure rates. The difference between grade B and C-1 PVR was significant (P = 2 * 10(-6)). No difference was observed in level 1 failure rates when operated eyes were phakic versus pseudophakic. Level 1 failure was significantly higher when all 4 quadrants of retina (4.4%) were detached than when only 1 quadrant (0.8%) had subretinal fluid. With grade B or C-1 PVR, cases with large or giant tears had significantly higher level 1 failure rates. No association was observed between number of retinal breaks and failure rates. Multivariate analysis showed grade C-1 PVR, 4 detached quadrants, and presence of choroidal detachment or significant hypotony were independently linked with a greater level 1 failure rate; the presence of a smaller retinal break was associated with a lesser level 1 failure rate. CONCLUSIONS: Choroidal detachment, significant hypotony, grade C-1 PVR, 4 detached quadrants, and large or giant retinal breaks were independent explanatory variables of retinal detachment repair failure. In contrast to earlier studies, the significance of phakic versus pseudophakic status was not confirmed. PMID- 24766874 TI - Advances in environmental and occupational disorders in 2013. AB - In this review of articles published in the Journal in 2013, we report on the significant advances in environmental and occupational disorders. Research advances have led to the identification and defined the structure and function of several major allergens. A meta-analysis confirmed the importance of mold exposure in patients with allergic rhinitis, and a new immunologic classification of aspergillosis emerged. Insights into the role of diesel exhaust particles in patients with severe asthma were clarified. Improvements in stinging insect allergy diagnostics were reported. Genetic, immunologic, and biomarker studies advanced the understanding of adverse drug reactions. New practice parameters for cockroach allergen control were presented. The pathologic role of viruses and bacterial agents in patients with asthma and chronic obstructive pulmonary disease were further defined. An excellent review of allergen bronchoprovocation testing was reported. The roles of bronchoprovocation and bronchodilator responsiveness in asthma diagnosis were further clarified. A biomarker for neutrophilic asthma was identified. Therapeutic advances in asthma research include the inhibition of IL-13 by lebrikizumab, use of montelukast in asthmatic smokers, and a thorough review of bronchial thermoplasty in patients with severe asthma. Lastly, maternal asthma was linked to a number of adverse neonatal outcomes. PMID- 24766875 TI - The diagnosis and management of acute and chronic urticaria: 2014 update. AB - These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. The AAAAI and ACAAI have jointly accepted responsibility for establishing "The diagnosis and management of acute and chronic urticaria: 2014 update." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. The JTFPP understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because a given test or agent's cost is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In extraordinary circumstances, when the cost/benefit ratio of an intervention is prohibitive, as supported by pharmacoeconomic data, commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion. The JTFPP is committed to ensuring that the practice parameters are based on the best scientific evidence that is free of commercial bias. To this end, the parameter development process includes multiple layers of rigorous review. These layers include the workgroup convened to draft the parameter, the task force reviewers, and peer review by members of each sponsoring society. Although the task force has the final responsibility for the content of the documents submitted for publication, each reviewer comment will be discussed, and reviewers will receive written responses to comments, when appropriate. To preserve the greatest transparency regarding potential conflicts of interest, all members of the JTFPP and the practice parameter workgroups will complete a standard potential conflict of interest disclosure form, which will be available for external review by the sponsoring organization and any other interested individual. In addition, before confirming the selection of a Work Group chairperson, the Joint Task Force will discuss and resolve all relevant potential conflicts of interest associated with this selection. Finally, all members of parameter workgroups will be provided a written statement regarding the importance of ensuring that the parameter development process is free of commercial bias. Practice parameters are available online at www.jcaai.org and www.allergyparameters.org. PMID- 24766877 TI - Early-life weight gain, prematurity, and asthma development. PMID- 24766879 TI - Genomic approaches for studying transcriptional and post-transcriptional processes. PMID- 24766878 TI - Biology of nasal polyposis. PMID- 24766880 TI - Exploratory analysis of health-related quality of life among the empty-nest elderly in rural China: an empirical study in three economically developed cities in eastern China. AB - BACKGROUND: Along with rapid economic development, the aging process in China is gradually accelerating. The living conditions of empty-nest rural elderly are worrisome. As a more vulnerable group, empty-nest elderly are facing more urgent health problems. This study explores the health-related quality of life (HRQOL) of empty-nest elderly in rural China and aims to arouse more social concern for their HRQOL. METHODS: Research subjects were empty-nest rural elderly from three cities: Nanjing, Suzhou, and Wenzhou (ages >= 60, n = 967). This study used the five-dimensional European quality of health scale (EQ-5D) and the 12-item Short Form Health Survey (SF-12) to measure the HRQOL of the respondents. Spearman correlation coefficient, stereotype logistic regression, ordered probit regression and multinomial logistic regression, and Structural equation model (SEM) methods are employed to study the relationship. RESULTS: (1) The Spearman correlation coefficient shows that the correlations of similar domains between the SF-12 and the EQ-5D scales are relatively strong. (2) Men's scores are higher than that of women's in general health (GH) and anxiety/depression (AD) models. (3) The scores of physical component summary (PCS), physical functioning (PF), mental health (MH), and usual activities (UA) decline with age. (4) Apart from PCS, vitality (VT), and role-emotional (RE) as dependent variables, the education passes all the significance tests. The higher the education is, the higher the scores of physical or psychological health are. (5) The scores of PCS and bodily pain (BP) of empty-nest elderly are divorced or higher in other marital status. (6) In SEM analysis, the effect of basic information of empty-nest elderly on SF 12 scale is more significant. CONCLUSIONS: First, the frequency histograms of EQ 5D show that the scores of empty-nest elderly in rural China are generally low. Second, in all SF-12 items, the HRQOL is low. Third, men's scores are higher than that of women's. The elderly with higher education reported higher scores than those with lower education. Fourth, the effect of socio-demographic variables of the rural Chinese empty-nest elderly on SF-12 scores is more significant, whereas the effect on EQ-5D scores is less significant. PMID- 24766881 TI - Is parenting style a predictor of suicide attempts in a representative sample of adolescents? AB - BACKGROUND: Suicidal ideation and suicide attempts are serious but not rare conditions in adolescents. However, there are several research and practical suicide-prevention initiatives that discuss the possibility of preventing serious self-harm. Profound knowledge about risk and protective factors is therefore necessary. The aim of this study is a) to clarify the role of parenting behavior and parenting styles in adolescents' suicide attempts and b) to identify other statistically significant and clinically relevant risk and protective factors for suicide attempts in a representative sample of German adolescents. METHODS: In the years 2007/2008, a representative written survey of N = 44,610 students in the 9th grade of different school types in Germany was conducted. In this survey, the lifetime prevalence of suicide attempts was investigated as well as potential predictors including parenting behavior. A three-step statistical analysis was carried out: I) As basic model, the association between parenting and suicide attempts was explored via binary logistic regression controlled for age and sex. II) The predictive values of 13 additional potential risk/protective factors were analyzed with single binary logistic regression analyses for each predictor alone. Non-significant predictors were excluded in Step III. III) In a multivariate binary logistic regression analysis, all significant predictor variables from Step II and the parenting styles were included after testing for multicollinearity. RESULTS: Three parental variables showed a relevant association with suicide attempts in adolescents - (all protective): mother's warmth and father's warmth in childhood and mother's control in adolescence (Step I). In the full model (Step III), Authoritative parenting (protective: OR: .79) and Rejecting-Neglecting parenting (risk: OR: 1.63) were identified as significant predictors (p < .001) for suicidal attempts. Seven further variables were interpreted to be statistically significant and clinically relevant: ADHD, female sex, smoking, Binge Drinking, absenteeism/truancy, migration background, and parental separation events. CONCLUSIONS: Parenting style does matter. While children of Authoritative parents profit, children of Rejecting-Neglecting parents are put at risk - as we were able to show for suicide attempts in adolescence. Some of the identified risk factors contribute new knowledge and potential areas of intervention for special groups such as migrants or children diagnosed with ADHD. PMID- 24766882 TI - Polysaccharide A of Bacteroides fragilis: actions on dendritic cells and T cells. AB - In a recent paper published in Cell Host & Microbe, Dasgupta et al. (2014) demonstrate that a component of the gut microbiota, Bacteroides fragilis, induces IL-10-producing regulatory T cells by driving TLR2-dependent plasmacytoid dendritic cell activation. PMID- 24766883 TI - Promiscuity is not always bad. AB - In the recent issue of Cell, Bonham et al. (2014) reveal that the sorting adaptor TIRAP regulates the assembly of the Myddosome upon Toll-like receptor activation from both the cell surface and endosomes through its promiscuous binding to lipids. PMID- 24766884 TI - Meet the terminator: The phosphatase PP2A puts brakes on IRF-3 activation. AB - Cellular interferon response to microbial infection is transient. In a recent paper in Immunity, Long et al. (2014) identify protein phosphatase 2A (PP2A) as a deactivator of phospho-interferon regulatory factor 3, the key transcription factor for interferon synthesis, thus providing one basis for the observed transiency. PMID- 24766885 TI - A cross-disciplinary perspective on the innate immune responses to bacterial lipopolysaccharide. AB - The study of innate immunity to bacteria has focused heavily on the mechanisms by which mammalian cells detect lipopolysaccharide (LPS), the conserved surface component of Gram-negative bacteria. While Toll-like receptor 4 (TLR4) is responsible for all the host transcriptional responses to LPS, recent discoveries have revealed the existence of several TLR4-independent responses to LPS. These discoveries not only broaden our view of the means by which mammalian cells interact with bacteria, but they also highlight new selective pressures that may have promoted the evolution of bacterial immune evasion strategies. In this review, we highlight past and recent discoveries on host LPS sensing mechanisms and discuss bacterial countermeasures that promote infection. By looking at both sides of the host-pathogen interaction equation, we hope to provide comprehensive insights into host defense mechanisms and bacterial pathogenesis. PMID- 24766886 TI - Autophagy in antimicrobial immunity. AB - Autophagy plays a key role in cellular homeostasis, responding to various environmental stresses. In particular, pathogen invasion leads to rapid induction of autophagy, which is critical for both innate and adaptive immune responses. In this review, we focus on the emerging molecular mechanisms of pathogen elimination by autophagy (a process known as xenophagy) and on the strategies developed by pathogens to subvert autophagy. We also address other functions of autophagy proteins in restricting pathogen invasion, independent of the formation of a canonical double-membrane autophagosome. PMID- 24766887 TI - CRISPR-Cas systems: Prokaryotes upgrade to adaptive immunity. AB - Clustered regularly interspaced short palindromic repeats (CRISPR), and associated proteins (Cas) comprise the CRISPR-Cas system, which confers adaptive immunity against exogenic elements in many bacteria and most archaea. CRISPR mediated immunization occurs through the uptake of DNA from invasive genetic elements such as plasmids and viruses, followed by its integration into CRISPR loci. These loci are subsequently transcribed and processed into small interfering RNAs that guide nucleases for specific cleavage of complementary sequences. Conceptually, CRISPR-Cas shares functional features with the mammalian adaptive immune system, while also exhibiting characteristics of Lamarckian evolution. Because immune markers spliced from exogenous agents are integrated iteratively in CRISPR loci, they constitute a genetic record of vaccination events and reflect environmental conditions and changes over time. Cas endonucleases, which can be reprogrammed by small guide RNAs have shown unprecedented potential and flexibility for genome editing and can be repurposed for numerous DNA targeting applications including transcriptional control. PMID- 24766888 TI - Preparing the first responders: building the inflammatory transcriptome from the ground up. AB - In cells of the immune system, inflammatory stimuli trigger highly coordinated cascades of gene activation that are precisely calibrated to the nature and strength of the stimulus. Herein, we describe the forces that control inflammatory gene transcription and highlight that many critical determinants of responsiveness are established prior to challenge. We discuss key steps in the transcription cycle that are regulated during gene activation and the importance of the underlying enhancer landscape. Further, we illustrate how the diversity in regulatory strategies employed at inflammatory genes provides novel opportunities for therapeutic intervention. PMID- 24766889 TI - What counts in the immunological synapse? AB - Molecular interactions at the interface between helper T cells and antigen presenting B cells govern the ability to produce specific antibodies, which is a central event in protective immunity generated by natural infection or man-made vaccines. In order for a T cell to deliver effective help to a B cell and guide affinity maturation, it needs to provide feedback that is proportional to the amount of antigen the B cell collects with its surface antibody. This review focuses on mechanisms by which T and B cells manage to count the products of antigen capture and encourage B cells with the best receptors to dominate the response and make antibody-producing plasma cells. We discuss what is known about the proportionality of T cells responses to presented antigens and consider the mechanisms that B cells may use to keep count of positive feedback from T cells. PMID- 24766890 TI - Plant PRRs and the activation of innate immune signaling. AB - Despite being sessile organisms constantly exposed to potential pathogens and pests, plants are surprisingly resilient to infections. Plants can detect invaders via the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Plant PRRs are surface-localized receptor like kinases, which comprise a ligand-binding ectodomain and an intracellular kinase domain, or receptor-like proteins, which do not exhibit any known intracellular signaling domain. In this review, we summarize recent discoveries that shed light on the molecular mechanisms underlying ligand perception and subsequent activation of plant PRRs. Notably, plant PRRs appear as central components of multiprotein complexes at the plasma membrane that contain additional transmembrane and cytosolic kinases required for the initiation and specificity of immune signaling. PRR complexes are under tight control by protein phosphatases, E3 ligases, and other regulatory proteins, illustrating the exquisite and complex regulation of these molecular machines whose proper activation underlines a crucial layer of plant immunity. PMID- 24766891 TI - Staying alive: cell death in antiviral immunity. AB - Programmed cell death is an integral part of host defense against invading intracellular pathogens. Apoptosis, programmed necrosis, and pyroptosis each serve to limit pathogen replication in infected cells, while simultaneously promoting the inflammatory and innate responses that shape effective long-term host immunity. The importance of carefully regulated cell death is evident in the spectrum of inflammatory and autoimmune disorders caused by defects in these pathways. Moreover, many viruses encode inhibitors of programmed cell death to subvert these host responses during infection, thereby facilitating their own replication and persistence. Thus, as both virus and cell vie for control of these pathways, the battle for survival has shaped a complex host-pathogen interaction. This review will discuss the multifaceted role that programmed cell death plays in maintaining the immune system and its critical function in host defense, with a special emphasis on viral infections. PMID- 24766892 TI - Stress, inflammation, and defense of homeostasis. AB - Inflammation is traditionally considered a defense response induced by infection or injury. However, inflammation can also be induced by tissue stress and malfunction in the absence of infection or overt tissue damage. Here we discuss the relationship between homeostasis, stress responses, and inflammation. Stress responses have cell-autonomous and cell-extrinsic components, the latter contributing to tissue level adaptation to stress conditions. Inflammation can be thought of as the extreme end of a spectrum that ranges from homeostasis to stress response to bona fide inflammatory response. Inflammation can be triggered by two types of stimuli: extreme deviations of homeostasis or challenges that cause a disruption of homeostasis. This perspective may help to explain qualitative differences and functional outcomes of diverse inflammatory responses. PMID- 24766893 TI - The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. AB - The innate immune system deploys a variety of sensors to detect signs of infection. Nucleic acids represent a major class of pathogen signatures that can trigger robust immune responses. The presence of DNA in the cytoplasm of mammalian cells is a danger signal that activates innate immune responses; however, how cytosolic DNA triggers these responses remained unclear until recently. In this review, we focus on the mechanism of DNA sensing by the newly discovered cGAS-cGAMP-STING pathway and highlight recent progress in dissecting the in vivo functions of this pathway in immune defense as well as autoimmunity. PMID- 24766895 TI - The multifaceted role of the intestinal microbiota in colon cancer. AB - In recent years, our understanding of the mechanisms underlying colorectal carcinogenesis has vastly expanded. Underlying inflammation within the intestine, diet, and most recently, the gut microbiota, have been demonstrated to influence the development of colorectal cancer. However, since cancer is ultimately a genetic disease, these factors are thought to create genotoxic stress within the intestinal environment to promote genetic and epigenetic alterations leading to cancer. In this review, we will focus on how gut microbes intersect with inflammation, diet, and host genetics to influence the development of colon cancer. PMID- 24766894 TI - Inflammasomes and metabolic disorders: old genes in modern diseases. AB - Modern medical and hygienic practices have greatly improved human health and longevity; however, increased human life span occurs concomitantly with the emergence of metabolic and age-related diseases. Studies over the past decade have strongly linked host inflammatory responses to the etiology of several metabolic diseases including atherosclerosis, type 2 diabetes (T2D), obesity, and gout. A common immunological factor to these diseases is the activation of the inflammasome and release of proinflammatory cytokines that promote disease progression. Here we review the molecular mechanism(s) of inflammasome activation in response to metabolic damage-associated molecular patterns (DAMPs) and discuss potential targets for therapeutic intervention. PMID- 24766896 TI - Bacteria fighting back: how pathogens target and subvert the host innate immune system. AB - The innate immune system has evolved under selective pressure since the radiation of multicellular life approximately 600 million years ago. Because of this long history, innate immune mechanisms found in modern eukaryotic organisms today are highly complex but yet built from common molecular strategies. It is now clear that evolution has selected a conserved set of antimicrobial peptides as well as pattern-recognition receptors (PRRs) that initiate cellular-based signals as a first line of defense against invading pathogens. Conversely, microbial pathogens employ their own strategies in order to evade, inhibit, or otherwise manipulate the innate immune response. Here, we discuss recent discoveries that have changed our view of immune modulatory mechanisms employed by bacterial pathogens, focusing specifically on the initial sites of microbial recognition and extending to host cellular signal transduction, proinflammatory cytokine production, and alteration of protein trafficking and secretion. PMID- 24766897 TI - Distribution and source of heavy metals in the surface sediments from the near shore area, north Jiangsu Province, China. AB - Samples of surface sediment and vibrocore were collected in the near-shore area of north Jiangsu Province for grain size, elements, (210)Pbexcess and (137)Cs analyses. In our study area, the diversity of metal concentration was controlled not by the grain size, but by the source. The element content of the old Yellow River Delta was used as baseline for our study area. Geoaccumulation indexes indicate that no station was polluted by Cu, Pb, Zn and As, but the Igeo values of As were close to zero in some stations. Slight pollution caused by Cd was observed in some stations. Correlation and enrichment factors suggest that Cu, Pb and Zn are lithogenic in origin, while As and Cd are mixed in origin. Especially, in some polluted stations Cd was obviously anthropogenic in origin. PMID- 24766898 TI - Stable isotopes of carbon and nitrogen in the study of organochlorine contaminants in albatrosses and petrels. AB - Carbon and nitrogen stable isotopes in albatrosses and petrels collected off southern Brazil were compared with concentrations of organochlorine contaminants (OCs). delta(13)C and delta(15)N values, as well as OCs concentrations, exhibited a high degree of variability among individuals and overlap among species. delta(13)C values reflected latitudinal differences among species, with lower values found in Wandering and Tristan Albatrosses and higher values found in Black-browed and Atlantic Yellow-nosed Albatrosses and White-chinned Petrels. Some relationships were found between OCs and stable isotopes, but in general a partial 'uncoupling' was observed between OCs concentrations and stable isotopes ratios (especially for delta(15)N). delta(13)C and delta(15)N values in Procellariiformes tissues during the non-breeding season appear to be a better indicator of foraging habitats than of trophic relationships, which may partially explain the high degree of variability between concentrations of OCs and stable isotopes ratios in birds with a diversified diet and wide foraging range. PMID- 24766899 TI - Ultrasound-guided transvaginal radiofrequency myolysis for symptomatic uterine myomas. AB - OBJECTIVE: To investigate the feasibility, efficacy and safety of ultrasound guided transvaginal radiofrequency myolysis for symptomatic uterine myomas. STUDY DESIGN: Forty-six premenopausal women with symptomatic uterine myomas received ultrasound-guided transvaginal radiofrequency myolysis as an outpatient procedure. Outcomes were assessed by measuring myoma volume at baseline and at 3 , 6- and 12-month follow-up; and by calculating the myoma volume reduction rate. Clinical improvement was assessed by calculating the menorrhagia score, the symptom severity score and the health-related quality-of-life score (Uterine Fibroids Symptom and Health-related Quality-of-life Questionnaire) before and after myolysis. RESULTS: The mean age of patients was 40.8 [standard deviation (SD) 6.5] years. The mean diameter of the dominant myoma at baseline was 4.8 (SD 1.1) cm and the mean volume of the dominant myoma at baseline was 67.4 (SD 51.1)cm(3). The size of the myoma decreased gradually and an overall volume reduction rate of 83.0% was achieved at 12-month follow-up. The mean symptom severity score decreased and mean health-related quality-of-life score increased; the Uterine Fibroids Symptom and Health-related Quality-of-life Questionnaire showed a significant clinical improvement after myolysis compared with baseline (p<0.001). The menorrhagia score decreased significantly from baseline (p<0.05), showing an improvement in menorrhagia at 3-, 6- and 12-month follow-up. No major complications were observed or reported. The re-operation rate was 8.7%. Fifteen and eighteen months after myolysis, two patients delivered infants with no complications during or after delivery. CONCLUSION: Ultrasound-guided transvaginal radiofrequency myolysis may be a safe, effective and minimally invasive outpatient procedure for the treatment of symptomatic uterine myomas. PMID- 24766901 TI - Occlusion of a high rectovaginal fistula by tissue adhesive. PMID- 24766900 TI - Diagnostic accuracy of endometrial thickness for the detection of intra-uterine pathologies and appropriateness of performed hysteroscopies among asymptomatic postmenopausal women. AB - OBJECTIVE: To measure the diagnostic accuracy of endometrial thickness for the detection of intra-uterine pathologies among asymptomatic postmenopausal women, and to test the diagnostic accuracy and appropriateness of performed hysteroscopies. STUDY DESIGN: Prospective study of 268 asymptomatic postmenopausal women with endometrial thickness >=4 mm referred to diagnostic hysteroscopy. The diagnostic accuracy of various endometrial thickness cut-off values was tested. Histological and hysteroscopic results were compared to measure the diagnostic accuracy of outpatient hysteroscopies. RESULTS: No endometrial thickness cut-off values had optimal diagnostic accuracy [positive likelihood ratio (LR+) >10 and negative likelihood ratio (LR-) <0.1]. The best endometrial thickness cut-off value for the detection of all intra-uterine pathologies was >=8 mm (LR+ 10.05 and LR- 0.22). An endometrial thickness cut-off value >=10 mm did not miss any cases of endometrial cancer. The success rate of diagnostic hysteroscopy was 89%, but 97% of these revealed a benign intra-uterine pathology. The diagnostic accuracy of hysteroscopy was optimal for all intra uterine pathologies, except endometrial hyperplasia (LR- 0.52). CONCLUSION: Using an endometrial thickness cut-off value >=4 mm, only 3% of performed hysteroscopies were useful for the detection of pre-malignant or malignant lesions. Despite the finding that endometrial thickness did not show optimal diagnostic accuracy, using the best cut-off value (>=8 mm) may be helpful to decrease the number of false-positive results. No cases of endometrial cancer were diagnosed in asymptomatic postmenopausal women with endometrial thickness <10mm. PMID- 24766902 TI - Bivalirudin for the treatment of patients with confirmed or suspected heparin induced thrombocytopenia. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an adverse immune-mediated response to unfractionated heparin and, less commonly, low molecular weight heparin. It is associated with a high thrombotic risk and the potential for limb and life-threatening complications. Argatroban is the only approved and currently available anticoagulant for HIT treatment in the USA. OBJECTIVES: To report safety and efficacy outcomes with bivalirudin for HIT treatment. METHODS: We retrospectively examined records from our registry of patients with a suspected, confirmed or previous history of HIT and who had received bivalirudin for anticoagulation in a single tertiary-care center over a 9-year period. RESULTS: We identified 461 patients who received bivalirudin: 220 (47.7%) were surgical patients, and 241 (52.3%) were medical patients. Of this population, 107 (23.2%) were critically ill, and 109 (23.6%) were dialysis-dependent. Suspected, confirmed and previous history of HIT were reported in 262, 124 and 75 patients, respectively. Of 386 patients with suspected or confirmed HIT, 223 patients (57.8%) had thrombosis at HIT diagnosis. New thrombosis was identified in 21 patients (4.6%) while they were on treatment with therapeutic doses of bivalirudin. No patient required HIT-related amputation. Major bleeding occurred in 35 patients (7.6%). We found a significant increase in major bleeding risk in the critically ill population (13.1%; odds ratio 2.4, 95% confidence interval 1.2 4.9, P = 0.014). The 30-day all-cause mortality rate was 14.5% (67 patients), and eight of 67 (1.7%) deaths were HIT-related. CONCLUSION: Bivalirudin may be an effective and safe alternative option for the treatment of both suspected and confirmed HIT, and appears to reduce the rate of HIT-related amputation. PMID- 24766903 TI - The assessment of material handling strategies in dealing with sudden loading: the effects of load handling position on trunk biomechanics. AB - Back injury caused by sudden loading is a significant risk among workers that perform manual handling tasks. The present study investigated the effects of load handling position on trunk biomechanics (flexion angle, L5/S1 joint moment and compression force) during sudden loading. Eleven subjects were exposed to a 6.8 kg sudden loading while standing upright, facing forward and holding load at three different vertical heights in the sagittal plane or 45 degrees left to the sagittal plane (created by arm rotation). Results showed that the increase of load holding height significantly elevated the peak L5/S1 joint compression force and reduced the magnitude of trunk flexion. Further, experiencing sudden loading from an asymmetric direction resulted in significantly smaller peak L5/S1 joint compression force, trunk flexion angle and L5/S1 joint moment than a symmetric posture. These findings suggest that handling loads in a lower position could work as a protective strategy during sudden loading. PMID- 24766904 TI - Role of pharmacists in collaborative care of travellers with chronic conditions. PMID- 24766905 TI - PET-CT scanner characterization for PET raw data use in biomedical research. AB - The purpose of this paper is to describe the experiments and methods that led to the geometrical interpretation of new-generation commercial PET-CT scanners, finalized to off-line PET-based treatment verification in ion beam therapy. Typically, the geometrical correspondence between the image domain (i.e., the dicom PET) and the sinogram domain (i.e., the PET raw data) is not explicitly described by scanner vendors. Hence, the proposed characterization can be applied to commercial PET-CT scanners used in biomedical research, for the development of technologies and methods requiring the use of PET raw data, without having access to confidential information from the vendors. PMID- 24766906 TI - Cycloserine-induced psychosis in a young female with drug-resistant tuberculosis. AB - OBJECTIVE: To report a case of cycloserine-induced acute psychosis in a young female while on second line antitubercular treatment (ATT) for tubercular meningitis. METHOD: Case report. RESULTS: A 20-year-old female, known case of tubercular meningitis on ATT since 8 months, presented with a 10-days history of headache, vomiting, and photophobia. A provisional diagnosis of drug-resistant tuberculosis was made, and second-line ATT including cycloserine (750 mg/day) and levofloxacin (750 mg/day) was added. Three days after the start of cycloserine and levofloxacin, the patient developed psychosis with delusions and hallucinations. Since the patient was on several drugs with potential to cause psychotic reaction, we considered a provisional diagnosis of drug-induced acute psychosis. Two days following cycloserine withdrawal, the patient improved significantly, and on the third day, she was absolutely normal with disappearance of psychotic symptoms. CONCLUSION: Our case highlights the importance of awareness regarding psychiatric adverse events of antitubercular agents and the reversible nature of the adverse events on drug withdrawal. We also suggest that caution should be exercised while administering cycloserine in MDR-TB patients because of a higher risk of psychiatric adverse events. PMID- 24766908 TI - The Columbia Mall shooting: reflections of a physician responder. PMID- 24766907 TI - Thorax irradiation triggers a local and systemic accumulation of immunosuppressive CD4+ FoxP3+ regulatory T cells. AB - BACKGROUND: Lymphocyte infiltration is a common feature of radiation-induced pneumonitis and fibrosis, but their contribution to the pathogenic processes is still unclear. Here, we addressed the impact of thorax irradiation on the T cell compartment with a focus on immunosuppressive regulatory T cells (Treg). METHODS: C57BL/6 wild type mice (WT) received anesthesia only (sham controls, 0 Gy) or were exposed to a single dose of whole thorax irradiation (15 Gy). Immune cells from lung tissue, spleen, and cervical lymph nodes were collected 10 to 84 days post-irradiation and phenotypically characterized by flow cytometry. RESULTS: Whole thorax irradiation provoked an increased influx of CD3+ T cells at 42 and 84 days post-irradiation. In contrast, local irradiation caused a sustained reduction in CD3+ T cells in peripheral lymphoid tissues. Interestingly, we observed a significant local and systemic increase in the fraction of CD4+ T cells expressing the transcription factor forkhead box P3 (FoxP3), the phenotypic marker for murine Treg, at day 21 post-irradiation. The accumulation of Treg was associated with increased levels of T cells expressing surface proteins characteristic for recruitment and immunosuppressive activity, e.g. CD103, CTLA-4 and CD73. Importantly, Treg isolated at this time point were able to suppress CD4+ effector T cells to a similar extent as Treg isolated from control mice. CONCLUSIONS: The response of the adaptive immune system to whole thorax irradiation is characterized by local immunoactivation and systemic immunosuppression. The transient accumulation of immunosuppressive CD4+ FoxP3+ Treg may be required to protect the lung against excessive inflammation-induced tissue damage. Further investigations shall define the mechanisms underlying the accumulation of Treg and their role for the pathogenesis of radiation-induced lung disease. PMID- 24766909 TI - The continuum between semelparity and iteroparity: plastic expression of parity in response to season length manipulation in Lobelia inflata. AB - BACKGROUND: Semelparity and iteroparity are considered to be distinct and alternative life-history strategies, where semelparity is characterized by a single, fatal reproductive episode, and iteroparity by repeated reproduction throughout life. However, semelparous organisms do not reproduce instantaneously; typically reproduction occurs over an extended time period. If variation in reproductive allocation exists within such a prolonged reproductive episode, semelparity may be considered iteroparity over a shorter time scale.This continuity hypothesis predicts that "semelparous" organisms with relatively low probability of survival after age at first reproduction will exhibit more extreme semelparity than those with high probability of adult survival. This contrasts with the conception of semelparity as a distinct reproductive strategy expressing a discrete, single, bout of reproduction, where reproductive phenotype is expected to be relatively invariant. Here, we manipulate expected season length- and thus expected adult survival--to ask whether Lobelia inflata, a classic "semelparous" plant, exhibits plasticity along a semelparous-iteroparous continuum. RESULTS: Groups of replicated genotypes were manipulated to initiate reproduction at different points in the growing season in each of three years. In lab and field populations alike, the norm of reaction in parity across a season was as predicted by the continuity hypothesis: as individuals bolted later, they showed shorter time to, and smaller size at first reproduction, and multiplied their reproductive organs through branching, thus producing offspring more simultaneously. CONCLUSIONS: This work demonstrates that reproductive effort occurs along a semelparous-iteroparous continuum within a "semelparous" organism, and that variation in parity occurs within populations as a result of phenotypic plasticity. PMID- 24766910 TI - Health-related quality of life and related factors of military police officers. AB - PURPOSE: The present study aimed to determine the effect of demographic characteristics, occupation, anthropometric indices, and leisure-time physical activity levels on coronary risk and health-related quality of life among military police officers from the State of Santa Catarina, Brazil. METHODS: The sample included 165 military police officers who fulfilled the study's inclusion criteria. The International Physical Activity Questionnaire and the Short Form Health Survey were used, in addition to a spreadsheet of socio-demographic, occupational and anthropometric data. Statistical analyses were performed using descriptive analysis followed by Spearman Correlation and multiple linear regression analysis using the backward method. RESULTS: The waist-to-height ratio was identified as a risk factor low health-related quality of life. In addition, the conicity index, fat percentage, years of service in the military police, minutes of work per day and leisure-time physical activity levels were identified as risk factors for coronary disease among police officers. CONCLUSIONS: These findings suggest that the Military Police Department should adopt an institutional policy that allows police officers to practice regular physical activity in order to maintain and improve their physical fitness, health, job performance, and quality of life. PMID- 24766911 TI - Caregiver-reported adherence to antiretroviral therapy among HIV infected children in Mekelle, Ethiopia. AB - BACKGROUND: Adherence to antiretroviral therapy (ART) in children is complicated may be because of many factors such as child characteristics, caregiver and family characteristics, regimen characteristics, etc. Therefore, it is important to identify factors associated with adherence in HIV infected children in order to reduce the risk of developing treatment failure or drug resistance through interventions. This survey was planned to find out the rate of adherence to ART and its associated factors among the children in Mekelle, Tigray region, Ethiopia. METHODS: A cross-sectional survey was conducted in two hospitals in Mekelle: Ayder Referral Hospital and Mekelle Hospital, during the months of February to March 2013. A structured questionnaire was administered to caregivers to assess patient's adherence. RESULTS: Out of a total of 193 patients, 83.4% as reported by caregivers were adherent to ART in the past seven days before the interview. On multivariate logistic regression model, it was found that the children whose caregivers were unmarried (AOR = 15.17, 95% CI: 3.36-68.43) and married (AOR = 3.54, 95% CI: 1.23-10.13) were more likely to adhere to their ART treatment than those whose caregivers were divorced/separated. Similarly, children whose caregivers' age groups of 25-34 (AOR = 22.27, 95% CI: 4.34-114.29) and 35-44 (AOR = 7.14, 95% CI: 1.65-30.95) were more likely to adhere than their counterparts. The major reasons reported by caregivers for missing medicines include: child being depressed (24.4%), drug side effects (16.3%), too many pills (15.5%) and difficulty in swallowing pills (13.3%). CONCLUSIONS: The prevalence of adherence to ART among children was found to be high and comparable to that of other similar setups. Nevertheless, encouraging the fundamental role of caregivers is so significant to improve adherence among those who missed a dose or more and consequently treatment outcomes of children with HIV. PMID- 24766912 TI - Serum C-X-C motif chemokine 13 is elevated in early and established rheumatoid arthritis and correlates with rheumatoid factor levels. AB - INTRODUCTION: We hypothesized that serum levels of C-X-C motif chemokine 13 (CXCL13), a B-cell chemokine, would delineate a subset of rheumatoid arthritis (RA) patients characterized by increased humoral immunity. METHODS: Serum from patients with established RA (the Dartmouth RA Cohort) was analyzed for CXCL13, rheumatoid factor (RF) levels, anticitrullinated peptide/protein antibody (ACPA) and total immunoglobulin G (IgG); other parameters were obtained by chart review. A confirmatory analysis was performed using samples from the Sherbrooke Early Undifferentiated PolyArthritis (EUPA) Cohort. The Wilcoxon rank-sum test, a t test and Spearman's correlation analysis were utilized to determine relationships between variables. RESULTS: In both the Dartmouth and Sherbrooke cohorts, CXCL13 levels were selectively increased in seropositive relative to seronegative RA patients (P = 0.0002 and P < 0.0001 for the respective cohorts), with a strong correlation to both immunoglobulin M (IgM) and IgA RF levels (P < 0.0001). There was a weaker relationship to ACPA titers (P = 0.03 and P = 0.006, respectively) and total IgG (P = 0.02 and P = 0.14, respectively). No relationship was seen with regard to age, sex, shared epitope status or inclusion high-sensitivity C reactive protein (hsCRP) in either cohort or regarding the presence of baseline erosions in the Sherbrooke Cohort, whereas a modest relationship with Disease Activity Score in 28 joints CRP (DAS28-CRP) was seen in the Dartmouth cohort but not the Sherbrooke cohort. CONCLUSION: Using both established and early RA cohorts, marked elevations of serum CXCL13 levels resided nearly completely within the seropositive population. CXCL13 levels exhibited a strong relationship with RF, whereas the association with clinical parameters (age, sex, DAS28-CRP and erosions) or other serologic markers (ACPA and IgG) was either much weaker or absent. Elevated serum CXCL13 levels may identify a subset of seropositive RA patients whose disease is shaped by or responsive to RF production. PMID- 24766913 TI - Under the radar: a cross-sectional study of the challenge of identifying at-risk alcohol consumption in the general practice setting. AB - BACKGROUND: Primary care providers are an important source of information regarding appropriate alcohol consumption. As early presentation to a provider for alcohol-related concerns is unlikely, it is important that providers are able to identify at-risk patients in order to provide appropriate advice. This study aimed to report the sensitivity, specificity, positive predictive value and negative predictive value of General Practitioner (GP) assessment of alcohol consumption compared to patient self-report, and explore characteristics associated with GP non-detection of at-risk status. METHOD: GP practices were selected from metropolitan and regional locations in Australia. Eligible patients were adults presenting for general practice care who were able to understand English and provide informed consent. Patients completed a modified AUDIT-C by touchscreen computer as part of an omnibus health survey while waiting for their appointment. GPs completed a checklist for each patient, including whether the patient met current Australian guidelines for at-risk alcohol consumption. Patient self-report and GP assessments were compared for each patient. RESULTS: GPs completed the checklist for 1720 patients, yielding 1565 comparisons regarding alcohol consumption. The sensitivity of GPs' detection of at-risk alcohol consumption was 26.5%, with specificity of 96.1%. Higher patient education was associated with GP non-detection of at-risk status. CONCLUSIONS: GP awareness of which patients might benefit from advice regarding at-risk alcohol consumption appears low. Given the complexities associated with establishing whether alcohol consumption is 'at-risk', computer-based approaches to routine screening of patients are worthy of exploration as a method for prompting the provision of advice in primary care. PMID- 24766914 TI - Decreased interleukin-10 serum levels in first-episode drug-naive schizophrenia: relationship to psychopathology. AB - Many lines of findings support the hypothesis of the inflammation-related pathways in the multifactorial pathogenesis of schizophrenia (SZ). Interleukin-10 (IL-10), a potential anti-inflammatory cytokine, was found to be altered in chronic patients with SZ. The aim of this study was to assess the serum levels of IL-10 in first-episode and drug-naive (FEDN) patients with SZ and its relationships with the psychopathological parameters. Serum IL-10 levels were analyzed using established procedures in 128 FEDN patients with SZ and 62 healthy controls. Schizophrenia symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) with cognitive factor derived from the five factor model of the PANSS. Compared to the healthy controls, the patients exhibited a significant decrease in IL-10 levels. Serum IL-10 was inversely correlated with the PANSS negative symptom, as well as with the PANSS cognitive factor subscores in patients. Our results suggested that decreased IL-10 may be implicated in the negative symptom and cognitive impairment at the acute stage of schizophrenia episode. PMID- 24766915 TI - Round block technique is a useful oncoplastic procedure for multicentric fibroadenomas. AB - PURPOSE: Multicentric fibroadenomas, defined as multiple fibroadenomas located at different quadrants of the breast, occur in 10-20% of women with fibroadenoma. The surgical management of multicentric fibroadenomas may be troublesome for surgeons and patients. In this study, we report our preliminary experience using the "round block technique" in the management of women with multicentric fibroadenomas of the breast. MATERIALS AND METHODS: Records of patients with breast diseases managed with the round block technique were searched for in the Changhua Christian Hospital oncoplastic breast surgery database. The patients' clinicopathologic characteristics, type of surgery, operation time, blood loss, and complications were recorded. The cosmetic outcome was evaluated by the patient and operating surgeon two months after the surgery. RESULTS: Twenty patients with multicentric fibroadenomas managed by the round block technique comprised the current study cohort. The mean age of the subjects was 36.5 +/- 10.4 years. Twelve (60%) patients had tumors on one side of the breast, and eight (40%) had bilateral breast lesions. The average number of tumors removed was 3.3 +/- 1.2 (range 2-6) per breast, and mean tumor size was 2.2 +/- 0.5 cm. Three (15%) patients developed mild ecchymosis of the breast undergoing operation, which resolved spontaneously. One (5%) patient had partial nipple ischemia/necrosis due to 2 tumors excised near the nipple-areolar complex. The aesthetic results were evaluated as good in 19 (95%) patients and fair in 1 (5%). CONCLUSIONS: The round block technique is a useful oncoplastic procedure for the management of multicentric fibroadenomas excised at the same time. PMID- 24766916 TI - Engaging in lifelong learning to lead the way. PMID- 24766917 TI - Engaging infection preventionists in the OR. PMID- 24766918 TI - A few minutes with Cathy Kleiner. PMID- 24766919 TI - Implementing AORN recommended practices for environmental cleaning. AB - In recent years, researchers have developed an increasing awareness of the role of the environment in the development of health care-associated infections. AORN's "Recommended practices for environmental cleaning" is an evidence-based document that provides specific guidance for cleaning processes, for the selection of appropriate cleaning equipment and supplies, and for ongoing education and quality improvement. This updated recommended practices document has an expanded focus on the need for health care personnel to work collaboratively to accomplish adequately thorough cleanliness in a culture of safety and mutual support. Perioperative nurses, as the primary advocates for patients while they are being cared for in the perioperative setting, should help ensure that a safe, clean environment is reestablished after each surgical procedure. PMID- 24766920 TI - Bullying, mentoring, and patient care. AB - The literature suggests that acts of bullying are a root cause of new nurses leaving their units or the profession entirely and have the potential to worsen the nursing shortage. As an effective way to address bullying in the perioperative setting, mentoring benefits the nursing profession. Mentoring can have a direct influence on nurses' longevity in a health care organization, thereby strengthening the nursing workforce. Magnet-designated hospitals support the importance of mentor-mentee relationships for positive employee retention and positive recruitment outcomes. One of the most important tasks that a mentor should undertake is that of a role model. Establishing a culture of mentoring requires authentic leadership, genuine caring and respect for employees, and open communication. The entire nursing profession benefits from a culture of mentoring, as do the patients and families who receive care. PMID- 24766921 TI - Establishing the surgical nurse liaison role to improve patient and family member communication. AB - Having clear personal communication with a surgical patient's family members decreases the anxiety and increases patient and family member satisfaction. Perioperative team members at one East Coast community hospital implemented a new approach to communication in the perioperative area to address patient satisfaction after patient survey scores declined in the areas of communication and calming fears. An additional consideration was the facility's plan to move to a new facility in which the surgical department would be split across two floors. A literature review revealed that adding a surgical nurse liaison can increase patient, family member, and staff member satisfaction. The administration approved creation of the position, with duties that included managing the waiting area, facilitating interaction between physicians and patients' family members, and assisting with family visits to the perianesthesia unit. After implementation of this position, results of surveys showed increases in patient satisfaction. One year after the position was established, staff members reported they were happy with the position as well. PMID- 24766922 TI - Back to basics: preventing surgical site infections. AB - A surgical site infection (SSI) is an unintended and oftentimes preventable consequence of surgery. There is a significant amount of literature related to preventing SSIs, and it is up to practitioners in each care setting to review the evidence and work together to implement SSI prevention measures, such as nasal decolonization, antibiotic prophylaxis, preoperative showers, preoperative oxygen supplementation, and antimicrobial sutures. In addition, practitioners can follow several recommendations to reduce the risk of SSIs, including following proper hand hygiene practices; wearing clean, facility-laundered scrub attire; following a surgical safety checklist; and speaking up when a break in sterile technique is witnessed. The benefits of preventing SSIs are preventing patient mortality and decreasing the burden that SSIs pose on the national health care system. It is up to health care leaders to drive and support SSI prevention initiatives. PMID- 24766923 TI - Why a column on ambulatory best practices? PMID- 24766924 TI - Overcoming language barriers for pediatric surgical patients and their family members. PMID- 24766925 TI - Telling our stories: writing exceptional exemplars. PMID- 24766926 TI - Responding to a national disaster: a partnership forged between two Australian hospitals. PMID- 24766927 TI - Prevention of venous thromboembolism. PMID- 24766929 TI - CA-MRSA skin infections: An ounce of prevention is worth a pound of cure. PMID- 24766930 TI - Knowledge and attitudes to personal genomics testing for complex diseases among Nigerians. AB - BACKGROUND: The study examined the knowledge and attitudes to personal genomics testing for complex diseases among Nigerians and identified how the knowledge and attitudes vary with gender, age, religion, education and related factors. METHODS: Data were collected using qualitative method in 2 districts of the Federal Capital Territory. In the study, eight (8) Focused Group Discussions (FGDs) and twenty seven (27) Key Informant Interviews (KIIs) were conducted. Participants for the research were recruited among healthy Nigerians, individuals with complex diseases, health care professionals, community leaders and health policy makers. RESULT: Analysis of the result showed that most respondents in both FGDs and KIIs had limited knowledge about genomics test initially. Their understanding of the test however improved after explanation on its concept. Participants showed positive attitude towards genomics tests. Nevertheless they expressed fear over direct to consumer personal genomics testing, testing unborn babies and disclosure of results to third parties. Culture and religion were found to influence the perspectives of respondents on genomics test particularly those aspects that could either directly contradict their beliefs and practices or lead to actions which contradict them. CONCLUSION: In conclusion, most Nigerians interviewed had limited knowledge of genomics test but with supportive attitude towards its use in predicting future risk of complex diseases after understanding the test concept. Genomics testing for complex diseases was not a common practice in Nigeria. PMID- 24766931 TI - Dynamic adaptation of large-scale brain networks in response to acute stressors. AB - Stress initiates an intricate response that affects diverse cognitive and affective domains, with the goal of improving survival chances in the light of changing environmental challenges. Here, we bridge animal data at cellular and systems levels with human work on brain-wide networks to propose a framework describing how stress-related neuromodulators trigger dynamic shifts in network balance, enabling an organism to comprehensively reallocate its neural resources according to cognitive demands. We argue that exposure to acute stress prompts a reallocation of resources to a salience network, promoting fear and vigilance, at the cost of an executive control network. After stress subsides, resource allocation to these two networks reverses, which normalizes emotional reactivity and enhances higher-order cognitive processes important for long-term survival. PMID- 24766932 TI - Hyperthyroidism and thyrotoxicosis. AB - Hyperthyroidism and thyrotoxicosis are hypermetabolic conditions that cause significant morbidity and mortality. The diagnosis can be difficult because symptoms can mimic many other disease states leading to inaccurate or untimely diagnoses and management. Thyroid storm is the most severe form of thyrotoxicosis, hallmarked by altered sensorium, and, if untreated, is associated with significant mortality. Thyroid storm should be considered in the differential of any patient presenting with altered mental status. The emergency medicine physician who can rapidly recognize thyrotoxicosis, identify the precipitating event, appropriately and comprehensively begin medical management, and facilitate disposition will undoubtedly save a life. PMID- 24766933 TI - Alcoholic metabolic emergencies. AB - Ethanol intoxication and ethanol use are associated with a variety of metabolic derangements encountered in the Emergency Department. In this article, the authors discuss alcohol intoxication and its treatment, dispel the myth that alcohol intoxication is associated with hypoglycemia, comment on electrolyte derangements and their management, review alcoholic ketoacidosis, and end with a section on alcoholic encephalopathy. PMID- 24766934 TI - Hypothyroidism: causes, killers, and life-saving treatments. AB - Hypothyroidism is a very common, yet often overlooked disease. It can have a myriad of signs and symptoms, and is often nonspecific. Identification requires analysis of thyroid hormones circulating in the bloodstream, and treatment is simply replacement with exogenous hormone, usually levothyroxine (Synthroid). The deadly manifestation of hypothyroidism is myxedema coma. Similarly nonspecific and underrecognized, treatment with exogenous hormone is necessary to decrease the high mortality rate. PMID- 24766935 TI - The changing face of diabetes in America. AB - So much has changed in the field of diabetes diagnosis and management in the United States. Unhealthy lifestyle choices have hastened an epidemic of childhood obesity, causing a paradigm shift in how childhood diabetes is conceptualized. Once thought a consequence of obesity, sedentary lifestyle, and genetics, diabetes with onset in adults has been found to have a variant with autoimmunity. As the lines among adult-onset, child-onset, and type 1 and type 2 diabetes mellitus become more blurred, best practices in management and prevention become more complicated. This article highlights key points regarding 2 variants, juvenile-onset type 2 diabetes mellitus and latent autoimmune diabetes of adults. PMID- 24766937 TI - Calcium, magnesium, and phosphate abnormalities in the emergency department. AB - Derangements of calcium, magnesium, and phosphate are associated with increased morbidity and mortality. These minerals have vital roles in the cellular physiology of the neuromuscular and cardiovascular systems. This article describes the pathophysiology of these mineral disorders. It aims to provide the emergency practitioner with an overview of the diagnosis and management of these disorders. PMID- 24766936 TI - Derangements of potassium. AB - Changes in potassium elimination, primarily due to the renal and GI systems, and shifting potassium between the intracellular and extracellular spaces cause potassium derangement. Symptoms are vague, but can be cardiac, musculoskeletal, or gastrointestinal. There are no absolute guidelines for when to treat, but it is generally recommended when the patient is symptomatic or has ECG changes. Treatment of hyperkalemia includes cardiac membrane stabilization with IV calcium, insulin and beta-antagonists to push potassium intracellularly, and dialysis. Neither sodium bicarbonate nor kayexelate are recommended. Treatment of symptomatic hypokalemia consists of PO or IV repletion with potassium chloride and magnesium sulfate. PMID- 24766938 TI - Altered mental status and endocrine diseases. AB - Although the altered mental status is a common presentation in the emergency department, altered mental status caused by endocrine emergencies is rare. The altered patient could have an endocrine cause that can quickly improve with appropriate diagnosis and interventions. When dealing with limited information and an obtunded patient, it is important to have a broad differential diagnosis, pick up on the physical examination findings, and evaluate laboratory abnormalities that could suggest an underlying endocrine emergency. This article outlines the findings and provides a description of altered patients with endocrine emergencies to facilitate the diagnosis and treatment in the emergency department. PMID- 24766939 TI - Disorders of sodium and water balance. AB - Dysnatremias occur simultaneously with disorders in water balance. The first priority is to correct dehydration; once the patient is euvolemic, the sodium level can be reassessed. In unstable patients with hyponatremia, the clinician should rapidly administer hypertonic saline. In unstable patients with hypernatremia, the clinician should administer isotonic intravenous fluid. In stable patients with either hyponatremia or hypernatremia, the clinician should aim for correction over 24 to 48 hours, with the maximal change in serum sodium between 8 to 12 mEq/L over the first 24 hours. This rate of correction decreases the chances of cerebral edema or osmotic demyelination syndrome. PMID- 24766940 TI - Approach to metabolic acidosis in the emergency department. AB - Acid-base disorders should be considered a process with the goal being to treat the patient and the underlying condition, not the numbers. A good understanding of the normal acid-base regulation in the body, as well as the most common derangements can prepare the emergency physician for this very common disorder that presents on every shift. PMID- 24766941 TI - Neonatal endocrine emergencies: a primer for the emergency physician. AB - The resuscitation principles of securing the airway and stabilizing hemodynamics remain the same in any neonatal emergency. However, stabilizing endocrine disorders may prove especially challenging. Several organ systems are affected simultaneously and the clinical presentation can be subtle. Although not all inclusive, the implementation of newborn screening tests has significantly reduced morbidity and mortality in neonates. Implementing routine screening tests worldwide and improving the accuracy of present tests remains the challenge for healthcare providers. With further study of these disorders and best treatment practices we can provide neonates presenting to the emergency department with the best possible outcomes. PMID- 24766942 TI - Current diagnosis and treatment of hyperglycemic emergencies. AB - Diabetic ketoacidosis and hyperosmolar hyperglycemic state are the most feared complications of uncontrolled diabetes seen in emergency medicine. The treatment of both conditions must be tailored to individual patients and relies on aggressive fluid resuscitation, insulin replacement, and electrolyte management. Emergency medicine providers must address the underlying causes and monitor for complications of therapy. Improved understanding of the underlying pathophysiology and application of evidence-based guidelines have significantly improved prognosis and decreased mortality. The purpose of this article is to review the diagnosis, presentation, and emergency department management of diabetic ketoacidosis and hyperosmolar hyperglycemic state with an emphasis on current management and treatment guidelines. PMID- 24766943 TI - Approach to metabolic alkalosis. AB - Metabolic alkalosis is a common disorder, accounting for half of all acid-base disturbances in hospitalized patients. It is the result of an increase in bicarbonate production, a decrease in bicarbonate excretion, or a loss of hydrogen ions. Most causes of metabolic alkalosis can be divided into 4 categories: chloride depletion alkalosis, mineralocorticoid excess syndromes, apparent mineralocorticoid excess syndromes, and excess alkali administration. Treatment is usually supportive and based on cause of the alkalosis. PMID- 24766944 TI - The clinical manifestations, diagnosis, and treatment of adrenal emergencies. AB - Emergency medicine physicians should be able to identify and treat patients whose clinical presentations, including key historical, physical examination, and laboratory findings are consistent with diagnoses of primary, secondary, and tertiary adrenal insufficiency, adrenal crisis, and pheochromocytoma. Failure to make a timely diagnosis leads to increased morbidity and mortality. As great mimickers, adrenal emergencies often present with a constellation of nonspecific signs and symptoms that can lead even the most diligent emergency physician astray. The emergency physician must include adrenal emergencies in the differential diagnosis when encountering such clinical pictures. PMID- 24766945 TI - Endocrine and metabolic emergencies in emergency medicine. PMID- 24766946 TI - Endocrine and metabolic emergencies. PMID- 24766949 TI - Toward better control of colorectal cancer. PMID- 24766948 TI - Glucose-regulated protein 78 and heparanase expression in oral squamous cell carcinoma: correlations and prognostic significance. AB - BACKGROUND: The aim of the present study was to investigate the expression of glucose-related protein 78 (GRP78) and heparanase (HPA) in oral squamous cell carcinoma (OSCC) and their relationship with clinicopathological parameters and potential implications for survival. METHODS: A total of 46 patients with OSCC and 10 normal individuals were recruited for the study. GRP78 and HPA expression were determined in the lesion tissues using immunohistochemical analysis. The correlation between GRP78 and HPA was assessed using the Spearman correlation analysis. The associations of GRP78 and HPA with clinicopathological characteristics and survival were examined using the x2-test, Kaplan-Meier, or Cox regression. RESULTS: Patients with OSCC showed a statistically significant higher prevalence of GRP78 and HPA expression than normal oral tissues. GRP78 and HPA expression was positively correlated with size, TNM stage, histological grade, lymphatic metastasis, and distant metastasis in OSCC patients. GRP78 expression was also positively correlated with HPA expression. Positive GRP78 and HPA expression was inversely correlated with survival in OSCC patients. CONCLUSIONS: HPA expression was found to be positively correlated with GRP78 expression. GRP78 and HPA are biomarkers that may have the potential to guide the treatment of oral cancer patients. PMID- 24766950 TI - E-cigarettes: closing regulatory gaps. PMID- 24766951 TI - Time to contain artemisinin resistance. PMID- 24766952 TI - Malaria: a molecular marker of artemisinin resistance. PMID- 24766954 TI - Susan Desmond-Hellmann: taking charge at the Gates Foundation. PMID- 24766955 TI - A manifesto for planetary health. PMID- 24766956 TI - A manifesto for planetary health. PMID- 24766947 TI - Clonality, recombination, and hybridization in the plumbing-inhabiting human pathogen Fusarium keratoplasticum inferred from multilocus sequence typing. AB - BACKGROUND: Recent work has shown that Fusarium species and genotypes most commonly associated with human infections, particularly of the cornea (mycotic keratitis), are the same as those most commonly isolated from plumbing systems. The species most dominant in plumbing biofilms is Fusarium keratoplasticum, a cosmopolitan fungus known almost exclusively from animal infections and biofilms. To better understand its diversity and population dynamics, we developed and utilized a nine-locus sequence-based typing system to make inferences about clonality, recombination, population structure, species boundaries and hybridization. RESULTS: High levels of genetic diversity and evidence for recombination and clonality were detected among 75 clinical and 156 environmental isolates of Fusarium keratoplasticum. The multilocus sequence typing system (MLST) resolved 111 unique nine-locus sequence types (STs). The single locus bifactorial determinants of mating compatibility (mating types MAT1-1 and MAT1 2), were found in a ratio of 70:30. All but one of the 49 isolates of the most common ST (FSSC 2d-2) came from human infections, mostly of the cornea, and from biofilms associated with contact lenses and plumbing surfaces. Significant levels of phylogenetic incongruence were found among loci. Putative clonal relationships among genotypes were estimated, showing a mixture of large clonal complexes and unrelated singletons. Discordance between the nuclear ribosomal rRNA and other gene genealogies is consistent with introgression of ribosomal RNA alleles of phylogenetic species FSSC 9 into F. keratoplasticum. No significant population subdivision based on clinical versus non-clinical sources was found. CONCLUSIONS: Incongruent phylogenetic trees and the presence of both mating types within otherwise identical STs were observed, providing evidence for sexuality in F. keratoplasticum. Cryptic speciation suggested in a published three-locus MLST system was not supported with the addition of new loci, but evidence of introgression of ribosomal RNA genes from another strongly supported phylogenetic species (FSSC 9), also known from plumbing systems and human infections, was detected in two isolates. Overall, F. keratoplasticum is a diverse and geographically unstructured species with a mixed clonal and recombinant life history. PMID- 24766957 TI - A manifesto for planetary health. PMID- 24766958 TI - Rubella outbreak in Japan. PMID- 24766959 TI - Opt-out HIV testing in adult critical care units. PMID- 24766960 TI - Chinese health foreign aid and policy: beyond medical aid. PMID- 24766961 TI - Reviving medicine as the art of humanity in China. PMID- 24766962 TI - Medication safety for children in China. PMID- 24766963 TI - Rate of caesarean section is alarming in China. PMID- 24766964 TI - The medical profession and violence against women. PMID- 24766965 TI - Hereditary hyperferritinaemia cataract syndrome. PMID- 24766966 TI - The author responds. PMID- 24766967 TI - Trunk muscle activation in the low back-injured population. PMID- 24766969 TI - Potential for alcohol and drug interactions in older adults: evidence from the Irish longitudinal study on ageing. AB - BACKGROUND: Older adults are susceptible to adverse effects from the concomitant use of prescription medications and alcohol. This study estimates the prevalence of exposure to alcohol interactive (AI) medications and concomitant alcohol use by therapeutic class in a large, nationally representative sample of older adults. METHODS: Cross-sectional analysis of a population based sample of older Irish adults aged >=60 years using data from The Irish Longitudinal Study on Ageing (TILDA) (N = 3,815). AI medications were identified using Stockley's Drug Interactions, the British National Formulary and the Irish Medicines Formulary. An in-home inventory of medications was used to characterise AI drug exposure by therapeutic class. Self-reported alcohol use was classified as non-drinker, light/moderate and heavy drinking. Comorbidities known to be exacerbated by alcohol were also recorded (diabetes mellitus, hypertension, peptic ulcer disease, liver disease, depression, gout or breast cancer), as well as sociodemographic and health factors. RESULTS: Seventy-two per cent of participants were exposed to AI medications, with greatest exposure to cardiovascular and CNS agents. Overall, 60% of participants exposed to AI medications reported concomitant alcohol use, compared with 69.5% of non-AI exposed people (p < 0.001). Almost 28% of those reporting anti-histamine use were identified as heavy drinkers. Similarly almost one in five, combined heavy drinking with anti-coagulants/anti-platelets and cardiovascular agents, with 16% combining heavy drinking with CNS agents. Multinomial logistic regression showed that being male, younger, urban dwelling, with higher levels of education and a history of smoking, were associated with an increased risk for concomitant exposure to alcohol consumption (both light/moderate and heavier) and AI medications. Current smokers and people with increasing co-morbidities were also at greatest risk for heavy drinking in combination with AI medications. CONCLUSIONS: The concurrent use of alcohol with AI medications, or with conditions known to be exacerbated by alcohol, is common among older Irish adults. Prescribers should be aware of potential interactions, and screen patients for alcohol use and provide warnings to minimize patient risk. PMID- 24766968 TI - Thromboprophylaxis patterns and determinants in critically ill patients: a multicenter audit. AB - INTRODUCTION: Heparin is safe and prevents venous thromboembolism in critical illness. We aimed to determine the guideline concordance for thromboprophylaxis in critically ill patients and its predictors, and to analyze factors associated with the use of low molecular weight heparin (LMWH), as it may be associated with a lower risk of pulmonary embolism and heparin-induced thrombocytopenia without increasing the bleeding risk. METHODS: We performed a retrospective audit in 28 North American intensive care units (ICUs), including all consecutive medical surgical patients admitted in November 2011. We documented ICU thromboprophylaxis and reasons for omission. Guideline concordance was determined by adding days in which patients without contraindications received thromboprophylaxis to days in which patients with contraindications did not receive it, divided by the total number of patient-days. We used multilevel logistic regression including time varying, center and patient-level covariates to determine the predictors of guideline concordance and use of LMWH. RESULTS: We enrolled 1,935 patients (62.3 +/- 16.7 years, Acute Physiology and Chronic Health Evaluation [APACHE] II score 19.1 +/- 8.3). Patients received thromboprophylaxis with unfractionated heparin (UFH) (54.0%) or LMWH (27.6%). Guideline concordance occurred for 95.5% patient days and was more likely in patients who were sicker (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.17, 1.75 per 10-point increase in APACHE II), heavier (OR 1.32, 95% CI 1.05, 1.65 per 10-m/kg2 increase in body mass index), had cancer (OR 3.22, 95% CI 1.81, 5.72), previous venous thromboembolism (OR 3.94, 95% CI 1.46,10.66), and received mechanical ventilation (OR 1.83, 95% CI 1.32,2.52). Reasons for not receiving thromboprophylaxis were high risk of bleeding (44.5%), current bleeding (16.3%), no reason (12.9%), recent or upcoming invasive procedure (10.2%), nighttime admission or discharge (9.7%), and life-support limitation (6.9%). LMWH was less often administered to sicker patients (OR 0.65, 95% CI 0.48, 0.89 per 10-point increase in APACHE II), surgical patients (OR 0.41, 95% CI 0.24, 0.72), those receiving vasoactive drugs (OR 0.47, 95% CI 0.35, 0.64) or renal replacement therapy (OR 0.10, 95% CI 0.05, 0.23). CONCLUSIONS: Guideline concordance for thromboprophylaxis was high, but LMWH was less commonly used, especially in patients who were sicker, had surgery, or received vasopressors or renal replacement therapy, representing a potential quality improvement target. PMID- 24766970 TI - Chlorpromazine versus every other antipsychotic for schizophrenia: a systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs. AB - It is one of the major psychiatric dogmas that the efficacy of all antipsychotic drugs is same. This statement originated from old, narrative reviews on first generation antipsychotics, but this old literature has never been meta-analysed. We therefore conducted a meta-analysis of randomised controlled trials on the efficacy of chlorpromazine versus any other antipsychotic in the treatment of schizophrenia. If the benchmark drug chlorpromazine were significantly more or less effective than other antipsychotics, the notion of equal efficacy would have to be rejected. We searched the Cochrane Schizophrenia Group's specialized register, MEDLINE, EMBASE, PsychInfo and reference lists of relevant articles. The primary outcome was response to treatment. We also analyzed mean values of schizophrenia rating scales at endpoint and drop-out rates. 128, mostly small, RCTs with 10667 participants were included. Chlorpromazine was compared with 43 other antipsychotics and was more efficacious than four (butaperazine, mepazine, oxypertine and reserpine) and less efficacious than other four antipsychotics (clomacran, clozapine, olanzapine and zotepine) in the primary outcome. There were no statistically significant efficacy differences between chlorpromazine and the remaining 28 antipsychotics. The most important finding was that, due to low numbers of participants (median 50, range 8-692), most comparisons were underpowered. Thus we infer that the old antipsychotic drug literature was inconclusive and the claim for equal efficacy of antipsychotics was never evidence-based. Recent meta-analyses on second-generation antipsychotics were in a better position to address this question and small, but consistent differences between drugs were found. PMID- 24766971 TI - The effects of nicotine on cognition are dependent on baseline performance. AB - Since cholinergic neurotransmission plays a major role in cognition, stimulation of the nicotinic acetylcholine receptor may be a target for cognitive enhancement. While nicotine improves performance on several cognitive domains, results of individual studies vary. A possible explanation for these findings is that the effect of nicotine administration may be dependent on baseline cognitive function, where subjects with a suboptimal cognitive performance may benefit from nicotine, while subjects who already perform optimally may show a decline in performance after nicotinic stimulation. We conducted a double-blind randomised placebo-controlled crossover trial, examining the effects of placebo, 1, and 2mg of nicotine on cognition in young (n=16, age 18-30 years) and healthy elderly (n=16, age 60-75 years) subjects. We hypothesised that the elderly would benefit more from nicotine compared to young subjects, as normal ageing is associated with decreases in cognitive function. Attention, working memory, visual memory, information-processing speed, psychomotor function, stereotypy, and emotion recognition were assessed. Compared to the young volunteers, the elderly performed significantly worse on psychomotor function and emotion recognition in the placebo condition. Nicotine had no effect in the young volunteers and decreased performance on working memory and visual memory in the elderly. Contrary to our hypothesis, the effect of nicotine was dependent on baseline performance in both the groups, with subjects with lower baseline performance benefiting from nicotine administration, while those with higher baseline performance performed worse after nicotine administration. This suggests that subjects with lower cognitive performance, irrespective of age, may benefit from nicotine. PMID- 24766972 TI - Clinical perspectives on reperfusion injury in acute myocardial infarction. AB - Prompt reperfusion therapy in acute myocardial infarction enhances clinical outcome. However, reperfusion itself may contribute to myocardial cell death. The current review outlines the multifocal mechanisms of reperfusion injury and focuses on understanding the potential role of each element and its contribution to the injury pattern inflicted upon the myocardium. We evaluate the spectrum of contemporary therapies that have been tested in an attempt to reduce myocardial injury. Finally, we explore promising innovative strategies targeting novel reperfusion injury pathways to protect ischemic myocardium during reperfusion. PMID- 24766973 TI - Rationale and design of the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prEvention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion trial: A comparison of oral rivaroxaban once daily with dose-adjusted vitamin K antagonists in patients with nonvalvular atrial fibrillation undergoing elective cardioversion. AB - BACKGROUND: Anticoagulation before, during, and after cardioversion is effective in reducing stroke risk in patients with atrial fibrillation. OBJECTIVE: The objective of this study is to explore the efficacy and safety of rivaroxaban 20 mg once daily (15 mg if creatinine clearance is 30-49 mL/min) compared with dose adjusted vitamin K antagonists (VKAs; international normalized ratio 2.0-3.0) in patients scheduled for elective cardioversion. METHODS: This is a prospective, randomized, open-label, parallel group comparison of approximately 1,500 patients from 17 countries with hemodynamically stable nonvalvular atrial fibrillation of >48 hours or unknown duration. Patients will be randomized 2:1 (rivaroxaban:VKA) using 2 cardioversion strategies: the first approach is early cardioversion with the precardioversion anticoagulation goal of 1 to 5 days using rivaroxaban or usual therapy (heparin + VKA). In these patients, transesophageal echocardiography will be encouraged to exclude atrial thrombi. The alternative approach is delayed cardioversion. Rivaroxaban or VKA will be administered for 21 to 56 days before cardioversion. All patients will receive study treatment for 6 weeks postcardioversion. The primary efficacy end point is a composite of all strokes, transient ischemic attacks, noncentral nervous system systemic emboli, myocardial infarctions, and cardiovascular deaths. Each primary end point component will be evaluated separately, and additional composites will be investigated. The principal safety end point is major bleeding. CLINICAL CONTEXT: This will be the first prospective study of a novel oral anticoagulant in the setting of cardioversion. It will provide important information regarding the use of rivaroxaban in the periods preceding and after cardioversion in a broad patient population. PMID- 24766975 TI - Rationale and design of the steroids in cardiac surgery trial. AB - BACKGROUND: Steroids may improve outcomes in high-risk patients undergoing cardiac surgery with the use of cardiopulmonary bypass (CBP). There is a need? for a large randomized controlled trial to clarify the effect of steroids in such patients. METHODS: We plan to randomize 7,500 patients with elevated European System for Cardiac Operative Risk Evaluation who are undergoing cardiac surgery with the use of CBP to methylprednisolone or placebo. The first coprimary outcome is 30-day all-cause mortality, and the most second coprimary outcome is a composite of death, MI, stroke, renal failure, or respiratory failure within 30 days. Other outcomes include a composite of MI or mortality at 30 days, new onset atrial fibrillation, bleeding and transfusion requirements, length of intensive care unit stay and hospital stay, infection, stroke, wound complications, gastrointestinal complications, delirium, postoperative insulin use and peak blood glucose, and all-cause mortality at 6 months. RESULTS: As of October 22, 2013, 7,034 patients have been recruited into SIRS in 82 centers from 18 countries. Patient's mean age is 67.3 years, and 60.4% are male. The average European System for Cardiac Operative Risk Evaluation is 7.0 with 22.1% having an isolated coronary artery bypass graft procedure, and 66.1% having a valve procedure. CONCLUSIONS: SIRS will lead to a better understanding of the safety and efficacy of prophylactic steroids for cardiac surgery requiring CBP. PMID- 24766976 TI - Prognosis of elderly patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention in 2001 to 2011: A report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) registry. AB - BACKGROUND: Elderly patients constitute a growing part of the population presenting with ST-elevation myocardial infarction (STEMI). The use of primary percutaneous coronary intervention (PCI) in this high-risk population remains poorly investigated. METHODS: Using the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), we identified consecutive patients with STEMI 80 years or older undergoing primary PCI during a 10-year period. Temporal trends in care and 1-year prognosis were investigated, and long-term outcome was compared with a reference group of patients with STEMI aged 70 to 79 years. Relative survival was calculated by dividing the observed survival rate with the expected survival rate of the general population. Adjusted end points were calculated using Cox regression. RESULTS: In total, 4,876 elderly patients with STEMI were included. During the study period, average age and presence of comorbidity increased, as well as the use of antithrombotic therapy. Procedural success remained constant. One-year mortality was exclusively reduced between the most recent vs the earliest cohort, whereas the risk of reinfarction, heart failure, stroke, and bleeding remained similar. The risk of death was higher for elderly patients early after PCI, after which the prognosis was slightly better compared with the general population. Long-term risk of adverse events increased markedly with age. CONCLUSIONS: The prognosis of patients older than 80 years treated with primary PCI for STEMI was relatively unchanged during the 10-year inclusion period, despite changes in patient characteristics and treatment. Advanced age increased the risk of adverse events, but survivors of the early phase after PCI had a slightly improved prognosis compared with the general population. PMID- 24766977 TI - Galectin-3 is independently associated with cardiovascular mortality in community dwelling older adults without known cardiovascular disease: The Rancho Bernardo Study. AB - BACKGROUND: Galectin-3 is a marker of myocardial fibrosis that has been implicated in the pathophysiologic pathway of fibrosis; its association with all cause and cardiovascular disease (CVD) mortality in a community-based cohort free of baseline CVD has not been reported. Our aim was to determine the association between galectin-3 levels and all-cause and CVD mortality in community-dwelling older adults without known CVD. METHODS: We measured plasma galectin-3 levels in 1,393 Rancho Bernardo Study participants without CVD with a mean age of 70 years. Participants were followed up for a mean of 11 years for coronary heart disease, CVD mortality, and all-cause mortality. RESULTS: During follow-up, 436 participants died (169 from CVD). In models adjusted for traditional CVD risk factors and renal function, galectin-3 was a significant predictor of CVD mortality (hazard ratio [HR] per SD log increase 1.30, 95% CI 1.10-1.53) and all cause mortality (HR 1.12, 1.01-1.24), but not coronary heart disease (HR 1.09, 0.92-1.30). After further adjusting for N-terminal pro B-type natriuretic peptide, galectin-3 remained an independent predictor (HR 1.24, 1.05-1.47) of CVD mortality. Galectin-3 improved the c statistic (0.847-0.851, P = .003) for prediction of CVD death. Net reclassification improvement (>0) with the addition of galectin-3 was 35% (P < .0001); the integrated discrimination index was also significant (P = .03). Participants with both galectin-3 and N-terminal pro B type natriuretic peptide above the median had increased risk of CVD death vs those with higher levels of only 1 of these markers (HR 1.74, 1.24-2.43). CONCLUSION: Higher levels of galectin-3 are independently associated with all cause and CVD mortality among community-dwelling older adults with no known CVD at baseline. PMID- 24766978 TI - Impact of the ENHANCE trial on the use of ezetimibe in the United States and Canada. AB - BACKGROUND: We previously found that the use of ezetimibe increased rapidly with different patterns between the United States (US) and Canada prior to the landmark Ezetimibe and Simvastatin in Hypercholesterolemia Enhance Atherosclerosis Regression (ENHANCE) trial, which was reported in January 2008, and failed to show that the drug slowed the progression of atherosclerosis. What is not known is how practice in the 2 countries changed after the ENHANCE trial. We examined ezetimibe use trends in the US and Canada before and after the reporting of the ENHANCE trial. METHODS: We conducted a population-based, retrospective, time-series analysis using the data collected by IMS Health in the US and CompuScript in Canada from January 1, 2002, to December 31, 2009. The main outcome measure was monthly number of prescriptions for ezetimibe-containing products. RESULTS: The monthly number of ezetimibe prescriptions/100,000 population rose from 6 to 1,082 in the US from November 2002 to January 2008, then significantly declined to 572/100,000 population by December 2009 after the release of the ENHANCE trial, a decrease of 47.1% (P < .001). In contrast, in Canada, use continuously rose from 2 to 495/100,000 population from June 2003 to December 2009 (P = .2). United States expenditures totaled $2.24 billion in 2009. CONCLUSIONS: Ezetimibe remains commonly used in both the US and Canada. Ezetimibe use has decreased in the US post-ENHANCE, whereas use has gradually but steadily increased in Canada. The diverging patterns of ezetimibe use in the US and Canada require further investigation, as they reveal that a common evidence base is eliciting very different utilization patterns in neighboring countries. PMID- 24766979 TI - Medical professional liability risk among US cardiologists. AB - BACKGROUND: Medical professional liability (MPL) remains a significant burden for physicians, in general, and cardiologists, in particular, as recent research has shown that average MPL defense costs are higher in cardiology than other specialties. Knowledge of the clinical characteristics and outcomes of lawsuits against cardiologists may improve quality of care and risk management. METHODS: We analyzed closed MPL claims of 40,916 physicians and 781 cardiologists insured by a large nationwide insurer for >=1 policy year between 1991 and 2005. RESULTS: The annual percentage of cardiologists facing an MPL claim was 8.6%, compared with 7.4% among physicians overall (P < .01). Among 530 claims, 72 (13.6%) resulted in an indemnity payment, with a median size of $164,988. Mean defense costs for claims resulting in payment were $83,593 (standard deviation (s.d.) $72,901). The time required to close MPL claims was longer for claims with indemnity payment than claims without (29.6 versus 18.9 months; P < .001). More than half of all claims involved a patient's death (304; 57.4%), were based on inpatient care (379; 71.5%), or involved a primary cardiovascular condition (416; 78.4%). Acute coronary syndrome was the most frequent condition (234; 44.2%). Medical professional liability claims involving noncardiovascular conditions were common (66; 12.5%) and included falls or mechanical injuries had while under a cardiologist's care and a failure to diagnose cancer. CONCLUSIONS: Rates of malpractice lawsuits are higher among cardiologists than physicians overall. A substantial portion of claims are noncardiovascular in nature. PMID- 24766980 TI - Cost effectiveness of a gene expression score and myocardial perfusion imaging for diagnosis of coronary artery disease. AB - BACKGROUND: Over 3 million patients annually present with symptoms suggestive of obstructive coronary artery disease (oCAD) in the United States (US), but a cardiac etiology is found in as few as 10% of cases. Usual care may include advanced cardiac testing with myocardial perfusion imaging (MPI), with attendant radiation risks and increased costs of care. We estimated the cost effectiveness of CAD diagnostic strategies including "no test," a gene expression score (GES) test, MPI, and sequential strategies combining GES and MPI. METHODS: We developed a Markov-based decision analysis model to simulate outcomes and costs in patients presenting to clinicians with symptoms suggestive of oCAD in the US. We estimated quality-adjusted life years (QALYs), total costs, and incremental cost effectiveness ratios (ICERs) for each strategy. RESULTS: In our base case, the 2 threshold GES strategy is the most cost-effective strategy at a threshold of $100,000 per QALY gained, with an ICER of approximately $72,000 per QALY gained relative to no testing. Myocardial perfusion imaging alone and the 1-threshold strategy are weakly dominated. In sensitivity analysis, ICERs fall as the probability of oCAD increases from the base case value of 15%. The ranking of ICERs among strategies is sensitive to test costs, including the time cost for testing. The analysis reveals ways to improve on prespecified GES thresholds. CONCLUSIONS: Diagnostic testing for oCAD with a novel GES strategy in a 2 threshold model is cost effective by conventional standards. This diagnostic approach is more efficient than usual care of MPI alone or a 1-threshold GES strategy in most scenarios. PMID- 24766981 TI - Inflammation and future risk of symptomatic heart failure in patients with stable coronary artery disease. AB - BACKGROUND: Heart failure (HF) carries poor prognosis in coronary artery disease (CAD) patients despite advances in therapy. Inflammation predicts recurrent cardiovascular events in CAD patients. It is unknown whether increased levels of inflammatory markers are associated with incident HF in these patients. AIM: The aims of this study were to evaluate the association between inflammatory markers and future HF risk in patients with stable CAD and to explore possible mediation by myocardial infarction (MI). METHODS: The study comprised 2,945 patients with stable CAD without HF at baseline during a median follow-up of 7.9 years. Inflammatory baseline markers were the basis of this study. RESULTS: Heart failure was diagnosed in 508 patients (17.2%). Patients who developed HF were older and had more often previous MI, diabetes, hypertension, and peripheral vascular disease. Baseline levels of C-reactive protein (CRP), fibrinogen, and white blood cells (WBCs) were significantly higher in patients who developed HF compared with those who did not. Age-adjusted incident HF rates were related to elevated baseline inflammatory markers in a dose-response manner. Adjusting for multiple confounders, the HF hazard ratios were 1.38 (95% CI 1.11-1.72), 1.33 (95% CI 1.07-1.66), and 1.36 (95% CI 1.10-1.68) for the third tertiles of CRP, fibrinogen, and WBC levels, respectively. Hazard ratio for the fifth quintile of a combined "inflammation score" was 1.83 (95% CI 1.40-2.39). Mediation by MI preceding the HF onset during follow-up accounted for 10.4%, 10.8%, and 8.6% of the association of subsequent HF with CRP, fibrinogen, and WBC, respectively. CONCLUSIONS: Increased levels of CRP, fibrinogen, and WBC are independently related to the incidence of HF in patients with stable CAD. PMID- 24766982 TI - Characteristics of plaque disruption by intravascular ultrasound in women presenting with myocardial infarction without obstructive coronary artery disease. AB - BACKGROUND: In a prospective study, we previously identified plaque disruption (PD: plaque rupture or ulceration) in 38% of women with myocardial infarction (MI) without angiographically obstructive coronary artery disease (CAD), using intravascular ultrasound (IVUS). Underlying plaque morphology has not been described in these patients and may provide insight into the mechanisms of MI without obstructive CAD. METHODS: Forty-two women with MI and <50% angiographic stenosis underwent IVUS (n = 114 vessels). Analyses were performed by a blinded core laboratory. Sixteen patients had PD (14 ruptures and 5 ulcerations in 18 vessels). Plaque area, % plaque burden, lumen area stenosis, eccentricity, and remodeling index were calculated for disrupted plaques and largest plaque by area in each vessel. RESULTS: Disrupted plaques had lower % plaque burden than the largest plaque in the same vessel (31.9% vs 49.8%, P = .005) and were rarely located at the site of largest plaque (1/19). Disrupted plaques were typically fibrous and were not more eccentric or remodeled than the largest plaque in the same vessel. CONCLUSIONS: Plaque disruption was often identifiable on IVUS in women with MI without obstructive CAD. Plaque disruption in this patient population occurred in fibrous or fibrofatty plaques and, contrary to expectations based on prior studies of plaque vulnerability, did not typically occur in eccentric, outwardly remodeled, or soft plaque in these patients. Plaque disruption rarely occurred at the site of the largest plaque in the vessel. These findings suggest that the pathophysiology of PD in women with MI without angiographically obstructive CAD may be different from MI with obstructive disease and requires further investigation. PMID- 24766974 TI - Resuscitation Outcomes Consortium-Amiodarone, Lidocaine or Placebo Study (ROC ALPS): Rationale and methodology behind an out-of-hospital cardiac arrest antiarrhythmic drug trial. AB - BACKGROUND: Despite their wide use, whether antiarrhythmic drugs improve survival after out-of-hospital cardiac arrest (OHCA) is not known. The ROC-ALPS is evaluating the effectiveness of these drugs for OHCA due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia (VF/VT). METHODS: ALPS will randomize 3,000 adults across North America with nontraumatic OHCA, persistent or recurring VF/VT after >=1 shock, and established vascular access to receive up to 450 mg amiodarone, 180 mg lidocaine, or placebo in the field using a double-blind protocol, along with standard resuscitation measures. The designated target population is all eligible randomized recipients of any dose of ALPS drug whose initial OHCA rhythm was VF/VT. A safety analysis includes all randomized patients regardless of their eligibility, initial arrhythmia, or actual receipt of ALPS drug. The primary outcome of ALPS is survival to hospital discharge; a secondary outcome is functional survival at discharge assessed as a modified Rankin Scale score <=3. RESULTS: The principal aim of ALPS is to determine if survival is improved by amiodarone compared with placebo; secondary aim is to determine if survival is improved by lidocaine vs placebo and/or by amiodarone vs lidocaine. Prioritizing comparisons in this manner acknowledges where differences in outcome are most expected based on existing knowledge. Each aim also represents a clinically relevant comparison between treatments that is worth investigating. CONCLUSIONS: Results from ALPS will provide important information about the choice and value of antiarrhythmic therapies for VF/VT arrest with direct implications for resuscitation guidelines and clinical practice. PMID- 24766983 TI - Circulating fibrosis biomarkers and risk of atrial fibrillation: The Cardiovascular Health Study (CHS). AB - BACKGROUND: Cardiac fibrosis is thought to play a central role in the pathogenesis of atrial fibrillation (AF). Retrospective studies have suggested that circulating fibrosis biomarkers are associated with AF, but prospective studies are limited. METHODS: We measured circulating levels of 2 fibrosis biomarkers, procollagen type III, N-terminal propeptide (PIIINP) and transforming growth factor beta1 among participants of the CHS, a population-based study of older Americans. We used Cox proportional hazards and competing risks models to examine adjusted risk of incident AF over a median follow-up of 8.8 years. RESULTS: Levels of PIIINP were assessed in 2,935 participants, of whom 767 developed AF. Compared with the median PIIINP level (4.45 MUg/L), adjusted hazard ratios (95% CIs) were 0.85 (0.72-1.00) at the 10th percentile, 0.93 (0.88-0.99) at the 25th percentile, 1.04 (0.95-1.04) at the 75th percentile, and 1.07 (0.90 1.26) at the 90th. Transforming growth factor beta1 levels, assessed in 1,538 participants with 408 cases of incident AF, were not associated with AF risk. CONCLUSION: In older adults, PIIINP levels were associated with risk of incident AF in a complex manner, with an association that appeared to be positive up to median levels but with little relationship beyond that. Further studies are required to confirm and possibly delineate the mechanism for this relationship. PMID- 24766986 TI - Sex difference in clinical outcomes after percutaneous coronary intervention in Korean population. AB - BACKGROUND: Conflicting data on sex-based differences in outcomes after percutaneous coronary intervention (PCI) among Western population exist. Little is known about the nature of sex-specific PCI outcomes in an Asian population. METHODS: We performed a pooled analysis using 23,604 patients from 11 prospective PCI clinical studies performed in Korea. The primary outcome was a major cardiovascular event, defined as composite of cardiovascular death, myocardial infarction, stent thrombosis, or stroke. Secondary outcomes were all-cause mortality and target vessel revascularization. RESULTS: Thirty-day and 2-year rates of major cardiovascular events were more frequent in women than in men, mainly because of a higher incidence of periprocedural myocardial infarction in women (30-day: 9.2% vs 7.1%; 2-year: 11.2% vs 8.9%). After multivariable adjustment, women had significantly higher risks of 30-day (hazard ratio [HR] 1.27, 95% CI 1.19-1.36) and 2-year major cardiovascular events (HR 1.21, 95% CI 1.13-1.30). Unadjusted 30-day and 2-year all-cause mortality was similar between women and men (30-day: 0.5% vs 0.4%; 2-year: 2.8% vs 2.8%). However, after multivariable adjustment, women had a lower adjusted risk of 2-year death (HR 0.82, 95% CI 0.77-0.87). No sex-based difference was observed for target vessel revascularization (HR 1.07, 95% CI 0.91-1.25). Overall, sex-specific findings for outcomes were consistent across multiple patient subgroups. CONCLUSION: Among Korean population undergoing contemporary PCI, women have a significantly higher risk of short- and long-term major cardiovascular events than do men but have better long-term survival. PMID- 24766985 TI - Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT AF). AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF. METHODS: The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause specific hospitalization. RESULTS: Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age >=75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization. CONCLUSIONS: Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients. PMID- 24766984 TI - Galectin 3 and incident atrial fibrillation in the community. AB - BACKGROUND: Galectin 3 (Gal-3) is a potential mediator of cardiac fibrosis, and Gal-3 concentrations predict incident heart failure. The same mechanisms that lead to cardiac fibrosis in heart failure may influence development of atrial fibrosis and atrial fibrillation (AF). We examined the association of Gal-3 and incident AF in the community. METHODS: Plasma Gal-3 concentrations were measured in 3,306 participants of the Framingham Offspring cohort who attended the sixth examination cycle (1995-1998, mean age 58 years, 54% women). Cox proportional hazards regression models were used to assess the association of baseline Gal-3 concentrations and incident AF. RESULTS: Over a median follow-up period of 10 years, 250 participants developed incident AF. Crude incidence rates of AF by increasing sex-specific Gal-3 quartiles were 3.7%, 5.9%, 9.1%, and 11.5% (log rank test P < .0001). In age- and sex-adjusted analyses, each 1-SD increase in loge-Gal-3 was associated with a 19% increased hazard of incident AF (hazard ratio 1.19, 95% CI 1.05-1.36, P = .009). This association was not significant after adjustment for traditional clinical AF risk factors (hazard ratio 1.12, 95% CI 0.98-1.28, P = .10). CONCLUSION: Higher circulating Gal-3 concentrations were associated with increased risk of developing AF over the subsequent 10 years in age- and sex-adjusted analyses but not after accounting for other traditional clinical AF risk factors. Our results do not support a role for Gal-3 in AF risk prediction. Further studies are needed to evaluate whether Gal-3 plays a role in the development of AF substrate similar to HF. PMID- 24766987 TI - Effect of 8-week exercise-based cardiac rehabilitation on cardiac autonomic function: A randomized controlled trial in myocardial infarction patients. AB - PURPOSE: The purpose of this study is to evaluate the effects of an 8-week exercise-based cardiac rehabilitation program on traditional and nonlinear heart rate variability (HRV) indexes, assessing the potential confounding influences of habitual physical activity (PA) and dietary intake. METHODS: In this parallel group trial, 96 patients (56 +/- 10 years old) were randomized to the exercise group (EG) or to the control group (CG) 4 weeks after an acute myocardial infarction. Exercise-based cardiac rehabilitation program consisted of aerobic exercise at 70% to 85% of maximal heart rate for 3 sessions per week plus usual care. The CG received only usual care. The baseline and final assessments comprised resting short-term HRV (primary outcome) by a Polar R-R recorder under controlled breathing (12 breaths per minute), habitual PA by accelerometers, and dietary intake by a 4-day food diary. RESULTS: Two patients in each group dropped out and were not included in the intention-to-treat analysis. In the remaining 92 patients (EG = 47 and CG = 45), at baseline, only a difference in the proportion of nitrate medication use was significant between groups. After 8 weeks, no significant changes were found between groups on traditional and nonlinear HRV indexes (eg, ln HF, EG from 5.7 +/- 1.5 to 5.9 +/- 1.3 and CG from 5.5 +/- 1.6 to 5.5 +/- 1.5), habitual PA, and dietary intake. CONCLUSION: Eight weeks of exercise-based cardiac rehabilitation program is an insufficient stimulus to improve cardiac autonomic function in post-myocardial infarction patients under optimal medication and with high levels of traditional and nonlinear HRV indexes at baseline. PMID- 24766988 TI - Do patients treated at academic hospitals have better longitudinal outcomes after admission for non-ST-elevation myocardial infarction? AB - BACKGROUND: Prior studies have found that academic hospitals provide more consistent use of guideline-recommended therapies in patients with non-ST-segment myocardial infarction (NSTEMI) compared with nonacademic centers, yet it is unclear whether these care differences translate into longer-term outcome differences. METHODS: Using data from the CRUSADE Registry linked to Center for Medicare & Medicaid Services claims, we compared 30-day and 1-year all-cause mortality among 12,194 older patients with NSTEMI (age >=65 years) treated at 103 academic centers and 28,335 patients treated at 302 nonacademic centers from February 2003 to December 2006. Outcomes were first adjusted for clinical characteristics, followed by adjustment for hospital performance, on 13 acute and discharge guideline-recommended therapies using a shared frailty model (an extension of the Cox proportional hazard model). RESULTS: Compared with older patients with NSTEMI treated at nonacademic hospitals, those treated at academic hospitals had greater and more consistent use of evidence-based acute and discharge therapies, were more likely to receive in-hospital revascularization (61.1% vs 54.2%; P < .0001), and had modestly lower risk-adjusted 30-day mortality after adjustment for patient-level clinical characteristics (8.9% vs 10.2%, adjusted hazard ratio [HR] 0.89, 95% CI 0.80-0.99). These differences were attenuated (HR 0.94, 95% CI 0.83-1.02) after further adjustment for hospital delivery of evidence-based treatments, yet did not persist out to 1 year (unadjusted HR 0.92, 95% CI 0.84-1.01, P = .089). CONCLUSIONS: Patients with NSTEMI treated at academic centers are more likely to receive guideline recommended therapies and had modestly better 30-day outcomes. Nevertheless, these differences do not persist out to 1 year. PMID- 24766989 TI - Health City Cayman Islands and the globalization of health services delivery. AB - We describe a new health care campus under development in the Cayman Islands, Health City, based on the low-cost "focused factory" model. The construction of a multispecialty hospital opening in February 2014 less than a 4-hour flight away from the United States and convenient to both Central and South America for patients who already travel to the United States for clinical care could reshape the US health care marketplace and enhance access to affordable specialty health care in the region. PMID- 24766990 TI - Atrial fibrillation in cardiac implantable electronic devices and the duck test. PMID- 24766991 TI - Variance of matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) concentrations in activated, concentrated platelets from healthy male donors. AB - BACKGROUND: The use of autologous blood concentrates, such as activated, concentrated platelets, in orthopaedic clinical applications has had mixed results. Research on this topic has focused on growth factors and cytokines, with little directed towards matrix metalloproteinases (MMPs) which are involved in post-wound tissue remodeling. METHODS: In this study, the authors measured the levels of MMP-2, MMP-9 and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), in activated platelets derived from blood of healthy, male volunteers (n = 92), 19 to 60 years old. The levels of the natural inhibitors of these proteases, tissue inhibitor of metalloproteinase 1 (TIMP-1), TIMP-2 and TIMP-4 were also assessed. RESULTS: Notably, there was no significant change in concentration with age in four of six targets tested. However, TIMP-2 and TIMP-4 demonstrated a statistically significant increase in concentration for subjects older than 30 years of age compared to those 30 years and younger (P = 0.04 and P = 0.04, respectively). CONCLUSION: TIMP-2 and TIMP-4 are global inhibitors of MMPs, including MMP-2 (Gelatinase A). MMP-2 targets native collagens, gelatin and elastin to remodel the extracellular matrix during wound healing. A decreased availability of pharmacologically active MMP-2 may diminish the effectiveness of the use of activated, concentrated platelets from older patients, and may also contribute to longer healing times in this population. PMID- 24766992 TI - Bias and discriminability during emotional signal detection in melancholic depression. AB - BACKGROUND: Cognitive disturbances in depression are pernicious and so contribute strongly to the burden of the disorder. Cognitive function has been traditionally studied by challenging subjects with modality-specific psychometric tasks and analysing performance using standard analysis of variance. Whilst informative, such an approach may miss deeper perceptual and inferential mechanisms that potentially unify apparently divergent emotional and cognitive deficits. Here, we sought to elucidate basic psychophysical processes underlying the detection of emotionally salient signals across individuals with melancholic and non melancholic depression. METHODS: Sixty participants completed an Affective Go/No Go (AGN) task across negative, positive and neutral target stimuli blocks. We employed hierarchical Bayesian signal detection theory (SDT) to model psychometric performance across three equal groups of those with melancholic depression, those with a non-melancholic depression and healthy controls. This approach estimated likely response profiles (bias) and perceptual sensitivity (discriminability). Differences in the means of these measures speak to differences in the emotional signal detection between individuals across the groups, while differences in the variance reflect the heterogeneity of the groups themselves. RESULTS: Melancholic participants showed significantly decreased sensitivity to positive emotional stimuli compared to those in the non melancholic group, and also had a significantly lower discriminability than healthy controls during the detection of neutral signals. The melancholic group also showed significantly higher variability in bias to both positive and negative emotionally salient material. CONCLUSIONS: Disturbances of emotional signal detection in melancholic depression appear dependent on emotional context, being biased during the detection of positive stimuli, consistent with a noisier representation of neutral stimuli. The greater heterogeneity of the bias across the melancholic group is consistent with a more labile disorder (i.e. variable across the day). Future work will aim to understand how these findings reflect specific individual differences (e.g. prior cognitive biases) and clarify whether such biases change dynamically during cognitive tasks as internal models of the sensorium are refined and updated in response to experience. PMID- 24766993 TI - Sarcopenia and sarcopenic obesity classifications and cardiometabolic risks in older women. AB - The purpose of this study was to examine the association between sarcopenia and sarcopenic obesity (SO) with cardiometabolic risk factors in postmenopausal women. 149 volunteers (67.17+/-6.12 years) underwent body composition assessment using dual energy X-ray absorptiometry (DXA) and had analyzed blood samples collected for lipid profile, glucose metabolism and C-reactive protein (CRP). Sarcopenia was defined as an appendicular fat-free mass (AFFM) divided by height squared <=5.45 kg/m(2) while SO was classified based on the residuals of a regression. Waist circumference (WC) and arterial blood pressure were also measured. Student's t-tests and correlations were used for analyses. Prevalence of sarcopenia and SO were respectively 16.8 and 21.5%. WC was significantly correlated with all the examined risk factors. AFFM relative to height squared was positively correlated with systolic blood pressure (SBP) and diastolic blood pressure (DBP), CRP, insulinaemia, HOMA score, and those classified as sarcopenic presented lower HOMA score when compared to nonsarcopenic. Regarding SO, although volunteers classified presented significantly higher fat mass (FM) and lower AFFM, it was not observed association with the examined risk factors. These findings support the association between WC and cardiometabolic risk factors in older women. In contrast, the approaches used to define sarcopenia and SO are not associated with cardiometabolic impairments. PMID- 24766994 TI - Diarylheptanoids and phenylphenalenones from Musa itinerans fruits. AB - Two diarylheptanoids, musaitinerins A and B, one heterodimeric phenylphenalenone musaitinerone and four known phenylphenalenones, identified as 4-hydroxy-2 methoxy-9-phenyl-1H-phenalen-1-one, musanolone E, hydroxyanigorufone and irenolone were isolated from the fruits of Musa itinerans Cheesm. Their structures were elucidated using spectroscopic analyses. The antimicrobial activity of these compounds was evaluated against Escherichia coli, Staphylococcus aureus and Candida albicans; the cytotoxic activity of these compounds was also evaluated against human erythromyeloblastoid leukemia (K562) and human alveolar carcinoma epithelial (A549) cell lines, respectively. Musaitinerone and musanolone E exhibited weak effects against the A549 cell line, as compared with adriamycin. However, these two compounds did not exhibit any growth inhibition against K562 cells, S. aureus, E. coli or C. albicans. The other compounds were inactive against all of the tested cell lines and microorganisms, even at concentrations as high as 50 MUM. PMID- 24766995 TI - Comparative mapping of chalkiness components in rice using five populations across two environments. AB - BACKGROUND: Chalkiness is a major constraint in rice production because it is one of the key factors determining grain quality (appearance, processing, milling, storing, eating, and cooking quality) and price. Its reduction is a major goal, and the primary purpose of this study was to dissect the genetic basis of grain chalkiness. Using five populations across two environments, we also sought to determine how many quantitative trait loci (QTL) can be consistently detected. We obtained an integrated genetic map using the data from five mapping populations and further confirmed the reliability of the identified QTL. RESULTS: A total of 79 QTL associated with six chalkiness traits (chalkiness rate, white core rate, white belly rate, chalkiness area, white core area, and white belly area) were mapped on 12 chromosomes using five populations (two doubled haploid lines and three recombinant inbred lines) across two environments (Hainan in 2004 and Wuhan in 2004). The final integrated map included 430 markers; 58.3% of the QTL clustered together (QTL clusters), 71.4% of the QTL clusters were identified in two or more populations, and 36.1% of the QTL were consistently detected in the two environments. The QTL could be detected again and showed dominance (qWBR1, qWBR8, qWBR12, and qCR5) or overdominance effects (qWCR7) for the rate of the white belly or white core, respectively, and all four QTL clusters derived from Zhenshan 97 controlling white belly rate were stably and reliably identified in an F2 population. CONCLUSIONS: Our results identified 79 QTL associated with six chalkiness traits using five populations across two environments and yielded an integrated genetic map, indicating most of the QTL clustered together and could be detected in different backgrounds. The identified QTL were stable and reliable in the F2 population, and they may facilitate our understanding of the QTL related to chalkiness traits in different populations and various environments, the relationships among the various chalkiness QTL, and the genetic basis for chalkiness. Thus, our results may be immediately used for map-based cloning of important QTL and in marker-assisted breeding to improve grain quality in rice breeding. PMID- 24766997 TI - Cingulum bundle white matter lesions influence antidepressant response in late life depression: a pilot study. AB - BACKGROUND: Late-life depression is associated with white matter hyperintense lesions (WMLs) occurring in specific fiber tracts. In this study, we sought to determine if greater WML severity in the cingulum bundle or uncinate fasciculus was associated with poor short-term antidepressant response. METHODS: Eleven depressed elders completed a baseline cranial 3T MRI and received antidepressant treatment following a medication algorithm. MRIs were analyzed to measure the fraction of each fiber tract's volume occupied by WMLs. Statistical analyses examined the effect of dichotomized fiber tract WML severity on three- and six month depression severity after controlling for age and baseline depression severity. RESULTS: Greater WML severity in the left hemispheric cingulum bundle adjacent to the hippocampus was associated with greater post-treatment depression severity at three- (F1,7=6.42, p=0.0390) and six-month assessments (F1,5=9.62, p=0.0268). Other fiber tract WML measures were not significantly associated with outcomes. LIMITATIONS: The study had a small sample size and analyses were limited to only a priori fiber tracts. CONCLUSIONS: This pilot study supports the hypothesis that focal damage to the cingulum bundle may contribute to poor short term antidepressant response. These findings warrant further investigation with a larger, more definitive study. PMID- 24766996 TI - Comparative performance of Patient Health Questionnaire-9 and Edinburgh Postnatal Depression Scale for screening antepartum depression. AB - OBJECTIVE: We sought to evaluate the psychometric properties of two widely used screening scales: the Patient Health Questionnaire (PHQ-9) and Edinburgh Postnatal Depression Scale (EPDS) among pregnant Peruvian women. METHODS: This cross-sectional study included 1517 women receiving prenatal care from February 2012 to March 2013. A structured interview was used to collect data using PHQ-9 and EPDS. We examined reliability, construct and concurrent validity between two scales using internal consistency indices, factor structures, correlations, and Cohen's kappa. RESULTS: Both scales had good internal consistency (Cronbach's alpha>0.8). Correlation between PHQ-9 and EPDS scores was fair (rho=0.52). Based on exploratory factor analysis (EFA), both scales yielded a two-factor structure. EFA including all items from PHQ-9 and EPDS yielded four factors, namely, "somatization", "depression and suicidal ideation", "anxiety and depression", and "anhedonia". The agreement between the two scales was generally fair at different cutoff scores with the highest Cohen's kappa being 0.46. CONCLUSIONS: Both the PHQ-9 and EPDS are reliable and valid scales for antepartum depression assessment. The PHQ-9 captures somatic symptoms, while EPDS detects depressive symptoms comorbid with anxiety during early pregnancy. Our findings suggest simultaneous administration of both scales may improve identification of antepartum depressive disorders in clinical settings. PMID- 24766999 TI - Effect of symptom severity on efficacy and safety of aripiprazole adjunctive to antidepressant monotherapy in major depressive disorder: a pooled analysis. AB - BACKGROUND: There is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole. METHODS: Data from 3 randomized, double blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery-Asberg Depression Rating Scale (MADRS) total score (mild, <=24; moderate, 25-30; severe, >=31). Treatment differences in change in MADRS total score and rates of response (>=50% MADRS improvement) and remission (response with MADRS total score <=10) were analyzed at endpoint. Adverse events were assessed within each subgroup. RESULTS: Aripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, -2.5 [-4.0 to -1.1]; moderate, -3.2 [-4.9 to -1.6]; severe, -4.5 [-6.8 to -2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness. LIMITATIONS: The original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups. CONCLUSIONS: In patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758. PMID- 24766998 TI - Effect of OPRM1 and stressful life events on symptoms of major depression in African American adolescents. AB - BACKGROUND: In a community sample of low-income African American adolescents, we tested the interactive effects of variation in the mu 1 opioid receptor (OPRM1) gene and the occurrence of stressful life events on symptoms of depression. METHOD: Interactive effects of 24 OPRM1 simple nucleotide polymorphisms (SNP) and adolescent report of stressful life events on depression were tested using multilevel regressions. SNPs were dummy coded to test both additive and dominate forms of coding. RESULTS: Five OPRM1 SNPs showed significant evidence of interaction with stressful life events to alter depression risk (or symptoms) after adjusting for multiple testing and the correlated nature of the SNPs. Follow-up analyses showed significant differences based on OPRM1 genotype at both lower and higher frequencies of stressful life events, suggesting that participants with a copy of the minor allele on OPRM1 SNPs rs524731, rs9478503, rs3778157, rs10485057, and rs511420 have fewer symptoms in low stress conditions but more symptoms in high stress conditions compared to major allele homozygotes. LIMITATIONS: The genetic variants associated with depression in African American adolescents may not translate to other ethnic groups. This study is also limited in that only one gene that functions within a complex biological system is addressed. CONCLUSIONS: This current study is the first to find an interaction between OPRM1 and life stress that is associated with depression. It also addressed an understudied population within the behavioral genetics literature. Further research should test additional genes involved in the opioid system and expand the current findings to more diverse samples. PMID- 24767000 TI - Dose-dependent effects of light on hyperthymic temperament. AB - BACKGROUND: In a previous study examining the association of hyperthymic temperament and daily light exposure (illuminance), we compared hyperthymic scores of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire version (TEMPS-A) acquired from residents in Sapporo and Oita in Japan, which are located at 43 degrees and 33 degrees of latitude. We found that residents of Oita had significantly higher hyperthymic scores than residents of Sapporo. Moreover, a comparison of 3 regions rather than 2 regions may show a dose-response relationship in hyperthymic temperament and illuminance. METHODS: Japan has 4 large islands-Hokkaido, Honshu, Shikoku, and Kyushu. Sapporo is in Hokkaido and Oita is in Kyushu. As the 3rd location, we recently collected TEMPS A data from 125 residents in Koshigaya which is located in Honshu at 36 degrees . We combined the data of the Koshigaya residents with the data of 94 residents from Sapporo and 95 from Oita. RESULTS: The mean yearly total sunshine of the past 20 years (1993-2012) was 1684.6h in Sapporo, 1862.9h in Koshigaya, and 2002.9h in Oita. Multiple regression analyses revealed that sunshine predicted significant variance of hyperthymic temperament in a dose-dependent manner. LIMITATIONS: The limitation of the present study is the lack of the consideration of the effects of temperature on hyperthymic temperament. Since correlations are fairly small, other factors are also at work for hyperthymic temperament. CONCLUSIONS: The present findings suggest that higher illuminance may maintain hyperthymic temperament via light effects in a dose-dependent manner. PMID- 24767001 TI - Item non-response on self-reported depression screening questionnaire among community-dwelling elderly. AB - BACKGROUND: In responses to self-reported depression screening questionnaires, item non-response, which refers to the absence of answers to specific questions, is problematic. The objective of this study were (1) to clarify the features of respondents with item non-response on a self-reported elderly depression screening questionnaire (15-item geriatric depression scale; GDS-15) as compared to respondents with full responses, and (2) to compare positive depression screening rates calculated using two methods: excluding respondents with item non response (complete case analysis; CCA) and estimating by multiplying mean scores from valid responses by the total number of GDS-15 items for respondents with item non-response. METHODS: This was a cross-sectional study conducted from 2010 to 2012. Of 4794 elderly subjects (65 years and older) living in one town in Japan 2836 community-dwelling elderly people (59.2%) were included in the analysis. RESULTS: Item non-response was observed in 25.0% of respondents. Respondents with item non-response had a higher rate of depression and mental and physical problems. Respondents with depression (estimated GDS-15 score >=6) and suicidal ideation both had a 1.6-times higher risk of item non-response on the GDS-15. The positive depression screening rate on GDS-15 by CCA was 16.5%, compared with 18.9% when calculated by the estimated GDS-15 score. LIMITATIONS: Our survey was conducted in one rural area and targeted only elderly people. CONCLUSION: The incidence of item non-response among community-dwelling elderly people was associated with depression of the respondent. Excluding subjects with item non-response when calculating positive depression screening rates in elderly individuals causes the rate to be underestimated. PMID- 24767002 TI - Increased fear-potentiated startle in major depressive disorder patients with lifetime history of suicide attempt. AB - BACKGROUND: Suicide is a common reason for psychiatric emergency and morbidity, with few effective treatments. Anxiety symptoms have emerged as potential modifiable risk factors in the time before a suicide attempt, but few studies have been conducted using laboratory measures of fear and anxiety. We operationally defined fear and anxiety as increased startle reactivity during anticipation of predictable (fear-potentiated startle) and unpredictable (anxiety potentiated startle) shock. We hypothesized that a lifetime history of suicide attempt (as compared to history of no suicide attempt) would be associated with increased fear-potentiated startle. METHODS: A post-hoc analysis of fear- and anxiety-potentiated startle was conducted in 28 medication-free patients with Major Depressive Disorder (MDD) divided according to suicide attempt history. RESULTS: The magnitude of fear-potentiated startle was increased in depressed patients with lifetime suicide attempts compared to those without a lifetime history of suicide attempt (F(1,26)=5.629, p=.025). There was no difference in anxiety-potentiated startle by suicide attempt history. LIMITATIONS: This is a post-hoc analysis of previously analyzed patient data from a study of depressed inpatients. Further replication of the finding with a larger patient sample is indicated. CONCLUSIONS: Increased fear-potentiated startle in suicide attempters suggests the role of amygdala in depressed patients with a suicide attempt history. Findings highlight the importance of anxiety symptoms in the treatment of patients at increased suicide risk. PMID- 24767003 TI - Antidepressant treatment history as a predictor of response to scopolamine: clinical implications. AB - BACKGROUND: The intravenous administration of scopolamine produces rapid antidepressant effects. Generally, failing multiple previous antidepressant trials is associated with a poor prognosis for response to future medications. This study evaluated whether treatment history predicts antidepressant response to scopolamine. METHODS: Treatment resistant patients (2 failed medication trials) (n=31) and treatment naive patients (no exposure to psychotropic medication) (n=31) with recurrent major depressive or bipolar disorder participated in a double-blind, placebo-controlled, crossover clinical trial. Following a placebo lead-in, participants randomly received P/S or S/P (P=3 placebo; S=3 scopolamine (4ug/kg) sessions 3 to 5 days apart). The Montgomery Asberg Depression Rating Scale (MADRS) was the primary outcome measure. A linear mixed model was used to examine the interaction between clinical response and treatment history, adjusting for baseline MADRS. RESULTS: Treatment resistant and treatment naive subjects combined responded significantly to scopolamine compared to placebo (F=15.06, p<0.001). Reduction in depressive symptoms was significant by the first post-scopolamine session (F=42.75, p<0.001). A treatment history by scopolamine session interaction (F=3.37, p=0.04) indicated treatment naive subjects had lower MADRS scores than treatment resistant patients; this was significant after the second scopolamine infusion (t=2.15, p=0.03). LIMITATIONS: Post-hoc analysis: Also, we used a single regimen to administer scopolamine, and smokers were excluded from the sample, limiting generalizability. CONCLUSIONS: Treatment naive and treatment resistant patients showed improved clinical symptoms following scopolamine, while those who were treatment naive showed greater improvement. Scopolamine rapidly reduces symptoms in both treatment history groups, and demonstrates sustained improvement even in treatment resistant patients. PMID- 24767004 TI - Cognitive control therapy and transcranial direct current stimulation for depression: a randomized, double-blinded, controlled trial. AB - BACKGROUND: Based on findings that major depressive disorder (MDD) is associated to decreased dorsolateral prefrontal cortical (DLPFC) activity; interventions that increase DLPFC activity might theoretically present antidepressant effects. Two of them are cognitive control therapy (CCT), a neurocognitive intervention that uses computer-based working memory exercises, and transcranial direct current stimulation (tDCS), which delivers weak, electric direct currents over the scalp. METHODS: We investigated whether tDCS enhanced the effects of CCT in a double-blind trial, in which participants were randomized to sham tDCS and CCT (n=17) vs. active tDCS and CCT (n=20). CCT and tDCS were applied for 10 consecutive workdays. Clinicaltrials.gov identifier: NCT01434836. RESULTS: Both CCT alone and combined with tDCS ameliorated depressive symptoms after the acute treatment period and at follow-up, with a response rate of approximately 25%. Older patients and those who presented better performance in the task throughout the trial (possibly indicating greater engagement and activation of the DLPFC) had greater depression improvement in the combined treatment group. LIMITATIONS: Our exploratory findings should be further confirmed in prospective controlled trials. DISCUSSION: CCT and tDCS combined might be beneficial for older depressed patients, particularly for those who have cognitive resources to adequately learn and improve task performance over time. This combined therapy might be specifically relevant in this subgroup that is more prone to present cognitive decline and prefrontal cortical atrophy. PMID- 24767005 TI - Comparing outcomes of adjunctive treatment in depression: aripiprazole versus bupropion. AB - BACKGROUND: Adjunctive therapy in depression is often used in patients with an inadequate response to antidepressant therapy. METHODS: Utilizing a chart review from a private, outpatient psychiatric clinic, patients with adjunctive medication added to their antidepressant were reviewed. Demographic information, diagnoses, medication history, and QIDS SR16 depression scores were collected and recorded at each visit and entered into a database. RESULTS: Significant reductions were observed in the QIDS score of aripiprazole (n=70) and bupropion (n=83) patients after the first visit. At the first visit, 70% of aripiprazole patients had lower QIDS score compared to baseline visit, with 17% achieving remission, whereas 66% of bupropion users had lower scores at the first visit compared to baseline visit, with 23% achieving remission. At the end of the observation period 50% of patients on aripiprazole achieved remission compared to 33% of bupropion patients. Both groups of patients had significant reductions in their QIDS symptom scores of sadness, concentration, and general interest. In addition, aripiprazole patients had a decrease in the thoughts of death and suicide score while bupropion patients had decreases in the low energy score. None of the differences in QIDS line-item scores between aripiprazole and bupropion patients were statistically significant. LIMITATIONS: This study was a small scale, retrospective study that did not have a placebo control group. CONCLUSION: Aripiprazole and bupropion were comparable in significantly lowering patients' QIDS SR16 scores and helping over 50% of the patients achieve remission. Differences in line-item QIDS score were also observed. PMID- 24767006 TI - Screening for bipolar disorder: does gender distort scores and case-finding estimates? AB - BACKGROUND: Gender differences in rates of bipolar disorder have been described, with most studies reporting males as over-represented in those diagnosed with a bipolar I disorder and females over-represented in those diagnosed with a bipolar II disorder. This could reflect true differences in prevalence or measurement error emerging from screening or case-finding measures. We examine the possible contribution of the latter by examining one screening measure-the Mood Swings Questionnaire (MSQ). METHODS: We analyse MSQ data from a large sample of age- and gender-matched bipolar I and bipolar II patients (and their composite group). Gender differences were examined in terms of prevalence and severity of MSQ symptoms, MSQ sub-scales scores and total MSQ scores, employing univariate and differential item functioning (DIF) analyses. RESULTS: Both male and female bipolar I patients reported higher total MSQ and higher mysticism MSQ sub-scale scores than their male and female bipolar II counterparts. There were no gender differences when bipolar I, bipolar II and composite bipolar groups were separately examined on both total and sub-scale MSQ scores, suggesting that gender does not impact on MSQ scoring. When item analyses of bipolar I and II groups were undertaken separately, a number of differences emerged, but as few were consistent across bipolar sub-types such differences could reflect chance and failure to control for multiple comparisons. The over-representation of some items in females and some in males may have contributed to the comparable total and sub-scale scores. LIMITATIONS: Large sample size and only one measure (i.e. MSQ) examined. CONCLUSION: As total and sub-scale MSQ scores were uninfluenced by gender we can conclude that this screening test is not confounded by gender and, if representative of other such screening measures, would indicate that any differential prevalence of the bipolar disorders identified in community studies possibly reflects gender differences in their occurrence rather than artefactual consequences of screening measures having a gender bias. PMID- 24767007 TI - The effect of comorbid major depressive disorder or bipolar disorder on cognitive behavioral therapy for social anxiety disorder. AB - BACKGROUND: Major depressive disorder (MDD) and bipolar disorder (BD) commonly co occur in individuals with social anxiety disorder (SAD), yet whether these comorbidities influence the outcomes of cognitive behavioral therapy (CBT) for SAD is unclear. METHODS: The present study examined the degree to which individuals with SAD and comorbid MDD (SAD+MDD; n=76), comorbid BD (SAD+BD; n=19), a comorbid anxiety disorder (SAD+ANX; n=27), or no comorbid diagnoses (SAD+NCO; n=41) benefitted from CBT for SAD. Individuals were screened using the Structured Clinical Interview for DSM-IV and then completed the Social Phobia Inventory and the Depression Anxiety Stress Scales before and after 12-weeks of group CBT for SAD. RESULTS: At pretreatment the SAD+MDD and SAD+BD groups reported higher social anxiety symptoms than the SAD+ANX and SAD+NCO groups. All groups reported large and significant improvement in social anxiety with CBT. However, at posttreatment the SAD+MDD and SAD+BD groups continued to have higher social anxiety symptoms than the SAD+NCO group, and the SAD+ANX group did not differ in social anxiety symptoms from any group. The sample also showed small and statistically significant improvement in depressive symptoms with CBT for SAD. LIMITATIONS: Information about medication was not collected in the present study, and we did not assess the long-term effects of CBT. CONCLUSION: Our results suggest that CBT for SAD is an effective treatment even in the presence of comorbid mood disorders in the short-term, although extending the course of treatment may be helpful for this population and should be investigated in future research. PMID- 24767008 TI - Serum level of brain derived neurotrophic factor (BDNF) among patients with bipolar disorder. AB - BACKGROUND: There is a growing body of evidence that serum brain derived neurotrophic factor (BDNF) is altered during the episodes of bipolar disorder. The aim of this study was to investigate serum BDNF levels in bipolar disorder patients during manic and depressive episodes and its clinical utility in bipolar disorder compared to other psychiatric disorders. METHODS: The study was conducted on 80 Egyptian patients, who were classified into 4 groups: group Ia (25 patients with depressive episodes), group Ib (25 patients with manic episodes), group II (15 patients having Schizophrenia) as pathological controls and group III (15 healthy subjects) as controls. All subjects were diagnosed according to DSM-IV, assessed using the Hamilton Rating Scale for depression (HAM D), and the Young Mania Rating Scale (YMRS). sBDNF concentrations were measured using the quantitative sandwich enzyme immunoassay technique. RESULTS: sBDNF showed significantly lower levels in patients with depressive episodes or manic episodes. The best cut-off for sBDNF in discriminating depressed patient from healthy control was <=33,000pg/ml (AUC=0.891, sensitivity of 84%, and specificity of 80%). Moreover, the best cut-off for sBDNF in discriminating mania patients' group from healthy control was <=29,500pg/ml, (AUC=0.984, asensitivity of 96%, and specificity of 86.7%). LIMITATIONS: Only a small sample size was considered which included only drug free patients. BDNF was measured in serum not in CSF or brain tissue. CONCLUSIONS: Low sBDNF levels are strongly associated with active phases of bipolar disorder, in depressive and manic episodes. PMID- 24767009 TI - Internet-based trauma-focused cognitive behavioural therapy for PTSD with and without exposure components: a randomised controlled trial. AB - BACKGROUND: Internet-delivered trauma-focused cognitive behavioural therapy is efficacious for PTSD; however, no studies have investigated the roles of individual treatment components or the safety of online treatments. AIMS: To compare the efficacy and safety of an online treatment for PTSD comprised of psychoeducation, stress management, cognitive restructuring and exposure components with the equivalent protocol without the exposure components, using a randomised controlled trial design. METHODS: Sixty-six individuals were randomised to a non-exposure condition and 59 to the full protocol with exposure components. Treatment duration was 8 weeks and pre-, post-treatment and three month follow-up outcomes were analysed using a mixed linear modelling approach. RESULTS: Both groups achieved improvements in symptoms with no differences between groups on any primary or secondary outcome measures, diagnostic remission rates or adverse events. LIMITATIONS: The study included several secondary measures that have not been previously validated and treatments were not time matched in terms of number of lessons. CONCLUSIONS: These findings indicate that trauma-focused cognitive behavioural therapy for PTSD with or without exposure components can be safe and efficacious. PMID- 24767010 TI - Association of the 3' region of the neuregulin 1 gene with bipolar I disorder in the Chinese Han population. AB - BACKGROUND: Based on the function of neuregulin 1 (NRG1) in neurodevelopment, susceptibility to bipolar disorder presumably involves this gene. The 3' region of NRG1 contains the majority of the coding exons, and transcripts from this region encode 8 of the 9 known NRG1 isoforms; therefore, this region is likely to be predominant versus the 5' region in terms of their relative contributions to NRG1 function. We investigated the association between the 3' region of the NRG1 gene and bipolar I disorder (BPI) in the Chinese Han population and performed further analyses depending on the presence or absence of psychotic features. METHODS: A total of 385 BPI patients and 475 healthy controls were recruited for this study. Thirty tag single nucleotide polymorphisms (SNPs) across the 3' region of the NRG1 gene were genotyped for allelic and haplotypic associations with BPI and subgroups with psychotic features (BPI-P) or without psychotic features (BPI-NP). RESULTS: Individual marker analysis showed that 2 SNPs (rs12547858 and rs6468121) in this region were significantly associated with BPI. Moreover, subgroup analyses showed significant but marginal associations of rs6468121 with BPI-P and rs3757933 with BPI-NP. Haplotype analyses showed that 6 haplotypes were associated with BPI only. LIMITATIONS: The sample size was relatively small. The investigated tag SNPs only represented 83% of the information on the targeted region. There might be a retrospective bias in the subgroup analyses. CONCLUSION: The results suggest that the 3' region of the NRG1 gene plays a role in BPI susceptibility in the Chinese Han population. In addition, the preliminary results show that BPI with psychotic features and BPI without psychotic features may constitute different sub-phenotypes; however, this finding should be confirmed in a larger population sample. PMID- 24767011 TI - Symptoms of depression and rates of neurocognitive impairment in HIV positive patients in Beijing, China. AB - BACKGROUND: In China an estimated 780,000 people are living with HIV (PLWH). In high-income countries PLWH are at increased risk of depression, with subsequent adverse consequences for quality of life, and HIV-related morbidity and mortality. There are few data from low-and middle-income countries. The aims of this country-specific investigation of the Asia Pacific NeuroAIDS Consortium (APNAC) study were to establish the point prevalence, severity and HIV-related and non-HIV related correlates of depressive symptoms in PLWH, in Beijing, China. METHOD: PLWH attending an outpatient clinic at Ditan Hospital, Beijing were recruited consecutively. Data sources were: study-specific questions about demographic characteristics, and health behaviours, the Centre for Epidemiological Studies Depression Scale (CES-D), the World Health Organisation Self-Reporting Questionnaire (SRQ-20) translated into Mandarin and administered as structured individual interviews, and a screen battery of four standard neuropsychological tests. RESULTS: In total 50/51 (98%) eligible patients agreed to participate. Overall 28% scored CES-D>=16 or SRQ20>=10 and 18% in these clinical ranges on both measures; 69% were classified as being neuropsychologically impaired (scoring below 1 SD of the control value on at least two tests). Higher depressive symptom scores were associated with lower education, alcohol overuse and diminished motor ability (all p<0.05), but not neuropsychological impairment CONCLUSION: Clinically significant depressive symptoms among this cohort of PLWH in Beijing occurred at 5 times the rate reported among a general Chinese urban population. No participants had been assessed for depression prior to the study and none were treated, indicating that consideration of psychological morbidity and its consequences for health behaviours should be incorporated into routine HIV care in China. PMID- 24767012 TI - Age-related differences in the influence of major mental disorders on suicidality: a Korean nationwide community sample. AB - BACKGROUND: We compared the influence of major mental disorders on suicidality according to age, adjusting for suicide-related correlates. METHODS: This study was based on the Korean national epidemiological survey of mental disorders including community-dwelling adults between 18 and 74 years of age (n=6022). Subjects were classified into three age groups; young (18-39), middle-aged (40 59), and late adulthood (60-74). Face-to-face interviews were conducted using the Korean version of the Composite International Diagnostic Interview. According to age groups, the influence of major depressive disorder (MDD), anxiety disorder, and alcohol use disorder on risk for suicidality were investigated by multiple logistic regression models adjusting for sex, years of education, marital status, income, employment, presence of chronic medical illness, and lifetime history of suicide attempt. RESULTS: After including MDD as a covariate, anxiety disorder remained a risk factor only in the middle-aged group (adjusted OR: 2.83, 95% CI: 1.54-5.22), and alcohol use disorder was a risk factor for suicidality only in the young group (adjusted OR: 2.81, 95% CI: 1.06-7.43). Conversely, MDD was the only mental disorder that significantly increased suicidality in all age groups. LIMITATIONS: This was a cross-sectional study and did not include subjects over 75 years of age. CONCLUSION: This study showed that the contribution of psychiatric disorders to risk for suicidality varied according to age group. Therefore, strategies for suicide prevention should be specifically designed for different age groups. PMID- 24767013 TI - Typologies of posttraumatic stress disorder in the U.S. adult population. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by heterogeneous clusters of re-experiencing, avoidance, numbing, and hyperarousal symptoms. However, data are lacking regarding the predominant, population-based typologies of this disorder, and how they are linked to trauma-related characteristics, psychiatric comorbidities, and health-related quality of life. METHODS: We used latent class analyses (LCAs) to evaluate predominant typologies of PTSD in a nationally representative sample of 2463 U.S. adults with PTSD. Multinomial logistic regression analyses were then conducted to evaluate trauma related characteristics, psychiatric comorbidities, and health-related quality of life variables associated with these typologies. RESULTS: LCAs revealed three predominant typologies of PTSD-Anxious-Re-experiencing (weighted prevalence=32.2%), Dysphoric (32.8%), and High Symptom (35.0%). Compared to the Dysphoric class, the Anxious-Re-experiencing and High Symptom classes were more likely to report sexual assault, physical assault, and military combat as their worst traumatic events; had an earlier age of onset and longer duration of PTSD; and were more likely to be diagnosed with nicotine dependence and borderline personality disorder, to have attempted suicide, and had poorer physical health related quality of life (HRQoL). The High Symptom class had increased odds of all disorders, suicide attempts, and the poorest HRQoL. LIMITATIONS: Diagnoses were based on DSM-IV criteria and cross-sectional analyses preclude examination of how PTSD typologies are temporally related to other variables. CONCLUSION: PTSD in the general U.S. adult population is characterized by three predominant typologies, which are differentially linked to trauma and clinical characteristics. These findings underscore the importance of personalized approaches to the assessment, monitoring, and treatment of PTSD that take into consideration the heterogeneous manifestations of this disorder. PMID- 24767014 TI - Effects of childhood trauma and clinical features on determining quality of life in patients with bipolar I disorder. AB - BACKGROUND: We explored how childhood trauma (CHT) affects the clinical expression of disorder and quality of life in patients with bipolar I (BP-I) disorder. METHODS: Euthymic patients (n=116) who subsequently received a diagnosis of BP-I disorder were consecutively included and were interviewed using the following sociodemographic and clinical data forms; Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Childhood Abuse and Neglect Questionnaire (CANQ) and the 36-item Medical Outcome Study Short Form Health Survey (SF-36). The quality of life of BP-I patients with and without a history of CHT were examined. RESULTS: The percentage of trauma was 61.2%. Patients who had CHT had higher frequencies of depressive episodes (t=-2.38, p=0.019), total episodes (t=-2.25, p=0.026), attempted suicide more often (chi(2)=18.12, p=0.003) and had lower scores on the pain subscale of the SF-36 (z=-2.817, p=0.005). In patients with mixed or rapid-cycling episodes, SF-36 subscale scores except general health and pain were found to be lower. LIMITATIONS: Our sample may fail to reflect the general BD population; the patients were included consecutively and consisted of a majority of female patients. CONCLUSIONS: CHT plays an important role in the clinical expression of BP-I disorder and having mixed/rapid cycling episodes negatively affects both physical and mental components, as measured by the SF-36. While both males and females reported experiencing sexual abuse, female BP-I patients complained about pain more often. It is suggested that treatment of BP-I patients with a history of CHT should differ from that provided for patients with no CHT history. PMID- 24767015 TI - MiRNA-206 and BDNF genes interacted in bipolar I disorder. AB - BACKGROUND: Several lines of evidence have suggested that has-mir-206 (miRNA-206) may regulate brain-derived neurotrophic factor (BDNF) protein synthesis. The primary aim of this study was to determine whether miRNA-206 gene (MIR206) may confer susceptibility to bipolar disorder type I (BD-I) and treatment response to mood stabilizers. Also, we intended to verify the hypothesis that a potential interplay of MIR206 and BDNF may influence the genetic risk for BD-I and treatment response. METHODS: The MIR206 rs16882131 and BDNF rs6265 polymorphisms were genotyped in 280 BD-I patients and 288 healthy controls. Treatment response to lithium and valproate was retrospectively determined. RESULTS: No association was observed in the individual polymorphism with regards to risk of BD-I and treatment response. Our results showed a significant gene to gene interaction between the MIR206 rs16882131 and BDNF rs6265 polymorphisms that contribute to BD I susceptibility and treatment response. Further analysis showed a significant interaction between MIR206 and BDNF on treatment score (F3, 138=8.61, P=0.046), and individuals with MIR206 T/T+TC and BDNF A/A genotypes had a significantly lower mean treatment score than those with MIR206 CC and BDNF A/A+A/G as well as those with MIR206 CC and BDNF G/G genotypes (P=0.018 and 0.013, respectively). LIMITATION: This is a preliminary investigation with relatively small sample size. CONCLUSION: Our findings provide initial evidence of the gene-to-gene interaction of MIR206 and BDNF in regards to the risk for BD-I as well as treatment response to mood stabilizers. PMID- 24767016 TI - Screening for bipolar depression in family medicine practices: prevalence and clinical correlates. AB - BACKGROUND: To compare individuals in primary care (PC) who screen positive for bipolar depression to those who screened positive for unipolar depression on mental health care ouctomes, PC service utilization, medical comorbidities, suicidal ideation, health-related quality of life (HRQoL) and psychosocial functioning. METHODS: In this cross-sectional study, participants (N=1197) answered self-reported measures of depressive symptoms (Center for epidemiologic studies depression scale), HRQoL (World Health Organization Quality of Life instrument-Abbreviated version), medical comorbidity (functional comorbidity index) and functioning (Functional Assessment Short test). Participants were partitioned into 'bipolar' and 'unipolar' depression groups based on a predefined cutoff on the Brazilian mood disorder questionnaire. RESULTS: The prevalence of bipolar depression was in PC was 4.6% (95% CI: 3.4-5.8). Participants with bipolar depression were more likely to endorse suicidal ideation, present with more medical comorbidities, report a worse physical HRQoL and have a higher rate of PC services utilization as compared to participants who screened positive for unipolar depression. Only six (10.9%) participants were recognized by the general practitioner as having a diagnosis of bipolar depression. LIMITATIONS: The cross sectional design prevents firm causal inferences from being drawn. A positive screen for BD does not substantiate the actual diagnosis. Co-morbid mental disorders were not accessed. CONCLUSIONS: Bipolar depression is common and under recognized in Brazilian PC services. A positive screen for bipolar depression was associated with worse clinical outcomes and greater PC service utilization. PMID- 24767017 TI - Resilience buffers the impact of traumatic events on the development of PTSD symptoms in firefighters. AB - BACKGROUND: Resilience is considered to be a powerful protective factor in buffering the detrimental impact of traumatic stress on the development of posttraumatic stress disorder (PTSD). However, there is a striking lack of research concerning the development of a model of resilience, especially one including both risk and protective factors. The aim of this study was to investigate the possible mediators and moderators influencing the relationship between traumatic stress and PTSD using a moderated mediation analysis. METHODS: Study participants included 552 Korean firefighters from four large cities. The subjects completed a series of self-report measures including the Life Event Checklist, the Perceived Stress Scale, the Occupational Stress Scale, the Impact of Event Scale-Revised, and the Connor-Davidson Resilience Scale. RESULTS: Traumatic stress had both a direct and an indirect, via perceived stress, impact on the development of PTSD symptoms. Additionally, the mediation of the association between traumatic stress and PTSD symptoms via perceived stress was moderated by individual resilience. In particular, under the same level of traumatic stress, firefighters with high levels of resilience (scores >=75, upper 25th percentile or >=90, upper 10th percentile) were protected from both the direct and indirect impacts of traumatic stress relative to those with lower levels of individual resilience. CONCLUSIONS: The current findings provide a comprehensive picture of individuals who should be considered at high risk for the development of PTSD symptoms following traumatic stress and identify the factors that should be targeted by efforts to prevent PTSD. PMID- 24767018 TI - Objective and subjective psychosocial functioning in bipolar disorder: an investigation of the relative importance of neurocognition, social cognition and emotion regulation. AB - BACKGROUND: People with bipolar disorder (BD) experience significant psychosocial impairment. Understandings of the nature and causes of such impairment is limited by the lack of research exploring the extent to which subjectively reported functioning should be valued as an indicator of objective dysfunction, or examining the relative influence of neurocognition, social cognition and emotion regulation on these important, but different aspects of psychosocial functioning in the context of mania and depression symptoms. This study aimed to address this paucity of research by conducting a comprehensive investigation of psychosocial functioning in a well characterised group of BD patients. METHODS: Fifty-one BD patients were compared to 52 healthy controls on objectively and subjectively assessed psychosocial outcomes. Relationships between current mood symptoms, psychosocial function and neurocognitive, social cognitive and emotion regulation measures were also examined in the patient group. RESULTS: Patients had significantly worse scores on the global objective and subjective functioning measures relative to controls. In the patient group, although these scores were correlated, regression analyses showed that variance in each of the measures was explained by different predictors. Depressive symptomatology was the most important predictor of global subjective functioning, and neurocognition had a concurrent and important influence with depressive symptoms on objective psychosocial function. Emotion regulation also had an indirect effect on psychosocial functioning via its influence on depressive symptomatology. LIMITATIONS: As this study was cross-sectional in nature, we are unable to draw precise conclusions regarding contributing pathways involved in psychosocial functioning in BD. CONCLUSIONS: These results suggest that patients' own evaluations of their subjective functioning represent important indicators of the extent to which their observable function is impaired. They also highlight the importance of incorporating cognitive and emotion regulation assessments into clinical practice when working to reduce psychosocial dysfunction with patients diagnosed with BD. PMID- 24767019 TI - Residue and dissipation kinetics of thiamethoxam in a vegetable-field ecosystem using QuEChERS methodology combined with HPLC-DAD. AB - The dissipation kinetics and residual levels of thiamethoxam in potato and soil under field ecosystem were determined using a QuEChERS method with HPLC-DAD. At fortification levels of 0.05, 0.1, 0.25, 0.5, 1.0 and 5.0 mg kg(-1), it was shown recovery was 99.4% (95.3-103.5%) for potato tubers, and 88.5% (86-91%) for soil with coefficient variation of the method (CV%) was less than 4% in potato tubers, and in soil less than 11%. For repeatability ranged from 1.27% to 4.77%. The LOD and LOQ were estimated to be 0.02 and 0.06 mg kg(-1), respectively. The half lives were 2.92 and 1.4 days, respectively. The terminal residues of thiamethoxam were below the maximum residue limit (MRL 0.2 mg kg(-1)) after 6 days, which considered to be safe for human beings. These results contribute to establishing the scientific basis of the dosage of thiamethoxam for use in vegetable-field ecosystems. PMID- 24767020 TI - Effect of adding different thickening agents on the viscosity properties and in vitro mineral availability of infant formula. AB - The effect of adding different thickening agents (locust bean gum (LBG), modified corn and rice starches (MCS, MRS)) to an infant formula on both in vitro mineral availability (Ca, Fe and Zn), quantified by atomic absorption spectrophotometry (AAS), and formula viscosity, after in vitro gastrointestinal digestion, was investigated. LBG was the most effective agent to increase formula thickness. However, it showed a negative effect on Ca, Fe and Zn in vitro solubility and dialysability. MCS and MRS only affected calcium solubility and dialysability when they were used at ?50% of the maximum legal limit. No negative effect was observed for Fe and Zn when modified starches were added at the different concentrations assessed. The phytate content in the thickening ingredients was also analysed. Despite finding a considerable amount of phytic acid in the raw ingredients, its final concentration in the infant formula was insufficient to decrease in vitro mineral availability. PMID- 24767021 TI - Encapsulation of rutin and naringenin in multilamellar vesicles for optimum antioxidant activity. AB - Rutin and naringenin, two phenolic compounds with antioxidant properties were encapsulated in lipid-based onion-type multilamellar vesicles (MLVs). After vesicles formation, the free, adsorbed/encapsulated analytes were well separated with size exclusion chromatography (SEC), and rutin and naringenin were quantified with UV-HPLC at 258 nm and 290 nm. A mathematical model was developed to separately calculate the encapsulation and the adsorption yields of both phenols. Naringenin was shown to be poorly encapsulated (<10%) but highly adsorbed on MLVs surface (>60%) whatever MLVs composition. Conversely, rutin showed high encapsulation efficiency (>60%). Entrapment of rutin was proved to be efficient since no leak was observed within 30 days in concentrated MLVs phase, while 16.0+/-0.3% of rutin was still encapsulated after 30 days when MLVs were diluted in water. Free rutin broke up into quercetin while the encapsulated one remained stable. DPPH assay confirmed that only free and adsorbed rutin participated in antioxidant activity. PMID- 24767022 TI - Biogenic amine and quality changes in lightly salt- and sugar-salted black carp (Mylopharyngodon piceus) fillets stored at 4 degrees C. AB - The effects of low salt and sugar dry-curing on the quality changes of black carp (Mylopharyngodon piceus) fillets stored at 4 degrees C were evaluated by sensory, physical, chemical, and microbiological methods. Fish samples were left untreated (control), or were dry-cured with 1.5% salt (T1) or 1.5% salt+1.2% sugar (T2). Curing treatments reduced chemical changes reflected in HxR, Hx, pH, and total volatile base nitrogen (TVB-N); decreased cooking loss; and increased overall sensory quality of fish (p<0.05) compared to untreated samples. Significantly lower values of cadaverine and putrescine were observed in T1 and T2 compared to the control after the 2nd and 4th day, respectively (p<0.05). There were significant differences (p<0.05) between T1 and T2 for pH, TVB-N, total aerobic counts (TAC), and sensory characteristics. Sensory characteristics were significantly correlated with TAC, TVB-N, putrescine, and cadaverine in all samples (p<0.01). PMID- 24767023 TI - gamma-Aminobutyric acid induces resistance against Penicillium expansum by priming of defence responses in pear fruit. AB - The results from this study showed that treatment with gamma-aminobutyric acid (GABA), at 100-1000 MUg/ml, induced strong resistance against blue mould rot caused by Penicillium expansum in pear fruit. Moreover, the activities of five defence-related enzymes (including chitinase, beta-1,3-glucanase, phenylalnine ammonialyase, peroxidase and polyphenol oxidase) and the expression of these corresponding genes were markedly and/or promptly enhanced in the treatment with GABA and inoculation with P. expansum compared with those that were treated with GABA or inoculated with pathogen alone. In addition, the treatment of pear with GABA had little adverse effect on the edible quality of the fruit. To the best of our knowledge, this is the first report that GABA can effectively reduce fungal disease of harvested fruit. Its mechanisms may be closely correlated with the induction of fruit resistance by priming activation and expression of defence related enzymes and genes upon challenge with pathogen. PMID- 24767024 TI - Adsorption characteristics of rebaudioside A and stevioside on cross-linked poly(styrene-co-divinylbenzene) macroporous resins functionalized with chloromethyl, amino and phenylboronic acid groups. AB - The adsorptive separation of each steviol glycoside from aqueous solutions by polymeric adsorbents has attracted a lot of interest in recent years. The adsorption properties of chloromethylated cross-linked poly(styrene-co divinylbenzene) macroporous resins, functionalised with chloromethyl, amino and phenylboronic acid groups, towards rebaudioside A and stevioside were studied. The results revealed that the resins with amino and phenylboronic acid groups preferred to adsorb stevioside rather than rebaudioside A, and their adsorption kinetics fitted a pseudo-second-order model. Isothermal equilibrium curves of rebaudioside A and stevioside showed a good fitness with the Langmuir and Freundlich models. The adsorption of rebaudioside A and stevioside onto resins was a spontaneous and exothermic process as indicated by the negative values in free energy and enthalpy. Results from the resin-packed column demonstrated that an effluent rich in rebaudioside A (purity 98%) was obtained prior to the breakthrough point of stevioside. PMID- 24767025 TI - Influence of the structural features of commercial mannoproteins in white wine protein stabilization and chemical and sensory properties. AB - The cloudy aspect formed in white wines due to protein instability is a visual defect. Sodium bentonite is the most commonly used fining agent to treat this instability, but has usually a negative impact on the wine's physicochemical and sensory characteristics. Aiming to find suitable alternatives, eleven commercial mannoproteins were chemically characterized concerning their sugar composition and protein content, and their effectiveness on wine protein stabilization. Also, their effect on the amount and nature of phenolic compounds, browning potential, chromatic and sensory characteristic was evaluated. Protein stabilization effectiveness was related to their chemical composition, namely their high mannose to glucose ratio. Additionally, some mannoproteins decreased the browning potential. Thus, mannoproteins could be an effective alternative for protein stabilization, preserving or even improving wine quality. PMID- 24767026 TI - Use of artichoke (Cynara scolymus) flower extract as a substitute for bovine rennet in the manufacture of Gouda-type cheese: characterization of aspartic proteases. AB - Artichoke (Cynara scolymus L.) flower extract was assayed with the aim of replacing animal rennet in the manufacture of Gouda-type cheeses from bovine milk. Floral extract coagulated milk within a suitable time for use on an industrial scale, while the yield of cheese obtained was equal to that achieved with bovine abomasum. Five proteolytic fractions with milk-clotting activity were isolated in a two-step purification protocol, three belonging to the cardosin group. Cheeses made with C. scolymus proteases must be brined for a longer period (40 h) to prevent overproteolysis and avoid the development of a background flavor. The type of coagulant (bovine or vegetable) had no significant effect on the cheeses' chemical parameters analyzed throughout ripening, and no significant organoleptic differences were detected between those manufactured with C. scolymus or animal rennet. The results indicate that C. scolymus flower extract is suitable for replacing animal rennet in the production of Gouda-type cheeses. PMID- 24767027 TI - The potential of aqueous fractionation of lupin seeds for high-protein foods. AB - Aqueous fractionation of protein from lupin seeds was investigated as an alternative to the conventional wet fractionation processes, which make use of organic solvents. The effect of extraction temperature was studied and the consequences for downstream processing were analysed. Omitting the extraction of oil with organic solvents resulted in a protein isolate that contained 0.02-0.07 g oil g(-1) protein isolate, depending on the exact extraction conditions. Nevertheless, the protein functionality of the aqueous fractionated lupin protein isolate was similar to the conventional lupin protein isolate. The protein isolate suspension could be concentrated to 0.25 g mL(-1) using ultrafiltration, which provides a relevant concentration for a range of high-protein products. Based on the results, we conclude that aqueous fractionation can be a method to lower the environmental impact of the extraction of proteins from legumes that contain water- and dilute salt-soluble proteins. PMID- 24767028 TI - Analysing the effects of frozen storage and processing on the metabolite profile of raw mullet roes using 1H NMR spectroscopy. AB - (1)H NMR spectroscopy was used to investigate changes in the low molecular weight metabolic profile of raw mullet (Mugil spp.) roes during frozen storage and upon processing. NMR data were analysed by Principal Component Analyses (PCA). In the model constructed using frozen roes, no statistical significant metabolic modifications were observed in the first six months of storage, while choline derivatives, dimethylamine, lactate, and most of the free amino acids were identified as changing with statistical significance (p<0.05) in response to frozen storage time of twelve months. The PCA model comparing the metabolic profiles of roes before and after processing showed that the major modifications occurring upon manufacturing were the increase of the choline derivative compounds, uracil, and free amino acids, and a large decrease of taurine, glucose, lactate, and creatine/phosphocreatine. All of the above mentioned modifications reflect the occurrence of chemical/biochemical reactions arising from degradation processes such as lipolysis and proteolysis. PMID- 24767029 TI - Fatty acid composition in tissues of the farmed Siberian sturgeon (Acipenser baerii). AB - The fatty acid (FA) compositions of the diet and diverse tissues of the farmed Siberian sturgeon (Acipenser baerii) were analyzed in detail to assess their nutritional quality. Twelve male fish were sampled for muscle, fat, liver, brain, gill, kidney and gonad and the tissue FA measured by gas-liquid chromatography. The FA profile of the diet diverged from the FA signatures of the tissues, where the sturgeons accumulated particular highly-unsaturated FA (HUFA). They were probably derived from the diet but, as previous studies have shown that fish can also have desaturase enzymes, endogenous synthesis of these FA cannot be excluded. The sturgeon muscle tissue contained HUFA in proportions comparable to those of other fish species that are considered good sources of n-3 polyunsaturated FA. The indices of atherogenicity and thrombogenicity were also within the values considered to be health-promoting. PMID- 24767030 TI - Gene cloning, functional expression and characterisation of a novel glycogen branching enzyme from Rhizomucor miehei and its application in wheat breadmaking. AB - A gene (RmGBE) encoding a glycogen branching enzyme from Rhizomucor miehei was cloned into the pET28a (+) vector and expressed in Escherichia coli, and biochemically analysed. RmGBE had an open reading frame of 2097bp encoding 698 amino acid residues. The purified enzyme was a monomer of 78.1kDa. RmGBE was optimally active at 25 degrees C and pH 7.5. It displayed excellent cold adaptation over a low temperature range of 10-30 degrees C, retaining over 85% of its relative activity. RmGBE showed the highest specificity to amylose, about ten times higher than to amylopectin. Addition of RmGBE to wheat bread resulted in a 26% increase in specific volume and a 38% decrease in crumb firmness in comparison with the control. Besides, the retrogradation of bread was significantly retarded along with the enzyme reaction. These properties make RmGBE highly useful in the food and starch industries. PMID- 24767031 TI - Phenolic composition of grape and winemaking by-products of Brazilian hybrid cultivars BRS Violeta and BRS Lorena. AB - The phenolic composition of grapes and winemaking by-products (skins from grape marc, and lees) from Brazilian hybrid cultivars BRS Violeta (red) and BRS Lorena (white) was studied. Two vintages, five classes of phenolic compounds, and recovery yields using three dehydration techniques were considered: oven-drying at 50 degrees C (D50); spray-drying (SD); and freeze-drying (FD). Recovery yields were higher using FD, although less expensive SD was a good alternative for Violeta lees. D50 caused great recovery reduction in Violeta but yielded similar results for Lorena. Violeta winemaking by-products were excellent sources of anthocyanins (mainly non-acylated and p-coumaroylated diglucosides), flavonols (mainly myricetin-based) and hydroxycinnamic derivatives (mainly caffeic-based). Lorena winemaking by-products contained lesser amounts of phenolic compounds, around a tenth of the values found in Violeta grapes for flavonols (mainly quercetin-based), hydroxycinnamic derivatives (mainly caffeic-based) and condensed tannins. Lorena cultivar contained small amounts of trans-resveratrol and its 3-glucoside, which were missing in Violeta cultivar. PMID- 24767032 TI - Effects of hydrothermal processes on antioxidants in brown, purple and red bran whole grain rice (Oryza sativa L.). AB - The impacts of parboiling and wet-cooking, alone and in combination, on the concentrations of lipophilic antioxidants (vitamin E and gamma-oryzanol), soluble (including proanthocyanidins and anthocyanins) and cell wall-bound phenolics, and antioxidant capacities in whole grain rice from six cultivars having different bran colours were investigated. Parboiling rough and brown rice increased the concentrations of lipophilic antioxidants in whole grain rice but decreased the concentrations of total phenolics and antioxidant capacities found in the soluble fraction. After hydrothermal processing of purple bran rice, the retention of extractable anthocyanins was low, but was high for simple phenolics. For proanthocyanidins found in red bran rice, the extractable oligomers with a degree of polymerization (DP) less than 4, increased up to 6-fold; while for oligomers with DP?4 and polymers, there was a significant decrease that was positively correlated with the DP and the temperature of the processing methods. The presence of hulls helped to retain water-soluble antioxidants during parboiling. PMID- 24767033 TI - Natural deep eutectic solvents providing enhanced stability of natural colorants from safflower (Carthamus tinctorius). AB - A certain combination of natural products in the solid state becomes liquid, so called natural deep eutectic solvents (NADES). Recently, they have been considered promising new green solvents for foods, cosmetics and pharmaceuticals due to their unique solvent power which can dissolve many non-water-soluble compounds and their low toxicity. However, in addition to the features as solvents, the stabilisation ability of NADES for compounds is important for their further applications. In the study, the stability analysis demonstrates that natural pigments from safflower are more stable in sugar-based NADES than in water or 40% ethanol solution. Notably, the stabilisation capacity of NADES can be adjusted by reducing water content with increasing viscosity. The strong stabilisation ability is due to the formation of strong hydrogen bonding interactions between solutes and NADES molecules. The stabilising ability of NADES for phenolic compounds shows great promise for their applications in food, cosmetic and pharmaceutical industries. PMID- 24767034 TI - Degradation of folic acid in fortified vitamin juices during long term storage. AB - Folic acid (FA) concentrations of nine fortified vitamin juices were determined with the aim to study the FA degradation and to investigate the deviation from the declared label value. The juices were received shortly after bottling and were analyzed monthly during controlled storage conditions (light and dark) over one year. The analyses were performed by HPLC-MS/MS, which included a fast "dilute and shoot" sample preparation. Average decreases in FA concentration of 46% were observed after one year. Fresh juices (shortly after bottling) showed the highest deviations from the declared label value (up to+89%). Label values did not reflect the actual concentration of FA in these products, making it difficult to determine the intake of this vitamin. PMID- 24767035 TI - Chemical and morphological characterization of Chardonnay and Gewurztraminer grapes and changes during chamber-drying under controlled conditions. AB - In this work, the morphological and chemical properties of Chardonnay and Gewurztraminer aromatic grapes (northern Spain) have been studied with the aim to assess their response to chamber-drying under controlled conditions and compare it with that of Pedro Ximenez grapes (southern Spain). Morphological characteristics, such as weight, size and roundness, and other of the skin such as thickness, enabled discrimination of the two types of grapes varieties. Changes in browning index, colour, antioxidant activity, aroma compounds determined by GC-MS and flavan-3-ols and flavonols concentrations determined by HPLC-DAD were studied during drying. Based on the results, Chardonnay and Gewurztraminer grapes contained increased amounts of flavan-3-ol derivatives, which are the greatest contributors to polymerization and condensation reactions. Also, their smaller size resulted in faster drying and leads to sugary musts that were lighter-coloured, less brown and more aromatic than Pedro Ximenez grapes. PMID- 24767037 TI - Honey characterization using computer vision system and artificial neural networks. AB - This paper reports the development of a computer vision system (CVS) for non destructive characterization of honey based on colour and its correlated chemical attributes including ash content (AC), antioxidant activity (AA), and total phenolic content (TPC). Artificial neural network (ANN) models were applied to transform RGB values of images to CIE L*a*b* colourimetric measurements and to predict AC, TPC and AA from colour features of images. The developed ANN models were able to convert RGB values to CIE L*a*b* colourimetric parameters with low generalization error of 1.01+/-0.99. In addition, the developed models for prediction of AC, TPC and AA showed high performance based on colour parameters of honey images, as the R(2) values for prediction were 0.99, 0.98, and 0.87, for AC, AA and TPC, respectively. The experimental results show the effectiveness and possibility of applying CVS for non-destructive honey characterization by the industry. PMID- 24767036 TI - Structural characterization of LbGp1 from the fruits of Lycium barbarum L. AB - A water-soluble polysaccharide with a protein content of 3.75%, designated as LbGp1, was isolated from the fruit of Lycium barbarum L. The average molecular weight of LbGp1 was 49.1 KDa determined by high performance gel permeation chromatography (HPGPC). Sugar composition analysis revealed that it was composed of Ara and Gal in a molar ratio of 5.6:1. The existence of O-glycopeptide bond in LbGp1 was demonstrated by beta-elimination reaction. Structure of LbGp1 was characterized based on monosaccharide composition, partial hydrolysis, methylation analysis and electrospray ionization mass spectrometer (ESI-MS). LbGp1 was identified to be a highly branched polysaccharide with a backbone of >6)Galp(1->linked galactose substituted at O-3 by galactosyl or arabinosyl groups. The branches were composed of (1->3)-linked-Galp, (1->4)-linked-Galp, (1 >2)-linked-Araf and (1->3)-linked-Araf, and arabinose was located at the terminal of the branches. PMID- 24767038 TI - Transglycosylation specificity of glycosyl donors in transglycosylation of stevioside catalysed by cyclodextrin glucanotransferase. AB - Specificity of glycosyl donors is a critical issue in transglycosylation of stevioside, the main methodology to improve edulcorant quality of stevioside. The most popular glucanotransferase applied in this reaction is cyclodextrin glucanotransferase (CGTase) that catalyses cyclisation, coupling, hydrolysis and disproportionation simultaneously; which results a crosstalk in the glycosyl donors that comes from initial reactants, reaction intermediates as well as side products in parallel reactions. In this work, the specificity of glycosyl donors was studied to understand the transglucosylation pathways with the designed experiments and material balance analysis on the products using a commercial CGTase. It has been found that cyclodextrins and starches provided the best transglucosylation yield, while the assayed mono- and disaccharides were not effective glycosyl donors to stevioside with the CGTase. It is proposed that alpha- and beta-cyclodextrins performed transglycosylation via coupling to produce intermediates of reducing sugar and followed by disproportionation with stevioside; while starches may perform the transglycosylation combined the cyclodextrins pathway and hydrolysis pathway of starches. PMID- 24767039 TI - Estrogenic endocrine disruptors present in sports supplements. A risk assessment for human health. AB - Sports supplements are becoming a regular dietary addition for consumers who view such products as a means of improving their health and performance. Previously estrogenic endocrine disruptors (EDs) were detected in 80% of 116 sports supplements investigated by biological in vitro reporter gene assays (RGAs). The aim of this study was to quantify the hormonal activity in 50 of these sports supplement samples using a validated estrogen RGA and perform an exposure and risk assessment for human health. Results showed that 17beta-estradiol equivalent levels were higher than those reported as being present in the typical human omnivore diet in 33 of the sports supplements and higher than the acceptable daily intake (ADI) in 13 of these products. The highest activity samples presented a potential to influence the human daily exposure to 17beta-estradiol like activity in various risk groups with a predicted hormonal impact of greatest concern in young boys and postmenopausal women. In conclusion, consumers of sports supplements may be exposed to high levels of estrogenic EDs. PMID- 24767040 TI - Free and bound phenolic profiles and antioxidant activity of milled fractions of different indica rice varieties cultivated in southern China. AB - This study quantified free and bound phytochemicals and their antioxidant activity in the endosperm and bran/embryo of different indica rice varieties. Phytochemicals mainly existed as free form in the bran/embryo and as both free and bound forms in the endosperm. The average values of total phenolic content, flavonoid content, FRAP, ABTS and ORAC values in the bran/embryo were 3.1, 10.4, 8.2, 11.2 and 11.4 times higher than those in the endosperm, respectively. In whole brown rice, the bran contributed 59.2%, 53.7%, 47.7%, 55.5% and 56.9% of total phenolics, flavonoids, FRAP, ABTS and ORAC values, respectively. Seven individual phenolics (gallic, protocatechuic, chlorogenic, caffeic, syringic, coumaric and ferulic acids) were detected with most coumaric and ferulic acids in the bran. All measurements exhibited varietal differences. These findings provide important information for improving human health by encouraging the consumption of whole brown rice and its use in food product development. PMID- 24767041 TI - Development and analytical validation of a simple multivariate calibration method using digital scanner images for sunset yellow determination in soft beverages. AB - This paper proposed a novel methodology for the quantification of an artificial dye, sunset yellow (SY), in soft beverages, using image analysis (RGB histograms) and partial least squares regression. The developed method presented many advantages if compared with alternative methodologies, such as HPLC and UV/VIS spectrophotometry. It was faster, did not require sample pretreatment steps or any kind of solvents and reagents, and used a low cost equipment, a commercial flatbed scanner. This method was able to quantify SY in isotonic drinks and orange sodas, in the range of 7.8-39.7 mg L(-1), with relative prediction errors lower than 10%. A multivariate validation was also performed according to the Brazilian and international guidelines. Linearity, accuracy, sensitivity, bias, prediction uncertainty and a recently proposed tool, the beta-expectation tolerance intervals, were estimated. The application of digital images in food analysis is very promising, opening the possibility for automation. PMID- 24767042 TI - Discrimination of varietal wines according to their volatiles. AB - A method is being proposed in order to discriminate bottled wines of different varieties when no other information is known. The advantages of the method consist in the fact that anyone who wants to certify the variety, which is written on the label or the area of origin, can use such a technique to achieve the conformity. Additionally, the method can be easily applied by laboratories equipped with a GC. The differentiation has been achieved by using only seven of the total extracted volatiles, mainly higher alcohols and higher alcohol esters, namely 3-methyl-1-butanol, 2,3-butanediol, ethyl lactate, 3-methyl-1-butyl acetate, 2-phenylethanol, phenyl ethyl acetate and p-hydroxy phenyl ethanol. These key compounds are not relevant to a single variety. The proposed method does not take into account variables such as the year of vintage and fermentation procedures (agitation, temperature). PMID- 24767043 TI - Browning control of fresh-cut lettuce by phytoncide treatment. AB - Phytoncide essential oil derived from pine leaves was applied for the control of enzymatic browning of fresh-cut lettuce. Changes in the browning characteristics of cut lettuce treated with phytoncide in an water or ethanol solution (1%, v/v) at 10 degrees C were investigated for 12days at 4 degrees C. Other samples dipped in distilled water or 95% ethanol were used as the controls. The samples treated with phytoncide in an ethanol solution showed significantly higher L* values and lower a* values, DeltaE values, browning index, phenolic compounds, and enzyme activities (PPO, POD, PAL) related to browning. The samples dipped in distilled water showed the opposite tendency. On the basis of changes in the browning characteristics, anti-browning effects of each treatment, phytoncide in an ethanol solution was the most effective treatment applied. These results suggest that phytoncide treatment could be used as an effective method for controlling enzymatic browning in fresh-cut lettuce. PMID- 24767044 TI - Fluorescence spectroscopy and multivariate methods for the determination of brandy adulteration with mixed wine spirit. AB - The addition of mixed wine spirit to brandy is easy way to adulterate brandy. To avoid the misleading of the consumers, it is necessary to develop reliable method to detect adulteration of brandy. In this work excitation emission matrix fluorescence in combination with parallel factor analysis (PARAFAC) and partial least squares (PLS) regression was used to determine the content of mixed wine spirit in adulterated brandy samples. Excitation emission matrix fluorescence spectra were measured in the emission wavelength range of 485-580 nm and in the excitation wavelength range of 363-475 nm. The model created using PARAFAC-PLS was able to predict the mixed wine spirit level in adulterated brandy with the root mean square error of prediction (RMSEP) value of 1.9% and a square of the correlation (R(2)) between the reference contents and the predicted values of 0.995. PMID- 24767045 TI - Biochemical characteristics of four marine fish skins in Korea. AB - In this study, we investigated the biochemical characteristics of the fish skins of four industrial species: olive flounder (Paralichthys olivaceus), black rockfish (Sebastes schlegeli), sea bass (Lateolabrax maculatus) and red sea bream (Pagrus major). There is high domestic demand in Korea for farming of these fish for human consumption. Crude protein contents in the skin of these fish ranged from 73% to 94% by dry weight; this was in part due to a high content of the structural protein, collagen. Among the four species, olive flounder had the thickest dermal and epidermal layers in the dorsal skin. This species was also associated with the highest extraction ratio of acid-soluble collagen. We also examined whether fish skin could be a cost-effective alternative to current fish meal sources. Our analysis indicates that, when supplemented with additional fish oils and essential amino acids, fish skin is a viable alternative for fish meal formulations. PMID- 24767046 TI - High-level coproduction, purification and characterisation of laccase and exopolysaccharides by Coriolus versicolor. AB - In this study, a two-stage pH-shift fermentation process was developed for the coproduction of laccase and exopolysaccharides (EPS) by Coriolus versicolor. At the same time, laccase and EPS were purified and characterised in detail. The results showed that the highest laccase and EPS production reached 7680 U l(-1) and 8.2 g l(-1). Furthermore, the flow behaviour of fermentation broth was Newtonian and the maximum MU(ap) was 2.7*10(-3) Pa s. The MW of laccase was 64 kDa and it showed a pI value of 4.2. The CD analysis showed that laccase had a high alpha-helical content (68%). The MW of the purified EPS was determined to be 1.8*10(6) Da, consisting of carbohydrates (87.6%) and proteins (12.4%). The EPS consisted of 17 amino acids, mainly serine (11.3%), glutamic acid (12.60%), leucine (13.3%) and phenylalanine (9.4%) in protein moiety, and three monosaccharides (galactose, mannose and xylose). PMID- 24767047 TI - Liver oxidation and inflammation in Fa/Fa rats fed glucomannan/spirulina-surimi. AB - The effect of high-fat squid-surimi diets enriched in glucomannan or glucomannan spirulina on lipemia, liver glutathione status, antioxidant enzymes and inflammation biomarkers was determined in Zucker Fa/Fa rats. Groups of eight rats each received for 7weeks the squid-surimi control (C), glucomannan-enriched squid surimi (G) and glucomannan-spirulina enriched squid-surimi (GS). Liver weight, cytochrome P450 7A1 expression and cholesterolemia were decreased in G and GS vs. C, improving glutathione red-ox index (p<0.05). G also showed increased glutathione reductase (GR) levels vs. C, but reduced the endothelial (eNOS) and increased the inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-alpha) levels (p<0.05). The GS diet improved superoxide dismutase, catalase, glutathione peroxidase and GR activities and eNOS, iNOS and TNF-alpha levels (p<0.05). The glucomannan enriched surimi-diet induced hypocholesterolemic, antioxidant and proinflammatory effects, while the addition of 3g/kg spirulina kept those hypocholesterolemic and antioxidant effects but reduced the inflammation observed. PMID- 24767048 TI - The effect of high moisture heat-acid treatment on the structure and digestion property of normal maize starch. AB - The objective of this study was to analyze the influence of thermal-acid treatment on the formation of resistant starch (RS). The maximum RS content in citric acid-heat treated starches (CAHT) reached 36.55%, which was 7 times higher of that in native starch. According to HPSEC-MALLS-RI analysis, amylopectin was more susceptible to hydrolysis than amylose during citric acid-heat treatment (CAH). X-ray measurement revealed that even though the starch crystalline pattern was changed from A-type to a more resistant B-type after CAH, the fraction of crystalline region decreased from 21.16% to 8.37%. The hydroxyls on the starch chains were substituted by the citric acid anhydrides during CAH according to FT IR analysis, which led to the formation of ester bond cross-linking structures in starch granules, and it could be the main contribution to the increase of RS content in CAHT samples. PMID- 24767049 TI - Composition of distilled Perique tobacco liqueur: a connoisseur's spirit or a health risk due to nicotine? AB - The use of tobacco leaves as a food ingredient has been controversially discussed, and alcoholic beverages containing distillates from fermented tobacco leaves can be found as niche products. Currently there is an absence of knowledge regarding the composition and toxicity of these products. One liqueur sample based on distilled Louisiana Perique tobacco was analysed using quantitative FTIR, GC-FID, LC/MS/MS and GC/MS/MS methodologies, and qualitatively using non targeted NMR and GC/MS techniques. Quantitative NMR was used for nicotine analysis. Nicotine was not detectable (LOD=0.2 mg/l). Other compounds associated with toxicity of tobacco or alcoholic beverages were either not detectable, or were found below the toxicity thresholds. A model experiment using fractionised distillation of a nicotine solution has confirmed that the compound was predominantly found in the tailing fractions of the distillate, which are discarded. In conclusion, there was no additional health risk associated with beverages diligently distilled from tobacco leaves, beside the effects of ethanol. This judgment clearly does not apply to beverages where tobacco leaves have only been macerated (and not distilled) or foods where the whole tobacco leaves are incorporated. PMID- 24767051 TI - 5-HMF and carbohydrates content in stingless bee honey by CE before and after thermal treatment. AB - This study aimed to assess 5-hydroximethylfurfural and carbohydrates (fructose, glucose, and sucrose) in 13 stingless bee honey samples before and after thermal treatment using a capillary electrophoresis method. The methods were validated for the parameters of linearity, matrix effects, precision, and accuracy. A factorial design was implemented to determine optimal thermal treatment conditions and then verify the postprocedural 5-HMF formation, but once 5-HMF were 0.99) were obtained in 0.2-4.2, 0.25-5.25, 0.4-10.0 and 0.007-0.054 mg L(-1) range for caffeine, Class III caramel, Class IV caramel and riboflavin, respectively. The PLS models were used to determine the concentration of analytes in different drink samples. The method provided comparable results with those found using the HPLC method. PMID- 24767057 TI - A GC-MS-based metabolomics study on the tubers of commercial potato cultivars upon storage. AB - Using gas chromatography-mass spectrometry (GC-MS) as a system for the detection of amino acids, organic acids, sugars, sugar alcohols, and fatty acids, we characterised six commercial potato cultivars (Hopehely, Katica, Lorett, Somogyi kifli, Venusz Gold, and White Lady) with different pedigrees, starch contents, cooking types, and dormancy periods, in five developmental stages from harvest to sprouting. The tubers were stored at 20-22 degrees C in the dark. The metabolite data were subjected to principal component analysis. No correlation between metabolite contents of freshly harvested tubers and starch content or cooking type of the cultivars was detected. The storage decreased the fructose and sucrose and increased the proline concentrations of tubers. Irrespective of the length of dormancy a substantial difference in metabolite composition at each time point upon storage was detected in each cultivar except Somogyi kifli, the only cultivar amongst those tested with a pure Solanum tuberosum origin and A cooking type. PMID- 24767058 TI - Assessment of heat treatment of various types of milk. AB - Raw milk (RM), reconstituted condensed milk (CM) and three types of reconstituted milk powders (SMPs) were heated indirectly at 80-140 degrees C for 4 s. Native beta-lactoglobulin after 90 degrees C treatment of RM was 1132+/-167 mg/L but no reliable quantities were estimated at temperatures >100 degrees C, whereas 218+/ 43 mg/L residual alpha-lactalbumin were found at 130 degrees C. Average lactulose contents from 51 to 1549 mg/L were detected at ?100 degrees C; average furosine was 1.9 and 126.5 mg/L in raw and 140 degrees C treated milks respectively. The behaviour of heated CM was similar to that of heated RM except for higher furosine concentration. Reconstituted SMPs contained high quantities of lactulose and furosine, the ratio of which was lower than in similarly treated RM. Among the market milks analysed, the group of high-pasteurised milks was highly variable; i.e. native beta-lactoglobulin was 69-2831 mg/L, lactulose 0-824 mg/L and furosine 3.3-68.8 mg/L. PMID- 24767059 TI - Stability of Lactobacillus rhamnosus GG in prebiotic edible films. AB - The concept of prebiotic edible films as effective vehicles for encapsulating probiotic living cells is presented. Four soluble fibres (inulin, polydextrose, glucose-oligosaccharides and wheat dextrin) were selected as prebiotic co components of gelatine based matrices plasticised with glycerol and used for the immobilisation of Lactobacillus rhamnosus GG. The addition of prebiotics was associated with a more compact and uniform film structure, with no detectable interspaces or micropores; probiotic inclusion did not significantly change the structure of the films. Glucose-oligosaccharides and polydextrose significantly enhanced L. rhamnosus GG viability during air drying (by 300% and 75%, respectively), whilst a 33% and 80% reduction in viable counts was observed for inulin and wheat dextrin. Contrarily, inulin was the most effective at controlling the sub-lethal effects on L. rhamnosus GG during storage. However, in all cases the supplementation of edible films with prebiotics ameliorated the storage stability of L. rhamnosus GG. PMID- 24767060 TI - Selective identification and quantification of saccharin by liquid chromatography and fluorescence detection. AB - High-pressure liquid chromatography with ultra-violet detection (HPLC-UV) is one of the most commonly used methods to identify and quantify saccharin in non alcoholic beverages. However, due to the wide variety of interfering UV spectra in saccharin-containing beverage matrices, the same method cannot be used to measure this analyte accurately. We have developed a new, highly effective method to identify and quantify saccharin using HPLC with fluorescence detection (HPLC FLD). The excitation wavelength (250 nm) and emission wavelength (440 nm) chosen increased selectivity for all matrices and ensured few changes were required in the mobile phase or other parameters. The presence of saccharin in non-diet beverages - a fraud commonly used to replace more expensive sucrose - was confirmed by comparing coincident peaks as well as the emission spectra of standards and samples. PMID- 24767061 TI - Quality of fresh and stored carrots depending on iodine and nitrogen fertilization. AB - INTRODUCTION: Iodine is an important mineral nutrient essential for a proper functioning of human and animal organism. Despite current programmes of iodine prophylaxis (mainly based on salt iodization) approximately 30-38% of human population has insufficient iodine intake. Crop plants can become an efficient vector of this element in the food chain. Iodine is not a nutrient for plants. For that reason, in addition to determining the possibility of increasing iodine content in crop plant it is necessary to describe its impact on yield quality. The aim of the study was to analyze the influence of soil fertilization with iodine and nitrogen on the quality of carrot roots and its storage ability. METHODS: In 2008-2010 the field study with carrot cv. 'Kazan F1' was conducted. A differential soil fertilization with iodine (in the form of I(-) or IO3(-)) and nitrogen (as NO3(-) or NH4(+)) was applied in the experiment: (1) control without N and I, (2) KI application without N, (3) KIO3 application without N, (4) KI+Ca(NO3)2, (5) KIO3+Ca(NO3)2, (6) KI+(NH4)2SO4 and (7) KIO3+(NH4)2SO4. The experiment was arranged in a split-plot design. Iodine (in both forms) was applied pre-sowing in a dose of 2 kg I ha(-1). Nitrogen in the form of Ca(NO3)2 and (NH4)2SO4 was introduced pre-sowing and as a top dressing, each dose of 100 kg N ha(-1). RESULTS AND DISCUSSION: A diverse, statistically significant influence of tested factors on the activity of free radical-scavenging (DPPH) and the content of: dry matter, glucose, fructose, sucrose, total soluble sugars, soluble solids - Brix %, phenolic compounds, phenylpropanoids, flavonols, anthocyanins and carotenoids was noted in carrot roots directly after the harvest as well as at the end of four-month storage. Iodine applied with relatively high doses of nitrogen decreased the quality of fresh carrot. After storage, opposite relations were noted for tested combinations (with I and N application) with respect to carrot quality when compared to results obtained after the harvest. The lowest storage ability was found for carrot treated with KI without N. Obtained results directly suggest the need for developing individual agronomic rules for iodine biofortification of carrot for: (a) consumption and/or processing directly after the harvest and (b) long-term storage. PMID- 24767062 TI - Evaluation of tannins interactions in grape (Vitis vinifera L.) skins. AB - Tannins have a central role in grapevine berries both for their physiological and enological implications. In the skin tissue they can be in vacuolar solution, or associated to the cell walls through weak or strong physicochemical interactions. The present work aims to separate vacuolar, non-covalently and covalently bonded tannins fractions. A specific extraction procedure was developed. A first extraction in ethanol at low temperature allowed the quantification of vacuolar tannins. An urea treatment followed by an ethanol extraction at room temperature was able to separate non-covalently bonded compounds. Finally an acid catalysis was used to break down proanthocyanidin covalent bonds. The method was validated on ripe grape samples of three cultivars, on berries developed in two sun exposure conditions. The Ethephon treatment effect was also evaluated. Beside the method development, a preliminary evaluation of the cultivar, exposition and Ethephon treatment effects are discussed. PMID- 24767063 TI - Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion. AB - The presence of hydroxyproline (Hyp)-containing peptides in human blood after collagen hydrolysate ingestion is believed to exert beneficial effects on human health. To estimate the effective beneficial dose of these peptides, we examined the relationship between ingested dose and food-derived Hyp levels in human plasma. Healthy volunteers (n=4) ingested 30.8, 153.8 and 384.6 mg per kg body weight of collagen hydrolysate. The average plasma concentration of Hyp containing peptides was dose-dependent, reaching maximum levels of 6.43, 20.17 and 32.84 nmol/ml following ingestion of 30.8, 153.8 and 384.6-mg doses of collagen hydrolysate, respectively. Ingesting over 153.8 mg of collagen hydrolysate significantly increased the average concentrations of the free and peptide forms of Hyp in plasma. The Hyp absorption limit was not reached with ingestion of as much as 384.6 mg of collagen hydrolysate. These finding suggest that ingestion of less than 30.8 mg of collagen hydrolysate is not effective for health benefits. PMID- 24767065 TI - Immunochemical investigation of allergenic residues in experimental and commercially-available wines fined with egg white proteins. AB - Proteinaceous egg whites are widely used as a fining agent during the production of red wines. Residues of egg white in the final wine could present a risk for individuals allergic to eggs. This study investigated the presence of allergenic residues in both red and white wines fined with egg whites. Experimental and commercially available wines fined with egg whites, with or without subsequent bentonite fining, were studied. Unfined wines were used as negative controls. The physicochemical characteristics of each wine were determined to assess their possible role in enhancing or hindering the elimination of allergenic residues from wine. The amount of egg white protein residues was investigated both by a specifically developed/validated ELISA test and by immunoblotting. Both immunochemical tests used the same anti-total egg white protein antibody and were highly sensitive to the allergen. No egg white protein was detected in the wines studied in either immunochemical test, irrespective of the physicochemical characteristics of the wine, the type and dosage of the fining agent and the oenological process used. The risk of adverse reactions in egg-allergic individuals should therefore be considered negligible, but the exemption from labelling should be allowed only when the absence of residues is confirmed by analytical controls. PMID- 24767064 TI - Cationic beta-lactoglobulin nanoparticles as a bioavailability enhancer: comparison between ethylenediamine and polyethyleneimine as cationizers. AB - Cationic beta-lactoglobulin (CBLG) was synthesized by two strategies: extensive conjugation of ethylenediamine (EDA) and limited cationization with polyethyleneimine (PEI). Both methods provided CBLG with satisfactory water solubility and resistance to peptic digestion. Compared with EDA-derived CBLG (C EDA), PEI-derived CBLG (C-PEI) exhibited a higher zeta potential (54.2 compared to 32.4mV for C-EDA), which resulted in significantly elevated mucoadhesion (439% and 118% higher than BLG and C-EDA, respectively) in a quartz crystal microbalance (QCM) study. In addition, PEI caused reduced conformational disruption on BLG compared to EDA as evidenced by FTIR measurement. This character, together with the steric hindrance provided by PEI, caused a phenomenal reduction in tryptic digestibility by at least 75% compared to C-EDA. In the presence of aqueous acetone, C-PEI aggregated spontaneously into nanoparticles with average size of 140 nm and narrow size distribution. These merits made C-PEI a useful material that provides desirable solubility and protection for orally administrated nutraceuticals or drugs. PMID- 24767066 TI - Bioaccessibility, in vitro antioxidant activities and in vivo anti-inflammatory activities of a purple tomato (Solanum lycopersicum L.). AB - The bioaccessibility, antioxidant activities and anti-inflammatory activities of phytochemicals in a purple tomato (Solanum lycopersicum L.) V118 was studied using a simulated gastrointestinal digestion model, chemical and cell based antioxidant assays. The total phenolic and carotenoid contents and the antioxidant activities were significantly lowered (37-72%) and degradation seemed to have occurred during the in vitro digestion. Results indicated that these phytochemicals were bioavailable to the cells as demonstrated by the cell based antioxidant assay. Extracts from the purple tomato showed significant and dose dependent anti-inflammatory effect in the in vivo carrageenan-induced paw oedema rat study (oedematous inhibition: 7.48% and 13.8%), suggesting that anthocyanins may play a role in the anti-inflammatory effect. Direct antioxidant actions as indicated by reduced MDA and NO production and indirect actions as shown in increased GPx and SOD activities in oedematous tissue support the conclusion that tomatoes containing anthocyanins can potentially provide better protection against oxidative stress related chronic diseases of humans. PMID- 24767067 TI - Thermal degradation of grape marc polyphenols. AB - Bioactive compounds of wine making by-products are of interest in food, cosmetics and pharmaceutical industries. Extraction of antioxidants under mild conditions is time-consuming, giving ground to the development of intensification processes where the operation at high temperature may deteriorate extract quality. This study examined thermal degradation of grape marc and its filtered extract (80, 100 and 150 degrees C). The decrease in anthocyanin content was modelled under non-isothermal conditions by first order kinetics, using the Arrhenius equation. Simulated degradation under isothermal heating showed that the grape marc is more sensitive by one order of magnitude to heat than the filtered extract. This tendency was also confirmed by analyses of the total phenolic content and antioxidant activity. It is suggested that an optimal combination of temperature, treatment time and also raw material environment could be found in process intensification. PMID- 24767068 TI - Determination of ten pyrethroids in various fruit juices: comparison of dispersive liquid-liquid microextraction sample preparation and QuEChERS method combined with dispersive liquid-liquid microextraction. AB - Dispersive liquid-liquid microextraction (DLLME) sample preparation and the quick, easy, cheap, effective, rugged and safe (QuEChERS) method combined with DLLME were developed and compared for the analysis of ten pyrethroids in various fruit juices using gas chromatography-electron capture detection (GC-ECD). QuEChERS-DLLME method has found its widespread applications to all the fruit juices including those samples with more complex matrices (orange, lemon, kiwi and mango) while DLLME was confined to the fruit juices with simpler matrices (apple, pear, grape and peach). The two methods provided acceptable recoveries and repeatability. In addition, the applicabilities of two methods were demonstrated with the real samples and further confirmed by gas chromatography mass spectrometry (GC-MS). PMID- 24767069 TI - Nutritional quality of grains of sorghum cultivar grown under different levels of micronutrients fertilization. AB - A pot experiment was carried out to investigate the effect of different levels of micronutrients (0, 2, 4, and 8 g/5 kg soil) and a fixed amount (6 g/5 kg soil) of macronutrients fertilizer on the antinutrients content, protein content and digestibility, total and extractable macro- and micro-elements, amino acid content and score of grains of sorghum cultivar (Gadambalia) grown for two consecutive season. Protein content and essential amino acids composition of sorghum grains significantly (P?0.05) increased with micronutrients level for both seasons. Tannins and phytate contents dropped significantly (P?0.05) with a concomitant increase in protein digestibility, macro- and micro-elements extractability for both seasons and treatments. The content of macro- and micro elements of the grains increased with micronutrients level during both seasons. The essential amino acids scores of the grains were significantly (P?0.05) increased for both seasons and treatments. PMID- 24767070 TI - Diatomite releases silica during spirit filtration. AB - The purpose of this study was to ascertain whether diatomite is an inert filter aid during spirit filtration. Surely, any compound with a negative effect on the spirit composition or the consumer's health could be dissolved. In this study different diatomites were treated with 36% vol. ethanol/water mixtures and the amounts and structures of the extracted compounds were determined. Furthermore, Brandy de Jerez was diatomite- and membrane-filtered at different temperatures and the silicon content was analysed. It was found that up to 0.36% by weight of diatomite dissolved in the aqueous ethanol and amorphous silica, in the form of hollow spherical microparticles, was the most abundant component. Silicon concentrations in Brandy de Jerez increased by up to 163.0% after contact with diatomite and these changes were more marked for calcined diatomite. In contrast, reductions of more than 30% in silicon concentrations were achieved after membrane filtration at low temperatures. PMID- 24767071 TI - Protein oxidation in processed cheese slices treated with pulsed light technology. AB - The effect of pulsed light technology on protein oxidation was studied in sliced processed cheese by measuring the protein-bound carbonyls with a spectrophotometric DNPH assay. Bovine serum albumin was also tested as a protein standard. Fluences of 0.7, 2.1, 4.2, 8.4 and 11.9 J/cm(2) were applied to vacuum packaged cheese slices and to an aqueous solution of the protein. Treatments up to 4.2 J/cm(2) did not promote protein oxidation immediately after flashing either in cheese or in the standard. Samples treated with 8.4 and 11.9 J/cm(2) showed significantly higher carbonyl amounts than non-treated ones. Protein oxidation increased along cheese storage at 4 degrees C, and differences among treatments remained. Further studies on the sensory properties will be needed to clarify the impact of pulsed light on processed cheese quality. PMID- 24767072 TI - Effect of glutathione addition in sparkling wine. AB - This study aims to evaluate the effect of the addition of glutathione (GSH) on secondary aromas and on the phenolic compounds of sparkling wine elaborated by traditional method. It was added 10 and 20 mg L(-1) of GSH to must and to base wine. The determination of aroma compounds was performed by gas chromatography. Phenolic compounds and glutathione content were analyzed by high performance liquid chromatography. Sparkling wines with addition of GSH to must showed lower levels of total phenolic compounds and hydroxycinnamic acids. Furthermore, the sparkling wine with addition of GSH to must showed higher levels of 2 phenylethanol, 3-methyl-1-butanol and diethyl succinate, and lower concentrations of ethyl decanoate, octanoic and decanoic acids. The GSH addition to the must show a greater influence on sparkling wine than to base wine, however GSH addition to base wine seems retain higher SO2 free levels. The concentration of GSH added showed no significant difference. PMID- 24767073 TI - Triacylglycerols profiling as a chemical tool to identify mushrooms submitted to gamma or electron beam irradiation. AB - In order to define irradiation treatment as a routine conservation methodology, it is imperative to develop chemometric indicators with the ability to distinguish irradiated from unirradiated foodstuffs. Electron spin resonance, photostimulated luminescence and thermoluminescence methods were employed to monitor radiation-induced markers, as well as different chemical compounds produced from the lipidic fraction of different foodstuffs. Apart from these methods, the specificity of triacylglycerol profiles has previously been detected in mushroom species, as has the effect of irradiation treatment in the triacylglycerol profiles of chestnut. Accordingly, the feasibility of using this as a chemometric indicator of irradiated mushrooms was evaluated. In line with the obtained results in literature, the effects of each type of irradiation were significantly different, as can be concluded from the correlations among discriminant functions and variables within each statistical test. Triacylglycerol profiling proved to be a useful tool to detect irradiated mushrooms, independently of the species or irradiation source, especially for doses above 1 kGy. PMID- 24767074 TI - Preconcentration of seleno-amino acids on a XAD resin and determination in regional olive oils by SPE UPLC-ESI-MS/MS. AB - This study describes a method for seleno-amino acids determination in Argentinean olive oils. Preliminary total selenium determination in olive oils probed low concentrations (62.8+/-1.6 to 117.4+/-3.0 MUg/kg) and the necessity of implementing a preconcentration method. To this end a XAD(r) resin was employed as sorbent for selenomethionine (Se-Met), selenomethylselenocysteine (Se MetSeCys), and selenocysteine (Se-Cys) preconcentration. Determinations were performed by UPLC-ESI-MS/MS. Recoveries were between 84% and 97% for the seleno amino acids studied, reaching a detection limit of 0.09 MUg/kg, a precision of 10% (RSD, n=6), and an enhancement factor of 60-fold (6 for the extraction system and 10 for the preconcentration approach). The only detected Se species in the olive oils was Se-MetSeCys in concentrations ranging from 2.0 to 8.3 MUg/kg. PMID- 24767075 TI - Effect of sample preparation procedure for the determination of As, Sb and Se in fruit juices by HG-ICP-OES. AB - Various sample preparation procedures for the simultaneous determination of As, Sb and Se in fruit juices by hydride generation inductively coupled plasma optical emission spectrometry (HG-ICP-OES) were examined. Applicability of total wet digestion with HNO3/H2O2, partial decomposition (solubilisation in aqua regia), 1:1 dilution with 2% (v/v) HNO3 and direct analysis were evaluated. Hydrides were generated in the reaction of an acidified sample with NaBH4 after pre-reduction with KI-ascorbic acid for total As and Sb, and boiling with HCl for total Se. Best results, i.e. limits of detection (LODs) of 0.51-0.73 ng mL(-1), precision (RSD) within 1.7-3.6% and recoveries for spiked samples between 101% and 106% were found using aqua regia treatment. This procedure simplifying and improving sample preparation step prior to As, Sb and Se measurements in fruit juices by HG-ICP-OES, thus could be adequate for the routine analysis in terms of the quality control of these drinks. PMID- 24767076 TI - The application of near infrared spectroscopy to study lipid characteristics and deterioration of frozen lean fish muscles. AB - Near infrared spectroscopy (NIR) was applied to estimate lipid composition and degradation of two lean fish species, saithe (Pollachius virens) and hoki (Macruronus novaezelandiae). Calibration models were developed, using partial least squares (PLS) regression, for total lipid content and composition, free fatty acids (FFA), thiobarbituric acid reactive substances (TBARS) and fluorescent interaction compounds (OFR). Coefficients of determination for calibration (R(2)cv) and root-mean-square error of cross validation (RMSECV) ranged from 0.82 to 0.99 and 0.66 to 3.69 for hoki and from 0.64 to 0.99 and 0.06 to 2.65 for saithe, respectively. The validations of the calibrations indicated that lipid composition and FFA of hoki and saithe can be estimated by NIR with good accuracy. Furthermore, NIR differentiate fish muscles with low, medium and high concentration of OFR and TBARS. Overall, the results demonstrate the potential for use of NIR spectroscopy as an objective and non-destructive method to inspect the lipid characteristics and quality of frozen lean fish. PMID- 24767077 TI - Determination of the wine preservative sulphur dioxide with cyclic voltammetry using inkjet printed electrodes. AB - During winemaking sulphur dioxide is added to prevent undesirable reactions. However, concerns over the harmful effects of sulphites have led to legal limits being placed upon such additives. There is thus a need for simple and selective determinations of sulphur dioxide in wine, especially during winemaking. The simultaneous detection of polyphenols and sulphur dioxide, using cyclic voltammetry at inert electrodes is challenging due to close oxidation potentials. In the present study, inkjet printed electrodes were developed with a suitable voltammetric signal on which the polyphenol oxidation is suppressed and the oxidation peak height for sulphur dioxide corresponds linearly to the concentration. Different types of working electrodes were printed. Electrodes consisting of gold nanoparticles mixed with silver showed the highest sensitivity towards sulphur dioxide. Low cost production of the sensor elements and ultra fast determination of sulphur dioxide by cyclic voltammetry makes this technique very promising for the wine industry. PMID- 24767078 TI - Multielemental analysis in vegetable edible oils by inductively coupled plasma mass spectrometry after solubilisation with tetramethylammonium hydroxide. AB - Trace metals have negative effects on the oxidative stability of edible oils and they are important because of possibility for oils characterisation. A single step procedure for trace elemental analysis of edible oils is presented. To this aim, a solubilisation with tetramethylammonium hydroxide (TMAH) was assayed prior to inductively coupled plasma mass spectrometry detection. Small amounts of TMAH were used, resulting in high elemental concentrations. This method was applied to edible oils commercially available in Argentine. Elements present in small amounts (Cu, Ge, Mn, Mo, Ni, Sb, Sr, Ti, and V) were determined in olive, corn, almond and sunflower oils. The limits of detection were between 0.004 MUg g(-1) for Mn and Sr, and 0.32 MUg g(-1) for Sb. Principal components analysis was used to correlate the content of trace metals with the type of oils. The two first principal components retained 91.6% of the variability of the system. This is a relatively simple and safe procedure, and could be an attractive alternative for quality control, traceability and routine analysis of edible oils. PMID- 24767079 TI - Antioxidant activity of gallic acid and methyl gallate in triacylglycerols of Kilka fish oil and its oil-in-water emulsion. AB - The anti-DPPH radical effect as well as anti-peroxide activity of gallic acid, methyl gallate, and alpha-tocopherol in a bulk Kilka fish oil and its oil-in water emulsion stabilized by soy protein isolate at 55 degrees C were investigated. Gallic acid with the lowest hydrophobicity (log P=-0.28) was found to be the most active antiradical agent (IC50=29.5 MUM), followed by methyl gallate (IC50=38.0 MUM, log P=-0.23) and alpha-tocopherol (IC50=105.3 MUM, log P=0.70). The anti-peroxide activity in the bulk oil system decreased in the order of methyl gallate>gallic acid>alpha-tocopherol. In the emulsion system, methyl gallate still behaved better than gallic acid, but the highest activity belonged to alpha-tocopherol. Based on the calculation of a number of kinetic parameters, the antioxidants, in general, showed better performances in the bulk oil system than in the emulsion system. PMID- 24767080 TI - Sensitized chemiluminescence of 2-phenyl-4,5-di(2-furyl)-1H imidazole/K3Fe(CN)6/propyl gallate system combining with solid-phase extraction for the determination of propyl gallate in edible oil. AB - In this paper, a novel chemiluminescence (CL) method has been developed for the determination of propyl gallate (PG). The proposed method was based on the enhancing effect of PG on the CL signal of 2-phenyl-4,5-di(2-furyl)-1H-imidazole (PDFI) and K3Fe(CN)6 reaction in an alkaline solution. Under the optimum conditions, the enhanced CL intensity was linearly related to the concentration of PG. The linear range of the calibration curve was 0.05-8 MUg/mL, and the corresponding detection limit (3sigma) was 0.036 MUg/mL. The relative standard deviation for determining 1.0 MUg/mL PG was 2.8% (n=11). The proposed method has been successfully applied to the determination of PG in edible oil. The edible oil samples were prepared by the solid-phase extraction (SPE) with a C18 column served as the stationary phase. Furthermore, the possible CL mechanism was also discussed briefly based on the photoluminescence (PL) and CL spectra. PMID- 24767081 TI - Synthesis and quorum sensing inhibitory activity of key phenolic compounds of ginger and their derivatives. AB - Phenolic components of ginger (Zingiber officinale Roscoe) viz. [6]-gingerol, [6] shogaol and zingerone exhibited quorum sensing inhibitory activity (QSI) against Chromobacterium violaceum and Pseudomonas aeruginosa. The inhibitory activity of all the compounds was studied by zone inhibition, pyocyanin, and violacein assay. All the compounds displayed good inhibition at 500ppm. [6]-Azashogaol, a new derivative of [6]-shogaol has been synthesized by Beckmann rearrangement of its oxime in the presence of ZnCl2. The structure elucidation of this new derivative was carried out by 1D ((1)H NMR and (13)C NMR) and 2D-NMR (COSY, HSQC and NOESY) spectral studies. This compound showed good QSI activity against P. aeruginosa. An isoxazoline derivative of [6]-gingerol was prepared and it exhibited good QSI activity. Present study illustrated that, the phenolic compounds of ginger and their derivatives form a class of compounds with promising QSI activity. PMID- 24767082 TI - Predicting soluble solid content in intact jaboticaba [Myrciaria jaboticaba (Vell.) O. Berg] fruit using near-infrared spectroscopy and chemometrics. AB - The aim of this study was to evaluate the potential of near-infrared reflectance spectroscopy (NIR) as a rapid and non-destructive method to determine soluble solid content (SSC) in intact jaboticaba [Myrciaria jaboticaba (Vell.) O. Berg] fruit. Multivariate calibration techniques were compared with pre-processed data and variable selection algorithms, such as partial least squares (PLS), interval partial least squares (iPLS), a genetic algorithm (GA), a successive projections algorithm (SPA) and nonlinear techniques (BP-ANN, back propagation of artificial neural networks; LS-SVM, least squares support vector machine) were applied to building the calibration models. The PLS model produced prediction accuracy (R(2)=0.71, RMSEP=1.33 degrees Brix, and RPD=1.65) while the BP-ANN model (R(2)=0.68, RMSEM=1.20 degrees Brix, and RPD=1.83) and LS-SVM models achieved lower performance metrics (R(2)=0.44, RMSEP=1.89 degrees Brix, and RPD=1.16). This study was the first attempt to use NIR spectroscopy as a non-destructive method to determine SSC jaboticaba fruit. PMID- 24767084 TI - Lipoxygenase inhibitory activity of alkyl protocatechuates. AB - Alkyl 3,4-dihydroxybenzoates (protocatechuates) inhibited linoleic acid peroxidation catalyzed by soybean lipoxygenase-1 (EC 1.13.11.12, Type 1). Their inhibitory activities displayed a parabolic function of their lipophilicity and maximized with alkyl chain lengths of between C11 and C14. Tetradecanyl protocatechuate exhibited the most potent inhibition with an IC50 of 0.05 MUM, followed by dodecyl (lauryl) protocatechuate with an IC50 of 0.06 MUM. However, their parent compound, protocatechuic acid, did not show this inhibitory activity up to 200 MUM, indicating that the alkyl chain length is significantly related to the inhibition activity. The allosteric (or cooperative) inhibition of soybean lipoxygenase-1 of longer alkyl protocatechuates is reversible but in combination with their iron binding ability to disrupt the active site competitively and to interact with the hydrophobic portion surrounding near the active site (sequential action). In the case of dodecyl protocatechuate, the enzyme quickly binds this protocatechuate and then its dodecyl group undergoes a slow interaction with the hydrophobic domain in close proximity to the active site in the enzyme. The inhibition kinetics analyzed by Lineweaver-Burk plots indicates that octyl protocatechuate is a competitive inhibitor and the inhibition constant (Ki) was obtained as 0.23 MUM but dodecyl protocatechuate is a slow binding inhibitor. PMID- 24767083 TI - Water-based oligochitosan and nanowhisker chitosan as potential food preservatives for shelf-life extension of minced pork. AB - Water-based chitosans in the forms of oligochitosan (OligoCS) and nanowhisker chitosan (CSWK) are proposed as a novel food preservative based on a minced pork model study. The high surface area with a positive charge over the neutral pH range (pH 5-8) of OligoCS and CSWK lead to an inhibition against Gram-positive (Staphylococcus aureus, Listeria monocytogenes, and Bacillus cereus) and Gram negative microbes (Salmonella enteritidis and Escherichia coli O157:H7). In the minced pork model, OligoCS effectively performs a food preservative for shelf life extension as clarified from the retardation of microbial growth, biogenic amine formation and lipid oxidation during the storage. OligoCS maintains almost all myosin heavy chain protein degradation as observed in the electrophoresis. The present work points out that water-based chitosan with its unique morphology not only significantly inhibits antimicrobial activity but also maintains the meat quality with an extension of shelf-life, and thus has the potential to be used as a food preservative. PMID- 24767085 TI - Hesperidin increases intestinal beta,beta-carotene 15-15' mono-oxygenase 1 (BCMO1) activity in Mongolian gerbils (Meriones unguiculatus) fed with beta carotene-free diet. AB - beta,beta-Carotene 15-15' mono-oxygenase 1 (BCMO1) is a key enzyme in vitamin A (VitA) metabolism in mammals. Dietary compounds, such as carotenoids and polyphenols, were reported to influence BCMO1 activity. The aim of this study was to evaluate the effect of hesperidin (Hes), on the VitA bioefficacy of beta carotene (Bc) from orange-fleshed sweet potato, using Mongolian gerbils, focussing on BCMO1 activity. Gerbils (n=50) depleted in VitA were divided into five groups fed with basal diet containing 3% white- or orange-fleshed sweet potatoes supplemented or not with Hes. Liver BCMO1 activity was low, with no significant differences between groups. Interestingly, intestinal mucosal BCMO1 activity was significantly higher in the gerbils fed without Bc or VitA than those fed with a VitA/Bc-supplemented diet. Finally, our results show that, under a low VitA status, Hes dramatically stimulated intestinal BCMO1 activity, an effect that could possibly be related to its action as an agonist of PPARgamma. PMID- 24767086 TI - The binding of 4-ethylguaiacol with polyaniline-based materials in wines. AB - 4-ethylguaiacol (4-EG) is one of the important compounds responsible for the "Brett character" (i.e. spicy and smoky aromas) found in wines contaminated with Brettanomyces yeast. In this trial, the ability of polyaniline-based materials (PANI-EB and PANI-ES) was tested as a potential fining agent for the removal of 4 EG in wine. First, a screening study was developed in order to determine the binding capacity of 4-EG by PANI materials in 12% ethanol solution. Then, the capturing ability of PANI against 4-EG was evaluated with a solution containing gallic acid (GA), 4-methyl-catechol (4-MC), in which the concentration of the phenolic compounds were maintained as in the real wine. The results obtained showed that the retention percentage varied between 0 to 100% (4-EG), 13.81% to 72.32% (GA), and 0 to 17.39% (4-MC), depending on the interaction time and amount of the PANI used. Finally, the capturing capacity of PANI-EB and PANI-ES against 4-EG was evaluated in a real wine sample containing originally 3.10+/-0.13 mg L( 1) of 4-EG and 2.55+/-0.10 g L(-1) of other total phenolic compounds. The analyses performed indicated that PANI-EB is more effective in removing 4-EG than PANI-ES, with retention percentages varying between 36 and 50%. PMID- 24767087 TI - Recent temporal variations of trace metal content in an Italian white wine. AB - For the first time in Italy, the temporal variations of Cd, Pb and Cu content in an Italian white wine were studied over the period 1995-2010. A previously set up and optimized Square-Wave Anodic Stripping Voltammetric technique was used. Cd showed a first decrease (~30%) due to the use of pesticides with progressively low Cd residues. Since 2000 Cd had constant and extremely low values (0.17+/-0.07 MUg L(-1)). A significant decrease (~74%) from 1995 to 2010 was observed for Pb (mean concentration, 18+/-10 MUg L(-1)) probably due to the recent decrease in Pb emissions in the atmosphere following the phasing out of metal from gasoline (in Italy since 2002). The Cu reduction (mean value, 32+/-15 MUg L(-1)) of ~74% from 1995 to 2010 was related to the use of phytoiatric products with a progressively low Cu content. PMID- 24767088 TI - Metal solubility enhancing peptides derived from barley protein. AB - Mineral supplements are required to be soluble as their bioavailability is highly correlated to their solubility in body fluids. In this study, metal binding capacity of barley protein hydrolysates and their purified fractions was investigated and expressed as increase in solubility of metal ions. Metal ions in the presence of hydrolysates exhibited a remarkable increase in solubility: 118, 32, 10, 29 and 35-fold for Fe(2+), Fe(3+), Ca(2+), Cu(2+) and Zn(2+), respectively. A mixture of low molecular weight peptides possesses a synergistic combination of both charged and hydrophobic residues and achieves the best binding metal ions. Electrostatic interactions via charged side chains and coordination binding with His and Cys, initially attract the metal ions and, afterward, hydrophobic interactions and aromatic ring stacking stabilize the positioning of metal ions in the structure of the peptide. Barley hordein hydrolysates show potential as dietary supplements that enhance both mineral solubility and bioavailability. PMID- 24767089 TI - Simultaneous determination of Se, trace elements and major elements in Se-rich rice by dynamic reaction cell inductively coupled plasma mass spectrometry (DRC ICP-MS) after microwave digestion. AB - A quick and accurate method was devised to determine Se, As, Ba, Ca, Cd, Cr, Cu, Fe, Mg, Mn, Ni, Pb, Sr and Zn in Se-rich rice samples by microwave digestion and inductively coupled plasma-mass spectrometry (ICP-MS). Spectral interferences on Se were eliminated using methane as a reaction gas in the dynamic reaction cell (DRC). Rhodium was used as an internal standard to compensate for sample matrix effects. A rice-certified reference material (CRM) (GBW 10010) was used to verify the accuracy of the method. The method detection limits were 0.001-0.03 mg/kg, analyte recoveries were 85-108% and precisions (RSDs) ranged from 2.1% to 5.8%. Correlation analysis showed that the Se concentrations in the Se-rich rice samples correlated well with the Cu concentrations (r=0.53, p<0.05). PMID- 24767090 TI - Improving the properties of fodder potato protein concentrate by enzymatic hydrolysis. AB - Protein hydrolysates of profitable properties were prepared from the fodder potato protein concentrate. The hydrolysis process was performed with the use of commercial available enzyme (Alcalase) over a 2 and 4 h incubation period. Chemical and amino acid composition as well as functional properties of resultant hydrolysates were determined. A 2 h long process occurred profitable to obtain preparations of well balanced amino acid composition as well as proved functional properties. The industrial preparation, modified within proteolytic enzyme, totally soluble (average 98%), was characterised by fivefold higher oil holding capacity (average 5.4 cm(3)/g) and much better foam capacity (more than 150%) as compared to the material underwent modification (13.00%, 2.1 cm(3)/g and 5.33%, respectively). Presented results suggested potential use of fodder potato protein not destined directly for food purposes as the suitable product for preparations characterised by high nutritive value and functional properties. PMID- 24767091 TI - Dry-cured ham restructured with fibrin. AB - The viability of a fibrinogen-thrombin system (FT) to bind fresh deboned hams for incorporation in the salting and ripening processes, to produce cured ham, was studied. The effects of the different processing variables (pH, NaCl concentration, temperature and gelation time) on FT, a meat emulsion mixed with FT, fresh pork portions and deboned hams restructured with FT were analyzed. The most stable and firmest fibrin gels were obtained after 6h of adding the FT, with less than 2% NaCl and pH 7-8.4. Scanning electron microscopy of the fibrin gel showed fibrillar structures with a high degree of cross-linking and a high density. Two structures were found in the binding area of restructured meat; one in the central part with similar characteristics to fibrin gels and, another in the area of contact between the meat surfaces, where a filamentous structure connected the fibrin gels with the muscle bundles. PMID- 24767092 TI - Characterization of antioxidant methylcellulose film incorporated with alpha tocopherol nanocapsules. AB - Biodegradable and antioxidant films based on methylcellulose (MC) and alpha tocopherol nanocapsule suspension (NCs) were developed. MC and NCs films were prepared by a casting method in three different proportions. The mechanical, wettability, colour, light transmission, antioxidant and release characteristics of the films were studied. The addition of NCs to MC films decreased the tensile strength (TS) and the elastic modulus (EM) (p<0.05) but increased the percentage elongation at break (%E) and thickness (p<0.05). NCs films showed a higher hydrophobicity when compared to that of film control. Lightness and yellowish color were intensified in the NCs films which, in their turn, demonstrated high antioxidant activity and excellent barrier properties against UV and visible light. A burst and prolonged release of alpha-tocopherol to food simulant was also reported. PMID- 24767093 TI - Successful application of Low Voltage Electron Microscopy to practical materials problems. AB - Low-voltage High-Resolution Electron Microscopy (LVHREM) has several advantages, including increased cross-sections for inelastic and elastic scattering, increased contrast per electron, decreased delocalization effects and reduced knock-on damage. Imaging at differing voltages has shown advantages for imaging materials that are knock-on damage sensitive. We show experimentally that different materials systems benefit from low voltage high-resolution microscopy. There are advantages for imaging single layer materials such as graphene at below the knock-on threshold; we present an example of imaging a graphene sheet at 40kV. We have also examined mesoporous silica decorated with Pd nanoparticles and carbon black functionalized with Pd/Pt nanoparticles. In these cases we show that the lower voltage imaging maintains the structure of the surrounding matrix during imaging, whereas aberration correction provides the higher resolution for imaging the nanoparticle lattice. Perhaps surprisingly we show that zeolites damage preferentially by ionization effects (radiolysis). The current literature suggests that below incident energies of 40kV the damage is mainly radiolitic, whereas at incident energies above 200kV the knock-on damage and material sputtering will be the dominant effect. Our experimental observations support this conclusion and the effects we have observed at 40kV are not indicative of knock-on damage. Other nanoscale materials such as thin silicon nanowires also benefit from lower voltage imaging. LVHREM imaging provides an excellent option to avoid beam damage to nanowires; our results suggest that LVHREM is suitable for nanowire-biological composites. Our experimental observations serve as a clear demonstration that even at 40keV accelerating voltage, LVHREM can be used without inducing beam damage to locate dislocations and other crystalline defects, which may have adverse effects on nanowire device performance. Low voltage operation will likely become the new mode of imaging for many electron microscopes, with the instrument being, in essence, tuned to extract all the information possible from each electron that transits the sample. PMID- 24767094 TI - Phase II trial of standard versus increased transfusion volume in Ugandan children with acute severe anemia. AB - BACKGROUND: Severe anemia (SA, hemoglobin <6 g/dl) is a leading cause of pediatric hospital admission in Africa, with significant in-hospital mortality. The underlying etiology is often infectious, but specific pathogens are rarely identified. Guidelines developed to encourage rational blood use recommend a standard volume of whole blood (20 ml/kg) for transfusion, but this is commonly associated with a frequent need for repeat transfusion and poor outcome. Evidence is lacking on what hemoglobin threshold criteria for intervention and volume are associated with the optimal survival outcomes. METHODS: We evaluated the safety and efficacy of a higher volume of whole blood (30 ml/kg; Tx30: n = 78) against the standard volume (20 ml/kg; Tx20: n = 82) in Ugandan children (median age 36 months (interquartile range (IQR) 13 to 53)) for 24-hour anemia correction (hemoglobin >6 g/dl: primary outcome) and 28-day survival. RESULTS: Median admission hemoglobin was 4.2 g/dl (IQR 3.1 to 4.9). Initial volume received followed the randomization strategy in 155 (97%) patients. By 24-hours, 70 (90%) children in the Tx30 arm had corrected SA compared to 61 (74%) in the Tx20 arm; cause-specific hazard ratio = 1.54 (95% confidence interval 1.09 to 2.18, P = 0.01). From admission to day 28 there was a greater hemoglobin increase from enrollment in Tx30 (global P <0.0001). Serious adverse events included one non fatal allergic reaction and one death in the Tx30 arm. There were six deaths in the Tx20 arm (P = 0.12); three deaths were adjudicated as possibly related to transfusion, but none secondary to volume overload. CONCLUSION: A higher initial transfusion volume prescribed at hospital admission was safe and resulted in an accelerated hematological recovery in Ugandan children with SA. Future testing in a large, pragmatic clinical trial to establish the effect on short and longer term survival is warranted. TRIAL REGISTRATION: ClinicalTrials.Gov identifier: NCT01461590 registered 26 October 2011. PMID- 24767095 TI - Risk and consequences of chemotherapy-induced neutropenic complications in patients receiving daily filgrastim: the importance of duration of prophylaxis. AB - BACKGROUND: To examine duration of daily filgrastim prophylaxis, and risk and consequences of chemotherapy-induced neutropenic complications (CINC) requiring inpatient care. METHODS: Using a retrospective cohort design and US healthcare claims data (2001-2010), we identified all cancer patients who initiated >=1 course of myelosuppressive chemotherapy and received daily filgrastim prophylactically in >=1 cycle. Cycles with daily filgrastim prophylaxis were pooled for analyses. CINC was identified based on hospital admissions with a diagnosis of neutropenia, fever, or infection; consequences were characterized in terms of hospital mortality, hospital length of stay (LOS), and CINC-related healthcare expenditures. RESULTS: Risk of CINC requiring inpatient care-adjusted for patient characteristics-was 2.4 (95% CI: 1.6-3.4) and 1.9 (1.3-2.8) times higher with 1-3 (N = 8371) and 4-6 (N = 3691) days of filgrastim prophylaxis, respectively, versus >=7 days (N = 2226). Among subjects who developed CINC, consequences with 1-3 and 4-6 (vs. >=7) days of filgrastim prophylaxis were: mortality (8.4% [n/N = 10/119] and 4.0% [3/75] vs. 0% [0/34]); LOS (means: 7.4 [N = 243] and 7.1 [N = 99] vs. 6.5 [N = 40]); and expenditures (means: $18,912 [N = 225] and $14,907 [N = 94] vs. $13,165 [N = 39]). CONCLUSIONS: In this retrospective evaluation, shorter courses of daily filgrastim prophylaxis were found to be associated with an increased risk of CINC as well as poorer outcomes among those developing this condition. Because of the limitations inherent in healthcare claims databases specifically and retrospective evaluations generally, additional research addressing these limitations is needed to confirm the findings of this study. PMID- 24767096 TI - A hot tumor blush in the heart: multimodality imaging characteristics of a right atrial hemangioma. PMID- 24767097 TI - The frequency and distribution of canine leishmaniosis diagnosed by veterinary practitioners in Europe. AB - This study aimed to evaluate the frequency and spatial distribution of canine leishmaniosis (CanL) in France, Greece, Italy, Portugal and Spain. An online questionnaire investigated the location and frequency of CanL cases diagnosed by veterinary practitioners. Further data from the practice management systems of veterinary clinics in France were provided by a financial benchmarking company in relation to all treatment and test invoice data from participating practices. The geographical and temporal web interest in leishmaniosis was explored using Google Trends. Veterinary practitioners from France, Greece, Italy, Portugal and Spain completed 1231 questionnaires. The percentage of practice-attending dogs with a veterinary diagnosis of CanL ranged from 0.71% in France to 7.80% in Greece. However, due to regional differences in response rates, particularly in France, the mean regional estimates may better reflect the disease burden. Benchmarking data relating to approximately 180,000 dogs estimated that 0.05% of dogs attending veterinary clinics were treated for CanL or euthanased with suspected CanL in France. The regional frequency of Google web queries for leishmaniosis generally reflected the spatial patterns of disease identified from the other data sources. In conclusion, CanL was a relatively common diagnosis in veterinary clinics in many regions of the countries studied. Knowledge of CanL in endemic areas can direct the use of preventative measures and help estimate the likelihood of infection in dogs visiting or inhabiting these countries. PMID- 24767099 TI - Foreword. The need for evidence-based guidelines to direct decisions regarding the appropriateness of our interventions. PMID- 24767098 TI - Stereotactic radiotherapy using tomotherapy for early-stage non-small cell lung carcinoma: analysis of intrafraction tumour motion. AB - INTRODUCTION: Intrafraction tumour motion in helical tomotherapy was investigated by comparing pre- and mid-fraction CT scans in patients with early non-small cell lung carcinoma (NSCLC) to assess the efficacy of a 7-mm margin around gross tumour volumes (GTVs) in stereotactic body radiation therapy (SBRT). METHODS: Thirty patients with early-stage NSCLC received SBRT in four or five fractions for a total of 141 treatments. A slow positron emission tomography/CT scan was fused with the simulation CT to determine the GTV. A planning target volume was created by placing an isotropic margin of 7 mm around the GTV. Data were retrospectively analyzed to assess translational tumour positional changes along the x, y and z axes and vector changes in millimeters from the pretreatment megavoltage (MV)-CT to the mid-fraction MV-CT. RESULTS: Average movements for all 141 treatment days along the x, y and z axes were 0.5 +/- 2.3, -0.3 +/- 3.0 and 0.9 +/- 3.0 mm, respectively. Average movements for each patient along the x, y and z axes were 0.5 +/- 1.5, -0.2 +/- 2.0 and 0.9 +/- 1.9 mm, respectively. Average vector displacement was 4.3 +/- 2.4 mm for all treatment days and 4.2 +/- 1.7 mm for each patient. Of 141 treatments, 137 (97.2%) fell within 7.0 mm in all axes. CONCLUSION: The addition of a 7-mm margin to the GTV for patients receiving SBRT for NSCLC using tomotherapy is adequate to account for tumour movement. Mid fraction CT scans proved to be valuable in assessing intrafraction tumour motion. PMID- 24767101 TI - Evidence-based carotid artery-based interventions for stroke risk reduction. PMID- 24767103 TI - Hepatitis C treatment outcome in relation to alcohol consumption and racial differences in southeastern Taiwan. AB - BACKGROUND/PURPOSE: Alcohol use may have negative impacts on hepatitis C virus (HCV) treatment due to low adherence, and racial differences can influence HCV sustained virological response (SVR) rate between East Asian and European ancestry. The objective of this study is to confirm the influence of alcohol consumption and racial differences on HCV treatment outcome in aboriginal and nonaboriginal people of southeastern Taiwan. METHODS: In this retrospective cohort study, a total of 195 patients were treated with peginterferon-alpha once weekly plus ribavirin for 24 weeks. The efficacy analysis was performed based on the SVR rate for patients who received at least one dose of the study medication or who completed treatment. The endpoints were denoted by virological response rate including the influences of alcohol use, HCV genotype, serum level of HCV virological load, and racial differences. RESULTS: No differences were observed in the baseline clinical characteristics between drinkers and nondrinkers, but a significant difference was noted in the body mass index between aboriginal and nonaboriginal populations (28.3 vs. 25.8; p < 0.01). With respect to the SVR rate, no difference was found between drinkers and nondrinkers, and between aboriginal and nonaboriginal people. The treatment efficacy of SVR in the whole group was significantly different between patients with HCV genotype 1 and nongenotype 1 (73.5% vs. 91.2%; p < 0.01). An analysis of the SVR rate in the aboriginal group showed no significant difference between patients with genotype 1 and nongenotype 1 (80.0% vs. 91.3%; p = 0.31). CONCLUSION: In southeastern Taiwan, alcohol consumption did not influence the HCV treatment outcome, and the SVR rates were similar between patients with HCV genotype 1 and nongenotype 1 infections in the aboriginal group. PMID- 24767102 TI - Robotic-assisted versus laparoscopic colorectal surgery: a meta-analysis of four randomized controlled trials. AB - BACKGROUND: Robotic-assisted laparoscopy is popularly performed for colorectal disease. The objective of this meta-analysis was to compare the safety and efficacy of robotic-assisted colorectal surgery (RCS) and laparoscopic colorectal surgery (LCS) for colorectal disease based on randomized controlled trial studies. METHODS: Literature searches of electronic databases (Pubmed, Web of Science, and Cochrane Library) were performed to identify randomized controlled trial studies that compared the clinical or oncologic outcomes of RCS and LCS. This meta-analysis was performed using the Review Manager (RevMan) software (version 5.2) that is provided by the Cochrane Collaboration. The data used were mean differences and odds ratios for continuous and dichotomous variables, respectively. Fixed-effects or random-effects models were adopted according to heterogeneity. RESULTS: Four randomized controlled trial studies were identified for this meta-analysis. In total, 110 patients underwent RCS, and 116 patients underwent LCS. The results revealed that estimated blood losses (EBLs), conversion rates and times to the recovery of bowel function were significantly reduced following RCS compared with LCS. There were no significant differences in complication rates, lengths of hospital stays, proximal margins, distal margins or harvested lymph nodes between the two techniques. CONCLUSIONS: RCS is a promising technique and is a safe and effective alternative to LCS for colorectal surgery. The advantages of RCS include reduced EBLs, lower conversion rates and shorter times to the recovery of bowel function. Further studies are required to define the financial effects of RCS and the effects of RCS on long-term oncologic outcomes. PMID- 24767105 TI - Molecular heterogeneity of head and neck squamous cell carcinoma defined by next generation sequencing. AB - Head and neck squamous cell carcinoma (HNSCC) can be divided into two different clinical entities based on their association with high-risk subtypes of human papilloma virus (HPV16 and HPV18). Dissimilarities in prognosis and molecular profiles have attracted much attention in recent years, in part because of increasing rates of HPV infection in HNSCC; however, the underlying mechanisms and detailed genetic profiles that set these tumors apart are still elusive. To elucidate oncogenic pathways in HNSCC with and without HPV infection, we used targeted next-generation sequencing to interrogate single-nucleotide polymorphisms (SNPs) in 50 cancer-related genes. We detected SNPs in 25 of these genes from HNSCC tissue specimens with and without HPV infection. In 5 of the 25 genes, variant patterns were similar regardless of HPV infection status. A greater number of sequence variants in genes from the tyrosine kinase receptors and their associated pathways were preferentially present in HPV(+) specimens. SNPs in genes related to tumor-suppressor functions were more prevalent in HPV(-) HNSCC specimens. The observations may help to elucidate mechanisms involved in the molecular pathogenesis of two clinically diverse subclasses of HNSCC. Over representation of SNPs in either HPV(+) or HPV(-) HNSCC is another indicator of potentially actionable sequence variants for targeted therapy. PMID- 24767104 TI - High prevalence of HIV and syphilis and associated factors among low-fee female sex workers in mainland China: a cross-sectional study. AB - BACKGROUND: The prevalence of HIV and syphilis among middle and high-fee female sex workers (FSWs) has been widely reported but little is known among low-fee FSWs. This study aims to determine the prevalence and associated factors of HIV and syphilis among low-fee FSWs in China. METHODS: A cross-sectional study design was used. A convenience sample of low-fee FSWs was recruited from venues by outreach workers in 12 cities. Structured questionnaire interviews and blood sampling for HIV and syphilis were carried out. Univariate and multivariate logistic regression were used for assessing potential associated factors. RESULTS: This study enrolled 781 low-fee FSWs. There were 37 (4.7%) HIV positive participants and 117 (15.0%) participants were infected with syphilis. Final multivariate analysis identified five factors associated with HIV infection: older age (OR:2.6, 95% CI:1.1-6.1), local household registration (OR:3.3, 95% CI:1.5-6.9), employed in Yunnan province (OR:2.7, 95% CI:1.1-6.7), soliciting in self-rented rooms and "market day" buildings (OR:3.9, 95% CI:1.5-10.0), injection drug use in the past 6 months (OR:13.5, 95% CI:4.5-40.1); and four factors associated with syphilis infection: older age (OR:1.8, 95% CI:1.2-2.9), employed in Yunnan province (OR:2.1, 95% CI:1.2-3.6), soliciting in self-rented rooms and "market day" buildings (OR:2.3, 95% CI:1.4-3.7) , and no consistent condom use with clients in the past 30 days (OR:1.6, 95% CI:1.0-2.6). CONCLUSIONS: A high prevalence of HIV and syphilis were found among low-fee FSWs. Those soliciting in self-rented rooms and "market day" buildings with the lowest income, and injection drug users (IDUs) in this population should take priority in further intervention strategies. PMID- 24767107 TI - Mucinous neoplasia of the appendix. PMID- 24767106 TI - Targeting endothelial CD146 attenuates colitis and prevents colitis-associated carcinogenesis. AB - Recently, enhanced CD146 expression was reported on endothelial cells in intestinal biopsies from patients with inflammatory bowel disease. However, the underlying mechanism remains unknown. Here, we found that overexpressed endothelial CD146 promoted the inflammatory responses in inflammatory bowel disease, which further potentiated the occurrence of colitis-associated colorectal carcinogenesis. Eliminating endothelial CD146 by conditional knockout significantly ameliorated the severity of inflammation in two different murine models of colitis, and decreased tumor incidence and tumor progression in a murine model of colitis-associated colorectal carcinogenesis. Mechanistic study showed that cytokine tumor necrosis factor-alpha (TNF-alpha) up-regulated the expression of endothelial CD146 through NF-kappaB transactivation. In turn, the enhanced endothelial CD146 expression promoted both angiogenesis and proinflammatory leukocyte extravasations, contributing to inflammation. Using an anti-CD146 antibody, AA98, alone or together with an anti-TNF-alpha antibody significantly attenuated colitis and prevented colitis-associated colorectal carcinogenesis in mice. Our study provides the first evidence that CD146 plays a dual role on endothelium, facilitating leukocyte extravasations and angiogenesis, thus promoting inflammation. This finding not only reveals the function and regulating mechanism of CD146 in inflammatory bowel disease, but also provides a promising therapeutic strategy for treating inflammatory bowel disease and preventing colitis-associated colorectal carcinogenesis. PMID- 24767108 TI - Decreased plasma neuroactive amino acids and increased nitric oxide levels in melancholic major depressive disorder. AB - BACKGROUND: Amino acid neurotransmitters and nitric oxide (NO) are involved in the pathogenesis of major depressive disorder (MDD). Here we want to establish whether changes in their plasma levels may serve as biomarker for the melancholic subtype of this disorder. METHODS: Plasma levels of glutamic acid (Glu), aspartic acid (Asp), glycine (Gly), gamma-aminobutyric acid (GABA), and NO were determined in 27 medicine-naive melancholic MDD patients and 30 matched controls. Seven of the MDD patients participated also in a follow-up study after 2 months' antidepressant treatment. The relationship between plasma and cerebral-spinal fluid (CSF) levels of these compounds was analyzed in an additional group of 10 non-depressed subjects. RESULTS: The plasma levels of Asp, Gly and GABA were significantly lower whereas the NO levels were significantly higher in melancholic MDD patients, also after 2 months of fluoxetine treatment. In the additional 10 non-depressed subjects, no significant correlation was observed between plasma and CSF levels of these compounds. CONCLUSION: These data give the first indication that decreased plasma levels of Asp, Gly and GABA and increased NO levels may serve as a clinical trait-marker for melancholic MDD. The specificity and selectivity of this putative trait-marker has to be investigated in follow-up studies. PMID- 24767109 TI - Possible roles of basic helix-loop-helix transcription factors in adaptation to drought. AB - Water deficiency decreases plant growth and productivity. Several mechanisms are activated in response to dehydration that allows plants to cope with stress, including factors controlling stomatal aperture and ramified root system development. In addition, ABA metabolism is also implicated in the regulation of drought responses. The basic helix-loop-helix (bHLH) proteins, a large family of conserved transcription factors that regulates many cellular processes in eukaryotic organisms, are also involved in several responses that are important for plants to cope with drought stress. This review discusses distinct mechanisms related to drought-adaptive responses, especially the possible involvement of the bHLH transcription factors such as MUTE, implicated in stomatal development; RD22, [corrected] an ABA-responsive gene; EGL3 and GL3, involved in thichome and root hair development; and SPT, which play roles in repressing leaf expansion. Transcription factors are potential targets for new strategies to increase the tolerance of cultivars to drought stress. Recognition of gene regulatory networks in crops is challenging, and the manipulation of bHLH genes as well as components that mediate bHLH transcription factor responses in different pathways could be essential to achieve abiotic stress tolerance in plants through genetic manipulation. PMID- 24767110 TI - Identification of a STOP1-like protein in Eucalyptus that regulates transcription of Al tolerance genes. AB - Tolerance to soil acidity is an important trait for eucalyptus clones that are introduced to commercial forestry plantations in pacific Asian countries, where acidic soil is dominant in many locations. A conserved transcription factor regulating aluminum (Al) and proton (H+) tolerance in land-plant species, STOP1 (SENSITIVE TOPROTON RHIZOTOXICITY 1)-like protein, was isolated by polymerase chain reaction-based cloning, and then suppressed by RNA interference in hairy roots produced by Agrobacterium rhizogenes-mediated transformation. Eucalyptus STOP1-like protein complemented proton tolerance in an Arabidopsis thaliana stop1 mutant, and localized to the nucleus in a transient assay of a green fluorescent protein fusion protein expressed in tobacco leaves by Agrobacterium tumefaciens mediated transformation. Genes encoding a citrate transporting MULTIDRUGS AND TOXIC COMPOUND EXTRUSION protein and an orthologue of ALUMINUM SENSITIVE 3 were suppressed in transgenic hairy roots in which the STOP1 orthologue was knocked down. In summary, we identified a series of genes for Al-tolerance in eucalyptus, including a gene for STOP1-like protein and the Al-tolerance genes it regulates. These genes may be useful for molecular breeding and genomic selection of elite clones to introduce into acid soil regions. PMID- 24767111 TI - Involvement of abscisic acid in the response of Medicago sativa plants in symbiosis with Sinorhizobium meliloti to salinity. AB - Legumes are classified as salt-sensitive crops with their productivity particularly affected by salinity. Abcisic acid (ABA) plays an important role in the response to environmental stresses as signal molecule which led us to study its role in the response of nitrogen fixation and antioxidant metabolism in root nodules of Medicago sativa under salt stress conditions. Adult plants inoculated with Sinorhizobium meliloti were treated with 1 MUM and 10 MUM ABA two days before 200 mM salt addition. Exogenous ABA together with the salt treatment provoked a strong induction of the ABA content in the nodular tissue which alleviated the inhibition induced by salinity in the plant growth and nitrogen fixation. Antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GR) were induced by ABA pre-treatments under salt stress conditions which together with the reduction of the lipid peroxidation, suggest a role for ABA as signal molecule in the activation of the nodular antioxidant metabolism. Interaction between ABA and polyamines (PAs), described as anti stress molecules, was studied being detected an induction of the common polyamines spermidine (Spd) and spermine (Spm) levels by ABA under salt stress conditions. In conclusion, ABA pre-treatment improved the nitrogen fixation capacity under salt stress conditions by the induction of the nodular antioxidant defenses which may be mediated by the common PAs Spd and Spm that seems to be involved in the anti-stress response induced by ABA. PMID- 24767112 TI - The maize pentatricopeptide repeat gene empty pericarp4 (emp4) is required for proper cellular development in vegetative tissues. AB - The empty pericarp4 (emp4) gene encodes a mitochondrion-targeted pentatricopeptide repeat (ppr) protein that is involved in the regulation of mitochondrial gene expression and is required for seed development. In homozygous mutant emp4-1 kernels the endosperm is drastically reduced and the embryo is retarded in its development and unable to germinate. With the aim of investigating the role of emp4 during post-germinative development, homozygous mutant seedlings were obtained by cultivation of excised immature embryos on a synthetic medium. In the mutants both germination frequency as well as the proportion of seedlings reaching the first and second leaf stages were reduced. The anatomy of the leaf blades and the root cortex was not affected by the mutation, however severe alterations such as the presence of empty cells or cells containing poorly organized organelles, were observed. Moreover both mitochondria and chloroplast functionality was impaired in the mutants. Our hypothesis is that mitochondrial impairment, the primary effect of the mutation, causes secondary effects on the development of other cellular organelles. Ultra-structural features of mutant leaf blade mesophyll cells are reminiscent of cells undergoing senescence. Interestingly, both structural and functional damage was less severe in seedlings grown in total darkness compared with those exposed to light, thus suggesting that the effects of the mutation are enhanced by the presence of light. PMID- 24767113 TI - Changes in actin dynamics are involved in salicylic acid signaling pathway. AB - Changes in actin cytoskeleton dynamics are one of the crucial players in many physiological as well as non-physiological processes in plant cells. Positioning of actin filament arrays is necessary for successful establishment of primary lines of defense toward pathogen attack, depolymerization leads very often to the enhanced susceptibility to the invading pathogen. On the other hand it was also shown that the disruption of actin cytoskeleton leads to the induction of defense response leading to the expression of PATHOGENESIS RELATED proteins (PR). In this study we show that pharmacological actin depolymerization leads to the specific induction of genes in salicylic acid pathway but not that involved in jasmonic acid signaling. Life imaging of leafs of Arabidopsis thaliana with GFP-tagged fimbrin (GFP-fABD2) treated with 1 mM salicylic acid revealed rapid disruption of actin filaments resembling the pattern viewed after treatment with 200 nM latrunculin B. The effect of salicylic acid on actin filament fragmentation was prevented by exogenous addition of phosphatidic acid, which binds to the capping protein and thus promotes actin polymerization. The quantitative evaluation of actin filament dynamics is also presented. PMID- 24767114 TI - Systems genetics: a paradigm to improve discovery of candidate genes and mechanisms underlying complex traits. AB - Understanding the control of any trait optimally requires the detection of causal genes, gene interaction, and mechanism of action to discover and model the biochemical pathways underlying the expressed phenotype. Functional genomics techniques, including RNA expression profiling via microarray and high-throughput DNA sequencing, allow for the precise genome localization of biological information. Powerful genetic approaches, including quantitative trait locus (QTL) and genome-wide association study mapping, link phenotype with genome positions, yet genetics is less precise in localizing the relevant mechanistic information encoded in DNA. The coupling of salient functional genomic signals with genetically mapped positions is an appealing approach to discover meaningful gene-phenotype relationships. Techniques used to define this genetic-genomic convergence comprise the field of systems genetics. This short review will address an application of systems genetics where RNA profiles are associated with genetically mapped genome positions of individual genes (eQTL mapping) or as gene sets (co-expression network modules). Both approaches can be applied for knowledge independent selection of candidate genes (and possible control mechanisms) underlying complex traits where multiple, likely unlinked, genomic regions might control specific complex traits. PMID- 24767115 TI - Filter strip as a method of choice for apoplastic fluid extraction from maize roots. AB - Apoplastic fluid was extracted from maize (Zea mays L.) roots using two procedures: collection from the surface of intact plant roots by filter paper strips (AF) or vacuum infiltration and/or centrifugation from excised root segments (AWF). The content of cytoplasmic marker (glucose-6-phosphate, G-6-P) and antioxidative components (enzymes, organic acids, phenolics, sugars, ROS) were compared in the extracts. The results obtained demonstrate that AF was completely free of G-6-P, as opposed to AWF where the cytoplasmic constituent was detected even at mildest centrifugation (200*g). Isoelectric focusing of POD and SOD shows the presence of cytoplasmic isoforms in AWF, and HPLC of sugars and phenolics a much more complex composition of AWF, due to cytoplasmic contamination. Organic acid composition differed in the two extracts, much higher concentrations of malic acid being registered in AF, while oxalic acid due to intracellular contamination being present only in AWF. EPR spectroscopy of DEPMPO spin trap in the extracts showed persistent generation of hydroxyl radical adduct in AF. The results obtained argue in favor of the filter strip method for the root apoplastic fluid extraction, avoiding the problems of cytoplasmic contamination and dilution and enabling concentration measurements in minute regions of the root. PMID- 24767116 TI - Cytochrome P450s from Cynara cardunculus L. CYP71AV9 and CYP71BL5, catalyze distinct hydroxylations in the sesquiterpene lactone biosynthetic pathway. AB - Cynara cardunculus (Asteraceae) is a cross pollinated perennial crop which includes the two cultivated taxa globe artichoke and cultivated cardoon. The leaves of these plants contain high concentrations of sesquiterpene lactones (STLs) among which cynaropicrin is the most represented, and has recently attracted attention because of its therapeutic potential as anti-tumor and anti photoaging agent. Costunolide is considered the common precursor of the STLs and three enzymes are involved in its biosynthetic pathway: i.e. the germacrene A synthase (GAS), the germacrene A oxidase (GAO) and the costunolide synthase (COS). Here we report on the isolation of two P450 genes, (i.e. CYP71AV9 and CYP71BL5), in a set of ~19,000 C. cardunculus unigenes, and their functional characterization in yeast and in planta. The metabolite analyses revealed that the co-expression of CYP71AV9 together with GAS resulted in the biosynthesis of germacra-1(10),4,11(13)-trien-12-oic acid in yeast. The co-expression of CYP71BL5 and CYP71AV9 with GAS led to biosynthesis of the free costunolide in yeast and costunolide conjugates in Nicotiana benthamiana, demonstrating their involvement in STL biosynthesis as GAO and COS enzymes. The substrate specificity of CYP71AV9 was investigated by testing its ability to convert amorpha-4,11-diene, (+) germacrene D and cascarilladiene to their oxidized products when co-expressed in yeast with the corresponding terpene synthases. PMID- 24767117 TI - Comparative expression analysis of resistant and susceptible Populus clones inoculated with Septoria musiva. AB - Septoria musiva is a major pathogen of Populus and can cause leaf spots and stem cankers in susceptible clones. In order to investigate defense mechanisms of Populus in response to S. musiva, differential gene expression in leaf tissues of two resistant (DN34, P. deltoides*nigra; NM6, P. nigra*maximowiczii) and two susceptible clones (DN164, P. deltoides*nigra; NC11505, P. maximowiczii*trichocarpa) was analyzed by RNA-Seq. Of the 511 million reads obtained, 78% and 0.01% were successfully aligned to the genomes of P. trichocarpa and S. musiva, respectively. Functional annotation of differentially expressed genes based on comparisons between resistant and susceptible clones revealed that there were significant differences in the expression of genes involved in disease/stress resistance and oxidation-reduction in mock-inoculated leaves. Four days post inoculation with S. musiva, 36 differentially expressed genes were found to be regulated in the same direction in both resistant clones. The 22 up-regulated loci in resistant clones included genes involved in protein fate, cell wall structure, and responsiveness to various biotic and abiotic stresses. In particular, Potri.008G187100 locus encodes a putative multi antimicrobial extrusion protein and Potri.006G272600 encodes a family1 glycosyltransferase required for pathogen resistance. The differentially expressed loci with increased expression in the susceptible clones corresponded to NB-ARC domain-containing disease resistance protein, phospholipase A 2A, MutT/nudix family protein, and an elicitor-activated gene 3-1 product. The results from this study indicate that strong defense mechanisms involved in oxidation-reduction, protein fate, secondary metabolism, and accumulation of defense-related gene products may contribute to Septoria resistance in DN34 and NM6, while increased expression of hypersensitive response-loci, particularly those encoding NB-ARC domain-containing disease resistance proteins, may contribute to the susceptibility of DN164 and NC11505 through interaction with pathogen effectors. PMID- 24767118 TI - Waterlogging during flowering and boll forming stages affects sucrose metabolism in the leaves subtending the cotton boll and its relationship with boll weight. AB - The work explored sucrose metabolism in the leaves subtending the cotton boll (SBL) and its role in boll weight after waterlogging in cotton. Results showed that net photosynthesis rate (Pn), relative water content, contents of Chlorophyll a and Chlorophyll b, initial ribulose-1,5-bisphosphate carboxylase oxygenase (Rubisco) activity and cytosolic fructose-1, 6-bisphosphatase (cy FBPase) activity decreased with waterlogging in the SBL on fruiting branches 2-3 (FB2-3) and FB6-7. Activities of sucrose synthase (SuSy) and sucrose phosphate synthase (SPS) increased to the maximum up to 6 days of waterlogging then decreased with prolonged waterlogging. Rubisco activation and specific leaf weight increased and gene expressions of SuSy, SPS and rubisco activase (RCA) were all up-regulated with the duration of waterlogging, especially for the SBL on FB6-7. The induction of activity and gene expression of SuSy was most significant indicating its crucial role in sucrose metabolism after waterlogging. For the SBL in the later period of boll development on upper FB10-11 and FB14-15, the pattern seemed opposite to that of FB2-3 and FB6c7 as compensation effect in vegetative growth existed. Correlation analysis revealed that initial Rubisco activity and cy-FBPase activity were the main limitation to Pn reduction after waterlogging. Reduction in Pn, sucrose transformation rate and initial Rubisco activity directly decrease boll weight in waterlogged cotton. Besides the role in sucrose metabolism after waterlogging, SuSy also had a positive significant correlation with the duration of rapid-accumulation period for seed fiber weight (P<0.05). These findings elucidated mechanisms to waterlogging that affected seed fiber weight, which resulted from alteration in carbohydrates, enzymes and genes. PMID- 24767119 TI - Changes in ethylene signaling and MADS box gene expression are associated with banana finger drop. AB - Banana finger drop was examined in ripening banana harvested at immature (iMG), early (eMG) and late mature green (lMG) stages, with contrasting ripening rates and ethylene sensitivities. Concomitantly, 11 ethylene signal transduction components (ESTC) and 6 MADS box gene expressions were comparatively studied in median (control zone, CZ) and pedicel rupture (drop zone DZ) areas in peel tissue. iMG fruit did not ripen or develop finger drop while eMG and lMG fruits displayed a similar finger drop pattern. Several ESTC and MADS box gene mRNAs were differentially induced in DZ and CZ and sequentially in eMG and lMG fruits. MaESR2, 3 and MaEIL1, MaMADS2 and MaMADS5 had a higher mRNA level in eMG and acted earlier, whereas MaERS1, MaCTR1, MaEIL3/AB266319, MaEIL4/AB266320 and MaEIL5/AB266321, MaMADS4 and to a lesser extent MaMADS2 and 5 acted later in lMG. In this fruit, MaERS1 and 3, MaCTR1, MaEIL3, 4 and MaEIL5/AB266321, and MaMADS4 were enhanced by finger drop, suggesting their specific involvement in this process. MaEIL1, MaMADS1 and 3, induced at comparable levels in DZ and CZ, are probably related to the overall fruit ripening process. These findings led us to consider that developmental cues are the predominant finger drop regulation factor. PMID- 24767120 TI - Microscopic and macroscopic monitoring of adaxial-abaxial pH gradients in the leaf apoplast of Vicia faba L. as primed by NaCl stress at the roots. AB - The pH is a basic chemical requirement in cellular and apoplastic compartments that influences various physiological processes in plants. Apoplastic pH shifts can modulate the apoplastic and symplastic distribution of plant hormones or influence proton motive force-driven uptake processes over the plasma-membrane. Changing environments are known to effect on the apoplastic H(+)-concentration in leaves and roots. The onset of NaCl-stress at the roots for instance primes a chloride-specific systemic alkalinization of the leaf apoplast. By means of microscopy- and macroscopy-based in planta ratio-imaging we surprisingly found that large adaxial-abaxial pH gradients were established throughout the leaf apoplast during the formation of the NaCl-induced alkalinization. Moreover, the root system is necessary to ensure the transient nature of the leaf apoplastic alkalinization. PMID- 24767121 TI - Assessment of photosystem II thermoluminescence as a tool to investigate the effects of dehydration and rehydration on the cyclic/chlororespiratory electron pathways in wheat and barley leaves. AB - Thermoluminescence emission from wheat leaves was recorded under various controlled drought stress conditions: (i) fast dehydration (few hours) of excised leaves in the dark (ii) slow dehydration (several days) obtained by withholding watering of plants under a day/night cycle (iii) overnight rehydration of the slowly dehydrated plants at a stage of severe dessication. In fast dehydrated leaves, the AG band intensity was unchanged but its position was shifted to lower temperatures, indicating an activation of cyclic and chlororespiratory pathways in darkness, without any increase of their overall electron transfer capacity. By contrast, after a slow dehydration the AG intensity was strongly increased whereas its position was almost unchanged, indicating respectively that the capacity of cyclic pathways was enhanced but that they remained inactivated in darkness. Under more severe dehydration, the AG band almost disappeared. Rewatering caused its rapid bounce significantly above the control level. No significant differences in AG emission could be found between the two drought sensitive and drought-tolerant wheat cultivars. The afterglow thermoluminescence emission in leaves provides an additional tool to follow the increased capacity and activation of cyclic electron flow around PSI in leaves during mild, severe dehydration and after rehydration. PMID- 24767122 TI - Insights into the microstructures of hygroscopic movement in plant seed dispersal. AB - As non-motile organisms, plants develop means to spread their progenies. Hygroscopic movement is a very common mechanism employed in seed dispersal. This type of movement is created when the tissue desiccates and the cell walls dry and shrink. A contraction force develops, the direction and strength of which depends on the architecture of the tissue. This force may be utilized for a simple release of seeds, their catapultion, and for pushing seeds along the soil to a germination locus. We review the formation of a bend, a twist and a coil within various dispersal apparatuses as a reaction to the dehydration of the tissue. We compare the microscopic structures of hygroscopic devices supporting slow or fast movement, adaptations to dry or wet climates, and single use versus repeated movement. We discuss the development of the disconnecting tissues in relation to the development of a hygroscopic mechanism. As plant cultivation is dependent on seed dispersal control, we demonstrate that during the domestication of sesame and wheat, seed dispersal is avoided not due to a defective hygroscopic tissue, but rather a missing dehiscence tissue. Seed dispersal is a crucial stage in the life cycle of plants. Thus, hygroscopic movement plays a central part in plant ecology and agriculture. PMID- 24767123 TI - Differential transcript accumulation and subcellular localization of Arabidopsis ribosomal proteins. AB - Arabidopsis cytoplasmic ribosomes are an assembly of four rRNAs and 81 ribosomal proteins (RPs). With only a single molecule of each RP incorporated into any given ribosome, an adequate level of each RP in the nucleolus is a prerequisite for efficient ribosome biogenesis. Using Genevestigator (microarray data analysis tool), we have studied transcript levels of 192 of the 254 Arabidopsis RP genes, as well as the sub-cellular localization of each of five two-member RP families, to identify the extent to which these two processes contribute to the nucleolar pool of RPs available for ribosome biogenesis. While transcript levels from different RP genes show up to a 300-fold difference across the RP population, this difference is drastically reduced to ~8-fold when considering RP gene families. Under various stimuli, while the transcript level for most RP genes remains unchanged some show a significantly increased or decreased level. Subcellular localization studies in tobacco not only showed differential targeting of RPs to the cytoplasm, nucleus and nucleolus, but also differential nucleolar import rates. This degree of variation in gene regulation and subcellular localization of RPs hints at the possibility of extra-ribosomal functions for some RP isoforms. PMID- 24767124 TI - Predicting transcriptional circuitry underlying seed coat development. AB - Filling, protection, and dispersal of angiosperm seeds are largely dependent on the development of the maternally derived seed coat. The development of the seed coat in plants such as Arabidopsis thaliana and Glycine max (soybean) is regulated by a complex network of genes and gene products responsible for the establishment and identity of this multicellular structure. Recent studies support the hypothesis that the structure, development, and function of the seed coat are under the control of transcriptional regulators that are specified in space and time. Furthermore, these transcriptional regulators can act in combination to orchestrate the expression of large gene sets. We discuss the underlying transcriptional circuits of the seed coat sub-regions through the interrogation of large-scale datasets, and also provide some ideas on how the identification and analysis of these datasets can be further improved in these two model oilseed systems. PMID- 24767125 TI - GEm-Related 5 (GER5), an ABA and stress-responsive GRAM domain protein regulating seed development and inflorescence architecture. AB - We have identified an abscisic acid (ABA) and stress-responsive GRAM (Glucosyltransferases, Rab-like GTPase activators and Myotubularins) domain protein GER5 (GEm-Related 5) closely related to GEM (GLABRA2 Expression Modulator), a novel regulator of cell division and cell fate determination in epidermal cells. A loss-of-function T-DNA line (ger5-2) and transgenic lines silencing (GER5(RNAi)) or overexpressing (GER5(OE)) GER5 displayed several defects in reproductive development affecting seed and embryo development. RNA in situ studies revealed GER5 and related GRAM genes (GEM and GEm-Related 1 (GER1)) have both overlapping and unique expression domains in male and female reproductive organs. Hormone immunolocalization experiments further indicate GER5 transcripts preferentially localize to reproductive tissues which accumulate ABA. Expression analysis revealed members of the GRAM family (GER5, GER1, GEM) display tissue-specific expression patterns and are responsive to phytohormones and abiotic stress, in addition to genetic lesions (aba1, aba2, ctr1) affecting ABA biosynthesis or ethylene signalling. Mature seeds of ger5-2 mutants also exhibit reduced sensitivity to ABA during seed germination assays. Microarray analysis of aborting and developing seeds isolated from ger5-2 mutants revealed underlying transcriptional changes in carbohydrate metabolism, hormone signalling and catabolic processes (e.g. protein degradation, autophagy). Taken together, our results indicate ABA-responsive GRAM genes play a novel role in regulating the reproductive development of plants, and raise intriguing questions regarding the functional relationship between members of the GRAM gene family. PMID- 24767127 TI - It may be not suitable to perform renal denervation in renal arteries with significant stenosis. PMID- 24767126 TI - Alteration of Notch signaling and functionality of adipose tissue derived mesenchymal stem cells in heart failure. AB - AIM: Circulating mesenchymal cells increase in heart failure (HF) patients and could be used therapeutically. Our aim was to investigate whether HF affects adipose tissue derived mesenchymal cell (adMSC) isolation, functional characteristics and Notch pathway. METHODS AND RESULTS: We compared 25 patients with different degrees of HF (11 NYHA classes I and II and 14 NYHA III and IV) with 10 age and gender matched controls. 100% adMSC cultures were obtained from controls, while only 72.7% and 35.7% from patients with mild or severe HF (p<0.0001). adMSC from HF patients showed higher markers of senescence (p16 positive cells: 14+/-2.3% in controls and 35.6+/-5.6% (p<0.05) and 69+/-14.7% (p<0.01) in mild or severe HF; gamma-H2AX positive cells: 3.7+/-1.2%, 19.4+/-4.1% (p<0.05) and 23.7+/-3.4% (p<0.05) respectively), lower proliferation index (Ki67 positive cells: 21.5+/-4.9%, 13.2+/-2.8% and 13.7+/-3.2%, respectively), reduced pluripotency-associated genes (Oct4 positive cells: 86.7+/-4.9%, 55+/-12% (p<0.05) and 43.3+/-8.7% (p<0.05), respectively; NANOG positive cells: 89.8+/ 3.7%, 39.6+/-14.4% (p<0.01) and 47+/-8.1%, respectively), and decreased differentiation markers (alpha-sarcomeric actin positive cells: 79.8+/-4.6%, 49+/ 18.1% and 47+/-12.1% (p<0.05) and CD31-positive endothelial cells: 24.5+/-2.9%, 0.5+/-0.5% (p<0.001) and 2.3+/-2.3% (p<0.001), respectively). AdMSC from HF patients also showed reduced Notch transcriptional activity (lowered expression of Hey 1 and Hey 2 mRNAs). Stimulation with TNF-alpha of adMSC isolated from controls affected the transcription of several components of the Notch pathway (reduction of Notch 4 and Hes 1 mRNAs and increase of Notch 2 and Hey 1 mRNAs). CONCLUSIONS: In HF yield and functionality of adMSC are impaired and their Notch signaling is downregulated. PMID- 24767128 TI - Left atrial regional phasic strain, strain rate and velocity by speckle-tracking echocardiography: normal values and effects of aging in a large group of normal subjects--our reply. PMID- 24767129 TI - The impact of Agent Orange on characteristics of coronary artery lesion and repeat revascularization. PMID- 24767130 TI - PPARbeta/delta attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells. AB - BACKGROUND: Chronic endoplasmic reticulum (ER) stress contributes to the apoptotic cell death in the myocardium, thereby playing a critical role in the development of cardiomyopathy. ER stress has been reported to be induced after high-fat diet feeding in mice and also after saturated fatty acid treatment in vitro. Therefore, since several studies have shown that peroxisome proliferator activated receptor (PPAR)beta/delta inhibits ER stress, the main goal of this study consisted in investigating whether activation of this nuclear receptor was able to prevent lipid-induced ER stress in cardiac cells. METHODS AND RESULTS: Wild-type and transgenic mice with reduced PPARbeta/delta expression were fed a standard diet or a high-fat diet for two months. For in vitro studies, a cardiomyocyte cell line of human origin, AC16, was treated with palmitate and the PPARbeta/delta agonist GW501516. Our results demonstrate that palmitate induced ER stress in AC16 cells, a fact which was prevented after PPARbeta/delta activation with GW501516. Interestingly, the effect of GW501516 on ER stress occurred in an AMPK-independent manner. The most striking result of this study is that GW501516 treatment also upregulated the protein levels of beclin 1 and LC3II, two well-known markers of autophagy. In accordance with this, feeding on a high-fat diet or suppression of PPARbeta/delta in knockout mice induced ER stress in the heart. Moreover, PPARbeta/delta knockout mice also displayed a reduction in autophagic markers. CONCLUSION: Our data indicate that PPARbeta/delta activation might be useful to prevent the harmful effects of ER stress induced by saturated fatty acids in the heart by inducing autophagy. PMID- 24767131 TI - Sarcopenic obesity and arterial stiffness, pressure wave reflection and central pulse pressure: the J-SHIPP study. PMID- 24767132 TI - Trans-catheter treatment of residual leak after PFO device closure. PMID- 24767133 TI - A meta-analysis of adjusted observational studies for mortality in transapical versus transfemoral aortic valve implantation. PMID- 24767134 TI - Optimal decongestive therapy in acute decompensated heart failure syndromes: far from being solved. PMID- 24767135 TI - Anterior mitral valve myxoma: a case report. PMID- 24767136 TI - Dopamine in acute decompensated heart failure: does left ventricular ejection fraction matter? PMID- 24767137 TI - HMGB1/IL-17A axis: an important mechanism for myocardial ischemia-reperfusion injury. PMID- 24767138 TI - Characteristics of lumbar scoliosis in patients with rheumatoid arthritis. AB - BACKGROUND: Although a substantial percentage of patients with rheumatoid arthritis (RA) experience low back pain, the characteristics of lumbar spine pathology in RA patients has been poorly investigated. In our institutions, lumbar spine radiographs indicated scoliosis in 26 patients. The present study aimed to clarify the characteristics of lumbar scoliosis in RA patients. METHODS: This is a retrospective study of 26 RA patients with lumbar scoliosis. Patient characteristics such as disease duration, disease stage and class according to Steinbrocker's classification, and medication for RA and osteoporosis were reviewed. Radiologic evaluation of scoliosis was performed at two different time points by measuring Cobb angles. The progression of scoliosis per year was calculated by dividing the change in Cobb angles by the number of years. Apical vertebral rotation, lateral listhesis, and the level of the intercrestal line at the first observation were also measured. The correlation between different factors and changes in the Cobb angles per year was analyzed. RESULTS: Majority of the patients had a long disease duration and were classified as stage 3 or 4 according to Steinbrocker's classification. During the observation period, most patients were treated with glucocorticoids. Unlike the previous studies on degenerative scoliosis, apical vertebral rotation, lateral listhesis, and the level of the intercrestal line at initial observation were not significantly related to the progression of scoliosis. Initial Cobb angles were inversely related to the progression of scoliosis. Patients who were treated with bisphosphonates showed slower progression of scoliosis. CONCLUSIONS: Our results indicate that the characteristics of lumbar scoliosis in RA patients differ from those of degenerative lumbar scoliosis. Bone fragility due to the long disease duration, poor control of disease activity, and osteoporosis is possibly related to its progression. PMID- 24767139 TI - Effect of advanced intercrossing on genome structure and on the power to detect linked quantitative trait loci in a multi-parent population: a simulation study in rice. AB - BACKGROUND: In genetic analysis of agronomic traits, quantitative trait loci (QTLs) that control the same phenotype are often closely linked. Furthermore, many QTLs are localized in specific genomic regions (QTL clusters) that include naturally occurring allelic variations in different genes. Therefore, linkage among QTLs may complicate the detection of each individual QTL. This problem can be resolved by using populations that include many potential recombination sites. Recently, multi-parent populations have been developed and used for QTL analysis. However, their efficiency for detection of linked QTLs has not received attention. By using information on rice, we simulated the construction of a multi parent population followed by cycles of recurrent crossing and inbreeding, and we investigated the resulting genome structure and its usefulness for detecting linked QTLs as a function of the number of cycles of recurrent crossing. RESULTS: The number of non-recombinant genome segments increased linearly with an increasing number of cycles. The mean and median lengths of the non-recombinant genome segments decreased dramatically during the first five to six cycles, then decreased more slowly during subsequent cycles. Without recurrent crossing, we found that there is a risk of missing QTLs that are linked in a repulsion phase, and a risk of identifying linked QTLs in a coupling phase as a single QTL, even when the population was derived from eight parental lines. In our simulation results, using fewer than two cycles of recurrent crossing produced results that differed little from the results with zero cycles, whereas using more than six cycles dramatically improved the power under most of the conditions that we simulated. CONCLUSION: Our results indicated that even with a population derived from eight parental lines, fewer than two cycles of crossing does not improve the power to detect linked QTLs. However, using six cycles dramatically improved the power, suggesting that advanced intercrossing can help to resolve the problems that result from linkage among QTLs. PMID- 24767140 TI - Risks and benefits of transfusion for children with severe anemia in Africa. AB - Severe anemia contributes significantly to child mortality in sub-Saharan Africa. Blood transfusion is used in emergencies but carries risks. In BMC Medicine, Olupot-Olupot and colleagues report the findings of a phase II trial in children with severe anemia in Eastern Uganda. They provide important early safety and efficacy data supporting large volume whole blood transfusion (30 ml/kg) compared with the World Health Organization recommendation of 20 ml/kg. Large volume transfusions result in more rapid and frequent correction of severe anemia; they can be expected to reduce the risk of transfusions, and help manage the scarce resource of donor blood. However, severe anemia arises from varying combinations of acute, sub-acute and chronic etiologies. The Fluid Expansion As Supportive Therapy study reminds us that the risks and benefits of even simple interventions are complex, and that rapid normalization of physiology may not always be the best strategy. There is no substitute for high quality evidence and to this end we strongly support Olupot-Oluput and colleagues' call for a definitive trial of large volume transfusions in severe anemia. Please see related research article http://www.biomedcentral.com/1741-7015/12/67/abstract. PMID- 24767141 TI - Long term sensory function after minor partial thickness burn: a pilot study to determine if recovery is complete or incomplete. AB - BACKGROUND: Acute burn damages skin architecture, including nerve endings, altering sensation and influencing recovery of quality of life and participation. It is established that sensation is reduced in scars after deep burn. However, it is unclear if sensory deficits exist in mild scars. The aim of this trial was to determine if sensory deficits persist in mature scars after minor partial thickness burn. METHODS: This observational pilot involved 30 patients with 'good quality' scars (defined as VSS <=5 at >=6 months post-burn). Sensory function was compared in scars and site matched uninjured skin using von Frey filaments and two-point discrimination (2-PD). Multivariable regression was used to predict the influence of burn and confounders on sensory outcomes. RESULTS: Both pressure and 2-PD distance were significantly greater in scar compared to uninjured sites, indicating reduced sensory function. For von Frey filaments, the median was 3.84 (IQR=1) in scars and 3.22 (IQR=1) for uninjured (p=0.001). For 2-PD, the median was 3.9cm (IQR=1.8) for scars and 2.6cm (IQR=1.6) for control sites (p=0.001). CONCLUSION: Measureable sensory deficits persist in mature, good quality burn scars. These deficits may influence long-term recovery after minor partial thickness burn. PMID- 24767142 TI - Spread of extended-spectrum beta-lactamase genes of blaOXA-10, blaPER-1 and blaCTX-M in Pseudomonas aeruginosa strains isolated from burn patients. AB - BACKGROUND: Pseudomonas aeruginosa is resistant to many antibiotics due to production of different classes of extended spectrum beta-lactamases (ESBLs). Prevalence of ESBLs among P. aeruginosa has been increased in recent years, demonstrate a serious health problem especially in burn units worldwide. OBJECTIVE: Present study was designed to determine the ESBL producing strains and identify the genes encoding three different ESBLs of bla PER-1, bla OXA-10 and bla CTX-M genes in P. aeruginosa isolates from burn patients. METHODS: In total 185 clinical isolates of P. aeruginosa were collected from infectious wounds of hospitalized burn patients. Antimicrobial susceptibility testing and phenotypic detection of ESBL were performed by disk diffusion method and Double disk Synergy Test (DDST). Polymerase Chain Reaction (PCR) was done for detection of bla OXA 10, bla PER-1 and bla CTX-M ESBL encoding genes. RESULTS: In total, 176 (95.13%) isolates were multidrug resistant. The DDST demonstrated 96 (51.9%) isolates as putative ESBL producers with 100% or highly resistance to ofloxacin, cephalexin, aztreonam (97.57%) and ceftriaxone (91.6%). By PCR amplification, bla PER-1, bla OXA-10 and bla CTX-M genes were detected in 52 (54.16%), 66 (68.75%) and 1 (1.04%) isolates of ESBL producers respectively. Forty-three isolates (44.79%) were simultaneously positive for both bla OXA-10 and bla PER-1 related genes. CONCLUSION: The rate of ESBL producing P. aeruginosa was notable in present study. Since there are only limited effective antibiotics against the bacterium, therefore all isolates must be investigated by antimicrobial susceptibility testing, which limits resistance development in burn units and helps the management of treatment strategy. PMID- 24767143 TI - Determination of extended spectrum beta-lactamases, metallo-beta-lactamases and AmpC-beta-lactamases among carbapenem resistant Pseudomonas aeruginosa isolated from burn patients. AB - BACKGROUND: Pseudomonas aeruginosa is an important cause of morbidity and mortality in patients with burns. METHOD: A total of 214 nonduplicated burn wound isolates of P. aeruginosa were recovered from burn patients. Identification of carbapenem resistant isolates and their antimicrobial susceptibility pattern was carried out using the phenotypic methods. The presence of genes encoding extended spectrum beta-lactamases (ESBLs) and metallo-beta-lactamases (MBLs) enzymes were determined by PCR. The genetic relationships between carbapenem resistant isolates were determined by Random Amplified Polymorphic DNA (RAPD)-PCR. RESULTS: Of 214 investigated P. aeruginosa isolates, 100 (46.7%) were carbapenem resistant. All carbapenem resistant P. aeruginosa were resistant to imipenem, meropenem, ertapenem, carbenicillin, aztreonam, gentamicin and ciprofloxacin but susceptible to polymyxin B. Among 100 carbapenem resistant P. aeruginosa isolates, 3%, 65% and 52% were identified as ESBLs, carbapenemase and AmpC overproduction positive isolates respectively. The most prevalent ESBLs and MBLs genes included blaOXA-10 (97%), blaTEM (61%), blaVIM (55%), blaPER (13%), blaIMP (3%) and blaAIM (1%). RAPD analysis yielded 13 distinct profiles among 92 isolates. A dominant RAPD type was designated as A that consisting of 80 isolates. CONCLUSION: This is the first report of Adelaide IMipenmase (AIM) MBLs producing P. aeruginosa from Iran and also of the high prevalence of AmpC overproduction isolates. According to the results of current study, P. aeruginosa isolates producing OXA-10, TEM, VIM, PER and IMP beta-lactamases are frequent and the population structures of these isolates are highly similar. PMID- 24767144 TI - CT and endoscopic evaluation of larynx and trachea in mucopolysaccharidoses. AB - BACKGROUND: Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by lysosomal enzyme deficiencies that result in systemic accumulation of glycosaminoglycans (GAGs). Accumulation of GAGs in the upper airway can lead to respiratory failure. The aim of this study was to investigate changes of the airway by flexible endoscopy and CT. METHODS: Thirty-five patients aging from 2 to 16 years (mean: 9.2+/-4.4 years) participated in this study. The majority had MPS I (n=5) or MPS II (n=25). The shape of the trachea and the cross-sectional trachea surface area (TSA) was determined at the Th1 and Th2 levels. Airway obstruction was evaluated from endoscopic findings and classified into 3 grades (Grades 0, 1, and 2). Forty-five patients in the control group who underwent tracheal CT for other conditions were retrospectively selected from the database. RESULTS: Tracheal morphology was abnormal in 50-60%, which showed a transversely collapsing narrow trachea. Tracheal deformity was severe in MPS II and MPS IV. The mean TSA of the MPS patients was 55.5+/-29.0 mm(2) at Th1 and 61.4+/-29.0 mm(2) at Th2, while that of the control group was 90.1+/-41.9 mm(2) and 87.9+/ 39.3 mm(2), respectively. Respiratory distress was noted in 15 of the 35 patients, among whom 7 patients showed tracheal deformity and 7 patients had laryngeal redundancy. Three patients had no abnormalities of the larynx or trachea, so other factors such as pharyngeal stenosis or lower airway stenosis might have contributed to their respiratory distress. CONCLUSION: CT and flexible endoscopy allow quantitative and morphological evaluation of airway narrowing, which is beneficial for airway management in MPS children. PMID- 24767146 TI - Silicon nanowires as field-effect transducers for biosensor development: a review. AB - The unique electronic properties and miniaturized dimensions of silicon nanowires (SiNWs) are attractive for label-free, real-time and sensitive detection of biomolecules. Sensors based on SiNWs operate as field effect transistors (FETs) and can be fabricated either by top-down or bottom-up approaches. Advances in fabrication methods have allowed for the control of physicochemical and electronic properties of SiNWs, providing opportunity for interfacing of SiNW-FET probes with intracellular environments. The Debye screening length is an important consideration that determines the performance and detection limits of SiNW-FET sensors, especially at physiologically relevant conditions of ionic strength (>100mM). In this review, we discuss the construction and application of SiNW-FET sensors for detection of ions, nucleic acids and protein markers. Advantages and disadvantages of the top-down and bottom-up approaches for synthesis of SiNWs are discussed. An overview of various methods for surface functionalization of SiNWs for immobilization of selective chemistry is provided in the context of impact on the analytical performance of SiNW-FET sensors. In addition to in vitro examples, an overview of the progress of use of SiNW-FET sensors for ex vivo studies is also presented. This review concludes with a discussion of the future prospects of SiNW-FET sensors. PMID- 24767145 TI - Radiation-induced meningiomas in multiple regions, showing rapid recurrence and a high MIB 1 labeling index: a case report and review of the literature. AB - Combined chemotherapy and prophylactic cranial irradiation has improved the prognosis of children with acute leukemia. However cranial irradiation carries a latent risk of the induction of secondary intracranial tumors. We encountered a patient who developed multiple intracranial radiation-induced meningiomas (RIMs) 25 years after prophylactic cranial irradiation for the treatment of acute leukemia in childhood. The patient had 3 intracranial lesions, 1 of which showed rapid growth within 6 months; another of the tumors also enlarged within a short period. All of the tumors were surgically treated, and immunohistochemistry indicated a high MIB-1 labeling index in each of the multiple lesions. In the literature, the MIB-1 labeling indices of 27 tumors from 21 patients were examined. Among them, 12 recurrent tumors showed higher MIB-1 labeling indices compared to the MIB-1 labeling indices of the non-recurrent tumors. Overall, 11 of the patients with RIM had multiple lesions and 8 cases developed recurrence (72.7%). RIM cases with multiple lesions had higher MIB-1 labeling indices compared to the MIB-1 labeling indices of cases with single lesions. Collectively, these data showed that the MIB-1 labeling index is as important for predicting RIM recurrences, as it is for predicting sporadic meningioma (SM) recurrences. RIMs should be treated more aggressively than SMs because of their greater malignant potential. PMID- 24767147 TI - Graphene prepared by one-pot solvent exfoliation as a highly sensitive platform for electrochemical sensing. AB - Graphene was easily obtained via one-step ultrasonic exfoliation of graphite powder in N-methyl-2-pyrrolidone. Scanning electron microscopy, transmission electron microscopy, Raman and particle size measurements indicated that the exfoliation efficiency and the amount of produced graphene increased with ultrasonic time. The electrochemical properties and analytical applications of the resulting graphene were systematically studied. Compared with the predominantly-used reduced graphene oxides, the obtained graphene by one-step solvent exfoliation greatly enhanced the oxidation signals of various analytes, such as ascorbic acid (AA), dopamine (DA), uric acid (UA), xanthine (XA), hypoxanthine (HXA), bisphenol A (BPA), ponceau 4R, and sunset yellow. The detection limits of AA, DA, UA, XA, HXA, BPA, ponceau 4R, and sunset yellow were evaluated to be 0.8 MUM, 7.5 nM, 2.5 nM, 4 nM, 10 nM, 20 nM, 2 nM, and 1 nM, which are much lower than the reported values. Thus, the prepared graphene via solvent exfoliation strategy displays strong signal amplification ability and holds great promise in constructing a universal and sensitive electrochemical sensing platform. PMID- 24767148 TI - Characterization of gold-thiol-8-hydroxyquinoline self-assembled monolayers for selective recognition of aluminum ion using voltammetry and electrochemical impedance spectroscopy. AB - Gold electrode surface is modified via covalent attachment of a synthesized thiol functionalized with 8-hydroxyquinoline, p-((8-hydroxyquinoline)azo) benzenethiol (SHQ), for the first time. The behavior of the nanostructured electrode surface (Au-SHQ) is characterized by electrochemical techniques including cyclic and differential pulse voltammetry (CV and DPV), and electrochemical impedance spectroscopy (EIS). The modified surface is stable in a wide range of potentials and pHs. A surface pKa of 6.0+/-0.1 is obtained for Au-SHQ electrode using surface acid/base titration curves constructed by CV and EIS measurements as a function of pH. These results helped to determine the charge state of the surface as a function of pH. The gold modified electrode surface showed good affinity for sensing the Al(III) ion at pH 5.5. The sensing process is based on (i) accumulation and complex formation between Al(III) from the solution phase and 8HQ function on the Au electrode surface (recognition step) and (ii) monitoring the impedance of the Au-SHQ-Al(III) complex against redox reaction rate of parabenzoquinone (PBQ) (signal transduction step). The PBQ is found to be a more suitable probe for this purpose, after testing several others. Thus, the sensor was tested for quantitative determination of Al(III) from the solution phase. At the optimized conditions, a linear response, from 1.0*10(-11) to 1.2*10(-5) M Al(III) in semi-logarithmic scale, with a detection limit of 8.32*10(-12) M and mean relative standard deviation of 3.2% for n=3 at 1.0*10(-7) M Al(III) is obtained. Possible interferences from coexisting cations and anions are also studied. The results show that many ions do not interfere significantly with the sensor response for Al(III). Validity of the method and applicability of the sensor are successfully tested by determination of Al(III) in human blood serum samples. PMID- 24767149 TI - Raman model development for the protein conformational state classification in different freeze-dried formulations. AB - The aim of this work is to build a multivariate calibration (MVC) model from Raman spectra for the prediction of the protein conformational state class (i.e. native-like or non-native) in different freeze-dried pharmaceutical formulations of a model protein lactate dehydrogenase (LDH). As this model would be intended to facilitate and better understand formulation and process development, it should allow acceptable classification performance despite variations in formulation type and batch. Therefore, it was attempted to (1) find which factors interfere the Raman spectra, (2) understand them, and (3) make the MVC model robust for them. A variance analysis within the Raman spectral data space identified significant spectral background variations among certain formulation types and batches in the studied samples. Raw material (i.e. LDH) batch variability and the presence of a Maillard reaction in formulations were the main reasons for this. We demonstrate the successful use of both exhaustive calibration and external parameter orthogonalization (EPO) pre-processing for making the Raman classification model more robust for the expected spectral interferences. PMID- 24767150 TI - Development of silver/gold nanocages onto indium tin oxide glass as a reagentless plasmonic mercury sensor. AB - We demonstrate the utilization of silver/gold nanocages (Ag/Au NCs) deposited onto transparent indium tin oxide (ITO) film glass as the basis of a reagentless, simple and inexpensive mercury probe. The localized surface plasmon resonance (LSPR) peak wavelength was located at ~800 nm. By utilizing the redox reaction between Hg(2+) ions and Ag atoms that existed in Ag/Au NCs, the LSPR peak of Ag/Au NCs was blue-shifted. Thus, we develop an optical sensing probe for the detection of Hg(2+) ions. The LSPR peak changes were lineally proportional to the concentration of Hg(2+) ions over the range from 10 ppb to 0.5 ppm. The detection limit was ~5 ppb. This plasmonic probe shows good selectivity and high sensitivity. The proposed optical probe is successfully applied to the sensing of Hg(2+) in real samples. PMID- 24767151 TI - Silver nanoplates-based colorimetric iodide recognition and sensing using sodium thiosulfate as a sensitizer. AB - A colorimetric method for the recognition and sensing of iodide ions (I(-)) has been developed by utilizing the reactions between triangular silver nanoplates (TAg-NPs) and I(-) in the presence of sodium thiosulfate (Na2S2O3). Specifically, I(-) together with Na2S2O3 can induce protection of TAg-NPs owing to the formation of insoluble AgI, as confirmed by the high-resolution transmission electron microscopy (HRTEM). In the absence of Na2S2O3, the etching reactions on TAg-NPs were observed not only by I(-) but also other halides ions. The Na2S2O3 plays as a sensitizer in this system, which improved the selectivity and sensitivity. The desired colorimetric detection can be achieved by measuring the change of the absorption peak wavelength corresponding to localized surface plasmon resonance (LSPR) with UV-vis spectrophotometer or recognized by naked eye observation. The results show that the shift of the maximum absorption wavelength (Deltalambda) of the TAg-NPs/Na2S2O3/I(-) mixture was proportional to the concentration of I(-) in the range 1.0*10(-9)-1.0*10(-6) mol L(-1). Moreover, no other ions besides I(-) can induce an eye discernible color change as low as 1.0*10(-7) mol L(-1). Finally, this method was successfully applied for I(-) determination in kelp samples. PMID- 24767152 TI - Colorimetric determination of sarcosine in urine samples of prostatic carcinoma by mimic enzyme palladium nanoparticles. AB - The proposed palladium nanoparticles (Pd NPs), which with the catalytic activity similar to the horseradish peroxidase (HRP) mimic enzyme, can effectively catalyze the H2O2-mediated oxidation of 3,3',5,5'-tetramethylbenzidine sulfate (TMB) accompanied with a color change from colorless to blue in solution. And as a result, the sensitive detection of sarcosine can be realized by the naked eye observation and ultraviolet spectrophotometry, using Pd NPs as catalyst and TMB as the substrate of the simulation enzyme catalytic reaction. Under the optimal condition, the catalytic system of Pd NPs mimic enzyme can be used for the detection of sarcosine. It has been found that the color change could be clearly observed with the naked eyes, and the absorbance intensity at 653 nm showed a fine linear fitting with the concentration of sarcosine in the range from 0.01 MUM to 50 MUM, and the detection limit (3sigma/S) for sarcosine was calculated to be 5.0 nM. In order to evaluate the feasibility and reliability, the method was also used for analyzing concentrations of sarcosine in human urine samples from diagnosed prostate cancer patients and healthy donors. It is expected to provide a convenient and efficient method for indirect evaluation for the diagnosis of prostatic carcinoma (PCa). PMID- 24767153 TI - [Early diagnosis of idiopathic pulmonary fibrosis]. PMID- 24767154 TI - [To establish a comprehensive system for the management of relapses after allogeneic hematopoietic stem cell transplantation]. PMID- 24767155 TI - [Reappraisal of the treatment strategies for adult acute lymphoblastic leukemia]. PMID- 24767156 TI - [New points and limits of 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults]. PMID- 24767157 TI - [The clinical analysis of allogeneic hematopoietic stem cell transplantation from human leukocyte antigen-identical siblings in 95 patients with myelodysplastic syndrome]. AB - OBJECTIVE: To evaluate the efficacy and optimize the timing of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from human leukocyte antigen (HLA)-identical siblings for myelodysplastic syndrome (MDS). METHODS: From January 2003 to December 2012, 95 patients with MDS or secondary acute myeloid leukemia (AML) were treated with HLA-identical allo-HSCT in our hospital. The median age was 43 (21-59) years. Conditioning regimens including modified busulfan (Bu)/cyclophosphamide (Cy) or Bu/ fludarabine (Flu) were used. All patients received transfusion of donor stem cells mobilized by granulocyte colony stimulating factor (G-CSF) from bone marrow and/or peripheral blood. Eleven patients had refractory anemia (RA) or RA with ringed sideroblasts, 53 of RA with excess blasts (RAEB), 15 of RAEB in transformation (RAEB-t), and 16 progressing to secondary AML. RESULTS: A total of 93 patients achieved sustained myeloid engraftment. The cumulative incidence of grade II-IV acute graft versus host disease (aGVHD) was 12.9% +/- 3.5%. The 3-year cumulative incidence of chronic graft versus host disease (cGVHD) was 80.3% +/- 4.9%. After a median follow-up of 28.7 months, 29 patients died. The 3-year estimated overall survival (OS) and disease-free survival (DFS) rates were 69.9% +/- 5.0% and 58.0% +/- 5.4% respectively. The cumulative relapse rate (RR) was 25.9% +/- 4.7%, while non relapse mortality (NRM) was 16.1% +/- 4.0%. Multivariate analyses showed that non II-IV aGVHD and cGVHD were favorable factors associated with OS. Low DFS rate was correlated with high scores of international prognostic scoring system (IPSS). Patients with RAEB-t and AML (n = 31) were divided into 3 groups: no chemotherapy before HSCT (Group 1), chemotherapy but not achieving remission (Group 2) and chemotherapy and achieving remission (Group 3). The 3-year OS rate was 100.0% in Group 3, which was significantly higher than those of Groups 1 and 2 with 33.9%, 32.7% respectively (P < 0.05). The difference of DFS and RR in the three groups did not reach statistic difference. CONCLUSIONS: Allo-HSCT from HLA-identical siblings is effective for patients with MDS. IPSS is of prognostic value for post transplantation outcome. For patients with progressive disease before transplantation, maximal control of blasts in bone marrow may improve the prognosis of advanced MDS. PMID- 24767158 TI - [Clinical outcome of FLT3-ITD (+) acute myeloid leukemia patients treated with allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To study the clinical outcome of patients with fms-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) positive acute myeloid leukemia (AML) treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to explore the potential prognostic factors to patients' survival including transplant types or disease status. METHODS: A total of 314 AML patients in our center from October 2006 to October 2012 were retrospectively analyzed, among whom, 54 patients were defined with FLT3-ITD positive. Survival rates and treatment-related mortality were further analyzed. RESULTS: For all 54 FLT3-ITD positive patients, the 3-year overall survival (3-OS) rate was 56% and 3-year leukemia-free survival (3-LFS) rate was 47%. The outcome of haplo-identical HSCT was similar as that of sibling donors (3-OS rate: 60% vs 54%; 3-LFS rate: 54% vs 45%, respectively) . There were 47 patients who received transplantation in first complete remission (CR1) . The other 7 patients were of disease relapse or in CR2 before transplantation. Not surprisingly, patients in CR1 had better prognosis than those in non-CR1. CONCLUSIONS: Allo-HSCT is an effective treatment for AML patients with FLT3-ITD positive mutation. The survival outcome of haplo-identical HSCT was comparable with that of sibling donors. Relapse of AML was the dominant factor related to the mortality of FLT3-ITD positive AML patients after allo HSCT. PMID- 24767159 TI - [The influence of liver dysfunction before transplantation and during conditioning period on the outcome of allogeneic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigate the characteristics of liver dysfunction pre-transplant and during conditioning period and its impacts on transplantation related hepatic complication, overall survival (OS) and transplant-related mortality (TRM). METHODS: A total of 196 patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at Peking University First Hospital were analyzed retrospectively. Liver function test for each patient was examined pre-transplant and during the period of conditioning. The correlation of liver dysfunction with hepatic complications, OS and TRM rates were analyzed. RESULTS: Liver dysfunction before transplantation was found in 38 (19.8%, 38/192) patients, while damage of liver function during conditioning was found in 159(81.1%) patients, 28 of whom developed grade 3 hepatic dysfunction. There was no life-threatening impairment of liver function. No matter pre-transplant or during conditioning, liver dysfunction did not suggest apparent influence on the engraftment of neutrophil or platelet or the incidence of hepatic complications including hepatic veno occlusive disease (HVOD), acute graft versus host disease (aGVHD) and chronic graft versus host disease (cGVHD). Univariate analysis revealed that factors affecting OS rate included age (P = 0.022), high risk stage (P = 0.003), AST and TBil elevation before transplantation (P = 0.019 and 0.015 respectively), III-IV hepatic aGVHD (P = 0.000) and HVOD(P = 0.000). Multivariate Cox regression analysis revealed that high risk stage (P = 0.002) and III-IV hepatic aGVHD (P = 0.000) were independent prognostic risk factors affecting both OS rate and TRM rate, while liver dysfunction before transplantation or during conditioning period had no apparent influence on OS rate or TRM rate. CONCLUSION: Allo-HSCT would be administrated for the patients with mild impairment of liver function grade 1 and 2. PMID- 24767160 TI - [The diagnostic value of protein induced by vitamin K absence or antagonist-II in non-infant patients with acquired deficiency of vitamin K-dependent coagulation factors]. AB - OBJECTIVE: To explore the diagnostic value of protein induced by vitamin K absence or antagonist -II(PIVKA-II) in non-infant with acquired deficiency of vitamin K-dependent coagulation factors(ADVKCF). METHODS: PIVKA-II levels were measured by ELISA in 50 patients with ADVKCF on day 0, 3, 7 after vitamin K treatment. Prothrombin time(PT), APTT, FII: C, FVII: C, FIX: C, and FX: C were analyzed simultaneously. Twenty healthy subjects were enrolled as controls. RESULTS: The average level of PIVKA-II in ADVKCF group was (3.83 +/- 1.40)ug/L, while (1.30 +/- 0.54) ug/L in the control group (P < 0.05). The PIVKA-II levels on day 0 and 3 did not show significant difference [(3.83 +/- 1.40) ug/L vs (3.79 +/- 0.66) ug/L, P > 0.05], but decreasing significantly on day 7 compared to the control group(P < 0.05). The PIVKA-II level was (3.78 +/- 1.30) ug/L in patients receiving plasma transfusion, while (3.91 +/- 1.49)ug/L in no-plasma-transfusion group (P > 0.05). Coagulation factors II, VII, IX and X activity which decreased significantly before treatment returned to normal range after one week use of vitamin K, leading to complete correction of prolonged APTT and PT (>100 seconds). CONCLUSIONS: The PIVKA-II level in ADVKCF patients is significantly higher than that of healthy subjects within one week treatment of vitamin K, which is not influenced by plasma transfusion. This study suggests that PIVKA-II is a more sensitive parameter than APTT, PT and the activity of coagulation factor, which could be a valuable factor in the early diagnosis of ADVKCF. PMID- 24767161 TI - [The diagnostic value of symptom index in gastroesophageal reflux-induced chronic cough]. AB - OBJECTIVE: To explore the diagnostic value and optimal cut-off point of symptom index (SI) in gastroesophageal reflux-induced chronic cough (GERC). METHODS: The recordings of multichannel intraluminal esophageal impedance and pH monitoring were retrospectively analyzed in 118 patients with suspicious GERC. SI for all the refluxes, acid reflux and non-acid reflux was calculated respectively by analyzing the temporal association between detected reflux and cough recorded on diary card. Based on the favorable response to the anti-reflux therapy, the diagnostic value for GERC of SI was evaluated and compared with that of the symptom association probability (SAP). RESULTS: GERC was definitely determined in 100 patients (84.7%). When SI for all the refluxes was used for the diagnosis of GERC, the cut-off point of >= 45% had the highest diagnostic efficacy, with the sensitivity of 56.0%, the specificity of 83.3% and Youden index of 0.393. SI for acid or non-acid reflux had the same optimal cut-off point of >= 30% and presented with the similar efficacy in the diagnosis of acid or non-acid GERC. Compared with SAP of >= 75%, SI for all the refluxes of >= 45% had a lower sensitivity (56.0% vs 75.0%, chi(2) = 7.988, P = 0.005), a higher specificity (83.3% vs 44.4%, chi(2) = 5.900, P = 0.015) and the comparable positive or negative predictive value in the diagnosis of GERC. The diagnostic accuracy for GERC was further improved when combining SI for all the refluxes with SAP. CONCLUSION: SI for all the refluxes has a diagnostic value similar to SAP and its optimal cut-off point for GERC may be >= 45%. PMID- 24767162 TI - [An analysis of hypoglycemic agents used among patients with type 2 diabetes in Beijing communities]. AB - OBJECTIVE: To compare the coverage rate of the hypoglycemic agents base on 2009 and 2012 versions of the national essential medicine list among patients with type 2 diabetes mellitus (T2DM) in Beijing communities. METHODS: A total of 900 patients with T2DM were enrolled in the study from four community health service centers in Beijing and followed up for one year. The following data were collected and analyzed, including patients characteristics, the proportion of patients with glycosylated hemoglobin A1c (HbA1c) less than 7% and the coverage rate of the hypoglycemic agents. RESULTS: (1) The coverage rate of using the hypoglycemic agents in 2012 version of the national essential medicine list was significantly higher than that in 2009 version (91.4% vs 42.9%, chi(2) = 481.09, P < 0.05). The coverage rates of the seven hypoglycemic agents in national essential medicine list were significantly different (chi(2) = 1519.65, P < 0.05) . The coverage rates of acarbose (48.9%), metformin(40.7%) and human insulin (31.1%) were higher than those of glimepiride (9.4%), glipizide (3.0%), glibenclamide (0.6%) and animal insulin (0.2%). (2) After one year follow-up, the proportion of the patients with HbA1c less than 7% was higher than that at the baseline(53.6% vs 32.3%, chi(2) = 77.26, P < 0.05). The coverage rate of using the hypoglycemic agents in 2012 version of the national essential medicine list was significantly higher than that in 2009 version (85.5% vs 37.4%, chi(2) = 376.367, P < 0.05). The coverage rates of acarbose (49.7%), metformin (36.3%) and insulin (30.4%) were still higher than those of glimepiride (6.3%), glipizide (2.2%) , glibenclamide (0.4%) and animal insulin(0.0%). CONCLUSION: The hypoglycemic agents in 2012 version of the national essential medicine list could meet the current need of the type 2 diabetes patients in Beijing communities better than those in 2009 version. PMID- 24767163 TI - [The genotype and epidemiological feature of the Enterobacteriaceae carrying carbapenemase in China]. AB - OBJECTIVE: To analyze the genotype and molecular epidemiology of carbapenem resistant Enterobacteriaceae. METHOD: A total of 201 carbapenem-resistant Enterobacteriaceae were isolated from 14 hospitals in 11 cities. The MICs of 14 antimicrobial drugs were detected using agar dilution method. Phenotypes of carbapenemase were screened using modified Hodge test and ethylene diamine tetraacetic acid (EDTA) test. Drug resistance genes were screened using PCR method. The strains carrying carbapenem resistance genes were confirmed by conjugation test. Homology analysis was carried out using pulsed-field gel electro-phoresis (PFGE) method and the epidemiological correlation is analyzed based on the Multilocus Sequence Typing (MLST) method in order to study the molecular epidemiology of carbapenem-resistant Enterobacteriaceae. RESULTS: Fifty three strains among 201 carbapenem-insensitive Enterobacteriaceae were detected positive carbapenem-resistant genes, among which included 33 Klebsiella pneumoniae, 9 Citrobacter freundii, 6 Escherichia coli and 5 Enterobacter cloacae. Among the 53 strains, 43 were from Beijing, 6 strains from Hangzhou, 3 strains from Nanjing and one from Fuzhou. Resistance genes-harboring plasmids were successfully transferred from 28 of 53 strains to Escherichia coli EC600. The PFGE spectrum showed that 33 Klebsiella pneumoniae were classified into three types, 9 Citrobacter freundii classified into four types, 5 Enterobacter cloacae classified into four types, while 6 Escherichia coli were the same type. Based on the results of MLST test, 29 Klebsiella pneumoniae strains producing KPC-2 type carbapenemase were all ST11, while among the four Klebsiella pneumonia carrying IMP-4 carbapenem resistant gene, three strains were ST876, one was ST147. CONCLUSIONS: Carbapenem-resistant genes were detected only in hospitals from Beijing, Hangzhou, Nanjing and Fuzhou, and type KPC-2 was the most common, followed by IMP-4 and IMP-8. High homology of resistant strains could be related to horizontal transfer of carbapenemase genes, which should cause great concern. PMID- 24767164 TI - [A correlation of pulse pressure and prognosis of refractory septic shock patients]. AB - OBJECTIVE: To explore the correlation of pulse pressure(PP) and outcome in refractory septic shock patients. METHODS: A total of 68 patients with refractory septic shock consecutively admitted in our ICU from January 2012 to December 2012 were retrospectively studied. Hemodynamic data and arterial lactate concentration were collected at the time of admission and 24 hours after admission. The outcome of Day 28 post-diagnosis was also recorded. RESULTS: (1) Compared with the survivors, heart rate (HR) at 24 hours after admission was higher in non survivors, while 24 h lactate clearance rate (rLac) was lower in them (P < 0.05). Other hemodynamic parameters showed no difference between the non-survivors and the survivors at 24 hours after admission, including central venous pressure (CVP), mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), PP, pulse pressure/heart rate (PP/HR), pulse pressure/mean arterial pressure (PP/MAP), pulse pressure/systolic pressure (PP/SBP), pulse pressure/diastolic pressure (PP/DBP), the value of SBP above MAP (SMP)and the value of DBP below MAP (MDP). (2)The mortality rate was higher in the patients with HR >= 100 b/min than those with HR<100 b/min, but without statistical significance (56.25% vs 36.11%, P = 0.096). Compared with the survivors, no matter with HR >= 100 b/min or HR<100 b/min, lactate (Lac) at the 24 hours after admission was higher in all the non-survivors (P < 0.05), while with lower rLac (P < 0.05). In those with HR >= 100 b/min, the following hemodynamic parameters were higher in the non-survivors than in the survivors, including PP, PP/HR, PP/MAP, PP/SBP, PP/DBP, SMP and MDP (all P values<0.05), while no statistical difference was observed in those with HR<100 b/min. (3) The mortality rate showed no statistical difference in those with MAP >= 85 mmHg (1 mmHg = 0.133 kPa) and with MAP < 85 mmHg (42.42% vs 48.57%, P = 0.611) . No matter MAP >= 85 mmHg or MAP < 85 mmHg, compared with the survivors, all the non-survivors had higher Lac at the 24 hours after admission (P < 0.05), while with lower rLac (P < 0.05). In those with MAP >= 85 mmHg, HR was higher in the non-survivors than the survivors (P < 0.05). In those with MAP < 85 mmHg, compared with the survivors, the non survivors had higher PP, PP/MAP, PP/SBP, PP/DBP, SMP and MDP (P < 0.05), while with lower DBP (P < 0.05). CONCLUSION: PP is correlated with the outcome in refractory septic shock patients. When the HR and MAP differ, PP has different effect on the outcome and contributes more to the tissue perfusion and outcome in those with higher HR and lower MAP. PMID- 24767165 TI - [A clinical analysis of idiopathic hypertrophic cranial pachymeningitis with a nodular space-occupying effect]. AB - OBJECTIVE: To explore the clinical features, neuroimaging and histopathological findings in patients with idiopathic hypertrophic cranial pachymeningitis (IHCP) with a nodular space occupying effect. METHODS: Four IHCP cases with a nodular space occupying effect diagnosed in our hospital were retrospectively studied. RESULTS: All the 4 patients were men with a mean onset age of 40.25 (33 ~ 50) years old. They all had long disease duration and relapses. The common symptoms of IHCP were chronic headache, multiple cranial nerve palsies and epileptic seizures. CT and MRI of the brain revealed prominent dural partial thickening, which indicated a mass or nodular space occupying effect that mimicked intracranial tumour-like meningioma. The histopathological findings of dura in 2 cases revealed connective tissue proliferation, scattered neutrophil granulocytes and plasmacytes infiltration. Combination therapy of corticosteroid or/and immunosuppressive drugs was effective for the IHCP patients. CONCLUSIONS: IHCP patients with a nodular space occupying effect usually onset with chronic headache and are often recurrent. The combination therapy of corticosteroid or/and immunosuppressive drugs is effective. The image of the brain presents prominent dural partial thickening, indicating a mass or nodular space occupying effect, which often lead to confusion with intracranial tumours or granulomatosis. PMID- 24767166 TI - [An association study of six-transmembrane protein of prostate 2 gene with metabolic index and tumour necrosis factor in Uygur population]. AB - OBJECTIVE: To explore the relationship between genetic polymorphisms of six transmembrane protein of prostate 2 (STAMP2) and metabolic index, TNFalpha in Xinjiang Uygur population. METHODS: STAMP2 gene functional regions were sequenced in Uygur Xinjiang population diagnosed as metabolic syndrome. Patients were divided into the following three groups by their TNFalpha concentration: the high level group (TNFalpha >= 7.95 ug/L, n = 313), the moderate level group (TNFalpha >5.34- < 7.95 ug/L, n = 268) and the low level group ( <= 5.34 ug/L, n = 313) . The selected representative variations were genotyped by TaqMan-PCR in 894 Uygur individuals. The association of the genetic variations of STAMP2 gene with metabolic index and TNFalpha was analyzed. RESULTS: Three representative variations were genotyped, including rs8122, rs1981529 and rs34741656. The genotype distribution and allele frequencies of rs8122 and rs1981529 were statistically different among the three groups (P < 0.05), while no difference was observed with rs34741656 (P > 0.05). By ANOVA analysis, statistical difference was showed between the rs1981529 polymorphism AA and AG in the concentration of TNFalpha (P < 0.05) . None of the polymorphisms was significantly associated with TC, HDL-C, LDL-C and TG (P > 0.05). CONCLUSION: Two STAMP2 gene polymorphisms, rs8122 and rs1981529 are associated with the concentration of TNFalpha in Xinjiang Uygur population. PMID- 24767167 TI - Rare case of acute dengue encephalitis with correlated MRI findings. AB - Dengue encephalitis is extremely rare, with most patients showing no significant abnormality on neuroimaging (CT/MRI). We report one of the very few documented cases of dengue encephalitis, with abnormal signal intensities on all major sequences on brain MRI. PMID- 24767168 TI - Insulin resistance and subclinical abnormalities of global and regional left ventricular function in patients with aortic valve sclerosis. AB - BACKGROUND: Insulin resistance, as a key mediator of metabolic syndrome, is thought to be associated with pathogenesis of calcific aortic valve disease and altered left ventricular (LV) function and structure. However, in patients with aortic valve sclerosis (AVS), the association between insulin resistance and subclinical impairment of LV function is not fully elucidated. METHODS: We studied 57 patients (mean age 70 +/- 8 years, 22 women) with asymptomatic AVS but normal LV ejection fraction in echocardiography. LV longitudinal and circumferential strain and strain rate was analyzed using two-dimensional speckle tracking echocardiography. Patients with uncontrolled hypertension and diabetes mellitus, chronic kidney disease, and concomitant coronary artery disease were excluded. They were divided into the insulin-resistant group (AVS+IR; N = 28) and no insulin-resistant group (AVS-IR; N = 29) according to the median value of homeostatic model assessment index. Computed tomography scans were also performed to measure the aortic valve calcium score and the visceral adipose tissue (VAT) area. In addition, age- and sex- adjusted 28 control subjects were recruited for the comparison. RESULTS: There were no significant differences in LV ejection fraction or mass index among the groups. The AVS+IR group had a higher aortic valve calcium score (median 94 versus 21, P = 0.022) and a larger VAT area (113 +/- 42 cm2 versus 77 +/- 38 cm2, P = 0.001) than the AVS-IR group. Notably, LV global longitudinal strain, strain rate (SR), and early diastolic SR were significantly lower in the AVS+IR group than in the AVS-IR group and in control subjects (strain: -16.2 +/- 1.6% versus -17.2 +/- 1.2% and -18.9 +/- 0.8%; SR: 1.18 +/- 0.26 s(-1) versus -1.32 +/- 0.21 s(-1) and -1.52 +/- 0.08 s(-1); early diastolic SR: -1.09 +/- 0.23 s(-1) versus -1.23 +/- 0.18 s(-1) and -1.35 +/- 0.12 s(-1); P < 0.05 for all comparison), whereas circumferential function were not significantly different. Multiple linear regression analyses revealed insulin resistance as an independent determinant of LV longitudinal strain (P = 0.017), SR (P = 0.047), and early diastolic SR (P = 0.049) regardless of LV mass index or VAT area. CONCLUSIONS: Insulin resistance is a powerful independent predictor of subclinical LV dysfunction regardless of concomitant visceral obesity and LV hypertrophy. Thus, it may be a novel therapeutic target to prevent subsequent heart failure in patients with AVS. PMID- 24767170 TI - Analyses of genetic and pathogenic variability among Botrytis cinerea isolates. AB - Seventy nine isolates of Botrytis cinerea were collected from different host plants and different locations of India and Nepal. All the isolates were identified as B. cinerea based on morphological features and were confirmed using B. cinerea specific primers. Differentiation among the isolates was assessed using morphological, genetic and biochemical approaches. To analyze morphological variability, differences in conidial size, presence or absence of sclerotia and their arrangement were observed. Genetic variability was characterized using RAPD analysis, presence or absence of transposons and mating type genes. Cluster analysis based on RAPD markers was used for defining groups on the basis of geographical region and host. The biochemical approach included determining differences in concentration of oxalic acid and activity of lytic enzymes. All the isolates were categorized into different pathogenic groups on the basis their variable reaction towards chickpea plants. Isolates with higher concentration of oxalic acid and greater activity of lytic enzymes were generally more pathogenic. Pathogenicity was also correlated to transposons. Isolates containing transposa group showed some degree of correlation with pathogenic behavior. However, isolates could not be grouped on the basis of a single approach which provides evidence of their wide diversity and high evolution potential. Sensitivity of sampled isolates was also tested against five botryticides. Most of the isolates from same region were inhibited by a particular fungicide. This feature provided interesting cues and would assist in devising novel and more effective measures for managing the disease. PMID- 24767169 TI - Is switching to an oral antibiotic regimen safe after 2 weeks of intravenous treatment for primary bacterial vertebral osteomyelitis? AB - BACKGROUND: Vertebral osteomyelitis (VO) may lead to disabling neurologic complications. Little evidence exists on optimal antibiotic management. METHODS: All patients with primary, non-implant VO, admitted from 2000-2010 were retrospectively analyzed. Patients with endocarditis, immunodeficiency, vertebral implants and surgical site infection following spine surgery were excluded. Persistence of clinical or laboratory signs of inflammation at 1 year were defined as treatment failure. Logistic regression was used to estimate the odds ratios (OR) of switch to an oral regimen after 2 weeks. RESULTS: Median antibiotic treatment was 8.1 weeks in 61 identified patients. Switch to oral antibiotics was performed in 72% of patients after a median intravenous therapy of 2.7 weeks. Switch to oral therapy was already performed after two weeks in 34% of the patients. A lower CRP at 2 weeks was the only independent predictor for switch to oral therapy (OR 0.7, 95% confidence interval 0.5-0.9, p = 0.041, per 10 mg/l increase). Staphylococcus aureus was the most frequently isolated microorganism (21%). Indications for surgery, other than biopsy, included debridement with drainage of epidural or paravertebral abscess (26 patients; 42%), and CT-guided drainage (3 patients).During the follow-up, no recurrences were observed but 2 patients died of other reasons than VO, i.e. the 1 year intention to treat success rate was 97%. CONCLUSIONS: Cure rates for non-implant VO were very high with partly short intravenous and overall antibiotic therapy. Switching to an oral antibiotic regimen after two weeks intravenous treatment may be safe, provided that CRP has decreased and epidural or paravertebral abscesses of significant size have been drained. PMID- 24767171 TI - Spatiotemporal pattern and risk factors of the reported novel avian-origin influenza A(H7N9) cases in China. AB - A total of 134 laboratory-confirmed human cases of the novel avian-origin influenza A(H7N9) were reported in China between February to July 2013. To illustrate the spatiotemporal patterns of H7N9 outbreaks in humans and investigate the risk factors associated with their distribution, we mapped the distribution of affected human cases and carried out directional distribution analysis and a direction test. We also collected data on anthropogenic, vegetation, climatic, and topographic factors, and used multiple logistic regression to examine the contribution of each factor. Two different spatiotemporal patterns were found: clustered and regular directional distributions in four distinct temporal phases in the Yangtze River Delta, and sporadic but spread in three direction across the provinces adjacent to the Yangtze River Delta. Mean monthly precipitation, mean monthly temperature, normalized difference vegetation index, and poultry consumption were significantly associated with the occurrence of human H7N9 infection. The model generated a map showing the high-risk areas for human H7N9 infection for mainland China. These findings provide an empirical basis for identifying priority areas for implementing preventive intervention to reduce the number of future human infections. PMID- 24767172 TI - Stress mediates the relationship between sexual orientation and behavioral risk disparities. AB - BACKGROUND: Growing evidence documents elevated behavioral risk among sexual minorities, including gay, lesbian, and bisexual individuals; however, tests of biological or psychological indicators of stress as explanations for these disparities have not been conducted. METHODS: Data were from the 2005-2010 National Health and Nutrition Examination Survey, and included 9662 participants; 9254 heterosexuals, 153 gays/lesbians and 255 bisexuals. Associations between sexual orientation and tobacco, alcohol, substance, and marijuana use, and body mass index, were tested using the chi-square test. Stress, operationalized as depressive symptoms and elevated C-reactive protein, was tested as mediating the association between sexual orientation and behavioral health risks. Multiple logistic regression was used to test for mediation effects, and the Sobel test was used to evaluate the statistical significance of the meditating effect. RESULTS: Gays/lesbians and bisexuals were more likely to report current smoking (p < .001), a lifetime history of substance use (p < .001), a lifetime history of marijuana use (p < .001), and a lifetime period of risky drinking (p = .0061). The largest disparities were observed among bisexuals. Depressive symptoms partially mediated the association between sexual orientation and current smoking (aOR 2.04, 95% CI 1.59, 2.63), lifetime history of substance use (aOR 3.30 95% CI 2.20, 4.96), and lifetime history of marijuana use (aOR 2.90, 95% CI 2.02, 4.16), among bisexuals only. C-reactive protein did not mediate the sexual orientation/behavior relationship. CONCLUSION: Higher prevalence of current smoking and lifetime history of substance use was observed among sexual minorities compared to heterosexuals. Among bisexuals, depressive symptoms accounted for only 0.9-3% of the reduction in the association between sexual orientation and marijuana use and tobacco use, respectively. More comprehensive assessments of stress are needed to inform explanations of the disparities in behavioral risk observed among sexual minorities. PMID- 24767173 TI - Small cell lung cancer: what are the treatment results in routine management? PMID- 24767174 TI - Picosecond ultrasonic measurements using an optical mask. AB - In this paper we describe results obtained using a variation of the picosecond ultrasonics technique. We place a transparent optical mask very close to the surface of the sample. The lower surface of the mask has a series of grooves to produce a variation of the intensity of the pump and probe light pulses across the surface of the sample. Because the light intensity varies with position, the application of the pump light pulse can generate surface acoustic waves with a wavelength equal to the period of the mask. We report results obtained in this way and discuss the possible practical applications of this new approach. PMID- 24767175 TI - Association study of 15q14 and 15q25 with high myopia in the Han Chinese population. AB - BACKGROUND: Refractive errors and high myopia are the most common ocular disorders, and both of them are leading causes of blindness in the world. Recently, genetic association studies in European and Japanese population identified that common genetic variations located in 15q14 and 15q25 were associated with high myopia. To validate whether the same variations conferred risk to high myopia in the Han Chinese population, we genotyped 1,461 individuals (940 controls and 521 cases samples) recruited of Han Chinese origin. RESULT: We found rs8027411 in 15q25 (P = 0.012 after correction, OR = 0.78) was significantly associated with high myopia but rs634990 in 15q14 (P = 0.54 after correction), OR = 0.88) was not. CONCLUSIONS: Our findings supported that 15q25 is a susceptibility locus for high myopia, and gene RASGRF1 was possible to play a role in the pathology of high myopia. PMID- 24767176 TI - Avascular necrosis in proximal humeral fractures in patients treated with operative fixation: a meta-analysis. AB - BACKGROUND: Proximal humeral fractures are common lesions of the elderly, but there are no established treatment guidelines. A surgical treatment for comminuted and displaced fractures of the proximal humerus was developed and is still evolving. The aim of this study was to perform a quantitative review to evaluate the risk of avascular necrosis (AVN) in patients with proximal humeral fractures who were treated by operative fixation compared with conservative treatment. METHODS: We searched the PubMed, MEDLINE, Springer, Elsevier Science Direct, Cochrane Library, Google Scholar, China National Knowledge Infrastructure (in Chinese), and Wanfang database (in Chinese) up to December 2013 to identify studies related to operative fixation and AVN in patients with proximal humeral fractures. RESULTS: Seven studies with a total of 291 patients (142 operative fixation cases and 149 conservative treatment cases) with proximal humeral fractures were considered in the meta-analysis. The overall meta-analysis showed no significant difference in the incidence of AVN between the two groups [odds ratio (OR) 1.42, 95% confidence interval (CI) 0.33-6.11, p = 0.64]. The subgroup meta-analysis by study design (retrospective/prospective), sample size (<=40/>40), and ethnicity (European/Asian) demonstrated similar results. However, the subgroup analysis by specific operative approach (plate fixation/tension band wiring fixation/others) indicated that plate fixation was associated with a higher rate of AVN than conservative treatment (OR 0.20, 95% CI 0.05-0.76, p = 0.019). CONCLUSIONS: Plate fixation was associated with a higher risk of AVN development than conservative treatment in patients with proximal humeral fractures. PMID- 24767178 TI - Treatment of depression with deep brain stimulation works by altering in specific ways the conscious perception of the core symptoms of sadness or anhedonia, not by modulating network circuitry. AB - An important advance in the management of treatment-resistant depression has recently been reported: deep brain stimulation (DBS) of the subgenual cingulate (Brodmann area 25 or Cg 25) or the nucleus accumbens (NAcc). These treatments produce a response rate, meaning significant clinical improvement, of about 50%, but only a few patients are returned completely to normal. The authors of these papers generally attribute the therapeutic response to restoration of an altered or perturbed neural network. In contrast, the idea advanced here is that DBS works by altering conscious perception of the core symptoms of sadness and anhedonia, not by modulating network circuitry. In the case of Cg25, the crucial thing about this site is that it is where conscious perception of sadness localizes. However, the stimulus frequency of DBS (130Hz) was too fast to support consciousness, which is associated with gamma frequencies (35-85Hz). Therefore, the imposed rapid frequency instantaneously blocked the subjective experience of sadness. In the case of the NAcc, the treatment worked by stimulating hot zones in the NAcc, which, in animal models, are known to intensify the perception of pleasure. This magnifier effect on the perception of pleasure was able to alleviate anhedonia. The response was not instantaneous but could begin within hours. In both cases, patients' realization that a core symptom had been relieved led to a moderate overall improvement in other symptoms. PMID- 24767177 TI - Stable 293 T and CHO cell lines expressing cleaved, stable HIV-1 envelope glycoprotein trimers for structural and vaccine studies. AB - BACKGROUND: Recombinant soluble, cleaved HIV-1 envelope glycoprotein SOSIP.664 gp140 trimers based on the subtype A BG505 sequence are being studied structurally and tested as immunogens in animals. For these trimers to become a vaccine candidate for human trials, they would need to be made in appropriate amounts at an acceptable quality. Accomplishing such tasks by transient transfection is likely to be challenging. The traditional way to express recombinant proteins in large amounts is via a permanent cell line, usually of mammalian origin. Making cell lines that produce BG505 SOSIP.664 trimers requires the co-expression of the Furin protease to ensure that the cleavage site between the gp120 and gp41 subunits is fully utilized. RESULTS: We designed a vector capable of expressing Env and Furin, and used it to create Stable 293 T and CHO Flp-InTM cell lines through site-specific recombination. Both lines produce high quality, cleaved trimers at yields of up to 12-15 mg per 1 * 109 cells. Trimer expression at such levels was maintained for up to 30 days (10 passages) after initial seeding and was consistently superior to what could be achieved by transient transfection. Electron microscopy studies confirm that the purified trimers have the same native-like appearance as those derived by transient transfection and used to generate high-resolution structures. They also have appropriate antigenic properties, including the presentation of the quaternary epitope for the broadly neutralizing antibody PGT145. CONCLUSIONS: The BG505 SOSIP.664 trimer-expressing cell lines yield proteins of an appropriate quality for structural studies and animal immunogenicity experiments. The methodology is suitable for making similar lines under Good Manufacturing Practice conditions, to produce trimers for human clinical trials. Moreover, any env gene can be incorporated into this vector system, allowing the manufacture of SOSIP trimers from multiple genotypes, either by transient transfection or from stable cell lines. PMID- 24767179 TI - Clusterin silencing inhibits proliferation and reduces invasion in human laryngeal squamous carcinoma cells. AB - BACKGROUND: Clusterin is, in its major form, a secreted heterodimeric disulfide linked glycoprotein (sCLU), which plays important roles in cell survival and death. In laryngeal squamous cell carcinomas (LSCC), sCLU is up-regulated and its expression is related to the invasiveness of these tumors. The purpose of this study was to explore the inhibiting role of sCLU gene silence in the invasive ability and growth of Hep-2 human laryngeal squamous carcinoma cells (Hep-2) by transfection of short hairpin RNA expression plasmids against sCLU (sCLU-shRNA) (in vivo) or small interference RNA (sCLU-siRNA) (in vitro). METHODS: sCLU-siRNA and the control siRNA were transfected into Hep-2 cells using Lipofectamine 2000. RT-PCR and Western blot were used to detect the effect of siRNA transfection on sCLU mRNA and sCLU protein expression. The invasive activity of sCLU-siRNA transfected Hep-2 cells was measured with the modified Boyden chamber assay and wound healing assay. The effects of sCLU-siRNA on cell proliferation were evaluated by MTT assay. Apoptosis was measured by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double-staining methods. We next evaluated the effects of sCLU silencing by sCLU-shRNA transfection in vivo on tumor growth and metastatic properties to the lung. Terminal deoxytransferase mediated dUTP nick end labeling (TUNEL) staining was used to observe the apoptosis in the xenografts. RESULTS: It showed that siRNA-mediated down regulation of sCLU expression in Hep-2 cells significantly inhibited cell proliferation and promoted apoptosis in vitro. Furthermore, siRNA-mediated down regulation of sCLU expression decreases in vitro cell migration and invasion ability. In vivo, the average volume of tumors in the sCLU-shRNA transfected group was significantly lower than in the control group (P<0.01), and the significant apoptosis detected with TUNEL was indicated in the sCLU-shRNA transfected groups (P<0.05). Significantly, we found that sCLU-shRNA could exert marked inhibition of the lung metastasis of Hep-2 cells in nude mice in vivo. CONCLUSIONS: sCLU gene silence can inhibit invasion and growth of LSCC. sCLU may provide a potential therapeutic target against human LSCC. PMID- 24767180 TI - The compulsive habit of cars. AB - The car dependence of people living in contemporary cities is a major concern for policy makers, who often find it difficult to persuade people into more sustainable transport modes. By contrast, recent insights from neuroscience have shown that a broad spectrum of behaviors can become habitual and, thus, resistant to change. Here, we outline the potential of collaboration between neuroscience and human geography aiming at a better understanding of habits that determine everyday commuting routines. PMID- 24767181 TI - Are skin diseases systemic ones?: I. PMID- 24767182 TI - Psoriasis as a systemic disease. AB - Psoriasis is an inflammatory immune-mediated disease that affects the skin and has pathogenic effects with systemic impact. The relationship between psoriasis and comorbidities remains controversial. The hypothesis of a causative role of psoriasis in its cardiovascular and metabolic comorbidities is based on pathophysiologic concepts establishing a link between chronic inflammation in psoriasis, endothelial dysfunction, formation of atherosclerotic plaques, and the different compounds of metabolic syndrome. Psoriasis management has to be multidisciplinary. It implicates identification and treatment of psychological disorders, addictions, and associated cardiovascular and metabolic diseases, together with improvement of quality of life of patients. PMID- 24767183 TI - Sarcoidosis as a systemic disease. AB - Sarcoidosis is a systemic disease, where for the abnormal localized collections of chronic inflammatory cells, the granuloma is cardinal, which may result in the formation of nodule(s) in the tissue of any organ of the body, with lungs and lymph nodes involvement being the most common. The granulomas are nonnecrotizing. The disease may either be asymptomatic or chronic. Its onset is gradual and may improve or clear up spontaneously. Clinical features of specific and nonspecific cutaneous lesions are described, emphasizing their role as a prelude to its systemic manifestations, afflicting respiratory, liver, spleen, musculoskeletal, ocular, cardiac, and neurologic systems. The salient briefs of diagnostic procedures are outlined, in addition to historical background and etiopathogenesis. Several currently available treatment modalities are outlined for instant reference. PMID- 24767184 TI - Autoimmune blistering dermatoses as systemic diseases. AB - Autoimmune blistering dermatoses are examples of skin-specific autoimmune disorders that can sometimes represent the cutaneous manifestation of a multiorgan disease due to potential common pathogenic mechanisms. As soon as a distinct autoimmune blistering dermatosis is diagnosed, it is imperative to consider its potential systemic involvement, as well as the autoimmune and inflammatory conditions that are frequently associated with it. In paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome, the internal organs (particularly the lungs) are affected by the autoimmune injury. Pemphigus erythematosus may manifest with overlapping serologic and immunohistologic features of lupus erythematosus. In patients with bullous pemphigoid, there is a greater prevalence of neurologic disease, possibly caused by cross-reactivity of the autoantibodies with isoforms of bullous pemphigoid antigens expressed in the skin and brain. Anti-laminin 332 pemphigoid shows an increased risk for adenocarcinomas. Patients with anti-p200 pemphigoid often suffer from psoriasis. A rare form of pemphigoid with antibodies against the alpha5 chain of type IV collagen is characterized by underlying nephropathia. Particularly interesting is the association of linear IgA disease or epidermolysis bullosa acquisita with inflammatory bowel disease. Dermatitis herpetiformis is currently regarded as the skin manifestation of gluten sensitivity. Bullous systemic lupus erythematosus is part of the clinical spectrum of systemic lupus erythematosus, a prototypic autoimmune disease with multisystem involvement. PMID- 24767185 TI - Neutrophilic dermatoses as systemic diseases. AB - Neutrophilic dermatoses (ND) are inflammatory skin conditions characterized by a sterile infiltrate of normal polymorphonuclear leukocytes. The main clinical forms of ND include Sweet syndrome, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and their atypical or transitional forms. ND are often idiopathic, but they may be associated with myeloid hematologic malignancies (Sweet syndrome), inflammatory bowel disease or rheumatoid arthritis (pyoderma gangrenosum), and monoclonal gammopathies (erythema elevatum diutinum, subcorneal pustular dermatosis). The possible infiltration of internal organs with neutrophils during the setting of ND underlies the concept of a neutrophilic systemic disease. ND may be seen as a polygenic autoinflammatory syndrome due to their frequent association with other autoinflammatory disorders (monogenic or polygenic) and the recent published efficacy of interleukin-1 blocking therapies in their management. PMID- 24767186 TI - Acne as a chronic systemic disease. AB - Acne is the most common skin disorder. In the majority of cases, acne is a disease that changes its skin distribution and severity over time; moreover, it can be a physically (scar development) and psychologically damaging condition that lasts for years. According to its clinical characteristics, it can be defined as a chronic disease according to the World Health Organization criteria. Acne is also a cardinal component of many systemic diseases or syndromes, such as congenital adrenal hyperplasia, seborrhea-acne-hirsutism-androgenetic alopecia syndrome, polycystic ovarian syndrome, hyperandrogenism-insulin resistance acanthosis nigricans syndrome, Apert syndrome, synovitis-acne-pustulosis hyperostosis-osteitis syndrome, and pyogenic arthritis-pyoderma gangrenosum-acne syndrome. Recent studies on the Ache hunter gatherers of Paraguay detected the lack of acne in association with markedly lower rates of obesity, diabetes mellitus, hyperlipidemia, and cardiovascular diseases, a finding that indicates either a nutritional or a genetic background of this impressive concomitance. PMID- 24767187 TI - Hidradenitis suppurrativa (acne inversa) as a systemic disease. AB - Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic follicular occlusive skin disorder characterized by recurrent abscesses, draining sinuses, and scarring, with a multifactorial pathogenesis. The answer to the question whether HS may be considered a systemic disease relies on the presence of accompanying systemic manifestations, on the proof of association with other diseases or conditions, and on the occurrence of systemic implications. We address these questions based on a systemic review of the existing literature. There are several reports in the literature of the coexistence of HS with other diseases, including pyoderma gangrenosum, PASH syndrome, Adamantiades-Behcet's disease, spondylarthropathy, Crohn's disease, SAPHO, pachyonychia congenita, Dowling-Degos disease, and the keratitis-ichthyosis-deafness (KID) syndrome. Case series exist only for Crohn's disease, while most other reports are anecdotal, thus, not providing high-quality scientific evidence. Based on well-designed studies, HS has been associated with the metabolic syndrome and with excess body weight or obesity. The link between HS and systemic associations may be attributed to common genetic or environmental factors or shared inflammatory pathways. PMID- 24767188 TI - Atopic dermatitis as a systemic disease. AB - Atopic dermatitis (AD) is a chronic inflammatory disease that seriously affects the quality of life of these patients. Both immune deviations and epidermal barrier deficiency have been defined as pathophysiologic mechanisms in the disease development. The atopic march, or the natural progression form atopic dermatitis in infancy to asthma and allergic rhinitis, is a classic example for the multiorgan involvement in atopy. It has been hypothesized that epidermal barrier impairment is the primary pathologic condition responsible for the atopic march. In recent decades, a growing body of evidence has accumulated that AD can be accompanied by a variety of systemic diseases, such as autoimmune disorders, ophthalmologic involvement, eosinophilic gastroenteritis, inflammatory bowel disease, nephritic syndrome, and metabolic diseases. This contribution reviews these associations and focuses on the possible common underlying mechanisms of AD and the associated syndromes. We present a concept on AD as a multiorgan systemic disease. PMID- 24767189 TI - Contact dermatitis as a systemic disease. AB - Systemic contact dermatitis (SCD) is a condition occurring in previously sensitized individuals after systemic re-exposure to the same or cross-reacting substance. Systemic route of administration means uptake of an allergen via percutaneous, transmucosal, oral, intravenous, intramuscular, and inhalational routes, as well as through implants. The intimate mechanisms behind SCD are not yet fully understood, but it is thought to be a T-cell mediated delayed type hypersensitivity reaction. The most common allergens recognized to date are nickel, aminoglycoside antibiotics, corticosteroids, balsam of Peru, and plants from the Anacardiacae and Compositae families. The most typical presentation of SCD, known as baboon syndrome, includes diffuse erythema of the buttocks, the upper inner surface of the thighs, and the axillary folds. Cases with the classical baboon pattern of distribution elicited by systemically introduced drugs without previous sensitization are encompassed by the acronym SDRIFE (Symmetric Drug-related Intertriginous and Flexural Exanthema). Interestingly, corticosteroids, although widely applied for anaphylaxis and other allergic conditions, can produce sensitization, and they are commonly mentioned as triggers of SCD. PMID- 24767190 TI - Chronic urticaria as a systemic disease. AB - Urticaria is one of the most common diseases seen in everyday dermatologic practice, characterized by the development of wheals, angioedema, or both. While acute urticaria is mostly related to allergic or pseudoallergic reaction to food, drugs, or infections, chronic urticaria is a more complex disease with different additional ethiopathologic mechanisms and evoking factors. While urticaria is an undisputed disease of the skin, growing evidence supports, like in other dermatologic diseases, the concept of urticaria as a systemic disease with clinical symptoms and signs predominantly presenting on the skin. In this review, we describe the evidence and association between chronic urticaria and a variety of disorders, such as autoimmune diseases, atopy, infections, metabolic conditions, and neoplastic disorders. Beyond the mechanistic association, the possible common underlying pathomechanisms, such as systemic immunologic processes, are discussed. PMID- 24767191 TI - Herpes zoster as a systemic disease. AB - Herpes zoster (shingles, zona) is a viral infection commonly affliccting the skin and the nervous system with an overall occurring rate of 3 to 5 cases per 1000 persons per year, with higher rates in middle or later life. With the advancement of medicine, more and more case reports have started to emerge showing different incidences of VZV, some new localizations, clinical presentations, and complications, which break the well-known fact that "VZV affects the skin and nervous system." Skin lesions are the most important ones for the early and exact diagnosis of herpes zoster (HZ), due to its visibility and well-defined clinical picture of lesions. The most frequent condition following the acute herpes zoster eruption is postherapeutic neuralgia (PHN). There have been other reports of the disease with otorinolaryngologic complications and ophthalmologic ones, such as ophthalmoparesis/plegia. There have also been reports of delayed contralateral hemiparesis/hemiplegia following the infection, as a manifestation of vaculitis due to a direct VZV invasion of the cerebral arteries. Encephalitis and destructive myelitis is similarly rare, but a serious complication. Some authors found that patients with inflammatory bowel disease are at a significantly increased risk for herpes zoster. As a gastroenterologic complication, there have been several instances of HZV infection with symptoms resembling an acute abdomen. The diagnosis is hard to pinpoint, and a vast array of examinations are required to identify it, sometimes even posthumously. Nephrologic representations and complications have also been reported. With more and more skin diseases being acknowledged as systemic ones, this viral infection is a more likely candidate for the same title. PMID- 24767192 TI - Vitiligo as a systemic disease. AB - Vitiligo is an acquired depigmentary skin disorder of unknown etiology. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located on various parts of the body. The involvement of skin melanocytes is the most visible one, but a systemic involvement of melanocytes can be observed. Some types of vitiligo (nonsegmental vitiligo) may also be associated with various diseases, mainly with autoimmune pathogenesis. Vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses, causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement. PMID- 24767193 TI - Behcet's disease as a systemic disease. AB - Behcet's disease usually begins with cutaneous manifestations, such as recurrent aphthous stomatitis, genital ulcers, erythema nodosum-like lesions, papulopustular findings, and pathergy phenomenon. Recurrent aphthous stomatitis is generally the first sign, and other findings may develop in the course of the disease. There is no specific diagnostic available for Behcet's disease. It is most prevalent among patients along the ancient Silk Road. The high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors. Behcet's disease usually appears in the third to fourth decade of life, and is rarely seen in children and adults over 50 years of age. It affects both genders equally, but the course of the disease is more severe in men. Eye involvement leading to loss of vision, plus vascular, articular, and central nervous system involvement are more commonly observed among men. Behcet's disease is a systemic inflammatory disorder. A complex genetic background, coupled with innate and adaptive immune system activation, causes the diverse clinical manifestations that characterize the clinical picture. PMID- 24767194 TI - Improving patients' satisfaction with care. PMID- 24767195 TI - MGuard(r) stent retrieval after failed implantation and withdrawal. AB - SUMMARY: We present two cases of right coronary artery occlusion in which MGuard(r) stent implantation failed for different causes, leading to a retrieval procedure adapted to the situation. Complete retrieval was possible in both cases. These cases illustrate the need for careful selection of the lesions that are going to be treated with this type of stent, for which pre-dilatation is recommended in severe lesions located just after an acute vessel angle, the evaluation of proximal angulation and calcification, as well as strategies for complete retrieval in case of implantation failure. PMID- 24767196 TI - [Chronic obstructive pulmonary disease and lung cancer: A dangerous combination?]. PMID- 24767198 TI - [Improve the diagnosis and treatment of acute kidney injury]. PMID- 24767197 TI - Neighborhood socioeconomic position and tuberculosis transmission: a retrospective cohort study. AB - BACKGROUND: Current understanding of tuberculosis (TB) genotype clustering in the US is based on individual risk factors. This study sought to identify whether area-based socioeconomic status (SES) was associated with genotypic clustering among culture-confirmed TB cases. METHODS: A retrospective cohort analysis was performed on data collected on persons with incident TB in King County, Washington, 2004-2008. Multilevel models were used to identify the relationship between area-level SES at the block group level and clustering utilizing a socioeconomic position index (SEP). RESULTS: Of 519 patients with a known genotyping result and block group, 212 (41%) of isolates clustered genotypically. Analyses suggested an association between lower area-based SES and increased recent TB transmission, particularly among US-born populations. Models in which community characteristics were measured at the block group level demonstrated that lower area-based SEP was positively associated with genotypic clustering after controlling for individual covariates. However, the trend in higher clustering odds with lower SEP index quartile diminished when additional block group covariates. CONCLUSIONS: Results stress the need for TB control interventions that take area-based measures into account, with particular focus on poor neighborhoods. Interventions based on area-based characteristics, such as improving case finding strategies, utilizing location-based screening and addressing social inequalities, could reduce recent rates of transmission. PMID- 24767199 TI - [Q fever endocarditis-a neglected pathogen of blood culture negative endocarditis]. PMID- 24767200 TI - [Standardization of management of malignant pleural effusion]. PMID- 24767201 TI - [The correlation of anemia and contrast-induced nephropathy in patients with chronic kidney disease undergoing percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the correlation of anemia and contrast-induced nephropathy (CIN) in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). METHODS: A total of 292 patients with CKD undergoing PCI admitted to Guangdong General Hospital from October 2010 to December 2012 were consecutively enrolled in this study. Anemia was defined as hemoglobin <130 g/L in male and <120 g/L in female. All patients were divided into the following two groups by their preoperative hemoglobin: anemic group (n = 101) and non-anemic group (n = 191). The incidence of CIN and other major adverse cardiac events in hospital were evaluated. The correlation between CIN and anemia was evaluated by multivariate logistic regression analysis. RESULTS: The incidence rates of CIN were 9.9% (29/292) in all subjects, 17.8% (18/101) in the anemic group and 5.8% (11/191) in the non-anemic group. Compared with the non anemic group, more patients in the anemic group required renal replacement therapy and intra-aortic balloon pump therapy, mechanical ventilation and manifested as acute heart failure (4.0% vs 0.0%, P = 0.006; 9.9% vs 1.0%, P < 0.001; 3.0% vs 0.0%, P = 0.017; 5.9% vs 1.0%, P = 0.015; respectively). Adjusted for age >75 years, basic renal function and the history of diabetic mellitus in the logistic regression analysis, anemia remained as a significant and independent risk predictor for CIN in patients with CKD (OR = 2.7, 95%CI 1.2-6.3, P = 0.017). CONCLUSIONS: Pre-procedure anemia is a significant and independent predictor of CIN in patients with CKD undergoing PCI. Caution and treatment for the pre-procedure anemia could be very useful for the prevention of CIN in those patients. PMID- 24767202 TI - [The incidence and risk factors of acute renal injury in patients with multiple soft tissue injuries]. AB - OBJECTIVE: To investigate the incidence and risk factors of acute kidney injury (AKI) in patients with multiple soft tissue contusion. METHODS: A total of 513 patients diagnosed as multiple soft tissue contusion in the First Affiliated Hospital of Xinjiang Medical University from January 1, 2008 to January 1, 2013 were retrospectively analyzed. Demographics, clinical data and laboratory examinations before and after AKI were collected and analyzed. RESULTS: The age of all subjects was 31.30(12-78) years old with the male to female ratio of 2.1: 1. AKI occurred in 74 cases with an incidence rate of 14.4%. No AKI was observed in patients with assault injuries, while AKI was found in 27 cases (36.5%) with car accident injuries and 4 cases (5.4%) with other injuries. AKI showed in 1 case(1.4%) with damaged area under 1%, in 4 cases (5.4%) with damaged area ranged from 1% to <3%, 10 cases (13.5%) with damaged area ranged from 3% to 5% and 19 cases (25.7%) with damaged area over 5% with significant difference among the groups (P < 0.01). Incidence rate of AKI was significantly higher in patients with chronic kidney disease (CKD) than those without CKD (54.5% vs 20.3%, P < 0.01). Two of the AKI cases died, with a mortality rate of 2.7%. Multivariate logistic regression analysis showed that the followings were the independent risk factors for the occurrence of AKI in patients with multiple soft tissue injuries: age (OR = 1.996), basic serum creatinine (OR = 0.976), basic evaluated GFR (eGFR) (OR = 0.964), serum potassium (OR = 2.117), myoglobin (OR = 0.950) and damaged area (OR = 1.811). CONCLUSIONS: Incidence rate of AKI is quite high in multiple soft tissue contusion. Age, basic serum creatinine, basic eGFR, serum potassium, myoglobin and damaged area are the independent risk factors for the occurrence of AKI in patients with multiple soft tissue injury. PMID- 24767203 TI - [The incidence of aspirin resistance and relevant influencing factors in patients on maintenance hemodialysis]. AB - OBJECTIVE: To explore aspirin resistance (AR) and its relevant influencing factors in patients on maintenance hemodialysis (MHD). METHODS: Patients on MHD who visited Beijing Chaoyang Hospital from June 1 to 30, 2011 were enrolled in this study. A total of 150 age and gender matched individuals with normal renal function were taken as control group. Anthropometric data, biochemistry parameters, ultrasonography and thromboelastograph (TEG) were inspected in the both groups. AR was defined as inhibiting rate of acetylsalicylic acid drugs [MA(AA)]>50% by TEG. RESULTS: Among the total 391 patients on MHD, hypercoagulation was found in 18 patients (4.6%), normal coagulation in 288 patients (73.7%) and hypocoagulation in 85 patients (21.7%). Pearson's correlation analysis revealed that the reaction time (R) and the thrombus maxithrombelastic degree (MA) values were not correlated with the levels of hemoglobin and platelet in MHD patients. A total of 306 patients with hypercoagulation and normal coagulation were chosen as the MHD group. Compared with the control group, higher high sensitivity C reactive protein (hsCRP), homocysteine (Hcy) and R value were observed in the MHD group (P < 0.05), while MA was significantly lower in the MHD group. Statistically higher incidence of AR was shown in the MHD group (48.0% vs 20.0%, P = 0.00). Patients in the MHD group were divided into the AR group and the aspirin sensitive (AS) group by the result of TEG. Compared with the AS group, patients in the AR group were found to be older with a higher female/male ratio, longer dialysis sustained time, higher ratio of diabetes history, higher hsCRP, Hcy and fasting blood glucose (FBG) and MA. They also manifested a higher incidence of cardiovascular and cerebrovascular diseases, peripheral vascular disease and arteriovenous fistulas with thrombosis with more spots of carotid artery and higher intima thickness of carotid artery (IMT) (all P values<0.05). Lower R value was shown in the AR group. Binary logistic regressive analysis revealed that the ratio of diabetes history, age and dialysis sustained time. Hcy and hsCRP were the independent risk factors for AR in patients on MHD. A total of 289 patients on MHD with atherosclerosis were followed up for the mean time of 18.0 months with no hemorrhage found in the process. Cox proportional hazards regression modeling demonstrated that AR was associated with the major adverse long-term outcome of the vascular events [HR = 0.40, 95%CI 0.29-0.72, P = 0.00]. CONCLUSIONS: The ratio of platelet activation in patients on MHD is significantly lower than in those with normal renal function. Small dose of aspirin could be prescribed for the patients on MHD with atherosclerosis to prevent vascular events. The incidence of AR is 48.0% in the MHD group and the independent risk factors for AR in MHD patients are the ratio of diabetes history, age, dialysis sustained time, Hcy and hsCRP. AR is associated with the major adverse long-term outcome of acute vascular events. PMID- 24767204 TI - [Q fever endocarditis: a report of four cases and literature review]. AB - OBJECTIVE: To improve the diagnosis and treatment of Q fever endocarditis. METHODS: From 2008 to 2013, four cases of Q fever endocarditis were diagnosed in Peking Union Medical College Hospital. Clinical features, laboratory test, management and prognosis were analyzed with literature review. RESULT: All four cases had long period of fever and heart murmur. Two patients represented with respiratory symptom and one with non-specific rash. General laboratory tests including complete blood cell count, ESR, C-reactive protein(CRP), liver function and radiology of lung did not show specific abnormalities. Signs of endocarditis were shown by ultrasound and important for diagnosis. Repeated blood culture was negative. All of the diagnoses were confirmed by serum antibody detection and the patients recovered well with treatment based on doxycycline or minocycline. CONCLUSIONS: Endocarditis is the most common form of chronic Q fever, which is easily misdiagnosed because its blood culture is negative and may accompanied with varied manifestation such as pneumonia and liver injury. For the patients with chronic fever and blood culture negative endocarditis, chronic Q fever should be considered as differential diagnosis. The confirmatory method for diagnosis is serum antibody detection. Early and sufficient treatment may improve the prognosis. PMID- 24767205 TI - [The efficacy and safety of methotrexate in refractory Crohn's disease]. AB - OBJECTIVE: To assess the efficacy and safety of methotrexate(MTX) on refractory Crohn's disease(CD). METHODS: A total of 35 consecutive refractory CD patients in the First Affiliated Hospital of Sun Yat-Sen University treated with MTX were retrospectively analyzed. Clinical data from June 2004 to December 2012 were collected from the database of inflammatory bowel disease (IBD) center. Clinical responses and drug side effects were recorded and analyzed. RESULTS: Thirty-five refractory CD patients were identified including 23 cases intolerant to azathioprine (AZA)/6-mercaptopurine(6-MP), six cases ineffective to AZA/6-MP, 19 cases dependent on steroid. After treatment of MTX for 12 weeks [15(5-20) mg/week], a clinical response was obtained in 80% patients (28/35), including 51.4% (18/35) in remission and 28.6% (10/35) in improvement. The median Crohn's disease activity index (CDAI) scores at the onset and 12 weeks after MTX therapy were 99.2 (75.8, 174.7) and 61.5 (36.0, 106.6) respectively. The median single dose and duration of MTX were 15 (5-20) mg/week and 6.0(0.5-53.0) months respectively. The median cumulative dose was 480 (20-2615) mg. Among the 26 patients dependent on steroid, 21 achieved discontinuation of steroid with a median time of 10 (6-20) weeks after treatment of MTX. Side effects were recorded in 12 patients (34.3%), but usually mild and improved after drug with drawal. CONCLUSIONS: MTX is an effective and steroid-sparing agent for refractory CD. Side effects of MTX are mild and tolerable. PMID- 24767206 TI - [The effects of tirofiban on acute non-ST segment elevation myocardial infarction patients not receiving early reperfusion intervention]. AB - OBJECTIVE: To study the efficacy and safety of tirofiban in patients with acute non-ST- segment elevation myocardial infarction (NSTEMI) without early reperfusion intervention. METHODS: A total of 151 NSTEMI patients without early reperfusion intervention were enrolled in the study and randomized to the tirofiban group (n = 76) and the control group(n = 75). Coronary angiography was performed at day 3 and day 7, while percutaneous coronary intervention (PCI) was performed when necessary. Parameters including thrombolysis in myocardial infarction (TIMI) flow, bleeding complications and clinic events within 30 days were compared between the two groups. RESULTS: Before PCI, no increase in the percentage of patient with TIMI flow better than TIMI-2 was observed by the treatment of tirofiban (69.3% vs 78.9%, P = 0.10). While after PCI, significant increase in the percentage of patient with TIMI flow better than TIMI-2 was manifested in the tirofiban group (96.0% vs 100.0%, P = 0.04). Tirofiban treatment also significantly decreased the rate of poor myocardial perfusion after PCI (19.7% vs 34.7%, P = 0.04). There were 0 and 4 major adverse cardiovascular events (MACE) within 30 days observed in the tirofiban group and the control group (0.0% vs 5.3%, P = 0.05). No difference between the two groups was found in the bleeding complications within 30 days including the mild hemorrhage (5 vs 4 cases, P = 0.75), severe hemorrhage (2 vs 1 cases, P = 0.56) or severe thrombocytopenia (2 vs 0 cases, P = 0.49). CONCLUSIONS: Tirofiban treatment does not increase the bleeding complications in NSTEMI patients without early PCI. Tirofiban can improve the TIMI flow and the myocardial perfusion after PCI with less MACE within 30 days. PMID- 24767207 TI - [The correlation study of liver enzymes level and risk of type 2 diabetes]. AB - OBJECTIVE: To investigate the correlation between serum liver enzymes and onset of type 2 diabetes mellitus (T2DM). METHODS: A total of 8 779 individuals subjected to a Zhengzhou community survey were enrolled in the study and were tested for the following serum biochemical parameters, including ALT, AST, gamma glutamyl transferase (GGT), TC, TG and blood glucose. All subjects were divided into four groups (Q1-Q4) according to the quartiles of their liver enzyme levels. Logistic regression was performed to explore the odd ratio (OR) for the onset of T2DM in groups of Q2-Q4 compared with the group of Q1.ROC curve was used to analyze the predictive value of elevated liver enzymes for the onset of T2DM. RESULTS: When the quartiles were defined by the GGT level, compared with the group of Q1, the OR for the group of Q4 was 4.043 (95%CI 2.759-5.924) in the male and 4.239 (95%CI 3.172-5.664) in the female, which was higher than the OR when the quartiles were defined by the ALT level. In the ROC curve, the AUC of GGT was larger than those of ALT, AST, BMI, waist circumference and TG, with 0.63 for the male and 0.68 for the female. CONCLUSIONS: Serum level of GGT is more closely correlated with the onset of T2MD than the level of ALT or AST. Even the increase of serum GGT within physiological range is a risk factor for the onset of T2DM. PMID- 24767208 TI - [The etiology of neurological disorders in 1 188 elder patients with neuroimaging at geriatric outpatient clinic]. AB - OBJECTIVE: To investigate the etiology of neurological disorders in elderly at outpatient clinic. METHODS: Elderly patients aged 60 years old or more who visited the geriatric neurological outpatient clinic of PLA General Hospital from July 1, 2009 to June 30, 2012 and underwent the brain MRI or CT imaging were retrospectively analyzed. The constituent ratio of common neurological disorders in all patients and patients from different age groups were statistically analyzed based on the information from PRIDE data management system. RESULTS: A total of 1 188 patients were enrolled in this study with well documented record of complaint examination of the nerve system and brain MRI or CT imaging. Common neurological disorders in those patients were cerebrovascular disease(22.39%), mild cognitive impairment and dementia (15.99%), movement disorders including Parkinson disease, Parkinsonism and essential tremor(9.09%), sleep disorders (6.73%) and psychological diseases(6.65%). Spinal degenerative diseases accompanied by neurological symptoms also accounted for 10.52%. Less common causes in those patients were benign paroxysmal positioning vertigo(3.96%), headache and neck pain (3.28%), cranial nerve diseases (2.78%) and intracranial tumors (2.61%). Constituent ratios of mild cognitive impairment and dementia in different age groups were associated with aging, and the same was observed with Parkinson disease. CONCLUSION: The common neurological disorders in the geriatric outpatients are cerebrovascular disease and neurodegenerative diseases including different type of dementia and Parkinson disease. Those disorders should be focused for the prevention and treatment of the nervous system diseases in the elderly. PMID- 24767209 TI - [A clinical analysis of eight proven cases of pulmonary mucormycosis]. AB - OBJECTIVE: To improve the understanding of pulmonary mucormycosis by analyzing the clinical manifestations, imaging features, diagnosis, treatment and prognosis of this disease. METHODS: The clinical data of eight patients diagnosed as pulmonary mucormycosis by histopathologic examination were retrospectively analyzed. RESULTS: Eight patients included six males and two females with age from 36 days to 66 years. Underlying conditions covered diabetes (n = 4), renal transplantation (n = 3), premature (n = 1) and long-term corticosteroid treatment in two cases. Imaging manifestations revealed multiple irregular lumps or nodules in three cases, multiple cavities with thick wall in three cases, diffuse lung infiltrate in one case and lung opacities in one case. The diagnoses of seven patients were confirmed by percutaneous needle lung biopsy and the remaining one was diagnosed with fiberoptic bronchoscopy biopsy. Surgery combined with amphotericin B liposome (60 mg/d for three weeks) was applied to one patient who was cured with no recurrence after a 22 month follow-up. Three cases were given amphotericin B liposome (a newborn with 7mg/d for 62 days, the other two 60 mg/d for 31 days and 70 mg/d for 71 days respectively). All had achieved marked response with follow up from 8 to 29 months, but one patient relapsed and died of recurrent lung mucormycosis. The other three patients were treated with itraconazole 400-200 mg/d from 21 days to 1 year with duration of follow up from 1 month to 20 months. One patient was not evaluable due to missing. Two patients relapsed and one died. CONCLUSION: Pulmonary mucormycosis is difficult to diagnose and treat with a high mortality. Percutaneous transthoracic lung biopsy is a useful diagnostic method. Amphotericin B liposome or itraconazole may be active against mucus. Early control of causes is essential to improve the prognosis and reduce the recurrence in patients with pulmonary mucormycosis. PMID- 24767212 TI - Ocular inflammatory disease in Canadian First Nations communities. PMID- 24767210 TI - Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A. AB - The complex genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, including transcripts regulated by either transforming growth factor, beta 1 (TGFbeta1) pathways, or microphthalmia-associated transcription factor (MITF)/SRY box containing gene 10 (SOX10) pathways. We extended this knowledge by discovering that melanoma cell lines with these two expression programs exhibit distinctive microRNA (miRNA) expression patterns. We also demonstrated that hypoxia-inducible factor 1 alpha (HIF1A) is increased in TGFbeta1 pathway expressing melanoma cells and that HIF1A upregulates miR-210, miR-218, miR-224, and miR-452. Reduced expression of these four miRNAs in TGFbeta1 pathway expressing melanoma cells arrests the cell cycle, while their overexpression in mouse melanoma cells increases the expression of the hypoxic response gene Bnip3. Taken together, these data suggest that HIF1A may regulate some of the gene expression and biological behavior of TGFbeta1 pathway-expressing melanoma cells, in part via alterations in these four miRNAs. PMID- 24767213 TI - Managing new antiplatelet and anticoagulant agents in the context of oculoplastic and orbital surgery. PMID- 24767216 TI - Analysis of uveitis in a Canadian aboriginal population. AB - OBJECTIVE: To compare patient demographics, uveitis characteristics, and outcomes in aboriginal First Nations (FN) versus non-aboriginal non-FN uveitis patients. DESIGN: Case-control study. PARTICIPANTS: Forty-three FN patients (80 eyes) and 45 control non-FN uveitis patients (69 eyes). METHODS: Retrospective chart review comparing patient demographics (age, sex, residency), disease characteristics (laterality, anatomic classifications, granulomatous and chronic inflammation, systemic associations, specific uveitis diagnoses), and disease severity-related outcomes (therapies, visual outcomes, complications) between FN versus control patients. RESULTS: Mean age at disease onset was significantly younger in FN patients (30.4 years) versus control patients (40.2 years; p < 0.0001). Bilateral uveitis was significantly more common in the FN group (86%) versus control patients (51%; p = 0.0005), and granulomatous uveitis was significantly more common in FN patients (53%) than among control patients (11%; p < 0.0001). There was no significant difference in rates of chronic uveitis between groups, identified in 74% of FN versus 60% of control subjects (p = 0.15). Anatomically, panuveitis was the prevalent form of uveitis within the FN group, occurring in 67% (versus 16% in control patients), whereas anterior uveitis was the prevalent anatomic classification in control patients, occurring in 73% (versus 26% in FN patients; p < 0.001). Vogt-Koyanagi-Harada (VKH) syndrome was the predominant causative uveitis diagnosis within the FN group, identified in 56% of FN patients versus 0% of control subjects (p < 0.001). Idiopathic uveitis was the predominant causative diagnosis within the control group and was identified in 40% of control patients, compared with 19% of FN uveitis patients (p = 0.002). All therapies except anterior segment surgeries (p = 0.88) were required more often in FN, including systemic corticosteroids (p = 0.002), injected corticosteroids (p = 0.042), systemic immunosuppression (p = 0.021), glaucoma therapy (p = 0.005), laser (p < 0.001), and posterior segment surgeries (p = 0.002). Complication rates were higher in FN patients (p < 0.001). Final visual outcome was worse in FN patients (35% FN <= 20/200 versus 9% control subjects; p = 0.001). CONCLUSIONS: Multiple findings differed strikingly between FN and control patients. Uveitis in FN patients was characterized by significantly younger age of onset. FN patients were more likely to have bilateral disease, panuveitis, and granulomatous disease. With respect to specific uveitic entities, VKH was more common in FN patients. FN patients also required more aggressive therapies, and yet had higher complication rates and had poorer visual outcomes. PMID- 24767215 TI - New oral anticoagulants and oculoplastic surgery. AB - The use of oral anticoagulants is increasing because of the rising prevalence of atrial fibrillation and other cardiovascular diseases that occur in an aging population. In the last decade, several new oral anticoagulants have emerged, comprising the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban and rivaroxaban. Although these new anticoagulants may not affect clear corneal cataract surgery, their use will impact the management of patients having eyelid, orbital, and nasolacrimal procedures. The objective of this review is to provide a concise and practical approach to the perioperative management of patients who require an oculoplastic procedure and are receiving these new anticoagulants. PMID- 24767217 TI - Northern Alberta remote teleglaucoma program: clinical outcomes and patient disposition. AB - OBJECTIVE: To review the diagnostic outcomes and clinical referral pathways of patients assessed and managed through a collaborative care patient-centred teleglaucoma program. STUDY DESIGN: Retrospective cohort study. METHODS: Eligible patients were those assessed by the referring optometrist or ophthalmologist to be open-angle glaucoma suspects or to have definite early open-angle glaucoma. A glaucoma specialist graded each case through virtual consultation. Clinical referral pathways were noted: in-person consultation with glaucoma specialist, repeat teleconsultation, collaborative glaucoma management with optometrist, or referral for nonglaucomatous ophthalmic pathology. RESULTS: A total of 247 patients were referred to the program from 2008 to 2012. Of all teleconsults, 31.1% were diagnosed with glaucoma, 42.1% were suspects, and 26.7% were unaffected. Of all patients, 27% were referred for in-person glaucoma evaluation; 69% of patients could be managed by their referring optometrist, with 48% of patients requiring repeat teleconsultation. Treatment was initiated before being seen for 87% of patients with definite glaucoma and 28% of glaucoma suspects. CONCLUSIONS: Of all patients seen through the remote teleglaucoma program, most did not require an in-person consultation with an ophthalmologist and could be managed through distance collaboration. For the approximately one third who were diagnosed with glaucoma based on virtual assessment, medication was started in the majority of cases and in-person consultation was arranged. Further studies to validate and consider cost-effectiveness of this system are under way. PMID- 24767218 TI - Effects of sub-Tenon's anaesthesia on ocular hemodynamics. AB - OBJECTIVE: To research the effects of sub-Tenon's anaesthesia (STA) on ocular hemodynamics in patients with cataract using colour Doppler imaging (CDI). DESIGN: Prospective clinical study. PARTICIPANTS: Thirty-four eyes of 34 patients with age-related cataract. METHODS: Peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) values of the ophthalmic artery (OA), central retinal artery, and central retinal vein were measured by CDI before and immediately after performing sub-Tenon block using 2 mL of 2% lidocaine with adrenaline (1:200 000). RESULTS: Both PSV and EDV values were significantly decreased after sub-Tenon injection in all the studied vessels of the patients. However, no important changes were observed in the RI values of the vessels. CONCLUSIONS: STA markedly reduced ocular blood flow. The reduction may be more acceptable compared with other retrobulbar block methods. Sub-Tenon block should be performed carefully to senile patients with cataract with vascular occlusive disorder. PMID- 24767219 TI - Surgical outcomes of isolated lens coloboma with or without cataract among young adults. AB - OBJECTIVE: To evaluate the visual and refractive outcomes after phacoemulsification surgery in eyes with isolated lens coloboma. DESIGN: Prospective, consecutive case series. PARTICIPANTS: Eighteen eyes with isolated lens coloboma of 13 patients were included in the study. Mean patient age was 13.9 +/- 6.5 years. METHODS: Patients underwent phacoemulsification surgery, with combined implantation of capsular tension ring (CTR) and intraocular lens. In colobomas of less than 120 degrees , a CTR was used, whereas in colobomas of more than 120 degrees , a Cionni-modified single eyelet CTR was used to achieve better capsular centration. The main outcome measures were uncorrected distance visual acuity, corrected distance visual acuity, refraction, and keratometry. RESULTS: Mean logMAR uncorrected distance visual acuity and corrected distance visual acuity improved significantly from 1.53 +/- 0.35 and 1.02 +/- 0.47 before surgery to 0.67 +/- 0.51 and 0.52 +/- 0.49 at the last visit of the follow-up (p < 0.001). Mean refractive cylinder and spherical equivalent decreased significantly from -6.73 +/- 1.73 and -6.72 +/- 4.07 D preoperatively to -1.40 +/- 1.39 and 0.83 +/- 1.31 D at the end of the follow-up (p = 0.001 and p = 0.01, respectively). Mean keratometric astigmatism at preoperative and postoperative visits were 1.58 +/- 0.97 and 1.65 +/- 0.94 D, respectively (p = 0.70). CONCLUSIONS: Phacoemulsification with CTR and intraocular lens implantation is an effective and safe option for providing a refractive correction and a significant visual improvement in eyes with isolated lens coloboma. PMID- 24767220 TI - Central corneal thickness and its relationship to Parkinson's disease severity. AB - OBJECTIVE: To investigate the effect of Parkinson's disease (PD) on blink rate (BR), tear breakup time test (TBUT), Schirmer's test, and corneal thickness, and the relationship of these effects with disease severity. DESIGN: Prospective controlled study. PARTICIPANTS: Fifty-five eyes from 55 patients with PD and 40 eyes from 40 healthy subjects were analyzed in the study. METHODS: The patients were divided into 2 groups according to their Hoehn-Yahr (H-Y) scores; patients classified as H-Y 1-2 were designated as the mild group, and those classified as H-Y 3-5 were designated as the moderate group. Subjects were screened for BR, TBUT, and Schirmer's test, and the central corneal thickness (CCT) was measured. RESULTS: The BR, Schirmer's test, TBUT, and CCT values of the patient group were significantly lower than those of the control group. The BR and TBUT of the mild group were significantly lower than those of the control group, but the decreases in the Schirmer's test values and CCT were not statistically significant. In addition, significant decreases in the BR, TBUT, Schirmer's test scores, and CCT were observed in the patient group as the H-Y score increased. CONCLUSIONS: A reduced BR and poor tear quality in the early stages of PD, as well as decreased tear production as the disease progresses, can result in reduced CCT. The possibility of a thin cornea should be taken into consideration while measuring the intraocular pressure in patients with severe PD. PMID- 24767221 TI - Incidence of discordant temporal artery biopsy in the diagnosis of giant cell arteritis. AB - OBJECTIVE: We investigated the rate of discordant biopsy results (i.e., 1 side negative, 1 side positive) in patients who underwent initial bilateral temporal artery biopsies for suspected giant cell arteritis (GCA). DESIGN: A cohort study. PARTICIPANTS: Consecutive patients undergoing temporal artery biopsy were enrolled. Of the 259 patients enrolled, 250 underwent initial bilateral temporal artery biopsies. METHODS: Positive biopsies were defined based on accepted histologic definitions. Healed arteritis was considered a positive result. Clinical information was collected for all patients using a questionnaire administered by an ophthalmologist. Pathology results, including biopsy length (as measured by the pathologist), and laboratory information (i.e., serum erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP] levels) were collected from digital patient records for statistical analysis. The main outcome was the rate of discordant biopsy in consecutive patients who underwent initial bilateral temporal artery biopsy. RESULTS: Giant cell arteritis was confirmed in 62 (24.2%) of the 250 patients, including 3 patients with biopsies recorded as healed arteritis. The rate of discordant biopsy was 4.4% with 11 unilaterally positive biopsies. There was no statistical difference between the length of the left- and right-sided biopsies in either the unilaterally or bilaterally positive groups (p = 0.13 and p = 0.79, respectively). The average maximum ESR value for the bilateral group (58.7 mm/h) was significantly higher than the average maximum ESR value for the unilateral group (30.7 mm/h, p = 0.03). The average maximum CRP value for the bilateral group was 59.2 mg/L and 28.6 mg/L for the unilateral group (p = 0.30). Discordance between the localization of symptoms and the side of positive biopsy occurred in 3 patients (i.e., 3 patients had left-sided symptoms only, yet a right-sided positive biopsy). CONCLUSIONS: The rate of discordant biopsies in patients who underwent initial bilateral temporal artery biopsies was considerable in our patient cohort. Given this reasonably high rate of discordance between sides, as well as the lack of correlation between side of positivity and laterality of presenting symptoms, we recommend initial bilateral temporal artery biopsies to enhance the diagnostic certainty of the disease. PMID- 24767222 TI - Optic neuropathy in thyroid eye disease: results of the balanced decompression technique. AB - OBJECTIVE: To determine the efficacy of combined endoscopic medial and external lateral orbital decompression for the treatment of compressive optic neuropathy (CON) in thyroid eye disease (TED). DESIGN: A retrospective review of all patients undergoing combined surgical orbital decompression for CON between 2000 and 2010 was conducted. PARTICIPANTS: Fifty-nine eyes of 34 patients undergoing combined surgical orbital decompression for CON. METHODS: Clinical outcome measures included visual acuity, Hardy-Rand-Rittler (HRR) colour plate testing, relative afferent pupillary defect, intraocular pressure measurement, and Hertel exophthalmometry. A CON score was calculated preoperatively and postoperatively based on the visual acuity and the missed HRR plates. A higher CON score correlates with more severe visual dysfunction. RESULTS: All patients had improvement of their optic neuropathy after surgical decompression. CON score was calculated for 54 eyes and decreased significantly from a mean of 13.2 +/- 10.35 preoperatively to a mean of 8.51 +/- 10.24 postoperatively (p < 0.0001). Optic neuropathy was completely resolved in 93.22% (55/59 eyes). Eighteen of 34 patients (52.94%) experienced development of new-onset postoperative strabismus that required subsequent surgical intervention. CONCLUSIONS: Endoscopic medial combined with external lateral orbital decompression is an effective technique for the treatment of TED-associated CON. PMID- 24767223 TI - Evaluation of thyroid eye disease: quality-of-life questionnaire (TED-QOL) in Korean patients. AB - OBJECTIVE: To assess impaired quality of life (QOL) of Korean patients with thyroid eye disease (TED) using the TED-QOL questionnaire, to evaluate the adaptability of the questionnaire, and to assess the correlation between TED-QOL and scales of disease severity. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Total of 90 consecutive adult patients with TED and Graves' disease were included in this study. METHODS: TED-QOL was translated into Korean and administered to the patients. The results were compared with clinical severity scores (clinical activity score, VISA (vision loss (optic neuropathy); inflammation; strabismus/motility; appearance/exposure) classification, modified NOSPECS (no signs or symptoms; only signs; soft tissue; proptosis; extraocular muscle; cornea; sight loss) score, Gorman diplopia scale, and European Group of Graves' Orbitopathy Classification). RESULTS: Clinical scores indicating inflammation and strabismus in patients with TED were positively correlated with overall and visual function-related QOL (Spearman coefficient 0.21-0.38, p < 0.05). Clinical scores associated with appearance were positively correlated with appearance-related QOL (Spearman coefficient 0.26-0.27, p < 0.05). In multivariate analysis, age, soft-tissue inflammation, motility disorder of modified NOSPECS, and motility disorder of VISA classification had positive correlation with overall and function-related QOL. Sex, soft-tissue inflammation, proptosis of modified NOSPECS, and appearance of VISA classification had correlation with appearance-related QOL. In addition, validity of TED-QOL was proved sufficient based on the outcomes of patient interviews and correlation between the subscales of TED-QOL. CONCLUSIONS: TED-QOL showed significant correlations with various objective clinical parameters of TED. TED-QOL was a simple and useful tool for rapid evaluation of QOL in daily outpatient clinics, which could be readily translated into different languages to be widely applicable to various populations. PMID- 24767224 TI - Comparison of satisfaction after direct browplasty in Asian patients with and without brow tattoo. AB - OBJECTIVE: To determine patient-based scar assessment after direct browplasty for correction of brow ptosis between Asian female patients with and without brow tattoos. DESIGN: A retrospective study with questionnaire via telephone interview. PARTICIPANTS: A total of 30 female Asian patients underwent direct browplasty from January 2008 to December 2011. METHODS: The Patient Scar Assessment Questionnaire (PSAQ) with 5 subscales including appearance, symptoms, consciousness, satisfaction with appearance, and satisfaction with symptoms was used at least 6 months after surgery in patients who underwent direct browplasty. PSAQ scores were compared between Group A (15 cases with brow tattoo lines) and Group B (15 cases without brow tattoo). A lower score indicates a favourable cosmetic outcome. RESULTS: Of the subscales of PSAQ, only "satisfaction with appearance" was significantly lower in Group A (1.4 +/- 0.5) than in Group B (2.0 +/- 1.0; p = 0.039). Mean scores of appearance, symptoms, satisfaction with symptoms, and overall scores were not different between 2 groups. CONCLUSIONS: According to the PSAQ, mean scores of appearance, symptoms, and consciousness regarding surgical scar after direct browplasty were relatively low. Asian patients who underwent direct browplasty were generally satisfied with overall appearance and comfort of their scar regardless of brow tattoo lines, despite the statistical difference in their satisfaction with appearance. PMID- 24767225 TI - Patterns and causes of epiphora referrals to a tertiary oculoplastic practice. AB - OBJECTIVE: To report the causative factors and surgical candidacy of patients referred to an oculoplastic surgery clinic for the complaint of epiphora. DESIGN: Prospective observational study. PARTICIPANTS: Consecutive patients (n = 159) referred to a tertiary care oculoplastic surgery clinic over a 12-month period for the complaint of epiphora. METHODS: The causative factor most responsible for tearing was determined based on clinical examination by the principal investigator, who was blinded to referral source. Patients were considered surgical candidates with a diagnosis of significant nasolacrimal duct obstruction, lid malposition, or pump dysfunction. The primary outcome was the percentage of referrals that were surgical candidates, classified by referral source. RESULTS: The most common cause of tearing was nasolacrimal duct obstruction, occurring in 53 of 159 (33%) patients. The percentage of surgical candidates was highest in referrals from ophthalmologists (82%), followed by optometrists (67%) and family physicians (55%; p = 0.011 for difference between ophthalmologists and family physicians). CONCLUSIONS: Epiphora may be because of a variety of causes, some of which are amendable to surgical treatment. In the absence of an obvious cause, a trial of lubrication by the family physician is warranted before referral being made to an oculoplastic surgeon. PMID- 24767226 TI - Cystoid macular edema: a correlation between macular volumetric parameters and visual acuity. AB - OBJECTIVE: To study in patients with cystoid macular edema (CME) the correlation between macular volumetric parameters on ocular coherence tomography (OCT) and visual acuity (VA). DESIGN: A retrospective consecutive cohort design was used. PARTICIPANTS: The sample included 167 examinations of 92 consecutive patients (130 eyes). METHODS: Patients underwent spectral-domain OCT for CME from the years 2008 to 2010 at a tertiary medical centre. Background and VA data were recorded from the files. The custom-developed Cystometer software was used to calculate volumetric parameters from the OCT videos. RESULTS: In univariate analyses, VA correlated best with cystoid macular volume (CMVol; R(2) = 8.57) and total macular volume (TMV; R(2) = 7.46). By underlying disease, the strongest correlation was found with CMVol (R(2) = 8.47) in patients with diabetic CME (n = 91) and with TMV (R(2) = 22.18) in patients with branch retinal vein occlusion (n = 46). In multiple regression analyses, TMV, age, and CMVol/TMV accounted for 17.57% of the variation in VA. In the diabetic CME group, CMVol/TMV and age accounted for 15.34% of the variation; in the branch retinal vein occlusion group, TMV accounted for 22.18% of the variation. CONCLUSIONS: Macular volumetric parameters measured by OCT and Cystometer software significantly correlate with VA in patients with CME, with variations by underlying CME causative factor. PMID- 24767227 TI - Vitrectomy for diabetic macular edema: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review, and perform meta-analysis on, the available data regarding the efficacy of vitrectomy for diabetic macular edema. DESIGN: Systematic review and meta-analysis of published randomized controlled trial data. METHODS: We searched PubMed and the Cochrane database for randomized, controlled trials investigating vitrectomy for diabetic macular edema. Structural (foveal thickness) and functional (visual acuity) outcomes were used as the primary outcome measures. RESULTS: Eleven studies met the criteria for inclusion in this review: these studies were heterogenous in their experimental and control interventions, follow-up period, and eligibility criteria. Seven studies compared vitrectomy with the natural history of diabetic maculopathy, with laser, or with intravitreal corticosteroid injection. Four studies compared vitrectomy with internal limiting membrane peeling to vitrectomy alone. One of the latter 4 studies was the only to investigate vitrectomy in patients with vitreomacular traction. Meta-analysis suggests a structural, and possibly functional, superiority of vitrectomy over observation at 6 months. Vitrectomy also appears superior to laser in terms of structural, but not functional, outcomes at 6 months. At 12 months, vitrectomy offers no structural benefit and a trend toward inferior functional outcomes when compared with laser. CONCLUSIONS: There is little evidence to support vitrectomy as an intervention for diabetic macular edema in the absence of epiretinal membrane or vitreomacular traction. Although vitrectomy appears to be superior to laser in its effects on retinal structure at 6 months, no such benefit has been proved at 12 months. Furthermore, there is no evidence to suggest a superiority of vitrectomy over laser in terms of functional outcomes. PMID- 24767228 TI - Characteristics of rhegmatogenous retinal detachments secondary to retinal dialyses. AB - OBJECTIVE: The pattern of retinal features in patients with retinal detachment caused by retinal dialyses is poorly described. The association with trauma has also been inconsistently reported. The authors aim to analyze patient and retinal characteristics in such cases and identify the proportion where trauma is likely causative mechanism. DESIGN: Retrospective case series. PARTICIPANTS: Sixty-three eyes from 63 patients with retinal detachment secondary to retinal dialysis. METHODS: Population was selected from consecutive patients presenting to a single surgeon at a tertiary referral vitreoretinal service (2001-2010). RESULTS: Sixty three patients were identified (4.4% incidence rate). The cohort had a mean age of 32 years with a male preponderance (67%). Seventy-one percent had a single break, 21% had 2 breaks, and 8% had 3 to 7 breaks. Six percent of eyes had dialyses smaller than 0.5 disc diameters. Eighty-one percent of eyes had inferotemporal dialyses, but other quadrants also were involved in 25%, or exclusively in 17.5%. The primary success rate for surgery was 92% (94% final success). The presence of proliferative vitreoretinopathy (PVR) was rare (4 cases) but was a significant factor in failure of retinal reattachment (p < 0.001). Twenty-two percent were regarded as traumatic (93% male; p < 0.05). Other variables were similar between traumatic and nontraumatic eyes. CONCLUSIONS: Most retinal dialyses are located inferotemporally; however, multiple dialyses, small dialyses, and dialyses that involve multiple quadrants may be seen. In patients with evidence of direct globe injury, no difference in the pattern of retinal presentation of the dialyses was observed. Although surgical success rates are high, patients with PVR had poor response to surgery. PMID- 24767229 TI - Long-term comparison using Ex-PRESS glaucoma shunt in black and white patients. AB - OBJECTIVE: To compare clinical outcomes, including patterns of failure, using the Ex-PRESS glaucoma shunt, in black and white patients with open-angle glaucoma. DESIGN: Retrospective comparative study. PARTICIPANTS: Sixty-three eyes of 50 black patients and 44 eyes of 34 white patients with open-angle glaucoma. METHODS: The Ex-PRESS shunt procedure was performed for uncontrolled glaucoma in a series of white and black patients with glaucoma. Success was defined as an intraocular pressure (IOP) between 5 and 18 mm Hg, 20% reduction from baseline, with or without suture lysis or adjuvant medication, but no additional glaucoma surgery. RESULTS: Mean length of follow-up was 29 months (range 12-81 months) for black patients and 25 months (range 12-66 months) for white patients. Mean preoperative IOP was 27 +/- 7.2 and 30 +/- 7.7 mm Hg for black and white patients, respectively. Mean postoperative IOP was 13 +/- 3.6 and 12 +/- 3.3 mm Hg for black and white patients, respectively. Using Kaplan-Meier survival curves, the success rates were 77.6% and 95% at 12 months for black and white patients, respectively. The log-rank test for comparison of survival curves indicated a significant difference between the 2 groups at 12 months (p = 0 .015) but revealed no difference at 2 years (p = 0.462). CONCLUSIONS: This study shows that patterns of failure between black and white patients treated with the Ex PRESS glaucoma shunt change significantly with the passage of time. Black patients experience failure early, whereas white patients experience failure later at a greater pace resulting in a similar survival rate at 2 years. PMID- 24767230 TI - Simultaneous placement of 2 glaucoma drainage devices for uncontrolled glaucoma. AB - OBJECTIVE: To report baseline characteristics and surgical outcomes of placement of simultaneous glaucoma drainage devices (GDDs) in eyes with considerably elevated intraocular pressure (IOP) despite maximal medical therapy. DESIGN: Retrospective case series. PARTICIPANTS: Twelve eyes of 12 patients underwent simultaneous placement of a Baerveldt 350 GDD and an Ahmed S3 GDD in the same eye. METHODS: The medical records were reviewed of consecutive patients who underwent simultaneous placement of a Baerveldt 350 GDD and an Ahmed S3 GDD in the same eye at the University of Michigan Kellogg Eye Center from 2006 to 2009. Baseline characteristics, preoperative and postoperative IOP, number of glaucoma medications, visual acuity, and complications were recorded. RESULTS: Mean follow up time was 28.6 +/- 22.8 months. The mean baseline cup/disc ratio was recorded at 0.94 +/- 0.07 horizontally and 0.92 +/- 0.09 vertically. The mean baseline IOP of 38.8 +/- 6.2 mm Hg was significantly reduced at all time points postoperatively, and the mean IOP at last follow-up was 15.1 +/- 4.9 mm Hg (p <= 0.0001). Mean number of glaucoma medications was significantly lower at last follow-up than preoperatively (1.4 +/- 1.3 vs 3.2 +/- 0.8; p = 0.001). There was no difference in mean logMAR visual acuity from before surgery to last follow-up (1.14 vs 1.12; p = 0.933). CONCLUSIONS: Simultaneous placement of 2 GDDs effectively reduces IOP in the immediate postoperative period and long-term, and may be useful in glaucomatous eyes with advanced disease and considerably elevated preoperative IOP. PMID- 24767231 TI - Qualitative and quantitative analysis of filtering blebs with optical coherence tomography. AB - OBJECTIVE: To provide a qualitative and quantitative analysis of filtering blebs with optical coherence tomography (OCT) in patients after primary trabeculectomy. DESIGN: Evaluation of diagnostic technology. PARTICIPANTS: We retrospectively studied 20 eyes of 20 patients who had a fornix-based flap in primary trabeculectomy: 14 with mitomycin C (MMC) and 6 without MMC. METHODS: Filtering blebs were examined using 2 types of OCTs working at a wavelength of 840 and 1310 nm. In this study, we analyzed both the OCT morphologic pattern and the internal structures of blebs, including bleb wall thickness, scleral flap thickness, and the route under the scleral flap, and quantified the reflectivity of the intrableb area. RESULTS: Blebs were classified according to the Hirooka scheme in 3 OCT morphologic patterns: cystoid, diffuse, and layer type. The MMC was associated with the surgical success (100%). A significant association was found between good functionality and cystoid type with both devices: 840-nm OCT (p = 0.02) and 1310-nm OCT (p = 0.04). A significant difference in morphologic patterns was found using the 2 OCTs. There were no significant differences between successful and unsuccessful filtering surgery for intrableb structures. The reflectivity of filtering blebs correlated very well to the postoperative intraocular pressure (IOP; R(2) = 0.90; p < 0.001) and to the reduction of IOP (R(2) = 0.58; p = 0.001). Our method to quantify the reflectivity showed a significant degree of intergrader consensus (intraclass correlation coefficient = 0.99; p < 0.001). CONCLUSIONS: Although 840-nm OCT was not developed to assess the anterior segment, it may be considered a useful tool to evaluate the functionality of blebs in the postoperative period. PMID- 24767232 TI - Long-term effects of PAP on ocular surface in obstructive sleep apnea syndrome. AB - OBJECTIVE: To assess the long-term effects of positive airway pressure (PAP) therapy on the ocular surface and eyelid in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). DESIGN: Single-centred, prospective, and double blinded study. PARTICIPANTS: Fifty-one patients with OSAHS. METHODS: Fifty-one patients with OSAHS were treated with PAP for a period of 18 months. The pre- and post-PAP values for eye examination scores (presence of floppy eyelid syndrome [FES], results of the Ocular Surface Disease Index [OSDI] questionnaire, Schirmer I test, tear film break-up time [TBUT] values, and corneal staining stages) were compared. RESULTS: Based on the apnea-hypopnea index, 17 patients were followed with moderate and 34 patients were followed with severe OSAHS. The presence of FES before and after PAP was 56.9% and 74.5% (p < 0.01). FES stage was determined as 1.41 +/- 0.98 before PAP and 0.78 +/- 0.78 after PAP (p < 0.01). Pre-PAP and post-PAP OSDI results were 47.79 +/- 21.04 and 42.17 +/- 19.97, respectively (p < 0.01). Schirmer values before and after PAP were 7.23 +/- 1.95 and 8.49 +/- 1.79 mm, respectively (p < 0.01). TBUT values before and after PAP were 7.11 +/- 1.82 and 8.68 +/- 1.76 seconds, respectively (p < 0.01). Scores of the corneal staining stages before and after PAP were 1.05 +/- 0.75 and 0.68 +/- 0.54, respectively (p < 0.01). CONCLUSIONS: OSAHS is associated with low Schirmer and TBUT values, and high scores in OSDI questionnaire, and high corneal staining stage. An appropriate PAP therapy helps to relieve both the systemic findings and the ocular surface problems most likely by providing a return to normal sleep patterns. We believe that long-term (at least 1 year) use of PAP improves the clinical picture of FES and can overcome the problem of ocular irritation that is encountered in the early stage of PAP. PMID- 24767233 TI - Single-stage surgery for symptomatic small-angle strabismus under topical anaesthesia. AB - OBJECTIVE: To report outcomes of single-stage surgery under topical anaesthesia for the treatment of small-angle strabismus. DESIGN: Case series. PARTICIPANTS: Thirteen patients, 7 males and 6 females, with a median age of 32 years (range, 20-59 years) were included. METHODS: Patients with symptomatic small-angle strabismus with stable deviations of no more than 20 prism diopters (PD) in horizontal and 10 PD in vertical were consecutively recruited from the Eye and ENT Hospital of Fudan University between January 2010 and April 2012. Single stage surgery was performed under topical anaesthesia. Outcome measures were PD, Amblyopia and Strabismus Questionnaire (ASQE) scores, and subjective reduction of symptoms. RESULTS: The median duration of symptoms was 40 months (range, 6-96 months). Nine patients had horizontal deviations, 3 had vertical deviations, and 1 had an exodeviation combined with a vertical deviation. All surgeries were completed without complications, and no patients experienced significant discomfort. All patients reported elimination of symptoms on postoperative day 1. Two patients required a second procedure at 1 week because of a return of symptoms. At 6-month follow-up, no patient reported recurrence of symptoms. The overall ASQE score improved from 70 preoperatively to 96 postoperatively (p = 0.001). CONCLUSIONS: These results suggest single-stage surgery under topical anaesthesia is an effective treatment for small-angle strabismus. A large, randomized, prospective study to confirm these findings is warranted. PMID- 24767234 TI - Intravitreal bevacizumab for exudative retinal detachment post laser therapy for retinopathy of prematurity. AB - Retinopathy of prematurity (ROP), a leading cause of pediatric blindness, predominantly affects premature and low-birth-weight infants. Although many cases are self-limiting, a minority progress to retinal detachment despite treatment. Exudative retinal detachments, although uncommon, have been reported after conventional laser therapy.(1-3) We report 2 cases of exudative retinal detachment after laser therapy for prethreshold and threshold ROP that responded favourably to a series of intravitreal bevacizumab injections. PMID- 24767235 TI - Catecholamine-induced cardiomyopathy: a complication following a retrobulbar block. PMID- 24767236 TI - Clinical and in vivo confocal microscopic findings of a patient with ocular ochronosis. PMID- 24767237 TI - Intraosseous orbital hydatid cyst: report of a rare case. PMID- 24767238 TI - Conjunctival squamous cell carcinoma with intraocular invasion after radiotherapy in epidermodysplasia verruciformis. PMID- 24767239 TI - A case of an adult regaining vision in the amblyopic eye. PMID- 24767240 TI - Regression of orbital and choroidal metastases from melanoma after treatment with vemurafenib. PMID- 24767241 TI - Abducens nerve in a patient with Duane retraction syndrome. PMID- 24767242 TI - Bilateral disc edema in a patient with Vogt-Koyanagi-Harada disease. PMID- 24767243 TI - Serous macular detachment associated with optic nerve head cupping in pigmentary glaucoma. PMID- 24767244 TI - Pulmonary nocardiosis initially manifesting as endogenous endophthalmitis. PMID- 24767245 TI - Injectable contraception: issues and opportunities. PMID- 24767246 TI - Recombinant S. cerevisiae expressing Old Yellow Enzymes from non-conventional yeasts: an easy system for selective reduction of activated alkenes. AB - BACKGROUND: Old Yellow Enzymes (OYEs) are flavin-dependent enoate reductases (EC 1.6.99.1) that catalyze the stereoselective hydrogenation of electron-poor alkenes. Their ability to generate up to two stereocenters by the trans hydrogenation of the C = C double bond is highly demanded in asymmetric synthesis. Isolated redox enzymes utilization require the addition of cofactors and systems for their regeneration. Microbial whole-cells may represent a valid alternative combining desired enzymatic activity and efficient cofactor regeneration. Considerable efforts were addressed at developing novel whole-cell OYE biocatalysts, based on recombinant Saccharomyces cerevisiae expressing OYE genes. RESULTS: Recombinant S. cerevisiae BY4741?Oye2 strains, lacking endogenous OYE and expressing nine separate OYE genes from non-conventional yeasts, were used as whole-cell biocatalysts to reduce substrates with an electron-poor double bond activated by different electron-withdrawing groups. Ketoisophorone, alpha methyl-trans-cinnamaldehyde, and trans-beta-methyl-beta-nitrostyrene were successfully reduced with high rates and selectivity. A series of four alkyl substituted cyclohex-2-enones was tested to check the versatility and efficiency of the biocatalysts. Reduction of double bond occurred with high rates and enantioselectivity, except for 3,5,5-trimethyl-2-cyclohexenone. DFT (density functional theory) computational studies were performed to investigate whether the steric hindrance and/or the electronic properties of the substrates were crucial for reactivity. The three-dimensional structure of enoate reductases from Kluyveromyces lodderae and Candida castellii, predicted through comparative modeling, resulted similar to that of S. cerevisiae OYE2 and revealed the key role of Trp116 both in substrate specificity and stereocontrol. All the modeling studies indicate that steric hindrance was a major determinant in the enzyme reactivity. CONCLUSIONS: The OYE biocatalysts, based on recombinant S. cerevisiae expressing OYE genes from non-conventional yeasts, were able to differently reduce the activated double bond of enones, enals and nitro-olefins, exhibiting a wide range of substrate specificity. Moreover whole-cells biocatalysts bypassed the necessity of the cofactor recycling and, tuning reaction parameters, allowed the synthetic exploitation of endogenous carbonyl reductases. Molecular modeling studies highlighted key structural features for further improvement of catalytic properties of OYE enzymes. PMID- 24767247 TI - Children's representations of school support for HIV-affected peers in rural Zimbabwe. AB - BACKGROUND: HIV has left many African children caring for sick relatives, orphaned or themselves HIV-positive, often facing immense challenges in the absence of significant support from adults. With reductions in development funding, public sector budgetary constraints, and a growing emphasis on the importance of indigenous resources in the HIV response, international policy allocates schools a key role in 'substituting for families' (Ansell, 2008) in supporting child health and well-being. We explore children's own accounts of the challenges facing their HIV-affected peers and the role of schools in providing such support. METHODS: Contextualised within a multi-method study of school support for HIV-affected children in rural Zimbabwe, and regarding children's views as a key resource for child-relevant intervention and policy, 128 school children (10-14) wrote a story about an HIV-affected peer and how school assisted them in tackling their problems. RESULTS: Children presented harrowing accounts of negative impacts of HIV on the social, physical and mental well-being of peers, and how these manifested in the school setting. Whilst relationships with fellow learners and teachers were said to provide a degree of support, this was patchy and minimal, generally limited to small-scale and often one-off acts of material help or kindness (e.g. teachers giving children pens and exercise books or peers sharing school lunches), with little potential to impact significantly on the wider social drivers of children's daily challenges. Despite having respect for the enormity of the challenges many HIV-affected peers were coping with, children tended to keep a distance from them. School was depicted as a source of the very bullying, stigma and social exclusion that undermined children's opportunities for well-being in their lives more generally. CONCLUSIONS: Our findings challenge glib assumptions that schools can serve as a significant 'indigenous' supports of the health and well-being of HIV-affected children in the absence of a very significant increase in outside training, support and additional resources. Schools are an extension of communities, with members of school communities subject to many of the same deprivations, anxieties and prejudices that drive the health-limiting exclusion, impoverishment and stigmatisation of HIV-affected children in their households and wider communities. PMID- 24767249 TI - Genome-wide Mycobacterium tuberculosis variation (GMTV) database: a new tool for integrating sequence variations and epidemiology. AB - BACKGROUND: Tuberculosis (TB) poses a worldwide threat due to advancing multidrug resistant strains and deadly co-infections with Human immunodeficiency virus. Today large amounts of Mycobacterium tuberculosis whole genome sequencing data are being assessed broadly and yet there exists no comprehensive online resource that connects M. tuberculosis genome variants with geographic origin, with drug resistance or with clinical outcome. DESCRIPTION: Here we describe a broadly inclusive unifying Genome-wide Mycobacterium tuberculosis Variation (GMTV) database, (http://mtb.dobzhanskycenter.org) that catalogues genome variations of M. tuberculosis strains collected across Russia. GMTV contains a broad spectrum of data derived from different sources and related to M. tuberculosis molecular biology, epidemiology, TB clinical outcome, year and place of isolation, drug resistance profiles and displays the variants across the genome using a dedicated genome browser. GMTV database, which includes 1084 genomes and over 69,000 SNP or Indel variants, can be queried about M. tuberculosis genome variation and putative associations with drug resistance, geographical origin, and clinical stages and outcomes. CONCLUSIONS: Implementation of GMTV tracks the pattern of changes of M. tuberculosis strains in different geographical areas, facilitates disease gene discoveries associated with drug resistance or different clinical sequelae, and automates comparative genomic analyses among M. tuberculosis strains. PMID- 24767250 TI - Targeted gene analysis: increased B-cell lymphoma 6 in preeclamptic placentas. AB - Preeclampsia is a leading cause for maternal and perinatal mortality and morbidity. Microarray-based transcriptional profiling has been widely used for identifying genes responsible for preeclampsia. These studies deliver multiple pictures of gene signatures, implying the complicated pathophysiology. In the present work, we designed our own gene array containing genes involved in various signaling transduction pathways and analyzed placental samples from patients with preeclampsia and controls. We verify that genes associated with angiogenesis and migration pathways are mostly altered in preeclamptic placentas. Interestingly, several genes including B-cell lymphoma 6 have been identified to be linked to preeclampsia. Increased expression of B-cell lymphoma 6 is correlated with enhanced FLT1 and LEPTIN, the hallmarks of preeclampsia. Moreover, the protein level of B-cell lymphoma 6 is elevated in preeclamptic placentas and is predominantly localized in the nucleus of villous cytotrophoblasts lying directly underneath the syncytial layer, suggestive of an involvement in the function of villous trophoblasts. Altered B-cell lymphoma 6, a key oncogene in B-cell lymphomagenesis, may be involved in the pathogenesis of preeclampsia, and further investigations are required to decipher the molecular mechanisms. PMID- 24767248 TI - Metabolic effects of the contraceptive skin patch and subdermal contraceptive implant in Mexican women: a prospective study. AB - BACKGROUND: The contraceptive skin patch (CSP) accepted by the U.S. FDA in 2001 includes ethinylestradiol and norelgestromine, whereas the subdermal contraceptive implant (SCI) has etonogestrel and is also approved by the FDA. In Mexico, both are now widely used for contraception but their effects on Mexican population are unknown. The objective of the study was to evaluate if these treatments induce metabolic changes in a sample of indigenous and mestizo Mexican women. METHODS: An observational, prospective, longitudinal, non-randomized study of women between 18 and 35 years of age assigned to CSP or SCI. We performed several laboratory tests: clinical chemistry, lipid profile, and liver and thyroid function tests. Also, serum levels of insulin, C-peptide, IGF-1, leptin, adiponectin, and C reactive protein were assayed. RESULTS: Sixty-two women were enrolled, 25 used CSP (0 indigenous; 25 mestizos) and 37 used SCI (18 indigenous; 19 mestizos). Clinical symptoms were relatively more frequent in the SCI group. Thirty-four contraceptive users gained weight without other clinical significant changes. After 4 months of treatment, significant changes were found in some biochemical parameters in both treatment groups. Most were clinically irrelevant. Interestingly, the percentage of users with an abnormal atherogenic index diminished from 75% to 41.6% after follow-up. CONCLUSIONS: The CSP slightly modified the metabolic variables. Most changes were nonsignificant, whereas for SCI users changes were more evident and perhaps beneficial. Results of this attempt to evaluate the effects of contraceptives in mestizo and native-American populations show that clinical symptoms are frequent in Mexican users of CSP and SCI. Although these medications may affect some metabolic variables, these changes seem clinically irrelevant. Induction of abnormalities in other physiological pathways cannot be ruled out. PMID- 24767251 TI - Involvement of miR-29b signaling in the sensitivity to chemotherapy in patients with ovarian carcinoma. AB - Although the molecular mechanisms driving chemoresistance and relapse of ovarian cancer have been widely studied, the key molecules have not been identified. In this study, the expression of miR-29b messenger RNA (mRNA) and its targeted genes, myeloid cell leukemia sequence 1, mitogen-activated protein kinase 10 (MAPK10), and autophagy-related protein 9A (ATG9A), were investigated in ovarian carcinomas, and their associations with clinicopathological characteristics and survival of patients with ovarian cancer were analyzed. The protein expression of MCL1, MAPK10, and ATG9A was measured using immunohistochemistry. miR-29b mRNA and ATG9A gene mRNA levels were measured by real-time polymerase chain reaction. Results demonstrated that the percentage of MCL1, MAPK10, and ATG9A protein positive cases were significantly higher, whereas miR-29b was significantly lower in ovarian serous, mucinous, and clear cell carcinomas than that in normal tissues. MAPK10 was significantly associated with higher histopathologic grading. The percentage of positive myeloid cell leukemia sequence 1, ATG9A, and MAPK10 protein expression and low miR-29b mRNA expression were significantly higher in cases with clinical stage III and IV ovarian cancer than in cases with clinical stage II ovarian cancer. High ATG9A protein and low miR-29b mRNA expression were significantly associated with relapse. Univariate Kaplan-Meier analysis showed a negative correlation between MAPK10 or ATG9A protein expression and overall as well as progression-free survival, whereas a positive correlation was observed between miR-29b mRNA expression and overall as well as progression-free survival. Multivariate Cox regression analysis showed that elevated MAPK10 or ATG9A protein and lowered miR-29b mRNA expression in ovarian carcinoma was an independent poor prognostic predictor. Our study suggested that miR-29b mRNA, MAPK10 protein expression, and ATG9A protein expression are closely related to chemosensitivity of ovarian carcinoma. PMID- 24767252 TI - The pulmonary histopathologic manifestations of the anti-PL7/antithreonyl transfer RNA synthetase syndrome. AB - The pulmonary histopathologic manifestations of the antisynthetase syndromes is poorly understood and reported. Eight cases of interstitial lung disease related to the presence of antitheonyl (PL7) transfer RNA synthetase autoantibodies along with a review of biopsy changes reported in the English literature are described. Most patients presented with dyspnea and cough, with myositis, skin changes including "mechanic's hands," and Raynaud phenomenon. Biopsy patterns of injury included usual interstitial pneumonia (n = 4), organizing pneumonia (n = 2), nonspecific interstitial pneumonia, and lymphoid interstitial pneumonia (n = 1 each), which, in a minority of instances, contrasted with predictions by thoracic radiologists based on high-resolution computed tomographic scans. This study emphasizes the integrated clinical, radiologic, and pathologic approach to interstitial lung disease, especially in connective tissue disorders, and points out the occurrence of usual interstitial pneumonia and organizing pneumonia in this patient group where nonspecific interstitial pneumonia has been the dominant pattern of clinical interest. PMID- 24767253 TI - Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders. AB - BACKGROUND: With over 50 different disorders and a combined incidence of up to 1/3000 births, lysosomal storage diseases (LSDs) constitute a major public health problem and place an enormous burden on affected individuals and their families. Many factors make LSD diagnosis difficult, including phenotype and penetrance variability, shared signs and symptoms, and problems inherent to biochemical diagnosis. Developing a powerful diagnostic tool could mitigate the protracted diagnostic process for these families, lead to better outcomes for current and proposed therapies, and provide the basis for more appropriate genetic counseling. METHODS: We have designed a targeted resequencing assay for the simultaneous testing of 57 lysosomal genes, using in-solution capture as the enrichment method and two different sequencing platforms. A total of 84 patients with high to moderate-or low suspicion index for LSD were enrolled in different centers in Spain and Portugal, including 18 positive controls. RESULTS: We correctly diagnosed 18 positive blinded controls, provided genetic diagnosis to 25 potential LSD patients, and ended with 18 diagnostic odysseys. CONCLUSION: We report the assessment of a next-generation-sequencing-based approach as an accessory tool in the diagnosis of LSDs, a group of disorders which have overlapping clinical profiles and genetic heterogeneity. We have also identified and quantified the strengths and limitations of next generation sequencing (NGS) technology applied to diagnosis. PMID- 24767254 TI - Human intestinal spirochetosis is significantly associated with sessile serrated adenomas/polyps. AB - It remains unclear whether or not human intestinal spirochetosis (HIS) has any associated symptoms or lesions. In this study, we assessed the prevalence of HIS in sessile serrated adenomas/polyps (SSA/Ps) and their possible association. Following identification of early cecal cancer with SSA/P accompanied by a colonization of HIS, we went on to conduct a retrospective case-control study using endoscopically resected SSA/P specimens to examine the frequency of HIS infection in SSA/Ps. Nineteen SSA/P cases and 172 controls were obtained. The rate of HIS infection was significantly higher at 52.6% (10/19) in the SSA/P cases compared to the controls at 8.1% (14/172). Our SSA/P series were associated with a remarkably higher rate of HIS than controls or than previously reported. This is the first report to provide evidence for potential association between HIS and SSA/Ps. PMID- 24767255 TI - Temsirolimus, the mTOR inhibitor, induces autophagy in adenoid cystic carcinoma: in vitro and in vivo. AB - Temsirolimus acts as a mammalian target of rapamycin (mTOR)-dependent autophagic inhibitor. In order to clarify its effects and mechanisms on human salivary adenoid cystic carcinoma (ACC), we examined whether temsirolimus induced autophagy as the mTOR inhibitor in ACC, both in vitro and in vivo. In this study, MTT assay showed that the inhibition effect of temsirolimus assumed an obvious dose-response relationship on ACC-M cells, and the 50% inhibitory concentration (IC(50)) approached 20 MUmol/l; numerous autophagosomes were observed by the transmission electron microscopy (TEM) in temsirolimus treatment groups; notably, expression of LC3 and Beclin1 was significantly up-regulated by temsirolimus. More importantly, the xenograft model provided further evidence of temsirolimus induced autophagy in vivo by inhibiting mTOR activation as well as up-regulation the expression of Beclin1. These results suggest that temsirolimus could act as an mTOR inhibitor to induce autophagy in adenoid cystic carcinoma both in vitro and in vivo. PMID- 24767256 TI - Species distribution and antifungal susceptibility of Candida spp. isolated from superficial candidiasis in outpatients in Iran. AB - OBJECTIVE: Candidiasis is the most prevalent fungal infection affecting human and animals all over the world. This study represents the epidemiological aspects of superficial candidiasis in outpatients and in vitro antifungal susceptibility of etiologic Candida species. PATIENTS AND METHODS: Clinical samples were taken from 173 patients including skin and nail scrapings (107; 61.8%), vaginal discharge (28; 16.2%), sputum (20; 11.6%), oral swabs (7; 4.0%), bronchoalveolar lavage (6; 3.5%) and 1 specimen (0.6%) of each eye tumor, gastric juice, urine, biopsy and urinary catheter and confirmed as candidiasis by direct microscopy, culture and histopathology. Susceptibility patterns of the isolated Candida species were determined using the disk diffusion and broth microdilution methods. RESULTS: Among 173 Candida isolates, C. albicans (72.3%) was the most prevalent species followed by C. parapsilosis (11.5%). Other identified species were C. glabrata, C. krusei, C. tropicalis, C. guilliermondii, C. intermedia and C. sake. Majority of the Candida isolates were susceptible to fluconazole (95.4%) followed by 5 flucytosine (89.6%), voriconazole (78.6%) itraconazole (48.0%) and ketoconazole (42.8%). Caspofungin was the most potent antifungal drug against C. albicans (MICs; 0.062-1 MUg/mL), ketoconazole for C. parapsilosis and C. tropicalis (MICs; 0.031-0.25 MUg/mL) and itraconazole for C. krusei, C. glabrata and C. guilliermondii (MICs; 0.031-1 MUg/mL). CONCLUSION: This study reinforces the significance of superficial candidiasis as an important fungal infection with multiple clinical presentations. Our results further indicate that susceptibility testing to commonly used antifungals is crucial in order to select the appropriate therapeutic strategies which minimize complications while improving patients' life. PMID- 24767257 TI - Bile duct adenoma: a case report and literature review. AB - BACKGROUND: Bile duct adenoma (BDA) is a comparatively rare disease clinically, therefore, there are relatively few reported cases about it both in China and abroad. CASE PRESENTATION: Herein, we present a 51-year-old man, diagnosed preoperatively with enhanced-contrast abdominal computed tomography, as having a nodule in the left hepatic. The patient underwent a liver tumor resection, and the histological examination revealed bile duct adenoma (BDA). CONCLUSIONS: BDA is an extremely rare benign tumor, which is difficult to distinguish BDA from hepatocellular carcinoma definitely preoperatively, surgical resection is needed as a way of treatment. PMID- 24767260 TI - The lemon juice syndrome and the hunger games. PMID- 24767261 TI - From one to the many: the social implications of nonlocal perception. PMID- 24767258 TI - Impact of alternative DNA structures on DNA damage, DNA repair, and genetic instability. AB - Repetitive genomic sequences can adopt a number of alternative DNA structures that differ from the canonical B-form duplex (i.e. non-B DNA). These non-B DNA forming sequences have been shown to have many important biological functions related to DNA metabolic processes; for example, they may have regulatory roles in DNA transcription and replication. In addition to these regulatory functions, non-B DNA can stimulate genetic instability in the presence or absence of DNA damage, via replication-dependent and/or replication-independent pathways. This review focuses on the interactions of non-B DNA conformations with DNA repair proteins and how these interactions impact genetic instability. PMID- 24767262 TI - Biofield-based therapies: a systematic review of physiological effects on practitioners during healing. AB - BACKGROUND: Several recent reviews have reached guardedly positive conclusions about the effectivenessof biofield therapies in healthcare.(1,2) These studies mainly involved randomized controlled trials to determine changes in condition related outcome measures, but few addressed the biological basis of these effects. STUDY OBJECTIVE AND RATIONALE: We performed a systematic review of studies designed to examine whether biofield therapists undergo physiological changes as they enter the healing state. If reproducible changes can be identified, they may serve as markers to reveal events that correlate with the healing process. METHODS: Databases were searched for controlled or non controlled studies of biofield therapies in which physiological measurements were made on practitioners in a healing state, with or without a healee present. Design and reporting criteria, developed in part to reflect the pilot nature of the included studies, were applied using a yes (1.0), partial (0.5), or no (0) scoring system. RESULTS: Of 67 identified studies, the inclusion criteria were met by 22, 10 of which involved human healees. Overall, the studies were of moderate to poor quality and many omitted information about the training and experience of the healer. The most frequently measured biomarkers were electroencephalography (EEG) and heart rate variability (HRV). EEG changes were inconsistent and not specific to biofield therapies. HRV results suggest an aroused physiology for Reconnective Healing, Bruyere healing, and Hawaiian healing but no changes were detected for Reiki or Therapeutic Touch. CONCLUSIONS: Despite a decades-long research interest in identifying healing-related biomarkers in biofield healers, little robust evidence of unique physiological changes has emerged to define the healers' state. PMID- 24767259 TI - Molecular basis of transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis. AB - Maintaining high transcriptional fidelity is essential for life. Some DNA lesions lead to significant changes in transcriptional fidelity. In this review, we will summarize recent progress towards understanding the molecular basis of RNA polymerase II (Pol II) transcriptional fidelity and DNA lesion-induced transcriptional mutagenesis. In particular, we will focus on the three key checkpoint steps of controlling Pol II transcriptional fidelity: insertion (specific nucleotide selection and incorporation), extension (differentiation of RNA transcript extension of a matched over mismatched 3'-RNA terminus), and proofreading (preferential removal of misincorporated nucleotides from the 3'-RNA end). We will also discuss some novel insights into the molecular basis and chemical perspectives of controlling Pol II transcriptional fidelity through structural, computational, and chemical biology approaches. PMID- 24767263 TI - Reductions in pain, depression, and anxiety symptoms after PTSD remediation in veterans. AB - A randomized controlled trial of veterans with clinical levels of PTSD symptoms found significant improvements after Emotional Freedom Techniques (EFT). Although pain, depression, and anxiety were not the primary targets of treatment, significant improvements in these conditions were noted. Subjects (N = 59) received six sessions of EFT coaching supplementary to primary care. They were assessed using the SA-45, which measures nine mental health symptom domains and also has two general scales measuring the breadth and depth of psychological distress. Anxiety and depression both reduced significantly, as did the breadth and depth of psychological symptoms. Pain decreased significantly during the intervention period (-41%, p < .0001). Subjects were followed up at three and six months, revealing significant relationships between PTSD, depression, and anxiety at several assessment points. At follow-up, pain remained significantly lower than at pretest. The results of this study are consistent with other reports showing that, as PTSD symptoms are reduced, general mental health improves, and pain levels drop. The ability of EFT to produce reliable and long-term gains after relatively brief interventions indicates its utility in reducing the estimated trillion-dollar cost of treating veteran mental health disorders in the coming years. PMID- 24767264 TI - Brief training of psychoneuroendocrinoimmunology-based meditation (PNEIMED) reduces stress symptom ratings and improves control on salivary cortisol secretion under basal and stimulated conditions. AB - CONTEXT: Meditation is proposed as an anti-stress practice lowering allostatic load and promoting well-being, with brief formats providing some of the benefits of longer interventions. OBJECTIVES: PsychoNeuroEndocrinoImmunology-based meditation (PNEIMED) combines the teaching of philosophy and practice of Buddhist meditation with a grounding in human physiology from a systemic and integrative perspective. We evaluated the effects of four-day PNEIMED training (30 h) on subjective and objective indices of stress in healthy adults. DESIGN: A non randomized, controlled, before-and-after study was conducted. Participants (n = 125, mostly health practitioners) answered a questionnaire rating stress symptom before (T0) and after (Tf) a PNEIMED course. In an additional sample (n = 40; smokers, overweight persons, women taking contraceptives, and subjects with oral pathologies were excluded), divided into PNEIMED-attending (intervention, n = 21) and non-meditating (control, n = 19) groups, salivary cortisol was measured upon awakening and during a challenging mental task. RESULTS: Self-rated distress scores were highly reduced after the PNEIMED course. In the intervention group, improvement of psychological well-being was accompanied by decrease in cortisol levels at awakening. No T0-vs-Tf changes in distress scores and morning cortisol were found in controls. Based on baseline-to-peak increment of cortisol response at T0, 26 subjects (n = 13 for each group) were classified as task-responders. The amplitude and duration of the cortisol response decreased after PNEIMED, whereas no effects were found in controls. CONCLUSIONS: Brief PNEIMED training yields immediate benefits, reducing distress symptoms and adrenocortical activity under basal and stimulated conditions. PNEIMED may represent an effective practice to manage stress and anxiety, particularly among subjects facing a multitude of job-related stressors, such as healthcare workers. PMID- 24767265 TI - A small mixed-method RCT of mindfulness instruction for urban youth. AB - OBJECTIVE: We aimed to explore the specific effects of mindfulness-based stress reduction (MBSR) for urban youth by comparing it with an active control program, designed to control for time, positive peer-group experience, and positive adult instructor. METHODS: Patients between the ages of 13-21 years who received primary pediatric care at our urban outpatient clinic were eligible for study participation. Those who were interested were consented and randomly assigned to an eight-week program of MBSR or Healthy Topics (HT), a health education curriculum. To increase sensitivity to outcomes of interest, mixed methods were used to assess psychological symptoms, coping, and program experience. Analysis of variance and regression modeling were used; interviews were audio-taped, transcribed, and coded for key themes. RESULTS: A total of 43 (26 MBSR, 17 HT) youths attended one or more sessions, of whom 35 [20 MBSR (77%), 15 HT (88%)] attended the majority of the sessions and were considered completers. Program completers were African American, 80% female, with average age of 15.0 years. Statistical analysis of survey data did not identify significant post-program differences between groups. Qualitative data show comparable positive experiences in both programs, but specific differences related to MBSR participants' use of mindfulness techniques to calm down and avoid conflicts, as well as descriptions of internal processes and self-regulation. CONCLUSIONS: Compared with an active control program, MBSR did not result in statistically significant differences in self-reported survey outcomes of interest but was associated with qualitative outcomes of increased calm, conflict avoidance, self-awareness, and self regulation for urban youths. Importantly, based on qualitative results, the HT program functioned as an effective active control for MBSR in this sample, facilitating a more rigorous methodological approach to MBSR research in this population. We believe the promising effects elucidated in the qualitative data have the potential for positive affective and behavioral outcomes. PMID- 24767266 TI - Increasing resident recruitment into family medicine: effect of a unique curriculum in integrative medicine. AB - INTRODUCTION: Healthcare reform is highlighting the need for more family practice and other primary care physicians. The Integrative Medicine in Residency (IMR) curriculum project helped family medicine residencies pilot a new, online curriculum promoting prevention, patient-centered care competencies, use of complementary and alternative medicine along with conventional medicine for management of chronic illness. A major potential benefit of the IMR program is enhanced recruitment into participating residencies, which is reported here. METHODS: Using an online questionnaire, accepted applicants to the eight IMR pilot programs (n = 152) and four control programs (n = 50) were asked about their interests in learning integrative medicine (IM) and in the pilot sites how the presence of the IMR curriculum affected their ranking decisions. RESULTS: Of residents at the IMR sites, 46.7% reported that the presence of the IMR was very important or important in their ranking decision. The IMR also ranked fourth overall in importance of ranking after geography, quality of faculty, and academic reputation of the residency. The majority of IMR residents (87.5%) had high to moderate interest in learning IM during their residency; control residents also had a high interest in learning IM (61.2%). CONCLUSIONS: The presence of the IMR curriculum was seen as a strong positive by applicants in ranking residencies. Increasing the adoption of innovative IM curricula, such as the IMR, by residency programs may be helpful in increasing applications of competitive medical students into primary care residencies as well as in responding to the expressed interest in learning the IM approach to patient care. PMID- 24767267 TI - The treatment of workaholism with meditation awareness training: a case study. PMID- 24767268 TI - Moxibustion and breech presentation, breathing exercises and asthma, coenzyme Q10 and heart failure, acupuncture and chronic low back pain, and cinnamon and diabetes. PMID- 24767269 TI - Bridging the compassion and empathy gap in medical school: the physician healer track at UTMB-Health. PMID- 24767270 TI - Growing population and ecosystem change increase human schistosomiasis around Lake Malawi. AB - Multiple anthropogenic environmental stressors with reinforcing effects to the deterioration of ecosystem stability can obscure links between ecosystem change and the prevalence of infectious diseases. Incomplete understanding may lead to ineffective public health and disease control strategies, as appears to be the case with increased urogenital schistosomiasis in humans around Lake Malawi over recent decades. Sedimentation and eutrophication help explain historical changes in intermediate host range and parasite transmission. Hence, control strategies should account for abiotic changes. PMID- 24767271 TI - Environmental factors in dysregulation of puberty timing and progression. PMID- 24767272 TI - Invited commentary. PMID- 24767273 TI - Endovascular treatment for type Ia major endoleak after endovascular aneurysm repair. PMID- 24767274 TI - Celiomesenteric and renal common trunk associated with distal thoracic aorta coarctation and three saccular aneurysms. PMID- 24767275 TI - Technical aspects of repair of juxtarenal abdominal aortic aneurysms using the Zenith fenestrated endovascular stent graft. AB - Fenestrated endovascular aortic repair has been used with increasing frequency to treat complex aortic aneurysms. The Zenith fenestrated stent graft system (Cook Medical Inc, Brisbane, Queensland, Australia) was approved for commercial use in the United States in April 2012, offering a custom-made design with up to three fenestrations to treat short-neck infrarenal and juxtarenal abdominal aortic aneurysms. This report and the Video presentation (online only) summarize the preoperative planning, stent graft design, and technique of implantation of a Zenith fenestrated stent graft using a totally percutaneous approach in an 80 year-old female patient with a 6-cm juxtarenal abdominal aortic aneurysm. The patient was dismissed home the next day without complications, and a computed tomography angiography at 12 months showed no endoleak or stent graft complications. PMID- 24767276 TI - Discussion. PMID- 24767277 TI - Reply: To PMID 23910457. PMID- 24767278 TI - Regarding "The effect of postoperative myocardial ischemia on long-term survival after vascular surgery". PMID- 24767279 TI - Reply: To PMID 23891491. PMID- 24767280 TI - Regarding "Discontinuation of preoperative clopidogrel is unnecessary in peripheral arterial surgery". PMID- 24767281 TI - Reply: To PMID 23911249. PMID- 24767282 TI - Regarding "Comparison of outcomes following endovascular repair of abdominal aortic aneurysms based on size threshold". PMID- 24767284 TI - [Perioperative blood management: from restrictive transfusion to individualized transfusion]. PMID- 24767283 TI - LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies. AB - BACKGROUND: Diagnosis within RASopathies still represents a challenge. Nevertheless, many efforts have been made by clinicians to identify specific clinical features which might help in differentiating one disorder from another. Here, we describe a child initially diagnosed with Neurofibromatosis-Noonan syndrome. The follow-up of the proband, the clinical evaluation of his father together with a gene-by-gene testing approach led us to the proper diagnosis. CASE PRESENTATION: We report a 8-year-old male with multiple cafe-au-lait macules, several lentigines and dysmorphic features that suggest Noonan syndrome initially diagnosed with Neurofibromatosis-Noonan syndrome. However, after a few years of clinical and ophthalmological follow-up, the absence of typical features of Neurofibromatosis type 1 and the lack of NF1 mutation led us to reconsider the original diagnosis. A new examination of the patient and his similarly affected father, who was initially referred as healthy, led us to suspect LEOPARD syndrome, The diagnosis was then confirmed by the occurrence in both patients of a heterozygous mutation c.1403 C > T, p.(Thr468Met), of PTPN11. Subsequently, the proband was also found to have type-1 Arnold-Chiari malformation in association with syringomyelia. CONCLUSION: Our experience suggests that differential clinical diagnosis among RASopathies remains ambiguous and raises doubts on the current diagnostic clinical criteria. In some cases, genetic tests represent the only conclusive proof for a correct diagnosis and, consequently, for establishing individual prognosis and providing adequate follow-up. Thus, molecular testing represents an essential tool in differential diagnosis of RASophaties. This view is further strengthened by the increasing accessibility of new sequencing techniques.Finally, to our knowledge, the described case represents the third report of the occurrence of Arnold Chiari malformation and the second description of syringomyelia with LEOPARD syndrome. PMID- 24767285 TI - [Promoting rational clinical use of blood by advanced blood management strategies]. PMID- 24767286 TI - [The dilemma of palliative care in advanced cancer patients and policy recommendations]. PMID- 24767287 TI - [Effects of multidisciplinary blood management strategy on transfusion and outcomes in patients undergoing valvular heart surgery]. AB - To evaluate the effect of multidisciplinary blood management strategy in adults patients undergoing valvular heart surgery. METHODS: A multidisciplinary patient blood management (PBM) strategy was instituted in Fuwai Hospital since January 2009. It includes Establishment of a multidisciplinary blood transfusion management team and designation of a coordinator; Enactment perioperative transfusion triggers (Hb < 80 g/L) for adults patients undergoing cardiac surgery; recommendation of antifibrinolytics, cell salvage, reduced cardiopulmonary bypass circuit; setting up Blood Consumption Announcement and Scoring System, which regularly publishes notifications of blood volume consumed per case, per single procedure and per surgeon. Clinical date before and after multidisciplinary patient blood management strategy will be presented. RESULTS: A total of 3 951 consecutive patients underwent Valvular Heart Surgery were analyzed. 1 713 cases were in pre-PBM group, and 2 238 cases were in post-PBM group. Both incidence and average units of allogeneic red blood cell transfusion perioperatively in post-PBM group were decreased (28.5% vs 75.3%, P = 0.000, and 1.2 U vs 4.0 U, P = 0.000). The postoperative length of stay in hospital and incidence of pneumonia were reduced in post-PBM group (8.2 d vs 10.5 d, P = 0.02, and 2.7% vs 3.5%, P = 0.04). The post-PBM group had lower in-hospital mortality (0.6% vs 1.2%, P = 0.000). CONCLUSION: Multidisciplinary patient blood management strategy significantly reduced blood transfusion, morbidity and mortality in patients underwent valvular heart surgery. It save plenty of blood resources. PMID- 24767288 TI - [Effects of washed autologous blood transfusion on erythrocytic fragility in salvaged blood from diabetics]. AB - OBJECTIVE: To explore the effects of washed autologous blood transfusion on the recovery and hemolysis of erythrocytes from diabetic patients subjected to off pump coronary artery bypass grafting (OP-CABG). METHODS: A total of Sixty patients were included in this study. The patients were assigned as two groups:control (C, n = 30) , and diabetic group (D, n = 30). Samples were taken from preoperation, prior to and after disposal of centrifuging and washing to determine the recovery and fragility of erythrocytes. Free hemoglobin and extracellular potassium were measured at 0, 4, 6, 12, 24 h after washing. RESULTS: The erythrocytic recovery did not have significant difference between two groups (C group 82.6% +/- 5.6%,D group 80.9% +/- 6.2%, P > 0.05) .Under the same processing, the erythrocyte fragility in the diabetic group were significantly higher than the control group in preoperation and before washing (Preoperation 0.36%: D group 84.9% +/- 6.7% C group 78.7% +/- 4.6%, P = 0.003; Preoperation 0.68%: D group 9.0% +/- 4.5% C group 1.9% +/- 0.8%, P = 0.000; Before washing 0.36%: D group 80.6% +/- 4.9% C group 78.0% +/- 5.8%, P = 0.000; Before washing 0.68%: D group 11.0% +/- 3.4% C group 2.4% +/- 0.9%, P = 0.000). However, after washing there were no significant differences of erythrocyte fragility between groups. Free hemoglobin and blood potassium at 4, 6, 12, 24 h after washing were significantly increased (P < 0.05) in a time-dependent manner in the two groups. But there was no obvious difference in the interior-group at the same time point. CONCLUSIONS: Autotransfusion has no significant extra damage on erythrocytes from diabetic patients undergoing OP-CABG, and the salvaged blood should be transfused as soon as possible to reduce hemolysis. PMID- 24767289 TI - [Pretreatment with cisplatin plus hyperthermia kills different tumor cells but preserves the erythrocyte function in the intra-operative blood salvage in vitro]. AB - OBJECTIVE: To investigate the effects of cisplatin plus hyperthermia on erythrocytes and killing human hepatocarcinoma (HepG2), gastro carcinoma (SGC7901) and colonic carcinoma (SW620) cells in the intra-operative blood salvage from cancer surgery in vitro. METHODS: HepG2, SGC7901 or SW620 cells were mixed into the aliquot of erythrocyte concentrated from each intra-operative blood salvage of 30 patients subjected to gastrointestinal cancer surgery. The mixture cells were divided into the following groups (n = 30): A group (37 degrees C); B group (42 degrees C); C, D, E groups (50, 100, or 200 ug/ml DDP); F, G, H, I groups (42 degrees C, 25, 50, 100, or 200 ug/ml DDP). After treating for 60 min, tumor cells and erythrocytes were separated by density gradient centrifugation. The Na(+)-K(+)-ATPase activity, cell count, osmotic fragility, and blood gas variables were determined in erythrocytes. Cell viability and colony formation were determined in tumor cells. RESULTS: Compared with A [(0.30 +/- 0.08) umol Pi/10(7)/h], the Na(+)-K(+)-ATPase activity was significantly decreased in E, H and I groups [(0.24 +/- 0.07), (0.25 +/- 0.06) and (0.24 +/- 0.07) umol Pi/10(7)/h] (P < 0.05). Extra-erythrocytic K(+) in E, H and I groups [(2.16 +/- 0.37), (2.16 +/- 0.38) and (2.56 +/- 0.50) mmol/L] were significantly increased compared with A group [(1.53 +/- 0.43) mmol/L] (P < 0.05). Compared with A group, osmotic fragility in E, H and I groups was significantly increased (P < 0.05). Among B, C, D, E, F, G groups, only in G group colony formations of HepG2, SGC7901, and SW620 (0% +/- 0%, 0% +/- 0% and 0.01% +/- 0.01%) at 14 d were completely inhibited (P < 0.01) compared with A group (78.54% +/- 7.83%, 72.28% +/- 6.58% and 66.69% +/- 6.69%). CONCLUSION: Pretreatment with cisplatin (50 ug/ml) plus hyperthermia (42 degrees C) for 60 min in vitro might be an effective strategy to clear tumor cells contamination but preserve erythrocytes, which is worthy to be optimized and used in the intra-operative blood salvage in cancer surgery. PMID- 24767290 TI - [Correlation study between ischemic stroke and polymorphism of human leucocyte antigen gene]. AB - OBJECTIVE: To explore the correlation between ischemic stroke (IS) and the polymorphism of human leucocyte antigen (HLA) gene. METHODS: Antigen, allele, haplotype of HLA-A, B, C, DRB1, DQB1 in 94 IS patients and 503 healthy controls were detected by PCR-SBT. RESULTS: (1) There were 11 antigens, 17 alleles in HLA A locus, 20 antigens, 34 alleles in HLA-B locus, 11 antigens, 16 alleles in HLA-C locus, 13 antigens, 26 alleles in HLA-DRB1 locus, 5 antigens, 13 alleles in HLA- DQB1 locus in IS group.(2) The allelic frequency of HLA-A*31: 01 (P = 0.016 9, RR = 2.827) , HLA-B* 37: 01 (P = 0.006 6, RR = 4.613) and HLA-DRB1*11: 06 (P = 0.000 2, RR = 37.981) in the IS patients was higher than that in healthy controls.(3) The haplotypic frequency of HLA-DRB1*11: 06-DQB1*03: 01 (P = 0.001, RR = 38.52) in the IS patients was higher than that in healthy controls. CONCLUSION: The susceptibility association of HLA-B*37: 01, HLA-DRB1*11: 06 and HLA-DRB1*11: 06 DQB1*03: 01 with IS and HLA gene play a genetic role in the occurrence of. PMID- 24767291 TI - [Comparison of clinical characteristics of patients with riboflavin responsive lipid storage myopathy versus polymyositis]. AB - OBJECTIVE: To compare the clinical characteristics of riboflavin responsive lipid storage myopathy (RR-LSM) versus polymyositis (PM). METHODS: The clinical data were collected and analyzed for 26 RR-LSM and 15 PM patients from 2003 to 2011 at Peking University First Hospital . RESULTS: The mean onset ages of RR-LSM and PM were (29 +/- 10) and (43 +/- 15) years while the durations before definite diagnosis were (8.2 +/- 8.0) and (2.6 +/- 3.7) years respectively. There were significant inter-group differences in onset age (P = 0.001) and duration before definite diagnosis (P = 0.003). No significant inter-group difference existed in the frequency of limb weakness, dysphagia, neck weakness, dyspnea or myalgia. Dysmasesia occurred in 65.38% of RR-LSM and 26.67% of PM patients and significant inter-group difference existed (P = 0.017). All RR-LSM patients had exercise intolerance with a fluctuating course. Both groups had extra-muscular symptoms and it was more obvious in PM. Mean creatine kinase (CK) level was (1475 +/- 1796) U/L in RR-LSM and (4062 +/- 3448) U/L in PM patients with significant inter group difference (P = 0.017). CONCLUSION: Comparing with PM patients, RR-LSM patients tend to have an earlier onset, a longer diagnosis delay time, fluctuating weakness, a higher frequency of dysmasesia. But there are fewer extra muscular symptoms and a smaller elevation of CK level. PMID- 24767292 TI - [Preliminary study of contrast-enhanced ultrasound in correlation between muscle perfusion deficits in lower extremity arterial disease and its collateralization]. AB - OBJECTIVE: To explore the value of contrast-enhanced ultrasound (CEUS) as a new method in evaluating the correlation between muscle perfusion deficits and collateralization in lower extremity arterial disease (LEAD). METHODS: Ultrasound contrast agent was injected into peripheral vein of 80 control subjects and 80 LEAD patients. Its appearance in calf muscle was detected by contrast-enhanced ultrasound. Time intensity curves (TIC) and time to peak intensity (TTP) were analyzed. And collateral formation was evaluated by computed tomography angiography (CTA) . RESULTS: TTP in LEAD group was statistically higher than that in control group (59.1 vs 38.6 s, P < 0.01) . The TTP difference between two investigators who evaluate the row data in a blinded way was 0.29 s and the area under receiver operating characteristic (ROC) curve 0.92. A TTP cutoff at 47.5 s was associated with 91% positive predictive value statistically. TTP in LEAD with bad collateralization was statistically higher than that in LEAD with good collateralization (67.9 vs 50.4 s, P < 0.01) . CONCLUSION: As a consistent method of evaluating muscle perfusion deficits, CEUS shows a good correlation with the extent of collateral formation in LEAD. PMID- 24767293 TI - [A comparative study on medium-long term results of conventional and eversion endarterectomy in management of carotid artery stenosis: a meta-analysis]. AB - OBJECTIVE: To evaluate the medium-long term effectiveness of eversion (eCEA) and conventional (cCEA) carotid endarterectomy on carotid artery stenosis. METHODS: We searched MEDLINE (1970-2012.12), Ovid (1970-2012), CBM (1970-2012.12) and CNKI (1970-2012.12) database. Relevant journals and dissertation were also hand searched. Study selection and assessment, data collection and analyses were undertaken by two reviewers independently according to the Cochrane Handbook for Systematic Reviews of Interventions. Meta-analyses were performed through software STATA 11.2. RESULTS: A total of 21 studies were deemed eligible (8 617 eCEA and 7 830 cCEA procedures), six of which were randomized and 14 non randomized. Base on 15 121 patients underwent carotid artery stenosis including 16 447 cases, eCEA was association with a shorter mean operation time (WMD -85.00 min, P < 0.001), internal carotid artery clamp time (WMD -3.9 min, P < 0.01) and less shunt usage (OR = 0.20, P < 0.01). Furthermore, eCEA was associated with significant reduction in 30-day mortality (OR = 0.59, P = 0.013), perioperative stroke (OR = 0.63, P = 0.044), residual restenosis (OR = 0.51, P = 0.019) and carotid artery occlusion (OR = 0.44, P = 0.001). Although eCEA did not reduce medium-long term all-caused mortality (OR = 0.81, P = 0.143) during follow-up time, eCEA presented with a significant reduction in late residual restenosis (OR = 0.34, P < 0.01) and carotid artery occlusion (OR = 0.30, P < 0.01). A sub analysis was performed on studies directly comparing eCEA with patch CEA (CEA+P), eCEA replicated the finding on perioperative stroke, 30-day mortality, and stroke related death within short term and late residual restenosis. Concerning outcomes of RCT, eCEA presents with a significant reduction in the residual restenosis (OR = 0.43, 95%CI: 0.27, 0.69, P < 0.01) and carotid artery occlusion (OR = 0.11, 95%CI: 0.02, 0.62, P = 0.012) during following-up time. CONCLUSIONS: Eversion CEA compared to conventional CEA may be associated with a short operation time and a short block time. eCEA appears to be associated with better 30-day mortality and stroke outcome than cCEA. Eversion CEA may be more effective for long-term prevention of restenosis, however, in the long term, it is not associated with a reduction in all-cause mortality. PMID- 24767294 TI - [Diagnostic value of hepatobiliary phase imaging with GD-EOB-DTPA for hepatocellular carcinomas in cirrhosis]. AB - OBJECTIVE: To assess the diagnostic value of hepatobiliary phase imaging with GD EOB-DTPA for hepatocellular carcinomas (HCC) in cirrhosis. METHODS: A total of 43 cirrhotic patients with 45 HCC lesions underwent the examinations of T2WI, DWI, T1WI in-phase and opposed-phase and dynamic contrast enhancement and hepatobiliary phase. Two separate analyses of imaging set with and without hepatobiliary phase images were performed. The confidence scores for HCC diagnosis, consistency, area under the receiver operating characteristic (ROC) curve and sensitivity and positive predictive values of two observers were compared. RESULTS: After adding hepatobiliary phase, there was a significant increase of confidence scores in diagnosing HCC by both observers (P < 0.05) and the consistency of two observers also increased. The area under the ROC curve improved by both observers, but no significant differences were detected (P > 0.05). The sensitivity increased significantly (P < 0.05) and no significant differences were observed for the positive predictive values by both observers (P > 0.05). CONCLUSION: Hepatobiliary phase imaging may improve the diagnostic confidence and sensitivity of GD-EOB-DTPA for HCC in cirrhosis. PMID- 24767295 TI - [Executive dysfunction in patients with temporal lobe epilepsy and its correlation with P300]. AB - OBJECTIVE: To explore the changes of executive function in patients with temporal lobe epilepsy and analyze its correlation with P300 event-related potentials. METHODS: Fifty patients with temporal lobe epilepsy and 30 age, gender and education-matched healthy control subjects were assessed by neuropsychological tests, including Montreal cognitive assessment (MoCA), working memory, verbal fluency, trail making, digit span, digit symbol and Stroop color-word interference to detect P300 event-related potentials. RESULTS: In temporal lobe epilepsy group, the scores in MoCA, verbal and non-verbal working memory, verbal fluency, digit span, digit symbol and Stroop test were lower than those of the normal control group. And trail making tests A and B became prolonged (P < 0.05). Comparing with normal control group, temporal lobe epilepsy patients had prolonged latency [(332 +/- 33)ms] and decreased P300 amplitude [(10 +/- 8)uV] (P < 0.05). Comparing epileptogenic focus group on the left and right sides, there was statistically significant difference in verbal working memory (P < 0.05). There was a negative correlation of P300 latency and MoCA, non-verbal working memory, digit span and digit symbol test scores (r = -0.29--0.45, P < 0.05). And a positive correlation of P300 amplitude and MoCA, non-verbal working memory, digit symbol conversion and Stroop scores was also found (r = 0.37-0.47, P < 0.05). P300 amplitude was more relevant to overall cognitive level and executive functions. CONCLUSION: Temporal lobe is involved in the regulation of executive functions. Besides a wide range of cognitive impairment, temporal lobe epilepsy patients have a number of executive dysfunctions, including working memory, cognitive flexibility, attention and inhibitory control ability. And an impairment of verbal working memory is evident in left-sided lesion. Their manifestations include decreased latency and amplitude of P300 on executive function tests. Therefore these two objective parameters may be employed to evaluate the cognitive impairment in patients with temporal lobe epilepsy. PMID- 24767296 TI - [Effects of thromboprophylaxis duration on coagulation indicators after total hip replacement]. AB - OBJECTIVE: To compare the effects of short-term and long-term thromboprophylaxis after total hip replacement on coagulation indicators in plasma sampled before and 1, 7 and 35 days post-operation. METHODS: A total of 40 patients scheduled for elective total hip replacement were randomly assigned into the short-term (n = 20) or long-term (n = 20) thromboprophylaxis groups on oral rivaroxaban 10 mg once daily for 7 or 35 days. The primary efficacy hemostatic variables included thrombin-antithrombin complexes (TAT), prothrombin fragment 1+2 (F1t2), D-dimer and fibrinogen (Fib) preoperatively and at Days 1, 7 and 35 postoperatively. And ultrasonography was performed on all patients preoperatively and at days 7 and 35 postoperatively to exclude deep vein thrombosis of lower extremities. RESULTS: None of them had deep vein thrombosis (DVT) of lower extremities. Among them, TAT, F1+2, D-dimer and Fib post-operation were higher than those preoperative baseline values. TAT and D-dimer peaked at day 1 postoperatively while the peaks of F1+2 and Fib appeared at day 7 postoperatively. At Day 35 post-operation, the levels of TAT and F1+2 in the long-term thromboprophylaxis group were significantly lower than those of the short-term thromboprophylaxis group (P < 0.05). CONCLUSION: The status of hypercoagulability may sustain at least 35 days after total hip replacement. Though not completely eliminated, it can still be reduced by prolonged thromboprophylaxis. However, according to ultrasonography, the effects of short-term and long-term thromboprophylaxis on the incidence rate of DVT remain to be further explored. PMID- 24767297 TI - [Clinical features in the diagnosis and treatment of ankle fracture with Wagsaffe fragment]. AB - OBJECTIVE: To explore the methods in the diagnosis and treatment of ankle fracture with Wagsaffe fragment. METHODS: Among 1 201 patients, there were 18 cases of concurrent Wagstaffe fractures at our hospital between January 2009 to January 2012. There were 11 males and 7 females with an average of 37.4 (17-54) years. The causes of injuries were fall (n = 10), sports-related injury (n = 4), traffic injury (n = 3) and high-altitude fall (n = 1). All of them had lateral malleolar fracture. Other injuries included internal malleolar fracture (n = 16), posterior malleolar fracture (n = 8) and disruption of medial deltoid ligament (n = 3). According to the Lauge-Hansen system, all fractures were of supination external rotation type. The fractures of fibula and Wagstaffe were explored through an anterolateral approach. The lateral malleolar fracture was fixed with plate While Wagstaffe fragment secured with lag screw or thread. Disrupted anterior tibiofibular ligament was restored. Other treatments included open reduction and internal fixation of medial and posterior malleolus, repair of medial deltoid ligament and screw fixation of disrupted tibiofibular syndesmosis. Ankle function was evaluated by the Baird-Jackson criteria. RESULTS: Wagstaffe fracture occurred at a rate of 1.5% in ankle fractures. Wagstaffe fracture was found in 4.4% of ankle fracture of supination-external rotation type. Seventeen patients were followed up over an average follow-up period of 16.8 (12-25) months. All radiographs showed union of all fractures and normal mortise. Baird Jackson ankle functional score was from 81 to 99. In all 17 patients, 9 were rated as excellent, 5 as good and 3 as fair. The excellent and good rate was 87.4%. At the latest follow-up, 14 patients resumed their preinjury activities. CONCLUSION: As an easily misdiagnosed condition, Wagstaffe fracture is associated with ankle diastase and prone to occur in ankle fracture of supination-external rotation type. Accurate reduction and stable fixation facilitate the restoration of stable syndesmosis in the treatment of ankle fracture with concurrent Wagsaffe fragment. PMID- 24767298 TI - [Value of modified Allis technique in closed reduction of posteriorly dislocated hip with Pipkin I/II fracture]. AB - OBJECTIVE: To explore the value of modified Allis technique in closed reduction of posteriorly dislocated hip. METHODS: For the control group, 98 cases of dislocated hips with Pipkin I/II fracture were studied retrospectively and their success reduction rates analyzed. For the experimental group, 36 cases with similar injury were studied prospectively. And the modified Allis technique was used and the success reduction rates were analyzed. RESULTS: Among the control group, 32 cases were reduced with a success rate of 67.3%. The success rate was 69.4% for the experimental group. And 97.2% of those unresponsive to the Allis technique were all successfully reduced by the modified Allis technique. CONCLUSION: The modified Allis technique is efficacious for posteriorly dislocated hips with Pipkin I/II fracture. PMID- 24767299 TI - [Adhesion prevention after Cesarean section by short-term biological barrier of modified chitosan]. AB - OBJECTIVE: To evaluate the efficacies of modified chitosan, an adhesive prevention substance, as a biological barrier for preventing adhesion after Cesarean section. METHODS: A total of 250 cases undergoing primary Cesarean section from January 2011 to June 2012 at our hospital were recruited. They were randomly divided into experiment (n = 130) and control (n = 120) groups. The experiment group received modified chitosan during Cesarean section while no adhesive prevention substance was offered for the control group. Postoperative flatus time, postoperative infection and pelvic adhesion were used to evaluate the clinical efficacies. RESULTS: For the experiment group, the average postoperative flatus time was (25 +/- 7) hours. Three cases had postoperative infections with a postoperative infection rate of 2.3%. There were 2 cases of pelvic adhesion (pelvic adhesion rate: 1.5%) during the postoperative follow-up period. For the control group, the average postoperative flatus time was (34 +/- 11) hours. Five cases had postoperative infections with a postoperative infection rate of 4.2%. There were 5 cases of pelvic adhesion (pelvic adhesion rate: 4.2%) during the postoperative follow-up period. There were significant inter-group differences in postoperative flatus time, postoperative infection and pelvic adhesion (P < 0.05). CONCLUSION: Modified chitosan can prevent pelvic adhesion after Cesarean section. PMID- 24767300 TI - [Effects of transplanted neural stem cells on synaptogenesis in APP/PS1 mice]. AB - OBJECTIVE: To explore the effects of transplanted neural stem cells (NSCs) on synaptogenesis in an Alzheimer' disease (AD) murine model and related mechanism. METHODS: Twenty 9-month-old APP/PS1 double transgenic mice were randomly divided into 2 groups. One group received NSCs transplantation (NSC group) in bilateral hippocampi while another group received an equal volume of 0.01 mol/L phosphate buffer saline (PBS group) as a negative control group. Ten wild-type mice were selected as the positive control group (WT group) without any treatment. After 8 week transplantation, the expressions of synaptophysin (SYN) and growth associated protein-43 (GAP-43) proteins in hippocampal areas were analyzed by immunofluorescence and Western blot. The number and structure of synapses in transplanted regions were observed by electron microscopy. RESULTS: (1) Immunofluorescence staining showed that NSC-induced neurons highly expressed SYN and GAP-43 at the protein levels; (2) the expression of SYN and GAP-43 significantly increased in the NSC group versus the PBS group (F = 58.367, P < 0.01; F = 75.296, P < 0.01). No difference existed in the SYN level between NSC and WT groups (P > 0.05). However, the GAP-43 expression was significantly higher than that of the WT group (P < 0.01); (3) ultrastructure showed that the number of synapses in the NSC group with normal morphology (12.1 +/- 2.1) increased than that in the PBS group (6.5 +/- 2.2) (F = 15.981, P < 0.01). No difference existed between NSC and WT groups (11.0 +/- 1.4) (P > 0.05). CONCLUSION: NSC-induced neurons increase the number of synapses by an up-regulation of synaptic proteins, SYN and GAP-43. Thus synaptogenesis may be a key factor in improving the symptom of AD mice. PMID- 24767301 TI - [Construction of recombinant adenovirus vector co-expressing VEGF165 and SDF-1 genes and its expression in ischemic cerebral tissue of rats]. AB - OBJECTIVE: To construct a recombinant adenoviral vector carrying and co expressing vascular endothelial growth factor 165 (VEGF165) and stromal cell derived factor 1 (SDF-1) and explore its co-expression in ischemic brain tissue in rats. METHODS: The VEGF165 and SDF-1 genes were directionally connected with internal ribosome entry site (IRES). And the double gene co-expression recombinant shuttle plasmid pDC316-VEGF165-IRES-SDF-1 was built with homologous recombination. The resultant plasmid pDC316-VEGF165-IRES-SDF-1 and backbone plasmid pBHGlox_E1, 3Cre were transfected into HEK293 cells by liposome and the recombinant adenoviral particles capable of infection were acquired. With the rounds of amplification, the purified adenoviral vector Ad5-VEGF165-IRES-SDF-1 was obtained with a titer of up to 1*10(10) IU/ml. The rat model of middle cerebral artery occlusion (MCAO) was established by intra-luminal suturing. And the viral vectors were transfused into the lateral ventricle by a stereotactic microinjection. The expressions of VEGF165 and SDF-1 in ischemic brain tissue were examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: The results of PCR, double enzyme digestion and gene sequencing showed that both the recombinant plasmid and the constructed adenoviral vector were expressed. And the adenoviral vector Ad5-VEGF165-IRES-SDF 1 could mediate a co-expression of VEGF165 and SDF-1 in ischemic cerebral tissue. CONCLUSION: The recombinant adenoviral vector carrying VEGF165 and SDF-1 are successfully constructed. And Ad5-VEGF165-IRES-SDF-1 may mediate a co-expression of VEGF165 and SDF-1 in ischemic cerebral tissue of rats. PMID- 24767302 TI - Retinal vessel oxygen saturation and vessel diameter in retinitis pigmentosa. AB - PURPOSE: To assess retinal vessel oxygen saturation and retinal vessel diameter in retinitis pigmentosa. METHODS: A retinal oximeter (Oxymap ehf., Reykjavik, Iceland) was used to measure retinal vessel oxygen saturation and vessel diameter in ten patients with retinitis pigmentosa (RP) (mean age 49 years, range 23-71 years). Results were compared with age- and gender-matched healthy individuals. All patients had advanced stage of the disease with visual fields restricted to the macular region. RESULTS: Oxygen saturation in retinal venules was 58.0 +/- 6.2% in patients with RP and 53.4 +/- 4.8% in healthy subjects (p = 0.017). Oxygen saturation in retinal arterioles was not significantly different between groups (p = 0.65). The mean diameter of retinal arterioles was 8.9 +/- 1.6 pixels in patients with RP and 11.4 +/- 1.2 in healthy controls (p < 0.0001). The corresponding diameters for venules were 10.1 +/- 1.2 (RP) and 15.3 +/- 1.7 (healthy, p < 0.0001). CONCLUSIONS: Increased venous saturation and decreased retinal vessel diameter suggest decreased oxygen delivery from the retinal circulation in retinitis pigmentosa. This is probably secondary to tissue atrophy and reduced oxygen consumption. PMID- 24767303 TI - A systematic review of explanatory factors of barriers and facilitators to improving asthma management in South Asian children. AB - BACKGROUND: South Asian children with asthma are less likely to receive prescriptions and more likely to suffer uncontrolled symptoms and acute asthma admissions compared with White British children. Understanding barriers are therefore vital in addressing health inequalities. We undertook a systematic review identifying explanatory factors for barriers and facilitators to asthma management in South Asian children. South Asians were defined as individuals of Indian, Pakistani or Bangladeshi descent. METHODS: Data Sources - Medline, HMIC, EMBASE, ASSIA, Web of Science, BNI, CINAHL, PsycINFO, OpenSIGLE, CRD, Scopus, NHS Evidence, Cochrane Library, Campbell Collaboration, RCPCH, ATS, ERS, Asthma UK, Google Scholar & Asthma Guidelines (BTS, GINA, ATS, Monash, NAEPP, Singapore & New Zealand) to August 2013.Inclusion Criteria - Qualitative, quantitative or mixed methods research with primary focus on identifying explanations for barriers and/or facilitators to asthma management in South Asian children aged 0 18 years with diagnosed/suspected asthma and/or carers and/or healthcare professionals.Data Extraction - Three authors independently reviewed, selected & extracted eligible articles with disagreements resolved by research team discussion. RESULTS: 15 studies encompassing 25,755 children, 18,483 parents/carers and 239 healthcare professionals were included. Barriers and explanatory factors identified were:1. Lack of asthma knowledge in families and healthcare professionals.2. Under-use of preventer medications.3. Non acceptance/denial of asthma.4. Over-reliance on Emergency Department management.5. Communication problems.6. Non-adherence to medication.7. Use of complementary therapies.Little facilitators regarding asthma management were identified. CONCLUSIONS: Several key issues were identified as likely to be ethnic-specific to South Asian families, rather than a reflection of minority status: impact of parental and professional knowledge and beliefs, health service utilisation pattern explanations and the impact of prejudice and stigmatisation. Other explanations such as language barriers are not strictly ethnic specific but instead reflect a minority position.Further research is required to identify why barriers exist, the mechanisms by which they impact on asthma management and how they can be overcome. Furthermore, understanding the difference between barriers and explanations that are ethnic-specific and those that are related to being a minority will enable the application of generic system-wide interventions where ethnicity is not the issue and ethnically-tailored interventions where needed. PMID- 24767304 TI - High density SNP and SSR-based genetic maps of two independent oil palm hybrids. AB - BACKGROUND: Oil palm is an important perennial oil crop with an extremely long selection cycle of 10 to 12 years. As such, any tool that speeds up its genetic improvement process, such as marker-assisted breeding is invaluable. Previously, genetic linkage maps based on AFLP, RFLP and SSR markers were developed and QTLs for fatty acid composition and yield components identified. High density genetic maps of crosses of different genetic backgrounds are indispensable tools for investigating oil palm genetics. They are also useful for comparative mapping analyses to identify markers closely linked to traits of interest. RESULTS: A 4.5 K customized oil palm SNP array was developed using the Illumina Infinium platform. The SNPs and 252 SSRs were genotyped on two mapping populations, an intraspecific cross with 87 palms and an interspecific cross with 108 palms. Parental maps with 16 linkage groups (LGs), were constructed for the three fruit forms of E. guineensis (dura, pisifera and tenera). Map resolution was further increased by integrating the dura and pisifera maps into an intraspecific integrated map with 1,331 markers spanning 1,867 cM. We also report the first map of a Colombian E. oleifera, comprising 10 LGs with 65 markers spanning 471 cM. Although not very dense due to the high level of homozygosity in E. oleifera, the LGs were successfully integrated with the LGs of the tenera map. Direct comparison between the parental maps identified 603 transferable markers polymorphic in at least two of the parents. Further analysis revealed a high degree of marker transferability covering 1,075 cM, between the intra- and interspecific integrated maps. The interspecific cross displayed higher segregation distortion than the intraspecific cross. However, inclusion of distorted markers in the genetic maps did not disrupt the marker order and no map expansion was observed. CONCLUSIONS: The high density SNP and SSR-based genetic maps reported in this paper have greatly improved marker density and genome coverage in comparison with the first reference map based on AFLP and SSR markers. Therefore, it is foreseen that they will be more useful for fine mapping of QTLs and whole genome association mapping studies in oil palm. PMID- 24767305 TI - [Comparison of fertiloscopy versus laparoscopy in the exploration of the infertility: analysis of the literature]. AB - BACKGROUND: Fertiloscopy is a recent technique designed to explore the tubo ovarian axis in unexplained infertility. It is a simple outpatient technique, allowing to perform operative procedures, but its position relative to laparoscopy is yet to be defined. MATERIAL AND METHODS: A thorough and extensive bibliographical search was undertaken to fully embrace the question, challenging Medline at the National Library of Medicine, Cochrane Library, National Guideline Clearinghouse, Health Technology Assessment Database. All the retrieved articles were classified as either descriptive or comparative studies and evaluated on a set of criteria. RESULTS: Most of the papers described case series coming from a few teams, focusing mainly on the technical aspect of the procedure, like the access rate to the posterior cul-de-sac, the success rate in visualizing the pelvis, the complications rate (mainly rectal perforation), and its operative performance in drilling ovaries for resistant polycystic ovarian syndrome. Comparative studies numbered six trials. They all followed the same design, fertiloscopy preceding conventional laparoscopy in patients taken as their own control. The concordance rate between the two modalities reaches 80% in terms of tubal pathology, adherences and endometriosis, with an estimated reduction of laparoscopies varying from 40% to 93%. CONCLUSION: The current literature shows a concordance between fertiloscopy and conventional laparoscopic findings for certain parameters in cases of tubal pathology, adherences and endometriosis. The relative positions of these two modalities in unexplained infertility still remain elusive. PMID- 24767306 TI - Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features. AB - BACKGROUND: To characterize cathepsin K (CTSK) mutations in a group of patients with pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics. METHODS: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study. RESULTS: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence; among them, only L7P and I249 were described previously. The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest. Patients with M1I mutation had fractures, at younger ages than the other pycnodysostosis cases in our cohort which were most probably related to the severity of mutation, since M1I initiates the translation, and mutation might lead to the complete absence of the protein. The typical finding of pycnodysostosis, acroosteolysis, could not be detected in two patients, although other patients carrying the same mutations had acroosteolysis. Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations. CONCLUSIONS: We described a large cohort of pycnodysostosis patients with genetic and phenotypic features, and, first Alu sequence insertion in pycnodysostosis. PMID- 24767307 TI - Maternal supplementation with n-3 long chain polyunsaturated fatty acids during perinatal period alleviates the metabolic syndrome disturbances in adult hamster pups fed a high-fat diet after weaning. AB - Perinatal nutrition is thought to affect the long-term risk of the adult to develop metabolic syndrome. We hypothesized that maternal supplementation with eicosapentaenoic acid and docosahexaenoic acid during pregnancy and lactation would protect offspring fed a high-fat diet from developing metabolic disturbances. Thus, two groups of female hamsters were fed a low-fat control diet, either alone (LC) or enriched with n-3 long chain polyunsaturated fatty acids (LC-PUFA) (LO), through the gestational and lactation periods. After weaning, male pups were randomized to separate groups that received either a control low-fat diet (LC) or a high-fat diet (HC) for 16 weeks. Four groups of pups were defined (LC-LC, LC-HC, LO-LC and LO-HC), based on the combinations of maternal and weaned diets. Maternal n-3 LC-PUFA supplementation was associated with reduced levels of basal plasma glucose, hepatic triglycerides secretion and postprandial lipemia in the LO-HC group compared to the LC-HC group. Respiratory parameters were not affected by maternal supplementation. In contrast, n-3 LC PUFA supplementation significantly enhanced the activities of citrate synthase, isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase compared to the offspring of unsupplemented mothers. Sterol regulatory element binding protein 1c, diacylglycerol O-acyltransferase 2, fatty acid synthase, stearoyl CoA desaturase 1 and tumor necrosis factor alpha expression levels were not affected by n-3 LC-PUFA supplementation. These results provide evidence for a beneficial effect of n-3 LC-PUFA maternal supplementation in hamsters on the subsequent risk of metabolic syndrome. Underlying mechanisms may include improved lipid metabolism and activation of the mitochondrial oxidative pathway. PMID- 24767308 TI - Structure-dependent effects of pyridine derivatives on mechanisms of intestinal fatty acid uptake: regulation of nicotinic acid receptor and fatty acid transporter expression. AB - Pyridines are widely distributed in foods. Nicotinic acid (NA), a carboxylated pyridine derivative, inhibits lipolysis in adipocytes by activation of the orphan NA receptor (HM74A) and is applied to treat hyperlipidemia. However, knowledge on the impact of pyridine derivatives on intestinal lipid metabolism is scarce. This study was performed to identify the structural determinants of pyridines for their effects on fatty acid uptake in enterocyte-like Caco-2 cells and to elucidate the mechanisms of action. The impact of 17 pyridine derivatives on fatty acid uptake was tested. Multiple regression analysis revealed the presence of a methyl group to be the structural determinant at 0.1 mM, whereas at 1 mM, the presence of a carboxylic group and the N-methylation presented further structural characteristics to affect the fatty acid uptake. NA, showing a stimulating effect on FA uptake, and N-methyl-4-phenylpyridinium (MPP), inhibiting FA uptake, were selected for mechanistic studies. Gene expression of the fatty acid transporters CD36, FATP2 and FATP4, and the lipid metabolism regulating transcription factors peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma was up-regulated upon NA treatment. Caco-2 cells were demonstrated to express the low-affinity NA receptor HM74 of which the gene expression was up-regulated upon NA treatment. We hypothesize that the NA-induced fatty acid uptake might result from NA receptor activation and related intracellular signaling cascades. In contrast, MPP increased transepithelial electrical resistance. We therefore conclude that NA and MPP, both sharing the pyridine motif core, exhibit their contrary effects on intestinal FA uptake by activation of different mechanisms. PMID- 24767309 TI - Aspartate alleviates liver injury and regulates mRNA expressions of TLR4 and NOD signaling-related genes in weaned pigs after lipopolysaccharide challenge. AB - Pro-inflammatory cytokines play a critical role in many models of liver injury. In addition, aspartate (Asp) plays an important role in many biological and physiological processes including liver physiology. We hypothesized that Asp could alleviate lipopolysaccharide (LPS)-induced liver injury. Forty-eight weanling pigs were assigned to four treatments including: (1) non-challenged control; (2) LPS challenged control; (3) LPS+0.5% Asp; (4) LPS+1.0% Asp. After 20 d feeding with control (0% Asp), 0.5% or 1.0% Asp supplemented diets, pigs were injected with saline or LPS. At 4 (early phase) and 24 h (late phase) post injection, blood and liver samples were obtained. Asp attenuated liver injury indicated by reduced serum aspartate aminotransferase activity and increased ratio of serum alanine aminotransferase and aspartate aminotransferase at 24 h, and less severe histological liver damage induced by LPS challenge at 4 or 24 h. In addition, Asp supplementation to LPS challenged pigs decreased mRNA expressions of tumor necrosis factor (TNF)-alpha and cyclooxygenase-2 linearly and quadratically at 4 h, and increased mRNA expressions of these pro inflammatory mediators linearly and quadratically at 24 h. Finally, Asp decreased mRNA expression of toll-like receptor 4 (TLR4) signaling related genes (TLR4, myeloid differentiation factor 88, IL-1 receptor-associated kinase 1, TNF-alpha receptor-associated factor (6), nucleotide-binding oligomerization domain protein (NOD) signaling related genes (NOD1, NOD2 and receptor-interacting serine/threonine-protein kinase 2) and nuclear factor-kappaB p65 linearly or quadratically at 4 h. However, Asp increased mRNA expressions of these signaling molecules linearly or quadratically at 24 h. These results indicate that, at early and late phases of LPS challenge, Asp exerts opposite regulatory effects on mRNA expression of hepatic pro-inflammatory cytokines and TLR4 and NOD signalling related genes, and improves liver integrity. PMID- 24767310 TI - Comparison of frequencies and prognostic effect of molecular subtypes between young and elderly breast cancer patients. AB - PURPOSE: To compare the distribution and prognostic effect of the breast cancer molecular subtypes in young and elderly breast cancer patients. PATIENTS AND METHODS: Our study population (n = 822) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. A total of 142/822 fresh frozen tissues were available with good quality RNA and analyzed by gene expression microarray. Gene expression molecular subtypes were determined by correlation to the expression centroids of 534 "intrinsic" genes. Sections of a tissue micro array containing formalin-fixed paraffin-embedded tumor tissue of 714/822 patients were immunohistochemically (IHC) stained for Ki67, EGFR, CK5/6. Tumor expression of ER, PR, HER2 was previously determined. IHC molecular subtypes were defined based on expression of these markers: Luminal A: ER+ and/or PR+, HER2- and Ki67-; Luminal B: ER+ and/or PR+ and ki67+; ERBB2: ER-, PR- and HER2+; Basal-like: ER-, PR-, HER2- and EGFR+ and/or CK5/6+; Unclassified: ER-, PR-, HER2-, EGFR- and CK5/6-. IHC molecular subtypes were validated against gene expression defined molecular subtypes. Assessment of distribution and prognostic effect of molecular subtypes was stratified to age (<65 versus >=65 years). RESULTS: Validation of molecular subtypes determined by IHC against gene expression revealed a substantial agreement in classification (Cohen's kappa coefficient 0.75). A statistically significant association (p = 0.02) was found between molecular subtypes and age, where Luminal tumors were more often found in elderly patients, while ERBB2, basal-like and unclassified subtypes were more often found in young patients. Molecular subtypes showed a prognostic association with outcome in young patients concerning relapse-free period (RFP) (p = 0.01) and relative survival (RS) (p < 0.001). No statistically significant prognostic effect was found for molecular subtypes in elderly patients (RFP p = 0.5; RS p = 0.1). Additional analyses showed that no molecular subtypes showed a statistically significant difference in outcome for elderly compare to young patients. CONCLUSION: We have shown that molecular subtypes have a different distribution and prognostic effect in elderly compared to young breast cancer patients, emphasizing the fact that biomarkers may have different distributions and prognostic effects and therefore different implications in elderly compared to their younger counterparts. Our results support the premise that breast cancer clinical behavior is significantly affected by patient age. We suggest that competing risks of death in elderly patients, ER-driven differences and micro-environmental changes in biology are underlying these age-dependent variations in patient prognosis. PMID- 24767311 TI - Management accounting use and financial performance in public health-care organisations: evidence from the Italian National Health Service. AB - Reforms of the public health-care sector have emphasised the role of management accounting (MA). However, there is little systematic evidence on its use and benefits. To fill this gap, we propose a contingency-based model which addresses three related issues, that is, whether: (i) MA use is influenced by contextual variables and MA design; (ii) top-management satisfaction with MA mediates the relationship between MA design and MA use; and (iii) financial performance is influenced by MA use. A questionnaire was mailed out to all Italian public health care organisations. Structural equation modelling was performed to validate the research hypotheses. The response rate was 49%. Our findings suggest that: (i) cost-containment strategies encourage more sophisticated MA designs; (ii) MA use is directly and indirectly influenced by contingency, organisational, and behavioural variables; (iii) a weakly significant positive relationship exists between MA use and financial performance. These findings are relevant from the viewpoint of both top managers and policymakers. The former must make sure that MA is not only technically advanced, but also properly understood and appreciated by users. The latter need to be aware that MA may improve performance in ways and along dimensions that may not fully translate into better financial results. PMID- 24767312 TI - C-reactive protein prior to percutaneous coronary intervention: do we still need to check the lipid panel? PMID- 24767313 TI - Intra-stent tissue evaluation within bare metal and drug-eluting stents > 3 years since implantation in patients with mild to moderate neointimal proliferation using optical coherence tomography and virtual histology intravascular ultrasound. AB - OBJECTIVE: We aimed to compare neointimal tissue characteristics between bare metal stents (BMS) and drug-eluting stents (DES) at long-term follow-up using optical coherence tomography (OCT) and virtual histology intravascular ultrasound (VH-IVUS). BACKGROUND: Neoatherosclerosis in neointima has been reported in BMS and in DES. METHODS: Thirty patients with 36 stented lesions [BMS (n=17) or DES (n=19)] >3years after implantation were prospectively enrolled. OCT and VH-IVUS were performed and analyzed independently. Stents with >=70% diameter stenosis were excluded. RESULTS: The median duration from implantation was 126.0months in the BMS group and 60.0months in the DES group (p <0.001). Lipid-laden intima (58.8% vs. 42.1%, p=0.317), thrombus (17.6% vs. 5.3%, p=0.326), and calcification (35.3% vs. 26.3%, p=0.559) did not show significant differences between BMS and DES. When divided into 3 time periods, the cumulative incidence of lipid-laden neointima from >3years to <9years was similar between BMS and DES (42.9% vs. 42.1%, p=1.000). Furthermore, it continued to gradually increase over time in both groups. OCT-derived thin-cap fibroatheroma (TCFA) was observed in 17.6% of BMS- and 5.3% of DES-treated lesions (p=0.326). No stents had evidence of intimal disruption. The percentage volume of necrotic core (16.1% [9.7, 20.3] vs. 9.7% [7.0, 16.5], p=0.062) and dense calcium (9.5% [3.8, 13.6] vs. 2.7% [0.4, 4.9], p=0.080) in neointima tended to be greater in BMS-treated lesions. Intra-stent VH TCFA (BMS vs. DES 45.5% vs. 18.2%, p=0.361) did not differ significantly. CONCLUSION: At long-term follow-up beyond 3 years after implantation, the intra stent neointimal tissue characteristics appeared similar for both BMS and DES. PMID- 24767315 TI - Detection of 34 plasticizers and 25 flame retardants in indoor air from houses in Sapporo, Japan. AB - Various plasticizers and flame retardants are contained in building materials and furniture produced for indoor environments. However, some of these material inclusions have been reported to cause endocrine-disrupting and mucosa-irritating effects. Because of the local climate, buildings in Sapporo are better insulated against cold weather than those in many other areas in Japan. In this study, we measured 59 compounds, including plasticizers (phthalates, adipates, and others) and flame retardants (organo-phosphates and brominated compounds), from indoor air samples from six houses in Sapporo. These compounds were measured separately in the gas phase and the particle phase using a two-stage cartridge equipped with a quartz fiber filter (1 MUm mesh) and C18 solid-phase extraction disk for sampling and analyzed by GC/MS and LC/MS/MS (for the detection of brominated flame retardants). Among the 59 compounds measured in this study, 34 compounds were detected from the indoor air of the six houses. The highest concentration among the 34 compounds found in a newly built house was 2,2,4-trimethyl-1,3 pentanediol monoisobutyrate (TXIB) at 20.8 MUg/m(3). Di(2-ethyl-1 hexyl)terephthalate (DEHT), which has been used in recent years as an alternative to di(2-ethyl-1-hexyl)phthalate (DEHP), was found in all six houses, although at low concentrations ranging from 0.005 to 0.027 MUg/m(3). To our knowledge, this is the first report of DEHT in indoor air in Japan. Among the compounds detected in this study, those with lower molecular weights tended to be captured in the C18 solid-phase extraction disk rather than in the quartz fiber filter. These results suggest that compounds with higher volatility exist preferentially in the gas phase, whereas compounds with lower volatility exist preferentially in the particulate phase in indoor air. PMID- 24767314 TI - Aortic valve ChromaFlo(r): a feasibility study of aortic regurgitation and effective annular aortic area assessment in a porcine model. AB - Aortic valve annular complex was rediscovered after the introduction of transcatheter aortic valve replacement; and imaging has been crucial in determining the annular geometry. Although the procedure has evolved, complications related to the annular mechanical response following valve implantation, such as aortic insufficiency, still occur in practice. We documented the feasibility of invasive assessment of aortic valve annular complex and the detection of induced aortic insufficiency via intravascular ultrasound with ChromaFlo(r) technology in a porcine model. PMID- 24767316 TI - Challenges to estimate surface- and groundwater flow in arid regions: the Dead Sea catchment. AB - The overall aim of the this study, which was conducted within the framework of the multilateral IWRM project SUMAR, was to expand the scientific basement to quantify surface- and groundwater fluxes towards the hypersaline Dead Sea. The flux significance for the arid vicinity around the Dead Sea is decisive not only for a sustainable management in terms of water availability for future generations but also for the resilience of the unique ecosystems along its coast. Coping with different challenges interdisciplinary methods like (i) hydrogeochemical fingerprinting, (ii) satellite and airborne-based thermal remote sensing, (iii) direct measurement with gauging station in ephemeral wadis and a first multilateral gauging station at the river Jordan, (iv) hydro-bio geochemical approach at submarine and shore springs along the Dead Sea and (v) hydro(geo)logical modelling contributed to the overall aim. As primary results, we deduce that the following: (i) Within the drainage basins of the Dead Sea, the total mean annual precipitation amounts to 300 mm a(-1) west and to 179 mm a(-1) east of the lake, respectively. (ii) The total mean annual runoff volumes from side wadis (except the Jordan River) entering the Dead Sea is approximately 58-66 * 10(6) m(3) a(-1) (western wadis: 7-15 * 10(6) m(3) a(-1); eastern wadis: 51 * 10(6) m(3) a(-1)). (iii) The modelled groundwater discharge from the upper Cretaceous aquifers in both flanks of the Dead Sea towards the lake amounts to 177 * 10(6) m(3) a(-1). (iv) An unexpected abundance of life in submarine springs exists, which in turn explains microbial moderated geo-bio-chemical processes in the Dead Sea sediments, affecting the highly variable chemical composition of on- and offshore spring waters.The results of this work show a promising enhancement of describing and modelling the Dead Sea basin as a whole. PMID- 24767319 TI - Utilization of bioreactance technique as indicator for preload responsiveness during living donor liver donation. AB - BACKGROUND: Fluid restriction has been used to decrease central venous pressure as a strategy of fluid management during living donor liver donation (LDLD). However, potential risks such as hemodynamic instability are also involved during the procedure. Monitoring of preload or preload responsiveness is therefore crucial during LDLD. The aim of this study was to explore the efficiency of an innovative bioreactance method that introduced the noninvasive cardiac output monitor (NICOM, Cheetah Medical, Vancouver, Wash, United States), as surrogate indicator for preload responsiveness during LDLD. METHODS: Twenty-six patients underwent LDLD and were enrolled in this study. Fluid was restricted until the organ was harvested. The ultrasonic cardiac output monitor (USCOM Ltd, Sydney, Australia) was applied to measure stroke volume (SV) before and after 500 mL of 6% hydroxyethyl starch 130/0.4 (Voluven, Fresenius Kabi, Friedberg, Germany) fluid challenge, and the value of SV variation (SVV) from NICOM was also recorded. Fluid responsiveness was defined if SV increased by more than 15%. Receiver operating characteristic (ROC) curve was performed. RESULTS: The area under the ROC curve was 0.6023. The optimal cutoff value of SVV from NICOM was 12% during LDLD. CONCLUSIONS: Our study has shown that SVV measured from the bioreactance technique is a poor indicator for monitoring preload responsiveness during LDLD. PMID- 24767318 TI - Magnetic resonance fat quantification in living donor liver transplantation. AB - OBJECTIVE: Hepatic steatosis can cause substantial problems for both donors and recipients in living donor liver transplantation (LDLT). The aim of this study is to evaluate the accuracy of the magnetic resonance IDEAL (iterative decomposition of water and fat with echo asymmetry and least squares estimation) sequence in quantifying the liver fat during LDLT. MATERIALS AND METHODS: A total of 63 liver donors (29 men and 34 women ranging from 18 to 47 years old with a mean age of 30) who received both magnetic resonance imaging (MRI) and intraoperative liver biopsy were enrolled in this study. MR IDEAL IQ sequences were performed by 1.5-T MRI (Discovery 450; GE Healthcare, Milwaukee, Wis, United States) to estimate the liver fatty content. Accuracy was assessed through linear regression between fat fraction image and pathology grading. Sensitivity and specificity of MR IDEAL IQ fat fractions were also calculated. RESULTS: A total of 63 LDLTs were performed and with pathology grading. No fatty content was found in 48 donors (76.2%; group 1), 5% to 10% fatty liver in 11 donors (17.4%; group 2), 11% to 15% fatty liver in 2 donors (3.2%; group 3), and >16% fatty change in 2 donors (3.2%; group 4). MR IDEAL fat fraction results were excellent in prediction of the normal and fatty content and with good correlation with the pathology grading (2.9 +/- 0.9, 8.3 +/- 4.2, P < .0001). Linear regression between IDEAL image and pathology grading indicated a high accuracy rate (R(2) = 0.813, R(2) = 0.9286) for all 4 groups. The sensitivity and specificity for detection of liver steatosis in MRI fat fraction image were 100% and 77.1% (P < .0001, 95% confidence interval 0.000 1.000). CONCLUSION: MR IDEAL IQ sequencing is a highly precise and accurate method in quantifying hepatic steatosis for the living donor. PMID- 24767320 TI - Corrected flow time is a good indicator for preload responsiveness during living donor liver donation. AB - BACKGROUND: Corrected flow time (FTc) has been utilized as preload indicator in recent literature. Accurate estimation of preload status during living donor liver donation (LDLD) is important due to fluid restriction. We evaluate the effectiveness of FTc as a surrogate of preload indicator during LDLD. MATERIALS AND METHODS: Twenty-five patients undergoing LDLD were enrolled in the study. Administration of intravenous fluid was restricted before lobectomy was performed. After the organ was harvest, fluid challenge with 500 mL of Voluven (130/0.42, Fresenius, Friedberg, Germany) was performed. Stroke volume (SV) was measured with ultrasonic cardiac output monitor (USCOM; USCOM Pty, Ltd, Sydney, Australia) before and after the fluid challenge. The FTc value obtained with USCOM before fluid challenge was recorded. Fluid responsiveness was defined as an increase in SV of more than 15%. Receiver operating characteristic (ROC) curve was performed. RESULTS: The area under ROC curve was 0.9. The optimal cutoff FTc value was 340 milliseconds during LDLD. CONCLUSIONS: FTc is a noninvasive, easily obtainable, and essentially good preload indicator during LDLD. PMID- 24767321 TI - Donors' quality of life evaluated by short form-36 analysis after living donor liver transplantation in a single-center experience. AB - BACKGROUND AND PURPOSE: The purpose of this study was to compare the quality of life of donors using the Short Form 36 (SF-36) analysis between the left and right graft periods of living donor liver transplantation. PATIENTS AND METHODS: In the left graft period (July 1991 to July 2003), 68 donors were eligible for analysis and 76 were eligible in the right graft period (August 2003 to October 2010). Nine right lobe grafts were included in the left graft period, and 52 right lobe grafts were included in the right graft period. We investigated the risks of donation and evaluated the following: blood loss, operation time, postoperative liver function, and duration of hospitalization. We also assessed quality of life in donors, who were mailed a structured questionnaire and the SF 36. RESULTS: Ten of the 68 donors in the left graft period and 12 of the 76 in the right graft period had postoperative complications. Most postoperative complications were treated without surgical procedures. There was no donor death in our series. Forty-eight donors in the left graft period and 36 in the right graft period responded to our investigation. Compared with published Japanese norms in SF-36, our donors scored similar or higher than the general population in both groups. Two donors in the left graft period and one in the right graft period regretted their decisions to donate. All donors returned to normalcy. CONCLUSIONS: These results suggested that the donors' quality of life was guaranteed in terms of the SF-36 investigation regardless of the donation period in our series. PMID- 24767322 TI - External biliary drainage in living donor liver transplantation using duct-to duct anastomosis. AB - PURPOSE: This study compared the incidence of biliary complication (BC) in adult living donor liver transplant recipients who underwent right-lobe duct-to-duct anastomosis (DDA) with or without external biliary drainage (EBD) and intended to optimize EBD tube clamping. METHODS: This study consisted of a retrospective assessment of EBD effect and a prospective trial for EBD tube-clamping optimization. The retrospective study included the EBD group (n = 208) and the non-EBD group (n = 145). The prospective study included 60 patients with EBD. RESULTS: In the retrospective study, single DDA was performed in 83.7% of the EBD group and 80.7% of the non-EBD group (P = .47). One-year overall incidence of BC was 14.4% in the EBD group and 16.8% in the non-EBD group (P = .48). The incidence of early anastomotic bile leakage was 1.0% in the EBD group and 4.8% in the non-EBD group (P = .036). In the prospective study, there was no difference in tube-clamping success rates between low- and high-output EBD groups. There was also no statistical difference between the success and failure groups in terms of graft duct size, liver function tests, and post-transplant days at tube clamping. CONCLUSIONS: The size of our EBD tube was too small for the graft duct size, therefore its main role appeared to be early biliary decompression, which helped prevent bile leakage and also simplified the route of cholangiogram in detecting early BC. Hence, EBD is worthy of performing in selected patients with a high risk of anastomotic bile leak. PMID- 24767323 TI - Magnetic resonance angiographic inflow-sensitive inversion recovery technique for vascular evaluation before liver transplantation. AB - BACKGROUND: The recipient's hepatic vascular anatomy is essential in living-donor liver transplantation (LDLT). Magnetic resonance angiographic inflow-sensitive inversion recovery (IFIR-MRA) is a new noncontrast technology for vascular evaluation, particularly for those patients with renal function impairment. The purpose of this study was to improve the image quality with different blood suppression inversion time (BSP TI) settings. METHODS: From October 2012 to March 2013, 21 recipient candidates underwent IFIR-MRA with the use of the GE 1.5T Discovery 450 for LDLT preoperation evaluation with different BSP TI settings. Subjective visualized image quality and depiction of hepatic arteries, portal veins, and inferior vena cava (IVC) were all evaluated on a vessel-to-vessel basis. A paired t test analysis was used to assess the difference in grading scales between the different BSP TI settings in IFIR-MRA. RESULTS: The 21 recipients (4 female, 17 male) had a mean age of 53.43 +/- 11.07 years. A significant difference (P < .001) existed in the arterial depiction scores between BSP TI 1,000 ms (3.10 +/- 0.70) and BSP TI 1,400 ms (3.57 +/- 0.7). There were no significant differences of quality scores in artery (3.71 +/- 0.56 vs 3.48 +/- 0.60), portal vein (3.57 +/- 0.60 vs 3.48 +/- 0.51), and IVC (2.71 +/- 1.19 vs 2.76 +/- 1.09), and no significant differences of depiction scores in portal vein (2.29 +/- 0.46 vs 2.48 +/- 0.51) and IVC (1.57 +/- 0.68 vs 1.62 +/- 0.15). CONCLUSIONS: The images with BSP TI 1,400 ms were the most optimal for IFIR noncontrast MRA imaging in LDLT. This new technology can replace traditional contrast-enhanced MRA, especially for patients with renal function impairment. PMID- 24767324 TI - Repeated introperative cholangiography is helpful for donor safety in the procurement of right liver graft with supraportal right bile duct variants in living-donor liver transplantation. AB - BACKGROUND: Despite recent advances in preoperative diagnostic imaging and operative techniques, biliary variation of the donor still remains a challenge in the procurement of graft. The supraportal right bile duct (BD) variant including presentation as trifurcation is a potential trap for injuring the remnant bile duct of donor. METHODS: Before living/related-donor liver transplantation (LRLT), cholangiogram with magnetic resonance images of each donor was performed as a routine. After exploration of the donor before hilar dissection, intraoperative chloangiography (IOC) was routinely performed. Among the supraportal right bile duct variants, if the preoperative cholangiography showed a suspected trifurcation of the bile duct, we then performed 3 sessions of IOC during liver graft procurement, including prior to hilar dissection, before the division of bile ducts and after the division. We reviewed the cholangiogram and the postoperative laboratory data of a consecutive series of 25 donors of LRLT. RESULTS: There was no division injury of the remnant bile duct of all of the donors. CONCLUSIONS: Repeated IOC is suggested as a routine for variants of supraportal right bile ducts especially trifurcation pattern in graft procurement to avoid the injury of donor remnant bile ducts. PMID- 24767325 TI - Risk factors for portal vein stenosis in living-donor liver transplantation. AB - BACKGROUND: In living-donor liver transplantation (LDLT), the recipient's portal vein is short. Furthermore, portal vein thrombosis and stenosis can be lethal complications. We had begun the systemic administration of gabexate mesilate, a strong serine protease inhibitor, which has cytoprotective effects of endothelial cells. It is often effective on disseminated intravascular coagulation. The purpose of this study was to examine the effects of gabexate mesilate and to reveal risk factors for portal vein stenosis in LDLT. METHODS: From 1991 to 2012, we performed 153 LDLTs. For the present cohort study, patients were divided into 2 groups. In group I, we treated with gabexate mesilate mildly (0-20 mg/kg/d; n = 29). In group II, we treated with gabexate mesilate at full dose (40 mg/kg/d; n = 124). We investigated the survival rates of both groups and performed univariate and multivariate analyses to identify the independent risk factors for portal vein stenosis. RESULTS: The survival rate of group II was significantly better than that of group I (P < .05). On univariate analysis, the risk factors identified to be associated with a P value of <.20 were old age (P = .0385), heavy body weight (P = .1840), tall height (P = .1122), small lumen diameter of portal vein (P = .1379), high volume of blood loss (P = .0589), small amount of gabexate mesilate infusion (P = .0103), and large graft weight (P = .1326). On multiple logistic regression analysis we identified old age (P = .0073) and small amount of gabexate mesilate infusion (P = .0339) to be the independent risk factors for portal vein stenosis. CONCLUSIONS: On multivariate analysis, we found that gabexate mesilate infusion contributed to the reduction of portal vein stenosis. PMID- 24767326 TI - Can coronary vein size predict hemodynamic instability during inferior vena cava clamping in liver transplantation? AB - OBJECTIVE: This study aimed to determine whether coronary vein size can serve as a predictor of hemodynamic instability during inferior vena cava clamping in living-donor liver transplantations. METHODS: Fifty-two patients' hemodynamic data before and after clamping were retrospectively analyzed and compared with the use of linear regression and repeated measurement. Data included arterial blood pressure, heart rate, central venous pressure, cardiac output, cardiac index, stroke volume, stroke volume variation, and systemic vascular resistance. RESULTS: The values of hemodynamic parameters at 1, 3, 10, and 30 minutes after clamping were compared with baseline data. All changes were found to be significant when the presence of the coronary vein was not considered. When the coronary vein was taken into consideration, linear regression analysis showed that only the percentage changes of cardiac index; stroke volume at 1, 3, and 10 minutes; and systemic vascular resistance at 1 minute after portal and inferior vena cava clamping were significantly correlated with the presence of the coronary vein. CONCLUSIONS: Coronary vein size is a weak predictor of hemodynamic tolerability and instability during portal vein and inferior vena cava clamping in this kind of surgery. PMID- 24767327 TI - Portal venous pressure in adult living donor liver transplantation. AB - OBJECTIVE: The relationship between portal pressure and small-for-size syndrome (SFSS) is unsettled. The purpose of this study was to evaluate the role of portal pressure in predicting SFSS. METHODS: Thirty-four patients with end-stage liver disease who received adult-to-adult living-donor liver transplantation (ALDLT) were included. Recipients were grouped based on whether they received portal flow modulation or not. The intraoperative portal vein flow volume (PVFV) and portal venous pressure (PVP) between the 2 groups were compared. The relationship of PVP to PVFV, graft weight-to-recipient weight ratio (GRWR), and graft weight-to recipient spleen size ratio (GRSSR) were analyzed. RESULTS: Persistent portal hypertension was found after ALDLT. The PVP was linearly correlated with PVFV but not with GRWR or GRSSR. With the use of the following criteria, (1) PVFV >250 mL/min/100 g graft weight, (2) GRWR <0.8%, and (3) GRSSR <0.6, modulation of the portal flow was performed in 3 cases. The receiver operating characteristic analysis showed that 23 mm Hg was the cutoff point for PVP, with a sensitivity of 83% and specificity of 43%. CONCLUSIONS: PVP is a weak parameter to use for portal flow modulation after ALDLT. It is sensitive but not specific to predict SFSS. PMID- 24767328 TI - Management of extensive retrohepatic vena cava defect in recipients of living donor liver transplantation. AB - Certain complexities, such as extensive vena caval injury, unexpected dense adhesions between liver and retrohepatic vena cava, and liver tumor abutting retrohepatic vena cava, sometimes warrant resection of vena cava during living donor liver transplantation. Because the donor graft is devoid of vena cava, reconstruction of the retrohepatic cava is required, which can be done with the use of either a cryopreserved venous graft or an artificial conduit. With only a few published reports, the experience in vena cava reconstruction with the use of expanded polytetrafluoroethylene (ePTFE) during living-donor liver transplantation remains limited. We present our experience of 4 patients who successfully underwent vena caval resection during liver transplantation for various indications, which was subsequently reconstructed with the use of ePTFE grafts. All of these patients except 1 recovered well without any undue complications, such as thrombosis or outflow inadequacies, thus proving this extensive surgical treatment to be a successful and life-saving procedure, though meticulous skills are prerequisite. PMID- 24767329 TI - Risk factors for inadvertent hypothermia during adult living-donor liver transplantation. AB - BACKGROUND: Hypothermia (core temperature <35 degrees C) causes multiple physiologic disturbances, including coagulopathy and cardiac dysfunction. Patients undergoing liver transplantation are at risk of inadvertent hypothermia and might be more vulnerable to its adverse effects. We sought to identify the factors contributing to hypothermia during living-donor liver transplantation (LDLT), which have not yet been studied in depth. METHODS: Medical records of 134 recipients who underwent adult-to-adult LDLT were reviewed. Core temperature at the following time points were taken: anesthetic induction, skin incision, start and end of the anhepatic phase, and hourly after hepatic reperfusion. RESULTS: Of 134 recipients, 29 (21.6%) developed hypothermia during surgery. Four independent risk factors for hypothermia were identified: small body weight-to-body surface area ratio, acute hepatic failure, high Model for End-Stage Liver Disease (MELD) score, and low graft-to-recipient weight ratio. The amount of core temperature drop was positively correlated with the number of involved risk factors. Each risk factor had a respective contribution according to the operative phases: body weight-to-body surface area ratio and the MELD score for the preanhepatic phase, acute deterioration of hepatic failure for the anhepatic phase, and graft-to recipient weight ratio was for the postreperfusion phase. CONCLUSIONS: Hypothermia was independently associated with the recipient's morphometric characteristics, emergency of end-stage liver disease, MELD score, and graft volume. These factors showed a cumulative effect, and the role of each factor was different according to the operative phase. These results should aid in the development of an optimal thermal strategy during LDLT. PMID- 24767330 TI - Analysis of predictors for lactate elimination after reperfusion in recipients of living-donor liver transplantation. AB - BACKGROUND: Graft-recipient weight ratio (GRWR) is the only documented predictor that influences the lactate elimination after reperfusion in living-donor liver transplantation (LDLT). This study was performed to investigate the predictors of lactate elimination after reperfusion in recipients of adult LDLT. METHODS: The medical records of 159 patients who underwent LDLT were analyzed. Lactate level (mmol/L) was measured from just before the initiation of surgery (P0) and 5, 60, and 120 minutes after reperfusion of graft (R0, R1, and R2, respectively). The change of lactate level after reperfusion was defined as difference between lactate level measured at R0 and R2. Patients were divided into accumulation and elimination groups. Donor and recipient factors were compared between the 2 groups. RESULTS: Lactate accumulation occurred in 80 of 159 recipients (50.3%), and elimination occurred in 79 (49.7%). GRWR and Model for End-Stage Liver Disease (MELD) score were higher in the elimination group. Lactate at R0 was lower in the elimination group. CONCLUSIONS: Higher GRWR and MELD score and lower lactate level immediate after reperfusion of graft were predictors of lactate elimination after reperfusion during adult LDLT. PMID- 24767331 TI - Factors associated with consciousness recovery time after liver transplantation in recipients with hepatic encephalopathy. AB - BACKGROUND: Hepatic encephalopathy (HE) occurs as a result of liver failure and is often considered to be a clinical indication for liver transplantation (LT). An assessment of post-transplantation consciousness level in recipients with HE is crucial, because recovery of consciousness implies reestablishment of transplant liver function and lack of perioperative brain damage. The purpose of this study is to evaluate factors associated with consciousness recovery time after LT in recipients with HE. METHODS: Out of 633 adult recipients who underwent LT, recipients who exhibited HE at the time of LT were analyzed retrospectively. The time between graft reperfusion and postoperative consciousness recovery was determined, and recipients were divided into 2 groups: group E with recovery of consciousness early (<=48 hours), and group L with recovery of consciousness late (>48 hours). Analyzed variables included recipient sex, age, graft type, Model for End-Stage Liver Disease score, HE history/duration/type/grade, and preoperative laboratory values, including blood ammonia concentration. RESULTS: HE was present at the time of LT in 69 (10.9%) of 633 recipients. Among the 69 recipients, 11 recipients who died or underwent reoperation before consciousness recovery were excluded, and 58 recipients (group E: n = 32; group L: n = 26) were enrolled into analysis. Multivariate analysis showed that HE duration >5 days (odds ratio [OR], 15.58; 95% confidence interval [CI], 1.35-179.56; P = .028) and HE type C (OR, 30.90; 95% CI, 1.67-573.48; P = .021) were the independent factors associated with late recovery from HE after LT. CONCLUSIONS: We suggest that recipients with long-duration or type C HE should be carefully managed during the post-transplantation period to prevent deterioration of HE. PMID- 24767332 TI - Negative prognostic impact of renal replacement therapy in adult living-donor liver transplant recipients: preoperative recipient condition and donor factors. AB - BACKGROUND: In deceased-donor liver transplantation settings, post transplantation acute renal failure with the induction of renal replacement therapy (RRT) is known to have negative effects on graft and patient survivals. However, the impact of RRT in living-donor liver transplantation (LDLT) has not been well investigated. The aim of this study was to elucidate risk factors requiring RRT and prognostic factors after its induction. METHODS: Clinical data on the consecutive 113 adult patients who underwent LDLT from March 2002 to May 2013 were retrospectively reviewed. They were divided into 2 groups: RRT (n = 33) and Non-RRT (n = 80). The primary reasons for receiving RRT were hepatorenal syndrome (n = 17), sepsis (n = 12), and renal hypoperfusion (n = 4). RESULTS: Although there were no significant differences in age or sex, the Model for End Stage Liver Disease (MELD) score was significantly higher in the RRT group than in the Non-RRT group (23 +/- 13 vs 16 +/- 7; P = .002). The graft-recipient weight ratio (GRWR) was significantly lower in the RRT group (0.86 +/- 0.3 vs 0.99 +/- 0.2; P = .025). The 1- and 5-year patient survival rates were significantly higher in the Non-RRT group than in the RRT group (respectively, 91.3% and 84.3% vs 42.9% and 25.5%; P < .001). In multivariate analysis, independent risk factors for receiving RRT were MELD score >20 (P = .044) and GRWR <0.7 (P = .039). In the RRT group, donor age >50 years (P = .042) and preoperative serum creatinine level >1.5 mg/dL (P = .049) were significant prognostic risk factors. CONCLUSIONS: In adult LDLT patients, the induction of RRT after LDLT was a negative predictor of survival. In addition to the preoperative recipient's condition, donor factors including graft size and donor age influenced prognosis after the induction of RRT. PMID- 24767334 TI - Expanded criteria for liver transplantation in patients with hepatocellular carcinoma. AB - Liver transplantation (LT) is one of the few effective treatment options for hepatocellular carcinoma (HCC). Our aim in this study was to evaluate the risk factors for HCC recurrence and propose new criteria for LT based on pretransplantation findings. One hundred eighty patients who underwent LT for HCC between 2002 and 2008 were reviewed retrospectively. Outcome measures included maximal tumor size and number of tumors revealed by radiological studies before transplantation, demographics, and tumor recurrence. Maximal tumor size >6 cm, >7 tumors, and alpha-fetoprotein (AFP) levels >1000 ng/mL were identified as independent prognostic factors of HCC recurrence in univariate and multivariate analysis. Disease-free survival rate in patients with a maximal tumor size <=6 cm, <=7 tumors, and/or AFP levels <=1000 ng/mL at 1, 3, and 5 years was 97.9%, 91.5%, and 90.0%, respectively, but the 1-, 3-, and 5-year disease-free survival rate of patients who had a maximal tumor size >6 cm, >7 tumors, and/or AFP levels >1000 ng/mL was 61.9%, 47.6%, and 47.6%, respectively (P < .001). In conclusion, LT can improve the survival of patients with advanced HCC if they have a maximal tumor size <=6 cm, tumor number <=7, and/or AFP levels <=1000 ng/mL. PMID- 24767333 TI - Successful active immunization using a hepatitis B virus vaccination protocol for a recipient with hepatitis B core antibody-positive liver graft. AB - INTRODUCTION: Donor shortages occasionally necessitate the use of hepatic allografts from hepatitis B core antibody-positive (HBcAb+) donors, with an attendant risk of post-transplantation hepatitis B virus (HBV) infection. The aim of the present study was to develop and evaluate a protocol of active immunization for prevention of post-transplantation de novo HBV infection in patients receiving liver grafts from HBcAb+ donors. PATIENTS AND METHODS: Ten patients who had received HBcAb+ liver grafts at Shinshu University Hospital between October 1996 and December 2012 were enrolled. All the recipients were negative for HBV serological tests, and HBV-DNA. Hepatitis B immunoglobulin (HBIG) was given routinely in the peritransplantation and post-transplantation periods, without antiviral drugs. Subcutaneous vaccination with recombinant HBV was given at a dosage of 20 MUg in adults and 5 MUg in children concomitant with HBIG until acquisition of active immunization. The timing to start HBV vaccination was dependent on the condition of the patient. RESULTS: The median follow-up period after liver transplantation was 140 months, and the median period after transplantation until the start of vaccination was 7.0 months. Nine patients (90%) acquired active immunity after a median number of 4 (range, 2-13) vaccinations (hepatitis B surface antibody >300 mIU/mL for 1 year, or >100 mIU/mL thereafter), and did not require HBIG administration thereafter. None had any side effects of HBV vaccination or developed hepatitis B infection during the study period. Four fast responders who achieved antibody high titers by active immunization within 9 months received pretransplantation vaccinations, whereas 5 slow responders did not. CONCLUSIONS: Our vaccination protocol provides a new effective strategy for prevention of de novo hepatitis B infection after liver transplantation in recipients with HBcAb+ liver grafts. Pretransplantation HBV vaccination was helpful for the post-transplantation vaccine response. PMID- 24767335 TI - The change of respiratory compliance before and after removal of ascites in living donor liver transplantation. AB - BACKGROUND: The study's purpose was to evaluate the effects of total removal of the asictes through laparotomy on the lung function of adult patients undergoing living donor liver transplantation. BASIS PROCEDURE: One hundred eleven patients were reviewed retrospectively. Patients were grouped into 3 groups: GI had ascites <1000 mL, GII between 1000 and 4000 mL, and GIII >4000 mL. The respiratory compliance (RC), end-tidal carbon dioxide (EtCO2), peak and plateau airway pressures, tidal volume, and ventilator modes used were compared from 5 minutes before to 20 minutes after laparotomy, by using linear regression and repeated measurements. The changes in the RC among groups were tested using one way analysis of variance (ANOVA), whereas the changes in percentage of the RC in the same group were tested using paired Student t test. MAIN FINDINGS: The changes in RC before and 10 minutes after laparotomy and total removal of the ascites were 45 +/- 12 to 47 +/- 13, 39 +/- 9 to 43 +/- 6, and 24 +/- 8 to 43 +/- 12 mL/cm H2O for GI, GII, and GIII, respectively. Linear regression analysis showed that the R(2) of the RC 20 minutes after removal of the ascites was 0.645. Pressure cycled ventilation (PCV) used in GIII significantly increased the tidal volume and low end tidal CO2 after laparotomy. CONCLUSIONS: Removal of the ascites in patients undergoing living donor liver transplantation (LDLT) tended to improve the RC in all groups, but significant change was only noted in patients with massive ascites (GIII). Resetting of the ventilator is required to prevent hyperventilation when the PCV mode is used in GIII. PMID- 24767336 TI - The efficacy of the ImmuKnow assay for evaluating the immune status in human immunodeficiency virus and hepatitis C virus-coinfected patients. AB - BACKGROUND: The survival of human immunodeficiency virus (HIV)-infected patients has significantly improved since the introduction of antiretroviral therapy (ART). However, the mortality due to hepatitis C virus (HCV)-related liver disease has not been reduced in HIV/HCV-coinfected patients, and HCV has recently become the most significant cause of death in HIV/HCV-coinfected patients. Liver transplantation might be one of the treatments of choice in such cases, but it is very difficult to evaluate the immune status of these patients due to ART, anti HCV treatment, and HIV-related immunocompromised state. AIM: The aim of this study was to evaluate the immune status in HIV/HCV-coinfected patients using the Cylex ImmuKnow assay, which was designed to monitor the global immune status by measuring the adenosine triphosphate (ATP) levels produced by activated CD4+ T cells. METHODS: Twenty-eight HIV/HCV-coinfected patients were included in this study. We evaluated their immune activity using the ImmuKnow assay, and compared the data with those of HCV mono-infected patients indicated for liver transplantation as well as healthy controls. RESULTS: The ATP levels of HIV/HCV coinfected patients were significantly higher than those of HCV mono-infected liver transplant recipients (P < .001), and were significantly lower than those of healthy controls (P = .001). CONCLUSION: The ImmuKnow assay was considered to be a useful tool to evaluate the immune status of HIV/HCV-coinfected patients. PMID- 24767337 TI - Analysis of the hepatic functional reserve, portal hypertension, and prognosis of patients with human immunodeficiency virus/hepatitis C virus coinfection through contaminated blood products in Japan. AB - BACKGROUND: As the survival of human immunodeficiency virus (HIV)-infected individuals has improved due to the widespread use of antiretroviral therapy, the mortality rate due to hepatitis C virus (HCV)-related liver disease has increased in HIV/HCV-coinfected patients. AIM: The aims of this study were to establish the appropriate therapeutic strategy for HIV/HCV-coinfected patients by evaluating the liver function, including the hepatic functional reserve and portal hypertension, and to investigate the prognosis of HIV/HCV-coinfected patients in Japan. PATIENTS AND METHODS: In addition to regular liver function tests, the hepatic functional reserve of 41 patients with HIV/HCV coinfection was evaluated using the indocyanine green retention rate and liver galactosyl serum albumin scintigraphy. The data for 146 patients with HIV/HCV coinfection through blood products were extracted from 4 major HIV centers in Japan. In addition to liver function tests, the platelet counts (PLT) were evaluated as a marker of portal hypertension. RESULTS: In spite of the relatively preserved general liver function test results, approximately 40% of the HIV/HCV-coinfected patients had an impaired hepatic functional reserve. In addition, while the albumin and bilirubin levels were normal, the PLT was <150,000/MUL in 17 patients. Compared with HCV mono-infected patients with a PLT <150,000/MUL, the survival of HIV/HCV coinfected patients was shorter (HCV, 5 years, 97%; 10 years, 86% and HIV/HCV, 5 years, 87%; 10 years, 73%; P < .05). CONCLUSION: These results must be taken into account to establish an optimal therapeutic strategy, including the appropriate timing of liver transplantation in HIV/HCV-coinfected patients in Japan. PMID- 24767338 TI - A single-center experience of the use of interleukin-2 receptor antagonists for various situations in liver transplant recipients. AB - BACKGROUND: Interleukin-2 receptor antagonists (IL2Ra) are used mainly for (1) induction as an adjunct to conventional immunosuppression, (2) induction to facilitate calcineurin inhibitor (CNI) or steroid minimization, and (3) induction to facilitate steroid avoidance in hepatitis C virus (HCV)-positive recipients. The aim of this study was to present our strategy for IL2Ra rescue therapy and its outcome. METHODS: A total of 20 patients were treated with IL2Ra at our institute for the following indications: (1) rescue for acute rejection (n = 13), (2) CNI sparing in cases of CNI toxicity (n = 5), and (3) induction for complicated cases (n = 2). RESULTS: Rescue therapy for steroid-resistant rejection and rejection in HCV-positive recipients was successful in 11 cases, but 2 grafts were lost due to uncontrollable rejection. CNI cessation was successfully achieved with IL2Ra treatment in 3 cases with thrombotic microangiopathy and 2 cases of encephalopathy, with complete cure of these life threatening complications of CNI. Induction with IL2Ra was successful in 2 complicated cases, 1 for CNI sparing due to renal failure and the other for adjunct immunosuppression in a case of positive lymphocytotoxic crossmatch. The overall patient/graft survival and the rate of infectious complications were comparable between those with and without IL2Ra treatment. CONCLUSIONS: IL2Ra could be safely and effectively used after liver transplantation in various situations. PMID- 24767339 TI - Experience of using everolimus in the early stage of living donor liver transplantation. AB - OBJECTIVES: The aim of our study was to review the experience of early use of everolimus for recipients after adult-to-adult living donor liver transplantation. METHODS: From February 2012 to December 2012, 80 recipients underwent living donor liver transplantation. Forty-three of them used everolimus as an adjunct to the calcineurin inhibitors (CNIs) in the early postoperative period. Thirty-nine patients had hepatocellular carcinoma (HCC) and poor renal function was noted in 9 patients. Ten of them were females and 33 were males. The age varied from 39 to 75 years old. The starting date of use was within 1 week in 33 patients, 2 weeks in 9 patients, and 1 patient was administered on postoperative day 20. The initial doses of everolimus were 0.25 mg every 12 hours and increased to 0.5 mg every 12 hours to target the level at 3-5 ng/mL. Doppler ultrasound was performed regularly postoperative days 1, 4, and 14. RESULTS: The mean time between liver transplantation and everolimus treatment was 12 +/- 8 days. The maximum dose of everolimus used was 1 mg/d with a target trough level between 3 and 5 ng/mL. At 3 months, a target trough level of 3 ng/mL was achieved. Six of 9 renal failure patients showed significant recovery of renal function, whereas 3 of them showed further deterioration and 1 required hemodialysis. During the follow-up period of 9 +/- 6 months, all showed good patency of hepatic artery without thrombosis. Three patients (7%) developed HCC recurrence, whereas 1 patient died at the 10th month postoperative due to sepsis. Elevation of lipid profile was noted in 5 patients. Stomatitis was the most frequent side effect and occurred in 15 patients. CONCLUSIONS: The early use of everolimus was safe and feasible. Also, it can be safely used in patients with prior renal failure while reducing the doses of CNIs. Although the recurrence rate of HCC was reduced, further study is ongoing to evaluate the long-term impact of everolimus on prevention of HCC recurrence. PMID- 24767340 TI - Safety and efficacy of once-daily modified-release tacrolimus in liver transplant recipients: a multicenter postmarketing surveillance in Japan. AB - INTRODUCTION: Modified-release formulation of tacrolimus (TAC-MR) has been developed with the intent of improving patient adherence and quality of life. A number of studies have indicated that the efficacy and safety of once-daily TAC MR were comparable with those of the original formulation, twice-daily tacrolimus. However, its dosage, trough level, safety, and efficacy in the multicenter clinical experience of Japanese liver transplant recipients have not been reported. METHODS: This postmarketing surveillance designed as an open label, prospective, noninterventional observational study was performed. The 24 patients were enrolled for de novo transplantation, and the 122 patients were enrolled for conversion to TAC-MR from 22 medical institutions in Japan. The observation period is 1 year in de novo transplantation, and 24 weeks in conversion. RESULTS: Regarding de novo transplant, the median daily TAC-MR dose was 0.041 mg/kg/d at 1 day after transplantation, and the median tacrolimus trough level was 5.5 ng/mL at 3 days after transplantation. The most common adverse drug reactions were infections, at an incidence rate of 25.0%. The most common infections were cytomegalovirus viremia, at an incidence rate of 12.5%. Both patient and graft survival rates at 1 year were 94.1% and the rejection rate was 20.8%. Regarding conversion to TAC-MR, the median daily conventional TAC dose before conversion was 1.8 mg/d, and the daily TAC-MR dose was 1.5 mg/d. The median TAC trough level was 3.6 ng/mL before conversion and 3.5 ng/mL 1 week after conversion. The most common adverse drug reactions were infections, at an incidence rate of 5.1%. Episodes of death or graft loss did not occur, and there were 3 episodes of rejection. After conversion to once-daily TAC-MR, the patients' adherence was improved. CONCLUSION: This study shows that a TAC-MR based immunosuppressive regimen is safe and effective as used in Japanese clinical practice. PMID- 24767341 TI - Fourteen successful consecutive cases of ABO-incompatible living donor liver transplantation: new simplified intravenous immunoglobulin protocol without local infusion therapy. AB - Since various innovative strategies including local infusion therapy and rituximab have been introduced, the survivals and outcomes of recipients in ABO incompatible (ABO-I) living donor liver transplantation (LDLT) have remarkably improved. Thus, ABO-I LDLT can be a feasible therapeutic option for the patient with end-stage liver disease if an ABO-compatible donor is not available. Although most ABO-I protocols are based on rituximab, plasma exchange, and local infusion therapy, treatment strategies have been changing according to a center's preference or their results. Nonetheless, the consensus of the ABO-I LDLT protocol remains undetermined. Herein, we present our experience with new simple ABO-I LDLT protocol and the excellent results for 14 patients from January 2011 to May 2013. All patients were administrated a single dose of rituximab over 7 days before transplantation followed by plasma exchange to lower anti-ABO antibody titer <=32. The basic immunosuppression protocol consisted of tacrolimus and steroids with mycophenolate mofetil starting 3 days before transplantation. Splenectomy was not performed routinely and local infusion therapy was not applied at the postoperative period. Instead, the patients received intravenous immunoglobulin (IVIG) after LDLT on days 1, 3, and 5. Neither antibody-mediated rejection nor biliary stricture were encountered in the patients, with a mean follow-up of 16.27 +/- 9.4 months. This new simplified ABO-I LDLT protocol seems to prevent antibody-mediated rejection and could be considered as the safe and effective modality to overcome the ABO blood-type barrier in LDLT. PMID- 24767342 TI - Assessment of four methodologies (microparticle enzyme immunoassay, chemiluminescent enzyme immunoassay, affinity column-mediated immunoassay, and flow injection assay-tandem mass spectrometry) for measuring tacrolimus blood concentration in Japanese liver transplant recipients. AB - Therapeutic drug monitoring (TDM) and subsequent dosage adjustment for individual patients in the treatment with tacrolimus are required after liver transplantation to prevent rejection and over-immunosuppression, which leads to severe infection and adverse reactions including nephrotoxicity. The purpose of this study was to evaluate the analytical performance among commercially available immunoassay methods, which were microparticle enzyme immunoassay (MEIA), chemiluminescent enzyme immunoassay (CLIA), and affinity column-mediated immunoassay (ACMIA), compared with an assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, the flow injection assay (FIA-MS/MS) was also evaluated to determine whether it could be available as a new method of analysis in tacrolimus therapy. The blood tacrolimus concentrations in samples from liver transplant recipients (n = 102) were measured using MEIA, CLIA, ACMIA, and LC-MS/MS. Additional blood samples from liver transplant recipients (n = 54) were analyzed using both FIA-MS/MS and LC-MS/MS. Because the assay performance and characteristics of MEIA, CLIA, ACMIA, and FIA-MS/MS are relatively different, the measured data should be carefully considered depending on the methodology. PMID- 24767343 TI - Long-term outcome of living donor liver transplantation for patients with alcoholic liver disease. AB - BACKGROUND: Because most liver transplantation (LT) studies for alcoholic liver disease (ALD) were performed on deceased donor LT, little was still known following living donor LT (LDLT). METHODS: The clinical outcomes of 126 ALD patients who underwent LDLT for 11 years in a high-volume LT center were assessed retrospectively. RESULTS: ALD cases were 5.7% of adult LDLT indication (n = 2196). ALD was 1.9% (4 of 207) during 2000 to 2001, whereas the proportion gradually increased up to 11.3% (34 of 301) in 2010. The model for end-stage liver disease score was 22.1 +/- 9.9, and 6-month abstinence was observed in 105 (83.3%). There were 123 (97.6%) related donors. Single-graft and dual-graft were implanted into 111 and 15 patients, respectively. Main graft type was single right liver graft (n = 108; 85.7%). Graft-to-recipient weight ratio was 1.02 +/- 0.16. Perioperative mortality within 3 months occurred in 5 (4.0%). Overall 1-, 3 , 5-, and 10-year patient survival rates were 92.1%, 88.0%, 85.8%, and 83.7%, respectively. Three patients died of alcohol abuse. De novo hepatitis B virus infection occurred in 2 of 26 patients after implantation of core antibody positive graft and no further cases happened after strict application of prophylaxis. CONCLUSIONS: The results of this study revealed that the survival outcome of LDLT in ALD patients is comparable with that of deceased donor LT. To achieve favorable long-term survival, a multidisciplinary approach can be an effective strategy, including the interaction between the patient, the physician, and the family members. PMID- 24767344 TI - Graft regeneration in pediatric living donor liver transplantation. AB - OBJECTIVE: Due to the shortage of cadaver liver grafts in Asia, more than 90% of biliary atresia (BA) patients require living donor liver transplantation (LDLT), but the factors that influence liver graft regeneration in pediatric patients are still unclear. The aim of this study was to evaluate the potential predisposing factors that encourage liver graft regeneration in pediatric liver transplantation (LT). METHODS: Case notes and Doppler ultrasound and computed tomography studies performed before and 6 months after transplantation of 103 BA patients who underwent LDLT were reviewed. The predisposing factors that triggered liver regeneration were compiled from statistical analyses and included the following: age, gender, body weight and height, spleen size, graft weight-to recipient weight ratio (GRWR), post-transplantation total portal flow, and vascular complications. RESULTS: Seventy-two pediatric recipients were enrolled in this study. The liver graft regeneration rate was 29.633 +/- 36.61% (range, 29.53-126.27%). The size of the spleen (P = .001), post-transplantation portal flow (P = .004), and age (P = .04) were correlated lineally with the regeneration rate. The GRWR was negatively correlated with the regeneration rate (P = .001) and was the only independent factor that affected the regeneration rate. When the GRWR was >3.4, patients tended to have poor and negative graft regeneration (P = .01). CONCLUSION: Large-for-size grafts have negative effect on regeneration rates because liver grafts that are too large can compromise total portal flow and increase vascular complications, especially when the GRWR is >3.4. Thus, optimal graft size is more essential than other factors in a pediatric LDLT patient. PMID- 24767345 TI - Clinical efficacy of simultaneous splenectomy in liver transplant recipients with hepatitis C virus. AB - BACKGROUND: Interferon (IFN) therapy is a well-established antiviral treatment for hepatitis C virus (HCV) - infected patients. However, susceptibility to thrombocytopenia is a major obstacle in its initiation or continuation, particularly in patients with HCV who underwent liver transplantation (LT). We previously showed that the coexistence of splenomegaly and thrombocytopenia could result in persistent thrombocytopenia after LT. Here we retrospectively evaluated the validity of this criterion for simultaneous splenectomy in recipients with HCV. PATIENTS AND METHODS: Subjects included 36 recipients with HCV who received LT between January 2006 and February 2012 at Hiroshima University. We analyzed the spleen volume, body surface area, platelet (PLT) count, and rate of completion or continuation with IFN therapy in these recipients. RESULT: Of these recipients, 30 did not require simultaneous splenectomy according to the criterion, and 24 actually did not receive simultaneous splenectomy. In this group, 21 (87.5%) started IFN therapy. Fifteen (71.4%) of these recipients completed or continued IFN therapy, whereas 13 (61.9%) achieved either a sustained virological response (SVR) or an end-of-treatment response. The PLT count increased to >100,000/mm(3) 1 month after LT in 16 (66.7%) recipients from this group. CONCLUSION: Our criterion detected the PLT count outcome after LT in recipients with HCV and achieved a better SVR result after IFN therapy. PMID- 24767346 TI - Long-term survival analysis of liver transplantation for hepatocellular carcinoma with bile duct tumor thrombus. AB - BACKGROUND: Long-term prognosis of liver transplantation (LT) for hepatocellular carcinoma (HCC) with macroscopic bile duct tumor thrombus (BDTT) has not been well assessed. This study intended to analyze the post-transplantation outcomes in patients who had HCC with macroscopic BDTT. METHODS: A retrospective study was performed with 14 patients who underwent LT for HCC with BDTT (0.7%) after selection from an institutional database of 2052 adult LT cases. RESULTS: Types of LT were living donor LT in 13 and deceased donor LT in 1. The extents of BDTT were Ueda type 1 in 4, type 2 in 3, and type 3 in 7. Milan criteria were met in 8 (57.1%). Concurrent bile duct resection was performed in 7 (50%). Mean model for end-stage liver disease score was 18.7 +/- 4.9. Mean graft-recipient weight ratio was 1.2 +/- 0.3. There was one case of perioperative mortality and one case of HCC-unrelated late mortality. Cumulative HCC recurrence rates were 15.4% at 1 year, 46.2% at 3 years, and 46.2% at 5 years. Overall patient survival rates were 92.9% at 1 year, 57.1% at 3 years, and 50% at 5 years. Univariate risk factor analyses revealed that only macrovascular invasion was a significant risk factor for HCC recurrence (P = .019). CONCLUSIONS: The results of this study revealed that LT for HCC with macroscopic BDTT has a high risk of post-transplantation HCC recurrence; therefore, further large-volume studies are necessary to elucidate the risk factors. PMID- 24767347 TI - Outcomes of orthotopic liver transplantation in non-malignant end-stage liver diseases. AB - BACKGROUND: Orthotopic liver transplantation (OLT) is an effective treatment for patients who have end-stage liver disease. The aim of this study is to compare outcomes of OLT in fulminant hepatic failure (FHF) and non-fulminant hepatic failure (non-FHF) patients. METHODS: A retrospective review of adult patients who underwent OLT for non-malignant end-stage liver diseases between 2002 and 2011 at Siriraj Hospital was performed. All explanted liver histopathology results were reviewed. The clinical factors and overall results of OLT were analyzed. RESULTS: Of the 137 patients, 72 patients had non-malignant diagnoses. Eleven patients were diagnosed with FHF, whereas 61 patients were in the non-FHF group. The most common indication for liver transplantation was chronic viral hepatitis. One- and 5-year survival rates (95% confidence interval) in the FHF group were 91% (51% 99%) and 91% (51%-99%), respectively, whereas those in the non-FHF group were 74% (61%-83%) and 66% (52%-77%), respectively. Multivariate cox regression analysis revealed no statistically significant difference of survival between both groups (P = .34). CONCLUSIONS: The post-OLT outcomes in non-malignant patients were comparable between FHF and non-FHF groups in terms of survival. OLT remains the only therapeutic option for the FHF patients. PMID- 24767348 TI - The needs and expectations of overseas liver transplant recipients' families in Taiwan: across different transplantation stages. AB - AIMS: This study explored the needs and expectations of Taiwanese overseas liver transplant recipients' families (OLTRFs) across three liver transplantation stages. PATIENTS AND METHODS: An exploratory qualitative method was applied to a purposive sample of OLTRFs who received guided face-to-face, semi-structured interviews. Data were subjected to content analysis. RESULTS: Nineteen OLTRF members (15 females, 4 males) aged between 29 and 71 years (mean, 55.1 years) for 19 patients who had end-stage liver diseases were interviewed regarding overseas liver transplantation (OLT) across three stages: pre-departure (first stage), stay in mainland China (second stage), and re-entry into Taiwan (third stage). Five types of needs across OLT stages were reported: (a) knowing precise operation schedule in advance (first to second stages); (b) sharing the caring burdens (second to third stages); (c) knowing the updated health status if possible (all stages); (d) obtaining timely psychological support (all stages); and (e) effective communications between health professionals in Taiwan and mainland China to ensure the caring quality (all stages). Furthermore, five expectations were reported: (a) more donor sources (first stage); (b) comprehensive caring strategies for OLT (first stage); (c) a comprehensive consultation system and timely assistance channels for OLT recipients and their families (second to third stages); (d) a legal and accessible therapy process (all stages); and (e) the cooperation with foreign countries and allowed experience sharing for better quality of patient care (all stages). CONCLUSIONS: Most ethnic Chinese believe that family is an integrated system; moreover, there is close attachment between OLT recipients and their families. The needs and expectations of the recipients' family across three transplantation stages were first reported in this project. With this knowledge, the health providers of related countries are empowered by a better understanding of the family's needs and expectations of these OLT recipients at different stages. PMID- 24767349 TI - Potential benefit of mixed lymphocyte reaction assay-based immune monitoring after living donor liver transplantation for recipients with autoimmune hepatitis. AB - BACKGROUND: Recipients with autoimmune hepatitis (AIH) have a higher incidence of both rejection and recurrence after liver transplantation (LT) when compared with cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). This is due to the lack of an immune monitoring system, making it difficult to control immunosuppressant agents. In this study, we examine the benefit of the carboxyfluorescein diacetate succinimidyl ester mixed lymphocyte reaction (CFSE-MLR) monitoring system for evaluating the immune status in recipients with AIH and PBC/PCS after LT. METHOD: Recipients who underwent LT (9 AIH and 11 PBC/PSC) from 2002 to 2013 at Hiroshima University were enrolled in this study. The correlation between the result of CFSE-MLR and the outcome, bacteremia, rejection, and/or recurrence was examined. RESULT: The cumulative survival rates for 5 years after LT revealed preferable outcomes for both groups (AIH 85.7%, PBC/PCS 80%). None of the recipients in the AIH group developed bacteremia during 90 days after LT, whereas three recipients from the PBC/PCS group (27%) developed bacteremia. The recurrence rate (AIH 33%, PBC/PSC 27%) was the same as the reported data; however, there was a lower incidence of acute rejection rate in our institution (AIH 11%, PBC/PSC 27%). In the CFSE-MLR assay, the stimulation index of CD4(+) T cells in the anti-self reaction was increased in recurrent cases, whereas no elevation of anti-donor reaction was observed in either CD4(+) or CD8(+) T cells. CONCLUSION: Optimization of the immunosuppressant agents based on the CSFE-MLR assay after LT achieved a preferable outcome in recipients with both AIH and PBC/PCS. Therefore, CFSE-MLR assay might be a useful tool for predicting the recurrence of autoimmune liver diseases by monitoring anti-self reactivity of CD4(+) T cells. PMID- 24767350 TI - Bile CXC motif chemokine 10 levels correlate with anti-donor cytotoxic T cell responses after liver transplantation. AB - BACKGROUND: CXC motif chemokine 10 (CXCL10), known as interferon-gamma-induced protein 10, is an inflammatory cytokine secreted by various cells in response to interferon-gamma. CXCR3, the receptor of CXCL10, is predominantly expressed on activated T, B, natural killer, and dendritic cells, as well as macrophages. CXCR3 promotes chemotaxis upon binding CXCL10. Serum CXCL10 levels have recently attracted attention as a post-transplantation biomarker for graft rejection. However, the correlation between the degree of T cell response to allostimulation and CXCL10 levels remains unclear. In this study, we investigated the serum and bile CXCL10 levels of patients who underwent living donor liver transplantation (LDLT) and compared them with the T cell responses to allostimulation. PATIENTS AND METHODS: Between February 2009 and August 2012, 41 patients underwent LDLT at Hiroshima University Hospital. Serum and bile CXCL10 levels were measured weekly for 4 weeks after surgery, while the T cell responses to allostimulation were evaluated using a mixed lymphocyte reaction with an intracellular carboxyfluorescein diacetate succinimidyl ester-labeling technique that we regularly use to monitor the immune response to anti-donor and anti-third-party stimulation after liver transplantation. The stimulation index (SI) and CD25 expression of the CD4+ and CD8+ T cell subsets in response to allostimulation were then analyzed using flow cytometry. RESULTS: Serum CXCL10 levels were significantly correlated with the SI values for CD8+ T cells in response to both types of allostimulation. Bile CXCL10 levels were significantly correlated with CD25 expression of CD8+ T cell subsets, especially in response to anti-donor stimulation. Patients with higher bile CXCL10 levels suffered from severe acute cellular rejection that was refractory to steroid pulse. CONCLUSION: Measurements of bile CXCL10 levels could predict anti-donor cytotoxic T cell responses in liver transplant recipients. PMID- 24767351 TI - Optimal initial dose of orally administered once-daily extended-release tacrolimus following intravenous tacrolimus therapy after liver transplantation. AB - INTRODUCTION: Once-daily extended-release tacrolimus (Tac-OD) is expected to reduce non-adherence in recipients after liver transplantation (LT). The aim of this study was to determine the optimal initial dose of orally administered Tac OD after intravenous tacrolimus (Tac-IV) therapy after LT. PATIENTS AND METHODS: This prospective study included 10 adult recipients who had undergone LT at our institute. The recipients were prescribed tacrolimus by continuous intravenous administration with a steroid as initial immunosuppression therapy. Tacrolimus was converted from intravenous administration to once-daily oral intake when gastrointestinal function returned. We evaluated tacrolimus concentrations in blood 9 times a day and area under the blood concentration-time curve (AUC) during conversion. The optimal initial dose of Tac-OD was determined based on simple regression analysis between the oral dose of Tac-OD and the total dose of Tac-IV during a 24-hour period. RESULTS: The AUC before and after conversion showed no differences. We found that the optimal initial dose of Tac-OD was 8 times the dose of Tac-IV. There was a relationship between the AUC and the trough level. No recipients experienced acute rejection or adverse effects such as renal failure, neurotoxicity, or cardiac failure during conversion. CONCLUSIONS: We successfully converted continuous Tac-IV to oral intake of Tac-OD by adjusting the dose using trough levels without acute rejection or adverse effects. The AUC of Tac-OD correlated with the trough level. The optimal initial dose ratio of Tac OD after Tac-IV was 8:1. PMID- 24767352 TI - Long-term complications after liver transplantation. AB - BACKGROUND: Along with an increased number of cases of liver transplantation (LT), perioperative mortality has decreased and short-term survival has improved. However, long-term complications have not been fully elucidated today. PURPOSE: Chronic complications were analyzed individually to find risk factors and to improve long-term outcomes after LT. SUBJECTS: There were 63 cases of LT from our outpatient clinic that were included in this study. Among them, 58 were performed using living donor LT and 5 were performed using deceased donor LT. Original diseases mainly consisted of hepatitis C virus (HCV; 45.9%) and hepatitis B virus (23.0%). FINDINGS: The median follow-up was 5.4 +/- 3.3 years (range, 0.1~17 years). Overall survival at 2, 3, 5, and 10 years was 89.3%, 83.4%, 81.3%, and 81.3%, respectively. Long-term complications mainly consisted of renal dysfunction (62.7%), dyslipidemia (29.4%), diabetes mellitus (21.6%), and arterial hypertension (21.6%). In univariate analysis, HCV (P = .03) and elapsed years after LT (P = .02) were identified as predictive factors for arterial hypertension and recipient age >50 (P = .03), and elapsed years after LT for renal dysfunction (P = .03), respectively. In multivariate Cox regression analysis, HCV (odds ratio [OR] 5.25, 95% confidence interval [CI] 1.05-34.06, P = .04) was identified as a predictive factor for arterial hypertension, and recipient age older than 50 years for renal dysfunction (OR 5.67, 95% CI 1.34 28.88, P = .02). The number of elapsed years after transplantation was also identified as a predictive factor for arterial hypertension/dyslipidemia/renal dysfunction (OR 13.88/14.15/4.10, 95% CI 1.91-298.26/2.18-290.78/1.09-18.03, P = .01/.003/.04). Fifty percent of the recipients developed renal dysfunction within 8 years after LT, and fluctuation of estimated glomerular filtration rate (eGFR) within 3 months after LT was successfully associated with an annual decrease of eGFR (r(2) value = 0.574, P < .0001). CONCLUSION: Renal dysfunction is the most frequent chronic complication after LT. As chronic individual eGFR can be now accurately predicted with deterioration speed, recipient strata for renal protection strategies should be precisely targeted. PMID- 24767353 TI - Hypertension and hepatitis C virus infection are strong risk factors for developing late renal dysfunction after living donor liver transplantation: significance of renal biopsy. AB - BACKGROUND: Late renal dysfunction (LRD) after liver transplantation develops due to several factors such as viral hepatitis, calcineurin inhibitor, diabetes mellitus, and hypertension. The aim of our study was to clarify the risk factors for LRD after living donor liver plantation (LDLT) by using simple criteria for LRD and paying special attention to the significance of renal biopsy. PATIENTS AND METHODS: Among the 98 recipients undergoing LDLT between March 2002 and June 2008, there were 77 patients who survived more than 1 year and had been followed at our clinic. LRD was simply defined as a postoperative serum creatinine level of 1.5/L or more at any point in time after 1 year from undergoing LDLT. The perioperative risk factors for developing LRD after LDLT were analyzed by uni- and multivariate analyses, and regardless of serum creatinine level, a renal biopsy was indicated when the patient developed clinical symptoms. RESULTS: Comparing the risk factors between 22 patients with LRD and 55 without LRD, univariate analysis revealed recipient's age, generation, hypertension, hepatitis C virus (HCV) antibody-positive, pretransplantation serum creatinine level, and graft-to-recipient weight ratio to be significant risk factors. By multivariate analysis, HCV and hypertension were selected as independent risk factors. Renal biopsy was indicated in the 4 patients with proteinuria, all of whom were positive for HCV. However, by histologic and/or electron micrographic analyses, only 1 patient was diagnosed with HCV-related membranous proliferative nephritis, 1 with diabetic nephropathy, and 2 with drug (tacrolimus) -induced renal dysfunction. CONCLUSION: Although HCV and hypertension were determined to be independent risk factors for LRD after LDLT, a renal biopsy should be performed when clinical symptoms develop regardless of creatinine levels to provide appropriate treatment. PMID- 24767354 TI - Correlation between mycophenolic acid blood level and renal dysfunction in stable liver transplant recipients receiving mycophenolate monotherapy. AB - PURPOSE: Mycophenolate mofetil (MMF) is frequently used after liver transplantation (OLT). Mycophenolic acid (MPA) metabolites are eliminated primarily via the kidneys. If renal function declines, clearance is significantly impaired. The aim of this study was to reveal the renal function-dependent changes of MPA level in stable adult OLT recipients receiving MMF monotherapy. METHODS: Sixty-five OLT recipients were selected from our OLT database of >3500 cases. All had undergone MMF monotherapy with a daily MMF dose of 1000 mg or 1500 mg for more than 2 years, primarily because they could not tolerate calcineurin inhibitors. Their clinical profiles, including MPA therapeutic drug monitoring (TDM) and renal function, were analyzed as a cross-sectional study. RESULTS: For the group treated with 1000 mg MMF (n = 40), the 12-hour MPA trough level was 1.20 +/- 0.35 MUg/mL with serum creatinine (Cr) level <=1.4 mg/dL in 13 patients; it was 2.78 +/- 1.19 MUg/mL with Cr >1.4 mg/dL in 16 patients not undergoing hemodialysis and 3.83 +/- 0.87 MUg/mL in 11 patients undergoing hemodialysis (P < .001). For the group treated with 1500 mg MMF (n = 25), the MPA trough level was 2.23 +/- 0.99 MUg/mL with Cr <=1.4 mg/dL in 6 patients; it was 2.81 +/- 0.99 MUg/mL with Cr >1.4 mg/dL in 18 patients not undergoing hemodialysis and 3.5 MUg/mL in 1 patient undergoing hemodialysis (P = .21). CONCLUSIONS: Considering the potential therapeutic range of MPA, the suggested MMF dosage for Korean adult OLT recipients requiring hemodialysis may be set around 1000 mg per day. We suggest adjusting the MMF dosage on an individualized basis according to the results of MPA TDM, particularly for patients with markedly impaired renal function. PMID- 24767355 TI - The ratio of plasma interleukin-18 is a sensitive biomarker for acute kidney injury after liver transplantation. AB - BACKGROUND: Acute kidney injury (AKI) is common after liver transplantation (OLT) and is associated with high morbidity and mortality. Previous studies have shown that interleukin-18 (IL-18) levels are associated with AKI. The purpose of this study was to determine whether plasma IL-18 levels were early predictors for AKI after liver transplantation. METHODS: Plasma samples were obtained from 26 patients who underwent OLT at induction of anesthesia (T1), 1 hour after the surgical incision (T2), the time of reperfusion (T3), as well as 1 (T4), 2 (T5), and 4 hours (T6) after reperfusion. Samples were also obtained at 24 hours after surgery (T7). The AKI criteria were taken according to the Acute Kidney Injury Network criteria. RESULTS: Twelve patients (46%) developed AKI after OLT. The area under the receiver operating curve of plasma IL-18 concentrations (T4/T1) to predict AKI occurrence was 0.842 at T5, 0.905 at T6, 0.726 at T7, and 0.726 at T5 to T7. CONCLUSION: Plasma IL-18 concentrations taken 1 hour after reperfusion were predictive of AKI. Therefore, changing IL-18 ratio may be an early predictor for AKI after OLT. PMID- 24767356 TI - Renal dysfunction after orthotopic liver transplantation. AB - BACKGROUND: Identification of risk factors of acute renal failure (ARF) after orthotopic liver transplantation (OLT) may avoid the development and attenuate the impact on patient outcome. Therefore, the incidence and risk factors of ARF after OLT at Siriraj Hospital were analyzed. METHODS: The study was retrospectively analyzed from the OLT patients at the Siriraj Hospital between January 2002 and December 2009. ARF was defined as an increased in serum creatinine level more than 1.5 times within the first week postoperation compared with the preoperative level. RESULTS: A total of 81 liver transplant patients were analyzed. The mean age was 52.45 years (range, 22 to 71) and there were 25 women (30.86%) and 56 men (69.14%). Indications for OLT were end-stage liver cirrhosis (n = 43, 53.09%), hepatocellular carcinoma (n = 36, 44.44%), and fulminant hepatic failure (n = 2, 2.47%). Fifty-eight patients (71.60%) developed ARF, and the perioperative mortality of these was 18.97%. The univariate analysis identified the presence of preoperative coagulopathy, prolonged intraoperative hypotension, more blood loss, and postoperative hypotension as the risk factors of ARF. By the multivariate analysis, prolonged intraoperative hypotension more than 30 minutes and presence of postoperative hypotension were the independent risk factors of ARF. During the intraoperative and postoperative periods, ARF group required more blood and blood components transfusion, longer intensive care unit stay, and higher in-hospital mortality. Seven patients (12.07%) in the ARF group required postoperative renal replacement therapy. Four patients (9.52%) developed chronic renal failure, and one of them required long-term hemodialysis. CONCLUSIONS: ARF was a common complication after OLT, which caused increased morbidity and mortality. Although some patients required dialysis, most of them recovered normal renal function. Prolonged intraoperative hypotension and presence of postoperative hypotension were the independent risk factors of ARF after OLT. PMID- 24767358 TI - Clinical significance of surveillance culture in liver transplant recipients. AB - BACKGROUND: Routine microbiologic surveillance is a method of infection control, but its clinical significance in transplant recipients is not known. We analyzed microbiologic data to evaluate the influence of cultured microorganisms between the point of surveillance and infectious episodes in liver transplant recipients. METHODS: We performed surveillance culture for sputum and peritoneal fluid in liver transplant recipients from January 2009 to December 2011, at the time of transplantation (T1), 5 days (T2), and 10 days (T3) postoperatively. RESULTS: Of the 179 recipients, 32.9% had a positive sputum culture result and 37.4% had a positive peritoneal culture result during surveillance. In the culture surveillance of sputum, 37 organisms were isolated from 35 recipients at T1, and the most common organism was Staphylococcus aureus (n = 13). At T2, 45 organisms were isolated from 39 recipients, including Klebsiella pneumoniae (n = 10), S aureus (n = 8), and Acinetobacter baumannii (n = 6). At T3, 18 organisms were isolated from 15 patients, including Stenotrophomonas maltophilia (n = 5) and K pneumonia (n = 4). In the peritoneal fluid, 11 organisms were isolated from 10 recipients at T1, including Pseudomonas aeruginosa (n = 2) and Enterococcus species (n = 2). At T2, 39 organisms were isolated from 36 recipients, including coagulase-negative Staphylococcus species (CNS; n = 8) and Enterococcus species (n = 7). At T3, 54 organisms were isolated from 51 recipients, including CNS (n = 17) and Candida species (n = 8). Among the 59 patients with positive culture results for sputum surveillance, 16.9% developed pneumonia caused by the same organisms. Among the 67 patients with positive peritoneal fluid culture, 16.4% developed an intra-abdominal infection caused by the same organisms cultured. The recipients with positive surveillance culture had a higher risk of pneumonia (20.3% [12/59] vs 1.6% [2/120]; P < .001) and intra-abdominal infection (31.3% [21/67] vs 18.7% [21/112]; P = .05). CONCLUSIONS: Periodic microbiologic surveillance may be useful in the prediction of post-transplantation pneumonia and intra-abdominal infection and could offer a potential target for empirical antimicrobial therapy in cases of infection. PMID- 24767357 TI - Optimizing outcome of recurrent hepatitis C virus genotype 4 after living donor liver transplantation: moving forward by looking back. AB - PURPOSE: Recurrence of HCV after LDLT is almost universal. Different factors affect response to treatment. Few data are available regarding outcome of recurrent HCV genotype 4. The purpose of this study is to improve outcome of recurrent HCV genotype 4 after LDLT. METHODS: An IRB approved chart review of 243 patients transplanted for ESLD, HCV genotype 4 over 4 years were reviewed. Protocol liver biopsies were taken 6 months after transplant. Patients received pegylated interferon and ribavirin in case of histological recurrence. Five patients had FCH were excluded. RESULTS: Thirty-seven patients were included. Sustained Virological Response (SVR) was achieved in 29 (78.3%). Patients with Metavir fibrosis stage (F0) and (F1) had SVR in 5/5 (100%) and 20/24 (83.3%). Two patients with F1 had to stop treatment because of thrombocytopenia and 2 were non responders. Three out of 6 patients (50%) with (F2) had SVR, 2 were non responders and one had to discontinue treatment because of severe depression. One of 2 patients (50%) with F3 had SVR and the other patient decompensated within 4 months before treatment and died. CONCLUSION: Protocol biopsies allow early detection of inflammatory changes in the graft before fibrosis occurs. Early treatment of recurrent HCV genotype 4 after LDLT results in better response. PMID- 24767359 TI - Cytomegalovirus disease after liver transplantation: a nationwide population based study. AB - BACKGROUND: Cytomegalovirus (CMV) disease is a significant complication after liver transplantation. The estimated incidence varies among studies, which have been conducted in single regional centers and with small cohorts. In this study, we investigated the occurrence of CMV disease among liver transplant recipients in a national cohort in Taiwan. METHODS: This retrospective study used data from the Taiwan National Health Insurance Research Database. All liver transplant recipients in the catastrophic illness database from 2000 to 2009 were enrolled. Cases of CMV disease were identified from the admission database with the use of the ICD-9-CM code 078. RESULTS: The national cohort consisted of 1,721 liver transplant recipients (1,200 men and 521 women) with a mean age of 43.9 +/- 8.9 years at the time of transplantation. The mean follow-up duration was 3.6 +/- 2.7 years. The mortality rate was 14.9% at 1 year and 20.5% at 5 years. During the study period, 84 patients (4.9%) were diagnosed with CMV disease. The overall prevalence of CMV disease was 14.5 per 100 person-years. The cumulative incidences of post-transplantation CMV infection at 3 months, 6 months, 1 year, 2 years, 5 years, and 10 years were 1.2%, 2.7%, 3.8%, 4.2%, 4.8%, and 4.9%, respectively. The most common CMV-related diseases were colitis, hepatitis, and pneumonia. CONCLUSIONS: The risk of CMV disease was significantly elevated in the first 6 months after liver transplantation in the Taiwanese cohort. PMID- 24767360 TI - Change of hepatitis B virus DNA and covalently closed circular DNA status in liver graft after liver transplantation. AB - Recurrence of hepatitis B virus (HBV) occurs despite prophylaxis, and covalently closed circular DNA (cccDNA) is thought to play a role owing to its resistance to prophylactic agents used. The aim of this study was to evaluate the changes of HBV DNA and cccDNA within the liver graft during liver transplantation (LT). Polymerase chain reaction (PCR) primers and probes were designed to measure total HBV DNA (tDNA) and cccDNA by real-time PCR. One hundred fifty samples from 70 patients who underwent LT for HBV were used for analysis. A 1st biopsy was taken from the donor before donor hepatectomy (Bx1), a 2nd from the recipient after reperfusion (Bx2), and a 3rd (Bx3) during follow-up after LT in 18 patients. Both tDNA and cccDNA after reperfusion were detected more frequently in pre-LT HBeAg(+) and high-HBV DNA titer recipients. However, the type and duration of antiviral agents and presence of mutation before LT did not influence the presence of tDNA or cccDNA in Bx2. tDNA positivity within the graft decreased from 41.4% to 22.2% during follow-up, but cccDNA did not (4.3% in Bx2 and 5.6% in Bx3). Although HBV recurrence was not related to pre-LT recipient HBeAg or HBV DNA titer, the presence of tDNA after reperfusion had strong correlation. The presence of tDNA within the graft is influenced by pre-LT viral replicative status, and although its presence decreases with prophylaxis, it is strongly correlated with recurrence. cccDNA does not have a role in predicting recurrence but is preserved within the graft despite prophylaxis. PMID- 24767361 TI - Self-management of infection control behavior of adult recipients of living-donor liver transplantation within 5 years after transplantation. AB - This study determines the present condition of self-management of infection control behavior of adult recipients who underwent living-donor liver transplantation (LDLT). The design was a qualitative study using a semistructured interview. The subjects were recipients who underwent LDLT at Kyoto University Hospital within 5 years to March 2011 and gave their consents to participate in this study. The subjects were 10 recipients (4 male and 6 female), and their average age was 56.7 years. Of 502 sentences about self-management behavior extracted from the verbatim records of all subjects, 61 sentences were about infection control behavior. Cluster analysis was used to classify these sentences into 5 groups: basic preventive behavior, application preventive behavior, active preventive behavior, change of preventive behavior depending on physical condition, and establishment of preventive behavior. PMID- 24767362 TI - Intrahepatic segmental portal vein thrombosis after living-related donor liver transplantation. AB - BACKGROUND: Intrahepatic segmental portal vein thrombosis after living-related liver transplantation (LRLT) is uncommon. The cause remains unclear. METHODS: After providing written informed consent, 25 recipients receiving LRLT at our institution from January 2011 to September 2013 were enrolled in this study. We performed triphase computerized tomographic (CT) study of the liver graft of each recipient 1 month after LRLT. The patencies of hepatic artery, portal vein, and hepatic vein were evaluated in detail. The triphase CT scans of the liver of each donor before transplantation also were reviewed. Thrombosis of the intrahepatic segmental portal vein was defined as the occlusion site of the portal vein being intrahepatic. Extrahepatic portal vein thrombosis was excluded in this study. RESULTS: Among the 25 patients, 2 (8%) developed thrombosis of intrahepatic segmental portal vein. One 47-year-old man received LRLT for hepatitis B viral infection-related liver cirrhosis (Child-Pugh class C) with 3 hepatocellular carcinomas (total tumor volume <8 cm). Another 53-year-old man received LRLT for alcoholic liver cirrhosis (Child-Pugh class C). Both had developed progressive jaundice and cholangitis 1 month after surgery. Intrahepatic biliary stricture was found on the follow-up magnetic resonance images. However, liver triphase CT study demonstrated occlusion of intrahepatic portal vein of segment 8 in each patient. Radiologic interventions and balloon dilatation therapy via percutaneous transhepatic biliary drainage route improved the symptoms and signs of cholangitis and obstructive jaundice for both. CONCLUSIONS: Thrombosis of intrahepatic segmental portal vein is not common but is usually associated with complications of intrahepatic bile duct. Early detection is important, and follow up CT study of liver is suggested. PMID- 24767363 TI - Complications analysis of polytetrafluoroethylene grafts used for middle hepatic vein reconstruction in living-donor liver transplantation. AB - BACKGROUND: We previously showed that ringed polytetrafluoroethylene (PTFE) grafts combined with small allograft patches showed high patency rates similar to those of iliac vein grafts and therefore that they can be used for middle hepatic vein (MHV) reconstruction. Although such use of PTFE graft showed high patency rates, its long-term safety regarding infection and other types of complications were not presented. In this study, we investigated the actual risk of complications directly associated with PTFE graft interposition for MHV reconstruction. METHODS: During the study period of 30 months, we performed 215 cases of adult living-donor liver transplantation with modified right lobe graft and PTFE grafts. We classified the potential complications directly associated with PTFE graft interposition as infectious and surgical complications. The medical records of study patients were retrospectively reviewed. RESULTS: MHV graft patency rate was 76.3% at 6 months and 36.7% at 12 months. Their 1-year graft and patient survival rates were 92.6% and 93.5%, respectively. The 1-year actual incidences of infectious complication and surgical complication were near zero and 1 case (0.5%), respectively. In 1 recipient, the PTFE graft penetrated into the stomach wall 6 months after transplantation, but the patient did not complain of any specific symptoms. The PTFE graft was removed with the use of laparotomy, and the patient recovered uneventfully. CONCLUSIONS: Although the incidence of PTFE graft-associated complication rate is very low, we suggest that it is necessary to closely monitor the PTFE graft, because unexpected complications can happen during long-term follow-up. PMID- 24767365 TI - Clinical outcome of internal stent for biliary anastomosis in liver transplantation. AB - BACKGROUND: This study analyzed the incidence and management of biliary complications after liver transplantation (LT) with or without internal stent. METHODS: The medical record of all patients who underwent LT and were hospitalized from December 2009 to March 2013 were reviewed. Patients were grouped into 2 groups (internal stent group vs no stent group). RESULTS: There were 29 deceased-donor liver transplantations (58%) and 21 living-donor liver transplantations (42%). There were 2 perioperative mortalities, and those 2 patients were excluded from this study. The overall biliary complication rate was 6.45% in the internal stent group and 17.65% in the no stent group. The rate of anastomotic stricture was 3.23% (n = 1) in the stent group and 11.76% (n = 2) in the no stent group. The rate of bile leak was 3.23% (n = 1) in the stent group and 0% in the no stent group. The rate of biliary obstruction was 0% in the stent group and 5.88% (n = 1) in the no stent group. CONCLUSIONS: The overall rate of biliary complications in the internal stent group was lower than in the no stent group, and most of the biliary complications could be treated successfully with endoscopic or radiologic intervention. PMID- 24767364 TI - Biliary complications in 108 consecutive recipients with duct-to-duct biliary reconstruction in living-donor liver transplantation. AB - BACKGROUND: Biliary complications remain the leading cause of postoperative complications after living-donor liver transplantation (LDLT) in patients undergoing duct-to-duct choledochocholedochostomy. The aim of this study was to analyze the causes of these complications. METHODS: One hundred eight patients who underwent LDLT with duct-to-duct biliary reconstruction at Mie University Hospital were enrolled in this study. The mean follow-up time was 58.4 months (range, 3-132). The most recent 18 donors underwent indocyanine green (ICG) fluorescence cholangiography for donor hepatectomy. The development of biliary complications was retrospectively analyzed. Biliary complications were defined as needing endoscopic or radiologic treatment. RESULTS: Biliary leakages and strictures occurred in 6 (5.6%) and 15 (13.9%) of the recipients, respectively, and 3 donors (2.7%) experienced biliary leakage. However, since the introduction of ICG fluorescence cholangiography, we have not encountered any biliary complications in either donors or recipients. Biliary leakage was an independent risk factor for the development of biliary stricture (P = .013). Twelve (80%) of the 15 recipients with biliary stricture had successful nonoperative endoscopic or radiologic management, and 3 patients underwent surgical repair with hepaticojejunosotomy. CONCLUSIONS: Biliary leakage was an independent factor for biliary stricture. ICG fluorescence cholangiography might be helpful to reduce biliary complications after LDLT in both donors and recipients. PMID- 24767366 TI - Prediction of biliary complications after living-donor liver transplantation based on serum cytokine profile. AB - Biliary tract complications are the main concern associated with living-donor liver transplantation (LDLT). Many laboratory parameters have been studied for the early detection of post-LDLT complications, including various cytokines. To explore immunologic activation status and its clinical significance, the cytokine secretion patterns of LDLT patients who developed biliary complications were analyzed. Serum samples from LDLT recipients were collected 1 day before and 3, 7, 14, and 30 days after transplantation. Each sample was tested for interleukin (IL) 2, IL-4, IL-6, IL-8, IL-10, IL-12, interferon-alpha, and tumor necrosis factor alpha with the use of multiplex bead flow cytometry. Fifteen patients without any complications and 6 patients with biliary complications showed differential serum cytokine profiles. The biliary complication group (4 biliary stricture and 2 biliary obstruction patients) displayed significantly increased concentrations of IL-2 and IL-12 on post-transplantation days 3 and 7 and of IL-4 on post-transplantation day 7. Profiling cytokine secretion in the serum of patients in the first month of LDLT may be helpful for the prediction and diagnosis of biliary complications within 1 year. PMID- 24767367 TI - Risk factors for development of new-onset diabetes mellitus and progressive impairment of glucose metabolism after living-donor liver transplantation. AB - BACKGROUND: New-onset diabetes mellitus (NODM) has a negative impact on graft and patient survivals. Hepatitis C virus (HCV) infection, high body mass index, increased donor and recipient ages, and calcineurin inhibitor (CNI) type have been identified as risk factors for the development of NODM. We aimed to elucidate the risk factors for the development of NODM and those for progressive glucose intolerance in adult living-donor liver transplant (LDLT) recipients. METHODS: We collected data from 188 primary liver transplant recipients (age > 16 years) who underwent LDLT from June 1991 to December 2011 at Hiroshima University Hospital. Risk factors for NODM and progressive impairment of glucose metabolism in pre-transplantation diabetes mellitus (DM) recipients were examined. RESULTS: Pre-transplantation DM was diagnosed in 32 recipients (19.3%). The overall incidence of NODM was 6.0% (8/134 recipients). Multivariate analysis revealed that old recipient age (>=55 years) is a unique predictive risk factor for developing NODM. The incident of pre-transplantation DM was significantly higher in recipients with HCV infection than in those without HCV. A high pre transplantation triglyceride level was an independent risk factor for progressive impairment of glucose tolerance among 32 LDLT recipients with pre-transplantation DM. All of the NODM patients were being treated with tacrolimus at the time of diagnosis. Switching the CNI from tacrolimus to cyclosporine allowed one-half of the patients (4/8) to withdraw from insulin-dependent therapy. NODM and post transplantation glucose intolerance had no negative impact on patient and graft outcomes. CONCLUSIONS: Older age of the recipient (>=55 years) was a significant risk factor for NODM. Hypertriglyceridemia in the recipients with DM is an independent risk factor for post-transplantation progressive impairment of glucose metabolism. NODM had no negative impact on outcomes in the LDLT recipients. PMID- 24767368 TI - New-onset diabetes and hypertension as complications of liver transplantation. AB - BACKGROUND: Among the many complications that can occur after liver transplantation are diabetes and hypertension. In this study, we evaluated the overall prevalence of and identified predictors for post-transplantation diabetes and hypertension. METHODS: This study was retrospective. We collected the data of the patients from the database in the liver transplant unit. RESULTS: Incidence of new-onset diabetes after transplantation (NODAT) was 25% and incidence of post transplantation hypertension was 20%. No predictors were found for NODAT. Predictors of post-transplantation hypertension were body mass index and use of cyclosporine. CONCLUSIONS: Diabetes and hypertension are common after liver transplantation. Predictors of post-transplantation hypertension are high body mass index and use of cyclosporine. PMID- 24767369 TI - Prevalence and treatment of new-onset diabetes mellitus after liver transplantation in Korean children: a single-center study. AB - The aim of this study was to investigate the prevalence, clinical characteristics, and management of new-onset diabetes mellitus (NODM) in Korean children with liver transplantation (LT). We retrospectively analyzed the medical records of 200 pediatric patients (5 months to 17 years old) who underwent LT at Asan Medical Center between January 1994 and December 2010; 26 pediatric patients who died at the maximal follow-up after LT or who were lost to follow-up were excluded from the study. Among these 174 children, NODM after LT developed in 18. The median interval time at the presentation of NODM after LT was 15 days (range, 1 day to 16.0 years), whereas the median patient age of NODM diagnosis was 10 years (range, 1.1 to 17.0 years). Insulin treatment with reduction in tacrolimus dosage, steroid tapering, and conversion from tacrolimus to cyclosporine with or without mycophenolate mofetil is highly effective in NODM after LT. In conclusion, careful diabetes mellitus monitoring and modification of immunosuppressive regimen should be required in pediatric patients after LT. PMID- 24767370 TI - The acoustic radiation force impulse elastography evaluation of liver fibrosis in posttransplantation dysfunction of living donor liver transplantation. AB - BACKGROUND: The acoustic radiation force impulse elastography (ARFI) is a new technology of elastography integrated into B-mode ultrasonography. It has been a reliable method to evaluate liver fibrosis of chronic liver disease in recent years, but less applied in the posttransplantation liver. The aim of the study was to evaluate liver fibrosis by the ARFI with correlation of pathological stages in living donor liver transplantation (LDLT). MATERIALS AND METHODS: From August 2010 to August 2012, there were 57 LDLT patients with liver biopsy (LB) due to posttransplantation dysfunction; all patients also received posttransplantation ARFI liver stiffness measurement (LSM) after transplantation for liver fibrosis staging. The ARFI elastography was performed using a Siemens Acuson S2000 ultrasound system with 4V1 transducers (Acusion, Siemens Medical Systems Co. Ltd. Erlangen, Germany). The ARFI LSM value was presented by shear wave velocity (SWV, m/s). The fibrosis staging as F0 to F4 was in accordance with the Metavir scoring system. RESULTS: A total of 57 patients had both posttransplantation LB and effective ARFI fibrosis staging for correlation. The ARFI LSM value increased with severity of liver fibrosis and had significant linear correlation with the results of histological fibrosis staging. The ARFI LSM sensitivities (Se), specificities (Sp), and cutoff values based on receiver operator characteristic curve were F0: 0.75 m/s (Se: 93.8%, Sp: 4%), F1: 1.06 m/s (Se: 95.5%, Sp: 25.7%), F2: 1.81 m/s (Se: 50%, Sp: 83.6%) and F3: 2.33 m/s (Se: 100%, Sp: 92.9%). Predictive value of ARFI LSM reported a significant difference between early fibrosis stage (F0-F1) and advanced fibrosis stage (F ? 2) (P < .05). CONCLUSION: In this study, ARFI demonstrated a strong linear correlation and severity of liver fibrosis with LB pathologic staging. ARFI can be an alternative and compensatory method for frequent LB in the posttransplantation liver. PMID- 24767371 TI - Loss of speech after living-related donor liver transplantation: detection of the lesion by diffusion tensor image. AB - INTRODUCTION: Loss of speech after living-related liver transplantation is uncommon. Either immunosuppressive agents, related sequelae, or a neurological event may cause it. CASE REPORT: A 46-year-old man developed dysarthria and dysphagia on the 10th day after living-related donor liver transplantation for alcoholic cirrhosis with Child-Pugh class C. Brain magnetic resonance images and electroencephalograms could not detect any lesion, but the diffusion tensor image showed a subacute lacunar infarction at right midbrain. The patient's speech improved 1 month after rehabilitation. CONCLUSIONS: Some unexpected neurological events, such as loss of speech, may occur after liver transplantation. The differential diagnosis becomes very important before active treatment. Magnetic resonance imaging supplemented with diffusion tensor imaging is an effective imaging study in establishing the diagnosis. PMID- 24767372 TI - Independent risk factors for massive ascites after living donor liver transplantation in adults. AB - OBJECTIVES: This study sought to define the perioperative recipient and donor factors that contribute to the occurrence of massive ascites after living donor liver transplantation (LDLT) in adults. METHODS: A retrospective review of medical records and computerized databases was performed, and 105 adult patients who underwent LDLT from 2005 to 2011 in the West China Hospital, Sichuan University, were included. Patients were divided into group 1 (n = 27, massive ascites defined as >7000 mL of ascitic fluid produced during the first 7 days after LDLT) or group 2 (n = 78, no massive ascites). Perioperative recipient and donor factors were assessed using a univariate analysis followed by 2 logistic regression analyses. RESULTS: The recipients' median age was 44 years (range, 27 to 69 years), and the male-to-female ratio was 92:13. Massive ascites developed in 27 patients (25.7%). The average amount of ascites in group 1 and group 2 patients within the first 7 postoperative days was 11,285 mL and 3311 mL, respectively. The univariate analysis showed that recipient's age, primary liver disease, preoperative MELD score, Child-Pugh score, operating time, postoperative sequential organ failure assessment (SOFA) score, postoperative total bilirubin, right hepatic vein graft diameter, and hepatic portal vein graft diameter were significantly different between the 2 groups (P < .05). The 2 logistic regressions showed that the Child-Pugh score, operating time, and right hepatic vein graft diameter were independent risk factors for massive ascites after LDLT. CONCLUSION: It is important to improve the perioperative liver function and portal hypertension and to shorten operating time to reduce massive ascites after LDLT. PMID- 24767373 TI - Expression pattern analysis of hepatocellular carcinoma tumor markers in viral hepatitis B and C patients undergoing liver transplantation and resection. AB - BACKGROUND: This study was conducted to compare the expression patterns of serum alpha-fetoprotein (AFP) and proteins induced by vitamin K absence or antagonist II (PIVKA-II) in hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) and resection at a high-volume single institution. METHODS: First, 663 liver transplant recipients with HCC were selected. They were divided into hepatitis B virus (HBV) (n = 628) and hepatitis C virus (HCV) groups (n = 35). Their medical records were retrospectively reviewed. Second, another cohort of 2709 patients who underwent HCC resection included 2258 HBV, 143 HCV, and 308 non-HBV non-HCV (NBNC) patients. RESULTS: In the transplantation group, pretransplantation AFP level >20 ng/mL was observed in 42.5% of HBV patients and 60% of HCV patients (P = .042). PIVKA-II level >40 mAU/mL was observed in 30.6% of HBV patients and 42.9% of HCV patients (P = .127). In the resection group, a preoperative AFP level >20 ng/mL was observed in 51.7% of HBV patients and 43.3% of HCV patients (P = .052). PIVKA-II level >40 mAU/mL was observed in 59.7% of HBV patients and 56.6% of HCV patients (P = .47). Preoperative AFP level >20 ng/mL and PIVKA-II level >40 mAU/mL were observed in 35.7% and 61% of NBNC patients, respectively. Receiver-operator characteristic curve analyses revealed that the expression pattern of PIVKA-II in patients with elevated AFP level was not predictable and vice versa, regardless of background liver diseases. CONCLUSIONS: This study indicates that serum AFP and PIVKA-II may be expressed variably regardless of the types of background liver disease. Further large volume multicenter studies are needed to evaluate the possibility of the etiology dependent expression of tumor markers. PMID- 24767374 TI - Elevation of C-reactive protein level and its correlation with psychiatric comorbidities in recipients after liver transplantation. AB - Orthotopic liver transplantation (OLT) is the gold standard procedure for treating end-stage liver disease resulting from a variety of causes. Psychiatric comorbidities are common problems among patients who have undergone OLT; however, the association between psychiatric comorbidity and biological factors in OLT has not been investigated. In our previous study, we found a positive correlation between serum C-reactive protein (CRP) level after OLT and the prevalence of psychiatric comorbidities in recipients. In this retrospective cohort analysis, we enrolled 279 recipients who underwent OLT during a 3-year period (from 2008 to 2011) at a single center. Our retrospective study showed that the recipients with a higher serum CRP level at 1 month after OLT had higher psychiatric comorbidities compared with the recipients with a normal serum CRP level. Additionally, an in vitro study demonstrated that the down-regulation of brain derived neurotrophic factor (BDNF) gene expression by CRP treatment in retinoic acid (RA) differentiated SH-SY5Y neuroblastoma cells. These clinical and experimental results indicated that the overexpression of CRP may induce psychiatric comorbidities through suppressed expression of the BDNF, suggesting that OLT recipients who developed psychiatric comorbidities might be accompanied by an immunological or acute-phase protein response. In conclusion, an activation of systemic inflammatory processes may be one of the predictable signatures for psychiatric comorbidities in OLT recipients. PMID- 24767375 TI - Prognostic value of oxygen consumption and ventilatory equivalent slope in female candidates referred for heart transplantation--experience of a single Asian center. AB - BACKGROUND: Ventilatory equivalent (ventilation/CO2 production, VE/VCO2) slope has been suggested to be a much more accurate predicator than peak oxygen consumption (VO2) during exercise for prognosis in patients with heart failure. However, patients tested were predominately male. METHODS: To investigate whether peak VO2 and VE/VCO2 slope predict the prognosis of female patients with heart failure, we retrospectively collected data of 39 female candidates referred for heart transplantation (HTx) from 2004 to 2011. Both peak VO2 and VE/VCO2 slope were obtained from the results of an exercise pulmonary function test. The outcome was death or mechanical devices implantation or HTx. Logistic regression was used for data analysis. RESULTS: Mean age and heart failure survival score were 55.8 +/- 13.7 years and 7.3 +/- 0.7, respectively. Each increment of VE/VCO2 slope decreased 2-year event-free rate (odds ratio [OR] = 0.88, 95% confidence interval [CI] = 0.79 to 0.98) in the female group. The predictions of VE/VCO2 slope for 1-year event-free survival did not reach statistical significance (OR = 0.92, 95% CI = 0.84 to 1.00). On the other hand, peak VO2 was not a strong predictor for 1- and 2-year event-free survival (OR = 1.22 and 1.16, 95% CI = 0.96 to 1.55 and 0.94 to 1.44, respectively). CONCLUSIONS: Impairment in exercise ventilation holds a clinical and long-term prognostic impact in female patients with heart failure. The role of peak VO2 during exercise in prognostic prediction among the cohort should be further investigated. PMID- 24767376 TI - Cardiac transplantation and concomitant coronary artery bypass grafting: our experiences in 11 cases. AB - INTRODUCTION: The shortage of donor hearts for transplantation could be alleviated by including the hearts of older donors. Previous literature revealed similar early and medium-term survival outcomes compared with those of younger donors. This study presents our experience with patients who underwent orthotopic heart transplantation and concomitant coronary artery bypass grafting at our institution. METHODS: We present our experience with 11 patients with end-stage cardiomyopathy (8 men and 3 women) undergoing orthotopic heart transplantation and concomitant coronary artery bypass grafting from September 2002 to November 2011 at our institute. RESULTS: All 11 donor organs would otherwise have been rejected, depriving potential recipients of organ transplantation. Two patients received concurrent 2-coronary-artery bypass, and the other 9 patients received concurrent single-coronary-artery bypass during orthotopic heart transplantation. All patients had an uneventful postoperative course, with follow-up completed 3 to 128 months after cardiac transplantation and concomitant coronary artery bypass grafting surgery. CONCLUSIONS: Our experiences suggest that donor hearts requiring coronary artery bypass grafting, which form a small but significant donor subgroup, can be used effectively and safely when matched to the recipients' age and medical condition. PMID- 24767377 TI - Factors contributing to poor sleep quality as perceived by heart transplant recipients in Taiwan. AB - BACKGROUND: The aims of this project were to explore the factors contributing to poor sleep quality at 1 to 3 years after heart transplantation (post-HT), and to explore economic problems and social support for HT recipients (HTRs). METHODS: This study used a cross-sectional retrospective triangulation approach combining qualitative and quantitative research method designs. Quantitative data included data from the visual analog scale and the Taiwanese version of the World Health Organization Quality of Life questionnaire. Qualitative data were derived from questions that explored physiological, psychological, and economic factors contributing to poor sleep quality postprocedure for HTRs. RESULTS: Sixty-four subjects (81% male, 19% female) participated in this research. Their ages ranged from 20 to 70 (M = 46.88 +/- 12.12) years old. Their post-HT timeframe ranged from 1 to 4.10 years; 33% received preoperative extracorporeal membrane oxygenation support. Sleeping disturbances were reported by 72.7% of subjects after HT. Poor sleeping quality at 2 to 3 years post-HT (P = .028) was a complaint, and was worse than at 1 to 2 years post-HT (P = .008). Six physiological (62.5%) and 3 psychological (37.5%) contributing factors were further identified in qualitative interviews. Physiological factors were the major causes affecting their sleep quality 2 to 3 years after HT, whereas psychological factors arose from various family roles, responsibilities, and economic-related pressures. CONCLUSIONS: Medical teams should find the causes that lead to sleep disturbances and use the findings to improve HTR sleep quality. When the family financial status is affected, these teams should offer assistance and suggestions for patients who are unable to work due to post-HT physical decline. Establishing and providing good family support systems or patient support groups may allow patients to obtain physical, psychological, and spiritual comfort. PMID- 24767378 TI - Importance of early appropriate intervention including antibiotics and wound care for device-related infection in patients with left ventricular assist device. AB - INTRODUCTION: A left ventricular assist device (LVAD) is essential for treating patients with advanced heart failure. However, LVAD-related infection is a significant cause of mortality and morbidity, with bloodstream infection (BSI) especially associated with high mortality. We investigated the incidence of infectious complications in patients who received an LVAD and evaluated the effects of early and appropriate intervention for LVAD-related infection. METHOD: We retrospectively reviewed 27 consecutive patients who underwent continuous-flow LVAD (CF-LVAD; n = 16) or pulsatile-flow LVAD (PF-LVAD; n = 11) implantation at the National Cerebral and Cardiovascular Center between April 2011 and March 2013. Incidences of LVAD-related infections, such as drive-line infection in patients with CF-LVAD, cannula infection in patients with PF-LVAD, and BSI in patients with both types, were examined (follow-up period, 342 +/- 229 days). The mandatory antibiotic prophylaxis protocol at our institution includes teicoplanin (400 mg) 2 days before LVAD implantation and doripenem (1000 mg) within 1 hour of skin incision. In addition, the driveline exit sites undergo sterile cleansing with diluted hydrogen peroxide and placement of an antimicrobial occlusive dressing for wound care, with dressing changes performed 2-3 times per day. RESULTS: More than 90% of all patients suffered from a drive-line infection within 12 months after LVAD implantation. However, BSI developed in only 12.5% of CF-LVAD and 10% of PF-LVAD patients within 12 months (log-rank test; P = .875). CONCLUSIONS: LVAD-related infections, such as drive-line and cannula infections, were common, whereas the incidence of BSI was low in our LVAD-implanted patients. Our results highlight the importance of early and appropriate intervention including antibiotics and wound care for device-related infections for reducing the incidence of potentially fatal BSI. PMID- 24767379 TI - Current status of heart transplantation in Taiwan. AB - PURPOSE: We reviewed the national results of heart transplantation in Taiwan. METHODS: From July 1987 to December 2012, 1354 patients underwent heart transplantation in 18 qualified heart centers in Taiwan. The transplantation volume and survival rate were reviewed. RESULTS: The median age of recipients was 49 years at surgery, with 37% in the International Society for Heart and Lung Transplantation (ISHLT)-1A, 30% in ISHLT-1B, and 32% in ISHLT-2. The allograft 1 , 3-, 5-, and 10-year survival rates were 78%, 68%, 61%, and 47%, respectively. Mostly difficult recipients were bridged by extracorporeal membrane oxygenation (ECMO) instead of ventricular assist device (VAD). CONCLUSION: The results of heart transplantation in Taiwan are comparable with ISHLT world results. In Taiwan, we use more ECMO than VAD for mechanical circulatory support to bridge critical recipients to heart transplantation. PMID- 24767380 TI - Risk factors and prognosis of patients with primary graft failure after heart transplantation: an Asian center experience. AB - BACKGROUND: Although primary graft failure (PGF) after heart transplantation is a feared complication, most reports have come from Western countries. We analyzed the incidence in our hospital and tried to determine the predictive risk factors for PGF that require mechanical circulatory support or high dosage of inotropic agents after heart transplantation. We observed the long-term prognosis of patients successfully surviving PGF. METHODS: For this retrospective review, 447 patients undergoing heart transplantation between January 1990 and January 2013 were enrolled in our study. We compared the clinical data between patients with PGF and without PGF. The risk factors associated with PGF were analyzed, and the long-term survival curve was analyzed using a Kaplan-Meier analysis. RESULTS: The incidence of PGF in our study was 36.2% (162 patients) and the overall PGF related mortality rate was 17% (30 day in-hospital mortality). Independent risk factors for PGF included preoperative recipient hypoalbuminemia, high central venous pressure, United Network for Organ Sharing (UNOS) status 1A, dependence on inotropic agents, ventilator, intra-aortic balloon pump (IABP), and extracorporeal membrane oxygenation (ECMO), and longer ischemic time. Patients with PGF had poorer long-term survival than patients without PGF; the 1-year survival rate was 40% versus 76% (P < .01). The rate of weaning from ECMO for PGF was 46% (12 of 26 patients) and they have similar 1-year survival rates as non EGF patients. CONCLUSIONS: Several recipient and donor variables significantly influenced the PGF after heart transplantation. The mortality rate was higher in patients with PGF. However, patients who survived PGF have similar mid-term and long-term survival as patients without PGF. PMID- 24767381 TI - The effect of statins on cardiac allograft survival. AB - PURPOSE: In addition to having a lipid-lowering effect, statins also have an anti inflammatory effect that may reduce allograft dysfunction by preventing cardiac allograft vasculopathy (CAV) and play an immunomodulatory role. We studied the effect of statins on cardiac allograft survival at the National Taiwan University Hospital (NTUH). MATERIALS AND METHODS: We retrospectively reviewed the patients undergoing heart transplantation at NTUH in the last 6 years. After transplantation, all patients received biochemical monitoring every month and echocardiographic examination regularly at NTUH. Protocol biopsy was performed in all except 18 pediatric patients. All patients received immunosuppressants, including tacrolimus or cyclosporine, everolimus or mycophenolate acid, and prednisolone. They were divided into statin and nonstatin groups according to whether or not a statin was taken. RESULTS: At NTUH, from 2007 to 2012, 168 heart transplantations were performed. The ages of the patients ranged from 6 to 74 years old with male predominance. The etiology was mainly dilated cardiomyopathy (52.4%) and ischemic cardiomyopathy (39.3%), including 7 retransplantations from severe CAV with heart failure. Twenty-three patients (17%) suffered from acute rejection. The overall 1-year actuarial survival rate was 86% +/- 2% and the 5 year survival rate was 79% +/- 3%. Seventy-eight patients (57.4%) took statins and the statin group has a better 5-year survival rate and freedom from cardiac death survival rate (P < .01). CONCLUSION: Our study showed that the use of statins after transplantation was associated with better survival. PMID- 24767382 TI - Antibody-mediated rejection after orthotopic heart transplantation: a 9-year single-institution experience. AB - OBJECTIVE: Over the past decade, antibody-mediated rejection (AMR) continues to be recognized as one of the major obstacles in cardiac transplantation, yet its clinical outcome has been reported only in small series studies. This investigation reviews our experience in treating 11 patients with AMR after heart transplantation. METHODS: We retrospectively analyzed a total of 11 patients who underwent cardiac transplantation from 2004 to 2012 at a single medical institute. The diagnosis of AMR was made according to criteria set by the International Society for Heart and Lung Transplantation (ISHLT) 2011 working formulation. RESULTS: The average age among the 11 patients was 50.4 +/- 16.9 years. The overall mortality rate was 54.5%. Five patients (45.4%) developed hemodynamic compromise in an average of 5 days after transplantation, presenting with sudden onset of fatal arrhythmia (n = 4; 80%) and immediate heart failure (n = 1; 20%). All 5 patients underwent immediate resuscitation and extracorporeal membrane oxygenation (ECMO) support, and 3 patients died (60%); in contrast, the other 6 patients suffered from progressively worsening cardiac function during long-term follow-up. Three patients (50%) died in this group. CONCLUSIONS: Clinical presentation of AMR varies. Long-term postoperative follow-up in the form of endomyocardial biopsy is recommended with immunohistochemistry C4d staining, with the anticipation of the possibility of future recurrence. PMID- 24767383 TI - Six-minute walk test among heart transplant recipients. AB - OBJECTIVE: Six-minute walk test (6MWT) is an important measure to assess the exercise capacity of cardiac patients. This study aimed to evaluate the correlations of 6MWT with findings of cardiopulmonary exercise testing (CPET), health-related quality of life (HRQoL), and obesity among heart transplantation recipients (HTR) at least 1 year after transplantation. METHOD: Clinically stable HTR were recruited for this study from the National Taiwan University Hospital, Taipei, Taiwan. The 6MWT was performed by a physical therapist following the American Thoracic Society standard. Each subject underwent a symptom-limited CPET to evaluate cardiorespiratory fitness and bioelectrical impendence analysis for determination of body composition. The HRQoL of study subjects was evaluated by the Medical Outcomes Trust 36-item health survey (SF-36). RESULTS: The study subjects included 43 HTR (age: 47.8+/-11.1 years; 37 men, 6 women) at 4.8+/-3.2 years after transplantation. The 6MWT distance was 539+/-108 m (89.9+/-18.2% of the predicted value). The peak oxygen uptake was 19.3+/-4.7 mL/kg/min. The body composition analysis showed body fat percentage 25.2+/-7.9%, body mass index 26.5+/-4.8, and waist circumference 94.8+/-13.3 cm. The 6MWT distance was significantly positively correlated with peak oxygen uptake, peak heart rate, peak work rate, and peak systolic blood pressure during CPET, and significantly negatively correlated with body fat percentage, body mass index, and waist circumference. The 6MWT distance was also significantly positively correlated with SF-36 HRQoL parameters including general health perception and standardized physical component scale. The peak HR during CPET and standardized physical component scale was significantly correlated with 6MWT distance in multivariate analysis. CONCLUSIONS: Our findings indicate that 6MWT is a simple and useful measure to assess the exercise capacity of clinically stable HTR. The 6MWT distance is positively correlated with HRQoL and negatively correlated with obesity among HTR. The prognostic significance of 6MWT for HTR requires further investigation. PMID- 24767384 TI - The status of heart transplantation in Taiwan, 2005-2010. AB - Heart transplantation (HT) is the standard therapy used to treat end-stage heart disease. Taiwan Organ Registry and Sharing Center (TORSC) is a registry and database of organ donations and transplantations. To understand the profiles of heart donors and recipients is crucial for efficient utilization. Data was provided by the TORSC and 487 HT were performed from 2005 to 2010. The main causes of donor brain death were head injury (n = 243; 51.1%) and cerebrovascular accidents/strokes (n = 147; 30.9%). The mean age of the recipients was 46.3 +/- 14.6 years, and 80.3% were men (n = 391). Physicians and nurses were responsible for most organ procurement. In multivariate analysis, considering donor and recipient gender, donor and recipient age, and donor-to-recipient weight ratio as independent variables, factors that were significantly predictive of graft survival were donor age (hazard rate [HR], 1.02; 95% confidence interval [CI], 1.00-1.03; P = .01) and recipient age (HR, 1.03; 95% CI, 1.01-1.04; P < .01). Our results showed that age is a determinant of allograft survival and healthcare professionals are the primary impetus for obtaining consent for organ donation. PMID- 24767385 TI - Ocular manifestations of patients receiving heart transplants: a single-center experience of 311 consecutive cases. AB - PURPOSE: The purpose of this study was to investigate ocular manifestations of patients undergoing heart transplantations. METHOD: We retrospectively reviewed the clinical data of 311 patients who underwent orthotropic heart transplantations from January 1989 to December 2007, including the demographic data, general conditions, medications, as well as the basic ophthalmic examinations, ophthalmic diagnosis, and management. RESULTS: Of the 311 heart transplant recipients, common diagnoses included cataract (96 cases; 30.87%), dry eye syndrome (24 cases; 7.72%), allergic conjunctivitis (78 cases; 25.08%), and glaucoma (19 cases; 6.11%). The patients after heart transplantation had much lower incidences of severe opportunistic infections than patients undergoing the same procedure one decade ago. However, autoimmune-related endocrinopathy such as diabetes and Graves' disease became more prevalent. Diabetes-related complications were unexpectedly frequent, including nonproliferative diabetic retinopathy (6 cases; 1.93%), proliferative diabetic retinopathy (6 cases; 1.93%), retinal vein occlusion (6 cases; 1.93%), and neovascular glaucoma (4 cases; 1.29%). The occurrence of cataract formation and steroid glaucoma was often due to post-transplantation steroid use. CONCLUSION: Ophthalmologists and cardiac surgeons should collaborate and perform regular ophthalmic examinations, especially for those who have new-onset diabetes and difficulty tapering off steroids. PMID- 24767386 TI - Quantitative evaluation of native lung hyperinflation after single lung transplantation for emphysema using three-dimensional computed tomography volumetry. AB - OBJECTIVE: Although double lung transplantation is performed more frequently for emphysema, single lung transplantation (SLT) continues to be performed owing to limited donor organ availability. Native lung hyperinflation (NLH) is a unique complication following SLT for emphysema. Three-dimensional computed tomography (3D-CT) volumetry has been introduced into the field of lung transplantation, which we used to assess NLH in emphysema patients undergoing SLT. The primary purpose of this study was to confirm the effectiveness of 3D-CT volumetry in the evaluation of NLH following SLT for emphysema. METHODS: In 5 emphysema patients undergoing SLT at Kyoto University Hospital, 3D-CT volumetry data, pulmonary function test results, and clinical and radiological findings were retrospectively evaluated. RESULTS: Three patients did not develop a significant mediastinal shift, whereas the other 2 patients developed a mediastinal shift. In the 3 patients without a mediastinal shift, 3D-CT volumetry did not show a significant increase in native lung volume. These patients had a history of sternotomy prior to lung transplantation and firm adhesion on the mediastinal side was detected during lung transplantation. One of 2 patients with a mediastinal shift developed severe dyspnea with significantly decreased pulmonary function, and 3D-CT volumetry showed a significant increase in the native lung volume. However, the other patient did not show any dyspnea and his native lung volume decreased postoperatively (preoperatively to 6 months postoperatively: +981 mL and -348 mL, respectively). CONCLUSION: Although bilateral lung transplantation has become preferable for emphysema patients owing to postoperative NLH with SLT, patients with a history of sternotomy prior to lung transplantation might be good candidates for SLT. 3D-CT volumetry may be a useful method for detection of NLH. PMID- 24767388 TI - Three types of simultaneous pancreas and kidney transplantation. AB - PURPOSE: The purposes of this study were to study and compare clinical and functional outcomes after simultaneous deceased donor pancreas and kidney transplantation (SPK DD), simultaneous deceased donor pancreas and living donor kidney transplantation (SPK DL), and simultaneous living donor pancreas and kidney transplantation (SPK LL). METHODS: From January 1, 1996 to September 1, 2005, 8918 primary, simultaneous pancreas and kidney transplantation (SPK) procedures were reported to the International Pancreas Transplant Registry. Of these, 8764 (98.3%) were SPK DD, 115 (1.3%) were SPK DL, and 39 (0.4%) were SPK LL. We compared these 3 groups with regard to several endpoints including patient and pancreas and kidney graft survival rates. RESULTS: The 1-year and 3-year patient survival rates for SPK DD were 95% and 90%, 97% and 95% for SPK DL, and 100% and 100% for SPK LL recipients, respectively (P >= .07). The 1-year and 3 year pancreas graft survival rates for SPK DD were 84% and 77%, 83% and 71% for SPK DL, and 90% and 84% for SPK LL recipients, respectively (P >= .16). The 1 year and 3-year kidney graft survival rates for SPK DD were 92% and 84%, 94% and 86% for SPK DL, and 100% and 89% for SPK LL recipients, respectively (P >= .37). CONCLUSIONS: Patient survival rates and graft survival rates for pancreas and kidney were similar among the 3 groups evaluated in this study. PMID- 24767387 TI - Results of surveillance bronchoscopy after cadaveric lung transplantation: a Japanese single-institution study. AB - BACKGROUND: The prevention and early detection of post-transplantation rejection and infection are key clinical points to achieve long-term survival after lung transplantation. Although surveillance bronchoscopy (SB) is performed in many transplantation centers, it is still controversial because of its undefined clinical significance and its possible complications. We evaluated the clinical utility of SB after cadaveric lung transplantation in Japan, where bilateral transplantation is officially limited to patients medically requiring bilateral grafts. PATIENTS AND METHODS: Twenty-eight patients who underwent cadaveric lung transplantation followed by SB were retrospectively analyzed with reference to the results of bronchoscopy. SB is routinely performed at 1, 2, 3, 6, and 12 months after lung transplantation and annually thereafter. Clinically indicated bronchoscopy (CIB) is considered in patients with suspected rejection or airway infection, and for follow-up examination after treatment for acute rejection. RESULTS: There were 206 bronchoscopies, including 189 SBs and 17 CIBs, performed in 28 patients who underwent cadaveric lung transplantation between 2000 and 2013 at Osaka University Hospital. Among SBs, 92 (49%) showed positive results of transbronchial lung biopsy (TBLB) or bronchoalveolar lavage (BAL), and intervention was applied following 34 SBs (18%). Among CIBs, 8 (47%) showed positive results of TBLB or BAL, with intervention performed in 3 patients (18%). A2-3 and B2R findings according to the revised International Society for Heart and Lung Transplantation (ISHLT) rejection score and airway infection/colonization were frequently observed within a year following lung transplantation. Cytomegalovirus infection was found in 7 SBs (6%) by TBLB only within 2 months after transplantation. Regarding complications, moderate bleeding occurred in 21 (11%), pneumothorax in 2 (1%), prolonged hypoxemia in 1 (0.5%), and pneumonia in 1 (0.5%) among the 189 SBs. CONCLUSION: SB frequently detects rejection and airway infection or colonization with minimum complications, especially within 12 months after cadaveric lung transplantation. PMID- 24767389 TI - Clinical outcome of pancreas transplantation from marginal donors in Japan. AB - In Japan, absolute shortage of donors still continues even after the law allowing organ transplantation from deceased donors came into force in 1997. With the passage of the waiting period after registration for pancreas transplantation (PTx), both deaths and serious cases of diabetic complications necessitating withdrawal of the registration have undoubtedly increased. Therefore, so-called "marginal donor" (MD) has been considered as a potential solution for shortage of donors in Japan. The aim of the present study is to evaluate feasibility of MD in terms of post-PTx outcomes using data from Japan Organ Transplantation Network. A total of 148 PTx were performed from deceased donors in Japan from 2000 to 2012. MD was defined as follows: (1) >45 years old; (2) hemodynamically unstable at harvest using a high-dose dopamine or more than 2 vasopressors; or (3) non-heart beating status. Postoperative outcomes after PTx were compared between the MD group and the non-MD group. Among the 148 PTx donors, 108 donors (73.0%) satisfied the criteria of MD. Early graft loss of pancreas graft during 3 months post-transplant was observed in 15 patients (10.1%), and the marginality (MD vs non-MD) was not significantly correlated with the early loss of pancreas graft. The overall patient survival of the MD group (1, 3, 5 years: 94.7%, 94.7%, 94.7%) was not significantly different from that of the non-MD group (1, 3, 5 years: 95.0%, 95.0%, 95.0%). Pancreas graft survival in the MD group (1, 3, 5 years: 80.9%, 73.2%, 66.0%) seemed to be slightly lower than that in the non-MD group (1, 3, 5 years: 92.5%, 85.2%, 77.4%), but no statistically significant differences were found between the 2 groups. These results suggest the feasibility of the use of MD for PTx. PMID- 24767390 TI - Evaluation of glucose metabolism after distal pancreatectomy according to the donor criteria of the living donor pancreas transplantation guidelines proposed by the Japanese Pancreas and Islet Transplantation Association. AB - BACKGROUND: Living donor pancreas transplantation (LDPT) reduces the number of deaths of diabetic patients on dialysis and of candidates on the waiting lists and helps to overcome the organ shortage. Stringent criteria must be applied to minimize the risk of metabolic complications for living donors. The Japanese Pancreas and Islet Transplantation Association (JPITA) proposed LDPT guidelines in 2010. In this study, we retrospectively evaluated glucose metabolism of the patients who underwent distal pancreatectomy (DP) according to the donor criteria of the LDPT guidelines proposed by the JPITA. METHODS: Fifty-two nondiabetic patients who underwent DP were divided into 2 groups according to the donor criteria: indication group (IG, n = 14) who had age <= 65, hemoglobin A1c (HbA1c) < 5.9%, and body mass index (BMI) < 25 kg/m(2). The other patients were placed in the no indication group (NG, n = 38). Clinical data and percent resected volume (PRV) of each pancreas as determined by multi-detector row computed tomography volumetry were compared between the 2 groups. RESULTS: During the follow-up period (median 12 months), 14 patients (27%) developed new-onset diabetes within a median onset time of 10 months (range 3-24 months) postoperatively. No patient in the IG developed new-onset diabetes. On the other hand, 37% of the patients in the NG developed new-onset diabetes. There were significant between-group differences in changes in preoperative serum fasting glucose and HbA1c levels, whereas there were no significant between-group differences in preoperative serum albumin or body weight. Multivariate analysis identified preoperative HbA1c (odds ratio 51.6, P = .002) and PRV (odds ratio 2.07, P = .033) as independent risk factors for new-onset diabetes. CONCLUSION: Living donor criteria in the LDPT guidelines proposed by the JPITA are appropriate for prevention of glucose metabolic complications in donors. Further long-term follow-up studies of living donors' metabolic function are needed to clarify the safety of the donor. PMID- 24767391 TI - Three-dimensional computed tomographic volumetric changes in pancreas before and after living donor surgery for pancreas transplantation: effect of volume on glucose metabolism. AB - In the present study, we aimed to compare the pancreas volumetric changes before and after living donor surgery for pancreas transplantation, using three dimensional (3D) computed tomography (CT) and glucose metabolism. Pancreatic volume (PV) measurement using 3D CT was performed in 13 consecutive donors who underwent distal pancreatectomy for simultaneous living donor pancreas and kidney transplantation. PV was measured using a workstation before and 3 months after living donor operation. As the parameters of glucose metabolism, hemoglobin A1c (HbA1c) level, fasting plasma glucose (FPG) level, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and insulinogenic index (IGI) were examined simultaneously with the PV measurement. The preoperative and postoperative PVs of pancreas was 30 +/- 5 mL and 42 +/- 9 mL, respectively. The postoperative PV was significantly higher than the preoperative PV (P < .01) and increased by approximately 40% at 3 months after surgery. The postoperative FPG and HbA1c levels were significantly higher than the preoperative values (P < .01). BMI decreased significantly after surgery (P < .01). No differences in HOMA-IR and IGI were noted between before and after surgery. Diabetes mellitus was not observed any of the 13 living donors during this period. Distal pancreatectomy for living donors caused an increase in the PV and maintained insulin resistance, but it was not sufficient to maintain glucose metabolism at the preoperative state. PMID- 24767392 TI - Utility of glucagon stimulation test in type 1 diabetes after pancreas transplantation. AB - BACKGROUND: Despite recent progress of immunosuppressive therapy with newly developed agents, long-term pancreatic graft survival after pancreas transplantation still remains low. Therefore, precise assessment of beta-cell function after pancreas transplantation is necessary. METHODS: Pancreatic beta cell secretory activity was measured by means of the peripheral plasma fasting serum C-peptide (CPR) response to 1 mg of glucagon intravenously in 23 patients after pancreas transplantation. The utility of DeltaCPR after injection was compared with other indices that reflect insulin secretion. RESULTS: When we performed the test, 6 patients still needed insulin injection after the transplantation. Mean CPR before and after glucagon intravenously were 1.9 +/- 0.98 ng/mL and 4.6 +/- 2.29 ng/mL, respectively. Fasting serum CPR, secretory unit of islet in transplantation (SUIT) index, and DeltaCPR after glucagon injection were significantly different between insulin users and nonusers. During follow-up (501 +/- 228 days), 3 patients could stop using insulin, and their increase of CPR (1.8 +/- 0.5 ng/mL) was significantly higher than that in continuous insulin users (0.3 +/- 0.3 ng/mL). CONCLUSION: Fasting CPR, SUIT index, and DeltaCPR after glucagon injection could reflect beta-cell function for post-pancreas transplant patients, and glucagon stimulation test could give us additional information to predict insulin-free treatment. PMID- 24767393 TI - Single-institution outcomes in the first year of pancreas transplantation from brain-dead donors. AB - BACKGROUND: Under a revision to the law in 2010, the number of pancreas transplantations from brain-dead donors has been increasing in Japan. We started a new Pancreatic Transplant Program at Fujita Health University Hospital in September 2012. METHODS: A total of 11 cases of pancreas transplantation from brain-dead donors performed at Fujita Health University Hospital were analyzed in terms of the background characteristics of the donors and recipients and the outcomes. RESULTS: The mean age of the recipients was 45.2 years, and all recipients had a long-term history of diabetes (mean: 32.5 years). In the simultaneous pancreas and kidney transplantation (SPK) cases, the patients also had a long history of hemodialysis (mean: 8.0 years). Although the average donor age was 42.5 years, 90% of the donors were marginal donors, defined according to the following factors: (1) >45 years old, (2) death from cardiovascular disease, (3) episodes of cardiac arrest, (4) use of high doses of catecholamines. The pancreatic graft survival rate was 100%, although 1 patient required a small amount of insulin to maintain euglycemia. In addition, the kidney graft survival rate was also 100% in the SPK cases. CONCLUSIONS: The new Pancreatic Transplant Program at Fujita Health University has provided excellent outcomes for type 1 diabetic patients. PMID- 24767394 TI - Iron overload after pediatric liver transplantation: a case report. AB - Iron is an essential nutrient for living cells; however, an excessive accumulation of iron leads to organ damage and directly affects systemic immunity. Iron overload is clinically classified as hereditary or secondary. Most of secondary iron overload is caused by frequent blood transfusions because there is no active mechanism to excrete iron from the body. As recommended in various guidelines, chelation therapy is effective for reducing iron burden and improving organ function. There have been few reports on iron overload through blood transfusion during the perioperative period of liver transplantation. This report presents a case of iron overload due to repeated transfusions after pediatric liver transplantation managed by chelation therapy. The patient, an 11-month-old female with biliary atresia, underwent living donor liver transplantation. She revealed refractory anemia and required frequent blood transfusion. Both serum ferritin and transferrin saturation tended to increase after repeated transfusions, leading to secondary iron overload. Iron chelation therapy was started to prevent progression to organ failure and infection due to iron overload, and yielded a favorable outcome. It is crucial to consider the possibility of secondary iron overload and to achieve early detection and treatment to avoid progression to irreversible organ damage. PMID- 24767395 TI - Use of pericholedochal plexus for portal flow reconstruction in diffuse portal vein thrombosis: case report. AB - Portal vein thrombosis (PVT) remains a challenging issue for liver transplantation surgeons. Most patients who have PVT undergo eversion thrombectomy. When thrombectomy is not successful due to diffuse PVT, other modalities are adapted, such as the use of a venous jump graft or portal tributaries. Here, we report our successful experience with reconstruction of portal flow using collateral plexus for a patient with grade 4 PVT. Thrombectomy did not restore portal flow. A pericholedochal plexus was found on the lateral wall of common bile duct. Direct end-to-end anastomosis was performed between the donor's portal vein and patient's choledochal plexus. Postoperative color Doppler ultrasound revealed normal portal flow. PMID- 24767396 TI - Monotherapy with tacrolimus for heart and liver transplant: a case report. AB - BACKGROUND: Multiple-organ transplantation cases are rare, partly due to the shortage of donor organs. However, recent reports of outcomes of multiple-organ transplantations show encouraging survival rates for recipients as compared to single-organ transplant recipients. CASE REPORT: A 33-year-old female who was a known hepatitis B carrier and who had been diagnosed with peripartum dilated cardiomyopathy was experiencing end-stage heart failure. The patient received orthotopic heart transplantation. After heart transplantation, the recipient received prednisolone, cyclosporine, and mycophenolate mofetil for immunosuppressive therapy. Seventy-one days later, the recipient began to develop progressive jaundice, ascites, and hepatoencephalopathy and was re-admitted to the hospital. Fulminant hepatitis was diagnosed. She was referred for emergency cadaveric liver transplantation 110 days after the heart transplantation because of her critical condition. After transplantation, she was improved and her condition maintained by a single immunosuppressive therapy, tacrolimus, with mean dose of 0.06 mg/kg/d. CONCLUSION: We presented a case that was complicated by fulminant hepatitis after heart transplantation and successfully rescued by liver transplantation. PMID- 24767397 TI - Multiple hepatic vein reconstruction using an all-in-one sleeve patch graft technique in living donor liver transplantation: a case report. AB - Maintaining hepatic inflow and appropriate venous drainage is important for maximizing the capacity of the retrieved graft in liver transplantation. Here, we report a successful case of multiple hepatic vein (HV) reconstruction using an all-in-one sleeve patch graft of the autologous great saphenous vein to ensure adequate blood flow through the HV. A patient with hepatocellular carcinoma caused by hepatitis C virus-induced cirrhosis underwent living donor liver transplantation using a right lobe graft. A preoperative dynamic computed tomography scan and intraoperative findings revealed that the graft had three middle HV tributaries, a superficial vein, segment VIII HV (V8), and segment V HV (V5). The openings of the superficial vein and V8 were located very close to that of the right hepatic vein (RHV) in the cutting surface. Each HV had significant diameter and drainage territory requiring reconstruction. An autologous great saphenous vein was used to create a sleeve patch to incorporate the close-packed HV openings. The autologous sleeve patch graft was sutured to the openings of the RHV and the superficial vein and the hole created on the sleeve patch graft was anastomosed to the openings of V8 directly on the back table to create an all-in one sleeve patch. For the V5 reconstruction, the recipient's intrahepatic portal vein graft was used to create an interpositional conduit from the recipient's V5 to the inferior vena cava. The postoperative course was uneventful and postoperative studies revealed good graft function with excellent blood flow in the HV. PMID- 24767398 TI - Laparoscope-assisted Hassab's operation for esophagogastric varices after living donor liver transplantation: a case report. AB - This is the first successful report of a laparoscope-assisted Hassab's operation for esophagogastric varices after living donor liver transplantation (LDLT). A 35 year-old man underwent LDLT using a right lobe graft as an aid for primary sclerosing cholangitis (PSC) in 2005. Follow-up endoscopic and computed tomography (CT) examinations showed esophagogastric varices with splenomegaly in 2009 that increased (esophageal varices [EV]: locus superior [Ls], moderator enlarged, beady varices [F2], medium in number and intermediate between localized and circumferential red color signs [RC2]; gastric varices [GV]: extension from the cardiac orifice to the fornix [Lg-cf], moderator enlarged, beady varices [F2], absent red color signs [RC0]). A portal venous flow to the esophagogastric varices through a large left gastric vein was also confirmed. Preoperative Child Pugh was grade B and score was 9. Because these esophagogastric varices had a high risk of variceal bleeding, we proceeded with a laparoscope-assisted Hassab's operation. Operative time was 464 minutes. Blood loss was 1660 mL. A graft liver biopsy was also performed and recurrence of PSC was confirmed histologically. It was suggested that portal hypertension and esophagogastric varices were caused by recurrence of PSC. Postoperative complications were massive ascites and enteritis. Both of them were treated successfully. This patient was discharged on postoperative day 43. Follow-up endoscopic study showed improvement in the esophagogastric varices (esophageal varices [EV]: locus superior [Ls], no varicose appearance [F0], absent red color signs [RC0], gastric varices [GV]: adjacent to the cardiac orifice [Lg-c], no varicose appearance [F0], absent red color signs [RC0]) at 6 months after the operation. We also confirmed the improvement of esophagogastric varices by serial examinations of CT. PMID- 24767399 TI - Functioning pancreas graft with thromboses of splenic and superior mesenteric arteries after simultaneous pancreas-kidney transplantation: a case report. AB - Graft thrombosis is the most common cause of early graft loss after pancreas transplantation. The grafted pancreas is difficult to salvage after complete thrombosis, especially arterial thrombosis, and graft pancreatectomy is required. We describe a patient presenting with a functioning pancreas graft with thromboses of the splenic artery (SA) and superior mesenteric artery (SMA) after simultaneous pancreas-kidney transplantation (SPK). A 37-year-old woman with a 20 year history of type 1 diabetes mellitus underwent SPK. The pancreaticoduodenal graft was implanted in the right iliac fossa with enteric drainage. A Carrel patch was anastomosed to the recipient's right common iliac artery, and the graft gastroduodenal artery was anastomosed to the common hepatic artery using an arterial I-graft. The donor portal vein was anastomosed to the recipient's inferior vena cava. Four days after surgery, graft thromboses were detected by Doppler ultrasound without increases in the serum amylase and blood glucose levels. Contrast enhanced computed tomography revealed thromboses in the SA, splenic vein and SMA. Selective angiography showed that blood flow was interrupted in the SA and SMA. However, pancreatic graft perfusion was maintained by the I-graft in the head of the pancreas and the transverse pancreatic artery in the body and tail of the pancreas. We performed percutaneous direct thrombolysis and adjuvant thrombolytic therapy. However, we had to stop the thrombolytic therapy because of gastrointestinal hemorrhage. Thereafter, the postoperative course was uneventful and the pancreas graft was functioning with a fasting blood glucose level of 75 mg/dL, HbA1c of 5.1%, and serum C-peptide level of 1.9 ng/mL at 30 months post-transplantation. PMID- 24767400 TI - Impact of the 2011 Great East Japan Earthquake on the resumption of alcohol consumption after living-donor liver transplantation for alcoholic cirrhosis: a report of two cases. AB - Alcoholic liver disease (ALD) is a leading indication for liver transplantation (LT) in Western countries. The rate of resumption of alcohol abuse is 7% to 95% after LT for ALD. A high prevalence of alcohol abuse has been observed in disaster-exposed populations; however, little is known about the association between resumption of alcohol abuse after LT and disasters. Between June 2007 and March 2011, 3 patients with alcoholic cirrhosis (2 men and 1 woman) underwent living-donor LT (LDLT) at Tohoku University Hospital, Sendai, Japan. The female patient died of graft failure 6 months after LDLT. The other patients (ages 55 and 56 years), who survived to discharge, resumed alcohol abuse after the 2011 Great East Japan Earthquake. Before transplantation, both patients had been abusing alcohol for >35 years, with a daily ethanol intake of 110 g and 140 g, respectively. The period of abstinence from alcohol consumption ranged from 4 to 6 months. After transplantation, patients showed good compliance with treatment and seemed at low risk of relapse until the earthquake. One patient was living in the nuclear evacuation zone at Fukushima, and resumed alcohol consumption after the evacuation. Another patient resumed alcohol consumption while temporarily living apart from his family during restoration work after the disaster. Extreme stress and changes in living arrangements after the Great East Japan Earthquake seemed to trigger the desire to drink. This is the first report on patients who underwent LT for ALD and who resumed alcohol consumption after a disaster. PMID- 24767401 TI - Fibrosing cholestatic hepatitis developing within one month after living donor liver transplantation for chronic hepatitis C-related cirrhosis: a case report. AB - Fibrosing cholestatic hepatitis (FCH) is a life-threatening consequence of hepatitis C virus (HCV) infection occurring in a small minority of liver transplantation (LT) recipients. We herein report a case of early-onset FCH after living donor LT in a 47-year-old woman with HCV-related cirrhosis. The patient underwent balloon-occluded retrograde transvenous obliteration of a splenorenal shunt to treat an impaired portal flow on the sixth postoperative day (POD 6) and a bypass operation for hepatic artery thrombosis on POD 12. Thereafter, the serum bilirubin levels increased gradually; however, computed tomography revealed no evidence of biliary stricture. The serum HCV-RNA level on POD 27 was >7.8 log IU/mL. Histopathology of a needle graft biopsy performed on POD 28 revealed FCH with extensive portal fibrosis accompanied by mild inflammation, hepatocyte ballooning, and ductular proliferation with cholestasis. The patient received combination therapy with pegylated interferon, ribavirin, and double-filtration plasmapheresis for the treatment of early-onset FCH. Both the recipient and the donor carried the major genotype single nucleotide polymorphism (TT) at rs8099917 near the interleukin-28B gene. Furthermore, the HCV genotype was treatment sensitive 2a. Nonetheless, the recipient died of hepatic failure on POD 211. Thus far, few cases of FCH occurring within 1 month after LT have been reported. In addition, the early onset of FCH may be an adverse prognostic factor. PMID- 24767402 TI - Successful treatment of severe anastomotic stricture of a choledochojejunostomy after living donor liver transplantation with transhepatic cholangioscopy-guided balloon dilatation. AB - Anastomotic stricture of the choledochojejunostomy is a common complication after living donor liver transplantation. Most anastomotic strictures can be treated by percutaneous transhepatic cholangiodrainage and/or double balloon endoscopy. However, in severe cases and/or in small infants, neither of these is possible. Our new technique, cholangiography accompanied by cholangioscopy, enabled successful guidewire placement and balloon dilatation in cases with severe anastomotic stricture. PMID- 24767403 TI - Successful liver transplantation in a patient with quadriparesis: a case report. AB - Major abdominal surgeries, including liver transplantation, are considered high risk procedures for patients with respiratory muscle dysfunction, such as patients with quadriparesis, due to possible fatal postoperative pulmonary complications. We report on a 57-year-old male patient with longstanding quadriparesis due to fifth cervical spine injury from a traffic accident who suffered from decompensated liver cirrhosis related to hepatitis C infection and hepatocellular carcinoma. A preoperative pulmonary function test showed forced expiratory volume in 1 minute (FEV1) 1.06 L, which was a risk for pulmonary complications. The patient required respiratory training. Cadaveric liver transplantation was performed successfully without surgical complications. The patient was extubated on the fourth day after surgery and initially did well. However, on the eighth postoperative day, an episode of status epilepticus from metabolic derangement developed. After controlling seizure with anticonvulsive medication and sedation, the patient was reintubated due to hypoventilation. Chest radiograph showed upper lung atelectasis. Due to this complication, tracheostomy was performed. The patient's condition gradually improved. He was ultimately discharged on the 45th postoperative day. Two months after the transplantation, liver functions were normal and the patient could breathe spontaneously without tracheostomy and had good quality of life. In conclusion, this is, to our knowledge, the first report of liver transplantation in a patient with quadriparesis. It shows that even with a very high risk for postoperative pulmonary complications, liver transplantation can be performed successfully with careful patient selection and effective respiratory care. PMID- 24767404 TI - Case report of FLT3-ITD-positive AML patient 11 years after living donor liver transplantation. AB - With the increasing number of long-term survivors of living donor liver transplantation, the occurrence of secondary cancer is sometimes reported. Solid tumors such as lymphomas are mainly observed. However, only 8 cases of leukemia have been reported so far. For patients younger than 15 years old, leukemia developed in 4 within 3 years after the liver transplantation, whereas acute lymphoblastic leukemia developed in only 1 patient. This is the first case report of a patient in whom FLT3-ITD-positive acute myeloid leukemia (AML) developed more than 10 years after living donor liver transplantation for congenital biliary atresia. AML developed in a 14-year-old boy 11 years after living donor liver transplantation from his father. The patient received the transplant at the age of 3 years and was treated with tacrolimus and methylprednisolone for transplant rejection. Eleven years posttransplantation, he visited the hospital with general malaise and anemia. Blood tests revealed an elevated white blood cell count of 60,100/MUL, and the patient was diagnosed with AML. Chromosome analysis revealed a t(6; 9) (p23 q34) translocation; moreover, genetic testing revealed a FLT3-ITD-positive mutation. We started treatment in accordance with the Tokyo Children's Cancer Study Group AML99 protocol. With chemotherapy treatment, the patient achieved complete remission. After chemotherapy, we performed stem cell transplantation from his father. Other patients were reported in relatively early stages after liver transplantation, but our case was more than 10 years posttransplantation. The association with the onset of congenital bile duct atresia and leukemia is still not clear, but we consider the possibility that long-term immunosuppressive drugs contribute to developing leukemia. PMID- 24767405 TI - Spontaneous rupture of hepatic metastasis from small cell neuroendocrine carcinoma of maxillary sinus. AB - BACKGROUND: Small cell neuroendocrine carcinoma of the maxillary sinus, a rare malignant tumor, has a poor prognosis because of its high incidence of metastasis. Moreover, metastatic cancer-induced hepatic rupture, characterized by hemoperitoneum, is infrequent, although several lines of evidences have reported that a wide variety of other neoplasms can cause this usually fatal manifestation. CASE PRESENTATION: We now present the first case of a 49-year-old man with spontaneous rupture of hepatic metastasis from small cell neuroendocrine carcinoma of the maxillary sinus and ultimately resulted in massive intraperitoneal bleeding, which was successfully controlled by subsequent surgery (partial hepatectomy). The postoperative clinical manifestation of the patient was uneventful. He was discharged on the 16th day after operation and without any complication. CONCLUSIONS: Small cell neuroendocrine carcinoma of the maxillary sinus is very scarce and unfortunately has a poor prognosis. It has potential to cause spontaneous metastatic rupture which can elicit fatal hemorrhage. Emergency surgery is effective, although the long-term outcome is still unsatisfactory. PMID- 24767406 TI - COL1A1 and miR-29b show lower expression levels during osteoblast differentiation of bone marrow stromal cells from Osteogenesis Imperfecta patients. AB - BACKGROUND: The majority of Osteogenesis Imperfecta (OI) cases are caused by mutations in one of the two genes, COL1A1 and COL1A2 encoding for the two chains that trimerize to form the procollagen 1 molecule. However, alterations in gene expression and microRNAs (miRNAs) are responsible for the regulation of cell fate determination and may be evolved in OI phenotype. METHODS: In this work, we analyzed the coding region and intron/exon boundaries of COL1A1 and COL1A2 genes by sequence analysis using an ABI PRISM 3130 automated sequencer and Big Dye Terminator Sequencing protocol. COL1A1 and miR-29b expression were also evaluated during the osteoblastic differentiation of mesenchymal stem cell (MSC) by qRT-PCR using an ABI7500 Sequence Detection System. RESULTS: We have identified eight novel mutations, where of four may be responsible for OI phenotype. COL1A1 and miR-29b showed lower expression values in OI type I and type III samples. Interestingly, one type III OI sample from a patient with Bruck Syndrome showed COL1A1 and miR-29b expressions alike those from normal samples. CONCLUSIONS: Results suggest that the miR-29b mechanism directed to regulate collagen protein accumulation during mineralization is dependent upon the amount of COL1A1 mRNA. Taken together, results indicate that the lower levels observed in OI samples were not sufficient for the induction of miR-29b. PMID- 24767407 TI - The prevalence of naturally acquired swimming ability among children in Bangladesh: a cross sectional survey. AB - BACKGROUND: Most rural homes in Bangladesh have ponds nearby to serve as household water sources. As a result children of all ages are exposed to water bodies on a daily basis. Children learn to swim early in childhood from peers and relatives in a natural process that involves play and structured learning. In a large, national injury survey in Bangladesh, the ability to swim was associated with reduced risk of drowning. This study determines the prevalence of swimming ability in children in Bangladesh as a step in assessing whether this is a potential component of a national drowning prevention program. METHODS: A descriptive study design using a subset of a national sample survey determined the prevalence of naturally acquired swimming ability (NASA) reported by children of rural and urban communities in Bangladesh. A total of 2,598 households (1,999 rural and 599 urban) housing 4,336 children (2,263 male and 2,073 female) aged 5 17 years were chosen from 4 randomly selected districts using multistage random sampling. NASA was defined as the ability to cross 25 meters of water deeper than the child's height using any body movement for self-propulsion. RESULTS: Reported NASA was greater in males (55.6%) than females (47.9%) and among rural children (57.8%) than urban children (25.5%) for children 5-17 years. The proportion reporting NASA increased with increasing age. At age 5, 5.8% of males and 6.3% of females reported NASA, rising to 84.3% of males and 70.7% of females by age 17. By age 17, 83.1% of rural children and 57.5% of urban children reported NASA. CONCLUSION: Most children in Bangladesh report being able to swim 25 meters and learning it by middle childhood. Reported NASA is higher for males than females and for rural children than urban children. High rates of swimming appear to be achievable in the absence of pools and a swim-teaching industry. This may facilitate development of a low cost, national drowning prevention program with swimming an integral part. PMID- 24767408 TI - Retinal vessel oxygen saturation and its correlation with structural changes in retinitis pigmentosa. AB - PURPOSE: To study the influence of retinal structural changes on oxygen saturation in retinitis pigmentosa (RP) patients. METHODS: Oximetry measurements were performed on 21 eyes of 11 RP patients and compared to 24 eyes of 12 controls. Retinal oxygen saturation was measured in all major retinal arterioles (A-SO2) and venules (V-SO2) with an oximetry unit of the retinal vessel analyser (IMEDOS Systems UG, Jena, Germany). Oximetry data were compared with morphological changes measured by Cirrus optical coherence tomography (OCT) (Carl Zeiss Meditec, Dublin, CA, USA, macular thickness protocol). RESULTS: In RP patients, the retinal A-SO2 and V-SO2 levels were higher at 99.3% (p = 0.001, anova based on mixed-effects model) and 66.8% (p < 0.001), respectively, and the difference between the two (A-V SO2) was lower at 32.5% (p < 0.001), when compared to the control group (92.4%; 54.0%; 38.4%, respectively). With the RP group, the A-V SO2 correlated positively, not only with central macular thickness, but also with retinal thickness, in zones 2 and 3 (p = 0.006, p = 0.007, p = 0.014). CONCLUSION: These data indicate that oxygen metabolism was altered in RP patients. Based on our preliminary results, retinal vessel saturation correlated with structural alterations in RP. This method could be valuable in monitoring disease progression and evaluating a potential therapeutic response. PMID- 24767409 TI - Sample-ready multiplex qPCR assay for detection of malaria. AB - BACKGROUND: Microscopy and antigen detecting rapid diagnostic tests are the diagnostic tests of choice in management of clinical malaria. However, due to their limitations, the need to utilize more sensitive methods such as real-time PCR (qPCR) is evident as more studies are now utilizing molecular methods in detection of malaria. Some of the challenges that continue to limit the widespread utilization of qPCR include lack of assay standardization, assay variability, risk of contamination, and the need for cold-chain. Lyophilization of molecular assays can overcome some of these limitations and potentially enable widespread qPCR utilization. METHODS: A recently published multiplex malaria qPCR assay was lyophilized by freezing drying into Sample-ReadyTM format (MMSR). MMSR assay contained all the required reagents for qPCR including primers and probes, requiring only the addition of water and sample to perform qPCR. The performance of the MMSR assay was compared to the non-freeze dried, "wet" assay. Stability studies were done by maintaining the MMSR assays at four different ambient temperatures of 4 degrees C, room temperature (RT), 37 degrees C and 42 degrees C over a period of 42 days, tested at seven-day intervals. Plasmodium falciparum and Plasmodium vivax DNAs were used for analysis of the MMSR assay either as single or mixed parasites, at two different concentrations. The CT values and the standard deviations (SD) were used in the analysis of the assay performance. RESULTS: The limit of detection for the MMSR assay was 0.244 parasites/MUL for Plasmodium spp. (PLU) and P. falciparum (FAL) assay targets compared to "wet" assay which was 0.39 and 3.13 parasites/MUL for PLU and FAL assay targets, respectively. The MMSR assay performed with high efficiencies similar to those of the "wet" assay and was stable at 37 degrees C for 42 days, with estimated shelf life of 5 months. When used to analyse field clinical samples, MMSR assay performed with 100% sensitivity and specificity compared to the "wet" assay. CONCLUSION: The MMSR assay has the same robust performance characteristics as the "wet" assay and is highly stable. Availability of MMSR assay allows flexibility and provides an option in choosing assay for malaria diagnostics depending on the application, needs and budget. PMID- 24767410 TI - A comprehensive analysis of Helicobacter pylori plasticity zones reveals that they are integrating conjugative elements with intermediate integration specificity. AB - BACKGROUND: The human gastric pathogen Helicobacter pylori is a paradigm for chronic bacterial infections. Its persistence in the stomach mucosa is facilitated by several mechanisms of immune evasion and immune modulation, but also by an unusual genetic variability which might account for the capability to adapt to changing environmental conditions during long-term colonization. This variability is reflected by the fact that almost each infected individual is colonized by a genetically unique strain. Strain-specific genes are dispersed throughout the genome, but clusters of genes organized as genomic islands may also collectively be present or absent. RESULTS: We have comparatively analysed such clusters, which are commonly termed plasticity zones, in a high number of H. pylori strains of varying geographical origin. We show that these regions contain fixed gene sets, rather than being true regions of genome plasticity, but two different types and several subtypes with partly diverging gene content can be distinguished. Their genetic diversity is incongruent with variations in the rest of the genome, suggesting that they are subject to horizontal gene transfer within H. pylori populations. We identified 40 distinct integration sites in 45 genome sequences, with a conserved heptanucleotide motif that seems to be the minimal requirement for integration. CONCLUSIONS: The significant number of possible integration sites, together with the requirement for a short conserved integration motif and the high level of gene conservation, indicates that these elements are best described as integrating conjugative elements (ICEs) with an intermediate integration site specificity. PMID- 24767411 TI - THAOS: gastrointestinal manifestations of transthyretin amyloidosis - common complications of a rare disease. AB - BACKGROUND: Transthyretin amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin monomers. Two main forms exist: hereditary and wild-type transthyretin amyloidosis, the former associated with transthyretin gene mutations. There are several disease manifestations; however, gastrointestinal complications are common in the hereditary form. The aim of this study was to explore the prevalence and distribution of gastrointestinal manifestations in transthyretin amyloidosis and to evaluate their impact on the patients' nutritional status and health-related quality of life (HRQoL). METHODS: The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with transthyretin amyloidosis and the registry is sponsored by Pfizer Inc. This study presents baseline data from patients enrolled in THAOS as of June 2013. The modified body mass index (mBMI), in which BMI is multiplied with serum albumin, was used to assess the nutritional status and the EQ-5D Index was used to assess HRQoL. RESULTS: Data from 1579 patients with hereditary transthyretin amyloidosis and 160 patients with wild-type transthyretin amyloidosis were analyzed. Sixty three percent of those with the hereditary form and 15% of those with the wild type form reported gastrointestinal symptoms at enrollment. Unintentional weight loss and early satiety were the most frequent symptoms, reported by 32% and 26% of those with transthyretin gene mutations, respectively. Early-onset patients (<50 years) reported gastrointestinal complaints more frequently than those with a late onset (p < 0.001) and gastrointestinal symptoms were more common in patients with the V30M mutation than in those with other mutations (p < 0.001). For patients with predominantly cardiac complications, the prevalence of gastrointestinal manifestations was not evidently higher than that expected in the general population. Both upper and lower gastrointestinal symptoms were significant negative predictors of mBMI and the EQ-5D Index Score (p < 0.001 for all). CONCLUSIONS: Gastrointestinal symptoms were common in patients with hereditary transthyretin amyloidosis and had a significant negative impact on their nutritional status and HRQoL. However, patients with wild-type transthyretin amyloidosis or transthyretin mutations associated with predominantly cardiac complications did not show an increased prevalence of gastrointestinal disturbances. PMID- 24767412 TI - An enhanced compost temperature sampling framework: case study of a covered aerated static pile. AB - Spatial and temporal temperature variations exist in a compost pile. This study demonstrates that systematic temperature sampling of a compost pile, as is widely done, tends to underestimate these variations, which in turn may lead to false conclusions about the sanitary condition of the final product. To address these variations, a proper scheme of temperature sampling needs to be used. A comparison of the results from 21 temperature data loggers randomly introduced into a compost pile with those from 20 systematically introduced data loggers showed that the mean, maximum and minimum temperatures in both methods were very similar in their magnitudes. Overall, greater temperature variation was captured using the random method. In addition, 95% of the probes introduced systematically had attained thermophilic sanitation conditions (>= 55 degrees C for three consecutive days), as compared to 76% from the group that were randomly introduced. Furthermore, it was found that, from a statistical standpoint, readings from at least 47 randomly introduced temperature loggers are necessary to capture the observed temperature variation. Lastly, the turning of the compost pile was found to increase the chance that any random particle would be exposed to the temperature >= 55 degrees C for three consecutive days. One turning was done during the study, and it increased the probability from 76% to nearly 85%. Using the Markov chain model it was calculated that if five turnings had been implemented on the evaluated technology, the likelihood that every particle would experience the required time-temperature condition would be 98%. PMID- 24767413 TI - High solids co-digestion of food and landscape waste and the potential for ammonia toxicity. AB - A pilot-scale study was completed to determine the feasibility of high-solids anaerobic digestion (HSAD) of a mixture of food and landscape wastes at a university in central Pennsylvania (USA). HSAD was stable at low loadings (2g COD/L-day), but developed inhibitory ammonia concentrations at high loadings (15 g COD/L-day). At low loadings, methane yields were 232 L CH4/kg COD fed and 229 L CH4/kg VS fed, and at high loadings yields were 211 L CH4/kg COD fed and 272 L CH4/kg VS fed. Based on characterization and biodegradability studies, food waste appears to be a good candidate for HSAD at low organic loading rates; however, the development of ammonia inhibition at high loading rates suggests that the C:N ratio is too low for use as a single substrate. The relatively low biodegradability of landscape waste as reported herein made it an unsuitable substrate to increase the C:N ratio. Codigestion of food waste with a substrate high in bioavailable carbon is recommended to increase the C:N ratio sufficiently to allow HSAD at loading rates of 15 g COD/L-day. PMID- 24767414 TI - [Secular growth acceleration in Spain. Spanish growth studies 2010. Spanish-born population and immigrant population]. PMID- 24767416 TI - Cryptococcus neoformans in sputum and lung aspiration cytology smears. PMID- 24767415 TI - Molecular characteristics and virulence factors in methicillin-susceptible, resistant, and heterogeneous vancomycin-intermediate Staphylococcus aureus from central-southern China. AB - BACKGROUND: Staphylococcus aureus is a leading cause of nosocomial infections. The purpose of this study was to evaluate the prevalence of methicillin-resistant S. aureus (MRSA) and heterogeneous vancomycin-intermediate S. aureus (hVISA), and compare the antimicrobial susceptibility, molecular characteristic, and virulence factors in methicillin-susceptible S. aureus (MSSA), MRSA, and hVISA from central southern China. METHODS: A total of 184 S. aureus were isolated from sterile body fluids. All isolates were subjected to population analysis profiling for the identification of hVISA phenotype and polymerase chain reaction analysis for genotyping and 31 virulence genes. RESULTS: The prevalence of MRSA isolates was 41.8% in central-southern China. Of 77 MRSA isolates, 17 (22.1%) were identified as hVISA. The most common MRSA and MSSA clones were ST239-MRSA-SCCmecIII-t030-agr I (55.8%) and ST188-MSSA-t189-agr-I (20.6%), respectively. The frequency of carriage of pvl, hemolysins, tst, and staphylococcal enterotoxin genes among MSSA isolates was significantly higher than that for MRSA isolates (p < 0.05); 98 MSSA isolates (53.3%) carried >= 10 tested virulence genes simultaneously, which was significantly higher than that of MRSA isolates (33.8%; p = 0.004). The 17 hVISA isolates carried a significantly small number of virulence genes; only two hVISA isolates carried >= 10 tested virulence genes simultaneously, and two hVISA isolates harbored only four virulence genes. Compared with other clonal complexes (CCs), CC1 and CC398 isolates harbored a higher frequency of exfoliatin genes, CC1 and CC59 harbored a higher frequency of pvl gene, and only CC1 isolates harbored lukED. CONCLUSION: The prevalence of hVISA was considerably high in central-southern China. Simultaneous carriage of multiple virulence genes was common in S. aureus isolates; the virulence genes were more diverse and frequent among MSSA isolates than among MRSA isolates. Furthermore, the distribution of some virulence genes was correlated with the different S. aureus CCs. PMID- 24767417 TI - High prevalence of Streptococcus agalactiae from vaginas of women in Taiwan and its mechanisms of macrolide and quinolone resistance. AB - BACKGROUND/PURPOSE: Streptococcus agalactiae (GBS), is the most common pathogen causing infections among perinatal women and neonatal babies. Nonetheless, there are few studies on the occurrence of GBS among the pregnant women and the mechanisms of GBS resistance to quinolones and macrolides in Taiwan. METHODS: GBS were isolated from vaginas of the pregnant and non-pregnant symptomatic women in Taiwan. The prevalence, antimicrobial susceptibility, and mechanisms of resistance against erythromycin and quinolone of total 188 isolates were studied. RESULTS: The isolation rate of GBS from pregnant women was significantly higher at 21.8% compare with the non-pregnant women of 13.2%. Antibiotic susceptibility test of the 188 GBS isolates revealed a high non-susceptible rate for erythromycin (50.0%) while the rate for levofloxacin was only 4.8%. Among 94 erythromycin non-susceptible GBS isolates, ermB gene was detected 83.1% (59/71) for those GBS that were non-susceptible to both clindamycin and tetracycline, which was significantly higher than GBS that are susceptible to clindamycin but resistant to tetracycline at 43.8% (7/16). No ermA or mef gene was detected in any isolate. Mutations were detected in the parC and gyrA genes in 14 out of 18 levofloxacin non-susceptible isolates. The predominant mutation type was the combination of Ser79Tyr in parC and Ser81Leu mutations in gyrA. CONCLUSION: GBS is the most common isolated pathogens in vaginal infections in Taiwan, resistance to tetracycline and erythromycin is higher than the rate observed for other regions of the world, while the resistance rate for levofloxacin was relatively lower in Taiwan. PMID- 24767419 TI - Application of minigenome technology in virology research of the Paramyxoviridae family. AB - Minigenomes (MGs) are complementary DNAs of the synthetic analogs of genomic RNA. MGs are widely used to study the life cycle of the Paramyxoviridae family of viruses. MG-based studies have provided valuable insights into the mechanisms of viral replication and transcription in this family, including the roles of viral proteins, the location and boundaries of the cis-acting elements, the functional domains of trans-acting proteins, techniques for the measurement of neutralizing antibody, virus-host interactions, and the structure and function of viral RNA. This article provides a brief overview of the principle and application of MG technology in studies involving members of the Paramyxoviridae family. The advantages, potential limitations, and future scope of MG technology are also discussed. PMID- 24767418 TI - Immune responses to latent tuberculosis antigen Rv2659c in Chinese populations. AB - BACKGROUND: The latency-associated antigen Rv2659c is a starvation-related protein of Mycobacterium tuberculosis (M. tuberculosis). It has potential use in tuberculosis (TB) control, but its immunological characteristics in Chinese populations are unclear. METHODS: In this study, immunological characteristics and potential diagnostic use of recombinant Rv2659c protein were assessed. Interferon-gamma (IFN-gamma) production from peripheral blood mononuclear cells (PBMC) was assayed by enzyme-linked immunospot (ELISPOT) in TB patients (80 cases), individuals who were purified protein derivative (PPD)-positive after Bacillus Calmette-Guerin (BCG) vaccination (27 cases), nontuberculous respiratory disease patients (30 cases), individuals who were identified by standard techniques as having latent TB infection (LTBI) (37 cases), and uninfected healthy individuals (75 cases). Serum immunoglobulin G (IgG) levels were assayed by enzyme-linked immunosorbent assay (ELISA) in TB patients (43 cases), LTBI individuals (36 cases) and uninfected healthy individuals (66 cases). RESULTS: When stimulated by rRv2659c, PBMC from LTBI individuals gave ELISPOT counts that were significantly higher than those from TB patients, BCG vaccinated individuals, non-TB respiratory disease patients and uninfected healthy individuals (p < 0.05). The rRv2659c stimulation gave detectable IFN-gamma production in a higher proportion of persons with LTBI compared with TB patients and uninfected healthy individuals. BCG vaccination and non-TB respiratory disease had little influence on the PBMC response to rRv2659c. The levels of serum IgG specific for rRv2659c were not significantly different between LTBI individuals and TB patients (p > 0.05). CONCLUSION: These results suggest that rRv2659c has potential for the diagnosis of LTBI. This is the first clinical report of human immune recognition of Rv2659c in Chinese populations. PMID- 24767420 TI - Establishment of a new immunological method for direct detection of Mycobacterium in solution. AB - BACKGROUND/PURPOSE: Tuberculosis (TB) is a crucial health problem. Prevention of the disease requires rapid diagnosis. Rapid liquid culture systems, nucleic acid amplification tests, and high-performance liquid chromatography (HPLC) are among the rapid tests used for detecting Mycobacterium species. However, these tests are expensive and require extensive equipment and expertise, which is hardly affordable in resource-poor countries. Although direct microscopy is performed routinely as an initial step for detection of the bacteria, it is not sufficiently sensitive. As a result, we thought of establishing a low-cost immunological test that can potentially replace direct microscopy with higher sensitivity and specificity. METHODS: The assay is based on pre-incubation of biotinylated rabbit antibody against Antigen 60 (A60) with a solution containing Bacillus Calmette-Guerin (BCG) or Mycobacterium tuberculosis (MTB) followed by incubation with a streptavidin-alkaline phosphatase (STA-ALP) conjugate. The test is devised in enzyme-linked immunosorbent assay (ELISA) and non-ELISA formats, therefore it does not require extensive facilities and expertise. RESULTS: The ELISA format showed a 100-fold improvement in the lower detection limit of BCG compared with direct microscopy. With the non-ELISA formats, there was a 2- and 16-fold improvement for the cartridge assay and the microfuge tube assay, respectively. CONCLUSION: In conclusion, we successfully detected BCG and MTB in solution using the new immunological method. Our results are very promising and the new immunological method could potentially replace direct microscopy with higher sensitivity and specificity. PMID- 24767421 TI - Immunological and parasitological parameters in Schistosoma mansoni-infected mice treated with crude extract from the leaves of Mentha x piperita L. AB - Schistosomiasis is a chronic disease caused by an intravascular trematode of the genus Schistosoma. Praziquantel is the drug used for treatment of schistosomiasis; nevertheless failure of treatment has been reported. Consequently, the identification of new effective schistosomicidal compounds is essential to ensure the effective control of schistosomiasis in the future. In this work we investigated the immunomodulatory and antiparasitic effects of the crude leaves extract of Mentha x piperita L. (peppermint) on murine Schistosomiasis mansoni. Female Balb/c mice were infected each with 50 S. mansoni cercariae and divided into three experimental groups: (I) untreated; (II) treated daily with M. x piperita L. (100mg/kg) and III) treated on 1/42/43 days post infection with Praziquantel (500mg/kg). Another group with uninfected and untreated mice was used as a control. Subsequently, seven weeks post-infection, S. mansoni eggs were counted in the feces, liver and intestine. Worms were recovered by perfusion of the hepatic portal system and counted. Sera levels of IL-10, IL-5, IL-13, IFN-gamma, IgG1, IgE and IgG2a were assayed by ELISA. Animals treated with a daily dose of M. x piperita L. showed increased sera levels of IL 10, IFN-gamma, IgG2a and IgE. Besides, M. x piperita L. treatment promoted reduction in parasite burden by 35.2% and significant decrease in egg counts in the feces and intestine. PMID- 24767422 TI - Surgery for colorectal liver metastases: the impact of resection margins on recurrence and overall survival. AB - BACKGROUND: Several reports have presented conflicting results regarding the association between resection margins (RMs) and outcome after surgery for colorectal liver metastases (CLM), especially in the era of modern chemotherapy. The purpose of this study was to evaluate the impact of RMs on overall survival (OS), time to recurrence (TTR) and local recurrence (LR) status, particularly for patients treated with preoperative chemotherapy. METHODS: A combined retrospective (1998 to 2008) and prospective (2008 to 2010) cohort study of consecutive patients with CLM without extrahepatic disease treated with primary resection at a medium volume centre. RESULTS: A total of 253 patients with known R status and 242 patients with defined margin width were included in the study. Patients were stratified according to margin width; A: R1, <1 mm (n=48, 19%), B: 1 to 4 mm (n=77), C: 5 to 9 mm (n=46) and D: >=10 mm (n=71). Median time to recurrence was 12.8 months, and after five years 21.5% had no recurrence. LR (inclusive combined recurrence in other hepatic sites or extrahepatic) occurred in 40 (16.5%) cases, most frequently seen with RMs below 5 mm. Five-year OS was 42.5% in R0 and 16.1% in R1 resections (P=0.011). Patients were also stratified according to preoperative chemotherapy (n=88), and the difference in five-year OS between R0 (45.1%) and R1 (14.7%) was maintained (P=0.037). By multiple Cox regression analysis R1 resections tended to an adverse outcome (P=0.067), also when adjusting for preoperative chemotherapy (P=0.081). CONCLUSIONS: R1 resections for colorectal liver metastases predict adverse outcome. RMs below 5 mm increased the risk for LR and shortened the time to recurrence. Preoperative chemotherapy did not alter an adverse outcome in R1 vs. R0 patients. PMID- 24767423 TI - Study protocol for a randomized controlled trial comparing the efficacy of a specialist and a generic parenting programme for the treatment of preschool ADHD. AB - BACKGROUND: The New Forest Parenting Programme (NFPP) is a home-delivered, evidence-based parenting programme to target symptoms of attention deficit/hyperactivity disorder (ADHD) in preschool children. It has been adapted for use with 'hard-to-reach' or 'difficult-to-treat' children. This trial will compare the adapted-NFPP with a generic parenting group-based programme, Incredible Years (IY), which has been recommended for children with preschool type ADHD symptoms. METHODS/DESIGN: This multicentre randomized controlled trial comprises three arms: adapted-NFPP, IY and treatment as usual (TAU). A sample of 329 parents of preschool-aged children with a research diagnosis of ADHD enriched for hard-to-reach and potentially treatment-resistant children will be allocated to the arms in the ratio 3:3:1. Participants in the adapted-NFPP and IY arms receive an induction visit followed by 12 weekly parenting sessions of 11/2 hours (adapted-NFPP) or 21/2 hours (IY) over 2.5 years. Adapted-NFPP will be delivered as a one-to-one home-based intervention; IY, as a group-based intervention. TAU participants are offered a parenting programme at the end of the study. The primary objective is to test whether the adapted-NFPP produces beneficial effects in terms of core ADHD symptoms. Secondary objectives include examination of the treatment impact on secondary outcomes, a study of cost-effectiveness and examination of the mediating role of treatment-induced changes in parenting behaviour and neuropsychological function. The primary outcome is change in ADHD symptoms, as measured by the parent-completed version of the SNAP-IV questionnaire, adjusted for pretreatment SNAP-IV score. Secondary outcome measures are: a validated index of behaviour during child's solo play; teacher reported SNAP-IV (ADHD scale); teacher and parent SNAP-IV (ODD) Scale; Eyberg Child Behaviour Inventory - Oppositional Defiant Disorder scale; Revised Client Service Receipt Inventory - Health Economics Costs measure and EuroQol (EQ5D) health-related quality-of-life measure. Follow-up measures will be collected 6 months after treatment for participants allocated to adapted-NFPP and IY. DISCUSSION: This trial will provide evidence as to whether the adapted-NFPP is more effective and cost-effective than the recommended treatment and TAU. It will also provide information about mediating factors (improved parenting and neuropsychological function) and moderating factors (parent and child genetic factors) in any increased benefit. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN39288126. PMID- 24767424 TI - The genetic basis of the symbiosis between Photorhabdus and its invertebrate hosts. AB - Photorhabdus is a pathogen of insects that also maintains a mutualistic association with nematodes from the family Heterorhabditis. Photorhabdus colonizes the gut of the infective juvenile (IJ) stage of the nematode. The IJ infects an insect and regurgitates the bacteria and the bacteria reproduce to kill the insect. The nematodes feed on the resulting bacterial biomass until a new generation of IJs emerges from the insect cadaver. Therefore, during its life cycle, Photorhabdus must (1) kill the insect host, (2) support nematode growth and development, and (3) be able to colonize the new generation of IJs. In this review, functional genomic studies that have been aimed at understanding the molecular mechanisms underpinning each of these roles will be discussed. These studies have begun to reveal that distinct gene sets may be required for each of these interactions, suggesting that there is only a minimal genetic overlap between pathogenicity and mutualism in Photorhabdus. PMID- 24767425 TI - Regulation of plant biomass utilization in Aspergillus. AB - The ability of fungi to survive in every known biotope, both natural and man made, relies in part on their ability to use a wide range of carbon sources. Fungi degrade polymeric carbon sources present in the environment (polysaccharides, proteins, and lignins) to use the monomeric components as nutrients. However, the available carbon sources vary strongly in nature, both between biotopes and in time. The degradation of polymeric carbon sources is mediated through the production of a broad range of enzymes, the production of which is tightly controlled by a network of regulators and linked to the activation of catabolic pathways to convert the released monomers. This review summarizes the knowledge of Aspergillus regulators involved in plant biomass utilization. PMID- 24767426 TI - Threonine aldolases. AB - Threonine aldolases catalyze the pyridoxal phosphate-dependent condensation between small amino acids (principally glycine) and aldehydes such as acetaldehyde. Carbon-carbon bond formation involves forming two adjacent chiral centers. As a rule, threonine aldolases are very stereoselective for alpha-carbon configuration but show modest selectivity at the beta-carbon. On the other hand, these enzymes accept a wide variety of synthetically useful acceptor aldehydes, making them important additions to the synthetic toolkit. This review briefly summarizes the reaction mechanism and then lists all published synthetic reactions by threonine aldolases as of early 2014. The current state of the art in crystallographic and protein engineering studies of these enzymes is also presented. PMID- 24767427 TI - Carbohydrate-binding modules of fungal cellulases: occurrence in nature, function, and relevance in industrial biomass conversion. AB - In this review, the present knowledge on the occurrence of cellulases, with a special emphasis on the presence of carbohydrate-binding modules (CBMs) in various fungal strains, has been summarized. The importance of efficient fungal cellulases is growing due to their potential uses in biorefinery processes where lignocellulosic biomasses are converted to platform sugars and further to biofuels and chemicals. Most secreted cellulases studied in detail have a bimodular structure containing an active core domain attached to a CBM. CBMs are traditionally been considered as essential parts in cellulases, especially in cellobiohydrolases. However, presently available genome data indicate that many cellulases lack the binding domains in cellulose-degrading organisms. Recent data also demonstrate that CBMs are not necessary for the action of cellulases and they solely increase the concentration of enzymes on the substrate surfaces. On the other hand, in practical industrial processes where high substrate concentrations with low amounts of water are employed, the enzymes have been shown to act equally efficiently with and without CBM. Furthermore, available kinetic data show that enzymes without CBMs can desorb more readily from the often lignaceous substrates, that is, they are not stuck on the substrates and are thus available for new actions. In this review, the available data on the natural habitats of different wood-degrading organisms (with emphasis on the amount of water present during wood degradation) and occurrence of cellulose binding domains in their genome have been assessed in order to identify evolutionary advantages for the development of CBM-less cellulases in nature. PMID- 24767428 TI - Benzoyl-CoA, a universal biomarker for anaerobic degradation of aromatic compounds. AB - Aromatic compounds are a major component of the global carbon pool and include a diverse range of compounds such as humic acid, lignin, amino acids, and industrial contaminants. Due to the prevalence of aromatic compounds in the environment, aerobic and anaerobic microorganisms have evolved mechanisms by which to metabolize that available carbon. Less well understood are the anaerobic pathways. We now know that anaerobic metabolism of a variety of monoaromatic compounds can be initiated in a number of different ways, and a key metabolite for these pathways is benzoyl-CoA. Chemicals can have different upstream anaerobic degradation pathways yet can still be assessed by targeting the downstream benzoyl-CoA pathway. In this pathway, we propose that the ring opening hydrolase, encoded by the bamA gene, is especially useful because, in contrast to the benzoyl-CoA reductase, it is detected under a number of respiratory settings, including denitrifying, iron-reducing, sulfate-reducing, and fermentative conditions, and has a wide distribution in the environment. This review examines the bamA gene in enrichment cultures and environmental DNA extracts to consider whether it can be used as a biomarker for anaerobic aromatic degradation. Given the number of potential upstream inputs from natural and man-made monoaromatic compounds, the benzoyl-CoA pathway and the bamA gene in particular may play an important role in the global carbon cycle that has thus far been overlooked. PMID- 24767429 TI - Identification of CDH23 mutations in Korean families with hearing loss by whole exome sequencing. AB - BACKGROUND: Patient genetic heterogeneity renders it difficult to discover disease-cause genes. Whole-exome sequencing is a powerful new strategy that can be used to this end. The purpose of the present study was to identify a hitherto unknown mutation causing autosomal recessive nonsyndromic hearing loss (ARNSHL) in Korean families. METHODS: We performed whole-exome sequencing in 16 individuals from 13 unrelated small families with ARNSHL. After filtering out population-specific polymorphisms, we focused on known deafness genes. Pathogenic effects of the detected mutations on protein structure or function were predicted via in silico analysis. RESULTS: We identified compound heterozygous CDH23 mutations in hearing-loss genes of two families. These include two previously reported pathological mutations, p.Pro240Leu and p.Glu1595Lys, as well as one novel mutation, p.Asn342Ser. The p.Pro240Leu mutation was found in both families. We also identified 26 non-synonymous variants in CDH23 coding exons from 16 hearing-loss patients and 30 Korean exomes. CONCLUSION: The present study is the first to show that CDH23 mutations cause hearing loss in Koreans. Although the precise contribution made by such mutations needs to be determined using a larger patient cohort, our data indicate that mutations in the CDH23 gene are one of the most important causes of non-syndromic hearing loss in East Asians. Further exome sequencing will identify common mutations or polymorphisms and contribute to the molecular diagnosis of, and development of new therapies for, hereditary hearing loss. PMID- 24767430 TI - Using participatory epidemiology to assess factors contributing to common enteric pathogens in Ontario: results from a workshop held at the Ontario Veterinary College, University of Guelph, Ontario. AB - BACKGROUND: Common enteric pathogens that cause gastrointestinal illness are transmitted to humans through food, water or direct contact. This poses a significant concern to public health as enteric pathogens can cause disease in a large number of people, and cost a substantial amount to treat and prevent. In order to gain a better understanding of the occurrence of enteric disease in Ontario, this study explored public health professionals' perceptions of major contributing factors for common enteric pathogens. METHODS: A case study was conducted as part of a two week training workshop in Participatory Epidemiology held at the Ontario Veterinary College, University of Guelph, in May 2013. Eight semi-structured interviews and four focus groups were conducted with representatives from the Public Health Agency of Canada, the University of Guelph, and three health regions in Southern Ontario. Written notes and pictures captured the qualitative information provided. Results were then analyzed using the mixed methods techniques of triangulation, convergence, and paradox. RESULTS: A total of fifty factors that contribute to enteric disease were identified across all interviews and focus groups. These contributing factors were grouped into key themes (travel, food handling, industry (farm-to-fork), water, geography, demographics, and behaviours) and were categorized as either a risk factor or susceptibility factor. Informants emphasized the complex relationships between the identified factors, and highlighted why these complexities make it difficult to determine where and how a person most likely acquired an enteric pathogen. Workshop participants observed differences in the type and quality of information collected during interviews and focus groups; we hypothesize that this may be attributed to the dynamics between group members (i.e. focus group discussions) as opposed to one-on-one interviews. CONCLUSIONS: The information gathered will serve as a starting point to further explore contributing factors for common enteric pathogens. The identified complexities would be best explored by conducting additional surveillance, as well as interviews and focus groups with a more diverse group of stakeholders. This type of qualitative study can enhance knowledge of enteric pathogen surveillance and contribute to the development of resources and initiatives to holistically address the occurrence of gastrointestinal illness. PMID- 24767431 TI - Cost-effectiveness of diagnostic strategies for the management of abnormal uterine bleeding (heavy menstrual bleeding and post-menopausal bleeding): a decision analysis. AB - BACKGROUND: Heavy menstrual bleeding (HMB) and post-menopausal bleeding (PMB) together constitute the commonest gynaecological presentation in secondary care and impose substantial demands on health service resources. Accurate diagnosis is of key importance to realising effective treatment, reducing morbidity and, in the case of PMB, reducing mortality. There are many tests available, including transvaginal scan (TVS), endometrial biopsy (EBx), saline infusion sonography and outpatient hysteroscopy (OPH); however, optimal diagnostic work-up is unclear. OBJECTIVES: To determine the most cost-effective diagnostic testing strategy for the diagnosis and treatment of (i) HMB and (ii) PMB. DATA SOURCES: Parameter inputs were derived from systematic quantitative reviews, individual patient data (IPD) from existing data sets and focused searches for specific data. In the absence of data estimates, the consensus view of an expert clinical panel was obtained. METHODS: Two clinically informed decision-analytic models were constructed to reflect current service provision for the diagnostic work-up of women presenting with HMB and PMB. The model-based economic evaluation took the form of a cost-effectiveness analysis from the perspective of the NHS in a contemporary, 'one-stop' secondary care clinical setting, where all indicated testing modalities would be available during a single visit. RESULTS: Two potentially cost-effective testing strategies for the initial investigation of women with HMB were identified: OPH alone or in combination with EBx. Although a combination testing strategy of OPH + EBx was marginally more effective, the incremental cost-effectiveness ratio (ICER) was approximately L21,000 to gain one more satisfied patient, whereas for OPH it was just L360 when compared with treatment with the levonorgestrel intrauterine system (LNG-IUS) without investigation. Initial testing with OPH was the most cost-effective testing approach for women wishing to preserve fertility and for women with symptoms refractory to empirical treatment with a LNG-IUS. For the investigation of PMB, selective use of TVS based on historical risk prediction for the diagnostic work up of women presenting with PMB generated an ICER compared with our reference strategy of 'no initial work-up' of L129,000 per extra woman surviving 5 years. The ICERs for the two other non-dominated testing strategies, combining history and TVS or combining OPH and TVS, were over L2M each. LIMITATIONS: In the absence of IPD, estimates of accuracy for test combinations presented some uncertainty where test results were modelled as being discordant. CONCLUSIONS: For initial investigation of women presenting to secondary care with HMB who do not require preservation of their fertility, our research suggests a choice between OPH alone or a combination of OPH and EBx. From our investigation, OPH appears to be the optimal first-line diagnostic test used for the investigation of women presenting to secondary care with HMB wishing to preserve their fertility or refractory to previous medical treatment with the LNG-IUS. We would suggest that the current recommendation of basing the initial investigation of women with PMB on the universal TVS measurement of endometrial thickness at a 5-mm threshold may need to be replaced by a strategy of restricting TVS to women with risk factors (e.g. increasing age-raised body mass index, diabetes or nulliparity), obtained from the preceding clinical assessment. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 24767433 TI - Diabetic heart disease: insights from cardiac mechanics. PMID- 24767432 TI - Nursing home research: the first International Association of Gerontology and Geriatrics (IAGG) research conference. AB - The International Association of Gerontology and Geriatrics held its first conference on nursing home research in St Louis, MO, in November 2013. This article provides a summary of the presentations. PMID- 24767434 TI - Extracardiac findings on echocardiography: blissful ignorance or a call to improve our training? PMID- 24767436 TI - Putting advanced applications into action. PMID- 24767437 TI - The international practice of vascular ultrasound. PMID- 24767439 TI - Novel monodisperse molecularly imprinted shell for estradiol based on surface imprinted hollow vinyl-SiO2 particles. AB - A novel monodisperse molecularly imprinted shell was prepared based on surface imprinted hollow vinyl-SiO2 particles and applied to selective recognition and adsorption of estradiol (E2). This method was carried out by introducing vinyltriethoxysilane to the surface of polystyrene (PS) spheres by a simple one step modification, followed by dissolution to remove the PS cores, and then by copolymerization of functional monomers via surface imprinted on the hollow vinyl SiO2 particles to prepare uniform E2-imprinted shells. Two interesting characteristics were found: first, the obtained hollow molecularly imprinted polymer shells (H-MIPs) had highly monodispersity, uniform spherical shape with a shell thickness of about 40 nm; and then, the method was simple, easy to operate by directing coating of a uniform shell on hollow particles via surface imprinting. The resultant H-MIPs demonstrated improvements in imprinting factor and binding kinetics, owing to the high selectivity to template molecules, surface imprinting technique and hollow porous structure. Furthermore, satisfactory recoveries of 97.0 and 94.8% with respective precisions of 2.5 and 2.7% were achieved by one-step extraction when H-MIPs were used for the preconcentration and selective separation of estradiol in milk samples at two spiked levels. The simple, effective H-MIPs based strategy provided new insights into the formation of various functionalized coating layers on different kinds of support materials with versatile potential applications. PMID- 24767438 TI - Ionic liquid-anionic surfactant based aqueous two-phase extraction for determination of antibiotics in honey by high-performance liquid chromatography. AB - An ionic liquid-anionic surfactant based aqueous two-phase extraction was developed and applied for the extraction of tetracycline, oxytetracycline and chloramphenicol in honey. The honey sample was mixed with Na2EDTA aqueous solution. The sodium dodecyl sulfate, ionic liquid 1-octyl-3-methylimidazolium bromide and sodium chloride were added in the mixture. After the resulting mixture was ultrasonically shaken and centrifuged, the aqueous two phase system was formed and analytes were extracted into the upper phase. The parameters affecting the extraction efficiency, such as the volume of ionic liquid, the category and amount of salts, sample pH value, extraction time and temperature were investigated. The limits of detection of tetracycline, oxytetracycline and chloramphenicol were 5.8, 8.2 and 4.2 MUg kg(-1), respectively. When the present method was applied to the analysis of real honey samples, the recoveries of analytes ranged from 85.5 to 110.9% and relative standard deviations were lower than 6.9%. PMID- 24767440 TI - Signal amplification in capillary electrophoresis based chemiluminescent immunoassays by using an antibody-gold nanoparticle-DNAzyme assembly. AB - A signal amplification strategy based on antibody-gold nanoparticle-DNAzyme assembly in capillary electrophoresis based chemiluminescent immunoassays (CE CLIA) was developed. In this CE-CLIA, antibody-AuNP-G-quadruplex/hemin was incubated with limited amount of antigen, and the formed immunocomplex and unreacted antibody-AuNP-G-quadruplex/hemin were then separated by CE and detected by CL. Due to the strong CL catalytic ability of G-quadruplex/hemin DNAzyme and a high loading ratio of DNAzyme on each AuNP, the assay was very sensitive. By taking carbohydrate antigen 19-9 (CA19-9), one of the most important carbohydrate tumor marker as the model analyte, the proposed CE-CLIA method for CA19-9 detection showed a linear range from 0.025 to 1.00 U/mL with a detection limit of 0.016 U/mL (signal/noise=3), which was more sensitive than the methods previously reported for CA19-9 quantification. The method was applied to quantify CA19-9 in human serum samples, and analytical results were in a good agreement with those obtained by using an established ELISA method. PMID- 24767441 TI - A new approach to determine vapor pressures of compounds in multicomponent systems by comprehensive two-dimensional gas chromatography coupled to time-of flight mass spectrometry. AB - A method is described to determine vapor pressures of compounds in multicomponent systems simultaneously. The method is based on temperature-gradient analysis by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GCxGC-TOFMS). Vapor pressures are determined with the aid of known vapor pressure values of reference compounds eluting before and after the analytes. Reference compounds with the same functionalities as the analytes are preferred, but when these are not available, the alkane series can be utilized. The number of compounds whose vapor pressures can be determined is limited only by the peak capacity of the chromatographic system. Although the lowest subcooled vapor pressure determined was 0.006 Pa, for tetrahydroaraucarolone in an atmospheric aerosol sample, vapor pressures as low as 10(-6) Pa can be measured with the described set-up. Even lower values can be measured with higher GC temperatures and longer analysis times. Since only a few picograms of compound is required, in a mixture of any complexity, the GCxGC-TOFMS method offers unique sensitivity, rapidity, and comprehensiveness. PMID- 24767442 TI - Fabrication of an ultrasensitive impedimetric buprenorphine hydrochloride biosensor from computational and experimental angles. AB - For the first time, an ultrasensitive impedimetric buprenorphine hydrochloride (BN) biosensor based on immobilization of bovine serum albumin (BSA) onto multi walled carbon nanotubes (MWCNTs)/glassy carbon electrode (BSA/MWCNTs/GCE) has been developed using initial characterization by computational methods and complementing them by experimental observations. Computational results showed that the BSA hydrophobically binds to MWCNTs which is energetically favorable and leads to spontaneous formation of the stable BSA/MWCNTs nanobiocomposite (bioconjugate). Computational results also showed that the interaction of BN with BSA is mainly driven by hydrophobic interactions. The interactions of BSA with MWCNTs and BN with BSA were also monitored by fluorescence and UV-vis spectroscopic techniques, and their results were consistent with the computational results. Morphology and electrochemical properties of the fabricated composite electrodes were examined by scanning electron microscopy (SEM), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). Besides complementing the computational studies, experimental results showed that the addition of MWCNTs to the surface of the GCE greatly facilitated the electron transfer reactions, and also showed that the presence of BSA inhibits the interfacial electron transfer in some extent due to the non-conductive properties of BSA. On the other hand, the presence of BN may form an electroactive complex with BSA which accelerates the interfacial electron transfer and leads to obvious Faradaic impedance changes. The Faradaic impedance responses were linearly related to BN concentration between 5.0 nM and 72.0 nM and a limit of detection (LOD, 3S(b)/b) of 1.5 nM was achieved. Finally, the proposed biosensor was successfully applied to determination of BN in urine samples of both healthy and addict volunteers. The results were satisfactory and comparable to those obtained by applying the reference method based on high performance liquid chromatography ultraviolet detection (HPLC-UV). It is expected that the distinctive features of BSA/MWCNTs nanobiocomposite would make it potentially advantageous for a broad range of biosensing, and clinical applications. PMID- 24767443 TI - A non-linearity criterion applied to the calibration curve method involved with ion-selective electrodes. AB - Some rational functions of the Pade type, y=y(x; n,m), were applied to the calibration curve method (CCM), and compared with a parabolic function. The functions were tested on the results obtained from calibration of ion-selective electrodes: NH4-ISE, Ca-ISE, and F-ISE. A validity of the functions y=y(x; 2,1), y=y(x; 1,1), and y=y(x; 2,0) (parabolic) was compared. A uniform, integral criterion of nonlinearity of calibration curves is suggested. This uniformity is based on normalization of the approximating functions within the frames of a unit area. PMID- 24767444 TI - Highly selective amperometric sensor for the trace level detection of hydrazine at bismuth nanoparticles decorated graphene nanosheets modified electrode. AB - A highly selective amperometric sensor was developed for the trace level determination of hydrazine at bismuth nanoparticles (Bi) decorated graphene nanosheets (GR) composite film modified glassy carbon electrode (GCE). GR-Bi nanocomposite has been successfully prepared via simple and facile chemical reduction approach and its structure was characterized by various techniques. Surface morphological and X-ray diffraction studies revealed the formation and high loading of Bi nanoparticles on graphene sheets. GR-Bi nanocomposite modified GCE exhibited greatly enhanced electrocatalytic performance towards electro oxidation of hydrazine in terms of decrease in overpotential and increase in oxidation peak current (Ip). The kinetic parameters such as electron transfer coefficient (alpha) and diffusion coefficient (Do) of the hydrazine oxidation were determined to be 0.70 and 2.65*10(-5) cm(2) s(-1), respectively. An amperometric sensor has been fabricated which detects trace level concentration of hydrazine. The sensor exhibited a wide linear range from 20 nM to 0.28 mM and a very low detection limit (LOD) of 5 nM. Remarkably, this is the lowest LOD achieved for the determination of hydrazine in neutral pH among other reported electrochemical hydrazine sensors. In addition, the sensor selectively detects hydrazine even in the presence of 1000 fold excess quantity of common interferrants. The practical feasibility of the sensor has been assessed in water and urine samples with good recoveries. Furthermore, the sensor exhibited appreciable stability, repeatability and reproducibility results. PMID- 24767445 TI - A new immobilization and sensing platform for nitrate quantification. AB - Nitrate reductase (NR) from Aspergillus niger was covalently coupled to the epoxy affixed gold nanoparticles (epoxy/AuNPs) with a conjugation yield of 35.40+/-0.01 MUg/cm(2) and 93.90+/-0.85% retention of specific activity. The bare and NR bound epoxy/AuNPs support was characterized using scanning electron microscopy and Fourier Transform Infrared Spectroscopy. The immobilized enzyme system was optimized with respect to pH, temperature and substrate concentrations and successfully employed for determination of nitrate contents in ground water. The minimum detection limit of the method was 0.05 mM with linearity from 0.1 to 10.0 mM. The % recoveries of added nitrates (0.1 and 0.2 mM) were >95.0% and within day and between-day coefficients of variations were 1.012% and 3.125% respectively. The method showed good correlation (R(2)=0.998) with the popular Griess reaction method. Epoxy/AuNPs bound NR showed good thermal and storage stabilities and retained 50% activity after 16 reuses. PMID- 24767446 TI - Ultrasensitive non-mediator electrochemical immunosensors using Au/Ag/Au core/double shell nanoparticles as enzyme-mimetic labels. AB - Determination of squamous cell carcinoma antigen (SCCA) in human serum plays an important role in diagnosis of cervical squamous cell carcinoma. In this work, Au/Ag/Au core/double shell nanoparticles (Au/Ag/Au NPs) were prepared by a simple approach and were used as novel enzyme-mimetic labels for development of a sandwich-type electrochemical immunosensor for SCCA. The nanostructure of Au/Ag/Au NPs could be well confirmed by transmission electron microscope (TEM) and UV-vis spectra. Au NPs decorated mercapto-functionalized graphene sheets (Au@SH-GS) were used as platform for immobilization of primary antibody (Ab1), while Au/Ag/Au NPs were employed as labels of secondary antibody (Ab2). Due to the excellent electrocatalytic activity of Au/Ag/Au NPs towards the reduction of hydrogen peroxide (H2O2), electrochemical amperometric responses to SCCA were achieved after the immuno-reaction. Under optimum conditions, the electrochemical immunosensor exhibited a wide linear range from 0.5 pg/mL to 40 ng/mL with a low detection limit of 0.18 pg/mL for SCCA. The designed immunosensor displayed an excellent analytical performance with good reproducibility, high selectivity and stability. PMID- 24767447 TI - Antibody mediated fluorescence enhancement of nucleoside analogue 1,3-diaza-2 oxophenoxazine (tC degrees ). AB - We report on the generation and analytical application of the monoclonal antibody G93-ED2 raised against the tricyclic fluorescent nucleoside analogue 1,3-diaza-2 oxophenoxazine (tC degrees ). G93-ED2 is specifically binding this deoxycytidine analogue and was found to raise its fluorescence intensity by a factor of 5. This unique feature makes it a valuable tool in fluorescence dependent immunoassays. G93-ED2 was successfully applied in a homogeneous fluorescence quenching immunoassay (DNA-Q) for the sequence specific determination of DNA. PMID- 24767448 TI - Prospects and difficulties in TiO2 nanoparticles analysis in cosmetic and food products using asymmetrical flow field-flow fractionation hyphenated to inductively coupled plasma mass spectrometry. AB - In this work, we proposed an analytical approach based on asymmetrical flow field flow fractionation combined to an inductively coupled plasma mass spectrometry (AsFlFFF-ICP-MS) for rutile titanium dioxide nanoparticles (TiO2NPs) characterization and quantification in cosmetic and food products. AsFlFFF-ICP-MS separation of TiO2NPs was performed using 0.2% (w/v) SDS, 6% (v/v) methanol at pH 8.7 as the carrier solution. Two problems were addressed during TiO2NPs analysis by AsFlFFF-ICP-MS: size distribution determination and element quantification of the NPs. Two approaches were used for size determination: size calibration using polystyrene latex standards of known sizes and transmission electron microscopy (TEM). A method based on focused sonication for preparing NPs dispersions followed by an on-line external calibration strategy based on AsFlFFF-ICP-MS, using rutile TiO2NPs as standards is presented here for the first time. The developed method suppressed non-specific interactions between NPs and membrane, and overcame possible erroneous results obtained when quantification is performed by using ionic Ti solutions. The applicability of the quantification method was tested on cosmetic products (moisturizing cream). Regarding validation, at the 95% confidence level, no significant differences were detected between titanium concentrations in the moisturizing cream prior sample mineralization (3865+/-139 mg Ti/kg sample), by FIA-ICP-MS analysis prior NPs extraction (3770+/-24 mg Ti/kg sample), and after using the optimized on-line calibration approach (3699+/-145 mg Ti/kg sample). Besides the high Ti content found in the studied food products (sugar glass and coffee cream), TiO2NPs were not detected. PMID- 24767449 TI - Multielemental inductively coupled plasma optical emission spectrometry analysis of nickeliferous minerals. AB - An inductively coupled plasma optical emission spectrometry method for the quantitative simultaneous determination of Al, Ca, Co, Cu, Cr, Fe, K, Mg, Mn, Na, Ni, P and Zn in Cuban laterite and serpentine minerals has been developed. Additionally, V and Ti can be quantitatively determined in laterite mineral; Li, Sr, and Zr can be detected in both mineral types and Pb can be detected just in laterite mineral. The microwave-assisted total acid digestion of samples was achieved with HCl+HNO3+HF and HNO3+HClO4+HF acid mixtures for laterite and serpentine samples, respectively. In non-robust plasma operating conditions, the matrix effect characteristics of the laterite sample were dictated by the principal component Fe; while the character of the Mg principal component matrix effect was some how modified by the concomitants Fe and Ni in serpentine sample. The selection of robust conditions decreased the matrix effect. Additionally, the simulation of the matrix samples by introducing the principal component Fe or Mg, correspondingly, in calibration dissolutions was needed to overcome completely the matrix effect over the analysis accuracy. Precision of analysis was very near or lower than 10% for most elements, except Sr (15%) in L-1; and K (15%) and Li (15%) in SNi sample. Accuracy of analysis was around or lowers than 10% for most elements, except K (15%), Na (19%), P (19%) and V (19%) in L-1 sample; and Ca (14%) and P (20%) in SNi sample. PMID- 24767450 TI - Determination of scandium in acid mine drainage by ICP-OES with flow injection on line preconcentration using oxidized multiwalled carbon nanotubes. AB - An on-line scandium preconcentration and determination system implemented with inductively coupled plasma optical emission spectrometry associated with flow injection was studied. Trace amounts of scandium were preconcentrated by sorption on a minicolumn packed with oxidized multiwalled carbon nanotubes, at pH 1.5. The retained analyte was removed from the minicolumn with 30% (v/v) nitric acid. A total enrichment factor of 225-fold was obtained within a preconcentration time of 300 s (for a 25 mL sample volume). The overall time required for preconcentration and elution of 25 mL of sample was about 6 min; the throughput was about 10 samples per hour. The value of the detection limit was 4 ng L(-1) and the precision for 10 replicate determinations at 100 ng L(-1) Sc level was 5% relative standard deviation, calculated from the peak heights obtained. The calibration graph using the preconcentration system was linear with a correlation coefficient of 0.9996 at levels near the detection limits up to at least 10 mg L( 1). After optimization, the method was successfully applied to the determination of Sc in an acid drainage from an abandoned mine located in the province of San Luis, Argentina. PMID- 24767451 TI - Advances in artificial olfaction: sensors and applications. AB - The artificial olfaction, based on electronic systems (electronic noses), includes three basic functions that operate on an odorant: a sample handler, an array of gas sensors, and a signal-processing method. The response of these artificial systems can be the identity of the odorant, an estimate concentration of the odorant, or characteristic properties of the odour as might be perceived by a human. These electronic noses are bio inspired instruments that mimic the sense of smell. The complexity of most odorants makes characterisation difficult with conventional analysis techniques, such as gas chromatography. Sensory analysis by a panel of experts is a costly process since it requires trained people who can work for only relatively short periods of time. The electronic noses are easy to build, provide short analysis times, in real time and on-line, and show high sensitivity and selectivity to the tested odorants. These systems are non-destructive techniques used to characterise odorants in diverse applications linked with the quality of life such as: control of foods, environmental quality, citizen security or clinical diagnostics. However, there is much research still to be done especially with regard to new materials and sensors technology, data processing, interpretation and validation of results. This work examines the main features of modern electronic noses and their most important applications in the environmental, and security fields. The above mentioned main components of an electronic nose (sample handling system, more advanced materials and methods for sensing, and data processing system) are described. Finally, some interesting remarks concerning the strengths and weaknesses of electronic noses in the different applications are also mentioned. PMID- 24767452 TI - Determination of cadmium and lead in edible oils by electrothermal atomic absorption spectrometry after reverse dispersive liquid-liquid microextraction. AB - The dispersive liquid-liquid microextraction of edible oils with a low volume of an acidic solution in the presence of isopropyl alcohol allows cadmium and lead to be completely separated into the aqueous phase. After centrifugation, the metals are determined by electrothermal atomization atomic absorption spectrometry using a palladium salt for chemical modification in the heating cycle. Using a 10 g oil sample, the enrichment factor is 140, which permits detection limits of 0.6 and 10 ng kg(-1) for cadmium and lead, respectively. The results agree with those obtained after sample mineralization. Data for the cadmium and lead levels for 15 samples of different characteristics are given. PMID- 24767454 TI - Experimental design and multiple response optimization. Using the desirability function in analytical methods development. AB - A review about the application of response surface methodology (RSM) when several responses have to be simultaneously optimized in the field of analytical methods development is presented. Several critical issues like response transformation, multiple response optimization and modeling with least squares and artificial neural networks are discussed. Most recent analytical applications are presented in the context of analytLaboratorio de Control de Calidad de Medicamentos (LCCM), Facultad de Bioquimica y Ciencias Biologicas, Universidad Nacional del Litoral, C.C. 242, S3000ZAA Santa Fe, ArgentinaLaboratorio de Control de Calidad de Medicamentos (LCCM), Facultad de Bioquimica y Ciencias Biologicas, Universidad Nacional del Litoral, C.C. 242, S3000ZAA Santa Fe, Argentinaical methods development, especially in multiple response optimization procedures using the desirability function. PMID- 24767453 TI - Rapid screening and identification of target constituents using full scan-parent ions list-dynamic exclusion acquisition coupled to diagnostic product ions analysis on a hybrid LTQ-Orbitrap mass spectrometer. AB - A highly sensitive and effective strategy for rapid screening and identification of target constituents has been developed using full scan-parent ions list dynamic exclusion (FS-PIL-DE) acquisition coupled to diagnostic product ions (DPIs) analysis on a hybrid LTQ-Orbitrap mass spectrometer. The FS-PIL-DE was adopted as a survey scan to trigger the MS/MS acquisition of all the predictable constituents contained in traditional Chinese medicines. Additionally, DPIs analysis can provide a criterion to judge the target constituents detected into certain chemical families. Results from analyzing polymethoxylated flavonoids (PMFs) in the leaves of Citrus reticulata Blanco demonstrated that FS-PIL-DE was capable of targeting a greater number of constituents than FS, FS-PIL and FS-DE, thereby increasing the coverage of constituent screening. As a result, 135 PMFs including 81 polymethoxyflavones, 54 polymethoxyflavanones or polymethoxychalcones were identified preliminarily. And this was the first time to systematically report the presence of PMFs in the leaves of Citrus reticulata Blanco, especially for polymethoxylated flavanones and chalcones, most of which were new compounds. The results indicated that the developed FS-PIL-DE coupled to DPIs analysis methodology could be employed as a rapid, effective technique to screen and identify target constituents from TCMs extracts and other organic matter mixtures whose compounds contained can also be classified into families based on the common carbon skeletons. PMID- 24767455 TI - A coumarin-derived fluorescent chemosensor for selectively detecting Cu2+: synthesis, DFT calculations and cell imaging applications. AB - A novel coumarin-based fluorescent probe L ((4E)-4-((7-hydroxy-4-methyl-2-oxo-2H chromen-8-yl) methyleneamino)-1,2-dihyydro-2,3-dimethyl-1-phenylpyrazol-5-one) has been developed as a simple and efficient chemosensor which exhibits a significant fluorescence reduction in the presence of metal cations. This sensor exhibits high selectivity and sensitivity toward Cu(2+) over other common cations. The mechanism for detecting copper was evaluated by time-dependent density functional theory (TD-DFT) calculations and the coordination mode was also confirmed by density functional theory (DFT) calculations. Furthermore, results of cell imaging in this study indicate that this new probe may be useful for detection and monitoring of Cu(2+) in biological applications. PMID- 24767456 TI - Analysis of biogenic amines in wines by salting-out assisted liquid-liquid extraction and high-performance liquid chromatography with fluorimetric detection. AB - Biogenic amines are nitrogenous organic compounds of low molecular weight that are either formed or metabolized in cells of living organisms and can be found in several food products, being produced mainly by amino acid decarboxylation. When ingested in high concentrations they can induce several health problems in humans. In alcoholic beverages, and especially in wine, they are formed during the vinification process as a result of the action of microorganisms. In this work it is proposed a new methodology for the determination of biogenic amines in wines, which includes a sample preparation approach based on salting-out assisted liquid-liquid extraction, the use of dansyl chloride for the derivatization and chromatographic separation by high-performance liquid chromatography with fluorimetric detection. The salting-out effect is used to promote phase separation between water and a water-miscible organic solvent, while improving the extraction of organic or inorganic species. Several extraction parameters were optimized, such as the dansyl chloride concentration, pH and the effects caused by the order in which the extraction and derivatization were performed. Extraction of amines, and consequent detection, depends on the presence of dansyl chloride in solution prior to extraction. The results showed the possibility to simultaneously perform the extraction and the derivatization, making sample preparation easier and less time-consuming. The methodology was successfully applied to the determination of biogenic amines in five wines (white, red and rose). This method has the potential to be a good alternative to existing methods since it is cheaper, easier and simplifies the sample preparation step. PMID- 24767457 TI - Microbiota diversity and gene expression dynamics in human oral biofilms. AB - BACKGROUND: Micro-organisms inhabiting teeth surfaces grow on biofilms where a specific and complex succession of bacteria has been described by co-aggregation tests and DNA-based studies. Although the composition of oral biofilms is well established, the active portion of the bacterial community and the patterns of gene expression in vivo have not been studied. RESULTS: Using RNA-sequencing technologies, we present the first metatranscriptomic study of human dental plaque, performed by two different approaches: (1) A short-reads, high-coverage approach by Illumina sequencing to characterize the gene activity repertoire of the microbial community during biofilm development; (2) A long-reads, lower coverage approach by pyrosequencing to determine the taxonomic identity of the active microbiome before and after a meal ingestion. The high-coverage approach allowed us to analyze over 398 million reads, revealing that microbial communities are individual-specific and no bacterial species was detected as key player at any time during biofilm formation. We could identify some gene expression patterns characteristic for early and mature oral biofilms. The transcriptomic profile of several adhesion genes was confirmed through qPCR by measuring expression of fimbriae-associated genes. In addition to the specific set of gene functions overexpressed in early and mature oral biofilms, as detected through the short-reads dataset, the long-reads approach detected specific changes when comparing the metatranscriptome of the same individual before and after a meal, which can narrow down the list of organisms responsible for acid production and therefore potentially involved in dental caries. CONCLUSIONS: The bacteria changing activity during biofilm formation and after meal ingestion were person-specific. Interestingly, some individuals showed extreme homeostasis with virtually no changes in the active bacterial population after food ingestion, suggesting the presence of a microbial community which could be associated to dental health. PMID- 24767458 TI - Use of a semi-field system to evaluate the efficacy of topical repellents under user conditions provides a disease exposure free technique comparable with field data. AB - BACKGROUND: Before topical repellents can be employed as interventions against arthropod bites, their efficacy must be established. Currently, laboratory or field tests, using human volunteers, are the main methods used for assessing the efficacy of topical repellents. However, laboratory tests are not representative of real life conditions under which repellents are used and field-testing potentially exposes human volunteers to disease. There is, therefore, a need to develop methods to test efficacy of repellents under real life conditions while minimizing volunteer exposure to disease. METHODS: A lotion-based, 15% N, N Diethyl-3-methylbenzamide (DEET) repellent and 15% DEET in ethanol were compared to a placebo lotion in a 200 sq m (10 m * 20 m) semi-field system (SFS) against laboratory-reared Anopheles arabiensis mosquitoes and in full field settings against wild malaria vectors and nuisance-biting mosquitoes. The average percentage protection against biting mosquitoes over four hours in the SFS and field setting was determined. A Poisson regression model was then used to determine relative risk of being bitten when wearing either of these repellents compared to the placebo. RESULTS: Average percentage protection of the lotion based 15% DEET repellent after four hours of mosquito collection was 82.13% (95% CI 75.94-88.82) in the semi-field experiments and 85.10% (95% CI 78.97-91.70) in the field experiments. Average percentage protection of 15% DEET in ethanol after four hours was 71.29% (CI 61.77-82.28) in the semi-field system and 88.24% (84.45 92.20) in the field. CONCLUSIONS: Semi-field evaluation results were comparable to full-field evaluations, indicating that such systems could be satisfactorily used in measuring efficacy of topically applied mosquito repellents, thereby avoiding risks of exposure to mosquito-borne pathogens, associated with field testing. PMID- 24767459 TI - [The use of polymerase chain reaction in the diagnosis of invasive meningococcal disease]. AB - INTRODUCTION AND OBJECTIVES AND AIMS: Invasive meningococcal disease (IMD) remains a serious public health problem. Although culture is the gold standard, previous antibiotic therapy reduces its sensibility. The aim of this study is the epidemiological analysis of IMD in our area, to assess the usefulness of polymerase chain reaction (PCR) to increase its diagnostic accuracy,and to show the association of antibiotic administration with the negative result of the culture. PATIENTS AND METHODS: A retrospective study was conducted on all children younger than 16 years with microbiologically (positive culture and/or PCR) confirmed IMD, admitted to our hospital between 2004-2012. RESULTS: Seventy five patients were included, of whom 52% had sepsis, 30.7% meningitis, and 17.3% with both of them. PCR was positive in all samples, whereas a positive was seen 50.7% of the cultures. Previously administered antibiotic was documented in 40 patients (53.3%), and 40% of them were confirmed by PCR only. CONCLUSIONS: PCR was the only test providing evidence for IMD diagnosis and serogroup determination in almost 39% of cases. PMID- 24767460 TI - [Congenital dislocation of the knee: report of 2 cases]. AB - Congenital dislocation of the knee is a rare disease. The diagnosis is made at birth by clinical findings, and confirmed radiologically. It has been associated with various etiologies from intrauterine fetal malpositions to genetic disorders. The prognosis depends on early treatment and whether there are other congenital anomalies. We report two new cases of congenital dislocation of the knee, observed in our hospital during the period of a month, diagnosed immediately after birth, and both with a good clinical outcome. PMID- 24767461 TI - [The way we were. On the centenary of the first Spanish Congress of Paediatrics in Palma de Mallorca (1914-2014)]. AB - Between the 19th and 25th April 1914, the First Spanish Congress of Paediatrics was held in Palma de Mallorca under the slogan "Protect the Children". The specialty had broken away a few years earlier from its secular connection with Obstetrics and Gynaecology, both in its teaching aspect as well as regarding healthcare. With the newly created Chairs in Childhood Diseases, in a way this Congress meant the coming-of age and debut int society of paediatrics in our country. Prof. Martinez Vargas, a university professor in Barcelona, was the Chairman, and soul of the congress. There was a need to face a very high rate of infant mortality. The Congress responded to that social and sanitary/health demand with the participation of over three hundred pediatricians, including foreign representatives from Belgium, France, Russia and Latin America. The activities were divided into four sections: Childcare, Child Medicine, Surgery and Health, and accredited lecturers gave master classes on the most pressing issues of child pathology of the time. One hundred years on, what we are today is the fruit gathered by those who preceded us. Some were brilliant figures in paediatrics and others, the majority, anonymous paediatricians. They dedicated their lives, their science and their best smile to child care. The way we were and the way we are. With legitimate pride and satisfaction, it is an honour for the Group on the History of Paediatrics and AEP Documentation to celebrate this centennial commemoration in the framework of the Annals of Paediatrics. PMID- 24767462 TI - Exophiala dermatitidis pneumonia successfully treated with long-term itraconazole therapy. AB - Exophiala dermatitidis pneumonia is extremely rare. Here we report a case of E. dermatitidis pneumonia successfully treated with long-term itraconazole therapy. A 63-year-old woman without a remarkable medical history developed a dry and chest pain. Chest radiographs revealed consolidation in the middle lobe of the lung. Cytologic examination by bronchoscopy showed filamentous fungi and E. dermatitidis was detected in the bronchoalveolar lavage fluid. After 5 months of itraconazole therapy, her symptoms improved and the area of consolidation diminished. Two weeks after discontinuing the itraconazole therapy, the area of consolidation reappeared. Itraconazole therapy was restarted and continued for 7 months. The abnormal shadow observed on the chest X-ray gradually diminished. Over a 27-month follow-up with periodic examination, there was no relapse and the patient had a favorable clinical course. PMID- 24767463 TI - Pyoderma gangrenosum successfully treated with antiretroviral therapy alone in a human immunodeficiency virus-infected individual. AB - We report a case of a 60-year-old man infected with human immunodeficiency virus (HIV) who was transferred to our hospital for management of multiple non-healing, painful ulcers on the lower extremities. The histological findings of the biopsy specimen were compatible with the diagnosis of pyoderma gangrenosum (PG). An association between HIV infection and the development of PG was considered after a thorough investigation. Antiretroviral therapy without the use of adjunctive immunosuppressive agents resulted in clinical improvement. Our case implies that antiretroviral therapy alone could heal PG in untreated HIV-infected patients. PMID- 24767464 TI - Characterization of methicillin-resistant Staphylococcus aureus isolated from tertiary care hospitals in Tokyo, Japan. AB - The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) remains problematic in both hospital and community settings. Investigations of MRSA existing in the local area are necessary to understand the detailed epidemiology of healthcare-associated MRSA (HA-MRSA). In the present study, molecular epidemiological analysis was performed on 584 MRSA isolated from four hospitals in Tokyo, Japan. In the pulsed-field gel electrophoresis (PFGE) analysis, four epidemic pulsotypes (I to IV) were found. The isolates of the epidemic pulsotype I mainly consisted of the SCCmec type II, toxic shock syndrome toxin 1 gene (tst) negative, spa type t002, and ST764 clones. The ST764 clone, which is a novel hybrid variant of the ST5 HA-MRSA lineage with the arginine catabolic mobile element (ACME), was first found in Niigata, Japan. However, no ACME genes were detected in the isolates of the epidemic pulsotype I. In contrast, the other isolates of the epidemic pulsotypes mainly consisted of the SCCmec type II, tst positive, spa type t002, and ST5 clones, which are the most predominant clones of HA-MRSA in Japan. Resistance rates of non-beta-lactams for the isolates of the epidemic pulsotype I were higher than those of the other epidemic pulsotypes. Our data showed that the novel ACME-negative ST764 clones are being distributed throughout multiple hospitals in Tokyo. The ST764 clones in Tokyo have the potential to acquire ACME in the future, because the ACME-positive ST764 clones have already been found in both hospital and community settings in other areas of Japan. PMID- 24767465 TI - Methicillin-susceptible Staphylococcus aureus CC398: first description in prosthetic joint infection and genetic background comparison with nasal carriage isolates. AB - Few reports described infections with CC398 methicillin-susceptible Staphylococcus aureus (MSSA). We compared the genetic background of CC398 MSSA strains from nasal carriage and knee arthroplasty infection. DNA microarray analysis shows acquisition of particular adhesin, iron capture system and immune defense evasion mechanisms. These characteristics could explain pathogenesis in this type of infection. PMID- 24767466 TI - Relationship between public subsidies and vaccination rates with the 23-valent pneumococcal vaccine in elderly persons, including the influence of the free vaccination campaign after the Great East Japan Earthquake. AB - Low vaccination rates with pneumococcal vaccine in elderly persons in Japan are thought to be related to low levels of public subsidy. To identify strategies to increase future pneumococcal vaccination rates, we examined the relationship between public subsidies and vaccination rates. We also investigated the influence of free vaccinations after the 2011 Great East Japan Earthquake on vaccination rates in the three Tohoku prefectures of Japan. We surveyed a total of 1742 municipalities in Japan about whether public subsidies were available and their monetary amount. Vaccination rates with the 23-valent pneumococcal vaccine were calculated as the "cumulative amount shipped to each municipality divided by the population aged >=65 years." There were no subsidies in 773 municipalities (44.4%). In those municipalities with public subsidies, larger subsidies were significantly associated with elevated vaccination rates (p < 0.0001). Compared to a mean vaccination rate of 25.4% throughout Japan, the vaccination rate was 52.1% in municipalities where the full cost was subsidized. The three prefectures (Iwate, Miyagi, and Fukushima) most affected by the Great East Japan Earthquake ranked as the top three prefectures for vaccination rates in Japan, presumably as a result of the free vaccination campaign for disaster victims. Our findings show that public subsidies play an important role in increasing the vaccination rate. The free vaccinations given to disaster victims after the Great East Japan Earthquake helped to achieve extremely high vaccination rates in the three Tohoku prefectures. We suggest that such public subsidies should be promoted throughout Japan. PMID- 24767467 TI - Predisposing factors, clinical characteristics and outcome of Pneumonocystis jirovecii pneumonia in HIV-negative patients. AB - Pneumocystis jirovecii (former carinii) pneumonia, is a life-threatening opportunistic infection occurring in immunocompromised hosts. The aim of this study was to investigate the predisposing factors, clinical features and outcome of Pneumocystis pneumonia (PCP) in HIV-negative patients. The medical records of 62 adult patients with PCP, hospitalized at the University Hospital of Heraklion, Crete, Greece during a 10-year period (2004-2013) were retrospectively reviewed. All patients were immunosuppressed prior to the development of PCP. Thirty one patients (50%) suffered malignant hematological disease, 16 (26%) solid tumor and 15 (24%) had chronic inflammatory disease. Only 17 (27%) had received long-term systemic corticosteroids. All had symptoms of pneumonia upon admission, while 12 (19%) were suffering respiratory failure. Twenty one (34%) had received trimethoprim/sulfamethoxazole (TMP-SMX) prophylaxis before the PCP onset. Eight patients (13%) were admitted to the ICU. Mortality attributable to PCP reached 29%. Mortality attributable to PCP was higher in patients with solid tumors. TMP SMX prophylaxis failed in a significant portion of the present cohort. Hence, PCP should be included in the differential diagnosis in immunocompromised patients with symptoms from the respiratory tract even if TMP-SMX has been given as prophylaxis. PMID- 24767468 TI - Autorefraction versus subjective refraction in a radially asymmetric multifocal intraocular lens. AB - PURPOSE: To evaluate whether the automated refraction (AR) correlates with subjective manifest (MR) refraction in eyes implanted with radially asymmetric multifocal intraocular lens (IOLs). METHODS: This retrospective study evaluated 52 eyes (52 patients) implanted with a radially asymmetric multifocal IOL (LS-312 MF30, Oculentis, Germany). At 3 months postoperatively, the AR and MR values were compared to determine the correlation between the sphere (S), the spherical equivalent (SE) and the astigmatic components J0 and J45. RESULTS: The difference of mean spherical measurement was +0.98D +/- 0.62, with the AR measuring more myopic. The difference of the mean spherical equivalent was +1.11D +/- 0.57, again with AR being more myopic. Both these differences were statistically significant (p < 0.001). The astigmatic components showed less differences, with the mean difference of the J0 being -0.09D +/- 0.43, and the J45 of +0.04D +/- 0.47, which were both not statistically significant (p = 0.123 and p = 0.531, respectively). Correlation analysis of the refractive parameters showed r(2) = 0.067, r(2) = 0.078, r(2) = 0.018 and r(2) = 0.015, respectively, all of which point to a low correlation between the AR and the MR. CONCLUSION: Autorefraction shows poor correlation to manifest subjective refraction with these radially asymmetric multifocal IOLs. The autorefraction systematically underestimates the spherical and spherical equivalent power, while the correlation between the astigmatic components was also low. Autorefraction seems not a valid starting point for manifest subjective refraction with these types of lenses, unless a corrective factor of about +1 dioptre is used. PMID- 24767469 TI - Features of breast cancer in developing countries, examples from North-Africa. AB - Epidemiological features of breast cancer appear to be different in developing countries compared to Western countries, with notably large proportions of young patients, male patients and aggressive forms of the disease. Using North-Africa (Morocco, Algeria, Tunisia, Libya and Egypt) as an example, we document the magnitude and explore possible explanations for such patterns. Articles and reports published since the seventies were reviewed. Results show that breast cancer incidence in females is 2-4 times lower in North-Africa than in Western countries while incidence in males is similar. Consequently, the relative proportion of male breast cancer is high (~2% of all breast cancers). Similarly, the incidence of aggressive forms of the disease, like inflammatory or triple negative breast cancer (in females), is not higher in North Africa than in Western countries, but their relative proportion in case series (up to 10% for inflammatory and 15-25% for triple negative) is significantly higher because of low incidence of other forms of the disease. In North Africa, the incidence among women aged 15-49 is lower than in Western countries, but the very low incidence among women aged more than 50, combined to the young age pyramid of North-Africa, makes the relative proportions of young patients substantially higher (50-60% versus 20% in France). Such epidemiological features result mainly from peculiar risk factor profiles, which are typical for many developing countries and include notably rapid changes in reproductive behaviours. These features have important implications for breast cancer control and treatment. PMID- 24767470 TI - Systematic review of outcomes of patients undergoing resection for colorectal liver metastases in the setting of extra hepatic disease. AB - BACKGROUND: Surgical resection for patients with colorectal liver metastases (CRLM) can offer patients a significant survival benefit. We hypothesised that patients with CRLM and extra hepatic disease (EHD) undergoing metastasectomy had comparable survival and describe outcomes based on the distribution of metastatic disease. METHODS: A systematic search using a predefined registered protocol was undertaken between January 2003 and June 2012. Primary exposure was hepatic resection for CRLM and primary outcome measure was overall survival. Meta regression techniques were used to analyse differences between patients with and without extra hepatic disease. FINDINGS: From a pool of 4996 articles, 50 were retained for data extraction (3481 CRLM patients with EHD). The median survival (MS) was 30.5 (range, 9-98) months which was achieved with an operative mortality rate of 0-4.2%. The 3-year and 5-year overall survival (OS) were 42.4% (range, 20.6-77%) and 28% (range, 0-61%) respectively. Patients with EHD of the lungs had a MS of 45 (range, 39-98) months versus lymph nodes (portal and para-aortic) 26 (range, 21-48) months versus peritoneum 29 (range, 18-32) months. The MS also varied by the amount of liver disease - 42.2months (180 ng/cm(2)) at room temperature due to its amphiphilic characteristics. Adsorbed mass of BSM was noticeably reduced after heating at 80 degrees C, possibly resulting from its aggregation. BSM showed excellent lubricity at self-mated sliding contacts between PDMS at room temperature or lower (friction coefficient~0.02), even when BSM solution was pre-heated up to 120 min at 80 degrees C. Gradual degradation of lubricity of BSM was observed with increasing temperature, but it was also reversibly recovered with decreasing temperature. Structural and functional stability of BSM against heating is proposed to originate from heavy glycosylation and lack of higher degree of protein structure in BSM. PMID- 24767507 TI - Multi-ion diffusiophoresis. AB - The movement of charged particles occurs in a salt concentration gradient by the mechanism of diffusiophoresis. Current analytical models for diffusiophoresis have been developed for a gradient generated by a symmetric Z:Z electrolyte at steady state. Recently, our lab has reported diffusioosmotic flows due to dissolving calcium carbonate (CaCO3) which generates three ions (Ca(2+), HCO3(-), and OH(-)), and this fluid motion cannot be described by current analytical models. In this communication, we derive an expression for the diffusioosmotic flow in a gradient involving multiple ions of different valences, assuming infinitesimally thin double layers. We also solve numerically the time-dependent concentration profiles for the three-ion case and find that the concentration profile of HCO3(-) is non-monotonic in solution. Finally, we examine quantitatively the assumption of electroneutrality in solution, finding that electroneutrality is a good approximation even for the multi-ion case, indicating that our electric field derived from the ion migration equation is quite accurate. PMID- 24767508 TI - Extraction of methylmercury and ethylmercury from aqueous solution using surface sulfhydryl-functionalized magnetic mesoporous silica nanoparticles. AB - Surface sulfhydryl-functionalized magnetic mesoporous silica nanoparticles were prepared, aiming to extract trace alkylmercury from aqueous solution. The prepared nanoparticles were characterized by TEM, ED, EDX, DLS, FTIR, and SERS. Compare with that the non-sulfhydryl-functionalized Fe3O4@SiO2 exhibited almost no affinity for CH3Hg(+) and CH3CH2Hg(+); the sulfhydryl-functionalized Fe3O4@SiO2 exhibited high adsorption affinity for them, resulting from chelating interaction by surface sulfhydryl group, and the adsorption was not significantly impacted by pH within the range of 3.5-9.0 or coexisting metal ions. The monolayer adsorption on surface of Fe3O4@SiO2-RSH could reach equilibrium in 2 min. Moreover, the CH3Hg(+) and CH3CH2Hg(+) adsorbed on Fe3O4@SiO2-RSH could be quickly separated from the matrix in a magnetic field and desorbed easily by acetonitrile and l-cysteine aqueous solution or HCl solution, and the recoveries were more than 80%. Findings of the present work highlight the potential for using Fe3O4@SiO2-RSH magnetic nanoparticles as effective and reusable adsorbents for extraction of ultra trace alkylmercury from environmental water samples. PMID- 24767509 TI - Multifunctional hybrid silica nanoparticles based on [Mo6Br14]2- phosphorescent nanosized clusters, magnetic gamma-Fe2O3 and plasmonic gold nanoparticles. AB - We report on the synthesis, characterization and photophysical study of new luminescent and magnetic hybrid silica nanoparticles. Our method is based on the co-encapsulation of single maghemite gamma-Fe2O3 nanoparticles and luminescent molybdenum cluster units [Mo6Br(i)8Br(a)6](2-) through a water-in-oil (W/O) microemulsion technique. The as-prepared core-shell [Cs2Mo6Br14-gammaFe2O3]@SiO2 nanoparticles (45-53 nm) possess a single magnetic core (6, 10.5 or 15 nm) and the cluster units are dispersed in the entire volume of the silica sphere. The [Cs2Mo6Br14-gammaFe2O3]@SiO2 nanoparticles have a perfect spherical shape with a good monodispersity and they display red and near-infrared (NIR) emission in water under UV excitation, whose intensity depends on the magnetic core size. The hybrid nanoparticles have been characterized by transmission electron microscopy (TEM), high annular angular dark field scanning transmission electron microscopy (HAADF-STEM), energy-dispersive X-ray spectroscopy (EDX), UV-Vis-NIR spectroscopy and magnetometer SQUID analysis. Small gold nanoparticles were successfully nucleated at the surface of the hybrid silica nanoparticles in order to add plasmonic properties. PMID- 24767510 TI - The formation of linear aggregates in magnetic hyperthermia: implications on specific absorption rate and magnetic anisotropy. AB - The design and application of magnetic nanoparticles for use as magnetic hyperthermia agents has garnered increasing interest over the past several years. When designing these systems, the fundamentals of particle design play a key role in the observed specific absorption rate (SAR). This includes the particle's core size, polymer brush length, and colloidal arrangement. While the role of particle core size on the observed SAR has been significantly reported, the role of the polymer brush length has not attracted as much attention. It has recently been reported that for some suspensions linear aggregates form in the presence of an applied external magnetic field, i.e. chains of magnetic particles. The formation of these chains may have the potential for a dramatic impact on the biomedical application of these materials, specifically the efficiency of the particles to transfer magnetic energy to the surrounding cells. In this study we demonstrate the dependence of SAR on magnetite nanoparticle core size and brush length as well as observe the formation of magnetically induced colloidal arrangements. Colloidally stable magnetic nanoparticles were demonstrated to form linear aggregates in an alternating magnetic field. The length and distribution of the aggregates were dependent upon the stabilizing polymer molecular weight. As the molecular weight of the stabilizing layer increased, the magnetic interparticle interactions decreased therefore limiting chain formation. In addition, theoretical calculations demonstrated that interparticle spacing has a significant impact on the magnetic behavior of these materials. This work has several implications for the design of nanoparticle and magnetic hyperthermia systems, while improving understanding of how colloidal arrangement affects SAR. PMID- 24767511 TI - Can testing of six individual muscles represent a screening approach to upper limb neuropathic conditions? AB - BACKGROUND: It has previously been demonstrated that an extensive upper limb neurological examination of individual muscle function, sensation in homonymous innervated territories, and nerve trunk allodynia is reliable and that the outcome reflects symptoms. Since this approach may appear complicated and time consuming, this study deals with the value of an examination limited to manual testing of only six muscles. METHODS: Two examiners blinded to symptom status performed manual muscle testing of six muscles in 82 upper limbs with or without pain, weakness, and/or numbness/tingling. The six muscles represent three antagonist pairs (pectoralis major/posterior deltoid, biceps/triceps, and radial flexor of wrist/short radial extensor of wrist). The inter-rater reliability of detecting muscular weaknesses and the relation of weakness to the mentioned symptoms were analysed by kappa-statistics. RESULTS: The two examiners recognized weaknesses in 48 and 55 limbs, respectively, with moderate agreement (median kappa = 0.58). Out of these, 35 and 32 limbs, respectively, were symptomatic. There was good correlation between findings and symptoms for one examiner (kappa = 0.61) and fair correlation for the other one (kappa = 0.33). Both reached high sensitivity (0.92, 0.84) but less satisfactory specificity (0.70, 0.50). Weaknesses agreed upon by the two examiners correlated moderately with symptoms (kappa = 0.57). CONCLUSIONS: Weakness in one or more muscles was present in almost all symptomatic limbs but in many non-symptomatic limbs as well. Manual testing of six muscles may represent a useful screening approach to upper limb neuropathic conditions, but a confirmative diagnosis requires further assessment. PMID- 24767512 TI - Consumer satisfaction with practice nursing: a cross-sectional survey in New Zealand general practice. AB - An important consideration in health service delivery is ensuring that services meet consumer needs. Whilst nursing services in primary care have grown internationally, there has been limited exploration of consumer satisfaction with these services. This paper reports a descriptive survey that sought to evaluate consumers' perceptions of New Zealand practice nurses (PNs). One thousand, five hundred and five patients who received nursing services at one of 20 participating New Zealand general practices completed a survey tool between December 2010 and December 2011. The 64-item self- report survey tool contained the 21-item General Practice Nurse Satisfaction (GPNS) scale. Data were analysed using both descriptive and inferential statistics. Internal consistency of the GPNS scale was high (Cronbach's alpha 0.97). Participants aged over 60 years and those of European descent were significantly less satisfied with the PN (P = 0.001). Controlling for these characteristics, participants who had visited the PN more than four times previously were 1.34 times (adjusted odds ratio 1.34 (95% CI: 1.06-1.70) more satisfied than the comparison group (up to 4 previous visits to PN). In addition to the further validation of the psychometric properties of the GPNS scale in a different setting, the study also revealed a high level of satisfaction with PNs, with increased satisfaction with an increased number of visits. Nevertheless, the lower levels of satisfaction with PNs in the older age group as well as those of European descent, warrants further examination. The study also highlights the need for PNs and consumers to discuss consumer's expectations of services and create a shared understanding of treatment goals. PMID- 24767513 TI - An improved genome release (version Mt4.0) for the model legume Medicago truncatula. AB - BACKGROUND: Medicago truncatula, a close relative of alfalfa, is a preeminent model for studying nitrogen fixation, symbiosis, and legume genomics. The Medicago sequencing project began in 2003 with the goal to decipher sequences originated from the euchromatic portion of the genome. The initial sequencing approach was based on a BAC tiling path, culminating in a BAC-based assembly (Mt3.5) as well as an in-depth analysis of the genome published in 2011. RESULTS: Here we describe a further improved and refined version of the M. truncatula genome (Mt4.0) based on de novo whole genome shotgun assembly of a majority of Illumina and 454 reads using ALLPATHS-LG. The ALLPATHS-LG scaffolds were anchored onto the pseudomolecules on the basis of alignments to both the optical map and the genotyping-by-sequencing (GBS) map. The Mt4.0 pseudomolecules encompass ~360 Mb of actual sequences spanning 390 Mb of which ~330 Mb align perfectly with the optical map, presenting a drastic improvement over the BAC-based Mt3.5 which only contained 70% sequences (~250 Mb) of the current version. Most of the sequences and genes that previously resided on the unanchored portion of Mt3.5 have now been incorporated into the Mt4.0 pseudomolecules, with the exception of ~28 Mb of unplaced sequences. With regard to gene annotation, the genome has been re annotated through our gene prediction pipeline, which integrates EST, RNA-seq, protein and gene prediction evidences. A total of 50,894 genes (31,661 high confidence and 19,233 low confidence) are included in Mt4.0 which overlapped with ~82% of the gene loci annotated in Mt3.5. Of the remaining genes, 14% of the Mt3.5 genes have been deprecated to an "unsupported" status and 4% are absent from the Mt4.0 predictions. CONCLUSIONS: Mt4.0 and its associated resources, such as genome browsers, BLAST-able datasets and gene information pages, can be found on the JCVI Medicago web site (http://www.jcvi.org/medicago). The assembly and annotation has been deposited in GenBank (BioProject: PRJNA10791). The heavily curated chromosomal sequences and associated gene models of Medicago will serve as a better reference for legume biology and comparative genomics. PMID- 24767514 TI - Congenital primary penile teratoma in a child. AB - Teratomas rarely present as a pediatric congenital primary penile mass. We describe a 14-month-old boy with a blister-like mass on his distal left penis. The subcutaneous mass measured 1.5 cm (length)*1.0 cm (width)*1.2 cm (height) on ultrasonography. There were clear margins between these structures and the lesion. At the age of 5 years, he received an extirpation surgery. Histologic analysis revealed that it was a mature teratoma. In our view, surgical resection should be the treatment of choice for a pediatric penile mass with the alertness of teratomas because of the possibility of malignant alteration and invasion of adjacent structures till unresectable. PMID- 24767515 TI - Posterior urethral polyp with type I posterior urethral valves: a rare association in a neonate. AB - Urethral polyp is a rare cause of bladder outlet obstruction, voiding dysfunction, and hematuria in the pediatric age group. Urethral polyps are rarely associated with other congenital urinary tract anomalies. In this study, we report a case of solitary posterior urethral polyp with type I posterior urethral valve in a 7-day-old neonate presented with urinary retention and deranged renal function. The polyp was diagnosed on cystoscopy. Transurethral resection of the polyp with posterior urethral valve fulguration was performed. Pathologic assessment revealed a fibroepithelial lesion, which was consistent with congenital posterior urethral polyp. PMID- 24767516 TI - Late-onset metastatic adenocarcinoma of the spermatic cord from primary gastric cancer. AB - BACKGROUND: Metastatic cancers of the paratesticular tissue are very rare; however, the most frequent primary site of spermatic cord metastasis is the gastrointestinal tract. CASE PRESENTATION: We recently observed two cases of late onset metastatic adenocarcinoma of the spermatic cord. Both patients complained of groin discomfort with a palpable mass in the scrotum and inguinal area. Radical orchiectomy and adjuvant chemotherapy were performed in both patients. Although the prognosis of patients with metastatic adenocarcinoma of the spermatic cord is typically poor, the prognosis of our patients was favorable after follow-up for 14 to 18 months. CONCLUSIONS: In patients with groin discomfort or swelling and a history of gastric cancer, metastatic adenocarcinoma should be included in the differential diagnosis for early detection of tumors. PMID- 24767517 TI - Improving the clinical significance of medical research. PMID- 24767518 TI - A theoretical analysis showed that blinding cannot eliminate potential for bias associated with beliefs about allocation in randomized clinical trials. AB - OBJECTIVES: To explore the theoretical justification for blinding in randomized trials and make recommendations concerning the implementation and interpretation of blinded randomized trials. STUDY DESIGN AND SETTING: A theoretical analysis was conducted of the potential for bias in randomized trials with successful blinding (ie, trials in which beliefs about allocation to treatment or control groups are independent of actual allocation). The analysis identified conditions that must be satisfied to ensure that blinding eliminates the potential for bias associated with beliefs about allocation. RESULTS: Even when beliefs about allocation are independent of actual allocation, they can still cause bias. The potential for bias is eliminated when the belief is uniformly one of complete ambivalence about allocation. CONCLUSION: Even when blinding succeeds in making beliefs about allocation independent of actual allocation, beliefs about allocation may still cause bias. It is difficult to determine the extent of bias in any particular trial. Bias could be eliminated by establishing a state of complete ambivalence about the allocation of every trial participant, but universal ambivalence may be difficult to achieve and may reduce the generalizability of the trial's findings. PMID- 24767519 TI - Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial. AB - BACKGROUND: Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation. METHODS/DESIGN: A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC < 0.7 and FEV1 < 80% of predicted), who receive reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-index < 0.6) and who experience a COPD exacerbation will be asked within 56 days to participate in a cohort-nested prospective randomised controlled trial (RCT). In this RCT, the intervention group will receive a strict physical therapy programme for patients with COPD. This protocol-directed physical therapy (pdPT) will be compared to a control group that will receive sham-treatment, meaning no or very low-intensity exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients' perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion. DISCUSSION: Ways to minimise potential problems regarding the execution of this study will be discussed. TRIAL REGISTRATION: The Netherlands National Trial Register NTR1972. PMID- 24767520 TI - Ulcerative and nonulcerative forms of bladder pain syndrome/interstitial cystitis do not differ in symptom intensity or response to onabotulinum toxin A. AB - OBJECTIVE: To determine whether intratrigonal Onabotulinum toxin A (OnabotA) injection produces a different symptomatic outcome and duration of effect on ulcerative (Ulc) and nonulcerative (NUlc) bladder pain syndrome/interstitial cystitis (BPS/IC) patients and to compare the urinary levels of neurotrophines (NGF, BDNF, and GDNF) in response to OnabotA. METHODS: Ten Ulc and 14 NUlc bladder pain syndrome/interstitial cystitis patients were included in this study. OnabotA (100 U) was injected in 10 trigonal sites, each receiving 10 U in 1 mL of saline. Outcome measures included pain visual analog scale (0-10), a 3-day voiding chart, O'Leary-Sant Score (OSS), and quality of life (QoL) from International Prostate Symptoms Score assessed before treatment, 1 month after injection, and every 3 months afterwards. Urinary NGF, BDNF, and GDNF were accessed using ELISA, at same time points. Treatment duration was determined at the time patients requested another injection. RESULTS: Patients had a mean age of 40 +/- 12 years in the Ulc and 47 +/- 13 years in the NUlc group (ns). Mean values at baseline of pain intensity, frequency, nocturia, OSS, QoL, and urinary NGF, BDNF, GDNF were identical in the 2 groups. Patients with the Ulc phenotype had a longer duration of symptoms (28.8 +/- 11 vs 19.2 +/- 8 months, P = .018). Both groups responded equally to OnabotA, with significant improvements in pain intensity, frequency, nocturia, OSS, QoL, and urinary NGF, BDNF, GDNF. The effect lasted for 9 +/- 2.8 (Ulc) and 10.5 +/- 2 (NUlc) months. CONCLUSION: In this cohort, Ulc and NUlc patients had similar symptoms at baseline and comparable clinical response to intratrigonal OnabotA. These findings suggest that pain may not be directly related with ulcers themselves. PMID- 24767521 TI - Best practices in shock wave lithotripsy: a comparison of regional practice patterns. AB - OBJECTIVE: To evaluate regional differences in adaptation of best practice recommendations for extracorporeal shock wave lithotripsy (SWL) across 4 distinct geographic regions. METHODS: A retrospective study was performed using a prospective database maintained by a mobile lithotripsy provider (ForTec Medical, Streetsboro, OH). SWL cases performed in Ohio, Northern Illinois/Southern Wisconsin, Florida, and New York were included. Treatment parameters evaluated included treatment rate, use of a power ramp-up protocol, use of a pretreatment pause after the initial 100 shocks, ancillary procedures, and need for retreatment. Regional and physician-specific patterns were examined. Statistical analyses using chi-square and analysis of variance were performed with a significance of P <.05. RESULTS: Data from 2240 SWL procedures were included in the study. Overall adaptation of power ramp-up protocols and treatment rates were high (93% and 93%), whereas use of pause was lower (75%, P <.001). Retreatment rates were low (4.3%), although ancillary procedures were performed in 34% of patients, and 8.3% of patients received stents for stones <1 cm. Regional differences were present in all parameters: Florida physicians used power ramp-up less (83%, P <.001) but had good use of pretreatment pause (98%, P <.001), both Wisconsin/Illinois and New York were less likely to use slow rate (87% and 84%, respectively, P <.001). CONCLUSION: The recommendations for slower shock wave rates and power ramp protocols have reached high penetration in urologic practices; however, the more recent recommendation for a pause after the initial 100 shocks has been less uniformly implemented. Inconsistencies in regional adaptation of best practices may identify opportunities for further education. PMID- 24767522 TI - Correlations of tumor size, RENAL, centrality index, preoperative aspects and dimensions used for anatomical, and diameter-axial-polar scoring with warm ischemia time in a single surgeon's series of robotic partial nephrectomy. AB - OBJECTIVE: To evaluate the association of tumor size, renal nephrometry systems (RNSs), including RENAL, centrality index (C-index), preoperative aspects and dimensions used for anatomical, and diameter-axial-polar scoring, and individual categories of these RNSs with warm ischemia time (WIT). METHODS: A single surgeon's series of robotic partial nephrectomy patients for whom RNS was available were identified from 2012 to 2013. Spearman's correlation was used to evaluate associations between the RNSs and individual categories and WIT. RESULTS: Analysis was performed based on 69 patients with a median tumor size of 3.5 cm (interquartile range 2.6-4.2). Overall, each scoring system and tumor size were found to have a statistically significant association with the WIT, with the C-index system exhibiting the strongest correlation (coefficient: -0.609, P <.001), which was confirmed in the series beyond the surgeon's learning curve. In the subgroup of relatively small renal masses (<3 cm), there was a statistically significant association between the C-index, preoperative aspects and dimensions used for anatomical, and diameter-axial-polar systems with WIT. However, for tumors >3 cm, none of the RNSs was found to have a statistically significant correlation with WIT, except for the tumor size (coefficient: 0.354, P = .027). For subcategories, axial scoring was found to have a consistent statistically significant correlation with WIT. CONCLUSION: Overall, each RNS and tumor size strongly correlated with WIT in patients undergoing robotic partial nephrectomy. However, the RNS outperformed tumor size in small (<3 cm) renal masses with an optimal discriminating power, whereas for relatively larger (>3 cm) tumors, WIT was significantly dependent on tumor size, and every centimeter may count. PMID- 24767523 TI - Editorial comment. PMID- 24767524 TI - Do patients know their nerve-sparing status after radical prostatectomy? AB - OBJECTIVE: To determine patients' knowledge regarding their nerve-sparing status (NSS) after radical prostatectomy (RP) and what factors during their clinical treatment are associated with this. METHODS: One hundred consecutive patients attending an erectile dysfunction clinic in Toronto, Canada, with a prior RP were surveyed from December 2010 to June 2011. Patients were questioned whether they had undergone a nerve-sparing procedure and, if so, whether it was unilateral or bilateral. Patients were assessed on both knowledge (known vs unknown) and accuracy (correct vs incorrect) regarding their NSS. Operative reports were used to determine the true NSS of each patient. RESULTS: Thirty-nine percent of patients had no knowledge of their NSS. Forty-five percent of patients were able to correctly identify their NSS, including only 19% of patients undergoing a non nerve-sparing procedure. On univariate analysis, factors associated with patients correctly knowing their NSS were age, having a nerve-sparing strategy dictated in the preoperative clinic note, nerve sparing included in the surgical consent form, and type of nerve-sparing procedure performed. On multivariate analysis, planned nerve-sparing approach dictated in the preoperative note (odds ratio [OR], 4.86), nerve sparing included in surgical consent (OR, 3.76), time since surgery (OR, 0.99), and having a bilateral nerve-sparing procedure (OR, 5.91) were associated with correctly identifying one's NSS. CONCLUSION: After RP, a significant proportion of patients with erectile dysfunction have no knowledge of whether they underwent a nerve-sparing procedure. By discussing with patients the planned nerve-sparing technique preoperatively and counseling them on their NSS postoperatively, urologists may be able to improve on patient recollection of their NSS. PMID- 24767525 TI - High-dose interleukin-2 therapy for metastatic renal cell carcinoma: a contemporary experience. AB - OBJECTIVE: To present our experience of high-dose interleukin-2 (HDIL-2) in a high-volume National Cancer Institute-designated center for patients with metastatic renal cell carcinoma (mRCC). METHODS: Patients with mRCC who received HDIL-2 monotherapy as a first- or second-line therapy during 2004-2011 were identified. Demographics, pathologic variables, renal function, time until the start of HDIL-2 therapy, number of cycles (1-3), responses (complete response, partial response, stable disease, and progressive disease), and primary renal cell carcinoma treatment were analyzed. Progression-free survival and overall survival (OS) were determined. RESULTS: Of 906 patients in the kidney cancer database, 91 patients with mRCC were treated with HDIL-2 and 18 patients (20.5%) underwent prior cytoreductive nephrectomy. Median age was 51 years, and 73.9% were men. Median follow-up was 45 months. Pretreatment renal function impairment led to more treatment cycles (2-3) than in those with adequate initial kidney function (92.3% vs 50.6%, respectively; P = .002). Lower tumor stage correlated with a better response (P = .023) and with longer time from diagnosis to initiation of HDIL-2 (P = .011). Complications included hypotension (67.4%), renal impairment (63%), impaired liver function (42.4%), and thrombocytopenia (31.5%). Four patients (4.5%) had a complete response, 10 (11.4%) had a partial response, and 28 (31.8%) had a stable disease. Median progression-free survival and OS were 8.6 and 35.5 months, respectively. The estimated 2-year OS rate was 60.6%. CONCLUSION: Incorporating HDIL-2 therapy in the treatment strategies for mRCC added to the patients' survival in this series. HDIL-2 therapy is well tolerated in patients with pre-existing renal impairment with no long-term renal toxicity. PMID- 24767526 TI - Comparison of clinical outcomes between "ideal" and "nonideal" transobturator male sling patients for treatment of postprostatectomy incontinence. AB - OBJECTIVE: To review the clinical outcomes of "ideal" vs "nonideal" postprostatectomy stress urinary incontinence (PPI) patients who underwent male sling placement. METHODS: The medical records of 95 consecutive patients with PPI who underwent male sling insertion (AdVance male sling, American Medical Systems, Minnetonka, MN) were reviewed. Patients were divided into "ideal" vs "nonideal" cohorts. The ideal group consisted of patients with mild to moderate incontinence (<4 pads/day or <300 g daily pad weight), ability to volitionally contract the external urinary sphincter, no history of pelvic radiation or cryotherapy, no history of previous anti-incontinence surgical procedures, the ability to generate a volitional detrusor contraction when voiding, and a postvoid residual urine volume <100 mL. Patients in the nonideal group did not satisfy all these criteria. RESULTS: Significant reductions in daily pad usage and weight were noted in both cohorts. In the ideal patient group, 66 of 72 patients (92%) would undergo the procedure again. Conversely, only 7 of 23 nonideal men (30%) would undergo the procedure again. CONCLUSION: Preoperative patient selection can influence favorable outcomes after the treatment of PPI with AdVance male slings. Attention to ideal vs nonideal patient characteristics should be used when counseling men considering male sling surgery. PMID- 24767527 TI - Editorial comment. PMID- 24767528 TI - Independently interpreted retrograde urethrography does not accurately diagnose and stage anterior urethral stricture: the importance of urologist-performed urethrography. AB - OBJECTIVE: To compare the accuracy of retrograde urethrogram (RUG) interpretation between the primary physician performing the procedure and the independent physician interpreting the films to evaluate the suitability of relying on independent physician interpretations for the purposes of preoperative urethral stricture surgery planning. METHODS: A retrospective review was performed on a cohort of 397 patients undergoing anterior urethroplasty over a 7-year period at a single center. Preoperative RUG findings as reported at the time by both the urologist performing the urethrography and the independent interpreter (radiologist) were abstracted and compared with stricture location and length as measured intraoperatively. RUG adequacy was defined as a comment on the presence, location, and length of the urethral stricture. RESULTS: Only 49% of independently reported RUG studies were deemed adequate, and 87% of independently reported studies correctly diagnosed the presence of a stricture. Forty-nine percent of independently reported studies correctly identified stricture location compared with 96% of primary physician-reported cases (P <.001). The reported stricture lengths were 3.23 +/- 2.25, 4.19 +/- 2.49, and 4.51 +/- 2.65 cm for the independently reported RUGs, primary physician-reported RUGs, and the intraoperative measurements, respectively. Differences between all the groups were statistically significant (P <.001). Independently reported length had a 0.47 R(2) coefficient of correlation to the intraoperative length (P <.001) compared with a 0.93 R(2) coefficient of correlation between primary physician reported length and intraoperative length (P <.001). CONCLUSION: Independently reported RUGs are not as accurate as primary physician-reported RUGs, and caution should be used when they are used for preoperative planning. PMID- 24767529 TI - Editorial comment. PMID- 24767531 TI - Reconstructing full-length ureteral defects using a spiral bladder muscle flap with vascular pedicles. AB - INTRODUCTION: This study investigates the efficacy of ureteral reconstruction using a spiral bladder muscle flap with vascular pedicles (ie, the superior vesical arteries) to repair full-length ureteral defects and explores a surgical approach for repairing long ureteral defects (>20 cm) using a bladder muscle flap. TECHNICAL CONSIDERATIONS: The characteristics of the ureteral reconstruction surgery include the following: (1) Surgeons fully expose the bladder in the retroperitoneal space. (2) While dissecting the superior vesical arteries, the integrities of the blood vessel trunk and the primary branches are maintained as much as possible. (3) While preparing the bladder muscle flap, the surgeons make an S-shaped cut along the route of the superior vesical arteries along the bladder. In general, the basal width of the muscle flap is approximately 2-3 cm in length, and the total length is approximately 1-2 cm longer than the defective ureter. (4) During the surgery, kidney descent and fixation and psoas hitch are performed to reduce end-to-end anastomotic tension. (5) The addition of a submucosal tunnel to prevent postoperative ureteral reflux is unnecessary. (6) A pedicled greater omentum graft is transferred to cover the reconstructed ureter to enhance blood supply when necessary. CONCLUSION: Ureteroplasty using a spiral bladder muscle flap with vascular pedicles (ie, the superior vesical arteries) is an ideal treatment to repair full-length ureteral defects. Moreover, this technique is particularly useful for ureteral defects longer than 20 cm. This procedure should be strongly promoted. PMID- 24767532 TI - Reply by the authors. PMID- 24767533 TI - Re: Li et al.: Percutaneous nephrolithotomy under local infiltration anesthesia: a single-center experience of 2000 Chinese cases (Urology 2013;82:1020-1025). PMID- 24767534 TI - Re: Kozacioglu et al.: Anatomy of the dorsal nerve of the penis, clinical implications (Urology 2014;83:121-125). PMID- 24767535 TI - Re: Bo et al.: Evaluation of bladder clots using a nonsurgical treatment (Urology 2014;83:498-499). PMID- 24767536 TI - Reply by the authors. PMID- 24767537 TI - Renal cell carcinoma with infrahepatic vena caval tumor thrombus treated with a novel combined retroperitoneal and transperitoneal pure laparoscopic procedure. AB - A 61-year-old male patient presented with intermittent gross hematuria. A right renal mass with infrahepatic vena caval tumor thrombus was found using magnetic resonance imaging. We undertook a novel combined retroperitoneal and transperitoneal pure laparoscopic nephrectomy with vena caval thrombectomy for this patient. The patient recovered well after surgery and discharged on day 6. A clear cell renal cell carcinoma with venous extension was confirmed by pathologic assay. To our knowledge, this is the first report of such a novel hybrid surgical strategy. PMID- 24767538 TI - Estimation of sex from the hyoid body in skeletal individuals from archeological sites. AB - Recent forensic studies have shown that the hyoid bone is a sexually dimorphic element of the human skeleton. Given the advanced techniques of collecting human remains in archeological and forensic contexts, the recovery of hyoid bones is now more frequent in skeletal samples. For that reason the authors propose a new method for estimating sex based on hyoid bodies from archeological sites. The study has been conducted on well-preserved hyoids of skeletal remains of 64 adult individuals (44 males and 20 females) dated from the pre-Roman to the medieval periods. The authors considered 10 linear measurements of the hyoid body. The most significant measurements showing sexual dimorphism are the body height, body length, and the maximum and minimum diameter of the articular facet for the greater horn. Discriminant function analysis achieved the allocation accuracy between 75.0% and 88.0%, depending on the measurement collected. This method represents a new, useful and easy way for increasing biological information when assessing the sex of adult human remains from an archeological sample. PMID- 24767539 TI - Effect of hydraulic retention time on lactic acid production and granulation in an up-flow anaerobic sludge blanket reactor. AB - In the present work, lactic acid (LA) production performance with granulation was investigated at various hydraulic retention times (HRTs), 8-0.5h. Glucose was used as a feedstock, and anaerobic mixed cultures were inoculated in an up-flow anaerobic sludge blanket reactor. As HRT decreased, the average diameter and hydrophobicity of the granules increased from 0.31 to 3.4mm and from 17.5% to 38.3%, respectively, suggesting the successful formation of granules. With decreasing HRT, LA productivity increased up to 16.7gLA/L-fermenter/h at HRT 0.5h. The existence of rod-shaped organisms with pores and internal channels at granule surface was observed by scanning electron microscope. Next generation sequencing revealed that Lactobacillus was the dominant microorganism, accounting for 96.7% of total sequences, comprising LA-producing granules. PMID- 24767540 TI - Lumbar pain as the single manifestation of an occult breast cancer. Usefulness of positron emission tomography. PMID- 24767542 TI - Human parallels to experimental myopia? A literature review on visual deprivation. AB - Raviola and Wiesel's monkey eyelid suture studies of the 1970s laid the cornerstone for the experimental myopia science undertaken since then. The aim has been to clarify the basic humoral and neuronal mechanisms behind induced myopization, its eye tissue transmitters in particular. Besides acquiring new and basic knowledge, the practical object of the research is to reduce the burden of human myopia around the world. Acquisition and cost of optical correction is one issue, but associated morbidity counts more, with its global load of myopia associated visual loss and blindness. The object of the present PubMed literature based review is to evaluate apparent similarities between experience from disturbed imaging in experimental laboratory science and varieties within the spectrum of childhood human myopia. So far, the main impression is that macroscopical optical deprivation appears absent in the prevalent types of human myopia, nor is myopia a regular sequel where early eye pathology has led to poor imaging and optical deprivation. Optical aberrations of a higher order are a relatively new issue in myopia research, and microstructural deprivation is only marginally dealt within the survey. Links between experimental and human myopia appear mainly occasional, and with only few examples in humans where factual parallels appear credible. Clinical and epidemiological data on refraction remain important, in particular with a view to life style and environmental factors. Such knowledge may further serve as inspiration to the laboratory research, which aims at solving the basic enigmas on a tissue level. PMID- 24767541 TI - Defining critical residues for substrate binding to 1-deoxy-D-xylulose 5 phosphate synthase--active site substitutions stabilize the predecarboxylation intermediate C2alpha-lactylthiamin diphosphate. AB - 1-Deoxy-D-xylulose 5-phosphate (DXP) synthase catalyzes the formation of DXP from pyruvate and D-glyceraldehyde 3-phosphate (GraP) in a thiamin diphosphate dependent manner, and is the first step in the essential pathway to isoprenoids in human pathogens. Understanding the mechanism of this unique enzyme is critical for developing new anti-infective agents that selectively target isoprenoid biosynthesis. The present study used mutagenesis and a combination of protein fluorescence, CD and kinetics experiments to investigate the roles of Arg420, Arg478 and Tyr392 in substrate binding and catalysis. The results support a random sequential, preferred order mechanism, and predict that Arg420 and Arg478 are involved in binding of the acceptor substrate, GraP. D-Glyceraldehyde, an alternative acceptor substrate lacking the phosphoryl group predicted to interact with Arg420 and Arg478, also accelerates decarboxylation of the predecarboxylation intermediate C2alpha-lactylthiamin diphosphate (LThDP) on DXP synthase, indicating that this binding interaction is not absolutely required, and that the hydroxyaldehyde sufficiently triggers decarboxylation. Unexpectedly, Tyr392 contributes to GraP affinity, and is not required for LThDP formation or its GraP-promoted decarboxylation. Time-resolved CD spectroscopy and NMR experiments indicate that LThDP is significantly stabilized on R420A and Y392F variants as compared with wild-type DXP synthase in the absence of acceptor substrate, but these substitutions do not appear to affect the rate of GraP promoted LThDP decarboxylation in the presence of high levels of GraP, and LThDP formation remains the rate-limiting step. These results suggest a role of these residues in promoting GraP binding, which in turn facilitates decarboxylation, and also highlight interesting differences between DXP synthase and other thiamin diphosphate-dependent enzymes. PMID- 24767543 TI - Molasses as a source of carbon dioxide for attracting the malaria mosquitoes Anopheles gambiae and Anopheles funestus. AB - BACKGROUND: Most odour baits for haematophagous arthropods contain carbon dioxide (CO2). The CO2 is sourced artificially from the fermentation of refined sugar (sucrose), dry ice, pressurized gas cylinders or propane. These sources of CO2 are neither cost-effective nor sustainable for use in remote areas of sub-Saharan Africa. In this study, molasses was evaluated as a potential substrate for producing CO2 used as bait for malaria mosquitoes. METHODS: The attraction of laboratory-reared and wild Anopheles gambiae complex mosquitoes to CO2 generated from yeast-fermentation of molasses was assessed under semi-field and field conditions in western Kenya. In the field, responses of wild Anopheles funestus were also assessed. Attraction of the mosquitoes to a synthetic mosquito attractant, Mbita blend (comprising ammonia, L-lactic acid, tetradecanoic acid and 3-methyl-1-butanol) when augmented with CO2 generated from yeast fermentation of either molasses or sucrose was also investigated. RESULTS: In semi-field, the release rate of CO2 and proportion of An. gambiae mosquitoes attracted increased in tandem with an increase in the quantity of yeast-fermented molasses up to an optimal ratio of molasses and dry yeast. More An. gambiae mosquitoes were attracted to a combination of the Mbita blend plus CO2 produced from fermenting molasses than the Mbita blend plus CO2 from yeast-fermented sucrose. In the field, significantly more female An. gambiae sensu lato mosquitoes were attracted to the Mbita blend augmented with CO2 produced by fermenting 500 g of molasses compared to 250 g of sucrose or 250 g of molasses. Similarly, significantly more An. funestus, Culex and other anopheline mosquito species were attracted to the Mbita blend augmented with CO2 produced from fermenting molasses than the Mbita blend with CO2 produced from sucrose. Augmenting the Mbita blend with CO2 produced from molasses was associated with high catches of blood-fed An. gambiae s.l. and An. funestus mosquitoes. CONCLUSION: Molasses is a suitable ingredient for the replacement of sucrose as a substrate for the production of CO2 for sampling of African malaria vectors and other mosquito species. The finding of blood-fed malaria vectors in traps baited with the Mbita blend and CO2 derived from molasses provides a unique opportunity for the study of host-vector interactions. PMID- 24767544 TI - De novo genome assembly of the soil-borne fungus and tomato pathogen Pyrenochaeta lycopersici. AB - BACKGROUND: Pyrenochaeta lycopersici is a soil-dwelling ascomycete pathogen that causes corky root rot disease in tomato (Solanum lycopersicum) and other Solanaceous crops, reducing fruit yields by up to 75%. Fungal pathogens that infect roots receive less attention than those infecting the aerial parts of crops despite their significant impact on plant growth and fruit production. RESULTS: We assembled a 54.9Mb P. lycopersici draft genome sequence based on Illumina short reads, and annotated approximately 17,000 genes. The P. lycopersici genome is closely related to hemibiotrophs and necrotrophs, in agreement with the phenotypic characteristics of the fungus and its lifestyle. Several gene families related to host-pathogen interactions are strongly represented, including those responsible for nutrient absorption, the detoxification of fungicides and plant cell wall degradation, the latter confirming that much of the genome is devoted to the pathogenic activity of the fungus. We did not find a MAT gene, which is consistent with the classification of P. lycopersici as an imperfect fungus, but we observed a significant expansion of the gene families associated with heterokaryon incompatibility (HI). CONCLUSIONS: The P. lycopersici draft genome sequence provided insight into the molecular and genetic basis of the fungal lifestyle, characterizing previously unknown pathogenic behaviors and defining strategies that allow this asexual fungus to increase genetic diversity and to acquire new pathogenic traits. PMID- 24767546 TI - Gunshot wounds (resulting from execution) of exhumed victims of the communist regime in Poland. AB - This study presents the results of the analysis of the remains of 23 executed male individuals aged between 21 and 63 years, recovered from Osobowicki Cemetery in Wroclaw (Poland), field 83B, in 2012. In 1948 and 1949, prisoners sentenced to death by firing squad--most of them associated with the post-war anti-communist underground independence movement in Poland--were buried there. The aim of the study was to analyse fatal wounds and the method of execution, and to compare the results to data from archival documents. The results were also compared with studies concerning executions during a later period, i.e. 1949-1954. The research on the method of execution during this period of history carried out during the exhumations in Osobowicki Cemetery was the first conducted on such a scale in Poland. Forensic analysis revealed a wide variety of gunshot wounds inflicted during executions, revealing both gunshots to the head, especially single shots to the back of the head, and cases corresponding to the use of a firing squad, probably equipped with machine guns. The results of the research indicate that capital punishment by shooting was carried out in ways both similar to those the specified in the regulations and completely different. PMID- 24767547 TI - Distribution of cortical granules and meiotic maturation of canine oocytes in bi phasic systems. AB - The aim of this study was to evaluate the influence of different bi-phasic systems with gonadotrophins and steroids on in vitro maturation rates of oocytes obtained from bitches at different reproductive stages (follicular, luteal, anoestrous). In System A (control) oocytes were matured for 72h in base medium (BM) with 10IUmL(-1) human chorionic gonadotrophin (hCG), 1MUgmL(-1) progesterone (P4) and 1MUgmL(-1) oestradiol (E2); in bi-phasic System B oocytes were matured for 48h in BM with hCG and for 24h in BM with P4; in bi-phasic System C oocytes were matured for 48h in BM with hCG, P4 and E2, and for 24h in BM with P4; in System D, oocytes were cultured in BM without hormonal supplementation. Data were analysed by ANOVA. There was a positive effect of the bi-phasic systems on germinal vesicle breakdown, metaphase I and metaphase II rates, irrespective of reproductive status (P<0.05). Bi-phasic systems were also beneficial for cortical granule distribution (an indication of cytoplasmic maturation) and its relationship to nuclear status: 74.5% of the oocytes cultured in System B and 85.4% of those cultured in System C presented both nuclear and cytoplasmic maturation (P<0.001). The stage of the oestrous cycle did not influence maturation rates. PMID- 24767545 TI - Optic nerve crush induces spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice. AB - BACKGROUND: Central nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets. RESULTS: Only 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (>=1.5, <=-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR. CONCLUSION: A number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure. PMID- 24767548 TI - Improved prefrontal activity in AD/HD children treated with atomoxetine: a NIRS study. AB - BACKGROUND/AIMS: Atomoxetine (ATX), a selective norepinephrine reuptake inhibitor, is the first approved non-stimulant drug for treatment of attention deficit/hyperactivity disorder (AD/HD). The present study examined the effects of long-term treatment with ATX on prefrontal hemodynamic activity in AD/HD children during a continuous performance task (CPT) using near-infrared spectroscopy (NIRS). METHODS: Prefrontal hemodynamic activity was measured in 12 children with AD/HD during experimental sessions conducted before and 6 months or more after starting ATX treatment. The average maintenance dose of ATX was 1.6 mg/kg/day. Fourteen age-matched typically developing children participated as a control group. RESULTS: In the control group, the CPT induced a significant increase in oxygenated hemoglobin (oxy-Hb) concentration in the bilateral dorsolateral prefrontal cortex (DLPFC). In the AD/HD group in the pre-ATX condition, the CPT did not induce a significant increase in oxy-Hb concentration in any of the NIRS channels, but induced a significant decrease in oxy-Hb concentration in the left ventrolateral prefrontal cortex (VLPFC). In the AD/HD group in the post-ATX condition, significant activation was observed in the right DLPFC and the decrease in oxy-Hb concentration in the left VLPFC disappeared. CONCLUSIONS: These results suggest that long-term treatment with ATX improved prefrontal hemodynamic activity in AD/HD children, and NIRS may be useful for assessment of the prefrontal hemodynamic response to ATX treatment. PMID- 24767549 TI - Exhaled breath profiling for diagnosing acute respiratory distress syndrome. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) is a common, devastating complication of critical illness that is characterized by pulmonary injury and inflammation. The clinical diagnosis may be improved by means of objective biological markers. Electronic nose (eNose) technology can rapidly and non-invasively provide breath prints, which are profiles of volatile metabolites in the exhaled breath. We hypothesized that breath prints could facilitate accurate diagnosis of ARDS in intubated and ventilated intensive care unit (ICU) patients. METHODS: Prospective single-center cohort study with training and temporal external validation cohort. Breath of newly intubated and mechanically ventilated ICU-patients was analyzed using an electronic nose within 24 hours after admission. ARDS was diagnosed and classified by the Berlin clinical consensus definition. The eNose was trained to recognize ARDS in a training cohort and the diagnostic performance was evaluated in a temporal external validation cohort. RESULTS: In the training cohort (40 patients with ARDS versus 66 controls) the diagnostic model for ARDS showed a moderate discrimination, with an area under the receiver-operator characteristic curve (AUC-ROC) of 0.72 (95% confidence interval (CI): 0.63-0.82). In the external validation cohort (18 patients with ARDS versus 26 controls) the AUC-ROC was 0.71 [95%-CI: 0.54 - 0.87]. Restricting discrimination to patients with moderate or severe ARDS versus controls resulted in an AUC-ROC of 0.80 [95%-CI: 0.70 - 0.90]. The exhaled breath profile from patients with cardiopulmonary edema and pneumonia was different from that of patients with moderate/severe ARDS. CONCLUSIONS: An electronic nose can rapidly and non-invasively discriminate between patients with and without ARDS with modest accuracy. Diagnostic accuracy increased when only moderate and severe ARDS patients were considered. This implicates that breath analysis may allow for rapid, bedside detection of ARDS, especially if our findings are reproduced using continuous exhaled breath profiling. TRIAL REGISTRATION: NTR2750, registered 11 February 2011. PMID- 24767550 TI - Comparative evaluation of platelet-rich fibrin and mineral trioxide aggregate as pulpotomy agents in permanent teeth with incomplete root development: a randomized controlled trial. AB - INTRODUCTION: The purpose of this study was to evaluate and compare, clinically and radiographically, the effects of platelet-rich fibrin (PRF) and mineral trioxide aggregate (MTA) as pulpotomy agents in permanent teeth with incomplete root development. METHODS: A total number of 70 children requiring pulpotomy in 70 permanent molars with incomplete root development were screened. Sixty-two patients met the inclusion criteria and were enrolled in the study. The patients were randomly allocated equally in 2 treatment groups. MTA pulpotomy was performed in group A (the control group), and PRF pulpotomy was performed in group B (the experimental group). The treated teeth were restored with amalgam followed by stainless steel crowns. Clinical and radiographic evaluations were performed after 6, 12, and 24 months. Thus, the data obtained were blindly analyzed using the chi-square test. RESULTS: There was no significant difference between the 2 groups in terms of clinical and radiologic success. Radiographically, all available cases (53 teeth) showed evidence of root growth and canal narrowing. Complete apical closure was observed in 88.8% in the PRF group (experimental group) and 80.07% of roots in the MTA group (control group), respectively, at 24 months. CONCLUSIONS: PRF could be used as a suitable biological and economic alternative to MTA in pulpotomy procedures of permanent teeth with incomplete root development. PMID- 24767551 TI - Traumatized immature teeth treated with 2 protocols of pulp revascularization. AB - INTRODUCTION: Pulp revascularization may be considered a promising alternative for traumatized necrotic immature teeth. The aim of this study was to evaluate traumatized immature teeth treated with 2 protocols of pulp revascularization. METHODS: Twenty-three teeth of young patients (7-17 years old) with necrotic upper incisors caused by dental trauma were divided into 2 groups; one group was treated with triple antibiotic paste (metronidazole, ciprofloxacin, and minocycline) (TAP) (n = 12), and the other was medicated with combination of calcium hydroxide and 2% chlorhexidine gel (CHP) (n = 11). Patients were treated and followed up for a period from 9-19 months in 2 dental institutions for evaluation of clinical and radiographic data. RESULTS: Most of the teeth were affected by lateral luxation (47.8%). Clinical evaluation in group TAP showed significant reduction in spontaneous pain (P = .01), pain on horizontal percussion (P = .007), and pain on palpation (P = .03), whereas group CHP showed significant reduction in pain on vertical percussion (P = .03). Crown discoloration was observed significantly more in teeth of group TAP (83.3%) (P < .002). On radiographic exam, periapical repair was found in all TAP-treated teeth (P = .03). Similarly, the same findings were found for all teeth treated with CHP with exception of 1 tooth (P = .21). Apical closure was significantly observed in both groups (P < .05). Increase in root length was demonstrated in 5 teeth (41.7%) and 3 teeth (27.3%) of groups TAP and CHP, respectively. Thickening of lateral dentinal walls was observed in 5 teeth of each group. CONCLUSIONS: Revascularization outcomes for traumatized patients treated with the tested protocols presented similar clinical and radiographic data. However, TAP caused esthetic problem leading to tooth discoloration, which can be considered a disadvantage when compared with CHP. PMID- 24767552 TI - Comparison of sealer penetration using the EndoVac irrigation system and conventional needle root canal irrigation. AB - INTRODUCTION: The aim of this study was to compare the effect of the EndoVac irrigation system (SybronEndo, Orange, CA) and conventional endodontic needle irrigation on sealer penetration into dentinal tubules. METHODS: Forty single rooted, recently extracted human maxillary central incisors were randomly divided into 2 groups according to the irrigation technique used: conventional endodontic needle irrigation and EndoVac irrigation. All teeth were instrumented using the ProFile rotary system (Dentsply Maillefer, Ballaigues, Switzerland) and obturated with gutta-percha and AH Plus sealer (Dentsply DeTrey, Konstanz, Germany) labeled with fluorescent dye. Transverse sections at 1, 3, and 5 mm from the root apex were examined using confocal laser scanning microscopy. The total percentage and maximum depth of sealer penetration were then measured. RESULTS: Mann-Whitney test results showed that EndoVac irrigation resulted in a significantly higher percentage of sealer penetration than conventional irrigation at both the 1- and 3-mm levels (P < .05). However, no difference was found at the 5-mm level. The 5 mm sections in each group showed a significantly higher percentage and maximum depth of sealer penetration than did the 1- and 3-mm sections (P < .05). CONCLUSIONS: The EndoVac irrigation system significantly improved the sealer penetration at the 1- to 3-mm level over that of conventional endodontic needle irrigation. PMID- 24767553 TI - Current trends in endodontic treatment by general dental practitioners: report of a United States national survey. AB - INTRODUCTION: In the United States almost 70% of root canal treatment (RCT) is performed by general dentists (GPs), yet little is known about their treatment protocols. METHODS: A paper survey was mailed to 2000 United States GPs with questions about the types of endodontic cases treated, routine treatment protocols, use of newer technologies, and endodontic continuing education (CE). RESULTS: Completed surveys were returned by 479 respondents (24%). GPs who perform RCT (84%) reported providing anterior (99%), bicuspid (95%), and molar (62%) RCT and retreatment (18%). Rubber dam was used always (60%), usually (16%), sometimes (13%), and never (11%). Newer technologies used by GPs included digital radiography (72%), magnification (80%), electronic apex locator (70%), and nickel titanium rotary instrumentation (74%). Compared with GPs with >20 years of experience, those in practice for <=10 years were more likely to use rubber dam (P < .05), nickel-titanium rotary instrumentation (P < .001), apex locators (P < .001), and magnification (P < .01); in contradistinction, GPs in practice >20 years were more likely to perform retreatments (P < .05). Women were less likely to perform retreatment or molar RCT (both P < .05). GPs with >5 hours of CE were more likely to use rotary instrumentation (P < .001), irrigant activation devices (P < .01), and apex locators (P < .001) and perform molar RCT (P < .001) and retreatment (P < .05), but no more likely to use rubber dam. CONCLUSIONS: Recent GP graduates (<=10 years) were more likely to adopt new technologies and use rubber dam than those who practiced for >20 years. More experienced GPs were more likely to take on complicated cases than those with fewer years of practice. There was no association between hours of CE and compliance with rubber dam usage. PMID- 24767554 TI - Clinical comparison of the effectiveness of single-file reciprocating systems and rotary systems for removal of endotoxins and cultivable bacteria from primarily infected root canals. AB - INTRODUCTION: This clinical study was conducted to compare the effectiveness of single-file reciprocating systems and rotary systems in removing endotoxins and cultivable bacteria from primarily infected root canals. METHODS: Forty-eight primarily infected root canals were selected and randomly divided into 4 groups: WaveOne (Dentsply Maillefer, Ballaigues, Switzerland) (n = 12); Reciproc (VDW, Munich, Germany) (n = 12), ProTaper (Dentsply Maillefer) (n = 12), and Mtwo (VDW) (n = 12). Samples were collected before and after chemomechanical preparation. The irrigation was performed by using 2.5% sodium hypochlorite. A chromogenic limulus amebocyte lysate assay test was used to quantify endotoxins. Culture techniques were used to determine bacterial colony-forming unit counts. RESULTS: In the baseline samples (ie, samples collected before chemomechanical preparation), endotoxins and cultivable bacteria were recovered from 100% of the root canal samples. No differences were found in the median percentage values of endotoxin reduction achieved with reciprocating systems (ie, WaveOne [95.15%] and Reciproc [96.21%]) and with rotary systems (ie, ProTaper [97.98%] and Mtwo [96.34%]) (P < .05). Both single-file reciprocating systems (ie, WaveOne [99.45%] and Reciproc [99.93%]) and rotary systems (ProTaper [99.85%] and Mtwo [99.41%]) were effective in reducing the cultivable bacteria (all P < .05). Moreover, the culture analysis revealed no differences in bacterial load reduction (P > .05). CONCLUSIONS: Both single-file reciprocating systems (ie, WaveOne and Reciproc instruments) and rotary systems (ie, ProTaper and Mtwo instruments) showed similar effectiveness in reducing endotoxins and cultivable bacteria from primarily infected root canals, but they were not able to eliminate them from all root canals analyzed. PMID- 24767555 TI - Use of cone-beam computed tomography to evaluate root canal morphology and locate root canal orifices of maxillary second premolars in a Chinese subpopulation. AB - INTRODUCTION: The aim of this study was to investigate root canal morphology and locate root canal orifices of maxillary second premolars in a Chinese subpopulation using cone-beam computed tomographic imaging. METHODS: A total of 392 cone-beam computed tomographic images of maxillary second premolars were obtained from 238 patients who required a preoperative assessment for implant surgery or orthodontic treatment. The number of roots and root canals and root canal configuration were investigated and categorized using Vertucci's criteria. The distance between the root canal orifice and the anatomic apex and the distance between root canal orifices in those teeth with 2 root canals were measured and evaluated. The Fisher exact test was used to analyze the correlation between the number of roots and sex. RESULTS: Among the 392 teeth, 86.5% (n = 339) had 1 root; 45.4% (n = 178) of the teeth had 1 root canal, and 54.3% (n = 213) had 2 root canals that ranged from type II-type V. The majority of teeth with 2 root canals showed a type IV canal configuration (n = 79, 20.2%) followed by type II (n = 64, 16.3%), type III (n = 45, 11.4%), and type V (n = 25, 6.4%). Only 1 tooth had 3 root canals. No significant difference was found between the number of roots and sex (P > .05). Among the 213 teeth with 2 root canals, the most frequent distribution of the distance between the root canal orifice and the anatomic apex was 5-10 mm (n = 157). The distance between the 2 orifices of 189 teeth was 1-4 mm. CONCLUSIONS: The frequency of teeth with 2 root canals was high in maxillary second premolars. The internal morphology of teeth with 2 root canals was variable. This study provided useful information about the root canal morphology of maxillary second premolars in a Chinese subpopulation. PMID- 24767556 TI - Evaluation of root and canal morphology of maxillary permanent first molars in a North American population by cone-beam computed tomography. AB - INTRODUCTION: The purpose of this study was to evaluate the number of roots and canal morphology of maxillary permanent first molars in a North American population. METHODS: Three hundred seventeen cases with bilateral maxillary first molars were included. All images from cone-beam computed tomography were carefully reviewed by 2 endodontists. Frequency of number of roots, presence of an additional mesiobuccal canal (MB2), and Vertucci canal type for each root were tabulated. Age, gender, and ethnicity differences were calculated with the chi(2) test. The intra-rater reliability was assessed by using the Cohen kappa statistic. RESULTS: The fused root rate was 0.9%. The occurrence of 3-rooted maxillary first molars differed between left and right sides (P = .03). MB2 occurrence only showed statistically significant differences among age groups (P = .005). In the mesiobuccal roots, the most common Vertucci classifications of canal types were type IV (2-2, 41.9%), type I (1, 28.3%), and type II (2-1, 26.3%). There was a statistically significant difference in Vertucci classification of canal type among 5 ethnic groups (African American, Asian, Hispanic, Other, and Non-Hispanic white, P < .001). CONCLUSIONS: Cone-beam computed tomography facilitates the identification of root and canal configuration. The information gained about the tooth anatomy and canal morphology before treatment could potentially facilitate root canal therapy. PMID- 24767557 TI - Mineral trioxide aggregate promotes the odonto/osteogenic differentiation and dentinogenesis of stem cells from apical papilla via nuclear factor kappa B signaling pathway. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) has been widely used in clinical apexification and apexogenesis. However, the effects of MTA on the stem cells from apical papilla (SCAPs) and the precise mechanism of apexogenesis have not been elucidated in detail. METHODS: Multiple colony-derived stem cells were isolated from the apical papillae, and the effects of MTA on the proliferation and differentiation of SCAPs were investigated both in vitro and in vivo. Activation of nuclear factor kappa B (NFkappaB) pathway in MTA-treated SCAPs was analyzed by immunofluorescence assay and Western blot. RESULTS: MTA at the concentration of 2 mg/mL did not affect the proliferation activity of SCAPs. However, 2 mg/mL MTA-treated SCAPs presented the ultrastructural changes, up regulated alkaline phosphatase, increased calcium deposition, up-regulated expression of odontoblast markers (dentin sialoprotein and dentin sialophosphoprotein) and odonto/osteoblast markers (runt-related transcription factor 2 and osteocalcin), suggesting that MTA enhanced the odonto/osteoblastic differentiation of SCAPs in vitro. In vivo results confirmed that MTA can promote the regular dentinogenesis of SCAPs. Moreover, MTA-treated SCAPs exhibited the up regulated cytoplasmic phos-IkappaBalpha and phos-P65, enhanced nuclear P65, and increased nuclear translocation of P65. When co-treated with BMS345541 (the specific NFkappaB inhibitor), MTA-mediated odonto/osteoblastic differentiation was significantly attenuated. CONCLUSIONS: MTA at the concentration of 2 mg/mL can improve the odonto/osteogenic capacity of SCAPs via the activation of NFkappaB pathway. PMID- 24767558 TI - Effect of endodontic cement on bone mineral density using serial dual-energy x ray absorptiometry. AB - INTRODUCTION: Materials with new compositions were tested in order to develop dental materials with better properties. Calcium silicate-based cements, including white mineral trioxide aggregate (WMTA), may improve osteopromotion because of their composition. Nano-modified cements may help researchers produce ideal root-end filling materials. Serial dual-energy x-ray absorptiometry measurement was used to evaluate the effects of particle size and the addition of tricalcium aluminate (C3A) to a type of mineral trioxide aggregate-based cement on bone mineral density and the surrounding tissues in the mandible of rabbits. METHODS: Forty mature male rabbits (N = 40) were anesthetized, and a bone defect measuring 7 * 1 * 1 mm was created on the semimandible. The rabbits were divided into 2 groups, which were subdivided into 5 subgroups with 4 animals each based on the defect filled by the following: Nano-WMTA (patent application #13/211.880), WMTA (as standard), WMTA without C3A, Nano-WMTA + 2% Nano-C3A (Fujindonjnan Industrial Co, Ltd, Fujindonjnan Xiamen, China), and a control group. Twenty and forty days postoperatively, the animals were sacrificed, and the semimandibles were removed for DXA measurement. RESULTS: The Kruskal-Wallis test followed by the Mann-Whitney U test showed significant differences between the groups at a significance level of P < .05. P values calculated by the Kruskal Wallis test were .002 for bone mineral density at both intervals and P20 day = .004 and P40 day = .005 for bone mineral content. CONCLUSIONS: This study showed that bone regeneration was enhanced by reducing the particle size (nano-modified) and C3A mixture. This may relate to the existence of an external supply of minerals and a larger surface area of nano-modified material, which may lead to faster release rate of Ca(2+), inducing bone formation. Adding Nano-C3A to Nano WMTA may improve bone regeneration properties. PMID- 24767559 TI - Tooth storage, dental pulp stem cell isolation, and clinical scale expansion without animal serum. AB - INTRODUCTION: Dental pulp stem cells (DPSCs) have therapeutic potential for dentin and dental pulp regeneration. For regenerative approaches to gain clinical acceptance, protocols are needed to determine feasible ways to store teeth, isolate DPSCs, and expand them to clinical scale numbers. METHODS: In this study, 32 third molars were obtained from patients and immediately placed in saline or tissue culture medium followed by overnight storage at 4 degrees C or immediate isolation of DPSCs. Upon isolation, cells were expanded in medium containing either fetal bovine serum (FBS) or human serum (HS). Cell proliferation (population doubling time [PDT]), cell surface marker expression, and multipotency were compared between DPSCs in FBS and DPSCs in HS. RESULTS: The time frame of storage and storage medium did not affect the ability to isolate DPSCs. However, using HS instead of FBS in the initial isolation of DPSCs significantly decreased (P < .01) the isolation success rate from 89% (FBS) to 23% (HS). Yet, incorporating fibronectin in the DPSC initial isolation (using HS) significantly (P < .01) increased the isolation success rate to 83%. Interestingly, it was found that the proliferation rate was significantly (P < .05) higher for DPSCs in HS (PDT = 1.59 +/- 0.46) than that for DPSCs in FBS (PDT = 2.84 +/- 2.5). Finally, there was no difference in the expression of CD73, CD90, CD105, or multipotency (as measured by osteogenic, adipogenic, and chondrogenic differentiation) between DPSCs in FBS and DPSCs in HS. CONCLUSIONS: These findings show a clinically feasible method of storing third molars for the isolation of DPSCs. Additionally, DPSCs can be isolated and expanded to clinical scale numbers in media devoid of FBS and still maintain their phenotypic properties. PMID- 24767561 TI - Histologic and micro-computed tomographic analyses of replanted teeth stored in different kind of media. AB - INTRODUCTION: Coconut water (CW) and soy milk (SM) have been proposed as storage media for avulsed teeth because of their nutrients that preserve cell viability. The present study investigated the periodontal healing process of dog teeth replanted after storage in CW, SM, and whole milk (WM) using micro-computed tomographic (MUCT) and histologic analyses compared with immediate tooth replantation. METHODS: Forty roots of 10 adult beagle dogs were extracted and subjected to the following protocols: immediate replantation after extraction (control), stored in CW with an adjusted pH, and SM and WM for 50 minutes before replantation. The animals were euthanized 28 days postoperatively, and the obtained specimens were scanned using a MUCT scanner and subjected to routine processing for histometric analyses under an optical microscope. RESULTS: CW and SM performed similarly to WM; however, SM showed significantly higher ankylosis than the control group. CONCLUSIONS: Additionally, this study showed that the combined use of histologic analysis and MUCT is a promising method to better identify tooth resorption and the repair process and to evaluate the total extension of the periodontium. CW as a storage medium is a promising transport media for avulsed teeth. PMID- 24767560 TI - MMP9 deficiency increased the size of experimentally induced apical periodontitis. AB - INTRODUCTION: Apical periodontitis is an inflammation and destruction of periapical tissues. Matrix metalloproteinase-9 (MMP-9) is thought to be involved in periapical lesion formation and progression. The aim of this study was to evaluate the lesion progression in MMP-9 knockout (KO) mice compared with that in control mice (wild type [WT]). METHODS: The pulps of mouse mandibular first molars were exposed; animals were killed at 0, 7, 14, 21, and 28 days after surgery. Hematoxylin-eosin-stained sections were observed for the description of pulpal, apical, periapical features, and the periapical lesion size. The periapical lesion size was further measured with micro-computed tomographic imaging. The number of osteoclasts was also counted by tartrate-resistant acid phosphatase histoenzymology. Real-time polymerase chain reaction and immunohistochemistry were used to analyze the expression levels of receptor activator of NF-kappaB (RANK), receptor activator of NF-kappaB ligand (RANKL), osteoprotegerin (OPG), interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), MMP-2, and MMP-8. RESULTS: There was a significant difference (P < .05) between the 2 types of animals regarding the periapical lesion size, which was larger in MMP-9 KO animals. No significant differences (P > .05) were found between WT and MMP-9 KO mice related to the osteoclast number as well as the pulpal, apical, and periapical features. More neutrophil cells were observed in MMP-9 KO animals than WT mice (P < .05). The expression levels of RANK, RANKL, OPG, IL-1beta, TNF-alpha, MMP-2, and MMP-8 were found up-regulated in MMP-9 KO mice (P < .05). CONCLUSIONS: MMP-9 KO animals developed larger periapical lesions with greater inflammatory response, indicating an important role of MMP-9 in the host's immune and inflammatory response to root canal and periradicular infection. PMID- 24767562 TI - New bacterial composition in primary and persistent/secondary endodontic infections with respect to clinical and radiographic findings. AB - INTRODUCTION: The aim of the present study was to analyze the microbiota of primary and secondary/persistent endodontic infections of patients undergoing endodontic treatment with respect to clinical and radiographic findings. METHODS: Samples from the root canals of 21 German patients were taken using 3 sequential sterile paper points. In the case of a root canal filling, gutta-percha was removed with sterile files, and samples were taken using sterile paper points. The samples were plated, and microorganisms were then isolated and identified morphologically by biochemical analysis and sequencing the 16S rRNA genes of isolated microorganisms. RESULTS: In 12 of 21 root canals, 33 different species could be isolated. Six (50%) of the cases with isolated microorganisms were primary, and 6 (50%) cases were endodontic infections associated with root-filled teeth. Twelve of the isolated species were facultative anaerobic and 21 obligate anaerobic. Monomicrobial infections were found for Enterococcus faecalis and Actinomyces viscosus. E. faecalis was most frequently isolated in secondary endodontic infections (33%). Moraxella osloensis was isolated from a secondary endodontic infection that had an insufficient root canal filling accompanied by a mild sensation of pain. A new bacterial composition compromising Atopobium rimae, Anaerococcus prevotii, Pseudoramibacter alactolyticus, Dialister invisus, and Fusobacterium nucleatum was recovered from teeth with chronic apical abscesses. CONCLUSIONS: New bacterial combinations were found and correlated to clinical and radiographic findings, particularly to chronic apical abscesses. M. osloensis was detected in root canals for the second time and only in German patients. PMID- 24767563 TI - Intracanal delivery of Resolvin E1 controls inflammation in necrotic immature rat teeth. AB - INTRODUCTION: Pulp necrosis in immature teeth and the resulting periodontal apical inflammation negatively affect root formation. Resolvin E1 (RvE1) is a lipid-derived endogenous pro-resolution molecule that controls inflammation. The aim of this investigation was to evaluate the impact of RvE1 applied as an intracanal medication on root formation in nonvital immature teeth. METHODS: To arrest root development, pulpectomy was performed in the lower first molars of 4 week-old Wistar rats. After 3 weeks, irrigation with 2.5% sodium hypochlorite and 0.9% sterile saline was performed, and either a triple antibiotic paste (TAP) or RvE1 in saline was applied into the root canals. In the control group, access openings drilled into molars were left exposed to the oral environment. Root development and periapical repair were evaluated radiographically and histologically at 3 and 6 weeks after treatment. RESULTS: RvE1 reduced periapical lesion size compared with the control at 3 weeks, which was similar to TAP. Inflammatory response in the RvE1-treated group was markedly reduced compared with both TAP and control specimens. At 6 weeks, root development was observed in both groups, but RvE1 treatment produced less cellularity with more regular calcified tissue deposition. CONCLUSIONS: RvE1 and TAP had a positive impact on reducing inflammation and promoting root formation. RvE1 was more effective in reducing inflammation at earlier stages. RvE1 has potential to be used as root canal dressing to control inflammation in endodontically compromised teeth before complete root formation. Stability of RvE1 within the root canal and its delivery are issues to be addressed before its clinical use. PMID- 24767564 TI - Direct effect of endodontic sealers on trigeminal neuronal activity. AB - INTRODUCTION: Endodontic sealers are selected on the basis of their antimicrobial properties and ability to provide a tight seal. Sealer extrusions, whether intentional or unintentional, are common during obturation procedures. Such events have been correlated with increased postoperative discomfort and persistent pain states. However, the mechanisms underlying this phenomenon are largely unknown. Thus, we sought to evaluate the effect of commonly used endodontic sealers on peripheral nociceptors. We hypothesized that endodontic sealers can directly activate trigeminal nociceptors in a concentration-dependent manner, resulting in release of calcitonin gene-related peptide (CGRP), a potent modulator of neurogenic inflammation. METHODS: Rat trigeminal sensory neurons were exposed in vitro to vehicle, zinc oxide-eugenol (ZOE)-based sealer, AH Plus, EndoSequence BC sealer, or RealSeal SE. Neuronal activation was measured by quantification of neuropeptide (CGRP) release. In addition, cultured neurons were also subjected to the set form of all 4 sealers. The concentration of CGRP released was quantified by using a radioimmunoassay. Data were analyzed by using one-way analysis of variance with Newman-Keuls multiple comparison post hoc test. RESULTS: Both ZOE-based sealer and AH Plus in their fresh form evoked greater CGRP release than the control groups. Conversely, EndoSequence BC and RealSeal sealers both reduced basal GCRP release at all concentrations tested. Evaluation of the set sealers revealed that only ZOE-based sealer evoked significant CGRP release compared with its control group. CONCLUSIONS: Overall, our results suggest that sealers can directly activate trigeminal nociceptors, leading to a robust release of CGRP, and may therefore lead to pain and neurogenic inflammation. This direct activation along with the immunologic response may underlie the symptoms and flare-up occurrences often seen with sealer extrusions. PMID- 24767565 TI - Apical root canal transportation and remaining dentin thickness associated with ProTaper Universal with and without PathFile. AB - INTRODUCTION: This study aimed to compare, using digital subtraction radiography, apical transportation in mesiobuccal root canals of extracted human maxillary molars instrumented with ProTaper Universal F3 and F4 files (Dentsply Maillefer, Ballaigues, Switzerland) with and without the prior creation of glide paths using the PathFile system and to compare, using cone-beam computed tomographic imaging, remaining dentin thickness (RDT) after complete preparation. METHODS: Forty mesiobuccal roots with curvatures of 20 degrees -35 degrees were used. In group A, glide paths were created with PathFile #1, #2, and #3 to the working length; in group B, no glide paths were used. All canals were instrumented up to F4 to the working length. Digital subtraction radiographic images were obtained in buccolingual and mesiodistal directions. Apical transportation associated with F3 or F4 was calculated based on the difference between the tip of the first and the last instrument analyzed in each group. RDT was calculated based on cone-beam computed tomographic images. RESULTS: Apical transportation was higher after F4 regardless of the use of the PathFile system. No statistically significant differences between groups A and B were observed in apical transportation after instrumentation with F3 or F4 (P > .05). Group A showed greater RDT values at 2 (buccal and mesial walls, P < .05) and 3 mm (buccal and distal walls, P < .05) from the apex but not at 1 mm. CONCLUSIONS: The use of the PathFile system before root canal preparation with ProTaper Universal F3 and F4 did not influence apical transportation but was associated with greater RDTs at 2 and 3 mm from the apex. PMID- 24767566 TI - Accuracy and reliability of working length determination by Gold Reciproc Motor in reciprocating movement. AB - INTRODUCTION: The purpose of this study was to assess the accuracy and reliability of the apex locator function of the Gold Reciproc Motor (VDW GmbH, Munich, Germany) during reciprocating movement. METHODS: Forty extracted incisors with mature apices were included in the study. The canal length was determined by introducing #10 file into the canal until it emerged at the apical foramen. The incisal edge of each tooth was adjusted to obtain 18 mm standard length and to produce a flat reference point. The teeth were embedded in Plexiglas tubes filled with alginate and measured by Root ZX (J. Morita Corp, Tokyo, Japan) and Bingo 1020 (Forum Engineering Technologies, Rishon Lezion, Israel) apex locators. The root canals were instrumented in a reciprocating mode using an R25 Reciproc file in the Gold Reciproc Motor until the green LEDs and orange LED were reached. According to the manufacturer, these LEDs represent the zone between the apical constriction and the apical foramen. RESULTS: No statistically significant differences were found between the length measurements of the 2 electronic apex locators and the third green LED, which is suggested by the manufacturers as the recommended working length. CONCLUSIONS: With the limitation of this ex vivo study, the Gold Reciproc Motor's integrated electronic apex locator was found to be as reliable and accurate as the Root ZX and Bingo 1020 apex locators in terms of length control during root canal preparation in the reciprocation mode. PMID- 24767567 TI - Analysis of the width of vertical root fracture in endodontically treated teeth by 2 micro-computed tomography systems. AB - INTRODUCTION: Early detection of vertical root fracture (VRF) is important for clinical endodontic practice. The purpose of this study was to measure the fracture width (distance between 2 sides of the fracture) of VRF teeth in vitro by using 2 micro-computed tomography (MU-CT) systems with different spatial resolution and voxel size. METHODS: Thirty-seven endodontically treated teeth with VRF were scanned by 80-MUm pixel size MU-CT. Fifteen teeth with no obvious fracture line, blurred image, or fracture space less than 100 MUm were scanned by 9-MUm pixel size MU-CT. RESULTS: Presence of 2 VRF lines was more common in premolars (82%) than in molars (53%). In 7 premolars (32%) and 9 molars (60%), the VRF lines extended to within the apical 3 mm of the root. All fracture lines were detected by 9-MUm pixel size MU-CT, but only 22 of 37 VRF teeth had vertical fracture identified by 80-MUm MU-CT. From MU-CT examination, none of the fracture lines showed consistent and uniform fracture space. If 2 fracture lines were present, they were typically in opposite (not linear) directions. There was a significant correlation between 2 fracture lines or fracture lines extending within the 3 mm of the apex and fracture width greater than 100 MUm. CONCLUSIONS: Application of 9-MUm MU-CT can be accurately used for early detection of VRF. Fracture characteristics (eg, number of fracture lines, extension of fracture line) may affect the fracture width. Appropriate use of MU-CT technology can be helpful for early diagnosis of VRF. PMID- 24767568 TI - Bioactive chitosan nanoparticles and photodynamic therapy inhibit collagen degradation in vitro. AB - INTRODUCTION: Collagen is the major structural protein of human dentin. Degradation of collagen by bacterial enzymes can facilitate microbial penetration, compromise structural/interfacial integrity, and lower resistance to fracture of dentin. We evaluated the ability of photodynamic therapy (PDT), bioactive chitosan nanoparticles (CSnp), or PDT in combination with CSnp to inhibit bacterial collagenase-mediated degradation of collagen. METHODS: Rat type 1 fibrillar collagen matrices were untreated or treated with 2.5% glutaraldehyde (GD), 2.5% GD followed by 1% CSnp, 1% CSnp, PDT (rose bengal activated with 540 nm light at 40 J/cm(2)), or 1% CSnp followed by PDT. Samples, except those used as untreated controls, were exposed to Clostridium histolyticum collagenase (125 CDU/mL) for 24 hours. The soluble digestion products were assessed by hydroxyproline assay, and the remaining adherent collagen was quantified by picrosirius red staining. Fourier transform infrared spectroscopy, immunoblotting, and scanning electron microscopy were used to study the interaction between CSnp/PDT with type 1 collagen. The data were analyzed by 1 way analysis of variance and post hoc Tukey test. RESULTS: As assessed by hydroxyproline release into the medium, collagen treated with CSnp, PDT, or a combination of CSnp and PDT exhibited less degradation than untreated controls (3.6-fold, 1.7-fold, and 7.9-fold reduction, respectively; P < .05). Compared with all other treatments, GD-treated collagen was the most resistant to collagenolytic degradation (239.6-fold reduction, P < .05). The abundance of post treatment residual collagen, as measured by picrosirius red staining, was inversely related to the extent of collagen degradation. Analysis of collagen cross-links with Fourier transform infrared spectroscopy showed that PDT or GD treatments enhanced collagen cross-linking. Immunoblotting of sedimented CSnp indicated that CSnp and collagenase bound with low affinity. However, CSnp-bound collagenase showed a significant reduction in collagenolytic activity compared with controls (P < .05). CONCLUSIONS: Combined photochemical cross-linking of rat tail collagen by PDT and binding to CSnp inhibit collagenolytic activity. PMID- 24767569 TI - Micro-computed tomographic analysis of the root canal morphology of mandibular incisors. AB - INTRODUCTION: This study aimed to describe the anatomy of mandibular central and lateral incisors using micro-computed tomographic imaging. METHODS: One hundred mandibular incisors were scanned in a micro-computed tomographic device using an isotropic resolution of 22.9 MUm. The anatomy of each tooth (length of the roots, presence and location of accessory canals and apical deltas, and number of canals) as well as the 2- and 3-dimensional morphologic aspects of the canal (area, roundness, diameter, volume, surface area, and structure model index) were evaluated. Data were statistically compared using the Student t test (alpha = 0.05). RESULTS: The mean lengths of the mandibular central and lateral incisors were 20.71 and 21.56 mm, respectively. Most of the central (60%) and lateral (74%) incisors had no accessory canals. An apical delta was observed in only 1 specimen. The cross-section analysis of the apical third showed the presence of 1, 2, or 3 canal orifices. No statistical difference was observed in the comparison of the 2- and 3-dimensional morphologic parameters between central and lateral incisors (P < .05). The qualitative analyses of the 3-dimensional models of the root canal systems of the central and lateral incisor teeth confirm that the most prevalent configurations were Vertucci's types I (50% and 62%, respectively) and III (28%). CONCLUSIONS: Overall, mandibular central and lateral incisors were similar in terms of the 2- and 3-dimensional analyzed parameters. Vertucci's types I and III were the most prevalent canal configurations of the mandibular incisors; however, 8 new types have also been described. PMID- 24767570 TI - Influence of single-file endodontics on apical transportation in curved root canals: an ex vivo micro-computed tomographic study. AB - INTRODUCTION: More information regarding the ability of single files to maintain the original canal position is required before adopting a single-file approach to cleaning and shaping. This study compares apical transportation in curved root canals when instrumenting with a single WaveOne (WO) file (Dentsply Tulsa Dental Specialties, Tulsa, OK) in a reciprocating motion with that incurred when using a sequence of Twisted Files (TFs; SybronEndo, Orange, CA) in a continuous rotating motion. METHODS: Forty mesial canals of mandibular molars were evenly allocated into 2 balanced groups (n = 20) with a 17-mm average canal length and 20 degrees average curvature. Canals were accessed in a conventional manner and instrumentation was completed with a single WO file or a series of TFs. The canals were instrumented according to the manufacturers' protocol. Apical transportation was assessed on a comparison of the pre- and postinstrumentation micro-computed tomographic scans at 1-, 2-, 3-, 4-, and 5-mm sections. One-way analysis of variance was performed to assess if a significant difference between systems exists. RESULTS: No significant difference (P > .05) was found between the WO and TF groups. Transportation in the mesial direction was of greater magnitude than distal transportation for both files systems. The mean transportation in the mesial direction was 100.1 +/- 8.8 MUm (WO group) and 101.0 +/- 10.9 MUm (TF group) (P = .5), whereas distal transportation was found to be 80.9 +/- 14.6 MUm (WO group) and 60.3 +/- 11.0 MUm (TF group) (P = .3). CONCLUSIONS: The results suggest that no difference exists between the WO file system and the conventional multifile TF system when considering apical transportation in curved canals. PMID- 24767571 TI - Shrinkage of backfill gutta-percha upon cooling. AB - INTRODUCTION: The temperature and related shrinking kinetics of gutta-percha injected from heat guns are not known; therefore, we investigated them in this study. METHODS: The temperatures of 3 different backfill gutta-percha brands extruded from 3 commercially available heat guns set to 200 degrees C were studied. To validate the results, temperature development of 1 gutta-percha brand injected from a heat gun during a simulated backfilling procedure was assessed in single-rooted human teeth containing thermocouples in a water bath of 37 degrees C. These values were compared with the counterparts obtained in a tabletop testing device for shrinkage at an ambient temperature of 37 degrees C. Using this device, linear shrinkage upon cooling was assessed for all 3 gutta-percha brands under investigation. Results were compared by parametric statistics (alpha = .05). RESULTS: The temperatures of extruded gutta-percha differed significantly (P < .05) between heat guns and gutta-percha brands. Mean temperatures ranging between 57.6 degrees +/- 4.5 degrees C and 103.9 degrees +/- 7.8 degrees C could be observed with different combinations. The temperature of extruded gutta percha in tabletop experiments equaled that observed in the root canals. However, the cooling of gutta-percha was (P < .05) faster in the tabletop measuring device compared with the root canal environment. Within the controlled temperature drop from 75 degrees C to 37 degrees C, the total shrinkage differed significantly (P < .05) between the 3 gutta-percha brands under investigation and ranged between 0.96% +/- 0.20% and 2.31% +/- 0.26% after 10 minutes (P < .05). Shrinking kinetics showed different patterns between the gutta-percha brands. CONCLUSIONS: Gutta-percha designed for thermoplastic application shrinks quickly and extensively upon cooling. PMID- 24767572 TI - Management of 2 teeth diagnosed with dens invaginatus with regenerative endodontics and apexification in the same patient: a case report and review. AB - INTRODUCTION: This review and case report present the treatment of a 10-year-old boy with both permanent maxillary lateral incisors demonstrating Oehlers type II dens invaginatus and pulpal involvement. Treatment was complicated by dental anxiety, supraventricular tachycardia, immature tooth development, and facial cellulitis. METHODS: An infected necrotic pulp of the permanent maxillary left lateral incisor was treated by apexification and endodontic treatment with mineral trioxide aggregate. The necrotic pulp of the permanent maxillary right lateral incisor was treated with canal debridement and dressing under general anesthesia. RESULTS: Periapical healing of both teeth occurred, with the right lateral incisor showing continued root growth, thickening of the dentinal root walls, and completed apex formation. This tooth responded normally to pulp testing. Twenty-eight months after initial treatment, the right lateral incisor displayed progressive sclerosis of the canal. CONCLUSIONS: This case demonstrates possible pulpal regeneration of an infected maxillary right lateral incisor with dens invaginatus and an immature apex after minimal canal debridement. PMID- 24767573 TI - How Italian hospital Web sites communicate risk management strategies: the case of hospital-acquired infections. AB - We aimed to investigate the Web site contents of Italian National Health System structures regarding health care-associated infection (HAI). For each Web site a form inquiring about the availability of information about HAI issues and their prevention was filled in. An HAI section was available in the Web site of 19.3% of facilities. In 1.6% of Web sites this information was available on the homepage. The most frequently reported information was related to infection control practitioners, HAI surveillance systems, and handwashing hygiene. In conclusion, the communication of risks related to clinical practice should be part of risk management systems and should assume a significant position in content strategy activities. PMID- 24767574 TI - Assessing the thoroughness of hand hygiene: "seeing is believing". AB - The thoroughness of hand hygiene (HH) was evaluated using a simulation method in which health care workers (HCWs) rubbed their hands with a fluorescent substance, washed with water, and placed their hands under an ultraviolet detector to identify areas missed. Most residue points were located in the tips of the nails (38.6%), followed by fingertips (17.4%). This stress-free "seeing is believing" program can encourage HCWs' active participation in sustaining the HH culture of health care institutions. PMID- 24767576 TI - Systematic review and meta-analysis of the duration of clinical effect of onabotulinumtoxinA in cervical dystonia. AB - BACKGROUND: Botulinum toxins are considered first-line therapy for treatment of cervical dystonia (CD) and must be injected on a repeat basis. Understanding the duration of clinical benefit of botulinum toxins and its impact on health care utilization are thus important in the contemporary environment. However, there is currently no overall consensus on the duration of effect of onabotulinumtoxinA in the treatment of CD. We performed a systematic review and meta-analysis to identify the duration of effect of onabotulinumtoxinA in CD and investigate factors that may influence it. METHODS: A systematic literature search identified prospective or retrospective studies reporting duration of effect of onabotulinumtoxinA for the treatment of CD. Inclusion criteria included peer reviewed, non-review, English-language articles published between January 1980 and January 2013. A formal meta-analysis using Comprehensive Meta-Analysis Version 2 was conducted to identify the duration of effect of onabotulinumtoxinA in the treatment of CD; both fixed and random effects models were performed. Subgroup analyses were performed to identify factors that influenced the duration of effect of onabotulinumtoxinA. RESULTS: A total of 18 studies (including >1,900 patients) met the inclusion criteria and were used for the meta-analysis. The mean duration of effect of onabotulinumtoxinA in CD was found to be 93.2 days (95% CI 91.8-94.6 days) for the fixed effects model and 95.2 days (95% CI 88.9 101.4 days) for the random effects model. A meta-regression found that dose of onabotulinumtoxinA and country of origin influenced the duration of effect of onabotulinumtoxinA, whereas quality score of the article and study type did not. In particular, doses >=180 Units were associated with longer durations of effect than doses <180 Units (107-109 days vs. 86-88 days, respectively; p < 0.01). Limitations included pooling studies that used discrete definitions of duration and had different designs and study quality. CONCLUSIONS: Based on the published literature, the mean duration of effect of onabotulinumtoxinA in CD was 93-95 days (13.2-13.5 weeks). This suggests that, in general, patients with CD treated with onabotulinumtoxinA should require ~4 treatments per year. PMID- 24767575 TI - Preoperative inspiratory muscle training to prevent postoperative pulmonary complications in patients undergoing esophageal resection (PREPARE study): study protocol for a randomized controlled trial. AB - BACKGROUND: Esophageal resection is associated with a high incidence of postoperative pneumonia. Respiratory complications account for almost half of the readmissions to the critical care unit. Postoperative complications can result in prolonged hospital stay and consequently increase healthcare costs. In cardiac surgery a preoperative inspiratory muscle training program has shown to prevent postoperative pneumonia and reduce length of hospital stay. While in some surgical centers inspiratory muscle training is already used in the preoperative phase in patients undergoing esophageal resection, the added value of this intervention on the reduction of pulmonary complications has not yet been investigated in large surgical populations other than cardiac surgery in a randomized and controlled study design. METHODS/DESIGN: The effect of a preoperative inspiratory muscle training program on the incidence of postoperative pneumonia in patients undergoing esophageal resection will be studied in a single blind multicenter randomized controlled trial (the PREPARE study). In total 248 patients (age >18 years) undergoing esophageal resection for esophageal cancer will be included in this study. They are randomized to either usual care or usual care with an additional inspiratory muscle training intervention according to a high-intensity protocol which is performed with a tapered flow resistive inspiratory loading device. Patients have to complete 30 dynamic inspiratory efforts twice daily for 7 days a week until surgery with a minimum of 2 weeks. The starting training load will be aimed to be 60% of maximal inspiratory pressure and will be increased based on the rate of perceived exertion.The main study endpoint is the incidence of postoperative pneumonia. Secondary objectives are to evaluate the effect of preoperative inspiratory muscle training on length of hospital stay, duration of mechanical ventilation, incidence of other postoperative (pulmonary) complications, quality of life, and on postoperative respiratory muscle function and lung function. DISCUSSION: The PREPARE study is the first multicenter randomized controlled trial to evaluate the hypothesis that preoperative inspiratory muscle training leads to decreased pulmonary complications in patients undergoing esophageal resection. TRIAL REGISTRATION: NCT01893008. PMID- 24767578 TI - Dynamic virtual fixture on the Euclidean group for admittance-type manipulator in deforming environments. AB - BACKGROUND: In a deforming anatomic environment, the motion of an instrument suffers from complex geometrical and dynamic constraints, robot assisted minimally invasive surgery therefore requires more sophisticated skills for surgeons. This paper proposes a novel dynamic virtual fixture (DVF) to enhance the surgical operation accuracy of admittance-type medical robotics in the deforming environment. METHODS: A framework for DVF on the Euclidean Group SE(3) is presented, which unites rotation and translation in a compact form. First, we constructed the holonomic/non-holonomic constraints, and then searched for the corresponded reference to make a distinction between preferred and non-preferred directions. Second, different control strategies are employed to deal with the tasks along the distinguished directions. The desired spatial compliance matrix is synthesized from an allowable motion screw set to filter out the task unrelated components from manual input, the operator has complete control over the preferred directions; while the relative motion between the surgical instrument and the anatomy structures is actively tracked and cancelled, the deviation relative to the reference is compensated jointly by the operator and DVF controllers. The operator, haptic device, admittance-type proxy and virtual deforming environment are involved in a hardware-in-the-loop experiment, human robot cooperation with the assistance of DVF controller is carried out on a deforming sphere to simulate beating heart surgery, performance of the proposed DVF on admittance-type proxy is evaluated, and both human factors and control parameters are analyzed. RESULTS: The DVF can improve the dynamic properties of human-robot cooperation in a low-frequency (0 ~ 40 rad/sec) deforming environment, and maintain synergy of orientation and translation during the operation. Statistical analysis reveals that the operator has intuitive control over the preferred directions, human and the DVF controller jointly control the motion along the non-preferred directions, the target deformation is tracked actively. CONCLUSIONS: The proposed DVF for an admittance-type manipulator is capable of assisting the operator to deal with skilled operations in a deforming environment. PMID- 24767577 TI - Detection and quantification of Flavobacterium psychrophilum in water and fish tissue samples by quantitative real time PCR. AB - BACKGROUND: Flavobacterium psychrophilum is the agent of Bacterial Cold Water Disease and Rainbow Trout Fry Syndrome, two diseases leading to high mortality. Pathogen detection is mainly carried out using cultures and more rapid and sensitive methods are needed. RESULTS: We describe a qPCR technique based on the single copy gene beta' DNA-dependent RNA polymerase (rpoC). Its detection limit was 20 gene copies and the quantification limit 103 gene copies per reaction. Tests on spiked spleens with known concentrations of F. psychrophilum (106 to 101 cells per reaction) showed no cross-reactions between the spleen tissue and the primers and probe. Screening of water samples and spleens from symptomless and infected fishes indicated that the pathogen was already present before the outbreaks, but F. psychrophilum was only quantifiable in spleens from diseased fishes. CONCLUSIONS: This qPCR can be used as a highly sensitive and specific method to detect F. psychrophilum in different sample types without the need for culturing. qPCR allows a reliable detection and quantification of F. psychrophilum in samples with low pathogen densities. Quantitative data on F. psychrophilum abundance could be useful to investigate risk factors linked to infections and also as early warning system prior to potential devastating outbreak. PMID- 24767581 TI - Dystrophin as a therapeutic biomarker: are we ignoring data from the past? PMID- 24767580 TI - On and off the horse: mechanisms and patterns of injury in mounted and unmounted equestrians. AB - INTRODUCTION: The purpose of this study is to determine whether discrepant patterns of horse-related trauma exist in mounted vs. unmounted equestrians from a single Level I trauma center to guide awareness of injury prevention. METHODS: Retrospective data were collected from the University of Kentucky Trauma Registry for patients admitted with horse-related injuries between January 2003 and December 2007 (n=284). Injuries incurred while mounted were compared with those incurred while unmounted. RESULTS: Of 284 patients, 145 (51%) subjects were male with an average age of 37.2 years (S.D. 17.2). Most injuries occurred due to falling off while riding (54%) or kick (22%), resulting in extremity fracture (33%) and head injury (27%). Mounted equestrians more commonly incurred injury to the chest and lower extremity while unmounted equestrians incurred injury to the face and abdomen. Head trauma frequency was equal between mounted and unmounted equestrians. There were 3 deaths, 2 of which were due to severe head injury from a kick. Helmet use was confirmed in only 12 cases (6%). CONCLUSION: This evaluation of trauma in mounted vs. unmounted equestrians indicates different patterns of injury, contributing to the growing body of literature in this field. We find interaction with horses to be dangerous to both mounted and unmounted equestrians. Intervention with increased safety equipment practice should include helmet usage while on and off the horse. PMID- 24767579 TI - Neuroprotective effects of the MAO-B inhibitor, PF9601N, in an in vivo model of excitotoxicity. AB - BACKGROUND: PF9601N [N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine] is an inhibitor of monoamine oxidase B (MAO-B), which has shown to possess neuroprotective properties in several in vitro and in vivo models of Parkinson's disease (PD). As there is evidence that excitotoxicity may be implicated in the pathophysiology of several neurodegenerative diseases, the aim of the present work was to investigate the effects of PF9601N in an acute in vivo model of excitotoxicity induced by the local administration of kainic acid during striatal microdialysis in adult rats. METHODS: The basal and evoked release of neurotransmitters was monitored by HPLC analysis of microdialysate samples and tissue damage was evaluated histologically "ex vivo." RESULTS: PF9601N (40 mg/kg, single i.p. administration) reduced the kainate-evoked release of glutamate and aspartate and increased taurine release, but it had no effect on the release of dopamine, DOPAC, and HVA. PF9601N pretreatment also resulted in a significant reduction in the kainate-induced astrocytosis, microgliosis, and apoptosis. CONCLUSIONS: The results suggest PF9601N to be a good candidate for the treatment of neurodegenerative diseases mediated by excitotoxicity. PMID- 24767582 TI - Standardized report for early complications of radical prostatectomy. AB - BACKGROUND: Radical prostatectomy (RP) is one of the curative treatment options for patients with prostate cancer to achieve long-term survival, but it is accompanied by potential complications. The Martin criteria used as a format for reporting complications has become standard in recent years. However, it has not been applied in RP in Asian countries. In the present study, we investigated the early complications of RP developing within 90 days in our institute according to the Martin criteria. METHODS: Between January 2003 and November 2011, patients with organ-confined adenocarcinoma of the prostate who received RP in our institute were retrospectively reviewed. The operation was done as open RP, or minimally invasive RP, including laparoscopic RP and robot-assisted laparoscopic RP (RaLP). The preoperative, operative, postoperative, and pathological parameters were recorded for analysis. Definitions of complications were adopted from previous reports. Surgical and medical complications developed within 90 days postoperatively were identified respectively; severity of each complication was classified according to Clavien-Dindo classification. Clavien-Dindo classification grade III or higher complications were viewed as major complications. RESULTS: A total of 359 patients were included; 280 (78%) underwent open RP, 45 (12.5%) received laparoscopic RP, and 34 (9.5%) had RaLP. The overall complication rate was 40.1%, and the major complication rate was 13.1%. There was no surgical mortality. Diarrhea requiring conservative treatment (13.6%), minor urine leakage (9.5%), and gout attack (4.2%) were the leading complications. Minimally invasive RP had higher rates of lymph leakage (p = 0.015) and upper-extremity neuropathy (p = 0.048). Body mass index >25 kg/m(2) and use of neoadjuvant hormone therapy were predictors for overall and major complications, whereas diabetes mellitus also predicted the development of major complications. Besides lower case volume and learning curve for RaLP, patients' higher age at surgery and higher risk for disease progression compared to the Western series may be responsible for the higher complication rates. CONCLUSION: The early complication rates of RP in our patients were slightly high compared to the Western series. By standardized report, being overweight, diabetes mellitus, and use of neoadjuvant hormone therapy were identified as predictors of early complications in our series. PMID- 24767583 TI - alpha-Synuclein oligomers distinctively permeabilize complex model membranes. AB - alpha-Synuclein oligomers are increasingly considered to be responsible for the death of dopaminergic neurons in Parkinson's disease. The toxicity mechanism of alpha-synuclein oligomers likely involves membrane permeabilization. Even though it is well established that alpha-synuclein oligomers bind and permeabilize vesicles composed of negatively-charged lipids, little attention has been given to the interaction of oligomers with bilayers of physiologically relevant lipid compositions. We investigated the interaction of alpha-synuclein with bilayers composed of lipid mixtures that mimic the composition of plasma and mitochondrial membranes. In the present study, we show that monomeric and oligomeric alpha synuclein bind to these membranes. The resulting membrane leakage differs from that observed for simple artificial model bilayers. Although the addition of oligomers to negatively-charged lipid vesicles displays fast content release in a bulk permeabilization assay, adding oligomers to vesicles with compositions mimicking mitochondrial membranes shows a much slower loss of content. Oligomers are unable to induce leakage in the artificial plasma membranes, even after long term incubation. CD experiments indicate that binding to lipid bilayers initially induces conformational changes in both oligomeric and monomeric alpha-synuclein, which show little change upon long-term incubation of oligomers with membranes. The results of the present study demonstrate that the mitochondrial model membranes are more vulnerable to permeabilization by oligomers than model plasma membranes reconstituted from brain-derived lipids; this preference may imply that increasingly complex membrane components, such as those in the plasma membrane mimic used in the present study, are less vulnerable to damage by oligomers. PMID- 24767584 TI - Effects of strengthening, stretching and functional training on foot function in patients with diabetic neuropathy: results of a randomized controlled trial. AB - BACKGROUND: Foot musculoskeletal deficits are seldom addressed by preventive medicine despite their high prevalence in patients with diabetic polyneuropathy. AIM: To investigate the effects of strengthening, stretching, and functional training on foot rollover process during gait. METHODS: A two-arm parallel-group randomized controlled trial with a blinded assessor was designed. Fifty-five patients diagnosed with diabetic polyneuropathy, 45 to 65 years-old were recruited. Exercises for foot-ankle and gait training were administered twice a week, for 12 weeks, to 26 patients assigned to the intervention group, while 29 patients assigned to control group received recommended standard medical care: pharmacological treatment for diabetes and foot care instructions. Both groups were assessed after 12 weeks, and the intervention group at follow-up (24 weeks). Primary outcomes involved foot rollover changes during gait, including peak pressure (PP). Secondary outcomes involved time-to-peak pressure (TPP) and pressure-time integral (PTI) in six foot-areas, mean center of pressure (COP) velocity, ankle kinematics and kinetics in the sagittal plane, intrinsic and extrinsic muscle function, and functional tests of foot and ankle. RESULTS: Even though the intervention group primary outcome (PP) showed a not statistically significant change under the six foot areas, intention-to-treat comparisons yielded softening of heel strike (delayed heel TPP, p=.03), better eccentric control of forefoot contact (decrease in ankle extensor moment, p<.01; increase in function of ankle dorsiflexion, p<.05), earlier lateral forefoot contact with respect to medial forefoot (TPP anticipation, p<.01), and increased participation of hallux (increased PP and PTI, p=.03) and toes (increase in PTI, medium effect size). A slower COP mean velocity (p=.05), and an increase in overall foot and ankle function (p<.05) were also observed. In most cases, the values returned to baseline after the follow-up (p<.05). CONCLUSIONS: Intervention discreetly changed foot rollover towards a more physiological process, supported by improved plantar pressure distribution and better functional condition of the foot ankle complex. Continuous monitoring of the foot status and patient education are necessary, and can contribute to preserving the integrity of foot muscles and joints impaired by polyneuropathy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01207284, registered in 20th September 2010. PMID- 24767585 TI - Did Hurricane Sandy influence the 2012 US presidential election? AB - Despite drawing on a common pool of data, observers of the 2012 presidential campaign came to different conclusions about whether, how, and to what extent "October surprise" Hurricane Sandy influenced the election. The present study used a mixed correlational and experimental design to assess the relation between, and effect of, the salience of Hurricane Sandy on attitudes and voting intentions regarding President Barack Obama and Mitt Romney in a large sample of voting-aged adults. Results suggest that immediately following positive news coverage of Obama's handling of the storm's aftermath, Sandy's salience positively influenced attitudes toward Obama, but that by election day, reminders of the hurricane became a drag instead of a boon for the President. In addition to theoretical implications, this study provides an example of how to combine methodological approaches to help answer questions about the impact of unpredictable, large-scale events as they unfold. PMID- 24767586 TI - Economic returns to occupational closure in the German skilled trades. AB - Recent sociological studies argue that wage differentials between occupations are partly attributable to occupational closure. Occupations set up barriers which restrict the supply of occupational labor, thereby generating an economic rent. In this article we study occupational closure in the skilled trades of Germany, where the Trade and Crafts code restricts self-employment in 41 occupations to those who are master craftsmen. Newly gathered occupational data about the Trade and Crafts code is mapped on micro data from the German Microcensus of 2006. The central finding of our empirical analyses is that self-employed workers with comparable levels of human capital and demographic characteristics earn structurally more in closed occupations. We argue that this earnings premium is a rent, obtained by self-employed because of the entry restriction that is laid down by the Trade and Crafts code. PMID- 24767587 TI - Not just a man's world: women's political leadership in the American labor movement. AB - Although women have long played an important role in working class struggles, most leadership positions in unions have been held by men. Organized labor's recent shift towards social movement unionism has lead to a sense of optimism among those pressing for more gender equality among labor's elite. Yet scholarship on gender and power in other settings, including political institutions, social movements, and formal organizations, suggests other factors may also play a role in determining women's leadership in labor unions. The current research, based on a rich dataset of 70 local unions, provides important insight into the political careers of women. Beyond an analysis of organized labor, this research has implications for understanding the interplay of gender and power in formal organizations and social movements more broadly. PMID- 24767588 TI - Measurement equivalence of the CES-D 8 depression-scale among the ageing population in eleven European countries. AB - Depression is one of the most prevalent mental disorders in later life. However, despite considerable research attention, great confusion remains regarding the association between ageing and depression. There is doubt as to whether a depression scale performs identically for different age groups and countries. Although measurement equivalence is a crucial prerequisite for valid comparisons across age groups and countries, it has not been established for the eight-item version of the Centre for Epidemiological Studies Depression Scale (CES-D8). Using multi-group confirmatory factor analysis, we assess configural, metric, and scalar measurement equivalence across two age groups (50-64 years of age and 65 or older) in eleven European countries, employing data from the Survey of Health, Ageing, and Retirement (SHARE). Results indicate that the construct of depression is comparable across age and country groups, allowing the substantive interpretation of correlates and mean levels of depressive symptoms. PMID- 24767589 TI - The impact of international service on the development of volunteers' intercultural relations. AB - Approximately one million people from the United States perform international volunteer service each year, representing a significant flow of ideas, people, resources, and aid across international borders. This quasi-experimental study assesses the longitudinal impact of international volunteer service on volunteers' intercultural relations, international social capital, and concern about international affairs. Using linear mixed regression models that control for a counterfactual comparison group of individuals that did not travel abroad, international volunteers are more likely to report significant increases in international social capital and international concern two to three years after returning from service. Results indicate that intercultural relations may also continue to increase years after returning from service. International service may be a useful approach to helping people gain skills and networks that are needed in an increasingly global society. PMID- 24767591 TI - Housework, children, and women's wages across racial-ethnic groups. AB - Motherhood affects women's household labor and paid employment, but little previous research has explored the extent to which hours of housework may explain per child wage penalties or differences in such penalties across racial-ethnic groups. In this paper, I use longitudinal Panel Study of Income Dynamics (PSID) data to examine how variations in household labor affect the motherhood penalty for White, Black, and Hispanic women. In doing so, I first assess how children affect hours of household labor across these groups and then explore the extent to which this household labor mediates the relationship between children and wages for these women. I find that household labor explains a portion of the motherhood penalty for White women, who experience the most dramatic increases in household labor with additional children. Black and Hispanic women experience slight increases in housework with additional children, but neither children nor housework affects their already low wages. PMID- 24767590 TI - Early-life social origins of later-life body weight: the role of socioeconomic status and health behaviors over the life course. AB - Using the 1957-2004 data from the Wisconsin Longitudinal Study, we apply structural equation modeling to examine gender-specific effects of family socioeconomic status (SES) at age 18 on body weight at age 65. We further explore SES and health behaviors over the life course as mechanisms linking family background and later-life body weight. We find that early-life socioeconomic disadvantage is related to higher body weight at age 65 and a steeper weight increase between midlife and late life. These adverse effects are stronger among women than men. Significant mediators of the effect of parents' SES include adolescent body mass (especially among women) as well as exercise and SES in midlife. Yet, consistent with the critical period mechanism, the effect of early life SES on late-life body weight persists net of all mediating variables. This study expands current understanding of life-course mechanisms that contribute to obesity and increase biological vulnerability to social disadvantage. PMID- 24767592 TI - Public housing into private assets: wealth creation in urban China. AB - State socialist economies provided public housing to urban citizens at nominal cost, while allocating larger and better quality apartments to individuals in elite occupations. In transitions to a market economy, ownership is typically transferred to existing occupants at deeply discounted prices, making home equity the largest component of household wealth. Housing privatization is therefore a potentially important avenue for the conversion of bureaucratic privilege into private wealth. We estimate the resulting inequalities with data from successive waves of a Chinese national income survey that details household assets and participation in housing programs. Access to privatization programs was relatively equal across urban residents in state sector occupations. Elite occupations had substantially greater wealth in the form of home equity shortly after privatization, due primarily to their prior allocations of newer and higher quality apartments. The resulting gaps in private wealth were nonetheless small by the standards of established market economies, and despite the inherent biases in the process, housing privatization distributed home equity widely across those who were resident in public housing immediately prior to privatization. PMID- 24767594 TI - Men's mobility into management from blue collar and white collar jobs: race differences across the early work-career. AB - Within the context of the "particularistic mobility thesis" we examine racial differences in the incidence, and determinants of, as well as timing to, mobility into management across the critical early career years at a refined level, namely, when groups share similar white collar and blue collar jobs. Findings from a Panel Study of Income Dynamics sample of men support theory and indicate that from both job levels a racial hierarchy exists: African Americans have the lowest rate of mobility, reach management through a route that is relatively formal and structured by a traditional range of stratification-based causal factors and take longest to reach management. Whites, in contrast, have the highest mobility rate, reach management through a relatively informal path that is less structured by traditional stratification-based factors, and reach management the quickest, and, across all three issues Latinos occupy an intermediate ground between African Americans and Latinos. Further, as predicted by theory, racial differences, particularly, relative to whites, are greater among those tracked from blue collar jobs than white collar jobs. Discussed are implications of the findings for understanding racial disadvantage in the American labor market across the work-career and on an inter-generational basis. PMID- 24767593 TI - Are white evangelical Protestants lower class? A partial test of church-sect theory. AB - Testing hypotheses derived from church-sect theory and contemporary research about changes in evangelical Protestants' social status, I use repeated cross sectional survey data spanning almost four decades to examine changes in the social-class hierarchy of American religious traditions. While there is little change in the social-class position of white evangelical Protestants from the early 1970s to 2010, there is considerable change across birth cohorts. Results from hierarchical age-period-cohort models show: (1) robust, across-cohort declines in social-class differences between white evangelical Protestants and liberal Protestants, affiliates of "other" religions, and the unaffiliated, (2) stability in social-class differences between white evangelical Protestants and moderate, Pentecostal, and nondenominational Protestants, (3) moderate across cohort growth in social-class differences between white evangelical Protestants and Catholics, and (4) these patterns vary across indicators of social class. The findings in this article provide partial support for church-sect theory as well as other theories of social change that emphasize the pivotal role of generations. PMID- 24767595 TI - The conditional returns to origin-country human capital among Turkish and Moroccan immigrants in Belgium. AB - This study extends the analysis of the economic returns to pre-migration human capital by examining the role of the receiving context, co-ethnic residential concentration, and post-migration investments in human capital. It uses large scale survey data on Turkish and Moroccan immigrants in Belgium. The analysis demonstrates that regarding employment, Moroccan immigrants, that is, those originating from former French colonies receive larger returns to their origin country education and work experience in French- vs. Dutch-speaking regions. Other than the positive interaction effect between co-ethnic residential concentration and work experience on employment, there is little evidence that co ethnic concentration increases the returns to origin-country human capital. Speaking the host-country language facilitates economic returns to origin-country work experience. Conversely, immigrants who acquire host-country credentials and work experience receive lower returns to origin-country education and experience, suggesting that, at least among low-skilled immigrants, pre- and post-migration human capital substitute rather than complement each other. PMID- 24767597 TI - Declining segregation through the lens of neighborhood quality: does middle-class and affluent status bring equality? AB - Middle- and upper-class status along with suburban residence are together considered symbolic of the American dream. However, the question of whether they mean access to better quality residential environments has gone largely unexplored. This study relies on data from the 2009 panel of the American Housing Survey and focuses on a range of neighborhood conditions, including indicators of physical and social disorder as well as housing value and a neighborhood rating. Contrary to the tenets of the spatial assimilation model, we find that middle class and affluent status do not consistently lead to superior conditions for all households. Neighborhood circumstances vary considerably based on householder race and ethnicity, with blacks and Hispanics experiencing the greatest disparities from whites. In addition, suburban residence does not attenuate such differences, and in some cases, well-to-do minorities do even worse than whites in neighborhood quality in suburbs. PMID- 24767596 TI - The relationship between incarceration and premature adult mortality: gender specific evidence. AB - We examine the relationship between incarceration and premature mortality for men and women. Analyses using the National Longitudinal Survey of Youth (NLSY79) reveal strong gender differences. Using two different analytic procedures the results show that women with a history of incarceration are more likely to die than women without such a history, even after controlling for health status and criminal behavior prior to incarceration, the availability of health insurance, and other socio-demographic factors. In contrast, there is no relationship between incarceration and mortality for men after accounting for these factors. The results point to the importance of examining gender differences in the collateral consequences of incarceration. The results also contribute to a rapidly emerging literature linking incarceration to various health hazards. Although men constitute the bulk of inmates, future research should not neglect the special circumstances of female former inmates and their rapidly growing numbers. PMID- 24767598 TI - Improving models of democracy: the example of lagged effects of economic development, education, and gender equality. AB - The author examines how time delayed effects of economic development, education, and gender equality influence political democracy. Literature review shows inadequate understanding of lagged effects, which raises methodological and theoretical issues with the current quantitative studies of democracy. Using country-years as a unit of analysis, the author estimates a series of OLS PCSE models for each predictor with a systematic analysis of the distributions of the lagged effects. The second set of multiple OLS PCSE regressions are estimated including all three independent variables. The results show that economic development, education, and gender have three unique trajectories of the time delayed effects: Economic development has long-term effects, education produces continuous effects regardless of the timing, and gender equality has the most prominent immediate and short term effects. The results call for the reassessment of model specifications and theoretical setups in the quantitative studies of democracy. PMID- 24767599 TI - Parturition in horses is dominated by parasympathetic activity of the autonomous nervous system. AB - External and internal stressors prolong parturition in different species. At parturition, sympathoadrenal activation should be avoided because an increased sympathetic tone may cause uterine atonia via beta2-receptors. We hypothesized that at physiological parturition, horses are under parasympathetic dominance, and stress-response mechanisms are not activated during delivery of the foal. To evaluate stress responses, heart rate, heart rate variability, catecholamines, and cortisol were analyzed in mares (n = 17) throughout foaling. Heart rate decreased from 2 hours before (51 +/- 1 beats/minute) to 2 hours after delivery (41 +/- 2 beats/minute; P < 0.05). Heart rate variability variables, standard deviation of the beat-to-beat interval, and root mean square of successive beat to-beat differences, changed over time (P < 0.05) with the highest values within 15 minutes after delivery. The number of mares with atrioventricular blocks and the number of atrioventricular blocks per mare increased over time (P < 0.01) and were significantly elevated from 15 minutes before to 45 minutes after birth of the foal. Salivary cortisol concentrations increased to a maximum at 30 minutes after delivery (25.0 +/- 3.4 ng/mL; P < 0.01). Plasma epinephrine and norepinephrine concentrations showed significant fluctuations from rupture of the allantochorion to expulsion of the fetal membranes (P < 0.01) but were not markedly elevated at any time. In conclusion, mares give birth under high parasympathetic tone. Cortisol release during and after foaling is most likely part of the endocrine pathways regulating parturition and not a labor-associated stress response. PMID- 24767600 TI - Radiolabelling and evaluation of a novel sulfoxide as a PET imaging agent for tumor hypoxia. AB - [18F]FMISO is the most widely validated PET radiotracer for imaging hypoxic tissue. However, as a result of the pharmacokinetics of [18F]FMISO a 2h wait between tracer administration and patient scanning is required for optimal image acquisition. In order to develop hypoxia imaging agents with faster kinetics, we have synthesised and evaluated several F-18 labelled anilino sulfoxides. In this manuscript we report on the synthesis, in vitro and in vivo evaluation of a novel fluoroethyltriazolyl propargyl anilino sulfoxide. The radiolabelling of the novel tracer was achieved via 2-[18F]fluoroethyl azide click chemistry. Radiochemical yields were 23 +/- 4% based on 2-[18F]fluoroethyl azide and 7 +/- 2% based on K[18F]F. The radiotracer did not undergo metabolism or defluorination in an in vitro assay using S9 liver fractions. Imaging studies using SK-RC-52 tumors in BALB/c nude mice have indicated that the tracer may have a higher pO2 threshold than [18F]FMISO for uptake in hypoxic tumors. Although clearance from muscle was faster than [18F]FMISO, uptake in hypoxic tumors was slower. The average tumor to muscle ratio at 2h post injection in large, hypoxic tumors with a volume greater than 686 mm3 was 1.7, which was similar to the observed ratio of 1.75 for [18F]FMISO. Although the new tracer showed improved pharmacokinetics when compared with the previously synthesised sulfoxides, further modifications to the chemical structure need to be made in order to offer significant in vivo imaging advantages over [18F]FMISO. PMID- 24767601 TI - The right to traditional, complementary, and alternative health care. AB - BACKGROUND: State parties to human rights conventions and declarations are often faced with the seemingly contradictory problem of having an obligation to protect people from harmful practices while also having an obligation to enable access to culturally appropriate effective healing. As people increasingly migrate across the globe, previous distinctions between 'traditional' and 'complementary and alternative medicine' practices are being transcended. There are connections across transnational healing pathways that link local, national, and global movements of people and knowledge. OBJECTIVE: This paper contributes to the development of the concept and practice of the right to health in all its forms, exploring the right to traditional, complementary, and alternative health (R2TCAH) across different contexts. DESIGN: The paper draws on four settings - England, South Africa, Kenya, and Jordan - and is based on key informant interviews and a literature review undertaken in 2010, and updated in 2013. The paper begins by reviewing the international legal context for the right to health. It then considers legal and professional regulations from the global north and south. RESULTS: Additional research is needed to establish the legal basis, compare regulatory frameworks, and explore patient and provider perspectives of regulation. This leads to being able to make recommendations on how to balance protection from harm and the obligation to ensure culturally appropriate services. Such an exploration must also challenge Western theories of human rights. Key concepts, such as individual harm, consent, and respect of the autonomy of the individual already established and recognised in international health law, could be adopted in the development of a template for future comparative research. CONCLUSIONS: Exploration of the normative content of the right to health in all its forms will contribute to supporting traditional, complementary, and alternative health service users and providers in terms of access to information, non-discrimination, clarification of state obligations, and accountability. PMID- 24767602 TI - Experimental support that ocular tremor in Parkinson's disease does not originate from head movement. AB - INTRODUCTION: Our recent report of ocular tremor in Parkinson's disease (PD) has raised considerable controversy as to the origin of the tremor. Using an infrared based eye tracker and a magnetic head tracker, we reported that ocular tremor was recordable in PD subjects with no apparent head tremor. However, other investigators suggest that the ocular tremor may represent either transmitted appendicular tremor or subclinical head tremor inducing the vestibulo-ocular reflex (VOR). The present study aimed to further investigate the origin of ocular tremor in PD. METHODS: Eye movements were recorded in 8 PD subjects both head free, and with full head restraint by means of a head holding device and a dental impression bite plate. Head movements were recorded independently using both a high sensitivity tri-axial accelerometer and a magnetic tracking system, each synchronized to the eye tracker. RESULTS: Ocular tremor was observed in all 8 PD subjects and was not influenced by head free and head fixed conditions. Both magnetic tracking and accelerometer recordings supported that the ocular tremor was fully independent of head position. CONCLUSION: The present study findings support our initial findings that ocular tremor is a fundamental feature of PD unrelated to head movements. Although the utility of ocular tremor for diagnostic purposes requires validation, current findings in large cohorts of PD subjects suggest its potential as a reliable clinical biomarker. PMID- 24767603 TI - Low-intensity internet-delivered treatment for generalized anxiety symptoms in routine care: protocol for a randomized controlled trial. AB - BACKGROUND: Worldwide prevalence of generalized anxiety disorder (GAD) is considered high; in Europe lifetime prevalence has been estimated at 4.3 to 5.9%. High levels of anxiety disorders have been reported in university students, affecting 25 to 30% of the population. Young adults are some of the most vulnerable for the onset of mental health disorders and any stressors may act as a catalyst for their onset. The absence of resources can often mean that many do not seek treatment. Other factors that impede access to resources include such things as a lack of trained professionals, personal stigma, and waiting lists. Anxiety disorders can be treated successfully; indeed brief forms of cognitive behavior therapy have been recommended. One potential avenue for research and development is that of delivering low-intensity interventions online for students with GAD. Therefore, the current study seeks to investigate the potential effectiveness for a low-intensity online CBT-based treatment for GAD in a service based setting; implemented as one step in a stepped-care model. METHODS/DESIGN: The research is a service-based effectiveness study utilizing a randomized waiting-list controlled design. The active intervention consists of six weekly modules of online CBT. Participants are assigned a supporter who provides weekly post-session feedback on progress and exercises. Participants will complete the GAD-7 as the primary outcome measure. Secondary outcomes include pathological worry, depression and measures of well-being. At three-months follow-up data will be collected using the GAD-7, BDI-II, PSWQ, ED-Q5 and WSAS. Post-session data will be collected on significant in-session events in treatment (HAT). A satisfaction with treatment measure will be administered post-treatment (SAT). DISCUSSION: The study will be a contribution to the potential for a low-intensity internet-delivered program implemented in a service-based setting; implemented as one step in a stepped-care model. The study will be a contribution to the already established work in online treatments for anxiety worldwide. The study will assess the utility of an innovative digital health solution (SilverCloud) to deliver such interventions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16303842. PMID- 24767604 TI - Antenatal exercise in overweight and obese women and its effects on offspring and maternal health: design and rationale of the IMPROVE (Improving Maternal and Progeny Obesity Via Exercise) randomised controlled trial. AB - BACKGROUND: Obesity during pregnancy is associated with adverse outcomes for the offspring and mother. Lifestyle interventions in pregnancy such as antenatal exercise, are proposed to improve both short- and long-term health of mother and child. We hypothesise that regular moderate-intensity exercise during the second half of pregnancy will result in improved maternal and offspring outcomes, including a reduction in birth weight and adiposity in the offspring, which may be protective against obesity in later life. METHODS/DESIGN: The IMPROVE (Improving Maternal and Progeny Risks of Obesity Via Exercise) study is a two-arm parallel randomised controlled clinical trial being conducted in Auckland, New Zealand. Overweight and obese women (BMI >=25 kg/m2) aged 18-40 years, with a singleton pregnancy of <20 weeks of gestation, from the Auckland region, are eligible for the trial. Exclusion criteria are ongoing smoking or medical contra indications to antenatal exercise.Participants are randomised with 1:1 allocation ratio to either intervention or control group, using computer-generated randomisation sequences in variable block sizes, stratified on ethnicity and parity, after completion of baseline assessments. The intervention consists of a 16-week structured home-based moderate-intensity exercise programme utilising stationary cycles and heart rate monitors, commencing at 20 weeks of gestation. The control group do not receive any exercise intervention. Both groups undergo regular fetal ultrasonography and receive standard antenatal care. Due to the nature of the intervention, participants are un-blinded to group assignment during the trial.The primary outcome is offspring birth weight. Secondary offspring outcomes include fetal and neonatal body composition and anthropometry, neonatal complications and cord blood metabolic markers. Maternal outcomes include weight gain, pregnancy and delivery complications, aerobic fitness, quality of life, metabolic markers and post-partum body composition. DISCUSSION: The results of this trial will provide valuable insights on the effects of antenatal exercise on health outcomes in overweight and obese mothers and their offspring. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000932864. PMID- 24767607 TI - [Pancreatic hemosuccus, a rare cause of upper gastrointestinal bleeding]. PMID- 24767606 TI - [Pulsed radiofrequency in the treatment of abdominal cutaneous nerve entrapament syndrome]. PMID- 24767605 TI - beta-catenin promotes the type I IFN synthesis and the IFN-dependent signaling response but is suppressed by influenza A virus-induced RIG-I/NF-kappaB signaling. AB - BACKGROUND: The replication cycle of most pathogens, including influenza viruses, is perfectly adapted to the metabolism and signal transduction pathways of host cells. After infection, influenza viruses activate several cellular signaling cascades that support their propagation but suppress those that interfere with viral replication. Accumulation of viral RNA plays thereby a central role. Its sensing by the pattern recognition receptors of the host cells leads to the activation of several signal transduction waves that result in induction of genes, responsible for the cellular innate immune response. Type I interferon (IFN) genes and interferon-stimulated genes (ISG) coding for antiviral-acting proteins, such as MxA, OAS-1 or PKR, are primary targets of these signaling cascades. beta- and gamma-catenin are closely related armadillo repeat-containing proteins with dual roles. At the cell membrane they serve as adapter molecules linking cell-cell contacts to microfilaments. In the cytosol and nucleus, the proteins form a transcriptional complex with the lymphoid enhancer factor/T-cell factor (LEF/TCF), regulating the transcription of many genes, thereby controlling different cellular functions such as cell cycle progression and differentiation. RESULTS: In this study, we demonstrate that beta- and gamma-catenin are important regulators of the innate cellular immune response to influenza A virus (IAV) infections. They inhibit viral replication in lung epithelial cells by enhancing the virus-dependent induction of the IFNB1 gene and interferon-stimulated genes. Simultaneously, the prolonged infection counteracts the antiviral effect of beta- and gamma-catenin. Influenza viruses suppress beta-catenin-dependent transcription by misusing the RIG-I/NF-kappaB signaling cascade that is induced in the course of infection by viral RNA. CONCLUSION: We identified beta- and gamma-catenin as novel antiviral-acting proteins. While these factors support the induction of common target genes of the cellular innate immune response, their functional activity is suppressed by pathogen evasion. PMID- 24767608 TI - Autoimmune liver disease: novelties in management. AB - Autoimmune liver disease is the second commonest cause of chronic liver disease in teenagers. There are several forms including autoimmune hepatitis, autoimmune sclerosing cholangitis, primary sclerosing cholangitis and various overlap syndromes, classified on the basis of different serum antibody profiles, histological features and appearances on cholangiography. Treatment with immunosupressants is usually effective, but often required medium to long-term, raising concerns about side effects and adherence to therapy. For a minority of children presenting in acute liver failure or with difficult-to-treat disease liver transplantation is a possible option, although risk of recurrence in the grafted liver remains lifelong. PMID- 24767609 TI - Tortoise shell-like mucosa of acute intestinal graft-versus-host disease. PMID- 24767610 TI - Gender and regional disparities of tuberculosis in Hunan, China. AB - INTRODUCTION: Major efforts have been made to improve the health care system in Hunan province, China. The aims of this study were to assess whether and to what extent these efforts have impacted on gender and regional disparities of Tuberculosis (TB) incidence in recent years, especially for less developed areas. METHODS: We obtained data from the 2005-2009 China Information System for Disease Control and Prevention (CISDCP)to conduct this study in Hunan province. Counties within the province were divided into four regions according to quartiles based on the 2007 per capita GDP. Index of Disparity (ID) and Relative Index of Inequality (RII) were used to measure the disparities of TB incidence in relation to gender and region. Bootstrap technique was used to increase the precision. RESULTS: The average annual incidence of TB was 111.75 per 100,000 in males and 43.44 per 100 000 in females in Hunan. The gender disparity was stable, with ID from 42.34 in 2005 to 43.92 in 2009. For regional disparity, ID, RII (mean) and RII (ratio) decreased significantly from 2005 to 2009 in males (P < 0.05) but remained stable among the female population. CONCLUSIONS: As interventions such as introduction of the New Rural Cooperative Scheme put in place to reduce health disparities in China, regional disparity in relation to incidence of TB decreased significantly, but the gender disparity remains in the Hunan province. PMID- 24767611 TI - Triple-incision laparoscopic distal gastrectomy for the resection of gastric cancer: comparison with conventional laparoscopy-assisted distal gastrectomy. AB - INTRODUCTION: Reduced port surgery and single-port surgery are currently in the spotlight as next-generation, minimally invasive surgical techniques. We performed a triple-incision laparoscopic distal gastrectomy (TIL-DG) for gastric cancer as a reduced port surgery. METHOD: A total of 76 patients underwent a TIL DG. A D1+ or D2 lymph node dissection was performed, and the Roux-en-Y method was used for reconstruction. The short-term patient outcomes of the TIL-DG group were compared with those of the conventional laparoscopy-assisted distal gastrectomy group (59 cases) to evaluate the feasibility of TIL-DG. RESULTS: No significant differences were observed between the TIL-DG group and the laparoscopy-assisted distal gastrectomy group in terms of mean operative time, blood loss, and the length of the postoperative hospital stay. The mean number of retrieved regional lymph nodes in the TIL-DG group was slightly higher than that in the laparoscopy assisted distal gastrectomy group. CONCLUSION: A triple-incision laparoscopic distal gastrectomy is a feasible and safe procedure. PMID- 24767612 TI - Interventions to reduce injuries when transferring patients: a critical appraisal of reviews and a realist synthesis. AB - OBJECTIVES: There has been extensive investment in programmes to reduce injuries among health care staff caused by moving and handling patients or residents. Given conflicting evidence regarding the effectiveness of such programmes, the present paper conducted a critical appraisal of systematic reviews assessing the effectiveness of interventions in reducing back pain and injuries among healthcare staff. A realist synthesis was conducted on a second set of reports to identify best practices for moving and handling programmes. DESIGN: A critical appraisal of systematic reviews and a realist synthesis to identify best practices for moving and handling programmes. DATA SOURCES: A literature search of five databases (Medline, EMBASE, CINAHL, PsycINFO and ScienceDirect) located 150 reports assessing programme outcomes published in refereed journals between 2000 and 2013. REVIEW METHODS: The critical appraisal included six systematic reviews. The realist synthesis included 47 studies that provided descriptive information about programme mechanisms. RESULTS: Five of the six systematic reviews covered interventions involving either staff training or training and equipment supply. One review covered multi-component interventions. All concluded that training staff by itself was ineffective. There were differing conclusions regarding the effectiveness of training and equipment interventions and multi component programmes. The reviews provided little information about the content of programme components. The realist synthesis noted the need for management commitment and support, and six core programme components; a policy requiring safe transfer practices, ergonomic assessment of spaces where people are transferred, transfer equipment including lifts, specific risk assessment protocols, adequate training of all care staff, and coordinators coaches or resource staff. These programme components are likely to be synergistic; omitting one component weakens the impact of the other components. CONCLUSIONS: Five systematic reviews provided little information regarding the core components of effective programmes. Given the absence of experimental trials for multi component programmes, the best available evidence for the effectiveness of multi component programmes is from pre-post studies and large-scale surveys. The realist synthesis provided detailed information about the core components for effective programmes. Further studies, which include qualitative data, are needed to provide evidence about the specific mechanisms through which components contribute to effective patient handling programmes. PMID- 24767613 TI - Attentional costs of visually guided walking: effects of age, executive function and stepping-task demands. AB - During walking, attention needs to be flexibly allocated to deal with varying environmental constraints. This ability may be affected by aging and lower overall executive function. The present study examined the influence of aging and executive function on the attentional costs of visually guided walking under different task demands. Three groups, young adults (n=15) and elderly adults with higher (n=16) and lower (n=10) executive function, walked on a treadmill in three conditions: uncued walking and walking with regular and irregular patterns of visual stepping targets projected onto the belt. Attentional costs were assessed using a secondary probe reaction time task and corrected by subtracting baseline single-task reaction time, yielding an estimate of the additional attentional costs of each walking condition. We found that uncued walking was more attentionally demanding for elderly than for young participants. In young participants, the attentional costs increased significantly from uncued to regularly cued to irregularly cued walking, whereas for the higher executive function group, attentional costs only increased significantly from regularly cued to irregularly cued walking. For the group with lower executive function, no significant differences were observed. The observed decreased flexibility of elderly, especially those with lower executive function, to allocate additional attentional resources to more challenging walking conditions may be attributed to the already increased attentional costs of uncued walking, presumably required for visuomotor and/or balance control of walking. PMID- 24767614 TI - Brief mindfulness meditation training alters psychological and neuroendocrine responses to social evaluative stress. AB - OBJECTIVE: To test whether a brief mindfulness meditation training intervention buffers self-reported psychological and neuroendocrine responses to the Trier Social Stress Test (TSST) in young adult volunteers. A second objective evaluates whether pre-existing levels of dispositional mindfulness moderate the effects of brief mindfulness meditation training on stress reactivity. METHODS: Sixty-six (N=66) participants were randomly assigned to either a brief 3-day (25-min per day) mindfulness meditation training or an analytic cognitive training control program. All participants completed a standardized laboratory social-evaluative stress challenge task (the TSST) following the third mindfulness meditation or cognitive training session. Measures of psychological (stress perceptions) and biological (salivary cortisol, blood pressure) stress reactivity were collected during the social evaluative stress-challenge session. RESULTS: Brief mindfulness meditation training reduced self-reported psychological stress reactivity but increased salivary cortisol reactivity to the TSST, relative to the cognitive training comparison program. Participants who were low in pre-existing levels of dispositional mindfulness and then received mindfulness meditation training had the greatest cortisol reactivity to the TSST. No significant main or interactive effects were observed for systolic or diastolic blood pressure reactivity to the TSST. CONCLUSIONS: The present study provides an initial indication that brief mindfulness meditation training buffers self-reported psychological stress reactivity, but also increases cortisol reactivity to social evaluative stress. This pattern may indicate that initially brief mindfulness meditation training fosters greater active coping efforts, resulting in reduced psychological stress appraisals and greater cortisol reactivity during social evaluative stressors. PMID- 24767615 TI - Nonadherence with ambulatory saliva sampling is associated with biased salivary testosterone estimates. AB - OBJECTIVE: Nonadherence with scheduled saliva sampling, as encountered in ambulatory settings, can bias the estimation of salivary cortisol concentrations. This study is the first to estimate if such nonadherence is also associated with biased salivary testosterone concentration estimates. METHODS: Using a standard ambulatory saliva-sampling protocol, we instructed pregnant women to collect saliva samples on two consecutive days at awakening, 1100h, 1500h, 2000h, and 2200h. We estimated testosterone concentrations in the saliva samples and participants' actual sampling times with an electronic medication event monitoring system. We classified a saliva sample as adherent if it was sampled within a specific time window relative to its scheduled sampling time. We used a mixed-model analysis to distinguish between trait (number of adherent saliva samples per participant) and state (adherence status of a specific sample) adherence. RESULTS: We included 60 pregnant women in this study. Seventy-five percent (448 of 600) of the scheduled samples indicated adherence with the sampling schedule. Participants' trait adherence was associated with their diurnal profiles of salivary testosterone estimates; that is, adherent participants had higher salivary testosterone estimates compared with nonadherent participants, F(1,58)=5.41, p=0.023, Cohen's d=0.67. The state adherence of a sample was associated with the salivary testosterone estimate of the related sample, F(1,469)=4.48, p=0.035, Cohen's d=0.20, with delayed sampling associated with lower salivary testosterone estimates. CONCLUSIONS: The results suggest that common ambulatory nonadherence with scheduled saliva sampling is associated with biased salivary testosterone estimates. They will inform further studies estimating salivary testosterone with ambulatory saliva-sampling designs and highlight the relevance of strategies to improve or confirm adherence, beyond routinely used instructions. PMID- 24767616 TI - Basal salivary oxytocin level predicts extra- but not intra-personal dimensions of emotional intelligence. AB - A wealth of literature suggests that oxytocin is an important mediator of social cognition, but much of the research to date has relied on pharmaceutical administration methods that can raise oxytocin to artificially high levels. The present study builds upon previous work by examining whether basal oxytocin level predicts intra- and extra-personal (i.e., self- and other-focused) elements of emotional intelligence (EI), independent of shared variance with current mood. The sample included 71 healthy young adults (46 women). Assessment measures included the Mayer-Salovey-Caruso Emotional Intelligence Test Version 2.0 (MSCEIT), the Trait Meta-Mood Scale, and the Profile of Mood States. Peripheral oxytocin levels were examined with enzyme-linked immunosorbent assay from saliva after solid phase extraction. Oxytocin level was unrelated to TMMS scores but was positively associated with performance in the Experiential EI domain of the MSCEIT. However, total mood disturbance was positively related to MSCEIT scores. Hierarchical regression analysis indicated that oxytocin level added unique variance to the prediction of MSCEIT performance beyond that of current mood. These results confirm an association between endogenous levels of oxytocin in healthy adults and a subset of EI abilities, including extra-personal emotion recognition and the channeling of emotions to enhance social proficiency. PMID- 24767617 TI - Cortical thickness correlates of socioemotional difficulties in adults with Turner syndrome. AB - Turner syndrome (TS) is a non-inherited genetic disorder associated with a specific cognitive phenotype and socioemotional impairments. The present study aimed at characterizing the neuroanatomical basis of socioemotional dysfunctions in TS using the Emotional Quotient inventory (EQ-I) and cortical morphology analysis in 17 individuals with TS (45,X) and 17-age and verbal IQ matched healthy females. Individuals with TS reported significantly greater socioemotional impairment than controls. Cortical thickness analysis showed that participants with TS had an overall thicker cortex than controls, with extensive alterations in the temporal, frontal, parietal and insular regions bilaterally. Using the total EQ-I score as regressor in the cortical thickness analysis revealed a number of brain regions where the relationship between cortical thickness and EQ-I score differed between groups; these areas included brain regions critically involved in socioemotional processes, such as bilateral insula, the anterior cingulate and the orbitofrontal cortex. These results show that socioemotional dysfunctions seen in women with TS are associated with significant alterations in brain morphology. PMID- 24767618 TI - Dexamethasone stimulated gene expression in peripheral blood indicates glucocorticoid-receptor hypersensitivity in job-related exhaustion. AB - Work-related stress can lead to various health problems ranging from job-related exhaustion to psychiatric and somatic diseases. Biomarkers of job-related exhaustion could help to improve our understanding of the biological mechanisms and might be useful to guide prevention and treatment strategies. The present study included 12 male cases suffering from job-related exhaustion and 12 matched healthy controls. Severity of exhaustion was assessed with the Maslach Burnout Inventory (MBI) and the Shirom-Melamed Burnout Measure (SMBM). Whole genome expression profiles derived from whole blood cells (baseline and following glucocorticoid-receptor (GR) stimulation with 1.5mg dexamethasone p.o.) and corresponding plasma cortisol levels were analyzed. All cases participated in regular aerobic exercise for 12 consecutive weeks and were then re-assessed at follow-up for exhaustion symptoms as well as for cortisol levels and gene expression profiles. At baseline, we found increased basal cortisol levels and an enhanced suppression of plasma cortisol concentrations following dexamethasone in cases suffering from job-related exhaustion. Gene expression analysis revealed that 1.6-fold more transcripts were significantly regulated by dexamethasone in cases as compared to controls. At follow-up after 12 weeks of regular exercise training which was accompanied by significantly improved exhaustion severity scores, cortisol levels and gene expression profiles of cases normalized to the levels observed in controls. In conclusion, we detected GR-induced neuroendocrine and gene expression changes in cases suffering from job-related exhaustion which are in line with an increased sensitivity of GR function. This GR dysregulation normalized with symptom recovery. PMID- 24767619 TI - Prospective associations between the cortisol awakening response and first onsets of anxiety disorders over a six-year follow-up--2013 Curt Richter Award Winner. AB - Cross-sectional associations have been found between anxiety disorders (ADs) and hypothalamic-pituitary-adrenal (HPA) axis functioning, as measured by levels of salivary cortisol, but prospective data are lacking, as are studies examining specific ADs. We have previously shown that one aspect of the diurnal rhythm of cortisol, the cortisol awakening response (CAR), prospectively predicts both new onsets and recurrences of major depressive disorder (MDD). Here we sought to examine whether it also predicts ADs. Participants (N=232) were drawn from the larger Northwestern-UCLA Youth Emotion Project, a two-site, longitudinal study of older adolescents, which aims to identify common and specific risk factors for mood and anxiety disorders. After baseline interviews for mental health diagnoses, a subset of adolescents completed a three-day cortisol sampling protocol measuring the CAR and other diurnal rhythm indices. Participants with past or current anxiety disorders at the time of cortisol measurement were excluded and Cox regression (survival analysis) was used to predict first onsets of ADs over the subsequent six years. AD onsets (N=25), the largest subset of which were social anxiety disorder (SAD) onsets (N=11), were observed over six annual follow up diagnostic interviews. Even when statistically adjusting for past and prospective MDD onsets and other covariates, a higher CAR significantly predicted increased first onsets of ADs (HR=2.20, p<.05). A higher CAR was also a strong and significant predictor of the subset of SAD onsets (HR=5.37, p<.005). Implications for the etiology of ADs, with a focus on SAD, are discussed. PMID- 24767621 TI - Circadian rhythmicity, variability and correlation of interleukin-6 levels in plasma and cerebrospinal fluid of healthy men. AB - BACKGROUND: Interleukin-6 (IL-6) is a cytokine with pleiotropic actions in both the periphery of the body and the central nervous system (CNS). Altered IL-6 secretion has been associated with inflammatory dysregulation and several adverse health consequences. However, little is known about the physiological circadian characteristics and dynamic inter-correlation between circulating and CNS IL-6 levels in humans, or their significance. METHODS: Simultaneous assessment of plasma and cerebrospinal fluid (CSF) IL-6 levels was performed hourly in 11 healthy male volunteers over 24h, to characterize physiological IL-6 secretion levels in both compartments. RESULTS: IL-6 levels showed considerable within- and between-subject variability in both plasma and CSF, with plasma/CSF ratios revealing consistently higher levels in the CSF. Both CSF and plasma IL-6 levels showed a distinctive circadian variation, with CSF IL-6 levels exhibiting a main 24h, and plasma a biphasic 12h, circadian component. Plasma peaks were roughly at 4 p.m. and 4 a.m., while the CSF peak was at around 7 p.m. There was no correlation between coincident CSF and plasma IL-6 values, but evidence for significant correlations at a negative 7-8h time lag. CONCLUSIONS: This study provides evidence in humans for a circadian IL-6 rhythm in CSF and confirms prior observations reporting a plasma biphasic circadian pattern. Our results indicate differential IL-6 regulation across the two compartments and are consistent with local production of IL-6 in the CNS. Possible physiological significance is discussed and implications for further research are highlighted. PMID- 24767622 TI - Posttraumatic growth and diurnal cortisol slope among women with metastatic breast cancer. AB - BACKGROUND: A cancer diagnosis leads to increased psychological and emotional distress. However, in the aftermath of a traumatic event, such as being diagnosed with breast cancer, an individual may also experience beneficial changes in life perspective, relationships with others, and more. These changes are collectively known as posttraumatic growth (PTG). Studies have demonstrated that cortisol levels have been linked with cancer survival, yet an investigation of the relationship between PTG and cortisol has yet to be conducted among cancer patients. METHODS: The relationship of PTG to cortisol levels was examined among 99 metastatic breast cancer patients. RESULTS: We found a significant correlation between PTG and diurnal cortisol slope (Spearman's rho=-0.21, p<0.05), indicating a link between positive psychological changes and healthier endocrine functioning in cancer patients. CONCLUSIONS: PTG in response to the stress of cancer was related to more normal (i.e., steeper) diurnal cortisol patterns. Longitudinal studies are recommended to investigate these mechanisms in relationship to cancer survival. PMID- 24767620 TI - Brief cognitive intervention can modulate neuroendocrine stress responses to the Trier Social Stress Test: buffering effects of a compassionate goal orientation. AB - BACKGROUND: The hypothalamic-pituitary-adrenal (HPA) axis is a critical mediator linking stress to health. Understanding how to modulate its reactivity could potentially help reduce the detrimental health effects of HPA axis activation. Social evaluative threat is a potent activator of this system. Access to control and coping responses can reduce its reactivity to pharmacological activation. Compassionate or affiliative behaviors may also moderate stress reactivity. Impact of these moderators on social evaluative threat is unknown. Here, we tested the hypotheses that interventions to increase control, coping, or compassionate (versus competitive) goals could reduce HPA-axis response to social evaluative threat. METHODS: Healthy participants (n=54) were exposed to social evaluative threat using the Trier Social Stress Test (TSST). They were randomly assigned to receive one of four different instructions prior to the stressor: Standard TSST instructions (SI), standard instructions with access to "control" (SI Control), or one of two cognitive interventions (CI) that (1) increased familiarity and helped participants prepare coping strategies (CI Coping), or (2) shifted goal orientation from self-promotion to helping others (CI Compassionate Goals). ACTH and cortisol were obtained before and after stress exposure via intravenous catheter. RESULTS: Control alone had no effect. CI Compassionate Goals significantly reduced ACTH and cortisol responses to the TSST; CI Coping raised baseline levels. Compassionate Goals reduced hormonal responses without reducing subjective anxiety, stress or fear, while increasing expression of pro social intentions and focus on helping others. CONCLUSIONS: Brief intervention to shift focus from competitive self-promotion to a goal orientation of helping others can reduce HPA-axis activation to a potent psychosocial stressor. This supports the potential for developing brief interventions as inoculation tools to reduce the impact of predictable stressors and lends support to growing evidence that compassion and altruistic goals can moderate the effects of stress. PMID- 24767623 TI - The impact of attentional training on the salivary cortisol and alpha amylase response to psychosocial stress: importance of attentional control. AB - INTRODUCTION: This study examined the effects of three consecutive days of attentional training on the salivary alpha amylase (sAA), cortisol, and mood response to the Trier Social Stress Test (TSST). The training was designed to elicit faster disengagement of attention away from threatening facial expressions and faster shifts of attention toward positive ones. METHOD: Fifty-six healthy participants between the ages of 18 and 30 participated in a double-blind, within subject experiment. Participants were randomly assigned to one of three attentional training conditions - supraliminal training: pictures shown with full conscious awareness, masked training: stimuli presented with limited conscious awareness, or control training: both supraliminal and masked pictures shown but no shifting of attention required. Following training, participants underwent the TSST. Self-reported mood and saliva samples were collected for the determination of emotional reactivity, cortisol, and sAA in response to stress post-training. RESULTS: Unexpectedly, participants in both attentional training groups exhibited a higher salivary cortisol response to the TSST relative to participants who underwent the control training, F (4, 86)=4.07, p=.005, etap(2)=.16. Supraliminal training was also associated with enhanced sAA reactivity, F (2, 44)=13.90, p=.000, etap(2)=.38, and a more hostile mood response (p=.021), to the TSST. Interestingly, the effect of attention training on the cortisol response to stress was more robust in those with high attentional control than those with low attentional control (beta=-0.134; t=-2.24, p=.03). CONCLUSION: This is among the first experimental manipulations to demonstrate that attentional training can elicit a paradoxical increase in three different markers of stress reactivity. These findings suggest that attentional training, in certain individuals, can have iatrogenic effects. PMID- 24767624 TI - Hair cortisol and cognitive performance in healthy older people. AB - Worse cognitive performance in older people has been associated with hypothalamic pituitary-adrenal axis dysregulation (in particular, higher cortisol levels). Analysis of hair cortisol concentrations (HCC) is a novel method to measure long term cortisol exposure, and its relationship with cognition in healthy older people has not yet been studied. We investigated whether HCC (measured in hair scalp) and diurnal salivary cortisol levels (awakening, 30min after awakening, and evening, across two days) were related to cognitive performance (assessed with the Trail-making Test A and B, Digit Span Forward and Backward, word list RAVLT and Stories subtest of the Rivermead) in 57 healthy older people (mean age=64.75 years, SD=4.17). Results showed that lower HCC were consistently related to worse working memory, learning, short-term verbal memory (RAVLT first trial and immediate recall) and long-term verbal memory. In contrast, higher mean levels and higher diurnal area under the curve of diurnal salivary cortisol were related to worse attention and short-term verbal memory (immediate story recall), respectively. Interestingly, a higher ratio of mean levels of diurnal salivary cortisol over HCC were related to worse performance on working memory and short term verbal memory, suggesting that those individuals with lower long-term cortisol exposure might be more vulnerable to the negative effect of HPA-axis dysregulation on these cognitive processes. Our findings suggest that both low long-term cortisol exposure and a possible dysregulation of the diurnal rhythm of the HPA-axis may account, at least in part, for the inter-individual variability in cognitive performance in healthy older people. PMID- 24767625 TI - Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure. AB - BACKGROUND: Epigenetic studies that utilize peripheral tissues to identify molecular substrates of neuropsychiatric disorders rely on the assumption that disease-relevant, cellular alterations that occur in the brain are mirrored and detectable in peripheral tissues such as blood. We sought to test this assumption by using a mouse model of Cushing's disease and asking whether epigenetic changes induced by glucocorticoids can be correlated between these tissue types. METHODS: Mice were treated with different doses of glucocorticoids in their drinking water for four weeks to assess gene expression and DNA methylation (DNAm) changes in the stress response gene Fkbp5. RESULTS: Significant linear relationships were observed between DNAm and four-week mean plasma corticosterone levels for both blood (R(2)=0.68, P=7.1*10(-10)) and brain (R(2)=0.33, P=0.001). Further, degree of methylation change in blood correlated significantly with both methylation (R(2)=0.49, P=2.7*10(-5)) and expression (R(2)=0.43, P=3.5*10(-5)) changes in hippocampus, with the notable observation that methylation changes occurred at different intronic regions between blood and brain tissues. CONCLUSION: Although our findings are limited to several intronic CpGs in a single gene, our results demonstrate that DNA from blood can be used to assess dynamic, glucocorticoid induced changes occurring in the brain. However, for such correlation analyses to be effective, tissue-specific locations of these epigenetic changes may need to be considered when investigating brain-relevant changes in peripheral tissues. PMID- 24767627 TI - A structural model of human ferroportin and of its iron binding site. AB - A structural model of human ferroportin has been built using two Escherichia coli proteins belonging to the major facilitator superfamily of transporters. A potential iron binding site was identified in the inward-open conformation of the model, and its relevance was tested through measurement of iron export of HEK293T cells expressing wild-type or mutated ferroportin. Aspartates 39 and 181 were found to be essential for the transport ability of the protein. Noteworthy, the D181V mutation is naturally found in type 4 hemochromatosis with reticuloendothelial system iron retention phenotype. The outward-open conformation of ferroportin was also predicted, and showed that significant conformational changes must occur in the inward- to outward-open transition of ferroportin. In particular, putative iron ligands move several angstroms away from each other, leading to the logical conclusion that the iron binding site is not occupied by the metal in the outward-open conformation of ferroportin. PMID- 24767626 TI - Prolactin-derived vasoinhibins increase anxiety- and depression-related behaviors. AB - The hormone prolactin (PRL) regulates neuroendocrine and emotional stress responses. It is found in the hypothalamus, where the protein is partially cleaved to vasoinhibins, a family of N-terminal antiangiogenic PRL fragments ranging from 14 to 18kDa molecular masses, with unknown effects on the stress response. Here, we show that the intracerebroventricular administration of a recombinant vasoinhibin, containing the first 123 amino acids of human PRL that correspond to a 14kDa PRL, exerts anxiogenic and depressive-like effects detected in the elevated plus-maze, the open field, and the forced swimming tests. To investigate whether stressor exposure affects the generation of vasoinhibins in the hypothalamus, the concentrations of PRL mRNA, PRL, and vasoinhibins were evaluated in hypothalamic extracts of virgin female rats immobilized for 30min at different time points after stress onset. The hypothalamic levels of PRL mRNA and protein were higher at 60min but declined at 360min to levels seen in non stressed animals. The elevation of hypothalamic PRL did not correlate with the stress-induced increase in circulating PRL levels, nor was it modified by blocking adenohypophyseal PRL secretion with bromocriptine. A vasoinhibin having an electrophoretic migration rate corresponding to 17kDa was detected in the hypothalamus. Despite the elevation in hypothalamic PRL, the levels of this hypothalamic vasoinhibin were similar in stressed and non-stressed rats. Stress reduced the rate of cleavage of PRL to this vasoinhibin as shown by the incubation of recombinant PRL with hypothalamic extracts from stressed rats. These results suggest that vasoinhibins are potent anxiogenic and depressive factors and that stress increases PRL levels in the hypothalamus partly by reducing its conversion to vasoinhibins. The reciprocal interplay between PRL and vasoinhibins may represent an effective mechanism to regulate anxiety and depression. PMID- 24767628 TI - Evaluation of self-administered tests for pelvic girdle pain in pregnancy. AB - BACKGROUND: Different tests are used in order to classify women with pelvic girdle pain (PGP). One limitation of the tests is that they need to be performed by an examiner. Self-administered tests have previously been described and evaluated by women who performed the tests directly before the examiner performed the original tests. Thus, an evaluation of the self-administered tests performed in a more natural setting, such as the women's home is needed.The purpose of this study was to investigate the agreement between self-administered tests performed at home and tests performed by an examiner on women with suspected PGP. Additionally to compare the classification made by an examiner and classification based on results of the self-administered tests and questionnaire. METHODS: One hundred and twenty three pregnant women with suspected PGP participated. Before the appointment at the clinic the women performed the self-administered tests and filled in a questionnaire. During the appointment one specialized physiotherapist performed the tests. Result of the two different sets of tests and the classifications made by the examiner and the self-administered tests including questionnaires were compared concerning percentage of agreement (POA), sensitivity and positive predicted value (PPV). RESULTS: The P4 and the bridging test had the highest POA (>= 74.8%), sensitivity (>= 75.5%) and PPV (>= 91.2%) for posterior PGP. For anterior PGP the MAT test had highest POA (76.4%), and PPV (69.5%), and the modified Trendelenburg test the highest sensitivity (93.0%). Agreement between the two classifications was 87%.A significantly higher number of positive P4 and bridging tests (p<0.01) and a significantly lower number of positive Trendelenburg tests, Active Straight Leg raise and Straight Leg Raise (p<0.05) were recorded by the examiner compared to the self-administered ones. CONCLUSIONS: Our results indicate that self-administered test and questionnaires are possible to use for testing and classification of women with suspected PGP. PMID- 24767630 TI - Combined pre-treatment MRI and 18F-FDG PET/CT parameters as prognostic biomarkers in patients with cervical cancer. AB - OBJECTIVE: To determine the associations of quantitative parameters derived from multiphase contrast-enhanced magnetic resonance imaging (CE-MRI), diffusion weighted (DW) MRI and 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/computed tomography (PET/CT) with clinico-histopathological prognostic factors, disease-free survival (DFS) and overall survival (OS) in patients with cervical cancer. METHODS AND MATERIALS: Our institutional review board approved this retrospective study of 49 patients (median age, 45 years) with histopathologically proven IB-IVB International Federation of Gynecology and Obstetrics (FIGO) cervical cancer who underwent pre-treatment pelvic MRI and whole-body 18F-FDG PET/CT between February 2009 and May 2012. Maximum diameter (maxTD), percentage enhancement (PE) and mean apparent diffusion coefficient (ADCmean) of the primary tumor were measured on MRI. Maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), total lesion glycolysis (TLG) were measured on 18F-FDG PET/CT. Correlations between imaging metrics and clinico histopathological parameters including revised 2009 FIGO stage, tumor histology, grade and lymph node (LN) metastasis at diagnosis were evaluated using the Wilcoxon rank sum test. Cox modeling was used to determine associations with DFS and OS. RESULTS: Median follow-up was 17 months. 41 patients (83.6%) were alive. 8 patients (16.3%) died of disease. Progression/recurrence occurred in 17 patients (34.6%). Significant differences were observed in ADCmean, SUVmax, MTV and TLG according to FIGO stage (p<0.001-0.025). There were significant correlations between ADCmean, MTV, TLG and LN metastasis (p=0.017-0.032). SUVmax was not associated with LN metastasis. FIGO stage (p=0.017/0.033), LN metastases (p=0.001/0.020), ADCmean (p=0.007/0.020) and MTV (p=0.014/0.026) were adverse predictors of both DFS/OS. maxTD (p=0.005) and TLG (p=0.024) were adverse predictors of DFS. PE and SUVmax did not correlate with DFS or OS (p=0.18-0.72). CONCLUSIONS: Quantitative parameters derived from pre-treatment DW-MRI (ADCmean) and from 18F-FDG PET/CT (MTV and TLG) were associated with high-risk features and may serve as prognostic biomarkers of survival in patients with cervical cancer. PMID- 24767629 TI - A study of plaque vascularization and inflammation using quantitative contrast enhanced US and PET/CT. AB - BACKGROUND: Contrast-enhanced ultrasound (CEUS) is an in vivo methodology to quantify carotid plaque vascularization. Increased metabolism in plaques, measured as FDG uptake in PET/CT examination, has been associated with markers of inflammation in histological samples. In this study, we tested the association between FDG uptake and vascularization measured by CEUS to assess whether CEUS can be used as an in vivo marker of plaque vulnerability. METHODS: After informed consent, subjects aged >60 years with carotid plaque height exceeding 2.5mm were recruited. CEUS was performed and analyzed using earlier described protocol and software, Contrast Quantification Program, which calculates the fraction of the plaque being contrast positive (CQP value). PET/CT examination was performed within 3 months of CEUS (median time 7 days). PET/CT images were acquired 90 min after FDG injection (2.7 MBq/kg). FDG uptake was measured as tissue background index (TBI), calculated using Spearman's rho as mean standard uptake value (SUV) of the plaque divided by mean SUV in the jugular vein (mean of 7 measuring points). Local ethics committee approved the study. RESULTS: We recruited 13 subjects (5 women) with a mean age of 71 years, 6 had a history of stroke or TIA, 1 had a history of ipsilateral stroke. CQP values showed a significant, positive correlation with TBI of carotid plaques, r=0.67, p<0.02. CONCLUSIONS: Plaque vascularization measured by CEUS correlates positively with FDG uptake measured by PET/CT in humans. This indicates an association between vascularization and inflammation and/or hypoxia, supporting the use of CEUS as a non-invasive method to detect plaque vulnerability. PMID- 24767631 TI - Introduction and commentary: Paving the way for biosimilars in oncology, part 3: Clinical and economic impact of oncology biosimilars. PMID- 24767632 TI - Pharmacoeconomics of cancer therapies: considerations with the introduction of biosimilars. AB - Biologics are important treatments for a number of cancers, but they are also significant drivers of globally escalating healthcare costs. Biosimilars have the potential to offer cost-savings with comparable efficacy and safety to innovator products. They are being used in the European Union, Canada, Japan, and Australia and may help with improving health outcomes while minimizing costs to patients and global healthcare systems. The overall value of a biosimilar is not determined solely by its pricing. Efficacy and safety relative to the reference biologic drug and competitive agents as well as development and manufacturing costs, treatment administration costs, and results from long-term safety monitoring are considered. Optimizing economic efficiency is one part of an ongoing healthcare decision-making process with all therapeutics that aims to attain high levels of quality-of-care and safety given available resources. Some analytic tools stakeholders use to determine the pharmacoeconomic value of a therapy that are highlighted in this review article are opportunity cost, cost effectiveness, and cost-minimization analyses. These methodologies can provide information to physicians, patients, and payers that may help reaffirm the value of a given biosimilar compared with its reference product throughout its life cycle. PMID- 24767633 TI - Biosimilars in oncology: from development to clinical practice. AB - Biologics play an integral role in the treatment of cancer not only for their therapeutic effects and ability to improve outcomes, but also as supportive care agents. Biologics are more complex to manufacture and take longer to bring to market. Because biologics are considerably more costly than small-molecule drugs, their use has placed an increasing economic demand on healthcare systems worldwide. Biosimilars are designed to be highly similar to existing branded biologics, but because biologics cannot be exactly copied, biosimilars should not be referred to as generic, exact versions of the innovator biologic. Biosimilars have the potential to increase access and provide lower cost options for cancer care as patent protection for some of the most widely used biologics begins to expire. Regulatory requirements for biosimilars are evolving, as are global harmonization and/or standardization strategies that can facilitate their robust clinical development. This review highlights critical factors involved with the integration of biosimilars into oncology treatment paradigms and practices. Clinicians will likely seek out practice guidelines and position statements from established scientific societies to help evaluate key information regarding biosimilars, such as efficacy, safety, comparability, and interchangeability with the reference biologic. Automatic substitution, nomenclature, extrapolation of clinical data from one indication to another, as well as parameters for ongoing pharmacovigilance are evolving considerations. Education of physicians and other healthcare providers, payers, and patients about biosimilars may facilitate informed decision making, promote acceptance of biosimilars into clinical practice, increase accessibility, and expedite associated health and economic benefits. PMID- 24767634 TI - Comparison of walking performance over the first 2 minutes and the full 6 minutes of the Six-Minute Walk Test. AB - BACKGROUND: Although the Six-Minute Walk Test (6MWT), as recommended by the American Thoracic Society, is widely used as a measure of functional endurance, it may not be applicable in some settings and populations. We sought to examine, therefore, performance over the first 2 minutes and the full 6 minutes of the 6MWT. Specifically, we investigated completion rates, distances walked, test retest reliability, and the relationship between distances walked over the first 2 and the full 6 minutes of the 6MWT. METHODS: Community-dwelling children and adults age 3-85 years (n = 337) were asked to walk back and forth on a 15.24 meter (50 ft) course as far as possible without running over a 6 minute period. Test completion and the distance covered by the participants at 2 and 6 minutes were documented. The reliability of distances covered at 2 and 6 minutes was determined by retesting a subsample of 54 participants 6 to 10 days later. The relationship between distances covered at 2 and 6 minutes was determined for the 330 participants completing the 6MWT. RESULTS: All 337 participants completed at least 2 minutes of walking, but 7 children less than 5 years of age ceased walking before 6 minutes had elapsed. For the remaining 330 participants the mean distance walked was 186 meters at 2 minutes and 543 meters at 6 minutes. The distances covered at 2 and 6 minutes were reliable between sessions (intraclass correlation coefficients = 0.888 and 0.917, respectively). The distances covered over 2 and 6 minutes were highly correlated (r = 0.968). CONCLUSIONS: The completion rate, values obtained, test-retest reliability, and relationship of the distances walked in 2 and 6 minutes support documentation of 2 minute distance during the 6MWT. The findings also provide support for use of a Two Minute Walk Test as the endurance component in the Motor Battery of the NIH Toolbox. PMID- 24767635 TI - Individuation in Slovene emerging adults: its associations with demographics, transitional markers, achieved criteria for adulthood, and life satisfaction. AB - The study investigated associations of Slovene emerging adults' age, gender, living situation, romantic relationship, and employment status with aspects of individuation in relation to mother and father. Controlling for demographic variables and transitional markers of adulthood, we further explored the contribution of individuation measures to individuals' perceptions of achieved criteria for adulthood and life satisfaction. The participants provided self reports on the Individuation Test for Emerging Adults, the Satisfaction With Life Scale, and the list of Achieved Criteria for Adulthood. Age and living out of parental home were positively associated with self-reliance in relation to both parents, whereas female gender was related to higher levels of connectedness and seeking parental support. Along with age and involvement in a romantic relationship, connectedness and self-reliance predicted adulthood criteria attainment and life satisfaction. The results support the models of individuation that emphasize growing autonomy and retaining connectedness to parents as pathways towards personal adjustments. PMID- 24767636 TI - Fertility outcomes after uterine artery occlusion in the management of women with symptomatic uterine fibroids. PMID- 24767637 TI - Uterine-sparing surgery for adenomyosis and/or adenomyoma. AB - Adenomyosis of the uterus is defined as the presence of endometrial tissue, including glands and stroma, situated at least 2.5 mm below the endometrial myometrial junction and widely distributed within the myometrium layer of the uterus. There is no consensus on the appropriate treatment for symptomatic uterine adenomyosis in women who want to preserve their uterus, partly because adenomyosis is somewhat enigmatic in diagnosis and owing to its clinical significance. Hysterectomy, through either exploratory laparotomy or minimally invasive procedures, is a definite treatment for uterine adenomyosis, once the women have completed childbirth or do not require future fertility. However, many women with a uterine pathology still have a strong desire to preserve the uterus, for which conservative and uterine-sparing procedures are increasingly used, and with which fertility preservation or quality-of-life improvement can be achieved. Although medical management can be effective, similar to the management of uterine fibroids (myoma), its effect is often transient and rapid regrowth of adenomyosis and relapse of symptoms and signs always occur once the treatment is stopped. Therefore, other strategies should be selected. Conservative and uterine sparing surgery might be one of the most familiar procedures of these uterine sparing procedures. In this article, the latest knowledge and research evidence on uterine-sparing surgery for uterine adenomyosis are reviewed. PMID- 24767639 TI - Is portable three-dimensional ultrasound a valid technique for measurement of postpartum urinary bladder volume? AB - OBJECTIVE: To determine the accuracy of bladder volume (BV) measurement and to identify factors that influenced the ultrasound bladder scanner (UBS) measurement of BV in postpartum women compared with transurethral catheterization. MATERIALS, METHODS AND RESULTS: A total of 190 paired measurements were performed on 190 women aged between 16 and 47 years. Majority of the women (36.9%) were in their first parity (range: 1-9). The mean BV was 159.46 mL [standard deviation (SD) = 99.78; range: 17-593 mL] on three-dimensional (3D) UBS and 143.76 mL (SD = 104.89; range: 2-588 mL) on catheterization. The mean difference between the two values was 15.70 mL (SD = 69.31, p < 0.001). The Foley's catheter was clamped for a minimum of 30 minutes and a maximum of 260 minutes. The UBS measurements were highly correlated with the BV obtained by catheterization (r = 0.819; p < 0.001). There was no significant difference between UBS and catheterized volume in a different volume subgroup. There were 35 cases (18.2%) with the difference in measurement of more than 25%. Twenty-five cases were associated with a catheterized volume less than 50 mL. There were a total of 33 cases with true BV of less than 50 mL, and only eight cases (24.24%) had an accurate measurement. The UBS tends to overestimate BV between 2 and 270 mL in this group. There was a significant linear relationship between the difference in measurement and body weight and duration of clamping. CONCLUSION: Measurement of BV in immediate postpartum period using UBS is comparable with urethral catheterization. The accuracy of measurement is affected by body weight and increasing amount of BV. PMID- 24767638 TI - The effects of different epidural analgesia formulas on labor and mode of delivery in nulliparous women. AB - OBJECTIVES: Patient-controlled epidural analgesia (PCEA) and continuous epidural infusion (CEI) are popular and effective methods for pain relief during labor; however, there are concerns about increasing rates of cesarean section (C/S) and instrumental delivery. This prospective study investigated the effect of PCEA and CEI with different formulas on labor and the mode of delivery in nulliparous women. MATERIALS AND METHODS: A total of 480 nulliparous women were randomized into four groups, with 120 in each. Group A received a loading dose of 10 mL of 1 mg/mL ropivacaine with 2 MUg/mL fentanyl, then an intermittent bolus of 5 mL with a background infusion of 5 mL/hour by PCEA. Group B received the same PCEA formula as Group A with 0.8 mg/mL bupivacaine. Group C received the same formula as Group A by CEI with 1 mg/mL ropivacaine at a rate of 10 mL/hour. Group D received the same formula as Group C with 0.8 mg/mL bupivacaine. The rates of C/S and instrumental delivery and the incidence of side effects were recorded. RESULTS: The rates of C/S were significantly different between Groups A and C, Groups A and D, and Groups B and D. The rates of instrumental delivery for normal spontaneous delivery were significantly different between Groups A and B, A and D, B and C, and C and D. CONCLUSION: The C/S rate was higher in Groups C and D; however, the instrumental delivery rate was lower in Groups A and C. We conclude that PCEA with 1 mg/mL ropivacaine might provide the greatest benefit for labor analgesia. PMID- 24767640 TI - Comparison of Quinn's Advantage fertilization medium and tissue culture medium 199 for in vitro maturation of oocytes. AB - OBJECTIVE: The purpose of the study was to compare the Quinn's Advantage fertilization medium (Q1) and the tissue culture medium 199 (TCM199) for in vitro maturation (IVM) of oocytes and ammonium production during IVM. MATERIALS AND METHODS: The immature murine oocytes were randomly added into Q1 and TCM199. Ammonium concentrations were measured at the start and after 18 hours of IVM, and the mature oocytes were fertilized and cultured into blastocysts. The blastocysts were then stained for inner cell mass (ICM) and trophectoderm. RESULTS: The maturation rate was higher in Q1 than in TCM199 (85.7% vs. 76.6%, p = 0.024). The fertilization and blastocyst rates were slightly higher in Q1, but not significant. Differential staining of the blastocysts showed slightly higher ICM ratio in the blastocysts derived from Q1. Mean ammonium concentrations in Q1 and TCM199 at Time 0 were 184.9 and 339.2 MUg/dL, respectively (p = 0.05), and after 18 hours of IVM were 268.7 and 443.6 MUg/dL, respectively (p = 0.045). Addition of ammonium chloride into Q1 adversely affects IVM. CONCLUSION: Q1 is superior to TCM199 in terms of oocyte maturation, which may be due to lower ammonium concentration. PMID- 24767641 TI - A comparative study of saffron aqueous extract and its active ingredient, crocin on the in vitro maturation, in vitro fertilization, and in vitro culture of mouse oocytes. AB - OBJECTIVE: Reactive oxygen species have effects on gamete quality and gamete interaction; they influence spermatozoa, oocytes, embryos, and their environment. In this study, we evaluated the antioxidant effect of different concentrations of saffron (Crocus sativus L.) aqueous extract (SAE) and its ingredient, crocin, on the improvement of in vitro maturation (IVM) and subsequent in vitro fertilization (IVF) and embryo development of mouse oocytes. MATERIALS AND METHODS: Cumulus oocyte complexes were collected from ovaries, and germinal vesicle oocytes were cultured in the presence of SAE and crocin. SAE was added at dosages of 5 MUg/mL, 10 MUg/mL, and 40 MUg/mL; dosages of crocin were 50 MUg/mL, 100 MUg/mL, and 400 MUg/mL. All dosages were added to maturation medium and a group without SAE or crocin was considered as the control group. Following IVM, metaphase II oocytes were fertilized and cultured in vitro in order to observe embryo development. RESULTS: Both SAE and crocin improved the rate of IVM, IVF, and in vitro culture. Addition of 40 MUg/mL SAE to maturation medium significantly increased the rate of IVM, IVF, and in vitro culture (p < 0.05). Furthermore 100 MUg/mL crocin significantly increased the IVM rate compared to the control group (p < 0.05). CONCLUSION: Use of SAE during IVM can affect on IVM, IVF, and early embryo development in a dose-dependent manner. SAE appears to have a stronger effect than pure crocin. PMID- 24767642 TI - Inappropriate use of standard error of the mean when reporting variability of study samples: a critical evaluation of four selected journals of obstetrics and gynecology. AB - OBJECTIVE: The study was designed to investigate the frequency of misusing standard error of the mean (SEM) in place of standard deviation (SD) to describe study samples in four selected journals published in 2011. Citation counts of articles and the relationship between the misuse rate and impact factor, immediacy index, or cited half-life were also evaluated. MATERIALS AND METHODS: All original articles in the four selected journals published in 2011 were searched for descriptive statistics reporting with either mean +/- SD or mean +/- SEM. The impact factor, immediacy index, and cited half-life of the journals were gathered from Journal Citation Reports Science edition 2011. Scopus was used to search for citations of individual articles. The difference in citation counts between the SD group and SEM group was tested by the Mann-Whitney U test. The relationship between the misuse rate and impact factor, immediacy index, or cited half-life was also evaluated. RESULTS: The frequency of inappropriate reporting of SEM was 13.60% for all four journals. For individual journals, the misuse rate was from 2.9% in Acta Obstetricia et Gynecologica Scandinavica to 22.68% in American Journal of Obstetrics & Gynecology. Articles using SEM were cited more frequently than those using SD (p = 0.025). An approximate positive correlation between the misuse rate and cited half-life was observed. CONCLUSION: Inappropriate reporting of SEM is common in medical journals. Authors of biomedical papers should be responsible for maintaining an integrated statistical presentation because valuable articles are in danger of being wasted through the misuse of statistics. PMID- 24767643 TI - Serum cytokeratin-19 fragment (Cyfra 21-1) is a prognostic indicator for epithelial ovarian cancer. AB - OBJECTIVES: Cytokeratin 19 is significant for indicating cancer cells, and Cyfra 21-1 is a fragment of cytokeratin 19. This retrospective study was designed to define the prognostic value of serum Cyfra 21-1 in epithelial ovarian cancers (EOC). MATERIALS AND METHODS: Serum Cyfra 21-1 concentration was obtained from 42 patients with EOC prior to treatment. Various prognostic aspects were examined using univariable and multivariable analyses. The standard serum marker cancer antigen 125 was measured simultaneously and compared in this analysis. RESULTS: Serum levels of both Cyfra 21-1 and cancer antigen 125 were associated with positive retroperitoneal lymph nodes and platinum resistance; higher levels of Cyfra 21-1 (3.0 ng/mL as the cut-off) were associated with shorter disease-free survival (16 months vs. 28 months, p = 0.001) and overall survival (29 months vs. 41 months, p = 0.007) than lower levels. Further univariable analysis showed that Cyfra 21-1, poor differentiation, and retroperitoneal lymph node metastasis were related to platinum resistance and mortality. Multivariable analysis indicated retroperitoneal lymph node metastasis and serum Cyfra 21-1 were independent risk factors for both disease-free survival and overall survival. CONCLUSION: The pretreatment level of serum Cyfra 21-1 had remarkable prognostic significance for EOC, indicating poor survival when it was elevated above 3.0 ng/mL. PMID- 24767644 TI - Effect of gonadotropin-releasing hormone agonist on ES-2 ovarian cancer cells. AB - OBJECTIVE: Gonadotropin-releasing hormone (GnRH) receptor is found in the ovarian tissue, including epithelial ovarian cancer (EOC), suggesting that GnRH agonists may have direct action on EOC. MATERIALS AND METHODS: Ovarian clear cell cancer (ES-2) cells were treated with low-dose GnRH agonist with/without low-dose paclitaxel (1 MUM D-Lys(6) with/without 0.5 MUM or 1.0 MUM paclitaxel). Growth and behavior of ES-2 cells were evaluated. RESULTS: Use of either D-Lys(6) or paclitaxel or a combination of the two did not affect the morphology and growth pattern of ES-2 cells. However, ability of migration and invasion of ES-2 cells was significantly decreased in either use of D-Lys(6) or paclitaxel and more apparent with the combination. Type I GnRH receptor expression of ES-2 was not altered significantly by the combination. CONCLUSION: GnRH agonist might modify the ES-2 ovarian cancer cells, and its role might be independent, additional or synergistic, suggesting the potential role of the use of GnRH agonist in the management of clear cell type of the ovarian cancer. However, the results of this study were derived using ES-2 ovarian cancer cells, and might not be valid in other cell types of ovarian cancers. PMID- 24767645 TI - Postdischarge rehospitalization and in-hospital mortality among Taiwanese women with hip fracture. AB - OBJECTIVES: To explore the factors concerning postdischarge rehospitalization and in-hospital mortality among Taiwanese women older than 50 years with hip fracture. MATERIALS AND METHODS: The National Health Insurance database from 2000 to 2006 was used to identity relevant cases. Women inpatients aged over 50 years with new-onset hip fracture in 2003 were identified. We analyzed the factors affecting postdischarge rehospitalization and in-hospital mortality. RESULTS: In 2003, there were 9467 new-onset hip fracture inpatients claimed among Taiwanese women aged over 50 years. The 3-year cumulative rates of rehospitalization after discharge and in-hospital mortality rate were 11.01% (1043) and 7.10% (672), respectively. The factors determined to be related to rehospitalization were patient age, hospital level, length of stay of the initial hospitalization due to hip fracture, and Charlson comorbidity index (CCI) score. The factors determined to be related to in-hospital mortality were age, urbanization level of region where patients were insured, hospital level, length of stay of the initial hospitalization due to hip fracture, and CCI score. CONCLUSION: Characteristics of women aged over 50 years with hip fracture remain an important issue based on high rehospitalization and in-hospital mortality rates. We have identified related risk factors that may be helpful in treating hip fracture among this population segment. PMID- 24767646 TI - Preimplantation genetic diagnosis by fluorescence in situ hybridization of reciprocal and Robertsonian translocations. AB - OBJECTIVE: The presence of reciprocal and Robertsonian chromosomal rearrangement is often related to recurrent miscarriage. Using preimplantation genetic diagnosis, the abortion rate can be decreased. Cases treated at our center were reviewed. MATERIALS AND METHODS: A retrospective analysis for either Robertsonian or reciprocal translocations was performed on all completed cycles of preimplantation genetic diagnosis at our center since the first reported case in 2004 until the end of 2010. Day 3 embryo biopsies were carried out, and the biopsied cell was checked by fluorescent in situ hybridization using relevant informative probes. Embryos with a normal or balanced translocation karyotype were transferred on Day 4. RESULTS: Thirty-eight preimplantation genetic diagnosis cycles involving 17 couples were completed. A total of 450 (82.6%) of the total oocytes were MII oocytes, and 158 (60.0%) of the two-pronuclei embryos were biopsied. In 41.4% of the fluorescent in situ hybridization analyses, the results were either normal or balanced. Embryos were transferred back after 21 cycles. Three babies were born from Robertsonian translocation carriers and another two from reciprocal translocation carriers. The miscarriage rate was 0%. Among the reciprocal translocation group, the live delivery rate was 8.3% per ovum pick-up cycle and 18.2% per embryo transfer cycle. Among the Robertsonian translocation group, the live delivery rate was 14.3% per ovum pick-up cycle and 20.0% per embryo transfer cycle. CONCLUSION: There is a trend whereby the outcome for Robertsonian translocation group carriers is better than that for reciprocal translocation group carriers. Aneuploidy screening may possibly be added in order to improve the outcome, especially for individuals with an advanced maternal age. The emergence of an array-based technology should help improve this type of analysis. PMID- 24767648 TI - Long-term survival outcome of laparoscopic staging surgery for endometrial cancer in Taiwanese experience. AB - OBJECTIVE: This study aims to evaluate the long-term safety and efficacy of laparoscopic staging surgery (LSS) for endometrial cancer in Taiwanese women. MATERIALS AND METHODS: This is a longitudinal study of prospectively registered 105 patients who underwent LSS for endometrial cancer between June 1995 and June 2008. RESULTS: The mean duration of surgery was 186.8 minutes, and the mean intraoperative blood loss was 220.38 mL. The median number of retrieved pelvic lymph nodes was 18. The intraoperative complication rate was 4.8%, including two cases of ureteral injury and one case each of bladder injury, bowel injury, and vascular injury. No patient required conversion to laparotomy. During the median follow-up of 55.3 months, six cases of recurrence (5.7%) and three tumor-related deaths (2.9%) were recorded. The 5-year disease-free survival and the overall survival were 93.39% and 98.05%, respectively. CONCLUSION: The study revealed favorable perioperative outcomes and better long-term survival than reported in the Taiwan Cancer Registry, and similar good surgical results to those reported in the Western studies. Therefore, LSS by experienced surgeons for endometrial cancer is a feasible and efficacious alternative to laparotomy. PMID- 24767647 TI - Fetal maxillary and mandibular length in normal pregnancies from 11 weeks' to 13(+6) weeks' gestation: a Taiwanese study. AB - OBJECTIVES: This study aims to establish the normal range of maxillary and mandibular lengths within the Taiwanese population at 11(+0) weeks to 13(+6) weeks of gestation in normal singleton pregnancy as a reference value for prenatal ultrasonographic examinations. MATERIALS AND METHODS: We examined nuchal translucency in 269 normal singleton pregnancies, with the gestational age ranging from 11 weeks to 13(+6) weeks in this study. Fetal biometric measurements, with an emphasis on maxillary and mandibular lengths, were obtained from the patients during consecutive routine prenatal ultrasonographic examinations. RESULTS: Maxillary and mandibular lengths were recorded successfully in 191 patients and 179 patients, respectively. The mean maternal age was 31 years (range 19-45 years), with a corresponding gestational age of 12 + 4 weeks (range, 11(+0)-13(+6) weeks). A first-degree correlation was found to exist between the gestational age and maxillary length (r = 0.596; p < 0.0001; y = 1.491 * GA - 10.523) as well as mandibular length (r = 0.465; p < 0.0001; y = 1.050 * GA - 6.50). CONCLUSION: Normative data for ultrasonographic measurements of maxillary and mandibular lengths within the Taiwanese population were presented. Our data can serve as a reference value in congenital anomaly screening during prenatal examination. PMID- 24767649 TI - Chromosomal deletions detected at amniocentesis. AB - OBJECTIVE: The aim of this study is to present the incidence, prenatal and postnatal findings, and modes of ascertainment in chromosomal deletions detected at amniocentesis. MATERIALS AND METHODS: We reviewed all the cases with chromosomal deletions, which were detected by amniocentesis in Mackay Memorial Hospital, Taipei, Taiwan, between January 1987 and December 2012. Data on the locations and types of deletion, reasons for performing amniocentesis, maternal age, gestational age at amniocentesis, fetal karyotypes, inheritance of deletions, and relative prenatal findings were collected. RESULTS: Amniocentesis was performed in 33,305 cases within this period of time. Among these, 31 cases of chromosomal deletions were considered for the study. The mean gestational age at amniocentesis was 21.0 weeks (range from 15 weeks to 32 weeks) and the mean maternal age at amniocentesis was 32.1 years (range from 26 years to 37 years). Nineteen cases (61.3%) manifested fetal structural abnormalities on ultrasound, nine (29.0%) presented no ultrasound abnormalities, and three had an unknown status. The main modes of ascertainment included abnormal ultrasound findings in 10 cases (32.2%), advanced maternal age in 11 cases (35.5%), abnormal maternal serum screening results in six cases (19.6%), and other reasons in four cases (13.0%). Of the 27 cases with known inheritance, the deletion was inherited in two (6.6%) and de novo in 25 (92.6%). Males accounted for 11 (35.5%) and females for 20 (64.5%) cases. Chromosomal deletions are more often to occur in chromosomal 5(4 cases, 12.9%), chromosomal 18 (4 cases, 12.9%), chromosomal 4 (3 cases, 9.7%), chromosomal 7 (3 cases, 9.7%), chromosomal 10 (3 cases, 9.7%), chromosomal 11 (3 cases, 9.7%), and chromosomal 1 (2 cases, 6.5%). There were four cases of chromosomal mosaicism: two involved chromosome 5, one involved chromosome 10, and one involved chromosome 18. Twenty-three cases (74.2%) had terminal deletions and the other eight cases (26.7%) had interstitial-type deletions. CONCLUSION: In summary, we have presented the results of prenatal diagnosis for chromosomal deletions using amniocentesis. Chromosomal deletions are more likely to occur in females and more often in chromosomal 5p and 18q. Prenatal diagnosis at amniocentesis is frequently associated with advanced maternal age, abnormal ultrasound findings, and abnormal maternal serum screening. The frequency of ascertainment in chromosome deletion seems to be directly correlated with advanced maternal age and abnormal ultrasound findings. In cases with terminal deletions, prenatal ultrasound plays a more important role for prenatal diagnosis. PMID- 24767650 TI - Detection of altered methylation status at 11p15.5 and 7q32 in placental mesenchymal dysplasia. AB - OBJECTIVE: This paper aims to present molecular cytogenetic and epigenetic evaluation of placental mesenchymal dysplasia (PMD). MATERIALS AND METHODS: A 33 year-old woman was referred to the hospital at 18 weeks of gestation because of a multicystic mass in the placenta. Ultrasound showed a normal amount of amniotic fluid and a normal singleton fetus. Amniocentesis revealed a karyotype of 46,XX. Array comparative genomic hybridization analysis of amniocytes revealed no genomic imbalance. Preterm labor and premature rupture of the membranes occurred, and a female fetus was delivered with no structural abnormality. The placenta was enlarged and filled with many grape-like vesicles. In the placental cystic mass, interphase fluorescence in situ hybridization revealed diploidy and array comparative genomic hybridization revealed no genomic imbalance. Quantitative fluorescent polymerase chain reaction (QF-PCR), methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), and methylation-specific PCR were performed in the placental cystic mass. RESULTS: MS-MLPA analysis showed hypermethylation (methylation index = 0.8) at H19 differentially methylated region (DMR) [imprinting center 1 (IC1)] at 11p15.5 and hypomethylation (methylation index = 0.2) at KvDMR1(IC2) at 11p15.5. Methylation-specific PCR assay identified hypomethylation of PEG1/MEST at 7q32, and hypermethylation at H19DMR and hypomethylation at KvDMR1 at 11p15.5. QF-PCR analysis identified androgenetic/biparental mosaicism in the placenta. The placental cystic mass was consistent with the diagnosis of PMD. CONCLUSION: MS-MLPA and methylation specific PCR are useful methods for rapid detection of epigenetic alternations in PMD, and QF-PCR is useful in the diagnosis of androgenetic/biparental mosaicism. PMID- 24767651 TI - A 1.37-Mb 12p11.22-p11.21 deletion coincident with a 367-kb 22q11.2 duplication detected by array comparative genomic hybridization in an adolescent girl with autism and difficulty in self-care of menstruation. AB - OBJECTIVE: To present an array comparative genomic hybridization (aCGH) characterization of a 12p11.22-p11.21 microdeletion and 22q11.2 microduplication in an adolescent girl with autism, mental retardation, facial dysmorphism, microcephaly, behavior problems, and an apparently balanced reciprocal translocation of t(8;12)(q24.3;p11.2). MATERIALS AND METHODS: A 13-year-old girl was referred to the hospital because of autism, mental retardation, and difficulty in the self-care of her menstruation. Cytogenetic analysis revealed an apparently balanced reciprocal translocation and a karyotype of 46,XX,t(8;12) (q24.3;p11.2)dn. The girl manifested microcephaly, hypertelorism, flat facial profile, prominent forehead, thick scalp hair, upslanting palpebral fissures, broad nasal bridge, bulbous nose, right simian crease, bilateral clinodactyly of the fifth fingers, bilateral pes cavus, learning difficulties, mental retardation, emotional instability, cognitive impairment, behavior problems, jumping-like gaits, and autistic spectrum disorder. aCGH was performed to evaluate genomic imbalance in this patient. RESULTS: aCGH analysis revealed a 1.37-Mb 12p11.22-p11.21 microdeletion or arr [hg 19] 12p11.22-p11.21 (30,645,008 32,014,774)*1 and a 367-kb 22q11.21 microduplication or arr [hg 19] 22q11.21 (18,657,470-19,024,306)*3. The 1.37-Mb 12p11.22-p11.21 microdeletion encompassed 26 genes including IPO8, CAPRIN2, and DDX11, and the 367-kb 22q11.21 microduplication encompassed 20 genes including USP18, DGCR6, PRODH, and DGCR2. CONCLUSION: An apparently balanced translocation may be in fact affected by concurrent deletion and duplication in two different chromosomal regions. Our presentation provides information on diagnostic phenotype of 12p11.22-p11.21 microdeletion and 22q11.2 microduplication. PMID- 24767652 TI - Mosaic tetrasomy 9p at amniocentesis: prenatal diagnosis, molecular cytogenetic characterization, and literature review. AB - OBJECTIVE: This study was aimed at prenatal diagnosis of mosaic tetrasomy 9p and reviewing the literature. MATERIALS AND METHODS: A 37-year-old woman underwent amniocentesis at 20 weeks' gestation because of advanced maternal age and fetal ascites. Cytogenetic analysis of cultured amniocytes revealed 21.4% (6/28 colonies) mosaicism for a supernumerary i(9p). Repeat amniocentesis was performed at 23 weeks' gestation. Array comparative genomic hybridization, interphase fluorescence in situ hybridization, and quantitative fluorescent polymerase chain reaction were applied to uncultured amniocytes, and conventional cytogenetic analysis was applied to cultured amniocytes. RESULTS: Array comparative genomic hybridization analysis of uncultured amniocytes detected a genomic gain at 9p24.3 9q21.11. Interphase fluorescence in situ hybridization analysis of uncultured amniocytes using a 9p24.3-specific probe RP11-31F19 (spectrum red) showed four red signals in 47.1% (49/104 cells) in uncultured amniocytes. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 47,XX, +idic(9)(pter >q21.11::q21.11->pter)[4]/46,XX[20] and 16.7% (4/24 colonies) mosaicism for tetrasomy 9p. Quantitative fluorescent polymerase chain reaction confirmed a maternal origin of tetrasomy 9p. The pregnancy was terminated, and a malformed fetus was delivered with hydrops fetalis and facial dysmorphism. The fetal blood cells had 32.5% (13/40 cells) mosaicism for tetrasomy 9p. CONCLUSION: Mosaic tetrasomy 9p at amniocentesis can be associated with fetal ascites and hydrops fetalis. The mosaic level of tetrasomy 9p may decrease after long-term tissue culture in amniocytes in case of mosaic tetrasomy 9p. PMID- 24767653 TI - Complete involution of prenatally-diagnosed fetal scalp hemangioma. AB - OBJECTIVE: Scalp hemangioma is a rare benign fetal tumor. Here, we describe the detailed imaging features and natural course of a fetal scalp hemangioma until 1 year of age. CASE REPORT: We encountered a case of scalp hemangioma at 23 weeks' gestation by prenatal ultrasonography and magnetic resonance imaging. The mass persisted postnatally, but spontaneously regressed after birth. CONCLUSION: Proper diagnosis with prenatal ultrasonography and magnetic resonance imaging is important when a scalp mass is suspected in utero. Continuation of the pregnancy after appropriate counseling is prudent, considering the favorable prognosis and the rate of spontaneous regression of uncomplicated cases. PMID- 24767654 TI - Prenatal diagnosis of hypomethylation at KvDMR1 and Beckwith-Wiedemann syndrome in a pregnancy conceived by intracytoplasmic sperm injection and in vitro fertilization and embryo transfer. AB - OBJECTIVE: We report prenatal diagnosis of hypomethylation at KvDMR1 and Beckwith Wiedemann syndrome (BWS) in a pregnancy conceived by intracytoplasmic sperm injection and in vitro fertilization and embryo transfer. CASE REPORT: A 34-year old, primigravid woman was referred to the hospital at 21 weeks' gestation because of advanced maternal age and an isolated omphalocele in the fetus. Her husband had the fertility problem of oligospermia. This pregnancy was achieved by intracytoplasmic sperm injection and in vitro fertilization and embryo transfer. Prenatal ultrasound revealed a 2.1 cm * 1.6 cm isolated omphalocele. The woman underwent amniocentesis. Array comparative genomic hybridization and methylation specific multiplex ligation-dependent probe amplification (MS-MLPA) were applied to the DNA extracted from the uncultured amniocytes. Conventional cytogenetic analysis and high-resolution melting analysis were performed on cultured amniocytes. Array comparative genomic hybridization revealed no genomic imbalance. MS-MLPA analysis revealed H19DMR(IC1) normal methylation and KvDMR1(IC2) hypomethylation. Conventional cytogenetic analysis revealed a karyotype of 46,XX. High-resolution melting analysis using a methylation-specific polymerase chain reaction assay confirmed normal methylation at H19DMR(IC1) and hypomethylation at KvDMR1(IC2). The altered methylation status at 11p15.5 and the phenotype of omphalocele were consistent with the diagnosis of BWS. CONCLUSION: In case of prenatally detected omphalocele associated with an obstetric history of assisted reproductive technology, a differential diagnosis of BWS should be considered. Methylation assays such as MS-MLPA and methylation-specific polymerase chain reaction using uncultured amniocytes are useful for rapid diagnosis of BWS under such circumstances. PMID- 24767655 TI - Correlation of ovarian fibroma with elevated serum CA-125. PMID- 24767656 TI - Rapid recovery of vulvar pyoderma gangrenosum in response to aggressive surgery and steroid treatment. PMID- 24767657 TI - Pyomyoma mimicking advanced ovarian cancer: a rare manifestation in a postmenopausal virgin. PMID- 24767658 TI - Superficial angiomyxoma on the vulva of an adolescent. PMID- 24767659 TI - Complete chronic uterine inversion with eventration of the vagina. PMID- 24767660 TI - Cervical priming with misoprostol for the termination of cesarean scar pregnancy. PMID- 24767661 TI - Perioperative blindness after debulking surgery for ovarian cancer. PMID- 24767663 TI - Sex ratio at a tertiary medical center in northern Taiwan--an analysis of amniocentesis. PMID- 24767662 TI - Combination of ultrasound-guided drainage and antibiotics therapy provides a cosmetic advantage for women with methicillin-resistant Staphylococcus aureus breast abscess. PMID- 24767664 TI - Interphase FISH on uncultured amniocytes at repeat amniocentesis for rapid diagnosis of true mosaicism in a case of level II mosaicism involving trisomy 21 in a single colony from an in situ culture of amniocytes. PMID- 24767665 TI - Directly transmitted 4.5-Mb triplication of 4q12-q13.1: prenatal diagnosis and molecular cytogenetic characterization. PMID- 24767667 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 15. PMID- 24767666 TI - Interphase FISH on uncultured amniocytes at repeat amniocentesis for rapid confirmation of low-level mosaicism for tetrasomy 18p. PMID- 24767668 TI - And what about the modified QuantiFERON test as a potential assay for early diagnosis of endometriosis? PMID- 24767669 TI - Y-chromosome centric (not pericentric) inversion results from centric fission. PMID- 24767670 TI - Should the desire for a child always be fulfilled? PMID- 24767672 TI - Utility of reassessment after neoadjuvant therapy and difficulties in interpretation. AB - We describe the main tools for MR assessment of the response of rectal cancer tumors after chemotherapy, before surgery. In locally advanced cases of rectal and lower rectal cancer, MR is useful in allowing the treatment strategy to be adjusted, enabling conservative surgery to be performed if the patient responds well. The different types of response (fibrous, desmoplastic and colloid), their appearances and difficulties in MR interpretation are described. We describe the features and performance of MR after neoadjuvant therapy for T and N staging, assessment of circumferential resection margin and diffusion weighted imaging. Quantitative (change in tumor volume) and qualitative (grade of tumor response) MR assessment can distinguish good responders from poor responders. PMID- 24767671 TI - Effectiveness of a programme of exercise on physical function in survivors of critical illness following discharge from the ICU: study protocol for a randomised controlled trial (REVIVE). AB - BACKGROUND: Following discharge home from the ICU, patients often suffer from reduced physical function, exercise capacity, health-related quality of life and social functioning. There is usually no support to address these longer term problems, and there has been limited research carried out into interventions which could improve patient outcomes. The aim of this study is to investigate the effectiveness and cost-effectiveness of a 6-week programme of exercise on physical function in patients discharged from hospital following critical illness compared to standard care. METHODS/DESIGN: The study design is a multicentre prospective phase II, allocation-concealed, assessor-blinded, randomised controlled clinical trial. Participants randomised to the intervention group will complete three exercise sessions per week (two sessions of supervised exercise and one unsupervised session) for 6 weeks. Supervised sessions will take place in a hospital gymnasium or, if this is not possible, in the participants home and the unsupervised session will take place at home. Blinded outcome assessment will be conducted at baseline after hospital discharge, following the exercise intervention, and at 6 months following baseline assessment (or equivalent time points for the standard care group). The primary outcome measure is physical function as measured by the physical functioning subscale of the Short-Form-36 health survey following the exercise programme. Secondary outcomes are health related quality of life, exercise capacity, anxiety and depression, self efficacy to exercise and healthcare resource use. In addition, semi-structured interviews will be conducted to explore participants' perceptions of the exercise programme, and the feasibility (safety, practicality and acceptability) of providing the exercise programme will be assessed. A within-trial cost-utility analysis to assess the cost-effectiveness of the intervention compared to standard care will also be conducted. DISCUSSION: If the exercise programme is found to be effective, this study will improve outcomes that are meaningful to patients and their families. It will inform the design of a future multicentre phase III clinical trial of exercise following recovery from critical illness. It will provide useful information which will help the development of services for patients after critical illness. TRIAL REGISTRATION: ClinicalTrials.gov NCT01463579. PMID- 24767673 TI - Perceived barriers to preventive dental care among Libyan dentists. AB - AIM: To explore the barriers to providing preventive dental care to patients, as perceived by Libyan dentists working in Benghazi. SETTINGS AND DESIGN: A cross sectional, questionnaire-based survey was conducted among dentists working in Benghazi, Libya. MATERIALS AND METHODS: All dentists registered with the Dental Association of Benghazi and with 2 or more years of practice were invited to participate. The questionnaire collected information on participants' demographic and professional characteristics as well as the patient-, practice- and dentist related barriers to providing preventive dental care. STATISTICAL ANALYSIS: Scores for each type of barrier were compared by demographic and professional characteristics in bivariate and multivariate analyses. RESULTS: One hundred and seventy five dentists returned the questionnaires (response rate: 79%) and 166 had complete information on all the variables selected for analysis (75%). The majority were females (70%), aged between 23 and 34 years (85%), was working in the public health sector (43%), and had up to 5 years of service (46%). Patient related barriers were scored the highest, followed by practice- and dentist related barriers. Dentists with mixed practice reported lower scores on patient- and practice-related barriers than those in public or private practice. CONCLUSION: Respondents were generally aware of the barriers to preventive dentistry and perceived the barriers as being more related to their patients than to their practices or themselves. However, these perceptions varied by practice sector. PMID- 24767674 TI - Risk of influenza A(nrH7N9) pandemic in the eastern Mediterranean region. PMID- 24767675 TI - Why 'down under' is a cut above: a comparison of rates of and reasons for caesarean section in England and Australia. AB - BACKGROUND: Most studies examining determinants of rising rates of caesarean section have examined patterns in documented reasons for caesarean over time in a single location. Further insights could be gleaned from cross-cultural research that examines practice patterns in locations with disparate rates of caesarean section at a single time point. METHODS: We compared both rates of and main reason for pre-labour and intrapartum caesarean between England and Queensland, Australia, using data from retrospective cross-sectional surveys of women who had recently given birth in England (n = 5,250) and Queensland (n = 3,467). RESULTS: Women in Queensland were more likely to have had a caesarean birth (36.2%) than women in England (25.1% of births; OR = 1.44, 95% CI = 1.28-1.61), after adjustment for obstetric characteristics. Between-country differences were found for rates of pre-labour caesarean (21.2% vs. 12.2%) but not for intrapartum caesarean or assisted vaginal birth. Compared to women in England, women in Queensland with a history of caesarean were more likely to have had a pre-labour caesarean and more likely to have had an intrapartum caesarean, due only to a previous caesarean. Among women with no previous caesarean, Queensland women were more likely than women in England to have had a caesarean due to suspected disproportion and failure to progress in labour. CONCLUSIONS: The higher rates of caesarean birth in Queensland are largely attributable to higher rates of caesarean for women with a previous caesarean, and for the main reason of having had a previous caesarean. Variation between countries may be accounted for by the absence of a single, comprehensive clinical guideline for caesarean section in Queensland. PMID- 24767676 TI - Urinary and breast milk biomarkers to assess exposure to naphthalene in pregnant women: an investigation of personal and indoor air sources. AB - BACKGROUND: Naphthalene exposures for most non-occupationally exposed individuals occur primarily indoors at home. Residential indoor sources include pest control products (specifically moth balls), incomplete combustion such as cigarette smoke, woodstoves and cooking, some consumer and building products, and emissions from gasoline sources found in attached garages. The study aim was to assess naphthalene exposure in pregnant women from Canada, using air measurements and biomarkers of exposure. METHODS: Pregnant women residing in Ottawa, Ontario completed personal and indoor air sampling, and questionnaires. During pregnancy, pooled urine voids were collected over two 24-hour periods on a weekday and a weekend day. At 2-3 months post-birth, they provided a spot urine sample and a breast milk sample following the 24-hour air monitoring. Urines were analyzed for 1-naphthol and 2-naphthol and breast milk for naphthalene. Simple linear regression models examined associations between known naphthalene sources, air and biomarker samples. RESULTS: Study recruitment rate was 11.2% resulting in 80 eligible women being included. Weekday and weekend samples were highly correlated for both personal (r = 0.83, p < 0.0001) and indoor air naphthalene (r = 0.91, p < 0.0001). Urine specific gravity (SG)-adjusted 2-naphthol concentrations collected on weekdays and weekends (r = 0.78, p < 0.001), and between pregnancy and postpartum samples (r = 0.54, p < 0.001) were correlated.Indoor and personal air naphthalene concentrations were significantly higher post-birth than during pregnancy (p < 0.0001 for signed rank tests); concurrent urine samples were not significantly different. Naphthalene in breast milk was associated with urinary 1 naphthol: a 10% increase in 1-naphthol was associated with a 1.6% increase in breast milk naphthalene (95% CI: 0.2%-3.1%). No significant associations were observed between naphthalene sources reported in self-administered questionnaires and the air or biomarker concentrations. CONCLUSIONS: Median urinary concentrations of naphthalene metabolites tended to be similar to (1-naphthol) or lower (2-naphthol) than those reported in a Canadian survey of women of reproductive age. Only urinary 1-naphthol and naphthalene in breast milk were associated. Potential reasons for the lack of other associations include a lack of sources, varying biotransformation rates and behavioural differences over time. PMID- 24767677 TI - Amino acid changes in the spike protein of feline coronavirus correlate with systemic spread of virus from the intestine and not with feline infectious peritonitis. AB - Recent evidence suggests that a mutation in the spike protein gene of feline coronavirus (FCoV), which results in an amino acid change from methionine to leucine at position 1058, may be associated with feline infectious peritonitis (FIP). Tissue and faecal samples collected post mortem from cats diagnosed with or without FIP were subjected to RNA extraction and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to detect FCoV RNA. In cats with FIP, 95% of tissue, and 81% of faecal samples were PCR-positive, as opposed to 22% of tissue, and 60% of faecal samples in cats without FIP. Relative FCoV copy numbers were significantly higher in the cats with FIP, both in tissues (P < 0.001) and faeces (P = 0.02). PCR-positive samples underwent pyrosequencing encompassing position 1058 of the FCoV spike protein. This identified a methionine codon at position 1058, consistent with the shedding of an enteric form of FCoV, in 77% of the faecal samples from cats with FIP, and in 100% of the samples from cats without FIP. In contrast, 91% of the tissue samples from cats with FIP and 89% from cats without FIP had a leucine codon at position 1058, consistent with a systemic form of FCoV. These results suggest that the methionine to leucine substitution at position 1058 in the FCoV spike protein is indicative of systemic spread of FCoV from the intestine, rather than a virus with the potential to cause FIP. PMID- 24767678 TI - Margin status in oral cancer: requirement for reassessment. PMID- 24767679 TI - A 3'UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like Kinase 1. AB - BACKGROUND: The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. METHODS: The coding region, the 5' and 3'UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3'UTR polymorphism. RESULTS: Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3'untranslated region (3'UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). CONCLUSION: The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors. PMID- 24767680 TI - Gasotransmitters: growing pains and joys. AB - Gasotransmitters are endogenously generated molecules of gas. Over the past decade we have come to realize that these gaseous signaling molecules are crucially important, being irreplaceable in wide biological applications. However, there are still many challenges for future gasotransmitter research to tackle. These include clarifying the interactions among gasotransmitters; understanding the significance of the cellular gasotransmitter signaling network; and adding new members to the modern family of gasotransmitters in addition to nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). Ammonia fulfills all criteria for being a gasotransmitter, and methane is another conceivable candidate. Following the original article postulating the concept of multiple gasotransmitters over a decade ago, this sequel article aims to further inspire interest and exploration into gasotransmitter research. PMID- 24767682 TI - Evaluation of the RIDAGENE real-time PCR assay for the detection of GI and GII norovirus. AB - The current study examined the efficacy of the RIDAGENE norovirus (NoV) real-time polymerase chain reaction assay (R-Biopharm, Darmstadt, Germany) for use in a routine diagnostic laboratory. The RIDAGENE assay had an overall sensitivity of 98% but was more sensitive for GII than GI NoV. The assay had a specificity of 98%. The RIDAGENE assay could detect a variety of GI and GII open reading frame 2 genotypes including GI.1, GI.3, GI.8, GI.13, GII.2, GII.3, GII.4 (including the following variants: 2006b, 2009, 2012, and 3 others that have not been assigned), GII.6, GII.12, and GII.13. The assay did not cross react with a number of gastroenteritis viruses including adenovirus, astrovirus, rotavirus, and sapovirus. The assay was straightforward to perform, and for a run of 50 specimens, a result was obtainable in roughly 4 hours. The RIDAGENE assay can be recommended as a valuable detection method for NoV. PMID- 24767681 TI - Allosteric sodium in class A GPCR signaling. AB - Despite their functional and structural diversity, G-protein-coupled receptors (GPCRs) share a common mechanism of signal transduction via conformational changes in the seven-transmembrane (7TM) helical domain. New major insights into this mechanism come from the recent crystallographic discoveries of a partially hydrated sodium ion that is specifically bound in the middle of the 7TM bundle of multiple class A GPCRs. This review discusses the remarkable structural conservation and distinct features of the Na(+) pocket in this most populous GPCR class, as well as the conformational collapse of the pocket upon receptor activation. New insights help to explain allosteric effects of sodium on GPCR agonist binding and activation, and sodium's role as a potential co-factor in class A GPCR function. PMID- 24767683 TI - Direct identification of bacteria in positive blood cultures: comparison of two rapid methods, FilmArray and mass spectrometry. AB - We evaluated the accuracy and performance of the FilmArray Direct from Positive Blood Culture system (BCID) (BioFire Diagnostics, Salt Lake City, UT, USA) and the VITEK Mass Spectrometry System (Vitek MS; bioMerieux, Durham, NC, USA) to identify bacterial isolates from 161 positive blood culture bottles. The BCID uses multiplex PCR to identify 90-95% of common isolates to the genus or species/complex level as well as mecA, Van A/B, and bla(KPC) genes in approximately 1 hour. Of 151 monomicrobic isolates, the FilmArray correctly identified 48/49 (98%) to the genus and 84/84 (100%) to the species/complex level, while 18/151 (12%) gave no identification, as expected from the database. Mass spectrometry correctly identified 142/151 (94%) monomicrobic cultures to the genus level, 137/151 (91%) to the species level, with only 8/151(5%) giving no identification. Although mass spectrometry has a much larger database, the filtration system was cumbersome in contrast to the 3-5 minutes hands-on-time for the BCID. PMID- 24767684 TI - Effect of comorbidity on risk of venous thromboembolism in patients with renal cell carcinoma. AB - PURPOSE: Venous thromboembolism (VTE) is associated with renal cell carcinoma (RCC), but data on the effect of comorbidities are limited. Therefore, our purpose was to determine the effect of comorbidity on VTE risk among patients with RCC. MATERIALS AND METHODS: A population-based cohort of all patients with RCC (n = 8,633) diagnosed in Denmark between 1995 and 2010 and a comparison cohort selected from the general population and matched on age, sex, and comorbidities (n = 83,055) were identified. Risk of subsequent VTE was estimated with 95% CI for the first 3 months, 1 year, and 5 years following cancer diagnosis. We stratified by Charlson comorbidity index (CCI) scores to estimate excess risk in patients with RCC vs. the comparison cohort within comorbidity strata. We also performed subanalyses for postoperative VTE and metastases. RESULTS: VTE risk was higher in the RCC compared with comparison cohort, particularly during the initial year following diagnosis (risk difference = 9.9 per 1,000 persons [95% CI: 7.7-12.2]). After stratifying by CCI, excess risk declined with increasing comorbidities. The risk difference was 12.3 per 1,000 persons (95% CI: 9.1-15.5) for CCI = 0 and 0.5 (95% CI: 6.0-7.0) for CCI = 4. Excess risk also declined with increasing comorbidities among patients with postoperative VTE and among those with metastases. CONCLUSIONS: RCC is associated with increased risk of VTE when compared with a matched general population cohort. Risk did not appear to increase with added comorbidity burden. Clinical attention to VTE risk in patients with RCC is appropriate regardless of the presence or absence of comorbidities. PMID- 24767685 TI - Multiparametric magnetic resonance imaging-ultrasound fusion-guided prostate biopsy: role in diagnosis and management of prostatic cancer. PMID- 24767686 TI - Commentary on "Racial disparity in renal cell carcinoma patient survival according to demographic and clinical characteristics." Chow WH, Shuch B, Linehan WM, Devesa SS, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.: Cancer 2013; 119(2):388-94. [Epub 2012 Nov 12]. doi: 10.1002/cncr.27690. AB - BACKGROUND: Patients with renal cell carcinoma (RCC) who are black tend to have poorer prognosis than similar patients who are white. This study examined whether the racial disparity in RCC patient survival varies by demographic and clinical characteristics. METHODS: Nearly 40,000 patients (4359 black and 34,991 white) diagnosed with invasive RCC from 1992 to 2007 were identified from 12 registries in the National Cancer Institute Surveillance, Epidemiology, and End Results program, covering approximately 14% of the US population. Relative survival rates through 2008 were computed using the actuarial method. RESULTS: Proportionally more blacks than whites were diagnosed with RCC under age 50 and with localized cancer. Overall, the 5-year relative survival rates were 72.6% (95% confidence interval 72.0%-73.2%) for white and 68.0% (66.2%-69.8%) for black patients. Survival was higher among women than men and among younger than older patients. Survival decreased with advancing tumor stage and, within each stage, decreased with increasing tumor size. Patients with clear cell RCC, a more common form among whites, had poorer prognosis than patients with papillary or chromophobe subtypes, which are more common among blacks. Survival for patients who received no surgical treatment (10.5% of white patients and 14.5% of black patients) was substantially lower than for patients treated with nephrectomy, with similar survival among whites and blacks. In all other demographic and clinical subgroups of patients, whites consistently had a survival advantage over blacks. CONCLUSIONS: Patients with RCC who are white consistently have a survival advantage over those RCC patients who are black, regardless of age, sex, tumor stage or size, histological subtype, or surgical treatment. PMID- 24767687 TI - Commentary on "Single nucleotide polymorphisms and risk of recurrence of renal cell carcinoma: a cohort study." Schutz FA, Pomerantz MM, Gray KP, Atkins MB, Rosenberg JE, Hirsch MS, McDermott DF, Lampron ME, Lee GS, Signoretti S, Kantoff PW, Freedman ML, Choueiri TK, Dana-Farber Cancer Institute, Boston, MA 02115.: Lancet Oncol 2013;14(1):81-87. [Epub 2012 Dec 7]. doi: 10.1016/S1470 2045(12)70517-X. Erratum in, Lancet Oncol 2013;14(3):e89. AB - BACKGROUND: Germline genetic polymorphisms might affect the risk of recurrence in patients with localised renal-cell carcinoma. We investigated the association between genetic polymorphisms and recurrence of renal-cell carcinoma. METHODS: We analysed germline DNA samples extracted from patients with localised renal-cell carcinoma treated at the Dana-Farber/Harvard Cancer Center (Boston, MA, USA). We selected a discovery cohort from a prospective database at the Dana Farber/Harvard Cancer Center and selected a validation cohort from department records at the Brigham and Women's Hospital (Boston, MA, USA). We validated the findings from the discovery cohort in the validation cohort. We genotyped 70 genes involved in the pathogenesis of renal-cell carcinoma (including the VHL/HIF/VEGF and PI3K/AKT/mTOR pathways, and genes involved in immune regulation and metabolism) for single nucleotide polymorphisms. We assessed the association between genotype and recurrence-free survival, adjusted for baseline characteristics, with the Cox proportional hazards model, the Kaplan-Meier method, and the log-rank test. We used a false discovery rate q value to adjust for multiple comparisons. FINDINGS: We included 554 patients (403 in the discovery cohort and 151 in the validation cohort). We successfully genotyped 290 single nucleotide polymorphisms in the discovery cohort, but excluded five because they did not have a variant group for comparison. The polymorphism rs11762213, which causes a synonymous aminoacid change in MET (144 G -> A, located in exon 2), was associated with recurrence-free survival. Patients with one or two copies of the minor (risk) allele had an increased risk of recurrence or death (hazard ratio [HR] 1.86, 95% CI 1.17-2.95; p=0.0084) in multivariate analysis. Median recurrence-free survival for carriers of the risk allele was 19 months (95% CI 9-not reached) versus 50 months (95% CI 37-75) for patients without the risk allele. In the validation cohort the HR was 2.45 (95% CI 1.01 5.95; p=0.048). INTERPRETATION: Patients with localised renal-cell carcinoma and the MET polymorphism rs11762213 might have an increased risk of recurrence after nephrectomy. If these results are further validated in a similar population, they could be incorporated into future prognostic instruments, potentially aiding the design of adjuvant clinical trials of MET inhibitors and management of renal-cell carcinoma. PMID- 24767688 TI - Commentary on: "Long-term functional outcomes after treatment for localized prostate cancer." Resnick MJ, Koyama T, Fan KH, Albertsen PC, Goodman M, Hamilton AS, Hoffman RM, Potosky AL, Stanford JL, Stroup AM, Van Horn RL, Penson DF. Department of Urologic Surgery and the Center for Surgical Quality and Outcomes Research, Vanderbilt University, Nashville, TN.: N Engl J Med 2013;368(5):436-45. doi: 10.1056/NEJMoa1209978. AB - BACKGROUND: The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. METHODS: The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. RESULTS: Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years. CONCLUSIONS: At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.). PMID- 24767689 TI - Commentary on "Cytoreductive radiofrequency ablation in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with sunitinib or interferon-alpha." Tsimafeyeu I, Zart JS, Chung B, Kidney Cancer Research Bureau, Moscow, Russian Federation.: BJU Int 2013; 112(1):32-8. [Epub 2013 Jun 7]. doi: 10.1111/bju.12107. AB - OBJECTIVES: To evaluate the role of cytoreductive radiofrequency ablation (cRFA) in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with immuno- or targeted therapy. To assess the efficacy of sunitinib in patients with metastatic RCC with unresected small primary tumours. PATIENTS AND METHODS: Three parallel single-arm prospective studies were conducted. Eligibility criteria were nearly identical for all trials and included: histopathologically confirmed RCC; metastatic measurable disease; size of primary tumour <5cm; good or intermediate prognosis according to the Memorial Sloan Kettering Cancer Center model; and no previous therapy. Study 1: Patients were treated with percutaneous cRFA under computed tomography guidance followed by interferon (IFN)-alpha, 9 MIU, s.c., three times per week. Study 2: Patients received cRFA followed by sunitinib in repeated 6-week cycles of 50mg/day orally for 4 weeks, then 2 weeks off treatment. Study 3: Patients with unresected primary RCC received sunitinib alone. The primary endpoint was progression-free survival (PFS). RESULTS: Baseline patient characteristics (age, gender, histology, Eastern Cooperative Oncology Group performance status, metastatic sites, primary tumour size) were similar in all three studies. Efficacy data for 114 evaluable patients showed an objective response rate of 8% (95% confidence interval [CI] 4.5, 10.5) for study 1, 28.9% (95% CI 15.2, 34) for study 2, and 31.6% (95% CI 20.3, 38.9) for study 3. The median (95% CI) PFS times were 9.1 (6.9, 10.2), 13.4 (9.8, 14.4) and 12.7 (11.3, 13.5) months for studies 1, 2 and 3, respectively. Objective response rate was significantly higher and PFS significantly longer in the sunitinib trials than in study 1 (P<0.01 all differences); no differences were found between studies 2 and 3 (objective response rate, P = 0.1; PFS, P = 0.6). Study 1 met its primary endpoint, showing that PFS was significantly longer than the expected 5 months (P = 0.02). The median (95% CI) objective survival (OS) times were greater in study 2 (cRFA/sunitinib) and study 3 (sunitinib-alone) than in study 1 (IFN-alpha) at 27.2 (22.6, 31.8) and 22.5 (20.7, 24.3) vs 19.5 (16.3, 22.7) months, respectively. Differences were significant (study 1 vs 2, hazard ratio [HR] = 0.55; P = 0.003; study 1 vs study 3 HR = 0.6, P = 0.01). OS was significantly longer in the cRFA/sunitinib group compared with the sunitinib-alone group (HR = 0.71; P = 0.04). There were no unexpected toxicities of medical treatment or complications of cRFA. CONCLUSIONS: cRFA is a safe and effective approach for select patients with metastatic RCC treated with immunotherapy. The cRFA technique did not improve PFS in patients treated with sunitinib; cRFA probably has impact on OS in these patients. This needs to be tested in a larger trial. Sunitinib was effective in patients with metastatic RCC with unresected small primary tumours. PMID- 24767690 TI - Raman spectroscopy as an ex vivo noninvasive approach to distinguish complete and incomplete spermatogenesis within human seminiferous tubules. AB - OBJECTIVE: To evaluate the potential clinical application of Raman spectroscopy (RS) as a tool that may identify spermatogenesis within human seminiferous tubules. DESIGN: RS scanning of human testicular tissue at different maturational stages; immunohistochemistry study and metabolomic analysis of nonobstructive azoospermic/obstructive azoospermic testes. SETTING: State-owned hospital. PATIENT(S): Fifty-two patients with clinical indications of nonobstructive azoospermia (NOA) and obstructive azoospermia (OA) who underwent infertility evaluation and treatment. INTERVENTION(S): None. MAIN OUTCOME MEASUREMENT(S): Raman spectra of seminiferous tubules, thickness of lamina propria (LP), immunohistochemistry of type I, III, and IV collagens and laminin, metabolites of human testes. RESULT(S): Tubules of OA patients had spectral intensities below 2,000 (au), while tubules of NOA patients had higher intensities, depending on the degree of spermatogenesis. RS was able to separate samples of NOA and OA testicular tissue with a sensitivity of 90% and specificity of 85.71%. The LP of NOA tubules were thickened and had increased deposition of type I and type III collagens. Gas chromatography-mass spectrometer (GC-MS) detected 12 metabolites that showed significant differences between NOA and OA testes. CONCLUSION(S): RS can noninvasively distinguish seminiferous tubules with complete and incomplete spermatogenesis and may serve as a novel and potentially useful tool to guide surgeons performing micro-testicular sperm extraction to improve sperm retrieval. PMID- 24767691 TI - [The threat of the carbapenemase-producing enterobacteriaceae in Spain: positioning report of the SEIMC study groups, GEIH and GEMARA]. AB - The emergence and spread of carbapenemase-producing Enterobacteriaceae (CPE), as the current paradigm of extensive drug-resistance and multi-drug resistance to antibiotics, is a serious threat to patient health and public health. The increase in OXA-48- and VIM-1-producing Klebsiella pneumoniae isolates represents the greatest impact of CPE in Spain. This evidence has lead the members of a representative panel of the Spanish Study Groups of Nosocomial Infections and Mechanisms of Action and Resistance to Antimicrobials of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIH/GEMARA-SEIMC) to make a position statement expressing the need for: (i) definitive and coordinated action by all health professionals and authorities involved, and (ii) an adaptation of health systems to facilitate their early control and minimize their impact. PMID- 24767692 TI - Prevalence and risk factors of depression among community dwelling elderly. AB - Depression in the elderly is associated with increased morbidity and mortality. The purpose of this study was to determine the prevalence and risk factors of depression among community-dwelling older population in an urban setting in Turkey. This cross-sectional study was conducted among 482 elderly individuals 65 years and over in an urban area. Cluster sampling method was used for sample size. Depression in the elderly had been diagnosed by a clinical interview and Geriatric Depression Scale. Data were collected by door-to-door survey. Chi square test was used for statistical analysis. P value, which was calculated by the results of chi square test and coefficient of phi (phi), below 0.05 was included in the analysis of logistic regression. Depression was significantly associated with female gender, being single or divorced, lower educational status, low income, unemployment, and lack of health insurance. However, logistic regression analysis revealed higher depression rates in the elderly with chronic obstructive pulmonary disease, psychiatric disease, cerebrovascular disease, low income and being dependent. Depression is common among community-dwelling older people in an urban area of Izmir, Turkey. Older adults living in community should be cautiously screened to prevent or manage depression. PMID- 24767693 TI - Implantable Cook-Swartz Doppler probe versus Synovis Flow Coupler for the post operative monitoring of free flap breast reconstruction. AB - BACKGROUND: The Cook-Swartz Doppler has long been a trusted tool for close monitoring of blood flow after microvascular reconstruction; however, device implantation requires additional operating time. Synovis Life Technologies, Inc. received FDA approval in 2010 for the Flow Coupler, which combines an end-to-end anastomotic coupler with a removable 20 MHz Doppler, allowing both procedures to be performed simultaneously. However, its short history of widespread use necessitates further evaluation in the clinical setting. The authors studied the Synovis Flow Coupler in comparison to the more well-established Cook-Swartz Doppler for effectiveness and reliability in detection of vascular compromise. METHODS: The authors reviewed 220 free flap breast reconstructions in 150 patients over a three-year period in which either the Cook-Swartz Doppler or the Synovis Flow Coupler was implanted to monitor blood flow. Outcomes measured include false-positive or false-negative rates (FPR, FNR); rates of OR take-back and salvage; and flap survival. RESULTS: FPR was 1.0% for the Cook-Swartz Doppler and 1.9% for the Synovis Flow Coupler (p>0.05). FNR was 0.0% for both groups. Take-back rates were 10.1% for the Cook-Swartz, and 4.5% for Synovis (p>0.05). Flap failure rates were 1.8% and 0.9% for the Cook-Swartz and Synovis devices, respectively (p>0.05). CONCLUSIONS: Our study reveals no statistically significant differences in outcomes for free flap breast reconstruction where either the Cook-Swartz Doppler or the Synovis Flow Coupler was used to monitor blood flow to the perforator flap. LEVEL OF EVIDENCE: III. PMID- 24767694 TI - Sex differences in Parkinson's disease. AB - Sex-related differences in Parkinson's disease (PD) have been recognised, but remain poorly understood. We aimed to further clarify real-life differences in disease experience according to sex, by evaluating quality of life (QoL), demographic and clinical characteristics of PD patients. A cross-sectional survey was conducted on 210 PD patients (129 men, 81 women) attending specialist neurological clinics across three centres. Outcome measures included the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS-III) and QoL as measured by the 39-item Parkinson's Disease Questionnaire (PDQ-39). A male to female ratio of 1.6:1 was observed. Men reported a greater disease burden than women as noted by higher UPDRS-III scores (27 +/- 13 versus 23 +/- 13, p=0.032), daily levodopa equivalent doses (898.1 +/- 481.3mg versus 750.7 +/- 427.2mg, p=0.037) and caregiver reliance (44% versus 29.5%, p=0.039). The UPDRS-III score was significantly associated with sex after controlling for age and disease duration, with men more severely affected (beta=-0.165, r(2)=0.101, p=0.028). The PDQ-39 showed men reported lower QoL in activities of daily living (ADL), cognition and communication sub-scales (p<0.05). An association was identified in men between PDQ-39 ADL and cognition sub-scales (r=0.660, p<0.001). Men with an appointed caregiver had a higher PDQ-39 Summary Index (t=3.222, degrees of freedom=122, p=0.002). PD was found to have greater overall impact on the health and well-being of male patients in sub-specialty clinical practice. Our study further supports the need for increased sex-delineated clinical assessment and consideration of potential differences required in the management of PD. PMID- 24767695 TI - Penicillin and cephalosporin allergy. PMID- 24767696 TI - Trends in eczema, rhinitis, and rye grass sensitization in a longitudinal asthma cohort. AB - BACKGROUND: Atopic conditions are prevalent in the Western world, with limited long-term data on atopic trends in patients with asthma. OBJECTIVE: To describe the trends in eczema, rhinitis, and allergic sensitization in a longitudinal childhood asthma cohort. METHODS: Four hundred eighty-four patients were recruited at 7 years of age and followed regularly to 50 years of age. Subjects completed an interviewer-administered questionnaire to define current eczema and rhinitis. Skin prick testing to rye grass also was performed. RESULTS: The participation rate over the past 4 decades has been maintained at 72% to 91%. There was a decrease in the prevalence of eczema in the past 12 months in groups with viral-associated wheeze (21% to 8%, P = .002), asthma (47% to 18%, P < .001), and severe asthma (69% to 28%, P < .001) from 14 to 21 years of age. Conversely, there was an increase in the prevalence of rhinitis in the previous 12 months in groups without asthma (1% to 6%, P = .04; 1% to 20%, P = .008), with viral-associated wheeze (16% to 28%, P = .006; 16% to 49%, P < .001), and with asthma (45% to 56%, P = .2; 45% to 73%, P = .014) from recruitment to 10 and 14 years of age, respectively. There were 2 peaks in prevalence in the sensitization to rye grass in this cohort from 7 to 10 years of age and from 14 to 21 years of age in all groups. CONCLUSION: The adolescence phase appears to be an important period in the body's response to allergens whereby eczema decreases in prevalence, whereas rhinitis and rye grass sensitization increase in prevalence. PMID- 24767697 TI - Allergen of the month--Fusarium. PMID- 24767698 TI - Pleomorphic adenoma and benign parotid tumors: extracapsular dissection vs superficial parotidectomy--review of literature and meta-analysis. AB - OBJECTIVE: This study compared extracapsular dissection (ED) vs superficial parotidectomy (SP) in the treatment of pleomorphic adenoma and benign parotid tumors. STUDY DESIGN: The research covered the years 1950-2011 in PubMed, Ovid MEDLINE, the Cochrane Database of Systematic Reviews, and Scopus. Of 1152 articles screened, 123 studies met the inclusion criteria. A review of the nomenclature of the different parotid surgery techniques was done. Recurrence rate, permanent facial nerve paralysis, and Frey syndrome of patients who underwent ED vs those who underwent SP were compared by meta-analysis. RESULTS: Our meta-analysis data comparing ED and SP found that: (1) the recurrence rate is higher in patients treated with SP; (2) SP has a higher incidence of cranial nerve VII paralysis; and (3) Frey syndrome is more common after SP. CONCLUSIONS: ED may be a viable option in the treatment of unilateral benign parotid tumors of the superficial lobe, sized less than 4 cm, without involvement of the facial nerve. PMID- 24767699 TI - Integration accuracy of laser-scanned dental models into maxillofacial cone beam computed tomography images of different voxel sizes with different segmentation threshold settings. AB - OBJECTIVE: The aims were to examine the influence of cone beam computed tomography (CBCT)-scanned voxels and segmentation threshold settings on the accuracy of surface-based registration. STUDY DESIGN: The samples were obtained from 10 adults. Each laser-scanned model was registered into a CBCT model by use of the iterative closest point algorithm. We calculated the shell-to-shell deviations between the 2 models and evaluated the results with color-mapping methods. The centroid coordinates were used to calculate the positional differences. Thresholds were expressed in relative Hounsfield units (RHU). RESULTS: There was a statistically significant difference in shell-to-shell deviations between the 0.20-mm-voxel group and the 0.40-mm-voxel group (P < .001). There was a statistically significant difference in anteroposterior and superoinferior directions between the 200- and 700-RHU threshold models in 2 groups (P < .05). CONCLUSIONS: The results indicated that the accuracy of the integration of laser-scanned dental models into CBCT images is higher with a high RHU threshold setting in 0.20- and 0.40-mm voxel sizes. PMID- 24767700 TI - An intraosseous sclerosing odontogenic tumor predominantly composed of epithelial cells: relation to (so-called) sclerosing odontogenic carcinoma and epithelial rich central odontogenic fibroma. AB - We report a case of an asymptomatic sclerosing odontogenic tumor in a 31-year-old woman. Radiologically, the tumor was well circumscribed, was predominantly radiolucent, and had a peripheral sclerotic margin. Histopathologically, the tumor showed small clusters, strands, and cords of small to medium-sized epithelial tumor cells in a sclerotic collagenous stroma. Immunohistochemically, the tumor cells were positive for broad-spectrum cytokeratins (CKs) (CK7, CK5/6, CK19, and CAM 5.2) and p63. Membranous staining for E-cadherin was present. There was weak to moderate nuclear expression of p16 in 30% of cells. Rare tumor cells were positive for p53. Progesterone receptors were expressed in about 60% of the tumor cells. The proliferative activity (Ki-67) was approximately 2%. A molecular genetic (fluorescence in situ hybridization) study showed no EWSR1 (EWS RNA binding protein 1) gene rearrangement. No recurrence or metastatic events have been documented at 1-year follow-up. This tumor represents a classification dilemma mainly between epithelial-rich central odontogenic fibroma and the so called sclerosing odontogenic carcinoma. PMID- 24767701 TI - Renal cell carcinoma treated with stereotactic radiotherapy with histological change confirmed on autopsy: a case report. AB - BACKGROUND: Treatment of primary renal cell carcinoma using radiotherapy with curative intent is rare, because renal cell carcinoma is generally regarded as a radiation-resistant tumor. Recently, stereotactic body radiation therapy has been radically applied for cancers in various organs including renal cell carcinoma. However, there were few reports describing pathological changes of renal cell carcinoma post stereotactic body radiation therapy. This is the first report we are aware of documenting late histological effects of stereotactic body radiation therapy on renal cell carcinoma and surrounding normal tissue. CASE PRESENTATION: A right renal tumor was identified in a Japanese 70-year-old man on follow-up computed tomography for his chronic hepatitis. T1N0M0 renal cell carcinoma was clinically diagnosed as the tumor was 3 cm in diameter and well-enhanced with intravenously infused contrast material in the arterial phase on computed tomography. No metastases in regional lymph nodes or distant sites were evident. Stereotactic body radiation therapy was selected as an alternative therapy to surgery because of his poor liver function. A total dose of 60 Gy in 10 fractions over 12 days was delivered using a 10-megavolt X-ray. The renal tumor gradually decreased in size and partial response had been achieved at 2 years after completing stereotactic body radiation therapy. Hepatocellular carcinoma was identified during follow-up in the patient and he died of progression of hepatocellular carcinoma with hepatic failure 2.5 years after completing stereotactic body radiation therapy. Autopsy was done and it showed almost complete necrosis of tumor tissues with a small amount of viable renal carcinoma cells. These pathological findings suggested marked effects of stereotactic body radiation therapy on clear cell renal cell carcinoma. CONCLUSION: Our case demonstrates a good pathological response with small foci of remnant viable cancer cells after stereotactic body radiation therapy of 60Gy in 10 fractions for small renal cell carcinoma. Although further experiences and longer follow-up are mandatory to conclude the optimal treatment schedule and efficacy of stereotactic body radiation therapy for renal cell carcinoma, stereotactic body radiation therapy may represent a novel less-invasive option for the treatment of primary renal cell carcinoma. PMID- 24767702 TI - Comparison of eight published static finite element models of the intact lumbar spine: predictive power of models improves when combined together. AB - Finite element (FE) model studies have made important contributions to our understanding of functional biomechanics of the lumbar spine. However, if a model is used to answer clinical and biomechanical questions over a certain population, their inherently large inter-subject variability has to be considered. Current FE model studies, however, generally account only for a single distinct spinal geometry with one set of material properties. This raises questions concerning their predictive power, their range of results and on their agreement with in vitro and in vivo values. Eight well-established FE models of the lumbar spine (L1-5) of different research centers around the globe were subjected to pure and combined loading modes and compared to in vitro and in vivo measurements for intervertebral rotations, disc pressures and facet joint forces. Under pure moment loading, the predicted L1-5 rotations of almost all models fell within the reported in vitro ranges, and their median values differed on average by only 2 degrees for flexion-extension, 1 degrees for lateral bending and 5 degrees for axial rotation. Predicted median facet joint forces and disc pressures were also in good agreement with published median in vitro values. However, the ranges of predictions were larger and exceeded those reported in vitro, especially for the facet joint forces. For all combined loading modes, except for flexion, predicted median segmental intervertebral rotations and disc pressures were in good agreement with measured in vivo values. In light of high inter-subject variability, the generalization of results of a single model to a population remains a concern. This study demonstrated that the pooled median of individual model results, similar to a probabilistic approach, can be used as an improved predictive tool in order to estimate the response of the lumbar spine. PMID- 24767703 TI - Can isolated annular dilatation cause significant ischemic mitral regurgitation? Another look at the causative mechanisms. AB - This study was to investigate the mechanisms of ischemic mitral regurgitation (IMR) by using a finite element (FE) approach. IMR is a common complication of coronary artery disease; and it usually occurs due to myocardial infarction. The pathophysiological mechanisms of IMR have not been fully understood, much debate remains about the exact contribution of each mechanism to IMR. Two patient specific FE models of normal mitral valves (MV) were reconstructed from multi slice computed tomography scans. Different grades of IMR during its pathogenesis were created by perturbation of the normal MV geometry. Effects of annular dilatation and papillary muscle (PM) displacement (both isolated and combined) on the severity of IMR were examined. We observed greater increase in IMR (in terms of regurgitant area and coaptation length) in response to isolated annular dilatation than that caused by isolated PM displacement, while a larger PM displacement resulted in higher PM forces. Annular dilation, combined with PM displacement, was able to significantly increase the severity of IMR and PM forces. Our simulations demonstrated that isolated annular dilatation might be a more important determinant of IMR than isolated PM displacement, which could help explain the clinical observation that annular size reduction by restrictive annuloplasty is generally effective in treating IMR. PMID- 24767705 TI - Teaching patient-centered communication skills: a telephone follow-up curriculum for medical students. AB - BACKGROUND: To encourage medical students' use of patient-centered skills in core clerkships, we implemented and evaluated a Telephone Follow-up Curriculum focusing on three communication behaviors: tailoring education to patients' level of understanding, promoting adherence by anticipating obstacles, and ensuring comprehension by having patients repeat the plans. METHODS: The intervention group consisted of two different cohorts of third-year medical students in longitudinal clerkships (n=41); traditional clerkship students comprised the comparison group (n = 185). Intervention students telephoned one to four patients 1 week after seeing them in outpatient clinics or inpatient care to follow up on recommendations. We used surveys, focus groups, and clinical performance examinations to assess student perception, knowledge and skills, and behavior change. RESULTS: Students found that the curriculum had a positive impact on patient care, although some found the number of calls excessive. Students and faculty reported improvement in students' understanding of patients' health behaviors, knowledge of patient education, and attitudes toward telephone follow up. Few students changed patient education behaviors or called additional patients. Intervention students scored higher in some communication skills on objective assessments. CONCLUSION: A patient-centered communication curriculum can improve student knowledge and skills. While some intervention students perceived that they made too many calls, our data suggest that more calls, an increased sense of patient ownership, and role modeling by clerkship faculty may ensure incorporation and application of skills. PMID- 24767704 TI - Atomic force microscopy determination of Young's modulus of bovine extra-ocular tendon fiber bundles. AB - Extra-ocular tendons (EOTs) transmit the oculorotary force of the muscles to the eyeball to generate dynamic eye movements and align the eyes, yet the mechanical properties of the EOTs remain undefined. The EOTs are known to be composed of parallel bundles of small fibers whose mechanical properties must be determined in order to characterize the overall behavior of EOTs. The current study aimed to investigate the transverse Young's modulus of EOT fiber bundles using atomic force microscopy (AFM). Fresh bovine EOT fiber bundle specimens were maintained under temperature and humidity control, and indented 100nm by the inverted pyramid tip of an AFM (Veeco Digital Instruments, NY). Ten indentations were conducted for each of 3 different locations of 10 different specimens from each of 6 EOTs, comprising a total of 1800 indentations. Young's modulus for each EOT was determined using a Hertzian contact model. Young's moduli for fiber bundles from all six EOTs were determined. Mean Young's moduli for fiber bundles were similar for the six anatomical EOTs: lateral rectus 60.12+/-2.69 (+/-SD)MPa, inferior rectus 59.69+/-5.34MPa, medial rectus 56.92+/-1.91MPa, superior rectus 59.66+/-2.64MPa, inferior oblique 57.7+/-1.36MPa, and superior oblique 59.15+/ 2.03. Variation in Young's moduli among the six EOTs was not significant (P>0.25). The Young's modulus of bovine EOT fibers is highly uniform among the six extraocular muscles, suggesting that each EOT is assembled from fiber bundles representing the same biomechanical elements. This uniformity will simplify overall modeling. PMID- 24767706 TI - Development and evaluation of the evidence-based medicine program in surgery: a spiral approach. AB - BACKGROUND: Evidence-based medicine (EBM) aims to provide skills that help physicians answer clinically important questions, determine new evidence, and incorporate the acquired knowledge in practice. EBM skills are necessary for the practice of modern medicine, since physicians should use up-to-date knowledge and information to justify their medical decisions. PURPOSE: We aimed to evaluate the EBM program implemented at Hacettepe University School of Medicine. METHODS: In 2004, a spiral program for the teaching and practice of EBM was developed for the first 3 years of medical school. Following this program, a practice of EBM was included in the fourth year during the surgery clerkship, after an introductory lecture. The students worked within collaborative teams of 3-5 and practiced EBM with actual cases seen in the surgical service in which they were involved. Each student was asked to complete a questionnaire that evaluated the more theoretical program from the first 3 years and the practical application in the fourth year. RESULTS: Nearly half of the students stated that the preclinical years of the EBM program were 'adequate', but only 30% of the students indicated that the program was practical. They stated that 'more practical approaches were used in the fourth year, whereas more theory-based approaches were used during the preclinical years'. More than 75% of the students declared that the practice of EBM in the fourth year was useful and appropriate for team-based learning. CONCLUSIONS: The EBM program was evaluated as 'adequate'. EBM courses should be included in the entire curriculum in an integrated manner. The students understand the main philosophy of EBM in the clinical year when involved in its practical application with actual patients. PMID- 24767707 TI - Diagnosis of reversible causes of coma. AB - Because coma has many causes, physicians must develop a structured, algorithmic approach to diagnose and treat reversible causes rapidly. The three main mechanisms of coma are structural brain lesions, diffuse neuronal dysfunction, and, rarely, psychiatric causes. The first priority is to stabilise the patient by treatment of life-threatening conditions, then to use the history, physical examination, and laboratory findings to identify structural causes and diagnose treatable disorders. Some patients have a clear diagnosis. In those who do not, the first decision is whether brain imaging is needed. Imaging should be done in post-traumatic coma or when structural brain lesions are probable or possible causes. Patients who do not undergo imaging should be reassessed regularly. If CT is non-diagnostic, a checklist should be used use to indicate whether advanced imaging is needed or evidence is present of a treatable poisoning or infection, seizures including non-convulsive status epilepticus, endocrinopathy, or thiamine deficiency. PMID- 24767708 TI - Ovarian cancer. AB - Epithelial ovarian cancer is the commonest cause of gynaecological cancer associated death. The disease typically presents in postmenopausal women, with a few months of abdominal pain and distension. Most women have advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage III), for which the standard of care remains surgery and platinum-based cytotoxic chemotherapy. Although this treatment can be curative for most patients with early stage disease, most women with advanced disease will develop many episodes of recurrent disease with progressively shorter disease-free intervals. These episodes culminate in chemoresistance and ultimately bowel obstruction, the most frequent cause of death. For women whose disease continues to respond to platinum based drugs, the disease can often be controlled for 5 years or more. Targeted treatments such as antiangiogenic drugs or poly (ADP-ribose) polymerase inhibitors offer potential for improved survival. The efficacy of screening, designed to detect the disease at an earlier and curable stage remains unproven, with key results expected in 2015. PMID- 24767709 TI - Gender difference in glyoxalase 1 activity of atherosclerotic carotid artery lesions. AB - OBJECTIVE: Age and gender are two factors that determine the risk of atherosclerosis. The latter effect is only partly understood. Dicarbonyls, in particular methylglyoxal, participate in the development of atherosclerosis, and their major detoxification route is the enzyme glyoxalase 1 (GLO1), which is known to decrease during aging. METHODS: GLO1 expression and activity were studied in atherosclerotic carotid artery lesions of 71 patients with respect to demographic and clinical characteristics. RESULTS: GLO1 activity was nonsignificantly reduced by >50% in individuals with carotid artery disease compared with control individuals. There was no significant difference in GLO1 expression between the groups; however, the GLO1 activity-to-protein ratio showed a significant reduction for the carotid artery disease patients compared with the controls. The reduction in the GLO1 activity-to-protein ratio was more pronounced in men and was associated with increased inflammation shown by a significant elevation in the expression-level of interleukin-1beta. CONCLUSIONS: These data suggest that GLO1 is regulated on the post-translational level by factors such as gender as well as factors that affect the overall burden of atherosclerosis. PMID- 24767710 TI - Impact of intraoperative adverse events during branched and fenestrated aortic stent grafting on postoperative outcome. AB - OBJECTIVE: Fenestrated and branched endovascular devices are increasingly used for complex aortic diseases, and despite the challenging nature of these procedures, early experiences from pioneering centers have been encouraging. The objectives of this retrospective study were to report our experience of intraoperative adverse events (IOAEs) during fenestrated and branched stent grafting and to analyze the impact on clinical outcomes. METHODS: Consecutive patients treated with fenestrated and branched stent grafting in a tertiary vascular center between February 2006 and October 2013 were evaluated. A prospectively maintained computerized database was scrutinized and updated retrospectively. Intraoperative angiograms were reviewed to identify IOAEs, and adverse events were categorized into three types: target vessel cannulation, positioning of graft components, and intraoperative access. Clinical consequences of IOAEs were analyzed to ascertain whether they were responsible for death or moderate to severe postoperative complications. RESULTS: During the study period, 113 consecutive elective patients underwent fenestrated or branched stent grafting. Indications for treatment were asymptomatic complex abdominal aortic aneurysms (CAAAs, n = 89) and thoracoabdominal aortic aneurysms (TAAAs, n = 24). Stent grafts included fenestrated (n = 79) and branched (n = 17) Cook stent grafts (Cook Medical, Bloomington, Ind), Ventana (Endologix, Irvine, Calif) stent grafts (n = 9), and fenestrated Anaconda (Vascutek Terumo, Scotland, UK) stent grafts (n = 8). In-hospital mortality rates for the CAAA and TAAA groups were 6.7% (6 of 89) and 12.5% (3 of 24), respectively. Twenty-eight moderate to severe complications occurred in 21 patients (18.6%). Spinal cord ischemia was recorded in six patients, three of which resolved completely. A total of 37 IOAEs were recorded in 34 (30.1%) patients (22 CAAAs and 12 TAAAs). Of 37 IOAEs, 15 (40.5%) resulted in no clinical consequence in 15 patients; 17 (45.9%) were responsible for moderate to severe complications in 16 patients, and five (13.5%) led to death in four patients. The composite end point death/nonfatal moderate to severe complication occurred more frequently in patients with IOAEs compared with patients without IOAEs (20 of 34 vs 12 of 79; P < .0001). CONCLUSIONS: In this contemporary series, IOAEs were relatively frequent during branched or fenestrated stenting procedures and were often responsible for significant complications. PMID- 24767711 TI - New-generation stent grafts for endovascular management of thoracic pseudoaneurysms after aortic coarctation repair. AB - OBJECTIVE: Late thoracic aneurysms develop in 5% to 12% of patients having undergone open repair for coarctation of the aorta (CoA). We report our early results for thoracic endovascular aortic repair for pseudoaneurysms after CoA repair. METHODS: From 2008 to 2013, data regarding demographics, aneurysm morphology, procedure, and follow-up were collected prospectively on all patients treated for pseudoaneurysms after CoA repair. Retrospective analysis of identified patients was then performed. RESULTS: Thirteen patients (six men, seven women) were treated. Patients were a median age, 45 years (interquartile range (IQR), 39-56; range, 27-66 years, and the median time after CoA repair to aneurysm treatment was 34 years (IQR, 24-40 years). All patients had saccular pseudoaneurysms of the aortic arch, with a median aneurysm size of 4.1 cm (IQR, 3.4-5.1 cm). The left subclavian artery (LSCA) was involved in 10 patients and was occluded at presentation in three. Four patients had concurrent LSCA revascularization with carotid-subclavian bypass, one had aortic arch hybrid repair, and the LSCA was intentionally covered in two patients. Patients underwent thoracic endovascular aortic repair using the conformable TAG (6 of 13; W. L. Gore & Associates, Flagstaff, Ariz), Valiant device (4 of 13; Medtronic, Minneapolis, Minn), and a custom-made Relay endograft with LSCA scallop (4 of 13; Bolton Medical, Barcelona, Spain). Technical success was 100%, with satisfactory deployment of the stent grafts in all patients. There was no 30-day mortality, stroke, or paraplegia. Median follow-up was 15 months (IQR, 9-19 months; range, 1 67 months). Two type II endoleaks from an intercostal artery were managed conservatively, and one type Ib endoleak was treated successfully with distal stent extension. CONCLUSIONS: In this cohort, new-generation stent grafts have good early clinical and radiologic outcomes, avoiding the need for redo open surgery. Management of the LSCA can be tailored to individual patients with new stent graft technology. Long-term follow-up of these patients is crucial to understanding whether endovascular management of this cohort is acceptable. PMID- 24767712 TI - Errors in the interpretation of copy number variations due to the use of public databases as a reference. AB - The identification of new cryptic deletions and duplications can be used to improve prognostic classification in cancer. To obtain accurate results, it is necessary to discriminate between somatic alterations in the tumor cell and germline polymorphisms. For this purpose, copy number variation (CNV) public databases have been used as a reference. Nevertheless, the use of these databases may lead to erroneous results. Our main goal was to explore the limitations of the use of CNV databases, such as the Database of Genomic Variants (DGV), as the reference. To that end, we used pediatric acute lymphoblastic leukemia (ALL) as a model. We analyzed the genome-wide copy number profile of 23 ALL patients and conducted a comparison of the results obtained using the DGV with those obtained using the normal sample from the patient as the reference. Using only the DGV, 19% of alterations and 41% of polymorphisms were erroneously catalogued. Our results support the hypothesis that with the use of databases such as the DGV as the reference, a high percentage of the variations can be erroneously classified. PMID- 24767713 TI - Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study. AB - The E318K mutation in the MITF gene has been associated with a high risk of melanoma, renal cell carcinoma, and pancreatic cancer; the risk of other cancers has not been evaluated so far. Herein, we examined the possible association of E318K and a novel variant of the MITF gene, V320I, with the risk of cancers of different sites of origin in a Polish population. We assayed for the presence of the E318K and V320I missense mutations in 4,226 patients with one of six various cancers (melanoma or cancer of the kidney, lung, prostate, colon, or breast) and 2,114 controls from Poland. The E318K mutation was detected in 4 of 2,114 participants (0.19%) in the Polish control population, the V320I in 3 of 2,114 participants (0.14%) in the control group. We found no statistically significant differences in the prevalence of the E318K and V320I variants among cases and controls. We found two carriers of the E318K variant among melanoma patients (P = 0.95), one carrier among breast cancer patients (P = 0.77), one carrier among colorectal cancer patients (P = 0.82), and one carrier among kidney cancer patients (P = 0.64). Our study demonstrates a lack of strong association of E318K and V320I with increased risk of melanoma or cancers of the kidney, breast, prostate, lung, or colon. PMID- 24767716 TI - Burns in Sierra Leone: a population-based assessment. AB - PURPOSE: Burns remain disproportionately prevalent in developing countries. This study aims to describe the epidemiology of burns in Sierra Leone to serve as a baseline for future programs. METHODS: A cluster randomized, cross-sectional, countrywide survey was conducted in 2012 in Sierra Leone. With a standardized questionnaire demographics and deaths during the previous 12 months of household members were assessed with the household representative. Thereafter, 2 randomly selected household members were interviewed, elucidating whether participants had ever had a burn in six body regions and determining burn mechanisms and patterns of health care seeking behavior. RESULTS: This study included 1843 households and 3645 individuals. 3.98% (145/3645) of individuals reported at least one burn injury. The highest proportions of burns were reported in the age groups 0-4 years old (23/426, 5.4%) and 5-14 years old (37/887, 4.17%). The majority of burns (129/145, 89.0%) were caused by a hot liquid/object and the upper, extremities were the most commonly burned body regions, with 36% (53/145) of cases. 21% (30/145) of individuals with burns sought care from a traditional healer. CONCLUSIONS: Burns are highly prevalent in Sierra Leone. Further research and resources should be allocated to the care and prevention of thermal injuries. PMID- 24767717 TI - Cytotoxicity testing of silver-containing burn treatments using primary and immortal skin cells. AB - A novel burn wound hydrogel dressing has been previously developed which is composed of 2-acrylamido-2-methylpropane sulfonic acid sodium salt with silver nanoparticles (silver AMPS). This study compared the cytotoxicity of this dressing to the commercially available silver products; ActicoatTM, PolyMem Silver((r)) and FlamazineTM cream. Human keratinocytes (HaCaT and primary HEK) and normal human fibroblasts (NHF) were exposed to dressings incubated on NuncTM polycarbonate inserts for 24, 48 and 72h. Four different cytotoxicity assays were performed including; Trypan Blue cell count, MTT, Celltiter-BlueTM and Toluidine Blue surface area assays. The results were expressed as relative cell viability compared to an untreated control. The cytotoxic effects of ActicoatTM and FlamazineTM cream were dependent on exposure time and cell type. After 24h exposure, ActicoatTM and FlamazineTM cream were toxic to all tested cell lines. Surprisingly, HaCaTs treated with ActicoatTM and FlamazineTM had an improved ability to survive at 48 and 72h while HEKs and NHFs had no improvement in survival with any treatment. The novel silver hydrogel and PolyMem Silver((r)) showed low cytotoxicity to all tested cell lines at every time interval and these results support the possibility of using the novel silver hydrogel as a burn wound dressing. Researchers who rely on HaCaT cells as an accurate keratinocyte model should be aware that they can respond differently to primary skin cells. PMID- 24767714 TI - Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors. AB - Single nucleotide polymorphism (SNP) array analysis is currently used as a first tier test for pediatric brain tumors at The Children's Hospital of Philadelphia. The results from 100 consecutive patients are summarized in the present report. Eighty-seven percent of the tumors had at least one pathogenic copy number alteration. Nineteen of 56 low grade gliomas (LGGs) demonstrated a duplication in 7q34, which resulted in a KIAA1549-BRAF fusion. Chromosome band 7q34 deletions, which resulted in a FAM131B-BRAF fusion, were identified in one pilocytic astrocytoma (PA) and one dysembryoplastic neuroepithelial tumor (DNT). One ganglioglioma (GG) demonstrated a 6q23.3q26 deletion that was predicted to result in a MYB-QKI fusion. Gains of chromosomes 5, 6, 7, 11, and 20 were seen in a subset of LGGs. Monosomy 6, deletion of 9q and 10q, and an i(17)(q10) were each detected in the medulloblastomas (MBs). Deletions and regions of loss of heterozygosity that encompassed TP53, RB1, CDKN2A/B, CHEK2, NF1, and NF2 were identified in a variety of tumors, which led to a recommendation for germline testing. A BRAF p.Thr599dup or p.V600E mutation was identified by Sanger sequencing in one and five gliomas, respectively, and a somatic TP53 mutation was identified in a fibrillary astrocytoma. No TP53 hot-spot mutations were detected in the MBs. SNP array analysis of pediatric brain tumors can be combined with pathologic examination and molecular analyses to further refine diagnoses, offer more accurate prognostic assessments, and identify patients who should be referred for cancer risk assessment. PMID- 24767715 TI - Up-to-date approach to manage keloids and hypertrophic scars: a useful guide. AB - Keloids and hypertrophic scars occur anywhere from 30 to 90% of patients, and are characterized by pathologically excessive dermal fibrosis and aberrant wound healing. Both entities have different clinical and histochemical characteristics, and unfortunately still represent a great challenge for clinicians due to lack of efficacious treatments. Current advances in molecular biology and genetics reveal new preventive and therapeutical options which represent a hope to manage this highly prevalent, chronic and disabling problem, with long-term beneficial outcomes and improvement of quality of life. While we wait for these translational clinical products to be marketed, however, it is imperative to know the basics of the currently existing wide array of strategies to deal with excessive scars: from the classical corticotherapy, to the most recent botulinum toxin and lasers. The main aim of this review paper is to offer a useful up-to date guideline to prevent and treat keloids and hypertrophic scars. PMID- 24767718 TI - Vascular anatomy of the patella: implications for total knee arthroplasty surgical approaches. AB - BACKGROUND: Iatrogenic disruption of the patellar vascular supply has been identified as a possible contributing factor to the commonly reported patellofemoral complications following total knee arthroplasty (TKA). We performed an anatomic cadaveric study evaluating the extra-osseous vascular anatomy of the patella, and correlated our findings to routine TKA surgical dissection to determine how to better preserve patellar vascularity. METHODS AND MATERIALS: In twenty-one cadaveric knees arterial cannulas were placed proximally and distally to the patella. A polyurethane compound was then injected producing a visible arterial network. Specimens underwent gross dissection. RESULTS: In all 21 specimens, the supreme genicular (SGA), medial/lateral superior genicular (MSGA/LSGA), medial/lateral inferior genicular and anterior tibial recurrent arteries communicate forming a peripatellar anastomotic ring supplying the intraosseous patellar system. Both the SGA (24%) and MSGA (76%) demonstrated dual medial ring contribution. Relating the arterial location to common TKA exposures suggested severe compromise of patellar vascularity. CONCLUSION: The medial sided vessels seem to contribute more significantly to the peripatellar anastomotic ring when compared to the lateral sided vessels. Careful soft tissue management has the potential to preserve key vascular structures that could maintain the intraosseous vascular supply to the patella. Understanding the anatomic locations of major arterial systems around the knee joint can potentially help during hemostasis, and can minimize blood loss during TKA. CLINICAL RELEVANCE: Recognition of major arterial systems around the knee joint has the potential to minimize iatrogenic disruption of the vascular supply and the complications that can follow (patella devascularization and blood lost). PMID- 24767719 TI - Short course daily prednisolone therapy during an upper respiratory tract infection in children with relapsing steroid-sensitive nephrotic syndrome (PREDNOS 2): protocol for a randomised controlled trial. AB - BACKGROUND: Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4- to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5- to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation. METHODS/DESIGN: The subjects will be 300 children with relapsing SSNS (>=2 relapses in preceding year), who will be randomised to receive either a 6 day course of daily prednisolone or no change to their current therapy (with the use of placebo to double blind) each time they develop an URTI over 12 months. A strict definition for URTI will be used. Subjects will be reviewed at 3, 6, 9 and 12 months to capture data regarding relapse history, ongoing therapy and adverse effect profile, including behavioural problems and quality of life. A formal health economic analysis will also be performed. The primary end point of the study will be the incidence of URTI-related relapse (3 days of Albustix +++) following the first infection during the 12-month follow-up period. DNA and RNA samples will be collected to identify a potential genetic cause for the disease. Subjects will be recruited from over 100 UK centres with the assistance of the Medicines for Children Research Network.PREDNOS 2 is funded by the National Institute for Health Research Health Technology Assessment Programme (11/129/261). DISCUSSION: We propose that PREDNOS 2 will be a pivotal study that will inform the future standard of care for children with SSNS. If it is possible to reduce the disease relapse rate effectively and safely, this will reduce the morbidity and cost associated with drug treatment, notwithstanding hospital admission and parental absence from employment. TRIAL REGISTRATION: Current Controlled Trials (ISRCTN10900733). PMID- 24767720 TI - The birthrate drop in Iran. AB - The recent steep decline in Iran's birthrate poses methodological and interpretive challenges insofar as statistical information on demographic factors cannot satisfactorily establish causalities or delineate processes of change. Our research suggests that this decline rests on the interplay of socio-cultural "idea" variables that augment factors of the developmental paradigm commonly used in population studies. Especially modernist ideas labeled "progress" in Iran have influenced reproductive behavior. Aiming to demonstrate the usefulness of idea oriented qualitative research for understanding demographic dynamics represented quantitatively in the literature, we contribute to an explanation of a particular case as well as to demographic research methods. PMID- 24767721 TI - Prevalence and associated factors of DSM-V insomnia in Norway: the Nord-Trondelag Health Study (HUNT 3). AB - BACKGROUND: Many studies have assessed the prevalence of insomnia, but the influence of non-participants has largely been ignored. The objective of the present study was to estimate the prevalence and associated factors of insomnia in a large adult population using DSM-V (diagnostic and statistical manual of mental disorders, 5th ed.) criteria, also taking non-participants into account. METHODS: This cross-sectional study used data from a questionnaire in The Nord Trondelag Health Study (HUNT 3) performed in 2006-2008, and a subsequent non participant study. The total adult population (n=93,860 aged > or =20 years) of Nord-Trondelag County, Norway, was invited. Of these, 40,535 responded to the insomnia questionnaire. Among 42,024 eligible non-participants, 6918 (17%) responded to two insomnia questions. RESULTS: Insomnia was diagnosed by applying modified DSM-V criteria. The age-adjusted insomnia prevalence was estimated using the age distribution of all adult inhabitants of Nord-Trondelag. Supplementary prevalence data were estimated by extrapolating data from the non-participant study. Additionally, the association between insomnia and self-reported health was estimated, adjusting for known confounders. The total age-adjusted prevalence of insomnia was 7.1% (95% confidence interval [CI], 6.9-7.4) (8.6% for women, 5.5% for men). Adjusting for non-participants, the prevalence estimate changed to 7.9% (95% CI, 7.3-8.6) (9.4% for women, 6.4% for men). Insomnia was more than eight times more likely (OR, 8.3; 95% CI, 6.2-11.1) among individuals with very poor versus very good self-reported health, adjusting for age, gender, employment status, chronic musculoskeletal complaints, anxiety and depression. CONCLUSIONS: The adjusted insomnia prevalence estimate in Nord-Trondelag was 7.9%. Insomnia was strongly associated with poor self-reported health. PMID- 24767722 TI - The link between social anxiety disorder, treatment outcome, and sleep difficulties among patients receiving cognitive behavioral group therapy. AB - OBJECTIVE: The aim of our study was to examine the association between sleep disturbances and social anxiety disorder (SAD). Another aim was to explore the impact of cognitive behavioral group therapy (CBGT) for SAD on co-occurring sleep difficulties. METHODS: Data were obtained retrospectively from patient files receiving CBGT for SAD. The sample included 63 patients with SAD (mean age, 30.42 years [standard deviation, 6.92 years]). There were 41 men and 22 women, of whom 41 participants completed the treatment protocol. Before treatment onset participants completed the Liebowitz Social Anxiety Scale (LSAS), the Beck Depression Inventory (BDI), the Pittsburgh Sleep Quality Index, and several sociodemographic questions. On completion of the treatment protocol, the same measures were completed, with the addition of the Sheehan Disabilities Scale (SDS). RESULTS: The results of our study suggest that: (1) subjective insomnia is associated with SAD severity even after controlling for depression severity and additional variables; (2) participants with SAD with co-occurring clinical levels of subjective insomnia present a more severe clinical picture both at treatment onset and termination; and (3) although CBGT lead to reduction in SAD and depression symptoms severity, it had no significant impact on co-occurring sleep difficulties. CONCLUSIONS: Sleep difficulties predict SAD severity regardless of depressive symptoms and may be linked to a more severe clinical picture. Clinicians should be aware of these sleep difficulties co-occurring with SAD and consider implementing specific sleep interventions. Future studies should incorporate larger samples sizes from clinical populations outside of Israel. PMID- 24767723 TI - Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in eastern China. AB - OBJECTIVE: Our study was designed to assess symptomatology and occurrences of narcolepsy in eastern China between 2003 and 2012. Herein we report the substantial changes in the occurrence and clinical features of narcolepsy over the last decade in China. METHODS: We performed a retrospective analysis of 162 Han Chinese patients with narcolepsy at Changzheng Hospital, Shanghai, China. Clinical histories and precipitating factors were recorded, in addition to narcolepsy and H1N1 winter flu pandemic (pH1N1) occurrences at Changzheng Hospital. The occurrences also were compared between the Changzheng Hospital and the People's Hospital, Beijing, China. RESULTS: In our sample, narcolepsy occurred 1.73 times more frequently in men than in women. Most of the participants were children, which peaked to 91% in 2010. Excessive daytime sleepiness (EDS), disrupted nocturnal sleep, cataplexy, and weight gain were the four major symptoms. We found that 40% of patients had identifiable precipitating factors. The occurrence of narcolepsy in 2010 showed an approximate three-fold difference from the baseline levels at the Changzheng Hospital, which showed positive relationships with occurrences of pH1N1 in Shanghai and the occurrence of narcolepsy at the People's Hospital. CONCLUSIONS: Our findings show the interactive effects of geography and H1N1 disease in relation to narcolepsy in Han Chinese populations, and strengthen the theoretic hypothesis that immune and mental factors facilitate the onset of narcolepsy. PMID- 24767724 TI - Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease. AB - BACKGROUND: Dopamine agonists (DAs) represent the first-line treatment in restless legs syndrome (RLS); however, in the long term, a substantial proportion of patients will develop augmentation, which is a severe drug-related exacerbation of symptoms and the main reason for late DA withdrawal. Polysomnographic features and mechanisms underlining augmentation are unknown. No practice guidelines for management of augmentation are available. METHODS: A clinical case series of 24 consecutive outpatients affected by RLS with clinically significant augmentation during treatment with immediate-release DA was performed. All patients underwent a full-night polysomnographic recording during augmentation. A switchover from immediate-release DAs (l-dopa, pramipexole, ropinirole, rotigotine) to the long-acting, extended-release formula of pramipexole was performed. RESULTS: Fifty percent of patients presented more than 15 periodic limb movements per hour of sleep during augmentation, showing longer sleep latency and shorter total sleep time than subjects without periodic limb movements. In all patients, resolution of augmentation was observed within two to four weeks during which immediate-release dopamine agonists could be completely withdrawn. Treatment efficacy of extended-release pramipexole has persisted, thus far, over a mean follow-up interval of 13 months. CONCLUSIONS: Pramipexole extended release could be an easy, safe, and fast pharmacological option to treat augmentation in patients with restless legs syndrome. As such it warrants further prospective and controlled investigations. This observation supports the hypothesis that the duration of action of the drug plays a key role in the mechanism of augmentation. PMID- 24767725 TI - Prevalence, pharmacotherapy and clinical correlates of diagnosed insomnia among Veterans Health Administration service users nationally. AB - OBJECTIVE: There is little information on diagnostic rates or treatment correlates of insomnia in real-world practice. Study objectives were to identify the 1-year prevalence, psychotropic pharmacotherapy and clinical correlates of diagnosed insomnia, nationally in the Veterans Health Administration (VHA). METHOD: The study used national administrative data on all individuals receiving VHA care in 2010. Receipt of insomnia, in addition to co-morbid diagnoses, was identified using relevant International Classification of Diseases (ICD)-9 diagnostic codes. The adjusted mean number of psychotropic prescription fills and co-morbid conditions associated with insomnia were identified using bivariate and multivariable regression models. RESULTS: Of the 5,531,379 individuals receiving VHA care in 2010, 190,378 (3.4%) received an insomnia diagnosis. Controlling for clinical characteristics, the presence of an insomnia diagnosis was associated with an average of four additional psychotropic prescription fills over the year. Among demographic characteristics, deployment to recent conflicts in Iraq/Afghanistan (adjusted odds ratio (AOR)=1.62) displayed the strongest independent association, while age, unexpectedly, did not display any association with insomnia. Among diagnostic variables, anxiety disorders other than post traumatic stress (AOR=2.12) and depressive disorders other than major depression (AOR=2.05) displayed the strongest independent associations with insomnia. CONCLUSION: The diagnosis of insomnia is associated with the filling of more psychotropic prescriptions, net of the presence of psychiatric co-morbidity in national VHA administrative data, and the prevalence of diagnosed insomnia is lower than that found in systematic surveys of the general population, a potential impediment to optimal treatment. PMID- 24767726 TI - Chronic intermittent hypoxia causes endothelial dysfunction in a mouse model of diet-induced obesity. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). OSA is prevalent in obese subjects and is associated with endothelial dysfunction and cardiovascular disorders. We tested the hypothesis that the deleterious effects of IH could be further modulated by diet-induced obesity. DESIGN: Thirty adult (8-10 weeks) male C57BL/6J mice were divided into four groups. Mice were subjected to CIH or intermittent air (IA) for 12h a day and fed either a high fat (HF) or a low fat control diet (CD) for 6weeks. We analyzed endothelial function using a wire myograph, and measured markers of oxidative stress (plasma malondialdehyde (MDA) and total antioxidant capacity (TAC)) using colorimetrical assays. We also measured C-reactive protein (CRP) using ELISA and endothelial nitric oxide (eNOS) gene expression using real time PCR. RESULTS: Stimulated endothelial dependent dilation was significantly impaired only in the group fed high fat diet and subjected to CIH (Emax: HFIH 78+/-2%, p<0.0001) when compared to the other groups (Emax: HFIA 95+/-0.7%, CDIH 94+/-2%, CDIA 97+/-1%). Also basal endothelial dependant dilation was attenuated in the HFIH group compared to the HFIA group (Emax: HFIH: 179+/-10% vs. HFIA: 149+/-11% in the presence of L-NAME). Levels of MDA were elevated in the CDIH group when compared to CDIA (0.68+/-0.04 vs. 0.41+/-0.03 MUM, p<0.05) but were greatest in the HFIH group (0.83+/-0.08 MUM, p<0.05). However, there was no significant increase in MDA levels in the HFIA group (0.45+/-0.03 MUM, p=NS) when compared to all other groups. Similar effects were observed with CRP levels; CRP levels were significantly higher in the CDIH group compared with intermittent air (10.39+/-0.38 vs. 8.70+/-0.21 MUg/ml, p<0.05) but the HFIH had the greatest levels of CRP (11.87+/-0.31 MUg/ml, p<0.05). In the HFIA group, CRP levels were not elevated (9.96+/-0.37 MUg/ml, p=NS). Nevertheless, total antioxidant capacity and eNOS gene expression were not significantly different in the groups. CONCLUSION: CIH caused endothelial dysfunction in mice fed an obesogenic diet. Inflammation and oxidative stress were increased in CIH and an obesogenic diet exacerbated these effects. PMID- 24767727 TI - Association between short time in bed, health-risk behaviors and poor academic achievement among Norwegian adolescents. AB - OBJECTIVE: To investigate the prevalence of short time in bed (<8h/day) and to examine the association between time in bed, overweight/obesity, health-risk behaviors and academic achievement in adolescents. METHODS: This study included a sample of adolescents (n=2432) aged 15-17 years in the southern part of Norway (participation rate, 98.7%). A self-report questionnaire was used to assess time in bed, body mass index, dietary habits, physical activity habits, sedentary behavior, smoking and snuffing habits, and academic achievement. RESULTS: A total of 32.3% of the students reported short time in bed (<8h/day) on an average school night. Several health-risk behaviors were associated with short sleep duration, including not being physically active for > or =60 min for > or =5 days/week (adjusted odds ratio, 1.33; 95% confidence interval, 1.05-1.68); using television/computer >2 h/day (1.63; 1.23-2.17); being a current smoker (2.46; 1.80-3.35) or snuffer (2.11; 1.57-2.85); having an irregular meal pattern (1.33; 1.05-1.68); intake of sweets/candy > or =4 times/week (0.51; 0.32-0.83); and poor academic achievement (1.62; 1.26-2.09). All odds ratios were adjusted for sex, age and parental education. CONCLUSIONS: In Norwegian adolescents, short time in bed is associated with several health-risk behaviors and poor academic achievement. PMID- 24767728 TI - Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature. AB - Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by wrinkled, inelastic skin, frequently associated with a neurologic involvement and multisystem disease. Next generation sequencing was performed in genetically unsolved patients with progeroid features, neurological and eye involvement to assess the underlying etiology. We describe an 6 month old child, diagnosed with a novel, homozygous nonsense mutation c.2339T>C in exon 18 of the ALDH18A1 gene, and reviewed all reported P5CS patients. So far 10 patients were described with mutations in ALDH18A1. Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay. Furthermore, abnormal fat distribution, retinal abnormalities, undescended testis, and retinitis pigmentosa have never been described in ALDH18A1. Some features described as unique in ALDH18A1 have been observed in PYCR1 patients, thus suggesting that the phenotypic overlap is higher than previously shown. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is diverse, with variable degree of progeria in children, but always in association with neurologic disease. We suggest genetic testing for possible ALDH18A1 mutations in all patients with progeroid features, like wrinkled or parchment-like skin, abnormal growth, especially with central nervous system involvement and microcephaly. PMID- 24767729 TI - Changes in fruit and vegetable consumption of third-grade students in body quest: food of the warrior, a 17-class childhood obesity prevention program. AB - OBJECTIVE: To increase fruit and vegetable (FV) consumption of youth in Body Quest: Food of the Warrior (BQ), a childhood obesity prevention program. DESIGN: Quasi-experimental. SETTING: Supplemental Nutrition Assistance Program-Education eligible schools (n = 60). PARTICIPANTS: Third-grade students (n = 2,477). INTERVENTION: Treatment groups (n = 1,674) self-reported foods consumed through the School Lunch Program for 17 weekly assessments; they participated in BQ curriculum, iPad app education, and weekly FV tastings. Control groups (n = 803) completed only pre- and post-assessments. MAIN OUTCOME MEASURE: Weekly FV consumed through School Lunch Program. ANALYSIS: ANCOVA and growth modeling. RESULTS: From before to after the program, the treatment group demonstrated significant, moderate increases in fruit (P < .01) and vegetable (P < .001) consumptions, increasing from 7 to 8 weekly FV servings. After the program, the treatment group consumed significantly (P < .001) more FV than the control group. Fruit and vegetable consumption increased to class 10 and then stabilized. From before to after the program, all FV predictors were significantly higher and included gender (vegetables), race (FV), and free/reduced lunch (fruit). CONCLUSIONS AND IMPLICATIONS: Nutrition programs can increase FV intake. Even moderate increases in FV intake can be an initial step for the prevention of chronic disease. PMID- 24767730 TI - Patient-reported frequency of acral surface inspection during skin examination in white and ethnic minority patients. AB - BACKGROUND: Acral lentiginous melanomas compose a higher proportion of melanomas and have a higher mortality in ethnic minorities than in whites. Early detection by acral surface inspection during skin examinations may lead to improved acral lentiginous melanoma outcomes. OBJECTIVE: This study compared patient-reported frequencies of acral skin examinations in ethnic and white populations. METHODS: Written surveys were collected from 1040 dermatology clinic patients. RESULTS: More whites reported performing self-skin examinations than ethnic minorities (P < .01), but there was no difference in the rates of hand (P = .7) or foot (P = .87) inspection during self-skin examination between whites and ethnic minorities. More whites (77.5%) than ethnic minorities (38.9%) reported having undergone a full-body skin examination (FBSE) from a health care provider (P < .01). During their most recent FBSE by a health care provider, more whites than ethnic minorities reported having their hands examined (P = .02), but there was no difference in reported hand inspection (P = .06) at any previous FBSE or foot inspection at any (P = .07) or the most recent (P = .59) FBSE between whites and ethnic minorities. LIMITATIONS: Single-center study using a new unvalidated survey is a limitation. CONCLUSION: Whites were found to more frequently report self-skin examination and FBSE than ethnic minorities, but significant differences in reported acral examinations were not detected. PMID- 24767732 TI - Recognizing and managing the immunologic reactions in leprosy. AB - Immunologic reactions are an important aspect of leprosy that significantly impacts the course of the disease and the associated disability. Reversal reaction (type 1), erythema nodosum leprosum (type 2), and Lucio phenomenon are the 3 leprosy reactions, and they are most commonly seen in patients with the lepromatous and borderline categories of the disease. Because these forms of leprosy are the most common types seen in the United States, it is particularly important for physicians to be able to recognize and treat them. The reactions may occur before, during, or after treatment with multidrug therapy. Reversal reactions are the most common cause of nerve damage in leprosy, and erythema nodosum leprosum may also lead to neuritis. Although there have not been enough studies to confirm the most effective management regimens, treatment of reversal reaction and Lucio phenomenon with prednisone and of erythema nodosum leprosum with thalidomide and/or prednisone may help improve symptoms and prevent further disability. PMID- 24767731 TI - Ipilimumab in patients with cancer and the management of dermatologic adverse events. AB - Ipilimumab is a fully human monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 to augment antitumor T-cell responses. Phase III studies have demonstrated survival benefit in both previously treated and treatment-naive patients with metastatic melanoma. In clinical trials, adverse events (AEs) related to treatment with ipilimumab were mostly grade 1/2 (as per Common Terminology Criteria for AEs, Version 4.02), and mostly reversible with appropriate management. Distinct immune-related AEs that may reflect the mechanism of action of ipilimumab have been identified, and occur commonly in the skin, typically presenting as a maculopapular rash, which can be accompanied by pruritus, pruritus with no skin lesions, alopecia, and vitiligo. Histologic analyses have revealed epidermal spongiosis, and perivascular CD4(+) T-cell infiltrates with some eosinophils in areas of rash. Timely implementation of toxicity-specific treatment guidelines that emphasize vigilance and early intervention allows mitigation of dermatologic AEs. Adherence to guidelines is necessary to maintain quality of life, ensure consistent dosing, and obtain the best possible clinical outcome. PMID- 24767733 TI - Anti-p200 pemphigoid. AB - Anti-p200 pemphigoid is a rare subepidermal blistering skin disease. Patients' autoantibodies label the dermal side of 1 mol/L NaCl-split human skin by indirect immunofluorescence microscopy and recognize a 200-kd protein by immunoblotting of human dermal extract. Clinically, anti-p200 pemphigoid is characterized by tense blisters and vesicles, erosions, and urticarial plaques, closely resembling bullous pemphigoid and the inflammatory variant of epidermolysis bullosa acquisita. Recently, 90% of anti-p200 pemphigoid sera were shown to recognize laminin gamma1. The C-terminus of laminin gamma1 was identified as an immunodominant region and in its recombinant form was used by immunoblotting and enzyme-linked immunosorbent assay for the serologic diagnosis of this disease. Subsequent ex vivo and in vivo studies were, however, unable to show pathogenic activity of antilaminin gamma1 antibodies. Both patients' sera and sera depleted from antilaminin gamma1 antibodies induced subepidermal splitting in an ex vivo model of autoantibody-mediated leukocyte-dependent neutrophil activation. Antilaminin gamma1 antibodies appear to be useful biomarkers that will further facilitate the diagnosis of anti-p200 pemphigoid. The true identity of the pathogenetically relevant autoantigen of this disease, which may either be a yet unknown isoform of laminin gamma1 or even another 200-kd protein of the dermoepidermal junction, still needs to be elucidated. PMID- 24767734 TI - Opportunities and challenges for seaweed in the biobased economy. AB - The unique chemical composition of seaweeds and their fast growth rates offer many opportunities for biorefining. In this article we argue that cascading biorefinery valorization concepts are viable alternatives to only using seaweeds as carbohydrate sources for the fermentative production of biofuels. However, many challenges remain with respect to use of seaweeds for chemical production, such as the large seasonal variation in the chemical composition of seaweeds. PMID- 24767735 TI - Caution required for handling genome editing technology. AB - Genome-editing technology, although a robust tool for genetic engineering, is creating indistinct regulatory boundaries between naturally occurring and modified organisms. However, researchers must act with caution in research and development to avoid misleading society. Furthermore, appropriate regulations should be proactively discussed and established for handling genome-editing technology. PMID- 24767736 TI - Effects of increased step width on frontal plane knee biomechanics in healthy older adults during stair descent. AB - BACKGROUND: Peak internal knee abduction moment is a common surrogate variable associated with medial compartment knee loading. Stair descent has been shown to yield a greater peak knee abduction moment compared to level-walking. Changes in step width (SW) may lead to changes in frontal plane lower extremity limb alignment in the frontal plane and alter peak knee abduction moment. The purpose of this study was to investigate the effects of increased SW on frontal plane knee biomechanics during stair descent in healthy older adults. METHODS: Twenty healthy adults were recruited for the study. A motion analysis system was used to obtain three-dimensional lower limb kinematics during testing. An instrumented 3 step staircase with two additional customized wooden steps was used to collect ground reaction forces (GRF) data during stair descent trials. Participants performed five stair descent trials at their self-selected speed using preferred, wide (26% leg length), and wider (39% leg length) SW. RESULTS: The preferred normalized SW in older adults during stair descent was 20% of leg length. Wide and wider SW during stair descent reduced both first and second peak knee adduction angles and abduction moments compared to preferred SW in healthy adults. CONCLUSIONS: Increased SW reduced peak knee adduction angles and abduction moments. The reductions in knee abduction moments may have implications in reducing medial compartment knee loads during stair descent. PMID- 24767737 TI - A veterinary guide to the fish gastrointestinal tract. AB - For veterinarians to better understand aquatic animal health, the most basic veterinary foundation begins with understanding piscine anatomy and physiology. General observations of fish behavior, anatomy, and food apprehension can provide more valuable diagnostic information than advanced laboratory testing alone. This article highlights anatomic differences of fish species occupying different environmental niches, using a case to show the use of modern veterinary diagnostics, and introduces additional topics in piscine gastroenterology related to toxins, nutrition, probiotics, and infectious diseases. PMID- 24767738 TI - Pathology of the exotic companion mammal gastrointestinal system. AB - A variety of disease agents can affect the gastrointestinal tract of the exotic companion mammal, some of which can pose zoonotic health concerns. Many conditions present with nonspecific clinical signs (lethargy, variable degrees of diarrhea, and for most sick rodents, presenting hunched with spiky fur), necessitating additional laboratory testing to reach a diagnosis. Primary tumors of the digestive tract are also presented as well as miscellaneous conditions ranging from toxins to trauma. PMID- 24767739 TI - Gastrointestinal anatomy and physiology of select exotic companion mammals. AB - The anatomy and gastrointestinal physiology of rabbits, guinea pigs, and chinchillas are different from those of other exotic companion mammals. Rabbits, guinea pigs, and chinchillas are all concentrate selectors, hindgut fermenters, and coprophagic. They are designed to intake large quantities of high-fibrous, low-energy-density foods. They use unique colonic separation mechanisms and have open-rooted, constantly growing dentition. Gastrointestinal disease, often secondary to diet or environmental factors, is common in these species. PMID- 24767740 TI - Diagnosis and clinical management of gastrointestinal conditions in exotic companion mammals (rabbits, guinea pigs, and chinchillas). AB - Gastrointestinal disorders are common in exotic mammals such as rabbits, guinea pigs and chinchillas. Presenting clinical signs of gastrointestinal disease can vary widely. Small herbivores require specific dietary support and therapeutic treatments. Ileus is a common clinical condition and can be a primary or secondary disease. Common forms of treatment for ileus include fluid therapy, pain relief, nutritional support, and prokinetic therapy. The prognosis of the exotic mammal patient with gastrointestinal disease depends on the timing of the diagnosis and initiation of treatment. Surgical conditions such as gastrointestinal obstruction can have a good outcome if diagnosed early. PMID- 24767741 TI - Liver lobe torsion in pet rabbits: clinical consequences, diagnosis, and treatment. AB - This article reviews diagnosis and management of liver lobe torsion in rabbits. Practitioners should recommend initial diagnostics including radiographs and blood work on rabbits presenting with nonspecific signs of gastrointestinal (GI) stasis to better determine possible etiology and make the best treatment recommendations. If hepatic enzyme elevation is found in a rabbit with GI stasis, abdominal ultrasound is recommended to rule out liver lobe torsion. Prompt diagnosis and liver lobectomy are recommended for best outcome in rabbits with liver lobe torsion. PMID- 24767742 TI - Update on the diagnosis and management of Macrorhabdus ornithogaster (formerly megabacteria) in avian patients. AB - Macrorhabdus ornithogaster, a yeast found only at the junction between the ventriculus and proventriculus, can infect a wide range of birds. Infection is often subclinical but can also result in gastrointestinal signs. Direct observation of the organism in the feces is a specific but somewhat insensitive means of diagnosis. At least three antifungal drugs are reported to be effective for treatment but resistance to one or more of these drugs may occur. PMID- 24767743 TI - Raptor gastroenterology. AB - Free-living raptors are frequently presented to wildlife rehabilitation centers. Conditions affecting the gastrointestinal tract can be the primary reason for presentation. The gastrointestinal tract can also be affected secondary to debilitation from other injuries or from the stress of the rehabilitation process. A thorough understanding of the anatomy, physiology, and natural history of these species is crucial to successful treatment and rehabilitation. This article addresses raptor gastroenterology with an emphasis on conditions affecting free-living birds. PMID- 24767744 TI - Diet and its role in the behavioral health and training of exotic species. AB - Food plays an important part in companion animal health, and also plays a significant role in influencing animal behavior. Avian and small mammal species show general trends in food preferences that can be used to reinforce desired behaviors. Motivation for food can be increased by various strategies. Nonfood reinforcers also offer additional options for reinforcing behaviors when food is of little value to an animal. Transitioning to less rich, healthier diets can help prevent reproductive hormone amplification. This article explores how delivering food is an opportunity to influence behavior in addition to providing nourishment. PMID- 24767745 TI - Nutritional support of reptile patients. AB - Providing nutritional support to reptile patients is a challenging and often misunderstood task. Ill reptiles are frequently anorexic and can benefit greatly from appropriate nutrition delivered via a variety of assist-feeding techniques. Neonatal reptiles can also be very challenging patients because many fail to thrive without significant efforts to establish normal feeding behaviors. This article presents ideas supporting the benefit of timely nutritional support as well as specific recommendations for implementation of assist feeding. Also discussed are a few nutritional issues that affect captive reptile species. PMID- 24767746 TI - Considerations and conditions involving protozoal inhabitation of the reptilian gastrointestinal tract. AB - In mammals, gastrointestinal protozoal organism inhabitation has been well studied, with hundreds of species defined as parasites. While the mammalian protozoal relationships have been identified and categorized by anatomy, tropism, pathogenicity, and life cycles, relatively few species of protozoal organism relationships have been categorized in reptiles. Species of parasites are still being segregated from each other, and conflicting information needs to be clarified to completely understand the data already available. This article presents the information available to help reptile practitioners make evidence based decisions regarding both the determination of a pathologic parasitic condition and direct appropriate treatment of patients. PMID- 24767747 TI - Veterinary Clinics of North America: Exotic Animal Practice. Gastroenterology. Preface. PMID- 24767748 TI - Cerebral microembolization during atrial fibrillation ablation: comparison of different single-shot ablation techniques. AB - BACKGROUND: Clinically silent cerebral ischemia (SCI) detected by diffusion weighted MRI has been reported in 5-40% of patients undergoing pulmonary vein isolation (PVI). Although initial reports suggested a high rate of SCI with phased radiofrequency (RF) ablation on use of the pulmonary vein ablation catheter (PVAC), the incidence was subsequently markedly reduced in consequence of procedural modifications in recent studies. We analyzed cerebral microembolization as assessed with transcranial Doppler during phased RF ablation and with two other single-shot AF ablation technologies: the cryoballoon (CB) and the nMARQTM multipolar irrigated RF ablation system. METHODS AND RESULTS: A total of 89 patients (mean age: 57, SD: 12years; 62 males) with paroxysmal or persistent AF underwent PVI. Phased RF was used according to the initial protocol in 7 patients (PVAC Group I), with procedural modifications and a newer (14.4) version of the RF generator in 37 patients (PVAC Group II) and with the most recent (version 15.1) generator in 18 patients (PVAC Group III). Ablation was performed with the CB in 13 and with the nMARQ system in 14 patients. The number of microemboli (mean+(SD)) detected in the middle cerebral arteries was 2703 (918) in PVAC Group I, 1087 (542) in PVAC Group II, 719 (469) in PVAC Group III, 1057 (784) with CB and 2166 (1047) with nMARQ (p<0.01). CONCLUSION: Significant decreases in MES counts were observed thanks to the procedural modifications and newer RF generator with phased RF. High MES counts comparable to those with the initial phased RF resulted from the use of nMARQ. PMID- 24767749 TI - Myocardial ischemia after arterial switch procedure detected by regadenoson stress cardiac magnetic resonance. PMID- 24767750 TI - Hypertension and elevated C-reactive protein: future risk of ischemic stroke in a prospective cohort study among inner Mongolians in China. PMID- 24767751 TI - Status of hypertension and coronary stenosis in asymptomatic type 2 diabetic patients: analysis from Coronary Computed Tomographic Angiography Registry. AB - BACKGROUND: Limited data exist regarding the prevalence of coronary artery disease (CAD) as well as clinical outcomes in asymptomatic diabetic patients with normotension, controlled hypertension, and uncontrolled hypertension. METHODS: We enrolled 935 consecutive asymptomatic type 2 diabetic patients without known CAD. Coronary computed tomography angiography was used to evaluate the prevalence and severity of CAD. Blood pressure was measured at baseline. Patients were assigned to one of the three groups: normotension (n=314), controlled hypertension (systolic blood pressure (SBP)< 140 mm Hg with treatment, n=458), or uncontrolled hypertension (SBP >= 140 mm Hg with or without treatment, n=163). RESULTS: Obstructive CAD (>= 50% stenosis) increased from the prevalence in normotensive patients (33%) to that in patients with controlled (40%) or uncontrolled hypertension (52%) (p=0.003). The incidence of obstructive CAD in multivessel or left main CAD also increased across the three groups (13%, 21%, 32%, respectively, p<0.001). A multivariate logistic regression analysis showed that uncontrolled hypertension was an independent predictor of obstructive CAD (adjusted odds ratio, 2.13; 95% confidence interval (CI), 1.42 to 3.21, p<0.001). During a median follow-up of 3.1 years, uncontrolled hypertension was associated with increased risk of cardiac death or myocardial infarction compared to the risk in normotensive patients (hazard ratio, 6.11; 95% CI, 1.65 to 22.6, p=0.007). CONCLUSION: In asymptomatic type 2 diabetic patients, uncontrolled hypertension was associated with increased risk of CAD and poor clinical outcomes. PMID- 24767752 TI - The link between renal denervation and reduction of cardiovascular risks: simplicity or not? PMID- 24767753 TI - Is 0.15 mmol/kg of contrast agent effective for delayed-enhancement magnetic resonance imaging at 1.5 T? PMID- 24767754 TI - Limitations in current clinical trials on renal denervation. PMID- 24767755 TI - Secular changes in rates of coronary heart disease, fatal coronary heart disease, and out-of-hospital fatal coronary heart disease. PMID- 24767756 TI - The U-shaped risk of estimated glomerular filtration rate for all-cause mortality and the role of serum uric acid. PMID- 24767757 TI - Early hemodynamics results of aortic valve replacement with the new St Jude Trifecta bioprosthesis. PMID- 24767758 TI - Influence of exercise training on T-wave alternans assessed during exercise test in heart failure patients. PMID- 24767759 TI - Hemodynamic and electrocardiographic effects of acai berry in healthy volunteers: a randomized controlled trial. PMID- 24767760 TI - Wavelet-based analysis of P waves identifies patients with lone atrial fibrillation: a cross-sectional pilot study. PMID- 24767761 TI - Multi-disciplinary clinic: next step in "Heart team" approach for TAVI. PMID- 24767762 TI - Alcohol septal ablation in hypertrophic cardiomyopathy. 3D contrast echocardiography allows localization and quantification of the extension of intraprocedural vascular recruitment. PMID- 24767763 TI - Transcatheter device closure of partial anomalous pulmonary venous return with "intrapulmonary duplicating drainage"--a newly described entity and a single center experience. PMID- 24767764 TI - CHA2DS2-VASc scoring system as an initial method for screening high-risk patients in acute myocardial infarction. PMID- 24767765 TI - Impact of high-dose statin pre-treatment and contrast-induced acute kidney injury on follow-up events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. PMID- 24767766 TI - Multiple organ dysfunction syndrome 2 weeks after radiofrequency ablation of atrial fibrillation. PMID- 24767768 TI - Respiratory microbiome in IPF: cause, effect, or biomarker? PMID- 24767767 TI - Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study. AB - BACKGROUND: The role of the lung microbiome in the pathogenesis of idiopathic pulmonary fibrosis is unknown. We investigated whether unique microbial signatures were associated with progression of idiopathic pulmonary fibrosis. METHODS: Patients (aged 35-80 years) with idiopathic pulmonary fibrosis within 4 years of diagnosis from the Correlating Outcomes with biochemical Markers to Estimate Time-progression (COMET) in idiopathic pulmonary fibrosis study were followed up for a maximum of 80 weeks. Progression-free survival was defined as time to death, acute exacerbation, lung transplant, or decrease in forced vital capacity (FVC) of 10% or greater or decrease in diffusion capacity of the lung (DLCO) of 15% or greater. DNA was isolated from 55 samples of bronchoscopic alveolar lavage. 454 pyrosequencing was used to assign operational taxonomic units (OTUs) to bacteria based on a 3% sequence divergence. Adjusted Cox models were used to identify OTUs that were significantly associated with progression free survival at a p<0.10. These OTUs were then used in the analysis of the principal components. The association between principal components and microbes with high factor loadings and progression-free survival were assessed with Cox regression analyses. The COMET study is registered with ClinicalTrials.gov, number NCT01071707. FINDINGS: Mean FVC was 70.1% (SD 17.0) and DLCO 42.3% (14.0) of predicted. Disease progression was significantly associated with increased relative abundance of two OTUs-Streptococcus OTU 1345 (relative risk 1.11, 95% CI 1.04-1.18; p=0.0009) and Staphylococcus OTU 1348 (1.16, 1.03-1.31, p=0.012). Thresholds for relative abundance of each OTU associated with progression-free survival were more than 3.9% for Streptococcus OTU 1345 (10.19, 2.94-35.35; p=0.0002) and more than 1.8% for Staphylococcus OTU 1348 (5.06, 1.71-14.93; p=0.003). INTERPRETATION: These preliminary data suggest progression of idiopathic pulmonary fibrosis is associated with the presence of specific members within the Staphylococcus and Streptococcus genera. Additional research will be needed to identify the specific bacterial species and to ascertain whether this is a causal association. FUNDING: National Institutes of Health. PMID- 24767769 TI - Role of the practice education facilitator (PEF): the Cambridgeshire model underpinned by a literature review of educational facilitator roles. PMID- 24767770 TI - Biologic correlates and significance of axonogenesis in prostate cancer. AB - Cancer-related axonogenesis and neurogenesis are recently described biologic phenomena. Our previously published data showed that nerve density and the number of neurons in the parasympathetic ganglia are increased in prostate cancer (PCa) and associated with aggressive disease. Tissue microarrays were constructed from 640 radical prostatectomy specimens with PCa. Anti-protein gene product 9.5 (PGP 9.5) antibodies were used to identify and quantify nerve density. Protein expression was objectively analyzed using deconvolution imaging, image segmentation, and image analysis. Data were correlated with clinicopathological variables and tissue biomarkers available in our database. Nerve density, as measured by PGP 9.5 expression, had a weak but significant positive correlation with the lymph node status (rho = 0.106; P = .0275). By Cox univariate analysis, PGP 9.5 was a predictor of time to biochemical recurrence, but not on multivariate analysis. Increased nerve density correlated with increased proliferation of PCa cells. It also correlated with expression of proteins involved in survival pathways (Phosphorylated alpha serine/threonine-protein kinase, NFkappaB, GSK-2, PIM-2, c-Myc, SKP-2, SRF, P27n, PTEN), with increased levels of hormonal regulation elements (androgen receptor, estrogen receptor alpha), and coregulators and repressors (SRC-1, SRC-2, AIB-1, DAX). Axonogenesis is a recently described phenomenon of paramount importance in the biology of PCa. Although the degree of axonogenesis is predictive of aggressive behavior in PCa, it does not add to the information present in current models on multivariate analysis. We present data that corroborate that axonogenesis is involved in biologic processes such as proliferation of PCa, through activation of survival pathways and interaction with hormonal regulation. PMID- 24767771 TI - Low-grade B-cell lymphoma presenting primarily in the bone marrow. AB - Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma. PMID- 24767772 TI - Pathologic highlights of dengue hemorrhagic fever in 13 autopsy cases from Myanmar. AB - Vascular permeability, thrombocytopenia, liver pathology, complement activation, and altered hemostasis accompanying a febrile disease are the hallmarks of the dengue hemorrhagic fever/dengue shock syndrome, a major arthropod-borne viral disease that causes significant morbidity and mortality throughout tropical countries. We studied tissues from 13 children who died of acute dengue hemorrhagic fever/dengue shock syndrome at the Childrens' Hospital, Yangon, Myanmar. Dengue viral RNA from each of the 4 dengue viruses (DENVs) was detected by reverse transcriptase polymerase chain reaction in 11 cases, and dengue viral proteins (envelope, NS1, or NS3) were detected in 1 or more tissues from all 13 cases. Formalin-fixed and frozen tissues were studied for evidence of virus infection using monoclonal antibodies against DENV structural and nonstructural antigens (E, NS1, and nonsecreting NS3). In the liver, DENV infection occurred in hepatocytes and Kupffer cells but not in endothelial cells. Liver damage was associated with deposition on hepatocytes of complement components of both classical and alternative pathways. Evidence of dengue viral replication was observed in macrophage-like cells in spleens and lymph nodes. No dengue antigens were detected in endothelial cells in any organ. Germinal centers of the spleen and lymph nodes showed a marked reduction in the number of lymphocytes that were replaced by eosinophilic deposits, which contained dengue antigens as well as immunoglobulins, and complement components (C3, C1q, and C9). The latter findings had previously been reported but overlooked as a diagnostic feature. PMID- 24767773 TI - School-located influenza vaccination: can collaborative efforts go the distance? PMID- 24767774 TI - Placing faculty development front and center in a multisite educational initiative: lessons from the I-PASS Handoff study. PMID- 24767775 TI - Children and the Patient Protection and Affordable Care Act: opportunities and challenges in an evolving system. AB - The Patient Protection and Affordable Care Act (ACA), passed in 2010, focused primarily on the problems of adults, but the changes in payment for and delivery of care it fosters will likely impact the health care of children. The evolving epidemiology of pediatric illness in the United States has resulted in a relatively small population of medically fragile children dispersed through the country and a large population of children with developmental and behavioral health issues who experience wide degrees of health disparities. Review of previous efforts to change the health care system reveals specific innovations in child health delivery that have been designed to address issues of child health. The ACA is complex and contains some language that improves access to care, quality of care, and the particular needs of the pediatric workforce. Most of the payment models and delivery systems proposed in the ACA, however, were not designed with the needs of children in mind and will need to be adapted to address their needs. To assure that the needs of children are met as systems evolve, child health professionals within and outside academe will need to focus their efforts in clinical care, research, education, and advocacy to incorporate child health programs into changing systems and to prevent unintended harm to systems designed to care for children. PMID- 24767777 TI - School-located influenza vaccination with third-party billing: what do parents think? AB - OBJECTIVE: School-located influenza vaccination (SLIV) may be instrumental in achieving high vaccination rates among children. Sustainability of SLIV programs may require third-party billing. This study assessed, among parents of elementary school students, the attitudes about SLIV and billing at school, as well as factors associated with being supportive of SLIV. METHODS: We conducted a survey (April 2010 to June 2010) of parents of 1000 randomly selected primarily low income children at 20 elementary schools at which SLIV with billing had occurred. RESULTS: Response rate was 70% (n = 699). Eighty-one percent agreed (61% strongly) they "would be okay" with SLIV for their child. Many agreed it was better to get vaccinated at their child's doctor's office because they could take care of other health issues (72%) and the doctor knows the child's medical history (65%). However, an equal percentage (47%) thought the best place for influenza vaccination was the child's doctor's office and the child's school. Twenty-five percent did not want to give health insurance information necessary for billing at school. Factors independently associated with strongly supporting SLIV included parental education of high school or less (relative risk 1.30; 95% confidence interval 1.09-1.58), Hispanic ethnicity (1.25; 1.08-1.45); believing the vaccine is efficacious (1.49; 1.23-1.84); and finding school delivery more convenient (2.37; 1.82-3.45). Having concerns about the safety of influenza vaccine (0.80; 0.72-0.88) and not wanting their child to be vaccinated without a parent (0.74; 0.64-0.83) were negatively associated. CONCLUSIONS: The majority of parents were supportive of SLIV, although parental concerns about not being present for vaccination and about the safety and efficacy of the vaccine will need to be addressed. PMID- 24767776 TI - School-located influenza vaccination with third-party billing: outcomes, cost, and reimbursement. AB - OBJECTIVE: To assess rates of immunization; costs of conducting clinics; and reimbursements for a school-located influenza vaccination (SLIV) program that billed third-party payers. METHODS: SLIV clinics were conducted in 19 elementary schools in the Denver Public School district (September 2010 to February 2011). School personnel obtained parental consent, and a community vaccinator conducted clinics and performed billing. Vaccines For Children vaccine was available for eligible students. Parents were not billed for any fees. Data were collected regarding implementation costs and vaccine cost was calculated using published private sector prices. Reimbursement amounts were compared to costs. RESULTS: Overall, 30% of students (2784 of 9295) received >=1 influenza vaccine; 39% (1079 of 2784) needed 2 doses and 80% received both. Excluding vaccine costs, implementation costs were $24.69 per vaccination. The percentage of vaccine costs reimbursed was 62% overall (82% from State Child Health Insurance Program (SCHIP), 50% from private insurance). The percentage of implementation costs reimbursed was 19% overall (23% from private, 27% from Medicaid, 29% from SCHIP and 0% among uninsured). Overall, 25% of total costs (implementation plus vaccine) were reimbursed. CONCLUSIONS: A SLIV program resulted in vaccination of nearly one third of elementary students. Reimbursement rates were limited by 1) school restrictions on charging parents fees, 2) low payments for vaccine administration from public payers and 3) high rates of denials from private insurers. Some of these problems might be reduced by provisions in the Affordable Care Act. PMID- 24767778 TI - Novel immunization reminder/recall approaches: rural and urban differences in parent perceptions. AB - OBJECTIVE: To assess the following among parents of young children: (1) preferences about the source of immunization reminder/recall (R/R) messages, (2) the degree of acceptability of different R/R modalities, and (3) factors that influence preferences, including rural and urban characteristics. METHODS: We conducted a survey among parents of children 19 to 35 months old who needed >=1 immunization according to the Colorado Immunization Information System (CIIS). Equal numbers of urban and rural respondents were randomly selected. Up to 4 surveys were mailed to each parent who had a valid address. RESULTS: After removing invalid addresses, the response rate was 55% (334 of 607). Half of parents (49.7%) had no preference about whether the public health department or their child's doctor sent reminders. Urban parents were more likely to prefer R/R come from their child's doctor (46.7%) compared to rural parents (33.7%), P = .003. Mail was the preferred R/R method (57.7%), then telephone (17.0%), e-mail (12.7%), and text message (10.7%). Although not preferred, 60.1% reported it would be acceptable to receive R/R by e-mail and 46.2% by text message. Factors associated with preferring to receive R/R from their child's doctor were urban residence and educational level of college graduate or greater. CONCLUSIONS: A large portion of parents are willing to be reminded about vaccinations by their health department rather than their child's provider and via novel modalities, such as e-mail or text messaging. Urbanicity and higher educational level were associated with preferring that R/R come from a provider. PMID- 24767779 TI - Liquid medication dosing errors in children: role of provider counseling strategies. AB - OBJECTIVE: To examine the degree to which recommended provider counseling strategies, including advanced communication techniques and dosing instrument provision, are associated with reductions in parent liquid medication dosing errors. METHODS: Cross-sectional analysis of baseline data on provider communication and dosing instrument provision from a study of a health literacy intervention to reduce medication errors. Parents whose children (<9 years) were seen in 2 urban public hospital pediatric emergency departments (EDs) and were prescribed daily dose liquid medications self-reported whether they received counseling about their child's medication, including advanced strategies (teachback, drawings/pictures, demonstration, showback) and receipt of a dosing instrument. The primary dependent variable was observed dosing error (>20% deviation from prescribed). Multivariate logistic regression analyses were performed, controlling for parent age, language, country, ethnicity, socioeconomic status, education, health literacy (Short Test of Functional Health Literacy in Adults); child age, chronic disease status; and site. RESULTS: Of 287 parents, 41.1% made dosing errors. Advanced counseling and instrument provision in the ED were reported by 33.1% and 19.2%, respectively; 15.0% reported both. Advanced counseling and instrument provision in the ED were associated with decreased errors (30.5 vs. 46.4%, P = .01; 21.8 vs. 45.7%, P = .001). In adjusted analyses, ED advanced counseling in combination with instrument provision was associated with a decreased odds of error compared to receiving neither (adjusted odds ratio 0.3; 95% confidence interval 0.1-0.7); advanced counseling alone and instrument alone were not significantly associated with odds of error. CONCLUSIONS: Provider use of advanced counseling strategies and dosing instrument provision may be especially effective in reducing errors when used together. PMID- 24767780 TI - The relative roles of types of extracurricular activity on smoking and drinking initiation among tweens. AB - OBJECTIVE: Youth involvement in extracurricular activities may help prevent smoking and drinking initiation. However, the relative roles of types of extracurricular activity on these risks are unclear. Therefore, we examined the association between substance use and participation in team sports with a coach, other sports without a coach, music, school clubs, and other clubs in a nationally representative sample of U.S. tweens. METHODS: We conducted telephone surveys with 6522 U.S. students (ages 10 to 14 years) in 2003. We asked participants if they had ever tried smoking or drinking, and we asked them about their participation in extracurricular activities. We used sample weighting to produce response estimates that were representative of the population of adolescents aged 10 to 14 years at the time of data collection. Logistic regression models that adjusted for appropriate sampling weights using jackknife variance estimation tested associations with trying smoking and drinking, controlling for sociodemographics, child and parent characteristics, friend/sibling/parent substance use, and media use. RESULTS: A little over half of the students reported participating in team sports with a coach (55.5%) and without a coach (55.4%) a few times per week or more. Most had minimal to no participation in school clubs (74.2%); however, most reported being involved in other clubs (85.8%). A little less than half participated in music, choir, dance, and/or band lessons. Over half of participants involved in religious activity did those activities a few times per week or more. In the multiple regression analysis, team sport participation with a coach was the only extracurricular activity associated with lower risk of trying smoking (adjusted odds ratio 0.68, 95% confidence interval 0.49, 0.96) compared to none or minimal participation. Participating in other clubs was the only extracurricular activity associated with lower risk of trying drinking (adjusted odds ratio 0.56, 95% confidence interval 0.32, 0.99) compared to none or minimal participation. CONCLUSIONS: Type of extracurricular involvement may be associated with risk of youth smoking and drinking initiation. Future research should seek to better understand the underlying reasons behind these differences. PMID- 24767781 TI - Potential distractions and unsafe driving behaviors among drivers of 1- to 12 year-old children. AB - OBJECTIVE: Driver distraction has been identified as a threat to individual drivers and public health. Motor vehicle collisions remain a leading cause of death for children, yet little is known about distractions among drivers of children. This study sought to characterize potential distractions among drivers of children. METHODS: A 2-site, cross-sectional, computerized survey of child passenger safety practices was conducted among adult drivers of 1- to 12-year-old children who presented for emergency care between October 2011 to May 2012. Drivers indicated the frequency with which they engaged in 10 potential distractions in the past month while driving with their child. Distractions were grouped in 4 categories: (1) nondriving, (2) cellular phone, (3) child, and (4) directions. Information about other unsafe driving behaviors and sociodemographic characteristics was collected. RESULTS: Nearly 90% of eligible parents participated. Analysis included 570 drivers (92.2%). Non-driving-related and cellular phone-related distractions were disclosed by >75% of participants. Fewer participants disclosed child (71.2%) and directions-related distractions (51.9%). Child age was associated with each distraction category. Cellular phone-related distractions were associated with the child riding daily in the family car, non Hispanic white, and higher education. Parents admitting to drowsy driving and being pulled over for speeding had over 2 times higher odds of disclosing distractions from each category. CONCLUSIONS: Distracted driving activities are common among drivers of child passengers and are associated with other unsafe driving behaviors. Child passenger safety may be improved by preventing crash events through the reduction or elimination of distractions among drivers of child passengers. PMID- 24767782 TI - Setting standards to determine core clerkship grades in pediatrics. AB - OBJECTIVE: One of the greatest challenges for clerkship directors is assigning a final grade and determining the precise point at which a student either passes or fails a clinical clerkship. The process of incorporating both subjective and objective assessment data to provide a final summative grade can be challenging. We describe our experience conducting a standard-setting exercise to set defensible cut points in a 4-tiered grading system in our pediatric clerkship. METHODS: Using the Hofstee standard-setting approach, 8 faculty members participated in an exercise to establish grade cut points. These faculty members were subsequently surveyed to assess their attitudes toward the standard-setting process as well as their reactions to these newly proposed standards. We applied the new cut points to a historic cohort of 116 Johns Hopkins University School of Medicine students from the academic year 2012-2013 to assess the potential impact on grade distributions. RESULTS: The resultant grading schema would lead to a significant increase in the number of students receiving a failing grade and a decrease in the number of students receiving a grade of honors in a historical cohort. Faculty reported that the Hofstee method was easy to understand and fair. All faculty members thought that grade inflation presently exists within the pediatric clerkship. CONCLUSIONS: This study demonstrates that practical standards using the Hofstee method can be set for medical students in a pediatric clerkship in which multiple performance measures are used. PMID- 24767783 TI - Latino parents' perspectives on barriers to autism diagnosis. AB - OBJECTIVE: Latino children are diagnosed with autism spectrum disorders (ASDs) at older ages and at the point of more severe symptoms. We sought to qualitatively describe community, family, and health care system barriers to ASD diagnosis in Latino children. METHODS: Five focus groups and 4 qualitative interviews were conducted with 33 parents of Latino children previously diagnosed with an ASD. Participants described Latino community perceptions of autism and barriers they experienced during the diagnostic process. Sessions were audiorecorded and transcribed. Transcripts were coded by 2 researchers, and data were analyzed using thematic analysis. RESULTS: Parents reported low levels of ASD information and high levels of mental health and disability stigma in the Latino community. Parents had poor access to care as a result of poverty, limited English proficiency, and lack of empowerment to take advantage of services. Providers sometimes dismissed parents' concerns. The ASD diagnostic process itself was slow, inconvenient, confusing, and uncomfortable for the child. These factors led many parents to normalize their child's early behaviors, deny that a problem existed, and lose trust in the medical system. CONCLUSIONS: Additional educational outreach to Latino families, destigmatization of ASD, streamlining the ASD diagnostic process, and providing additional support to Latino parents of at-risk children may decrease delays in ASD diagnosis among Latino children. PMID- 24767784 TI - Low caregiver health literacy is associated with higher pediatric emergency department use and nonurgent visits. AB - OBJECTIVE: We sought to determine the association between low caregiver health literacy and child emergency department (ED) use, both the number and urgency of ED visits. METHODS: This year long cross-sectional study utilized the Newest Vital Sign questionnaire to measure the health literacy of caregivers accompanying children to a pediatric ED. Prior ED visits were extracted from a regional database. ED visit urgency was classified by resources utilized during the index ED visit. Regression analyses were used to model 2 outcomes-prior ED visits and ED visit urgency-stratified by chronic illness. Analyses were weighted by triage level. RESULTS: Overall, 503 caregivers completed the study; 55% demonstrated low health literacy. Children of caregivers with low health literacy had more prior ED visits (adjusted incidence rate ratio 1.5; 95% confidence interval 1.2, 1.8) and increased odds of a nonurgent index ED visit (adjusted odds ratio 2.4; 95% confidence interval 1.3, 4.4). Among children without chronic illness, low caregiver health literacy was associated with an increased proportion of nonurgent index ED visits (48% vs. 22%; adjusted odds ratio 3.2; 1.8, 5.7). CONCLUSIONS: Over half of caregivers presenting with their children to the ED have low health literacy. Low caregiver health literacy is an independent predictor of higher ED use and use of the ED for nonurgent conditions. In children without a chronic illness, low health literate caregivers had more than 3 times greater odds of presenting for a nonurgent condition than those with adequate health literacy. PMID- 24767785 TI - Factors associated with early intervention referral and evaluation: a mixed methods analysis. AB - OBJECTIVE: To identify parent, child, community, and health care provider characteristics associated with early intervention (EI) referral and multidisciplinary evaluation (MDE) by EI. METHODS: We conducted a mixed methods secondary analysis of data from a randomized controlled trial of a developmental screening program in 4 urban primary care practices. Children <30 months of age not currently enrolled in EI and their parents were included. Using logistic regression, we tested whether parent, child, community, and health care provider characteristics were associated with EI referral and MDE completion. We also conducted qualitative interviews with 9 pediatricians. Interviews were recorded, transcribed, and coded. We identified themes using modified grounded theory. RESULTS: Of 2083 participating children, 434 (21%) were identified with a developmental concern. A total of 253 children (58%) with a developmental concern were referred to EI. A total of 129 children (30%) received an MDE. Failure in 2 or more domains on developmental assessments was associated with EI referral (adjusted odds ratio [AOR] 3.15, 95% confidence interval [CI] 1.89-5.24) and completed MDE (AOR 2.16, 95% CI 1.19-3.93). Faxed referral to EI, as opposed to just giving families a phone number to call was associated with MDE completion (AOR 2.94, 95% CI 1.48-5.84). Pediatricians reported that office processes, family preference, and whether they thought parents understood the developmental screening tool influenced the EI referral process. CONCLUSIONS: In an urban setting, one third of children with a developmental concern were not referred to EI, and two thirds of children with a developmental concern were not evaluated by EI. Our results suggest that practice-based strategies that more closely connect the medical home with EI such as electronic transmission of referrals (e.g., faxing referrals) may improve completion rates of EI evaluation. PMID- 24767786 TI - Multilevel surface engineering of nanostructured TiO2 on carbon-fiber-reinforced polyetheretherketone. AB - As an implantable material, carbon-fiber-reinforced polyetheretherketone (CFRPEEK) possesses an adjustable elastic modulus similar to that of cortical bone and is a prime candidate to replace metallic surgical implants. However, the bioinertness and poor osteogenic properties of CFRPEEK limit its clinical application as orthopedic implants. In this work, titanium ions are introduced energetically into CFRPEEK by plasma immersion ion implantation (PIII). Scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) reveal the formation of nanopores with the side wall and bottom embedded with ~20 nm TiO2 nanoparticles on the CFRPEEK surface. Nanoindentation measurements confirm the stability and improved elastic resistance of the structured surfaces. In vitro cell adhesion, viability assay, and real-time PCR analyses disclose enhanced adhesion, proliferation, and osteo-differentiation of rat bone mesenchymal stem cells (bMSCs). The multilevel structures on CFRPEEK also exhibit partial antibacterial activity to Staphylococcus aureus and Escherichia coli. Our results indicate that a surface with multifunctional biological properties can be produced by multilevel surface engineering and application of CFRPEEK to orthopedic and dental implants can be broadened and expedited based on this scheme. PMID- 24767788 TI - Multifunctional PEG-GO/CuS nanocomposites for near-infrared chemo-photothermal therapy. AB - The synergistic therapy, the combination of photothermal therapy and chemotherapy, has become a potential treatment in the battles with cancer. Here, we developed a synergistic therapy tool that based on CuS nanoparticles-decorated graphene oxide functionalized with polyethylene glycol (PEG-GO/CuS) for cervical cancer treatment. The as-synthesized PEG-GO/CuS nanocomposites with excellent biocompatibility was revealed to have high storage capacity for anticancer drug of doxorubicin (Dox) and high photothermal conversion efficiency, and were effectively employed for the ablation of tumor. In addition, the therapeutic efficacy of Dox-loaded PEG-GO/CuS (PEG-GO/CuS/Dox) nanocomposites was evaluated in vitro and in vivo for cervical cancer therapy. In vitro cell cytotoxicity tests of PEG-GO/CuS/Dox demonstrate about 1.3 and 2.7-fold toxicity than PEG GO/CuS and free Dox under 5 min irradiation with NIR laser at 1.0 W/cm(2), owing to both PEG-GO/CuS-mediated photothermal ablation and cytotoxicity of light triggered Dox release. In mouse models, mouse cervical tumor growth was found to be significantly inhibited by the chemo-photothermal effect of PEG-GO/CuS/Dox nanocomposites, resulting in effective tumor reduction. Overall, compared with chemotherapy or photothermal therapy alone, the combined treatment demonstrates better therapeutic efficacy of cancer in vitro and in vivo. These findings highlight the promise of the highly versatile multifunctional nanoparticles in biomedical application. PMID- 24767787 TI - Immunogenicity of coiled-coil based drug-free macromolecular therapeutics. AB - A two-component CD20 (non-internalizing) receptor crosslinking system based on the biorecognition of complementary coiled-coil forming peptides was evaluated. Exposure of B cells to Fab'-peptide1 conjugate decorates the cell surface with peptide1; further exposure of the decorated cells to P-(peptide2)x (P is the N-(2 hydroxypropyl)methacrylamide (HPMA) copolymer backbone) results in the formation of coiled-coil heterodimers at the cell surface with concomitant induction of apoptosis. The aim of this study was to determine the potential immunogenicity of this therapeutic system that does not contain low molecular weight drugs. Enantiomeric peptides (L- and D-CCE and L- and D-CCK), HPMA copolymer-peptide conjugates, and Fab' fragment-peptide conjugates were synthesized and the immunological properties of peptide conjugates evaluated in vitro on RAW264.7 macrophages and in vivo on immunocompetent BALB/c mice. HPMA copolymer did not induce immune response in vitro and in vivo. Administration of P-peptide conjugates with strong adjuvant resulted in antibody response directed to the peptide. Fab' was responsible for macrophage activation of Fab'-peptide conjugates and a major factor in the antibody induction following i.v. administration of Fab'-conjugates. There was no substantial difference in the ability of conjugates of D-peptides and conjugates of L-peptides to induce Ab response. PMID- 24767789 TI - The effect of enoxacin on osteoclastogenesis and reduction of titanium particle induced osteolysis via suppression of JNK signaling pathway. AB - The aim of this study was to assess the effect of enoxacin on osteoclastogenesis and titanium particle-induced osteolysis. Wear particles liberated from the surface of prostheses are associated with aseptic prosthetic loosening. It is well established that wear particles induce inflammation, and that extensive osteoclastogenesis plays a critical role in peri-implant osteolysis and subsequent prosthetic loosening. Therefore, inhibiting extensive osteoclast formation and bone resorption could be a potential therapeutic target to prevent prosthetic loosening. In this study, we demonstrated that enoxacin, a fluoroquinolone antibiotic, exerts potent inhibitory effects on titanium particle induced osteolysis in a mouse calvarial model. Interestingly, the number of mature osteoclasts decreased after treatment with enoxacin in vivo, suggesting that osteoclast formation might be inhibited by enoxacin. We then performed in vitro studies to confirm our hypothesis and revealed the mechanism of action of enoxacin. Enoxacin inhibited osteoclast formation by specifically abrogating RANKL-induced JNK signaling. Collectively, these results suggest that enoxacin, an antibiotic with few side effects that is widely used in clinics, had significant potential for the treatment of particle-induced peri-implant osteolysis and other diseases caused by excessive osteoclast formation and function. PMID- 24767792 TI - Temporal variation in methanogen communities of four different full-scale anaerobic digesters treating food waste-recycling wastewater. AB - Methanogen communities were investigated using 454 pyrosequencing in four different full-scale anaerobic digesters treating food waste-recycling wastewater. Seasonal samples were collected for 2 years, and 24 samples were available for microbial analysis from a plug flow thermophilic (PT) digester, a continuously-stirred tank thermophilic (CT) digester, an upflow anerobic sludge blanket mesophilic (UM) digester, and a continuously-stirred tank mesophilic (CM) digester. Methanoculleus, Methanobacterium, Methanothermobacter, and Methanosaeta were revealed to be key methanogens in full-scale anaerobic digestion process treating food waste-recycling wastewater. In the PT digester, Methanoculleus was dominant (96.8%). In the CT digester, Methanoculleus was dominant (95.4%) during the first year of operation, but the dominant genus was shifted to Methanothermobacter (98.5%) due to pH increase. In the UM digester, Methanosaeta was dominant (87.2%). In the CM digester, Methanoculleus was constantly dominant (74.8%) except during CM5 when Methanosaeta was dominant (62.6%) due to the low residual acetate concentration (0.1 g/L). PMID- 24767790 TI - Tissue-engineered cartilage with inducible and tunable immunomodulatory properties. AB - The pathogenesis of osteoarthritis is mediated in part by inflammatory cytokines including interleukin-1 (IL-1), which promote degradation of articular cartilage and prevent human mesenchymal stem cell (MSC) chondrogenesis. In this study, we combined gene therapy and functional tissue engineering to develop engineered cartilage with immunomodulatory properties that allow chondrogenesis in the presence of pathologic levels of IL-1 by inducing overexpression of IL-1 receptor antagonist (IL-1Ra) in MSCs via scaffold-mediated lentiviral gene delivery. A doxycycline-inducible vector was used to transduce MSCs in monolayer or within 3D woven PCL scaffolds to enable tunable IL-1Ra production. In the presence of IL-1, IL-1Ra-expressing engineered cartilage produced cartilage-specific extracellular matrix, while resisting IL-1-induced upregulation of matrix metalloproteinases and maintaining mechanical properties similar to native articular cartilage. The ability of functional engineered cartilage to deliver tunable anti-inflammatory cytokines to the joint may enhance the long-term success of therapies for cartilage injuries or osteoarthritis. PMID- 24767791 TI - Therapeutic use of H2O2-responsive anti-oxidant polymer nanoparticles for doxorubicin-induced cardiomyopathy. AB - Doxorubicin (DOX) is a commonly used anti-neoplastic agent but its clinical use is limited due to serious hepatic and cardiac side effects. DOX-induced toxicity is mainly associated with overproduction of reactive species oxygen (ROS) such as hydrogen peroxide (H2O2). We have recently developed H2O2-responsive anti-oxidant polymer, polyoxalate containing vanillyl alcohol (PVAX), which is designed to rapidly scavenge H2O2 and release vanillyl alcohol with anti-oxidant, anti inflammatory and anti-apoptotic properties. In this study, we report that PVAX nanoparticles are novel therapeutic agents for treating DOX-induced cardiac and hepatic toxicity. Intraperitoneal injection of PVAX nanoparticles (4 mg/kg/day) resulted in significant inhibition in apoptosis in liver and heart of DOX-treated mice by suppressing the activation of poly (ADP ribose) polymerase 1 (PARP-1) and caspase-3. PVAX treatment also prevented DOX-induced cardiac dysfunction. Furthermore, survival rate (vehicle = 35% vs. PVAX = 75%; p < 0.05) was significantly improved in a PVAX nanoparticles-treated group compared with vehicle treated groups. Taken together, we anticipate that PVAX nanoparticles could be a highly specific and potent treatment modality in DOX-induced cardiac and hepatic toxicity. PMID- 24767793 TI - Bioethanol production from hemicellulose rich Populus nigra involving recombinant hemicellulases from Clostridium thermocellum. AB - Bioethanol was produced from poplar leafy biomass rich in hemicelluloses content involving recombinant Clostridium thermocellum hemicellulases and pentose sugar utilizing Candida shehatae. FT-IR analysis revealed effective AFEX pretreatment of poplar leaves. Repetitive batch strategy yielded ~1.5-fold rise in cell biomass and specific activity of both, acetylxylanesterase (Axe) and GH43 hemicellulase. TLC and HPAEC exhibited xylose and arabinose release from hydrolyzed biomass. SSF trial with 1% (wv(-1)) pretreated poplar and mixed enzymes showed ~1.5-fold higher ethanol titre as compared with SHF. The shake flask SSF with 5% (wv(-1)) pretreated poplar furnished 4.56 and 5.43gL(-1) ethanol with Axe and mixed enzymes, respectively. Whereas, bioreactor scale-up exhibited ~1.25-fold increase in ethanol titres (5.68, 6.75gL(-1)) as compared with shake flask with an yield of 0.295 (gg(-1)) and 0.351 (gg(-1)), respectively with Axe and mixed enzymes. PMID- 24767794 TI - Serial biomechanical comparison of edematous, normal, and collagen crosslinked human donor corneas using optical coherence elastography. AB - PURPOSE: To noninvasively evaluate the effects of corneal hydration and collagen crosslinking (CXL) on the mechanical behavior of the cornea. SETTING: Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA. DESIGN: Experimental study. METHODS: An optical coherence elastography (OCE) technique was used to measure the displacement behavior of 5 pairs of debrided human donor globes in 3 serial states as follows: edematous, normal thickness, and after riboflavin-ultraviolet A-mediated CXL. During micromotor-controlled axial displacements with a curved goniolens at physiologic intraocular pressure (IOP), serial optical coherence tomography scans were obtained to allow high-resolution intrastromal speckle tracking and displacement measurements over the central 4.0 mm of the cornea. RESULTS: With no imposed increase in IOP, the mean lateral to imposed axial displacement ratios were 0.035 MUm/MUm +/- 0.037 (SD) in edematous corneas, 0.021 +/- 0.02 MUm/MUm in normal thickness corneas, and 0.014 +/- 0.009 MUm/MUm in post CXL corneas. The differences were statistically significant (P<.05, analysis of variance) and indicated a 40% increase in lateral stromal resistance with deturgescence and a further 33% mean increase in relative stiffness with CXL. CONCLUSIONS: Serial perturbations of the corneal hydration state and CXL had significant effects on corneal biomechanical behavior. With an axially applied stress from a nonapplanating contact lens, displacements along the direction of the collagen lamellae were 2 orders of magnitude lower than axial deformations. These experiments show the ability of OCE to quantify clinically relevant mechanical property differences under physiologic conditions. FINANCIAL DISCLOSURES: Proprietary or commercial disclosures are listed after the references. PMID- 24767795 TI - Patterned corneal collagen crosslinking for astigmatism: computational modeling study. AB - PURPOSE: To test the hypothesis that spatially selective corneal stromal stiffening can alter corneal astigmatism and assess the effects of treatment orientation, pattern, and material model complexity in computational models using patient-specific geometries. SETTING: Cornea and Refractive Surgery Service, Academic Eye Institute, Cleveland, Ohio, USA. DESIGN: Computational modeling study. METHODS: Three-dimensional corneal geometries from 10 patients with corneal astigmatism were exported from a clinical tomography system (Pentacam). Corneoscleral finite element models of each eye were generated. Four candidate treatment patterns were simulated, and the effects of treatment orientation and magnitude of stiffening on anterior curvature and aberrations were studied. The effect of material model complexity on simulated outcomes was also assessed. RESULTS: Pretreatment anterior corneal astigmatism ranged from 1.22 to 3.92 diopters (D) in a series that included regular and irregular astigmatic patterns. All simulated treatment patterns oriented on the flat axis resulted in mean reductions in corneal astigmatism and depended on the pattern geometry. The linear bow-tie pattern produced a greater mean reduction in astigmatism (1.08 D +/- 0.13 [SD]; range 0.74 to 1.23 D) than other patterns tested under an assumed 2-times increase in corneal stiffness, and it had a nonlinear relationship to the degree of stiffening. The mean astigmatic effect did not change significantly with a fiber- or depth-dependent model, but it did affect the coupling ratio. CONCLUSIONS: In silico simulations based on patient-specific geometries suggest that clinically significant reductions in astigmatism are possible with patterned collagen crosslinking. Effect magnitude was dependent on patient-specific geometry, effective stiffening pattern, and treatment orientation. FINANCIAL DISCLOSURES: Proprietary or commercial disclosures are listed after the references. PMID- 24767796 TI - Liquid chromatography/mass spectrometry to study oxidative degradation of environmentally relevant pharmaceuticals by electrochemistry and ozonation. AB - In this work, the potential of electrochemical oxidation as a tool for the rapid prediction of transformation products in water appearing after ozonation is investigated. These two approaches were compared by choosing the two environmentally relevant model compounds diclofenac and metoprolol and comparison of their transformation products after electrochemical oxidation and treatment with ozone. Within these two approaches, certain similarities were observed in the resulting chromatograms: Six transformation products of the electrochemical oxidation of metoprolol were also detected in the ozone samples. For diclofenac two transformation products matched. Additionally, five of the electrochemically generated oxidation products were reported in literature to occur after water treatment processes. The application of a boron-doped diamond working electrode for electrochemical oxidation allowed the generation of hydroxyl radicals, which was shown by spin trapping experiments with p-chlorobenzoic acid. This allowed the generation of certain transformation products previously not obtained by electrochemical oxidation. Concluding, the hyphenation of electrochemistry with liquid chromatography and mass spectrometry offers a useful tool in transformation studies. PMID- 24767797 TI - Precision of the reportable result. Simultaneous optimisation of number of preparations and injections for sample and reference standard in quantitative liquid chromatography. AB - In pharmaceutical analysis, the precision of the reportable result, i.e. the result which is to be compared to the specification limit, is relevant for the evaluation of the suitability of the analytical procedure. But also for other applications, the precision of the result is important and an optimisation often of interest. However, increasing the number of determinations (e.g. injections or preparations) will reduce only the variability (or standard error) of the corresponding precision level. Therefore, the knowledge of the individual variance contributions, obtained from reliable precision studies is important to determine on a scientific basis which format of the (reportable) result, i.e. the number of injections and sample preparations (or even series), should be used. In case of relative analytical procedures such as LC, the calibration model and format, i.e. the number of determinations of the reference standard is one of the factors (besides instrument, operator, reagents, etc.) affecting the between series variance contribution at intermediate precision/reproducibility level. Consequently, the precision of the reportable result is only valid for the calibration format used to obtain intermediate precision/reproducibility. Instead of repeating the whole precision study to optimize the calibration format, the present paper describes a statistical approach using variability results from the original precision study. PMID- 24767798 TI - Room temperature fabrication of post-modified zeolitic imidazolate framework-90 as stationary phase for open-tubular capillary electrochromatography. AB - Metal-organic frameworks (MOFs) are attractive as porous stationary phase for open-tubular capillary electrochromatography (OT-CEC) due to their fascinating structures and unusual properties. Here we report a directly covalent bonding approach to prepare uniform and dense MOF film on the inner wall of fused silica capillary at room temperature for OT-CEC. Zeolitic imidazolate framework-90 (ZIF 90) as a model MOF because it not only possesses large surface area and high stability but also provides the free aldehyde groups to bond to the inner surface of capillary via covalent bond. X-ray diffraction, scan electron microscopy, and UV-vis spectrophotometry were used to confirm the bonding of the ZIF-90 to the inner wall of the silica capillary. The ZIF-90 coating not only increased the phase ratio of open-tubular column, but also improved the interactions of tested analytes and the coating. Owing to the porous structure of ZIF-90 and hydrophobic interactions between the analytes and the organic ligands of ZIF-90, three groups of isomers, neutral and basic compounds and nonsteroidal anti-inflammatory drugs were well separated on the ZIF-90 bonded column. The precisions (relative standard deviation, RSD) of retention time, half peak width and peak area for three consecutive runs were 0.3-1.2%, 1.3-6.0% and 1.5-5.2%, respectively. The run-to-run, day-to-day, and column-to-column precisions (RSDs) for the electroosmotic flow of the ZIF-90 bonded column were 0.2%, 0.4%, and 1.9%, respectively. Moreover, the ZIF-90 bonded column could stand more than 230 runs without observable change in the separation efficiency. PMID- 24767799 TI - Evaluation of strong cation-exchange polymers for the determination of drugs by solid-phase extraction-liquid chromatography-tandem mass spectrometry. AB - This paper presents eight distinct strong cation-exchange resins, all of which were derived from precursor resins that had been synthesised using either precipitation polymerisation or non-aqueous dispersion polymerisation. The precursor resins were transformed into the corresponding strong cation-exchange resins by hypercrosslinking followed by polymer analogous reactions, to yield materials with high specific surface areas and strong cation-exchange character. These novel resins were then evaluated as strong cation-exchange (SCX) sorbents in the solid-phase extraction (SPE) of a group of drugs from aqueous samples. Following preliminary experiments, the two best-performing resins were then evaluated in solid-phase extraction-liquid chromatography-tandem mass spectrometry (SPE/LC-MS/MS) to determine a group of drugs from sewage samples. In general, use of these sorbents led to excellent recovery values (75-100%) for most of the target drugs and negligible matrix effects (ME) (<20% ion suppression/enhancement of the analyte signal), when 50mL and 25mL of effluent and influent sewage water samples, respectively, were percolated through the resins. Finally, a validated method based on SPE/LC-MS/MS was used to quantify the target drugs present in different sewage samples. PMID- 24767800 TI - A rapid, quantitative liquid chromatography-mass spectrometry screening method for 71 active and 11 natural erectile dysfunction ingredients present in potentially adulterated or counterfeit products. AB - A rapid LC-MS/MS method has been developed to simultaneously separate 71 erectile dysfunction (ED) drugs and 11 natural ingredients that are sometimes found alongside ED drugs, present in suspected adulterated or counterfeit samples. The separation was achieved in 10min using 2.6MUm fused-core C18 particles in a 100*2.1mm column coupled to an LTQ Orbitrap XL mass spectrometer operated in positive electrospray mode. Using a straightforward methanolic extraction procedure, recovery from real samples (tablets, capsules, oral liquids and herbal products) was 92-111% and the lower and upper limits of detection and quantification were in the sub ng/mL and the sub MUg/mL ranges, respectively. The intra- and inter-assay precision were <=3.2% and 10.4% respectively across three concentrations of standards (50, 250 and 1000ng/mL) measured for 4 representative drugs spiked into a tablet-based matrix. This behavior was consistently observed for all the other compounds. The mass accuracy was less than 3ppm. Moreover, an advantage of this method is that the full scan event in the acquisition method associated with the high resolution of the Orbitrap XL allows post-analysis identification, in an untargeted approach, of additional species in the complex matrices. Our LC-MS/MS method for ED drugs was successfully applied to 32 samples and the drug identifications were in 100% agreement with those obtained by the conventional methods HPLC-UV and GC-MS. Following the complete validation of the ED method, it has been introduced in the current counterfeit identification procedures at Health Canada. PMID- 24767801 TI - Hand preference of individuals with blindness in everyday activities: The effects of age of sight loss, age, and gender. AB - The research aims of the present study were: (a) to assess the hand preference of blind persons in everyday activities on the basis of gender, type of blindness, and age; and (b) to conduct the above analysis at both the item level and the latent trait level, after concluding the optimum factor structure of the instrument. Participants were 82 individuals with visual impairments and blindness. Their mean age was 29.99 years. Handedness was evaluated using a modified version of the Edinburgh Handedness Inventory (Oldfield, 1971). When comparing handedness preferences across age of sight loss, gender, and age groups results indicated that there were significant differences in preference for several everyday tasks across age of sight loss and age groups but not gender. These results were also confirmed at the latent-trait mean level. The present findings add to the extant literature that highlighted hand preferences for individuals with visual impairments and blindness. PMID- 24767802 TI - The serological profiles of subgroup of primary Sjogren's syndrome correlation with the clinical features of parotid glands. AB - OBJECTIVE: To investigate the difference of serological profile in pSS and their correlation with the clinical characteristics of parotid glands. METHODS: This retrospective study includes 289 patients who fulfilled the 2002 American European Consensus Group Criteria for pSS. The patients were categorized by the clinical features of parotid glands: Group 1 (massive group), Group 2 (infection group), Group 3 (swelling group) and Group 4 (others). The demographic data and serological profiles among these groups were compared. Statistical analyses of the results between groups were performed using the Student t test, Fisher's exact test, chi-square and analysis of variance. RESULTS: There was a difference of serological profile in the different clinical characteristics of parotid glands of pSS. Serum Ig G value of Group 1 was the greatest, and complement C4 was lowest in the four groups. Serum Ig E value of Group 2 was the greatest and ESR of Group 3 was the greatest in the four groups. CONCLUSION: This study has determined the differences of serological profile in the different clinical features of parotid glands of pSS patients, which may help advance our understanding of the disease and improve patient management. PMID- 24767803 TI - Robotic vs. open radical cystectomy in bladder cancer: A systematic review and meta-analysis. AB - AIMS: To evaluate the safety and efficacy of robot-assisted radical cystectomy (RARC) compared with open radical cystectomy (ORC) in the treatment of bladder cancer. METHODS: A systematic search of Medline, Embase databases and the Cochrane Library was performed to identify studies that compared RARC and ORC and were published up to December 2012. Outcomes of interest included demographic and clinical characteristics, perioperative, pathologic variables and complications. RESULTS: Although there was a significant difference in the operating time in favor of ORC (WMD: 70.69 min; p < 0.001), patients having RARC might benefit from significantly fewer total complications (OR: 0.54; p < 0.001), less blood loss (WMD: -599.03 ml; p < 0.001), shorter length of hospital stay (WMD: -4.56 d; p < 0.001), lower blood transfusion rate (OR: 0.13; p = 0.002), less transfusion needs (WMD: -2.14 units; p < 0.001), shorter time to regular diet (WMD: -1.57 d; p = 0.002), more lymph node yield (WMD: 2.18 n; p = 0.001) and fewer positive lymph node (OR: 0.64; p = 0.03). There was no significant difference between the RARC and ORC regarding positive surgical margins. CONCLUSIONS: In early experience, our data suggest that RARC appears to be a safe, feasible and minimally invasive alternative to its open counterpart when performed by experienced surgeons in selected patients. PMID- 24767804 TI - What do we know about survivorship after treatment for extremity sarcoma? A systematic review. AB - OBJECTIVE: The varied presentations and treatments of extremity bone and soft tissue sarcoma mean that the issues faced by survivors are diverse and complex. The aim of this systematic review was to investigate what is known about this topic with a view to identifying areas for further research or service development. METHODS: This was a review of the English language literature identified from Medline and Ovid and hand searches published between January 2000 and September 2012. Results were compiled according to physical, psychological and social domains of survivorship. RESULTS: Of 182 studies identified, 22 met the inclusion criteria. There is a wide range of outcome measures used and a need for more objective measures. Unsurprisingly, survivors of extremity sarcoma typically demonstrate lower levels of physical functioning than healthy controls. In addition, survivors demonstrate a substantial psychological morbidity. CONCLUSIONS: Services for survivors of extremity sarcoma should include rehabilitation and psychological support, sexual health services, expert pain management, and support to return to work. PMID- 24767805 TI - The ALPPS procedure for hepatocellular carcinoma. AB - BACKGROUND: The main limiting factor to major hepatic resections is the amount of the future liver remnant (FLR). Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy (ALPPS) is a procedure which induces a rapid hypertrophy of the FLR in patients with non-resectable liver tumours. METHODS: ALPPS is a surgical technique of in-situ splitting of the liver along the main portal scissura or the right side of the falciform ligament, in association with portal vein ligation in order to induce a rapid hypertrophy of the left FLR. RESULTS: The median FLR volume increase was 18.7% within one week after the first step and 38.6% after the second step. At the first step the median operating time was 300 min, blood transfusions were not required in any case, median blood loss was 150 cc. At the second step median operating time was 180 min, median blood loss was 50 cc, none of the patients required intra-operative blood. All patients are alive at a median follow up of 9 months. CONCLUSIONS: This novel strategy seems to be feasible even in the context of a cirrhotic liver, and demonstrates the capacity to reach a sufficient FLR within a shorter interval of time. PMID- 24767806 TI - Effectiveness of jaw relaxation for burn dressing pain: randomized clinical trial. AB - Patients hospitalized for burn injuries experience severe pain, both immediately after the injury and during daily therapeutic procedures such as dressing changes. Relaxation is increasingly suggested as a pain control technique that can be used by nurses in daily practice. Yet the effects of relaxation on burn pain are not clear. The aim of this study was to investigate whether jaw relaxation will decrease pain intensity of burn dressing. Accordingly, a randomized clinical trial (n = 100) was conducted between 2009 and 2010 to compare jaw relaxation and usual care. Consenting patients were randomly assigned to either experimental or control groups using minimization. The experimental group practiced jaw relaxation for 20 minutes before entering the dressing room. Data were collected by visual analog scale (VAS), and several structured questions were asked of the experimental group. No significant difference was seen between mean pain intensity scores in the experimental and control groups after dressing (p = .676). Regarding the ineffectiveness of jaw relaxation for pain intensity of burn dressing, future studies are suggested to concentrate on longer durations of relaxation time and continuing the procedure in dressing room. Simultaneous study of the effect of this technique on residual, breakthrough, and procedural burn pain is also recommended. PMID- 24767808 TI - Can an auditory illusion trick the brain into turning down tinnitus? AB - Tinnitus, the phantom perception of sound with no external source, affects an estimated 10-15% of the adult population. Current treatments for this oftentimes distressing condition are of limited effectiveness. The "central gain" model proposes that tinnitus arises from an increase in the responsiveness, or gain, of neurons in central auditory pathways, triggered by damage to the auditory periphery. It has been suggested that tinnitus might be treated by compensating for the peripheral damage, thereby restoring normal levels of input to the central pathways, and hence reducing central gain. Unfortunately, when tinnitus originates with permanent damage to the auditory periphery, it may be impossible to compensate for this damage directly. However, we hypothesize that tinnitus may be treated by tricking the brain into believing that it temporarily receives normal levels of input at frequencies where peripheral damage has occurred. We identify an auditory illusion that seems capable, in principle, of achieving this objective. If effective, this approach would offer a safe, accessible, and non invasive treatment for tinnitus. PMID- 24767807 TI - A validation study concerning the effects of interview content, retention interval, and grade on children's recall accuracy for dietary intake and/or physical activity. AB - BACKGROUND: Practitioners and researchers are interested in assessing children's dietary intake and physical activity together to maximize resources and minimize subject burden. OBJECTIVE: Our aim was to investigate differences in dietary and/or physical activity recall accuracy by content (diet only; physical activity only; diet and physical activity), retention interval (same-day recalls in the afternoon; previous-day recalls in the morning), and grade (third; fifth). DESIGN: Children (n=144; 66% African American, 13% white, 12% Hispanic, 9% other; 50% girls) from four schools were randomly selected for interviews about one of three contents. Each content group was equally divided by retention interval, each equally divided by grade, each equally divided by sex. Information concerning diet and physical activity at school was validated with school provided breakfast and lunch observations, and accelerometry, respectively. Dietary accuracy measures were food-item omission and intrusion rates, and kilocalorie correspondence rate and inflation ratio. Physical activity accuracy measures were absolute and arithmetic differences for moderate to vigorous physical activity minutes. STATISTICAL ANALYSES PERFORMED: For each accuracy measure, linear models determined effects of content, retention interval, grade, and their two-way and three-way interactions; ethnicity and sex were control variables. RESULTS: Content was significant within four interactions: intrusion rate (content*retention-interval*grade; P=0.0004), correspondence rate (content*grade; P=0.0004), inflation ratio (content*grade; P=0.0104), and arithmetic difference (content*retention-interval*grade; P=0.0070). Retention interval was significant for correspondence rate (P=0.0004), inflation ratio (P=0.0014), and three interactions: omission rate (retention-interval*grade; P=0.0095), intrusion rate, and arithmetic difference (both already mentioned). Grade was significant for absolute difference (P=0.0233) and five interactions mentioned. Content effects depended on other factors. Grade effects were mixed. Dietary accuracy was better with same-day than previous-day retention interval. CONCLUSIONS: Results do not support integrating dietary intake and physical activity in children's recalls, but do support using shorter rather than longer retention intervals to yield more accurate dietary recalls. Additional validation studies need to clarify age effects and identify evidence-based practices to improve children's accuracy for recalling dietary intake and/or physical activity. PMID- 24767809 TI - Chemosensory rehabilitation and malnutrition in the newborn: how far, how close? AB - Olfaction is critical to the hedonic appreciation of foods, caloric regulation of food intake, quality of life and taste preferences since birth. However, malnutrition in newborns down-regulates chemosensory function. Thus, olfactory measures might be used as early markers of chemosensory dysfunction in malnutrition, and may also be useful in assessing feeding adjustments during nutritional rehabilitation. Olfactory anomalies originated by malnutrition would be reversed by nutritional rehabilitation following flavor-enhancing odorants. PMID- 24767810 TI - The suppression of endogenous adrenalin in the prolongation of ketamine anesthesia. AB - This study investigated whether or not the anesthetic effect of ketamine in rats is dependent on adrenal gland hormones. The study was performed on two main rat groups, intact and adrenalectomized. Rat were divided into subgroups and given appropriate doses of ketamine, metyrapone or metyrosine. Durations of anesthesia in the groups were then recorded. Endogenous catecholamine levels were measured in samples taken from peripheral blood. This experimental results showed that ketamine did not induce anesthesia in intact rats at doses of 15 or 30mg/kg, and that at 60mg/kg anesthesia was established for only 11min. However, ketamine induced significant anesthesia even at a dose of 30mg/kg in animals in which production of endogenous catecholamine (adrenalin, noradrenalin dopamine) was inhibited with metyrosine at a level of 45-47%. Ketamine at 60mg/kg in animals in which endogenous catecholamine was inhibited at a level of 45-47% established anesthesia for 47.6min. However, ketamine at 30 and 60mg/kg induced longer anesthesia in adrenalectomized rats with higher noradrenalin and dopamine levels but suppressed adrenalin production. Adrenalin plays an important role in the control of duration of ketamine anesthesia, while noradrenalin, dopamine and corticosterone have no such function. If endogenous adrenalin is suppressed, ketamine can even provide sufficient anesthesia at a 2-fold lower dose. This makes it possible for ketamine to be used in lengthy surgical procedures. PMID- 24767811 TI - Viral infections in pregnancy: advice for healthcare workers. AB - BACKGROUND: Healthcare workers (HCWs) have the potential for increased exposure to infectious disease resulting from the provision of patient care. Pregnancy can confer specific problems in some infections for the mother and her unborn child. AIMS: To discuss the viral infections encountered in the UK that constitute a particular risk to the pregnant HCW: human immunodeficiency virus, hepatitis B virus, hepatitis C virus, varicella-zoster virus, herpes simplex virus, human parvovirus B19, cytomegalovirus, rubella, measles, enteroviruses, mumps and influenza. Evidence for nosocomial transmission, clinical aspects specific to pregnancy, and recommendations to protect the pregnant HCW at work are included. METHODS: Medline, EMBASE and Pubmed were searched using a list of keywords specific to each viral infection, including 'nosocomial', 'occupational' and 'healthcare workers'. References from the bibliographies of articles identified were reviewed for relevant material. FINDINGS: The evidence for increased risk in the healthcare setting for many of these infections, outside of outbreaks, is weak, possibly because of the application of standard protective infection control measures or because risk of community exposure is greater. The pregnant HCW should be advised on protective behaviour in both settings. Potential interventions include vaccination and reducing the likelihood of exposure through universal precautions, infection control and redeployment. CONCLUSION: Protection of the pregnant HCW is the responsibility of the individual, antenatal care provider and employer, and is made possible through awareness of the risks and potential interventions both before and after exposure. If exposure occurs or if the HCW develops an infective illness, urgent specialist advice is required. PMID- 24767812 TI - Congenital glaucoma in Wagner syndrome. AB - Wagner syndrome is a rare inherited vitreoretinopathy. We describe 3 related patients with Wagner syndrome who presented with congenital glaucoma at age 3 months and required multiple surgical interventions to control their intraocular pressure. All experienced visual loss and glaucomatous optic neuropathy. PMID- 24767813 TI - A game theory based framework for assessing incentives for local area collaboration with an application to Scottish salmon farming. AB - Movements of water that transport pathogens mean that in net-pen aquaculture diseases are often most effectively managed collaboratively among neighbours. Such area management is widely and explicitly applied for pathogen management in marine salmon farms. Effective area management requires the active support of farm managers and a simple game-theory based framework was developed to identify the conditions required under which collaboration is perceived to be in their own best interest. The model applied is based on area management as practiced for Scottish salmon farms, but its simplicity allows it to be generalised to other area-managed net-pen aquaculture systems. In this model managers choose between purchasing tested pathogen-free fish or cheaper, untested fish that might carry pathogens. Perceived pay-off depends on degree of confidence that neighbours will not buy untested fish, risking input of pathogens that spread between farms. For a given level of risk, confidence in neighbours is most important in control of moderate-impact moderate-probability diseases. Common low-impact diseases require high confidence since there is a high probability a neighbour will import, while testing for rare high-impact diseases may be cost-effective regardless of neighbours actions. In some cases testing may be beneficial at an area level, even if all individual farms are better off not testing. Higher confidence is required for areas with many farms and so focusing management on smaller, epidemiologically imperfect, areas may be more effective. The confidence required for collaboration can be enhanced by the development of formal agreements and the involvement of outside disinterested parties such as trade bodies or government. PMID- 24767814 TI - Estimation of impact of contagious bovine pleuropneumonia on pastoralists in Kenya. AB - Contagious bovine pleuropneumonia (CBPP) is an infectious disease which impacts cattle production in sub-Saharan Africa. To adequately allocate resources for its control, there is a need to assess its impact on cattle producers. The present study estimated the impact of CBPP on pastoralists through analysis of various strategies employed for its control in cattle herds including: preventive vaccination, antimicrobial treatment, slaughter of clinical cases and other combinations of these control strategies. The assessment was based on a loss expenditure frontier framework to identify a control strategy with minimum cost from both expenditures on control strategies and output losses due to mortalities, reduced milk yield, reduced weight gain and reduced fertility rate. The analysis was undertaken in a stochastic spreadsheet model. The control strategy with minimum cost per herd was preventive vaccination with an estimated cost of US$ 193 (90% CI; 170-215) per 100 cows per year, while slaughter of clinical cases had an estimated cost of US$ 912 (90% CI; 775-1055) per 100 cows per year. The impact of CBPP to the nation was estimated at US$ 7.6 (90% CI; 6.5 8.7) million per year. Yet, if all pastoralists whose cattle are at high risk of infection adopted preventive vaccination, the aggregate national impact would be US$ 3.3 (90% CI; 2.9-3.7) million per year, with savings amounting to US$ 4.3 million through reallocation of control expenditures. The analysis predicted that control of CBPP in Kenya is profitable through preventive vaccination. However, further research is recommended for the technical and financial feasibility of implementing a vaccine delivery system in pastoral areas where CBPP is endemic. PMID- 24767815 TI - Syndromic surveillance using laboratory test requests: a practical guide informed by experience with two systems. AB - Syndromic surveillance systems can enhance early disease warning, endemic disease monitoring, or help to accumulate proof of disease freedom. In order to provide immediate feedback to achieve these goals, the health data sources scanned should be acquired continuously, in an automated fashion, and should be stored electronically. Recognizing that data from diagnostic test requests often meet these requirements, two systems designed to automatically extract surveillance information from animal laboratory databases have been developed and are described in this paper. These systems are designed to contribute to early disease detection, as well as the timely management of epidemiological information, in a province of Canada and in Sweden, the areas served by the diagnostic laboratories concerned. Classifying in-coming requests into syndromes, the first step, was the most time-consuming and the least portable step between the two systems. The remaining steps were more easily adjusted from one system to implementation in the other. These steps included: retrospective evaluation of data to create baseline profiles following the removal of excessive noise and aberrations; the identification of temporal effects; prospective evaluation of detection algorithms; and finally real-time monitoring and implementation. Building upon the institutions' existing data management software, all steps to use those data for the purposes of syndromic surveillance were set up using open source software; as a result this approach could be readily adopted by other institutions. Relatively straight-forward development and maintenance is expected to lead to the incorporation of these systems into each institution's surveillance processes, becoming an indispensable tool for diagnosticians and epidemiologists, as well as stimulating further technical development of such systems. PMID- 24767816 TI - Effect of each guanidinium group on the RNA recognition and cellular uptake of Tat-derived peptides. AB - The six arginine (Arg) residues in the human immunodeficiency virus transactivator of transcription protein (HIV Tat protein) basic region (residues 47-57) are crucial for two bioactivities: RNA recognition and cellular uptake. Herein, we report a systematic study to investigate the role of the guanidinium group on Arg at each position in Tat-derived peptides for the two bioactivities. Tat-derived peptides, in which each guanidinium-bearing arginine was replaced with a urea-bearing citrulline (Cit) or an ammonium-bearing Lys, were synthesized by solid phase peptide synthesis. RNA recognition of the peptides was studied by electrophoretic mobility shift assays, and cellular uptake into Jurkat cells was determined by flow cytometry. Our results showed that removing the positive charge and altering the hydrogen bonding capacity of Arg affect the two biological functions differently. Furthermore, the effects are position dependent. These findings should be useful for the development of functional molecules containing guanidinium, urea, and ammonium groups for RNA recognition to affect biological processes and for cellular uptake for drug delivery. PMID- 24767817 TI - Synthesis and evaluation of immunostimulant plasmalogen lysophosphatidylethanolamine and analogues for natural killer T cells. AB - Plasmalogen lysophosphatidylethanolamine (pLPE) had been identified as a self antigen for natural killer T cells (NKT cells). It is very important in the development, maturation and activation of NKT cells in thymus. Besides, pLPE is a novel type of antigen for NKT cells. To evaluate the structure-activity relationship (SAR) of this new antigen, pLPE and its analogues referred to different aliphatic chains and linkages at the sn-1 position of the glycerol backbone were synthesized, and the biological activities of these analogues was characterized. It is discovered that the linkages between phosphate and lipid moiety are not important for the antigens' activities. The pLPE analogues 1, 3, 4, 7 and 9, which have additional double bonds on lipid parts, were identified as new NKT agonists. Moreover, the analogues 4, 7 and 9 were discovered as potent Th2 activators for NKT cells. PMID- 24767818 TI - Design, synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from beta-amino acid as proteasome inhibitors. AB - A series of novel tripeptidyl epoxyketone derivatives constructed from beta-amino acid were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome inhibitory activities and selected compounds were tested for their anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and NCI-H929. Among them, eleven compounds exhibited proteasome inhibitory rates of more than 50% at the concentration of 1 MUg/mL and nine compounds showed anti-proliferation activities with IC50 values at low micromolar level. Compound 20h displayed the most potent proteasome inhibitory activities (IC50: 0.11 +/- 0.01 MUM) and anti-proliferation activities with IC50 values at 0.23 +/- 0.01 and 0.17 +/- 0.02 MUM against two tested cell lines. Additionally, the poly-ubiquitin accumulation in the western blot analysis supported that proteasome inhibition in a cellular system was induced by compound 20h. All these experimental results confirmed that beta-amino acid can be introduced as a building block for the development of proteasome inhibitors. PMID- 24767819 TI - Structure-activity relationship study, target identification, and pharmacological characterization of a small molecular IL-12/23 inhibitor, APY0201. AB - Interleukin-12 (IL-12) and IL-23 are proinflammatory cytokines and therapeutic targets for inflammatory and autoimmune diseases, including inflammatory bowel diseases, psoriasis, rheumatoid arthritis, and multiple sclerosis. We describe the discovery of APY0201, a unique small molecular IL-12/23 production inhibitor, from activated macrophages and monocytes, and demonstrate ameliorated inflammation in an experimental model of colitis. Through a chemical proteomics approach using a highly sensitive direct nanoflow LC-MS/MS system and bait compounds equipped with the FLAG epitope associated regulator of PIKfyve (ArPIKfyve) was detected. Further study identified its associated protein phosphoinositide kinase, FYVE finger-containing (PIKfyve), as the target protein of APY0201, which was characterized as a potent, highly selective, ATP competitive PIKfyve inhibitor that interrupts the conversion of phosphatidylinositol 3-phosphate (PtdIns3P) to PtdIns(3,5)P2. These results elucidate the function of PIKfyve kinase in the IL-12/23 production pathway and in IL-12/23-driven inflammatory disease pathologies to provide a compelling rationale for targeting PIKfyve kinase in inflammatory and autoimmune diseases. PMID- 24767820 TI - Prevalence and management of uncontrolled hypertension in French patients aged over 80 years. AB - BACKGROUND: The rate of uncontrolled hypertensives aged >80 years is not well known. The available literature on this topic has used the threshold <140/90 mmHg, whereas there is now a consensus for a different target: systolic blood pressure (SBP)<150 mmHg. AIMS: This prospective observational population-based study sought to assess the frequency and management of uncontrolled hypertension in French patients aged >=80 years. METHODS: Nine hundred and seventy-one treated hypertensive outpatients were evaluable (204 recruited by cardiologists, 767 by general practitioners [GPs]; mean age 84.8 +/- 3.8 years; 57.8% women). RESULTS: The frequency of SBP >= 150 mmHg was 36.6% (44.6% in cardiologists' patients and 34.4% in GPs' patients). The frequency of satisfaction with SBP >= 150 mmHg was 22.0% for cardiologists (32.6% if diastolic blood pressure [DBP] <90 mmHg and 9.5% if >=90 mmHg; P=0.008) and 30.4% for GPs (51.7% if DBP <90 mmHg and 13.2% if >=90 mmHg; P<0.0001). Non-diabetic status (for cardiologists) and DBP <90 mmHg (for cardiologists and GPs) were independent determinants of SBP being considered acceptable. Accordingly, in patients with an SBP level >= 150 mmHg that was considered too high, treatment was reinforced more often if DBP was >=90 mmHg (82.3%) than <90 mmHg (68.5%). CONCLUSION: In France, hypertension is uncontrolled in more than one in three elderly hypertensives. Physicians are aware that SBP should be lowered to <150 mmHg in patients aged>80 years, but when the target is not reached they are less likely to increase treatment if DBP is <90 mmHg. PMID- 24767821 TI - Age of linear enamel hypoplasia formation based on Massler and colleagues' and Reid and Dean's standards in a Polish sample dated to 13th-18th century CE. AB - In the study of enamel hypoplasia formation ages basically two standards of dental development are being applied. According to some authors, different methods produce different results, thus it is critical to decide which method to use. This study focuses on the comparison of three methods for estimating ages of linear enamel hypoplasia (LEH) formation. The skeletal material derives from three burial grounds localized on the territory of Poland, dated to 13th-18th c. CE. In total 642 teeth of 77 individuals were qualified for the study. The position of LEHs on the crown surface was measured and then converted to age at formation using the regression equations proposed by Goodman and Rose, Goodman and Song, and the data provided by Reid and Dean. There were 51.9% of individuals and 17.9% of teeth affected by LEH. The lowest age estimates were provided by the Goodman and Rose's method then higher by the Goodman and Song's method and the highest using the Reid and Dean's data. The age ranges and peaks of LEH provided by the three methods differed more for the maxillary than for the mandibular teeth. Crown formation ages supplied by Reid and Dean account for intra- and inter-tooth as well as inter-population variation in the timing of tooth development and also for variation in crown heights. This approach undoubtedly increases reliability of the results. Thus, it seems advisable to use the Reid and Dean's standard when calculating ages of enamel hypoplasia formation. PMID- 24767822 TI - Reconstructing cultural behavior from dental wear studies: is para-facets analysis approach scientifically valid? AB - It is common knowledge, that in archaic populations teeth were used as tools, this behavior can be studied by evaluating attrition patterns. Parafacets were defined as nonmasticatory wear areas that have no antagonist matching wear facets. The presence of the parafacets led to far-reaching conclusions regarding cultural interactions between Near Eastern Neanderthals and anatomically modern humans. This study was aimed to examine the identification of parafacets in some of the Qafzeh specimens. Based on findings of our research we suggest that the attrition facets mistakenly considered as parafacets are in fact the result of the static and dynamic occlusion. Therefore the observations induce much less dramatic interpretation. We here propose several guidelines that would be beneficial in that they aim to evaluate the parafacets with heightened accuracy. PMID- 24767823 TI - Arachidonic acid metabolism in the human placenta: identification of a putative lipoxygenase. AB - Arachidonic acid (ARA) metabolites maintain pregnancy and control parturition. We generated a network of 77 proteins involved in placental ARA metabolism to identify novel proteins in this pathway. We identified a long pathway within this network which showed that secretory and cytosolic phospholipase A2 proteins act in concert. The functions of all network proteins expressed in the placental decidua were determined by database searches. Thus ARA metabolism was linked to carbohydrate metabolism. One protein, transmembrane protein 62 (TMEM62), expressed in decidua was previously uncharacterized, and was identified as a putative lipoxygenase. TMEM62 may play a role in pregnancy and/or parturition. PMID- 24767825 TI - Pseudosarcomatous myofibroblastic proliferation of the urinary bladder: a rare entity. AB - Pseudosarcomatous myofibroblastic proliferations are very unusual entities of unknown etiology. Despite its benign nature, this entity can easily be misdiagnosed (both clinically and histologically) as a malignant neoplasm. Hereby, we report a case of a 15-year-old woman who presented to our hospital with a broad-based polypoid mass located in the left posterior wall of the urinary bladder. The patient underwent a transurethral resection of the lesion. Morphologic and immunohistochemical findings suggested the diagnosis of pseudosarcomatous myofibroblastic proliferation. The patient is free of recurrence 5 years after surgery. PMID- 24767824 TI - Cystectomy with urinary diversion for benign disease: indications and outcomes. AB - OBJECTIVE: To analyze what factors contribute to a worse outcome after cystectomy and urinary diversion for benign disease as measured by the frequency of severe complications. METHODS: A retrospective review was performed of consecutive patients who underwent a cystectomy for benign disease. The primary outcome was the type and severity of complications, according to Clavien-Dindo scale. RESULTS: A total of 139 patients underwent cystectomy with diversion for benign diseases over the study period. The most common indications for surgery were spinal cord injury (32%) and radiation damage to the bladder (18%). The average preoperative age-adjusted Charlson comorbidity index was 4.6. Seventy-four patients (53%) underwent supratrigonal cystectomy. Mean surgery duration was 344+/-103 minutes, and the mean estimated blood loss was 476+/-379 mL. The most common complications were perioperative blood transfusion, prolonged ileus, and pyelonephritis. Seventy-nine patients (57%) had a complication grade>=II on the Clavien-Dindo scale. This did not differ based on indication for surgery, age, gender, body mass index, age-adjusted Charlson comorbidity index, estimated blood loss, or type of cystectomy. After adjustment, only duration of surgery in 10 minute increments (odds ratio, 1.07; 95% confidence interval, 1.02-1.12; P=.007) was associated with an increased incidence of serious complication. CONCLUSION: Most of the patients experience some complication after cystectomy and urinary diversion for benign indications. Duration of surgery is an important variable that can affect outcome. PMID- 24767826 TI - Heidelberg Spectralis infrared video imaging: a clinical tool for diagnosing ocular torsional instability. AB - Heidelberg Spectralis infrared video imaging provides a diagnostic modality for the assessment of dynamic torsional instability of the eyes. It accurately detects monocular changes in both vertical and torsional eye position as fixation is switched from one eye to the other without the need for illuminating either eye. Heidelberg Spectralis infrared video imaging is useful for depicting the subtle torsional components of dissociated vertical divergence, latent nystagmus in patients with infantile esotropia. PMID- 24767827 TI - Exudative vasculopathy in a child with Leber congenital amaurosis. AB - Leber congenital amaurosis is a severe retinal dystrophy that causes blindness or severe visual impairment, usually before the age of 1 year. We present the case of a 13-year-old girl with Leber congenital amaurosis who developed an exudative vasculopathy. She was successfully treated with cryotherapy and argon green laser. To our knowledge, only 4 cases of this condition in patients with Leber congenital amaurosis have been reported previously. This phenotype may be related to c.2991+1655A>G (p.Cys998X) mutations in the CEP290 gene. PMID- 24767828 TI - Inferior oblique anterior transposition for the unilateral hypertropia associated with bilateral inferior rectus muscle aplasia. AB - Bilateral inferior rectus muscle aplasia in the absence of craniofacial abnormality is a rare but possibly under-recognized form of strabismus. Unilateral hypertropia in primary position seems to be a recurrent feature of this condition. We report a case of a 20-year-old woman with left hypertropia in primary position who was found on computed tomography to have bilateral inferior rectus muscle aplasia. A unilateral inferior oblique anterior transposition resulted in correction of the vertical deviation in primary position. PMID- 24767829 TI - Displacement of optical centers in over-the-counter readers: a potential cause of diplopia. AB - Induced prism in spectacle lenses, which may result from inadvertent displacement of optical centers, may worsen an existing heterophoria or even cause diplopia, yet over-the-counter reading glasses (OTC readers) are not always assessed by clinicians when evaluating patients with diplopia or asthenopia. To gauge the magnitude of this potential problem, we used a focimeter and prescription aligner to assess the frequency and extent of clinically significant manufacturing variations in a random selection of 160 OTC readers. The optical centers were vertically displaced by >=3 mm in 11%, with a maximum displacement of 7 mm in 1 pair. Average interpupillary distance was 64 mm (range, 58-74.5 mm), with interpupillary distance outside the normal range of 60-70 mm in 5%. Monocular pupillary distance was asymmetric by >=5 mm in 4%. A 0.75 D power difference between lenses was measured in one pair of OTC readers. Some OTC readers have misaligned optical centers and other manufacturing defects that are of a magnitude sufficient to exacerbate a heterophoria and cause asthenopia or diplopia. PMID- 24767830 TI - Successful treatment of juvenile xanthogranuloma using bevacizumab. AB - Juvenile xanthogranuloma (JXG) is an uncommon non-Langerhans cell histiocytic disorder that occurs predominantly in infants. Traditional treatment of ocular JXG involves the administration of topical or local corticosteroids. We treated 2 children with JXG refractory to local corticosteroid therapy with off-label intraocular bevacizumab. To our knowledge, this is the first report of successful use of bevacizumab for ocular JXG. PMID- 24767832 TI - Effect of insulating posts geometry on particle manipulation in insulator based dielectrophoretic devices. AB - In this study, the effect of the geometry of insulating posts on microparticle trapping in insulator based dielectrophoresis (iDEP) was analyzed. The motivation for this research was to study how to improve particle trapping and enrichment by modifying the shape of insulating posts used in iDEP microdevices, while keeping post spacing constant. Mixtures of inert polystyrene particles were employed for demonstrating the effects of insulator shape on particle capture and enrichment. A series of experiments were carried out using an array of devices with different insulating post shapes. All the different post shapes employed had a width of 200 MUm and were arranged in a square array of 250 MUm center-to-center, thus, the spacing between posts was 50 MUm in all cases. Mathematical modeling with COMSOL Multiphysics was employed to assess the magnitude of electric field gradients achieved with each one of the geometries tested. The results showed that the electric potential required to obtain effective particle trapping and enrichment can be significantly reduced by modifying the geometry of the insulating posts, without having to modify the separation distance between posts, thus, preserving the porosity of the microchannels. The separation of a mixture of 1-MUm and 2-MUm diameter particles was achieved in the form of dielectropherograms employing two different insulating post geometries (circle and diamond). Concentrated particles were released as peaks from the insulating post arrays where higher peak resolution separation was obtained with the sharper diamond geometry. Concentration enrichment above one order or magnitude was obtained for both particle types in both dielectropherograms. The results demonstrate that more efficient iDEP separations can be achieved at lower applied electric potentials by carefully selecting the geometry of the insulating structures. PMID- 24767831 TI - Long term effect of gut microbiota transfer on diabetes development. AB - The composition of the gut microbiome represents a very important environmental factor that influences the development of type 1 diabetes (T1D). We have previously shown that MyD88-deficient non-obese diabetic (MyD88-/-NOD) mice, that were protected from T1D development, had a different composition of gut microbiota compared to wild type NOD mice. The aim of our study was to investigate whether this protection could be transferred. We demonstrate that transfer of gut microbiota from diabetes-protected MyD88-deficient NOD mice, reduced insulitis and significantly delayed the onset of diabetes. Gut bacteria from MyD88-deficient mice, administered over a 3-week period, starting at 4 weeks of age, stably altered the family composition of the gut microbiome, with principally Lachnospiraceae and Clostridiaceae increased and Lactobacillaceae decreased. The transferred mice had a higher concentration of IgA and TGFbeta in the lumen that was accompanied by an increase in CD8(+)CD103(+) and CD8alphabeta T cells in the lamina propria of the large intestine. These data indicate not only that gut bacterial composition can be altered after the neonatal/weaning period, but that the composition of the microbiome affects the mucosal immune system and can delay the development of autoimmune diabetes. This result has important implications for the development of probiotic treatment for T1D. PMID- 24767834 TI - Implementation of gradients of organic solvent in micellar liquid chromatography using DryLab((r)): separation of basic compounds in urine samples. AB - In micellar liquid chromatography (MLC), chromatographic peaks are more evenly distributed compared to conventional reversed-phase liquid chromatography (RPLC). This is the reason that most procedures are implemented using isocratic elution. However, gradient elution may be still useful in MLC to analyse mixtures of compounds within a wide range of polarities, decreasing the analysis time. Also, it benefits the determination of moderately to low polar compounds in physiological fluids performing direct injection: an initial micellar eluent with a low organic solvent content, or a pure micellar (without surfactant) solution, will provide better protection of the column against the proteins in the physiological fluid, and once the proteins are swept away, the elution strength can be increased using a positive linear gradient of organic solvent to reduce the analysis time. This work aims to encourage analysts to implement gradients of organic solvent in MLC, which is rather simple and allows rapid analytical procedures without pre-treatment or the need of re-equilibration. The implementation of gradient elution is illustrated through the separation of eight basic compounds (beta-blockers) in urine samples directly injected into the chromatograph, the most hydrophobic showing large retention in both conventional RPLC and MLC. The use of the DryLab((r)) software to optimise gradients of organic solvent with eluents containing a fixed amount of surfactant above the critical micellar concentration is shown to provide satisfactory predictions, and can facilitate greatly the implementation of gradient protocols. PMID- 24767833 TI - Development of a multianalyte method based on micro-matrix-solid-phase dispersion for the analysis of fragrance allergens and preservatives in personal care products. AB - An effective, simple and low cost sample preparation method based on matrix solid phase dispersion (MSPD) followed by gas chromatography-mass spectrometry (GC-MS) or gas chromatography-triple quadrupole-mass spectrometry (GC-MS/MS) has been developed for the rapid simultaneous determination of 38 cosmetic ingredients, 25 fragrance allergens and 13 preservatives. All target substances are frequently used in cosmetics and personal care products and they are subjected to use restrictions or labeling requirements according to the EU Cosmetic Directive. The extraction procedure was optimized on real non-spiked rinse-off and leave-on cosmetic products by means of experimental designs. The final miniaturized process required the use of only 0.1g of sample and 1 mL of organic solvent, obtaining a final extract ready for analysis. The micro-MSPD method was validated showing satisfactory performance by GC-MS and GC-MS/MS analysis. The use of GC coupled to triple quadrupole mass detection allowed to reach very low detection limits (low ng g(-1)) improving, at the same time, method selectivity. In an attempt to improve the chromatographic analysis of preservatives, the inclusion of a derivatization step was also assessed. The proposed method was applied to a broad range of cosmetics and personal care products (shampoos, body milk, moisturizing milk, toothpaste, hand creams, gloss lipstick, sunblock, deodorants and liquid soaps among others), demonstrating the extended use of these substances. The concentration levels were ranging from the sub parts per million to the parts per mill. The number of target fragrance allergens per samples was quite high (up to 16). Several fragrances (linalool, farnesol, hexylcinnamal, and benzyl benzoate) have been detected at levels >0.1% (1,000 MUg g(-1)). As regards preservatives, phenoxyethanol was the most frequently found additive reaching quite high concentration (>1,500 MUg g(-1)) in five cosmetic products. BHT was detected in eight samples, in two of them (a baby care product and a lipstick) at high concentrations (>1,000 MUg g(-1)). Methyl paraben was also found at high levels (>1,700 MUg g(-1)) in three leave-on samples. Finally, triclosan was found at the maximum concentration limit (0.3%) laid down by the European regulation in two deodorant samples, and the total paraben concentration was close to the maximum concentration permitted (0.8%) in one leave-on sample (body milk). PMID- 24767835 TI - Performance of different C18 columns in reversed-phase liquid chromatography with hydro-organic and micellar-organic mobile phases. AB - Column selection in reversed-phase liquid chromatography (RPLC) can become a challenge if the target compounds interact with the silica-based packing. One of such interactions is the attraction of cationic solutes to the free silanols in silica-based columns, which is a slow sorption-desorption interaction process that gives rise to tailed and broad peaks. The effect of silanols is minimised by the addition of a competing agent in the mobile phase, such as the anionic surfactant sodium dodecyl sulphate (SDS). In micellar-organic RPLC, the adsorption of an approximately fixed amount of SDS monomers gives rise to a stable modified stationary phase, with properties remarkably different from those of the underlying bonded phase. The chromatographic behaviour (in terms of selectivity, analysis time and peak shape) of eight C18 columns in the analysis of weakly acidic phenols and basic beta-blockers was examined with hydro-organic and micellar-organic mobile phases. The behaviour of the columns differed significantly when the cationic basic drugs were eluted with hydro-organic mobile phases. With micellar-organic mobile phases, the adsorption of surfactant, instead of making the columns similar, gave rise to a greater diversity of behaviours (especially in terms of selectivity and analysis time), for both groups of phenols and beta-blockers, which should be explained by the residual effect of the underlying bonded stationary phase and the different amount of surfactant covering the packing. Therefore, the implementation of a micellar organic procedure in RPLC will depend significantly on the selected type of C18 column. PMID- 24767836 TI - Separation of amaranthine-type betacyanins by ion-pair high-speed countercurrent chromatography. AB - Betacyanins, red-violet plant pigments, were fractionated by ion-pair high-speed countercurrent chromatography (IP-HSCCC) from leaves extract of Iresine lindenii Van Houtte, an ornamental plant of the family Amaranthaceae. An HSCCC solvent system consisting of TBME-1-BuOH-ACN-H2O (1:3:1:5, v/v/v/v) was applied using ion pair forming heptafluorobutyric acid (HFBA). Significantly different elution profiles of betacyanin diastereomeric pairs (derivatives based on betanidin and isobetanidin) observed in the HSCCC in comparison to HPLC systems indicate a complementarity of both techniques' fractionation capabilities. The numerous diastereomeric pairs can be selectively separated from each other using the HSCCC system simplifying the pigment purification process. Apart from the three well known highly abundant pigments (amaranthine, betanin and iresinin I) together with their isoforms, three new acylated (feruloylated and sinapoylated) betacyanins as well as known pigment hylocerenin (previously isolated from cacti fruits) were characterized in the plant for the first time and they are new for the whole Amaranthaceae family. PMID- 24767838 TI - Synthesis and evaluation of new NIR-fluorescent probes for cathepsin B: ICT versus FRET as a turn-ON mode-of-action. AB - Recent years have seen tremendous progress in the design and study of molecular imaging geared towards biological and biomedical applications. The expression or activity of specific enzymes including proteases can be monitored by cutting edge molecular imaging techniques. Cathepsin B plays key roles in tumor progression via controlled degradation of extracellular matrix. Consequently, this protease has been attracting significant attention in cancer research, and many imaging probes targeting its activity have been developed. Here, we describe the design, synthesis and evaluation of two novel near infrared (NIR) fluorescent probes for detection of cathepsin B activity with different turn-ON mechanisms. One probe is based on an ICT activation mechanism of a donor-two-acceptor pi-electron dye system, while the other is based on the FRET mechanism obtained by a fluorescent dye and a quencher. The two probes exhibit significant fluorescent turn-ON response upon cleavage by cathepsin B. The NIR fluorescence of the ICT probe in its OFF state was significantly lower than that of the FRET-based probe. This effect results in a higher signal-to-noise ratio and consequently increased sensitivity and better image contrast. PMID- 24767839 TI - Tomensides A-D, new antiproliferative phenylpropanoid sucrose esters from Prunus tomentosa leaves. AB - To search for novel cytotoxic constituents against cancer cells as lead structures for drug development, four new 3-phenylpropanoid-triacetyl sucrose esters, named tomensides A-D (1-4), and three known analogs (5-7) were isolated from the leaves of Prunus tomentosa. Their structures were elucidated by spectroscopic analyses (1D, 2D NMR, CD and HRESIMS). The cytotoxic activities of all isolates against four human cancer cell lines (MCF-7, A549, HeLa and HT-29) were assayed, and the results showed that these isolates displayed stronger inhibitory activities compared with positive control 5-fluorouracil. Tomenside A (1) was the most active compound with IC50 values of 0.11-0.62 MUM against the four tested cell lines. The structure-activity relationship (SAR) of the isolates was also discussed. The primary screening results indicated that these 3 phenylpropanoid-triacetyl sucrose esters might be valuable source for new potent anticancer drug candidates. PMID- 24767837 TI - Recent advances in bone-targeted therapies of metastatic prostate cancer. AB - Prostate cancer is one of the most common malignancies affecting men worldwide, with bone being the most common site of metastasis in patients that progress beyond organ confinement. Bone metastases are virtually incurable and result in significant disease morbidity and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Several attractive molecules or pathways have been identified as new potential therapeutic targets for bone metastases caused by metastatic castration-resistant prostate cancer. In this review, we present the recent advances in molecular targeted therapies for prostate cancer bone metastasis focusing on therapies that target the bone cells and the bone microenvironment. The therapies covered in this review include agents that inhibit bone resorption, agents that stimulate bone formation, and agents that target the bone matrix. Suggestions to devise more effective molecular targeted therapies are proposed. Hopefully, with better understanding of the biology of the disease and the development of more robust targeted therapies, the survival and quality of life of the affected individuals could be significantly improved. PMID- 24767840 TI - Discovery of BRD4 bromodomain inhibitors by fragment-based high-throughput docking. AB - Bromodomains (BRDs) recognize acetyl-lysine modified histone tails mediating epigenetic processes. BRD4, a protein containing two bromodomains, has emerged as an attractive therapeutic target for several types of cancer as well as inflammatory diseases. Using a fragment-based in silico screening approach, we identified two small molecules that bind to the first bromodomain of BRD4 with low-micromolar affinity and favorable ligand efficiency (0.37 kcal/mol per non hydrogen atom), selectively over other families of bromodomains. Notably, the hit rate of the fragment-based in silico approach is about 10% as only 24 putative inhibitors, from an initial library of about 9 million molecules, were tested in vitro. PMID- 24767841 TI - Chrotacumines G-J, chromone alkaloids from Dysoxylum acutangulum with osteoclast differentiation inhibitory activity. AB - Four new chromone alkaloids, chrotacumines G-J (1-4), have been isolated from the barks of Dysoxylum acutangulum. Their structures and absolute configurations were elucidated on the basis of NMR and CD data. Chrotacumines G and J (1 and 4) showed osteoclast differentiation inhibitory activity in a dose dependent manner. PMID- 24767842 TI - Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors. AB - There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes. PMID- 24767843 TI - 2-Amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists. AB - Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 MUM with 10 MUM ADP. Several 2-amino-1,3,4 thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3. PMID- 24767844 TI - Synthesis of a cluster-forming sialylthio-D-galactose fullerene conjugate and evaluation of its interaction with influenza virus hemagglutinin and neuraminidase. AB - In order to obtain self assembling, multivalent ligand for influenza virus hemagglutinin alpha-N-acetylneuraminyl-(2-6)-D-galactopyranose has been synthesized and bonded to a water soluble fullerene derivative using 1,3-dipolar cycloaddition click reaction. The aggregating amphiphilic compound did not inhibit the influenza virus hemagglutinin, but it proved to be an inhibitor of its neuraminidase with a 50% inhibitory concentration of 81 MUM. PMID- 24767845 TI - Dihydrothiophene-condensed chromones from a marine-derived fungus Penicillium oxalicum and their structure-bioactivity relationship. AB - Four dihydrothiophene-condensed chromones including two new compounds oxalicumones D-E (1-2) and known oxalicumones A-B (3-4), along with five other known chromones were isolated from a culture broth of the marine gorgonian associated fungus Penicillium oxalicum SCSGAF 0023. The structures of 1-2 were elucidated by spectroscopic analysis. Eleven derivatives 3a-3i and 4a-4b were obtained from the acylation of 3 and 4, respectively. Compounds 1-4, 3a-3e, 3g 3h, and 4b showed significant cytotoxicity against several carcinoma cell lines with IC50 <= 10 MUM. And their structure-bioactivity relationship was discussed. PMID- 24767846 TI - Design and synthesis of highly potent HIV-1 protease inhibitors with novel isosorbide-derived P2 ligands. AB - The design, synthesis, and biological evaluation of a series of six HIV-1 protease inhibitors incorporating isosorbide moiety as novel P2 ligands are described. All the compounds are very potent HIV-1 protease inhibitors with IC50 values in the nanomolar or picomolar ranges (0.05-0.43 nM). Molecular docking studies revealed the formation of an extensive hydrogen-bonding network between the inhibitor and the active site. Particularly, the isosorbide-derived P2 ligand is involved in strong hydrogen bonding interactions with the backbone atoms. PMID- 24767847 TI - Mechanistic aspects of the tyrosinase oxidation of hydroquinone. AB - Contradictory reports on the behaviour of hydroquinone as a tyrosinase substrate are reconciled in terms of the ability of the initially formed ortho-quinone to tautomerise to the thermodynamically more stable para-quinone isomer. Oxidation of phenols by native tyrosinase requires activation by in situ formation of a catechol formed via an enzyme generated ortho-quinone. In the special case of hydroquinone, catechol formation is precluded by rapid tautomerisation of the ortho-quinone precursor to catechol formation. PMID- 24767848 TI - Discovery of the first potent and selective Mycobacterium tuberculosis Zmp1 inhibitor. AB - The Mycobacterium tuberculosis extracellular zinc metalloprotease 1 (Zmp1) has been proposed to play a key role in phagosome maturation and to enhance the survival of Mycobacterium tuberculosis in the host. Consequently, small molecule inhibitors of Zmp1 are of pivotal importance as a tool to better understand the pathogenicity of Zmp1 and as lead candidates for pharmacological intervention. Here we combined in silico structure-based inhibitor design with biochemical studies to discover and characterize the first potent competitive Zmp1 inhibitor showing a Ki of 94 nM and a high selectivity for Zmp1 with respect to human Neprilysin. PMID- 24767849 TI - Design, synthesis and biological evaluation of Pontin ATPase inhibitors through a molecular docking approach. AB - A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth. Further biological studies revealed that the most active compound induced apoptotic cell death together with necrosis, this latter effect being likely related to the cellular balance of ATP regulation. PMID- 24767850 TI - Biological evaluation of tanshindiols as EZH2 histone methyltransferase inhibitors. AB - EZH2 is the core subunit of Polycomb repressive complex 2 catalyzing the methylation of histone H3 lysine-27 and closely involved in tumorigenesis. To discover small molecule inhibitors for EZH2 methyltransferase activity, we performed an inhibitor screen with catalytically active EZH2 protein complex and identified tanshindiols as EZH2 inhibitors. Tanshindiol B and C potently inhibited the methyltransferase activity in in vitro enzymatic assay with IC50 values of 0.52MUM and 0.55MUM, respectively. Tanshindiol C exhibited growth inhibition of several cancer cells including Pfeiffer cell line, a diffuse large B cell lymphoma harboring EZH2 A677G activating mutation. Tanshindiol treatment in Pfeiffer cells significantly decreased the tri-methylated form of histone H3 lysine-27, a substrate of EZH2, as revealed by Western blot analysis and histone methylation ELISA. Based on enzyme kinetics and docking studies, we propose that tanshindiol-mediated inhibition of EZH2 activity is competitive for the substrate S-adenosylmethionine. Taken together, our findings strongly suggest that tanshindiols possess a unique anti-cancer activity whose mechanism involves the inhibition of EZH2 activity and would provide chemically valuable information for designing a new class of potent EZH2 inhibitors. PMID- 24767851 TI - In vitro effect of a synthesized sulfonamido-based gallate on articular chondrocyte metabolism. AB - Autologous chondrocyte implantation (ACI) is a promising strategy for cartilage repair and reconstitution. However, limited cell numbers and the dedifferentiation of chondrocytes present major difficulties to the success of ACI therapy. Therefore, it is important to find effective pro-chondrogenic agents that restore these defects to ensure a successful therapy. In this study, we synthesized a sulfonamido-based gallate, namely N-[4-(4,6-dimethyl-pyrimidin-2 ylsulfamoyl)-phenyl]-3,4,5-trihydroxy-benzamide (EJTC), and investigated its effects on rabbit articular chondrocytes through an examination of its specific effects on cell proliferation, morphology, viability, GAG synthesis, and cartilage-specific gene expression. The results show that EJTC can effectively promote chondrocyte growth and enhance the secretion and synthesis of cartilage ECM by upregulating the expression levels of the aggrecan, collagen II, and Sox9 genes. The expression of the collagen I gene was effectively downregulated, which indicates that EJTC inhibits chondrocytes dedifferentiation. Chondrocyte hypertrophy, which may lead to chondrocyte ossification, was also undetectable in the EJTC-treated groups. The recommended dose of EJTC ranges from 3.125 MUg/mL to 7.8125 MUg/mL, and the most profound response was observed with 7.8125 MUg/mL. This study may provide a basis for the development of a novel agent for the treatment of articular cartilage defects. PMID- 24767852 TI - Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor. AB - Bis-aryloxadiazoles are common scaffolds in medicinal chemistry due to their wide range of biological activities. Previously, we identified a 1,2,4-bis aryloxadiazole that blocks mammary branching morphogenesis through activation of the aryl hydrocarbon receptor (AHR). In addition to defects in mammary differentiation, AHR stimulation induces toxicity in many other tissues. We performed a structure activity relationship (SAR) study of 1,2,4-bis aryloxadiazole to determine which moieties of the molecule are critical for AHR activation. We validated our results with a functional biological assay, using desmosome formation during mammary morphogenesis to indicate AHR activity. These findings will aid the design of oxadiazole derivative therapeutics with reduced off-target toxicity profiles. PMID- 24767853 TI - Sharing the responsibility for driver distraction across road transport systems: a systems approach to the management of distracted driving. AB - Distracted driving is acknowledged universally as a large and growing road safety problem. Compounding the problem is that distracted driving is a complex, multifaceted issue influenced by a multitude of factors, organisations and individuals. As such, management of the problem is not straightforward. Numerous countermeasures have been developed and implemented across the globe. The vast majority of these measures have derived from the traditional reductionist, driver centric approach to distraction and have failed to fully reflect the complex mix of actors and components that give rise to drivers becoming distracted. An alternative approach that is gaining momentum in road safety is the systems approach, which considers all components of the system and their interactions as an integrated whole. In this paper, we review the current knowledge base on driver distraction and argue that the systems approach is not currently being realised in practice. Adopting a more holistic, systems approach to distracted driving will not only improve existing knowledge and interventions from the traditional approach, but will enhance our understanding and management of distraction by considering the complex relationships and interactions of the multiple actors and the myriad sources, enablers and interventions that make up the distracted driving system. It is only by recognising and understanding how all of the system components work together to enable distraction to occur, that we can start to work on solutions to help mitigate the occurrence and consequences of distracted driving. PMID- 24767854 TI - Doxorubicin delivery enhanced by electroporation to gastrointestinal adenocarcinoma cells with P-gp overexpression. AB - Electroporation (EP) can effectively support the penetration of macromolecules from the extracellular space into cells. Electropores induced by the influence of electromagnetic field generate additional paths of transport for macromolecules. The aim of this study was evaluation of the electroporation effect on doxorubicin transport efficiency to human colon (LoVo and LoVo/DX) and gastric (EPG85-257/P and EPG85-257/RDB) adenocarcinoma cells with overexpression of P-glycoprotein and murine macrophage cell line (P388/D1). In our EP experiments cells were placed into a cuvette with aluminum electrodes and pulsed with five square electric pulses of 1300 V/cm and duration of 50 MUs each. Cells were also treated with low doxorubicin concentration ([DOX]=1.7 MUM). The ultrastructure (TEM) and changes of P-glycoprotein expression of tumor cells subjected to electric field were monitored. The mitochondrial cell function and trypan blue staining were evaluated after 24h. Our results indicate the most pronounced effect of EP with DOX and disturbed ultrastructure in resistant gastric and colon cells with decrease of P-gp expression. Electroporation may be an attractive delivery method of cytostatic drugs in chemotherapy, enabling reduction of drug dose, exposure time and side effects. PMID- 24767855 TI - Osteoma of the internal auditory canal. PMID- 24767856 TI - Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis. AB - Hepatitis B virus (HBV) X protein (HBx) and pre-S2 deletion mutant large surface antigens are oncoproteins that induce hepatocellular carcinoma (HCC). The interaction of these two oncoproteins in hepatocytes and its significance in tumorigenesis remain to be elucidated. In this study, we observed the co expression of HBx with surface antigens in ground-glass hepatocytes in 5 of 20 hepatitis B surface antigen-positive livers. In vitro, hepatocytes co-expressing HBx and a pre-S2 mutant showed enhanced expression of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated mammalian target of rapamycin signals. Transgenic mice harboring both HBx and pre-S2 mutant construct plasmids developed HCCs at an average of 15.1 months, earlier than animals carrying either HBx (16.9 months) or pre-S2 mutant (24.5 months) alone. The oncogenic signals of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal regulated kinase 1/2, and phosphorylated mammalian target of rapamycin were sequentially and differentially activated at different stages in tumorigenesis. Phosphorylated mTOR was consistently activated in transgenic and human HCCs. We conclude that ground-glass hepatocytes co-expressing HBx and surface antigens exhibit enhanced oncogenic effects and tumorigenesis in chronic HBV infections. The mTOR signal cascade may be the key regulator in HBV tumorigenesis and may be useful targets in the design of HCC therapy. PMID- 24767858 TI - Combination of hepatocellular markers is useful for prognostication in gastric hepatoid adenocarcinoma. AB - Hepatoid or alpha-fetoprotein (AFP)-producing adenocarcinomas of stomach growing in a solid pattern are highly aggressive tumors. It is difficult to detect hepatoid differentiation solely based on findings from hematoxylin and eosin stainings, especially in small biopsy specimens. Gastric adenocarcinomas with hepatoid differentiation should be distinguished from solid-type gastric adenocarcinoma because of their different biological behavior. We immunohistochemically analyzed hepatocellular markers (AFP, glypican 3, and Hepatocyte paraffin 1 [HepPar-1]) and possible markers of gastric hepatoid adenocarcinoma (Sal-like protein 4 [SALL4] and palate, lung, and nasal epithelium carcinoma-associated protein [PLUNC]) to detect hepatoid differentiation in 45 gastric hepatoid adenocarcinomas and 47 nonhepatoid solid-type poorly differentiated adenocarcinomas. There were a higher incidence of vascular invasion (P = .0055) and distant metastasis (P = .0458) in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. AFP, SALL4, HepPar-1, and glypican 3 were significantly higher in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. All 5 markers were positive in both the hepatoid/solid and the tubular component. In hepatoid adenocarcinoma, the frequency of distant metastasis was significantly higher in SALL4-negative cases than in SALL4-positive cases (P = .0381). HepPar-1 was associated with liver metastasis (P = .0452). PLUNC was correlated with lymph node metastasis (P = .0375). There was a significant difference in the survival rate between HepPar-1 positive and HepPar-1-negative groups (P = .0437). The coexpression of PLUNC and SALL4 and the other coexpression of HepPar-1 and PLUNC were associated with poorer prognosis (P = .0181 and P = .0443, respectively). AFP, SALL4, HepPar-1, and glypican 3 are useful for the detection of hepatoid differentiation. A combination of PLUNC, HepPar-1, and SALL4 could be a reliable prognostic indicator in hepatoid adenocarcinoma of the stomach. PMID- 24767857 TI - ARID1A/BAF250a as a prognostic marker for gastric carcinoma: a study of 2 cohorts. AB - ARID1A/BAF250a has been recently implicated as a tumor suppressor in gastric cancer. We sought to clarify the clinical significance of BAF250a/ARID1A in relation to other clinical parameters and relevant biomarkers in gastric carcinoma. Cases from 2 separate cohorts of patients with gastric carcinoma from Vancouver (n = 173) and Toronto (n = 80) were selected for the construction of tissue microarrays, which were used to assess the immunohistochemical status of BAF250a (anti-ARID1A), mismatch repair proteins and p53, as well as in situ hybridization for HER2 amplification and Epstein-Barr virus infection. The Toronto cohort contained a higher proportion of early stage cases (P = .019) and a smaller proportion of cases from the proximal stomach (P < .001). Overall, immunohistochemical loss of BAF250a was observed in 22.5% of gastric adenocarcinomas from the Vancouver group and 20% from Toronto. In both cohorts, loss of BAF250a was positively associated with loss of mismatch repair protein expression (P < .0001 and P = .035, respectively). Loss of BAF250a expression was independently associated with poor overall survival in the Toronto cohort (P = .0015), whereas no significant association with survival was observed in the Vancouver cohort. BAF250a loss was not significantly associated with any additional clinical parameters in either cohort. HER2 amplification was confirmed as a negative prognostic factor in both cohorts. These findings suggest that ARID1A/BAF250a may be of prognostic significance in a subset of patients with early stage gastric cancer and that pathological assessment should increasingly use a multimarker approach. PMID- 24767859 TI - Matricellular protein CCN1 (CYR61) expression is associated with high-grade ductal carcinoma in situ. AB - Cysteine-rich protein 61, connective tissue growth factor, and nephroblastoma overexpressed gene (CCN) comprise a family of matricellular proteins that have multiple physiologic functions including development, tissue repair, cell adhesion, migration, and proliferation. The expression of CCN1, cyclin D1, beta catenin, and p53 was explored by immunohistochemistry in different grades of ductal carcinoma in situ (DCIS) cases. These cases did not contain any infiltrating carcinoma components. In addition, all cysteine-rich protein 61 gene exons (encoding the CCN1 protein) were sequenced in 30 samples. Allred and H scores were calculated for expression in both DCIS and the surrounding benign breast tissue. All cases of DCIS showed degrees of cytoplasmic CCN1 staining with median H-scores of 170, 160, and 60 in grades 3, 2, and 1, respectively (P = .043). Twelve of 28 DCIS 3, 1 of 15 DCIS 2, and 0 of 18 DCIS 1 also showed nuclear staining for CCN1. The cytoplasmic staining difference was preserved when the cases were divided into estrogen receptor (ER)+/DCIS grade 1, ER+/DCIS 2 and 3, and ER-/DCIS 2 and 3 by the H-score (P = .037). Cyclin D1 expression was positively correlated with the CCN1 cytoplasmic H-score in all DCIS samples (P = .038). Membranous beta-catenin expression correlated with the grade of intraepithelial carcinoma by both H-score (P = .047) and Allred score (P = .026). Our results suggest that CCN1 has a role in the development of intraepithelial carcinoma. CCN1 expression correlates with grade of DCIS independent of ER status. It can induce cell cycle progression through cyclin D1. It is warranted to study high expression of CCN1 in DCIS as an independent risk factor in a larger cohort. PMID- 24767860 TI - Papillary renal cell carcinoma revisited: a comprehensive histomorphologic study with outcome correlations. AB - Papillary renal cell carcinoma (P-RCC) is the second most common type of malignant renal epithelial tumor and can be subclassified into type 1, which demonstrates simple cuboidal low-grade epithelium and type 2, which demonstrates pseudostratified high-grade epithelium with abundant eosinophilic cytoplasm. Despite this clinically useful subclassification, P-RCCs exhibit considerable histomorphologic diversity, with many cases having features differing from classically described type 1 and type 2 tumors. To our knowledge, there has been no recent study that has methodically evaluated the histomorphologic features of a series of P-RCCs. To address this, we evaluated a cohort of P-RCCs diagnosed between 1997 and 2004 with long-term clinical follow-up data (n = 56). Histomorphologic features previously described in the spectrum of type 1 and type 2 P-RCCs were recorded for each tumor, including nuclear grade, complete tumor capsule, and cytoplasmic eosinophilia as well as several other features. The current TNM staging (American Joint Committee on Cancer, seventh edition) was assigned to all cases. Histomorphologic features were diverse, demonstrating classic type 1 P-RCC and classic type 2 P-RCC morphology and several tumors with nonclassic features. Four patients in this cohort had distant metastasis. The primary tumor was equally divided between type 1 (2 cases) and type 2 (2 cases) morphology in the cases with metastasis. All P-RCC cases with metastases demonstrated presence of high nuclear grade and high tumor stage in the primary tumor. Cluster analysis using staging parameters and histomorphologic features divided tumors into 2 primary clusters. All primary tumors associated with metastasis were in the same cluster. PMID- 24767861 TI - TNFAIP8 overexpression is associated with platinum resistance in epithelial ovarian cancers with optimal cytoreduction. AB - Here, we correlated tumor necrosis factor alpha-induced protein 8 (TNFAIP8) messenger RNA (mRNA) expression with clinicopathological parameters and investigated the involvement of TNFAIP8 overexpression in platinum resistance of epithelial ovarian cancer (EOC). The status of TNFAIP8 protein was evaluated by Western blot analysis (n = 25) and immunohistochemistry (n = 134). TNFAIP8 mRNA expression was assessed with real-time polymerase chain reaction in fresh frozen EOC tissues (n = 40). TNFAIP8 overexpression at both mRNA and protein levels in platinum-resistant disease was clearly higher than that in platinum-sensitive disease (P < .05). Platinum resistance was independently correlated with residual tumor size (P = .025), ascites (P = .027), and TNFAIP8 overexpression (P = .003). In particular, TNFAIP8 overexpression was correlated with platinum resistance in EOCs with optimal cytoreduction (P = .001). TNFAIP8 mRNA expression was strongly associated with residual tumor size (P = .019). In conclusion, our findings indicate that TNFAIP8 overexpression is an independent predictor of platinum resistance and may be a potential biomarker for targeted therapy. PMID- 24767862 TI - BRAF/KRAS gene sequencing of sebaceous neoplasms after mismatch repair protein analysis. AB - Sebaceous neoplasms are cutaneous markers for the autosomal-dominant Muir-Torre syndrome (MTS). This phenotypic variant of Lynch syndrome (LS) is caused by germline mutations in DNA mismatch repair (MMR) genes. Microsatellite instability or loss of protein expression suggests a mutation or promoter hypermethylation in 1 of the MMR genes. BRAF gene sequencing may help to distinguish between patients with sporadic and LS-associated colorectal carcinomas with loss of MLH1 expression. LS-associated carcinomas are virtually negative for BRAF mutations, but a subset harbors KRAS mutations. The aim of our study was to test sebaceous neoplasms for V600E BRAF or KRAS mutations to determine if these mutations are associated with somatic or germline MMR defects, analogous to colorectal carcinomas. Over a 4-year period, 32 cases comprising 21 sebaceous adenomas, 3 sebaceomas, and 8 sebaceous carcinomas with sufficient material for testing were collected. MMR immunohistochemistry showed that 7 neoplasms had combined loss of MLH1-PMS2, 16 neoplasms had combined loss of MSH2-MSH6, 2 neoplasms had solitary loss of MSH6, and 7 sebaceous neoplasms had intact protein expression. BRAF/KRAS testing revealed all sebaceous neoplasms contained a wild-type BRAF gene. Two (15%) of 13 patients with MTS were found to harbor a KRAS mutation and loss of MLH1 expression. We conclude that a V600E BRAF mutation may not be helpful in distinguishing sporadic from MTS-associated sebaceous neoplasms. Further studies are needed to determine if KRAS mutations are restricted to patients with MTS or are also present in sporadic sebaceous neoplasms. PMID- 24767863 TI - Helicobacter pylori protein HP0986 (TieA) interacts with mouse TNFR1 and triggers proinflammatory and proapoptotic signaling pathways in cultured macrophage cells (RAW 264.7). AB - HP0986 protein of Helicobacter pylori has been shown to trigger induction of proinflammatory cytokines (IL-8 and TNF-alpha) through the activation of NF kappaB and also to induce Fas mediated apoptosis of human macrophage cells (THP 1). In this study, we unravel mechanistic details of the biological effects of this protein in a murine macrophage environment. Up regulation of MCP-1 and TNF alpha in HP0986-induced RAW 264.7 cells occurred subsequent to the activation and translocation of NF-kappaB to the cell nucleus. Further, HP0986 induced apoptosis of RAW 264.7 cells through Fas activation and this was in agreement with previous observations made with THP-1 cells. Our studies indicated activation of TNFR1 through interaction with HP0986 and this elicited the aforementioned responses independent of TLR2, TLR4 or TNFR2. We found that mouse TNFR1 activation by HP0986 facilitates formation of a complex comprising of TNFR1, TRADD and TRAF2, and this occurs upstream of NF-kappaB activation. Furthermore, FADD also forms a second complex, at a later stage, together with TNFR1 and TRADD, resulting in caspase-8 activation and thereby the apoptosis of RAW 264.7 cells. In summary, our observations reveal finer details of the functional activity of HP0986 protein in relation to its behavior in a murine macrophage cell environment. These findings reconfirm the proinflammatory and apoptotic role of HP0986 signifying it to be an important trigger of innate responses. These observations form much needed baseline data entailing future in vivo studies of the functions of HP0986 in a murine model. PMID- 24767864 TI - Oncostatin M acting via OSMR, augments the actions of IL-1 and TNF in synovial fibroblasts. AB - OBJECTIVE: To identify how the gp130-signaling cytokine oncostatin M (OSM), acting alone or in concert with IL-1beta or TNFalpha, affects synovial fibroblast expression of genes relevant to inflammation and bone erosion in inflammatory arthritis. METHODS: Synovial fibroblasts (SFs) were isolated from non-arthritic wild type (WT) or OSM receptor deficient (OSMR(-/-)) mice and stimulated with OSM, IL-1beta or TNFalpha and their combinations. Cytokine gene expression was assessed by quantitative RT-PCR. ELISA, flow cytometry and immunohistochemistry identified protein expression. Gene expression patterns were confirmed in SFs isolated from patients with osteoarthritis (OASFs) and rheumatoid arthritis (RASFs). RESULTS: Expression of OSM and its receptors, gp130, OSMR and LIFR, was increased in synovial tissue from the mouse antigen-induced arthritis model. In isolated WT mouse synovial fibroblasts OSM alone, or in synergy with IL-1beta, or together with TNFalpha, potently induced expression of the pro-inflammatory cytokine IL-6. OSM also induced a sustained increase in mRNA levels of the pro osteoclastic cytokine RANKL. Combining OSM with IL-1beta, but not with TNFalpha, further increased RANKL expression. Importantly these effects of OSM were all dependent on the expression of OSMR. Furthermore, OSM also increased expression of its own receptors, gp130 and OSMR and the IL-1 receptor, IL1-R1; the latter effects were also observed in both human OASFs and RASFs. CONCLUSION: Together our data suggests that OSM signaling via OSMR in SFs has the potential to contribute significantly to joint destruction in inflammatory arthritis. It not only induces expression of pro-inflammatory and pro-osteoclastic cytokines but can also augment its own actions and that of IL-1 by inducing expression of OSMR and IL-1R1. PMID- 24767865 TI - Comparative analyses of individual and multiple alterations of p53, PTEN and p16 in non-small cell lung carcinoma, glioma and breast carcinoma samples. AB - p53, p16 and PTEN are the most commonly altered tumor suppressor genes in human cancers. In the present study, we compared the presence of individual and multiple alterations of these tumor suppressors in non-small cell lung carcinoma (NSCLC), glioma and breast carcinoma, in order to evaluate specificity of each tumor type regarding the number of altered genes, as well as their combinations. We tested the mutational status, loss of heterozygosity and methylation status of these genes. Effects of gene alterations on patients' survival were also assessed. In NSCLC samples, single gene alterations occurred rarely, while there was considerable increase in incidence of double gene alterations. Furthermore, coexistence of aberrant p53, PTEN and p16 was the most frequent and had significant adverse effect on the survival of NSCLC patients. On the contrary, in glioma and breast cancer specimens, substantial number of cases had aberrant single gene only. Moreover, glioma and breast carcinoma also differ in genotypes that were predominant. Specifically, in glioma samples, prevalent were co alterations of PTEN and p16, followed by aberrant only PTEN. In breast cancer samples, alterations in all three genes as well as in p53 and p16 were the most common. Moreover, PTEN was altered exclusively with aberrant p53, with statistically significant correlation among them. Overall, our results suggest that NSCLC, glioma and breast cancer need different approaches in molecular diagnosis and treatment with particular attention toward the number and combination of targeted genes. PMID- 24767866 TI - Rhinovirus and the developing lung. AB - Human rhinovirus (HRV) infections are now widely accepted as the commonest cause of acute respiratory illnesses (ARIs) in children. Advanced PCR techniques have enabled HRV infections to be identified as causative agents in most common ARIs in childhood including bronchiolitis, acute asthma, pneumonia and croup. However, the long-term implications of rhinovirus infections are less clear. The aim of this review is to examine the relationship between rhinovirus infections and disorders of the lower airways in childhood. PMID- 24767867 TI - Oxygen toxicity. AB - Oxygen is one of the most widely available and used therapeutic agents in the world. However, it is all too easy forget that oxygen is a prescribable drug with specific biochemical and physiologic actions, a distinct range of effective doses and well-defined adverse effects at high doses. The human body is affected in different ways depending on the type of exposure. Short exposures to high partial pressures at greater than atmospheric pressure lead to central nervous system toxicity, most commonly seen in divers or in hyperbaric oxygen therapy. Pulmonary and ocular toxicity results from longer exposure to elevated oxygen levels at normal atmospheric pressure. PMID- 24767868 TI - Carriage of antibiotic-resistant Haemophilus influenzae strains in children undergoing adenotonsillectomy. AB - Haemophilus influenzae is one of the major pathogenic bacteria in upper respiratory tract of children. In this study, the presence of various H. influenzae genotypes were followed-up for at least 13 weeks, starting from one week before surgery. Forty-one children with chronic adenoid hypertrophy were prospectively enrolled to the study. The consecutive swabs of adenoid and tonsils, two before adenotonsillectomy and two after the surgery together with homogenates of adenotonsillar tissues and lysates of the CD14(+) cells fraction were acquired from 34 children undergoing adenotonsillectomy. Up to ten isolates from each patient at each collection period were genotyped using a PFGE method and their capsular type and antibiotic susceptibility was determined. Of the 1001 isolates examined, we identified 325 isolates grouped into 16 persistent genotypes, which colonized throats for more than seven weeks and were not eliminated by the surgery. The other 506 isolates grouped into 48 transient genotypes that had been eliminated by the surgery. The resistance to ampicillin were found in 23.8% of the transient strains, and 4.7% of the newly acquired strains following the surgical intervention. In contrast, none of the persistent strains were resistant to ampicillin; however, these strains showed apparently higher level of resistance to co-trimoxazole when compared to transient strains. The transient and persistent strains did not significantly differ in bacterial viability in the biofilms formed in vitro. Some of the strains were identified in two or three different patients and were considered as the strains circulating in the region between 2010 and 2012. PMID- 24767869 TI - A new approach in the design of electronic portal imaging devices for portal dosimetry in radiotherapy. AB - A CCD-based EPID using new crystal-assembly X-ray (CAX) converters is investigated for radiotherapy dosimetry. The proposed EPID design consists in replacing the common phosphor X-ray converters of current CCD-based EPIDs with high-stopping-power CAX converters. A Test Imaging Device (TID), consisting of a 30-mm-thick CAX converter made of Bismuth Germanate (BGO), coupled to a highly sensitive CCD camera, was used to evaluate the accessible imaging and dosimetric performance of the proposed design. The system response to dose and its dependence on photon beam energy were investigated. The effects of ghosting, dose rate, field size and phantom thickness were evaluated as well. The same measurements were also performed with our clinically used aSi-EPID so that comparisons of performance could be directly inferred. The TID displayed no detectable ghosting or sensitivity to dose rate. Its response to MU exposure was found to be linear within about +/-1%. The level of glare induced in the TID and the aSi-EPID were equivalent. The TID resolution was higher than that of the aSi EPID on the axis, but was found to decrease with off-axis distance. Finally, the image quality, assessed on the basis of signal-to-noise ratio in low dose radiographs of the larynx of a patient, was higher for the TID. The imaging performance accessible with the TID proved to be satisfying and its dosimetric capability was found to be superior to that of the current aSi-EPID. PMID- 24767870 TI - In the context of radiosurgery - pros and cons of rescanning as a solution for treating moving targets with scanned particle beams. AB - The treatment of mobile targets with scanned particle beams is challenging, and the effects of motion will be especially pronounced in hypo-fractionated treatment regimes due to the lack of statistical smoothing through fractionation and the prolonged delivery times per session. Therefore, motion mitigation techniques will play a major role for radiosurgery approaches. This article concentrates on the motion mitigation technique called rescanning. It alludes the existence of many scanning/rescanning flavors and raises awareness of the importance of an optimized flavor choice. Furthermore, it is discussed that rescanning can compensate for the lack of statistical wash-out, target dose conformity, however, will remain degraded. Therefore, especially in the context of radiosurgery, rescanning should be combined with other motion mitigation techniques like breath hold, gating and/or tracking. PMID- 24767871 TI - Microfluidic analysis of red blood cell deformability. AB - A common indicator of rheological dysfunction is a measurable decrease in the deformability of red blood cells (RBCs). Decreased RBC deformability is associated with cellular stress or pathology and can impede the transit of these cells through the microvasculature, where RBCs play a central role in the oxygenation of tissues. Therefore, RBC deformability has been recognized as a sensitive biomarker for rheological disease. In the current study, we present a strategy to measure RBC cortical tension as an indicator of RBC deformability based on the critical pressure required for RBC transit through microscale funnel constrictions. By modeling RBCs as a Newtonian liquid drop, we were able to discriminate cells fixed with glutaraldehyde concentrations that vary as little as 0.001%. When RBCs were sampled from healthy donors on different days, the RBC cortical tension was found to be highly reproducible. Inter-individual variability was similarly reproducible, showing only slightly greater variability, which might reflect biological differences between normal individuals. Both the sensitivity and reproducibility of cortical tension, as an indicator of RBC deformability, make it well-suited for biological and clinical analysis of RBC microrheology. PMID- 24767872 TI - Escalating burden of breast cancer in southern Thailand: analysis of 1990-2010 incidence and prediction of future trends. AB - BACKGROUND: Thailand is undergoing an epidemiologic transition, with decreasing incidence of infectious diseases and increasing rates of chronic conditions, including cancer. Breast cancer has the highest incidence rates among females both in the southern region Thailand and throughout Thailand. However, there is a lack of research on the epidemiology of this and other cancers. METHODS: Here we use cancer incidence data from the Songkhla Cancer Registry to characterize and analyze the incidence of breast cancer in Southern Thailand. We use joinpoint analysis, age-period-cohort models and nordpred analysis to investigate the incidence of breast cancer in Southern Thailand from 1990 to 2010 and project future trends from 2010 to 2029. RESULTS: We found that age-adjusted breast cancer incidence rates in Southern Thailand increased by almost 300% from 1990 to 2010 going from 10.0 to 27.8 cases per 100,000 person-years. Both period and cohort effects played a role in shaping the increase in incidence. Three distinct incidence projection methods consistently suggested that incidence rates will continue to increase in the future with incidence for women age 50 and above increasing at a higher rate than for women below 50. CONCLUSIONS: To date, this is the first study to examine Thai breast cancer incidence from a regional registry. This study provides a basis for future planning strategies in breast cancer prevention and to guide hypotheses for population-based epidemiologic research in Thailand. PMID- 24767873 TI - Plasmacytoid dendritic cell depletion in DOCK8 deficiency: rescue of severe herpetic infections with IFN-alpha 2b therapy. PMID- 24767874 TI - Comparison of rhinovirus antibody titers in children with asthma exacerbations and species-specific rhinovirus infection. AB - BACKGROUND: Asthma exacerbations are associated with human rhinovirus (HRV) infections, and more severe exacerbations are associated with HRV-C. We have previously shown that the HRV-C-specific antibody response is low in healthy adult sera and that most of the antibody to HRV-C is cross-reactive with HRV-A. OBJECTIVES: To compare the antibody response to each HRV species in asthmatic and nonasthmatic children in whom the type of HRV infection was known. METHODS: Total and specific IgG1 binding to HRV viral capsid protein antigens of HRV-A, -B, and C were tested in the plasma from nonasthmatic children (n = 47) and children presenting to the emergency department with asthma exacerbations (n = 96). HRV, found in most of the children at the time of their exacerbation (72%), was analyzed using molecular typing. RESULTS: Asthmatic children had higher antibody responses to HRV. The titers specific to HRV-A, and to a lesser extent HRV-B, were higher than in nonasthmatic controls. The species-specific responses to HRV C were markedly lower than titers to HRV-A and HRV-B in both asthmatic and nonasthmatic children (P < .001). The titers both at presentation and after convalescence were not associated with the HRV genotype detected during the exacerbation. CONCLUSIONS: The higher total anti-HRV antibody titers of asthmatic children and their higher anti-HRV-A and -B titers show their development of a heightened antiviral immune response. The low species-specific HRV-C titers found in all groups, even when the virus was found, point to a different and possibly less efficacious immune response to this species. PMID- 24767875 TI - Aspirin desensitization in patients with aspirin-induced and aspirin-tolerant asthma: a double-blind study. AB - BACKGROUND: Numerous open trials have demonstrated the beneficial clinical effects of aspirin desensitization (AD) in patients with aspirin-induced asthma (AIA). These beneficial effects might be attributable to aspirin's potent anti inflammatory properties, but that supposition requires further corroboration. OBJECTIVE: We sought to compare the clinical and biochemical responses to chronic oral AD in 20 patients with AIA and 14 patients with aspirin-tolerant asthma (ATA). All of the patients had chronic rhinosinusitis and nasal polyposis, and these responses were investigated in a pilot, double-blind, placebo-controlled study. METHODS: Twelve patients with AIA and 6 patients with ATA were randomly assigned to receive 624 mg of aspirin, and 8 patients with AIA and 8 patients with ATA received placebo. Both aspirin and placebo were administered once daily for 6 months. Nasal symptoms, Sino-Nasal Outcome Test (SNOT20) scores, peak nasal inspiratory flows, Asthma Control Questionnaire scores, spirometric parameters, peak expiratory flows, blood eosinophilia, and corticosteroid doses were assessed on a monthly basis. Levels of urinary leukotriene E4 and the stable plasma prostaglandin (PG) D2 metabolite 9alpha,11beta-PGF2 were evaluated at baseline and after 1, 3, 5, and 6 months. RESULTS: Only the patients with AIA subjected to AD reported improvements in smell and reductions in sneezing and nasal blockade. The SNOT20 and Asthma Control Questionnaire scores of these patients decreased, and their peak nasal inspiratory flows increased. The dosages of inhaled corticosteroids were reduced. There were no changes in leukotriene E(4) or 9alpha,11beta-PGF(2) levels after AD. CONCLUSION: The clinically beneficial effects of AD on nasal and bronchial symptoms occurred only in the patients with AIA. PMID- 24767876 TI - Diagnosis of immunodeficiency caused by a purine nucleoside phosphorylase defect by using tandem mass spectrometry on dried blood spots. AB - BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare form of autosomal recessive combined primary immunodeficiency caused by a enzyme defect leading to the accumulation of inosine, 2'-deoxy-inosine (dIno), guanosine, and 2'-deoxy-guanosine (dGuo) in all cells, especially lymphocytes. Treatments are available and curative for PNP deficiency, but their efficacy depends on the early approach. PNP-combined immunodeficiency complies with the criteria for inclusion in a newborn screening program. OBJECTIVE: This study evaluate whether mass spectrometry can identify metabolite abnormalities in dried blood spots (DBSs) from affected patients, with the final goal of individuating the disease at birth during routine newborn screening. METHODS: DBS samples from 9 patients with genetically confirmed PNP-combined immunodeficiency, 10,000 DBS samples from healthy newborns, and 240 DBSs from healthy donors of different age ranges were examined. Inosine, dIno, guanosine, and dGuo were tested by using tandem mass spectrometry (TMS). T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) levels were evaluated by using quantitative RT-PCR only for the 2 patients (patients 8 and 9) whose neonatal DBSs were available. RESULTS: Mean levels of guanosine, inosine, dGuo, and dIno were 4.4, 133.3, 3.6, and 3.8 MUmol/L, respectively, in affected patients. No indeterminate or false-positive results were found. In patient 8 TREC levels were borderline and KREC levels were abnormal; in patient 9 TRECs were undetectable, whereas KREC levels were normal. CONCLUSION: TMS is a valid method for diagnosis of PNP deficiency on DBSs of affected patients at a negligible cost. TMS identifies newborns with PNP deficiency, whereas TREC or KREC measurement alone can fail. PMID- 24767877 TI - Molecular targets on mast cells and basophils for novel therapies. AB - Mast cells and basophils (MCs/Bs) play a crucial role in type I allergy, as well as in innate and adaptive immune responses. These cells mediate their actions through soluble mediators, some of which are targeted therapeutically by, for example, H1- and H2-antihistamines or cysteinyl leukotriene receptor antagonists. Recently, considerable progress has been made in developing new drugs that target additional MC/B mediators or receptors, such as serine proteinases, histamine 4 receptor, 5-lipoxygenase-activating protein, 15-lipoxygenase-1, prostaglandin D2, and proinflammatory cytokines. Mediator production can be abrogated by the use of inhibitors directed against key intracellular enzymes, some of which have been used in clinical trials (eg, inhibitors of spleen tyrosine kinase, phosphatidylinositol 3-kinase, Bruton tyrosine kinase, and the protein tyrosine kinase KIT). Reduced MC/B function can also be achieved by enhancing Src homology 2 domain-containing inositol 5' phosphatase 1 activity or by blocking sphingosine 1-phosphate. Therapeutic interventions in mast cell-associated diseases potentially include drugs that either block ion channels and adhesion molecules or antagonize antiapoptotic effects on B-cell lymphoma 2 family members. MCs/Bs express high-affinity IgE receptors, and blocking their interactions with IgE has been a prime goal in antiallergic therapy. Surface-activating receptors, such as CD48 and thymic stromal lymphopoietin receptors, as well as inhibitory receptors, such as CD300a, FcgammaRIIb, and endocannabinoid receptors, hold promising therapeutic possibilities based on preclinical studies. The inhibition of activating receptors might help prevent allergic reactions from developing, although most of the candidate drugs are not sufficiently cell specific. In this review recent advances in the development of novel therapeutics toward different molecules of MCs/Bs are presented. PMID- 24767878 TI - Short-term prophylaxis in a patient with acquired C1-INH deficiency. PMID- 24767880 TI - Renal infarction versus pyelonephritis in a woman presenting with fever and flank pain. AB - Patients with fever, flank pain, and dysuria frequently are encountered in the emergency department. Acute pyelonephritis is the most likely diagnosis; however, its clinical and radiologic presentation consistently overlap with that of acute renal infarction. Ultrasound is unable to distinguish early infarction from nonabscessed acute pyelonephritis. Hence, computed tomography or magnetic resonance imaging are needed. We report the case of a 68-year-old woman who presented with fever, flank pain, and dysuria, along with respiratory distress and tachycardia. Elevated values for inflammatory indexes suggested a diagnosis of acute pyelonephritis, and subsequent contrast-enhanced computed tomography showed hypodense wedge-shaped areas in both kidneys. However, the presence of a thin rim of capsular enhancement (cortical rim sign), the absence of perirenal inflammatory changes, and the location of the lesions apart from defined calyces suggested the alternative diagnosis of renal infarction. The underlying cause was not identified until an episode of acute dyspnea revealed paroxysmal arrhythmia. Our case demonstrates that a thorough knowledge of the imaging findings of renal infarction and acute pyelonephritis is essential to correctly making the diagnosis. PMID- 24767879 TI - CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in the skin. AB - BACKGROUND: CCR10 and CCL27 make up the most skin-specific chemokine receptor/ligand pair implicated in skin allergy and inflammatory diseases, including atopic dermatitis and psoriasis. This pair is thought to regulate the migration, maintenance, or both of skin T cells and is suggested to be therapeutic targets for treatment of skin diseases. However, the functional importance of CCR10/CCL27 in vivo remains elusive. OBJECTIVE: We sought to determine the expression and function of CCR10 in different subsets of skin T cells under both homeostatic and inflammatory conditions to gain a mechanistic insight into the potential roles of CCR10 during skin inflammation. METHODS: Using heterozygous and homozygous CCR10 knockout/enhanced green fluorescent protein knockin mice, we assessed the expression of CCR10 on regulatory and effector T cells of healthy and inflamed skin induced by chemicals, pathogens, and autoreactive T cells. In addition, we assessed the effect of CCR10 knockout on the maintenance and functions of different T cells and inflammatory status in the skin during different phases of the immune response. RESULTS: CCR10 expression is preferentially induced on memory-like skin-resident T cells and their progenitors for their maintenance in homeostatic skin but not expressed on most skin-infiltrating effector T cells during inflammation. In CCR10 knockout mice the imbalanced presence and dysregulated function of resident regulatory and effector T cells result in over-reactive and prolonged innate and memory responses in the skin, leading to increased clearance of Leishmania species infection in the skin. CONCLUSION: CCR10 is a critical regulator of skin immune homeostasis. PMID- 24767881 TI - Insight facilitation with add-on tDCS in schizophrenia. AB - Impaired insight in schizophrenia patients has been linked with prefrontal deficits. In this open-label study, we examined for potential insight facilitation effects of add-on tDCS (with anodal stimulation of left DLPFC and cathodal stimulation over left temporo-parietal junction) in schizophrenia patients (N=21) with persistent auditory hallucinations despite adequate antipsychotic treatment. Following tDCS, there was a significant improvement in insight with concurrent significant reduction in auditory hallucination severity. Improvement in insight correlated significantly with improvement in severity of auditory hallucinations. These findings suggest improvement of insight with add on tDCS in schizophrenia with persistent auditory hallucinations. PMID- 24767882 TI - First international consensus guidelines for breast cancer in young women (BCY1). AB - The 1st International Consensus Conference for Breast Cancer in Young Women (BCY1) took place in November 2012, in Dublin, Ireland organized by the European School of Oncology (ESO). Consensus recommendations for management of breast cancer in young women were developed and areas of research priorities were identified. This manuscript summarizes these international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA). PMID- 24767883 TI - Invited review: Current representation and future trends of predicting amino acid utilization in the lactating dairy cow. AB - In current dairy production systems, an average of 25% of dietary N is captured in milk, with the remainder being excreted in urine and feces. About 60% of total N losses occur postabsorption. Splanchnic tissues extract a fixed proportion of total inflow of each essential AA (EAA). Those EAA removed by splanchnic tissues and not incorporated into protein are subjected to catabolism, with the resulting N converted to urea. Splanchnic affinity varies among individual EAA, from several fold lower than mammary glands' affinity for the branched-chain AA to similar or higher affinity for Phe, Met, His, and Arg. On average, 85% of absorbed EAA appear in peripheral circulation, indicating that first-pass removal is not the main source of loss. Essential AA in excess of the needs of the mammary glands return to general circulation. High splanchnic blood flow dictates that a large proportion of EAA that return to general circulation flow through splanchnic tissues. In association with this constant recycling, EAA are removed and catabolized by splanchnic tissues. This results in splanchnic catabolism equaling or surpassing the use of many EAA for milk protein synthesis. Recent studies have demonstrated that EAA, energy substrates, and hormones activate signaling pathways that in turn regulate local blood flow, tissue extraction of EAA, and rates of milk protein synthesis. These recent findings would allow manipulation of dairy diets to maximize mammary uptake of EAA and reduce catabolism by splanchnic tissues. Dairy cattle nutrient requirement systems consider EAA requirements in aggregate as metabolizable protein (MP) and assume a fixed efficiency of MP use for milk protein. Lysine and Met sufficiency is only considered after MP requirements have been met. By doing so, requirement systems limit the scope of diet manipulation to achieve improved gross N efficiency. Therefore, this review focuses on understanding the dynamics of EAA metabolism in mammary and splanchnic tissues that would lead to improved requirement prediction systems. Inclusion of variable individual EAA efficiencies derived from splanchnic and mammary responses to nutrient and hormonal signals should help reduce dietary protein levels. Supplementing reduced crude protein diets with individual EAA should increase gross N efficiency to more than 30%, reducing N excretion by the US dairy industry by 92,000 t annually. PMID- 24767884 TI - Transcriptional regulators transforming growth factor-beta1 and estrogen-related receptor-alpha identified as putative mediators of calf rumen epithelial tissue development and function during weaning. AB - Molecular mechanisms regulating rumen epithelial development remain largely unknown. To identify gene networks and regulatory factors controlling rumen development, Holstein bull calves (n=18) were fed milk replacer only (MRO) until 42 d of age. Three calves each were euthanized at 14 and 42 d of age for tissue collection to represent preweaning, and the remaining calves were provided diets of either milk replacer + orchard grass hay (MH; n=6) to initiate weaning without development of rumen papillae, or milk replacer + calf starter (MG; n=6) to initiate weaning and development of rumen papillae. At 56 and 70 d of age, 3 calves from the MH and MG groups were euthanized for collection of rumen epithelium. Total RNA and protein were extracted for microarray analysis and to validate detected changes in selected protein expression, respectively. As expected, calves fed MRO had no rumen papillae and development of papillae was greater in MG versus MH calves. Differentially expressed genes between the MRO diet at d 42 (preweaning) versus the MG or MH diets at d 56 (during weaning) were identified using permutation analysis of differential expression. Expression of 345 and 519 transcripts was uniquely responsive to MG and MH feeding, respectively. Ingenuity Pathway Analysis (Qiagen, Redwood City, CA) indicated that the top-ranked biological function affected by the MG diet was the cell cycle, and TFGB1, FBOX01, and PPARA were identified as key transcriptional regulators of genes responsive to the MG diet and associated with development of rumen papillae. Increased expressions of TGFB1 mRNA and protein in response to the MG diet were confirmed by subsequent analyses. The top-ranking biological function affected by the MH diet was energy production. Receptors for IGF-1 and insulin, ESRRA, and PPARD were identified by ingenuity pathway analysis as transcriptional regulators of genes responsive to the MH diet. Further analysis of TGFB1 and ESRRA mRNA expression in rumen epithelium obtained from a separate ontogenic study of Holstein calves (n=26) euthanized every 7d from birth to 42 d of age showed increases in transcript expression with advancing age, supporting their roles in mediating rumen epithelial development and function during weaning. Additional evaluation of gene expression in the rumen epithelium of adult cows ruminally infused with butyrate also suggested that observed changes in ESRRA mRNA expression in developing calf rumen may be mediated by increased butyrate concentration. Our results identify TGFB1 and ESRRA as likely transcriptional regulators of rumen epithelial development and energy metabolism, respectively, and provide targets for modulation of rumen development and function in the growing calf. PMID- 24767885 TI - Short communication: Expression of T-box 2 and 3 in the bovine mammary gland. AB - To increase our understanding of the mechanisms by which growth hormone (GH) and insulin-like growth factor (IGF)-I influence bovine mammary gland development, the potential roles of T-box2 (TBX2) and T-box3 (TBX3) were investigated. Although no information regarding expression of either transcription factor in the bovine mammary gland exists, it is known that TBX3 and its closely related family member, TBX2, are required for mammary gland development in humans and mice. Additionally, TBX3 mutations in humans and mice lead to ulnar mammary syndrome. Evidence is present in bone that TBX3 is required for proliferation and its expression is regulated by GH, an important regulator of mammary gland development and milk production. We hypothesized that TBX2 and TBX3 are expressed in the bovine mammary gland and that GH, IGF-I, or both increase TBX2 and TBX3 expression in bovine mammary epithelial cells (MEC). Bovine mammary gland tissue, MAC-T cells, primary MEC, and fibroblasts were obtained and TBX2 and TBX3 expression was determined by real-time reverse transcription PCR. In addition, TBX2 and TBX3 expression was examined in cells treated with 100 or 500 ng/mL of GH or 100 or 200 ng/mL of IGF-I for 24 or 48 h. Both TBX2 and TBX3 were expressed in bovine mammary tissue. Surprisingly, expression of TBX2 was only detected in mammary fibroblast cells, whereas TBX3 was expressed in all 3 cell types. Growth hormone did not alter TBX3 expression in MAC-T cells or MEC. However, IGF-I increased TBX3 expression in MAC-T, but not in primary MEC. We did not observe a change in TBX2 or TBX3 expression in fibroblasts treated with GH and IGF. Therefore, we concluded that (1) TBX2 and TBX3 are expressed in bovine mammary gland, (2) their expression is cell-type specific, and (3) IGF-I stimulates TBX3 expression in MAC-T cells. PMID- 24767886 TI - Antialcoholic liver activity of whey fermented by Lactobacillus casei isolated from koumiss. AB - Whey fermented liquid (WFL) was studied for its hepatoprotective effects by using chronic alcohol-induced mice. Whey fermented liquid, prepared by inoculating whey with 4% (vol/vol) Lactobacillus casei and then incubating at 41 degrees C for 8h, was used to orally treat alcohol-induced mice at 3 dosages for 5 wk. Ethanol consumption significantly reduced the activity of superoxide dismutase and glutathione peroxidase, while lowering glutathione content and increasing levels of aspartate aminotransferase, alanine aminotransferase, total triglyceride, malondialdehyde, and cytochrome P450 2E1. Treatment with WFL significantly attenuated the increased levels of alanine aminotransferase, aspartate aminotransferase, triglyceride, and cytochrome P450 2E1, while decreasing superoxide dismutase, glutathione peroxidase, malondialdehyde, and glutathione levels. Pathological changes in the livers of mice who had ingested alcohol were improved by the administration of WFL. These results suggest that WFL may exert a protective effect against alcoholic liver disease by increasing antioxidant activity, which supports the use of WFL as an antialcoholic liver disease treatment. PMID- 24767887 TI - Genetic correlations between claw health and feet and leg conformation in Norwegian Red cows. AB - The aim of this study was to estimate genetic correlations between claw disorders and feet and leg conformation traits in Norwegian Red cows. A total of 188,928 cows with claw health status recorded at claw trimming from 2004 to September 2013 and 210,789 first-lactation cows with feet and leg conformation scores from 2001 to September 2013 were included in the analyses. Traits describing claw health were corkscrew claw, infectious claw disorders (dermatitis, heel horn erosion, and interdigital phlegmon), and laminitis-related claw disorders (sole ulcer, white line disorder, and hemorrhage of sole and white line). The feet and leg conformation traits were rear leg rear view (new and old definition), rear leg side view, foot angle, and hoof quality. Feet and leg conformation traits were scored linearly from 1 to 9, with optimum scores depending on the trait. Claw disorders were defined as binary (0/1) traits for each lactation. Threshold sire models were used to model claw disorders, whereas the feet and leg conformation traits were described by linear sire models. Three multivariate analyses were performed, each including the 5 feet and leg conformation traits and 1 of the 3 claw disorders at a time. Posterior means of heritability of liability of claw disorders ranged from 0.10 to 0.20 and heritabilities of feet and leg conformation traits ranged from 0.04 to 0.11. Posterior standard deviation of heritability was <=0.01 for all traits. Genetic correlations between claw disorders and feet and leg conformation traits were all low or moderate, except between corkscrew claw and hoof quality (-0.86), which are supposed to measure the same trait. The genetic correlations between rear leg rear view (new) and infectious claw disorders (-0.20) and laminitis-related claw disorders (0.26), and between hoof quality and laminitis-related claw disorders (-0.33) were moderate. Eight of the 15 genetic correlations between claw disorders and feet and leg conformation traits had 0 included in the 95% highest posterior density interval. These results imply that selection for feet and leg conformation is not an efficient approach to genetically improve claw health in Norwegian Red cattle. PMID- 24767888 TI - Effect of supranutritional maternal and colostral selenium supplementation on passive absorption of immunoglobulin G in selenium-replete dairy calves. AB - Selenium (Se) is an essential micronutrient for ruminant animals affecting both performance and immune functions. Adding 3 mg of Se/L (in the form of Na selenite) to colostrum has been shown to improve IgG absorption in Se-deficient newborn dairy calves. The objective of our study was to determine the effect of supranutritional maternal and colostral Se supplementation on IgG status of Se replete dairy calves. The study design was a 2 * 2 * 2 factorial design. During the last 8 wk before calving, dairy cows at a commercial dairy were fed either 0 (control cows) or 105 mg of Se-yeast once weekly (supranutritional Se-yeast supplemented cows), in addition to Na selenite at 0.3 mg of Se/kg of DM in their ration. After birth, calves were fed pooled colostrum from control or supranutritional Se-yeast-supplemented cows to which 0 or 3 mg of Se/L (in the form of Na selenite) was added. Concentrations of whole-blood (WB) Se and serum Se measured at birth and at 48 h and 14 d of age, and serum IgG concentrations measured at 48 h and 14 and 60 d of age were determined. Calves born to Se-yeast supplemented cows had higher WB-Se and serum-Se concentrations for the first 2 wk, and higher IgG absorption efficiency (62% at 48 h), resulting in higher serum IgG concentrations (43% at 48 h and 65% at 14 d) and higher total serum-IgG content (50% at 48 h and 75% at 14 d), compared with calves born to control cows. Calves that received colostrum with added Na selenite had higher WB-Se concentrations for the first 2 wk, but only at 14 d of age were serum-Se concentrations, serum-IgG concentrations (53% higher), and total serum-IgG content (56% higher) higher, compared with calves that were fed colostrum without added Na selenite. Calves born to Se-yeast-supplemented cows that received colostrum from Se-yeast cows without added Na selenite had a higher IgG absorption efficiency compared with all other treatment groups. Our results support that feeding cows supranutritional Se-yeast supplement during the dry period or spiking colostrum with Na selenite both improve IgG status of Se replete calves. PMID- 24767889 TI - The effect of palatability of protein source on dietary selection in dairy calves. AB - Evidence has shown that soybean meal is perceived as more palatable than canola meal by dairy calves in short-term preference tests. This study evaluated the effect of protein source on longer-term dietary selection of dairy calves. In experiment 1, 40 Holstein bull calves (11.4 +/- 4.3 d of age) were randomly assigned to 1 of 2 choice diets for 6 wk: base starter pellet (S; 12% crude protein; CP) and high-protein pellet (40% CP) containing either (1) soybean meal (SB) or (2) canola meal (CM). In wk 7 to 8, all calves were offered a single pelleted diet containing the protein source to which they were previously exposed. In experiment 2, 22 Holstein bull calves (9.9 +/- 4.6d of age) were offered, for 6 wk, a choice of 2 mixed pelleted diets: (1) 70% S and 30% SB (SB mix), or (2) 70% S and 30% CM (CM mix). In wk 7 to 8, calves were randomly assigned to 1 of 2 choice diets, as in experiment 1: (1) SB + S, or (2) CM + S. All feeds were provided ad libitum. Calves received 6 L/d of milk replacer [0.75 kg/d of dry matter (DM)] for the duration of both experiments. Feed intake was recorded daily and calves were weighed every 14 d. Feeds were sampled weekly to analyze DM and nutrient intake. Mixed diets in experiment 2 were analyzed for CP in wk 4 and 6 to assess feed sorting (calculated as actual CP intake as a percentage of predicted intake). In experiment 1, calves offered SB + S in wk 1 to 6 consumed more high-protein pellet than calves offered CM + S [73 vs. 42% of DM intake (DMI)] and, consequently, more CP (168 vs. 117 g/d). Solid feed DMI and average daily gain were similar between treatments. When offered a single diet in wk 7 to 8, calves offered starter containing soybean meal increased intake to a greater extent than calves offered the starter containing canola meal. In experiment 2, calves preferred the SB mix to CM mix (preference ratio: 0.7). Calves consumed more CP than predicted from SB mix in wk 4 and 6 (108 +/- 2.0%), indicating that they were sorting in favor of SB. In contrast, calves consumed less CP than predicted from CM mix in wk 4 (81.48 +/- 4.1%), indicating that they were sorting against CM. When assigned to choice treatments in wk 7 to 8 of experiment 2, calves offered SB + S consumed more protein pellet than calves offered CM + S (81 vs. 31% DMI) and consumed more CP (378 vs. 196 g/d). Average daily gain was greater for calves offered SB + S but DMI was similar. Overall, these results suggest that dietary selection was influenced by innate feed preferences, and milk-fed calves may not be sensitive to protein imbalances in their diet. PMID- 24767890 TI - Short communication: Naturally sensitive Bacillus thuringiensis EG10368 produces thurincin H and acquires immunity after heterologous expression of the one-step amplified thurincin H gene cluster. AB - Heterologous expression of bacteriocin genetic determinants (or operons) has long been a research interest for the functional analysis of genes involved in bacteriocin biosynthesis, regulation, modification, and immunity. Previously, construction of genomic libraries of the bacteriocin producer strains was usually required to identify new bacteriocin operons, a method that is tedious and time consuming. For the first time, we directly amplified an 8.14-kb bioinformatically identified thurincin H gene cluster using a one-step PCR method with 100% accuracy. This amplified gene cluster was cloned into plasmid pHT315, resulting in plasmid pGW139, and subsequently transformed to Bacillus thuringiensis EG10368, a strain naturally sensitive to thurincin H. Heterologous expression of the gene cluster makes the sensitive B. thuringiensis EG10368 produce thurincin H at a higher level compared with the wild-type producer, B. thuringiensis SF361. Moreover, B. thuringiensis EG10368pGW139 acquired complete immunity to thurincin H. The results indicated that one-step PCR is a promising tool to accurately amplify long bacteriocin gene clusters used in bacteriocin functional analysis studies and it is an effective way to produce bacteriocins at a higher level, without the need to clone large chromosomal fragments. PMID- 24767891 TI - High-quality forage can replace concentrate when cows enter the deposition phase without negative consequences for milk production. AB - Mobilization and deposition in cows are different strategies of metabolism; hence, the aim was to study the possibility of reducing the crude protein (CP) supply during deposition to limit the use of protein supplements and minimize the environmental impact. A total of 61 Jersey and 107 Holstein cows were assigned to 4 mixed rations in a 2 * 2 factorial design with 2 concentrate to forage ratios (CFR) and 2 CP levels: high CFR (40:60) and recommended CP [16% of dry matter (DM); HCFR-RP], high CFR (40:60) and low CP (14% of DM; HCFR-LP), low CFR (30:70) and recommended CP (16% of DM; LCFR-RP), and low CFR (30:70) and low CP (14% of DM; LCFR-LP), where RP met the Danish recommendations. Cows were fed concentrate in an automatic milking unit. After calving, cows were fed HCFR-RP until entering deposition, defined as 11 kg (Jersey) or 15 kg (Holstein) of weight gain from the lowest weight after calving. Subsequently, cows either remained on HCFR-RP or changed to one of the other mixed rations. Comparing strategies during wk 9 to 30 of lactation showed higher dry matter intake (DMI) of mixed ration on HCFR compared with LCFR and on RP compared with LP. The DMI of the concentrate was higher on LCFR than on HCFR and higher on LP than on RP, resulting in overall higher DMI on HCFR and RP than on LCFR and LP. Crude protein intakes were higher on RP than on LP and starch intakes were higher on HCFR than on LCFR. Intakes of neutral detergent fiber tended to be higher on LCFR than on HCFR. Intakes of net energy for lactation were affected by CFR and CP level, with a higher intake on HCFR and RP than on LCFR and LP. No interactions were found between CFR and CP level for any feed intake variables. Yields of milk and energy-corrected milk were higher on RP than on LP, with no difference in yield persistency after the ration change. Milk composition did not differ among strategies but the protein to fat ratio was higher on HCFR than on LCFR and tended to be lower on RP than on LP. Differences in fatty acid composition were small, and de novo synthesis was high (>60%). Energy efficiency was higher on LCFR than on HCFR and no interaction with breed or parity was found. The N efficiency was higher on LP than RP, but with an interaction with breed due to lower N efficiency in Jersey than Holstein cows on HCFR-RP but higher N efficiency in Jersey than Holstein on LCFR-LP. In dairy production, concentrate in the mixed ration can be substituted with high quality forage during deposition without negative effects on milk yield and composition when a sufficient CP level is ensured. PMID- 24767893 TI - Intratumoral peripheral small papillary tufts: a diagnostic clue of renal tumors associated with Birt-Hogg-Dube syndrome. AB - In this article, we searched for the common histologic characteristic of renal tumors in patients with Birt-Hogg-Dube syndrome (BHDS). We selected 6 patients with histologically confirmed renal tumor in BHDS. Germline FLCN gene mutation has been identified in 5 patients. Multifocality and bilaterality of the renal tumors were pathologically or radiologically confirmed in 5 and 2 cases, respectively. Histologic subtypes of the dominant tumor included 3 previously described hybrid oncocytic tumors, one composite chromophobe/papillary/clear cell renal cell carcinoma (RCC) and one unclassified RCC resembling hybrid chromophobe/clear cell RCC. In one case, chromophobe RCC and clear cell RCC were separately observed. Small papillary lesions located in the peripheral area of the tumor, which we designated as intratumoral peripheral small papillary tufts, were identified in all patients. In conclusion, multifocality/bilaterality of renal tumors, discordance of histologic subtypes, and the presence of intratumoral peripheral small papillary tufts may be important clues to identify BHDS-associated renal tumors. PMID- 24767892 TI - Preliminary findings on the association between clients' perceived helpfulness of substance abuse treatment and outcomes: does race matter? AB - BACKGROUND: Few studies examine the helpfulness and effectiveness of substance abuse treatment from the clients' perspective. METHODS: The current secondary analysis examined the perceived helpfulness of substance abuse treatment components and its relationship to treatment outcomes among 387 Black and White adults participating in a multisite randomized clinical trial (RCT) of Motivational Enhancement Therapy. Throughout the 16-week RCT, participants self reported substance use. Upon completion of treatment, participants completed a self-report measure assessing the perceived helpfulness of treatment components. RESULTS: Black participants rated 9 out of 12 treatment components (e.g., "learning skills that will help me cope with my problems") as being more helpful than their White counterparts, even after controlling for age, gender, employment status, primary drug type, and treatment assignment. However, perceived helpfulness ratings were not associated with substance use outcomes among Black or White participants. CONCLUSIONS: Clients' perceived helpfulness of treatment components is an important factor to consider in improving the delivery of substance abuse treatment, especially for Black adults. PMID- 24767894 TI - Electronic expert consultation using digital still images for evaluation of atypical small acinar proliferations of the prostate: a comparison with immunohistochemistry. AB - This study was performed on a series of prostate needle biopsies with diagnosis of atypical small acinar proliferation (ASAP) to verify to what extent the application of immunohistochemistry (IHC) for p504s and p63 markers as well as expert consultation by still images could affect the diagnosis. The results of these 2 methods were compared. Immunohistochemistry staining for p504s and p63 was performed on sections from 42 patients with a primary diagnosis of ASAP. Meanwhile, digital still images were taken from hematoxylin and eosin-stained slides of cases and were sent to an expert uropathologist, blind to IHC staining interpretations. The results of IHC staining were compared with diagnostic interpretations of the consultant pathologist. In 13 cases, the focus of concern was not detectable on IHC slides. In the remaining 29 cases, IHC showed a benign and malignant expression pattern in 17 and 9 patients, respectively. In 3 cases, IHC findings were inconclusive and retained the diagnosis of ASAP. The consultant pathologist diagnosed 11 cases of benign and 7 cases of malignant processes. He retained the diagnosis of ASAP in 11 cases. There was high concordance between the results of IHC and electronic consultation in the group of benign cases. All 11 cases with the diagnosis of benignancy by electronic consultation showed a benign IHC pattern. Among 7 cases with the diagnosis of malignancy by the consultant pathologist, 5 were classified as malignant, 1 as benign, and 1 as inconclusive IHC groups. Considering problems with IHC staining of prostate needle biopsy, including loss of focus of interest, expert consultation using still images can provide very useful diagnostic information. This approach can be used as an adjunct to other diagnostic activities like IHC or even as an independent source of information to reach more accurate diagnoses in ASAP cases, particularly in institutions with limited resources. PMID- 24767895 TI - Livin, a novel marker in lymphoma type distinction. AB - Despite advances in immunohistochemical and molecular diagnostics, there are persistent difficulties in differentiating between several subtypes of non Hodgkin lymphoma (NHL) and classic Hodgkin lymphoma (CHL). Considering high level of livin expression in hematologic malignancies, we aimed to examine the utility of livin expression ratio, as an ancillary biomarker, in distinguishing CHL from NHL in ambiguous cases. We evaluated livin expression in 38 CHL, 23 NHL, and 39 nonneoplastic lymph nodes in paraffin-embedded blocks. Tissue microarray-based semiquantitative immunoflourecent staining was applied for protein expression. Criterion standard of diagnosis was based on selection of only definite cases and not the cases suspected by hemathopathologists. A significant difference was found in the livin/GAPDH mean ratio (M.R) of expression between NHL and CHL cases. A receiver operating characteristic curve analysis confirmed 0.6370 to be the best diagnostic cut-off value for the livin/GAPDH expression M.R in diffuse large B-cell lymphoma (DLBCL) (area under the curve = 0.944); it yielded 92% sensitivity, 94% specificity, likelihood ratios positive 17.5, and likelihood ratios negative 0.07 for diagnosing DLBCL from CHL. Mean ratio of livin/Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) expression seems to be a valuable index in differentiating DLBCL from CHL. We suggested an optimal cut-off point for livin/GAPDH expression M.R with a high sensitivity and specificity. Thus, in diagnostically difficult cases of DLBCL and CHL, focus on livin as marker may provide useful corroborative information. PMID- 24767896 TI - Sinus augmentation by orthodontic movement as an alternative to a surgical sinus lift: a clinical report. AB - Maxillary sinus pneumatization may significantly reduce the alveolar bone height. As a result, the sinus membrane may need to be apically repositioned, with or without grafts, before or at the time of implant placement. The sinus lift, however, is a relatively invasive surgical procedure that can lead to complications and sometimes unsuccessful results. This clinical report presents an orthodontic movement to enlarge the amount of bone at the sinus region for implant placement. The approach avoided surgery in a patient who used tobacco and exhibited recurrent sinusitis. PMID- 24767897 TI - Mini-implants as provisional anchorage for the replacement of missing anterior teeth: a clinical report. AB - This clinical report describes an adult patient referred for orthodontic treatment with mini-implants as anchorage to correct the root angulation of maxillary lateral incisors. The purpose of this report was to demonstrate the versatility of mini-implants placed in a vertical direction in esthetic areas. During orthodontic treatment, some aspects must be observed to preserve the interim restoration against the occlusal loads to avoid screw fracture. A fixed appliance was placed to correct the position of the maxillary anterior teeth and to complete the treatment. Acceptable esthetics and function were achieved. PMID- 24767898 TI - A method of assessing the effectiveness of the friction fit interface by measuring reverse torque. AB - STATEMENT OF THE PROBLEM: The connection between abutments and implants is fundamental to successful prosthetic rehabilitation, and the loosening or fracture of the parts are undesirable outcomes. PURPOSE: The purpose of this study was to measure the reverse torque values of 2 different types of Morse taper implants. MATERIAL AND METHODS: Ten Morse taper implants were used, with their respective abutments. They were divided into 2 groups (n = 5): Group DH, implant interface with a double hexagon and Group OI, octagonal implant interface. Each abutment received 2 consecutive insertion torques (32 Ncm) at a 10-minute interval and 1 reverse torque after 5 minutes. The data were analyzed with the Student t test (alpha= .05). RESULTS: The Student t test demonstrated no significant differences between the values of the insertion and removal torques of the 2 groups (Group DH, P= .22 and Group OI, P= .42) or the removal torque values of the groups (P= .12). CONCLUSION: The results suggest that the strength required to loosen the abutment screws as measured by reverse torque is similar for both a double hexagon interface (DH) and an octagonal interface (OI). PMID- 24767899 TI - Microhardness of light- and dual-polymerizable luting resins polymerized through 7.5-mm-thick endocrowns. AB - STATEMENT OF THE PROBLEM: The complete polymerization of luting resins through thick indirect restorations is still questioned. PURPOSE: The purpose of this study was to evaluate the degree of polymerization of light- and dual polymerizable luting resins under thick indirect composite resin and ceramic endocrowns by means of Vickers microhardness measurements. MATERIAL AND METHODS: The Vickers microhardness measurements of a light-polymerizable microhybrid composite resin and a dual-polymerizable luting cement directly polymerized in a natural tooth mold for 40 seconds with a high-power light-emitting diode lamp (control) were compared with measurements after indirect irradiation through 7.5 mm-thick composite resin and ceramic endocrowns for 3 * 90 seconds. A test-to control microhardness values ratio of 0.80 at a depth of 0.5 mm below the surface was assumed as the criterion for adequate conversion. RESULTS: For the Vickers microhardness measurements of a dual-polymerizable luting cement, no differences (P>.05) were found between Vickers microhardness control values and values reported after polymerization through composite resin and ceramic endocrowns. For The Vickers microhardness measurements (+/-SD) of a light-polymerizable microhybrid composite resin, control values were significantly (P<.05) higher (111 +/-3.3) than those reported after polymerization through composite resin (100.5 +/-3.8) and ceramic (99.7 +/-2.3) endocrowns. However, the hardness values of The Vickers microhardness measurements of a light-polymerizable microhybrid composite resin polymerized through the endocrowns were approximately 10% to 12% lower than those of the control values. Two-way ANOVA showed the influence of the luting material on the Vickers microhardness values (P<.05). The effect of endocrown material was not significant (P>.05). CONCLUSIONS: Under the conditions of this in vitro study, Vickers microhardness values of the dual-polymerizable resin cement and the light-polymerizable restorative composite resin irradiated for 3 * 90 seconds with a high irradiance light-emitting diode lamp through 7.5 mm-thick endocrowns reached at least 80% of the control Vickers microhardness values, which means that both materials can be adequately polymerized when they are used for luting thick indirect restorations. PMID- 24767900 TI - Periimplant bone-level reduction in relation to hydroxyapatite-coated dental implants that act as mandibular overdenture retainers: results at 6 to 10 years. AB - STATEMENT OF PROBLEM: Edentulism in combination with chronic alveolar ridge resorption can lead to a debilitating oral state which conventional complete dentures cannot alleviate. The provision of anterior mandibular implants positively contributes to both function and an improved quality of life for these patients. However, individuals who could most benefit from the treatment are usually older and more likely to have or develop serious health issues. PURPOSE: The purpose of the study was to assess the long-term success of one of the simpler implant treatments available and to consider the impact of a number of factors, including sex, age, health issues, and tobacco habits. This study also assessed the specific implant used, the Calcitek hydroxyapatite coated cylinder. MATERIAL AND METHODS: Forty-one patients who received 102 implants for mandibular overdenture retention from 1 operator between 1996 and 2002 were included in the study. Measurements were made from a series of radiographs to assess the effect of periimplant bone loss on surviving implants after a period of implant function of between 6 and 10 years. RESULTS: The loss of 1 implant lowered the survival rate to 99%. The overall annual bone loss observed was 0.16 mm/year. Individuals with a significant comorbidity exhibited a slight but significant increase in annual bone loss. CONCLUSIONS: The implant system in this study performed to an acceptable level in a mixed cohort of older individuals, including those with a serious comorbidity or tobacco habit. PMID- 24767901 TI - WITHDRAWN: Effect of post space conditioning and luting resin on the retentive strength of fiber-reinforced composite resin posts. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24767902 TI - Design concepts of a removable partial dental prosthesis with implant-supported abutments. AB - A clinical report is presented that describes the restoration of a severe anterior maxillary ridge defect and pneumatized sinuses with a rotation-path partial removable dental prosthesis and implant-supported abutments. Other treatment options were considered and rejected based on patient preferences and limitations, which included avoiding invasive surgeries. The principles of integrating fixed and removable prosthesis design were applied. However, the clasp design was modified to take into account the direct bone-to-implant contact of the abutments. An esthetic and functional outcome was obtained without any overly invasive surgery. PMID- 24767904 TI - Corneal pachymetry: new ways to look at an old measurement. PMID- 24767903 TI - The use of MDP-based materials for bonding to zirconia. AB - STATEMENT OF PROBLEM: A strong and stable bond between the luting resin and overlying ceramic restoration is critical to longevity, but no technique has been established for how to provide such a bond when the core material is zirconia. PURPOSE: The purpose of this study was to evaluate the effect of different materials containing 10-methacryloyloxydecyl dihydrogen phosphate (MDP) on the bond strength to yttria-tetragonal zirconia polycrystal (Y-TZP) ceramic. MATERIAL AND METHODS: Forty Y-TZP slices (Lava) were cemented to substrates (8 groups; n=5 in each) with or without the previous application of an experimental primer (0.5% MDP) or an MDP-based adhesive (Clearfil S3 Bond Plus or Scotchbond Universal) with either an MDP (Clearfil SA) or a non-MDP (RelyX Ultimate) luting resin. Specimens were cut, stored in distilled water, and microtensile tested (5 beams per specimen) at 48 hours and again at 6 months after luting procedures. The data were analyzed by 4-way ANOVA (alpha=.05) and the Tukey test (alpha=.05). The mode of failure was classified with a stereomicroscope, and the treated surfaces were analyzed with energy-dispersive x-ray spectroscopy. RESULTS: Both adhesive (P<.001) and time (P<.001) significantly affected bond strength. The interaction of any of the factors was not significant. The use of an MDP-containing adhesive and the shorter storage time were associated with higher bond strengths. At 48 hours, an overall incidence of 50.5% of Type 1 mode of failure (adhesive at ceramic/resin interface) occurred, as opposed to 68% after 6 months of water storage. Energy-dispersive x-ray spectroscopy results showed peaks of carbon and phosphorus when MDP-based materials were used. CONCLUSIONS: The application of an MDP-based adhesive may improve bond strength to zirconia. However, microtensile bond strength results for all groups did not remain stable over 6 months. PMID- 24767905 TI - Hydration of the anterior stroma in phacoemulsification cataract surgery. AB - We describe a simple technique to hydrate the anterior stroma in cataract surgery using a 30-gauge needle. At the end of phacoemulsification, the needle is inserted into the stroma to create a watertight seal of the clear corneal incision. PMID- 24767906 TI - Modification of Siepser sliding suture technique for iris repair and endothelial keratoplasty. AB - We describe a technique for closed-chamber iris repair that prevents knot and suture tail exposure into the anterior chamber. This modification of the Siepser sliding slipknot suture technique is particularly important in the setting of combined or future endothelial keratoplasty to prevent mechanical damage to donor endothelium during transplantation. PMID- 24767907 TI - Objective assessment of nuclear cataract: comparison of double-pass and Scheimpflug systems. AB - PURPOSE: To compare the objective assessment of lens density by 2 systems (double pass Optical Quality Analysis System and Pentacam Scheimpflug) in eyes with age related nuclear cataract. SETTING: Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. DESIGN: Cross-sectional study. METHODS: In eyes with age-related nuclear cataract, the objective lens density (0 to 100 points) was determined using the Scheimpflug system while subjective grading was achieved using the Lens Opacities Classification System III (LOCS III). The objective scatter index (OSI) (0 to 25) was assessed using the double-pass system. RESULTS: This study enrolled 47 patients (70 eyes). The mean OSI was 4.08 +/- 2.22 (SD), and the mean Scheimpflug-measured lens density was 16.44 +/- 4.36; the 2 parameters were correlated (r = 0.764, P<.01). There was a positive linear correlation between the OSI and LOCS III grading scores for nuclear opalescence and nuclear color (r = 0.772 and r = 0.752, respectively; P<.01). The cumulated dissipated energy (CDE) was strongly correlated with the OSI (r = 0.768) and Scheimpflug-measured lens density (r = 0.753). CONCLUSIONS: The OSI based on the double-pass system was correlated with the Scheimpflug-measured lens density, subjective lens grading, and CDE. The OSI may improve the preoperative evaluation of nuclear cataract and help predict phacodynamics in cataract surgery. PMID- 24767908 TI - Long-term outcomes of triamcinolone acetonide-assisted anterior vitrectomy during complicated cataract surgery with vitreous loss. AB - PURPOSE: To report the long-term outcomes of triamcinolone acetonide-assisted anterior vitrectomy during complicated cataract surgery with vitreous loss. SETTING: Tel Aviv Medical Center, Tel Aviv, Israel. DESIGN: Case series. METHODS: Consecutive patients who had triamcinolone acetonide-assisted anterior vitrectomy for complicated cataract surgery with vitreous loss between January 2010 and January 2012 were studied. The main outcome measures were the results of the ocular examination and spectral-domain optical coherence tomography of the macula at the last follow-up visit 12 months or more postoperatively. The ocular examination included corrected distance visual acuity (CDVA), intraocular pressure (IOP), and anterior segment and fundus biomicroscopy. RESULTS: The study included 15 patients (15 eyes) with a mean age of 71 years (range 50 to 92 years). The mean follow-up was 21 months (range 12 to 29 months). At the last follow-up, the mean CDVA was statistically significantly better than preoperatively (0.24 logMAR +/- 0.31 [SD] versus 0.89 +/- 0.81 logMAR) (P=.0033); all patients had improved CDVA over the preoperative values. Except for 1 patient with a macular scar, all the patients had a CDVA between 20/40 and 20/20. At last follow-up, 1 patient required 2 IOP-lowering medications that had been used preoperatively as well. The mean IOP was 15.3 +/- 2.4 mm Hg. There were no cases of residual vitreous strands in the anterior chamber, inflammatory reactions, triamcinolone acetonide crystals, retinal breaks, retinal detachment, or pseudophakic cystoid macular edema. CONCLUSION: Triamcinolone acetonide-assisted anterior vitrectomy during complicated cataract surgery with vitreous loss was safe and effective. PMID- 24767910 TI - C constant: new concept for ray tracing-assisted intraocular lens power calculation. AB - PURPOSE: To evaluate the accuracy of the C constant for ray tracing-assisted intraocular lens (IOL) power calculation. DESIGN: Case series. SETTING: Public university hospital and private clinic. METHODS: Preoperatively, all intraocular distances were measured using laser biometry. Various IOL designs were studied; powers ranged from -5.0 diopters (D) to +38.0 D. The IOL power calculation was performed with the Olsen formula using the C constant and compared with the Haigis, Hoffer Q, Holladay 1, and the SRK/T formulas on optimized datasets. Outcome measures were the error of the prediction, expressed as the arithmetic error, and the absolute error between the observed refraction and the predicted refraction. RESULTS: Two thousand forty-three cases from the 2 centers were studied. No significant differences were found between the Haigis, Hoffer Q, Holladay 1, and SRK/T formulas with the exception of the SRK/T formula, which performed better than the other thin-lens formulas in eyes with an axial length (AL) greater than 27.0 mm (P<.01). Compared with the SRK/T formula, the Olsen formula showed an improvement of 15% and 14% in the mean absolute error and a 39% and 85% reduction in the number of large errors (>1.0 D) for the 2 series, respectively (P<.0001). Contrary to the Olsen formula, all thin-lens formulas showed a significant bias in terms of the AL, keratometry reading, and anterior segment length (P<.0001). CONCLUSION: The C constant is a promising concept for ray tracing-assisted IOL power calculation. PMID- 24767909 TI - Repeatability of lens densitometry using Scheimpflug imaging. AB - PURPOSE: To evaluate the repeatability of different lens densitometry analysis modes performed with Scheimpflug imaging using the Pentacam HR device. SETTING: University eye hospital, Frankfurt am Main, Germany. DESIGN: Cross-sectional study. METHODS: Eyes were analyzed under mydriasis during 2 examinations performed by the same examiner. Three single measurements were taken to assess lens densitometry via 3 modes as follows: peak (maximum), linear (vertical axis), and 3-dimensional (3-D). Measurements were also taken using 3 cylindrical reference blocks (P) with different diameters (2.0 mm, 4.0 mm, 6.00 mm) composing the whole lens depth. Repeatability was tested using Bland-Altman analysis. As statistical parameters, the coefficient of repeatability (CoR) and the relative repeatability (RR) were applied. RESULTS: The study analyzed 105 eyes. The CoR of the peak modus was 5.6 (RR, 29.8%); of the linear modus, 0.9 (RR, 8.8%); and of the 3-D modus, 0.36 (RR, 3.6%). The values of the P mode were lower, with a CoR between 0.19 and 0.30 (RR, 2.1%-3.3%). CONCLUSIONS: Lens densitometry using Scheimpflug imaging was highly repeatable. However, repeatability was dependent on the analysis mode used. Repeatability decreased with increasing opacification. PMID- 24767911 TI - Cross-cultural validation of the National Eye Institute Visual Function Questionnaire. AB - PURPOSE: To assess the native and the previously Rasch-modified National Eye Institute Visual Function Questionnaire (NEI VFQ) scales in a Chinese population. SETTING: Eye Hospital of Wenzhou Medical University, Wenzhou, China. DESIGN: Questionnaire development. METHODS: Patients on the waiting list for cataract surgery completed the 39-item NEI VFQ (NEI VFQ-39). Rasch analysis was performed in 3 steps as follows: (1) Assess the psychometric properties of the original NEI VFQ. (2) Reassess the previously proposed Rasch-modified NEI VFQ scales by Pesudovs et al. (2010) in Chinese populations. (3) Compare the scores of previously recommended scales of the NEI VFQ with new Rasch-modified scales of the same questionnaire using Bland-Altman plots. RESULTS: Four hundred thirty five patients (median age 70 years; range 35 to 90 years) completed the NEI VFQ 39. Response categories for 4 question types were dysfunctional and therefore repaired. The original NEI VFQ-39 and NEI VFQ-25 showed good measurement precision. However, both versions showed multidimensionality, misfitting items, suboptimum targeting, and nonfunctioning subscales. Using the previously proposed Rasch-modified scales of the NEI VFQ yielded valid measurement of each construct in the 39-item and 25-item questionnaire. Comparison between the earlier proposed NEI VFQ scales and the new versions developed in this population showed good agreement. CONCLUSIONS: The original NEI VFQ was once again found to be flawed. The previously proposed Rasch-analyzed versions of the NEI VFQ and the new Chinese versions showed good agreement. PMID- 24767912 TI - Corneal wavefront-guided customized laser in situ keratomileusis after penetrating keratoplasty. AB - PURPOSE: To assess the efficacy and safety of corneal wavefront-guided custom laser in situ keratomileusis (LASIK) to correct refractive errors and higher order aberrations (HOAs) after penetrating keratoplasty (PKP). SETTING: Beyoglu Eye Training and Research Hospital, Istanbul, Turkey. DESIGN: Noncomparative case series. METHODS: The study comprised consecutive patients who were unable to tolerate spectacles or contact lenses for the correction of anisometropia after PKP and had corneal wavefront-guided custom LASIK. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, manifest refraction spherical equivalent (MRSE), and corneal HOAs were recorded before and after LASIK. RESULTS: The study evaluated 11 eyes (10 patients). The mean follow-up after LASIK was 24.3 months +/- 11.7 (SD) (range 9 to 36 months). The mean MRSE was 2.97 +/- 1.66 diopters (D) (range -0.50 to -5.38 D) preoperatively and -0.88 +/- 0.96 D (range -2.75 to 0.5 D) postoperatively. The mean total higher-order root mean square (RMS) was 4.65 +/- 1.14 MUm (range 2.26 to 5.94 MUm) preoperatively and 2.71 +/- 1.31 MUm (range 1.22 to 5.33 MUm) postoperatively. Postoperatively, the UDVA improved in 7 eyes and remained unchanged in 4 eyes. The CDVA improved in all eyes postoperatively even cases in which the attempted astigmatic correction was not totally achieved. CONCLUSIONS: Corneal wavefront-guided custom LASIK after PKP did not totally correct both refractive errors and HOAs because of the high volume of laser ablation required and inadequate corneal stromal thickness. PMID- 24767913 TI - Effect of phaco tip diameter on efficiency and chatter. AB - PURPOSE: To evaluate 3 phacoemulsification tips of different sizes and determine which size is most efficient in lens fragment removal using 3 ultrasound (US) approaches. SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Porcine lens nuclei were formalin-soaked for 2 hours then divided into 2.0 mm cubes; 1.1 mm, 0.9 mm, and 0.7 mm phaco tips were used with torsional and micropulsed US. The 1.1 mm tips were unavailable for torsional US, so 0.9 mm and 0.7 mm tips were used. Efficiency (amount of time for lens removal) and chatter (number of lens fragment repulsions from the tip) were determined. RESULTS: The mean phacoemulsification efficiency was highest with the 0.9 mm tip for all US variations. There were statistically significant differences between the 0.9 mm and 0.7 mm tips with micropulsed US (0.8 seconds +/- 0.29 [SD] versus 1.4 +/- 0.93 seconds; P=.0112) and transversal US (0.8 +/- 0.17 seconds versus 1.4 +/- 0.89 seconds; P=.0065). There was no significant difference between 0.9 mm and 0.7 mm tips with torsional US or between the 1.1 mm and 0.9 mm tips with micropulsed or transversal US; however, trends were identical, with 0.9 mm tips performing better than 0.7 mm and 1.1 mm tips. CONCLUSION: With all 3 systems, the 0.9 mm tip was most efficient, with the fewest outliers and smallest standard deviation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24767914 TI - Phacoemulsification efficiency with a radiused phaco tip. AB - PURPOSE: To evaluate radiused and nonradiused phacoemulsification tips to determine which tip is more efficient in removal of lens fragments using 3 ultrasound (US) modalities. SETTING: John A. Moran Eye Center Laboratories, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Porcine lens nuclei were formalin-soaked for 2 hours or 3 hours and then divided into 2.0 mm cubes. Thirty-degree, 0.9 mm beveled radiused tips and nonradiused tips were used with torsional, transverse, and micropulsed US modalities. Bent tips were used with torsional and transversal US, and straight tips were used with micropulsed US. Efficiency (time to lens removal) and chatter (number of lens fragment repulsions from the tip) were determined. RESULTS: The mean phacoemulsification efficiency was statistically significantly decreased (increased time for removal) with the radiused tip compared with the nonradiused tip for torsional US only (2-hour soaked lenses: 2.14 seconds +/- 1.94 [SD] versus 1.18 +/- 0.69 seconds [P < .05]; 3-hour soaked lenses: 5.07 +/- 4.2 seconds versus 2.52 +/- 1.99 seconds [P < .05]). There was no difference in chatter results. CONCLUSION: The radiused tip showed decreased efficiency with torsional US only. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24767915 TI - New device for creating a continuous curvilinear capsulorhexis. AB - PURPOSE: To describe the evolution of a new device to facilitate continuous curvilinear capsulorhexis (CCC) creation. SETTING: Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado, USA. DESIGN: Experimental study. METHODS: Bench-side ex vivo testing of unique prototypes for guidance and assistance of CCC in bovine and human eyes was performed. Five designs were sequentially tested as follows: a flexible circular blade of nickel titanium alloy (nitinol), a flexible nitinol guide wire, a flexible elastomeric suction device, a combination approach of a nitinol guide wire and flexible silicone ring, and a freestanding micropatterned silicone ring. RESULTS: The first 3 designs were not amenable to insertion through a sub-2.4 mm corneal incision and failed to maintain adequate downward force to cut the capsule and/or prevent radial tears. The fourth design was successfully inserted through a 2.4 mm incision and maintained adequate downward pressure and contact to guide a manual CCC without radial tears. The final design was insertable through a 2.4 mm incision and exhibited self-adhesive characteristics after placement on the anterior capsule of an ophthalmic viscosurgical device-filled anterior chamber. CONCLUSIONS: Given the steep learning curve of manual capsulorhexis and the high cost of capsulotomy-assistive devices, such as the femtosecond laser, an alternative approach for creating a CCC is desirable. Performance of a highly precise manual CCC through a small incision using a medical-grade silicone device with an adhesive micropatterned design is a viable and cost-effective option for use in cataract surgery across a wide range of user experience. FINANCIAL DISCLOSURE: All authors are named as the inventors in a patent filed by the University of Colorado covering the details in this report. PMID- 24767916 TI - Visualization of the macula during elective pars plana vitrectomy in the presence of a dual-optic accommodating intraocular lens. AB - We describe the case of a 69-year-old patient who had pars plana vitrectomy (PPV) for epiretinal membrane removal 18 months after cataract surgery with implantation of a dual-optic accommodating IOL (Synchrony). During PPV, visualization of the macula was perfect, and the postoperative visual outcome was excellent. To our knowledge, this is the first report of retinal visualization during PPV in the presence of a dual-optic accommodating IOL. When choosing a presbyopia-correcting IOL, surgeons should consider the advantage of macula visualization with an IOL with monofocal optics. FINANCIAL DISCLOSURE(S): Dr. Marques is a consultant to Abbott Medical Optics, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 24767917 TI - Clear lens extraction as treatment for uncontrolled primary angle-closure glaucoma. PMID- 24767918 TI - Age of cataract extraction in post-refractive surgery patients. PMID- 24767919 TI - Optimizing the cataract order of the list in modern surgery. PMID- 24767920 TI - May consultation #2. PMID- 24767921 TI - Cataract Surgical Problem: May consultation #1. PMID- 24767922 TI - May consultation #3. PMID- 24767923 TI - May consultation #4. PMID- 24767924 TI - May consultation #5. PMID- 24767925 TI - May consultation #6. PMID- 24767926 TI - May consultation #7. PMID- 24767927 TI - May consultation #8. PMID- 24767928 TI - Reply: To PMID 23871556. PMID- 24767929 TI - Correction factor for ablation algorithms considering decentration and transition zones. PMID- 24767930 TI - Reply: To PMID 24355716. PMID- 24767931 TI - Is this really sutureless scleral intraocular lens fixation? PMID- 24767932 TI - Intraoperative miosis in femtosecond laser-assisted cataract surgery. PMID- 24767933 TI - Reply: To PMID 24355719. PMID- 24767934 TI - Sutureless intrascleral posterior chamber intraocular lens fixation. PMID- 24767935 TI - Reply: To PMID 24461497. PMID- 24767936 TI - On/off switching of capillary vessel flow controls mitochondrial and glycolysis pathways for energy production. AB - Capillary vessel flow in the base of the fingernail can be observed by microscopy. This flow is switched off under some conditions, such as coldness, surprise, and anger and is switched on again under other conditions, such as warming, relaxation, and mild exercise. In other words, capillary vessels perform two functions: switching flow on and off. It is speculated that the switch-off function is necessary to direct energy production to the glycolysis pathway, while the switch-on function is necessary for the mitochondrial pathway. This is because glycolysis takes place under anaerobic conditions, while oxidative phosphorylation in the mitochondria proceeds under aerobic conditions in the body. To switch off circulation, the negative electric charges on the surface of erythrocytes and the capillary wall may be decreased by stimulation of the sympathetic nerves and secretion of steroid hormones. Negative charge usually acts as repulsive force between erythrocytes and between erythrocytes and the capillary wall. By decreasing the negative charge, erythrocytes can aggregate and also adhere to the capillary wall. These behaviors may be related to the capillary flow switch-off function. Here, it is emphasized that the capillary vessels possess not only a switch-on function but also a switch-off function for circulation. PMID- 24767937 TI - Possible link between right ventricular coronary sinusoids and noncompaction sinusoids in pulmonary atresia with intact ventricular septum patients that later develop left ventricular noncompaction. AB - Patients who have pulmonary atresia with intact ventricular septum have been shown to have a number of various myocardium anomalies like ischemia, fibrosis, infarction, rupture, disarray, spongious myocardium and ventricular endocardial fibroelastosis. Multiple connections have been found between right ventricular myocardial sinusoids and small branches of intramural coronary arteries. Noncompation of ventricular myocardium has been shown to be the result of myocardial ischemia or excessive pressure preventing the reduction of embryonic sinusoids. The persistence of intertrabecular recesses that are connected to both the ventricular cavity and coronary circulation is the result of this process. In this text, we describe a PA-IVS patient who underwent patent ductus arteriosus stenting and pulmonary valve perforation to create antegrade flow and later developed left ventricular noncompaction. We posit that there is a connection between right ventricular coronary sinusoids and noncompaction sinusoids. As our patient's RV outflow tract stenosis and RV pressure increased, the coronary circulation connected to coronary sinuses became sufficient and LV function improved, which further supports our hypothesis. PMID- 24767938 TI - That which does not kill us makes us stronger--does Nietzsche's quote apply to islets? A re-evaluation of the passenger leukocyte theory, free radicals, and glucose toxicity in islet cell transplantation. AB - In clinical islet transplantation, isolated islets are embolized into the liver via the portal vein (PV); however, up to 70% of the islets are lost in the first few days after transplantation (i.e., too quickly to be mediated by the adaptive immune system). Part of early loss is due to instant blood-mediated inflammatory reaction, an immune/thrombotic process caused by islets interacting with complement. We have shown that glucose toxicity (GT) also plays a critical role based upon the observation that islets embolized into the PVs of diabetic athymic mice are rapidly lost but, if recipients are not diabetic, the islet grafts persist. Using donor islets resistant to the beta-cell toxin streptozotocin, we have shown that intraportal islets engrafted in non-diabetic athymic mice for as little as 3 days will maintain normoglycemia when streptozotocin is administered destroying the recipient's native pancreas beta-cells. What is the mechanism of GT in beta-cells? Chronic exposure to hyperglycemia over-exerts beta-cells and their electron transport chains leak superoxide radicals during aerobic metabolism. Here we reinterpret old data and present some compelling new data supporting a new model of early intraportal islet graft loss. We hypothesize that diabetes stimulates overproduction of superoxide in both the beta-cells of the islet grafts and the endothelial cells lining the intraportal microvasculature adjacent to where the embolized islets become lodged. This double dose of oxidant damage stresses both the islets, which are highly susceptible to free radicals because of inherent low levels of scavenging enzymes, and the adjacent hepatic endothelial cells. This, superimposed upon localized endothelial damage caused by embolization, precipitates inflammation and coagulation which further damages islet grafts. Based upon this model, we predict that pre-exposing islets to sub lethal hyperoxia should up-regulate islet free radical scavenging enzyme levels and promote initial engraftment; reinterpretation of 30 years old "passenger leukocyte" data and preliminary new data support this. Other data suggests that pre-exposure of recipients to hyperoxia could up-regulate antioxidant enzymes in the hepatic endothelium. The combination of both effects could markedly enhance early intraportal islet graft survival and engraftment. Finally, if our model is correct, current in vitro and in vivo tests used to test batches of harvested islets for viability and function prior to transplantation are poorly conceived (n.b., it is already well-known that results using these tests often do not predict clinical islet transplantation success) and a different testing paradigm is suggested. PMID- 24767939 TI - Big brains, meat, tuberculosis and the nicotinamide switches: co-evolutionary relationships with modern repercussions on longevity and disease? AB - Meat eating has been an important trigger for human evolution however the responsible component in meat has not been clearly identified. Here we propose that the limiting factors for expanding brains and increasing longevity were the micronutrient nicotinamide (vitamin B3) and the metabolically related essential amino-acid, tryptophan. Meat offers significant sourcing challenges and lack causes a deficiency of nicotinamide and tryptophan and consequently the energy carrier nicotinamide adenine dinucleotide (NAD) that gets consumed in regulatory circuits important for survival, resulting in premature ageing, poor cognition and brain atrophy. If a trophic supply of dietary nicotinamide/tryptophan is so essential for building brains, constraining their size and connectivity, we hypothesise that back-up mechanisms to ensure the supply evolved. One strategy may be increasing the reliance on gut symbionts to break down celluloses that produces NADH and only nicotinamide indirectly, and may cause diarrhoea. We suggest that a direct supplier was the chronic mycobacterial infection tuberculosis (TB) that is a surprise candidate but it co-evolved early, does not inevitably cause disease (90-95% of those infected are healthy), and secretes (and is inhibited by) nicotinamide. We hypothesise that TB evolved first as a symbiont that enabled humans to cope with short-lived shortages of meat and only later behaved as a pathogen when the supply deteriorated chronically, for those in poverty. (TB immunology and epidemiology is riddled with paradoxes for a conventional pathogen). We test this in pilot data showing that sharp declines in TB (and diarrhoea) - 'environmental enteropathy' strongly correlate with increasing meat consumption and therefore nicotinamide exposure, unlike later onset cancers and Parkinson's disease that increased in incidence, perhaps - as we propose a hypothetical hypervitaminosis B3 (to include obesity and the metabolic syndrome) - as the trade-off for increased brain power and longevity, a recently evolved human characteristic. PMID- 24767940 TI - Statin therapy may prevent development of tuberculosis in diabetic state. AB - Host cholesterol is widely getting recognized as an important factor in the pathogenesis of tuberculosis in multiple ways. Therefore it is logically expected that cholesterol reduction by statins is going to have a positive outcome in the context of tuberculosis management. But at the present moment statin therapy in non diabetic individuals is believed to pose a small risk for development of diabetes mellitus, a prevalent disease throughout the globe that is known to be associated with tuberculosis infection. Consequently, in diabetic individuals statins are commonly prescribed drugs for multiple positive outcomes. Therefore it seems that statin therapy in diabetes mellitus has the potential to prevent the increased occurrence of tuberculosis in diabetic state. PMID- 24767941 TI - The prostatic urethra as a Venturi effect urine-jet pump to drain prostatic fluid. AB - Several experiments show that prostatic fluid is continuously produced and it is drained from the prostate during urination and ejaculation. The mechanism which causes prostatic fluid to drain from the prostatic acini during urination is currently unclear. Also in current opinion such structures of the prostatic urethra as the urethral crest and the colliculus seminalis have no apparent functional significance. This article describes a mechanism for the draining of the prostatic acini that involves these prostatic urethral structures. It is hypothesized that the prostatic urethra works as a pump using the Venturi effect, in which urine is the carrying or motive liquid during voiding, in order to drain prostatic fluid (the carried liquid) from the acini. The urethral crest and the colliculus seminalis take part in controlling flow rates and liquid pressures for this pump to be effective. The calculated estimation of a pressure drop in the region of the colliculus seminalis during micturition was obtained using morphometric and uroflowmetric data and was used to confirm this hypothesis of prostatic acini drainage. As a consequence of this, a previously unknown function for these intra-prostatic urethral structures is described. PMID- 24767942 TI - Dual effects of miR-155 on macrophages at different stages of atherosclerosis: LDL is the key? AB - Atherosclerosis is a chronic, maladaptive, nonresolving inflammatory response which underlies the leading cause of death in the world today. During the process, macrophages play a central role in both the initiation and development stages of disease pathogenesis. MicroRNAs are a class of small non-coding RNAs that regulate almost all biological processes. MiR-155 is multi-target molecule specifically expressed in atherosclerotic plaques and pro-inflammatory macrophages. However, the effects of miR-155 on atherogenesis have been controversial. Several lines of evidence collectively indicated that, both as inducers and carriers of miR-155, LDL and its oxidized derivatives could modulate miR-155-mediated inflammatory and apoptotic responses in lesional macrophages at different stages of atherosclerosis. During early lesion formation, both native and mildly-oxidized LDL facilitated endogenous miR-155-mediated macrophage activation and recruitment. In the meantime, they may also increase the accumulation of exogenous LDL-bound miR-155, along with lipid intake and foam cell formation. During advanced stages, the levels of exogenous miR-155 and extensively-oxidized LDL could gradually increase and become highly enough to synergistically induce macrophage apoptosis and atheroma formation. Taken together, we hypothesized that native LDL and oxidized LDL played a key role in modulating the effects of miR-155 on macrophages at different stages of atherosclerosis. PMID- 24767944 TI - New insights and challenges in mismatch repair: getting over the chromatin hurdle. AB - DNA mismatch repair (MMR) maintains genome stability primarily by repairing DNA replication-associated mispairs. Because loss of MMR function increases the mutation frequency genome-wide, defects in this pathway predispose affected individuals to cancer. The genes encoding essential eukaryotic MMR activities have been identified, as the recombinant proteins repair 'naked' heteroduplex DNA in vitro. However, the reconstituted system is inactive on nucleosome-containing heteroduplex DNA, and it is not understood how MMR occurs in vivo. Recent studies suggest that chromatin organization, nucleosome assembly/disassembly factors and histone modifications regulate MMR in eukaryotic cells, but the complexity and importance of the interaction between MMR and chromatin remodeling has only recently begun to be appreciated. This article reviews recent progress in understanding the mechanism of eukaryotic MMR in the context of chromatin structure and dynamics, considers the implications of these recent findings and discusses unresolved questions and challenges in understanding eukaryotic MMR. PMID- 24767943 TI - The endogenous exposome. AB - The concept of the Exposome is a compilation of diseases and one's lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or occupational exposures; or endogenous chemicals that are formed from normal metabolism, inflammation, oxidative stress, lipid peroxidation, infections, and other natural metabolic processes such as alteration of the gut microbiome. In this review, we have focused on the endogenous exposome, the DNA damage that arises from the production of endogenous electrophilic molecules in our cells. It provides quantitative data on endogenous DNA damage and its relationship to mutagenesis, with emphasis on when exogenous chemical exposures that produce identical DNA adducts to those arising from normal metabolism cause significant increases in total identical DNA adducts. We have utilized stable isotope labeled chemical exposures of animals and cells, so that accurate relationships between endogenous and exogenous exposures can be determined. Advances in mass spectrometry have vastly increased both the sensitivity and accuracy of such studies. Furthermore, we have clear evidence of which sources of exposure drive low dose biology that results in mutations and disease. These data provide much needed information to impact quantitative risk assessments, in the hope of moving towards the use of science, rather than default assumptions. PMID- 24767945 TI - Holliday junction resolution: regulation in space and time. AB - Holliday junctions (HJs) can be formed between sister chromatids or homologous chromosomes during the recombinational repair of DNA lesions. A variety of pathways act upon HJs to remove them from DNA, in events that are critical for appropriate chromosome segregation. Despite the identification and characterization of multiple enzymes involved in HJ processing, the cellular mechanisms that regulate and implement pathway usage have only just started to be delineated. A conserved network of core cell-cycle kinases and phosphatases modulate HJ metabolism by exerting spatial and temporal control over the activities of two structure-selective nucleases: yeast Mus81-Mms4 (human MUS81 EME1) and Yen1 (human GEN1). These regulatory cycles operate to establish the sequential activation of HJ processing enzymes, implementing a hierarchy in pathway usage that ensure the elimination of chromosomal interactions which would otherwise interfere with chromosome segregation. Mus81-Mms4/EME1 and Yen1/GEN1 emerge to define a special class of enzymes, evolved to satisfy the cellular need of safeguarding the completion of DNA repair when on the verge of chromosome segregation. PMID- 24767946 TI - Reprint of "Functional overlaps between XLF and the ATM-dependent DNA double strand break response". AB - Developing B and T lymphocytes generate programmed DNA double strand breaks (DSBs) during the V(D)J recombination process that assembles exons that encode the antigen-binding variable regions of antibodies. In addition, mature B lymphocytes generate programmed DSBs during the immunoglobulin heavy chain (IgH) class switch recombination (CSR) process that allows expression of different antibody heavy chain constant regions that provide different effector functions. During both V(D)J recombination and CSR, DSB intermediates are sensed by the ATM dependent DSB response (DSBR) pathway, which also contributes to their joining via classical non-homologous end-joining (C-NHEJ). The precise nature of the interplay between the DSBR and C-NHEJ pathways in the context of DSB repair via C NHEJ remains under investigation. Recent studies have shown that the XLF C-NHEJ factor has functional redundancy with several members of the ATM-dependent DSBR pathway in C-NHEJ, highlighting unappreciated major roles for both XLF as well as the DSBR in V(D)J recombination, CSR and C-NHEJ in general. In this review, we discuss current knowledge of the mechanisms that contribute to the repair of DSBs generated during B lymphocyte development and activation with a focus on potential functionally redundant roles of XLF and ATM-dependent DSBR factors. PMID- 24767948 TI - Comparison of counter-current chromatography and preparative high performance liquid chromatography applied to separating minor impurities in drug preparations. AB - Drug impurity profiling and identification are carried out along with the drug discovery process. Due to its inherent low concentration in drug products, the isolation and purification of impurities present a challenge to drug development processes. In our development of honokiol and quercetin as anticancer drug candidates, counter-current chromatography (CCC) and preparative HPLC were used for the impurity profiling and identification of honokiol and quercetin. Several performance parameters such as separation column volume, maximum sample loading, separation time, solvent consumption and sample throughput were investigated in order to compare the separation efficiency. We found that the sample loading capacity and therefore the throughput of preparative HPLC were not satisfactory, while CCC provided larger sample loading (especially for a sample with poor solubility), consumed less solvent and produced higher throughput than preparative HPLC. Six impurities of honokiol including one new compound were isolated in the present work. PMID- 24767947 TI - The contribution of dormant origins to genome stability: from cell biology to human genetics. AB - The ability of a eukaryotic cell to precisely and accurately replicate its DNA is crucial to maintain genome stability. Here we describe our current understanding of the process by which origins are licensed for DNA replication and review recent work suggesting that fork stalling has exerted a strong selective pressure on the positioning of licensed origins. In light of this, we discuss the complex and disparate phenotypes observed in mouse models and humans patients that arise due to defects in replication licensing proteins. PMID- 24767949 TI - Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy. AB - The nuclear retinoid X receptor agonist, bexarotene, has been implicated in recovery of cognitive function in mouse models of Alzheimer's disease (AD). Since AD genetic mouse models also show abnormal neural hyperexcitability, which may play a destructive role in memory storage and retrieval, we studied whether bexarotene exerted dynamic network effects on electroencephalography cortical spike discharge rate and spectral frequency in an AD (hAPP J20 model) and non-AD (Kv1.1 null) mouse models of epilepsy. We find that oral treatment with bexarotene over 1 week acutely reduced spike discharges in both models and seizures in the Kv1.1 null mouse model without major alterations in the background frequency of brain rhythms. The effect was reversible and exhibited a similar rapid onset in hippocampal slices. While the exact mechanisms are unknown, bexarotene counteracts both amyloid-beta-induced and amyloid-beta independent increases in cortical network hyperexcitability. PMID- 24767950 TI - Longitudinal assessment of default-mode brain function in aging. AB - Age-related changes in the default-mode network (DMN) have been identified in prior cross-sectional functional magnetic resonance imaging studies. Here, we investigated longitudinal change in DMN activity and connectivity. Cognitively intact participants (aged 49-79 years at baseline) were scanned twice, with a 6 year interval, while performing an episodic memory task interleaved with a passive control condition. Longitudinal analyses showed that the DMN (control condition > memory task) could be reliably identified at both baseline and follow up. Differences in the magnitude of task-induced deactivation in posterior DMN regions were observed between baseline and follow-up indicating reduced deactivation in these regions with increasing age. Although no overall longitudinal changes in within-network connectivity were found across the whole sample, individual differences in memory change correlated with change in connectivity. Thus, our results show stability of whole-brain DMN topology and functional connectivity over time in healthy older adults, whereas within-region DMN analyses show reduced deactivation between baseline and follow-up. The current findings provide novel insights into DMN functioning that may assist in identifying brain changes in patient populations, as well as characterizing factors that distinguish between normal and pathologic aging. PMID- 24767951 TI - Can total knee arthroplasty be safely performed among nonagenarians? An evaluation of morbidity and mortality within a total joint replacement registry. AB - As the nonagenarian patient population continues to grow, more patients aged 90 and over will become candidates for total knee arthroplasty (TKA). This study evaluated the patient characteristics and incidence of postoperative morbidity and mortality of 216 nonagenarian TKA patients among 81,835 primary TKA patients followed by a total joint replacement registry. Nonagenarians had a greater number of comorbidities preoperatively, experienced a higher rate of deep vein thrombosis and 30 day mortality, and had a longer hospital length of stay. However, nonagenarians did not have an increased risk of infection nor pulmonary embolism and postoperative mortality was within expected rates for individuals 90 years and older. Higher readmission rates, however, highlight the benefits of close follow up during a prolonged postoperative period. PMID- 24767952 TI - Impact of short periods with worsened or improved INR control on life expectancy and QALYs in patients with atrial fibrillation. AB - INTRODUCTION: Warfarin-treated patients with poor international normalized ratio (INR) control, measured with time in therapeutic range (TTR) or the standard deviation of transformed INR (SDTINR), have an increased risk for clinical events. To what extent only a short period with an altered INR control may influence outcomes remains unknown. This study assessed the impact of transient periods of worsened or improved INR control on life expectancy and quality adjusted life years (QALYs) among warfarin-treated patients with atrial fibrillation (AF) using both metrics. MATERIALS AND METHODS: Warfarin-treated patients with AF, registered in the patient record system Journalia during years 1985-2000, were included. Information on all-cause mortality was collected from the Cause of Death Register. Hypothetical scenarios where patients were assumed to have a transiently altered INR control during 30days were modeled statistically using hazard functions, and the impact on remaining life expectancy and QALYs was assessed. RESULTS: When using SDTINR, a 70-year old man within the 20th best INR control percentile was estimated to lose 7.4days of life or 0.0100 QALYs from a 30-day long worsened INR control to that of an average 70-year old male patient. Correspondingly, 4.0days of life or 0.0059 QALYs would be gained if a 70-year old man within the 20th worst INR control percentile would have an average INR control during 30days. The magnitudes were smaller when TTR was used to determine INR control. CONCLUSIONS: Even short periods of an altered INR control is expected to have impact on life expectancy and QALYs among patients with AF. PMID- 24767953 TI - Platelets and migraine. AB - The pathogenesis of migraine, the third most frequent disease worldwide, is complex and multifaceted. Recent evidence suggests that this condition should be considered as a primary neurovascular disorder. The pathogenesis is sustained by a relative reduction of cerebral blood flow, which is then followed by reactive hyperaemia, sterile inflammation and hypersensitization of pain pathways. The leading triggers of the initial vasoconstriction entail both hereditary or acquired cerebrovascular disorders, namely local endothelial or smooth muscle dysfunction, arteriovenous malformations autoimmune and inflammatory disorders, along with cerebral microembolism. The existence of a potential relationship between platelet biology and migraine has been hypothesized more than 30 years ago, paving the way to a series of subsequent studies. Despite the clinical evidence that patients with essential thrombocythemia have a high frequency of headache symptoms, the epidemiological trials that have investigated the platelet count in patients with an accurate diagnosis of migraine failed to report significant associations. Conversely, several lines of evidence attest that serotonin metabolism is substantially impaired in migraine patients, thus contributing to trigger or enhance vasoconstriction and hypersensitization of neuronal elements. Although abnormalities of nitric oxide metabolism should be confirmed in larger studies, published data suggests that this compound may be effective to amplify the reactive vasodilatation that specifically follows the initial reduction of cerebral blood flow. Another plausible link between platelet biology and migraine is represented by inflammation. Increased release of several proinflammatory cytokines, especially interleukins 1, 6 and 8 and tumor necrosis factor-alpha, may occur after formation of platelet-leukocyte aggregates, and these mediators can further contribute to increase sterile inflammation in the brain and facilitate pain signalling. PMID- 24767954 TI - Hypertensive patients' preferences for complementary and alternative medicine and the influence of these preferences on the adherence to prescribed medication. AB - PURPOSE: This study aimed to understand hypertensive patients' perceptions of and adherence to prescribed medication. METHODS: A qualitative research study based on 23 purposely selected participants from a community health clinic in Malaysia. The participants underwent in-depth semi-structured interviews, and the data were analyzed using qualitative content analysis method. RESULTS: The participants were presented with six types of perceptions of medication. The majority of the participants had negative perceptions of Western medicine (WM), self-adjusted their prescribed medication with complementary and alternative medicine (CAM) and concealed their self-adjusting habits from their doctors. Participants who thought positively of WM took their prescribed medication regularly. Most of the participants perceived the nature of WM as not being curative because of its side effects. Patients have the right to choose their preferred medication when they understand their illness. CONCLUSION: Local health care systems should provide patients with alternative health services that suit their requests. PMID- 24767956 TI - A study of the effect of relaxing music on heart rate recovery after exercise among healthy students. AB - BACKGROUND: Music has been employed in various clinical settings to reduce anxiety. However, meta-analysis has shown music to have little influence on haemodynamic parameters. This study aimed at investigating the effect of relaxing music on heart rate recovery after exercise. METHOD: Twenty-three student volunteers underwent treadmill exercise and were assessed for heart rate recovery and saliva analysis; comparing exposure to sedative music with exposure to silence during the recovery period immediately following exercise. RESULTS: No differences were found between music and non-music exposure regarding: heart rate recovery, resting pulse rate, and salivary cortisol. Music was no different to silence in affecting these physiological measures, which are all associated with anxiety. CONCLUSIONS: Relaxing music unaccompanied by meditation techniques or other such interventions may not have a major role in reducing anxiety in certain experimental settings. PMID- 24767955 TI - The effect of prenatal Hatha yoga on affect, cortisol and depressive symptoms. AB - Perinatal depression impacts maternal and child health, and little is known about effective interventions. The effects of prenatal Hatha yoga on cortisol, affect and depressive symptoms were investigated in 51 women. Twice during pregnancy, yoga group participants reported on affect and provided a saliva sample before and after a 90-min prenatal Hatha yoga session. Corresponding measures were obtained from yoga and control group participants on days of usual activity. Depressive symptoms were assessed in pregnancy and post partum. Cortisol was lower (p < .01) and positive affect higher (p < .001) on yoga compared to usual activity days. Negative affect and contentment (p < .05) improved more in response to the yoga session. Yoga group participants showed fewer postpartum (p < .05) but not antepartum depressive symptoms than control group participants. Findings indicate that prenatal Hatha yoga may improve current mood and may be effective in reducing postpartum depressive symptoms. PMID- 24767957 TI - Use of complementary medicines among HIV-infected children in Lagos, Nigeria. AB - BACKGROUND: Complementary medicine (CM) use is common among children with chronic illnesses such as epilepsy and asthma. Lack of data on the profile of CM use among children with human immunodeficiency virus (HIV) infection necessitated this study. METHODS: Parents or caregivers of HIV-infected children attending the paediatric HIV-clinic in a teaching hospital in Lagos, Nigeria, were randomly selected and interviewed with a semi-structured (open- and close-ended) questionnaire. Clinical details of the patients were extracted from their case files. RESULTS: A total of 187 parents/caregivers were interviewed. Most of the parents/caregivers (181; 96.8%) have used CMs for their children. Mind-body interventions (181; 36.6%) and biological products (179; 36.2%) were frequently used. Relatives, friends and neighbours influenced CM use in 37.1% of the children. CMs were used mostly to treat weight loss (79; 43.7%), cold (40; 22.1%), and fever (39; 21.6%). CONCLUSION: CM use is common among HIV-infected children in Lagos. PMID- 24767958 TI - A weight loss program in a chiropractic practice: a retrospective analysis. AB - CONTEXT: Obesity is a global problem and places individuals at risk for developing chronic metabolic disorders. The need for investigating simple, effective and sustaining approaches to weight loss cannot be overstated. METHODS: We performed a retrospective file analysis of patient files attending a 13-week weight loss program. Inclusion for analysis were files of adults (i.e., >18 years) completing the program consisting of chiropractic adjustments/spinal manipulative therapy augmented with diet/nutritional intervention, exercise and one-on-one counseling. RESULTS: Sixteen of 30 people (i.e., 53.33%) completed the program. Statistically and clinically significant changes were noted in weight and BMI measures based on pre-treatment (average weight = 190.46 lbs. and BMI = 30.94 kg/m(2)) and comparative measurements (average weight = 174.94 lbs. and BMI = 28.50 kg/m(2)). CONCLUSION: A cohort of patients under enrolled in a weight loss program was described. This provides supporting evidence on the effectiveness of a multi-modal approach to weight loss implemented in a chiropractic clinic. PMID- 24767959 TI - An exploration of heart rate response to differing music rhythm and tempos. AB - The aim of this study was to investigate acute cardiac response and heart rate variability (HRV) when listening to differing forms of music. Eleven healthy men aged between 18 and 25 years old were included in the study. HRV was recorded at rest for ten minutes with no music, then were asked to listen to classical baroque or heavy metal music for a period of 20 min. It was noted that heart rate variability did not affect HRV indices for time and frequency. In conclusion, music with different tempos does not influence cardiac autonomic regulation in men. However more studies are suggested to explore this topic in greater detail. PMID- 24767960 TI - Clinical indicators for the initiation of endotracheal suction in children: An integrative review. AB - BACKGROUND: Critical decisions and interpretation of observations by the nurse caring for the paediatric intensive care (PIC) patient can have dramatic and potential adverse impact on the clinical stability of the patient. A common PIC procedure is endotracheal tube (ETT) suction, however there is inconsistent evidence regarding the clinical indicators to guide and support nursing action. Justification for performing this procedure is not clearly defined within the literature. Further, a review of the literature has failed to establish clear standards for determining if the procedure is warranted, especially for paediatric patients. OBJECTIVE: The objective of the review is to identify current clinical indicators used in practice to determine why ETT suction should be performed. METHOD: An integrative review using a systematic approach to summarise the empirical and theoretical evidence within the literature as it relates to clinical practice was used. RESULTS: Consensus of opinion indicates that ETT suctioning should only be performed when clinically indicated. There is no general consensus regarding which clinical indicators should be measured and used to guide the decision to perform ETT suctioning. CONCLUSION: Research is required to identify the clinical indicators that could be used to design a valid and clinically appropriate tool to use to assist in the decision making process to perform ETT suction. PMID- 24767961 TI - Individuality of movements in music--finger and body movements during playing of the flute. AB - The achievement of mastery in playing a composition by means of a musical instrument typically requires numerous repetitions and corrections according to the keys and notations of the music piece. Nevertheless, differences in the interpretation of the same music piece by highly skilled musicians seem to be recognizable. The present study investigated differences within and between skilled flute players in their finger and body movements playing the same piece several times on the same and on different days. Six semiprofessional and four professional musicians played an excerpt of Mozart's Flute Concerto No. 2 several times on three different days. Finger and body movements were recorded by 3D motion capture and analyzed by linear and nonlinear classification approaches. The findings showed that the discrete and continuous movement timing data correctly identified individuals up to 100% by means of their finger movements and up to 94% by means of their body movements. These robust examples of identifying individual movement patterns contradict the prevailing models of small, economic finger movements that are favored in the didactic literature for woodwind players and question traditional recommendations for teaching the learning of motor skills. PMID- 24767962 TI - BDNF polymorphism and differential rTMS effects on motor recovery of stroke patients. AB - BACKGROUND: The brain-derived neurotrophic factor (BDNF) gene often shows a single nucleotide polymorphism that is thought to influence synaptic plasticity. It also affects the modulatory effects of repetitive transcranial magnetic stimulation (rTMS) on motor cortex excitability. OBJECTIVE: This study investigated whether BDNF polymorphism influences the effect of rTMS on the motor recovery of patients with stroke. METHODS: Forty-four patients (mean age 53.8 years) experiencing unilateral motor weakness after stroke were recruited. rTMS was applied over the primary motor cortex of the affected hemisphere at 10 Hz with 1000 pulses/day for 10 days. Each patient's motor functions were assessed using the Fugl-Meyer assessment (FMA) and the box and block test (BBT) before, immediately after and 2 months after the intervention. BDNF genotyping was performed via PCR assays of whole blood samples. The patients' data were grouped and analysed into Val/Val and Met allele groups according to the presence or absence of the BDNF polymorphism. RESULTS: Nine patients (20.5%) were classified into the Val/Val group, and thirty-seven patients (79.5%) were classified into the Met allele group. The patients' baseline motor functions did not differ between the two groups. The FMA and BBT scores showed significant improvement immediately after and 2 months after rTMS in both groups. In addition, the time and groups were found to interact significantly, with the Val/Val group improving to a greater extent than the Met allele group in terms of their FMA and BBT scores. CONCLUSIONS: The findings suggest that the BDNF gene polymorphism negatively influences the effect of rTMS on the motor recovery of upper extremities in stroke patients. PMID- 24767963 TI - Probability of pregnancy after sterilization: a comparison of hysteroscopic versus laparoscopic sterilization. AB - OBJECTIVE: To compare the expected probability of pregnancy after hysteroscopic versus laparoscopic sterilization based on available data using decision analysis. STUDY DESIGN: We developed an evidence-based Markov model to estimate the probability of pregnancy over 10 years after three different female sterilization procedures: hysteroscopic, laparoscopic silicone rubber band application and laparoscopic bipolar coagulation. Parameter estimates for procedure success, probability of completing follow-up testing and risk of pregnancy after different sterilization procedures were obtained from published sources. RESULTS: In the base case analysis at all points in time after the sterilization procedure, the initial and cumulative risk of pregnancy after sterilization is higher in women opting for hysteroscopic than either laparoscopic band or bipolar sterilization. The expected pregnancy rates per 1000 women at 1 year are 57, 7 and 3 for hysteroscopic sterilization, laparoscopic silicone rubber band application and laparoscopic bipolar coagulation, respectively. At 10 years, the cumulative pregnancy rates per 1000 women are 96, 24 and 30, respectively. Sensitivity analyses suggest that the three procedures would have an equivalent pregnancy risk of approximately 80 per 1000 women at 10 years if the probability of successful laparoscopic (band or bipolar) sterilization drops below 90% and successful coil placement on first hysteroscopic attempt increases to 98% or if the probability of undergoing a hysterosalpingogram increases to 100%. CONCLUSION: Based on available data, the expected population risk of pregnancy is higher after hysteroscopic than laparoscopic sterilization. Consistent with existing contraceptive classification, future characterization of hysteroscopic sterilization should distinguish "perfect" and "typical" use failure rates. IMPLICATIONS: Pregnancy probability at 1 year and over 10 years is expected to be higher in women having hysteroscopic as compared to laparoscopic sterilization. PMID- 24767964 TI - Grey Turner's sign suggesting retroperitoneal haemorrhage. PMID- 24767965 TI - The immune response and within-host emergence of pandemic influenza virus. AB - Zoonotic influenza viruses that are a few mutations away from pandemic viruses circulate in animals, and can evolve into airborne-transmissible viruses in human beings. Paradoxically, such viruses only occasionally emerge in people; the four influenza pandemics that occurred in the past 100 years were caused by zoonotic viruses that acquired efficient transmissibility. Emergence of a pandemic virus in people can happen when transmissible viruses evolve in individuals with zoonotic influenza and replicate to titres allowing transmission. We postulate that this step in the genesis of a pandemic virus only occasionally occurs in human beings, because the immune response triggered by zoonotic influenza virus also controls transmissible mutants that emerge during infection. Therefore, an impaired immune response might be needed for within-host emergence of a pandemic virus and replication to titres allowing transmission. Immunocompromised individuals--eg, those with comorbidities, of advanced age, or receiving immunosuppressive treatment--could be at increased risk of generating transmissible viruses and initiating chains of human-to-human infection. PMID- 24767966 TI - Allele frequencies for 22 autosomal short tandem repeat loci obtained by PowerPlex Fusion in a sample of 1501 individuals from the Japanese population. AB - Allele frequencies for 22 autosomal short tandem repeat loci (D3S1358, D1S1656, D2S441, D10S1248, D13S317, Penta E, D16S539, D18S51, D2S1338, CSF1PO, Penta D, TH01, vWA, D21S11, D7S820, D5S818, TPOX, D8S1179, D12S391, D19S433, FGA, and D22S1045) were obtained from 1501 unrelated individuals sampled from the Japanese population. PMID- 24767967 TI - Genetic polymorphism data on 15 autosomal STR markers in a Western Romanian population sample. AB - The allelic frequency distribution and statistical genetic parameters of forensic relevance for 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, Penta E, Penta D, vWA, TPOX, D18S51, D5S818 and FGA) in a population sample of 336 non-related individuals residing in the Western part of Romania are presented. PMID- 24767968 TI - Poverty and mental health: towards a research agenda for low and middle-income countries. Commentary on Tampubolon and Hanandita (2014). PMID- 24767969 TI - A contemporary series of patients undergoing open debridement for necrotizing pancreatitis. AB - BACKGROUND: For patients with acute pancreatitis complicated by infected necrosis, minimally invasive techniques have taken hold without substantial comparison with open surgery. We present a contemporary series of open necrosectomies as a benchmark for newer techniques. METHODS: Using a prospective database, we retrospectively identified consecutive patients undergoing debridement for necrotizing pancreatitis (2006 to 2009). The primary endpoint was in-hospital mortality. RESULTS: Sixty-eight patients underwent debridement for pancreatic/peripancreatic necrosis. In-hospital mortality was 8.8% (n = 6). Infection (n = 43, 63%) and failure-to-thrive (n = 13, 19%) comprised the most common indications for necrosectomy. The false negative rate (FNR) for infection of percutaneous aspirate was 20.0%. Older age (P = .02), Acute Physiology and Chronic Health Evaluation II score upon admission (P = .03) or preoperatively (P < .01), preoperative intensive care unit admission (P = .01), and postoperative organ failure (P = .03) were associated with mortality. CONCLUSIONS: Open debridement for necrotizing pancreatitis results in a low mortality, providing a useful comparator for other interventions. Given the high FNR of percutaneous aspirate, debridement should not be predicated on proven infection. PMID- 24767970 TI - Validation study of a modern treatment algorithm for nipple discharge. AB - BACKGROUND: Nipple discharge occurs in 2% to 5% of women. We evaluated the effectiveness of a previously proposed treatment algorithm for these patients. METHODS: Patients with pathologic nipple discharge and a negative mammogram and subareolar ultrasound were offered follow-up from 2005 to 2011 according to the algorithm. RESULTS: A total of 192 patients, mean age 56 years, were studied. Risk of carcinoma among the entire cohort was 5%. Breast surgeon was consulted for 142 (74%) patients: 48 (34%) underwent initial subareolar excision and 94 (66%) were clinically followed. The rate of carcinoma was 17% (8/48) after initial subareolar excision, 0% (0/13) for those without imaging abnormalities, 23% (8/35) with imaging abnormalities, and 1% (1/94) with clinical follow-up. Of patients who underwent follow-up, 21% (n = 20) underwent subareolar excision because of imaging abnormality (n = 1, 1%) or persistent discharge (n = 19, 20%). Most patients had ductal carcinoma in situ (n = 5, 56%). CONCLUSIONS: Patients with nipple discharge can be prospectively identified based on radiographic findings and clinical examination for safe clinical follow-up. Most will have resolution avoiding a surgical procedure. PMID- 24767971 TI - Semiautomated detection and quantification of aortic plaques from three dimensional transesophageal echocardiography. AB - BACKGROUND: Aortic atherosclerosis is a risk factor for cerebrovascular events. Two-dimensional transesophageal echocardiographic quantification of descending aortic plaques is time-consuming and underestimates plaque burden. The aim of this study was to assess the feasibility and accuracy of a novel semiautomated program that uses three-dimensional (3D) transesophageal echocardiography to identify and quantify aortic plaque severity as determined by plaque thickness, volume, and number. The relationship between maximum plaque thickness and volume was also examined. METHODS: Descending aortic 3D transesophageal echocardiographic images from 58 patients were analyzed for plaque thickness, volume, and number using semiautomated custom software. The reference standard was manual assessment by an expert reader using 3D multiplanar reconstructions. Agreement and kappa values were calculated to determine the program's accuracy against the reference standard. Correlation and bias were examined using linear regression and Bland-Altman statistics. Pearson's correlation was used to examine the relationship between maximum plaque thickness and volume. RESULTS: Analysis was possible in all patients. Overall agreement for the absolute presence or absence of plaque per patient was 95%. Agreement regarding the number of plaques per patient and plaque severity was high at 95% and 85%, respectively. Plaque volume was slightly underestimated by the program compared with manual measurements. The correlation between plaque thickness and volume was 0.56. CONCLUSIONS: The results of this study demonstrate that semiautomated plaque analysis of 3D transesophageal echocardiographic descending aortic data sets is feasible and accurate in determining plaque severity as measured by plaque thickness, volume, and number. This methodology allows the standardization of plaque quantification, which will improve its utility in clinical trials. A greater understanding of the importance of plaque thickness versus volume is needed. PMID- 24767972 TI - Left atrial strain provides incremental value for embolism risk stratification over CHA2DS2-VASc score and indicates prognostic impact in patients with atrial fibrillation. AB - BACKGROUND: The aim of this study was to investigate whether left atrial (LA) strain has incremental value over the CHA2DS2-VASc score for stratifying the risk for embolism in patients with atrial fibrillation (AF) and whether LA strain predicts poststroke mortality. METHODS: Consecutive patients with paroxysmal or persistent AF with acute embolism (82 patients) or without (204 controls) were prospectively enrolled. Global peak LA longitudinal strain during ventricular systole (LAS) was assessed during AF rhythm. Global LAS was compared between the groups in the first cross-sectional study. Then, the 82 patients with acute embolism were prospectively followed during the second prospective cohort study. RESULTS: Global LAS was lower in patients with acute embolism than in controls (P < .001). Global LAS < 15.4% differentiated patients with acute embolism from controls, with an area under the curve of 0.83 (P < .0001). In multivariate analysis, global LAS was independently associated with acute embolism (odds ratio, 0.74; 95% confidence interval, 0.67-0.82; P < .001) and had an incremental value over the CHA2DS2-VASc score (P < .0001). Furthermore, 26 patients with acute embolisms died during a median follow-up period of 425 days. Global LAS independently predicted mortality after embolism. CONCLUSIONS: In this observational study, LA strain provided incremental diagnostic information over that provided by the CHA2DS2-VASc score, suggesting that LA strain analysis could improve the current risk stratification of embolism in patients with AF. LA strain can also predict poststroke mortality. PMID- 24767973 TI - The ratio of early mitral inflow velocity to global diastolic strain rate as a useful predictor of cardiac outcomes in patients with atrial fibrillation. AB - BACKGROUND: Although the ratio of early mitral inflow velocity (E) to global diastolic strain rate (E'sr) has been correlated with left ventricular filling pressure, its relationship with cardiac outcomes in patients with atrial fibrillation (AF) has never been evaluated. The aim of this study was to examine the ability of E/E'sr ratio in predicting cardiac outcomes in patients with AF. METHODS: In 190 patients with persistent AF, comprehensive echocardiography was performed, with assessment of E'sr from three standard apical views using the index beat method. Cardiac events were defined as death and hospitalization for heart failure. RESULTS: There were 50 cardiac events, including 22 deaths and 28 hospitalizations for heart failure, during an average follow-up period of 20 months (interquartile range, 14-32 months). Multivariate analysis showed old age, chronic heart failure, and increased E/E'sr ratio (per 10-cm E/E'sr increase; hazard ratio, 1.258; 95% confidence interval, 1.132-1.398, P < .001) were associated with increased cardiac events. In direct comparison, E/E'sr ratio outperformed the ratio of E to early diastolic mitral annular velocity (E') in predicting adverse cardiac events in both univariate and multivariate models (P <= .046). Additionally, the addition of E/E'sr ratio to a clinical model including age, chronic heart failure, diabetes, hypertension, left atrial volume index, left ventricular ejection fraction, and E/E' still provided an extra benefit in the prediction of adverse cardiac events (P = .010). CONCLUSIONS: E/E'sr ratio is a useful parameter and is stronger than E/E' ratio in predicting adverse cardiac events, and it may offer additional prognostic benefit over conventional clinical and echocardiographic parameters in patients with AF. PMID- 24767974 TI - Preliminary experience of laparoscopic renal artery aneurysm clipping surgery. AB - Developments in endovascular therapy and laparoscopy have led to the expansion of minimally invasive surgical techniques in the treatment of renal artery aneurysm (RAA). In this study, we introduced a new surgical technique that combined the clipping technique widely used in neurosurgery with laparoscopic surgery to clip the aneurysm. RAA clipping was performed by retroperitoneal laparoscopy, and the procedures were completed with no conversions to open surgery. In addition, no perioperative complications were recorded. Our preliminary experience suggests that laparoscopic RAA clipping surgery is feasible and appears to be safe. Laparoscopic RAA clipping surgery has advantages of a simplified surgical process, short warm ischemia time, and excellent cosmetic results. PMID- 24767975 TI - Impact of early versus late clopidogrel discontinuation on stent thrombosis following percutaneous coronary intervention with first- and second-generation drug-eluting stents. AB - Premature antiplatelet therapy discontinuation (ATD) after drug-eluting stent (DES) implantation is known to predict stent thrombosis (ST). However, recent data suggest that a shorter antiplatelet therapy duration is safe with newer generation DESs. The study aimed to compare the impact of early and late clopidogrel ATDs on ST in a real-world registry of first- and second-generation DES use. A total of 6,236 patients who underwent DES implantation were analyzed retrospectively: 4,217 received first-generation DESs (sirolimus- and paclitaxel eluting stents) and 2,019 received second-generation DESs (everolimus-eluting stents). Within each DES cohort, patients were categorized into timing of clopidogrel discontinuation within 1 year: early (<3 months), late (3 to 12 months), and continued. ST rates and clinical outcomes at 1 year were analyzed. There were 341 patients (8.1%) in the first-generation DES group and 126 patients (6.2%) in the second-generation DES group who discontinued clopidogrel within the first year. Definite and probable ST rates were 3.8% for early ATD, 2.5% for late ATD, and 0.5% for continued (p = 0.001) in the first-generation DES cohort, whereas there were no definite or probable ST events in early and late ATDs and 0.5% for continued in the second-generation DES cohort. Major adverse cardiac event rates were 9.9% for early ATD, 5.6% for late ATD, and 0.9% for continued (p <0.001) in the first-generation DES cohort and 5.5% for early ATD, 7.4% for late ATD, and 1.5% for continued (p <0.001) in the second-generation DES cohort. In conclusion, ATD within the first year is associated with increased ST events with first-generation DESs, whereas ATD appears safe with second-generation DESs with regard to ST. However, ATD is associated with greater mortality and major adverse cardiac events in both first- and second-generation DESs. Thus, this study supports ATD if required based on physician discretion with the use of second generation DESs but cannot rule out potential benefit for longer duration of dual antiplatelet therapy even when second-generation DESs are used. PMID- 24767976 TI - Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo--part II: rheological characterization and in vivo assessment through dermatopharmacokinetic and pilot clinical studies. AB - Vitiligo is a non contagious acquired pigmentation disorder with limited treatment possibilities. Clobetasol propionate (CP) is the drug-of-choice for vitiligo which suppresses the immune system by reducing immunoglobulin action and causes the restoration of melanocytes leading to repigmentation of skin. However, despite being effective, its low and variable bioavailability prompt for development of novel carrier that could effectively target CP to site of action without producing undesirable side-effects. Low solubility of CP in subsequent poor in vivo bioavailability was overcome by formulating microemulsion based gel of CP (MBC) which would enhance the percutaneous transport of CP into and across the skin barrier. Comprehensive characterization of MBC was carried out for viscosity, gel strength and rheological behavior. In vitro studies revealed much higher drug release, skin penetration and enhanced skin accumulation as compared to control (Cream of CP). In vitro and in vivo occlusion studies demonstrated similar occlusiveness for MBC and control. MBC exhibited 3.16 times higher stratum corneum CP levels compared to control. Visualization of cutaneous uptake in vivo using laser scanning microscopy confirmed targeting of CP to epidermis and dermis. Dermatopharmacokinetic studies of MBC showed enhanced drug deposition of CP in skin layers. MBC was assessed for in vivo efficacy by single blind randomized pilot clinical study. The efficacy was assessed by vitiligo area scoring index (VASI) method. After completion of trial, repigmentation of vitiligo patches in patients were evaluated and scored. MBC was superior in terms of faster repigmentation and efficacy when compared with control (p value<0.5). Hence, it was concluded that CP loaded MBC possess enhanced skin localization as well as therapeutic activity in vitiligo patients. PMID- 24767977 TI - Measuring output factors and beam profiles formed by multileaf collimators using Fricke gel dosimeter. AB - The accuracy and precision are necessary factors in radiotherapy, especially for measurements involving output factors and beam profiles; in this case multileaf collimators (MLCs) and dosimeter systems are not employed to obtain an adequate absorbed dose. In this work, output factors and beam profiles using multileaf collimators were obtained through the Fricke Xylenol Gel (FXG) dosimeter irradiated with 6 MV photon beams. From the results, FXG dosimetry demonstrated to be an adequate dosimetric tool for radiotherapy applications using MLC. PMID- 24767978 TI - Treatment of small cell lung cancer. AB - Treatment of small cell lung cancer (SCLC) remains a significant challenge for the oncologists. Attempts to improve the results of first-line treatment have all failed so far and no real progress has been made in last years, emphasizing the need for novel strategies of treatment and the development of validated biomarkers. Patients with limited disease and good performance status should be considered for concomitant chemoradiotherapy, followed by prophylactic cranial irradiation. Patients with extensive disease should be treated with a platinum based chemotherapy (cisplatin or carboplatin); chest radiotherapy can be considered in patients achieving extra-thoracic complete response and prophylactic cranial irradiation is recommended for patients responsive to initial chemotherapy. A large number of molecular-targeted drugs and immunomodulators are currently in clinical development: however, only a better understanding of molecular biology of SCLC and the identification of molecular markers predictive of response to targeted agents will lead to advances in the treatment of SCLC. PMID- 24767979 TI - Minimally invasive mitral valve surgery using single dose antegrade Custodiol cardioplegia. AB - OBJECTIVE: Our unit began a minimally invasive mitral surgery (MIMS) program utilising antegrade Custodiol solution as the sole cardioplegia. The aim of this paper is to report our results of this program. PATIENTS/METHODS: Early clinical outcomes were identified and assessed for the first consecutive 100 MIMS patients with comparisons made to a historical group operated via a sternotomy (n=113). The efficacy of myocardial protection was assessed using surrogate outcomes of myocardial protection with serial sodium concentrations also analysed. RESULTS: Six hours postoperatively 12 patients required inotropic support. Peak troponin-I in the first 24 hours was 5.1 (0.8-40 MUg/L [median(range)]. Sodium levels decreased following administration of Custodiol but by six hours postoperatively the sodium had returned to greater than 130 mmol/L in all but five patients. Blood transfusion was smaller in the MIMS versus historical group (RBC 17% vs. 65%). MIMS patients had a shorter duration of ventilation, hospital stay and one year mortality rate (0%). CONCLUSIONS: In this series of patients undergoing MIMS, single dose antegrade Custodiol offers satisfactory and safe myocardial protection. Early clinical outcomes were also satisfactory. Whilst our findings are observational, they nevertheless support the use of this less invasive approach to mitral surgery using single dose Custodiol for myocardial protection. PMID- 24767980 TI - High expression of Cullin1 indicates poor prognosis for NSCLC patients. AB - BACKGROUND: Cullin1 is a scaffold protein of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex which ubiquitinates a broad range of proteins participating in biochemical events like cell-cycle progression, signal transduction, and transcription. Cullin1 is involved in the progression of several cancers, such as melanoma, breast cancer, and gastric cancer. METHODS: To investigate the role of Cullin1 in the development of non-small-cell lung cancer (NSCLC), we examined the expression of Cullin1 in 8-paired fresh NSCLC tissues. We then constructed immunohistochemistry (IHC) on 114 paraffin-embedded slices and evaluated the correlation between Cullin1 expression and clinicopathologic variables, as well as patients' overall survival. RESULTS: We found that Cullin1 was highly expressed in NSCLC tissues and significantly associated with NSCLC's histological differentiation (P=0.002), clinical stage (P=0.010) and Ki-67 (P=0.021). Furthermore, we showed a strong correlation between high Cullin1 expression and worse overall survival rates in NSCLC patients (P<0.001). Cox regression analysis revealed that Cullin1 expression was an independent prognostic factor to predict 5-year patient outcome in NSCLC cancer (P=0.033). CONCLUSION: These data suggested that Cullin1 might promote the progression of NSCLC and be a biotarget for NSCLC's therapy. PMID- 24767981 TI - [Update in mechanical ventilation: conclusions]. PMID- 24767982 TI - Next generation restoration genetics: applications and opportunities. AB - Restoration ecology is a young scientific discipline underpinning improvements in the rapid global expansion of ecological restoration. The application of molecular tools over the past 20 years has made an important contribution to understanding genetic factors influencing ecological restoration success. Here we illustrate how recent advances in next generation sequencing (NGS) methods are revolutionising the practical contribution of genetics to restoration. Novel applications include a dramatically enhanced capacity to measure adaptive variation for optimal seed sourcing, high-throughput assessment and monitoring of natural and restored biological communities aboveground and belowground, and gene expression analysis as a measure of genetic resilience of restored populations. Challenges remain in data generation, handling and analysis, and how best to apply NGS for practical outcomes in restoration. PMID- 24767983 TI - Plastid survival in the cytosol of animal cells. AB - Some marine slugs sequester plastids from their algae food, which can remain photosynthetically functional in the animal's digestive gland cells in the absence of algal nuclei. The sequestered plastids (kleptoplasts) appear to maintain functional photosystems through a greater autonomy than land plant plastids. If so, kleptoplast robustness is a plastid-intrinsic property, and it depends on the animal to manage an alien organelle on the loose in order to maintain it long term. PMID- 24767984 TI - The clinical significance of the gut microbiota in cystic fibrosis and the potential for dietary therapies. AB - Cystic fibrosis (CF) is characterised by many comorbidities related to aberrant mucosa and chronic inflammation in the respiratory and digestive systems. The intestinal mucosa serves as the primary interface between the gut microbiota and endocrine, neural and immune systems. There is emerging evidence that aberrant intestinal mucosa in CF may associate with an altered gut microbiota. Compared to healthy subjects, the overall bacterial abundance and species richness seems to be reduced in CF, accompanied by a trend in suppression of Firmicutes and Bacteroidetes spp. and an augmentation of potentially pathogenic species. There is also some concordance of gut and respiratory microbiotas in CF infants over time. The clinical significance of these observations awaits investigation. The gut microbiota have some potential in CF management by affecting inflammatory and immune responses, and influencing aberrant mucosa. As an important modifiable factor, diet therapies such as probiotics and prebiotics have shown initial promise in improving CF related conditions associated with chronic inflammation. More studies are needed to confirm this, as well as the efficacy of other dietary strategies such as modulating dietary fat and indigestible carbohydrate. Similarly, dietary modification of gut microbiota to optimise nutritional status in CF may be feasible, although more CF-specific studies are warranted. PMID- 24767985 TI - Early preschool processing abilities predict subsequent reading outcomes in bilingual Spanish-Catalan children with Specific Language Impairment (SLI). AB - Children with Specific Language Impairment (SLI) have severe language difficulties without showing hearing impairments, cognitive deficits, neurological damage or socio-emotional deprivation. However, previous studies have shown that children with SLI show some cognitive and literacy problems. Our study analyses the relationship between preschool cognitive and linguistic abilities and the later development of reading abilities in Spanish-Catalan bilingual children with SLI. The sample consisted of 17 bilingual Spanish-Catalan children with SLI and 17 age-matched controls. We tested eight distinct processes related to phonological, attention, and language processing at the age of 6 years and reading at 8 years of age. Results show that bilingual Spanish-Catalan children with SLI show significantly lower scores, as compared to typically developing peers, in phonological awareness, phonological memory, and rapid automatized naming (RAN), together with a lower outcome in tasks measuring sentence repetition and verbal fluency. Regarding attentional processes, bilingual Spanish-Catalan children with SLI obtained lower scores in auditory attention, but not in visual attention. At the age of 8 years Spanish-Catalan children with SLI had lower scores than their age-matched controls in total reading score, letter identification (decoding), and in semantic task (comprehension). Regression analyses identified both phonological awareness and verbal fluency at the age of 6 years to be the best predictors of subsequent reading performance at the age of 8 years. Our data suggest that language acquisition problems and difficulties in reading acquisition in bilingual children with SLI might be related to the close interdependence between a limitation in cognitive processing and a deficit at the linguistic level. LEARNING OUTCOMES: After reading this article, readers will be able to: identify their understanding of the relation between language difficulties and reading outcomes; explain how processing abilities influence reading performance in bilingual Spanish-Catalan children with SLI; and recognize the relation between language and reading via a developmental model in which the phonological system is considered central for the development of decoding abilities and comprehension. PMID- 24767986 TI - Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. AB - Broadly neutralizing antibodies (bNAbs) to HIV-1 envelope glycoprotein (Env) can prevent infection in animal models. Characterized bNAb targets, although key to vaccine and therapeutic strategies, are currently limited. We defined a new site of vulnerability by solving structures of bNAb 8ANC195 complexed with monomeric gp120 by X-ray crystallography and trimeric Env by electron microscopy. The site includes portions of gp41 and N-linked glycans adjacent to the CD4-binding site on gp120, making 8ANC195 the first donor-derived anti-HIV-1 bNAb with an epitope spanning both Env subunits. Rather than penetrating the glycan shield by using a single variable-region CDR loop, 8ANC195 inserted its entire heavy-chain variable domain into a gap to form a large interface with gp120 glycans and regions of the gp120 inner domain not contacted by other bNAbs. By isolating additional 8ANC195 clonal variants, we identified a more potent variant, which may be valuable for therapeutic approaches using bNAb combinations with nonoverlapping epitopes. PMID- 24767987 TI - Constant growth rate can be supported by decreasing energy flux and increasing aerobic glycolysis. AB - Fermenting glucose in the presence of enough oxygen to support respiration, known as aerobic glycolysis, is believed to maximize growth rate. We observed increasing aerobic glycolysis during exponential growth, suggesting additional physiological roles for aerobic glycolysis. We investigated such roles in yeast batch cultures by quantifying O2 consumption, CO2 production, amino acids, mRNAs, proteins, posttranslational modifications, and stress sensitivity in the course of nine doublings at constant rate. During this course, the cells support a constant biomass-production rate with decreasing rates of respiration and ATP production but also decrease their stress resistance. As the respiration rate decreases, so do the levels of enzymes catalyzing rate-determining reactions of the tricarboxylic-acid cycle (providing NADH for respiration) and of mitochondrial folate-mediated NADPH production (required for oxidative defense). The findings demonstrate that exponential growth can represent not a single metabolic/physiological state but a continuum of changing states and that aerobic glycolysis can reduce the energy demands associated with respiratory metabolism and stress survival. PMID- 24767988 TI - A mitochondrial RNAi screen defines cellular bioenergetic determinants and identifies an adenylate kinase as a key regulator of ATP levels. AB - Altered cellular bioenergetics and mitochondrial function are major features of several diseases, including cancer, diabetes, and neurodegenerative disorders. Given this important link to human health, we sought to define proteins within mitochondria that are critical for maintaining homeostatic ATP levels. We screened an RNAi library targeting >1,000 nuclear-encoded genes whose protein products localize to the mitochondria in multiple metabolic conditions in order to examine their effects on cellular ATP levels. We identified a mechanism by which electron transport chain (ETC) perturbation under glycolytic conditions increased ATP production through enhanced glycolytic flux, thereby highlighting the cellular potential for metabolic plasticity. Additionally, we identified a mitochondrial adenylate kinase (AK4) that regulates cellular ATP levels and AMPK signaling and whose expression significantly correlates with glioma patient survival. This study maps the bioenergetic landscape of >1,000 mitochondrial proteins in the context of varied metabolic substrates and begins to link key metabolic genes with clinical outcome. PMID- 24767989 TI - The intracellular Na(+)/H(+) exchanger NHE7 effects a Na(+)-coupled, but not K(+) coupled proton-loading mechanism in endocytosis. AB - Vesicular H(+)-ATPases and ClC-chloride transporters are described to acidify intracellular compartments, which also express the highly conserved Na(+)/H(+) exchangers NHE6, NHE7, and NHE9. Mutations of these exchangers cause autism spectrum disorders and neurodegeneration. NHE6, NHE7, and NHE9 are hypothesized to exchange cytosolic K(+) for H(+) and alkalinize vesicles, but this notion has remained untested in K(+) because their intracellular localization prevents functional measurements. Using proton-killing techniques, we selected a cell line that expresses wild-type NHE7 at the plasma membrane, enabling measurement of the exchanger's transport parameters. We found that NHE7 transports Li(+) and Na(+), but not K(+), is nonreversible in physiological conditions and is constitutively activated by cytosolic H(+). Therefore, NHE7 acts as a proton-loading transporter rather than a proton leak. NHE7 mediates an acidification of intracellular vesicles that is additive to that of V-ATPases and that accelerates endocytosis. This study reveals an unexpected function for vesicular Na(+)/H(+) exchangers and provides clues for understanding NHE-linked neurological disorders. PMID- 24767990 TI - Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. AB - Stable wakefulness requires orexin/hypocretin neurons (OHNs) and OHR2 receptors. OHNs sense diverse environmental cues and control arousal accordingly. For unknown reasons, OHNs contain multiple excitatory transmitters, including OH peptides and glutamate. To analyze their cotransmission within computational frameworks for control, we optogenetically stimulated OHNs and examined resulting outputs (spike patterns) in a downstream arousal regulator, the histamine neurons (HANs). OHR2s were essential for sustained HAN outputs. OHR2-dependent HAN output increased linearly during constant OHN input, suggesting that the OHN->HAN(OHR2) module may function as an integral controller. OHN stimulation evoked OHR2 dependent slow postsynaptic currents, similar to midnanomolar OH concentrations. Conversely, glutamate-dependent output transiently communicated OHN input onset, peaking rapidly then decaying alongside OHN->HAN glutamate currents. Blocking glutamate-driven spiking did not affect OH-driven spiking and vice versa, suggesting isolation (low cross-modulation) of outputs. Therefore, in arousal regulators, cotransmitters may translate distinct features of OHN activity into parallel, nonredundant control signals for downstream effectors. PMID- 24767991 TI - Phosphorylation of the proapoptotic BH3-only protein bid primes mitochondria for apoptosis during mitotic arrest. AB - Mitosis is a moment of exquisite vulnerability for a metazoan cell. Failure to complete mitosis accurately can lead to aneuploidy and cancer initiation. Therefore, if the exit from mitosis is delayed, normal cells are usually removed by apoptosis. However, how failure to complete mitosis activates apoptosis is still unclear. Here, we demonstrate that a phosphorylated form of the BH3-only protein Bid regulates apoptosis if mitotic exit is delayed. Bid is phosphorylated on serine 66 as cells enter mitosis, and this phosphorylation is lost during the metaphase-to-anaphase transition. Cells expressing a nonphosphorylatable version of Bid or a BH3-domain mutant were resistant to mitotic-arrest-induced apoptosis. Thus, we show that Bid phosphorylation primes cells to undergo mitochondrial apoptosis if mitotic exit is delayed. Avoidance of this mechanism may explain the selective pressure for cancer cells to undergo mitotic slippage. PMID- 24767992 TI - Analysis of double-stranded RNA from microbial communities identifies double stranded RNA virus-like elements. AB - Double-stranded RNA (dsRNA) can function as genetic information and may have served as genomic material before the existence of DNA-based life. By developing a method to purify dsRNA, we have investigated the diversity of dsRNA in microbial populations. We detect large dsRNAs in multiple microbial populations. Analysis of an aquatic microbial population reveals that some dsRNA sequences match metagenomic DNA, suggesting that microbes contain pools of sense-antisense transcripts. In addition, ~30% of the dsRNA sequences are not present in the corresponding DNA pool and are strongly biased toward encoding novel proteins. Of these "dsRNA unique" sequences, only a small percentage share similarity to known viruses, a large fraction assemble into RNA virus-like contigs, and the remaining fraction has an unexplained origin. These results have uncovered dsRNA virus-like elements and underscore that dsRNA potentially represents an additional reservoir of genetic information in microbial populations. PMID- 24767993 TI - Reduced insulin/IGF-1 signaling restores germ cell immortality to Caenorhabditis elegans Piwi mutants. AB - Defects in the Piwi/piRNA pathway lead to transposon desilencing and immediate sterility in many organisms. We found that the C. elegans Piwi mutant prg-1 became sterile after growth for many generations. This phenotype did not occur for RNAi mutants with strong transposon-silencing defects and was separable from the role of PRG-1 in transgene silencing. Brief periods of starvation extended the transgenerational lifespan of prg-1 mutants by stimulating the DAF-16/FOXO longevity transcription factor. Constitutive activation of DAF-16 via reduced daf 2 insulin/IGF-1 signaling immortalized prg-1 strains via RNAi proteins and histone H3 lysine 4 demethylases. In late-generation prg-1 mutants, desilencing of repetitive segments of the genome occurred, and silencing of repetitive loci was restored in prg-1; daf-2 mutants. This study reveals an unexpected interface between aging and transgenerational maintenance of germ cells, where somatic longevity is coupled to a genome-silencing pathway that promotes germ cell immortality in parallel to the Piwi/piRNA system. PMID- 24767994 TI - Regulated splicing of the alpha6 integrin cytoplasmic domain determines the fate of breast cancer stem cells. AB - Although the alpha6beta1 integrin has been implicated in the function of breast and other cancer stem cells (CSCs), little is known about its regulation and relationship to mechanisms involved in the genesis of CSCs. We report that a CD44(high)/CD24(low) population, enriched for CSCs, is comprised of distinct epithelial and mesenchymal populations that differ in expression of the two alpha6 cytoplasmic domain splice variants: alpha6A and alpha6B. alpha6Bbeta1 expression defines the mesenchymal population and is necessary for CSC function, a function that cannot be executed by alpha6A integrins. The generation of alpha6Bbeta1 is tightly controlled and occurs as a consequence of an autocrine vascular endothelial growth factor (VEGF) signaling that culminates in the transcriptional repression of a key RNA-splicing factor. These data alter our understanding of how alpha6beta1 contributes to breast cancer, and they resolve ambiguities regarding the use of total alpha6 (CD49f) expression as a biomarker for CSCs. PMID- 24767995 TI - Botch is a gamma-glutamyl cyclotransferase that deglycinates and antagonizes Notch. AB - Botch promotes embryonic neurogenesis by inhibiting the initial S1 furin-like cleavage step of Notch maturation. The biochemical process by which Botch inhibits Notch maturation is not known. Here, we show that Botch has gamma glutamyl cyclotransferase (GGCT) activity that deglycinates Notch, which prevents the S1 furin-like cleavage. Moreover, Notch is monoglycinated on the gamma glutamyl carbon of glutamate 1,669. The deglycinase activity of Botch is required for inhibition of Notch signaling both in vitro and in vivo. When the gamma glutamyl-glycine at position 1,669 of Notch is degylcinated, it is replaced by 5 oxy-proline. These results reveal that Botch regulates Notch signaling through deglycination and identify a posttranslational modification of Notch that plays an important role in neurogenesis. PMID- 24767996 TI - Lhx1 controls terminal differentiation and circadian function of the suprachiasmatic nucleus. AB - Vertebrate circadian rhythms are organized by the hypothalamic suprachiasmatic nucleus (SCN). Despite its physiological importance, SCN development is poorly understood. Here, we show that Lim homeodomain transcription factor 1 (Lhx1) is essential for terminal differentiation and function of the SCN. Deletion of Lhx1 in the developing SCN results in loss of SCN-enriched neuropeptides involved in synchronization and coupling to downstream oscillators, among other aspects of circadian function. Intact, albeit damped, clock gene expression rhythms persist in Lhx1-deficient SCN; however, circadian activity rhythms are highly disorganized and susceptible to surprising changes in period, phase, and consolidation following neuropeptide infusion. Our results identify a factor required for SCN terminal differentiation. In addition, our in vivo study of combinatorial SCN neuropeptide disruption uncovered synergies among SCN-enriched neuropeptides in regulating normal circadian function. These animals provide a platform for studying the central oscillator's role in physiology and cognition. PMID- 24767997 TI - SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. AB - Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes. PMID- 24767998 TI - Polycystin signaling is required for directed endothelial cell migration and lymphatic development. AB - Autosomal dominant polycystic kidney disease is a common form of inherited kidney disease that is caused by mutations in two genes, PKD1 (polycystin-1) and PKD2 (polycystin-2). Mice with germline deletion of either gene die in midgestation with a vascular phenotype that includes profound edema. Although an endothelial cell defect has been suspected, the basis of this phenotype remains poorly understood. Here, we demonstrate that edema in Pkd1- and Pkd2-null mice is likely to be caused by defects in lymphatic development. Pkd1 and Pkd2 mutant embryos exhibit reduced lymphatic vessel density and vascular branching along with aberrant migration of early lymphatic endothelial cell precursors. We used cell based assays to confirm that PKD1- and PKD2-depleted endothelial cells have an intrinsic defect in directional migration that is associated with a failure to establish front-rear polarity. Our studies reveal a role for polycystin signaling in lymphatic development. PMID- 24768000 TI - Cilia-mediated hedgehog signaling in Drosophila. AB - Cilia mediate Hedgehog (Hh) signaling in vertebrates and Hh deregulation results in several clinical manifestations, such as obesity, cognitive disabilities, developmental malformations, and various cancers. Drosophila cells are nonciliated during development, which has led to the assumption that cilia mediated Hh signaling is restricted to vertebrates. Here, we identify and characterize a cilia-mediated Hh pathway in Drosophila olfactory sensory neurons. We demonstrate that several fundamental key aspects of the vertebrate cilia pathway, such as ciliary localization of Smoothened and the requirement of the intraflagellar transport system, are present in Drosophila. We show that Cos2 and Fused are required for the ciliary transport of Smoothened and that cilia mediate the expression of the Hh pathway target genes. Taken together, our data demonstrate that Hh signaling in Drosophila can be mediated by two pathways and that the ciliary Hh pathway is conserved from Drosophila to vertebrates. PMID- 24767999 TI - Pkd1 regulates lymphatic vascular morphogenesis during development. AB - Lymphatic vessels arise during development through sprouting of precursor cells from veins, which is regulated by known signaling and transcriptional mechanisms. The ongoing elaboration of vessels to form a network is less well understood. This involves cell polarization, coordinated migration, adhesion, mixing, regression, and shape rearrangements. We identified a zebrafish mutant, lymphatic and cardiac defects 1 (lyc1), with reduced lymphatic vessel development. A mutation in polycystic kidney disease 1a was responsible for the phenotype. PKD1 is the most frequently mutated gene in autosomal dominant polycystic kidney disease (ADPKD). Initial lymphatic precursor sprouting is normal in lyc1 mutants, but ongoing migration fails. Loss of Pkd1 in mice has no effect on precursor sprouting but leads to failed morphogenesis of the subcutaneous lymphatic network. Individual lymphatic endothelial cells display defective polarity, elongation, and adherens junctions. This work identifies a highly selective and unexpected role for Pkd1 in lymphatic vessel morphogenesis during development. PMID- 24768001 TI - Primordial dwarfism gene maintains Lin28 expression to safeguard embryonic stem cells from premature differentiation. AB - Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does not affect pluripotency but instead primes embryonic stem cells (ESCs) for differentiation via downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show that Larp7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28 mRNA stability. We propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a sufficient number of cell divisions prior to differentiation and ultimately to maintain proper organismal size. PMID- 24768002 TI - Experimental Lactococcus garvieae infection in zebrafish and first evidence of its ability to invade non-phagocytic cells. AB - Zebrafish has been used for studying infections and host-pathogen interactions in different bacterial fish pathogens. In the present study we evaluated the ability of Lactococcus garvieae to infect zebrafish when inoculated intraperitoneally with 2 * 10(7)UFC of this pathogen. L. garvieae can colonize and invade zebrafish at multiple anatomical sites causing a lethal acute septicemic infection with clinical signs and lesions consistent with those observed in lactococcosis outbreaks. Immunohistochemical studies showed the presence of L. garvieae into macrophages as well as into non-phagocytic zebrafish cells of liver (hepatocytes). The internalization capacity showed by L. garvieae in zebrafish cells was confirmed in the rainbow trout cell line RTG-2. Our results provide the first evidence that L. garvieae is able to invade non-phagocytic host cells. PMID- 24768003 TI - Beta2 toxin is not involved in in vitro cell cytotoxicity caused by human and porcine cpb2-harbouring Clostridium perfringens. AB - Clostridium perfringens is a common cause of intestinal disease in animals and humans. Its pathogenicity is attributed to the toxins it can produce, including the beta2 toxin. The presence of cpb2, the gene encoding the beta2 toxin, has been associated with diarrhoea in neonatal piglets and humans. However, the exact role of the beta2 toxin in the development of diarrhoea is still unknown. In this study we investigated the level of cytotoxicity to porcine IPI-21 and human Caco 2 cell-lines caused by porcine and human cpb2-harbouring C. perfringens and the significance of the beta2 toxin for the induction of cell cytotoxicity. Supernatants of porcine cpb2-harbouring C. perfringens strains were cytotoxic to both cell lines. Cell cytotoxicity caused by supernatant of human cpb2-harbouring C. perfringens strains was variable among strains. However, removal of the beta2 toxin by anti-beta2 toxin antibodies or degradation of the beta2 toxin by trypsin did not reduce the cytotoxic effect of any of the supernatants. These data suggest that beta2 toxin does not play a role in the development of cell cytotoxicity in in vitro experiments. In vivo studies are necessary to definitely define the role of beta2 toxin in the development of cell cytotoxicity and subsequent diarrhoea. PMID- 24768004 TI - After adjusting for bias in meta-analysis seasonal influenza vaccine remains effective in community-dwelling elderly. AB - OBJECTIVE: To compare the performance of the bias-adjusted meta-analysis to the conventional meta-analysis assessing seasonal influenza vaccine effectiveness among community-dwelling elderly aged 60 years and older. STUDY DESIGN AND SETTING: Systematic literature search revealed 14 cohort studies that met inclusion and exclusion criteria. Laboratory-confirmed influenza, influenza-like illness, hospitalization from influenza and/or pneumonia, and all-cause mortality were study outcomes. Potential biases were identified using bias checklists. The magnitude and uncertainty of biases were assessed by expert opinion. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using random effects model. RESULTS: After incorporating biases, overall effect estimates regressed slightly toward no effect, with the largest relative difference between conventional and bias-adjusted ORs for laboratory-confirmed influenza (OR, 0.18; 95% CI: 0.01, 3.00 vs. OR, 0.23; 95% CI: 0.03, 2.04). In most of the studies, CIs widened reflecting uncertainties about the biases. The between-study heterogeneity reduced considerably with the largest reduction for all-cause mortality (I(2) = 4%, P = 0.39 vs. I(2) = 91%, P < 0.01). CONCLUSION: This case study showed that after addressing potential biases influenza vaccine was still estimated effective in preventing hospitalization from influenza and/or pneumonia and all-cause mortality. Increasing the number of assessors and incorporating empirical evidence might improve the new bias-adjustment method. PMID- 24768005 TI - Exploring interaction effects in small samples increases rates of false-positive and false-negative findings: results from a systematic review and simulation study. AB - OBJECTIVE: To give a comprehensive comparison of the performance of commonly applied interaction tests. METHODS: A literature review and simulation study was performed evaluating interaction tests on the odds ratio (OR) or the risk difference (RD) scales: Cochran Q (Q), Breslow-Day (BD), Tarone, unconditional score, likelihood ratio (LR), Wald, and relative excess risk due to interaction (RERI)-based tests. RESULTS: Review results agreed with results from our simulation study, which showed that on the OR scale, in small sample sizes (eg, number of subjects <= 250) the type 1 error rates of the LR test was 0.10; the BD and Tarone tests showed results around 0.05. On the RD scale, the LR and RERI tests had error rates around 0.05. On both scales, tests did not differ regarding power. When exposure prevented the outcome RERI-based tests were relatively underpowered (eg, N = 100; RERI power = 5% vs. Wald power = 18%). With increasing sample size, difference decreased. CONCLUSION: In small samples, interaction tests differed. On the OR scale, the Tarone and BD tests are recommended. On the RD scale, the LR and RERI-based tests performed best. However, RERI-based tests are underpowered compared with other tests, when exposure prevents the outcome, and sample size is limited. PMID- 24768006 TI - Donor category and seasonal climate associated with embryo production and survival in multiple ovulation and embryo transfer programs in Holstein cattle. AB - The present study investigated the effect of Holstein donor category (cows vs. heifers) and climate variation (hot vs. cooler season) on the efficiency of in vivo embryo production programs as well as embryo survival after transferred to Holstein recipient cows. A total of 1562 multiple ovulation (MO) procedures (cows: n = 609, and heifers: n = 953) and 4076 embryo transfers (ETs) performed in two dairy herds were evaluated. Donor cows had greater number of CLs (10.6 +/- 0.6 vs. 7.5 +/- 0.4; P < 0.0001) and ova/embryos recovered (7.6 +/- 0.6 vs. 4.6 +/- 0.4; P < 0.0001) compared with donor heifers. However, fertilization rate (47.9 vs. 82.4%; P < 0.0001) and proportion of transferable embryos (31.5 vs. 67.4%; P < 0.0001) were lower in donor cows than heifers, respectively. Regardless of donor category, the proportion of freezable embryos was less (P < 0.001) during hot season than in cooler season (21.4 vs. 32.8%). However, greater decline in the proportion of freezable embryos during the hot season was observed in cows (21.7 vs. 10.7%) compared with heifers (46.2 vs. 38.1%; P = 0.01). In contrast, the season on which the embryo was produced (hot or cool) did not affect pregnancy rate on Day 31 (30.5 vs. 31.7%; P = 0.45) and 45 (25.3 vs. 25.1%; P = 0.64) of pregnancy. Regardless of the season in which the embryos were produced, embryonic survival after transferring embryos retrieved from donor cows was greater on Days 31 (36.0 vs. 30.7%; P = 0.001) and 45 (28.3 vs. 23.1%; P = 0.001) of pregnancy when compared with embryos from donor heifers. In conclusion, MO embryo production efficiency decreased during the hot seasons both in cows and heifers; however, the decline was more pronounced in donor cows. Regardless of the embryo source, similar pregnancy rate was observed in the recipient that received embryos produced during the hot and cooler seasons. Curiously, embryos originating from donor cows had higher embryonic survival when transferred to recipient cows than embryos originating from heifers. PMID- 24768007 TI - Intraovarian effect of dominant follicle and corpus luteum on number of follicles during a follicular wave in heifers. AB - The intraovarian relationships among dominant follicle (DF), corpus luteum (CL), and number of follicles between Days 0 to 5 (Day 0 = ovulation) in wave 1 (n = 65 waves) and Days 9 to 13 in wave 2 (n = 62) were analyzed in separate experiments in Bos taurus heifers. Ovaries were grouped into intraovarian patterns of DF-CL, DF alone, CL alone, and neither DF nor CL. In wave 1, the pattern frequencies of DF-CL or neither DF nor CL (34% each) were greater (P < 0.0004) than for DF alone or CL alone (16% each). The number of growing follicles >=5.0 mm, was greater (P < 0.0001) in ovaries with the DF, even when the DF was removed from the tally (P < 0.03). In a factorial analysis of wave 1, there was a positive main effect of DF (3.9 +/- 0.2 vs. 2.2 +/- 0.2 follicles; P < 0.0001), but the main effect of CL and the interaction of DF and CL were not significant. In a factorial analysis of wave 2, there were more (P < 0.0001) follicles greater than 6 mm in ovaries with a DF when the DF was included and an approaching difference (P < 0.09) when the DF was excluded. The main effect of CL and the interaction of DF and CL were not significant. The hypothesis that both the DF and CL have a positive intraovarian effect on number of follicles in waves 1 and 2 was only partly supported; the DF, but not the CL, had an effect in the factorial analyses. Previous reports in cattle and sheep of a positive intraovarian effect of CL on number of follicles are questionable in that location of the DF was not considered. PMID- 24768008 TI - Genetic causes of male infertility. AB - Male infertility, affecting around half of the couples with a problem to get pregnant, is a very heterogeneous condition. Part of patients are having a defect in spermatogenesis of which the underlying causes (including genetic ones) remain largely unknown. The only genetic tests routinely used in the diagnosis of male infertility are the analyses for the presence of Yq microdeletions and/or chromosomal abnormalities. Various other single gene or polygenic defects have been proposed to be involved in male fertility. Yet, their causative effect often remains to be proven. The recent evolution in the development of whole genome based techniques may help in clarifying the role of genes and other genetic factors involved in spermatogenesis and spermatogenesis defects. PMID- 24768009 TI - Editorial comment. PMID- 24768010 TI - Distinct metabolic characteristics and risk of stone recurrence in patients with multiple stones at the first-time presentation. AB - OBJECTIVE: To characterize the clinical and metabolic abnormalities of patients presenting with multiple stones and determine their risk of new stone formation. MATERIALS AND METHODS: This retrospective case-controlled study consisted of 911 patients who had ureter stones for the first time and 107 age- and sex-matched patients without stones. The patients were classified into 2 groups: those with a single ureter stone (n = 690) and those with 1 or more additional stones somewhere in the ureter or kidney (n = 221). All patients underwent 24-hour urinary metabolic evaluation. The 240 patients (26.3%) who were followed for >12 months (median follow-up, 35.0 months) were included in recurrence analyses. Stone recurrence was defined as "new stone formation," namely, the radiographic appearance of stones that had not been present in previous examinations. RESULTS: The multiple-stone group had significantly lower urinary citrate excretion than the single-stone (P = .011) and control (P = .003) groups. Compared with the single-stone group, it also had a higher incidence of hypocitraturia (P = .011) and stone recurrence (27 of 84 [32.1%] vs 29 of 156 [18.6%] patients; P = .025). Multivariate Cox regression analyses revealed that stone multiplicity (hazard ratio, 2.343; 95% confidence interval, 1.302-4.220; P = .005) was an independent predictor of recurrent stone formation. Kaplan-Meier curves showed identical results. CONCLUSION: The patients with multiple stones had distinct metabolic characteristics, particularly hypocitraturia and a significantly higher risk of recurrence than patients with 1 stone. Patients with multiple stones, even if it is their first stone episode, should undergo metabolic evaluation and possibly also potassium citrate therapy to prevent future stones. PMID- 24768011 TI - Reply: To PMID 24768012. PMID- 24768012 TI - Editorial comment. PMID- 24768013 TI - Safety of hexaminolevulinate for blue light cystoscopy in bladder cancer. A combined analysis of the trials used for registration and postmarketing data. AB - OBJECTIVE: To detail and put into perspective, safety of hexaminolevulinate blue light cystoscopy (HAL-BLC), including repeated use, based on combined data of controlled trials used for registration of HAL and postmarketing experience. METHODS: Safety data of 2 randomized comparative studies (group 1) and 4 within patient control studies (group 2) were combined. Postmarketing data from >200,000 patients were analyzed. RESULTS: In group 1, 533 patients were examined with HAL BLC and 499 with white light (WL) cystoscopy. In group 2, 791 patients were examined with both WL and HAL-BLC. Between 73% and 93% of these patients had concomitant diseases. Between 41% and 58% of the patients had at least 1 adverse event (AE), although predominantly mild to moderate. The majority was considered as not related to HAL-BLC and reported in the urinary tract. No serious adverse events (SAEs) were considered definitely related to HAL-BLC, but in 6 patients serious AEs were of an uncertain relationship. Four possibly related hypersensitivity reactions have been reported. Repeated use did not reveal additional toxicity, also supported by data from 3 European centers. CONCLUSION: This combined and detailed analysis of patients from 6 HAL-BLC studies with very comparable criteria shows that HAL-BLC is safe and poses very little additional risks other than expected for WL cystoscopy for bladder tumor resection in this specific patient population. This is supported by 9 years of postmarketing experience. Repeated use also seems safe. PMID- 24768014 TI - The impact of radical prostatectomy operative time on outcomes and costs. AB - OBJECTIVE: To examine the impact of radical prostatectomy (RP) operative time on outcomes and cost, we performed a population-based assessment of operative time as a predictor of outcomes. Although operative time has been used as a metric to evaluate RP surgeon learning curves, the effect of RP operative times on outcomes remains understudied. MATERIALS AND METHODS: We used US Surveillance, Epidemiology, and End Results-Medicare linked data to identify 7534 men aged>=66 years diagnosed with prostate cancer during 2003-2007 who underwent RP for localized prostate cancer through 2009. We categorized RP operative time into quartiles (short, intermediate, long, and very long) and used propensity score analyses to assess its impact on perioperative complications, mortality, length of hospitalization, readmissions, emergency room visits, and costs. RESULTS: Quartiles ranged from 0 to 172 minutes for short, 173 to 214 minutes for intermediate, 215 to 268 minutes for long, and >=269 minutes for very long RP operative times. After propensity score adjustment, longer operative time was associated with more surgery-related complications (short, 12.0%; intermediate, 12.3%; long, 14.4%; and very long, 22.8%; P<.001), longer median (interquartile range) length of stay in days (short, 2 [2-3]; intermediate, 2 [2-3]; long, 2 [1 3]; and very long, 2 [1-3]; P<.001), and higher median costs (short, $10,647; intermediate, $10,957; long, $11,405; and very long, $11,966; P<.001). CONCLUSION: Longer RP operative time is associated with more complications, longer lengths of hospital stay, and higher costs. Increasing operative efficiency may reduce complications, length of stay, and health-care costs. PMID- 24768015 TI - A case of penetrating glass foreign body within the renal cortex. AB - A 32-year-old patient sustained a penetrating injury to the left flank and kidney after a fall backward onto a glass table. On computed tomography imaging, a 12*10*4 cm glass shard was identified penetrating the renal cortex. The patient was taken to the operating room to remove the foreign object. A rubber-shodded clamp was used to successfully remove the glass shard without complication. Although we commonly encounter stab wounds at our trauma center, the penetrating object is rarely present. The presence of the glass object resulted in a technically challenging and rare case. PMID- 24768016 TI - Ewing sarcoma of the scrotum. AB - Nonosseous Ewing sarcoma commonly occurs in the extremities or deep soft tissues. However, cutaneous and subcutaneous locations have been reported. A 3-year-old boy presented with a 2-year history of a painless, slowly growing mid-scrotal mass. Pathology after surgical excision revealed the lesion to be Ewing sarcoma. The patient is free of metastatic disease and is currently undergoing chemotherapy. Soft-tissue malignancies must be kept in the differential diagnosis of any solid paratesticular mass in a child. Although rhabdomyosarcoma is the most common, as this case demonstrates, other rare sarcomas are also possible. PMID- 24768017 TI - Urethrography interpretation skills of urology and radiology residents at tertiary care medical centers. AB - OBJECTIVE: To assess the ability of urology and radiology residents to interpret retrograde urethrograms (RUGs) and voiding cystourethrograms (VCUGs). METHODS: A standardized examination of 10 combination RUGs and VCUGs of the male urethra was administered to urology and radiology residents from all levels of training at Washington University, Stanford University, and Northwestern University. Residents were asked to evaluate stricture location(s) and length, if present. RESULTS: Sixty residents participated, consisting of 26 from Washington University, 15 from Stanford University, and 19 from Northwestern University. Average years of training for urology and radiology were 3.6 and 2.8 years, respectively (P=.01). Normal RUGs and VCUGs were recognized by 18 of 31 radiologists (58%) and 19 of 29 urologists (65.5%; P=.5). Anterior strictures were correctly identified in 145 of 403 (36%) and 165 of 377 (43.8%) responses by radiologists and urologists, respectively (P=.03). Posterior strictures were correctly identified in 20 of 62 (32.3%) and 10 of 58 (17.2%) responses by radiologists and urologists, respectively (P=.09). When both groups of residents were combined, anterior strictures were identified correctly more often than posterior strictures (39.7% vs 25%; P<.01). Overall accuracy was 24.2% (75 of 310) for the radiology group and 27.9% (81 of 290) for the urology group (P=.30). In the presence of multiple strictures, accuracy declined to 7.26% (9 of 124) for the radiology group and 9.48% (11 of 116) for the urology group (P=.5), with a combined accuracy of 8.33% (20 of 240). CONCLUSION: Radiology and urology residents in the United States have poor skills at interpreting urethrography, especially when multiple strictures or posterior strictures are present. A formal educational program for RUG and VCUG interpretation should be designed and implemented into the radiology and urology resident curriculum. PMID- 24768018 TI - Two-stage repair with long channel technique for primary severe hypospadias. AB - OBJECTIVE: To introduce a 2-stage repair with long channel technique for primary severe hypospadias. PATIENTS AND METHODS: Between March 2010 and November 2013, 16 children with primary severe hypospadias underwent 2-stage repair with long channel technique. The technique applied in the first stage was almost the same as Bracka 2-stage repair. The second stage was usually performed 6 months later. A small transverse skin incision, distal to the meatal opening and about 1 cm in length, was made. Dissection was carried out deep into the surface of corpora cavernosa and a plane between the subcutaneous tissue and corpora cavernosa was reached. A long channel between the subcutaneous tissue and corpora cavernosa was created from the para-meatus incision to the apex of glans. A rectangle, pedicle scrotal septal skin flap was elevated and tubularized into neourethra around a stenting tube. The neourethra was delivered through the subcutaneous channel and fixed at the apex of glans. RESULTS: The mean operation time of the first and second stages was 65 and 55 minutes, respectively. The mean age at the first and second operation was 28 and 36 months, respectively. The mean follow-up was 10 months. No fistula, glans dehiscence, urethral stricture, and meatal stenosis were recorded. One scrotal surgical wound infection occurred after second stage and healed successfully with antibiotics treatment. The overall cosmetic and functional outcomes after second stage were excellent. CONCLUSION: Two-stage repair with long channel technique was applicable for primary severe hypospadias, with excellent short-term outcomes. PMID- 24768019 TI - A comparison of renal function outcomes after nephron-sparing surgery and radical nephrectomy for nonsyndromic unilateral Wilms tumor. AB - OBJECTIVE: To better understand the impact of nephron-sparing surgery (NSS) on renal function in patients with nonsyndromic unilateral Wilms tumor (uWT), a group of such patients treated with NSS were compared with a stage-matched cohort managed with radical nephrectomy (RN). The recommended management of nonsyndromic uWT is RN. However, NSS may decrease the risk of long-term renal disease and associated comorbidities. MATERIALS AND METHODS: An international, multi institutional review was conducted of nonsyndromic uWT cases managed with NSS and compared with a stage-matched RN cohort. Data were collected on demographics, oncologic characteristics and outcomes, serum creatinine, and estimated glomerular filtration rate (eGFR) calculated via Schwartz formula. RESULTS: Fifteen patients who underwent NSS (6 females and 9 males) met study criteria and were diagnosed at a median age of 2.5 years (range, 0.2-8.2 years) and followed for a median of 8.4 years (range, 0.5-31.8 years). The stage-matched RN cohort consisted of 15 patients (8 females and 7 males) diagnosed at a median age of 3.7 years (0.3-7.4) and followed for a median of 2.1 years (0.6-10.5 years). The median preoperative eGFR was 91.7 (39.4-237.7) and 149.9 (93.8-215.9) for NSS and RN, respectively, P=.026. The median eGFR at last follow-up was 135.3 (57.5 185.8) and 131.0 (98.6-161.2) for NSS and RN, respectively, P=.95. The median change in eGFR during the study period was a gain of 28.6 (-51.9 to 83.0) for the NSS cohort vs a loss of 19.1 (-54.7 to 25.2) for the RN cohort, P=.007. CONCLUSION: In a highly selected patient population with nonsyndromic uWT, NSS provides excellent renal function preservation when compared with RN. These data require validation via prospective investigation on a larger scale. PMID- 24768020 TI - Reply: To PMID 24768009. PMID- 24768021 TI - Anterior fascial fixation does not reduce the parastomal hernia rate after radical cystectomy and ileal conduit. AB - OBJECTIVE: To compare the rate of parastomal hernia in patients undergoing anterior fascial fixation of the ileal conduit with that in patients without fascial fixation. Limited data exist on whether anterior fascial fixation of the ileal conduit impacts the rate of parastomal hernia. METHODS: A total of 496 consecutive patients undergoing radical cystectomy and ileal conduit reconstruction from 1995 to 2012 were retrospectively evaluated for parastomal hernia. All patients had a 2-fingerbreadth aperture and the ileal conduit brought through the rectus muscle and sheath. Patients were divided into 1 of 3 groups based on stoma fixation and/or reinforcement: anterior fascial fixation, posterior reinforcement, or no fascial fixation. A parastomal hernia was defined as a palpable bulge at the stoma site. Multivariate logistic regression was conducted for the primary end point of parastomal hernia, controlling for other patient- and treatment-related factors that might affect the rate of parastomal hernia. RESULTS: Median follow-up was 16 months (range, 1-189 months). The parastomal hernia rate was significantly greater in the anterior fascial suture group (43 of 281; 15.3%) than the no fascial suture group (12 of 164; 7.3%; P=.02). Multivariate logistic regression analysis modeled for the occurrence of a parastomal hernia demonstrated that anterior fascial fixation was an independent predictor of the development of parastomal hernia (odds ratio, 2.3; 95% confidence interval, 1.03-5.14; P=.04). CONCLUSION: Anterior fascial fixation of the ileal conduit does not reduce the risk of parastomal hernia formation compared with the patients treated without fascial fixation. Surgeons should consider avoiding anterior suture fixation during ileal conduit creation. PMID- 24768022 TI - Breast cancer patients' experiences within and outside the safety net. AB - BACKGROUND: Following reforms to the breast-cancer referral process for our city's health Safety Net (SN), we compared the experiences from first abnormality to definitive diagnosis of breast-cancer patients referred to Siteman Cancer Center from SN and non-SN (NSN) providers. MATERIALS AND METHODS: SN-referred patients with any stage (0-IV) and NSN-referred patients with late-stage (IIB-IV) breast cancer were prospectively identified after diagnosis during cancer center consultations conducted between September 2008 and June 2010. Interviews were taped and transcribed verbatim; transcripts were independently coded by two raters using inductive methods to identify themes. RESULTS: Of 82 eligible patients, 57 completed interviews (33/47 SN [70%] and 24/35 NSN [69%]). Eighteen SN-referred patients (52%) had late-stage disease at diagnosis, as did all NSN patients (by design). A higher proportion of late-stage SN patients (67%) than either early-stage SN (47%) or NSN (33%) patients reported feelings of fear and avoidance that deterred them from pursuing care for concerning breast findings. A higher proportion of SN late-stage patients than NSN patient reported behaviors concerning for poor health knowledge or behavior (33% versus 8%), but reported receipt of timely, consistent communication from health care providers once they received care (50% versus 17%). Half of late-stage SN patients reported improper clinical or administrative conduct by health care workers that delayed referral and/or diagnosis. CONCLUSIONS: Although SN patients reported receipt of compassionate care once connected with health services, they presented with higher-than-expected rates of late-stage disease. Psychological barriers, life stressors, and provider or clinic delays affected access to and navigation of the health care system and represent opportunities for intervention. PMID- 24768023 TI - Trehalose solution protects mesothelium and reduces bowel adhesions. AB - BACKGROUND: Preventing interbowel adhesions still remains a challenge. Peritoneal mesothelial damage can induce postoperative adhesions. Our study evaluated the effects of 3% trehalose solution on mesothelial protection and adhesion prevention. Also, we compared this novel solution with Seprafilm regarding efficacy. METHODS: Mesothelial damage was induced on the cultured human mesothelial cell (Met-5A) and rabbit cecum-serosal surface by air-drying for 60 min, and trehalose solution was applied. Cell integrity was tested by measuring lactate dehydrogenase, and serosal-morphologic changes were analyzed using scanning electron microscopy. Intra-abdominal adhesions were induced in rabbits by the combination of abrasion and air-drying procedures. Animals were divided into four groups: control, 3% trehalose solution, Seprafilm, and 3% trehalose solution with Seprafilm. Adhesions were evaluated blindly 7 d later. RESULTS: Lactate dehydrogenase release from the Met-5A cells was reduced dose-dependently by trehalose (P < 0.05). Morphologic studies clearly showed that mesothelial cells on the serosal surface were kept intact by 3% trehalose solution. In a rabbit adhesion model, 3% trehalose solution reduced adhesions between bowel and bowel or bowel and surrounding structures (P < 0.01 versus control and Seprafilm). Seprafilm reduced adhesions between abdominal wall and underlying viscera (P < 0.01 versus control and 3% trehalose solution). Three-percent trehalose solution with Seprafilm showed additive effects of adhesion prevention, reducing adhesion formation at the previously mentioned sites. CONCLUSIONS: Three percent trehalose solution protects mesothelial cells and leads to reduced adhesions between bowel and bowel or bowel and surrounding structures. This effect seems to be resulted from the characteristics of the solution covering most areas that potentially develop adhesions. PMID- 24768025 TI - [Therapeutic inertia in asthma]. PMID- 24768024 TI - Visualizing surgical quality data with treemaps. AB - BACKGROUND: Treemaps are space-constrained visualizations for displaying hierarchical data structures using nested rectangles. The visualization allows large amounts of data to be examined in one display. The objective of this research was to examine the effects of using treemap visualizations to help surgeons assess surgical quality data from the American College of Surgeons created the National Surgical Quality Improvement Program database in a quick and timely manner. STUDY DESIGN: A controlled human subjects experiment was conducted to assess the ability of individuals to make quick and accurate judgments on surgery data by visualizing a treemap, with data hierarchically displayed by surgeon group, surgeon, and patient. Participants were given 20 task questions to complete involving examining the treemap and comparing surgeons' patients based on outcomes (dead or alive) and length of stay days. The outcomes measured were error (incorrect or correct) and task completion time. RESULTS: 120 participants completed 20 task questions for a total of 2400 responses. The main effects of layout and node size were found to be significant for absolute error, P < 0.0505 and P < 0.0185, respectively. The average judgment time to complete a task was 24 s with an accuracy rate of approximately 68%. CONCLUSIONS: This study served as a proof of concept to determine if treemaps could be beneficial in assessing surgical data retrospectively by allowing surgeons and healthcare administrators to make quick visual judgments. The study found that factors about the layout design affect judgment performance. Future research is needed to examine whether implementing the treemap within a dashboard system will improve on judgment accuracy for surgical quality questions. PMID- 24768026 TI - [Ovarian metastasis as the initial manifestation of a colorectal cancer]. PMID- 24768027 TI - [Rhabdomyolysis secondary to simvastatin and phenofibrate]. AB - Statins, which are used as first-line drugs in the prevention of cardiovascular disease, are usually safe, but in some cases there may be muscular toxicity. Statin-associated myopathy, can present as myalgia, myositis or rhabdomyolysis. Only 0.44 per 10,000 treated and per year, develop rhabdomyolysis. There are many risk factors associated with the patient and with the pharmacological treatment. A risk of muscle injury of 1-5% has been reported with some statins combined with fibrates. The fibrate with the highest risk of myopathy in combination with statins is gemfibrozil, while phenofibrate seems to be the safest. The case is presented of a 60 year-old woman with clinical symptoms and laboratory findings that suggested rhabdomyolysis secondary to a combination of simvastatin and phenofibrate. This case reminds physicians of the need to closely monitor these patients, in addition to alert them to the onset of muscle pain or weakness. PMID- 24768028 TI - [Anisakis infection with atypical presentation: Report of a case]. PMID- 24768030 TI - Drosophila gains traction as a repurposed tool to investigate metabolism. AB - The use of fruit flies has recently emerged as a powerful experimental paradigm to study the core aspects of energy metabolism. The fundamental need for lipid and carbohydrate processing and storage across species dictates that the central regulators that control metabolism are highly conserved through evolution. Accordingly, the Drosophila system is being used to identify human disease genes and has the potential to model successfully human disorders that center on excessive caloric intake and metabolic dysfunction, including diet-induced lipotoxicity and type 2 diabetes. We review here recent progress on this front and contend that increasing such efforts will yield unexpectedly high rates of experimental return, thereby leading to novel approaches in the treatment of obesity and its comorbidities. PMID- 24768029 TI - [Resistant arterial hypertension in Primary Care patients in Spain. PRESCAP Study 2010]. AB - OBJECTIVE: To determine the prevalence and clinical and epidemiological characteristics of Primary Care patients with resistant hypertension (RHT) in Spain. PATIENTS AND METHODS: A cross-sectional multicenter study was conducted on hypertensive patients aged 18 or over and seen in a Primary Care clinic. RHT was considered as the presence of uncontrolled blood pressure in patients treated with at least 3 drugs, one of which is a diuretic. RESULTS: Of the 12,961 hypertensive patients in the PRESCAP 2010 study, 962 (7.4%) fulfilled criteria for RHT, of whom 51% were women, and with a mean age (SD) 68.8 [11.4] years. Patients with RHT were older (68.80 [10.69] years vs. 66.06 [11.44] years, P<.001), had a higher prevalence of obesity (55.2 vs. 38.6%, P<.001), a higher waist circumference (103.90 [13.89] vs. 99.32 [13.69] cm, P<.001), and a higher prevalence of DM (48.3 vs. 29.5%, P<.001). The prevalence of target organ damage (73.0 vs. 61.4%, P<.001) and cardiovascular disease (46.7 vs. 26.8%, P<.001) were higher in patients with resistant hypertension. The multivariate analysis showed that the variables associated with resistant hypertension were the presence of cardiovascular disease, diabetes mellitus, sedentary life style, microalbuminuria, body mass index, duration of AHT, and triglycerides. CONCLUSIONS: The prevalence of RHT in Primary Care patients is related to inappropriate lifestyles, the presence of target organ damage, and cardiovascular disease. PMID- 24768031 TI - Immunology: a 360 tour. PMID- 24768032 TI - Sonoelectrochemical degradation of triclosan in water. AB - The sonoelectrochemical degradation of triclosan in aqueous solutions with high frequency ultrasound (850kHz) and various electrodes was investigated. Diamond coated niobium electrode showed the best results and was used as standard electrode, leading to effective degradation and positive synergistic effect. The influence of different parameters on the degradation degree and energy efficiency were evaluated and favorable reaction conditions were found. It could be shown that 92% of triclosan (1mgL(-1) aqueous solution) was degraded within 15min, following pseudo-first order kinetics. PMID- 24768033 TI - Surviving change: the metabolic journey of hematopoietic stem cells. AB - Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that maintain blood production and are uniquely wired to adapt to diverse cellular fates during the lifetime of an organism. Recent studies have highlighted a central role for metabolic plasticity in facilitating cell fate transitions and in preserving HSC functionality and survival. This review summarizes our current understanding of the metabolic programs associated with HSC quiescence, self renewal, and lineage commitment, and highlights the mechanistic underpinnings of these changing bioenergetics programs. It also discusses the therapeutic potential of targeting metabolic drivers in the context of blood malignancies. PMID- 24768034 TI - Stimulus-response bindings in priming. AB - People can rapidly form arbitrary associations between stimuli and the responses they make in the presence of those stimuli. Such stimulus-response (S-R) bindings, when retrieved, affect the way that people respond to the same, or related, stimuli. Only recently, however, has the flexibility and ubiquity of these S-R bindings been appreciated, particularly in the context of priming paradigms. This is important for the many cognitive theories that appeal to evidence from priming. It is also important for the control of action generally. An S-R binding is more than a gradually learned association between a specific stimulus and a specific response; instead, it captures the full, context dependent behavioral potential of a stimulus. PMID- 24768035 TI - Extracapsular dissection of the parapharyngeal space for a pleomorphic adenoma: a 10-year review. AB - Pleomorphic adenomas of the parapharyngeal space are difficult to remove with a margin of normal tissue. We reviewed 29 cases of extracapsular dissection of a parapharyngeal pleomorphic adenoma and found that extracapsular dissection does not increase the probability of recurrence of the tumour. PMID- 24768036 TI - Antonio Bayes de Luna - the man behind the BaMa ECG Symposia. AB - Since 2005 Professor Antonio Bayes de Luna and Dr Miquel Fiol have invited experts in electrocardiography to consensus meeting in Barcelona and Mallorca. The meetings have resulted in consensus papers related to different electrocardiography topics. An interview with Professor Bayes de Luna was conducted. PMID- 24768037 TI - A literature synthesis of health promotion research in salons and barbershops. AB - CONTEXT: Barbershops and beauty salons are located in all communities and frequented by diverse groups of people, making them key settings for addressing health disparities. No studies have reviewed the growing body of literature describing studies promoting health in these settings. This review summarized the literature related to promoting health within barbershops and beauty salons to inform future approaches that target diverse populations in similar settings. EVIDENCE ACQUISITION: We identified and reviewed published research articles describing formative research, recruitment, and health-related interventions set in beauty salons and barbershops. PubMed and other secondary search engines were searched in 2010 and again in 2013 for English-language papers indexed from 1990 through August 2013. The search yielded 113 articles, 71 of which were formerly reviewed, and 54 were eligible for inclusion. EVIDENCE SYNTHESIS: Included articles were categorized as formative research (n=27); recruitment (n=7); or intervention (n=20). Formative research studies showed that owners, barbers/stylists, and their customers were willing participants, clarifying the feasibility of promoting health in these settings. Recruitment studies demonstrated that salon/shop owners will join research studies and can enroll customers. Among intervention studies, level of stylist/barber involvement was categorized. More than 73.3% of intervention studies demonstrated statistically significant results, targeted mostly racial/ethnic minority groups and focused on a variety of health topics. CONCLUSIONS: Barbershops and beauty salons are promising settings for reaching populations most at risk for health disparities. Although these results are encouraging, more rigorous research and evaluation of future salon- and barbershop-based interventions are needed. PMID- 24768038 TI - Osteoblast-derived sphingosine 1-phosphate to induce proliferation and confer resistance to therapeutics to bone metastasis-derived prostate cancer cells. AB - Sphingosine 1-phosphate (S1P) plays important roles in cell proliferation, differentiation or survival mainly through its surface G-protein-coupled receptors S1P1-5. Bone represents the major site of metastasis for prostate cancer (CaP) cells, which rely on bone-derived factors to support their proliferation and resistance to therapeutics. In the present work we have found that conditioned medium (CM) from the MC3T3 osteoblastic cell line or primary murine and human osteoblast-like cells, as well as co-culture with MC3T3 stimulate proliferation of CaP lines in S1P-dependent manner. In addition, osteoblastic-derived S1P induces resistance of CaP cells to therapeutics including chemotherapy and radiotherapy. When S1P release from osteoblastic cells is decreased (inhibition of SphK1, knock-down of SphK1 or the S1P transporter, Spns2 by siRNA) or secreted S1P neutralized with anti-S1P antibody, the proliferative and survival effects of osteoblasts on CaP cells are abolished. Because of the paracrine nature of the signaling, we studied the role of the S1P receptors expressed on CaP cells in the communication with S1P secreted by osteoblasts. Strategies aimed at down-regulating S1P1, S1P2 or S1P3 (siRNA, antagonists), established the exclusive role of the S1P/S1P1 signaling between osteoblasts and CaP cells. Bone metastases from CaP are associated with osteoblastic differentiation resulting in abnormal bone formation. We show that the autocrine S1P/S1P3 signaling is central during differentiation to mature osteoblasts by regulating Runx2 level, a key transcription factor involved in osteoblastic maturation. Importantly, differentiated osteoblasts exhibited enhanced secretion of S1P and further stimulated CaP cell proliferation in a S1P dependent manner. By establishing the dual role of osteoblast-borne S1P on both osteoblastic differentiation and CaP cell proliferation and survival, we uncover the importance of S1P in the bone metastatic microenvironment, which may open a novel area of study for the treatment of CaP bone metastasis by targeting S1P. PMID- 24768039 TI - Standardized decision support in next generation sequencing reports of somatic cancer variants. AB - Of hundreds to thousands of somatic mutations that exist in each cancer genome, a large number are unique and non-recurrent variants. Prioritizing genetic variants identified via next generation sequencing technologies remains a major challenge. Many such variants occur in tumor genes that have well-established biological and clinical relevance and are putative targets of molecular therapy, however, most variants are still of unknown significance. With large amounts of data being generated as high throughput sequencing assays enter the clinical realm, there is a growing need to better communicate relevant findings in a timely manner while remaining cognizant of the potential consequences of misuse or overinterpretation of genomic information. Herein we describe a systematic framework for variant annotation and prioritization, and we propose a structured molecular pathology report using standardized terminology in order to best inform oncology clinical practice. We hope that our experience developing a comprehensive knowledge database of emerging predictive markers matched to targeted therapies will help other institutions implement similar programs. PMID- 24768040 TI - Sequencing of antiangiogenic agents in the treatment of metastatic colorectal cancer. AB - Significant advances have been made with respect to our understanding of the critical role of agents targeting angiogenic pathways in the treatment of metastatic colorectal cancer (mCRC). The approval of 3 agents that target angiogenic signaling, bevacizumab, ziv-aflibercept, and regorafenib, provides strong evidence that angiogenesis is an important process in mCRC. The addition of bevacizumab to combination chemotherapy in the first- and second-line treatment of mCRC has resulted in meaningful improvement in overall and progression-free survival. The standard of care for mCRC has evolved to incorporate cytotoxic chemotherapy as the backbone regimens (eg, FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin], FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]) with or without bevacizumab, and epidermal growth factor receptor-targeted therapies (eg, cetuximab, panitumumab) in the setting of wild type KRAS. The development of ziv-aflibercept in combination with FOLFIRI has improved clinical efficacy in the second-line treatment of mCRC. Regorafenib, a small-molecule multikinase inhibitor, has recently been approved by the US Food and Drug Administration as single-agent therapy in the treatment of refractory and progressive mCRC. Each of these agents has been integrated into an evidence based-albeit, still evolving-treatment continuum for initial treatment, treatment after first progression, and treatment after second progression. However, the most effective strategy for the use of these agents, and others in development remains unclear. This review provides an overview of the current clinical evidence for the use of antiangiogenic agents targeting in the treatment of mCRC. PMID- 24768041 TI - Histone variants at the transcription start-site. AB - The function of a eukaryotic cell crucially depends on accurate gene transcription to ensure the right genes are expressed whereas unrequired genes are repressed. Therefore, arguably, one of the most important regions in the genome is the transcription start-site (TSS) of protein-coding and non-coding genes. Until recently, understanding the mechanisms that define the location of the TSS and how it is created has largely focused on the role of DNA sequence specific transcription factors. However, within the nucleus of a eukaryotic cell, transcription occurs in a highly compacted nucleosomal environment, and it is becoming clear that accessibility of the TSS is a key controlling step in transcriptional regulation. It has traditionally been thought that transcription can only proceed once the nucleosomes at the TSS have been evicted. New work suggests otherwise, however, and the focus of this review is to challenge this belief. PMID- 24768043 TI - Giovanni Strippoli: Finding the pleasures in nephrology. PMID- 24768044 TI - Modern outcome and risk analysis of surgically resected occult N2 non-small cell lung cancer. AB - BACKGROUND: This study was performed to assess the incidence, survival, and risk factors associated with unsuspected pathologic N2 disease in patients with resectable clinical N0-1 non-small cell lung cancer. METHODS: Between January 2002 and December 2010, 1,821 patients with clinical N0-1 non-small cell lung cancer underwent pulmonary resection and mediastinal lymph node dissection. Clinical outcomes and risk factors for pathologic N2 disease were retrospectively analyzed for this cohort. RESULTS: Unsuspected pathologic N2 disease was identified in 196 patients (10.8%). The most common type of resection was lobectomy (81.6%). Adjuvant therapy was administered in 177 patients (90.3%). The median follow-up time was 28 months (range, 1 to 101 months). N2 involvement was single-station in 121 (66.8%) and multiple-station in 65 (33.2%). The 5-year overall and disease-free survival rates were 56.1% and 35.0%, respectively. The 5 year survival rates of single-station and multiple-station N2 were 66.6% and 36.4%, respectively (p < 0.001). Adenocarcinoma, clinical N1, tumor size (>3 cm), and a right middle lobe tumor were identified as independent risk factors for unsuspected multiple-station N2 disease by multivariate analysis. Incidence of unsuspected multiple-station N2 disease in low-risk classes (aggregate score, 0 to <=2) was only 5.5%. CONCLUSIONS: The incidence of unsuspected N2 disease in our cohort was similar to that of previous reports. Survival outcomes were favorable for unsuspected single-station N2 disease but were poor for unsuspected multiple-station N2 disease. Clinical N0-1 non-small cell lung cancer patients with risk class of low score for unsuspected multiple-station N2 disease can be exempted from aggressive mediastinal staging. PMID- 24768045 TI - Melatonin regulates the development and function of bovine Sertoli cells via its receptors MT1 and MT2. AB - Melatonin and its receptors are found in the testis of many species, where they mediate testicular functions. The present study aimed to investigate the expression of melatonin receptors (MT1 and MT2) in bovine Sertoli cells (SCs), using reverse transcription polymerase chain reaction (RT-PCR) and western blot. In addition, we assessed the mRNA levels of spermatogenesis-related genes (real time PCR) and secretion of inhibin B after treatment with various concentrations (0, 80, 160, and 320 pg/mL) of melatonin at different time points (24, 48, or 72 h). We found that bovine SCs express MT1 and MT2 receptors, which were regulated by melatonin in time- and dose-dependent manners after treatment with melatonin. Exogenous melatonin up-regulated the expression of spermatogenesis-related genes, including Cyclin D1, Cyclin E, Pdgfa, Dhh, Occludin, and Claudin, and decreased the mRNA levels of P21 and Kit1 in a time or dose-dependent manner. Meanwhile, melatonin supplementation significantly affected Inhba, Inhbb and Inha mRNA expression. These findings were consistent with inhibin B levels detected in the culture medium. In conclusion, exogenous melatonin acts via its receptors and appears to play regulatory roles in the development and function of bovine SCs. PMID- 24768046 TI - Constructs of electrospun PLGA, compressed collagen and minced urothelium for minimally manipulated autologous bladder tissue expansion. AB - Bladder regeneration based on minced bladder mucosa in vivo expansion is an alternative to in vitro culturing of urothelial cells. Here, we present the design of a hybrid, electrospun poly(lactic-co-glycolide) (PLGA) - plastically compressed (PC) collagen scaffold that could allow in vivo bladder mucosa expansion. Optimisation of electrospinning was performed in order to obtain increased pore sizes and porosity to consolidate the construct and to support neovascularisation and tissue ingrowth. Tensile tests showed an increase in average tensile strength from 0.6 MPa for PC collagen to 3.57 MPa for the hybrid construct. The optimised PLGA support scaffold was placed between two collagen gels, and the minced tissue was distributed either on top or both on top and inside the construct prior to PC; this was then cultured for up to four weeks. Morphology, histology and SEM demonstrated that the construct maintained its integrity throughout cell culture. Cells from minced tissue migrated, expanded and re-organised to a confluent cell layer on the top of the construct after two weeks and formed a multilayered urothelium after four weeks. Cell morphology and phenotype was typical for urothelial mucosa during tissue culture. PMID- 24768047 TI - Low-density lipoprotein-coupled N-succinyl chitosan nanoparticles co-delivering siRNA and doxorubicin for hepatocyte-targeted therapy. AB - Developing safe and effective carriers of small interference RNA (siRNA) is a significant demand for the systemic delivery of siRNA. In this study, low-density lipoprotein (LDL) was isolated from human plasma and loaded with cholesterol conjugated siRNA to silence the multidrug resistant gene of tumors. Chol siRNA/LDL-coupled N-succinyl chitosan nanoparticles loaded with doxorubicin (Dox siRNA/LDL-SCS-NPs) were then prepared and characterised. The Dox-siRNA/LDL-SCS NPs had average particle size of 206.4 +/- 9.2 nm, entrapment efficiency of 71.06% +/- 1.42%, and drug-loading amount of 12.35% +/- 0.87%. In vitro antitumor activity revealed that cell growth was significantly inhibited. The accumulation of Dox by fluorescence microscopy and flow cytometry showed that LDL-coupled nanoparticles were more easily taken up than Dox-SCS-NPs. Results of confocal microscopy and reverse transcription-PCR revealed the highly efficient uptake of siRNA and the decrease in mdr1 mRNA expression. LDL-coupled nanoparticles protected siRNA from macrophage phagocytosis by dynamic observation using live cell station. In vivo tumor-targeting suggested that Cy7-labelled Dox-LDL-SCS-NPs were markedly accumulated in an analyzed in situ liver tumor model. Results indicated that LDL-SCS-NPs were effective tumor-targeting vectors and that the preparation form may provide a new strategy for co-delivering siRNA and antitumor drugs. PMID- 24768048 TI - Candidate neural substrates for off-edge motion detection in Drosophila. AB - BACKGROUND: In the fly's visual motion pathways, two cell types-T4 and T5-are the first known relay neurons to signal small-field direction-selective motion responses [1]. These cells then feed into large tangential cells that signal wide field motion. Recent studies have identified two types of columnar neurons in the second neuropil, or medulla, that relay input to T4 from L1, the ON-channel neuron in the first neuropil, or lamina, thus providing a candidate substrate for the elementary motion detector (EMD) [2]. Interneurons relaying the OFF channel from L1's partner, L2, to T5 are so far not known, however. RESULTS: Here we report that multiple types of transmedulla (Tm) neurons provide unexpectedly complex inputs to T5 at their terminals in the third neuropil, or lobula. From the L2 pathway, single-column input comes from Tm1 and Tm2 and multiple-column input from Tm4 cells. Additional input to T5 comes from Tm9, the medulla target of a third lamina interneuron, L3, providing a candidate substrate for L3's combinatorial action with L2 [3]. Most numerous, Tm2 and Tm9's input synapses are spatially segregated on T5's dendritic arbor, providing candidate anatomical substrates for the two arms of a T5 EMD circuit; Tm1 and Tm2 provide a second. Transcript profiling indicates that T5 expresses both nicotinic and muscarinic cholinoceptors, qualifying T5 to receive cholinergic inputs from Tm9 and Tm2, which both express choline acetyltransferase (ChAT). CONCLUSIONS: We hypothesize that T5 computes small-field motion signals by integrating multiple cholinergic Tm inputs using nicotinic and muscarinic cholinoceptors. PMID- 24768049 TI - PI(4,5)P2 produced by the PI4P5K SKTL controls apical size by tethering PAR-3 in Drosophila epithelial cells. AB - BACKGROUND: The control of apical-basal polarity in epithelial layers is a fundamental event in many processes, ranging from embryonic development to tumor formation. A key feature of polarized epithelial cells is their ability to maintain an asymmetric distribution of specific molecular complexes, including the phosphoinositides PI(4,5)P2 and PI(3,4,5)P3. The spatiotemporal regulation of these phosphoinositides is controlled by the concerted action of phosphoinositide kinases and phosphatases. RESULTS: Using the Drosophila follicular epithelium as a model system in vivo, we show here that PI(4,5)P2 is crucial to maintain apical basal polarity. PI(4,5)P2 is essentially regulated by the PI4P5 kinase Skittles (SKTL), whereas neither the phosphatase PTEN nor the PI(4,5)P3 kinase DP110 lead to loss of apical-basal polarity. By inactivating SKTL and thereby strongly reducing PI(4,5)P2 levels in a single cell of the epithelium, we observe the disassembly of adherens junctions, actin cytoskeleton reorganization, and apical constriction leading to delamination, a process similar to that observed during epithelial-mesenchymal transition. We provide evidence that PI(4,5)P2 controls the apical targeting of PAR-3/Bazooka to the plasma membrane and that the loss of this polarized distribution is sufficient to induce a similar cell shape change. Finally, we show that PI(4,5)P2 is excluded from the cell apex and that PAR-3 diffuses laterally just prior to the apical constriction in a context of endogenous invagination. CONCLUSIONS: All together, these results indicate that the PIP5 kinase SKTL, by controlling PI(4,5)P2 polarity, regulates PAR-3 localization and thus the size of the apical domain. PMID- 24768050 TI - Cytokinin controls polarity of PIN1-dependent auxin transport during lateral root organogenesis. AB - The plant hormones auxin and cytokinin mutually coordinate their activities to control various aspects of development [1-9], and their crosstalk occurs at multiple levels [10, 11]. Cytokinin-mediated modulation of auxin transport provides an efficient means to regulate auxin distribution in plant organs. Here, we demonstrate that cytokinin does not merely control the overall auxin flow capacity, but might also act as a polarizing cue and control the auxin stream directionality during plant organogenesis. Cytokinin enhances the PIN-FORMED1 (PIN1) auxin transporter depletion at specific polar domains, thus rearranging the cellular PIN polarities and directly regulating the auxin flow direction. This selective cytokinin sensitivity correlates with the PIN protein phosphorylation degree. PIN1 phosphomimicking mutations, as well as enhanced phosphorylation in plants with modulated activities of PIN-specific kinases and phosphatases, desensitize PIN1 to cytokinin. Our results reveal conceptually novel, cytokinin-driven polarization mechanism that operates in developmental processes involving rapid auxin stream redirection, such as lateral root organogenesis, in which a gradual PIN polarity switch defines the growth axis of the newly formed organ. PMID- 24768051 TI - Whole-body acoel regeneration is controlled by Wnt and Bmp-Admp signaling. AB - Whole-body regeneration is widespread in the Metazoa, yet little is known about how underlying molecular mechanisms compare across phyla. Acoels are an enigmatic phylum of invertebrate worms that can be highly informative about many questions in bilaterian evolution, including regeneration. We developed the three-banded panther worm, Hofstenia miamia, as a new acoelomorph model system for molecular studies of regeneration. Hofstenia were readily cultured, with accessible embryos, juveniles, and adults for experimentation. We developed molecular resources and tools for Hofstenia, including a transcriptome and robust systemic RNAi. We report the identification of molecular mechanisms that promote whole body regeneration in Hofstenia. Wnt signaling controls regeneration of the anterior-posterior axis, and Bmp-Admp signaling controls regeneration of the dorsal-ventral axis. Perturbation of these pathways resulted in regeneration abnormal phenotypes involving axial feature duplication, such as the regeneration of two heads following Wnt perturbation or the regeneration of ventral cells in place of dorsal ones following bmp or admp RNAi. Hofstenia regenerative mechanisms are strikingly similar to those guiding regeneration in planarians. However, phylogenetic analyses using the Hofstenia transcriptome support an early branching position for acoels among bilaterians, with the last common ancestor of acoels and planarians being the ancestor of the Bilateria. Therefore, these findings identify similar whole-body regeneration mechanisms in animals separated by more than 550 million years of evolution. PMID- 24768052 TI - Replicative stress induces intragenic transcription of the ASE1 gene that negatively regulates Ase1 activity. AB - Intragenic transcripts initiate within the coding region of a gene, thereby producing shorter mRNAs and proteins. Although intragenic transcripts are widely expressed [1], their role in the functional regulation of genes remains largely unknown. In budding yeast, DNA replication stress activates the S phase checkpoint that stabilizes replication forks and arrests cells in S phase with a short spindle [2-4]. When yeast cells were treated with hydroxyurea (HU) to block DNA synthesis and induce replication stress, we found that Ase1, a conserved spindle midzone protein [5], appeared as two short protein isoforms in addition to the full-length protein. We further demonstrated that the short isoforms result from intragenic transcription of ASE1, which depends on the S phase checkpoint. Blocking generation of the short isoforms leads to a destabilized S phase spindle, characterized by increased spindle dynamics and frequent spindle collapse. Because the short Ase1 isoforms localize at the spindle in HU-treated cells and overexpression of the short Ase1 isoforms impairs the spindle midzone localization of full-length Ase1, it is likely that the presence of short Ase1 isoforms stabilizes the spindle by antagonizing full-length Ase1. Together, our results reveal intragenic transcription as a unique mechanism to downregulate gene functions in response to DNA replication stress. PMID- 24768053 TI - Leaf mimicry in a climbing plant protects against herbivory. AB - Mimicry refers to adaptive similarity between a mimic organism and a model. Mimicry in animals is rather common, whereas documented cases in plants are rare, and the associated benefits are seldom elucidated [1, 2]. We show the occurrence of leaf mimicry in a climbing plant endemic to a temperate rainforest. The woody vine Boquila trifoliolata mimics the leaves of its supporting trees in terms of size, shape, color, orientation, petiole length, and/or tip spininess. Moreover, sequential leaf mimicry occurs when a single individual vine is associated with different tree species. Leaves of unsupported vines differed from leaves of climbing plants closely associated with tree foliage but did not differ from those of vines climbing onto leafless trunks. Consistent with an herbivory avoidance hypothesis, leaf herbivory on unsupported vines was greater than that on vines climbing on trees but was greatest on vines climbing onto leafless trunks. Thus, B. trifoliolata gains protection against herbivory not merely by climbing and thus avoiding ground herbivores [3] but also by climbing onto trees whose leaves are mimicked. Unlike earlier cases of plant mimicry or crypsis, in which the plant roughly resembles a background or color pattern [4-7] or mimics a single host [8, 9], B. trifoliolata is able to mimic several hosts. PMID- 24768054 TI - The earliest pterodactyloid and the origin of the group. AB - The pterosaurs were a diverse group of Mesozoic flying reptiles that underwent a body plan reorganization, adaptive radiation, and replacement of earlier forms midway through their long history, resulting in the origin of the Pterodactyloidea, a highly specialized clade containing the largest flying organisms. The sudden appearance and large suite of morphological features of this group were suggested to be the result of it originating in terrestrial environments, where the pterosaur fossil record has traditionally been poor [1, 2], and its many features suggested to be adaptations to those environments [1, 2]. However, little evidence has been available to test this hypothesis, and it has not been supported by previous phylogenies or early pterodactyloid discoveries. We report here the earliest pterosaur with the diagnostic elongate metacarpus of the Pterodactyloidea, Kryptodrakon progenitor, gen. et sp. nov., from the terrestrial Middle-Upper Jurassic boundary of Northwest China. Phylogenetic analysis confirms this species as the basalmost pterodactyloid and reconstructs a terrestrial origin and a predominantly terrestrial history for the Pterodactyloidea. Phylogenetic comparative methods support this reconstruction by means of a significant correlation between wing shape and environment also found in modern flying vertebrates, indicating that pterosaurs lived in or were at least adapted to the environments in which they were preserved. PMID- 24768055 TI - A soft handoff of attention between cerebral hemispheres. AB - Each cerebral hemisphere initially processes one half of the visual world. How are moving objects seamlessly tracked when they traverse visual hemifields? Covert tracking of lateralized objects evokes a difference between slow-wave electrophysiological activity observed from contralateral and ipsilateral electrodes in occipitoparietal regions. This event-related potentials (ERP) waveform, known as contralateral delay activity (CDA) [1, 2], is sensitive to the number of objects tracked [1, 2] and responds dynamically to changes in this quantity [3]. When a tracked object crosses the midline, an inversion in CDA polarity revealed the dropping of the object's representation by one hemisphere and its acquisition by the other. Importantly, our data suggest that the initially tracking hemisphere continues to represent the object for a period after that object crosses the midline. Meanwhile, the receiving hemisphere begins to represent the object before the object crosses the midline, leading to a period in which the object is represented by both hemispheres. Further, this overlap in representation is reduced if the midline crossing is unpredictable. Thus, this process is sensitive to observer expectations and does not simply reflect overlapping receptive fields near the midline. PMID- 24768056 TI - Seasonal fluctuations in the response of Italian Mediterranean buffaloes to synchronization of ovulation and timed artificial insemination. AB - A comprehensive study of the efficiency of synchronization of ovulation and timed artificial insemination (TAI) was undertaken in a large group of Italian Mediterranean buffaloes at a commercial dairy. A total of 2791 synchronization protocols were carried out on 857 animals over 3 years. Of these protocols, 823 (29.5%) did not proceed beyond Day 7 (due to the absence of a vascularized CL) and 620 (22.2%) were discontinued on Day 10 (due to the absence of follicles >1.0 cm and tonic uteri); hence, 1443 (51.7%) protocols did not progress to TAI. Data were analyzed for four periods: P1, transition to spring (from breeding season to low breeding season); P2, low breeding season; P3, transition to fall (low breeding season to breeding season); and P4, breeding season. No differences were found among the four periods in terms of the proportion of protocols that did not result in TAI. Of the 857 buffaloes, 660 (77%) conceived and delivered a calf. The average number of TAI per pregnancy was 2.1 and ranged from 1.9 to 2.3 across years. Logistic regression analysis showed that buffaloes that calved during P3 had a higher odds ratio for pregnancy (1.380; P < 0.05) than buffaloes that calved in other periods. Pregnancy was also influenced by the calving to service period (odds ratio = 0.977; P < 0.01) and the pregnancy per AI (P/AI) at successive TAI (odds ratio = 1.480; P < 0.01). The pregnancy per AI at the first TAI (424/857, 49.5%) was greater (P < 0.01) than in subsequent TAI. The occurrence of late embryonic mortality (between Days 27 and 45 after TAI) was similar among the four periods. These findings indicated that there are distinct seasonal differences in the response of Italian Mediterranean buffaloes to synchronization and TAI. PMID- 24768057 TI - Effect of heterologous and homologous seminal plasma on stallion sperm quality. AB - Removing most of the seminal plasma (SP) from stallion semen has been shown to improve survival during cooled storage, yet adding small quantities of SP may improve pregnancy rates or cryosurvival. Furthermore, there is considerable controversy about whether the stallion's own SP or heterologous SP produces the best effect, possibly because of the variation between stallions in SP proteins or because some homologous SP remained in the sperm preparation. The SP is removed completely from stallion spermatozoa prepared by colloid centrifugation. Thus, the aim of the present study was (1) to investigate the effect of adding back SP to colloid centrifuged spermatozoa to determine its effect on spermatozoa; and (2) to investigate whether the stallion's own SP had a greater or lesser effect than heterologous SP. Conventional semen doses were sent from a stud overnight to the laboratory using standard transport conditions. Once at the laboratory, the semen samples were used for single layer centrifugation with Androcoll-E, and the resulting sperm preparations were treated with heterologous SP. Adding SP had a small but significant effect on sperm motility but no effect on the proportion of spermatozoa that had acrosome reacted. There were significant increases in hydrogen peroxide production and chromatin damage (P < 0.001). When homologous and heterologous SP were compared, considerable variation was observed between stallions, so that it was not possible to predict whether homologous or heterologous SP, or no SP, will produce the best motility for spermatozoa from any given stallion. Therefore, it is necessary to test different combinations of spermatozoa and SP to find the optimal effect on motility. The SP from most stallions increased reactive oxygen species and chromatin damage. In conclusion, the interaction between SP and spermatozoa depends on the origin of both SP and spermatozoa. If it is desirable to add SP to stallion sperm samples, it should be done directly before insemination rather than before storage, because of increased hydrogen peroxide production and sperm chromatin damage. PMID- 24768058 TI - Molecular characterization, sexually dimorphic expression, and functional analysis of 3'-untranslated region of vasa gene in half-smooth tongue sole (Cynoglossus semilaevis). AB - Vasa is a highly conserved ATP-dependent RNA helicase expressed mainly in germ cells. The vasa gene plays a crucial role in the development of germ cell lineage and has become an excellent molecular marker in identifying germ cells in teleosts. However, little is known about the structure and function of the vasa gene in flatfish. In this study, the vasa gene (Csvasa) was isolated and characterized in half-smooth tongue sole (Cynoglossus semilaevis), an economically important flatfish in China. In the obtained 6425-bp genomic sequence, 23 exons and 22 introns were identified. The Csvasa gene encodes a 663 amino acid protein, including highly conserved domains of the DEAD-box protein family. The amino acid sequence also shared a high homology with other teleosts. Csvasa expression was mainly restricted to the gonads, with little or no expression in other tissues. Real-time quantitative polymerase chain reaction analysis revealed that Csvasa expression levels decreased during embryonic and early developmental stages and increased with the primordial germ cell proliferation. A typical sexually dimorphic expression pattern of Csvasa was observed during early development and sex differentiation, suggesting that the Csvasa gene might play a differential role in the proliferation and differentiation of male and female primordial germ cells (PGCs). Csvasa mRNA expression levels in neomales were significantly lower than those in normal males and females, indicating that the Csvasa gene might be implicated in germ cell development after sex reversal by temperature treatment. In addition, medaka (Oryzias latipes) PGCs could be transiently labeled by microinjection of synthesized mRNA containing the green fluorescence protein gene and 3' untranslated region of Csvasa, which confirmed that the Csvasa gene has the potential to be used as a visual molecular marker of germ cells and laid a foundation for manipulation of PGCs in tongue sole reproduction. PMID- 24768059 TI - Application of a Scale for the Assessment and Rating of Ataxia (SARA) in Friedreich's ataxia patients according to posturography is limited. AB - BACKGROUND: A scale for the Assessment and Rating of Ataxia (SARA) was developed for evaluation of autosomal dominant cerebellar ataxias (ADCA) and was also recommended for clinical trials of Friedreich's ataxia patients (FRDA). FRDA, unlike ADCA, is characterized as being a sensory type of ataxia for which the disease-specific Friedreich ataxia rating scale (FARS) was developed. The objective of this study was to determine whether SARA and FARS scores are associated with posturographic parameters in FRDA patients. METHOD: Adult patients with genetically confirmed FRDA (n=11) and ADCA (n=13) were evaluated by SARA, FARS and posturography. RESULTS: FRDA patients' postural stability parameters, in stance with visual control, correlated with balance impairment in FARS (r=0.622; p<0.05) and SARA (r=0.735; p<0.05). Without visual control, only FARS correlated with balance impairment (r=0.732; p<0.05). CONCLUSION: The SARA, in FRDA patients, correlates with stance with visual control but not without visual control which emphasizes sensory ataxia. This suggests that application of the SARA in Friedreich's ataxia patients according to posturography is possible but presumably limited and FARS, although being a more time consuming scale, may have advantages over SARA in FRDA patients. PMID- 24768060 TI - High HIV incidence in a cohort of male injection drug users in Delhi, India. AB - BACKGROUND: India has an estimated 177,000 injection drug users (IDU) with a national HIV prevalence of 7.14%. Reliable estimates of HIV incidence are not available for this population. METHODS: We report HIV incidence in a cohort of male, HIV-negative IDUs recruited through peer-referral, targeted outreach and as walk-in clients in Delhi from May to October, 2011. Fourth-generation Antigen Antibody tests were used to diagnose new infections and results were confirmed using Western blot tests. HIV incidence based on HIV seroconversion was calculated as number of events/person-years. Cox regression was used to identify significant (p<0.05) seroconversion predictors. RESULTS: A total of 2790 male HIV negative IDUs were recruited at baseline; 67.4% (n=1880) returned for their first follow-up visit and 96% (n=1806) underwent HIV testing. Participants were followed for a median of 9.7 months. A total of 112 new HIV infections occurred over a cumulative 1398.5 person-years of follow-up resulting in an incidence rate of 8.01 new infections/100 person-years (95% CI: 6.65-9.64); 74% of these participants reported risky injection practices in the past month. In multivariate analysis, moderate-high risk injection behaviors (Adjusted Hazard Ratio [AHR] 2.59; 95% CI 1.45-4.62) were associated with a higher risk of new infections. CONCLUSIONS: Male IDUs in Delhi continue to practice unsafe injection practices leading to high sero-incidence despite the availability of HIV prevention services offered through targeted intervention programs. PMID- 24768061 TI - Use of a single alcohol screening question to identify other drug use. AB - BACKGROUND: People who consume unhealthy amounts of alcohol are more likely to use illicit drugs. We tested the ability of a screening test for unhealthy alcohol use to simultaneously detect drug use. METHODS: Adult English speaking patients (n=286) were enrolled from a primary care waiting room. They were asked the screening question for unhealthy alcohol use "How many times in the past year have you had X or more drinks in a day?", where X is 5 for men and 4 for women, and a response of one or more is considered positive. A standard diagnostic interview was used to determine current (past year) drug use or a drug use disorder (abuse or dependence). Oral fluid testing was also used to detect recent use of common drugs of abuse. RESULTS: The single screening question for unhealthy alcohol use was 67.6% sensitive (95% confidence interval [CI], 50.2 82.0%) and 64.7% specific (95% CI, 58.4-70.6%) for the detection of a drug use disorder. It was similarly insensitive for drug use detected by oral fluid testing and/or self-report. CONCLUSIONS: Although a patient with a drug use disorder has twice the odds of screening positive for unhealthy alcohol use compared to one without a drug use disorder, suggesting patients who screen positive for alcohol should be asked about drug use, a single screening question for unhealthy alcohol use was not sensitive or specific for the detection of other drug use or drug use disorders in a sample of primary care patients. PMID- 24768063 TI - Antifungal activities and chemical composition of some medicinal plants. AB - The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists and natural-products scientists are combing the earth for phytochemicals and leads, which could be developed for treatment of infectious diseases. The aim of this study was to investigate the antifungal activities of the essential oils of some medicinal plants such as Stachys pubescens, Thymus kotschyanus, Thymus daenensis and Bupleurum falcatum against Fusarium oxysporum, Aspergillus flavus and Alternaria alternata. The essential oils were used to evaluate their MICs and MFCs compared to the amphotricin B as a standard drug. The essential oils were also analyzed by GC/MS. Essential oils isolated from the S. pubescens, T. kotschyanus and B. falcatum showed strong antifungal activities. The essential oil of T. daenensis exhibited a moderate activity against the selected fungi in comparison with the other plants' essential oils. In addition, the results showed that 26, 23, 22 and 15 components were identified from the essential oils of T. kotschyanus, S. pubescens, T. daenensis and B. falcatum, respectively. These oils exhibited a noticeable antifungal activity against the selected fungi. Regarding obtained results and that natural antimicrobial substances are inexpensive and have fewer side effects, they convey potential for implementation in fungal pathogenic systems. PMID- 24768062 TI - Bone regeneration via novel macroporous CPC scaffolds in critical-sized cranial defects in rats. AB - OBJECTIVES: Calcium phosphate cement (CPC) is promising for dental and craniofacial applications due to its ability to be injected or filled into complex-shaped bone defects and molded for esthetics, and its resorbability and replacement by new bone. The objective of this study was to investigate bone regeneration via novel macroporous CPC containing absorbable fibers, hydrogel microbeads and growth factors in critical-sized cranial defects in rats. METHODS: Mannitol porogen and alginate hydrogel microbeads were incorporated into CPC. Absorbable fibers were used to provide mechanical reinforcement to CPC scaffolds. Six CPC groups were tested in rats: (1) control CPC without macropores and microbeads; (2) macroporous CPC+large fiber; (3) macroporous CPC+large fiber+nanofiber; (4) same as (3), but with rhBMP2 in CPC matrix; (5) same as (3), but with rhBMP2 in CPC matrix+rhTGF-beta1 in microbeads; (6) same as (3), but with rhBMP2 in CPC matrix+VEGF in microbeads. Rats were sacrificed at 4 and 24 weeks for histological and micro-CT analyses. RESULTS: The macroporous CPC scaffolds containing porogen, absorbable fibers and hydrogel microbeads had mechanical properties similar to cancellous bone. At 4 weeks, the new bone area fraction (mean+/-sd; n=5) in CPC control group was the lowest at (14.8+/-3.3)%, and that of group 6 (rhBMP2+VEGF) was (31.0+/-13.8)% (p<0.05). At 24 weeks, group 4 (rhBMP2) had the most new bone of (38.8+/-15.6)%, higher than (12.7+/-5.3)% of CPC control (p<0.05). Micro-CT revealed nearly complete bridging of the critical sized defects with new bone for several macroporous CPC groups, compared to much less new bone formation for CPC control. SIGNIFICANCE: Macroporous CPC scaffolds containing porogen, fibers and microbeads with growth factors were investigated in rat cranial defects for the first time. Macroporous CPCs had new bone up to 2 fold that of traditional CPC control at 4 weeks, and 3-fold that of traditional CPC at 24 weeks, and hence may be useful for dental, craniofacial and orthopedic applications. PMID- 24768064 TI - [Dormancy of Candida albicans ATCC10231 in the presence of amphotericin B. Investigation using the scanning electron microscope (SEM)]. AB - OBJECTIVES: The aim of this study was to visualize the morphology of Candida albicans ATCC10231 in the absence and in the presence of amphotericin B at 0.4 MUg/mL, to better understand the phenomenon responsible for a large portion of cases of treatment failure called "dormancy phenomenon". The main objective was to determine the morphological changes adopted by C. albicans in the lag phase extended before resuming normal growth. MATERIALS AND METHODS: In order to define the morphological characteristics and surface properties of the cells in the absence and in the presence of amphotericin B at 0.4 MUg/mL, cells were cultured in Sabouraud medium at 30 degrees C, and the morphology index was determined by reference to the classification of forms in C. albicans determined by Merson Davies and Odds. Then, the technique of scanning electron microscopy (SEM) coupled with image analysis was used to measure the surface and determined the morphological properties using the plugin analysis three-dimensional (3D) integrated into the ImageJ software. RESULTS: The dormant phase in C. albicans ATCC10231 grown in Sabouraud liquid at 30 degrees C in the presence of amphotericin B at 0.4 MUg/mL extends to 21 hours. The index morphology obtained for the two samples (in the absence and presence of amphotericin B) indicates that the cell even in the presence of amphotericin B retains its yeast form (Mi<1.5) The analysis of microphotography obtained by scanning electron microscopy (SEM) has shown that the cell in the presence of amphotericin B is partially deformed; the deformation is estimated at 33.25%, with various changes in the cell surface. CONCLUSION: This study showed that the morphology of C. albicans ATCC10231 in the presence of amphotericin B at 0.4 MUg/mL changes with partial deformation of the cell. This rate is insufficient to induce cell death, which partly explains the phenomenon of dormancy adopted by C. albicans prior to cell repair and resume normal growth. PMID- 24768066 TI - [Cracking knee in an 8-year-old child]. PMID- 24768065 TI - The Mertk receptor tyrosine kinase promotes T-B interaction stimulated by IgD B cell receptor cross-linking. AB - The Mertk receptor tyrosine kinase facilitates macrophage and DC apoptotic-cell clearance and regulates immune tolerance. Mertk may also contribute to B-cell activation, because Mertk-KO mice fail to develop autoantibodies when allo activated by T cells. We investigated this possibility with a well-characterized model in which injection of mice with goat anti-IgD antibody causes membrane IgD cross-linking that induces T-independent B cell activation and antigen presentation to T cells. Goat anti-mouse IgD antibody-injected C57BL/6 Mertk-KO mice had normal initial B cell activation and proliferation, but significantly lower T cell activation and proliferation, as well as lower IgE and IgG anti-goat IgG responses, as compared to C57BL/6 WT controls. B cell antigen processing, analyzed by evaluating B cell fluorescence following injection of monoclonal anti IgD antibody labeled with biotin or FITC, was comparable between Mertk-KO mice and WT mice. IgD Ab primed B cells from Mertk-KO mice exhibited significantly lower ability in activating memory T cells isolated from WT mice injected with the same antigen 10 days before. These observations suggest that Mertk expression is required for optimal B-cell antigen presentation, which is, in turn, required in this model for optimal T cell activation and subsequent T cell-dependent B cell differentiation. PMID- 24768067 TI - [Impact of the instrumental vaginal delivery on pain perception at two months]. AB - INTRODUCTION: Although instrumental vaginal delivery reduces the risk of neonatal mortality, it increases the risk of specific morbidity including prolonged neonatal discomfort. Previous studies suggest that neonatal exposure to acute pain could have long-term effects on the pain response later in life. The aim of the study was to investigate whether instrumental vaginal delivery may alter the response to a noxious stimulus at the age of two months. METHOD: Newborn infants were enrolled in this prospective observational study after parental consent. A group of children born by instrumental vaginal delivery (group 2) were compared to matched controls born by vaginal delivery (group 1). Pain was assessed in each newborn infant between two and four hours after birth using the scale of pain and discomfort of the newborn baby (EDIN). These children were reassessed for pain response to immunizations (Infanrix((r)) and Prevenar((r))) at two months of age using the DAN scale. RESULTS: Thirteen children were enrolled in this study, six in group 1 and seven in group 2. Gestational age, birth weight, Apgar score, and umbilical arterial blood were similar in both groups. The EDIN measured between H2 and H4 was significantly higher in group 2 (median, 4 [IQ, 3] versus 0 [3.25], P<0.05). While the DAN score before and during immunization was similar in the two groups, it was statistically higher in group 2 than in group 1 (4 [3] versus 2 [2.25], P<0.01) within the15 min following the injections. CONCLUSION: These results indicate that birth by instrumental vaginal delivery causes discomfort after birth and increases the pain response to immunization at the age of two months. This study supports the hypothesis that instrumental vaginal delivery may alter pain perception later in life. PMID- 24768068 TI - [Should we consider newborn screening for Pompe disease?]. PMID- 24768069 TI - [Treatment of scabies and Ascabiol((r)) supply disruption: what about the pediatric population?]. AB - Scabies is a disease in steady increase in Ile-de-France region. Standard treatment, Ascabiol((r)) (benzyl benzoate/sulfiram), is back-order for several months and its return remains uncertain. Facing this drug shortage, French Drug Agency (ANSM) has imported a drug from Germany, Antiscabiosum 10 % (benzyl benzoate), to treat patients having contraindications for other scabicides available in France (ivermectin, esdepallethrine). However, infants less than 1 year (<15 kg) and asthmatics infants have no alternative treatment. A multidisciplinary workgroup explored the various existing therapeutic alternatives in France and worldwide. From ANSM's recommendations and group's experience, a decision algorithm was proposed for treating patients. However, pediatric context implied the use of off-label drugs. Proposed treatments widely known by practitioners, prescriptions-types, dose, modalities of use and dispensation, and flyers to patients were realized to optimize treatment efficacy. PMID- 24768070 TI - [Low pneumococcal conjugated vaccine immunization coverage in low-income families: a study in Ile-de-France]. AB - INTRODUCTION/OBJECTIVES: Socio-economic inequalities in access to vaccination are poorly documented in France. This study analyzed socio-economic inequalities in pneumococcal conjugate vaccine (PCV7) immunization coverage, the cost of which is about 180 ? for three doses. METHODS: We conducted a cross-sectional survey including children aged 0-5 years living in Paris and its immediate suburbs, selected by a stratified two-stage random sampling design. Data were collected in a face-to-face interview. Vaccination coverage, confirmed by a document, was measured for the first dose and the full primary vaccination series. Poisson regression was used to analyze the association between PCV7 vaccination coverage and several socio-economic and demographic factors. RESULTS: Vaccination coverage for the first dose was 93.7% and 76.7% for the full primary vaccination series. The first-dose vaccination coverage in children from lower income families (first quartile of income) was lower than that of children from higher income families (83.2% versus 97.3%, P=0.033). A similar result was also observed for the full primary vaccination series, although this result was not statistically significant (65.5% versus 87.6%, P=0.09). Full coverage was lower in children with only basic health insurance (70.2%) than in children with additional health insurance either through social assistance (81.4%) or through private insurance (76.1%), but these differences were not significant. CONCLUSIONS: The association of low PCV7 vaccination coverage with low family income suggests the existence of financial barriers to vaccination in the poorest families. However, the lack of a statistical association with the type of health insurance could also indicate the existence of obstacles to vaccination other than purely financial. PMID- 24768071 TI - [Prevalence of geohelminth infections in children living in Kinshasa]. AB - BACKGROUND: Data on geohelminth infections in children in the Democratic Republic of Congo are sparse. The objective of this study was to document and compare the profile and prevalence in children living in Kinshasa. METHODS: A prospective cohort study was conducted from May to October 2009 in children in the Biyela health area in Kinshasa, Democratic Republic of Congo. Stool samples were collected from representative members of these two populations and analyzed for geohelminths (GH) using the Kato-Katz technique. RESULTS: In this series, 438 school-age children were included. There were 235 children recruited in schools and 203 in households (77.8%). Overall prevalence of geohelminths was 66.9%. The specific prevalence was 69.4% in children recruited in schools and 64.0% in children recruited in households. The frequency of Ascaris lumbricoides, Trichuris trichiura, and Ancylostoma species were, respectively, 56.2%, 38.7%, and 1.7% in schools and 39.9%, 51.7%, and 1.0% in households. A. lumbricoides was significantly more prevalent in schools (56.2% vs 39.9%; OR=2.0; 95%CI: 1.3-3.0), T. trichiura was significantly less prevalent in schools (38.7% vs 51.7%; OR=0.6; 95% CI: 0.4-0.9). There were no significant differences in the prevalence of Ancylostoma between schools and households. CONCLUSION: GH is a health problem among Biyela children. Preventive measures and education of the population need to be emphasized in attempts to reduce the prevalence of geohelminths in these children. PMID- 24768072 TI - [GACI syndrome: a case report with a neonatal beginning]. AB - GACI (generalized arterial calcification of infancy) is a rare autosomal recessive disorder characterized by arterial and periarticular calcifications. Most children die in the first months of life of cardiovascular complications. Hypophosphatemic rickets (HR) resistant to medical treatment may complete the phenotype and is associated with a milder phenotype. This report discusses the case of a girl who presented neonatal ectopic periarticular calcifications with spontaneous regression, and then at the age of 3 years developed HR. There was no clinical improvement after treatment with calcitriol and phosphate, and correction of alkaline phosphatase induced the recurrence of periarticular and tissular calcifications : the treatment was reduced and the bone distortion treated by surgery. GACI diagnosis was confirmed by genetic analysis. At the age of 4.5 years, she developed a retinal abnormality and decreased radial pulse: these clinical signs are usually observed in pseudoxanthoma elasticum (PXE). It is now established that GACI and PXE belong to the same entity characterized by arterial and tissular calcifications of which this original case report is an illustration. PMID- 24768073 TI - [Infant botulism after honey exposure]. AB - Infant botulism is a rare neuroparalytic disease caused by the neurotoxin of Clostridium botulinum. Initial clinical features are constipation, poor feeding, descending hypotonia, drooling, irritability, weak crying and cranial nerve dysfunctions. We describe the clinical progression and the epidemiological investigation carried out in a 3-month-old infant. Better knowledge of the disease should allow faster diagnosis and adequate management. We emphasize the risks associated with honey exposure in children less than one year old and that honey should not be fed to infants under 12 months of age. PMID- 24768074 TI - Take a screen-free day! PMID- 24768075 TI - Accountable care organizations: what you need to know. PMID- 24768076 TI - Re: "An introduction to 'business essentials': purposes and plans". PMID- 24768077 TI - Are combined CT scans of the thorax being overused? AB - PURPOSE: A news article in June 2011 reported that Medicare claims showed considerable overuse of "double" CT scans of the thorax (ie, combined scans without contrast followed by with contrast) at a number of hospitals. Most radiologists agree that they should be done only on rare occasions. The aim of this study was to determine what proportion of all thoracic CT scans are combined scans in the Medicare population. METHODS: The data sources were the Medicare Part B Physician/Supplier Procedure Summary Master Files for 2001 to 2011. The 3 Current Procedural Terminology codes for thoracic CT (with contrast, without contrast, and without plus with contrast) were selected. Utilization rates per 1,000 beneficiaries and the percentage that were combined scans were calculated. RESULTS: The utilization rate of combined scans increased from 2001 through 2006, remained steady in 2007, but then decreased sharply thereafter. The compound annual rate of change from 2007 to 2011 was -10.4%. From 2001 through 2006, combined thoracic CT scans constituted 6.0% to 6.1% of all thoracic CT scans. However, from 2006 to 2011, this percentage progressively declined, reaching a low of 4.2% in 2011. CONCLUSIONS: Despite the 2011 news report, only a very small percentage of thoracic CT scans nationwide are done both without and with contrast. Moreover, that percentage dropped by almost one-third from 2006 to 2011, suggesting that the practice is declining. The figure of 4.2% can be used as a benchmark against which to judge radiology facilities in the future. PMID- 24768078 TI - Application of ACR appropriateness guidelines for spine MRI in the emergency department. PMID- 24768079 TI - Use of graph theory measures to identify errors in record linkage. AB - Ensuring high linkage quality is important in many record linkage applications. Current methods for ensuring quality are manual and resource intensive. This paper seeks to determine the effectiveness of graph theory techniques in identifying record linkage errors. A range of graph theory techniques was applied to two linked datasets, with known truth sets. The ability of graph theory techniques to identify groups containing errors was compared to a widely used threshold setting technique. This methodology shows promise; however, further investigations into graph theory techniques are required. The development of more efficient and effective methods of improving linkage quality will result in higher quality datasets that can be delivered to researchers in shorter timeframes. PMID- 24768080 TI - Attitude of Iranian physicians and nurses toward a clinical decision support system for pulmonary embolism and deep vein thrombosis. AB - This research project sought to design and implement a computerized clinical decision support system (CDSS) that was able to identify patients who were at risk of pulmonary embolism (PE) and deep vein thrombosis (DVT), as well as produce reminders for prophylactic action for these diseases. The main purpose of the CDSS was to attempt to reduce the morbidity and mortality caused by embolism and thrombosis in patients admitted to hospitals. After implementation of this system in one of the large educational hospitals of Iran, a standard questionnaire was used, and interviews were conducted with physicians and nurses to evaluate the performance of the designed system for reducing the incidence of pulmonary embolism and thrombosis. From physicians and nurses' point of view, a system which assists the medical staff in making better decisions regarding patient care, and also reminds pulmonary embolism and thrombosis preventive procedures with timely warnings, can influence patient care quality improvement and lead to the improved performance of the medical staff in preventing the incidence of pulmonary embolism and thrombosis. PMID- 24768081 TI - Epileptic seizure detection in EEGs signals using a fast weighted horizontal visibility algorithm. AB - This paper proposes a fast weighted horizontal visibility graph constructing algorithm (FWHVA) to identify seizure from EEG signals. The performance of the FWHVA is evaluated by comparing with Fast Fourier Transform (FFT) and sample entropy (SampEn) method. Two noise-robustness graph features based on the FWHVA, mean degree and mean strength, are investigated using two chaos signals and five groups of EEG signals. Experimental results show that feature extraction using the FWHVA is faster than that of SampEn and FFT. And mean strength feature associated with ictal EEG is significant higher than that of healthy and inter ictal EEGs. In addition, an 100% classification accuracy for identifying seizure from healthy shows that the features based on the FWHVA are more promising than the frequency features based on FFT and entropy indices based on SampEn for time series classification. PMID- 24768082 TI - Fixed structure compensator design using a constrained hybrid evolutionary optimization approach. AB - This paper presents an efficient technique for designing a fixed order compensator for compensating current mode control architecture of DC-DC converters. The compensator design is formulated as an optimization problem, which seeks to attain a set of frequency domain specifications. The highly nonlinear nature of the optimization problem demands the use of an initial parameterization independent global search technique. In this regard, the optimization problem is solved using a hybrid evolutionary optimization approach, because of its simple structure, faster execution time and greater probability in achieving the global solution. The proposed algorithm involves the combination of a population search based optimization approach i.e. Particle Swarm Optimization (PSO) and local search based method. The op-amp dynamics have been incorporated during the design process. Considering the limitations of fixed structure compensator in achieving loop bandwidth higher than a certain threshold, the proposed approach also determines the op-amp bandwidth, which would be able to achieve the same. The effectiveness of the proposed approach in meeting the desired frequency domain specifications is experimentally tested on a peak current mode control dc-dc buck converter. PMID- 24768083 TI - Test-retest reliability of sensor-based sit-to-stand measures in young and older adults. AB - This study investigated test-retest reliability of sensor-based sit-to-stand (STS) peak power and other STS measures in young and older adults. In addition, test-retest reliability of the sensor method was compared to test-retest reliability of the Timed Up and Go Test (TUGT) and Five-Times-Sit-to-Stand Test (FTSST) in older adults. Ten healthy young female adults (20-23 years) and 31 older adults (21 females; 73-94 years) participated in two assessment sessions separated by 3-8 days. Vertical peak power was assessed during three (young adults) and five (older adults) normal and fast STS trials with a hybrid motion sensor worn on the hip. Older adults also performed the FTSST and TUGT. The average sensor-based STS peak power of the normal STS trials and the average sensor-based STS peak power of the fast STS trials showed excellent test-retest reliability in young adults (intra-class correlation (ICC)>=0.90; zero in 95% confidence interval of mean difference between test and retest (95%CI of D); standard error of measurement (SEM)<=6.7% of mean peak power) and older adults (ICC>=0.91; zero in 95%CI of D; SEM<=9.9%). Test-retest reliability of sensor based STS peak power and TUGT (ICC=0.98; zero in 95%CI of D; SEM=8.5%) was comparable in older adults, test-retest reliability of the FTSST was lower (ICC=0.73; zero outside 95%CI of D; SEM=14.4%). Sensor-based STS peak power demonstrated excellent test-retest reliability and may therefore be useful for clinical assessment of functional status and fall risk. PMID- 24768084 TI - Immediate effect of Masai Barefoot Technology shoes on knee joint moments in women with knee osteoarthritis. AB - Footwear modification can beneficially alter knee loading in patients with knee osteoarthritis. This study evaluated the effect of Masai Barefoot Technology shoes on reductions in external knee moments in patients with knee osteoarthritis. Three-dimensional motion analysis was used to examine the effect of Masai Barefoot Technology versus control shoes on the knee adduction and flexion moments in 17 women (mean age, 63.6 years) with radiographically confirmed knee osteoarthritis. The lateral and anterior trunk lean values, knee flexion and adduction angles, and ground reaction force were also evaluated. The influence of the original walking pattern on the changes in knee moments with Masai Barefoot Technology shoes was evaluated. The knee flexion moment in early stance was significantly reduced while walking with the Masai Barefoot Technology shoes (0.25+/-0.14Nm/kgm) as compared with walking with control shoes (0.30+/ 0.19 Nm/kgm); whereas the knee adduction moment showed no changes. Masai Barefoot Technology shoes did not increase compensatory lateral and anterior trunk lean. The degree of knee flexion moment in the original walking pattern with control shoes was correlated directly with its reduction when wearing Masai Barefoot Technology shoes by multiple linear regression analysis (adjusted R2=0.44, P<0.01). Masai Barefoot Technology shoes reduced the knee flexion moment during walking without increasing the compensatory trunk lean and may therefore reduce external knee loading in women with knee osteoarthritis. PMID- 24768085 TI - Energy cost of walking in children with spastic cerebral palsy: relationship with age, body composition and mobility capacity. AB - The energy cost (EC) of walking is different for typically developing (TD) and children with cerebral palsy (CP). The associated factors of EC are not fully understood in children with CP. We assessed the relationship between EC and age, body surface area (BSA), and gross motor function measure (GMFM). We retrospectively examined data collected between 2003 and 2011 on 276 children aged 4-18 years who were classified as Gross Motor Function Classification System level I, n=79; II, n=123; and III, n=74. Energy cost was assessed while children walked 6-8 min at a comfortable, self-selected speed using their typical walking aids and/or orthoses as part of a clinical gait analysis. During the test, participants wore a breath-by-breath portable gas analysis system, measuring oxygen consumption. To calculate EC (J/kg/m), oxygen consumption was converted to J/kg/min and divided by walking speed. Data were analyzed using linear regression model. Energy cost correlated inversely with age (beta=-0.16, R2=0.02, P=0.01), BSA (beta=-3.35, R2=0.11, P<0.0001), and GMFM (beta=-0.12, R2=0.42, P<0.0001). In the multiple linear regression model, GMFM was the most potent correlate of EC, BSA explained another 10% of the variance (R2=0.53), and age was a marginally significant correlate of EC (P=0.08). In summary, in children with CP in our study, EC decreased as GMFM and BSA increased, and GMFM was the most potent correlate of EC. PMID- 24768086 TI - A preliminary study on atrial epicardial mapping signals based on Graph Theory. AB - In order to get a better understanding of atrial fibrillation, we introduced a method based on Graph Theory to interpret the relations of different parts of the atria. Atrial electrograms under sinus rhythm and atrial fibrillation were collected from eight living mongrel dogs with cholinergic AF model. These epicardial signals were acquired from 95 unipolar electrodes attached to the surface of the atria and four pulmonary veins. Then, we analyzed the electrode correlations using Graph Theory. The topology, the connectivity and the parameters of graphs during different rhythms were studied. Our results showed that the connectivity of graphs varied from sinus rhythm to atrial fibrillation and there were parameter gradients in various parts of the atria. The results provide spatial insight into the interaction between different parts of the atria and the method may have its potential for studying atrial fibrillation. PMID- 24768087 TI - Segmentation accuracy of long bones. AB - The use of three-dimensional imaging methodologies in new applications in the orthopaedic field has introduced a need for high accuracy, in addition to a correct diagnosis. The aim of this study was to quantify the absolute dimensional errors between models reconstructed from computed tomography and magnetic resonance images compared to a ground truth for various regions of the bone. Clinical CT and MRI scans were acquired from nine lower leg cadavers and the bones were subsequently cleaned from soft tissues. 3D models of the tibia were created from the segmented CT and MRI images and compared to optical scans of the cleaned bones (considered as ground truth). The 3D reconstruction using CT images resulted in an RMS error of 0.55 mm, corresponding to an overestimated CT bone model compared to the cleaned bone. MR imaging resulted in an RMS error of 0.56 mm; however, the MRI bone model was on average a small underestimation of the cleaned bone. Different regions of the bones were analysed, indicating a difference in accuracy between diaphysis and epiphysis. This study demonstrates a high accuracy for both CT and MRI imaging, supporting the feasibility of using MRI technology for the 3D reconstruction of bones in medical applications. PMID- 24768088 TI - Glucocorticoids and macrophage migration inhibitory factor (MIF) are neuroendocrine modulators of inflammation and neuropathic pain after spinal cord injury. AB - Traumatic spinal cord injury (SCI) activates the hypothalamic-pituitary-adrenal (HPA) axis, a potent neuroendocrine regulator of stress and inflammation. SCI also elicits a profound and sustained intraspinal and systemic inflammatory response. Together, stress hormones and inflammatory mediators will affect the growth and survival of neural and non-neural cells and ultimately neurologic recovery after SCI. Glucocorticoids (GCs) are endogenous anti-inflammatory steroids that are synthesized in response to stress or injury, in part to regulate inflammation. Exogenous synthetic GCs are often used for similar purposes in various diseases; however, their safety and efficacy in pre-clinical and clinical SCI is controversial. The relatively recent discovery that macrophage migration inhibitory factor (MIF) is produced throughout the body and can override the anti-inflammatory effects of GCs may provide unique insight to the importance of endogenous and exogenous GCs after SCI. Here, we review both GCs and MIF and discuss the potential relevance of their interactions after SCI, especially their role in regulating maladaptive mechanisms of plasticity and repair that may contribute to the onset and maintenance of neuropathic pain. PMID- 24768089 TI - The effects of a moisture-wicking fabric shirt on the physiological and perceptual responses during acute exercise in the heat. AB - This study investigated the effects that a form fitted, moisture-wicking fabric shirt, promoted to have improved evaporative and ventilation properties, has on the physiological and perceptual responses during exercise in the heat. Ten healthy male participants completed two heat stress tests consisting of 45 min of exercise (50% VO2peak) in a hot environment (33 degrees C, 60% RH). One heat stress test was conducted with the participant wearing a 100% cotton short sleeved t-shirt and the other heat stress test was conducted with the participant wearing a short sleeved synthetic shirt (81% polyester and 19% elastane). Rectal temperature was significantly lower (P < 0.05) in the synthetic condition during the last 15 min of exercise. Furthermore, the synthetic polyester shirt retained less sweat (P < 0.05). As exercise duration increases, the ventilation and evaporation properties of the synthetic garment may prove beneficial in the preservation of body temperature during exercise in the heat. PMID- 24768090 TI - Exploring positive hospital ward soundscape interventions. AB - Sound is often considered as a negative aspect of an environment that needs mitigating, particularly in hospitals. It is worthwhile however, to consider how subjective responses to hospital sounds can be made more positive. The authors identified natural sound, steady state sound and written sound source information as having the potential to do this. Listening evaluations were conducted with 24 participants who rated their emotional (Relaxation) and cognitive (Interest and Understanding) response to a variety of hospital ward soundscape clips across these three interventions. A repeated measures ANOVA revealed that the 'Relaxation' response was significantly affected (n(2) = 0.05, p = 0.001) by the interventions with natural sound producing a 10.1% more positive response. Most interestingly, written sound source information produced a 4.7% positive change in response. The authors conclude that exploring different ways to improve the sounds of a hospital offers subjective benefits that move beyond sound level reduction. This is an area for future work to focus upon in an effort to achieve more positively experienced hospital soundscapes and environments. PMID- 24768091 TI - Shoulder muscle loading and task performance for overhead work on ladders versus Mobile Elevated Work Platforms. AB - A high incidence of Musculoskeletal Disorders (MSDs) has been reported in the construction sector. The use of ladders in the workplace has long been identified as a significant risk that can lead to workplace accidents. However, it is unclear if platform types have an effect on the physical risk factors for MSDs in overhead work. The aim of this study is to perform a pilot study on the effects of hand activity on both shoulder muscle loading and task performance while working on ladders versus Mobile Elevated Working Platforms (MEWPs). It is hypothesised that work on ladders would result in greater muscle loading demands, increased levels of discomfort, and reduced performance due to the restrictions on postures that could be adopted. A field study (n = 19) of experienced electricians on a construction site found that workers spent approximately 28% of their working time on ladders versus 6% on MEWPs. However, the durations of individual tasks were higher on MEWPs (153 s) than on ladders (73 s). Additionally, maximum levels of perceived discomfort (on a VAS 0-100) were reported for the shoulders (27), neck (23), and lower regions of the body (22). A simulated study (n = 12) found that task performance and discomfort were not significantly different between platform types (ladder vs. MEWP) when completing either of three tasks: cabling, assembly and drilling. However, platform and task had significant effects (p < 0.05) on median electromyographic (EMG) activity of the anterior deltoid and upper trapezius. EMG amplitudes were higher for the deltoid than the upper trapezius. For the deltoid, the peak amplitudes were, on average, higher for ladder work over MEWP work for the hand intensive cabling (32 vs. 27% Maximal Voluntary Exertion (MVE)) and the assembly task (19 vs. 6% MVE). Conversely, for drilling, the peak EMG amplitudes were marginally lower for ladder compared to the MEWP (3.9 vs. 5.1% MVE). The general implication was that working on the MEWP involved lower shoulder muscle loading for cabling and assembly task. A difference due to platform type was not present for drilling work. PMID- 24768092 TI - Brainstem auditory evoked potential monitoring and neuro-endoscopy: two tools to ensure hearing preservation and surgical success during microvascular decompression. AB - BACKGROUND: The effectiveness of microvascular decompression (MVD) has made trigeminal neuralgia (TN), hemifacial spasm (HFS), glossopharyngeal neuralgia, and other cranial nerve rhizopathy diseases treatable by surgery. To ensure hearing preservation and surgical success, we have presented our experience in the application of brainstem auditory evoked potential (BAEP) monitoring and neuro-endoscopy during MVD. METHODS: From July 2007 to October 2012, a total of 93 patients in our institution received MVD for cranial nerve rhizopathies. Among these patients, 43 had both BAEP monitoring and endoscope-assisted microsurgery for their MVD. None of the patients had undergone previous surgical treatment. Postoperative outcomes were assessed based on the medical records and clinical follow-up. RESULTS: This study included 32 women and 11 men. There were 36 HFS cases and seven TN cases, and the median patient age at the time of MVD was 48 years. The median duration of symptoms before MVD was 4.2 years, and the median follow-up duration was 3.5 years (range 1.5 months-5 years). All of the patients had either immediate or delayed complete relief from the symptoms after MVD. One TN patient underwent gamma knife radiosurgery 3 years after MVD, and two HFS cases had recurrent slight spasms, which warranted no further treatment. There was no surgical mortality. The major complications included one HFS patient with delayed and permanent hearing loss and facial palsy, which occurred 1 week after MVD. The surgical success rate was 100%, and the hearing complication rate was 2%. CONCLUSION: The results of this retrospective study emphasized the importance of BAEP monitoring and neuro-endoscopy during MVD. It is well known that BAEP monitoring can preserve hearing function, and the endoscope offers neurosurgeons a second look to identify the nerve root entry zone and confirms the position of the Teflon felt. These two tools are especially useful in difficult cases. PMID- 24768093 TI - Sex, thrombosis and inherited thrombophilia. AB - The incidence of venous thromboembolism (VTE) is two-fold higher in women than in men during reproductive age, which is likely explained by the use of hormonal contraceptives and by pregnancy in this phase of life. After adjustment for these factors, men have a two-fold higher risk of developing a first VTE compared with women, which is in line with earlier observations that men have a two-fold higher risk of recurrent VTE. These findings indicate that the intrinsic risk of VTE is higher in men than in women. Hormonal contraceptives increase the risk of VTE and the risk varies per type, dose, and administration route. In women with a high baseline risk of VTE, avoidance of some hormonal contraceptives should be considered, as well as thrombosis prophylaxis during pregnancy. Presence of hereditary thrombophilia increases the risk of a first VTE episode. This review focuses on the differences in risk of VTE between men and women, hormonal risk factors for women, and how these interact with common types of hereditary thrombophilia. PMID- 24768094 TI - Trophoblast specialisations during pregnancy in the tammar wallaby, Macropus eugenii: a morphological and lectin histochemical study. AB - INTRODUCTION: The tammar wallaby has a short gestation (26.5 days) and vascular modifications to expedite transport during that brief pregnancy. Here we examine trophoblast structural attributes that would facilitate materno-fetal exchange. MATERIALS AND METHODS: Four specimens of Macropus eugenii between days 23 and 26 gestation were examined using electron microscopy and 24 lectins to characterise glycosylated secretions and their internalisation. RESULTS: Two trophoblast phenotypes were found, flattened cells generally in contact with the underlying uterine epithelium and giant cells associated with histiotrophe. The latter appeared to penetrate uterine clefts, occasionally detach and become necrotic. Lectin histochemistry and ultrastructure indicated the presence of many lysosomes and residual bodies especially in trophoblast giant cells; these contained glycans, mainly apically, which were also detected in secretions and cell debris. Trophoblast basal membranes bore extensive filopodia. Giant cells were less common in vascular trilaminar areas and here the trophoblast barrier became thinner near term. DISCUSSION: Loss of Maackia amurensis agglutinin binding suggested cleavage of terminal sialic acid residues as an early post internalisation event in the trophoblast. Lectin staining indicated degradation occurred in an apical-basal direction, and the heavily glycosylated basal membrane appeared specialised for transport out of the cell. CONCLUSION: Granules seen ultrastructurally and histochemically, particularly in giant trophoblast cells of the bilaminar area, suggest that internalised histiotrophe is broken down here and nutrients transferred to the embryo via the specialised basal plasma membrane. The trilaminar vascular area contained mostly flattened trophoblast cells, supporting the suggestion that gaseous exchange is its primary function. PMID- 24768095 TI - IL-1beta and TGF-beta weaken the placental barrier through destruction of tight junctions: an in vivo and in vitro study. AB - INTRODUCTION: Chorioamnionitis is a gestational pathological condition characterized by acute inflammation of the amniochorionic membranes and placentas leading to high concentrations of IL-1beta, Il-6, Il-8 and TGF-beta in the amniotic fluid. In normal conditions, the permeability of foeto-maternal barrier is due to the assembly and maintenance of different cellular junctional domains. METHODS: In the present study, first we aimed to evaluate the protein expression (by immunohistochemistry and western blotting) and mRNA (by real time PCR) levels of the molecular components of tight junctions (Zonula occludens-1 and occludin), and of adherent junctions (VE-cadherin and beta-catenin) in placentas from chorioamnionitis compared to that in normal pregnancies. RESULTS: Western blotting results showed a significant down-regulation of occludin in placentas affected with chorioamnionitis. No differences were detected for the other proteins analysed. We evaluated whether occludin expression was regulated by IL 1beta, IL-6, IL-8 and TGF-beta by means of in vitro studies using HUVEC cultures and demonstrated a key role of IL-1beta and TGF-beta in the disappearance of occludin at cellular border. CONCLUSIONS: We conclude by suggesting a pivotal role of these two cytokines in facilitating intra-placental infection via para cellular way due to the disassembly of tight junctions at trophoblastic and endothelial cells in placental tissues. PMID- 24768096 TI - Injury outcomes in African American and African Caribbean women: the role of intimate partner violence. AB - INTRODUCTION: Intimate partner violence has been linked to increased and repeated injuries, as well as negative long-term physical and mental health outcomes. This study examines the prevalence and correlates of injury in women of African descent who reported recent intimate partner violence and control subjects who were never abused. METHODS: African American and African Caribbean women aged 18 to 55 years were recruited from clinics in Baltimore, MD, and the US Virgin Islands. Self-reported demographics, partner violence history, and injury outcomes were collected. Associations between violence and injury outcomes were examined with logistic regression. RESULTS: All injury outcomes were significantly more frequently reported in women who also reported recent partner violence than in women who were never abused. Multiple injuries were nearly 3 times more likely to be reported in women who had experienced recent abuse (adjusted odds ratio 2.75; 95% confidence interval 1.98-3.81). Reported injury outcomes were similar between the sites except that women in Baltimore were 66% more likely than their US Virgin Islands counterparts to report ED use in the past year (P = .001). In combined-site multivariable models, partner violence was associated with past-year ED use, hospitalization, and multiple injuries. DISCUSSION: Injuries related to intimate partner violence may be part of the explanation for the negative long-term health outcomes. In this study, partner violence was associated with past-year ED use, hospitalization, and multiple injuries. Emergency nurses need to assess for intimate partner violence when women report with an injury to ensure that the violence is addressed in order to prevent repeated injuries and negative long-term health outcomes. PMID- 24768097 TI - Historical perspectives of The American Association for Thoracic Surgery: Irving L. Kron. PMID- 24768098 TI - Innovation and instrumentation: endovascular repair of the aortic arch. PMID- 24768101 TI - Multimodal imaging of a rare type of giant aortic arch aneurysm with malformation of the aortic arch. PMID- 24768099 TI - Percutaneous edge-to-edge repair in high-risk and elderly patients with degenerative mitral regurgitation: midterm outcomes in a single-center experience. AB - OBJECTIVE: The study objective was to report the midterm outcomes of MitraClip implantation in inoperable or high-risk surgical candidates with degenerative mitral regurgitation. METHODS: From October 2008, data of all high-risk or elderly patients with severe degenerative mitral regurgitation who underwent MitraClip implantation were prospectively collected. RESULTS: Forty-eight high risk consecutive patients with severe degenerative mitral regurgitation underwent MitraClip implantation (mean age, 78.5 +/- 10.8 years; 56.6% of the patients were aged >= 80 years). Mean Society of Thoracic Surgeons score was 12% +/- 10%, and 71% were in New York Heart Association class III or IV. Mean left ventricular ejection fraction was 57% +/- 11%. The device was successfully implanted in 47 of 48 patients (98%). In-hospital mortality was 2%. The median intensive care unit stay was 22 hours; patients were discharged from the hospital in an average of 4.5 +/- 2.4 days. Predischarge echocardiography showed a mitral regurgitation reduction to grade 2+ or less in 43 of 47 patients (91.5%). Actuarial survival was 89% +/- 5.2% and 70.2% +/- 9% at 1 and 2 years, respectively (82% +/- 9% in patients aged <80 years and 95% +/- 4.4% in patients aged >= 80 years at 1 year; P = .9). Freedom from mitral regurgitation 3+ or greater was 80% +/- 7% at 1 year and 76.6% +/- 7% at 2 years. At 1 year, 93% of survivors were in New York Heart Association class I or II (100% of patients aged <80 years and 88% of patients aged >= 80 years; P = .4). Significant quality of life improvements were documented. A significant improvement in 6-minute walk test performance was observed. CONCLUSIONS: MitraClip therapy is a valuable alternative to surgery in high-risk and elderly patients with degenerative mitral regurgitation. Clinical benefits also are obtained in octogenarians. PMID- 24768100 TI - Longevity after mechanical aortic root replacement--do men live longer? AB - OBJECTIVE: To investigate whether longevity after mechanical aortic root replacement is influenced by the patient's gender. METHODS: From February 1998 to June 2011, 476 patients (376 men, 100 women, mean age, 53+/-12 years; range, 18 88) underwent composite aortic root replacement. Of these patients, 398 (312 men) were included in the present analysis. The indications for root replacement were aortic valve dysfunction (mostly stenosis) and concomitant aneurysmal disease in 334 (83.9%), acute type A aortic dissection in 51 (12.8%), and infective endocarditis in 10 (2.5%). Other indications were technical or anatomic considerations (0.8%). RESULTS: The women who presented for surgery were significantly older (men, 52+/-12 years vs women, 56+/-12 years; P=.01). However, no significant differences were found with regard to previous cardiac surgery (5.3%, 20 men [6.4%] vs 1 woman [1.2%]; P=.06), concomitant procedures (38%; 117 men [37.5%] vs 35 women [40.7%]; P=.62), or additive EuroSCORE (men, 5.1+/-2.2; women, 5.2+/-2.2; P=.55). The mean diameter of the ascending aorta was not significantly different between the 2 groups (men, 54+/-9 mm; women, 56+/-14 mm; P=.97). The median follow-up period was 7.4 years (range, 0-13; 2366 cumulative patient-years), with no significant difference in hospital mortality (men, 6.7% vs women, 10.5%; P=.25). Overall, men enjoyed significantly better longevity than did women. After 10 years, 73%+/-3% of the men and only 60%+/-6% of the women were alive (P=.03). Although no long-term survival benefit for either gender was found in an age-matched subgroup among young patients (P=.66), men experienced much more favorable longevity after 55 years of age (P=.04). Consequently, the longevity in men-but not in women-was equal to an age-matched normal population. CONCLUSIONS: Overall, long-term survival after mechanical aortic root replacement was significantly better among men. However, comparing age-matched subgroups<=55 years old, no significantly different life expectancy was found after mechanical root replacement. PMID- 24768102 TI - Use of polytetrafluoroethylene vascular graft to cover the kinking protector of left ventricular assist device facilitates later pump exchange. PMID- 24768103 TI - Long-term outcomes of artificial chordal replacement with tourniquet technique in mitral valve repair: a single-center experience of 700 cases. AB - OBJECTIVE: Artificial chordal replacement has been shown to be effective and durable, with numerous techniques reported. However, the outcomes of each technique have remained poorly defined. We report the long-term outcomes of the tourniquet technique. METHODS: We reviewed the data from 700 patients who had undergone mitral valve repair with the tourniquet technique from 1992 to 2010. We analyzed the operative outcomes, long-term survival rate, freedom from reoperation, and freedom from recurrent moderate or severe mitral regurgitation (MR). We also performed Cox regression analysis to explore the predictors of recurrent MR after mitral valve repair using the tourniquet technique. RESULTS: The mean age was 54.7+/-14.9 years; 212 patients (30.3%) had anterior leaflet prolapse, 142 (20.3%) had posterior leaflet prolapse, and 346 (49.4%) had bileaflet prolapse. Operative mortality was 1.3%. In 26 cases (3.7%), mitral valve repair was unsuccessful and was converted to replacement. Of those successfully repaired, the 12-year survival rate, freedom from mitral reoperation, freedom from recurrent moderate or severe MR, and freedom from recurrent leaflet prolapse was 85.9%, 88.7%, 72.3%, and 89.0%, respectively. The significant predictors of recurrent MR were anterior leaflet prolapse, age, New York Heart Association class III or IV, left ventricular end-systolic dimension, no annuloplasty ring or band, and postoperative residual mild or greater MR. CONCLUSIONS: The tourniquet technique is a simple and effective method to repair leaflet prolapse, with a low incidence of recurrent prolapse. The incidence of recurrent MR was high in the anterior leaflet prolapse group. Age, no annuloplasty ring or band, and residual MR were strong predictors of recurrent MR. PMID- 24768104 TI - Molecular epidemiology and antimicrobial susceptibility of Campylobacter coli clinical isolates. AB - INTRODUCTION: Campylobacter spp. is a major cause of acute bacterial diarrhea in humans worldwide, and C. coli is responsible for 10% of the cases. MATERIALS AND METHODS: A study was made of the antimicrobial susceptibility using the E test((r)), and the clonal relationship using PCR-RFLP, of the flaA gene, as well as PFGE techniques on 43 C. coli clinical isolates. RESULTS: Only 49% and 2% of the isolates were susceptible to erythromycin and ciprofloxacin, respectively. Imipenem and clindamyicn, with 100% and 84% of the strains, respectively, being susceptible, were the most active antimicrobials. The PCR-RFLP of flaA gene technique grouped fourteen isolates into six clusters, while the PFGE technique grouped eleven isolates into five clusters. CONCLUSION: Ciprofloxacin and erythromycin are not suitable for the treatment of C. coli infections. Clindamycin could be considered as a therapeutic alternative in cases of enteritis, while imipenem is the best alternative for extra-intestinal infections. Both PFGE and PCR-RFLP can be useful to detect clones. PMID- 24768105 TI - Biodiesel production from non-edible Silybum marianum oil using heterogeneous solid base catalyst under ultrasonication. AB - The aim of this study is to investigate modified TiO2 doped with C4H4O6HK as heterogeneous solid base catalyst for transesterification of non-edible, Silybum marianum oil to biodiesel using methanol under ultrasonication. Upon screening the catalytic performance of modified TiO2 doped with different K-compounds, 0.7 C4H4O6HK doped on TiO2 was selected. The preparation of the catalyst was done using incipient wetness impregnation method. Having doped modified TiO2 with C4H4O6HK, followed by impregnation, drying and calcination at 600 degrees C for 6 h, the catalyst was characterized by XRD, FTIR, SEM, BET, TGA, UV and the Hammett indicators. The yield of the biodiesel was proportional to the catalyst basicity. The catalyst had granular and porous structures with high basicity and superior performance. Combined conditions of 16:1 molar ratio of methanol to oil, 5 wt.% catalyst amount, 60 degrees C reaction temperature and 30 min reaction time was enough for maximum yield of 90.1%. The catalyst maintained sustained activity after five cycles of use. The oxidative stability which was the main problem of the biodiesel was improved from 2.0 h to 3.2h after 30 days using ascorbic acid as antioxidant. The other properties including the flash point, cetane number and the cold flow ones were however, comparable to international standards. The study indicated that Ti-0.7-600-6 is an efficient, economical and environmentally, friendly catalyst under ultrasonication for producing biodiesel from S. marianum oil with a substantial yield. PMID- 24768106 TI - Ultrasonic degradation of acetaminophen in water: effect of sonochemical parameters and water matrix. AB - This paper deals about the sonochemical water treatment of acetaminophen (ACP, N acetyl-p-aminophenol or paracetamol), one of the most popular pharmaceutical compounds found in natural and drinking waters. Effect of ultrasonic power (20-60 W), initial ACP concentration (33-1323 MUmol L(-1)) and pH (3-12) were evaluated. High ultrasonic powers and, low and natural acidic pH values favored the efficiency of the treatment. Effect of initial substrate concentration showed that the Langmuir-type kinetic model fit well the ACP sonochemical degradation. The influence of organic compounds in the water matrix, at concentrations 10-fold higher than ACP, was also evaluated. The results indicated that only organic compounds having a higher value of the Henry's law constant than the substrate decrease the efficiency of the treatment. On the other hand, ACP degradation in mineral natural water showed to be strongly dependent of the initial substrate concentration. A positive matrix effect was observed at low ACP concentrations (1.65 MUmol L(-1)), which was attributed to the presence of bicarbonate ion in solution. However, at relative high ACP concentrations a detrimental effect of matrix components was noticed. Finally, the results indicated that ultrasonic action is able to transform ACP in aliphatic organic compounds that could be subsequently eliminated in a biological system. PMID- 24768107 TI - Letter to the Editor: specificity of electrodermal reactivity testing for suicidal propensity in Thorell et al. PMID- 24768108 TI - Lithium increases nitric oxide levels in subjects with bipolar disorder during depressive episodes. AB - BACKGROUND: Altered nitric oxide (NO) signaling has been associated with the pathophysiology of Bipolar Disorder (BD), directly affecting neurotransmitter release and synaptic plasticity cascades. Lithium has shown to regulate NO levels in preclinical models. However, no study has addressed peripheral NO levels in unmedicated BD. Also, lithium's effects on NO levels have not been studied in humans. METHODS: Plasma NO was evaluated in subjects with BD I and II during a depressive episode (n = 26). Subjects had a score of >=18 in the 21-item Hamilton Depression Rating Scale and were followed-up during a 6-week trial with lithium. Plasma NO levels were also compared to matched healthy controls (n = 28). NO was determined by chemiluminescence method. RESULTS: Lithium treatment significantly increased plasma NO levels after 6 weeks of treatment in comparison to baseline levels in bipolar depression (p = 0.016). Baseline NO levels during depressive episodes showed no difference when matching up to healthy controls (p = 0.66). CONCLUSION: The present findings suggest that lithium upregulates NO signaling in unmedicated BD with short illness duration. Further studies with larger samples are needed to confirm the effects of lithium on NO pathway and its association with synaptic plasticity and therapeutics of BD. PMID- 24768109 TI - Behavioral phenotyping of Nestin-Cre mice: implications for genetic mouse models of psychiatric disorders. AB - Genetic mouse models based on the Cre-loxP system have been extensively used to explore the influence of specific gene deletions on different aspects of behavioral neurobiology. However, the interpretation of the effects attributed to the gene deletion might be obscured by potential side effects secondary to the Cre recombinase transgene insertion or Cre activity, usually neither controlled nor reported. Here, we performed a comprehensive behavioral analysis of endophenotypes of neuropsychiatric disorders in the extensively used Nestin(Cre) mouse line, commonly employed to restrict genetic modifications to the CNS. We observed no alterations in locomotion, general exploratory activity, learning and memory, sociability, startle response and sensorimotor gating. Although the overall response to stimuli triggering anxiety-like behaviors remained unaltered in Nestin(Cre) mice, a strong impairment in the acquisition of both contextual- and cued-conditioned fear was observed. These results underline the importance of adequately controlling the behavioral performance of the employed Cre-lines per se in pre-clinical neurobehavioral research. PMID- 24768110 TI - DMU-212 inhibits tumor growth in xenograft model of human ovarian cancer. AB - DMU-212 has been shown to evoke a mitochondrial apoptotic pathway in transformed fibroblasts and breast cancer. However, recently published data indicated the ability of DMU-212 to evoke apoptosis in both mitochondria- and receptor-mediated manner in two ovarian cancer cell lines, namely A-2780 and SKOV-3, which showed varied sensitivity to the compound tested. The pronounced cytotoxic effects of DMU-212 observed in A-2780 cells were related to the execution of extracellular apoptosis pathway and cell cycle arrest in G2/M phase. In view of the great anticancer potential of DMU-212 against A-2780 cell line, the aim of the current study was to assess antiproliferative activity of DMU-212 in xenograft model of ovarian cancer. To evaluate in vitro metabolic properties of cells that were to be injected into SCID mice, uptake and decline of DMU-212 in A-2780 ovarian cancer cell line was investigated. It was found that the concentration of the test compound in A-2780 cells was growing within first eight hours, and then the gradual decline was observed. A-2780 cells stably transfected with pcDNA3.1/Zeo( )-Luc vector were subcutaneously inoculated into the right flanks of SCID mice. After seven days of the treatment with DMU-212 (50mg/kg b.w), tumor growth appeared to be suppressed in the animals treated with the compound tested. At day 14 of the experiment, tumor burden in mice treated with DMU-212 was significantly lower, as compared to untreated controls. Our findings suggest that DMU-212 might be considered as a potential anticancer agent used in ovarian cancer therapy. PMID- 24768111 TI - New era for treatment in differentiated thyroid cancer. PMID- 24768113 TI - Extracellular loop 4 of the proline transporter PutP controls the periplasmic entrance to ligand binding sites. AB - The Na(+)/proline symporter (PutP), like several other Na(+)-coupled symporters, belongs to the so-called LeuT-fold structural family, which features ten core transmembrane domains (cTMs) connected by extra- and intracellular loops. The role of these loops has been discussed in context with the gating function in the alternating access model of secondary active transport processes. Here we report the complete spin-labeling site scan of extracellular loop 4 (eL4) in PutP that reveals the presence of two alpha-helical segments, eL4a and eL4b. Among the eL4 residues that are directly implicated in the functional dynamics of the transporter, Phe314 in eL4b anchors the loop by means of hydrophobic contacts to cTM1 close to the ligand binding sites. We propose that ligand-induced conformational changes at the binding sites are transmitted via the anchoring residue to eL4 and through eL4 further to adjacent cTMs, leading to closure of the extracellular gate. PMID- 24768114 TI - Small-angle X-ray scattering- and nuclear magnetic resonance-derived conformational ensemble of the highly flexible antitoxin PaaA2. AB - Antitoxins from prokaryotic type II toxin-antitoxin modules are characterized by a high degree of intrinsic disorder. The description of such highly flexible proteins is challenging because they cannot be represented by a single structure. Here, we present a combination of SAXS and NMR data to describe the conformational ensemble of the PaaA2 antitoxin from the human pathogen E. coli O157. The method encompasses the use of SAXS data to filter ensembles out of a pool of conformers generated by a custom NMR structure calculation protocol and the subsequent refinement by a block jackknife procedure. The final ensemble obtained through the method is validated by an established residual dipolar coupling analysis. We show that the conformational ensemble of PaaA2 is highly compact and that the protein exists in solution as two preformed helices, connected by a flexible linker, that probably act as molecular recognition elements for toxin inhibition. PMID- 24768112 TI - Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. AB - BACKGROUND: Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (>=18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0.5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25. FINDINGS: Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10.8 months) than in the placebo group (5.8 months; hazard ratio [HR] 0.59, 95% CI 0.45-0.76; p<0.0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98.6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87.6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76.3%), diarrhoea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%). INTERPRETATION: Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING: Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary). PMID- 24768115 TI - Translation initiation factor eIF3b contains a nine-bladed beta-propeller and interacts with the 40S ribosomal subunit. AB - The multisubunit eukaryotic translation initiation factor 3, among which the subunit b (eIF3b) is a major scaffold protein, plays essential roles in protein synthesis. Here, we report the crystal structure of the WD40 domain of Chaetomium thermophilum eIF3b, revealing a nine-bladed beta-propeller fold. Sequence analysis indicates that this propeller architecture is common to all eIF3b orthologs. Revisiting the cryoelectron microscopy (cryo-EM) map of the 43S preinitiation complex suggests an interaction of the eIF3b with the 40S ribosomal subunit involving the ribosomal protein S9e and the 18S rRNA. This model is strongly supported by the direct binding of eIF3b to 40S ribosomes and to the isolated ribosomal protein rpS9e in vitro. PMID- 24768116 TI - Reliability of center of pressure measures within and between sessions in individuals post-stroke and healthy controls. AB - BACKGROUND: Knowing the reliability of the center of pressure (COP) is important for interpreting balance deficits post-stroke, especially when the balance deficits can necessitate the use of short duration trials. The novel aspect of this reliability study was to examine the center of pressure measures using two adjacent force platforms between and within sessions in stroke and controls. After stroke, it is important to understand the contribution of the paretic and non-paretic leg to the motor control of standing balance. Because there is a considerable body of knowledge on COP reliability on a single platform, we chose to examine reliability using two adjacent platforms which has not been examined previously in stroke. METHODS: Twenty participants post-stroke and 22 controls performed an arm raise, load drop and quiet stance balance task while standing on two adjacent force platforms, on two separate days. Intraclass correlations coefficient (ICC2,1) and percentage standard error of measurement (SEM%) were calculated for COP velocity, ellipse area, anterior-posterior (AP) displacement, and medial-lateral (ML) displacement. RESULTS: Between sessions, COP velocity was the most reliable with high ICCs and low SEM% across groups and tasks and ellipse area was less reliable with low ICCs across groups and tasks. COP measures were less reliable during the arm raise than load drop post-stroke. Within session reliability was high for COP velocity and ML displacement requiring no more than six trials across tasks. CONCLUSIONS: The COP velocity was the most reliable measure with high ICCs between sessions and the high reliability was achieved with fewer trials in both groups in a single session. PMID- 24768117 TI - Effects of unilateral leg muscle fatigue on balance control in perturbed and unperturbed gait in healthy elderly. AB - This study assessed effects of unilateral leg muscle fatigue (ULMF) on balance control in gait during the stance and swing phases of the fatigued leg in healthy elderly, to test the assumption that leg muscle strength limits balance control during the stance-phase. Ten subjects (aged 63.4, SD 5.5 years) walked on a treadmill in 4 conditions: unperturbed unfatigued, unperturbed fatigued, perturbed unfatigued, and perturbed fatigued. The perturbations were lateral trunk pulls just before contralateral heel contact. ULMF was evoked by unilateral squat exercise until task failure. Isometric knee extension strength was measured to verify the presence of muscle fatigue. Between-stride standard deviations and Lyapunov exponents of trunk kinematics were used as indicators of balance control. Required perturbation force and the deviation of trunk kinematics from unperturbed gait were used to assess perturbation responses. Knee extension strength decreased considerably (17.3% SD 8.6%) as a result ULMF. ULMF did not affect steady-state gait balance. Less force was required to perturb subjects when the fatigued leg was in the stance-phase compared to the swing-phase. Subjects showed a faster return to the unperturbed gait pattern in the fatigued than in the unfatigued condition, after perturbations in swing and stance of the fatigued leg. The results of this study are not in line with the hypothesized effects of leg muscle fatigue on balance in gait. The healthy elderly subjects were able to cope with substantial ULMF during steady-state gait and demonstrated faster balance recovery after laterally directed mechanical perturbations in the fatigued than in the unfatigued condition. PMID- 24768118 TI - Primary lung adenocarcinoma with morule-like components: a unique histologic hallmark of aggressive behavior and EGFR mutation. AB - BACKGROUND: Lung adenocarcinoma with morule-like components is an unusual variant of lung adenocarcinoma, comprising uniform, tightly packed spindle-shaped cells, which fill the lumen of the glandular structures of the carcinoma. The aim of the study was to outline the clinicopathologic features of this variant. PATIENTS AND METHODS: We examined a series of 904 surgically resected adenocarcinomas. We defined morule-like components as small buds of spindle-cell proliferation in the tumor lumen of the glandular structures of the carcinoma and calculated their proportion of total tumor mass. Targeted genotyping was performed for KRAS, EGFR, HER2, and BRAF. ALK rearrangements were analyzed immunohistochemically. Immunopositive cases were confirmed using RT-PCR and/or FISH. RESULTS: We detected 17 cases of adenocarcinoma with morule-like components. This variant, representing only 1.9% was associated with unfavorable outcomes and a mutation in the EGFR. Histologic examination revealed adenocarcinoma with morule-like components accounting for 5-50% of tumors. Among the morule-like components, 10 (58.8%) of the 17 samples showed intracytoplasmic lumina formation containing eosinophilic mucinous material. The presence of micropapillary components in adenocarcinoma with morule-like components suggests that morule-like components could be merely excessive growth of the micropapillary pattern. However, our results indicated no statistical differences in the MIB-1 indices of the morule like components and the adjacent tumor components or the micropapillary components. The univariate and multivariate analyses revealed a correlation between the presence of a morule-like components and an unfavorable outcome. CONCLUSIONS: Our study clearly indicated that adenocarcinoma with morule-like components is distinct unfavorable prognostic and predictor for EGFR mutation. PMID- 24768119 TI - Working memory in schizophrenia: behavioral and neural evidence for reduced susceptibility to item-specific proactive interference. AB - BACKGROUND: Susceptibility to item-specific proactive interference (PI) contributes to interindividual differences in working memory (WM) capacity and complex cognition relying on WM. Although WM deficits are a well-recognized impairment in schizophrenia, the underlying pathophysiological effects on specific WM control functions, such as the ability to resist item-specific PI, remain unknown. Moreover, opposing hypotheses on increased versus reduced PI susceptibility in schizophrenia are both justifiable by the extant literature. METHODS: To provide first insights into the behavioral and neural correlates of PI-related WM control in schizophrenia, a functional magnetic resonance imaging experiment was conducted in a sample of 20 patients and 20 well-matched control subjects. Demands on item-specific PI were experimentally manipulated in a recent probes task (three runs, 64 trials each) requiring subjects to encode and maintain a set of four target items per trial. RESULTS: Compared with healthy control subjects, schizophrenia patients showed a significantly reduced PI susceptibility in both accuracy and latency measures. Notably, reduced PI susceptibility in schizophrenia was not associated with overall WM impairments and thus constituted an independent phenomenon. In addition, PI-related activations in inferior frontal gyrus and anterior insula, typically assumed to support PI resistance, were reduced in schizophrenia, thus ruling out increased neural efforts as a potential cause of the patients' reduced PI susceptibility. CONCLUSIONS: The present study provides first evidence for a diminished vulnerability of schizophrenia patients to item-specific PI, which is presumably a consequence of the patients' more efficient clearing of previously relevant WM traces and the accordingly reduced likelihood for item-specific PI to occur. PMID- 24768120 TI - Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease. AB - BACKGROUND: Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinson's disease (PD), and a recent study suggests efficacy in mid stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. METHODS: Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50-75, on medication >=6 months but <=4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n = 15) or DBS + ODT (n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. RESULTS: As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. CONCLUSIONS: This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD. PMID- 24768121 TI - Restless legs syndrome and pregnancy: a review. AB - Restless legs syndrome (RLS) is a common sensorimotor neurological disorder that is diagnosed according to the revised criteria of the International RLS Study Group (IRLSSG). The pathophysiology of RLS is still unknown and its prevalence is influenced by ethnicity, age, and gender. RLS is divided into two types by etiology: primary or idiopathic and secondary. Primary RLS is strongly influenced by a genetic component while secondary RLS is caused by other associated conditions such as end-stage renal disease or peripheral neuropathy. Another common condition associated with RLS is pregnancy. The prevalence of RLS during pregnancy is two to three times higher than in the normal population and is influenced by the trimester and the number of parity. The main mechanisms that may contribute to the pathophysiology of RLS during pregnancy are hormonal changes and iron and folate status. Standard medications for treating RLS during pregnancy are not established. Most medications have been used according to the evidence from non-pregnant patients. Therefore, consideration of the medical treatment for treating RLS during pregnancy should be balanced between the benefit of relieving the symptoms and maternal and fetal risk. In general, the prognosis of RLS during pregnancy is good and symptoms are usually relieved after delivery. PMID- 24768123 TI - Polymeric ionic liquid bucky gels as sorbent coatings for solid-phase microextraction. AB - Novel cross-linked polymeric ionic liquid (PIL) bucky gels were formed by free radical polymerization of polymerizable ionic liquids gelled with multi-walled carbon nanotubes (MWCNT) and used as sorbent coatings for solid-phase microextraction (SPME). The combination of PIL with MWCNTs significantly enhanced the pi-pi interaction between the sorbent coatings and the aromatic analytes. Compared to the neat PIL-based sorbent coating, the PIL bucky gel sorbent coatings demonstrated higher extraction efficiency for the extraction of polycyclic aromatic hydrocarbons (PAHs). A partitioning extraction mechanism was observed for the PIL/MWCNT-based sorbent coatings indicating that the addition of MWCNTs did not seem to affect the extraction mechanism of the sorbent coating. The analyte-to-coating partition coefficients (logKfs) were estimated and the limits of detection (LOD) for selected PIL bucky gel sorbent coating were determined to be in the range of 1-2.5 ng L(-1). Recovery studies were also performed for PAHs in river and tap water to validate the applicability of the developed method. PMID- 24768122 TI - Current and investigational drug strategies for glioblastoma. AB - Medical treatments for glioblastoma face several challenges. Lipophilic alkylators remain the mainstay of treatment, emphasising the primacy of good blood-brain barrier penetration. Temozolomide has emerged as a major contributor to improved patient survival. The roles of procarbazine and vincristine in the procarbazine, lomustine and vincristine (PCV) schedule have attracted scrutiny and several lines of evidence now support the use of lomustine as effective single-agent therapy. Bevacizumab has had a convoluted development history, but clearly now has no major role in first-line treatment, and may even be detrimental to quality of life in this setting. In later disease, clinically meaningful benefits are achievable in some patients, but more impressively the combination of bevacizumab and lomustine shows early promise. Over the last decade, investigational strategies in glioblastoma have largely subscribed to the targeted kinase inhibitor paradigm and have mostly failed. Low prevalence dominant driver lesions such as the FGFR-TACC fusion may represent a niche role for this agent class. Immunological, metabolic and radiosensitising approaches are being pursued and offer more generalised efficacy. Finally, trial design is a crucial consideration. Progress in clinical glioblastoma research would be greatly facilitated by improved methodologies incorporating: (i) routine pharmacokinetic and pharmacodynamic assessments by preoperative dosing; and (ii) multi-stage, multi-arm protocols incorporating new therapy approaches and high resolution biology in order to guide necessary improvements in science. PMID- 24768124 TI - Integrative refolding and purification of histidine-tagged protein by like-charge facilitated refolding and metal-chelate affinity adsorption. AB - This work proposed an integrative method of protein refolding and purification by like-charged resin facilitated refolding and metal-chelate affinity adsorption. Hexahistidine-tagged enhanced green fluorescence protein (EGFP) was overexpressed in Escherichia coli as inclusion bodies (IBs), and then the protein was refolded and purified from urea-solubilized IBs by this method. A metal-chelating resin was fabricated by coupling iminodiacetic acid (IDA) to agarose gel (Sepharose FF). The anionic resin was used to facilitate the refolding of like-charged EGFP from IBs. After refolding, nickel ions were introduced for the affinity purification of the target protein by metal-chelating adsorption. It was found that the resin was effective in facilitating EGFP refolding. For 0.1mg/mL EGFP IBs refolding, the fluorescence recovery (FR) by direct dilution was only 64%; addition of only 0.05 g/mL resin increased the FR to over 90%. Moreover, the FR increased with increasing resin concentration. Owning to the shielding effect of the oppositely charged impurities embedded in IBs on the surface charges of the IDA resin, more resin particles were required to exert an aggregation inhibition effect in the IBs protein refolding. Additionally, compared with direct-dilution refolding, inclusion of like-charged resins not only offered an enhanced FR of EGFP, but also bound some opposite-charged contaminant proteins, leading to a preliminary purification effect. Afterwards, the refolded EGFP was recovered by metal-chelating adsorption at an FR of 85% and purity of 93%. This work has thus extended the like-charge facilitated protein refolding strategy to the integrative protein refolding and purification. PMID- 24768125 TI - Automated high-throughput protein purification using an AKTApurifier and a CETAC autosampler. AB - As the pace of drug discovery accelerates there is an increased focus on screening larger numbers of protein therapeutic candidates to identify those that are functionally superior and to assess manufacturability earlier in the process. Although there have been advances toward high throughput (HT) cloning and expression, protein purification is still an area where improvements can be made to conventional techniques. Current methodologies for purification often involve a tradeoff between HT automation or capacity and quality. We present an AKTA combined with an autosampler, the AKTA-AS, which has the capability of purifying up to 240 samples in two chromatographic dimensions without the need for user intervention. The AKTA-AS has been shown to be reliable with sample volumes between 0.5 mL and 100 mL, and the innovative use of a uniquely configured loading valve ensures reliability by efficiently removing air from the system as well as preventing sample cross contamination. Incorporation of a sample pump flush minimizes sample loss and enables recoveries ranging from the low tens of micrograms to milligram quantities of protein. In addition, when used in an affinity capture-buffer exchange format the final samples are formulated in a buffer compatible with most assays without requirement of additional downstream processing. The system is designed to capture samples in 96-well microplate format allowing for seamless integration of downstream HT analytic processes such as microfluidic or HPLC analysis. Most notably, there is minimal operator intervention to operate this system, thereby increasing efficiency, sample consistency and reducing the risk of human error. PMID- 24768126 TI - Identification and quantification of sea lamprey gonadotropin-releasing hormones by electrospray ionization tandem mass spectrometry. AB - Gonadotropin-releasing hormones (GnRH) are neuropeptide hormones that regulate reproduction in vertebrates. Twenty-five unique chordate GnRH isoforms have been identified, all with very similar molecular architecture. Identification and quantification of endogenous GnRH in biological samples is extremely challenging due to the high levels of sequence similarity among these GnRH peptides and complexity of the biological matrices laden with large numbers of other peptides and protein degradation fragments, and due to low levels of GnRH abundance. In this study, three lamprey GnRH (lGnRH-I, -II, and -III) were extracted from sea lamprey brain tissue and plasma samples by solid-phase extraction (SPE) and identified by a high resolution Q-TOF mass spectrometry (MS). A rapid quantitation method was developed and validated to determine the concentrations of these three lGnRHs by using a UPLC coupled tandem MS in positive ESI multiple reaction monitoring (MRM) mode. Luteinizing hormone-release hormone (LHRH, one of the mammalian GnRHs) was used as the internal standard. The developed quantitation method was fully validated for its recovery, matrix effect, linearity, repeatability, precision and accuracy, and storage stability. This method exhibited excellent linearity in a broad concentration range for all three lGnRHs (R(2)>0.99) and limits of detection (LOD; as low as 0.007 ng/mL). Brain and plasma samples from a total of 280 sea lampreys were analyzed with the developed method to investigate the biological relevance of the lGnRH levels. The concentrations of these three lGnRHs were detected at levels of pictogram per microgram brain tissue and milliliter of plasma. The obtained analytical performance parameters and collected data from real biological samples have proven that this is a robust, sensitive, and fully validated LC-MS/MS method to simultaneously quantify three neuropeptide hormones in complex biological matrices. PMID- 24768127 TI - Multi-residue analytical methodology-based liquid chromatography-time-of-flight mass spectrometry for the analysis of pharmaceutical residues in surface water and effluents from sewage treatment plants and hospitals. AB - An analytical method that facilitated the analysis of 11 pharmaceuticals residue (caffeine, prazosin, enalapril, carbamazepine, nifedipine, levonorgestrel, simvastatin, hydrochlorothiazide, gliclazide, diclofenac-Na, and mefenamic acid) with a single pre-treatment protocol was developed. The proposed method included an isolation and concentration procedure using solid phase extraction (Oasis HLB), a separation step using high-performance liquid chromatography, and a detection procedure that applies time-of-flight mass spectrometry. The method was validated for drinking water (DW), surface water (SW), sewage treatment plant (STP) influent and effluent, and hospital (HSP) influent and effluent. The limits of quantification were as low as 0.4, 1.6, 5, 3, 2.2 and 11 ng/L in DW, SW, HSP influent and effluent, STP effluent, and STP influent, respectively. On average, good recoveries higher than 75% were obtained for most of the target analytes in all matrices. Matrix effect was evaluated for all samples matrices. The proposed method successfully determined and quantified the target compounds in raw and treated wastewater of four STPs and three hospitals in Malaysia, as well as in two SW sites. The results showed that a number of the studied compounds pose moderate to high persistency in sewage treatment effluents as well as in the recipient rivers, namely; caffeine, simvastatin, and hydrochlorothiazide. Ten out of 11 compounds were detected and quantified in 13 sampling points. Caffeine was detected with the highest level, with concentrations reaching up to 9099 ng/L in STP influent. PMID- 24768128 TI - Phytoestrogens for menopausal vasomotor symptoms: a Cochrane review summary. PMID- 24768129 TI - Association of the (TAAAA)n repeat polymorphism of SHBG gene with the age at menopause in Greek postmenopausal women. AB - OBJECTIVE: To assess the potential association of the pentanucleotide (TAAAA)n repeat polymorphism in the promoter of SHBG gene with the age at menopause in a Greek female population. STUDY DESIGN: Cross-sectional study. Two hundred and ten postmenopausal women aged 46-63 years were enrolled. The age at the last menstrual period and anthropometric parameters were recorded in all participants. Blood sampling for genotyping of the (TAAAA)n polymorphism of SHBG gene was performed. MAIN OUTCOME MEASURE(S): Frequency and association of the (TAAAA)n alleles with age at menopause. RESULTS: The alleles with seven and eight TAAAA repeats were associated with the age at menopause. The age at menopause was higher in carriers than in non-carriers of the (TAAAA)7 allele (50.2+/-3.1 years vs. 48.0+/-4.8 years, p=0.026). Furthermore, the age at menopause was lower in women carrying the (TAAAA)8 allele (47.5+/-4.8 years) than in women not carrying this allele (48.8+/-4.4 years, p=0.048). CONCLUSIONS: The (TAAAA)7 and (TAAAA)8 alleles of the SHBG (TAAAA)n polymorphism may contribute to variation in the timing of natural menopause in postmenopausal women of Northwestern Greece. PMID- 24768130 TI - It is all in the factors: effects of cognitive remediation on symptom dimensions. AB - BACKGROUND: Cognitive remediation (CR) aims primarily to improve cognition and functional outcomes. However, a limited number of studies reported a positive effect on symptoms. This limited effect may be because the symptom clusters considered are too broad and heterogeneous. This study explores, for the first time, the effect of CR on five empirically defined symptom dimensions of schizophrenia. METHOD: Participants were patients with schizophrenia taking part in a randomised controlled trial comparing CR plus treatment as usual (CR, N=43) to treatment as usual (TAU, N=42). All participants were assessed at baseline and 14-weeks (i.e. at the conclusion of treatment for the CR group) with the Positive and Negative Symptoms Scale (PANSS). Five symptom dimensions were derived from the PANSS scores: Positive (POS), Negative (NEG), Disorganised (DIS), Excited (EXC) and Emotional Distressed (EMD). RESULTS: After CR, the therapy group had a significant reduction in DIS and NEG symptom dimensions compared to the TAU group. The traditional PANSS factors showed no effect of CR on symptoms. CONCLUSION: CR can have not only a positive effect on disorganisation but also on negative symptoms. Using detailed symptom dimensions can characterise more accurately the effect of CR on symptom of schizophrenia. PMID- 24768132 TI - Mathematics achievement scores and early psychosis in school-aged children. PMID- 24768131 TI - The relationship between default mode network connectivity and social functioning in individuals at familial high-risk for schizophrenia. AB - Unaffected first-degree relatives of individuals with schizophrenia (i.e., those at familial high-risk [FHR]), demonstrate social dysfunction qualitatively similar though less severe than that of their affected relatives. These social difficulties may be the consequence of genetically conferred disruption to aspects of the default mode network (DMN), such as the dMPFC subsystem, which overlaps with the network of brain regions recruited during social cognitive processes. In the present study, we investigate this possibility, testing DMN connectivity and its relationship to social functioning in FHR using resting state fMRI. Twenty FHR individuals and 17 controls underwent fMRI during a resting-state scan. Hypothesis-driven functional connectivity analyses examined ROI-to-ROI correlations between the DMN's hubs, and regions of the dMPFC subsystem and MTL subsystem. Connectivity values were examined in relationship to a measure of social functioning and empathy/perspective-taking. Results demonstrate that FHR exhibit reduced connectivity specifically within the dMPFC subsystem of the DMN. Certain ROI-to-ROI correlations predicted aspects of social functioning and empathy/perspective-taking across all participants. Together, the data indicate that disruption to the dMPFC subsystem of the DMN may be associated with familial risk for schizophrenia, and that these intrinsic connections may carry measurable consequences for social functioning. PMID- 24768134 TI - Contact angle and surface free energy of experimental resin-based dental restorative materials after chewing simulation. AB - OBJECTIVE: To investigate contact angle and surface free energy of experimental dental resin composites containing novel delivery systems of polymeric hollow beads and low-surface tension agents after chewing simulation test. METHODS: A delivery system of novel polymeric hollow beads differently loaded with two low surface tension agents was used in different amounts to modify commonly formulated experimental dental resin composites. The non-modified resin was used as standard. Surface roughness Ra, contact angle Theta, total surface free energy gammaS, its apolar gammaS(LW), polar gammaS(AB), Lewis acid gammaS(+) and base gammaS(-) terms were determined and the results prior to and after chewing simulation test were compared. Significance was p<0.05. RESULTS: After chewing simulation Ra increased, Theta decreased, Ra increased for two test materials and gammaS decreased or remained constant for the standard or the test materials after chewing simulation. Ra of one test material was higher than of the standard, Theta and gammaS of the test materials remained lower than of the standard and, indicating their highly hydrophobic character (Theta~60-75 degrees , gammaS~30mJm(-2)). gammaS(LW), and gammaS(-) of the test materials were lower than of the standard. Some of the test materials had lower gammaS(AB) and gammaS(+) than of the standard. SIGNIFICANCE: Delivery systems based on novel polymeric hollow beads highly loaded with low-surface tension agents were found to significantly increase contact angle and thus to reduce surface free energy of experimental dental resin composites prior to and after chewing simulation test. PMID- 24768133 TI - Basal low antioxidant capacity correlates with cognitive deficits in early onset psychosis. A 2-year follow-up study. AB - The objective of the study is to examine the association of baseline total antioxidant status (TAS) and glutathione (GSH) levels with short- and long-term cognitive functioning in patients with early onset first-episode psychosis, comparing affective and non-affective psychoses. We analysed 105 patients with an early onset-first episode psychosis (age 9-17 years) and 97 healthy controls. Blood samples were taken at admission for measurement of TAS and GSH, and cognitive performance was assessed at baseline and at 2years of follow-up. Regression analysis was used to assess the relationship between TAS/GSH levels at baseline and cognitive performance at both time points, controlling for confounders. Baseline TAS and GSH levels were significantly lower in patients than healthy controls. In patients, baseline TAS was positively associated with the global cognition score at baseline (p=0.048) and two years later (p=0.005), while TAS was not associated with cognitive functioning in healthy controls. Further, baseline TAS in patients was specifically associated with the memory domain at baseline and with the memory and attention domains two years later. Stratifying by affective and non-affective psychoses, significant associations were only found between TAS and cognition in the non-affective psychosis group. Baseline GSH levels were not associated with cognitive functioning at either time point in either group. The antioxidant defence capacity in early onset first episode psychotic patients is directly correlated with global cognition at baseline and at 2years of follow-up, especially in non-affective psychosis. PMID- 24768135 TI - Screening of a heptamer-type sgRNA library for potential therapeutic agents against hematological malignancies. AB - tRNase-Z(L)-utilizing efficacious (TRUE) gene silencing is an RNA-mediated gene expression control technology that has therapeutic potential. This technology is based on the property of tRNase Z(L) that it can cleave any target RNA at any desired site under the direction of an appropriate artificial small guide RNA (sgRNA). To search for novel potential therapeutic sgRNAs for hematological malignancies, we screened a library composed of 156 sgRNAs, and found that 20 sgRNAs can efficiently induce apoptosis in leukemia and/or myeloma cells. Furthermore, we demonstrated that 4 of the 20 sgRNAs can reduce growth rates of HL60 cells in mouse xenograft models. PMID- 24768136 TI - Meningeal disease masquerading as transient ischemic attack. AB - BACKGROUND: Cortical subarachnoid hemorrhage and meningitis sometimes present as episodes of transient neurologic dysfunction mimicking transient ischemic attack (TIA). In the present study, we sought to determine the frequency of meningeal disease among patients treated in a TIA clinic. METHODS: Data from patients consecutively admitted to a TIA clinic were retrospectively analyzed. Patients were classified as ischemic events (TIA or minor stroke) or nonischemic events using clinical data and findings from brain imaging and ultrasound studies. RESULTS: Of 529 patients (mean age 63.5 years), 134 (25.3%) were classified as nonischemic events. Meningeal disease was the likely cause of clinical symptoms in 9 patients (1.7%; 95% confidence interval, .6%-2.8%) including 5 patients with meningitis (1 meningeal sarcoidosis, 1 rheumatoid meningitis, 1 myelomatous meningitis, 1 lymphomatous meningitis, and 1 herpes simplex virus 1 meningoencephalitis) and 4 patients with cortical subarachnoid hemorrhage (probably or possibly related to cerebral amyloid angiopathy in 3 patients). Clinical symptoms comprised motor deficit, sensory deficit, aphasia, and dysarthria. Transient neurologic dysfunction was recurrent in 7 of 9 patients. Duration of transient episodes ranged from 5-30 minutes. No patient suffered headache. No patient had nuchal rigidity. Magnetic resonance imaging (MRI) showed evidence of meningeal or meningocerebral disease in all 9 patients. CONCLUSIONS: Our study confirmed that serious meningeal disease could present as TIA, but this disease was relatively uncommon among patients treated in a TIA clinic. The findings highlight the diagnostic value of MRI in patients with suspected TIA. PMID- 24768138 TI - Acute respiratory distress syndrome induction by pulmonary ischemia-reperfusion injury in large animal models. AB - Acute respiratory distress syndrome (ARDS) is a common critical pulmonary complication after esophagectomy and other thoracic surgeries (e.g., lung transplantation, pulmonary thromboendarterectomy). Direct pulmonary ischemia reperfusion injury (PIRI) is known to play the main role in induction of ARDS in these cases. Large animal models are an appropriate choice for ARDS as well as PIRI study because of their physiological and anatomic similarities to the human body. With regard to large animal models, we reviewed different methods of inducing in situ direct PIRI and the commonly applied methods for diagnosing and monitoring ARDS or PIRI in an experimental research setting. PMID- 24768137 TI - Changes in serum growth factors in stroke rehabilitation patients and their relation to hemiparesis improvement. AB - Predicting recovery from hemiparesis after stroke is important for rehabilitation. A few recent studies reported that the levels of some growth factors shortly after stroke were positively correlated with the clinical outcomes during the chronic phase. The aim of this study was to examine the relationships between the serum levels of growth factors (vascular endothelial growth factor [VEGF], insulin-like growth factor-I [IGF-I], and hepatocyte growth factor [HGF]) and improvement in hemiparesis in stroke patients who received rehabilitation in a postacute rehabilitation hospital. Subjects were 32 stroke patients (cerebral infarction: 21 and intracerebral hemorrhage [ICH]: 11). We measured serum levels of VEGF, IGF-I, and HGF and 5 items of the Stroke Impairment Assessment Set (SIAS) for hemiparesis on admission and at discharge. Age-matched healthy subjects (n=15) served as controls. Serum levels of VEGF and HGF in cerebral infarct patients on admission were higher than those in control subjects, and the serum levels of IGF-I in stroke patients were lower than those in controls. The level of HGF in ICH patients on admission was negatively correlated with gains in SIAS, and higher outliers in HGF concentration were correlated with lower gains in SIAS. Focusing on the extremely high levels of these factors may be a predictor of the low recovery from hemiparesis after stroke. PMID- 24768139 TI - Comparing characteristics and outcomes in infants with prenatal and postnatal diagnosis of esophageal atresia. AB - BACKGROUND: Previous studies of infants with esophageal atresia (EA) suggest those diagnosed prenatally have worse outcomes because of a higher incidence of associated anomalies. The purpose of this study was to compare characteristics and outcomes of infants with EA diagnosed after fetal center evaluation to those diagnosed postnatally. METHODS: The records of all neonates treated for EA at our institution from 2002-2012 were reviewed. Infants with a prenatal diagnosis of EA were compared with those postnatally diagnosed using chi-square and Student t test as appropriate. RESULTS: Of 91 patients treated with EA during the study period, 15 (16%) were diagnosed prenatally at our fetal center. Although those prenatally diagnosed had a higher incidence of pure EA and polyhydramnios, the gestational age and birth weight in that group were similar to those diagnosed postnatally. There were no differences in outcomes between groups with regard to the incidence of major cardiac anomalies, surgical complications, hospital length of stay, and survival. CONCLUSIONS: Treatment at a tertiary care center provides excellent outcomes for all infants with EA, despite an 80% frequency of concurrent anomalies. Prenatal diagnosis of EA and attentive obstetric management of polyhydramnios decrease the risk for prematurity and prematurity-associated morbidity. PMID- 24768140 TI - Applying peripheral vascular injury guidelines to penetrating trauma. AB - INTRODUCTION: Treatment of traumatic vascular injury is evolving because of endovascular therapies. National guidelines advocate for embolization of injuries to lower extremity branch vessels, including pseudoaneurysms or arteriovenous fistulas, in hemodynamically normal patients without hard signs of vascular injury. However, patient stability and injury type may limit endovascular applicability at some centers. We hypothesized that for penetrating trauma, indications for endovascular treatment of peripheral vascular injuries, as outlined by national guidelines, are infrequent. METHODS: We reviewed records of patients sustaining penetrating peripheral vascular injuries treated at our university-based urban trauma center from 2006-2010. Patient demographics and outcomes were analyzed. RESULTS: In 92 patients with penetrating peripheral vascular injuries, 82 were managed operatively and 10 were managed nonoperatively. Seventeen (18%) were hemodynamically unstable on arrival, 44 (48%) had multiple vessels injured, and 76 (83%) presented at night and/or on the weekend. No pseudoaneurysms or arteriovenous fistulas were seen initially or at follow-up. Applying national guidelines to our cohort, only two patients (2.2%) met recommended criteria for endovascular treatment. CONCLUSIONS: According to national guidelines, indications for endovascular treatment of penetrating peripheral vascular injury are infrequent. Nearly two-thirds of patients with penetrating peripheral vascular injuries were hemodynamically unstable or had multiple vessels injured, making endovascular repair less desirable. Additionally, over 80% presented at night and/or on the weekend, which could delay treatment at some centers due to mobilization of the endovascular team. Trauma centers need to consider their resources when incorporating national guidelines in their treatment algorithms of penetrating vascular trauma. PMID- 24768141 TI - Schlafen 12 expression modulates prostate cancer cell differentiation. AB - BACKGROUND: Schlafen proteins have previously been linked to leukocyte and intestinal epithelial differentiation. We hypothesized that Schlafen 12 (SLFN12) overexpression in human prostate epithelial cells would modulate expression of prostate-specific antigen (PSA) and dipeptidyl peptidase 4 (DPP4), markers of prostatic epithelial differentiation. MATERIALS AND METHODS: Differentiation of the human prostate cancer cell lines LNCaP and PC-3 was compared after infection with an adenoviral vector coding for SLFN12 (Ad-SLFN12) or green fluorescent protein (GFP) only expressing virus (control). Transcript levels of SLFN12, PSA, and DPP4 were evaluated by real-time reverse transcription PCR and protein levels by Western blotting. Because mixed lineage kinase (MLK) and one of its downstream effectors (extracellular signal-regulated kinases [ERK]) have previously been implicated in some aspects of prostate epithelial differentiation, we conducted further studies in which LNCaP cells were cotreated with dimethyl sulfoxide (control), PD98059 (ERK inhibitor), or MLK inhibitor during transfection with Ad SLFN12 for 72 h. RESULTS: Treatment of LNCaP or PC-3 cells with Ad-SLFN12 reduced PSA expression by 56.6+/-4.6% (P<0.05) but increased DPP4 transcript level by 4.8+/-1.0 fold (P<0.05) versus Ad-GFP-treated controls. Further studies in LNCaP cells showed that Ad-SLFN12 overexpression increased the ratio of the mature E cadherin protein to its precursor protein. Furthermore, SLFN12 overexpression promoted DPP4 expression either when MLK or ERK was blocked. ERK inhibition did not reverse SLFN12-induced changes in PSA, E-cadherin, or DPP4. CONCLUSIONS: SLFN12 may regulate differentiation in prostate epithelial cells, at least in part independently of ERK or MLK. Understanding how SLFN12 influences prostatic epithelial differentiation may ultimately identify targets to influence the phenotype of prostatic malignancy. PMID- 24768142 TI - Predictive factors for lymph node metastasis in early gastric cancer with signet ring cell histology and their impact on the surgical strategy: analysis of single institutional experience. AB - BACKGROUND: The prognosis of early gastric cancer (EGC) with signet ring cell histology is more favorable than other undifferentiated gastric adenocarcinomas. An accurate assessment of potential lymph node metastasis is important for the appropriate treatment of EGC with signet ring cell histology. Therefore, this study analyzed the predictive factors associated with lymph node metastasis in patients with this type of EGC. METHODS: A total of 136 EGC with signet ring cell histology patients who underwent D2 radical gastrectomy were reviewed in this study. The clinicopathologic features were analyzed to identify predictive factors for lymph node metastasis. RESULTS: The overall rate of lymph node metastasis in EGC with signet ring cell histology was 10.3%. Using a univariate analysis, the risk factors for lymph node metastasis were identified as the tumor size, depth of tumor invasion, and lymphovascular invasion. The multivariate analysis revealed that tumor size >2 cm, submucosal invasion, and lymphovascular invasion were independent risk factors of lymph node metastasis (P < 0.05). CONCLUSIONS: The risk of lymph node metastasis of EGC with signet ring cell histology was high in those with tumor sizes >=2 cm, submucosal tumors, and lymphovascular invasion. A minimally invasive treatment, such as endoscopic resection, might be possible in highly selective cases of EGC with signet ring cell histology with intramucosal invasion, tumor size <2 cm, and no lymphovascular invasion. PMID- 24768143 TI - Impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass on the hypoglycemic effect and glucagon-like peptide-1 in rats with type 2 diabetes mellitus. AB - BACKGROUND: The impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass (RYGB) on the hypoglycemic effect and glucagon-like peptide-1 (GLP-1) in rats with type 2 diabetes mellitus (T2DM) was investigated, and interactions were preliminarily analyzed. METHODS: A total of 45 rats with T2DM were divided into four groups: sham operation (S, n = 10), sham operation with the hepatic branch of the vagus resected (SV, n = 11), RYGB (n = 12), and RYGB without preservation of the vagus (RYGBV, n = 12). Body mass, fasting blood glucose (FBG), fasting serum insulin, and concentrations of fasting serum GLP-1 were examined in the first, second, fourth, and eighth week before and after surgery. The effects of RYGB and the hepatic branch of the vagus on GLP-1 levels in the eighth postoperative week were also analyzed. RESULTS: RYGB caused a significant reduction in the weight of rats with T2DM (P < 0.05), improved the levels of serum GLP-1 and insulin (P < 0.05), and decreased FBG level (P < 0.05). Retention of the hepatic branch of the vagus maintained weight reduction for a longer period (P < 0.05) and increased the levels of serum GLP-1 and insulin (P < 0.05), but had no impact on FBG level (P > 0.05). CONCLUSIONS: RYGB had better therapeutic efficacy in rats with T2DM. Care should be taken during RYGB surgery to preserve the hepatic branch of the vagus. PMID- 24768144 TI - Infection and inflammation imaging. PMID- 24768145 TI - Synthesis and in vivo preclinical evaluation of an (18)F labeled uPA inhibitor as a potential PET imaging agent. AB - INTRODUCTION: The urokinase plasminogen activator (uPA) system is a proteolytic cascade involved in tumor invasion and metastasis. uPA and its inhibitor PAI-1 are described as biomarkers for breast cancer with the highest level of evidence. The present study describes the synthesis and first in vivo application of an activity based uPA PET probe. METHODS: Based on the design of a small irreversible and selective uPA inhibitor we developed an (18)F-labeled activity based probe for uPA imaging. Human uPA expressing MDA-MB-231-luc2-GFP cells were inoculated in the mammary fat pads of nude mice and treated with the probe once tumors reached a volume of 150mm(3). Scans were performed at 0.25, 0.75, 1.5, 4 and 6h post injection. To evaluate tumor uptake in vivo and ex vivo data were gathered. Biodistribution data of the organs and tissues of interest were collected at all time points. Due to a relatively low tumor uptake, probe stability was further evaluated. RESULTS: The uPA targeting PET tracer was produced in high purity and with good specific radioactivity. In vivo PET data showed a maximum tumor uptake of 2,51+/-0,32 %ID/g at 4h p.i. A significant correlation between in vivo and ex vivo tumor uptake calculation was found (R=0.75; p<0.01). Due to a high blood signal at all time points, probe stability was further examined revealing high plasma protein binding and low plasma stability. CONCLUSIONS: In vivo and ex vivo results clearly demonstrate that uPA expressing tumors can be detected with non-invasive PET imaging. Stability tests suggest that further optimization is needed to provide a better tumor-to background contrast. PMID- 24768146 TI - Evaluation of metabolism, plasma protein binding and other biological parameters after administration of (-)-[(18)F]Flubatine in humans. AB - INTRODUCTION: (-)-[(18)F]Flubatine is a PET tracer with high affinity and selectivity for the nicotinic acetylcholine alpha4beta2 receptor subtype. A clinical trial assessing the availability of this subtype of nAChRs was performed. From a total participant number of 21 Alzheimer's disease (AD) patients and 20 healthy controls (HCs), the following parameters were determined: plasma protein binding, metabolism and activity distribution between plasma and whole blood. METHODS: Plasma protein binding and fraction of unchanged parent compound were assessed by ultracentrifugation and HPLC, respectively. The distribution of radioactivity (parent compound+metabolites) between plasma and whole blood was determined ex vivo at different time-points after injection by gamma counting after separation of whole blood by centrifugation into the cellular and non-cellular components. In additional experiments in vitro, tracer distribution between these blood components was assessed for up to 90min. RESULTS: A fraction of 15%+/-2% of (-)-[(18)F]Flubatine was found to be bound to plasma proteins. Metabolic degradation of (-)-[(18)F]Flubatine was very low, resulting in almost 90% unchanged parent compound at 90min p.i. with no significant difference between AD and HC. The radioactivity distribution between plasma and whole blood changed in vivo only slightly over time from 0.82+/-0.03 at 3min p.i. to 0.87+/-0.03 at 270min p.i. indicating the contribution of only a small amount of metabolites. In vitro studies revealed that (-)-[(18)F]Flubatine was instantaneously distributed between cellular and non-cellular blood parts. DISCUSSION: (-)-[(18)F]Flubatine exhibits very favourable characteristics for a PET radiotracer such as slow metabolic degradation and moderate plasma protein binding. Equilibrium of radioactivity distribution between plasma and whole blood is reached instantaneously and remains almost constant over time allowing both convenient sample handling and facilitated fractional blood volume contribution assessment. PMID- 24768147 TI - (99m)Tc-labeled SWL specific peptide for targeting EphA2 receptor. AB - INTRODUCTION: EphA2, one member of the Eph receptor family, is widely expressed in multiple aggressive cancers. SWL, a small peptide identified by phage display, has high binding affinity to EphA2, suggesting that it could be exploited for targeted molecular imaging. Therefore, a novel peptide-based probe, (99m)Tc-HYNIC SWL, was developed and its potential to specifically target EphA2-positive tumors was investigated. METHODS: The SWL peptide was labeled with hydrazinonicotinic acid (HYNIC), followed by (99m)Tc labeling. Immunofluorescence staining was carried out to detect the expression of EphA2 in A549 lung cancer cells and OCM-1 melanoma cells. Saturation binding experiments were performed by incubating A549 cells with increasing concentrations of radiolabeled peptide in vitro. To test the probe in vivo, nude mice bearing either A549 or OCM-1 derived tumors were established, injected with (99m)Tc-HYNIC-SWL, and subjected to SPECT imaging. Mice injected with excess unlabeled SWL were used as a specific control. Ex vivo gamma-counting of dissected tissues from the mice was also performed to evaluate biodistribution. RESULTS: Immunofluorescence staining showed that A549 cells intensively expressed EphA2, while OCM-1 cells had little expression. (99m)Tc HYNIC-SWL displayed high binding affinity with A549 cells (KD=2.6+/-0.7nM). From the SPECT images and the results of the biodistribution study, significantly higher uptake of the tracer was seen in A549 tumors (1.44+/-0.12 %ID/g) than in OCM-1 tumors (0.43+/-0.20 %ID/g) at 1h after injection. Pre-injection with excess unlabeled peptide in A549-bearing nude mice, significantly reduced tumor uptake of the radiolabeled probe (0.58+/-0.20 %ID/g) was seen. These data suggest that (99m)Tc-HYNIC-SWL specifically targets EphA2 in tumors. CONCLUSIONS: The expression of EphA2 can be noninvasively investigated using (99m)Tc-HYNIC-SWL by SPECT imaging. The in vitro and in vivo characteristics of (99m)Tc-HYNIC-SWL make it a promising probe for EphA2-positive tumor imaging. PMID- 24768148 TI - Synthesis and evaluation of [(11)C]PyrATP-1, a novel radiotracer for PET imaging of glycogen synthase kinase-3beta (GSK-3beta). AB - INTRODUCTION: The dysfunction of glycogen synthase kinase-3beta (GSK-3beta) has been implicated in a number of diseases, including Alzheimer's disease. The ability to non-invasively quantify GSK-3beta activity in vivo is therefore of critical importance, and this work is focused upon development of inhibitors of GSK-3beta radiolabeled with carbon-11 to examine quantification of the enzyme using positron emission tomography (PET) imaging. METHODS: (11)C PyrATP-1 was prepared from the corresponding desmethyl-piperazine precursor in an automated synthesis module. In vivo rodent and primate imaging studies were conducted on a Concorde MicroPET P4 scanner to evaluate imaging properties and in vitro autoradiography studies with rat brain samples were carried out to examine specific binding. RESULTS: 2035+/-518MBq (55+/-14mCi) of [(11)C]PyrATP-1 was obtained (1%-2% non-corrected radiochemical yield at end-of-synthesis based upon [(11)C]CO2) with high chemical (>95%) and radiochemical (>99%) purities, and good specific activities (143+/-52GBq/MUmol (3874+/-1424Ci/mmol)), n=5. In vivo microPET imaging studies revealed poor brain uptake in rodents and non-human primates. Pretreatment of rodents with cyclosporin A resulted in moderately increased brain uptake suggesting Pgp transporter involvement. Autoradiography demonstrated high levels of specific binding in areas of the rodent brain known to be rich in GSK-3beta. CONCLUSION: (11)C PyrATP-1 is readily synthesized using standard carbon-11 radiochemistry. However the poor brain uptake in rodents and non-human primates indicates that the radiotracer is not suitable for the purposes of quantifying GSK-3beta in neurological and psychiatric disorders. PMID- 24768150 TI - Significance of enhanced cerebral gray-white matter contrast at 80 kVp compared to conventional 120 kVp CT scan in the evaluation of acute stroke. AB - We aimed to determine whether 80 kVp conventional nonenhanced head CT scans have better gray-white matter contrast than standard 120 kVp scans performed on the same patients. Thirty head CT scans acquired at 80 kVp (CT dose index [CTDI]vol 46) were compared to prior studies in the same patients performed at 120 kVp (CTDIvol 59). Signal (Hounsfield units [HU]), noise (sd HU), and contrast-to noise ratio per dose (CNRD) were assessed in multiple cerebral gray and white matter regions of interest. A noise correction factor was used to compensate for scanning at different CTDIvol values. Average gray matter signal at 80 kVp and 120 kVP was 33.9 +/- 3.5 HU and 29 +/- 4.6 HU, respectively (p<0.0001); the averages for white matter were 22.5 +/- 3.1 HU and 21.6 +/- 4.6 HU, respectively (p=0.11). Corrected noise was 3 +/- 0.6 and 2.7 +/- 0.6, respectively, for gray matter (p=0.0001), and 2.8 +/- 0.6 and 2.6 +/- 0.5, respectively, for white matter (p=0.00001). The gray-white matter CNRD was 4.0 +/- 1.2 at 80 kVp and 2.8 +/- 1 at 120 kVp (p<0.00001). Cerebral gray-white matter CNRD is increased by 40% at 80 kVp compared to conventional 120 kVp CT scans. These findings justify further clinical evaluation in the acute stroke setting. PMID- 24768149 TI - In vivo evaluation of (18)F-labeled TCO for pre-targeted PET imaging in the brain. AB - INTRODUCTION: The tetrazine-trans-cylooctene cycloaddition using radiolabeled tetrazine or radiolabeled trans-cyclooctene (TCO) has been reported to be a very fast, selective and bioorthogonal reaction that could be useful for in vivo radiolabeling of molecules. We wanted to evaluate the in vivo biodistribution profile and brain uptake of (18)F-labeled TCO ([(18)F]TCO) to assess its potential for pre-targeted imaging in the brain. METHODS: We evaluated the in vivo behavior of [(18)F]TCO via an ex vivo biodistribution study complemented by in vivo MUPET imaging at 5, 30, 60, 90, 120 and 240 min post tracer injection. An in vivo metabolite study was performed at 5 min, 30 min and 120 min post [(18)F]TCO injection by RP-HPLC analysis of plasma and brain extracts. Incubation with human liver microsomes was performed to further evaluate the metabolite profile of the tracer. RESULTS: MUPET imaging and ex-vivo biodistribution revealed an high initial brain uptake of [(18)F]TCO (3.8%ID/g at 5 min pi) followed by a washout to 3.0%ID/g at 30 min pi. Subsequently the brain uptake increased again to 3.7%ID/g at 120 min pi followed by a slow washout until 240 min pi (2.9%ID/g). Autoradiography confirmed homogenous brain uptake. On the MUPET images bone uptake became gradually visible after 120 min pi and was clearly visible at 240 min pi. The metabolite study revealed a fast metabolization of [(18)F]TCO in plasma and brain into three main polar radiometabolites. CONCLUSIONS: Although [(18)F]TCO has previously been described to be a useful tracer for radiolabeling of tetrazine modified targeting molecules, our study indicates that its utility for in vivo chemistry and pre targeted imaging will be limited. Although [(18)F]TCO clearly enters the brain, it is quickly metabolized with a non-specific accumulation of radioactivity in the brain and bone. PMID- 24768151 TI - Endovascular coiling of a ruptured basilar apex aneurysm with associated pseudoaneurysm. AB - Acute intracranial pseudoaneurysms secondary to aneurysmal rupture are a rare entity with no clear evidence-based guidelines for treatment to our knowledge. There are numerous examples of successful treatment of pseudoaneurysms both surgically and endovascularly, the latter mainly within the anterior circulation. Risk of pseudoaneurysm rupture in the acute state during endovascular procedures with subsequent difficulty in controlling the bleeding without sacrificing the feeder artery has led to some reservation in using endovascular treatments more broadly. We report a rare case of a 52-year-old-woman who presented with acute subarachnoid hemorrhage and was found to have a ruptured 5 mm * 8 mm bi-lobulated basilar apex aneurysm on CT angiography. Digital subtraction angiography demonstrated an associated anterior pseudoaneurysm that was formed secondary to the aneurysm rupture. The true aneurysm was successfully coiled with careful avoidance of the pseudoaneurysmal sac. Pseudoaneurysms are frequently identified for the first time during digital subtraction angiography. Recognizing their presence is essential for treatment planning. Acute pseudoaneurysms associated with true aneurysmal rupture can be safely and successfully treated by endovascular coiling of the true aneurysm. Care must be taken to avoid manipulation of the pseudoaneurysmal sac during the embolization. PMID- 24768152 TI - A pathophysiologic approach for subacute encephalopathy with seizures in alcoholics (SESA) syndrome. AB - Subacute encephalopathy with seizures in alcoholics (SESA) syndrome is a unique disease entity characterized by typical clinical and electroencephalographic (EEG) features in the setting of chronic alcoholism. We present two patients with distinctive serial MRI and EEG findings which suggest a clue to the underlying pathophysiologic mechanisms of SESA syndrome. Two patients with chronic alcoholism and alcoholic liver cirrhosis presented with generalized seizures and confused mental status. Brain MRI demonstrated restricted diffusion, increased T2 weighted signal intensity, and hyperperfusion in the presumed seizure focus and nearby posterior regions of the cerebral hemispheres. EEG showed periodic lateralized epileptiform discharges which were prominent in the posterior regions of the cerebral hemispheres ipsilateral to the side of brain MRI abnormalities. Even after patients clinically improved, these brain abnormalities persisted with progressive atrophic changes on follow-up brain MRI. These patients had not only the distinguishing clinical and EEG features of SESA syndrome, but also showed novel brain MRI abnormalities. These changes on MRI displayed characteristics of seizure-related changes. The posterior dominance of abnormalities on MRI and EEG suggests that the pathophysiologic mechanisms of SESA syndrome may share those of posterior reversible encephalopathy syndrome. PMID- 24768153 TI - Active Wnt/beta-catenin signaling is required for embryonic thymic epithelial development and functionality ex vivo. AB - The Wnt/beta-catenin signaling pathway plays an important role in the commitment and development of thymic epithelial precursors. Here we document similarities of thymic epithelial development during embryogenesis in human and mouse. We stained for thymic epithelial surface markers (EpCAM1, Ly51, K8) and ligand/receptor pair (Wnt4, Fz4). Our results confirm the relevance of using murine test systems to model human embryonic thymic epithelial cell development. We have efficiently transduced murine embryonic epithelial cells using mock (GFP) and Wnt/beta catenin-inhibiting (ICAT-encoding) recombinant adenoviral vectors. The effect of Wnt4 was assayed in the form of Wnt4-containing supernatant. Gene expressional changes were assessed by Q-PCR and also morphology using conventional and confocal fluorescent microscopy. Functional aberration caused by ICAT was assessed through evaluation of thymocyte maturation. Our results demonstrate that ICAT and Wnt4 have reciprocal effects during embryonic thymic epithelial cell development. While Wnt4 is capable of increasing the expression level of characteristic intracellular (FoxN1), surface (MHCII) and secreted (IL7) molecules, Wnt/beta-catenin inhibition through ICAT can moderately decrease their expression. Morphological changes induced by ICAT resulted in the development of hollow, inflated thymic lobes with reduced epithelial cell numbers. The ICAT treated thymic lobes also showed significant impairment in supporting thymocyte development and maturation. PMID- 24768154 TI - Pulse oximetry screening: do we have enough evidence now? PMID- 24768156 TI - Biodegradable iodinated polydisulfides as contrast agents for CT angiography. AB - Current clinical CT contrast agents are mainly small molecular iodinated compounds, which often suffer from short blood pool retention for more comprehensive cardiovascular CT imaging and may cause contrast-induced nephropathy. In this work, we prepared polydisulfides containing a traditional iodinated CT contrast agent in order to optimize the pharmacokinetics of the agent and improve its safety. Initially acting as a macromolecular agent and achieving sharp blood vessel delineation, the polydisulfides can be reduced by endogenous thiols via disulfide-thiol exchange reaction to oligomers that can be readily excreted via renal filtration. Short polyethylene glycol (PEG) chain was also introduced to the polymers to further modify the in vivo properties of the agents. Strong and prolonged vascular enhancement has been generated with two new agents in mice (5-10 times higher blood pool enhancement than iodixanol). The polydisulfide agents gradually degraded and excreted via renal filtration. The gradual excretion process could prevent contrast-induced nephropathy. These results suggest that the biodegradable macromolecular CT contrast agents are promising safe and effective blood contrast agents for CT angiography and image guided interventions. PMID- 24768157 TI - The BDNF-Val66Met polymorphism modulates parental rearing effects on adult psychiatric symptoms: a community twin-based study. AB - PURPOSE: To test whether firstly, different parental rearing components were associated with different dimensions of psychiatric symptoms in adulthood, secondly BDNF-Val66Met polymorphism moderated this association and thirdly, this association was due to genetic confounding. METHOD: Perceived parental rearing according to Parental Bonding Instrument (PBI), psychiatric symptoms evaluated with the Brief Symptom Inventory (BSI) and the BDNF-Val66Met polymorphism were analyzed in a sample of 232 adult twins from the general population. RESULTS: In the whole sample, paternal care was negatively associated with depression. Maternal overprotection was positively associated with paranoid ideation, obsession-compulsion and somatization. Gene-environment interaction effects were detected between the BDNF-Val66Met polymorphism and maternal care on phobic anxiety, paternal care on hostility, maternal overprotection on somatization and paternal overprotection also in somatization. In the subsample of MZ twins, intrapair differences in maternal care were associated with anxiety, paranoid ideation and somatization. CONCLUSIONS: Met carriers were, in general, more sensitive to the effects of parental rearing compared to Val/Val carriers in relation to anxiety and somatization. Contra-intuitively, our findings suggest that high rates of maternal care might be of risk for Met carriers regarding anxiety. Results from analyses controlling for genetic confounding were in line with this finding. PMID- 24768155 TI - Pulse oximetry with clinical assessment to screen for congenital heart disease in neonates in China: a prospective study. AB - BACKGROUND: Several pioneering studies have provided evidence for the introduction of universal pulse oximetry screening for critical congenital heart disease. However, whether the benefits of screening reported in studies from high income countries would translate with similar success to low-income countries is unknown. We assessed the feasibility and reliability of pulse oximetry plus clinical assessment for detection of major congenital heart disease, especially critical congenital heart disease, in China. METHODS: We did a pilot study at three hospitals in Shanghai to assess the accuracy of pulse oximetry plus clinical assessment for detection of congenital heart disease. We made a data collection plan before recruitment. We then undertook a large, prospective, and multicentre screening study in which we screened all consecutive newborn babies (aged 6-72 h) born at 18 hospitals in China between Aug 1, 2011, and Nov 30, 2012. Newborn babies with positive screen results (either an abnormal pulse oximetry or abnormal clinical assessment) were referred for echocardiography within 24 h of screening. We identified false-negative results by clinical follow up and parents' feedback. We calculated sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios for pulse oximetry alone, and in combination with clinical assessment, for detection of major and critical congenital heart disease. FINDINGS: In the pilot study, 6785 consecutive newborn babies were screened; 46 of 49 (94%) cases of asymptomatic major congenital heart disease and eight of eight (100%) cases of asymptomatic critical disease were detected by pulse oximetry and clinical assessment. In the prospective multicentre study, we screened 122,738 consecutive newborn babies (120,707 asymptomatic and 2031 symptomatic), and detected congenital heart disease in 1071 (157 critical and 330 major). In asymptomatic newborn babies, the sensitivity of pulse oximetry plus clinical assessment was 93.2% (95% CI 87.9 96.2) for critical congenital heart disease and 90.2% (86.4-93.0) for major disease. The addition of pulse oximetry to clinical assessment improved sensitivity for detection of critical congenital heart disease from 77.4% (95% CI 70.0-83.4) to 93.2% (87.9-96.2). The false-positive rate for detection of critical disease was 2.7% (3298 of 120,392) for clinical assessment alone and 0.3% (394 of 120,561) for pulse oximetry alone. INTERPRETATION: Pulse oximetry plus clinical assessment is feasible and reliable for the detection of major congenital heart disease in newborn babies in China. This simple and accurate combined method should be used in maternity hospitals to screen for congenital heart disease. FUNDING: Key Clinical Research Project sponsored by Ministry of Health, Shanghai Public Health Three-Year Action Plan sponsored by Shanghai Municipal Government, and National Basic Research Project of China. PMID- 24768158 TI - A single nucleotide polymorphism in SLC1A1 gene is associated with age of onset of obsessive-compulsive disorder. AB - Different genetic polymorphisms in the SLC1A1 have been shown to be associated with obsessive-compulsive disorder. Rs301430 is a T/C functional polymorphism affecting the gene expression and extrasynaptic glutamate concentration.We observed that Rs301430 influence age at onset in obsessive-compulsive disorder. PMID- 24768159 TI - Tyrosine hydroxylase expression and activity in nigrostriatal dopaminergic neurons of MPTP-treated mice at the presymptomatic and symptomatic stages of parkinsonism. AB - Progressive degeneration of nigrostriatal dopaminergic (DA-ergic) neurons is a key component in the pathogenesis of Parkinson's disease, which develops for a long time at the preclinical stage with no motor dysfunctions due to the initiation of compensatory processes. The goal of this study was to evaluate the changes in surviving nigrostriatal DA-ergic neurons with focus on tyrosine hydroxylase (TH) in MPTP-treated mice at the presymptomatic and early symptomatic stages of parkinsonism. According to our data, a partial degeneration of DA-ergic neurons at the presymptomatic stage was accompanied by: (i) no change in TH mRNA content in the substantia nigra (SN) suggesting a compensatory increase of TH gene expression in individual neurons; (ii) a decrease of TH protein content in the nigrostriatal system and no change in individual neurons, suggesting a slowdown of TH translation. When comparing DA-ergic neurons at the early symptomatic stage and presymptomatic stage, it becomes evident: (i) a decrease of TH mRNA content in the SN and hence gene expression in individual neurons; (ii) a decrease of TH content in the striatum and its increase in the SN and individual neurons suggesting an acceleration of TH translation. TH activity, an index of the rate of DA synthesis, was unchanged in the SN and decreased in the striatum to the same degree at both stages of parkinsonism. In the meantime, TH activity in individual neurons appeared to be compensatory increased, but to a higher degree at the symptomatic stage than at the presymptomatic one. These data first show that DA depletion, which provokes motor dysfunction, is not a result of the decrease of TH activity and the rate of DA synthesis but is rather related to either a decrease of DA release or an increase of DA uptake in striatal DA-ergic axons. PMID- 24768160 TI - Religious socialization of youth involved in child welfare. AB - Increased religiosity is associated with a variety of improved outcomes, especially for youth in disadvantaged contexts. Although youth involved in child welfare may experience protective effects of religious participation or values, little is known about the impact of maltreatment on religious development. Using the National Survey of Child and Adolescent Well-Being, a nationally representative study of child welfare involved families, correlates of religious attendance and importance of religion for youth were investigated using weighted logistic regression at two waves 18 months apart. Youth self-reports of religious attendance and their ratings of its importance were associated with religious attendance of their caregivers, whether birth-parents or foster parents. Foster parents were more likely to attend religious services than birth parents. Increases in youth attendance from Wave 1 to Wave 2 were associated with high youth religious importance at Wave 1, whereas decreases in attendance were associated with moving between home and foster placements. Increases in religious importance from Wave 1 to Wave 2 were associated with religious attendance at Wave 1 and with the youth being Black. PMID- 24768161 TI - Prenatal drug exposure, behavioral problems, and drug experimentation among African-American urban adolescents. AB - PURPOSE: To examine how prenatal drug exposure (PDE) to heroin/cocaine and behavioral problems relate to adolescent drug experimentation. METHODS: The sample included African-American adolescents (mean age = 14.2 years, SD = 1.2) with PDE (n = 73) and a nonexposed community comparison (n = 61). PDE status was determined at delivery through toxicology analysis and maternal report. Internalizing/externalizing problems were assessed during adolescence with the Behavior Assessment System for Children, Second Edition. Drug experimentation was assessed by adolescent report and urine analysis. Logistic regression evaluated the likelihood of drug experimentation related to PDE and behavioral problems, adjusting for age, gender, PDE, perceived peer drug use, and caregiver drug use. Interaction terms examined gender modification. RESULTS: Sixty-seven subjects (50%) used drugs: 25 (19%) used tobacco/alcohol only and 42 (31%) used marijuana/illegal drugs. Ninety-four subjects (70%) perceived peer drug use. PDE significantly increased the risk of tobacco/alcohol experimentation (odds ratio = 3.07, 95% confidence interval [CI] 1.09-8.66, p = .034) but not after covariate adjustment (adjusted odds ratio [aOR] = 1.16, 95% CI .31-4.33, p > .05). PDE was not related to the overall or marijuana/illegal drug experimentation. The likelihood of overall drug experimentation was doubled per SD increase in externalizing problems (aOR = 2.28, 95% CI 1.33-3.91, p = .003) and, among girls, 2.82 times greater (aOR = 2.82, 95% CI 1.34-5.94, p = .006) per SD increase in internalizing problems. Age and perceived peer drug use were significant covariates. CONCLUSIONS: Drug experimentation was relatively common (50%), especially in the context of externalizing problems, internalizing problems (girls only), older age, and perceived peer drug use. Findings support the Problem Behavior Theory and suggest that adolescent drug prevention addresses behavioral problems and promotes prosocial peer groups. PMID- 24768162 TI - Bullying as a longitudinal predictor of adolescent dating violence. AB - PURPOSE: One suggested approach to preventing adolescent dating violence is to prevent behavioral precursors to dating violence, such as bullying. However, no longitudinal study has examined bullying as a behavioral precursor to dating violence. In this study, longitudinal data were used to examine (1) whether direct and indirect bullying perpetration in the sixth grade predicted the onset of physical dating violence perpetration by the eighth grade and (2) whether the associations varied by sex and race/ethnicity of the adolescent. METHODS: Data were collected in school from sixth graders in three primarily rural counties and then again when students were in the eighth grade. Analyses were conducted with 1,154 adolescents who had not perpetrated dating violence at the sixth-grade assessment. The sample was 47% male, 29% black, and 10% of another race/ethnicity than black or white. RESULTS: Direct bullying, defined as hitting, slapping, or picking on another kid in the sixth grade, predicted the onset of physical dating violence perpetration by the eighth grade, controlling for indirect bullying and potential confounders. Although indirect bullying, defined as spreading false rumors and excluding students from friendship groups, was associated with the onset of physical dating violence perpetration in bivariate analyses, it did not predict the onset of physical dating violence when controlling for direct bullying. None of the associations examined varied by sex or race/ethnicity of the adolescents. CONCLUSIONS: Our findings suggest that efforts targeted at preventing direct bullying may also prevent the onset of physical dating violence. PMID- 24768163 TI - School violence and bullying among sexual minority high school students, 2009 2011. AB - PURPOSE: School-based victimization has short- and long-term implications for the health and academic lives of sexual minority students. This analysis assessed the prevalence and relative risk of school violence and bullying among sexual minority and heterosexual high school students. METHODS: Youth Risk Behavior Survey data from 10 states and 10 large urban school districts that assessed sexual identity and had weighted data in the 2009 and/or 2011 cycle were combined to create two large population-based data sets, one containing state data and one containing district data. Prevalence of physical fighting, being threatened or injured with a weapon, weapon carrying, and being bullied on school property and not going to school because of safety concerns was calculated. Associations between these behaviors and sexual identity were identified. RESULTS: In the state data, sexual minority male students were at greater risk for being threatened or injured with a weapon, not going to school because of safety concerns and being bullied than heterosexual male students. Sexual minority female students were at greater risk than heterosexual female students for all five behaviors. In the district data, with one exception, sexual minority male and female students were at greater risk for all five behaviors than heterosexual students. CONCLUSIONS: Sexual minority students still routinely experience more school victimization than their heterosexual counterparts. The implementation of comprehensive, evidence-based programs and policies has the ability to reduce school violence and bullying, especially among sexual minority students. PMID- 24768164 TI - RagA, but not RagB, is essential for embryonic development and adult mice. AB - The mechanistic target of rapamycin complex 1 (mTORC1) integrates cues from growth factors and nutrients to control metabolism. In contrast to the growth factor input, genetic disruption of nutrient-dependent activation of mTORC1 in mammals remains unexplored. We engineered mice lacking RagA and RagB genes, which encode the GTPases responsible for mTORC1 activation by nutrients. RagB has limited expression, and its loss shows no effects on mammalian physiology. RagA deficiency leads to E10.5 embryonic death, loss of mTORC1 activity, and severe growth defects. Primary cells derived from these mice exhibit no regulation of mTORC1 by nutrients and maintain high sensitivity to growth factors. Deletion of RagA in adult mice is lethal. Upon RagA loss, a myeloid population expands in peripheral tissues. RagA-specific deletion in liver increases cellular responses to growth factors. These results show the essentiality of nutrient sensing for mTORC1 activity in mice and its suppression of PI3K/Akt signaling. PMID- 24768165 TI - WLS retrograde transport to the endoplasmic reticulum during Wnt secretion. AB - Wnts are transported to the cell surface by the integral membrane protein WLS (also known as Wntless, Evi, and GPR177). Previous studies of WLS trafficking have emphasized WLS movement from the Golgi to the plasma membrane (PM) and then back to the Golgi via retromer-mediated endocytic recycling. We find that endogenous WLS binds Wnts in the endoplasmic reticulum (ER), cycles to the PM, and then returns to the ER through the Golgi. We identify an ER-targeting sequence at the carboxyl terminus of native WLS that is critical for ER retrograde recycling and contributes to Wnt secretory function. Golgi-to-ER recycling of WLS requires the COPI regulator ARF as well as ERGIC2, an ER-Golgi intermediate compartment protein that is also required for the retrograde trafficking of the KDEL receptor and certain toxins. ERGIC2 is required for efficient Wnt secretion. ER retrieval is an integral part of the WLS transport cycle. PMID- 24768166 TI - Development of caged non-hydrolyzable phosphoamino acids and application to photo control of binding affinity of phosphopeptide mimetic to phosphopeptide recognizing protein. AB - The design and synthesis of caged non-hydrolyzable phospho-serine, -threonine, and -tyrosine derivatives that generate parent non-hydrolyzable phosphoamino acids, containing a difluoromethylene unit instead of the oxygen of a phosphoester, after UV-irradiation are described. The caged non-hydrolyzable amino acids were incorporated into peptides by standard Fmoc solid-phase peptide synthesis, and the obtained peptides were successfully converted to the parent non-hydrolyzable phosphopeptides by UV-irradiation. Application of the caged non hydrolyzable phosphoserine-containing peptide to photo-control the binding affinity of the peptide to 14-3-3beta protein is also reported. PMID- 24768167 TI - Response to Gu and FitzGerald: Interoceptive inference: from decision-making to organism integrity. PMID- 24768168 TI - Cardiac involvement secondary to mediastinal lymphoma in a cat: regression with chemotherapy. AB - Mediastinal lymphoma with neoplastic invasion into the heart was diagnosed in a 9 year-old castrated male domestic short hair cat. The neoplastic infiltrate was seen throughout the atria and atrial septum, surrounded the aortic root, and resulted in narrowing of the right ventricular outflow tract. Chemotherapy resulted in resolution of the echocardiographic abnormalities and the cat's clinical signs until the patient was euthanized 58 days later following development of neurologic signs. Mediastinal lymphoma with myocardial invasion and response to chemotherapy has not been documented previously in the veterinary literature. PMID- 24768169 TI - Retrospective diagnosis of congenital cytomegalovirus infection in children with autism spectrum disorder but no other major neurologic deficit. AB - AIM: Congenital cytomegalovirus (CMV) infection can cause a variety of neurological deficits of delayed onset in infants who are asymptomatic at birth. The aim of this study was to investigate the prevalence of congenital CMV infection among children with autism spectrum disorder (ASD) in Nagasaki, Japan. METHODS: Twenty-nine children with ASD who were born in Nagasaki and had no other major neurological deficits were recruited. Two of the patients were excluded due to significant perinatal events. The remaining 27 children were investigated retrospectively for congenital CMV infection by analyzing dried blood spot samples or dried umbilical cords for CMV DNA using real-time PCR. RESULTS: CMV DNA was detected in two (7.4%) of the 27 children. Neither of the patients had perinatal histories suggestive of congenital CMV disease or other neurological deficits, including hearing impairment and epilepsy. The severity of their autistic disorders varied considerably. CONCLUSIONS: The rate of congenital CMV infection in this study (two of 27 children with ASD), which was significantly (p=0.004) higher than the incidence of congenital CMV infection in Nagasaki (0.31%, 10/3230 live births), suggests the involvement of congenital CMV infection in a portion of children with ASD, although definite diagnosis was not obtained due to limited clinical data of the study subjects. PMID- 24768170 TI - Effects of salinity on anatomical features and physiology of a semi-mangrove plant Myoporum bontioides. AB - The effect of different concentrations of NaCl, 0, 100, 200, 300 and 400 mM, on the anatomical features and physiology of Myoporum bontioides was investigated. The photosynthetic rates (Pn) were significantly reduced by salt stress, with the lowest values at 400 mM NaCl. The content of malondialdehyde (MDA), proline and soluble sugar, as well as the activities of peroxidase (POD) and catalase (CAT) increased at the beginning, but became similar to the control as the experiment proceeded. The NaCl effect on superoxide dismutase (SOD) was different from the other parameters, with a significant reduction at 400 mM NaCl at Day 7. Salt glands were found in both upper and lower epidermis, and the ratios of the thickness of palisade to spongy mesophyll tissues increased with NaCl concentrations. The medullary ray was clearly damaged by NaCl at levels of 200 and 300 mM. These results demonstrated that M. bontioides could adapt to a relatively low salinity, and was not a halophilous species. PMID- 24768171 TI - Impact of sea-level rise and coral mortality on the wave dynamics and wave forces on barrier reefs. AB - A one-dimensional wave model was used to investigate the reef top wave dynamics across a large suite of idealized reef-lagoon profiles, representing barrier coral reef systems under different sea-level rise (SLR) scenarios. The modeling shows that the impacts of SLR vary spatially and are strongly influenced by the bathymetry of the reef and coral type. A complex response occurs for the wave orbital velocity and forces on corals, such that the changes in the wave dynamics vary reef by reef. Different wave loading regimes on massive and branching corals also leads to contrasting impacts from SLR. For many reef bathymetries, wave orbital velocities increase with SLR and cyclonic wave forces are reduced for certain coral species. These changes may be beneficial to coral health and colony resilience and imply that predicting SLR impacts on coral reefs requires careful consideration of the reef bathymetry and the mix of coral species. PMID- 24768172 TI - Managing ocean information in the digital era--events in Canada open questions about the role of marine science libraries. AB - Information is the foundation of evidence-based policies for effective marine environmental protection and conservation. In Canada, the cutback of marine science libraries introduces key questions about the role of such institutions and the management of ocean information in the digital age. How vital are such libraries in the mission of studying and protecting the oceans? What is the fate and value of the massive grey literature holdings, including archival materials, much of which is not in digital form but which often contains vital data? How important is this literature generally in the marine environmental sciences? Are we likely to forget the history of the marine pollution field if our digital focus eclipses the need for and access to comprehensive collections and skilled information specialists? This paper explores these and other questions against the backdrop of unprecedented changes in the federal libraries, marine environmental science and legislation in Canada. PMID- 24768173 TI - Effect of coastal urbanization on sandy beach coleoptera Phaleria maculata (Kulzer, 1959) in northern Chile. AB - The beetle Phaleria maculata is a common inhabitant of the upper intertidal fringe of Chilean beaches. Anthropogenic intervention in coastal areas has increased intensely, leading to changes in the flora and fauna of sandy beaches. To examine the impact of human activities on P. maculata, we studied several beaches along the northern Chilean coast. Beaches were characterized based on morphodynamics and the level of intervention, leading to the estimation of an "Urbanization Index" based on various indicators. The analysis showed a significant inverse correlation between the rate of urbanization and night sky quality. Larval and adult beetles were almost absent on beaches with high levels of urbanization. The results of simple and multiple correlations based on nMDS ordination showed an inverse relationship between increases in urbanization and the abundance of beetles. Because darkling beetles are very sensitive to human interventions on sandy beaches, we suggest that they are ideal indicator organisms for the health of these environments. PMID- 24768174 TI - Spatial and temporal characterizations of water quality in Kuwait Bay. AB - The spatial and temporal patterns of water quality in Kuwait Bay have been investigated using data from six stations between 2009 and 2011. The results showed that most of water quality parameters such as phosphorus (PO4), nitrate (NO3), dissolved oxygen (DO), and Total Suspended Solids (TSS) fluctuated over time and space. Based on Water Quality Index (WQI) data, six stations were significantly clustered into two main classes using cluster analysis, one group located in western side of the Bay, and other in eastern side. Three principal components are responsible for water quality variations in the Bay. The first component included DO and pH. The second included PO4, TSS and NO3, and the last component contained seawater temperature and turbidity. The spatial and temporal patterns of water quality in Kuwait Bay are mainly controlled by seasonal variations and discharges from point sources of pollution along Kuwait Bay's coast as well as from Shatt Al-Arab River. PMID- 24768175 TI - Linking the toxic metals to benthic community alteration: a case study of ecological status in the Bohai Bay. AB - Ecological effects and quality status of sediments in the Bohai Bay (North China) were studied by incorporating the traditional chemical analysis and benthic community structure. In the present study, paired sediments from 20 stations were sampled for chemical analysis and benthic assemblages. The overall results demonstrated that sediment impairment mainly appeared in the southern part of the Bay. The results obtained from the principal component analysis regarding benthic data and potential explanatory factors indicated that As, Hg and petroleum hydrocarbons (PHs) were responsible for the distribution of macrofaunal assemblages. Canonical correspondence analysis further showed As was significantly correlated to the benthic alteration, which provided evidence of ecological relevance to chemical substances of concern. Overall, this study revealed the metal contamination in the Bohai Bay was not as severe as previously regarded. Yet, further investigation is still needed considering the complexity of sediment matrices. PMID- 24768176 TI - Independent replication of mitochondrial genes supports the transcriptional program in developing fiber cells of cotton (Gossypium hirsutum L.). AB - The mitochondrial genomes of flowering plants exist both as a "master circle" chromosome and as numerous subgenomic sublimons that are generated by intramolecular recombination. Differential stability or replication of these sublimons allows individual mitochondrial gene copy numbers to vary independently between different cell types and developmental stages. Our objective was to determine the relationship between mitochondrial gene copy number and transcript abundance in the elongating fiber cells of Upland cotton (Gossypium hirsutum L.). We compared RNA and DNA from cotton fiber cells at five developmental time points from early elongation through secondary cell wall thickening from the Ligon lintless 2 (Li2) short fiber mutant and its wild type near isogenic line (NIL) DP5690. Mitochondrial gene copy number decreased from 3 to 8-DPA in the developing cotton fiber cells while transcript levels remained low. As secondary cell wall biosynthesis began in developing fibers, the expression levels and copy numbers of mitochondrial genes involved in energy production and respiration were up-regulated in wild type cotton DP5690. However, the short fiber mutant Li2, failed to increase expression of these genes, which include three subunits of ATP synthase, atp1, atp8 and atp9 and two cytochrome genes cox1 and cob. At the same time, Li2 failed to increase the copy numbers of these highly expressed genes. Surprisingly, we found that when mitochondrial genes were highly transcribed, they also had very high copy numbers. This observation suggests that in developing cotton fibers, increased mitochondrial sublimon replication may support increases in gene transcription. PMID- 24768177 TI - Identification of sex-linked DNA markers by AFLP in Portunus trituberculatus. AB - To investigate the mechanism of sex determination of crabs, amplified fragment length polymorphism DNA analysis was applied to identify sex-specific markers for Portunus trituberculatus. Eleven pairs of primers were used to amplify DNA isolated from male and female crabs. A total of 481 and 499 fragments were amplified for females and males, respectively, and the ratios of polymorphic fragments were 20.59-65.52% and 27.27-62.22%, respectively. Distribution difference values between female and male groups for 10 polymorphisms were greater than 40%; Cluster analysis revealed that Nei's genetic distances for 57 polymorphisms clustered according to sex. The results indicate that a difference at the DNA level exists between female and male crabs and provide data for further study on sex determination. PMID- 24768178 TI - ABCC8 genetic variants and risk of diabetes mellitus. AB - Diabetes mellitus (DM) is a major health problem worldwide and it will rapidly increase. This disease is characterized by hyperglycemia caused by defects in insulin secretion, insulin action or both. DM has three types: T1DM, T2M and gestational DM (GDM), of them T2DM is more frequent. Multiple genes and their interactions are involved in insulin secretion pathway. Sulfonylurea receptor encoded by ABCC8 gene, together with inward-rectifier potassium ion channel (Kir6.2) regulates insulin secretion by ATP-sensitive K(+) (KATP) channel located in the plasma membranes. Disruption of these molecules by different mutations is responsible for risk of DM. Several single nucleotide polymorphisms (SNPs) of ABCC8 gene and their interaction are involved in pathogenicity of DM. This review summarizes the current evidence of contribution of ABC8 genetic variants to the development of DM. PMID- 24768179 TI - Generation and characterization of the sea bass Dicentrarchus labrax brain and liver transcriptomes. AB - The sea bass Dicentrarchus labrax is the center of interest of an increasing number of basic or applied research investigations, even though few genomic or transcriptomic data is available. Current public data only represent a very partial view of its transcriptome. To fill this need, we characterized brain and liver transcriptomes in a generalist manner that would benefit the entire scientific community. We also tackled some bioinformatics questions, related to the effect of RNA fragment size on the assembly quality. Using Illumina RNA-seq, we sequenced organ pools from both wild and farmed Atlantic and Mediterranean fishes. We built two distinct cDNA libraries per organ that only differed by the length of the selected mRNA fragments. Efficiency of assemblies performed on either or both fragments size differed depending on the organ, but remained very close reflecting the quality of the technical replication. We generated more than 19,538Mbp of data. Over 193million reads were assembled into 35,073 contigs (average length=2374bp; N50=3257). 59% contigs were annotated with SwissProt, which corresponded to 12,517 unique genes. We compared the Gene Ontology (GO) contig distribution between the sea bass and the tilapia. We also looked for brain and liver GO specific signatures as well as KEGG pathway coverage. 23,050 putative micro-satellites and 134,890 putative SNPs were identified. Our sampling strategy and assembly pipeline provided a reliable and broad reference transcriptome for the sea bass. It constitutes an indisputable quantitative and qualitative improvement of the public data, as it provides 5 times more base pairs with fewer and longer contigs. Both organs present unique signatures consistent with their specific physiological functions. The discrepancy in fragment size effect on assembly quality between organs lies in their difference in complexity and thus does not allow prescribing any general strategy. This information on two key organs will facilitate further functional approaches. PMID- 24768180 TI - Vitamin-D pathway genes and HIV-1 disease progression in injection drug users. AB - Vitamin-D has pleiotropic effects on calcium and bone metabolism, cellular growth control, cell differentiation and modulation of both innate and acquired immune response. Previous studies revealed the association of vitamin-D receptor gene (VDR) polymorphism with infection diseases including HIV-1 infection. To assess for association between polymorphisms of vitamin-D pathway genes CYP27B1, vitamin D binding protein (VDBP) and VDR with HIV-1 infection, disease progression to acquired immunodeficiency syndrome (AIDS) was analysed according to CDC93 criteria in a cohort of 185 HIV-1 seroprevalent patients belonging to the injection drug users. Genotype data was obtained from rs10877012, rs3782130 and rs4646536 markers at CYP27B1 locus; rs7041 and rs4588 at VDBP locus; and rs11568820, rs4516035, rs2228570, rs1544410 and rs17878969 at VDR locus. Distribution of genotypes between patients grouped by outcome was compared by contingency table analysis. Marker-marker interaction was assessed by a MDR analysis. Assuming an additive model for VDR markers, a Kaplan-Meier survival analysis was employed to evaluate association with disease progression. Among vitamin-D pathway genes, VDR locus reveals specific 5'UTR and 3'UTR diplotype combinations associated with both, slower and faster progression to AIDS. Marker marker interaction analysis indicates a strong interaction between VDR markers and a redundant effect for CYP27B1 markers. According to our results, VDR locus association follows an additive model in which increased genetic risk score for the VDR is directly correlated with AIDS progression rates. Our data supports a role of vitamin-D pathway gene variability on HIV-1 disease progression. PMID- 24768181 TI - Cloning, expression and antiviral bioactivity of red-crowned crane interferon alpha. AB - Interferon-alpha (IFN-alpha) genes have been cloned from a variety of animals, but information regarding crane IFN-alpha has not been reported to date. In this study, we cloned a full-length Red-crowned Crane interferon-alpha (crIFN-alpha) gene sequence consisting of a 486bp partial 5' UTR, 741bp complete ORF and 559bp partial 3' UTR. This gene encodes a protein of 246 amino acids and shares 60 to 80% identity with avian IFN-alpha and less than 45% identity with mammalian IFN alpha. The expression of crIFN-alpha with an N-terminal His-tag was investigated in Escherichia coli, and the protein was purified on a nickel column. To obtain activated proteins, crIFN-alpha inclusion bodies were renatured by dialysis. In vitro cytopathic inhibition assays indicated that the recombinant crIFN-alpha could inhibit the replication of vesicular stomatitis virus in chicken fibroblasts. These antiviral activities were abrogated by rabbit anti-crIFN-alpha antibodies in vitro. In addition, an immunofluorescence assay indicated that crIFN-alpha could be expressed in chicken fibroblasts and was primarily located in the cytoplasm. Taken together, our results suggest that the crIFN-alpha gene may play an important role in inhibiting the replication of viruses. PMID- 24768183 TI - Identification of a novel MYOC mutation, p.(Trp373), in a family with open angle glaucoma. AB - MYOC gene variants are associated with autosomal dominant primary open angle glaucoma (POAG). In this study, we describe a previously unreported MYOC variant segregating with a POAG phenotype in an Australian family. Two individuals affected with POAG and three unaffected individuals from the same family were recruited through the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Direct sequencing of all MYOC coding exons identified the novel heterozygous single nucleotide transition MYOC:c.1119G>A, p.(Trp373), predicted to encode an aberrant truncated MYOC protein in two affected siblings. Two unaffected siblings and an unaffected niece were negative for the MYOC sequence variant. PMID- 24768182 TI - Role of cytokine gene polymorphisms on prognosis in hepatocellular carcinoma after radical surgery resection. AB - This study aimed to determine whether SNPs of cytokine genes influence survival of hepatocellular carcinoma (HCC) patients after radical surgery resection. We evaluated 14 SNPs of eight cytokine genes in 263 patients treated with radical surgery resection of HCC. Categorical variables were compared by the chi(2) test and Fisher's exact test. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of resected HCC patients according to the genotype. Among the 14 studied SNPs of cytokine genes, only the TNF-alpha-863 (CA+CC) genotypes were revealed to be significant independent predictors of prolonged overall survival (OS) after HCC radical surgery resection (HR: 0.586, 95% CI: 0.355-0.968), considering for other clinical factors in a Cox proportional hazard model. Meanwhile, no significant association was found between the 14 SNPs and relapse-free survival (RFS) of resected HCC patients. In addition, combination analysis with the Th1 cytokine (IFN-gamma, IL-2, IL-12B, TGF-beta1) or Th2 cytokine (IL-6, IL-10) genetic polymorphisms by the Kaplan Meier method and Cox multivariate analysis did not reveal any significant association between OS and RFS of resected HCC patients. PMID- 24768184 TI - A challenge for miRNA: multiple isomiRs in miRNAomics. AB - Accumulating evidence suggests that a single microRNA (miRNA) locus can generate a series of sequences during miRNA maturation process. These multiple sequences, called miRNA variants, or isomiRs, have different lengths and different 5' and 3' ends. Some of these isomiRs are detected as varied nucleotides and 3' additional non-template nucleotides. As physiological miRNA isoforms, they have drawn attention for possible regulatory biological roles. The present work mainly reviews miRNA/isomiR biogenesis, isomiR expression patterns, and functional and evolutionary implications, especially between isomiRs from homologous and clustered miRNA loci. The phenomenon of multiple isomiRs and their biological roles indicates that analysis performed at the miRNA and isomiR levels should be included in miRNA studies. This may enrich and complicate miRNA biogenesis and coding-non-coding RNA regulatory networks. PMID- 24768186 TI - pKILLIN: a versatile positive-selection cloning vector based on the toxicity of Killin in Escherichia coli. AB - The invention of DNA cloning over 40 years ago marked the advent of molecular biology. The technique has now become a routine practice in any modern biomedical laboratory. Although positive-selection of recombinants in DNA cloning seems to be superior to blue/white selection based on the disruption of the lacZ gene, it is rarely practiced due to its high background, lack of multiple cloning sites, and inability to express the genes of interest or purify the protein products. Here we report the creation of a new positive-selection cloning vector dubbed pKILLIN, which overcomes all of the above pitfalls. The essence behind its high cloning efficiency is the extreme toxicity and small size of the toxic domain of killin, a recently discovered p53 target gene. Insertion inactivation of killin within the multiple cloning site via either blunt- or sticky-end ligation not only serves as a highly efficient cloning trap, but also may allow any cloned genes to be expressed as His-tagged fusion proteins for subsequent purification. Thus, pKILLIN is a versatile positive-selection vector ideal for cloning PCR products, making DNA libraries, as well as routine cloning and bacterial expression of genes. PMID- 24768185 TI - Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome. AB - OBJECTIVE: This study is to investigate the role of glucose-regulated protein 78 (GRP78) in the pulmonary microvascular remodeling during hepatopulmonary syndrome (HPS) development. METHODS: The rat models with liver cirrhosis and HPS were induced by multiple pathogenic factors for 4 to 8 wk. The concentrations of alanine transferase (ALT) and endotoxin in plasma were detected in the models, followed by the detection of GRP78 expression. RT-PCR, quantitative real-time PCR and Western blotting were employed to assess the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), respectively. Immunohistochemistry staining was used to examine the expression of a specific vascular marker, factor VIII-related antigen (FVIII-RAg), and several cell proliferation- and apoptosis-related proteins, including CHOP/GADD153, caspase 12, Bcl-2 and nuclear factor (NF)-kappaB. RESULTS: The levels of endotoxin and ALT in plasma were gradually increased as the disease progressed, so did GRP78, which were in a positive correlation. The expression levels of VEGF (both mRNA and protein) and FVIII-RAg were significantly elevated in the HPS models, indicating active angiogenesis, which was also positively correlated with GRP78 expression. Furthermore, the expression levels of the pro-apoptotic proteins of CHOP/GADD153 and caspase-12 were dramatically decreased, while the anti-apoptotic proteins of Bcl-2 and NF-kappaB were significantly elevated, in the HPS models. There were also close correlation between these proteins and GRP78. CONCLUSIONS: Over-expression of GRP78 in lungs may be the critical pathogenic factor for HPS. Through promoting cell proliferation and survival and inhibiting apoptosis, GRP78 may promote the pulmonary microvascular remodeling in HPS pathogenesis. Our results provide a potential therapeutic target for clinical prevention and treatment for HPS and related complications. PMID- 24768187 TI - LDL-C levels in US patients at high cardiovascular risk receiving rosuvastatin monotherapy. AB - BACKGROUND: Statin therapy is recommended as the first-line pharmacotherapeutic approach for lowering LDL-C levels in patients at high cardiovascular risk. OBJECTIVE: To assess LDL-C levels among patients at high cardiovascular risk treated with rosuvastatin monotherapy. METHODS: This retrospective cohort study used patient records from the GE Centricity Electronic Medical Records (GE Centricity EMR) database and administrative claims data from Humana Medicare to identify patients at high cardiovascular risk with a first prescription for rosuvastatin monotherapy (index date) from January 1, 2008 through December 31, 2010. Eligible adult patients had an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis or a Current Procedural Terminology (CPT) procedure code indicating coronary heart disease or atherosclerotic vascular disease, >=1 LDL-C measurement 3 to 12 months after the index date, and continuous data during 1-year baseline and 1-year follow-up. Mean LDL-C levels and distribution of patients around <70 mg/dL and <100 mg/dL thresholds overall and by daily rosuvastatin dose were assessed. RESULTS: Among 6004 GE Centricity EMR patients (mean [SD] age, 66 [10] years; 56% men) and 11,320 Humana Medicare patients (mean [SD] age, 74 [8] years; 44% men) who met selection criteria, the most frequently prescribed rosuvastatin dose was 10 mg, and the mean (SD) follow up LDL-C level was 89 (37) mg/dL for GE Centricity EMR patients and 92 (36) mg/dL for Humana Medicare patients. Overall, lower mean LDL-C levels were observed as rosuvastatin dose increased. However, less than one-third of GE Centricity EMR and Humana Medicare patients had an LDL-C level <70 mg/dL, and approximately two thirds had an LDL-C level <100 mg/dL. CONCLUSION: More effective lipid-lowering strategies, such as statin up-titration or combination therapy, may be needed to achieve therapeutic goals in a substantial proportion of high-risk patients. PMID- 24768188 TI - Whole-body-MR imaging including DWIBS in the work-up of patients with head and neck squamous cell carcinoma: a feasibility study. AB - OBJECTIVES: To assess the feasibility of whole-body magnetic resonance imaging (WB-MRI) including diffusion-weighted whole-body imaging with background-body signal-suppression (DWIBS) for the evaluation of distant malignancies in head and neck squamous cell carcinoma (HNSCC); and to compare WB-MRI findings with (18)F fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) and chest-CT. METHODS: Thirty-three patients with high risk for metastatic spread (26 males; range 48-79 years, mean age 63 +/- 7.9 years (mean +/- standard deviation) years) were prospectively included with a follow-up of six months. WB-MRI protocol included short-TI inversion recovery and T1-weighted sequences in the coronal plane and half-fourier acquisition single-shot turbo spin-echo T2 and contrast-enhanced-T1-weighted sequences in the axial plane. Axial DWIBS was reformatted in the coronal plane. Interobserver variability was assessed using weighted kappa and the proportion specific agreement (PA). RESULTS: Two second primary tumors and one metastasis were detected on WB-MRI. WB MRI yielded seven clinically indeterminate lesions which did not progress at follow-up. The metastasis and one second primary tumor were found when combining (18)F-FDG-PET/CT and chest-CT findings. Interobserver variability for WB-MRI was kappa=0.91 with PA ranging from 0.82 to 1.00. For (18)F-FDG-PET/CT kappa could not be calculated due to a constant variable in the table and PA ranged from 0.40 to 0.99. CONCLUSIONS: Our WB-MRI protocol with DWIBS is feasible in the work-up of HNSCC patients for detection and characterization of distant pathology. WB-MRI can be complementary to (18)F-FDG-PET/CT, especially in the detection of non (18)F-FDG avid second primary tumors. PMID- 24768190 TI - Breastfeeding in Gaucher disease: is enzyme replacement therapy safe? PMID- 24768189 TI - Value of volume measurements in evaluating abdominal aortic aneurysms growth rate and need for surgical treatment. AB - PURPOSE: To examine whether indices other than the traditionally used abdominal aortic aneurysm (AAA) maximum diameter, such as AAA volume, intraluminal thrombus (ILT) thickness and ILT volume, may be superior to evaluate aneurismal enlargement. MATERIALS AND METHODS: Thirty-four small AAAs (initially presenting a maximum diameter <5.5cm which is the threshold for surgical repair) with an initial and a follow-up CT were examined. Median increase and percentile annual change of these variables was calculated. Correlation between growth rates as determined by the new indices under evaluation and those of maximum diameter were assessed. AAAs were divided according to outcome (surveillance vs. elective repair after follow-up which is based on the maximum diameter criterion) and according to growth rate (high vs. low) based on four indices. Contingency between groups of high/low growth rate regarding each of the four indices on one hand and those regarding need for surgical repair on the other was assessed. RESULTS: A strong correlation between growth rates of maximum diameter and those of AAA and ILT volumes could be established. Evaluation of contingency between groups of outcome and those of growth rate revealed significant associations only for AAA and ILT volumes. Subsequently AAAs with a rapid volumetric increase over time had a likelihood ratio of 10 to be operated compared to those with a slower enlargement. Regarding increase of maximum diameter, likelihood ratio between AAAs with rapid and those with slow expansion was only 3. CONCLUSION: Growth rate of aneurysms regarding 3Dimensional indices of AAA and ILT volumes is significantly associated with the need for surgical intervention while the same does not hold for growth rates determined by 2Dimensional indices of maximum diameter and ILT thickness. PMID- 24768191 TI - Short-term effects of extended-release niacin with and without the addition of laropiprant on endothelial function in individuals with low HDL-C: a randomized, controlled crossover trial. AB - BACKGROUND: Reduced plasma concentration of high-density lipoprotein cholesterol (HDL-C) is associated with vulnerability to oxidative stress and propensity to endothelial dysfunction. Niacin directly activates both GPR-109A in leukocytes and the heme oxygenase-1 pathway, promoting strong anti-inflammatory and antioxidative effects, as well as induces immediate production of prostaglandin D2, leading to endothelial vasodilation. OBJECTIVE: This study investigated the short-term effects of extended-release niacin (ERN) administered with or without the prostaglandin D2 receptor antagonist laropiprant on endothelial function in patients with low HDL-C. METHODS: Asymptomatic men and women aged between 20 and 60 years who had plasma HDL-C levels <40 mg/dL were treated with ERN monotherapy 1 g/d or ERN/laropiprant 1 g/20 mg (ERN/LRP) in a crossover study design. The sequence of treatments was decided by simple randomization. Plasma samples and flow-mediated dilation (FMD) of the brachial artery were obtained at baseline, day 7 of treatment period 1, day 7 of washout, and day 7 of treatment period 2. RESULTS: Eighteen patients were enrolled (mean [SD] age, 42 [17] years; 11 men). Triglyceride levels decreased by 4% and 3%, and HDL size decreased by 5.8% and 6.2%, with ERN and ERN/LRP, respectively (both, P < 0.05). There were no changes in HDL-C levels or in cholesteryl esterase transfer protein activity with either treatment. The median increases in FMD were 4.5% and 4.1% with ERN and ERN/LRP, which receded after washout. On intergroup analysis, there were no differences with respect to variation in plasma HDL-C, triglycerides, C-reactive protein, direct bilirubin, or FMD. CONCLUSIONS: In these patients, the addition of laropiprant did not influence the effects of niacin on endothelial function. Based on these findings, short-term niacin treatment might improve endothelial function in patients with low HDL-C levels. ClinicalTrials.gov identifier: NCT01942291. PMID- 24768192 TI - Patient-reported compliance with thromboprophylaxis using an oral factor Xa inhibitor (rivaroxaban) following total hip and total knee arthroplasty. AB - This prospective study examines patient non-compliance (NC) for an oral factor Xa inhibitor (Rivaroxaban) when used as venous thromboembolic (VTE) prophylaxis following lower limb arthroplasty. A total of 3145 patients underwent surgery from May 2010 to December 2011. At 6 weeks patients completed an anonymous self administered questionnaire. Postoperatively 2947 (94%, 2947/3145) received Rivaroxaban. 2824 (96%, 2824/2947) completed all in-hospital doses. Seven percent (203/2824) of patients did not attend the 6-week follow-up. Two thousand one hundred sixty-three (83%, 2163/2621) completed all prescribed doses, 98 (4%, 98/2621) were NC and 360 (14%, 360/2621) had incomplete data. Gender, age, body mass index and preoperative hemoglobin all correlated with NC (p < 0.05). Type and side of surgery did not correlate with compliance (p > 0.05). Patient reported NC for Rivaroxaban is 4% which compares favorably to other VTE prophylaxis modalities. PMID- 24768193 TI - Inhibition of blood vessel formation by a chondrocyte-derived extracellular matrix. AB - In this study, the chondrocyte-derived extracellular matrix (CECM) was evaluated for its activity to inhibit vessel invasion in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) and rabbit chondrocytes were plated on a bio membrane made of CECM or human amniotic membrane (HAM). The adhesion, proliferation, and tube formation activity of HUVECs and chondrocytes were examined. The CECM and HAM powders were then mixed individually in Matrigel and injected subcutaneously into nude mice to examine vessel invasion in vivo after 1 week. Finally, a rabbit model of corneal neovascularization (NV) was induced by 3 point sutures in the upper cornea, and CECM and HAM membranes were implanted onto the corneal surface at day 5 after suture injury. The rabbits were sacrificed at 7 days after transplantation and the histopathological analysis was performed. The adhesion and proliferation of HUVECs were more efficient on the HAM than on the CECM membrane. However, chondrocytes on each membrane showed an opposite result being more efficient on the CECM membrane. The vessel invasion in vivo also occurred more deeply and intensively in Matrigel containing HAM than in the one containing CECM. In the rabbit NV model, CECM efficiently inhibited the neovessels formation and histological remodeling in the injured cornea. In summary, our findings suggest that CECM, an integral cartilage ECM composite, shows an inhibitory effect on vessel invasion both in vitro and in vivo, and could be a useful tool in a variety of biological and therapeutic applications including the prevention of neovascularization after cornea injury. PMID- 24768194 TI - Aluminium hydroxide stabilised MnFe2O4 and Fe3O4 nanoparticles as dual-modality contrasts agent for MRI and PET imaging. AB - Magnetic nanoparticles (NPs) MnFe2O4 and Fe3O4 were stabilised by depositing an Al(OH)3 layer via a hydrolysis process. The particles displayed excellent colloidal stability in water and a high affinity to [(18)F]-fluoride and bisphosphonate groups. A high radiolabeling efficiency, 97% for (18)F-fluoride and 100% for (64)Cu-bisphosphonate conjugate, was achieved by simply incubating NPs with radioactivity solution at room temperature for 5 min. The properties of particles were strongly dependant on the thickness and hardness of the Al(OH)3 layer which could in turn be controlled by the hydrolysis method. The application of these Al(OH)3 coated magnetic NPs in molecular imaging has been further explored. The results demonstrated that these NPs are potential candidates as dual modal probes for MR and PET. In vivo PET imaging showed a slow release of (18)F from NPs, but no sign of efflux of (64)Cu. PMID- 24768195 TI - Influence of pDNA availability on transfection efficiency of polyplexes in non proliferative cells. AB - We succeeded in visualizing plasmid DNA (pDNA) in the nucleus and cytosol of non proliferative cells after transfection with linear polyethylenemine (lPEI) and histidinylated lPEI (His16-lPEI). This was possible with confocal microscope by using pDNA labelled with quantum dots. Indeed pDNA labelled with Cy3 leads to false positive nuclear localization because the saturation of the fluorescence signal overestimated the volume occupied by Cy3-pDNA. Moreover, Cy3 brightness was too weak to detect low amount of pDNA. About 20 to 40 pDNA copies were detected in the nucleus after the transfection of pDNA labelled with quantum dots. Transfection efficiency and cellular imaging data suggested that the cytosolic availability of pDNA, including endosome escape and/or polyplexes dissociation, is crucial for its nuclear delivery. In vitro transcription assay and transfection of cells allowing cytosolic gene expression concluded to better cytosolic availability of pDNA within His16-lPEI polyplexes. Cryo-TEM analyses revealed that His16-lPEI polyplexes exhibited a spherical shape and an amorphous internal structure which differed from the high degree of order of lPEI polyplexes. Altogether, this comparative study indicated that the high transfection efficiency of non-proliferative cells with His16-lPEI polyplexes was related to the amorphous structure and the facilitated dissociation of the assemblies. PMID- 24768196 TI - [Desulfovibrio desulfuricans bacteremia]. PMID- 24768197 TI - [Alternating hemiplegia of childhood: ATP1A3 gene analysis in 16 patients]. AB - BACKGROUND AND OBJECTIVE: Alternating hemiplegia in childhood (AHC) is a disease characterized by recurrent episodes of hemiplegia, tonic or dystonic crisis and abnormal ocular movements. Recently, mutations in the ATP1A3 gene have been identified as the causal mechanism of AHC. The objective is to describe a series of 16 patients with clinical and genetic diagnosis of AHC. PATIENTS AND METHOD: It is a descriptive, retrospective, multicenter study of 16 patients with clinical diagnosis of AHC in whom mutations in ATP1A3 were identified. RESULTS: Six heterozygous, de novo mutations were found in the ATP1A3 gene. The most frequent mutation was G2401A in 8 patients (50%) followed by G2443A in 3 patients (18.75%), G2893A in 2 patients (12.50%) and C2781G, G2893C and C2411T in one patient, respectively (6.25% each). CONCLUSIONS: In the studied population with AHC, de novo mutations were detected in 100% of patients. The most frequent mutations were D801N y la E815K, as reported in other series. PMID- 24768198 TI - [Statin therapy does not influence in the form onset of differentiated thyroid carcinoma]. PMID- 24768199 TI - [Scleromyxedema]. PMID- 24768200 TI - [Non-alcoholic fatty liver in children and adolescents with excess weight and obesity]. AB - BASIS AND OBJECTIVE: Hepatic steatosis, also known as non-alcoholic fatty liver (NAFL), is the most frequent liver disease in obese children. Due to an increase in infantile obesity, it is experiencing a significant increment in incidence. Our objetives are: Estimate the prevalence of NAFL in children with excess weight and obesity using the glutamate pyruvate transaminase (GPT) value as a biochemical test and an abdominal ultrasound, and correlate the presence of hepatic steatosis with various anthropometric and biochemical parameters. PATIENTS AND METHOD: Cross-sectional prevalence study which includes children with excess weight and obesity between the ages of 5 and 15 years, between the years 2004-2012. The independent variables included were: age, sex, weight, size, body mass index (BMI), waist circumference (WC), waist size index (WSI), insulinemia, Homeostasis model assessment-insulin resistance (HOMA-R), total cholesterol, triglycerides (TG), high density lipoproteins (HDL), low density lipoproteins (LDL), glutamic-oxaloacetic transaminase (GOT), GPT and gamma glutamyl transpeptidase (GGT). RESULTS: One hundred and twenty-six patients, with an average age of 11.94 (3.12) years were recruited. A percentage of 19.66 of the patients presented elevated GPT pathology. Of the 126 abdominal ultrasounds performed, 38 patients presented hepatic steatosis (30.15%). The levels of insulinemia, HOMA-R and LDL were significantly higher in patients with altered GPT, compared to those with normal GPT values (P=.015, P=.008 and P=.002, respectively). The patients with an objective HGNA in ultrasound, also showed greater levels of insulinemia, WC, WSI, total cholesterol, TG, LDL, GLT, GPT and GGT than the patients with normal ultrasounds, thereby achieving statistical significance in insulinemia, HOMA-R, LDL and GPT values. CONCLUSIONS: NAFL is a relatively frequent disorder in obese children and adolescents. In our study, 2 of 10 children -using GPT- and 3 of every 10 -using abdominal ultrasound- present the same. The biochemical marker which best defines it is an elevation in GPT. A modification in lifestyle which includes weight loss as a principal means of avoiding complications in adult life, is essential and necessary. PMID- 24768201 TI - [Chronic ulcer in nasal vestibule]. PMID- 24768202 TI - [Platypnea-orthodeoxia syndrome and Budd-Chiari syndrome: an unreported association]. PMID- 24768203 TI - [Facial tumors and lumbar plaque]. PMID- 24768204 TI - Effectiveness of interactive discussion group in suicide risk assessment among general nurses in Taiwan: a randomized controlled trial. AB - The evidence of suicide prevention training for nurses is scarce. Strategies to enhance general nurses' ability in suicide risk assessment are critical to develop effective training programs in general medical settings. This study was aimed to examine the effectiveness of an interactive discussion group in a suicide prevention training program for general nurses. In this randomized study with two groups of pre-post study design, the sample was recruited from the Medical, Surgical, and Emergency/Intensive Care Sectors of a 2000-bed general hospital via stratified randomization. Among the 111 nurses, 57 participants randomly assigned to the control group received a two-hour baseline suicide gatekeeper lecture, and 54 participants assigning to the experimental group received an additional five-hour group discussion about suicide risk assessment skills. Using a case vignette, the nurses discussed and assessed suicide risk factors specified in a 10-item Chinese SAD PERSONS Scale during a group discussion intervention. The findings revealed that the nurses achieved significant and consistent improvements of risk identification and assessment after the intervention without influencing their mental health status for assessing suicide risks. The result suggested an effective approach of interactive group discussion for facilitating critical thinking and learning suicide risk assessment skills among general nurses. PMID- 24768205 TI - A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma. AB - The role of TGF-beta-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of lncRNAs in TGF beta signaling is still unknown. In this study, we observed that the lncRNA activated by TGF-beta (lncRNA-ATB) was upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis. lncRNA-ATB upregulated ZEB1 and ZEB2 by competitively binding the miR-200 family and then induced EMT and invasion. In addition, lncRNA-ATB promoted organ colonization of disseminated tumor cells by binding IL-11 mRNA, autocrine induction of IL-11, and triggering STAT3 signaling. Globally, lncRNA-ATB promotes the invasion-metastasis cascade. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-beta signaling, could predispose HCC patients to metastases and may serve as a potential target for antimetastatic therapies. PMID- 24768207 TI - The villain with a thousand faces. PMID- 24768206 TI - Gestational diabetes mellitus alters apoptotic and inflammatory gene expression of trophobasts from human term placenta. AB - AIM: Increased placental growth secondary to reduced apoptosis may contribute to the development of macrosomia in GDM pregnancies. We hypothesize that reduced apoptosis in GDM placentas is caused by dysregulation of apoptosis related genes from death receptors or mitochondrial pathway or both to enhance placental growth in GDM pregnancies. METHODS: Newborn and placental weights from women with no pregnancy complications (controls; N=5), or with GDM (N=5) were recorded. Placental villi from both groups were either fixed for TUNEL assay, or snap frozen for gene expression analysis by apoptosis PCR microarrays and qPCR. RESULTS: Maternal, placental and newborn weights were significantly higher in the GDM group vs. Controls. Apoptotic index of placentas from the GDM group was markedly lower than the Controls. At a significant threshold of 1.5, seven genes (BCL10, BIRC6, BIRC7, CASP5, CASP8P2, CFLAR, and FAS) were down regulated, and 13 genes (BCL2, BCL2L1, BCL2L11, CASP4, DAPK1, IkappaBkappaE, MCL1, NFkappaBIZ, NOD1, PEA15, TNF, TNFRSF25, and XIAP) were unregulated in the GDM placentas. qPCR confirmed the consistency of the PCR microarray. Using Western blotting we found significantly decreased placental pro-apoptotic FAS receptor and FAS ligand (FASL), and increased mitochondrial anti-apoptotic BCL2 post GDM insult. Notably, caspase-3, which plays a central role in the execution-phase of apoptosis, and its substrate poly (ADP-ribose) polymerase (PARP) were significantly down regulated in GDM placentas, as compared to non-diabetic Control placentas. CONCLUSION: Maternal GDM results in heavier placentas with aberrant placental apoptotic and inflammatory gene expression that may account, at least partially, for macrosomia in newborns. PMID- 24768208 TI - Multi-center evaluation of the adenovirus R-gene US assay for the detection of adenovirus in respiratory samples. AB - BACKGROUND: Adenoviruses (AdV) cause a variety of upper and lower respiratory tract infections, with the potential for severe outcomes, especially in persons with immune suppression or other underlying diseases. The ADENOVIRUS US R-gene (AdV R-gene, Argene/bioMerieux) is a FDA cleared real-time PCR assay that utilizes primers and fluorescent probes that target a conserved region of the hexon gene and an internal control DNA. OBJECTIVES: This prospective multi-center study evaluated the clinical performance of AdV R-gene for AdV detection in respiratory specimens from symptomatic patients of all ages. STUDY DESIGN: Nucleic acids from nasopharyngeal washes/aspirates (NPW/A; n=393) and NP flocked swabs (NPS, Copan) (n=1183) were extracted using NucliSENS easyMAG (bioMerieux) and AdV R-gene PCR was performed using the SmartCycler (Cepheid). AdV R-gene results were compared to R-Mix culture (Quidel/Diagnostic Hybrids). For a subset of samples (n=946) AdV R-gene and R-Mix results were also compared to A549 cell culture. RESULTS: In first intention analysis for NPS the AdV R-gene positive percent agreement (PPA), and negative percent agreement (NPA) were 91.7% and 96.2%, respectively, and for NPW/A were 100% and 94.4%, respectively, compared to R-Mix culture. In second intention analysis, discordant samples only were tested with an AdV real-time PCR assay (Viracor-IBT Labs) and amplicon sequencing. For NPS, the sensitivity, specificity, PPV and NPV for AdV R-gene were 98.9%, 100%, 100%, and 99.9%, respectively and for R-Mix culture were 51.7%, 99.7%, 93.8%, and 96.3%, respectively. For NPW/A, the sensitivity, specificity, PPV and NPV for AdV R-gene were 100%, 99.7%, 97.6%, and 100%, respectively, and for R-Mix culture were 52.5%, 100%, 100%, and 94.9%, respectively. Overall, AdV was detected by AdV R-gene and R-Mix in 7.4% and 4.1% NPS, respectively, and in 10.7% and 5.3% NPW/A, respectively. Children 5yr and younger had the highest rates of AdV infections. In a subset of specimens (n=946) the sensitivity of AdV R-gene, R-Mix, and A549 cell culture were 95.0%, 55.4% and 66.3%. CONCLUSIONS: AdV R-gene is sensitive and specific for the detection of AdV in NPW/A and NPS samples. AdV R-gene is simple to use and provides a rapid time to results (within 2.5-3h). PMID- 24768209 TI - Beyond ubiquitination: proteolytic and nonproteolytic roles of HOS1. AB - The E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1 (HOS1) functions as a cold signaling attenuator by degrading the INDUCER OF CBF EXPRESSION 1 transcription factor, which is a key regulator of the cold-induced transcriptome and freezing tolerance in plants. Recent studies demonstrate that HOS1 also plays nonproteolytic roles in gene expression regulation. HOS1 acts as a chromatin remodeling factor that modulates FLOWERING LOCUS C chromatin in cold regulation of flowering time. It associates with the nuclear pore complex to facilitate nucleocytoplasmic mRNA export to maintain circadian periodicity over a range of light and temperature conditions. In this review, we summarize recent advances in molecular mechanisms underlying HOS1 function during plant development in response to fluctuating environmental conditions. PMID- 24768211 TI - Blood culture contaminants. AB - Blood cultures are an essential diagnostic tool. However, contamination may impact on patients' care and lead to increased patient stay, additional tests, and inappropriate antibiotic use. The aim of this study was to review the literature for factors that influence the rate of blood culture contamination. A comprehensive literature search was performed using Medline and CINAHL on blood culture contamination. Hospitals/units should have in place a protocol for staff on how to take blood cultures, incorporating use of an aseptic technique. Studies have shown that several key factors in the process may lower contamination rates such as adherence to a protocol, sampling by peripheral venepuncture route rather than via an intravascular catheter, use of sterile gloves, cleaning tops of blood culture bottles with antiseptics and inoculating blood culture bottles before other blood tubes, samples being taken by a phlebotomy team, monitoring contamination rates, and providing individual feedback and retraining for those with contaminants. Although skin antisepsis is advocated there is still debate on which antiseptic is most effective, as there is no conclusive evidence, only that there is benefit from alcohol-containing preparations. In conclusion, hospitals should aim to minimize their blood culture contamination rates. They should monitor their rate regularly and aim for a rate of <=3%. PMID- 24768210 TI - Effect of altitude on brain intracellular pH and inorganic phosphate levels. AB - Normal brain activity is associated with task-related pH changes. Although central nervous system syndromes associated with significant acidosis and alkalosis are well understood, the effects of less dramatic and chronic changes in brain pH are uncertain. One environmental factor known to alter brain pH is the extreme, acute change in altitude encountered by mountaineers. However, the effect of long-term exposure to moderate altitude has not been studied. The aim of this two-site study was to measure brain intracellular pH and phosphate bearing metabolite levels at two altitudes in healthy volunteers, using phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS). Increased brain pH and reduced inorganic phosphate (Pi) levels were found in healthy subjects who were long-term residents of Salt Lake City, UT (4720ft/1438m), compared with residents of Belmont, MA (20ft/6m). Brain intracellular pH at the altitude of 4720ft was more alkaline than that observed near sea level. In addition, the ratio of inorganic phosphate to total phosphate signal also shifted toward lower values in the Salt Lake City region compared with the Belmont area. These results suggest that long-term residence at moderate altitude is associated with brain chemical changes. PMID- 24768212 TI - Firearms regulation, violence and the mentally ill: a contemporary Antipodean appraisal. AB - As recent cases of mass murder at Utoya Island in Norway, and in the United States (US) at Virginia Tech, Virginia; Tucson, Arizona; Aurora, Colorado; and Newtown, Connecticut all illustrate, acts of extreme violence involving high powered weapons and committed by persons with a presumed or confirmed mental illness tend to arouse intense public and political debates about the efficacy of firearm regulation and control. Following these tragedies, in the US at least, various law reform measures have been proposed and in some cases implemented designed principally to make it more difficult for mentally ill persons to gain access to firearms. In this article it is contended that measures like these are at best tinkering with the margins of gun control and also have the tendency to reinforce the stigma and discrimination experienced by persons with a mental illness, while perpetuating stereotypes of them as dangerous to themselves and others. Despite these limitations, and while firearm regulation policies and practices vary widely across the globe, most nations still seek in some way to limit access to guns by persons with a mental illness. This article explores in more detail how such policies and practices have been applied in the Australian State of New South Wales and the lessons to be learned elsewhere from this experience. PMID- 24768213 TI - Erythromycin resistance features and biofilm formation affected by subinhibitory erythromycin in clinical isolates of Staphylococcus epidermidis. AB - BACKGROUND/PURPOSE: Subminimal inhibitory concentration (sub-MIC) of antibiotics can modify the phenotype of biofilm formation in bacteria. However, the relationship between resistance phenotypes, genotypes, and the biofilm formation phenotype in response to sub-MIC antibiotics remains unclear. METHODS: Here, we collected 96 clinical isolates of Staphylococcus epidermidis (S. epidermidis) and investigated the erythromycin (ERY) susceptibility, the biofilm formation in respond to sub-MIC ERY, the presence and transcription expression of erm genes. Serial passage of induction resistance was used against ERY-susceptible isolates and biofilm formation in response to their new sub-MIC ERY was determined. RESULTS: The incidence of biofilm phenotype modification in ERY-resistant isolates was significantly higher than that of ERY-susceptible isolates [27/85 (31.8%) vs. 0/11 (0%), p = 0.031]. Yet, ERY-susceptible isolates displayed the phenomenon of biofilm phenotype modification (7/11), after induction of resistance to ERY. The ermC gene was absolutely dominant among the three macrolide resistant genes including erm (A, B, C) [6/96 (6.2%), 6/96 (6.2%), and 91/96 (94.8%), respectively]. With statistic stratification analysis, a linear and positive correlation was identified between the two factors in the biofilm enhanced strains, a linear and negative correlation in biofilm-inhibited strains, and a weakly positive correlation in biofilm-unaffected strains (R(2) = 0.4992, 0.3686, and 0.0512, respectively). CONCLUSION: The results suggest that the ERY resistance phenotype and the transcription expression of ermC gene could be considered as important signs to estimate whether the biofilm formation phenotype in S. epidermidis clinical isolates can be easily affected by sub-MIC ERY. PMID- 24768214 TI - "Add-on" is scientifically more accurate than "placebo control" in multiple inflammatory bowel disease (IBD) trials. PMID- 24768216 TI - Rituximab use in pediatric central demyelinating disease. AB - BACKGROUND: Rituximab is a B-cell therapy used off-label to reduce relapses in adult demyelinating diseases. There is limited knowledge of its clinical use in pediatric neuromyelitis optica and multiple sclerosis. Demyelinating diseases in children can have high morbidity, and B-cell therapies hold promise for those with a severe course. Our study investigates the clinical experience of safety and efficacy with rituximab in children with demyelinating diseases of the central nervous system. METHODS: This is a retrospective case series of 11 patients with pediatric neuromyelitis optica and multiple sclerosis who received at least one rituximab infusion at the Pediatric Multiple Sclerosis Clinic, University of California, San Francisco. Each patient was infused up to 1000 mg twice 2 weeks apart. Patients were monitored prospectively, and relapse events, laboratories, and adverse reactions were recorded. RESULTS: Eight children with neuromyelitis optica, two with relapsing-remitting multiple sclerosis and one with secondary-progressive multiple sclerosis received rituximab treatment. The median number of cycles was 3. Most patients (82%, n = 9) experienced reduction of relapses after initiating rituximab. There were no serious infections. Infusion reactions were reported in three patients and managed successfully in subsequent infusions with increased pretreatment (dexamethasone and diphenhydramine) and use of slower infusion rates. Rituximab was not discontinued in any child because of side effects; two switched treatment therapy after 4.5 and 11 months because of relapses. CONCLUSIONS: The use of rituximab in our pediatric neuromyelitis optica and multiple sclerosis cohort was overall safe and effective. Larger studies should confirm our observations. PMID- 24768215 TI - Deconvolution filtering: temporal smoothing revisited. AB - Inferences made from analysis of BOLD data regarding neural processes are potentially confounded by multiple competing sources: cardiac and respiratory signals, thermal effects, scanner drift, and motion-induced signal intensity changes. To address this problem, we propose deconvolution filtering, a process of systematically deconvolving and reconvolving the BOLD signal via the hemodynamic response function such that the resultant signal is composed of maximally likely neural and neurovascular signals. To test the validity of this approach, we compared the accuracy of BOLD signal variants (i.e., unfiltered, deconvolution filtered, band-pass filtered, and optimized band-pass filtered BOLD signals) in identifying useful properties of highly confounded, simulated BOLD data: (1) reconstructing the true, unconfounded BOLD signal, (2) correlation with the true, unconfounded BOLD signal, and (3) reconstructing the true functional connectivity of a three-node neural system. We also tested this approach by detecting task activation in BOLD data recorded from healthy adolescent girls (control) during an emotion processing task. Results for the estimation of functional connectivity of simulated BOLD data demonstrated that analysis (via standard estimation methods) using deconvolution filtered BOLD data achieved superior performance to analysis performed using unfiltered BOLD data and was statistically similar to well-tuned band-pass filtered BOLD data. Contrary to band-pass filtering, however, deconvolution filtering is built upon physiological arguments and has the potential, at low TR, to match the performance of an optimal band-pass filter. The results from task estimation on real BOLD data suggest that deconvolution filtering provides superior or equivalent detection of task activations relative to comparable analyses on unfiltered signals and also provides decreased variance over the estimate. In turn, these results suggest that standard preprocessing of the BOLD signal ignores significant sources of noise that can be effectively removed without damaging the underlying signal. PMID- 24768217 TI - Malignant transformation of a desmoplastic infantile ganglioglioma in an infant carrier of a nonsynonymous TP53 mutation. AB - INTRODUCTION: Desmoplastic infantile ganglioglioma is a rare intracranial neoplasm classified as World Health Organization grade I tumor under neuronal and mixed neuronal-glial tumors (2007 World Health Organization brain tumor classification). It is usually a good prognosis, but 40% of patients require further medical, radiation, and/or surgical intervention, and 15% develop leptomeningeal spread or die from desmoplastic infantile ganglioglioma. Transformation to malignant glioblastoma occurs, but the genetic alterations associated with the transformation are generally unknown. METHODS: We describe a desmoplastic infantile ganglioglioma in a 2-month-old boy, which showed aggressive behavior, requiring debulking at 2.5 months of age and chemotherapy at 10 months of age after tumor progression. At 8.5 years of age he developed malignant transformation to glioblastoma. Chromosome microarray analysis using oligo array and genomic sequencing was performed on the biopsy specimen from 2 months of age and on the subsequent transformed malignant glioblastoma. RESULTS: After being clinically stable for 7.5-years, transformation to glioblastoma transformation occurred. He did well for 1 year but subsequently died from tumor progression. Chromosome microarray analysis using oligo array performed on the biopsy specimen obtained at 2 months of age did not reveal significant abnormalities; but there were significant genomic deletions and duplications associated with the glioblastoma. These included multiple genomic losses involving 4q and Y, gains of 5q, and amplification of 12q14. Genomic sequencing revealed a single nucleotide variant, p.R248Q in exon 7 of TP53, in the primary desmoplastic infantile ganglioglioma and the glioblastoma multiforme. CONCLUSIONS: The nonsynonymous variant (p.R248Q in exon 7) of the TP53 gene is predicted to alter the structure of the L2/L3 motif of the DNA binding domain of p53 protein. It was detected in the primary desmoplastic infantile ganglioglioma and glioblastoma multiforme. This child illustrates the rare recurrence of desmoplastic infantile ganglioglioma with malignant transformation to glioblastoma caused by a nonsynonymous TP53 mutation, providing explanation for other rare benign tumor transformations. The TP53 gene is a known primary site of genetic alteration that predisposes to malignant tumors, and this case indicates that it might also be involved in the behavior and outcome of desmoplastic infantile ganglioglioma. Therefore more genetic testing is recommended on desmoplastic infantile ganglioglioma tumors, which may provide biologic prognostic markers. PMID- 24768218 TI - What is good governance in the context of drug policy? AB - The concept of governance is applied in a wide range of contexts, but this paper focuses on governance in relation to public administration, i.e. states and how they take action, and specifically governance of particular policy areas. In the current context of financial austerity and an era of globalisation, policy-makers face pressures and challenges from a growing range of interests and local, national and supranational actors. Drug policy is an example of a particularly contentious and polarised area in which governance-related challenges abound. In response to these challenges, interest has grown in developing agreed policy governance standards and processes and articulating policy-making guidelines, including the use of available evidence to inform policy-making. Attempts have been made to identify 'policy fundamentals' - factors or aspects of policy-making apparently associated with successful policy development and implementation (Hallsworth & Rutter, 2011; Laughrin, 2011) and, in the drug policy field, Hughes et al. (2010) reflecting on the co-ordination of Australian drug policy highlighted some of what they considered principles of good governance. But how useful is the concept of 'good governance'; how well can it be defined, and to what purpose? As part of a wider project considering the governance of drug policy, RAND Europe and the UK Drug Policy Commission undertook a targeted review of other research and sought expert views, from within and beyond drug policy, on principles, processes, structures and stakeholders associated with good drug policy governance. From this emerged some perceived characteristics of good governance that were then used by the UK Drug Policy Commission to assess the extent to which drug policy making in the UK fits with these perceived good governance characteristics, and to suggest possible improvements. Particular consideration was given to the range of interests at stake, the overarching aims of drug policy and the development and inclusion of an evidence base where possible. This paper draws on findings of the study to highlight challenges associated with defining good governance, provides an example of a framework for assessing drug policy governance and discusses the feasibility, transferability and potential benefits of such an undertaking. PMID- 24768219 TI - Considerations about paediatric dosing: from birth to adulthood, pharmacokinetics and pharmacodynamics. PMID- 24768220 TI - Genetic and environmental determinants of the susceptibility of Amerindian derived populations for having hypertriglyceridemia. AB - Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explain the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia. PMID- 24768221 TI - Shoulder function after surgical treatment of displaced fractures of the humeral shaft: a randomized trial comparing antegrade intramedullary nailing with minimally invasive plate osteosynthesis. AB - BACKGROUND: Minimally invasive plate osteosynthesis for humeral shaft fractures has been described recently, but there are no randomized studies comparing the clinical results for shoulder function between this technique and locking intramedullary nailing. METHODS: A prospective randomized study was performed. Forty-one humeral shaft fractures (40 patients) were randomized to be treated with a minimally invasive plate (n = 21) or a locking intramedullary nail (n = 19). Clinical and radiographic outcome assessments were conducted at 1 year postoperatively. Shoulder function was the primary outcome, as measured by the University of California, Los Angeles Shoulder Scale. Elbow function was measured by the Broberg-Morrey score, and fracture consolidation and complications were the main secondary outcomes. RESULTS: At 1 year postoperatively, no significant difference was found with regard to shoulder function according to the University of California, Los Angeles scale between the minimally invasive plate and locking intramedullary nail (31.4 points vs 31.2 points, P = .98). There was also no difference in elbow function (94.8 points vs 94.1 points, P = .96). Complications were similar between the groups, without significant differences regarding infection (P > .99), symptomatic shoulder stiffness (P = .488), and neurapraxia of the lateral cutaneous nerve of the forearm (P = .475). Fracture union was achieved in all but 1 patient (2.4%) in the intramedullary nail group within 1 year after the surgical procedure. CONCLUSION: There is no significant difference in shoulder function between antegrade intramedullary nailing and minimally invasive plate osteosynthesis for the treatment of displaced humeral shaft fractures, despite the limited power of our study. PMID- 24768222 TI - Proximal radial diaphyseal segment resection for posttraumatic proximal radioulnar synostosis: a prospective study of 15 cases. AB - BACKGROUND: Proximal radioulnar synostosis is a complication after elbow injuries. Various treatment methods have been reported and are associated with unpredictable outcomes. In a prospective study, we evaluated the medium-term effects of proximal radial resection on wrist and elbow function and forearm rotation in 15 cases. METHODS: We treated 15 patients with posttraumatic proximal radioulnar synostosis by resection of 1 cm of the proximal radial diaphysis. On the preoperative examination and last follow-up, the Mayo Elbow Performance Score, grip force, visual analog scale for elbow and wrist score, radiographic ulnar variance changes, and elbow range of motion were measured. The Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score and the general satisfaction of the patients were assessed at the final follow-up. RESULTS: The mean duration of follow-up was 31 +/- 13 months. The mean active postoperative supination/pronation arc was 101 degrees +/- 45 degrees . The mean increase measured in the ulnar variance at the final follow-up was 3.3 +/- 1.5 mm (P = .02). The mean final QuickDASH score was 13.3 +/- 12.1. The preoperative and final Mayo scores were 57 +/- 10 and 91 +/- 7, respectively (P = .01). The general satisfaction with the results of the operation was 86.6%. CONCLUSIONS: We suggest that proximal radial resection for the treatment of posttraumatic proximal radioulnar synostosis shows acceptable results in adults regarding the recovery of range of motion and patient satisfaction. This technique might be considered as a salvage procedure, particularly in cases with previous failed heterotopic resection at the proximal radioulnar joint, resulting in disturbed anatomy. LEVEL OF EVIDENCE: Level IV, case series, treatment study. PMID- 24768223 TI - Frontal plane compensatory strategies associated with self-selected walking speed in individuals post-stroke. AB - BACKGROUND: Approximately two out of three individuals post-stroke experience walking impairments. Frontal plane compensatory strategies (i.e. pelvic hiking and circumduction) are observed in post-stroke gait in part to achieve foot clearance in response to reduced knee flexion and ankle dorsiflexion. The objective of this study was to investigate the relationship between self-selected walking speed and the kinematic patterns related to paretic foot clearance during post-stroke walking. METHODS: Gait analysis was performed at self-selected walking speed for 21 individuals post-stroke. Four kinematic variables were calculated during the swing phase of the paretic limb: peak pelvic tilt (pelvic hiking), peak hip abduction (circumduction), peak knee flexion, and peak ankle dorsiflexion. Paretic joint angles were analyzed across self-selected walking speed as well as between functionally relevant ambulation categories (Household <0.4m/s, Limited Community 0.4-0.8m/s, Community >0.8m/s). FINDINGS: While all subjects exhibited similar foot clearance, slower walkers exhibited greater peak pelvic hiking and less knee flexion, ankle dorsiflexion, and circumduction compared to faster walkers (P<.05). Additionally, four of the fastest walkers compensated for poor knee flexion and ankle dorsiflexion through large amounts of circumduction. INTERPRETATION: These findings suggest that improved gait performance after stroke, as measured by self-selected walking speed, is not necessarily always accomplished through gait patterns that more closely resemble healthy gait for all variables. It appears the ability to walk fast is achieved by either sufficient ankle dorsiflexion and knee flexion to achieve foot clearance or the employment of circumduction to overcome a deficit in either ankle dorsiflexion or knee flexion. PMID- 24768224 TI - Tendon properties and muscle architecture for knee extensors and plantar flexors in boys and men. AB - BACKGROUND: The purpose of this study was to compare the elastic properties and size of tendinous structures and muscle architecture for knee extensors and plantar flexors in boys and men. METHODS: Twenty-two early pubescent boys (9.6 12.7yrs) and 23 young adult men (19.8-26.2yrs) participated in this study. The maximal strain and thickness of tendinous structures for knee extensors and plantar flexors were measured using ultrasonography. In addition, the fascicle lengths of vastus lateralis and medial gastrocnemius muscles were measured. FINDINGS: The maximal strain of tendinous structures for plantar flexors was significantly greater in boys than in men, while there was no difference in the maximal strain for knee extensors between the two groups. The relative thickness (to body mass(1/3)) of Achilles tendon was significantly greater in boys than in men, although there was no difference in that of patellar tendon between the two groups. The relative fascicle length (to limb length) of vastus lateralis muscle was significantly lower in boys than in men, although there was no difference in that of medial gastrocnemius muscle between the two groups. INTERPRETATION: These results suggest that the amount of changes in the elastic properties and sizes of tendinous structures and in the fascicle lengths from early pubescence to maturity is different for different muscle groups (in particular, the knee extensors and the plantar flexors). PMID- 24768225 TI - Slipped capital femoral epiphysis, fixation by single screw in situ: A kinematic and radiographic study. AB - BACKGROUND: Slipped capital femoral epiphysis is known to produce characteristic deformities in the proximal femur, which affect hip motion and may cause a limp. This paper assessed the 3D gait kinematics in adolescents after single screw fixation of moderate to severe, stable, unilateral slipped capital femoral epiphysis. Our goals were to characterize the 3D kinematic patterns and to investigate the correlation between the severity of radiological deformity and severity of gait disturbance. METHODS: This was a retrospective study of patients seen at our institution between 2000 and 2009. Antero-posterior and frog lateral X-rays were reviewed to measure: Southwick's lateral slip angle, the alpha angle of Notzli and Klein's line offset. Quantitative 3D gait data was collected using a state of the art motion capture system. Kinematic waveforms were compared using a functional data analysis version of the t-test. FINDINGS: There were 30 patients with an average age at pinning of 13y (10-17y). Mean gait profile scores were significantly abnormal for slipped side (10.8 degrees ) versus sound side (6.8 degrees ), slipped side versus normal (5.6 degrees ) and sound side versus normal. There was little statistically significant correlation between severity of radiographic deformity and degree of gait disturbance. INTERPRETATION: Major kinematic pattern deviations could be associated with (a) morphology of the proximal femur and potential femoral acetabular impingement problems and (b) leg length discrepancy. Gait analysis was able to quantify the kinematic deviations due to the anatomical deformities. PMID- 24768226 TI - Door-to-block time: prioritizing acute pain management for femoral fractures in the ED. PMID- 24768227 TI - Asystole after the first dose of lansoprazole. AB - Allergic reactions due to drug intake are responsible from an important amount of emergency admissions. Patients mostly complain of urticarial lesions. But clinical picture may sometimes include a large scale of signs and symptoms ranging from a simple confusion to serious conditions like coma and even cardiopulmonary arrest. In this article, a case of anaphylactic shock and respiratory arrest after lansoprazole intake is presented. Delays in reaching basic and advanced life support decrease chance of positive results of life support in anaphylactic shock victims. It is important to remember that any medication we usually prescribe in our daily practice for treatment of any disease has a potential to kill the patient. PMID- 24768228 TI - School bullying, cyberbullying, or both: correlates of teen suicidality in the 2011 CDC Youth Risk Behavior Survey. AB - While school bullying has been shown to be associated with depression and suicidality among teens, the relationship between these outcomes and cyberbullying has not been studied in nationally representative samples. Data came from the 2011 CDC Youth Risk Behavior Survey (YRBS), a nationally representative sample of high-school students (N=15,425). We calculated weighted estimates representative of all students in grades 9-12 attending school in the US. Logistic regression was used to calculate adjusted odds ratios. Overall, girls are more likely to be report being bullied (31.3% vs. 22.9%), in particularly to be cyberbullied (22.0% vs. 10.8%), while boys are only more likely to report exclusive school bullying (12.2% vs. 9.2%). Reports of 2-week sadness and all suicidality items were highest among teens reporting both forms of bullying, followed by those reporting cyberbullying only, followed by those reporting school bullying only. For example, among those reporting not being bullied 4.6% reported having made a suicide attempt, compared to 9.5% of those reporting school bullying only (adjusted odd ratio (AOR) 2.3, 95% C.I. 1.8-2.9), 14.7% of those reporting cyberbullying only (AOR 3.5 (2.6-4.7)), and 21.1% of those reporting victimization of both types of bullying (AOR 5.6 (4.4-7)). Bullying victimization, in school, cyber, or both, is associated with higher risk of sadness and suicidality among teens. Interventions to prevent school bullying as well as cyberbullying are needed. When caring for teens reporting being bullied, either at school or in cyberbullying, it's important to screen for depression and suicidality. PMID- 24768229 TI - Effects of fibrinogen concentration on fibrin glue and bone powder scaffolds in bone regeneration. AB - Fibrin polymers are widely used in the tissue engineering field as biomaterials. Although numerous researchers have studied the fabrication of scaffolds using fibrin glue (FG) and bone powder, the effects of varied fibrinogen content during the fabrication of scaffolds on human mesenchymal stem cells (hMSCs) and bone regeneration remain poorly understood. In this study, we formulated scaffolds using demineralized bone powder and various fibrinogen concentrations and analyzed the microstructure and mechanical properties. Cell proliferation, cell viability, and osteoblast differentiation assays were performed. The ability of the scaffold to enhance bone regeneration was evaluated using a rabbit calvarial defect model. Micro-computed tomography (micro-CT) showed that bone powders were uniformly distributed on the scaffolds, and scanning electron microscopy (SEM) showed that the fibrin networks and flattened fibrin layers connected adjacent bone powder particles. When an 80 mg/mL fibrinogen solution was used to formulate scaffolds, the porosity decreased 41.6 +/- 3.6%, while the compressive strength increased 1.16 +/- 0.02 Mpa, when compared with the values for the 10 mg/mL fibrinogen solution. Proliferation assays and SEM showed that the scaffolds prepared using higher fibrinogen concentrations supported and enhanced cell adhesion and proliferation. In addition, mRNA expression of alkaline phosphatase and osteocalcin in cells grown on the scaffolds increased with increasing fibrinogen concentration. Micro-CT and histological analysis revealed that newly formed bone was stimulated in the scaffold implantation group. Our results demonstrate that optimization of the fibrinogen content of fibrin glue/bone powder scaffolds will be beneficial for bone tissue engineering. PMID- 24768230 TI - Performance of self-sampled HPV test in comparison with liquid based cytology. AB - OBJECTIVE: Strong evidences shows that HPV testing is more sensitive than cytology in detecting high-grade CIN. HPV test can be performed on samples collected by women themselves by means of self-sampling devices. This study compares the results of self-sampled HPV tests with the results of liquid based cytology (LBC). STUDY DESIGN: Seven hundred women scheduled for cervical cytology self-collected a cervicovaginal sample for HPV testing and then underwent a clinician-collected LBC at the European Institute of Oncology. The HPV and LBC results were compared with the McNemar test. RESULTS: All HSIL (N=5) resulted hrHPV positive. LBC resulted LSIL or worse in 38 (5.4%) women (out of 700). Self sampled HPV was positive in 96 women (13.7%). A LSIL or worse LBC result was found in 15 (2.5%) patients, out of the 604 hrHPV negative women and in 23 (24%) patients, out of the 96 hrHPV positive women. Positive cytology after a self sampled HPV positive result had an Odds Ratio of 12.4 (95% CI: 5.8-26.6). CONCLUSION: Self-collected HPV testing identifies a group of women at high risk of positive LBC and high grade SIL. PMID- 24768231 TI - Is myomectomy in women aged 45 years and older an effective option? AB - OBJECTIVES: The aim of this study was to evaluate the recurrence and reoperation rate after myomectomy in women aged 45 years and older, who want to preserve their uterus. STUDY DESIGN: We performed a retrospective review of women aged >=45 years that underwent myomectomy between January 2000 and December 2010. The inclusion criteria were premenopausal status, myomectomy through abdominal or laparoscopic surgery, and at least 12 months interval from surgery. The clinical outcomes, including symptomatic change, recurrence of myoma on transvaginal ultrasonography (TVS), and reoperation data were collected and analyzed. RESULTS: A total 92 patients were included in this study. The median age of the patient was 47 years (range 45-53 years), and the median follow-up duration was 30.5 months (range 12-95 months). On follow-up TVS, the recurrence of myoma was detected in 20 of 82 (24.4%) patients. Ten (10.9%) patients were not subjected to follow-up TVS. However, during their pelvic examination, the uterus was normal size, and all the 10 patients experienced symptomatic improvement and none of them needed additional surgical management. Using the Kaplan-Meier method, the cumulative recurrence rate at 36 months after myomectomy was calculated as 17.1%. Three patients underwent hysterectomy during the follow-up periods, and only one underwent hysterectomy due to myoma. The overall reoperation rate after myomectomy in this age group was 3.3%, and the reoperation for myoma rate was only 1.1%. CONCLUSION: Considering the natural regression of myoma after menopause, myomectomy might be an effective option for women aged 45 years and older, who want to preserve their uterus. PMID- 24768232 TI - Feto-maternal outcome of pregnancy complicated by vulvar cancer: a systematic review of literature. AB - Vulvar cancer is an extremely rare complication during pregnancy, and its effect on pregnancy and survival is not well understood. A systematic literature review was conducted in order to examine the fetal and maternal outcomes and optimal management of pregnancy complicated by vulvar cancer. PubMed/MEDLINE were used to identify case reports with searching keywords "pregnancy" and "vulvar cancer" between January 1955 and February 2014 that identified 36 cases for analysis. Mean age was 30.7. The most common presenting symptom and gestational age were vulvar mass/swelling (75.0%) and the second trimester of pregnancy (54.8%), respectively. Vulvar biopsy at the time of initial presentation to care during pregnancy was performed in only 46.7% of cases. Among delayed cases for biopsy, mean duration of delay was 12.8 weeks and the majority had a delay for more than 8 weeks (62.5%). The majority of vulvar cancer was squamous histology (47.2%) and stage I disease (60.0%). Vulvectomy and inguinal-femoral lymphadenectomy were performed in 97.1% and 63.9%, respectively. Abdominal delivery was recorded in 46.2% of cases. Live birth and full term delivery rates were 96.3% and 74.0%, respectively. For survival analysis, delay in diagnosis and advanced stage disease were commonly associated with decreased disease-free survival (5-year rate, delay in diagnosis >8 versus <=8 weeks, 0% versus 69.1%, hazard ratio (HR) 7.86, 95% confidence interval (CI) 2.03-30.6, p=0.001; and stage III-IV versus stage I-II, 0% versus 59.8%, HR 3.35, 95% CI 1.16-9.68, p=0.011) and overall survival (5-year rate, delay in diagnosis >8 versus <=8 weeks, 0% versus 67.1%, hazard ratio (HR) 14.8, 95% CI 1.77-124, p=0.001; and stage III-IV versus stage I II, 0% versus 86.4%, HR 8.22, 95% CI 2.06-33.2, p<0.001). In conclusion, while the majority of cases resulted in good pregnancy outcomes, diagnosis of vulvar cancer during pregnancy is frequently delayed. Since delayed diagnosis is a significant prognosticator of decreased survival outcomes, early recognition is integral in the management of pregnancy complicated by vulvar cancer. PMID- 24768233 TI - The use of a peritoneal gas drain following gynecological laparoscopy: a systematic review. AB - We performed a systematic review of the randomized controlled trials (RCTs) reporting on the use of a peritoneal gas drain following gynecological laparoscopy. The standard medical databases were searched for studies published prior to with no restrictions for language, country of origin, blinding or sample size. We defined the primary endpoints: shoulder and total pain at 4-6, 24 and 48h following laparoscopy and secondary endpoints: women satisfaction, requirement of analgesia and antiemetics. The quality of the included RCTs was assessed by the guideline of the Cochrane Collaboration. Based on the data from 5 moderate quality RCTs we concluded that there is very little evidence of an overall benefit from using a peritoneal gas drain following gynecological laparoscopy The possible reduction of shoulder and total pain is not associated with a reduction in the requirement of analgesia and antiemetics when compared to the control group. PMID- 24768234 TI - Subclinical hypothyroidism in patients with polycystic ovary syndrome: distribution and its association with lipid profiles. AB - OBJECTIVE: The aim of this study was to examine the distribution of subclinical hypothyroidism (SCH) in patients with polycystic ovary syndrome (PCOS). We also aimed to investigate the associations between thyroid stimulating hormone (TSH) and lipid profiles and to determine the values at which TSH levels affected dyslipidemia risk in this population. STUDY DESIGN: Women with PCOS (n=428) from a Chinese Han population were recruited and stratified into five groups based on TSH levels. Multiple linear regression analysis was performed to investigate the associations between serum TSH and lipid profiles. Receiver operating characteristic (ROC) analysis was used to find the optimal TSH cut-off point for dyslipidemia risk. RESULTS: The SCH distribution was observed similarly in PCOS patients with different phenotypes (Chi-squares=2.184, P=0.535). There was a significant positive correlation between TSH and low density lipoprotein cholesterol (LDLc) (P=0.001), even after adjustment for age, body mass index, waist to hip ratio, fasting plasma glucose, homeostatic model assessment-insulin resistance and free androgen index (P<0.001). The optimal TSH cut-off point to indicate elevated LDLc risk was 4.07 mIU/L by ROC analysis. CONCLUSION: Our data indicate that TSH is strongly associated with higher LDLc concentrations in PCOS patients. The optimal TSH cut-off point for elevated LDLc risk in this cohort was 4.07 mIU/L. These findings demonstrate that more attention might be paid to PCOS paients prior to overt clinical presentation. PMID- 24768235 TI - Efficacy and nontarget effects of transarterial chemoembolization in bridging of hepatocellular carcinoma patients to liver transplantation: a histopathologic study. AB - PURPOSE: To histologically evaluate the efficacy and nontarget effects induced by transarterial chemoembolization as a "bridge" treatment of hepatocellular carcinoma (HCC) before liver transplantation (LT) and its relation to patient survival. MATERIALS AND METHODS: Between October 2003 and January 2011, 51 patients with HCC underwent LT after chemoembolization with iodized oil, small spherical particles, and carboplatin. The decision for LT was made according to national guidelines. The efficacy and nontarget effects of chemoembolization were determined histologically in explanted livers, and their impact on patients' survival after LT was analyzed. RESULTS: A total of 126 chemoembolization procedures were performed in 51 patients; the median number of procedures per patient was three (range, one to six). The extent of HCC necrosis was less than or equal to 50% in 32% of treated HCCs, more than 50% and less than or equal to 90% in 17%, and more than 90%-99% in 14%; 38% showed complete necrosis of the lesion. The most common nontarget effects were focal necrosis of the liver parenchyma adjacent to the embolized HCC nodule (28%), intralesional (micro)abscess (26%), intralesional hemorrhage (22%), and peritumoral bile duct necrosis (12%). Based on histopathologic examination, 35% of patients had HCC that did not meet Milan criteria. None of these findings was significantly associated with patient survival after LT. CONCLUSIONS: Transarterial chemoembolization induces histopathologically confirmed HCC necrosis with a high degree of efficacy, but histologically proven complete HCC necrosis was not predictive of survival in this cohort of patients. Although histopathologic examination revealed (clinically relevant) nontarget effects in a subset of patients, they did not impair survival. PMID- 24768236 TI - Clinical features and endovascular management of iliac artery fibromuscular dysplasia. AB - PURPOSE: To identify the spectrum of clinical presentation of iliac artery fibromuscular dysplasia (FMD) and to evaluate the outcomes of endovascular management of iliac artery FMD for claudication. MATERIALS AND METHODS: All patients in a single institution with a diagnosis of FMD between January 1980 and December 2010 were identified. Iliac artery FMD was present in 14 patients. Associated risk factors included hypertension (79%), hyperlipidemia (64%), smoking history (36%), coronary artery disease (21%), diabetes (0%), and obesity (36%). RESULTS: In eight (57%) patients, iliac artery FMD was incidentally found on imaging. Lifestyle-limiting claudication involving one or both extremities was present in six (43%) patients. All six patients were reported to have mild peripheral arterial disease based on ankle-brachial index measurements (0.7-0.9). These six patients underwent 10 endovascular procedures for claudication, including angioplasty (n = 8) and self-expanding stent placement (n = 2). Mean symptom-free survival was 56.3 months. CONCLUSIONS: Iliac artery FMD that is amenable to endovascular treatment may be found incidentally or may manifest with disabling claudication. PMID- 24768237 TI - Re: McKean-Cowdin et al.: prevalence of amblyopia or strabismus in asian and non hispanic white preschool children (Ophthalmology 2013;120:2117-24). PMID- 24768238 TI - Health burden associated with visual impairment in Singapore: the Singapore epidemiology of eye disease study. AB - OBJECTIVE: To assess the impact of visual impairment (VI) on health-related quality of life and to compare the health burden of VI and other health conditions in Singapore. DESIGN: Population-based cross-sectional study. PARTICIPANTS: We studied the 10 009 adults (3353 Chinese, 3397 Indians, and 3259 Malays) who underwent a comprehensive eye assessment and completed the European Quality of Life-5 Dimensions (EQ-5D) questionnaire in the Singapore Epidemiology of Eye Disease Study. METHODS: We estimated the effects of VI, obesity, hypertension, diabetes, and hyperlipidemia on the EQ-5D index score using linear regression models and the association between VI and self-reported EQ-5D health problems using logistic regression models. We compared prevalence-based quality adjusted life-year (QALY) loss associated with VI and other health conditions. For each condition, QALY loss was calculated for 100 000 persons in 1 year using associated reduction in EQ-5D index score estimated in regression analysis as disutility. MAIN OUTCOME MEASURES: The EQ-5D index score and annual QALY loss. RESULTS: The EQ-5D index score decreased with increasing VI severity in all 3 ethnicities. For example, after adjusting for sociodemographic characteristics, the difference in EQ-5D index score between adults with bilateral severe VI and those without VI was -0.044 (95% confidence interval [CI], -0.089 to 0.001) in Chinese, -0.127 (95% CI, -0.237 to -0.017) in Indians, and -0.085 (95% CI, -0.148 to -0.022) in Malays. In all 3 ethnicities, VI was associated with reporting of problems in mobility (e.g., odds ratio [OR], 3.69 for Chinese with bilateral severe VI; 95% CI, 1.21-12.13) and usual activities (e.g., OR, 6.51 for Chinese with bilateral severe VI; 95% CI, 1.59-26.58). In Indians, VI was also associated with anxiety or depression (e.g., OR, 2.68 for bilateral severe VI; 95% CI, 1.11 6.50). The annual QALY loss associated with VI was 511.8 in Chinese, 608.8 in Indians, and 706.7 in Malays, greater than that associated with other health conditions examined in this study. CONCLUSIONS: Visual impairment is associated with substantial health burden among Asians in Singapore. The relatively high burden of VI highlights the importance of VI prevention. The ethnic difference exhibited in this burden warrants further study. PMID- 24768239 TI - Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. AB - OBJECTIVE: To determine the effect of suppression of vascular endothelial growth factor (VEGF) by monthly injection of ranibizumab on posterior retinal nonperfusion (RNP) in patients with diabetic macular edema (DME). DESIGN: Unplanned retrospective analysis of prospectively collected data from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS: Six hundred sixty-six patients with DME. METHODS: An independent reading center measured the area of RNP on fluorescein angiograms obtained in the phase 3 RISE and RIDE trials. MAIN OUTCOME MEASURES: The percentage of patients with no posterior RNP. RESULTS: The percentage of patients with no posterior RNP decreased in the sham group between baseline and month 24, but remained relatively stable in the 2 ranibizumab groups. After month 24, the sham group crossed over to receive monthly injections of ranibizumab 0.5 mg, and the differences between the sham and ranibizumab groups were reduced. The percentage of patients who showed an increase in posterior RNP from baseline increased over time in all 3 groups, but at a faster rate in the sham group, resulting in statistically significant differences at every time point between months 3 (9.6% vs. 18.5%; P = 0.016) and 24 (16.1% vs. 37.6%; P<0.0001) for ranibizumab 0.5 mg versus sham and from months 6 (12.3% vs. 23.0%; P = 0.013) through 24 (15.0% vs. 37.6%; P<0.0001) for ranibizumab 0.3 mg. Initiation of ranibizumab in the sham group at month 24 was followed by reduction in the percentage of patients with an increase in posterior RNP from baseline at months 30 and 36, whereas the 2 ranibizumab groups continued their gradual rise. CONCLUSIONS: Just as high VEGF levels contribute to progression of retinal nonperfusion in retinal vein occlusion, the same is true in patients with DME, suggesting that regardless of the underlying disease process, high levels of VEGF can cause closure of retinal vessels. However, our data also suggest that VEGF induced worsening of retinal perfusion in DME is superimposed on another cause of more gradually worsening perfusion, possibly glucotoxicity. Thus, monthly injections of ranibizumab can slow, but not completely prevent, retinal capillary closure in patients with DME. PMID- 24768240 TI - Three-year treatment outcomes in the Ahmed Baerveldt comparison study. AB - PURPOSE: To compare 3-year outcomes and complications of the Ahmed FP7 Glaucoma Valve (AGV) (New World Medical, Cucamonga, CA) and the Baerveldt Glaucoma Implant (BGI) 101-350 (Abbott Medical Optics, Abbott Park, IL) for the treatment of refractory glaucoma. DESIGN: Multicenter, randomized, controlled clinical trial. PARTICIPANTS: A total of 276 patients: 143 in the AGV group and 133 in the BGI group. METHODS: Patients aged 18 to 85 years with refractory glaucoma and intraocular pressures (IOPs) >= 18 mmHg in whom an aqueous shunt was planned were randomized to an AGV or a BGI. MAIN OUTCOME MEASURES: The IOP, visual acuity (VA), supplemental medical therapy, complications, and failure (IOP >21 mmHg or not reduced by 20% from baseline, IOP <5 mmHg, reoperation for glaucoma or removal of implant, or loss of light perception vision). RESULTS: At 3 years, IOP (mean +/- standard deviation) was 14.3 +/- +/- 4.7 mmHg (AGV group) and 13.1 +/- 4.5 mmHg (BGI group) (P = 0.086) on 2.0 +/- 1.4 and 1.5 +/- 1.4 glaucoma medications, respectively (P = 0.020). The cumulative probabilities of failure were 31.3% (standard error [SE], 4.0%) (AGV) and 32.3% (4.2%) (BGI) (P = 0.99). Postoperative complications associated with reoperation or vision loss of >2 Snellen lines occurred in 24 patients (22%) (AGV) and 38 patients (36%) (BGI) (P = 0.035). The mean change in the logarithm of the minimum angle of resolution VA at 3 years was similar (AGV: 0.21 +/- 0.88, BGI: 0.26 +/- 0.74) in the 2 treatment groups at 3 years (P = 0.66). The cumulative proportion of patients (SE) undergoing reoperation for glaucoma before the 3-year postoperative time point was 14.5% (3.0%) in the AGV group compared with 7.6% (2.4%) in the BGI group (P = 0.053, log rank). The relative risk of reoperation for glaucoma in the AGV group was 2.1 times that of the BGI group (95% confidence interval, 1.0-4.8; P = 0.045, Cox proportional hazards regression). CONCLUSIONS: Implantation of the AGV was associated with the need for significantly greater adjunctive medication to achieve equal success relative to implantation of the BGI and resulted in a greater relative risk of reoperation for glaucoma. More subjects experienced serious postoperative complications in the BGI group than in the AGV group. PMID- 24768242 TI - Re: Wilkins et al.: randomized trial of multifocal intraocular lenses versus monovision after bilateral cataract surgery (Ophthalmology 2013;120:2449-55). PMID- 24768241 TI - Five-year incidence, progression, and risk factors for age-related macular degeneration: the age, gene/environment susceptibility study. AB - OBJECTIVE: To investigate the incidence and progression of age-related macular degeneration (AMD) and associated risk factors. DESIGN: Population-based, prospective, cohort study. PARTICIPANTS: We included 2868 participants from the Age Gene/Environment Susceptibility-Reykjavik Study with retinal data at baseline and 5-year follow-up. METHODS: Digital macular photographs were graded for presence of AMD. Participants completed a questionnaire and extensive clinical battery. Biomarkers were assessed. Risk factors for AMD were analyzed using multivariate regression analysis with odds ratios (ORs) and 95% CIs. MAIN OUTCOME MEASURES: We assessed AMD, defined as early or late. RESULTS: Among 2196 participants free of AMD at baseline, 14.9% developed incident AMD. In multivariate models, incident AMD was significantly associated with age (OR per year, 1.14; 95% CI, 1.11-1.17), current smoking (OR, 2.07; 95% CI, 1.38-3.11), former smoking (OR, 1.36; 95% CI, 1.04-1.79), plasma high-density lipoprotein (HDL) cholesterol level (OR, 1.62 per mmol/L; 95% CI, 1.19-2.22), and body mass index (BMI; OR, 1.04 per kg/m(2); 95% CI, 1.01-1.07). Among 563 participants with early AMD at baseline, 22.7% progressed to late AMD (11.0% pure geographic atrophy [GA] and 11.7% exudative AMD). On multivariate analyses, age was significantly associated with progression to GA (OR 1.14; 95% CI, 1.07-1.21) and exudative AMD (OR, 1.08; 95% CI, 1.01-1.14). Adjusting for age, female sex was associated with exudative AMD (OR, 2.10; 95% CI, 1.10-3.98) and plasma HDL cholesterol with GA (OR, 2.03 per mmol/L; 95% CI, 1.02-4.05). CONCLUSIONS: By age 85, 57.4% of participants had signs of AMD. Age, smoking, plasma HDL cholesterol, BMI, and female sex are associated with AMD. Elevated HDL cholesterol is associated with GA development. PMID- 24768244 TI - Neuroaesthetics. AB - Neuroaesthetics is an emerging discipline within cognitive neuroscience that is concerned with understanding the biological bases of aesthetic experiences. These experiences involve appraisals of natural objects, artifacts, and environments. Because aesthetic encounters are common in everyday life, exploration of their biological bases can deepen our understanding of human behavior in important domains such as mate selection, consumer behavior, communication, and art. We review recent evidence showing that aesthetic experiences emerge from the interaction between sensory-motor, emotion-valuation, and meaning-knowledge neural systems. Neuroaesthetics draws from and informs traditional areas of cognitive neuroscience including perception, emotion, semantics, attention, and decision-making. The discipline is at a historical inflection point and is poised to enter the mainstream of scientific inquiry. PMID- 24768243 TI - Characterizing functional complaints in patients seeking outpatient low-vision services in the United States. AB - PURPOSE: To characterize functional complaints of new low-vision rehabilitation patients. DESIGN: Prospective observational study. PARTICIPANTS: The Low Vision Rehabilitation Outcomes Study recruited 819 patients between 2008 and 2011 from 28 clinical centers in the United States. METHODS: New patients referred for low vision rehabilitation were asked, "What are your chief complaints about your vision?" before their appointment. Full patient statements were transcribed as free text. Two methods assessed whether statements indicated difficulty in each of 13 functional categories: (1) assessment by 2 masked clinicians reading the statement, and (2) a computerized search of the text for specific words or word fragments. Logistic regression models were used to predict the influence of age, gender, and visual acuity on the likelihood of reporting a complaint in each functional category. MAIN OUTCOME MEASURES: Prevalence and risk factors for patient concerns within various functional categories. RESULTS: Reading was the most common functional complaint (66.4% of patients). Other functional difficulties expressed by at least 10% of patients included driving (27.8%), using visual assistive equipment (17.5%), mobility (16.3%), performing in-home activities (15.1%), lighting and glare (11.7%), and facial recognition and social interactions (10.3%). Good agreement was noted between the masked clinician graders and the computerized algorithm for categorization of functional complaints (median kappa of 0.84 across the 13 categories). Multivariate logistic regression models demonstrated that the likelihood of reading difficulties increased mildly with age (odds ratio, 1.4 per 10-year increment in age; 95% confidence interval, 1.3-1.6), but did not differ with visual acuity (P = 0.09). Additionally, men were more likely to report driving difficulties and difficulties related to lighting, whereas women were more likely to report difficulty with either in-home activities or facial recognition or social interaction (P<0.05 for all). Mobility concerns, defined as walking difficulty and out-of-home activities, showed no relationship to gender, age, or visual acuity. CONCLUSIONS: Reading was the most commonly reported difficulty, regardless of the patient's diagnosis. Neither visual acuity nor gender were predictive of reading concerns, although, age showed a small effect. Addressing reading rehabilitation should be a cornerstone of low-vision therapy. PMID- 24768245 TI - Initial and post-treatment total oxidant-antioxidant status and oxidative stress index in male patients with manic episode. AB - We investigated serum total oxidative and anti-oxidative status in manic patients. Group1 was formed as ECT+antipsychotic, group2 was antipsychotic and healthy volunteers as group3. The anti-oxidative status was significantly lower in group1 than group3. No significant change was found between pre and post treatment oxidative and anti-oxidative status, whereas significantly increased oxidative stress index has been found in group2. Total anti-oxidative status in manic states seems to be inadequate which remains to be maintained after the treatment. PMID- 24768246 TI - Relatives' illness attributions mediate the association of expressed emotion with early psychosis symptoms and functioning. AB - The mechanisms underlying the association between expressed emotion (EE) and the prognosis in early psychosis are still not well understood. Based on the attributional model, this study investigated the association of criticism and Emotional Over-Involvement (EOI) with symptoms and functioning in At-Risk Mental State (ARMS) and First-Episode Psychosis (FEP) patients, and whether these associations were mediated by relatives' attributions of control and blame. Forty four patients (20 ARMS and 24 FEP) and their relatives were included. Findings indicated that relatives' criticism was associated with positive, negative, and general symptoms. EOI was related to negative and general symptoms. Both indices were related with impaired functioning. Most of the relations between EE indices and illness severity were mediated by relatives' attributions of blame toward the patient. Relatives' self-blaming attributions and attributions of control over the disorder by either relatives or patients were not associated with patients' variables or EE. Findings highlight the importance of family emotional environment in the early stages of psychosis, as well as the mediating role that relatives' beliefs can exert in those relationships. Family interventions aimed to assist relatives to change attributions that blame patient should be included in clinical protocols in order to prevent the entrenchment of high-EE. PMID- 24768247 TI - Lack of effect of risperidone or olanzapine dose reduction on subjective experiences in stable patients with schizophrenia. AB - Sixty-one patients with schizophrenia stably treated with risperidone or olanzapine were randomly assigned to dose-reduction-by-half group or dose maintenance group. Subjective experiences were assessed at baseline and 28 weeks using three different self-rating scales. No significant differences in changes of subjective experiences were observed between the two groups. PMID- 24768248 TI - The mediating role of non-suicidal self-injury in the relationship between impulsivity and suicidal behavior among inpatients receiving treatment for substance use disorders. AB - Several theories posit a direct role of impulsivity in suicidal behavior. The interpersonal-psychological theory of suicidal behavior (IPTS) argues that the relationship between impulsivity and suicidal behavior is explained by the painful and/or provocative experiences (PPEs) often encountered by impulsive individuals. It thus seems plausible that nonsuicidal self-injury (NSSI), itself associated with impulsivity, might account for the relationship between impulsivity and suicidal behavior. We examined data from 93 adult inpatients (54.8% male) seeking treatment for substance use disorders. Patients completed a structured interview assessing prior suicidal behavior and a series of self report questionnaires examining impulsivity, NSSI, and psychopathology. Four impulsivity dimensions (negative urgency, positive urgency, lack of premeditation, lack of perseverance) were associated with lifetime number of suicide attempts and/or suicide potential. Furthermore, results supported our hypotheses, as all but one relation was better accounted for by NSSI and, in the one exception, the direct effect was non-significant. Findings are consistent with the IPTS and suggest that suicidal behavior may not be a direct manifestation of impulsivity, but facilitated through exposure to PPEs capable of altering an individual's relationship to pain and fear of death. PMID- 24768249 TI - Trichotillomania and emotion regulation: is symptom severity related to alexithymia? AB - Previous research on trichotillomania (TTM) has demonstrated an emotion regulation function of hair pulling behavior. One condition that can impede the regulation of emotions is alexithymia. The present study aimed to explore the relationship between the degree of alexithymia and the severity of hair pulling behavior in individuals with TTM. Multiple strategies were used to recruit a sample of 105 participants via the internet. All participants were diagnosed with TTM by an experienced clinician via a subsequent phone-interview. Multiple linear regression analysis was performed to test the potential predictive value of the different facets of alexithymia (20-item Toronto Alexithymia Scale) on the severity of TTM (Massachusetts General Hospital Hair-Pulling Scale). Both the difficulty in identifying feelings (DIF) facet of alexithymia (p=0.045) and depression (p=0.049) were significant predictors of the severity of TTM. In conclusion, alexithymia seems to play a role in hair pulling behavior in individuals with TTM. However, the significant association was small in terms of the overall variance explained, thus warranting further research. If replicated in prospective studies, then these results indicate that therapeutic approaches aimed at supporting patients in recognizing and differentiating feelings might be useful for the treatment of TTM. PMID- 24768250 TI - An exploratory study of the relationship between neurological soft signs and theory of mind deficits in schizophrenia. AB - Indirect evidence suggests partially common pathogenetic mechanisms for Neurological Soft Signs (NSS), neurocognition, and social cognition in schizophrenia. However, the possible association between NSS and mentalizing impairments has not yet been examined. In the present study, we assessed the ability to attribute mental states to others in patients with schizophrenia and predicted that the presence of theory of mind deficits would be significantly related to NSS. Participants were 90 clinically stable patients with a DSM-IV diagnosis of schizophrenia. NSS were assessed using the Neurological Evaluation Scale (NES). Theory of mind deficits were assessed using short verbal stories designed to measure false belief understanding. The findings of the study confirmed our hypothesis. Impaired sequencing of complex motor acts was the only neurological abnormality correlated with theory of mind deficits. By contrast, sensory integration, motor coordination and the NES Others subscale had no association with patients' ability to pass first- or second-order false belief tasks. If confirmed by future studies, the current findings provide the first preliminary evidence for the claim that specific NSS and theory of mind deficits may reflect overlapping neural substrates. PMID- 24768251 TI - Effects of antipsychotic drugs on insight in schizophrenia. AB - Lack of insight is predominant in schizophrenia though the causes are still unclear. The present study was carried on to investigate the effect of three Second Generation Antipsychotics (SGAs) and Haloperidol on insight and the associations among different clusters of symptoms and insight. Fifty-five patients have been recruited at the moment of pharmacological switch needed for psychotic exacerbation, from other antipsychotic drugs to Olanzapine, Aripiprazole, Ziprasidone and Haloperidol. Patients have been followed for 6 months and evaluated at baseline, after 3 months and after 6 months. Regarding the insight improvement, all SGAs resulted more effective than Haloperidol, while no difference was detected among different SGAs. Concerning psychopathology, all SGAs showed a better efficacy than Haloperidol, positive symptoms apart. All SGAs showed a similar efficacy on all domains, except for negative symptoms which resulted less responsive to ziprasidone and haloperidol. An association between improvement of insight and psychopathology was detected. Furthermore, insight appears to be related to psychopathology severity, particularly to negative symptoms. However, the observed different effectiveness of Ziprasidone on negative symptoms and insight suggests that these psychopathological features may be not strictly related and, thus, they may be sustained by different psychopathological processes. PMID- 24768252 TI - Comparative study of cognitive impairment between medicated and medication-free patients with remitted major depression: class-specific influence by tricyclic antidepressants and newer antidepressants. AB - Patients with major depressive disorder (MDD) are known to present with cognitive deficits; however, the presence of these deficits in the remitted state have been inconsistent. One of the most important factors potentially contributing to inconsistencies between studies may be the influence of medications. To explore the influence of antidepressants on cognitive performance in remitted MDD, we evaluated memory and executive functions using Wechsler Memory Scale-Revised and Stroop Color and Word Test, and compared performance among 50 medicated (29 treated with tricyclic antidepressants [TCA], 21 treated with selective serotonin reuptake inhibitors or serotonin noradrenalin reuptake inhibitors) and 19 medication-free MDD patients and 31 controls. The results showed that all 3 MDD groups had significantly lower performance for verbal memory compared with controls. Both medicated groups showed significantly lower performance for visual memory compared with controls; however, the medication-free group did not differ from controls. For the executive function, only the TCA group showed a significantly lower performance compared with controls. These results suggest that cognitive impairment remained even in remitted patients with MDD, however, part of this impairment may be influenced by class-specific antidepressant side effects. PMID- 24768253 TI - Obliterative portal venopathy: a study of 48 children. AB - Childhood obliterative portal venopathy presents at any age and may be genetic in origin. We report 48 children with obliterative portal venopathy, based on strict histologic criteria, investigated between 1972 and 2011. Diagnosis requires histology and is suggested by ultrasonography findings. Portal hypertension is the main complication but is absent in some cases. Prognosis is relatively good, but the detection of cardiopulmonary complications is essential. PMID- 24768255 TI - [Hematemesis in an 80-year-old patient with chest pain and nausea]. PMID- 24768254 TI - Adverse drug event detection in pediatric oncology and hematology patients: using medication triggers to identify patient harm in a specialized pediatric patient population. AB - OBJECTIVE: To investigate the use of a trigger tool for the detection of adverse drug events (ADE) in a pediatric hospital specializing in oncology, hematology, and other catastrophic diseases. STUDY DESIGN: A medication-based trigger tool package analyzed electronic health records from February 2009 to February 2013. Chart review determined whether an ADE precipitated the trigger. Severity was assigned to ADEs, and preventability was assessed. Preventable ADEs were compared with the hospital's electronic voluntary event reporting system to identify whether these ADEs had been previously identified. The positive predictive values (PPVs) of the entire trigger tool and individual triggers were calculated to assess their accuracy to detect ADEs. RESULTS: Trigger occurrences (n = 706) were detected in 390 patients from 6 medication triggers, 33 of which were ADEs (overall PPV = 16%). Hyaluronidase had the greatest PPV (60%). Most ADEs were category E harm (temporary harm) per the National Coordinating Council for Medication Error Reporting and Prevention index. One event was category H harm (intervention to sustain life). Naloxone was associated with the most grade 4 ADEs per the Common Terminology Criteria for Adverse Events v4.03. Twenty-one (64%) ADEs were preventable, 3 of which were submitted via the voluntary reporting system. CONCLUSION: Most of the medication-based triggers yielded low PPVs. Refining the triggers based on patients' characteristics and medication usage patterns could increase the PPVs and make them more useful for quality improvement. To efficiently detect ADEs, triggers must be revised to reflect specialized pediatric patient populations such as hematology and oncology patients. PMID- 24768256 TI - [Giant hepatic artery aneurysm: Management of an infrequent entity]. PMID- 24768257 TI - A new economic instrument for financing accelerated landfill aftercare. AB - The key aspects of landfill operation that remain unresolved are the extended timescale and uncertain funding of the post-closure period. This paper reviews the topic and proposes an economic instrument to resolve the unsustainable nature of the current situation. Unsustainability arises from the sluggish degradation of organic material and also the slow flushing of potential pollutants that is exacerbated by low-permeability capping. A landfill tax or aftercare provision rebate is proposed as an economic instrument to encourage operators to actively advance the stabilization of landfilled waste. The rebate could be accommodated within existing regulatory and tax regimes and would be paid for: (i) every tonne of nitrogen (or other agreed leachate marker) whose removal is advanced via the accelerated production and extraction of leachate; (ii) every tonne of non commercially viable carbon removed via landfill gas collection and treatment. The rebates would be set at a level that would make it financially attractive to operators and would encourage measures such as leachate recirculation, in situ aeration, and enhanced flushing. Illustrative calculations suggest that a maximum rebate of up to ~?50/tonne MSW would provide an adequate incentive. PMID- 24768258 TI - Attention-Deficit/Hyperactivity Disorder-like Phenotype in a Mouse Model with Impaired Actin Dynamics. AB - BACKGROUND: Actin depolymerizing proteins of the actin depolymerizing factor (ADF)/cofilin family are essential for actin dynamics, which is critical for synaptic function. Two ADF/cofilin family members, ADF and n-cofilin, are highly abundant in the brain, where they are present in excitatory synapses. Previous studies demonstrated the relevance of n-cofilin for postsynaptic plasticity, associative learning, and anxiety. These studies also suggested overlapping functions for ADF and n-cofilin. METHODS: We performed pharmacobehavioral, electrophysiologic, and electron microscopic studies on ADF and n-cofilin single mutants and double mutants (named ACC mice) to characterize the importance of ADF/cofilin activity for synapse physiology and mouse behavior. RESULTS: The ACC mice, but not single mutants, exhibited hyperlocomotion, impulsivity, and impaired working memory. Hyperlocomotion and impulsive behavior were reversed by methylphenidate, a psychostimulant commonly used for the treatment of attention deficit/hyperactivity disorder (ADHD). Also, ACC mice displayed a disturbed morphology of striatal excitatory synapses, accompanied by strongly increased glutamate release. Blockade of dopamine or glutamate transmission resulted in normal locomotion. CONCLUSIONS: Our study reveals that ADHD can result from a disturbed balance between excitation and inhibition in striatal circuits, providing novel insights into the mechanisms underlying this neurobehavioral disorder. Our results link actin dynamics to ADHD, suggesting that mutations in actin regulatory proteins may contribute to the etiology of ADHD in humans. PMID- 24768259 TI - BIOB: a mathematical model for the biodegradation of low solubility hydrocarbons. AB - Modeling oil biodegradation is an important step in predicting the long term fate of oil on beaches. Unfortunately, existing models do not account mechanistically for environmental factors, such as pore water nutrient concentration, affecting oil biodegradation, rather in an empirical way. We present herein a numerical model, BIOB, to simulate the biodegradation of insoluble attached hydrocarbon. The model was used to simulate an experimental oil spill on a sand beach. The biodegradation kinetic parameters were estimated by fitting the model to the experimental data of alkanes and aromatics. It was found that parameter values are comparable to their counterparts for the biodegradation of dissolved organic matter. The biodegradation of aromatics was highly affected by the decay of aromatic biomass, probably due to its low growth rate. Numerical simulations revealed that the biodegradation rate increases by 3-4 folds when the nutrient concentration is increased from 0.2 to 2.0 mg N/L. PMID- 24768260 TI - Regulation of CYP11B1 and CYP11B2 steroidogenic genes by hypoxia-inducible miR 10b in H295R cells. AB - Although numerous studies have shown that hypoxia affects cortisol and aldosterone production in vivo, the underlying molecular mechanisms regulating the steroidogenic genes of these steroid hormones are still poorly known. MicroRNAs are post-transcriptional regulators that control diverse biological processes and this study describes the identification and validation of the hypoxia-inducible microRNA, miR-10b, as a negative regulator of the CYP11B1 and CYP11B2 steroidogenic genes in H295R human adrenocortical cells. Using the human TaqMan Low Density miRNA Arrays, we determined the miRNA expression patterns in H295R cells under normoxic and hypoxic conditions, and in cells overexpressing the human HIF-1alpha. Computer analysis using three in silico algorithms predicted that the hypoxia-inducible miR-10b molecule targets CYP11B1 and CYP11B2 mRNAs. Gene transfection studies of luciferase constructs containing the 3' untranslated region of CYP11B1 or CYP11B2, combined with miRNA overexpression and knockdown experiments provide compelling evidence that CYP11B1 and CYP11B2 mRNAs are likely targets of miR-10b. PMID- 24768261 TI - Benthic foraminifera assemblages as elemental pollution bioindicator in marine sediments around fish farm (Vrgada Island, Central Adriatic, Croatia). AB - Effects on sediments of fish farming activity near Vrgada Island was analysed through living and total foraminiferal assemblages and concentration of major, minor and trace elements from three sediment cores. Elemental concentrations of sediments are in accordance with carbonate characteristics of the surrounding area and show mostly natural element variations between sampling locations and throughout the cores, with no significant increases due to fish farming activity. Only phosphorus concentration shows elevate values below the fish cage, assigned to fish pellets. Foraminiferal communities are dominated by epifaunal and stress tolerant species, while diversity indices point to normal marine conditions. The type of substrate and phosphorus content in sediments principally influence foraminiferal community composition, while other elemental concentrations have no perceptible effect on the assemblages. Some foraminiferal species Ammoniatepida, Ammoniabeccarii, Elphidiumcrispum, Elphidiummacellum and genus Haynesina are confirmed to be tolerant to elevated nutrient (phosphorus) content, while Ammonia parkinsoniana shows sensitivity to pollution. Postmortem processes cause decrease of foraminiferal density and species richness with core depth. All results point to negligible influence of fish farming and relatively stable environmental conditions at all sampling locations. PMID- 24768262 TI - Occurrence and distribution of phthalate esters in riverine sediments from the Pearl River Delta region, South China. AB - Sixty-eight sediment samples collected from Dongjiang River, Xijiang River, Beijiang River and Zhujiang River in the Pearl River Delta (PRD) region, Southern China, were analyzed for 16 phthalate esters (PAEs). PAEs were detected in all riverine sediments analyzed, which indicate that PAEs are ubiquitous environmental contaminants. The Sigma16PAEs concentrations in riverine sediments in the PRD region ranged from 0.567 to 47.3 MUg g(-1) dry weight (dw), with the mean and median concentrations of 5.34 MUg g(-1) dw and 2.15 MUg g(-1) dw, respectively. Elevated PAEs concentrations in riverine sediments in the PRD region were found in the highly urbanized and industrialized areas. Of the 16 PAEs, diisobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP) and di(2 ethylhexyl) phthalate (DEHP) dominated the PAEs, with the mean and median concentrations of 1.12 MUg g(-1)dw, 0.420 MUg g(-1) dw and 3.72 MUg g(-1) dw, and 0.429 MUg g(-1) dw, 0.152 MUg g(-1) dw and 1.55 MUg g(-1) dw, respectively, and accounted for 94.2-99.7% of the Sigma16PAEs concentrations. Influenced by local sources and the properties of PAEs, a gradient trend of concentrations and a fractionation of composition from more to less industrialized and urbanized areas were discovered. As compared to the results from other studies, the riverine sediments in the PRD region were severely contaminated with PAEs. Information about PAEs contamination status and its effect on the aquatic organisms in the PRD region may deserve further attention. PMID- 24768263 TI - Analysis of water quality and circulation of four recreational Miami beaches through the use of Lagrangian Coherent Structures. AB - Four popular, recreational beaches in Miami, FL are Hobie Beach, Virginia Key Beach, Crandon Park Beach, and Bill Baggs Cape Florida State Park. While all of the beaches are within a few miles of each other in Biscayne Bay, they have greatly differing water qualities, as determined by the testing for fecal indicator bacteria performed by the Florida Department of Health. Using the geodesic theory of transport barriers, we identify Lagrangian Coherent Structures (LCSs) in each area. We show how these material curves, which shape circulation and mixing patterns, can be used to explain the incongruous states of the water at beaches that should be comparable. The LCSs are computed using a hydrodynamic model and verified through field experimentation at each beach. PMID- 24768264 TI - Therapeutic drug monitoring of intracellular anti-infective agents. AB - Many microorganisms, including viruses, some bacteria and fungi, replicate within the cells. Therefore, the efficacy of therapy and the selection of resistances could be related to intracellular concentration of the drugs and to their ability to cross biological membranes and penetrate into various tissue compartments. The efficacy of treatment may be limited by pharmacological factors. Dose-response relationship exists for many agents, and failure to maintain adequate concentrations may allow the development of viral or bacterial resistance, thereby decreasing the probability of response of current and subsequent therapies. The major target of antivirals and many other anti-infective agents is within infected cells. Therefore, clinical outcome ultimately should be related to intracellular drug concentrations. Intracellular pharmacokinetics provides information regarding drug disposition in a compartment where microorganism replication occurs and combined with plasma data may be useful in understanding therapeutic failure in relation to cellular resistance. With a focus on possible methodological biases, this review reports the current state of the art in intracellular, particularly in peripheral blood mononuclear cells, therapeutic drug monitoring of the following anti-infective drugs: antivirals, antifungals and antibiotics. Although measurement of intracellular concentrations needs to be still standardized focusing on each single drug, this review showed some relationships between intracellular concentrations of few anti-infective drugs and their efficacy and/or toxicity. Such relationships should be interpreted with caution, as intracellular concentrations reflect the total amount of drug within the cell and not the effective unbound fraction. The number of clinical studies in that area is, however, rather limited, and not always adequately designed. Then, intracellular drug determination has to be considered a test for research only and not to be carried out as routine. PMID- 24768265 TI - Magnetic nanoparticles with a pH-sheddable layer for antitumor drug delivery. AB - A dually responsive nanocarrier with a multilayer core-shell architecture was prepared based on Fe3O4@SiO2 nanoparticles successively coated with poly(benzyl L aspartate) (PBLA) and poly(ethylene glycol) (PEG) for the purpose of tumor specific drug delivery applications. In this system, PEG chains are connected to the surface via pH-sensitive benzoic-imine bonds and serve as a pH-sheddable hydrophilic corona. Meanwhile, the PBLA segments serve as a hydrophobic middle layer used to load the drugs via hydrophobic interactions. The Fe3O4@SiO2 nanoparticle functions as a superparamagnetic core used to direct the drug loaded nanocarrier to the target pathological site. The obtained materials were characterized with FT-IR, (1)H NMR, dynamic light scattering, zeta-potential, TEM, TGA, and hysteresis loop analysis. An anticancer drug doxorubicin (DOX) was selected as the model drug loaded into the nanocarrier, which was relatively stable under physiological conditions due to its neutral hydrophilic shell, and could quickly release the drug in response to increased acidity via shedding of the PEG shells through cleavage of the intermediate benzoic-imine bonds. Meanwhile, the neutral shell shedding would reveal a positively charged nanoparticle surface that is readily taken up by tumor cells. These pH- and magnetic-responsive nanoparticles showed significant potential for use in the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy. PMID- 24768266 TI - Facile fabrication of core cross-linked micelles by RAFT polymerization and enzyme-mediated reaction. AB - Polymeric micelles formed in aqueous solution by assembly of amphiphilic block copolymers have been extensively investigated due to their great potential as drug carriers. However, the stability of polymeric assembly is still one of the major challenges in delivering drugs to tissues and cells. Here, we report a facile route to fabricate core cross-linked (CCL) micelles using an enzymatic polymerization as the cross-linking method. We present synthesis of poly(ethylene glycol)-block-poly(N-isopropyl acrylamide-co-N-(4-hydroxyphenethyl) acrylamide) diblock copolymer PEG-b-P(NIPAAm-co-NHPAAm) via reversible addition-fragmentation chain transfer (RAFT) polymerization. The diblock copolymer was then self assembled into non-cross-linked (NCL) micelles upon heating above the lower critical solution temperature (LCST), and subsequently cross-linked using horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) as enzyme and oxidant. The characterization of the diblock copolymer and micelles were studied by NMR, DLS, UV-vis, and fluorescence spectroscopy. The fluorescence study reveals that the cross-linking process endows the micelles with much lower critical micelle concentration (CMC). In addition, the drug release study shows that the CCL micelles have lower release amount of doxorubicin (DOX) than the NCL micelles due to the enhanced stability of the CCL micelles by core cross-linking process. PMID- 24768267 TI - User-driven prioritization of features for a prospective InterPersonal Health Record: perceptions from the Italian context. AB - In this paper we present two large user studies in which we gather evidence about the adoption and satisfaction level of users in regard to electronic records that manage health related information from two distinct but complementary perspectives: that of General Practitioners (GPs) about their Electronic Medical Records (EMRs); and that of citizens/patients about their Personal Health Records (PHRs). In these user studies we also probe the user attitudes towards innovative functionalities from these two perspectives and, on the basis of the collected perceptions, we apply an original ranking method to infer what features are valued most and hence could inspire design to make PHRs more situated into the users' lives and drive a higher adoption of these tools. On the basis of the perceived shortcomings of current records, we envision an InterPersonal Health Record (IPHR) that is a sort of hybrid electronic record that merges together typical EMR- and PHR-related features and is endowed with specific functionalities aimed at enhancing interpersonal relationships, communication and collaboration between citizens/patients and their GPs through the record and about its contents. This study is then a contribution in understanding the current attitudes and expectations of potential users towards full-fledged prospective PHRs, as well as a first step in identifying those requirements and priority areas on which to focus further for the design and deployment of more community- and communication-oriented tools in the primary health care domain. PMID- 24768268 TI - [Severe burns related to steam inhalation therapy]. AB - INTRODUCTION: Despite lack of proven effectiveness and its potential to cause severe burns, steam inhalation therapy (SIT) is still used as a treatment for benign respiratory conditions. OBJECTIVE: To characterize cases of burns related to steam inhalation therapy (BRSIT) in order to formulate appropriate preventive criteria. PATIENTS AND METHODS: A review was conducted on cases of BRSIT admitted to a Burns Unit between 2006 and 2012, analysing epidemiological data, clinical aspects, severity and course. RESULTS: A total of 530 patients were admitted; 375 (70%) with scalds, and 15 with BRSIT (2.8% of burns; 4% of scalds). SIT was indicated in most cases for mild upper airway infections. The median age of patients was 7 years (2.5m-14 y). The burned area (BA) was >=10% in 60% of cases (max. BA 22%). Injuries involved trunk, genital area, and extremities; only in one case was the face affected. The mean hospital length-of-stay was 14 days (3 30 d). Five patients (33%) were admitted to the PICU, most of them (60%) younger than 3 years. Eight patients (53%) underwent surgical treatment (skin grafting). In a 12-year-old patient whooping cough was diagnosed in the Burns Unit, and a 2.5-year-old patient developed staphylococcal toxic shock syndrome. No patient died. The final course was satisfactory in all patients. CONCLUSIONS: BRSIT can be severe and cause significant use of health resources. Professionals caring for children, particularly paediatricians, should seriously consider their prevention, avoiding treatments with SIT, and educating parents in order not to use it on their own. PMID- 24768269 TI - Can an early 24-hour EEG predict the response to the ketogenic diet? A prospective study in 34 children and adults with refractory epilepsy treated with the ketogenic diet. AB - PURPOSE: We examined whether early EEG changes in a 24-h EEG at 6 weeks of treatment were related to the later clinical response to the ketogenic diet (KD) in a 6-month period of treatment. METHODS: We examined 34 patients with heterogeneous epilepsy syndromes (21 children, 13 adults) and found 9 clinical responders (>=50% seizure reduction); this is a responder rate of 26%. We visually counted the interictal epileptic discharge index (IED index) in % during 2h of wakefulness and in the first hour of sleep (method 1), and also globally reviewed EEG changes (method 2), while blinded to the effect of the KD. RESULTS: At group level we saw a correlation between nocturnal reduction of IED-index at 6 weeks and seizure reduction in the follow-up period. A proportional reduction in IED index of 30% from baseline in the sleep EEG, was associated with being a responder to the diet (Pearson Chi-square p=0.04). EEG scoring method 2 observed a significantly larger proportion of patients with EEG-improvement in sleep in KD responders than in non-responders (p=0.03). At individual level, however, EEG changes did not correlate very strongly to the response to the diet, as IED reduction in sleep was also seen in 15% (method 1) to 26% (method 2) of the non responders. CONCLUSION: Nocturnal reduction of IEDs is related to the response to the KD, however in daily clinical practice, an early EEG to predict seizure reduction should not be advised for individual patients. PMID- 24768270 TI - Effect of adrenocorticotropic hormone therapy for epileptic spasms developing after the age of 1 year. AB - PURPOSE: Epileptic spasms sometimes begin after the first year of life, and such seizures are recognized as late-onset spasms (LOS). The prognosis of LOS is poor, and a treatment strategy has not been established. This study aimed to assess the short- and long-term effects of adrenocorticotropic hormone (ACTH) therapy for LOS. METHODS: We investigated the rate of LOS in 22 patients (14 boys and 8 girls) treated with ACTH therapy. The age at onset of LOS and at the start of ACTH therapy ranged from 12 to 94 months (median, 31.6 +/- 22.1 months) and from 12.5 to 116 months (median, 37.5 +/- 23.7 months), respectively. We investigated the response rate of LOS treated with ACTH therapy, and compared the clinical features between responders (short-term) and nonresponders. RESULTS: Nine (41%) of the 22 patients showed cessation of epileptic spasms within 3 months. The epileptic spasms ceased in four of these nine patients for more than 1 year. The age at onset of LOS was significantly associated with short-term seizure cessation (p<0.05). Patients who achieved short-term cessation of seizures received ACTH therapy within 6 months from the onset of LOS. CONCLUSION: ACTH therapy is a potentially effective treatment when started within 6 months from the onset of LOS. A younger age at onset of LOS is associated with a favorable outcome. PMID- 24768271 TI - Are the educational differences in incidence of cardiovascular disease explained by underlying familial factors? A twin study. AB - To isolate the effect of education from the influence of potential underlying factors, we investigated the association of education with the risk of cardiovascular disease (CVD) and ischemic heart disease (IHD) using twin data to adjust for familial factors shared within twins, including genetic make-up and childhood environment. The study was based on data from the Danish Twin Registry linked to administrative and heath registers in Statistics Denmark. A total of 11,968 monozygotic and 20,464 dizygotic same sexed twins were followed from 1980 to 2009, including more than 8000 events of CVD. Unpaired and intra-pair analyses were compared. In the unpaired analyses, an inverse educational gradient in CVD- and IHD risk was observed. This association was not replicated in the intra-pair analyses that control for shared familial factors exploiting that twins share their intrauterine- and childhood environment and are matched partly or fully on genetic setup. The attenuation of association of education with CVD and IHD in the intra-pair analyses suggests that shared familial factors account for a substantial part of the observed association of education with CVD and IHD in Denmark. PMID- 24768272 TI - Pharmaceuticalisation and ethical review in South Asia: issues of scope and authority for practitioners and policy makers. AB - Ethical review by expert committee continues to be the first line of defence when it comes to protecting human subjects recruited into clinical trials. Drawing on a large scale study of biomedical experimentation across South Asia, and specifically on interviews with 24 ethical review committee [ERC] members across India, Sri Lanka and Nepal, this article identifies some of the tensions that emerge for ERC members as the capacity to conduct credible ethical review of clinical trials is developed across the region. The article draws attention to fundamental issues of scope and authority in the operation of ethical review. On the one hand, ERC members experience a powerful pull towards harmonisation and a strong alignment with international standards deemed necessary for the global pharmaceutical assemblage to consolidate and extend. On the other hand, they must deal with what is in effect the double jeopardy of ethical review in developing world contexts. ERC members must undertake review but are frequently made aware of their responsibility to protect interests that go beyond the 'human subject' and into the realms of development and national interest [for example, in relation to literacy and informed consent]. These dilemmas are indicative of broader questions about where ethical review sits in institutional terms and how it might develop to best ensure improved human subject protection given growth of industry-led research. PMID- 24768273 TI - Epidemiological ramifications of diagnosing diabetes with HbA1c levels. AB - AIMS: To compare the prevalence of diabetes by history and using the fasting plasma glucose (FPG) criterion alone, the HbA1c criterion alone or either one in those not known to have diabetes. METHODS: Analysis of NHANES population >=20years old from 1999 through 2010. RESULTS: In those diagnosed by laboratory tests, 86% met the FPG criterion and 53% met the HbA1c criterion. The prevalence of diabetes (history or laboratory test) was significantly increased when the FPG criterion was used compared with the HbA1c criterion in the entire (11.5% vs 10.5%, P=0.018) and Caucasian (10.6% vs 9.2%, P=0.022) populations. In contrast, there were no significant differences in the prevalence when only the FPG criterion was used compared with only the HbA1c criterion in Hispanics (12.9% vs 12.1% P=0.386) and African Americans (14.5 vs 14.3%, P=0.960). Using history and either criterion in those not known to have it, diabetes increased by 61% in this 12year period in adults >=20years old. CONCLUSIONS: Using the FPG rather than the HbA1c criterion to diagnose diabetes in those without a history significantly increased the total prevalence of diabetes in Caucasians but not in African Americans or Hispanics. PMID- 24768274 TI - Development of Mandarin spoken language after pediatric cochlear implantation. AB - OBJECTIVE: The purpose of this study was to evaluate early spoken language development in young Mandarin-speaking children during the first 24 months after cochlear implantation, as measured by receptive and expressive vocabulary growth rates. Growth rates were compared with those of normally hearing children and with growth rates for English-speaking children with cochlear implants. METHOD: Receptive and expressive vocabularies were measured with the simplified short form (SSF) version of the Mandarin Communicative Development Inventory (MCDI) in a sample of 112 pediatric implant recipients at baseline, 3, 6, 12, and 24 months after implantation. Implant ages ranged from 1 to 5 years. Scores were expressed in terms of normal equivalent ages, allowing normalized vocabulary growth rates to be determined. Scores for English-speaking children were re-expressed in these terms, allowing direct comparisons of Mandarin and English early spoken language development. RESULTS: Vocabulary growth rates during the first 12 months after implantation were similar to those for normally hearing children less than 16 months of age. Comparisons with growth rates for normally hearing children 16-30 months of age showed that the youngest implant age group (1-2 years) had an average growth rate of 0.68 that of normally hearing children; while the middle implant age group (2-3 years) had an average growth rate of 0.65; and the oldest implant age group (>3 years) had an average growth rate of 0.56, significantly less than the other two rates. Growth rates for English-speaking children with cochlear implants were 0.68 in the youngest group, 0.54 in the middle group, and 0.57 in the oldest group. Growth rates in the middle implant age groups for the two languages differed significantly. CONCLUSIONS: The SSF version of the MCDI is suitable for assessment of Mandarin language development during the first 24 months after cochlear implantation. Effects of implant age and duration of implantation can be compared directly across languages using normalized vocabulary growth rates. These comparisons for Mandarin and English reveal comparable results, despite the diversity of these languages, underscoring the universal role of plasticity in the developing auditory system. PMID- 24768276 TI - TMPRSS:ERG fusion in prostate cancer: from experimental approaches to prognostic studies. PMID- 24768275 TI - Voice related quality of life in pediatric patients with a history of prematurity. AB - OBJECTIVE: To determine incidence of dysphonia in patients with history of prematurity and evaluate the correlation between dysphonia and risk factors unique to premature infants. The aim of this study is to determine parent perceived vocal quality in patients with history of prematurity and whether duration of intubation, number of intubations, and incidence of patent ductus arteriosus repair were correlated with these perceptions. METHODS: Cohort study of premature patients presenting to outpatient clinics from January 2010 to January 2013 in tertiary care center. Patients gestational age <=37 weeks at birth without history of tracheostomy or known vocal fold pathology were eligible. A volunteer sample was obtained from patients presenting in Otolaryngology clinics from January 2010 to January 2013 whose parents agreed to complete surveys. Outcomes were assessed via parental completion of pediatric voice outcomes score (pVOS) and pediatric voice-related quality of life (pVRQOL) instruments. The primary outcome assessed was the incidence of dysphonia in infants with a history of prematurity without known vocal pathology. Additionally, patient factors associated with dysphonia were evaluated. The hypothesis tested was formulated prior to data collection. RESULTS: Sixty-nine participants were included. Mean age at follow-up was 28 (3-197) months. Mean gestational age was 29 (23-37) weeks. Mean intubation duration was 3 (0-22) weeks and median number of intubations was 1 (range 0-5). Voice outcome scores varied widely with pVRQOL scores demonstrating a mean of 89.2+/-18.1 (25-100) and pVOS with a mean of 11.4+/-2.2 (0-13). Univariate analysis utilized Spearman correlation coefficients for continuous variables and Wilcoxon Two-sample test for categorical groups. Significance was set at p<0.05. All significant univariate associations were placed in a multivariate model. Duration of intubation >=4 weeks was the only factor which correlated with dysphonia on multivariate analysis (p=0.0028, OR=6.4, 95% CI=1.9-21.6). CONCLUSIONS: The data suggest that prolonged intubation is associated with poorer long term parent perceived voice quality in premature patients. Further study is required to correlate parent perceptions with objective vocal quality data and physical findings of vocal pathology. These data may increase the clinician's suspicion for and evaluation of dysphonia in this population. PMID- 24768277 TI - Establishment of a recording method for surface electromyography in the iliopsoas muscle. AB - We examined the availability and reliability of surface electromyography (EMG) signals from the iliopsoas muscle (IL). Using serial magnetic resonance images from fifty healthy young males, we evaluated whether the superficial region of IL was adequate for attaching surface EMG electrodes. Subsequently, we assessed EMG cross-talk from the sartorius muscle (SA)-the nearest to IL-using a selective cooling method in fourteen subjects. The skin above SA was cooled, and the median frequencies of EMG signals from IL and SA were determined. The maximum voluntary contraction during isometric hip flexion was measured before and after selective cooling, and surface EMG signals from SA and IL were measured. The superficial area of IL was adequately large (13.2+/-2.7cm(2)) for recording surface EMG in all fifty subjects. The maximum perimeter for the medial-lateral skin facing IL was noted at a level 3-5cm distal to the anterior superior iliac spine. Following cooling, the median frequency for SA decreased significantly (from 70.1 to 51.9Hz, p<0.001); however, that for IL did not alter significantly. These results demonstrated that EMG cross-talk from SA was negligible for surface EMG signals from IL during hip flexion. PMID- 24768278 TI - Interlimb symmetry of dynamic knee joint stiffness and co-contraction is maintained in early stage knee osteoarthritis. AB - Individuals with knee OA often exhibit greater co-contraction of antagonistic muscle groups surrounding the affected joint which may lead to increases in dynamic joint stiffness. These detrimental changes in the symptomatic limb may also exist in the contralateral limb, thus contributing to its risk of developing knee osteoarthritis. The purpose of this study is to investigate the interlimb symmetry of dynamic knee joint stiffness and muscular co-contraction in knee osteoarthritis. Muscular co-contraction and dynamic knee joint stiffness were assessed in 17 subjects with mild to moderate unilateral medial compartment knee osteoarthritis and 17 healthy control subjects while walking at a controlled speed (1.0m/s). Paired and independent t-tests determined whether significant differences exist between groups (p<0.05). There were no significant differences in dynamic joint stiffness or co-contraction between the OA symptomatic and OA contralateral group (p=0.247, p=0.874, respectively) or between the OA contralateral and healthy group (p=0.635, p=0.078, respectively). There was no significant difference in stiffness between the OA symptomatic and healthy group (p=0.600); however, there was a slight trend toward enhanced co-contraction in the symptomatic knees compared to the healthy group (p=0.051). Subjects with mild to moderate knee osteoarthritis maintain symmetric control strategies during gait. PMID- 24768279 TI - En masse reduction of an incarcerated inguinal hernia. Emergency laparoscopic management. PMID- 24768280 TI - Endoscopic management of a perforation during diagnostic colonoscopy using OVESCO((r)) clip. PMID- 24768281 TI - Assessing and improving cross-border chemical incident preparedness and response across Europe. AB - Good practices in emergency preparedness and response for chemical incidents include practices specific to the different functions of exposure assessment (e.g., within the monitoring function, the use of mobile monitoring equipment; within the modelling function, the use of rapid dispersion models with integrated mapping software) and generic practices to engage incident response stakeholders to maximise exposure assessment capabilities (e.g., sharing protocols and pre prepared information and multi-agency training and exercising). Such practices can optimise cross-border collaboration. A wide range of practices have been implemented across MSs during chemical incident response, particularly during incidents that have cross-border and trans-boundary impacts. This paper proposes a self-assessment methodology to enable MSs, or organisations within MSs, to examine exposure assessment capabilities and communication pathways between exposure assessors and public health risk assessors. Where gaps exist, this methodology provides links to good practices that could improve response, communication and collaboration across local, regional and national borders. A fragmented approach to emergency preparedness for chemical incidents is a major obstacle to improving cross-border exposure assessment. There is no one existing body or structure responsible for all aspects of chemical incident preparedness and response in the European Union. Due to the range of different organisations and networks involved in chemical incident response, emergency preparedness needs to be drawn together. A number of recommendations are proposed, including the use of networks of experts which link public health risk assessors with experts in exposure assessment, in order to coordinate and improve chemical incident emergency preparedness. The EU's recent Decision on serious cross-border threats to health aims to facilitate MSs' compliance with the International Health Regulations, which require reporting and communication regarding significant chemical incidents. This provides a potential route to build on in order to improve chemical incident preparedness and response across Europe. PMID- 24768282 TI - Lasiojasmonates A-C, three jasmonic acid esters produced by Lasiodiplodia sp., a grapevine pathogen. AB - In this study, a strain (BL 101) of a species of Lasiodiplodia, not yet formally described, which was isolated from declining grapevine plants showing wedge shaped cankers, was investigated for its ability to produce in vitro bioactive secondary metabolites. From culture filtrates of this strain three jasmonic acid esters, named lasiojasmonates A-C and 16-O-acetylbotryosphaerilactones A and C were isolated together with (1R,2R)-jasmonic acid, its methyl ester, botryosphaerilactone A, (3S,4R,5R)-4-hydroxymethyl-3,5-dimethyldihydro-2-furanone and (3R,4S)-botryodiplodin. The structures of lasiojasmonates A-C were established by spectroscopic methods as (1R*,2R*,3'S*,4'R*,5'R*)-4-hydroxymethyl 3,5-dimethyldihydro-2-furanone, (1R*,2R*,3'S*,4'R*,5'R*,10'R*,12'R*,13'R*,14'S*) and (1R*,2R*,3'S*,4'R*,5'R*,10'S*,12'R*,13'R*,14'S*)-4-(4-hydroxymethyl-3,5 dimethyltetrahydro-furan-2-yloxymethyl)-3,5-dimethyldihydro-2-furanones jasmonates (1, 4 and 5). The structures of 16-O-acetylbotryosphaerilactones A and C were determined by comparison of their spectral data with those of the corresponding acetyl derivatives obtained by acetylation of botryosphaerilactone A. The metabolites isolated, except 4 and 5, were tested at 1mg/mL on leaves of grapevine cv. Cannonau and cork oak using the leaf puncture assay. They were also tested on detached grapevine leaves at 0.5mg/mL and tomato cuttings at 0.1mg/mL. In all phytotoxic assays only jasmonic acid was found to be active. All metabolites were inactive in the zootoxic assay at 50 MUg/mL. PMID- 24768283 TI - The effect of drought stress on the expression of key genes involved in the biosynthesis of triterpenoid saponins in liquorice (Glycyrrhiza glabra). AB - Glycyrrhiza glabra is an important medicinal plant throughout the world. Glycyrrhizin is a triterpenoid that is among the most important secondary metabolites produced by liquorice. Drought stress is proposed to enhance the levels of secondary metabolites. In this study, the effect of drought stress on the expression of important genes involved in the glycyrrhizin biosynthetic pathway was examined. Drought stress at the seedling stage was applied to 8-day old plants using polyethylene glycol. Subsequently, the samples were collected 0, 4, 8 or 24 h post-treatment. At the adult plant stage, 10-month-old plants were subjected to drought stress by discontinuing irrigation. Subsequently, samples were collected at 2, 16 and 28 days after drought imposition (S(2d), S(16d) and S(28d), respectively). We performed semi-quantitative RT-PCR assays to evaluate the gene expression levels of sequalene synthase (SQS), beta-amyrin synthase (bAS), lupeol synthase (LUS) and cycloartenol synthase (CAS) during stress. Finally, the glycyrrhizin content of stolons was determined via HPLC. The results revealed that due to osmotic stress, the gene expression levels of SQS and bAS were increased, whereas those of CAS were relatively unchanged at the seedling stage. At the adult plant stage, the expression levels of SQS and bAS were increased under drought stress conditions, whereas the gene expression level of CAS remained relatively constant. The glycyrrhizin content in stolons was increased only under severe drought stress conditions (S(28d)). Our results indicate that application of controlled drought stress up-regulates the expression of key genes involved in the biosynthesis of triterpenoid saponins and directly enhances the production of secondary metabolites, including glycyrrhizin, in liquorice plants. PMID- 24768284 TI - Crinine-type alkaloids from Hippeastrum aulicum and H. calyptratum. AB - An ongoing search for alkaloids in the Amaryllidaceae species using GC-MS resulted in the identification of two crinine-type alkaloids, aulicine (1) and 3 O-methyl-epimacowine, (2) from the indigenous Brazilian species Hippeastrum aulicum and Hippeastrum calyptratum, respectively. In addition, two alkaloids, 11 oxohaemanthamine (3) and 7-methoxy-O-methyllycorenine (4) were both isolated from H. aulicum. Furthermore, we provide here complete NMR spectroscopic data for the homolycorine analogues nerinine (5) and albomaculine (6). The absolute stereochemistry of the 5,10b-ethano bridge in the crinine variants was determined by circular dichroism and X-ray crystallographic analysis, thus presenting the first direct evidence for the presence of crinine-type alkaloids in the genus Hippeastrum. PMID- 24768285 TI - Avenaol, a germination stimulant for root parasitic plants from Avena strigosa. AB - Root exudates from the allelopathic plant, black oat (Avena strigosa Schreb.), were found to contain at least six different germination stimulants for root parasitic plants, but no known strigolactones (SLs). One of these germination stimulants was purified and named avenaol. Its HR-ESI-TOFMS analysis indicated that the molecular formula of avenaol is C20H24O7, and thus it contains an additional carbon compared with known C19-SLs. Its structure was determined as 5 ((E)-(5-(3-hydroxy-1,5,5-trimethyl-2-oxobicyclo[4.1.0]heptan-7-yl)-2 oxodihydrofuran-3(2H)-ylidene)methoxy)-3-methylfuran-2(5H)-one, by 1D and 2D NMR spectroscopy, and ESI- and EI-MS spectrometry. Although avenaol contains the C-D moiety, the common structural feature for all known SLs, it lacks the B ring and has an additional carbon atom between the A and C rings. Avenaol is a potent germination stimulant of Phelipanche ramosa seeds, but only a weak stimulant for seeds of Striga hermonthica and Orobanche minor. PMID- 24768286 TI - The 2013 Arvid Wretlind lecture: evolving concepts in parenteral nutrition. AB - Fifty years after the clinical introduction of total parenteral nutrition (TPN) the Arvid Wretlind lecture is an opportunity to critically analyse the evolution and changes that have marked its development and clinical use. The standard crystalline amino acid solutions, while devoid of side effects, remain incomplete regarding their composition (e.g. glutamine). Lipid emulsions have evolved tremendously and are now included in bi- and tri-compartmental feeding bags enabling a true "total" PN provided daily micronutrients are prescribed. The question of exact individual energy, macro- and micro-nutrient requirements is still unsolved. Many complications attributed to TPN are in fact the consequence of under- or over-feeding: the historical hyperalimentation concept is the main cause, along with the use of fixed weight based predictive equations (incorrect in 70% of the critically ill patients). In the late 80's many complications (hyperglycemia, sepsis, fatty liver, exacerbation of inflammation, mortality) were attributed to TPN leading to its near abandon in favour of enteral nutrition (EN). Enteral feeding, although desirable for many reasons, is difficult causing a worldwide recurrence of malnutrition by insufficient feed delivery. TPN indications have evolved towards its use either alone or in combination with EN: several controversial trials published 2011-13 have investigated TPN timing, an issue which is not yet resolved. The initiation time varies according to the country between admission (Australia and Israel), day 4 (Swiss) and day 7 (Belgium, USA). The most important issue may prove to be and individualized and time dependent prescription of feeding route, energy and substrates. PMID- 24768287 TI - Constructing creationists: French and British narratives and policies in the wake of the resurgence of anti-evolution movements. AB - Creationism is an ambiguous term used in a variety of contexts: political, scientific, religious and educational. This paper attempts to trace the discourse on creationism in two European countries (France and the United Kingdom) and show how different cultural backgrounds shape the construction of its meaning. The striking difference between the total redefinition of the narration on creationism in France after the Harun Yahya's case, and the practically oriented steady development of the discussion in the United Kingdom seems to result from two different political sensitivities, deeply rooted in local cultures. The goal of my paper is doublefold. It attempts to present the emergence of two distinct incommensurable conceptualisations of a social problem and in the same time it tries to answer how to discuss them in a democratic framework. PMID- 24768288 TI - Pulmonary hemorrhage in very-low-birth-weight infants. PMID- 24768289 TI - Prevalence and factors associated with depressive symptoms in mothers with infants or toddlers. AB - BACKGROUND: The objective of this study is to explore the prevalence of and factors associated with depressive symptoms in mothers with young children. METHODS: This is a cross-sectional face-to-face study performed between January 1, 2010 and June 30, 2011. Mothers of premature infants with a gestational age of less than 37 weeks were recruited. Premature infants with any congenital anomaly or severe congenital heart disease were excluded. Controls were mothers of full term infants with birth weight over 2500 g and without admission to a neonatal intensive care unit. Outcome measures included the Center for Epidemiologic Studies Depression Scale for maternal depressive symptoms, the Family Apgar Index for family support, and the Chinese Maudsley Personality Inventory for personality traits. RESULTS: A total of 102 mothers of preterm infants and 111 mothers of full-term infants were recruited. The prevalence of depressive symptoms was 27.7% (59/213) in all mothers of this study, 29.4% (30/102) in mothers of preterm infants, and 26.1% (29/111) in mothers of full-term infants. Predictors of maternal depressive symptoms included the following: extended family structure, lack of postpartum confinement, low family support, and a personality characterized by neuroticism. CONCLUSION: Depressive symptoms were common among mothers of young children. Family function and neurotic personality were highly correlated with depressive symptoms in mothers caring for young children. Pediatric health care providers are suggested to screen for maternal depressive symptoms and provide family-oriented support in Taiwan. PMID- 24768290 TI - Intravenous lidocaine for the emergency department treatment of acute radicular low back pain, a randomized controlled trial. AB - BACKGROUND: Acute radicular back pain is a frequent complaint of patients presenting to the Emergency Department. STUDY OBJECTIVE: Determine the efficacy of intravenous lidocaine when compared to ketorolac for the treatment of acute radicular low back pain. METHODS: Randomized double-blind study of 41 patients aged 18-55 years presenting with acute radicular low back pain. Patients were randomized to receive either 100 mg lidocaine or 30 mg ketorolac intravenously over 2 min. A 100-mm visual analog scale (VAS) was used to assess pain at Time 0 (baseline), and 20, 40, and 60 minutes. Changes in [median] VAS scores were compared over time (within groups) by the signed-rank test and between groups by the rank-sum test. A 5-point Pain Relief Scale (PRS) was administered at the conclusion of the study (60 min) and again at 1 week by telephone follow-up; [median] scores were compared between groups by rank-sum. RESULTS: Forty-four patients were recruited; 41 completed the study (21 lidocaine, 20 ketorolac). Initial VAS scores were not significantly different between the lidocaine and ketorolac groups (83; 95% confidence interval [CI] 74-98 vs. 79; 95% CI 64-94; p = 0.278). Median VAS scores from baseline to 60 min significantly declined in both groups (lidocaine [8; 95% CI 0-23; p = 0.003]; ketorolac [14; 95% CI 0-28; p = 0.007]), with no significant difference in the degree of reduction between groups (p = 0.835). Rescue medication was required by 67% receiving lidocaine, compared to 50% receiving ketorolac. No significant change in PRS between groups was found at the conclusion or at the follow-up. CONCLUSION: Intravenous lidocaine failed to clinically alleviate the pain associated with acute radicular low back pain. PMID- 24768291 TI - Surgeon volume and elective resection for colon cancer: an analysis of outcomes and use of laparoscopy. AB - BACKGROUND: Surgeon volume may be an important predictor of quality and cost outcomes. We evaluated the association between surgeon volume and quality and cost of surgical care in patients with colon cancer. STUDY DESIGN: We performed a retrospective study of patients who underwent resection for colon cancer, using data from the University HealthSystem Consortium from 2008 to 2011. Outcomes evaluated included use of laparoscopy, ICU admission, postoperative complications, length of stay, and total direct hospital costs by surgeon volume. Surgeon volume was categorized according to high (HVS), medium (MVS), and low (LVS) average annual volumes. RESULTS: A total of 17,749 patients were included in this study. The average age of the cohort was 65 years and 51% of patients were female. After adjustment for potential confounders, compared with LVS, HVS and MVS were more likely to use laparoscopy (HVS, odds ratio [OR] 1.27, 95% CI 1.15, 1.39; MVS, OR 1.16 95% CI 1.65, 1.26). Postoperative complications were significantly lower in patients operated on by HVS than LVS (OR 0.77 95% CI 0.76, 0.91). The HVS patients were less likely to require reoperation than those in the LVS group (OR 0.70, 95% CI 0.53, 0.92) Total direct costs were $927 (95% CI $1,567 to -$287) lower in the HVS group compared with the LVS group. CONCLUSIONS: Higher quality, lower cost care was achieved by HVS in patients undergoing surgery for colon cancer. An assessment of differences in processes of care by surgeon volume may help further define the mechanism for this observed association. PMID- 24768292 TI - Efficacy and safety of phenylephrine in the management of low systolic blood pressure after renal transplantation. AB - BACKGROUND: Phenylephrine can be used to treat postoperative hypotension after renal transplantation. However, its effect on the renal allograft is unknown. We evaluated the safety and efficacy of this approach. STUDY DESIGN: A retrospective cohort study of 307 renal transplant recipients between November 2005 and October 2011 was conducted, including 75 who required phenylephrine, 46 of whom were deceased donors renal transplant (DDRT) recipients and 29 who were living donor transplant (LDRT) recipients. These were compared with 75 controls matched by sex, age, type of transplant, and etiology of renal failure. The primary outcome was rate of delayed graft function (DGF). The following statistical tools were used: paired t-test for continuous data, McNemar's test for categorical data, and a nonlinear mixed decay model for change in serum creatinine (Cr). RESULTS: Of 46 DDRT recipients who required phenylephrine, 17 developed DGF compared with 10 matched controls (relative risk [RR] 2.9, CI 1.4 to 6.0, p = 0.0040). Only one LDRT recipient required hemodialysis (DGF). No differences were noted in the number of hemodialysis treatments required (mean 2.7 in treatment group vs 3.4 in control). No significant differences were observed between phenylephrine and control groups in renal function on postoperative days 30, 90, and 365 Cr or graft survival. The immediate postoperative normalization of Cr was slower in the DDRT phenylephrine group compared with DDRT controls (p < 0.0001), but no difference in Cr was noted before discharge (p = 0.49). CONCLUSIONS: Although there is a brief association between phenylephrine administration and a slower rate of transplanted kidney recovery, there is no clinically or statistically significant impaired outcome in the phenylephrine group at time of discharge. Administration of phenylephrine to support low blood pressure after renal transplant appears safe. PMID- 24768293 TI - Reducing postoperative venous thromboembolism complications with a standardized risk-stratified prophylaxis protocol and mobilization program. AB - BACKGROUND: Data revealed that our urban, academic, safety net medical center was a high outlier for postoperative venous thromboembolism (VTE). Our goal was to implement and determine the efficacy of a standardized intervention for reducing postoperative VTE complications. STUDY DESIGN: We developed a strategy to decrease VTE complications, based on standardized electronic physician orders that specify early postoperative mobilization and mandatory VTE risk stratification for every patient, using the "Caprini" grading system. The derived scores dictate the nature and duration of VTE prophylaxis, including on an outpatient basis. Electronic reminders about appropriate VTE prophylaxis are automatically generated before and after operations, and on discharge. Both mechanical (pneumatic compression boots) and pharmacologic prophylaxis (unfractionated or low molecular weight heparin) are used, as indicated by risk level. We conducted a before-and-after trial, comparing National Surgical Quality Improvement Program (NSQIP) VTE outcomes (deep vein thromboses and pulmonary emboli) before and after implementing the standardized risk-stratified protocol combined with a postoperative mobilization program. Measured outcomes included NSQIP-reported raw and risk-adjusted VTE outcomes during 2 years before and after implementing the VTE prevention program. RESULTS: The incidence of deep venous thromboses decreased by 84%, from 1.9% to 0.3% (p < 0.01), with implementation of VTE prevention efforts; the pulmonary emboli incidence fell by 55%, from 1.1% to 0.5% (p < 0.01). Risk-adjusted VTE outcomes steadily declined from an odds ratio of 3.41 to 0.94 (p < 0.05). CONCLUSIONS: A patient care program, emphasizing early postoperative mobilization along with mandatory VTE risk stratification and commensurate electronic prophylaxis recommendations, significantly reduced the likelihood of VTE complications among our patients. PMID- 24768295 TI - A new human IgG avidity test, using mixtures of recombinant antigens (rROP1, rSAG2, rGRA6), for the diagnosis of difficult-to-identify phases of toxoplasmosis. AB - The preliminary diagnostic utility of two mixtures of Toxoplasma gondii recombinant antigens (rROP1+rSAG2 and rROP1+rGRA6) in IgG ELISA and IgG avidity test has been evaluated. A total of 173 serum samples from patients with toxoplasmosis and seronegative people were examined. The sensitivity of IgG ELISA for rROP1+rSAG2 and rROP1+rGRA6 was 91.1% and 76.7%, respectively, while the reactivity for sera from patients where acute toxoplasmosis was suspected was higher, at 100% and 95.4%, respectively, than for people with chronic infection, at 88.2% and 70.6%. In this study a different trend in avidity maturation of IgG antibodies for two mixtures of proteins in comparison with native antigen was observed. The results suggest that a new IgG avidity test using the mixtures of recombinant antigens may be useful for the diagnosis of difficult-to-identify phases of toxoplasmosis. For this reason, selected mixtures after the additional tests on groups of sera with well-defined dates of infection could be used as a better alternative to the native antigens of the parasite in the serodiagnosis of human T. gondii infection. PMID- 24768294 TI - Clinical utility of Aspergillus galactomannan and PCR in bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in patients with haematological malignancies. AB - Interpretation of Aspergillus galactomannan (GM) and PCR results in bronchoalveolar lavage (BAL) fluid for the diagnosis of invasive pulmonary aspergillosis (IPA) in patients with haematological malignancies requires clarification. A total of 116 patients underwent BAL for investigation of new lung infiltrates: 40% were neutropenic, 68% and 36% were receiving mould-active antifungal agents and beta-lactam antibiotics. The diagnosis of proven IPA (n = 3), probable IPA (n = 15), and possible invasive fungal disease (IFD, n = 50) was made without inclusion of GM results. BAL GM (at cut-off of 0.8) had lower diagnostic sensitivity for IPA than PCR (61% versus 78%) but higher specificity (93% versus 79%). Both tests had excellent negative predictive values (85-90%), supporting their utility in excluding IPA. The use of BAL GM and PCR results increased the certainty of Aspergillus aetiology in 7 probable IPA cases where fungal hyphae were detected in respiratory samples by microscopy, and upgraded 24 patients from possible IFD to probable IPA. Use of BAL GM and PCR improves the diagnosis of IPA. PMID- 24768296 TI - First case of nontuberculous mycobacterial lung disease caused by Mycobacterium marseillense in a patient with systemic lupus erythematosus. AB - Mycobacterium marseillense was designated as a new species within Mycobacterium avium complex. We report the first case of M. marseillense lung disease in a patient with systemic lupus erythematosus. All serial isolates were identified as M. marseillense by multilocus sequence analysis, based on hsp65, 16S-23S rRNA internal transcribed spacer, and 16S rRNA fragments. PMID- 24768297 TI - PTENalpha, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism. AB - PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTENalpha, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTENalpha is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENalpha translation, which requires a CUG-centered palindromic motif. We show that PTENalpha induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENalpha impairs mitochondrial respiratory chain function. PTENalpha interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes. PMID- 24768299 TI - Learning precisely timed spikes. AB - To signal the onset of salient sensory features or execute well-timed motor sequences, neuronal circuits must transform streams of incoming spike trains into precisely timed firing. To address the efficiency and fidelity with which neurons can perform such computations, we developed a theory to characterize the capacity of feedforward networks to generate desired spike sequences. We find the maximum number of desired output spikes a neuron can implement to be 0.1-0.3 per synapse. We further present a biologically plausible learning rule that allows feedforward and recurrent networks to learn multiple mappings between inputs and desired spike sequences. We apply this framework to reconstruct synaptic weights from spiking activity and study the precision with which the temporal structure of ongoing behavior can be inferred from the spiking of premotor neurons. This work provides a powerful approach for characterizing the computational and learning capacities of single neurons and neuronal circuits. PMID- 24768298 TI - Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4. AB - Obesity promotes systemic insulin resistance through inflammatory changes that lead to the release of cytokines from activated macrophages. Although the mechanism is unclear, the second messenger cAMP has been found to attenuate macrophage activity in response to a variety of hormonal signals. We show that, in the setting of acute overnutrition, leptin triggers catecholamine-dependent increases in cAMP signaling that reduce inflammatory gene expression via the activation of the histone deacetylase HDAC4. cAMP stimulates HDAC4 activity through the PKA-dependent inhibition of the salt-inducible kinases (SIKs), which otherwise phosphorylate and sequester HDAC4 in the cytoplasm. Following its dephosphorylation, HDAC4 shuttles to the nucleus where it inhibits NF-kappaB activity over proinflammatory genes. As variants in the Hdac4 gene are associated with obesity in humans, our results indicate that the cAMP-HDAC4 pathway functions importantly in maintaining insulin sensitivity and energy balance via its effects on the innate immune system. PMID- 24768300 TI - Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus >midbrain pathway for feeding behavior. AB - Brain function is mediated by neural circuit connectivity, and elucidating the role of connections is aided by techniques to block their output. We developed cell-type-selective, reversible synaptic inhibition tools for mammalian neural circuits by leveraging G protein signaling pathways to suppress synaptic vesicle release. Here, we find that the pharmacologically selective designer Gi-protein coupled receptor hM4D is a presynaptic silencer in the presence of its cognate ligand clozapine-N-oxide (CNO). Activation of hM4D signaling sharply reduced synaptic release probability and synaptic current amplitude. To demonstrate the utility of this tool for neural circuit perturbations, we developed an axon selective hM4D-neurexin variant and used spatially targeted intracranial CNO injections to localize circuit connections from the hypothalamus to the midbrain responsible for feeding behavior. This synaptic silencing approach is broadly applicable for cell-type-specific and axon projection-selective functional analysis of diverse neural circuits. PMID- 24768302 TI - Blood transfusion in patients having caesarean section: a prospective multicentre observational study of practice in three Pakistan hospitals. AB - BACKGROUND: Increasing awareness of the risks of blood transfusion has prompted examination of red cell transfusion practice in obstetrics. A six-month prospective observational study was performed to examine blood transfusion practices in patients undergoing caesarean delivery at three hospitals in Pakistan. METHODS: In the three hospitals (two private, one public) 3438 caesarean deliveries were performed in the study period. Data were collected on patient demographics, indications for transfusion, ordering physicians, consent, associations with obstetric factors, estimated allowable blood loss, calculated blood loss, pre- and post-transfusion haemoglobin and discharge haemoglobin. RESULTS: A total number of 397 (11.5%) patients who underwent caesarean section received a blood transfusion. The highest transfusion rate of 16% was recorded in the public tertiary care hospital compared to 5% in the two private hospitals. Emergency caesarean delivery and multiparity were associated with blood transfusion (P<0.05). More emergency caesarean sections were performed in the public compared to the private hospitals (85.4% vs. 41.6%). More multiparous patients underwent caesarean section in the public hospital (57.8% vs. 40.4%). Attending physicians took the decision for transfusion in 98% of cases. In 343 (86%) patients, blood transfusion was given even when the haemoglobin was >7g/dL. The method for documenting the indication or consent for transfusion was not found in any of the three hospitals. CONCLUSION: Blood transfusion was prescribed more readily in the public hospital. Identification of a transfusion trigger and the development of institutional guidelines to reduce unnecessary transfusion are required. PMID- 24768301 TI - Utility of a low-cost wireless force platform as a potential clinical test of balance recovery after neuraxial anaesthesia. AB - INTRODUCTION: Recovery of balance after neuraxial anaesthesia can remain delayed after simple clinical tests have demonstrated motor recovery. Dynamic posturography tracks the small movements or sway of a person standing as still as possible on a force platform and has been investigated as an objective measure of the ability to walk following anaesthesia. These are expensive laboratory devices, limiting their clinical utility. One measured variable is path length, the cumulative distance travelled in the horizontal plane by the centre of pressure of a person standing on the platform over 1min. Path length might potentially be measured using the Nintendo(r) Wii-Fit Balance BoardTM. METHODS: The feasibility of intercepting raw wireless data from a Wii-Fit Balance BoardTM using custom software to calculate path length was explored. Subsequently, path lengths were measured using both this and a laboratory platform simultaneously. In a random order 20 volunteers (a) stood for 1min, feet together, eyes open (conventional baseline test); and (b) stood for 1min, feet together, eyes closed (simulating residual anaesthesia with increased sway). For each device, the ratio b:a was calculated as an index of performance reduction when eyes were closed. RESULTS: Path lengths ranged from 58.5 to 243cm, mean bias 9cm (Wii Fitlaboratory platform) and 95% confidence limits of 0.04 to -0.13. CONCLUSIONS: The path lengths were in close agreement and the Wii-Fit Balance BoardTM may be worthy of further investigation as a tool to objectively assess readiness to ambulate following neuraxial anaesthesia. PMID- 24768303 TI - Ultrasound-guided spinal anaesthesia in obstetrics: is there an advantage over the landmark technique in patients with easily palpable spines? AB - BACKGROUND: Data are scarce on the advantage of ultrasound-guided spinal anaesthesia in patients with easily identifiable bony landmarks. In this study, we compared the use of ultrasound to the landmark method in patients with no anticipated technical difficulty, presenting for caesarean delivery under spinal anaesthesia. METHODS: A total of 150 pregnant women were recruited in this randomized, controlled study. Ultrasound examination and spinal anaesthesia were performed by three anaesthetists with experience in ultrasound-guided neuraxial block. Patients were randomized to either the Ultrasound Group (n=75) or the Landmark Group (n=75). In both groups the level of L3-4 or L4-5 was identified by ultrasound (transverse and longitudinal approach) or palpation. The primary outcome was the procedure time, measured from the time of skin puncture by the introducer to the time of viewing cerebrospinal fluid at the hub of the spinal needle. Secondary outcomes were the number of skin punctures, number of passes, and incidence of successful spinal blockade. RESULTS: The average procedure time, number of skin punctures and needle passes, were similar in both groups. The number of patients with successful spinal anaesthesia after one puncture was not statistically different between the groups. CONCLUSION: The present results indicate that when performed by anaesthetists experienced in both ultrasound and landmark techniques, the use of ultrasound does not appear to increase the success rate of spinal anaesthesia, or reduce the procedure time or number of attempts in obstetric patients with easily palpable spines. PMID- 24768304 TI - Achondroplasia: anaesthetic challenges for caesarean section. AB - Pregnancy in women with achondroplasia presents major challenges for anaesthetists and obstetricians. We report the case of a woman with achondroplasia who underwent general anaesthesia for an elective caesarean section. She was 99cm in height and her condition was further complicated by severe kyphoscoliosis and previous back surgery. She was reviewed in the first trimester at the anaesthetic high-risk clinic. A multidisciplinary team was convened to plan her peripartum care. Because of increasing dyspnoea caesarean section was performed at 32weeks of gestation. She received a general anaesthetic using a modified rapid-sequence technique with remifentanil and rocuronium. The intraoperative period was complicated by desaturation and high airway pressures. The woman's postoperative care was complicated by respiratory compromise requiring high dependency care. PMID- 24768305 TI - Lawsuits against Mirena(r): potential impact on public health. PMID- 24768306 TI - Validating fragment-based drug discovery for biological RNAs: lead fragments bind and remodel the TPP riboswitch specifically. AB - Thiamine pyrophosphate (TPP) riboswitches regulate essential genes in bacteria by changing conformation upon binding intracellular TPP. Previous studies using fragment-based approaches identified small molecule "fragments" that bind this gene-regulatory mRNA domain. Crystallographic studies now show that, despite having micromolar Kds, four different fragments bind the TPP riboswitch site specifically, occupying the pocket that recognizes the aminopyrimidine of TPP. Unexpectedly, the unoccupied site that would recognize the pyrophosphate of TPP rearranges into a structure distinct from that of the cognate complex. This idiosyncratic fragment-induced conformation, also characterized by small-angle X ray scattering and chemical probing, represents a possible mechanism for adventitious ligand discrimination by the riboswitch, and suggests that off pathway conformations of RNAs can be targeted for drug development. Our structures, together with previous screening studies, demonstrate the feasibility of fragment-based drug discovery against RNA targets. PMID- 24768307 TI - Synthetic inositol phosphate analogs reveal that PPIP5K2 has a surface-mounted substrate capture site that is a target for drug discovery. AB - Diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) is one of the mammalian PPIP5K isoforms responsible for synthesis of diphosphoinositol polyphosphates (inositol pyrophosphates; PP-InsPs), regulatory molecules that function at the interface of cell signaling and organismic homeostasis. The development of drugs that inhibit PPIP5K2 could have both experimental and therapeutic applications. Here, we describe a synthetic strategy for producing naturally occurring 5-PP InsP4, as well as several inositol polyphosphate analogs, and we study their interactions with PPIP5K2 using biochemical and structural approaches. These experiments uncover an additional ligand-binding site on the surface of PPIP5K2, adjacent to the catalytic pocket. This site facilitates substrate capture from the bulk phase, prior to transfer into the catalytic pocket. In addition to demonstrating a "catch-and-pass" reaction mechanism in a small molecule kinase, we demonstrate that binding of our analogs to the substrate capture site inhibits PPIP5K2. This work suggests that the substrate-binding site offers new opportunities for targeted drug design. PMID- 24768308 TI - Genome mining reveals a minimum gene set for the biosynthesis of 32-membered macrocyclic thiopeptides lactazoles. AB - Although >100 thiopeptides have been discovered, the number of validated gene clusters involved in their biosynthesis is lagging. We use genome mining to identify a silent thiopeptide biosynthetic gene cluster responsible for biosynthesis of lactazoles. Lactazoles are structurally unique thiopeptides with a 32-membered macrocycle and a 2-oxazolyl-6-thiazolyl pyridine core. We demonstrate that lactazoles originate from the simplest cluster, containing only six unidirectional genes (lazA to lazF). We show that lazC is involved in the macrocyclization process, leading to central pyridine moiety formation. Substitution of the endogenous promoter with a strong promoter results in an approximately 30-fold increase in lactazole A production and mutagenesis of lazC precursor gene in production of two analogs. Lactazoles do not exhibit antimicrobial activity but may modulate signaling cascades triggered by bone morphogenetic protein. Our approach facilitates the production of a more diverse set of thiopeptide structures, increasing the semisynthetic repertoire for use in drug development. PMID- 24768309 TI - Susac's syndrome during pregnancy - the first Croatian case. AB - Susac's syndrome (SS) is an infrequent neurological disorder characterized by the clinical triad of encephalopathy, branch retinal artery occlusion and hearing loss due to an autoimmune endotheliopathy associated with anti-endothelial cell antibodies. At the onset of the disease SS rarely appears with the complete clinical triad. The most important diagnostic procedures involved in the diagnosis of SS are brain MRI, audiometric testing and retinal fluorescein angiography. Presence of at least two components of the SS clinical triad accompanied by specific brain MRI findings is highly suggestive of SS. We report a case of a young pregnant woman with a history of encephalopathy, hearing loss and walking impairment. Brain MRI revealed a spectrum of findings previously described in patients with SS. We induced labor at 37 weeks' gestation to start with immunosuppressive treatment and avoid possible fetal toxicity. To the best of our knowledge this is the first report of SS in Croatia. PMID- 24768310 TI - Hand dexterity and direct disease related cost in multiple sclerosis. AB - METHODS: The nine hole peg test (9HPT) is an emerging outcome measure in clinical trials in multiple sclerosis (MS). In this study we investigated how performance on the 9HPT at baseline is related to annualized direct MS related cost. METHODS: We enrolled patients with a definite diagnosis of MS from two Canadian MS centers. 9HPT and demographic information were recorded at baseline, and patients prospectively recorded all MS related costs for 6months. Costs were compared among five groups according to the baseline 9HPT, and we built a multiple linear regression model including cost (dependent variable) and 9HPT at baseline, age, disease duration, sex and disease course (independent predictor variables). RESULTS: We analyzed data from 298 patients. Cost significantly increased with increasing 9HPT scores (p<0.0001), with the costs for health care providers, changes to the home or car and long-term care dominating in the most disabled patient groups. The 9HPT score was a significant predictor of cost in the regression model (p=0.006). CONCLUSION: Performance on the 9HPT is closely related to cost. Our data add another aspect of patient relevance to using the 9HPT as an outcome measure in clinical trials. PMID- 24768311 TI - Resolution of unilateral obstructive hydrocephalus complicating expanding thrombosed basilar apex aneurysm after anticoagulation treatment. PMID- 24768312 TI - Four novel connexin 32 mutations in X-linked Charcot-Marie-Tooth disease. Phenotypic variability and central nervous system involvement. AB - Charcot-Marie-Tooth (CMT) disease, the most common hereditary neuropathy, is clinically and genetically heterogeneous. X-linked CMT (CMTX) is usually caused by mutations in the gap junction protein b 1 gene (GJB1) coding for connexin 32 (Cx32). The clinical manifestations of CMTX are characterized by significant variability, with some patients exhibiting central nervous system (CNS) involvement. We report four novel mutations in GJB1, c.191G>A (p.Cys64Tyr), c.508G>T (p.Val170Phe), c.778A>G (p.Lys260Glu) and c.300C>G (p.His100Gln) identified in four unrelated Greek families. These mutations were characterized by variable phenotypic expression, including a family with the Roussy-Levy syndrome, and three of them were associated with mild clinical CNS manifestations. PMID- 24768313 TI - Bickerstaff encephalitis and atypical features - Bickerstaff's papers revisited. PMID- 24768315 TI - The diagnosis and management of a case of leishmaniosis in a dog imported to Australia. AB - This case study discusses in detail for the first time the diagnosis and management of a case of leishmaniosis in a dog imported to Australia. The dog presented with epistaxis and a non-regenerative anaemia five years after being imported from Europe. Protozoa were identified within macrophages in bone marrow and splenic cytology. A Leishmania indirect fluorescent antibody test was performed and was positive while an Ehrlichia canis antibody test was negative. Polymerase chain reaction of the ITS-1 and ITS-2 regions of skin, lymph node, spleen and bone marrow were all positive for Leishmania infantum. The dog was treated with amphotericin B with a strong clinical response. The importance of thorough diagnostics in non-endemic areas, particularly Australia, is discussed. Treatment with amphotericin B is discussed. Vigilance, disease reporting and response frameworks are recommended for non-endemic areas. PMID- 24768314 TI - Tractography reveals diffuse white matter abnormalities in Myotonic Dystrophy Type 1. AB - Cerebral involvement in Myotonic Dystrophy Type 1 (DM1) is well-established but not well characterized. This study applied new Diffusion Tensor Imaging (DTI) tractography to characterize white matter disturbance in adults with DM1. Forty five participants with DM1 and 44 control participants had MRIs on a Siemens 3T TIM Trio scanner. Data were processed with TRActs Constrained by UnderLying Anatomy (TRACULA) and 7 tracts were evaluated. Bilateral disturbances in white matter integrity were seen in all tracts in participants with DM1 compared to controls. There were no right-left hemisphere differences. The resulting DTI metrics were correlated with cognitive functioning, particularly working memory and processing speed. Motor speed was not significantly correlated with white matter microstructural integrity and, thus, was not the core explanation for the working memory and processing speed findings. White matter integrity was correlated with important clinical variables including the muscular impairment rating scale (MIRS). CTG repeat length was moderately associated with white matter status in corticospinal tract and cingulum. Sleepiness (Epworth Sleepiness Scale) was moderately associated with white matter status in the superior longitudinal fasciculus and cingulum. Overall, the results add to an emerging literature showing widespread white matter disturbances in both early-onset and adult-onset DM1. Results suggest that further investigation of white matter pathology is warranted in DM1 and that non-invasive measures such as DTI have a potentially important clinical value in characterizing the status of individuals with DM1. PMID- 24768316 TI - Occurrence and molecular characterization of Cryptosporidium spp. in yaks (Bos grunniens) in China. AB - Compared with dairy and beef cattle, few data are available on the occurrence and distribution of Cryptosporidium species in yaks, which live in a very different habitat. In this study, 327 fecal specimens were collected from yaks in 4 counties in Qinghai Province of China and screened for Cryptosporidium by nested PCR analysis of the 18S rRNA gene. A total of 98 (30.0%) specimens were positive for Cryptosporidium. The occurrence of Cryptosporidium varied significantly among age groups; infection rates were 49.3% in weaned calves, 31.7% in yearlings, and 17.4% in adults. PCR products of all Cryptosporidium-positive specimens were successfully sequenced, with 56 specimens (57.1%) having C. bovis, 33 (33.7%) having C. ryanae, 2 (2.0%) having C. andersoni, 1 (1.0%) having C. ubiquitum, 1 (1.0%) having C. xiaoi, 2 (2.0%) having a novel genotype, and 3 (3.1%) having mixed infections of C. bovis and C. ryanae. There were some age-related differences in the distribution of Cryptosporidium species in post-weaned yaks examined. To our knowledge, this is the first report of C. andersoni, C. ubiquitum, C. xiaoi and a novel Cryptosporidium genotype in yaks. PMID- 24768318 TI - Disabled women's maternal and newborn health care in rural Nepal: a qualitative study. AB - OBJECTIVE: there is little evidence about disabled women's access to maternal and newborn health services in low-income countries and few studies consult disabled women themselves to understand their experience of care and care seeking. Our study explores disabled women's experiences of maternal and newborn care in rural Nepal. DESIGN: we used a qualitative methodology, using semi-structured interviews. SETTING: rural Makwanpur District of central Nepal. PARTICIPANTS: we purposively sampled married women with different impairments who had delivered a baby in the past 10 years from different topographical areas of the district. We also interviewed maternal health workers. We compared our findings with a recent qualitative study of non-disabled women in the same district to explore the differences between disabled and non-disabled women. FINDINGS: married disabled women considered pregnancy and childbirth to be normal and preferred to deliver at home. Issues of quality, cost and lack of family support were as pertinent for disabled women as they were for their non-disabled peers. Health workers felt unprepared to meet the maternal health needs of disabled women. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: integration of disability into existing Skilled Birth Attendant training curricula may improve maternal health care for disabled women. There is a need to monitor progress of interventions that encourage institutional delivery through the use of disaggregated data, to check that disabled women are benefiting equally in efforts to improve access to maternal health care. PMID- 24768317 TI - First survey of endoparasites in pet ferrets in Italy. AB - Endoparasites are infrequently reported in ferrets. A cross-sectional survey was conducted to determine the prevalence of intestinal parasites in pet ferrets in southern Italy. Fresh fecal samples were randomly collected from 50 ferrets housed in pet shops or privately owned. All fecal samples were processed using the FLOTAC pellet technique to identify and count helminthic eggs/larvae and protozoan cysts/oocysts. In addition, the samples were analyzed also by the Remel XpectGiardia/Cryptosporidium immunoassay. Intestinal parasites were detected in 15 out of 50 ferrets (30%). Eggs of ancylostomids were found in 28.0% (14/50) of the animals and oocysts of Sarcocystis were detected in one ferret (2.0%). None of the samples was positive for Cryptosporidium or Giardia. To the authors' knowledge, this is the first report of sarcosporidiosis in a pet ferret in Italy. PMID- 24768319 TI - The PGE2-EP2-mast cell axis: an antiasthma mechanism. AB - Despite the fact that cyclooxygenase and its products, prostaglandins, have been traditionally associated with the development of inflammation, PGE2 was implicated early on as potentially beneficial in asthma. During the 1970s and 1980s, several studies reported the bronchodilator effect of PGE2 in asthma patients. In parallel, it was being shown to exert an inhibitory effect on mast cells in vitro. In spite of this, data supporting the beneficial role for PGE2 in asthma were scarce and sometimes controversial. Many years later, in vitro and in vivo studies suggested a range of biological activities attributable to PGE2, others than the ability to relax smooth muscle, that potentially explained some of the observed positive effects in asthma. The identification and cloning of the four PGE2 receptors made available new tools with which to fine-tune investigation of the anti-inflammatory, pro-inflammatory, immunoregulatory, and bronchodilation mechanisms of PGE2. Among these, several suggested involvement of mast cells, a cell population known to play a fundamental role in acute and chronic asthma. Indeed, it has been shown that PGE2 prevents human and murine MC activity in vitro through activation of the EP2 receptor, and also that both exogenously administered and endogenous PGE2 inhibit airway MC activity in vivo in mouse models of asthma (likely through an EP2-mediated mechanism as well). In the last few years, we have furthered into the functional connection between PGE2 induced mast cells inhibition and attenuated damage, in asthma and allergy models. The validity of the findings supporting a beneficial effect of PGE2 in different asthma phases, the direct effect of PGE2 on mast cells populations, and the functional implications of the PGE2-MC interaction on airway function are some of the topics addressed in this review, under the assumption that increased understanding of the PGE2-EP2-mast cell axis will likely lead to the discovery of novel antiasthma targets. PMID- 24768320 TI - Molecular basis of mast cell disease. AB - Mastocytosis is an incurable and sometimes fatal haematological disorder grossly described as the accumulation of abnormal mast cells in the bone marrow and other organs causing tissue and organ damage. The clinical manifestations of this disease are extremely variable; disease phenotypes range from indolent to aggressive, and often present with associated non-mast cell haematological disorders (AHNMD), mainly myeloproliferative neoplasm and myelodysplastic syndromes. Recent efforts to genetically dissect the mechanisms that define aggressive and non-aggressive mastocytosis have generated a list of recurrent somatic mutations in mastocytosis patients that are associated with and may predict the evolution towards aggressive disease phenotypes. Here we review these mutations and discuss the molecular mechanisms associated with these mutations in an effort to better understand the biology of this disease and to predict its onset and evolution, with the ultimate goal of devising new and improved treatment strategies. PMID- 24768321 TI - DptR2, a DeoR-type auto-regulator, is required for daptomycin production in Streptomyces roseosporus. AB - Daptomycin, a novel cyclic lipopeptide antibiotic against Gram-positive bacteria, is produced by Streptomyces roseosporus. Though its biosynthetic mechanism, structural shuffling and fermentation optimization have been extensively studied, little is understood about its production regulation at the transcriptional levels. Here we reported that dptR2, encoding a DeoR-type regulator located close to the daptomycin biosynthesis gene cluster in S. roseosporus SW0702, is required for daptomycin production, but not for the expression of daptomycin gene cluster, suggesting that DptR2 was not a pathway-specific regulator. Furthermore, EMSA and qRT-PCR analysis suggested that DptR2 was positively auto-regulated by binding to its own promoter. Meanwhile, the binding sites on the dptR2 promoter were determined by a DNase I footprinting assay, and the essentiality of the inverted complementary sequences in the protected region for DptR2 binding was assessed. Our results for the first time reported the regulation of daptomycin production at the transcriptional level in S. roseosporus. PMID- 24768322 TI - Herpes simplex virus encephalitis: clinical manifestations, diagnosis and outcome in 106 adult patients. AB - BACKGROUND: Herpes simplex virus (HSV) is one of the most common causes of sporadic encephalitis worldwide. OBJECTIVE: We aimed to determine clinical characteristics and prognosis of HSV encephalitis (HSVE) cases reviewed retrospectively from several collaborating centers. STUDY DESIGN: We searched hospital archives of the last 10 years for patients with HSVE diagnosis, i.e. clinical presentation compatible with encephalitis and brain involvement on magnetic resonance imaging (MRI) and/or detection of HSV DNA in the cerebrospinal fluid by polymerase chain reaction (PCR). Clinical characteristics were noted and patients were phone-interviewed. HSVE cases were grouped and analyzed as proven and probable, based on virological confirmation by PCR. Univariate and multivariate analyses were used to determine factors associated with prognosis. RESULTS: A total of 106 patients (63 males and 43 females; mean age, 44 years; range, 18-83 years) were included. Most common symptoms were changes in mental status, fever, headache, and seizure. HSV PCR was positive in 69% of patients tested, while brain involvement was detected on MRI in 95%. Acyclovir was started mostly within five days of main symptom and continued for >=14 days. Case fatality rate was 8%, while 69% of patients recovered with sequelae. Favorable prognosis was observed in 73% of patients. Multivariate analysis identified the duration of disease before hospital admission (odds ratio (OR)=1.24) and the extent of brain involvement on MRI at the time of admission (OR=37.22) as two independent risk factors associated with poor prognosis. CONCLUSIONS: Although HSVE fatality regressed considerably with acyclovir treatment, many patients survive with sequelae. Our results emphasize the importance of early diagnosis and prompt treatment of HSVE. PMID- 24768323 TI - Influenza-like illness after yellow fever vaccination. PMID- 24768324 TI - Cytotoxic dimeric quinolone-terpene alkaloids from the root bark of Zanthoxylum rhetsa. AB - Four quinolone-terpene alkaloids, chelerybulgarine (1), 2'-episimulanoquinoline (3), 2,11-didemethoxyvepridimerine B (4), and rhetsidimerine (5) were isolated from the root bark of Zanthoxylum rhetsa DC. Chelerybulgarine (1) is a C-C linked terpene alkaloid where the C-6 of dihydrochelerythrine is linked to C-11 of the sesquiterpenoid 10beta-methoxybulgarene. 2'-Episimulanoquinoline is a dimeric alkaloid containing dihydrochelerythrine and 8-methoxy-N-methylflindersine moieties, whereas 2,11-didemethoxyvepridimerine B and rhetsidimerine are dimeric prenylated quinolone alkaloids. Seven of the isolated compounds exhibited weak cytotoxicity when tested against a panel of six human stomach-cancer cell lines. PMID- 24768325 TI - SUPERA interwoven nitinol Stent Outcomes in Above-Knee IntErventions (SAKE) study. AB - PURPOSE: To report experience with the novel interwoven-wire self-expanding nitinol SUPERA stent (IDEV Technologies, Inc/Abbott Laboratories, Inc, Webster, Texas) for the treatment of severely diseased superficial femoral and popliteal arteries. MATERIALS AND METHODS: Consecutive patients with severely diseased superficial femoral and popliteal arteries who received SUPERA stents (n = 80 patients [98 limbs]; mean age, 70.8 y; 80% male) were retrospectively identified. Patients were followed for an average of 14.3 months after intervention. RESULTS: Total occlusions were present in 39% of the lesions, 21% had tissue loss, and 61% demonstrated calcification on fluoroscopy. Patients were prescribed dual antiplatelet therapy (aspirin and clopidogrel) for at least 30 days unless contraindicated, followed by aspirin alone indefinitely. The mean (+/- SD) lesion length was 143 mm (+/- 98). Based on need for clinical intervention, primary patency was 96.9% at 6 months and 85.8% at 12 months (Kaplan-Meier estimates). Assisted primary patency and secondary patency rates at 12 months were 96.8% and 100%, respectively. Ankle-brachial index increased from 0.60 at baseline to 0.83 at last follow-up (P < .001). No stent fractures were found by fluoroscopy inspection in 19 limbs (16 patients) that required reintervention. CONCLUSIONS: Based on experience with multiple operators at a single clinical center, the interwoven nitinol stent design provides a viable option for high-grade obstructive disease in the femoropopliteal artery. PMID- 24768326 TI - Technical details and clinical outcomes of transpopliteal venous stent placement for postthrombotic chronic total occlusion of the iliofemoral vein. AB - PURPOSE: To evaluate the technical aspects and early clinical results of stent placement for managing postthrombotic chronic total occlusion (CTO) of the iliofemoral vein through ipsilateral popliteal access. MATERIALS AND METHODS: A retrospective analysis of 110 patients (44 men; mean age, 51 y; 118 limbs; 102 left limbs) with postthrombotic CTO of the iliofemoral vein treated with stent placement in a single institution from January 2007-December 2011 was conducted. All occlusions were initially accessed via ipsilateral popliteal veins under the guidance of venography or ultrasonography. Technical aspects, quality of life, stent patency, and Villalta scores were recorded at follow-up evaluation. Risk factors of in-stent restenosis and early in-stent thrombosis were evaluated using Cox proportional hazards regression model. RESULTS: Percutaneous recanalization was successful in 112 of 118 limbs (95%). The mean duration of the procedure was 43 minutes (range, 10-120 min). The quality of life and Villalta scores were significantly improved (P < .01). The 3-year primary, assisted primary, and secondary cumulative stent patency rates were 70%, 90%, and 94%. During a median follow-up period of 25 months (range, 1-52 mo), the relief rates of severe leg pain (visual analog scale > 5) and severe leg swelling (grade 3) were 72% (49 of 68) and 70% (64 of 91), respectively, and the healing of ulcers was successful in 78% (36 of 46) of the cases. After stent placement, the limbs with visible remaining collateral circulation had a higher rate of early in-stent thrombosis (22.5% vs 6.1%; P = .007). The patients with long stents extending below the inguinal ligament had a higher rate of in-stent restenosis (hazard ratio = 1.77 6.5; P = .0146). CONCLUSIONS: Transpopliteal venous stent placement is an effective, safe, and feasible method of managing postthrombotic CTO of the iliofemoral vein. The stent extending below the inguinal ligament is the major risk factor of in-stent restenosis. The visible remaining collateral circulation after stent placement may indicate persistent hemodynamically significant stenosis. PMID- 24768328 TI - Rapid chondrolysis following an unoperated lateral meniscus tear in a young professional rugby player. AB - Rapid chondrolysis following a lateral meniscectomy is a rare complication. We present the first reported case of rapid chondrolysis of the lateral compartment, which developed 6 months after a meniscus tear that was not surgically treated in a young 18-year-old professional rugby player. The possible hypotheses to explain this complication are presented, and certain previously published causes were excluded (iatrogenic during surgery, undiagnosed increased rotatory instability, chondrotoxicity of bupivacaine). Overloading of the cartilage surface of the lateral compartment from meniscal extrusion can cause cartilage necrosis. PMID- 24768327 TI - Recall rate of screening ultrasound with automated breast volumetric scanning (ABVS) in women with dense breasts: a first quarter experience. AB - PURPOSE: The aim of this study was to determine the recall rate of screening ultrasound with automated breast volumetric scanning (ABVS) in women with dense breasts (BI-RADS density classification 3 or 4 on mammogram). MATERIALS AND METHODS: In this retrospective cohort study, at the end of the "first quarter" (August-October 2013) of use, our practice database was searched for all ABVS examinations performed and specifically, the positive examinations (defined as abnormal/BI-RADS 0) for which patients were recalled for additional imaging evaluation with handheld ultrasound (HHUS); the latter group was reviewed with respect to final BI-RADS and pathology if relevant. RESULTS: During the 3-month study time period, 558 ABVS studies were performed: 453 (81%) were initially BI RADS 1 or 2 and 105 (19%) were BI-RADS 0-incomplete and recalled, corresponding with an overall recall rate of 19%; specifically, the recall rate trended down from 24.7% in August to 12.6% in October. To date, 98 of the 105 recalled women have returned for HHUS, with the resultant final BI-RADS as follows: 25/98=25% BI RADS 1, 46/98=47% BI-RADS 2, 13/98=13% BI-RADS 3, 14/98=15% BI-RADS 4, and 0/98=0% BI-RADS 5. All biopsies performed to date of the ABVS-detected BI-RADS 4 lesions have yielded benign results, with the most common pathology being fibroadenoma. CONCLUSION: The recall rate of screening ABVS in women with dense breasts at our institution was under 20% overall during its first quarter of use, and trended down from nearly 25% in the first month to under 13% in the third. The clinical implication is that ABVS does have a learning curve, but that is a potentially feasible way to meet the increasing demands for screening ultrasound in women with dense breasts. PMID- 24768329 TI - Subtype-specific KRAS mutations in advanced lung adenocarcinoma: a retrospective study of patients treated with platinum-based chemotherapy. AB - BACKGROUND: Platinum-based chemotherapy is the most common treatment in advanced stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy. METHODS: 505 Caucasian stage III-IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression free and overall survival (PFS and OS, respectively) and therapeutic response were analysed. RESULTS: Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P=0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P=0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P=0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233days; versus 175days in the G12x group; P=0.145). CONCLUSIONS: While KRAS mutation status per se is neither prognostic nor predictive in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions. PMID- 24768330 TI - Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to imatinib: a prospective randomised trial in China. AB - OBJECTIVES: For advanced gastrointestinal stromal tumour (GIST) patients who are responding to imatinib mesylate, the role of surgery has not been formally demonstrated. This multicenter randomised controlled trial was designed to assess whether surgery to treat residual disease for patients with recurrent/metastatic GISTs responding to imatinib mesylate (IM) improved progression free survival (PFS) compared with IM treatment alone. METHODS: Between 3 and 12months after starting IM for recurrent/metastatic GISTs, eligible patients were randomised to two arms: Arm A (surgery for residual disease) and Arm B (IM treatment alone). In Arm A (19pts), surgery was performed to remove residual macroscopic lesions as completely as possible, and IM treatment continued after surgery. In Arm B (22pts), IM was given alone at a dose of 400mg per day until disease progression. The primary end-point was PFS measured from the date IM started. This study was registered in the ChiCTR registry with the ID number ChiCTR-TRC-00000244. RESULTS: This randomised trial was closed early due to poor accrual. Only 41 patients were enrolled as opposed to 210 patients planned. 2-year PFS was 88.4% in the surgery arm and 57.7% in the IM-alone arm (P=0.089). Median overall survival (mOS) was not reached in the surgery arm and 49months in patients with IM-alone arm (P=0.024). CONCLUSIONS: While no significant differences were observed in the two arms, this study suggests that surgical removal of the metastatic lesion may improve the outcome of advanced GIST patients and should stimulate additional research on this topic. PMID- 24768331 TI - Novel fate-tracing strategies show that hepatic stellate cells mediate fibrosis in vivo. PMID- 24768333 TI - Application of cerebral oxygen saturation to prediction of the futility of resuscitation for out-of-hospital cardiopulmonary arrest patients: a single center, prospective, observational study: can cerebral regional oxygen saturation predict the futility of CPR? AB - BACKGROUND: Cerebral regional oxygen saturation (rSO2) can be measured immediately and noninvasively just after arrival at the hospital and may be useful for evaluating the futility of resuscitation for a patient with out-of hospital cardiopulmonary arrest (OHCA). We examined the best practices involving cerebral rSO2 as an indicator of the futility of resuscitation. METHODS: This study was a single-center, prospective, observational analysis of a cohort of consecutive adult OHCA patients who were transported to the University of Tokyo Hospital from October 1, 2012, to September 30, 2013, and whose cerebral rSO2 values were measured. RESULTS: During the study period, 69 adult OHCA patients were enrolled. Of the 54 patients with initial lower cerebral rSO2 values of 26% or less, 47 patients failed to achieve return of spontaneous circulation (ROSC) in the receiver operating characteristic curve analysis (optimal cutoff, 26%; sensitivity, 88.7%; specificity, 56.3%; positive predictive value, 87.0%; negative predictive value, 60.0%; area under the curve [AUC], 0.714; P = .0033). The AUC for the initial lower cerebral rSO2 value was greater than that for blood pH (AUC, 0.620; P = .1687) or lactate values (AUC, 0.627; P = .1081) measured upon arrival at the hospital as well as that for initial higher (AUC, 0.650; P = .1788) or average (AUC, 0.677; P = .0235) cerebral rSO2 values. The adjusted odds ratio of the initial lower cerebral rSO2 values of 26% or less for ROSC was 0.11 (95% confidence interval, 0.01-0.63; P = .0129). CONCLUSIONS: Initial lower cerebral rSO2 just after arrival at the hospital, as a static indicator, is associated with non-ROSC. However, an initially lower cerebral rSO2 alone does not yield a diagnosis performance sufficient for evaluating the futility of resuscitation. PMID- 24768332 TI - Barrett's Esophagus Translational Research Network (BETRNet): the pivotal role of multi-institutional collaboration in esophageal adenocarcinoma research. PMID- 24768334 TI - Spontaneous ureteral rupture and review of the literature. AB - INTRODUCTION: Spontaneous ureteral rupture is defined as non-traumatic urinary leakage from the ureter. This is a diagnosis that, although uncommon, is important for emergency physicians to know about. The literature is relatively sparse. MATERIALS AND METHODS: This was a retrospective review of patients who were diagnosed with spontaneous ureteral rupture. From 2006 to 2012, 18 patients were diagnosed by radiography (computed tomography or intravenous urogram) with spontaneous ureteral rupture. These cases all showed extravasation of the contrast outside the excretory system. We evaluated underlying causes, diagnostic and therapeutic procedures, and outcomes. RESULTS: There were 9 men and 9 women with a median age of 59 years (range, 22-82 years). In 56% of patients, a ureteral stone was the cause; in 17% of, a ureteral stricture; in 1 patient, a ureteral tumor; and in the remaining 22%, no cause was identified. In 13 patients (72.2%), primary ureteroscopy to place D-J stents was performed. The average duration of ureteral catheter stenting was 21 days (range, 8-45 days). The other 5 patients (27.8%) were managed conservatively with antibiotic treatment and the outcome was good. CONCLUSIONS: Ureteral stones most commonly cause spontaneous ureteral rupture. In our experience, most patients received ureteroscopy and Double-J stenting. Conservative management with antibiotics also had good outcomes. Most patients had sudden onset of abdominal or flank pain. Spontaneous ureteral rupture should be kept in the differential diagnosis of patients with acute abdominal or flank pain in the emergency department. PMID- 24768335 TI - Obstetrical catastrophe averted: successful outcome of an abdominal pregnancy. AB - Abdominal pregnancy is defined as an implantation in peritoneal cavity, exclusive of tubal, ovarian, or intraligmentary pregnancy.These pregnancies are rarely encountered and can go undiagnosed until advanced period of gestation [1]. Frequency of abdominal pregnancy has been directly related to the frequency of ectopic gestation as constituting 2% of ectopics and nearly 0.01% of all pregnancies [2-4]. These pregnancies are seen more commonly in developing countries and poses special challenges to the clinician. Advanced abdominal pregnancy is life-threatening condition and carries high risk of hemorrhage, disseminated intravascular coagulation, bowel injury, and fistulae [5]. The perinatal outcome is mainly influenced by the availability of blood supply and site of implantation [6]. Most of the fetus die in utero because of compromised environment, and those who survive face problems due to congenital malformations [3,7]. Patients of abdominal pregnancy can have variable clinical presentation, and physical examination may be inconclusive for making diagnosis [7,8]. Clinical features like irregular bleeding per vaginum, abdominal pain, dyspepsia, altered bowel habits, malpresentation, and extremely anteriorly placed cervix should raise the suspicion [2,3,8,9]. Diagnostic challenge with oxytocin stimulation, abdominal x-ray, hysterosalpingography, and ultrasonography has been used as tools to assist in diagnosis [10,11]. Magnetic resonance imaging is found to complement sonography in making accurate diagnosis and can be useful to demonstrate the relationship between fetus, the cervix, and the myometrium [12]. We hereby report a successful operative delivery of a live baby after a term extrauterine abdominal pregnancy in a multigravida in whom the diagnosis was made after laparotomy. PMID- 24768336 TI - Etiology and management of exercise-associated hyponatremic encephalopathy (EAHE). PMID- 24768337 TI - Is abdomen release really necessary for prone ventilation in acute respiratory distress syndrome? AB - Prone ventilation for refractory acute respiratory distress syndrome (ARDS) mandates free abdomen by rolls in between chest wall and pelvic bones for better ventilation and control of airway pressure. We observed that, in patients with severe ARDS, prone ventilation with movable free abdomen produced high plateau pressure reduced by applying simple support to abdominal wall. Here, we have proposed a possible hypothesis to explain the paradoxical event in this particular group of patients. The increased alveolar volume in prone position is counteracted by reduction in rib cage diameter caused by weight of abdomen. In patients with severe ARDS in prone position, gravitational pressure transmits through abdominal support, resulting in better chest wall expansion and leading to more oxygenation and opening of the alveoli in ventral lung along with the dorsal lung portion that is usually better ventilated in prone position. There is no clinical trial regarding this particular observation. We suggest randomized trials to prove our observational findings. PMID- 24768338 TI - Validation of an abbreviated version of the Denver HIV risk score for prediction of HIV infection in an urban ED. AB - OBJECTIVE: We sought to evaluate the performance of an abbreviated version of the Denver HIV Risk Score in 2 urban emergency departments (ED) with known high undiagnosed HIV prevalence. METHODS: We performed a secondary analysis of data collected prospectively between November 2005 and December 2009 as part of an ED based nontargeted rapid HIV testing program from 2 sites. Demographics; HIV testing history; injection drug use; and select high-risk sexual behaviors, including men who have sex with men, were collected by standardized interview. Information regarding receptive anal intercourse and vaginal intercourse was either not collected or collected inconsistently and was thus omitted from the model to create its abbreviated version. RESULTS: The study cohort included 15184 patients with 114 (0.75%) newly diagnosed with HIV infection. HIV prevalence was 0.41% (95% confidence interval [CI], 0.21%-0.71%) for those with a score less than 20, 0.29% (95% CI, 0.14%-0.52%) for those with a score of 20 to 29, 0.65% (95% CI, 0.48%-0.87%) for those with a score of 30 to 39, 2.38% (95% CI, 1.68% 3.28%) for those with a score of 40 to 49, and 4.57% (95% CI, 2.09%-8.67%) for those with a score of 50 or higher. External validation resulted in good discrimination (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.71-0.79). The calibration regression slope was 0.92 and its R(2) was 0.78. CONCLUSIONS: An abbreviated version of the Denver HIV Risk Score had comparable performance to that reported previously, offering a promising alternative strategy for HIV screening in the ED where limited sexual risk behavior information may be obtainable. PMID- 24768339 TI - Intralobar fibres of the occipital lobe: a post mortem dissection study. AB - INTRODUCTION: The atlas by Heinrich Sachs (1892) provided an accurate description of the intralobar fibres of the occipital lobe, with a detailed representation of the short associative tracts connecting different parts of the lobe. Little attention has been paid to the work of Sachs since its publication. In this study, we present the results of the dissection of three hemispheres, performed according to the Klingler technique (1935). Our anatomical findings are then compared to the original description of the occipital fibres anatomy as detailed by Sachs. METHODS: Three hemispheres were dissected according to Klingler's technique (1935). Specimens were fixed in 10% formalin and frozen at -15 degrees C for two weeks. After defreezing, dissection of the white matter fibres was performed with blunt dissectors. Coronal sections were obtained according to the cuts originally described by Sachs. In addition, medial to lateral and lateral to medial dissection of the white matter of the occipital lobe was also performed. RESULTS: A network of short association fibres was demonstrated in the occipital lobe, comprising intralobar association fibres and U-shaped fibres, which are connecting neighbouring gyri. Lateral to the ventricles, longitudinal fibres of the stratum sagittale were also identified that are arranged as external and internal layers. Fibres of the forceps major were also found to be in direct contact with the ventricular walls. We were able to replicate all tracts originally described by Sachs. In addition, a previously unrecognised tract, connecting the cuneus to the lingual gyrus, was identified. This tract corresponds to the "sledge runner", described in tractography studies. CONCLUSIONS: The occipital lobe shows a rich network of intralobar fibres, arranged around the ventricular wall. Good concordance was observed between the Klingler dissection technique and the histological preparations of Sachs. PMID- 24768340 TI - How are innate emotions evoked? PMID- 24768342 TI - Chronic obstructive pulmonary disease audit - turning data into better care for patients. PMID- 24768341 TI - Alzheimer's disease biomarker discovery using SOMAscan multiplexed protein technology. AB - Blood proteins and their complexes have become the focus of a great deal of interest in the context of their potential as biomarkers of Alzheimer's disease (AD). We used a SOMAscan assay for quantifying 1001 proteins in blood samples from 331 AD, 211 controls, and 149 mild cognitive impaired (MCI) subjects. The strongest associations of protein levels with AD outcomes were prostate-specific antigen complexed to alpha1-antichymotrypsin (AD diagnosis), pancreatic prohormone (AD diagnosis, left entorhinal cortex atrophy, and left hippocampus atrophy), clusterin (rate of cognitive decline), and fetuin B (left entorhinal atrophy). Multivariate analysis found that a subset of 13 proteins predicted AD with an accuracy of area under the curve of 0.70. Our replication of previous findings provides further evidence that levels of these proteins in plasma are truly associated with AD. The newly identified proteins could be potential biomarkers and are worthy of further investigation. PMID- 24768343 TI - Determining return-to-sport status with a multi-component assessment strategy: a case study in rugby. AB - BACKGROUND: The effectiveness of rehabilitation programmes are often distorted by the athlete's desire to return and can result in injury recurrence. Athletic assessments allow for objective and reliable measurements to track rehabilitation progress. This case study used a multi-component assessment strategy to assess a rugby player's lower-extremity strength and symmetry as a primary determinate of their return-to-sport status. CASE DESCRIPTION: A professional rugby league player was assessed for lower-extremity isokinetic strength and sprint kinetics pre- and 10-weeks post-rehabilitation programme following two consecutive knee injuries involving surgical intervention. OUTCOMES: Pre-testing analysis showed clinical and functional strength deficits in the injured leg as high as 34% compared to the non-injured leg. Pre- to post-testing showed: increases in peak torque (49%) and decreased asymmetries by 50%; unilateral horizontal force increased (injured: 50%, non-injured: 19%) during sprinting; force production asymmetries decreased up to 18%. DISCUSSION: The rugby player showed clinical and functional strength deficiencies return to normal ranges following a rehabilitation programme. A return-to-sport decision was made by the athlete's supporting health team based on the sizeable asymmetry decreases and return-to normative ranges for knee and hip strength and sprint kinetics. The athlete returned to the 2013 National Rugby League season without any major injuries. PMID- 24768344 TI - Pseudoangiosarcomatous squamous cell carcinoma developing on a burn scar: a case report and review of the literature. AB - Pseudoangiosarcomatous squamous cell carcinoma, also known as pseudovascular, pseudovascular adenoid and pseudoangiomatous squamous cell carcinoma, is an exceedingly rare, aggressive variant of cutaneous squamous cell carcinoma with extreme acantholysis resulting in angiosarcoma-like areas. Histologically, a pseudoangiosarcomatous pattern includes complex anastomosing channels and spaces lined with neoplastic cells. The neoplastic cells exhibit cytokeratin and vimentin positivity but yield negative results with CD31 and CD34. This case report describes pseudoangiosarcomatous squamous cell carcinoma developing on a burn scar on the ankle. In this report, we emphasize the importance of establishing a diagnosis with histological and immunohistochemical examination, and we review the described incidence of the age and sites with the prognosis for the treatment of pseudoangiosarcomatous squamous cell carcinoma of the skin. PMID- 24768345 TI - Awareness and attitude of doctors and nurses at a teaching hospital to skin donation and banking. AB - INTRODUCTION: This study sought to determine the awareness and attitude of doctors and nurses in a teaching hospital to skin donation and banking, and to identify needs for personnel educational programmes. METHODS: A cross sectional survey on doctors and nurses was carried out using a 44-item questionnaire that included a Likert scale on attitudes. Predictors of favourable attitudes were determined. RESULTS: Eighty (49.7%) doctors and 81 (50.3%) nurses participated in the study. Many participants, 126 (78.3%), knew that skin could be donated, but only 96 (59.6%) participants were aware of skin banking. The main source of information was during professional training (17.4%). Only 41 (25.5%) participants were willing to donate skin after death. Body disfigurement was the major reason (20.5%) against skin donation. Participants who were doctors, were aware of skin banking, and who were previous blood donors had higher attitudes scores (p<0.001, p=0.004, p=0.007 respectively). Being a doctor and having heard of skin banking were predictors of favourable attitudes to skin donation and banking. CONCLUSION: Knowledge transfer during health professional training on the usefulness of banked skin in patients with major burns may lead to improved attitude of health professionals and acceptance of this modality of burn management. PMID- 24768346 TI - Running with my patient. PMID- 24768349 TI - A novel approach for successful closure of sinonasal fistulae. AB - Medial canthus sinonasal fistula is associated with troublesome aesthetic and functional issues. Corneal irritation and drying results from escape of both air and secretions from the nasal cavity across the ocular surface as well as misting of spectacles if worn. Reconstruction of such fistulae is associated with a high rate of recurrence and thus presents a difficult surgical challenge. METHODS: This paper describes the senior author's surgical approach to manage medial canthus sinonasal fistulae utilizing an interpolated forehead flap combined with extended galeafrontalis and pericranial flap for stepped closure. The technique of flap elevation and inset is discussed, with emphasis on key manoeuvres to prevent sinus recurrence. A retrospective review of consecutive cases is presented. RESULTS: Four patients were treated using this technique over 12 months. In all cases, fistulae developed following adjuvant radiotherapy for tumour resection. Flap elevation was performed in combination with a bicoronal approach in 2 patients and via direct forehead approach in 2 patients. No post operative complications or recurrence of fistula have occurred over 12 months follow-up. CONCLUSION: The success of this technique is attributed to inclusion of a galeafrontalis and pericranial extension to the forehead flap. In addition, the fistula site must be prepared to accommodate the flap by dissection of a wide subcutaneous pocket. This stepped method of closure provides an effective barrier to air and nasal secretions and also achieves an excellent aesthetic outcome. PMID- 24768348 TI - Structural delineation of a quaternary, cleavage-dependent epitope at the gp41 gp120 interface on intact HIV-1 Env trimers. AB - All previously characterized broadly neutralizing antibodies to the HIV-1 envelope glycoprotein (Env) target one of four major sites of vulnerability. Here, we define and structurally characterize a unique epitope on Env that is recognized by a recently discovered family of human monoclonal antibodies (PGT151 PGT158). The PGT151 epitope is comprised of residues and glycans at the interface of gp41 and gp120 within a single protomer and glycans from both subunits of a second protomer and represents a neutralizing epitope that is dependent on both gp120 and gp41. Because PGT151 binds only to properly formed, cleaved trimers, this distinctive property, and its ability to stabilize Env trimers, has enabled the successful purification of mature, cleaved Env trimers from the cell surface as a complex with PGT151. Here we compare the structural and functional properties of membrane-extracted Env trimers from several clades with those of the soluble, cleaved SOSIP gp140 trimer. PMID- 24768350 TI - [Infections of central venous catheters in home parenteral nutrition: a retrospective monocentric study over 2 years]. AB - BACKGROUND AND STUDY AIMS: Infection of the central venous catheter (CVC) is the main aggravating factor of parenteral nutrition. The aim of this study was to determine the ecology of these infections in our home parenteral nutrition center and to evaluate our care protocol. PATIENTS AND METHODS: The present study was monocentric and retrospective, and was conducted in the parenteral nutrition service of the Marseille University Hospital between 1 January 2011 and 31 May 2012. During this period, all the children who presented fever and a positive hemoculture in a medical emergency were taken into account, and the characteristics of the infection were analyzed. RESULTS: After 17 months, 17 children had been subject to an infection in their central catheter: 47 bacteremia were identified, which is equivalent to 5.4 infections for 1000 days of CVC. An average 2.8 hemocultures were performed during this time. The most common bacterium was Staphylococcus hominis. The children affected by a digestive stoma or by a gastrostomy were not subject to more infections and their ecology was not different. All the children were referred to the hospital and treated with an intravenous antibiotic through the CVC. DISCUSSION: As expected during the time of the study, the infection rate was very high. This finding led us to reassess our prevention protocol. It is also very likely that the number of infections was overestimated due to the protocol for sampling in the hemocultures and their subsequent analysis. Lastly, some children relapsed easily, although no predisposing factor was found in the present study. The therapy chosen was in agreement with the best practices and the ecology recovered. CONCLUSION: The high number of infections observed during the study encourages a prospective evaluation of current practices. PMID- 24768347 TI - Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. AB - Broadly neutralizing HIV antibodies are much sought after (a) to guide vaccine design, both as templates and as indicators of the authenticity of vaccine candidates, (b) to assist in structural studies, and (c) to serve as potential therapeutics. However, the number of targets on the viral envelope spike for such antibodies has been limited. Here, we describe a set of human monoclonal antibodies that define what is, to the best of our knowledge, a previously undefined target on HIV Env. The antibodies recognize a glycan-dependent epitope on the prefusion conformation of gp41 and unambiguously distinguish cleaved from uncleaved Env trimers, an important property given increasing evidence that cleavage is required for vaccine candidates that seek to mimic the functional HIV envelope spike. The availability of this set of antibodies expands the number of vaccine targets on HIV and provides reagents to characterize the native envelope spike. PMID- 24768351 TI - [Failure of amiodarone in supraventricular tachycardia in an infant: drug interaction with Gaviscon((r))?]. PMID- 24768352 TI - [The emergency department: an appropriate place for identifying troubled teens]. AB - OBJECTIVES: The main objective of this study was to estimate the prevalence of psychological distress among adolescents seen in emergency departments, and the secondary objective was to highlight their main reasons for consulting. METHODS: Cross-sectional study in three multicenter emergency departments receiving adolescents in Ile-de-France conducted in 2010. All adolescents completed a questionnaire including the ADRS (Adolescent Depression Rating Scale, a screening questionnaire for depression) and a series of questions relating to somatization and risk behaviors. RESULTS: The study included 346 adolescents, 320 of which were fully analyzed. The ADRS score was considered normal (score < 3) for 70.6% of the sample (n = 226), 19.4% of adolescents (n = 62) had moderate depressive symptoms (3 <= score < 6), and 10.0% severe depressive symptoms (score >= 6) (n = 32). The majority of patients consulted for trauma and less than 10% for acute psychiatric problems; 17% of adolescents who came to the emergency department for a nonpsychiatric reason had an ADRS >= 3, i.e., with mental distress. CONCLUSION: The routine use of a self-administered questionnaire in the emergency services could identify adolescents with moderate to severe depressive symptoms. PMID- 24768353 TI - Qualitative research in CKD: an overview of methods and applications. AB - There recently has been a paradigm shift in health care policies and research toward greater patient centeredness. A core tenet of patient-centered care is that patients' needs, values, and preferences are respected in clinical decision making. Qualitative research methods are designed to generate insights about patients' priorities, values, and beliefs. However, in the past 5 years (2008 2013), only 23 (0.4%) of the 6,043 original articles published in the top 5 nephrology journals (assessed by impact factor) were qualitative studies. Given this observation, it seems important to promote awareness and better understanding within the nephrology community about qualitative research and how the findings can contribute to improving the quality and outcomes of care for patients with chronic kidney disease. This article outlines examples of how qualitative research can generate insight into the values and preferences of patients with chronic kidney disease, provides an overview of qualitative health research methods, and discusses practical applications for research, practice, and policy. PMID- 24768354 TI - Prevention of supine hypotensive syndrome in pregnant women treated with transcranial magnetic stimulation. AB - In our studies of transcranial magnetic stimulation in pregnant women with major depressive disorder, two subjects had an episode of supine hypotensive syndrome and one subject had an episode of dizziness without hypotension. Prevention of the supine hypotensive syndrome in pregnant women receiving transcranial magnetic stimulation is described. PMID- 24768355 TI - Current ante-mortem techniques for diagnosis of bovine tuberculosis. AB - Bovine tuberculosis (TB), mainly caused by Mycobacterium bovis, is a zoonotic disease with implications for Public Health and having an economic impact due to decreased production and limitations to the trade. Bovine TB is subjected to official eradication campaigns mainly based on a test and slaughter policy using diagnostic assays based on the cell-mediated immune response as the intradermal tuberculin test and the gamma-interferon (IFN-gamma) assay. Moreover, several diagnostic assays based on the detection of specific antibodies (Abs) have been developed in the last few years with the aim of complementing the current diagnostic techniques in the near future. This review provides an overview of the current ante-mortem diagnostic tools for diagnosis of bovine TB regarding historical background, methodologies and sensitivity (Se) and specificity (Sp) obtained in previous studies under different epidemiological situations. PMID- 24768356 TI - Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. AB - Prostate cancer (CaP) is the most commonly diagnosed malignancy in men in the Western world. In North America, more than 275,000 men are diagnosed annually, whereby approximately 1 in 6 men will be diagnosed with CaP in their lifetime, and 1 in 34 men will die from castration-resistant metastatic disease. Unfortunately, current clinical prognostic factors explain only a proportion of the observed variation in clinical outcome from patient to patient. Furthermore, overtreatment of indolent and low-risk cancers leads to inappropriate morbidity following radiotherapy or surgery. As such, better predictors of individualized prognosis and treatment response are urgently needed to triage patients to customized and intensified CaP treatment. Recent developments in next-generation sequencing have made it possible to identify prognostic and predictive signatures based on genomic profiles. We discuss the genetic basis of CaP progression from localized to systemic disease (e.g., point mutations, copy-number alterations, and structural variants) in relation with unique features of CaP biology, including intraprostatic and interprostatic heterogeneity, multifocality and multiclonality, TMPRSS2:ERG, and other ETS-family gene fusions. Finally, we focus on the use of genomic markers as prognostic factors for local failure and for systemic disease, as novel risk-stratification tools, in triaging patients to existing treatment options, and ultimately the potential of genomics for the identification of molecular targets for therapy of CaP. PMID- 24768358 TI - The Burden of Narcolepsy Disease (BOND) study: health-care utilization and cost findings. AB - OBJECTIVES: The aim of this study was to characterize health-care utilization, costs, and productivity in a large population of patients diagnosed with narcolepsy in the United States. METHODS: This retrospective, observational study using data from the Truven Health Analytics MarketScan Research Databases assessed 5 years of claims data (2006-2010) to compare health-care utilization patterns, productivity, and associated costs among narcolepsy patients (identified by International Classification of Diseases, Ninth Revision (ICD9) narcolepsy diagnosis codes) versus matched controls. A total of 9312 narcolepsy patients (>18 years of age, continuously insured between 2006 and 2010) and 46,559 matched controls were identified. RESULTS: Compared with controls, narcolepsy subjects had approximately twofold higher annual rates of inpatient admissions (0.15 vs. 0.08), emergency department (ED) visits w/o admission (0.34 vs. 0.17), hospital outpatient (OP) visits (2.8 vs. 1.4), other OP services (7.0 vs. 3.2), and physician visits (11.1 vs. 5.6; all p<0.0001). The rate of total annual drug transactions was doubled in narcolepsy versus controls (26.4 vs. 13.3; p<0.0001), including a 337% and 72% higher usage rate of narcolepsy drugs and non-narcolepsy drugs, respectively (both p<0.0001). Mean yearly costs were significantly higher in narcolepsy compared with controls for medical services ($8346 vs. $4147; p<0.0001) and drugs ($3356 vs. $1114; p<0.0001). CONCLUSIONS: Narcolepsy was found to be associated with substantial personal and economic burdens, as indicated by significantly higher rates of health-care utilization and medical costs in this large US group of narcolepsy patients. PMID- 24768357 TI - Minimal changes in the systemic immune response after nephrectomy of localized renal masses. AB - OBJECTIVES: Renal cell carcinoma (RCC) is an immunogenic tumor, and multiple immunostimulatory therapies are in use or under development for patients with inoperable tumors. However, a major drawback to the use of immunotherapy for RCC is that renal tumors are also immunosuppressive. As a result, current immunotherapies are curative in<10% of patients with RCC. To better understand the systemic immune response to RCC, we performed a comprehensive examination of the leukocyte and cytokine/chemokine composition in the peripheral blood of patients with localized clear cell renal tumors pre- and post-nephrectomy. METHODS AND MATERIALS: Peripheral blood samples were taken from 53 consented subjects with renal masses before cytoreductive nephrectomy and again at clinic visits approximately 30 days after nephrectomy. Samples were also obtained from 10 healthy age- and gender-matched controls. Blood samples from clear cell RCC subjects were analyzed by multi-parameter flow cytometry to determine leukocyte subset composition and multiplex array to evaluate plasma proteins. RESULTS: Pre nephrectomy, clear cell tumors were associated with systemic accumulations of both "exhausted" CD8+ T cells, as indicated by surface BTLA expression, and monocytic CD14(+)HLA-DR(neg)CD33(+) myeloid-derived suppressor cells (MDSC). Subjects with T3 clear cell RCC also had a unique pro-tumorigenic and inflammatory cytokine/chemokine profile characterized by high serum concentrations of IL-1beta, IL-2, IL-5, IL-7, IL-8, IL-17, TNF-alpha, MCP-1 and MIP-1beta. At an early post-nephrectomy time point (~30 d), we found the systemic immune response to be largely unaltered. The only significant change was a decrease in the mean percentage of circulating BTLA(+)CD8(+) T cells. All other cellular and soluble immune parameters we examined were unaltered by the removal of the primary tumor. CONCLUSIONS: In the first month following surgery, nephrectomy may relieve systemic CD8 T cell exhaustion marked by BTLA expression, but continuing inflammation and MDSC presence likely counteract this positive effect. Future determination of how this systemic immune signature becomes altered during metastatic progression could provide novel targets for neoadjuvant immunotherapy in RCC. PMID- 24768359 TI - Results of surgical management of acute thromboembolic lower extremity ischemia. AB - OBJECTIVE: Acute lower extremity ischemia secondary to arterial thromboembolism is a common problem. Contemporary data regarding this problem are sparse. This report examines a 10-year single-center experience and describes the surgical management and outcomes observed. METHODS: Procedural codes were used to identify consecutive patients treated surgically for acute lower extremity embolization from January 2002 to September 2012. Patients presenting >7 days after onset of symptoms, occlusion of grafts/stents, and cases secondary to trauma or iatrogenic injury were excluded. Data collected included demographics, medical comorbidities, presenting clinical characteristics, procedural specifics, and postoperative outcomes. Results were evaluated using descriptive statistics, product-limit survival analysis, and logistic regression multivariable modeling. RESULTS: The study sample included 170 patients (47% female). Mean age was 69.1 +/- 16.0 years. Of these, 82 patients (49%) had a previous history of atrial fibrillation, and four (2%) were therapeutically anticoagulated (international normalized ratio >=2.0) at presentation. Presentation for 83% was >6 hours after symptom onset, and 9% presented with a concurrent acute stroke. Femoral artery exploration with embolectomy was the most common procedural management and was used for aortic, iliac, and infrainguinal occlusion. Ten patients (6%) required bypass for limb salvage during the initial operation. Local instillation of thrombolytic agents as an adjunct to embolectomy was used in 16%, fasciotomies were performed in 39%, and unexpected return to the operating room occurred in 24%. Ninety-day amputation above or below the knee was required during the index hospitalization in 26 patients (15%). In-hospital or 30-day mortality was 18%. Median (interquartile range) length of stay was 8 days (4, 16 days), and 36% of patients were discharged to a nursing facility. Recurrent extremity embolization occurred in 23 patients (14%) at a median interval of 1.6 months. The 5-year amputation freedom and survival estimates were 80% and 41%, respectively. Predictors of 90-day amputation included prior vascular surgery, gangrene, and fasciotomy. Predictors of 30-day mortality included age, history of coronary artery disease, prior vascular surgery, and concurrent stroke. CONCLUSIONS: Despite advances in contemporary medical care, lower extremity arterial embolization remains a condition that is associated with significant morbidity and mortality. Furthermore, the condition is resource-intensive to treat and is likely preventable (initially or in recurrence) in a substantial subset of patients. PMID- 24768360 TI - Discussion. PMID- 24768361 TI - Outcomes of endovascular and contemporary open surgical repairs of popliteal artery aneurysm. AB - OBJECTIVE: The purpose of this study was to compare outcomes after endovascular repair (ER) and contemporary open repair (OR) of popliteal artery aneurysms (PAAs). METHODS: Clinical data of PAA patients treated between 2005 and 2012 were reviewed. Primary end points were major adverse events (MAEs) including mortality, major amputation, patency, complications, and reinterventions. RESULTS: A total of 149 PAAs were treated in 120 patients (mean age, 74 +/- 10 years). ER was performed in 42 limbs of 35 men (mean age, 81 +/- 6.5 years), in 32 electively and in 10 emergently. Technical success was 98%. The 30-day MAEs were more frequent after emergent repair (50% vs 9%; odds ratio [OR], 9.67; 95% confidence interval [CI], 1.74-54; P = .01); mortality and amputation rate was 0% after elective repair, 20% after emergent repair. Mean follow-up was 2.6 years (1 month-6.5 years); 3-year freedom from MAEs was lower after emergent repair than after elective repair (40% vs 66%; hazard ratio [HR], 3.13; 95% CI, 1.10-8.85; P = .03). OR was performed in 107 limbs of 91 patients (90 men; mean age, 71 +/- 9.6 years), in 93 electively and in 14 emergently. The 30-day MAEs were more frequent after emergent repair (43% vs 5%; OR, 13; 95% CI, 3.29-53; P < .001); mortality was 1% after elective repair, 0% after emergent cases. Amputation rate was 0% for both elective and emergent repairs. Mean follow-up was 3.8 years (1 month-8.4 years); 3-year freedom from MAEs was lower after emergent repair (50% vs 80%; HR, 3.78; 95% CI, 1.55-9.20; P = .003). The 30-day MAE rates were equivalent between ER and OR independent of urgency of repair (elective: OR, 1.82; 95% CI, 0.41-8.09; P = .43; emergent: OR, 1.33; 95% CI, 0.26-6.81; P = .73). In elective interventions, ER had a trend to decreased freedom from MAEs (66% vs 80% at 3 years; HR, 1.93; 95% CI, 0.92-4.07; P = .08); freedom from reintervention was lower after ER (72% vs 88%; HR, 2.41; 95% CI, 1.02-5.70; P = .046). In emergent interventions, 1-year freedom from MAEs was similar (40% vs 50%; HR, 1.36; 95% CI, 0.49-3.74; P = .55). Emergent ER and poor runoff predicted MAEs. CONCLUSIONS: Our study failed to prove the superiority of ER over OR. If anatomy is suitable, ER of PAA in the elderly and high-risk patients is justified. For emergent PAA repairs, MAEs are frequent after both ER and OR; ER has not changed the severe prognosis of acute limb ischemia from PAA. A multicenter randomized controlled trial of PAA patients with acute presentation is warranted. PMID- 24768362 TI - Trends in the incidence, treatment, and outcomes of acute lower extremity ischemia in the United States Medicare population. AB - OBJECTIVE: Acute lower extremity ischemia (ALI) is a common vascular surgery emergency associated with high rates of morbidity and mortality. The purpose of this study was to assess contemporary trends in the incidence of ALI, the methods of treatment, and the associated mortality and amputation rates in the U.S. Medicare population. METHODS: This was an observational study using Medicare claims data between 1998 and 2009. Outcomes examined included trends in the incidence of ALI; trends in interventions for ALI; and trends in amputation, mortality, and amputation-free survival rates. RESULTS: Between 1998 and 2009, the incidence of hospitalization for ALI decreased from 45.7 per 100,000 to 26.0 per 100,000 (P for trend < .001). The percentage of patients undergoing surgical intervention decreased from 57.1% to 51.6% (P for trend < .001), whereas the percentage of patients undergoing endovascular interventions increased from 15.0% to 33.1% (P for trend < .001). In-hospital mortality rates decreased from 12.0% to 9.0% (P for trend < .001), whereas 1-year mortality rates remained stable at 41.0% and 42.5% (P for trend not significant). In-hospital amputation rates remained stable at 8.1% and 6.4% (P for trend not significant), whereas 1-year amputation rates decreased from 14.8% to 11.0% (P for trend < .001). In-hospital amputation-free survival after hospitalization for ALI increased from 81.2% to 85.4% (P for trend < .001); however, 1-year amputation-free survival remained unchanged. CONCLUSIONS: Between 1998 and 2009, the incidence of ALI among the U.S. Medicare population declined significantly, and the percentage of patients treated with endovascular techniques markedly increased. During this time, 1-year amputation rates declined. Furthermore, although in-hospital mortality rates declined after presentation with ALI, 1-year mortality rates remained unchanged. PMID- 24768363 TI - Differential expression of Hedgehog/Notch and transforming growth factor-beta in human abdominal aortic aneurysms. AB - OBJECTIVE: The molecular mechanisms leading to the development of abdominal aortic aneurysms (AAAs) remain poorly understood. The aim of this study was to determine the expression of Sonic Hedgehog (SHh), transforming growth factor beta (TGF-beta), and Notch signaling components in human aneurysmal and nonaneurysmal aorta in vivo. METHODS: Paired tissue samples were obtained from aneurysmal and nonaneurysmal (control) segments of the aortic wall of eight patients with suitable anatomy undergoing open repair of infrarenal AAAs. Protein and messenger RNA (mRNA) expression levels were determined by Western blot and quantitative real-time polymerase chain reaction analysis. RESULTS: Aneurysm development resulted in a significant reduction in vascular smooth muscle (vSMC) differentiation genes alpha-actin and SMC22alpha at both mRNA and protein levels. In parallel experiments, an 80.0% +/- 15% reduction in SHh protein expression was observed in aneurysmal tissue compared with control. SHh and Ptc-1 mRNA levels were also significantly decreased, by 82.0% +/- 10% and 75.0% +/- 5%, respectively, in aneurysmal tissue compared with nonaneurysmal control tissue. Similarly, there was a 50.0% +/- 9% and 60.0% +/- 4% reduction in Notch receptor 1 intracellular domain and Hrt-2 protein expression, respectively, in addition to significant reductions in Notch 1, Notch ligand Delta like 4, and Hrt-2 mRNA expression in aneurysmal tissue compared with nonaneurysmal tissue. There was no change in Hrt-1 expression observed in aneurysmal tissue compared with control. In parallel experiments, we found a 2.2 +/- 0.2-fold and a 5.6 +/- 2.2-fold increase in TGF-beta mRNA and protein expression, respectively, in aneurysmal tissue compared with nonaneurysmal tissue. In vitro, Hedgehog signaling inhibition with cyclopamine in human aortic SMCs resulted in decreased Hedgehog/Notch signaling component and vSMC differentiation gene expression. Moreover, cyclopamine significantly increased TGF-beta1 mRNA expression by 2.6 +/ 0.9-fold. CONCLUSIONS: These results suggest that SHh/Notch and TGF-beta signaling are differentially regulated in aneurysmal tissue compared with nonaneurysmal tissue. Changes in these signaling pathways and the resulting changes in vSMC content may play a causative role in the development of AAAs. PMID- 24768364 TI - Radiation-induced skin injury after complex endovascular procedures. AB - BACKGROUND: Radiation-induced skin injury is a serious potential complication of fluoroscopically guided interventions. Transient erythema occurs at doses of 2 to 5 Gy, whereas permanent epilation, ulceration, and desquamation are expected at doses above this level. Complex endovascular procedures (CEPs), such as fenestrated endovascular aortic aneurysm repair (FEVAR), are associated with high radiation doses, yet the prevalence of radiation-induced skin injury is unknown. We hypothesized that skin injury after these exposures is likely to be underrecognized and underreported. This study examined the frequency and severity of deterministic effects and evaluated patient characteristics that might predispose to radiation injury in CEP. METHODS: CEP was defined as a procedure with a radiation dose >=5 Gy (National Council on Radiation Protection and Measurements threshold for substantial radiation dose level [SRDL]). Radiation dose and operating factors were recorded for all CEPs performed in a hybrid room during a 30-month period. Patient medical records were retrospectively reviewed for evidence of skin injury. Patients were seen in follow-up daily until discharge and then at weeks 2 and 6, months 3 and 6, and 1 year. Phone interviews were conducted to determine the presence of any skin-related complaints. Peak skin dose (PSD) distributions were calculated for FEVARs with custom software employing input data from fluoroscopic machine logs. These calculations were validated against Gafchromic film (Ashland Inc, Covington, Ky) measurements. Dose was summed for the subset of patients with multiple procedures within 6 months of the SRDL event, consistent with Joint Commission recommendations. RESULTS: Sixty one CEPs reached a reference air kerma (RAK) of 5 Gy (50 FEVARs, six embolizations, one thoracic endovascular aortic repair, one endovascular aneurysm repair, one carotid intervention, and two visceral interventions). The patient cohort was 79% male and had a mean body mass index of 31. The average RAK was 8 +/- 2 Gy (5.0-15.9 Gy). Sixteen patients had multiple CEPs within 6 months of the SRDL event, with a mean cumulative RAK of 12 +/- 3 Gy (7.0-18.4 Gy). The mean FEVAR PSD was 6.6 +/- 3.6 Gy (3.7-17.8 Gy), with a mean PSD/RAK ratio of 0.78. Gafchromic film dose measurements were not statistically different from PSD estimations, with a constant of proportionality of 0.99. Three patients were lost to follow-up before their first postoperative visit. No radiation skin injuries were found. CONCLUSIONS: This study represents the largest analysis of deterministic skin injury after CEPs, and our results suggest that it is less frequent than expected and not increased in CEPs. PMID- 24768365 TI - Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion. AB - BACKGROUND: The addition of local ultrasound (US) with a contrast agent to standard intra-arterial thrombolysis can accelerate the thrombolytic treatment of stroke and myocardial infarction. The contrast agent consists of microsized gas filled bubbles that collapse when exposed to US, causing destabilization of the clot and making the clot surface more susceptible to fibrinolytics. In this study, we investigated the effect of additional US and microbubbles on standard low-dose intra-arterial thrombolysis in a porcine model of extensive peripheral arterial occlusion. METHODS: Extensive arterial thrombosis was induced in 10 pigs in the 4-cm external iliac artery by clamping and injection of 100 IU of bovine thrombin. A transcutaneous laser Doppler flow probe and an ultrasonic perivascular flow probe assessed microcirculation and arterial flow respectively. The urokinase-only (UK) group (n = 4) received standard thrombolytic therapy: intra-arterial bolus injection of 500,000 IU, followed by a continuous low-dose urokinase (50,000 IU/h) infusion through an intra-arterial catheter and local intermittent application of US, 1 second on, 5 seconds off, to visualize vascular patency during the first hour of therapy and to ensure microbubbles replenished the proximal portion of the occluded artery. The urokinase plus microbubbles (UK+) group (n = 6) received the same urokinase therapy with a concomitant intravenous infusion of microbubbles and local intermittent application of US. The contrast infusion protocol consisted of a bolus of two vials of 5 mL in the first 15 minutes and then three times 5 mL slowly hand-injected continuously during the next 45 min. After 3 hours of therapy, the animals were euthanized, and thrombi were harvested and weighed. All organs were cut in thin slices and macroscopically inspected for potential (hemorrhagic) adverse events, and tissue samples were taken. RESULTS: Median thrombus weights were 1.1 g (range, 0.8-1.3 g) in the UK+ group vs 1.6 g (range, 1.3-1.9 g) in the UK group (P = .01). Arterial blood flow increased in four of six pigs in the UK+ group by a mean 61% vs in one of four in the UK group, with 1%. Microcirculation and lower limb arterial pressure levels improved after the start of therapy in the UK+ group, contrary to a trend of decline in the UK group. No signs of bleeding complications were observed in either group. CONCLUSIONS: In this experimental pilot study, the addition of contrast-enhanced US accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. Further clinical studies are warranted. PMID- 24768366 TI - Cromolyn ameliorates acute and chronic injury in a rat lung transplant model. AB - BACKGROUND: Mast cells have been associated with obliterative bronchiolitis (OB) in human pulmonary allografts, although their role in the development of OB remains unknown. METHODS: In this study, we evaluated the role of mast cells in pulmonary allograft rejection using an orthotopic rat pulmonary allograft model that utilizes chronic aspiration of gastric fluid to reliably obtain OB. Pulmonary allograft recipients (n = 35) received chronic aspiration of gastric fluid with (n = 10) and without (n = 16) treatment with a mast cell membrane stabilizer, cromolyn sodium, or chronic aspiration with normal saline (n = 9) as a control. RESULTS: The acute graft injury associated with long ischemic time in the model (6 hours total ischemic time; typical acute graft injury rate ~30%) was apparently blocked by cromolyn, because peri-operative mortality associated with the acute graft injury was not observed in any of the animals receiving cromolyn (p = 0.045). Further, the rats receiving cromolyn developed significantly fewer OB lesions than those treated with gastric fluid alone (p < 0.001), with a mean reduction of 46% of the airways affected. CONCLUSIONS: These findings provide impetus for further studies aimed at elucidating the effects of cromolyn and the role of mast cells in pulmonary allotransplantation. PMID- 24768367 TI - Use of a novel hybrid vascular graft for sutureless revascularization of the renal arteries during open thoracoabdominal aortic aneurysm repair. AB - OBJECTIVE: The aim of this study was to assess the safety and short-term effectiveness of a novel hybrid vascular graft used to address renal revascularization during open thoracoabdominal aortic aneurysm (TAAA) repair, performing a sutureless distal anastomosis. METHODS: Between 2012 and 2013, 25 patients (16 men; mean age, 66 +/- 8 years) underwent revascularization of one (24 patients) or both (one patient) renal arteries with the Gore Hybrid Vascular Graft (GHVG; W. L. Gore and Associates, Flagstaff, Ariz) during open TAAA repair. Specific indications included remote location of the ostium of the renal artery, severe atherosclerotic wall degeneration, focal dissection, and stenosis. All surviving patients underwent computed tomography angiography and follow-up visit at 1 month. Preoperative characteristics, intraoperative data, and short-term results were compared with those of 49 concurrent TAAA patients operated on within the same period by standard renal revascularization (SRR) techniques. RESULTS: All GHVG target renal vessels (26 of 26) were successfully revascularized without technical concerns. No significant differences were found between GHVG and SRR groups in preoperative and intraoperative data, except for a relative prevalence of aortic dissection (28% vs 6%; P = .026) and renal artery stenosis (44% vs 12%; P = .003) in the GHVG group and for intraoperative renal bare stenting that was predominantly used in the SRR group (12% vs 28%; P = .036). The 30-day mortality was 4% in both groups. Postoperative acute renal failure (doubling of creatinine level and creatinine level >3.0 mg/dL) occurred in two GHVG patients (8%) and seven SRR patients (14%; P = NS). Perioperative peak decrease of estimated glomerular filtration rate was lower in the GHVG group (26 +/- 18 mL/min/1.73 m(2) vs 37 +/- 22 mL/min/1.73 m(2); P = .034). At 1-month computed tomography angiography, renal artery patency was 92% for the GHVG vessels, 91% for the contralateral to GHVG renal vessels, and 92% for the SRR group arteries. No GHVG-related complications requiring reintervention or cases of new-onset renal failure requiring dialysis were observed at follow-up. CONCLUSIONS: Renal revascularization during open TAAA repair by the GHVG with distal sutureless anastomosis is feasible, especially in cases of aortic dissection, remote location of the renal vessel, and severe atherosclerotic disease of the ostium. Short-term results are satisfactory, at least comparable to those of SRR. Larger series and longer follow-up are needed to assess clinical advantages and durability of this new device. PMID- 24768368 TI - Interfacility transfer and mortality for patients with ruptured abdominal aortic aneurysm. AB - OBJECTIVE: Patients receiving interfacility transfer to a higher level of medical care for ruptured abdominal aortic aneurysms (rAAAs) are an important minority that are not well characterized and are typically omitted from outcomes and quality indicator studies. Our objective was to compare patients transferred for treatment of rAAAs with those treated without transfer, with particular emphasis on mortality and resource utilization. METHODS: We linked longitudinal data from 2005 to 2010 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases and Emergency Department Databases from California, Florida, and New York. Patients were identified using International Classification of Diseases Ninth Revision-Clinical Modification codes. Our main outcome variables were mortality, length of stay, and cost. Data included discharge information on the transfer-out and transfer-in hospital. We used univariate and multivariate analysis to identify variables independently associated with transfer and in hospital mortality. RESULTS: Of 4439 rAAA patients identified with intent to treat, 847 (19.1%) were transferred before receiving operative repair. Of those transferred, 141 (17%) died without undergoing AAA repair. By multivariate analysis, increasing age in years (odds ratio [OR] 0.98; 95% confidence interval [CI], 0.97-0.99; P < .001), private insurance vs Medicare (OR, 0.62; 95% CI, 0.47 0.80; P < .001), and increasing comorbidities as measured by the Elixhauser Comorbidity Index (OR, 0.90; 95% CI, 0.86-0.95; P < .001) were negatively associated with transfer. Weekend presentation (OR, 1.23; 95% CI, 1.02-1.47; P = .03) was positively associated with transfer. Transfer was associated with a lower operative mortality (adjusted OR, 0.81; 95% CI, 0.68-0.97; P < .02) but an increased overall mortality when including transferred patients who died without surgery (OR, 1.30; 95% CI, 1.05-1.60; P = .01). Among the transferred patients, there was no significant difference in travel distance between those who survived and those who died (median, 28.7 vs 25.8 miles; P = .07). Length of stay (median, 10 vs 9 days; P = .008), and hospital costs ($161,000 vs $146,000; P = .02) were higher for those transferred. CONCLUSIONS: The survival advantage for patients transferred who received treatment was eclipsed by increased mortality of the transfer process. Including 17% of transferred patients who died without receiving definitive repair, mortality was increased for patients transferred for rAAA repair compared with those not transferred after adjusting for demographic, clinical, and hospital factors. Transferred patients used significantly more hospital resources. Improving systems and guidelines for interfacility transfer may further improve the outcomes for these patients and decrease associated hospital resource utilization. PMID- 24768369 TI - Salivary testosterone measurements in growing pigs: validation of an automated chemiluminescent immunoassay and its possible use as an acute stress marker. AB - This study aimed to validate the use of an automated chemiluminescent immunoassay analyser for salivary testosterone measurements in growing pigs and study how circadian pattern during daytime and stress can influence its values. The test method had intra- and inter-assay coefficient of variation lower than 10%. The method showed good linearity and recovery, and detection limits were low enough to detect salivary testosterone levels. No significant differences were observed in testosterone concentrations at different sampling time, and age and gender did not influence circadian pattern. In addition, this assay was used to quantify testosterone in two models of acute stress and, in both cases, significant increases (P< 0.01) in salivary testosterone were detected. Therefore, the automated assay system tested for porcine testosterone determinations would be suitable for its use in saliva samples and, furthermore, salivary testosterone levels could be used as a possible marker of acute stress in pigs. PMID- 24768370 TI - Acute chest pain and emergency room echocardiogram assessment of a young woman with a large retrocardiac mediastinic bronchogenic cyst. PMID- 24768371 TI - First in man: amniotic stem cell injection promotes scar remodeling and healing processes in late-stage fibrosis. PMID- 24768372 TI - Baha'al-Dawlah Razi (d. 1508AD) and an early clinical description of supraventricular tachycardia. PMID- 24768373 TI - Left ventricular hypertrabeculation/noncompaction in an Eritrean war invalid with neuromuscular disease. PMID- 24768375 TI - Vascular response after percutaneous sympathectomy: not all devices are equal. PMID- 24768374 TI - A nationwide population-based retrospective cohort study: increased risk of acute myocardial infarction in systemic lupus erythematous patients. PMID- 24768376 TI - Severe right axis deviation during acute myocardial infarction. PMID- 24768377 TI - Increased reactive oxygen species production in epicardial adipose tissues from coronary artery disease patients is associated with brown-to-white adipocyte trans-differentiation. PMID- 24768378 TI - Risk of cardiovascular disease in patients on thrice-weekly versus twice-weekly hemodialysis. PMID- 24768379 TI - Chronobiological rhythms of acute cardiovascular events and underlying mechanisms. PMID- 24768380 TI - The potential usefulness of serum melatonin level to predict heart failure in patients with hypertensive cardiomyopathy. PMID- 24768381 TI - Cardiac calcification at transthoracic echocardiography predicts stress echo results: a multicentre study. PMID- 24768382 TI - Synchronous prevalence of obesity and elevated blood pressure among children and adolescents in Shandong, China. PMID- 24768383 TI - Fatal left-dominant arrhythmogenic cardiomyopathy involving a 25-year old professional football player: could it have been prevented? PMID- 24768384 TI - The DESERVE study: diffusion weighted-MRI based evaluation of the effectiveness of endovascular clamping during carotid artery stenting with the Mo.Ma device. PMID- 24768386 TI - Management and optical coherence tomography imaging of an acute coronary artery injury induced by radiofrequency catheter ablation. PMID- 24768385 TI - Association of computed tomography-derived left atrial size with major cardiovascular events in the general population: the Heinz Nixdorf Recall Study. AB - BACKGROUND: Echocardiography based data suggests that left atrial (LA) size is associated with cardiovascular morbidity and mortality. Once non-contrast cardiac CT is performed for prevention purposes, information on the LA is readily available. We aimed to determine whether LA area from non-contrast cardiac CT is associated with incident major cardiovascular (CV) events, independent of CV risk factors and coronary artery calcium (CAC), based on a general population cohort. METHODS: Subjects aged 45-75 years without prevalent CV disease from the population-based Heinz Nixdorf Recall Study were enrolled between 2000 and 2003. LA area at the level of the mitral valve was quantified from non-contrast cardiac CT. Major CV events (coronary event, stroke, CV death) were assessed during follow-up. The association of LA with events was assessed using Cox regression analysis. RESULTS: Overall, 3958 subjects (59.2 +/- 7.7 years, 53% female) were included. Mean LA area was 17.64 +/- 4.22 cm(2) (range: 7.16-44.13 cm(2)). During 8.0 +/- 1.5 years of follow-up, 221 major CV events occurred. In univariate analysis, increase of LA size by 1 standard deviation was associated with nearly 50% excess events (HR (95%CI): 1.48 (1.32-1.65)), which remained significant after adjustment for CV risk factors (HR (95%CI): 1.25 (1.09-1.43)) and when additionally adjusting for CAC (HR (95%CI): 1.22 (1.07-1.40)). Associations for LA size were similar for each endpoint and again independent of risk factors and CAC (coronary event: HR (95%CI): 1.21 (1.01-1.45); stroke: 1.31 (1.05-1.63); CV death: 1.33 (1.03-1.71)). CONCLUSION: LA size is associated with incident major CV events independent of risk factors and CAC-score. Once cardiac CT imaging is performed, assessment of LA size may complement information of this imaging modality. PMID- 24768387 TI - Rationale and design of a study to evaluate the effects of sitagliptin on atherosclerosis in patients with diabetes mellitus: PROLOGUE study. PMID- 24768388 TI - Tako-tsubo cardiomyopathy triggered by Influenza A virus infection. PMID- 24768389 TI - Percutaneous closure of a giant pseudoaneurysm of the ascending aorta after valve replacement. PMID- 24768390 TI - Impact of combined supine and prone myocardial perfusion imaging using an ultrafast cardiac gamma camera for detection of inferolateral coronary artery disease. AB - BACKGROUND: Although combined supine and prone acquisitions improve the detection of inferolateral obstructive coronary artery disease (CAD), the predictors of inaccurate detection of inferolateral ischemia have not been reported by using cadmium zinc telluride (CZT) myocardial perfusion imaging (MPI). METHODS AND RESULTS: Vasodilator stress (99m)Tc tetrofosmin MPI using CZT camera and coronary angiography was performed in 322 patients within an interval of 2 months. Prone MPI was performed immediately after supine MPI. Narrowing of the luminal diameter >= 75% was considered significant. The presence of an abnormality on both supine and prone images was considered significant. Combined supine and prone imaging, compared with supine-only quantification, was more specific (93% vs. 72%, respectively, p<0.0001) and accurate (88% vs. 74%, p<0.0001) without compromising sensitivity (82% vs. 68%, p=0.10). The area under the curve for detecting inferolateral ischemia was 0.769 (95% CI 0.705-0.833) for supine imaging and 0.802 (95% CI 0.730-0.875) for combined supine and prone imaging (p<0.05). Multivariable analysis revealed that previous inferolateral myocardial infarction was an independent predictor of a false diagnosis (odds ratio=3.45, 95% confidence interval [CI] 1.62-7.37, p<0.001). CONCLUSIONS: Combined supine and prone quantitative CZT MPI enhances the detection of inferolateral CAD without adversely affecting its sensitivity. However, we recommend inferolateral ischemia be monitored in patients with a history of previous inferolateral MI because previous inferolateral MI is a predictor of inaccurate diagnosis. PMID- 24768391 TI - Coexistence of two distinct fascinating cardiovascular disorders: heterotaxy syndrome with left ventricular non-compaction and vasospastic angina. PMID- 24768392 TI - A challenge in cardiology: the oncosurgery. PMID- 24768393 TI - Three dimensional insight to Austin Flint murmur. PMID- 24768394 TI - Stenting for atherosclerotic renal-artery stenosis: a blind alley? PMID- 24768395 TI - Strong association between activated valvular interstitial cells and histopathological lesions in porcine model of induced mitral regurgitation. PMID- 24768396 TI - Constrictive pericarditis in Erdheim-Chester disease: an integrated echocardiographic and magnetic resonance approach. PMID- 24768397 TI - Sympathetic stimulation affects atrial vulnerability in paroxysmal supraventricular tachycardia patients with atrial fibrillation. PMID- 24768398 TI - Red cell distribution width as predictive marker in CHF: testing of model performance by reclassification methods. PMID- 24768399 TI - Cardiopulmonary exercise testing is more accurate than ECG-stress testing in diagnosing myocardial ischemia in subjects with chest pain. AB - BACKGROUND: Cardiopulmonary exercise stress testing (CPET) is used to grade the severity of heart failure and to assess its prognosis. However it is unknown whether CPET may improve diagnostic accuracy of standard ECG stress testing to identify or exclude obstructive coronary artery disease (O-CAD) in patients with chest pain. METHODS: We prospectively studied 1265 consecutive subjects (55 +/- 8 years, 156 women) who were evaluated with ECG stress testing (ET) for chest pain. No one had a documented O-CAD. All patients performed an incremental CPET with ECG recordings on an electronically braked cycle ergometer. RESULTS: Of 1265 patients, 73 had a positive CPET and 1192 had a negative CPET. Seventy-three patients with a positive CPET and 71 patients with a negative CPET agreed to undergo nuclear SPECT imaging and coronary angiography. Follow-up lasted 48 +/- 7 months. As compared with ET, sensitivity, specificity, PPV and NPV were all improved significantly (ET: 48%, 55%, 33%, 95%; CPET: 88%, 98%, 73%, 99%, respectively, P<0.001). Patients with both peak VO2>91% of predicted VO2 max and absence of VO2-related signs of myocardial ischemia had no evidence of O-CAD in 100% of cases. Cardiac events occurred in 32 patients with a positive CPET and 8 patients with a negative CPET (log rank 18.2, P<0.0001). CONCLUSIONS: In patients with chest pain, CPET showed a better diagnostic and predictive accuracy than traditional ET to detect/exclude myocardial ischemia. Its use should be encouraged among physicians as a first line diagnostic tool in clinical practice. PMID- 24768400 TI - Abu Bakr Muhammad ibn Zakariya Razi (AD 865-925) and early description of clinical trials. PMID- 24768401 TI - The management of lower gastrointestinal bleeding. AB - Lower gastrointestinal (LGI) bleeding is generally less severe than upper gastrointestinal (UGI) bleeding with spontaneous cessation of bleeding in 80% of cases and a mortality of 2-4%. However, unlike UGI bleeding, there is no consensual agreement about management. Once the patient has been stabilized, the main objective and greatest difficulty is to identify the location of bleeding in order to provide specific appropriate treatment. While upper endoscopy and colonoscopy remain the essential first-line examinations, the development and availability of angiography have made this an important imaging modality for cases of active bleeding; they allow diagnostic localization of bleeding and guide subsequent therapy, whether therapeutic embolization, interventional colonoscopy or, if other techniques fail or are unavailable, surgery directed at the precise site of bleeding. Furthermore, newly developed endoscopic techniques, particularly video capsule enteroscopy, now allow minimally invasive exploration of the small intestine; if this is positive, it will guide subsequent assisted enteroscopy or surgery. Other small bowel imaging techniques include enteroclysis by CT or magnetic resonance imaging. At the present time, exploratory surgery is no longer a first-line approach. In view of the lesser gravity of LGI bleeding, it is most reasonable to simply stabilize the patient initially for subsequent transfer to a specialized center, if minimally invasive techniques are not available at the local hospital. In all cases, the complexity and diversity of LGI bleeding require a multidisciplinary collaboration involving the gastroenterologist, radiologist, intensivist and surgeon to optimize diagnosis and treatment of the patient. PMID- 24768402 TI - DSC investigation of the effect of the new sigma ligand PPCC on DMPC lipid membrane. AB - The new sigma ligand cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4 phenylpiperidin-1-yl) methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(+/-) PPCC] is a promising tool for the treatment of various diseases. With the aim to investigate the absorption of (+/-)-PPCC by the cell membranes, in this study we evaluated the influence on thermotropic behavior of membrane model exerted by PPCC both as free base or as oxalic salt. To fulfill this purpose differential scanning calorimetry was used. The findings highlight that PPCC affects the thermodynamic parameters of phospholipids in different manner depending on whether it is in the salt or base form as well as function of the amount of drugs dispersed in the lipid matrix. The salt form of PPCC was uptaken by the membrane model faster than the free base. In addition, preliminary information on the use of a lipophilic carrier for PPCC was obtained. PMID- 24768403 TI - Highly efficient delivery of siRNA to a heart transplant model by a novel cell penetrating peptide-dsRNA binding domain. AB - Small interfering RNAs (siRNAs) delivery remains a bottleneck for RNA interference (RNAi) - based therapies in the clinic. In the present study, a fusion protein with two cell-penetrating peptides (CPP), Hph1-Hph1, and a double stranded RNA binding domain (dsRBD), was constructed for the siRNA delivery: dsRBD was designed to bind siRNA, and CPP would subsequently transport the dsRBD/siRNA complex into cells. We assessed the efficiency of the fusion protein, Hph1-Hph1-dsRBD, as a siRNA carrier. Calcium-condensed effects were assessed on GAPDH and green fluorescent protein (GFP) genes by western blot, real time polymerase chain reaction (RT-PCR), and flow cytometry analysis in vitro. Evaluations were also made in an in vivo heart transplantation model. The results demonstrated that the fusion protein, Hph1-Hph1-dsRBD, is highly efficient at delivering siRNA in vitro, and exhibits efficiency on GAPDH and GFP genes similar to or greater than lipofectamine. Interestingly, the calcium-condensed effects dramatically enhanced cellular uptake of the protein-siRNA complex. In vivo, Hph1 Hph1-dsRBD transferred and distributed ^ targeted siRNA throughout the whole mouse heart graft. Together, these results indicate that Hph1-Hph1-dsRBD has potential as an siRNA carrier for applications in the clinic or in biomedical research. PMID- 24768404 TI - Natural melanin: a potential pH-responsive drug release device. AB - This work proposes melanin as a new nanocarrier for pH-responsive drug release. Melanin is an abundant natural polymer that can be easily extracted from cuttlefish as nanoparticles with a suitable size range for drug delivery. However, despite its high potentiality, the application of this biopolymer in the pharmaceutical and biomedical fields is yet to be explored. Herein, melanin nanoparticles were impregnated with metronidazole, chosen as model antibiotic drug, using supercritical carbon dioxide. The drug release profile was investigated at acidic and physiologic pH, and the dominant mechanism was found to follow a non-Fickian transport. Drug release from melanin shows a strong pH dependency, which allied to its biocompatibility and lack of cytotoxicity envisages its potential application as nanocarrier in formulations for colon and intestine targeted drug delivery. PMID- 24768405 TI - In situ covalently cross-linked PEG hydrogel for ocular drug delivery applications. AB - Avastin((r)) has been clinically proved to be effective in the treatment of intraocular neovascularization diseases. However, the short half-life of Avastin((r)) need frequent administration to maintain its therapeutic efficiency. In this paper, we attempted to develop an in situ PEG hydrogels with great biocompatibility for sustained release of Avastin((r)) to inhibit the corneal neovascularization. PEG hydrogels was formed via thiol-maleimide reaction using 4 arm PEG-Mal and 4-arm PEG-SH. The transparent hydrogel was rapidly formed under physiological conditions. By varying the concentration of 4-arm PEG-SH, PEG hydrogel with different gelling time, pore size, swelling ratio and mechanical property could be obtained. In vitro cytotoxicity indicated that the developed PEG hydrogel had no apparent cytotoxicity on L-929 cells after 7 days of incubation. In vitro release study showed the encapsulated Avastin((r)) was sustained release from PEG hydrogels within a period of 14 days study. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis further confirmed that the released Avastin((r)) did not undergo apparent hydrolysis within 14 days. As a conclusion, we could conclude that the developed PEG hydrogels as an injectable hydrogels might be suitable for extended Avastin((r)) release to treat the corneal neovascularization. PMID- 24768406 TI - Microencapsulation of mechano growth factor E peptide for sustained delivery and bioactivity maintenance. AB - Mechano growth factor (MGF) and its C-terminal E-peptide with 24 amino acids, MGF Ct24E, have superiority in resolving the delayed or failed bone repair derived from shortness of suitable biomechanical stimulation. The chitosan/tripolyphosphate microspheres encapsulated with MGF-Ct24E (CS/TPP/MGF Ct24E) are prepared using emulsion-ionic cross-linking method in order to achieve the sustained release and preserve the bioactivity of MGF-Ct24E. The microspheres are micron-sized and spherical in shape with smooth surface morphology. The TPP component disintegrates in advance of CS matrix and the MGF-Ct24E maintains sustained delivery during in vitro hydrolytic degradation. With the disappearance of TPP, the total weight loss of CS/TPP/MGF-Ct24E is 32% and the release amount of MGF-Ct24E reaches 84.6% after degrading for 2 weeks. In vitro bioactivity assays reveal that the MGF-Ct24E can accelerate MC3T3-E1 cells proliferation and delay their differentiation as well. The encapsulated MGF-Ct24E shows long-term effects after being loaded in the CS/TPP microspheres and the cells exhibit excellent morphology on the surface of microspheres. The continuous delivery of MGF-Ct24E provides a new perspective on resolving the unsatisfactory bone reconstruction associated with microgravity and stress shielding. PMID- 24768407 TI - Effect of olmesartan on the levels of circulating endothelial progenitor cell after drug-eluting stent implantation in patients receiving statin therapy. AB - BACKGROUND: The endothelial progenitor cell (EPC) plays an important role in repairing vascular injury. Statins and angiotensin II receptor blockers increase the level of circulating EPCs. However, it is unknown whether the angiotensin II receptor blocker olmesartan synergistically acts with statins to increase the levels of circulating EPCs. Moreover, the association between the levels of circulating EPCs and endothelial dysfunction after implantation of drug-eluting stents (DESs) has not been evaluated. METHODS: Nine patients with stable coronary artery disease underwent percutaneous coronary intervention (PCI) and received DES implantation. All patients received olmesartan in addition to statin therapy after PCI. The dose of olmesartan was based on the physician's discretion as per the patients' blood pressure. The levels of circulating EPCs were analyzed at baseline, post-PCI, and 1, 2, 3, and 8 months after PCI. Coronary angiography and the acetylcholine provocation test were performed on all patients at 8 months. RESULTS: Although the angiotensin II level significantly changed, the levels of circulating EPCs did not change during 8 months of olmesartan treatment (3.1+/ 0.6cells/ml, 2.5+/-0.8cells/ml, 2.0+/-0.6cells/ml, 2.9+/-0.9cells/ml, 3.0+/ 0.4cells/ml, 3.4+/-0.8cells/ml, p=0.64). The patients were subsequently divided into two groups based on whether the level of circulating EPCs was less or greater than 4cells/ml at 8 months. There were no significant differences in the mean vessel diameter of each segment (proximal, proximal edge, distal edge, and distal) after the acetylcholine provocation test between the two groups. CONCLUSIONS: Low-to-moderate doses of olmesartan might not increase the level of circulating EPCs in patients receiving statin therapy. There might be no association between the levels of circulating EPCs and the degree of coronary vasospasm in the acetylcholine provocation test 8 months after DES implantation. PMID- 24768408 TI - Phenotypic overlap in hypertrophic cardiomyopathy: apical hypertrophy, midventricular obstruction, and apical aneurysm. AB - BACKGROUND: Within the diverse phenotypic spectrum of hypertrophic cardiomyopathy (HCM), subgroups of patients with apical hypertrophy (APH), midventricular obstruction (MVO), and apical aneurysm (APA) have emerged. While previous studies have suggested the existence of considerable overlap between APH, MVO, and APA, there are still many unanswered questions. Therefore, we attempted to clarify the relationship of the above three phenotypes of HCM with respect to prevalence, overlap, and outcomes. METHODS: Among the 544 study HCM patients (mean follow-up period: 11.6+/-7.4 years), 170 with APH (31.3%), 51 with MVO (9.4%), and 24 with APA (4.4%) were examined. RESULTS: There was phenotypic overlap between APH and MVO in 17 patients, APH and APA in 14 patients, and MVO and APA in 14 patients. Furthermore, a combination of APH, MVO, and APA was observed in eight patients. Detailed analysis of the relationship between overlapping phenotypes and the prognosis showed that APA patients without a history of APH had an extremely poor outcome (probability of the combined endpoint of sudden death and potentially lethal arrhythmic events >=50%). Conversely, APH patients without MVO had a strikingly good outcome (probability of the combined endpoint <5%). Other patients had an intermediate outcome (probability of the combined endpoint 10 40%). CONCLUSIONS: Our results suggest that overlap between these three forms of HCM is substantial, and that detailed classification of the overlapping phenotypes is clinically meaningful. PMID- 24768409 TI - Cognitive mediators and disparities in the relation between teen depressiveness and smoking. AB - BACKGROUND: Depressiveness and tobacco use in adolescents are linked, however, there is limited evidence about the cognitive mediators involved and how the role of mediators may differ by gender and racial/ethnic subgroups. METHODS: We used a racially/ethnically diverse population-based cross-sectional sample of middle and high school students (n=24,350). Logistic regression models measured the associations of depressiveness with tobacco smoking status, and whether smoking related knowledge and attitudes (KA) and smoking refusal self-efficacy (SE) attenuated the associations indicating preliminary evidence of mediation. RESULTS: Depressiveness was associated with intention to smoke (OR=2.41; 95% CI=2.22, 2.61), experimental smoking (OR=1.93; 95% CI=1.72, 2.17) and established smoking (OR=1.85; 95% CI=1.57, 2.18). The percent attenuation of these associations due to the inclusion of smoking-related KA and smoking refusal SE was 58% for intention to smoke (p<0.001), 68% for experimental smoking (p<0.001) and 86% for established smoking (p<0.001). The association of depressiveness with established smoking did not remain statistically significant (OR=1.16; CI=0.97, 1.40) after including smoking-related KA and smoking refusal SE. Attenuation was more pronounced in males and white students. CONCLUSIONS: The results suggest that smoking-related KA and smoking refusal SE attenuated the relation between depressiveness and smoking, indicating that they may serve as mediators of the link between depressiveness and smoking. Tobacco use prevention programs targeting teens with the aim of increasing anti-smoking KA and smoking refusal SE may benefit from addressing depressiveness, particularly by using gender and racially/ethnically tailored strategies. The cross-sectional nature of the data precludes causal inferences. PMID- 24768410 TI - Contingency management for smoking cessation among treatment-seeking patients in a community setting. AB - BACKGROUND: Contingency management (CM) is an efficacious intervention for reducing cigarette smoking. However, CM is rarely adopted as a smoking cessation treatment in the community. This study analyzed the effectiveness of a CM procedure in combination with a cognitive-behavioral treatment (CBT) for smoking cessation among treatment-seeking patients from the general population. METHODS: A total of 92 patients were randomly assigned to one of two treatment conditions: CBT (N=49) or CBT+CM (N=43). The CM procedure included a voucher program through which nicotine abstinence was reinforced on a schedule of escalating magnitude of reinforcement with a reset contingency. Self-reported smoking status was confirmed with both carbon monoxide (CO) level in expired air and cotinine levels in urine. RESULTS: Of the patients who received CBT+CM 97.7%, completed 6 weeks of treatment, versus 81.6% of those who received CBT (p=.03). At the post treatment assessment, 95.3% of the patients assigned to the CBT+CM condition achieved abstinence in comparison to the 59.2% in the CBT group (p=.000). At the one-month follow-up, 72.1% of the patients who received CBT+CM maintained smoking abstinence, versus 34.7% in the CBT group (p=.001). At the six-month follow-up, 51.2% of the patients who received CBT+CM maintained smoking abstinence in comparison to the 28.6% in the CBT group (p=.04). CONCLUSIONS: Results from this randomized clinical trial showed that adding CM to a CBT is effective, and is feasible as an intervention approach with treatment-seeking patients in a community setting. PMID- 24768411 TI - Antileishmanial activity of essential oil from Chenopodium ambrosioides and its main components against experimental cutaneous leishmaniasis in BALB/c mice. AB - Chenopodium ambrosioides have been used during centuries by native people to treat parasitic diseases. AIMS OF THE STUDY: To compare the in vivo anti leishmanial activity of the essential oil (EO) from C. ambrosioides and its major components (ascaridole, carvacrol and caryophyllene oxide). MATERIALS AND METHODS: Anti-leishmanial effect was evaluated in BALB/c mice infected with Leishmania amazonensis and treated with the EO, main compounds and artificial mix of pure components by intralesional route at 30 mg/kg every 4 days during 14 days. Diseases progression and parasite burden in infected tissues were determined. RESULTS: EO prevented lesion development compared (p<0.05) with untreated animals and treated with vehicle. In addition, the efficacy of EO was also statistically superior (p<0.05) compared with the glucantime-treated animals. No potential effects were observed with pure components treatment. Mix of pure compounds cause death of animals after 3 days of treatment. CONCLUSIONS: Our results demonstrate the superiority of EO against experimental cutaneous leishmaniasis caused by L. amazonensis. PMID- 24768412 TI - Prevalence of food allergy in New York City school children. PMID- 24768413 TI - Basic research in PCOS: are we reaching new frontiers? AB - Polycystic ovarian syndrome (PCOS) is the leading cause for anovulatory infertility. It is diagnosed by two of the following three clinical criteria: oligomenorrhoea, hyperandrogenism and polycystic appearance of the ovaries. Weight loss and physical activity can lead to ovulation and conception. Lowering of serum insulin normalizes androgen concentrations whereas ovulation induction often causes ovarian hyperstimulation. Theca cells from PCOS ovaries may be more responsive to insulin than cells from non-PCOS ovaries. Herein we review the research efforts at the genomic and cell function levels, as well as animal models, which have been made to elucidate the underlying mechanism that leads to PCOS. It appears that, despite the impressive amount of data that have been generated in these studies, the mechanism of this syndrome is still only partially understood. Polycystic ovarian syndrome (PCOS) is the leading cause for infertility, which is caused by anovulation. It is diagnosed by two of the following three clinical criteria: irregular and prolonged menstrual cycles, overt symptoms of excess androgens, which is revealed by acne and excess hair, and ultrasonographic appearance of the ovaries with multiple small follicles spread mainly near the ovarian surface, which gave it its name. Intentional weight loss and physical activity can lead to resumption of ovulation and not infrequently to conception as well. It was shown that lowering of serum insulin accounts for normalization of serum androgen levels, whereas ovulation induction with FSH often causes ovarian hyperstimulation. It is suggested that theca cells from PCOS ovaries may be more responsive to insulin than cells from non-PCOS ovaries. In this article we review the efforts to define the genes responsible for the syndrome and the studies at the cell function level, as well as animal models, which have been done to elucidate the underlying mechanism that leads to PCOS. Overall, it appears that despite the impressive amount of data that have been generated in these studies, the mechanism of this syndrome is still only partially understood. PMID- 24768414 TI - Use of mixed culture bacteria for photofermentive hydrogen of dark fermentation effluent. AB - Hydrogen production (HP) from dark fermentation effluent of starch wastewater via vertical tubular photo-bioreactor was investigated. The reactor was inoculated with mixed culture of bacteria and operated at light intensity of 190 W/m(2). Hydraulic retention time (HRT) and organic loading rate (OLR) was varied between 0.9 to 4.0 h and 3.2 to 16 g COD/l.d., respectively. Increasing the HRT from 0.9 to 2.5 h, significantly (P<0.05) increased HP from 1+/-0.04 to 3.05+/-0.19 l/d, respectively. However, minimal increase in HP occurred when increasing the HRT up to 4.0 h. The HP remained unaffected when increasing the OLR from 3.2 to 6.4 g COD/l.d. Further increase in the OLR up to 8.2 and 16 g COD/l.d., resulted in a drop in HP i.e. 0.96 and 0.19 l/d, respectively. Microbial community analysis of the reactor samples showed the presence and dominance of hydrogen producing purple non-sulfur phototrophic (PNS) bacterium, Rhodopseudomonas palustris in the reactor. PMID- 24768415 TI - The optimization of biomass and lipid yields of Chlorella sorokiniana when using wastewater supplemented with different nitrogen sources. AB - The potential of nitrogen sources supplementing domestic wastewater for the cultivation of microalgae was assessed. Urea, potassium nitrate, sodium nitrate and ammonium nitrate were evaluated for their effect on cultivation and lipid production of Chlorella sorokiniana. Urea showed the highest biomass yield of 0.220 g L(-1) and was selected for further experimentation. Urea concentrations (0-10 g L(-1)) were assessed for their effect on growth and microalgal physiology using pulse amplitude modulated fluorometry. A concentration of 1.5 g L(-1) urea produced 0.218 g L(-1) biomass and 61.52% lipid by relative fluorescence. Physiological stress was evident by the decrease in relative Electron Transport Rate from 10.45 to 6.77 and quantum efficiency of photosystem II charge separation from 0.665 to 0.131. Gas chromatography analysis revealed that C16:0, C18:0, C18:1, C18:2 and C18:3 were the major fatty acids produced by C. sorokiniana. Urea proved to be an effective nitrogen supplement for cultivation of C. sorokiniana in wastewater. PMID- 24768416 TI - The influence of axillary reverse mapping related factors on lymphedema in breast cancer patients. AB - PURPOSE: Upper extremity lymphedema (LE) is a harmful breast cancer complication. It has been reported that patient- or treatment-related risk factors of LE. Axillary reverse mapping (ARM) has been performed to prevent LE during axillary lymph node dissection (ALND) by visualizing the upper extremity lymphatics. We investigated whether ARM related factors included novel predictive risk factors of LE. METHODS: ARM revealed fluorescent axillary nodes (ARM nodes) in 76 patients by fluorescence imaging. Only ARM nodes within the ALND field were removed. Twenty-four (32%) patients developed LE (LE+) and 52 did not (LE-) during a median 24-month post-surgical follow-up period. We retrospectively evaluated the clinical features and ARM factors of LE+ and LE-. RESULTS: The positive ARM node rate among LE+ was 42%, significantly greater frequency than that among LE- (13%: p <= 0.05). Cranial collectors (lymphatic ducts along or above the axillary vein) were significantly more frequent in LE- (44%) than in LE+ (21%: p <= 0.05). Multivariate analysis revealed postoperative radiation and positive ARM nodes to be positive risk factors and cranial collectors to be a negative risk factor of LE. CONCLUSIONS: ARM factors could predict the incidence of LE post-axillary surgeries in breast cancer patients. PMID- 24768417 TI - Histologic and immunohistochemical analysis of the antiatherogenic effects of myocardial bridging in the adult human heart. AB - BACKGROUND: Myocardial bridging is a common anatomic variation of the human heart in which an epicardial coronary artery takes an intramural course within the myocardium. Studies have proposed that myocardial bridges offer a "protective effect" from atherosclerosis within the involved coronary artery. METHODS: We examined 250 formalin-fixed human hearts with gross dissection and histologic and immunohistochemical techniques. The bridged arteries were divided into premyocardial, myocardial, and postmyocardial segments. Atherogenic activity was assessed by comparing proliferative activity (Ki-67), smooth muscle alpha-actin, and macrophages. In addition, atherosclerotic lesions were carefully categorized according to the Stary classification. RESULTS: The presence of myocardial bridges was confirmed in 92 hearts (36.8%). The most common location of a myocardial bridge was over the anterior interventricular artery in 38 (41.3%) hearts. Overall, the bridged segments demonstrated weaker Ki-67 activity, a decreased number of smooth muscle cells and macrophages, and lower modal Stary classifications for atherosclerosis severity as compared to pre- and postbridge segments of the same coronary artery. CONCLUSION: Atherosclerotic lesions in vessel sections deep to the myocardial bridges were found to be less developed in contrast to the pre- and postbridge segments of the same coronary arteries. Although the precise mechanism of atherogenic protection is unknown, it has been proposed that compression by the contracting myocardium stimulates the release of anticoagulant and growth factors, which could have a synergistic effect in protecting the endothelium from denudation, inflammation, and resultant atherosclerosis. PMID- 24768418 TI - Surgically assisted maxillary expansion imparts three-dimensional nasal change. AB - PURPOSE: The impact of surgically assisted maxillary expansion (SAME) on facial soft tissue structures has not been adequately studied using 3-dimensional (3D) objective analysis. The purpose of this study was to analyze nasolabial soft tissue after SAME using 3D photographic technology. MATERIALS AND METHODS: This was a retrospective cohort study of patients undergoing SAME in which pre- and postexpansion 3D photographs (3D VECTRA Photosystem, Canfield, Fairfield, NJ) were analyzed. Nasolabial anthropometric measurements were performed using the 3D postprocessing software (Mirror). A follow-up period of at least 6 months was required for final evaluation. Two observers verified the landmarks on each dataset before measuring. Statistical analysis involved the paired t test, the Simes correction for multiple comparisons, and repeated measures analysis of covariance (ANCOVA) to control for age, gender, and the time lag between pre- and postoperative assessments. RESULTS: Twelve patients (24 photogrammetric datasets) were included. The male-to-female ratio was 0.5 (mean age, 17.3 yr). Nasal changes after SAME showed significant increases (P < .05) in alar width (from 33.1 to 34.5 mm), sill width (from 9.2 to 9.7 mm), and columella projection (from 94.1 to 95.1 mm) after the Simes correction. ANCOVA showed a significant increase in alar base width. Distinct changes in nostril shape and dimension were found, but lacked statistical significance. CONCLUSION: Three-dimensional analysis shows widening of the alar width and alar base width after SAME. The magnitude of nasal change parallels that of expansion at the piriform aperture. PMID- 24768419 TI - Arteriovenous fistula of the middle meningeal artery--a rare complication after arthroscopic temporomandibular joint surgery readily amenable to endovascular treatment. AB - The development of a traumatic arteriovenous fistula after arthroscopic surgery of the temporomandibular joint (TMJ) is an unusual event that has been limited to a few case reports. These have generally involved the superficial temporal artery and surrounding venous outlets. No cases of either postoperative or post traumatic arteriovenous fistulas involving the extracranial middle meningeal artery (MMA), which is located on the medial surface of the TMJ, have been previously reported. We report, to our knowledge, the first case of this unusual complication and describe its successful endovascular management. PMID- 24768420 TI - Surgical treatment of vascular malformations of the facial bones. AB - PURPOSE: To characterize intraosseous vascular malformations and describe the most appropriate approach for treatment according to clinical experience and a review of the published data. MATERIALS AND METHODS: We performed a retrospective review of 11 vascular malformations (7 venous and 4 arteriovenous) of the facial bones treated during a 10-year period using en bloc resection or intraoral aggressive curettage alone or preceded by endovascular embolization. Corrective surgery was planned to address any residual bone deformities. The cases were reviewed at a mean follow-up point of 6 years. RESULTS: Facial symmetry was restored in the cases requiring reconstruction. Tooth sparing was possible in the case of jaw and/or maxillary localization. Recanalization occurred in 14% of the venous and 33% of the arteriovenous malformations. CONCLUSIONS: Facial intraosseous venous malformations can be successfully treated using surgery alone. Facial intraosseous arteriovenous malformations will be better addressed using combined approaches. Aggressive curettage will obviate the need for extensive surgical resection in selected cases. PMID- 24768421 TI - Reduction malarplasty according to esthetic facial unit analysis: retrospective clinical study of 23 cases. AB - PURPOSE: Because the zygoma is located in the middle third of the face, its prominence, contour, and width will have a large effect on the facial impression. Unlike whites who will mainly complain of a hypoplastic zygoma, Asians will commonly present with a prominent zygoma. The purposes of the present retrospective study were to evaluate the indications for reduction malarplasty and to analyze the complications of patients who underwent reduction malarplasty. PATIENTS AND MATERIALS: According to the esthetic facial unit concept, a patient with a hyperplastic anterior midface can undergo reduction body malarplasty (RBM). If a patient complains of a hyperplastic anterior and posterior mid-face, the clinician can perform reduction body and arch malarplasty (RBAM). The subjects included 23 adult patients (5 males and 18 females; mean age 22 years; 11 RBM and 12 RBAM; mean follow-up period 30 months). RESULTS: The early and late postoperative complications and patient satisfaction with their appearance were investigated retrospectively. Complications after RBM included transient skin numbness around the zygoma in 1, a nonfractured zygomatic arch in 1, and a nonunionized zygomatic body in 1. After RBAM, 3 patients complained of transient skin numbness around the zygoma and 2 of transient injury to facial nerve. The skin numbness and facial nerve weakness resolved within a few months. For the nonfractured zygomatic arch and nonunionized zygomatic body, repeat fixation with miniplates and screws was performed. All the patients were satisfied with the surgical results. CONCLUSIONS: If an appropriate type of reduction malarplasty has been chosen using the esthetic facial unit concept, reduction malarplasty can effectively improve the facial esthetics without serious postoperative complications. PMID- 24768422 TI - Does increased free flap size in the head and neck region impact clinical outcome? AB - PURPOSE: There are few studies analyzing the long-term clinical effects related to increasing the size of head and neck free tissue reconstructions. The purpose of this study was to compare long-term clinical outcomes of patients undergoing very large area (>=200 cm(2)) and large area (100 to 199 cm(2)) free tissue reconstructions of head and neck defects. PATIENTS AND METHODS: Institutional review board approval was obtained before conducting this retrospective cohort study at the authors' university-based tertiary care hospitals. The authors analyzed the charts of consecutive patients with free flaps of at least 100 cm(2) treated from July 2000 to December 2011. Very large area flaps were arbitrarily defined as larger than 200 cm(2). Intraoperative variables, flap success rates, overall survival, and total hospital and intensive care unit (ICU) stays for the 2 groups were analyzed. Fisher exact tests or chi(2) tests were used for categorical variables and Student t tests were used for continuous variables. Log rank tests were conducted to investigate whether overall survival was significantly different between the 2 groups. Statistical significance was defined as a P value less than .05. RESULTS: The charts of 121 consecutive patients were analyzed. Thirty-eight patients (31%) had very large area flaps (277.1 +/- 79.4 cm(2); range, 200 to 576 cm(2)) and 83 patients (69%) had large area flaps (140.1 +/- 25.5 cm(2)). There was no difference between flap groups in presenting T4 stage disease (P = .448). Ninety-eight percent of the very large area flaps and 93% of the large area flaps survived. Total hospital stays for the very large area and large area flap groups were 12.8 +/- 8.2 and 12.3 +/- 8.3 days, respectively (P = not significant). In contrast, ICU stays were increased for the very large area flap group at 7.1 +/- 7.5 versus 4.0 +/- 4.0 days for the large area flap group (P = .022). The overall median patient survival for the very large area flap group was 7.6 months (95% confidence interval, 5.7-10.0) and that for the large area flap group was 8.4 months (95% confidence interval, 5.4 12.9; P = .376). CONCLUSION: Performing very large area flaps for head and neck reconstruction did not negatively affect clinical outcome. Comparable success rates, total hospital stays, and overall survival can be safely achieved in this difficult patient population. More studies need to be conducted on resource usage. PMID- 24768423 TI - Inverted periosteal flap: an alternative to the buccal advancement flap for tension-free, watertight closure. AB - The buccal advancement flap has been universally used in oral and maxillofacial surgery for closure of alveolar ridge incisions. It involves scoring of the buccal periosteum to enhance flap mobility and then stretching the buccal tissues medially (palatally or lingually) to obtain tension-free, watertight closure of a wound. Its applications have included, but have not been limited to, alveolar ridge augmentation procedures and closure of oral-antral communications. However, the buccal advancement flap technique has several major disadvantages. First, because the buccal flap is advanced crestally and medially, this technique invariably results in a significant reduction in vestibular depth. This can cause patients discomfort, such that they have described a sensation that their buccal mucosa has been sutured to their alveolar mucosa. In addition to being uncomfortable, this vestibular shortening can adversely affect patients' options for future prosthetic rehabilitation. Second, because the buccal flap is advanced medially, the mucogingival junction will be obliged to follow; therefore, the width of the keratinized tissue on the buccal aspect of the alveolus will be diminished. Third, if the buccal flap has been advanced a large distance, even with aggressive periosteal scoring and release, true tension-free closure can be very difficult to achieve, increasing the risk of wound dehiscence. The inverted periosteal flap is a new technique for flap design and closure that has several advantages over the buccal advancement flap. In my experience, the inverted periosteal flap will preserve the vestibular depth, maintain the keratinized gingival dimensions, and provide true tension-free closure. Thus, this flap could be ideal for any oral and maxillofacial surgical procedure in which tension-free, watertight closure is desired. PMID- 24768424 TI - Serum AMH levels in the differential diagnosis of hyperandrogenemic conditions. AB - OBJECTIVE: To investigate the diagnostic potential of anti-Mullerian hormone (AMH) in the differential diagnosis of various hyperandrogenemic conditions. STUDY DESIGN: Among 2241 consecutive women of reproductive age who were seen at a tertiary care university hospital with complaints of acne, hirsutism, androgenetic alopecia, and menstrual dysfunction (oligomenorrhea and/or amenorrhea), 107 patients with serum 17alpha-hydroxyprogesterone (17alpha-OHP) levels higher than 2 ng/ml were recruited for this study. An ACTH stimulation test was performed, and basal serum hormonal parameters and AMH levels were measured for all patients. RESULTS: 25 patients were diagnosed with late-onset congenital adrenal hyperplasia (LOCAH), and 59 patients with polycystic ovary syndrome (PCOS) had significantly higher serum AMH levels than all other groups. CONCLUSION: Among hyperandrogenemic patients with serum 17alpha-OHP levels >2 ng/ml, serum AMH levels might be introduced as a marker to be utilized clinically in the differential diagnosis of hyperandrogenemic patients, especially for identifying patients with PCOS. PMID- 24768425 TI - Management of caesarean scar pregnancy with large gestational mass: case report. PMID- 24768426 TI - Serotonin syndrome in patients with peripheral neuropathy: a diagnostic challenge. AB - According to the Hunter Serotonin Toxicity Criteria, the presence of either clonus or hyperreflexia is a must for making a diagnosis of serotonin syndrome (SS). We report five patients with SS who had areflexia because of associated polyneuropathy. None of the patients fulfilled the Hunter criteria for SS. However, all five patients had features suggestive of neuromuscular hyperactivity, autonomic hyperactivity and altered mental status and fulfilled the Sternbach criteria for SS. All patients responded to cyproheptadine within 5 days to 2 weeks duration. These cases highlight the limitations of the Hunter criteria for SS in patients with associated polyneuropathy. PMID- 24768427 TI - Estrogen receptor expression and vessel density in the vagina wall in postmenopausal women with prolapse. AB - After menopause, critically estrogen low levels result in modifications in vaginal wall. This cross-sectional study aims to determine whether there is a change in the number of vessels in the lamina propria of the vagina after menopause in parallel to the ER-alpha expression on the vaginal wall. Twelve women who underwent a genital surgery for genital prolapse up to grade II were selected. They were divided into two groups: a premenopausal group (PG) consisting of six women who were 18-40 years old with FSH levels =12 mIU/ml and regular cycles, and a menopausal group (MG) consisting of six women at least one year after menopause who were <65 years old with FSH levels =40 mIU/ml. Slides were stained for ER-alpha immunohistochemistry, and an endothelial cell marker CD3 was used to label vessels which were identified by using a system for morphometry. The number of vessels was significantly higher in the PG than in the MG both on the anterior wall (PG: 1.055 +/- 145.8 vessels/mm(2), MG: 346.6 +/- 209.9 vessels/mm(2), p<0.0001) and on the posterior wall (PG: 1064 +/- 303.3 vessels/mm(2), MG: 348.6 +/- 167.3 vessels/mm(2), p=0.0005). The ER-alpha score was significantly higher in the PG than the score for the MG on both the anterior and posterior walls (PG: 6.0 +/- 0.52, MG: 2.5 +/- 0.89, p=0.007; PG: 5.8 +/- 0.79, MG: 2.7 +/- 0.95, p=0.03, respectively). There was a positive correlation between the ER-alpha score and the vessel concentration on the anterior (r=0.6656, p=0.018) and posterior (r=0.6738, p=0.016) vaginal walls. Age was strongly negatively correlated with vessel concentration on the vaginal walls (respectively r=-0.9033, p<0.0001, r=-0.7440, p=0.0055). Therefore, postmenopausal women with genital prolapse have a smaller number of vessels on the vaginal wall compared to normoestrogenic controls with the same pathological condition. Hypoestrogenism and advancing age are factors that are associated to these changes. PMID- 24768428 TI - [Protocol of treatment of vitamin D deficiency]. PMID- 24768429 TI - ECP and solid organ transplantation. AB - Since its introduction in photomedicine in 1983 ECP (extracorporeal photopheresis) has over the past decades been established as a safe and effective treatment approach for the palliative management of patients with cutaneous T cell lymphoma, the Sezary syndrome variant in particular. Subsequently its effectiveness has been well documented in a number of additional T-cell-mediated diseases, particularly in the treatment and prevention of acute and chronic graft vs. -host disease. More recently, ECP has been successfully used to treat acute heart allograft rejection and chronic allograft dysfunction after lung transplantation without increasing infectious complications. As recently documented ECP was also used as a part of CNI (calcineurin inhibitors) sparing or staggering protocols. For this group of patients it is proposed that its efficacy may be partly attributed through direct induction of lymphocyte apoptosis (Tambur et al., 2000) [1] and subsequent production of regulatory T cells (Treg) (Lamioni et al., 2007) [2,3] without causing general immunosuppression. However, the exact indications for use of ECP within this framework are not yet finalized. PMID- 24768430 TI - Cognitive status moderates the relationship between out-of-home behavior (OOHB), environmental mastery and affect. AB - Studies on the relationship between behavioral competence, such as the competence of exerting out-of-home behavior (OOHB), and well-being in older adults have rarely addressed cognitive status as a potentially moderating factor. We included 35 persons with early-stage dementia of the Alzheimer's type (DAT), 76 individuals with mild cognitive impairment (MCI) and 146 cognitively healthy (CH) study participants (grand mean age: M=72.9 years; SD=6.4 years). OOHB indicators were assessed based on a multi-method assessment strategy, using both GPS (global positioning system) tracking technology and structured self-reports. Environmental mastery and positive as well as negative affect served as well being indicators and were assessed by established questionnaires. Three theoretically postulated OOHB dimensions of different complexity (out-of-home walking behavior, global out-of-home mobility, and out-of-home activities) were supported by confirmatory factor analysis (CFA). We also found in the DAT group that environmental mastery was substantially and positively related to less complex out-of-home walking behavior, which was not the case in MCI and CH individuals. In contrast, more complex out-of-home activities were associated with higher negative affect in the DAT as well as the MCI group, but not in CH persons. These findings point to the possibility that relationships between OOHB and well-being depend on the congruence between available cognitive resources and the complexity of the OOHB dimension considered. PMID- 24768431 TI - Habitual physical activity (HPA) as a factor in sustained executive function in Alzheimer-type dementia: a cohort study. AB - Evidence from studies on healthy older adults and mild cognitive impairment (MCI) populations suggests that physical activity interventions have a positive effect on executive function. In this study, we consider whether HPA is positively associated with executive function in Alzheimer's disease (AD). Eighty-two participants with a diagnosis of mild to moderate AD completed six measures of executive function. Objective measures of physical status were taken. In addition, informants completed questionnaires on the participants' HPA and other lifestyle factors. A composite measure of executive function was the primary outcome. A multistage multiple regression was used to determine how much variance HPA accounted for. The final model comprised disease severity, cognitive reserve, cognitive activities, neuropsychiatric status and HPA status. The final model accounted for a total of 57% of the variance of executive performance, of which HPA itself accounted for 8% of the variance. HPA status is associated executive performance in an AD population even after controlling for key covariates. The findings encourage clinicians to recommend HPA and its cognitive benefits to AD patients and their carers. PMID- 24768432 TI - Phenotypic and genotypic characterisation of Staphylococcus aureus causing musculoskeletal infections. AB - One of the most common pathogens causing musculoskeletal infections remains Staphylococcus aureus. The aim of this multicentre study was to perform a phenotypic and genotypic characterisation of clinical S. aureus isolates recovered from musculoskeletal infections and to investigate differences between isolates cultured from Orthopaedic Implant Related Infections (OIRI) and those from Non-Implant Related Infections (NIRI). OIRI were further differentiated in two groups: Fracture Fixation-Device Infections (FFI) and Prosthetic Joint Infections (PJI). Three-hundred and five S. aureus strains were collected from 4 different Swiss and 2 French hospitals (FFI, n=112; PJI, n=105; NIRI, n=88). NIRI cases were composed of 27 Osteomyelitis (OM), 23 Diabetic Foot Infections (DFI), 27 Soft Tissue Infections (STI) and 11 postoperative Spinal Infections (SI). All isolates were tested for their ability to form biofilm, to produce staphyloxanthin and their haemolytic activity. They were typed by agr (accessory gene regulator) group, spa type and screened by PCR for the presence of genes of the most relevant virulence factors such as MSCRAMMs, Panton Valentine Leukotoxin (PVL), enterotoxins, exotoxins and toxic shock syndrome toxin. Overall, methicillin susceptible S. aureus (MSSA) was more prevalent than methicillin resistant S. aureus (MRSA) in this collection. The OIRI group trended towards a higher incidence of MRSA, gentamicin resistance and haemolysis activity than the NIRI group. Within the OIRI group, PJI isolates were more frequently strong biofilm formers than isolates from the FFI group. A statistically significant difference was observed between OIRI and NIRI isolates for the sdrE gene, the cna gene, the clfA gene and the bbp gene. Certain spa types (t230 and t041) with a specific genetic virulence pattern were only found in isolates cultured from OIRI. In conclusion, our study highlights significant trends regarding the virulence requirements displayed by S. aureus isolates associated with implant related infections in comparison to non-implant related infections. However, future studies including whole genome sequencing will be required to further examine genomic differences among the different infection cases. PMID- 24768433 TI - Is cemented metal-polyethylene 22.2mm hip arthroplasty a gold standard? Results of a series of 105 primary arthroplasties at a minimum of ten years follow-up. AB - INTRODUCTION: Although Charnley-Kerboull metal-on-polyethylene 22.2mm cemented total hip arthroplasty (THA) is considered to be the gold standard in France, results with this prosthesis are conflicting, in particular in relation to Scandinavian registers. The goal of this retrospective study was to confirm the validity of this prosthesis at a minimum of 10years follow-up. HYPOTHESIS: Survival of this type of THA would fulfill NICE conditions (survival at 10 years of at least 90%). MATERIALS AND METHODS: One hundred and five primary THA were performed in 93 patients (30 men and 63 women) mean age 72.6 years old (60-86) between January 1998 and March 2001. After a mean follow-up of 10.6 years (10-13 years), 21 patients (23 THA) were lost to follow-up and 32 (35 THA) had died leaving 40 patients (47 THA) for clinical analysis (Merle d'Aubigne and Oxford scores) and X-ray assessment. Survival was calculated with revision for any cause and radiological loosening with or without revision as end-points. RESULTS: The mean Oxford score at the final follow-up was 22/60 (13-45), the PMA score was 14.2 (11-17). Eight patients underwent revision surgery after a mean 7.5 years (2 11) (1 early dislocation and 7 acetabular cup loosenings). Survival at 10 years was 89.4% (CI95%: 78-95) for all causes of revision and 78% (CI95%: 61-91) for loosening with (n=7) or without (n=3) revision. No cases of septic or femoral loosening were observed. Twelve of the 47 revised hip replacements (25.5%) presented wear>=2mm. DISCUSSION: Although functional results were acceptable for this elderly population, survival did not reach the NICE value and was lower than results in the literature for this type of implant. Cup loosening and wear were the main causes of revision. LEVEL OF EVIDENCE IV: retrospective. PMID- 24768434 TI - Prediction of province-level outbreaks of foot-and-mouth disease in Iran using a zero-inflated negative binomial model. AB - To identify events that could predict province-level frequency of foot-and-mouth disease (FMD) outbreaks in Iran, 5707 outbreaks reported from April 1995 to March 2002 were studied. A zero-inflated negative binomial model was used to estimate the probability of a 'no-outbreak' status and the number of outbreaks in a province, using the number of previous occurrences of FMD for the same or adjacent provinces and season as covariates. For each province, the probability of observing no outbreak was negatively associated with the number of outbreaks in the same province in the previous month (odds ratio [OR]=0.06, 95% confidence interval [CI]: 0.01, 0.30) and in 'the second previous month' (OR=0.10, 95% CI: 0.02, 0.51), the total number of outbreaks in the second previous month in adjacent provinces (OR=0.57, 95% CI: 0.36, 0.91) and the season (winter [OR=0.18, 95% CI: 0.06, 0.55] and spring [OR=0.27, 95% CI: 0.09, 0.81], compared with summer). The expected number of outbreaks in a province was positively associated with number of outbreaks in the same province in previous month (coefficient [coef]=0.74, 95% CI: 0.66, 0.82) and in the second previous month (coef=0.23, 95% CI: 0.16, 0.31), total number of outbreaks in adjacent provinces in the previous month (coef=0.32, 95% CI: 0.22, 0.41) and season (fall [coef=0.20, 95% CI: 0.07, 0.33] and spring [coef=0.18, 95% CI: 0.05, 0.31], compared to summer); however, number of outbreaks was negatively associated with the total number of outbreaks in adjacent provinces in the second previous month (coef=-0.19, 95% CI: -0.28, 0.09). The findings indicate that the probability of an outbreak (and the expected number of outbreaks if any) may be predicted based on previous province information, which could help decision-makers allocate resources more efficiently for province-level disease control measures. Further, the study illustrates use of zero inflated negative binomial model to study diseases occurrence where disease is infrequently observed. PMID- 24768435 TI - Schmallenberg virus-two years of experiences. AB - In autumn 2011, a novel species of the genus Orthobunyavirus of the Simbu serogroup was discovered close to the German/Dutch border and named Schmallenberg virus (SBV). Since then, SBV has caused a large epidemic in European livestock. Like other viruses of the Simbu serogroup, SBV is transmitted by insect vectors. Adult ruminants may show a mild transient disease, while an infection during a critical period of pregnancy can lead to severe congenital malformation, premature birth or stillbirth. The current knowledge about the virus, its diagnosis, the spread of the epidemic, the impact and the possibilities for preventing infections with SBV is described and discussed. PMID- 24768436 TI - Meta-analysis on the efficacy of routine vaccination against foot and mouth disease (FMD) in China. AB - Foot and mouth disease (FMD) outbreaks have been reported in China for many years. Recently, due to the rapid economic development, the price of meat and its demand have grown quickly. This trend has resulted in an increase in the number of livestock moving from south-east Asian countries into China. Foot and mouth disease is becoming one of the most important trans-boundary animal diseases affecting the livelihood of livestock owners in China. To contribute to the long term goal to control and eradicate FMD from China, the Chinese government has adopted a series of control measures which includes compulsory routine vaccination against the disease. In this paper, the surveillance results of the routine vaccination programme were systemically reviewed. The results from 28 published papers were combined and analysed through a meta-analysis approach. The results of the meta-analysis indicated that the vaccination programme has been very successful in China with more than 70% of animals protected against serotypes Asia-1 and O. PMID- 24768437 TI - Control of contagious bovine pleuropneumonia: knowledge, attitudes, perceptions and practices in Narok district of Kenya. AB - CBPP is an important transboundary disease in sub-Saharan Africa whose control is urgent. Participatory data collection involving 52 focus group discussions in 37 village clusters and key informant interviews, a cross-sectional study involving 232 households and a post-vaccination follow up involving 203 households was carried out in 2006-2007 in Narok South district of Kenya. This was to investigate knowledge, attitudes, perceptions and practices (KAPP) associated with control of CBPP as well as the adverse post-vaccination reactions in animals in order to advice the control policy. The community perceived trans-boundary CBPP threat to their cattle. They had traditional disease coping mechanisms and were conversant with CBPP prevention and control with 49.8% (95%CI: 42.8-56.7%) giving priority to CBPP control. However, 12.9% (95%CI: 9.0-18.1%) of pastoralists had no knowledge of any prevention method and 10.0% (95%CI: 6.5 14.7%) would not know what to do or would do nothing in the event of an outbreak. Although 43.5% (95%CI: 37.1-50.2%) of pastoralists were treating CBPP cases with antimicrobials, 62.5% (95%CI: 52.1-71.7%) of them doubted the effectiveness of the treatments. Pastoralists perceived vaccination to be the solution to CBPP but vaccination was irregular due to unavailability of the vaccine. Vaccination was mainly to control outbreaks rather than preventive and exhibited adverse post vaccination reactions among 70.4% (95%CI: 63.6-76.5%) of herds and 3.8% (95%CI: 3.5-4.2%) of animals. Consequently, nearly 25.2% (95%CI: 18.5-33.2%) of pastoralists may resist subsequent vaccinations against CBPP. Pastoralists preferred CBPP vaccination at certain times of the year and that it is combined with other vaccinations. In conclusion, pastoralists were not fully aware of the preventive measures and interventions and post-vaccination reactions may discourage subsequent CBPP vaccinations. Consequently there is need for monitoring and management of post vaccination reactions and awareness creation on CBPP prevention and interventions and their merits and demerits. CBPP vaccine was largely unavailable to the pastoralists and the preference of the pastoralists was for vaccination at specified times and vaccine combinations which makes it necessary to avail the vaccine in conformity with the pastoralists preferences. In addition, planning vaccinations should involve pastoralists and neighbouring countries. As the results cannot be generalized, further studies on CBPP control methods and their effectiveness are recommended. PMID- 24768438 TI - Inherited peripheral neuropathies due to mitochondrial disorders. AB - Mitochondrial disorders (MIDs) are frequently responsible for neuropathies with variable severity. Mitochondrial diseases causing peripheral neuropathies (PNP) may be due to mutations of mitochondrial DNA (mtDNA), as is the case in MERRF and MELAS syndromes, or to mutations of nuclear genes. Secondary abnormalities of mtDNA (such as multiple deletions of muscle mtDNA) may result from mitochondrial disorders due to mutations in nuclear genes involved in mtDNA maintenance. This is the case in several syndromes caused by impaired mtDNA maintenance, such as Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO) due to recessive mutations in the POLG gene, which encodes the catalytic subunit of mtDNA polymerase (DNA polymerase gamma), or Mitochondrial Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE), due to recessive mutations in the TYMP gene, which encodes thymidine phosphorylase. The last years have seen a growing list of evidence demonstrating that mitochondrial bioenergetics and dynamics might be dysfunctional in axonal Charcot-Marie-Tooth disease (CMT2), and these mechanisms might present a common link between dissimilar CMT2-causing genes. PMID- 24768439 TI - [Aspect of brain MRI in mitochondrial respiratory chain deficiency. A diagnostic algorithm of the most common mitochondrial genetic mutations]. AB - Mitochondrial diseases are due to deficiency of the respiratory chain and are characterized by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Some clinical presentations are highly suggestive of given gene mutations, allowing rapid genetic diagnosis. However, owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is frequently difficult and genotype/phenotype correlations remain elusive. For this reason, brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we report the most frequent neuroradiological signs in mitochondrial respiratory chain deficiency and we propose a diagnostic algorithm based on neuroimaging features, so as to direct molecular genetic tests in patients at risk of mitochondrial respiratory chain deficiency. This algorithm is based on the careful analysis of five areas on brain MRI: (1) basal ganglia (hyperintensities on T2 or calcifications); (2) cerebellum (hyperintensities on T2 or atrophy); (3) brainstem (hyperintensities on T2 or atrophy); (4) white matter (leukoencephalopathy); (5) cortex (sub-tentorial atrophy); (6) stroke-like episodes. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests. PMID- 24768441 TI - Patients with schizophrenia selectively impaired in temporal order judgments. AB - The ability to order events in time plays a pervasive role in cognitive functions, but has only rarely been explored in patients with schizophrenia. Results we obtained recently suggested that patients have difficulties following events over time. However, this impairment concerned implicit responses at very short asynchronies, and it is not known whether it generalizes to subjective temporal order judgments. Here, we make a direct comparison between temporal order judgments and simultaneity/asynchrony discrimination in the same patients. Two squares were displayed on the screen either simultaneously or with an asynchrony of 24 to 96ms. In one session 20 patients and 20 controls made a temporal order judgment and in the other they discriminated between simultaneous and asynchronous stimuli. Controls recorded similar performances in the two tasks at asynchronies above 50ms, whereas patients displayed a sizeable impairment in temporal order judgment selectively. This impairment occurred in the easiest conditions, with the largest SOAs (Stimulus Onset Asynchronies) and only in the temporal order judgment. The results are the first evidence that patients with schizophrenia have a selective difficulty determining temporal order, even for asynchronies producing a clear perception of asynchrony. This impairment may mediate difficulties engaging oneself in everyday life events. PMID- 24768442 TI - A qualitative study investigating the use of a mobile phone short message service designed to improve HIV adherence and retention in care in Canada (WelTel BC1). AB - Patient engagement in care and adherence to medication are critical to achieving the full benefits of antiretroviral therapy (ART) among people with HIV infection. A randomized controlled trial in Kenya, WelTelKenya1, showed that an interactive mobile phone text-messaging intervention can improve adherence and viral load suppression. We conducted a pilot study to adapt the WelTel intervention for HIV-infected clients (n = 25) at an HIV clinic in Vancouver, British Columbia. Between April and June 2012, we recruited five participants from five groups: youth (14-24 years), mature (>=50 years), English as a second language, remote (>=3 hours travel time to clinic), and nonsuppressed (CD4+ T cell count <200 cells/mm(3) and viral load >=250 copies/mL on two consecutive occasions). Participants described the intervention as a useful way to communicate with health care providers, thus increasing the ability to access services, report side effects, and attend appointments. PMID- 24768440 TI - Genetic influences on cognitive endophenotypes in schizophrenia. AB - BACKGROUND: Cognitive deficits are prominent in schizophrenia and represent promising endophenotypes for genetic research. METHODS: The current study investigated the importance of two conceptually distinct genetic aggregates, one based on copy number variations (uncommon deletion burden), and one based on single nucleotide polymorphisms identified in recent risk studies (genetic risk score). The impact of these genetic factors, and their interaction, was examined on cognitive endophenotypes defined by principal component analysis (PCA) in a multi-center sample of 50 patients with schizophrenia and 86 controls. PCA was used to identify three different types of executive function (EF: planning, fluency, and inhibition), and in separate analyses, a measure general cognitive ability (GCA). RESULTS: Cognitive deficits were prominent among individuals with schizophrenia, but no group differences were evident for either genetic factor. Among patients the deletion burden measures predicted cognitive deficits across the three EF components and GCA. Further, an interaction was noted between the two genetic factors for both EF and GCA and the observed patterns of interaction suggested antagonistic epistasis. In general, the set of genetic interactions examined predicted a substantial portion of variance in these cognitive endophenotypes. LIMITATIONS: Though adequately powered, our sample size is small for a genetic study. CONCLUSIONS: These results draw attention to genetic interactions and the possibility that genetic influences on cognition differ in patients and controls. PMID- 24768443 TI - Axillary dissection versus no axillary dissection in older T1N0 breast cancer patients: 15-year results of trial and out-trial patients. AB - BACKGROUND: Our randomized trial found no survival advantage for axillary dissection (AD) compared observation only (no AD) in older patients with early breast cancer and a clinically negative axilla, indicating that AD is unnecessary. We compared characteristics and outcomes in out-trial patients with those in trial patients to provide indications as to whether AD can be safely omitted outside the trial setting. METHODS: The trial started in 1996, recruiting 238 patients age 65-80 years with cT1cN0 breast cancer, randomized to conservative surgery with or without AD. Over the recruitment period, 109 eligible patients who refused to participate in the trial, also received conservative breast surgery with or without AD depending on patient preference/surgeon opinion. Trial and out-trial patients received conventionally fractioned whole breast radiation and tamoxifen for five years. Endpoints were breast cancer mortality, overall survival, and cumulative incidence of axillary disease in patients not receiving AD. RESULTS: After 15 years of follow-up, breast cancer mortality and overall survival did not differ between the AD and no AD arms, in either the trial or out-trial cohorts. The 15-year cumulative incidence of axillary relapse was 6% in the no AD arm of the trial group, and zero in the no AD arm of the out-trial group. CONCLUSIONS: Outside the trial setting, older patients with T1N0 breast cancer can be safely treated by conservative surgery, postoperative radiotherapy and tamoxifen for five years (if ER-positive). Axillary surgery is appropriate only for the small proportion of patients who develop overt axillary disease during follow-up. PMID- 24768444 TI - Correlation between the extent of intraperitoneal disease and nodal metastasis in node-positive ovarian cancer patients. AB - AIMS: To investigate correlations between extent of disease (ED), frequency and location of nodal metastases in node-positive EOC patients. METHODS: Data were collected from 116 consecutive patients who underwent systematic lymphadenectomy during primary surgery. Patients were grouped in ED1 (disease confined in pelvis), ED2 (disease extended to abdomen), and ED3 (distant metastases). Univariate and multivariate analysis were performed for overall survival and progression-free survival (PFS). RESULTS: Correspondence analysis revealed associations between ED1 and negative nodes, ED2 and positive aortic/pelvic nodes, and ED3 and positive external and common iliac nodes. The most representative group for nodal metastases in ED1 was aortic nodes (77.8%). The number of positive pelvic nodes increased with ED; the RR was 0.58 for ED2 and 0.25 for ED3 (p = 0.004). The RR for positive external iliac nodes was 0.66 in ED2 and 0.31 in ED3 (p = 0.002); the RR for positive common iliac nodes was 0.76 and 0.17, respectively (p = 0.001). Multivariate analysis revealed that aortic nodal metastasis was associated with PFS (p = 0.03; HR, 1.95). CONCLUSION: Distribution and percentage of nodal metastases varied with ED. The risk of pelvic nodal metastasis, increased with ED. Location of positive nodes was correlated with PFS. PMID- 24768446 TI - Coumestrol suppresses hypoxia inducible factor 1alpha by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells. AB - Among many signals to regulate hypoxia inducible factor 1alpha (HIF-1alpha), sphingosine kinase 1 (SPHK1) is also involved in various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, molecular mechanisms of coumestrol were investigated on the SPHK1 and HIF-1alpha signaling pathway in hypoxic PC-3 prostate cancer cells. Coumestrol significantly suppressed SPHK1 activity and accumulation of HIF-1alpha in a time- and concentration-dependent manner in hypoxic PC-3 cells. In addition, coumestrol inhibited the phosphorylation status of AKT and glycogen synthase kinase-3beta (GSK 3beta) signaling involved in cancer metabolism. Furthermore, SPHK1 siRNA transfection, sphigosine kinase inhibitor (SKI), reactive oxygen species (ROS) enhanced the inhibitory effect of coumestrol on the accumulation of HIF-1alpha and the expression of pAKT and pGSK 3beta in hypoxic PC-3 cells by combination index. Overall, our findings suggest that coumestrol suppresses the accumulation of HIF-1alpha via suppression of SPHK1 pathway in hypoxic PC-3 cells. PMID- 24768445 TI - Quality of life in patients with peritoneal surface malignancies after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: An increasing number of patients are presenting with peritoneal carcinomatosis and more centers are performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). While morbidity and mortality are shown to be acceptable, quality of life after surgery should be assessed. METHODS: 63 patients who had CRS and HIPEC from 2001 to 2012 and who were still alive and on follow up were included. The EORTC-QLQ-C30 was administered to the patients. RESULTS: Median age was 53 years (14-71). 44% had ovarian primaries, 21% had appendicael primaries and 19% had colorectal primaries. Median follow-up was 1.08 years (0.06-9.8). The median time from surgery to the questionnaire was 1.3 years (0.24-10.18). There was no statistical difference in scores when comparing by age, gender, recurrence, gender, PCI score, presence of a complication and type of primary cancer. Scores were highest less than 6 months after surgery, dropped subsequently but rose again after 2 years. Our patients had better scores compared to a control group of outpatient cancer patients at our institution as well as the reference EORTC group. CONCLUSIONS: In keeping with previous quality of life studies done for CRS and HIPEC patients, we have shown that our patients can achieve a good quality of life after CRS and HIPEC even with recurrent disease. PMID- 24768448 TI - Typing of Melissococcus plutonius isolated from European and Japanese honeybees suggests spread of sequence types across borders and between different Apis species. AB - Melissococcus plutonius is an important pathogen of honeybee larvae and causes European foulbrood (EFB) not only in European honeybees (Apis mellifera) but also in other native honeybees. We recently confirmed the first EFB case in Japanese native honeybees (Apis cerana japonica) and isolated M. plutonius from this case. In this study, to obtain a better understanding of the ecology of M. plutonius and the epidemiology of EFB, we analyzed M. plutonius isolates that originated from European and Japanese honeybees in Japan using an existing multilocus sequence typing scheme. These analyzed Japanese isolates were resolved into six sequence types (STs), three of which were novel STs. Among these six STs, ST3 and ST12 were the two most common and found in isolates from both European and Japanese honeybees (or their environment). Moreover, these two STs were identified not only in Japan but also in other countries, suggesting the spread of some STs across borders and different honeybee species. PMID- 24768447 TI - Glutamate transporter control of ambient glutamate levels. AB - Accurate knowledge of the ambient extracellular glutamate concentration in brain is required for understanding its potential impacts on tonic and phasic receptor signaling. Estimates of ambient glutamate based on microdialysis measurements are generally in the range of ~2-10MUM, approximately 100-fold higher than estimates based on electrophysiological measurements of tonic NMDA receptor activity (~25 90nM). The latter estimates are closer to the low nanomolar estimated thermodynamic limit of glutamate transporters. The reasons for this discrepancy are not known, but it has been suggested that microdialysis measurements could overestimate ambient extracellular glutamate because of reduced glutamate transporter activity in a region of metabolically impaired neuropil adjacent to the dialysis probe. We explored this issue by measuring diffusion gradients created by varying membrane densities of glutamate transporters expressed in Xenopus oocytes. With free diffusion from a pseudo-infinite 10MUM glutamate source, the surface concentration of glutamate depended on transporter density and was reduced over 2 orders of magnitude by transporters expressed at membrane densities similar to those previously reported in hippocampus. We created a diffusion model to simulate the effect of transport impairment on microdialysis measurements with boundary conditions corresponding to a 100MUm radius probe. A gradient of metabolic disruption in a thin (~100MUm) region of neuropil adjacent to the probe increased predicted [Glu] in the dialysate over 100-fold. The results provide support for electrophysiological estimates of submicromolar ambient extracellular [Glu] in brain and provide a possible explanation for the higher values reported using microdialysis approaches. PMID- 24768449 TI - First detection of equine coronavirus (ECoV) in Europe. AB - Equine coronavirus (ECoV) is involved mainly in enteric infections. Following the recent description of ECoV in 2000, this study reports for the first time the presence of ECoV in France and, on a wider scale, in Europe. ECoV was molecularly detected from diarrheic and respiratory specimens. Sequencing and phylogenetic analyses demonstrated that European strains are most closely related to the reference North American strain (ECoV-NC99) than the Asian strain (ECoV Tokachi09). PMID- 24768450 TI - Monitoring urbanization and its implications in a mega city from space: spatiotemporal patterns and its indicators. AB - Rapid and invasive urbanization has been associated with depletion of natural resources (vegetation and water resources), which in turn deteriorates the landscape structure and conditions in the local environment. Rapid increase in population due to the migration from rural areas is one of the critical issues of the urban growth. Urbanisation in India is drastically changing the land cover and often resulting in the sprawl. The sprawl regions often lack basic amenities such as treated water supply, sanitation, etc. This necessitates regular monitoring and understanding of the rate of urban development in order to ensure the sustenance of natural resources .Urban sprawl is the extent of urbanization which leads to the development of urban forms with the destruction of ecology and natural landforms. The rate of change of land use and extent of urban sprawl can be efficiently visualized and modelled with the help of geoinformatics. The knowledge of urban area, especially the growth magnitude, shape geometry, and spatial pattern is essential to understand the growth and characteristics of urbanization process. Urban pattern, shape and growth can be quantified using spatial metrics. This communication quantifies the urbanisation and associated growth pattern in Delhi. Spatial data of four decades were analysed to understand land over and land use dynamics. Further the region was divided into 4 zones and into circles of 1 km incrementing radius to understand and quantify the local spatial changes. Results of the landscape metrics indicate that the urban center was highly aggregated and the outskirts and the buffer regions were in the verge of aggregating urban patches. Shannon's Entropy index clearly depicted the outgrowth of sprawl areas in different zones of Delhi. PMID- 24768451 TI - Crosstalk between the nucleotide excision repair and Fanconi anemia/BRCA pathways. AB - Cells have evolved multiple distinct DNA repair pathways to efficiently correct a variety of genotoxic lesions, and decades of study have led to an improved understanding of the mechanisms and regulation of these individual pathways. However, there is now an increasing appreciation that extensive crosstalk exists among DNA repair pathways and that this crosstalk serves to increase the efficiency and diversity of response to damage. The Fanconi anemia (FA)/BRCA and nucleotide excision repair (NER) pathways have been shown to share common factors, and often work in concert to repair damage. Genomic studies are now revealing that many tumors harbor somatic mutations in FA/BRCA or NER genes, which may provide a growth advantage, but which could also be exploited therapeutically. PMID- 24768453 TI - Dairy cows produce cytokine and cytotoxic T cell responses following vaccination with an antigenic fraction from Streptococcus uberis. AB - Streptococcus uberis is a major cause of mastitis in dairy cows worldwide and currently, there is no vaccine commercially available against this form of mastitis. In the current study, cell-free extracts (CFE) were prepared from each of three different S. uberis strains, designated as #3, #24 and #363 representative of the three main sequence types of S. uberis that cause mastitis in New Zealand. These proteins were formulated into vaccines with Emulsigen-D and the immunogenicity of the vaccines was determined in both calves and dairy cows. Two groups of calves (n=5/group) were vaccinated subcutaneously with CFE from strain #24 or strains #3, #24 and #363 formulated with Emulsigen-D, respectively. A third group (n=5) was vaccinated with CFE from the three strains formulated with Emulsigen-D and also containing recombinant bovine granulocyte macrophage colony-stimulating factor while, a control group (n=5) was not vaccinated. Vaccinated animals produced strong antibody responses to the S. uberis antigens and an antigen-specific cytotoxic effect against blood monocytes/macrophages that had phagocytosed S. uberis, with no significant differences in responses observed between the three vaccinated groups. In a second trial, the safety and immunogenicity of the vaccine containing CFE from all three strains of S. uberis and Emulsigen-D was determined in dairy cows. A group of six cows were vaccinated subcutaneously at 3 and 1 week prior to dry off and revaccinated 2-3 weeks before calving. Immune responses in blood and mammary gland secretions (MGS) were monitored during the dry period and in the subsequent lactation. The vaccine was well tolerated with no adverse effect from vaccination observed in any of the cows. Vaccination induced an antigen-specific cytotoxic effect against blood monocytes/macrophages that had phagocytosed S. uberis, moderate antigen-specific IFN-gamma responses in blood and strong antibody responses in both blood and MGS. In conclusion, the results suggest vaccination of cattle with S. uberis CFE by the subcutaneous route can induce both cellular and humoral responses. PMID- 24768452 TI - Mechanism and regulation of incisions during DNA interstrand cross-link repair. AB - A critical step in DNA interstrand cross-link repair is the programmed collapse of replication forks that have stalled at an ICL. This event is regulated by the Fanconi anemia pathway, which suppresses bone marrow failure and cancer. In this perspective, we focus on the structure of forks that have stalled at ICLs, how these structures might be incised by endonucleases, and how incision is regulated by the Fanconi anemia pathway. PMID- 24768454 TI - Hepatocellular carcinoma in 2014: current situation and future prospects. AB - The leading causes of chronic liver disease associated with HCC are hepatitis B and C viruses throughout the world, and alcohol and NASH in France. After increasing for 20-30 years in France, the rise in the incidence of HCC appears to be slowing and the death rates appear to be falling. Screening for HCC by liver ultrasound is performed every 6 months. Assay of serum alpha-fetoprotein has no benefit. In developed countries, failure to identify patients with cirrhosis and inadequate adherence to guidelines greatly reduces the effectiveness of screening for HCC. PMID- 24768455 TI - Adipose tissue-derived stem cells expressing cardiac progenitor markers: the best source of mesenchymal stem cells for cardiovascular repair? PMID- 24768456 TI - Occurrence of Takotsubo cardiomyopathy and use of antidepressants. PMID- 24768457 TI - Association of handgrip strength to cardiovascular mortality in pre-diabetic and diabetic patients: a subanalysis of the ORIGIN trial. PMID- 24768458 TI - Stent infection is another safety issue that needs to be addressed. PMID- 24768459 TI - Pulmonary embolism related to central venous catheter triggered by trans esophageal echocardiography bubble test: caught red-handed! PMID- 24768460 TI - Transthoracic echocardiography appropriateness in outpatients of the Italian national health system, according to the American Society of Echocardiography criteria: evaluation and comparison with USA and UK. PMID- 24768461 TI - Angiographic success and procedural complications in patients undergoing retrograde percutaneous coronary chronic total occlusion interventions: a weighted meta-analysis of 3,482 patients from 26 studies. AB - BACKGROUND: The efficacy and safety profile of retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study. We sought to perform a weighted meta-analysis of the success and complication rates of retrograde CTO PCI. METHODS: We conducted a meta-analysis of 26 studies published between 2006 and April 2013 reporting in-hospital outcomes of retrograde CTO PCI. Data on procedural success, frequency of death, emergent coronary artery bypass graft surgery (CABG), stroke, myocardial infarction (MI), perforation, tamponade, stent thrombosis, major vascular or bleeding events, contrast nephropathy, and radiation skin injury were collected. RESULTS: A total of 26 studies with 3482 patients and 3493 target CTO lesions were included. Primary retrograde CTO PCI was attempted in 52.4%. Pooled estimates of outcomes were as follows: procedural success 83.3% [95% confidence interval (CI): 79.0% to 87.7%]; death 0.7% (95% CI: 0.5% to 1.2%); urgent CABG 0.7% (95% CI: 0.4% to 1.2%); tamponade 1.4% (95% CI: 1.0% to 2.2%); collateral perforation 6.9% (95% CI: 4.6% to 10.4%); coronary perforation 4.3% (95% CI: 1.2% to 15.4%); donor vessel dissection 2% (95% CI: 0.9% to 4.5%); stroke 0.5% (95% CI: 0.2% to 1.0%); MI 3.1% (95% CI: 0.2% to 5.0%); Q wave MI 0.6% (95% CI: 0.4% to 1.1%); vascular access complications 2% (95% CI: 0.9% to 4.5%); contrast nephropathy 1.8% (95% CI: 0.8% to 3.7%); and wire fracture and equipment entrapment 1.2% (95% CI: 0.6% to 2.5%). CONCLUSIONS: Retrograde CTO PCI is associated with high procedural success rate and acceptable risk for procedural complications. PMID- 24768462 TI - Diuretics or ultrafiltration in acute heart failure syndrome? Or two inadequate answers to the main question? PMID- 24768463 TI - Pulmonary hypertension in young adults with repaired coarctation of the aorta: an unrecognised factor associated with premature mortality and heart failure. AB - BACKGROUND: Adults with repaired coarctation of the aorta (CoA) are at risk for premature cardiovascular death or heart failure (HF). We sought to evaluate risk factors for death or HF in young adults with repaired CoA in childhood. METHODS: The medical records of a cohort of 159 adults diagnosed with CoA repaired at a mean age of 4.1 +/- 5.7 years were retrospectively reviewed to identify predictors of a combined endpoint of all cause death or hospitalisation for HF by using Cox proportional hazard models. RESULTS: Over a follow-up of 26 +/- 8 years (median 27 years) after repair, 5 patients died and 7 developed HF requiring hospitalisation. Pulmonary artery systolic pressure >40 mm Hg (PH) was the main predictor of death or admission for HF (HR 32; 95% CI 4.0-250; p=0.001). Neither systemic hypertension, recoarctation, aortic aneurysm, intracardiac lesions nor treatment with beta-blockers or ACEi/ARBs were statistically related to death or HF. Restrictive left ventricular physiology (RLVP) was the main predictor of PH by logistic regression analysis (OR 31; 95% CI 10-92; p<0.001). Patients with severe PH (pulmonary artery systolic pressure >60 mm Hg) showed RLVP (9/10), severe elevation of end-diastolic LV pressure at cardiac catheterization (8/8) and subendocardial late gadolinium enhancement on MRI (5/5). Pathological examination of an explanted heart demonstrated extensive left ventricular subendocardial fibrosis. CONCLUSIONS: Pulmonary hypertension related to restrictive left ventricular physiology was the strongest predictor of death or HF in young adults with CoA repaired in childhood. Persistent subendocardial fibrosis might be the structural substrate in some patients. PMID- 24768464 TI - Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. AB - Patients affected by chronic heart failure (CHF) present significant impairment of health-related quality of life (HRQoL). Iron deficiency (ID) is a common comorbidity in CHF with negative impact in prognosis and functional capacity. The role of iron in energy metabolism could be the link between ID and HRQoL. There is little information about the role of ID on HRQoL in patients with CHF. We evaluate the impact of ID on HRQoL and the interaction with the anaemia status, iron status, clinical baseline information and HRQoL, measured with the Minnesota Living with Heart Failure questionnaire (MLHFQ) was obtained at baseline in an international cohort of 1278 patients with CHF. Baseline characteristics were median age 68 +/- 12, 882 (69%) were males, ejection fraction was 38% +/- 15 and NYHA class was I/II/III/IV (156/247/487/66). ID (defined as ferritin level< 100 ug/L or serum ferritin 100-299 ug/L in combination with a TSAT<20%) was present in 741 patients (58%). 449 (35%) patients were anaemic. Unadjusted global scores of MLHFQ (where higher scores reflect worse HRQoL) were worse in ID and anaemic patients (ID+: 42 +/- 25 vs. ID-: 37 +/- 25; p-value=0.001 and A+: 46 +/- 25 vs. A-: 37 +/- 25; p-value<0.001). The combined influence of ID and anaemia was explored with different multivariable regression models, showing that ID but not anaemia was associated with impaired HRQoL. ID has a negative impact on HRQoL in CHF patients, and this is independent of the presence of anaemia. PMID- 24768465 TI - Incidence of symptomatic and asymptomatic venous thromboembolism after elective knee arthroscopic surgery: a retrospective study with routinely applied venography. AB - PURPOSE: The purpose of this study was to assess the incidence of total venous thromboembolism (VTE) after knee arthroscopy with routinely applied venography. METHODS: We reviewed 537 consecutive patients undergoing arthroscopic knee surgery from March 2012 to July 2013. The surgical procedure was categorized as simple anterior cruciate ligament reconstruction (ACLR), posterior cruciate ligament reconstruction (PCLR), or reconstruction of both cruciate ligaments. All patients having arthroscopy in our institution were routinely examined with venography on the third postoperative day. Clinical signs of DVT were checked and recorded before venography. RESULTS: Eighty (14.9%) of 537 patients were diagnosed with VTE by venography. Of the 80 detected cases of VTE, only 20 (3.7%) patients presented with clinical signs of DVT, indicating that there were 60 (11.2%) asymptomatic cases. No patient died or presented with a clinically suspected pulmonary embolism (PE). Sex, body mass index (BMI), operative time, and duration of tourniquet application were not significant risk factors for DVT. Patient age (P < .0001) is a strongly significant risk factor for deep venous thrombosis (DVT). Compared with patients who underwent simple arthroscopic procedures, complex procedures-the reconstruction of 1 (P < .005) or both knee cruciate ligaments (P < .0005)-led to a significantly higher postoperative incidence of DVT. CONCLUSIONS: The total incidence of VTE diagnosed with venography after arthroscopic knee surgery was 14.9%, of which only 3.7% of cases were symptomatic, indicating 11.2% cases of silent VTE. Advanced age and complex arthroscopic surgery are strongly associated with VTE. LEVEL OF EVIDENCE: Level IV, prognostic case series. PMID- 24768466 TI - Meniscus allograft transplantation for discoid lateral meniscus: clinical comparison between discoid lateral meniscus and nondiscoid lateral meniscus. AB - PURPOSE: This study was performed to compare the clinical results of meniscus allograft transplantation (MAT) after total meniscectomy in torn discoid lateral meniscus (DLM) and nondiscoid lateral meniscus (NLM). METHODS: We conducted a retrospective study of 36 patients who underwent MAT. The discoid and nondiscoid groups consisted of 16 and 20 patients, respectively. The mean follow-up period was 32 months. We checked range of motion (ROM), visual analog scale (VAS) score, International Knee Documentation Committee (IKDC) subjective score, Lysholm score, Tegner activity score for clinical evaluation; magnetic resonance imaging (MRI) was checked for objective evaluation. RESULTS: The mean last follow-up VAS score, IKDC subjective score, Lysholm score, Tegner activity score, and subjective satisfaction of the patient were not significantly different between the discoid group and the nondiscoid group. The ROM of the discoid group was significantly decreased compared with that of the nondiscoid group (P < .05). Follow-up MRI was performed in 17 patients (9 from the discoid group and 8 from the nondiscoid group). Mean extrusion of the graft was 2.0 mm in the discoid group and 2.4 mm in the nondiscoid group (P = .344). Relative percentage of extrusion (RPE) was 22.8% in the discoid group and 22.7% in the nondiscoid group (P = .519). CONCLUSIONS: According to the minimal 2-year follow-up observations, MAT in patients with a torn discoid meniscus is an effective method for reducing the pain caused by meniscal deficiency and improving the function of the knee joint. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24768468 TI - Return to activity after medial patellofemoral ligament repair or reconstruction. AB - PURPOSE: This study aimed to determine the ability of patients to return to activity after medial patellofemoral ligament (MPFL) reconstruction or repair for patellar instability. METHODS: A systematic review was performed using multiple databases. Studies reporting outcomes with Tegner scores after repair or reconstruction of the MPFL were included. Surgical technique, Tegner scores, and episodes of recurrent patellar instability were recorded. RESULTS: Ten articles with a total of 402 patients were included. The mean preoperative Tegner score was 4.7 (2.9 to 7.5). The mean postoperative Tegner score was 5.8 (4.0 to 7.7). Forty-nine patients (12.2%) had a recurrent episode of instability, 11 of whom required additional corrective procedures. There was a statistically significant larger failure rate among those who underwent MPFL repair (26.9%) than those who underwent reconstruction (6.6%) or medial retinacular repair/plication (16.5%). CONCLUSIONS: Recurrent dislocation was higher in patients who underwent MPFL repair rather than reconstruction. However, repair and reconstruction had similar Tegner scores. Repair or reconstruction of the soft tissue structures contributing to patellofemoral instability is successful in returning patients to preinjury activity levels. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV studies. PMID- 24768467 TI - Clinical results of hamstring autografts in anterior cruciate ligament reconstruction: a comparison of femoral knot/press-fit fixation and interference screw fixation. AB - PURPOSE: To compare the clinical outcomes of femoral knot/press-fit anterior cruciate ligament (ACL) reconstruction with conventional techniques using femoral interference screws. METHODS: Among patients who underwent arthroscopic ACL reconstruction with hamstring autografts, 73 were treated with either a femoral knot/press-fit technique (40 patients, group A) or femoral interference screw fixation (33 patients, group B). The clinical results of the 2 groups were retrospectively compared. The inclusion criteria were primary ACL reconstruction in active patients. The exclusion criteria were fractures, multiligamentous injuries, patients undergoing revision, or patients with contralateral ACL deficient knees. In the femoral knot/press-fit technique, semitendinosus and gracilis tendons were prepared as 2 loops with knots. After passage through a bottleneck femoral tunnel, the grafts were fixed with a press-fit method (grafts' knots were stuck in the bottleneck of the femoral tunnel). A tie with Mersilene tape (Ethicon, Somerville, NJ) over a bone bridge for each tendon loop and an additional bioabsorbable interference screw were used for tibial fixation. RESULTS: The mean follow-up period was 38 months (range, 24 to 61 months). A significant improvement in knee function and symptoms was reported in most patients, as shown by improved Tegner scores, Lysholm knee scores, and International Knee Documentation Committee assessments (P < .01). The results of instrumented laxity testing, thigh muscle assessment, and radiologic assessment were clearly improved when compared with the preoperative status (P < .01). No statistically significant difference in outcomes could be observed between group A and group B (P = not significant). CONCLUSIONS: In this nonrandomized study, femoral knot/press-fit ACL reconstruction did not appear to provide increased anterior instability compared with that of conventional femoral interference screw ACL reconstruction. Favorable outcomes with regard to knee stability and patient satisfaction were achieved in most of our ACL-reconstructed patients using femoral knot/press-fit fixation with hamstring tendon autograft. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24768469 TI - Management of testicular torsion. PMID- 24768470 TI - Publications: best practice or why transparency is synonymous of quality. PMID- 24768471 TI - Roux-en-Y hepaticoduodenostomy as surgical treatment of major bile duct injuries in totally gastrectomized patients. PMID- 24768472 TI - Relationship between leukocyte telomere length and personality traits in healthy subjects. AB - BACKGROUND: It has been shown that certain personality traits are related to mortality and disease morbidity, but the biological mechanism linking them remains unclear. Telomeres are tandem repeat DNA sequences located at the ends of chromosomes, and shorter telomere length is a predictor of mortality and late life disease morbidity. Thus, it is possible that personality traits influence telomere length. In the present study, we examined the relationship of leukocyte telomere length with personality traits in healthy subjects. SUBJECTS AND METHODS: The subjects were 209 unrelated healthy Japanese who were recruited from medical students at 4th-5th grade. Assessment of personality traits was performed by the Revised NEO Personality Inventory (NEO-PI-R) and the Temperament and Character Inventory (TCI). Leukocyte relative telomere length was determined by a quantitative real-time PCR method for a ratio of telomere/single copy gene. RESULTS: In the stepwise multiple regression analysis, shorter telomere length was related to lower scores of neuroticism (P<0.01) and conscientiousness (P<0.05) of the NEO-PI-R, and lower scores of harm avoidance (P<0.05) and reward dependence (P<0.05) of the TCI. CONCLUSIONS: The present study suggests that leukocyte telomere length is associated with some personality traits, and this association may be implicated in the relationship between personality traits and mortality. PMID- 24768473 TI - Drug policy and global regulatory capitalism: the case of new psychoactive substances (NPS). AB - The recent emergence of vibrant markets in 'new psychoactive substances' or 'legal highs' has posed significant new challenges for drug policy. These partly concern what to do about them but the speed and complexity of change has also raised difficulties for how policy responses should be developed. Existing drug policy systems appear too slow and cumbersome to keep up with the pace of change, remaining locked in large part within 'old' ways of thinking that centre almost exclusively around the deployment (or not) of the criminal law and its related enforcement apparatus. In this paper, it is argued that we need to rethink the problem through the lens of regulation, in order to learn lessons from other sectors where more agile responses to changing markets and business innovation have often proved possible. By examining examples drawn from these other areas, an alternative policy-making framework can be developed, involving a more flexible mix of state regulation, civil society action and private law mechanisms. This new approach is founded on a recognition of the networked and polycentric character of effective market governance in an era of global regulatory capitalism. PMID- 24768474 TI - Accuracy of magnetic resonance imaging in differentiating between benign and malignant vertebral lesions: role of diffusion-weighted imaging, in-phase/opposed phase imaging and apparent diffusion coefficient. AB - OBJECTIVE: To determine the ability of MRI to distinguish between benign and malignant vertebral lesions. MATERIAL AND METHODS: We included 85 patients and studied a total of 213 vertebrae (both pathologic and normal). For each vertebra, we determined whether the lesion was hypointense in T1-weighted sequences and whether it was hyperintense in STIR and in diffusion-weighted sequences. We calculated the in-phase/out-of-phase quotient and the apparent diffusion coefficient for each vertebra. We combined parameters from T1-weighted, diffusion weighted, and STIR sequences to devise a formula to distinguish benign from malignant lesions. RESULTS: The group comprised 60 (70.6%) women and 25 (29.4%) men with a mean age of 67+/-13.5 years (range, 33-90 y). Of the 85 patients, 26 (30.6%) had a known primary tumor. When the lesion was hypointense on T1-weighted sequences, hyperintense on STIR and diffusion-weighted sequences, and had a signal intensity quotient greater than 0.8, the sensitivity was 97.2%, the specificity was 90%, and the diagnostic accuracy was 91.2%. If the patient had a known primary tumor, these values increased to 97.2%, 99.4%, and 99%, respectively. CONCLUSION: Benign lesions can be distinguished from malignant lesions if we combine the information from T1-weighted, STIR, and diffusion weighted sequences together with the in-phase/out-of-phase quotient of the lesion detected in the vertebral body on MRI. PMID- 24768476 TI - Cold water immersion in the management of delayed-onset muscle soreness: is dose important? A randomised controlled trial. AB - BACKGROUND: Cold Water Immersion (CWI) is commonly used to manage delayed onset muscle soreness (DOMS) resulting from exercise. Scientific evidence for an optimal dose of CWI is lacking and athletes continue to use a range of a treatment protocols and water temperatures. OBJECTIVES: To compare the effectiveness of four different water immersion protocols and a passive control intervention in the management of DOMS. DESIGN: Randomised controlled trial with blinded outcome assessment. SETTING: University Research Laboratory. PARTICIPANTS: 50 healthy participants with laboratory induced DOMS randomised to one of five groups: Short contrast immersion (1 min 38 degrees C/1 min 10 degrees C * 3), Short intermittent CWI (1 min * 3 at 10 degrees C); 10 min CWI in 10 degrees C; 10 min CWI in 6 degrees C; or control (seated rest). MAIN OUTCOME MEASURES: muscle soreness, active range of motion, pain on stretch, muscle strength and serum creatine kinase. RESULTS: 10 min of CWI in 6 degrees C was associated with the lowest levels of muscle soreness and pain on stretch however values were not statistically different to any of the other groups. There were no statistically significant differences between groups for any other outcomes. CONCLUSION: Altering the treatment duration, water temperature or dosage of post exercise water immersion had minimal effect on outcomes relating to DOMS. PMID- 24768477 TI - Prognostic, predictive abilities and concordance of BCL2 and TP53 protein expression in primary breast cancers and axillary lymph-nodes: a retrospective analysis of the Belgian three arm study evaluating anthracycline vs CMF adjuvant chemotherapy. AB - Given recent data on genetic heterogeneity within and individual's tumor, we investigated if there were differences in the prognostic and predictive abilities of BCL2 and TP53 protein expression in primary breast cancer (TU) and corresponding axillary lymph-nodes (LN). We used patient samples from the adjuvant Belgian three-arm study which randomized between anthracycline containing regimens and traditional CMF. The endpoints analyzed were overall survival (OS), event-free survival (EFS) and interactions between chemotherapy regimens. At a median follow-up of 15.6 years, BCL2 and TP53 (in both TU and LN) were significantly associated with OS but only in the first 5 years. Likewise, BCL2 and TP53 (in both TU and LN) were associated with EFS in the first 2 years after randomization, with no association after 2 years. BCL2 and TP53 remained statistically significant after adjustment for the standard clinical-pathological characteristics in regard to OS and EFS in the respective first years after randomization, (p value < 0.001 for both markers). Furthermore, an interaction was found between high BCL2 expression in the TU (but not in LN) and benefit to CMF over anthracycline-based chemotherapy (interaction p value EFS: 0.042; OS = 0.01). No interaction was found for TP53 expression neither in TU nor in LN. We conclude that BCL2 and TP53 were predictive biomarkers for better and worse survival respectively, but only in the first two to five years after diagnosis. BCL2 expression in the TU but not in the LN was predictive of increased benefit to CMF vs anthracycline-based chemotherapy. PMID- 24768475 TI - Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. AB - Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness. PMID- 24768478 TI - Prediction of non-sentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node. AB - Completion axillary lymph node dissection (cALND) is the golden standard if breast cancer involves the sentinel lymph node (SLN). However, most non-sentinel lymph nodes (NSLN) are not involved, cALND has a considerable complication rate and does not improve outcome. We here present and validate our predictive model for positive NSLNs in the cALND if the SLN is positive. Consecutive early breast cancer patients from one center undergoing cALND for a positive SLN were included. We assessed demographic and clinicopathological variables for NSLN involvement. Uni- and multivariate analysis was performed. A predictive model was built and validated in two external centers. 21.9% of 470 patients had at least one involved NSLN. In univariate analysis, seven variables were significantly correlated with NSLN involvement: tumor size, grade, lymphovascular invasion (LVI), number of positive and negative SLNs, size of SLN metastasis and intraoperative positive SLN. In multivariate analysis, LVI, number of negative SLNs, size of SLN metastasis and intraoperative positive pathological evaluation were independent predictors for NSLN involvement. The calculated risk resulted in an AUC of 0.76. Applied to the external data, the model was accurate and discriminating for one (AUC = 0.75) and less for the other center (AUC = 0.58). A discriminative predictive model was constructed to calculate the risk of NSLN involvement in case of a positive SLN. External validation of our model reveals differences in performance when applied to data from other institutions concluding that such a predictive model requires validation prior to use. PMID- 24768479 TI - Commentary on: escalation of care and failure to rescue: a multicenter, multiprofessional, qualitative study. PMID- 24768480 TI - Escalation of care and failure to rescue: a multicenter, multiprofessional qualitative study. AB - BACKGROUND: The escalation of care process has not been explored in surgery, despite the role of communication failures in adverse events. This study aimed to develop a conceptual framework of the influences on escalation of care in surgery allowing solutions to facilitate management of sick patients to be developed. METHODS: A multicenter qualitative study was conducted in three hospitals in London, UK. A total of 41 participants were recruited, including 16 surgeons, 11 surgical PGY1s, six surgical nurses, four intensivists, and four critical care outreach team members. Participants were submitted to semistructured interviews that were analyzed using grounded theory methodology. RESULTS: A decision to escalate was based upon five key themes: patient, individual, team, environmental, and organizational factors. Most participants felt that supervision and escalation of care were problematic in their hospital, with unclear escalation protocols and poor availability of senior surgical staff the most common concerns. Mobile phones and direct conversation were identified to be more effective when escalating care than hospital pager systems. Transparent escalation protocols, increased senior clinician supervision, and communication skills training were highlighted as strategies to improve escalation of care. CONCLUSION: This is the first study to describe escalation of care in surgery, a key process for protecting the safety of deteriorating surgical patients. Factors affecting the decision to escalate are complex, involving clinical and professional aspects of care. An understanding of this process could pave the way for interventions to facilitate escalation in order to improve patient outcome. PMID- 24768481 TI - High-resolution ultrasonography for the diagnosis of brachial plexus root lesions. AB - The aim of this study was to investigate the feasibility of using high-resolution ultrasonography in the diagnosis of brachial plexus (BP) root lesions. A prospective study of ultrasonographic evaluation of BP nerve roots was performed in 37 patients with BP root lesions (29 with root injuries, 8 with tumors). The pre-operative ultrasonographic findings were compared with the surgical and pathohistological findings. All C5-7 roots were detected by ultrasonography in all patients, whereas 92% (68/74) of C8 and 51% (38/74) of T1 nerve roots were visualized. Among 29 patients with BP root avulsion, partial injuries or totally interrupted BP roots were detected in all patients. Cystic masses and neuromas were detected in 16 and 23 patients, respectively. In 8 patients with BP root tumors, 8 hypo-echoic masses were detected inside or partly outside of intervertebral foramina connecting to nerve roots. Surgical exploration revealed that there were 57 BP root avulsions in 29 patients. However, 2 T1 nerve root avulsions had been missed by pre-operative ultrasonography. Pathohistology revealed that all 8 BP root tumors pre-operatively diagnosed by ultrasonography were schwannomas. High-resolution ultrasonography can provide a convenient and accurate imaging modality for quick diagnosis and location of BP root lesions. PMID- 24768482 TI - Low-echo sphere phantoms and methods for assessing imaging performance of medical ultrasound scanners. AB - Tissue-mimicking phantoms and software for quantifying the ability of human observers to detect small low-echo spheres as a function of depth have been developed. Detectability is related to the imager's ability to delineate the boundary of a 3-D object such as a spiculated tumor. The phantoms accommodate a broad range of transducer shapes and sizes. Three phantoms are described: one with 2-mm-diameter spheres (for higher frequencies), one with 3.2-mm-diameter spheres (for lower frequencies) and one with 4-mm-diameter spheres (for lower frequencies). The spheres are randomly distributed in each phantom. The attenuation coefficients of spheres and surroundings are nearly identical; thus, compromising shadowing or enhancement distal to spheres does not occur. Reproducibility results are given for pairs of independent data sets involving eight different combinations of scanner, transducer and console settings. The following comparison results are also reported: (i) only the selected frequency differs; (ii) transducers and scan parameters are nearly the same but manufacturers differ; (iii) ordinary B-scanning, spatial compounding and tissue harmonic imaging are addressed. The phantoms and software promise to be valuable tools for scanning system and setup comparisons and for acceptance testing. PMID- 24768483 TI - False-negative appendicitis at ultrasound: nature and association. AB - The objective was to describe nature and factors associated with false-negative ultrasound (US) for adult appendicitis. Patients with pathologically proven appendicitis and pre-operative US from January 2011 to May 2013 were included in this retrospective case-control study. They were divided into true-positive and false-negative groups, matched by age and gender. There were 112 patients (40 men, mean age = 40 y, 56 true positives) included. Two factors were found differ significantly: abdominal wall thickness and pain score. Greater abdominal wall thickness (18.6 mm vs. 14.9 mm, p = 0.001) and lower pain score (6.6 vs. 7.5, p = 0.018) were statistically associated with false negativity. The two groups did not differ significantly in terms of weight, height, body mass index, symptom duration, Alvarado score, US examination time, appendix position/size, perforation rate and operator. In conclusion, lower pain score and increased abdominal wall thickness are associated with false negativity in US examinations. PMID- 24768484 TI - 3-D visualization and non-linear tissue classification of breast tumors using ultrasound elastography in vivo. AB - The goal of the study described here was to introduce new methods for the classification and visualization of human breast tumors using 3-D ultrasound elastography. A tumor's type, shape and size are key features that can help the physician to decide the sort and extent of necessary treatment. In this work, tumor type, being either benign or malignant, was classified non-invasively for nine volunteer patients. The classification was based on estimating four parameters that reflect the tumor's non-linear biomechanical behavior, under multi-compression levels. Tumor prognosis using non-linear elastography was confirmed with biopsy as a gold standard. Three tissue classification parameters were found to be statistically significant with a p-value < 0.05, whereas the fourth non-linear parameter was highly significant, having a p-value < 0.001. Furthermore, each breast tumor's shape and size were estimated in vivo using 3-D elastography, and were enhanced using interactive segmentation. Segmentation with level sets was used to isolate the stiff tumor from the surrounding soft tissue. Segmentation also provided a reliable means to estimate tumors volumes. Four volumetric strains were investigated: the traditional normal axial strain, the first principal strain, von Mises strain and maximum shear strain. It was noted that these strains can provide varying degrees of boundary enhancement to the stiff tumor in the constructed elastograms. The enhanced boundary improved the performance of the segmentation process. In summary, the proposed methods can be employed as a 3-D non-invasive tool for characterization of breast tumors, and may provide early prognosis with minimal pain, as well as diminish the risk of late-stage breast cancer. PMID- 24768485 TI - Gray-scale ultrasonography combined with elastography imaging for the evaluation of papillary thyroid microcarcinoma: as a prognostic clinicopathology factor. AB - Ultrasonography (US) is the preferred imaging modality for papillary thyroid microcarcinoma (PTMC). The aim of this study was to evaluate the importance of gray-scale ultrasound combined with elastography to predict extrathyroidal extension and cervical lymph node (LN) metastasis in patients with PTMC. We retrospectively evaluated gray-scale ultrasonic and elastographic results from 119 consecutive cases of PTMC with 138 nodules and correlated the histopathological findings. The results indicated that pathological extrathyroidal extension was significantly associated with T staging on US, extrathyroidal extension on US, bilaterality on US, boundary, strain ratio and hard malignancy as measured with the Rago score. Central LN metastasis on pathology was significantly associated with central LN metastasis on US, lateral LN metastasis on US, multifocality on US and bilaterality on US. Lateral LN metastasis on US was significantly associated with lateral LN metastasis on pathology. On multivariate analysis, T staging on US, extrathyroidal extension on US and hard malignancy as measured with the Rago score were significantly associated with pathological extrathyroidal extension. Lateral LN metastasis on US and bilaterality on US were independent factors in predicting central LN metastasis on pathology. Lateral LN metastasis on US was the predictive factor for lateral LN metastasis on pathology. US should be helpful in the diagnosis of PTMC and in the evaluation of possible PTMC recurrence on US in routine clinical practice. PMID- 24768486 TI - Multimodal evaluation of 2-D and 3-D ultrasound, computed tomography and magnetic resonance imaging in measurements of the thyroid volume using universally applicable cross-sectional imaging software: a phantom study. AB - A precise estimate of thyroid volume is necessary for making adequate therapeutic decisions and planning, as well as for monitoring therapy response. The goal of this study was to compare the precision of different volumetry methods. Thyroid shaped phantoms were subjected to volumetry via 2-D and 3-D ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). The 3-D US scans were performed using sensor navigation and mechanical sweeping methods. Volumetry calculation ensued with the conventional ellipsoid model and the manual tracing method. The study confirmed the superiority of manual tracing with CT and MRI volumetry of the thyroid, but extended this knowledge also to the superiority of the 3-D US method, regardless of whether sensor navigation or mechanical sweeping is used. A novel aspect was successful use of the same universally applicable cross-imaging software for all modalities. PMID- 24768487 TI - Variations in temperature distribution and tissue lesion formation induced by tissue inhomogeneity for therapeutic ultrasound. AB - Tissue inhomogeneity might have an important effect on the treatment accuracy of therapeutic ultrasound. Both computer simulation and measurement were performed to study the influence of tissue inhomogeneity on the temperature distribution and tissue lesion formation induced by focused ultrasound. The inhomogeneous tissue is considered a combination of a homogeneous medium and a phase aberration screen in this article. Temperature distributions and lesion dimensions were predicted using the combination of acoustic non-linear and bio-heat transfer equations. To verify the theoretical predictions, polyethylene plates with phase distributions of different correlation lengths and standard deviations were made to mimic inhomogeneous tissues such as human abdominal tissue, and a series of experiments were performed, including acoustic and thermal measurements. The results indicate that the tissue inhomogeneity caused phase aberration of the ultrasound beam. With increasing standard deviation and correlation length of phase aberration, the scattering level of the acoustic field increased, while ultrasound-induced peak temperature and lesion size decreased. This study provides a theoretical and experimental basis for future development of accurate treatment plans for high-intensity focused ultrasound. PMID- 24768488 TI - Severity of spontaneous echo contrast in the jugular vein associated with ischemic stroke. AB - This study evaluated the relationship between spontaneous echo contrast (SEC) in the internal jugular vein (JV), atherosclerotic markers and ischemic stroke. One hundred twenty patients with acute ischemic stroke and 120 controls were recruited. SEC score correlated with plasma level of fibrinogen (coefficient: 0.105, p = 0.022), hemoglobin (coefficient: 0.122, p = 0.008) and presence of JV reflux (coefficient: 0.314, p < 0.001) and peak flow velocity (coefficient: 0.244, p < 0.001) in the corresponding JV, but did not correlate with carotid plaque score (coefficient: 0.042, p = 0.358) or intima-media thickness (coefficient: 0.067, p = 0.303). Multivariate regression analysis revealed that fibrinogen level, SEC score, intima-media thickness, plaque score and history of coronary artery disease were associated with acute ischemic stroke. In conclusion, the severity of SEC in the JV might represent the tendency toward thrombogenesis in diseased cerebral circulation possibly through mechanisms other than arterial atherosclerosis. PMID- 24768489 TI - Thermal fixation of swine liver tissue after magnetic resonance-guided high intensity focused ultrasound ablation. AB - The aim of this study was to investigate experimental conditions for efficient and controlled in vivo liver tissue ablation by magnetic resonance (MR)-guided high-intensity focused ultrasound (HIFU) in a swine model, with the ultimate goal of improving clinical treatment outcome. Histological changes were examined both acutely (four animals) and 1 wk after treatment (five animals). Effects of acoustic power and multiple sonication cycles were investigated. There was good correlation between target size and observed ablation size by thermal dose calculation, post-procedural MR imaging and histopathology, when temperature at the focal point was kept below 90 degrees C. Structural histopathology investigations revealed tissue thermal fixation in ablated regions. In the presence of cavitation, mechanical tissue destruction occurred, resulting in an ablation larger than the target. Complete extra-corporeal MR-guided HIFU ablation in the liver is feasible using high acoustic power. Nearby large vessels were preserved, which makes MR-guided HIFU promising for the ablation of liver tumors adjacent to large veins. PMID- 24768490 TI - Quantification of enhancement of renal parenchymal masses with contrast-enhanced ultrasound. AB - The purpose of this study was to investigate the value of quantitative assessment of enhancement in diagnosing renal cell carcinoma (RCC) with contrast-enhanced ultrasound (CEUS). A total of 73 solid renal parenchymal masses underwent both conventional ultrasound and CEUS. We compared the difference in maximum diameters on conventional ultrasound and CEUS between the benign and malignant groups. Enhancement features derived from a time-intensity curve were also analyzed. The diameters of renal cancer were found to be larger on CEUS than on conventional ultrasound (p < 0.05). When cutoff values of 4.74 s for washout time and 8.52% for enhancement intensity at 60 s for diagnosing RCCs were applied, the sensitivity, specificity and area under the receiver operating characteristic curve were 67.3%, 95.2%, 86.5% and 65.4%, 81.0%, 68.4%, respectively. The sensitivity and specificity for these two enhancement characteristics combined as a criterion for differentiating RCCs from benign lesions were 44.0% and 99.1%, respectively. Early washout in the area of maximal intensity in the interior of the lesion and prolonged washout in the whole area of the lesion are specific CEUS manifestations suggestive of RCC. PMID- 24768491 TI - What can be done to maintain men's health: perspectives from the EAU Young Academic Urologists Working Party Men's Health Group. PMID- 24768492 TI - Re: Giorgio Gandaglia, Maxine Sun, Jim C. Hu, et al. Gonadotropin-releasing hormone agonists and acute kidney injury in patients with prostate cancer. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2014.01.026. PMID- 24768493 TI - Long-term efficacy of the transobturator and retropubic midurethral slings for stress urinary incontinence: single-center update from a randomized controlled trial. PMID- 24768494 TI - Seek and ye shall find: the importance of careful macroscopic examination and thorough sampling in 2522 cholecystectomy specimens. AB - Gallbladder dysplasia and carcinoma (GBDC) vary greatly in incidence worldwide. We aimed to determine their prevalence in an Irish population, to assess the influence of tissue sampling protocols upon GBDC diagnosis, and to correlate various macroscopic and microscopic features with GBDC. We retrospectively reviewed histology reports of cholecystectomy specimens accessioned from 2000 to 2013. A total of 2522 cholecystectomy reports were reviewed, from 1860 female and 662 male patients. Male patients were significantly older (54.8 vs 46.8 years). There were 29 cases of dysplasia (1.15%) and 12 cases of carcinoma (0.48%), of which 10 were primary gallbladder cancers (0.4%). In 83.4% of cases, there was pathologic or radiologic evidence of cholelithiasis. Histologic findings included chronic (91.1%) or acute (15.4%) cholecystitis, cholesterosis (10.9%), adenomyomatous hyperplasia (2.1%), xanthogranulomatous inflammation (2.02%), and "porcelain" gallbladder (0.2%). Patients with GBDC were more likely to have a macroscopically identifiable lesion (29.4% vs 1.8%, positive predictive value, 18.18%, negative predictive value, 99.03%). Gallbladder dysplasia and carcinoma patients also had larger gallstones (median, 19 vs 12 mm) and were more likely to have adenomyomatous hyperplasia (8.8% vs 2.05%). When cases with a macroscopically identifiable lesion or clinical details suggestive of a gallbladder tumour were excluded (n = 2385), GBDC was significantly more frequently diagnosed if multiple tissue blocks had been sampled (2.91% vs 0.76%; relative risk (RR), 3.836). Rates of GBDC in Irish cholecystectomy specimens are low. The absence of a macroscopically identifiable lesion has a high (but not 100%) negative predictive value for GBDC. Sampling with more than 1 block significantly increases pickup rates of GBDC in these cases. PMID- 24768495 TI - Thyroid bed fine needle aspiration in patients after thyroidectomy--a useful follow-up tool with proposed diagnostic categories. AB - After thyroidectomy for primary thyroid malignancies, patients are closely monitored for recurrence or metastasis. Fine needle aspiration (FNA) has been used as the appropriate diagnostic modality for occult masses identified radiographically in the thyroid bed. In this study, we report our institutional experience with FNA of the thyroid bed and propose practical diagnostic categories. A retrospective chart review of all thyroid bed FNAs between April 2008 and January 2013 was performed, and a cohort of 39 patients was retrieved. The cytology diagnoses were divided into 5 categories including nondiagnostic, inflammatory/reactive, bland follicular cells, suspicious for neoplasm/malignancy, and malignant. The follow-up histologic and/or clinical findings were collected for each category. The 39 patients included 9 males and 30 females (ages 15-79 years). Prior thyroidectomies were due to papillary thyroid carcinoma (31 cases), follicular carcinoma (3 cases), medullary carcinoma (1 case), Hurthle cell carcinoma (1 case), malignancy unspecified (1 case), follicular adenoma (1 case), and multinodular goiter (1 case). Overall, 33% (13 cases) of thyroid bed FNAs were nondiagnostic, and 10% (4 cases) were categorized as "inflammatory/reactive." None of the patients in these 2 categories demonstrated evidence of clinical recurrence. One patient with a "bland follicular cells" thyroid bed FNA diagnosis had metastatic papillary thyroid carcinoma on follow-up histology. Of 14 patients in the "suspicious" and "malignant" categories, 10 had malignant follow-up diagnosis on histology. In conclusion, thyroid bed FNA with standardized diagnostic categories is a useful modality for follow-up in patients who have undergone thyroidectomy. PMID- 24768496 TI - Characterization of a cylindrical rod by inversion of acoustic scattering data. AB - In this paper, a new approach is proposed for nondestructive characterization of immersed and embedded isotropic rod-shaped samples by inversion of acoustic scattering data. The normal mode expansion technique is used for modelling the scattered field and the compression incident and compression scattered waves are considered. Genetic algorithm is the inversion technique used for estimating the elastic wave velocities and density of the rods from their measured backscattered pressure spectrum. The inversion technique is capable of computing the parameter values that best fit a particular set of data. A perturbation study is conducted on the sensitivity of the resonance frequencies to changes in elastic properties and density of the rods. The numerical results indicate that proper selection of resonance frequencies leads to accurate measurement of elastic constants and density. The proposed approach showed very good convergence and the results obtained were found to agree very well with available data. PMID- 24768497 TI - Preliminary study on rotary ultrasonic machining of CFRP/Ti stacks. AB - Reported drilling methods for CFRP/Ti stacks include twist drilling, end milling, core grinding, and their derived methods. The literature does not have any report on drilling of CFRP/Ti stacks using rotary ultrasonic machining (RUM). This paper, for the first time, reports a study on drilling of CFRP/Ti stacks using RUM. It also compares results on drilling of CFRP/Ti stacks using RUM with reported results on drilling of CFRP/Ti stacks using other methods. When drilling CFRP/Ti stacks using RUM, cutting force, torque, and CFRP surface roughness were lower, hole size variation was smaller, CFRP groove depth was smaller, tool life was longer, and there was no obvious Ti exit burr and CFRP entrance delamination. Ti surface roughness when drilling of CFRP/Ti stacks using RUM was about the same as those when using other methods. PMID- 24768498 TI - The 50 highest cited papers in hip and knee arthroplasty. PMID- 24768499 TI - In reply. PMID- 24768500 TI - Revision hip arthroplasty using a modular revision hip system in cases of severe bone loss. AB - We sought to identify outcomes of the Restoration Modular Hip System in cases of severe femoral bone stock deficiency. We performed a retrospective review of 55 revTHAs with a mean follow-up of 32 months (24-60 months). Outcomes included the WOMAC and HHS. Preoperative bone loss was categorized as Paprosky 3A (n = 13), 3B (n = 14), and 4 (n = 17). Periprosthetic fractures were classified as Vancouver B2 (n = 6) and B3 (n = 5). 53 of 55 stems were in situ at time of final review. WOMAC improved from 46 +/- 18 to 70 +/- 22 and HHS improved from 47 +/- 15 to 78 +/- 15. Complications were identified in 9 patients, which included dislocation (3), subsidence (2), infection (2), and periprosthetic fracture (2). In cases of significant proximal femoral bone deficiency, this stem demonstrated improvement in clinical outcomes with good results at short-term follow up. PMID- 24768501 TI - [Consensus document on the clinical use of melatonin in children and adolescents with sleep-onset insomnia]. AB - Sleep problems are highly prevalent among our children and adolescents. Its treatment is mainly based on cognitive behavioural therapies and habit modification procedures. However, the use of sleep promoting drugs and substances is widespread without being supported by clinical guidelines. Exogenous melatonin is a neurohormone marketed as a nutritional supplement that is being increasingly used in the management of sleep problems, and with no control over its use. The consensus document is presented on the use of melatonin in sleep-onset insomnia prepared by representatives of the Spanish Paediatric Association, the Spanish Society of Sleep, the Spanish Society of Paediatric Outpatients and Primary Care, the Spanish Society for Adolescent Medicine, the Spanish Society of Child Psychiatry, and the Spanish Society of Paediatric Neurology. PMID- 24768502 TI - Consultation on dengue vaccines: progress in understanding protection, 26-28 June 2013, Rockville, Maryland. AB - There is an unmet need for a dengue vaccine to further prevent the spread of this disease and contain the growing pandemic. To this end several vaccine companies and academic groups are actively pursuing the development of a tetravalent vaccine to prevent dengue. In the last few years progress has been made in this area, including the first results of a vaccine efficacy trial and improved understanding of the immune responses to the infection. Despite this progress, development of dengue vaccines faces important challenges including the need for a vaccine that induces balanced immune responses against all dengue strains and an incomplete understanding of the mechanism(s) of protection against infection and disease. This is a summary of a Consultation on dengue vaccines held in June 26-28, 2013 by the National Institute of Allergy and Infectious Diseases (part of the US National Institutes of Health) and the Dengue Vaccine Initiative (part of the International Vaccine Institute). The primary goal of this consultation was to review the progress in dengue vaccine development, evaluate the known mechanism of protection of dengue vaccines and discuss avenues for future research. PMID- 24768503 TI - Exonic single nucleotide polymorphisms within TLR3 associated with infant responses to serogroup C meningococcal conjugate vaccine. AB - The introduction of the serogroup C meningococcal (MenC) conjugate vaccination has successfully controlled the burden of disease associated with this serogroup in many countries. However, considerable inter-individual variation is observed in immune responses to MenC vaccine, and little is understood of the determinants of this variability. Previously, we reported an association between single nucleotide polymorphisms (SNPs) in TLR3 and CD44 and the persistence of MenC vaccine immunity. Here we further examine polymorphisms within these two candidate genes and immune responses to MenC vaccine. MenC-specific IgG concentrations and serum bactericidal assay (SBA) titres were measured one month after a primary course of MenC vaccination in 318 human infants. Tagging SNPs (TagSNPs) within TLR3 and CD44 were genotyped and regional imputations carried out to screen these genes for variations associated with immunological responses to MenC vaccine. This study reports an association between an exonic variant (rs3775290, P=0.025) in TLR3 and MenC IgG concentrations, as well as an association between three SNPs in CD44 (rs3794109, P=0.021; rs3794110, P=0.022; rs112762, P=0.049) and MenC SBA titres. These data support our previous findings of an association between SNPs in TLR3 and CD44, and present novel findings implicating exonic variants in these genes with MenC vaccine responses. PMID- 24768504 TI - Vitamin D supplementation and fall risk. PMID- 24768505 TI - Vitamin D supplementation and falls: a trial sequential meta-analysis. AB - BACKGROUND: Vitamin D supplementation is often recommended to prevent falls, although vitamin D trials and meta-analyses of these trials have reported conflicting results for this outcome. We aimed to assess if there was a need for further research. METHODS: We explored the value of doing further randomised controlled trials assessing the effects of vitamin D supplements on falls with trial sequential analysis with a risk reduction threshold of 15%. All analyses were done using the numbers of participants who had a fall in intention-to-treat analyses. Trial sequential analysis performs a cumulative meta-analysis, but reduces the risk of false-positive results from repetitive statistical testing by maintaining the overall risk of type 1 error at 5%. FINDINGS: In 20 existing randomised controlled trials (n=29,535), the effect estimate for vitamin D with or without calcium on falls lay within the futility boundary, providing evidence that vitamin D supplementation does not alter the relative risk by 15% or more. In a sensitivity analysis using a risk reduction threshold of 10%, the effect estimate also lay within the futility boundary. In subgroup analyses using a risk reduction threshold of 15%, the effect estimate also lay within the futility boundary for trials of vitamin D supplementation (16 trials, n=22,291) and trials of vitamin D with calcium (six trials, n=9919). INTERPRETATION: In pooled analyses, supplementation with vitamin D, with or without calcium, does not reduce falls by 15% or more. Future trials with similar designs are unlikely to alter these conclusions. At present, there is little justification for prescribing vitamin D supplements to prevent falls. FUNDING: Health Research Council of New Zealand. PMID- 24768507 TI - Can improving bioavailability improve the bioactivity of curcumin? PMID- 24768508 TI - Expected utility of voluntary vaccination in the middle of an emergent Bluetongue virus serotype 8 epidemic: a decision analysis parameterized for Dutch circumstances. AB - In order to put a halt to the Bluetongue virus serotype 8 (BTV-8) epidemic in 2008, the European Commission promoted vaccination at a transnational level as a new measure to combat BTV-8. Most European member states opted for a mandatory vaccination campaign, whereas the Netherlands, amongst others, opted for a voluntary campaign. For the latter to be effective, the farmer's willingness to vaccinate should be high enough to reach satisfactory vaccination coverage to stop the spread of the disease. This study looked at a farmer's expected utility of vaccination, which is expected to have a positive impact on the willingness to vaccinate. Decision analysis was used to structure the vaccination decision problem into decisions, events and payoffs, and to define the relationships among these elements. Two scenarios were formulated to distinguish farmers' mindsets, based on differences in dairy heifer management. For each of the scenarios, a decision tree was run for two years to study vaccination behaviour over time. The analysis was done based on the expected utility criterion. This allows to account for the effect of a farmer's risk preference on the vaccination decision. Probabilities were estimated by experts, payoffs were based on an earlier published study. According to the results of the simulation, the farmer decided initially to vaccinate against BTV-8 as the net expected utility of vaccination was positive. Re-vaccination was uncertain due to less expected costs of a continued outbreak. A risk averse farmer in this respect is more likely to re vaccinate. When heifers were retained for export on the farm, the net expected utility of vaccination was found to be generally larger and thus was re vaccination more likely to happen. For future animal health programmes that rely on a voluntary approach, results show that the provision of financial incentives can be adjusted to the farmers' willingness to vaccinate over time. Important in this respect are the decision moment and the characteristics of the disease. Farmers' perceptions of the disease risk and about the efficacy of available control options cannot be neglected. PMID- 24768506 TI - Advantages of fluorescence-guided laparoscopic surgery of pancreatic cancer labeled with fluorescent anti-carcinoembryonic antigen antibodies in an orthotopic mouse model. AB - BACKGROUND: Our laboratory has previously developed fluorescence-guided surgery of pancreatic and other cancers in orthotopic mouse models. Laparoscopic surgery is being used more extensively in surgical oncology. This report describes the efficacy of laparoscopic fluorescence-guided surgery of pancreatic cancer in an orthotopic mouse model. STUDY DESIGN: Mouse models of human pancreatic cancer were established with fragments of the BxPC-3 red fluorescent protein-expressing human pancreatic cancer using surgical orthotopic implantation. Mice were randomized to bright-light laparoscopic surgery (BLLS) or to fluorescence-guided laparoscopic surgery (FGLS). Fluorescence-guided laparoscopic surgery was performed with a light-emitting diode light source through a 495-nm emission filter in order to resect the primary tumors and any additional separate submillimeter tumor deposits within the pancreas, the latter of which was not possible with BLLS. Tumors were labeled with anti-CEA AlexaFluor 488 antibodies 24 hours before surgery with intravenous injection. Perioperative fluorescence images were obtained to evaluate tumor size. Mice were followed postoperatively to assess for recurrence and at termination to evaluate tumor burden. RESULTS: At termination, the FGLS-treated mice had less pancreatic tumor volume than the BLLS treated mice (5.75 mm(2) vs 28.43 mm(2), respectively; p = 0.012) and lower tumor weight (21.1 mg vs 174.4 mg, respectively; p = 0.033). Fluorescence-guided laparoscopic surgery compared with BLLS also decreased local recurrence (50% vs 80%, respectively; p = 0.048) and distant recurrence (70% vs 95%, respectively; p = 0.046). More mice in the FGLS group than the BLLS group were free of tumor at termination (25% vs 5%, respectively). Median disease-free survival was lengthened from 2 weeks with BLLS (95% CI, 1.635-2.365) to 7 weeks with FGLS (95% CI, 5.955-8.045; p = 0.001). CONCLUSIONS: Fluorescence-guided laparoscopic surgery is more effective than BLLS and, therefore, has important potential for surgical oncology. PMID- 24768509 TI - Neonatal extracorporeal membrane oxygenation: Initial experience of Hospital de Sao Joao. AB - The purpose of this series is to report the initial ECMO experience of the Neonatal Intensive Care Unit of Hospital de Sao Joao. The first three clinical cases are reported. Case report 1: a 39 weeks gestational age girl with severe lung hypoplasia secondary to a bilateral congenital diaphragmatic hernia. Case report 2: a 39 weeks gestational age girl with a right congenital diaphragmatic hernia and a tracheal stenosis. Case report 3: a 34 weeks gestational age boy, with 61 days of life, with a Bordetella pertussis pneumonia, severe pulmonary hypertension, shock, hyperleukocytosis and seizures. PMID- 24768510 TI - Clinical efficacy and safety in relapsed/refractory diffuse large B-cell lymphoma: a systematic literature review. AB - This systematic literature review was designed to assess information on the clinical efficacy and safety of interventions used in the treatment of refractory or relapsed diffuse large B-cell lymphoma (R/R DLBCL) and to perform a meta analysis if possible. We searched databases (PubMed, EMBASE, and Cochrane Library for articles from 1997 to August 2, 2012 reported in English), conference abstracts, bibliographic reference lists, and the ClinicalTrials.gov database for phase II to IV studies with results. Studies had to report on patients with R/R DLBCL who were not eligible to receive high-dose therapy (HDT) with stem cell transplantation (SCT) (autologous or allogeneic). Mixed-type non-Hodgkin lymphoma (NHL) studies were required to report R/R DLBCL outcomes separately. We identified 55 studies that presented outcomes data separately for patients with R/R DLBCL. Of 7 comparative studies, only 4 were randomized controlled trials (RCTs). In the 2 RCTs with a common regimen, the patient populations differed too greatly to perform a valid meta-analysis. The 48 single-arm studies identified were typically small (n < 50 in most), with 31% reporting median progression-free survival (PFS) or overall survival (OS) specifically for the R/R DLBCL population. In these studies, median OS ranged from 4 to 13 months. The small number of RCTs in R/R DLBCL precludes identifying optimal treatments. Small sample size, infrequent reporting of OS and PFS separated by histologic type, and limited information on patient characteristics also hinder comparison of results. Randomized studies are needed to demonstrate which current therapies have advantages for improving survival and other important clinical outcomes in patients with R/R DLBCL. PMID- 24768511 TI - Metformin vs insulin in the management of gestational diabetes: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness of metformin compared with insulin in achieving glycemic control and investigate the maternal and neonatal outcomes in gestational diabetes mellitus. METHODS: We searched four electronic databases from inception through December 2012. Terms for Gestational diabetes/gestational diabetes mellitus/diabetes pregnancy AND/OR Metformin/hypoglycemic drugs/Hypoglycemic Agents/Antidiabetic Medications were used in the search. Two investigators independently reviewed titles and abstracts, performed data abstraction on full articles, and assessed study quality. Meanwhile, manual search of other resources and the search on Google Scholar were also carried out to identify more related articles .Rev Man 5.0 was used to analyze the data. RESULTS: Six randomized clinical trials involving 1420 subjects were included. The current limited data suggested that using metformin in gestational diabetes subjects did not significantly increase adverse maternal outcomes and neonatal outcomes, also with less weight gain and neonatal hypoglycemia, but a higher incidence of premature birth. CONCLUSIONS: Metformin will not increase the incidence of adverse maternal outcomes and neonatal outcomes. PMID- 24768512 TI - Do interventions by allied health professionals discussing adherence to insulin improve this adherence? AB - It is assumed that interventions to improve the adherence to insulin by allied health professionals discussing adherence to insulin will improve this adherence. However, there is little evidence to support this, as interventions by a pharmacist or nurse educator have not been shown conclusively to improve adherence to insulin. PMID- 24768513 TI - Odorous gaseous emissions as influence by process condition for the forced aeration composting of pig slaughterhouse sludge. AB - Compost sustainability requires a better control of its gaseous emissions responsible for several impacts including odours. Indeed, composting odours have stopped the operation of many platforms and prevented the installation of others. Accordingly, present technologies collecting and treating gases emitted from composting are not satisfactory and alternative solutions must be found. Thus, the aim of this paper was to study the influence of composting process conditions on gaseous emissions. Pig slaughterhouse sludge mixed with wood chips was composted under forced aerationin 300 L laboratory reactors. The process conditions studied were: aeration rate of 1.68, 4.03, 6.22, 9.80 and 13.44 L/h/kg of wet sludge; incorporation ratio of 0.55, 0.83 and 1.1 (kg of wet wood chips/kg of wet sludge), and; bulking agent particles size of <10, 10<20 and 20<30 mm. Out going gases were sampled every 2 days and their composition was analysed using gas chromatography coupled with mass spectrometry (GC-MS). Fifty-nine compounds were identified and quantified. Dividing the cumulated mass production over 30 days of composting, by odour threshold, 9 compounds were identified as main potential odour contributors: hydrogen sulphide, trimethylamine, ammonia, 2 pentanone, 1-propanol-2-methyl, dimethyl sulphide, dimethyl disulphide, dimethyl trisulphide and acetophenone. Five gaseous compounds were correlated with both aeration rate and bulking agent to waste ratio: hydrogen sulphide, trimethylamine, ammonia, 2-pentanone and 1-propanol-2-methyl. However, dropping the aeration rate and increasing the bulking agent to waste ratio reduced gaseous odour emissions by a factor of 5-10, when the required threshold dilution factor ranged from 10(5) to 10(6), to avoid nuisance at peak emission rates. Process influence on emissions of dimethyl sulphide, dimethyl disulphide, dimethyl trisulphide were poorly correlated with both aeration rate and bulking agent to waste ratio as a reaction with hydrogen sulphide was suspected. Acetophenone emissions originated from the wood chips. Olfactory measurements need to be correlated to gaseous emissions for a more accurate odour emission evaluation. PMID- 24768514 TI - A comparison of waste management throughout Asian countries. PMID- 24768516 TI - IWWG News & Views. PMID- 24768515 TI - Occupational exposure in the fluorescent lamp recycling sector in France. AB - The fluorescent lamp recycling sector is growing considerably in Europe due to increasingly strict regulations aimed at inciting the consumption of low energy light bulbs and their end-of-life management. Chemical risks were assessed in fluorescent lamp recycling facilities by field measurement surveys in France, highlighting that occupational exposure and pollutant levels in the working environment were correlated with the main recycling steps and processes. The mean levels of worker exposure are 4.4 mg/m(3), 15.4 MUg/m(3), 14.0 MUg/m(3), 247.6 MUg/m(3), respectively, for total inhalable dust, mercury, lead and yttrium. The mean levels of airborne pollutants are 3.1mg/m(3), 9.0 MUg/m(3), 9.0 MUg/m(3), 219.2 MUg/m(3), respectively, for total inhalable dust, mercury, lead and yttrium. The ranges are very wide. Surface samples from employees' skin and granulometric analysis were also carried out. The overview shows that all the stages and processes involved in lamp recycling are concerned by the risk of hazardous substances penetrating into the bodies of employees, although exposure of the latter varies depending on the processes and tasks they perform. The conclusion of this study strongly recommends the development of a new generation of processes in parallel with more information sharing and regulatory measures. PMID- 24768517 TI - Adsorption properties of biologically active derivatives of quaternary ammonium surfactants and their mixtures at aqueous/air interface II. Dynamics of adsorption, micelles dissociation and cytotoxicity of QDLS. AB - The main aim of our study was analysis of adsorption dynamics of mixtures containing quaternary derivatives of lysosomotropic substance (QDLS). Two types of equimolar mixtures were considered: the ones containing two derivatives of lysosomotropic substances (DMALM-12 and DMGM-12) as well as the catanionic mixtures i.e. the systems containing QDLS and DBSNa. Dynamic surface tension measurements of surfactant mixtures were made. The results suggested that the diffusivity of the mixed system could be treated as the average value of rates of diffusion of individual components, micelles and ion pairs, which are present in the mixtures studied. Moreover, an attempt was made to explain the influence of the presence of micelles in the mixtures on their adsorption dynamics. The compounds examined show interesting biological properties which can be useful, especially for drug delivery in medical treatment. In vitro cytotoxic activities of the mixtures studied towards human cancer cells were evaluated. Most of the mixtures showed a high antiproliferative potential, especially the ones containing DMALM-12. Each cancer cell line used demonstrated different sensitivity to the same dose of the mixtures tested. PMID- 24768518 TI - Cardiorespiratory and anaesthetic effects of two continuous rate infusions of dexmedetomidine in alfaxalone anaesthetized dogs. AB - Six Beagles were used in this prospective randomised crossover experimental study. Dexmedetomidine was administered at 0, 1 or 2 MUg/kg IV for group C, LDA and HDA, respectively. Animals were induced and maintained with alfaxalone at 0.07 mg/kg/min with a CRI dexmedetomidine dose of 0, 0.5 or 1 MUg/kg/h for group C, LDA and HDA, respectively. Cardiorespiratory variables, arterial blood gases and depth of anaesthesia were recorded. The recovery times and quality of recovery were scored. Group HDA produced a greater increase in the depth of anaesthesia than LDA. However, with both protocols, CI was halved compared to normal values in dogs. The use of oxygen before and during the anaesthetic maintenance is advisable, mainly if dexmedetomidine is going to be use as a pre medicant and maintenance agent. The quality of recovery was better in groups receiving dexmedetomidine, without causing an increase in recovery time. PMID- 24768519 TI - Gene regulatory networks in the immune system. AB - We describe examples of genomic control circuits that underlie developmental transitions and cellular activation states within the immune system. The architectures of simple gene regulatory networks (GRNs) are highlighted to emphasize conservation of regulatory motifs. The regulatory logic and the cell fate dynamics of each simple GRN, the latter revealed by mathematical and computational modeling, are elaborated. This framework is being expanded to enable the assembly and analysis of complex GRNs using genomic, computational, and high-throughput experimental methodologies. The paradigm will provide new insights into immune cell development and function, and into the pathophysiology of autoimmune and inflammatory disorders, as well as immune malignancies. PMID- 24768520 TI - Response to "Re: Urethral plate grafting improves the results of tubularized incised plate urethroplasty in primary hypospadias". PMID- 24768521 TI - Pediatric chronic orchialgia: patient population and patterns of care. AB - OBJECTIVE: A major hurdle in management of any chronic pain syndrome is understanding the population in which it occurs. We describe our pediatric population of patients with peripubertal and postpubertal chronic orchialgia. PATIENTS AND METHODS: Pediatric patients >= 10 years of age seen between 2002 and 2012 were identified by ICD code 608.9, Male Genital Disorder NOS. Patients were included if they had orchialgia without identifiable cause lasting >3 months. Patient history, diagnostic evaluations, treatments, and outcomes were assessed. RESULTS: Seventy-nine pediatric patients were identified. The mean age was 13.3 years (range 10-18); mean duration of orchialgia was 16.3 months (range 3-85). Thirty-three of 79 (42%) had concomitant medical conditions and/or psychiatric behavioral issues. The mean follow-up was 7.1 months (range 0-70.4) with 41/79 (52%) having more than one office visit follow-up. Eleven patients were referred to a pediatric pain clinic; 10 out of 11 (91%) were evaluated there. Overall, 16 out of 41 (39%) had resolution of pain: nine out of 41 (22%) responding to conservative management vs seven of 10 (70%) responding to pain clinic management (3 to anti-neuropathic medications, 4 to nerve block). CONCLUSION: Many pediatric patients with chronic orchialgia have co-morbidities amenable to multidisciplinary collaborative coordination of care. Referral to pediatric pain clinic can be of significant benefit. PMID- 24768522 TI - Oncologic outcomes following robot-assisted radical cystectomy with minimum 5 year follow-up: the Roswell Park cancer institute experience. AB - BACKGROUND: Long-term oncologic outcomes following robot-assisted radical cystectomy (RARC) remain scarce. OBJECTIVE: To report long-term oncologic outcomes following RARC at a single institution. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective review of 99 patients who underwent RARC for urothelial carcinoma of bladder between 2005 and 2009. INTERVENTION: RARC was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes included recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS), measured by the Kaplan-Meier method. The association between primary outcomes and perioperative and pathologic factors was assessed using a multivariable Cox proportional hazards model. RESULTS AND LIMITATIONS: Fifty-one (52%) patients had stage pT3 or higher disease. Eight (8%) patients had positive margins and 30 (30%) had positive lymph nodes (LNs), with a median of 21 LNs removed. Median follow-up for patients alive was 74 mo. The 5-yr RFS, CSS, and OS rates were 52.5%, 67.8%, and 42.4%, respectively. Tumor stage, LN stage, and margin status were each significantly associated with RFS, CSS, and OS. On multivariable analysis, tumor and LN stage were independent predictors of RFS, CSS, and OS, while positive margin status and Charlson comorbidity index predicted worse OS and CSS. Adjuvant chemotherapy predicted RFS only. Retrospective design and lack of open comparison are main limitations of this study. CONCLUSIONS: Long-term oncologic outcomes following RARC demonstrate RFS and CSS estimates similar to those reported in literature for open radical cystectomy. Randomized controlled trials can better define outcomes of any alternative technique. PATIENT SUMMARY: Survival data 5 yr after RARC for bladder cancer demonstrate that survival outcomes are dependent on the same oncologic parameters as previously reported for open surgery. PMID- 24768523 TI - Site-specific phosphorylation of Tau protein is associated with deacetylation of microtubules in mouse spermatogenic cells during meiosis. AB - Tau is one of the microtubule-associated proteins and a major component of paired helical filaments, a hallmark of Alzheimer's disease. Its expression has also been indicated in the testis. However, its function and modification in the testis have not been established. Here, we analyzed the dynamics of phosphorylation patterns during spermatogenesis. The expression of Tau protein and its phosphorylation were shown in the mouse testis. Immunohistochemistry revealed that the phosphorylation was strongly detected during meiosis. Correspondingly, the expression of acetylated tubulin was inversely weakened during meiosis. These results suggest that phosphorylation of Tau protein contributes to spermatogenesis, especially in meiosis. PMID- 24768524 TI - Mutant p53 reactivation by small molecules makes its way to the clinic. AB - The TP53 tumor suppressor gene is mutated in many human tumors, including common types of cancer such as colon and ovarian cancer. This illustrates the key role of p53 as trigger of cell cycle arrest or cell death upon oncogenic stress. Most TP53 mutations are missense mutations that result in single amino acid substitutions in p53 and expression of high levels of dysfunctional p53 protein. Restoration of wild type p53 function in such tumor cells will induce robust cell death and allow efficient eradication of the tumor. Therapeutic targeting of mutant p53 in tumors is a rapidly developing field at the forefront of translational cancer research. Various approaches have led to the identification of small molecules that can rescue mutant p53. These include compounds that target specific p53 mutations, including PK083 and PK5174 (Y220C mutant p53) and NSC319726 (R175H mutant p53), as well as PRIMA-1 and its analog APR-246 that affect a wider range of mutant p53 proteins. APR-246 has been tested in a Phase I/II clinical trial with promising results. PMID- 24768525 TI - Quantified self and human movement: a review on the clinical impact of wearable sensing and feedback for gait analysis and intervention. AB - The proliferation of miniaturized electronics has fueled a shift toward wearable sensors and feedback devices for the mass population. Quantified self and other similar movements involving wearable systems have gained recent interest. However, it is unclear what the clinical impact of these enabling technologies is on human gait. The purpose of this review is to assess clinical applications of wearable sensing and feedback for human gait and to identify areas of future research. Four electronic databases were searched to find articles employing wearable sensing or feedback for movements of the foot, ankle, shank, thigh, hip, pelvis, and trunk during gait. We retrieved 76 articles that met the inclusion criteria and identified four common clinical applications: (1) identifying movement disorders, (2) assessing surgical outcomes, (3) improving walking stability, and (4) reducing joint loading. Characteristics of knee and trunk motion were the most frequent gait parameters for both wearable sensing and wearable feedback. Most articles performed testing on healthy subjects, and the most prevalent patient populations were osteoarthritis, vestibular loss, Parkinson's disease, and post-stroke hemiplegia. The most widely used wearable sensors were inertial measurement units (accelerometer and gyroscope packaged together) and goniometers. Haptic (touch) and auditory were the most common feedback sensations. This review highlights the current state of the literature and demonstrates substantial potential clinical benefits of wearable sensing and feedback. Future research should focus on wearable sensing and feedback in patient populations, in natural human environments outside the laboratory such as at home or work, and on continuous, long-term monitoring and intervention. PMID- 24768526 TI - The influence of ankle dorsiflexion and self-reported patient outcomes on dynamic postural control in participants with chronic ankle instability. AB - We investigated the influence of ankle dorsiflexion range of motion (DF-ROM) and self-reported patient outcomes on dynamic postural control assessed with the Star Excursion Balance Test (SEBT) in individuals with chronic ankle instability (CAI). Twenty-nine participants with self-reported CAI volunteered. The primary outcome measurements were categorized into clinician-and patient-generated. Clinician-generated outcome measurements included anterior (SEBT-A), posteriormedial (SEBT-PM) and posteriorlateral (SEBT-PL) reach distances (cm) normalized by leg length (cm) of the SEBT, maximum weight-bearing dorsiflexion (WB-DF) (cm), and open-chain DF-ROM ( degrees ). Self-reported patient-generated outcome measures included the foot and ankle ability measure and the level of perceived pain, stiffness, stability, and function of their involved ankle on a 10-cm visual analog scale (VAS). Pearson product moment correlations were used to examine the relationship of the SEBT performances with DF-ROM and self-reported patient outcome measures. A multiple linear regression was performed to determine the influence of patient- and clinician-generated measures on the SEBT. SEBT-A performance was significantly and fairly correlated with WB-DF (r=0.410, p=0.014), perceived ankle stiffness (r=0.477, p=0.014), and open-chain DF-ROM (r=0.404, p=0.015). The strongest predictor of the variance in SEBT-A was the combination of the variance in WB-DF and VAS-stiffness (R2=0.348, p=0.004). There were no significant correlations with the SEBT-PM and SEBT-PL. WB-DF and VAS stiffness may represent targets for intervention that need to be addressed to produce the best outcome in participants with CAI when altered dynamic postural control is detected on the SEBT-A. PMID- 24768527 TI - Seasonal variations and spatial distributions of perfluoroalkyl substances in the rivers Elbe and lower Weser and the North Sea. AB - The spatial distributions and seasonal variations of perfluoroalkyl substances (PFASs) in surface waters were investigated for the German rivers Elbe and lower Weser, and the North Sea. ?PFAS concentrations ranged from 4.1 to 250ngL(-1) in the River Elbe, from 3.8 to 16ngL(-1) in the lower Weser, and from 0.13 to 10ngL( 1) in the North Sea. The most abundant compound was perfluorobutanesulfonate (PFBS) with a proportion of 24% in river water and 31% in seawater samples. The concentrations of perfluorohexanoic acid (PFHxA) and perfluorooctanoic acid (PFOA) in Elbe River water showed significant seasonal variation in 2011. The seasonal variations might be related to the variations of water discharge. The highest concentrations of PFOA and PFHxA were detected in August. Pearson correlations showed that perfluorobutanoic acid (PFBA) and PFBS had different sources from other PFASs, and the current manufacturing and use of C4-based products could explain the distinction. The estimated fluxes of individual substances and ?PFASs in the River Elbe showed no significant seasonal variation. The annual fluxes of PFASs to the North Sea were estimated to be 335+/-100kgyear( 1) from the River Elbe and 102+/-22kgyear(-1) from the River Weser. PMID- 24768528 TI - A lectin from the green seaweed Caulerpa cupressoides reduces mechanical hyper nociception and inflammation in the rat temporomandibular joint during zymosan induced arthritis. AB - Seaweed lectins have been widely investigated as anti-nociceptive and anti inflammatory agents. This study analyzed the anti-nociceptive and anti inflammatory responses of a lectin from the green seaweed Caulerpa cupressoides (CcL) on zymosan-induced arthritis of the rat temporomandibular joint (TMJ). Rats received i.v. CcL 30 min prior to injection of zymosan (2mg/art.) or 0.9% saline into the left TMJ. Mechanical hyper-nociception was measured by the electronic von Frey method at baseline and 4h after zymosan injection. Animals were euthanized 6h after zymosan injection and the synovial fluid was collected for leukocyte counting and myeloperoxidase activity assessment. Other animals were treated with ZnPP-IX (3mg/kg; s.c.), a specific heme oxygenase-1 pathway inhibitor, and naloxone (10 MUg/art.), a nonselective opioid receptor antagonist. TMJ tissues were excised to perform histopathological and immunohistochemistry analyses. CcL (0.1, 1 or 10mg/kg) significantly reduced zymosan-induced hyper nociception (81, 83 and 89.5%, respectively) and inhibited the leukocyte influx (77.3, 80.7 and 98.5%, respectively) compared with the zymosan-only group, as confirmed by myeloperoxidase activity; however, treatment with naloxone or ZnPP IX did not revert the effects of CcL (10mg/kg), suggesting that the naloxone sensitive opioid and heme oxygenase-1 pathways are not involved. CcL also reduced the leukocyte influx and the expression of IL-1beta and TNF-alpha in the TMJ, based on histopathological and immunohistochemistry analyses, respectively. Therefore, CcL reduces TMJ hyper-nociception and inflammation with a mechanism that is partially dependent on TNF-alpha and IL-1beta inhibition. CcL reveals a potentially valuable alternative tool for future studies of TMJ disorders. PMID- 24768529 TI - Perceptions of Australian emergency staff towards patients presenting with deliberate self-poisoning: a qualitative perspective. AB - INTRODUCTION/BACKGROUND: Attitude of staff towards patients who present to the emergency department following deliberate self-poisoning may be integral to the outcome of these events. There is little in-depth understanding of emergency staff perceptions about this vulnerable group. AIM: Explore staff perceptions about caring for patients who present to the emergency department following deliberate self-poisoning. DESIGN: Qualitative descriptive study. METHODS: Two open-ended questions enabled 186 clinicians to describe their perceptions about caring for people who present to the emergency department following deliberate self-poisoning. Data were analysed using qualitative data analysis procedures. RESULTS: Three themes emerged from the data representing staff perceptions about caring for patients who deliberately self-poisoned and included depends on the patient, treat everyone the same, and skilled and confident to manage these patients. CONCLUSION: Staff reported mixed reactions to patients presenting with deliberate self-poisoning. These included feelings of empathy or frustration, and many lacked the skills and confidence to effectively manage these patients. RELEVANCE TO PRACTICE: Health networks are required to ensure that emergency staff have specialist support, knowledge, skills, and guidelines to provide effective care for this vulnerable population. PMID- 24768530 TI - Comment on: "Nurses' perceptions of the factors which cause violence and aggression in the emergency department: a qualitative study". Int. Emerg. Nurs. 22(3) (2014), 134-139 by Angland, S., et al. PMID- 24768531 TI - Hyperglycemia, hypoglycemia, and glycemic complexity are associated with worse outcomes after surgery. AB - PURPOSE: The purpose of this study was to determine if glycemic complexity, along with hypoglycemia and hyperglycemia, was associated with worse outcomes after cardiac surgery. MATERIALS AND METHODS: We conducted a retrospective analysis of 970 patients who had insulin infusions designed to keep blood glucose levels between 80 and 110 mg/dL. Glycemic complexity was calculated using jackknifed approximate entropy. Logistic regression was used to adjust for confounders. RESULTS: A total of 495 patients (51%) developed complications, and 32 patients (3.3%) died. Along with older age, comorbidities, and complicated surgeries, any hypoglycemia (glucose<71 mg/dL) and the number of glucose values greater than 140 mg/dL were independent predictors of complications. Increased risk of mortality, after adjusting for other risk factors, was associated with older age, longer perfusion time, receiving intraoperative transfusions, and greater jackknifed approximate entropy of the glucose time series. CONCLUSION: We found that hypoglycemia (glucose<71 mg/dL) and hyperglycemia (glucose>140 mg/dL) were associated with increased risk of complications, whereas greater complexity of the glucose time series was associated with mortality. PMID- 24768532 TI - Critical care ultrasound training: a survey of US fellowship directors. AB - PURPOSE: The purpose of this study is to describe the current state of bedside ultrasound use and training among critical care (CC) training programs in the United States. MATERIALS AND METHODS: This was a cross-sectional survey of all program directors for Accreditation Council for Graduate Medical Education accredited programs during the 2012 to 2013 academic year in CC medicine, surgical CC, pulmonary and critical care, and anesthesia CC. Availability, current use, and barriers to training in CC ultrasound were assessed. RESULTS: Sixty of 195 (31%; 95% confidence interval [CI], 24%-38%) program directors responded. Most of the responding programs had an ultrasound system available for use (54/60, 90%; 95% CI, 79%-96%) and identified ultrasound training as useful (59/60, 98%; 95% CI, 91%-100%) but lacked a formal curriculum (25/60, 42%; 95% CI, 29%-55%) or trained faculty (mean percentage of faculty trained in ultrasound: pulmonary and critical care, 25%; surgical CC, 33%; anesthesia CC, 20%; CC medicine, 7%), and relied on informal teaching (45/60, 77%; 95% CI, 62% 85%). Faculty with expertise (53/60, 88%; 95% CI, 77%-95%), simulation training (60/60, 100%; 95% CI, 94%-100%), establishing and meeting required number of examinations (47/60, 78%; 95% CI, 66%-88%), and regular review sessions (49/60, 82%; 95% CI, 70%-90%) were identified as necessary to improve ultrasound training. Most responding programs (32/35 91%; 95% CI, 77%-98%) without a formal curriculum plan to create one in the next 5 years. CONCLUSIONS: This study identified deficiencies in current training, suggesting a need for a formal curriculum for bedside ultrasound training in CC fellowship programs. PMID- 24768533 TI - The Intermountain Risk Score predicts mortality in trauma patients. AB - PURPOSE: Intermountain Risk Score (IMRS) uses the admission complete blood count and basic metabolic profile to predict mortality. Intermountain Risk Score has been validated in medical patients but has not been evaluated in trauma. This study tested whether IMRS is predictive of mortality in a trauma population at a level I trauma center. METHODS: Admitted trauma patients with complete blood count and basic metabolic profile from October 2005 to December 2011 were evaluated. Thirty-day and 1-year IMRS were calculated using multivariable modeling. Mortality was determined using the medical record and Social Security Administration death data. RESULTS: Three thousand six hundred thirty-seven females and 5901 males were evaluated. Intermountain Risk Score was highly predictive of death at 30 days (c-statistics, c = 0.772 for females; c = 0.783 males) and 1 year (c = 0.778 for females; c = 0.831 males). Cox regression analysis, adjusted for injury severity score, blunt vs penetrating, and length of stay, showed increased mortality risks among patients in the moderate- and high risk IMRS-defined groups at both 30 days and 1 year, with hazard ratios ranging from 4.96 to 57.88 (all P < .001). CONCLUSION: Intermountain Risk Score strongly predicts mortality in trauma patients at this single level I trauma center. The ability to accurately determine a patient's mortality risk at admission makes IMRS a potentially clinically important tool. PMID- 24768534 TI - Functional electrical stimulation with cycling in the critically ill: a pilot case-matched control study. AB - PURPOSE: The purpose was to determine (a) safety and feasibility of functional electrical stimulation (FES)-cycling and (b) compare FES-cycling to case-matched controls in terms of functional recovery and delirium outcomes. MATERIALS AND METHODS: Sixteen adult intensive care unit patients with sepsis ventilated for more than 48 hours and in the intensive care unit for at least 4 days were included. Eight subjects underwent FES-cycling in addition to usual care and were compared to 8 case-matched control individuals. Primary outcomes were safety and feasibility of FES-cycling. Secondary outcomes were Physical Function in Intensive Care Test scored on awakening, time to reach functional milestones, and incidence and duration of delirium. RESULTS: One minor adverse event was recorded. Sixty-nine out of total possible 95 FES sessions (73%) were completed. A visible or palpable contraction was present 80% of the time. There was an improvement in Physical Function in Intensive Care Test score of 3.9/10 points in the intervention cohort with faster recovery of functional milestones. There was also a shorter duration of delirium in the intervention cohort. CONCLUSIONS: The delivery of FES-cycling is both safe and feasible. The preliminary findings suggest that FES-cycling may improve function and reduce delirium. Further research is required to confirm the findings of this study and evaluate the efficacy of FES-cycling. PMID- 24768535 TI - Modification of PCNA by ISG15 plays a crucial role in termination of error-prone translesion DNA synthesis. AB - In response to DNA damage, PCNA is mono-ubiquitinated and triggers translesion DNA synthesis (TLS) by recruiting polymerase-eta. However, it remained unknown how error-prone TLS is turned off after DNA lesion bypass to prevent mutagenesis. Here we showed that ISG15 modification (ISGylation) of PCNA plays a key role in TLS termination. Upon UV irradiation, EFP, an ISG15 E3 ligase, bound to mono ubiquitinated PCNA and promoted its ISGylation. ISGylated PCNA then tethered USP10 for deubiquitination and in turn the release of polymerase-eta from PCNA. Eventually, PCNA was deISGylated by UBP43 for reloading of replicative DNA polymerases and resuming normal DNA replication. However, ISGylation-defective Lys-to-Arg mutations in PCNA or knockdown of any of ISG15, EFP, or USP10 led to persistent recruitment of mono-ubiquitinated PCNA and polymerase-eta to nuclear foci, causing an increase in mutation frequency. These findings establish a crucial role of PCNA ISGylation in termination of error-prone TLS for preventing excessive mutagenesis. PMID- 24768537 TI - Quiescence-induced LncRNAs trigger H4K20 trimethylation and transcriptional silencing. AB - A complex network of regulatory pathways links transcription to cell growth and proliferation. Here we show that cellular quiescence alters chromatin structure by promoting trimethylation of histone H4 at lysine 20 (H4K20me3). In contrast to pericentric or telomeric regions, recruitment of the H4K20 methyltransferase Suv4 20h2 to rRNA genes and IAP elements requires neither trimethylation of H3K9 nor interaction with HP1 proteins but depends on long noncoding RNAs (lncRNAs) that interact with Suv4-20h2. Growth factor deprivation and terminal differentiation lead to upregulation of these lncRNAs, increase in H4K20me3, and chromatin compaction. The results uncover a lncRNA-mediated mechanism that guides Suv4-20h2 to specific genomic loci to establish a more compact chromatin structure in growth-arrested cells. PMID- 24768536 TI - Single-molecule imaging of FtsK translocation reveals mechanistic features of protein-protein collisions on DNA. AB - In physiological settings, DNA translocases will encounter DNA-bound proteins, which must be dislodged or bypassed to allow continued translocation. FtsK is a bacterial translocase that promotes chromosome dimer resolution and decatenation by activating XerCD-dif recombination. To better understand how translocases act in crowded environments, we used single-molecule imaging to visualize FtsK in real time as it collided with other proteins. We show that FtsK can push, evict, and even bypass DNA-bound proteins. The primary factor dictating the outcome of collisions was the relative affinity of the proteins for their specific binding sites. Importantly, protein-protein interactions between FtsK and XerD help prevent removal of XerCD from DNA by promoting rapid reversal of FtsK. Finally, we demonstrate that RecBCD always overwhelms FtsK when these two motor proteins collide while traveling along the same DNA molecule, indicating that RecBCD is capable of exerting a much greater force than FtsK when translocating along DNA. PMID- 24768538 TI - Structural and biochemical insights to the role of the CCR4-NOT complex and DDX6 ATPase in microRNA repression. AB - MicroRNAs (miRNAs) control gene expression by regulating mRNA translation and stability. The CCR4-NOT complex is a key effector of miRNA function acting downstream of GW182/TNRC6 proteins. We show that miRNA-mediated repression requires the central region of CNOT1, the scaffold protein of CCR4-NOT. A CNOT1 domain interacts with CNOT9, which in turn interacts with the silencing domain of TNRC6 in a tryptophan motif-dependent manner. These interactions are direct, as shown by the structure of a CNOT9-CNOT1 complex with bound tryptophan. Another domain of CNOT1 with an MIF4G fold recruits the DEAD-box ATPase DDX6, a known translational inhibitor. Structural and biochemical approaches revealed that CNOT1 modulates the conformation of DDX6 and stimulates ATPase activity. Structure-based mutations showed that the CNOT1 MIF4G-DDX6 interaction is important for miRNA-mediated repression. These findings provide insights into the repressive steps downstream of the GW182/TNRC6 proteins and the role of the CCR4 NOT complex in posttranscriptional regulation in general. PMID- 24768539 TI - K33-Linked Polyubiquitination of Coronin 7 by Cul3-KLHL20 Ubiquitin E3 Ligase Regulates Protein Trafficking. AB - Ubiquitin chains are formed as structurally distinct polymers via different linkages, and several chain types including K33-linkage remain uncharacterized. Here, we describe a role for K33-polyubiquitination in protein trafficking. We show that the Cullin 3 (Cul3) substrate adaptor KLHL20 is localized to the trans Golgi network (TGN) and is important for post-Golgi trafficking by promoting the biogenesis of TGN-derived transport carriers. The Cul3-KLHL20 ubiquitin E3 ligase catalyzes a nondegradable, K33-linked polyubiquitination on coronin 7 (Crn7), which facilitates Crn7 targeting to TGN through a ubiquitin-dependent interaction with Eps15. Blockage of K33-chain formation, Crn7 ubiquitination, or disruption of Crn7-Eps15 interaction impairs TGN-pool F-actin assembly, a process essential for generating transport carriers. Enforced targeting of Crn7 to TGN bypasses the requirement of K33-ubiquitination for TGN-pool F-actin assembly and post-Golgi trafficking. Our study reveals a role of KLHL20-mediated K33-ubiquitination of Crn7 in post-Golgi transport and identifies a cellular recognition mechanism for this ubiquitin chain type. PMID- 24768541 TI - Tibial plateau coverage in UKA: a comparison of patient specific and off-the shelf implants. AB - Poor tibial component fit can lead to issues including pain, loosening and subsidence. Morphometric data, from 30 patients undergoing UKA were utilized; comparing size, match and fit between patient-specific and off-the-shelf implants. CT images were prospectively obtained and implants modeled in CAD, utilizing sizing templates with off-the-shelf and CAD designs with patient specific implants. Virtual surgery was performed, maximizing tibial plateau coverage while minimizing implant overhang. Each implant evaluated to examine tibial fit. Patient-specific implants provided significantly greater cortical rim surface area coverage versus off-the-shelf implants: 77% v. 43% medially and 60% v. 37% laterally. Significantly less cortical rim overhang and undercoverage were observed with patient-specific implants. Patient-specific implants provide superior cortical bone coverage and fit while minimizing overhang and undercoverage seen in off-the-shelf implants. PMID- 24768540 TI - A DDX6-CNOT1 complex and W-binding pockets in CNOT9 reveal direct links between miRNA target recognition and silencing. AB - CCR4-NOT is a major effector complex in miRNA-mediated gene silencing. It is recruited to miRNA targets through interactions with tryptophan (W)-containing motifs in TNRC6/GW182 proteins and is required for both translational repression and degradation of miRNA targets. Here, we elucidate the structural basis for the repressive activity of CCR4-NOT and its interaction with TNRC6/GW182s. We show that the conserved CNOT9 subunit attaches to a domain of unknown function (DUF3819) in the CNOT1 scaffold. The resulting complex provides binding sites for TNRC6/GW182, and its crystal structure reveals tandem W-binding pockets located in CNOT9. We further show that the CNOT1 MIF4G domain interacts with the C terminal RecA domain of DDX6, a translational repressor and decapping activator. The crystal structure of this complex demonstrates striking similarity to the eIF4G-eIF4A complex. Together, our data provide the missing physical links in a molecular pathway that connects miRNA target recognition with translational repression, deadenylation, and decapping. PMID- 24768542 TI - Risk versus reward: total joint arthroplasty outcomes after various solid organ transplantations. AB - Clinical outcomes were retrospectively reviewed for 76 primary total hip (THA) and total knee arthroplasties (TKA) performed after kidney, liver, cardiac, and lung transplantation with follow-up of 30.2 and 41.2 months, respectively. For the THA and TKA cohorts, there were a high rate of medical complications (29% and 33%), increased hospital length of stay (4.2 and 3.7 days), and more reoperations (7.2% and 9.1%). Only 1 (1.8%) periprosthetic infection was documented for THAs but 3 (14.2%) TKAs required two-stage revisions for infection. All transplant cohorts demonstrated significant increases (P < 0.05) in HHS and KSS scores with majority of patients reporting overall good or excellent outcomes (82%-100%). These results suggest that various organ transplant patients may accept higher surgical risks for rewarding outcomes. PMID- 24768543 TI - Comparison of intravenous versus topical tranexamic acid in total knee arthroplasty: a prospective randomized study. AB - The purpose of this study was to compare the efficacy of topical Tranexamic Acid (TXA) versus Intravenous (IV) Tranexamic Acid for reduction of blood loss following primary total knee arthroplasty (TKA). This prospective randomized study involved 89 patients comparing topical administration of 2.0g TXA, versus IV administration of 10mg/kg. There were no differences between the two groups with regard to patient demographics or perioperative function. The primary outcome measure, perioperative change in hemoglobin level, showed a decrease of 3.06 +/- 1.02 in the IV group and 3.42 +/- 1.07 in the topical group (P = 0.108). There were no statistical differences between the groups in preoperative hemoglobin level, lowest postoperative hemoglobin level, or total drain output. One patient in the topical group required blood transfusion (P = 0.342). Based on our study, topical Tranexamic Acid has similar efficacy to IV Tranexamic Acid for TKA patients. PMID- 24768544 TI - Patient and intraoperative factors influencing satisfaction two to five years after primary total knee arthroplasty. AB - The purpose of this study was to compare patient demographics and factors recorded at the time of surgery between patients that were either satisfied or dissatisfied with their TKA at mid-term follow-up. From our prospective outcomes database, 989 primary TKAs with complete preoperative and intraoperative data were identified. At mean follow-up of 3.5 years, 94/989 TKAs (9.5%) were not satisfied with their TKA. African American patients were 3.0 times more likely to be dissatisfied than Caucasians (95% CI = 1.5-6.0, P = .003). Patients with less severe degenerative changes were 2.1 times more likely to be dissatisfied (95% CI = 1.3-3.2, P = .001). PMID- 24768546 TI - WITHDRAWN: Porous Metal Augments Show Excellent Mid-to-Long Term Survival in Complex Acetabular Reconstruction. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24768545 TI - Extreme variability in posterior slope of the proximal tibia: measurements on 2395 CT scans of patients undergoing UKA? AB - Data regarding the posterior slope of the tibia (PTS) are limited and sometimes conflicting. The purpose of this study was to determine the native posterior tibial slope in patients undergoing a medial or lateral UKA. A retrospective review was performed on 2395 CT scans in patients indicated for UKA, and the PTS of the osteoarthritic compartment was measured relative to a plane set perpendicular to the sagittal, tibial mechanical axis. The mean preoperative PTS in patients undergoing medial UKA was 6.8 degrees +3.3 degrees , with 34.3% between 4 degrees and 7 degrees . The mean preoperative PTS in patients undergoing lateral UKA was 8.0 degrees +3.3 degrees , with 27.5% between 4 degrees and 7 degrees . If attempting to recreate a patient's preoperative tibial slope, a routine target of 5 degrees to 7 degrees will produce a posterior slope less than the patient's native anatomy in 47% of patients undergoing UKA. This is the first, large CT-based review of posterior slope variation of the proximal tibia in patients undergoing UKA. PMID- 24768547 TI - Definition of periprosthetic joint infection. PMID- 24768548 TI - [Micropenis]. AB - Micropenis represents a clinical sign that should be diagnosed at birth (or in utero) by the detection of a normally structured penis with a length 2.5 SD below the mean for age. Micropenis can be classified as due to deficient testosterone secretion or action. Evaluation of the gonadotropic and testicular function during the mini-puberty is often helpful in evaluating the etiology. Management of micropenis should focus on achieving a suitable penis length, in order to allow an adequate urination, normal sexual intercourses and a good self-body image. Irrespective of the underlying cause, a short course of T should be tried in patients with micropenis to assess the ability of the penis to respond to it. Topical 5a-dihydrotestosterone gel has also been reported to be effective. Children with hypopituitarism and GH deficiency respond to appropriate hormonal therapy. Psychological counseling is helpful and often necessary. PMID- 24768549 TI - [New therapeutic approaches to food allergies]. PMID- 24768550 TI - Mutations in ASPH cause facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs, or Traboulsi syndrome. AB - We have previously described a syndrome characterized by facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB, or Traboulsi syndrome). In view of the consanguineous nature of the affected families and the likely autosomal-recessive inheritance pattern of this syndrome, we undertook autozygosity mapping and whole-exome sequencing to identify ASPH as the disease locus, in which we identified two homozygous mutations. ASPH encodes aspartyl/asparaginyl beta-hydroxylase (ASPH), which has been found to hydroxylate aspartic acid and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins. The truncating and missense mutations we identified are predicted to severely impair the enzymatic function of ASPH, which suggests a possible link to other forms of ectopia lentis given that many of the genes implicated in this phenotype encode proteins that harbor EGF domains. Developmental analysis of Asph revealed an expression pattern consistent with the proposed link to the human syndrome. Indeed, Asph-knockout mice had a foreshortened snout, which corresponds to the facial abnormalities in individuals with Traboulsi syndrome. These data support a genetic basis for a syndromic form of ectopia lentis and the role of aspartyl hydroxylation in human development. PMID- 24768551 TI - Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland. AB - Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants' phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery. PMID- 24768553 TI - More apples fewer chips? the effect of school fruit schemes on the consumption of junk food. AB - OBJECTIVES: Using Italian data, we evaluate the effects on the consumption of unhealthy snacks of a European Union-wide campaign providing fruit and vegetables to school children and promoting healthy diet habits. METHODS: We use scanner data of supermarket sales in the city of Rome. Using a difference-in-difference approach, we compare the sales of these snacks before and after the campaign in supermarkets located within a 500 m radius of schools that participated to the program (the treated group) and in supermarkets located outside that radius (control group). RESULTS: We find that the campaign has been effective in reducing the increase in the sales of unhealthy snacks in treated stores - relative to control stores - only in the case of regular stores, which tend to locate in the wealthier areas of Rome. No effect is found, instead, for discount stores, where people with a higher risk of developing obesity are more likely to shop. CONCLUSIONS: Our results suggest that the European School Fruit campaign has restrained the consumption of junk food in the sub-group of the population (wealthier families) who is less likely to be exposed to overweight and obesity problems, but has not been effective at all for the sub-group more at risk. PMID- 24768554 TI - Comments on "Contribution of neuromonitoring to the safety of tracheal extubation after total thyroidectomy. Prospective study with needle electrodes". PMID- 24768555 TI - Usefulness of oximetry for sleep apnea screening in frail hospitalized elderly. AB - BACKGROUND: Sleep Apnea Syndrome (SAS) prevalence increases with age. In the elderly, symptoms are less specific (falls, cognitive or functional decline, polymedication). Polysomnography, the gold standard technique to diagnose SAS, is challenged by sleep laboratories' waiting lists and high associated costs. Nocturnal oximetry is an easy-to-use tool widely available outside the sleep medicine field identifying intermittent hypoxia, the landmark of SAS. It might be an interesting and easy way to screen for SAS in the functionally and cognitively impaired elderly living in long-term care settings. OBJECTIVES: The primary goal of this study was to assess the accuracy of the variability index of nocturnal pulse oximetry to detect moderate to severe SAS in patients older than 75 hospitalized in stable condition. The secondary goals were to assess the accuracy of the other indices of pulse oximetry (oxygen desaturation index [ODI]), and to determine the prevalence of moderate to severe SAS in our population. METHODS: In hospital sleep studies with simultaneous respiratory polygraphy and nocturnal pulse oximetry were performed. Comorbidities were assessed by the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) in association with a comprehensive geriatric assessment. RESULTS: Eighty patients (mean age 85.3 +/- 5.3 years) were included. Seventy-two percent of the patients exhibited moderate to severe SAS (95% CI 58.9-82.9), including 59.5% of severe SAS (apnea + hypopnea index >30/hour). SaO2 variability index using a threshold of 0.51, the sensitivity and negative predictive value (NPV) were 100%. With a value above 0.88, positive predictive value and specificity were high (respectively 96.6% and 93.8%). ODI of 3% or higher and 4% or higher were highly specific but less sensitive. CONCLUSION: Prevalence of moderate to severe SAS in multimorbid hospitalized elderly patients is high. Automatic analysis of the variability of nocturnal SaO2 is a reliable tool for geriatricians to screen and rule out moderate to severe SAS. Our study suggests an important role of pulse oximetry as the first step in the diagnostic strategy for moderate to severe SAS in this population. PMID- 24768556 TI - Tips and hints for the transition: What adult hepatologists should know when accept teens with a pediatric hepatobiliary disease. AB - The number of children with chronic hepatobiliary disease surviving into adulthood is more and more increasing, but no established model of transition does exist in this category of patients. Here, we summarize medical problems expected at the time of their transition, and any impacts on morbidity and mortality in adulthood. Information provided would turn useful to adult hepatologists and practitioners responsible for ensuring continuity of care for young adults affected by diseases they are not usually accustomed to. PMID- 24768557 TI - Post-dural puncture headache and posterior reversible encephalopathy syndrome: a misdiagnosis or co-presentation? AB - Posterior reversible encephalopathy syndrome (PRES) is a rare neurological condition associated with a variety of underlying conditions, including preeclampsia. The headache associated with PRES may be indistinguishable from post-dural puncture headache, which may result in diagnostic delay. We report a case of PRES that was initially diagnosed as post-dural puncture headache. The case was unique because there were no features of preeclampsia, initial presentation was typical of post-dural puncture headache, and there was a five day interval between the onset of headache and the development of seizures and cortical blindness, pathognomonic of PRES. It remains unclear whether this was an atypical presentation of PRES, initially misdiagnosed as post-dural puncture headache, or whether delayed treatment of headache triggered PRES. PMID- 24768558 TI - Treatment of adenomyomectomy in women with severe uterine adenomyosis using a novel technique. AB - The advised treatment for severe adenomyosis is hysterectomy, but for patients wishing to preserve their uterus, novel conservative surgery, adenomyomectomy, can be performed. The technique needs to be developed to reduce spontaneous uterine rupture, adhesion and recurrence rates. This study aimed to investigate the safety and therapeutic outcomes of adenomyomectomy. Prospectively, 103 Iranian patients with documented severe adenomyosis were candidates for adenomyomectomy over a period of 7 years (from April 2004 to March 2011). The surgical procedure involved resection of adenomatosis lesions with a thin (? 0.5 cm) margin (wedge-shaped removal) after sagittal incision in the uterine body. Reconstruction of the layers was performed and inverted sutures were used for the serosal layer ends. Of 103 patients, 55.34% presented with infertility, 16.50% with IVF failure, 8.74% with recurrent abortion and 19.42% with abnormal uterine bleeding. Of 70 patients who attempted pregnancy, naturally (n=21) or by assisted reproduction treatment (n=49), 30% achieved a clinical pregnancy, and 16 resulted in a full-term live birth. Dysmenorrhoea and hypermenorrhoea were reduced post surgery. Only one patient had relapsed adenomyosis. Adenomyomectomy is a conservative and effective treatment for adenomyosis. This study describes an efficient procedure to treat severe adenomyosis. Adenomyosis is uterine thickening that occurs when endometrial tissue, which normally lines the uterus, moves into the outer muscular walls of the uterus. The advised treatment for the severe forms of adenomyosis is hysterectomy (removal of the patient's uterus), but for the patient who wishes to preserve her uterus, a novel conservative surgery referred to as 'adenomyomectomy' (removal of the abnormal tissues) can be performed. This technique must be developed for reduction of spontaneous uterine rupture, adhesions and recurrence rate. This study aims to investigate the safety and therapeutic outcomes of adenomyomectomy. Prospectively, 103 Iranian patients with documented severe adenomyosis were candidates for adenomyomectomy over a period of 7 years (from April 2004 to March 2011). The surgical procedure was resection of adenomatosis lesions with a thin margin. Of 103 patients, 55.34% presented with infertility, 16.50% with IVF failure, 8.74% with recurrent abortion and 19.42% with abnormal uterus bleeding. Of 70 patients who attempted pregnancy either naturally (n=21) or using assisted reproduction technology (n=49), 30% became pregnant, and 16 pregnancies reached full term. There was a significant reduction in dysmenorrhoea and hypermenorrhoea. Only one patient had relapsed adenomyosis. Based on these results, we conclude that adenomyomectomy is the conservative and effective option to treat adenomyosis with preservation of the uterus. The procedure described in this study can be an efficient procedure to treat severe adenomyosis. PMID- 24768552 TI - Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. AB - Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 * 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 * 10(-15), ~3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation. PMID- 24768559 TI - Neoplasia in the ileoanal pouch following colectomy in patients with ulcerative colitis and primary sclerosing cholangitis. AB - BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is typically associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). PSC IBD patients are at an increased risk for colorectal neoplasia. The ileal pouch anal anastomosis (IPAA) is a treatment option for patients with medically refractory UC or neoplasia. However, little is known about the development of pouch neoplasia in PSC-UC patients following an IPAA. We aim to describe the incidence of pouch neoplasia in PSC-UC patients after an IPAA. METHODS: We conducted a retrospective chart review of patients with a confirmed diagnosis of PSC and IBD who underwent colectomy with IPAA followed by pouch surveillance between 1995 and 2012. RESULTS: Sixty-five patients were included in the cohort and were followed up from the time of colectomy/IPAA for a median of 6years. The most common indications for surgery were low-grade dysplasia (LGD) and refractory colitis. Only 3 patients developed evidence of neoplasia (LGD n=1, high-grade dysplasia n=1, adenocarcinoma n=1). The cumulative 5-year incidence of pouch neoplasia was 5.6% (95% confidence intervals [CI], 1.8%-16.1%). CONCLUSION: Based on our short-term follow-up, surveying the pouch frequently appears to be an unnecessary practice in PSC-IBD patients. Longer follow-up will be needed to develop an optimal surveillance strategy for the development of dysplasia and cancer in such patients. PMID- 24768561 TI - Bacterial persisters: formation, eradication, and experimental systems. AB - Persisters are multidrug-tolerant bacteria that could account for the relapse of infections. For a long time, persisters have been assumed to be nonreplicating dormant bacteria, but the growth status of these recalcitrant cells is still debated. Toxin-antitoxin (TA) modules have an important role in the formation of persisters and several studies show that they can form in response to different triggers. These findings, together with the invention of new tools to study persisters, could have important implications for the development of novel therapeutics to eradicate persisting subpopulations. PMID- 24768562 TI - An improved algorithm for the automatic detection and characterization of slow eye movements. AB - Slow eye movements (SEMs) are typical of drowsy wakefulness and light sleep. SEMs still lack of systematic physical characterization. We present a new algorithm, which substantially improves our previous one, for the automatic detection of SEMs from the electro-oculogram (EOG) and extraction of SEMs physical parameters. The algorithm utilizes discrete wavelet decomposition of the EOG to implement a Bayes classifier that identifies intervals of slow ocular activity; each slow activity interval is segmented into single SEMs via a template matching method. Parameters of amplitude, duration, velocity are automatically extracted from each detected SEM. The algorithm was trained and validated on sleep onsets and offsets of 20 EOG recordings visually inspected by an expert. Performances were assessed in terms of correctly identified slow activity epochs (sensitivity: 85.12%; specificity: 82.81%), correctly segmented single SEMs (89.08%), and time misalignment (0.49 s) between the automatically and visually identified SEMs. The algorithm proved reliable even in whole sleep (sensitivity: 83.40%; specificity: 72.08% in identifying slow activity epochs; correctly segmented SEMs: 93.24%; time misalignment: 0.49 s). The algorithm, being able to objectively characterize single SEMs, may be a valuable tool to improve knowledge of normal and pathological sleep. PMID- 24768560 TI - PIP2: choreographer of actin-adaptor proteins in the HIV-1 dance. AB - The actin cytoskeleton plays a key role during the replication cycle of human immunodeficiency virus-1 (HIV-1). HIV-1 infection is affected by cellular proteins that influence the clustering of viral receptors or the subcortical actin cytoskeleton. Several of these actin-adaptor proteins are controlled by the second messenger phosphatidylinositol 4,5-biphosphate (PIP2), an important regulator of actin organization. PIP2 production is induced by HIV-1 attachment and facilitates viral infection. However, the importance of PIP2 in regulating cytoskeletal proteins and thus HIV-1 infection has been overlooked. This review examines recent reports describing the roles played by actin-adaptor proteins during HIV-1 infection of CD4+ T cells, highlighting the influence of the signaling lipid PIP2 in this process. PMID- 24768563 TI - Biomechanical study of tarsometatarsal joint fusion using finite element analysis. AB - Complications of surgeries in foot and ankle bring patients with severe sufferings. Sufficient understanding of the internal biomechanical information such as stress distribution, contact pressure, and deformation is critical to estimate the effectiveness of surgical treatments and avoid complications. Foot and ankle is an intricate and synergetic system, and localized intervention may alter the functions to the adjacent components. The aim of this study was to estimate biomechanical effects of the TMT joint fusion using comprehensive finite element (FE) analysis. A foot and ankle model consists of 28 bones, 72 ligaments, and plantar fascia with soft tissues embracing all the segments. Kinematic information and ground reaction force during gait were obtained from motion analysis. Three gait instants namely the first peak, second peak and mid-stance were simulated in a normal foot and a foot with TMT joint fusion. It was found that contact pressure on plantar foot increased by 0.42%, 19% and 37%, respectively after TMT fusion compared with normal foot walking. Navico-cuneiform and fifth meta-cuboid joints sustained 27% and 40% increase in contact pressure at second peak, implying potential risk of joint problems such as arthritis. Von Mises stress in the second metatarsal bone increased by 22% at midstance, making it susceptible to stress fracture. This study provides biomechanical information for understanding the possible consequences of TMT joint fusion. PMID- 24768564 TI - The prognostic and risk-stratified value of heart-type fatty acid-binding protein in septic patients in the emergency department. AB - PURPOSE: To evaluate the prognostic and risk-stratified ability of heart-type fatty acid-binding protein (H-FABP) in septic patients in the emergency department (ED). MATERIALS AND METHODS: From August to November 2012, 295 consecutive septic patients were enrolled. Circulating H-FABP was measured. The predictive value of H-FABP for 28-day mortality, organ dysfunction on ED arrival, and requirement for mechanical ventilation or a vasopressor within 6 hours after ED arrival was assessed by the receiver operating characteristic curve and logistic regression and was compared with Acute Physiology and Chronic Health Evaluation (APACHE) II score, Mortality in Emergency Department Sepsis (MEDS) score, and Sequential Organ Failure Assessment score. RESULTS: The 28-day mortality, APACHE II, MEDS, and Sequential Organ Failure Assessment scores were much higher in H-FABP-positive patients. The incidence of organ dysfunction at ED arrival and requirement for mechanical ventilation or a vasopressor within 6 hours after ED arrival was higher in H-FABP-positive patients. Heart-type fatty acid-binding protein was an independent predictor of 28-day mortality and organ dysfunction. The area under the receiver operating characteristic curve for H FABP predicting 28-day mortality and organ dysfunction was 0.784 and 0.755, respectively. Combination of H-FABP and MEDS improved the performance of MEDS in predicting organ dysfunction, and the difference of AUC was statistically significant (P<.05). The combinations of H-FABP and MEDS or H-FABP and APACHE II also improved the prognostic value of MEDS and APACHE II, but the areas under the curve were not statistically different. CONCLUSIONS: Heart-type fatty acid binding protein was helpful for prognosis and risk stratification of septic patients in the ED. PMID- 24768565 TI - Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Some patients with idiopathic pulmonary fibrosis (IPF) develop severe acute respiratory failure (ARF) requiring admission to an intensive care unit (ICU) and ventilatory support. A limited number of observational studies have reported that noninvasive ventilation (NIV) can be an effective treatment to support breathing and to prevent use of invasive mechanical ventilation in these patients. This study aimed to retrospectively investigate the clinical status and outcomes in IPF patients receiving NIV for ARF and to identify those clinical and laboratory characteristics, which could be considered risk factors for its failure. METHODS: This is a retrospective analysis of short-term outcomes in 18 IPF patients being administered NIV for ARF. This study was conducted in a 4-bed respiratory ICU (RICU) in a university hospital. Eighteen IPF patients who were administered NIV between January 1, 2005, and April 30, 2013, were included. The outcome measures are the need for endotracheal intubation despite NIV treatment and mortality rate during their RICU stay. The length of the patients' stay in the RICU and their survival rate following RICU admission were also evaluated. RESULTS: Noninvasive ventilation was successful in 8 patients and unsuccessful in 10 who required endotracheal intubation. All the patients in the NIV failure group died within 20.2+/-15.3 days of intubation. The patients in the NIV success group spent fewer days in the RICU (11.6+/-4.5 vs 24.6+/-13.7; P=.0146). The median survival time was significantly shorter for the patients in the NIV failure with respect to the success group (18.0 [95% confidence interval {CI}, 9.0-25.0] vs 90.0 [95% CI, 65.0-305.0] days; P<.0001); the survival rate at 90 days was, likewise, lower in the NIV failure group (0% vs 34%+/-19.5%). At admission, the patients in the failure group had significantly higher respiratory rate values (36.9+/-7.8 vs 30.5+/-3.3 breaths/min; P=.036), plasma N-terminal fragment of the prohormone of B-type natriuretic peptide (NT-proBNP) levels (4528.8+/-4012.8 vs 634.6+/-808.0 pg/mL; P=.023) and serum C-reactive protein values (72.0+/-50.0 vs 20.7+/-24.0 MUg/mL; P=.0289) with respect to those in the success group. Noninvasive ventilation failure was correlated to the plasma NT proBNP levels at RICU admission (P=.0326) with an odds ratio of 12.2 (95% CI, 1.2 to infinity) in the patients with abnormally high values (>900 pg/mL). CONCLUSIONS: The outcome of IPF patients who were administered NIV was quite poor. The use of NIV was, nevertheless, found to be associated with clinical benefits in selected IPF patients, preventing the need for intubation and reducing the rate of complications/death. Elevated plasma NT-proBNP levels at the time of ICU admission is a simple clinical marker for poor NIV outcome. PMID- 24768566 TI - From data patterns to mechanistic models in acute critical illness. AB - The complexity of the physiologic and inflammatory response in acute critical illness has stymied the accurate diagnosis and development of therapies. The Society for Complex Acute Illness was formed a decade ago with the goal of leveraging multiple complex systems approaches to address this unmet need. Two main paths of development have characterized the society's approach: (i) data pattern analysis, either defining the diagnostic/prognostic utility of complexity metrics of physiologic signals or multivariate analyses of molecular and genetic data and (ii) mechanistic mathematical and computational modeling, all being performed with an explicit translational goal. Here, we summarize the progress to date on each of these approaches, along with pitfalls inherent in the use of each approach alone. We suggest that the next decade holds the potential to merge these approaches, connecting patient diagnosis to treatment via mechanism-based dynamical system modeling and feedback control and allowing extrapolation from physiologic signals to biomarkers to novel drug candidates. As a predicate example, we focus on the role of data-driven and mechanistic models in neuroscience and the impact that merging these modeling approaches can have on general anesthesia. PMID- 24768567 TI - Act fast and ventilate soft: the Dusseldorf hands-on translation of the acute respiratory distress syndrome Berlin definition. AB - Early identification of acute respiratory distress syndrome (ARDS) and forceful implementation of standardized therapy algorithms are the mandatory basis of an effective therapy to improve patient outcome. Recently, a new definition of ARDS was implemented, which simplified the diagnostic criteria for ARDS. Evidence based therapies are rare, but some cornerstone interventions can be recommended. Lung-protective ventilation with high positive end-expiratory pressure and low tidal volume and early prone positioning in severe cases improve survival rate. We here present an integrated "Dusseldorf hands-on translation" in the form of a "one-page" standard operating procedure in order to fasten and standardize both diagnosis and therapeutic algorithms on an intensive care unit. PMID- 24768568 TI - The power and perils of animal models with urogenital anomalies: handle with care. AB - Congenital abnormalities of the urogenital tracts form a major part of clinical practice for paediatric urologists, but their knowledge of normal and abnormal development is often limited. Advances in understanding frequently come from studying experimental findings from animal models, however, most clinicians underestimate both the power and perils of extrapolating scientific knowledge from animals. In this review, the key issues that urologists need to understand in order to link animal studies to clinical practice are discussed. Urologists must avoid the traps of anthropomorphism (assuming humans are always the same as animal models) or anthropocentrism (assuming humans are too different from animal models). This review used two common disorders: hypospadias and undescended testes. PMID- 24768570 TI - Symptomatic hypotonic hyponatremia presenting at high altitude. PMID- 24768569 TI - Impact of laparoscopy for diagnosis and treatment in patients with disorders of sex development. AB - OBJECTIVE: To review laparoscopy in patients with disorders of sex development (DSD) in order to clarify its usefulness in diagnosis, devising subsequent therapeutic strategies and managing patients with various conditions. PATIENTS AND METHODS: Between April 1992 and December 2012, 29 laparoscopic surgeries were performed in 25 DSD patients. Among them, ten were diagnostic laparoscopy including gonadal biopsy, and 19 were therapeutic laparoscopy. Surgical procedures and complications were evaluated. RESULTS: For diagnostic laparoscopy, laparoscopic gonadal biopsy was performed in three patients. Inspection, with or without open gonadal biopsy, was performed on four out of seven patients with 46XY DSD or mixed gonadal dysgenesis (MGD). Additional surgery was planned and performed based on diagnostic laparoscopic findings in six out of seven patients. In the three patients with ovotesticular DSD, the gonadal pathology was diagnosed as: testis/ovary in one, testis/ovotestis in one and ovary/ovotestis in one--this was from the laparoscopic inspection and/or gonadal biopsy. However, the final diagnoses were bilateral ovotestis in two patients and ovary/ovotestis in one patient. For therapeutic laparoscopy, surgical procedures were: gonadectomy in 17 patients (bilateral in 13, unilateral in three, partial in two); hysterectomy in two patients; orchiopexy in one; and sigmoid vaginoplasty in one patient (included multiple procedures). There were no severe perioperative complications. In the four patients with a history of diagnostic laparoscopy, no severe intra abdominal adhesions that would disturb therapeutic laparoscopic surgery were observed. CONCLUSION: While diagnostic laparoscopy was helpful in devising a therapeutic surgical strategy in most of the patients with DSD who were suspected as having complex gonadal status or Mullerian duct derivatives, attention must be paid to precisely diagnosing the gonadal status in ovotesticular DSD. On the other hand, therapeutic laparoscopic surgeries were valuable procedures in treating DSD patients, even with a history of previous diagnostic laparoscopy. PMID- 24768571 TI - Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma. AB - BACKGROUND: To determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naive metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-alpha) in a phase III study. METHODS: The relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan-Meier non parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test. RESULTS: In the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P<0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan-Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P<0.0001). CONCLUSIONS: A positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-alpha. These results indicate that PFS can act as a surrogate end-point for OS in the first line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS. PMID- 24768572 TI - Age at diagnosis and distant metastasis in breast cancer--a surprising inverse relationship. AB - INTRODUCTION: Predictors for site of distant metastasis and impact on survival in breast cancer are incompletely understood. METHODS: Clinico-pathological risk factors for site of distant metastasis and survival were analysed in patients with invasive breast cancer treated between 1986 and 2006. RESULTS: Of 3553 patients, with median follow-up 6.32years, 825 (23%) developed distant metastasis. The site of metastasis was bone in 196/825 (24%), viscera in 540/825 (65%) and unknown in 89 (11%). Larger primary invasive tumour size, higher tumour grade and axillary nodal positivity increased risk of metastasis to all sites. Lobular carcinoma was more likely to first metastasise to bone compared to invasive ductal carcinoma (NST). Oestrogen receptor (ER) negative, progesterone receptor (PgR) negative and/or Human epidermal growth factor (HER2) positive tumours were more likely to metastasise to viscera. A striking relationship between increasing age at diagnosis and a reduction in risk of distant metastasis to bone and viscera was observed. Median time to death from onset of metastatic disease was 1.52 (Interquartile range (IQR) 0.7-2.9)years for patients with bone metastasis and 0.7 (IQR 0.2-1.5)years for visceral metastasis. On multivariate analysis, despite the decrease in risk of distant metastasis with increasing age, there was an elevated hazard for death in patients >50years at diagnosis of metastasis if they developed bone metastasis, with a similar trend observed in the >70years age group if they developed visceral metastasis. CONCLUSION: These findings indicate that there are biological mechanisms underlying the impact of age on the development of distant metastasis and subsequent death. This may have important implications in the treatment of breast cancer. PMID- 24768573 TI - Measuring the actual timing of liquid-reward delivery using a thermistor. AB - BACKGROUND: Determining the exact timing of reward delivery is critical in neurophysiological experiments. Despite the importance of this parameter, techniques for precisely measuring the exact delivery time of a liquid reward have been underdeveloped. Although there is always some latency between the computer command and reward delivery, the former has been used routinely to mark reward onset time. NEW METHOD: To address this issue, we developed two methods of estimating the time of liquid reward delivery. First, electrical conduction between two contacts at the outlet of a pipe was detected. This technique was impractical during normal experiments but was a direct and reliable method of measuring the precise timing of water outflow. Second, a self-heating thermistor inside the fluid delivery pipe was used. The thermistor detected a decrease in temperature upon commencement of water flow. RESULTS: The electrical contact began 50-80ms after the computer command. The thermistor-based delivery timing estimation was ~40ms later than that measured by the electrical contact. The time lag was constant with minimal variance between trials within the same experimental setup. COMPARISON WITH EXISTING METHOD: As far as the time difference between the two methods is measured, the timing of water outflow can be estimated using the thermistor-based device. This is the first method of estimating the onset time of water flow during experiments. CONCLUSIONS: Our new system could be used to quantify setup-dependent changes in the timing of reward delivery, improving the sophistication of reward assessments in neurophysiological experiments. PMID- 24768575 TI - Tactile and bone-conduction auditory brain computer interface for vision and hearing impaired users. AB - BACKGROUND: The paper presents a report on the recently developed BCI alternative for users suffering from impaired vision (lack of focus or eye-movements) or from the so-called "ear-blocking-syndrome" (limited hearing). We report on our recent studies of the extents to which vibrotactile stimuli delivered to the head of a user can serve as a platform for a brain computer interface (BCI) paradigm. NEW METHOD: In the proposed tactile and bone-conduction auditory BCI novel multiple head positions are used to evoke combined somatosensory and auditory (via the bone conduction effect) P300 brain responses, in order to define a multimodal tactile and bone-conduction auditory brain computer interface (tbcaBCI). In order to further remove EEG interferences and to improve P300 response classification synchrosqueezing transform (SST) is applied. SST outperforms the classical time frequency analysis methods of the non-linear and non-stationary signals such as EEG. The proposed method is also computationally more effective comparing to the empirical mode decomposition. The SST filtering allows for online EEG preprocessing application which is essential in the case of BCI. RESULTS: Experimental results with healthy BCI-naive users performing online tbcaBCI, validate the paradigm, while the feasibility of the concept is illuminated through information transfer rate case studies. COMPARISON WITH EXISTING METHOD(S): We present a comparison of the proposed SST-based preprocessing method, combined with a logistic regression (LR) classifier, together with classical preprocessing and LDA-based classification BCI techniques. CONCLUSIONS: The proposed tbcaBCI paradigm together with data-driven preprocessing methods are a step forward in robust BCI applications research. PMID- 24768574 TI - The use of fMRI to detect neural responses to cognitive interference and planning: evidence for a contribution of task related changes in heart rate? AB - fMRI signals during rest are strongly correlated with heart rate variations. These heart rate/fMRI associations may influence the results of brain activation studies, particularly if heart rate is affected by the task. To assess the contribution of task-related heart rate changes on fMRI brain activation related to executive processing, we co-registered the electrocardiogram with fMRI in 91 subjects during an interference task (color-word Stroop) and during a planning task (Tower of London; ToL). We found that both Stroop interference and ToL planning significantly increased heart rate in the scanner and confirmed significant main effects of heart rate regressors on the fMRI signals. Nevertheless, statistical contrasts that test for increased fMRI during Stroop interference and ToL planning were not significantly influenced by inclusion of heart rate regressors. We conclude therefore that fMRI changes associated with heart rate changes do not impact strongly on higher-order fMRI effects in these commonly used executive function tasks, but routinely adding a correction seems prudent. PMID- 24768577 TI - Gait compensations in rats after a temporary nerve palsy quantified using temporo spatial and kinematic parameters. AB - BACKGROUND: The aim of this work was to test a method for measuring the gait of rats with sufficient sensitivity to detect subtle locomotor changes due to pathology, injury and recovery. METHOD: The gait of female Sprague-Dawley rats was assessed using an optical motion tracking system and the DigiGaitTM imaging system during normal locomotion, shortly after temporary nerve block to the left hind limb and after full recovery. RESULTS: The effect of low treadmill speeds (10-30 cm/s) was initially investigated. Significant changes were detected in the spatiotemporal gait parameters, consistent with those previously reported. The overall ranges of motion in the hip, knee and ankle joints were 37.5 degrees (+/ 7.1 degrees ), 50.2 degrees (+/-9.4 degrees ) and 61.6 degrees (+/-9.1 degrees ) and did not appear to change with speed, indicating that for low speed variations, kinematic comparisons across speeds may be possible. Following the induction of a temporary sciatic nerve block, the range of motion of the left ankle and knee during swing decreased by 23 degrees and 33 degrees , respectively (p<0.05). A compensatory change of a greater range of motion at the hip was noted in the contralateral limb (p<0.01). 90 min post injection, most of the gait parameters had returned to normal, however, minor walking deficits were still present. COMPARISON WITH EXISTING METHOD(S): Discriminant analysis showed that a combination of dynamic and kinematic parameters provides a more robust method for the classification of gait changes. CONCLUSIONS: This more detailed method, employing both dynamic analysis and joint kinematics simultaneously, was found to be a reliable approach for the quantification of gait in rats. PMID- 24768576 TI - A male-specific QTL for social interaction behavior in mice mapped with automated pattern detection by a hidden Markov model incorporated into newly developed freeware. AB - BACKGROUND: Owing to their complex nature, social interaction tests normally require the observation of video data by a human researcher, and thus are difficult to use in large-scale studies. We previously established a statistical method, a hidden Markov model (HMM), which enables the differentiation of two social states ("interaction" and "indifference"), and three social states ("sniffing", "following", and "indifference"), automatically in silico. NEW METHOD: Here, we developed freeware called DuoMouse for the rapid evaluation of social interaction behavior. This software incorporates five steps: (1) settings, (2) video recording, (3) tracking from the video data, (4) HMM analysis, and (5) visualization of the results. RESULTS: Using DuoMouse, we mapped a genetic locus related to social interaction. We previously reported that a consomic strain, B6 Chr6C(MSM), with its chromosome 6 substituted for one from MSM/Ms, showed more social interaction than C57BL/6 (B6). We made four subconsomic strains, C3, C5, C6, and C7, each of which has a shorter segment of chromosome 6 derived from B6 Chr6C, and conducted social interaction tests on these strains. DuoMouse indicated that C6, but not C3, C5, and C7, showed higher interaction, sniffing, and following than B6, specifically in males. COMPARISON WITH EXISTING METHOD: The data obtained by human observation showed high concordance to those from DuoMouse. The results indicated that the MSM-derived chromosomal region present in C6-but not in C3, C5, and C7-associated with increased social behavior. CONCLUSIONS: This method to analyze social interaction will aid primary screening for difference in social behavior in mice. PMID- 24768578 TI - Fish in behavior research: unique tools with a great promise! AB - Fish represent the most diverse class of vertebrates on Earth and also an unprecedented, but as of yet still largely untapped, resource for comparative analyses that can illuminate answers to questions about both how organisms work and how they evolved. The current review is a general discussion of some of the basic principles of why adding new species such as fish to the short list of biomedical model organisms (mainly the house mouse and the rat) has merit. In addition to the general points, it also reviews some questions about a newcomer, the zebrafish, which is rapidly gaining popularity in brain and behavior research. It discusses some examples demonstrating the advantages and disadvantages of the zebrafish mainly in the context of biomedical research. It is followed by other articles that further elaborate on these questions. PMID- 24768579 TI - [Left ventricle assist device: rehabilitation and management programmes]. AB - Progress in the medical management of patients with heart failure with systolic dysfunction has been accompanied by a significant improvement in survival and quality of life. These strategies have also resulted in changes in the clinical profile as well as an increase in the number of patients with advanced heart failure. The technological developments in left ventricular assist devices provide real hope for these patients. This article related our experience of management and the rehabilitation program realized. PMID- 24768580 TI - Placebo use in vaccine trials: recommendations of a WHO expert panel. AB - Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease. PMID- 24768581 TI - Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC patients. AB - AIM: Non-small cell lung cancer (NSCLC)-patients with an epidermal growth factor receptor (EGFR)-mutation have median progression-free survival (PFS) of 12 months on tyrosine kinase inhibitors (TKIs). Resistance is mediated by the EGFR T790M mutation in the majority of patients. Longitudinal follow-up data are lacking. We retrospectively evaluated EGFR-mutated NSCLC-patients who were rebiopsied after TKI-treatment. A subgroup was sequentially rebiopsied along the course of the disease. PATIENTS AND METHODS: Advanced EGFR-mutated NSCLC-patients who had both a pre-TKI biopsy and post-TKI biopsy available were included. Information on treatments and (re)biopsies was collected chronologically. Primary endpoint was the incidence of the T790M-mutation. RESULTS: Sixty-six patients fulfilled the inclusion criteria. In first post-TKI biopsies, T790M-mutation was detected in 34 patients (52%) of patients. Twenty-seven patients had subsequent post-TKI rebiopsies with mutation analysis available; in 10 patients (37%) the T790M status in subsequent post-TKI rebiopsies was not consistent with the T790M-status of the first post-TKI biopsy. Progression free survival (PFS) on TKI-treatment was 12.0 months. Objective response rate on TKI-treatment was 81%. Patients developing T790M-mutation at post-TKI biopsy had longer median PFS compared to T790M-negative patients (14.2 versus 11.1 months respectively (P=0.034)) and longer overall survival (45.9 months versus 29.8 months respectively (P=0.213)). Transformation to SCLC was detected in 1 patient (2%). CONCLUSION: Incidence of T790M-mutation at first post-TKI biopsy in this cohort of EGFR-mutated NSCLC patients was 52%. Detection of T790M-mutation was not consistent over time; some patients who were T790M-positive at first post-TKI biopsy became T790M-negative in later post-TKI rebiopsies and vice versa. T790M-positive patients showed longer PFS than T790M-negative patients. Whether the low incidence of transformation to SCLC is justifying post-TKI rebiopsy in EGFR-mutated NSCLC patients with acquired TKI-resistance in regular clinical practice is debatable. PMID- 24768582 TI - How many names for a rose: inconsistent classification of multiple foci of lung cancer due to ambiguous rules. AB - OBJECTIVES: Stage classification is important because it allows consistent definition of patient groups, and thus provides a foundation for comparison of outcomes. For patients with multiple pulmonary foci of lung cancer, however, the classification rules are ambiguous and confusing. MATERIALS AND METHODS: We surveyed experts and clinicians who regularly evaluate patients with lung cancer to see how similar or different their interpretation of the official stage classification was for such patients. RESULTS: We found a great deal of inconsistency in how four clinical scenarios were classified. No method of classification was chosen by a majority when there were more than two choices allowed by the classification rules. In a scenario with pulmonary foci of cancer of different histologic types, 86% classified this as separate primary cancers and 14% as multifocal lung cancer. CONCLUSION: The marked variability in classification must be taken into account when interpreting reported outcomes of patients with multiple pulmonary foci of lung cancer. PMID- 24768583 TI - IgG4-related kidney disease: MRI findings with emphasis on the usefulness of diffusion-weighted imaging. AB - OBJECTIVES: To investigate the imaging findings of immunoglobulin G4 (IgG4) related kidney disease (IgG4-KD) on magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) and to evaluate the usefulness of DWI in lesion detection. METHODS: This retrospective cohort study included 31 patients with IgG4-KD who underwent MRI covering both kidneys. Two radiologists reviewed in consensus the MR images to determine the distribution pattern (location, laterality, and multiplicity) and the visually assessed signal intensity (hypointense, isointense or hyperintense) of the renal lesions compared to the normal renal parenchyma on each sequence. Per-patient sensitivity for detecting IgG4-KD and the number of detectable lesions were compared in T2-weighted images, DWI, and dynamic contrast-enhanced images. RESULTS: IgG4-KD typically manifested as bilateral (83.9%), multiple (93.5%), and renal parenchymal (87.1%) nodules appearing isointense (93.5%) on T1-weighted images, hypointense (77.4%) on T2 weighted images, hyperintense (100%) on DWI (b=1000), and hypointense (83.3%) in the arterial phase and with a progressive enhancement pattern on dynamic contrast enhanced images. The sensitivity of DWI for detecting IgG4-KD was significantly higher than that of T2-weighted images (100% vs. 77.4%, P=0.034). The median number of detectable lesions was significantly greater in DWI (n=9) than in T2 weighted images (n=2) and dynamic contrast-enhanced images (n=5) (P<=0.008). CONCLUSIONS: The characteristic MRI findings of IgG4-KD were bilateral, multiple, renal parenchymal nodules with T2 hypointensity, diffusion restriction, and a progressive enhancement pattern. As DWI was useful in the detection of IgG4-KD, adding DWI to conventional MRI for patients suspected of having IgG4-KD may enhance the diagnosis. PMID- 24768584 TI - Cudratricusxanthone A protect pancreatic beta cells from cytokines-mediated toxicity through the inhibition of NF-kappaB and STAT pathways. AB - Cudratricusxanthone A (CTXA) has an isoprenylated xanthone skeleton that is known to exert a variety of biological activities, including anti-inflammatory, neuroprotective, hepatoprotective, anti-proliferative, and mono-amine oxidase inhibitory effects. In this study, we investigated the effect of CTXA on IL-1beta (5 ng/ml) and IFN-gamma (100 U/ml)-induced beta-cell damage. Pre-treatment with CTXA increased the viability and reactive oxygen species (ROS) inhibition of cytokine-treated RINm5F cells at concentrations of 1-10 MUM. CTXA prevented nitric oxide (NO) production, and this effect was correlated with reduced levels of protein and mRNA expression of inducible nitric oxide synthase (iNOS). The molecular mechanism by which CTXA inhibits iNOS gene expression appeared to involve the inhibition of NF-kappaB activation. Moreover, pancreatic beta-cells treated with cytokines upregulated the phosphorylation of STAT-1, STAT-3 and STAT 5; however, pretreatment with CTXA attenuated these effects. Additionally, in a second set of experiments in which rat islets were used, the protective effects of CTXA in rat islets were essentially the same as those observed when RINm5F cells were used. CTXA prevented cytokines-induced NO production, iNOS expression, JAK/STAT activation, and NF-kappaB activation and inhibition of glucose stimulated insulin secretion (GSIS). Collectively, these results suggest that CTXA can be used for the prevention of functional beta-cell damage. PMID- 24768586 TI - Lepidic predominant adenocarcinoma with aerogenous spread of mucin in a young patient -- a case report. AB - We present a unique case of a 26 year-old female non-smoker who expired following treatment for presumed pneumonias. At autopsy, lepidic predominant adenocarcinoma with aerogenous spread of mucin without evidence of invasion, a rare diagnosis that previously would have fallen under the umbrella of "bronchioloalveolar carcinoma," was found. Histopathology showed mucin-secreting neoplastic cells lining the alveolar walls, as well as exfoliated and dense aggregates of mucinous debris filling the alveoli. The immediate cause of death was respiratory failure, most likely due to the significant amount of tumor-produced mucin that filled the alveolar spaces, which literally drowned the patient. PMID- 24768585 TI - Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN. AB - Mammalian target of rapamycin (mTOR) has been reported to contribute to the development of HIV-associated nephropathy (HIVAN). We hypothesized that HIV may be activating renal tissue mTOR pathway through renin angiotensin system (RAS) via Angiotensin Receptor Type II receptor (AT2R). Renal tissues of Vpr transgenic and Tg26 (HIVAN) mice displayed enhanced phosphorylation of mTOR and p70S6K. Aliskiren, a renin inhibitor attenuated phosphorylation of both mTOR and p70S6K in renal tissues of HIVAN mice. Interestingly, Angiotensin Receptor Type I (AT1R) blockade did not modulate renal tissue phosphorylation of mTOR in HIVAN mice; on the other hand, AT2R blockade attenuated renal tissue phosphorylation of mTOR in HIVAN mice. In vitro studies, both renin and Ang II displayed enhanced mouse tubular cell (MTC) phosphorylation of p70S6K in a dose dependent manner. HIV/MTC also displayed enhanced phosphorylation of both mTOR and p70S6K; interestingly this effect of HIV was further enhanced by losartan (an AT1R blocker). On the other hand, AT2R blockade attenuated HIV-induced tubular cell phosphorylation of mTOR and p70S6K, whereas, AT2R agonist enhanced phosphorylation of mTOR and p70S6K. These findings indicate that HIV stimulates mTOR pathway in HIVAN through the activation of renin angiotensin system via AT2R. PMID- 24768587 TI - Elevated circulating miR-150 and miR-342-3p in patients with irritable bowel syndrome. AB - BACKGROUND AND AIMS: MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression and are thus of interest as diagnostic markers, and as clues to etiology and targets of intervention. This pilot study examined whether circulating miRNAs are differentially expressed in patients with IBS. METHODS: miRNA microarrays (NanoString) were run on the whole blood of 43 participants. RESULTS: hsa-miR-150 and hsa-miR-342-3p were found to be significantly elevated (FDR adjusted p<=0.05, >=1.6 fold change) in IBS patients compared to healthy controls. Neither of these miRNAs showed any relationship to race or sex. hsa-miR 150 is associated with inflammatory bowel disorders and pain, and interacts with a protein kinase (AKT2) through which it may affect inflammatory pathways. hsa miR-342-3p is predicted to interact with mRNAs involved in pain signaling, colonic motility, and smooth muscle function. CONCLUSIONS: This preliminary study reports the association of two miRNAs, detected in whole blood, with IBS. These miRNAs link to pain and inflammatory pathways both of which are thought to be dysregulated in IBS. Larger sample sizes are needed to confirm their importance and potential as biomarkers. PMID- 24768589 TI - Matrix metalloproteinase-12 immunolocalization in the degenerating human intervertebral disc and sand rat spine: Biologic implications. AB - Matrix metalloproteinase-12 (MMP-12; macrophage metalloelastase) degrades a number of extracellular matrix components which are present in the intervertebral disc, including type IV collagen, fibronectin, laminin, chondroitin sulfates, elastin and fibrinogen. MMP-12 has recently discovered relationships with cytokines and chemokines which also relate to disc cell biology. To date, no study has assessed immunolocalization of MMP-12 in degenerating human intervertebral disc tissue. Immunocytochemical localization was performed on 18 human disc specimens and on lumbar spines of the sand rat, a small animal model with well-recognized age-related disc degeneration. In the human disc, intracellular localization was present in both the annulus and nucleus portions of the disc. The sand rat degenerating disc also showed MMP-12 disc localization, with additional presence in chondrocytes of the vertebral endplate of older animals. This is the initial characterization of the presence of MMP-12 in the human and sand rat disc, and in chondrocytes of the vertebral endplate in older sand rats with degenerating discs. Findings are important because they document the presence of an additional MMP-12 in disc tissue, thus expanding our understanding of disc extracellular matrix remodeling, and because they provide novel information on the presence of MMP-12 in the cartilage endplate as it undergoes sclerosis during disc degeneration in the aging sand rat. PMID- 24768588 TI - Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis. AB - Sarcoidosis is an immune-mediated multisystem disease characterized by the formation of non-caseating granulomas. The pathogenesis of sarcoidosis is unclear, with proposed infectious or environmental antigens triggering an aberrant immune response in susceptible hosts. Multiple pro-inflammatory signaling pathways have been implicated in mediating macrophage activation and granuloma formation in sarcoidosis, including IFN-gamma/STAT-1, IL-6/STAT-3, and NF-kappaB. It is difficult to distinguish sarcoidosis from other granulomatous diseases or assess disease severity and treatment response with histopathology alone. Therefore, development of improved diagnostic tools is imperative. Herein, we describe an efficient and reliable technique to classify granulomatous disease through selected gene expression and identify novel genes and cytokine pathways contributing to the pathogenesis of sarcoidosis. We quantified the expression of twenty selected mRNAs extracted from formalin-fixed paraffin embedded (FFPE) tissue (n = 38) of normal lung, suture granulomas, sarcoid granulomas, and fungal granulomas. Utilizing quantitative real-time RT-PCR we analyzed the expression of several genes, including IL-6, COX-2, MCP-1, IFN-gamma, T-bet, IRF-1, Nox2, IL 33, and eotaxin-1 and revealed differential regulation between suture, sarcoidosis, and fungal granulomas. This is the first study demonstrating that quantification of target gene expression in FFPE tissue biopsies is a potentially effective diagnostic and research tool in sarcoidosis. PMID- 24768590 TI - Challenges in the diagnosis of Clostridium difficile infection. PMID- 24768591 TI - Probiotics for antibiotic-associated diarrhea: PLACIDE swings the pendulum. PMID- 24768592 TI - Patient-controlled propofol for sedation in endoscopic retrograde cholangiopancreatography: an alternative to anesthesia-administered sedation? PMID- 24768594 TI - Repeated assessments of symptom severity improve predictions for risk of death among patients with cancer. AB - CONTEXT: Although prior studies show the importance of self-reported symptom scores as predictors of cancer survival, most are based on scores recorded at a single point in time. OBJECTIVES: To show that information on repeated assessments of symptom severity improves predictions for risk of death and to use updated symptom information for determining whether worsening of symptom scores is associated with a higher hazard of death. METHODS: This was a province-based longitudinal study of adult outpatients who had a cancer diagnosis and had assessments of symptom severity. We implemented a time-to-death Cox model with a time-varying covariate for each symptom to account for changing symptom scores over time. This model was compared with that using only a time-fixed (baseline) covariate for each symptom. The regression coefficients of each model were derived based on a randomly selected 60% of patients, and then, the predictive performance of each model was assessed via concordance probabilities when applied to the remaining 40% of patients. RESULTS: This study had 66,112 patients diagnosed with cancer and more than 310,000 assessments of symptoms. The use of repeated assessments of symptom scores improved predictions for risk of death compared with using only baseline symptom scores. Increased pain and fatigue and reduced appetite were the strongest predictors for death. CONCLUSION: If available, researchers should consider including changing information on symptom scores, as opposed to only baseline information on symptom scores, when examining hazard of death among patients with cancer. Worsening of pain, fatigue, and appetite may be a flag for impending death. PMID- 24768593 TI - Association between type-2 diabetes mellitus and post-discharge outcomes in heart failure patients: findings from the RICA registry. AB - AIMS: Heart failure (HF) and diabetes are common clinical conditions that may coexist. The main objective was to analyze the association of type-2 diabetes mellitus (T2DM) on prognosis in hospitalized patients with HF. METHODS: We evaluated the association between T2DM with all-cause mortality and readmissions in the Spanish National Registry on Heart Failure-"Registro Nacional de Insuficiencia Cardiaca" (RICA). This is a multi-center and prospective cohort study that includes patients admitted for decompensated HF from 2008 to 2011. Study endpoints were all-cause mortality and hospital readmission. We determined the adjusted hazard ratio (HR) by a multivariable Cox regression model. RESULTS: A total of 1082 patients (mean age 77.6+/-8.5) were included of whom 490 (45.3%) had diabetes and 592 patients (54.7%) had preserved left ventricular ejection fraction (LVEF). During one-year follow-up, 287 patients died (151 patients with diabetes) and 383 patients were readmitted (197 patients with diabetes). After adjusting for baseline characteristics T2DM was significantly associated with all cause mortality (HR 1.54; 95%CI 1.20-1.97, p=0.001) and readmissions (HR 1.46; 95%CI 1.18-1.80, p<0.001). Age, dementia, peripheral vascular disease, NYHA class, renal insufficiency, hyponatremia and anemia were also independently associated with outcomes. There were no differences in mortality (p=0.415) and readmissions (p=0.514) according to preserved or reduced LVEF. CONCLUSION: T2DM is very common in patients hospitalized for HF. This condition is a strong and independent co-morbidity of all-cause mortality and readmission for both HF with preserved and reduced LVEF. PMID- 24768596 TI - Opioid availability and palliative care in Nepal: influence of an international pain policy fellowship. AB - Globally, cancer incidence and mortality are increasing, and most of the burden is shifting to low- and middle-income countries (LMICs), where patients often present with late-stage disease and severe pain. Unfortunately, LMICs also face a disproportionate lack of access to pain-relieving medicines such as morphine, despite the medical and scientific literature that shows morphine to be effective to treat moderate and severe cancer pain. In 2008, an oncologist from Nepal, one of the poorest countries in the world, was selected to participate in the International Pain Policy Fellowship, a program to assist LMICs, to improve patient access to pain medicines. Following the World Health Organization public health model for development of pain relief and palliative care, the Fellow, working with colleagues and mentors, has achieved initial successes: three forms of oral morphine (syrup, immediate-release tablets, and sustained-release tablets) are now manufactured in the country; health-care practitioners are receiving training in the use of opioids for pain relief; and a new national palliative care association has developed a palliative care training curriculum. However, long-term implementation efforts, funding, and technical assistance by governments, philanthropic organizations, and international partners are necessary to ensure that pain relief and palliative care become accessible by all in need in Nepal and other LMICs. PMID- 24768595 TI - A study to improve communication between clinicians and patients with advanced heart failure: methods and challenges behind the working to improve discussions about defibrillator management trial. AB - We report the challenges of the Working to Improve Discussions About Defibrillator Management trial, our novel, multicenter trial aimed at improving communication between cardiology clinicians and their patients with advanced heart failure (HF) who have implantable cardioverter defibrillators (ICDs). The study objectives are (1) to increase ICD deactivation conversations, (2) to increase the number of ICDs deactivated, and (3) to improve psychological outcomes in bereaved caregivers. The unit of randomization is the hospital, the intervention is aimed at HF clinicians, and the patient and caregiver are the units of analysis. Three hospitals were randomized to usual care and three to intervention. The intervention consists of an interactive educational session, clinician reminders, and individualized feedback. We enroll patients with advanced HF and their caregivers, and then we regularly survey them to evaluate whether the intervention has improved communication between them and their HF providers. We encountered three implementation barriers. First, there were institutional review board concerns at two sites because of the palliative nature of the study. Second, we had difficulty in creating entry criteria that accurately identified an HF population at high risk of dying. Third, we had to adapt our entry criteria to the changing landscape of ventricular assist devices and cardiac transplant eligibility. Here we present our novel solutions to the difficulties we encountered. Our work has the ability to enhance conduct of future studies focusing on improving care for patients with advanced illness. PMID- 24768598 TI - Improving search over Electronic Health Records using UMLS-based query expansion through random walks. AB - OBJECTIVE: Most of the information in Electronic Health Records (EHRs) is represented in free textual form. Practitioners searching EHRs need to phrase their queries carefully, as the record might use synonyms or other related words. In this paper we show that an automatic query expansion method based on the Unified Medicine Language System (UMLS) Metathesaurus improves the results of a robust baseline when searching EHRs. MATERIALS AND METHODS: The method uses a graph representation of the lexical units, concepts and relations in the UMLS Metathesaurus. It is based on random walks over the graph, which start on the query terms. Random walks are a well-studied discipline in both Web and Knowledge Base datasets. RESULTS: Our experiments over the TREC Medical Record track show improvements in both the 2011 and 2012 datasets over a strong baseline. DISCUSSION: Our analysis shows that the success of our method is due to the automatic expansion of the query with extra terms, even when they are not directly related in the UMLS Metathesaurus. The terms added in the expansion go beyond simple synonyms, and also add other kinds of topically related terms. CONCLUSIONS: Expansion of queries using related terms in the UMLS Metathesaurus beyond synonymy is an effective way to overcome the gap between query and document vocabularies when searching for patient cohorts. PMID- 24768597 TI - Inhibitors of signal peptide peptidase (SPP) affect HSV-1 infectivity in vitro and in vivo. AB - Recently we have shown that the highly conserved herpes simplex virus glycoprotein K (gK) binds to signal peptide peptidase (SPP), also known as minor histocompatibility antigen H13. In this study we have demonstrated for the first time that inhibitors of SPP, such as L685,458, (Z-LL)2 ketone, aspirin, ibuprofen and DAPT, significantly reduced HSV-1 replication in tissue culture. Inhibition of SPP activity via (Z-LL)2 ketone significantly reduced viral transcripts in the nucleus of infected cells. Finally, when administered during primary infection, (Z-LL)2 ketone inhibitor reduced HSV-1 replication in the eyes of ocularly infected mice. Thus, blocking SPP activity may represent a clinically effective and expedient approach to the reduction of viral replication and the resulting pathology. PMID- 24768599 TI - Human leukocyte antigen G is associated with esophageal squamous cell carcinoma progression and poor prognosis. AB - Human leukocyte antigen G (HLA-G) is a non-classical HLA class I molecule thought to play a key role in maternal-fetal tolerance and cancer immune evasion. This study aimed to investigate the HLA-G expression in lesion sections and plasma sHLA-G levels of primary esophageal squamous cell carcinoma (ESCC) patients and its clinical significance in diagnosis and prognosis of ESCC. 60 ESCC patients and 28 healthy controls were recruited, and the positive expression of HLA-G in ESCC lesions and adjacent normal tissues were 70% (42/60) and 8.6% (5/60) (P<0.05), respectively, while no expression was found in normal controls. HLA-G1 and HLA-G5 were determined to be dominating isoforms measured by RT-PCR. There was a significant difference in plasma sHLA-G levels between patients with ESCC (15.04 U/ml, range 4.33-250.00 U/ml) and healthy controls (6.81 U/ml, range 0 29.27 U/ml) (P<0.01). The plasma IL-10 level was higher in ESCC patients than the controls (23.86 pg/ml vs. 12.81 pg/ml, P<0.01). HLA-G expression in lesion tissues was correlated with cancer cell differentiation (P=0.033), lymph node metastasis (P=0.035) of ESCC. However, no obvious correlations were demonstrated between the plasma sHLA-G levels and the clinicopathological parameters. There was a significant correlation between sHLA-G and IL-10 expression (r=0.353, P=0.006) in patients with Esophageal squamous cell carcinoma. HLA-G positive expression showed poorer prognosis of ESCC. HLA-G positive expression might serve as a potential marker in the diagnosis or prediction of ESCC. PMID- 24768600 TI - Autoimmune regulator expression in thymomas with or without autoimmune disease. AB - BACKGROUND: The autoimmune regulator (AIRE) regulates autoimmunity and self antigen expression, such as acetylcholine receptor (AchR), in the thymus. Regulatory T cells (Tregs) can down-regulate autoimmunity, but also promote tumor growth. The objective of this study was to examine the levels of AIRE, AchR, and Foxp3 expression in thymomas. METHODS: The relative levels of AIRE, AchR, and Foxp3 mRNA transcripts and the frequency of AIRE+, AchR+, and Foxp3+ cells were determined by quantitative RT-PCR and immunohistochemistry in 79 thymoma tissue samples from 21 patients with simple thymoma (the Tm group), 39 patients with myasthenia gravis (the MG group) and 19 patients with myasthenia gravis and one other autoimmune disease (the AD group). The numbers of peripheral blood CD4+CD25+Foxp3+ Tregs were determined by flow cytometry analysis. RESULTS: The relative levels of AIRE and AchR mRNA transcripts in the MG group were significantly lower than that in the Tm group (p=0.04, p=0.03), but higher than that in the AD group (p=0.03, p=0.04). The relative levels of Foxp3 mRNA transcripts in the Tm group were significantly higher than that in the MG and AD groups (p=0.03 for both). A similar pattern of the percentages of AIRE+, AchR+, and Foxp3+ cells in the thymoma tissues and the numbers of peripheral blood Tregs were detected in these patients. The levels of AIRE mRNA transcripts were correlated positively with that of the AchR and Foxp3 in this population. The levels of AIRE and AchR mRNA transcripts in the A/AB/B1 types of thymomas were significantly higher than that in the B2/B3/C types of thymomas in this population. CONCLUSION: Significantly lower levels of AIRE, AchR, and Foxp3 expression are associated with the development of thymoma-related autoimmune diseases. PMID- 24768601 TI - Adherence influencing factors in patients taking oral anticancer agents: a systematic review. AB - BACKGROUND: The use of oral anticancer agents increased steadily in the last decades. Although oral anticancer agent adherence is important for a successful treatment, many patients are insufficiently adherent. PURPOSE: To evaluate adherence influencing factors in patients taking oral anticancer agents. METHODS: A systematic literature search was performed in Medline and Embase. Titles and abstracts and in case of relevance, full-texts were screened according to predefined inclusion criteria. The risk of bias was assessed. Both were carried out independently by two reviewers. Relevant data on study characteristics and results were extracted in standardized tables by one reviewer and checked by a second. A meta-analysis was not performed because of clinical and methodological heterogeneity between the studies to avoid misleading results. Data were synthesized in narrative way using a standardized procedure. RESULTS: Twenty-two relevant studies were identified. The study quality was moderate. Especially the risk of bias regarding the measurement of influencing factors and adherence was mostly unclear. Social support, intake of aromatase inhibitors, and lower out-of pocket costs for OACA seem to have a positive effect on adherence. Depression and the number of different medications seem to have a negative effect on adherence. Low age and very high age seem to be associated with lower adherence. The remaining factors showed either mostly no influence or were heterogeneous regarding the effect direction and statistical significance. CONCLUSIONS: There are some factors that seem to have influence on adherence in patients taking OACA. However, due to the heterogeneity no general conclusions can be made also for these factors that can be applied to all indications, medications, settings, countries etc. The results should rather be considered as indications for factors that can have an influence on adherence to OACA. PMID- 24768602 TI - From myopia to clarity: sharpening the focus of ecosystem management through the lens of palaeoecology. AB - Maintaining biodiversity and ecosystem services in a changing environment requires a temporal perspective that informs realistic restoration and management targets. Such targets need to be dynamic, adaptive, and responsive to changing boundary conditions. However, the application of long-term data from palaeoecology is often hindered as the management and policy implications are not made explicit, and because data sets are often not accessible or amenable to stakeholders. Focussing on this translation gap, we explore how a palaeoecological perspective can change the focus of biodiversity management and conservation policy. We embed a long-term perspective (decades to millennia) into current adaptive management and policy frameworks, with the aim of encouraging better integration between palaeoecology, conservation management, and mainstreaming viable provision of ecosystem services. PMID- 24768604 TI - Anti-ENA profiles related with anti-SS-A/Ro. The detection of Ro52 and Ro60 according to the presence of SS-B/La, and ANA pattern and titer. AB - Anti-Ro52 (Ro52) and anti-Ro60 (Ro60) antibodies are associated with different clinical entities. We investigated their relationship with the presence of anti SS-B/La (SSB) antibody, the pattern and titer of antinuclear antibody (ANA), and the variations in antibody profiles related with anti-SS-A/Ro (SSA) positivity. Our aim was to develop a strategy to increase the efficiency of anti-extractable nuclear antigen (ENA) determinations. Statistical analyses were based on the Chi squared test for categorical variables, the Mann-Whitney U test to compare profiles, and the odds ratio (OR) and 95% confidence interval (95% CI) to estimate the risk of variability. We analyzed 800 SSA-positive samples with Ro52 or Ro60 reactivity. The most frequent profiles were Ro52+Ro60+SSB (n=349, 43.6%); Ro52+Ro60 (n=126, 15.8%); Ro52 (n=121, 15.1%) and Ro60 (n=71, 8.9%). In samples positive only for SSA and an ANA titer <=1:640, the most likely profile was positivity for either Ro52 or Ro60, whereas when the ANA titer was >1:640, positivity for both Ro52 and Ro60 simultaneously was more likely (p<0.001). In samples positive for both SSA and SSB, the most likely profile was Ro52+Ro60+SSB regardless of the ANA titer (p=0.001). When only SSA was positive and the ANA staining pattern was nucleolar, centromeric or cytoplasmic, Ro52 positivity was most likely (p<0.001). When both SSA and SSB were positive, both Ro52 and Ro60 were likely to be positive regardless of the ANA staining pattern. In 28.7% of the patients the profile was variable. Variability was significantly greater in those with the SSA profile (23/67) than with the SSA+SSB profile (15/105; OR=1.9, 95% CI=1.1-3.3; p=0.025), and the difference in variability was greatest between the Ro52+Ro60 profile (8/23) and the Ro52+Ro60+SSB profile (8/68; OR=4.2, 95% CI=1.9-9.5; p<0.001). We conclude that to increase efficiency in the immunology laboratory, positivity for Ro52 and Ro60 individually or simultaneously can be deduced from SSB status and the ANA pattern and titer. In general, for the most frequent anti-ENA findings, priority should be given to retesting autoantibodies not detected in the initial analysis. PMID- 24768603 TI - Biological effects of leukotriene E4 on eosinophils. AB - Studies demonstrate the existence of novel receptors for cysteinyl leukotrienes (CysLTs) that are responsive to leukotriene (LT) E4 and might be pathogenic in asthma. Given the eosinophilic infiltration in this disorder, we investigated eosinophil expression of P2Y12 and gpr99 and their capacity to respond to LTE4. Receptor transcript expression was investigated via quantitative PCR and surface protein expression via flow cytometry. We investigated LTE4 influences on eosinophils including Ca(+2) flux, cAMP induction, modulation of adhesion molecule expression, apoptosis and degranulation. Eosinophils displayed both transcript and surface protein expression of P2Y12 and gpr99. We could not find evidence of LTE4 activation of eosinophils, however, LTE4 induced cAMP expression, and preincubation of eosinophils with LTE4 inhibited degranulation. Even though eosinophils are an important source of CysLTs in AERD, eosinophils are not themselves the pro-inflammatory biological target and, in contrast, LTE4 via cAMP primarily elicits anti-inflammatory responses. PMID- 24768605 TI - NMR spectroscopy in pharmaceutical and biomedical analysis. PMID- 24768606 TI - Mismatch repair protein immunohistochemistry: a useful population screening strategy for Lynch syndrome. AB - Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, shows a highly penetrant, autosomal dominant pattern of inheritance. Distinction of LS colorectal carcinoma instances from the much more common sporadic colorectal carcinoma cases is of paramount importance. Revised Bethesda Guidelines were developed to diagnose LS by evaluating a combination of clinical and pathologic data. The aim of the present study was to evaluate the usefulness of the pathology items included in the Revised Bethesda Guidelines. We have prospectively studied a series of 1624 consecutive colorectal carcinomas with an algorithm including immunohistochemical analysis of mismatch repair proteins and molecular study of microsatellite instability and BRAF c.1799 T > A (p.V600E) gene mutations. Patients with tumors showing LS features were referred for germline mutation analysis. By applying our algorithmic approach, we were able to identify LS features in 89 colorectal cancer patients, of whom only 27 met Revised Bethesda Guidelines pathology criteria. Of the 89 patients, 47 were then studied at the Genetic Counseling Unit, and LS was confirmed in 18, of whom 7 had not been identified by the Revised Bethesda Guidelines. Our study shows that the Revised Bethesda Guidelines failed to detect 70% of patients at risk of LS. Our algorithmic approach is a realistic and effective tool for LS identification. We strongly recommend the implementation of universal population screening for LS among all patients with newly diagnosed colorectal carcinoma. PMID- 24768607 TI - Biological correlates of prostate cancer perineural invasion diameter. AB - Perineural invasion is a symbiotic relationship between cancer cells and nerves and is most frequently seen in "neurotropic" cancers such as prostate cancer. It results in increased perineural space cancer cell growth and decreased apoptosis and induces nerve growth. Tissue microarrays were constructed from 640 radical prostatectomy specimens with prostate cancer. The perineural diameter was measured as previously described. Multiple biomarkers have been previously performed on this tissue microarray cohort, and all data were kept in the same database. The biomarker results database was queried for correlations between perineural invasion diameter and tissue biomarkers. Increased perineural invasion diameter correlated with increased proliferation of prostate cancer cells and with apoptosis. It also correlated with proteins involved in survival pathways such as nuclear factor kappaB, c-Myc, phosphorylated AKT, and its downstream effector FHKR, but not with GSK. Unlike nerve density, it did not correlate with decreased PTEN expression. Increased perineural invasion diameter was associated with higher levels of hormonal receptors such as androgen receptor, but not estrogen receptor. Also associated with perineural invasion diameter were coregulators and corepressors including SRC1 and TIF2. Perineural invasion diameter had the strongest correlation with tumor volume (rho = 0.579, P = .000), not identified with nerve density. These data demonstrate that perineural invasion has the same biologic correlations as neural density. However, we found a distinct and very strong correlation with increased tumor volume. These data confirm that perineural invasion is the ultimate and most successful interaction between cancer cells and nerve fibers, resulting in increased tumor growth. PMID- 24768608 TI - The mechanical fibrillation pattern of the atrial myocardium is associated with acute and long-term success of electrical cardioversion in patients with persistent atrial fibrillation. AB - BACKGROUND: Electrophysiological studies demonstrate that a short atrial fibrillation cycle length (AFCL) is related with poor outcome of electrical cardioversion (ECV) of atrial fibrillation (AF). We found previously that the mechanical AFCL (AFCL-tvi) and atrial fibrillatory velocity (AFV-tvi) may be determined noninvasively using color tissue velocity imaging (TVI) and closely relates to the electrophysiological AFCL. OBJECTIVE: To evaluate the relation between AFCL-tvi, AFV-tvi, and success of ECV in patients with AF. METHODS: We prospectively studied 133 patients with persistent AF by performing echocardiography before ECV and measured the AFCL-tvi and AFV-tvi in the right atrium and left atrium. Recurrent AF was monitored. RESULTS: Nineteen (14%) patients had failure of ECV, 42 (32%) remained in sinus rhythm after 1-year follow-up, and 72 (54%) had a recurrence of persistent AF. Patients with immediate ECV failure had a lower median AFV-tvi measured in the right atrium than did patients with a successful ECV: 0.7 cm/s (0.2-1.0 cm/s) vs. 1.7 cm/s (0.9-2.8 cm/s) (P = .008). Patients with maintenance of sinus rhythm after 1 year had a longer AFCL-tvi measured in the left atrium than did patients with recurrence of AF (150 ms vs 137 ms; P = .017) and had a higher AFV-tvi in both atria (1.4 vs. 0.9 cm/s in the left atrium; P = .013 and 2.2 vs 1.4 cm/s in the right atrium; P = .011). Multivariate analyses showed that all atrial TVI parameters were independently associated with the maintenance of sinus rhythm after 1 year. CONCLUSION: Higher atrial fibrillatory wall velocities and longer AFCLs determined by echocardiography are associated with acute and long-term success of ECV. PMID- 24768609 TI - Epicardial linear electroporation ablation and lesion size. AB - BACKGROUND: Electroporation can be used as a nonthermal method to ablate myocardial tissue. However, like with all electrical ablation methods, determination of the energy supplied into the myocardium enhances the clinically required controllability over lesion creation. OBJECTIVE: To investigate the relationship between the magnitude of epicardial electroporation ablation and the lesion size using an electrically isolating linear suction device. METHODS: In 5 pigs (60-75 kg), the pericardium was opened after medial sternotomy. A custom linear suction device with a single 35 * 6-mm electrode inside a 42-mm-long and 7 mm-wide plastic suction cup was used for electroporation ablation. Single cathodal applications of 30, 100, or 300 J were delivered randomly at 3 different epicardial left ventricular sites. Coronary angiography was performed before ablation, immediately after ablation, and after 3 months survival. Lesion size was measured histologically after euthanization. RESULTS: The mean depth of 30, 100, and 300 J lesions was 3.2 +/- 0.7, 6.3 +/- 1.8, and 8.0 +/- 1.5 mm, respectively (P = .0003). The mean width of 30, 100, and 300 J lesions was 10.1 +/- 0.8, 15.1 +/- 1.5, and 17.1 +/- 1.3 mm, respectively (P<.0001). Significant tissue shrinkage was observed at the higher energy levels. No luminal arterial narrowing was observed after 3 months: 2.3 +/- 0.3 mm vs 2.3 +/- 0.4 mm (P = .85). CONCLUSION: The relationship between the amount of electroporation energy delivered through a linear suction device with a single linear electrode and the mean myocardial lesion size is significant in the absence of major adverse events or permanent damage to the coronary arteries. PMID- 24768610 TI - To the Editor--PQ-segment depression in short QT syndrome: a commendable observation, yet some facts need further exploration. PMID- 24768612 TI - Myotonic dystrophy type 1 mimics and exacerbates Brugada phenotype induced by Nav1.5 sodium channel loss-of-function mutation. AB - BACKGROUND: Myotonic dystrophy type 1 (DM1), a muscular dystrophy due to CTG expansion in the DMPK gene, can cause cardiac conduction disorders and sudden death. These cardiac manifestations are similar to those observed in loss-of function SCN5A mutations, which are also responsible for Brugada syndrome (BrS). OBJECTIVE: The purpose of this study was to investigate DM1 effects on clinical expression of a loss-of-function SCN5A mutation causing BrS. METHODS: We performed complete clinical evaluation, including ajmaline test, in 1 family combining DM1 and BrS. We screened the known BrS susceptibility genes. We characterized an SCN5A mutation using whole-cell patch-clamp experiments associated with cell surface biotinylation. RESULTS: The proband, a 15-year-old female, was a survivor of out-of-hospital cardiac arrest with ventricular fibrillation. She combined a DMPK CTG expansion from the father's side and an SCN5A mutation (S910L) from the mother's side. S910L is a trafficking defective mutant inducing a dominant negative effect when transfected with wild-type Nav1.5. This loss-of-function SCN5A mutation caused a Brugada phenotype during the mother's ajmaline test. Surprisingly, in the father, a DM1 patient without SCN5A mutation, ajmaline also unmasked a Brugada phenotype. Furthermore, association of both genetic abnormalities in the proband exacerbated the response to ajmaline with a massive conduction defect. CONCLUSION: Our study is the first to describe the deleterious effect of DM1 on clinical expression of a loss-of function SCN5A mutation and to show a provoked BrS phenotype in a DM1 patient. The modification of the ECG pattern by ajmaline supports the hypothesis of a link between DM1 and Nav1.5 loss of -function. PMID- 24768613 TI - An in vitro toxicity evaluation of gold-, PLLA- and PCL-coated silica nanoparticles in neuronal cells for nanoparticle-assisted laser-tissue soldering. AB - The uptake of silica (Si) and gold (Au) nanoparticles (NPs) engineered for laser tissue soldering in the brain was investigated using microglial cells and undifferentiated and differentiated SH-SY5Y cells. It is not known what effects NPs elicit once entering the brain. Cellular uptake, cytotoxicity, apoptosis, and the potential induction of oxidative stress by means of depletion of glutathione levels were determined after NP exposure at concentrations of 10(3) and 10(9)NPs/ml. Au-, silica poly (epsilon-caprolactone) (Si-PCL-) and silica poly-L lactide (Si-PLLA)-NPs were taken up by all cells investigated. Aggregates and single NPs were found in membrane-surrounded vacuoles and the cytoplasm, but not in the nucleus. Both NP concentrations investigated did not result in cytotoxicity or apoptosis, but reduced glutathione (GSH) levels predominantly at 6 and 24h, but not after 12 h of NP exposure in the microglial cells. NP exposure induced GSH depletion was concentration-dependent in both cell lines. Si-PCL-NPs induced the strongest effect of GSH depletion followed by Si-PLLA-NPs and Au-NPs. NP size seems to be an important characteristic for this effect. Overall, Au-NPs are most promising for laser-assisted vascular soldering in the brain. Further studies are necessary to further evaluate possible effects of these NPs in neuronal cells. PMID- 24768611 TI - Alpha blockade potentiates CPVT therapy in calsequestrin-mutant mice. AB - BACKGROUND: Spontaneous calcium release evoking delayed afterdepolarization is believed to cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a lethal human arrhythmia provoked by exercise or emotional stress. beta-Adrenergic blockers are the drug of choice, but fail to achieve complete arrhythmia control in some patients. These individuals often require flecainide, device implantation, and/or sympathetic denervation. OBJECTIVE: To optimize the arrhythmia therapy by pharmacological inhibition of the sympathetic nervous system in the homozygous calsequestrin knockout (CASQ2(Delta/Delta)) mouse model of CPVT2. METHODS: A heart telemetry device was implanted for continuous electrocardiographic recording at rest and during provocation testing. Calcium transients and abnormal calcium release were studied in cardiomyocytes isolated from adult mice. Adrenergic receptor expression was determined by using Western blotting and confocal microscopy. RESULTS: Adult CASQ2(Delta/Delta) mice suffer from complex ventricular arrhythmia at rest and ventricular tachycardia during treadmill exercise and after epinephrine injection. beta-Adrenergic blockers, propranolol and metoprolol, attenuated arrhythmia at rest but not after stress. Reserpine had no efficacy in controlling arrhythmia. Agents with alpha-blocking activity, phentolamine or labetalol, abolished both exercise- and epinephrine induced arrhythmia. In contrast, injection of alpha-adrenergic agonist phenylephrine reproducibly provoked ventricular tachycardia. Isolated cardiomyocytes from CASQ2(Delta/Delta) mice had delayed calcium release waves upon exposure to sympathetic agonists, which were abolished by phentolamine. Hearts of calsequestrin-mutant mice expressed more alpha1-adrenergic receptor than did wild type control mice (P < .05). CONCLUSION: We identified a contribution of the alpha-adrenergic pathway to the pathogenesis of catecholamine induced arrhythmia. alpha-Blockade emerges as an effective therapy in the murine model of CPVT2 and should be tried in humans resistant to beta-blockers. PMID- 24768614 TI - DRD1 rare variants associated with tardive-like dystonia: a pilot pathway sequencing study in dystonia. AB - The dystonias are a clinical heterogeneous group with a complex genetic background. To gain more insight in genetic risk factors in dystonia we used a pathway sequence approach in patients with an extreme dystonia phenotype (n = 26). We assessed all coding and non-coding variants in candidate genes in D1-like subclass of dopamine receptor genes (DRD1, DRD5) and the synaptic vesicle pathway linked to torsinA (TOR1A, STON2, SNAPIN, KLC1 and THAP1), spanning 96 Kb. Two rare missense variants in DRD1 were found: c.68G>A(p.Arg23His) in the screening group and c.776C>A(p.Ser259Tyr) in an additional screen of 15 selected dystonia patients. Genetic burden analysis of DRD1 rare variants in patients (4.8%) versus European American controls from ESP (0.72%) reveals an OR 5.35 (95% CI 1.29 23.1). No rare missense SNVs in the synaptic vesicle pathway were found. Sequencing of TOR1A showed variant enrichment in haplotype 2, possibly accountable for contradictive results in previous association studies. Two new rare SNVs were detected in THAP1, including a nonsense mutation (p.Gln167Ter) and a splice site variant (c.72-1G>A). Screening for rare SNV of candidate pathways in a phenotype extreme population appears to be a promising alternative method to identify genetic risk factors in complex disorders like primary torsion dystonia. These findings indicate a role for rare genetic variation in dopamine processing genes in dystonia pathophysiology. PMID- 24768615 TI - Dual tasking during postural stepping responses increases falls but not freezing in people with Parkinson's disease. AB - PURPOSE: Although falls in people with Parkinson's disease (PD) associate with dual tasking and freezing of gait (FoG), it is not known whether falls during dual tasking are due to FoG. This study investigated the effects of a cognitive task on the occurrence of falls and FoG when subjects with PD step in response to a postural perturbation. METHODS: Ten subjects with PD and a history of FoG as well as 10 age-matched subjects without PD stepped in response to large, backward displacements of the support surface, with and without performing a fluency task of listing items in a category. Subjects with PD performed the task in the "off" and "on" dopaminergic medication states. We recorded the percentage of trials with FoG (a lack of step in response to the perturbation), foot-lift latencies, and trials with falls into a safety harness. RESULTS: Dual tasking significantly increased the incidence of falls in people with PD, but subjects without PD did not fall in any condition. Dual tasking did not significantly increase trials without steps or foot-lift latencies. Falls were often coincident with a lack of step (FoG) in the single-task condition, but the increased falls with dual tasking occurred on trials with steps. Levodopa tended to decrease FoG and falls with or without dual tasking. However, medication did not significantly alter the effects of dual tasking on FoG or falls. CONCLUSIONS: For people with PD and FoG, forward falls may not always be caused by FoG, particularly under attention distracting conditions. PMID- 24768616 TI - Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging. AB - PURPOSE: The purpose of this study was to investigate whether the signal intensity of the substantia nigra pars compacta (SNc) and locus coeruleus (LC) on neuromelanin-sensitive magnetic resonance imaging (MRI) can discriminate early stage parkinsonism disorders, for which differential diagnosis is generally difficult. METHODS: Neuromelanin-sensitive MRI at 3 T was performed in 53 patients with early parkinsonism and 22 healthy controls. After an observation period of >1.5 year, the patients were clinically diagnosed with Parkinson's disease (PD; n = 30), multiple system atrophy with predominant parkinsonism (MSA P; n = 10), or progressive supranuclear palsy syndrome (PSPS; n = 13). The signal intensity of the lateral, central, and medial parts of the SNc and the LC were measured and the contrast ratios (CR) against adjacent white-matter structures was calculated. RESULTS: The CR of the lateral SNc was lower in the PD and MSA-P groups than in the PSPS and control groups (p = 0.0001-0.05). The CR of the LC was lower in the PD group than in the other groups (p = 0.0001-0.05). Sensitivity and specificity of the CRs for discriminating PD from MSA-P was 60% and 90%, respectively, those for PD/PSPS were 63-88% and 77-92%, respectively, and those for MSA-P/PSPS were 80% and 85%, respectively. These properties were comparable or better to MIBG scintigraphy. CONCLUSIONS: Neuromelanin-sensitive MRI can depict differences in signal intensity of the lateral SNc and the LC among the parkinsonism disorders at their early stages. PMID- 24768617 TI - MBIS: multivariate Bayesian image segmentation tool. AB - We present MBIS (Multivariate Bayesian Image Segmentation tool), a clustering tool based on the mixture of multivariate normal distributions model. MBIS supports multichannel bias field correction based on a B-spline model. A second methodological novelty is the inclusion of graph-cuts optimization for the stationary anisotropic hidden Markov random field model. Along with MBIS, we release an evaluation framework that contains three different experiments on multi-site data. We first validate the accuracy of segmentation and the estimated bias field for each channel. MBIS outperforms a widely used segmentation tool in a cross-comparison evaluation. The second experiment demonstrates the robustness of results on atlas-free segmentation of two image sets from scan-rescan protocols on 21 healthy subjects. Multivariate segmentation is more replicable than the monospectral counterpart on T1-weighted images. Finally, we provide a third experiment to illustrate how MBIS can be used in a large-scale study of tissue volume change with increasing age in 584 healthy subjects. This last result is meaningful as multivariate segmentation performs robustly without the need for prior knowledge. PMID- 24768618 TI - Will systems biology translate into ever higher healthcare costs, or are there savings to be made? PMID- 24768619 TI - Bone tissue engineering: state of the union. AB - The quest to surpass the clinical efficacy of the allogeneic bone graft has had limited success, an outcome that is symbolic of tissue engineering as a whole. In this 'State of the Union'-type review, we highlight recent advances in the design of bone regenerative therapeutics using the primary elements of stem cells, growth factors and scaffolds, and identify major obstacles in their paths to the clinic. We underscore the need for rigorous performance criteria in the design of holistic tissue regenerative therapeutics, and an increased emphasis on the product production, storage and handling issues that will ultimately influence clinical success. PMID- 24768620 TI - Laparoscopic appendectomy. PMID- 24768621 TI - Repeated intravenous administrations of teneurin-C terminal associated peptide (TCAP)-1 attenuates reinstatement of cocaine seeking by corticotropin-releasing factor (CRF) in rats. AB - The teneurin c-terminal associated peptides (TCAP) have been implicated in the regulation of the stress response, possibly via a corticotropin-releasing factor (CRF)-related mechanism. We have previously shown that repeated intracerebroventricular (ICV) injections of TCAP-1 attenuate the reinstatement of cocaine seeking by CRF in rats. Here, we determined whether intravenous (IV) administrations of TCAP-1 would likewise attenuate CRF-induced reinstatement, and whether this effect would vary depending on the rat's history of cocaine self administration. Rats were trained to self-administer cocaine for 10 days, during once daily sessions that were either 3h ("short access"; ShA) or 6h ("long access"; LgA). Rats were then given five daily injections of TCAP-1 (0, 300, or 3,000 pmol, IV) in their home cage. Subsequently, they were returned to the self administration chambers where extinction of cocaine seeking and testing for CRF induced reinstatement of cocaine seeking was carried out. Repeated IV administrations of TCAP-1 were efficacious in attenuating CRF-induced reinstatement of cocaine seeking, but at different doses in ShA and LgA rats. Taken together, the findings extend previous work showing a consistent effect of repeated ICV TCAP-1 on CRF-induced reinstatement of cocaine seeking, and point to a potential therapeutic benefit of TCAP-1 in attenuating cocaine seeking behaviors. PMID- 24768622 TI - Primary ciliary dyskinesia and humoral immunodeficiency--is there a missing link? AB - BACKGROUND: Primary ciliary dyskinesia (PCD) and humoral mmunodeficiency (HID) are both rare disorders which cause recurrent upper and lower respiratory tract infections. OBJECTIVE: To examine the concurrence of PCD and HID in a patient cohort with known PCD. METHODS: Retrospective review of the patient files. RESULTS: We describe 11 patients of a cohort of 168 patients with PCD (6.5%) with a combination of PCD and some form of HID. The patients all presented with typical clinical symptoms for PCD, however the role of the concomitant immunological abnormalities is not clear. CONCLUSION: PCD and HID coincided in 6.5% of the patients. We suggest that a common pathophysiological pathway results in both disorders. PMID- 24768623 TI - Analytical performance of newly developed multiplex human papillomavirus genotyping assay using Luminex xMAPTM technology (MebgenTM HPV Kit). AB - Regional differences in human papillomavirus (HPV) genotypes and the presence of mixed HPV infections may affect adversely the efficacy of the HPV vaccine. Therefore, a simple and high-throughput HPV genotyping system is required. Recently, a novel HPV genotyping kit (the MebgenTM HPV kit) was developed. This kit uses multiplex PCR and Luminex xMAPTM technology to detect 13 types of high risk HPVs and an internal control in a 96-well format. In the present study, the analytical performance of the kit was examined using HPV plasmid DNA. All 13 types of HPVs were detected with a minimum detection sensitivity of 250 copies/test, and highly specific signals were observed. HPV 16 plasmid was detected in samples containing mixtures with other HPV-type plasmids in ratios ranging from 1:1 to 1:1000. No cross reactivity was observed with DNA from 27 types of other infectious microbes. A clinical evaluation was carried out using cervical samples from 356 patients with persistent abnormal smears diagnosed at mass public health screenings for cervical cancer. The samples were preserved in TacasTM medium until analysis. HPV was detected in 162 (45.5%) samples including 110 (67.9%) with single infections and 52 (32.1%) with multiple infections. The type distribution of the 13 high-risk HPVs was as follows: 28.4% HPV 16, 11.7% HPV 18, 6.8% HPV 31, 3.1% HPV 33, 3.7% HPV 35, 9.3% HPV 39, 1.9% HPV 45, 8.6% HPV 51, 37.0% HPV 52, 9.3% HPV 56, 16.7% HPV 58, 3.7% HPV 59, and 1.9% HPV 68. To evaluate sample stability over time, changes in the detection of HPV DNA derived from HeLa and SiHa cells were measured in 3 types of liquid-based cytology media. HPV DNA was detected in Tacas and ThinprepTM samples after storage at 4 degrees C or 30 degrees C for 4 weeks and within 1 week of collection in SurepathTM samples. These results suggest that this newly developed HPV genotyping kit is suitable for use in both clinical applications and large-scale epidemiological studies. PMID- 24768624 TI - [The modified Brussels scale as a predictor of mortality in the Intensive Care Unit]. AB - PURPOSE: To compare discrimination and calibration of the modified Brussels score with the Simplified Acute Physiology Score version 3 (SAPS-3) in predicting mortality. DESIGN: A prospective cohort study was carried out. SETTING: The Respiratory Intensive Care Unit (RICU) of Mexico General Hospital. PATIENTS: A total of 251 patients out of 285 admissions to the RICU in 2012 were included. The mean age was 48.4+/-17.1 years, and 132 of the patients were men (52.8%). INTERVENTIONS: None. VARIABLES OF INTEREST: Demographic data, SAPS-3 score upon admission and the modified Brussels score on the day 1 of stay in the RICU. RESULTS: On day 1, the modified Brussels and SAPS-3 scores were 4.7 +/- 3.8 and 54.7 +/- 17.8, respectively. Areas under the ROC curve for the modified Brussels score on day 1 and the SAPS-3 were 0.837 +/- 0.025 (95% CI 0.787-0.887) and 0.813 +/- 0.027 (95% CI 0.761-0.865), respectively. Hosmer-Lemeshow goodness-of-fit values were 5,885 (P=.660) and 4,026 (P=.855), respectively. CONCLUSIONS: The modified Brussels score on day 1 offers excellent discrimination and calibration in predicting mortality in the RICU, comparable to that of the SAPS-3. PMID- 24768625 TI - Could urine be useful for the diagnosis of Chlamydia trachomatis pneumonia in infancy? AB - A 9-week-old infant presented with respiratory distress. The presumptive diagnosis of Chlamydia trachomatis pneumonia was ultimately made in a novel manner by a positive nucleic acid amplification test on a urine sample. PMID- 24768626 TI - Rapid method for recovery of strongylid third stage larvae of parasitic nematodes from small soil samples. AB - Livestock with access to pasture is generally exposed to infections with parasitic nematode species by uptake of infective third stage larvae (L3) with the grass. L3 can survive on pasture and particularly also in the soil up to several months and sometimes even longer, depending on temperature and humidity. As indicators for health and productivity of grazing animals it is important to determine the intensity and species spectrum of parasitic nematode larvae by analysing grass as well as soil samples. A rapid method for the recovery of L3 using a centrifugal-flotation technique from soil samples of 50-500 g was developed. The method takes advantage of the low specific weight of larvae to separate them from equal sized soil and debris particles by centrifuging them in a saturated sugar solution. A stack of differently sized sieves is used to achieve elimination of larger particles, dust and sugar from the sample to enable easy counting of larvae. Independent of the number of larvae used for inoculation of the samples a mean recovery of 75.3% was obtained. The recovery rates obtained ranged between 60.8% and 88.0% which demonstrates a considerably lower variability compared to earlier approaches and therefore a more precise estimation of the actual numbers of parasite larvae in soil is achieved. Further advantages over already developed methods are the use of easy, affordable and eco friendly materials, the simplicity of the procedure and a faster processing time with the possibility to examine up to 20 samples per day. PMID- 24768627 TI - Impairment of GABA release in the hippocampus at the time of the first spontaneous seizure in the pilocarpine model of temporal lobe epilepsy. AB - The alterations in GABA release have not yet been systematically measured along the natural course of temporal lobe epilepsy. In this work, we analyzed GABA extracellular concentrations (using in vivo microdialysis under basal and high K(+)-evoked conditions) and loss of two GABA interneuron populations (parvalbumin and somatostatin neurons) in the ventral hippocampus at different time-points after pilocarpine-induced status epilepticus in the rat, i.e. during development and progression of epilepsy. We found that (i) during the latent period between the epileptogenic insult, status epilepticus, and the first spontaneous seizure, basal GABA outflow was reduced to about one third of control values while the number of parvalbumin-positive cells was reduced by about 50% and that of somatostatin-positive cells by about 25%; nonetheless, high K(+) stimulation increased extracellular GABA in a proportionally greater manner during latency than under control conditions; (ii) at the time of the first spontaneous seizure (i.e., when the diagnosis of epilepsy is made in humans) this increased responsiveness to stimulation disappeared, i.e. there was no longer any compensation for GABA cell loss; (iii) thereafter, this dysfunction remained constant until a late phase of the disease. These data suggest that a GABAergic hyper-responsiveness can compensate for GABA cell loss and protect from occurrence of seizures during latency, whereas impaired extracellular GABA levels can favor the occurrence of spontaneous recurrent seizures and the maintenance of an epileptic state. PMID- 24768628 TI - The protective effects of Trolox-loaded chitosan nanoparticles against hypoxia mediated cell apoptosis. AB - Antioxidants have potentials to treat hypoxia-mediated oxidative stress related diseases. However, their therapeutic efficacy is restricted due to its poor cellular uptake efficiency and poor cell membrane permeability. To resolve these issues, we prepare the hydroxyethylated chitosan nanoparticles as drug carriers for the delivery of 6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid (Trolox), which was considered as a model compound. The experiment on cellular uptake and subcellular localization of Trolox-loaded chitosan nanoparticles (Trolox-CSNPs) indicate that Trolox-CSNPs enter the cells via the caveolae mediated endocytosis pathway and traffic with endosomes. Furthermore, compared with Trolox, Trolox-CSNPs exert a higher protective effect against the hypoxia mediated oxidative stress. Molecular basis of apoptosis study reveals that Trolox CSNPs can directly block the mitochondria dependent apoptotic pathway through up regulation of Bcl-2 expression and inhibiting the activation of Bax, Caspase-3 expression. In conclusion, the hydroxyethylated chitosan is a promising drug nanocarrier to deliver antioxidants for the treatment of hypoxia-mediated disease. From the clinical editor: Antioxidants are potentially beneficial in oxidative stress-related diseases, although cellular uptake of most antioxidants is suboptimal. In this study, hydroxyethylated chitosan nanoparticles are demonstrated as promising drug carriers in a Trolox-model system. PMID- 24768629 TI - Atg5 deficit exaggerates the lysosome formation and cathepsin B activation in mice brain after lipid nanoparticles injection. AB - The present study was designed to investigate the role of autophagy-lysosome signaling in the brain after application of nanoparticles. Here, lipid nanoparticles (LNs) induced elevations of Atg5, P62, LC3 and cathepsin B in mice brain. The transmission electron microscopy revealed a dramatic elevation of lysosome vacuoles colocalized with LNs cluster inside the neurons in mice brain. Immunoblot data revealed abnormal expression of cathepsin B in brain cortex following LNs injection, whereas its expression was further elevated in Atg5(+/-) mice. The importance of Atg5 in the LNs-induced autophagy-lysosome cascade was further supported by our finding that neurovascular response was exaggerated in Atg5(+/-) mice. In addition, the siRNA knockdown of Atg5 significantly blunted the increasing of LC3 and P62 in LNs-treated Neuro-2a cells. Taken together, we propose that LNs induce autophagy-lysosome signaling and neurovascular response at least partially via an Atg5-dependent pathway. FROM THE CLINICAL EDITOR: These authors investigated autophagy-lysosome signaling in the mouse brain after application of lipid nanoparticles and report that these nanoparticles induce autophagy-lysosome signaling and neurovascular response at least partially via an Atg5-dependent pathway. PMID- 24768630 TI - Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer. AB - CRLX101 is a nanopharmaceutical consisting of cyclodextrin-based polymer molecule and camptothecin. The CRLX101 nanoparticle is designed to concentrate and slowly release camptothecin in tumors over an extended period of time. Tumor biopsy and blood samples collected from patients with advanced solid malignancies before and after CRLX101 treatment are subjected to immunohistochemistry and pharmacogenomics. The expression of Topoisomerase-1, Ki-67, CaIX, CD31 and VEGF decreased after CRLX101 treatment. The expressions of these proteins are inversely proportional with survival duration of the patients. The Drug Metabolism Enzymes and Transporters (DMET) array shows an allele frequency in patients similar to global populations with none of the SNPs associated with toxicity. The results suggest that the observed lower toxicity is not likely to be due to different genotypes in SNPs. CRLX101 demonstrates a promising anti tumor activity in heavily pre-treated or treatment-refractory solid tumor malignancies presumably by inhibition of proliferation and angiogenesis correlating with tumor growth inhibition. From the clinical editor: In this cancer treatment study clinical samples collected from patients were subjected to immunohistochemistry and pharmacogenomics. The expressions of key proteins that are inversely proportional with survival duration of the patients decreased after treatment with CRLX101, a camptothecin slow-release nanoparticle conjugate. This anti-tumor activity in heavily pre-treated and treatment resistant solid tumors, promises a novel therapeutic approach. PMID- 24768631 TI - Skin barrier disruptions in tape stripped and allergic dermatitis models have no effect on dermal penetration and systemic distribution of AHAPS-functionalized silica nanoparticles. AB - The skin is a potential site of entry for nanoparticles (NP) but the role of disease-associated barrier disturbances on the path and extent of skin penetration of NP remains to be characterized. Silica nanoparticles (SiO2-NP) possess promising potential for various medical applications. Here, effects of different skin barrier disruptions on the penetration of N-(6-aminohexyl) aminopropyltrimethoxysilane (AHAPS) functionalized SiO2-NP were studied. AHAPS SiO2-NP (55+/-6 nm diameter) were topically applied on intact, tape stripped or on inflamed skin of SKH1 mice with induced allergic contact dermatitis for one or five consecutive days, respectively. Penetration of AHAPS-SiO2-NP through the skin was not observed regardless of the kind of barrier disruption. However, only after subcutaneous injection, AHAPS-SiO2-NP were incorporated by macrophages and transported to the regional lymph node only. Adverse effects on cells or tissues were not observed. In conclusion, AHAPS-SiO2-NP seem to not cross the normal or perturbed mouse skin. From the clinical editor: Skin is a potential site of entry for nanoparticles; however, it is poorly understood how skin diseases may alter this process. In tape-stripped skin and allergic contact dermatitis models the delivery properties of AHAPS-SiO2 nanoparticles remained unchanged, and in neither case were these NP-s able to penetrate the skin. No adverse effects were noted on the skin in these models and control mice. PMID- 24768632 TI - Antitubercular constituents from Premna odorata Blanco. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Premna odorata Blanco (Lamiaceae) is a medicinal plant traditionally used in Albay Province, in southeastern Luzon, Philippines to treat tuberculosis. This study aimed to determine the antitubercular property of the crude extract and sub-extracts of the leaves, and to isolate the bioactive principles from the active fractions. MATERIALS AND METHODS: Through extraction, solvent polarity-based fractionation and silica gel chromatography purification of the DCM sub-extract, compound mixtures from the bioactive fractions were isolated and screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv using the colorimetric Microplate Alamar Blue assay (MABA). RESULTS: The crude methanolic extract and sub-extracts showed poor inhibitory activity against Mycobacterium tuberculosis H37Rv (MIC>=128ug/mL). However, increased inhibitory potency was observed for fractions eluted from the DCM sub-extract (MIC=54 to 120ug/mL). Further purification of the most active fraction (MIC=54ug/mL) led to the isolation of a 1-heneicosyl formate (1), 4:1 mixture of beta-sitosterol (2), stigmasterol (3) and diosmetin (4), which were identified through GC-MS analysis (with dereplication) and NMR experiments. The MIC of compound 1 was 8ug/mL. CONCLUSIONS: The results of this study provide scientific basis for the traditional use of Premna odorata as treatment for tuberculosis. PMID- 24768633 TI - Evaluation of sex, race, body mass index and pre-vaccination serum progesterone levels and post-vaccination serum anti-anthrax protective immunoglobulin G on injection site adverse events following anthrax vaccine adsorbed (AVA) in the CDC AVA human clinical trial. AB - BACKGROUND: Anthrax vaccine adsorbed (AVA) administered intramuscularly (IM) results in fewer adverse events (AEs) than subcutaneous (SQ) administration. Women experience more AEs than men. Antibody response, female hormones, race, and body mass index (BMI) may contribute to increased frequency of reported injection site AEs. METHODS: We analyzed data from the CDC AVA human clinical trial. This double blind, randomized, placebo controlled trial enrolled 1563 participants and followed them through 8 injections (AVA or placebo) over a period of 42 months. For the trial's vaccinated cohort (n=1267), we used multivariable logistic regression to model the effects of study group (SQ or IM), sex, race, study site, BMI, age, and post-vaccination serum anti-PA IgG on occurrence of AEs of any severity grade. Also, in a women-only subset (n=227), we assessed effect of pre vaccination serum progesterone level and menstrual phase on AEs. RESULTS: Participants who received SQ injections had significantly higher proportions of itching, redness, swelling, tenderness and warmth compared to the IM study group after adjusting for other risk factors. The proportions of redness, swelling, tenderness and warmth were all significantly lower in blacks vs. non-black participants. We found arm motion limitation, itching, pain, swelling and tenderness were more likely to occur in participants with the highest anti-PA IgG concentrations. In the SQ study group, redness and swelling were more common for obese participants compared to participants who were not overweight. Females had significantly higher proportions of all AEs compared to males. Menstrual phase was not associated with any AEs. CONCLUSIONS: Female and non-black participants had a higher proportion of AVA associated AEs and higher anti-PA IgG concentrations. Antibody responses to other vaccines may also vary by sex and race. Further studies may provide better understanding for higher proportions of AEs in women and non-black participants. PMID- 24768634 TI - Inflammatory responses following intramuscular and subcutaneous immunization with aluminum-adjuvanted or non-adjuvanted vaccines. AB - Aluminum-adjuvanted vaccines are administered through an intramuscular injection (IM) in the US and EU, however, a subcutaneous injection (SC) has been recommended in Japan because of serious muscle contracture previously reported following multiple IMs of antibiotics. Newly introduced adjuvanted vaccines, such as the human papillomavirus (HPV) vaccines, have been recommended through IM. In the present study, currently available vaccines were evaluated through IM in mice. Aluminum-adjuvanted vaccines induced inflammatory nodules at the injection site, which expanded into the intra-muscular space without any muscle degeneration or necrosis, whereas non-adjuvanted vaccines did not. These nodules consisted of polymorph nuclear neutrophils with some eosinophils within the initial 48h, then monocytes/macrophages 1 month later. Inflammatory nodules were observed 6 months after IM, had decreased in size, and were absorbed 12 months after IM, which was earlier than that after SC. Cytokine production was examined in the injected muscular tissues and AS04 adjuvanted HPV induced higher IL-1beta, IL-6, KC, MIP-1, and G-CSF levels in muscle tissues than any other vaccine, but similar serum cytokine profiles were observed to those induced by the other vaccines. Currently available vaccines did not induce muscular degeneration or fibrotic scar as observed with muscle contracture caused by multiple IMs of antibiotics in the past. PMID- 24768635 TI - ATF3 attenuates cyclosporin A-induced nephrotoxicity by downregulating CHOP in HK 2 cells. AB - Calcineurin inhibitors such as cyclosporin A (CsA) are widely used to treat organ transplantation-associated complications. However, CsA use is limited due to renal dysfunction. This study attempts to characterize the mechanism of CsA induced nephrotoxicity using a human embryonic kidney cell line (HK-2). We performed microarray-based whole-genome expression analysis in HK-2 cells. CsA treatment induced the expression of endoplasmic reticulum (ER) stress-related and apoptosis-inducing genes at 6 and 24h, respectively, indicating that ER-stress predisposed the cells to apoptosis. G1 phase cell-cycle arrest was also observed via ER stress in CsA-treated cells. Furthermore, we found an inverse relationship between activating transcription factor 3 (ATF3), a stress-inducible protein, and C/EBP homologous protein (CHOP), an apoptosis-inducing protein. Moreover, when ATF3 knockdown cells were exposed to CsA, a prompt induction of CHOP was observed, which stimulated ROS production and induced cell death-related genes as compared to wild type. Taken together, our data demonstrate that ATF3 plays a pivotal role in the attenuation of CsA-induced nephrotoxicity by downregulating CHOP and ROS production mediated by ER stress. PMID- 24768636 TI - Integrative omics analysis reveals differentially distributed proteins in dimorphic euspermatozoa of the squid, Loligo bleekeri. AB - In the coastal squid Loligo bleekeri, each male produces one of two types of fertilization-competent spermatozoa (eusperm) that exhibit morphological and behavioral differences. Large "consort" males produce short-tailed spermatozoa that display free-swimming behavior when ejaculated into seawater. Small "sneaker" males, on the other hand, produce long-tailed spermatozoa that exhibit a self-swarming trait after ejaculation. To understand the molecular basis for adaptive traits employed by alternative male mating tactics, we performed the transcriptome deep sequencing (RNA-seq) and proteome analyses to search for differences in testicular mRNAs and sperm proteins, respectively. From mature male testes we identified a total of 236,455 contigs (FPKM ?1) where 3789 and 2789 were preferentially (?10-fold) expressed in consort and sneaker testes, respectively. A proteomic analysis detected 4302 proteins in the mature sperm as post-translational products. A strongly biased (?10-fold) distribution occurred in 55 consort proteins and 61 sneaker proteins. There was no clear mRNA-protein correlation, making a ballpark estimate impossible for not only overall protein abundance but also the degree of biased sperm type expressed in the spermatozoa. A family encoding dynein heavy chain gene, however, was found to be biased towards sneakers, whereas many enzymes involving energy metabolism were heavily biased towards consort spermatozoa. The difference in flagellar length matched exactly the different amount of tubulins. From these results we hypothesize that discrete differential traits in dimorphic eusperm arose from a series of innovative alterations in the intracellular components of spermatozoa. PMID- 24768638 TI - Efficient isolation and elution of cellular proteins using aptamer-mediated protein precipitation assay. AB - Protein precipitation is one of the most widely used methods for antigen detection and purification in biological research. We developed a reproducible aptamer-mediated magnetic protein precipitation method that is able to efficiently capture, purify and isolate the target proteins. We discovered DNA aptamers having individually high affinity and specificity against human epidermal growth factor receptor (EGFR) and human insulin receptor (INSR). Using aptamers and magnetic beads, we showed it is highly efficient technique to enrich endogenous proteins complex and is applicable to identify physiologically relevant protein-protein interactions with minimized nonspecific binding of proteins. The results presented here indicate that aptamers would be applicable as a useful and cost-effective tool to identify the presence of the particular target protein with their specific protein partners. PMID- 24768637 TI - Crystal structure of the NHERF1 PDZ2 domain in complex with the chemokine receptor CXCR2 reveals probable modes of PDZ2 dimerization. AB - The formation of CXCR2-NHERF1-PLCbeta2 macromolecular complex in neutrophils regulates CXCR2 signaling and plays a key role in neutrophil chemotaxis and transepithelial neutrophilic migration. However, NHERF1 by itself, with only two PDZ domains, has a limited capacity in scaffolding the multiprotein-complex formation. Here we report the crystal structure of the NHERF1 PDZ2 domain in complex with the C-terminal CXCR2 sequence. The structure reveals that the PDZ2 CXCR2 binding specificity is achieved by numerous hydrogen bonds and hydrophobic contacts with the last four CXCR2 residues contributing to specific interactions. The structure also reveals two probable modes of PDZ2 dimerization where the two canonical ligand-binding pockets are well separated and orientated in a unique parallel fashion. This study provides not only the structural basis for the PDZ mediated NHERF1-CXCR2 interaction, but also an additional example of how PDZ domains may dimerize, which both could prove valuable in understanding NHERF1 complex-scaffolding function in neutrophils. PMID- 24768639 TI - The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats. AB - The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs. PMID- 24768640 TI - H2S attenuates cognitive deficits through Akt1/JNK3 signaling pathway in ischemic stroke. AB - Neuronal damage in the hippocampal formation which is more sensitive to ischemic stimulation and easily injured will cause severe learning and memory impairment. Therefore, inhibiting hippocampal neuron injuries is the main contributor for learning and memory impairment during cerebral ischemia. Hydrogen sulfide (H2S) is a new type of neurotransmitter that regulates the nervous, circulatory and immune systems as well as various adverse factors that can reduce cerebral vascular or brain parenchyma injury. During an ischemic stroke, H2S inhibits hippocampal neuronal damage, reducing learning and memory impairment. However, this molecular mechanism has not been elucidated clearly. In this study, we established four-vessel occlusion model in rats with cerebral ischemia. We found that NaHS (28 mmol/kg, intraperitoneally, for 7 days before ischemia), donor of H2S, significantly shortened the distance and time of loading onto the hidden platform in the positioning navigation process, decreased the latency in the space exploration process when cognitive testing with Morris water maze was performed during ischemic stroke in rats. NaHS also significantly shortened latency and reduced the number of errors in the platform diving experiment. The survival rate of neurons in the CA1 area of the hippocampus and the phosphorylation of Akt in the neurons were increased, the phosphorylation ASK1 and JNK3 were inhibited by NaHS. After an intracerebroventricular injection of LY294002 (inhibitor of PI3K/Akt, 10 MUL, 100 nmol in 25% DMSO in PBS), the above effects of NaHS were attenuated. These findings suggest that H2S may improve the survival rate of hippocampal neurons and reduce the impairment of learning and memory by increasing the phosphorylation of Akt, inhibiting the phosphorylation of ASK1 and JNK3 in rats with induced ischemic stroke. PMID- 24768641 TI - Gpm6b deficiency impairs sensorimotor gating and modulates the behavioral response to a 5-HT2A/C receptor agonist. AB - The neuronal tetraspan proteins, M6A (Gpm6a) and M6B (Gpm6b), belong to the family of proteolipids that are widely expressed in the brain. We recently reported Gpm6a deficiency as a monogenetic cause of claustrophobia in mice. Its homolog proteolipid, Gpm6b, is ubiquitously expressed in neurons and oligodendrocytes. Gpm6b is involved in neuronal differentiation and myelination. It interacts with the N-terminal domain of the serotonin transporter (SERT) and decreases cell-surface expression of SERT. In the present study, we employed Gpm6b null mutant mice (Gpm6b(-/-)) to search for behavioral functions of Gpm6b. We studied male and female Gpm6b(-/-) mice and their wild-type (WT, Gpm6b(+/+)) littermates in an extensive behavioral test battery. Additionally, we investigated whether Gpm6b(-/-) mice exhibit changes in the behavioral response to a 5-HT2A/C receptor agonist. We found that Gpm6b(-/-) mice display completely normal sensory and motor functions, cognition, as well as social and emotionality like (anxiety, depression) behaviors. On top of this inconspicuous behavioral profile, Gpm6b(-/-) mice of both genders exhibit a selective impairment in prepulse inhibition of the acoustic startle response. Furthermore, in contrast to WT mice that show the typical locomotion suppression and increase in grooming activity after intraperitoneal administration of DOI [(+/-)-1-(2,5-dimethoxy-4 iodophenyl)-2-aminopropane hydrochloride], Gpm6b(-/-) mice demonstrate a blunted behavioral response to this 5-HT2A/C receptor agonist. To conclude, Gpm6b deficiency impairs sensorimotor gating and modulates the behavioral response to a serotonergic challenge. PMID- 24768642 TI - D1-like antagonist blocks conditioned place preference induced by ejaculation in male rats. AB - Mating behavior, particularly ejaculation, induces a state of sexual reward, which is evaluated by the conditioned place preference test. Several studies have shown that opioid receptors are involved in inducing the state of sexual reward, mainly because this state is blocked with naloxone, a mu opioid receptor antagonist. Dopamine has been implicated in sexual motivation, coital behavior and sexual reward, however, some experiments show that D2-like or non-specific dopaminergic antagonists are not capable of blocking the conditioned place preference induced by ejaculation; therefore, the role of dopamine on sexual reward has not been demonstrated, or has been frequently discarded. We show that a dose of SCH 23390 (a specific dopamine D1-like receptor antagonist), which does not modify locomotion, blocks the conditioned place preference induced by ejaculation and the conditioned place preference induced by SKF 38393 (D1-like agonist). Our results indicate that dopamine, across the D1-like receptors, is involved in the sexual reward induced by ejaculation. PMID- 24768643 TI - Mice over-expressing BDNF in forebrain neurons develop an altered behavioral phenotype with age. AB - Evidence from clinical studies suggests that abnormal activity of brain derived neurotrophic factor (BDNF) contributes to the pathogenesis of autism spectrum disorders (ASDs). A genetically modified line of mice over-expressing a BDNF transgene in forebrain neurons was used to investigate if this mutation leads to changes in behavior consistent with ASD. The mice used in these experiments were behaviorally tested past 5 months of age when spontaneous seizures were evident. These seizures were not observed in age-matched wildtype (WT) mice or younger mice from this transgenic line. The BDNF mice in these experiments weighed less than their WT littermates. The BDNF transgenic (BDNF-tg) mice demonstrated similar levels of sociability in the social approach test. Conversely, the BDNF tg mice demonstrated less obsessive compulsive-like behavior in the marble burying test, less anxiety-like behavior in the elevated plus maze test, and less depressive-like behavior in the forced swim test. Changes in behavior were found in these older mice that have not been observed in younger mice from this transgenic line, which may be due to the development of seizures as the mice age. These mice do not have an ASD phenotype but may be useful to study adult onset epilepsy. PMID- 24768644 TI - Development of prenatal lateralization: evidence from fetal mouth movements. AB - BACKGROUND: Human lateralized behaviors relate to the asymmetric development of the brain. Research of the prenatal origins of laterality is equivocal with some studies suggesting that fetuses exhibit lateralized behavior and other not finding such laterality. Given that by around 22weeks of gestation the left cerebral hemisphere compared to the right is significantly larger in both male and female fetuses we expected that the right side of the fetal face would show more movement with increased gestation. This longitudinal study investigated whether fetuses from 24 to 36weeks of gestation showed increasing lateralized behaviors during mouth opening and whether lateralized mouth movements are related to fetal age, gender and maternal self-reported prenatal stress. PARTICIPANTS: Following ethical approval, fifteen healthy fetuses (8 girls) of primagravid mothers were scanned four times from 24 to 36-gestation. Two types of mouth opening movements - upper lip raiser and mouth stretch - were coded in 60 scans for 10min. RESULTS: We modeled the proportion of right mouth opening for each fetal scan using a generalized linear mixed model, which takes account of the repeated measures design. There was a significant increase in the proportion of lateralized mouth openings over the period increasing by 11% for each week of gestational age (LRT change in deviance=10.92, 1df; p<0.001). No gender differences were found nor was there any effect of maternally reported stress on fetal lateralized mouth movements. There was also evidence of left lateralization preference in mouth movement, although no evidence of changes in lateralization bias over time. This longitudinal study provides important new insights into the development of lateralized mouth movements from 24 to 36 weeks of gestation. PMID- 24768645 TI - Lead-induced effects on learning/memory and fear/anxiety are correlated with disturbances in specific cholinesterase isoform activity and redox imbalance in adult brain. AB - The aim of the present study was to investigate whether the underlying mechanism of lead (Pb)-induced effects on learning/memory and fear/anxiety behavior involves changes either on AChE G4 (most abundant in brain) or on G1 isoform activity, and/or to a putative local disruption of oxidant/antioxidant balance. Adult male mice were randomly divided into two groups (18 animals/group): a vehicle group [500ppm (mg/L) CH3COONa/day for 4weeks in their drinking water] and a Pb-treated group [500ppm Pb(CH3COO)2/day for 4weeks in their drinking water]. At the end of the treatment period, mice were subjected to the behavioral tasks. Learning/memory was tested by step-through passive avoidance test, whereas fear/anxiety was studied using the elevated plus-maze and thigmotaxis tests. Pb levels in mice brain were determined using atomic absorption spectrometry. AChE activity was determined colorimetrically, and GSH and MDA levels fluorometrically in whole brain minus cerebellum, cerebral cortex, midbrain, hippocampus, striatum and cerebellum. The possible correlations between learning/memory or fear/anxiety behavior with the AChE activity and/or the lipid peroxidation levels and GSH content were also examined. Pb consumption caused significant deficits on mice learning/memory ability and increased anxiety. The consumption of the Pb solution inhibited the activity of the two AChE isoforms in all brain regions tested. Moreover, Pb exposure increased lipid peroxidation and decreased GSH levels in all brain regions examined. Spearman correlation analysis revealed that the coefficients between the particular behaviors, AChE activity and redox balance were brain region- and AChE isoform-specific. PMID- 24768646 TI - Eating attitudes of anorexia nervosa, bulimia nervosa, binge eating disorder and obesity without eating disorder female patients: differences and similarities. AB - The objective was to compare eating attitudes, conceptualized as beliefs, thoughts, feelings, behaviors and relationship with food, of anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) patients and a group of obese (OBS) without eating disorders (ED). Female patients from an Eating Disorder (ED) Unit with AN (n=42), BN (n=52) and BED (n=53) and from an obesity service (n=37) in Brazil answered the Disordered Eating Attitude Scale (DEAS) which evaluate eating attitudes with 5 subscales: relationship with food, concerns about food and weight gain, restrictive and compensatory practices, feelings toward eating, and idea of normal eating. OBS patients were recruited among those without ED symptoms according to the Binge Eating Scale and the Questionnaire on Eating and Weight Patterns. ANOVA was used to compare body mass index and age between groups. Bonferroni test was used to analyze multiple comparisons among groups. AN and BN patients presented more dysfunctional eating attitudes and OBS patients less dysfunctional (p<0.001). For DEAS total score, AN and BN patients were similar and all other were different (p<0.001). Similarities suggested between BN and BED were true just for the "Relationship with food" and "Idea of normal eating." BED patients were worst than OBS for "Relationship with food" and as dysfunctional as AN patients - besides their behavior could be considered the opposite. Differences and similarities support a therapeutic individualized approach for ED and obese patients, call attention for the theoretical differences between obesity and ED, and suggest more research focused on eating attitudes. PMID- 24768647 TI - Economics of food intake in mice: energy yield of the reinforcer. AB - One of the Zeitgeists of the field for the study of ingestive behavior is that organisms are endowed with internal self-regulatory mechanisms that ensure optimal nutrition. However, the alarming increase in the prevalence of obesity challenges us to reconsider the extent to which internal regulatory mechanisms affect food intake, especially in a free market economy. Cued by the pioneering work of George Collier and his students, we have been examining food intake (demand) in mice when the effort or price of food is manipulated. We present two new experiments in mice that investigate the effect of energy yield per unit of food earned on working for food. The first experiment shows that when the nominal energy yield of each food pellet is halved by cellulose dilution, mice show relatively inelastic calorie-related demand despite the fact the cellulose diluted diet is unpalatable. The second experiment shows that the size of the pellet reinforcer does not have a major effect on food demand except in the extreme condition of small reward and high unit price. New analyses of distributions of responding are presented which suggest that mice work for "target" numbers of food rewards with only a small influence of price or energy gain. PMID- 24768649 TI - Salivary oxytocin mediates the association between emotional maltreatment and responses to emotional infant faces. AB - Childhood emotional maltreatment has been associated with a higher risk for maltreating one's own offspring. In the current study, we explored a possible role of oxytocin in mediating the association between childhood emotional maltreatment and participants' interpretation of infant facial expressions. Oxytocin levels were measured in 102 female participants using saliva samples. They rated the mood of thirteen infants with happy, sad and neutral facial expressions. Emotional maltreatment indirectly influenced responses to happy infant faces by modulating oxytocin levels: higher self-reported emotional maltreatment was related to higher levels of salivary oxytocin which were in turn related to a more positive evaluation of happy infant expressions, but not to the evaluation of sad infant expressions. Oxytocin receptor polymorphism rs53576 did not moderate the relation between maltreatment experiences and salivary oxytocin levels. Early emotional maltreatment might indirectly affect emotional information processing by altering the oxytonergic system. PMID- 24768648 TI - FTO polymorphisms moderate the association of food reinforcement with energy intake. AB - Food reinforcement (RRVfood) is related to increased energy intake, cross sectionally related to obesity, and prospectively related to weight gain. The fat mass and obesity-associated (FTO) gene is related to elevated body mass index and increased energy intake. The primary purpose of the current study was to determine whether any of 68 FTO single nucleotide polymorphisms (SNPs) or a FTO risk score moderate the association between food reinforcement and energy or macronutrient intake. Energy and macronutrient intake was measured using a laboratory ad libitum snack food consumption task in 237 adults of varying BMI. Controlling for BMI, the relative reinforcing value of reading (RRVreading) and proportion of African ancestry, RRVfood predicted 14.2% of the variance in energy intake, as well as predicted carbohydrate, fat, protein and sugar intake. In individual analyses, six FTO SNPs (rs12921970, rs9936768, rs12446047, rs7199716, rs8049933 and rs11076022, spanning approximately 251kbp) moderated the relationship between RRVfood and energy intake to predict an additional 4.9-7.4% of variance in energy intake. We created an FTO risk score based on 5 FTO SNPs (rs9939609, rs8050136, rs3751812, rs1421085, and rs1121980) that are related to BMI in multiple studies. The FTO risk score did not increase variance accounted for beyond individual FTO SNPs. rs12921970 and rs12446047 served as moderators of the relationship between RRVfood and carbohydrate, fat, protein, and sugar intake. This study shows for the first time that the relationship between RRVfood and energy intake is moderated by FTO SNPs. Research is needed to understand how these processes interact to predict energy and macronutrient intake. PMID- 24768650 TI - Modulatory effect of 17-beta estradiol on performance of ovariectomized rats on the Shock-Probe test. AB - 17-beta estradiol (E2) has been shown to modulate fear conditioning by influencing freezing behavior following re-exposure to either the conditioning context or a cue associated with shock. Fear-related behaviors other than freezing may be influenced differently by E2 replacement. Accordingly, the present study examined whether E2 modulates fear conditioning using the Shock Probe test, which allows for the observation of multiple fear responses. Ovariectomized (OVX) rats were divided into three groups: no E2 replacement (Shock-Oil; 0.1ml/kg sesame oil), high E2 replacement (Shock-E2; 3 daily doses of 10MUg/kg, s.c.), and a no shock, no E2 replacement (Naive-oil) group. During the acquisition phase, the two shock groups (Shock-Oil and Shock-E2) demonstrated comparable fear expression on all measures. During the retention tests, rats without E2 replacement demonstrated intact contextual-fear conditioning but impaired cued-fear conditioning, while rats with E2 replacement demonstrated the opposite pattern. In the context paired with shock, the Shock-Oil group spent more time burying the probe than both the Naive-oil group and Shock-E2 group. The Shock-E2 group avoided the probe area relative to the other two groups when tested in the context unpaired with shock. The present findings demonstrate the importance of using multiple behaviors to measure fear conditioning and suggest that high E2 replacement impairs contextual and facilitates cued fear conditioning. PMID- 24768651 TI - Conditioned mate-guarding behavior in the female rat. AB - Female and male rats are often described as having a promiscuous mating strategy, yet simple Pavlovian conditioning paradigms, in which a neutral odor or strain related cues are paired with preferred sexual reward states during an animal's first sexual experiences, shift this strategy toward copulatory and mate preferences for partners bearing the familiar odor or strain cue. We examined whether female rats given exclusive rewarding copulation with one particular male would display mate-guarding behavior, a strong index of monogamous mating. Ovariectomized, hormone-primed female Long-Evans rats were given their first 10 paced sexual experiences at 4-day intervals with a particular unscented male of the same strain. A final test was conducted in an open field 4-days later in which the primed, partnered female was given access to the male partner and a fully-primed competitor female. In this situation, the partnered females mounted the competitor female repeatedly if she came near the vicinity of the male. This behavior prevented the male from copulating with the competitor, and was not displayed if partnered females could not pace the rate of copulatory behavior efficiently during the training trials, nor was it displayed by the competitor females. Fos expression was examined in both the partnered and competitor females after the final open field test. Partnered females had significantly higher expression within the supraoptic nucleus and nucleus accumbens shell compared to partnered females that did not develop this behavior or competitor females. These data show that females engaged in paced copulation with the same male display mate-guarding when exposed to that male and a competitor female. Increased activation of the SON and NAc may underlie this behavior. PMID- 24768652 TI - Molecular profiling of contact dermatitis skin identifies allergen-dependent differences in immune response. AB - BACKGROUND: Allergic contact dermatitis (ACD) is the most common occupational disease. Although murine contact hypersensitivity provides a framework for understanding ACD, it carries important differences from its human counterpart. Unlike the contact hypersensitivity model, which is induced by potent sensitizers (ie, dinitrofluorobenzene), human ACD is induced by weak-to-moderate sensitizers (ie, nickel), which cannot induce reactions in mice. Distinct hapten-specific immune-polarizing responses to potent inducers were suggested in mice, with unclear relevance to human ACD. OBJECTIVE: We explored the possibility of distinct T-cell polarization responses in skin to common clinically relevant ACD allergens. METHODS: Gene-expression and cellular studies were performed on common allergens (ie, nickel, fragrance, and rubber) compared with petrolatum-occluded skin, using RT-PCR, gene arrays, and immunohistochemistry. RESULTS: Despite similar clinical reactions in all allergen groups, distinct immune polarizations characterized different allergens. Although the common ACD transcriptome consisted of 149 differentially expressed genes across all allergens versus petrolatum, a much larger gene set was uniquely altered by individual allergens. Nickel demonstrated the highest immune activation, with potent inductions of innate immunity, TH1/TH17 and a TH22 component. Fragrance, and to a lesser extent rubber, demonstrated a strong TH2 bias, some TH22 polarization, and smaller TH1/TH17 contributions. CONCLUSIONS: Our study offers new insights into the pathogenesis of ACD, expanding the understanding of T-cell activation and associated cytokines in allergen-reactive tissues. It is the first study that defines the common transcriptome of clinically relevant sensitizers in human skin and identifies unique pathways preferentially activated by different allergens, suggesting that ACD cannot be considered a single entity. PMID- 24768653 TI - [Comparison of level of satisfaction of users of home care: integrated model vs. dispensaries model]. AB - OBJECTIVE: To determine the level of satisfaction of users that receive home health care through two different models of primary health care: integrated model and dispensaries model. DESIGN: cross-sectional, observational study. LOCATION: Two primary care centers in the province of Barcelona. PARTICIPANTS: The questionnaire was administered to 158 chronic patients over 65 years old, of whom 67 were receiving health care from the integrated model, and 91 from the dispensaries model. MAIN MEASUREMENTS: The Evaluation of Satisfaction with Home Health Care (SATISFAD12) questionnaire was, together with other complementary questions about service satisfaction of home health care, as well as social demographic questions (age, sex, disease, etc). RESULTS: The patients of the dispensaries model showed more satisfaction than the users receiving care from the integrated model. There was a greater healthcare continuity for those patients from the dispensaries model, and a lower percentage of hospitalizations during the last year. The satisfaction of the users from both models was not associated to gender, the health perception,or independence of the CONCLUSIONS: The user satisfaction rate of the home care by primary health care seems to depend of the typical characteristics of each organisational model. The dispensaries model shows a higher rate of satisfaction or perceived quality of care in all the aspects analysed. More studies are neede to extrapolate these results to other primary care centers belonging to other institutions. PMID- 24768655 TI - [Attitudes of physicians and nurses towards health prevention and promotion activities in Primary Care]. AB - OBJECTIVE: To determine the attitudes of physicians and registered nurses in the Andalusian Public Health System towards preventive and health promotion (PHP) interventions in the context of Primary Health Care and the relationship with occupational variables and self-reported competence in PHP. DESIGN: Multicenter, observational, descriptive study. LOCATION: Primary Health Care (PHC), Andalusia, Spain. PARTICIPANTS: A total of 282 professionals (physicians and nurses) from 22 Healthcare centers of the Andalusian public health system and who participated in the validation of CAPPAP were included. PRINCIPAL MEASUREMENTS: The attitude of physicians and registered nurses towards PHP activities consisted of five dimensions: improvements necessary, perception of peers attitude, importance, obstacles, and improvement opportunities. The validated CAPPAP questionnaire was used. Occupational variables and questions about self-reported competence in PHP were also included. RESULTS: All dimensions of CAPPAP exceeded the midpoint of the scale (2.5), with their values varying between 3.06 (SD: 0.76) in "improvement necessary", and 4.39 (SD: 0.49) in "importance". The self-declared social, occupational, and competences variables have a statistically significant relationship with the dimensions of the attitude of the professionals except: job experience in PHC, training and implementation of scheduled PHP activities. CONCLUSIONS: The attitudes of physicians and registered nurses towards PHP activities are acceptable, and work must be done to sustain it. Healthcare organizations should implement interventions adapted to different professional profiles. They should also increase activities to improve professional skills in order to provide the appropriate care. PMID- 24768654 TI - [Accesibility and use of spirometry in primary care centers in Catalonia]. AB - OBJECTIVE: Examine the accessibility and use of forced spirometry (FS) in public primary care facilities centers in Catalonia. DESIGN: Cross-sectional study using a survey. PARTICIPANTS: Three hundred sixty-six Primary Care Teams (PCT) in Catalonia. Third quarter of 2010. MEASUREMENTS: Survey with information on spirometers, training, interpretation and quality control, and the priority that the quality of spirometry had for the team. Indicators FS/100 inhabitants/year, FS/month/PCT; FS/month/10,000 inhabitants. MAIN RESULTS: Response rate: 75%. 97.5% of PCT had spirometer and made an average of 2.01 spirometries/100 inhabitants (34.68 spirometry/PCT/month). 83% have trained professionals.>50% centers perform formal training but no information is available on the quality. 70% performed some sort of calibration. Interpretation was made by the family physician in 87.3% of cases. In 68% of cases not performed any quality control of exploration. 2/3 typed data manually into the computerized medical record.>50% recognized a high priority strategies for improving the quality. CONCLUSION: Despite the accessibility of EF efforts should be made to standardize training, increasing the number of scans test and promote systematic quality control. PMID- 24768656 TI - [Effectiveness of institutional policies to prevent adolescent alcohol use: The view of experts and adolescents]. AB - OBJECTIVE: The objective of this study is to obtain the views of a sample of adolescents and experts on adolescence, family, school, local policies and media, regarding the effectiveness of institutional policies to prevent adolescent alcohol use. SETTING: Four educational centers in the province of Seville. Head office of the Alcohol and Society Foundation in Madrid. DESIGN: Qualitative study using the method proposed by Grounded theory (Glaser and Strauss, 1967). METHODOLOGY: Data were collected from 10 discussion groups guided by semistructured interviews. The data were analyzed using Atlas ti 5 software. PARTICIPANTS: A total of 32 national experts and 40 adolescents of both sexes aged 15 to 20 years living in the province of Seville, selected by theoretical intentional sampling. RESULTS: The experts believed that most of the evaluated preventive actions were effective, while adolescents disputed the preventive impact of most of them. Adolescents proposed actions focused on the reduction of supply of alcohol. Experts proposed a mixed model as the most effective strategy to prevent alcohol consumption in adolescents, combining supply and demand reduction policies, depending on specific short and long term objectives. CONCLUSIONS: We have obtained, not only an overview of what is working (or not) from the view of adolescents and experts, but also the key points that should be taken into account for designing effective prevention policies. PMID- 24768658 TI - [Healthy heart: Results of a community education program on cardiovascular health]. AB - OBJECTIVE: To improve the knowledge of the population about heart-healthy habits through a training program supplemented by a web site and community activities. DESIGN: A controlled clinical trial with intervention done through participation in the Cardiovascular Health Training Classroom (CHTC) LOCATION: A town of 80,000 inhabitants. PARTICIPANTS: PATIENTS: both sexes, aged 55 to 70 years, with at least one cardiovascular risk factor (CVRF). INTERVENTION: The intervention group (IG) consisted of patients who participated in the CHTC. Intervention was carried out through a 20-hour presential group course in which a support web site was offered and complementary activities were organized. Classes were taught by three Primary Care nurses. MAIN MEASUREMENTS: The primary endpoint was knowledge of CVRF. The secondary variables were age, sex, CVRF, lifestyle, visits to health centers, pharmaceutical use adherence, and satisfaction with the program. RESULTS: Data from patients in the first 10 courses (n=150) were evaluated. A statistically significant improvement was observed in overall knowledge of CVRF in the IG (87.3% to 100%) compared with control group (GC) (84.5% to 92.7%), p<.001, as well as an improvement in physical activity is (IG: 71.2% to 83.1% versus CG: 72.6% to 78.2%), p=.05. The total number of Primary Care visits (medical and nursing) decreased in the IG more than in the CG. The satisfaction rate of the course was very high. CONCLUSIONS: This experience is effective in improving cardiovascular health knowledge and promoting some healthy habits. PMID- 24768659 TI - [Exploratory factor analysis of the VIDA questionnaire for the evaluation of the instrumental activities of daily living]. PMID- 24768660 TI - Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFbeta-1 signaling. AB - The aims of the present study were to investigate, in diabetes mellitus (DM), the mechanism of NOX4 up-regulation, its link with 5' adenosine monophosphate activated protein kinase (AMPK) inactivation and transforming growth factor (TGF) beta-1 signaling in determining the accumulation of kidney extracellular matrix (ECM), and the possible action of cocoa enriched with polyphenols (CH) in these events. After 16 weeks of DM, spontaneously hypertensive rats showed increased kidney TGFbeta-1 levels and expression of phosphorylated smad2, collagen IV and fibronectin in parallel with elevated NOX4 expression and reduced phosphorylated AMPK. CH treatment in diabetic rats prevented all of these abnormalities. In immortalized human mesangial cells exposed to high glucose (HG), or TGFbeta-1, CH, nicotinamide adenine dinucleotide phosphate blocker, or silencing NOX4 ameliorated enhanced phosphorylated smad2 and collagen IV. Reduction in phosphorylated AMPK induced by HG or TGFbeta-1 was ameliorated by CH or activation of AMPK, which reduced phosphorylation of smad2 and collagen IV via reduction in NOX4 expression. The effects of CH were abolished by AMPK blockade. These results suggest that inactivation in AMPK leads to NOX4 up-regulation, activation of TGFbeta-1 signaling and increased ECM accumulation. Additionally, increased TGF-beta1 per se leads to the amplification of ECM production by reducing AMPK and promoting the activation of NOX4. It is suggested that the activation of AMPK by CH followed by reduction in NOX4/TGFbeta-1 signaling may have a therapeutic potential in diabetic nephropathy. PMID- 24768661 TI - The dietary ingredient, genistein, stimulates cathelicidin antimicrobial peptide expression through a novel S1P-dependent mechanism. AB - We recently discovered that a signaling lipid, sphingosine-1-phosphate (S1P), generated by sphingosine kinase 1, regulates a major epidermal antimicrobial peptide's [cathelicidin antimicrobial peptide (CAMP)] expression via an NF-kappaB >C/EBPalpha-dependent pathway, independent of vitamin D receptor (VDR) in epithelial cells. Activation of estrogen receptors (ERs) by either estrogens or phytoestrogens also is known to stimulate S1P production, but it is unknown whether ER activation increases CAMP production. We investigated whether a phytoestrogen, genistein, simulates CAMP expression in keratinocytes, a model of epithelial cells, by either a S1P-dependent mechanism(s) or the alternate VDR regulated pathway. Exogenous genistein, as well as an ER-beta ligand, WAY-200070, increased CAMP mRNA and protein expression in cultured human keratinocytes, while ER-beta antagonist, ICI182780, attenuated the expected genistein- and WAY-200070 induced increase in CAMP mRNA/protein expression. Genistein treatment increased acidic and alkaline ceramidase expression and cellular S1P levels in parallel with increased S1P lyase inhibition, accounting for increased CAMP production. In contrast, siRNA against VDR did not alter genistein-mediated up-regulation of CAMP. Taken together, genistein induces CAMP production via an ER-beta->S1P->NF kappaB->C/EBPalpha- rather than a VDR-dependent mechanism, illuminating a new role for estrogens in the regulation of epithelial innate immunity and pointing to potential additional benefits of dietary genistein in enhancing cutaneous antimicrobial defense. PMID- 24768663 TI - The underestimated value of OECD 421 and 422 repro screening studies: putting it in the right perspective. AB - To assess the efficacy of reproduction/developmental screening studies (OECD 421 and 422), a retrospective evaluation of 134 studies was performed. The major findings were: (1) for up to half of the studies with developmental and reproductive toxicity, these effects would have been missed in other types of studies, which underscores that reproduction/developmental screening studies should not be waived by default based on negative 28-day and/or prenatal developmental data, (2) the required number of animals as stated in the guidelines, is appropriate for detecting developmental and reproductive toxicity, and (3) adding measurements like anogenital distance, internal sex determination and nipple retention, plus extending the postnatal period would add predictive value. Overall, the current reproduction/developmental screening studies are effective in providing unique data, especially considering the limited number of animals used. Some simple additions would enrich its value in risk assessment even further. PMID- 24768657 TI - Effectiveness of two types of intervention on antibiotic prescribing in respiratory tract infections in Primary Care in Spain. Happy Audit Study. AB - OBJECTIVE: To evaluate the effectiveness of two types of intervention in reducing antibiotic prescribing in respiratory tract infections (RTI). DESIGN: Before after audit-based study. SETTING: Primary Care centres in Spain. PARTICIPANTS: General practitioners (GPs) registered all patients with RTIs for 15 days in winter 2008 (pre-intervention), and again in winter 2009 (post-intervention). INTERVENTIONS: Intervention activities included meetings, with the presentation and discussion of the results, and several training meetings on RTI guidelines, information brochures for patients, workshops on point-of-care tests - rapid antigen detection tests and C-reactive protein rapid test - and provision of these tests in the clinic. All GPs, with the exception of those in Catalonia, made up the full intervention group (FIG); conversely, Catalan doctors underwent the same intervention, except for the workshop on rapid tests (partial intervention group, PIG). Multilevel logistic regression was performed taking the prescription of antibiotics as the dependent variable. RESULTS: Out of a total of 309 GPs involved in the first register, 281 completed the intervention and the second register (90.9%), of which 210 were assigned to the FIG, and 71 to the PIG. The odds ratio of antibiotic prescribing after the intervention was 0.99 (95% CI: 0.89-1.10) among GPs assigned to PIG, and 0.50 (95% CI: 0.44-0.57, p<0.001) among those who were allocated to FIG. The reduction in antibiotic prescribing in FIG was more marked in flu infection, common cold, acute pharyngitis, acute tonsillitis, and acute bronchitis. CONCLUSIONS: Active participation of GPs with the performance of point-of-care tests in the clinic is accompanied by a drastic reduction of antibiotic use in RTIs, primarily in infections considered as mainly viral. PMID- 24768662 TI - Microglia toxicity in preterm brain injury. AB - Microglia are the resident phagocytic cells of the central nervous system. During brain development they are also imperative for apoptosis of excessive neurons, synaptic pruning, phagocytosis of debris and maintaining brain homeostasis. Brain damage results in a fast and dynamic microglia reaction, which can influence the extent and distribution of subsequent neuronal dysfunction. As a consequence, microglia responses can promote tissue protection and repair following brain injury, or become detrimental for the tissue integrity and functionality. In this review, we will describe microglia responses in the human developing brain in association with injury, with particular focus on the preterm infant. We also explore microglia responses and mechanisms of microglia toxicity in animal models of preterm white matter injury and in vitro primary microglia cell culture experiments. PMID- 24768664 TI - Hookworm infestation as unexpected cause of recurrent pancreatitis. AB - Parasite infestation is still associated with significant morbidity and mortality. Hookworm infestation is a very rare cause of pancreatitis. This parasitic infestation might be asymptomatic. Acute pancreatitis as a result of the hookworms migrating into the ampulla of Vater with chronic inflammation was a very rare complication. Were port a case of hookworm infestation that was associated with significant complication of recurrent pancreatitis. The patient was treated with mebendazole. He was asymptomatic and had gained weight at the 3 month follow-up. Our case demonstrates that pancreatitis secondary to hookworm infection can occur and may resolve after anthelmintic treatment. PMID- 24768665 TI - Red cell distribution width as a predictor of mortality in organophosphate insecticide poisoning. AB - OBJECTIVE: Suicide by organophosphate insecticide (OPI) poisoning is a major clinical concern (predominantly in developing countries), and 200000 deaths occur annually worldwide. Red cell distribution width (RDW) has been used to predict outcome in several clinical conditions. Here, we aimed to investigate the relationship between the RDW and 30-day mortality during OPI poisoning. METHODS: This retrospective analysis was performed between January 2008 and July 2013 in patients admitted to the emergency department after OPI poisoning. A Kaplan-Meier 30-day survival curve was analyzed in patients stratified according to the optimal cut-off point of RDW defined using a receiver operating characteristic (ROC) curve. Multivariate Cox proportional hazards analyses were conducted to determine the independent prognostic factors for 30-day mortality. RESULTS: Among 102 patients, 21 died, yielding a mortality of 20.6%. Elevated RDW was significantly associated with early mortality in patients with OPI poisoning. Levels of RDW that exceeded 13.5% (hazard ratio, 2.64; 95% confidence interval [CI], 1.05-6.60) were associated with increased mortality in the multivariate analysis. The area under the ROC curve of RDW was 0.675 (95% CI, 0.522-0.829). CONCLUSIONS: This study showed that RDW is an independent predictor of 30-day mortality in patients with OPI poisoning. PMID- 24768666 TI - A systematic review of smoking cessation interventions in the emergency setting. AB - STUDY OBJECTIVE: Cigarette smoking remains the leading cause of preventable death in the United States, and tobacco use rates are known to be higher among emergency department (ED) patients than in the general population. Despite recommendations from the Society for Academic Emergency Medicine and the American College of Emergency Physicians, many emergency clinicians remain uncertain about the benefits of providing ED-based smoking cessation interventions. To address this gap in knowledge, we performed a systematic review of cessation interventions initiated in the adult or pediatric ED setting. METHODS: We conducted an electronic search of the MEDLINE and CINAHL databases through February 2014 and hand searched references from potentially relevant articles. We identified eligible studies, evaluated bias and validity, and extracted data and synthesized findings. RESULTS: Seventeen studies underwent critical appraisal, with 13 included in qualitative synthesis. The majority (11/13, 85%) of investigations did not report significant differences in tobacco abstinence between cessation intervention groups. The 2 studies reporting significant differences in cessation both used motivational interviewing-based interventions. Two studies evaluated patient satisfaction with ED-based tobacco cessation interventions, and both reported greater than 90% satisfaction. CONCLUSIONS: Findings indicate that ED visits in combination with ED-initiated tobacco cessation interventions are correlated with higher cessation rates than those reported in the National Health Interview Survey. Clear data supporting the superiority of one intervention type were not identified. Lack of a standardized control group prevented quantitative evaluation of pooled data, and future research is indicated to definitively evaluate intervention efficacy. PMID- 24768667 TI - Long-term prognostic value of stress echocardiography in patients presenting to the ED with spontaneous chest pain. AB - PURPOSE: The aims of this study were to evaluate the long-term prognostic value of stress echocardiography (SE) in patients evaluated in emergency department (ED) and to determine SE parameters that best predicted outcome. METHODS: Between June 2008 and July 2012, 626 patients with an episode of spontaneous chest pain underwent SE (exercise stress echocardiography or dobutamine stress echocardiography [DSE]). Between December 2012 and January 2013, all patients were contacted to verify the occurrence of cardiac events. Patients were divided in 3 subgroups according to peak stress Wall Motion Score Index (pWMSI): normal peak wall motion (pWMSI, 1; group A1), mild to moderate peak asynergy (pWMSI, 1.1 1.7; group A2), and severe peak asynergy (pWMSI, >1.7; group A3). RESULTS: Stress echocardiography showed inducible ischemia in 159 patients (25%); it was negative in 425 (68%) and inconclusive in 42 (7%). Patients with cardiac events more frequently showed inducible ischemia (50% vs 26%; P = .015) compared with patients with good prognosis; a normal SE (14% vs 61%) was significantly less common. At a multivariate regression analysis, an increased pWMSI (relative risk: 9.816, 95% confidence interval: 3.665-26.290; P < .0001) was independently associated with a bad outcome. Cumulative event-free survival was significantly worse with an increasing degree of peak wall motion asynergy (99% in group A1; 96%, group A2; and 88% in group A3; P = .011 between A1 and A2 groups, P = .012 between A2 and A3 groups, and P < .0001 between A1 and A3 groups). CONCLUSIONS: Stress echocardiography showed an optimal prognostic value among ED patients evaluated for chest pain. The presence of an extensive asynergic area at peak stress was associated with an adverse prognosis. PMID- 24768668 TI - Free phenytoin toxicity. AB - Phenytoin has a narrow therapeutic window, and when managing cases of toxicity, clinicians are very wary of this fact. Typically, if patient presents with symptoms suggestive of phenytoin toxicity, total serum phenytoin is promptly ordered. That could be falsely low especially in elderly or critically ill patients, which may lead to a low albumin level resulting in this discrepancy. The free phenytoin can be best estimated using the Sheiner-Tozer equation. Herein, we describe a case of an elderly male patient who presented with drowsiness, gait changes, and elevated liver enzymes and a normal total serum phenytoin level of 18 ng/dL (normal, 10-20 ng/dL).After taking his albumin level into account, his free phenytoin level was calculated to be 27 ng/dL, and the phenytoin was discontinued leading to resolution of his symptoms as well as a return of his liver function panel values to baseline. PMID- 24768669 TI - Wax on, wax off: a rare case of catatonia. AB - Catatonia was first described by a German psychiatrist, Karl Kahlbaum, in 1874. It is a behavioral syndrome marked by an inability to move normally, which can occur in the context of many underlying general medical and psychiatric disorders. A wide variety of neurologic, metabolic, drug-induced, and psychiatric causes of catatonia have been reported. We present a unique case of late onset catatonia in a 56-year-old man with no prior medical or psychiatric history initially presenting with stroke-like symptoms. The patient was awake and alert, with spontaneous eye opening, but completely nonverbal and not following any commands. Specifically, the patient demonstrated stupor, catalepsy, mutism, and negativism. After extensive emergency department testing, including negative computed tomography head, negative magnetic resonance imaging brain, negative electroencephalogram, and normal laboratory results, the patient was diagnosed with new-onset bipolar disorder with depressive features presenting as catatonia. Recognizing catatonia is important because it may be caused or exacerbated by treatment of the underlying disorder. Failure to institute treatment early in the course of catatonia is associated with a poor prognosis. PMID- 24768670 TI - Endogenous Klebsiella pneumoniae endophthalmitis. AB - Klebsiella pneumonia is a common human pathogen, and endogenous endophthalmitis is a vision-threatening infection presentedwith pain, redness, decreased vision acuity, and intraocular inflammation. Endogenous endophthalmitis caused by Klebsiella pneumoniae is uncommon and usually happens in patients with immunosuppression conditions. Diabetes is a predisposing risk factor, and liver abscess is a major source of Klebsiella pneumonia endogenous endophthalmitis (KPEE). Here, we report a case of KPEE in a patient who lost his vision in one eye after treatment. PMID- 24768671 TI - Bun/creatinine ratio-based hydration for preventing stroke-in-evolution after acute ischemic stroke. AB - BACKGROUND: Blood urea nitrogen (BUN)/creatinine (Cr) ratio was recently reported to be an independent predictor of stroke-in-evolution (SIE) among patients who had suffered acute ischemic stroke. We aim to determine if providing hydration therapy to patients with a BUN/Cr >=15 reduces the occurrence of SIE after acute ischemic stroke. METHODS: This prospective interventional study included 189 patients (hydration group, n = 92; control group, n = 97) with acute ischemic stroke and a BUN/Cr >=15. Hydration group received intravenous bolus (300-500 mL) saline followed by a maintenance saline infusion (40-80 mL/h for the first 72 h), while control group received maintenance saline infusion (40-60 mL/h for the first 24 h and 0-60 mL/h for 24-72 h). The study endpoint was the proportion of patients who developed SIE within the first three days of emergency department admission. RESULTS: There were no significant differences in demographic or clinical characteristics between both groups. Patients in the hydration group received a significantly larger (all P < 0.001) median volume of infused saline than patients in the control group on Days 1 (2400 vs 1440 mL), 2 (1440 vs 0 mL), and 3 (1000 vs 0 mL). The proportion of patients who experienced SIE was significantly lower in the hydration group (9/92; 9.8%) compared with the control group (21/97; 21.6%) (Fig. 1, P = 0.026). CONCLUSIONS: Our preliminary findings suggest that providing patients with acute ischemic stroke hydration therapy on the basis of their presenting BUN/Cr ratio may help reduce the occurrence of SIE and therefore improve prognosis. PMID- 24768672 TI - Transient reporter gene expression in oocysts and sporozoites of Cryptosporidium parvum controlled by endogenous promoters. AB - The apicomplexan protozoan Cryptosporidium parvum is an enteric parasite that affects a variety of mammal hosts including humans, and causes serious diarrheal disease in immunocompromised individuals, notably AIDS patients. Despite many advances in the development of transgenic techniques in many protozoan parasites over the past two decades, rare reports have been documented on the genetic manipulation on C. parvum. Achievement of the DNA-based transfection chiefly depends on the selection of an effective parasite genus-specific promoter. This report described the successful yellow (YFP-YFP) or red (RFP) fluorescent protein expression in oocysts and sporozoites of C. parvum controlled by the endogenous promoters of actin, alpha tubulin, and myosin genes using the restricted enzyme mediated integration technique. One expression cassette in pBluescript backbone, YFP-YFP or RFP fused between 5' and 3' untranslated regions of actin gene, displayed the highest transfection efficiency with fluorescence rate around 50%. The established DNA-based transient transfection assay may contribute to a better understanding of the biology of Cryptosporidium species and their relationship with hosts and may also result in the development of more efficient molecule based vaccines and drugs. PMID- 24768673 TI - Evolution of the melanocortin system. AB - The melanocortin system is one of the most complex of the hormonal systems. It involves different agonists encoded in the multiplex precursor proopiomelanocortin (POMC) or in different genes as beta-defensins, endogenous antagonist, like agouti-signalling protein (ASIP) or agouti-related protein (AGRP), and five different melanocortin receptors (MCRs). Rounds of whole genome duplication events have preceded the functional and molecular diversification of the family in addition some co-evolutionary and tandem duplication processes have been proposed. The evolutionary patterns of the different partners are controversial and different hypotheses have emerged from a study of the sequenced genomes. In this review, we summarize the different evolutionary hypotheses proposed for the different melanocortin partners. PMID- 24768674 TI - Circulating breeding and pre-breeding prolactin and LH are not associated with clutch size in the zebra finch (Taeniopygia guttata). AB - Clutch size is a fundamental predictor of avian fitness, widely-studied from evolutionary and ecological perspectives, but surprisingly little is known about the physiological mechanisms regulating clutch size variation. The only formal mechanistic hypothesis for avian clutch-size determination predicts an anti gonadal effect of circulating prolactin (PRL) via the inhibition of luteinizing hormone (LH), and has become widely-accepted despite little experimental support. Here we investigated the relationship between pre-breeding and breeding plasma PRL and LH and clutch-size in captive-breeding female zebra finches (Taeniopygia guttata). Using a repeated-measures design, we followed individual females from pre-breeding, through multiple breeding attempts, and attempted to decrease PRL using the D2-receptor agonist, bromocriptine. Clutch size was independent of variation in pre-breeding PRL or LH, although pre-breeding LH was negatively correlated with the time between pairing and the onset of laying. Clutch size was independent of variation in plasma PRL on all days of egg-laying. Bromocriptine treatment had no effect on plasma PRL, but in this breeding attempt clutch size was also independent of plasma PRL. Finally, we found no evidence for an inverse relationship between plasma PRL and LH levels, as predicted if PRL had inhibitory effects via LH. Thus, our data fail to provide any support for the involvement of circulating PRL in clutch size determination. These findings suggest that alternative models for hormonal control of avian clutch size need to be considered, perhaps involving downstream regulation of plasma PRL at the level of the ovary, or other hormones that have not been considered to date. PMID- 24768675 TI - Approach to presenting a clinical journal club. PMID- 24768676 TI - Kinetic analyses reveal potent and early blockade of hepatitis C virus assembly by NS5A inhibitors. AB - BACKGROUND & AIMS: All-oral regimens combining different classes of direct-acting antivirals (DAA) are highly effective for treatment of patients with chronic hepatitis C. NS5A inhibitors will likely form a component of future interferon sparing treatment regimens. However, despite their potential, the detailed mechanism of action of NS5A inhibitors is unclear. To study their mechanisms, we compared their kinetics of antiviral suppression with those of other classes of DAA, using the hepatitis C virus genotype 1a cell culture-infectious virus H77S.3. METHODS: We performed detailed kinetic analyses of specific steps in the hepatitis C virus life cycle using cell cultures incubated with protease inhibitors, polymerase inhibitors, or NS5A inhibitors. Assays were designed to measure active viral RNA synthesis and steady-state RNA abundance, polyprotein synthesis, virion assembly, and infectious virus production. RESULTS: Despite their high potency, NS5A inhibitors were slow to inhibit viral RNA synthesis compared with protease or polymerase inhibitors. By 24 hours after addition of an NS5A inhibitor, polyprotein synthesis was reduced <50%, even at micromolar concentrations. In contrast, inhibition of virus release by NS5A inhibitors was potent and rapid, with onset of inhibition as early as 2 hours. Cells incubated with NS5A inhibitors were rapidly depleted of intracellular infectious virus and RNA-containing hepatitis C virus particles, indicating a block in virus assembly. CONCLUSIONS: DAAs that target NS5A rapidly inhibit intracellular assembly of genotype 1a virions. They also inhibit formation of functional replicase complexes, but have no activity against preformed replicase, thereby resulting in slow shut-off of viral RNA synthesis. PMID- 24768679 TI - When should the beta-blocker window in cirrhosis close? PMID- 24768678 TI - Efficacy, dose reduction, and resistance to high-dose fluticasone in patients with eosinophilic esophagitis. AB - BACKGROUND & AIMS: We evaluated the efficacy and safety of high-dose swallowed fluticasone propionate (FP) and dose reduction in patients with eosinophilic esophagitis (EoE) and analyzed esophageal transcriptomes to identify mechanisms. METHODS: We conducted a randomized, multisite, double-blind, placebo-controlled trial of daily 1760 mcg FP in participants age 3-30 years with active EoE. Twenty eight participants received FP, and 14 participants received placebo. After 3 months, participants given FP who were in complete remission (CR) received 880 mcg FP daily, and participants in the FP or placebo groups who were not in CR continued or started, respectively, 1760 mcg FP daily for 3 additional months. The primary end point was histologic evidence for CR. Secondary end points were partial remission (PR), symptoms, compliance, esophageal gene expression, esophageal eosinophil count, and the relationship between clinical features and FP responsiveness. RESULTS: After 3 months, 65% of subjects given FP and no subjects given placebo were in CR (P = .0001); 12% of those given FP and 8% of those given placebo were in PR. In the FP group, 73% of subjects remained in CR, and 20% were in PR after the daily dose was reduced by 50%. Extending FP therapy in FP-resistant participants did not induce remission. FP decreased heartburn severity (P = .041). Compliance, age, sex, atopic status, or anthropomorphic features were not associated with response to FP. Gene expression patterns in esophageal tissues of FP responders were similar to those of patients without EoE; there was evidence for heterogeneous steroid signaling in subjects who did not respond to FP and preliminary evidence for transcripts predictive of FP responsiveness. CONCLUSIONS: Daily administration of a high dose of FP induces histologic remission in 65%-77% of patients with EoE after 3 months. A 50% dose reduction remained effective in 73%-93% of patients who initially responded to FP. Nonresponders had evidence of steroid resistance; histologic and molecular markers may predict resistance. Clinicaltrials.gov number: NCT00426283. PMID- 24768680 TI - Low rate of large polyps (>9 mm) within 10 years after an adequate baseline colonoscopy with no polyps. AB - BACKGROUND & AIMS: Guidelines recommend a 10-year interval between screening colonoscopies with negative results for average-risk individuals. However, many patients are examined at shorter intervals. We investigated outcomes of individuals with no polyps who had repeat colonoscopy in <10 years. METHODS: Data were collected using the National Endoscopic Database, from 69 gastroenterology centers, on 264,184 asymptomatic subjects who underwent screening colonoscopies from 2000 through 2006, were found to have no polyps, and received another colonoscopy examination within <10 years. RESULTS: No polyps were found in 147,375 patients during a baseline colonoscopy; 17,525 patients (11.9%) had a follow-up colonoscopy within <10 years, including 1806 (10.3%) who received the follow-up colonoscopy within <1 year. The most common reason for repeating the examination within 1 year was that the first was compromised by inadequate bowel preparation or incomplete examination. Of these patients, 6.5% (95% confidence interval: 5.3-7.6) had large polyp(s) >9 mm-a proportion similar to the prevalence in the average-risk screening population. Reasons that examinations were repeated within 1-5 years included average-risk screening (15.7%), family history of colon polyps or cancer (30.1%), bleeding (31.2%), gastrointestinal symptoms (11.8%), or a positive result from a fecal blood test (5.5%). If the baseline examination was adequate, the incidence of large polyps within 1-5 years after baseline colonoscopy was 3.1% (95% confidence interval: 2.7-3.5) and within years 5-10 years was 3.7% (95% confidence interval: 3.3-4.1). CONCLUSIONS: Repeat colonoscopies within 10 years are of little benefit to patients who had adequate examinations and were found to have no polyps. Repeat colonoscopies are beneficial to patients when the baseline examination was compromised. PMID- 24768681 TI - Retinoic acid signaling and mouse embryonic stem cell differentiation: Cross talk between genomic and non-genomic effects of RA. AB - Retinoic acid (RA), the active derivative of vitamin A, a fat-soluble vitamin, plays key roles in cell growth and differentiation by activating nuclear receptors, RARs (alpha, beta and gamma), which are ligand dependent regulators of transcription. The past years highlighted several novelties in the field that increased the complexity of RA effects. Indeed, in addition to its classical genomic effects, RA also has extranuclear and non-transcriptional effects. RA induces the rapid and transient activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of RARs at a conserved serine residue located in the N-terminal domain and their coregulators. In order to investigate the relevance of RARs' phosphorylation in cell differentiation, mouse embryonic stem (mES) cells were used as a model. When treated with RA, these pluripotent cells give rise to neuronal cells. Cells invalidated for each RAR were generated as well as stable rescue lines expressing RARs mutated in phosphor acceptor sites. Such a strategy revealed that RA-induced neuronal differentiation involves the RARgamma2 subtype and requires RARgamma2 phosphorylation. Moreover, in gene expression profiling experiments, the phosphorylated form of RARgamma2 was found to regulate a small subset of genes through binding a novel RA response element consisting of two direct repeats with a 7 base pair spacer. These new findings suggest an important role for RAR phosphorylation during cell differentiation, and pave the way for further investigations with other cell types and during embryonic development. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. PMID- 24768677 TI - Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. AB - BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 * 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 * 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 * 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 * 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 * 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases. PMID- 24768682 TI - Genetic diversity of VAR2CSA ID1-DBL2Xb in worldwide Plasmodium falciparum populations: impact on vaccine design for placental malaria. AB - In placental malaria (PM), sequestration of infected erythrocytes in the placenta is mediated by an interaction between VAR2CSA, a Plasmodium falciparum protein expressed on erythrocytes, and chondroitin sulfate A (CSA) on syncytiotrophoblasts. Recent works have identified ID1-DBL2Xb as the minimal CSA binding region within VAR2CSA able to induce strong protective immunity, making it the leading candidate for the development of a vaccine against PM. Assessing the existence of population differences in the distribution of ID1-DBL2Xb polymorphisms is of paramount importance to determine whether geographic diversity must be considered when designing a candidate vaccine based on this fragment. In this study, we examined patterns of sequence variation of ID1-DBL2Xb in a large collection of P. falciparum field isolates (n=247) from different malaria-endemic areas, including Africa (Benin, Senegal, Cameroon and Madagascar), Asia (Cambodia), Oceania (Papua New Guinea), and Latin America (Peru). Detection of variants and estimation of their allele frequencies were performed using next-generation sequencing of DNA pools. A considerable amount of variation was detected along the whole gene segment, suggesting that several allelic variants may need to be included in a candidate vaccine to achieve broad population coverage. However, most sequence variants were common and extensively shared among worldwide parasite populations, demonstrating long term persistence of those polymorphisms, probably maintained through balancing selection. Therefore, a vaccine mixture including such stable antigen variants will be putatively applicable and efficacious in all world regions where malaria occurs. Despite similarity in ID1-DBL2Xb allele repertoire across geographic areas, several peaks of strong population differentiation were observed at specific polymorphic loci, pointing out putative targets of humoral immunity subject to positive immune selection. PMID- 24768683 TI - Polymorphisms and ambiguous sites present in DNA sequences of Leishmania clones: looking closer. AB - In genetic studies of Leishmania parasites, co-dominant markers are chosen for their ability to detect heterozygous polymorphisms, to infer the occurrence of inbreeding and to resolve genetic variability. The majority of DNA sequence based reports perform conventional dye terminator cycle sequencing where perfectly ambiguous sites or double peaks in the chromatogram are interpreted as heterozygous strains. However, molecular peculiarities of the parasite such as aneuploidy, mixed populations and homologous recombination advise that data from regular DNA sequence analysis should be carefully evaluated. We report here a closer look at ambiguous sites observed in 6pgd DNA sequences obtained for a multilocus sequence analysis project on Leishmania (Viannia) strains. After comparing 286 DNA sequences from biological and molecular clones of six L. (Viannia) strains we could distinguish events that contribute to genetic variation in Leishmania (recombination, mutation, chromosomal mosaics). Also, the results suggest how diversity might not be completely revealed through regular DNA sequence analysis and demonstrate the importance for molecular epidemiology research to be aware of such possibilities while choosing samples for studies. PMID- 24768684 TI - First report of the prevalence of extended-spectrum beta-lactamase producing Escherichia coli in two Mongolian hospitals. PMID- 24768685 TI - Vitamin A increases nerve growth factor and retinoic acid receptor beta and improves diabetic neuropathy in rats. AB - All-trans retinoic acid (ATRA) promotes the endogenous expression of both nerve growth factor (NGF) and retinoic acid receptor beta (RAR-beta). We have previously shown that the administration of ATRA partly reverts the damage induced by diabetic neuropathy (DN). In this investigation, we evaluated the effects of vitamin A, a commercial, inexpensive compound of retinoic acid, on the therapy of DN. A total of 70 rats were randomized into 4 groups. Group A was the control, and groups B, C, and D received a total dose of 60 mg/kg streptozotocin intraperitoneally. When signs of DN developed, groups C and D were treated either with vitamin A (20,000 IU) or with ATRA 25 mg/kg for 60 days. Plasma glucose, contents of NGF, thermal and nociceptive tests, and RAR-beta expression were evaluated. All diabetic rats developed neuropathy. The treatment with vitamin A and ATRA reverted similarly the sensorial disturbances, which was associated with increased contents of NGF and RAR-beta expression. Our results indicate that the administration of vitamin A has the same therapeutic effect as ATRA on peripheral neuropathy and suggest its potential therapeutic use in patients with diabetes. PMID- 24768686 TI - RNA epigenetics. AB - Mammalian messenger RNA (mRNA) and long noncoding RNA (lncRNA) contain tens of thousands of posttranscriptional chemical modifications. Among these, the N(6) methyl-adenosine (m(6)A) modification is the most abundant and can be removed by specific mammalian enzymes. m(6)A modification is recognized by families of RNA binding proteins that affect many aspects of mRNA function. mRNA/lncRNA modification represents another layer of epigenetic regulation of gene expression, analogous to DNA methylation and histone modification. PMID- 24768687 TI - Technical guide for genetic advancement of underdeveloped and intractable Clostridium. AB - In recent years, the genus Clostridium has risen to the forefront of both medical biotechnology and industrial biotechnology owing to its potential in applications as diverse as anticancer therapy and production of commodity chemicals and biofuels. The prevalence of hyper-virulent strains of C. difficile within medical institutions has also led to a global epidemic that demands a more thorough understanding of clostridial genetics, physiology, and pathogenicity. Unfortunately, Clostridium suffers from a lack of sophisticated genetic tools and techniques which has hindered the biotechnological exploitation of this important bacterial genus. This review provides a comprehensive summary of biotechnological progress made in clostridial genetic tool development, while also aiming to serve as a technical guide for the advancement of underdeveloped clostridial strains, including recalcitrant species, novel environmental samples, and non-type strains. Relevant strain engineering techniques, from genome sequencing and establishment of a gene transfer methodology through to deployment of advanced genome editing procedures, are discussed in detail to provide a blueprint for future clostridial strain construction endeavors. It is expected that a more thorough and rounded-out genetic toolkit available for use in the clostridia will bring about the construction of superior bioprocessing strains and a more complete understanding of clostridial genetics, physiology, and pathogenicity. PMID- 24768688 TI - A new insect cell glycoengineering approach provides baculovirus-inducible glycogene expression and increases human-type glycosylation efficiency. AB - Insect cells are often glycoengineered using DNA constructs encoding foreign glyocoenzymes under the transcriptional control of the baculovirus immediate early promoter, ie1. However, we recently found that the delayed early baculovirus promoter, 39K, provides inducible and higher levels of transgene expression than ie1 after baculovirus infection (Lin and Jarvis, 2013). Thus, the purpose of this study was to assess the utility of the 39K promoter for insect cell glycoengineering. We produced two polyclonal transgenic insect cell populations in parallel using DNA constructs encoding foreign glycoenzymes under either ie1 (Sfie1SWT) or 39K (Sf39KSWT) promoter control. The surface of Sfie1SWT cells was constitutively sialylated, whereas the Sf39KSWT cell surface was only strongly sialylated after baculovirus infection, indicating Sf39KSWT cells were inducibly-glycoengineered. All nine glycogene-related transcript levels were induced by baculovirus infection of Sf39KSWT cells and most reached higher levels in Sf39KSWT than in Sfie1SWT cells at early times after infection. Similarly, galactosyltransferase activity, sialyltransferase activity, and sialic acid levels were induced and reached higher levels in baculovirus-infected Sf39KSWT cells. Finally, two different recombinant glycoproteins produced by baculovirus infected Sf39KSWT cells had lower proportions of paucimannose-type and higher proportions of sialylated, complex-type N-glycans than those produced by baculovirus-infected Sfie1SWT cells. Thus, the 39K promoter provides baculovirus inducible expression of foreign glycogenes, higher glycoenzyme activity levels, and higher human-type N-glycan processing efficiencies than the ie1 promoter, indicating that this delayed early baculovirus promoter has great utility for insect cell glycoengineering. PMID- 24768690 TI - Memory enhancement and erasure. PMID- 24768689 TI - Molecular and biochemical characterizations of three fructose-1,6-bisphosphate aldolases from Clonorchis sinensis. AB - Fructose-1,6-bisphosphate aldolase (FbA) is a ubiquitous enzyme in glycolysis. In the present study, we screened out three distinct genes encoding FbA isozymes (CsFbAs, CsFbA-1/2/3) from Clonorchis sinensis (C. sinensis) and characterized their sequences and structures profiles as well as biochemical properties. The amino acid sequences of CsFbAs shared homology with those of Class I FbAs from other species. The putative quaternary structures revealed that CsFbA-2 and CsFbA 3 were tetramers, while CsFbA-1 was dimer. Recombinant CsFbA-2 and CsFbA-3 (rCsFbA-2/3) were confirmed to be Class I FbAs for their stable enzymatic activities in the presence of EDTA or metal ions. However, recombinant CsFbA-1 (rCsFbA-1) did not show the catalytic activity, which might be due to the inappropriate fold and interaction between its subunits. Both rCsFbA-2 and rCsFbA 3 showed similar enzymatic properties such as optimal temperatures and broad pH ranges that similar to human FbA isozymes. They showed relatively higher affinities for fructose-1,6-bisphosphate (FBP) than fructose-1-phosphate (F-1-P). Their kcat ratios of FBP to F-1-P were in accordance with those of human FbA-A or C. In addition, CsFbAs were differentially transcribed in the developmental stages of C. sinensis, suggesting their essential roles throughout the life stages. Extensive distribution of CsFbAs in adult worms indicated that ubiquitous activities of CsFbAs took place in these organs. Collectively, these results suggested that long-term parasitic environment might adapt these isozymes similar to host FbAs for metabolic requirement. Our study will provide new insight into CsFbAs in the glycometabolism of C. sinensis and relationship between the host and the parasite. PMID- 24768692 TI - Successful execution of working memory linked to synchronized high-frequency gamma oscillations. AB - Neuronal oscillations have been hypothesized to play an important role in cognition and its ensuing behavior, but evidence that links a specific neuronal oscillation to a discrete cognitive event is largely lacking. We measured neuronal activity in the entorhinal-hippocampal circuit while mice performed a reward-based spatial working memory task. During the memory retention period, a transient burst of high gamma synchronization preceded an animal's correct choice in both prospective planning and retrospective mistake correction, but not an animal's incorrect choice. Optogenetic inhibition of the circuit targeted to the choice point area resulted in a coordinated reduction in both high gamma synchrony and correct execution of a working-memory-guided behavior. These findings suggest that transient high gamma synchrony contributes to the successful execution of spatial working memory. Furthermore, our data are consistent with an association between transient high gamma synchrony and explicit awareness of the working memory content. PMID- 24768691 TI - Reconstruction of the mouse otocyst and early neuroblast lineage at single-cell resolution. AB - The otocyst harbors progenitors for most cell types of the mature inner ear. Developmental lineage analyses and gene expression studies suggest that distinct progenitor populations are compartmentalized to discrete axial domains in the early otocyst. Here, we conducted highly parallel quantitative RT-PCR measurements on 382 individual cells from the developing otocyst and neuroblast lineages to assay 96 genes representing established otic markers, signaling pathway-associated transcripts, and novel otic-specific genes. By applying multivariate cluster, principal component, and network analyses to the data matrix, we were able to readily distinguish the delaminating neuroblasts and to describe progressive states of gene expression in this population at single-cell resolution. It further established a three-dimensional model of the otocyst in which each individual cell can be precisely mapped into spatial expression domains. Our bioinformatic modeling revealed spatial dynamics of different signaling pathways active during early neuroblast development and prosensory domain specification. PMID- 24768693 TI - A feminist, narrative analysis of drinking stories. PMID- 24768694 TI - Nesfatin-1/nucleobindin-2 like immunoreactivity in the olfactory system, brain and pituitary of frog, Microhyla ornata. AB - Nesfatin-1 is a recently discovered anorectic protein derived from the precursor nucleobindin-2 (NUCB2). While nesfatin-1 has been widely studied in mammals, and goldfish, there are no reports of nesfatin-1 in amphibians. Using immunohistochemistry and Western blot analysis, this study assessed the distribution of NUCB2/nesfatin-1 in the brain of frog Microhyla ornata. NUCB2/nesfatin-1 like immunoreactivity was found in the olfactory receptor neurons, Bowman's glands and in the olfactory epithelium of medial diverticulum. In the brain, immunoreactive perikarya were seen in the anterior preoptic area, magnocellular nucleus, suprachiasmatic nucleus, ventromedial thalamic nucleus, posterior thalamic nucleus, nucleus infundibularis ventralis and dorsalis, and the cerebellar nucleus. NUCB2/nesfatin-1like immunoreactivity was also detected in the pineal and pituitary glands of frog. The presence of NUCB2/nesfatin-1 in the key brain regions suggest possible roles for this protein in the regulation of physiological processes in frogs. PMID- 24768696 TI - A neuroanatomical analysis of the effects of a memory impairing dose of scopolamine in the rat brain using cytochrome c oxidase as principle marker. AB - Acetylcholine plays a role in mnemonic and attentional processes, but also in locomotor and anxiety-related behavior. Receptor blockage by scopolamine can therefore induce cognitive as well as motor deficits and increase anxiety levels. Here we show that scopolamine, at a dose that has previously been found to affect learning and memory performance (0.1 mg/kg i.p.), has a widespread effect on cytochrome c oxidase histochemistry in various regions of the rat brain. We found a down-regulation of cytochrome c oxidase in the nucleus basalis, in movement related structures such as the primary motor cortex and the globus pallidus, memory-related structures such as the CA1 subfield of the hippocampus and perirhinal cortex and in anxiety-related structures like the amygdala, which also plays a role in memory. However choline acetyltransferase levels were only affected in the CA1 subfield of the hippocampus and both, choline acetyltransferase and c-Fos expression levels were decreased in the amygdala. These findings corroborate strong cognitive behavioral effects of this drug, but also suggest possible anxiety- and locomotor-related changes in subjects. Moreover, they present histochemical evidence that the effects of scopolamine are not ultimately restricted to cognitive parameters. PMID- 24768695 TI - The dynamics of pain: evidence for simultaneous site-specific habituation and site-nonspecific sensitization in thermal pain. AB - Repeated exposure to noxious stimuli changes their painfulness, due to multiple adaptive processes in the peripheral and central nervous systems. Somewhat paradoxically, repeated stimulation can produce an increase (sensitization) or a decrease (habituation) in pain. Adaptation processes may also be body-site specific or operate across body sites, and considering this distinction may help explain the conditions under which habituation versus sensitization occurs. To dissociate the effects of site-specific and site-nonspecific adaptation processes, we examined reported pain in 100 participants during counterbalanced sequences of noxious thermal stimulation on multiple skin sites. Analysis of pain ratings revealed 2 opposing sequential effects: repeated stimulations of the same skin site produced temperature-dependent habituation, whereas repeated stimulations across different sites produced sensitization. Stimulation trials were separated by ~20 seconds, and sensitization was unrelated to the distance between successively stimulated sites, suggesting that neither temporal nor spatial summation occurred. To explain these effects, we propose a dynamic model with 2 adaptation processes, one site-specific and the other site-nonspecific. The model explains 93% of the variance in the group-mean pain ratings after controlling for current stimulation temperature, with its estimated parameters showing evidence for habituation for the site-specific process and sensitization for the site-nonspecific process. The 2 pain adaptation processes revealed in this study, and the ability to disentangle them, may hold keys to understanding multiple pain-regulatory mechanisms and their disturbance in chronic pain syndromes. PERSPECTIVE: This article presents novel evidence for simultaneous site-specific habituation and site-nonspecific sensitization in thermal pain, which can be disentangled (and the direction and strength of each process estimated) by a dynamic model. The dissociation of site-specific and site nonspecific adaptation processes may hold keys to understanding multiple pain regulatory mechanisms in both healthy and patient populations. PMID- 24768697 TI - Mitochondrial dysfunction in early life resulted from perinatal bisphenol A exposure contributes to hepatic steatosis in rat offspring. AB - An emerging literature suggests that bisphenol A (BPA), a widespread endocrine disrupting chemical, when exposure occurs in early life, may increase the risk of metabolic syndrome. In this study, we investigated the hypothesis that perinatal exposure to BPA predisposed offspring to fatty liver disease: the hepatic manifestation of metabolic syndrome, and its possible mechanism. Pregnant Wistar rats were administered with BPA (40MUg/kg/day) or vehicle during gestation and lactation. Liver histology, biochemical analysis, transcriptome, and mitochondrial function were examined in male offspring at postnatal 3, 15 and 26 weeks. At 3 weeks of age, abnormal liver morphology and function were not observed in the BPA-exposed offspring, but a decrease in mitochondrial respiratory complex (MRC) activity (I and III) and significant changes in gene expression involved in mitochondrial fatty acid metabolism were observed compared with controls. At 15 weeks, micro-vesicular steatosis in liver, up-regulated genes involved in lipogenesis pathways, increased ROS generation and Cytc release were observed in the BPA-exposed offspring. Then, extensive fatty accumulation in liver and elevated serum ALT were observed in BPA-exposed offspring at 26 weeks. In the longitudinal observation, hepatic mitochondrial function including MRC activity, ATP production, ROS generation and mitochondrial membrane potential were progressively worsened in the BPA-exposed offspring. Perinatal BPA exposure contributes to the development of hepatic steatosis in the offspring of rats, which may be mediated through impaired hepatic mitochondrial function and up regulated hepatic lipid metabolism. PMID- 24768698 TI - High glucose increases Cdk5 activity in podocytes via transforming growth factor beta1 signaling pathway. AB - Podocytes are highly specialized and terminally differentiated glomerular cells that play a vital role in the development and progression of diabetic nephropathy (DN). Cyclin-dependent kinase 5 (Cdk5), who is an atypical but essential member of the Cdk family of proline-directed serine/threonine kinases, has been shown as a key regulator of podocyte differentiation, proliferation and morphology. Our previous studies demonstrated that the expression of Cdk5 was significantly increased in podocytes of diabetic rats, and was closely related with podocyte injury of DN. However, the mechanisms of how expression and activity of Cdk5 are regulated under the high glucose environment have not yet been fully elucidated. In this study, we showed that high glucose up-regulated the expression of Cdk5 and its co-activator p35 with a concomitant increase in Cdk5 kinase activity in conditionally immortalized mouse podocytes in vitro. When exposed to 30 mM glucose, transforming growth factor-beta1 (TGF-beta1) was activated. Most importantly, we found that SB431542, the Tgfbr1 inhibitor, significantly decreased the expression of Cdk5 and p35 and Cdk5 kinase activity in high glucose treated podocytes. Moreover, high glucose increased the expression of early growth response-1 (Egr-1) via TGF-beta1-ERK1/2 pathway in podocytes and inhibition of Egr-1 by siRNA decreased p35 expression and Cdk5 kinase activity. Furthermore, inhibition of Cdk5 kinase activity effectively alleviated podocyte apoptosis induced by high glucose or TGF-beta1. Thus, the TGF-beta1-ERK1/2-Egr-1 signaling pathway may regulate the p35 expression and Cdk5 kinase activity in high glucose-treated podocytes, which contributes to podocyte injury of DN. PMID- 24768699 TI - Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. AB - Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1mm in the everolimus-treated and control groups were 1.9 +/- 0.9 and 9.4 +/- 3.2 (t-test, p<0.001), respectively. pS6 was suppressed during eve r olimus treatment. Although apoptosis and autophagy were not induced in everolimus treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation. PMID- 24768701 TI - Occurrence and behaviour of 105 active pharmaceutical ingredients in sewage waters of a municipal sewer collection system. AB - The concentrations and behaviour of 105 different active pharmaceutical ingredients (APIs) in the aqueous phase of sewage water within a municipal sewer collection system have been investigated. Sewage water samples were gathered from seven pump stations (one of which was located within a university hospital) and from sewage water treatment influent and effluent. The targeted APIs were quantified using a multi-residue method based on online solid phase extraction liquid chromatography tandem mass spectrometry. The method was thoroughly validated and complies with EU regulations on sample handling, limits of quantification, quality control and selectivity. 51 APIs, including antibiotics, antidepressants, hypertension drugs, analgesics, NSAIDs and psycholeptics, were found frequently within the sewer collection system. API concentrations and mass flows were evaluated in terms of their frequency of detection, daily variation, median/minimum/maximum/average concentrations, demographic dissimilarities, removal efficiencies, and mass flow profiles relative to municipal sales data. Our results suggest that some APIs are removed from, or introduced to, the aqueous phase of sewage waters within the studied municipal collection system. PMID- 24768702 TI - Ferric and cobaltous hydroacid complexes for forward osmosis (FO) processes. AB - Cupric and ferric hydroacid complexes have proven their advantages as draw solutes in forward osmosis in terms of high water fluxes, negligible reverse solute fluxes and easy recovery (Ge and Chung, 2013. Hydroacid complexes: A new class of draw solutes to promote forward osmosis (FO) processes. Chemical Communications 49, 8471-8473.). In this study, cobaltous hydroacid complexes were explored as draw solutes and compared with the ferric hydroacid complex to study the factors influencing their FO performance. The solutions of the cobaltous complexes produce high osmotic pressures due to the presence of abundant hydrophilic groups. These solutes are able to dissociate and form a multi-charged anion and Na(+) cations in water. In addition, these complexes have expanded structures which lead to negligible reverse solute fluxes and provide relatively easy approaches in regeneration. These characteristics make the newly synthesized cobaltous complexes appropriate as draw solutes. The FO performance of the cobaltous and ferric-citric acid (Fe-CA) complexes were evaluated respectively through cellulose acetate membranes, thin-film composite membranes fabricated on polyethersulfone supports (referred as TFC-PES), and polybenzimidazole and PES dual-layer (referred as PBI/PES) hollow fiber membranes. Under the conditions of DI water as the feed and facing the support layer of TFC-PES FO membranes (PRO mode), draw solutions at 2.0 M produced relatively high water fluxes of 39-48 LMH (L m(-2) hr(-1)) with negligible reverse solute fluxes. A water flux of 17.4 LMH was achieved when model seawater of 3.5 wt.% NaCl replaced DI water as the feed and 2.0 M Fe-CA as the draw solution under the same conditions. The performance of these hydroacid complexes surpasses those of the synthetic draw solutes developed in recent years. This observation, along with the relatively easy regeneration, makes these complexes very promising as a novel class of draw solutes. PMID- 24768700 TI - The different roles of myosin IIA and myosin IIB in contraction of 3D collagen matrices by human fibroblasts. AB - Contraction of 3D collagen matrices by fibroblasts frequently is used as an in vitro model of wound closure. Different iterations of the model - all conventionally referred to as "contraction" - involve different morphological patterns. During floating matrix contraction, cells initially are round without stress fibers and subsequently undergo spreading. During stressed matrix contraction, cells initially are spread with stress fibers and subsequently undergo shortening. In the current studies, we used siRNA silencing of myosin IIA (MyoIIA) and myosin IIB (MyoIIB) to test the roles of myosin II isoforms in fibroblast interactions with 3D collagen matrices and collagen matrix contraction. We found that MyoIIA but not MyoIIB was required for cellular global inward contractile force, formation of actin stress fibers, and morphogenic cell clustering. Stressed matrix contraction required MyoIIA but not MyoIIB. Either MyoIIA or MyoIIB was sufficient for floating matrix contraction (FMC) stimulated by platelet-derived growth factor. Neither MyoIIA or MyoIIB was necessary for FMC stimulated by serum. Our findings suggest that myosin II-dependent motor mechanisms for collagen translocation during extracellular matrix remodeling differ depending on cell tension and growth factor stimulation. PMID- 24768703 TI - Transport, motility, biofilm forming potential and survival of Bacillus subtilis exposed to cold temperature and freeze-thaw. AB - In cold climate regions, microorganisms in upper layers of soil are subject to low temperatures and repeated freeze-thaw (FT) conditions during the winter. We studied the effects of cold temperature and FT cycles on the viability and survival strategies (namely motility and biofilm formation) of the common soil bacterium and model pathogen Bacillus subtilis. We also examined the effect of FT on the transport behavior of B. subtilis at two solution ionic strengths (IS: 10 and 100 mM) in quartz sand packed columns. Finally, to study the mechanical properties of the bacteria-surface bond, a quartz crystal microbalance with dissipation monitoring (QCM-D) was used to monitor changes in bond stiffness when B. subtilis attached to a quartz substrate (model sand surface) under different environmental conditions. We observed that increasing the number of FT cycles decreased bacterial viability and that B. subtilis survived for longer time periods in higher IS solution. FT treatment decreased bacterial swimming motility and the transcription of flagellin encoding genes. Although FT exposure had no significant effect on the bacterial growth rate, it substantially decreased B. subtilis biofilm formation and correspondingly decreased the transcription of matrix production genes in higher IS solution. As demonstrated with QCM-D, the bond stiffness between B. subtilis and the quartz surface decreased after FT. Moreover, column transport studies showed higher bacterial retention onto sand grains after exposure to FT. This investigation demonstrates how temperature variations around the freezing point in upper layers of soil can influence key bacterial properties and behavior, including survival and subsequent transport. PMID- 24768704 TI - Occurrence and removal of free estrogens, conjugated estrogens, and bisphenol A in manure treatment facilities in East China. AB - The occurrence of four free estrogens, four conjugated estrogens, and bisphenol A (BPA) was investigated in three cow farms, four swine farms, and five chicken farms. The daily total estrogen (free and conjugated) excretions of a cow were 145.23-179.27 MUg/d mainly through feces (92%), while swine excreted 42.56-219.25 MUg/d of estrogens mainly through urine (98-99%). Estrogen conjugates contributed 14.6-48.8% to the total estrogen excretions in cow feces and more than 98% in swine urine. A chicken excreted 0.66-12.78 MUg/d of total estrogens through feces, among which 34.2-100% was contributed by conjugated estrogens. The total estrogen removal efficiencies of manure anaerobic digesters and composters were 14.7-21.8% and less than 70.1%, respectively. Estrogens (E1, 17beta-E2, E1-3S, and E2-3S) still existed in treated manure at concentrations up to 2695 +/- 181 ng/L (anaerobic digestate) and at contents up to 80.8 +/- 6.0 ng/g (compost). BPA was found in feces and compost samples at similar contents (nd-25 ng/g), and approximately 60-70% of BPA was removed in wastewater treatment facilities. PMID- 24768705 TI - Long-term RNA persistence of porcine rubulavirus (PorPV-LPMV) after an outbreak of a natural infection: the detection of viral mRNA in sentinel pigs suggests viral transmission. AB - The persistence of porcine rubulavirus (PorPV-LPMV) in five pigs that had survived an outbreak of a natural infection was determined. After the resolution of the outbreak, each animal was housed in an isolation pen together with one sentinel pig. Approximately every 2 months thereafter one group of animals was euthanized and tissue samples taken for virological and serological analysis. Infectious virus was not isolated from any samples; antibodies to PorPV-LPMV were detected in convalescent pigs by virus neutralisation test and blocking ELISA but not in sentinel pigs. PorPV-LPMV mRNA of the nucleoprotein (NP) and phosphoprotein (P) genes was detected by a nested polymerase chain reaction (nPCR) in samples of trigeminal and optic nerves, cervical spinal cord, tonsils, salivary gland, lung and pancreas from convalescent pigs. mRNA was also detected in the midbrain, corpus callosum, or olfactory bulb in four out of five pigs by nRT-PCR, this result was confirmed by the sequencing of a 260bp PCR product of P gene region. The highest average viral copies/MUg of total RNA occurred in the olfactory bulb and pancreas tissues of convalescent pigs and midbrain, tonsil and pancreas of sentinel pigs housed with the convalescent pigs. Satellitosis and gliosis of the midbrain, olfactory bulb, corpus callosum, medulla oblongata or choroid plexus were microscopically observed in four convalescent pigs. The control pig remained negative in all tests. The results indicate that PorPV-LPMV mRNA persists and induces a durable humoral immune response in pigs that have recovered from a natural infection. After a possible reactivation of the virus, it was transmitted to sentinel pigs in contact with the convalescent pigs. PMID- 24768706 TI - Modelling capillary oxygen supply capacity in mixed muscles: capillary domains revisited. AB - Developing effective therapeutic interventions for pathological conditions associated with abnormal oxygen transport to muscle fibres critically depends on the objective characterisation of capillarity. Local indices of capillary supply have the potential to identify the onset of fine-scale tissue pathologies and dysregulation. Detailed tissue geometry, such as muscle fibre size, has been incorporated into such measures by considering the distribution of Voronoi polygons (VP) generated from planar capillary locations as a representation of capillary supply regions. Previously, detailed simulations have predicted that this is generally accurate for muscle tissue with uniform oxygen uptake. Here we extend this modelling framework to heterogeneous muscle for the assessment of capillary supply capacity under maximal sustainable oxygen consumption. We demonstrate for muscle with heterogeneous fibre properties that VP theoretically provide a computationally simple but often accurate representation of trapping regions (TR), which are predicted from biophysical transport models to represent the areas of tissue supplied by individual capillaries. However, this use of VP may become less accurate around large fibres, and at the interface of fibres of largely different oxidative capacities. In such cases, TR may provide a more robust representation of capillary supply regions. Additionally, given VP can only approximate oxygen delivery by capillaries, we show that their generally close relationship to TR suggests that (1) fibre type distribution may be tightly regulated to avoid large fibres with high oxidative capacities, (2) the anatomical fibre distribution is also tightly regulated to prevent a large surface area of interaction between metabolically dissimilar fibres, and (3) in chronically hypoxic tissues capillary distribution is more important in determining oxygen supply than the spatial heterogeneity of fibre demand. PMID- 24768707 TI - The inhibition of human T cell proliferation by the caspase inhibitor z-VAD-FMK is mediated through oxidative stress. AB - The caspase inhibitor benzyloxycarbony (Cbz)-l-Val-Ala-Asp (OMe) fluoromethylketone (z-VAD-FMK) has recently been shown to inhibit T cell proliferation without blocking caspase-8 and caspase-3 activation in primary T cells. We showed in this study that z-VAD-FMK treatment leads to a decrease in intracellular glutathione (GSH) with a concomitant increase in reactive oxygen species (ROS) levels in activated T cells. The inhibition of anti-CD3-mediated T cell proliferation induced by z-VAD-FMK was abolished by the presence of low molecular weight thiols such as GSH, N-acetylcysteine (NAC) and l-cysteine, whereas d-cysteine which cannot be metabolised to GSH has no effect. These results suggest that the depletion of intracellular GSH is the underlying cause of z-VAD-FMK-mediated inhibition of T cell activation and proliferation. The presence of exogenous GSH also attenuated the inhibition of anti-CD3-induced CD25 and CD69 expression mediated by z-VAD-FMK. However, none of the low molecular weight thiols were able to restore the caspase-inhibitory properties of z-VAD-FMK in activated T cells where caspase-8 and caspase-3 remain activated and processed into their respective subunits in the presence of the caspase inhibitor. This suggests that the inhibition of T cell proliferation can be uncoupled from the caspase-inhibitory properties of z-VAD-FMK. Taken together, the immunosuppressive effects in primary T cells mediated by z-VAD-FMK are due to oxidative stress via the depletion of GSH. PMID- 24768709 TI - The final SAMMPRIS results: a review. PMID- 24768708 TI - Erlotinib promotes endoplasmic reticulum stress-mediated injury in the intestinal epithelium. AB - Erlotinib, a popular drug for treating non-small cell lung cancer (NSCLC), causes diarrhea in approximately 55% of patients receiving this drug. In the present study, we found that erlotinib induced barrier dysfunction in rat small intestine epithelial cells (IEC-6) by increasing epithelial permeability and down regulating E-cadherin. The mRNA levels of various pro-inflammatory cytokines (Il 6, Il-25 and Il-17f) were increased after erlotinib treatment in IEC-6 cells. Erlotinib concentration- and time-dependently induced apoptosis and endoplasmic reticulum (ER) stress in both IEC-6 and human colon epithelial cells (CCD 841 CoN). Intestinal epithelial injury was also observed in male C57BL/6J mice administrated with erlotinib. Knockdown of C/EBP homologous protein (CHOP) with small interference RNA partially reversed erlotinib-induced apoptosis, production of IL-6 and down-regulation of E-cadherin in cultured intestinal epithelial cells. In conclusion, erlotinib caused ER stress-mediated injury in the intestinal epithelium, contributing to its side effects of diarrhea in patients. PMID- 24768710 TI - Biological mechanisms underlying growth and rupture of saccular intracranial aneurysm. PMID- 24768712 TI - Flavonoids inhibit iNOS production via mitogen activated proteins in lipoteichoic acid stimulated cardiomyoblasts. AB - Infective endocarditis is caused by oral commensal bacteria which are important etiologic agents in this disease and can induce release of nitric oxide (NO), promoting an inflammatory response in the endocardium. In this study, we investigated the properties of kaempherol, epigallocatechin, apigenin, and naringin in embryonic mouse heart cells (H9c2) treated with lipoteichoic acid (LTA) obtained from Streptococcus sanguinis. NO production was measured with the Griess method. Expression of inducible nitric oxide synthase (iNOS) was detected by reverse transcriptase polymerase chain reaction (RT-PCR). In addition, western blot assays and immunofluorescence staining were used to assess translocation of nuclear factor kappa beta (NF-kappaB), degradation of IkappaB, and activity of the mitogen activated protein (MAP) kinases extracellular signal-regulated kinase (ERK 1/2), p38, and c-Jun N-terminal kinase (JNK). And the effects of these flavonoids on cell viability were also assessed. Our results showed that flavonoids blocked activation of ERK, JNK, and p38 in cardiomyocytes treated with LTA. Moreover, the flavonoids showed no cytotoxic effects and blocked NF-kappaB translocation and IkappaB degradation and inhibited LTA-induced NF-kappaB promoter activity, iNOS expression and NO production. In conclusion these effects are consistent with some of the observed anti-inflammatory properties of other flavonoids. PMID- 24768713 TI - Short-term radon activity concentration changes along the Underground Educational Tourist Route in the Old Uranium Mine in Kletno (Sudety Mts., SW Poland). AB - Short-term (222)Rn activity concentration changes along the Underground Educational Tourist Route in the Old Uranium Mine in Kletno were studied, based on continuous measurements conducted between 16 May 2008 and 15 May 2010. The results were analysed in the context of numbers of visitors arriving at the facility in particular seasons and the time per day spent inside by staff and visitors. This choice was based on partially published earlier findings (Fijalkowska-Lichwa and Przylibski, 2011). Results for the year 2009 were analysed in depth, because it is the only period of observation covering a full calendar year. The year 2009 was also chosen for detailed analysis of short-term radon concentration changes, because in each period of this year (hour, month, season) fluctuations of noted values were the most visible. Attention has been paid to three crucial issues linked to the occurrence and behaviour of radon and to the radiological protection of workers and visitors at the tourist route in Kletno. The object of study is a complex of workings in a former uranium mine situated within a metamorphic rock complex in the most radon-prone area in Poland. The facility has been equipped with a mechanical ventilation system, which is turned on after the closing time and at the end of the working day for the visitor service staff, i.e. after 6 p.m. Short-term radon activity concentration changes along the Underground Educational Tourist Route in the Old Uranium Mine in Kletno are related to the activity of the facility's mechanical ventilation. Its inactivity in the daytime results in the fact that the highest values of (222)Rn activity concentration are observed at the time when the facility is open to visitors, i.e. between 10 a.m. and 6 p.m. The improper usage of the mechanical ventilation system is responsible for the extremely unfavourable working conditions, which persist in the facility for practically all year. The absence of appropriate radiological protection (i.e. preventive measures like shortening working day, dosimetric measurements in the workplace) is a serious problem in the Kletno adit. PMID- 24768711 TI - Sex and exercise interact to alter the expression of anabolic androgenic steroid induced anxiety-like behaviors in the mouse. AB - Anabolic androgenic steroids (AAS) are taken by both sexes to enhance athletic performance and body image, nearly always in conjunction with an exercise regime. Although taken to improve physical attributes, chronic AAS use can promote negative behavior, including anxiety. Few studies have directly compared the impact of AAS use in males versus females or assessed the interaction of exercise and AAS. We show that AAS increase anxiety-like behaviors in female but not male mice and that voluntary exercise accentuates these sex-specific differences. We also show that levels of the anxiogenic peptide corticotrophin releasing factor (CRF) are significantly greater in males, but that AAS selectively increase CRF levels in females, thus abrogating this sex-specific difference. Exercise did not ameliorate AAS-induced anxiety or alter CRF levels in females. Exercise was anxiolytic in males, but this behavioral outcome did not correlate with CRF levels. Brain-derived neurotrophic factor (BDNF) has also been implicated in the expression of anxiety. As with CRF, levels of hippocampal BDNF mRNA were significantly greater in males than females. AAS and exercise were without effect on BDNF mRNA in females. In males, anxiolytic effects of exercise correlated with increased BDNF mRNA, however AAS-induced changes in BDNF mRNA and anxiety did not. In sum, we find that AAS elicit sex-specific differences in anxiety and that voluntary exercise accentuates these differences. In addition, our data suggest that these behavioral outcomes may reflect convergent actions of AAS and exercise on a sexually differentiated CRF signaling system within the extended amygdala. PMID- 24768714 TI - A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum. AB - Anti-apoptotic Bcl-2 contributes to cancer formation and progression by promoting the survival of altered cells. Hence, it is a prime target for novel specific anti-cancer therapeutics. In addition to its canonical anti-apoptotic role, Bcl-2 has an inhibitory effect on cell-cycle progression. Bcl-2 acts at two different intracellular compartments, the mitochondria and the endoplasmic reticulum (ER). At the mitochondria, Bcl-2 via its hydrophobic cleft scaffolds the Bcl-2-homology (BH) domain 3 (BH3) of pro-apoptotic Bcl-2-family members. Small molecules (like BH3 mimetics) can disrupt this interaction, resulting in apoptotic cell death in cancer cells. At the ER, Bcl-2 modulates Ca(2+) signaling, thereby promoting proliferation while increasing resistance to apoptosis. Bcl-2 at the ER acts via its N-terminal BH4 domain, which directly binds and inhibits the inositol 1,4,5 trisphosphate receptor (IP3R), the main intracellular Ca(2+)-release channel. Tools targeting the BH4 domain of Bcl-2 reverse Bcl-2's inhibitory action on IP3Rs and trigger pro-apoptotic Ca(2+) signaling in cancer B-cells, including chronic lymphocytic leukemia (CLL) cells and diffuse large B-cell lymphoma (DLBCL) cells. The sensitivity of DLBCL cells to BH4-domain targeting tools strongly correlated with the expression levels of the IP3R2 channel, the IP3R isoform with the highest affinity for IP3. Interestingly, bio-informatic analysis of a database of primary CLL patient cells also revealed a transcriptional upregulation of IP3R2. Finally, this review proposes a model, in which cancer cell survival depends on Bcl-2 at the mitochondria and/or the ER. This dependence likely will have an impact on their responses to BH3-mimetic drugs and BH4-domain targeting tools. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau. PMID- 24768715 TI - Temporal oligodendrocyte lineage progression: in vitro models of proliferation, differentiation and myelination. AB - Oligodendrocytes are neuroglial cells responsible, within the central nervous system, for myelin sheath formation that provides an electric insulation of axons and accelerate the transmission of electrical signals. In order to be able to produce myelin, oligodendrocytes progress through a series of differentiation steps from oligodendrocyte precursor cells to mature oligodendrocytes (migration, increase in morphologic complexity and expression pattern of specific markers), which are modulated by cross talk with other nerve cells. If during the developmental stage any of these mechanisms is affected by toxic or external stimuli it may result into impaired myelination leading to neurological deficits. Such being the case, several approaches have been developed to evaluate how oligodendrocyte development and myelination may be impaired. The present review aims to summarize changes that oligodendrocytes suffer from precursor cells to mature ones, and to describe and discuss the different in vitro models used to evaluate not only oligodendrocyte development (proliferation, migration, differentiation and ability to myelinate), but also their interaction with neurons and other glial cells. First we discuss the temporal oligodendrocyte lineage progression, highlighting the differences between human and rodent, usually used as tissue supply for in vitro cultures. Second we describe how to perform and characterize the different in vitro cultures, as well as the methodologies to evaluate oligodendrocyte functionality in each culture system, discussing their advantages and disadvantages. Finally, we briefly discuss the current status of in vivo models for oligodendrocyte development and myelination. PMID- 24768716 TI - The dual face of connexin-based astroglial Ca(2+) communication: a key player in brain physiology and a prime target in pathology. AB - For decades, studies have been focusing on the neuronal abnormalities that accompany neurodegenerative disorders. Yet, glial cells are emerging as important players in numerous neurological diseases. Astrocytes, the main type of glia in the central nervous system , form extensive networks that physically and functionally connect neuronal synapses with cerebral blood vessels. Normal brain functioning strictly depends on highly specialized cellular cross-talk between these different partners to which Ca(2+), as a signaling ion, largely contributes. Altered intracellular Ca(2+) levels are associated with neurodegenerative disorders and play a crucial role in the glial responses to injury. Intracellular Ca(2+) increases in single astrocytes can be propagated toward neighboring cells as intercellular Ca(2+) waves, thereby recruiting a larger group of cells. Intercellular Ca(2+) wave propagation depends on two, parallel, connexin (Cx) channel-based mechanisms: i) the diffusion of inositol 1,4,5-trisphosphate through gap junction channels that directly connect the cytoplasm of neighboring cells, and ii) the release of paracrine messengers such as glutamate and ATP through hemichannels ('half of a gap junction channel'). This review gives an overview of the current knowledge on Cx-mediated Ca(2+) communication among astrocytes as well as between astrocytes and other brain cell types in physiology and pathology, with a focus on the processes of neurodegeneration and reactive gliosis. Research on Cx-mediated astroglial Ca(2+) communication may ultimately shed light on the development of targeted therapies for neurodegenerative disorders in which astrocytes participate. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau. PMID- 24768717 TI - Suppressive responses by visual food cues in postprandial activities of insular cortex as revealed by magnetoencephalography. AB - 'Hara-Hachibu' in Japanese means a subjective sense by which we stop eating just before the motivation to eat is completely lost, a similar concept to caloric restriction (CR). Insular cortex is a critical platform which integrates sensory information into decision-making processes in eating behavior. We compared the responses of insular cortex, as assessed by magnetoencephalography (MEG), immediately after presentation of food images in the Fasting condition with those in the 'Hara-Hachibu' condition. Eleven healthy, right-handed males [age, 27.2+/ 9.6 years; body mass index, 22.6+/-2.1kg/m(2) (mean+/-SD)] were enrolled in a randomized, two-crossover experiment (Fasting and 'Hara-Hachibu' conditions). Before the MEG recordings in the 'Hara-Hachibu' condition, the participants consumed rice balls as much as they judged themselves to have consumed shortly before reaching satiety. During the MEG recordings, they viewed food pictures projected on a screen. The intensities of MEG responses to viewing food pictures were significantly lower in the 'Hara-Hachibu' condition than those in the Fasting condition (P<0.05). The intensities of the MEG responses to the visual food stimuli in the 'Hara-Hachibu' condition was positively associated with the factor-3 (food tasted) (r=0.693, P=0.018) and aggregated scores (r=0.659, P=0.027) of the Power of Food Scale, a self-report measure of hedonic hunger. These findings may help to elucidate the neural basis of variability of appetite phenotypes under the condition of CR among individuals, and to develop possible strategies for the maintenance of adequate CR in daily life. PMID- 24768718 TI - Hormones and hibernation: possible links between hormone systems, winter energy balance and white-nose syndrome in bats. AB - This article is part of a Special Issue "Energy Balance". Hibernation allows mammals to survive in cold climates and during times of reduced food availability. Drastic physiological changes are required to maintain the energy savings that characterize hibernation. These changes presumably enable adjustments in endocrine activity that control metabolism and body temperature, and ultimately influence expression of torpor and periodic arousals. Despite challenges that exist when examining hormonal pathways in small-bodied hibernators, bats represent a potential model taxon for comparative neuroendocrinological studies of hibernation due to their diversity of species and the reliance of many species on heterothermy. Understanding physiological mechanisms underlying hibernation in bats is also important from a conservation physiology perspective due to white-nose syndrome, an emerging infectious disease causing catastrophic mortality among hibernating bats in eastern North America. Here we review the potential influence of three key hormonal mechanisms--leptin, melatonin and glucocorticoids--on hibernation in mammals with an emphasis on bats. We propose testable hypotheses about potential effects of WNS on these systems and their evolution. PMID- 24768719 TI - Identification and characterization of the biosynthetic gene cluster of divergolides from Streptomyces sp. W112. AB - Divergolides are a group of structurally unprecedented ansamacrolactam antibiotics with antibacterial and antitumor activities. A biosynthetic gene cluster predicted to encode the biosynthesis of divergolides was cloned and sequenced from endophytic Streptomyces sp. W112. The gene cluster of divergolides (div) spans a DNA region of 61-kb and consists of 20 open reading frames (ORFs) that encode polyketide synthases (PKSs), enzymes for the synthesis of AHBA and PKS extender units, and post-PKS modifications, proposed regulators, and putative transporters. Disruption of the AHBA synthase gene (divK) completely abolished the production of divergolides proved its involvement in the biosynthesis of divergolides. Bioinformatics analysis suggested that the regulatory gene div8 in div gene cluster might encode a positive regulator for the biosynthesis of divergolides. Constitutive overexpression of div8 improved the production of divergolides E, implying that div gene cluster maybe responsible for the biosynthesis of divergolides. These findings set the stage for fully investigating the biosynthesis of divergolides and rational engineering of new divergolide analogs by genetic modifications, and pave the way to further improve the production of divergolides. PMID- 24768720 TI - Phenotypic and genetic analysis of the German Malus Germplasm Collection in terms of type 1 and type 2 red-fleshed apples. AB - Red fruit flesh is a desirable trait in apple breeding, because red-fleshed apples are a novelty and therefore considered to be more attractive to consumers and contain more health beneficial compounds. The red fruit flesh coloration is based on an increased level of cyanidin 3-galactoside, an anthocyanin whose biosynthesis is regulated by the MYB-type transcription factors MdMYB10 or MdMYB110a, respectively. A repeated segment in the MdMYB10 promoter allele R6 results in a gain-of-function mutation visible as red pigmentation of fruit skin and flesh and all vegetative tissues. Red-fleshed apple genotypes containing this R6 allele belong to the type 1 red-fleshed apple, which is known to be linked to some negative traits like astringent taste and internal flesh browning disorder. In type 2 red-fleshed apples the fruit flesh coloration is not inevitably linked with skin and leaf color. This red-fleshed apple phenotype, which is a result of increased expression of MdMYB110a, seems to be more useful for breeding, but it can be found rather seldom. In the present study 357 Malus accessions of the German Malus Germplasm Collection were evaluated for red fruit flesh coloration and the presence of the MdMYB10 R1 (not mutated) and R6 promoter alleles. Among them a total of 40 accessions were identified which contain the R6 allele. 37 accessions showed a red coloration of the fruit flesh. All these accessions belong to type 1 red-fleshed apple. No type 2 red-fleshed apple could be found. Three accessions with R6 allele had non-red-fleshed apples. 312 other non-red fleshed accessions contained only the R1 allele. Five non-red-fleshed accessions contained a new promoter allele with an unexpected size of ~1 kbp. Sequencing of this allele detected the insertion of a non-autonomous apple transposon. PMID- 24768721 TI - A comparative study of class 1 integrons in Acinetobacter baumannii. AB - Multidrug resistance (MDR) in Acinetobacter baumannii is increasingly reported and has become a significant public concern. The method responsible for the acquisition of resistance genes via integrons from the environment or intra species in A. baumannii remains to be understood. This study was performed to investigate the transmission route of these integrons using a comparative analysis of published A. baumannii complete genomes. The phylogenetic analysis of A. baumannii type 1 integrases (IntI1) showed that the integrons could be transferred across the two evolutionary lineages, the international clone I (IC I) and clone II (IC II) strains. In addition, the integrons in A. baumannii strains were mainly responsible for the transfer of resistance genes for two types of long-term usage antibiotics and antiseptics, such as aminoglycosides, chloramphenicol and the quaternary-ammonium-compound family. The in silico comparative analysis of known integron integrases revealed that the intI genes were phylogenetically related among A. baumannii strains and some microorganisms living in a sediment community, implicating that the integrons of A. baumannii might have originated from those microorganisms belonging to the beta preoteobacterial class in the sediment environment. The data suggest that the gain of class 1 integrons in A. baumannii strains may have started before the antibiotic era. This report shows that the origins of A. baumannii class 1 integrons may be the soil environment and that the resistance genes included in integrons are horizontally transferred across all the A. baumannii genomes, including IC I and IC II. PMID- 24768722 TI - Identification and expression of microRNA in the brain of hibernating bats, Myotis lucifugus. AB - Recent research has highlighted roles for non-coding RNA i7n the regulation of stress tolerance in bats. In this study, we propose that microRNA could also play an important role in neuronal maintenance during hibernation. To explore this possibility, RT-PCR was employed to investigate the expression of eleven microRNAs from the brain tissue of euthermic control and torpid bats. Results show that eight microRNAs (miR-21, -29b, -103, -107, -124a, -132, -183 and -501) increased (1.2-1.9 fold) in torpid bats, while the protein expression of Dicer, a microRNA processing enzyme, did not significantly change during torpor. Bioinformatic analysis of the differentially expressed microRNA suggests that these microRNAs are mainly involved in two processes: (1) focal adhesion and (2) axon guidance. To determine the extent of microRNA sequence conservation in the bat, we successfully identified bat microRNA from sequence alignments against known mouse (Mus musculus) microRNA. We successfully identified 206 conserved pre microRNA sequences, leading to the identification of 344 conserved mature microRNA sequences. Sequence homology of the identified sequences was found to be 94.76+/-3.95% and 98.87+/-2.24% for both pre- and mature microRNAs, respectively. Results suggest that brain function related to the differentiation of neurons and adaptive neuroprotection may be under microRNA control during bat hibernation. PMID- 24768723 TI - Genome-wide analysis of terpene synthases in soybean: functional characterization of GmTPS3. AB - Terpenes (terpenoids or isoprenoids) constitute a large class of plant natural products and play numerous functional roles in primary and secondary metabolism as well as inecological interactions. This study presents a genomic analysis of 23 putative soybean (Glycine max) terpene synthase genes (GmTPSs) distributed over 10 of 20 chromosomes. The GmTPSs are grouped into six types based on gene architecture and sequence identity. Sequence alignment indicates that most GmTPSs contain the conserved aspartate-rich DDX2D motif, and two clades encoded by TPS-a and TPS-b contain variations of an arginine-rich RRX8W motif. Quantitative real time PCR analysis demonstrated that GmTPSs were predominantly expressed in reproductive organs. Heterologous expression followed by enzymatic assay suggested that GmTPS3 functions as a geraniol synthase. We also generated transgenic tobacco plants ectopically expressing GmTPS3. In dual-choice feeding preference and force-feeding assays, the transgenic tobacco lines expressing GmTPS3 exhibited enhanced resistance to cotton leafworms and an increased level of geraniol. Taken together, these data provide a comprehensive understanding of the TPS family in soybeans and suggest a promising approach to engineering transgenic plants with enhanced insect resistance. PMID- 24768724 TI - Molecular cloning and expression analysis of a new bilin lyase: the cpcT gene encoding a bilin lyase responsible for attachment of phycocyanobilin to Cys-153 on the beta-subunit of phycocyanin in Arthrospira platensis FACHB314. AB - To study the assembly of phycocyanin beta subunit, the gene cpcT was first cloned from Arthrospira platensis FACHB314. To explore the function of cpcT, the DNA of phycocyanin beta subunit and cpcT were transformed into Escherichia coli BL21 with the plasmid pET-hox1-pcyA, which contained the genes hemeoxygenase 1 (Hox1) and ferredoxin oxidoreductase (PcyA) needed to produce phycocyanobilin. The transformed strains showed specific phycocyanin fluorescence, and the fluorescence intensity was stronger than the strains with only phycocyanin beta subunit, indicating that CpcT can promote the assembly of phycocyanin to generate fluorescence. To study the possible binding sites of apo-phycocyanin and phycocyanobilin, the Cys-82 and Cys-153 of the beta subunit were individually mutated, giving two kinds of mutants. The results show that Cys-153 maybe the active site for beta subunit binding to phycocyanobilins, which is catalyzed by CpcT in A. platensis FACHB314. PMID- 24768725 TI - Identification and analysis of a Marsupenaeus japonicus ferritin that is regulated at the transcriptional level by WSSV infection. AB - Marsupenaeus japonicus is a shrimp species of great value in the Chinese aquaculture industry. Given the susceptibility to viral diseases, research efforts have focused on the molecular characteristics of the shrimp's immune mechanisms. Ferritin is well known for its iron storage function, but studies have also addressed its immune function in response to pathogens. In this study, an M. japonicus ferritin cDNA was identified by homology cloning and rapid amplification of cDNA ends-PCR. The full-length cDNA is 1244 bp long and contains an open reading frame (513 bp) that encodes a highly conserved protein of 170 amino acids. Quantitative real-time PCR detection of ferritin revealed high expression in eight tested tissues, with the highest levels in hemocytes consistent with the iron storage capacity of ferritin. We infected M. japonicus with white spot syndrome virus and validated the model by viral copy analysis and histopathology, which demonstrated an increase in viral copies along with acute degeneration of tissues. Transcripts of ferritin increased by 3.1-fold, 2.1-fold, and 1.5-fold in the hepatopancreas, gill, and midgut at 24h post-injection, suggesting that ferritin played an important role in the immune response of M. japonicus. PMID- 24768726 TI - Morphology of antennal sensilla of the brown spruce longhorn beetle, Tetropium fuscum (Fabr.) (Coleoptera: Cerambycidae). AB - The antennal sensilla of the brown spruce longhorn beetle, Tetropium fuscum (Fabr.) (Coleoptera: Cerambycidae) were examined with particular focus on the sensilla present on the apical flagellomere. T. fuscum antennae are composed of 11 segments, namely the scape, pedicel, and nine flagellomeres. Nine types of sensilla were observed: three types of sensilla chaetica, sensilla trichodea, two types of sensilla basiconica, grooved peg sensilla, thick-walled sensilla, and Bohm bristles. Seven of these types were present on the apical flagellomere, the exceptions were sensilla chaetica type 3 and Bohm bristles. There were no significant differences in the distribution or density of sensilla present on the ninth flagellomere of males and females, except that males had significantly more sensilla chaetica type 1, which are put forward as the putative contact chemoreceptors for T. fuscum. PMID- 24768727 TI - Recent development of poly(ethylene glycol)-cholesterol conjugates as drug delivery systems. AB - Poly(ethylene glycol)-cholesterol (PEG-Chol) conjugates are composed of "hydrophilically-flexible" PEG and "hydrophobically-rigid" Chol molecules. PEG Chol conjugates are capable of forming micelles through molecular self-assembly and they are also used extensively for the PEGylation of drug delivery systems (DDS). The PEGylated DDS have been shown to display optimized physical stability properties in vitro and longer half-lives in vivo when compared with non PEGylated DDS. Cell uptake studies have indicated that PEG-Chol conjugates are internalized via clathrin-independent pathways into endosomes and Golgi apparatus. Acid-labile PEG-Chol conjugates are also able to promote the content release of PEGylated DDS when triggered by dePEGylation at acidic conditions. More importantly, biodegradable PEG-Chol molecules have been shown to decrease the "accelerated blood clearance" phenomenon of PEG-DSPE. Ligands, peptides or antibodies which have been modified with PEG-Chols are oftentimes used to formulate active targeting DDS, which have been shown in many systems recently to enhance the efficacy and lower the adverse effects of drugs. Production of PEG Chol is simple and efficient, and production costs are relatively low. In conclusion, PEG-Chol conjugates appear to be very promising multifunctional biomaterials for many uses in the biomedical sciences and pharmaceutical industries. PMID- 24768728 TI - Formulating SLMs as oral pulsatile system for potential delivery of melatonin to pediatric population. AB - The formulation development of melatonin (MLT) for infants and children with neurodevelopmental difficulties was fully investigated. This population have a higher prevalence of sleep disorders and present special challenges for drug administration and swallowing. To solve these issues, solid lipid microparticles (SLMs) were designed to obtain an oral flexible dosage form constituted by GRAS excipients and a free flow pulsatile delivery system for MLT, able to maintain its release through 8h. Three groups of SLMs were produced by spray congealing and characterized as regards particle size, morphology, flowability, solid state, drug content and release behavior. The SLMs manipulation with milk and yogurt and the MLT stability in these foods were also investigated. Microparticles with different excipient composition were selected to obtain a pulsatile release pattern over 8h. The final delivery platform displayed a prompt release from group I SLMs together with a lag phase of groups II and III SLMs, followed by a repeated MLT release from group II and a prolonged MLT release related to the last group. Finally, MLT was compatible and stable in milk and yogurt suggesting that microparticles sprinkled into food is acceptable for MLT administration to children unable to swallow capsules or tablets. PMID- 24768729 TI - Polio vaccines: WHO position paper, January 2014--recommendations. AB - This article presents the World Health Organizations (WHO) evidence and recommendations for the use of polio vaccination from the WHO position paper on polio vaccines - January 2014 recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the WHO position on the introduction of at least one dose of inactivated polio vaccine (IPV) into routine immunization schedules as a strategy to mitigate the potential risk of re-emergence of type 2 polio following the withdrawal of Sabin type 2 strains from oral polio vaccine (OPV). The current document replaces the position paper on the use of polio vaccines published in 2010 [2]. Footnotes to this paper provide a number of core references. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its November 2013 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. PMID- 24768731 TI - Accurately measuring the quality and effectiveness of lumbar surgery in registry efforts: determining the most valid and responsive instruments. AB - BACKGROUND CONTEXT: Prospective registries have emerged as a feasible way to capture real-world care across large patient populations. However, the proven validity of more robust and cumbersome patient-reported outcomes instruments (PROis) must be balanced with what is feasible to apply in large-scale registry efforts. PURPOSE: To determine the relative validity and responsiveness of common PROis in accurately determining effectiveness of lumbar fusion for degenerative lumbar spondylolisthesis in registry efforts. STUDY DESIGN: Prospective cohort study. PATIENT SAMPLE: Fifty-eight patients undergoing transforaminal lumbar interbody fusion (TLIF) for degenerative lumbar spondylolisthesis OUTCOME MEASURES: Patient-reported outcome measures for pain (numeric rating scale for back and leg pain [NRS-BP, NRS-LP]), disability (Oswestry Disability Index [ODI]), general health (Short Form [SF]-12), quality of life (QOL) (EuroQol five dimensions [EQ-5D]), and depression (Zung depression scale [ZDS]) were assessed. METHODS: Fifty-eight patients undergoing primary TLIF for lumbar spondylolisthesis were entered into an institutional registry and prospectively followed for 2 years. Baseline and 2-year patient-reported outcomes were assessed. To assess the validity of PROis to discriminate between effective and noneffective improvements, receiver operating characteristic curves were generated for each outcomes instrument. An area under the curve (AUC) of >=0.80 was considered an accurate discriminator. The difference between standardized response means (SRMs) in patients reporting meaningful improvement versus not was calculated to determine the relative responsiveness of each instrument. RESULTS: For pain and disability, ODI had AUC=0.94, suggesting it as an accurate discriminator of meaningful improvement. Oswestry Disability Index was most responsive to postoperative improvement (SRM difference: 2.18), followed by NRS BP and NRS-LP. For general health and QOL, SF-12 physical component score (AUC: 0.90), ZDS (AUC: 0.89), and SF-12 mental component score (AUC: 0.85) were all accurate discriminators of meaningful improvement, however, EQ-5D was most accurate (AUC: 0.97). EuroQol five dimensions was also most responsive (SRM difference: 2.83). CONCLUSIONS: For pain and disability, ODI was the most valid and responsive measure of effectiveness of lumbar fusion. Numeric rating scale-BP and NRS-LP should not be used as substitutes for ODI in measuring effectiveness of care in registry efforts. For health-related QOL, EQ-5D was the most valid and responsive measure of improvement, however, SF-12 and ZDS are valid alternatives with less responsiveness. PMID- 24768730 TI - The effectiveness of seasonal trivalent inactivated influenza vaccine in preventing laboratory confirmed influenza hospitalisations in Auckland, New Zealand in 2012. AB - BACKGROUND: Few studies report the effectiveness of trivalent inactivated influenza vaccine (TIV) in preventing hospitalisation for influenza-confirmed respiratory infections. Using a prospective surveillance platform, this study reports the first such estimate from a well-defined ethnically diverse population in New Zealand (NZ). METHODS: A case test-negative design was used to estimate propensity adjusted vaccine effectiveness. Patients with a severe acute respiratory infection (SARI), defined as a patient of any age requiring hospitalisation with a history of a fever or a measured temperature >=38 degrees C and cough and onset within the past 7 days, admitted to public hospitals in South and Central Auckland were eligible for inclusion in the study. Cases were SARI patients who tested positive for influenza, while non-cases (controls) were SARI patients who tested negative. Results were adjusted for the propensity to be vaccinated and the timing of the influenza season. RESULTS: The propensity and season adjusted vaccine effectiveness (VE) was estimated as 39% (95% CI 16;56). The VE point estimate against influenza A (H1N1) was lower than for influenza B or influenza A (H3N2) but confidence intervals were wide and overlapping. Estimated VE was 59% (95% CI 26;77) in patients aged 45-64 years but only 8% ( 78;53) in those aged 65 years and above. CONCLUSION: Prospective surveillance for SARI has been successfully established in NZ. This study for the first year, the 2012 influenza season, has shown low to moderate protection by TIV against influenza positive hospitalisation. PMID- 24768732 TI - Lumbar disc nomenclature: version 2.0: Recommendations of the combined task forces of the North American Spine Society, the American Society of Spine Radiology and the American Society of Neuroradiology. AB - BACKGROUND CONTEXT: The paper ''Nomenclature and classification of lumbar disc pathology, recommendations of the combined task forces of the North American Spine Society, the American Society of Spine Radiology and the American Society of Neuroradiology,'' was published in 2001 in Spine ((c) Lippincott, Williams & Wilkins). It was authored by David Fardon, MD, and Pierre Milette, MD, and formally endorsed by the American Society of Spine Radiology (ASSR), American Society of Neuroradiology (ASNR), and North American Spine Society (NASS). Its purpose was to promote greater clarity and consistency of usage of spinal terminology, and it has served this purpose well for over a decade. Since 2001, there has been sufficient evolution in our understanding of the lumbar disc to suggest the need for revision and updating of the original document. The revised document is presented here, and it represents the consensus recommendations of contemporary combined task forces of the ASSR, ASNR, and NASS. This article reflects changes consistent with current concepts in radiologic and clinical care. PURPOSE: To provide a resource that promotes a clear understanding of lumbar disc terminology amongst clinicians, radiologists, and researchers. All the concerned need standard terms for the normal and pathologic conditions of lumbar discs that can be used accurately and consistently and thus best serve patients with disc disorders. STUDY DESIGN: This article comprises a review of the literature. METHODS: A PubMed search was performed for literature pertaining to the lumbar disc. The task force members individually and collectively reviewed the literature and revised the 2001 document. The revised document was then submitted for review to the governing boards of the ASSR, ASNR, and NASS. After further revision based on the feedback from the governing boards, the article was approved for publication by the governing boards of the three societies, as representative of the consensus recommendations of the societies. RESULTS: The article provides a discussion of the recommended diagnostic categories pertaining to the lumbar disc: normal; congenital/developmental variation; degeneration; trauma; infection/inflammation; neoplasia; and/or morphologic variant of uncertain significance. The article provides a glossary of terms pertaining to the lumbar disc, a detailed discussion of these terms, and their recommended usage. Terms are described as preferred, nonpreferred, nonstandard, and colloquial. Updated illustrations pictorially portray certain key terms. Literature references that provided the basis for the task force recommendations are included. CONCLUSIONS: We have revised and updated a document that, since 2001, has provided a widely acceptable nomenclature that helps maintain consistency and accuracy in the description of the anatomic and physiologic properties of the normal and abnormal lumbar disc and that serves as a system for classification and reporting built upon that nomenclature. PMID- 24768733 TI - Percutaneous dorsal instrumentation for thoracolumbar extension-distraction fractures in patients with ankylosing spinal disorders: a case series. AB - BACKGROUND CONTEXT: Thoracolumbar extension-distraction fractures are rare injuries mainly restricted to patients suffering from ankylosing spinal disorders. The most appropriate surgical treatment of these unstable spinal injuries remains to be clarified. PURPOSE: To report on a cohort of 10 patients treated with closed reduction and percutaneous dorsal instrumentation. STUDY DESIGN: Case series. PATIENT SAMPLE: Ten consecutive patients with ankylosing spinal disorders and thoracolumbar extension-distraction fractures (Type B3 according to the AOSpine Thoracolumbar Spine Injury Classification System). OUTCOME MEASURES: Postoperative reduction, alignment, and implant position were analyzed by computed tomography. Loss of reduction was assessed on lateral radiographs by using the Cobb technique. Ambulation ability and pain were assessed at follow-up. METHODS: Minimally invasive dorsal percutaneous instrumentation was performed in 10 consecutive patients (3 men, 7 women) with a mean age of 81.5 (range 72-90) years between May 2010 and December 2012. The mean postoperative follow-up time was 7.9 (range 4-28) months. RESULTS: All 10 patients were treated with closed reduction and dorsal instrumentation; in no case was conversion to an open approach required. The mean operation time was 60.2 (range 32-135) minutes. None of the patients presented neurologic deficits. Cement-augmented screws were implanted in two cases. Sufficient radiographic correction was achieved in all patients; no case of loss of reduction was noted at final follow-up. In one case, complete hardware removal was performed 9 months after the index operation because of persistent back pain at the level of the implant. One patient died of postoperative inferior vena cava obstruction. At discharge, all patients were able to ambulate without the need for crutches or opioid analgesics. At final follow-up, all patients ambulated with full weight bearing; four patients reported persistent back pain. CONCLUSIONS: In fragile patients with ankylosing spinal disorders and thoracolumbar extension-distraction fractures, closed reduction and percutaneous dorsal instrumentation provide a satisfying midterm functional outcome while minimizing perioperative risks compared with conventional dorsoventral procedures. PMID- 24768735 TI - Gene expression regulation of Bcl2, Bax and cytochrome-C by geraniol on chronic MPTP/probenecid induced C57BL/6 mice model of Parkinson's disease. AB - Parkinson's disease (PD) is a common disabling movement disorder owing to progressive depletion of dopamine in nigrostriatal region, and can be experimentally accelerated by the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP). MPTP-treated mice are a representative animal model for searching for the therapeutic agents for PD without adverse effect. In this study we investigated the effect of geraniol (GE) on chronic MPTP/probenecid (MPTP/p) induced apoptotic changes in nigrostriatal region. We observed that chronic exposure to MPTP/p led to increased expression of apoptotic markers, results in neurodegeneration and motor behavioral impairments in mice. Pretreatment with GE to MPTP/p significantly improved motor functions and ameliorated striatal antioxidant balance. In addition, GE attenuated the expression of apoptotic markers evident by the normalized Bcl-2/Bax ratio and decreased expression of cytochrome-C and caspase-9 in the substantia nigra and striatum of MPTP/p induced mice model of PD. The findings of the present study suggested that GE, a new therapeutic potential avenue may have beneficial effects in slowing or preventing the progression of PD and other neurodegenerative disorders. PMID- 24768734 TI - Self-designed posterior atlas polyaxial lateral mass screw-plate fixation for unstable atlas fracture. AB - BACKGROUND CONTEXT: Most atlas fractures can be effectively treated nonoperatively with external immobilization unless there is an injury to the transverse atlantal ligament. Surgical stabilization is most commonly achieved using a posterior approach with fixation of C1-C2 or C0-C2, but these treatments usually result in loss of the normal motion of the C1-C2 and C0-C1 joints. PURPOSE: To clinically validate feasibility, safety, and value of open reduction and fixation using an atlas polyaxial lateral mass screw-plate construct in unstable atlas fractures. STUDY DESIGN: Retrospective review of patients who sustained unstable atlas fractures treated with polyaxial lateral mass screw plate construct. PATIENT SAMPLE: Twenty-two patients with unstable atlas fractures who underwent posterior atlas polyaxial lateral mass screw-plate fixation were analyzed. OUTCOME MEASURES: Visual analog scale, neurologic status, and radiographs for fusion. METHODS: From January 2011 to September 2012, 22 patients with unstable atlas fractures were treated with this technique. Patients' charts and radiographs were reviewed. Bone fusion, internal fixation placement, and integrity of spinal cord and vertebral arteries were assessed via intraoperative and follow-up imaging. Neurologic function, range of motion, and pain levels were assessed clinically on follow-up. RESULTS: All patients were followed up from 12 to 32 months, with an average of 22.5+/-18.0 months. A total of 22 plates were placed, and all 44 screws were inserted into the atlas lateral masses. The mean duration of the procedure was 86 minutes, and the average estimated blood loss was 120 mL. Computed tomography scans 9 months after surgery confirmed that fusion was achieved in all cases. There was no screw or plate loosening or breakage in any patient. All patients had well-preserved range of motion. No vascular or neurologic complication was noted, and all patients had a good clinical outcome. CONCLUSIONS: An open reduction and posterior internal fixation with atlas polyaxial lateral mass screw-plate is a safe and effective surgical option in the treatment of unstable atlas fractures. This technique can provide immediate reduction and preserve C1-C2 motion. PMID- 24768736 TI - Haplotype-based approach for noninvasive prenatal diagnosis of congenital adrenal hyperplasia by maternal plasma DNA sequencing. AB - Prenatal diagnosis of congenital adrenal hyperplasia (CAH) is of clinical significance because in utero treatment is available to prevent virilization of an affected female fetus. However, traditional prenatal diagnosis of CAH relies on genetic testing of fetal genomic DNA obtained using amniocentesis or chorionic villus sampling, which is associated with an increased risk of miscarriage. The aim of this study was to demonstrate the feasibility of a new haplotype-based approach for the noninvasive prenatal testing of CAH due to 21-hydroxylase deficiency. Parental haplotypes were constructed using target-region sequencing data of the parents and the proband. With the assistance of the parental haplotypes, we recovered fetal haplotypes using a hidden Markov model (HMM) through maternal plasma DNA sequencing. In the genomic region around the CYP21A2 gene, the fetus inherited the paternal haplotype '0' alleles linked to the mutant CYP21A2 gene, but the maternal haplotype '1' alleles linked to the wild-type gene. The fetus was predicted to be an unaffected carrier of CAH, which was confirmed by genetic analysis of fetal genomic DNA from amniotic fluid cells. This method was further validated by comparing the inferred SNP genotypes with the direct sequencing data of fetal genomic DNA. The result showed an accuracy of 96.41% for the inferred maternal alleles and an accuracy of 97.81% for the inferred paternal alleles. The haplotype-based approach is feasible for noninvasive prenatal testing of CAH. PMID- 24768737 TI - Adult cerebral adrenoleukodystrophy and Addison's disease in a female carrier. AB - We described a 38-year-old woman of rapidly progressive dementia with white matter encephalopathy and death. She had Addison's disease but the adrenal glands were hyperplastic. Brain magnetic resonance imaging revealed diffuse white matter lesion predominantly in the frontal lobe with band-like contrast enhancement. l Methyl-11C-methionine positron emission tomography revealed accumulation of tracer in bilateral frontal lobes. Stereotactic biopsy demonstrated demyelination changes. A number of urinary organic acids were elevated. Adrenoleukodystrophy was diagnosed by elevated plasma very long chain fatty acid and ABCD1 gene mutation (C1544C/T). Adrenoleukodystrophy should be considered as a differential diagnosis in women with rapidly progressive white matter encephalopathy. PMID- 24768738 TI - Characterization of NADPH-cytochrome P450 reductase gene from the cotton bollworm, Helicoverpa armigera. AB - A complete cDNA encoding the NADPH-cytochrome P450 reductase (haCPR) and its genomic sequence from the cotton bollworm Helicoverpa armigera were cloned and sequenced. The open reading frame of haCPR codes for a protein of 687 amino acid residues with a calculated molecular mass of 77.4kDa. The haCPR gene spans over 11 kb and its coding region is interrupted by 11 introns. haCPR is ubiquitously expressed in various tissues and at various stages of development. Escherichia coli produced haCPR enzyme exhibited catalytic activity for NADPH-dependent reduction of cytochrome c, following Michaelis-Menten kinetics. The functionality of CPR was further demonstrated by its capacity to support cytochrome P450 (e.g. haCYP9A14 and chicken CYP1A5) mediated O-dealkylation activity of alkoxyresorufins. The flavoprotein-specific inhibitor (diphenyleneiodonium chloride, DPI) showed a potent inhibition to haCPR activity (IC50=1.69 MUM). Inhibitory effect of secondary metabolites in the host plants (tannic acid, quercetin and gossypol) on CPR activity (with an IC50 value ranged from 15 to 90 MUM) was also observed. PMID- 24768739 TI - The characteristics of sox gene in Dugesia japonica. AB - Sox genes play important roles in animal developmental processes, including embryogenesis, neural cell stemness, neurogenesis, sex determination, among others. Here, the full length sox gene in planarian Dugesia japonica, named DjsoxB, was cloned using rapid amplification of cDNA ends (RACE). Phylogenetic analysis demonstrates that DjsoxB is highly conserved evolutionarily in metazoans. Whole-mount in situ hybridization found DjsoxB mRNA to be mainly expressed in the head, intestine and mouth in both sexually mature and immature planarians. Moreover, DjsoxB transcripts were detected in the blastema after amputation and throughout the head regeneration processes. The data from real time PCR showed that the mRNA expression levels of DjsoxB were distinctly up regulated from 3 to 7days after amputation. These results suggest that DjsoxB gene might be active in CNS formation and functional recovery during head regeneration, maintenance of adult CNS function and the development of other tissues (e.g. intestine) in D. japonica. PMID- 24768740 TI - Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study. AB - Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-kappaB (NF-kappaB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-kappaB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine. PMID- 24768741 TI - Genetic variants and animal models in SNCA and Parkinson disease. AB - Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the alpha-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The alpha-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD. PMID- 24768743 TI - Comparison and evaluation of immobilization methods for preparing bacterial probes using acidophilic bioleaching bacteria Acidithiobacillus thiooxidans for AFM studies. AB - We evaluated different strategies for constructing bacterial probes for atomic force microscopy studies of bioleaching Acidithiobacillus thiooxidans interacting with pyrite mineral surfaces. Of three available techniques, the bacterial colloidal probe technique is the most reliable and provides a versatile platform for quantifying true interactive forces between bioleaching microorganisms and mineral surfaces. PMID- 24768744 TI - Source apportionment of atmospheric mercury pollution in China using the GEOS Chem model. AB - China is the largest atmospheric mercury (Hg) emitter in the world. Its Hg emissions and environmental impacts need to be evaluated. In this study, China's Hg emission inventory is updated to 2007 and applied in the GEOS-Chem model to simulate the Hg concentrations and depositions in China. Results indicate that simulations agree well with observed background Hg concentrations. The anthropogenic sources contributed 35-50% of THg concentration and 50-70% of total deposition in polluted regions. Sensitivity analysis was performed to assess the impacts of mercury emissions from power plants, non-ferrous metal smelters and cement plants. It is found that power plants are the most important emission sources in the North China, the Yangtze River Delta (YRD) and the Pearl River Delta (PRD) while the contribution of non-ferrous metal smelters is most significant in the Southwest China. The impacts of cement plants are significant in the YRD, PRD and Central China. PMID- 24768742 TI - Does the brain shrink as the waist expands? AB - Recent studies suggest that being overweight or obese is related to worse cognitive performance, particularly executive function. Obesity may also increase the risk of Alzheimer's disease. Consequently, there has been increasing interest in whether adiposity is related to gray or white matter (GM, WM) atrophy. In this review, we identified and critically evaluated studies assessing obesity and GM or WM volumes either globally or in specific regions of interest (ROIs). Across all ages, higher adiposity was consistently associated with frontal GM atrophy, particularly in prefrontal cortex. In children and adults <40 years of age, most studies found no relationship between adiposity and occipital or parietal GM volumes, whereas findings for temporal lobe were mixed. In middle-aged and aged adults, a majority of studies found that higher adiposity is associated with parietal and temporal GM atrophy, whereas results for precuneus, posterior cingulate, and hippocampus were mixed. Higher adiposity had no clear association with global or regional WM in any age group. We conclude that higher adiposity may be associated with frontal GM atrophy across all ages and parietal and temporal GM atrophy in middle and old age. PMID- 24768745 TI - Anatomical and genotype-specific mechanosensory responses in Drosophila melanogaster larvae. AB - Afferent neurons commonly exhibit a somatotopic arrangement in the central nervous system that organizes spatially discrete sensory input. We are interested in how that spatial input gets integrated into motor commands. With resources for screening genes and neural circuits, and given that the cells and ion channels that transduce tactile stimuli in Drosophila larvae are remarkably well characterized, larval mechanosensation is an ideal system for investigating how specific behaviors emerge from localized sensory input. We observed that crawling larvae are more reactive to a 20mN tactile stimulus on the head than on the tail or abdomen. Behavioral responses that were evoked by the stimuli also depended on where the stimulus was delivered. Differences in relative sensitivity were observed in different genotypes, e.g., a null white mutant and hypomorphic smn mutant are significantly more reactive to tail touches than Canton-S larvae. Responses were inhibited by silencing chemical transmission in a combination of multidendritic and chordotonal neurons, but not by inhibiting any specific subset of neurons. Extracellular recordings from segmental nerves revealed that sensory evoked responses exhibit spike-timing dependence at the neural circuit level. Tactile stimuli reduced endogenous firing frequency and increased bursting periods when applied during periods of motor activity. The same stimulus initiated bursts of activity when applied during inactive periods. Together, these data depict the spatial and temporal complexity of mechanosensation as it applies to action selection, and provide a foundation for addressing how neural circuits in the CNS adjust their activity to afferent input. PMID- 24768746 TI - Motor learning in common marmosets: vestibulo-ocular reflex adaptation and its sensitivity to inhibitors of Purkinje cell long-term depression. AB - Adaptation of the horizontal vestibulo-ocular reflex (HVOR) provides an experimental model for cerebellum-dependent motor learning. We developed an eye movement measuring system and a paradigm for induction of HVOR adaptation for the common marmoset. The HVOR gain in dark measured by 10 degrees (peak-to-peak amplitude) and 0.11-0.5Hz turntable oscillation was around unity. The gain-up and gain-down HVOR adaptation was induced by 1h of sustained out-of-phase and in phase 10 degrees -0.33Hz combined turntable-screen oscillation in the light, respectively. To examine the role of long-term depression (LTD) of parallel fiber Purkinje cell synapses, we intraperitonially applied T-588 or nimesulide, which block the induction of LTD in vitro or in vivo preparations, 1h before the test of HVOR adaptation. T-588 (3 and 5mg/kg body weight) did not affect nonadapted HVOR gains, and impaired both gain-up and gain-down HVOR adaptation. Nimesulide (3 and 6mg/kg) did not affect nonadapted HVOR gains, and impaired gain-up HVOR adaptation dose-dependently; however, it very little affected gain-down HVOR adaptation. These findings are consistent with the results of our study of nimesulide on the adaptation of horizontal optokinetic response in mice (Le et al., 2010), and support the view that LTD underlies HVOR adaptation. PMID- 24768747 TI - Surgery on spinal epidural metastases (SEM) in renal cell carcinoma: a plea for a new paradigm. AB - BACKGROUND CONTEXT: Prediction models for outcome of decompressive surgical resection of spinal epidural metastases (SEM) have in common that they have been developed for all types of SEM, irrespective of the type of primary tumor. It is our experience in clinical practice, however, that these models often fail to accurately predict outcome in the individual patient. PURPOSE: To investigate whether decision making could be optimized by applying tumor-specific prediction models. For the proof of concept, we analyzed patients with SEM from renal cell carcinoma that we have operated on. STUDY DESIGN/SETTING: Retrospective chart analysis 2006 to 2012. PATIENT SAMPLE: Twenty-one consecutive patients with symptomatic SEM of renal cell carcinoma. OUTCOME MEASURES: Predictive factors for survival. METHODS: Next to established predictive factors for survival, we analyzed the predictive value of the Motzer criteria in these patients. The Motzer criteria comprise a specific and validated risk model for survival in patients with renal cell carcinoma. RESULTS: After multivariable analysis, only Motzer intermediate (hazard ratio [HR] 17.4, 95% confidence interval [CI] 1.82 166, p=.01) and high risk (HR 39.3, 95% CI 3.10-499, p=.005) turned out to be significantly associated with survival in patients with renal cell carcinoma that we have operated on. CONCLUSIONS: In this study, we have demonstrated that decision making could have been optimized by implementing the Motzer criteria next to established prediction models. We, therefore, suggest that in future, in patients with SEM from renal cell carcinoma, the Motzer criteria are also taken into account. PMID- 24768748 TI - Massive cervical pneumorrhachis secondary orbital fracture. PMID- 24768750 TI - Can brief measures effectively screen for pain and somatic malingering? Examination of the Modified Somatic Perception Questionnaire and Pain Disability Index. AB - BACKGROUND CONTEXT: Recent rise in fraudulent disability claims in the United States has resulted in psychologists being increasingly called upon to use psychological tests to determine whether disability claims based on psychological or somatic/pain complaints are legitimate. PURPOSE: To examine two brief measures, Modified Somatic Perception Questionnaire (MSPQ) and the Pain Disability Index (PDI), and their ability to screen for malingering in relation to the Bianchini et al. criteria for malingered pain-related disability published in The Spine Journal (2005). STUDY DESIGN: Examined brief self-report measures between litigating and nonlitigating pain samples. PATIENT SAMPLE: We compared 144 disability litigants, predominantly presenting a history of musculoskeletal injuries with psychiatric overlay, with 167 nonlitigating pain patients who were predominantly in treatment for chronic back pain issues and other musculoskeletal conditions. OUTCOME MEASURES: Modified Somatic Perception Questionnaire, Pain Disability Index, Minnesota Multiphasic Personality Inventory-2 Restructured Form, Test of Memory Malingering, Letter Memory Test, Victoria Symptom Validity Test, Structured Interview of Reported Symptoms-second edition, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders somatoform disorders module. METHODS: We examined a sample of 144 individuals undergoing compensation-seeking evaluations in relation to 167 nonlitigating pain patients. RESULTS: Group differences on both the MSPQ and PDI were calculated, as well as sensitivities, specificities, and positive and negative predictive powers for both measures at selected cutoffs. CONCLUSIONS: The results suggest that both the MSPQ and PDI are useful to screen for pain malingering in forensic evaluations, especially the MSPQ, which performed the best in differentiating between the groups. PMID- 24768749 TI - Detrimental effects of discectomy on intervertebral disc biology can be decelerated by growth factor treatment during surgery: a large animal organ culture model. AB - BACKGROUND CONTEXT: Lumbar discectomies are common surgical interventions that treat radiculopathy by removing herniated and loose intervertebral disc (IVD) tissues. However, remaining IVD tissue can continue to degenerate resulting in long-term clinical problems. Little information is available on the effects of discectomy on IVD biology. Currently, no treatments exist that can suspend or reverse the degeneration of the remaining IVD. PURPOSE: To improve the knowledge on how discectomy procedures influence IVD physiology and to assess the potential of growth factor treatment as an augmentation during surgery. STUDY DESIGN: To determine effects of discectomy on IVDs with and without transforming growth factor beta 3 (TGFbeta3) augmentation using bovine IVD organ culture. METHODS: This study determined effects of discectomy with and without TGFbeta3 injection using 1-, 6-, and 19-day organ culture experiments. Treated IVDs were injected with 0.2 MUg TGFbeta3 in 20 MUL phosphate-buffered saline+bovine serum albumin into several locations of the discectomy site. Cell viability, gene expression, nitric oxide (NO) release, IVD height, aggrecan degradation, and proteoglycan content were determined. RESULTS: Discectomy significantly increased cell death, aggrecan degradation, and NO release in healthy IVDs. Transforming growth factor beta 3 injection treatment prevented or mitigated these effects for the 19-day culture period. CONCLUSIONS: Discectomy procedures induced cell death, catabolism, and NO production in healthy IVDs, and we conclude that post discectomy degeneration is likely to be associated with cell death and matrix degradation. Transforming growth factor beta 3 injection augmented discectomy procedures by acting to protect IVD tissues by maintaining cell viability, limiting matrix degradation, and suppressing NO. We conclude that discectomy procedures can be improved with injectable therapies at the time of surgery although further in vivo and human studies are required. PMID- 24768751 TI - The morphology and clinical significance of the dorsal meningovertebra ligaments in the cervical epidural space. AB - BACKGROUND CONTEXT: The dural sac is anchored within the vertebral canal by connective tissue called meningovertebral ligaments in the epidural space. During flavectomy and laminectomy, inadvertent disruption of the dorsal meningovertebral ligaments may lead to dura laceration and cerebrospinal fluid (CSF) leaks. All the described dorsal meningovertebral ligaments were located in the lumbar region. A rare study is available about dorsal meningovertebral ligaments of the cervical spinal dura to the adjacent vertebrae. PURPOSE: To identify and describe the dorsal meningovertebral ligaments at each cervical level and discuss their clinical significance. STUDY DESIGN: A dissection-based study of 22 embalmed cadavers. METHODS: The anatomy was studied in 22 whole cervical cadavers (11 females, 11 males), prepared with formaldehyde, whose ages at the time of death ranged from 55 to 78 years. The vertebral canal was divided to expose the dural sac and the spinal nerve roots. At all levels of the cervical vertebra, the morphology, quantity, origin, insertion, and spatial orientation of the dorsal meningovertebral ligaments were determined and the length, width or diameter, and thickness of the ligaments were measured with vernier calipers. RESULTS: The dorsal meningovertebral ligaments in the cervical region anchored the posterior dural sac to the ligamentum flavum or laminae. The number of attachment points on the ligamentum flavum was relatively larger than that on the lamina, and the occurrence rate of dorsal meningovertebral ligaments was 100% at C1-C2 and C4- C5. The thickest ligaments were observed at the C1 and C2 vertebrae. The length of the ligaments varied from 1.50 to 35.22 mm, and the orientation of the ligaments mostly was craniocaudal. The morphology of the dorsal meningovertebral ligaments was divided into four types: strip type, cord type, grid type, and thin slice type. CONCLUSIONS: In the cervical spine, the dorsal meningovertebral ligaments exist between the posterior dural sac and the ligamentum flavum or lamina. The dorsal meningovertebral ligaments may be of clinical importance to surgeons. Dissecting the dorsal meningovertebral ligaments before the cervical flavectomy and laminectomy may be an important step in reducing postoperative dura laceration and CSF leaks, which may result in significant benefits for patients and health-care organizations. PMID- 24768752 TI - The effect of different surface treatments on the bond strength of PEEK composite materials. AB - OBJECTIVES: To evaluate the effect of different surface treatments on the bond strength between polyetheretherketone (PEEK) composite materials and each of two different luting cements. METHODS: One hundred specimens were randomly divided into five groups (n=20/group) as follows: (A) no treatment, (B) 98% sulfuric acid, (C) 9.5% hydrofluoric acid, (D) argon plasma treatment, and (E) sandblast with 50MUm Al2O3 particles. Each group was divided into two subgroups of different cements: RelyXTM Unicem and SE Bond/Clearfil AP-XTM. The cements were bonded onto the specimens. All specimens were stored in distilled water at 37 degrees for 24h. Bond strength was measured in a shear test, and failure modes were assessed by stereomicroscopy. The surfaces were observed by SEM after the different pretreatments. RESULTS: Etching with 98% sulfuric acid and argon plasma treatment can significantly enforce the bond strength of RelyXTM Unicem or SE Bond/Clearfil AP-XTM to PEEK composite materials in comparison to the group of no treatment, hydrofluoric acid or sandblasting (p<0.05). No adhesion was established on the groups of no treatment and hydrofluoric acid when RelyXTM Unicem was used. Applying the SE Bond/Clearfil AP-XTM system, no statistical differences were found whether hydrofluoric acid was applied or not (p>0.05). The shear bond strength value of using SE Bond/Clearfil AP-XTM was higher than that of using RelyXTM Unicem with the same surface conditioning method (p<0.05). SIGNIFICANCE: The use of SE Bond/Clearfil AP-XTM after the surface of PEEK composite material treated with sulfuric acid or argon plasma can be recommended as an effective bonding method. PMID- 24768753 TI - Reversible paralysis of Schistosoma mansoni by forchlorfenuron, a phenylurea cytokinin that affects septins. AB - Septins are guanosine-5'-triphosphate-binding proteins involved in wide-ranging cellular processes including cytokinesis, vesicle trafficking, membrane remodelling and scaffolds, and with diverse binding partners. Precise roles for these structural proteins in most processes often remain elusive. Identification of small molecules that inhibit septins could aid in elucidating the functions of septins and has become increasingly important, including the description of roles for septins in pathogenic phenomena such as tumorigenesis. The plant growth regulator forchlorfenuron, a synthetic cytokinin known to inhibit septin dynamics, likely represents an informative probe for septin function. This report deals with septins of the human blood fluke Schistosoma mansoni and their interactions with forchlorfenuron. Recombinant forms of three schistosome septins, SmSEPT5, SmSEPT7.2 and SmSEPT10, interacted with forchlorfenuron, leading to rapid polymerization of filaments. Culturing developmental stages (miracidia, cercariae, adult males) of schistosomes in FCF at 50-500 MUM rapidly led to paralysis, which was reversible upon removal of the cytokinin. The reversible paralysis was concentration-, time- and developmental stage-dependent. Effects of forchlorfenuron on the cultured schistosomes were monitored by video and/or by an xCELLigence-based assay of motility, which quantified the effect of forchlorfenuron on fluke motility. The findings implicated a mechanism targeting a molecular system controlling movement in these developmental stages: a direct effect on muscle contraction due to septin stabilization might be responsible for the reversible paralysis, since enrichment of septins has been described within the muscles of schistosomes. This study revealed the reversible effect of forchlorfenuron on both schistosome motility and its striking impact in hastening polymerization of septins. These novel findings suggested routes to elucidate roles for septins in this pathogen, and exploitation of derivatives of forchlorfenuron for anti-schistosomal drugs. PMID- 24768754 TI - Changes in bone Pb accumulation: cause and effect of altered bone turnover. AB - This paper assesses the magnitude of Pb uptake in cortical and trabecular bones in healthy animals and animals with altered balance in bone turnover, and the impact of exposure to Pb on serum markers of bone formation and resorption. The results reported herein provide physiological evidence that Pb distributes differently in central compartments in Pb metabolism, such as cortical and trabecular bones, in healthy animals and animals with altered balance in bone turnover, and that exposure to Pb does have an impact on bone resorption resulting in OC-dependent osteopenia. These findings show that Pb may play a role in the etiology of osteoporosis and that its concentration in bones varies as a result of altered bone turnover characteristic of this disease, a long standing question in the field. In addition, data collected in this study are consistent with previous observations of increased half-life of Pb in bone at higher exposures. This evidence is relevant for the necessary revision of current physiologically based kinetic models for Pb in humans. PMID- 24768755 TI - "Resuscitation" of marginal liver allografts for transplantation with machine perfusion technology. AB - As the rate of medically suitable donors remains relatively static worldwide, clinicians have looked to novel methods to meet the ever-growing demand of the liver transplant waiting lists worldwide. Accordingly, the transplant community has explored many strategies to offset this deficit. Advances in technology that target the ex vivo "preservation" period may help increase the donor pool by augmenting the utilization and improving the outcomes of marginal livers. Novel ex vivo techniques such as hypothermic, normothermic, and subnormothermic machine perfusion may be useful to "resuscitate" marginal organs by reducing ischemia/reperfusion injury. Moreover, other preservation techniques such as oxygen persufflation are explored as they may also have a role in improving function of "marginal" liver allografts. Currently, marginal livers are frequently discarded or can relegate the patient to early allograft dysfunction and primary non-function. Bench to bedside advances are rapidly emerging and hold promise for expanding liver transplantation access and improving outcomes. PMID- 24768756 TI - IgG4 cholangiopathy: current concept, diagnosis, and pathogenesis. AB - IgG4 related cholangiopathy, a distinctive type of cholangitis of unknown origin, is characterized by increased serum levels of IgG4, massive infiltration of IgG4 positive plasma cells with storiform fibrosis and/or obliterative phlebitis in the thickened bile duct wall, and good response to steroids. Patients with IgG4 cholangiopathy are frequently associated with autoimmune pancreatitis; IgG4 cholangiopathy is recognized as a biliary manifestation of IgG4-related disease. This condition can be diagnosed by a combination of imaging, serology, histopathology, and steroid responsiveness; however, cholangiographic features are often difficult to differentiate from primary sclerosing cholangitis, pancreatic cancer, or cholangiocarcinoma. The Japanese clinical diagnostic criteria for IgG4-related sclerosing cholangitis established in 2012 are useful in the diagnosis of IgG4-cholangiopathy. Although the precise pathogenic mechanism remains unclear, the development of IgG4-cholangiopathy may involve: susceptible genetic factors, abnormal innate and acquired immunity, decreased naive regulatory T cells, and specific B cell responses. Further studies on genetic backgrounds, disease specific antigens, and the role of IgG4 are necessary to clarify the pathogenesis. PMID- 24768757 TI - An apology for beta blockers. PMID- 24768758 TI - IFNL3 polymorphisms predict response to therapy in chronic hepatitis C genotype 2/3 infection. AB - BACKGROUND & AIMS: Single nucleotide polymorphisms (SNPs) near the interferon lambda 3 (IFNL3, previously known as IL28B) region are the strongest baseline predictors of sustained virologic response (SVR) to pegylated interferon and ribavirin therapy in hepatitis C virus (HCV) genotype 1 infection. Whether IFNL3 SNPs influence treatment response in genotype 2 and 3 (HCV-2/3) infection remains controversial. This study sought to clarify in a large cohort, whether SNPs in the IFNL3 region are associated with treatment response in HCV-2/3 patients. METHODS: The cohort comprised 1002 HCV-2/3 Caucasians patients treated with pegylated interferon-alpha and ribavirin who underwent genotyping for the SNPs rs12979860 and rs8099917. RESULTS: Overall, 736 (73.5%) patients achieved SVR (81.9%, 67.9%, and 57.8% for rs12979860 CC, CT, and TT [p = 0.0001]; 78%, 68.7%, and 46.3% for rs8099917 TT, TG, and GG [p = 0.0001]). By logistic regression, both rs12979860 CC and rs8099917 TT were independent predictors of SVR with an odds ratio (OR) of 2.39 (1.19-3.81) p = 0.0001 and OR 1.85 (1.15-2.23) p = 0.0001, respectively. IFNL3 responder genotypes were more frequent in relapsers than null-responders (p = 0.0001 for both SNPs). On-treatment rapid virological response (RVR) was predictive of SVR only in those individuals with IFNL3 non responder genotypes (rs12979860 CT/TT and rs8099917 TG/GG). CONCLUSIONS: This adequately powered study in patients with HCV genotypes 2 or 3 infection clearly demonstrates that IFNL3 genotypes are the strongest baseline predictor of SVR, in keeping with the known association for genotype 1 infection. IFNL3 genotyping can aid in therapeutic decision making for these patients. PMID- 24768759 TI - Recent sensing technologies for pathogen detection in milk: a review. AB - Quality control utilising Hazard Analysis and Critical Control Points in the dairy industry generates a large volume of samples. The associated costs are significant. The development and application of fast, sensitive and cost effective analytical systems for pathogen detection in milk could aid the industry in the reduction of overheads, find new uses in dairy farming and production precision management and unlock new markets. Recent progress in pathogen sensing technologies for milk analysis, in particular nucleic acid amplification and biosensors, is reviewed here. The importance of representative samples, detection probability and Practical Detection Limit is clarified. Methods for sample pretreatment are discussed in association with the most applicable detection methods. The major findings are summarised and future perspectives are drawn to inspire new ideas in the scientific community. PMID- 24768760 TI - Graphene oxide-DNA based sensors. AB - Since graphene oxide (GO) is readily available and exhibits exceptional optical, electrical, mechanical and chemical properties, it has attracted increasing interests for use in GO-DNA based sensors. This paper reviews the advances in GO DNA based sensors using DNA as recognition elements. In solution, GO is as an excellent acceptor of fluorescence resonance energy transfer (FRET) to quench the fluorescence in dye labeled DNA sequences. This review discusses the emerging GO DNA based sensors related to FRET for use in the detection of DNA, proteins, metal ions, cysteine (Cys), and others. The application of the electrochemical GO DNA based sensors is also summarized because GO possesses exceptional electrochemical properties. The detection mechanisms and the advantages of GO are also revealed and discussed. GO-DNA based sensors perform well at low cost, and high sensitivity, and provide low detection limits. Additionally, GO-DNA based sensors should appear in the near future as scientists explore their usefulness and properties. Finally, future perspectives and possible challenges in this area are outlined. PMID- 24768761 TI - Effects of cattail biomass on sulfate removal and carbon sources competition in subsurface-flow constructed wetlands treating secondary effluent. AB - Sulfate is frequently found in the influent of subsurface-flow constructed wetlands (SSF CWs) used as tertiary treatments. To reveal the effects of plants and litters on sulfate removal, as well as the competition for organic carbon among microorganisms in SSF CWs, five laboratory-scale SSF CW microcosms were set up and were operated as a batch system with HRT 5 d. The results showed that the presence of Typha latifolia had little effect on sulfate removal in CWs, with or without additional carbon sources. Cattail litter addition greatly improved sulfate removal in SSF CWs. This improvement was linked to the continuous input of labile organic carbon, which lowers the redox level and supplies a habitat for sulfate reducing bacteria (SRB). The presence of SRB in cattail litter indicated the possibility of sulfate removal around the carbon supplier, but the quantity of microbes in cattail litter was much lower than that in gravel. Stoichiometry calculations showed that the contribution of SRB to COD removal (21-26%) was less than that of methane-producing bacteria (MPB) (47-61%) during the initial stage but dominated COD removal (42-65%) during the terminal stage. The contributions of aerobic bacteria (AB) and denitrification bacteria (DB) to COD removal were always lower than that of SRB. It was also observed that the variations in COD: S ratio had a great influence on the relative abundance of genes between SRB and MPB and both of them could be used as good predictors of carbon competition between SRB and MPB in CWs. PMID- 24768762 TI - Photochemical activation increases the porcine corneal stiffness and resistance to collagenase digestion. AB - In this study, we explore the effect of photochemical activation induced corneal cross-linking, utilizing Rose Bengal (RB) and 532 nm green light irradiation (RB PCL), on porcine corneal biomechanical rigidity and the biochemical resistance against collagenase digestion. A protocol with a wavelength of 532 nm and illumination intensity of 0.4W/cm(2) for 250 s to deliver a dose of 100 J/cm(2) was chosen. Using confocal microscopy, we demonstrated that the diffusion depth of RB into porcine cornea was approximately 150 MUm and mostly localized in anterior stroma 25 min followed by RB application. After photochemical cross linking, an increase in tensile strength (by average 200%) and Young's modulus (by average 200%) in porcine corneas was observed. The corneal buttons treated by RB-PCL showed doubling of collagenase digestion time from 10.8 +/- 3.1 days in the blank group to 19.7 +/- 6.2 days in the RB-PCL group, indicating increased resistance to enzymatic digestion. In conclusion, Collagen cross-linking by RB PCL increased both the biomechanical stiffness and the biochemical resistance against collagenase digestion in porcine corneas, therefore to allow stabilizing and solidifier the cornea. The advantages and disadvantages of RB-PCL versus UVA/riboflavin cross-linking technique (UV-CXL) are fully explored. Due to the nature of minimal penetration of RB into corneal stroma, the RB-PCL method could potentially be used in patients with corneal thickness less than 400 MUm where UV CXL is limited. PMID- 24768763 TI - Comparison of auditory responses determined by acoustic stimulation and by mechanical round window stimulation at equivalent stapes velocities. AB - Active middle ear implants (AMEIs) have been studied to overcome the limitations of conventional hearing aids such as howling, occlusion, and social discrimination. AMEIs usually drive the oval window (OW) by means of transmitting vibrational force through the ossicles and the vibrational force corresponding to sound is generated from a mechanical actuator. Recently, round window (RW) stimulation using an AMEI such as a floating mass transducer (FMT) to deliver sound to the cochlea has been introduced and hearing improvement in clinical use has been reported. Although previous studies demonstrated that the auditory response to RW stimulation was comparable to a sound-evoked auditory response, few studies have investigated the quantification of the physiologic performance of an AMEI through RW stimulation on the inner ear in vivo. There is no established relationship between the cochlear responses and mechanical stimulation to RW. The aim of this study is to assess the physiologic response in RW stimulation by an AMEI. The transferred energy through the RW to the inner ear could estimate the response corresponding to acoustic stimulation in order to quantify the AMEI output in the ossicular chain or OW stimulation. The parameters of the auditory brainstem responses (ABRs) were measured and compared based on stapes velocities similar enough to be regarded as the same for acoustic stimulation to the external auditory canal (EAC) and mechanical stimulation to the RW in an in vivo system. In conclusion, this study showed that the amplitudes and latencies of the ABRs of acoustic and RW stimulation showed significant differences at comparable stapes velocities in an in vivo system. These differences in the ABR amplitudes and latencies reflect different output functions of the cochlea in response to different stimulation pathways. Therefore, it is necessary to develop a new method for quantifying the output of the cochlea in the case of RW stimulation. PMID- 24768764 TI - Time-frequency analysis of transient evoked-otoacoustic emissions in individuals with auditory neuropathy spectrum disorder. AB - The aim of the study was to describe and quantify the cochlear active mechanisms in individuals with Auditory Neuropathy Spectrum Disorders (ANSD). Transient Evoked Otoacoustic Emissions (TEOAEs) were recorded in 15 individuals with ANSD and 22 individuals with normal hearing. TEOAEs were analyzed by Wavelet transform method to describe and quantify the characteristics of TEOAEs in narrow-band frequency regions. It was noted that the amplitude of TEOAEs was higher and latency slightly shorter in individuals with ANSD compared to normal hearing individuals at low and mid frequencies. The increased amplitude and reduced latencies of TEOAEs in ANSD group could be attributed to the efferent system damage, especially at low and mid frequencies seen in individuals with ANSD. Thus, wavelet analysis of TEOAEs proves to be another important tool to understand the patho-physiology in individuals with ANSD. PMID- 24768765 TI - Hydra actinoporin-like toxin-1, an unusual hemolysin from the nematocyst venom of Hydra magnipapillata which belongs to an extended gene family. AB - Cnidarians rely on their nematocysts and the venom injected through these unique weaponry systems to catch prey and protect themselves from predators. The development and physiology of the nematocysts of Hydra magnipapillata, a classic model organism, have been intensively studied, yet the composition and biochemical activity of their venom components are mostly unknown. Here, we show that hydra actinoporin-like toxins (HALTs), which have previously been associated with Hydra nematocysts, belong to a multigene family comprising six genes, which have diverged from a single common ancestor. All six genes are expressed in a population of Hydra magnipapillata. When expressed recombinantly, HALT-1 (Delta HYTX-Hma1a), an actinoporin-like protein found in the stenoteles (the main penetrating nematocysts used in prey capture), reveals hemolytic activity, albeit about two-thirds lower than that of the anemone actinoporin equinatoxin II (EqTII, Delta-AITX-Aeq1a). HALT-1 also differs from EqTII in the size of its pores, and likely does not utilize sphingomyelin as a membrane receptor. We describe features of the HALT-1 sequence which may contribute to this difference in activity, and speculate on the role of this unusual family of pore-forming toxins in the ecology of Hydra. PMID- 24768767 TI - GARNL1, a major RalGAP alpha subunit in skeletal muscle, regulates insulin stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins. AB - Insulin and muscle contraction each stimulate translocation of the glucose transporter GLUT4 to the plasma membrane in skeletal muscle, an important process regulating whole-body glucose homeostasis. RalA mediates insulin-stimulated GLUT4 translocation; however, it is unclear how this small GTPase is regulated in skeletal muscle in response to insulin. Here, we identified GARNL1/RalGAPalpha1, a major alpha subunit of the Ral-GTPase activating protein in skeletal muscle, as a protein whose phosphorylation and binding to the regulatory 14-3-3 proteins is stimulated by insulin and also by muscle contraction. The insulin-stimulated interaction with 14-3-3 involved PKB/Akt-mediated phosphorylation of Thr(735) on GARNL1/RalGAPalpha1. Knockdown of GARNL1/RalGAPalpha1 increased, while overexpression of GARNL1/RalGAPalpha1(Thr735Ala) mutant protein decreased, the RalA activation and the RalA-dependent GLUT4 translocation in response to insulin in muscle cells. These findings show that GARNL1/RalGAPalpha1 is the missing link that connects the insulin-PKB/Akt signaling pathway with the activation of the RalA small GTPase in muscle cells. GARNL1/RalGAPalpha1 and its phosphorylation and/or binding to 14-3-3s are critical for GLUT4 trafficking through RalA in muscle cells. PMID- 24768766 TI - Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects. AB - We evaluated whether aliskiren, valsartan, or a combination of both was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9. C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3h post-MI: saline (S), aliskiren (A; 50mg/kg/day), valsartan (V; 40mg/kg/day), or A+V and compared to no MI controls at 28days post-MI. All groups had similar infarct areas, and survival rates were higher in the null mice. The treatments influenced systolic function and hypertrophy index, as well as extracellular matrix (ECM) and inflammatory genes in the remote region, indicating that primary effects were on the viable myocardium. Saline treated WT mice showed increased end systolic and diastolic volumes and hypertrophy index, along with reduced ejection fraction. MMP-9 deletion improved LV function post-MI. Aliskiren attenuated the increase in end systolic volume and hypertrophy index, while valsartan improved end diastolic volumes and aliskiren+valsartan improved the hypertrophy index only when MMP-9 was absent. Extracellular matrix and inflammatory gene expression showed distinct patterns among the treatment groups, indicating a divergence in mechanisms of remodeling. This study shows that MMP-9 regulates aliskiren and valsartan effects in mice. These results in mice provide mechanistic insight to help translate these findings to post-MI patients. PMID- 24768768 TI - Hepassocin activates the EGFR/ERK cascade and induces proliferation of L02 cells through the Src-dependent pathway. AB - Hepassocin (HPS) is a secreted protein with mitogenic activity on primary hepatocytes and protects hepatocytes from chemically-induced injury. Our previous studies showed that HPS stimulates proliferation of hepatocytes in an ERK pathway dependent manner. However, the molecular mechanism of HPS-induced activation of the ERK pathway remains unclear. In this study, we found that HPS induced the phosphorylation of the epidermal growth factor receptor (EGFR) in the human L02 hepatocyte cell line, and this event was concomitant with the activation of the non-receptor tyrosine kinase Src. Specific inhibition of EGFR kinase activity by gefitinib or down-regulation of EGFR by specific EGFR siRNAs prevented HPS induced activation of the ERK pathway and proliferation of L02 cells. Furthermore, inhibition of Src activity significantly blocked HPS-induced activation of the EGFR, which was suggestive of a ligand-independent transactivation mechanism of EGFR itself as well as ERK phosphorylation and proliferation of L02 cells. These results indicate that EGFR plays an important role in the mitogenic signaling induced by HPS in L02 cell lines and may further stimulate research on the role of HPS in hepatocytes within biological processes in human health and disease. PMID- 24768769 TI - Ethnobotany, phytochemistry and pharmacology of Stephania rotunda Lour. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Stephania rotunda Lour. (Menispermaceae) is an important traditional medicinal plant that is grown in Southeast Asia. The stems, leaves, and tubers have been used in the Cambodian, Lao, Indian and Vietnamese folk medicine systems for years to treat a wide range of ailments, including asthma, headache, fever, and diarrhoea. AIM OF THE REVIEW: To provide an up-to date, comprehensive overview and analysis of the ethnobotany, phytochemistry, and pharmacology of Stephania rotunda for its potential benefits in human health, as well as to assess the scientific evidence of traditional use and provide a basis for future research directions. MATERIAL AND METHODS: Peer-reviewed articles on Stephania rotunda were acquired via an electronic search of the major scientific databases (Pubmed, Google Scholar, and ScienceDirect). Data were collected from scientific journals, theses, and books. RESULTS: The traditional uses of Stephania rotunda were recorded in countries throughout Southeast Asia (Cambodia, Vietnam, Laos, and India). Different parts of Stephania rotunda were used in traditional medicine to treat about twenty health disorders. Phytochemical analyses identified forty alkaloids. The roots primarily contain l tetrahydropalmatine (l-THP), whereas the tubers contain cepharanthine and xylopinine. Furthermore, the chemical composition differs from one region to another and according to the harvest period. The alkaloids exhibited approximately ten different pharmacological activities. The main pharmacological activities of Stephania rotunda alkaloids are antiplasmodial, anticancer, and immunomodulatory effects. Sinomenine, cepharanthine, and l-stepholidine are the most promising components and have been tested in humans. The pharmacokinetic parameters have been studied for seven compounds, including the three most promising compounds. The toxicity has been evaluated for liriodenine, roemerine, cycleanine, l-tetrahydropalmatine, and oxostephanine. CONCLUSION: Stephania rotunda is traditionally used for the treatment of a wide range of ailments. Pharmacological investigations have validated different uses of Stephania rotunda in folk medicine. The present review highlights the three most promising compounds of Stephania rotunda, which could constitute potential leads in various medicinal fields, including malaria and cancer. PMID- 24768770 TI - Site specific solubility improvement using solid dispersions of HPMC-AS/HPC SSL- mixtures. AB - Many upcoming drug candidates are pH-dependent poorly soluble weak bases in the pH range of the gastrointestinal tract. This often leads to a high in vivo variability and bioavailability issues. Aiming to overcome these limitations, the design of solid dispersions for site specific dissolution improvement or maintenance of a potent supersaturation over the entire gastro-intestinal pH range, is proposed to assure a reliable drug therapy. Solid dispersions containing different ratios of Dipyridamole (DPD) or Griseofulvin (GRI) and the enteric polymer hydroxypropylmethylcellulose-acetate succinate (HPMC-AS) and the water soluble low-viscosity hydroxypropylcellulose (HPC-SSL) were prepared by hot melt extrusion (HME). The solid dispersions were evaluated for their solid state, dissolution characteristics applying a three pH-step dissolution method following an acidic to neutral pH transition and stability. The use of HPMC-AS in binary mixtures with DPD and GRI facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug, which even inverted the pH-dependent solubility profile of the weakly basic model drug (Dipyridamole). I.e. a potent site specific delivery system was created. With ternary solid dispersions of API, HPMC-AS and HPC-SSL, tailored release profiles with superior supersaturation over the applied pH-range could be obtained. At the same time, binary and ternary mixtures showed favorable stability properties at a temperature difference between glass transition temperature and the applied storage temperature of down to 16 degrees C. PMID- 24768771 TI - The role of dynamics in modulating ligand exchange in intracellular lipid binding proteins. AB - Lipids are essential for many biological processes and crucial in the pathogenesis of several diseases. Intracellular lipid-binding proteins (iLBPs) provide mobile hydrophobic binding sites that allow hydrophobic or amphipathic lipid molecules to penetrate into and across aqueous layers. Thus iLBPs mediate the lipid transport within the cell and participate to a spectrum of tissue specific pathways involved in lipid homeostasis. Structural studies have shown that iLBPs' binding sites are inaccessible from the bulk, implying that substrate binding should involve a conformational change able to produce a ligand entry portal. Many studies have been reported in the last two decades on iLBPs indicating that their dynamics play a pivotal role in regulating ligand binding and targeted release. The ensemble of reported data has not been reviewed until today. This review is thus intended to summarize and possibly generalize the results up to now described, providing a picture which could help to identify the missing notions necessary to improve our understanding of the role of dynamics in iLBPs' molecular recognition. Such notions would clarify the chemistry of lipid binding to iLBPs and set the basis for the development of new drugs. PMID- 24768772 TI - Dynamical properties of alpha-synuclein in soluble and fibrillar forms by Quasi Elastic Neutron Scattering. AB - In the present paper, Quasi Elastic Neutron Scattering (QENS) results, gathered at different energy resolution values at the ISIS Facility (RAL, UK), on alpha synuclein in soluble and fibrillar forms as a function of temperature and exchanged wave-vector Q are shown. The measurements reveal a different dynamic behavior of the soluble and fibrillar forms of alpha-synuclein as a function of thermal stress. In more detail, the dynamics of each protein form reflects its own complex conformational heterogeneity. Furthermore, the effect of a well known bioprotectant, trehalose, that influences alpha-synuclein fibrillation, on both soluble and fibrillar forms of alpha-synuclein is discussed. PMID- 24768773 TI - Structural basis for the substrate specificity and the absence of dehalogenation activity in 2-chloromuconate cycloisomerase from Rhodococcus opacus 1CP. AB - 2-Chloromuconate cycloisomerase from the Gram-positive bacterium Rhodococcus opacus 1CP (Rho-2-CMCI) is an enzyme of a modified ortho-pathway, in which 2 chlorophenol is degraded using 3-chlorocatechol as the central intermediate. In general, the chloromuconate cycloisomerases catalyze not only the cycloisomerization, but also the process of dehalogenation of the chloromuconate to dienelactone. However Rho-2-CMCI, unlike the homologous enzymes from the Gram negative bacteria, is very specific for only one position of the chloride on the substrate chloromuconate. Furthermore, Rho-2-CMCI is not able to dehalogenate the 5-chloromuconolactone and therefore it cannot generate the dienelactone. The crystallographic structure of the homooctameric Rho-2-CMCI was solved by molecular replacement using the coordinates of the structure of chloromuconate cycloisomerase from Pseudomonas putida PRS2000. The structure was analyzed and compared to the other already known structures of (chloro)muconate cycloisomerases. In addition to this, molecular docking calculations were carried out, which allowed us to determine the residues responsible for the high substrate specificity and the lack of dehalogenation activity of Rho-2-CMCI. Our studies highlight that a histidine, located in a loop that closes the active site cavity upon the binding of the substrate, could be related to the dehalogenation inability of Rho-2-CMCI and in general of the muconate cycloisomerases. PMID- 24768774 TI - Structural and functional insights into peptidyl-tRNA hydrolase. AB - Peptidyl-tRNA hydrolase is an essential enzyme which acts as one of the rescue factors of the stalled ribosomes. It is an esterase that hydrolyzes the ester bond in the peptidyl-tRNA molecules, which are products of ribosome stalling. This enzyme is required for rapid clearing of the peptidyl-tRNAs, the accumulation of which in the cell leads to cell death. Over the recent years, it has been heralded as an attractive drug target for antimicrobial therapeutics. Two distinct classes of peptidyl-tRNA hydrolase, Pth and Pth2, have been identified in nature. This review gives an overview of the structural and functional aspects of Pth, along with its sequence and structural comparison among various species of bacteria. While the mode of binding of the substrate to Pth and the mechanism of hydrolysis are still speculated upon, the structure based drug design using this protein as the target is still largely unexplored. This review focuses on the structural features of Pth, giving a direction to structure-based drug design on this protein. PMID- 24768775 TI - Quantifying the costs and benefits of privacy-preserving health data publishing. AB - Cost-benefit analysis is a prerequisite for making good business decisions. In the business environment, companies intend to make profit from maximizing information utility of published data while having an obligation to protect individual privacy. In this paper, we quantify the trade-off between privacy and data utility in health data publishing in terms of monetary value. We propose an analytical cost model that can help health information custodians (HICs) make better decisions about sharing person-specific health data with other parties. We examine relevant cost factors associated with the value of anonymized data and the possible damage cost due to potential privacy breaches. Our model guides an HIC to find the optimal value of publishing health data and could be utilized for both perturbative and non-perturbative anonymization techniques. We show that our approach can identify the optimal value for different privacy models, including K anonymity, LKC-privacy, and ?-differential privacy, under various anonymization algorithms and privacy parameters through extensive experiments on real-life data. PMID- 24768776 TI - Improving the in vitro ethoxyresorufin-O-deethylase (EROD) assay with RTL-W1 by metabolic normalization and use of beta-naphthoflavone as the reference substance. AB - The ethoxyresorufin-O-deethylase (EROD) assay is a widely applied method for the evaluation of the dioxin-like activity of single substances and environmental samples. As for most enzyme assays, the specific activity is normally related to total protein contents, the determination of which has clear limitations in high throughput assays. EROD induction potentials are usually expressed as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) equivalents, a substance highly toxic to humans. In order to compensate for these shortcomings, two modifications of the EROD protocol are proposed: (1) EROD activity is normalized to the metabolic activity of the cells as determined by a modified thiazolyl blue tetrazolium (MTT) assay and expressed as metabolic cell equivalents (MCE) based on MTT data rather than to protein contents. Via MCE data, cytotoxicity information can always be reported in parallel to EROD data; with the protocol presented here, MTT and EROD data are collected simultaneously. (2) Among several reference substances tested (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), beta naphthoflavone and benzo[a]pyrene), beta-naphthoflavone proved to be the most suitable reference for the routine in vitro EROD assay, although TCDD has generally been preferred for purely scientific reasons. PMID- 24768777 TI - Temporal effects of separation on suicidal thoughts and behaviours. AB - Divorce has been identified as a risk factor for suicide. However, little research has been conducted on the time trajectory of the influence of relationship separation on suicidal outcomes. This study aimed to assess the effects over time of relationship breakdown and separation on suicidality. Data were drawn from 6616 Australian adults participating in the PATH through Life Project, a population-based longitudinal study. Suicidal ideation was reported by 406 participants (6.1%), and 99 (1.5%) reported a suicide plan or attempt in the past year. The effects of separation on suicidality were strongest soon after separation, with a nearly three-fold increase in ideation (adjusted OR = 2.73, p < 0.001) and an eight-fold increase in plans/attempts (adjusted OR = 7.75, p < 0.001) in the two years following separation, gradually diminishing subsequently. The period up to four years before a separation was also found to be a time of increased risk for suicidal thoughts and behaviours, while marriage was protective. Separation is a strong risk factor for suicidality and mental health services should target recently separated individuals. PMID- 24768778 TI - Testing devices or experimental systems? Cancer clinical trials take the genomic turn. AB - Clinical trials are often described as machine-like systems for generating specific information concerning drug safety and efficacy, and are understood as a component of the industrial drug development processes. This paper argues that contemporary clinical trials in oncology are not reducible to mere drug testing. Drawing on ethnographic fieldwork and interviews with researchers in the field of oncology from 2010 to 2013, we introduce a conceptual contrast between trials as testing machines and trials as clinical experimental systems to draw attention to the ways trials are increasingly being used to ask open-ended scientific questions. When viewed as testing machines, clinical trials are seen as a means to produce answers to straightforward questions and deviations from the protocol are seen as bugs in the system; but practitioners can also treat trials as clinical experimental systems to investigate as yet undefined problems and where heterogeneity becomes a means to produce novel biological or clinical insights. The rise of "biomarker-driven" clinical trials in oncology, which link measurable biological characteristics such as genetic mutations to clinical features such as a patient's response to a particular drug, exemplifies a trend towards more experimental styles of clinical work. These transformations are congruent with changes in the institutional structure of clinical research in oncology, including a movement towards more flexible, networked research arrangements, and towards using individual patients as model systems for asking biological questions. PMID- 24768779 TI - HIV-related social intolerance and risky sexual behavior in a high HIV prevalence environment. AB - Although most countries state that fighting social intolerance against persons with HIV is part of their national HIV strategy, the impact of reducing intolerance on risky sexual behavior is largely unknown. In this paper, we estimate the effect of social intolerance against HIV+ persons on risky sexual behavior in rural Malawi using data from roughly 2000 respondents from the 2004 and 2006 waves of the Malawi Longitudinal Study of Families and Health (MLSFH). The effect of social intolerance on risky behavior is a priori ambiguous. On the one hand, higher social intolerance or stigma can lead people to disassociate from the stigmatized group and hence promote risky behavior. On the other hand, intolerance can be viewed as a social tax on being HIV+ and thus higher intolerance may reduce risky behavior. We find that a decrease in social intolerance is associated with a decrease in risky behavior, including fewer partners and a lower likelihood of having extra-marital relations. This effect is mainly driven by the impact of social intolerance on men. Overall the results suggests that reducing social intolerance might not only benefit the HIV positive but might also forestall the spread of HIV. PMID- 24768780 TI - Conditional health-related benefits of higher education: an assessment of compensatory versus accumulative mechanisms. AB - A college degree is associated with a range of health-related benefits, but the effects of higher education are known to vary across different population subgroups. Competing theories have been proposed for whether people from more or less advantaged backgrounds or circumstances will gain greater health-related benefits from a college degree. This study draws on data from the National Longitudinal Study of Adolescent Health (Add Health) and recently developed models for analyzing heterogeneous treatment effects to examine how the effect of obtaining a college degree on the self-rated health of young adults varies across the likelihood of obtaining a college degree, a summary measure of advantage/disadvantage. Results indicate that a college degree has a greater effect on self-rated health for people from advantaged backgrounds. This finding differs from two recent studies, and possible reasons for the contrasting findings are discussed. PMID- 24768781 TI - An explanatory model of peer education within a complex medicines information exchange setting. AB - Studies of the effectiveness and value of peer education abound, yet there is little theoretical understanding of what lay educators actually do to help their peers. Although different theories have been proposed to explain components of peer education, a more complete explanatory model has not been established empirically that encompasses the many aspects of peer education and how these may operate together. The Australian Seniors Quality Use of Medicines Peer Education Program was developed, in conjunction with community partners, to improve understanding and management of medicines among older people - an Australian and international priority. This research investigated how peer educators facilitated learning about quality use of medicines among older Australians. Participatory action research was undertaken with volunteer peer educators, using a multi-site case study design within eight geographically-defined locations. Qualitative data from 27 participatory meetings with peer educators included transcribed audio recordings and detailed observational and interpretive notes, which were analysed using a grounded theory approach. An explanatory model arising from the data grouped facilitation of peer learning into four broad mechanisms: using educator skills; offering a safe place to learn; pushing for change; and reflecting on self. Peer educators' life experience as older people who have taken medicines was identified as an overarching contributor to peer learning. As lay persons, peer educators understood the potential disempowerment felt when seeking medicines information from health professionals and so were able to provide unique learning experiences that encouraged others to be 'active partners' in their own medicines management. These timely findings are linked to existing education and behaviour change theories, but move beyond these by demonstrating how the different elements of what peer educators do fit together. In-depth examination of peer educators' practice in this context offers potential insights into the practice of lay workers in other related complex health promotion programs. PMID- 24768782 TI - Significant role of CYP450 genetic variants in cyclophosphamide based breast cancer treatment outcomes: a multi-analytical strategy. AB - BACKGROUND: Cyclophosphamide (CP), an alkylating chemotherapeutic drug, is catalyzed by the Phase I cytochrome P450 (CYPs) isozymes - CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C9 and CYP2C19. Hence this study aimed to elucidate the influence of genetic variants in CYP450 metabolizing enzymes on breast cancer treatment outcomes, using multi-analytical approaches. METHODS: Treatment response was noticed in 111 patients whereas 234 patients were followed for myelo toxicity. Eight known functional single nucleotide polymorphisms (SNPs) in six CYP450 genes were selected for the study on the basis of CP metabolizing enzyme polymorphisms. The possible functional effects of CYP450 polymorphisms were determined by online Web servers F-SNP. Multifactor dimensionality reductions (MDR), haplotype analysis were combined with logistic regression to characterize gene-gene interaction model with treatment outcomes. RESULTS: Haplotype analysis revealed significant association of G(rs10509681)-*1(rs1799853)-*3(rs1057910) G(rs4244285) on chromosome 10 with overall toxicity (P=0.024) and grade 2-4 leucopenia (P=0.03). On MDR analysis, CYP3A5*3, CYP2C19*2, CYP2B6*5 yielded the highest testing accuracy for treatment response (0.60) and CYP2C8*3, CYP2C9*2 for overall toxicity (0.50). CONCLUSION: Multi-analytical approaches may provide a better clinical prediction of pharmacogenetic based treatment outcomes in breast cancer patients. PMID- 24768783 TI - The vitamin E-binding protein afamin increases in maternal serum during pregnancy. AB - BACKGROUND: Afamin is a liver-derived plasma glycoprotein with vitamin E-binding properties and a putative function in fertility. This study evaluated serum afamin concentrations during and postpartum to uncomplicated pregnancies and investigated a potential association between afamin concentrations and pregnancy outcome. METHODS: Afamin serum concentrations were measured in women with uncomplicated pregnancies in a retrospective cohort (n=466) at different gestational ages and a prospective observational study (n=76) in the first, second and third trimester. Furthermore, afamin was determined in the first trimester in a cross-sectional pilot study including women with preeclampsia (PE), pregnancy-induced hypertension (PIH) and women without pregnancy complications (n=13 each). Finally, expression of afamin was investigated in human placental tissue by RT-PCR and immunohistochemistry. RESULTS: Afamin concentrations increased linearly almost two-fold during pregnancy in both retrospective and prospective studies in women without pregnancy complications with median afamin serum concentrations of 61.9 mg/l, 79.6 mg/l, and 98.6 mg/l in the first, second, and third trimester, respectively. After delivery, median afamin concentrations decreased to baseline values of 54.6 mg/l. In the pilot study with pregnancy complications, women with PE displayed significantly higher median afamin concentrations than did women with uncomplicated pregnancy (70.0 mg/l vs. 55.4 mg/l, P=0.007). Expression analyses revealed no placental afamin expression at either mRNA or protein level in uncomplicated pregnancy. CONCLUSION: A linear increase in the maternally expressed glycoprotein afamin during pregnancy may serve as basic reference for subsequent investigations of afamin in pregnancy-related disorders. PMID- 24768784 TI - Preanalytical standardization of sphingosine-1-phosphate, sphinganine-1-phosphate and sphingosine analysis in human plasma by liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: Preanalytical standardization is required for a reliable quantification of the signaling molecules sphingosine-1-phosphate (S1P), sphinganine-1-phosphate (SA1P) and sphingosine (SPH). METHODS: Methanolic protein precipitation of 15MUL EDTA-plasma was applied prior to analysis. Sphingolipids were separated in 3min by hydrophilic interaction liquid chromatography (HILIC, SeQuantTM ZIC(r)-HILIC column) followed by tandem mass spectrometry. Stability of analytes in whole blood and plasma was investigated. Sphingolipid concentrations were determined in human plasma (n=50) and mice deficient in sphingosine kinase 1 (SK1) and 2 (SK2) (n=5). RESULTS: Storing EDTA whole blood >60min after blood withdrawal at room temperature resulted in an increase in S1P and SPH concentrations of >=25%. Significant changes in SPH levels of +37% were observed after 60min of storage of EDTA plasma at room temperature. Repeated freeze-thaw cycles of EDTA plasma resulted in increased S1P and SPH levels. Concentrations in human EDTA plasma were between 55.5 and 145.2ng/mL for S1P and between 8.9 and 35.3ng/mL for SA1P. Concentrations of S1P were 36% lower and 96% higher in EDTA plasma from SK1- and SK2-deficient mice, respectively, compared to the wild type. CONCLUSIONS: Preanalytical standardization is a precondition for the analysis of sphingolipids in human blood. PMID- 24768785 TI - Serum and urinary procollagen III aminoterminal propeptide as a biomarker of obstructive nephropathy in children. AB - BACKGROUND: Ureteropelvic junction obstruction (UPJO) is the most common cause of chronic renal failure in children. Rapid diagnosis is important to preserve function and/or to slow down renal injury. This study was to examine serum and urinary procollagen III aminoterminal propeptide (sPIIINP/uPIIINP) protein as potential biomarkers of obstruction in hydronephrosis. METHODS: The study included 29 children with unilateral UPJO who underwent pyeloplasty (Group 1), 30 children with mild, nonobstructive hydronephrosis (Group 2), and 30 healthy children. In Group 1, serum and voided urine samples were obtained at preoperative, 3 days, and 3, 6 and 12 months after pyeloplasty, respectively. Meanwhile, additional urine from the affected pelvis was collected at surgery. Serum and voided urine were evaluated for PIIINP in each group using immunoenzymatic enzyme-linked immunosorbent assay (ELISA) commercial kits and were expressed in picograms per milligram creatine (cr.). RESULTS: The preoperative sPIIINP and uPIIINP levels were significantly greater in Group 1 than in other 2 groups. Three months after pyeloplasty, sPIIINP and uPIIINP levels had decreased significantly in Group 1 together with significant improvement of split renal function. Receiver operator characteristic (ROC) analyses revealed a good diagnostic profile for uPIIINP/cr. in identifying children with abnormal split renal function (<40%) [area under the curve (AUC) 0.789]. CONCLUSIONS: Increasing uPIIINP levels are associated with worsening obstruction. Additional studies are required to confirm a potential application uPIIINP as a useful biomarker for the diagnosis and progression of congenital obstructive nephropathy. PMID- 24768786 TI - Analytical performances of a new enzymatic assay for hemoglobin A1c. AB - BACKGROUND: HbA1c is considered the gold standard for the follow-up of diabetic patients and a new diagnostic tool for diabetes mellitus, which implies the availability of reliable assay methods. We have evaluated a new assay developed by Abbott Laboratories, based on the enzymatic quantification of HbA1c by a fructosyl dipeptide oxidase using Architect analyzers. METHODS: Precision, linearity, correlation with a HPLC method, accuracy and potential impact interferences on HbA1c measurement have been evaluated. RESULTS: Intra-day and between-day CVs were lower than 1.2% and linearity was excellent from 19 mmol/mol (3.9%) to 163 mmol/mol (17.1%). The results were well correlated with those obtained by the HPLC (Variant II device, kit NU - BioRad): HbA1c [Architect, mmol/mol]=0.986*HbA1c [Variant II, mmol/mol]+0.713 (r=0.998, n=109). This method provided consistent results with IFCC titrated quality control samples. Classical interferences in HbA1c assays (i.e. labile HbA1c, carbamylated hemoglobin, triglycerides or bilirubin) did not have an impact on HbA1c quantification by this method. CONCLUSION: This new enzymatic assay proved to be a robust and reliable method for HbA1c measurement suitable for routine practice in clinical chemistry laboratories. PMID- 24768787 TI - Iron homeostasis and anemia markers in early breast cancer. AB - Iron plays a fundamental role in cell life and its concentration in living organisms is precisely regulated. Different molecules for iron storage and transport are used to maintain its intracellular homeostasis which is often altered in cancer cells. Specifically, recent studies have demonstrated that in breast cancer cells, the expression/activity of several iron-related proteins, such as ferritin, hepcidin and ferroportin, is deregulated and that these alterations may have a prognostic impact in patients with breast cancer. Moreover, molecules that regulate iron metabolism could become therapeutic targets. This review focuses on recent findings on iron metabolism particularly in breast cancer and on the development of new biomarkers that may be used in the clinical routine for the diagnosis, prognosis and management of cancer-associated anemia as well as for monitoring personalized treatments. PMID- 24768788 TI - EPR analysis of cyanide complexes of wild-type human neuroglobin and mutants in comparison to horse heart myoglobin. AB - Electron paramagnetic resonance (EPR) data reveal large differences between the ferric ((13)C-)cyanide complexes of wild-type human neuroglobin (NGB) and its H64Q and F28L point mutants and the cyanide complexes of mammalian myo- and haemoglobin. The point mutations, which involve residues comprising the distal haem pocket in NGB, induce smaller, but still significant changes, related to changes in the stabilization of the cyanide ligand. Furthermore, for the first time, the full (13)C hyperfine tensor of the cyanide carbon of cyanide-ligated horse heart myoglobin (hhMb) was determined using Davies ENDOR (electron nuclear double resonance). Disagreement of these experimental data with earlier predictions based on (13)C NMR data and a theoretical model reveal significant flaws in the model assumptions. The same ENDOR procedure allowed also partial determination of the corresponding (13)C hyperfine tensor of cyanide-ligated NGB and H64QNGB. These (13)C parameters differ significantly from those of cyanide ligated hhMb and challenge our current theoretical understanding of how the haem environment influences the magnetic parameters obtained by EPR and NMR in cyanide ligated haem proteins. PMID- 24768789 TI - Interaction of metallo- and free base meso-tetrakis(N-methylpyridium-4 yl)porphyrin with a G-quadruplex: effect of the central metal ions. AB - The effects of the central metal ion on complex formation between meso-tetrakis(N methylpyridium-4-yl)porphyrin (TMPyP) and the thrombin-binding aptamer G quadruplex, 5'G2T2G2TGTG2T2G2, were examined in this study. The central metal ions were vanadium and zinc. At a [porphyrin]/[G-quadruplex] ratio of less than one, the absorption and CD spectra were unaffected by the mixing ratio for all three porphyrins, suggesting that the binding mode is homogeneous. Relatively small changes in the absorption spectrum when forming the complexes with the G quadruplex, the positive CD signal, and the large accessibility of the I(-) quencher, suggested that all these porphyrins are not intercalated between the G quartet. Stabilization of the G-quadruplex by ZnTMPyP was most effective. The effect of VOTMPyP on G-quadruplex stabilization was moderate, whereas TMPyP slightly destabilized G-quadruplex. From this observation, the involvement of the ligation of one G-quartet component to the central metal ion in G-quadruplex stabilization by metallo-TMPyP is suggested. PMID- 24768790 TI - Assessment of PEG on polymeric particles surface, a key step in drug carrier translation. AB - Injectable drug nanocarriers have greatly benefited in their clinical development from the addition of a superficial hydrophilic corona to improve their cargo pharmacokinetics. The most studied and used polymer for this purpose is poly(ethylene glycol), PEG. However, in spite of its wide use for over two decades now, there is no general consensus on the optimum PEG chain coverage density and size required to escape from the mononuclear phagocyte system and to extend the circulation time. Moreover, cellular uptake and active targeting may have conflicting requirements in terms of surface properties of the nanocarriers which complicate even more the optimization process. These persistent issues can be largely attributed to the lack of straightforward characterization techniques to assess the coverage-density, the conformation or the thickness of a PEG layer grafted or adsorbed on a particulate drug carrier and is certainly one of the main reasons why so few clinical applications involving PEG coated particle-based drug delivery systems are under clinical trial so far. The objective of this review is to provide the reader with a brief description of the most relevant techniques used to assess qualitatively or quantitatively PEG chain coverage density, conformation and layer thickness on polymeric nanoparticles. Emphasis has been made on polymeric particle (solid core) either made of copolymers containing PEG chains or modified after particle formation. Advantages and limitations of each technique are presented as well as methods to calculate PEG coverage-density and to investigate PEG chains conformation on the NP surface. PMID- 24768791 TI - pH-responsive dendritic core-multishell nanocarriers. AB - In this paper we describe novel pH-responsive core-multishell (CMS) nanocarrier (pH-CMS), obtained by introducing an aromatic imine linker between the shell and the core. At a pH of 5 and lower the used imine linker was rapidly cleaved as demonstrated by NMR studies. The CMS nanocarriers were loaded with the dye Nile red (NR) and the anticancer drug doxorubicin (DOX), respectively. The transport capacities were determined using UV/Vis spectroscopy, and the sizes of the loaded and unloaded CMS nanocarriers were investigated using dynamic light scattering (DLS). We could show that CMS nanocarriers efficiently transported NR in supramolecular aggregates, while DOX was transported in a unimolecular fashion. After cellular uptake the DOX-loaded pH-responsive nanocarriers showed higher toxicities than the stable CMS nanocarriers. This is due to a more efficient DOX release caused by the cleavage of the pH-labile imine bond at lower pH within the intracellular compartments. PMID- 24768792 TI - Electrospinning of polymeric nanofibers for drug delivery applications. AB - Electrospinning has been recognized as a simple and versatile method for fabrication of polymer nanofibers. Various polymers that include synthetic, natural, and hybrid materials have been successfully electrospun into ultrafine fibers. The inherently high surface to volume ratio of electrospun fibers can enhance cell attachment, drug loading, and mass transfer properties. Drugs ranging from antibiotics and anticancer agents to proteins, DNA, RNA, living cells, and various growth factors have been incorporated into electrospun fibers. This article presents an overview of electrospinning techniques and their application in drug delivery. PMID- 24768793 TI - Lipid-based biofuel production from wastewater. AB - Increasing world population, urbanization and industrialization are driving global increases in wastewater production. Wastewater comprises significant amounts of chemical energy primarily in the form of organic molecules (in particular lipids), which are currently not being recovered comprehensively. Within biological wastewater treatment (BWWT) systems, specialized microorganisms assimilate and store lipids anaerobically. These intracellular stores represent interesting feedstocks for biofuel synthesis. Here, we review our current understanding of the genetic and functional basis for bacterial lipid accumulation and processing, and relate this to lipid accumulating bacterial populations which occur naturally in BWWT plants. A grand challenge for microbial ecologists and engineers now lies in translating this knowledge into the design of new BWWT processes for the comprehensive recovery of lipids from wastewater streams and their subsequent conversion into biofuel. PMID- 24768794 TI - Effects of urotensin II on intracellular pH regulation in cultured human internal mammary artery smooth muscle cells. AB - The Na(+)-H(+) exchanger (NHE) and the Na(+)-HCO3(-) co-transporter (NBC) have been confirmed as two major active acid extruders in many mammalian cells. Whether the NHE and NBC functional co-exist in human internal mammary artery smooth muscle cells (HIMASMCs) remains unclear. The aims of the present study were to investigate the acid-extruding mechanisms and to explore the effects of urotensin-II (U-II), a powerful vasoconstrictor, on pHi regulators in HIMASMCs. We investigated the changes of pHi by BCECF-fluorescence in HIMASMCs. We found that (a) two Na(+)-dependent acid extruders, i.e. NHE and NBC, functionally co exist; (b) U-II (3-100 nM) induced a concentration-dependent intracellular acidosis; and (c) U-II (3-100 nM) caused a concentration-dependent increase on NHE activity, while decrease on NBC activity. In summary, we demonstrate for the first time that two acid-extruders, NHE and NBC, functionally co-exist in HIMASMCs. Moreover, U-II induces a concentration-dependent intracellular acidosis through the balanced effect of its effect on increasing NHE activity and decreasing NBC activity. PMID- 24768795 TI - Serum levels of novel adipokines in patients with acute ischemic stroke: potential contribution to diagnosis and prognosis. AB - This study evaluated serum levels of novel adipokines in acute ischemic stroke (AIS) and their association with prognosis. We enrolled 168 patients with AIS and 58 stroke-free age- and sex-matched individuals (controls). Clinical parameters, carotid ultrasound, metabolic profile, vaspin, apelin, visfatin, and ghrelin were assayed. Stroke-patients were sampled at hospital admission and were prospectively followed-up (median 16 months) for the cardiovascular endpoint (cardiovascular death/stroke/myocardial infarction). At admission, stroke patients appeared with higher levels of systolic blood pressure, hsCRP and worse metabolic profile (p<0.05), (p>0.05). Compared to controls, AIS group had significantly higher serum concentrations of visfatin (22.92+/-9.72ng/ml vs 16.56+/-7.82ng/ml, p=0.006) and lower of vaspin (0.94+/-0.43ng/ml vs 1.84+/ 0.82ng/ml, p=0.019) and ghrelin (3.47+/-1.44ng/ml vs 5.93+/-2.78ng/ml, p<0.001), while apelin did not differ between groups. Similar differences in adipokines were found between stroke subgroups with and without significant ipsilateral carotid stenosis (>50%) (p<0.05). In stepwise logistic regression analysis adjusted for diabetes, hypertension, dyslipidemia and age, visfatin (p=0.026) and ghrelin (p=0.012) proved to be independent predictors of AIS. During follow-up, 27 patients achieved cardiovascular endpoint. In addition to coronary artery disease and NIHSS score, visfatin serum levels was associated with cardiovascular endpoint (HR: 1.255, 95% CI: 1.025-1.576). Our results suggested the association of AIS with higher visfatin and lower vaspin and ghrelin serum levels. Visfatin levels can be a predictor of cardiovascular mortality and morbidity in AIS. PMID- 24768796 TI - Validation of a multiplex electrochemiluminescent immunoassay platform in human and mouse samples. AB - BACKGROUND: Despite the widespread use of multiplex immunoassays, there are very few scientific reports that test the accuracy and reliability of a platform prior to publication of experimental data. Our laboratory has previously demonstrated the need for new assay platform validation prior to use of biologic samples from large studies in order to optimize sample handling and assay performance. METHODS: In this study, our goal was to test the accuracy and reproducibility of an electrochemiluminescent multiplex immunoassay platform (Meso Scale Discovery, MSD(r)) and compare this platform to validated, singleplex immunoassays (R&D Systems(r)) using actual study subject (human plasma and mouse bronchoalveolar lavage fluid (BAL) and plasma) samples. RESULTS: We found that the MSD platform performed well on intra- and inter-assay comparisons, spike and recovery and cross-platform comparisons. The mean intra-assay CV% and range for MSD were 3.49 (0.0-10.4) for IL-6 and 2.04 (0.1-7.9) for IL-8. The correlation between values for identical samples measured on both MSD and R&D was R=0.97 for both analytes. The mouse MSD assay had a broader range of CV% with means ranging from 9.5 to 28.5 depending on the analyte. The range of mean CV% was similar for single plex ELISAs at 4.3-23.7 depending on the analyte. Regardless of species or sample type, CV% was more variable at lower protein concentrations. CONCLUSIONS: In conclusion, we validated a multiplex electrochemiluminescent assay system and found that it has superior test characteristics in human plasma compared to mouse BALF and plasma. Both human and MSD assays compared favorably to well-validated singleplex ELISAs. PMID- 24768797 TI - Daclizumab (anti-CD25) in multiple sclerosis. AB - Multiple sclerosis (MS) is a typical CD4 T cell-mediated autoimmune disease of the central nervous system (CNS) that leads to inflammation, demyelination, axonal damage, glial scarring and a broad range of neurological deficits. While disease-modifying drugs with a good safety profile and moderate efficacy have been available for 20 years now, a growing number of substances with superior therapeutic efficacy have recently been introduced or are in late stage clinical testing. Daclizumab, a humanized neutralizing monoclonal antibody against the alpha-chain of the Interleukin-2 receptor (IL-2Ralpha, CD25), which had originally been developed and approved to prevent rejection after allograft renal transplantation, belongs to the latter group. Clinical efficacy and safety of daclizumab in MS has so far been tested in several smaller phase II trials and recently two large phase II trials (combined 912 patients), and has shown efficacy regarding reduction of clinical disease activity as well as CNS inflammation. A phase III clinical trial is ongoing till March 2014 (DECIDE study, comparison with interferon (IFN) beta-1a in RRMS). Furthermore, the existing safety data from clinical experience in kidney transplantation and in MS appears favorable. Apart from the promising clinical data mechanistic studies along the trials have provided interesting novel insights not only about the mechanisms of daclizumab treatment, but in general about the biology of IL-2 and IL-2 receptor interactions in the human immune system. Besides blockade of recently activated CD25(+) T cells daclizumab appears to act through additional mechanisms including the expansion of immune regulatory CD56(bright) natural killer (NK) cells, the blockade of cross-presentation of IL-2 by dendritic cells (DC) to T cells, and the reduction of lymphoid tissue inducer cells. PMID- 24768798 TI - A biosynthetic pathway for hexanoic acid production in Kluyveromyces marxianus. AB - Hexanoic acid can be used for diverse industrial applications and is a precursor for fine chemistry. Although some natural microorganisms have been screened and evolved to produce hexanoic acid, the construction of an engineered biosynthetic pathway for producing hexanoic acid in yeast has not been reported. Here we constructed hexanoic acid pathways in Kluyveromyces marxianus by integrating 5 combinations of seven genes (AtoB, BktB, Crt, Hbd, MCT1, Ter, and TES1), by which random chromosomal sites of the strain are overwritten by the new genes from bacteria and yeast. One recombinant strain, H4A, which contained AtoB, BktB, Crt, Hbd, and Ter, produced 154mg/L of hexanoic acid from galactose as the sole substrate. However, the hexanoic acid produced by the H4A strain was re assimilated during the fermentation due to the reverse activity of AtoB, which condenses two acetyl-CoAs into a single acetoacetyl-CoA. This product instability could be overcome by the replacement of AtoB with a malonyl CoA-acyl carrier protein transacylase (MCT1) from Saccharomyces cerevisiae. Our results suggest that Mct1 provides a slow but stable acetyl-CoA chain elongation pathway, whereas the AtoB-mediated route is fast but unstable. In conclusion, hexanoic acid was produced for the first time in yeast by the construction of chain elongation pathways comprising 5-7 genes in K. marxianus. PMID- 24768799 TI - A pseudoisochromatic test of color vision for human infants. AB - Despite the development of experimental methods capable of measuring early human color vision, we still lack a procedure comparable to those used to diagnose the well-identified congenital and acquired color vision anomalies in older children, adults, and clinical patients. In this study, we modified a pseudoisochromatic test to make it more suitable for young infants. Using a forced choice preferential looking procedure, 216 3-to-23-mo-old babies were tested with pseudoisochromatic targets that fell on either a red/green or a blue/yellow dichromatic confusion axis. For comparison, 220 color-normal adults and 22 color deficient adults were also tested. Results showed that all babies and adults passed the blue/yellow target but many of the younger infants failed the red/green target, likely due to the interaction of the lingering immaturities within the visual system and the small CIE vector distance within the red/green plate. However, older (17-23 mo) infants, color- normal adults and color defective adults all performed according to expectation. Interestingly, performance on the red/green plate was better among female infants, well exceeding the expected rate of genetic dimorphism between genders. Overall, with some further modification, the test serves as a promising tool for the detection of early color vision anomalies in early human life. PMID- 24768800 TI - Decision-dependent aftereffects for faces. AB - Adaptation-related aftereffects (AEs) have been found in the perception of face identity, in that perception of an ambiguous face is typically biased away from the identity of a preceding unambiguous adaptor face. In previous studies, we could show that both perceptual ambiguity and physical similarity play a role in determining perceived face identity AEs, Cortex 49 (2013) 1963-1977, Plos One 8 (2013) e70525. Here, we tested further the role of ambiguity by manipulating participants' task such that the very same target stimuli were either ambiguous or unambiguous regarding stimulus classification. We created two partially overlapping continua spanning three unfamiliar face identities each, by morphing identity A via B to C, and B via C to D. In a first session, participants were familiarised with faces A and C and asked to classify faces of the A-B-C continuum as either identity A or C in an AE paradigm. Following adaptation to A or C, we observed contrastive AEs for the ambiguous identity B, but not for the unambiguous identities A or C. In a second session, the same participants were familiarised with faces B and D, followed by tests of AEs for the B-C-D continuum now involving a B-D classification task. We again observed contrastive AEs but only for target identity C (ambiguous for the decision) and not for B or D (unambiguous). Our results suggest that perceptual ambiguity, as given by the task-context, determines whether or not AEs are induced. PMID- 24768801 TI - Design synthesis of polypyrrole-Co3O4 hybrid material for the direct electrochemistry of Hemoglobin and Glucose Oxidase. AB - We designed and synthesized a novel organic-inorganic hybrid material polypyrrole Co3O4 (Ppy-Co3O4), then mixed it with ionic liquid (IL) to form stable composite films for the immobilization of Hemoglobin (Hb) and Glucose Oxidase (GOD). The combination of Ppy and Co3O4 as well as IL created a platform with exceptional characteristics, and the content of Ppy had an effect on the direct electron transfer (DET) of Hb/GOD. Notably, when weight percentage of pyrrole monomer was 20%, the heterogenous electron transfer rate constant (ks) for Hb and GOD was estimated to be 1.71s(-1) and 1.67s(-1), respectively. In the meantime, electrochemical and spectroscopic measurements showed that Hb/GOD remained their bioactivity, and achieved fast electron transfer on the Ppy-Co3O4/IL composite film modified electrode. Furthermore, the Ppy-Co3O4/IL/Hb composite film modified electrode was used as a biosensor, and exhibited a long linear range and lower detection limit to H2O2. The apparent Michaelis-Menten constant (Km) was found to be 0.53mM. The sensing design based on the Ppy-Co3O4 hybrid material was demonstrated to be effective and promising in developing protein and enzyme biosensors. PMID- 24768802 TI - Kynurenine production mediated by indoleamine 2,3-dioxygenase aggravates liver injury in HBV-specific CTL-induced fulminant hepatitis. AB - Indoleamine 2,3-dioxygenase (IDO), an enzyme that is ubiquitously distributed in mammalian tissues and cells, converts tryptophan to kynurenine, and is also known as a key molecule that promotes apoptosis in lymphocytes and neurons. In this study, we established hepatitis B virus (HBV)-transgenic (Tg)/IDO-knockout (KO) mice and examined the influence of IDO in a murine fulminant hepatitis model induced by HBV-specific cytotoxic T lymphocytes (CTL). An increase of IDO expression in the livers of HBV-Tg/IDO-wild-type (WT) mice administered HBV specific CTL was confirmed by real-time polymerase chain reaction, western blotting, and evaluating IDO activity. Plasma alanine aminotransferase (ALT) levels in HBV-Tg/IDO-KO mice after HBV-specific CTL injection significantly decreased compared with those in HBV-Tg/IDO-WT mice. An inhibitor of IDO, 1 methyl-d-tryptophan (1-MT), could also attenuated the observed liver injury induced by this HBV-specific CTL. The expression levels of cytokine and chemokine mRNAs in the livers of HBV-Tg/IDO-WT mice were higher than those in the livers of HBV-Tg/IDO-KO mice. The administration of kynurenine aggravated the liver injury in HBV-Tg/IDO-KO mice injected with HBV-specific CTL. Simultaneous injection of recombinant murine interferon (IFN-gamma) and kynurenine also increased the ALT levels in HBV-Tg/IDO-KO mice. The liver injury induced by IFN-gamma and kynurenine was improved in HBV-Tg/tumor necrosis factor-alpha-KO mice. CONCLUSION: Kynurenine and IFN-gamma induced by the administration with HBV specific CTL are cooperatively involved in the progression of liver injury in acute hepatitis model. Our results may lead to a new therapy for the acute liver injury caused by HBV infection. PMID- 24768803 TI - The estrogen receptor beta-PI3K/Akt pathway mediates the cytoprotective effects of tocotrienol in a cellular Parkinson's disease model. AB - Tocotrienols (T3s) are members of the vitamin E family, have antioxidant properties, and are promising candidates for neuroprotection in the pathogenesis of neurodegenerative disorders such as Parkinson's disease (PD). However, whether their antioxidant capacities are required for their cytoprotective activity remains unclear. In this regard, the antioxidant-independent cytoprotective activity of T3s has received considerable attention. Here, we investigated the signaling pathways that are induced during T3-dependent cytoprotection of human neuroblastoma SH-SY5Y cells, as these cells are used to model certain elements of PD. T3s were cytoprotective against 1-methyl-4-phenylpyridinium ion (MPP(+)) and other PD-related toxicities. gammaT3 and deltaT3 treatments led to marked activation of the PI3K/Akt signaling pathway. Furthermore, we identified estrogen receptor (ER) beta as an upstream mediator of PI3K/Akt signaling following gammaT3/deltaT3 stimulation. Highly purified gammaT3/deltaT3 bound to ERbeta directly in vitro, and knockdown of ERbeta in SH-SY5Y cells abrogated both gammaT3/deltaT3-dependent cytoprotection and Akt phosphorylation. Since membrane bound ERbeta was important for the signal-related cytoprotective effects of gammaT3/deltaT3, we investigated receptor-mediated caveola formation as a candidate for the early events of signal transduction. Knockdown of caveolin-1 and/or caveolin-2 prevented the cytoprotective effects of gammaT3/deltaT3, but did not affect Akt phosphorylation. This finding suggests that T3s and, in particular, gammaT3/deltaT3, exhibit not only antioxidant effects but also a receptor signal-mediated protective action following ERbeta/PI3K/Akt signaling. Furthermore, receptor-mediated caveola formation is an important event during the early steps following T3 treatment. PMID- 24768804 TI - RNAi silencing of P/Q-type calcium channels in Purkinje neurons of adult mouse leads to episodic ataxia type 2. AB - Episodic ataxia type-2 (EA2) is a dominantly inherited human neurological disorder caused by loss of function mutations in the CACNA1A gene, which encodes the CaV2.1 subunit of P/Q-type voltage-gated calcium channels. It remains however unknown whether the deficit of cerebellar CaV2.1 in adult is in direct link with the disease. To address this issue, we have used lentiviral based-vector RNA interference (RNAi) to knock-down CaV2.1 expression in the cerebellum of adult mice. We show that suppression of the P/Q-type channels in Purkinje neurons induced motor abnormalities, such as imbalance and ataxic gait. Interestingly, moderate channel suppression caused no basal ataxia, while beta-adrenergic activation and exercise mimicked stress induced motor disorders. Moreover, stress induced ataxia was stable, non-progressive and totally abolished by acetazolamide, a carbonic anhydrase inhibitor used to treat EA2. Altogether, these data reveal that P/Q-type channel suppression in adult mice supports the episodic status of EA2 disease. PMID- 24768806 TI - Investigation on the spectrum-effect relationships of Da-Huang-Fu-Zi-Tang in rats by UHPLC-ESI-Q-TOF-MS method. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Da-Huang-Fu-Zi-Tang (DHFZT) is a crucial TCM formula commonly used for the treatment of acute pancreatitis in Chinese clinical application. Our previous work found that DHFZT could act against pancreatic injury in rats with severe acute pancreatitis (SAP). The goal of this paper was to study the underlying correlations between the chemical spectra and the protective effect of DHFZT on pancreatic acinar cell to reveal the real bioactive compounds in DHFZT. MATERIALS AND METHODS: The fingerprint chromatograms of rat serum after oral administration of DHFZT were established by UHPLC-ESI-Q-TOF-MS technique. At the same time, the model of anti-acute pancreatitis on cells was established by adding 10(-7) mol/L cerulein to AR42J cell line, and the protective effects of the serum on pancreatic acinar cell from injury was evaluated by detecting the efficacy of amylase. Then, the spectrum-effect relationships between UHPLC fingerprints and anti-acute pancreatitis activities were evaluated using canonical correlation analysis (CCA) statistical method. The chromatogram separation was performed on a C18 reversed phase UHPLC column (2.1 mm * 100 mm, 3.5 MUm, Agilent), the column temperature was set at 35 degrees C. The mobile phase consisted of 0.1% formic acid and acetonitrile with gradient elution. The serum samples were analyzed both in negative and positive ion mode. The mother and productive ions were scanned within the mass range of m/z 100-1200 and 50-1200, respectively. A thorough analysis of a great deal of information of the constituents in the rat serum was undertaken. The structure identification of the detected compounds was achieved by using high resolution MS values as well as the MS/MS fragments. RESULTS: Eighteen peaks in rat serum after oral administration of DHFZT were detected within only 30 min recorded chromatograms. The structure of the 18 compounds were then given out, of which 10 were the original form of compounds absorbed from DHFZT, 8 were the metabolites of the compounds existed in rat serum. According to the CCA results, talatisamine, rhein glucoside, rhein isomer methylation, hypaconine, hydroxyl-chrysophanol, emodin glucuronide conjugation, and chrysophanol glucuronide conjugation were finally found to be the main anti-acute pancreatitis components in DHFZT. CONCLUSIONS: The model presented in this paper successfully discovered the spectrum-effect relationships of DHFZT, which showed a representative way to discover the primary active ingredients from the complicated herbal drugs. PMID- 24768805 TI - Relationship between oscillatory activity in the cortico-basal ganglia network and parkinsonism in MPTP-treated monkeys. AB - Parkinsonism is associated with changes in oscillatory activity patterns and increased synchronization of neurons in the basal ganglia and cortex in patients and animal models of Parkinson's disease, but the relationship between these changes and the severity of parkinsonian signs remains unclear. We examined this relationship by studying changes in local field potentials (LFPs) in the internal pallidal segment (GPi) and the subthalamic nucleus (STN), and in encephalographic signals (EEG) from the primary motor cortex (M1) in Rhesus monkeys which were rendered progressively parkinsonian by repeated systemic injections of small doses of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Observations during wakefulness and sleep (defined by EEG and video records) were analyzed separately. The severity of parkinsonism correlated with increases in spectral power at frequencies below 15.5Hz in M1 and GPi and reductions in spectral power at frequencies above 15.6Hz with little change in STN. The severity of parkinsonism also correlated with increases in the coherence between M1 EEG and basal ganglia LFPs in the low frequency band. Levodopa treatment reduced low-frequency activity and increased high-frequency activity in all three areas, but did not affect coherence. The state of arousal also affected LFP and EEG signals in all three structures, particularly in the STN. These results suggest that parkinsonism-associated changes in alpha and low-beta band oscillatory activity can be detected early in the parkinsonian state in M1 and GPi. Interestingly, oscillations detectable in STN LFP signals (including oscillations in the beta-band) do not appear to correlate strongly with the severity of mild-to-moderate parkinsonism in these animals. Levodopa-induced changes in oscillatory M1 EEG and basal ganglia LFP patterns do not necessarily represent a normalization of abnormalities caused by dopamine depletion. PMID- 24768807 TI - Paeonol protects against premature senescence in endothelial cells by modulating Sirtuin 1 pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Paeonol is a phenolic compound isolated mainly from Moutan cortex, root bark of Chinese Peony tree. Moutan cortex holds a significant value in traditional Chinese medicine for alleviating various oxidative stress-related diseases mainly atherosclerosis and myocardial infarction. The present study seeks to identify the protective mechanisms of paeonol in oxidative stress-induced premature senescence in endothelial cells. MATERIALS AND METHODS: HUVECs were pretreated with paeonol or DMSO control at different doses for 24h prior to an exposure of 200MUM of reactive oxygen species (ROS) inducer, hydrogen peroxide (H2O2). The protective effects of paeonol against H2O2-induced senescence were evaluated and the activation of Sirtuin 1 pathway by paeonol pretreatment was investigated in HUVECs. RESULTS: Paeonol attenuated H2O2-induced cell growth arrest at G0/G1 phase, reduced the percentage of SA-beta-Gal positive cells and increased BrdU incorporation. In addition, enzymatic Sirt1 activation assay indicated that paeonol significantly increased lysyl deactylase activity of Sirt1 enzyme with a fold change of 2.4+/-0.195 (p<0.05). Furthermore, pretreatment with paeonol significantly decreased the levels of p53, acetyl H3K14 and H4K16 protein expression upregulated by H2O2 stimulation. The changes in the histone protein levels were accompanied with an increase in Sirt1 protein expression level. CONCLUSION: These findings suggest that paeonol protects endothelial cells against oxidative stress-induced premature senescence by modulating the expressions of Sirt1 protein and its substrates. PMID- 24768808 TI - Biofeedback-guided control of abdominothoracic muscular activity reduces regurgitation episodes in patients with rumination. AB - BACKGROUND & AIMS: Rumination syndrome is characterized by effortless recurrent regurgitation of recently ingested food into the mouth, with consequent expulsion or re-chewing and swallowing. We investigated whether rumination is under volitional control and can be reversed by behavioral treatment. METHODS: We performed a prospective study of 28 patients who fulfilled the Rome criteria for rumination and had no organic disorders on the basis of a thorough evaluation. The diagnosis of rumination was confirmed by intestinal manometry (abdominal compression associated with regurgitation). Patients were trained to modulate abdominothoracic muscle activity under visual control of electromyographic recordings. Recordings were made after challenge meals, before training (baseline), and during 3 treatment sessions. Outcome was measured by questionnaires administered daily for 10 days before training, immediately after training, and at 1, 3, and 6 months after training. RESULTS: By the end of the 3 sessions, patients had effectively learned to reduce intercostal activity (by 50% +/- 2%; P < .001 vs basal) and anterior wall muscle activity (by 30% +/- 6%; P < .001 vs basal). Patients reported 27 +/- 1 regurgitation episodes/day at baseline and 8 +/- 2 episodes/day immediately after treatment. Regurgitation episodes decreased further to 4 +/- 1 episodes at 6 months after training. CONCLUSIONS: Rumination is produced by an unperceived somatic response to food ingestion that disrupts abdominal accommodation and can be effectively corrected by biofeedback guided control of abdominothoracic muscular activity. PMID- 24768809 TI - Epidemiology and familial risk of synchronous and metachronous colorectal cancer: a population-based study in Utah. AB - BACKGROUND & AIMS: Patients diagnosed with colorectal cancer (CRC) are at risk for synchronous and metachronous lesions at the time of diagnosis or during follow-up evaluation. We performed a population-based study to evaluate the rate, predictors, and familial risk for synchronous and metachronous CRC in Utah. METHODS: All newly diagnosed cases of CRC between 1980 and 2010 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. RESULTS: Of the 18,782 patients diagnosed with CRC, 134 were diagnosed with synchronous CRC (0.71%) and 300 were diagnosed with metachronous CRC (1.60%). The risk for synchronous CRC was significantly higher in men (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.02-2.06) and in patients aged 65 years or older (OR, 1.50; 95% CI, 1.02-2.21). Synchronous CRCs were located more often in the proximal colon (OR, 1.70; 95% CI, 1.20-2.41). First-degree relatives of cases with synchronous (OR, 1.86; 95% CI, 1.37-2.53), metachronous (OR, 2.34; 95% CI, 1.62-3.36), or solitary CRC (OR, 1.75; 95% CI, 1.63-1.88) were at increased risk for developing CRC, compared with relatives of CRC-free individuals. Four percent of first-degree relatives of patients with synchronous or metachronous cancer developed CRC at younger ages than the age recommended for initiating CRC screening (based on familial risk), and therefore would not have been screened. CONCLUSIONS: Of patients diagnosed with CRC, 2.3% are found to have synchronous lesions or develop metachronous CRC during follow-up evaluation. Relatives of these patients have a greater risk of CRC than those without a family history of CRC. These results highlight the importance of obtaining a thorough family history and adhering strictly to surveillance guidelines during management of high-risk patients. PMID- 24768810 TI - Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. AB - BACKGROUND & AIMS: Little is known about differences in rates of fibrosis progression between patients with nonalcoholic fatty liver (NAFL) vs nonalcoholic steatohepatitis (NASH). We conducted a systematic review and meta-analysis of all studies that assessed paired liver biopsy specimens to estimate the rates of fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD) including NAFL and NASH. METHODS: Through a systematic search of multiple databases and author contact, up to June 2013, we identified studies of adults with NAFLD that collected paired liver biopsy specimens at least 1 year apart. From these, we calculated a pooled-weighted annual fibrosis progression rate (number of stages changed between the 2 biopsy samples) with 95% confidence intervals (CIs), and identified clinical risk factors associated with progression. RESULTS: We identified 11 cohort studies including 411 patients with biopsy-proven NAFLD (150 with NAFL and 261 with NASH). At baseline, the distribution of fibrosis for stages 0, 1, 2, 3, and 4 was 35.8%, 32.5%, 16.7%, 9.3%, and 5.7%, respectively. Over 2145.5 person-years of follow-up evaluation, 33.6% had fibrosis progression, 43.1% had stable fibrosis, and 22.3% had an improvement in fibrosis stage. The annual fibrosis progression rate in patients with NAFL who had stage 0 fibrosis at baseline was 0.07 stages (95% CI, 0.02-0.11 stages), compared with 0.14 stages in patients with NASH (95% CI, 0.07-0.21 stages). These findings correspond to 1 stage of progression over 14.3 years for patients with NAFL (95% CI, 9.1-50.0 y) and 7.1 years for patients with NASH (95% CI, 4.8-14.3 y). CONCLUSIONS: Based on a meta-analysis of studies of paired liver biopsy studies, liver fibrosis progresses in patients with NAFL and NASH. PMID- 24768811 TI - Eight weeks of exercise training increases aerobic capacity and muscle mass and reduces fatigue in patients with cirrhosis. AB - BACKGROUND & AIMS: Patients with cirrhosis have reduced exercise tolerance, measured objectively as decreased peak exercise oxygen uptake (peak VO2). Reduced peak VO2 is associated with decreased survival time. The effect of aerobic exercise training on peak VO2 has not been well studied in patients with cirrhosis. We evaluated the safety and efficacy of 8 weeks of supervised exercise on peak VO2, quadriceps muscle thickness, and quality of life. METHODS: In a prospective pilot study, stable patients (79% male, 57.6 +/- 6.7 years old) with Child-Pugh class A or B cirrhosis (mean Model for End-Stage Liver Disease score, 10 +/- 2.2) were randomly assigned to groups that received exercise training (n = 9) or usual care (controls, n = 10) at the University of Alberta Hospital in Canada from February through June 2013. Supervised exercise was performed on a cycle ergometer 3 days/week for 8 weeks at 60%-80% of baseline peak VO2. Peak VO2, quadriceps muscle thickness (measured by ultrasound), thigh circumference, answers from Chronic Liver Disease Questionnaires, EQ-visual analogue scales, 6 minute walk distance, and Model for End-Stage Liver Disease scores were evaluated at baseline and at week 8. Analysis of covariance was used to compare variables. RESULTS: At week 8, peak VO2 was 5.3 mL/kg/min higher in the exercise group compared with controls (95% confidence interval, 2.9-7.8; P = .001). Thigh circumference (P = .001), thigh muscle thickness (P = .01), and EQ-visual analogue scale determined self-perceived health status (P = .01) was also significantly higher in the exercise group compared with controls at week 8; fatigue subscores of the Chronic Liver Disease Questionnaires were lower in the exercise group compared with controls (P = .01). No adverse events occurred during cardiopulmonary exercise testing or training. CONCLUSIONS: In a controlled prospective pilot trial, 8 weeks of supervised aerobic exercise training increased peak VO2 and muscle mass and reduced fatigue in patients with cirrhosis. No relevant adverse effects were observed. Larger trials are needed to evaluate the effects of exercise in patients with cirrhosis. ClinicalTrials.gov number: NCT01799785. PMID- 24768812 TI - Chemoprophylaxis of Clostridium difficile infections in high-risk hospitalized patients. PMID- 24768814 TI - Vascular complications of acute pancreatitis. PMID- 24768813 TI - Coffee: a panacea or snake oil for the liver? PMID- 24768815 TI - ILDR1: Novel mutation and a rare cause of congenital deafness in the Saudi Arabian population. AB - Hearing impairment is the common human sensorineural disorder and is a genetically heterogeneous phenotype for which more than 100 genomic loci have been mapped so far. ILDR1 located on chromosome 3q13.33, encodes a putative transmembrane receptor containing an immunoglobulin-like domain. We used a combination of autozygosity mapping and candidate gene sequencing to identify a novel mutation in ILDR1, as a causative gene for autosomal-recessive non syndromic hearing loss (arNSHL) in a consanguineous Saudi family with three affected children. Autozygosity mapping identified a shared region between the affected individuals encompassing ILDR1 on chromosome 3q13.12-3q22.1. Sequencing revealed homozygous 9 base pair duplication, resulting in an in-frame duplication of three amino acids p.(Asn109_Pro111dup). The mutation was segregating with the disease phenotype and is predicted to be pathogenic by SIFT and PROVEAN. The identified mutation is located in the immunoglobulin-type domain of the ILDR1 protein. In silico analysis using I-TASSER server and PyMOL offers the first predictions on the structural and functional consequences of this mutation. To our knowledge, this is the first ILDR1 mutation identified in a Saudi family. Identification of ILDR1 mutation in only one of 100 Saudi familial and sporadic individuals with hearing loss suggests that this mutation is unique to this family and that ILDR1 should be considered as a rare cause of congenital deafness among Saudi Arabian population. Our data also confirms the evidence for ILDR1 allelic heterogeneity and expands the number of familial arNSHL-associated ILDR1 gene mutations. PMID- 24768816 TI - Genetics of cleft lip and/or cleft palate: association with other common anomalies. AB - Cleft lip and/or cleft palate (CL/P) collectively are well known as being amongst the most common birth defects but we still have difficulty explaining why the majority of cases occur. In general, sporadic cases with no family history may be more related to environmental risks, while the presence of one or more affected relative in the same family strongly suggests that genetic factors are the main contributor. Orofacial clefts can occur in conjunction with other defects (syndromic CL/P) or as an isolated defect (non-syndromic - NSCL/P). CL/P syndromes have been studied intensively and appear to have a stronger genetic aetiology. Here we report on the relationship between syndromic and NSCL/P as a phenotypic spectrum resulting from coding or non-coding mutations respectively. We review certain abnormalities that are most frequently associated with CL/P, including dental, heart, brain, skin and certain types of cancer and examine some of the genes that are involved. We include the outcome of recent NSCL/P GWAS data and we will discuss how the genes at these loci might contribute towards clarifying the genetics of CL/P. PMID- 24768817 TI - Elucidation of the specific function of the conserved threonine triad responsible for human L-asparaginase autocleavage and substrate hydrolysis. AB - Our long-term goal is the design of a human l-asparaginase (hASNase3) variant, suitable for use in cancer therapy without the immunogenicity problems associated with the currently used bacterial enzymes. Asparaginases catalyze the hydrolysis of the amino acid asparagine to aspartate and ammonia. The key property allowing for the depletion of blood asparagine by bacterial asparaginases is their low micromolar KM value. In contrast, human enzymes have a millimolar KM for asparagine. Toward the goal of engineering an hASNase3 variant with micromolar KM, we conducted a structure/function analysis of the conserved catalytic threonine triad of this human enzyme. As a member of the N-terminal nucleophile family, to become enzymatically active, hASNase3 must undergo autocleavage between residues Gly167 and Thr168. To determine the individual contribution of each of the three conserved active-site threonines (threonine triad Thr168, Thr186, Thr219) for the enzyme-activating autocleavage and asparaginase reactions, we prepared the T168S, T186V and T219A/V mutants. These mutants were tested for their ability to cleave and to catalyze asparagine hydrolysis, in addition to being examined structurally. We also elucidated the first N-terminal nucleophile plant-type asparaginase structure in the covalent intermediate state. Our studies indicate that, while not all triad threonines are required for the cleavage reaction, all are essential for the asparaginase activity. The increased understanding of hASNase3 function resulting from these studies reveals the key regions that govern cleavage and the asparaginase reaction, which may inform the design of variants that attain a low KM for asparagine. PMID- 24768819 TI - Carcino-embryonic antigen detection based on fluorescence resonance energy transfer between quantum dots and graphene oxide. AB - The mixture of graphene oxide (GO) and aptamer labeled fluorophore is widely used in developing fluorescent sensors for the analysis of biomolecules, according to the light signal 'off-on' procedure. Moreover, the laser-induced fluorescence coupled affinity probe capillary electrophoresis (APCE) technique has been broadly applied for the separation of micromolecules. Here, a strategy is proposed for analysis of content of carcino-embryonic antigen (CEA) based on the combination of GO and quantum dots labeling aptamer (QD-aptamer) by capillary electrophoresis (CE). The method has three advantages: (i) combined with CE, only few samples are required and efficiency of separation is high, (ii) fluorescent detection can be carried out after separation of GO and fluorescence probe combined with targets by CE, while fluorescence detection sensitivity had been greatly improved, and (iii) the issues of APCE, including the effect of excess fluorescence probe and maximizing separation between analytes, could be solved by introducing GO. It has been proved that QD-aptamer-CEA complex can completely dissociate from GO. Results show that the fluorescence intensity has a linear relationship with the concentration of CEA in the range from 0.257 to 12.9 ng/mL, and the limit of detection is approximately 5 pg/mL (S/N=3). The proposed method with high specificity has been applied for the accurate analysis of content of CEA in patient's serum. PMID- 24768818 TI - Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors. AB - The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and alphaD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a beta-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer. PMID- 24768820 TI - Concanavalin A-polysaccharides binding affinity analysis using a quartz crystal microbalance. AB - There is no comparative data available on the binding constants of Concanavalin A (Con A) and glycogen and Con A-mannan using quartz crystal microbalance (QCM), cost and time efficient system for biosensor analysis. It is hypothesized that a QCM can be used in its flow injection mode to monitor the binding affinity of polysaccharides to an immobilized lectin, Con A. The biosensor is prepared by immobilizing Con A on a 5MHz gold crystal by carbodiimide crosslinking chemistry. The attachment efficiency is monitored by Fourier Transform Infrared Spectroscopy. Equilibrium association and dissociation constants describing Con A polysaccharides interaction are determined in a saturation binding experiment, where increasing concentrations of polysaccharides are run on a Con A-immobilized gold crystal surface, and the frequency shifts recorded on the frequency counter. The molecular weights (MW) of glycogen from Oyster and mannan from Saccharomyces cerevisiae are determined by size exclusion chromatography. The MW for glycogen and mannan are 604+/-0.002 kDa and 54+/-0.002 kDa, respectively. The equilibrium association and dissociation constants for Con A-glycogen and Con A-mannan interactions are KA=3.93+/-0.7*10(6) M(-1)/KD=0.25+/-0.06 MUM and (n=3), respectively. Their respective frequency and motional resistance shifts relationship (DeltaF/DeltaR) are 37.29+/-1.55 and 34.86+/-0.85 Hz/Omega (n=3), which support the validity of Sauerbrey's rigidity approximation. This work suggests that Con A-mannan complex could be potentially utilized for insulin delivery and the targeting of glucose-rich substances and glycoproteins when fast drug release is desired. PMID- 24768821 TI - Cannabinoid receptor-dependent metabolism of 2-arachidonoylglycerol during aging. AB - 2-Arachidonoylglycerol (2-AG) is one of the principal endocannabinoids involved in the protection against neurodegenerative processes. Cannabinoids primarily interact with the seven-segment transmembrane cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), both of which are expressed in the central nervous system (CNS). The level of 2-AG is controlled through key enzymes responsible for its synthesis or degradation. We have previously observed a deregulation of 2-AG metabolism in physiological aging. The aim of this study was to analyze how 2-AG metabolism is modulated by CB1/CB2 receptors during aging. To this end, both CB1 and CB2 receptor expression and the enzymatic activities (diacylglycerol lipase (DAGL), lysophosphatidate phosphohydrolase (LPAase) and monoacylglycerol lipase (MAGL)) involved in 2-AG metabolism were analyzed in the presence of cannabinoid receptor (CBR) agonists (WIN and JWH) and/or antagonists (SR1 and SR2) in synaptosomes from adult and aged rat cerebral cortex (CC). Our results demonstrate that: (a) aging decreases the expression of both CBRs; (b) LPAase inhibition, due to the individual action of SR1 or SR2, is reverted in the presence of both antagonists together; (c) LPAase activity is regulated mainly by the CB1 receptor in adult and in aged synaptosomes while the CB2 receptor acquires importance when CB1 is blocked; (d) modulation via CBRs of DAGL and MAGL by both antagonists occurs only in aged synaptosomes, stimulating DAGL and inhibiting MAGL activities; (e) only DAGL stimulation is reverted by WIN. Taken together, the results of the present study show that CB1 and/or CB2 receptor antagonists trigger a significant modulation of 2-AG metabolism, underlining their relevance as therapeutic strategy for controlling endocannabinoid levels in physiological aging. PMID- 24768822 TI - Safety on stairs: influence of a tread edge highlighter and its position. AB - BACKGROUND: Falls sustained when descending stairs are the leading cause of accidental death in older adults. Highly visible edge highlighters/friction strips (often set back from the tread edge) are sometimes used to improve stair safety, but there is no evidence for the usefulness of either. OBJECTIVE: To determine whether an edge highlighter and its location relative to the tread edge affect foot placement/clearance and accidental foot contacts when descending stairs. METHOD: Sixteen older adults (mean+/-1SD age; 71+/-7years) with normal vision (experiment 1) and eight young adults (mean+/-1SD age; 24+/-4years) with visual impairment due to simulated age-related cataract (experiment 2) completed step descent trials during which a high contrast edge highlighter was either not present, placed flush with the tread edge, or set back from the edge by 10mm or 30mm. Foot placement/clearance and the number of accidental foot contacts were compared across conditions. RESULTS: In experiment 1, a highlighter set back by 30mm led to a reduction in final foot placement (p<0.001) and foot clearance (p<0.001) compared to a highlighter placed flush with the tread edge, and the percentage of foot clearances that were less than 5mm increased from 2% (abutting) to 17% (away30). In experiment 2, a highlighter placed flush with the tread edge led to a decrease in within-subject variability in final foot placement (p=0.004) and horizontal foot clearance (p=0.022), a decrease in descent duration (p=0.009), and a decrease in the number of low clearances (<5mm, from 8% to 0%) and the number of accidental foot contacts (15% to 3%) when compared to a tread edge with no highlighter present. CONCLUSIONS: Changes to foot clearance parameters as a result of highlighter presence and position suggest that stairs with high-contrast edge highlighters positioned flush with the tread edge will improve safety on stairs, particularly for those with age related visual impairment. PMID- 24768823 TI - Age-related changes in angiogenesis in human dermis. AB - Present research is aimed to examine the number of dermal blood vessels, vascular endothelial growth factor (VEGF), delta-like ligand 4(Dll4) and Jagged-1 (Jag-1) in dermal blood vessels of human from 20weeks of pregnancy to 85years old. Numbers and proliferative activity of dermal fibroblast-like cells were also examined. Blood vessels were viewed with immunohistochemical staining for von Willebrand factor or CD31. VEGF, Dll4, Jag-1, and proliferating cell nuclear antigen (PCNA) were detected immunohistochemically. Results showed that the numbers of fibroblast-like cells, PCNA positive fibroblast-like cells, von Willebrand factor positive or CD31 positive blood vessels in dermis are dramatically decreased with age. The intensity of immunohistochemical staining for VEGF or Jag-1 in blood vessels of dermis is increased from antenatal to deep old period. The degree of immunohistochemical staining of dermal blood vessels for Dll4 has gone up from 20-40weeks of pregnancy to early life period (0 20years), and further decreased below antenatal values. Age-related decrease in the number of dermal blood vessels is suggested to be due to an impairment of VEGF signaling and to be mediated by Dll4 and Jag-1. It may be supposed that diminishing in blood supply of dermis occurring with age is a cause of a decrease in the number and proliferative pool of dermal fibroblasts. PMID- 24768824 TI - Proton/sodium pumping pyrophosphatases: the last of the primary ion pumps. AB - Membrane-bound pyrophosphatases (M-PPases) are homodimeric enzymes that couple the generation and utilization of membrane potentials to pyrophosphate (PPi) hydrolysis and synthesis. Since the discovery of the link between PPi use and proton transport in purple, non-sulphur bacteria in the 1960s, M-PPases have been found in all three domains of life and have been shown to have a crucial role in stress tolerance and in plant maturation. The discovery of sodium-pumping and sodium/proton-pumping M-PPases showed that the pumping specificity of these enzymes is not limited to protons, further suggesting that M-PPases are evolutionarily very ancient. The recent structures of two M-PPases, the Vigna radiata H(+)-pumping M-PPase and Thermotoga maritima Na(+)-pumping M-PPase, provide the basis for understanding the functional data. They show that M-PPases have a novel fold and pumping mechanism, different to the other primary pumps. This review discusses the current structural understanding of M-PPases and of ion selection among various M-PPases. PMID- 24768826 TI - Androgen deficiency and type 2 diabetes mellitus. AB - The rising incidence of T2DM is well recognised and associated with trends in obesity and ageing. It is estimated that 2.8% of the world population had a diagnosis of diabetes mellitus in 2000, which is projected to rise to 4.3% by 2030. Diabetes, obesity and ageing are also associated with an increased risk of isolated male hypogonadotropic hypogonadism, often labelled 'late onset hypogonadism' (LOH) to distinguish it from hypogonadism secondary to distinct hypothalamopituitary pathology. Whether the incidence of hypogonadism is increasing is open to question; the past decade, however, has witnessed a marked increase in the prescription of testosterone replacement therapy. Testosterone deficiency appears to be particularly common in type 2 diabetes with a prevalence of 33% observed in one cohort of 103 men (mean age 54.7). However, the diagnosis of androgen deficiency states is not necessarily straightforward, depending amongst other factors, upon whether a biochemical threshold or a syndromic approach (mandating the presence of certain key clinical features) is employed. The pathogenic mechanisms underlying obesity and diabetes related hypogonadism remain unclear with several competing theories, most of which are not mutually exclusive. Whilst a large body of epidemiological evidence associates testosterone deficiency with increased risk of cardiovascular disease and mortality, little evidence exists to support a protective effect of testosterone replacement. The benefits of androgen replacement in younger men with pituitary disease are well established, however, the potential benefits and safety of androgen replacement in older men is much less well developed. At present, replacement therapy in older men is advocated principally for the amelioration of sexual symptoms. This review will seek to explore issues around the pathogenesis, diagnosis, clinical consequences and management of male hypogonadism as it relates to T2DM. PMID- 24768825 TI - A study of the differences in the request of glycated hemoglobin in primary care in Spain: A global, significant, and potentially dangerous under-request. AB - OBJECTIVES: The study was performed to compare the variability and appropriateness in the request of glycated hemoglobin (HbA1c) in primary care in Spain. DESIGN AND METHODS: 76 Spanish laboratories from diverse regions across Spain filled out the number of HbA1c tests requested by general practitioners (GPs) during the year 2012. Every patient seen at the different primary care centers was included in the study. Each participating laboratory was required to provide organizational data. The number of HbA1c requests per 1000 inhabitants was calculated and compared between regions. To investigate whether HbA1c was appropriately requested to manage and to diagnose Diabetes Mellitus (DM), the number of necessary HbA1c was calculated, according to the disease prevalence in Spain (6.9%) and the guidelines regarding DM management and diagnosis. RESULTS: 17679195 patients were included in the study. A total of 1544551 HbA1c tests were ordered. No significant difference in the number of HbA1c requests per 1000 inhabitants was seen according to hospital setting (rural, urban or rural-urban). No significant differences were noticed between 3 Spanish regions, except the Valencian Community that presented higher values. Regarding the request appropriateness, 3280183 additional tests would have been necessary to manage diabetic patients and to diagnose new patients with the disease. CONCLUSION: There was a high variability regarding the request of HbA1c; the test was under requested in all the participating health departments. This emphasizes the need to accomplish interventions to improve an appropriate use. PMID- 24768827 TI - Beta-blockers in cirrhosis: therapeutic window or an aspirin for all? PMID- 24768829 TI - Bacterial translocation in liver cirrhosis: site and role in fibrogenesis. PMID- 24768828 TI - Weight trajectories through infancy and childhood and risk of non-alcoholic fatty liver disease in adolescence: the ALSPAC study. AB - BACKGROUND & AIMS: Adiposity is a key risk factor for NAFLD. Few studies have examined prospective associations of infant and childhood adiposity with subsequent NAFLD risk. We examined associations of weight-for-height trajectories from birth to age 10 with liver outcomes in adolescence, and assessed the extent to which associations are mediated through fat mass at the time of outcome assessment. METHODS: Individual trajectories of weight and height were estimated for participants in the Avon Longitudinal Study of Parents and Children using random-effects linear-spline models. Associations of birthweight (adjusted for birth length) and weight change (adjusted for length/height change) from 0-3 months, 3 months-1 y, 1-3 y, 3-7 y, and 7-10 y with ultrasound scan (USS) determined liver fat and stiffness, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) at mean age 17.8 y were assessed with linear and logistic regressions. Mediation by concurrent fat mass was assessed with adjustment for fat mass at mean age 17.8 y. RESULTS: Birth weight was positively associated with liver stiffness and negatively with ALT and AST. Weight change from birth to 1 y was not associated with outcomes. Weight change from 1-3 y, 3-7 y, and 7-10 y was consistently positively associated with USS and blood-based liver outcomes. Adjusting for fat mass at mean age 17.8 y attenuated associations toward the null, suggesting associations are largely mediated by concurrent body fatness. CONCLUSIONS: Greater rates of weight-for-height change between 1 y and 10 y are consistently associated with adverse liver outcomes in adolescence. These associations are largely mediated through concurrent fatness. PMID- 24768830 TI - beta-Adrenoceptors differentially regulate vascular tone and angiogenesis of rat aorta via ERK1/2 and p38. AB - beta-Adrenoceptors (beta-ARs) modulate ERK1/2 and p38 in different cells, but little is known about the contribution of these signaling pathways to the function of beta-ARs in vascular tissue. Immunoblotting analysis of rat aortic rings, primary endothelial (ECs) and smooth muscle cells (SMCs) isolated from aorta showed that beta-AR stimulation with isoprenaline activated p38 in aortic rings and in both cultured cell types, whereas it had a dual effect on ERK1/2 phosphorylation, decreasing it in ECs while increasing it in SMCs. These effects were reversed by propranolol, which by itself increased p-ERK1/2 in ECs. Isoprenaline beta-AR mediated vasodilation of aortic rings was potentiated by the ERK1/2 inhibitor, U0126, in the presence or absence of endothelium or L-NAME, whereas inhibition of p38 had no impact. Isoprenaline moderately decreased sprouting from aorta rings in the Matrigel angiogenesis assay; conversely propranolol not only prevented isoprenaline inhibition, but stimulated angiogenesis. ERK1/2 inhibition decreased angiogenesis, while a dramatic stimulation was observed by p38 blockade. Our results suggest that ERK1/2 activation after beta-ARs stimulation in the smooth muscle hinders the vasodilator effect of isoprenaline, but in the endothelium beta-ARs decreases ERK1/2 and increases p38 activity reducing therefore angiogenesis. PMID- 24768831 TI - Applicability of the "Frame of Reference" approach for environmental monitoring of offshore renewable energy projects. AB - This paper assesses the applicability of the Frame of Reference (FoR) approach for the environmental monitoring of large-scale offshore Marine Renewable Energy (MRE) projects. The focus is on projects harvesting energy from winds, waves and currents. Environmental concerns induced by MRE projects are reported based on a classification scheme identifying stressors, receptors, effects and impacts. Although the potential effects of stressors on most receptors are identified, there are large knowledge gaps regarding the corresponding (positive and negative) impacts. In that context, the development of offshore MRE requires the implementation of fit-for-purpose monitoring activities aimed at environmental protection and knowledge development. Taking European legislation as an example, it is suggested to adopt standardized monitoring protocols for the enhanced usage and utility of environmental indicators. Towards this objective, the use of the FoR approach is advocated since it provides guidance for the definition and use of coherent set of environmental state indicators. After a description of this framework, various examples of applications are provided considering a virtual MRE project located in European waters. Finally, some conclusions and recommendations are provided for the successful implementation of the FoR approach and for future studies. PMID- 24768832 TI - The status of water reuse in European textile sector. AB - The textile finishing industry is known as a very fragmented and heterogeneous industrial sector dominated mainly by small and medium enterprises (SMEs). As with many other industrial sectors in Europe, it is obliged to act more sustainably in regard to increasingly limited natural resources such as water. This paper presents in-depth survey of wastewater reuse programmes over the last ten years covering the European textile finishing industry. Different wastewater treatment solutions developed are presented and discussed. Special attention is given to the project AquaFit4Use (7th Framework Programme), where almost five years of project work has resulted in valuable know-how practices in water reuse for the most water consuming sectors in Europe i.e. paper, food, chemical and textile. Only the latter is discussed in this paper. The main negative impacts by the textile finishing sector on the environment are still related to intensive water consumption and wastewater discharge, characterised by greater amounts of organic chemicals and colouring agents, low biodegradability, and high salinity. End of pipe treatment of such complex effluents in order to produce reusable water is not feasible. Therefore, separation of waste effluents regarding their pollution level and their separate treatment was the basic approach used in the project. As a result waste effluents with a big reuse potential could be effectively treated by combination of conventional treatment technologies. Proposed water treatment scenarios enable more than 40% reduction in fresh water consumption. Since different guidelines of minimum water quality to be safely reuse in textile processes exist at this stage this issue is discussed as well. PMID- 24768833 TI - Scale deposits in kraft pulp bleach plants with reduced water consumption: a review. AB - The general tendency in the pulp industry towards reduced fresh water consumption and minimum effluent causes major deposit problems in mills. Chemical pulp bleach plants are affected by several types of mineral deposits, the most frequent being calcite, barite and calcium oxalate. In this review, the phenomena leading to scaling in chemical pulp bleaching are discussed, together with strategies for limiting deposits. The merits of various chemical methods in estimating scaling risks are compared. Chemical speciation methods are used throughout this review to gain a better understanding and prediction of scaling phenomena. Coupled chemical process simulations are anticipated to be a crucial way of solving deposition problems in bleach plants. PMID- 24768834 TI - Emissions of CO2 and CH4 from sludge treatment reed beds depend on system management and sludge loading. AB - Sludge treatment reed beds (STRB) are considered as eco-friendly and sustainable alternatives to conventional sludge treatment methods, although little is known about greenhouse gas emissions from such systems. We measured CO2 and CH4 emissions and substrate characteristics in a STRB, an occasionally loaded sludge depot (SD) and a natural reed wetland (NW). The aim was to compare (i) emissions among the sites in relation to substrate characteristics and (ii) emissions before and after sludge loading in the STRB. The STRB emitted twice as much CO2 (1200 mg m(-2) h(-1)) as the SD, whereas the SD emitted four times more CH4 (2 mg m(-2) h(-1)) than the STRB. The NW had the lowest emissions of both gases. The differences in gas emissions among the sites were primarily explained by differences in the availability of oxygen in the substrate. As a consequence of overloading and poor management, the SD had no vegetation and a poor dewatering capacity, which resulted in anaerobic conditions favoring CH4 emission. In contrast, the well-managed STRB had more aerobic conditions in the sludge residue resulting in low CH4 emission rates. We conclude that well-designed and well managed STRBs have a low climate impact relative to conventional treatment alternatives, but that overloading and poor sludge management enhances the emissions of CH4. PMID- 24768835 TI - Mineralization of wastewater from the pharmaceutical industry containing chloride ions by UV photolysis of H2O2/Fe(II) and ultrasonic irradiation. AB - The mineralization of pharmaceutical wastewater containing chloride ions using a UV/H2O2/Fe(II) process was studied. The addition of Fe(II) to the UV/H2O2 system did not improve the degradation efficiency due to inhibition of the photo-Fenton reaction, at acid pH, in the presence of chloride ions in these wastewaters. The increase of pH from 2 to 7 increased the degree of mineralization under UV photolysis of H2O2 because more HO radicals are available by HOCl dissociation reaction. Under the selected operation conditions ([H2O2]o = 11,500 ppm, [Fe(II)] = 0 ppm, [TOC]o = 125 ppm and pH = 7), 100% of TOC removal was attained in 120 min. A significant synergistic effect of combining photolysis (UV/H2O2) and sonolysis was observed. Sonophotolysis (UV/H2O2/ultrasound) technique significantly increased the degree of mineralization (100% TOC removal in 90 min using 6500 ppm H2O2) when compared with each individual process. Sonochemical reaction was favored by the presence of chloride ions since the concentration of contaminants at the gas-liquid interface increased. Free radicals reaction was the controlling mechanism in the UV/H2O2/ultrasound system. HO radicals were the main oxidative intermediate species in the process, although hydroperoxyl radicals (HO2) also played a role. The contribution of thermal-pyrolytic reaction (in gas-phase) to sonophotolysis process was negligible. PMID- 24768836 TI - Removal of odorous compounds from poultry manure by microorganisms on perlite- bentonite carrier. AB - Laboratory-scale experiments were conducted using poultry manure (PM) from a laying hen farm. Six strains of bacteria and one strain of yeast, selected on the base of the previous study, were investigated to evaluate their activity in the removal of odorous compounds from poultry manure: pure cultures of Bacillus subtilis subsp. spizizenii LOCK 0272, Bacillus megaterium LOCK 0963, Pseudomonas sp. LOCK 0961, Psychrobacter faecalis LOCK 0965, Leuconostoc mesenteroides LOCK 0964, Streptomyces violaceoruber LOCK 0967, and Candida inconspicua LOCK 0272 were suspended in water solution and applied for PM deodorization. The most active strains in the removal of volatile odorous compounds (ammonia, hydrogen sulfide, dimethylamine, trimethylamine, isobutyric acid) belonged to B. subtilis subsp. spizizenii, L. mesenteroides, C. inconspicua, and P. faecalis. In the next series of experiments, a mixed culture of all tested strains was immobilized on a mineral carrier being a mixture of perlite and bentonite (20:80 by weight). That mixed culture applied for PM deodorization was particularly active against ammonia and hydrogen sulfide, which were removed from the exhaust gas by 20.8% and 17.5%, respectively. The experiments also showed that during deodorization the microorganisms could reduce the concentrations of proteins and amino acids in PM. In particular, the mixed culture was active against cysteine and methionine, which were removed from PM by around 45% within 24 h of deodorization. PMID- 24768837 TI - Establishing ecological reference conditions and tracking post-application effectiveness of lanthanum-saturated bentonite clay (Phoslock(r)) for reducing phosphorus in aquatic systems: an applied paleolimnological approach. AB - Innovative management strategies for nutrient enrichment of freshwater are important in the face of this increasing global problem, however many strategies are not assessed over long enough time periods to establish effectiveness. Paleolimnological techniques using diatoms as biological indicators were utilized to establish ecological reference conditions, environmental variation, and the effectiveness of lanthanum-saturated bentonite clay (brand name: Phoslock((r))) applied to reduce water column phosphorus (P) concentrations in four waterbodies in Ontario, Canada, and eastern Australia. In sediment cores from the two Canadian sites, there were short-lived changes to diatom assemblages, relative to inferred background conditions, and a temporary reduction in both measured and diatom-inferred total phosphorus (TP) before returning to pre-application conditions (particularly in the urban stormwater management pond which has a high flushing rate and responds rapidly to precipitation and surface run-off). The two Australian sites (a sewage treatment pond and a shallow recreational lake), recorded no reduction in diatom-inferred TP. Based on our pre-application environmental reconstruction, changes to the diatom assemblages and diatom inferred TP appeared to be driven by larger, climatic factors. While laboratory tests involving this product showed sharp reductions in water column TP, management strategies require detailed information on pre-application environmental conditions and variations in order to accurately assess the effectiveness of new technologies for lake management. PMID- 24768838 TI - Understanding resilience in industrial symbiosis networks: insights from network analysis. AB - Industrial symbiotic networks are based on the principles of ecological systems where waste equals food, to develop synergistic networks. For example, industrial symbiosis (IS) at Kalundborg, Denmark, creates an exchange network of waste, water, and energy among companies based on contractual dependency. Since most of the industrial symbiotic networks are based on ad-hoc opportunities rather than strategic planning, gaining insight into disruptive scenarios is pivotal for understanding the balance of resilience and sustainability and developing heuristics for designing resilient IS networks. The present work focuses on understanding resilience as an emergent property of an IS network via a network based approach with application to the Kalundborg Industrial Symbiosis (KIS). Results from network metrics and simulated disruptive scenarios reveal Asnaes power plant as the most critical node in the system. We also observe a decrease in the vulnerability of nodes and reduction in single points of failure in the system, suggesting an increase in the overall resilience of the KIS system from 1960 to 2010. Based on our findings, we recommend design strategies, such as increasing diversity, redundancy, and multi-functionality to ensure flexibility and plasticity, to develop resilient and sustainable industrial symbiotic networks. PMID- 24768839 TI - Sorption and transport of sulfamethazine in agricultural soils amended with invasive-plant-derived biochar. AB - Sulfonamides (SAs) are one of the most frequently used antibiotics in the veterinary industry, showing high mobility in soils. Objectives of this research were to determine the sorption, distribution coefficients and involvement of different ionic forms of sulfamethazine (SMZ), a representative SAs, and to evaluate the transport of SMZ in biochar treated soils. Biochars were produced from an invasive plant, burcucumber (Sicyos angulatus L.), under slow pyrolysis conditions at peak temperatures of 300 degrees C (biochar-300) and 700 degrees C (biochar-700), respectively. The abilities of the biochars to retain SMZ in loamy sand and sandy loam soils were examined under different pHs and SMZ loadings. Soil column experiments were performed with and without biochars addition. Results showed that biochar-700 had a high degree of SMZ retention, with resultant decreased pH in both soils. Modeled effective sorption coefficients (KD,eff) values indicated that the observed high SMZ retention at pH 3 could be attributed to the pi-pi electron donor-acceptor interaction and electrostatic cation exchange, whereas at pH 5 and 7, cation exchange was the main mechanisms responsible. There was no temporal retardation of SMZ in biochar treated soil as compared to the untreated soil. However, biochar-700 treatment achieved up to 89% and 82% increase in the SMZ retention in sandy loam and loamy sand soils, respectively. The overall results demonstrated that burcucumber biochar produced at higher temperature was effective in reducing the mobility of SMZ in the studied soils. PMID- 24768840 TI - The energy-water-food nexus: strategic analysis of technologies for transforming the urban metabolism. AB - Urban areas are considered net consumers of materials and energy, attracting these from the surrounding hinterland and other parts of the planet. The way these flows are transformed and returned to the environment by the city is important for addressing questions of sustainability and the effect of human behavior on the metabolism of the city. The present work explores these questions with the use of systems analysis, specifically in the form of a Multi-sectoral Systems Analysis (MSA), a tool for research and for supporting decision-making for policy and investment. The application of MSA is illustrated in the context of Greater London, with these three objectives: (a) estimating resource fluxes (nutrients, water and energy) entering, leaving and circulating within the city watershed system; (b) revealing the synergies and antagonisms resulting from various combinations of water-sector innovations; and (c) estimating the economic benefits associated with implementing these technologies, from the point of view of production of fertilizer and energy, and the reduction of greenhouse gases. Results show that the selection of the best technological innovation depends on which resource is the focus for improvement. Urine separation can potentially recover 47% of the nitrogen in the food consumed in London, with revenue of $33 M per annum from fertilizer production. Collecting food waste in sewers together with growing algae in wastewater treatment plants could beneficially increase the amount of carbon release from renewable energy by 66%, with potential annual revenues of $58 M from fuel production. PMID- 24768841 TI - Constitutive and functional expression of runt-related transcription factor-2 by microglial cells. AB - Runt-related transcription factor-2 (Runx2) is the master regulator of osteoblastogenesis with an ability to promote differentiation of mesenchymal stem cells into the osteoblastic lineage. We have previously shown constitutive and functional expression of Runx2 by astroglial cells. In this study, we investigated the possible expression of Runx2 by both murine microglia and microglial cell line BV-2 cells. Runx2 expression was seen in cultured microglia and BV-2 cells, while sustained exposure to 1mM ATP led to a significant but transient increase in mRNA and corresponding protein expression of Runx2 within 24 h. The increase in Runx2 expression was invariably prevented by several chemicals with antagonistic properties for P2X7 purinergic receptor, calmodulin and calcineurin in BV-2 cells, with a P2X7 receptor agonist more than quadrupling Runx2 expression. A significant increase in Runx2 expression was seen in osteoclastic cells, but not in osteoblastic or chondrocytic cells, when exposed to a high concentration of ATP. In BV2-cells with control siRNA, a significant decrease was found in the number of cells with at least one process within 3 h after the exposure to 1mM ATP, followed by an increase up to 24 h. However, Runx2 siRNA significantly deteriorated the property to induce delayed process extension during 6-24 h after exposure to ATP along with drastically decreased Runx2 protein levels. These results suggest that Runx2 is constitutively and functionally expressed by microglial cells with responsiveness to ATP for upregulation in the murine brain. PMID- 24768843 TI - The effects of artificial wing wear on the flight capacity of the honey bee Apis mellifera. AB - The wings of bees and other insects accumulate permanent wear, which increases the rate of mortality and impacts foraging behavior, presumably due to effects on flight performance. In this study, we investigated how experimental wing wear affects flight performance in honey bees. Variable density gases and high-speed videography were used to determine the maximum hovering flight capacity and wing kinematics of bees from three treatment groups: no wing wear, symmetric and asymmetric wing wear. Wing wear was simulated by clipping the distal-trailing edge of one or both of the wings. Across all bees from treatment groups combined, wingbeat frequency was inversely related to wing area. During hovering in air, bees with symmetric and asymmetric wing wear responded kinematically so as to produce wingtip velocities similar to those bees with no wing wear. However, maximal hovering flight capacity (revealed during flight in hypodense gases) decreased in direct proportion to wing area and inversely to wing asymmetry. Bees with reduced wing area and high asymmetry produced lower maximum wingtip velocity than bees with intact or symmetric wings, which caused a greater impairment in maximal flight capacity. These results demonstrate that the magnitude and type of wing wear affects maximal aerodynamic power production and, likely, the control of hovering flight. Wing wear reduces aerodynamic reserve capacity and, subsequently, the capacity for flight behaviors such as load carriage, maneuverability, and evading predators. PMID- 24768842 TI - Rapid behavioural gregarization in the desert locust, Schistocerca gregaria entails synchronous changes in both activity and attraction to conspecifics. AB - Desert Locusts can change reversibly between solitarious and gregarious phases, which differ considerably in behaviour, morphology and physiology. The two phases show many behavioural differences including both overall levels of activity and the degree to which they are attracted or repulsed by conspecifics. Solitarious locusts perform infrequent bouts of locomotion characterised by a slow walking pace, groom infrequently and actively avoid other locusts. Gregarious locusts are highly active with a rapid walking pace, groom frequently and are attracted to conspecifics forming cohesive migratory bands as nymphs and/or flying swarms as adults. The sole factor driving the onset of gregarization is the presence of conspecifics. In several previous studies concerned with the mechanism underlying this transformation we have used an aggregate measure of behavioural phase state, Pgreg, derived from logistic regression analysis, which combines and weights several behavioural variables to characterise solitarious and gregarious behaviour. Using this approach we have analysed the time course of behavioural change, the stimuli that induce gregarization and the key role of serotonin in mediating the transformation. Following a recent critique that suggested that using Pgreg may confound changes in general activity with genuine gregarization we have performed a meta-analysis examining the time course of change in the individual behaviours that we use to generate Pgreg. We show that the forced crowding of solitarious locusts, tactile stimulation of the hind femora, and the short-term application of serotonin each induce concerted changes in not only locomotion-related variables but also grooming frequency and attraction to other locusts towards those characteristic of long-term gregarious locusts. This extensive meta-analysis supports and extends our previous conclusions that solitarious locusts undergo a rapid behavioural gregarization upon receiving appropriate stimulation for a few hours that is mediated by serotonin, at the end of which their behaviour is largely indistinguishable from locusts that have been in the gregarious phase their entire lives. PMID- 24768844 TI - Strategies to inhibit entry of HBV and HDV into hepatocytes. AB - Although there has been much research into the pathogenesis and treatment of hepatitis B virus (HBV) and hepatitis D virus (HDV) infections, we still do not completely understand how these pathogens enter hepatocytes. This is because in vitro infection studies have only been performed in primary human hepatocytes. Development of a polarizable, HBV-susceptible human hepatoma cell line and studies of primary hepatocytes from Tupaia belangeri have provided important insights into the viral and cellular factors involved in virus binding and infection. The large envelope (L) protein on the surface of HBV and HDV particles has many different functions and is required for virus entry. The L protein mediates attachment of virions to heparan sulfate proteoglycans on the surface of hepatocytes. The myristoylated N-terminal preS1 domain of the L protein subsequently binds to the sodium taurocholate cotransporting polypeptide (NTCP, encoded by SLC10A1), the recently identified bona fide receptor for HBV and HDV. The receptor functions of NTCP and virus entry are blocked, in vitro and in vivo, by Myrcludex B, a synthetic N-acylated preS1 lipopeptide. Currently, the only agents available to treat chronic HBV infection target the viral polymerase, and no selective therapies are available for HDV infection. It is therefore important to study the therapeutic potential of virus entry inhibitors, especially when combined with strategies to induce immune-mediated killing of infected hepatocytes. PMID- 24768845 TI - Infection route of rice grassy stunt virus, a tenuivirus, in the body of its brown planthopper vector, Nilaparvata lugens (Hemiptera: Delphacidae) after ingestion of virus. AB - Rice grassy stunt virus (RGSV), a tenuivirus, is transmitted by the brown planthopper (BPH), Nilaparvata lugens (Hemiptera, Delphacidae), in a persistent propagative manner. In this study, immunofluorescence microscopy was used to investigate the infection route of RGSV in the internal organs of BPH after acquiring the virus by feeding on RGSV-infected rice plants. The sequential infection study revealed that RGSV initially infected the midgut epithelium, then crossed the basal lamina into the midgut visceral muscles, from where RGSV apparently spread into the hemolymph, then into the salivary glands of its BPH vector. The mechanism underlying this infection route of RGSV in its BPH vector may confer an advantage for the direct spread of RGSV from the initially infected epithelium to the salivary glands in BPH, contributing to efficient transmission of RGSV by its insect vector. PMID- 24768846 TI - Taxonomic reorganization of family Partitiviridae and other recent progress in partitivirus research. AB - Phylogenetic analyses have prompted a taxonomic reorganization of family Partitiviridae (encapsidated, bisegmented dsRNA viruses that infect plants, fungi, or protozoa), the focus of this review. After a brief introduction to partitiviruses, the taxonomic changes are discussed, including replacement of former genera Partitivirus, Alphacryptovirus, and Betacryptovirus, with new genera Alphapartitivirus, Betapartitivirus, Gammapartitivirus, and Deltapartitivirus, as well as redistribution of species among these new genera. To round out the review, other recent progress of note in partitivirus research is summarized, including discoveries of novel partitivirus sequences by metagenomic approaches and mining of sequence databases, determinations of fungal partitivirus particle structures, demonstrations of fungal partitivirus transmission to new fungal host species, evidence for other aspects of partitivirus-host interactions and host effects, and identification of other fungal or plant viruses with some similarities to partitiviruses. Some outstanding questions are also discussed. PMID- 24768847 TI - Isolation and characterization of a new class of DNA aptamers specific binding to Singapore grouper iridovirus (SGIV) with antiviral activities. AB - The Singapore grouper iridovirus (SGIV), a member of the genus Ranavirus, is a major viral pathogen that has caused heavy economic losses to the grouper aquaculture industry in China and Southeast Asia. No efficient method of controlling SGIV outbreaks is currently available. Systematic evolution of ligands by exponential enrichment (SELEX) is now widely used for the in vitro selection of artificial ssDNA or RNA ligands, known as aptamers, which bind to targets through their stable three-dimensional structures. In our current study, we generated ssDNA aptamers against the SGIV, and evaluated their ability to block SGIV infection in cultured fish cells and cultured fish in vivo. The anti SGIV DNA aptamers, LMB-761, LMB-764, LMB-748, LMB-439, LMB-755, and LMB-767, were selected from a pool of oligonucleotides randomly generated using a SELEX iterative method. The analysis of the secondary structure of the aptamers revealed that they all formed similar stem-loop structures. Electrophoretic mobility shift assays showed that the aptamers bound SGIV specifically, as evidenced by a lack cross-reactivity with the soft shell turtle iridovirus. The aptamers produced no cytotoxic effects in cultured grouper spleen cells (GS). Assessment of cytopathic effects (CPE) and viral titer assays showed that LMB 761, LMB-764, LMB-748, LMB-755, and LMB-767 significantly inhibited SGIV infection in GS cells. The in vivo experiments showed that LMB-761 and LMB-764 reduced SGIV-related mortality, and no negative effects were observed in orange spotted grouper, Epinephelus coioides, indicating that these DNA aptamers may be suitable antiviral candidates for controlling SGIV infections in fish reared in marine aquaculture facilities. PMID- 24768848 TI - Evaluation of tetravalent and conserved synthetic peptides vaccines derived from Dengue virus Envelope domain I and II. AB - Dengue is a major worldwide public health problem, especially in the tropical and subtropical regions of the world. Primary infection with a single Dengue virus (DENV) serotype causes a mild, self-limiting febrile illness called dengue fever. However, a subset of patients experiencing a secondary infection with a different serotype progress to the severe form of the disease, called dengue hemorrhagic fever. In this study, the vaccine potential of three tetravalent and conserved synthetic peptides derived from DENV envelope domain I (named Pep01) and II (named Pep02 and Pep03) was evaluated. Human dengue IgM/IgG positive serum (n=16) showed reactivity against Pep01, Pep02 and Pep03 in different degrees. Mice immunization experiments showed that these peptides were able to induce a humoral response characterized by antibodies with low neutralizing activity. The spleen cells derived from mice immunized with the peptides showed a significant cytotoxic activity (only for Pep02 and Pep03), a high expression of IL-10 (P<0.01) and a reduced expression of TNF-alpha and IFN-gamma (P<0.001) compared to DENV-1 infected splenocytes. Thus these peptides, and specially the Pep03, can induce a humoral response characterized by antibodies with low neutralizing activities and probably a T cell response that could be beneficial to induce an effective immune response against all DENV serotypes and do not contributed to the immunopathogenesis. However, further studies in peptide sequence will be required to induce the production of neutralizing antibodies against all four DENV serotypes and also to improve immunogenicity of these peptides. PMID- 24768849 TI - Preoperative MRI criteria for trials on less radical surgery in Stage IB1 cervical cancer. AB - OBJECTIVE: The aim of this study is to identify a patient group with a low-risk of parametrial involvement (PMI) in Stage IB1 cervical cancer using preoperative magnetic resonance imaging (MRI) parameters. METHODS: In total, 190 Stage IB1 cervical cancer patients with clinically visible lesions who had undergone Type C2 radical hysterectomy and preoperative MRI were included in this study. Clinical records, pathology reports, and preoperative MRI findings were reviewed retrospectively. RESULTS: Of the 190 patients, 19 (10%) had pathologic PMI. The largest tumor diameter identified by MRI ranged from zero (no definite mass on the cervix) to 60 mm, with a median of 21 mm. Patients were identified as being either low-risk (tumor size <=25 mm and no evidence of PMI, n=127) or high-risk (tumor size >25 mm and/or findings indicating PMI, n=63) based on MRI parameters. The rate of pathologic PMI in low- and high-risk patients was 0.0% and 30.2%, respectively (P<0.001). Five-year progression-free survival in low-risk patients was 95.9%, which is significantly better than the rate of 85.6% for patients in the high-risk group (P=0.039). CONCLUSIONS: Preoperative MRI parameters can help identify patients with a low-risk of PMI and, therefore, possible candidates for trials on less radical surgery. PMID- 24768850 TI - A cut-off value of 2 cm in tumor size is of prognostic value in surgically treated FIGO stage IB cervical cancer. AB - OBJECTIVES: Limited knowledge exists about the value of tumor size in surgically treated cervical cancer (CX) using a tumor size of 2 cm as cut-off value. METHODS: A total of 366 cases of CX FIGO stage IB who received upfront surgery were evaluated regarding tumor size, the prediction of pelvic lymph node involvement, and recurrence-free and overall survival during a median follow-up time of 94 months. Tumors <=2.0 cm were defined as small, tumors 2.1-4.0 cm as medium sized and those larger than 4 cm as bulky disease. RESULTS: Small tumors were seen in 28.7%, medium sized in 52.5% and bulky tumors in 18.9%. There was a significant higher frequency of pelvic lymph node involvement with increasing tumor size (13.3% vs. 23.4% vs. 43.5%, respectively; p<0.001) and an increase of recurrent disease (6.7% vs. 18.8% vs. 29.4%, respectively; p<0.001). The 5-year overall survival rate was significantly reduced with increasing tumor size (94.0% vs. 85.1% vs. 69.9%, respectively; p<0.001). Pelvic lymph node involvement and maximal tumor size were independent prognostic factors for both recurrence-free and overall survival in multivariate analysis. CONCLUSIONS: The results support that tumor size is of prognostic impact in FIGO stage IB cervical carcinomas. A further substaging is suggested for tumors up to 4.0 cm maximum dimension using a cut-off value of 2.0 cm as discriminator. Patients with tumors <=2.0 cm may represent low risk disease. PMID- 24768852 TI - A high-throughput open-array qPCR gene panel to identify housekeeping genes suitable for myometrium and leiomyoma expression analysis. AB - OBJECTIVE: To evaluate 51 different housekeeping genes for their use as internal standards in myometrial and matched leiomyoma samples in proliferative and secretory phases. METHODS: RNA from 6 myometrium and matched leiomyoma samples was obtained from pre-menopausal women who underwent hysterectomy. Reverse transcription and real-time quantitative PCR were achieved using TaqMan high density open-array human endogenous control panel. RESULTS: Expression stability of 51 candidate genes was determined by GeNorm and NormFinder softwares. We identified 10 housekeeping genes, ARF1, MRPL19, FBXW2, PUM1, UBE2D2, EIF2B1, HPRT1, GUSB, ALAS1, and TRIM27, as the best set of normalization genes for comparing relative expression between leiomyoma and myometrium samples in proliferative and secretory phases. CONCLUSIONS: Adequate reference genes for accurate normalization are essential to compare gene expression between leiomyoma and myometrial samples. Ideal housekeeping genes must have stable expression patterns regardless of the sample type and menstrual cycle phase. In this study, we propose a set of 10 candidate genes with greater expression stability than those housekeeping genes commonly used in leiomyoma and myometrium tissues. Their use will improve the sensitivity and specificity of the gene expression analysis in these tissues. PMID- 24768851 TI - Safety and tolerance of radical hysterectomy for cervical cancer in the elderly. AB - BACKGROUND: Despite institutional studies that suggest that radical hysterectomy for cervical cancer is well tolerated in the elderly, little population-level data are available on the procedure's outcomes in older women. We performed a population-based analysis to determine the morbidity, mortality, and resource utilization of radical hysterectomy in elderly women with cervical cancer. METHODS: Patients recorded in the Nationwide Inpatient Sample with invasive cervical cancer who underwent abdominal radical hysterectomy between 1998 and 2010 were analyzed. Patients were stratified by age: <50, 50-59, 60-69, and >=70 years. We examined the association between age and the outcomes of interest using chi square tests and multivariable generalized estimating equations. RESULTS: A total of 8199 women were identified, including 768 (9.4%) women age 60-69 and 462 (5.6%) women >=70 years of age. All cause morbidity increased from 22.1% in women <50, to 24.7% in those 50-59 years, 31.4% in patients 60-69 years and 34.9% in women >70years of age (P<0.0001). Compared to women<50, those >70 were more likely to have intraoperative complications (4.8% vs. 9.1%, P=0.0003), surgical site complications (10.9% vs. 17.5%, P<0.0001), and medical complications (9.9% vs. 19.5%, P<0.0001). The risk of non-routine discharge (to a nursing facility) was 0.5% in women <50 vs. 12.3% in women >=70 (P<0.0001). Perioperative mortality women >=70 years of age was 30 times greater than that of women <50 (P<0.0001). CONCLUSION: Perioperative morbidity and mortality are substantially greater in elderly women who undergo radical hysterectomy for cervical cancer. Non-surgical treatments should be considered in these patients. PMID- 24768853 TI - Congener specific analysis, spatial distribution and screening-level risk assessment of polychlorinated naphthalenes in water and sediments from two tributaries of the River Chenab, Pakistan. AB - The number of reports regarding PCN screening-levels and ecological risk assessment in environmental compartments is limited. This study presents information on congener specific analysis, distribution pattern of PCN and ecological risk assessment via PCN exposure/contamination through water and sediment from two tributaries of the River Chenab, Pakistan. A total twenty eight samples of water and sediment were collected during Jan, 2013 to June, 2013 to analyze the ?39PCN congeners. ?39PCN concentrations ranged between 8.94 and 414 ng g(-1) dw and 178-489 ng l(-1) in sediment and water, respectively. Water exhibited higher TEQ values while in case of sediments TEQ values were at higher than the previously reported data from other parts of the world. This is the first report of PCNs' distribution pattern and screening-level risk assessment from Pakistan. The results of toxicity exposure of PCN warrant auxiliary devotion in future, to this group of contaminant. PMID- 24768854 TI - Reply to the Editor--PQ-segment depression in short QT syndrome patients: a novel marker for diagnosing short QT syndrome? PMID- 24768855 TI - Fluorescent transgenic zebrafish as a biosensor for growth-related effects of methyl parathion. AB - Transgenic fish models are potential alternative subjects in toxicological studies, since they can provide in vivo information on the deleterious effects of different substances. Here, we used a transgenic zebrafish (Danio rerio) lineage, which expresses a destabilized fluorescent protein (DsRED) driven by the myosin light chain promoter (Mylz2), in order to propose a new research tool for environmental biomonitoring. For validating the MYO-RED lineage, we exposed fish to the organophosphorated pesticide methyl parathion (MP). The effect of MP on fish growth was assessed by evaluating weight, length, condition factor and muscle fiber diameter. All factors suffered reduction at both tested concentrations (0.13MUM and 13MUM of MP). Similarly, fluorescence intensity decreased in a concentration-dependent manner, suggesting muscle protein catabolism. However, DsRED gene expression lowered only at the higher MP concentration. Results indicate that the MYO-RED transgenic zebrafish is an interesting model for detecting the growth-related effects of pollutants. Destabilized proteins such as reporter genes are apparently sensitive biomarkers, since effects were observed even at the lower, environmentally acceptable concentration. Therefore, this transgenic fish is a promising candidate model for sensitive, fast, and easy environmental monitoring. PMID- 24768856 TI - Embryonic exposure to sodium arsenite perturbs vascular development in zebrafish. AB - Exposure to arsenic in its inorganic form, arsenite, causes adverse effects to many different organs and tissues. Here, we have investigated arsenite-induced adverse effects on vascular tissues in the model organism zebrafish, Danio rerio. Zebrafish embryos were exposed to arsenite at different exposure windows and the susceptibility to vascular tissue damage was recorded at 72hours post fertilization (hpf). Intersegmental vessel sprouting and growth was most perturbed by exposure to arsenite during the 24-48hpf window, while disruption in the condensation of the caudal vein plexus was more often observed at the 48 72hpf exposure window, reflecting when these structures develop during normal embryogenesis. The vascular growth rate was decreased by arsenite exposure, and deviated from that of control embryos at around 24-26.5hpf. We further mapped changes in expression of key regulators of angiogenesis and vasculogenesis. Downregulation of vascular endothelial growth factor receptor 1/fms-related tyrosine kinase 1 (vegfr1/flt1) expression was evident already at 24hpf, coinciding with the decreased vascular growth rate. At later time points, matrix metalloproteinase 9 (mmp9) expression was upregulated, suggesting that arsenite affects the composition of the extracellular matrix. In total, the expression of eight key factors involved in different aspects of vascularization was significantly altered by arsenic exposure. In conclusion, our results show that arsenite is a potent vascular disruptor in the developing zebrafish embryo, a finding that calls for an evaluation of arsenite as a developmental vascular toxicant in mammalian model systems. PMID- 24768857 TI - Self-reporter shikonin-Act-loaded solid lipid nanoparticle: formulation, physicochemical characterization and geno/cytotoxicity evaluation. AB - Shikonin and some of its derivative have approved apoptotic potential in different human cancer cell lines, and moreover have a dominant fluorescent emission at ~600nm. Here, to enhance shikonin-Act anti-proliferation properties, it was successfully incorporated in Solid Lipid Nanoparticles (SLNs) by the hot homogenization and entrapment efficiency (EE) of drug in SLNs was determined by ultrafiltration method. Scanning electron microscopy (SEM), laser diffractometry and zeta-sizer indicated that shikonin-Act-SLN were spherical and regular particles in the range of 70-120nm with polydispersity index (PI) of less than 0.10. The physical stability of shikonin-Act-loaded SLN in aqueous dispersion was evaluated in terms of size, PI, EE and drug leakage and the results showed that SLNs were stable upon storing three month. Long term in vitro release of the shikonin-Act was also approved. Cellular uptake of the shikonin-Act-SLN was examined by the in vitro fluorescent microscopy and facs flow cytometry analyses. In vivo rat imaging approved the penetrating capability of shikonin-Act-SLN emission through living tissues. In vitro anti-proliferation and genotoxicity evaluation by MTT and comet assay confirmed that shikonin-Act-SLN showed higher cytotoxic/antitumor potential than intact shikonin in terms of IC50 and DNA damage. This work provide sufficient information about improving of the therapeutic efficacy of the shikonin-Act, and also using of the shikonin-Act-SLN in bio-distribution studies during drug delivery investigation by incorporating in lipidic and colloidal drug delivery particles such as SLNs. PMID- 24768858 TI - Methodological considerations for mutagen exposure in C. elegans. AB - Maintenance of the genome requires the continual repair of DNA lesions. Exposure of nematodes to DNA damage-inducing agents is a powerful method to rapidly ascribe a role for specific genes in DNA repair and to define epistatic relationships to other repair genes which allows for the construction of repair pathways. Despite the extensive use of these agents, however, differences in dosing, timing, and handling makes it difficult to compare results across laboratories. We provide herein a consideration of the parameters that influence the results of these exposures and detailed protocols for the exposure to mutagenic inducing agents. PMID- 24768859 TI - Direct electrochemistry of glucose oxidase and glucose biosensing on a hydroxyl fullerenes modified glassy carbon electrode. AB - Direct electrochemistry of glucose oxidase (GOD) was achieved when GOD-hydroxyl fullerenes (HFs) nano-complex was immobilized on a glassy carbon (GC) electrode and protected with a chitosan (Chit) membrane. The ultraviolet-visible absorption spectrometry (UV-vis), transmission electron microscopy (TEM), and circular dichroism spectropolarimeter (CD) methods were utilized for additional characterization of the GOD, GOD-HFs and Chit/GOD-HFs. Chit/HFs may preserve the secondary structure and catalytic properties of GOD. The cyclic voltammograms (CVs) of the modified GC electrode showed a pair of well-defined quasi-reversible redox peaks with the formal potential (E degrees ') of 353 +/- 2 mV versus Ag/AgCl at a scan rate of 0.05 V/s. The heterogeneous electron transfer constant (ks) was calculated to be 2.7 +/- 0.2s(-1). The modified electrode response to glucose was linear in the concentrations ranging from 0.05 to 1.0mM, with a detection limit of 5 +/- 1 MUM. The apparent Michaelis-Menten constant (Km(app)) was 694 +/- 8 MUM. Thus, the modified electrode could be applied as a third generation biosensor for glucose with high sensitivity, selectivity and low detection limit. PMID- 24768860 TI - DNA methylation detection by a novel fluorimetric nanobiosensor for early cancer diagnosis. AB - A very sensitive and convenient fluorescence nanobiosensor for rapid detection of DNA methylation based on Fe3O4/Au core/shell nanoparticles has been developed. Specific site of CpG islands of adenomatous polyposis coli (APC), a well studied tumor suppressor gene, was used as the detection target DNA sequence. The characteristics of nanoparticles were determined by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), UV-visible spectroscopy and X-ray diffraction (XRD) spectroscopy. Fe@Au nanoparticles functionalized by bounding of single stranded DNA (ssDNA) probe through sulfhydryl group at the 5' phosphate end. Then unmethylated and methylated complementary target ssDNA were hybridized with the immobilized ssDNA probe. Dipyridamole, a pharmaceutical agent used for the first time as a fluorescence probe which significantly interacted with hybridized unmethylated and methylated DNA. Upon the addition of the target unmethylated and methylated ssDNA, the fluorescence intensity increased in linear range by concentration of unmethylated ssDNA from 1.6 * 10(-15) to 6.6 * 10(-13)M with detection limit of 1.2 * 10(-16)M and on the other hand, fluorescence intensity declined linearly with concentration of 3.2 * 10(-15)-8.0 * 10(-13)M methylated DNA and detection limit was 3.1 * 10(-16)M. We have also shown that nanobiosensor could distinguish ratio of methylation in series of partially methylated DNA targets with identical sequences. A density functional theory (DFT) calculation was also performed to investigate the interaction between Dipyridamole with unmethylated and methylated cytosine. Finally real sample analysis suggested that nanobiosensor could have practical application for methylation detection in human plasma sample. PMID- 24768861 TI - Fluorescent-free detection on nanobiochips based on wavelength-dependent single plasmonic nanoparticles by differential interference contrast microscopy. AB - A selective fluorescent-free detection method of biomolecules on nanoarray biochips was developed based on wavelength-dependent single plasmonic nanoparticles by differential interference contrast (DIC) microscopy. As a model target protein molecule, human cardiac troponin I (cTnI) was bound between primary anti-cTnI oriented on gold-nanopatterned chips (GNCs) and secondary silver nanoparticle (SNP) anti-cTnI. SNPs were employed as non-fluorescent probes to determine the immuno-reaction. Gold and silver exhibited clear peaks with DIC contrast at different wavelengths because plasmonic noble metals display extraordinarily large apparent refractive indices near their plasmon resonance wavelengths. Therefore, when the SNPs-cTnI antibody was bound to GNC, the normalized maximum intensity of the DIC contrast was blue-shifted. A linear relationship of the calibration curve was obtained between the DIC intensity and cTnI concentration in the range of 85 aM-10 fM without spectroscopic interference. This combination method of wavelength-dependent DIC microscopy and plasmonic nanoparticles could overcome the limitations of the potential for nonspecific labeling by promiscuous antibodies and the lack of reagents or biomarkers for disease-specific applications. PMID- 24768862 TI - Fluorescence immunoassay of octachlorostyrene based on Forster resonance energy transfer between CdTe quantum dots and rhodamine B. AB - Octachlorostyrene (OCS), a persistent and bioaccumulative toxicant (PBT), was assayed by fluorescence immunoassay based on the Forster resonance energy transfer (FRET) between CdTe quantum dots (QDs) and rhodamine B-labeled OCS (RB OCS). Anti-OCS antibody produced in this lab is adsorbed on a microtiter plate. The RB-OCS competes with OCS for the highly specific immunoreaction with the anti OCS antibodies adsorbed on the microtiter plate. The solution is then isolated and mixed with CdTe QDs as fluorescent donor which excite the emission of RB-OCS through FRET. As a result, the emission of CdTe QDs at 530 nm decreases, whereas the emission of RB-OCS at 580 nm increases. The ratio of fluorescence intensity at 580 nm to that at 530 nm is proportional to the RB-OCS concentration at a fixed CdTe QDs concentration, and consequently proportional to the OCS concentration. Selective and sensitive responses to OCS are achieved with a linear range of 8-80 nM and a LOD of 3.8 nM. Because OCS is quantified based on the fluorescence ratio, the sensor-to-sensor difference is greatly eliminated, making the proposed method a useful approach for in site scanning of OCS. PMID- 24768863 TI - Fast and quantitative differentiation of single-base mismatched DNA by initial reaction rate of catalytic hairpin assembly. AB - The widely used catalytic hairpin assembly (CHA) amplification strategy generally needs several hours to accomplish one measurement based on the prevailingly used maximum intensity detection mode, making it less practical for assays where high throughput or speed is desired. To make the best use of the kinetic specificity of toehold domain for circuit reaction initiation, we developed a mathematical model and proposed an initial reaction rate detection mode to quantitatively differentiate the single-base mismatch. Using the kinetic mode, assay time can be reduced substantially to 10 min for one measurement with the comparable sensitivity and single-base mismatch differentiating ability as were obtained by the maximum intensity detection mode. This initial reaction rate based approach not only provided a fast and quantitative differentiation of single-base mismatch, but also helped in-depth understanding of the CHA system, which will be beneficial to the design of highly sensitive and specific toehold-mediated hybridization reactions. PMID- 24768864 TI - DNA nanosensor based on biocompatible graphene quantum dots and carbon nanotubes. AB - An ultrasensitive nanosensor based on fluorescence resonance energy transfer (FRET) between biocompatible graphene quantum dots and carbon nanotubes for DNA detection was reported. We take advantage of good biocompatibility and strong fluorescence of graphene quantum dots, base pairing specificity of DNA and unique fluorescence resonance energy transfer between graphene quantum dots and carbon nanotubes to achieve the analysis of low concentrations of DNA. Graphene quantum dots with high quantum yield up to 0.20 were prepared and served as the fluorophore of DNA probe. FRET process between graphene quantum dots-labeled probe and oxidized carbon nanotubes is easily achieved due to their efficient self-assembly through specific pi-pi interaction. This nanosensor can distinguish complementary and mismatched nucleic acid sequences with high sensitivity and good reproducibility. The detection method based on this nanosensor possesses a broad linear span of up to 133.0 nM and ultralow detection limit of 0.4 nM. The constructed nanosensor is expected to be highly biocompatible because of all its components with excellent biocompatibility. PMID- 24768865 TI - Dynamics of small genetic circuits subject to stochastic partitioning in cell division. AB - In prokaryotes, partitioning errors during cell division are expected to be a non negligible source of cell-to-cell diversity in protein numbers. Here, we make use of stochastic simulations to investigate how different degrees of partitioning errors in division affect the cell-to-cell diversity of the dynamics of two genetic circuits, a bistable switch and a clock. First, we find that on average, the stability of the switch decreases with increasing partitioning errors. Despite this, anti-correlations between sister cells, introduced by the partitioning errors, enhance the chances that one of them will remain in the mother cell's state in the next generation, even if the switch is unstable. This reduces the variance of the proportion of phenotypes across generations. In the genetic clock, we find that the robustness of the period decreases with increasing partitioning errors. Nevertheless, the population synchrony is remarkably robust to most errors, only significantly decreasing for the most extreme degree of errors. We conclude that errors in partitioning affect the dynamics of genetic circuits, but the effects are network-dependent and qualitatively different from noise in gene expression. PMID- 24768866 TI - Sanctions as honest signals--the evolution of pool punishment by public sanctioning institutions. AB - In many species, mutual cooperation is stabilized by forms of policing and peer punishment: if cheaters are punished, there is a strong selective pressure to cooperate. Most human societies have complemented, and sometimes even replaced, such peer punishment mechanisms with pool punishment, where punishment is outsourced to central institutions such as the police. Even before free-riding occurs, such institutions require investments, which could serve as costly signals. Here, we show with a game theoretical model that this signaling effect in turn can be crucial for the evolution of punishment institutions: In the absence of such signals, pool punishment is only stable with second-order punishment and can only evolve when individuals have the freedom not to take part in any interaction. With such signals, individuals can opportunistically adjust their behavior, which promotes the evolution of stable pool punishment even in situations where no one can stand aside. Thus, the human propensity to react opportunistically to credible punishment threats is often sufficient to establish stable punishment institutions and to maintain high levels of cooperation. PMID- 24768867 TI - Modeling rates of infection with transient maternal antibodies and waning active immunity: application to Bordetella pertussis in Sweden. AB - Serological surveys provide reliable information from which to calculate forces (instantaneous rates) of infection, but waning immunity and clinical consequences that depend on residual immunity complicate interpretation of results. We devised a means of calculating these rates that accounts for passively acquired maternal antibodies that decay or active immunity that wanes, permitting re-infection. We applied our method to pertussis (whooping cough) in Sweden, where vaccination was discontinued from 1979 to 1995. A national cross-sectional serosurvey of antibodies to pertussis toxin, which peak soon after infection and then decay, was conducted shortly after vaccination resumed. Together with age-specific contact rates in Finland, contemporary forces of infection enable us to evaluate the recent assertion that the probability of infection upon contact is age independent. We find elevated probabilities among children, adolescents and young adults, whose contacts may be more intimate than others. Products of contact rates and probabilities of infection permit transmission modeling and estimation of the intrinsic reproduction number. In contrast to another recent estimate, ours approximates the ratio of life expectancy and age at first infection. Our framework is sufficiently general to accommodate more realistic sojourn distributions and additional lifetime infections. PMID- 24768868 TI - Conversion of glycerol to 1,3-propanediol by Citrobacter freundii and Hafnia alvei - newly isolated strains from the Enterobacteriaceae. AB - In this study, nearly 4000 bacterial strains from the family of Enterobacteriaceae isolated from different environments were screened for ability to convert glycerol to 1,3-propanediol (1,3-PD). The aim of the research was to isolate 1,3-PD producers from the natural environment, identify and characterize the best isolates. Three selective media were tested to usefulness in the isolation of bacteria from the family Enterobacteriaceae. Only, 28% of examined isolates could synthesize 1,3-PD from glycerol. 1,3-PD producing bacteria were identified by API 20E tests and 16S rRNA sequences to be Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter freundii and Hafnia alvei. It is the first time, when the fermentation glycerol to 1,3-PD by H. alvei was investigated. The selected strains (C. freundii AD119 and H. alvei AD27) were analyzed on a bioreactor scale under constant pH value 7.0 at temperature of 30 degrees C and 37 degrees C. After 40h in batch fermentation, H. alvei AD27 produced 11.3g/L of 1,3-PD at 37 degrees C. For C. freundii AD119, the best results were obtained at temperature of 30 degrees C. After 24h of fermentation, the 1,3-PD concentration reached above 23 g/L of 1,3-PD. PMID- 24768869 TI - Comparative determination of two probiotics by QCM and OWLS-based immunosensors. AB - The regular consumption of foods containing probiotic bacteria has beneficial physiological effects on the health and the digestion system. There is a need for novel analytical approaches for the determination of these bacteria that are faster than the classical plate counting method. For this purpose, two label-free biosensors were investigated and presented in this paper: Quartz Crystal Microbalance (QCM) and Optical Waveguide Lightmode Spectroscopy (OWLS) based direct immunosensors were developed for real-time direct detection of probiotic bacteria in fermented dairy products. Bifidobacterium bifidum O1356 and Lactobacillus acidophilus O1132 were detected by polyclonal anti-B. bifidum IgG and anti-L. acidophilus IgG immobilized on the sensors' surface. Sulfo-LC-SPDP cross linking agent was used to bind antibodies to the gold surface of the QCM's AT-cut quartz wafer. Concerning OWLS, antibodies were covalently bound to the amino groups of the silanized surface of the waveguide by glutaraldehyde. The dynamic measuring range was found between 1.0E+3 and 5.0E+5CFUmL(-1) in 100 fold diluted fermented milk products by QCM and with OWLS. Considering the current legislation of the probiotic content in probiotic products, the two developed immunosensors can be applied for rapid quantification of L. acidophilus and B. bifidum in fermented milk. These examinations offer effective alternatives to the microbiological plate counting method. PMID- 24768870 TI - Mechanisms explaining the relationship between metabolically healthy obesity and cardiovascular risk. PMID- 24768871 TI - Reply: 2013 ACC/AHA guideline on the assessment of cardiovascular risk. PMID- 24768872 TI - Trends in referral to cardiac rehabilitation after myocardial infarction: data from the National Cardiovascular Data Registry 2007 to 2012. PMID- 24768873 TI - Adenosine-mediated effects of ticagrelor: evidence and potential clinical relevance. AB - This review constitutes a critical evaluation of recent publications that have described an additional mode of action of the P2Y12 receptor antagonist ticagrelor. The effect is mediated by inhibition of the adenosine transporter ENT1 (type 1 equilibrative nucleoside transporter), which provides protection for adenosine from intracellular metabolism, thus increasing its concentration and biological activity, particularly at sites of ischemia and tissue injury where it is formed. Understanding the mode of action of ticagrelor is of particular interest given that its clinical profile, both in terms of efficacy and adverse events, differs from that of thienopyridine P2Y12 antagonists. PMID- 24768875 TI - Heart failure preserved ejection fraction with coronary artery disease: time for a new classification? PMID- 24768874 TI - Omentin prevents myocardial ischemic injury through AMP-activated protein kinase- and Akt-dependent mechanisms. AB - OBJECTIVES: This study examined the impact of omentin on myocardial injury in a mouse model of ischemia/reperfusion (I/R) and explored its underlying mechanisms. BACKGROUND: Obesity is a major risk factor for ischemic heart disease. Omentin is a circulating adipokine that is down-regulated by obesity. METHODS: In patients who underwent successful reperfusion treatment after acute myocardial infarction, cardiac function and perfusion defect were assessed by using scintigraphic images. Mice were subjected to myocardial ischemia followed by reperfusion. RESULTS: This study found that high levels of plasma omentin were associated with improvement of heart damage and function after reperfusion therapy in patients with acute myocardial infarction. Systemic administration of human omentin to mice led to a reduction in myocardial infarct size and apoptosis after I/R, which was accompanied by enhanced phosphorylation of AMP-activated protein kinase (AMPK) and Akt in the ischemic heart. Fat-specific overexpression of human omentin also resulted in reduction of infarct size after I/R. Blockade of AMPK or Akt activity reversed omentin-induced inhibition of myocardial ischemic damage and apoptosis in mice. In cultured cardiomyocytes, omentin suppressed hypoxia/reoxygenation-induced apoptosis, which was blocked by inactivation of AMPK or Akt. CONCLUSIONS: Our data indicate that omentin functions as an adipokine that ameliorates acute ischemic injury in the heart by suppressing myocyte apoptosis through both AMPK- and Akt-dependent mechanisms. PMID- 24768876 TI - Implications of coronary artery disease in heart failure with preserved ejection fraction. AB - OBJECTIVES: This study investigated the characteristics, evaluation, prognostic impact, and treatment of coronary artery disease (CAD) in patients with heart failure and preserved ejection fraction (HFpEF). BACKGROUND: CAD is common in patients with HFpEF, but it remains unclear how CAD should be categorized, evaluated for, and treated in HFpEF. METHODS: Clinical, hemodynamic, echocardiographic, treatment, and outcome characteristics were examined in consecutive patients with previous HFpEF hospitalizations who underwent coronary angiography. RESULTS: Of the 376 HFpEF patients examined, 255 (68%) had angiographically-proven CAD. Compared with HFpEF patients without CAD, patients with CAD were more likely to be men, to have CAD risk factors, and to be treated with anti-ischemic medications. However, symptoms of angina and heart failure were similar in patients with and without CAD, as were measures of cardiovascular structure, function, and hemodynamics. Compared with patients without CAD, HFpEF patients with CAD displayed greater deterioration in ejection fraction and increased mortality, independent of other predictors (hazard ratio: 1.71, 95% confidence interval: 1.03 to 2.98; p = 0.04). Complete revascularization was associated with less deterioration in ejection fraction and lower mortality compared with patients who were not completely revascularized, independent of other predictors (hazard ratio: 0.56, 95% confidence interval: 0.33 to 0.93; p = 0.03). CONCLUSIONS: CAD is common in patients with HFpEF and is associated with increased mortality and greater deterioration in ventricular function. Revascularization may be associated with preservation of cardiac function and improved outcomes in patients with CAD. Given the paucity of effective treatments for HFpEF, prospective trials are urgently needed to determine the optimal evaluation and management of CAD in HFpEF. PMID- 24768877 TI - Do not miss the elephant in the room: look at the red blood cells. PMID- 24768878 TI - 2013 ACC/AHA guideline on the assessment of cardiovascular risk. PMID- 24768879 TI - The MOGE(S) classification for a phenotype-genotype nomenclature of cardiomyopathy: more questions than answers? PMID- 24768880 TI - Reply: The MOGE(S) classification for a phenotype-genotype nomenclature of cardiomyopathy: more questions than answers? PMID- 24768881 TI - Reply: Do not miss the elephant in the room: look at the red blood cells. PMID- 24768882 TI - Multimodality imaging of a cardiac pheochromocytoma. PMID- 24768883 TI - Causes of early stent thrombosis in patients presenting with acute coronary syndrome: an ex vivo human autopsy study. AB - OBJECTIVES: The study interrogated an autopsy registry to investigate the histopathologic features of early stent thrombosis (ST) in patients presenting with acute coronary syndrome (ACS). BACKGROUND: The occurrence of early ST following percutaneous coronary intervention (PCI) for ACS remains a clinical problem despite advances in stent technology in both bare-metal and drug-eluting stents. METHODS: Sixty-seven stented coronary lesions from 59 patients who presented with ACS and died within 30 days were included. Stented segments were cross sectioned at 3 to 4 mm intervals and evaluated by light microscopy, and morphometric analysis was performed. RESULTS: Early ST (<30 days of PCI) was identified in 34 (58%) of the 59 patients. Early ST was dependent on the underlying plaque morphology and underlying thrombus burden: presence of necrotic core prolapse was more frequent in thrombosed lesions compared with patent lesions (70% vs. 43%, p = 0.045) and maximal underlying thrombus thickness was significantly greater in thrombosed versus patent lesions. All 3 patients with false lumen stenting had ST. Detailed analysis revealed that the percent of necrotic core prolapse, medial tear, or incomplete apposition was significantly greater in the early ST compared with patent group (28% vs.11%, p < 0.001; 27% vs. 15% p = 0.004; and 34% vs. 18% p = 0.008, respectively). Multivariate analysis revealed that maximal depth of strut penetration, % strut with medial tear, and % struts with incomplete apposition were the primary indicators of early ST. CONCLUSIONS: The current autopsy study highlights the impact of thrombus burden and suboptimal stent implantation in unstable lesions as a trigger of early ST, suggesting that improvement in implantation technique and refinement of stent design may improve clinical outcomes of ACS patients. PMID- 24768884 TI - Tumor embolism from a right atrial myxoma leads to acute right heart failure after surgery and atrial septal patch dehiscence. PMID- 24768885 TI - Mitigating the risk of early stent thrombosis. PMID- 24768886 TI - We should use the OCT-based clinical term "acute coronary syndrome with intact fibrous cap (ACS-IFC)" rather than the pathology term "plaque erosion". PMID- 24768887 TI - Chemoenzymatic synthesis of polymeric materials using lipases as catalysts: a review. AB - In the past two decades, enzymatic polymerization has rapidly developed and become an important polymer synthesis technique. However, the range of polymers resulting from enzymatic polymerization could be further expanded through combination with chemical methods. This review systematically introduces recent developments in the combination of lipase-catalyzed polymerization with atom transfer radical polymerization (ATRP), kinetic resolution, reversible addition fragmentation chain transfer (RAFT), click reaction and carbene chemistry to construct polymeric materials like block, brush, comb and graft copolymers, hyperbranched and chiral polymers. Moreover, it presents a thorough and descriptive evaluation of future trends and perspectives concerning chemoenzymatic polymerization. It is expected that combining enzymatic polymerization with multiple chemical methods will be an efficient tool for producing more highly advanced polymeric materials. PMID- 24768888 TI - Sequential sludge digestion after diverse pre-treatment conditions: sludge removal, methane production and microbial community changes. AB - A lab-scale sequential sludge digestion process which consists of a mesophilic anaerobic digester (MAD) and a thermophilic aerobic digester (TAD) was developed. Thermal, thermal-alkaline and long-term alkaline pre-treatments were applied to the feed sludge to examine their effects on sludge removal and methane production. Especially after thermal-alkaline pre-treatment, high COD removal was maintained; methane production rate was also drastically increased by improving the hydrolysis step of sludge degradation. Polymerase chain reaction-denaturing gel gradient electrophoresis indicated that bacterial communities were represented by three phyla (Firmicutes, Proteobacteria, Actinobacteria) and that Clostridium straminisolvens was the major bacterial species in MAD. Quantitative real-time PCR results indicated that Methanosaeta concilli was the major archaeal species in MAD, and that Ureibacillus sp. was the most abundant bacterial species in TAD. PMID- 24768889 TI - Lewis acid-catalyzed in situ transesterification/esterification of microalgae in supercritical ethanol. AB - The activities of several Lewis acid catalysts such SnCl2, FeCl3, ZnCl2, AlCl3, and NbCl5 for the in situ transesterification/esterification of lipid contained within a microalga (Chlorella pyrenoidosa) in ethanol at 350 degrees C were examined to identify the most suitable catalyst in term of crude biodiesel (CBD) yield. Of those catalysts tested, ZnCl2 showed the highest performance toward the CBD production. Using ZnCl2 as catalyst, effects of reaction temperature (200-370 degrees C), time (0-120 min), ethanol to microalga ratio (EtOH:MA) (5/5-40/5), catalyst loading (0-30 wt.%), and algae moisture (0-80 wt.%) on the yields of product fractions and the properties of CBD were studied. The presence of ZnCl2 not only promoted the production of CBD but also showed activities toward the deoxygenation and denitrogenation of CBD. The moisture content in the starting material is the most influential factor affecting the yield and properties of CBD. PMID- 24768890 TI - Microwave-assisted conversion of microcrystalline cellulose to 5 hydroxymethylfurfural catalyzed by ionic liquids. AB - Ionic liquid (IL) has been widely investigated in 5-HMF production from biomass. However, most of studies employed IL as reaction solvent which requires a large amount of IL. In the present study, IL was utilized as catalyst in the conversion of microcrystalline cellulose (MCC) to 5-HMF under microwave irradiation (MI) in N,N-dimethylacetamide (DMAc) containing LiCl. 1,1,3,3-tetramethylguanidine (TMG) based ILs, including 1,1,3,3-tetramethylguanidine tetrafluoroborate ([TMG][BF4]) and 1,1,3,3-tetramethylguanidine lactate ([TMG]L) which were commonly used in the absorption of SO2 and CO2 from flue gas, were synthesized and applied in the conversion of MCC to 5-HMF for the first time. Of the catalysts employed, [TMG]BF4 showed high catalytic activity in 5-HMF production from MCC. The condition including the ratio of IL to MCC, temperature and time for MCC conversion was optimized using Central Composite Design (CCD) and Response Surface Methodology (RSM). The highest 5-HMF yield of 28.63% was achieved with the optimal condition. PMID- 24768891 TI - Fate of selected emerging micropollutants during mesophilic, thermophilic and temperature co-phased anaerobic digestion of sewage sludge. AB - The removal of endocrine disrupting compounds (EDCs) and non-steroidal anti inflammatory drugs (NSAIDs) was studied in three lab-scale anaerobic digestion (AD) systems; a single-stage mesophilic, a single-stage thermophilic and a two stage thermophilic/mesophilic. All micropollutants underwent microbial degradation. High removal efficiency (>80%) was calculated for diclofenac, ibuprofen, naproxen and ketoprofen; whereas triclosan, bisphenol A and the sum of nonylphenol (NP), nonylphenol monoethoxylate (NP1EO) and nonylphenol diethoxylate were moderately removed (40-80%). NSAIDs removal was not affected by the type of AD system used; whereas slightly higher EDCs removal was observed in two-stage system. In this system, most microcontaminants were removed in thermophilic digester. Biotransformation of NP1EO and NP was affected by the temperature applied to bioreactors. Under mesophilic conditions, higher removal of NP1EO and accumulation of NP was noticed; whereas the opposite was observed under thermophilic conditions. For most analytes, higher specific removal rates were calculated under thermophilic conditions and 20 days SRT. PMID- 24768892 TI - Different combinations of Notch ligands and receptors regulate V2 interneuron progenitor proliferation and V2a/V2b cell fate determination. AB - The broad diversity of neurons is vital to neuronal functions. During vertebrate development, the spinal cord is a site of sensory and motor tasks coordinated by interneurons and the ongoing neurogenesis. In the spinal cord, V2-interneuron (V2 IN) progenitors (p2) develop into excitatory V2a-INs and inhibitory V2b-INs. The balance of these two types of interneurons requires precise control in the number and timing of their production. Here, using zebrafish embryos with altered Notch signaling, we show that different combinations of Notch ligands and receptors regulate two functions: the maintenance of p2 progenitor cells and the V2a/V2b cell fate decision in V2-IN development. Two ligands, DeltaA and DeltaD, and three receptors, Notch1a, Notch1b, and Notch3 redundantly contribute to p2 progenitor maintenance. On the other hand, DeltaA, DeltaC, and Notch1a mainly contribute to the V2a/V2b cell fate determination. A ubiquitin ligase Mib, which activates Notch ligands, acts in both functions through its activation of DeltaA, DeltaC, and DeltaD. Moreover, p2 progenitor maintenance and V2a/V2b fate determination are not distinct temporal processes, but occur within the same time frame during development. In conclusion, V2-IN cell progenitor proliferation and V2a/V2b cell fate determination involve signaling through different sets of Notch ligand-receptor combinations that occur concurrently during development in zebrafish. PMID- 24768893 TI - Sulf1 influences the Shh morphogen gradient during the dorsal ventral patterning of the neural tube in Xenopus tropicalis. AB - Genetic studies have established that heparan sulphate proteoglycans (HSPGs) are required for signalling by key developmental regulators, including Hedgehog, Wnt/Wg, FGF, and BMP/Dpp. Post-synthetic remodelling of heparan sulphate (HS) by Sulf1 has been shown to modulate these same signalling pathways. Sulf1 codes for an N-acetylglucosamine 6-O-endosulfatase, an enzyme that specifically removes the 6-O sulphate group from glucosamine in highly sulfated regions of HS chains. One striking aspect of Sulf1 expression in all vertebrates is its co-localisation with that of Sonic hedgehog in the floor plate of the neural tube. We show here that Sulf1 is required for normal specification of neural progenitors in the ventral neural tube, a process known to require a gradient of Shh activity. We use single-cell injection of mRNA coding for GFP-tagged Shh in early Xenopus embryos and find that Sulf1 restricts ligand diffusion. Moreover, we find that the endogenous distribution of Shh protein in Sulf1 knockdown embryos is altered, where a less steep ventral to dorsal gradient forms in the absence of Sulf1, resulting in more a diffuse distribution of Shh. These data point to an important role for Sulf1 in the ventral neural tube, and suggests a mechanism whereby Sulf1 activity shapes the Shh morphogen gradient by promoting ventral accumulation of high levels of Shh protein. PMID- 24768894 TI - Hunger, inhibitory control and distress-induced emotional eating. AB - Self-reported emotional eating has been found to significantly moderate distress induced food intake, with low emotional eaters eating less after a stress task than after a control task and high emotional eaters eating more. The aim of the present study was to explore possible underlying mechanisms by assessing possible associations with (1) ability to experience the typical post-stress reduction of hunger and (2) inhibitory control. We studied these effects in 54 female students who were preselected on the basis of extremely high or low scores on an emotional eating questionnaire. Using a within subject design we measured the difference of actual food or snack intake after a control or a stress task (Trier Social Stress Test). As expected, the moderator effect of emotional eating on distress-induced food intake was found to be only present in females with a failure to report the typical reduction of hunger immediately after a stress task (an a-typical hunger stress response). Contrary to our expectations, this moderator effect of emotional eating was also found to be only present in females with high ability to stop motor impulses (high inhibitory control). These findings suggest that an a-typical hunger stress response but not poor inhibitory control may underlie the moderator effect of emotional eating on distress-induced food intake. However, inhibitory control may play a role whether or not there is a moderator effect of self-reported emotional eating on distress-induced food intake. PMID- 24768895 TI - Supplementing chicken broth with monosodium glutamate reduces energy intake from high fat and sweet snacks in middle-aged healthy women. AB - Monosodium L-glutamate (MSG) and inosine monophosphate-5 (IMP) are flavor enhancers for umami taste. However, their effects on appetite and food intake are not well-researched. The objective of the current study was to test their additions in a broth preload on subsequent appetite ratings, energy intake and food choice. Eighty-six healthy middle-aged women with normal body weight received three preload conditions on 3 test days 1 week apart - a low-energy chicken flavor broth (200 ml) as the control preload, and broths with added MSG alone (0.5 g/100 ml, MSG broth) or in combination with IMP (0.05 g/100 ml) (MSG+ broth) served as the experimental conditions. Fifteen minutes after preload administration subjects were provided an ad libitum testing meal which consisted of 16 snacks varying in taste and fat content. MSG and MSG+ enhanced savory taste and broth properties of liking and pleasantness. In comparison with control, the MSG preload resulted in less consumption of total energy, as well as energy from sweet and high-fat snacks. Furthermore, MSG broth preload reduced added sugar intake. These findings were not observed after MSG+ preload. Appetite ratings were not different across the three preloads. Results suggest a potential role of MSG addition to a low-energy broth preload in subsequent energy intake and food choice. This trial was registered at clinicaltrials.gov as NCT01761045. PMID- 24768896 TI - Double trouble. Trait food craving and impulsivity interactively predict food-cue affected behavioral inhibition. AB - Impulsivity and food craving have both been implicated in overeating. Recent results suggest that both processes may interactively predict increased food intake. In the present study, female participants performed a Go/No-go task with pictures of high- and low-calorie foods. They were instructed to press a button in response to the respective target category, but withhold responses to the other category. Target category was switched after every other block, thereby creating blocks in which stimulus-response mapping was the same as in the previous block (nonshift blocks) and blocks in which it was reversed (shift blocks). The Food Cravings Questionnaires and the Barratt Impulsiveness Scale were used to assess trait and state food craving and attentional, motor, and nonplanning impulsivity. Participants had slower reaction times and more omission errors (OE) in high-calorie than in low-calorie blocks. Number of commission errors (CE) and OE was higher in shift blocks than in nonshift blocks. Trait impulsivity was positively correlated with CE in shift blocks while trait food craving was positively correlated with CE in high-calorie blocks. Importantly, CE in high-calorie-shift blocks were predicted by an interaction of food craving * impulsivity such that the relationship between food craving and CE was particularly strong at high levels of impulsivity, but vanished at low levels of impulsivity. Thus, impulsive reactions to high-calorie food-cues are particularly pronounced when both trait impulsivity and food craving is high, but low levels of impulsivity can compensate for high levels of trait food craving. Results support models of self-regulation which assume that interactive effects of low top-down control and strong reward sensitive, bottom-up mechanisms may determine eating-related disinhibition, ultimately leading to increased food intake. PMID- 24768897 TI - Sympathetic nerve fibers in human cervical and thoracic vagus nerves. AB - BACKGROUND: Vagus nerve stimulation (VNS) therapy has been used for chronic heart failure and is believed to improve imbalance of autonomic control by increasing parasympathetic activity. Although it is known that there is neural communication between the VN and the cervical sympathetic trunk, there are few data regarding the quantity and/or distribution of the sympathetic components within the vagus nerve (VN). OBJECTIVE: To examine the sympathetic components within the human VN and correlate them with the presence of cardiac and neurologic diseases. METHODS: We performed immunohistochemistry on 31 human cervical and thoracic VNs (total 104 VNs) from autopsies and reviewed the patients' records. We correlated the quantity of sympathetic nerve fibers within the VNs with cardiovascular and neurologic disease states. RESULTS: All 104 VNs contain tyrosine hydroxylase (TH) positive (sympathetic) nerve fibers; the mean TH-positive areas were 5.47% in the right cervical VN, 3.97% in the left cervical VN, 5.11% in the right thoracic VN, and 4.20% in the left thoracic VN. The distribution of TH-positive nerve fibers varied from case to case: central, peripheral, or scattered throughout nerve bundles. No statistically significant differences in nerve morphology were seen between diseases in which VNS is considered effective (depression and chronic heart failure) and other cardiovascular diseases or neurodegenerative disease. CONCLUSION: Human VNs contain sympathetic nerve fibers. The sympathetic component within the VN could play a role in physiologic effects reported with VNS. The recognition of sympathetic nerve fibers in the VNs may lead to better understanding of the therapeutic mechanisms of VNS. PMID- 24768898 TI - Induction of suppressive phenotype in monocyte-derived dendritic cells by leukemic cell products and IL-1beta. AB - Professional antigen-presenting cells, dendritic cells (DCs) play an important role in controlling tumors. It is known that solid tumor cell products inhibit DC differentiation. Recently a similar effect produced by leukemic cell products has been demonstrated. In this case, leukemic cell products induced the secretion of IL-1beta by monocytes undergoing differentiation. The aim of the present work was to characterize and to compare the development of monocyte-derived DCs under the influence of leukemic cell products (K562 supernatant) or exogenous IL-1beta. It became clear that leukemic cell products and IL-1beta differentially modulate some of the parameters studied on monocytes stimulated to differentiate into DCs. In the presence of K562 supernatant, the expression of the macrophage markers CD16 and CD68 were higher than in immature DCs control. Contrasting with IL 1beta, leukemic cell products possibly favor the development of cells with macrophage markers. In addition, CD80 and CD83 expressions were also higher in the presence of tumor supernatant whereas HLA-DR was lower. In the presence of IL 1beta, only CD80 was increased. Furthermore, it was observed that when monocytes were induced to differentiate into DCs in the presence of tumor supernatant and then activated, they expressed less CD80 and CD83 than activated DCs control. A reduced expression of CD83 following activation was also seen in cells differentiated with IL-1beta. TGF-beta and VEGF were found in the tumor supernatants. Moreover, the exposure to tumor supernatant or IL-1beta stimulated IL-10 production while decreased IL-12 production by activated DCs. Finally, these results suggest that the addition of products released by leukemic cells or, more discreetly, the addition of IL-1beta affects DC differentiation, inducing a suppressive phenotype. PMID- 24768899 TI - Low density lipoprotein promotes human naive T cell differentiation to Th1 cells. AB - Oxidized LDL (oxLDL) in the arterial wall and its incorporation into foam cells leads to inflammation and nucleation of atherosclerotic plaque; this is opposed by HDL. OxLDL and HDL regulate activation of macrophages and endothelial cells, and study of T cell participation has been limited to mature, differentiated cells such as Th1 cells, which perpetuate atherogenesis by promoting cell mediated responses and inflammation. Immature naive T cells, just emerged from the thymus, have remained largely unstudied. We hypothesized that LDL and HDL provide selective modulation of immature naive T cell differentiation and participation in plaque development. In our in vitro model, naive cells become activated and differentiate to mature effector T cells that are Th1, Th2 or Treg cells. Addition of oxLDL favored differentiation to Th1 cells, reduced Th2 cell activity and prolonged cell survival. In contrast, HDL inhibited T cell proliferation and reduced cell survival. The data suggest a novel mechanism where oxLDL enhances differentiation of human naive CD4+ T cells to Th1 cells capable of promoting inflammation and plaque progression, and this is opposed by HDL. PMID- 24768900 TI - Tolerance to cocaine in brain stimulation reward following continuous cocaine infusions. AB - This study examined tolerance to cocaine's threshold-lowering effect in brain stimulation reward (BSR) following continuous cocaine infusions and secondly, used the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L NAME) to determine NO's involvement in the development of cocaine tolerance. Animals were continuously infused with saline or cocaine (30 mg/kg per day) via osmotic minipump for 14 days and injected daily with saline or L-NAME (30 mg/kg, i.p.) following BSR testing. Saline-treated animals continuously infused with saline showed stable BSR thresholds across the 14-day infusion period. Saline treated animals continuously infused with cocaine showed markedly lowered BSR thresholds on Day 1 followed by a progressive increase in BSR thresholds across the infusion period - indicating the development of tolerance. L-NAME-treated animals continuously infused with cocaine showed stimulation thresholds that were not significantly different from saline-treated animals continuously infused with cocaine. A cocaine challenge injection (10 mg/kg, i.p.) administered 3 and again at 10 days following minipump removal revealed that saline-treated animals continuously infused with saline showed lowered BSR thresholds. Saline-treated animals continuously infused with cocaine displayed lowered BSR thresholds that were not significantly different from saline-infused animals. L-NAME treated animals continuously infused with cocaine showed higher BSR thresholds to a challenge 3 days following pump removal. However, stimulation thresholds for this group failed to reach statistical significance on both days (i.e., Days 3 and 10) following pump removal. Results showed that animals continuously infused with cocaine develop robust tolerance to cocaine's threshold-lowering effect during the 14-day infusion period. Tolerance to cocaine's threshold-lowering effect was short-lived and dissipated soon after minipump removal. L-NAME treatment failed to significantly alter the development of tolerance to cocaine's threshold lowering suggesting that NO does not have a primary role in the development of cocaine tolerance. PMID- 24768901 TI - Perilipin-5 is regulated by statins and controls triglyceride contents in the hepatocyte. AB - BACKGROUND & AIMS: Perilipin-5 (PLIN5) is a member of the perilipin family of lipid droplet (LD)-associated proteins. PLIN5 is expressed in oxidative tissues including the liver, and is critical during LD biogenesis. Studies showed that statins reduce hepatic triglyceride contents in some patients with non-alcoholic fatty liver disease and in rodent models of diet-induced hepatosteatosis. Whether statins alter triglyceride synthesis, storage, and/or utilization within the hepatocyte is unknown, though. Here we tested the hypothesis that statins alter the metabolism of LD in the hepatocyte during physiological conditions, such as fasting-induced steatosis. METHODS: Mice were gavaged with saline or atorvastatin, and the expression of LD-associated genes was determined in fed and fasted animals. The accumulation of triglycerides and LD was studied in mouse or human primary hepatocytes in response to statins, and following knock-down of SREBP2 or PLIN5. RESULTS: We show that statins decrease the levels of PLIN5, but not other LD-associated genes, in both mouse liver and mouse/human primary hepatocytes, which is paralleled by a significant reduction in both intracellular triglycerides and the number of LD. We identify an atypical negative sterol regulatory sequence in the proximal promoter of mouse/human PLIN5 that recruits the transcription factor SREBP2 and confers response to statins. Finally, we show that the statin-dependent reduction of hepatocyte triglyceride contents is mimicked by partial knock-down of PLIN5; conversely, ectopic overexpression of PLIN5 reverts the statin effect. CONCLUSIONS: PLIN5 is a physiological regulator of triglyceride metabolism in the liver, and likely contributes to the pleiotropic effects of statins. PMID- 24768902 TI - Ghrelin receptors in human gastrointestinal tract during prenatal and early postnatal development. AB - The aim of our study was to investigate the appearance, density and distribution of ghrelin cells and GHS-R1a and GHS-R1b in the human stomach and duodenum during prenatal and early postnatal development. We examined chromogranin-A and ghrelin cells in duodenum, and GHS-R1a and GHS-R1b expression in stomach and duodenum by immunohistochemistry in embryos, fetuses, and infants. Chromogranin-A and ghrelin cells were identified in the duodenum at weeks 10 and 11 of gestation. Ghrelin cells were detected individually or clustered within the base of duodenal crypts and villi during the first trimester, while they were presented separately within the basal and apical parts of crypts and villi during the second and third trimesters. Ghrelin cells were the most numerous during the first (~11%) and third (~10%) trimesters of gestation development. GHS-R1a and GHS-R1b were detected at 11 and 16 weeks of gestation, showed the highest level of expression in Brunner's gland and in lower parts of duodenal crypts and villi during the second trimester in antrum, and during the third trimester in corpus and duodenum. Our findings demonstrated for the first time abundant duodenal expression of ghrelin cells and ghrelin receptors during human prenatal development indicating a role of ghrelin in the regulation of growth and differentiation of human gastrointestinal tract. PMID- 24768903 TI - Alarin-induced antidepressant-like effects and their relationship with hypothalamus-pituitary-adrenal axis activity and brain derived neurotrophic factor levels in mice. AB - Alarin is a newly identified member of the galanin family of peptides. Galanin has been shown to exert regulatory effects on depression. Similar to galanin in distribution, alarin is also expressed in the medial amygdala and hypothalamus, i.e., regions interrelated with depression. However, it remains a puzzle whether alarin is involved in depression. Accordingly, we established the depression-like mouse model using behavioral tests to ascertain the possible involvement of alarin, with fluoxetine as a positive control. With the positive antidepressant like effects of alarin, we further examined its relationship to HPA axis activity and brain-derived neurotrophic factor (BDNF) levels in different brain areas in a chronic unpredictable mild stress (CUMS) paradigm. In the acute studies, alarin produced a dose-related reduction in the immobility duration in tail suspension test (TST) in mice. In the open-field test, intracerebroventricular (i.c.v.) injection of alarin (1.0 nmol) did not impair locomotion or motor coordination in the treated mice. In the CUMS paradigm, alarin administration (1.0 nmol, i.c.v.) significantly improved murine behaviors (FST and locomotor activity), which was associated with a decrease in corticotropin-releasing hormone (CRH) mRNA levels in the hypothalamus, as well as a decline in serum levels of CRH, adrenocorticotropic hormone (ACTH) and corticosterone (CORT), all of which are key hormones of the HPA axis. Furthermore, alarin upregulated BDNF mRNA levels in the prefrontal cortex and hippocampus. These findings suggest that alarin may potentiate the development of new antidepressants, which would be further secured with the identification of its receptor(s). PMID- 24768904 TI - Light harvesting and photocurrent generation by nanostructured photoelectrodes sensitized with a photosynthetic pigment: a new application for microalgae. AB - Here in this study, successful conversion of visible light into electricity has been achieved through utilizing microalgal pigments as a sensitizer of nanostructured photo-electrode of dye-sensitized solar cells (DSSCs). For the first time, photosynthetic pigments extracted from microalgae grown in wastewater is employed to imitate photosynthesis process in bio-molecule-sensitized solar cells. Two designs of photoanode were employed: 10 MUm nanoparticular TiO2 electrode and 20 MUm long self-ordered, vertically oriented nanotube arrays of titanium dioxide films. Microalgal photosynthetic pigments are loaded on nanostructured electrodes and their photovoltaic performances have been investigated. To optimize the performance of solar cell, the time course of dye loading on the nanocrystalline TiO2 films is investigated. The performance of the cells is characterized by measuring the current-voltage (I-V) curves under AM1.5 (100 mW cm(-2)) irradiation condition. The highest efficiency of around ~ 1%, quite comparable to green plants, is found for sensitizer-loading time of 1h. PMID- 24768905 TI - Unexpected extensive lysine acetylation in the trump-card antibiotic producer Streptomyces roseosporus revealed by proteome-wide profiling. AB - Lysine acetylation is emerging as a ubiquitous and conserved posttranslational modification in living cells. While the role of lysine acetylation in regulating primary metabolism is well-established, its function in secondary metabolism remains largely elusive. To gain insight into the nature, extent and biological function of lysine acetylation in Streptomyces reseosporus, a producer of daptomycin, dubiously dubbed as the trump card antibiotic, we used immunoaffinity based acetyllysine peptide enrichment integrated with high resolution mass spectrometry to comprehensively characterize lysine acetylated proteins in this microbe. We identified a total of 667 proteins with 1143 unique sites, representing the largest acetylproteome reported to date in bacteria. Acetylated proteins belong to various functional classes such as metabolism and gene expression according to the gene ontology. We demonstrated for the first time that proteins involved in the biosynthesis of diverse secondary metabolites are acetylated, such as a nonribosomal peptide synthetase, enzymes essential for hydroxamate siderophore and phosphinic acid natural products biosynthesis, implying an important role of acetylation in these processes. Taken together, this proteomic analysis revealed a surprising breadth of cellular processes affected by lysine acetylation and also furnishes some fresh intervention nodes for the rational improvement of the antibiotic producer. BIOLOGICAL SIGNIFICANCE: Despite considerable efforts have been devoted to elucidating the mechanism underlying secondary metabolism in Streptomyces, which are prolific producers of secondary metabolites with diverse biological activities, such as bacteriocides and antitumors, the full map of regulation and corresponding network is still far from perfect. Protein lysine acetylation is an evolutionarily conserved protein post-translational modification, abundantly existing in proteins with diverse biological context. We took advantage of integrated high throughput PTM proteomics followed by intensive bioinformatic analysis to profile lysine acetylome of Streptomyces roseosporus. In total, 1134 unique Kac sites in 667 lysine acetylated substrates were identified, representing the largest aceylomics in prokaryotes to date. Significantly, a nonribosomal peptide synthetase, an enzyme essential for hydroxamate siderophore and phosphinic acid natural products biosynthesis, was found to be acetylated. Given the conservation of these enzymes in biosynthesis of diverse secondary metabolites, lysine acetylation likely plays an important role in regulating secondary metabolism in Streptomyces. PMID- 24768906 TI - Comparative proteomic profiling of triple-negative breast cancer reveals that up regulation of RhoGDI-2 is associated to the inhibition of caspase 3 and caspase 9. AB - There are no targeted therapeutic modalities for triple-negative breast cancer (TNBC), thus it is associated with poor prognosis and worst clinical outcome. Here, our aim was to identify deregulated proteins in TNBC with potential therapeutic applications. Proteomics profiling of TNBC and normal breast tissues through two-dimensional electrophoresis and ESI-MS/MS mass spectrometry revealed the existence of 16 proteins (RhoGDI-2, HSP27, SOD1, DJ1, UBE2N, PSME1, FTL, SH3BGRL, and eIF5A-1) with increased abundance in carcinomas. We also evidenced for the first time the deregulation of COX5, MTPN and DB1 proteins in TNBC that may represent novel tumor markers. Particularly, we confirmed the overexpression of the Rho-GDP dissociation inhibitor 2 (RhoGDI-2) in distinct breast cancer subtypes, as well as in metastatic cell lines derived from lung, prostate, and breast cancer. Remarkably, targeted disruption of RhoGDI-2 by RNA interference induced mitochondrial dysfunction, and facilitated caspase-3 and -9 activation in two breast cancer cell lines. Moreover, suppression of RhoGDI-2 resulted in a robust sensitization of breast cancer cells to cisplatin therapy. In conclusion, we identified novel proteins deregulated in TNBC, and confirmed the overexpression of RhoGDI-2. We propose that RhoGDI-2 inhibition may be exploited as a potential therapeutic strategy along cisplatin-based chemotherapy in breast cancer. BIOLOGICAL SIGNIFICANCE: There are no useful biomarkers neither targeted therapeutic modalities for triple-negative breast cancer, which highly contributes to the poor prognosis of this breast cancer subtype. In this work, we used two-dimensional electrophoresis and ESI-MS/MS spectrometry to identify novel deregulated proteins in breast cancer tissues. Particularly, our results showed that RhoGDI-2, a protein that has been associated to metastasis and poor survival in human cancers, is overexpressed in different subtypes of breast tumors, as well as in metastatic cell lines derived from lung, prostate, and breast cancer. Our data also provided novel insights about the role of RhoGDI-2 in apoptosis through intrinsic pathway inhibition. Importantly, they suggested that targeted modulation of RhoGDI-2 levels might be a useful strategy for breast cancer therapy. PMID- 24768907 TI - In between - Proteomics of dog biological fluids. AB - Dogs are relevant to biomedical research in connection both to veterinary medicine for their role as pets and to basic investigations for their use as animal models in pathology, pharmacology and toxicology studies. Proteomic analysis of biological fluids is less advanced for dogs than for other animal species but a wealth of information has already been gathered, which we summarize in this review. As a remarkable feature, we also assemble here for due reference a number of 2-DE serum/plasma or urine patterns in health and disease; some of them correspond to unpublished data from the University of Veterinary Medicine Vienna. PMID- 24768908 TI - Substrate topography determines the fate of chondrogenesis from human mesenchymal stem cells resulting in specific cartilage phenotype formation. AB - To reproduce a complex and functional tissue, it is crucial to provide a biomimetic cellular microenvironment that not only incorporates biochemical cues, but also physical features including the nano-topographical patterning, for cell/matrix interaction. We developed spatially-controlled nano-topography in the form of nano-pillar, nano-hole and nano-grill on polycaprolactone surface via thermal nanoimprinting. The effects of chondroitin sulfate-coated nano topographies on cell characteristics and chondrogenic differentiation of human mesenchymal stem cell (MSC) were investigated. Our results show that various nano topographical patterns triggered changes in MSC morphology and cytoskeletal structure, affecting cell aggregation and differentiation. Compared to non patterned surface, nano-pillar and nano-hole topography enhanced MSC chondrogenesis and facilitated hyaline cartilage formation. MSCs experienced delayed chondrogenesis on nano-grill topography and were induced to fibro/superficial zone cartilage formation. This study demonstrates the sensitivity of MSC differentiation to surface nano-topography and highlights the importance of incorporating topographical design in scaffolds for cartilage tissue engineering. From the clinical editor: These authors have developed spatially-controlled nano-topography in the form of nano-pillar, nano-hole and nano-grill on polycaprolactone surface via thermal nanoimprinting, and the effects of chondroitin sulfate-coated nano-topographies on cell characteristics and chondrogenic differentiation of human mesenchymal stem cells (MSC) were investigated. It has been concluded that MSC differentiation is sensitive to surface nano-topography, and certain nano-imprinted surfaces are more useful than others for cartilage tissue engineering. PMID- 24768909 TI - Experimental studies and statistical analysis of membrane fouling behavior and performance in microfiltration of microalgae by a gas sparging assisted process. AB - Response surface methodology (RSM) and central composite design (CCD) were applied for modeling and optimization of cross-flow microfiltration of Chlorella sp. suspension. The effects of operating conditions, namely transmembrane pressure (TMP), feed flow rate (Qf) and optical density of feed suspension (ODf), on the permeate flux and their interactions were determined. Analysis of variance (ANOVA) was performed to test the significance of response surface model. The effect of gas sparging technique and different gas-liquid two phase flow regimes on the permeate flux was also investigated. Maximum flux enhancement was 61% and 15% for Chlorella sp. with optical densities of 1.0 and 3.0, respectively. These results indicated that gas sparging technique was more efficient in low concentration microalgae microfiltration in which up to 60% enhancement was achieved in slug flow pattern. Additionally, variations in the transmission of exopolysaccharides (EPS) and its effects on the fouling phenomenon were evaluated. PMID- 24768910 TI - Simultaneous organic carbon and nitrogen removal in an anoxic-oxic activated sludge system under various operating conditions. AB - This study investigated a bench-scale anoxic-oxic activated sludge system for integrated removal of COD and nitrogen. The experimental unit includes four chambers and continuous feeding in first chamber without recycle of nitrified liquid from aerobic to anoxic chamber unlike the conventional anoxic-oxic process. Recycled excessive sludge was used for the purpose of recycling nitrified mixed liquor. Synthetic wastewater with average loading rates of 0.53 kg COD/m(3)/d and 0.067 kg NH4(+)-N/m(3)/d was fed to the reactor system at hydraulic residence times (HRT) of 24 and 18 h. The results of 100 days operation showed high removal efficiencies of organic matter of about 97% as total COD and more than 99% removal of ammonia-nitrogen. In anoxic-oxic operation phase, total inorganic nitrogen (TIN) removal was about 66% by pre-denitrification. Moreover, the solid liquid separation through final clarifier was excellent without any suspended solid in the effluent. PMID- 24768911 TI - Dynamics of nitrogen transformation depending on different operational strategies in laboratory-scale tidal flow constructed wetlands. AB - The influence of different flooded/drained (F/D) time ratios and different effluent flow rates on the dynamics of nitrogen transformations in three laboratory-scale tidal flow constructed wetland systems (TFCWs-A, B, and C) under varying NH4(+)-N and COD influent loadings was investigated in this study. Good organic matter removal performance up to 90% was achieved for all experimental TFCWs under inflow concentrations of 300 and 150 mg/L regardless of F/D and effluent flow rate. The ammonium removal efficiency of wetland with F/D=3h:3h (55%) was higher than that of the wetland with F/D=5h:1h (47%) under an ammonium inflow concentration of 60 mg/L, indicating the positive effect of longer drained and shorter flooded time on tidal-operated wetlands under nitrification. In addition, more uniform oxygen distribution and better nitrification capacity within the wetland might be achieved with a relatively slow effluent flow rate of 0.025 L/s. TFCWs were shown to be a robust and reliable option to achieve high TN removal of 70% due to its repeated cycle of "wet" and "dry" periods, particularly for the treatment of wastewater with high organic content. Moreover, F/D and effluent flow rates of tidal flow constructed wetlands exhibited no significant effect on phosphorus removal in this study. Other techniques, such as pretreatment or post treatment, require further investigation. PMID- 24768912 TI - A study of air pollutants influencing life expectancy and longevity from spatial perspective in China. AB - Life expectancy and longevity are influenced by air pollutants and socioeconomic status, but the extend and significance are still unclear. Better understanding how the spatial differences of life expectancy and longevity are affected by air pollutants is needed for generating public health and environmental strategies since the whole of China is now threatened by deteriorated air quality. 85 major city regions were chosen as research areas. Geographically Weighted Regression (GWR) and Stepwise Regression (SR) were used to find the spatial correlations between health indicators and air pollutants, adjusted by per capita GDP(1). The results were, regions with higher life expectancy were mainly located in the east area and areas with good air quality, a regional difference of 10 MUg/m(3) in ambient air SO2(2) could cause adjusted 0.28 year's difference in life expectancy, a regional difference of 10 MUg/m(3) in ambient air PM10(3) could lead to a longevity ratio difference of 2.23, and per capita GDP was positively associating with life expectancy but not longevity ratio, with a regional difference of 10,000 RMB(4) associating with adjusted 0.49 year's difference in life expectancy. This research also showed the evidences that there exist spatially differences for ambient air PM10 and SO2 influencing life expectancy and longevity in China, and this influences were clearer in south China. PMID- 24768913 TI - Exposure of farm laborers and dairy cattle to formaldehyde from footbath use at a dairy farm in New York State. AB - Formalin footbaths are commonly used in the dairy industry to prevent cattle hoof diseases. Although formalin is a well-documented disinfectant, it is also a carcinogen and irritant. The aim of this study was to estimate the exposure of farm workers and dairy cattle to formaldehyde from footbaths located in a milking facility and a heifer facility at a dairy farm in western New York, USA. The dairy farm included approximately 3900 dairy cattle including young stock; of these, 1670 cows were milked three times per day in a 60-stall carousel milking parlor, and approximately 800 heifers were located at the heifer facility where footbaths with formalin were in use. The formaldehyde concentration of the air was measured using a FormaldemeterTM htV approximately 50cm above the 3% formalin footbaths in the milking (one footbath location) and heifer (three footbath locations) facilities on three consecutive days. The measured formaldehyde concentrations varied between 0.00 and 2.28ppm, falling within the safety guidelines established by the Occupation Safety and Health Administration (OSHA) of the United States. Significant differences were found in the formaldehyde concentrations at the different footbath locations in the heifer facility, potentially due to the varying levels of ventilation at each location. Changes in the ambient temperature during the 3-day sampling period did not significantly affect the concentrations. We believe that the substantial ventilation at both the heifer and milking facilities ensured that the formaldehyde concentrations did not exceed OSHA guidelines, thus permitting the safe use of formalin footbaths in this farm. PMID- 24768914 TI - Down-regulating ribonuclease inhibitor enhances metastasis of bladder cancer cells through regulating epithelial-mesenchymal transition and ILK signaling pathway. AB - Accumulating evidences implicate that ribonuclease inhibitor (RI) plays a suppressing role in cancer development. However, the mechanisms underlying antitumor of RI remain largely unknown. Epithelial-mesenchymal transition (EMT) is regarded as a key event in tumor progression. The reports have demonstrated that EMT was implicated in metastasis of bladder cancer. Therefore, we suppose that RI might involve regulating EMT of bladder cancer. Here bladder cancer T24 cells were transfected with pGensil-1-siRNA-RI vectors. HE staining, living cell observation, Phalloidine-FITC staining of microfilament, cell adhesion, scratch migration, and Matrigel invasion were examined respectively. RI expression and colocalization with ILK were detected using confocal microscope. Proteins associated with EMT were determined with Western blotting and immunohistochemistry in vivo and in vitro. Effects of RI expression on tumor growth, metastasis and EMT related proteins in BALB/C nude mouse and clinical human bladder cancer specimens were valued with histological, immunohistochemical and immunofluorescent examination respectively. We demonstrated that down regulating RI increased cell proliferation, migration and invasion, changed cell morphology and adhesion, and rearranged cytoskeleton by inducing EMT and ILK signaling pathway in bladder cancer cells. In addition, we showed that down regulating RI promoted tumorigenesis and metastasis of bladder cancer in vivo. Finally, we found that bladder cancer with invasive capability had higher Vimentin, Snail, Slug and Twist as well as lower E-cadherin and RI expression in clinical human specimens. Our results suggest that RI could play a novel role in inhibiting metastasis of bladder through regulating EMT and ILK signaling pathway. PMID- 24768915 TI - Pre-selecting resistance against individual Bti Cry toxins facilitates the development of resistance to the Bti toxins cocktail. AB - The bioinsecticide Bacillus thuringiensis subsp. israelensis is a larvicide used worldwide for mosquito control, which contains three Cry toxins and one Cyt toxin. We investigated for the first time in Aedes aegypti (1) the evolution of resistance and cross-resistance of strains selected with each Cry toxin, and (2) the effect of pre-selection with Cry toxin on the evolution of resistance to a mix of Bti toxins. Cross resistance was higher between Cry4Ba and Cry11Aa than between Cry4Aa and either Cry4Ba or Cry11Aa, suggesting both common and specific mechanisms of resistance. Pre-selecting resistance to each Cry toxins facilitated the development of resistance to the full Bti toxins cocktail. PMID- 24768916 TI - The FIT Game: preliminary evaluation of a gamification approach to increasing fruit and vegetable consumption in school. AB - OBJECTIVE: Incentive-based interventions designed to increase fruit and vegetable (FV) consumption tend to yield positive, short-term outcomes. Because consumption most often returns to baseline levels when incentives are removed, sustainable long-duration interventions may be needed to impact public health. Anticipating that low-cost interventions will be more appealing to schools, the present study explored a low-cost, game-based intervention. METHOD: An alternating-treatments design was used to evaluate the effects of the FIT Game on objectively measured FV consumption in one elementary school (n=251) in Utah. During the Fall 2013 semester, game-based rewards were provided to heroic characters within a fictional narrative read by teachers on days when the school, as a whole, met a fruit or vegetable consumption goal in accord with the alternating-treatments design. RESULTS: On intervention days, fruit and vegetable consumption increased by 39% and 33%, (p<0.01, p<0.05; binomial tests), respectively. Teacher surveys indicated that students enjoyed the game and grade 1-3 teachers recommended its use in other schools. CONCLUSION: This game-based intervention provides a promising step towards developing a low-cost, effective, and sustainable FV intervention that schools can implement without outside assistance. PMID- 24768918 TI - Knowledge of UK physical activity guidelines: implications for better targeted health promotion. AB - OBJECTIVE: The aim of this study is to investigate the correlates of knowledge of the UK physical activity (PA) guidelines. METHOD: A Northern Ireland-wide population survey (2010/2011) of 4653 adults provided cross-sectional data on PA, knowledge of guidelines and socio-demographic characteristics. Multinomial logistic regression was used to investigate the associations between knowledge and socio-demographic characteristics (Model 1); and modifiable health behaviours (Model 2). RESULTS: Results showed that 47% of respondents were unaware of PA guidelines. Males who had a lower level of education (OR 5.91; 95% CI 1.67, 20.94), lived in more deprived areas (OR 4.80; 95% CI 1.87, 12.30), low income (OR 2.36; 95% CI 1.63, 3.41) and did no PA (OR 2.74; 95% CI 1.31, 5.76) were more likely to be unaware of the guidelines. Females who were younger (OR 1.03; 95% CI 1.02, 1.05) and reported poor health (OR 2.71; 95% CI 1.61, 4.58) were more likely to be unaware of the guidelines. CONCLUSION: There is a lack of awareness about the levels of PA needed to promote health. An understanding of the characteristics of those who are unaware of the guidelines has important implications for the design of targeted, effective health promotion. PMID- 24768917 TI - Physical inactivity and long-term rates of community-acquired sepsis. AB - OBJECTIVE: The authors sought to determine the association between physical inactivity (characterized by exercise and television watching levels) and long term rates of community-acquired sepsis. METHODS: The study utilized a population based cohort of 30,183 adult (>=45 years) community dwelling adults. Subjects reported weekly exercise (low=none, medium=1-3times/week, high=>=4times/week) and daily television watching (low=<1h/day, medium=1-3h/day, high=>=4h/day) levels. The authors evaluated the association between exercise, television watching and rates of sepsis, defined as hospital treatment for a serious infection with >=2 Systemic Inflammatory Response Syndrome (SIRS) criteria. RESULTS: Among 30,183 participants, 1500 experienced a sepsis event. Reported weekly exercise was: high 8798 (29.2%), medium 10,695 (35.4%), and low 10,240 (33.9%). Where available, reported daily television watching was: low 4615 (19.6%), medium 11,587 (49.3%) and high 7317 (31.1%). Decreased weekly exercise was associated with increased adjusted sepsis rates (high - referent; medium - HR 1.02, 95% CI 0.96-1.20; low - 1.33, 1.13-1.56). Daily television watching was not associated with sepsis rates. Sepsis rates were highest among those with both low exercise and high television watching levels (HR 1.49, 95% CI: 1.10-2.01). CONCLUSIONS: Physical inactivity may be associated with increased long-term rates of community-acquired sepsis. PMID- 24768919 TI - Determination of puerarin in rat plasma using PEGylated magnetic carbon nanotubes by high performance liquid chromatography. AB - This paper described a novel application of PEGylated magnetic carbon nanotubes as solid-phase extraction nanosorbents for the determination of puerarin in rat plasma by high performance liquid chromatography (HPLC). A solvothermal method was employed for the synthesis of monodisperse magnetites anchored onto multi walled carbon nanotubes (MWCNTs@Fe3O4). In order to enhance the water solubility of MWCNTs@Fe3O4 that ensured sufficient contact between nanosorbents and analytes in the sampling procedure, the obtained nanomaterials were further noncovalently functionalized using a phospholipids-polyethylene glycol (DSPE-PEG). The PEGylated MWCNTs@Fe3O4 nanomaterials had an extremely large surface area and exhibit a strong interaction capability for puerarin with pi-pi stacking interactions. The captured puerarin/nanosorbents were easily isolated from the plasma by placing a magnet, and desorbed by acetonitrile. The experimental variables affecting the extraction efficiency were investigated. The calibration curve of puerarin was linear from 0.01 to 20 MUg/ml, and the limit of detection was 0.005 MUg/ml. The precisions ranged from 2.7% to 3.5% for within-day measurement, and for between-day variation was in the range of 3.1-5.9%. The method recoveries were acquired from 95.2% to 98.0%. Moreover, the analytical performance obtained by PEGylated magnetic MWCNTs was also compared with that of magnetic MWCNTs. All results showed that our proposed method was an excellent alternative for the analysis of puerarin in rat plasma. PMID- 24768920 TI - Emission rates of selected volatile organic compounds from skin of healthy volunteers. AB - Gas chromatography with mass spectrometric detection (GC-MS) coupled with solid phase micro-extraction as pre-concentration method (SPME) was applied to identify and quantify volatile organic compounds (VOCs) emitted by human skin. A total of 64 C4-C10 compounds were quantified in skin emanation of 31 healthy volunteers. Amongst them aldehydes and hydrocarbons were the predominant chemical families with eighteen and seventeen species, respectively. Apart from these, there were eight ketones, six heterocyclic compounds, six terpenes, four esters, two alcohols, two volatile sulphur compounds, and one nitrile. The observed median emission rates ranged from 0.55 to 4,790 fmol cm(-2)min(-1). Within this set of analytes three volatiles; acetone, 6-methyl-5-hepten-2-one, and acetaldehyde exhibited especially high emission rates exceeding 100 fmol cm(-2)min(-1). Thirty three volatiles were highly present in skin emanation with incidence rates over 80%. These species can be considered as potential markers of human presence, which could be used for early location of entrapped victims during Urban Search and Rescue Operations (USaR). PMID- 24768921 TI - LC-MS/MS and GC-MS/MS measurement of plasma and urine di-paracetamol and 3-nitro paracetamol: proof-of-concept studies on a novel human model of oxidative stress based on oral paracetamol administration. AB - Paracetamol (acetaminophen) is a widely used safe analgesic drug when administered at therapeutic doses. Given the chemical reactivity of its phenolic group towards electrophilic species, we assumed that detection of paracetamol metabolites distinctly different from its known phase I metabolite N-acetyl-p benzoquinone imine (NAPQI) and the phase II glucuronic, sulfuric and mercapturic acids in biological samples upon oral administration of paracetamol (e.g., a 500 mg tablet) may represent a novel model of oxidative stress in humans. Such potential paracetamol metabolites are di-paracetamol and 3-nitro-paracetamol, in analogy to the well-investigated endogenous biomarkers di-tyrosine and 3-nitro tyrosine. Di-paracetamol and 3-nitro-paracetamol are known to be formed both by enzymatic and non-enzymatic routes. In the present work we report on mouse and human pilot studies on the formation and appearance of di-paracetamol and 3-nitro paracetamol in blood of mice intraperitoneally administered paracetamol, as well as in plasma and urine samples of healthy subjects who received a 500-mg paracetamol tablet or placebo. For the analysis of di-paracetamol and 3-nitro paracetamol in plasma and urine samples, analytes were extracted by solvent extraction with ethyl acetate and subsequently analyzed by LC-MS/MS without and with derivatization with pentafluorobenzyl bromide. GC-MS/MS was used to detect 3 nitro-paracetamol and quantify paracetamol as pentafluorobenzyl derivatives. Our studies indicate that di-paracetamol and 3-nitro-paracetamol appear in plasma and urine when paracetamol is given orally to healthy humans at the therapeutic dosage of 5-7 mg/kg. The molar ratio of di-paracetamol to paracetamol in urine was determined to be 1:535 in the paracetamol group and 1:6844 in the placebo group; the molar ratio of 3-nitro-paracetamol to paracetamol in urine was determined to be 1:199 in the paracetamol group and 1:8657 in the placebo group. Our studies suggest that a fraction of circulating and excretory di-paracetamol and 3-nitro-paracetamol may be formed artefactually during sample workup including derivatization. Further studies based on the quantitative determination of di-paracetamol and 3-nitro-paracetamol in biological samples by LC-MS/MS and/or GC-MS/MS using stable-isotope labeled analogues as internal standards are warranted to test the utility of paracetamol as a probe of oxidative stress in animals and in humans in health and disease. PMID- 24768922 TI - Proteins feel more than they see: fine-tuning of binding affinity by properties of the non-interacting surface. AB - Protein-protein complexes orchestrate most cellular processes such as transcription, signal transduction and apoptosis. The factors governing their affinity remain elusive however, especially when it comes to describing dissociation rates (koff). Here we demonstrate that, next to direct contributions from the interface, the non-interacting surface (NIS) also plays an important role in binding affinity, especially polar and charged residues. Their percentage on the NIS is conserved over orthologous complexes indicating an evolutionary selection pressure. Their effect on binding affinity can be explained by long range electrostatic contributions and surface-solvent interactions that are known to determine the local frustration of the protein complex surface. Including these in a simple model significantly improves the affinity prediction of protein complexes from structural models. The impact of mutations outside the interacting surface on binding affinity is supported by experimental alanine scanning mutagenesis data. These results enable the development of more sophisticated and integrated biophysical models of binding affinity and open new directions in experimental control and modulation of biomolecular interactions. PMID- 24768923 TI - Expression of zebrafish anterior gradient 2 in the semicircular canals and supporting cells of otic vesicle sensory patches is regulated by Sox10. AB - AGR2 is a member of the protein disulfide isomerase (PDI) family, which is implicated in cancer cell growth and metastasis, asthma, and inflammatory bowel disease. Despite the contributions of this protein to several biological processes, the regulatory mechanisms controlling expression of the AGR2 gene in different organs remain unclear. Zebrafish anterior gradient 2 (agr2) is expressed in several organs, including the otic vesicles that contain mucus secreting cells. To elucidate the regulatory mechanisms controlling agr2 expression in otic vesicles, we generated a Tg(-6.0 k agr2:EGFP) transgenic fish line that expressed EGFP in a pattern recapitulating that of agr2. Double immunofluorescence studies were used to demonstrate that Agr2 and GFP colocalize in the semicircular canals and supporting cells of all sensory patches in the otic vesicles of Tg(-6.0 k agr2:EGFP) embryos. Transient/stable transgenic analyses coupled with 5'-end deletion revealed that a 100 bp sequence within the 2.6 to -2.5 kbp region upstream of agr2 directs EGFP expression specifically in the otic vesicles. Two HMG-binding motifs were detected in this region. Mutation of these motifs prevented EGFP expression. Furthermore, EGFP expression in the otic vesicles was prevented by knockdown of the sox10 gene. This corresponded with decreased agr2 expression in the otic vesicles of sox10 morphants during different developmental stages. Electrophoretic mobility shift assays were used to show that Sox10 binds to HMG-binding motifs located within the -2.6 to -2.5 kbp region upstream of agr2. These results demonstrate that agr2 expression in the otic vesicles of zebrafish embryos is regulated by Sox10. PMID- 24768924 TI - Engineering chromatin states: chemical and synthetic biology approaches to investigate histone modification function. AB - Patterns of histone post-translational modifications (PTMs) and DNA modifications establish a landscape of chromatin states with regulatory impact on gene expression, cell differentiation and development. These diverse modifications are read out by effector protein complexes, which ultimately determine their functional outcome by modulating the activity state of underlying genes. From genome-wide studies employing high-throughput ChIP-Seq methods as well as proteomic mass spectrometry studies, a large number of PTMs are known and their coexistence patterns and associations with genomic regions have been mapped in a large number of different cell types. Conversely, the molecular interplay between chromatin effector proteins and modified chromatin regions as well as their resulting biological output is less well understood on a molecular level. Within the last decade a host of chemical approaches has been developed with the goal to produce synthetic chromatin with a defined arrangement of PTMs. These methods now permit systematic functional studies of individual histone and DNA modifications, and additionally provide a discovery platform to identify further interacting nuclear proteins. Complementary chemical- and synthetic-biology methods have emerged to directly observe and modulate the modification landscape in living cells and to readily probe the effect of altered PTM patterns on biological processes. Herein, we review current methodologies allowing chemical and synthetic biological engineering of distinct chromatin states in vitro and in vivo with the aim of obtaining a molecular understanding of histone and DNA modification function. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function. PMID- 24768925 TI - Mixing and transport during pharmaceutical twin-screw wet granulation: experimental analysis via chemical imaging. AB - Twin-screw granulation is a promising continuous alternative for traditional batch high shear wet granulation (HSWG). The extent of HSWG in a twin screw granulator (TSG) is greatly governed by the residence time of the granulation materials in the TSG and degree of mixing. In order to determine the residence time distribution (RTD) and mixing in TSG, mostly visual observation and particle tracking methods are used, which are either inaccurate and difficult for short RTD, or provide an RTD only for a finite number of preferential tracer paths. In this study, near infrared chemical imaging, which is more accurate and provides a complete RTD, was used. The impact of changes in material throughput (10-17 kg/h), screw speed (500-900 rpm), number of kneading discs (2-12) and stagger angle (30-90 degrees ) on the RTD and axial mixing of the material was characterised. The experimental RTD curves were used to calculate the mean residence time, mean centred variance and the Peclet number to determine the axial mixing and predominance of convective over dispersive transport. The results showed that screw speed is the most influential parameter in terms of RTD and axial mixing in the TSG and established a significant interaction between screw design parameters (number and stagger angle of kneading discs) and the process parameters (material throughput and number of kneading discs). The results of the study will allow the development and validation of a transport model capable of predicting the RTD and macro-mixing in the TSG. These can later be coupled with a population balance model in order to predict granulation yields in a TSG more accurately. PMID- 24768927 TI - Microbiota of Demodex mites from rosacea patients and controls. AB - Proliferation of Demodex mites is associated with rosacea. Furthermore, Demodex associated bacteria were suggested to play a role in the pathogenesis of rosacea. We decided to analyze Demodex microbiota. Mites were collected by standardized skin surface biopsies from patients with erythematotelangiectatic, papulopustular rosacea or from control subjects. The microbiota from each mite was characterized by 16S rRNA clone library approach. The 16S rRNA clone library consisted of 367 clones obtained from 73 extracts originating from 5 samples per study group (ETR, PPR or healthy subjects). A total of 86 species were identified with 36 as Demodex-specific microbiota. In the papulopustular group, proportions of Proteobacteria and Firmicutes increased whereas proportion of Actinobacteria decreased. Here, we report preliminary results on the microbiota of Demodex mites based on a molecular approach showing an unexpected diversity. Differences according to the host status need to be confirmed but open new perspectives for diagnostic of rosacea. PMID- 24768926 TI - Remote ischemic preconditioning differentially affects NADPH oxidase isoforms during hepatic ischemia-reperfusion. AB - AIMS: We investigated the function of major superoxide-generating enzymes after remote ischemic preconditioning (IPC) and hepatic ischemia-reperfusion (IR), with the specific aim of assessing the importance of the most relevant NADPH oxidase (NOX) isoforms, NOX2 and NOX4, in the mechanism of action. MAIN METHODS: 60-min partial liver ischemia was induced in Sprague-Dawley rats in the presence or absence of remote IPC (2 * 10-min limb IR), and hepatic microcirculatory variables were determined through intravital video microscopy and lightguide spectrophotometry during reperfusion. Inflammatory enzyme activities (myeloperoxidase (MPO) and xanthine oxidoreductase (XOR)), cytokine production (TNF-alpha and HMGB-1), liver necroenzyme levels (AST, ALT and LDH) and NOX2 and NOX4 protein expression changes (Western blot analysis) were assayed biochemically. KEY FINDINGS: In this setting, remote IPC significantly decreased the IR-induced hepatic NOX2 expression, but the NOX4 expression remained unchanged. The remote IPC provided significant, but incomplete protection against the leukocyte-endothelial cell interactions and flow deterioration. Hepatocellular damage (AST, ALT and LDH release), cytokine levels, and XOR and MPO activities also diminished. SIGNIFICANCE: Remote IPC limited the IR-induced microcirculatory dysfunction, but the protective effect did not affect all NOX homologs (at least not NOX4). The residual damage and inflammatory activation could well be linked to the unchanging NOX4 activity. PMID- 24768928 TI - Altered expression of cytokines in mice infected intranasally with two syncytial variants of Herpes simplex virus type 1. AB - Immune evasion strategies are important for the onset and the maintenance of viral infections. Many viruses have evolved mechanisms to counteract or suppress the host immune response. We have previously characterized two syncytial (syn) variants of Herpes simplex 1 (HSV-1) strain F, syn14-1 and syn17-2, obtained by selective pressure with a natural carrageenan. These variants showed a differential pathology in vaginal and respiratory mucosa infection in comparison with parental strain. In this paper, we evaluated the modulation of immune response in respiratory mucosa by these HSV-1 variants. We observed altered levels of Tumor Necrosis Factor-alpha and Interleukin-6 in lungs of animals infected with the syn14-1 and syn17-2 variants compared with the parental strain. Also, we detected differences in the recruitment of immune cells to the lung in syn variants infected mice. Both variants exhibit one point mutation in the sequence of the gene of glycoprotein D detected in the ectodomain of syn14-1 and the cytoplasmic tail of syn17-2. Results obtained in the present study contribute to the characterization of HSV-1 syn variants and the participation of the cellular inflammatory response in viral pathogenesis. PMID- 24768929 TI - Follistatin-like protein 1 is a critical mediator of experimental Lyme arthritis and the humoral response to Borrelia burgdorferi infection. AB - Follistatin-like protein 1 (FSTL-1) has recently been described as a critical mediator of CIA and a marker of disease activity. Lyme arthritis, caused by Borrelia burgdorferi, shares similarities with autoimmune arthritis and the experimental murine model collagen-induced arthritis (CIA). Because FSTL-1 is important in CIA and autoimmune arthritides, and Lyme arthritis shares similarities with CIA, we hypothesized that FSTL-1 may be an important mediator of Lyme arthritis. We demonstrate for the first time that FSTL-1 is induced by B. burgdorferi infection and is required for the development of Lyme arthritis in a murine model, utilizing a gene insertion to generate FSTL-1 hypomorphic mice. Using qPCR and qRT-PCR, we found that despite similar early infectious burden, FSTL-1 hypomorphic mice have improved spirochetal clearance in the face of attenuated arthritis and inflammatory cytokine production. Further, FSTL-1 mediates pathogen-specific antibody production and antigen recognition when assessed by ELISA and one- and two-dimensional immunoblotting. This study is the first to describe a role for FSTL-1 in the development of Lyme arthritis and anti Borrelia response, and the first to demonstrate a role for FSTL-1 in response to infection, highlighting the potential for FSTL-1 as a target in the treatment of B. burgdorferi infection. PMID- 24768930 TI - What do differences between multi-voxel and univariate analysis mean? How subject , voxel-, and trial-level variance impact fMRI analysis. AB - Multi-voxel pattern analysis (MVPA) has led to major changes in how fMRI data are analyzed and interpreted. Many studies now report both MVPA results and results from standard univariate voxel-wise analysis, often with the goal of drawing different conclusions from each. Because MVPA results can be sensitive to latent multidimensional representations and processes whereas univariate voxel-wise analysis cannot, one conclusion that is often drawn when MVPA and univariate results differ is that the activation patterns underlying MVPA results contain a multidimensional code. In the current study, we conducted simulations to formally test this assumption. Our findings reveal that MVPA tests are sensitive to the magnitude of voxel-level variability in the effect of a condition within subjects, even when the same linear relationship is coded in all voxels. We also find that MVPA is insensitive to subject-level variability in mean activation across an ROI, which is the primary variance component of interest in many standard univariate tests. Together, these results illustrate that differences between MVPA and univariate tests do not afford conclusions about the nature or dimensionality of the neural code. Instead, targeted tests of the informational content and/or dimensionality of activation patterns are critical for drawing strong conclusions about the representational codes that are indicated by significant MVPA results. PMID- 24768931 TI - Neural dynamics necessary and sufficient for transition into pre-sleep induced by EEG neurofeedback. AB - The transition from being fully awake to pre-sleep occurs daily just before falling asleep; thus its disturbance might be detrimental. Yet, the neuronal correlates of the transition remain unclear, mainly due to the difficulty in capturing its inherent dynamics. We used an EEG theta/alpha neurofeedback to rapidly induce the transition into pre-sleep and simultaneous fMRI to reveal state-dependent neural activity. The relaxed mental state was verified by the corresponding enhancement in the parasympathetic response. Neurofeedback sessions were categorized as successful or unsuccessful, based on the known EEG signature of theta power increases over alpha, temporally marked as a distinct "crossover" point. The fMRI activation was considered before and after this point. During successful transition into pre-sleep the period before the crossover was signified by alpha modulation that corresponded to decreased fMRI activity mainly in sensory gating related regions (e.g. medial thalamus). In parallel, although not sufficient for the transition, theta modulation corresponded with increased activity in limbic and autonomic control regions (e.g. hippocampus, cerebellum vermis, respectively). The post-crossover period was designated by alpha modulation further corresponding to reduced fMRI activity within the anterior salience network (e.g. anterior cingulate cortex, anterior insula), and in contrast theta modulation corresponded to the increased variance in the posterior salience network (e.g. posterior insula, posterior cingulate cortex). Our findings portray multi-level neural dynamics underlying the mental transition from awake to pre-sleep. To initiate the transition, decreased activity was required in external monitoring regions, and to sustain the transition, opposition between the anterior and posterior parts of the salience network was needed, reflecting shifting from extra- to intrapersonal based processing, respectively. PMID- 24768932 TI - Early sensitivity for eyes within faces: a new neuronal account of holistic and featural processing. AB - Eyes are central to face processing however their role in early face encoding as reflected by the N170 ERP component is unclear. Using eye tracking to enforce fixation on specific facial features, we found that the N170 was larger for fixation on the eyes compared to fixation on the forehead, nasion, nose or mouth, which all yielded similar amplitudes. This eye sensitivity was seen in both upright and inverted faces and was lost in eyeless faces, demonstrating it was due to the presence of eyes at fovea. Upright eyeless faces elicited largest N170 at nose fixation. Importantly, the N170 face inversion effect (FIE) was strongly attenuated in eyeless faces when fixation was on the eyes but was less attenuated for nose fixation and was normal when fixation was on the mouth. These results suggest the impact of eye removal on the N170 FIE is a function of the angular distance between the fixated feature and the eye location. We propose the Lateral Inhibition, Face Template and Eye Detector based (LIFTED) model which accounts for all the present N170 results including the FIE and its interaction with eye removal. Although eyes elicit the largest N170 response, reflecting the activity of an eye detector, the processing of upright faces is holistic and entails an inhibitory mechanism from neurons coding parafoveal information onto neurons coding foveal information. The LIFTED model provides a neuronal account of holistic and featural processing involved in upright and inverted faces and offers precise predictions for further testing. PMID- 24768933 TI - Spatial and temporal relationships of electrocorticographic alpha and gamma activity during auditory processing. AB - Neuroimaging approaches have implicated multiple brain sites in musical perception, including the posterior part of the superior temporal gyrus and adjacent perisylvian areas. However, the detailed spatial and temporal relationship of neural signals that support auditory processing is largely unknown. In this study, we applied a novel inter-subject analysis approach to electrophysiological signals recorded from the surface of the brain (electrocorticography (ECoG)) in ten human subjects. This approach allowed us to reliably identify those ECoG features that were related to the processing of a complex auditory stimulus (i.e., continuous piece of music) and to investigate their spatial, temporal, and causal relationships. Our results identified stimulus-related modulations in the alpha (8-12 Hz) and high gamma (70-110 Hz) bands at neuroanatomical locations implicated in auditory processing. Specifically, we identified stimulus-related ECoG modulations in the alpha band in areas adjacent to primary auditory cortex, which are known to receive afferent auditory projections from the thalamus (80 of a total of 15,107 tested sites). In contrast, we identified stimulus-related ECoG modulations in the high gamma band not only in areas close to primary auditory cortex but also in other perisylvian areas known to be involved in higher-order auditory processing, and in superior premotor cortex (412/15,107 sites). Across all implicated areas, modulations in the high gamma band preceded those in the alpha band by 280 ms, and activity in the high gamma band causally predicted alpha activity, but not vice versa (Granger causality, p<1e(-8)). Additionally, detailed analyses using Granger causality identified causal relationships of high gamma activity between distinct locations in early auditory pathways within superior temporal gyrus (STG) and posterior STG, between posterior STG and inferior frontal cortex, and between STG and premotor cortex. Evidence suggests that these relationships reflect direct cortico-cortical connections rather than common driving input from subcortical structures such as the thalamus. In summary, our inter-subject analyses defined the spatial and temporal relationships between music-related brain activity in the alpha and high gamma bands. They provide experimental evidence supporting current theories about the putative mechanisms of alpha and gamma activity, i.e., reflections of thalamo-cortical interactions and local cortical neural activity, respectively, and the results are also in agreement with existing functional models of auditory processing. PMID- 24768934 TI - Advancing the 3Rs in regulatory toxicology - Carcinogenicity testing: Scope for harmonisation and advancing the 3Rs in regulated sectors of the European Union. AB - Different government agencies operating in the European Union regulate different types of chemical products but all require testing for carcinogenicity to support applications for product marketing and commercialisation. A conference was held in Brussels in 2013 where representatives of the pharmaceutical, animal health, chemical and plant protection industries, together with representatives of regulatory agencies, universities and other stakeholders, met under the auspices of The European Partnership for Alternative Approaches to Animal Testing (EPAA) to discuss the varying requirements for carcinogenicity testing, and how these studies might be refined to improve hazard evaluation and risk assessment while implementing principles of the 3Rs (replacement, refinement and reduction in animal studies). While there are some similarities, the regulatory approaches in pharmaceutical, animal health, chemical and plant protection sectors have varying degrees of flexibility in requirements for carcinogenicity testing, to an extent reflecting concerns over the magnitude and duration of human exposure, either directly as in therapeutic exposure to pharmaceuticals, or indirectly through the ingestion of residues of veterinary drugs or plant protection chemicals. The article discusses these differences and other considerations for modified carcinogenicity testing paradigms on the basis of scientific and 3Rs approaches. PMID- 24768935 TI - Safety assessment of the calcium-binding protein, apoaequorin, expressed by Escherichia coli. AB - Calcium-binding proteins are ubiquitous modulators of cellular activity and function. Cells possess numerous calcium-binding proteins that regulate calcium concentration in the cytosol by buffering excess free calcium ion. Disturbances in intracellular calcium homeostasis are at the heart of many age-related conditions making these proteins targets for therapeutic intervention. A calcium binding protein, apoaequorin, has shown potential utility in a broad spectrum of applications for human health and well-being. Large-scale recombinant production of the protein has been successful; enabling further research and development and commercialization efforts. Previous work reported a 90-day subchronic toxicity test that demonstrated this protein has no toxicity by oral exposure in Sprague Dawley rodents. The current study assesses the allergenic potential of the purified protein using bioinformatic analysis and simulated gastric digestion. The results from the bioinformatics searches with the apoaequorin sequence show the protein is not a known allergen and not likely to cross-react with known allergens. Apoaequorin is easily digested by pepsin, a characteristic commonly exhibited by many non-allergenic dietary proteins. From these data, there is no added concern of safety due to unusual stability of the protein by ingestion. PMID- 24768936 TI - The association of food characteristics and individual differences with ratings of craving and liking. AB - Craving and liking are related to eating-related problems, but less is known about the association of specific food characteristics (e.g., sugar, fat) with craving/liking. The relation of individual differences in eating behavior with these craving and liking patterns is also relatively unknown. We examine the nomothetic impact of sugar, fat and processing on food craving and liking and the moderation of these effects by idiographic factors (e.g., Body Mass Index [BMI], hunger). One hundred and five overweight and obese women completed craving and liking ratings on 180 foods that differed in levels of sugar, fat and processing. Food craving was linked positively to fat content, but negatively to sugar. Food liking was associated negatively with sugar content and processing level. Addictive-like eating predicted elevated overall food craving and liking, and increased craving and liking for processed foods. Attempted restriction efforts were unrelated to craving and liking. BMI was associated with less craving for fattier foods and lower liking for the average food. Hunger was associated with increased craving for the average food. These findings highlight the role of fat in cravings and differences in craving and liking based on BMI, loss of control over eating, and hunger. These findings are relevant to theories of problematic eating and the development of eating-related interventions. PMID- 24768938 TI - Exploring the statistical and clinical impact of two interim analyses on the Phase II design with option for direct assignment. AB - PURPOSE: The primary goal of Phase II clinical trials is to understand better a treatment's safety and efficacy to inform a Phase III go/no-go decision. Many Phase II designs have been proposed, incorporating randomization, interim analyses, adaptation, and patient selection. The Phase II design with an option for direct assignment (i.e. stop randomization and assign all patients to the experimental arm based on a single interim analysis (IA) at 50% accrual) was recently proposed [An et al., 2012]. We discuss this design in the context of existing designs, and extend it from a single-IA to a two-IA design. METHODS: We compared the statistical properties and clinical relevance of the direct assignment design with two IA (DAD-2) versus a balanced randomized design with two IA (BRD-2) and a direct assignment design with one IA (DAD-1), over a range of response rate ratios (2.0-3.0). RESULTS: The DAD-2 has minimal loss in power (<2.2%) and minimal increase in T1ER (<1.6%) compared to a BRD-2. As many as 80% more patients were treated with experimental vs. control in the DAD-2 than with the BRD-2 (experimental vs. control ratio: 1.8 vs. 1.0), and as many as 64% more in the DAD-2 than with the DAD-1 (1.8 vs. 1.1). We illustrate the DAD-2 using a case study in lung cancer. CONCLUSION: In the spectrum of Phase II designs, the direct assignment design, especially with two IA, provides a middle ground with desirable statistical properties and likely appeal to both clinicians and patients. PMID- 24768937 TI - Associations between family food behaviors, maternal depression, and child weight among low-income children. AB - Although low-income children are at greater risk for overweight and obesity than their higher income counterparts, the majority of poor children are not overweight. The current study examined why such variation exists among diverse young children in poor families. Cross-sectional data were collected on 164 low income, preschool aged children and their mothers living in two Rhode Island cities. Over half of the sample was Hispanic (55%). Mothers completed measures of family food behaviors and depression while trained assistants collected anthropometric data from children at seven day care centers and a Supplemental Nutrition Assistance Program outreach project. Multivariate analysis of covariance revealed that higher maternal depression scores were associated with lower scores on maternal presence when child eats (P < .05), maternal control of child's eating routines (P < .03), and food resource management skills (P < .01), and with higher scores on child control of snacking (P < .03) and negative mealtime practices (P < .05). Multiple regression results revealed that greater maternal presence whenever the child ate was significantly associated with lower child BMI z scores (beta = .166, P < .05). Logistic regression analyses indicated that higher scores on food resource management skills reduced the odds of child overweight (odds ratios = .72-.95, P < .01). Maternal depression did not modify the relationship between family food behaviors and child weight. Overall, caregiver presence whenever a child eats, not just at meals, and better parental food resource management skills may promote healthier weights in low-income preschoolers. Further research is needed to identify the mechanisms that connect caregiver presence and food resource management skills to healthier weights for this age group. PMID- 24768939 TI - The Multidomain Intervention to preveNt disability in ElDers (MINDED) project: rationale and study design of a pilot study. AB - Disability is hardly reversible at old age, negatively impacts on the elders' quality of life, and significantly threatens the sustainability of public health services. Therefore, preventive interventions become necessary for successfully avoiding its onset. The translation of the successful clinical approach represented by the geriatric comprehensive assessment at the community-level and the specific targeting of frailty (a well-established geriatric syndrome) might represent a promising possibility. This approach may allow the implementation of preventive interventions before the irreversible features of disability onset. Unfortunately, there is a lack of evidence on the effectiveness of primary prevention programs against disability in community-dwelling elders. Moreover, the novelty of the topic makes it difficult for the immediate design and conduction of a full-scale trial. For these reasons, a pilot project aimed at obtaining the preliminary information for the design of a subsequent definitive trial is required. In the present article, we describe the objectives, design, and methods of the Multidomain Intervention to preveNt Disability in ElDers (MINDED) project. MINDED is articulated into three sequential phases. First, a screening tool for indentifying non-disabled frail older persons in the community (ideal target population for preventive interventions against disability) will be validated. Then, the organization of a multidisciplinary team in the development and design of a multidomain preventive plan against disability will be verified/optimized. Finally, a randomized controlled trial measuring the effect size of a multicomponent intervention (based on physical exercise, nutrition, and cognitive training) against incident mobility disability versus usual care in community-dwelling frail elders will be conducted. PMID- 24768940 TI - Design and participant characteristics of a randomized-controlled trial of telemedicine for smoking cessation among rural smokers. AB - INTRODUCTION: In rural America cigarette smoking is prevalent, few cessation services are available, and healthcare providers lack the time and resources to help smokers quit. This paper describes the design and participant characteristics of Connect2Quit (C2Q), a randomized control trial (RCT) that tests the effectiveness and cost-effectiveness of integrated telemedicine counseling delivered by 2-way webcams mounted on desktop computers in participant's physician office examining rooms (ITM) versus quitline counseling delivered by telephone in participant's homes (Phone) for helping rural smokers quit. METHODS/DESIGN: C2Q was implemented in twenty primary care and safety net clinics. Integrated telemedicine consisted of real-time video counseling, delivered to patients in their primary care physician's (PCP) office. Phone counseling, was delivered to patients in their homes. All participants received educational materials and guidance in selecting cessation medications. RESULTS: The 566 participants were predominantly Caucasian (92%); 9% were Latino. Most (65%) earned <200% of Federal Poverty Level. One out of three lacked home internet access, 40% were not comfortable using computers, and only 4% had been seen by a doctor via telemedicine in the past. Hypertension, chronic lung disease, and diabetes were highly prevalent. Participants smoked nearly a pack a day and were highly motivated to quit. DISCUSSION: C2Q is reaching a rural low income population, with comorbid chronic diseases, that would benefit greatly from quitting smoking. ITM is a good delivery model, which integrates care by holding counseling sessions in the patient's PCP office and keeps the primary care team updated on patients' progress. TRIAL REGISTRATION: CLINICAL TRIALS REGISTRATION: NCT00843505. PMID- 24768941 TI - Continuous acetone-butanol-ethanol (ABE) fermentation and gas production under slight pressure in a membrane bioreactor. AB - Two rounds of acetone-butanol-ethanol (ABE) fermentation under slight pressure were carried out in the continuous and closed-circulating fermentation (CCCF) system. Spores of the clostridium were observed and counted, with the maximum number of 2.1 * 10(8) and 2.3 * 10(8)ml(-1) separately. The fermentation profiles were comparable with that at atmospheric pressure, showing an average butanol productivity of 0.14 and 0.13 g L(-1)h(-1). Moreover, the average gas productivities of 0.28 and 0.27 L L(-1)h(-1) were obtained in two rounds of CCCF, and the cumulative gas production of 52.64 and 25.92 L L(-1) were achieved, with the hydrogen volume fraction of 41.43% and 38.08% respectively. The results suggested that slight pressures have no obvious effect on fermentation performance, and also indicated the significance and feasibility of gas recovery in the continuous ABE fermentation process. PMID- 24768942 TI - Oleaginous fungal lipid fermentation on combined acid- and alkali-pretreated corn stover hydrolysate for advanced biofuel production. AB - A combined hydrolysis process, which first mixed dilute acid- and alkali pretreated corn stover at a 1:1 (w/w) ratio, directly followed by enzymatic saccharification without pH adjustment, has been developed in this study in order to minimize the need of neutralization, detoxification, and washing during the process of lignocellulosic biofuel production. The oleaginous fungus Mortierella isabellina was selected and applied to the combined hydrolysate as well as a synthetic medium to compare fungal lipid accumulation and biodiesel production in both shake flask and 7.5L fermentor. Fungal cultivation on combined hydrolysate exhibited comparable cell mass and lipid yield with those from synthetic medium, indicating that the integration of combined hydrolysis with oleaginous fungal lipid fermentation has great potential to improve performance of advanced lignocellulosic biofuel production. PMID- 24768943 TI - Pyrolysis characteristics and kinetics of aquatic biomass using thermogravimetric analyzer. AB - The differences in pyrolysis process of three species of aquatic biomass (microalgae, macroalgae and duckweed) were investigated by thermogravimetric analysis (TGA). Three stages were observed during the pyrolysis process and the main decomposition stage could be divided further into three zones. The pyrolysis characteristics of various biomasses were different at each zone, which could be attributed to the differences in their components. A stepwise procedure based on iso-conversional and master-plots methods was used for the kinetic and mechanism analysis of the main decomposition stage. The calculation results based on the kinetic model was in good agreement with the experimental data of weight loss, and each biomass had an increasing activation energy of 118.35-156.13 kJ/mol, 171.85-186.46 kJ/mol and 258.51-268.71 kJ/mol in zone 1, 2 and 3, respectively. This study compares the pyrolysis behavior of various aquatic biomasses and provides basis for further applications of the biomass thermochemical conversion. PMID- 24768944 TI - Role of epigenetic mechanisms in epithelial-to-mesenchymal transition of breast cancer cells. AB - The epithelial-to-mesenchymal transition (EMT) is a crucial process during normal development that allows dynamic and reversible shifts between epithelial and mesenchymal cell states. Cancer cells take advantage of the complex, interrelated cellular networks that regulate EMT to promote their migratory and invasive capabilities. During the past few years, evidence has accumulated that indicates that genetic mutations and changes to epigenetic mechanisms are key drivers of EMT in cancer cells. Recent studies have begun to shed light on the epigenetic reprogramming in cancer cells that enables them to switch from a noninvasive form to an invasive, metastatic form. The authors review the current knowledge of alterations of epigenetic machinery, including DNA methylation, histone modifications, nucleosome remodeling and expression of microRNAs, associated with EMT and tumor progression of breast cancer cells. Last, existing and upcoming drug therapies targeting epigenetic regulators and their potential benefit for developing novel treatment strategies are discussed. PMID- 24768946 TI - Genetic variations of SOCS1 are associated with chronic hepatitis B virus infection. AB - Suppressor of cytokine signaling (SOCS)-1 is involved in viral infection through regulation of both innate and adaptive immunity. The SOCS1 gene polymorphisms may affect the outcome of viral infection. The relationship between SOCS1 polymorphisms and hepatitis B virus (HBV) infection has not yet been explored. This study genotyped SOCS1 rs243327 and rs33932899 polymorphisms in 477 patients with chronic HBV infection, 93 HBV infection resolvers and 215 healthy controls. In statistical analysis, p-values less than 0.05 in multiple comparisons were corrected by Bonferroni method and presented as pc. The results showed that the allele T-containing genotypes (CT+TT) of rs243327 were higher in HBV patients than resolvers and lower in resolvers than healthy controls although the difference was not significant. The allele T of rs243327 was significantly lower in resolvers than controls (p = 0.033). The genotype GC and allele C of rs33932899 were significantly less frequent in HBV patients than controls (pc < 0.001 and p < 0.001, respectively). The haplotype T/G of rs243327/rs33932899 was significantly more frequent in HBV patients than resolvers (pc < 0.001) or controls (pc = 0.009). These data indicate that SOCS1 polymorphisms might affect the susceptibility and outcome of HBV infection. PMID- 24768945 TI - Clinical applications of epigenetics in cardiovascular disease: the long road ahead. AB - Epigenetic processes, defined as heritable changes in gene expression that occur without changes to the DNA sequence, have emerged as a promising area of cardiovascular disease research. Epigenetic information transcends that of the genotype alone and provides for an integrated etiologic picture of cardiovascular disease pathogenesis because of the interaction of the epigenome with the environment. Epigenetic biomarkers, which include DNA methylation, histone modifications, and RNA-based mechanisms, are both modifiable and cell-type specific, which makes them not only responsive to the environment, but also an attractive target for drug development. However, the enthusiasm surrounding possible applications of cardiovascular epigenetics currently outpaces available evidence. In this review, the authors synthesize the evidence linking epigenetic changes with cardiovascular disease, emphasizing the gap between the translational potential and the clinical reality of cardiovascular epigenetics. PMID- 24768947 TI - Interleukin-10 gene promoter polymorphisms in celiac patients from north-eastern Italy. AB - Celiac disease is a complex chronic intestinal disorder driven by an immune response against the gliadin fraction of gluten: many factors are involved in the pathogenesis of the disease, and among these Interleukin-10 could play an important role. In the present study, the -1082A>G, -819T>C and -592A>C IL10 functional polymorphisms were analyzed in 565 celiac patients and 576 healthy controls from north-eastern Italy, stratified for HLA class II celiac disease risk haplotypes. No significant differences were observed for the three IL10 polymorphisms distribution between celiac patients and controls with the exception of a slightly increased risk for the -1082A allele in HLA-DQ8 male individuals. Although our findings suggest that the IL10 genetic variants analyzed do not have a major role in the susceptibility to the development of celiac disease in north-eastern Italian patients, we think that the possible involvement of IL10 gene in CD should deserve further investigation and that large-scale studies are recommended to confirm our findings. PMID- 24768948 TI - Clinical, molecular, and T cell subset analyses in a small cohort of Chinese patients with hyper-IgM syndrome type 1. AB - Type 1 hyper-IgM syndrome (HIGM1) is a rare primary immunodeficiency disease caused by mutations in the CD40L gene. Patients often present with recurrent infections and autoimmune manifestations. We investigated the clinical and molecular characteristics of HIGM1 in thirteen patients from the Chinese mainland and examined the proportion of CD4(+)CD25(+)FoxP3(+)Treg, Th17, and Th1 cells in the peripheral blood. We identified ten distinct CD40L mutations in eleven patients: one missense mutation, one nonsense mutation, one insertion mutation (in frame), and seven deletions. Six of these mutations were novel. We observed the percentage of Tregs in the peripheral blood of HIGM1 patients decreased markedly compared with that in healthy controls, but no statistically significant differences was found in the percentages of Th17 and Th1. The identified mutations reflect the heterogeneity of the CD40L gene in HIGM1. Precise genetic diagnosis of HIGM1 will enable appropriate therapeutic interventions, reliable detection of carriers, and genetic counseling. Skewed Treg, Th17/Treg, and Th1/Treg profiles may be associated with immune responses to autoimmunity or infection, which requires replication in larger studies. PMID- 24768949 TI - Identification of patients with increased immunological risk among potential kidney recipients in the Polish population. AB - Pretransplant identification of allosensitized patients is possible thanks to new technologies, which allow for accurate detection of clinically relevant alloantibodies. Implementation of these methods in the screening of patients awaiting transplantation increased their chance for successful donor-recipient matching. Here, 1460 patients reported to the Polish National Waiting List were screened with the Luminex Screen (LS) solid phase test for anti-HLA antibodies. The patients with detected anti-HLA antibodies were assayed with the Luminex Single Antigen (LSA) tests in order to establish defined antigen specificity of the alloantibodies. The results were compared with data on the immunization assessed with the routine complement-dependent-cytotoxicity panel-reactive antibody assay (PRA CDC). The study showed significantly higher sensitivity of the LS method when compared with PRA CDC. It has been shown that LSA test is a useful technique identifying the specificities of alloantibodies. In particular, LSA allowed to assess donor specific antibodies (DSA) to previous mismatches (MM) and to determine acceptable HLA mismatches of the potential donors. The introduction of solid phase tests in routine pretransplant diagnostics allowed for faster and more accurate assessment of the immunological risk of the recipients and optimal donor-recipient matching. Hence, the presented algorithm of solid phase assays has become a new standard for the identification of allosensitized patients awaiting kidney transplantation in Poland. PMID- 24768950 TI - Maladaptive behavioral consequences of conditioned fear-generalization: a pronounced, yet sparsely studied, feature of anxiety pathology. AB - Fear-conditioning experiments in the anxiety disorders focus almost exclusively on passive-emotional, Pavlovian conditioning, rather than active-behavioral, instrumental conditioning. Paradigms eliciting both types of conditioning are needed to study maladaptive, instrumental behaviors resulting from Pavlovian abnormalities found in clinical anxiety. One such Pavlovian abnormality is generalization of fear from a conditioned danger-cue (CS+) to resembling stimuli. Though lab-based findings repeatedly link overgeneralized Pavlovian-fear to clinical anxiety, no study assesses the degree to which Pavlovian overgeneralization corresponds with maladaptive, overgeneralized instrumental avoidance. The current effort fills this gap by validating a novel fear potentiated startle paradigm including Pavlovian and instrumental components. The paradigm is embedded in a computer game during which shapes appear on the screen. One shape paired with electric-shock serves as CS+, and other resembling shapes, presented in the absence of shock, serve as generalization stimuli (GSs). During the game, participants choose whether to behaviorally avoid shock at the cost of poorer performance. Avoidance during CS+ is considered adaptive because shock is a real possibility. By contrast, avoidance during GSs is considered maladaptive because shock is not a realistic prospect and thus unnecessarily compromises performance. Results indicate significant Pavlovian-instrumental relations, with greater generalization of Pavlovian fear associated with overgeneralization of maladaptive instrumental-avoidance. PMID- 24768952 TI - Strong seed-bank effects in bacterial evolution. AB - Bacterial genomes are mosaics with fragments showing distinct phylogenetic origins or even being unrelated to any other genetic information (ORFan genes). Thus the analysis of bacterial population genetics is in large part a collection of explanations for anomalies in relation to classical population genetic models such as the Wright-Fisher model and the Kingman coalescent that do not adequately describe bacterial population genetics, genomics or evolution. The concept of "species" as an evolutionary coherent biological group that is genetically isolated and shares genetic information through recombination among its members cannot be applied to any bacterial group. Recently, a simple probabilistic model considering the role of strong seed-bank effects in population genetics has been proposed by Blath et al. This model suggests the existence of a genetic pool with high diversity that is not subject to classical selection and extinction. We reason that certain bacterial population genetics anomalies could be explained by the prevalence of strong seed-bank effects among bacteria. To address this possibility we analyzed the genome of the bacterium Azotobacter vinelandii and show that genes that code for functions that are essential for the bacterium biology do not have a relation of ancestry with closely related bacteria, or are ORFan genes. The existence of essential genes that are not inherited from the most recent ancestor cannot be explained by classical population genetics models and is irreconcilable with the current view of genes acquired by horizontal transfer as being accessory or adaptive. PMID- 24768951 TI - Perinatal biomarkers in prematurity: early identification of neurologic injury. AB - Over the past few decades, biomarkers have become increasingly utilized as non invasive tools in the early diagnosis and management of various clinical conditions. In perinatal medicine, the improved survival of extremely premature infants who are at high risk for adverse neurologic outcomes has increased the demand for the discovery of biomarkers in detecting and predicting the prognosis of infants with neonatal brain injury. By enabling the clinician to recognize potential brain damage early, biomarkers could allow clinicians to intervene at the early stages of disease, and to monitor the efficacy of those interventions. This review will first examine the potential perinatal biomarkers for neurologic complications of prematurity, specifically, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL) and posthemorrhagic hydrocephalus (PHH). It will also evaluate knowledge gained from animal models regarding the pathogenesis of perinatal brain injury in prematurity. PMID- 24768953 TI - Cytosolic Trypanosoma cruzi nucleoside diphosphate kinase generates large granules that depend on its quaternary structure. AB - Nucleoside diphosphate kinase (NDPK) is a key enzyme in the control of cellular concentrations of nucleoside triphosphates, and has been shown to play important roles in many cellular processes. In this work we investigated the subcellular localization of the canonical NDPK1 from Trypanosoma cruzi (TcNDPK1), the etiological agent Chagas's Disease, and evaluated the effect of adding an additional weak protein-protein interaction domain from the green fluorescent protein (GFP). Immunofluorescence microscopy revealed that the enzyme from wild type and TcNDPK1 overexpressing parasites has a cytosolic distribution, being the signal more intense around the nucleus. However, when TcNDPK1 was fused with dimeric GFP it relocalizes in non-membrane bounded granules also located adjacent to the nucleus. In addition, these granular structures were dependent on the quaternary structure of TcNDPK1 and GFP since mutations in residues involved in their oligomerization dramatically decrease the amount of granules. This phenomenon seems to be specific for TcNDPK1 since other cytosolic hexameric enzyme from T. cruzi, such as the NADP(+)-linked glutamate dehydrogenase, was not affected by the fusion with GFP. In addition, in parasites without GFP fusions granules could be observed in a subpopulation of epimastigotes under metacyclogenesis and metacyclic trypomastigotes. Organization into higher protein arrangements appears to be a singular feature of canonical NDPKs; however the physiological function of such structures requires further investigation. PMID- 24768954 TI - Identification and quantification of host proteins in the vesicular fluid of porcine Taenia solium cysticerci. AB - The host-parasite relationship in cestode infections is complex. One feature of this bidirectional molecular communication is the uptake of host proteins by the parasite. Here we describe the presence of several host proteins in the vesicular fluid of Taenia solium cysticerci dissected from the central nervous system and the skeletal muscle of naturally infected pigs. Using two-dimensional electrophoresis we compared the protein patterns of vesicular fluids of cysticerci vs. the sera of cysticercotic pigs. We found that the vesicular fluids of both groups of cysts showed 17 protein spots matching with the pig's sera spots. After mass spectrometry sequencing of these spots, five host proteins were identified: hemoglobin, albumin, serpin A3-8, haptoglobin, rho GTPase-activating protein 36-like. Three of the 17 spots corresponded to host protein fragments: hemoglobin, albumin and serpin A3-8. IgG heavy and light chains were also identified by Western blot using a specific antibody. Quantitative estimations indicated that the host proteins represented 11-13% of the protein content in the vesicular fluids. We also calculated the relative abundance of these host proteins in the vesicular fluids; all were represented in similar relative abundances as in host sera. This suggests that uptake of host proteins by cysticerci proceeds through an unspecific mechanism such as non-specific fluid pinocytosis. PMID- 24768955 TI - Ultrastructural analysis of beta-lapachone-induced surface membrane damage in male adult Schistosoma mansoni BH strain worms. AB - The present study provides, for the first time, conclusions on the in vitro schistosomicidal properties of beta-lap. Adult male Schistosoma mansoni worms of the BH strain were used for the study. Motility, mortality, cell viability and alterations in the tegument were employed as schistosomicidal parameters. Alterations in motility were observed 6h after incubation in concentrations of 50 and 100 MUM. beta-lap decreased significantly the worm viability, reducing the formation of formazan in 17.7%, 27.4% and 54.8% at concentrations of 25, 50 and 100 MUM, respectively. Mortality in concentrations of 50 and 100 MUM was of 67% and 100%, respectively, after 24h. The death of the parasite was preceded by progressive surface membrane damage, characterized by tegument peeling, spine reduction and erosion, blister formation and rupture, and the emergence of holes. In addition to this, in the anterior portion, intense general edema, areas of cracking with a wrinkled surface, furrows and a fibrous appearance were also observed. The results of the present study thus provide a sound basis for further in-depth studies of the schistosomicidal properties of beta-lap, both in the laboratory and in the field. PMID- 24768956 TI - Influence of infection by Toxoplasma gondii on purine levels and E-ADA activity in the brain of mice experimentally infected mice. AB - The aim of this study was to assess the purine levels and E-ADA activity in the brain of mice (BALB/c) experimentally infected with Toxoplasma gondii. In experiment I (n=24) the mice were infected with RH strain of T. gondii, while in experiment II (n=36) they were infected with strain ME-49 of T. gondii. Our results showed that, for RH strain (acute phase), an increase in both periods in the levels of ATP, ADP, AMP, adenosine, hypoxanthine, xanthine (only on day 6 PI) and uric acid (only on day 6 PI). By the other hand, the RH strain led, on days 4 and 6 PI, to a reduction in the concentration of inosine. ME-49, a cystogenic strain, showed some differences in acute and chronic phase, since on day 6 PI the levels of ATP and ADP were increased, while on day 30 these same nucleotides were reduced. On day 60 PI, ME-49 induced a reduction in the levels of ATP, ADP, AMP, adenosine, inosine and xanthine, while uric acid was increased. A decrease of E ADA activity was observed in brain on days 4 and 6 PI (RH), and 30 PI (ME-49); however on day 60 PI E-ADA activity was increased for infection by ME-49 strain. Therefore, it was possible to conclude that infection with T. gondii changes the purine levels and the activity of E-ADA in brain, which may be associated with neurological signs commonly observed in this disease. PMID- 24768957 TI - Predictors of surgical site infection in women undergoing hysterectomy for benign gynecologic disease: a multicenter analysis using the national surgical quality improvement program data. AB - STUDY OBJECTIVE: To estimate the rate and predictors of surgical site infection (SSI) after hysterectomy performed for benign indications and to identify any association between SSI and other postoperative complications. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: National Surgical Quality Improvement Program data. PATIENTS: Women who underwent abdominal or laparoscopic hysterectomy performed for benign indications from 2005 to 2011. INTERVENTIONS: Univariable and multivariable logistic regression analyses were used to identify predictors of SSI and its association with other postoperative complications. Odds ratios were adjusted for patient demographic data, comorbidities, preoperative laboratory values, and operative factors. MEASUREMENTS AND MAIN RESULTS: Of 28 366 patients, 758 (3%) were diagnosed with SSI. SSI occurred more often after abdominal than laparoscopic hysterectomy (4% vs 2%; p < .001). Among patients who underwent abdominal hysterectomy, predictors of SSI included diabetes, smoking, respiratory comorbidities, overweight or obesity, American Society of Anesthesiologists class >= 3, perioperative blood transfusion, and operative time >180 minutes. Among those who underwent laparoscopic hysterectomy, predictors of SSI included perioperative blood transfusion, operative time >180 minutes, serum creatinine concentration >= 2 mg/dL, and platelet count >= 350 000 cells/mL(3). For patients with deep or organ/space SSI, significant predictors included perioperative blood transfusion and American Society of Anesthesiologists class >= 3 for abdominal hysterectomy, and non-white race, renal comorbidities, preoperative or perioperative blood transfusion, and operative time >180 minutes for laparoscopic hysterectomy. SSI was associated with longer hospital stay and higher rates of repeat operation, sepsis, renal failure, and wound dehiscence. SSI was not associated with increased 30-day mortality. CONCLUSIONS: SSI occurred more often after abdominal hysterectomy than laparoscopic hysterectomy performed to treat benign gynecologic disease. SSI was associated with increased postoperative complications but not mortality. Several risk factors for SSI after each abdominal and laparoscopic hysterectomy were identified in this study. PMID- 24768958 TI - Nerve-sparing radical hysterectomy made easy by laparoscopy. AB - STUDY OBJECTIVE: To evaluate the technical feasibility of nerve-sparing radical hysterectomy performed laparoscopically. PATIENTS: Thirty-five women with cervical cancer stage Ia1 or Ib1. INTERVENTIONS: All patients underwent laparoscopic nerve-sparing hysterectomy. MEASUREMENTS AND MAIN RESULTS: Oncologic results were comparable to those of conventional laparoscopic radical hysterectomy. There was complete recovery of bladder function after removal of the Foley catheter. Results of urodynamic studies at 3 weeks after surgery were normal. CONCLUSION: Oncologic and functional results are comparable to those of conventional laparoscopic radical hysterectomy. Magnification enabled by laparoscopy is helpful in better dissection and preservation of nerve anatomy. PMID- 24768959 TI - Management of complications encountered with Essure hysteroscopic sterilization: a systematic review. AB - Essure hysteroscopic sterilization has been US Food and Drug Administration approved in the United States since 2002. Complications associated with the Essure device include improper placement (malpositioning), unintended pregnancy, pain, infection, and nickel allergy. The rarity of complications, compounded by underreporting, makes it difficult to determine best practices insofar as management. This systematic review synthesizes the national and global experience with management of Essure-related complications and suggests treatment options when data allow. PMID- 24768960 TI - To excise or ablate endometriosis? A prospective randomized double-blinded trial after 5-year follow-up. AB - STUDY OBJECTIVE: To compare reduction of pain after laparoscopy for ablation or excision of endometriosis. DESIGN: Prospective, randomized, double-blind study (Canadian Task Force classification I). SETTING: Endometriosis and pelvic pain clinic at a university teaching hospital. PATIENTS: Women of reproductive age with pelvic pain and visually proved endometriosis. INTERVENTIONS: Subjects completed a questionnaire rating various kinds of pain using visual analog scales (VAS). After visual identification subjects were randomized to treatment via ablation or excision by supervised training gynecologists as primary surgeons. Follow-up questionnaires documented pain levels every 3 months for 1 year and then every 6 months for 5 years. MEASUREMENTS AND MAIN RESULTS: Change in pain VAS scores during 5 years after the operation and rates of pregnancy, repeat surgery, and use of hormone therapy were evaluated. There was a reduction in all pain scores over the 5-year follow-up in both treatment groups. A significantly greater reduction in dyspareunia VAS scores was observed in the excision group at 5 years (p = .03 at univariate analysis, and p = .007 at multivariate analysis). More women in the ablation group continued to receive medical treatment of endometriosis at 5 years (p = .004). CONCLUSIONS: Surgical treatment of endometriosis provides symptom reduction for up to 5 years. In some limited areas such as deep dyspareunia, excision is more effective than ablation. PMID- 24768961 TI - Highly dispersive PdCoB catalysts for dechlorination of chlorophenols. AB - Highly dispersive PdCoB nano-particles were prepared by precipitation-reduction with NaBH4 at 273 K. Characterization showed that the dispersion of amorphous alloy PdCoB nano-particles increased with decrease in both Pd/Co ratio and preparation temperature. The size of PdCoB-L(273) (Pd/Co ratio of 0.0005) nano particles prepared at 273 K was 5 nm and BET specific surface area was estimated to be 177 m(2)/g, much higher than those of bimetallic catalysts reported in literature. During the hydrodechlorination of 4-chlorophenol, PdCoB catalysts were effective within pH range from 2.5 to 11. The activity of PdCoB can be promoted by the increase in B/Co ratio on the surface. PdCoB-L(273) sample presented the highest efficiency, and the reaction constants described in different terms for 4-chlorophenol, 2,4-dichlorophenol and 2,4,6-trichlorophenol were much higher than those obtained over PdFe in literature, probably ascribed to smaller particle sizes, less agglomerations and strong synergistic effect between Pd, Co and B species. PMID- 24768962 TI - Effect of temperature on the reductive dechlorination of 1,2,3,4 tetrachlorodibenzofuran in anaerobic PCDD/F-contaminated sediments. AB - The effect of temperature on the reductive dechlorination in sediments of the PCDD/F-contaminated Kymijoki River, Finland was assessed with 1,2,3,4 tetrachlorodibenzofuran (1,2,3,4-TeCDF) at various temperatures and with co amendment of 2,3,4,6-tetrachlorophenol (2,3,4,6-TeCP) in laboratory microcosms. The dechlorination rate of 1,2,3,4-TeCDF increased with incubation temperature, with TeCDF half-lives of 2.1 y at 21 degrees C, 3.9 y at 15 degrees C, and 19.0 y at 4 degrees C. Co-amendment with 2,3,4,6-TeCP reduced the TeCDF half-life to 1.8 y at 21 degrees C. 1,2,3,4-TeCDF was dechlorinated mainly in the lateral position to 1,3,4-TrCDF and then to 1,3-DiCDF over 29 months, but incubation temperature affected the relative molar ratios of the dechlorination products. The abundance of the Dehalococcoides-like Chloroflexi community did not substantially change in microcosms over 24 months incubation at the different temperatures. The dechlorination activity of 1,2,3,4-TeCDF was significantly limited at lower temperatures, which should be considered in predicting the environmental fate of aged PCDD/Fs in sediments of the Kymijoki River. PMID- 24768963 TI - The structure-mechanical relationship of palm vascular tissue. AB - The structure-mechanical relationship of palm sheath is studied with numerical and experimental methods. The cellular structure of the vascular tissue is rebuilt with an image-based reconstruction method and used to create finite element models. The validity of the models is firstly verified with the results from the tensile tests. Then, the cell walls inside each of the specific regions (fiber cap, vessel, xylem, etc.) are randomly removed to obtain virtually imperfect structures. By comparing the magnitudes of performance degradation in the different imperfect structures, the influences of each region on the overall mechanical performances of the vascular tissue are discussed. The longitudinal stiffness and yield strength are sensitive to the defects in the vessel regions. While in the transverse directions (including the radial and tangential directions), the parenchymatous tissue determines the mechanical properties of the vascular tissue. Moreover, the hydraulic, dynamic response and energy absorption behavior of the vascular tissue are numerically explored. The flexibility of natural palm tissue enhances its impact resistance. Under the quasi-static compression, the cell walls connecting the fiber cap and the vessel dissipate more energy. The dominant role of the fiber cap in the plastic energy dissipation under high-speed impact is observed. And the radially-arranged fiber cap also allows the palm tissue to improve its tangential mechanical performances under hydraulic pressure. PMID- 24768964 TI - Genetic manipulation of the cardiac mitochondrial phosphate carrier does not affect permeability transition. AB - The Mitochondrial Permeability Transition (MPT) pore is a voltage-sensitive unselective channel known to instigate necrotic cell death during cardiac disease. Recent models suggest that the isomerase cyclophilin D (CypD) regulates the MPT pore by binding to either the F0F1-ATP synthase lateral stalk or the mitochondrial phosphate carrier (PiC). Here we confirm that CypD, through its N terminus, can directly bind PiC. We then generated cardiac-specific mouse strains overexpressing or with decreased levels of mitochondrial PiC to assess the functionality of such interaction. While PiC overexpression had no observable pathologic phenotype, PiC knockdown resulted in cardiac hypertrophy along with decreased ATP levels. Mitochondria isolated from the hearts of these mouse lines and their respective non-transgenic controls had no divergent phenotype in terms of oxygen consumption and Ca(2+)-induced MPT, as assessed by swelling and Ca(2+) retention measurements. These results provide genetic evidence indicating that the mitochondrial PiC is not a critical component of the MPT pore. PMID- 24768965 TI - Gout in African Americans. AB - PURPOSE: African Americans have a substantially higher prevalence of risk factors for gout than Caucasians. The aim of the present study was to compare the risk for incident gout among African Americans and Caucasians. METHODS: Incidence rates of physician-diagnosed gout among 11,559 Caucasian men and 931 African American men aged 35 to 57 years and at high cardiovascular risk, observed for 7 years as a part of the Multiple Risk Factor Intervention Trial, were analyzed. Cox regression models were used to account for potential confounding by age, body mass index, diuretic use, hypertension and diabetes status, aspirin and alcohol consumption, and kidney disease. RESULTS: At baseline, after accounting for risk factors, African Americans had a 14% lower prevalence of hyperuricemia than Caucasians. Incidence of gout increased with increasing prevalence of risk factors in both Caucasians and African Americans. Ethnic disparities in incidence rates were most apparent among those without other risk factors for gout. In separate Cox regression models, after accounting for risk factors, African American ethnicity was associated with a hazard ratio of 0.78 (95% confidence interval [CI], 0.66-0.93) for physician-diagnosed gout and 0.88 (95% CI, 0.85 0.90) for incident hyperuricemia. Significant interactions were observed; the association was the strongest (hazard ratio 0.47; 0.37-0.60). These associations were unaffected by addition of serum urate as a covariate or by using alternate case definitions for gout. CONCLUSIONS: After accounting for the higher prevalence of risk factors, African American ethnicity is associated with a significantly lower risk for gout and hyperuricemia compared with Caucasian ethnicity. PMID- 24768966 TI - Inpatient-outpatient transitions for patients with resident primary care physicians: access and readmission. AB - BACKGROUND: Transition from hospitalization to postdischarge care is a vulnerable period for patients. How the experience of this transition differs for patients with resident primary care physicians is unknown. METHODS: In a single, large academic primary care practice, we examined an inception cohort of consecutive hospitalizations and postdischarge visits of hospitalized patients with resident or faculty primary care physicians between 2008 and 2013. We compared patient demographics, readmission risk, and access to outpatient care between resident and faculty primary care physicians by using generalized estimating equations to account for repeated hospitalizations. RESULTS: We documented 8161 hospitalizations among patients with resident primary care physicians and 20,844 hospitalizations among patients with faculty primary care physicians. Hospitalized patients with resident primary care physicians were generally younger, more likely to be on Medicaid, and more likely to be African American (P < .001). Patients with resident primary care physicians were less likely to be seen within 7 and 30 days of discharge (adjusted relative risk, 0.83; 95% confidence interval [CI], 0.81-0.93 at 7 days; adjusted relative risk, 0.88; 95% CI, 0.85-0.92 at 30 days) and had an increased risk of readmission within 30 days (adjusted odds ratio, 1.25; 95% CI, 1.13-1.37). They also were considerably less likely to see their own provider at first follow-up (relative risk, 0.55; 95% CI, 0.52-0.59). CONCLUSIONS: Hospitalized patients with resident primary care physicians had lower rates of timely postdischarge follow-up, higher rates of readmission, and a lower likelihood of seeing their own provider than did patients with faculty primary care physicians. These findings highlight the challenges facing academic centers for patients with resident primary care physicians. PMID- 24768968 TI - Ca-carboxymethyl xanthan gum mini-matrices: Swelling, erosion and their impact on drug release mechanism. AB - The effect of Ca(2+) ion concentration on swelling, erosion, and drug release mechanism of Ca(2+) ion cross-linked carboxymethyl xanthan gum (Ca-CMXG) matrices was investigated. By adding CaCl2 solution, carboxymethyl xanthan gum (CMXG) was converted into Ca-CMXG matrix, which was evaluated for swelling, erosion and drug release in different dissolution media. The amount of Ca(2+) ion alters the viscosity of gel layer formed around the matrices resulting in decreased water penetration into swollen layer. The changes in amount of Ca(2+) ion considerably influenced the swelling and erosion of the matrix leading to different drug release profiles. The simultaneous swelling and erosion of matrices that were controlled by the degree of cross-linking prejudiced the drug release mechanism. The release data fitted well into the Korsmeyer-Peppas equation and the combined effect of diffusion and erosion described the overall drug transport mechanism. PMID- 24768967 TI - Antitumor activity of Pleurotus ostreatus polysaccharide fractions on Ehrlich tumor and Sarcoma 180. AB - The medicinal properties of fungi of the genus Pleurotus have attracted great interest due to their therapeutic properties. Polysaccharides synthesized by Pleurotus, including the beta-glucans are considered the main responsible for its therapeutic properties. This study aimed to evaluate the efficacy of polysaccharidic fractions extracted from mycelial biomass of Pleurotus ostreatus DSM 1833 in inhibiting the development of Ehrlich Tumor (ET) and Sarcoma 180 (S 180). FC, FI and FII fractions provided 60.6, 76.5 and 73.6% of ET inhibition, respectively (mean value of about 70%) while FS, FIII-1 and FIII-2 showed no inhibition against ET. FII and FIII-2 resulted in 85.6 and 93.6% (mean value of about 90%) while FIII-1, FC and FS resulted in 54.1 and 0%, respectively, of S 180 inhibition. The yields of the fractions FS, FI, FII, FIII-1 and FIII-2 obtained from P. ostreatus mycelial biomass were 11.6, 1.3, 0.4, 0.65 and 0.35%, respectively. FII fraction (30mg/kg) apparently had no toxic effect on healthy animals, since no difference between the body weights of animals in substance control (SC) and negative control (NC) groups was observed. PMID- 24768969 TI - Naturally derived biofunctional nanofibrous scaffold for skin tissue regeneration. AB - Significant wound healing activity of Aloe vera (AV) and higher elastic strength of Silk fibroin (SF) along with mammalian cell compatibility makes AV and SF an attractive material for tissue engineering. The purpose of the present work was to combine their unique properties, with the advantage of electrospinning to prepare a hybrid transdermal biomaterial for dermal substitutes. The physico chemical characterization of the developed scaffold showed finer morphology expressing amino and esteric groups with improved hydrophilic properties and favorable tensile strain of 116% desirable for skin tissue engineering. Their biological response showed favorable fibroblast proliferation compared to control which almost increased linearly by (p<0.01) 34.68% on day 3, (p<0.01) 19.13% on day 6, and (p<0.001) 97.86% on day 9 with higher expression of CMFDA, collagen and F-actin proteins. The obtained results prove that the nanofibrous scaffold with synergistic property of AV and SF would be a potential biomaterial for skin tissue regeneration. PMID- 24768970 TI - Chitosan-coated electrospun PLA fibers for rapid mineralization of calcium phosphate. AB - In this work, hydroxyapatite (HA) mineralized on chitosan (CS)-coated poly(lactic acid) (PLA) nanofiber mat was prepared and compared in terms of mineralization characteristics. Significant calcium phosphate crystals formed on various concentrations of CS-coated PLA fiber mat with better uniformity after 2h of incubation in 10 times simulated body fluid (10* SBF). X-ray diffraction results further indicated that the composition of the deposited mineral was a mixture of dicalcium phosphate dehydrates and apatite. Chitosan, a cationic polysaccharide, can promote more nucleation and growth of calcium phosphate under conditions of 0.4% chitosan concentrations. These results indicated that HA-mineralized on CS coated PLA fiber mat can be prepared directly via simply using CS coating followed by SBF immersion, and the results also suggest that this composite can mimic structural, compositional, and biological functions of native bone and can serve as a good candidate for bone tissue engineering (BTE). PMID- 24768971 TI - Novel macroporous palladium cation crosslinked chitosan membranes for heterogeneous catalysis application. AB - A novel palladium supported on chitosan porous membrane heterogeneous catalyst has been prepared by freeze-drying of Pd(2+)-crosslinked chitosan gel solution. The prepared membrane catalyst has three-dimensional porous structure (porosity: >70%). The crosslinking effects of Pd(2+) to chitosan were good for the improvement of the mechanical properties and thermal stabilities. Pd(2+) cations have been shown not only as the crosslinker, but also as the catalytic active sites. The reductive palladium species of the recycled membrane catalysts was found in the nanometer scale (20-40nm). Excellent cross-coupling yields were achieved using as low as 0.12mol% palladium catalyst loading for the Heck-type reaction of aromatic halides with acrylates. The catalyst could be recycled six times without obvious decreased conversion. PMID- 24768972 TI - Evaluation of antioxidant and immuno-enhancing activities of Purslane polysaccharides in gastric cancer rats. AB - In the last three decades, numerous polysaccharides and polysaccharide-protein complexes have been isolated from plant or animal and used as a promising source of therapeutic agents for cancer. In this study, we examined the effects of Purslane polysaccharides (PPs) on the oxidative injury and immune status in N methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric cancer rats. PPs administration (200, 400 or 800mg/kg body weight) could not only increase the body weight, peripheral white blood cells (WBC) count, thymus and spleen indexes, but also remarkably promote splenocytes proliferation of gastric cancer rats. Furthermore, the production of serum cytokines in gastric cancer rats, such as interleukin-2 (IL-2), interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF alpha) was enhanced by PPs treatment. Besides, treatment with PPs was found to provide a dose-dependent protection against MNNG-induced oxidative injury by enhancing SOD, CAT, GSH-Px activities of gastric cancer rats. Taken together, we concluded that enhancement of antioxidants and immune response might be responsible for the anticancer effect of PPs in gastric cancer. PMID- 24768973 TI - Preparation, characterization and antibacterial activity of chitosan-g-poly acrylonitrile/silver nanocomposite. AB - Chitosan-grafted-poly acrylonitrile silver nanocomposites (Cs-g-PAN/Ag) were prepared via in-situ chemical reduction of Ag ions in graft copolymerization of acrylonitrile onto chitosan. Graft copolymerization process was provided by FTIR and gravimetric methods. UV spectra and TEM images show silver nanoparticles with average 15-20nm dispersed homogeneously in CS-g-PAN/Ag nanocomposite-ray and TGA evident the change in crystallography and thermal stability in consequence of presence Ag nanoparticles. Cs-g-PAN/Ag nanocomposite showed excellent antimicrobial performance towards bacteria such as Escherichia coli and Staphylococcus aureus. PMID- 24768975 TI - Developmental cardiotoxicity effects of four commonly used antiepileptic drugs in embryonic chick heart micromass culture and embryonic stem cell culture systems. AB - Antiepileptic drugs (AEDs) are commonly used drugs in pregnant women with epilepsy. Prenatal exposure to AEDs increases the risk of major or minor congenital malformation during embryonic development. The precise mode of action and intracellular mechanisms of these AEDs during embryonic development remains unclear. To determine relative teratogenic risk of AEDs, four AED drugs including valproic acid (VPA), phenytoin (PHT), phenobarbital (PB), and trimethadione (TMD) were tested using two in vitro systems (the embryonic chick heart micromass (MM) culture and the in vitro differentiating mouse embryonic stem cells into cardiomyocytes culture systems). Cardiomyocyte cultures (the heart MM and ES cell derived cardiomyocytes) were treated with or without different concentrations of PHT, PB, TMD (10-100 MUM), and VPA (100-2000 MUM). 5-Fluorouracil (5-FU) (1-10 MUM) and l-ascorbic acid (10-1000 MUM) were used as positive and negative controls. It was found that these four commonly used AEDs and 5-FU tested have the potential to inhibit embryonic heart cell differentiation (p<0.05) without inducing any cytotoxicity. VPA at higher concentrations (>=800 MUM), and 5-FU at all doses proved to be cytotoxic in the differentiating ES cell culture system. The results demonstrated in this study suggest that the use of these four commonly prescribed AEDs during pregnancy may have an effect on embryonic heart development, and may be associated with congenital cardiovascular defects. PMID- 24768974 TI - Manduca sexta proprophenoloxidase activating proteinase-3 (PAP3) stimulates melanization by activating proPAP3, proSPHs, and proPOs. AB - Melanization participates in various insect physiological processes including antimicrobial immune responses. Phenoloxidase (PO), a critical component of the enzyme system catalyzing melanin formation, is produced as an inactive precursor prophenoloxidase (proPO) and becomes active via specific proteolytic cleavage by proPO activating proteinase (PAP). In Manduca sexta, three PAPs can activate proPOs in the presence of two serine proteinase homologs (SPH1 and SPH2). While the hemolymph proteinases (HPs) that generate the active PAPs are known, it is unclear how the proSPHs (especially proSPH1) are activated. In this study, we isolated from plasma of bar-stage M. sexta larvae an Ile-Glu-Ala-Arg-p nitroanilide hydrolyzing enzyme that cleaved the proSPHs. This proteinase, PAP3, generated active SPH1 and SPH2, which function as cofactors for PAP3 in proPO activation. Cleavage of the purified recombinant proSPHs by PAP3 yielded 38 kDa bands similar in mobility to the SPHs formed in vivo. Surprisingly, PAP3 also can activate proPAP3 to stimulate melanization in a direct positive feedback loop. The enhanced proPO activation concurred with the cleavage activation of proHP6, proHP8, proPAP1, proPAP3, proSPH1, proSPH2, proPOs, but not proHP14 or proHP21. These results indicate that PAP3, like PAP1, is a key factor of the self reinforcing mechanism in the proPO activation system, which is linked to other immune responses in M. sexta. PMID- 24768976 TI - Polymeric nanomicelles for sustained delivery of anti-cancer drugs. AB - In the first section of this paper, the existing and emerging nanotechnology based cancer therapies--nanoparticles, drug conjugates, nanomicelles--are reviewed. In a second part, we present our original and unpublished findings on the sustained release of anti-cancer drugs such as paclitaxel, doxorubicin and camptothecin using block copolymer micelles [PEG-b-poly(dioxanone-co-methyl dioxanone)]. Copolymers with variable lengths of hydrophobic and hydrophilic blocks have been synthesized and successfully loaded with paclitaxel, doxorubicin and camptothecin anti-cancer drugs, with micelles size in the range 130-300 nm. Drug encapsulation efficiencies varied between 15% and 70% depending on drug and copolymer composition. The drug binding constants, which give a good insight into drug encapsulation and release, were evaluated from UV spectroscopy as we reported previously for anti-TB drugs. Through variation of the methyl dioxanone content of the copolymer, our systems can be tailored for sustained release of the different drugs. PMID- 24768977 TI - Population-based study on the effect of socioeconomic factors and race on management and outcomes of 35,535 inpatient ectopic pregnancies. AB - STUDY OBJECTIVE: To evaluate whether socioeconomic variables influence the management and outcomes of ectopic pregnancies. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Hospitals in the United States participating in the Health Care Cost and Utilization Project. PATIENTS: Women (n = 35 535) with a primary discharge diagnosis of ectopic pregnancy. INTERVENTIONS: Effect of socioeconomic factors and race/ethnicity on management and adverse outcomes of ectopic pregnancy. MEASUREMENTS AND MAIN RESULTS: During the 9-year study, 35 535 ectopic pregnancies were identified. The development of hemoperitoneum in 8706 patients (24.50%) was the most common complication. Asian race was the sociodemographic variable most predictive of hemoperitoneum (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.24-1.61; p < .01) and transfusion (OR, 1.62; 95% CI, 1.39-1.89; p < .01), and Medicare status was most influential on prolonged hospitalization (OR, 1.83; 95% CI, 1.36-2.47; p < .01). Major complications were not affected by socioeconomic factors. Laparotomy in 25 075 patients (70.6%) was the most common treatment option. Patients of Asian or Pacific Islander descent were least likely to be treated non-surgically (OR, 0.62; 95% CI, 0.51-0.76; p < .01), whereas Medicare recipients were most likely to be treated non-surgically (OR, 1.70; 95% CI, 1.32-2.18; p < .01). All non white groups were less likely to undergo a laparoscopic approach. CONCLUSION: Major complications from ectopic pregnancy are not influenced by socioeconomic variables; however, less serious complications and management approaches are persistently affected. PMID- 24768978 TI - Minilaparoscopic radical hysterectomy (mLPS-RH) vs laparoendoscopic single-site radical hysterectomy (LESS-RH) in early stage cervical cancer: a multicenter retrospective study. AB - STUDY OBJECTIVE: To compare the perioperative outcomes of laparoendoscopic single site radical hysterectomy (LESS-RH) and minilaparoscopic radical hysterectomy (mLPS-RH). DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: Seven institutions in Italy. PATIENTS: Forty-six patents with early cervical cancer (FIGO stage IA2-IB1/IIA1) were included in the study. Nineteen patients (41.3%) underwent LESS-RH, and 27 (58.7%) underwent mLPS-RH. Pelvic lymph node dissection was performed in all patients. INTERVENTIONS: In the LESS RH group, all surgical procedures were performed through a single umbilical multichannel port. In the mLPS-RH group, the procedure was completed using a 5-mm umbilical optical trocar and 3 additional 3-mm ancillary trocars, placed suprapubically and in the left and right lower abdominal regions. MEASUREMENTS AND MAIN RESULTS: There was no difference in clinicopathologic characteristics at the time of diagnosis between the LESS-RH and mLPS-RH groups. Median operative time was 270 minutes (range, 149-380 minutes) for LESS-RH, and was 180 minutes (range, 90-240 minutes) for mLPS-RH (p = .001). No further differences were detected between the 2 groups insofar as type of radical hysterectomy, number of lymph nodes removed, or perioperative outcomes. In the LESS-RH group, conversion to laparotomy was necessary in 1 patient (5.3%) because of external iliac vein injury, and in another patient, conversion to standard laparoscopy was required because of truncal obesity. In the mLPS-RH group, no conversions were observed; however, a repeat operation was performed to repair a ureteral injury. The percentage of patients discharged 1 day after surgery was significantly higher in the LESS-RH group (57.9%) compared with the mLPS-RH group (25.0%) (p = .03). After a median follow-up of 27 months (range, 9-73 months), only 1 patient, who had undergone mLPS-RH, experienced pelvic recurrence and died of the disease. CONCLUSIONS: Both LESS-RH and mLPS-RH are feasible ultra-minimally invasive approaches for performance of radical hysterectomy plus pelvic lymph node dissection. Further technical improvements are required to enable wider use of these techniques for more complex procedures. PMID- 24768979 TI - Conservative management of placenta accreta: hysteroscopic resection of retained tissues. AB - STUDY OBJECTIVE: To evaluate the feasibility and the results of hysteroscopic removal of tissue after conservative management of retained placenta accreta. DESIGN: Retrospective study (Canadian Task Force classification II-3). SETTING: Tertiary care university hospital. PATIENTS: Twelve consecutive patients with hysteroscopic resection of retained tissues after conservative management of placenta accreta. INTERVENTION: Hysteroscopic removal of retained placenta tissue using a 24F bipolar resectoscope. MEASUREMENTS AND MAIN RESULTS: Twelve patients with retained placenta tissue, complete in 2 and partial in 10, were included. Mean retained placenta size on magnetic resonance imaging was 54 mm (range, 13 110 mm). Complete removal was achieved in all but 1 patient who underwent a secondary hysterectomy after the first incomplete hysteroscopic resection. Complete evacuation of the uterus was completed after 1 procedure in 5 patients, after 2 procedures in 2 patients, and after 3 procedures in 4 patients. All but 2 patients had normal menstrual bleeding after hysteroscopy. Four pregnancies occurred in our series, resulting in 1 ectopic pregnancy, 1 miscarriage, and 2 deliveries. CONCLUSION: Hysteroscopic resection of retained placenta seems to be a safe and effective procedure to prevent major complications and to preserve fertility in cases of conservative management of placenta accreta. PMID- 24768980 TI - Post-hysterectomy dyspareunia. PMID- 24768981 TI - A randomized, single blind, placebo-controlled trial for the pain reduction during the outpatient hysteroscopy after ketoprofen or intravaginal misoprostol. AB - STUDY OBJECTIVE: To assess the efficacy of ketoprofen vs intravaginal misoprostol for pain relief during outpatient hysteroscopy. DESIGN: Prospective, randomized, single-blind, placebo-controlled clinical trial (Canadian Task Force classification I). SETTING: Tertiary medical center. PATIENTS: One hundred fifty women referred for hysteroscopy between January and October 2013. INTERVENTIONS: Women were randomized to receive vaginal misoprostol, 400 MUg, with 100 mL of 5% intravenous glucose (misoprostol arm); intravenous ketoprofen, 50 mg/mL, in 100 mL 5% glucose with intravaginal placebo (ketoprofen arm); or vaginal placebo tablets, 100 mL 5% intravenous glucose (placebo arm) before outpatient hysteroscopy. MEASUREMENTS AND MAIN RESULTS: A visual analog scale (VAS) was used for 1-dimensional pain assessment. Patients were asked to mark a VAS score before, during, and at 5 and 15 minutes after the procedure. Median VAS scores during and directly after the anesthesia-free hysteroscopy were significantly lower in the misoprostol group than in the ketoprofen (p = .02) or placebo (p = .006) groups. There were no statistical differences between the 3 arms in median VAS score assessed at 15 minutes after the procedure (p = .16). There were no differences in procedure time between groups (p = .16). CONCLUSION: When administrated 4 hours before the procedure, 400 MUg vaginal misoprostol seems to reduce the pain during and immediately after hysteroscopy. The effect does not depend on patient age, hormone status, parity, or type of outpatient hysteroscopy (operative or diagnostic). PMID- 24768982 TI - Laparoscopically-assisted, hysteroscopic removal of an interstitial pregnancy with a fertility-preserving technique. AB - Described is a novel surgical management of an unruptured interstitial pregnancy with preservation of the ipsilateral fallopian tube and uterine cornua. The patient was a 34-year-old woman, gravida 3, para 1, with an unruptured left interstitial pregnancy at 9 weeks' gestation, who desired preservation of fertility. The ectopic pregnancy was entirely removed via laparoscopically assisted hysteroscopy with a fertility-preserving surgical technique, with minimal blood loss, preservation of reproductive organs, restoration of anatomy, a patent ipsilateral fallopian tube, and expedient return to normal reproductive function. After the procedure, serial human chorionic gonadotropin levels were obtained until they were <5 mIU/mL. A hysterosalpingogram obtained 2 months after the procedure showed normal uterine and fallopian tube contour and bilateral tubal patency. We conclude that this laparoscopically assisted hysteroscopic technique is a safe and efficient fertility-preserving approach to management of an unruptured interstitial pregnancy. PMID- 24768983 TI - Diamond detector for alpha-particle spectrometry. AB - An artificially grown high purity diamond was used as a detector for alpha particle spectrometry. Diamond detectors can match the performance of silicon detectors employed in standard continuous air monitoring systems. Its radiation hardness and electronic properties make them ideal to work under extreme condition such as high temperature and ambient lights. A 50 MUm thickness single crystal diamond detector has been compared with a 300 MUm passivated implanted planar silicon detector, under ambient conditions. PMID- 24768984 TI - Minocycline, an antibiotic with inhibitory effect on microglial activation, attenuates the maintenance and reinstatement of methamphetamine-seeking behavior in rat. AB - Methamphetamine (METH) is a major criminal justice and public health problem. Repeated use of METH causes dependence in humans and there are currently no particular pharmacological treatments for METH addiction. Glial cell activation is linked with METH abuse and METH administration causes activation of these cells in many areas of the brain. Many studies have demonstrated that glial cell modulators can modulate drug abuse effects. In this study, we examined the effect of the putative microglial inhibitor, minocycline on maintenance and prime induced reinstatement of METH seeking behavior using the conditioned place preference (CPP) paradigm. CPP induced with METH (1 mg/kg, i.p. for 3 days) lasted for 11 days after cessation of METH treatment and priming dose of METH (0.5 mg/kg, i.p.) reinstated the extinguished METH-induced CPP. Daily treatment of minocycline (40 mg/kg, i.p.) followed by establishment of CPP blocked the maintenance of METH-induced CPP and also could attenuate priming-induced reinstatement. Furthermore, daily bilateral intra-accumbal injection of minocycline (10 and 20 MUg/0.5 MUl saline), during extinction period blocked the maintenance of METH CPP but just the highest dose of that could attenuate priming induced reinstatement. We showed that minocycline administration during extinction period could facilitate extinction and maybe abolish the ability of drug-related cues evoke reinstatement, suggesting that minocycline might be considered as a promising therapeutic agent in preventing relapse in METH dependent individuals. PMID- 24768985 TI - Distinct functional connectivity of limbic network in the washing type obsessive compulsive disorder. AB - Neurobiological models of obsessive-compulsive disorder (OCD) emphasize disturbances of the corticostriatal circuit, but it remains unclear as to how these complex network dysfunctions correspond to heterogeneous OCD phenotypes. We aimed to investigate corticostriatal functional connectivity alterations distinct to OCD characterized predominantly by contamination/washing symptoms. Functional connectivity strengths of the striatal seed regions with remaining brain regions during the resting condition and the contamination symptom provocation condition were compared among 13 OCD patients with predominant contamination/washing symptoms (CON), 13 OCD patients without these symptoms (NCON), and 18 healthy controls. The CON group showed distinctively altered functional connectivity between the ventral striatum and the insula during both the resting and symptom provoking conditions. Also, the connectivity strength between the ventral striatum and the insula significantly correlated with contamination/washing symptom severity. As common connectivity alterations of the whole OCD subjects, corticostriatal circuits involving the orbitofrontal and temporal cortices were again confirmed. To our knowledge, this is the first study that examined specific abnormalities in functional connectivity of contamination/washing symptom dimension OCD. The findings suggest limbic network dysfunctions to play a pivotal role in contamination/washing symptoms, possibly associated with emotionally salient error awareness. Our study sample allowed us to evaluate the corticostriatal network dysfunction underlying the contamination/washing symptom dimension, which leaves other major symptom dimensions to be explored in the future. PMID- 24768987 TI - Ultrasonic force microscopy on poly(vinyl alcohol)/SrTiO(3) nano-perovskites hybrid films. AB - Atomic Force Microscopy (AFM) and Ultrasonic Force Microscopy (UFM) have been applied to the characterization of composite samples formed by SrTiO3 (STO) nanoparticles (NPs) and polyvinyl alcohol (PVA). The morphological features of the STO NPs were much better resolved using UFM than contact-mode AFM topography. For high STO concentrations the individual STO NPs formed nanoclusters, which gathered in microaggregates. The STO aggregates, covered by PVA, exhibited no AFM frictional contrast, but were clearly distinguished from the PVA matrix using UFM. Similar aggregation was observed for NPs in the composite samples and for NPs deposited on top of a flat silicon substrate from milliQ water solution in the absence of polymer. In the hybrid films, most STO nanoparticles typically presented a lower UFM contrast than the PVA matrix, even though stiffer sample regions such as STO should give rise to a higher UFM contrast. STO NPs with intermediate contrast were characterized by an UFM halo of lower contrast at the PVA/STO interface. The results may be explained by considering that ultrasound is effectively damped on the nanometer scale at PVA/STO interfaces. According to our data, the nanoscale ultrasonic response at the PVA/STO interface plays a fundamental role in the UFM image contrast. PMID- 24768986 TI - International typing study of Clostridium difficile. AB - We report the results of an international Clostridium difficile typing study to cross reference strain designations for seven typing methodologies and facilitate inter-laboratory communication. Four genotypic and three phenotypic methods were used to type 100 isolates and compare the results to 39 PCR ribotypes identified among the collection. PMID- 24768988 TI - The added value of the 90-day repeated dose oral toxicity test for industrial chemicals with a low (sub)acute toxicity profile in a high quality dataset. AB - A survey conducted on the EU Notification of New Substances (NONS) database suggested that for industrial chemicals with a profile of low toxicity in (sub)acute toxicity tests there is little added value to the conduct of the 90 day repeated dose study. Avoiding unnecessary animal testing is a central aim of the EU REACH chemicals legislation; therefore we sought to verify the profile using additional data. The OECD's eChemPortal was searched for substances that had both a 28-day and a 90-day study and their robust study summaries were then examined from the ECHA CHEM database. Out of 182 substances with high quality 28 day and 90-day study results, only 18 reported no toxicity of any kind in the (sub)acute tests. However, for 16 of these there were also no reported signs of toxicity at or close to the limit dose (1000mg/kgbw/d) in the 90-day study. Restricting the 'low (sub)acute toxicity in a high quality dataset' profile to general industrial chemicals of no known biological activity, whilst allowing irritant substances, increases the data set and improves the prediction to 95% (20 substances out of 21 substances). The low toxicity profile appears to be of low prevalence within industrial chemicals (10-15%), nevertheless, avoidance of the conduct of a redundant 90-day study for this proportion of the remaining REACH phase-in substances would avoid the use of nearly 50,000 animals and save industry 50million Euros, with no impact on the assessment of human health. PMID- 24768989 TI - Airborne asbestos exposures associated with gasket and packing replacement: a simulation study and meta-analysis. AB - Exposures to airborne asbestos during the removal and installation of internal gaskets and packing associated with a valve overhaul were characterized and compared to published data according to different variables (e.g., product, equipment, task, tool, setting, duration). Personal breathing zone and area samples were collected during twelve events simulating gasket and packing replacement, clean-up and clothing handling. These samples were analyzed using PCM and TEM methods and PCM-equivalent (PCME) airborne asbestos concentrations were calculated. A meta-analysis was performed to compare these data with airborne asbestos concentrations measured in other studies involving gaskets and packing. Short-term mechanic and assistant airborne asbestos concentrations during valve work averaged 0.013f/cc and 0.008f/cc (PCME), respectively. Area samples averaged 0.008f/cc, 0.005f/cc, and 0.003f/cc (PCME) for center, bystander, and remote background, respectively. Assuming a tradesman conservatively performs 1-3 gasket and/or packing replacements daily, an average 8-h TWA was estimated to be 0.002-0.010f/cc (PCME). Combining these results in a meta-analysis of the published exposure data showed that the majority of airborne asbestos exposures during work with gaskets and packing fall within a consistent and low range. Significant differences in airborne concentrations were observed between power versus manual tools and removal versus installation tasks. Airborne asbestos concentrations resulting from gasket and packing work during a valve overhaul are consistent with historical exposure data on replacement of asbestos containing gasket and packing materials involving multiple variables and, in nearly all plausible scenarios, result in average airborne asbestos concentrations below contemporaneous occupational exposure limits for asbestos. PMID- 24768990 TI - Ecological risk assessment of the presence of pharmaceutical residues in a French national water survey. AB - In this study, we focused on the list of 33 chemicals that was established through a French national prioritisation strategy. Assessing the potential risks to the environment was a step-wise procedure: (i) we determined the Predicted Environmental Concentration (PEC) of all molecules measured in the national survey based on the highest recommended dose used, (ii) we used the Measured Environmental Concentration (MEC) and the Predicted No-Effect Concentration (PNEC) to establish the Risk Quotient (RQ) based on either a PEC/PNEC (estimated risk) or MEC/PNEC (real risk) ratio. The risk assessment was performed using a binary ecological classification suggesting that appreciable risk is likely (RQ?1). Of the 15 molecules quantified in the survey, 12 had a PEC higher than the action limit value of 0.01MUg/L. According to the EU Guideline, environmental risk was estimated as likely for the following five compounds: acetaminophen (RQ=1.6), ibuprofen (RQ=600), diclofenac (RQ=15), oxazepam (RQ=2.1) and carbamazepine (RQ=3.2). Only ibuprofen was identified as posing real environmental risk based on its MEC (RQ=1.9). PMID- 24768991 TI - ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: implications for Parkinson's disease. AB - Mitochondrial transcription factor A (TFAM) regulates mitochondrial biogenesis, which is downregulated by extracellular signal-regulated protein kinases (ERK1/2) in cells treated chronically with the complex I inhibitor 1-methyl-4 phenylpyridinium (MPP+). We utilized mass spectrometry to identify ERK1/2 dependent TFAM phosphorylation sites. Mutation of TFAM at serine 177 to mimic phosphorylation recapitulated the effects of MPP+ in decreasing the binding of TFAM to the light strand promoter, suppressing mitochondrial transcription. Mutant TFAM was unable to affect respiratory function or rescue the effects of MPP+ on respiratory complexes. These data disclose a novel mechanism by which ERK1/2 regulates mitochondrial function through direct phosphorylation of TFAM. PMID- 24768992 TI - Routine pathology evaluation of hydrocele and spermatocele specimens is associated with significant costs and no identifiable benefit. AB - PURPOSE: Hydrocelectomy and spermatocelectomy are routine scrotal surgeries. A significant number of the surgical specimens are sent for pathology analysis. However, to our knowledge no study has been done to examine outcomes and necessity, which results in significant potentially unnecessary costs to the patient and the health care system. We evaluated outcomes and surgical pathology analysis of hydroceles and spermatoceles. MATERIALS AND METHODS: We performed a retrospective, single institution chart review of all patients who underwent initial surgery for hydrocele or spermatocele between January 2000 and August 2013. We determined the number of cases in which a surgical specimen was sent for pathology examination. The cost for each specimen was estimated at the department of pathology. RESULTS: A total of 264 routine scrotal cases were performed during the 14-year period. Surgical specimens were sent for pathology analysis in 102 hydrocelectomy cases (51%) and in 57 spermatocelectomy cases (90%). No pathology specimen showed any indication of malignancy. The estimated direct total cost of pathology analysis was $49,449 in this cohort. CONCLUSIONS: No malignancy was detected in 159 hydrocele and spermatocele specimens during the 14 study years, suggesting that the pathology analysis is of little clinical benefit. Forgoing surgical pathology analysis of these specimens would result in significant cost savings to the patient and the health care system. PMID- 24768993 TI - A bacteriophage capsid protein provides a general amyloid interaction motif (GAIM) that binds and remodels misfolded protein assemblies. AB - Misfolded protein aggregates, characterized by a canonical amyloid fold, play a central role in the pathobiology of neurodegenerative diseases. Agents that bind and sequester neurotoxic intermediates of amyloid assembly, inhibit the assembly or promote the destabilization of such protein aggregates are in clinical testing. Here, we show that the gene 3 protein (g3p) of filamentous bacteriophage mediates potent generic binding to the amyloid fold. We have characterized the amyloid binding and conformational remodeling activities using an array of techniques, including X-ray fiber diffraction and NMR. The mechanism for g3p binding with amyloid appears to reflect its physiological role during infection of Escherichia coli, which is dependent on temperature-sensitive interdomain unfolding and cis-trans prolyl isomerization of g3p. In addition, a natural receptor for g3p, TolA-C, competitively interferes with Abeta binding to g3p. NMR studies show that g3p binding to Abeta fibers is predominantly through middle and C-terminal residues of the Abeta subunit, indicating beta strand-g3p interactions. A recombinant bivalent g3p molecule, an immunoglobulin Fc (Ig) fusion of the two N-terminal g3p domains, (1) potently binds Abeta fibers (fAbeta) (KD=9.4nM); (2); blocks fAbeta assembly (IC50~50nM) and (3) dissociates fAbeta (EC50=40-100nM). The binding of g3p to misfolded protein assemblies is generic, and amyloid-targeted activities can be demonstrated using other misfolded protein systems. Taken together, our studies show that g3p(N1N2) acts as a general amyloid interaction motif. PMID- 24768994 TI - The Schizosaccharomyces pombe Hikeshi/Opi10 protein has similar biochemical functions to its human homolog but acts in different physiological contexts. AB - Human Hikeshi (HsHikeshi) is a nuclear import carrier for Hsp70s and is required for cell survival after heat shock. The Hikeshi homolog in Schizosaccharomyces pombe (SpHikeshi/Opi10) localizes to the nuclear rim, interacts with the Hsp70 homolog Ssa2, and mediates its nuclear import in a reconstituted mammalian nuclear transport system. However, SpHikeshi/Opi10 is not required for heat stress response and survival after heat stress. Instead, SpHikeshi/Opi10 is required for the normal expression of stress response genes under optimal conditions and for cell growth during glucose deprivation. Here, the functions of SpHikeshi/Opi10 are discussed and compared to the functions of HsHikeshi. PMID- 24768995 TI - Tumour-suppressive microRNA-224 inhibits cancer cell migration and invasion via targeting oncogenic TPD52 in prostate cancer. AB - Our recent study of the microRNA expression signature of prostate cancer (PCa) revealed that microRNA-224 (miR-224) is significantly downregulated in PCa tissues. Here, we found that restoration of miR-224 significantly inhibits PCa cell migration and invasion. Additionally, we found that oncogenic TPD52 is a direct target of miR-224 regulation. Silencing of the TPD52 gene significantly inhibits cancer cell migration and invasion. Moreover, TPD52 expression is upregulated in cancer tissues and negatively correlates with miR-224 expression. We conclude that loss of tumour-suppressive miR-224 enhances cancer cell migration and invasion in PCa through direct regulation of oncogenic TPD52. PMID- 24768996 TI - Facile and high-yield synthesis of N-(4-diethylamino)benzyl-4-[11C]methoxy-N-(p tolyl)benzenesulfonamide as a new potential PET selective CB2 radioligand. AB - The reference standard N-(4-diethylamino)benzyl-4-methoxy-N-(p tolyl)benzenesulfonamide (3c) (CB2, Ki=0.5 nM; CB1, Ki=1297 nM; selectivity CB1/CB2=2594) and its corresponding precursor N-(4-diethylamino)benzyl-4-hydroxy N-(p-tolyl)benzenesulfonamide (3d) were synthesized from 4 (diethylamino)benzaldehyde and p-toluidine in 3 steps with 75-84% overall chemical yield. The target tracer N-(4-diethylamino)benzyl-4-[(11)C]methoxy-N-(p tolyl)benzenesulfonamide ([(11)C]3c) was synthesized from the phenol hydroxyl precursor by O-[(11)C]-methylation with [(11)C]CH3OTf, followed by HPLC combined with SPE purification in 40-50% decay corrected radiochemical yields with 370-740 GBq/MUmol specific activity at the end of bombardment (EOB). PMID- 24768998 TI - Inflammatory responses in the Japanese pufferfish (Takifugu rubripes) head kidney cells stimulated with an inflammasome-inducing agent, nigericin. AB - A cytosolic receptor complex called inflammasome is responsible for mounting inflammatory response by releasing pro-inflammatory cytokines, interleukin (IL) 1beta and IL-18. However, inflammatory cascades mediated by the inflammasome are unknown in a lower vertebrate like fish. Therefore, in an in vitro experiment, in order to obtain a preliminary information, we conducted transcriptomic analysis of 18 cytokines including pro-inflammatory cytokines in the Japanese pufferfish (Takifugu rubripes) head kidney (HK) cells stimulated with an inflammasome inducing agent, nigericin, and a combination of nigericin and LPS by a multiplex RT-PCR assay (GenomeLab Genetic Analysis System, GeXPS; Beckman Coulter Inc.). Furthermore, expression of IL-1beta, IL-6, IL-18, nuclear factor (NF)-kappaB, nucleotide-binding oligomerization domain 2 (NOD2) and NOD-like receptor X1 (NLRX1) genes was examined in HK cells by a quantitative real-time PCR. Additionally, to confirm functionality of activated inflammatory immunity, we also assessed phagocytic activity, superoxide anion production (NBT assay) and lysozyme activity in the nigericin-stimulated HK cells. An increased gene expression of pro-inflammatory cytokines (IL-1beta and IL-18), NF-kappaB and NOD2 was recorded in nigericin and combined nigericin+LPS- stimulated HK cells. Enhanced cellular (phagocytic activity and NBT assay) and humoral (lysozyme activity) immune parameters in the stimulated cells confirmed induction of inflammatory response. Results suggested probable activation of inflammasome components for processing of the inflammatory cytokines in the Japanese pufferfish. PMID- 24768997 TI - The Drosophila tankyrase regulates Wg signaling depending on the concentration of Daxin. AB - The canonical Wnt signaling pathway plays critical roles during development and homeostasis. Dysregulation of this pathway can lead to many human diseases, including cancers. A key process in this pathway consists of regulation of beta catenin concentration through an Axin-recruited destruction complex. Previous studies have demonstrated a role for tankyrase (TNKS), a protein with poly(ADP ribose) polymerase, in the regulation of Axin levels in human cells. However, the role of TNKS in development is still unclear. Here, we have generated a Drosophila tankyrase (DTNKS) mutant and provided compelling evidence that DTNKS is involved in the degradation of Drosophila Axin (Daxin). We show that Daxin physically interacts with DTNKS, and its protein levels are elevated in the absence of DTNKS in the eye discs. In S2 cells, DTNKS suppressed the levels of Daxin. Surprisingly, we found that Daxin in turn down-regulated DTNKS protein level. In vivo study showed that DTNKS regulated Wg signaling and wing patterning at a high Daxin protein level, but not at a normal level. Taken together, our findings identified a conserved role of DTNKS in regulating Daxin levels, and thereby Wg/Wnt signaling during development. PMID- 24768999 TI - Molecular cloning and expression analysis of Pleurodeles waltl complement component C3 under normal physiological conditions and environmental stresses. AB - C3 is a component of the complement system that plays a central role in immunity, development and tissue regeneration. In this study, we isolated the C3 cDNA of the Iberian ribbed newt Pleurodeles waltl. This cDNA encodes a 1637 amino acid protein with an estimated molecular mass of 212.5 kDa. The deduced amino acid sequence showed that P. waltl C3 contains all the conserved domains known to be critical for C3 function. Quantitative real-time PCR (qRT-PCR) demonstrated that under normal physiological conditions, P. waltl C3 mRNA is expressed early during development because it is likely required for neurulation. Then, its expression increased as the immune system developed. In adults, the liver is the richest source of C3, though other tissues can also contribute. Further analysis of C3 expression demonstrated that C3 transcription increased when P. waltl larvae were exposed to pH or temperature stress, suggesting that environmental modifications might affect this animal's defenses against pathogens. PMID- 24769001 TI - Diverging frequency-modulated 50-kHz vocalization, locomotor activity and conditioned place preference effects in rats given repeated amphetamine treatment. AB - Behavioral sensitization and tolerance to repetitive exposure to addictive drugs are commonly used for the assessment of the early stages of the drug dependence progress in animals. The orchestra of tools for studying the progress of drug dependence in laboratory rodents has been considerably enriched in the 1980s by the introduction of ultrasonic vocalization (USV) detection and characterization. However, the relationship between the results of this technology and those of traditional behavioral tests is not clear. We attempted to elucidate some of the respective ambiguities by comparing the effects of an intermittent amphetamine treatment, which was aimed both at the induction of sensitization and tolerance to this drug and at testing the persistence of these effects, on the locomotor activity and 50-kHz USV responses to both the drug and the context of drug exposure in adult male rats showing diverging susceptibility for sensitization to amphetamine. Categorization of the rats into low and high responders/callers based on sensitization of their frequency-modulated 50-kHz USV responsiveness showed some correspondence with conditioned place preference effects, but not with responses to amphetamine. The study showed distinct changes in the rate and latency of the frequency-modulated 50-kHz USV responses to repetitive amphetamine treatment, which were reminiscent of classical behavioral signs of sensitization and tolerance. These results show the utility of the appetitive USV for monitoring of early phases of complex processes leading to drug dependence. However, USV, locomotor activity and conditioned place preference seem to reflect different aspects of these phenomena. PMID- 24769000 TI - Mahogunin ring finger 1 suppresses misfolded polyglutamine aggregation and cytotoxicity. AB - Polyglutamine diseases are a family of inherited neurodegenerative diseases caused by the expansion of CAG repeats within the coding region of target genes. Still the mechanism(s) by which polyglutamine proteins are ubiquitinated and degraded remains obscure. Here, for the first time, we demonstrate that Mahogunin 21 ring finger 1 E3 ubiquitin protein ligase is depleted in cells that express expanded-polyglutamine proteins. MGRN1 co-immunoprecipitates with expanded polyglutamine huntingtin and ataxin-3 proteins. Furthermore, we show that MGRN1 is predominantly colocalized and recruits with polyglutamine aggregates in both cellular and transgenic mouse models. Finally, we demonstrate that the partial depletion of MGRN1 increases the rate of aggregate formation and cell death, whereas the overexpression of MGRN1 reduces the frequency of aggregate formation and provides cytoprotection against polyglutamine-induced proteotoxicity. These observations suggest that stimulating the activity of MGRN1 ubiquitin ligase might be a potential therapeutic target to eliminate the cytotoxic threat in polyglutamine diseases. PMID- 24769002 TI - Neurodegenerative changes are prevented by Erythropoietin in the pmn model of motoneuron degeneration. AB - Motoneuron diseases are fatal neurodegenerative disorders characterized by a progressive loss of motoneurons, muscle weakness and premature death. The progressive motor neuronopathy (pmn) mutant mouse has been considered a good model for the autosomal recessive childhood form of spinal muscular atrophy (SMA). Here, we investigated the therapeutic potential of Erythropoietin (Epo) on this mutant mouse. Symptomatic or pre-symptomatic treatment with Epo significantly prolongs lifespan by 84.6% or 87.2% respectively. Epo preserves muscle strength and significantly attenuates behavioural motor deficits of mutant pmn mice. Histological and metabolic changes in the spinal cord evaluated by immunohistochemistry, western blot, and high-resolution (1)H-NMR spectroscopy were also greatly prevented by Epo-treatment. Our results illustrate the efficacy of Epo in improving quality of life of mutant pmn mice and open novel therapeutic pathways for motoneuron diseases. PMID- 24769003 TI - Measurement of landing mosquito density on humans. AB - In traditional vector surveillance systems, adult mosquito density and the rate of mosquito-human host contact are estimated from the mosquito numbers captured in mechanical traps. But the design of the traps, their placement in the habitat and operating time, microclimate, and other environmental factors bias mosquito responses such that trapped mosquito numbers may be at variance with the numbers actually making human contact. As an alternative to mechanical traps, direct measurement of landing mosquito density enables real-time estimation of the mosquito-human-host-contact parameter. Based on this paradigm, we studied methods to measure mosquito landing responses to a human host. Our results showed: (a) an 18% difference (P<0.0001) in the mean number of female Aedes albopictus (Skuse) making initial contact with the skin (9.11+/-0.74min(-1)) compared with the number remaining on the skin for 5s (7.42+/-0.69min(-1)); (b) an increase (P<0.05) in the mean per minute (min(-1)) landing responses of Culex nigripalpus Theobald and Cx. quinquefasciatus Say with increased sampling time; (c) no difference (P>0.55) in the average number of Ae. albopictus landing on the arm (8.6+/-1.6min(-1)) compared with the leg (9.2+/-2.5min(-1)) of the same human subject; (d) differences among day-to-day landing patterns for the mosquito species we studied but measurable periodicity (P<0.05) in each case when daily patterns were averaged for four or more diel periods; and (e) an effect on landing mosquito density from air temperature (P<0.0001) for Ae. albopictus and Cx. nigripalpus and dew point temperature (P<0.0001) for Cx. quinquefasciatus. Results from this study were used to develop a procedure for safely and accurately measuring mosquito landing density on a human subject. PMID- 24769004 TI - Maternal sleep deprivation inhibits hippocampal neurogenesis associated with inflammatory response in young offspring rats. AB - Although sleep complaints are very common among pregnant women, the potential adverse effects of sleep disturbance on the offspring are not well studied. Growing evidence suggests that maternal stress can induce an inflammatory environment on the fetal development. But people are not sure about the consequences of prenatal stress such as the inflammatory responses induced by maternal sleep deprivation (MSD). In the present study, we investigated the effects of MSD on long-term behavioral and cognitive consequences in offspring and its underlying inflammatory response pathway. The pregnant Wistar rats received prolonged sleep deprivation (72h) on gestational day (GD) 4, 9, and 18, respectively. The post-natal day (PND) 21 offspring showed impaired hippocampus dependent spatial learning and memory in the Morris Water Maze task and anhedonia in sucrose preference experiment. Quantification of BrdU(+) and DCX(+) cells revealed a significant decrease in hippocampus neurogenesis in prepuberty offspring, especially for the late MSD (GD 18) group. Real-time RT-PCR showed that after MSD, the expression of pro-inflammatory cytokines (IL-1beta, IL-6 and TNFalpha) increased in the hippocampus of offspring on PND 1, 7, 14 and 21, whereas anti-inflammatory cytokine IL-10 reduced at the same time. Immunofluorescence found that the cells of activated microglia were higher in the brains of MSD offspring. Taken together, these results suggested that the MSD induced inflammatory response is an important factor for neurogenesis impairment and neurobehavioral outcomes in prepuberty offspring. PMID- 24769005 TI - Conformational changes induced by detergents during the refolding of chemically denatured cysteine protease ppEhCP-B9 from Entamoeba histolytica. AB - EhCP-B9, a cysteine protease (CP) involved in Entamoeba histolytica virulence, is a potential target for disease diagnosis and drug design. After purification from inclusion bodies produced in Escherichia coli, the recombinant EhCP-B9 precursor (ppEhCP-B9) can be refolded using detergents as artificial chaperones. However, the conformational changes that occur during ppEhCP-B9 refolding remain unknown. Here, we comprehensively describe conformational changes of ppEhCP-B9 that are induced by various chemical detergents acting as chaperones, including non-ionic, zwitterionic, cationic and anionic surfactants. We monitored the effect of detergent concentration and incubation time on the secondary and tertiary structures of ppEhCP-B9 using fluorescence and circular dichroism (CD) spectroscopy. In the presence of non-ionic and zwitterionic detergents, ppEhCP-B9 adopted a beta-enriched structure (ppEhCP-B9(beta1)) without proteolytic activity at all detergent concentrations and incubation times evaluated. ppEhCP-B9 also exhibits a beta-rich structure in low concentrations of ionic detergents, but at concentrations above the critical micelle concentration (CMC), the protein acquires an alpha+beta structure, similar to that of papain but without proteolytic activity (ppEhCP-B9(alpha+beta1)). Interestingly, only within a narrow range of experimental conditions in which SDS concentrations were below the CMC, ppEhCP-B9 refolded into a beta-sheet rich structure (ppEhCP-B9(beta2)) that slowly transforms into a different type of alpha+beta conformation that exhibited proteolytic activity (ppEhCP-B9(alpha+beta2)) suggesting that enzymatic activity is gained as slow transformation occurs. PMID- 24769006 TI - Potent inhibitory effect of alpha-viniferin on human cytochrome P450. AB - alpha-Viniferin isolated from Caragana chamlagu is a trimer of resveratrol, and has several biological activities, which include anti-inflammatory, anti-oxidant, anti-arthritis, and anti-tumor activities. Herb-drug interactions are the source of the most harmful complications in patients coadministered herbal and modern medicines, and are caused by modulation of the activities of drug metabolizing enzymes. Here, the authors investigated the inhibitory effects of alpha-viniferin on the activities of 9 human cytochrome P450 (CYP) isoforms using a cocktail of probe substrates and LC-MS/MS in pooled human liver microsomes (HLMs). alpha Viniferin strongly inhibited 7 of the 9 CYP isoforms (except CYP2A6 and CYP2E1). Furthermore, alpha-viniferin strongly inhibited CYP2C19-mediated omeprazole 5 hydroxylation and CYP3A4-catalyzed midazolam 1-hydroxylation with IC50 values of 0.93 and 1.2 MUM, respectively. alpha-Viniferin strongly inhibited the activities of these two CYPs dose dependently, but not time-dependently. Lineweaver-Burk plots and secondary plots indicated a typical pattern of mix-mode inhibition for CYP2C19 and 3A4. This is the first investigation conducted on the inhibitory effect of alpha-viniferin on CYP2C19 and 3A4 in HLMs to predict a potential herb drug interaction. PMID- 24769007 TI - Exposure of mice to benzo(a)pyrene impairs endometrial receptivity and reduces the number of implantation sites during early pregnancy. AB - Benzo(a)pyrene (BaP) is a ubiquitous environmental pollutant. Studies have demonstrated it to be an endocrine-disrupting chemical that can cause adverse effects on the female reproductive system. However, the effect of BaP on early pregnancy has not been reported. We investigated the effect of BaP on endometrial receptivity and embryo implantation. Pregnant mice were dosed with BaP at 0.2, 2 and 20 mg/kg/day from day 1 (D1) to day 5 (D5) of gestation. Exposure to BaP impaired the morphology of the endometrium and decreased the number of implantation sites (p0.2=0.006, p2=0.167, p20=0.003). Levels of estrodiol (p<0.001, for three treatment group compare with control group) and progesterone 4 in plasma were elevated in BaP-treatment groups (p0.2<0.001, p2<0.001, p20=0.032). Expression of estrogen receptor-alpha was up-regulated (p0.2=0.002, p2=0.131, p20=0.024) whereas expression of the progesterone receptor was down regulated (p0.2<0.001, p2=0.064, p20=0.021). Levels of receptivity-related genes HoxA10 (p0.2<0.001, p2=0.135, p20<0.001) and E-cadherin (p0.2=0.002, p2=0.624, p20=0.137) were changed by BaP. These results revealed that BaP can disrupt the balance of estrogen and progesterone, influence expression of their receptors and downstream related genes, lead to changes in endometrium receptivity, and reduce of the number of implantation sites. PMID- 24769008 TI - Nicotine, an alpha7 nAChR agonist, reduces lipopolysaccharide-induced inflammatory responses and protects fetuses in pregnant rats. AB - OBJECTIVE: The objective of the study was to examine the effects of nicotine, an alpha7 nicotinic acetylcholine receptor agonist, on lipopolysaccharide (LPS) induced inflammatory responses in rats during pregnancy. STUDY DESIGN: Pregnant Sprague Dawley rats were randomly divided into groups (n = 6 rats/group): group 1 rats each received a single intraperitoneal injection of LPS (25 MUg/kg) on gestation day 16; group 2 rats were first pretreated with nicotine (1 mg/kg per day, subcutaneously) on gestation days 14 and 15 and then were treated with single injections of LPS on gestational day 16; group 3 rats were treated with the vehicle (saline) used for groups 2 and 3 (controls). Maternal blood was collected at 6 hours and 24 hours after LPS and vehicle treatments and assayed for tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6), and interleukin-10 (IL-10). In addition, the number of live pups and pup weights were obtained at the time of delivery. RESULTS: LPS treatment significantly (P < .001) elevates maternal blood levels of TNF-alpha and IL-6 but not IL-10 (P > .05). Nicotine treatment significantly reduces LPS-induced TNF-alpha and IL-6 concentrations (P < .001) but does not change (P > .05) IL-10 levels. The number of live pups in the LPS group are significantly lower (P < .001) than the vehicle treated controls, and nicotine treatment significantly (P < .011) reverses this change. Similarly, fetal weights are lower following LPS (P < .016) and higher (P < .024) in the group treated with nicotine plus LPS. CONCLUSION: Nicotine reduces the LPS induced inflammatory responses and rescues the fetus in rats during pregnancy. Thus, nicotine exerts dramatic antiinflammatory effects. These observations have important implications for control of inflammatory responses during pregnancy. PMID- 24769009 TI - The effectiveness of multifetal pregnancy reduction in trichorionic triplet gestation. AB - OBJECTIVE: The objective of the study was to assess in trichorionic triplet pregnancies the effectiveness of elective reduction to twins. STUDY DESIGN: This was a nationwide retrospective cohort study. We compared the time to delivery and perinatal mortality in trichorionic triplet pregnancies electively reduced to twins with ongoing trichorionic triplets and primary dichorionic twins. RESULTS: We identified 86 women with reduced trichorionic triplet pregnancies, 44 with ongoing trichorionic triplets, and 824 with primary twins. Reduced triplets had a median gestational age at delivery of 36.1 weeks (interquartile range [IQR], 33.3 37.5 weeks) vs 33.3 (IQR, 28.1-35.2) weeks for ongoing triplets and 37.1 (IQR, 35.3-38.1) weeks for primary twins (P < .001). The total number of surviving children in the reduced group was 155 (90%) vs 114 (86%) in the ongoing triplet group. After reduction, 75 of women (87%) had all their fetuses surviving, compared with 36 (82%) (relative risk [RR], 1.3; 95% confidence interval [CI], 0.72-2.3) for ongoing triplets and 770 (93%) (RR, 0.91; 95% CI, 0.82-1) for primary twins. There were 6 women without any surviving children (7%) after reduction vs 5 (11.4%) (RR, 0.81; 95% CI, 0.47-1.4) among women with ongoing triplets and 32 (3.9%) (RR, 1.7; 95% CI, 0.8-3.7) in women with primary twins. CONCLUSION: In women with a triplet pregnancy, fetal reduction increases gestational age at birth with 3 weeks as compared with ongoing triplets. However, there the impact on neonatal survival is limited. PMID- 24769010 TI - Cesarean scar pregnancy: noninvasive and effective treatment with high-intensity focused ultrasound. AB - OBJECTIVE: The aim of this preliminary study was to investigate whether ultrasound-guided high-intensity focused ultrasound (HIFU) can play a role in treating cesarean scar pregnancy (CSP). STUDY DESIGN: Between November 2011 and December 2012, 16 patients with CSP were treated with ultrasound-guided HIFU ablation. Successful treatment was defined as disappearance of CSP mass, undetectable serum beta human chorionic gonadotropin, and no serious complications such as severe bleeding, uterine rupture, or hysterectomy. RESULTS: All patients were successfully treated in the outpatient department and none required readmission. After 2-5 treatment sessions, the mean time for achieving undetectable serum beta human chorionic gonadotropin was 4.94 +/- 2.32 weeks, and the mean time for CSP mass disappearance was 6.69 +/- 3.36 weeks. Three patients experienced moderate abdominal pain that subsided in 1-2 days, and nine patients experienced mild vaginal bleeding (<30 mL) that resolved within 2-3 days. All 16 patients had recovered their normal menstruation function at follow-up. CONCLUSION: These preliminary results suggest that ultrasound-guided HIFU ablation is a noninvasive, feasible, and effective method for the treatment of CSP. PMID- 24769011 TI - Preeclampsia in high risk women is characterized by risk group-specific abnormalities in serum biomarkers. AB - OBJECTIVE: To determine if early pregnancy serum biomarkers in high-risk women who develop preeclampsia vary according to risk factor. STUDY DESIGN: We performed a secondary analysis of the Maternal-Fetal Medicine Units Network randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in high-risk women. Serum biomarker levels at enrollment (before initiation of aspirin or placebo) were compared between women who did and did not develop preeclampsia, both for the group as a whole and within each of 4 high risk groups (insulin-dependent diabetes, hypertension, multiple gestation, and previous preeclampsia) using a regression model adjusting for gestational age at collection and prepregnancy body mass index. RESULTS: 1258 women were included (233 with insulin-dependent diabetes, 387 with chronic hypertension, 315 with a multiple gestation, 323 with previous preeclampsia). Multiple early pregnancy serum biomarkers differed between women who did and did not develop preeclampsia. Each high-risk group had a unique and largely nonoverlapping pattern of biomarker abnormality. Differences between those who did and did not develop preeclampsia were noted in vascular cell adhesion molecule in the diabetes group; human chorionic gonadotropin, soluble tumor necrosis factor receptor-2, tumor necrosis factor-alpha, selectin and angiogenin in the chronic hypertension group; interleukin-6, placental growth factor, soluble fms-like tyrosine kinase plus endoglin to placental growth factor ratio in the multiple gestation group; and angiogenin in the previous preeclampsia group. CONCLUSION: Patterns of serum biomarkers vary by high-risk group. These data support the hypothesis that multiple pathogenic pathways lead to the disease recognized clinically as preeclampsia. PMID- 24769012 TI - Cardiovascular effects of aerobic exercise training in formerly preeclamptic women and healthy parous control subjects. AB - OBJECTIVE: Women who have had preeclampsia demonstrate higher prevalence of metabolic syndrome (MetS), impaired vascular function, and increased sympathetic activity and are at increased risk of cardiovascular disease. The aim of this study was to assess the effects of 12 weeks of exercise training (70-80% maximum volume of oxygen utilization) in women who had had preeclampsia on physical fitness, components of MetS, vasculature, and autonomic functions compared with healthy control subjects. STUDY DESIGN: Our prospective case-control study included 24 normotensive women who had had preeclampsia and 20 control subjects who were matched for age and postpartum interval (all 6-12 months after delivery). Before and after training, we measured all components of MetS (ie, BP, lipids, glucose/insulin, and albuminuria), carotid intima media thickness (IMT) and brachial and superficial femoral artery endothelial function that used flow mediated dilation (FMD). Autonomic activity was quantified with power spectral analysis (low-frequency/high-frequency power [LF/HF] ratio). RESULTS: At baseline, women who had had preeclampsia demonstrated higher values of most components of MetS. Compared with the control subjects, women who had had preeclampsia had increased IMT (580 +/- 92 MUm vs 477 +/- 65 MUm, respectively), impaired endothelial function (FMD brachial artery, 5.3% +/- 2.2% vs 10.8% +/- 3.5%, respectively; FMD superficial femoral artery, 4.9% +/- 2.1% vs 8.7% +/- 3.2%, respectively) and increased LF/HF power ratio (2.2 +/- 1.0 vs 1.3 +/- 0.4, respectively; all P < .05). In both groups, exercise training decreased values of most components of MetS and IMT, improved FMD, and concurrently reduced LF/HF. Despite these improvements, vascular and autonomic variables did not normalize by 12 weeks of training in women who had had preeclampsia. CONCLUSION: This study demonstrates that exercise training in women who had had preeclampsia and control subjects improves components of MetS, endothelial function, vascular wall thickness, and autonomic control. Nonetheless, trained women who had had preeclampsia only reached a cardiovascular status that is comparable with sedentary healthy control subjects. PMID- 24769013 TI - Antifungal agents for secondary prophylaxis based on response to initial antifungal therapy in allogeneic hematopoietic stem cell transplant recipients with prior pulmonary aspergillosis. AB - We performed a prospective study to evaluate the efficacy and safety of secondary antifungal prophylaxis (SAP) for patients with a history of invasive pulmonary aspergillosis (IPA) in allogeneic hematopoietic stem cell transplantation (allo HSCT). In this study, the prophylactic agents used were chosen based on treatment response to initial antifungal therapy. One hundred and thirty-six patients undergoing allo-HSCT with prior IPA were enrolled in this multicenter study. The agents of SAP included itraconazole in 24, voriconazole in 74, caspofungin in 32, and liposomal amphotericin B in 6. Eighty-eight patients had stable IPA and 48 had active IPA at the time of transplantation. The success rate of SAP was 91.2%. Twelve patients developed breakthrough invasive fungal disease (IFD), and none discontinued antifungal agents because drug-related adverse events. The incidence of breakthrough IFD was neither different among the different antifungal agents (P = .675) nor between patients with active and stable IPA (P = .080). The 1-year cumulative incidence of IFD and IPA relapse was 27.3% +/- 4.5% and 24.7% +/- 4.4%, respectively. Our data indicate that SAP with antifungal agents based on initial antifungal therapy has favorable efficacy and safety in allo-HSCT recipients with prior IPA. Active IPA might not increase the risk of breakthrough IFD after transplantation. PMID- 24769015 TI - Induction of cytochrome P450 3A1 expression by diallyl disulfide: protective effects against cyclophosphamide-induced embryo-fetal developmental toxicity. AB - The protective effects of diallyl disulfide (DADS) on cyclophosphamide (CP) induced developmental toxicity and the possible mechanisms involved in this protection were investigated in rats. In order to study the mechanisms involved in the protection, we examined the effects of DADS on the expression of cytochrome P450 (CYP) 3A1 in the maternal liver and placenta and oxidative stress in the maternal hepatic tissues caused by CP. CP caused severe embryo-fetal developmental toxicity and hepatic oxidative stress. In contrast, DADS treatment significantly attenuated CP-induced developmental toxicity and oxidative damage in the maternal liver. DADS also significantly increased expression of CYP3A1 in the maternal liver and placenta. These results indicate that the protective effects of DADS against CP-induced developmental toxicity may be due to its ability to promote detoxification of CP, primarily by inducing CYP3A1 expression in the maternal liver and placenta, and its potent antioxidant effects. PMID- 24769014 TI - Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation. AB - Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach. PMID- 24769016 TI - Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. AB - Polyhexamethyleneguanidine phosphate (PHMG-P) has been widely used as a disinfectant because of its strong bactericidal activity and low toxicity. However, in 2011, the Korea Centers for Disease Control and Prevention and the Ministry of Health and Welfare reported that a suspicious outbreak of pulmonary disease might have originated from humidifier disinfectants. The purpose of this study was to assess the toxicity of PHMG-P following direct exposure to the lung. PHMG-P (0.3, 0.9, or 1.5 mg/kg) was instilled into the lungs of mice. The levels of proinflammatory markers and fibrotic markers were quantified in lung tissues and flow cytometry was used to evaluate T cell distribution in the thymus. Administration of PHMG-P induced proinflammatory cytokines elevation and infiltration of immune cells into the lungs. Histopathological analysis revealed a dose-dependent exacerbation of both inflammation and pulmonary fibrosis on day 14. PHMG-P also decreased the total cell number and the CD4(+)/CD8(+) cell ratio in the thymus, with the histopathological examination indicating severe reduction of cortex and medulla. The mRNA levels of biomarkers associated with T cell development also decreased markedly. These findings suggest that exposure of lung tissue to PHMG-P leads to pulmonary inflammation and fibrosis as well as thymic atrophy. PMID- 24769017 TI - Decorin gene expression in the differentiation of the skeletal connective tissues of the developing limb. AB - Tendons and cartilages are connective tissues of essential importance in the musculoskeletal system. During digit development, cartilage and tendon primordia develop from the undifferentiated mesenchymal cells originated in the lateral plate mesoderm. The specification of these tissues begins with the establishment of cellular aggregates, which prefigure the tendons and phalanges. Transforming growth factor beta proteins (TGFbetas) are the inductive signals responsible not only for the initiation of chondrogenesis and tenogenesis during digit formation, but also for joint specification. An early role of this family of secreted proteins during these processes is to promote mesenchymal cell precursors condensation. Here we show that Decorin presents an overlapping pattern of expression with TGFbeta2 in joint and tendon blastemas of the embryonic digits. Furthermore, Decorin expression is induced by TGFbeta signaling, and DECORIN promotes aggregation of digit mesenchymal cell precursors. In addition, we provide gene expression studies suggesting that Cadherin-11 may function as an effector of Decorin in this experimental model. PMID- 24769018 TI - Mycotoxins in a changing global environment--a review. AB - Mycotoxins are toxic metabolites produced by fungal species that commonly contaminate staple foods and feeds. They represent an unavoidable problem due to their presence in globally consumed cereals such as rice, maize and wheat. Most mycotoxins are immunosuppressive agents and some are carcinogens, hepatotoxins, nephrotoxins, and neurotoxins. Worldwide trends envision a stricter control of mycotoxins, however, the changing global environment may not be the ideal setting to control and reduce the exposure to these toxins. Although new technologies allow us to inspect the multi-mycotoxin presence in foods, new sources of exposure, gaps in knowledge of mycotoxins interactions, appearance of "emergent" mycotoxins and elucidation of consequent health effects can complicate their control even more. While humans are adapting to cope with environmental changes, such as food scarcity, decreased food quality, mycotoxin regulations, crop production and seasonality, and other climate related modifications, fungal species are also adapting and increased cases of mycotoxin adverse health effects are likely to occur in the future. To guarantee access to quality food for all, we need a way to balance global mycotoxin standards with the realistic feasibility of reaching them, considering limitations of producers and designing strategies to reduce mycotoxin exposure based on sound research. PMID- 24769019 TI - Validation and application of a reporter gene assay for the determination of estrogenic endocrine disruptor activity in milk. AB - Endocrine disruptors (EDs) are compounds known to interfere with the endocrine system by disturbing the action or pathways of natural hormones which may lead to infertility or cancer. Our diet is considered to be one of the main exposure routes to EDs. Since milk and dairy products are major components of our diet they should be monitored for ED contamination. Most assays developed to date utilise targeted, chromatography based methods which lack information on the biological activity and mixture effects of the monitored compounds. A biological reporter gene assay (RGA) was developed to assess the total estrogen hormonal load in milk. It has been validated according to EU decision 2002/657/EC. Analytes were extracted by liquid-liquid extraction with acetonitrile followed by clean up on a HLB column which yielded good recovery and small matrix effects. The method has been shown to be estrogen specific, repeatable and reproducible, with covariance values below 20%. In conclusion, this method enables the detection of low levels of estrogen hormonal activity in milk with a detection capability of 36 pg g(-)(1) EEQ and has been successfully applied in testing a range of milk samples. PMID- 24769020 TI - Magnetic domain structure and crystallographic orientation of electrical steels revealed by a forescatter detector and electron backscatter diffraction. AB - The magnetic properties of non-oriented electrical steels (NOES) are an important factor in determining the efficiency of electric vehicle drivetrains. Due to the highly variable texture of NOES, the relationships between crystal orientation, the magnetic domain structure, and the final magnetic properties are complicated and not fully understood. In this study, a NOES sample was characterized with a method capable of imaging surface magnetic domains using scanning electron microscopy (SEM) with an electron backscatter diffraction (EBSD) system equipped with a forescatter detector. This method used type II magnetic contrast without a specialized SEM setup, and imaged with a resolution limit of approximately 250 300nm. The domain structure of the NOES sample was successfully related to beta, which was defined as the angle between the closest magnetic easy axis and the surface of the sample (the RD-TD plane). However, it was shown that if the easy axes were aligned between neighbouring grains with respect to the grain boundary normal, the domain structure could align with an easy axis that was not the closest to the surface, and complex domain structures could be become wider. This structure and width change of complex domain structures has not been previously observed from single crystal or large-grained material studies. The successful application of this method to reveal the influence of surrounding grains can be used to better understand the magnetic properties of NOES. PMID- 24769021 TI - Sperm production responds to perceived sperm competition risk in male Drosophila melanogaster. AB - Postcopulatory sexual selection arising from female multiple mating leads to the evolution of ejaculates that maximize a male's reproductive success under sperm competition. Where the risk of sperm competition is variable, optimal fitness may be achieved by plastically altering ejaculate characteristics in response to the prevailing sperm competition environment. In the model species Drosophila melanogaster, males expecting to encounter sperm competition mate for longer and transfer more accessory proteins and sperm. Here we show that after being housed with a single rival for one week, the seminal vesicles of male D. melanogaster contain a significantly greater proportion of live sperm than those of males maintained alone, indicating adaptive adjustment of sperm quality in response to the perceived risk of sperm competition. This effect is due to an increase in the number of live sperm produced, indicating that males upregulate sperm production in response to the presence of rivals. Our data suggest that males show plasticity in the rate of spermatogenesis that is adaptive in the context of a fluctuating sperm competition environment. PMID- 24769022 TI - Down regulation of sodium channels in the central nervous system of hibernating snails. AB - Hibernation, as behavior, is an evolutionary mode of adaptation of animal species to unfavorable environmental conditions. It is generally characterized by suppressed metabolism, which also includes down regulation of the energy consuming ion-channel functioning. Experimental data regarding decreased ion channel function are scarce. Therefore, our goal was to study the possible down regulation of voltage-gated sodium channel (NaV) subtypes in the neurons of hibernating snails. Our immunohistochemical experiments revealed that the expression of NaV1.8-like channels in the central nervous system was substantially down regulated in hibernating animals. In contrast to NaV1.8-like, the NaV1.9-like channels were present in neurons independently from hibernating and non-hibernating states. Our western blot data supported the immunohistochemical results according to which the band of the NaV1.8-like channel protein was less intensively labeled in the homogenate of the hibernating snails. The NaV1.9-like immunoreactivity was equally present both in hibernating and active snails. Micro-electrophysiological experiments show that in hibernating snails both NaV1.8- and NaV1.9-like currents are substantially decreased compared to that of the active snails. The contradictory electrophysiological and immunohistochemical or western blot data suggest that the molecular mechanisms of the "channel arrest" could be different in diverse NaV channel subtypes. Climate changes will affect temperature extremes and a question is how different species beyond their physiological tolerance will or able to adapt to changing environment. Hibernation is an important mode of adaptation to extreme climatic variations, and pursuant to this the present results may contribute to the study of the behavioral ecology. PMID- 24769023 TI - Creatine supplementation and venous thrombotic events. PMID- 24769024 TI - A case of cryptogenic dyspnea: disseminated cryptococcosis. PMID- 24769025 TI - The changing 'face' of endocarditis in Kentucky: an increase in tricuspid cases. AB - BACKGROUND: Advancements in medical technology and increased life expectancy have been described as contributing to the evolution of endocarditis. We sought to determine whether there has been a change in the incidence, demographics, microbiology, complications, and outcomes of infective endocarditis over a 10 year time span. METHODS: We screened 28,420 transthoracic and transesophageal echocardiogram reports performed at the Gill Heart Institute for the following indications: fever, masses, emboli (including stroke), sepsis, bacteremia, and endocarditis in 2 time periods: 1999 to 2000 and 2009 to 2010. Data were collected from diagnosed endocarditis cases. RESULTS: Overall, 143 cases of infective endocarditis were analyzed (48 in 1999-2000 and 95 in 2009-2010). The endocarditis incidence per number of admissions remained nearly constant at 0.113% for 1999-2000 and 0.148% for 2009-2010 (P = .153). However, tricuspid valve involvement increased markedly from 6% to 36% (P < .001). Also, reported history of intravenous drug use increased from 15% to 40% (P = .002). Valvular complications doubled from 17% to 35% (P = .031). Septic pulmonary emboli increased from 10% to 25% (P = .047). Despite these noted differences, inpatient mortality remained unchanged at 25% and 28% (P = .696) for the 2 time periods, respectively. CONCLUSIONS: The incidence of endocarditis at the University of Kentucky Medical Center has not changed and mortality remains high, but the "face of endocarditis" in Kentucky has evolved with an increased incidence of tricuspid valve involvement, valvular complications, and embolic events. PMID- 24769026 TI - Survival of men with prostate cancer undergoing radical prostatectomy in Ontario. AB - PURPOSE: Radical prostatectomy is traditionally reserved for men with at least 10 year life expectancy. Numerous studies show that survival estimates by physicians are inaccurate. We determined how well men undergoing radical prostatectomy for cancer are prognosticated by comparing observed and expected survival. MATERIALS AND METHODS: We performed an observational cohort study using population based data sets to identify each man in Ontario, Canada between 1992 and 2011 who was diagnosed with prostate cancer and underwent radical prostatectomy within 6 months. Observed 10-year survival rates were calculated using the Kaplan-Meier method. Two expected 10-year survival rates were calculated using 1) population life tables and 2) the ADG(r) score, an accurate, validated index that predicts mortality risk based on patient comorbidities. RESULTS: A total of 36,045 men with a median age of 62 years were included in the study. Median observation time was 8.1 years. Observed 10-year survival was 88.9% (95% CI 88.4-89.3), significantly greater than the expected 10-year survival of 83.3% according to life tables and 76.0% according to ADG score. The observed-to-expected death ratio was 0.66 (range 0.64-0.68) and 0.46 (range 0.45-0.48) using life tables and the ADG score, respectively. CONCLUSIONS: Ontario men who undergo radical prostatectomy for cancer have 10-year survival that significantly exceeds that of the population and individuals with similar comorbidities. This indicates that physicians and patients involved in deciding who should undergo radical prostatectomy have done an excellent job at identifying patients with prostate cancer with high survival. We are uncertain how these results apply to patients and physicians outside Ontario. PMID- 24769027 TI - Glans preservation contributes to postoperative restoration of male sexual function: a multicenter clinical study of glans preserving surgery. AB - PURPOSE: We evaluated whether glans preserving surgery would be more helpful for patients to regain satisfactory sexual competency postoperatively than conventional partial amputation. MATERIALS AND METHODS: From 2004 to 2012 at 4 centers a total of 135 men treated with glans preserving surgery and 36 treated with partial amputation were selected for evaluation from a total of 273 consecutive patients with penile cancer. Subjective evaluation for patient sexual performance was investigated using the IIEF-15. Objective evaluation was done using the audiovisual sexual stimulation test with the RigiScan(r) Plus. The degree of satisfaction with penile appearance, and patient confidence and partner acceptability for intercourse were evaluated by 5-point scales. RESULTS: Patients treated with glans preserving surgery had better performance in 4 IIEF-15 domains (erectile function, orgasmic function, intercourse satisfaction and overall satisfaction) and 1 RigiScan parameter (tip rigidity) (each p <0.01). They also had significantly higher appearance satisfaction (64.4% vs 13.9%) and intercourse confidence (55.6% vs 5.6%) than men who underwent partial amputation. Sexual partners in the glans preserving group also showed significantly higher appearance satisfaction (51.1% vs 5.6%) and intercourse acceptability (37.8% vs 16.7%) than in the partial amputation group. CONCLUSIONS: Glans preserving surgery effectively preserves the functional anatomy and cosmetic appearance of the glans penis. Glans preservation contributes to minimizing postoperative erectile dysfunction and negative psychological impediments, and promotes return to satisfactory sexual performance. Patients treated with glans preservation have more advantages in obtaining sexual acceptance from their partners than those who undergo amputation. PMID- 24769028 TI - GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer. AB - PURPOSE: Recurrent prostate cancer remains a major problem. Staging, grading and prostate specific antigen level at surgery are helpful but still imperfect predictors of recurrence. For this reason there is an imperative need for additional biomarkers that add to the prediction of currently used prognostic factors. MATERIALS AND METHODS: We evaluated the extent of promoter methylation of genes previously reported as aberrantly methylated in prostate cancer (AIM1, APC, CCND2, GPX3, GSTP1, MCAM, RARbeta2, SSBP2 and TIMP3) by quantitative fluorogenic methylation-specific polymerase chain reaction. We used cancer tissue from a nested case-control study of 452 patients surgically treated for prostate cancer. Recurrence cases and controls were compared and the association between methylation extent and recurrence risk was estimated by logistic regression adjusting for patient age at prostatectomy, prostatectomy year, stage, grade, surgical margins and preprostatectomy prostate specific antigen. All statistical tests were 2-sided with p <=0.05 considered statistically significant. RESULTS: The extent of GSTP1 methylation was higher in patients with recurrence than in controls (p = 0.01), especially patients with early disease, ie organ confined or limited extraprostatic extension (p = 0.001). After multivariate adjustment GSTP1 promoter methylation at or above the median was associated with an increased risk of recurrence, including in men with early disease (each p = 0.05). CONCLUSIONS: Greater GSTP1 promoter methylation in cancer tissue was independently associated with the risk of recurrence in patients with early prostate cancer. This suggests that GSTP1 promoter methylation may be a potential tissue based recurrence marker. PMID- 24769029 TI - Functional magnetic resonance imaging during urodynamic testing identifies brain structures initiating micturition. AB - PURPOSE: Normal voiding in neurologically intact patients is triggered by the release of tonic inhibition from suprapontine centers, allowing the pontine micturition center to trigger the voiding reflex. Supraspinal mechanisms of voluntary voiding in humans are just beginning to be described via functional neuroimaging. We further elucidated brain activity processes during voiding using functional magnetic resonance imaging in normal females to gain better understanding of normal voiding as well as changes that may occur in voiding dysfunction. MATERIALS AND METHODS: We screened 13 healthy premenopausal female volunteers using baseline clinic urodynamics to document normal voiding parameters. We then recorded brain activity via functional magnetic resonance imaging and simultaneous urodynamics, including the pressure flow voiding phase. After motion correction of functional magnetic resonance images we performed activation and connectivity analyses in 10 subjects. RESULTS: Group analysis revealed consistent activation areas, including regions for motor control (cerebellum, thalamus, caudate, lentiform nucleus, red nucleus, supplementary motor area and post-central gyrus), emotion (anterior/posterior cingulate gyrus and insula), executive function (left superior frontal gyrus) and a focal region in the pons. Connectivity analysis demonstrated strong interconnectivity of the pontine micturition center with many short-range and long-range cortical clusters. CONCLUSIONS: Our study is one of the first reports of brain activation centers associated with micturition initiation in normal healthy females. Results show activation of a brain network consisting of regions for motor control, executive function and emotion processing. Further studies are planned to create and validate a model of brain activity during normal voiding in women. PMID- 24769030 TI - Optimization of prostate biopsy: the role of magnetic resonance imaging targeted biopsy in detection, localization and risk assessment. AB - PURPOSE: Optimization of prostate biopsy requires addressing the shortcomings of standard systematic transrectal ultrasound guided biopsy, including false negative rates, incorrect risk stratification, detection of clinically insignificant disease and the need for repeat biopsy. Magnetic resonance imaging is an evolving noninvasive imaging modality that increases the accurate localization of prostate cancer at the time of biopsy, and thereby enhances clinical risk assessment and improves the ability to appropriately counsel patients regarding therapy. In this review we 1) summarize the various sequences that comprise a prostate multiparametric magnetic resonance imaging examination along with its performance characteristics in cancer detection, localization and reporting standards; 2) evaluate potential applications of magnetic resonance imaging targeting in prostate biopsy among men with no previous biopsy, a negative previous biopsy and those with low stage cancer; and 3) describe the techniques of magnetic resonance imaging targeted biopsy and comparative study outcomes. MATERIALS AND METHODS: A bibliographic search covering the period up to October 2013 was conducted using MEDLINE(r)/PubMed(r). Articles were reviewed and categorized based on which of the 3 objectives of this review was addressed. Data were extracted, analyzed and summarized. RESULTS: Multiparametric magnetic resonance imaging consists of anatomical T2-weighted imaging coupled with at least 2 functional imaging techniques. It has demonstrated improved prostate cancer detection sensitivity up to 80% in the peripheral zone and 81% in the transition zone. A prostate cancer magnetic resonance imaging suspicion score has been developed, and is depicted using the Likert or PI-RADS (Prostate Imaging Reporting and Data System) scale for better standardization of magnetic resonance imaging interpretation and reporting. Among men with no previous biopsy, magnetic resonance imaging increases the frequency of significant cancer detection to 50% in low risk and 71% in high risk patients. In low risk men the negative predictive value of a combination of negative magnetic resonance imaging with prostate volume parameters is nearly 98%, suggesting a potential role in avoiding biopsy and reducing over detection/overtreatment. Among men with a previous negative biopsy 72% to 87% of cancers detected by magnetic resonance imaging guidance are clinically significant. Among men with a known low risk cancer, repeat biopsy using magnetic resonance targeting demonstrates a high likelihood of confirming low risk disease in low suspicion score lesions and of upgrading in high suspicion score lesions. Techniques of magnetic resonance imaging targeted biopsy include visual estimation transrectal ultrasound guided biopsy; software co-registered magnetic resonance imaging-ultrasound, transrectal ultrasound guided biopsy; and in-bore magnetic resonance imaging guided biopsy. Although the improvement in accuracy and efficiency of visual estimation biopsy compared to systematic appears limited, co-registered magnetic resonance imaging-ultrasound biopsy as well as in-bore magnetic resonance imaging guided biopsy appear to increase cancer detection rates in conjunction with increasing suspicion score. CONCLUSIONS: Use of magnetic resonance imaging for targeting prostate biopsies has the potential to reduce the sampling error associated with conventional biopsy by providing better disease localization and sampling. More accurate risk stratification through improved cancer sampling may impact therapeutic decision making. Optimal clinical application of magnetic resonance imaging targeted biopsy remains under investigation. PMID- 24769031 TI - Obesity and long-term survival after radical prostatectomy. AB - PURPOSE: Obesity is a modifiable risk factor associated with worse outcomes for many cancers, yet implications for prostate cancer are not well understood. Notably the impact of body mass index on long-term survival after treatment is unclear. We performed a retrospective cohort study on a large series of men who underwent radical prostatectomy to assess the impact of obesity on long-term biochemical recurrence-free survival, prostate cancer specific survival and overall survival. MATERIALS AND METHODS: Between 1982 and 2012, 11,152 men underwent radical prostatectomy at a single tertiary referral center. Patients were stratified according to body mass index as normal weight (body mass index less than 25 kg/m(2)), overweight (body mass index 25 to less than 30 kg/m(2)), mild obesity (body mass index 30 to less than 35 kg/m(2)) and moderate/severe obesity (body mass index 35 kg/m(2) or greater), comprising 27.6%, 56.0%, 14.1% and 2.3% of the cohort, respectively. Covariates included age, preoperative prostate specific antigen, surgery year, Gleason score, pathological stage, surgical margin and race. Predictors of biochemical recurrence-free survival, prostate cancer specific survival and overall survival were identified using Cox proportional hazard models. RESULTS: Median followup was 5 years (range 1 to 27). Actuarial 20-year biochemical recurrence-free survival for mild and moderate/severe obesity was 65% and 51%, respectively, compared to 76% for normal weight men (p <=0.001). In a multivariate model obesity was a significant predictor of biochemical recurrence-free survival (mild HR 1.30, p = 0.002; moderate/severe HR 1.45, p = 0.028) and overall survival (mild HR 1.41, p = 0.003; moderate/severe HR 1.81, p = 0.033). However, only mild obesity was significantly associated with prostate cancer specific survival (HR 1.51, p = 0.040), whereas moderate/severe obesity was not (HR 1.58, p = 0.356). CONCLUSIONS: Obese men have higher rates of biochemical recurrence than normal weight patients during long-term followup. Obesity at the time of surgery independently predicts overall survival and biochemical recurrence-free survival but not prostate cancer specific survival. PMID- 24769032 TI - Tissue engineering of the bladder--reality or myth? A systematic review. AB - PURPOSE: We systematically reviewed preclinical studies in the literature to evaluate the potential of tissue engineering of the bladder. Study outcomes were compared to the available clinical evidence to assess the feasibility of tissue engineering for future clinical use. MATERIALS AND METHODS: Preclinical studies of tissue engineering for bladder augmentation were identified through a systematic search of PubMed and EmbaseTM from January 1, 1980 to January 1, 2014. Primary studies in English were included if bladder reconstruction after partial cystectomy was performed using a tissue engineered biomaterial in any animal species, with cystometric bladder capacity as an outcome measure. Outcomes were compared to clinical studies available at http://www.clinicaltrials.gov and published clinical studies. RESULTS: A total of 28 preclinical studies are included, demonstrating remarkable heterogeneity in study characteristics and design. Studies in which preoperative bladder volumes were compared to postoperative volumes were considered the most clinically relevant (18 studies). Bladder augmentation through tissue engineering resulted in a normal bladder volume in healthy animals, with the influence of a cellular component being negligible. Furthermore, experiments in large animal models (pigs and dogs) approximated the desired bladder volume more accurately than in smaller species. The initial clinical experience was based on seemingly predictive healthy animal models with a promising outcome. Unfortunately these results were not substantiated in all clinical trials, revealing dissimilar outcomes in different clinical/disease backgrounds. Thus, the translational predictability of a model using healthy animals might be questioned. CONCLUSIONS: Through this systematic approach we present an unbiased overview of all published preclinical studies investigating the effect of bladder tissue engineering on cystometric bladder capacity. Preclinical research in healthy animals appears to show the feasibility of bladder augmentation by tissue engineering. However, in view of the disappointing clinical results based on healthy animal models new approaches should also be evaluated in preclinical models using dysfunctional/diseased bladders. This endeavor may aid in the development of clinically applicable tissue engineered bladder augmentation with satisfactory long-term outcome. PMID- 24769033 TI - Diffusion tensor magnetic resonance imaging and fiber tractography of the sacral plexus in children with spina bifida. AB - PURPOSE: It is still largely unknown how neural tube defects in spina bifida affect the nerves at the level of the sacral plexus. Visualizing the sacral plexus in 3 dimensions could improve our anatomical understanding of neurological problems in patients with spina bifida. We investigated anatomical and microstructural properties of the sacral plexus of patients with spina bifida using diffusion tensor imaging and fiber tractography. MATERIALS AND METHODS: Ten patients 8 to 16 years old with spina bifida underwent diffusion tensor imaging on a 3 Tesla magnetic resonance imaging system. Anatomical 3-dimensional reconstructions were obtained of the sacral plexus of the 10 patients. Fiber tractography was performed with a diffusion magnetic resonance imaging toolbox to determine fractional anisotropy, and mean, axial and radial diffusivity in the sacral plexus of the patients. Results were compared to 10 healthy controls. RESULTS: Nerves of patients with spina bifida showed asymmetry and disorganization to a large extent compared to those of healthy controls. Especially at the myelomeningocele level it was difficult to find a connection with the cauda equina. Mean, axial and radial diffusivity values at S1-S3 were significantly lower in patients. CONCLUSIONS: To our knowledge this 3 Tesla magnetic resonance imaging study showed for the first time sacral plexus asymmetry and disorganization in 10 patients with spina bifida using diffusion tensor imaging and fiber tractography. The observed difference in diffusion values indicates that these methods may be used to identify nerve abnormalities. We expect that this technique could provide a valuable contribution to better analysis and understanding of the problems of patients with spina bifida in the future. PMID- 24769034 TI - GALNT4 predicts clinical outcome in patients with clear cell renal cell carcinoma. AB - PURPOSE: We investigated the clinical significance of GALNT4 expression in patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: Enrolled in this study were 104 patients treated with curative nephrectomy at Zhongshan Hospital, Shanghai during 2004. Of the cohort 23 patients died of disease, 33 experienced recurrence and 3 died of another cause. GALNT4 density was assessed by immunohistochemistry in patient specimens. Univariate and multivariate Cox models, and ROC analysis were used to analyze the impact of prognostic factors on overall and relapse-free survival. Kaplan-Meier analysis with the log rank test was done to compare clinical outcomes between subgroups. RESULTS: Intratumor GALNT4 expression was significantly lower than peritumor expression. Low GALNT4 expression was associated with poor overall and relapse-free survival (p = 0.001 and 0.004, respectively). Intratumor GALNT4 expression, which negatively correlated with tumor size (p = 0.032), necrosis (p = 0.013) and TNM stage (p = 0.017), was an independent prognostic indicator for overall and relapse-free survival (HR 3.088, p = 0.020 and 2.173, p = 0.047, respectively). Extending the TNM staging system according to GALNT4 expression showed a better prognostic value for overall and relapse-free survival (AUC 0.786, p = 0.029 and 0.761, p = 0.040, respectively). CONCLUSIONS: Intratumor GALNT4 expression is a potential independent prognostic factor for overall and relapse-free survival in patients with clear cell renal cell carcinoma. Further external validation and functional analysis should be performed to assess its potential prognostic and therapeutic value in patients with clear cell renal cell carcinoma. PMID- 24769035 TI - SPARC was overexpressed in human endometrial cancer stem-like cells and promoted migration activity. AB - OBJECTIVES: We previously demonstrated that side-population (SP) cells found in human endometrial cancer tissue have features of cancer stem cells (CSCs). Endometrial cancer SP cells show enhanced migration, the potential to differentiate into the mesenchymal cell lineage, and they are associated with the epithelial-mesenchymal transition (EMT). In this study, we analyzed the expression and function of a specific protein, SPARC (secreted protein acidic and rich in cysteine) which we found to be up-regulated in endometrial cancer. METHODS: We performed microarray expression analysis to screen for up-regulated genes in CSCs using a set of RK12V-SP cells and -non-SP (NSP) cells. We used the MetaCore package to identify the Gene GO pathway MAPs associated with the up regulated genes. Here, we investigated the expression and functions of SPARC, one of the genes up-regulated in endometrial CSCs. We established SPARC overexpressing cells by transfecting endometrial cancer cells (Ishikawa cells [IK SPARC cells]). We characterized these cells' growth rate, tumorigenicity, migration and invasion activity. The levels and locations of SPARC protein expression in Hec1SP cells-derived tumors and endometrial cancer tissues were examined by immunohistochemistry. RESULTS: SPARC was detected by microarray expression analysis during screens for up-regulated genes in SP and NSP CSC. The level of SPARC expression was enhanced in Hec1 SP cells compared with that in Hec1 non-SP cells. SPARC enhanced fibronectin expression and promoted migration activity in IK cells. SPARC expression suppressed tumor growth but promoted formation of tumor stroma. SPARC was expressed in endometrial cancer tissues, in particular, poorly differentiated endometrioid adenocarcinoma, clear and serous adenocarcinoma,but not in normal endometrial tissue. CONCLUSION: This is the first report of overexpression of SPARC in endometrial cancer stem-like cells. SPARC expression is associated with cell migration and stroma formation. PMID- 24769036 TI - Oxaliplatin salvage for recurrent ovarian cancer: a single institution's experience in patient populations with platinum resistant disease or a history of platinum hypersensitivity. AB - OBJECTIVE: Hypersensitivity reactions can preclude platinum re-challenge for patients receiving second-line and higher carboplatin/cisplatin salvage therapy. The objective is to report our patient experience with oxaliplatin in recurrent or progressive epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC), including those with prior hypersensitivity reaction. METHODS: A single institution, retrospective review from 1995 to 2012 of patients receiving oxaliplatin for treatment of recurrent or progressive EOC, PPC, or FTC was performed. Data collected included patient demographics, diagnosis date, prior chemotherapy regimens, platinum-free interval(s), prior hypersensitivity reactions, oxaliplatin toxicity, length of therapy, disease response, and last follow-up. Those who received >=1 cycles were included. A response to therapy was determined after >=2 cycles. RESULTS: Forty-four patients were identified. All had prior carboplatin and 38.6% had prior cisplatin therapy. Twenty-three had a prior platinum hypersensitivity reaction. Patients received a median of 2 prior platinum containing regimens and 5 chemotherapy lines prior to oxaliplatin exposure. One patient experienced grade 3 pain. No grade 4 toxicities occurred. No treatment delays for pancytopenia noted. Nausea and dysesthesias were controlled medically and weren't dose-limiting. No nephropathy or neuropathy progressed on oxaliplatin or were dose-limiting. Disease response was observed in 43.2%. Of the responders, 36.8% had a prior platinum hypersensitivity reaction. Median number of 5 cycles of an oxaliplatin containing regimen was given. Median follow-up was 15.5 months. CONCLUSIONS: In our experience, oxaliplatin is well tolerated and should be considered for platinum challenge after hypersensitivity even in patients with platinum resistant disease with a reasonable chance of response. PMID- 24769037 TI - Monosodium glutamate neurotoxicity increases beta amyloid in the rat hippocampus: a potential role for cyclic AMP protein kinase. AB - BACKGROUND: Glutamate excitotoxicity and cyclic AMP-activated protein kinase (AMPK) are both recognized as important mediators in neurodegenerative disorders including Alzheimer's disease (AD). OBJECTIVES: To investigate whether oral or subcutaneous monosodium glutamate (MSG) neurotoxicity mimics some features of AD and whether these can be reversed by the AMPK activator Pioglitazone. METHODS: Male Wistar rats aged 5 weeks were administered oral or subcutaneous MSG for 10 days with or without daily oral Pioglitazone. Two additional groups given only saline orally or subcutaneously acted as controls. At age 10 weeks the rats were subjected to neurobehavioral testing, then sacrificed for measurement of AMPK, beta-amyloid and Fas ligand in the hippocampus. RESULTS: Oral and subcutaneous MSG both induced a lowering of hippocampal AMPK by 43% and 31% respectively (P<0.05 for both) and >2-fold increase in hippocampal Fas ligand, a mediator of apoptosis (P<0.001 for both). MSG treatment also induced a significant increase in beta-amyloid in the hippocampus by >4-fold and >5-fold in the oral and subcutaneous groups. This was associated with increased latency before crossing to the white half in the black-white alley and before the first rear in the holeboard test, suggesting increased anxiety. Pioglitazone decreased hippocampal beta-amyloid accumulation and Fas ligand, but did not ameliorate the neurobehavioural deficits induced by MSG. CONCLUSIONS: MSG treatment enhances beta-amyloid accumulation in the rat hippocampus. Our results suggest a role for AMPK reduction in mediating the neurotoxic effects of glutamate, including beta amyloid accumulation. PMID- 24769038 TI - Interactions of amikacin with the RNA model of the ribosomal A-site: computational, spectroscopic and calorimetric studies. AB - Amikacin is a 2-deoxystreptamine aminoglycoside antibiotic possessing a unique l HABA (l-(-)-gamma-amino-alpha-hydroxybutyric acid) group and applied in the treatment of hospital-acquired infections. Amikacin influences bacterial translation by binding to the decoding region of the small ribosomal subunit that overlaps with the binding site of aminoacylated-tRNA (A-site). Here, we have characterized thermodynamics of interactions of amikacin with a 27-mer RNA oligonucleotide mimicking the aminoglycoside binding site in the bacterial ribosome. We applied isothermal titration and differential scanning calorimetries, circular dichroism and thermal denaturation experiments, as well as computer simulations. Thermal denaturation studies have shown that amikacin affects only slightly the melting temperatures of the A-site mimicking RNA model suggesting a moderate stabilization of RNA by amikacin. Isothermal titration calorimetry gives the equilibrium dissociation constants for the binding reaction between amikacin and the A-site oligonucleotide in the micromolar range with a favorable enthalpic contribution. However, for amikacin we observe a positive entropic contribution to binding, contrary to other aminoglycosides, paromomycin and ribostamycin. Circular dichroism spectra suggest that the observed increase in entropy is not caused by structural changes of RNA because amikacin binding does not destabilize the helicity of the RNA model. To investigate the origins of this positive entropy change we performed all-atom molecular dynamics simulations in explicit solvent for the 27-mer RNA oligonucleotide mimicking one A-site and the crystal structure of an RNA duplex containing two A-sites. We observed that the diversity of the conformational states of the l-HABA group sampled in the simulations of the complex was larger than for the free amikacin in explicit water. Therefore, the larger flexibility of the l-HABA group in the bound form may contribute to an increase of entropy upon binding. PMID- 24769039 TI - Novel serum-tolerant lipoplexes target the folate receptor efficiently. AB - Gene transfer using non-viral vectors is a promising approach for the safe delivery of nucleic acid therapeutics. In this study, we investigate a lipid based system for targeted gene delivery to malignant cells overexpressing the folate receptor (FR). Cationic liposomes were formulated with and without the targeting ligand folate conjugated to distearoylphosphatidyl ethanolamine polyethylene glycol 2000 (DSPE-PEG2000), the novel cytofectin 3beta[N(N(1),N(1) dimethlaminopropylsuccinamidoethane)-carbamoyl]cholesterol (SGO4), which contains a 13atom, 15A spacer element, and the helper lipid, dioleoylphosphatidylethanolamine (DOPE). Physicochemical parameters of the liposomes and lipoplexes were obtained by zeta sizing, zeta potential measurement and cryo-TEM. DNA-binding and protection capabilities of liposomes were confirmed by gel retardation assays, EtBr intercalation and nuclease protection assays. The complexes were assessed in an in vitro system for their effect on cell viability using the MTT assay, and gene transfection activity using the luciferase assay in three cell lines; HEK293 (FR-negative), HeLa (FR(+)-positive), KB (FR(++) positive). Low cytotoxicities were observed in all cell lines, while transgene activity promoted by folate-tagged lipoplexes in FR-positive lines was tenfold greater than that by untargeted constructs and cell entry by folate complexes was demonstrably by FR mediation. These liposome formulations have the design capacity for in vivo application and may therefore be promising candidates for further development. PMID- 24769040 TI - Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines as highly potent EGFR-TK inhibitors with Src-family activity. AB - The epidermal growth factor receptor is an important target in molecular cancer therapy. Herein, the enzymatic inhibition potential of a series of chiral and non chiral pyrrolopyrimidine based derivatives have been investigated and optimised. Overall, seven new compounds were identified having enzymatic IC50 values comparable to or better than the commercial drug Erlotinib. High activity was also confirmed towards the epidermal growth factor receptor L858R and L861Q mutants. Based on calculated druglike properties, eight compounds were further evaluated towards a panel of 52 other kinases revealing interesting Src-family kinase and colony stimulating factor 1 receptor kinase inhibitory activity. Cell proliferation studies with the cell lines A431, C-33A, AU-565, K-562 and genetically engineered Ba/F3-EGFR(L858R) cells also showed several molecules to be more active than Erlotinib, and thus confirming these pyrrolopyrimidines as attractive drug candidates or lead structures. PMID- 24769041 TI - Characterization of pituitary growth hormone and its receptor in the green iguana (Iguana iguana). AB - Pituitary growth hormone (GH) has been studied in most vertebrate groups; however, only a few studies have been carried out in reptiles. Little is known about pituitary hormones in the order Squamata, to which the green iguana (gi) belongs. In this work, we characterized the hypophysis of Iguana iguana morphologically. The somatotrophs (round cells of 7.6-10 MUm containing 250- to 300-nm secretory granules where the giGH is stored) were found, by immunohistochemistry and in situ hybridization, exclusively in the caudal lobe of the pars distalis, whereas the lactotrophs were distributed only in the rostral lobe. A pituitary giGH-like protein was obtained by immuno-affinity chromatography employing a heterologous antibody against chicken GH. giGH showed molecular heterogeneity (22, 44, and 88 kDa by SDS-PAGE/Western blot under non reducing conditions and at least four charge variants (pIs 6.2, 6.5, 6.9, 7.4) by isoelectric focusing. The pituitary giGH cDNA (1016 bp), amplified by PCR and RACE, encodes a pre-hormone of 218 aa, of which 190 aa correspond to the mature protein and 28 aa to the signal peptide. The giGH receptor cDNA was also partially sequenced. Phylogenetic analyses of the amino acid sequences of giGH and giGHR homologs in vertebrates suggest a parallel evolution and functional relationship between the GH and its receptor. PMID- 24769042 TI - Corticotropin-releasing factor-binding protein (CRF-BP) inhibits CRF- and urotensin-I-mediated activation of CRF receptor-1 and -2 in common carp. AB - Corticotropin-releasing factor-binding protein (CRF-BP) is considered a key determinant for CRF receptor (CRF-R) activation by CRF and several related peptides. Earlier studies have shown that the CRF system is highly conserved in gene structures throughout evolution, yet little is known about the evolutionary conservation of its biological functions. Therefore, we address the functional properties of CRF-BP and CRF-Rs in a teleost fish (common carp; Cyprinus carpio L.). We report the finding of two similar, yet distinct, genes for both CRF-R1 and CRF-R2 in this species. The four receptors are differentially responsive to CRF, urotensin-I (UI), sauvagine, and urocortin-2 (Ucn-2) and -3 (Ucn-3) as shown by luciferase assays. In vitro, carp CRF-BP inhibits CRF- and UI-mediated activation of the newfound CRF-Rs, but its potency to do so varies between receptor and peptide ligand. This is the first paper to establish the functionality and physiological interplay between CRF-BP, CRF-Rs and CRF-family peptides in a teleostean species. PMID- 24769043 TI - The stress response predicts migration failure but not migration rate in a semelparous fish. AB - Recent findings from iteroparous species suggest that glucocorticoid secretion following acute stress can mediate behavior and survival strategies, ultimately influencing fitness. However, these correlates of the stress response may not exist in semelparous animals given the inability to maximize fitness by delaying reproduction. We measured baseline and stress-induced cortisol concentrations in semelparous sockeye salmon (Oncorhynchus nerka) following exposure to an acute stressor at the mouth of the Fraser River in British Columbia. The homing fish were then radio-tagged and tracked throughout their in-river migration. Findings reveal that the stress response (i.e. change from baseline to stress-induced cortisol) was predictive of mortality; fish failing to leave the release site had a significantly greater stress response (mean+/-SE=1004.0+/-75.3ng/mL) compared to fish capable of successfully migrating beyond one of the most difficult areas of passage over 100 river kilometers upstream (mean+/-SE=780.7+/-66.7ng/mL). However, there were no associations between swimming behaviors, both immediately following release and to last point of detection, and the stress response. This study also introduced an unique method of tagging migrating salmon that allows for rapid capture and sampling and thus provides the first assessment of true baseline cortisol concentrations at river-entry for migrating Pacific salmon in the wild. Results show the stress response to be linked to survival in a semelparous species and therefore set the stage for further exploration into how the evolutionary theories underlying relationships between stress responsiveness and fitness may differ between semelparous and iteroparous species. PMID- 24769044 TI - Hepatocystin contributes to interferon-mediated antiviral response to hepatitis B virus by regulating hepatocyte nuclear factor 4alpha. AB - Hepatocystin/80K-H is known as a causative gene for autosomal dominant polycystic liver disease. However, the role of hepatocystin in hepatitis B virus-related liver disease remains unknown. Here, we investigated the role of hepatocystin on the cytokine-mediated antiviral response against hepatitis B virus infection. We investigated the antiviral effect and mechanism of hepatocystin by ectopic expression and RNAi knockdown in cell culture and mouse livers. Hepatocystin suppressed the replication of hepatitis B virus both in vitro and in vivo. This inhibitory effect was HBx-independent and mediated by the transcriptional regulation of viral genome via the activation of exogenous signal-regulated kinase 1/2 and the reduced expression of hepatocyte nuclear factor 4alpha, a transcription factor essential for hepatitis B virus replication. The amino terminal region of hepatocystin was essential for regulation of this antiviral signaling pathway. We also found that hepatocystin acts as a critical component in interferon-mediated mitogen-activated protein kinase signaling pathway, and the interferon-induced antiviral activity against hepatitis B virus is associated with the expression levels of hepatocystin. We demonstrated that hepatocystin plays a critical role in modulating the susceptibility of hepatitis B virus to interferon, suggesting that the modulation of hepatocystin expression is important for cytokine-mediated viral clearance during hepatitis B virus infection. PMID- 24769045 TI - Dipeptidyl peptidase-IV inhibition prevents blood-retinal barrier breakdown, inflammation and neuronal cell death in the retina of type 1 diabetic rats. AB - Diabetic retinopathy, a leading cause of vision loss in working-age population, is often associated with inflammation and apoptosis. We have previously reported that sitagliptin, a DPP-IV inhibitor, exerts beneficial effects in the retina of type 2 diabetic animals. The present study aimed to evaluate whether sitagliptin can exert protective effects in the retina of type 1 diabetic animals by a mechanism independent of insulin secretion and glycemia normalization. Streptozotocin-induced diabetic rats were treated orally with sitagliptin (5mg/kg/day) for the last two weeks of 4 weeks of diabetes. Sitagliptin treatment did not change the weight and glucose, HbA1c or insulin levels. However, it prevented the diabetes-induced increase in DPP-IV/CD26 activity and levels in serum and retina. Sitagliptin also prevented the increase in blood-retinal barrier (BRB) permeability and inhibited the changes in immunoreactivity and endothelial subcellular distribution of occludin, claudin-5 and ZO-1 proteins induced by diabetes. Furthermore, sitagliptin decreased the retinal inflammatory state and neuronal apoptosis. Sitagliptin inhibited the BRB breakdown in a type 1 diabetic animal model, by a mechanism independent of normalization of glycemia, by preventing changes in tight junctions (TJs) organization. Sitagliptin also exerted protective effects against inflammation and pro-apoptotic state in the retina of diabetic rats. Altogether, these results suggest that sitagliptin might be envisaged to be used to prevent or delay some of the alterations associated with the development of diabetic retinopathy. PMID- 24769047 TI - Systems biology and systems genetics - novel innovative approaches to study host pathogen interactions during influenza infection. AB - Influenza represents a serious threat to public health with thousands of deaths each year. A deeper understanding of the host-pathogen interactions is urgently needed to evaluate individual and population risks for severe influenza disease and to identify new therapeutic targets. Here, we review recent progress in large scale omics technologies, systems genetics as well as new mathematical and computational developments that are now in place to apply a systems biology approach for a comprehensive description of the multidimensional host response to influenza infection. In addition, we describe how results from experimental animal models can be translated to humans, and we discuss some of the future challenges ahead. PMID- 24769046 TI - Dose dependent effects of nitrate supplementation on cardiovascular control and microvascular oxygenation dynamics in healthy rats. AB - High dose nitrate (NO3(-)) supplementation via beetroot juice (BR, 1 mmol/kg/day) lowers mean arterial blood pressure (MAP) and improves skeletal muscle blood flow and O2 delivery/utilization matching thereby raising microvascular O2 pressure (PO2mv). We tested the hypothesis that a low dose of NO3(-) supplementation, consistent with a diet containing NO3(-) rich vegetables (BRLD, 0.3 mmol/kg/day), would be sufficient to cause these effects. Male Sprague-Dawley rats were administered a low dose of NO3(-) (0.3 mmol/kg/day; n=12), a high dose (1 mmol/kg/day; BRHD, n=6) or tap water (control, n=10) for 5 days. MAP, heart rate (HR), blood flow (radiolabeled microspheres) and vascular conductance (VC) were measured during submaximal treadmill exercise (20 m/min, 5% grade, equivalent to ~60% of maximal O2 uptake). Subsequently, PO2mv (phosphorescence quenching) was measured at rest and during 180 s of electrically-induced twitch contractions (1 Hz, ~6 V) of the surgically-exposed spinotrapezius muscle. BRLD and BRHD lowered resting (control: 139 +/- 4, BRLD: 124 +/- 5, BRHD: 128 +/- 9 mmHg, P<0.05, BRLD vs. control) and exercising (control: 138 +/- 3, BRLD: 126 +/- 4, BRHD: 125 +/- 5 mmHg, P<0.05) MAP to a similar extent. For BRLD this effect occurred in the absence of altered exercising hindlimb muscle(s) blood flow or spinotrapezius PO2mv (rest and across the transient response at the onset of contractions, all P>0.05), each of which increased significantly for the BRHD condition (all P<0.05). Whereas BRHD slowed the PO2mv kinetics significantly (i.e., >mean response time, MRT; control: 16.6 +/- 2.1, BRHD: 23.3 +/- 4.7s) following the onset of contractions compared to control, in the BRLD group this effect did not reach statistical significance (BRLD: 20.9 +/- 1.9s, P=0.14). These data demonstrate that while low dose NO3(-) supplementation lowers MAP during exercise it does so in the absence of augmented muscle blood flow, VC and PO2mv; all of which are elevated at a higher dose. Thus, in healthy animals, a high dose of NO3(-) supplementation seems necessary to elicit significant changes in exercising skeletal muscle O2 delivery/utilization. PMID- 24769048 TI - Computational analysis of the importance of flow synchrony for cardiac ventricular assist devices. AB - This paper presents a patient customised fluid-solid mechanics model of the left ventricle (LV) supported by a left ventricular assist device (LVAD). Six simulations were conducted across a range of LVAD flow protocols (constant flow, sinusoidal in-sync and sinusoidal counter-sync with respect to the cardiac cycle) at two different LVAD flow rates selected so that the aortic valve would either open (60mLs(-1)) or remain shut (80mLs(-1)). The simulation results indicate that varying LVAD flow in-sync with the cardiac cycle improves both myocardial unloading and the residence times of blood in the left ventricle. In the simulations, increasing LVAD flow during myocardial contraction and decreasing it during diastole improved the mixing of blood in the LV cavity. Additionally, this flow protocol had the effect of partly homogenising work across the myocardium when the aortic valve did not open, reducing myocardial stress and thereby improving unloading. PMID- 24769049 TI - A magnetic particles-based chemiluminescence enzyme immunoassay for rapid detection of ovalbumin. AB - Egg allergy is an important public health and safety concern, so quantification and administration of food or vaccines containing ovalbumin (OVA) are urgently needed. This study aimed to establish a rapid and sensitive magnetic particles chemiluminescence enzyme immunoassay (MPs-CLEIA) for the determination of OVA. The proposed method was developed on the basis of a double antibodies sandwich immunoreaction and luminol-H2O2 chemiluminescence system. The MPs served as both the solid phase and separator, the anti-OVA MPs-coated polyclonal antibodies (pAbs) were used as capturing antibody, and the horseradish peroxidase (HRP) labeled monoclonal antibody (mAb) was taken as detecting antibody. The parameters of the method were evaluated and optimized. The established MPs-CLEIA method had a linear range from 0.31 to 100ng/ml with a detection limit of 0.24ng/ml. The assays showed low reactivities and less than 5% of intraassay and interassay coefficients of variation (CVs), and the average recoveries were between 92 and 97%. Furthermore, the developed method was applied in real samples analysis successfully, and the correlation coefficient with the commercially available OVA kit was 0.9976. Moreover, it was more rapid and sensitive compared with the other methods for testing OVA. PMID- 24769050 TI - The effect of relationship status on health with dynamic health and persistent relationships. AB - The dynamic evolution of health and persistent relationship status pose econometric challenges to disentangling the causal effect of relationships on health from the selection effect of health on relationship choice. Using a new econometric strategy we find that marriage is not universally better for health. Rather, cohabitation benefits the health of men and women over 45, being never married is no worse for health, and only divorce marginally harms the health of younger men. We find strong evidence that unobservable health-related factors can confound estimates. Our method can be applied to other research questions with dynamic dependent and multivariate endogenous variables. PMID- 24769051 TI - Do more health insurance options lead to higher wages? Evidence from states extending dependent coverage. AB - Little is known about how health insurance affects labor market decisions for young adults. This is despite the fact that expanding coverage for people in their early 20s is an important component of the Affordable Care Act. This paper studies how having an outside source of health insurance affects wages by using variation in health insurance access that comes from states extending dependent coverage to young adults. Using American Community Survey and Census data, I find evidence that extending health insurance to young adults raises their wages. The increases in wages can be explained by increases in human capital and the increased flexibility in the labor market that comes from people no longer having to rely on their own employers for health insurance. The estimates from this paper suggest the Affordable Care Act will lead to wage increases for young adults. PMID- 24769052 TI - Physiological aspects of fruit ripening: the mitochondrial connection. AB - Fruit ripening is a genetically programmed process which leads to an assortment of physiological and metabolic changes that irreversibly alter its characteristics. Depending on the species, fruit maturation can be either climacteric or non-climacteric. In both cases there is a metabolic shift from normal development conditions toward the fully mature state, but climacteric fruit is characterized by a sharp increase in respiration. In non-climacteric fruit, that generally does not display this feature, respiration changes can be affected by processes related to postharvest storage. This review describes some of the many ways in which mitochondrial metabolism is implicated in this crucial reproductive stage, such as the connection between ethylene production and respiration rate, the involvement of alternative oxidase (AOX) and plant uncoupling mitochondrial protein (PUMP) during the ripening and the common alterations of this organelle in fruits affected by different stress conditions. PMID- 24769053 TI - Cytoplasmic male sterility and mitochondrial metabolism in plants. AB - Cytoplasmic male sterility (CMS) is a common feature encountered in plant species. It is the result of a genomic conflict between the mitochondrial and the nuclear genomes. CMS is caused by mitochondrial encoded factors which can be counteracted by nuclear encoded factors restoring male fertility. Despite extensive work, the molecular mechanism of male sterility still remains unknown. Several studies have suggested the involvement of respiration on the disruption of pollen production through an energy deficiency. By comparing recent works on CMS and respiratory mutants, we suggest that the "ATP hypothesis" might not be as obvious as previously suggested. PMID- 24769054 TI - Long term trends in medical emergency team activations and outcomes. AB - AIM OF STUDY: . To analyze long-term medical emergency team (MET) operational trends including number of MET calls, trigger criteria for activation and clinical outcomes at a tertiary level, university hospital with a mature MET system. MATERIALS AND METHODS: The characteristics of 19,030 MET calls between 2000 and 2012 were analyzed in a single-centre, retrospective observational study. Rates indexed per 1000 hospital admissions for MET calls, cardiac arrests, unplanned admissions to the intensive care unit (ICU) and hospital mortality were used as performance measures of the MET. Descriptive statistics (mean+/-standard deviation) were applied and trends analyzed by one-way ANOVA with year 2000 set as the baseline using Dunn's correction for multiple comparisons, p<0.05. RESULTS: Activations of the MET increased between 2000 and 2012 (19+/-3-30+/-4) and there were changes in reasons for activations over time. Clinical concern (worried) was the most common (22%) trigger criterion in 2000 followed by hypotension (21%) and decreased level of consciousness (17%). In 2012, hypotension was the most common trigger (32%), followed by decreased level of consciousness (19%) and clinical concern (15%). Rates of cardiorespiratory arrest (1.4+/-0.7-1.1+/-0.4) and unplanned ICU admission (5.0+/-1.2-5.9+/-1.0) did not change between 2000 and 2012. Hospital mortality decreased from 2005 onwards (15+/-3.4-12+/-2.2). CONCLUSIONS: MET activity progressively increased during the study period and there was a change in pattern of specific triggering criteria. The sustained decrease in hospital mortality independent of cardiac arrest and unplanned ICU admissions rates suggests patient benefit from the MET system. PMID- 24769056 TI - Emerging topics in human tumor virology. PMID- 24769055 TI - Endogenous small RNA clusters in plants. AB - In plants, small RNAs (sRNAs) usually refer to non-coding RNAs (ncRNAs) with lengths of 20-24 nucleotides. sRNAs are involved in the regulation of many essential processes related to plant development and environmental responses. sRNAs in plants are mainly grouped into microRNAs (miRNAs) and small interfering RNAs (siRNAs), and the latter can be further classified into trans-acting siRNAs (ta-siRNAs), repeat-associated siRNAs (ra-siRNAs), natural anti-sense siRNAs (nat siRNAs), etc. Many sRNAs exhibit a clustered distribution pattern in the genome. Here, we summarize the features and functions of cluster-distributed sRNAs, aimed to not only provide a thorough picture of sRNA clusters (SRCs) in plants, but also shed light on the identification of new classes of functional sRNAs. PMID- 24769057 TI - Exosome and microvesicle mediated phene transfer in mammalian cells. AB - Extracellular vesicles (EVs), e.g. exosomes and microvesicles, emerge as new signaling organelles in the exchange of information between cells at the paracrine and systemic level. It is clear that these virus like particles carry complex biological information that can elicit a pleiotropic response in recipient cells with potential relevance in physiology as well as in cancer and other pathological conditions. Numerous studies convincingly show that the molecular composition of EVs closely reflects their cell or tissue of origin. Thus, the signaling status of donor cells, more specifically their endosomal compartments, may largely determine the biological output in recipient cells, a process that we then may conceptualize as vesicle mediated phene transfer. Whereas more conventional modes of cell-cell communication mostly depend on extracellular ligand concentration and cell-surface receptor availability, the magnitude of the EV signaling response relies on the capture and uptake by target cells, allowing release of the EV content. Numerous reports point at the intriguing possibility that, among thousands of mRNAs, miRNAs, and proteins, single EV constituents effectuate the biological response, e.g. stimulation of angiogenesis and cancer cell metastasis, in recipient cells; however, we find it conceivable that strategies targeted at general mechanisms of EV function should provide more rational avenues for therapeutic intervention directed at the EV system. Such strategies include manipulation of EV formation in the endolysosomal system, EV stability in the extracellular milieu, and EV entry into target cells. Here, we provide important insights into potential mechanisms of EV transport in mammalian cells and how these may be targeted. PMID- 24769060 TI - The long and winding road of progress in the use of in vitro data for risk assessment purposes: From "carnation test" to integrated testing strategies. AB - This paper introduces the special issue on quantitative in vitro-in vivo extrapolations (QIVIVE). It highlights important issues in the development of in vitro toxicology towards its implementation in toxicological risk assessment. PMID- 24769059 TI - Effects of tamoxifen on the sex determination gene and the activation of sex reversal in the developing gonad of mice. AB - Tamoxifen, as well as most endocrine-disrupting chemicals, affects the reproductive system and sexual development, but little is known about its disruption of the molecular pathways regulating mammalian sex determination. In fetal mice, the expression levels and pattern of key genes involved in controlling sexually dimorphic balance were analyzed both in vivo and in vitro by using whole-mount in situ hybridization and quantitative-PCR. Developmental tamoxifen exposure induced abnormal up-regulation of the testis differentiation marker Pdfgra in Leydig cells and of Sox9 and Fgf9 in Sertoli cells in XX gonad. Immunohistochemistry analysis confirmed the over-expression of SOX9 protein. Accordingly, the ovary development marker Foxl2 was depressed at both the mRNA and protein levels. The increase in testosterone and the reduction in 17beta estradiol and progesterone were observed by using the in vitro assay with organotypic cultures. Taken together, results indicated that tamoxifen induced the ectopic expression of well-established sex-specific genes during the critical developmental period, thus resulting in abnormal testicular development in the XX gonad of mammals. This study facilitates a better understanding of the molecular mechanisms of antiestrogens and possibly of compounds that interrupt estrogen signaling by other modes of action, and the association with the pathogenesis of human sexual developmental disorders. PMID- 24769058 TI - Sorting it out: regulation of exosome loading. AB - Extracellular vesicles (EVs), a term that includes both exosomes of endocytic origin and vesicles derived from plasma membranes, are continuously secreted by cells to the extracellular environment, and represent a novel vehicle for cell cell communication. Exosomes contain specific repertoires of proteins and RNAs, indicating the existence of mechanisms that control the sorting of molecules into them. Although the molecular mechanisms that regulate the loading of proteins into exosomes have been studied for years, the sorting of RNA has been elusive until recently. Here we review the molecular mechanisms that control the sorting of molecules into exosomes, with special attention to the sorting of RNA. We also discuss how the cellular context affects the composition of exosomes, and thus the outcome of the communication between the exosome-producer and recipient cells, with particular focus on the communication between tumor cells and with cells of the tumor microenvironment. PMID- 24769061 TI - 24-epibrassinolide and 20-hydroxyecdysone affect photosynthesis differently in maize and spinach. AB - The aim of the work was to examine the effect of brassinosteroid (24 epibrassinolide; 24E) and ecdysteroid (20-hydroxyecdysone; 20E) on various parts of primary photosynthetic processes in maize and spinach. Additionally, the effect of steroids on gaseous exchange, pigment content and biomass accumulation was studied. The efficiency of the photosynthetic whole electron-transport chain responded negatively to the 24E or 20E treatment in both species, but there were interspecific differences regarding Photosystem (PS) II response. A positive effect on its oxygen-evolving complex and a slightly better energetical connectivity between PSII units were observed in maize whereas the opposite was true for spinach. The size of the pool of the PSI end electron acceptors was usually diminished due to 24E or 20E treatment. The treatment of plants with 24E or 20E applied individually positively influenced the content of photosynthetic pigments in maize (not in spinach). On the other hand, it did not affect gaseous exchange in maize but resulted in its reduction in spinach. Plants treated with combination of both steroids mostly did not significantly differ from the control plants. We have demonstrated for the first time that 20E applied in low (10nM) concentration can affect various parts of photosynthetic processes similarly to 24E and that brassinosteroids regulate not only PSII but also other parts of the photosynthetic electron transport chain - but not necessarily in the same way. PMID- 24769062 TI - Comparison of a novel extraction-based colorimetric (ABTS) method with membrane introduction mass spectrometry (MIMS): trichloramine dynamics in pool water. AB - Trichloramine is a hazardous disinfection by-product, which is present in chlorinated swimming pools. Although it is primarily taken up by inhalation, the concentration in pool water is important to monitor pool water quality and to assess trichloramine mitigation strategies. To date, scarce data is available on trichloramine concentration in pool water due to the lack of a suitable and easily applicable analytical method. This study presents a novel low cost, colorimetric method which is easy to operate and suitable for on-site measurements of trichloramine concentrations >=0.05 MUM (>=0.01 mg L(-1) as Cl2). The analytical method (termed "extraction-based ABTS method") consists of, (i) trichloramine stripping from pool water samples, (ii) passing it through a solid phase filter, composed of silica gel impregnated with sulfamic acid to eliminate interferences and (iii) trichloramine reaction with the indicator 2,2-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) to produce the coloured ABTS(*-) radical, which is measured at lambda = 405 nm to determine the trichloramine concentration in the pool water sample. A comparison of the extraction-based ABTS method with membrane introduction mass spectrometry (MIMS) for 28 pool samples revealed a good correlation of the two methods. The trichloramine concentration in pool samples is correlated to HOCl, which is the most important factor for its formation. Other parameters such as combined chlorine and pH play a minor role while no correlation between trichloramine and the urea or the TOC concentration was observed. On-site measurements with MIMS in a wading pool over 6 days with a time resolution of 1 h confirmed that trichloramine concentrations strongly responded to changes in free chlorine concentrations. A diurnal measurement of trichloramine with a time resolution of 20 min revealed that trichloramine concentrations reacted quickly and sensitively to the bather load and that urea is probably not the main precursor for its formation. PMID- 24769063 TI - From sensorimotor learning to memory cells in prefrontal and temporal association cortex: a neurocomputational study of disembodiment. AB - Memory cells, the ultimate neurobiological substrates of working memory, remain active for several seconds and are most commonly found in prefrontal cortex and higher multisensory areas. However, if correlated activity in "embodied" sensorimotor systems underlies the formation of memory traces, why should memory cells emerge in areas distant from their antecedent activations in sensorimotor areas, thus leading to "disembodiment" (movement away from sensorimotor systems) of memory mechanisms? We modelled the formation of memory circuits in six-area neurocomputational architectures, implementing motor and sensory primary, secondary and higher association areas in frontotemporal cortices along with known between-area neuroanatomical connections. Sensorimotor learning driven by Hebbian neuroplasticity led to formation of cell assemblies distributed across the different areas of the network. These action-perception circuits (APCs) ignited fully when stimulated, thus providing a neural basis for long-term memory (LTM) of sensorimotor information linked by learning. Subsequent to ignition, activity vanished rapidly from APC neurons in sensorimotor areas but persisted in those in multimodal prefrontal and temporal areas. Such persistent activity provides a mechanism for working memory for actions, perceptions and symbols, including short-term phonological and semantic storage. Cell assembly ignition and "disembodied" working memory retreat of activity to multimodal areas are documented in the neurocomputational models' activity dynamics, at the level of single cells, circuits, and cortical areas. Memory disembodiment is explained neuromechanistically by APC formation and structural neuroanatomical features of the model networks, especially the central role of multimodal prefrontal and temporal cortices in bridging between sensory and motor areas. These simulations answer the "where" question of cortical working memory in terms of distributed APCs and their inner structure, which is, in part, determined by neuroanatomical structure. As the neurocomputational model provides a mechanistic explanation of how memory-related "disembodied" neuronal activity emerges in "embodied" APCs, it may be key to solving aspects of the embodiment debate and eventually to a better understanding of cognitive brain functions. PMID- 24769064 TI - Supramolecular gels of poly-alpha-cyclodextrin and PEO-based copolymers for controlled drug release. AB - The aim of this work was to prepare syringeable supramolecular gels of alpha cyclodextrin-polymer (poly-alphaCD) with various poly(ethylene oxide) (PEO)-based copolymers, which can be suitable to form depots for controlled drug release. A series of water-soluble poly-alphaCDs was synthesized from alphaCD by crosslinking with epichlorohydrin in alkaline medium. The chemical composition of the polymers was characterized by NMR (alphaCD content>53%) and the molecular weight was evaluated using static light scattering (SLS). Supramolecular assemblies occurred by mixing poly-alphaCD (20-40% w/v) with a PEO-based polymer (i.e., PEG, Pluronic(r) F127 or Tetronic(r) 908) (10-15% w/v). Phase separation was observed and the alphaCD content in each phase was determined by means of the phenol-sulfuric acid colorimetric method. Formation of poly-alphaCD/PEO-based polymer 3D-supramolecular complexes was confirmed by diffusion-ordered NMR spectroscopy (DOSY) and X-ray diffractometry. The supramolecular assemblies showed good cytocompatibility against SAOS-2 cells and in the HET-CAM test. The supramolecular gels were able to sustain the release of vancomycin for at least 5 days at 37 degrees C, more efficiently than dispersions of each polymer component in separate. These results open new possibilities in the design of novel controlled delivery systems for the treatment of bone infections. PMID- 24769065 TI - Mannose derivative and lipid A dually decorated cationic liposomes as an effective cold chain free oral mucosal vaccine adjuvant-delivery system. AB - To develop convenient, effective cold chain-free subunit vaccines, a mannose-PEG cholesterol conjugate (MPC) was synthesized as a lectin binding molecule and anchored onto liposomes which entrapped lipid A and model antigen to form a vaccine adjuvant-delivery system targeting antigen presenting cells. With MPC, soy phosphatidylcholine, stearylamine and monophosphoryl lipid A as emulsifiers dissolved in oil phase (O), and sucrose and BSA in water phase (W), the O/W emulsions were prepared and subsequently lyophilized. The lyophilized product was stable enough to be stored at room temperature and, upon rehydration, formed MPC /lipid A-liposomes (MLLs) with a size under 300 nm and antigen association rates of around 36%. The MLLs given to mice via oral mucosal (o.m.) administration showed no side effects but induced potent immune responses as evidenced by the high levels of IgG in the sera and IgA in the salivary, intestinal and vaginal secretions of mice. High levels of IgG2a and IFN-gamma in treated mice revealed that MLLs via o.m. vaccination induced a mixed Th1/Th2 response against antigens, establishing both humoral and cellular immunity. Thus, the MLLs may be a potent cold chain-free oral mucosal vaccine adjuvant-delivery system. PMID- 24769067 TI - Production of bone marrow, liver, thymus (BLT) humanized mice on the C57BL/6 Rag2(-/-)gammac(-/-)CD47(-/-) background. AB - C57BL/6 Rag2(-/-)gammac(-/-)CD47(-/-) triple-knockout mice engrafted with fetal human bone marrow, liver, thymus (TKO-BLT) not only develop high levels of multi lineage hematopoiesis but also organized lymphoid tissues including mesenteric lymph nodes, splenic follicles and gut-associated lymphoid tissues of human origin. A unique advantage of these mice is that they sustain human cell and tissue engraftment long-term without the development of graft versus host disease. Thus they can be used for long-term studies not previously feasible with other models. The production of TKO-BLT mice to obtain healthy mice with high level reconstitution of human cells and tissues requires specialized methods that are presented in detail. PMID- 24769068 TI - Effectiveness of aquatic exercise for musculoskeletal conditions: a meta analysis. AB - OBJECTIVE: To investigate the effectiveness of aquatic exercise in the management of musculoskeletal conditions. DATA SOURCES: A systematic review was conducted using Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, and The Cochrane Central Register of Controlled Trials from earliest record to May 2013. STUDY SELECTION: We searched for randomized controlled trials (RCTs) and quasi-RCTs evaluating aquatic exercise for adults with musculoskeletal conditions compared with no exercise or land-based exercise. Outcomes of interest were pain, physical function, and quality of life. The electronic search identified 1199 potential studies. Of these, 1136 studies were excluded based on title and abstract. A further 36 studies were excluded after full text review, and the remaining 26 studies were included in this review. DATA EXTRACTION: Two reviewers independently extracted demographic data and intervention characteristics from included trials. Outcome data, including mean scores and SDs, were also extracted. DATA SYNTHESIS: The Physiotherapy Evidence Database (PEDro) Scale identified 20 studies with high methodologic quality (PEDro score >=6). Compared with no exercise, aquatic exercise achieved moderate improvements in pain (standardized mean difference [SMD]=-.37; 95% confidence interval [CI], .56 to -.18), physical function (SMD=.32; 95% CI, .13-.51), and quality of life (SMD=.39; 95% CI, .06-.73). No significant differences were observed between the effects of aquatic and land-based exercise on pain (SMD=-.11; 95% CI, -.27 to .04), physical function (SMD=-.03; 95% CI, -.19 to .12), or quality of life (SMD= .10; 95% CI, -.29 to .09). CONCLUSIONS: The evidence suggests that aquatic exercise has moderate beneficial effects on pain, physical function, and quality of life in adults with musculoskeletal conditions. These benefits appear comparable across conditions and with those achieved with land-based exercise. Further research is needed to understand the characteristics of aquatic exercise programs that provide the most benefit. PMID- 24769066 TI - Mouse models for infectious diseases caused by Staphylococcus aureus. AB - Staphylococcus aureus - a commensal of the human skin, nares and gastrointestinal tract - is also a leading cause of bacterial skin and soft tissue infection (SSTIs), bacteremia, sepsis, peritonitis, pneumonia and endocarditis. Antibiotic resistant strains, designated MRSA (methicillin-resistant S. aureus), are common and represent a therapeutic challenge. Current research and development efforts seek to address the challenge of MRSA infections through vaccines and immune therapeutics. Mice have been used as experimental models for S. aureus SSTI, bacteremia, sepsis, peritonitis and endocarditis. This work led to the identification of key virulence factors, candidate vaccine antigens or immune therapeutics that still require human clinical testing to establish efficacy. Past failures of human clinical trials raised skepticism whether the mouse is an appropriate model for S. aureus disease in humans. S. aureus causes chronic persistent infections that, even with antibiotic or surgical intervention, reoccur in humans and in mice. Determinants of S. aureus evasion from human innate and adaptive immune responses have been identified, however only some of these are relevant in mice. Future research must integrate these insights and refine the experimental mouse models for specific S. aureus diseases to accurately predict the failure or success for candidate vaccines and immune therapeutics. PMID- 24769069 TI - Individuals with chronic traumatic brain injury improve walking speed and mobility with intensive mobility training. AB - OBJECTIVE: To determine the feasibility and impact of different dosages of Intensive Mobility Training (IMT) on mobility, balance, and gait speed in individuals with chronic traumatic brain injury (TBI). DESIGN: Prospective, single group design with 3-month follow-up. SETTING: University research laboratory. PARTICIPANTS: Volunteer sample of participants with chronic TBI (N=10; >=3 mo post-TBI; able to ambulate 3.05 m with or without assistance; median age, 35.4 y; interquartile range, 23.5-46 y; median time post-TBI, 9.91 y; interquartile range, 6.3-14.2 y). Follow-up data were collected for all participants. INTERVENTIONS: Twenty days (5 d/wk for 4 wk), with 150 min/d of repetitive, task-specific training equally divided among balance; gait training; and strength, coordination, and range. MAIN OUTCOME MEASURES: Pain and fatigue were recorded before and after each session to assess feasibility. Treatment outcomes were assessed before training (pre), after 10 sessions (interim), after 20 sessions (post), and at 3-months follow-up and included the Berg Balance Scale and gait speed. RESULTS: Participants averaged 150.1+/-2.7 minutes per session. Median presession and postsession pain scores were 0 (out of 10) for 20 sessions; median presession fatigue scores ranged from 0 to 2.5 (out of 10); and postsession scores ranged from 3 to 5.5 (out of 10). Four outcome measures demonstrated significant improvement from the pretest to interim, with 7 out of 10 participants exceeding the minimal detectable change (MDC) for fast walking speed. At the posttest, 2 additional measures were significant, with more participants exceeding the MDCs. Changes in fast walking speed and Timed Up and Go test were significant at follow-up. CONCLUSIONS: Limited fluctuations in pain and fatigue scores indicate feasibility of IMT in this population. Participants demonstrated improvements in walking speed, mobility, and balance postintervention and maintained gains in fast walking speed and mobility at 3 months. PMID- 24769070 TI - Whole body oxygen uptake and evoked torque during subtetanic isometric electrical stimulation of the quadriceps muscles in a single 30-minute session. AB - OBJECTIVE: To evaluate the time course of fatigue in torque output and oxygen uptake during isometric subtetanic neuromuscular electrical stimulation (NMES) to facilitate the design of NMES-based rehabilitation protocols that can accumulate a defined aerobic exercise volume within a given time period. DESIGN: Single-arm intervention study with within-subject comparisons. SETTING: University research laboratory. PARTICIPANTS: Volunteer sample of healthy men (N=11; mean age, 34.2 +/- 11.5 y; range, 19-53 y; body mass, 79.1 +/- 11.7 kg; range, 58-100 kg). INTERVENTION: A single 30-minute session of continuous bilateral isometric quadriceps NMES at 4 Hz evoking a mean twitch amplitude of 12% of the maximum voluntary contraction. MAIN OUTCOME MEASURES: Whole body oxygen consumption rate (Vo2), and evoked torque were measured simultaneously throughout. RESULTS: Mean increment in Vo2 was 596 +/- 238 mL/min, and average exercise intensity during the session was 3 +/-.47 metabolic equivalents. The Vo2 and torque declined slowly at a rate of -.54%+/-.31% and -.47%+/-.57% per minute, respectively. CONCLUSIONS: Despite having a higher incremental Vo2, the observed fatigue rate was considerably less than that previously reported during intermittent isometric tetanic stimulation, suggesting that subtetanic isometric NMES is more sustainable for exercise interventions aimed at accumulating a therapeutic aerobic exercise volume. PMID- 24769071 TI - Enhanced electrochemiluminescence from luminol at carboxyl graphene for detection of alpha-fetoprotein. AB - In this study, a novel sensitive electrochemiluminescence (ECL) immunosensor was constructed by carboxyl graphene (GR) for enhancing luminol-O2 system emission. Here, carboxyl GR was used to enhance the ECL intensity of luminol that had excellent electron transfer ability and good solubility. The sensing platform was constructed by depositing carboxyl GR on electrodes and immobilizing antibodies on the surface of carboxyl GR through amidation. The specific immunoreaction between alpha-fetoprotein (AFP) and antibodies resulted in a decrease of ECL intensity, and the intensity decreased linearly with AFP concentrations in the range of 5 pg ml(-1) to 14 ng ml(-1) with a detection limit of 2.0 pg ml(-1). The proposed immunosensor exhibits high specificity, good reproducibility, and longtime stability. It may become a promising technique for protein detection. PMID- 24769072 TI - MiRNA expression profile reveals a prognostic signature for esophageal squamous cell carcinoma. AB - In this study, we analyzed the microRNA (miRNA) expression profile of 119 paired ESCC samples by microarray and identified a four-miRNA signature that predicted patient survival. The signature derived from the training set (n=60) had a good prognostic value in the test set (n=59) and the independent cohort (n=58), indicating the replicability of its prognostic value. Furthermore, the stratified analysis showed that the signature could predict the survival of TNM stage II and stage III patients, indicating that the four-miRNA signature could help to more accurately predict ESCC patient survival. PMID- 24769073 TI - LRH1 promotes pancreatic cancer metastasis. AB - The transcriptional factor liver receptor homolog 1 (LRH1) regulates pancreatic development, and may participate in pancreatic oncogenesis through activation of growth factor signaling transduction cascades. We measured transcriptional activity of beta-catenin in response to LRH1 stimulation by a Topflash reporter assay. The pancreatic cancer (PC) phenotype was then characterized by cell migration, wound healing, invasion, and sphere formation in vitro, as well as tumor formation and distant metastatic spread in vivo. We compared results between vector control and LRH1-overexpressing stable PC cell lines. In addition, tumor burden, angiogenesis, histologic characteristics, and hepatic spread were assessed in orthotopic and experimental liver metastatic murine models. Expression of downstream LRH1 related genes was evaluated by Western blot and immunohistochemistry in PC cell lines and human tumor specimens. Specific inhibition of LRH1 expression and function was accomplished by shRNAs "knockdown" experiments. It was found that LRH1 enhanced transcriptional activity of beta catenin and the expression of downstream target genes (c-Myc, MMP2/9), as well as promoted migration, wound healing, invasion, and sphere formation of PC cell lines. Specific inhibition of LRH1 by shRNAs reduced cell migration, invasion, sphere formation and expression of c-Myc and MMP2/9 target genes. Mice injected with LRH1 overexpressing stable PC cells developed tumors with increased size and exhibited striking hepatic metastatic spread. More important, LRH1 was overexpressed in PC tumors compared to adjacent normal pancreas. Our findings demonstrate that LRH1 overexpression is associated with increased PC growth and metastatic spread, indicating that LRH1-targeted therapy could inhibit tumor progression. PMID- 24769075 TI - Precision medicine--delivering the goods? AB - Personalized (or precision) medicine aims to individualize therapeutic interventions, based on OMICS data such as genomics, proteomics, metabolomics etc', profiling together with histopathological insights to the type, stage, and the grade of the disease, as well as on the potential response of a particular patient to a particular treatment regimen. With next generation sequencing technologies, it is now possible to identify all germline variants of an individual in an affordable cost and thus paving the way for clinicians to provide healthcare from an individual perspective. In this special issue of Cancer Letters termed "Trends in Personalized Cancer Research" we bring together physicians and scientists summarizing the state-of-the-art in precision medicine from hematological malignancies and solid tumors with the current gold standard diagnostic and therapy to basic and translational research utilizing nanotechnology and RNA interference strategies for future personalized theranostics in oncology. PMID- 24769074 TI - Suppression of pancreatic cancer by sulfated non-anticoagulant low molecular weight heparin. AB - Sulfated non-anticoagulant heparins (S-NACHs) might be preferred for potential clinical use in cancer patients without affecting hemostasis as compared to low molecular weight heparins (LMWHs). We investigated anti-tumor effects, anti angiogenesis effects, and mechanisms of S-NACH in a mouse model of pancreatic cancer as compared to the LMWH tinzaparin. S-NACH or tinzaparin with or without gemcitabine were administered, and tumor luminescent signal intensity, tumor weight, and histopathology were assessed at the termination of the study. S-NACH and LMWH efficiently inhibited tumor growth and metastasis, without any observed bleeding events with S-NACH as compared to tinzaparin. S-NACH distinctly increased tumor necrosis and enhanced gemcitabine response in the mouse pancreatic cancer models. These data suggest the potential implication of S-NACH as a neoadjuvant in pancreatic cancer. PMID- 24769076 TI - Recent advances in imaging-guided interventions for prostate cancers. AB - The numbers of patients diagnosed with prostate cancers is increasing due to the widespread application of prostate-specific antigen screening and subsequent prostate biopsies. The methods of systemic administration of therapeutics are not target-specific and thus cannot efficiently destroy prostate tumour cells while simultaneously sparing the surrounding normal tissues and organs. Recent advances in imaging-guided minimally invasive therapeutic techniques offer considerable potential for the effective management of prostate cancers. An objective understanding of the feasibility, effectiveness, morbidity, and deficiencies of these interventional techniques is essential for both clinical practice and scientific progress. This review presents the recent advances in imaging-guided interventional techniques for the diagnosis and treatment of prostate cancers. PMID- 24769078 TI - Web-based tracking methods in longitudinal studies. AB - The use of online resources to reduce the attrition of program participants in longitudinal studies is examined. Higher-risk individuals, those involved in illegal activities, and females with last name changes are typically more difficult to locate. The effectiveness of using online resources for these participants is addressed. These resources include social networking sites, people-finder search engines, telephone and address directories, judicial records, and death records. The strengths and limitations of these resources are presented and discussed. Longitudinal studies using these resources are examined to evaluate their successful follow-up rates. The results of these studies indicate that participant characteristics are more important to successful follow up than the length of time since participation or sample size. The use of multiple online sites increased follow-up rates, especially for those who are typically difficult to locate. The variables and websites to consider are discussed, and six lessons learned are offered. The prospective use of online participant involvement is especially important for successful longitudinal evaluation and program planning. PMID- 24769079 TI - HLA epitope based matching for transplantation. AB - As important risk factors for transplant rejection and failure, HLA antibodies are now recognized as being specific for epitopes which can be defined structurally with amino acid differences between HLA alleles. Donor-recipient compatibility should therefore be assessed at the epitope rather than the antigen level. HLAMatchmaker is a computer algorithm that considers each HLA antigen as a series of small configurations of polymorphic residues referred to as eplets as essential components of HLA epitopes. It includes epitopes on antigens encoded by all HLA-A, B, C, DR, DQ and DP loci as well as MICA. HLA epitopes have two characteristics namely antigenicity, i.e. the reactivity with antibody and immunogenicity, i.e. the ability of eliciting an antibody response. This article addresses the relevance of determining epitope-specificities of HLA antibodies, the effect of epitope structure on technique-dependent antibody reactivity and the identification of acceptable mismatches for sensitized patients considered for transplantation. Permissible mismatching for non-sensitized patients aimed to prevent or reduce HLA antibody responses could consider epitope loads of mismatched antigens and the recently developed nonself-self paradigm of epitope immunogenicity. PMID- 24769077 TI - O-GlcNAc signaling in cancer metabolism and epigenetics. AB - The covalent attachment of beta-D-N-acetylglucosamine monosaccharides (O-GlcNAc) to serine/threonine residues of nuclear and cytoplasmic proteins is a major regulatory mechanism in cell physiology. Aberrant O-GlcNAc modification of signaling proteins, metabolic enzymes, and transcriptional and epigenetic regulators has been implicated in cancer. Relentless growth of cancer cells requires metabolic reprogramming that is intertwined with changes in the epigenetic landscape. This review highlights the emerging role of protein O GlcNAcylation at the interface of cancer metabolism and epigenetics. PMID- 24769081 TI - Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. AB - Molecular hydrogen (H2) has been accepted to be an inert and nonfunctional molecule in our body. We have turned this concept by demonstrating that H2 reacts with strong oxidants such as hydroxyl radical in cells, and proposed its potential for preventive and therapeutic applications. H2 has a number of advantages exhibiting extensive effects: H2 rapidly diffuses into tissues and cells, and it is mild enough neither to disturb metabolic redox reactions nor to affect signaling reactive oxygen species; therefore, there should be no or little adverse effects of H2. There are several methods to ingest or consume H2; inhaling H2 gas, drinking H2-dissolved water (H2-water), injecting H2-dissolved saline (H2-saline), taking an H2 bath, or dropping H2-saline into the eyes. The numerous publications on its biological and medical benefits revealed that H2 reduces oxidative stress not only by direct reactions with strong oxidants, but also indirectly by regulating various gene expressions. Moreover, by regulating the gene expressions, H2 functions as an anti-inflammatory and anti-apoptotic, and stimulates energy metabolism. In addition to growing evidence obtained by model animal experiments, extensive clinical examinations were performed or are under investigation. Since most drugs specifically act to their targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has promising potential for clinical use against many diseases. PMID- 24769082 TI - A generalized free-solvent model for the osmotic pressure of multi-component solutions containing protein-protein interactions. AB - The free-solvent model has been shown to have excellent predictability of the osmotic pressure for single and binary non-interactive proteins in aqueous solutions. Here the free-solvent model is extended to be more generalized by including the contributions of intra- and inter-protein interactions to the osmotic pressure of a solution in the form of homo- and hetero-multimers. The solute-solvent interactions are considered to be unique for each homo- and hetero multimer in solution. The effect of the various generalized free-solvent model parameters on the osmotic pressure are examined for a single protein solution with a homo-dimer, a binary protein solution with no protein-protein interactions, and a binary protein solution with a hetero-dimer. Finally, the limitations associated with the generalized free-solvent model are discussed. PMID- 24769083 TI - Protective effect of polysaccharides from Sargassum horneri against oxidative stress in RAW264.7 cells. AB - This study was designed to investigate chemical composition and the protective effects of polysaccharides isolated from Sargassum horneri against hydrogen peroxide (H2O2)-induced oxidative injury in RAW264.7 cells. Results showed that isolated polysaccharides (SHSc) and the major fractions (SHS1, SHS0.5) contained sulfate ester, and SHS1 was high fucose-containing sulfated polysaccharide. After preincubation with three isolated polysaccharides, RAW264.7 cells viability were significantly restored and decreased in cellular LDH release (P<0.05). SHS1 and SHS0.5 decreased intracellular ROS level, intracellular NO and malonic dialdehyde (MDA) level (P<0.05), restoring activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) (P<0.05), decreasing inducible nitric oxide synthase (iNOS) (P<0.05). Moreover, preincubation of SHS1 with RAW264.7 cells resulted in the increase of the gene expression level of endogenous antioxidant enzymes such as MnSOD and GSH-Px (P<0.05). These results clearly showed that SHSc and its fractions could attenuate H2O2-induced stress injury in RAW264.7 cells, and a similar efficiency in protecting RAW264.7 cells against H2O2-induced oxidative injury between SHS1 and Vitamin C. Taken together, our findings suggested that SHS1 can effectively protect RAW264.7 cells against oxidative stress by H2O2, which might be used as a potential natural antioxidant in the functional food and pharmaceutical industries. PMID- 24769080 TI - Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights. AB - Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer. PMID- 24769084 TI - Preparation and drug release properties of chitosan/organomodified palygorskite microspheres. AB - The novel composite microspheres, based on the hybridization of chitosan (CS) and organomodified palygorskite (OPAL), were prepared by emulsion cross-linking technique and applied as a drug carrier. Palygorskite, a kind of natural one dimensional clay, was modified with hexadecyl betaine (BS-16) to improve the compatibility and affinity with chitosan matrix, and worked as a perfect micron filler to enhance drug encapsulation and retard drug migration. The structure of the microspheres was characterized by fourier transform infrared spectroscopy (FT IR), scanning electron microscopy (SEM) and X-ray diffraction (XRD) techniques. The swelling behavior of the microspheres and the effect of the amount of OPAL and BS-16 on the properties of the drug loading and releasing have been investigated. Compared to the pure chitosan microspheres (CM), the composite one with 20wt% OPAL modified by 20mmol/100g BS-16 possessed the higher encapsulation efficiency and the slower and continuous cumulative release for diclofenac sodium (DS) in phosphate buffer solution (pH 6.8). The study of drug release kinetics in vitro found that the drug release mechanism of the microspheres changed from the simple diffusion-control to diffusion and dissolution-control as the OPAL content in matrix increased from 0 to 20wt%. PMID- 24769085 TI - Construction and expression of mutagenesis strain of aroG gene from Escherichia coli K-12. AB - 3-Deoxy-d-arabino-heptulonate-7-phosphate (DAHP) synthase is one of the key enzymes, which catalyzes the first step in the aromatic amino acid biosynthetic pathway and yields the three amino acids tyrosine (Tyr), tryptophan (Typ), and phenylalanine (Phe). In Escherichia coli (E. coli), three differently regulated DAHP synthases carry out the first regulated step in the aromatic amino acid biosynthetic pathway. The three DAHP synthases encoded by the genes aroG, aroF, and aroH are inhibited by phenylalanine, tyrosine and tryptophan, respectively. In this work, the aroG gene was cloned and mutated by site-directed mutagenesis using overlap extension PCR (SOE-PCR) technique. The feedback-resistant DAHP synthase encoded by aroG was achieved by replacing the residue Pro150 of aroG with Leu as to increase net carbon flow down the common pathway. SDS-PAGE and Western blots were used to assess the protein expression level of aroGM which showed the strain harboring the mutated aroGM150 gene achieving over-expression compared to the strain containing an empty plasmid pET-28b((+)). PMID- 24769086 TI - Use and application of gelatin as potential biodegradable packaging materials for food products. AB - The manufacture and potential application of biodegradable films for food application has gained increased interest as alternatives to conventional food packaging polymers due to the sustainable nature associated with their availability, broad and abundant source range, compostability, environmentally friendly image, compatibility with foodstuffs and food application, etc. Gelatin is one such material and is a unique and popularly used hydrocolloid by the food industry today due to its inherent characteristics, thereby potentially offering a wide range of further and unique industrial applications. Gelatin from different sources have different physical and chemical properties as they contain different amino acid contents which are responsible for the varying characteristics observed upon utilization in food systems and when being utilized more specifically, in the manufacture of films. Packaging films can be successfully produced from all gelatin sources and the behaviour and characteristics of gelatin-based films can be altered through the incorporation of other food ingredients to produce composite films possessing enhanced physical and mechanical properties. This review will present the current situation with respect to gelatin usage as a packaging source material and the challenges that remain in order to move the manufacture of gelatin-based films nearer to commercial reality. PMID- 24769087 TI - Effect of microwave-assisted dry heating with xanthan on normal and waxy corn starches. AB - Normal corn starch (CS) and waxy corn starch (WCS) were impregnated with xanthan gum (1% based on starch) and heat-treated using a microwave in a dry state for 0, 4, or 6min (CS-X0, CS-X4, CS-X6, WCS-X0, WCS-X4, WCS-X6), respectively. Effects of the microwave-assisted dry heating (MADH) on pasting, morphological, and structural properties were evaluated. The results revealed that the viscosity of both the CS and WCS with xanthan increased compared with untreated samples after MADH, and the effect on WCS was more obvious. The syneresis values showed that the water-holding ability of CS-X6 and WCS-X6 increased, and that value of CS was lower than that of WCS after MADH with xanthan. The MADH with xanthan reduced the To, Tc, Tp, and DeltaH values of both the CS and WCS. After MADH, the particle morphology of the starch-xanthan connected more densely, especially WCS, and the gelatinized samples exhibited a strong and smooth laminar structure. The Fourier transform Infrared Spectroscopy (FTIR) displayed that the absorption peak width of both CS-X6 and WCS-X6 became larger. X-ray diffraction showed that the crystallinity of CS-X6 and WCS-X6 decreased slightly as a result of MADH, and the crystalline pattern remained A-type. PMID- 24769088 TI - Electrospun chitosan/sericin composite nanofibers with antibacterial property as potential wound dressings. AB - Chitosan and sericin are natural and low cost biomaterials. Both biomaterials displayed good compatibility to human tissues and antibacterial properties for biomedical application. In this study, we have successfully fabricated chitosan/sericin composite nanofibers by electrospinning. The obtained composite nanofibers were characterized using scanning electron microscopy (SEM), Fourier transform infrared spectrometer (FT-IR), X-ray diffraction (XRD), and thermogravimetric analysis (TGA) studies. The composite nanofibers had good morphology with diameter between 240nm and 380nm. In vitro methyl thiazolyl tetrazolium (MTT) assays demonstrated that the chitosan/sericin composite nanofibers were biocompatible and could promote the cell proliferation. Furthermore, the composite nanofibers showed good bactericidal activity against both of Gram-positive and Gram-negative bacteria. Thus, the chitosan/sericin composite nanofibers are promising for wound dressing applications. PMID- 24769089 TI - Composite films of poly(vinyl alcohol)-chitosan-bacterial cellulose for drug controlled release. AB - Mono and multilayer composite films of poly(vinyl alcohol)-chitosan-bacterial cellulose (PVA/chitosan/BC) have been prepared to achieve controlled release of ibuprofen sodium salt (IbuNa) as model drug. The composite films have been characterized by Fourier transformed infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Surface morphology was investigated by scanning electron microscopy (SEM). Equilibrium swelling was measured in water at two different pH values and in vitro release of IbuNa in pH 1.2 and pH 7.4 media was studied. The release experiments revealed that drug release is pH sensitive. The release kinetics of IbuNa could be described by the Fickian model of diffusion with a good agreement. The IbuNa release rate was decreasing for all the films as the BC concentration was increased in the films composition, the decrease being higher for the multilayer films. PMID- 24769090 TI - Fibroblast growth factor (Fgf) 21 is a novel target gene of the aryl hydrocarbon receptor (AhR). AB - The toxic effects of dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (-105/+1 base pair). Fgf21-null mice administered 200MUg/kg of TCDD died within 20days, whereas wild type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver. PMID- 24769091 TI - Testicular distribution and toxicity of a novel LTA4H inhibitor in rats. AB - JNJ 40929837, a novel leukotriene A4 hydrolase inhibitor in drug development, was reported to induce testicular toxicity in rats. The mechanism of toxicity was considered to be rodent specific and not relevant to humans. To further investigate this finding in rats, the distribution and toxicokinetics of JNJ 40929837 and its two metabolites, M1 and M2, were investigated. A quantitative whole body autoradiography study showed preferential distribution and retention of JNJ 40929837-derived radioactivity in the testes consistent with the observed site of toxicity. Subsequent studies with unlabeled JNJ 40929837 showed different metabolite profiles between the plasma and testes. Following a single oral 50mg/kg dose of JNJ 40929837, M2 was the primary metabolite in plasma whereas M1 was the primary metabolite in testes. The exposure of M1 was 386-fold higher in the testes compared to plasma whereas M2 had limited exposure in testes. Furthermore, the Tmax of M1 was 48h in testes suggesting a large accumulation potential of this metabolite in testes compared to plasma. Following six months of repeated daily oral dosing, M1 accumulated approximately five-fold in the testes whereas the parent did not accumulate. These results indicate that the toxicokinetic profiles of JNJ 40929837 and its two metabolites in testes are markedly different compared to plasma and support the importance of understanding the toxicokinetic profiles of compounds and their metabolites in organs/tissues where toxicity is observed. PMID- 24769092 TI - Cytomegalovirus microRNAs. AB - The discovery that animals, plants and DNA viruses encode microRNAs (miRNAs) has transformed our understanding of the regulation of gene expression. miRNAs are ubiquitous small non-coding RNAs that regulate gene expression post transcriptionally, generally by binding to sites within the 3' untranslated regions (UTR) of messenger RNA (mRNA) transcripts. To date, over 250 viral miRNAs have been identified primarily in members of the herpesvirus family. These viral miRNAs target both viral and cellular genes in order to regulate viral replication, the establishment and maintenance of viral latency, cell survival, and innate and adaptive immunity. This review will focus on our current knowledge of the targets and functions of human cytomegalovirus (HCMV) miRNAs and their functional equivalents in other herpesviruses. PMID- 24769093 TI - Retroviral microRNAs. AB - Eukaryotic cells and several DNA viruses encode miRNAs to regulate the expression of specific target genes. It has been controversial whether RNA viruses can encode such miRNAs as miRNA excision may lead to cleavage of the viral RNA genome. We will focus on the retrovirus family, HIV-1 in particular, and discuss the production of virus-encoded miRNAs and their putative function in the viral replication cycle. An intricate scenario of multi-layer virus-host interactions becomes apparent with small RNAs as the regulatory molecules. PMID- 24769095 TI - Carcass quality, physico-chemical parameters, muscle fibre traits and myosin heavy chain composition of m. longissimus lumborum from Pulawska and Polish Large White pigs. AB - In 54 Pulawska pigs and 60 Polish Large White pigs (PLW), slaughtered at 30 and 100 kg body weight, carcass and meat quality of m. longissimus lumborum were studied. Analysis revealed that in both examined body weight groups, hot carcass weight, carcass yield percentage, meat content, and weight of ham and carcass ham percentage were significantly lower and backfat thickness higher for Pulawska pigs compared to PLW pigs, while PLW pigs exhibited significantly longer carcasses, greater loin eye area, and, in the case of lighter pigs, smaller proportion of loin in the carcass. Muscles of Pulawska pigs, in the lighter group, had higher IMF content and a* value, while in the heavier group they exhibited higher pH(45), pH(24) and a* values, lower L*, drip loss, WHC, and thermal loss compared with PLW pigs. PLW pigs had higher WB and hardness values and more glycolytic muscles characterised by higher TNF. PMID- 24769094 TI - Pregnancy anxiety and prenatal cortisol trajectories. AB - Pregnancy anxiety is a potent predictor of adverse birth and infant outcomes. The goal of the current study was to examine one potential mechanism whereby these effects may occur by testing associations between pregnancy anxiety and maternal salivary cortisol on 4 occasions during pregnancy in a sample of 448 women. Higher mean levels of pregnancy anxiety over the course of pregnancy predicted steeper increases in cortisol trajectories compared to lower pregnancy anxiety. Significant differences between cortisol trajectories emerged between 30 and 31 weeks of gestation. Results remained significant when adjusted for state anxiety and perceived stress. Neither changes in pregnancy anxiety over gestation, nor pregnancy anxiety specific to only a particular time in pregnancy predicted cortisol. These findings provide support for one way in which pregnancy anxiety may influence maternal physiology and contribute to a growing literature on the complex biological pathways linking pregnancy anxiety to birth and infant outcomes. PMID- 24769096 TI - Polymerase chain reaction assay targeting cytochrome b gene for the detection of dog meat adulteration in meatball formulation. AB - A polymerase chain reaction (PCR) assay for the assessment of dog meat adulteration in meatballs was developed. The assay selectively amplified a 100-bp region of canine mitochondrial cytochrome b gene from pure, raw, processed and mixed backgrounds. The specificity of the assay was tested against 11 animals and 3 plants species, commonly available for meatball formulation. The stability of the assay was proven under extensively autoclaving conditions that breakdown target DNA. A blind test from ready to eat chicken and beef meatballs showed that the assay can repeatedly detect 0.2% canine meat tissues under complex matrices using 0.04 ng of dog DNA extracted from differentially treated meatballs. The simplicity, stability and sensitivity of the assay suggested that it could be used in halal food industry for the authentication of canine derivatives in processed foods. PMID- 24769097 TI - Color, sensory and textural attributes of beef frankfurter, beef ham and meat free sausage containing tomato pomace. AB - The present investigation focuses on the textural properties, sensory attributes and color changes of beef frankfurter, beef ham and meat-free sausage produced by different levels of bleached tomato pomace. The texture and color profile were performed using an instrumental texture analyzer and colorimeter. The findings indicated that tomato pomace-added sausages had higher water holding capacity (WHC) compared to that of commercial samples. The frankfurters containing 5 and 7% (w/w) tomato pomace had the highest redness (a*), chroma (C*) and color differences (DeltaE) values, while the meat-free sausages containing 7% (w/w) tomato pomace had significant (p<0.05) values for lightness (L*) and yellowness (b*). Furthermore, there were no significant (p>0.05) color differences between beef ham samples (with and without tomato pomace). A significant progression in the textural hardness and chewiness of systems containing tomato pomace was observed as well as higher sensory scores by panelists. According to sensorial evaluations, bleached tomato pomace improved the consumer acceptability and preference. PMID- 24769098 TI - Molecular detection of nine clinically important non-O157 Escherichia coli serogroups from raw sheep meat in Chaharmahal-va-Bakhtiari province, Iran. AB - STEC isolates and also stx-negative Escherichia coli isolates from sheep meat from the Chaharmahal-va-Bakhtiari province, Iran were analyzed for nine clinically important non-O157 serotypes by PCR. A total of 90 E. coli isolates were tested. Stx-positive and eae-positive E. coli isolates did not belong to the nine most clinically relevant non-O157 STECs. Of the 80 non-STEC isolates, two belonged to the O103 and two belonged to the O128 groups. Stx-negative E. coli O103 and O128 strains isolated have potential in acquiring stx genes and continuing into the digestive system of consumers. Further studies are needed to analyze virulence characteristics of these E. coli strains to determine their potential role in causing disease in humans. For the sake of public health, it is important to monitor and investigate non-O157 diarrheagenic E. coli strains in meat in order to control and prevent them. PMID- 24769099 TI - A comparative study of beef quality after ageing longissimus muscle using a dry ageing bag, traditional dry ageing or vacuum package ageing. AB - The objective of this study was to investigate beef quality of longissimus muscle after ageing in dry ageing bags, traditional dry ageing or vacuum for 8 or 19 days. Lower ageing weight loss, odour score and microbial growth were found in meat aged in dry ageing bags than after traditional dry ageing. The sensory panel detected no differences for most of the sensory attributes between samples using the two dry ageing methods, except for the odour of the cutting surface. The dry aged steaks had more umami and butter fried meat taste compared with vacuum-aged steaks. Ageing time affected most of the sensory traits in this study, which improved as ageing time increased from 8 to 19 days. In a consumer test, meat aged for 21 days in dry ageing bags was preferred than the samples aged in vacuum. This may be due to the higher tenderness and juiciness obtained during storage in dry ageing bags than meat aged in vacuum. PMID- 24769100 TI - Effects of chronic administration of beta-blockers on airway responsiveness in a murine model of heart failure. AB - Lung function abnormalities, both at rest and during exercise, are frequently observed in patients with chronic heart failure (HF), also in absence of respiratory disease. It has been documented that, in HF, chronic adrenergic stimulation down-regulates beta-adrenoceptors (beta-ARs) and modifies airway relaxant responses. This study was designed to investigate in an animal model of HF whether a treatment with a beta-AR blocker, metoprolol, could modify the altered airway hyperresponsiveness. In rats, randomly assigned to 3 experimental groups sham-operated rats (SH), rats with HF induced by left anterior descending coronaric occlusion (HF n = 10), and rats treated with metoprolol 100 mg/kg/die (MET = 10), HF was evaluated after 10 weeks and resulted in increases in plasma norepinephrine and epinephrine and left ventricular end diastolic pressure. beta2 ARs and G-protein-betaAR2-kinase (GRK2) mRNA levels were determined by real time reverse transcriptase PCR. Carbachol-precontracted isolated tracheal rings were used to functionally assess airway smooth muscle relaxation. In pulmonary tissues, beta2-AR mRNA level was significantly decreased in HF groups (-48.73 +/- 5.18%, P < 0.01); in the same groups the GRK2 mRNA-levels were significantly enhanced (+222.50 +/- 6.13%, P < 0.001); in lung deriving from MET groups the levels of mRNA were significantly increased (+339.86 +/- 11.26%, P < 0.001), while the GRK2 mRNA-levels unchanged (-59.02 +/- 3.97%, P < 0.001), when compared to SH groups. Relaxation of tracheal strips in response to salbutamol was significantly reduced in HF groups; in tracheal rings, deriving from MET groups, the relaxant effects of salbutamol were significantly enhanced (SH, Emax: 34.87 +/- 2.98%, pD2: 7.45 +/- 0.27; HF, Emax: 34.87 +/- 2.98%, pD2: 7.45 +/- 0.27; MET, Emax: 85.43 +/- 6.80%, pD2: 6.95 +/- 0.59, P < 0.001). In HF, the down regulation of pulmonary beta-ARs results in a significant attenuation of airway relaxation. These effects have been reversed by a treatment with metoprolol, suggesting a potential role of beta-AR blockers in the treatment of patients suffering from HF and chronic obstructive airway diseases. PMID- 24769101 TI - Ribogenomics: the science and knowledge of RNA. AB - Ribonucleic acid (RNA) deserves not only a dedicated field of biological research - a discipline or branch of knowledge - but also explicit definitions of its roles in cellular processes and molecular mechanisms. Ribogenomics is to study the biology of cellular RNAs, including their origin, biogenesis, structure and function. On the informational track, messenger RNAs (mRNAs) are the major component of ribogenomes, which encode proteins and serve as one of the four major components of the translation machinery and whose expression is regulated at multiple levels by other operational RNAs. On the operational track, there are several diverse types of RNAs - their length distribution is perhaps the most simplistic stratification - involving in major cellular activities, such as chromosomal structure and organization, DNA replication and repair, transcriptional/post-transcriptional regulation, RNA processing and routing, translation and cellular energy/metabolism regulation. An all-out effort exceeding the magnitude of the Human Genome Project is of essence to construct just mammalian transcriptomes in multiple contexts including embryonic development, circadian and seasonal rhythms, defined life-span stages, pathological conditions and anatomy-driven tissue/organ/cell types. PMID- 24769102 TI - Implications of changes in solids retention time on long term evolution of sludge filterability in anaerobic membrane bioreactors treating high strength industrial wastewater. AB - Long-term experiments were conducted to assess the impact of changing the solids retention time (SRT) on sludge filterability in anaerobic membrane bioreactors (AnMBRs), treating corn-based bioethanol thin stillage. Well established parameters, such as capillary suction time (CST) and specific resistance to filtration (SRF), developed for sludge dewatering, were used to evaluate the SRT effect on sludge filterability. Our results clearly demonstrated that SRT is one of the most important factors influencing sludge filterability in AnMBRs. SRT effects the accumulation of fine particles and solutes, which were found to affect attainable flux and fouling, in reactor broth. A better filterability was observed at a SRT of 20 days compared to elevated SRTs, i.e. 50 days. A clear correlation between sludge filtration characteristics and membrane filtration resistance could not be established especially at short SRTs, whereas many parameters such as total suspended solids (TSS), CST, soluble microbial products (SMP) and supernatant filterability were found to be mutually correlated. Net membrane fluxes between 9 and 13 L m(-2) h(-1) were obtained at 0.5 m s(-1) cross flow velocity and the long term fouling was controlled by using frequent filtration and backwash cycles. PMID- 24769104 TI - Intraneural convection enhanced delivery of AAVrh20 for targeting primary sensory neurons. AB - Gene therapy using adeno-associated virus (AAV) is an attractive strategy to treat disorders of the peripheral nervous system (PNS), such as chronic pain or peripheral neuropathies. Although intrathecal (IT) administration of AAV has been the standard in the field for targeting the PNS, it lacks anatomical specificity and results in wide rostro-caudal distribution of the vector. An alternative approach is to deliver AAV directly to the peripheral nerve axon. The present study employed convection-enhanced delivery (CED) of a novel AAV serotype, AAVrh20, expressing enhanced green fluorescent protein (EGFP) into rat sciatic nerve investigating its efficacy, anatomical selectivity, and safety, compared to the IT route. Intraneural CED resulted in transduction confined to the ipsilateral L4 and L5 DRG while IT administration led to promiscuous DRG transduction encompassing the entire lumbar region bilaterally. The transduction rate for intraneural AAV administration was similar to IT delivery (24% for L4 and 31.5% for L5 DRG versus 50% for L4 and 19.5% for L5 DRG). The use of hyperosmotic diluent did not further improve the transduction efficiency. AAVrh20 was superior to reference serotypes previously described to be most active for each route. Intraneural CED of AAV was associated with transient allodynia that resolved spontaneously. These findings establish intraneural CED as an alternative to IT administration for AAV mediated gene transfer to the PNS and, based on a reference rodent model, suggest AAVrh20 as a superior serotype for targeting the PNS. PMID- 24769105 TI - Temporal alterations in aquaporin and transcription factor HIF1alpha expression following penetrating ballistic-like brain injury (PBBI). AB - OBJECTIVES: Brain edema is a primary factor in the morbidity and mortality of traumatic brain injury (TBI). The various isoforms of aquaporin 4 (AQP4) and aquaporin 9 (AQP9) are important factors influencing edema following TBI. Others have reported that these AQPs are regulated by the transcription factor hypoxia inducible factor (HIF) 1alpha. Therefore, we examined the temporal alterations in the multiple isoforms of AQP4 and AQP9, and its possible upstream regulation by HIF1alpha, and evaluated whether different severities of penetrating injury influence these mechanisms. METHODS: In the penetrating ballistic-like brain injury (PBBI) model, a temporary cavity and resultant injury was formed by the rapid inflation/deflation (i.e. <40ms) of an elastic balloon attached to the end of the custom probe, injuring 10% of total rat brain volume. Tissue from the ipsilateral core and perilesional injury zones was collected. Total RNA was isolated at 4, 12, and 24h, 3 and 7days post-injury (sham and PBBI, n=6 per group). cDNA was synthesized using oligodT primers. Quantitative real time PCR was performed using Taqman expression assays for aqp4 (recognizing all isoforms), aqp9, and hif1alpha. Using separate animals, tissue lysate was collected at 4 and 24h, 3 and 7days post-injury and analyzed by immunoblot for protein expression of multiple isoforms of AQP4, the single known isoform of AQP9 and for expression of transcription factor HIF1alpha (sham, probe only control, and PBBI, n=8-10 per group). RESULTS: Global aqp4 mRNA was decreased at 24h (p<0.01) with PBBI. Three of the four known protein isoforms of AQP4 were detected, M1 (34kDa), M23 (32kDa) and isoform 3 (30kDa). AQP4 M1 decreased at 3 and 7days post-injury (p<0.001; p<0.01). AQP4 M23 levels were highly variable with no significant changes. AQP4 isoform 3 levels were decreased 3days post-PBBI (p<0.05). From 4, 12, and 24h aqp9 mRNA levels were decreased with injury (p<0.01, p<0.05, p<0.01) while AQP9 levels were decreased at 3 and 7days after PBBI (p<0.001, p<0.01). At 12 and 24h post-PBBI hif1alpha mRNA levels increased (p<0.05, p<0.01) but at 3 and 7days mRNA levels decreased (p<0.05, p<0.01). From 24h and 3 and 7days HIF1alpha protein levels were decreased (p<0.0001, p<0.0001, p<0.0001). In comparison to probe control, PBBI led to greater decreases in protein for AQP4 M1 (trend), AQP4 isoform 3 (trend), AQP9 (p<0.05) and HIF1alpha (p<0.05). CONCLUSION: PBBI is characterized by a loss of AQP4 M1, AQP4 isoform 3 and AQP9 at delayed time points. The severity of the injury (PBBI versus probe control) increased these effects. Therefore, AQP9 and the AQP4 M1 isoform may be regulated by HIF1alpha, but not AQP4 isoform 3. This delayed loss of aquaporins may markedly reduce the ability of the brain to efflux water, contributing to the protracted edema that is a characteristic following severe penetrating TBI. Factors contributing to edema differ with different types and severities of TBI. For example, cellular based edema is more prominent in diffuse non-penetrating TBI whereas vasogenic edema is more prevalent with TBI involving hemorrhage. Molecular regulation leading to edema will likely also differ, such that treatments which have been suggested for non-hemorrhagic moderate TBI, such as the suppression of aquaporins, may be detrimental in more severe forms of TBI. PMID- 24769103 TI - Dynorphin up-regulation in the dentate granule cell mossy fiber pathway following chronic inhibition of GluN2B-containing NMDAR is associated with increased CREB (Ser 133) phosphorylation, but is independent of BDNF/TrkB signaling pathways. AB - Emerging evidence suggests that neuronal responses to N-methyl-d-aspartate (NMDAR) activation/inactivation are influenced by subunit composition. For example, activation of synaptic NMDAR (comprised of GluN2A>GluN2B) phosphorylates cAMP-response-element-binding protein (CREB) at Ser 133, induces BDNF expression and promotes neuronal survival. Activation of extrasynaptic NMDAR (comprised of GluN2B>GluN2) dephosphorylates CREB (Ser 133), reduces BDNF expression and triggers neuronal death. These results led us to hypothesize that chronic inhibition of GluN2B-containing NMDAR would increase CREB (Ser 133) phosphorylation, increase BDNF levels and subsequently alter downstream dynorphin (DYN) and neuropeptide Y (NPY) expression. We focused on DYN and NPY because these neuropeptides can decrease excitatory neurotransmission and seizure occurrence and we reported previously that seizure-like events are reduced following chronic treatment with GluN2B antagonists. Consistent with our hypothesis, chronic treatment (17-21days) of hippocampal slice cultures with the GluN2B-selective antagonists ifenprodil or Ro25,6981 increased both CREB (Ser 133) phosphorylation and granule cell mossy fiber pathway DYN expression. Similar treatment with the non-subtype-selective NMDAR antagonists d-APV or memantine had no significant effect on either CREB (Ser 133) phosphorylation or DYN expression. In contrast to our hypothesis, BDNF levels were decreased following chronic treatment with Ro25,6981, but not ifenprodil, d-APV or memantine. Blockade of BDNF actions and TrkB activation did not significantly augment hilar DYN expression in vehicle-treated cultures and had no effect in Ro25,6981 treated cultures. These findings suggest that chronic exposure to GluN2B-selective NMDAR antagonists increased DYN expression through a putatively pCREB-dependent, but BDNF/TrkB-independent mechanism. PMID- 24769106 TI - Mitochondrial transcription factor A (Tfam) is a pro-inflammatory extracellular signaling molecule recognized by brain microglia. AB - Microglia represent mononuclear phagocytes in the brain and perform immune surveillance, recognizing a number of signaling molecules released from surrounding cells in both healthy and pathological situations. The microglia interact with several damage-associated molecular pattern molecules (DAMPs) and recent data indicate that mitochondrial transcription factor A (Tfam) could act as a specific DAMP in peripheral tissues. This study tested the hypothesis that extracellular Tfam induces pro-inflammatory and cytotoxic responses of the microglia. Three different types of human mononuclear phagocytes were used to model human microglia: human peripheral blood monocytes from healthy donors, human THP-1 monocytic cells, and human primary microglia obtained from autopsy samples. When combined with interferon (IFN)-gamma, recombinant human Tfam (rhTfam) induced secretions that were toxic to human SH-SY5Y neuroblastoma cells in all three models. Similar cytotoxic responses were observed when THP-1 cells and human microglia were exposed to human mitochondrial proteins in the presence of IFN-gamma. rhTfam alone induced expression of pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and IL-8 by THP-1 cells. This induction was further enhanced in the presence of IFN-gamma. Upregulated secretion of IL-6 in response to rhTfam plus IFN-gamma was confirmed in primary human microglia. Use of specific inhibitors showed that the rhTfam-induced cytotoxicity of human THP-1 cells depended partially on activation of c-Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (MAPK). Overall, our data support the hypothesis that, in the human brain, Tfam could act as an intercellular signaling molecule that is recognized by the microglia to cause pro-inflammatory and cytotoxic responses. PMID- 24769107 TI - Neural crest-derived dental stem cells--where we are and where we are going. AB - OBJECTIVES: There are five types of post-natal human dental stem cells that have been identified, isolated and characterized. Here, we review the information available on dental stem cells as well as their potential applications in dentistry, regenerative medicine and the development of other therapeutic approaches. DATA: Data pertinent to dental stem cells and their applications, published in peer-reviewed journals from 1982 to 2013 in English were reviewed. SOURCES: Sources were retrieved from PubMed databases as well as related references that the electronic search yielded. STUDY SELECTION: Manuscripts describing the origin, retrieval, characterization and application of dental stem cells were obtained and reviewed. CONCLUSIONS: Dental stem cell populations present properties similar to those of mesenchymal stem cells, such as the ability to self-renew and the potential for multilineage differentiation. While they have greater capacity to give rise to odontogenic cells and regenerate dental pulp and periodontal tissue, they have the capacity to differentiate into all three germ line cells, proving that a population of pluripotent stem cells exists in the dental tissues. CLINICAL SIGNIFICANCE: Dental stem cells have the capacity to differentiate into endoderm, mesoderm and ectoderm tissues. Consequently they do not only have applications in dentistry, but also neurodegenerative and ischemic diseases, diabetes research, bone repair, and other applications in the field of tissue regeneration. PMID- 24769108 TI - Quality of obturation achieved by an endodontic core-carrier system with crosslinked gutta-percha carrier in single-rooted canals. AB - OBJECTIVES: The present study examined the quality of obturation in root canals obturated by GuttaCore, a gutta-percha-based core-carrier system with a cross linked thermoset gutta-percha carrier, by comparing the incidence of gaps and voids identified from similar canals obturated by cold lateral compaction or warm vertical compaction. METHODS: Thirty single-rooted premolars with oval-shaped canals were shaped and cleaned, and obturated with one of the three obturation techniques (N=10): GuttaCore, warm vertical compaction or cold lateral compaction. Filled canals were scanned with micro-computed tomography (micro-CT); reconstructed images were analysed for the volumetric percentage of gaps and voids at three canal levels (0-4mm, 4-8mm and 8-12mm from working length). The roots were subsequently sectioned at the 4-mm, 8-mm and 12-mm levels for analyses of the percentage of interfacial gaps, and area percentage of interfacial and intracanal voids, using scanning electron microscopy (SEM) to examine negative replicas of root sections. Data were analysed with parametric or non-parametric statistical methods at alpha=0.05. RESULTS: Both micro-CT and SEM data indicated that canals obturated with GuttaCore core-carriers had the lowest incidence of interfacial gaps and voids, although the results were not significantly different from canals obturated by warm vertical compaction. Both the GuttaCore and the warm vertical compaction groups, in turn, had significantly lower incidences of gaps and voids than the cold lateral compaction group. CONCLUSIONS: Because of the similarity in obturation quality between GuttaCore and warm vertical compaction, practitioners may find the GuttaCore core-carrier technique a valuable alternative for obturation of oval-shaped canals. CLINICAL SIGNIFICANCE: The quality of obturation achieved by GuttaCore in single-rooted canals is not significantly different from that achieved by warm vertical compaction. PMID- 24769109 TI - Involvement of ILK/ERK1/2 and ILK/p38 pathways in mediating the enhanced osteoblast differentiation by micro/nanotopography. AB - The hierarchical micro/nanotextured topography (MNT) on titanium (Ti) implant surface significantly enhances osteoblast differentiation. We have demonstrated that integrin-linked kinase (ILK) is a key underlying signal molecule and beta catenin is one of its downstream mediators in MNT-regulated osteoblast behavior. Here we propose that mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 and c-Jun NH2-terminal kinase (JNK), are other mediators downstream of ILK, and this study aims to confirm this. Firstly, the levels of ILK and MAPK activity in MG63 cells on MNT are examined by Western blot analysis. The ILK, ERK1/2 and p38 signals are significantly up-regulated by MNT, whereas the JNK activity is undetectable by Western blot. The MG63 cell morphology, proliferation and differentiation are studied in the absence and presence of the MAPK subgroup inhibitors to confirm their roles in cell functions on the Ti surface. The MAPK subgroup inhibitors obviously change the cell shape and depress cell proliferation. Blocking the ERK1/2 or p38 signaling, but not the JNK signaling, significantly down-regulates the cell osteogenesis-related gene expression, ALP production, collagen secretion and matrix mineralization. Afterwards, the ILK expression is down-regulated using ILK-specific siRNA (ILKsi) and then the MAPK activity is determined. ILKsi significantly attenuates the phosphorylated ERK1/2 and p38 levels on MNT, explicitly demonstrating that the ERK1/2 and p38 signalings are downstream effectors of ILK. In conclusion, these data demonstrate that both ILK/ERK1/2 and ILK/p38 pathways are involved in the mechanisms mediating the enhanced osteoblast differentiation by biomaterial surface topography, hopefully directing the biomaterial modification and biofunctionalization. PMID- 24769110 TI - Biomimetic L-aspartic acid-derived functional poly(ester amide)s for vascular tissue engineering. AB - Functionalization of polymeric biomaterials permits the conjugation of cell signaling molecules capable of directing cell function. In this study, l phenylalanine and l-aspartic acid were used to synthesize poly(ester amide)s (PEAs) with pendant carboxylic acid groups through an interfacial polycondensation approach. Human coronary artery smooth muscle cell (HCASMC) attachment, spreading and proliferation was observed on all PEA films. Vinculin expression at the cell periphery suggested that HCASMCs formed focal adhesions on the functional PEAs, while the absence of smooth muscle alpha-actin (SMalphaA) expression implied the cells adopted a proliferative phenotype. The PEAs were also electrospun to yield nanoscale three-dimensional (3-D) scaffolds with average fiber diameters ranging from 130 to 294nm. Immunoblotting studies suggested a potential increase in SMalphaA and calponin expression from HCASMCs cultured on 3-D fibrous scaffolds when compared to 2-D films. X-ray photoelectron spectroscopy and immunofluorescence demonstrated the conjugation of transforming growth factor-beta1 to the surface of the functional PEA through the pendant carboxylic acid groups. Taken together, this study demonstrates that PEAs containing aspartic acid are viable biomaterials for further investigation in vascular tissue engineering. PMID- 24769111 TI - Potential lack of "standardized" processing techniques for production of allogeneic and xenogeneic bone blocks for application in humans. AB - In the present study, the structure of two allogeneic and three xenogeneic bone blocks, which are used in dental and orthopedic surgery, were histologically analyzed. The ultimate goal was to assess whether the components postulated by the manufacturer can be identified after applying conventional histological and histochemical staining techniques. Three samples of each material, i.e. allogeneic material-1 and -2 as well as xenogeneic material-1, -2 and -3, were obtained commercially. After decalcification and standardized embedding processes, conventional histological staining was performed in order to detect inorganic matrix, cellular or organic matrix components. Allogeneic material-1 showed trabecular bone-like structures, which were free of cellular components as well as of organic matrix. The allogeneic material-2 showed trabecular bone structures, in which connective tissue and cellular remnants were embedded. Additionally, some connective tissue, which resembled fat-like tissue, was found within this material. The xenogeneic material-1 showed trabecular bone-like structures and contained organic components comparable to that demonstrated for the allogeneic material-2. The xenogeneic material-2 showed trabecular bone structures with single cells located in lacunae. The xenogeneic material-3 also showed trabecular structures. Neither cellular nor organic matrix components were found within this material. According to the data of the present study, the allogeneic material-1 and the xenogeneic material-3 were the only investigated materials for which the obtained histological data were in accordance with the manufacturers advertised information. The remaining three materials showed discrepancies-although the manufacturers of all five bone substitute materials stated that their blocks were free of organic/cellular remnants. These data are of great clinical and material science interest. It seems that even patented processing techniques are not always able to deliver reproducible materials. Although the manufacturers of all five bone blocks stated that their blocks were free of organic/cellular remnants, our histological analysis revealed that three out of five bone blocks did contain such remnants. Such specimens might be able to induce an immune response within the recipient. PMID- 24769112 TI - Control of in vivo mineral bone cement degradation. AB - The current study aimed to prevent the formation of hydroxyapatite reprecipitates in brushite-forming biocements by minimizing the availability of free Ca(2+) ions in the cement matrix. This was achieved by both maximizing the degree of cement setting to avoid unreacted, calcium-rich cement raw materials which can deliver Ca(2+) directly to the cement matrix after dissolution, and by a reduction in porosity to reduce Ca(2+) diffusion into the set cement matrix. In addition, a biocement based on the formation of the magnesium phosphate mineral struvite (MgNH4PO4.6H2O) was tested, which should prevent the formation of low-solubility hydroxyapatite reprecipitates due to the high magnesium content. Different porosity levels were fabricated by altering the powder-to-liquid ratio at which the cements were mixed and the materials were implanted into mechanically unloaded femoral defects in sheep for up to 10 months. While the higher-porosity brushite cement quantitatively transformed into crystalline octacalcium phosphate after 10 months, slowing down cement resorption, a lower-porosity brushite cement modification was found to be chemically stable with the absence of reprecipitate formation and minor cement resorption from the implant surface. In contrast, struvite-forming cements were much more degradable due to the absence of mineral reprecipitates and a nearly quantitative cement degradation was found after 10 months of implantation. PMID- 24769113 TI - Semi-degradable poly(beta-amino ester) networks with temporally controlled enhancement of mechanical properties. AB - Biodegradable polymers are clinically used in numerous biomedical applications, and classically show a loss of mechanical properties within weeks of implantation. This work demonstrates a new class of semi-degradable polymers that show an increase in mechanical properties through degradation via a controlled shift in a thermal transition. Semi-degradable polymer networks, poly(beta-amino ester)-co-methyl methacrylate, were formed from a low glass transition temperature crosslinker, poly(beta-amino ester), and high glass transition temperature monomer, methyl methacrylate, which degraded in a manner dependent upon the crosslinker chemical structure. In vitro and in vivo degradation revealed changes in mechanical behavior due to the degradation of the crosslinker from the polymer network. This novel polymer system demonstrates a strategy to temporally control the mechanical behavior of polymers and to enhance the initial performance of smart biomedical devices. PMID- 24769115 TI - Hypoxia-induced angiogenesis is increased by the controlled release of deferoxiamine from gelatin hydrogels. AB - The objective of this study is to design biodegradable hydrogels for the controlled release of deferoxiamine (DFO) and evaluate their biological activity. When the DFO was added to human umbilical vein endothelial cells cultured in 5.0% O2, the level of hypoxia-inducible factor-1alpha and vascular endothelial growth factor significantly increased compared with that without DFO. The expression of angiogenesis-related genes was accordingly increased by the DFO addition. An aqueous solution of mixed gelatin and DFO was freeze-dried, and dehydrothermally treated at 140 degrees C for 24h to prepare a gelatin hydrogel incorporating DFO. In the release test with phosphate-buffered saline solution (PBS) at 37 degrees C, an initial DFO release of 60% was observed, followed by no release. When placed in PBS containing collagenase, the hydrogel was enzymatically degraded with time, and consequently released DFO in a degradation-dependent manner. After the hydrogel incorporating DFO was injected intramuscularly into a mouse model of hind limb ischemia, the number of new blood vessels formed was significantly higher than that with free DFO and DFO-free hydrogel. It is concluded that the DFO-containing hydrogel shows promising for inducing angiogenesis locally. PMID- 24769116 TI - Semi-interpenetrating networks of hyaluronic acid in degradable PEG hydrogels for cartilage tissue engineering. AB - Hydrolytically biodegradable poly(ethylene glycol) (PEG) hydrogels offer a promising platform for chondrocyte encapsulation and tuning degradation for cartilage tissue engineering, but offer no bioactive cues to encapsulated cells. This study tests the hypothesis that a semi-interpenetrating network of entrapped hyaluronic acid (HA), a bioactive molecule that binds cell surface receptors on chondrocytes, and crosslinked degradable PEG improves matrix synthesis by encapsulated chondrocytes. Degradation was achieved by incorporating oligo (lactic acid) segments into the crosslinks. The effects of HA molecular weight (MW) (2.9*10(4) and 2*10(6)Da) and concentration (0.5 and 5mgg(-1)) were investigated. Bovine chondrocytes were encapsulated in semi-interpenetrating networks and cultured for 4weeks. A steady release of HA was observed over the course of the study with 90% released by 4weeks. Incorporation of HA led to significantly higher cell numbers throughout the culture period. After 8days, HA increased collagen content per cell, increased aggrecan-positive cells, while decreasing the deposition of hypertrophic collagen X, but these effects were not sustained long term. Measuring total sulfated glycosaminoglycan (sGAG) and collagen content within the constructs and released to the culture medium after 4weeks revealed that total matrix synthesis was elevated by high concentrations of HA, indicating that HA stimulated matrix production although this matrix was not retained within the hydrogels. Matrix-degrading enzymes were elevated in the low-, but not the high-MW HA. Overall, incorporating high-MW HA into degrading hydrogels increased chondrocyte number and sGAG and collagen production, warranting further investigations to improve retention of newly synthesized matrix molecules. PMID- 24769114 TI - Cardiac differentiation of cardiosphere-derived cells in scaffolds mimicking morphology of the cardiac extracellular matrix. AB - Stem cell therapy has the potential to regenerate heart tissue after myocardial infarction (MI). The regeneration is dependent upon cardiac differentiation of the delivered stem cells. We hypothesized that timing of the stem cell delivery determines the extent of cardiac differentiation as cell differentiation is dependent on matrix properties such as biomechanics, structure and morphology, and these properties in cardiac extracellular matrix (ECM) continuously vary with time after MI. In order to elucidate the relationship between ECM properties and cardiac differentiation, we created an in vitro model based on ECM-mimicking fibers and a type of cardiac progenitor cell, cardiosphere-derived cells (CDCs). A simultaneous fiber electrospinning and cell electrospraying technique was utilized to fabricate constructs. By blending a highly soft hydrogel with a relatively stiff polyurethane and modulating fabrication parameters, tissue constructs with similar cell adhesion property but different global modulus, single fiber modulus, fiber density and fiber alignment were achieved. The CDCs remained alive within the constructs during a 1week culture period. CDC cardiac differentiation was dependent on the scaffold modulus, fiber volume fraction and fiber alignment. Two constructs with relatively low scaffold modulus, ~50-60kPa, most significantly directed the CDC differentiation into mature cardiomyocytes as evidenced by gene expressions of cardiac troponin T (cTnT), calcium channel (CACNA1c) and cardiac myosin heavy chain (MYH6), and protein expressions of cardiac troponin I (cTnI) and connexin 43 (CX43). Of these two low-modulus constructs, the extent of differentiation was greater for lower fiber alignment and higher fiber volume fraction. These results suggest that cardiac ECM properties may have an effect on cardiac differentiation of delivered stem cells. PMID- 24769117 TI - Leukocyte mimetic polysaccharide microparticles tracked in vivo on activated endothelium and in abdominal aortic aneurysm. AB - We have developed injectable microparticles functionalized with fucoidan, in which sulfated groups mimic the anchor sites of P-selectin glycoprotein ligand-1 (PSGL-1), one of the principal receptors supporting leukocyte adhesion. These targeted microparticles were combined with a fluorescent dye and a T2(*) magnetic resonance imaging (MRI) contrast agent, and then tracked in vivo with small animal imaging methods. Microparticles of 2.5MUm were obtained by a water-in-oil emulsification combined with a cross-linking process of polysaccharide dextran, fluorescein isothiocyanate dextran, pullulan and fucoidan mixed with ultrasmall superparamagnetic particles of iron oxide. Fluorescent intravital microscopy observation revealed dynamic adsorption and a leukocyte-like behaviour of fucoidan-functionalized microparticles on a calcium ionophore induced an activated endothelial layer of a mouse mesentery vessel. We observed 20times more adherent microparticles on the activated endothelium area after the injection of functionalized microparticles compared to non-functionalized microparticles (197+/-11 vs. 10+/-2). This imaging tool was then applied to rats presenting an elastase perfusion model of abdominal aortic aneurysm (AAA) and 7.4T in vivo MRI was performed. Visual analysis of T2(*)-weighted MR images showed a significant contrast enhancement on the inner wall of the aneurysm from 30min to 2h after the injection. Histological analysis of AAA cryosections revealed microparticles localized inside the aneurysm wall, in the same areas in which immunostaining shows P-selectin expression. The developed leukocyte mimetic imaging tool could therefore be relevant for molecular imaging of vascular diseases and for monitoring biologically active areas prone to rupture in AAA. PMID- 24769118 TI - Isoquinoline alkaloids as a novel type of AKR1C3 inhibitors. AB - AKR1C3 is an important human enzyme that participates in the reduction of steroids and prostaglandins, which leads to proliferative signalling. In addition, this enzyme also participates in the biotransformation of xenobiotics, such as drugs and procarcinogens. AKR1C3 is involved in the development of both hormone-dependent and hormone-independent cancers and was recently demonstrated to confer cell resistance to anthracyclines. Because AKR1C3 is frequently upregulated in various cancers, this enzyme has been suggested as a therapeutic target for the treatment of these pathological conditions. In this study, nineteen isoquinoline alkaloids were examined for their ability to inhibit a recombinant AKR1C3 enzyme. As a result, stylopine was demonstrated to be the most potent inhibitor among the tested compounds and exhibited moderate selectivity towards AKR1C3. In the follow-up cellular studies, stylopine significantly inhibited the AKR1C3-mediated reduction of daunorubicin in intact cells without considerable cytotoxic effects. This inhibitor could therefore be used as a model AKR1C3 inhibitor in research or evaluated as a possible therapeutic anticancer drug. Furthermore, based on our results, stylopine can serve as a model compound for the design and future development of structurally related AKR1C3 inhibitors. PMID- 24769119 TI - ROS production in brown adipose tissue mitochondria: the question of UCP1 dependence. AB - Whether active UCP1 can reduce ROS production in brown-fat mitochondria is presently not settled. The issue is of principal significance, as it can be seen as a proof- or disproof-of-principle concerning the ability of any protein to diminish ROS production through membrane depolarization. We therefore undertook a comprehensive investigation of the significance of UCP1 for ROS production, by comparing the ROS production in brown-fat mitochondria isolated from wildtype mice (that display membrane depolarization) or from UCP1(-/-) mice (with a high membrane potential). We tested the significance of UCP1 for glycerol-3-phosphate supported ROS production by three methods (fluorescent dihydroethidium and the ESR probe PHH for superoxide, and fluorescent Amplex Red for hydrogen peroxide), and followed ROS production also with succinate, acyl-CoA or pyruvate as substrate. We studied the effects of the reverse electron flow inhibitor rotenone, the UCP1 activity inhibitor GDP, and the uncoupler FCCP. We also examined the effect of a physiologically induced increase in UCP1 amount. We noted GDP effects that were not UCP1-related. We conclude that only ROS production supported by exogenously added succinate was affected by the presence of active UCP1; ROS production supported by any other tested substrate (including endogenously generated succinate) was unaffected. This conclusion indicates that UCP1 is not involved in control of ROS production in brown-fat mitochondria. Extrapolation of these data to other tissues would imply that membrane depolarization may not necessarily decrease physiologically relevant ROS production. This article is a part of a Special Issue entitled: 18th European Bioenergetics Conference (Biochim. Biophys. Acta, Volume 1837, Issue 7, July 2014). PMID- 24769120 TI - Mortality among participants in a lead surveillance program. AB - BACKGROUND: There is evidence that adult lead exposure increases cancer risk. IARC has classified lead as a 'probable' carcinogen, primarily based on stomach and lung cancer associations. METHODS: We studied mortality among men in a lead surveillance program in 11 states,. categorized by their highest blood lead (BL) test (0-<5 ug/dl, 5-<25 ug/dl, 25-<40 ug/dl and 40+ ug/dl). RESULTS: There were 58,368 men with a median 12 years of follow-up (6 to 17 years from lowest to higher BL category), and 3337 deaths. Half of the men had only one BL test. There was a strong healthy worker effect (all cause SMR=0.69, 95% CI: 0.66-0.71). The highest BL category had elevated lung and larynx cancer SMRs (1.20, 95% CI: 1.03 1.39, n=174, and 2.11, 95% CI: 1.05-3.77, n=11, respectively); there were no significant excesses of any other cause-specific SMR. Lung cancer RRs by increasing BL category were 1.0, 1.34, 1.88, and 2.79 (test for trend p=<0.0001), unchanged by adjustment for follow-up time. The lung cancer SMR in the highest BL category with 20+ years follow-up was 1.35 (95% CI: 0.92-1.90). CONCLUSIONS: We found an association of blood lead level with lung cancer mortality. Our data are limited by lack of work history (precluding analyses by duration of exposure), and smoking data, although the strong positive trend in RRs by increasing blood lead category in internal analysis is unlikely to be caused by smoking differences. Other limitations include different lengths of follow-up in different lead categories, reliance on few blood lead tests to characterize exposure, and few deaths for some causes. PMID- 24769121 TI - Balance confidence and falls in nondemented essential tremor patients: the role of cognition. AB - OBJECTIVES: To examine (1) the effect of cognitive ability on balance confidence and falls, (2) the relationship of balance confidence and falls with quantitative measures of gait, and (3) measures that predict falls, in people with essential tremor (ET). DESIGN: Cross-sectional study. SETTING: General community. PARTICIPANTS: People with ET (n=132) and control subjects (n=48). People with ET were divided into 2 groups based on the median score on the Modified Mini-Mental State Examination: those with lower cognitive test scores (ET-LCS) and those with higher cognitive test scores (ET-HCS). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Six-item Activities of Balance Confidence (ABC-6) Scale and falls in the previous year. RESULTS: Participants with ET-LCS had lower ABC-6 scores and a greater number of falls than those with ET-HCS (P<.05 for all measures) or control subjects (P<.01 for all measures). Quantitative gait measures were significantly correlated with ABC-6 score and falls. Gait speed (P<.007) and ABC-6 score (P<.02) were significant predictors of falls. Receiver operating characteristic curve analysis revealed that gait speed <0.9m/s and ABC 6 score <51% were associated with moderate sensitivity and specificity in identifying fallers. CONCLUSIONS: People with ET-LCS have impaired gait and report lower balance confidence and a higher number of falls than their counterparts (ET-HCS) and than control subjects. We have identified assessments that are easily administered (gait speed, ABC-6 Scale) and are associated with falls in ET. PMID- 24769122 TI - Handgrip strength but not appendicular lean mass is an independent predictor of functional outcome in hip-fracture women: a short-term prospective study. AB - OBJECTIVE: To investigate the contribution of muscle mass and handgrip strength in predicting the functional outcome after hip fracture in women. DESIGN: Observational study. SETTING: Rehabilitation hospital. PARTICIPANTS: White women (N=123 of 149) who were consecutively admitted to a rehabilitation hospital because of their first fracture of the hip. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We measured appendicular lean mass (aLM) by dual-energy x-ray absorptiometry (DXA) 21.1 +/- 8.7 (mean +/- SD) days after hip fracture occurrence in the 123 women. On the same day, we assessed grip strength at the nondominant arm with a dynamometer. At the end of acute inpatient rehabilitation we measured the ability to function in activities of daily living by using the Barthel Index, and lower limb performance by using the Timed Up and Go (TUG) test. RESULTS: We found significant correlations between handgrip strength measured before rehabilitation and Barthel Index scores after rehabilitation (rho=.50; P<.001), Barthel Index effectiveness (rho=.45; P<.001), and the TUG test (rho=-.41; P<.001). Conversely, we found no significant correlations between aLM/height(2) and Barthel Index scores after rehabilitation (rho=.075; P=.41), Barthel Index effectiveness (rho=.06; P=.53), or the TUG test (rho=.005; P=.96). Significant associations between grip strength and all the outcome measures persisted after adjustment for 8 potential confounders, including Barthel Index scores before rehabilitation, age, number of medications, number of comorbidities, pressure ulcers, concomitant infections, time between fracture occurrence and assessment, and aLM/height(2). CONCLUSIONS: Grip strength, but not DXA-assessed aLM, significantly predicted short-term functional outcome in women after a hip fracture. PMID- 24769123 TI - Effect of interferential current stimulation in management of hemiplegic shoulder pain. AB - OBJECTIVE: To study the immediate effects of interferential current stimulation (IFC) on shoulder pain and pain-free passive range of motion (PROM) of the shoulder in people with hemiplegic shoulder pain (HSP). DESIGN: Double-blind, placebo-controlled clinical trial. SETTING: Institutional physical therapy clinic, neurologic rehabilitation center. PARTICIPANTS: A population-based sample of people with HSP (N=30) was recruited. INTERVENTION: Participants were divided into 2 groups--an IFC group and a placebo group--by using a match-paired method (age, sex, and Brunnstrom motor recovery stage). In the IFC group, participants received IFC for 20 minutes with an amplitude-modulated frequency at 100 Hz in vector mode. The current intensity was increased until the participants felt a strong tingling sensation. MAIN OUTCOME MEASURES: Pain intensity and pain-free PROM of the shoulder until the onset of pain were measured at baseline and immediately after treatment. RESULTS: Participants reported a greater reduction in pain during the most painful movement after treatment with IFC than with placebo (P<.05). The IFC group showed a greater improvement in posttreatment pain free PROM than the placebo group in shoulder flexion (P<.01), abduction (P<.01), internal rotation (P<.01), and external rotation (P<.01). CONCLUSIONS: This study provides evidence that IFC is effective for the relief of pain during movement and also increases the pain-free PROM of the shoulder in people with HSP. PMID- 24769124 TI - Specific diversity of the entomopathogenic fungi Beauveria and Metarhizium in Mexican agricultural soils. AB - Prior knowledge of the local population structure of entomopathogenic fungi is considered an important requisite when developing microbial control strategies against major pests of crops such as white grubs. An extensive survey in the estate of Guanajuato, one of the main agricultural regions of Mexico, was carried out to determine the abundance and diversity of entomopathogenic fungi in soil. Soil collected from 11 locations was baited for entomopathogenic fungi using Galleria mellonella. In addition, all isolates were morphologically identified and selected isolates of Beauveria and Metarhizium isolates identified using Bloc and ITS or Elongation Factor 1-alpha and ITS sequence information respectively. Genotypic diversity was then studied using microsatellite genotyping. The proportion of isolates belonging to each genus varied amongst all locations. The species Beauveria bassiana, B. pseudobassiana and Metarhizium robertsii were found, with B. bassiana being the most abundant and widely distributed. Microsatellite genotyping showed that the 36 B. bassiana isolates were grouped in 29 unique haplotypes, but with no separation according to geographical origin. PMID- 24769125 TI - Motor cortex glutathione deficit in ALS measured in vivo with the J-editing technique. AB - This study compared in vivo levels of the antioxidant glutathione (GSH) in the motor cortex of 11 ALS patients with those in 11 age-matched healthy volunteers (HV). Using the standard J-edited spin-echo difference MRS technique, GSH spectra were recorded on a 3.0 T GE MR system from a single precentral gyrus voxel. GSH levels expressed as ratios to the unsuppressed voxel tissue water (W) were 31% lower in ALS patients than in HV (p=.005), and 36% lower in ALS than in HV (p=.02) when expressed as ratios to the total creatine peak (tCr), supporting a role for oxidative stress in ALS. Levels of the putative neuronal marker N acetylaspartate (NAA) relative to W did not differ between ALS and HV (p=.26), but were lower by 9% in ALS than in HV (p=.013) when expressed as ratios relative to tCr. This discrepancy is attributed to small but opposite changes in NAA and tCr in ALS that, as a ratio, resulted in a statistically significant group difference, further suggesting caution in using tCr as an internal reference under pathological conditions. PMID- 24769126 TI - Using the Community Multiscale Air Quality (CMAQ) model to estimate public health impacts of PM2.5 from individual power plants. AB - We estimated PM2.5-related public health impacts/ton emitted of primary PM2.5, SO2, and NOx for a set of power plants in the Mid-Atlantic and Lower Great Lakes regions of the United States, selected to include varying emission profiles and broad geographic representation. We then developed a regression model explaining variability in impacts per ton emitted using the population distributions around each plant. We linked outputs from the Community Multiscale Air Quality (CMAQ) model v 4.7.1 with census data and concentration-response functions for PM2.5 related mortality, and monetized health estimates using the value-of-statistical life. The median impacts for the final set of plants were $130,000/ton for primary PM2.5 (range: $22,000-230,000), $28,000/ton for SO2 (range: $19,000 33,000), and $16,000/ton for NOx (range: $7100-26,000). Impacts of NOx were a median of 34% (range: 20%-75%) from ammonium nitrate and 66% (range: 25%-79%) from ammonium sulfate. The latter pathway is likely from NOx enhancing atmospheric oxidative capacity and amplifying sulfate formation, and is often excluded. Our regression models explained most of the variation in impact/ton estimates using basic population covariates, and can aid in estimating impacts averted from interventions such as pollution controls, alternative energy installations, or demand-side management. PMID- 24769127 TI - Metabolism and function of mitochondrial cardiolipin. AB - Since it has been recognized that mitochondria are crucial not only for energy metabolism but also for other cellular functions, there has been a growing interest in cardiolipin, the specific phospholipid of mitochondrial membranes. Indeed, cardiolipin is a universal component of mitochondria in all eukaryotes. It has a unique dimeric structure comprised of two phosphatidic acid residues linked by a glycerol bridge, which gives rise to unique physicochemical properties. Cardiolipin plays an important role in the structural organization and the function of mitochondrial membranes. In this article, we review the literature on cardiolipin biology, focusing on the most important discoveries of the past decade. Specifically, we describe the formation, the migration, and the degradation of cardiolipin and we discuss how cardiolipin affects mitochondrial function. We also give an overview of the various phenotypes of cardiolipin deficiency in different organisms. PMID- 24769128 TI - A new anti-lipopolysaccharide factor (ALF) gene with its SNP polymorphisms related to WSSV-resistance of Litopenaeus vannamei. AB - Anti-lipopolysaccharide factors (ALFs) of crustacean play an important role against bacteria or virus infection. In this study, the cDNA sequence and genomic sequence of one new isoform of ALF designated as nLvALF1 were reported. The open reading frame (ORF) of nLvALF1 consisted of 369 bp encoding 123 amino acids and the genomic structure of nLvALF1 comprised four introns and three exons. The predicted pI of the deduced protein was 8.82 and the molecular weight (MW) was 13.72 KDa. The deduced amino acid sequence of nLvALF1 contained a typical functional domain of ALF: LPS-binding domain. Phylogenetic analysis showed that nLvALF1 had the closest relationship with FcALF1 from Fenneropenaeus chinensis. The nLvALF1 was specifically expressed in lymphoid organ (Oka) of shrimp. Its transcriptional level was significantly up-regulated after white spot syndrome virus (WSSV) challenge, suggesting that nLvALF1 might participate in defense against WSSV in Litopenaeus vannamei. In order to search potential genetic markers associated with WSSV-resistance, we scanned the polymorphisms of the genomic fragment with 397 bp where the LPS-binding domain encoding sequence located and 18 SNPs were found. The distribution frequency of these SNPs was analyzed in WSSV susceptible shrimp and resistant shrimp separately. Significant differences existed in allelic frequencies at loci g.1361-T > C, g.1370-T > C, g.1419-T > A between the WSSV-resistant group and the WSSV susceptible/susceptible group (P < 0.05). The specific haplotype CT consisted of g.1415-C > A and g.1419-T > A was associated with susceptibility to WSSV (P < 0.05). These findings provide theoretical support for selection of WSSV-resistant varieties of L. vannamei. PMID- 24769129 TI - Ribonuclease inhibitor up-regulation inhibits the growth and induces apoptosis in murine melanoma cells through repression of angiogenin and ILK/PI3K/AKT signaling pathway. AB - Human ribonuclease inhibitor (RI), a cytoplasmic protein, is constructed almost entirely of leucine rich repeats. RI could suppress activities of ribonuclease and angiogenin (ANG) through closely combining with them. ANG is a potent inducer of blood vessel growth and has been implicated in the establishment, growth, and metastasis of tumors. ILK/PI3K/AKT signaling pathway also plays important roles in cell growth, cell-cycle progression, tumor angiogenesis, and cell apoptosis. Our previous experiments demonstrated that RI might effectively inhibit some tumor growth and metastasis. Our recent study showed that ILK siRNA inhibited the growth and induced apoptosis in bladder cancer cells as well as increased RI expression, which suggest a correlation between RI and ILK. However, the exact molecular mechanism of RI in anti-tumor and in the cross-talk of ANG and ILK signaling pathway remains largely unknown. Here we investigated the effects of up regulating RI on the growth and apoptosis in murine melanoma cells through angiogenin and ILK/PI3K/AKT signaling pathway. We demonstrated that up-regulating RI obviously decreased ANG expression and activity. We also discovered that RI overexpression could remarkably inhibit cell proliferation, regulate cell cycle and induce apoptosis. Furthermore, up-regulation of RI inhibited phosphorylation of ILK downstream signaling targets protein kinase B/Akt, glycogen synthase kinase 3-beta (GSK-3beta), and reduced beta-catenin expression in vivo and vitro. More importantly, RI significant inhibited the tumor growth and angiogenesis of tumor bearing C57BL/6 mice. In conclusion, our findings, for the first time, suggest that angiogenin and ILK signaling pathway plays a pivotal role in mediating the inhibitory effects of RI on melanoma cells growth. This study identifies that RI may be a useful molecular target for melanoma therapy. PMID- 24769130 TI - Daidzein exhibits anti-fibrotic effect by reducing the expressions of Proteinase activated receptor 2 and TGFbeta1/smad mediated inflammation and apoptosis in Bleomycin-induced experimental pulmonary fibrosis. AB - Pulmonary fibrosis (PF) is a progressive lethal disorder. In this study, the effect of daidzein, a soyisoflavone against Bleomycin (BLM) induced PF in rats was elucidated. A single intratracheal instillation of BLM (3 U/kg.bw) was administered in rats to induce PF. Daidzein (0.2 mg/kg) was administered subcutaneously, twice a week for a period of 28 days. Daidzein restored the histological alteration and aberrant collagen deposition, suppressed the mast cells, and reduced the expressions of Cyclooxygenase 2 (COX2) and Nuclear factor kappa B (Nf-kB) in lung tissue of BLM-induced rats. Treatment with daidzein reduced the expression of Matrix metalloproteinase 2 (MMP-2) and increased the expression of Tissue inhibitor of matrixmetalloproteinases 1 (TIMP 1). Recently, Proteinase activated receptor 2 (PAR2) has been reported to play a major role in the progression of PF. Confocal microscopic and immunoblot analysis revealed that BLM injured rat lungs exhibited increased expression of PAR2 that was reduced upon treatment with daidzein. During BLM induction, Transforming growth factor beta (TGFbeta1) was found to be up-regulated along with p-smad2/3, a mediator of TGFbeta signaling. Further, daidzein regulated the apoptosis by modulating the expressions of Bcl-2, Bax and caspase 3. This study provides evidence on the anti fibrotic role of daidzein in BLM-induced experimental fibrosis. PMID- 24769131 TI - Comparative engineering of Escherichia coli for cellobiose utilization: Hydrolysis versus phosphorolysis. AB - Microbial biocatalysts capable of cellobiose assimilation are of interest in bioconversion of cellulosic materials. This study provides a careful comparison in the two mechanisms of cellobiose assimilation, hydrolysis versus phosphorolysis, between two otherwise isogenic E. coli strains. Relative to cells assimilating cellobiose hydrolytically, phosphorolysis cells tolerated common inhibitors better under both anaerobic and aerobic conditions. Additionally, phosphorolysis cells were able to direct the favorable energy metabolism to recombinant protein production, resulting in up to five fold more recombinant proteins. In a mixed sugar fermentation (5% (w/v) cellobiose+5.0% (w/v) xylose), however, xylose utilization in phosphorolysis cells came to a complete halt after only about 60% consumption whereas the hydrolysis cells were able to ferment both sugars to near completion. These results provide insights into the new metabolic engineering strategy. To our best knowledge, this is the first comparison study in E. coli on the two cellobiose assimilation mechanisms. PMID- 24769132 TI - Endocan is useful biomarker of survival and severity in sepsis. AB - INTRODUCTION: Coagulation abnormalities which occur as a consequence of endothelial changes are recognized as diagnostic criteria for sepsis, but significance of these changes in the outcome prognosis and prediction of the course of sepsis is still not accurately defined. MATERIALS AND METHODS: 60 patients who fulfilled the criteria for diagnosis of sepsis were included in our study. Patients were categorized in two groups according to sepsis severity and organ failure and MODS development was assessed in the first 48 h from ICU admission. Prothrombin time (PT), activated partial thromboplastin time (aPTT) and endothelial cell specific molecule-1(endocan) levels, as well as procalcitonin (PCT) and C-reactive protein (CRP) were determined within the first 24h of the onset of the disease. Predictive APACHE II (Acute Physiology and Chronic Health Evaluation II) and SOFA (Sequential Organ Failure Assessment) scores were calculated on the day of ICU admission. Data were used to determine an association between day 1 biomarker levels, organ dysfunction score values and the development of organ failure, multiple organ dysfunction syndrome (MODS), and mortality during 28 days. These connections were determined by plotting of receiver operating characteristic (ROC) curves. Differences between groups were assessed by Mann-Whitney U test. Categorical variables were compared using chi square test. RESULTS: Concentration of endocan was significantly higher in the group of patients with sepsis induced organ failure, MODS development and in the group of non- survivors in contrast to group with less severe form of the disease, without multiorgan failure, and in contrast to group of survivors (p<0.05). Values of areas under the ROC curves showed that endocan levels had good discriminative power for more severe course of sepsis, MODS development and possible discriminative power for mortality prediction (AUC: 0.81, 0.67, 0.71 retrospectively), better than PCT for fatality (AUC:053) and better than APACHE II (AUC:0.55) and SOFA (AUC: 0.57) scores for organ failure. CONCLUSIONS: Results of our study show that endocan can be used as strong and significant predictor of sepsis severity and outcome, perhaps even better than SOFA and APACHE II scores. PMID- 24769133 TI - Safety in numbers? Investigating Australian driver behaviour, knowledge and attitudes towards cyclists. AB - A key tenet of the safety in numbers theory is that as the number of people cycling increases, more drivers will also be cyclists and therefore will give greater consideration to cyclists when driving. We tested this theory in relation to self-reported behaviour, attitudes and knowledge in relation to cycling. An online survey was conducted of Australian drivers (n=1984) who were also cyclists (cyclist-drivers) and drivers who did not cycle (drivers). Cyclist-drivers were 1.5 times more likely than drivers to report safe driving behaviours related to sharing the roads with cyclists (95% CI: 1.1-1.9, p<0.01). Cyclist-drivers had better knowledge of the road rules related to cycling infrastructure than drivers; however knowledge of road rules related to bike lanes was low for both groups. Drivers were more likely than cyclist-drivers to have negative attitudes (e.g. cyclists are unpredictable and repeatedly overtaking cyclists is frustrating). Findings from this study highlight the need for increased education and awareness in relation to safe driving behaviour, road rules and attitudes towards cyclists. Specific recommendations are made for approaches to improve safety for cyclists. PMID- 24769134 TI - Expression and purification of integral membrane metallopeptidase HtpX. AB - Little is known about the catalytic mechanism of integral membrane (IM) peptidases. HtpX is an IM metallopeptidase that plays a central role in protein quality control by preventing the accumulation of misfolded proteins in the membrane. Here we report the recombinant overexpression and purification of a catalytically ablated form of HtpX from Escherichia coli. Several E. coli strains, expression vectors, detergents, and purification strategies were tested to achieve maximum yields of pure and well-folded protein. HtpX was successfully overexpressed in E. coli BL21(DE3) cells using a pET-derived vector attaching a C terminal His8-tag, extracted from the membranes using octyl-beta-d-glucoside, and purified to homogeneity in the presence of this detergent in three consecutive steps: cobalt-affinity, anion-exchange, and size-exclusion chromatography. The production of HtpX in milligram amounts paves the way for structural studies, which will be essential to understand the catalytic mechanism of this IM peptidase and related family members. PMID- 24769135 TI - Anion inhibition studies of two alpha-carbonic anhydrases from Lotus japonicus, LjCAA1 and LjCAA2. AB - The model organism for the investigation of symbiotic nitrogen fixation in legumes Lotus japonicus encodes two carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the alpha-class, LjCAA1 and LjCAA2. Here we report the kinetic characterization and inhibition of these two CAs with inorganic and complex anions and other molecules interacting with zinc proteins, such as sulfamide, sulfamic acid, and phenylboronic/arsonic acids. LjCAA1 showed a high catalytic activity for the CO2 hydration reaction, with a k(cat) of 7.4*10(5) s(-1) and a k(cat)/K(m) of 9.6*10(7) M(-1) s(-1) and was inhibited in the low micromolar range by N,N-diethyldithiocarbamate, sulfamide, sulfamic acid, phenylboronic/arsonic acid (K(I)s of 4-62 MUM). LjCAA2 showed a moderate catalytic activity for the physiologic reaction, with a k(cat) of 4.0*10(5) s(-1) and a k(cat)/K(m) of 4.9*10(7) M(-1) s(-1). The same anions mentioned above for the inhibition of LjCAA1 showed the best activity against LjCAA2 (K(I)s of 7-29 MUM). Nitrate and nitrite, anions involved in nitrogen fixation, showed lower affinity for the two enzymes, with inhibition constants in the range of 3.7-7.0 mM. Halides and sulfate also behaved in a distinct manner towards the two enzymes investigated here. As LjCAA1/2 participate in the pH regulation processes and CO2 metabolism within the nitrogen-fixing nodules of the plant, our studies may shed some light regarding these complex biochemical processes. PMID- 24769136 TI - Selective hydrolysis of hen egg white lysozyme at Asp-X peptide bonds promoted by oxomolybdate. AB - The activity of oxomolybdate(VI) towards hen egg white lysozyme (HEWL) was examined under physiological and slightly acidic pH conditions. Purely hydrolytic cleavage of HEWL in the presence of 10 to 100 mM of oxomolybdate(VI) after incubation at pH 5.0 and 60 degrees C for 2 to 7 days was observed in SDS-PAGE experiments. Four cleavage sites, which all occurred at Asp-X sequences and included the Asp18-Asn19, Asp48-Gly49, Asp52-Trp53 and Asp101-Gly102 peptide bonds, were identified with Edman degradation. The molecular interaction between [MoO4](2-) and HEWL was studied by circular dichroism (CD) and (1)H-(15)N heteronuclear single quantum correlation (HSQC) NMR spectroscopy. CD spectroscopy revealed a significant decrease in the alpha-helical content of HEWL upon addition of oxomolybdate, while (1)H-(15)N HSQC NMR spectroscopy identified the residues which were most affected upon interaction with [MoO4](2-). (95)Mo NMR measurements, performed on oxomolybdate solutions containing HEWL, identified the monomeric [MoO4](2-) form as active species in the hydrolytic reaction. The hydrolysis of the Asp-Gly model peptide in the presence of oxomolybdate(VI) was studied by (1)H NMR, further supporting a hydrolytic mechanism where polarisation of the carbonyl is followed by internal nucleophilic attack on the Asp residue. PMID- 24769137 TI - Relationship satisfaction moderates the associations between male partner responses and depression in women with vulvodynia: a dyadic daily experience study. AB - Vulvodynia is a prevalent vulvovaginal pain condition that interferes with women's psychological health. Given the central role of sexuality and relationships in vulvodynia, relationship satisfaction may be an important moderator of daily partner responses to this pain and associated negative sequelae, such as depression. Sixty-nine women (M age=28.12 years, SD=6.68) with vulvodynia and their cohabiting partners (M age=29.67 years, SD=8.10) reported their daily relationship satisfaction, and male partner responses on sexual intercourse days (M=3.74, SD=2.47) over 8 weeks. Women also reported their depressive symptoms. Relationship satisfaction on the preceding day moderated the associations between partner responses and women's depressive symptoms in several significant ways: (1) On days after women reported higher relationship satisfaction than usual, their perception of greater facilitative male partner responses was associated with their decreased depression; (2) on days after women reported lower relationship satisfaction than usual, their perception of greater negative male partner responses was associated with their increased depression; (3) on days after men reported higher relationship satisfaction than usual, their self-reported higher negative responses were associated with decreased women's depression, and higher solicitous responses were associated with increased women's depression, whereas (4) on days after men reported lower relationship satisfaction than usual, their self-reported higher negative responses were related to increased women's depression, and higher solicitous responses were associated with decreased women's depression. Targeting partner responses and relationship satisfaction may enhance the quality of interventions aimed at reducing depression in women with vulvodynia. PMID- 24769138 TI - The sensory innervation of the calvarial periosteum is nociceptive and contributes to headache-like behavior. AB - Headaches are thought to result from the activation and sensitization of nociceptors that innervate deep cephalic tissues. A large body of evidence supports the view that some types of headaches originate intracranially, from activation of sensory neurons that innervate the cranial meninges. However, the notion of an extracranial origin of headaches continues to be entertained, although the identity of deep extracranial cephalic tissues that might contribute to headaches remains elusive. Here we employed anatomical, electrophysiological, and behavioral approaches in rats to test the hypothesis that the sensory innervation of the calvarial periosteum is nociceptive. Neural tracing indicated that the calvarial periosteum overlying the frontal and parietal bones is innervated primarily by small and medium-sized neurons in the trigeminal ganglion's ophthalmic division. In vivo single-unit recording in the trigeminal ganglion revealed that calvarial periosteal afferents have slowly conducting axons, are mechanosensitive, and respond to inflammatory mediators, consistent with a nociceptive function. Two distinct neuronal populations were distinguished based on their peripheral axonal trajectory: one that reached the periosteum through extracranial branches of the trigeminal nerve, and another that took an intracranial trajectory, innervating the cranial dura and apparently reaching the periosteum via the calvarial sutures. In behavioral studies, inflammatory stimulation of these afferents promoted periorbital tactile hypersensitivity, a sensory change linked to primary headaches. Activation and sensitization of calvarial periosteal afferents could play a role in mediating primary headaches of extracranial and perhaps also intracranial origin, as well as secondary headaches such as postcraniotomy and posttraumatic headaches. Targeting calvarial periosteal afferents may be effective in ameliorating these headaches. PMID- 24769139 TI - Intraspecific differences in the immunochemical reactivity and neutralization of venom from Argentinean Bothrops (Rhinocerophis) alternatus by specific experimental antivenoms. AB - The venoms of Bothrops (Rhinocerophis) alternatus (B.a.) from different regions of Argentina have shown biochemical, toxicological and immunological variations. Considering these variations, we produced nine experimental antisera (rabbit, IgG) against venoms from snakes of nine different regions and a pool of venom, comprised of equal amounts of venoms from each region. The immunologic studies (ELISA, Westernblot) showed significant cross reactivity among all regional antivenoms with all regional venoms, with no significant differences regarding the specificity of the immunogens used for the production of antivenom. Neutralization of hemorrhage was variable (although all the antivenoms neutralized this activity in all venoms) and the neutralization of coagulant and phospholipase activities were evident in all cases. Some antivenoms neutralized toxic activities that were absent or very low in the venoms used as immunogen, on other non-homologous venoms (e.g. thrombin like activity). Despite the different toxic potencies of regional venoms, antivenoms developed using venoms of snakes from a particular region showed high immunochemical reactivity and cross neutralizing capacity on snake venoms from different and distant regions, in occasions over those of the homologous antivenoms. These findings could be used to improve the generation of pools of venoms for the production of antivenoms. PMID- 24769140 TI - Elucidating ERK2 function in the heart. PMID- 24769141 TI - Influence of supplementing vitamin C to yearling steers fed a high sulfur diet during the finishing period on meat color, tenderness and protein degradation, and fatty acid profile of the longissimus muscle. AB - The objective was to determine the influence of vitamin C (VC) supplemented for approximately 102 d during the finishing period on color, tenderness, and fatty acid profile of longissimus thoracis (LT; n=136) from steers fed a 0.55% sulfur diet. Treatments included 4 supplemental VC concentrations: 1) 0 (CON), 2) 5 (5VC), 3) 10 (10VC), or 4) 20 (20VC) gVC.h(-1)?d(-1) in a common diet. Increasing supplemental VC decreased (P<0.01) L*, but increased (P<0.01) vitamin E and tended to increase (P<=0.07) calcium and iron content of steaks. No VC (P>=0.25) effect was noted for WBSF, calpain-1 autolysis, troponin T degradation, or most fatty acid profiles. A quadratic effect (P<=0.03) was observed for cholesterol and CLA content of LT. Under the conditions of our study, supplementing VC to steers fed a 0.55% sulfur diet late in the finishing period did not influence color or tenderness, but increased the vitamin E content. PMID- 24769142 TI - Presence and molecular characterization of the major serovars of Listeria monocytogenes in ten Sardinian fermented sausage processing plants. AB - The aim of the present study was to investigate the occurrence of Listeria monocytogenes in ten Sardinian fermented sausage processing plants. A total of 230 samples were collected and 40 L. monocytogenes isolates were obtained and subjected to serotyping and investigated for the presence of ten virulence associated genes using multiplex PCR assays. The isolates were further subjected to PFGE and investigated for their adhesion abilities in polystyrene microtiter plates. L. monocytogenes was found in 6% of food contact surfaces, in sausages at the end of acidification (3%) and ripening (8%). Serotyping revealed the presence of four serovars: 1/2c (37.5%), 1/2b (27.5%), 4b (22.5%) and 1/2a (12.5%). All virulence-associated genes were detected in 67.5% of the isolates. Isolates from processing environment, semi-processed and finished products showed high pulsotype diversity and the majority of isolates presented weak adhesion capability. The detection of the pathogen in fermented sausages confirms the ability of L. monocytogenes to overcome the hurdles of the manufacturing process. PMID- 24769143 TI - Weibull analysis characterizes the breaking properties of dry-cured ham slices. AB - The breaking strength (sigma) and stress-strain relation of several muscles [biceps femoris (BF), semitendinosus (ST) and semimembranosus (SM)] and the subcutaneous fat (SF) from a Spanish dry cured ham (Protected Designation of Origin of white ham from "Teruel") have been analysed by the uniaxial tensile test in order to predict the mechanical behaviour of this meat product. Thirty pieces were analysed and the stress-strain curves were obtained. A great dispersion of the sigma values was observed. This leads to the necessity of employing statistical analyses to illustrate the extent to which strength values may vary. The Weibull analysis was applied to estimate the fracture probability. SM and SF showed the highest characteristic strength. The low values of the Weibull modulus indicate that dry-cured ham tissues behave as brittle materials. The stress-strain curves present characteristic forms for BF, ST and SM, which may be associated with their composition and the extent to which they are affected by the curing process. PMID- 24769144 TI - Antioxidant and antimicrobial activity of Kitaibelia vitifolia extract as alternative to the added nitrite in fermented dry sausage. AB - Fermented dry sausages (FDS) without nitrite added, fortified with bioactive phenol and flavonoid compounds originating from the ethanol extract of Kitaibelia vitifolia were food matrix for investigation of its antioxidant and antimicrobial potency. These activities were researched in order to improve the sausages' shelf life, safety, and provide health benefits to consumers as well. The oxidative stability of the FDS, containing two different levels of natural preservative, was evaluated using five different contemporary methods for antioxidative activity. The activity was tested on the 20th day of the refrigerated storage. Minimum inhibitory concentrations of the sausage extract were determined against six microorganisms, using a micro dilution method. Determined optimal effective concentration of dissolved K. vitifolia extract (12.5 g/kg of meat dough) revealed strong antioxidant activity, and moderate antimicrobial activity against Escherichia coli (minimum inhibitory concentrations=15.625 MUg/mL). The modified sausages had typical chemical-physical characteristics of FDS, controlled on 0, 13, 26 d of ripening and 20, 40 and 60 d of storage. PMID- 24769145 TI - Impact of high pressure treatment and intramuscular fat content on colour changes and protein and lipid oxidation in sliced and vacuum-packaged Iberian dry-cured ham. AB - The effect of high hydrostatic pressure (HHP) (600MPa) and intramuscular fat content (IMF) on colour parameters and oxidative stability of lipids and proteins in sliced vacuum-packaged Iberian dry-cured ham during refrigerated storage (120 days at 2 degrees C) was investigated. Several studies have investigated the influence of HHP on lipid oxidation of meat products. However, its effects on protein carbonylation, as also the influence of IMF content on this carbonylation are poorly understood. HHP treatment had a significant effect on lean lightness after 0 and 120 days of storage while IMF content increased lightness and yellowness over time. Regarding oxidative stability, the effect of HHP treatment depended on IMF content samples with a high IMF having greater lipid instability while samples with a low IMF underwent more protein carbonylation. PMID- 24769146 TI - Sakacin Q produced by Lactobacillus curvatus ACU-1: functionality characterization and antilisterial activity on cooked meat surface. AB - This work was conducted to evaluate the antilisterial activity of sakacin Q produced by Lactobacillus curvatus ACU-1 on the surface of cooked pork meat. A genetic re-characterization of the producer strain and a study of the structural genes involved in bacteriocin production were carried out as complementary data. Studies indicated that the bacteriocin was not attached to the producer cells favoring pre-purifications steps. Bacteriocin effectiveness was not compromised by adsorption to meat and fat tissues. Several ways of dispensing the bacteriocin onto the meat surface, namely cell culture, cell free supernatant (CFS), a mixture of both and freeze-dried reconstituted CFS, were investigated. The use of the latter was the most effective one to control Listeria growth within studied systems. L. curvatus ACU-1 and its bacteriocin presented promising technological characteristics that made them suitable for meat biopreservation. PMID- 24769147 TI - Fatty acid composition of lamb meat from the autochthonous Jezersko-Solcava breed reared in different production systems. AB - Thirty two autochthonous Jezersko-Solcava lambs were used to investigate the effect of production (pasture vs. stable) and weaning system (suckling vs. weaned) on fatty acid composition of Longissimus dorsi intramuscular fat in a 2 * 2 factorial design. Pasture lambs had lower intramuscular fat concentration (P<0.0001) more PUFA and trans C18:1, more ALA (P=0.0322), ARA (<0.0001) and EPA (0.0149) but less SFA (P<0.0001) than stable lambs. Weaning system affected PUFA (P=0.0040) and MUFA (P=0.0070) but not SFA and trans C18:1 fatty acids. The interaction of production system and weaning system was significant mainly for trans C18:1 and trans C18:2 fatty acids. Finally, lamb meat from all four treatments which are traditionally used in rearing of Jezersko-Solcava lambs are favourable from the nutritive point of view, due to their low n-6/n-3 ratio. PMID- 24769148 TI - Microbial assessment of an upward and downward dehiding technique in a commercial beef processing plant. AB - Preventing microbial contamination during dehiding is challenging, and skinning methods are of critical importance for the hygienic status of beef carcasses. Two skinning methods are usually employed: upward hide pulling (UHP) and downward hide pulling (DHP). This study has compared the microbiological contamination of carcasses using both systems in a beef processing plant in the process of changing its dehiding method from UHP to DHP. 100 cm(2) areas from eight carcass sites (ham, chuck, rump, bung, flank, brisket, shin and neck) were sampled on 36 skinned carcasses dehided by each technique. Total viable counts (TVCs) and Enterobacteriaceae counts for each site were determined. No significant differences were observed in total (pooled-samples) carcass contamination regardless of the method used. However, significant differences (p<0.05) in TVCs were observed at the flank, shin, brisket and neck. These differences can be attributed to possible deficiencies in the implementation of the HACCP pre requisite programmes, and are not necessarily associated with the skinning method per se. PMID- 24769149 TI - Effects of an enriched housing environment on sensory aspects and fatty-acid composition of the longissimus muscle of light-weight finished lambs. AB - We analysed the effect of enriched housing on the sensory meat quality and fatty acid composition of longissimus muscle in 60 entire Rasa Aragonesa lambs, housed indoors for 5 weeks in six pens (10 lambs/pen, 0.95 m(2)/lamb, initial weight 17.13+/-0.18 kg and carcass mean 12.23+/-0.23 kg); three control pens (barren) and three enriched pens (straw, platform with ramps and a small ramp). The final weight, carcass weight, fatness scores and cooking losses of meat from enriched lambs (EG) were higher and pH 24 was lower (P <= 0.05). The EG lambs had more C18:0 and total SFA (P <= 0.05). Lamb odour and grass odour were more intense in EG (P <= 0.05). Overall liking was higher for EG (P <= 0.05) and associated with tenderness (P <= 0.0001). The results suggest that environmental enrichment can have effects on fatty acid composition and sensory meat quality. PMID- 24769150 TI - Health information impact on the relative importance of beef attributes including its enrichment with polyunsaturated fatty acids (omega-3 and conjugated linoleic acid). AB - This paper uses Choice Experiments (CE) to investigate Spanish consumers' preferences towards beef meat enriched with polyunsaturated fatty acids (omega-3 and conjugated linoleic acid). Data were gathered from self-completed questionnaires in a controlled environment with two different samples (320 and 322 consumers) differentiated by the information received. The surveys were carried out in three main Spanish cities (Barcelona, Zaragoza and Pamplona), representing the average consumer. A variation of the "Dual Response Choice Experiments" (DRCE) design was used due to its ability to emphasize the purchase context. Results showed that consumers who received information attach higher preference for enriched meat with polyunsaturated fatty acids. The utility associated with the higher content of fat increase for informed consumers, showing a substitute effect. Informed consumers are willing to accept meat with a higher amount of visible fat if it is enriched with beneficial fatty acids. PMID- 24769151 TI - Effect of glasswort (Salicornia herbacea L.) on the texture of frankfurters. AB - This study was aimed at evaluation of the effect of glasswort levels (0, 0.5, 1, and 1.5%) on the textural properties of frankfurters formulated with 0.75% NaCl. The addition of glasswort improved protein solubility (P<0.05) and apparent viscosity of frankfurters formulated with 0.75% NaCl, resulting in increased cooking yield and emulsion stability. This phenomenon might be mainly related to salts and dietary fiber within glasswort. In addition, the textural properties of frankfurter prepared with 0.75% NaCl and 1.5% glasswort showed similar properties (P>0.05) compared to those of control (1.5% NaCl). Our result suggests that the use of glasswort can be an effective approach to manufacture reduced-salt meat products. Moreover, the addition of 1.5% glasswort in frankfurters formulated with 0.75% NaCl is the optimum level without adverse effect on the texture. PMID- 24769152 TI - On the interfacial fracture of porcelain/zirconia and graded zirconia dental structures. AB - Porcelain fused to zirconia (PFZ) restorations are widely used in prosthetic dentistry. However, their susceptibility to fracture remains a practical problem. The failure of PFZ prostheses often involves crack initiation and growth in the porcelain, which may be followed by fracture along the porcelain/zirconia (P/Z) interface. In this work, we characterized the process of fracture in two PFZ systems, as well as a newly developed graded glass-zirconia structure with emphases placed on resistance to interfacial cracking. Thin porcelain layers were fused onto Y-TZP plates with or without the presence of a glass binder. The specimens were loaded in a four-point-bending fixture with the thin porcelain veneer in tension, simulating the lower portion of the connectors and marginal areas of a fixed dental prosthesis (FDP) during occlusal loading. The evolution of damage was observed by a video camera. The fracture was characterized by unstable growth of cracks perpendicular to the P/Z interface (channel cracks) in the porcelain layer, which was followed by stable cracking along the P/Z interface. The interfacial fracture energy GC was determined by a finite-element analysis taking into account stress-shielding effects due to the presence of adjacent channel cracks. The resulting GC was considerably less than commonly reported values for similar systems. Fracture in the graded Y-TZP samples occurred via a single channel crack at a much greater stress than for PFZ. No delamination between the residual glass layer and graded zirconia occurred in any of the tests. Combined with its enhanced resistance to edge chipping and good esthetic quality, graded Y-TZP emerges as a viable material concept for dental restorations. PMID- 24769153 TI - Chemical biology of peptidoglycan acetylation and deacetylation. AB - Post-synthetic modification of the bacterial cell wall represents an important strategy for pathogenic bacteria to evade innate immunity and control autolysins. Modifications to the glycan backbone of peptidoglycan are generally restricted to the C-6 hydroxyl and C-3 amino moieties, with the most common being acetylation and deacetylation. In this review we discuss the pathways for O-acetylation, de-O acetylation and N-deacetylation with an emphasis on the chemical-biological approaches used in their investigation. The current challenges in the field and the prospects of targeting these systems with novel therapeutics are also explored. PMID- 24769154 TI - Generic oscillation patterns of the developing systems and their role in the origin and evolution of ontogeny. AB - The role of generic oscillation patterns in embryonic development on a macroscopic scale is discussed in terms of active shell model. These self oscillations include periodic changes in both the mean shape of the shell surface and its spatial variance. They lead to origination of a universal oscillatory contour in the form of a non-linear dependence of the average rudiment's curvature upon the curvature variance. The alternation of high and low levels of the variance makes it possible to pursue the developmental dynamics irrespective to the spatiotemporal order of development and characters subject to selection and genetic control. Spatially homogeneous and heterogeneous states can alternate in both time and space being the parametric modifications of the same self organization dynamics, which is a precondition of transforming of the oscillations into spatial differences between the parts of the embryo and then into successive stages of their formation. This process can be explained as a "retrograde developmental evolution", which means the late evolutionary appearance of the earlier developmental stages. The developing system progressively retreats from the initial self-organization threshold replacing the self-oscillatory dynamics by a linear succession of stages in which the earlier developmental stages appear in the evolution after the later ones. It follows that ontogeny is neither the cause, nor the effect of phylogeny: the phenotype development can be subject to directional change under the constancy of the phenotype itself and, vice versa, the developmental evolution can generate new phenotypes in the absence of the external environmental trends of their evolution. PMID- 24769155 TI - Evolutionary constraints or opportunities? AB - Natural selection is traditionally viewed as a leading factor of evolution, whereas variation is assumed to be random and non-directional. Any order in variation is attributed to epigenetic or developmental constraints that can hinder the action of natural selection. In contrast I consider the positive role of epigenetic mechanisms in evolution because they provide organisms with opportunities for rapid adaptive change. Because the term "constraint" has negative connotations, I use the term "regulated variation" to emphasize the adaptive nature of phenotypic variation, which helps populations and species to survive and evolve in changing environments. The capacity to produce regulated variation is a phenotypic property, which is not described in the genome. Instead, the genome acts as a switchboard, where mostly random mutations switch "on" or "off" preexisting functional capacities of organism components. Thus, there are two channels of heredity: informational (genomic) and structure functional (phenotypic). Functional capacities of organisms most likely emerged in a chain of modifications and combinations of more simple ancestral functions. The role of DNA has been to keep records of these changes (without describing the result) so that they can be reproduced in the following generations. Evolutionary opportunities include adjustments of individual functions, multitasking, connection between various components of an organism, and interaction between organisms. The adaptive nature of regulated variation can be explained by the differential success of lineages in macro-evolution. Lineages with more advantageous patterns of regulated variation are likely to produce more species and secure more resources (i.e., long-term lineage selection). PMID- 24769156 TI - Left ventricular noncompaction associated with a compound heterozygous MYBPC3 mutation. PMID- 24769157 TI - Exome sequencing identifies ZFPM2 as a cause of familial isolated congenital diaphragmatic hernia and possibly cardiovascular malformations. AB - Using exome sequencing we identify a heterozygous nonsense mutation in ZFPM2 as a cause of familial isolated congenital diaphragmatic hernia in 2 affected siblings. This mutation displays variable phenotypic expression being present in a third sibling with a mild diaphragmatic eventration and a cardiovascular malformation. The same variant is seen in 2 additional family members, both of whom are asymptomatic, thus highlighting that ZFPM2 haploinsufficiency is associated with reduced penetrance. Our finding adds further evidence for ZFPM2 having a role in diaphragm and cardiovascular development. PMID- 24769158 TI - Fibrillation of beta amyloid peptides in the presence of phospholipid bilayers and the consequent membrane disruption. AB - Fibrillation of beta amyloid (Abeta) peptides and the accumulation of amyloid plaques are considered as an important clinical hallmark to identify Alzheimer's disease (AD). The physiological connection between Abeta plaques and the disruption of neuronal cells has not been clearly understood. One hypothesis to explain the Abeta neurotoxicity is that the fibrillation process induces disruption to the cellular membrane. We studied the Abeta fibrillation process in two biologically relevant conditions with the peptide either pre-incorporated into or externally added to the synthetic phospholipid bilayers. These two sample preparation conditions mimic the physiological membrane proximities of Abeta peptides before and after the enzymatic cleavage of amyloid precursor protein (APP). Using thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM), we were able to monitor the kinetics and morphological evolution of fibril formation, which was highly sensitive to the two sample preparation protocols. While the external addition protocol generates long and mature fibrils through normal fibrillation process, the pre-incubation protocol was found to stabilize the immature protofibrils. Fluorescence spectroscopy studies with doubly-labeled phospholipids indicated that there may be a lipid uptake process associated with the fibril formation. Solid state nuclear magnetic resonance (NMR) spectroscopy provided evidence for high resolution structural variations in fibrils formed with different protocols, and in particular the stabilization of long-range contact between N- and C-terminal beta strands. In addition, disruption of phospholipid bilayers was supported by measurements with 31P chemical shifts and relaxation time constants. PMID- 24769159 TI - Absorption and folding of melittin onto lipid bilayer membranes via unbiased atomic detail microsecond molecular dynamics simulation. AB - Unbiased molecular simulation is a powerful tool to study the atomic details driving functional structural changes or folding pathways of highly fluid systems, which present great challenges experimentally. Here we apply unbiased long-timescale molecular dynamics simulation to study the ab initio folding and partitioning of melittin, a template amphiphilic membrane active peptide. The simulations reveal that the peptide binds strongly to the lipid bilayer in an unstructured configuration. Interfacial folding results in a localized bilayer deformation. Akin to purely hydrophobic transmembrane segments the surface bound native helical conformer is highly resistant against thermal denaturation. Circular dichroism spectroscopy experiments confirm the strong binding and thermostability of the peptide. The study highlights the utility of molecular dynamics simulations for studying transient mechanisms in fluid lipid bilayer systems. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID- 24769160 TI - Developmental expression of GPR3 in rodent cerebellar granule neurons is associated with cell survival and protects neurons from various apoptotic stimuli. AB - G-protein coupled receptor 3 (GPR3), GPR6, and GPR12 belong to a family of constitutively active Gs-coupled receptors that activate 3'-5'-cyclic adenosine monophosphate (cAMP) and are highly expressed in the brain. Among these receptors, the endogenous expression of GPR3 in cerebellar granule neurons (CGNs) is increased following development. GPR3 is important for neurite outgrowth and neural maturation; however, the physiological functions of GPR3 remain to be fully elucidated. Here, we investigated the survival and antiapoptotic functions of GPR3 under normal and apoptosis-inducing culture conditions. Under normal culture conditions, CGNs from GPR3-knockout mice demonstrated lower survival than did CGNs from wild-type or GPR3-heterozygous mice. Cerebellar sections from GPR3 /- mice at P7, P14, and P21 revealed more caspase-3-positive neurons in the internal granular layer than in cerebellar sections from wild-type mice. Conversely, in a potassium-deprivation model of apoptosis, increased expression of these three receptors promoted neuronal survival. The antiapoptotic effect of GPR3 was also observed under hypoxic (1% O2/5% CO2) and reactive oxygen species (ROS)-induced apoptotic conditions. We further investigated the signaling pathways involved in the GPR3-mediated antiapoptotic effect. The addition of the PKA inhibitor KT5720, the MAP kinase inhibitor U0126, and the PI3 kinase inhibitor LY294002 abrogated the GPR3-mediated antiapoptotic effect in a potassium-deprivation model of apoptosis, whereas the PKC inhibitor Go6976 did not affect the antiapoptotic function of GPR3. Furthermore, downregulation of endogenous GPR3 expression in CGNs resulted in a marked reduction in the basal levels of ERK and Akt phosphorylation under normal culture conditions. Finally, we used a transient middle cerebral artery occlusion (tMCAO) model in wild-type and GPR3-knockout mice to determine whether GPR3 expression modulates neuronal survival after brain ischemia. After tMCAO, GPR3-knockout mice exhibited a significantly larger infarct area than did wild-type mice. Collectively, these in vitro and in vivo results suggest that the developmental expression of constitutively active Gs-coupled GPR3 activates the ERK and Akt signaling pathways at the basal level, thereby protecting neurons from apoptosis that is induced by various stimuli. PMID- 24769162 TI - Overproduction of 2-phenylethanol by industrial yeasts to improve organoleptic properties of bakers' products. AB - 2-Phenylethanol (PEA), an important alcohol derived from phenylalanine, is involved in aroma and flavour of bakers' products. Four spontaneous mutants of an industrial bakers' yeast, V1 strain, were isolated for their resistance to p fluoro-DL-phenylalanine (PFP), a toxic analogue of L-phenylalanine. Mutants overproduced this amino acid and showed variations in their internal pool for several other amino acids. Moreover, a rise in PEA production after growth in industrial medium (MAB) was observed in three of the mutants, although their growth and fermentative capacities were slightly impaired. However, concentration of PEA remained higher during dough fermentation and also after baking, thus improving taste and aroma in bread. PMID- 24769163 TI - Tracking and modeling norovirus transmission during mechanical slicing of globe tomatoes. AB - Recent epidemiological evidence indicates that preparation of fresh produce for use as ingredients in ready-to-eat food in commercial settings has been a significant source of the norovirus (NoV) infections in the U.S. This research investigated the dissemination of NoV from a single tomato to many others via the use of an 11-horizontal blade slicer commonly found in restaurants or sandwich shops. A total of eight trials were conducted. The source of contamination in each trial was a soak-inoculated, air-dried globe tomato containing ~8log10 murine norovirus (MNV). Each trial began by slicing a single un-inoculated tomato in the slicer, followed by slicing an inoculated tomato. This was then followed by slicing 9 to 27 un-inoculated tomatoes. A similar and constant hand pressure on the slicer was used in every trial. Three slices from each tomato were collected for virus elution, concentration, and extraction before RT-PCR detection of MNV. The change in MNV per sliced tomato was averaged over all eight trials, and two mathematical models were fit to the average data using a logarithmic model or a power model. Regression analysis determined that the equation that best fit the data was y=-0.903*ln(x)+7.945, where y=log10 MNV per slicing and x=tomato slicing number. An acceptable fit (R(2)=0.913) was indicated. The MNV levels transferred (y) generally decreased as the number of tomatoes sliced (x) increased, with some exceptions. Infrequent but erratic transfers, where the MNV level of a subsequent tomato was higher than that of a preceding tomato, occurred in later transfer of some trials. In contrast, the first and second transfers of each trial were always shown to have sharply decreased levels of MNV from the inoculum. The MNV log10 reduction per slicing event changes throughout the process: with a predicted 0.63log10 reduction from tomato 1 to tomato 2 (76% reduction); a 0.07log10 reduction predicted from tomato 13 to tomato 14 (a 14% reduction); and 0.03log10 reduction predicted from tomato 27 to tomato 28 (a 7% reduction). Virus transfer is clearly variable even given the consistent slicing procedure used throughout each trial. This study illustrates the complex nature of risk prediction associated with NoV cross contamination during food preparation in commercial establishments. PMID- 24769164 TI - Decreased ethyl carbamate generation during Chinese rice wine fermentation by disruption of CAR1 in an industrial yeast strain. AB - Saccharomyces cerevisiae metabolizes arginine to ornithine and urea during wine fermentations. In the fermentation of Chinese rice wine, yeast strains of S. cerevisiae do not fully metabolize urea, which will be secreted into the spirits and spontaneously reacts with ethanol to form ethyl carbamate, a potential carcinogenic agent for humans. To block the pathway of urea production, we genetically engineered two haploid strains to reduce the arginase (encoded by CAR1) activity, which were isolated from a diploid industrial Chinese rice wine strain. Finally the engineered haploids with opposite mating type were mated back to diploid strains, obtaining a heterozygous deletion strain (CAR1/car1) and a homozygous defect strain (car1/car1). These strains were compared to the parental industrial yeast strain in Chinese rice wine fermentations and spirit production. The strain with the homozygous CAR1 deletion showed significant reductions of urea and EC in the final spirits in comparison to the parental strain, with the concentration reductions by 86.9% and 50.5% respectively. In addition, EC accumulation was in a much lower tempo during rice wine storage. Moreover, the growth behavior and fermentation characteristics of the engineered diploid strain were similar to the parental strain. PMID- 24769161 TI - Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. AB - Rett syndrome (RTT) is a rare neurodevelopmental disorder affecting almost exclusively females, caused in the overwhelming majority of the cases by loss-of function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). High circulating levels of oxidative stress (OS) markers in patients suggest the involvement of OS in the RTT pathogenesis. To investigate the occurrence of oxidative brain damage in Mecp2 mutant mouse models, several OS markers were evaluated in whole brains of Mecp2-null (pre-symptomatic, symptomatic, and rescued) and Mecp2-308 mutated (pre-symptomatic and symptomatic) mice, and compared to those of wild type littermates. Selected OS markers included non protein-bound iron, isoprostanes (F2-isoprostanes, F4-neuroprostanes, F2-dihomo isoprostanes) and 4-hydroxy-2-nonenal protein adducts. Our findings indicate that oxidative brain damage 1) occurs in both Mecp2-null (both -/y and stop/y) and Mecp2-308 (both 308/y males and 308/+ females) mouse models of RTT; 2) precedes the onset of symptoms in both Mecp2-null and Mecp2-308 models; and 3) is rescued by Mecp2 brain specific gene reactivation. Our data provide direct evidence of the link between Mecp2 deficiency, oxidative stress and RTT pathology, as demonstrated by the rescue of the brain oxidative homeostasis following brain specifically Mecp2-reactivated mice. The present study indicates that oxidative brain damage is a previously unrecognized hallmark feature of murine RTT, and suggests that Mecp2 is involved in the protection of the brain from oxidative stress. PMID- 24769165 TI - Effectiveness of depuration for hepatitis A virus removal from mussels (Mytilus galloprovincialis). AB - The efficacy and kinetic of depuration of hepatitis A virus (HAV) were evaluated under experimental conditions with Mediterranean mussels (Mytilus galloprovincialis) subjected previously to bioaccumulation processes. Seven independent trials (70kg of mussels each) were performed in a closed experimental system using two different water temperatures (13 and 17 degrees C) during 7days. The real time RT-PCR technique with TaqMan probes was used for viral quantification. Qualitative infectivity assays were conducted to test the presence of infectious viral particles at the end of the depuration period. The depuration trials showed an average reduction of HAV levels of aproximately 1.1 Log units (>90%). However, the average final viral loads in shellfish samples remain at relatively high levels (6.5*10(3) RNA copies/g digestive tissue) and still infectious. A positive correlation between the initial and the final numbers of the viral RNA copies was observed. The reduction of HAV showed a two phase removal kinetic, an initial logarithmic trendline, with a rapid reduction of viruses during the first 24-48h of depuration, and a subsequent stabilization with a slower depuration rate until the end of the process. PMID- 24769166 TI - Alterations of the emotional processing system may underlie preserved rapid reaction time in tinnitus. AB - Although alterations of the limbic system have been linked to tinnitus persistence, the neural networks underlying such alteration are unclear. The present study investigated the effect of tinnitus on emotional processing in middle-aged adults using functional magnetic resonance imaging and stimuli from the International Affective Digital Sounds database. There were three groups of participants: bilateral hearing loss with tinnitus (TIN), age- and gender-matched controls with bilateral hearing loss without tinnitus (HL) and matched normal hearing controls without tinnitus (NH). In the scanner, subjects rated sounds as pleasant, unpleasant, or neutral. The TIN and NH groups, but not the HL group, responded faster to affective sounds compared to neutral sounds. The TIN group had elevated response in bilateral parahippocampus and right insula compared to the NH group, and left parahippocampus compared to HL controls for pleasant relative to neutral sounds. A region-of-interest analysis detected increased activation for NH controls in the right amygdala when responding to affective stimuli, but failed to find a similar heightened response in the TIN and HL groups. All three groups showed increased response in auditory cortices for the affective relative to neutral sounds comparisons. Our results suggest that the emotional processing network is altered in tinnitus to rely on the parahippocampus and insula, rather than the amygdala, and this alteration may maintain a select advantage for the rapid processing of affective stimuli despite the hearing loss. The complex interaction of tinnitus and the limbic system should be accounted for in development of new tinnitus management strategies. PMID- 24769167 TI - Chemical stimulation of the intracranial dura activates NALP3 inflammasome in trigeminal ganglia neurons. AB - Inflammasomes are molecular platforms that upon activation by cellular infection or stress trigger the maturation of proinflammatory cytokines such as interleukin (IL)-1beta to engage innate immune defenses. Increased production of IL-1beta in pain and inflammation such as headache is well documented. However, limited evidence addresses the participation of inflammasomes in inflammatory pain. The present study used rat inflammatory dural stimulation-induced model of intracranial pain to assess whether headache-related pain can induce the activation of NACHT, LRR, and PYD-containing protein (NALP)-3 inflammasome pathway in the trigeminal ganglia (TG) and which cells express NALP3 inflammasome proteins and IL-1beta. Chemical stimulation of the intracranial dura caused a total drug dose- and time-dependent induction of activated caspase-1 and mature IL-1beta proteins. Application of a selective caspase-1 inhibitor diminished these effects. Immunohistochemistry revealed that both NALP3 inflammasome and IL 1beta immunoreactivity were existed mainly in small to medium-sized C-type neurons and increased over time, with intense cytoplasmic staining after 3 days of dural inflammation. Overall, the present observation indicated that dural inflammation promoted assembly of the multiprotein NALP3 complex, activated caspase-1, and induced processing of IL-1beta, which provides an indirect evidence of the participation of NALP3 inflammasome in the cascade of events involved in the genesis of headaches by promoting IL-1beta maturation in the TG. This may contribute to strategies for headache control. PMID- 24769168 TI - Algorithm to find high density EEG scalp coordinates and analysis of their correspondence to structural and functional regions of the brain. AB - BACKGROUND: Interpretation and analysis of electroencephalography (EEG) measurements relies on the correspondence of electrode scalp coordinates to structural and functional regions of the brain. NEW METHOD: An algorithm is introduced for automatic calculation of the International 10-20, 10-10, and 10-5 scalp coordinates of EEG electrodes on a boundary element mesh of a human head. The EEG electrode positions are then used to generate parcellation regions of the cerebral cortex based on proximity to the EEG electrodes. RESULTS: The scalp electrode calculation method presented in this study effectively and efficiently identifies EEG locations without prior digitization of coordinates. The average of electrode proximity parcellations of the cortex were tabulated with respect to structural and functional regions of the brain in a population of 20 adult subjects. COMPARISON WITH EXISTING METHODS: Parcellations based on electrode proximity and EEG sensitivity were compared. The parcellation regions based on sensitivity and proximity were found to have 44.0 +/- 11.3% agreement when demarcated by the International 10-20, 32.4 +/- 12.6% by the 10-10, and 24.7 +/- 16.3% by the 10-5 electrode positioning system. CONCLUSIONS: The EEG positioning algorithm is a fast and easy method of locating EEG scalp coordinates without the need for digitized electrode positions. The parcellation method presented summarizes the EEG scalp locations with respect to brain regions without computation of a full EEG forward model solution. The reference table of electrode proximity versus cortical regions may be used by experimenters to select electrodes that correspond to anatomical and functional regions of interest. PMID- 24769169 TI - Command-line cellular electrophysiology for conventional and real-time closed loop experiments. AB - BACKGROUND: Current software tools for electrophysiological experiments are limited in flexibility and rarely offer adequate support for advanced techniques such as dynamic clamp and hybrid experiments, which are therefore limited to laboratories with a significant expertise in neuroinformatics. NEW METHOD: We have developed lcg, a software suite based on a command-line interface (CLI) that allows performing both standard and advanced electrophysiological experiments. Stimulation protocols for classical voltage and current clamp experiments are defined by a concise and flexible meta description that allows representing complex waveforms as a piece-wise parametric decomposition of elementary sub waveforms, abstracting the stimulation hardware. To perform complex experiments lcg provides a set of elementary building blocks that can be interconnected to yield a large variety of experimental paradigms. RESULTS: We present various cellular electrophysiological experiments in which lcg has been employed, ranging from the automated application of current clamp protocols for characterizing basic electrophysiological properties of neurons, to dynamic clamp, response clamp, and hybrid experiments. We finally show how the scripting capabilities behind a CLI are suited for integrating experimental trials into complex workflows, where actual experiment, online data analysis and computational modeling seamlessly integrate. COMPARISON WITH EXISTING METHODS: We compare lcg with two open source toolboxes, RTXI and RELACS. CONCLUSIONS: We believe that lcg will greatly contribute to the standardization and reproducibility of both simple and complex experiments. Additionally, on the long run the increased efficiency due to a CLI will prove a great benefit for the experimental community. PMID- 24769170 TI - Minimum requirements for accurate and efficient real-time on-chip spike sorting. AB - BACKGROUND: Extracellular recordings are performed by inserting electrodes in the brain, relaying the signals to external power-demanding devices, where spikes are detected and sorted in order to identify the firing activity of different putative neurons. A main caveat of these recordings is the necessity of wires passing through the scalp and skin in order to connect intracortical electrodes to external amplifiers. The aim of this paper is to evaluate the feasibility of an implantable platform (i.e., a chip) with the capability to wirelessly transmit the neural signals and perform real-time on-site spike sorting. NEW METHOD: We computationally modelled a two-stage implementation for online, robust, and efficient spike sorting. In the first stage, spikes are detected on-chip and streamed to an external computer where mean templates are created and sent back to the chip. In the second stage, spikes are sorted in real-time through template matching. RESULTS: We evaluated this procedure using realistic simulations of extracellular recordings and describe a set of specifications that optimise performance while keeping to a minimum the signal requirements and the complexity of the calculations. COMPARISON WITH EXISTING METHODS: A key bottleneck for the development of long-term BMIs is to find an inexpensive method for real-time spike sorting. Here, we simulated a solution to this problem that uses both offline and online processing of the data. CONCLUSIONS: Hardware implementations of this method therefore enable low-power long-term wireless transmission of multiple site extracellular recordings, with application to wireless BMIs or closed-loop stimulation designs. PMID- 24769172 TI - The role of serotonin in drug use and addiction. AB - The use of psychoactive drugs is a wide spread behaviour in human societies. The systematic use of a drug requires the establishment of different drug use associated behaviours which need to be learned and controlled. However, controlled drug use may develop into compulsive drug use and addiction, a major psychiatric disorder with severe consequences for the individual and society. Here we review the role of the serotonergic (5-HT) system in the establishment of drug use-associated behaviours on the one hand and the transition and maintenance of addiction on the other hand for the drugs: cocaine, amphetamine, methamphetamine, MDMA (ecstasy), morphine/heroin, cannabis, alcohol, and nicotine. Results show a crucial, but distinct involvement of the 5-HT system in both processes with considerable overlap between psychostimulant and opioidergic drugs and alcohol. A new functional model suggests specific adaptations in the 5 HT system, which coincide with the establishment of controlled drug use associated behaviours. These serotonergic adaptations render the nervous system susceptible to the transition to compulsive drug use behaviours and often overlap with genetic risk factors for addiction. Altogether we suggest a new trajectory by which serotonergic neuroadaptations induced by first drug exposure pave the way for the establishment of addiction. PMID- 24769173 TI - Anti-Parkinson effects of a selective alpha2C-adrenoceptor antagonist in the MPTP marmoset model. AB - Current dopamine replacement therapies, in Parkinson's disease (PD), result in aversive side effects and rapid drug dose escalation over time. Therefore, a non dopaminergic treatment would be an advantageous supplement to lower the dose of dopamine replacement treatment postponing the occurrence of side effects. The noradrenergic system plays an important role in the facilitation or maintenance of the activity of the nigrostriatal dopamine pathways. Here the putative anti Parkinson effects of the oral selective alpha2C-adrenoceptor antagonist (JNJ27063699 0.1-10mg/kg p.o.) and of vehicle (fruit syrup) were evaluated in the MPTP-marmoset model. Dose-related anti-Parkinson effects were assessed by means of a behavioural rating scale covering parkinsonian symptoms, body weight and body temperature, and two test systems assessing locomotor activity and complex motor skills of hand-eye coordination for controlled movements in MPTP- or saline pretreated marmosets. JNJ27063699, at the middle and higher doses, consistently improved locomotor activity and hand-eye coordination capabilities, which indicates an improvement in the coordination of motor control -or movements- in MPTP-pretreated monkeys. No additional effects on the parkinsonian symptoms or side effects were observed on other test systems. Overall, the findings link deficit in motor coordination with dysfunctional adrenergic signalling and it suggest that selective alpha2C adrenergic antagonism may contribute to behavioural improvement in the MPTP-monkey model of PD. In multi-drug medication JNJ27063699 might have potential in the treatment of motor deficit in PD. PMID- 24769171 TI - Adenylyl cylases 1 and 8 mediate select striatal-dependent behaviors and sensitivity to ethanol stimulation in the adolescent period following acute neonatal ethanol exposure. AB - Neonatal alcohol exposure in rodents causes dramatic neurodegenerative effects throughout the developing nervous system, particularly in the striatum, acutely after exposure. These acute neurodegenerative effects are augmented in mice lacking adenylyl cyclases 1 and 8 (AC1/8) as neonatal mice with a genetic deletion of both AC isoforms (DKO) have increased vulnerability to ethanol induced striatal neurotoxicity compared to wild type (WT) controls. While neonatal ethanol exposure is known to negatively impact cognitive behaviors, such as executive functioning and working memory in adolescent and adult animals, the threshold of ethanol exposure required to impinge upon developmental behaviors in mice has not been extensively examined. Therefore, the purpose of this study was to determine the behavioral effects of neonatal ethanol exposure using various striatal-dependent developmental benchmarks and to assess the impact of AC1/8 deletion on this developmental progression. WT and DKO mice were treated with 2.5 g/kg ethanol or saline on postnatal day (P)6 and later subjected to the wire suspension, negative geotaxis, postural reflex, grid hang, tail suspension and accelerating rotarod tests at various time points. At P30, mice were evaluated for their hypnotic responses to 4.0 g/kg ethanol by using the loss of righting reflex assay and ethanol-induced stimulation of locomotor activity after 2.0 g/kg ethanol. Ethanol exposure significantly impaired DKO performance in the negative geotaxis test while genetic deletion of AC1/8 alone increased grid hang time and decreased immobility time in the tail suspension test with a concomitant increase in hindlimb clasping behavior. Locomotor stimulation was significantly increased in animals that received ethanol as neonates, peaking significantly in ethanol treated DKO mice compared to ethanol-treated WT controls, while sedation duration following high-dose ethanol challenge was unaffected. These data indicate that the maturational parameters examined in the current study may not be sensitive enough to detect effects of a single ethanol exposure during the brain growth spurt period. Genetic deletion of AC1/8 reveals a role for these cylases in attenuating ethanol-induced behavioral effects in the neonatally-exposed adolescent. PMID- 24769174 TI - Effects of moderate prenatal ethanol exposure and age on social behavior, spatial response perseveration errors and motor behavior. AB - Persistent deficits in social behavior are among the major negative consequences associated with exposure to ethanol during prenatal development. Prior work from our laboratory has linked deficits in social behavior following moderate prenatal alcohol exposure (PAE) in the rat to functional alterations in the ventrolateral frontal cortex [21]. In addition to social behaviors, the regions comprising the ventrolateral frontal cortex are critical for diverse processes ranging from orofacial motor movements to flexible alteration of behavior in the face of changing consequences. The broader behavioral implications of altered ventrolateral frontal cortex function following moderate PAE have, however, not been examined. In the present study we evaluated the consequences of moderate PAE on social behavior, tongue protrusion, and flexibility in a variant of the Morris water task that required modification of a well-established spatial response. PAE rats displayed deficits in tongue protrusion, reduced flexibility in the spatial domain, increased wrestling, and decreased investigation, indicating that several behaviors associated with ventrolateral frontal cortex function are impaired following moderate PAE. A linear discriminant analysis revealed that measures of wrestling and tongue protrusion provided the best discrimination of PAE rats from saccharin-exposed control rats. We also evaluated all behaviors in young adult (4 5 months) or older (10-11 months) rats to address the persistence of behavioral deficits in adulthood and possible interactions between early ethanol exposure and advancing age. Behavioral deficits in each domain persisted well into adulthood (10-11 months), however, there was no evidence that aging enhances the effects of moderate PAE within the age ranges that were studied. PMID- 24769176 TI - Adjuvant treatment and analysis of failures in patients with high-risk FIGO Stage Ib-II endometrial cancer: an Italian multicenter retrospective study (CTF study). AB - OBJECTIVES: The purpose of this retrospective study was to assess the clinical outcome of patients with high-risk, early-stage endometrioid endometrial cancer (stage Ib or II with myometrial invasion >50%, grade 2-3). METHODS: We assessed 192 patients who underwent hysterectomy, bilateral salpingo-oophorectomy and pelvic lymphadenectomy, had histologically negative pelvic nodes, and had negative CT findings for aortic node involvement. RESULTS: Tumor relapsed in 36 patients after a median time of 21.2 months. The recurrence was vaginal in 7 (19.4%), distant in 16 (44.4%), aortic in 8 (22.2%), and involved multiple sites in 5 (13.9%). There was a trend to a lower vaginal recurrence rate in the 143 patients who received adjuvant radiotherapy (+chemotherapy) compared with the 46 who did not (2.1% versus 8.7%). Distant or aortic recurrences were lower in the 37 patients who received adjuvant chemotherapy (+radiotherapy) than in the 152 who did not (2.7% versus 18.4%, p=0.02). Of the 29 patients who received sequential adjuvant chemotherapy and radiotherapy, none developed local recurrence and only one had distant recurrence. There was a trend for a better 5 year progression-free survival and overall survival for the patients who received chemotherapy (+radiotherapy) compared with those who did not (86.0% versus 71.3%, and 92.3% versus 75.6%, respectively). CONCLUSIONS: Our data appear to suggest that adjuvant chemotherapy reduces the risk of distant or aortic recurrences and that sequential adjuvant chemotherapy and radiotherapy achieve an excellent local and distant control of disease in these clinical settings. PMID- 24769175 TI - Relationship of vitamin D insufficiency to AIDS-associated Kaposi's sarcoma outcomes: retrospective analysis of a prospective clinical trial in Zimbabwe. AB - OBJECTIVES: The prevalence of vitamin D insufficiency in Africans with AIDS associated Kaposi sarcoma (AIDS-KS) and the role of vitamin D in AIDS-KS progression are unknown. We hypothesized that a high prevalence of vitamin D deficiency would be found in Zimbabweans with AIDS-KS and that low baseline vitamin D would correlate with progression of AIDS-KS. METHODS: Ninety subjects were enrolled in a prospective pilot study investigation of the effect of antiretroviral therapy in the treatment of AIDS-KS in Harare, Zimbabwe. Co formulated abacavir, lamivudine, and zidovudine was initiated; chemotherapy was provided at the discretion of the provider. Participants were followed for 96 weeks. 25-Hydroxyvitamin D was measured in stored specimens collected at study entry. The relationship between vitamin D and clinical response was described by odds ratio and 95% confidence interval. RESULTS: Samples were available for 85 participants; 45 (53%) subjects had inadequate (<75 nmol/l) 25-hydroxyvitamin D. HIV-1 RNA was significantly higher among those with insufficient vitamin D (4.7 vs. 4.5 log, p = 0.04). Tumor response, survival, and KS-IRIS were not associated with vitamin D (p >= 0.3). CONCLUSIONS: Vitamin D insufficiency was common among Zimbabweans with AIDS-KS but not associated with outcomes after initiation of antiretroviral therapy. PMID- 24769177 TI - Reproducibility of hypocapnic cerebrovascular reactivity measurements using BOLD fMRI in combination with a paced deep breathing task. AB - It has recently been proposed that hypocapnic cerebrovascular reactivity (CVR) can be assessed by measuring the blood oxygenation level dependent (BOLD) response to paced deep breathing (PDB) tasks inducing mild hypocapnia and vasoconstriction. In this work, we aim to assess the test-retest reproducibility and inter-subject variability of BOLD CVR measurements obtained using a PDB task and different methods to analyse the associated BOLD signal. The respiratory protocol consisted of alternating 40s of PDB with normal free breathing; expired CO2 pressure levels (PETCO2) were continuously monitored. CVR was quantified using either a timecourse curve analysis (TCA) approach, where the magnitude of response peaks is emphasized, or general linear modelling (GLM) including optimisation of the BOLD response latencies. The GLM fit was carried out using two types of response regressors: one that was computed as the convolution of PETCO2 traces with a gamma function and another that consisted of the convolution of PDB paradigm blocks with a physiological model of the respiratory response. Haemodynamic response latencies were optimised either on a voxel basis or for the whole imaging region. We found that the GLM method based on PDB task or PETCO2 traces and voxelwise optimisation of response latencies provided the most reproducible measures of CVR. For the average grey matter CVR, the inter-subject coefficient of variation (CVinter) / intra-subject coefficient of variation (CVintra) / intra-class correlation coefficient (ICC) were 20%/8%/0.8 and 27%/8%/0.9, using the task and PETCO2 timecourses, respectively. In terms of the spatial reproducibility, the group mean (+/-standard deviation) of the spatial ICC (ICCspatial) was 1.04+/-0.23 and 1.02+/-0.26, for the task and PETCO2 timecourses, respectively. These results indicate generally good reproducibility of the hypocapnic CVR maps obtained using the proposed PDB task and analysis methodology. This suggests that such protocol may therefore offer a promising alternative to conventional vasoactive challenges, which avoids their discomfort and difficulty. PMID- 24769178 TI - N-acetyl-l-methionine is a superior protectant of human serum albumin against photo-oxidation and reactive oxygen species compared to N-acetyl-L-tryptophan. AB - BACKGROUND: Sodium octanoate (Oct) and N-acetyl-l-tryptophan (N-AcTrp) are widely used as stabilizers during pasteurization and storage of albumin products. However, exposure to light photo-degrades N-AcTrp with the formation of potentially toxic compounds. Therefore, we have examined the usefulness of N acetyl-l-methionine (N-AcMet) in comparison with N-AcTrp for long-term stability, including photo stability, of albumin products. METHODS: Recombinant human serum albumin (rHSA) with and without additives was photo-irradiated for 4weeks. The capability of the different stabilizers to scavenge reactive oxygen species (ROS) was examined by ESR spectrometry. Carbonyl contents were assessed by a spectrophotometric method using fluoresceinamine and Western blotting, whereas the structure of rHSA was examined by SDS-PAGE, far-UV circular dichroism and differential scanning calorimetry. Binding was determined by ultrafiltration. RESULTS: N-AcMet was found to be a superior ROS scavenger both before and after photo-irradiation. The number of carbonyl groups formed was lowest in the presence of N-AcMet. According to SDS-PAGE, N-AcMet stabilizes the monomeric form of rHSA, whereas N-AcTrp induces degradation of rHSA during photo-irradiation. The decrease in alpha-helical content of rHSA was the smallest in the presence of Oct, without or with N-AcMet. Photo-irradiation did not affect the denaturation temperature or calorimetric enthalpy of rHSA, when N-AcMet was present. CONCLUSION: The weakly bound N-AcMet is a superior protectant of albumin, because it is a better ROS-protector and structural stabilizer than N-AcTrp, and it is probable and also useful for other protein preparations. GENERAL SIGNIFICANCE: N AcMet is an effective stabilizer of albumin during photo-irradiation, while N-Ac Trp promotes photo-oxidative damage to albumin. PMID- 24769179 TI - Outcomes of hanging-induced cardiac arrest patients who underwent therapeutic hypothermia: a multicenter retrospective cohort study. AB - OBJECTIVES: The aim of this study was to analyze the outcomes of patients with hanging-induced cardiac arrest who underwent therapeutic hypothermia (TH). METHOD: In this multicenter, retrospective registry-based study, discharged patients after out-of-hospital cardiac arrest and treatment with TH were enrolled between June 2007 and March 2013. Several prehospital and hospital variables were examined for an outcome analysis with multivariable logistic regression. RESULTS: A total of 964 patients who had cardiac arrest were enrolled in this study. All patients underwent TH during post-cardiac arrest care after return of spontaneous circulation (ROSC). Of all patients, 105 were assigned to the hanging group and 859 to the non-hanging group. Six patients (6%) with good neurologic outcomes (Cerebral Performance Category 1 or 2) in the hanging group at the time of discharge were found. A shorter time interval between witnessed arrest and ROSC and a Glasgow Coma Scale over 4 after ROSC are statistically significant variables of good neurologic outcomes after hanging-induced cardiac arrest treated with TH. CONCLUSION: A small number of patients who underwent TH after a hanging-induced cardiac arrest provided good neurologic outcomes, and some variables influenced these outcomes. PMID- 24769180 TI - Alpha particle induced DNA damage and repair in normal cultured thyrocytes of different proliferation status. AB - Childhood exposure to ionizing radiation increases the risk of developing thyroid cancer later in life and this is suggested to be due to higher proliferation of the young thyroid. The interest of using high-LET alpha particles from Astatine 211 ((211)At), concentrated in the thyroid by the same mechanism as (131)I [1], in cancer treatment has increased during recent years because of its high efficiency in inducing biological damage and beneficial dose distribution when compared to low-LET radiation. Most knowledge of the DNA damage response in thyroid is from studies using low-LET irradiation and much less is known of high LET irradiation. In this paper we investigated the DNA damage response and biological consequences to photons from Cobolt-60 ((60)Co) and alpha particles from (211)At in normal primary thyrocytes of different cell cycle status. For both radiation qualities the intensity levels of gammaH2AX decreased during the first 24h in both cycling and stationary cultures and complete repair was seen in all cultures but cycling cells exposed to (211)At. Compared to stationary cells alpha particles were more harmful for cycling cultures, an effect also seen at the pChk2 levels. Increasing ratios of micronuclei per cell nuclei were seen up to 1Gy (211)At. We found that primary thyrocytes were much more sensitive to alpha particle exposure compared with low-LET photons. Calculations of the relative biological effectiveness yielded higher RBE for cycling cells compared with stationary cultures at a modest level of damage, clearly demonstrating that cell cycle status influences the relative effectiveness of alpha particles. PMID- 24769181 TI - Automatic segmentation of odor maps in the mouse olfactory bulb using regularized non-negative matrix factorization. AB - Segmentation of functional parts in image series of functional activity is a common problem in neuroscience. Here we apply regularized non-negative matrix factorization (rNMF) to extract glomeruli in intrinsic optical signal (IOS) images of the olfactory bulb. Regularization allows us to incorporate prior knowledge about the spatio-temporal characteristics of glomerular signals. We demonstrate how to identify suitable regularization parameters on a surrogate dataset. With appropriate regularization segmentation by rNMF is more resilient to noise and requires fewer observations than conventional spatial independent component analysis (sICA). We validate our approach in experimental data using anatomical outlines of glomeruli obtained by 2-photon imaging of resting synapto pHluorin fluorescence. Taken together, we show that rNMF provides a straightforward method for problem tailored source separation that enables reliable automatic segmentation of functional neural images, with particular benefit in situations with low signal-to-noise ratio as in IOS imaging. PMID- 24769183 TI - Phenotyping the central nervous system of the embryonic mouse by magnetic resonance microscopy. AB - Genetic mouse models of neurodevelopmental disorders are being massively generated, but technologies for their high-throughput phenotyping are missing. The potential of high-resolution magnetic resonance imaging (MRI) for structural phenotyping has been demonstrated before. However, application to the embryonic mouse central nervous system has been limited by the insufficient anatomical detail. Here we present a method that combines staining of live embryos with a contrast agent together with MR microscopy after fixation, to provide unprecedented anatomical detail at relevant embryonic stages. By using this method we have phenotyped the embryonic forebrain of Robo1/2(-/-) double mutant mice enabling us to identify most of the well-known anatomical defects in these mutants, as well as novel more subtle alterations. We thus demonstrate the potential of this methodology for a fast and reliable screening of subtle structural abnormalities in the developing mouse brain, as those associated to defects in disease-susceptibility genes of neurologic and psychiatric relevance. PMID- 24769182 TI - Efficient gradient computation for dynamical models. AB - Data assimilation is a fundamental issue that arises across many scales in neuroscience - ranging from the study of single neurons using single electrode recordings to the interaction of thousands of neurons using fMRI. Data assimilation involves inverting a generative model that can not only explain observed data but also generate predictions. Typically, the model is inverted or fitted using conventional tools of (convex) optimization that invariably extremise some functional - norms, minimum descriptive length, variational free energy, etc. Generally, optimisation rests on evaluating the local gradients of the functional to be optimized. In this paper, we compare three different gradient estimation techniques that could be used for extremising any functional in time - (i) finite differences, (ii) forward sensitivities and a method based on (iii) the adjoint of the dynamical system. We demonstrate that the first-order gradients of a dynamical system, linear or non-linear, can be computed most efficiently using the adjoint method. This is particularly true for systems where the number of parameters is greater than the number of states. For such systems, integrating several sensitivity equations - as required with forward sensitivities - proves to be most expensive, while finite-difference approximations have an intermediate efficiency. In the context of neuroimaging, adjoint based inversion of dynamical causal models (DCMs) can, in principle, enable the study of models with large numbers of nodes and parameters. PMID- 24769184 TI - Dissociable neural representations of wrist motor coordinate frames in human motor cortices. AB - There is a growing interest in how the brain transforms body part positioning in the extrinsic environment into an intrinsic coordinate frame during motor control. To explore the human brain areas representing intrinsic and extrinsic coordinate frames, this fMRI study examined neural representation of motor cortices while human participants performed isometric wrist flexions and extensions in different forearm postures, thereby applying the same wrist actions (representing the intrinsic coordinate frame) to different movement directions (representing the extrinsic coordinate frame). Using sparse logistic regression, critical voxels involving pattern information that specifically discriminates wrist action (flexion vs. extension) and movement direction (upward vs. downward) were identified within the primary motor and premotor cortices. Analyses of classifier weights further identified contributions of the primary motor cortex to the intrinsic coordinate frame and the ventral and dorsal premotor cortex and supplementary motor area proper to the extrinsic coordinate frame. These results are consistent with existing findings using non-human primates and demonstrate the distributed representations of independent coordinate frames in the human brain. PMID- 24769185 TI - Structural degree predicts functional network connectivity: a multimodal resting state fMRI and MEG study. AB - Communication between neuronal populations in the human brain is characterized by complex functional interactions across time and space. Recent studies have demonstrated that these functional interactions depend on the underlying structural connections at an aggregate level. Multiple imaging modalities can be used to investigate the relation between the structural connections between brain regions and their functional interactions at multiple timescales. We investigated if consistent modality-independent functional interactions take place between brain regions, and whether these can be accounted for by underlying structural properties. We used functional MRI (fMRI) and magnetoencephalography (MEG) recordings from a population of healthy adults together with a previously described structural network. A high overlap in resting-state functional networks was found in fMRI and especially alpha band MEG recordings. This overlap was characterized by a strongly interconnected functional core network in temporo posterior brain regions. Anatomically realistically coupled neural mass models revealed that this strongly interconnected functional network emerges near the threshold for global synchronization. Most importantly, this functional core network could be explained by a trade-off between the product of the degrees of structurally-connected regions and the Euclidean distance between them. For both fMRI and MEG, the product of the degrees of connected regions was the most important predictor for functional network connectivity. Therefore, irrespective of the modality, these results indicate that a functional core network in the human brain is especially shaped by communication between high degree nodes of the structural network. PMID- 24769186 TI - Attentional modulations of somatosensory alpha, beta and gamma oscillations dissociate between anticipation and stimulus processing. AB - What are the spectral signatures of somatosensory attention? Here we show that the answer to this question depends critically on the sensory context in which attention is deployed. We recorded magnetoencephalography (MEG) in humans and investigated tactile spatial attention in two different sensory contexts: in anticipation and during the processing of sustained tactile stimuli. We observe a double dissociation between these contexts and two key electrophysiological correlates of attention: in anticipation we primarily observe an attentional suppression of contralateral alpha and beta oscillations (8-12 and 15-30 Hz, respectively), whereas during stimulus processing we primarily observe an attentional amplification of contralateral gamma oscillations (55-75 Hz). This dissociation is well explained by the different neural states that occur prior and during the stimulus, and on which attention can exert its influence. In line with analogous observations in the visual modality, this suggests that the neural implementation of attention must be understood in relation to context and existing brain states. Consequently, different signatures of attention may contribute to perception in different contexts and, as our data reveals for the attentional modulation of alpha oscillations, these are not always required for attention to improve perception. At the same time, these data demonstrate that the attentional modulations of alpha and gamma oscillations (during, respectively, attentional orienting and attentional selection), are generalizable phenomena across the different sensory modalities. PMID- 24769187 TI - Peripheral nervous system origin of phantom limb pain. AB - Nearly all amputees continue to feel their missing limb as if it still existed, and many experience chronic phantom limb pain (PLP). What is the origin of these sensations? There is currently a broad consensus among investigators that PLP is a top-down phenomenon, triggered by loss of sensory input and caused by maladaptive cortical plasticity. We tested the alternative hypothesis that PLP is primarily a bottom-up process, due not to the loss of input but rather to exaggerated input, generated ectopically in axotomized primary afferent neurons in the dorsal root ganglia (DRGs) that used to innervate the limb. In 31 amputees, the local anesthetic lidocaine was applied intrathecally and/or to the DRG surface (intraforaminal epidural block). This rapidly and reversibly extinguished PLP and also nonpainful phantom limb sensation (npPLS). Control injections were ineffective. For intraforaminal block, the effect was topographically appropriate. The suppression of PLP and npPLS could also be demonstrated using dilute lidocaine concentrations that are sufficient to suppress DRG ectopia but not to block the propagation of impulses generated further distally in the nerve. PLP is driven primarily by activity generated within the DRG. We recommend the DRG as a target for treatment of PLP and perhaps also other types of regional neuropathic pain. PMID- 24769188 TI - Response to letter to the Editor. PMID- 24769190 TI - Hemibody pain relieved by microvascular decompression of the contralateral caudal medulla: case report. AB - Microvascular decompression (MVD) of cranial nerves has become an established treatment for trigeminal and (vago)glossopharyngeal neuralgia and for hemifacial spasm. The authors present the case of a 64-year-old man who had a 3.5-year history of severe, drug-resistant hemibody pain with sensory and autonomic disturbance. The ipsilateral trigeminal, cochlear, and glossopharyngeal function also was affected. The contralateral posterior inferior cerebellar artery was seen on magnetic resonance imaging to be indenting the caudal medulla anterolaterally, causing displacement. After MVD of the medulla, there was an immediate and complete resolution of the pain and almost complete resolution of the sensory and autonomic disturbances. The pain later recurred mildly and transiently. The residual symptoms had resolved by 2 years. PMID- 24769189 TI - Emotion regulatory function of parent attention to child pain and associated implications for parental pain control behaviour. AB - We investigated the function of parental attention to child pain in regulating parental distress and pain control behaviour when observing their child performing a painful (cold pressor) task (CPT); we also studied the moderating role of parental state anxiety. Participants were 62 schoolchildren and one of their parents. Parental attention towards or away from child pain (ie, attend to pain vs avoid pain) was experimentally manipulated during a viewing task pairing unfamiliar children's neutral and pain faces. Before and after the viewing task, parental distress regulation was assessed by heart rate (HR) and heart rate variability (HRV). In a subsequent phase, parents observed their own child perform a CPT task, allowing assessment of parental pain control behaviour (indexed by latency to stop their child's CPT performance) and parental distress, which was assessed via self-report before and after observation of child CPT performance. Eye tracking during the viewing task and self-reported attention to own child's pain confirmed successful attention manipulation. Further, findings indicated that the effect of attentional strategy on parental emotion regulation (indexed by HR, self-report) and pain control behaviour depended on parents' state anxiety. Specifically, whereas low anxious parents reported more distress and demonstrated more pain control behaviour in the Attend to Pain condition, high anxious parents reported more distress and showed more pain control behaviour in the Avoid Pain condition. This inverse pattern was likewise apparent in physiological distress indices (HR) in response to the initial viewing task. Theoretical/clinical implications and further research directions are discussed. PMID- 24769191 TI - PeptidePicker: a scientific workflow with web interface for selecting appropriate peptides for targeted proteomics experiments. AB - One challenge in Multiple Reaction Monitoring (MRM)-based proteomics is to select the most appropriate surrogate peptides to represent a target protein. We present here a software package to automatically generate these most appropriate surrogate peptides for an LC/MRM-MS analysis. Our method integrates information about the proteins, their tryptic peptides, and the suitability of these peptides for MRM which is available online in UniProtKB, NCBI's dbSNP, ExPASy, PeptideAtlas, PRIDE, and GPMDB. The scoring algorithm reflects our knowledge in choosing the best candidate peptides for MRM, based on the uniqueness of the peptide in the targeted proteome, its physiochemical properties, and whether it previously has been observed. The modularity of the workflow allows further extension and additional selection criteria to be incorporated. We have developed a simple Web interface where the researcher provides the protein accession number, the subject organism, and peptide-specific options. Currently, the software is designed for human and mouse proteomes, but additional species can be easily be added. Our software improved the peptide selection by eliminating human error, considering multiple data sources and all of the isoforms of the protein, and resulted in faster peptide selection - approximately 50 proteins per hour compared to 8 per day. BIOLOGICAL SIGNIFICANCE: Compiling a list of optimal surrogate peptides for target proteins to be analyzed by LC/MRM-MS has been a cumbersome process, in which expert researchers retrieved information from different online repositories and used their own reasoning to find the most appropriate peptides. Our scientific workflow automates this process by integrating information from different data sources including UniProt, Global Proteome Machine, NCBI's dbSNP, and PeptideAtlas, simulating the researchers' reasoning, and incorporating their knowledge of how to select the best proteotypic peptides for an MRM analysis. The developed software can help to standardize the selection of peptides, eliminate human error, and increase productivity. PMID- 24769192 TI - Connectivity between catalytic landscapes of the metallo-beta-lactamase superfamily. AB - The expansion of functions in an enzyme superfamily is thought to occur through recruitment of latent promiscuous functions within existing enzymes. Thus, the promiscuous activities of enzymes represent connections between different catalytic landscapes and provide an additional layer of evolutionary connectivity between functional families alongside their sequence and structural relationships. Functional connectivity has been observed between individual functional families; however, little is known about how catalytic landscapes are connected throughout a highly diverged superfamily. Here, we describe a superfamily-wide analysis of evolutionary and functional connectivity in the metallo-beta-lactamase (MBL) superfamily. We investigated evolutionary connections between functional families and related evolutionary to functional connectivity; 24 enzymes from 15 distinct functional families were challenged against 10 catalytically distinct reactions. We revealed that enzymes of this superfamily are generally promiscuous, as each enzyme catalyzes on average 1.5 reactions in addition to its native one. Catalytic landscapes in the MBL superfamily overlap substantially; each reaction is connected on average to 3.7 other reactions whereas some connections appear to be unrelated to recent evolutionary events and occur between chemically distinct reactions. These findings support the idea that the highly distinct reactions in the MBL superfamily could have evolved from a common ancestor traversing a continuous network via promiscuous enzymes. Several functional connections (e.g., the lactonase/phosphotriesterase and phosphonatase/phosphodiesterase/arylsulfatase reactions) are also observed in structurally and evolutionary distinct superfamilies, suggesting that these catalytic landscapes are substantially connected. Our results show that new enzymatic functions could evolve rapidly from the current diversity of enzymes and range of promiscuous activities. PMID- 24769193 TI - Effect of wind speed and relative humidity on atmospheric dust concentrations in semi-arid climates. AB - Atmospheric particulate have deleterious impacts on human health. Predicting dust and aerosol emission and transport would be helpful to reduce harmful impacts but, despite numerous studies, prediction of dust events and contaminant transport in dust remains challenging. In this work, we show that relative humidity and wind speed are both determinants in atmospheric dust concentration. Observations of atmospheric dust concentrations in Green Valley, AZ, USA, and Juarez, Chihuahua, Mexico, show that PM10 concentrations are not directly correlated with wind speed or relative humidity separately. However, selecting the data for high wind speeds (>4m/s at 10 m elevation), a definite trend is observed between dust concentration and relative humidity: dust concentration increases with relative humidity, reaching a maximum around 25% and it subsequently decreases with relative humidity. Models for dust storm forecasting may be improved by utilizing atmospheric humidity and wind speed as main drivers for dust generation and transport. PMID- 24769194 TI - A novel biological role of dehydroascorbic acid: Inhibition of Na(+)-dependent transport of ascorbic acid. AB - A U937 cell clone, in which low micromolar concentrations of ascorbic acid (AA) and dehydroascorbic acid (DHA) are taken up at identical rates, was used to investigate possible interactions between transport systems mediating cellular uptake of the two forms of the vitamin. Results obtained with different experimental approaches showed that DHA potently and reversibly inhibits AA uptake through Na(+)-AA cotransporters. Hence, a progressive increase in extracellular DHA concentrations in the presence of a fixed amount of AA caused an initial decrease in the net amount of vitamin C accumulated, and eventually, at higher levels, it caused an accumulation of the vitamin solely based on DHA uptake through hexose transporters. DHA-dependent inhibition of AA uptake was also detected in various other cell types. Taken together, our results provide evidence of a novel biological effect mediated by concentrations of DHA compatible with those produced at inflammatory sites. PMID- 24769195 TI - Exendin-4 inhibits endothelial protein C receptor shedding in vitro and in vivo. AB - Exendin-4 (EX4), a glucagon-like peptide-1 receptor agonist, has been reported to attenuate myocardial ischemia and reperfusion (I/R) injury, inflammatory and oxidative responses. Increasing evidence has demonstrated that beyond its role in activation of protein C, endothelial cell protein C receptor (EPCR) is involved in vascular inflammation. EPCR activity is markedly decreased by ectodomain cleavage and release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-alpha converting enzyme (TACE). However, little is known about the effects of EX4 on EPCR shedding. Data from this study showed that EX4 induced potent inhibition of phorbol-12-myristate 13 acetate (PMA), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta induced EPCR shedding in human umbilical vein endothelial cells (HUVECs), and cecal ligation and puncture (CLP)-induced EPCR shedding in mice. EX4 also inhibited expression and activity of TACE induced by PMA in HUVECs. In addition, treatment with EX4 resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of EX4 as an anti-sEPCR shedding reagent against PMA and CLP-mediated EPCR shedding. PMID- 24769196 TI - Marketing messages in pharmacological papers and scientific chapters: the case of palmitoylethanolamide and its formulations. PMID- 24769197 TI - Clinical utility of whole-exome sequencing in rare diseases: Galactosialidosis. AB - Rare genetic disorders can go undiagnosed for years as the entire spectrum of phenotypic variation is not well characterized given the reduced number of patients reported in the literature and the low frequency at which these occur. Moreover, the current paradigm for clinical diagnostics defines disease diagnosis by a specified spectrum of phenotypic findings; when such parameters are either missing, or other findings not usually observed are seen, the phenotype driven approach to diagnosis may result in a specific etiological diagnosis not even being considered within the differential diagnosis. The novel implementation of genomic sequencing approaches to investigate rare genetic disorders is allowing not only the discovery of new genes, but also the phenotypic expansion of known Mendelian genetic disorders. Here we report the detailed clinical assessment of a patient with a rare genetic disorder with undefined molecular diagnosis. We applied whole-exome sequencing to this patient and unaffected parents in order to identify the molecular cause of her disorder. We identified compound heterozygous mutations in the CTSA gene, responsible for causing galactosialidosis; the molecular diagnosis was further confirmed by biochemical studies. This report expands on the clinical spectrum of this rare lysosomal disorder and exemplifies how genomic approaches are further elucidating the characterization and understanding of genetic diseases. PMID- 24769198 TI - Reverse transcription loop-mediated isothermal amplification assay for rapid detection of Papaya ringspot virus. AB - Papaya ringspot virus (PRSV) and Papaya leaf distortion mosaic virus (PLDMV), which causes disease symptoms similar to PRSV, threaten commercial production of both non-transgenic-papaya and PRSV-resistant transgenic papaya in China. A reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay to detect PLDMV was developed previously. In this study, the development of another RT-LAMP assay to distinguish among transgenic, PRSV-infected and PLDMV-infected papaya by detection of PRSV is reported. A set of four RT-LAMP primers was designed based on the highly conserved region of the P3 gene of PRSV. The RT-LAMP method was specific and sensitive in detecting PRSV, with a detection limit of 1.15*10(-6)MUg of total RNA per reaction. Indeed, the reaction was 10 times more sensitive than one-step RT-PCR. Field application of the RT-LAMP assay demonstrated that samples positive for PRSV were detected only in non-transgenic papaya, whereas samples positive for PLDMV were detected only in commercialized PRSV-resistant transgenic papaya. This suggests that PRSV remains the major limiting factor for non-transgenic-papaya production, and the emergence of PLDMV threatens the commercial transgenic cultivar in China. However, this study, combined with the earlier development of an RT-LAMP assay for PLDMV, will provide a rapid, sensitive and cost-effective diagnostic power to distinguish virus infections in papaya. PMID- 24769199 TI - Rapid detection of BoHV-1 genomic DNA by loop-mediated isothermal amplification assay. AB - Bovine herpes virus-1 (BoHV-1) is a serious viral pathogen of domestic and wild cattle. Herein, we report development of a new molecular diagnostic assay for rapid and sensitive detection of BoHV-1 utilizing the loop-mediated isothermal amplification (LAMP) technique. BoHV-1-LAMP assay was optimized to amplify the target DNA by incubation the Bst-DNA polymerase enzyme with a set of specially constructed six primers, based on the gE-gene of BoHV-1 virus, at 65 degrees C for 60min. BoHV-1-LAMP products were detected by visual inspection using SYBR Green-I stain and had a ladder-like appearance by gel electrophoresis analysis. Negative results obtained with DNA from other tested fish viruses confirmed the specificity of the assay. The analytical sensitivity of the BoHV-1-LAMP assay was 1fg of BoHV-1 DNA (dilution of 10(6)). The developed assay could successfully detect BoVH-1 DNA from clinical samples. Results of this study indicate that the developed BoHV-1-LAMP is rapid and highly sensitive assay not only for detection of BoHV-1 in clinical samples, but also for differentiation between wild-type (gE positive) and gE-negative BoHV-1 viruses, which will improve the control programs of BoHV-1 in Egypt. PMID- 24769200 TI - Solvent effect on the crystal morphology of 2,6-diamino-3,5-dinitropyridine-1 oxide: a molecular dynamics simulation study. AB - The attachment energy (AE) calculations were performed to predict the growth morphology of 2,6-diamino-3,5-dinitropyridine-1-oxide (ANPyO) in vacuum. The molecular dynamics (MD) method was applied to simulate the interaction of trifluoroacetic acid solvent with the habit faces and the corrected AE model was adopted to predict the growth habit of ANPyO in the solvent. The results indicate that the growth morphology of ANPyO in vacuum is dominated by (110), (100), (10 1) and (11-2) faces. The corrected AE energies change in the order of (110)>(10 1)>(11-2)>(100), which causes the crystal morphology to become very close to a flake in trifluoroacetic acid solvent and accords well with the results obtained from experiments. The radial distribution function analysis shows that the solvent molecules adsorb on the ANPyO faces mainly via the solvent-crystal face interactions of hydrogen bonds, Coulomb and Van der Waals forces. In addition to the above results, the analysis of diffusion coefficient of trifluoroacetic acid molecules on the crystal growth faces shows that the growth habit is also affected by the diffusion capacity of trifluoroacetic acid molecules. These suggestions may be useful for the formulation design of ANPyO. PMID- 24769201 TI - Co-culture with human synovium-derived mesenchymal stem cells inhibits inflammatory activity and increases cell proliferation of sodium nitroprusside stimulated chondrocytes. AB - Rheumatoid arthritis (RA) and osteoarthritis (OA) are primarily chronic inflammatory diseases. Mesenchymal stem cells (MSCs) have the ability to differentiate into cells of the mesodermal lineage, and to regulate immunomodulatory activity. Specifically, MSCs have been shown to secrete insulin like growth factor 1 (IGF-1). The purpose of the present study was to examine the inhibitory effects on inflammatory activity from a co-culture of human synovium derived mesenchymal stem cells (hSDMSCs) and sodium nitroprusside (SNP) stimulated chondrocytes. First, chondrocytes were treated with SNP to generate an in vitro model of RA or OA. Next, the co-culture of hSDMSCs with SNP-stimulated chondrocytes reduced inflammatory cytokine secretion, inhibited expression of inflammation activity-related genes, generated IGF-1 secretion, and increased the chondrocyte proliferation rate. To evaluate the effect of IGF-1 on inhibition of inflammation, chondrocytes pre-treated with IGF-1 were treated with SNP, and then the production of inflammatory cytokines was analyzed. Treatment with IGF-1 was shown to significantly reduce inflammatory cytokine secretion in SNP-stimulated chondrocytes. Our results suggest that hSDMSCs offer a new strategy to promote cell-based cartilage regeneration in RA or OA. PMID- 24769202 TI - Functional role of NF-kappaB in expression of human endothelial nitric oxide synthase. AB - The transcription factor NF-kappaB has an essential role in inflammation in endothelial cells. Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) prevents vascular inflammation. However, the molecular mechanism underlying NF-kappaB-mediated regulation of eNOS expression has not been clearly elucidated. We here found that NF-kappaB-activating stimuli, such as lipopolysaccharide, tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta, suppressed eNOS mRNA and protein levels by decreasing mRNA stability, without affecting promoter activity. TNF-alpha-mediated suppression of eNOS expression, mRNA stability, and 3'-untranslated region (3'UTR) activity were inhibited by NF-kappaB inhibitors and Dicer knockdown, but not by p38 MAPK and MEK inhibitors, suggesting the involvement of NF-kappaB-responsive miRNAs in eNOS expression. Moreover, TNF alpha increased MIR155HG expression and promoter activity as well as miR-155 biogenesis, and these increases were blocked by NF-kappaB inhibitors. Transfection with antagomiR-155 blocked TNF-alpha-mediated suppression of eNOS 3'UTR activity, eNOS mRNA and protein levels, and NO and cGMP production. These data provide evidence that NF-kappaB is a negative regulator of eNOS expression via upregulation of miR-155 under inflammatory conditions. These results suggest that NF-kappaB is a potential therapeutic target for preventing vascular inflammation and endothelial dysfunction induced by suppression of miR-155 mediated eNOS expression. PMID- 24769203 TI - Cell type-specific reciprocal regulation of HIF1A gene expression is dependent on 5'- and 3'-UTRs. AB - In the present study, we demonstrated the reciprocal regulation of hypoxia inducible factor 1 alpha (HIF1A) gene expression via untranslated region-(UTR) dependent mechanisms. A 151 nucleotide sequence found in the HIF1A 5'-UTR is sufficient for significant translational up-regulation. On the other hand, the 3' UTR of HIF1A has been implicated in mRNA degradation. In the non-metastatic breast cancer cell line MCF7, the 3'-UTR-dependent down-regulatory machinery predominates over the 5'-UTR-dependent up-regulation of HIF1A. However, 5'-UTR dependent up-regulation is dominant among metastatic cell lines (MDA-MB453, U87MG). It is therefore likely that the predominance of 5'-UTR-dependent translational enhancement of HIF1A is critical for the malignant phenotype of cancer cells. PTBP-1, but not HuR, is a candidate RNA binding protein for the translational control of HIF1A. PMID- 24769204 TI - Sperm-induced Ca2+ release during egg activation in mammals. AB - This review discusses the role that the sperm-specific phospholipase C zeta (PLCzeta) is proposed to play during the fertilization of mammalian eggs. At fertilization, the sperm initiates development by causing a series of oscillations in cytosolic concentrations of calcium [Ca(2)] within the egg. PLCzeta mimics the sperm at fertilization, causing the same pattern of Ca(2+) release as seen at fertilization. Introducing PLCzeta into mouse eggs also mimics a number of other features of the way in which the fertilizing sperm triggers Ca(2+) oscillations. We discuss the localization of PLCzeta within the egg and present a hypothesis about the localization of PLCzeta within the sperm before the initiation of fertilization. PMID- 24769205 TI - High uric acid directly inhibits insulin signalling and induces insulin resistance. AB - BACKGROUND AND AIM: Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance. However, how high uric acid (HUA) level causes insulin resistance remains unclear. We aimed to determine the direct role of HUA in insulin resistance in vitro and in vivo in mice. METHODS: An acute hyperuricemia mouse model was created by potassium oxonate treatment, and the impact of HUA level on insulin resistance was investigated by glucose tolerance test, insulin tolerance test and insulin signalling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt. HepG2 cells were exposed to HUA treatment and N-acetylcysteine (NAC), reactive oxygen species scavenger; IRS1 and Akt phosphorylation was detected by Western blot analysis after insulin treatment. RESULTS: Hyperuricemic mice showed impaired glucose tolerance with insulin resistance. Hyperuricemia inhibited phospho-Akt (Ser473) response to insulin and increased phosphor-IRS1 (Ser307) in liver, muscle and fat tissues. HUA induced oxidative stress, and the antioxidant NAC blocked HUA-induced IRS1 activation and Akt inhibition in HepG2 cells. CONCLUSION: This study supplies the first evidence of HUA directly inducing insulin resistance in vivo and in vitro. Increased uric acid level may inhibit IRS1 and Akt insulin signalling and induce insulin resistance. The reactive oxygen species pathway plays a key role in HUA-induced insulin resistance. PMID- 24769206 TI - MTHFR promotes heterochromatin maintenance. AB - Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in the folate cycle, catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5 methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Methionine serves as the precursor of the active methyl donor S adenosylmethionine, which provides methyl groups for many biological methylations. It has been reported that MTHFR is highly phosphorylated under unperturbed conditions and T34 is the priming phosphorylation site. In this report, we generated a phospho-specific antibody that recognized T34 phosphorylated form of MTHFR and revealed that MTHFR was phosphorylated at T34 in vivo and this phosphorylation peaked during mitosis. We further demonstrated that the cyclin-dependent kinase 1 (CDK1)/Cyclin B1 complex is the kinase that mediates MTHFR phosphorylation at T34 and the MTHFR immunocomplex purified from mitotic cells exhibited lower enzymatic activity. Inhibition of MTHFR expression resulted in a decrease of H3K9me3 levels, and an increase of transcription of the centromeric heterochromatin markers. Taken together, our results demonstrated that CDK1/Cyclin B1 phosphorylates MTHFR on T34 and MTHFR plays a role in the heterochromatin maintenance at the centromeric region. PMID- 24769207 TI - Interferon-mediated ISG15 conjugation restricts dengue virus 2 replication. AB - ISGylation, an ubiquitin-like post-translational modification by ISG15, has been reported to participate in the interferon (IFN)-mediated antiviral response. In this study, we analyzed the functional role of ISGylation in dengue virus 2 (DENV 2) replication. Overexpression of ISG15 was found to significantly suppress the amount of extracellular infectious virus released, while intracellular viral RNA was unaffected. This effect was not observed with a conjugation-defective ISG15 mutant. In addition, extracellular virus infectivity was decreased by ISG15 overexpression. To further clarify the role of ISGylation in the anti-DENV-2 response, we depleted endogenous ISG15 by RNA interference and analyzed the virus production in the absence or presence of type-I IFN. Results showed a significant reduction in extracellular DENV-2 RNA levels for cells treated with IFN, and that these DENV-2 RNA levels could be partially restored by the ISG15 knockdown. Among various DENV-2 proteins, NS3 and NS5 were subjected to the ISGylation. These results demonstrate that IFN-inducible ISGylation suppresses DENV-2 particle release, and that ISG15 is one of the mediators of IFN-induced inhibition of DENV 2 replication. ISG15 therefore functions as a host antiviral factor against DENV 2 infection. PMID- 24769208 TI - TEIF associated centrosome activity is regulated by EGF/PI3K/Akt signaling. AB - Centrosome amplification, which is a characteristic of cancer cells, has been understood as a driving force of genetic instability in the development of cancer. In previous work, we demonstrated that TEIF (transcriptional element interacting factor) distributes in the centrosomes and regulates centrosome status under both physiologic and pathologic conditions. Here we identify TEIF as a downstream effector in EGF/PI3K/Akt signaling. The addition of EGF or transfection of active Akt stimulates centrosome TEIF distribution, resulting in an increase of centrosome splitting and amplification, while inhibitors of either PI3K or Akt attenuate these changes in TEIF and the associated centrosome status. A consensus motif for Akt phosphorylation (RHRVLT) proved to be involved in centrosomal TEIF localization, and the 469-threonine of this motif may be phosphorylated by Akt both in vitro and in vivo. Elimination of this phosphorylated site on TEIF caused reduced centrosome distribution and centrosome splitting or amplification. Moreover, TEIF closely co-localized with C-NAP1 at the proximal ends of centrioles, and centriolar loading of TEIF stimulated by EGF/Akt could displace C-NAP1, resulting in centrosome splitting. These findings reveal linkage of the EGF/PI3K/Akt signaling pathway to regulation of centrosome status which may act as an oncogenic pathway and induce genetic instability in carcinogenesis. PMID- 24769210 TI - Th2 lymphocytes migrating to the bone marrow under high-altitude hypoxia promote erythropoiesis via activin A and interleukin-9. AB - The mechanism of accelerated erythropoiesis under the hypoxic conditions of high altitude (HA) remains largely obscure. Here, we investigated the potential role of bone marrow (BM) T cells in the increased production of erythrocytes at HA. We found that mice exposed to a simulated altitude of 6,000 m for 1-3 weeks exhibited a significant expansion of BM CD4+ cells, mainly caused by increasing T helper 2 (Th2) cells. Using a coculture model of BM T cells and hematopoietic stem/progenitor cells, we observed that BM CD4+ cells from hypoxic mice induced erythroid output more easily, in agreement with the erythroid-enhancing effect observed for Th2-condition-cultured BM CD4+ cells. It was further demonstrated that elevated secretion of activin A and interleukin-9 by BM Th2 cells of hypoxic mice promoted erythroid differentiation of hematopoietic stem/progenitor cells and the growth of erythroblasts, respectively. Our study also provided evidence that the CXCL12-CXCR4 interaction played an important role in Th2 cell trafficking to the BM under HA conditions. These results collectively suggest that Th2 cells migrating to the BM during HA exposure have a regulatory role in erythropoiesis, which provides new insight into the mechanism of high altitude polycythemia. PMID- 24769209 TI - Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells. AB - Cholesterol has been shown to promote cell proliferation/migration in many cells; however the mechanism(s) have not yet been fully identified. Here we demonstrate that cholesterol increases Ca(2+) entry via the TRPM7 channel, which promoted proliferation of prostate cells by inducing the activation of the AKT and/or the ERK pathway. Additionally, cholesterol mediated Ca(2+) entry induced calpain activity that showed a decrease in E-cadherin expression, which together could lead to migration of prostate cancer cells. An overexpression of TRPM7 significantly facilitated cholesterol dependent Ca(2+) entry, cell proliferation and tumor growth. Whereas, TRPM7 silencing or inhibition of cholesterol synthesis by statin showed a significant decrease in cholesterol-mediated activation of TRPM7, cell proliferation, and migration of prostate cancer cells. Consistent with these results, statin intake was inversely correlated with prostate cancer patients and increase in TRPM7 expression was observed in samples obtained from prostate cancer patients. Altogether, we provide evidence that cholesterol mediated activation of TRPM7 is important for prostate cancer and have identified that TRPM7 could be essential for initiation and/or progression of prostate cancer. PMID- 24769211 TI - The polysaccharides from porphyra yezoensis suppress the denaturation of bighead carp myofibrillar protein. AB - In this study, investigated was the effect of the porphyra yezoensis polysaccharides (PPs) on the denaturation of bighead carp (Aristichthys nobilis) myofibrillar protein (Mf) during frozen storage at -18 degrees C for 90d. The PPs (2.5%, 5%, and 7.5%, respectively) was added to 100g of Mf. The changes in the Ca adenylpyrophosphatase (ATPase) activity and unfrozen water content in Mf were examined to evaluate he denaturation of Mf during frozen storage. Ca-ATPase activity decreased gradually during frozen storage at -18 degrees C upon addition of PPs. By contrast, Ca-ATPase activity in the control group dropped drastically during the first 45d of storage and then further decreased gradually for up to 90d of storage, indicating a biphasic denaturation pattern. PPs addition significantly increased sulfhydryl contents in the Mf of the treatment groups compared with that of the control group (p<0.05) during frozen storage at -18 degrees C. PMID- 24769212 TI - Extraction optimization and bioactivities of an extracellular polysaccharide produced by Aspergillus fumigatus. AB - Aspergillus fumigatus produces an extracellular polysaccharide, AFEPS, when grew in NaOH solution pretreated rice-straw medium. A three-level, three-factor Box Behnken design (BBD) response surface methodology (RSM) was applied to optimize the extraction parameters of AFEPS. RSM analysis indicated good correspondence between experimental and predicted values. The optimal conditions for polysaccharide were: precipitation time 10.9h, pH 5.2 and ethanol concentration 90%. AFEPS was composed of arabinose, xylose and glucose in a molar ratio of 1.05:5.36:10.83, its average molecular weight was estimated to be about 36.2kDa. Evaluation of the antioxidant activity in vitro suggested that AFEPS had high scavenging activity for superoxide anion and hydroxyl radicals. AFEPS exhibited excellent antitumor activities both in vitro and in vivo while showing no damage to normal cells. PMID- 24769213 TI - Engineering of chimeric catalase-Angiopep-2 for intracellular protection of brain endothelial cells against oxidative stress. AB - Blood-brain barrier (BBB) disruption and brain microvascular endothelial cells (BMVECs) death caused by excessive production of hydrogen peroxide (H2O2) have been implicated in several neurological conditions. To overcome this problem, H2O2-degrading enzyme with ability to enter the BMVECs is required. In the present study, genetic fusion of gene encoding human catalase and gene encoding Angiopep-2 (AP2), a brain targeting peptide, was performed. The fusion protein was successfully expressed in Escherichia coli and purified to homogeneity. The protein retained heme content and specific enzymatic activity in the same order of magnitude as that of native enzyme. Study of the BMVECs internalization showed that 0.1MUM of the fusion protein can enter the cell within 15min, while internalization of the native protein was not observed at this condition. In addition, treatment of the BMVECs with 20 units of the fusion protein for 30min showed protection against H2O2 up to 5.0mM, whereas this protective effect was not observed from treatment with the native protein. Therefore, construction of chimeric human catalase and AP2 provides an insight into the development of potential therapeutic antioxidant with ability to penetrate the BBB for protection against neurodegenerative disorders. PMID- 24769214 TI - Antimicrobial activity of silver/starch/polyacrylamide nanocomposite. AB - A novel silver/starch/polyacrylamide nanocomposite hydrogel was prepared by grafting acrylamide onto starch in presence of silver nitrate by use of ammonium persulphate as an initiator and N,N-methylene-bisacrylamide as a crosslinking agent, then reducing the silver ions enclosed in the hydrogel structure to silver nanoparticles by treating the hydrogel with sodium hydroxide solution. All factors which affect the grafting/crosslinking reaction were optimized and the concentration of silver ion was changed from 0ppm to 50ppm. The produced nanocomposite hydrogel was characterized for its nanosilver content and the UV spectra showed similar absorption spectra at wavelength 405nm for all AgNO3 concentrations but the plasmon showed increase in the intensity of the absorption peak as AgNO3 concentration incorporated to the hydrogel structure increases. The nanocomposite hydrogel was also characterized for its antimicrobial activity toward two types of bacteria and two types of fungi. The results showed that the hydrogel with 0ppm silver content has no antimicrobial activity, and that the antimicrobial activity expressed as inhibition zone increases as the silver content increases from 5ppm to 50ppm. PMID- 24769215 TI - Biosynthesis of poly(4-hydroxybutyrate) in recombinant Escherichia coli grown on glycerol is stimulated by propionic acid. AB - One of the most promising polyhydroxyalkanoates (PHAs) for medical applications is poly(4-hydroxybutyrate) (P4HB) due to its biodegradability, biocompatibility and mechanical properties. Currently, the major hurdle for expanding P4HB applications is the production and recovery cost. In this study, we investigated the stimulating factors for P4HB biosynthesis with the ultimate goal of reducing production cost. We found that addition of propionic acid to the culture medium stimulates the P4HB accumulation in recombinant Escherichia coli JM109 grown on glycerol. This stimulating effect was significantly weakened by addition of exogenous methionine, whereas it was not influenced by addition of cysteine. These results suggest that propionic acid enhances P4HB synthesis by reducing the intracellular methionine pool. Utilizing these findings for P4HB production in batch cultures on glycerol, the volumetric yield of P4HB could be improved 4 fold from 0.9g/L to 3.7g/L by adding 2g/L propionic acid into the medium. PMID- 24769216 TI - Social capital and the utilization of maternal and child health services in India: a multilevel analysis. AB - This study examines the association between social capital and the utilization of antenatal care, professional delivery care, and childhood immunizations using a multilevel analytic sample of 10,739 women who recently gave birth and 7403 children between one and five years of age in 2293 communities and 22 state groups from the 2005 India Human Development Survey. Exploratory factor analysis was used to create and validate six social capital measures that were used in multilevel logistic regression models to examine whether each form of social capital had an independent, contextual effect on health care use. Results revealed that social capital operated at the community level in association with all three care-seeking behaviors; however, the results differed based on the type of health care utilized. Specifically, components of social capital that led to heterogeneous bridging ties were positively associated with all three types of health care use, whereas components of social capital that led to strong bonding ties were negatively associated with the use of preventive care, but positively associated with professional delivery care. PMID- 24769217 TI - The variation of cancellous bones at lumbar vertebra, femoral neck, mandibular angle and rib in ovariectomized sheep. AB - This study aimed to compare the variation of cancellous bones at four skeletal sites: lumbar vertebra, femoral neck, mandibular angle and rib in ovariectomized sheep. Sixteen adult sheep were randomly divided into two groups: eight sheep were ovariectomized served as experimental group; the other eight untreated sheep were served as control group. Bone mineral density was assessed by dual-energy X ray absorptiometry on lumbar vertebrae at baseline and twelve months after ovariectomy. After 12 months, lumbar vertebrae L3 and L4, femoral necks, mandibular angles and the fourth ribs were harvested for micro-CT scanning, histological analysis and biomechanical test. The results showed that bone mineral density of lumbar vertebra decreased significantly in twelfth month (p<0.05). The results of micro-CT showed that the bone volume/total volume decreased by 45.6%, 36.1% 21.3% and 18.7% in lumbar vertebrae, femoral necks, mandibular angles and ribs in experimental group (p<0.05) respectively. The trabecular number showed the same downtrend (p<0.05). Histological analysis showed trabecular area/tissue area decreased by 32.1%, 23.2% and 20.7% in lumbar vertebrae, femoral necks and mandibular angles respectively (p<0.05), but no significant difference in ribs. Specimens elastic modulus from lumbar vertebra, femoral neck and mandibular angle were 952+/-76MPa (628+/-70MPa), 961+/-173MPa (610+/-72MPa) and 595+/-60MPa (444+/-31MPa) in control group (experimental group) respectively. These datum indicated that the sensibility of cancellous bones to oestrogen deficiency in ovariectomized sheep was site-specific on a pattern as follows: lumbar vertebra, femoral neck, mandibular angle and rib. PMID- 24769218 TI - DNA methylation levels of SOCS1 and LINE-1 in oral epithelial cells from aggressive periodontitis patients. AB - OBJECTIVE: DNA methylation has been shown to be critical in the regulation of inflammatory genes. Infections are able to trigger susceptibility to disease and it can be considered as potential epimutagenic factors in reshaping the epigenome. Therefore, what would be the DNA methylation status in cells present in an infected and inflamed oral environment? The aim was to verify the DNA methylation pattern in oral epithelium cells from aggressive periodontitis (AgP) patients in a specific gene involved in the inflammation control, as suppressor of cytokine signalling (SOCS)1 and in a broader way through long interspersed nuclear element (LINE)-1. DESIGN: Genomic DNA from oral cells of 30 generalized AgP patients and 30 healthy patients were purified and modified by sodium bisulfite. DNA methylation patterns were analyzed using combined bisulfite restriction analysis (COBRA) for SOCS1 and LINE-1. RESULTS: An overall scenario of demethylation was seen for both groups, whereas the healthy group presented a higher percentage of demethylation (p<0.001), also presenting the majority of total demethylated samples (83.3% versus 70.8% in the AgP group). Total LINE-1 methylation or at each specific loci presented significant differences amongst groups. CONCLUSION: Epithelial cells, present in an infected and inflamed oral environment, show different DNA methylation status from those present in a healthy oral environment, regarding the SOCS1 and LINE-1. In addition, the investigation allows detecting alterations in the DNA in a non-limited manner, since the results observed might reflect a generalized condition of the oral epithelial cells, besides reflecting the condition of the gingival epithelium cells. PMID- 24769219 TI - Atherogenic cholesterol-rich diet and periodontal disease. AB - OBJECTIVE: This study investigated the effect of an atherogenic cholesterol-rich diet (AT) on the alveolar bone loss in rats with ligature-induced experimental periodontitis (EP). METHODS: Female Wistar adult rats were assigned either a control (Co) or an AT diet fed for 9 weeks. The AT diet was high in saturated fat, cholesterol and energy. At week 2, animals were subjected to a unilateral ligature (L) around the left first molar (Co+L and AT+L). The contra lateral first right molar (not ligated) of both groups (Co and AT) were used as untreated controls. At week 9, blood was drawn, rats were euthanized, hemi-mandibles removed and stained digital photographs (buccal and lingual surfaces) and radiographs were obtained for quantification of alveolar bone loss (ABL). The ABL was determined by distance and area methods (mm(2)) and X-rays were used for periodontal bone support (PBS), (%). RESULTS: Rats in the AT group exhibited a 17% increase in energy intake, gained significant body weight and showed the highest serum total-cholesterol (T-C) and non-high density lipoprotein cholesterol (HDL-C) levels (p<0.001). The amount of lost periodontal bone was the greatest in AT+L rats. AT feedings significantly increased the buccal area and distance of bone loss when compared with the unligated-teeth (p<0.001). The rats in the AT+L group also achieved the lowest percentage of PBS (p<0.001). The AT and Co+L rats showed similar PBS. This method more clearly elucidated the effect of the cholesterol-rich AT, with and without the influence of molar ligature, compared to the morphometric analysis. CONCLUSION: The alveolar bone loss of EP was magnified by ingestion of an atherogenic diet high in saturated fatty acids and cholesterol. PMID- 24769220 TI - A functional neuroimaging review of obesity, appetitive hormones and ingestive behavior. AB - Adequate energy intake is vital for the survival of humans and is regulated by complex homeostatic and hedonic mechanisms. Supported by functional MRI (fMRI) studies that consistently demonstrate differences in brain response as a function of weight status during exposure to appetizing food stimuli, it has been posited that hedonically driven food intake contributes to weight gain and obesity maintenance. These food reward theories of obesity are reliant on the notion that the aberrant brain response to food stimuli relates directly to ingestive behavior, specifically, excess food intake. Importantly, functioning of homeostatic neuroendocrine regulators of food intake, such as leptin and ghrelin, are impacted by weight status. Thus, data from studies that evaluate the effect on weight status on brain response to food may be a result of differences in neuroendocrine functioning and/or behavior. In the present review, we examine the influence of weight and weight change, exogenous administration of appetitive hormones, and ingestive behavior on BOLD response to food stimuli. PMID- 24769221 TI - Ocular vascular occlusive disorders: natural history of visual outcome. AB - Ocular vascular occlusive disorders collectively constitute the most common cause of visual disability. Before a disease can be managed, it is essential to understand its natural history, so as to be able to assess the likely effectiveness of any intervention. I investigated natural history of visual outcome in prospective studies of 386 eyes with non-arteritic anterior ischemic optic neuropathy (NA-AION), 16 eyes with non-arteritic posterior ischemic optic neuropathy, 697 eyes with central retinal vein occlusion (CRVO), 67 eyes with hemi-CRVO (HCRVO), 216 eyes with branch retinal vein occlusion (BRVO), 260 eyes with central retinal artery occlusion (CRAO), 151 eyes with branch retinal artery occlusion (BRAO) and 61 eyes with cilioretinal artery occlusion (CLRAO). My studies have shown that every one of these disorders consists of multiple distinct clinical sub-categories with different visual findings. When an ocular vascular occlusive disorder is caused by giant cell arteritis, which is an ophthalmic emergency, it would be unethical to do a natural history study of visual outcome in them, because in this case early diagnosis and immediate, intensive high-dose steroid therapy is essential to prevent any further visual loss, not only in the involved eye but also in the fellow, normal eye. In NA-AION in eyes seen <=2 weeks after the onset, visual acuity (VA) improved in 41% of those with VA 20/70 or worse, and visual field (VF) improved in 26% of those with moderate to severe VF defect. In non-ischemic CRVO eyes with VA 20/70 or worse, VA improved in 47% and in ischemic CRVO in 23%; moderate to severe VF defect improved in 79% in non-ischemic CRVO and in 27% in ischemic CRVO. In HCRVO, overall findings demonstrated that initial VA and VF defect and the final visual outcome were different in non-ischemic from ischemic HCRVO - much better in the former than the latter. In major BRVO, in eyes with initial VA of 20/70 or worse, VA improved in 69%, and moderate to severe VF defect improved in 52%. In macular BRVO with 20/70 or worse initial VA, it improved in 53%, and initial minimal-mild VF defect was stable or improved in 85%. In various types of CRAO there are significant differences in both initial and final VA and VF defects. In CRAO eyes seen within 7 days of onset and initial VA of counting fingers or worse, VA improved in 82% with transient non-arteritic CRAO, 67% with non-arteritic CRAO with cilioretinal artery sparing, 22% with non-arteritic CRAO. Central VF improved in 39% of transient non-arteritic CRAO, 25% of non-arteritic CRAO with cilioretinal artery sparing and 21% of non-arteritic CRAO. Peripheral VF improved in non-arteritic CRAO in 39% and in transient non-arteritic CRAO in 39%. In transient CRAO, finally peripheral VFs were normal in 93%. In non-arteritic CRAO eyes initially 22% had normal peripheral VF and in the rest it improved in 39%. Final VA of 20/40 or better was seen in 89% of permanent BRAO, and in 100% of transient BRAO and non-arteritic CLRAO. In permanent BRAO eyes, among those seen within 7 days of onset, central VF defect improved in 47% and peripheral VF in 52%, and in transient BRAO central and peripheral VFs were normal at follow-up. My studies showed that AION, CRVO, BRVO, CRAO and BRAO, each consist of multiple distinct clinical sub-categories with different visual outcome. Contrary to the prevalent impression, these studies on the natural history of visual outcome have shown that there is a statistically significant spontaneous visual improvement in each category. The factors which influence the visual outcome in various ocular vascular occlusive disorders are discussed. PMID- 24769222 TI - Preserving ignitable liquid residues on soil using Triclosan as an anti-microbial agent. AB - When a fire is suspected to be intentionally set, fire debris samples can be collected and analyzed for ignitable liquid residues (ILRs). In some cases, samples will contain highly organic substrates such as soil or rotting wood. These substrates will contain a high bacterial load, which can result in systematic and irreversible damage to the ILR due to microbial degradation. This paper explores ways to preserve ILR by sterilizing fire debris samples without interfering with their subsequent analysis. There are many methods reported in the literature for sterilizing soil, such as freezing, irradiation, autoclaving, and various chemical fumigation techniques. However, these methods either do not kill all bacterial species, cannot be easily applied in the field or would interfere with the analysis of the ILRs. For this work, various anti-microbial compounds including triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) were tested for their efficacy at killing bacteria present in the soil. Triclosan was highly effective in qualitative growth studies and was therefore used to measure bacterial growth (or lack thereof) by spectroscopic analysis as well as passive headspace analysis. These experiments showed that triclosan was able to sterilize soil samples in less than 60s, maintain their sterility for at least 77h and preserve gasoline residues on a soil matrix for at least 30 days. PMID- 24769223 TI - Novel insights into exosome-induced, tumor-associated inflammation and immunomodulation. AB - The immune system of cancer patients is often suppressed. Accumulating evidence suggests that exosomes released from tumor cells may play an essential role in this process but the mechanisms are not fully understood. Here we review recent papers showing that exosomes trigger the release of cytokines/chemokines from immune cells. We suggest that this process will either result in the stimulation of anti-tumor immune reactions or in a systemic immunosuppression. The direction appears to be largely dependent on the duration of interactions between immune cells and exosomes leading to the accumulation of inflammatory factors, i.e. on the length of the exposure to these factors. We propose that a long-term interaction of the immune system with elevated levels of tumor exosomes contributes to the development of immunosuppression in cancer patients. PMID- 24769224 TI - Global characterization and target identification of piRNAs and endo-siRNAs in mouse gametes and zygotes. AB - A set of small RNAs known as rasRNAs (repeat-associated small RNAs) have been related to the down-regulation of Transposable Elements (TEs) to safeguard genome integrity. Two key members of the rasRNAs group are piRNAs and endo-siRNAs. We have performed a comparative analysis of piRNAs and endo-siRNAs present in mouse oocytes, spermatozoa and zygotes, identified by deep sequencing and bioinformatic analysis. The detection of piRNAs and endo-siRNAs in the spermatozoa and revealed also in zygotes, hints to their potential delivery to oocytes during fertilization. However, a comparative assessment of the three cell types indicates that both piRNAs and endo-siRNAs are mainly maternally inherited. Finally, we have assessed the role of the different rasRNA molecules in connection with amplification processes by way of the "ping-pong cycle". Our results suggest that the ping-pong cycle can act on other rasRNAs, such as tRNA- and rRNA-derived fragments, thus not only being restricted to TEs during gametogenesis. PMID- 24769225 TI - MRI evaluation of BBB disruption after adjuvant AcSDKP treatment of stroke with tPA in rat. AB - The primary limitation of thrombolytic treatment of ischemic stroke with tissue plasminogen activator (tPA) is the hemorrhagic risk. We tested AcSDKP (N-acetyl seryl-aspartyl-lysyl-proline), as an auxiliary therapeutic agent, to reduce blood brain barrier (BBB) disruption in a combination tPA thrombolytic treatment of stroke. Wistar rats subjected to embolic stroke were randomly assigned to either the tPA monotherapy group (n=9) or combination of tPA and AcSDKP treatment group (n=9) initiated at 4 h after ischemia. Magnetic resonance imaging (MRI) measurements were performed before and after the treatments. Immunohistochemical staining and measurements were performed to confirm MRI findings. Longitudinal MRI permeability measurements with gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) demonstrated that combination treatment of acute embolic stroke with AcSDKP and tPA significantly reduced BBB leakage, compared to tPA monotherapy, at 3 and 6 days (18.3+/-9.8 mm3 vs. 65.0+/-21.0 mm3, p<0.001) after the onset of stroke, although BBB leakage was comparable between the two groups prior to the treatments (6.8+/-4.4 mm3 vs. 4.3+/-3.3 mm3, p>0.18). The substantial reduction of BBB leakage observed in the combination treatment group was closely associated with reduced ischemic lesions measured by T2 maps (113.6+/ 24.9 mm3 vs. 188.1+/-60.8 mm3, p<0.04 at 6 days). Histopathological analysis of the same population of rats showed that the combination treatment significantly reduced parenchymal fibrin deposition (0.063+/-0.059 mm2 vs. 0.172+/-0.103 mm2, p<0.03) and infarct volume (146.7+/-35.9 mm3 vs. 199.3+/-60.4 mm3, p<0.05) compared to the tPA monotherapy at 6days after stroke. MRI provides biological insight into the therapeutic benefit of combination treatment of stroke with tPA and AcSDKP 4h after onset, and demonstrates significantly improved cerebrovascular integrity with neuroprotective effects compared with tPA monotherapy. PMID- 24769226 TI - Ultrastructural localization of tyrosine hydroxylase in tree shrew nucleus accumbens core and shell. AB - Many behavioral, physiological, and anatomical studies utilize animal models to investigate human striatal pathologies. Although commonly used, rodent striatum may not present the optimal animal model for certain studies due to a lesser morphological complexity than that of non-human primates, which are increasingly restricted in research. As an alternative, the tree shrew could provide a beneficial animal model for studies of the striatum. The gross morphology of the tree shrew striatum resembles that of primates, with separation of the caudate and putamen by the internal capsule. The neurochemical anatomy of the ventral striatum, specifically the nucleus accumbens, has never been examined. This major region of the limbic system plays a role in normal physiological functioning and is also an area of interest for human striatal disorders. The current study uses immunohistochemistry of calbindin and tyrosine hydroxylase (TH) to determine the ultrastructural organization of the nucleus accumbens core and shell of the tree shrew (Tupaia glis belangeri). Stereology was used to quantify the ultrastructural localization of TH, which displays weaker immunoreactivity in the core and denser immunoreactivity in the shell. In both regions, synapses with TH immunoreactive axon terminals were primarily symmetric and showed no preference for targeting dendrites versus dendritic spines. The results were compared to previous ultrastructural studies of TH and dopamine in rat and monkey nucleus accumbens. Tree shrews and monkeys show no preference for the postsynaptic target in the shell, in contrast to rats which show a preference for synapsing with dendrites. Tree shrews have a ratio of asymmetric to symmetric synapses formed by TH-immunoreactive terminals that is intermediate between rats and monkeys. The findings from this study support the tree shrew as an alternative model for studies of human striatal pathologies. PMID- 24769227 TI - Distinct dopaminergic control of the direct and indirect pathways in reward-based and avoidance learning behaviors. AB - The nucleus accumbens (NAc) plays a pivotal role in reward and aversive learning and learning flexibility. Outputs of the NAc are transmitted through two parallel routes termed the direct and indirect pathways and controlled by the dopamine (DA) neurotransmitter. To explore how reward-based and avoidance learning is controlled in the NAc of the mouse, we developed the reversible neurotransmission blocking (RNB) technique, in which transmission of each pathway could be selectively and reversibly blocked by the pathway-specific expression of transmission-blocking tetanus toxin and the asymmetric RNB technique, in which one side of the NAc was blocked by the RNB technique and the other intact side was pharmacologically manipulated by a transmitter agonist or antagonist. Our studies demonstrated that the activation of D1 receptors in the direct pathway and the inactivation of D2 receptors in the indirect pathway are key determinants that distinctly control reward-based and avoidance learning, respectively. The D2 receptor inactivation is also critical for flexibility of reward learning. Furthermore, reward and aversive learning is regulated by a set of common downstream receptors and signaling cascades, all of which are involved in the induction of long-term potentiation at cortico-accumbens synapses of the two pathways. In this article, we review our studies that specify the regulatory mechanisms of each pathway in learning behavior and propose a mechanistic model to explain how dynamic DA modulation promotes selection of actions that achieve reward-seeking outcomes and avoid aversive ones. The biological significance of the network organization consisting of two parallel transmission pathways is also discussed from the point of effective and prompt selection of neural outcomes in the neural network. PMID- 24769228 TI - Intrathecal administration of roscovitine prevents remifentanil-induced postoperative hyperalgesia and decreases the phosphorylation of N-methyl-D aspartate receptor and metabotropic glutamate receptor 5 in spinal cord. AB - N-methyl-D-aspartate receptor (NMDAR) and metabotropic glutamate receptor 5 (mGluR5) play an important role in nociceptive processing and central sensitization. Our previous study showed that tyrosine phosphorylation of NMDAR subunit 2B (NR2B) at Tyr1472 in spinal dorsal horn contributes to the postoperative hyperalgesia induced by remifentanil. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity, learning, memory and pain signaling via regulating the phosphorylation of NMDAR and mGluR5. In the present study, a rat model of postoperative pain was used to investigate the role of Cdk5 in spinal dorsal horn in remifentanil-induced hyperalgesia and the intervention of pretreatment with Cdk5 inhibitor roscovitine. Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous) significantly enhanced mechanical allodynia and thermal hyperalgesia induced by plantar incision during the postoperative period (each lasting between 2 h and 48 h), which were attenuated by pretreatment with roscovitine. Correlated with the pain behavior changes, Western blotting revealed that there was a significant increase in the expression of Cdk5 and its activator p35/p25, and further the kinase activity of Cdk5 in spinal dorsal horn after intraoperative infusion of remifentanil. The phosphorylation of NR2A at Ser1232, the phosphorylation of NR2B at Tyr1472 and the phosphorylation of mGluR5 at Ser1167 were also significantly up-regulated. Furthermore, these increases were attenuated by pretreatment with roscovitine. These results suggested that Cdk5 may contribute to remifentanil-induced postoperative hyperalgesia via regulating the phosphorylation of NMDAR and mGluR5 in spinal dorsal horn. These findings provide experimental evidence for the further application of Cdk5 inhibitor in preventing remifentanil-induced hyperalgesia. PMID- 24769229 TI - PrimeIndel: four-prime-number genetic code for indel decryption and sequence read alignment. AB - BACKGROUND: To decrypt a doubly heterozygous sequence (DHS) in order to define the indel mutation for mutation reporting, an algorithm recursively searching the overlapped nucleotide using an offset of nucleotide positions can decrypt the indel without using a reference sequence. However, as genetic code is letter based, special computer programs are required to run the decryption algorithm. METHODS: The previous text-based algorithm was converted to a number-based algorithm by expressing DNA sequence from a 4-letter genetic code to a 4-prime number genetic code, i.e., converting A, C, G, T to 2, 3, 5, and 7. This algorithm based on prime-number genetic code is called PrimeIndel and is executable by spreadsheet. Using prime number coded DNA sequence, the overlapped nucleotide between any 2 positions of the DHS is represented by the greatest common divisor (GCD) of the multiplication product of 2 prime numbers. This algorithm can also be used for aligning multiple overlapping sequence reads by in silico DHS formation. The indel size of the in-silico formed DHS indicates the positions in the paired sequences for correct alignment. RESULTS: DHSs were successfully decrypted by the prime number-based algorithm and sequence reads were aligned correctly. CONCLUSIONS: DNA sequence expressed in prime numbers can be used for the decryption of DHS and the alignment of sequence reads using a well-known mathematical function GCD of a spreadsheet program. PrimeIndel is a useful tool for mutation reporting in clinical laboratories. The software is downloadable from http://www.patho.hku.hk/staff/list/cwlam.htm. PMID- 24769230 TI - Site-dependent changes in structure and function of lapine articular cartilage 4 weeks after anterior cruciate ligament transection. AB - OBJECTIVE: The aim of this study was to investigate the site-dependent changes in the structure and function of articular cartilage in the lapine knee joint at a very early stage of osteoarthritis (OA), created experimentally by anterior cruciate ligament transection (ACLT). METHODS: Unilateral ACLT was performed in eight mature New Zealand white rabbits. ACL transected and contralateral (C-L) joints were prepared for analysis at 4 weeks after ACLT. Three rabbits with intact joints were used as a control group (CNTRL). Femoral groove, medial and lateral femoral condyles, and tibial plateaus were harvested and used in the analysis. Biomechanical tests, microscopy and spectroscopy were used to determine the biomechanical properties, composition and structure of the samples. A linear mixed model was chosen for statistical comparisons between the groups. RESULTS: As a result of ACLT, the equilibrium and dynamic moduli were decreased primarily in the femoral condyle cartilage. Up to three times lower moduli (P < 0.05) were observed in the ACLT group compared to the control group. Significant (P < 0.05) proteoglycan (PG) loss in the ACLT joint cartilage was observed up to a depth of 20-30% from the cartilage surface in femoral condyles, while significant PG loss was confined to more superficial regions in tibial plateaus and femoral groove. The collagen orientation angle was increased (P < 0.05) up to a cartilage depth of 60% by ACLT in the lateral femoral condyle, while smaller effects, but still significant, were observed at other locations. The collagen content was increased (P < 0.05) in the middle and deep zones of the ACLT group compared to the control group samples, especially in the lateral femoral condyle. CONCLUSION: Femoral condyle cartilage experienced the greatest structural and mechanical alterations in very early OA, as produced by ACLT. Degenerative alterations were observed especially in the superficial collagen fiber organization and PG content, while the collagen content was increased in the deep tissue of femoral condyle cartilage. The current findings provide novel information of the early stages of OA in different locations of the knee joint. PMID- 24769231 TI - NFATs are good for your cartilage! PMID- 24769232 TI - Proteomic mapping of the lung vascular endothelial cell surface in Schistosoma bovis-infected hamsters. AB - Schistosomes are blood trematodes that are perfectly adapted to living in their intravascular habitat and to achieve this they have developed mechanisms enabling them to evade the immune and haemostatic responses of the host and to regulate endothelial cell function to favour their own survival. The objective of this work was to analyse the changes induced by Schistosoma bovis schistosomula in the proteome expressed by infected hamsters, over 10 and 20 days, on the endothelial surface of their pulmonary vasculature. To accomplish this, we subjected the lungs of non-infected and S. bovis-infected hamsters to vascular perfusion with a biotin ester reactive. Analysis by liquid chromatography and tandem mass spectrometry analysis (LC-MS/MS) of endothelial surface proteins resulted in the identification of a total of 459 non-redundant proteins in the lung vasculature of infected and non-infected hamsters. Here we report the proteins identified, classified according to their biological function and cellular location, further analysing the differences in lung vascular proteomes between non-infected and S. bovis-infected hamsters for ten and twenty days. This work provides the first data on the vascular surface proteome of the lung after S. bovis infection and identifies some of the changes induced in it during infection. BIOLOGICAL SIGNIFICANCE: To identify the changes induced by schistosomula larvae of Schistosoma bovis in the proteome of the pulmonary vasculature of the host, we compared the proteins expressed on the vascular endothelium of the lungs of non infected and infected hamsters over 10 and 20 days. Mass spectrometry analysis (LC-MS/MS) of the proteins isolated from the vascular endothelium resulted in the identification of a total of 459 non-redundant proteins in the lung of infected and non-infected hamsters. The proteins identified are classified according to their biological function and cellular location, further analysing the differences in lung vascular proteomes between non-infected and S. bovis-infected hamsters. This work provides the first data on the vascular surface proteome of the lung after S. bovis infection and identifies some of the changes induced in it during infection suggesting the possible involvement of these proteins during parasite infection. PMID- 24769233 TI - Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. AB - Extracellular vesicles (EVs) are present in human cerebrospinal fluid (CSF), yet little is known about their protein composition. The aim of this study is to provide a comprehensive analysis of the proteome of CSF EVs by electron microscopy and high resolution tandem mass spectrometry (MS/MS) in conjunction with bioinformatics. We report an extensive catalog of 1315 proteins identified in EVs isolated from two different CSF pools by ultracentrifugation, including 230 novel EV proteins. Out of 1315 proteins, 760 were identified in both CSF pools and about 30% of those were also quantitatively enriched in the EV fraction versus the soluble CSF fraction. The proteome of CSF EVs was enriched in exosomal markers such as alix and syntenin-1, heat shock proteins and tetraspanins and contained a high proportion of brain-derived proteins (n=373). Interestingly, several known biomarkers for neurodegenerative diseases such as the amyloid precursor protein, the prion protein and DJ-1 were identified in the EV fractions. Our dataset represents the first comprehensive inventory of the EV proteome in CSF, underscoring the biomarker potential of this organelle. Further comparative studies on CSF EVs isolated from patients diagnosed with neurological disorders are warranted. Data are available via ProteomeXchange with identifier PXD000608. Biological significance In this study we analyzed the protein composition of extracellular vesicles isolated from pooled samples of human cerebrospinal fluid (CSF). CSF is a colorless fluid surrounding the brain and the spinal cord, important for the physiology of the central nervous system, ensuing mechanical protection, regulation of brain blood flow and elimination of byproducts of the brain. Since brain (patho)physiology is reflected in CSF, this biological fluid represents an ideal source of soluble and vesicle-based biomarkers for neurological diseases. Here we confirm the presence of exosome like extracellular vesicles in CSF, underscoring a potential role in the physiology of the brain. These extracellular vesicles provide a rich source of candidate biomarkers, representing a brain "fluid biopsy". Most interestingly, the involvement of extracellular vesicles in transferring toxic proteins such as alpha-synuclein and beta-amyloid has been postulated as one of the mechanisms involved in the spreading of neurodegeneration to different brain areas. In line with this, we show that human CSF extracellular vesicles contain prionogenic proteins such as the amyloid precursor protein and the prion protein. Delineating the protein composition of extracellular vesicles in CSF is a first and crucial step to comprehend their origin and their function in the central nervous system and to establish their biomarker potential. PMID- 24769235 TI - The role of von Willebrand factor as a biomarker of tumor development in hepatitis B virus-associated human hepatocellular carcinoma: a quantitative proteomic based study. AB - Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), the sixth most common cancer worldwide. To explore potential biomarkers for HCC, iTRAQ coupled with mass spectrometry was used to analyze proteins in plasma from individuals with HBV-associated HCC, nonmalignant cirrhosis, chronic hepatitis B, and healthy individuals. Twenty-one aberrantly expressed proteins were identified from HCC patients as compared with nontumor controls. Overexpression of von Willebrand factor (vWF) was confirmed by Western blotting, and immunohistochemical analysis from liver biopsies and ELISA from plasma samples revealed a correlation between vWF expression and HCC clinicopathologic staging. Furthermore, siRNA-induced vWF silencing reduced HBV replication by over two-fold via the interferon-signaling pathway and impaired the invasion and migration of HCC cells in vitro. These results indicate that vWF can serve as a biomarker, and perhaps an alternative target for therapeutic intervention of HCC progression and HBV viral infection. BIOLOGICAL SIGNIFICANCE: We report comparative plasma proteome profiles of HBV-associated HCC and nonmalignant chronic liver diseases, including chronic hepatitis B and cirrhosis. The quantification of these datasets showed altered abundance of 21 proteins in HBV-related HCC and provides a reference point for future applied and basic research. In addition, we have demonstrated that the candidate protein vWF is involved in the pathogenesis of HBV infection and replication, and also associated with clinicopathologic staging of HCC patients with HBV infection. Overall these findings provide information on the mechanism of HCC development, which may assist in the development of novel cancer and HBV therapeutic drugs. PMID- 24769234 TI - Conditional independence mapping of DIGE data reveals PDIA3 protein species as key nodes associated with muscle aerobic capacity. AB - Profiling of protein species is important because gene polymorphisms, splice variations and post-translational modifications may combine and give rise to multiple protein species that have different effects on cellular function. Two dimensional gel electrophoresis is one of the most robust methods for differential analysis of protein species, but bioinformatic interrogation is challenging because the consequences of changes in the abundance of individual protein species on cell function are unknown and cannot be predicted. We conducted DIGE of soleus muscle from male and female rats artificially selected as either high- or low-capacity runners (HCR and LCR, respectively). In total 696 protein species were resolved and LC-MS/MS identified proteins in 337 spots. Forty protein species were differentially (P<0.05, FDR<10%) expressed between HCR and LCR and conditional independence mapping found distinct networks within these data, which brought insight beyond that achieved by functional annotation. Protein disulphide isomerase A3 emerged as a key node segregating with differences in aerobic capacity and unsupervised bibliometric analysis highlighted further links to signal transducer and activator of transcription 3, which were confirmed by western blotting. Thus, conditional independence mapping is a useful technique for interrogating DIGE data that is capable of highlighting latent features. BIOLOGICAL SIGNIFICANCE: Quantitative proteome profiling revealed that there is little or no sexual dimorphism in the skeletal muscle response to artificial selection on running capacity. Instead we found that noncanonical STAT3 signalling may be associated with low exercise capacity and skeletal muscle insulin resistance. Importantly, this discovery was made using unsupervised multivariate association mapping and bibliometric network analyses. This allowed our interpretation of the findings to be guided by patterns within the data rather than our preconceptions about which proteins or processes are of greatest interest. Moreover, we demonstrate that this novel approach can be applied to 2D gel analysis, which is unsurpassed in its ability to profile protein species but currently has few dedicated bioinformatic tools. PMID- 24769236 TI - Regulation of PPAR-alpha pathway by Dicer revealed through proteomic analysis. AB - Dicer is a crucial RNase III enzyme in miRNA biogenesis pathway. Although numerous studies have been carried out to investigate the role of miRNAs and Dicer in the regulation of biological processes, few studies have examined proteomic alterations upon knockout of Dicer. We employed a Cre-loxP-based inducible knockout mouse system to investigate the proteome regulated by Dicer dependent miRNAs. We utilized spiked liver lysates from metabolically labeled mice to quantify the subtle changes in the liver proteome upon deletion of Dicer. We identified 2137 proteins using high resolution tandem mass spectrometry analysis. The upregulated proteins included several enzymes involved in peroxisomal beta-oxidation of fatty acids and a large majority of the upregulated proteins involved in lipid metabolism were known PPARalpha targets. MRM-based assays were carried out to confirm the upregulation of enzymes including peroxisomal bifunctional enzyme, phosphoenolpyruvate carboxykinase 1, cytochrome P450 3A13, cytochrome P450 3A41 and myristoylated alanine-rich protein kinase C substrate. Further, miRNA-124 which is predicted to regulate expression of peroxisomal bifunctional enzyme was confirmed to be downregulated in the Dicer knockout mice. Our study demonstrates the strength of coupling knockout mouse models and quantitative proteomic strategies to investigate functions of individual proteins in vivo. BIOLOGICAL SIGNIFICANCE: Dicer dependent miRNA biogenesis is the major pathway for generation of mature miRNAs. We developed SILAC mouse-based proteomics screen to identify protein targets of Dicer dependent miRNAs in liver of Dicer knockout mice. We spiked liver lysates of induced and uninduced Dicer knockout mice with liver lysate of SILAC labeled mice for identification of dysregulated proteome. We quantitated 1217 proteins of which 257 were upregulated in induced Dicer knockout mice. We observed enrichment of PPAR-alpha targets and proteins involved in lipid metabolism among upregulated proteins. We further carried out MRM-based validation of peroxisomal bifunctional enzyme, phosphoenolpyruvate carboxykinase 1, Cyp3A13, Cyp3A41 and myristoylated alanine-rich protein kinase C substrate. We further validated upregulation of peroxisomal bifunctional enzyme using Western blot analysis and downregulation of its predicted upstream miRNA, miR-124 using qRT-PCR. Our study demonstrates that upon ablation of Dicer, certain Dicer-dependent miRNAs are dysregulated which result in dysregulation of their target proteins such as proteins associated with lipid metabolism. Our study illustrates the use of SILAC strategy for quantitative proteomic investigations of animal model systems. PMID- 24769237 TI - Enhanced sensitivity and multiplexing with 2D LC/MRM-MS and labeled standards for deeper and more comprehensive protein quantitation. AB - Mass spectrometry (MS)-based protein quantitation is increasingly being employed to verify candidate protein biomarkers. Multiple or selected reaction monitoring mass spectrometry (MRM-MS or SRM-MS) with isotopically labeled internal standards has proven to be a successful approach in that regard, but has yet to reach its full potential in terms of multiplexing and sensitivity. Here, we report the development of a new MRM method for the quantitation of 253 disease-associated proteins (represented by 625 interference-free peptides) in 13 LC fractions. This 2D RPLC/MRM-MS approach extends the depth and breadth of the assay by 2 orders of magnitude over pre-fractionation-free assays, with 31 proteins below 10 ng/mL and 41 proteins above 10 ng/mL now quantifiable. Standard flow rates are used in both chromatographic dimensions, and up-front depletion or antibody-based enrichment is not required. The LC separations utilize high and low pH conditions, with the former employing an ammonium hydroxide-based eluent, instead of the conventional ammonium formate, resulting in improved LC column lifetime and performance. The high sensitivity (determined concentration range: 15 mg/mL to 452 pg/mL) and robustness afforded by this method makes the full MRM panel, or subsets thereof, useful for the verification of disease-associated plasma protein biomarkers in patient samples. BIOLOGICAL SIGNIFICANCE: The described research extends the breadth and depth of protein quantitation in undepleted and non-enriched human plasma by employing standard-flow 2D RPLC/MRM-MS in conjunction with a complex mixture of isotopically labeled peptide standards. The proteins quantified are mainly putative biomarkers of non-communicable (i.e., non-infectious) disease (e.g., cardiovascular or cancer), which require pre-clinical verification and validation before clinical implementation. Based on the enhanced sensitivity and multiplexing, this quantitative plasma proteomic method should prove useful in future candidate biomarker verification studies. PMID- 24769238 TI - Inhibition of MMP-2 expression affects metabolic enzyme expression levels: proteomic analysis of rat cardiomyocytes. AB - In this study we examined the effect of inhibition of MMP-2 expression, using siRNA, on the cardiomyocyte proteome. Isolated cardiomyocytes were transfected with MMP-2 siRNA and incubated for 24h. Control cardiomyocytes from the same heart were transfected with scrambled siRNA following the same protocol. Comparison of control cardiomyocyte proteomes with proteomes from MMP-2 suppressed cardiomyocytes revealed 13 protein spots of interest (9 protein spots increased; 4 decreased). Seven protein spots were identified as mitochondrial enzymes involved in energy production and represent: ATP synthase beta subunit, dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, cytochrome c oxidase subunit 5A, electron transfer flavoprotein subunit beta, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5 and a fragment of mitochondrial precursor of long-chain specific acyl CoA dehydrogenase. Furthermore, precursor of heat shock protein 60 and Cu-Zn superoxide dismutase were identified. Two protein spots corresponding to MLC1 were also detected. In addition, ATP synthase activity was measured and was increased by approximately 30%. Together, these results indicate that MMP-2 inhibition represents a novel cardioprotective therapy by promoting alterations in the levels of mitochondrial enzymes for improved energy metabolism and by preventing degradation of contractile proteins needed for normal excitation contraction coupling. BIOLOGICAL SIGNIFICANCE: During ischemia and reperfusion of cardiomyocytes, abnormality in excitation-contraction coupling and decreased energy metabolism often lead to myocardial infarction, but the cellular mechanisms are not fully elucidated. We show for the first time that intracellular inhibition of MMP-2 in cardiomyocytes increases contractility of aerobically perfused myocytes, which was accompanied by increased expression of contractile proteins (e.g., MLC-1). We also showed that MMP-2 inhibition produced a cardiomyocyte proteome that is consistent with improved mitochondrial energy metabolism (e.g., increased expression and activity of mitochondrial beta ATP synthase). Thus, MMP-2 appears to be involved in homeostatic regulation of protein turnover. Our results are significant since they point to targeting MMP-2 activity as a novel therapeutic option to limit myocardial damage by decreasing proteolytic degradation of mitochondrial metabolic enzymes and myocardial contractile proteins during ischemia. In addition, the development of novel pharmacological agents that selectively targets cardiac MMP-2 represents a novel approach to treat and prevent other heart diseases. PMID- 24769239 TI - Quantitative variations of the mitochondrial proteome and phosphoproteome during fermentative and respiratory growth in Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae is a facultative aerobe able to adapt its metabolism according to the carbon substrate. The mechanisms of these adaptations involve at least partly the mitochondria but are not yet well understood. To address the possible role of protein phosphorylation event in their regulation, it is necessary in a first instance to determine precisely the phosphorylation sites that show changes depending on the carbon source. In this aim we performed an overall quantitative proteomic and phosphoproteomic study of isolated mitochondria extracted from yeast grown on fermentative (glucose or galactose) and respiratory (lactate) media. Label free quantitative analysis of protein accumulation revealed significant variation of 176 mitochondrial proteins including 108 proteins less accumulated in glucose medium than in lactate and galactose media. We also showed that the responses to galactose and glucose are not similar. Stable isotope dimethyl labeling allowed the quantitative comparison of phosphorylation levels between the different growth conditions. This study enlarges significantly the map of yeast mitochondrial phosphosites as 670 phosphorylation sites were identified, of which 214 were new and quantified. Above all, we showed that 90 phosphosites displayed a significant variation according to the medium and that variation of phosphorylation level is site dependent. BIOLOGICAL SIGNIFICANCE: This proteomic and phosphoproteomic study is the first extensive study providing quantitative data on phosphosites responses to different carbon substrates independent of the variations of protein quantities in the yeast S. cerevisiae mitochondria. The significant changes observed in the level of phosphorylation according to the carbon substrate open the way to the study of the regulation of mitochondrial proteins by phosphorylation in fermentative and respiratory media. In addition, the identification of a large number of new phosphorylation sites show that the characterization of mitochondrial phosphoproteome is not yet completed. PMID- 24769240 TI - Characterization of protective extracellular membrane-derived vesicles produced by Streptococcus pneumoniae. AB - Extracellular vesicles are produced by many pathogenic microorganisms and have varied functions that include secretion and release of microbial factors, which contribute to virulence. Very little is known about vesicle production by Gram positive bacteria, as well as their biogenesis and release mechanisms. In this work, we demonstrate the active production of vesicles by Streptococcus pneumoniae from the plasma membrane, rather than being a product from cell lysis. We biochemically characterized them by proteomics and fatty acid analysis, showing that these vesicles and the plasma membrane resemble in essential aspects, but have some differences: vesicles are more enriched in lipoproteins and short-chain fatty acids. We also demonstrate that these vesicles act as carriers of surface proteins and virulence factors. They are also highly immunoreactive against human sera and induce immune responses that protect against infection. Overall, this work provides insights into the biology of this important Gram-positive human pathogen and the role of extracellular vesicles in clinical applications. BIOLOGICAL SIGNIFICANCE: Pneumococcus is one of the leading causes of bacterial pneumonia worldwide in children and the elderly, being responsible for high morbidity and mortality rates in developing countries. The augment of pneumococcal disease in developed countries has raised major public health concern, since the difficulties to treat these infections due to increasing antibiotic resistance. Vaccination is still the best way to combat pneumococcal infections. One of the mechanisms that bacterial pathogens use to combat the defense responses of invaded hosts is the production and release of extracellular vesicles derived from the outer surface. Little is known about this phenomenon in Gram-positives. We show that pneumococcus produces membrane-derived vesicles particularly enriched in lipoproteins. We also show the utility of pneumococcal vesicles as a new type of vaccine, as they induce protection in immunized mice against infection with a virulent strain. This work will contribute to understand the role of these structures in important biological processes such as host-pathogen interactions and prevention of human disease. PMID- 24769241 TI - Should clinical studies involving "regenerative injection therapy," strive to incorporate a triad of outcome measures instead of only including clinical outcome measures? PMID- 24769242 TI - Computational modeling of neural plasticity for self-organization of neural networks. AB - Self-organization in biological nervous systems during the lifetime is known to largely occur through a process of plasticity that is dependent upon the spike timing activity in connected neurons. In the field of computational neuroscience, much effort has been dedicated to building up computational models of neural plasticity to replicate experimental data. Most recently, increasing attention has been paid to understanding the role of neural plasticity in functional and structural neural self-organization, as well as its influence on the learning performance of neural networks for accomplishing machine learning tasks such as classification and regression. Although many ideas and hypothesis have been suggested, the relationship between the structure, dynamics and learning performance of neural networks remains elusive. The purpose of this article is to review the most important computational models for neural plasticity and discuss various ideas about neural plasticity's role. Finally, we suggest a few promising research directions, in particular those along the line that combines findings in computational neuroscience and systems biology, and their synergetic roles in understanding learning, memory and cognition, thereby bridging the gap between computational neuroscience, systems biology and computational intelligence. PMID- 24769243 TI - Inhibition of enterovirus 71 infection by antisense octaguanidinium dendrimer conjugated morpholino oligomers. AB - Enterovirus 71 (EV-71) infections are generally manifested as mild hand, foot and mouth disease, but have been reported to cause severe neurological complications with high mortality rates. Treatment options remain limited due to the lack of antivirals. Octaguanidinium-conjugated morpholino oligomers (vivo-MOs) are single stranded DNA-like antisense agents that can readily penetrate cells and reduce gene expression by steric blocking of complementary RNA sequences. In this study, inhibitory effects of three vivo-MOs that are complementary to the EV-71 internal ribosome entry site (IRES) and the RNA-dependent RNA polymerase (RdRP) were tested in RD cells. Vivo-MO-1 and vivo-MO-2 targeting the EV-71 IRES showed significant viral plaque reductions of 2.5 and 3.5 log10PFU/ml, respectively. Both vivo-MOs reduced viral RNA copies and viral capsid expression in RD cells in a dose-dependent manner. In contrast, vivo-MO-3 targeting the EV-71 RdRP exhibited less antiviral activity. Both vivo-MO-1 and 2 remained active when administered either 4h before or within 6h after EV-71 infection. Vivo-MO-2 exhibited antiviral activities against poliovirus (PV) and coxsackievirus A16 but vivo-MO-1 showed no antiviral activities against PV. Both the IRES-targeting vivo MO-1 and vivo-MO-2 inhibit EV-71 RNA translation. Resistant mutants arose after serial passages in the presence of vivo-MO-1, but none were isolated against vivo MO-2. A single T to C substitution at nucleotide position 533 was sufficient to confer resistance to vivo-MO-1. Our findings suggest that IRES-targeting vivo-MOs are good antiviral candidates for treating early EV-71 infection, and vivo-MO-2 is a more favorable candidate with broader antiviral spectrum against enteroviruses and are refractory to antiviral resistance. PMID- 24769245 TI - Arbidol as a broad-spectrum antiviral: an update. AB - Arbidol (ARB) is a Russian-made small indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It also demonstrates inhibitory activity against other viruses, enveloped or not, responsible for emerging or globally prevalent infectious diseases such as hepatitis B and C, gastroenteritis, hemorrhagic fevers or encephalitis. In this review, we will explore the possibility and pertinence of ARB as a broad-spectrum antiviral, after a careful examination of its physico chemical properties, pharmacokinetics, toxicity, and molecular mechanisms of action. Recent studies suggest that ARB's dual interactions with membranes and aromatic amino acids in proteins may be central to its broad-spectrum antiviral activity. This could impact on the virus itself, and/or on cellular functions or critical steps in virus-cell interactions, thereby positioning ARB as both a direct-acting antiviral (DAA) and a host-targeting agent (HTA). In the context of recent studies in animals and humans, we will discuss the prospective clinical use of ARB in various viral infections. PMID- 24769244 TI - Maraviroc intensification in patients with suppressed HIV viremia has limited effects on CD4+ T cell recovery and gene expression. AB - Addition of the CCR5 inhibitor Maraviroc (MVC) to ongoing antiretroviral therapy increases CD4+ T cell counts in some virologically suppressed patients with suboptimal CD4+ T cell recovery. To understand the mechanisms by which MVC elicits increases in CD4+ T cell counts, the present study was undertaken to identify host factors (i.e. genes) that are modulated and are correlated with CD4+ T cell recovery during the 24weeks of MVC intensification in 32 subjects. Median changes of CD4+ T cell counts over 24weeks of MVC compared to baseline were 38cells/mm(3) (p<0.001). The median slope of CD4+ T cell recovery was 39cells/mm(3) per year before initiation of MVC and 76cells/mm(3) per year during MVC intensification, however, this increase was not statistically significant (p=0.33). Microarray analysis (N=31,426 genes) identified a single differentially expressed gene, tumor necrosis factor alpha (TNF), which was modestly (1.44-fold, p<0.001) downregulated by MVC at week 24 compared to baseline. TNF differential expression was evaluated using an independent method of droplet digital PCR, but the difference was not significant (p=0.6). Changes in gene expression did not correlate with CD4+ T cell recovery or any changes in the CD4+ T cell maturation, proliferation and activation phenotypes. In summary, our data suggest that modest improvements of CD4+ T cell counts during MVC intensification cannot be explained by changes in gene expression elicited by MVC. However, the modest changes in T cell composition, including reduction of the percentages of Tregs, proliferating CD4+ T cells and senescent CD8+ T cells, suggest immunologically favorable effects of MVC. PMID- 24769246 TI - Extracting recurrent scenarios from narrative texts using a Bayesian network: application to serious occupational accidents with movement disturbance. AB - A probabilistic approach has been developed to extract recurrent serious Occupational Accident with Movement Disturbance (OAMD) scenarios from narrative texts within a prevention framework. Relevant data extracted from 143 accounts was initially coded as logical combinations of generic accident factors. A Bayesian Network (BN)-based model was then built for OAMDs using these data and expert knowledge. A data clustering process was subsequently performed to group the OAMDs into similar classes from generic factor occurrence and pattern standpoints. Finally, the Most Probable Explanation (MPE) was evaluated and identified as the associated recurrent scenario for each class. Using this approach, 8 scenarios were extracted to describe 143 OAMDs in the construction and metallurgy sectors. Their recurrent nature is discussed. Probable generic factor combinations provide a fair representation of particularly serious OAMDs, as described in narrative texts. This work represents a real contribution to raising company awareness of the variety of circumstances, in which these accidents occur, to progressing in the prevention of such accidents and to developing an analysis framework dedicated to this kind of accident. PMID- 24769247 TI - Biological activities of new monohydroxylated brassinosteroid analogues with a carboxylic group in the side chain. AB - Thirteen monohydroxylated brassinosteroids analogues were synthesized and tested for their biological activity in plant and animal systems. The cytotoxic activity of the products was studied using human normal and cancer cell lines with 28 homocastasterone as positive control, their brassinolide type activity was established using the bean second-internode test with 24-epibrassinolide as standard. PMID- 24769249 TI - The instability of commercial control materials in quality control of mean corpuscular volume. AB - BACKGROUND: Mean corpuscular volume (MCV) of stabilized whole blood used for quality control (QC) of hematology analyzers exhibits a tendency to increase during storage. The aim of this study is to evaluate the extent of biases over time with 3 most widely used control materials and to map out a strategy to overcome the data shift of MCV on daily QC practice. METHODS: QC results of TESTPoint tested by ADVIA 2120i, e-CHEK tested by XE 2100, and 6C Cell Control tested by DxH 800 were analyzed. RESULTS: MCV of all control materials showed a tendency to increase over time. By the fifth week, most of the materials showed biases larger than one standard deviation, with some exceeding a bias of four standard deviations. CONCLUSIONS: Laboratories should apply appropriate QC strategies in MCV tests by considering their individual quality and efficiency requirements. PMID- 24769250 TI - Incorporating heterogeneity into the transmission dynamics of a waterborne disease model. AB - We formulate a mathematical model that captures the essential dynamics of waterborne disease transmission to study the effects of heterogeneity on the spread of the disease. The effects of heterogeneity on some important mathematical features of the model such as the basic reproduction number, type reproduction number and final outbreak size are analysed accordingly. We conduct a real-world application of this model by using it to investigate the heterogeneity in transmission in the recent cholera outbreak in Haiti. By evaluating the measure of heterogeneity between the administrative departments in Haiti, we discover a significant difference in the dynamics of the cholera outbreak between the departments. PMID- 24769248 TI - Mineralocorticoid receptors in immune cells: emerging role in cardiovascular disease. AB - Mineralocorticoid receptors (MRs) contribute to the pathophysiology of hypertension and cardiovascular disease in humans. As such, MR antagonists improve cardiovascular outcomes but the molecular mechanisms remain unclear. The actions of the MR in the kidney to increase blood pressure are well known, but the recent identification of MRs in immune cells has led to novel discoveries in the pathogenesis of cardiovascular disease that are reviewed here. MR regulates macrophage activation to the pro-inflammatory M1 phenotype and this process contributes to the pathogenesis of cardiovascular fibrosis in response to hypertension and to outcomes in mouse models of stroke. T lymphocytes have recently been implicated in the development of hypertension and cardiovascular fibrosis in mouse models. MR activation in vivo promotes T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets while decreasing the number of anti-inflammatory T regulatory lymphocytes. The mechanism likely involves activation of MR in antigen presenting dendritic cells that subsequently regulate Th1/Th17 polarization by production of cytokines. Alteration of the balance between T helper and T regulatory lymphocytes contributes to the pathogenesis of hypertension and atherosclerosis and the associated complications. B lymphocytes also express the MR and specific B lymphocyte derived antibodies modulate the progression of atherosclerosis. However, the role of MR in B lymphocyte function remains to be explored. Overall, recent studies of MR in immune cells have identified new mechanisms by which MR activation may contribute to the pathogenesis of organ damage in patients with cardiovascular risk factors. Conversely, inhibition of leukocyte MR may contribute to the protective effects of MR antagonist drugs in cardiovascular patients. Further understanding of the role of MR in leukocyte function could yield novel drug targets for cardiovascular disease. PMID- 24769251 TI - Geometric phase shifts in biological oscillators. AB - Many intracellular processes continue to oscillate during the cell cycle. Although it is not well-understood how they are affected by discontinuities in the cellular environment, the general assumption is that oscillations remain robust provided the period of cell divisions is much larger than the period of the oscillator. Here, I will show that under these conditions a cell will in fact have to correct for an additional quantity added to the phase of oscillation upon every repetition of the cell cycle. The resulting phase shift is an analogue of the geometric phase, a curious entity first discovered in quantum mechanics. In this letter, I will discuss the theory of the geometric phase shift and demonstrate its relevance to biological oscillations. PMID- 24769252 TI - Qualitative analysis of subcutaneous Lispro and regular insulin injections for stress hyperglycemia: a pilot numerical study. AB - Increased glucose variability (GV) is an independent risk factor for mortality in the critically ill; unfortunately, the optimal insulin therapy that minimizes GV is not known. We simulate the glucose-insulin feedback system to study how stress hyperglycemia (SH) states, taken to be a non-uniform group of physiologic disorders with varying insulin resistance (IR) and similar levels of hyperglycemia, respond to the type and dose of subcutaneous (SQ) insulin. Two groups of 100 virtual patients are studied: those receiving and those not receiving continuous enteral feeds. Stress hyperglycemia was facilitated by doubling the gluconeogenesis rate and IR was stepwise varied from a borderline to a high value. Lispro and regular insulin were simulated with dosages that ranged from 0 to 6 units; the resulting GV was analyzed after each insulin injection. The numerical model used consists of a set of non-linear differential equations with two time delays and five adjustable parameters. The results show that regular insulin decreased GV in both patient groups and rarely caused hypoglycemia. With continuous enteral feeds and borderline to mild IR, Lispro showed minimal effect on GV; however, rebound hyperglycemia that increased GV occurred when the IR was moderate to high. Without a nutritional source, Lispro worsened GV through frequent hypoglycemia episodes as the injection dose increased. The inferior performance of Lispro is a result of its rapid absorption profile; half of its duration of action is similar to the glucose ultradian period. Clinical trials are needed to examine whether these numerical results represent the glucose-insulin dynamics that occur in intensive care units, and if such dynamics are present, their clinical effects should be evaluated. PMID- 24769253 TI - Drug discovery in pulmonary arterial hypertension: attacking the enigmatic root of a deadly weed. PMID- 24769254 TI - Base-paired structure in the 5' untranslated region is required for the efficient amplification of negative-strand RNA3 in the bromovirus melandrium yellow fleck virus. AB - Melandrium yellow fleck virus belongs to the genus Bromovirus, which is a group of tripartite plant RNA viruses. This virus has an approximately 200-nucleotide direct repeat sequence in the 5' untranslated region (UTR) of RNA3 that encodes the 3a movement protein. In the present study, protoplast assays suggested that the duplicated region contains amplification-enhancing elements. Deletion analyses of the 5' UTR of RNA3 showed that mutations in the short base-paired region, which is located dozens of bases upstream of the initiation codon of the 3a gene, greatly reduced the accumulation of RNA3. Disruption and restoration of the base-paired structure caused the accumulation of RNA3 to be decreased and restored, respectively. In vitro translation/replication assays demonstrated that the base-paired structure is important for the efficient amplification of negative-stand RNA3. A similar base-paired structure in RNA3 of another bromovirus, brome mosaic virus (BMV), also facilitated the efficient amplification of BMV RNA3, but only in combination with melandrium yellow fleck virus (MYFV) replicase and not with BMV replicase, thereby suggesting specific interactions between base-paired structures and MYFV replicase. PMID- 24769255 TI - SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease. AB - At the post-transcriptional level, expression of protein-coding genes is controlled by a series of RNA regulatory events including nuclear processing of primary transcripts, transport of mature mRNAs to specific cellular compartments, translation and ultimately, turnover. These processes are orchestrated through the dynamic association of mRNAs with RNA binding proteins and ribonucleoprotein (RNP) complexes. Accurate formation of RNPs in vivo is fundamentally important to cellular development and function, and its impairment often leads to human disease. The survival motor neuron (SMN) protein is key to this biological paradigm: SMN is essential for the biogenesis of various RNPs that function in mRNA processing, and genetic mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP assembly. We discuss advances in our understanding of SMN activity as a chaperone of RNPs and how disruption of SMN-dependent RNA pathways can cause motor neuron disease. PMID- 24769256 TI - Salvianolic acid B protects against acute ethanol-induced liver injury through SIRT1-mediated deacetylation of p53 in rats. AB - Salvianolic acid B (SalB) is isolated from the traditional Chinese medical herb salvia miltiorrhiza. It has many biological and pharmaceutical activities. This study aimed to investigate the effect of SalB on acute ethanol-induced hepatic injury in rats and to explore the role of SIRT1 in this process. The results showed that pretreatment with SalB significantly reduced ethanol-induced elevation in aminotransferase activities, decreased hepatotoxic cytokine levels such as Interleukin-6 (IL-6), and increased the antioxidant enzyme activity. Moreover, SalB pretreatment reversed the increase in NF-kappaB, cleaved caspase-3 and decrease in B-cell lymphoma-extra large (Bcl-xL) caused by ethanol exposure. Importantly, SalB pretreatment significantly increased the expression of SIRT1, a NAD(+)-dependent deacetylase, whereas the increase in SIRT1 was accompanied by decreased acetyl-p53 expression. In HepG2 cells, SalB pretreatment increased SIRT1 expression in a time and dose-dependent manner and such an increase was abrogated by siRNA knockdown of SIRT1. Additionally, inhibition of SIRT1 significantly increased the acetylation of p53, and blocked SalB-induced acetylation of p53 down-regulation. Collectively, this study indicated that SalB can alleviate acute ethanol-induced hepatocyte apoptosis through SIRT1-mediated deacetylation of p53 pathway. PMID- 24769257 TI - Global gene expression profiling of human bronchial epithelial cells exposed to airborne fine particulate matter collected from Wuhan, China. AB - BACKGROUND: Many studies have linked ambient fine particulate matter (PM2.5) air pollution to different cardiopulmonary diseases in the general population. However the complex mechanisms underlying PM2.5-induced adverse health effects are not yet to be fully elucidated. METHOD: In this study, we aimed to identify genes and pathways that may contribute to PM2.5-induced lung toxicity in humans through genome-wide approaches. Human bronchial epithelial (HBE) cells, exposed to various concentrations of PM2.5 collected from Wuhan, China, showed decreased cell viability in a dose-dependent manner. HBE cells were exposed to 200 MUg/ml and 500 MUg/ml PM2.5 and microarrays were used to obtain a global view of the transcriptomic responses. RESULTS: A total of 970 and 492 genes were identified that significantly changed after 200 MUg/ml and 500 MUg/ml PM2.5 exposures, respectively. PM2.5 induced a large number of genes involved in inflammatory and immune response, response to oxidative stress, and response to DNA damage stimulus, which might contribute to PM2.5 related cardiopulmonary diseases. Pathway analysis revealed that different dose of PM2.5 triggered partially common disturbed pathways. Flow cytometry assay evidenced that there were statistically significant differences in the G1 phase of cell cycle after low or high-dose PM2.5 exposure when compared to the unexposed controls. Only high-dose PM2.5 significantly increased the proportion of cells in the S phase of cell cycle. CONCLUSION: We identified many genes and pathways that altered significantly in HBE cells after PM2.5 exposures. These findings are important in providing further understanding of the mechanisms underlying PM2.5-induced adverse health effects. PMID- 24769258 TI - Effects of environmental levels of cadmium, lead and mercury on human renal function evaluated by structural equation modeling. AB - A relationship between exposure to heavy metals, including lead and cadmium, and renal dysfunction has long been suggested. However, modeling of the potential additive, or synergistic, impact of metals on renal dysfunction has proven to be challenging. In these studies, we used structural equation modeling (SEM), to investigate the relationship between heavy metal burden (serum and urine levels of lead, cadmium and mercury) and renal function using data from the NHANES database. We were able to generate a model with goodness of fit indices consistent with a well-fitting model. This model demonstrated that lead and cadmium had a negative relationship with renal function, while mercury did not contribute to renal dysfunction. Interestingly, a linear relationship between lead and loss of renal function was observed, while the maximal impact of cadmium occurred at or above serum cadmium levels of 0.8 MUg/L. The interaction of lead and cadmium in loss of renal function was also observed in the model. These data highlight the use of SEM to model interaction between environmental contaminants and pathophysiology, which has important implications in mechanistic and regulatory toxicology. PMID- 24769259 TI - Effect of ozone exposure and infection on bronchoalveolar lavage: sex differences in response patterns. AB - Female mice exhibit a better survival rate than males after infection, but if infection follows an ozone-induced oxidative stress, male survival exceeds that of females. Our goal was to study bronchoalveolar lavage factors that contribute to these sex differences in outcome. We studied parameters at 4, 24, and 48 h after ozone exposure and infection, including markers of inflammation, oxidative stress, and tissue damage, and surfactant phospholipids and surfactant protein A (SP-A). A multianalyte immunoassay at the 4h time point measured 59 different cytokines, chemokines, and other proteins. We found that: (1) Although some parameters studied revealed sex differences, no sex differences were observed in LDH, total protein, MIP-2, and SP-A. Males showed more intragroup significant differences in SP-A between filtered air- and ozone-exposed mice compared to females. (2) Oxidized dimeric SP-A was higher in FA-exposed female mice. (3) Surfactant phospholipids were typically higher in males. (4) The multianalyte data revealed differences in the exuberance of responses under different conditions - males in response to infection and females in response to oxidative stress. These more exuberant, and presumably less well-controlled responses associate with the poorer survival. We postulate that the collective effects of these sex differences in response patterns of lung immune cells may contribute to the clinical outcomes previously observed. PMID- 24769261 TI - Respiratory effects of buprenorphine/naloxone alone and in combination with diazepam in naive and tolerant rats. AB - Respiratory depression has been attributed to buprenorphine (BUP) misuse or combination with benzodiazepines. BUP/naloxone (NLX) has been marketed as maintenance treatment, aiming at preventing opiate addicts from self-injecting crushed pills. However, to date, BUP/NLX benefits in comparison to BUP alone remain debated. We investigated the plethysmography effects of BUP/NLX in comparison to BUP/solvent administered by intravenous route in naive and BUP tolerant Sprague-Dawley rats, and in combination with diazepam (DZP) or its solvent. In naive rats, BUP/NLX in comparison to BUP significantly increased respiratory frequency (f, P<0.05) without altering minute volume (VE). In combination to DZP, BUP/NLX significantly increased expiratory time (P<0.01) and decreased f (P<0.01), tidal volume (VT, P<0.001), and VE (P<0.001) while BUP only decreased VT (P<0.5). In BUP-tolerant rats, no significant differences in respiratory effects were observed between BUP/NLX and BUP. In contrast, in combination to DZP, BUP/NLX did not significantly alter the plethysmography parameters, while BUP increased inspiratory time (P<0.001) and decreased f (P<0.01) and VE (P<0.001). In conclusion, differences in respiratory effects between BUP/NLX and BUP are only significant in combination with DZP, with increased depression in naive rats but reduced depression in BUP-tolerant rats. However, BUP/NLX benefits in humans remain to be determined. PMID- 24769260 TI - In vitro metabolism of benzo[a]pyrene and dibenzo[def,p]chrysene in rodent and human hepatic microsomes. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and often carcinogenic contaminants released into the environment during natural and anthropogenic combustion processes. Benzo[a]pyrene (B[a]P) is the prototypical carcinogenic PAH, and dibenzo[def,p]chrysene (DBC) is a less prevalent, but highly potent transplacental carcinogenic PAH. Both are metabolically activated by isoforms of the cytochrome P450 enzyme superfamily to form reactive carcinogenic and cytotoxic metabolites. Metabolism of B[a]P and DBC was studied in hepatic microsomes of male Sprague-Dawley rats, naive and pregnant female B6129SF1/J mice, and female humans, corresponding to available pharmacokinetic data. Michaelis-Menten saturation kinetic parameters including maximum rates of metabolism (VMAX, nmol/min/mg microsomal protein), affinity constants (KM, MUM), and rates of intrinsic clearance (CLINT, ml/min/kg body weight) were calculated from substrate depletion data. CLINT was also estimated from substrate depletion data using the alternative in vitro half-life method. VMAX and CLINT were higher for B[a]P than DBC, regardless of species. Clearance for both B[a]P and DBC was highest in naive female mice and lowest in female humans. Clearance rates of B[a]P and DBC in male rat were more similar to female human than to female mice. Clearance of DBC in liver microsomes from pregnant mice was reduced compared to naive mice, consistent with reduced active P450 protein levels and elevated tissue concentrations and residence times for DBC observed in previous in vivo pharmacokinetic studies. These findings suggest that rats are a more appropriate model organism for human PAH metabolism, and that pregnancy's effects on metabolism should be further explored. PMID- 24769262 TI - Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, alpha-PHPP and alpha-POP, with 11 newly distributed designer drugs in illegal products. AB - Our continuous survey of illegal products in Japan revealed the new distribution of 15 designer drugs. We identified four synthetic cannabinoids, i.e., NNEI (1), 5-fluoro-NNEI (2), 5-chloro-NNEI (3) and NNEI indazole analog (4), and seven cathinone derivatives, i.e., MPHP (5), alpha-PHPP (6), alpha-POP (7), 3,4 dimethoxy-alpha-PVP (8), 4-fluoro-alpha-PVP (9), alpha-ethylaminopentiophenone (10) and N-ethyl-4-methylpentedrone (11). We also determined LY-2183240 (12) and its 2'-isomer (13), which were reported to inhibit endocannabinoid uptake, a methylphenidate analog, 3,4-dichloromethylphenidate (14), and an MDA analog, 5 APDB (15). No chemical and pharmaceutical data for compounds 3, 4, 6 and 7 had been reported, making this the first report on these compounds. PMID- 24769263 TI - Bonferroni, Holm, and Hochberg corrections: fun names, serious changes to p values. PMID- 24769264 TI - A new approach for molecular diagnosis of TAR syndrome. AB - Thrombocytopenia-absent radius (TAR) syndrome is a rare genetic disorder inherited in an autosomal recessive fashion. In most patients chromosomes at 1q21.1 harbor a 200-kb deletion consisted of many genes, including RBM8A. We aimed to examine a cost-effective method for investigation a consanguineous family clinically diagnosed as TAR syndrome. A comprehensive sequencing of RBM8A identified several SNPs including two low-frequency regulatory SNPs (rs139428292 and rs201779890) in the father, the mother and the proband in which they carried A/G, G/- and A/- alleles for rs139428292, respectively. They also had G/G genotype in the father, G/- in both mother and proband for rs201779890. In addition a SNP (rs872786) was found in mother as T/- allele while father and proband have possessed A/A and A/- alleles, respectively. Further investigation determined a rare null allele in the proband using quantitative real-time PCR. We concluded that compound inheritance of a rare null allele and one of the two low frequency noncoding SNPs (rs139428292) in RBM8A are crucial for TAR syndrome. Quantitative real-time PCR and Sanger sequencing may recruit for molecular diagnosis of TAR rather than molecular cytogenetic study. PMID- 24769265 TI - Tests and investigations for colorectal cancer screening. AB - Worldwide, colorectal (CRC) is the third most common form of cancer, after lung and breast cancer, and the fourth most common cause of cancer death, although in developed countries CRC incidence is higher and it accounts for an even higher proportion of cancer deaths. Successful treatment of early-stage CRC confers substantial survival advantage, and there is now overwhelming evidence that screening average-risk individuals for CRC reduces the incidence and disease specific mortality. In spite of considerable research for new biomarkers for CRC, the detection of blood in faeces remains the most effective screening tool. The best evidence to date for population-based CRC screening comes from randomised controlled trials that used a guaiac-based faecal occult blood test (gFOBt) as the first-line screening modality, whereby test-positive individuals are referred for follow-up investigations, usually colonoscopy. A major innovation in the last ten years or so has been the development of other more analytically sensitive and specific screening techniques for blood in faeces. The faecal immunochemical test for haemoglobin (FIT) confers substantial benefits over gFOBt in terms of analytical sensitivity, specificity and practicality and FIT are now recommended for CRC screening by the European guidelines for quality assurance in colorectal cancer screening and diagnosis. The challenge internationally is to develop high quality CRC screening programmes for which uptake is high. This is especially important for developing countries witnessing an increase in the incidence of CRC as populations adopt more westernised lifestyles. This review describes the tests available for CRC screening and how they are being used worldwide. The reader will gain an understanding of developments in CRC screening and issues that arise in choosing the most appropriate screening test (or tests) for organised population-based screening internationally and optimising the performance of the chosen test (or tests). Whilst a wide range of literature has been cited, this is not a systematic review. The authors provide FOBT CRC screening for a population of 14.6 million in the south of England and the senior author (SPH) was the lead author of the European guidelines for quality assurance in colorectal cancer screening and diagnosis and leads the World Endoscopy Organization Colorectal Cancer Committee's Expert Working Group on 'FIT for Screening'. PMID- 24769266 TI - Functional connectivity of distant cortical regions: role of remote synchronization and symmetry in interactions. AB - Functional MRI (fMRI) of ongoing brain activity at rest i.e. without any overt directed behavior has revealed patterns of coherent activity, so called resting state functional networks. The dynamical organization of nodes into these functional networks is closely related to the underlying structural connections. However, functional correlations have also been observed between cortical regions without apparent neural links, and mechanisms generating functional connectivity between distant cortical regions are largely unknown. It has been suggested that indirect connections and collective effects governed by the network properties of the cortex play a significant role. We use numerical simulations to investigate these mechanisms with reference to remote synchronization and network symmetry. Neural activity and the inferred hemodynamic response of the network nodes are modeled as sets of self-sustained oscillators, which are embedded in topologies of complex functional brain interactions. The coupling topology is based on connectivity maps derived from fMRI and DTI experiments. Consequently, our network model includes important information on whether direct or indirect neural connections exist between functionally associated regions. In the simulated functional networks, remote synchrony between pairs of nodes clearly arises from symmetry in the interactions, which are quantified by the number of shared neighbors. A larger joint neighborhood positively correlates with a higher level of synchrony. Therefore, our results indicate that a large overlapping neighborhood in complex networks of brain interactions gives rise to functional similarity between distant cortical regions. PMID- 24769267 TI - Sex differences in addictive disorders. AB - Gender-dependent differences in the rate of initiation and frequency of misuse of addicting drugs have been widely described. Yet, men and women also differ in their propensity to become addicted to other rewarding stimuli (e.g., sex, food) or activities (e.g., gambling, exercising). The goal of the present review is to summarize current evidence for gender differences not only in drug addiction, but also in other forms of addictive behaviours. Thus, we first reviewed studies showing gender-dependent differences in drug addiction, food addiction, compulsive sexual activity, pathological gambling, Internet addiction and physical exercise addiction. Potential risk factors and underlying brain mechanisms are also examined, with particular emphasis given to the role of sex hormones in modulating addictive behaviours. Investigations on factors allowing the pursuit of non-drug rewards to become pathological in men and women are crucial for designing gender-appropriate treatments of both substance and non substance addictions. PMID- 24769269 TI - Protein engineering for development of new hydrolytic biocatalysts. AB - Hydrolytic enzymes play important roles as biocatalysts in chemical synthesis. The chemical versatility and structurally sturdy features of Candida antarctica lipase B has placed this enzyme as a common utensil in the synthetic tool-box. In addition to catalyzing acyl transfer reactions, a number of promiscuous activities have been described recently. Some of these new enzyme activities have been amplified by mutagenesis. Epoxide hydrolases are of interest due to their potential as catalysts in asymmetric synthesis. This current update discusses recent development in the engineering of lipases and epoxide hydrolases aiming to generate new biocatalysts with refined features as compared to the wild-type enzymes. Reported progress in improvements in reaction atom economy from dynamic kinetic resolution or enantioconvergence is also included. PMID- 24769268 TI - Individual differences in impulsive and risky choice: effects of environmental rearing conditions. AB - The present experiment investigated early-rearing environment modulation of individual differences in impulsive and risky choice. Rats were reared in an isolated condition (IC; n=12), in which they lived alone without novel stimuli, or an enriched condition (EC; n=11), in which they lived among conspecifics with novel stimuli. The impulsive choice task involved choices between smaller-sooner (SS) versus larger-later (LL) rewards. The risky choice task involved choices between certain-smaller (C-S) versus uncertain-larger (U-L) rewards. Following choice testing, incentive motivation to work for food was measured using a progressive ratio task and correlated with choice behavior. HPLC analyses were conducted to determine how monoamine concentrations within the prefrontal cortex (PFC) and nucleus accumbens (NAC) related to behavior in different tasks. IC rats were more impulsive than EC rats, but they did not differ in risky choice behavior. However, choice behavior across tasks was significantly correlated (i.e., the more impulsive rats were also riskier). There were no group differences in monoamine levels, but noradrenergic and serotonergic concentrations were significantly correlated with impulsive and risky choice. Furthermore, serotonin and norepinephrine concentrations in the NAC significantly correlated with incentive motivation and the timing of the reward delays within the choice tasks. These results suggest a role for domain general processes in impulsive and risky choice and indicate the importance of the NAC and/or PFC in timing, reward processing, and choice behavior. PMID- 24769270 TI - The effect of a randomized trial of home telemonitoring on medical costs, 30-day readmissions, mortality, and health-related quality of life in a cohort of community-dwelling heart failure patients. AB - BACKGROUND: Telemonitoring has been advocated as a way of decreasing costs and improving outcomes, but no study has looked at true Medicare payments and 30-day readmission rates in a randomized group of well treated patients. OBJECTIVE: The aim of this work was to analyze Medicare claims data to identify effects of home telemonitoring on medical costs, 30-day rehospitalization, mortality, and health related quality of life. METHODS: A total of 204 subjects were randomized to usual-care and monitored groups and evaluated with the SF-36 and Minnesota Living With Heart Failure Questionnaire (MLHF). Hospitalizations, Medicare payments, and mortality were also assessed. Monitored subjects transmitted weight, blood pressure, and heart rate, which were monitored by an experienced heart failure nurse practitioner. RESULTS: Subjects were followed for 802 +/- 430 days; 75 subjects in the usual-care group (316 hospitalizations) and 81 in the monitored group (327 hospitalizations) were hospitalized at least once (P = .51). There were no differences in Medicare payments for inpatient or emergency department visits, and length of stay was not different between groups. There was no difference in 30-day readmissions (P = .627) or mortality (P = .575). Scores for SF-36 and MLHF improved (P < .001) over time, but there were no differences between groups. The percentage of patients readmitted within 30 days was lower with telemonitoring for the 1st year, but this did not persist. CONCLUSIONS: Telemonitoring did not result in lower total costs, decreased hospitalizations, improved symptoms, or improved mortality. A decrease in 30-day readmission rates for the 1st year did not result in decreased total cost or better outcomes. PMID- 24769271 TI - Integration of internal and external facial features in 8- to 10-year-old children and adults. AB - Investigation of whole-part and composite effects in 4- to 6-year-old children gave rise to claims that face perception is fully mature within the first decade of life (Crookes & McKone, 2009). However, only internal features were tested, and the role of external features was not addressed, although external features are highly relevant for holistic face perception (Sinha & Poggio, 1996; Axelrod & Yovel, 2010, 2011). In this study, 8- to 10-year-old children and adults performed a same-different matching task with faces and watches. In this task participants attended to either internal or external features. Holistic face perception was tested using a congruency paradigm, in which face and non-face stimuli either agreed or disagreed in both features (congruent contexts) or just in the attended ones (incongruent contexts). In both age groups, pronounced context congruency and inversion effects were found for faces, but not for watches. These findings indicate holistic feature integration for faces. While inversion effects were highly similar in both age groups, context congruency effects were stronger for children. Moreover, children's face matching performance was generally better when attending to external compared to internal features. Adults tended to perform better when attending to internal features. Our results indicate that both adults and 8- to 10-year-old children integrate external and internal facial features into holistic face representations. However, in children's face representations external features are much more relevant. These findings suggest that face perception is holistic but still not adult-like at the end of the first decade of life. PMID- 24769272 TI - The role of inner and outer face parts in holistic processing: a developmental study. AB - The effects of inner-outer feature interactions with unfamiliar faces were investigated in 6- and 10-year-old children and adults (20-30 years) to determine their contribution in holistic face vision. Participants completed a two alternative forced-choice (2AFC) task under two conditions. The congruent condition used whole, inner-only, and outer-only stimuli. The incongruent condition used stimuli combining the inner features from one face with outer features from a novel face, or vice versa. Results yielded strong congruency effects which were moderated by pronounced feature-type asymmetries specific to developmental stage. Adults showed an inner-feature preference during congruent trials, but no asymmetry for incongruent trials. Children showed no asymmetry for congruent trials, but an outer-feature preference for incongruent trials. These findings concur with recent theoretical developments indicating that adults and children are likely to differ in the types of feature-specific information they preferentially encode in face perception, and that holistic effects are moderated differently in adults and children as a function of feature type. PMID- 24769273 TI - Serum paraoxonase-1 activity is more closely related to HDL particle concentration and large HDL particles than to HDL cholesterol in Type 2 diabetic and non-diabetic subjects. AB - OBJECTIVES: We determined relationships of the anti-oxidative enzyme, paraoxonase 1 (PON-1), with high density lipoprotein (HDL) subfractions, and tested whether these relationships are stronger than those with HDL cholesterol and apolipoprotein A-I (apoA-I) in subjects with and without type 2 diabetes mellitus (T2DM). DESIGN AND METHODS: Serum PON-1 (arylesterase activity) and HDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 67 T2DM patients and in 56 non-diabetic subjects. RESULTS: PON-1 activity, HDL cholesterol and apoA-I were decreased in T2DM (all p<0.05). The HDL particle concentration was unaltered, but large HDL particles, medium HDL particles and HDL particle size were decreased, whereas small HDL particles were increased in T2DM (all p<0.05). PON-1 was more closely related to HDL cholesterol than to apoA I (p=0.001). In turn, the positive relationship of PON-1 with the HDL particle concentration and with large HDL particles was stronger than that with HDL cholesterol (both p<0.01). The inverse relationship of PON-1 with T2DM was only modestly attenuated by HDL cholesterol or HDL particle characteristics. CONCLUSIONS: PON-1 activity is more closely related to the HDL particle concentration or large HDL particles than to HDL cholesterol. Impaired PON-1 activity in T2DM is not to a considerable extent explained by altered HDL subfraction levels. PMID- 24769274 TI - A useful multi-analyte blood test for cerebrotendinous xanthomatosis. AB - OBJECTIVES: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Blood (normally serum or plasma) testing for CTX is performed by a small number of specialized laboratories, routinely by gas chromatography-mass spectrometry (GC-MS) measurement of elevated 5alpha-cholestanol. We report here on a more sensitive biochemical approach to test for CTX particularly useful for confirmation of CTX in the case of a challenging diagnostic sample with 5alpha cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10 MUg/mL or 1.0 mg/dL). DESIGN AND METHODS: We have previously described liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI MS/MS) methodology utilizing keto derivatization to enable the sensitive quantification of plasma ketosterol BA precursors that accumulate in CTX. We have expanded this methodology to perform isotope dilution LC-ESI-MS/MS quantification of a panel of plasma ketosterol BA precursors, with internal standards readily generated using isotopically-enriched derivatization reagent. RESULTS: Quantification of plasma ketosterol BA precursors (7alpha-hydroxy-4-cholesten-3 one, 7alpha,12alpha-dihydroxy-4-cholesten-3-one and 7alpha,12alpha-dihydroxy 5beta-cholestan-3-one) in a single LC-ESI/MS/MS test provided better discrimination between a CTX-positive and negative samples analyzed (n=20) than measurement of 5alpha-cholestanol alone. CONCLUSIONS: Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CTX negative and positive samples. A multiplexed LC-ESI MS/MS test quantifying a panel of plasma ketosterols, with simple sample preparation, rapid analysis time and readily available internal standards, can be performed by most clinical laboratories. Wider availability of testing will benefit those affected with CTX. PMID- 24769275 TI - Low normal thyroid function attenuates serum alanine aminotransferase elevations in the context of metabolic syndrome and insulin resistance in white people. AB - OBJECTIVES: Thyroid hormones play a key role in hepatic lipid metabolism. Although hypothyroidism is associated with increased prevalence of non-alcoholic fatty liver disease (NAFLD), the relationship of NAFLD with low normal thyroid function is unclear. We tested the association of serum alanine transferase (ALT), as a surrogate of NAFLD, with variations in thyroid function within the normal range. DESIGN AND METHODS: Thyroid stimulating hormone (TSH), free T4, ALT, insulin resistance (homeostasis model assessment (HOMA-IR)) and adiponectin were measured in 82 non-diabetic white subjects with TSH and free thyroxine (free T4) levels within the reference range. Nineteen participants were classified with metabolic syndrome (MetS). RESULTS: ALT was higher in MetS subjects (p<0.05), coinciding increased HOMA-IR (p<0.001). TSH and free T4 levels were not different in subjects with and without MetS. In all subjects combined, ALT was correlated positively with HOMA-IR and inversely with adiponectin (both p<0.001). Remarkably, ALT was correlated inversely with TSH in subjects with MetS (r= 0.642, p=0.003), but not in subjects without MetS (r=-0.132, p=0.30). Accordingly, in age- and sex-adjusted multivariable linear regression analysis the relationship of ALT with TSH was modified by the presence of MetS (interaction: beta=-0.244, p=0.026), and likewise by HOMA-IR (interaction: beta= 0.203, p=0.037). TSH also interacted with adiponectin on ALT (interaction: beta=0.204, p=0.037). CONCLUSIONS: Low normal thyroid function may attenuate ALT elevations in the context of MetS and insulin resistance. It is conceivable that effect modification of low normal thyroid function on adiponectin-mediated pathways may be involved. PMID- 24769276 TI - Presepsin - the new kid on the sepsis block. PMID- 24769277 TI - Changes in serum RANKL and OPG with sexual development and their associations with bone turnover and bone mineral density in a cohort of girls. AB - OBJECTIVES: To characterize the variations of serum osteoprotegerin (OPG) and RANK ligand (RANKL) with sexual development in adolescent girls, and to estimate their associations with bone turnover and bone mineral density (BMD). DESIGN AND METHODS: We studied 300 girls evaluated at 13 and 17years of age. Fasting blood samples were collected and the following substances were quantified: RANKL, OPG, C-terminal telopeptide of type I collagen (CTX), and procollagen type I N propeptide (PINP). BMD was measured at the distal forearm. Correlation coefficients were used to quantify associations between those variables at 13 and 17 years of age. Random-effects linear models were used to quantify associations between bone parameters and sexual development (years from menarche). RESULTS: RANKL was positively correlated with bone resorption (CTX) in early and late adolescence (r13=0.15 and r17=0.23) and the OPG/RANKL ratio correlated inversely with CTX at 17 (r17=-0.24). No significant associations were found between RANKL and OPG and bone formation (PINP). In early adolescence, there was an inverse correlation of BMD with CTX (r13=-0.52) but no significant correlations were found between osteoclast regulators and BMD. We observed a linear decrease in serum RANKL with increasing sexual development (-0.09 pmol/L per year, 95% CI: 0.10, -0.07) alongside an increase in OPG (0.02pmol/L, 95% CI: 0.01, 0.04). CONCLUSIONS: Serum RANKL and OPG levels varied markedly with sexual development in adolescence. These cytokines were not predictive of bone turnover or BMD at 13, but serum RANKL bioactivity was associated with bone resorption in late adolescence. PMID- 24769278 TI - Urinary homovanillic and vanillylmandelic acid in the diagnosis of neuroblastoma: report from the Italian Cooperative Group for Neuroblastoma. AB - BACKGROUND: Urinary homovanillic and vanillylmandelic acid (HVA and VMA) are well known biomarkers for the management of neuroblastoma (NB). Very few and contradictory publications on their diagnostic performance are present in the literature. The aim of this study is to review the results of HVA/Cr and VMA/Cr obtained by the reference laboratory of the Italian Cooperative Group for NB within a 7-year period using HPLC-EC. PROCEDURE: Updated reference intervals based on age as a continuous variable were calculated by using a multivariate statistical analysis. The diagnostic performance of the two biomarkers has been established by calculating their specificity and sensitivity and by receiver operating characteristics (ROC) curves for different ages and stages of disease. RESULTS: Accurate age-related reference intervals were obtained from 648 HVA/Cr and 671 VMA/Cr results derived from patients in which the diagnosis of neuroendocrine tumors was excluded. Sensitivity, specificity and ROC curves were obtained from 169 HVA/Cr and 179 VMA/Cr results from confirmed NB patients. The best diagnostic performance was obtained in stage 4S tumors and in children <18months. CONCLUSIONS: This is the first report, to our knowledge, that analyzes in depth the diagnostic performance of HVA/Cr and VMA/Cr for NB in different stages and age subgroups. In addition, the present work provides cut-off points able to discriminate between NB patients and negative subjects suspected to have NB and could be of help in taking medical decisions. PMID- 24769279 TI - Human speech- and reading-related genes display partially overlapping expression patterns in the marmoset brain. AB - Language is a characteristic feature of human communication. Several familial language impairments have been identified, and candidate genes for language impairments already isolated. Studies comparing expression patterns of these genes in human brain are necessary to further understanding of these genes. However, it is difficult to examine gene expression in human brain. In this study, we used a non-human primate (common marmoset; Callithrix jacchus) as a biological model of the human brain to investigate expression patterns of human speech- and reading-related genes. Expression patterns of speech disorder- (FoxP2, FoxP1, CNTNAP2, and CMIP) and dyslexia- (ROBO1, DCDC2, and KIAA0319) related genes were analyzed. We found the genes displayed overlapping expression patterns in the ocular, auditory, and motor systems. Our results enhance understanding of the molecular mechanisms underlying language impairments. PMID- 24769280 TI - Spectro-temporal correlates of lexical access during auditory lexical decision. AB - Lexical access during speech comprehension comprises numerous computations, including activation, competition, and selection. The spatio-temporal profile of these processes involves neural activity in peri-auditory cortices at least as early as 200 ms after stimulation. Their oscillatory dynamics are less well understood, although reports link alpha band de-synchronization with lexical processing. We used magnetoencephalography (MEG) to examine whether these alpha related oscillations reflect the speed of lexical access, as would be predicted if they index lexical activation. In an auditory semantic priming protocol, monosyllabic nouns were presented while participants performed a lexical decision task. Spatially-localizing beamforming was used to examine spectro-temporal effects in left and right auditory cortex time-locked to target word onset. Alpha and beta de-synchronization (10-20 Hz ERD) was attenuated for words following a related prime compared to an unrelated prime beginning about 270 ms after stimulus onset. This timing is consistent with how information about word identity unfolds incrementally in speech, quantified in information-theoretic terms. These findings suggest that alpha de-synchronization during auditory word processing is associated with early stages of lexical access. PMID- 24769281 TI - IGF1 induces cell proliferation in human pituitary tumors - functional blockade of IGF1 receptor as a novel therapeutic approach in non-functioning tumors. AB - Insulin-like growth factor (IGF1) and its receptor display potent proliferative and antiapoptotic activities and are considered key players in malignancy. The objective of the study was to explore the role of IGF1 and its downstream pathways in the proliferation of non-functioning pituitary tumor cells and to develop a targeted therapeutic approach for the treatment of these tumors. Cultures of human non-functioning pituitary adenomas and the non-secreting immortalized rat pituitary tumor cell line MtT/E were incubated with IGF1, IGF1 receptor inhibitor or both, and cell viability, proliferation and signaling were examined. Our results show that IGF1 elevated cell proliferation and enhanced cell cycle progression as well as the expression of cyclins D1 and D3. IGF1 also induced the phosphorylation of ERK, Akt and p70S6K. On the other hand, the selective IGF1R inhibitor NVP-AEW541 abrogated IGF1-induced cell proliferation as well as IGF1 receptor phosphorylation and downstream signaling. PMID- 24769282 TI - Hormonal regulation of pigment epithelium-derived factor (PEDF) expression in the endometrium. AB - Pigment epithelium-derived factor (PEDF) is highly expressed in the female reproductive system and is subjected to regulation by steroid hormones in the ovary. As the uterine endometrium exhibits morphological and functional changes in response to estrogen (E2) and progesterone (P4), we aimed at characterizing the expression of PEDF in this component of the female reproductive tract and further at exploring the hormonal regulation of its expression. We found that PEDF is expressed in human and mouse endometrium. We further showed that this expression is subjected to regulation by steroid hormones, both in vivo and in vitro, as follows: E2 decreased PEDF expression and P4 increased its levels. In human endometrial samples, PEDF levels were dynamically altered along the menstrual cycle; they were low at the proliferative and early secretory phases and significantly higher at the late secretory phase. The expression levels of PEDF were inversely correlated to that of vascular endothelial growth factor (VEGF). We also showed that PEDF receptor was expressed in the endometrium and that its stimulation reduced VEGF expression. Illustrating the pattern of PEDF expression during the menstrual cycle may contribute to our understanding of the endometrial complexity. PMID- 24769283 TI - Taurine supplementation does not decrease homocysteine levels and liver injury induced by a choline-deficient diet. AB - AIMS: The aim of this study is to examine the effects of taurine supplementation on homocysteine (Hcy) metabolism and liver injury in rats fed a choline-deficient diet. MAIN METHODS: Thirty rats were divided into three groups (n=10), to receive one of the following diets for 4 weeks: control diet (C), choline-deficient diet (CDD), or choline-deficient diet supplemented with taurine (CDDT). The CDD and the CDDT consisted of AIN-93 without the recommended choline content of 2.5%, and the CDDT was supplemented by the addition of 2.5% taurine. KEY FINDINGS: Four weeks of ingesting a CDD resulted in a significant increase in plasma Hcy (50%) as well as a decrease in liver S-adenosylmethionine (SAM) concentration and S adenosylmethionine/S-adenosylhomocysteine ratio. No changes were found in plasma methionine and cysteine plasma levels compared to control group. Four weeks of ingesting a CDD also caused a significant (P<0.05) increase in hepatic total fat, hepatic malondialdehyde (MDA), and plasma alanine aminotransferase (ALT) levels. In addition, reduced hepatic glutathione (GSH) levels and reduced/oxidized glutathione ratios (GSH/GSSG) were found in rats fed a CDD compared to controls. Taurine supplementation of the CDD normalized genes involved in the remethylation pathway, BHMT and CHDH, which were impaired by CDD alone. However, taurine supplementation failed to prevent CDD-induced Hcy metabolism disturbances and hepatic injury. Also, taurine added to CDD caused decreased expression of PEMT, CHKa, and CHKb, key genes involved in phosphatidylcholine (PC) synthesis and liver fat accumulation. SIGNIFICANCE: Taurine supplementation failed to ameliorate impaired Hcy metabolism and liver injury caused by CDD intake. PMID- 24769284 TI - Metabolite-binding ribozymes. AB - Catalysis in the biological context was largely thought to be a protein-based phenomenon until the discovery of RNA catalysts called ribozymes. These discoveries demonstrated that many RNA molecules exhibit remarkable structural and functional versatility. By virtue of these features, naturally occurring ribozymes have been found to be involved in catalyzing reactions for fundamentally important cellular processes such as translation and RNA processing. Another class of RNAs called riboswitches directly binds ligands to control downstream gene expression. Most riboswitches regulate downstream gene expression by controlling premature transcription termination or by affecting the efficiency of translation initiation. However, one riboswitch class couples ligand-sensing to ribozyme activity. Specifically, the glmS riboswitch is a nucleolytic ribozyme, whose self-cleavage activity is triggered by the binding of GlcN6P. The products of this self-cleavage reaction are then targeted by cellular RNases for rapid degradation, thereby reducing glmS expression under conditions of sufficient GlcN6P. Since the discovery of the glmS ribozyme, other metabolite binding ribozymes have been identified. Together, these discoveries have expanded the general understanding of noncoding RNAs and provided insights that will assist future development of synthetic riboswitch-ribozymes. A very broad overview of natural and synthetic ribozymes is presented herein with an emphasis on the structure and function of the glmS ribozyme as a paradigm for metabolite binding ribozymes that control gene expression. This article is part of a Special Issue entitled: Riboswitches. PMID- 24769285 TI - Global analysis of riboswitches by small-angle X-ray scattering and calorimetry. AB - Riboswitches are phylogenetically widespread non-coding mRNA domains that directly bind cellular metabolites and regulate transcription, translation, RNA stability or splicing via alternative RNA structures modulated by ligand binding. The details of ligand recognition by many riboswitches have been elucidated using X-ray crystallography and NMR. However, the global dynamics of riboswitch-ligand interactions and their thermodynamic driving forces are less understood. By compiling the work of many laboratories investigating riboswitches using small angle X-ray scattering (SAXS) and isothermal titration calorimetry (ITC), we uncover general trends and common themes. There is a pressing need for community wide consensus experimental conditions to allow results of riboswitch studies to be compared rigorously. Nonetheless, our meta-analysis reveals considerable diversity in the extent to which ligand binding reorganizes global riboswitch structures. It also demonstrates a wide spectrum of enthalpy-entropy compensation regimes across riboswitches that bind a diverse set of ligands, giving rise to a relatively narrow range of physiologically relevant free energies and ligand affinities. From the strongly entropy-driven binding of glycine to the predominantly enthalpy-driven binding of c-di-GMP to their respective riboswitches, these distinct thermodynamic signatures reflect the versatile strategies employed by RNA to adapt to the chemical natures of diverse ligands. Riboswitches have evolved to use a combination of long-range tertiary interactions, conformational selection, and induced fit to work with distinct ligand structure, charge, and solvation properties. This article is part of a Special Issue entitled: Riboswitches. PMID- 24769286 TI - New isoquinolinequinone alkaloids from the South China Sea nudibranch Jorunna funebris and its possible sponge-prey Xestospongia sp. AB - Two new renieramycin-type bistetrahydroisoquinolinequinone alkaloids, fennebricins A (1) and B (5), and one new isoquinolinequinone alkaloid, N-formyl 1,2-dihydrorenierol (7), were isolated from the skin of the South China Sea nudibranch Jorunna funebris and its possible sponge-prey Xestospongia sp., together with eight known metabolites, including three bistetrahydroisoquinolinequinones (2-4) and five isoquinolinequinones (8-12). Their structures were elucidated by analysis of spectroscopic data including 1D and 2D NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS) and by comparison with data for related known compounds. All the metabolites except for 7 occurred simultaneously in the two animals, supporting recent ecological studies that the nudibranch J. funebris preys on the sponge of the genus Xestospongia. PMID- 24769287 TI - Noreudesmane sesquiterpenoids from the leaves of Nicotiana tabacum. AB - Six new 14-noreudesmane sesquiterpenoids, nicotabacosides A-F (1-6), along with five known sesquiterpenoids (7-11), were isolated from the leaves of Nicotiana tabacum. The structures of compounds 1-6 were elucidated as isorishitin 3-O-beta D-glucopyranoside (1), rishitin 3-O-beta-D-glucopyranoside (2), rishitin 2-O-beta D-glucopyranoside (3), 1, 6-dehydro-rishitin 3-O-beta-D-glucopyranoside (4), 2 hydroxyl-ligudentatol 3-O-beta-D-glucopyranoside (5) and oxyglutinosone 3-O-beta D-glucopyranoside (6) based on extensive spectroscopic analyses (HRESIMS, UV, IR, 1D and 2D NMR). Their absolute configurations were determined by X-ray single crystal diffraction and comparison of their electronic circular dichroism (ECD) spectra. PMID- 24769288 TI - Freezing beyond gait in Parkinson's disease: a review of current neurobehavioral evidence. AB - Besides the continuous motor impairments that characterize Parkinson's disease (PD), patients are frequently troubled by sudden paroxysmal arrests or brief episodes of movement breakdown, referred to as 'freezing'. Freezing of gait (FOG) is common in advanced PD and typically occurs in walking conditions that challenge dynamic motor-cognitive control. Mounting evidence suggests that episodic motor phenomena during repetitive upper limb (e.g. writing), lower limb (e.g. foot tapping) and speech sequences resemble FOG and may share some underlying neural mechanisms. However, the precise association between gait and non-gait freezing phenomena remains controversial. This review aimed to clarify this association based on literature on non-gait freezing published between 2000 and 2013. We focused on clinical and epidemiological features of the episodes and their relevance to current influential models of FOG, including recent neuroimaging studies that used a non-gait freezing paradigm as a proxy for FOG. Although not capturing the full complexity of FOG, the neurobehavioral insights obtained with non-gait freezing paradigms will contribute to an increased understanding of disturbed brain-behavior output in PD. PMID- 24769289 TI - One-carbon metabolism in neurodevelopmental disorders: using broad-based nutraceutics to treat cognitive deficits in complex spectrum disorders. AB - Folate and choline, two nutrients involved in the one-carbon metabolic cycle, are intimately involved in regulating DNA integrity, synthesis, biogenic amine synthesis, and methylation. In this review, we discuss evidence that folate and choline play an important role in normal cognitive development, and that altered levels of these nutrients during periods of high neuronal proliferation and synaptogenesis can result in diminished cognitive function. We also discuss the use of these nutrients as therapeutic agents in a spectrum of developmental disorders in which intellectual disability is a prominent feature, such as in Fragile-X, Rett syndrome, Down syndrome, and Autism spectrum disorders. A survey of recent literature suggests that nutritional supplements have mild, but generally consistent, effects on improving cognition. Intervening with supplements earlier rather than later during development is more effective in improving cognitive outcomes. Given the mild improvements seen after treatments using nutrients alone, and the importance of the genetic profile of parents and offspring, we suggest that using nutraceutics early in development and in combination with other therapeutics are likely to have positive impacts on cognitive outcomes in a broad spectrum of complex neurodevelopmental disorders. PMID- 24769290 TI - Disentangling the molecular genetic basis of personality: from monoamines to neuropeptides. AB - The present review/perspectives article provides a short overview of our current understanding of the molecular genetics of personality. In the first part, the most important gene candidates such as COMT or SLC6A4 gene are presented. Since several seminal review studies have recently been published on different facets of molecular genetics and personality/emotionality, we focus the second half of the present article on new relevant research directions. This includes a stronger focus on animal research based testing of candidate genes (e.g. neuropeptides such as oxytocin and vasopressin) and the use of a priori genotyping to increase statistical power. Moreover, we stress the importance of integrating cross cultural data in future research designs and of inclusion of epigenetic measures in neuroscientifically oriented personality research. Finally, the Affective Neuroscience Personality Scales are introduced as a new promising tool for biologically oriented psychology/psychiatry research. PMID- 24769292 TI - The ontogenesis of language lateralization and its relation to handedness. AB - Dominance of the left hemisphere for many aspects of speech production and perception is one of the best known examples of functional hemispheric asymmetries in the human brain. Classic theories about its ontogenesis assume that it is determined by the same ontogenetic factors as handedness because the two traits are correlated to some extent. However, the strength of this correlation depends on the measures used to assess the two traits, and the neurophysiological basis of language lateralization is different from that of handedness. Therefore, we argue that although the two traits show partial pleiotropy, there is also a substantial amount of independent ontogenetic influences for each of them. This view is supported by several recent genetic and neuroscientific studies that are reviewed in the present article. PMID- 24769291 TI - Developmental studies of the hippocampus and hippocampal-dependent behaviors: insights from interdisciplinary studies and tips for new investigators. AB - The hippocampus is not fully developed at birth and, with respect to spatial cognition, only begins to show signs of adult-like function at three postnatal weeks in rodents. Studying the developmental period spanning roughly two to four weeks of age permits an understanding of the neural framework necessary for the emergence of spatial navigation and, quite possibly, human episodic memory. However, due to developmental factors, behavior data collection and interpretation can be severely compromised if inappropriate designs are applied. As such, we propose methodological considerations for the behavioral assessment of hippocampal function in developing rats that take into account animal size, growth rate, and sensory and motor ability. We further summarize recent key interdisciplinary studies that are beginning to unravel the molecular machinery and physiological alterations responsible for hippocampal maturation. In general, hippocampal development is a protracted process during which unique contributions to spatial cognition and complex recognition memory come "on line" at different postnatal ages creating a unique situation for elucidating the neural bases of specific components of higher cognitive abilities. PMID- 24769293 TI - Assessment of genotoxic and molecular mechanisms of cancer risk in smoking and smokeless tobacco users. AB - Inexpensive forms of tobacco are widely used in developing countries such as India. We have evaluated genotoxicity endpoints (chromosome aberrations, micronucleus frequency, comet assay) and polymorphisms of the XRCC1 and p53 genes among smokers and smokeless tobacco (SLT) users in rural Tamilnadu, South India. Cytogenetic, DNA damage and SNP analyses were performed on peripheral blood samples; micronucleus frequency was measured in peripheral blood and buccal mucosa exfoliated cells. Both categories of tobacco users had elevated levels of genotoxic damage. SNP analysis of tobacco users revealed that 17% carry the XRCC1 gln399gln genotype and 19% carry the p53 pro72pro genotype. Both genotypes are associated with increased risk of cancer. PMID- 24769295 TI - The influence of herbs and spices on overall liking of reduced fat food. AB - Most adults consume more fat than is recommended in the Dietary Guidelines for Americans. We examined whether adding herbs and spices to reduced-fat foods would improve their consumer liking. We recruited adults 18-65 years old to taste three lunch conditions: full fat (FF), reduced fat with no added spice (RF), and reduced fat plus spice (RFS). Subjects rated their liking of a meatloaf entree, vegetable side dish, pasta side dish, and overall meal on a 9-point hedonic Likert scale. Subjects came weekly for 3 weeks to consume meals and were randomized to the condition order. We enrolled 148 subjects who were predominantly female (n = 101, 68%), had a mean age of 35.9 years, and body mass index of 24.4 kg/m2. Subjects reported habitual diets as 36% of total calories from fat (2005 Block Food Frequency Questionnaire). Reducing fat content alone significantly dropped overall liking of the meal compared with FF and RFS conditions (6.29 RF vs. 7.05 FF, P < 0.0001; 6.29 RF vs. 6.98 RFS, P <= 0.0001). The RFS overall meal was liked as well as the FF condition. FF and RFS conditions were liked significantly more than RF conditions for each meal item. Liking of FF and RFS meatloaf and vegetables were not significantly different from one another. Pasta FF and RFS conditions were rated significantly differently from each other (7.33 FF vs. 6.61 RFS, P < 0.0001). Adding herbs and spices to reduced fat foods restored liking of the overall meal, meatloaf, and vegetables to that of FF conditions, and significantly improved the liking of RF pasta. Herbs and spices can be a useful tool to improve liking of foods consistent with national guidelines. PMID- 24769294 TI - Using participant hedonic ratings of food images to construct data driven food groupings. AB - Little is known regarding how individuals' hedonic ratings of a variety of foods interrelate and how hedonic ratings correspond to habitual dietary intake. Participant ratings of food appeal of 104 food images were collected while participants were in a fed state (n = 129). Self-reported frequency of intake of the food items, perceived hunger, body mass index (BMI), and dietary restraint were also assessed. Principal components analysis (PCA) was employed to analyze hedonic ratings of the foods, to identify component structures and to reduce the number of variables. The resulting component structures comprised 63 images loading on seven components including Energy-Dense Main Courses, Light Main Courses and Seafood as well as components more analogous to traditional food groups (e.g., Fruits, Grains, Desserts, Meats). However, vegetables were not represented in a unique, independent component. All components were positively correlated with reported intake of the food items (r's = .26-.52, p <.05), except for the Light Main Course component (r = .10). BMI showed a small positive relation with aggregated food appeal ratings (r = .19; p <.05), which was largely driven by the relations between BMI and appeal ratings for Energy-Dense Main Courses (r = .24; p <.01) and Desserts (r = .27; p <.01). Dietary restraint showed a small significant negative relation to Energy-Dense Main Courses (r = .21; p <.05), and Meats (r = -.18; p <.05). The present investigation provides novel evidence regarding how individuals' hedonic ratings of foods aggregate into food components and how these component ratings relate to dietary intake. The notable absence of a vegetable component suggests that individuals' liking for vegetables is highly variable and, from an empirical standpoint, not related to how they respond hedonically to other food categories. PMID- 24769296 TI - Dietary sources of fiber intake in Brazil. AB - The objective of this study was to estimate the household availability of fibers in Brazil and to identify the dietary sources of this nutrient. Data from the 2008-2009 Household Budget Survey were used to estimate national household availability and density of fibers and also according to stratifications defined by income level, five regions and area (rural or urban). The contribution of the different food groups, classified by the nature, extent and purpose of processing, to total fibers available in Brazilian households was also determined. The mean density of per capita fibers was 7.6 g/1000 kcal. Higher availability and density of fibers was observed in households situated in rural areas and among low-income families. The main dietary sources of fiber were beans, bread, rice, fruit, vegetables and manioc flour. Fiber intake was found to be insufficient. Therefore, actions promoting a healthy diet are needed to improve the dietary quality of the Brazilian population. PMID- 24769298 TI - Implementation of an electronic clinical reminder to improve rates of lung cancer screening. PMID- 24769299 TI - The role of reorganization energy in rational enzyme design. AB - Computational design is becoming an integral component in developing novel enzymatic activities. Catalytic efficiencies of man-made enzymes however are far behind their natural counterparts. The discrepancy between laboratory and naturally evolved enzymes suggests that a major catalytic factor is still missing in the computational process. Reorganization energy, which is the origin of catalytic power of natural enzymes, has not been exploited yet for design. As exemplified in case of KE07 Kemp eliminase, this quantity is optimized by directed evolution. Mutations beneficial for evolution, but without direct impact on catalysis can be identified based on contributions to reorganization energy. We propose to incorporate the reorganization energy in scaffold selection to provide highly evolvable initial designs. PMID- 24769297 TI - Depression, dietary habits, and cardiovascular events among women with suspected myocardial ischemia. AB - BACKGROUND: Dietary habits and depression are associated with cardiovascular disease risk. Patients with depression often report poor eating habits, and dietary factors may help explain commonly observed associations between depression and cardiovascular disease. METHODS: From 1996 to 2000, 936 women were enrolled in the Women's Ischemia Syndrome Evaluation at 4 US academic medical centers at the time of clinically indicated coronary angiography and then assessed (median follow-up, 5.9 years) for adverse outcomes (cardiovascular disease death, heart failure, myocardial infarction, stroke). Participants completed a protocol including coronary angiography (coronary artery disease severity) and depression assessments (Beck Depression Inventory scores, antidepressant use, and depression treatment history). A subset of 201 women (mean age, 58.5 years; standard deviation, 11.4) further completed the Food Frequency Questionnaire for Adults (1998 Block). We extracted daily fiber intake and daily servings of fruit and vegetables as measures of dietary habits. RESULTS: In separate Cox regression models adjusted for age, smoking, and coronary artery disease severity, Beck Depression Inventory scores (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.01-1.10), antidepressant use (HR, 2.4; 95% CI, 1.01-5.9), and a history of treatment for depression (HR, 2.4; 95% CI, 1.1-5.3) were adversely associated with time to cardiovascular disease outcomes. Fiber intake (HR, 0.87; 95% CI, 0.78-0.97) and fruit and vegetable consumption (HR, 0.36; 95% CI, 0.19-0.70) were associated with a decreased time to cardiovascular disease event risk. In models including dietary habits and depression, fiber intake and fruit and vegetable consumption remained associated with time to cardiovascular disease outcomes, whereas depression relationships were reduced by 10% to 20% and nonsignificant. CONCLUSIONS: Among women with suspected myocardial ischemia, we observed consistent relationships among depression, dietary habits, and time to cardiovascular disease events. Dietary habits partly explained these relationships. These results suggest that dietary habits should be included in future efforts to identify mechanisms linking depression to cardiovascular disease. PMID- 24769300 TI - Simple procedure for determination of valproic acid in dried blood spots by gas chromatography-mass spectrometry. AB - Valproic acid (VA) is a drug widely used to treat epilepsy and bipolar disorder, at recommended serum concentrations ranging form 50 to 100MUg ml(-1). A novel option for therapeutic drug monitoring that has been emerging recently its testing using dried blood spots on paper (DBS), but there are no reports of its application to assaying VA. In this study, a methodology was developed for the determination of VA in 6mm diameter DBS, equivalent to around 12MUl of blood, using gas chromatography combined with mass spectrometry. DBS were extracted with a mixture of acetonitrile and methanol (1:3, v/v). The method is linear from 5 to 250MUgml(-1) with intra-assay and inter-assay precision of 2.67-8.15% and 2.28 3.67%, respectively. Accuracy was 102.84-104.42%. VA was stable in DBS stored at 45 degrees C for up to 21 days. VA concentrations in DBS correlated with concentrations assayed in serum, with r=0.9948. Mean ratio between VA concentrations in serum and DBS in clinical samples was 1.883. Dried blood spots are a viable option for collection and transport of samples and for assaying VA in the context of therapeutic drug monitoring, especially in Developing Countries. PMID- 24769301 TI - Automated isotope dilution liquid chromatography-tandem mass spectrometry with on line dilution and solid phase extraction for the measurement of cortisol in human serum sample. AB - A candidate reference measurement procedure involving automated isotope dilution coupled with liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) with on line dilution and solid phase extraction (SPE) has been developed and critically evaluated. We constructed the LC-MS/MS with on-line dilution and SPE system. An isotopically labelled internal standard, cortisol-d4, was added to serum sample. After equilibration, the methanol was added to the sample, and deproteination was performed. Then, the sample was applied to the LC-MS/MS system. The limit of detection (LOD) and limit of quantification (LOQ) were 0.2 and 1ngg(-1), respectively. Excellent precision was obtained with within-day variation (RSD) of 1.9% for ID-LC-MS/MS analysis (n=6). This method, which demonstrates simple, easy, good accuracy, high precision, and is free from interferences from structural analogues, qualifies as a reference measurement procedure. PMID- 24769302 TI - Induction of micronuclei and nuclear abnormalities in tadpoles of the common toad (Rhinella arenarum) treated with the herbicides Liberty(r) and glufosinate ammonium. AB - The assessment of micronucleated erythrocytes (ME) in blood represents a widely used method for the detection of chromosomal damage by chemical agents, such as herbicides that may occur as water contaminants. We investigated the changes in some circulating blood-cell parameters of tadpoles of the common toad (Rhinella arenarum) that were exposed during 48 or 96 h to three sub-lethal concentrations (3.75, 7.5, and 15 mg/L) of a commercial formulation of a glufosinate-ammonium (GLA)-based herbicide (Liberty((r)), LY((r))) as well as to the corresponding active ingredient GLA. The frequency of ME and other erythrocyte nuclear abnormalities (ENA, i.e., lobed nuclei, binucleates or segmented nuclei, kidney shaped nuclei, notched nuclei, and picnotic nuclei) were evaluated and compared with positive (cyclophosphamide, CP, 40 mg/L) and negative (de-chlorinated tap water) controls. The results indicate that the exposure of R. arenarum tadpoles to LY((r)) induces a concentration-dependent increase in ME frequency. The ENA frequency at 48 h was also significantly higher than that in the negative control group for all the chemicals assayed (CP, LY((r)) and GLA) whereas at 96 h, increases in ENA over the negative control group were found only for CP and GLA (7.5 mg/L). Our study demonstrates that the commercial formulation of a GLA-based herbicide induces micronucleus formation in R. arenarum tadpoles, in contrast to the active ingredient. According to these results, the inert ingredients of the commercial formulation played an important role in the production of genotoxic damage in erythrocytes of amphibian tadpoles. PMID- 24769303 TI - Agmatine protects against intracerebroventricular streptozotocin-induced water maze memory deficit, hippocampal apoptosis and Akt/GSK3beta signaling disruption. AB - Centrally administered streptozotocin (STZ), is known to cause Alzheimer's like memory deterioration. It mainly affects insulin signaling pathways such as PI3/Akt and GSK-3beta which are involved in cell survival. Previous studies indicate that STZ increases the ratio of Bax/Bcl-2 and thereby induces caspase-3 activation and apoptosis. Agmatine, a polyamine derived from l-arginine decarboxylation, is recently shown to exert some neuroprotective effects. This study aimed to assess if agmatine reverses STZ-induced memory deficits, hippocampal Akt/GSK-3beta signaling disruption and caspase-3 activation. Adult male Sprague-Dawely rats weighing 200-250 g were used. The canules were implanted bilaterally into lateral ventricles. STZ was administered on days 1 and 3 (3 mg/kg) and agmatine treatment (40 or 80 mg/kg) was started from day 4 and continued in an every other day manner till day 14. The animal's learning and memory capability was assessed on days 15-18 using Morris water maze. After complement of behavioral studies the hippocampi was isolated and the amounts of hippocampal cleaved caspase-3 (the landmark of apoptosis), Bax/Bcl-2 ratio, total and phosphorylated forms of GSK-3beta and Akt were analyzed by western blot. The results showed that agmatine in 80 but not 40 mg/kg reversed the memory deterioration induced by STZ. Western blot analysis revealed that STZ prompted elevation of caspase-3; Bax/Bcl-2 ratio and disrupted Akt/GSK-3beta signaling in the hippocampus. Agmatine treatment prevented apoptosis and Akt/GSK-3beta signaling impairment induced by STZ. This study disclosed that agmatine treatment averts not only STZ-induced memory deterioration but also hippocampal apoptosis and Akt/GSK-3beta signaling disruption. PMID- 24769305 TI - Coronary computed tomography as a cost-effective test strategy for coronary artery disease assessment - a systematic review. AB - Cardiovascular imaging imparts a huge burden on healthcare spending. Coronary CT angiography (CCTA) may provide a cost effective means of diagnosing coronary artery disease (CAD) and reducing downstream cost of testing. We performed a systematic search of literature for randomized controlled trials or prospective or retrospective non-randomized comparative studies or case series, decision analytic models and technology reports in which some or all of the patients underwent CCTA and looking at the cost effectiveness, comparative effectiveness and downstream test utilization associated with the use of CCTA. We found 42 articles matching our criteria. CCTA either as first line or as a layering test may represent a cost effective strategy for initial evaluation of patients with CAD prevalence of 10%-50% in both near-term and long-term diagnostic periods. For CAD prevalence >=70%, ICA as initial test may represent cost effective strategy for diagnosis of stable chest pain. CCTA may represent cost-effective strategy when performed as a layering test to equivocal initial stress imaging before performing ICA. Use of CCTA is cost- and time-effective strategy for evaluation of low risk (<30% CAD prevalence) acute chest pain patients in emergency department and can be used for safe exclusion of acute coronary syndrome (ACS). Use of coronary calcium score as an initial test may require further evidence to be deemed cost-effective strategy. CCTA may represent a cost effective and may be associated with less downstream testing for diagnosis of stable chest pain patients in low to intermediate risk patients whereas for low risk acute chest pain patients, use of CCTA is associated with expedited patient management, less cost and safe exclusion of ACS. PMID- 24769304 TI - Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice. AB - DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA 6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5 HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5 HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation. PMID- 24769306 TI - PPARgamma activation does not affect endothelin activity in non-diabetic patients with hypertension or hypercholesterolemia. AB - OBJECTIVES: This study tested the hypothesis that pioglitazone reduces endothelin 1 activity in the forearm vasculature in non-diabetic patients with hypertension or hypercholesterolemia and variable degrees of insulin resistance. METHODS: We conducted a single center, randomized, double-blind, placebo controlled, cross over trial in 80 patients with either hypertension or hypercholesterolemia and further classified as insulin-sensitive or insulin-resistant based on a published insulin sensitivity index. Participants received pioglitazone 45 mg daily or matching placebo for eight weeks. The main endpoint was the change in forearm vascular endothelin-1 activity, as assessed by intra-arterial infusion of the endothelin type A receptor blocker BQ-123, measured at the end of each 8-week treatment period. RESULTS: Pioglitazone lowered plasma insulin (P < 0.001), improved insulin sensitivity (P < 0.001), increased HDL (P < 0.001), and reduced triglycerides (P = 0.003), free fatty acids (P = 0.005), and C-reactive protein (P = 0.001). However, pioglitazone did not affect the vasodilator response to BQ 123 in the whole group (P = 0.618) and in the diagnosis or insulin sensitivity subgroups. Hence, in non-diabetic patients with hypertension or hypercholesterolemia, PPARgamma activation with pioglitazone does not affect endothelin-1 activity, despite enhancing insulin sensitivity and reducing plasma insulin and C-reactive protein levels. CONCLUSIONS: In non-diabetic patients with hypertension or hypercholesterolemia, pioglitazone improves insulin sensitivity, lipid profile, and inflammation but does not affect endothelin activity. Our data suggest that the determinants of endothelin-1 vascular activity in vivo may differ and/or be more complex than those suggested by the results of previous in vitro studies. PMID- 24769307 TI - Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex. AB - Glucagon-like peptide-1 (GLP-1) is a novel treatment modality for type 2 diabetes mellitus. However, GLP-1 has been suggested as a therapeutic target for Alzheimer's disease (AD). In rodent studies, GLP-1 reduces amyloid beta (Abeta) and facilitates synaptic plasticity. Therefore, in the present study, we investigated how GLP-1 facilitates synaptic plasticity and reduces the Abeta in vivo. Exendin-4, a GLP-1 receptor agonist that can cross the blood brain barrier, was subcutaneously administered to adult mice. We then extracted the total and the plasma membrane proteins from the mouse neocortex. Exendin-4 significantly increased the phosphorylation level of cAMP response element-binding protein (CREB). Consistently, the expression level of brain-derived neurotrophic factor (BDNF), a transcriptional target of CREB, was increased. Furthermore, exendin-4 increased the membrane protein level of the AMPA receptor GluR1 subunit and postsynaptic density protein-95 (PSD-95), whereas GluR2 was unaffected. These exendin-4-dependent increases in membrane GluR1, total PSD-95 and BDNF were abrogated by pretreatment with temozolomide (TMZ), a DNA-alkylating agent, indicating that these alterations were dependent on exendin-4-induced transcriptional activity. In addition, we found that exendin-4 increased the level of the alpha-C terminal fragment (alpha-CTF) of amyloid precursor protein (APP). Furthermore, protein levels of both mature and immature ADAM10, the alpha secretase of APP in the plasma membrane, were increased, whereas the total mature and immature ADAM10 levels were unchanged. These exendin-4-dependent increases in alpha-CTF and ADAM10 were not affected by TMZ. These findings suggested that GLP 1 facilitates the GluR1 membrane insertion through CREB activation and increases alpha-secretase activity through ADAM10 membrane trafficking. Upregulation of GluR1 and ADAM10 at the plasma membrane were also observed in mice with intracerebroventricular administration of Abeta oligomer, indicating that a part of benefit of exendin-4 against AD may depend on the GluR1 and ADAM10 membrane trafficking. PMID- 24769308 TI - Protective effects of a novel 5-HT3 receptor antagonist, N-n-butyl-3-methoxy quinoxaline-2-carboxamide (6o) against chronic unpredictable mild stress-induced behavioral changes and biochemical alterations. AB - Stimulation of high oxidative stress in the brain is considered as an important factor for neurotoxicity towards the pathophysiology of chronic stress-induced depression disorder. In the present research, a potential 5-HT3 receptor antagonist N-n-butyl-3-methoxy quinoxaline-2-carboxamide (6o) having good Log P (2.60) and pA2 (7.7) values was examined for its effect on the behavioral and biochemical changes induced by the chronic unpredictable mild stress (CUMS) model. In the current investigation mice were introduced to different stress procedures daily for a period of 28 days to induce a depressive-like behavior. The results show that CUMS caused a depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and locomotor activity and increase in immobility in the forced swim test (FST). Moreover, it was found that oxidative stress markers such as lipid peroxide and nitrite levels were significantly increased, whereas, antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were decreased in the brain tissue of CUMS-subjected mice. "Compound 6o" (1 and 2 mg/kg, p.o.) and fluoxetine treatment (20 mg/kg, p.o.) for a period of 21 days altered the CUMS induced behavioral (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxide, increased brain nitrite; decreased GSH, SOD and CAT levels) alterations. Moreover normal mice treated with "compound 6o" (2 mg/kg, p.o.) showed a significant decrease in the duration of immobility in FST as compared to normal vehicle treated mice. In conclusion, "compound 6o" produced antidepressant-like effects in behavioral despair paradigm in chronically stressed mice by restoring antioxidant enzyme activity. PMID- 24769309 TI - Atorvastatin evokes a serotonergic system-dependent antidepressant-like effect in mice. AB - Atorvastatin is a statin largely used in the treatment of hypercholesterolemia and recently revealed as a neuroprotective agent. The antidepressant-like effect of acute atorvastatin treatment in mice has been previously demonstrated by our laboratory. The purpose of this study was to explore the contribution of the serotonergic system in the antidepressant-like effect of atorvastatin in mice. Data demonstrate that the serotonin (5-HT) depleting agent p-chlorophenylalanine methyl ester (PCPA, 100 mg/kg, i.p.) completely abolished atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. Besides atorvastatin, fluoxetine (10 mg/kg, p.o.), a serotonin selective reuptake inhibitor (SSRI) was able to exert an antidepressant-like effect, but any of them changed 5-HT content in the hippocampus or frontal cortex. The 5H-T1A (WAY100635, 0.1 mg/kg, s.c) or the 5 HT2A/2C (ketanserin, 5 mg/kg, s.c.) receptor antagonists prevented atorvastatin antidepressant-like effect. In addition, a combinatory antidepressant-like effect was observed when mice received the co-administration of sub-effective doses of atorvastatin (0.01 mg/kg, p.o.) and the SSRI fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.). Taken together, these results indicate that the antidepressant-like effect of atorvastatin depends on the serotonergic system modulation. PMID- 24769310 TI - Interference correction by extracting the information of interference dominant regions: application to near-infrared spectra. AB - Interference such as baseline drift and light scattering can degrade the model predictability in multivariate analysis of near-infrared (NIR) spectra. Usually interference can be represented by an additive and a multiplicative factor. In order to eliminate these interferences, correction parameters are needed to be estimated from spectra. However, the spectra are often mixed of physical light scattering effects and chemical light absorbance effects, making it difficult for parameter estimation. Herein, a novel algorithm was proposed to find a spectral region automatically that the interesting chemical absorbance and noise are low, that is, finding an interference dominant region (IDR). Based on the definition of IDR, a two-step method was proposed to find the optimal IDR and the corresponding correction parameters estimated from IDR. Finally, the correction was performed to the full spectral range using previously obtained parameters for the calibration set and test set, respectively. The method can be applied to multi target systems with one IDR suitable for all targeted analytes. Tested on two benchmark data sets of near-infrared spectra, the performance of the proposed method provided considerable improvement compared with full spectral estimation methods and comparable with other state-of-art methods. PMID- 24769311 TI - Comparison of two different cryopreservation protocols for freezing goat semen. AB - In this study, two different semen cryopreservation protocols were compared to freeze goat semen. The ejaculates (n=12) were collected by using electro ejaculator from six mature bucks (two ejaculates per each buck). Each ejaculate was divided into two groups as Protocol 1 (P1) and Protocol 2 (P2). In P1, semen was diluted directly in an extender containing 15% egg yolk, 300mM Tris, 28mM glucose, 95mM citric acid 5% glycerol to a concentration of 200*10(6)sperm/mL. In P2, after the removal of seminal plasma by centrifugation, the semen sample was diluted with the first portion of milk extender consist of 100mg/mL skimmed milk powder and 27.75mM glucose (without glycerol) to a concentration of 400*10(6)sperm/mL. The second portion of the milk extender containing 14% glycerol was added to semen gradually in order to achieve sperm concentration 200*10(6)sperm/mL and 7% glycerol level in the final volume. Extended semen was loaded in 0.25mL straws, held for 2h at 4 degrees C, frozen in nitrogen vapor and stored in liquid nitrogen. Post-thaw motility and live sperm rate (mean+/-SEM) were significantly lower (P<0.05) in P1 as compared to P2 (47.50+/-1.23% vs. 55.63+/-1.72%; 80.04+/-1.29% vs. 84.04+/-1.08%, respectively). However, live intact, total intact, abnormal, reacted acrosome and DNA damaged sperm rates were similar (P>0.05) in both protocols. It was concluded that both protocols used in this study provided reasonable post-thaw parameters; however, P2 yielded better motility and live sperm rate compared to P1. PMID- 24769312 TI - Evaluation of intracellular and extracellular trehalose as a cryoprotectant of stem cells obtained from umbilical cord blood. AB - Cord blood is a source of hematopoietic stem cells used in transplantation in which hematopoietic reconstitution is necessary. This transplant modality requires the cryopreservation of hematopoietic stem cells (HSCs). Dimethyl sulfoxide has been used as a cryoprotectant (CPA) in the cryopreservation of HSCs; however, it has been demonstrated that Me2SO exhibits toxic side effects to the human body. Due to its stability upon freezing, disaccharides such as trehalose have been investigated as a cryoprotectant. This study investigated the hypothesis that a cryopreservation solution containing intracellular and extracellular trehalose improves the recovery of stem cells after cryopreservation. After thawing, the cells were tested for their viability using the 7AAD stain, CD45+/CD34+ cells were assessed using flow cytometry and the MTT viability assay, and the proportion of hematopoietic progenitor cells was measured using the CFU assay. Our results showed the effectiveness of the solution containing intracellular and extracellular trehalose in the cryopreservation of cord blood cells, demonstrating that trehalose may be an optimal cryoprotectant when present both inside and outside of cells. PMID- 24769313 TI - Thermal expansion of vitrified blood vessels permeated with DP6 and synthetic ice modulators. AB - This study provides thermal expansion data for blood vessels permeated with the cryoprotective cocktail DP6, when combined with selected synthetic ice modulators (SIMs): 12% polyethylene glycol 400, 6% 1,3-cyclohexanediol, and 6% 2,3 butanediol. The general classification of SIMs includes molecules that modulate ice nucleation and growth, or possess properties of stabilizing the amorphous state, by virtue of their chemical structure and at concentrations that are not explained on a purely colligative basis. The current study is part of an ongoing effort to characterize thermo-mechanical effects on structural integrity of cryopreserved materials, where thermal expansion is the driving mechanism to thermo-mechanical stress. This study focuses on the lower part of the cryogenic temperature range, where the cryoprotective agent (CPA) behaves as a solid for all practical applications. By combining results obtained in the current study with literature data on the thermal expansion in the upper part of the cryogenic temperature range, unified thermal expansion curves are presented. PMID- 24769314 TI - Stromal transforming growth factor-beta 1 is crucial for reinforcing the invasive potential of low invasive cancer. AB - OBJECTIVE: Tumour cells alter the characteristics of the adjacent stroma to create a supportive microenvironment during cancer progression. In vitro and in vivo experiments were carried out to verify the role of stromal TGF-beta1 in reinforcing of the invasive potential in low invasive cancer. MATERIALS AND METHODS: Isolated NF or CAF was co-cultured with low invasive HSC-2 cells to evaluate whether stromal TGF-beta1 induced PDPN expression by Transwell invasion and influenced tumour growth in orthotopic xenografts. RESULTS: Stimulation by TGF-beta1 promoted PDPN expression and Transwell invasion through SMAD signalling as well as activation of Src, P38 mitogen activated protein kinase and extracellular regulated kinase 1/2. PDPN induction was TbetaRII-dependent. Tumour growth of HSC-2 OSCC in a mouse xenograft was intensified in the tumour CAF microenvironment. CONCLUSIONS: Stromal TGF-beta1 signalling promoted PDPN expression in cancer cells, thereby enhancing tumour growth and leading to a more invasive phenotype. PMID- 24769315 TI - Salivary pellicle composition and multispecies biofilm developed on titanium nitrided by cold plasma. AB - OBJECTIVE: The aim of this study was to evaluate the composition of the salivary pellicle (SP) and multispecies biofilm developed on titanium nitrided by cold plasma. METHODS: Titanium discs were allocated into a control group (Ti) and an experimental group (TiN - titanium-nitrided by cold plasma). The disc surface topography was characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The chemical composition of the disc surface was determined by X-ray photoelectron spectroscopy (XPS). Stimulated, clarified, and filtered saliva was used to form pellicles on the discs. Proteome analysis of the adsorbed SP proteins was performed by liquid chromatography-mass spectrometry (LC MS). The surface free energy (SFE) was evaluated before and after SP formation. A multispecies biofilm composed of Actinomyces naeslundii, Streptococcus oralis, Streptococcus mutans, Fusobacterium nucleatum, Veillonella dispar, and Candida albicans was developed on the SP-coated discs. Viable microorganism counts were determined. The biomass and average thickness of biofilms were analyzed by confocal laser-scanning microscopy (CLSM) with COMSTAT software. The biofilm organization was visualized by SEM. RESULTS: The surface topography was similar in both groups. The SFE of the TiN group did not differ from that of the Ti group (p>0.05), although the adsorption of pellicle proteins increased the SFE in both pellicle-coated groups (p<0.001). Different proteins were identified on the Ti and TiN surfaces. The amount of biofilm was similar for both groups (p=0.416), but the counts of F. nucleatum and S. oralis were higher in the TiN group (p<0.001). Similar biofilms were characterized by the COMSTAT data, CLSM images, and SEM images. CONCLUSION: The titanium nitrided by cold plasma exhibited differences in SP composition and multispecies microbial biofilm population compared to the control titanium surface. PMID- 24769316 TI - Iron overload in allogeneic hematopoietic cell transplantation outcome: a meta analysis. AB - An elevated ferritin level before allogeneic hematopoietic cell transplantation (HCT) is an adverse prognostic factor for overall survival (OS) and nonrelapse mortality. Because ferritin is an imperfect surrogate of iron stores, the prognostic role of iron overload remains unclear. We conducted a patient-level meta-analysis of 4 studies that used magnetic resonance imaging to estimate pre HCT liver iron content (LIC). An elevated LIC was not associated with a significant increase in mortality: the hazard ratio (HR) for mortality associated with LIC > 7 mg/g dry weight (primary endpoint) was 1.4 (P = .18). In contrast, ferritin >1000 ng/mL was a significant prognostic factor (HR for mortality, 1.7; P = .036). There was, however, no significant association between ferritin > 2500 and mortality. This meta-analysis suggests that iron overload, as assessed by LIC, is not a strong prognostic factor for OS in a general adult HCT population. Our data also suggest that ferritin is an inadequate surrogate for iron overload in HCT. PMID- 24769317 TI - Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post transplantation relapse and survival. AB - Minimal residual disease (MRD) quantification is an important predictor of outcome after treatment for acute lymphoblastic leukemia (ALL). Bone marrow ALL burden >= 10(-4) after induction predicts subsequent relapse. Likewise, MRD >= 10(-4) in bone marrow before initiation of conditioning for allogeneic (allo) hematopoietic cell transplantation (HCT) predicts transplantation failure. Current methods for MRD quantification in ALL are not sufficiently sensitive for use with peripheral blood specimens and have not been broadly implemented in the management of adults with ALL. Consensus-primed immunoglobulin (Ig), T cell receptor (TCR) amplification and high-throughput sequencing (HTS) permit use of a standardized algorithm for all patients and can detect leukemia at 10(-6) or lower. We applied the LymphoSIGHT HTS platform (Sequenta Inc., South San Francisco, CA) to quantification of MRD in 237 samples from 29 adult B cell ALL patients before and after allo-HCT. Using primers for the IGH-VDJ, IGH-DJ, IGK, TCRB, TCRD, and TCRG loci, MRD could be quantified in 93% of patients. Leukemia associated clonotypes at these loci were identified in 52%, 28%, 10%, 35%, 28%, and 41% of patients, respectively. MRD >= 10(-4) before HCT conditioning predicted post-HCT relapse (hazard ratio [HR], 7.7; 95% confidence interval [CI], 2.0 to 30; P = .003). In post-HCT blood samples, MRD >=10(-6) had 100% positive predictive value for relapse with median lead time of 89 days (HR, 14; 95% CI, 4.7 to 44, P < .0001). The use of HTS-based MRD quantification in adults with ALL offers a standardized approach with sufficient sensitivity to quantify leukemia MRD in peripheral blood. Use of this approach may identify a window for clinical intervention before overt relapse. PMID- 24769318 TI - Validation of the disease risk index for outcome of patients undergoing allogeneic hematopoietic stem cell transplantation after T cell depletion. AB - Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may under-rate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva's University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T cell-depleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n = 3) for meaningful analysis. For non-TDEP patients, the 4 year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients. PMID- 24769319 TI - Optical survey of initial expression of synaptic function in the embryonic chick trigeminal sensory nucleus. AB - We examined the initial expression of synaptic function in the embryonic chick trigeminal nucleus using voltage-sensitive dye recording. Brainstem preparations with three trigeminal nerve afferents, the ophthalmic nerve (N.V1), maxillary nerve (N.V2) and mandibular nerve (N.V3), were dissected from 5.5- to 6.5-day-old chick embryos. In our previous study [Sato et al., 1999], we detected slow signals corresponding to glutamatergic excitatory postsynaptic potentials and identified the principal sensory nucleus of the trigeminal nerve (Pr5), spinal sensory nucleus of the trigeminal nerve (Sp5) and trigeminal motor nucleus. In this study, we examined the effects of removing Mg(2+) from the physiological solution, which enhanced N-methyl-d-aspartate receptor function in the sensory nuclei. In 6.5-day-old (St 29) embryos, the slow signal was observed in Pr5 and Sp5 only when N.V1 was stimulated, whereas it appeared in Mg(2+)-free solution with every nerve stimulation. In 6-day-old (St 28) embryos, the slow signal was observed in Sp5 with N.V1 stimulation, and the appearance of synaptic function in Mg(2+)-free solution varied, depending on the nerves and preparations used. In 5.5-day-old (St 27) embryos, synaptic function was not detected even when external Mg(2+) was removed. These results indicate that the initial expression of synaptic function in the trigeminal system occurs earlier than previously considered, and that the developmental organization of synaptic function differs among the three trigeminal nerves and between the two sensory nuclei. PMID- 24769320 TI - Brn4 and TH synergistically promote the differentiation of neural stem cells into dopaminergic neurons. AB - Neural stem cells (NSCs) are pluripotent cells capable of differentiation into dopaminergic (DA) neurons, which are the major cell types damaged in Parkinson's disease (PD). Therefore, NSCs are considered the most promising cell source for cell replacement therapy of PD. However, the poor differentiation and maturation of DA neurons and decreased cell survival after transplantation are a challenge. We have previously demonstrated that Brn4, a member of the POU domain family of transcription factors, induced the differentiation of NSCs into neurons and promoted their maturation. In this study, we directly transduced tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis, into NSCs to induce DA neuronal differentiation. However, these DA neurons were morphologically immature and seldom expressed dopamine transporter (DAT), a late marker of mature DA neurons. In contrast, TH co-transfected with Brn4 generated increased number of mature DA neurons. Furthermore, Brn4 significantly induced the expression of glial cell line-derived neurotrophic factor (GDNF) with its receptors GFRalpha-1 and Ret, which may contribute to the maturation and survival of differentiated DA neurons. Our findings may be of future importance for the use of NSCs in cell replacement therapy of PD. PMID- 24769321 TI - Deficits of synaptic functions in hippocampal slices prepared from aged mice null alpha7 nicotinic acetylcholine receptors. AB - Alpha 7 (alpha7) nicotinic acetylcholine receptor (alpha7-nAChR) is one of most high expressed nAChR subtypes in the brain. The activation of nAChRs enhances animal cognitive, learning and memory abilities. However, the role of genetic knockout (KO) of alpha7-nAChRs in animal cognition-associated behaviors is still obscure. An early report showed that alpha7-nAChR KO mice did not exhibit behavioral phenotypes, concerning the roles of alpha7-nAChRs in normal, cognition associated behaviors. Later, alpha7-nAChR KO mice were found a deficit in animal spatial discrimination. The roles of alpha7-nAChRs in the alterations of hippocampal synaptic function during aging process are largely unknown. Here, we address this question by examining synaptic function using field potential recording in hippocampal slice preparations from adult (12-14 months old) and aged (22-24 months old) alpha7-nAChR KO and age-matched wild-type (WT) mice. We found that compared to aged WT mice, aged alpha7-nAChR KO mice exhibited significantly reduced size of evoked field synaptic potential and impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses. However, adult alpha7 nAChR KO mice did not show a clear deficit in LTP although the basic synaptic transmission was also reduced compared to adult WT mice. In both age groups, there was no significant difference of paired-pulse facilitation between alpha7 nAChR KO and WT mice. Collectively, this study provides direct evidence, for the first time, that the impaired synaptic function occurs in aged alpha7-nAChR KO mice, suggesting an importance of alpha7-nAChRs in maintaining cognitive function during aging process. PMID- 24769322 TI - Ketogenic diet alters dopaminergic activity in the mouse cortex. AB - The present study was conducted to determine if the ketogenic diet altered basal levels of monoamine neurotransmitters in mice. The catecholamines dopamine (DA) and norephinephrine (NE) and the indolamine serotonin (5HT) were quantified postmortem in six different brain regions of adult mice fed a ketogenic diet for 3 weeks. The dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindole acetic acid (5HIAA) were also measured. Tissue punches were collected bilaterally from the motor cortex, somatosensory cortex, nucleus accumbens, anterior caudate-putamen, posterior caudate-putamen and the midbrain. Dopaminergic activity, as measured by the dopamine metabolites to dopamine content ratio - ([DOPAC]+[HVA])/[DA] - was significantly increased in the motor and somatosensory cortex regions of mice fed the ketogenic diet when compared to those same areas in brains of mice fed a normal diet. These results indicate that the ketogenic diet alters the activity of the meso-cortical dopaminergic system, which may contribute to the diet's therapeutic effect in reducing epileptic seizure activity. PMID- 24769323 TI - Heart protective effects and mechanism of quercetin preconditioning on anti myocardial ischemia reperfusion (IR) injuries in rats. AB - In this study, we investigated the effects and mechanism of quercetin preconditioning on anti-myocardial ischemia reperfusion (IR) injuries in vivo. Meanwhile, their potential anti-oxidative stress and anti-inflammation effect were assessed. SD rats were orally given quercetin 250 mg/kg. Myocardium apoptosis was determined with TUNEL staining. The biomarkers related to myocardial ischemia injury were determined. Simultaneously, hemodynamic parameters were monitored as left ventricular systolic pressure (LVSP), LV end diastolic pressure (LVEDP) and maximal rate of increase and decrease of left ventricular pressure (dP/dtmax). The oxidative stress indicators and inflammatory factors were also evaluated. Western blot method was used for analysis of PI3K, Akt, p-Akt, Bax and Bcl-2 protein expressions. The results showed that quercetin significantly reduced apoptosis rate, improved cardiac function, decreased levels of creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Quercetin also restrained the oxidative stress related to myocardial ischemia injury as evidenced by decreased malondialdehyde (MDA), and elevated GSH, superoxide dismutase (SOD), catalase (CAT), glutathione-peroxidase (GSH-Px), glutathione reductase (GR) activity. Meanwhile, the inflammatory cascade was inhibited as evidenced by decreased cytokines such as tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP) and interleukin-1beta (IL 1beta). Our results still showed that quercetin pretreatment significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the level of cleaved Bax, and increasing the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, quercetin pretreatment markedly increased the phosphorylation of Akt. Blockade of PI3K activity by LY294002, dramatically abolished its anti-apoptotic effect and lowered Akt phosphorylation level. It can be concluded that quercetin pretreatment was protected against myocardium IR injury by decreasing oxidative stress, repressing inflammatory cascade, inhibiting apoptosis in vivo and PI3K/Akt pathway involved in the anti-apoptotic effect. PMID- 24769324 TI - On the derivation of approximations to cellular automata models and the assumption of independence. AB - Cellular automata are discrete agent-based models, generally used in cell-based applications. There is much interest in obtaining continuum models that describe the mean behaviour of the agents in these models. Previously, continuum models have been derived for agents undergoing motility and proliferation processes, however, these models only hold under restricted conditions. In order to narrow down the reason for these restrictions, we explore three possible sources of error in deriving the model. These sources are the choice of limiting arguments, the use of a discrete-time model as opposed to a continuous-time model and the assumption of independence between the state of sites. We present a rigorous analysis in order to gain a greater understanding of the significance of these three issues. By finding a limiting regime that accurately approximates the conservation equation for the cellular automata, we are able to conclude that the inaccuracy between our approximation and the cellular automata is completely based on the assumption of independence. PMID- 24769325 TI - Phase I study of the safety and pharmacokinetics of plerixafor in children undergoing a second allogeneic hematopoietic stem cell transplantation for relapsed or refractory leukemia. AB - The safety, pharmacokinetics, and biological effect of plerixafor in children as part of a conditioning regimen for chemo-sensitization in allogeneic hematopoietic stem cell transplantation (HSCT) have not been studied. This is a phase I study of plerixafor designed to evaluate its tolerability at dose of .24 mg/kg given intravenously on day -4 (level 1); day -4 and day -3 (level 2); or day -4, day -3, and day -2 (level 3) in combination with fludarabine, thiotepa, melphalan, and rabbit antithymocytic globulin for a second allogeneic HSCT in children with refractory or relapsed leukemia. Immunophenotype analysis was performed on blood and bone marrow before and after plerixafor administration. Twelve patients were enrolled. Plerixafor at all 3 levels was well tolerated without dose-limiting toxicity. Transient gastrointestinal side effects of National Cancer Institute-grade 1 or 2 in severity were the most common adverse events. The area under the concentration-time curve increased proportionally to the dose level. Plerixafor clearance was higher in males and increased linearly with body weight and glomerular filtration rate. The clearance decreased and the elimination half-life increased significantly from dose level 1 to 3 (P < .001). Biologically, the proportion of CXCR4(+) blasts and lymphocytes both in the bone marrow and peripheral blood increased after plerixafor administration. PMID- 24769326 TI - Relationship of BK polyoma virus (BKV) in the urine with hemorrhagic cystitis and renal function in recipients of T Cell-depleted peripheral blood and cord blood stem cell transplantations. AB - Hematopoietic stem cell transplant (HSCT) recipients are at significant risk for BK virus (BKV) reactivation, hemorrhagic cystitis (HC), and renal dysfunction. We prospectively monitored 98 patients who had received HSCT by serial BKV PCR in the urine through day (D) +100 to analyze the relationship between BK viruria and HC, serum creatinine (Cr), and creatinine clearance (CrCl) through D +180 or death. Patients, median age 52 years (range, 20 to 73), received T cell-depleted (50%) or cord blood allografts (21%). Median pre-HSCT BKV IgG titers were 1:10,240. Incremental increase in BKV IgG titers correlated with developing BK viruria >= 10(7) copies/mL. By D +100, 53 (54%) patients had BK viruria. BKV load in the urine increased at engraftment and persisted throughout D +100. HC developed in 10 patients (10%); 7 of 10 with BK viruria. In competing risk analyses, BK viruria >= 10(7) copies/mL, older age, cytomegalovirus reactivation, and foscarnet use were risk factors for HC. Cr and CrCl at 2, 3, and 6 months after HSCT were similar between patients with and without BK viruria. PMID- 24769327 TI - Identifying religious and/or spiritual perspectives of adolescents and young adults receiving blood and marrow transplants: a prospective qualitative study. AB - The potential benefits (or detriments) of religious beliefs in adolescent and young adults (AYA) are poorly understood. Moreover, the literature gives little guidance to health care teams or to chaplains about assessing and addressing the spiritual needs of AYA receiving hematopoietic stem cell transplants (HSCT). We used an institutional review board-approved, prospective, longitudinal study to explore the use of religion and/or spirituality (R/S) in AYA HSCT recipients and to assess changes in belief during the transplantation experience. We used the qualitative methodology, grounded theory, to gather and analyze data. Twelve AYA recipients were interviewed within 100 days of receiving HSCT and 6 participants were interviewed 1 year after HSCT; the other 6 participants died. Results from the first set of interviews identified 5 major themes: using R/S to address questions of "why me?" and "what will happen to me;" believing God has a reason; using faith practices; and benefitting from spiritual support people. The second set of interviews resulted in 4 major themes: believing God chose me; affirming that my life has a purpose; receiving spiritual encouragement; and experiencing strengthened faith. We learned that AYA patients were utilizing R/S far more than we suspected and that rather than losing faith in the process of HSCT, they reported using R/S to cope with illness and HSCT and to understand their lives as having special purpose. Our data, supported by findings of adult R/S studies, suggest that professionally prepared chaplains should be proactive in asking AYA patients about their understanding and use of faith, and the data can actively help members of the treatment team understand how AYA are using R/S to make meaning, address fear, and inform medical decisions. PMID- 24769328 TI - Continuous reduced nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a single-institution's three decade experience. AB - This study analyzed changes in patients, transplantation, graft characteristics, and outcome among 827 patients who received their first allo-SCT in a single center between 1983 and 2010. In the 2001 to 2010 decade, compared with the 1983 to 1990 and 1991 to 2000 decades, patients were significantly older and presented with higher risk diseases, reduced intensity conditioning and alternative donors were used more often, and stem cell sources changed from bone marrow to peripheral blood stem cells and cord blood. In the 2001 to 2010 decade, we observed a significant decrease in nonrelapse mortality (NRM) (P = .0007 and P < .0001, respectively) and an increase in relapse incidence (P = .04 and P = .009, respectively), but overall survival (OS) was increased (P = .11 and P = .009, respectively), and there was a trend towards an increased progression-free survival (P = .30 and P = .09, respectively), as compared with the 1983 to 1990 and 1991 to 2000 decades. Chronic graft-versus-host disease (GVHD) was significantly increased, whereas grades III to IV acute GVHD remained stable. These data suggest that, despite the fact that older and higher risk patients with more comorbidities underwent transplantation in the last 10 years, NRM decreased while the incidence of relapse increased and the OS improved. PMID- 24769330 TI - Re: Targeting NOS as a therapeutic approach for heart failure. PMID- 24769329 TI - A comparison of bronchoalveolar lavage versus lung biopsy in pediatric recipients after stem cell transplantation. AB - Bronchoalveolar lavage (BAL) has been a useful initial diagnostic tool in the evaluation of pulmonary complications after hematopoietic stem cell transplantation (HSCT); however, the diagnostic sensitivity, prevalence, and outcome after BAL versus lung biopsy (LB) in pediatric HSCT patients remains to be determined. We reviewed 193 pediatric HSCT recipients who underwent a total of 235 HSCTs. Sixty-five patients (34%) underwent a total of 101 BALs for fever, respiratory distress, and/or pulmonary infiltrates on chest radiograph and/or computed tomography scan. The 1-year probability of undergoing BAL was 43.0% after allogeneic stem cell transplantation (alloSCT) and 8.5% after autologous stem cell transplantation (autoSCT) (P = .001). Sixteen of the 193 patients (8%) patients underwent 19 LBs. The probability of undergoing LB at 1 year after HSCT was 9.3%. No grade III or IV adverse events related to either procedure were observed. Of the 101 BALs performed, 40% (n = 40) were diagnostic, with a majority revealing a bacterial pathogen. Among the 19 LBs performed, 94% identified an etiology. In multivariate analysis, myeloablative conditioning alloSCT conferred the highest risk of requiring a BAL (hazard ratio [HR],8.5; P = .0002). The probability of 2-year overall survival was 20.2% in patients who underwent BAL, 17.5% for patients who underwent biopsy, and 67.4% for patients who had neither procedure. In multivariate analysis, only the requirement of a BAL was independently associated with an increased risk of mortality (HR, 2.96; P < .0001). In summary, in this cohort of pediatric HSCT recipients, BAL and LB were used in approximately 35% and 8% of pediatric HSCTs with diagnostic yields of approximately 40% and 94%, respectively, and were both associated with poor long-term outcomes. PMID- 24769331 TI - Ultrasound backscatter measurements of intact human proximal femurs- relationships of ultrasound parameters with tissue structure and mineral density. AB - Ultrasound reflection and backscatter parameters are related to the mechanical and structural properties of bone in vitro. However, the potential of ultrasound reflection and backscatter measurements has not been tested with intact human proximal femurs ex vivo. We hypothesize that ultrasound backscatter can be measured from intact femurs and that the measured backscattered signal is associated with cadaver age, bone mineral density (BMD) and trabecular bone microstructure. In this study, human femoral bones of 16 male cadavers (47.0+/ 16.1 years, range: 21-77 years) were investigated using pulse-echo ultrasound measurements at the femoral neck in the antero-posterior direction and at the trochanter major in the anteroposterior and lateromedial directions. Recently introduced ultrasound backscatter parameters, independent of cortical thickness, e.g., time slope of apparent integrated backscatter (TSAB) and mean of the backscatter difference technique (MBD) were obtained and compared with the structural properties of trabecular bone samples, extracted from the locations of ultrasound measurements. Moreover, more conventional backscatter parameters, e.g., apparent integrated backscatter (AIB) and frequency slope of apparent integrated backscatter (FSAB) were analyzed. Bone mineral density of the intact femurs was evaluated using dual energy X-ray absorptiometry (DXA). AIB and MDB measured from the femoral neck correlated significantly (p<0.01) with the neck BMD (R2=0.44 and 0.45), cadaver age (R2=0.61 and 0.41) and several structural parameters, e.g., bone volume fraction (R2=0.33 and 0.39, p<0.05 and p<0.01), respectively. To conclude, ultrasound backscatter parameters, measured from intact proximal femurs, are significantly related (p<0.05) to structural properties and mineral density of trabecular bone. PMID- 24769332 TI - AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. AB - Antagonism of the calcium-sensing receptor in the parathyroid gland leads to parathyroid hormone (PTH) release. Calcilytics are a new class of molecules designed to exploit this mechanism. In order to mimic the known bone-anabolic pharmacokinetic (PK) profile of s.c. administered PTH, such molecules must trigger sharp, transient and robust release of PTH. The results of two early clinical studies with the orally-active calcilytic AXT914, a quinazolin-2ne derivative are reported. These were GCP-compliant, single and multiple dose studies of PK/PD and tolerability in healthy volunteers and postmenopausal women. The first study, examined single ascending doses (4 to 120 mg) and limited multiple doses (60 or 120 mgq.d. for 12 days) of AXT914. The second study was a randomized, double-blind, active- and placebo-controlled, 4-week repeat-dose parallel group study of healthy postmenopausal women (45 and 60 mg AXT914, placebo, 20 MUg Forteo/teriparatide/PTH(1-34) fragment). AXT914 was well tolerated at all doses and reproducibly induced the desired PTH-release profiles. Yet, 4 weeks of 45 or 60 mg AXT914 did not result in the expected changes in circulating bone biomarkers seen with teriparatide. However total serum calcium levels increased above baseline in the 45 and 60 mg AXT914 treatment groups (8.0% and 10.7%, respectively), compared to that in the teriparatide and placebo groups (1.3% and 1.0%, respectively). Thus the trial was terminated after a planned interim analysis due to lack of effect on bone formation biomarkers and dose limiting effects on serum calcium. In conclusion, AXT914 was well tolerated but the observed transient and reproducible PTH-release after repeat oral administration of AXT914 which showed an exposure profile close to that of s c. PTH, did not translate into a bone anabolic response and was associated with a persistent dose-related increase in serum calcium concentrations. PMID- 24769333 TI - 68Ga DOTA-TATE PET/CT allows tumor localization in patients with tumor-induced osteomalacia but negative 111In-octreotide SPECT/CT. AB - Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO. Here, we report the data of 5 consecutive patients suffering from TIO, who underwent both 111Indium-octreotide scintigraphy (111In OCT) SPECT/CT as well as 68Ga DOTA-TATE PET/CT for tumor detection. While 111In OCT SPECT/CT allowed tumor detection in only 1 of 5 patients, 68Ga DOTA-TATE PET/CT was able to localize the tumor in all patients. Afterwards, anatomical imaging of the region of interest was performed with CT and MRI. Thus, successful surgical resection of the tumor was achieved in all patients. Serum phosphate levels returned to normal and all patients reported relief of symptoms within weeks. Moreover, an iliac crest biopsy was obtained from every patient and revealed marked osteomalacia in all cases. Follow-up DXA revealed an increase in BMD of up to 34.5% 1-year postoperative, indicating remineralization. No recurrence was observed. In conclusion our data indicates that 68Ga DOTA-TATE PET/CT is an effective and promising diagnostic tool in the diagnosis of TIO, even in patients in whom 111In-OCT prior failed to detect a tumor. PMID- 24769334 TI - Chlorine gas exposure disrupts nitric oxide homeostasis in the pulmonary vasculature. AB - Exposure to chlorine (Cl2) gas during industrial accidents or chemical warfare leads to significant airway and distal lung epithelial injury that continues post exposure. While lung epithelial injury is prevalent, relatively little is known about whether Cl2 gas also promotes injury to the pulmonary vasculature. To determine this, rats were subjected to a sub-lethal Cl2 gas exposure (400 ppm, 30 min) and then brought back to room air. Pulmonary arteries (PA) were isolated from rats at various times post-exposure and contractile (phenylephrine) and nitric oxide (NO)-dependent vasodilation (acetylcholine and mahmanonoate) responses measured ex vivo. PA contractility did not change, however significant inhibition of NO-dependent vasodilation was observed that was maximal at 24-48 h post exposure. Superoxide dismutase restored NO-dependent vasodilation suggesting a role for increased superoxide formation. This was supported by ~2-fold increase in superoxide formation (measured using 2-hydroethidine oxidation to 2-OH-E+) from PA isolated from Cl2 exposed rats. We next measured PA pressures in anesthetized rats. Surprisingly, PA pressures were significantly (~4 mmHg) lower in rats that had been exposed to Cl2 gas 24 h earlier suggesting that deficit in NO-signaling observed in isolated PA experiments did not manifest as increased PA pressures in vivo. Administration of the iNOS selective inhibitor 1400W, restored PA pressures to normal in Cl2 exposed, but not control rats suggesting that any deficit in NO-signaling due to increased superoxide formation in the PA, is offset by increased NO-formation from iNOS. These data indicate that disruption of endogenous NO-signaling mechanisms that maintain PA tone is an important aspect of post-Cl2 gas exposure toxicity. PMID- 24769335 TI - CAR-mediated repression of Foxo1 transcriptional activity regulates the cell cycle inhibitor p21 in mouse livers. AB - 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor (CAR), is a well-known strong primary chemical mitogen for the mouse liver. Despite extensive investigation of the role of CAR in the regulation of cell proliferation, our knowledge of the intricate mediating mechanism is incomplete. In this study, we demonstrated that long-term CAR activation by TCPOBOP increased liver-to-body weight ratio and decreased tumour suppressor Foxo1 expression and transcriptional activity, which were correlated with reduced expression of genes regulated by Foxo1, including the cell-cycle inhibitor Cdkn1a(p21), and upregulation of the cell-cycle regulator Cyclin D1. Moreover, we demonstrated the negative regulatory effect of TCPOBOP-activated CAR on the association of Foxo1 with the target Foxo1 itself and Cdkn1a(p21) promoters. Thus, we identified CAR-mediated repression of cell cycle inhibitor p21, as mediated by repression of FOXO1 expression and transcriptional activity. CAR-FOXO1 cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. PMID- 24769336 TI - Analysis of the solution structure of Thermosynechococcus elongatus photosystem I in n-dodecyl-beta-D-maltoside using small-angle neutron scattering and molecular dynamics simulation. AB - Small-angle neutron scattering (SANS) and molecular dynamics (MD) simulation were used to investigate the structure of trimeric photosystem I (PSI) from Thermosynechococcus elongatus (T. elongatus) stabilized in n-dodecyl-beta-d maltoside (DDM) detergent solution. Scattering curves of detergent and protein detergent complexes were measured at 18% D2O, the contrast match point for the detergent, and 100% D2O, allowing observation of the structures of protein/detergent complexes. It was determined that the maximum dimension of the PSI-DDM complex was consistent with the presence of a monolayer belt of detergent around the periphery of PSI. A dummy-atom reconstruction of the shape of the complex from the SANS data indicates that the detergent envelope has an irregular shape around the hydrophobic periphery of the PSI trimer rather than a uniform, toroidal belt around the complex. A 50 ns MD simulation model (a DDM ring surrounding the PSI complex with extra interstitial DDM) of the PSI-DDM complex was developed for comparison with the SANS data. The results suggest that DDM undergoes additional structuring around the membrane-spanning surface of the complex instead of a simple, relatively uniform belt, as is generally assumed for studies that use detergents to solubilize membrane proteins. PMID- 24769337 TI - Mechanistic studies on the flavin-dependent N6-lysine monooxygenase MbsG reveal an unusual control for catalysis. AB - The mechanism of Mycobacterium smegmatis G (MbsG), a flavin-dependent l-lysine monooxygenase, was investigated under steady-state and rapid reaction conditions using primary and solvent kinetic isotope effects, substrate analogs, pH and solvent viscosity effects as mechanistic probes. The results suggest that l lysine binds before NAD(P)H, which leads to a decrease in the rate constant for flavin reduction. l-lysine binding has no effect on the rate of flavin oxidation, which occurs in a one-step process without the observation of a C4a hydroperoxyflavin intermediate. Similar effects were determined with several substrate analogs. Flavin oxidation is pH independent while the kcat/Km and kred/KD pH profiles for NAD(P)H exhibit single pKa values of ~6.0, with increasing activity as the pH decreases. At lower pH, the enzyme becomes more uncoupled, producing more hydrogen peroxide and superoxide. Hydride transfer is partially rate-limiting at neutral pH and becomes more rate-limiting at low pH. An inverse solvent viscosity effect on kcat/Km for NAD(P)H was observed at neutral pH whereas a normal solvent viscosity effect was observed at lower pH. Together, the results indicate a unique mechanism where a rate-limiting and pH sensitive conformational change occurs in the reductive half-reaction, which affects the efficiency of lysine hydroxylation. PMID- 24769338 TI - Quorum sensing-dependent metalloprotease VvpE is important in the virulence of Vibrio vulnificus to invertebrates. AB - Vibrio vulnificus, a Gram-negative bacterium, is an opportunistic human pathogen responsible for fatal septicemia caused by contaminated sea foods in eastern Asia. Quorum sensing (QS) is a cell-density dependent gene regulation mechanism that controls the expression of many virulence genes in various bacteria and V. vulnificus has been also suggested to express their virulence genes through the QS system. In this study, we investigated the role of QS system and QS-regulated exoproteases in the virulence of V. vulnificus using several invertebrate host models, Tenebrio molitor, an insect, Caenorhabditis elegans, a nematode, and brine shrimp (Artemia), an aquatic crustacean. When the culture supernatant of smcR (major QS regulator of V. vulnificus) mutant was injected to T. molitor larvae, it failed to induce the melanization of T. molitor larvae, while the culture supernatant of luxO (upstream negative regulator of smcR) mutant more strongly induced the melanization than wild type. These results demonstrated that QS system of V. vulnificus is crucial for virulence to T. molitor larvae. Among several QS-dependently expressed exoproteases of V. vulnificus, vvpE encoding a metalloprotease was mainly responsible for the melanization of T. molitor larvae, in that the culture supernatant of vvpE mutant failed to induce the melanization. This result was confirmed using the C. elegans and Artemia salina model systems, in which the vvpE mutant strains were attenuated in killing C. elegans and A. salina, compared with wild type, indicating that VvpE is important in the infection of V. vulnificus. In conclusion, we suggest that QS system and a QS dependent exoprotease, VvpE are crucial for the V. vulnificus virulence to invertebrates. PMID- 24769340 TI - Serum acid sphingomyelinase is upregulated in chronic hepatitis C infection and non alcoholic fatty liver disease. AB - Sphingolipids constitute bioactive molecules with functional implications in homeostasis and pathogenesis of various diseases. However, the role of sphingolipids as possible disease biomarkers in chronic liver disease remains largely unexplored. In the present study we used mass spectrometry and spectrofluorometry methods in order to quantify various sphingolipid metabolites and also assess the activity of an important corresponding regulating enzyme in the serum of 72 healthy volunteers as compared to 69 patients with non-alcoholic fatty liver disease and 69 patients with chronic hepatitis C virus infection. Our results reveal a significant upregulation of acid sphingomyelinase in the serum of patients with chronic liver disease as compared to healthy individuals (p<0.001). Especially in chronic hepatitis C infection acid sphingomyelinase activity correlated significantly with markers of hepatic injury (r=0.312, p=0.009) and showed a high discriminative power. Accumulation of various (dihydro ) ceramide species was identified in the serum of patients with non-alcoholic fatty liver disease (p<0.001) and correlated significantly to cholesterol (r=0.448, p<0.001) but showed a significant accumulation in patients with normal cholesterol values as well (p<0.001). Sphingosine, a further bioactive metabolite, was also upregulated in chronic liver disease (p<0.001). However, no significant correlation to markers of hepatic injury was identified. CONCLUSION: Chronic hepatitis C virus infection and non-alcoholic fatty liver disease induce a significant upregulation of serum acid sphingomyelinase which appears as a novel biomarker in chronic hepatopathies. Further studies are required to elucidate the potential of the sphingolipid signaling pathway as putative therapeutic target in chronic liver disease. PMID- 24769341 TI - The uses and limitations of the analysis of cellular phosphoinositides by lipidomic and imaging methodologies. AB - The advent of mass spectrometric methods has facilitated the determination of multiple molecular species of cellular lipid classes including the polyphosphoinositides, though to date methods to analyse and quantify each of the individual three PtdInsP and three PtdInsP2 species are lacking. The use of imaging methods has allowed intracellular localization of the phosphoinositide classes but this methodology does not determine the acyl structures. The range of molecular species suggests a greater complexity in polyphosphoinositide signaling than yet defined but elucidating this will require further method development to be achieved. This article is part of a Special Issue entitled Tools to study lipid functions. PMID- 24769339 TI - Polyunsaturated fatty acids inhibit stimulated coupling between the ER Ca(2+) sensor STIM1 and the Ca(2+) channel protein Orai1 in a process that correlates with inhibition of stimulated STIM1 oligomerization. AB - Polyunsaturated fatty acids (PUFAs) have been found to be effective inhibitors of cell signaling in numerous contexts, and we find that acute addition of micromolar PUFAs such as linoleic acid effectively inhibit of Ca(2+) responses in mast cells stimulated by antigen-mediated crosslinking of FcepsilonRI or by the SERCA pump inhibitor, thapsigargin. In contrast, the saturated fatty acid, stearic acid, with the same carbon chain length as linoleic acid does not inhibit these responses. Consistent with this inhibition of store-operated Ca(2+) entry (SOCE), linoleic acid inhibits antigen-stimulated granule exocytosis to a similar extent. Using the fluorescently labeled plasma membrane Ca(2+) channel protein, AcGFP-Orai1, together with the labeled ER Ca(2+) sensor protein, STIM1-mRFP, we monitor stimulated coupling of these proteins that is essential for SOCE with a novel spectrofluorimetric resonance energy transfer method. We find effective inhibition of this stimulated coupling by linoleic acid that accounts for the inhibition of SOCE. Moreover, we find that linoleic acid induces some STIM1-STIM1 association, while inhibiting stimulated STIM1 oligomerization that precedes STIM1-Orai1 coupling. We hypothesize that linoleic acid and related PUFAs inhibit STIM1-Orai1 coupling by a mechanism that involves perturbation of ER membrane structure, possibly by disrupting electrostatic interactions important in STIM1 oligomerization. Thisarticle is part of a Special Issue entitled Tools to study lipid functions. PMID- 24769342 TI - Changes in mitochondrial membrane composition and oxidative status during rapid growth, maturation and aging in zebrafish, Danio rerio. AB - Considering membranes and membrane components as possible pacemakers of the main processes taking place inside mitochondria, changes in phospholipids or fatty acids could play a central role linking different mechanisms involved in cumulative damage to cell molecules and dysfunction during periods of high stress, such as rapid growth and aging. Changes affecting either lipid class or fatty acid compositions could affect phospholipid and membrane properties and alter mitochondrial function and cell viability. In the present study, mitochondrial oxidative status and mitochondrial membrane phospholipid compositions were analyzed throughout the life-cycle of zebrafish. TBARS content significantly increased in 18-month-old fish while aconitase activity decreased in 24-month-old fish, which have been related with oxidative damage to molecules. Mitochondria-specific superoxide dismutase decreased in 24-month-old animals although this change was not statistically significant. Age affected both mitochondrial phospholipid content and the peroxidation index of most phospholipid classes suggesting that oxidative damage to mitochondrial lipids was occurring. PMID- 24769343 TI - Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature. AB - Xylazine is not a controlled substance; it is marketed as a veterinary drug and used as a sedative, analgesic and muscle relaxant. In humans, it could cause central nervous system depression, respiratory depression, bradycardia, hypotension, and even death. There have been publications of 43 cases of xylazine intoxication in humans, in which 21 (49%) were non-fatal scenarios and 22 (51%) resulted in fatalities. Most of the non-fatal cases required medical intervention. Over recent years xylazine has emerged as an adulterant in recreational drugs, such as heroin or speedball (a cocaine and heroin mixture). From the 43 reported cases, 17 (40%) were associated with the use of xylazine as an adulterant of drugs of abuse. Its chronic use is reported to be associated with physical deterioration and skin ulceration. Literature shows some similar pharmacologic effects between xylazine and heroin in humans. These similar pharmacologic effects may create synergistic toxic effects in humans. Therefore, fatalities among drug users may increase due to the use of xylazine as an adulterant. Xylazine alone has proven harmful to humans and even more when it is combined with drugs of abuse. A comprehensive review of the literature of non fatal and fatal xylazine intoxication cases including those in which the substance was used as adulterant is presented, in order to increase the awareness in the forensic community, law enforcement, and public health agencies. PMID- 24769344 TI - Particles internalization, oxidative stress, apoptosis and pro-inflammatory cytokines in alveolar macrophages exposed to cement dust. AB - Exposure to cement dust is one of the most common occupational dust exposures worldwide, but the mechanism of toxicity has not been fully elucidated. Cement dust (N) and clinker (C) samples collected from Nigeria and another sample of cement dust (U) collected from USA were evaluated using alveolar macrophage (NR8383) cell culture to determine the contribution of different sources of cement dust in the severity of cement dust toxicity. Cement dust particles internalization and morphologic alterations using transmission electron microscopy (TEM), cytotoxicity, apoptotic cells induction, intracellular reactive oxygen species generation, glutathione reduction, TNF-alpha, IL-1beta, and CINC-3 secretion in alveolar macrophages (NR8383) exposed to cement dust and clinker samples were determined. Particles were internalized into the cytoplasmic vacuoles, with cells exposed to U showing increased cell membrane blebbing. Also, NR8383 exposed to U show more significant ROS generation, apoptotic cells induction and decreased glutathione. Interleukin-1beta and TNF-alpha secretion were significantly more in cells exposed to both cement dust samples compared with clinker, while CINC-3 secretion was significantly more in cells exposed to clinker (p < 0.05). Endocytosis, oxidative stress induced-apoptosis and induction of pro-inflammatory cytokines may be key mechanisms of cement dust immunotoxicity in the lung and toxicity may be factory dependent. PMID- 24769345 TI - Fear shapes information acquisition in decisions from experience. AB - Before making decisions, people often need to explore their environment to learn about initially uncertain outcomes. To date, it remains unknown to what extent a person's emotional state shapes exploration in such decisions from experience. It has been suggested that fear regulates people's informational interface with the external world through its physiological expression (e.g., a more effective sampling of the visual field from widened eyes). We investigated whether-as suggested by appraisal tendency theories of emotions-the "emotional feeling" of fear triggers analogous changes in exploration, in terms of increased information sampling in decisions from experience. In two studies, one with naturally occurring emotional states and one with induced emotional states, we found that fearful (relative to happy) people sampled substantially more information before making a final choice. These different degrees of exploration influenced the experience of rarity and, in turn, final choices. We discuss the extent to which increased information acquisition is adaptive. PMID- 24769346 TI - Synthesis, cytotoxic study and docking based multidrug resistance modulator potential analysis of 2-(9-oxoacridin-10(9H)-yl)-N-phenyl acetamides. AB - The present study describes the synthesis of fifteen 2-(9-oxoacridin-10(9H)-yl)-N phenyl acetamide derivatives (13a-o) through condensation of 2-chloro-N-phenyl acetamides (12a-o) with acridone molecule (10). All the synthesized compounds were screened for their anti-cancer activity against three diverse cell lines including breast (MCF-7), cervical (HeLa) and lung adenocarcinoma (A-549) employing standard MTT assay. Among synthesized molecules, 13k and 13l showed good cytotoxicity activity against considered three cancer cell lines. Additionally, in silico studies of multidrug resistance modulator (MDR) effects of these compounds was performed by docking simulation in the ATP binding site of P-gp. The results of docking simulation displayed important interactions of these molecules in the active site of this protein and predicted their MDR modulator behavior. PMID- 24769347 TI - Design, synthesis, and evaluation of novel fluoroquinolone-flavonoid hybrids as potent antibiotics against drug-resistant microorganisms. AB - Based on a rationally conceived pharmacophore model to build a multi-target bacterial topoisomerase inhibitor, twenty-one fluoroquinolone-flavonoid hybrids were synthesized. Some obtained hybrids show excellent antibacterial activity against drug-resistant microorganisms with narigenin-ciprofloxacin being the most active, showing 8, 43, 23 and 88 times better activity than ciprofloxacin against Escherichia coli ATCC 35218, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 25923 and Candida albicans ATCC 90873, respectively. Drug accumulation and DNA supercoiling assays of two active analogues revealed potent inhibition of both the DNA gyrase and efflux pump, confirming the desired dual mode of action. Molecular docking study disclosed that the introduced flavonoid moiety not only provides several additional interactions but also does not disturb the binding mode of the floxacin moiety. Our data also demonstrated that development of antifungals is possible from fluoroquinolones modified at C-7 position. PMID- 24769348 TI - New indolylarylsulfones as highly potent and broad spectrum HIV-1 non-nucleoside reverse transcriptase inhibitors. AB - New indolylarylsulfone HIV-1 NNRTIs were synthesized to evaluate unexplored substitutions of the benzyl/phenylethyl group linked at the indole-2-carboxamide. Against the NL4-3 HIV-1 WT strain, 17 out 20 compounds were superior to NVP and EFV. Several compounds inhibited the K103N HIV-1 mutant strain at nanomolar concentration and were superior to EFV. Some derivatives were superior to EFV against the Y181C and L100I HIV-1 mutant strains. Against the NL4-3 HIV-1 strain, the enantiomers 24 and 25 showed small differences of activity. In contrast, 24 turned out significantly more potent than 25 against the whole panel of mutant HIV-1 strains. The docking studies suggested that the difference in the observed inhibitory activities of 24 and 25 against the K03N mutation could be due to a kinetic rather than affinity differences. PMID- 24769349 TI - Discovery of novel diarylpyrimidines as potent HIV NNRTIs via a structure-guided core-refining approach. AB - Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel DAPY derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities. Among them, 16 compounds significantly inhibited HIV-1 IIIB replication with EC50 values lower than 66 nM. Particularly, compound 7a was the most potent inhibitor against HIV-1 wild-type and double RT mutant HIV-1 strain K103N/Y181C, with an EC50 value of 2.5 nM (SI = 13,740) and 0.33 MUM (SI = 107), respectively. Unexpectedly, compound 8c was found to show moderate anti-HIV-2 potency (EC50 = 5.57 MUM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were also discussed in detail. PMID- 24769350 TI - Polycyclic propargylamine and acetylene derivatives as multifunctional neuroprotective agents. AB - The aim of this study was to design drug-like molecules with multiple neuroprotective mechanisms which would ultimately inhibit N-methyl-D-aspartate (NMDA) receptors, block L-type voltage gated calcium channels (VGCC) and inhibit apoptotic processes as well as the monoamine oxidase-B (MAO-B) enzyme in the central nervous system. These types of compounds may act as neuroprotective and symptomatic drugs for disorders such as Alzheimer's and Parkinson's disease. In designing the compounds we focused on the structures of rasagiline and selegiline, two well known MAO-B inhibitors and proposed neuroprotective agents. Based on this consideration, the compounds synthesised all contain the propargylamine functional group of rasagiline and selegiline or a derivative thereof, conjugated to various polycyclic cage moieties. Being non-polar, these polycyclic moieties have been shown to aid in the transport of conjugated compounds across the blood-brain barrier, as well as cell membranes and have secondary positive neuroprotective effects. All novel synthesised polycyclic derivatives proved to have significant anti-apoptotic activity (p < 0.05) which was comparable to the positive control, selegiline. Four compounds (12, 15 and 16) showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18% to 59% in micromolar concentrations and compared favourably to the reference compounds. In the MAO-B assay, 8-phenyl-ethynyl-8 hydroxypentacycloundecane (10), exhibited MAO-B inhibition of 73.32% at 300 MUM. This compound also reduced the percentage of apoptotic cells by as much as 40% when compared to the control experiments. PMID- 24769351 TI - Synthesis of new N-acryl-1-amino-2-phenylethanol and N-acyl-1-amino-3 aryloxypropanols and evaluation of their antihyperlipidemic, LDL-oxidation and antioxidant activity. AB - As a part of our drug discovery program, we identified an alkaloidal amide i.e. Aegeline (V) isolated from the leaves of Aegle marmelos as a dual acting agent (antihyperlipidemic and antihyperglycemic). In continuation of this program, we synthesized new N-acyl-1-amino-2-alcohols (N-acrylated-1-amino-2-phenylethanol and N-acylated-1-amino-3-aryloxypropanols) via Ritter reaction and screened for their in-vivo antihyperlipdemic activity in Triton induced hyperlipidemia model, LDL-oxidation and antioxidant activity. Compounds 3, 11 and 13 showed good antihyperlipidemic activity, LDL-oxidation as well as antioxidant activity and comparable activity with marketed antidyslipidemic drug. PMID- 24769352 TI - Synthesis of stable aromatic and heteroaromatic sulfonyl-amidoximes and evaluation of their antioxidant and lipid peroxidation activity. AB - We describe herein the synthesis of stable aromatic and heteroaromatic sulfonyl amidoximes, from the reaction of amidoximes with the corresponding sulfonyl chlorides, in low to excellent yields. Evaluation of their antioxidant activity has shown that 17 out of 28 compounds highly compete DMSO for hydroxyl radicals, while five of them inhibit lipid peroxidation. Combining the reducing and anti lipid peroxidation ability it seems that compounds 13 and 31 could be used as lead molecules. PMID- 24769353 TI - Zinc finger E-box-binding homeobox 2 (ZEB2) regulated by miR-200b contributes to multi-drug resistance of small cell lung cancer. AB - Zinc finger E-box-binding homeobox 2 (ZEB2) was closely related to the oncogenesis, development and response to chemotherapy of cancer. However, its biological functions in small cell lung cancer (SCLC) remain unknown. The aim of this study is to investigate the roles of ZEB2 in chemoresistance of SCLC and its possible molecular mechanism. Expression of ZEB2 was examined in sixty-eight cases of SCLC tissues by immunohistochemistry. Knockdown of ZEB2 was carried out in SCLC multidrug resistant cells (H69AR) to assess its influence on chemoresistance. The results showed that ZEB2 was expressed in 23.5% (16/68) of SCLC. Overexpression of ZEB2 was associated with the poor pathologic stage of SCLC (P < 0.001 by the Fisher's Exact Test) and the shorter survival time (by the Kaplan-Meier method). Inhibition of ZEB2 expression using small interfering RNA in H69AR cells sensitized cancer cells to chemotherapeutic drugs through increasing drug-induced cell apoptosis accompanied with S phase arrest. In silico analysis demonstrated that there are complementary binding sites between miR-200b and ZEB2 3'-UTR, and identified miR-200b as a potential regulator of ZEB2. We found that miR-200b was down-regulated in the resistant cells and enforced expression of miR-200b by miRNA mimics increased cell sensitivity. Overexpression of miR-200b led to the downregulation of ZEB2 at protein level. Luciferase reporter gene assay showed that 3'UTR ZEB2 activity was regulated by miR-200b. Our results suggest that ZEB2 modulates drug resistance and is regulated by miR 200b. All findings provide insight into the ZEB2 signaling mechanism and ZEB2 may be a potentially novel target for multi-drug resistance in SCLC. PMID- 24769354 TI - The HIF1A rs2057482 polymorphism is associated with risk of developing premature coronary artery disease and with some metabolic and cardiovascular risk factors. The Genetics of Atherosclerotic Disease (GEA) Mexican Study. AB - The aim of the present study was to establish the role of HIF1A gene polymorphisms in the risk of developing premature coronary artery disease (CAD) in a well-characterized clinical cohort. Three polymorphisms in HIF1A (rs11549465, rs11549467, rs2057482) gene were genotyped in 949 patients with premature CAD, and 676 healthy controls (with negative calcium score by computed tomography). Under a dominant model adjusted for age, visceral to subcutaneous adipose tissue (VAT/SAT) ratio, hypertension, type 2 diabetes mellitus (T2DM), HDL-C levels, hypercholesterolemia and hypertriglyceridemia, the rs2057482 T allele was associated with decreased risk of premature CAD when compared to healthy controls (OR = 0.616, P(dom) = 0.020). The effect of the studied polymorphisms on various metabolic parameters and cardiovascular risk factors was explored. In this analysis, the rs2057482 T allele was associated with decreased risk of obesity, central obesity, hypertension, hypercholesterolemia, hypertriglyceridemia and increased risk of T2DM. Under a dominant model adjusted by age, the HIF1A rs2057482 T polymorphism was associated with high VAT/SAT ratio (P = 0.009) and HDL-C levels (P = 0.04) in healthy controls. The results suggest that HIF1A rs2057482 polymorphism is involved in the risk of developing CAD and is associated with some metabolic parameters and cardiovascular risk factors. PMID- 24769355 TI - Myeloid-derived suppressor cells are increased in frequency but not maximally suppressive in peripheral blood of Type 1 Diabetes Mellitus patients. AB - Type 1 Diabetes Mellitus (T1D) results from the destruction of insulin-producing beta cells in the pancreas by autoreactive T cells. Myeloid derived suppressor cells (MDSCs) are a recently identified immune cell subset that down-regulate T cells. Whether defects in MDSC numbers or function may contribute to T1D pathogenesis is not known. We report here that MDSCs are unexpectedly enriched in peripheral blood of both mice and patients with autoimmune diabetes. Peripheral blood MDSCs from T1D patients suppressed T cell proliferation in a contact dependent manner; however, suppressive function could be enhanced with in vitro cytokine induction. These findings suggest that native T1D MDSCs are not maximally suppressive and that strategies to promote MDSC suppressive function may be effective in preventing or treating T1D. PMID- 24769356 TI - Disclosing adult wrongdoing: maltreated and non-maltreated children's expectations and preferences. AB - Little is known about the process by which children disclose adult wrongdoing, a topic of considerable debate and controversy. In the current study, we investigated children's evaluations of disclosing adult wrongdoing by focusing on children's preferences for particular disclosure recipients and perceptions of the consequences of disclosure in hypothetical vignettes. We tested whether children thought that disclosure recipients would believe a story child as a truth teller and what actions the recipients would take against the "instigator" who committed the transgression. Maltreated and non-maltreated 4- to 9-year-olds (N=235) responded to questions about vignettes that described a parent's or stranger's transgression. Older children preferred caregiver recipients over police officer recipients when disclosing a parent's transgression but not a stranger's transgression. Maltreated children's preference for caregiver recipients over police officer recipients developed more gradually than that of non-maltreated children. Older children expected disclosure recipients to be more skeptical of the story child's account, and older children and maltreated children expected disclosure recipients to intervene formally less often when a parent, rather than a stranger, was the instigator. Results contribute to understanding vulnerable children's development and highlight the developmental, experiential, and socio-contextual factors underlying children's disclosure patterns. PMID- 24769357 TI - Differential phosphorylation of Akt1 and Akt2 by protein kinase CK2 may account for isoform specific functions. AB - Akt (also known as PKB) is a survival kinase frequently up-regulated in cancer; three isoforms of Akt exist, and among them Akt1 and Akt2 are the most widely and highly expressed. They share the same structure and activation mechanism and have many overlapping functions; nevertheless isoform-specific roles and substrates have been reported, which are expected to rely on sequence diversities. In particular, a special role in differentiating Akt1 and Akt2 isoforms has been assigned to the linker region, a short segment between the PH and the catalytic domains. We have previously found that a residue in the linker region (Ser129) is directly phosphorylated by protein kinase CK2 in Akt1; the phosphorylation of the homologous residue in Akt2 (Ser131) has never been analyzed. Here we show that Akt2, endogenously or ectopically expressed in different cell lines, is not phosphorylated on Ser131 by CK2, while in vitro recombinant Akt2 is a CK2 substrate. These data support the hypothesis that in vivo a steric hindrance occurs which prevents the access to the CK2 site. Additionally, we have found that Ser129 phosphorylation is involved in the recognition of the Akt1-specific substrate palladin; this observation provides an explanation of why Akt2, lacking Ser131 phosphorylation in the linker region, has a low efficiency in targeting palladin. CK2-dependent phosphorylation is therefore a crucial event which, discriminating between Akt1 and Akt2, can account for different substrate specificities, and, more in general, for fine tuning of Akt activity in the control of isoform-dependent processes. PMID- 24769359 TI - Molecular modelling, spectroscopic characterization and biological studies of tetraazamacrocyclic metal complexes. AB - Macrocyclic complexes of the type [MLX]X2; where L is (C30H28N4), a macrocyclic ligand, M=Cr(III) and Fe(III) and X=Cl-, CH3COO- or NO3-, have been synthesized by template condensation reaction of 1,8-diaminonaphthalene and acetylacetone in the presence of trivalent metal salts in a methanolic medium. The complexes have been formulated as [MLX]X2 due to 1:2 electrolytic nature of these complexes. The complexes have been characterized with the help of elemental analyses, molar conductance measurements, magnetic susceptibility measurements, electronic, infrared, far infrared, Mass spectral studies and molecular modelling. Molecular weight of these complexes indicates their monomeric nature. On the basis of all these studies, a five coordinated square pyramidal geometry has been proposed for all these complexes. These metal complexes have also been screened for their in vitro antimicrobial activities. PMID- 24769358 TI - Association of global DNA methylation and global DNA hydroxymethylation with metals and other exposures in human blood DNA samples. AB - BACKGROUND: The association between human blood DNA global methylation and global hydroxymethylation has not been evaluated in population-based studies. No studies have evaluated environmental determinants of global DNA hydroxymethylation, including exposure to metals. OBJECTIVE: We evaluated the association between global DNA methylation and global DNA hydroxymethylation in 48 Strong Heart Study participants for which selected metals had been measured in urine at baseline and DNA was available from 1989-1991 (visit 1) and 1998-1999 (visit 3). METHODS: We measured the percentage of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5 hmC) in samples using capture and detection antibodies followed by colorimetric quantification. We explored the association of participant characteristics (i.e., age, adiposity, smoking, and metal exposure) with both global DNA methylation and global DNA hydroxymethylation. RESULTS: The Spearman's correlation coefficient for 5-mC and 5-hmC levels was 0.32 (p = 0.03) at visit 1 and 0.54 (p < 0.001) at visit 3. Trends for both epigenetic modifications were consistent across potential determinants. In cross-sectional analyses, the odds ratios of methylated and hydroxymethylated DNA were 1.56 (95% CI: 0.95, 2.57) and 1.76 (95% CI: 1.07, 2.88), respectively, for the comparison of participants above and below the median percentage of dimethylarsinate. The corresponding odds ratios were 1.64 (95% CI: 1.02, 2.65) and 1.16 (95% CI: 0.70, 1.94), respectively, for the comparison of participants above and below the median cadmium level. Arsenic exposure and metabolism were consistently associated with both epigenetic markers in cross-sectional and prospective analyses. The positive correlation of 5-mC and 5-hmC levels was confirmed in an independent study population. CONCLUSIONS: Our findings support that both epigenetic measures are related at the population level. The consistent trends in the associations between these two epigenetic modifications and the characteristics evaluated, especially arsenic exposure and metabolism, suggest the need for understanding which of the two measures is a better biomarker for environmental epigenetic effects in future large-scale epidemiologic studies. PMID- 24769360 TI - Lattice dynamical investigations for Raman and infrared frequencies of Te doped Bi1-xTa1-xTe2xO4; 095%) of ILV2-specific targeted integration via SRR circumvents the need for a deficiency in non-homologous end joining (NHEJ) pathway in the recipient strain. Unlike the split-marker technique, which is particularly suitable for targeted gene replacement, the SRR strategy should prove useful for promoter analyses, gene tagging and/or complementation analyses in filamentous fungi. PMID- 24769369 TI - Understanding mRNA trafficking: are we there yet? AB - There has been unexpected insight into the part that an mRNA plays in the function of the protein it encodes gleaned from visualizing where an mRNA resides in the cytoplasm. mRNAs can localize to distal domains of the cytoplasm in cells with vast cytoplasmic domains such as the central and peripheral nervous system or oocytes and embryos, but can localize within other somatic cell types as well. Localized translation of such mRNAs in the nervous system can supply distant cellular structures, such as synapses, with required proteins for proper function or development. Similarly, the spatially and temporally localized translation of mRNA early in development spatially segregates developmental cues within the egg to facilitate regional cell fate specification and body plan establishment. All mRNAs do not arrive at these sites of localization, an indication that the mechanisms to get these mRNAs to their destination are specially programmed into the mRNA sequence. Molecular recognition of mRNAs to be localized and the putative connection between the RNA and the cytoskeleton for trafficking to their destination are critical steps in the process. In this review I will present the recent years' progress in understanding these two steps in the mRNA localization process at the molecular level, which is among the most critical determinants for localized translation, since only mRNAs that reach the destination can be locally translated. PMID- 24769368 TI - Oestrogen receptor-alpha regulates non-canonical Hedgehog-signalling in the mammary gland. AB - Mesenchymal dysplasia (mes) mice harbour a truncation in the C-terminal region of the Hh-ligand receptor, Patched-1 (mPtch1). While the mes variant of mPtch1 binds to Hh-ligands with an affinity similar to that of wild type mPtch1 and appears to normally regulate canonical Hh-signalling via smoothened, the mes mutation causes, among other non-lethal defects, a block to mammary ductal elongation at puberty. We demonstrated previously Hh-signalling induces the activation of Erk1/2 and c-src independently of its control of smo activity. Furthermore, mammary epithelial cell-directed expression of an activated allele of c-src rescued the block to ductal elongation in mes mice, albeit with delayed kinetics. Given that this rescue was accompanied by an induction in estrogen receptor-alpha (ERalpha) expression and that complex regulatory interactions between ERalpha and c-src are required for normal mammary gland development, it was hypothesized that expression of ERalpha would also overcome the block to mammary ductal elongation at puberty in the mes mouse. We demonstrate here that conditional expression of ERalpha in luminal mammary epithelial cells on the mes background facilitates ductal morphogenesis with kinetics similar to that of the MMTV-c-src(Act) mice. We demonstrate further that Erk1/2 is activated in primary mammary epithelial cells by Shh-ligand and that this activation is blocked by the inhibitor of c src, PP2, is partially blocked by the ERalpha inhibitor, ICI 182780 but is not blocked by the smo-inhibitor, SANT-1. These data reveal an apparent Hh-signalling cascade operating through c-src and ERalpha that is required for mammary gland morphogenesis at puberty. PMID- 24769370 TI - From endosomes to the trans-Golgi network. AB - The retrograde trafficking from endosomes to the trans-Golgi network (TGN) is one of the major endocytic pathways to divert proteins and lipids away from lysosomal degradation. Retrograde transported cargos enter the TGN via two itineraries from either the early endosome/recycling endosome or the late endosome and involve various machinery components such as retromer, sorting nexins, clathrin, small GTPases, tethering factors and SNAREs. Recently, the pathway has been recognized for its role in signal transduction, physiology and pathogenesis of human diseases. PMID- 24769371 TI - Association between mechanical ventilation and neurodevelopmental disorders in a nationwide cohort of extremely low birth weight infants. AB - Mechanical ventilation for preterm infants independently contributes to poor neurodevelopmental performance. However, few studies have investigated the association between the duration of mechanical ventilation and the risk for various developmental disorders in extremely low birth weight (ELBW) (<1000g) infants. Using a large nationwide database, we did a 10-year retrospective follow up study to explore the effect of mechanical ventilation on the incidence of cerebral palsy (CP), autism spectrum disorder (ASD), intellectual disability (ID), and attention-deficit/hyperactivity disorder (ADHD) in ELBW infants born between 1998 and 2001. Seven hundred twenty-eight ELBW infants without diagnoses of brain insults or focal brain lesions in the initial hospital stay were identified and divided into three groups (days on ventilator: ?2, 3-14, ?15 days). After adjusting for demographic and medical factors, the infants in the ?15 days group had higher risks for CP (adjusted hazard ratio: 2.66; 95% confidence interval: 1.50-4.59; p<0.001) and ADHD (adjusted hazard ratio: 1.95; 95% confidence interval: 1.02-3.76; p<0.05), than did infants in the ?2 days group. The risk for ASD or ID was not significantly different between the three groups. We conclude that mechanical ventilation for ?15 days increased the risk for CP and ADHD in ELBW infants even without significant neonatal brain damage. Developing a brain-protective respiratory support strategy in response to real time cerebral hemodynamic and oxygenation changes has the potential to improve neurodevelopmental outcomes in ELBW infants. PMID- 24769372 TI - Atlas aims to show possible environmental effects on UK health. PMID- 24769373 TI - Liquid chromatography/electrospray ionisation-tandem mass spectrometry quantification of GM2 gangliosides in human peripheral cells and plasma. AB - GM2 gangliosidosis is a group of inherited neurodegenerative disorders resulting primarily from the excessive accumulation of GM2 gangliosides (GM2) in neuronal cells. As biomarkers for categorising patients and monitoring the effectiveness of developing therapies are lacking for this group of disorders, we sought to develop methodology to quantify GM2 levels in more readily attainable patient samples such as plasma, leukocytes, and cultured skin fibroblasts. Following organic extraction, gangliosides were partitioned into the aqueous phase and isolated using C18 solid-phase extraction columns. Relative quantification of three species of GM2 was achieved using LC/ESI-MS/MS with d35GM1 18:1/18:0 as an internal standard. The assay was linear over the biological range, and all GM2 gangliosidosis patients were demarcated from controls by elevated GM2 in cultured skin fibroblast extracts. However, in leukocytes only some molecular species could be used for differentiation and in plasma only one was informative. A reduction in GM2 was easily detected in patient skin fibroblasts after a short treatment with media from normal cells enriched in secreted beta-hexosaminidase. This method may show promise for measuring the effectiveness of experimental therapies for GM2 gangliosidosis by allowing quantification of a reduction in the primary storage burden. PMID- 24769374 TI - Nucleosome acetylation sequencing to study the establishment of chromatin acetylation. AB - The establishment of posttranslational chromatin modifications is a major mechanism for regulating how genomic DNA is utilized. However, current in vitro chromatin assays do not monitor histone modifications at individual nucleosomes. Here we describe a strategy, nucleosome acetylation sequencing, that allows us to read the amount of modification at each nucleosome. In this approach, a bead bound trinucleosome substrate is enzymatically acetylated with radiolabeled acetyl CoA by the SAGA complex from Saccharomyces cerevisae. The product is digested by restriction enzymes that cut at unique sites between the nucleosomes and then counted to quantify the extent of acetylation at each nucleosomal site. We find that we can sensitively, specifically, and reproducibly follow enzyme mediated nucleosome acetylation. Applying this strategy, when acetylation proceeds extensively, its distribution across nucleosomes is relatively uniform. However, when substrates are used that contain nucleosomes mutated at the major sites of SAGA-mediated acetylation, or that are studied under initial rate conditions, changes in the acetylation distribution can be observed. Nucleosome acetylation sequencing should be applicable to analyzing a wide range of modifications. Additionally, because our trinucleosomes synthesis strategy is highly modular and efficient, it can be used to generate nucleosomal systems in which nucleosome composition differs across the array. PMID- 24769375 TI - Single tag for total carbohydrate analysis. AB - Anthranilic acid (2-aminobenzoic acid, 2-AA) has the remarkable property of reacting rapidly with every type of reducing carbohydrate. Reactivity of 2-AA with carbohydrates in aqueous solutions surpasses all other tags reported to date. This unique capability is attributed to the strategically located -COOH which accelerates Schiff base formation. Monosaccharides, oligosaccharides (N-, O , and lipid linked and glycans in secretory fluids), glycosaminoglycans, and polysaccharides can be easily labeled with 2-AA. With 2-AA, labeling is simple in aqueous solutions containing proteins, peptides, buffer salts, and other ingredients (e.g., PNGase F, glycosidase, and transferase reaction mixtures). In contrast, other tags require relatively pure glycans for labeling in anhydrous dimethyl sulfoxide-acetic acid medium. Acidic conditions are known to cause desialylation, thus requiring a great deal of attention to sample preparation. Simpler labeling is achieved with 2-AA within 30-60 min in mild acetate-borate buffered solution. 2-AA provides the highest sensitivity and resolution in chromatographic methods for carbohydrate analysis in a simple manner. Additionally, 2-AA is uniquely qualified for quantitative analysis by mass spectrometry in the negative mode. Analyses of 2-AA-labeled carbohydrates by electrophoresis and other techniques have been reported. Examples cited here demonstrate that 2-AA is the universal tag for total carbohydrate analysis. PMID- 24769376 TI - Smart watch accelerometry for analysis and diagnosis of tremor. AB - BACKGROUND: Distinguishing the postural re-emergent tremor of Parkinson disease from essential tremor can be difficult clinically. Use of accelerometry to aid diagnosis is limited to laboratory settings. We sought to record and differentiate these tremors using a smart watch device in an outpatient clinic. NEW METHOD: 41 patients were enrolled. Recordings were made with a smart watch device on the predominantly affected hand (all patients), and simultaneously with an analog accelerometer (10 patients) with hands at rest and outstretched. Tremor peak frequency, peak power, and power of the first four harmonics was calculated and compared between the two devices. Mean power at the first four harmonics was calculated and used to classify tremor as parkinsonian or essential. Test characteristics were calculated to compare the device and clinical diagnoses. RESULTS: Mean harmonic peak power was both highly sensitive and specific for distinction of Parkinson disease postural tremor from essential tremor with an optimal threshold for our sample (sensitivity 90.9%, 95% CI 58.7-99.8%; specificity 100%, 95% CI 76.8-100%; Cohen's kappa=0.91, SE=0.08). COMPARISON WITH EXISTING METHODS: The smart watch and analog devices had nearly perfect concordance of peak frequency and proportional harmonic power. The smart watch recordings in clinic took 3-6 min. CONCLUSIONS: A smart watch device can provide accurate and diagnostically relevant information about postural tremor. Its portability and ease of use could help translate such techniques into routine clinic use or to the community. PMID- 24769377 TI - Effects of Lactobacillus rhamnosus on allergic march model by suppressing Th2, Th17, and TSLP responses via CD4(+)CD25(+)Foxp3(+) Tregs. AB - Allergic march (AM) is characterized by the progression of clinical signs of atopic dermatitis (AD) to allergic asthma or rhinitis, but its pathogenesis is not completely understood. We developed mouse model of AM with three 1-week exposures (separated by 2-week interval) to an OVA or saline (control) followed by OVA challenge. The development of AM was confirmed by phenotypes of AD and allergic asthma. Increases in IL-4, IL-17, and thymic stromal lymphopoietin (TSLP) responses were associated with the progression of AM, and these responses were suppressed by treatment with Lcr35. Moreover, Lcr35 treatment led to an increase in the number of CD4(+)CD25(+) Foxp3(+) regulatory T (Treg) cells in the mesenteric lymph nodes (MLNs) of AM mice. In conclusion, the oral application of Lcr35 prevented the development of AM in this model by suppressing Th2, Th17, and TSLP responses via a mechanism that may involve CD4(+)CD25(+)Foxp3(+) Tregs in MLNs. PMID- 24769379 TI - A new pyrene-based Schiff-base: a selective colorimetric and fluorescent chemosensor for detection of Cu(II) and Fe(III). AB - A new receptor 1 was prepared, for the detection of Cu2+ and Fe3+ in solutions as a colorimetric and fluorescent sensor, respectively. Receptor 1 shows highly selective and sensitive recognition toward Cu2+ and Fe3+ by naked eye UV-Vis and fluorescent color changes in aqueous solution (DMSO/H2O=8/2, v/v), respectively. The sensitivity toward Cu2+ or Fe3+ was not interfered with by the presence of other metal ions such as Mg2+, Cd2+, Ag+, Zn2+, Ni2+, Co2+, Mn2+, Cr3+, Ca2+, Na+, Pb2+, K+, Fe2+, Li+ and Hg2+ ions. Receptor 1 can be used for semi quantitative recognition of Cu2+ ions at ppm level. The fluorescence microscopy experiments showed that the receptor is efficient for detection of Fe3+ in vitro, developing a good image of the biological organelles. PMID- 24769380 TI - Incorporation of flow injection analysis with dual-wavelength overlapping resonance Rayleigh scattering for rapid determination of malachite green and its metabolite in fish. AB - A flow injection analysis (FIA) system combined with dual-wavelength overlapping resonance Rayleigh scattering (DWO-RRS) has been established and validated for rapid determination of malachite green (MG) and its metabolite in fish samples. Under experimental condition, MG would react with Erythrosin (Ery) to form ion association complexes, resulting in the occurrence of two RRS peaks and a dramatic enhancement of RRS intensity. The maximum RRS peaks were located at 286 nm and 337 nm. It is noted that the increments of both of these two peaks were proportional to the concentration of MG. The detection limit of DWO-RRS was 1.5 ng/mL, which was comparable to several reported methods. Moreover, the results of real sample analysis exhibited an acceptable recovery between 97.5% and 103.6%, indicating that the method had good reproducibility. PMID- 24769378 TI - Plasmacytoid dendritic cells of the gut: relevance to immunity and pathology. AB - Plasmacytoid dendritic cells (pDCs) are bone marrow-derived immune cells with the ability to express copious amounts of type I and III interferon (IFN) and can differentiate into antigen-presenting dendritic cells as a result of stimulation by pathogen-derived nucleic acid. These powerful combined functionalities allow pDCs to bridge the innate and adaptive immune systems resulting in a concerted pathogen response. The contribution of pDCs to gastrointestinal immunity is only now being elucidated and is proving to be a critical component in systemic immunity. This review will explore the immunology of pDCs and will discuss their involvement in human disease and tolerance with an emphasis on those in the gastrointestinal lymphoid tissue. PMID- 24769381 TI - Study of inclusion complex between 2,6-dinitrobenzoic acid and beta-cyclodextrin by 1H NMR, 2D 1H NMR (ROESY), FT-IR, XRD, SEM and photophysical methods. AB - The formation of host-guest inclusion complex of 2,6-dinitrobenzoic acid (2,6 DNB) with nano-hydrophobic cavity of beta-cyclodextrin (beta-CD) in solution phase has been studied by UV-visible spectroscopy and electrochemical analysis (cyclic voltammetry, CV). The effect of acid-base concentrations of 2,6-DNB has been studied in presence and absence of beta-CD to determination for the ground state acidity constant (pKa). The binding constant of inclusion complex at 303 K was calculated using Benesi-Hildebrand plot and thermodynamic parameter (DeltaG) was also calculated. The solid inclusion complex formation between beta-CD and 2,6-DNB was confirmed by 1H NMR, 2D 1H NMR (ROESY), FT-IR, XRD and SEM analysis. A schematic representation of this inclusion process was proposed by molecular docking studies using patch dock server. PMID- 24769382 TI - Synthesis of silver nanoparticles from Melia dubia leaf extract and their in vitro anticancer activity. AB - Silver nanoparticles have a significant role in the pharmaceutical science. Especially, silver nanoparticles synthesized by the plant extracts lead a significant role in biological activities such as antimicrobial, antioxidant and anticancer. Keeping this in mind, the present work investigation has been taken up with the synthesized silver nanoparticles using the plant extract of Melia dubia and it characterizes by using UV-visible, XRD and SEM-EDS. The effect of the silver nanoparticles on human breast cancer (KB) cell line has been tested. Silver nanoparticles showed remarkable cytotoxicity activity against KB cell line with evidence of high therapeutic index value are the results are discussed. PMID- 24769383 TI - Solvent effect on the relative quantum yield and fluorescence quenching of 2DAM. AB - The relative quantum yield of diethyl 2-acetamido-2-((3-oxo-3H-benzo[f]chromen-1 yl)methyl)malonate [2DAM] is estimated using single point method with quinine sulfate as standard reference. The quantum yield varies between 0.1161 and 0.3181 depending on the nature of the solvent. The rates of radiative and non radiative decay constants are also calculated. The fluorescence quenching of [2DAM] by aniline is studied at room temperature, by steady state, in five different solvents namely acetonitrile (AN), 1,4 dioxane (DX), 1,2 dichloroethane (DCE), tetrahydrofuran (THF) and toluene (TOL), in order to explore various possible quenching mechanisms. The experimental results show a positive deviation in Stern Volmer plots for all solvents. Various parameters for the quenching process are determined by ground state complex, sphere of action static quenching model and finite sink approximation model. The magnitudes of these rate parameters indicate that positive deviation in the Stern Volmer (SV) plot is due to both static and dynamic processes. Further, finite sink approximation model is used to check whether these bimolecular reactions were diffusion limited or not. The values of distance parameter R' and diffusion co efficient D are determined and then compared with the values of encounter distance R and diffusion coefficient D calculated using Stokes-Einstein equation. PMID- 24769384 TI - Plasmon-assisted degradation of methylene blue with Ag/AgCl/montmorillonite nanocomposite under visible light. AB - Metal-semiconductor compounds, such as Ag/AgX (X=Cl, Br, I), enable visible light absorption and separation of photogenerated electron-hole through surface plasmon resonance (SPR) effect. However, the electron-hole generated and separated by light are vulnerable in Ag/AgX phase because of the occurrence of secondary recombined. In order to more effectively utilize the SPR photocatalytic effect, nanoparticles are located in a matrix. In this article, Ag/AgCl nanoparticles were synthesized in montmorillonite (MMT) matrix using dispersion method and light irradiation. The structure, composition and optical properties of such material were investigated by transmission electron microscopy (TEM), UV-visible diffuse reflectance spectroscopy (UV-Vis DRS), X-ray diffraction (XRD) and FTIR. Powder X-ray diffraction showed intercalation of Ag/AgCl nanoparticles into the clay layers. The as-prepared plasmonic photocatalyst exhibited an enhanced and stable photoactivity for the degradation of methylene blue (MB) under visible light. The high activity was attributed to the surface plasmon resonance (SPR) exhibited by Ag nanoparticles on the surface of AgCl. The detection of reactive species by radical scavengers displays that O2- and OH- are the main reactive species for the degradation of MB under visible light irradiation. The studies showed that 20 min illumination under visible light can complete degradation of methylene blue (MB), and indicate a high stability of photocatalytic degradation. The mechanism of separation of the photo-generated electrons and holes at the Ag/AgCl-MMT nanocomposite was discussed. PMID- 24769385 TI - A split-mouth randomized clinical trial of conventional and heavy flowable composites in class II restorations. AB - OBJECTIVE: The aim of this study was to evaluate the 2-year clinical performance of class II restorations made with a composite resin with two different viscosities. METHODS: 47 patients received two class II restorations (n=94), one made with GrandioSO (conventional viscosity - CV), and the other with GrandioSO Heavy Flow (flowable viscosity - FV), subjecting both materials to the same clinical conditions. The self-etching adhesive Futurabond M was used for all restorations. The composites were inserted using the incremental technique. The restorations were evaluated using the modified USPHS criteria according to the periods: baseline, 6 months, 1 year and 2 years after restorative procedures. RESULTS: After 24 months, 40 patients attended the recall and 78 restorations were evaluated. In all periods, no secondary caries was observed. After 6 months, there were slightly overall changes of scores for most parameters. After 24 months, the higher number of changes from score Alfa to Bravo was observed for marginal discolouration (32.5% - CV and 39.5% - FV) and colour match (15% - CV and 31.6% - FV), followed by proximal contact (25% - CV and 23.7% - FV) and marginal adaptation (20% - CV and 21.1% - FV). For wear, surface texture and postoperative sensitivity the changes were very small. Just two restorations were lost during the 24-month follow up. Less than 5% of all restorations showed postoperative sensitivity. Chi-square test showed no significant differences between the two materials for all parameters analysed. CONCLUSION: After 2 years of clinical service, no significant differences were observed between GrandioSO conventional and GrandioSO Heavy Flow for the parameters analysed. Both materials provided acceptable clinical behaviour in class II restorations. CLINICAL SIGNIFICANCE: This study presents the possibility of using a flowable composite with high filler content, for performing class II restorations. PMID- 24769386 TI - Factors relating to usage patterns of amalgam and resin composite for posterior restorations--a prospective analysis. AB - OBJECTIVES: This study prospectively analyzed the use of amalgam and resin composite posterior restorations placed by general dentists in relation to dentist, patient and cavity factors. METHODS: One thousand posterior restorations placed by a representative sample of general dentists working in the Ministry of Health (MOH), Kuwait, during routine clinical practice were included. Information about the restorations was recorded using a survey questionnaire. Descriptive statistics and multivariate logistic regression analysis were used to determine the factors associated with the use of amalgam versus tooth coloured restoratives. RESULTS: Dentists chose amalgam for 30.8% of the 1000 restorations. Dentists with longer work experience (>15 years) were more likely to choose amalgam (OR=2.61, 95% CI=1.06, 6.40). Younger dentists (<=30 years) were less likely to choose amalgam (OR=0. 45, 95% CI=0.26, 0.77). Amalgam was more likely to be chosen for patients with poor oral hygiene (OR=1.58, 95% CI=1.08, 2.32) and a higher number (>=4) of restorations (OR=1.44, 95% CI=1.07, 1.94) with large cavity sizes (OR=6.33, 95% CI=3.88, 10.32). Tooth-coloured restorations were more likely to be chosen for cavities of smaller sizes. CONCLUSIONS: The use of resin composite materials as the dominant choice among dentists in Kuwait reflects the trend worldwide. Nevertheless, clinicians still find a use for amalgam in posterior load-bearing teeth and in the high-caries risk population. CLINICAL SIGNIFICANCE: The findings give insight into factors influencing material usage under different clinical conditions and provides information about the perceived deficiencies or shortcomings of resin composite materials in a general dental practice setting. This information can be useful for identifying perceived barriers to the usage of newer restorative materials and finding ways to overcome them. PMID- 24769387 TI - NDM carbapenemases in the United Kingdom: an analysis of the first 250 cases. AB - OBJECTIVES: Gram-negative bacteria with diverse carbapenemases, including New Delhi metallo-beta-lactamase (NDM) enzymes, have been increasingly recorded in the UK since 2007. We analysed patient data for NDM-positive isolates confirmed by the national reference laboratory from UK laboratories from February 2008 to July 2013. METHODS: Isolates resistant to carbapenems and with imipenem MICs reduced >=8-fold by EDTA were tested by PCR for genes encoding acquired class B carbapenemases. MICs were determined by BSAC agar dilution methodology. When requested by the sender, or when they were members of apparent clusters, NDM positive isolates were typed by variable number tandem repeat (VNTR) analysis or PFGE. Data provided by the sending laboratories were collated and reviewed. RESULTS: From February 2008 to July 2013 the reference laboratory confirmed 326 NDM-positive isolates from 250 patients, submitted by 83 laboratories. Most (85%, 213/250) patients were already hospitalized when the NDM-positive bacteria were detected, were male (61%, 152/250) and were aged >60 years (58%, 145/250). Travel history was available for only 40% of patients, but 52% (53/101) of these had documented healthcare contact within or travel to the Indian subcontinent. Most NDM-positive isolates (94%, 306/326) were Enterobacteriaceae with just 6% (20/326) non-fermenters; the predominant hosts were Klebsiella spp. (55%, 180/326) and Escherichia coli (25%, 80/326). Almost all NDM-positive isolates were resistant to multiple antibiotic classes, but 90% remained susceptible to colistin. CONCLUSIONS: Gram-negative bacteria with NDM carbapenemases are a growing challenge, especially for elderly hospitalized patients, including those with healthcare contact in the Indian subcontinent, and leave few therapeutic options. UK outbreaks remain rare and contained. PMID- 24769388 TI - Radioactivity in the Mediterranean flora of the Kastela Bay, Croatia. AB - This study refers to background activity concentrations of (238)U, (226)Ra, (232)Th, (208)Tl, (40)K, and (137)Cs in soil and plants of the Kastela Bay, Croatia and related plant-soil concentration ratios (CR's). Fourteen different Mediterranean plant species growing in natural conditions have been included and were divided into three major plant groups (grasses and herbs, shrub, tree). Radionuclide activity concentrations were determined by means of high resolution gamma-ray spectrometry. Soil parameters (pH, electrical conductivity, and organic matter content) were also analysed. CR ranges were within one order of magnitude for (40)K (10(-2)-10(-1)), (238)U, and (226)Ra (10(-3)-10(-2)), and two orders of magnitude for (232)Th, (208)Tl, and (137)Cs (10(-4)-10(-2)). There was no statistical difference between the plant groups in radionuclide uptake. Overall statistical analyses indicated a moderate negative relationship between soil concentrations and CR values, and no relationship with soil parameters, except a negative one for (137)Cs. Comparison with literature showed more agreement with studies that were done in the Mediterranean than with ICRP and IAEA databases. Our data not only describe the natural radioactivity of the Bay, but also create a dataset that could be relevant for further radioecological assessments of the Kastela Bay. PMID- 24769389 TI - Representative doses to members of the public from atmospheric releases of (131)I at the Mayak Production Association facilities from 1948 through 1972. AB - Scoping epidemiology studies performed by researchers from the Southern Urals Biophysics Institute revealed an excess prevalence of thyroid nodules and an increased incidence of thyroid cancer among residents of Ozersk, Russia, who were born in the early 1950s. Ozersk is located about 5 km from the facilities where the Mayak Production Association produced nuclear materials for the Russian weapons program. Reactor operations began in June 1948 and chemical separation of plutonium from irradiated fuel began in February 1949. The U.S.-Russia Joint Coordinating Committee on Radiation Effects Research conducted a series of projects over a 10-year period to assess the radiation risks in the Southern Urals. This paper uses data collected under Committee projects to present examples of reconstructed time-dependent thyroid doses to reference individuals living in Ozersk from (131)I released to the atmosphere for all relevant exposure pathways. Between 3.22 * 10(16) and 4.31 * 10(16) Bq of (131)I may have been released during the 1948-1972 time period, and a best estimate is 3.76 * 10(16) Bq. In general, younger children incur greater thyroid doses from (131)I than adults. A child born in 1947 is estimated to have received a cumulative thyroid dose of 2.3 Gy for 1948-1972, with a 95% confidence interval of 0.51-7.3 Gy. Annual doses were the highest in 1949 and a child who was 5 years old in 1949 is estimated to have a received an annual thyroid dose of 0.93 Gy with a 95% confidence interval of 0.19-3.5 Gy. PMID- 24769390 TI - Synthesis and in vitro and in vivo evaluations of poly(ethylene glycol)-block poly(4-vinylbenzylphosphonate) magnetic nanoparticles containing doxorubicin as a potential targeted drug delivery system. AB - The main challenge in antitumor chemotherapy is to enhance the curative effect and minimize the adverse effects of an anticancer drug. Administration of functionalized magnetic iron oxide nanoparticles is one of the strategies to improve sensitivity to cancer chemotherapy, and these nanoparticles are attractive materials that have been widely used in medicine for various applications, including diagnostic imaging and therapeutic applications. In this study, we describe the synthesis and characterization of drug-loaded iron oxide nanoparticles. Our aim was to obtain a biocompatible and injectable nanocarrier with anticancer activity. Iron oxide nanoparticles (IONs) were synthesized by alkali co-precipitation of iron salts followed by coating with our original surface modification agent, poly(ethylene glycol)-block-poly(4 vinylbenzylphosphonate) copolymer (PEG-PIONs). An anticancer drug doxorubicin (DOX), which clinical use is associated with cardiotoxicity, was loaded onto PEG PIONs (PEG-PIONs/DOX), and to the best of our knowledge, this formulation showed higher drug encapsulation efficiency (drug loading capacity of the nanocarrier was 11.7%) than other formulations previously reported. PEG-PIONs/DOX had a hydrodynamic diameter of about 35nm and were stable in biological conditions over a period more than one month and showed stable and continuous in vitro drug release and antiproliferative effects on cancer cells. Fluorescent imaging indicated internalization of the PEG-PIONs/DOX in the cytoplasm of cancer cells. Biodistribution studies showed that PEG-PIONs/DOX preferentially accumulate in the tumor region via enhanced permeability and retention effect. In addition, analysis of the serum levels of enzymes indicated that PEG-PIONs/DOX reduced the cardiotoxicity associated with free DOX. These results indicate that PEG PIONs/DOX have the potential for targeted delivery of antitumor drugs via systemic administration. PMID- 24769391 TI - Electrochemical characterization of poly-beryllon II modified carbon paste electrode and its application to selective determination of pyrocatechol and hydroquinone. AB - A poly-beryllon II film modified carbon paste electrode (PBL-II/CPE) has been constructed by electropolymerization method. Electrochemical characterization of the PBL-II/CPE was investigated by electrochemical impedance spectroscopy (EIS). The electrochemical behaviors of pyrocatechol (PC) and hydroquinone (HQ) were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) at the PBL-II/CPE in pH 7.0 phosphate buffer solution (PBS). The anodic peak currents were dramatically enhanced about threefold for PC at PBL-II/CPE. In addition, the modified electrode exhibits good selectivity toward selective determination of PC and HQ. By using DPV method, low detection limits of 0.8MUM for PC and 1.0MUM for HQ were obtained, respectively. Many outstanding advantages, such as wide linear ranges, low detection limits, excellent sensitivity, selectivity and stability confirmed that the PBL-II/CPE has promising analytical performance. Meanwhile, the electrode was successfully used for the determination of PC and HQ in local tap water sample and the results are satisfactory. PMID- 24769392 TI - Overview of the preparation of organic polymeric nanoparticles for drug delivery based on gelatine, chitosan, poly(d,l-lactide-co-glycolic acid) and polyalkylcyanoacrylate. AB - Polymeric nanoparticles are greatly advancing the field of nanomedicine due to their ability for targeted and controlled drug release. There are two types of materials which form polymeric nanoparticles; natural or synthetic. In this review article, natural polymeric nanoparticles including; gelatine and chitosan and synthetic polymeric nanoparticles such as poly(lactide-co-glycolic acid) and poly-n-alkyl(cyano)acrylate will be discussed. The various preparation methods of these nanoparticles and the impact of critical parameters such as molecular weight, charge or choice of stabilizer will be described, as these control the overall mean size and surface of the nanoparticle which is a critical factor for drug delivery. PMID- 24769393 TI - A mechanistic view of lipid membrane disrupting effect of PAMAM dendrimers. AB - The effect of 5th generation polyamidoamine (PAMAM G5) dendrimers on multilamellar dipalmitoylphosphocholine (DPPC) vesicles was investigated. PAMAM was added in two different concentrations to the lipids (10(-3) and 10(-2) dendrimer/lipid molar ratios). The thermal behavior of the evolved systems was characterized by DSC; while the structure and the morphology were investigated with small- and wide-angel X-ray scattering (SWAXS), freeze-fracture electron microscopy (FFTEM) and phosphorus-31 nuclear magnetic resonance ((31)P NMR) spectroscopy, respectively. IR spectroscopy was used to study the molecular interactions between PAMAM and DPPC. The obtained results show that the dendrimers added in 10(-3) molar ratio to the lipids generate minor perturbations in the multilamellar structure and thermal character of liposomes, while added in 10(-2) molar ratio dendrimers cause major disturbance in the vesicular system. The terminal amino groups of the dendrimers are in strong interaction with the phosphate headgroups and through this binding dendrimers disrupt the regular multilamellar structure of DPPC. Besides highly swollen, fragmented bilayers, small vesicles are formed. PMID- 24769395 TI - Peptide XIB13 reduces capillary leak in a rodent burn model. AB - OBJECTIVE: Edema due to capillary leak is a generalized and life threatening event in sepsis and major burns for which there is no causal treatment. Local burn wounds are an ideal model to investigate the impact of a new therapeutic agent on edema formation. We aimed to identify peptide sequences of cingulin that can attenuate stress-induced endothelial cytoskeleton disarrangement in vitro and which reduce burn-induced edema in vivo. METHODS: Cingulin-derived peptides were screened in high content cell culture assays monitoring actin displacement and endothelial cell/cell contacts. The ears of male hairless mice (n=44) were inflicted with full thickness burns using a hot air jet. Mice with and without burn injuries were treated with Xib13 or solvent by continuous intraperitoneal application for 3 days. Edema, microcirculation, leukocyte-endothelial interactions and angiogenesis - measured as non-perfused area - were investigated over a 12-day period using intravital fluorescence microscopy. RESULTS: Xib13 reduced endothelial stress formation and stabilized endothelial tight junctions in cell-cultures. In the burn model, Xib13 improved angiogenesis compared to controls (non-perfused area on day 12: 5.7+/-1.5% vs. 12.0+/-2.1%; p<0.05). Edema was significantly reduced at all observation points in Xib13-treated animals as compared to controls (day 12: 67.6+/-2.6% vs. 83.2+/-6.4%). CONCLUSION: Xib13 improved angiogenesis, reduced edema formation and showed no side effects on other physiological parameters. Since edema formation is a serious parameter for burn conversion and is associated with survival it could provide a new treatment option for patients with burn injuries. PMID- 24769396 TI - Characteristics of functional state of arteriolar and venular skin microvessels in patients with essential arterial hypertension. AB - The aim of the study was to evaluate the vasomotor activity of skin precapillary arterioles, depending on the condition of blood outflow from the capillary bed in patients with essential arterial hypertension (AH). The study included 30 normotensive subjects (NT) and 63 patients with AH, who were tested with a laser Doppler flowmetry with wavelet analysis of blood flow oscillations on the right forearm and ambulatory blood pressure monitoring (ABPM) on the left shoulder. Antihypertensive therapy was stopped for all patients 14 days prior to the experiment or AH was diagnosed for the first time. The hypertensive patients were divided into 2 groups, depending on the amplitude of the respiratory blood flow oscillations in skin microvessels. The first group included 30 patients without blood outflow violations of the capillary bed (AHVN), the second group consisted of 33 patients with various intensity of functional disorders in venular sector of microvasculature (AHVS). If the value of the amplitude of blood flow oscillations can be related to the tone" definition, then AHVN patients have a significant increase in neurogenic component of vascular tone (p<0.002) and violation of microvessel vasomotor endothelial function (p=0.065) in regard to NT, and AHVS patients to NT have a significant reduction of myogenic component tone of precapillary arterioles (p<0.05). AHVN patients compared to AHVS patients have a higher precapillary arteriolar tone due to endothelial (p<0.01), neurogenic (p<0.01) and myogenic (p<0.01) components of the vascular tone. Despite the lower values of the precapillary arteriolar tone, AHVS patients have higher BP values both at daytime (p<0.0005), and in nocturnal hours (p<0.05), and the functional state of venular sector is connected with nocturnal BP reduction. Obtained results indicate that hypertensive patients can have significant differences in the functional state of microvessels. The assessment of the initial skin microvasculatory regulatory mechanism status could potentially be useful for individual choice of antihypertensive therapy. PMID- 24769394 TI - Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress. AB - Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular reductant. G6PD deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. Here, we show that G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re-expression of wild type G6PD, but not the K403 acetylation mimetic mutant, rescues cells from oxidative injury. Moreover, we show that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2 mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. We also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress. PMID- 24769397 TI - Glycan specificity of a testis-specific lectin chaperone calmegin and effects of hydrophobic interactions. AB - BACKGROUND: Testis-specific chaperone calmegin is required for the generation of normal spermatozoa. Calmegin is known to be a homologue of endoplasmic reticulum (ER) residing lectin chaperone calnexin. Although functional similarity between calnexin and calmegin has been predicted, detailed information concerned with substrate recognition by calmegin, such as glycan specificity, chaperone function and binding affinity, are obscure. METHODS: In this study, biochemical properties of calmegin and calnexin were compared using synthetic glycans and glycosylated or non-glycosylated proteins as substrates. RESULTS: Whereas their amino acid sequences are quite similar to each other, a certain difference in secondary structures was indicated by circular dichroism (CD) spectrum. While both of them inhibited protein heat-aggregation to a similar extent, calnexin exhibited a higher ability to facilitate protein folding. Similarly to calnexin, calmegin preferentially recognizes monoglucosylated glycans such as Glc1Man9GlcNAc2 (G1M9). While the surface hydrophobicity of calmegin was higher than that of calnexin, calnexin showed stronger binding to substrate. We reasoned that lectin activity, in addition to hydrophobic interaction, contributes to this strong affinity between calnexin and substrate. CONCLUSIONS: Although their similarity in carbohydrate binding specificities is high, there seems to be some differences in the mode of substrate recognition between calmegin and calnexin. GENERAL SIGNIFICANCE: Properties of calmegin as a lectin-chaperone were revealed in comparison with calnexin. PMID- 24769398 TI - The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters. AB - BACKGROUND: The mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters (NSS). Due to their important role, dysfunctions are associated with several psychiatric and neurological diseases and they also serve as targets for a wide range of therapeutic and illicit drugs. Despite the central physiological and pharmacological importance, direct evidence on structure-function relationships on mammalian NSS proteins has so far been unsuccessful. The crystal structure of the bacterial NSS protein, LeuT, has been a turning point in structural investigations. SCOPE OF REVIEW: To provide an update on what is known about the binding sites for substrates and inhibitors in the LeuT. The different binding modes and binding sites will be discussed with special emphasis on the possible existence of a second substrate binding site. It is the goal to give an insight into how investigations on ligand binding in LeuT have provided basic knowledge about transporter conformations and translocation mechanism which can pave the road for a deeper understanding of drug binding and function of the mammalian transporters. MAJOR CONCLUSIONS: The LeuT is a suitable model for the structural investigation of NSS proteins including the possible location of drug binding sites. It is still debated whether the LeuT is a suitable model for the molecular mechanisms behind substrate translocation. GENERAL SIGNIFICANCE: Structure and functional aspects of NSS proteins are central for understanding synaptic transmission. With the purification and crystallization of LeuT as well as the dopamine transporter from Drosophila melanogaster, the application of biophysical methods such as fluorescence spectroscopy, neutron- or x-ray scattering and NMR for understanding its function becomes increasingly available. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins. PMID- 24769399 TI - Reduction in urinary organophosphate pesticide metabolites in adults after a week long organic diet. AB - BACKGROUND: Conventional food production commonly uses organophosphate (OP) pesticides, which can have negative health effects, while organic food is deemed healthier because it is produced without these pesticides. Studies suggest that organic food consumption may significantly reduce OP pesticide exposure in children who have relatively higher pesticide exposure than adults due to their different diets, body weight, behaviour and less efficient metabolism. OBJECTIVES: A prospective, randomised, crossover study was conducted to determine if an organic food diet reduces organophosphate exposure in adults. METHODS: Thirteen participants were randomly allocated to consume a diet of at least 80% organic or conventional food for 7 days and then crossed over to the alternate diet. Urinary levels of six dialkylphosphate metabolites were analysed in first morning voids collected on day 8 of each phase using GC-MS/MS with detection limits of 0.11-0.51 MUg/L. RESULTS: The mean total DAP results in the organic phase were 89% lower than in the conventional phase (M=0.032 [SD=0.038] and 0.294 [SD=0.435] respectively, p=0.013). For total dimethyl DAPs there was a 96% reduction (M=0.011 [SD=0.023] and 0.252 [SD=0.403] respectively, p=0.005). Mean total diethyl DAP levels in the organic phase were half those of the conventional phase (M=0.021 [SD=0.020] and 0.042 [SD=0.038] respectively), yet the wide variability and small sample size meant the difference was not statistically significant. CONCLUSIONS: The consumption of an organic diet for one week significantly reduced OP pesticide exposure in adults. Larger scale studies in different populations are required to confirm these findings and investigate their clinical relevance. PMID- 24769400 TI - Prospective analysis of adverse events in surgical treatment of degenerative spondylolisthesis. AB - BACKGROUND CONTEXT: Surgical adverse event (AE) monitoring is imprecise, of uncertain validity, and tends toward underreporting. Reports focus on specific procedures rather than outcomes in the context of presenting diagnosis. Specific intraoperative (intraop) or postoperative (postop) AEs that may be independently associated with degenerative spondylolisthesis (DS) have never been reported. PURPOSE: The primary purpose was to assess the AE profile of surgically treated patients with L4-L5 DS. The secondary goal was to identify potential risk factors that correlate with those AEs. STUDY DESIGN/SETTING: Prospective cohort and academic quaternary spine center. PATIENT SAMPLE: Ninety-two patients with L4-L5 DS were treated surgically, discharged from Vancouver General Hospital between January 1, 2009 and December 31, 2010. OUTCOME MEASURES: Incidence rates and odds ratios. METHODS: Prospective AE data were analyzed using univariate analyses, forward selection regression models, and Spearman correlation coefficients. Results were compared with outcomes reported in the Spine Patient Outcomes Research Trial. RESULTS: No AEs were seen in 57.6% of patients, one AE in 17.4%, and two or more AEs in 17.4%. Dural tears (6.5%) and intraop bone-implant interface failure requiring revision (3.3%) were the most common intraop AEs. Postoperatively, the most frequent AEs were urinary tract infection (10.9%), delirium (5.4%), neuropathic pain (4.4%), deep wound infection (3.3%), and superficial wound infection (3.3%). The odds of an intraop AE increased by 9% (95% confidence interval [CI] 1-18) per year of age at admission. Adjusted Charlson comorbidity index (CCI) did not correlate with number of AEs experienced. The odds of postop delirium correlated with CCI (odds ratio [OR] 3.39, 95% CI 1.12-10.24) and dural tear (OR 35.84, 95% CI 1.72-747.45). Length of stay was statistically significant and was influenced by two or more AEs, CCI, postop loss of correction, cerebrospinal fluid leak, deep wound infection, noninfected wound drainage, and gender. CONCLUSIONS: Risk of intraop AEs, but not postop AEs, increased with increasing age. Having multiple comorbidities does not predispose to more AEs. Infections predominate among the postop AEs. Patients at increased risk of delirium or of having an increased length of hospital stay may more easily be predicted. Studies specifically designed to prospectively assess AEs have the potential to more accurately identify postop AE rates. PMID- 24769401 TI - Negative pressure wound therapy reduces incidence of postoperative wound infection and dehiscence after long-segment thoracolumbar spinal fusion: a single institutional experience. AB - BACKGROUND CONTEXT: Wound dehiscence and surgical site infections (SSIs) can have a profound impact on patients as they often require hospital readmission, additional surgical interventions, lengthy intravenous antibiotic administration, and delayed rehabilitation. Negative pressure wound therapy (NPWT) exposes the wound site to negative pressure, resulting in the improvement of blood supply, removal of excess fluid, and stimulation of cellular proliferation of granulation tissue. PURPOSE: To assess the incidence of wound infection and dehiscence in patients undergoing long-segment thoracolumbar fusion before and after the routine use of NPWT. STUDY DESIGN: Retrospective study. PATIENT SAMPLE: One hundred sixty patients undergoing long-segment thoracolumbar spine fusions were included in this study. OUTCOME MEASURES: Postoperative incidence of wound infection and dehiscence. METHODS: All adult patients undergoing thoracolumbar fusion for spinal deformity over a 6-year period at Duke University Medical Center by the senior author (CB) were included in this study. In 2012, a categorical change was made by the senior author (CB) that included the postoperative routine use of incisional NPWT devices after primary wound closure in all long-segment spine fusions. Before 2012, NPWT was not used. After primary wound closure, a negative pressure device is contoured to the size of the incision and placed over the incision site for 3 postoperative days. We retrospectively review the first 46 cases in which NPWT was used and compared them with the immediately preceding 114 cases to assess the incidence of wound infection and dehiscence. RESULTS: One hundred sixty (NPWT: 46 cases, non-NPWT: 114 cases) long-segment thoracolumbar spine fusions were performed for deformity correction. Baseline characteristics were similar between both cohorts. Compared with the non-NPWT cohort, a 50% decrease in the incidence of wound dehiscence was observed in the NPWT patient cohort (6.38% vs. 12.28%, p=.02). Similarly, compared with the non-NPWT cohort, the incidence of postoperative SSIs was significantly decreased in the NPWT cohort (10.63% vs. 14.91%, p=.04). CONCLUSIONS: Routine use of incisional NPWT was associated with a significant reduction in the incidence of postoperative wound infection and dehiscence. PMID- 24769402 TI - Neurobiology of social attachments. AB - Many types of social attachments can be observed in nature. We discuss the neurobiology of two types (1) intraspecific (with a partner) and (2) parental (with the offspring). Stimuli related to copulation facilitate the first, whereas pregnancy, parturition and lactation facilitate the second. Both types develop as consequence of cohabitation. These events seem to stimulate similar neural pathways that increase (1) social recognition, (2) motivation, reward; and (3) decrease fear/anxiety. Subregions of the amygdala and cortex facilitate social recognition and also disinhibition to decrease rejection responses. The interrelationship between MeA, BNST, LS may mediate the activation of NAcc via the mPOA to increase motivation and reward. Cortical areas such as the ACC discriminate between stimuli. The interaction between OT and D2-type receptors in NAcc shell facilitates intraspecific attachment, but D1-type appears to facilitate parental attachment. This difference may be important for maternal females to direct their attention, motivation and expression of attachment toward the appropriate target. PMID- 24769403 TI - Grey matter reduction associated with posttraumatic stress disorder and traumatic stress. AB - In recent decades, many imaging studies have reported brain structural alterations in posttraumatic stress disorder (PTSD). However, due to differences in the selection of control subjects, it is difficult to conclude whether the observed alterations were related to disease or traumatic stress. The present study was to provide a quantitative voxelwise meta-analysis of grey matter (GM) changes in PTSD relative to either trauma-exposed controls without PTSD (TEC) or non-traumatised healthy controls (HC) separately and to conduct a systematic review of voxel-based morphometry (VBM) studies that compared trauma-exposed individuals with HC to explore the effect of traumatic stress. GM reduction was identified in the medial prefrontal cortex in PTSD compared to both TEC and HC. Additional GM reduction was also observed in PTSD in the left hippocampus, left middle temporal gyrus and right superior frontal gyrus compared with TEC. Additionally, GM decreased in the left occipital cortex in PTSD compared with HC. The present study delimited the significant differences among VBM results in PTSD research when different control groups were chosen. PMID- 24769404 TI - A rapid two-step algorithm detects and identifies clinical macrolide and beta lactam antibiotic resistance in clinical bacterial isolates. AB - PURPOSE: Aiming to identify macrolide and beta-lactam resistance in clinical bacterial isolates rapidly and accurately, a two-step algorithm was developed based on detection of eight antibiotic resistance genes. METHODS: Targeting at genes linked to bacterial macrolide (msrA, ermA, ermB, and ermC) and beta-lactam (blaTEM, blaSHV, blaCTX-M-1, blaCTX-M-9) antibiotic resistances, this method includes a multiplex real-time PCR, a melting temperature profile analysis as well as a liquid bead microarray assay. Liquid bead microarray assay is applied only when indistinguishable Tm profile is observed. RESULTS: The clinical validity of this method was assessed on clinical bacterial isolates. Among the total 580 isolates that were determined by our diagnostic method, 75% of them were identified by the multiplex real-time PCR with melting temperature analysis alone, while the remaining 25% required both multiplex real-time PCR with melting temperature analysis and liquid bead microarray assay for identification. Compared with the traditional phenotypic antibiotic susceptibility test, an overall agreement of 81.2% (kappa=0.614, 95% CI=0.550-0.679) was observed, with a sensitivity and specificity of 87.7% and 73% respectively. Besides, the average test turnaround time is 3.9h, which is much shorter in comparison with more than 24h for the traditional phenotypic tests. CONCLUSIONS: Having the advantages of the shorter operating time and comparable high sensitivity and specificity with the traditional phenotypic test, our two-step algorithm provides an efficient tool for rapid determination of macrolide and beta-lactam antibiotic resistances in clinical bacterial isolates. PMID- 24769405 TI - Nested-quantitative PCR approach with improved sensitivity for the detection of low titer levels of Candidatus Liberibacter asiaticus in the Asian citrus psyllid, Diaphorina citri Kuwayama. AB - Candidatus Liberibacter asiaticus (CLas) is a phloem-limited bacterium transmitted by the Asian citrus psyllid, Diaphorina citri, and the presumptive causal agent of citrus greening disease. The current method of detection for CLas within plant and insect samples is by a presence/absence qPCR assay using the CLas 16S rDNA gene target. Although qPCR is highly sensitive, low bacterial titers or suboptimal qPCR conditions can result in false-negatives. Using a nested qPCR assay, we determined the false-negative rate of the 16S presence/absence qPCR assay was greater than 50%. Studies to determine the performance parameters of the qPCR assays for CLas 16S and Wingless (Wg), the D. citri endogenous gene, using plasmid and psyllid DNA, revealed suboptimal and variable performance of the 16S assay in psyllid samples. Average efficiencies and sensitivity limits of the plasmid assays were 99.0% and 2.7 copies of template for Wg, respectively, and 98.5% and 2.2-22.1 copies for 16S, respectively. Variability in efficiency was significantly greater in psyllid samples for both gene targets compared to the corresponding plasmid assays, and efficiencies as low as 76% were obtained for 16S. A secondary structure analysis revealed the formation of two stem-loop structures that block the forward and probe binding sites in the 16S template, which could hinder amplification. In summary, our results suggest that suboptimal qPCR efficiency is not uncommon for the 16S presence/absence qPCR assay, which combined with lowCLas titers in some samples, could contribute significantly to the under-reporting of CLas infection in psyllid and plant samples. PMID- 24769406 TI - Isolation of PCR quality microbial community DNA from heavily contaminated environments. AB - Asphalts, biochemically degraded oil, contain persistent, water-soluble compounds that pose a significant challenge to the isolation of PCR quality DNA. The adaptation of existing DNA purification protocols and commercial kits proved unsuccessful at overcoming this hurdle. Treatment of aqueous asphalt extracts with a polyamide resin afforded genomic microbial DNA templates that could readily be amplified by PCR. Physicochemically distinct asphalt samples from five natural oil seeps successfully generated the expected 291 bp amplicons targeting a region of the 16S rRNA gene, illustrating the robustness of the method. DNA recovery yields were in the 50-80% range depending on how the asphalt sample was seeded with exogenous DNA. The scope of the new method was expanded to include soil with high humic acid content. DNA from soil samples spiked with a range of humic acid concentrations was extracted with a commercial kit followed by treatment with the polyamide resin. The additional step significantly improved the purity of the DNA templates, especially at high humic acid concentrations, based on qPCR analysis of the bacterial 16S rRNA genes. The new method has the advantages of being inexpensive, simple, and rapid and should provide a valuable addition to protocols in the field of petroleum and soil microbiology. PMID- 24769407 TI - Arthroscopic Iliopsoas Fractional Lengthening for Internal Snapping of the Hip: Clinical Outcomes With a Minimum 2-Year Follow-up. AB - BACKGROUND: Internal snapping of the hip is caused by the iliopsoas (IP) tendon sliding over the iliopectineal eminence or the femoral head. In many cases that require hip arthroscopic surgery, there is coexistent painful internal snapping. In such cases, fractional lengthening of the IP tendon has been suggested as an adjunctive procedure. PURPOSE: To examine the outcomes and effectiveness of arthroscopic IP tendon fractional lengthening as a solution to coexistent internal hip snapping in patients undergoing hip arthroscopic surgery for a labral tear and/or femoroacetabular impingement. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between June 2010 and June 2011, data were prospectively collected for all patients with internal snapping of the hip who underwent primary arthroscopic IP tendon fractional lengthening, with a minimum 2-year follow-up. All patients were interviewed by telephone with specific questions regarding the resolution or persistence of snapping. Patients were assessed preoperatively and postoperatively using the following patient-reported outcome (PRO) measures: Non-Arthritic Hip Score (NAHS), Hip Outcome Score-Activity of Daily Living (HOS-ADL) and Sport-Specific Subscale (HOS-SSS), and modified Harris Hip Score (mHHS). Pain was recorded on a visual analog scale (VAS), and satisfaction was measured on a scale from 0 to 10. RESULTS: A total of 55 patients were included, with all PROs showing statistically significant improvement postoperatively (NAHS: 57.6 +/- 20.6 preoperatively vs. 80.2 +/- 19.2 at 2 years; HOS-ADL: 60.9 +/- 21.4 preoperatively vs. 81.8 +/- 20.6 at 2 years; HOS-SSS: 43.4 +/- 24.6 preoperatively vs. 70.0 +/- 26.7 at 2 years; and mHHS: 62.3 +/- 16.4 preoperatively vs. 80.5 +/- 18.3 at 2 years) (P < .001 for all). Forty-five patients (81.8%) reported good/excellent satisfaction (>=7). Overall, 45 patients (81.8%) reported resolution of painful snapping. Patients who had resolution of snapping had statistically significant superior outcomes compared with those with persistent snapping using the change in the NAHS value (25.8 +/- 16.1 vs. 8.0 +/- 22.5, respectively; P = .005), change in the HOS-ADL value (23.6 +/- 18.0 vs. 8.5 +/- 15.2, respectively; P = .017), change in the HOS-SSS value (30.7 +/- 26.9 vs. 8.7 +/- 23.6, respectively; P = .021), and change in the mHHS value (23.3 +/- 20.1 vs. 4.4 +/- 9.9, respectively; P = .005). CONCLUSION: A majority of patients reported resolution of painful snapping and improvement in symptoms. Nonetheless, the rate of persistence of internal snapping at a minimum 2 years postoperatively was higher than that reported in previous studies. PMID- 24769408 TI - Supramalleolar Osteotomy With Bone Marrow Stimulation for Varus Ankle Osteoarthritis: Clinical Results and Second-Look Arthroscopic Evaluation. AB - BACKGROUND: Supramalleolar osteotomy (SMO), which redistributes the load line within the ankle joint, has been reported as an effective treatment for varus ankle osteoarthritis. However, no study has examined cartilage regeneration in the medial compartment of the ankle after SMO. HYPOTHESIS/PURPOSE: This study aimed to investigate the clinical and radiological outcomes of SMO and to identify the association between the outcomes of SMO and cartilage regeneration evaluated by second-look arthroscopy. The hypothesis was that cartilage regeneration would be an important predictor of the outcomes of SMO and that arthroscopic marrow stimulation would aid in cartilage regeneration. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 31 ankles were retrospectively evaluated after arthroscopic marrow stimulation with SMO for varus ankle osteoarthritis; second-look arthroscopy was conducted for all these ankles. Clinical outcome measures included a visual analog scale (VAS) for pain and the American Orthopaedic Foot and Ankle Society (AOFAS) score. Radiological outcome variables included the tibial-ankle surface angle (TAS), talar tilt (TT), and tibial-lateral surface angle (TLS), and progression of degenerative arthritis of the ankle was assessed. In the second-look arthroscopy, cartilage regeneration was evaluated using the International Cartilage Repair Society (ICRS) grade. RESULTS: The mean +/- standard deviation VAS and AOFAS scores were 7.1 +/- 0.8 and 62.9 +/- 4.0 preoperatively, and they significantly improved to 3.4 +/- 1.3 and 83.1 +/- 7.5, respectively (P < .001, for both) at the time of the second look arthroscopy (mean, 13.2 months postoperatively). However, at final follow-up (mean, 27.4 months postoperatively), they were significantly decreased to 4.1 +/- 1.6 and 79.9 +/- 8.0, respectively, compared with the values at second-look arthroscopy (P < .001, for both). The mean TAS, TT, and TLS improved significantly after SMO but showed no significant correlation with the clinical outcomes and ICRS grade (P > .05 for all three). At second-look arthroscopy, the ICRS overall repair grades were normal in 1 (3%), nearly normal in 7 (23%), abnormal in 13 (42%), and severely abnormal in 10 (32%). Progressive degenerative arthritis was observed in 13 cases (42%). The ICRS grade was significantly associated with the clinical outcomes (P < .0001) and development of degenerative arthritis of the ankle joint (P = .002). CONCLUSION: This study showed improved clinical outcomes after SMO for varus ankle osteoarthritis in comparison to the preoperative assessments. Furthermore, the ICRS grade was significantly associated with the clinical outcomes of SMO at final follow-up and significantly associated with the development of degenerative arthritis of the ankle joint. Therefore, arthroscopic marrow stimulation should be considered with SMO to ensure adequate cartilage regeneration. However, given the ICRS grades observed at the time of the second-look arthroscopies and the progression of degenerative arthritis in 42%, the long-term prognosis in this group of patients is uncertain. PMID- 24769409 TI - Short- to Medium-term Outcomes After a Modified Brostrom Repair for Lateral Ankle Instability With Immediate Postoperative Weightbearing. AB - BACKGROUND: Anatomic techniques of ankle ligament repair have the advantage of restoring the anatomy and kinematics of the joint. This study presents a technique for anatomic reconstruction of the lateral ligament complex by way of lateral ligament advancement using suture anchors associated with immediate protected full weightbearing; 2- to 5-year clinical outcomes are reported. HYPOTHESIS: This technique of providing an anatomic reconstruction with a secure fixation will enable early rehabilitation with immediate, protected weightbearing, with favorable outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Fifty-five patients with chronic lateral ankle instability who failed nonoperative management underwent modified Brostrom repair (lateral ligament fibular advancement) between 2005 and 2008. The anterior talofibular ligament and calcaneofibular ligament were released from the fibula and advanced using 2 double-loaded metallic suture anchors (3.5 mm). Full weightbearing in a walking boot was allowed from the first postoperative day. Patients were assessed preoperatively and at a minimum 2-year follow-up using the Foot and Ankle Outcome Score. Complication, failure (recurrent instability), and return-to-sport rates were also recorded. RESULTS: Six patients (11%) were lost to follow-up, leaving a study group of 49 patients (23 men, 26 women). The mean age at the time of surgery was 25 years (range, 18-37 years), with a mean duration of symptoms of 1.8 years (range, 6 months to 5 years). The mean follow-up time was 42 months (range, 24-60 months). Significant improvement was seen in the Foot and Ankle Outcome Score from preoperatively to postoperatively (from 36 to 75.4, P < .001): the pain subscale improved from 35 to 75 (P < .001), the symptom subscale from 29 to 77 (P = .01), the function subscale from 45 to 77 (P < .001), the function in sports and recreation subscale from 38 to 70 (P < .001), and the foot and ankle related quality of life subscale from 35 to 78 (P < .001). No significant difference in range of motion with the contralateral side was seen (P = .34). The failure rate was 6%, with 3 patients reporting residual instability after a traumatic retear. Two cases of superficial wound infection were seen. One case of temporary neurapraxia of the superficial peroneal nerve was observed. The return to-sport rate was 94%. CONCLUSION: This study demonstrates that anterior talofibular ligament and calcaneofibular ligament advancement using suture anchor fixation is an effective procedure for the treatment of chronic lateral ankle instability and allows immediate weightbearing. PMID- 24769410 TI - Simultaneous Reconstruction of the Anterior Cruciate Ligament and Medial Collateral Ligament in Patients With Chronic ACL-MCL Lesions: A Minimum 2-Year Follow-up Study. AB - BACKGROUND: In cases of chronic anterior cruciate ligament (ACL)-medial collateral ligament (MCL) lesions, nonoperative treatment of the MCL lesion may lead to chronic valgus instability and rotatory instability. The optimal management for patients who have combined ACL-MCL injuries remains controversial. PURPOSE: To present a case series of 21 patients who underwent simultaneous ACL MCL reconstruction with a 2- to 5-year follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From October 2007 to December 2010, a total of 21 patients with chronic ACL-MCL injuries, for which the 2 ligaments were reconstructed during the same surgical procedure, were studied. All patients were available for follow-up for at least 2 years. The International Knee Documentation Committee (IKDC) subjective knee scores, valgus and sagittal stability, anteromedial rotatory stability, range of motion, and complications were assessed both preoperatively and postoperatively. RESULTS: At follow-up, valgus and sagittal laxity were not observed in any of the patients. The mean medial knee opening was significantly reduced to 0.80 +/- 0.96 mm (range, -1.2 to 2.6 mm) postoperatively compared with 8.0 +/- 1.3 mm (range, 6.1 to 10.7 mm) preoperatively (P < .01). The mean postoperative side-to-side difference measured with the KT-1000 arthrometer was reduced to 0.8 +/- 0.9 mm (range, -1.2 to 2.3 mm) compared with 8.4 +/- 1.6 mm (range, 6.2 to 13.2 mm) preoperatively (P < .01). Preoperative anteromedial instability was seen in 71% of patients (15/21), whereas none of the patients had anteromedial rotatory instability at the last follow-up. The mean IKDC subjective score improved overall from 45.3 +/- 12.0 (range, 28.7-69.0) preoperatively to 87.7 +/- 8.2 (range, 65.5-100.0) at the last follow-up (P < .01). Most patients (20/21) had normal or nearly normal range of motion of the knee joint; only 1 patient (5%) had a limitation of flexion of 15 degrees compared with the contralateral knee at the last follow-up. CONCLUSION: In patients with chronic ACL-MCL lesions, simultaneous reconstruction of the ACL and MCL can significantly improve the medial, sagittal, and rotatory stability of the knee at short-term follow-up. PMID- 24769411 TI - Ozone-initiated VOC and particle emissions from a cleaning agent and an air freshener: risk assessment of acute airway effects. AB - Emissions of volatile organic compounds and ultrafine particles from a kitchen cleaning agent (cream) and plug-in air freshener were investigated in a 20 m(3) walk-in climate chamber at low (~5 ppb) and high ozone (~50 ppb) test concentrations and 0.6 air exchange rate. The products emitted terpenes, inter alia limonene, dihydromyrcenol, geraniol, linalool, and glycol ethers. The ozone initiated reaction products of these compounds were measured by air sampling on Tenax TA followed by thermal desorption GC-MS and air sampling on DNPH cartridges followed by liquid extraction and HPLC-UV analysis. Particle formation was monitored simultaneously. A number of oxygenated and poly-oxygenated reaction products were identified and risk assessed for acute airway effects: formaldehyde, acetaldehyde, acetone, 4-acetyl-1-methylcyclohexene, 6-methyl-5 heptene-2-one, 3-isopropenyl-6-oxo-heptanal, and 4-oxo-pentanal. These compounds generally increased initially at the high ozone concentration, while the terpenes decayed, concurrent with their consumption of ozone. At high ozone concentration, the plug-in air freshener resulted in concentrations of formaldehyde and 4 oxopentanal that may give rise to concern about sensory irritation and airflow limitation, respectively. At high ozone concentration, the kitchen cleaning agent and air freshener resulted in peak particle mass concentrations at 81 MUg/m(3) (8.5*10(5) #/cm(3)) and 24 MUg/m(3) (2.3*10(4) #/cm(3)), respectively. At low ozone concentration, the particle concentration peaked at 4 MUg/m(3) (1.0*10(5) #/cm(3)) after the application of the kitchen cleaning agent, while no increase was observed for the air freshener. The particles, in view of their organic composition and concentration, are not considered to cause acute airway effects. Testing under realistic conditions that mimic user pattern behavior is warranted to obtain acute and longer-term exposure data at realistic indoor ozone concentrations. PMID- 24769412 TI - mSpray: a mobile phone technology to improve malaria control efforts and monitor human exposure to malaria control pesticides in Limpopo, South Africa. AB - Recent estimates indicate that malaria has led to over half a million deaths worldwide, mostly to African children. Indoor residual spraying (IRS) of insecticides is one of the primary vector control interventions. However, current reporting systems do not obtain precise location of IRS events in relation to malaria cases, which poses challenges for effective and efficient malaria control. This information is also critical to avoid unnecessary human exposure to IRS insecticides. We developed and piloted a mobile-based application (mSpray) to collect comprehensive information on IRS spray events. We assessed the utility, acceptability and feasibility of using mSpray to gather improved homestead- and chemical-level IRS coverage data. We installed mSpray on 10 cell phones with data bundles, and pilot tested it with 13 users in Limpopo, South Africa. Users completed basic information (number of rooms/shelters sprayed; chemical used, etc.) on spray events. Upon submission, this information as well as geographic positioning system coordinates and time/date stamp were uploaded to a Google Drive Spreadsheet to be viewed in real time. We administered questionnaires, conducted focus groups, and interviewed key informants to evaluate the utility of the app. The low-cost, cell phone-based "mSpray" app was learned quickly by users, well accepted and preferred to the current paper-based method. We recorded 2865 entries (99.1% had a GPS accuracy of 20 m or less) and identified areas of improvement including increased battery life. We also identified a number of logistic and user problems (e.g., cost of cell phones and cellular bundles, battery life, obtaining accurate GPS measures, user errors, etc.) that would need to be overcome before full deployment. Use of cell phone technology could increase the efficiency of IRS malaria control efforts by mapping spray events in relation to malaria cases, resulting in more judicious use of chemicals that are potentially harmful to humans and the environment. PMID- 24769413 TI - Association between risk of birth defects occurring level and arsenic concentrations in soils of Lvliang, Shanxi province of China. AB - The risk of birth defects is generally accredited with genetic factors, environmental causes, but the contribution of environmental factors to birth defects is still inconclusive. With the hypothesis of associations of geochemical features distribution and birth defects risk, we collected birth records and measured the chemical components in soil samples from a high prevalence area of birth defects in Shanxi province, China. The relative risk levels among villages were estimated with conditional spatial autoregressive model and the relationships between the risk levels of the villages and the 15 types of chemical elements concentration in the cropland and woodland soils were explored. The results revealed that the arsenic levels in cropland soil showed a significant association with birth defects occurring risk in this area, which is consistent with existing evidences of arsenic as a teratogen and warrants further investigation on arsenic exposure routine to birth defect occurring risk. PMID- 24769415 TI - Cisapride protects against cardiac hypertrophy via inhibiting the up-regulation of calcineurin and NFATc-3. AB - Cisapride has been shown to have electrophysiological effects on the heart. The aim of this study was to investigate whether cisapride has effects on cardiac hypertrophy. Rat and cellular models of cardiac hypertrophy were used in this study. Cell surface area (CSA), mRNA and protein expression were used to evaluate cardiac hypertrophy. Cardiac function was measured by echocardiography. Cisapride attenuated ISO-induced increase in CSA in a dose-dependent manner in cultured neonatal rat cardiomyocytes. A significant anti-hypertrophic effect was achieved by cisapride 0.01MUM (P<0.05). Cisapride repressed the increased mRNA levels of ANP, BNP, beta-MHC in ISO-treated cells (P<0.05). However, mallotoxin or GR113808 did not influence anti-hypertrophic effects of cisapride. In addition, cisapride inhibited the increase of intracellular Ca(2+) ([Ca(2+)]i) and the upregulation of protein levels of calcineurin and NFATc-3 (P<0.05) as well as prevented the downregulation of p-NFATc-3 (P<0.01) induced by ISO. Consistently, cisapride (0.5mg/kg/day) produced inhibitory effects on cardiac hypertrophy, including the suppression of ANP, BNP, beta-MHC, calcineurin, and NFATc-3; elevation of p-NFATc 3; reduction of cross-sectional area of cardiomyocytes in rat heart; and restoration of cardiac dysfunction by improving left ventricular diastolic and systolic performance. Importantly, cisapride 0.5 and 5.0mg/kg/day did not cause prolongation of QT and QTc intervals in rats. In conclusion, cisapride possesses a prominent anti-hypertrophic property which is likely to be conferred by its ability to downregulate Ca(2+)/calcineurin/NFAT and the present data provide new insight into this drug action. PMID- 24769416 TI - Somatostatin 4 receptor activation modulates G-protein coupled inward rectifying potassium channels and voltage stimulated calcium signals in dorsal root ganglion neurons. AB - Somatostatin has a wide biological profile resulting from its actions on the five receptor subtypes (sst1-5). Recently somatostatin was shown to exert analgesic effects via activation of the sst4 receptor. Although the analgesia in pain models is established, the precise molecular mechanism has yet to be fully elucidated. This research aimed to identify possible anti-nociceptive mechanisms, showing functional links of the sst4 receptor to G-protein coupled inward rectifying potassium (GIRK) channels and reduction of voltage stimulated calcium influx within the pain processing pathway. Whole cell voltage clamp experiments and calcium imaging experiments were conducted on DRG neurons prepared from adult rats. Application of an sst4 receptor selective agonist, J-2156, on DRG neurons induced a GIRK modulated potassium current, and inhibited voltage sensitive calcium current. Both mechanisms are thought to contribute to the analgesic properties of sst4 receptor agonists. PMID- 24769414 TI - Effects of anacetrapib on plasma lipids, apolipoproteins and PCSK9 in healthy, lean rhesus macaques. AB - Inhibition of cholesteryl ester transfer protein (CETP) has been vigorously pursued as a potential therapy to treat patients who are at an elevated risk for coronary artery disease. Anacetrapib, a novel CETP inhibitor, has been shown clinically to raise HDL cholesterol and reduce LDL cholesterol when provided as monotherapy or when co-administered with a statin. Preclinically, the effects of anacetrapib on the functionality and composition of HDL have been extensively studied. In contrast, the effects of anacetrapib on other parameters related to lipoprotein metabolism and cardiovascular risk have been difficult to explore. The aim of the present investigation was to evaluate the effects of anacetrapib in rhesus macaques and to compare these to effects reported in dyslipidemic humans. Our results from two separate studies show that administration of anacetrapib (150 mg/kg q.d. for 10 days) to rhesus macaques results in alterations in CETP activity (reduced by more than 70%) and HDL cholesterol (increased by more than 110%) which are similar to those reported in dyslipidemic humans. Levels of LDL cholesterol were reduced by more than 60%, an effect slightly greater than what has been observed clinically. Treatment with anacetrapib in this model was also found to lead to statistically significant reductions in plasma PCSK9 and to reduce cholesterol excursion in the combined chylomicron and remnant lipoprotein fraction isolated from plasma by fast protein liquid chromatography. Collectively, these data suggest that rhesus macaques may be a useful translational model to study the mechanistic effects of CETP inhibition. PMID- 24769417 TI - Th2-type inflammation under conditions of pre-existing chronic disease is associated with liver damage in patients with avian influenza H7N9 virus. AB - Most patients infected with avian H7N9 influenza virus develop severe disease, including respiratory failure, acute respiratory distress syndrome (ARDS), and multi-organ failure. The pathogenesis of H7N9 infection is not fully understood. This study revealed that H7N9-infected patients who had fatal outcomes or critical illness all had pre-existing chronic diseases. The patients did not have obvious systemic inflammation compared to the healthy controls. However, their fatal outcomes and critically severe illness were significantly associated with high serum levels of tumor necrosis factor (TNF)-alpha. Interestingly, the degree of liver damage in these patients significantly correlated with their serum levels of Th2 cytokines, interleukin (IL)-4, and IL-9. Taken together, our results suggest that Th2-type inflammation in H7N9-infected patients with pre existing chronic diseases likely contributes to the pathogenesis of H7N9 infection and is linked to poor clinical outcomes. PMID- 24769418 TI - Crystallographic characterization of the nitric oxide derivative of R-state human hemoglobin. AB - Nitric oxide (NO) is a signaling agent that is biosynthesized in vivo. NO binds to the heme center in human hemoglobin (Hb) to form the HbNO adduct. This reaction of NO with Hb has been studied for many decades. Of continued interest has been the effect that the bound NO ligand has on the geometrical parameters of the resulting heme-NO active site. Although the crystal structure of a T-state human HbNO complex has been published previously, that of the high affinity R state HbNO derivative has not been reported to date. We have crystallized and solved the three-dimensional X-ray structure of R-state human HbNO to 1.90 A resolution. The differences in the FeNO bond parameters and H-bonding patterns between the alpha and beta subunits contribute to understanding of the observed enhanced stability of the alpha(FeNO) moieties relative to the beta(FeNO) moieties in human R-state HbNO. PMID- 24769419 TI - Mitochondrial hyperpolarization during chronic complex I inhibition is sustained by low activity of complex II, III, IV and V. AB - The mitochondrial oxidative phosphorylation (OXPHOS) system consists of four electron transport chain (ETC) complexes (CI-CIV) and the FoF1-ATP synthase (CV), which sustain ATP generation via chemiosmotic coupling. The latter requires an inward-directed proton-motive force (PMF) across the mitochondrial inner membrane (MIM) consisting of a proton (DeltapH) and electrical charge (Deltapsi) gradient. CI actively participates in sustaining these gradients via trans-MIM proton pumping. Enigmatically, at the cellular level genetic or inhibitor-induced CI dysfunction has been associated with Deltapsi depolarization or hyperpolarization. The cellular mechanism of the latter is still incompletely understood. Here we demonstrate that chronic (24h) CI inhibition in HEK293 cells induces a proton-based Deltapsi hyperpolarization in HEK293 cells without triggering reverse-mode action of CV or the adenine nucleotide translocase (ANT). Hyperpolarization was associated with low levels of CII-driven O2 consumption and prevented by co-inhibition of CII, CIII or CIV activity. In contrast, chronic CIII inhibition triggered CV reverse-mode action and induced Deltapsi depolarization. CI- and CIII-inhibition similarly reduced free matrix ATP levels and increased the cell's dependence on extracellular glucose to maintain cytosolic free ATP. Our findings support a model in which Deltapsi hyperpolarization in CI-inhibited cells results from low activity of CII, CIII and CIV, combined with reduced forward action of CV and ANT. PMID- 24769420 TI - Circumferential distribution of the neointima at six-month and two-year follow-up after a bioresorbable vascular scaffold implantation: a substudy of the ABSORB Cohort B Clinical Trial. AB - AIMS: To investigate the extent and the circumferential distribution of the neointima tissue developed following an Absorb bioresorbable vascular scaffold (BVS) implantation. METHODS AND RESULTS: Twenty-three patients who were treated with the Absorb BVS and had optical coherence tomographic examination after scaffold implantation, at six-month and at two-year follow-up, were included in the current analysis. The lumen and the scaffold borders were detected and the circumferential thickness of the neointima was measured at one degree intervals. The symmetry of the neointima was defined as: minimum/maximum thickness. The lumen area was decreased at six months compared to baseline but it did not change between six-month and two-year follow-up (baseline: 7.49 [6.13-8.00] mm2, six months: 6.31 (4.75-7.06) mm2, two years: 6.01 [4.67-7.11] mm2, p=0.373). However, the mean neointima thickness (six months: 189 [173-229] m, two years: 258 [222 283] m, p<0.0001) and the symmetry index of the neointima (six months: 0.06 [0.02 0.09], two years: 0.27 [0.24-0.36], p<0.0001) were increased at two years. Full circumferential coverage of the vessel wall by neointima tissue was seen in 91% of the studied frames at two years. CONCLUSIONS: This study demonstrates that after an Absorb BVS implantation neointima tissue develops that covers almost the whole circumference of the vessel wall. In contrast to the metallic stents, the neointima tissue does not compromise the luminal dimensions. Further research is required to evaluate the neointimal characteristics and assess the potential value of the device in passivating high-risk plaques. PMID- 24769421 TI - TRPV1 expression regulation... A further step in defining its biology: commentary for K. Zavala et al. "The anticancer antibiotic mithramycin-A inhibits TRPV1 expression in dorsal root ganglion neurons" [Neurosci. Lett. (2014) doi:10.1016/j.neulet.2014.01.021]. PMID- 24769422 TI - Vitamin D status and the risk of multiple sclerosis: a systematic review and meta analysis. AB - To estimate the associations between vitamin D status and multiple sclerosis (MS). We searched electronic databases of the human literature in PubMed, EMBASE and the Cochrane Library up to February, 2014 using the following keywords: 'vitamin D' or '25(OH)D' and 'status' or 'deficiency' or 'insufficiency' and 'multiple sclerosis'. A systematic review and meta-analysis were conducted on observational studies that reported the association between blood vitamin D levels and MS. Eleven studies met the inclusion criteria. 1007 patients and 829 controls were included. Results of our meta-analysis show that MS patients had lower mean levels of 25-hydroxyvitamin D [25(OH)D] than healthy controls (weighted mean difference[MD], -14.52, 95% confidence interval [CI], -23.83 to 5.22). There were statistically significant heterogeneity (P<0.00001; I(2)=92%). The significant heterogeneity may be due to the differences in ethnicity, country, season of blood sampling and age of the participants studied. To sum up, low vitamin D levels are associated with an increased risk of MS. PMID- 24769424 TI - Immunosenescence: Influenza vaccination and the elderly. AB - Aging is associated with a decline in the normal function of the immune system, both cellular and humoral, which often leads to a state of 'immunosenescence'. It is necessary that we understand the fundamental cellular and molecular basis of immune senescence and immune responsiveness to prevent age-related diseases, such as viral and bacterial infections, in order to develop appropriate preventative and novel therapeutic measures. Vaccination has been a highly effective prophylactic in protecting vulnerable populations worldwide from many pathogens. Novel vaccine research to enhance protection against these diseases remains a global area of innovation and improvement. This review discusses the impact of immune senescence on the response to influenza vaccines, and the recent progress in translating the knowledge into developing effective influenza vaccines for the elderly to promote healthy aging. PMID- 24769423 TI - Effect of aging on microRNAs and regulation of pathogen recognition receptors. AB - Immunosenescence is the multifactorial age-associated immune deteriorization that leads to increased susceptibility to infections and decreased responses to vaccines. Recent studies have shown a fundamental role for microRNAs (miRNAs) in regulating immune responses, and nearly all the miRNAs involved in immune regulation show modulation during aging. Aging-associated miRNAs are largely negative regulators of the immune innate response and target central nodes of aging-associated networks, in particular, NF-kappaB, the downstream effector of TLR signals that leads to induction of proinflammatory responses. Multiple miRNAs have been reported to share similar regulatory activity. Here we review miRNA regulation of human innate immune recognition in aging, including both activation and resolution of inflammation, critical issues in detection, and areas of active investigation into our understanding of immunosenescence. PMID- 24769425 TI - Permanent junctional reciprocating tachycardia in children: a multicenter experience. AB - BACKGROUND: Permanent junctional reciprocating tachycardia (PJRT) is an uncommon form of supraventricular tachycardia in children. Treatment of this arrhythmia has been considered difficult because of a high medication failure rate and risk of cardiomyopathy. Outcomes in the current era of interventional treatment with catheter ablation have not been published. OBJECTIVE: To describe the presentation and clinical course of PJRT in children. METHODS: This is a retrospective review of 194 pediatric patients with PJRT managed at 11 institutions between January 2000 and December 2010. RESULTS: The median age at diagnosis was 3.2 months, including 110 infants (57%; aged <1 year). PJRT was incessant in 47%. The ratio of RP interval to cycle length was higher with incessant than with nonincessant tachycardia. Tachycardia-induced cardiomyopathy was observed in 18%. Antiarrhythmic medications were used for initial management in 76%, while catheter ablation was used initially in only 10%. Medications achieved complete resolution in 23% with clinical benefit in an additional 47%. Overall, 140 patients underwent 175 catheter ablation procedures with a success rate of 90%. There were complications in 9% with no major complications reported. Patients were followed for a median of 45.1 months. Regardless of treatment modality, normal sinus rhythm was present in 90% at last follow-up. Spontaneous resolution occurred in 12% of the patients. CONCLUSION: PJRT in children is frequently incessant at the time of diagnosis and may be associated with tachycardia-induced cardiomyopathy. Antiarrhythmic medications result in complete control in few patients. Catheter ablation is effective, and serious complications are rare. PMID- 24769426 TI - Individual telomere length decay in patients with spondyloarthritis. AB - Telomere length was sequentially determined in peripheral blood leukocytes (PBL) from patients with ankylosing spondylitis (AS; n = 44) and psoriatic arthritis (PsA; n = 42) followed through 2.93 +/- 0.99 years, using a quantitative PCR (qPCR) assay. The initial telomere size from PsA patients was higher than those with cutaneous psoriasis only (n = 53), possibly due to the inflammatory condition. The qPCR assay was sensitive enough to evidence a significant telomere length shortening in PBL from practically all subjects and PsA patients showed a higher rate of loss of telomere sequence than patients with AS during the follow up time. PMID- 24769427 TI - Diabetes as a risk factor to cancer: functional role of fermented papaya preparation as phytonutraceutical adjunct in the treatment of diabetes and cancer. AB - Oncologists and diabetologists quote scientific data from epidemiological and in vitro studies to show that high levels of insulin and glucose, in combination with oxidative stress and chronic inflammation, can heighten the risk of developing cancer amongst patients with diabetes. Although the cancers that have been consistently associated with type 2 diabetes include pancreatic, colorectal, breast and liver cancer, the preponderance of the disease risk factors such as obesity, inflammation, hyperglycemia, hyperinsulinaemia (as a result of insulin resistance and oxidative beta-cell damage) and the indirect influence of anti diabetic medications are increasingly being defined. Fermented papaya preparation (FPP) has defined antioxidant and immune-modulating potentials. The ability of FPP influence signaling cascades associated with cell growth and survival presents a rational for chemopreventive adjunct that can be used in combination with traditional redox based therapies that target oxidative stress in the cancer micro environment. It is further suggested that the demonstrated efficacy FPP to control blood glucose, excessive inflammation and modulate free radical-induced oxidative damage which are triggers of liver, bladder, breast and prostate cancers in type 2 diabetics, may favorably mitigate the side effects of ensuing diabetes and cancer therapy. What remains paramount is early cancer detection and early determination of propensity risks for diabetes. The education of patients, proper dietary management and compliance with therapeutic regime directed at cancer and diabetes encapsulate challenges of global magnitude. PMID- 24769428 TI - Nucleotide excision repair related gene polymorphisms and genetic susceptibility, chemotherapeutic sensitivity and prognosis of gastric cancer. AB - Human genomic DNA is in a dynamic balance of damage and repair. Cells employ multiple and specific repair pathways, such as nucleotide excision repair (NER), as unrepaired DNA damage has deleterious consequences and could give rise to carcinogenesis. Gene polymorphisms play a crucial role in predicting the risk and prognosis of cancer. Polymorphisms of NER-related genes could alter the ability of NER to effectively monitor and repair DNA damage, and thus may be associated with genetic susceptibility, chemotherapeutic sensitivity and prognosis of cancer. In recent years, increasing studies have focused on the association between polymorphisms of NER genes and gastric cancer, the world's fourth most common cancer and the second most common cause for cancer-related death. Here we reviewed the recent studies on the associations between polymorphisms of NER genes and gastric cancer from perspectives of genetic susceptibility, chemotherapeutic sensitivity and prognosis. PMID- 24769429 TI - Development of motor planning for dexterity tasks in trisomy 21. AB - We examined the macroscopic aspects of motor planning in two manual dexterity tasks, comparing children, adolescents, and young adults with trisomy 21 (T21) with typically developing controls from a developmental perspective. We analyzed the order in which objects were picked up from a table during two manual tasks of the Movement Assessment Battery for Children (M-ABC). Participants with T21 were always slower than controls. Task completion times depended on the strategy used by participants to gather up the pegs or coins. A structured strategy, in which the participants picked the items up moving methodically along each row/column, contributed to rapid task completion by younger children and participants with T21. This study highlights the ability of children with T21 to select and maintain an efficient strategy that takes account of their motor difficulties. Developmental trajectories help to explain T21 functioning in these dexterity tasks. PMID- 24769430 TI - Modality effect on contextual integration in people with Williams syndrome. AB - In this study meaningful social stimuli were used as probes in a task requiring the judgment of semantic appropriateness to investigate contextual integration ability to test the ability of people with Williams syndrome (WS) to integrate information, as opposed to the use of meaningless syllables in audiovisual studies (the McGurk effect). Participants were presented with background auditory primes followed by targets that were either congruent or incongruent with the prime. Two modes of target were presented: a visual target (AV task) or an auditory target (AA task). Participants were asked to respond yes to contextually appropriate pairs and no to those that were contextually inappropriate. The congruency effect was measured as an index of successful central coherence. Similar to normally developing controls, people with WS showed shorter response latencies and greater accuracy in recognizing congruent pairs compared with incongruent pairs. Their performance did not differ from that of controls matched by mental age, but was inferior to that of controls matched by chronological age. The results revealed generalized contextual integration for auditory primes in both tasks, consistent with previous studies using visual presentation of social related stimuli in people with WS (Hsu, 2013a, 2013c). Further demonstration of the presence of a modality effect on contextual coherence implies that cross modal learning may be advantageous compared with unimodal learning. PMID- 24769431 TI - Reliability and validity of the Pragmatics Observational Measure (POM): a new observational measure of pragmatic language for children. AB - There is a need for a reliable and valid assessment of childhood pragmatic language skills during peer-peer interactions. This study aimed to evaluate the psychometric properties of a newly developed pragmatic assessment, the Pragmatic Observational Measure (POM). The psychometric properties of the POM were investigated from observational data of two studies - study 1 involved 342 children aged 5-11 years (108 children with ADHD; 108 typically developing playmates; 126 children in the control group), and study 2 involved 9 children with ADHD who attended a 7-week play-based intervention. The psychometric properties of the POM were determined based on the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) taxonomy of psychometric properties and definitions for health-related outcomes; the Pragmatic Protocol was used as the reference tool against which the POM was evaluated. The POM demonstrated sound psychometric properties in all the reliability, validity and interpretability criteria against which it was assessed. The findings showed that the POM is a reliable and valid measure of pragmatic language skills of children with ADHD between the age of 5 and 11 years and has clinical utility in identifying children with pragmatic language difficulty. PMID- 24769432 TI - Comparison between a Mandarin Chinese version of the Childhood Autism Spectrum Test and the Clancy Autism Behaviour Scale in mainland China. AB - A Mandarin Chinese version of the Childhood Autism Spectrum Test (CAST) and Clancy Autism Behaviour Scale (CABS) were applied to 150 children aged 4-11 years old from clinical settings and mainstream schools in Beijing. All the children were further assessed using the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R). The validity of two instruments on screening of ASC was examined and compared using receiver operating characteristic (ROC) curve analysis. The validity of CAST (sensitivity: 89%, specificity: 80%, PPV: 70%) was better than the CABS (sensitivity: 58%, specificity: 84%, PPV: 65%). The area under the curve (AUC) of the CAST (AUC=0.90) was significantly higher than the CABS (AUC=0.79, p=0.0002). The Mandarin CAST demonstrated a better validity in distinguishing children with ASC from children without ASC. It is an acceptable candidate as a screening instrument for ASC in large epidemiological study in Chinese population. PMID- 24769434 TI - Heart rate variability and treatment outcome in major depression: a pilot study. AB - Variations in heart rate variability (HRV) have been associated with major depressive disorder (MDD), but the relationship of baseline HRV to treatment outcome in MDD is unclear. We conducted a pilot study to examine associations between resting baseline HRV and MDD treatment outcome. We retrospectively tested several parameters of HRV in an MDD treatment study with escitalopram (ESC, N=26) to generate a model of how baseline HRV related to treatment outcome, and cross validated the model in a separate trial of MDD treatment with Iyengar yoga (IY, N=16). Lower relative power of very low frequency (rVLF) HRV at baseline predicted improvement in depressive symptoms when adjusted for age and gender (R2>.43 and p<0.05 for both trials). Although vagal parasympathetic measures were correlated with antidepressant treatment outcome, their predictive power was not significant after adjusting for age and gender. In conclusion, baseline resting rVLF was associated with depression treatment outcome in two independent MDD treatment studies. These results should be interpreted with caution due to limited sample size, but a strength of this study is its validation of the rVLF predictor in an independent sample. rVLF merits prospective confirmation as a candidate biomarker. PMID- 24769433 TI - Mice lacking the transcriptional coactivator PGC-1alpha exhibit alterations in inhibitory synaptic transmission in the motor cortex. AB - Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a transcriptional coactivator known to regulate gene programs in a cell specific manner in energy-demanding tissues, and its dysfunction has been implicated in numerous neurological and psychiatric disorders. Previous work from the Cowell laboratory indicates that PGC-1alpha is concentrated in inhibitory interneurons and is required for the expression of the calcium buffer parvalbumin (PV) in the cortex; however, the impact of PGC-1alpha deficiency on inhibitory neurotransmission in the motor cortex is not known. Here, we show that mice lacking PGC-1alpha exhibit increased amplitudes and decreased frequency of spontaneous inhibitory postsynaptic currents in layer V pyramidal neurons. Upon repetitive train stimulation at the gamma frequency, decreased GABA release is observed. Furthermore, PV-positive interneurons in PGC-1alpha -/- mice display reductions in intrinsic excitability and excitatory input without changes in gross interneuron morphology. Taken together, these data show that PGC-1alpha is required for normal inhibitory neurotransmission and cortical PV-positive interneuron function. Given the pronounced motor dysfunction in PGC-1alpha -/- mice and the essential role of PV-positive interneurons in maintenance of cortical excitatory:inhibitory balance, it is possible that deficiencies in PGC 1alpha expression could contribute to cortical hyperexcitability and motor abnormalities in multiple neurological disorders. PMID- 24769435 TI - Elucidating the mechanisms of protein antigen adsorption to the CAF/NAF liposomal vaccine adjuvant systems: effect of charge, fluidity and antigen-to-lipid ratio. AB - The reverse vaccinology approach has recently resulted in the identification of promising protein antigens, which in combination with appropriate adjuvants can stimulate customized, protective immune responses. Although antigen adsorption to adjuvants influences vaccine efficacy and safety, little is generally known about how antigens and adjuvants interact at the molecular level. The aim of this study was to elucidate the mechanisms of interactions between the equally sized, but oppositely charged model protein antigens alpha-lactalbumin and lysozyme, and i) the clinically tested cationic liposomal adjuvant CAF01 composed of cationic dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB) or ii) the neutral adjuvant formulation NAF01, where DDA was replaced with zwitterionic distearoylphosphatidylcholine (DSPC). The effect of liposome charge, bilayer rigidity, isoelectric point and antigen-to-lipid ratio was investigated using dynamic light scattering, transmission electron microscopy, differential scanning calorimetry, intrinsic fluorescence and Langmuir monolayers. The net anionic alpha-lactalbumin adsorbed onto the cationic liposomes, while there was no measureable attractive interaction with the zwitterionic liposomes. In contrast, the net cationic lysozyme showed very little interaction with either types of liposome. Adsorption of alpha-lactalbumin altered its tertiary structure, affected lipid membrane packing below and above the phase transition temperature, and neutralized the liposomal surface charge, resulting in reduced colloidal stability and liposome aggregation. Langmuir studies revealed that alpha-lactalbumin was not squeezed out of DDA monolayers upon compression, which suggests additional hydrophobic interactions. Such interactions are thus likely to affect the way vaccine antigens are presented to antigen-presenting cells, and may play an important role for the efficacy of the vaccine-induced immune response. These studies thus exemplify the importance of characterizing the molecular interactions between the vaccine antigen and adjuvant along with immunogenicity and efficacy studies. PMID- 24769436 TI - Membrane-active peptides: binding, translocation, and flux in lipid vesicles. AB - Recently, new and improved methods have been developed to measure translocation of membrane-active peptides (antimicrobial, cytolytic, and amphipathic cell penetrating peptides) across lipid bilayer membranes. The hypothesis that translocation of membrane-active peptides across a lipid bilayer is determined by the Gibbs energy of insertion of the peptide into the bilayer is re-examined in the light of new experimental tests. The original hypothesis and its motivation are first revisited, examining some of the specific predictions that it generated, followed by the results of the initial tests. Translocation is understood as requiring two previous steps: binding and insertion in the membrane. The problem of peptide binding to membranes, its prediction, measurement, and calculation are addressed. Particular attention is given to understanding the reason for the need for amphipathic structures in the function of membrane-active peptides. Insertion into the membrane is then examined. Hydrophobicity scales are compared, and their influence on calculations is discussed. The relation between translocation and graded or all-or-none peptide induced flux from or into lipid vesicles is also considered. Finally, the most recent work on translocation is examined, both experimental and from molecular dynamics simulations. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID- 24769437 TI - A pilot randomized controlled trial of D-cycloserine and distributed practice as adjuvants to constraint-induced movement therapy after stroke. AB - Background. Phase III trials of rehabilitation of paresis after stroke have proven the effectiveness of intensive and extended task practice, but they have also shown that many patients do not qualify, because of severity of impairment, and that many of those who are treated are left with clinically significant deficits. Objective. To test the value of 2 potential adjuvants to normal learning processes engaged in constraint-induced movement therapy (CIMT): greater distribution of treatment over time and the coadministration of d-cycloserine, a competitive agonist at the glycine site of the N-methyl-D-aspartate glutamate receptor. Methods. A prospective randomized single-blind parallel-group trial of more versus less condensed therapy (2 vs 10 weeks) and d-cycloserine (50 mg) each treatment day versus placebo (in a 2 * 2 design), as potential adjuvants to 60 hours of CIMT. Results. Twenty-four participants entered the study, and 22 completed it and were assessed at the completion of treatment and 3 months later. Neither greater distribution of treatment nor treatment with d-cycloserine significantly augmented retention of gains achieved with CIMT. Conclusions. Greater distribution of practice and treatment with d-cycloserine do not appear to augment retention of gains achieved with CIMT. However, concentration of CIMT over 2 weeks ("massed practice") appears to confer no advantage either. PMID- 24769438 TI - High serum organochlorine pesticide concentrations in diabetics of a cotton producing area of the Benin Republic (West Africa). AB - The Borgou region of northern Benin is a major cotton producing area and consistently uses higher amounts of pesticides than other areas of the country. Organochlorine pesticides (OCPs), poorly handled, have been widely used and are still illegally present. We therefore hypothesized that serum OCP levels would be high in Borgou. As part of a case-control study on diabetes status and pesticide exposure, we measured the distribution of serum concentrations of 14 OCPs by gas chromatography with mass spectrometry. A sample of 118 diabetic subjects was selected using a four-stage cluster sampling with 54.2% of men and 45.8% of women; 43% lived in urban areas, 14.4% were obese and 39.8% had high economic status. The four detected OCPs were p,p'-DDT, p,p'-DDE, beta-HCH and trans nonachlor with respective geometric means (geometric standard deviation) of 497.1 (4.5), 20.6 (7.9), 2.9 (3.4), and 2.0 (2.3) ng/g of total serum lipids. OCP levels were significantly higher in obese, wealthier and more educated subjects and in those living in urban areas as compared to the other groups, particularly for p,p'-DDE, p,p'-DDT and beta-HCH. Levels of DDT and DDE were higher than reported in other countries where DDT is no longer permitted. The low DDT/DDE ratio of 0.05 suggests past human exposure through food contamination. There is thus a need to reinforce governmental regulations for a more responsible use of pesticides in the country, in order to reduce health risks associated with persistent organic pollutants. PMID- 24769439 TI - Preclinical randomised safety, efficacy and physiologic study of the silicon dioxide inert-coated Axetis and bare metal stent: short-, mid- and long-term outcome. AB - AIMS: To evaluate the short-, mid- and long-term safety, efficacy and vascular physiology of Axetis silicon dioxide (SiO2, abrading the micropores) inert-coated stent implantation in a randomised preclinical setting. METHODS AND RESULTS: Coronary arteries of domestic pigs were randomised to receive either Axetis or BMS (same design) stents with one-, three- and six-month follow-up (FUP), controlled by coronary angiography, optical coherence tomography (OCT), intravascular ultrasound (IVUS) and histology (n=32). The time-dependent vasomotor reaction of coronary arteries to stenting was measured using modified myography (n=12). Complete endothelialisation of the Axetis stent was confirmed by OCT, IVUS and histology at one-month FUP. Histopathology revealed continuous healing of the vessel wall with a gradual reduction of inflammation and fibrin score during the six-month FUP in both stent types. Significantly smaller neointimal area and %area stenosis were measured in Axetis stents compared with BMS at each FUP time point. Vascular reactivity measurements showed significantly better endothelium-dependent vasodilation of stented arteries with Axetis implantation. CONCLUSIONS: Implantation of the Axetis SiO2-coated stent resulted in a significantly better safety, efficacy and vessel physiology profile compared with BMS of the same design with a continuous decrease in vessel inflammation during the six-month FUP. PMID- 24769440 TI - Water promotes the sealing of nanoscale packing defects in folding proteins. AB - A net dipole moment is shown to arise from a non-Debye component of water polarization created by nanoscale packing defects on the protein surface. Accordingly, the protein electrostatic field exerts a torque on the induced dipole, locally impeding the nucleation of ice at the protein-water interface. We evaluate the solvent orientation steering (SOS) as the reversible work needed to align the induced dipoles with the Debye electrostatic field and computed the SOS for the variable interface of a folding protein. The minimization of the SOS is shown to drive protein folding as evidenced by the entrainment of the total free energy by the SOS energy along trajectories that approach a Debye limit state where no torque arises. This result suggests that the minimization of anomalous water polarization at the interface promotes the sealing of packing defects, thereby maintaining structural integrity and committing the protein chain to fold. PMID- 24769441 TI - Let-7c inhibits metastatic ability of mouse hepatocarcinoma cells via targeting mannoside acetylglucosaminyltransferase 4 isoenzyme A. AB - Aberrant glycosylation may promote tumor invasion and metastasis. To investigate whether microRNA (miRNA) is involved in glycosylation-related metastasis, we examined the role of let-7c, a well-known tumor-suppressor miRNA, in glycosylation in murine hepatocarcinoma cell lines Hca-F and Hca-P. We found that let-7c level was higher in Hca-P cells (with lower lymphatic metastasis potential) than in Hca-F cells (with higher lymphatic metastasis potential). Overexpression of let-7c decreased hyper-N-glycosylation of Hca-F cells and repressed their metastatic and invasive ability. Mannoside acetylglucosaminyltransferase 4, isoenzyme A (Mgat4a) is a key glycosyltransferase in the pathway of synthesizing complex N-glycans. Bioinformatics analysis indicates that Mgat4a may be a target of let-7c, which has been verified by dual-luciferase reporter gene assay. Furthermore, the anti metastatic effect of overexpressed let-7c is similar to that of Mgat4a siRNAs transfection. Hence, our results suggest that let-7c may inhibit the metastatic ability of Hca-F cells, at least partially, via repressing Mgat4a activity. PMID- 24769442 TI - API5 confers tumoral immune escape through FGF2-dependent cell survival pathway. AB - Identifying immune escape mechanisms used by tumors may define strategies to sensitize them to immunotherapies to which they are otherwise resistant. In this study, we show that the antiapoptotic gene API5 acts as an immune escape gene in tumors by rendering them resistant to apoptosis triggered by tumor antigen specific T cells. Its RNAi-mediated silencing in tumor cells expressing high levels of API5 restored antigen-specific immune sensitivity. Conversely, introducing API5 into API5(low) cells conferred immune resistance. Mechanistic investigations revealed that API5 mediated resistance by upregulating FGF2 signaling through a FGFR1/PKCdelta/ERK effector pathway that triggered degradation of the proapoptotic molecule BIM. Blockade of FGF2, PKCdelta, or ERK phenocopied the effect of API5 silencing in tumor cells expressing high levels of API5 to either murine or human antigen-specific T cells. Our results identify a novel mechanism of immune escape that can be inhibited to potentiate the efficacy of targeted active immunotherapies. PMID- 24769443 TI - LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. AB - Therapeutic antibodies that target T-cell co-inhibitory molecules display potent antitumor effects in multiple types of cancer. LSECtin is a cell surface lectin of the DC-SIGN family expressed in dendritic cells that inhibits T-cell responses. LSECtin limits T-cell activity in infectious disease, but it has not been studied in cancer. Here we report the finding that LSECtin is expressed commonly in melanomas where it blunts tumor-specific T-cell responses. When expressed in B16 melanoma cells, LSECtin promoted tumor growth, whereas its blockade slowed tumor growth in either wild-type or LSECtin-deficient mice. The tumor-promoting effects of LSECtin were abrogated in Rag1(-/-) mice or in response to CD4(+) or CD8(+) T-cell depletion. Mechanistic investigations determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating the cell cycle kinases CDK2, CDK4, and CDK6. Accordingly, as expressed in B16, tumor cells LSECtin inhibited tumor-specific T-cell responses relying upon proliferation in vitro and in vivo. Notably, LSECtin interacted with the co-regulatory molecule LAG-3, the blockade of which restored IFNgamma secretion that was reduced by melanoma-derived expression of LSECtin. Together, our findings reveal that common expression of LSECtin in melanoma cells engenders a mechanism of immune escape, with implications for novel immunotherapeutic combination strategies. PMID- 24769444 TI - NCOA1 Directly Targets M-CSF1 Expression to Promote Breast Cancer Metastasis. AB - In breast cancer, overexpression of the nuclear coactivator NCOA1 (SRC-1) is associated with disease recurrence and resistance to endocrine therapy. To examine the impact of NCOA1 overexpression on morphogenesis and carcinogenesis in the mammary gland (MG), we generated MMTV-hNCOA1 transgenic [Tg(NCOA1)] mice. In the context of two distinct transgenic models of breast cancer, NCOA1 overexpression did not affect the morphology or tumor-forming capability of MG epithelial cells. However, NCOA1 overexpression increased the number of circulating breast cancer cells and the efficiency of lung metastasis. Mechanistic investigations showed that NCOA1 and c-Fos were recruited to a functional AP-1 site in the macrophage attractant CSF1 promoter, directly upregulating colony-simulating factor 1 (CSF1) expression to enhance macrophage recruitment and metastasis. Conversely, silencing NCOA1 reduced CSF1 expression and decreased macrophage recruitment and breast cancer cell metastasis. In a cohort of 453 human breast tumors, NCOA1 and CSF1 levels correlated positively with disease recurrence, higher tumor grade, and poor prognosis. Together, our results define an NCOA1/AP-1/CSF1 regulatory axis that promotes breast cancer metastasis, offering a novel therapeutic target for impeding this process. PMID- 24769445 TI - Skeletal muscle plasticity induced by seasonal acclimatization in carp involves differential expression of rRNA and molecules that epigenetically regulate its synthesis. AB - Ribosomal biogenesis controls cellular growth in living organisms, with the rate limiting step of this process being the transcription of ribosomal DNA (rDNA). Considering that epigenetic mechanisms allow an organism to respond to environmental changes, the expression in muscle of several molecules that regulate epigenetic rRNA synthesis, as well as rDNA transcription, were evaluated during the seasonal acclimatization of the carp. First, the nucleotide sequences encoding the components forming the NoRC (ttf-I, tip5) and eNoSC (sirt1, nml, suv39h1), two chromatin remodeling complexes that silence rRNA synthesis, as well as the sequence of ubf1, a key regulator of rDNA transcription, were obtained. Subsequently the transcriptional regulation of the aforementioned molecules, and other key molecules involved in rRNA synthesis (mh2a1, mh2a2, h2a.z, h2a.z.7, nuc, p80), was assessed. The carp sequences for TTF-I, TIP5, SIRT1, NML, SUV39H1, and UBF1 showed a high conservation of domains and key amino acids in comparison with other fish and higher vertebrates. The mRNA contents in muscle for ttf-I, tip5, sirt1, nml, suv39h1, mh2a1, mh2a.z, and nuc were up-regulated during winter in comparison with summer, whereas the mRNA levels of mh2a2, ubf1, and p80 were down-regulated. Also, the contents of molecules involved in processing the rRNA (snoRNAs) and pRNA, a stabilizer of NoRC complex, were analyzed, finding that these non-coding RNAs were not affected by seasonal acclimatization. These results suggest that variations in the expression of rRNA and the molecules that epigenetically regulate its synthesis are contributing to the muscle plasticity induced by seasonal acclimatization in carp. PMID- 24769446 TI - Tramiprosate protects neurons against ischemic stroke by disrupting the interaction between PSD95 and nNOS. AB - Tramiprosate, a small aminosulphonate compound, is present in various species of red marine algae. In this study, we examined whether tramiprosate protects neurons and improves functional recovery following ischemic stroke in rats subjected to the intraluminal filament model of MCAO and further explored the underlying mechanisms. Tramiprosate dose-dependently reduced the infarct volume after MCAO, and the therapeutic time window of tramiprosate (50 mg/kg) for cerebral ischemia was at least 6 h. Moreover, functional assays and histochemical staining were performed. Significant neurological functional recovery was found after tramiprosate (50 mg/kg) administration in all three functional assays performed (modified neurological severity score, foot-fault test and adhesive removal somatosensory test). Tramiprosate significantly attenuated OGD- or NMDA induced injury in NGF-differentiated PC12 cells and primary cortical neurons. Furthermore, the neuroprotective effect of tramiprosate was partially blunted by the NMDA receptor (NMDAR) antagonist MK801 both in vitro and in vivo, indicating that tramiprosate might confer neuroprotection against stroke via the NMDAR. Based on co-immunoprecipitation and western blotting, tramiprosate decreased the intensity of the association between nNOS and PSD95, and tramiprosate also inhibited the translocation of nNOS from the cytosol to the membrane without affecting the total nNOS expression level both in vitro and in vivo. In conclusion, tramiprosate dose-dependently provides neuroprotection in vitro and in vivo against ischemic stroke, and the neuroprotective effect of tramiprosate may be partially attributed to disruption of the interaction between PSD95 and nNOS and inhibition of nNOS translocation. PMID- 24769447 TI - In-bag morcellation. AB - In-bag morcellation seems to be a viable alternative to open power morcellation and offers the advantage of minimal to no spillage of tissue or fluids during morcellation. We report our initial experience and technique using this approach. PMID- 24769448 TI - AAGL practice report: Practice Guidelines on the Prevention of Apical Prolapse at the Time of Benign Hysterectomy. AB - Pelvic organ prolapse may adversely impact physical, sexual and emotional health. Women with symptomatic prolapse often experience altered bladder and bowel function, increased pelvic pressure, diminution of sexual satisfaction, and altered body image. With increasing vaginal descent, various bladder, bowel, and prolapse symptoms are increased. Approximately 200,000 women undergo inpatient procedures for prolapse in the United States each year, with regional and racial differences in rates of surgery reported. The demand for health care services related to pelvic floor disorders will increase at twice the rate of the population itself. PMID- 24769449 TI - Safety culture in the gynecology robotics operating room. AB - STUDY OBJECTIVE: To measure the safety culture in the robotics surgery operating room before and after implementation of the Robotic Operating Room Computerized Checklist (RORCC). DESIGN: Prospective study. SUBJECTS: Gynecology surgical staff (n = 32). SETTING: An urban community hospital. INTERVENTIONS: The Safety Attitudes Questionnaire domains examined were teamwork, safety, job satisfaction, stress recognition, perceptions of management, and working conditions. Questions and domains were described using percent agreement and the Cronbach alpha. Paired t-tests were used to describe differences before and after implementation of the checklist. MEASUREMENTS AND MAIN RESULTS: Mean (SD) staff age was 46.7 (9.5) years, and most were women (78%) and worked full-time (97%). Twenty respondents (83% of nurses, 80% of surgeons, 66% of surgical technicians, and 33% of certified registered nurse anesthetists) completed the Safety Attitudes Questionnaire; 6 were excluded because of non-matching identifiers. Before RORCC implementation, the highest quality of communication and collaboration was reported by surgeons and surgical technicians (100%). Certified registered nurse anesthetists reported only adequate levels of communication and collaboration with other positions. Most staff reported positive responses for teamwork (48%; alpha = 0.81), safety (47%; alpha = 0.75), working conditions (37%; alpha = 0.55), stress recognition (26%; alpha = 0.71), and perceptions of management (32%; alpha = 0.52). No differences were observed after RORCC implementation. CONCLUSION: Quality of communication and collaboration in the gynecology robotics operating room is high between most positions; however, safety attitude responses are low overall. No differences after RORCC implementation and low response rates may highlight lack of staff support. PMID- 24769450 TI - Preparation of surface-imprinted polymer grafted with water-compatible external layer via RAFT precipitation polymerization for highly selective and sensitive electrochemical determination of brucine. AB - A novel brucine imprinted polymer was prepared on multi-walled carbon nanotubes by reversible addition-fragmentation chain transfer (RAFT) precipitation polymerization. The polymer was further grafted with hydrophilic poly(glycerol monomethacrylate) brushes to improve its water-compatibility. The obtained molecularly imprinted material showed enhanced accessibility to brucine and improved selective recognition property in water medium. When the material was supported on an ionic liquid functionalized graphene coated glassy carbon electrode for the electrochemical determination of brucine, the resulting electrochemical sensor presented good analytical performance. Under the optimized conditions, the peak current was linear to brucine concentration in the ranges of 0.006-0.6 MUM and 0.6-5.0 MUM with sensitivities of 15.3 MUA/MUMmm(2) and 5.4 MUA/MUM mm(2), respectively; the detection limit was 2 nM (S/N=3). The sensor was successfully applied to the determination of brucine in practical samples and the recovery for the standards added was 94-104%. PMID- 24769451 TI - Caffeine electrochemical sensor using imprinted film as recognition element based on polypyrrole, sol-gel, and gold nanoparticles hybrid nanocomposite modified pencil graphite electrode. AB - In the present study, a novel sensitive and selective nanocomposite imprinted electrochemical sensor for the indirect determination of caffeine has been prepared. The imprinted sensor was fabricated on the surface of pencil graphite electrode (PGE) via one-step electropolymerization of the imprinted polymer composed of conductive polymer, sol-gel, gold nanoparticles (AuNPs), and caffeine. Due to such combination like the thin film of molecularly imprinted polymer (MIP) with specific binding sites, the sensor responded quickly to caffeine. AuNPs were introduced for the enhancement of electrical response by facilitating charge transfer processes of [Fe(CN)6](3-)/[Fe(CN)6](4-) which was used as an electrochemical active probe. The fabrication process of the sensor was characterized by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Several important parameters controlling the performance of the sensor were investigated and optimized. The imprinted sensor has the advantages of high porous surface structure, inexpensive, disposable, excellent stability, good reproducibility and repeatability. The linear ranges of the MIP sensor were in the range from 2.0 to 50.0 and 50.0 to 1000.0 nmol L(-1), with the limit of detection (LOD) of 0.9 nmol L(-1) (S/N=3). Furthermore, the proposed method was successfully intended for the determination of caffeine in real samples (urine, plasma, tablet, green tea, energy and soda drink). PMID- 24769452 TI - Competency based training is a framework for incompetence. PMID- 24769453 TI - A new Riff: Rif1 eats its cake and has it too. AB - Rif1 protein is present in eukaryotic cells from yeast to human. In yeast, Rif1 is important for telomere homeostasis. Despite conservation in its domain organization, human Rif1 is not part of the telomere complex but was recently reported to work at DNA double-strand breaks (DSBs) with 53BP1 to inhibit 5' strand degradation (resection) and stimulate a subset of nonhomologous end joining (NHEJ) reactions. Martina et al report in this issue of EMBO reports that yeast Rif1 is also recruited to DSBs, but in contrast to its human counterpart, it promotes resection. The authors propose that Rif1 stimulates resection by limiting the access of Rad9, an ortholog of 53BP1, to DSBs. PMID- 24769454 TI - Synthetic peptides derived from the C-terminal 6kDa region of Plasmodium falciparum SERA5 inhibit the enzyme activity and malaria parasite development. AB - BACKGROUND: Plasmodium falciparum serine repeat antigen 5 (PfSERA5) is an abundant blood stage protein that plays an essential role in merozoite egress and invasion. The native protein undergoes extensive proteolytic cleavage that appears to be tightly regulated. PfSERA5 N-terminal fragment is being developed as vaccine candidate antigen. Although PfSERA5 belongs to papain-like cysteine protease family, its catalytic domain has a serine in place of cysteine at the active site. METHODS: In the present study, we synthesized a number of peptides from the N- and C-terminal regions of PfSERA5 active domain and evaluated their inhibitory potential. RESULTS: The final proteolytic step of PfSERA5 involves removal of a C-terminal ~6kDa fragment that results in the generation of a catalytically active ~50kDa enzyme. In the present study, we demonstrate that two of the peptides derived from the C-terminal ~6kDa region inhibit the parasite growth and also cause a delay in the parasite development. These peptides reduced the enzyme activity of the recombinant protein and co-localized with the PfSERA5 protein within the parasite, thereby indicating the specific inhibition of PfSERA5 activity. Molecular docking studies revealed that the inhibitory peptides interact with the active site of the protein. Interestingly, the peptides did not have an effect on the processing of PfSERA5. CONCLUSIONS: Our observations indicate the temporal regulation of the final proteolytic cleavage step that occurs just prior to egress. GENERAL SIGNIFICANCE: These results reinforce the role of PfSERA5 for the intra-erythrocytic development of malaria parasite and show the role of carboxy terminal ~6kDa fragments in the regulation of PfSERA5 activity. The results also suggest that final cleavage step of PfSERA5 can be targeted for the development of new anti-malarials. PMID- 24769455 TI - Locomotor activating effects of cocaine and scopolamine combinations in rats: isobolographic analysis. AB - Muscarinic cholinergic receptors are currently receiving renewed interest as viable targets for treating various psychiatric disorders. Dopaminergic and muscarinic systems interact in complex ways. The goal of this study was to quantify the interaction between a systemically administered psychomotor stimulant and muscarinic antagonist at the behavioral level. Through isobolographic analysis of locomotor activity data, we assessed the effects of three cocaine/scopolamine mixtures in terms of deviation from simple dose addition (additivity), at four effect levels. All three mixtures produced some more-than-additive (synergistic) effects, as lower doses were needed to produce the given effects relative to the calculated effect of additive doses. A mixture with comparable contributions from cocaine and scopolamine produced significantly more-than-additive effects at all but the lowest effect level examined. A mostly cocaine mixture was more-than-additive only at low effect levels, whereas a mostly-scopolamine mixture produced effects more consistent with additivity, with only the highest effect level barely reaching significant synergism. Our study confirms and quantifies previous findings that suggested synergistic effects of stimulants and muscarinic antagonists. The synergism implies that cocaine and scopolamine stimulate locomotor activity through nonidentical pathways, and was most pronounced for a mixture containing cocaine and scopolamine in comparable proportions. PMID- 24769456 TI - [Pancreaticobiliary maljunction and the revised diagnostic criteria]. PMID- 24769457 TI - [Imaging diagnosis for pancreaticobiliary maljunction]. PMID- 24769458 TI - [Nation wide survey of pancreaticobiliary maljunction]. PMID- 24769459 TI - [Pancreaticobiliary reflux and biliary malignancy in individuals with a normal pancreaticobiliary junction]. PMID- 24769460 TI - [Present state and problems of the surgical treatment for the pancreatobiliary maljunction]. PMID- 24769461 TI - [Front-line studies on pancreatobiliary maljunction (discussion)]. PMID- 24769462 TI - [Acoustic radiation force impulse elastography for liver disease staging in human immunodeficiency virus and hepatitis C virus co-infection]. AB - BACKGROUND: Survival of human immunodeficiency virus (HIV)-infected patients has improved due to the widespread use of anti-retroviral therapy. However, mortality has increased when HIV-infected patients are co-infected with hepatitis C virus (HCV), and the liver disease in such patients is rapidly progressive compared with that in HCV monoinfected patients. Therefore, accurate staging of the liver disease is critical when determining appropriate treatment. AIM: To clarify the efficacy of acoustic radiation force impulse (ARFI) elastography for the evaluation of liver fibrosis and hepatic functional reserve in HIV/HCV co infected patients. METHODS: The correlation of shear wave velocity (Vs), measured by ARFI elastography, with liver fibrosis or hepatic functional reserve was analyzed. RESULTS: Vs was significantly correlated with platelet count, splenic volume, hyaluronic acid, type IV collagen, and LHL15 (receptor index: uptake ratio of the liver to the liver plus heart at 15min) in 99mTc-GSA (technetium-99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin) scintigraphy. CONCLUSION: ARFI elastography was useful for the staging of liver disease in HIV/HCV co-infected patients and it facilitated minimally invasive and accessible evaluation of fibrosis and functional reserve. PMID- 24769464 TI - [Case report of chemotherapeutic control of a gastric cancer producing granulocyte-colony stimulating factor]. AB - A 79-year-old man presented with a history of vomiting. Laboratory data indicated leukocytosis (26360/MUl), and elevated granulocyte-colony stimulating factor (G CSF) level (155 pg/ml). Upper gastrointestinal endoscopy revealed a type 3 gastric cancer, and subsequent G-CSF immunohistochemical staining of a biopsy specimen was positive. He was therefore diagnosed with a G-CSF-producing gastric cancer. Computed tomography revealed multiple liver metastases. Chemotherapy was initiated, resulting in a partial response for 5 months. G-CSF-producing gastric cancer is rare; thus, we take this opportunity to report our case and to summarize the G-CSF-producing gastric cancer cases reported in Japan. PMID- 24769463 TI - [Bevacizumab-induced reversible posterior leukoencephalopathy syndrome in a patient with metastatic colorectal cancer]. AB - We report a rare case of a 67-year-old woman with metastatic colorectal cancer whose bevacizumab (B-mab) +m-FOLFOX6 treatment was complicated by reversible posterior leukoencephalopathy syndrome (RPLS). In July 2011, she underwent a right hemicolectomy for cecal carcinoma with peritoneal dissemination; therefore, m-FOLFOX6 was started in September 2011. In November 2011, she was hospitalized to add B-mab to the existing regimen. Subsequently, she developed hypertension on day 4 after the first B-mab infusion, followed by headache, convulsions, and disturbance of consciousness on day 5. T2-weighted and fluid-attenuated inversion recovery (FLAIR) non-enhanced magnetic resonance imaging of the brain revealed bilateral high signal intensities in the posterior lobes. She was diagnosed with RPLS and referred to our department where she was treated with antihypertensives and anticonvulsives. Her symptoms entirely resolved over 12 days. Medical oncologists should be aware that multidrug chemotherapies with B-mab may increase the risk of fatal neurological complications such as RPLS. PMID- 24769465 TI - [Virtual enteroscopy for the evaluation of stenosis in a case of chronic multiple ulcers of the small intestine]. AB - A 39-year-old female presented to our hospital with diarrhea, vomiting, anemia, and hypoalbuminemia. Virtual enteroscopy was performed to evaluate the small bowel; we found annular stenoses at 89, 100, 116, 147, and 154 cm from the ligament of Treitz. Small bowel resection was performed, and annular ulcers were confirmed at 58, 71, 90, 130, 138, 218, and 225 cm from the ligament of Treitz. Clinical records and pathological examination failed to determine the cause of these ulcers, and we diagnosed chronic multiple ulcers of the small intestine. Thus, we believe that virtual enteroscopy can be beneficial in preoperatively diagnosing multiple ulcers and stenoses in the small bowel. PMID- 24769466 TI - [Case of leptomeningeal carcinomatosis with esophageal carcinoma presenting with neurological signs]. AB - A 72-year-old male was admitted because of hearing impairment, blurred vision, right hemifacial numbness, and difficulty walking. Brain magnetic resonance imaging revealed two enhancing lesions with infiltration around the cranial nerves indicating either metastatic brain tumors or meningeal carcinomatosis. Cytological examination of the cerebrospinal fluid revealed malignant cells with keratotic changes. Upper gastrointestinal endoscopy was performed, which revealed type 1 squamous cell carcinoma of the esophagus;this led to the diagnosis of leptomeningeal carcinomatosis. In this report, we present a rare case of esophageal carcinoma accompanied by meningeal carcinomatosis diagnosed on the basis of neurological symptoms. PMID- 24769467 TI - [Case of small bowel angioectasia in which the resection site was angiographically detected using intraoperative dye infusion]. AB - A 37-year-old Japanese man undergoing treatment for dilated cardiomyopathy was presented with weakness and melena. He had conjunctival pallor and difficulty in standing;his blood pressure was 81/62 mmHg. Abdominal computed tomography revealed contrast dye leakage into the small intestine. He was diagnosed with hemorrhagic shock secondary to intestinal bleeding;we administered large volumes of intravenous fluid along with performing a blood transfusion. We then performed angiography to determine the site of bleeding angioectasia and placed a catheter into the affected artery. We identified the resection site using an intraoperative dye infusion via the catheter, and successfully performed small bowel resection. He was subsequently discharged without complications. PMID- 24769468 TI - [Case of ischemic ileitis complicated by portal venous gas]. AB - A 65-year-old woman was admitted with sudden-onset abdominal pain. Abdominal computed tomography revealed hepatic portal venous gas. Physical and laboratory examination suggested that a conservative approach was appropriate; however, 4 days later, the pain recurred and severe ischemic enteritis was diagnosed. A stenosis was identified 60 cm distal to the start of the ileum, and partial resection of the small intestine was performed. The diagnosis of ischemic enteritis was confirmed. Ischemic enteritis affecting the small intestine is uncommon, and enteritis causing intestinal stenosis with hepatic portal vein gas is even rarer. PMID- 24769469 TI - [Multiple large hepatocellular adenomas in a patient with glycogen storage disease type Ia]. AB - A man diagnosed at birth with glycogen storage disease type Ia was found to have multiple hepatocellular adenomas at 15 years of age. At 18 years of age, he underwent transarterial tumor embolization in segments 4 and 5. At 27 years of age, the tumor in segment 4 had increased in size on follow-up computed tomography, and he was referred to our hospital. Because the tumor was large, increasing in size, and we could not exclude malignancy, we performed resection of segments 4 and 8 of the liver and partial resection of segment 5 for excisional biopsy. The pathological diagnosis was multiple inflammatory hepatocellular adenomas. PMID- 24769470 TI - When is it safe to return to driving following first-ever seizure? AB - OBJECTIVES: The risk of recurrence following a first-ever seizure is 40-50%, warranting driving restriction during the early period of highest risk. This restriction must be balanced against the occupational, educational and social limitations that result from patients being ineligible to drive. The recommended duration of non-driving after a first seizure varies widely between jurisdictions, influenced by various factors including the community perception of an acceptable relative level of risk for an accident (the accident risk ratio; ARR). Driving restrictions may be based on individualised risk assessments or across-the-board guidelines, but these approaches both require accurate data on the risk of seizure recurrence. METHODS: 1386 patients with first-ever seizure were prospectively analysed. Seizure recurrence was evaluated using survival analysis. The duration of non-driving required for a range of risks of seizure recurrence and ARRs was calculated. Additionally, the actual occurrence of seizures while driving was prospectively determined during follow-up. RESULTS: For a risk of seizure recurrence to fall to 2.5% per month, corresponding to a monthly risk of a seizure while driving of 1.04 per thousand and an ARR of 2.6, non-driving periods of 8 months are required for unprovoked first-ever seizure, and 5 months for provoked first-ever seizure. Of patients with a seizure recurrence, 14 (2%) occurred while driving, with the monthly risk falling to less than 1/1000 after 6 months. CONCLUSIONS: Our data provide a quantitative approach to decisions regarding a return to driving in patients with first-ever provoked or unprovoked seizure. PMID- 24769471 TI - Cognitive correlates in amyotrophic lateral sclerosis: a population-based study in Italy. AB - BACKGROUND: There is less data available regarding the characteristics of cognitive impairment in patients with amyotrophic lateral sclerosis (ALS) in a population-based series. METHODOLOGY: Patients with ALS incident in Piemonte, Italy, between 2009 and 2011 underwent an extensive neuropsychological battery. Cognitive status was classified as follows: normal cognition, frontotemporal dementia (ALS-FTD), executive cognitive impairment (ALS-ECI), non-executive cognitive impairment (ALS-NECI), behavioural impairment (ALS-Bi), non classifiable cognitive impairment. We also assessed 127 age-matched and gender matched controls identified through patients' general practitioners. RESULTS: Out of the 281 incident patients, 207 (71.9%) underwent the neuropsychological testing; of these, 19 were excluded from the analysis due previous conditions affecting cognition. Ninety-one (49.7%) patients were cognitively normal, 23 (12.6%) had ALS-FTD, 36 (19.7%) ALS-ECI, 10 (5.5%) ALS-NECI, 11 (6.0%) ALS-Bi and 11 (6.0%) non-classifiable cognitive impairment, 1 had comorbid Alzheimer's disease. Patients with ALS-FTD were older, had a lower education level, and had a shorter survival than any other cognitive group. Of the nine cases with C9ORF72 mutation, six had ALS-FTD, two ALS-ECI and one was cognitively normal; one of the five patients with SOD1 mutations and one of the five patients with TARBDP mutations had ALS-Bi. CONCLUSIONS: About 50% of Italian patients with ALS had some degree of cognitive impairment, in keeping with a previous Irish study, despite the largely different genetic background of the two populations. The lower educational attainment in patients with ALS-FTD indicated a possible role of cognitive reserve in ALS-related cognitive impairment. ALS-ECI and ALS-NECI may represent discrete cognitive syndromes in the continuum of ALS and FTD. PMID- 24769472 TI - Exercise, dominant hand and neurodegeneration. PMID- 24769474 TI - Stroke in Asia: geographical variations and temporal trends. AB - Asian countries are in various stages of epidemiological transition and therefore exhibit a great diversity in disease patterns. Collectively, they comprise almost two-third of the world's total mortality due to stroke. The purpose of this review is to explore existing epidemiological data on stroke, highlight the temporal trends in stroke epidemiology in various regions of Asia and predict future patterns based on these observations. Our search revealed that there is a lack of good epidemiological data from most Asian countries. Whatever data exist are not comparable due to lack of standardised methodology for ascertaining stroke and its subtypes. For this and other reasons, these estimates exhibit country-to-country variation and also within-country variability. We have also reviewed temporal trends in stroke incidence and prevalence in 12 Asian countries and the evolution of stroke subtypes over the past two decades. Important observations include a rise in stroke incidence in most Asian countries, an earlier age at onset compared with the West, a relative increase in the proportion of ischaemic strokes and a decline in haemorrhagic strokes. Among ischaemic stroke subtypes, lacunar strokes, which were once the commonest variety, are now declining. Emerging data suggest that large artery atherosclerosis and in particular that of intracranial vessels is the predominant aetiology in most Asian countries. The review also identified important gender differences in terms of stroke risk factors, prevalence and outcomes. There is need for sound epidemiological data from most countries to understand the disease better and plan policy-level interventions to decrease the burden. We identify a need for standard format or guidelines for conducting stroke epidemiological studies especially in developing Asian countries. This region must be identified as a priority region for stroke-related interventions and preventive strategies by global healthcare authorities and organisations. PMID- 24769473 TI - Imaging outcomes for trials of remyelination in multiple sclerosis. AB - Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are feasible from a time and practicality point of view, as well as being sensitive and specific to myelin, while also being reproducible and clinically meaningful. Conventional MRI sequences have limited specificity for myelination. We evaluate the imaging modalities which are potentially more specific to myelin content in vivo, such as magnetisation transfer ratio (MTR), restricted proton fraction f (from quantitative magnetisation transfer measurements), myelin water fraction and diffusion tensor imaging (DTI) metrics, in addition to positron emission tomography (PET) imaging. Although most imaging applications to date have focused on the brain, we also consider measures with the potential to detect remyelination in the spinal cord and in the optic nerve. At present, MTR and DTI measures probably offer the most realistic and feasible outcome measures for such trials, especially in the brain. However, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin, or correlation with clinical features, and it should be useful to employ more than one outcome to maximise understanding and interpretation of findings with these sequences. PET may be less feasible for current and near-future trials, but is a promising technique because of its specificity. In the optic nerve, visual evoked potentials can indicate demyelination and should be correlated with an imaging outcome (such as optic nerve MTR), as well as clinical measures. PMID- 24769475 TI - A familial ALS case carrying a novel p.G147C SOD1 heterozygous missense mutation with non-executive cognitive impairment. PMID- 24769476 TI - Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease. AB - OBJECTIVE: Recent studies have suggested that proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with atherosclerosis and plays a potential role in inflammation. However, the correlation between PCSK9 and white blood cell count (WBCC) has not yet been assessed. The objective of the present study was to examine the association of the WBCC and its subset counts with plasma PCSK9 levels in patients with stable coronary artery disease (CAD). METHODS: In this cross-sectional study, a total of 251 consecutive, stable CAD patients who were not treated with lipid-lowering drugs were enrolled at our center between October 2012 and October 2013. The baseline clinical characteristics were collected, and the plasma PCSK9 levels were determined using ELISA. The associations of plasma PCSK9 levels with the WBCC and its subsets were investigated. RESULTS: In the overall population, plasma PCSK9 levels were positively associated with the WBCC (r = 0.167, p = 0.008). Multivariable regression analysis revealed that the plasma PCSK9 levels were significantly and independently associated with the WBCC (beta = 0.217, p < 0.001) and its subsets (neutrophil beta = 0.152, p < 0.05; lymphocyte beta = 0.241, p < 0.001). However, the relationships between PCSK9 and WBCC and its subsets remained significant in men (WBCC r = 0.234, p = 0.001; neutrophil r = 0.181, p = 0.014; lymphocyte r = 0.226, p = 0.002) but were not significant in women when the analysis was performed based on gender. CONCLUSIONS: These data demonstrate that the plasma PCSK9 levels are independently associated with the WBCC and its subsets, suggesting a potential interaction between PCSK9 and chronic inflammation in patients with CAD. PMID- 24769477 TI - A study of substrate specificity for a CTD phosphatase, SCP1, by proteomic screening of binding partners. AB - RNA polymerase II carboxyl-terminal domain (RNAPII CTD) phosphatases are a newly emerging family of phosphatases. Recently a CTD-specific phosphatase, small CTD phosphatase 1 (SCP1), has shown to act as an evolutionarily conserved transcriptional corepressor for inhibiting neuronal gene transcription in non neuronal cells. In this study, using the established NIH/3T3 and HEK293T cells, which are expressing human SCP1 proteins under the tight control of expression by doxycycline, a proteomic screening was conducted to identify the binding partners for SCP1. Although the present findings provide the possibility for new avenues to provide to a better understanding of cellular physiology of SCP1, now these proteomic and some immunological approaches for SCP1 interactome might not represent the accurate physiological relevance in vivo. In this presentation, we focus the substrate specificity to delineate an appearance of the dephosphorylation reaction catalyzed by SCP1 phosphatase. We compared the phosphorylated sequences of the immunologically confirmed binding partners with SCP1 searched in HPRD. We found the similar sequences from CdcA3 and validated the efficiency of enzymatic catalysis for synthetic phosphopeptides the recombinant SCP1. This approach led to the identification of several interacting partners with SCP1. We suggest that CdcA3 could be an enzymatic substrate for SCP1 and that SCP1 might have the relationship with cell cycle regulation through enzymatic activity against CdcA3. PMID- 24769478 TI - Simultaneous measurement of a range of particle sizes during Abeta1-42 fibrillogenesis quantified using fluorescence correlation spectroscopy. AB - Low molecular weight oligomers of amyloid beta (Abeta) are important drivers of Alzheimer's disease. A decrease in Abeta monomer levels in human cerebrospinal fluid (CSF) is observed in Alzheimers' patients and is a robust biomarker of the disease. It has been suggested that the decrease in monomer levels in CSF is due to the formation of Abeta oligomers. A robust technique capable of identifying Abeta oligomers in CSF is therefore desirable. We have used fluorescence correlation spectroscopy and a five Gaussian distribution model (5GDM) to monitor the aggregation of Abeta1-42 in sodium phosphate buffer and in artificial cerebrospinal fluid (ACSF). In buffer, several different sized components (monomer, oligomers, protofibrils and fibrils) can be identified simultaneously using 5GDM. In ACSF, the faster kinetics of fibrillogenesis leads to the formation of fibrils on very short timescales. This analysis method can also be used to monitor the aggregation of other proteins, nanoparticles or colloids, even in complex biological fluids. PMID- 24769479 TI - Reconstitution of a sequential reaction of two nitrogenase-like enzymes in the bacteriochlorophyll biosynthetic pathway of Rhodobacter capsulatus. AB - The parental structure of bacteriochlorophyll a, bacteriochlorin, is formed by a sequential operation of two nitrogenase-like enzymes, dark-operative protochlorophyllide oxidoreductase (DPOR) and chlorophyllide a oxidoreductase (COR). Both DPOR and COR consist of two components, Fe protein and MoFe protein cognates. Here we determined kinetic parameters of COR and established the reconstitution system for the formation of bacteriochlorin (3-vinyl bacteriochlorophyllide a) from porphyrin (protochlorophyllide) with purified components of DPOR and COR from Rhodobacter capsulatus. This reconstitution system confirmed the recent finding that COR catalyzes 8-vinyl reduction of 8 vinyl chlorophyllide a in addition to the known activity of C7C8 double bond reduction, and provides a promising model to investigate how two nitrogenase-like enzymes are coordinated in bacteriochlorophyll biosynthesis. PMID- 24769480 TI - A Receptor-Like Kinase Mediates Ammonium Homeostasis and Is Important for the Polar Growth of Root Hairs in Arabidopsis. AB - Ammonium (NH4+) is both a necessary nutrient and an important signal in plants, but can be toxic in excess. Ammonium sensing and regulatory mechanisms in plant cells have not been fully elucidated. To decipher the complex network of NH4+ signaling, we analyzed [Ca2+]cyt-associated protein kinase (CAP) genes, which encode signaling components that undergo marked changes in transcription levels in response to various stressors. We demonstrated that CAP1, a tonoplast localized receptor-like kinase, regulates root hair tip growth by maintaining cytoplasmic Ca2+ gradients. A CAP1 knockout mutant (cap1-1) produced elevated levels of cytoplasmic NH4+. Furthermore, root hair growth of cap1-1 was inhibited on Murashige and Skoog medium, but NH4+ depletion reestablished the Ca2+ gradient necessary for normal growth. The lower net NH4+ influx across the vacuolar membrane and relatively alkaline cytosolic pH of cap1-1 root hairs implied that mutation of CAP1 increased NH4+ accumulation in the cytoplasm. Furthermore, CAP1 functionally complemented the npr1 (nitrogen permease reactivator protein) kinase yeast mutant, which is defective in high-affinity NH4+ uptake via MEP2 (methylammonium permease 2), distinguishing CAP1 as a cytosolic modulator of NH4+ levels that participates in NH4+ homeostasis-regulated root hair growth by modulating tip-focused cytoplasmic Ca2+ gradients. PMID- 24769481 TI - Methylcrotonyl-CoA Carboxylase Regulates Triacylglycerol Accumulation in the Model Diatom Phaeodactylum tricornutum. AB - The model marine diatom Phaeodactylum tricornutum can accumulate high levels of triacylglycerols (TAGs) under nitrogen depletion and has attracted increasing attention as a potential system for biofuel production. However, the molecular mechanisms involved in TAG accumulation in diatoms are largely unknown. Here, we employed a label-free quantitative proteomics approach to estimate differences in protein abundance before and after TAG accumulation. We identified a total of 1193 proteins, 258 of which were significantly altered during TAG accumulation. Data analysis revealed major changes in proteins involved in branched-chain amino acid (BCAA) catabolic processes, glycolysis, and lipid metabolic processes. Subsequent quantitative RT-PCR and protein gel blot analysis confirmed that four genes associated with BCAA degradation were significantly upregulated at both the mRNA and protein levels during TAG accumulation. The most significantly upregulated gene, encoding the beta-subunit of methylcrotonyl-CoA carboxylase (MCC2), was selected for further functional studies. Inhibition of MCC2 expression by RNA interference disturbed the flux of carbon (mainly in the form of leucine) toward BCAA degradation, resulting in decreased TAG accumulation. MCC2 inhibition also gave rise to incomplete utilization of nitrogen, thus lowering biomass during the stationary growth phase. These findings help elucidate the molecular and metabolic mechanisms leading to increased lipid production in diatoms. PMID- 24769483 TI - Marked for Destruction: MANNOSIDASE4 and 5 Process N-Linked Glycans into ER Associated Degradation Tags. PMID- 24769482 TI - Arabidopsis miR156 Regulates Tolerance to Recurring Environmental Stress through SPL Transcription Factors. AB - Plants are sessile organisms that gauge stressful conditions to ensure survival and reproductive success. While plants in nature often encounter chronic or recurring stressful conditions, the strategies to cope with those are poorly understood. Here, we demonstrate the involvement of ARGONAUTE1 and the microRNA pathway in the adaptation to recurring heat stress (HS memory) at the physiological and molecular level. We show that miR156 isoforms are highly induced after HS and are functionally important for HS memory. miR156 promotes sustained expression of HS-responsive genes and is critical only after HS, demonstrating that the effects of modulating miR156 on HS memory do not reflect preexisting developmental alterations. miR156 targets SPL transcription factor genes that are master regulators of developmental transitions. SPL genes are posttranscriptionally downregulated by miR156 after HS, and this is critical for HS memory. Altogether, the miR156-SPL module mediates the response to recurring HS in Arabidopsis thaliana and thus may serve to integrate stress responses with development. PMID- 24769484 TI - Early and late changes in quality of life following transcatheter aortic valve implantation using the transfemoral and transapical approaches. AB - AIMS: To evaluate the effects of access route upon clinical results and quality of life (QoL) in patients undergoing either transfemoral (TF-TAVI) or transapical balloon-expandable transcatheter aortic valve implantation (TA-TAVI) in the real world. METHODS AND RESULTS: A prospective analysis was performed upon 264 consecutive patients receiving TF-TAVI or TA-TAVI. QoL was assessed using the EQ 5D questionnaire. At baseline, TA-TAVI patients reported significantly more problems in mobility, self-care, usual activities and lower overall health status domains (p<0.01 for all). At 30 days, the TF-TAVI group reported fewer problems with usual activity (p=0.01) and pain/discomfort (p<0.01), and higher EQ-5D index and visual analogue scale (VAS) (p=0.01 and p<0.01, respectively) than the TA TAVI group. Nevertheless, the absolute improvements (DeltaEQ-5D index and DeltaEQ 5D VAS) were larger in the TA-TAVI group, with most dramatically marked QoL absolute improvements (p<0.01 and p=0.02, respectively). By one year, notwithstanding higher all-cause mortality in the sicker TA-TAVI group, there were no differences between groups in any EQ-5D domain. Indeed, surviving TA-TAVI group's greater absolute improvements remained (p<0.01). CONCLUSIONS: QoL is greater at the earlier time point of 30 days in the TF-TAVI cohort but equatable by one year. However, the magnitude of improvement in QoL is greater in the TA TAVI patients at both 30 days and one year. PMID- 24769485 TI - Genotoxic effects of exposure to radiofrequency electromagnetic fields (RF-EMF) reported by the REFLEX project are not reproducible. PMID- 24769486 TI - Preliminary assessment of mutagenic and anti-mutagenic potential of some aminoalkanolic derivatives of xanthone by use of the Vibrio harveyi assay. AB - The Vibrio harveyi assay was used to evaluate mutagenic and anti-mutagenic effects of four new aminoalkanolic derivatives of xanthone with anticonvulsant activity, to select the potentially safe compounds for further in vivo studies in animal models. The study showed that at a concentration of 40 ng/ml the test compounds were not mutagenic. Additionally, two of the investigated compounds, namely the (R,S)-N-methyl-1-amino-2-propanol derivative of 6-methoxyxanthone (compound III) and the (R)-N-methyl-2-amino-1-butanol derivative of 7 chloroxanthone (compound IV) were strong inhibitors of the mutagenicity induced by 4-nitroquinoline-N-oxide (4-NQO) in V. harveyi strains BB7M and BB7XM. The inhibition percentages for compound IV were 49 (in BB7M) and 69 (in BB7XM), whereas for compound III these percentages were 47 (in BB7M) and 42 (in BB7XM), respectively. The present study demonstrates that four bioactive derivatives of xanthone display no mutagenic activity in the V. harveyi assay. In addition, compounds III and IV demonstrated considerable anti-mutagenic activity in this test. Based on the results obtained here, these compounds could be selected for further studies in animal models, while compounds III and IV should be tested further for their anti-mutagenic properties. PMID- 24769487 TI - The effect of aristolochic acid I on expression of NAD(P)H:quinone oxidoreductase in mice and rats--a comparative study. AB - Aristolochic acid is the cause of aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN) and their associated urothelial malignancies. Using Western blotting, we investigated the expression of NAD(P)H: quinone oxidoreductase (NQO1), the most efficient cytosolic enzyme that reductively activates aristolochic acid I (AAI) in mice and rats. In addition, the effect of AAI on the expression of the NQO1 protein and its enzymatic activity in these experimental animal models was examined. We found that NQO1 protein levels in cytosolic fractions isolated from liver, kidney and lung of mice differed from those expressed in these organs of rats. In mice, the highest levels of NQO1 protein and NQO1 activity were found in the kidney, followed by lung and liver. In contrast, the NQO1 protein levels and enzyme activity were lowest in rat kidney cytosol, whereas the highest amounts of NQO1 protein and activity were found in lung cytosols, followed by those of liver. NQO1 protein and enzyme activity were induced in liver and kidney of AAI-pretreated mice compared with those of untreated mice. NQO1 protein and enzyme activity were also induced in rat kidney by AAI. Furthermore, the increase in hepatic and renal NQO1 enzyme activity was associated with AAI bio-activation and elevated AAI-DNA adduct levels were found in ex vivo incubations of cytosolic fractions with DNA and AAI. In conclusion, our results indicate that AAI can increase its own metabolic activation by inducing NQO1, thereby enhancing its own genotoxic potential. PMID- 24769488 TI - Assessment of titanium dioxide nanoparticle effects in bacteria: association, uptake, mutagenicity, co-mutagenicity and DNA repair inhibition. AB - Due to their unique properties, the use of nanoparticles (NPs) is expanding; these same properties may affect their potential risk to humans. However, standard methods for genotoxicity assessment may not be adequate for NPs; altered tests reported here have been developed to address perceived inadequacies. The bacterial reverse mutation assay is an essential part of the battery of tests to determine genotoxicity. The utility of this test for assessing NPs is currently questioned, due to negative results seemingly caused by failure of particle uptake. To probe uptake issues, we examined the physical state in different media, dose and time dependent association, uptake and mutagenicity of titanium dioxide (TiO2) NPs in Salmonella typhimurium and Escherichia coli. The NPs suspended in water were characterized using dynamic light scattering, NP tracking analysis and transmission electron microscopy. NP association with bacteria was assessed by flow cytometry. Association was found to be time and dose dependent, with maximal association by 60 min. Therefore mutagenicity was assessed after a 60 min pre-incubation in a miniaturized assay demonstrating enhanced sensitivity. To assess potential indirect effects on bacterial mutagenicity, the effect of TiO2 NPs on the action of standard mutagens or on DNA repair capability was also investigated. TiO2 NPs did not affect mutant yields in standard strains of S. typhimurium or E. coli, including those detecting oxidative damage, using the modified methods. Nor did TiO2 NPs affect the action of standard mutagens or DNA excision repair capability. Despite particle association with the bacteria, subsequent analysis using electron microscopy and energy dispersive x-ray spectroscopy indicated that the NPs were not internalized. This work demonstrates that additional studies, including flow cytometry, are valuable tools for understanding the action of NPs in biological systems. PMID- 24769489 TI - Whether or not the genotoxic effects of exposure to continuous wave (CW) radio frequency electromagnetic fields (RF-EMF) in HL-60 cells are reproducible, is still an open question. PMID- 24769490 TI - Provider payment bares teeth: dentist reimbursement and the use of check-up examinations. AB - Oral diseases are one of the most common diseases globally, yet maximizing health benefits from available resources continues to be a pivotal challenge. Similar to recall appointments in many other medical settings, dental check-up examinations are an essential element of regular treatment. Check-ups are important for ensuring good health but their frequent consumption also implies substantial aggregate health care costs. Although it is crucial to determine appropriate utilization amounts, little is known about the role of financial incentives for both patient and provider. Our analyses relied on ten-year administrative panel data from the Scottish National Health Service including about 1.3 million dental treatment claims which were issued between January 1998 and September 2007. Controlling for unobserved heterogeneity, we estimated a series of fixed-effects models to identify the impact of changes in provider payment and patients' cost sharing on check-up utilization. A significantly higher utilization of examinations was observed if dentists were paid fee-for service compared with salary. Comparably little variation in check-up use was attributable to different extents of patient co-payment. These findings establish that different provider payment methods have a substantial impact on check-up utilization. Because recall appointments in many other medical settings have similar features as dental check ups, these findings may be relevant for health care decision makers who seek to optimize incentive schemes for all kinds of health care. PMID- 24769491 TI - Neighborhoods and mental health: exploring ethnic density, poverty, and social cohesion among Asian Americans and Latinos. AB - This study examines the associations of neighborhood ethnic density and poverty with social cohesion and self-rated mental health among Asian Americans and Latinos. Path analysis is employed to analyze data from the 2002-2003 National Latino and Asian American Study (NLAAS) and the 2000 U.S. Census (N = 2095 Asian Americans living in N = 259 neighborhoods; N = 2554 Latinos living in N = 317 neighborhoods). Findings reveal that neighborhood ethnic density relates to poor mental health in both groups. Social cohesion partially mediates that structural relationship, but is positively related to ethnic density among Latinos and negatively related to ethnic density among Asian Americans. Although higher neighborhood poverty is negatively associated with mental health for both groups, the relationship does not hold in the path models after accounting for social cohesion and covariates. Furthermore, social cohesion fully mediates the association between neighborhood poverty and mental health among Latinos. This study highlights the necessity of reconceptualizing existing theories of social relationships to reflect complex and nuanced mechanisms linking neighborhood structure and mental health for diverse racial and ethnic groups. PMID- 24769492 TI - Cryptic polyreactivity of IgG expressed by splenic marginal zone B-cell lymphoma. AB - Polyreactive antibodies represent a significant fraction of immune repertoires and play an important role in the immune defense and immune homeostasis. Polyreactive B-cell receptors (BCR), however, are frequently expressed by B-cell lymphomas. It was suggested that polyreactive BCR on lymphoma cells might deliver stimulation signals by binding to various endogenous or exogenous antigens, thus promoting the survival of the malignant cells. In addition to natural polyreactive antibodies, immune repertoires contain antibodies that acquire polyreactivity after exposure to different redox-active substances such as reactive oxygen species, iron ions and heme. Here, we demonstrate that an antibody cloned from a patient's splenic marginal zone B-cell lymphoma acquires physiologically relevant binding affinity to various autoantigens following exposure to heme. We elucidated the mechanisms underlying polyreactive antigen binding. The results obtained in this study imply that antigen-binding receptors expressed on some malignant cells acquire polyreactivity after exposure to redox substances that are released at sites of inflammation or as a result of cellular damage. The acquisition of novel BCR specificities under hemolytic or inflammatory conditions may play an important role in the physiopathology of certain B-cell malignancies. PMID- 24769493 TI - In vivo mapping of a protective linear neutralizing epitope at the N-terminus of alpha hemolysin from Staphylococcus aureus. AB - Staphylococcus aureus is responsible for a large and diverse burden of human disease associated with significant morbidity and mortality. The dynamic challenge of this pathogen is exemplified by the emergence of highly virulent community-associated methicillin-resistant S. aureus strain USA300, which threatens both healthy and vulnerable individuals and constitutes a public health imperative in the United States. Though S. aureus employs many virulence factors that enable infectivity and evasion of host defenses, evidence suggests that the increased production of alpha hemolysin may be a critical contributor to the increased virulence of USA300. To enable and inform immunological targeting of alpha hemolysin, we sought to precisely map a neutralizing epitope that we hypothesized existed in the N-terminal domain. Using an in vivo mapping strategy employing peptide immunogens and an optimized in vitro toxin neutralization assay, we identified a linear neutralizing determinant in the N-terminal 19 amino acids of alpha hemolysin. Affinity purified rabbit antibody against this neutralizing epitope was shown to be highly effective at mitigating dermonecrosis in inbred and outbred mice challenged with USA300. To our knowledge, this is the first description of a linear neutralizing epitope in alpha hemolysin, and the delineation of this determinant should inform and facilitate the rational design and development of an efficacious, epitope-focused or multivalent vaccine against S. aureus. PMID- 24769494 TI - The adapter proteins ADAP and Nck cooperate in T cell adhesion. AB - Nck adapter proteins link receptor and receptor-associated tyrosine kinases with proteins implicated in the regulation of the actin cytoskeleton. Nck is involved in a multitude of receptor-initiated signaling pathways and its physiological role thus covers aspects of tissue development and homeostasis, malignant transformation/invasiveness of tumour cells and also immune cell function. In T cells, changes of cell polarity and morphology associated with cellular activation and effector function crucially rely on the T cell receptor-mediated recruitment and activation of different actin-regulatory proteins to orchestrate and drive cytoskeletal reorganization at the immunological synapse. In a former approach to determine the interactome of Nck in human T cells, we identified the adapter protein ADAP as a Nck-interacting protein. This adhesion and degranulation-promoting adapter protein had already been implicated in the inside out activation of integrins. Employing co-immunoprecipitations, we demonstrate that both Nck family members Nck1 and Nck2 coprecipitate with ADAP. Specifically, Nck interacts via its Src homology 2 domain with phosphorylated tyrosine Y595DDV and Y651DDV sites of ADAP. Moreover, we show that endogenous ADAP is phosphorylated in primary human T cell blasts and thus associates with Nck. At the functional level, ADAP and Nck adapter proteins cooperatively facilitate T cell adhesion to the LFA-1 ligand ICAM-1. Our data indicate that the ADAP/Nck complex might provide a means to link integrin activation with the actin cytoskeleton. PMID- 24769495 TI - Trypanosoma cruzi calreticulin inhibits the complement lectin pathway activation by direct interaction with L-Ficolin. AB - Trypanosoma cruzi, the agent of Chagas' disease, the sixth neglected tropical disease worldwide, infects 10-12 million people in Latin America. Differently from T. cruzi epimastigotes, trypomastigotes are complement-resistant and infective. CRPs, T-DAF, sialic acid and lipases explain at least part of this resistance. In vitro, T. cruzi calreticulin (TcCRT), a chaperone molecule that translocates from the ER to the parasite surface: (a) Inhibits the human classical complement activation, by interacting with C1, (b) As a consequence, an increase in infectivity is evident and, (c) It inhibits angiogenesis and tumor growth. We report here that TcCRT also binds to the L-Ficolin collagenous portion, thus inhibiting approximately between 35 and 64% of the human complement lectin pathway activation, initiated by L-Ficolin, a property not shared by H Ficolin. While L-Ficolin binds to 60% of trypomastigotes and to 24% of epimastigotes, 50% of the former and 4% of the latter display TcCRT on their surfaces. Altogether, these data indicate that TcCRT is a parasite inhibitory receptor for Ficolins. The resulting evasive activities, together with the TcCRT capacity to inhibit C1, with a concomitant increase in infectivity, may represent T. cruzi strategies to inhibit important arms of the innate immune response. PMID- 24769497 TI - Gallic acid interacts with alpha-synuclein to prevent the structural collapse necessary for its aggregation. AB - The accumulation of protein aggregates containing amyloid fibrils, with alpha synuclein being the main component, is a pathological hallmark of Parkinson's disease (PD). Molecules which prevent the formation of amyloid fibrils or disassociate the toxic aggregates are touted as promising strategies to prevent or treat PD. In the present study, in vitro Thioflavin T fluorescence assays and transmission electron microscopy imaging results showed that gallic acid (GA) potently inhibits the formation of amyloid fibrils by alpha-synuclein. Ion mobility-mass spectrometry demonstrated that GA stabilises the extended, native structure of alpha-synuclein, whilst NMR spectroscopy revealed that GA interacts with alpha-synuclein transiently. PMID- 24769498 TI - Multistability and switching in a superconducting metamaterial. AB - The field of metamaterial research revolves around the idea of creating artificial media that interact with light in a way unknown from naturally occurring materials. This is commonly achieved using sub-wavelength lattices of electronic or plasmonic structures, so-called meta-atoms. One of the ultimate goals for these tailored media is the ability to control their properties in situ. Here we show that superconducting quantum interference devices can be used as fast, switchable meta-atoms. We find that their intrinsic nonlinearity leads to simultaneously stable dynamic states, each of which is associated with a different value and sign of the magnetic susceptibility in the microwave domain. Moreover, we demonstrate that it is possible to switch between these states by applying nanosecond-long pulses in addition to the microwave-probe signal. Apart from potential applications for this all-optical metamaterial switch, the results suggest that multistability can also be utilized in other types of nonlinear meta atoms. PMID- 24769496 TI - The major cockroach allergen Bla g 4 binds tyramine and octopamine. AB - Bla g 4 is a male cockroach specific protein and is one of the major allergens produced by Blattella germanica (German cockroach). This protein belongs to the lipocalin family that comprises a set of proteins that characteristically bind small hydrophobic molecules and play a role in a number of processes such as: retinoid and pheromone transport, prostaglandin synthesis and mammalian immune response. Using NMR and isothermal titration calorimetry we demonstrated that Bla g 4 binds tyramine and octopamine in solution. In addition, crystal structure analysis of the complex revealed details of tyramine binding. As tyramine and octopamine play important roles in invertebrates, and are counterparts to vertebrate adrenergic transmitters, we speculate that these molecules are physiological ligands for Bla g 4. The nature of binding these ligands to Bla g 4 sheds light on the possible biological function of the protein. In addition, we performed a large-scale analysis of Bla g 4 and Per a 4 (an allergen from American cockroach) homologs to get insights into the function of these proteins. This analysis together with a structural comparison of Blag 4 and Per a 4 suggests that these proteins may play different roles and most likely bind different ligands. Accession numbers: The atomic coordinates and the structure factors have been deposited to the Protein Data Band under accession codes: 4N7C for native Bla g 4 and 4N7D for the Se-Met Bla g 4 structure. PMID- 24769499 TI - Evaluation of plasma chemerin levels in patients with non-dipper blood pressure patterns. AB - BACKGROUND: Chemerin is a novel adipokine that plays a role in inflammation and atherosclerosis. Although there are several correlations between hypertension and the inflammatory system, there is still insufficient information about the relationship between blood pressure variability and inflammatory markers. In this study, we aimed to determine whether chemerin levels are elevated in non-dipper patients compared with dippers and healthy controls. MATERIAL AND METHODS: This study was composed of a group of 90 patients: 60 hypertensive patients and 30 healthy control subjects (12 males, mean age 53.2 +/- 15.4 years). Ambulatory blood pressure monitoring devices (ABPM) were connected to all patients. Using data from the ABPM, hypertensive patients were divided into 2 groups: 30 dipper patients (12 males, mean age 52.5 +/- 15.1 years) and 30 non-dipper patients (11 males, mean age 54.6 +/- 13.0 years). Complete blood count and biochemistry were measured by standard methods and plasma chemerin concentrations were quantified by ELISA. RESULTS: Non-dipper patients demonstrated higher chemerin levels compared to dippers and normotensives (219.7 +/- 16.3 vs. 182.4 +/- 21.4 ng/ml; 219.7 +/- 16.3 vs. 85.4 +/- 38.1 ng/ml, respectively, p<0.001 for both comparisons). A receiver operating characteristic curve analysis revealed that the optimal cut-off value for chemerin to predict a non-dipping pattern was 201.4, with 90% sensitivity and 90% specificity. There was a positive correlation between chemerin levels and all ambulatory blood pressure values in all hypertensive patients. CONCLUSIONS: Chemerin, which plays a role in inflammation and atherosclerosis, was higher in non-dippers compared to dippers and normotensives. Additionally, chemerin shows positive correlations with blood pressure. PMID- 24769500 TI - Information processing through a bio-based redox capacitor: signatures for redox cycling. AB - Redox-cycling compounds can significantly impact biological systems and can be responsible for activities that range from pathogen virulence and contaminant toxicities, to therapeutic drug mechanisms. Current methods to identify redox cycling activities rely on the generation of reactive oxygen species (ROS), and employ enzymatic or chemical methods to detect ROS. Here, we couple the speed and sensitivity of electrochemistry with the molecular-electronic properties of a bio based redox-capacitor to generate signatures of redox-cycling. The redox capacitor film is electrochemically-fabricated at the electrode surface and is composed of a polysaccharide hydrogel with grafted catechol moieties. This capacitor film is redox-active but non-conducting and can engage diffusible compounds in either oxidative or reductive redox-cycling. Using standard electrochemical mediators ferrocene dimethanol (Fc) and Ru(NH3)6Cl3 (Ru(3+)) as model redox-cyclers, we observed signal amplifications and rectifications that serve as signatures of redox-cycling. Three bio-relevant compounds were then probed for these signatures: (i) ascorbate, a redox-active compound that does not redox-cycle; (ii) pyocyanin, a virulence factor well-known for its reductive redox-cycling; and (iii) acetaminophen, an analgesic that oxidatively redox cycles but also undergoes conjugation reactions. These studies demonstrate that the redox-capacitor can enlist the capabilities of electrochemistry to generate rapid and sensitive signatures of biologically-relevant chemical activities (i.e., redox-cycling). PMID- 24769501 TI - Redox reaction characteristics of riboflavin: a fluorescence spectroelectrochemical analysis and density functional theory calculation. AB - Riboflavin (RF), the primary redox active component of flavin, is involved in many redox processes in biogeochemical systems. Despite of its wide distribution and important roles in environmental remediation, its redox behaviors and reaction mechanisms in hydrophobic sites remain unclear yet. In this study, spectroelectrochemical analysis and density functional theory (DFT) calculation were integrated to explore the redox behaviors of RF in dimethyl sulfoxide (DMSO), which was used to create a hydrophobic environment. Specifically, cyclic voltafluorometry (CVF) and derivative cyclic voltafluorometry (DCVF) were employed to track the RF concentration changing profiles. It was found that the reduction contained a series of proton-coupled electron transfers dependent of potential driving force. In addition to the electron transfer-chemical reaction electron transfer process, a disproportionation (DISP1) process was also identified to be involved in the reduction. The redox potential and free energy of each step obtained from the DFT calculations further confirmed the mechanisms proposed based on the experimental results. The combination of experimental and theoretical approaches yields a deep insight into the characteristics of RF in environmental remediation and better understanding about the proton-coupled electron transfer mechanisms. PMID- 24769502 TI - Ions at hydrophobic interfaces. AB - We review the present understanding of the behavior of ions at the air-water and oil-water interfaces. We argue that while the alkali metal cations remain strongly hydrated and are repelled from the hydrophobic surfaces, the anions must be classified into kosmotropes and chaotropes. The kosmotropes remain strongly hydrated in the vicinity of a hydrophobic surface, while the chaotropes lose their hydration shell and can become adsorbed to the interface. The mechanism of adsorption is still a subject of debate. Here, we argue that there are two driving forces for anionic adsorption: the hydrophobic cavitational energy and the interfacial electrostatic surface potential of water. While the cavitational contribution to ionic adsorption is now well accepted, the role of the electrostatic surface potential is much less clear. The difficulty is that even the sign of this potential is a subject of debate, with the ab initio and the classical force field simulations predicting electrostatic surface potentials of opposite sign. In this paper, we will argue that the strong anionic adsorption found in the polarizable force field simulations is the result of the artificial electrostatic surface potential present in the classical water models. We will show that if the adsorption of anions were as large as predicted by the polarizable force field simulations, the excess surface tension of the NaI solution would be strongly negative, contrary to the experimental measurements. While the large polarizability of heavy halides is a fundamental property and must be included in realistic modeling of the electrolyte solutions, we argue that the point charge water models, studied so far, are incompatible with the polarizable ionic force fields when the translational symmetry is broken. The goal for the future should be the development of water models with very low electrostatic surface potential. We believe that such water models will be compatible with the polarizable force fields, which can then be used to study the interaction of ions with hydrophobic surfaces and proteins. PMID- 24769504 TI - Managing loss of glycemic control in middle-aged patients with diabetes: the role of GLP-1 receptor agonists in combination-therapy regimens. AB - Middle-aged patients with type 2 diabetes mellitus may have languished on monotherapy or a stable therapy for a substantial period without reconsideration of comorbidities or current control of glycated hemoglobin A1c (HbA1c). In many patients who lose glycemic control, postprandial hyperglycemia has not been addressed. This is especially true when HbA1c levels are close to--but not at- goal. Glucagon-like peptide-1 receptor agonists are injectable agents that can be added to oral therapy to address postprandial hyperglycemia. These agents may be a useful alternative to insulin therapy as add-on therapy when dual oral therapy is no longer sufficient and additional glucose lowering is required. Compared with insulin, glucagon-like peptide-1 receptor agonists have provided comparable glucose lowering with less hypoglycemia and without weight gain. PMID- 24769505 TI - Treating patients with diabetes of long duration: GLP-1 receptor agonists and insulin in combination. AB - Patients with long-standing type 2 diabetes mellitus (T2DM) can be clinically challenging for physicians to treat because these patients often lack sufficient beta-cell function to respond to some oral glucose-lowering agents, may have profound comorbidities, and may have renal impairment that limits the use of traditional agents. These complications, in addition to older age, also increase the risk of hypoglycemia, which can be a major barrier to treatment success. Individualizing treatment targets to balance the benefits of glycemic control with risks of hypoglycemia is the first step to successfully treating these patients. Careful selection of combination therapy strategies to address limited beta-cell function, renal function, and cardiovascular status, along with attention to selection of agents associated with lower risk of hypoglycemia, is important. Basal insulin analogs are often used in patients with long-standing diabetes to address insulinopenic states. Incretin-based therapies, particularly GLP-1 receptor agonists, provide postprandial control with lower risks of hypoglycemia than prandial insulin. The author discusses the management of patients with long-standing diabetes who may have limited beta-cell function and require transition to insulin therapy with gradual intensification. PMID- 24769506 TI - Managing recent-onset diabetes: choosing durable, well-tolerated therapies and understanding the role of incretin-based therapies. AB - Management of recent-onset diabetes offers osteopathic physicians the opportunity to work with patients to set treatment goals and expectations for this progressive yet manageable disease, as well as intervene early to reduce the risk of diabetes-related complications. Starting effective therapy early--and intensifying therapy appropriately--to achieve and maintain glycemic goals has been shown to reduce microvascular risks and produce legacy effects that may have macrovascular benefits. Metformin remains a cornerstone of therapy for those patients who can tolerate it. Early combination therapy that is well tolerated reduces risks of hypoglycemia or unwanted weight gain, improves patient adherence, and addresses the multifactoral pathophysiology of even recent-onset diabetes. Incretin-based therapies have been shown to be effective across the spectrum of type 2 diabetes mellitus, including recent-onset diabetes. The present article reviews the use of incretin-based therapies early in the disease process of type 2 diabetes mellitus. PMID- 24769507 TI - Utilization of economical substrate-derived carbohydrates by solventogenic clostridia: pathway dissection, regulation and engineering. AB - Solventogenic clostridia can produce acetone, butanol and ethanol (ABE) by using different carbohydrates. For economical reasons, the utilization of cheap and renewable biomass in clostridia-based ABE fermentation has recently attracted increasing interests. With the study of molecular microbiology and development of genetic tools, the understanding of carbohydrate metabolism in clostridia has increased in recent years. Here, we review the pioneering work in this field, with a focus on dissecting the pathways and describing the regulation of the metabolism of economical substrate-derived carbohydrates by clostridia. Recent progress in the metabolic engineering of carbohydrate utilization pathways is also described. PMID- 24769508 TI - Plant nitrogen uptake drives responses of productivity to nitrogen and water addition in a grassland. AB - Increased atmospheric nitrogen (N) deposition and altered precipitation regimes have profound impacts on ecosystem functioning in semiarid grasslands. The interactions between those two factors remain largely unknown. A field experiment with N and water additions was conducted in a semiarid grassland in northern China. We examined the responses of aboveground net primary production (ANPP) and plant N use during two contrasting hydrological growing seasons. Nitrogen addition had no impact on ANPP, which may be accounted for by the offset between enhanced plant N uptake and decreased plant nitrogen use efficiency (NUE). Water addition significantly enhanced ANPP, which was largely due to enhanced plant aboveground N uptake. Nitrogen and water additions significantly interacted to affect ANPP, plant N uptake and N concentrations at the community level. Our observations highlight the important role of plant N uptake and use in mediating the effects of N and water addition on ANPP. PMID- 24769509 TI - Acetylshikonin induces apoptosis of hepatitis B virus X protein-expressing human hepatocellular carcinoma cells via endoplasmic reticulum stress. AB - Since it has been known that shikonin derived from a medicinal plant possesses anti-cancer activity, we wonder whether acetylshikonin (ASK), a derivate of shikonin, can be used to treat hepatocellular carcinoma cells expressing hepatitis B virus X protein (HBX), an oncoprotein from hepatitis B virus. When ASK was added to Hep3B cells stably expressing HBX, it induced apoptosis in a dose-dependent manner. ASK induced upregulation and export of Nur77 to the cytoplasm and activation of JNK. Likewise, suppression of Nur77 and JNK inactivation protected the cells from ASK-induced apoptosis, indicating that Nur77 upregulation and JNK activation were required for ASK-mediated apoptosis. Furthermore, ASK increased the expression of Bip and ubiquitination levels of cellular proteins, features of endoplasmic reticulum (ER) stress, via the production of reactive oxygen species in a dose-dependent manner. Suppression of reactive oxygen species with N-acetylcysteine reduced levels of Bip protein and ubiquitination levels of cellular proteins during ASK treatment, leading to protection of cells from apoptosis. Cycloheximide treatment reduced ASK-induced ER stress, suggesting that protein synthesis is involved in ASK-induced ER stress. Moreover, we showed using salubrinal, an ER stress inhibitor that reactive oxygen species production, JNK activation, and Nur77 upregulation and its translocation to cytoplasm are necessary for ER-induced stress. Interestingly, we found that JNK inactivation suppresses ASK-induced ER stress, whereas Nur77 siRNA treatment does not, indicating that JNK is required for ASK induced ER stress. Accordingly, we report that ASK induces ER stress, which is prerequisite for apoptosis of HBX-expressing hepatocellular carcinoma cells. PMID- 24769510 TI - Calcium regulation in aortic smooth muscle cells during the initial phase of tunicamycin-induced endo/sarcoplasmic reticulum stress. AB - Endo/sarcoplasmic reticulum stress and the unfolded protein response have been implicated as underlying mechanisms of cell death in many pathological conditions. We have confirmed that long-term exposure to 10uM tunicamycin induced the endo/sarcoplasmic reticulum stress in cultured vascular smooth muscle cells. Since tunicamycin is reported to induce the stress response by inhibiting protein glycosylation, we attempted to investigate a causal link between accumulation of unfolded proteins and dysregulation of cellular calcium transport. However, we found that tunicamycin caused an immediate release of calcium from the endo/sarcoplasmic reticulum, which was sensitive to thapsigargin, and an influx of calcium through the plasma membrane, resulting in a significant increase in cytoplasmic calcium and depletion of endo/sarcoplasmic reticulum calcium. Furthermore, we observed that tunicamycin also induced contraction in intact vascular smooth muscle. By applying established procedures and antagonists, we established that tunicamycin did not directly activate physiological calcium channels, such as store-operated channels, voltage gated calcium channels, ryanodine receptors or inositol trisphosphate receptors. Instead, we found that its effects on cellular calcium fluxes closely resembled those of the known calcium ionophore, ionomycin. We have concluded that tunicamycin directly permeabilizes the plasma membrane and endo/sarcoplasmic reticulum to calcium, and is, therefore, inappropriate for studying the relationship between accumulation of unfolded proteins and endo/sarcoplasmic reticulum calcium dysregulation during the endo/sarcoplasmic reticulum stress response. In contrast, we also report that two other well-known endo/sarcoplasmic reticulum stress inducers, brefeldin A and dithiothreitol, did not exhibit similar increases in calcium permeability. PMID- 24769511 TI - Protective effect of 7-O-succinyl macrolactin A against intestinal inflammation is mediated through PI3-kinase/Akt/mTOR and NF-kappaB signaling pathways. AB - Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha, are pivotal for the development of inflammatory bowel disease (IBD), and down regulation of the cytokines and cytokine-induced inflammatory responses therefore constitute pharmacological targets for the development of therapeutic strategies in IBD. In the current study, we found that 7-O-succinyl macrolactin A (SMA), a macrolide, potently inhibited TNF-alpha-induced adhesion of monocytes to colonic epithelial cells in a concentration-dependent manner, similar to rapamycin, a mTOR inhibitor. In addition, oral administration of SMA resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration, as well as microscopic damage score in a histomorphological examination of HE-stained colon tissue. More importantly, SMA was more efficacious in inhibition of intestinal inflammation than 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, the most commonly prescribed agent for the treatment of IBD. Such anti-inflammatory activity showed correlation with significant suppression of adhesion molecules (ICAM-1 and VCAM 1), T-helper 1-type cytokines (TNF-alpha, IL-6), and chemokines (MCP-1, IL-8). In addition to inhibition of NF-kappaB nuclear translocation, SMA also caused significant suppression of TNF-alpha-induced phosphorylation of PI3K, Akt, mTOR and p70S6 kinase, similar to the effect of rapamycin, an immunosuppressant macrolide. Taken together, the current results suggest that managing both mTOR and NF-kappaB activation pathways using SMA may be a good therapeutic intervention for the treatment of IBD. PMID- 24769512 TI - Diosmin pretreatment improves cardiac function and suppresses oxidative stress in rat heart after ischemia/reperfusion. AB - Reperfusion of ischemic tissue leads to the generation of oxygen derived free radicals which plays an important role in cellular damage. Objective of the current study is to evaluate the cardio-protective and antioxidant effect of diosmin on ischemia-reperfusion related cardiac dysfunction, oxidative stress and apoptosis. Diosmin (50 and 100 mg/kg body weight (bw)) was given every day to the rats orally throughout the experimental period. Ischemia/reperfusion protocol was carried out ex vivo using langendorff perfusion method and the cardiac functional recovery was assessed in terms of percentage rate pressure product. Coronary effluents of LDH and CK-MB activities, antioxidant enzyme activities, lipid peroxidation products, activity of TCA cycle enzymes were evaluated. Moreover, in vitro superoxide anion and hydroxyl radical scavenging potential of diosmin was also quantified. Finally, quantitative real-time PCR was used for assessing Bcl-2 mRNA expression in heart. Cardiac functional recovery was impaired after reperfusion compared with continuously perfused heart. It was significantly prevented by diosmin treatment. Impaired antioxidant enzyme activities and elevated lipid peroxidation products level were also significantly suppressed. The activity of TCA cycle enzymes was protected against reperfusion stress. Down regulated Bcl-2 was also significantly increased. This study concluded that diosmin pretreatment prevents all the impaired patterns including cardiac function, oxidative stress and apoptosis associated with reperfusion in control heart by its antioxidant role. PMID- 24769514 TI - Side branch complication after a single-stent crossover technique: prediction with frequency domain optical coherence tomography. AB - OBJECTIVES: To identify preprocedural predictors of side branch (SB) complications after coronary bifurcation stent implantation using frequency domain optical coherence tomography (FD-OCT). BACKGROUND: Coronary bifurcation lesions are common but difficult to treat. Longitudinal reconstruction images of FD-OCT have high image quality and less motion artifacts. METHODS: Among 49 patients (age: 69.9 years) who underwent elective coronary stenting, 52 bifurcation lesions without baseline SB stenosis were studied. SB complication was defined as angiographic worsening of SB stenosis (>75%). On the basis of preprocedural FD-OCT imaging, plaque distribution, SB angle, carina tip angle (CT angle), and length between proximal branching point to carina tip (BP-CT length) were evaluated. RESULTS: SB complication was observed in 22 lesions. The eccentric plaque distribution oriented toward the opposite side of SB at the CT was significantly more frequent in lesions with SB complication compared with those without (77.3 vs. 16.7%, P<0.01). CT angle and BP-CT length were significantly smaller in lesions with SB complication compared with those without [29.5 degrees (interquartile range (IQR) 22.3-44.3 degrees ) vs. 65.0 degrees (IQR 42.5-90.0 degrees )], P<0.001; 1.20 mm (IQR 0.70-1.73 mm) vs. 2.25 mm (IQR 1.78-3.20 mm), P<0.001, respectively]. The receiver-operating characteristic curve indicated a CT angle less than 50 degrees (area under the curve=0.81, sensitivity 86%, specificity 70%) and BP-CT length less than 1.70 mm (area under the curve=0.84, sensitivity 77%, specificity 77%) as the best cutoff values for predicting the SB complication after main vessel stent implantation. CONCLUSION: This FD-OCT study showed that narrower CT angle and shorter BP-CT length were the independent predictors for SB complications after bifurcation stenting. PMID- 24769515 TI - Correlation between the serum alkaline phosphatase level and the severity of coronary artery disease. AB - OBJECTIVES: The serum alkaline phosphatase (ALP) level has shown to be a prognostic factor in myocardial infarction and peripheral vascular disease by its promoting effect on vascular calcification. A few recent studies also showed that elevated ALP levels were associated with mortality and unfavorable prognosis in coronary artery disease (CAD). Herein, we aimed to investigate the correlation between serum ALP levels and the severity of CAD by assessing the Gensini score. MATERIALS AND METHODS: A total of 470 patients with stable angina pectoris were evaluated retrospectively.Upon admission, their ALP levels were measured with an automated analyzer by the enzymatic method, and the severity of CAD was documented for each patient according to their Gensini score. Patients with a Gensini score greater than 40 were defined to have an advanced CAD. Serum ALP levels higher than 129 mg/dl in men and higher than 104 mg/dl in women were defined as the elevated ALP groups. RESULTS: The mean ALP level was 97.3+/-56.4, ranging from 15 to 485 U/l with 66.0/82.5/106.0 U/l percentile values, and elevated ALP levels were obtained in 79 cases (16.8%). In 70% of the patients (n=329), advanced CAD was diagnosed. The mean Gensini score was 85.6+/-29.4 in the advanced CAD group and 12.8+/-15.8 in the remainder of the patients. The advanced CAD group included more men, patients with diabetes mellitus, hypertension, and a reduced left ventricular ejection fraction, and patients with lower levels of high-density lipoprotein cholesterol and higher levels of creatinine, red cell distribution width, and mean platelet volume. ALP levels (105.4+/-60.7 vs. 78.4+/-38.7 U/l, P<0.001) and the frequency of patients with elevated ALP levels (22 vs. 5.0%, P<0.001) were significantly higher in the advanced CAD group. Regression analysis showed a significant correlation between increased levels of serum ALP and advanced CAD in univariate (odds ratio 1.015, 95% confidence interval 1.008-1.1291, P<0.001) and multivariate analyses (odds ratio 1.013, 95% confidence interval 1.003-1.023, P=0.01). CONCLUSION: Elevated ALP levels are associated with higher Gensini scores and a more severe form of CAD. PMID- 24769516 TI - Polymorphisms of microRNA-binding sites in integrin genes are associated with oral squamous cell carcinoma susceptibility and progression. AB - Integrins, which act as an important role in the connection between cells and extra-cellular environments, are important cell surface receptors. Integrins have been demonstrated to play critical roles in many aspects of the progression of oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in microRNA-binding sites of integrin genes and the susceptibility and progression of OSCC in Chinese Han Population. We recruited 167 OSCC patients and 200 cancer-free controls from three independent medical centers. Genotyping was completed successfully for the five selected integrin SNPs: rs1062484 (integrin alpha3), rs11902171 (integrin alphav), rs17468 (integrin beta1), rs3809865 (integrin beta3), and rs2675 (integrin beta5). The results demonstrated that the A allele of rs3809865 T/A (a T-to-A nucleotide change), a functional polymorphism in the 3'UTR of integrin beta3 gene, was associated with OSCC risk (p < 0.05). In addition, the association analysis between this SNP and integrin beta3 mRNA expression level in the patients' peripheral blood mononuclear cells indicated that OSCC patients carrying the A allele would have a lower integrin beta3 expression level (p = 0.047). Meanwhile, survival analysis showed that the C allele of rs2675 A/C (nucleotide change from A to C), another 3'UTR polymorphism in integrin beta5 gene, was related with progression of OSCC. Overall, our results suggest that rs3809865 and rs2675 may contribute to OSCC risk and progression in Chinese Han Population. These two SNPs may be used as potential diagnostic and prognostic biomarkers for OSCC in future. PMID- 24769517 TI - Response to the commentary of Segrot et al on the Swedish SFP trial. PMID- 24769518 TI - Galectin-3 and matrix metalloproteinase-9: Perspective in management of hepatocellular carcinoma. AB - AIM: Hepatocellular carcinoma (HCC) is the fifth most common cancer in men and the seventh in women. HCC varies widely in incidence through the world, with rising incidence in Egypt. This study aimed to estimate the serum levels of matrix metalloproteinase-9 (MMP-9) and its substrate galectin-3 in order to evaluate their diagnostic accuracy and their relation to HCC-related clinical features. METHODS: For this purpose, serum levels of these biochemical markers were assessed in 50 HCC patients, 30 cirrhotic patients in addition to 10 healthy subjects as a control group using enzyme linked immune-sorbent assay (ELISA). RESULTS: In the present study, circulating level of galectin-3, MMP-9 increased significantly in HCC as compared to the control group (P = 0.044 and 0.04, respectively). However, no significant difference was observed between cirrhotic and HCC patients (P = 0.231 and 0.193, respectively). Our study found that HCC patients with metastatic spread had a significant elevation of both serum galectin-3 and MMP-9 levels (P = 0.028 and <0.0001, respectively). In addition, galectin-3 level significantly increased in HCC patients with poor prognosis suffering from portal vein invasion (P = 0.014). Moreover, MMP-9 increased significantly with increasing stage of Barcelona-Clinic Liver Cancer Group diagnostic and treatment strategy (P = 0.01). CONCLUSION: MMP-9 and galectin-3 could be used as a guide for prognosis of HCC since they may play a role in HCC progression and metastasis. However, they are not useful markers for HCC diagnosis. PMID- 24769519 TI - Recurrent pseudocellulitis due to gemcitabine: underrecognized and underreported? AB - Pseudocellulitis has been previously described with the use of chemotherapy agent gemcitabine. This condition is thought to occur due to vascular toxicity and increased localized permeability of the skin capillaries. We report herein a case of recurrent pseudocellulitis due to gemcitabine in a patient with metastatic pancreatic cancer. We believe this condition is underreported and underrecognized. Furthermore, it may be misdiagnosed as cellulitis and inappropriately treated with systemic antibiotics. As the diagnosis is clinical and the condition is self-limited, referral to other specialists is usually not required. Awareness of gemcitabine-induced pseudocellulitis is important in order to reassure the patients, their families, and non-oncology providers and to avoid unnecessary (and often costly) diagnostic work-up. PMID- 24769520 TI - The effects of a palliative care program on antidepressant use and continuing maintenance medications in near end-of-life oncology patients (the HEALED study). AB - RATIONAL: The use of antidepressants and maintenance medications for cancer patients in a palliative care setting is controversial. The effectiveness of antidepressants and consequences of discontinuing maintenance medications are unknown in this population. OBJECTIVE: Compare the quality of life of patients taking and not taking antidepressants at entry to a palliative care clinic, and to observe maintenance medication use in this population, along with consequences of stopping them. METHODS: Prospective, monthly review of medications, quality of life, and hospitalizations were recorded from oncology patients that attended a palliative care clinic. In addition, a retrospective chart review of medications and hospitalizations of oncology patients that did and did not attend a palliative care clinic was performed. RESULTS: Forty-three prospective patients were enrolled. Patients had similar quality of life whether or not they were taking antidepressants (p = 0.52). Number of maintenance medications at entry and at final evaluation did not change (p = 0.45). No hospitalizations were caused by discontinuation of maintenance medications. QOL of patients did not decline after coming to the clinic based on the baseline and second FACT-G questionnaires (p = 0.84). Fifty-six patients were included in the retrospective portion of this study. The non-palliative care patients had higher proportions of maintenance medications and rates of hospitalizations when compared to the palliative care patients. CONCLUSION: Quality of life is essentially the same between palliative care patients, whether they are receiving antidepressants or not. PMID- 24769522 TI - Combined NIRS and IVUS imaging detects vulnerable plaque using a single catheter system: a head-to-head comparison with OCT. AB - AIMS: The presence of thin-cap fibroatheromas (TCFA) is associated with high risk of acute coronary syndrome, hence their early detection may identify high-risk patients. In the present study we investigated the ability of a combined imaging catheter with near-infrared spectroscopy (NIRS) plus intravascular ultrasound (IVUS) to detect TCFA in patients with stable coronary artery disease. METHODS AND RESULTS: Optical coherence tomography (OCT) and combined NIRS-IVUS assessment were performed on identical coronary segments. IVUS analysis provided per-segment minimal cross-sectional area (CSA), plaque length (PL), plaque burden (PB), plaque volume (PV), and remodelling index (RI). OCT was used as the gold-standard reference to define TCFA (fibrous cap thickness <65 MUm). Plaque lipid content was estimated by NIRS (lipid core burden index [LCBI]). OCT-defined TCFA was present in 18 of 76 segments. IVUS revealed that OCT-defined TCFA were positively remodelled lesions with greater PB and PV, smaller CSA, and longer PL, while NIRS revealed greater LCBI per 2 mm segment (LCBI2mm) (all p<0.001). Greatest accuracy for OCT-defined TCFA detection was achieved using LCBI2mm >315 with RI >1.046 as a combined criterion value. CONCLUSIONS: OCT-defined TCFA are characterised by positive vessel remodelling, high plaque burden and greater lipid core burden as assessed by dual NIRS-IVUS imaging. PMID- 24769521 TI - Negative affectivity and EEG asymmetry interact to predict emotional interference on attention in early school-aged children. AB - Negative affectivity (NA) is a broad construct that has been associated with the development of psychopathologies, such as anxiety, and with exaggerated attention to threatening stimuli. EEG asymmetry reflects biological individual differences in emotional reactivity that may underlie the association between NA and attention to threat. The present study included a sample of 31 five-seven year olds (M age in months=74.39, SD=6.57) to test the hypothesis that greater NA, combined with greater right anterior and posterior asymmetries, predicts increased attention interference following threat stimuli. Children completed an executive attention task which presented task-irrelevant threat (angry) and non threat (neutral) faces prior to each trial. EEG asymmetry was measured at baseline for anterior, anterior-temporal and posterior scalp regions and child NA was measured via maternal report. As predicted, children showing greater NA and greater right anterior-temporal asymmetry showed more attention interference following angry faces. Additionally, two trend-level effects emerged: children showing greater NA and greater left anterior-temporal asymmetry showed less attention interference following angry faces, and children showing greater NA and greater left posterior asymmetry showed less attention interference, but only following neutral faces. Discussion focuses on the utility of using EEG asymmetry in the study of temperament, attentional biases, and the biological processes by which temperament confers risk for psychopathology. PMID- 24769523 TI - Intracellular freezing in the infective juveniles of Steinernema feltiae: an entomopathogenic nematode. AB - Taking advantage of their optical transparency, we clearly observed the third stage infective juveniles (IJs) of Steinernema feltiae freezing under a cryo stage microscope. The IJs froze when the water surrounding them froze at -2 degrees C and below. However, they avoid inoculative freezing at -1 degrees C, suggesting cryoprotective dehydration. Freezing was evident as a sudden darkening and cessation of IJs' movement. Freeze substitution and transmission electron microscopy confirmed that the IJs of S. feltiae freeze intracellularly. Ice crystals were found in every compartment of the body. IJs frozen at high sub-zero temperatures (-1 and -3 degrees C) survived and had small ice crystals. Those frozen at -10 degrees C had large ice crystals and did not survive. However, the pattern of ice formation was not well-controlled and individual nematodes frozen at -3 degrees C had both small and large ice crystals. IJs frozen by plunging directly into liquid nitrogen had small ice crystals, but did not survive. This study thus presents the evidence that S. feltiae is only the second freeze tolerant animal, after the Antarctic nematode Panagrolaimus davidi, shown to withstand extensive intracellular freezing. PMID- 24769524 TI - Sexual odor discrimination and physiological profiles in adult male rats after a neonatal, short term, reversible nasal obstruction. AB - The present study was designed to examine behavioral responses (interpreted as preferences) to olfactory cues (nest bedding odor and odors of estrous and anestrus females) in adult male rats after they had a short term reversible, bilateral, nasal obstruction (RbNO) as developing rat pups. These results were compared to behavior of control (untreated) and sham operated male littermates. Behavioral tests and physiological parameters were analyzed 90 days after recovery of nasal breathing. Experiments investigated the time spent in arms or the center of a maze of male rats in response to odors from the nest bedding or from adult females. There were no differences in responses between untreated, sham and RbNO adult male rats to fresh and nest bedding odors. RbNO males spent more time in the center of the maze when given a choice of estrus or anestrus female odors, or bedding odors from untreated or sham operated female rats. In contrast untreated and sham male rats preferred the odors of estrous females and of untreated or sham females. Plasma corticosterone levels in the males increased during the behavioral tests. Plasma testosterone levels were significantly lower in RbNO males compared to untreated males and did not increase during the behavioral tests compared to sham operated males. Males from all groups had similar preferences for the odor of bedding from adult RbNO females. Plasma levels of cholesterol and triglycerides were increased in RbNO adults. In conclusion, short term nasal obstruction in males while juvenile has long term consequences on hormones and behavioral preferences, thus potential partner selection when adult. PMID- 24769525 TI - Differential expression of the cerebral cortex proteome in physically trained adult rats. AB - Exercise has beneficial effects on brain function, including the promotion of plasticity and the enhancement of learning and memory performance. To further explore the molecular changes in the protein expression levels in the cerebral cortex of physically trained rats, male Wistar rats 8 months old were selected and subjected to swimming training in a rectangular glass tank for 30 min/day, 6 days/week and 3% of load for 4 weeks. Two dimensional gel electrophoresis followed by mass spectrometrical identification assigning spots to proteins and determination of coomassie-densities of the protein spots were carried out. The up-regulated spots were found to be statistically significant with a p-value of <0.05. Proteins related to energy metabolism like GAPDH and ATP synthase and synaptic plasticity related proteins like actin, tubulin and 14-3-3 zeta/delta were up-regulated in the cerebral cortex of swim trained rats. Thus, our results suggest that exercise elicits a differential protein expression pattern with significant changes in proteins relevant to cortical function and these proteins may be incorporated with neuronal recovery in terms of neurite formation and remodeling of synaptic connections. PMID- 24769526 TI - Neuroprotective effect of tempol (4 hydroxy-tempo) on neuronal death induced by sciatic nerve transection in neonatal rats. AB - Peripheral nerve injury in newborn rats triggers extensive neuronal death within the spinal cord. Because most neurodegeneration is related to oxidative stress and apoptosis, the use of antioxidants may be of therapeutic interest. Tempol is promising because of its ability to chelate reactive oxygen species and to minimize or even prevent tissue damage. Here, we evaluated neuroprotective effects of tempol following neonatal sciatic nerve transection. Two-day-old pups underwent sciatic nerve axotomy followed by tempol (12, 24 and 48 mg/kg) treatment (i.p.) at 10 min, 6 h, and every 24 h up to 1 week after injury. The rats were then killed for lumbar intumescence analysis. Nissl staining, TUNEL, synaptophysin immunolabeling and qRT-PCR (Caspase 3, Bax and Bcl2) were carried out. The results indicated that tempol treatment, at 24 mg/kg, increased up to 21% spinal cord motoneuron survival (p<0.001), also preserving pre-synaptic terminals in the neuropile. Likewise, the TUNEL-positive cell number decreased in tempol-treated animals. qRT-PCR results indicated differential increase in Caspase 3 (3-fold), Bax (13-fold) and Bcl2 (28-fold) gene expression, after 12 h following axotomy and tempol treatment. In conclusion, tempol administration has proven to be neuroprotective after neonatal nerve injury, leading to improved motoneuron survival, synapse preservation and minimizing apoptosis. PMID- 24769527 TI - 'Graphenization' of 2D simple monatomic liquids. AB - We present molecular dynamics (MD) simulations of the formation of 2D materials with a honeycomb structure from 2D simple monatomic liquids with honeycomb interaction potential (Rechtsman et al 2005 Phys. Rev. Lett. 95 228301). Models are observed by cooling from the melt at various cooling rates. Thermodynamics of the phase transitions is analyzed in detail. Depending on the cooling rate, amorphous or crystalline honeycomb structures have been found. Structural properties of the crystalline honeycomb structure are studied via radial distribution function (RDF), coordination number and ring distribution, including 2D visualization of the atomic configurations. We find evidence for the existence of polycrystalline honeycomb structures and new structural defects, not previously reported. The atomic mechanism that forms the solid phase of a honeycomb structure from the liquid state has been analyzed by monitoring the spatio-temporal arrangement of atoms in 6-fold rings and/or atoms with the coordination number [Formula: see text], occurring upon cooling from the melt. Since knowledge of how real 2D solids with honeycomb structures form from the vapor or liquid phase is still completely lacking, our simulations highlight the situation and give a deeper understanding of the structure and thermodynamics of real 2D materials such as graphene, silicene, germanene, etc. PMID- 24769528 TI - Quantitative phosphoproteomic analysis of porcine muscle within 24 h postmortem. AB - Protein phosphorylation can regulate most of the important processes in muscle, such as metabolism and contraction. The postmortem (PM) metabolism and rigor mortis have essential effects on meat quality. In order to identify and characterize the protein phosphorylation events involved in meat quality development, a quantitative mass spectrometry-based phosphoproteomic study was performed to analyze the porcine muscle within 24h PM using dimethyl labeling combined with the TiSH phosphopeptide enrichment strategy. In total 305 unique proteins were identified, including 160 phosphoproteins with 784 phosphorylation sites. Among these, 184 phosphorylation sites on 93 proteins had their phosphorylation levels significantly changed. The proteins involved in glucose metabolism and muscle contraction were the two largest clusters of phosphoproteins with significantly changed phosphorylation levels in muscle within 24 h PM. The high phosphorylation level of heat shock proteins (HSPs) in early PM may be an adaptive response to slaughter stress and protect muscle cell from apoptosis, as observed in the serine 84 of HSP27. This work indicated that PM muscle proteins underwent significant changes at the phosphorylation level but were relatively stable at the total protein level, suggesting that protein phosphorylation may have important roles in meat quality development through the regulation of proteins involved in glucose metabolism and muscle contraction, thereby affecting glycolysis and rigor mortis development in PM muscle. BIOLOGICAL SIGNIFICANCE: The manuscript describes the characterization of postmortem (PM) porcine muscle within 24 h postmortem from the perspective of protein phosphorylation using advanced phosphoproteomic techniques. In the study, the authors employed the dimethyl labeling combined with the TiSH phosphopeptide enrichment and LC-MS/MS strategy. This was the first high-throughput quantitative phosphoproteomic study in PM muscle of farm animals. In the work, both the proteome and phosphoproteome were analyzed, and the large number of identified peptides, phosphopeptides and phosphorylation sites can greatly enrich the current farm animal protein database. The proteins involved in glycometabolism, muscle contraction and heat shock proteins (HSPs) showed significantly changed phosphorylation levels during PM meat development. This work indicated that PM muscle proteins underwent significant changes at phosphorylation level but were relatively stable at the total protein level, suggesting that protein phosphorylation may have important roles in meat development through the regulation of proteins involved in metabolism and muscle contraction, thereby affecting glycolysis and rigor mortis development in PM muscle. The work can promote the understanding of PM muscle metabolism and meat quality development, and be helpful for future meat quality control. PMID- 24769529 TI - Pregabalin-Associated Heart Failure Decompensation in a Patient With a History of Stage I Heart Failure. AB - OBJECTIVE: To describe an elderly male patient with a prior history of New York Heart Association (NYHA) class I heart failure (HF) who presented with cardiac decompensation related to pregabalin therapy and to review the literature involving the effects of pregabalin in HF patients. CASE SUMMARY: An 84-year-old man with NYHA class I HF (left-ventricular ejection fraction between 45% and 50%) presented to the emergency department with acute HF decompensation approximately 10 days after initiation of pregabalin for the management of peripheral neuropathy. Discontinuation of pregabalin and administration of furosemide resulted in resolution of symptoms. Shortness of breath; facial, neck, and peripheral edema; and weight gain all improved within 2 days. Three months following discontinuation of furosemide and pregabalin, the patient remained stable without any recurring symptoms or progression in HF. DISCUSSION: Pregabalin is associated with a 10% to 15% prevalence of peripheral edema and weight gain, with cases reported in patients both with and without HF. Whereas most reported HF exacerbations have occurred in patients with NYHA class II to IV HF, this case is one of the first to be reported in a patient with NYHA class I. According to the Naranjo probability scale (score of 4), it was possible that the patient's HF symptoms were related to pregabalin. The mechanism of action of pregabalin-induced HF is unknown, but pregabalin has been shown to act as a calcium channel antagonist. CONCLUSION: Although further studies are needed, this case suggests that close monitoring of patients with NYHA class I HF should be considered when initiating pregabalin therapy. PMID- 24769530 TI - Unique behaviour of dinitrogen-bridged dimolybdenum complexes bearing pincer ligand towards catalytic formation of ammonia. AB - It is vital to design effective nitrogen fixation systems that operate under mild conditions, and to this end we recently reported an example of the catalytic formation of ammonia using a dinitrogen-bridged dimolybdenum complex bearing a pincer ligand, where up to twenty three equivalents of ammonia were produced based on the catalyst. Here we study the origin of the catalytic behaviour of the dinitrogen-bridged dimolybdenum complex bearing the pincer ligand with density functional theory calculations, based on stoichiometric and catalytic formation of ammonia from molecular dinitrogen under ambient conditions. Comparison of di- and mono-molybdenum systems shows that the dinitrogen-bridged dimolybdenum core structure plays a critical role in the protonation of the coordinated molecular dinitrogen in the catalytic cycle. PMID- 24769531 TI - Endovascular management of total juxtarenal aortic occlusive disease in high-risk patients: technical considerations and clinical outcome. AB - BACKGROUND: To report our single-center experience in the endovascular treatment of juxtarenal aorto-iliac occlusions. METHODS: Between December 2008 and December 2012, 13 patients with total juxtarenal aorto-iliac occlusion, considered at high risk for open revascularization, were treated by endovascular means at our Department. Inclusion criteria were severe intermittent claudication, rest pain and distal tissue loss. Antegrade recanalization from percutaneous brachial access and retrograde angioplasty and stenting from percutaneous or surgical femoral accesses were performed. The renal arteries (RAs) were protected using filters or balloons. Aorto-iliac bare-metal stents were deployed in all patients. RESULTS: No death was registered. Technical success was 100%. In 11 patients (84.6%) the Ankle-Brachial Index increased to 0.9-1. Renal arteries were involved in 7 cases (53.8%): 3 chimney stent grafts deployment, 2 aorto-iliac stent fenestrations and 2 aorto-iliac stents placement above the renal arteries without renal function impairment. Complication rate was 38.5%: 2 cases of thrombus dislodgement into the RAs, 1 distal artery embolization, 1 common iliac artery rupture and 1 pseudo-aneurysm. All complications were treated percutaneously, except for the distal embolization treated surgically. The patient with iliac artery rupture underwent acute renal insufficiency requiring temporary dialysis after hemorrhagic shock because of retroperitoneal hematoma. Mean follow-up was 18 months (range 6-30 months). The primary and secondary patency was respectively 92.3% and 100%. CONCLUSION: Endovascular recanalization of juxtarenal aorto-iliac occlusion in selected patients is feasible and safe, with good early and mid-term results and should be considered in high risk patients. PMID- 24769533 TI - Photobody Localization of Phytochrome B Is Tightly Correlated with Prolonged and Light-Dependent Inhibition of Hypocotyl Elongation in the Dark. AB - Photobody localization of Arabidopsis (Arabidopsis thaliana) phytochrome B (phyB) fused to green fluorescent protein (PBG) correlates closely with the photoinhibition of hypocotyl elongation. However, the amino-terminal half of phyB fused to green fluorescent protein (NGB) is hypersensitive to light despite its inability to localize to photobodies. Therefore, the significance of photobodies in regulating hypocotyl growth remains debatable. Accumulating evidence indicates that under diurnal conditions, photoactivated phyB persists into darkness to inhibit hypocotyl elongation. Here, we examine whether photobodies are involved in inhibiting hypocotyl growth in darkness by comparing the PBG and NGB lines after the red light-to-dark transition. Surprisingly, after the transition from 10 MUmol m-2 s-1 red light to darkness, PBG inhibits hypocotyl elongation three times longer than NGB. The disassembly of photobodies in PBG hypocotyl nuclei correlates tightly with the accumulation of the growth-promoting transcription factor PHYTOCHROME-INTERACTING FACTOR3 (PIF3). Destabilizing photobodies by either decreasing the light intensity or adding monochromatic far-red light treatment before the light-to-dark transition leads to faster PIF3 accumulation and a dramatic reduction in the capacity for hypocotyl growth inhibition in PBG. In contrast, NGB is defective in PIF3 degradation, and its hypocotyl growth in the dark is nearly unresponsive to changes in light conditions. Together, our results support the model that photobodies are required for the prolonged, light dependent inhibition of hypocotyl elongation in the dark by repressing PIF3 accumulation and by stabilizing the far-red light-absorbing form of phyB. Our study suggests that photobody localization patterns of phyB could serve as instructive cues that control light-dependent photomorphogenetic responses in the dark. PMID- 24769532 TI - Canine distemper virus infection leads to an inhibitory phenotype of monocyte derived dendritic cells in vitro with reduced expression of co-stimulatory molecules and increased interleukin-10 transcription. AB - Canine distemper virus (CDV) exhibits a profound lymphotropism that causes immunosuppression and increased susceptibility of affected dogs to opportunistic infections. Similar to human measles virus, CDV is supposed to inhibit terminal differentiation of dendritic cells (DCs), responsible for disturbed repopulation of lymphoid tissues and diminished antigen presenting function in dogs. In order to testify the hypothesis that CDV-infection leads to an impairment of professional antigen presenting cells, canine DCs have been generated from peripheral blood monocytes in vitro and infected with CDV. Virus infection was confirmed and quantified by transmission electron microscopy, CDV-specific immunofluorescence, and virus titration. Flow cytometric analyses revealed a significant down-regulation of the major histocompatibility complex class II and co-stimulatory molecules CD80 and CD86 in CDV-infected DCs, indicative of disturbed antigen presenting capacity. Molecular analyses revealed an increased expression of the immune inhibitory cytokine interleukin-10 in DCs following infection. Results of the present study demonstrate that CDV causes phenotypical changes and altered cytokine expression of DCs, which represent potential mechanisms to evade host immune responses and might contribute to immune dysfunction and virus persistence in canine distemper. PMID- 24769534 TI - Quantitative assessment of automatic reconstructions of branching systems obtained from laser scanning. AB - BACKGROUND AND AIMS: Automatic acquisition of plant architecture is a major challenge for the construction of quantitative models of plant development. Recently, 3-D laser scanners have made it possible to acquire 3-D images representing a sampling of an object's surface. A number of specific methods have been proposed to reconstruct plausible branching structures from this new type of data, but critical questions remain regarding their suitability and accuracy before they can be fully exploited for use in biological applications. METHODS: In this paper, an evaluation framework to assess the accuracy of tree reconstructions is presented. The use of this framework is illustrated on a selection of laser scans of trees. Scanned data were manipulated by experienced researchers to produce reference tree reconstructions against which comparisons could be made. The evaluation framework is given two tree structures and compares both their elements and their topological organization. Similar elements are identified based on geometric criteria using an optimization algorithm. The organization of these elements is then compared and their similarity quantified. From these analyses, two indices of geometrical and structural similarities are defined, and the automatic reconstructions can thus be compared with the reference structures in order to assess their accuracy. KEY RESULTS: The evaluation framework that was developed was successful at capturing the variation in similarities between two structures as different levels of noise were introduced. The framework was used to compare three different reconstruction methods taken from the literature, and allowed sensitive parameters of each one to be determined. The framework was also generalized for the evaluation of root reconstruction from 2-D images and demonstrated its sensitivity to higher architectural complexity of structure which was not detected with a global evaluation criterion. CONCLUSIONS: The evaluation framework presented quantifies geometric and structural similarities between two structures. It can be applied to the characterization and comparison of automatic reconstructions of plant structures from laser scanner data and 2-D images. As such, it can be used as a reference test for comparing and assessing reconstruction procedures. PMID- 24769535 TI - Legume genomics: understanding biology through DNA and RNA sequencing. AB - BACKGROUND: The legume family (Leguminosae) consists of approx. 17 000 species. A few of these species, including, but not limited to, Phaseolus vulgaris, Cicer arietinum and Cajanus cajan, are important dietary components, providing protein for approx. 300 million people worldwide. Additional species, including soybean (Glycine max) and alfalfa (Medicago sativa), are important crops utilized mainly in animal feed. In addition, legumes are important contributors to biological nitrogen, forming symbiotic relationships with rhizobia to fix atmospheric N2 and providing up to 30 % of available nitrogen for the next season of crops. The application of high-throughput genomic technologies including genome sequencing projects, genome re-sequencing (DNA-seq) and transcriptome sequencing (RNA-seq) by the legume research community has provided major insights into genome evolution, genomic architecture and domestication. SCOPE AND CONCLUSIONS: This review presents an overview of the current state of legume genomics and explores the role that next-generation sequencing technologies play in advancing legume genomics. The adoption of next-generation sequencing and implementation of associated bioinformatic tools has allowed researchers to turn each species of interest into their own model organism. To illustrate the power of next generation sequencing, an in-depth overview of the transcriptomes of both soybean and white lupin (Lupinus albus) is provided. The soybean transcriptome focuses on analysing seed development in two near-isogenic lines, examining the role of transporters, oil biosynthesis and nitrogen utilization. The white lupin transcriptome analysis examines how phosphate deficiency alters gene expression patterns, inducing the formation of cluster roots. Such studies illustrate the power of next-generation sequencing and bioinformatic analyses in elucidating the gene networks underlying biological processes. PMID- 24769538 TI - Physiological integration modifies delta15N in the clonal plant Fragaria vesca, suggesting preferential transport of nitrogen to water-stressed offspring. AB - BACKGROUND AND AIMS: One of the most striking attributes of clonal plants is their capacity for physiological integration, which enables movement of essential resources between connected ramets. This study investigated the capacity of physiological integration to buffer differences in resource availability experienced by ramets of the clonal wild strawberry plant, Fragaria vesca. Specifically, a study was made of the responses of connected and severed offspring ramets growing in environments with different water availability conditions (well watered or water stressed) and nitrogen forms (nitrate or ammonium). METHODS: The experimental design consisted of three factors, 'integration' (connected, severed) 'water status' (well watered, water stressed) and 'nitrogen form' (nitrate, ammonium), applied in a pot experiment. The effects of physiological integration were studied by analysing photochemical efficiency, leaf spectral reflectance, photosynthesis and carbon and nitrogen isotope discrimination, the last of which has been neglected in previous studies. KEY RESULTS: Physiological integration buffered the stress caused by water deprivation. As a consequence, survival was improved in water-stressed offspring ramets that remained connected to their parent plants. The nitrogen isotope composition (delta(15)N) values in the connected water-stressed ramets were similar to those in ramets in the ammonium treatment; however, delta(15)N values in connected well-watered ramets were similar to those in the nitrate treatment. The results also demonstrated the benefit of integration for offspring ramets in terms of photochemical activity and photosynthesis. CONCLUSIONS: This is the first study in which carbon and nitrogen isotopic discrimination has been used to detect physiological integration in clonal plants. The results for nitrogen isotope composition represent the first evidence of preferential transport of a specific form of nitrogen to compensate for stressful conditions experienced by a member clone. Water consumption was lower in plants supplied with ammonium than in plants supplied with nitrate, and therefore preferential transport of ammonium from parents to water-stressed offspring could potentially optimize the water use of the whole clone. PMID- 24769537 TI - The first complete chloroplast genome of the Genistoid legume Lupinus luteus: evidence for a novel major lineage-specific rearrangement and new insights regarding plastome evolution in the legume family. AB - BACKGROUND AND AIMS: To date chloroplast genomes are available only for members of the non-protein amino acid-accumulating clade (NPAAA) Papilionoid lineages in the legume family (i.e. Millettioids, Robinoids and the 'inverted repeat-lacking clade', IRLC). It is thus very important to sequence plastomes from other lineages in order to better understand the unusual evolution observed in this model flowering plant family. To this end, the plastome of a lupine species, Lupinus luteus, was sequenced to represent the Genistoid lineage, a noteworthy but poorly studied legume group. METHODS: The plastome of L. luteus was reconstructed using Roche-454 and Illumina next-generation sequencing. Its structure, repetitive sequences, gene content and sequence divergence were compared with those of other Fabaceae plastomes. PCR screening and sequencing were performed in other allied legumes in order to determine the origin of a large inversion identified in L. luteus. KEY RESULTS: The first sequenced Genistoid plastome (L. luteus: 155 894 bp) resulted in the discovery of a 36-kb inversion, embedded within the already known 50-kb inversion in the large single copy (LSC) region of the Papilionoideae. This inversion occurs at the base or soon after the Genistoid emergence, and most probably resulted from a flip-flop recombination between identical 29-bp inverted repeats within two trnS genes. Comparative analyses of the chloroplast gene content of L. luteus vs. Fabaceae and extra-Fabales plastomes revealed the loss of the plastid rpl22 gene, and its functional relocation to the nucleus was verified using lupine transcriptomic data. An investigation into the evolutionary rate of coding and non-coding sequences among legume plastomes resulted in the identification of remarkably variable regions. CONCLUSIONS: This study resulted in the discovery of a novel, major 36-kb inversion, specific to the Genistoids. Chloroplast mutational hotspots were also identified, which contain novel and potentially informative regions for molecular evolutionary studies at various taxonomic levels in the legumes. Taken together, the results provide new insights into the evolutionary landscape of the legume plastome. PMID- 24769536 TI - Regulatory roles of phosphoinositides in membrane trafficking and their potential impact on cell-wall synthesis and re-modelling. AB - BACKGROUND: Plant cell walls are complex matrices of carbohydrates and proteins that control cell morphology and provide protection and rigidity for the plant body. The construction and maintenance of this intricate system involves the delivery and recycling of its components through a precise balance of endomembrane trafficking, which is controlled by a plethora of cell signalling factors. Phosphoinositides (PIs) are one class of signalling molecules with diverse roles in vesicle trafficking and cytoskeleton structure across different kingdoms. Therefore, PIs may also play an important role in the assembly of plant cell walls. SCOPE: The eukaryotic PI pathway is an intricate network of different lipids, which appear to be divided in different pools that can partake in vesicle trafficking or signalling. Most of our current understanding of how PIs function in cell metabolism comes from yeast and mammalian systems; however, in recent years significant progress has been made towards a better understanding of the plant PI system. This review examines the current state of knowledge of how PIs regulate vesicle trafficking and their potential influence on plant cell-wall architecture. It considers first how PIs are formed in plants and then examines their role in the control of vesicle trafficking. Interactions between PIs and the actin cytoskeleton and small GTPases are also discussed. Future challenges for research are suggested. PMID- 24769539 TI - Assessing the effects of management on forest growth across France: insights from a new functional-structural model. AB - BACKGROUND AND AIMS: The structure of a forest stand, i.e. the distribution of tree size features, has strong effects on its functioning. The management of the structure is therefore an important tool in mitigating the impact of predicted changes in climate on forests, especially with respect to drought. Here, a new functional-structural model is presented and is used to assess the effects of management on forest functioning at a national scale. METHODS: The stand process based model (PBM) CASTANEA was coupled to a stand structure module (SSM) based on empirical tree-to-tree competition rules. The calibration of the SSM was based on a thorough analysis of intersite and interannual variability of competition asymmetry. The coupled CASTANEA-SSM model was evaluated across France using forest inventory data, and used to compare the effect of contrasted silvicultural practices on simulated stand carbon fluxes and growth. KEY RESULTS: The asymmetry of competition varied consistently with stand productivity at both spatial and temporal scales. The modelling of the competition rules enabled efficient prediction of changes in stand structure within the CASTANEA PBM. The coupled model predicted an increase in net primary productivity (NPP) with management intensity, resulting in higher growth. This positive effect of management was found to vary at a national scale across France: the highest increases in NPP were attained in forests facing moderate to high water stress; however, the absolute effect of management on simulated stand growth remained moderate to low because stand thinning involved changes in carbon allocation at the tree scale. CONCLUSIONS: This modelling approach helps to identify the areas where management efforts should be concentrated in order to mitigate near-future drought impact on national forest productivity. Around a quarter of the French temperate oak and beech forests are currently in zones of high vulnerability, where management could thus mitigate the influence of climate change on forest yield. PMID- 24769540 TI - The efficacy and safety of docetaxel plus thalidomide vs. docetaxel alone in patients with androgen-independent prostate cancer: a systematic review. AB - The aim of this systematic review was taken to investigate the efficacy and safety of docetaxel plus thalidomide vs. docetaxel alone for treating androgen independent prostate cancer (AIPC). Data were collected from different databases independently by three researchers according to the pre-defined inclusion and exclusion criteria. Total three studies were finally included, indicating that docetaxel plus thalidomide exhibited better survival prognosis and greater prostate-specific antigen (PSA) decline than docetaxel alone. There were no significant differences of hematologic toxicities in two regimens, while the frequency of non-hematologic toxicities was higher in patients with docetaxel plus thalidomide. Briefly, the available evidence indicates potential survival advantage in docetaxel plus thalidomide over docetaxel alone. PMID- 24769541 TI - Axonal regeneration in zebrafish. AB - In contrast to mammals, fish and amphibia functionally regenerate axons in the central nervous system (CNS). The strengths of the zebrafish model, that is, transgenics and mutant availability, ease of gene expression analysis and manipulation and optical transparency of larvae lend themselves to the analysis of successful axonal regeneration. Analyses in larval and adult zebrafish suggest a high intrinsic capacity for axon regrowth, yet signaling pathways employed in axonal growth and pathfinding are similar to those in mammals. However, the lesioned CNS environment in zebrafish shows remarkably little scarring or expression of inhibitory molecules and regenerating axons use molecular cues in the environment to successfully navigate to their targets. Future zebrafish research, including screening techniques, will complete our picture of the mechanisms behind successful CNS axon regeneration in this vertebrate model organism. PMID- 24769542 TI - Ameliorative effect of mepenzolate bromide against pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis is thought to involve lung injury caused by reactive oxygen species (ROS), which in turn is followed by abnormal fibrosis. A transforming growth factor (TGF)-beta1-induced increase in myofibroblast number plays an important role in this abnormal fibrosis. We recently found that mepenzolate bromide (mepenzolate), which has been used clinically to treat gastrointestinal disorders, has ROS-reducing properties. In the present study, we examined the effect of mepenzolate on bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. The severity of pulmonary fibrosis was assessed by histopathologic evaluation and determination of hydroxyproline levels. Lung mechanics (elastance) and respiratory function [forced vital capacity (FVC)] were assessed using a computer-controlled ventilator. Respiratory function was also evaluated by monitoring percutaneous arterial oxygen saturation (SpO2). Intratracheal administration of mepenzolate prior to bleomycin treatment reduced the extent of pulmonary fibrosis and changes in lung mechanics and led to a significant recovery of both FVC and SpO2 compared with control. Furthermore, mepenzolate produced a therapeutic effect even when it was administered after the development of fibrosis. Administration of mepenzolate also prevented bleomycin induced pulmonary cell death and inflammatory responses and increased myofibroblast number. Mepenzolate also decreased NADPH oxidase activity and active TGF-beta1 level or increased glutathione S-transferase (GST) activity in the presence of bleomycin treatment. These results show that the intratracheal administration of mepenzolate reduced bleomycin-induced pulmonary fibrosis and lung dysfunction in mice. These effects may be due to this drug's inhibitory effect on NADPH oxidase and TGF-beta1 activities and its stimulatory effect on GST. PMID- 24769543 TI - Macitentan does not interfere with hepatic bile salt transport. AB - Treatment of pulmonary arterial hypertension with the endothelin receptor antagonist bosentan has been associated with transient increases in liver transaminases. Mechanistically, bosentan inhibits the bile salt export pump (BSEP) leading to an intrahepatic accumulation of cytotoxic bile salts, which eventually results in hepatocellular damage. BSEP inhibition by bosentan is amplified by its accumulation in the liver as bosentan is a substrate of organic anion-transporting polypeptide (OATP) transport proteins. The novel endothelin receptor antagonist macitentan shows a superior liver safety profile. Introduction of the less acidic sulfamide moiety and increased lipophilicity yield a hepatic disposition profile different from other endothelin receptor antagonists. Passive diffusion rather than OATP-mediated uptake is the driving force for macitentan uptake into the liver. Interaction with the sodium taurocholate cotransporting polypeptide and BSEP transport proteins involved in hepatic bile salt homeostasis is therefore limited due to the low intrahepatic drug concentrations. Evidence for this conclusion is provided by in vitro experiments in drug transporter-expressing cell lines, acute and long-term studies in rats and dogs, absence of plasma bile salt changes in healthy human volunteers after multiple dosing, and finally the liver safety profile of macitentan in the completed phase III morbidity/mortality SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) trial. PMID- 24769545 TI - Neuromodulation of parietal and motor activity affects motor planning and execution. AB - Transcranial direct current stimulation (tDCS) is a non-invasive tool, which effectively modulates behavior, and related brain activity. When applied to the primary motor cortex (M1), tDCS affects motor function, enhancing or decreasing performance of both healthy participants and brain-damaged patients. Beyond M1, the posterior parietal cortex (PPC) is also crucially involved in controlling and guiding movement. Therefore, we explored whether the modulation of cortical excitability within PPC can also affect hand motor function in healthy right handed participants. In Experiment 1, anodal tDCS (2 mA, 10 min) was applied to PPC and to M1 of both hemispheres. Skilled motor function of the non-dominant left hand, measured using the Jebsen-Taylor Hand Function Test (JTT), improved after anodal tDCS of the right, contralateral M1, as well as after the anodal stimulation of the left, ipsilateral PPC. Conversely, in Experiment 2, cathodal tDCS of the left PPC, or of the right M1, reduced motor performance of the left hand. Finally, Experiment 3 shows that the anodal tDCS of the left PPC selectively facilitated action planning, while the anodal tDCS of the right M1 modulated action execution only. This evidence shows that motor improvement induced by left parietal and right motor stimulations relies on substantial different mechanisms, opening up novel perspectives in the neurorehabilitation of stroke patients with motor and apraxic disorders. PMID- 24769546 TI - E-cigarettes: does the new emperor of tobacco harm reduction have any clothes? PMID- 24769544 TI - Hypercontractility of intestinal longitudinal smooth muscle induced by cytokines is mediated by the nuclear factor-kappaB/AMP-activated kinase/myosin light chain kinase pathway. AB - Recent studies have identified AMP-activated kinase (AMPK) as a target of Ca(2+)/calmodulin-dependent kinase kinase (CaMKKbeta) and a negative regulator of myosin light-chain (MLC) kinase (MLCK). The present study examined whether a change in expression or activity of AMPK is responsible for hypercontractility of intestinal longitudinal muscle during inflammation or in response to proinflammatory cytokines. In mouse colonic longitudinal muscle cells, acetylcholine (ACh) stimulated AMPK and MLCK phosphorylation and activity and induced MLC20 phosphorylation and muscle contraction. Blockade of CaMKKbeta with STO609 (7-oxo-7H-benzimidazo[2,1-a]benz[de]isoquinoline-3-carboxylic acid acetate) inhibited AMPK and MLCK phosphorylation and augmented MLCK activity, MLC20 phosphorylation, and smooth muscle cell contraction. In muscle cells isolated from the colon of TNBS (2,4,6-trinitrobenzenesulfonic acid)-treated mice or from strips treated with interleukin-1beta or tumor necrosis factor-alpha, nuclear factor kappaB was activated as indicated by an increase in p65 phosphorylation and IkappaBalpha degradation, and AMPK was phosphorylated at a cAMP-dependent protein kinase (PKA)-specific site (Ser(485)) that is distinct from the stimulatory CaMKKbeta site (Thr(172)), resulting in attenuation of ACh stimulated AMPK activity and augmentation of MLCK activity and muscle cell contraction. Inhibition of nuclear factor-kappaB activity with MG-132 (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal Z-LLL-CHO) or PKA activity with myristoylated PKA inhibitor 14-22 amide blocked phosphorylation of AMPK at Ser(485) and restored MLCK activity and muscle cell contraction to control levels. The results imply that PKA released from IkappaBalpha complex phosphorylated AMPK at a PKA-specific site and inhibited its activity, thereby relieving the inhibitory effect of AMPK on MLCK and increasing MLCK activity and muscle cell contraction. We conclude that hypercontractility of intestinal longitudinal muscle induced by inflammation or proinflammatory cytokines is mediated by nuclear factor kappaB/PKA-dependent inhibition of AMPK and activation of MLCK. PMID- 24769547 TI - In cell scalaradial interactome profiling using a bio-orthogonal clickable probe. AB - A bio-orthogonal click-chemistry procedure was developed to allow the in cell interactome profiling of scalaradial, an anti-inflammatory marine natural product. The results were validated through the application of the classical in vitro chemical proteomics and several bio-physical methods; peroxiredoxins, 14-3 3 isoforms and proteasomes were recognized as main scalaradial targets. PMID- 24769550 TI - Drug-induced liver toxicity studies: research into human metabolites clarifies their role in drug development. PMID- 24769549 TI - Piezoelectric, elastic, structural and dielectric properties of the Si(1 x)Ge(x)O(2) solid solution: a theoretical study. AB - We apply first principles quantum mechanical techniques to the study of the solid solution Si1-xGexO2 of alpha-quartz where silicon atoms are progressively substituted with germanium atoms, to different extents, as a function of the substitutional fraction x. For the first time, the whole range of the substitution (x = 0.0, 0.1[Formula: see text], 0.[Formula: see text], 0.5, 0.[Formula: see text], 0.8[Formula: see text], 1.0), including pure end-members alpha-SiO2 and alpha-GeO2, is explored. An elongated supercell (doubled along the c crystallographic axis) is built with respect to the unit cell of pure alpha quartz and a set of 13 symmetry-independent configurations is considered. Their structural, energetic, dielectric, elastic and piezoelectric properties are computed and analyzed. All the calculations are performed using the CRYSTAL14 program with a Gaussian-type function basis set with pseudopotentials, and the hybrid functional PBE0; all geometries are fully optimized at this level of theory. In particular, for each configuration, fourth-rank elastic and compliance tensors and third-rank direct and converse piezoelectric tensors are computed. It has already been shown that the structural distortion of the solid solution increases, almost linearly, as the substitutional fraction x increases. The piezoelectric properties of the Si1-xGexO2 solid solution are found to increase with x, with a similar quasi-linear behavior. The electromechanical coupling coefficients are enhanced as well and the linear trend recently predicted by Ranieri et al (2011 Inorg. Chem. 50 4632) can be confirmed from first principles calculations. These doped crystals do represent good candidates for technological applications requiring high piezoelectric coupling and high thermal stability. PMID- 24769551 TI - Metal-organic frameworks for artificial photosynthesis and photocatalysis. AB - Solar energy is an alternative, sustainable energy source for mankind. Finding a convenient way to convert sunlight energy into chemical energy is a key step towards realizing large-scale solar energy utilization. Owing to their structural regularity and synthetic tunability, metal-organic frameworks (MOFs) provide an interesting platform to hierarchically organize light-harvesting antennae and catalytic centers to achieve solar energy conversion. Such photo-driven catalytic processes not only play a critical role in the solar to chemical energy conversion scheme, but also provide a novel methodology for the synthesis of fine chemicals. In this review, we summarize the fundamental principles of energy transfer and photocatalysis and provide an overview of the latest progress in energy transfer, light-harvesting, photocatalytic proton and CO2 reduction, and water oxidation using MOFs. The applications of MOFs in organic photocatalysis and degradation of model organic pollutants are also discussed. PMID- 24769552 TI - Impact of hormonal contraception on prothrombotic activity in vessels. AB - One of the most common, efficient and convenient methods of contraception is hormonal contraception. Due to its popularity among young women, the safety of this method should be taken into consideration. Alternative ways of hormonal application are used and additional prothrombotic factors are being researched in order to minimize prothrombotic activity. The paper presents current data on the relationship between hormonal contraception and vascular complications based on peer-reviewed medical journals that were published between the years 2001 and 2013. PMID- 24769553 TI - Biological and clinical effects of sulodexide in arterial disorders and diseases. AB - Arteries, veins and capillaries share the feature of hosting the "endothelial organ", an ubiquitous structure lining the surface of the entire circulatory tree. Endothelial cells and their supporting elements as the basement membrane, the intracellular matrix, and the surface covering glycocalyx, although displaying significant regional differences, maintain a common response to injury and to pharmacological stimuli. Sulodexide (SDX), a highly purified extractive glycosaminoglycan (GAG), shows many biological actions indicating effectiveness in arterial disorders and diseases. In fact, SDX besides inhibiting experimental arterial thrombogenesis displays, especially by the oral route, a number of vascular protective actions that are largely independent of those affecting blood coagulation. Among the activities relevant to arterial disorders, the agent provides restoration of damaged glycocalyx and of degraded intracellular matrix, as well as antiproliferative, antinflammatory, antioxidant, anti-proteolytic and anti-ischemic activities. Among the latter properties, the inhibiting effect on the enzyme family of matrix metalloproteinases (MMPs), and especially on the expression of MMP9 and its precursor, seems of crucial importance given the role of these matrix degrading enzymes in the pathogenesis and progression of atherothrombosis in coronary, carotid and peripheral arteries. These important biological data, many of them very recent, supply clues for the interpretation of a number of previous clinical trials in arterial diseases. Studies published in the years 1990-2005, showing significant reduction of cardiovascular events after a myocardial infarction, as well as a marked improvement in the walking ability in patients with peripheral arterial disease, deserve today an active re appraisal likely conducive to new clinical research protocols in the field of primary and secondary prevention of cardiovascular disease of atherothrombotic nature. PMID- 24769554 TI - Conserved function of Rho-related Rop/RAC GTPase signaling in regulation of cell polarity in Physcomitrella patens. AB - Cell polarity is fundamentally important to growth and development in higher plants, from pollen tubes to root hairs. Basal land plants (mosses and ferns) also have cell polarity, developing protonemal apical cells that show polar tip growth. Flowering plants have a distinct group of Rho GTPases that regulate polarity in polarized cell growth. Rop/RAC signaling module components have been identified in non-flowering plants, but their roles remain unclear. To understand the importance and evolution of Rop/RAC signaling in polarity regulation in land plants, we examined the functions of PpRop and PpRopGEF in protonemal apical cells of the moss Physcomitrella patens. Inducible overexpression of PpRop2 or PpRopGEF3 caused depolarized growth of tip-growing apical cells. PpRop2 overexpression also caused aberrant cross wall formation. Fluorescent protein tagged PpRop2 localized to the plasma membrane, including the cross wall membrane, and fluorescent-tagged PpRopGEF3 showed polarized localization to the tip region in apical cells. Thus, our results suggest common functions of PpRop and PpRopGEF in the tip-growing apical cells and the importance of a conserved Rop/RAC signaling module in the control of cell polarity in land plants. PMID- 24769555 TI - The ABSORB EXTEND study: preliminary report of the twelve-month clinical outcomes in the first 512 patients enrolled. AB - AIMS: The safety and performance of the Absorb Bioresorbable Vascular Scaffold (Absorb BVS) system (Abbott Vascular, Santa Clara, CA, USA) has been previously established in 131 patients from cohort A and cohort B of the first-in-man ABSORB trial. Following this trial, ABSORB EXTEND was initiated as a global continued access study (outside of the USA) to expand experience with the Absorb BVS system to different geographies with broader inclusion criteria to include the treatment of longer lesions and multiple vessels. We report in this manuscript the twelve month clinical outcomes of the first 512 patients in this population. METHODS AND RESULTS: ABSORB EXTEND is a prospective, single-arm, open-label clinical study which will enrol up to 800 patients at up to 100 sites. Included are patients with lesions <=28 mm in length and reference vessel diameter of 2.0-3.8 mm (as assessed by on-line QCA or IVUS). Treatment of a maximum of two de novo native coronary artery lesions is permitted when each lesion is located in a different epicardial vessel. An independent clinical events committee adjudicates all endpoint-related events. At one year, for the first 512 patients enrolled in the study, the composite endpoints of ischaemia-driven MACE and ischaemia-driven target vessel failure were 4.3% and 4.9%, respectively. The cumulative rate of ARC defined definite and probable scaffold thrombosis for this population was 0.8% at one year. CONCLUSIONS: This interim analysis of the ABSORB EXTEND study shows low rates of MACE and scaffold thrombosis. The study is registered on clinicaltrials.gov (unique identifier NCT01023789). PMID- 24769556 TI - Hybrid mesoporous colloid photonic crystal array for high performance vapor sensing. AB - A hybrid mesoporous photonic crystal vapor sensing chip was developed by introducing fluorescent dyes into mesoporous colloidal crystals. The sensing chip was capable of discriminating various kinds of vapors, as well as their concentrations, according to their fluorescence and reflective responses to vapor analytes. PMID- 24769557 TI - Recovery of hand function with robot-assisted therapy in acute stroke patients: a randomized-controlled trial. AB - In the last few years, not many studies on the use of robot-assisted therapy to recover hand function in acute stroke patients have been carried out. This randomized-controlled observer trial is aimed at evaluating the effects of intensive robot-assisted hand therapy compared with intensive occupational therapy in the early recovery phases after stroke with a 3-month follow-up. Twenty acute stroke patients at their first-ever stroke were enrolled and randomized into two groups. The experimental treatment was performed using the Amadeo Robotic System. Control treatment, instead, was carried out using occupational therapy executed by a trained physiotherapist. All participants received 20 sessions of treatment for 4 consecutive weeks (5 days/week). The following clinical scales, Fugl-Meyer Scale (FM), Medical Research Council Scale for Muscle Strength (hand flexor and extensor muscles) (MRC), Motricity Index (MI) and modified Ashworth Scale for wrist and hand muscles (MAS), were performed at baseline (T0), after 20 sessions (end of treatment) (T1) and at the 3-month follow-up (T2). The Barthel Index was assessed only at T0 and T1. Evidence of a significant improvement was shown by the Friedman test for the FM [experimental group (EG): P=0.0039, control group (CG): P<0.0001], Box and Block Test (EG: P=0.0185, CG: P=0.0086), MI (EG: P<0.0001, CG: P=0.0303) and MRC (EG: P<0.0001, CG: P=0.001) scales. These results provide further support to the generalized therapeutic impact of intensive robot-assisted treatment on hand recovery functions in individuals with acute stroke. The robotic rehabilitation treatment may contribute toward the recovery of hand motor function in acute stroke patients. The positive results obtained through the safe and reliable robotic rehabilitation treatment reinforce the recommendation to extend it to a larger clinical practice. PMID- 24769558 TI - Annexin A8 controls leukocyte recruitment to activated endothelial cells via cell surface delivery of CD63. AB - To enable leukocyte adhesion to activated endothelium, the leukocyte receptor P selectin is released from Weibel-Palade bodies (WPB) to the endothelial cell surface where it is stabilized by CD63. Here we report that loss of annexin A8 (anxA8) in human umbilical vein endothelial cells (HUVEC) strongly decreases cell surface presentation of CD63 and P-selectin, with a concomitant reduction in leukocyte rolling and adhesion. We confirm the compromised leukocyte adhesiveness in inflammatory-activated endothelial venules of anxA8-deficient mice. We find that WPB of anxA8-deficient HUVEC contain less CD63, and that this is caused by improper transport of CD63 from late multivesicular endosomes to WPB, with CD63 being retained in intraluminal vesicles. Consequently, reduced CD63 cell surface levels are seen following WPB exocytosis, resulting in enhanced P-selectin re internalization. Our data support a model in which anxA8 affects leukocyte recruitment to activated endothelial cells by supplying WPB with sufficient amounts of the P-selectin regulator CD63. PMID- 24769559 TI - Levels, composition profiles and risk assessment of polycyclic aromatic hydrocarbons (PAHs) in sludge from ten textile dyeing plants. AB - As components of synthetic dyes, polycyclic aromatic hydrocarbons (PAHs) are present as contaminants in textile dyeing sludge due to the recalcitrance in wastewater treatment process, which may pose a threat to environment in the process of sludge disposal. In order to evaluate PAHs in textile dyeing sludge, comprehensive investigation comprising 10 textile dyeing plants was undertaken. Levels, composition profiles and risk assessment of 16 EPA-priority PAHs were analyzed in this study. The total concentrations of 16 PAHs (?16 PAHs) varied from 1463 +/- 177 ng g(-1) to 16,714 +/- 1,507 ng g(-1) with a mean value of 6386 ng g(-1). The composition profiles of PAHs were characterized by 3- and 4-ring PAHs, among which phenanthrene, anthracene and fluoranthene were the most dominant components. The mean benzo[a]pyrene equivalent (BaPeq) concentration of ?16 PAHs in textile dyeing sludge was 423 ng g(-1), which was 2-3 times higher than concentrations reported for urban soil. According to ecological risk assessment, the levels of PAHs in the textile dyeing sludge may cause a significant risk to soil ecosystem after landfill or dumping on soil. PMID- 24769560 TI - Blood cadmium levels are associated with a decline in lung function in males. AB - BACKGROUND: Cadmium exposure was found to cause a decline in lung function among the general population, but these findings were limited to smokers and gender differences were not explored. OBJECTIVES: To examine the relationship between cadmium and chronic obstructive pulmonary disease (COPD) according to gender and smoking status in Korea. METHODS: Cross-sectional data from the Korean National Health and Nutrition Examination Survey from 2008 to 2011 were analyzed. COPD was defined by a pre-bronchodilator forced expiratory volume in 1s divided by forced vital capacity of <0.70. A logistic regression model was used to elucidate the association between blood cadmium levels and COPD according to gender and smoking status. RESULTS: Among 3861 eligible participants, 3622 were included in the analysis. The prevalence of COPD demonstrated an increasing trend in males (P for trend<0.001), but not in females (P for trend=0.67). After adjusting for covariates, a higher blood cadmium level, but within the normal range, was associated with COPD in males, including those who had never-smoked (P for trend <0.001 and P for trend=0.008). However, a higher blood cadmium level was not significantly associated with COPD in females, including those who had never smoked (P for trend=0.39 and P for trend=0.43). CONCLUSIONS: A higher blood cadmium level, within the normal range, was associated with COPD in males, including those who had never smoked. However, there was no significant association between blood cadmium levels and COPD in females. PMID- 24769561 TI - Dioxins, furans and dioxin-like PCBs in human blood: causes or consequences of diabetic nephropathy? AB - Nephropathy, or kidney disease, is a major, potential complication of diabetes. We assessed the association of 6 chlorinated dibenzo-p-dioxins, 9 chlorinated dibenzofurans and 8 polychlorinated biphenyls (PCBs) in blood with diabetic nephropathy in the 1999-2004 National Health and Nutrition Examination Survey (unweighted N=2588, population estimate=117,658,357). Diabetes was defined as diagnosed or undiagnosed (glycohemoglobin >= 6.5%) and nephropathy defined as urinary albumin to creatinine ratio >30 mg/g, representing microalbuminuria or macroalbuminuria. For the 8 chemicals analyzed separately, values above the 75th percentile were considered elevated, whereas for the other 15 compounds values above the maximum limit of detection were considered elevated. Seven of 8 dioxins and dioxin-like compounds, analyzed separately, were found to be associated with diabetic nephropathy. The chemicals associated with diabetic nephropathy were: 1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin; 1,2,3,4,6,7,8,9-Octachlorodibenzo-p dioxin; 2,3,4,7,8-Pentachlorodibenzofuran; PCB 126; PCB 169; PCB 118; and PCB 156. Three of the 8 dioxins and dioxin-like compounds; 1,2,3,4,6,7,8,9 Octachlorodibenzo-p-dioxin; 2,3,4,7,8-Pentachlorodibenzofuran and PCB 118; expressed as log-transformed continuous variables; were associated with diabetes without nephropathy. When 4 or more of the 23 chemicals were elevated the odds ratios were 7.00 (95% CI=1.80-27.20) for diabetic nephropathy and 2.13 (95% CI=0.95-4.78) for diabetes without nephropathy. Log-transformed toxic equivalency (TEQ) was associated with both diabetic nephropathy, and diabetes without nephropathy, the odds ratios were 2.35 (95% CI=1.57-3.52) for diabetic nephropathy, and 1.44 (95% CI=1.11-1.87) for diabetes without nephropathy. As the kidneys function to remove waste products from the blood, diabetic nephropathy could be either the cause or the consequence (or both) of exposure to dioxins, furans and dioxin-like PCBs. PMID- 24769562 TI - Associations between prenatal exposure to air pollution, small for gestational age, and term low birthweight in a state-wide birth cohort. AB - A range of health effects, including adverse pregnancy outcomes, have been associated with exposure to ambient concentrations of particulate matter (PM) and ozone (O3). The objective of this study was to determine whether maternal exposure to fine particulate matter (PM2.5) and O3 during pregnancy is associated with the risk of term low birthweight and small for gestational age infants in both single and co-pollutant models. Term low birthweight and small for gestational age were determined using all birth certificates from North Carolina from 2003 to 2005. Ambient air concentrations of PM2.5 and O3 were predicted using a hierarchical Bayesian model of air pollution that combined modeled air pollution estimates from the EPA's Community Multi-Scale Air Quality (CMAQ) model with air monitor data measured by the EPA's Air Quality System. Binomial regression, adjusted for multiple potential confounders, was performed. In adjusted single-pollutant models for the third trimester, O3 concentration was positively associated with small for gestational age and term low birthweight births [risk ratios for an interquartile range increase in O3: 1.16 (95% CI 1.11, 1.22) for small for gestational age and 2.03 (95% CI 1.80, 2.30) for term low birthweight]; however, inverse or null associations were observed for PM2.5 [risk ratios for an interquartile range increase in PM2.5: 0.97 (95% CI 0.95, 0.99) for small for gestational age and 1.01 (95% CI 0.97, 1.06) for term low birthweight]. Findings were similar in co-pollutant models and linear models of birthweight. These results suggest that O3 concentrations in both urban and rural areas may be associated with an increased risk of term low birthweight and small for gestational age births. PMID- 24769563 TI - Cytogenetic analysis of oral mucosa cells, induced by chlorhexidine, essential oils in ethanolic solution and triclosan mouthwashes. AB - OBJECTIVES: The aim of this study was to evaluate DNA damage and cytokinetic defects, proliferative potential and cell death caused by the frequent use of mouthrinses containing chlorhexidine, triclosan and essential oils in ethanolic solution, compared to a placebo mouthwash. STUDY DESIGN: This double-blind, prospective, randomized clinical trial included 80 Caucasian patients. Subjects were divided into four groups: Group I used a mouthrinse, Triclosan; Group II used physiological saline; Group III used chlorhexidine; Group IV a mouthrinse with essential oils in ethanolic solution. All subjects used the mouthrinses for two weeks (15 ml, twice a day, rinsing for 30s). Two cell samples per subject were collected, before and after mouthrinse use (on day 0 and day 15). Samples were processed as follows: cell collection from cheeks with a cytobrush; cell centrifuge; slide preparation, fixation and staining; and fluorescent microscope analysis. 2000 exfoliated cells were screened for nuclear abnormalities, particularly the presence of micronuclei by means of cytome assay. RESULTS: No significant differences between study times (before and after use of mouthwash) were identified for any of the variables studied (p>0.05). Differences between mouthrinse groups were also compared but no significant differences were found (p>0.05). CONCLUSIONS: This study did not observe any genotoxic effect resulting from mouthrinse use. PMID- 24769564 TI - Distribution patterns of microplastics within the plankton of a tropical estuary. AB - The Goiana Estuary was studied regarding the seasonal and spatial variations of microplastics (<5mm) and their quantification relative to the zooplankton. The total density (n 100 m(-3)) of microplastics represented half of the total fish larvae density and was comparable to fish eggs density. Soft, hard plastics, threads and paint chips were found in the samples (n=216). Their origins are probably the river basin, the sea and fisheries (including the lobster fleet). In some occasions, the amount of microplastics surpassed that of Ichthyoplankton. The highest amount of microplastics was observed during the late rainy season, when the environment is under influence of the highest river flow, which induces the runoff of plastic fragments to the lower estuary. The density of microplastics in the water column will determine their bioavailability to planktivorous organisms, and then to larger predators, possibly promoting the transfer of microplastic between trophic levels. These findings are important for better informing researchers in future works and as basic information for managerial actions. PMID- 24769565 TI - Transittability of complex networks and its applications to regulatory biomolecular networks. AB - We have often observed unexpected state transitions of complex systems. We are thus interested in how to steer a complex system from an unexpected state to a desired state. Here we introduce the concept of transittability of complex networks, and derive a new sufficient and necessary condition for state transittability which can be efficiently verified. We define the steering kernel as a minimal set of steering nodes to which control signals must directly be applied for transition between two specific states of a network, and propose a graph-theoretic algorithm to identify the steering kernel of a network for transition between two specific states. We applied our algorithm to 27 real complex networks, finding that sizes of steering kernels required for transittability are much less than those for complete controllability. Furthermore, applications to regulatory biomolecular networks not only validated our method but also identified the steering kernel for their phenotype transitions. PMID- 24769566 TI - Cleavage of SNAP25 and its shorter versions by the protease domain of serotype A botulinum neurotoxin. AB - Various substrates, catalysts, and assay methods are currently used to screen inhibitors for their effect on the proteolytic activity of botulinum neurotoxin. As a result, significant variation exists in the reported results. Recently, we found that one source of variation was the use of various catalysts, and have therefore evaluated its three forms. In this paper, we characterize three substrates under near uniform reaction conditions using the most active catalytic form of the toxin. Bovine serum albumin at varying optimum concentrations stimulated enzymatic activity with all three substrates. Sodium chloride had a stimulating effect on the full length synaptosomal-associated protein of 25 kDa (SNAP25) and its 66-mer substrates but had an inhibitory effect on the 17-mer substrate. We found that under optimum conditions, full length SNAP25 was a better substrate than its shorter 66-mer or 17-mer forms both in terms of kcat, Km, and catalytic efficiency kcat/Km. Assay times greater than 15 min introduced large variations and significantly reduced the catalytic efficiency. In addition to characterizing the three substrates, our results identify potential sources of variations in previous published results, and underscore the importance of using well-defined reaction components and assay conditions. PMID- 24769567 TI - Redox active motifs in selenoproteins. AB - Selenoproteins use the rare amino acid selenocysteine (Sec) to act as the first line of defense against oxidants, which are linked to aging, cancer, and neurodegenerative diseases. Many selenoproteins are oxidoreductases in which the reactive Sec is connected to a neighboring Cys and able to form a ring. These Sec containing redox motifs govern much of the reactivity of selenoproteins. To study their fundamental properties, we have used (77)Se NMR spectroscopy in concert with theoretical calculations to determine the conformational preferences and mobility of representative motifs. This use of (77)Se as a probe enables the direct recording of the properties of Sec as its environment is systematically changed. We find that all motifs have several ring conformations in their oxidized state. These ring structures are most likely stabilized by weak, nonbonding interactions between the selenium and the amide carbon. To examine how the presence of selenium and ring geometric strain governs the motifs' reactivity, we measured the redox potentials of Sec-containing motifs and their corresponding Cys-only variants. The comparisons reveal that for C-terminal motifs the redox potentials increased between 20-25 mV when the selenenylsulfide bond was changed to a disulfide bond. Changes of similar magnitude arose when we varied ring size or the motifs' flanking residues. This suggests that the presence of Sec is not tied to unusually low redox potentials. The unique roles of selenoproteins in human health and their chemical reactivities may therefore not necessarily be explained by lower redox potentials, as has often been claimed. PMID- 24769569 TI - Current-driven domain wall depinning from an anisotropy boundary in nanowires. AB - The interaction of a current-driven domain wall with an anisotropy boundary in nanowires with perpendicular magnetic anisotropy is investigated. A local reduction of the anisotropy constant is used to create an artificial boundary where the domain wall gets pinned. Micromagnetic simulations and analytical calculations, based on a one-dimensional model, are employed to describe the interaction of the domain wall and the anisotropy boundary and to determine the depinning current densities. Two different pinning regimes-an intrinsic and an extrinsic-can be identified in dependence with the characteristic of the boundary. A very good agreement between simulated and analytically obtained data is achieved. PMID- 24769568 TI - Association between vitamin D receptor gene polymorphisms and breast cancer risk: a meta-analysis of 39 studies. AB - BACKGROUND: The associations between vitamin D receptor (VDR) gene polymorphisms and breast cancer risk were comprehensively investigated to clarify issues that remain controversial. METHODOLOGY/PRINCIPAL FINDINGS: An electronic search was conducted of several databases, including PubMed, the Cochrane library, Web of Science, EMBASE, CBM and CNKI, for papers that describe the association between Fok1, poly-A repeat, Bsm1, Taq1 or Apa1 polymorphisms of the VDR gene and breast cancer risk. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effect model (FEM) or random-effect model (REM), depending on the absence or presence of significant heterogeneity. A total of 39 studies met the inclusion criteria. A meta-analysis of high-quality studies showed that the Fok1 polymorphism of the VDR gene was associated with an increased risk of breast cancer (ff vs. Ff+FF, OR: 1.09, 95%CI: 1.02 to 1.16, p = 0.007). No significant associations were observed between the other polymorphisms and breast cancer risk. No positive results were detected by pooling the results of all relevant studies. CONCLUSION: A meta-analysis of high-quality studies demonstrated that the Fok1 polymorphism of the VDR gene was closely associated with breast cancer risk. PMID- 24769570 TI - The role of anthracyclines in the treatment of early breast cancer. AB - We review the use of anthracyclines, their associated cardiotoxicity, and the role of taxanes in the treatment of early breast cancer. The efficacy of anthracyclines has been proven in multiple large cohort trials and meta-analyses. The addition of a taxane to an anthracycline-based regimen in the adjuvant setting has improved the disease-free survival and overall survival in patients with early breast cancer. The use of the monoclonal antibody trastuzumab combined with an anthracycline and taxane regimen has had significant benefit both in disease-free survival and overall survival in patients with human epidermal growth factor receptor 2(HER2)-positive disease. However, the development of significant cardiotoxicity related to anthracyclines and the emergence of newer agents that appear to limit the cardiotoxicity but with similar anticancer efficacy have called the role of anthracyclines into doubt. Taxane/trastuzumab based chemotherapy without anthracyclines is now a widely accepted adjuvant regimen in patients with HER2-positive early breast cancer. Indeed, the use of taxanes in early breast cancer has overtaken the use of anthracyclines, particularly in women with HER2-positive breast cancer. Concerns regarding anthracycline cardiotoxicity and positive data from taxane-based regimens likely have contributed to this change in practice. Ongoing trials will determine whether taxane-based chemotherapy has equivalent efficacy to anthracycline-based regimens in adjuvant therapy of HER2-negative early breast cancer. Moving forward, the use of anthracyclines as initial chemotherapy in early breast cancer may continue to be replaced by taxane-based and novel regimens in the future. PMID- 24769571 TI - [A novel coronavirus, MERS-CoV]. AB - A novel human coronavirus was identified in Saudi Arabia and Qatar as the causative agent of severe acute respiratory diseases in 2012. The virus was termed Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and is taken notice of important coronavirus caused severe diseases to human after the outbreak of severe acute respiratory syndrome (SARS) coronavirus. There is a lot of unknown characterization regarding MERS-CoV because of less than one year after finding the first case. MERS-CoV was related to the 2C betacoronavirus clade and is closely related to Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5. Thus, bats are thought to be natural hosts of this virus. Recently, there were reports supposed to be cases of human to human infection. There are growing concerns about spread of infection. PMID- 24769572 TI - [Severe fever with thrombocytopenia syndrome in Japan]. AB - Severe fever with thrombocytopenia syndrome (SFTS) is characterized by sudden onset of fever, leukopenia, thrombocytopenia, and gastrointestinal tract symptoms and approximately 12% of patients die from disseminated intravascular coagulation and/or multiple organ failures. Agent of the disease is a novel bunyavirus SFTS virus, and is transmitted by bite of a possible vector tick, Haemaphysalis longicornis, and through direct contact with virus-containing patient body fluids, or through unknown routes. SFTS case reports have been limited in China, and more than two thousand cases were reported in 2011 and 2012. In late 2012, a woman living in Yamaguchi prefecture in Japan showed symptoms reminiscent of those of SFTS and died 6 days after the onset of symptoms. Virus was isolated from her acute serum in Vero cells and a next generation-sequencing identified it as SFTS virus. SFTS viral genome and proteins were detected in the patient's serum. Based on the first demonstration of SFTS in Japan, a retrospective study started. Until March of 2013, totally 8 patients were diagnosed as having SFTS and the most early case was in 2005. Phylogenetic analysis of virus sequences revealed that Japanese isolates form an independent branch distinct from Chinese isolates, indicating that SFTS has been present not only in China but also in Japan. PMID- 24769573 TI - [Reverse genetics system for flaviviruses]. AB - Flaviviruses such as Japanese encephalitis virus, West Nile virus, yellow fever virus, dengue virus, and tick-borne encephalitis virus belong to a family Flaviviridae. These viruses are transmitted to vertebrates by infected mosquitoes or ticks, producing diseases, which have a serious impact on global public health. Reverse genetics is a powerful tool for studying the viruses. Although infectious full-length clones have been obtained for multiple flaviviruses, their early-stage development had the difficulty because of the instability problem of the viral cDNA in E. coli. Several strategies have been developed to circumvent the problem of infectious clone instability. The current knowledge accumulated on reverse genetics system of flaviviruses and its application are summarized in this review. PMID- 24769574 TI - [Reverse genetics of Hepatitis B virus]. AB - A global expansion of Hepatitis B virus (HBV) infection continues still now, and it poses a still big problem. Since the Australia antigen was discovered, HBV research has been continued by various methods, such as clinical medicine and epidemiology. However, the simple and efficient infection experimental systems (in vitro and in vivo) have not been established, because the host range of HBV is narrow. Therefore, the techniques of reverse genetics have contributed to HBV research greatly. We have established the HBV clones of various genotypes from the chronic hepatitis B patients, and have analyzed using the techniques of reverse genetics. Based on our results, it has become clear gradually how HBV pathogenesis related to the genotypes. In this paper, we would like to introduce the outline of research analyzed by reverse genetics about HBV. PMID- 24769575 TI - [The 60th Annual Japanese Society for Virology Meeting. Global researches on virus infections: Summary]. PMID- 24769576 TI - [Joint collaboration in infectious diseases in China, the University of Tokyo]. AB - Recent rapid developments in Asian and African countries bring an opportunity of cross-species transmission of pathogens through unprecedented contacts between people and wild animals. Furthermore, increase of global exchanges of people and products facilitates a rapid spread of infectious diseases worldwide. China has an enormous population with diverse ethnic groups within its wide territory; furthermore, it is experiencing very rapid urbanization. These conditions make China a potential epicenter of emerging infectious diseases. One good example is the SARS incidence in 2003. Therefore, it is essential to include China in a network of research groups of infectious diseases. Here we summarize the ongoing collaborations between the Institute of Medical Science, the University of Tokyo, and its Chinese counterparts. PMID- 24769577 TI - [Researches on virology at the Tohoku University Research Center in the Philippines]. AB - Tohoku University Graduate School of Medicine has established the Tohoku-RITM Collaborative Research Center on Emerging and Re-emerging Diseases at Research Institute for Tropical Medicine (RITM) in the Philippines in 2008. Our aim of the center is to conduct operational researches, which can contribute to control of infectious diseases in the Philippines. Therefore most of our researches in the Philippines are being conducted in the fields. Main research themes include severe acute respiratory infections in children, influenza disease burden study, molecular epidemiology of rabies, and viral etiology of acute diarrhea. The study on severe acute respiratory infections in children in Leyte Island has recruited hospitalized cases with severe pneumonia. We showed that enterovirus 68 was one of important causative agents in severe pneumonia cases. We also conducted other analyses including molecular epidemiology of respiratory syncytial virus (RSV) and pathogenesis of human rhinoviruses (HRV). Based on these studies, we initiated more comprehensive researches in the Philippines since 2010. PMID- 24769578 TI - [J-GRID and SATREPS programs in Thailand]. AB - Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections (RCC-ERI) was established in 2005 as a research collaboration center cooperated by Research Institute for Microbial Diseases (RIMD), Osaka University and Department of Medical Sciences, Ministry of Public Health of Thailand. In addition, Mahidol-Osaka Center for Infectious Diseases (MOCID) was established in 2010, also as another research collaboration center cooperated by RIMD, Osaka University and Faculty of Tropical Medicine, Mahidol University. Epidemiological and basic studies on human pathogenic viruses have been conducted in RCC-ERI and MOCID. In this report, brief overviews of the research activities of both centers, as well as the phenotypic studies on the envelope glycoproteins of HIV-1 Thai strains that have been performed at RCC-ERI, are presented. SATREPS is a Japanese government program by the Japan Science and Technology Agency (JST) and the Japan International Cooperation Agency (JICA) that promotes international joint research targeting global issues. Our research group at RIMD have collaborated with the Ministry of Public Health - National Institute of Health (NIH) and Mahidol University in Thailand from 2008 as a four-years project. Our aim on this collaboration is to generate human monoclonal antibodies neutralizing infectious viral agents, hopefully to apply them to clinical field as "therapeutic antibodies". Here we introduce our trials in this project, especially on the generation of human monoclonal antibodies against dengue virus as well as against influenza virus that have been performed as collaboration between Thai and Japanese research groups. PMID- 24769579 TI - [Research activities in Kobe-Indonesia Collaborative Research Centers]. AB - Kobe-Indonesia Collaborative Research Center was established in Institute of Tropical Disease (ITD), Airlangga University, Surabaya, Indonesia in 2007 under the program of ''Founding Research Centers for Emerging and Reemerging Infectious Diseases'' supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan, and then it has been under the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) since 2010. Japanese researchers have been stationed at ITD, conducting joint researches on influenza, viral hepatitis, dengue and infectious diarrhea. Also, another Japanese researcher has been stationed at Faculty of Medicine, University of Indonesia, Jakarta, carrying out joint researches on'' Identification of anti-hepatitis C virus (HCV) substances and development of HCV and dengue vaccines'' in collaboration with University of Indonesia and Airlangga University through the Science and Technology Research Partnership for Sustainable Development (SATREPS) supported by the Japan Science and Technology Agency (JST) and Japan International Cooperation Agency (JICA) since 2009. In this article, we briefly introduce the background history of Kobe University Research Center in Indonesia, and discuss the research themes and outcomes of J-GRID and SATREPS activities. PMID- 24769580 TI - [Summary of research works on viruses in the Vietnam Research Station, Institute of Tropical Medicine, Nagasaki University]. AB - Institute of Tropical Medicine, Nagasaki University (NEKKEN) and National Institute of Hygiene and Epidemiology, Vietnam (NIHE) jointly conducted a project from 2006 on Emerging and Re-emerging Infectious Diseases (ERID) granted by the Ministry of Education, Science, Culture and Technology (MEXT) of Japan. Fifteen independent researches have been carried out by 7 scientists who stationed in the Vietnam Research Station (VRS), and by approximately 60 visiting scientists. A wide variety of viruses have been studied in the research activities in the VRS, of those, topics of'' Nipah virus infection in bats in Vietnam'', ''Nam Dinh virus, a newly discovered insect nidovirus'', and'' Risk factors of dengue fever in southern Vietnam'' were summarized. It is important to develop a mechanism to facilitate young scientists to use the VRS in their research works, and then a scope to establish the VRS as a gateway to a successful career path for young scientists in the field of the infectious diseases would be realized. PMID- 24769581 TI - [Kenya Research Station and viral infectious disease research]. AB - The Institute of Tropical Medicine, Kenya Research Station, Nagasaki University was established by a fund of the Ministry of Education (MEXT) in 2005. Currently, the station has been on ''The Clinical and Epidemiological Research Program of Tropical Medicine and Emerging Infectious Diseases-Establishment of Education and Research System between Africa and Japan- ''. The project has been supported by about 20 Japanese staff and 85 Kenyan staff, and in the research station, 10 research teams have worked on their researches for the prevention of tropical medicine and emerging diseases collaborating with other researches and The JICA Grassroots Technical Cooperation Project has also started in 2012. In April 2010, Nagasaki University, Africa Station has been established along with Kenya Research Station, and it made possible for other faculties to join research in Kenya. School of Dentistry has started oral health survey in Mbita, while School of Fishery, School of Engineering and School of Health Science have a plan of a joint project targeting areas by Lake Victoria. Our aim is to develop a foundation which enables all researchers from different fields to carry out their research for improvement health and living standards of the locals. PMID- 24769582 TI - [Two research projects on infectious diseases conducted in Noguchi Memorial Institute for Medical Research, University of Ghana by Tokyo Medical and Dental University]. AB - Ghana-Tokyo Medical and Dental University Research Collaboration Center has been established since 2008 when our Program was chosen together with the Program in the Philippines proposed by Tohoku University as an additional small-scale research center of the Overseas Research Program on Emerging and Reemerging Diseases that is funded by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government and started in 2005. This 5-year government-supported Program has changed its name to develop into a more active world-level program called Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) and entered the second 5-year phase in 2010, and our Program is playing an important role among other research centers located in Asia and Africa. Currently, two research projects are carried out in parallel in Noguchi Memorial Institute for Medical Research by Tokyo Medical and Dental University: one is a J-GRID project and the other is the one of Science and Technology Research Partnership for Sustainable Development (SATREPS) which is a joint project between Japan International Cooperation Agency (JICA) and Japan Science and Technology Agency (JST). This special article is describing what these two projects are all about. PMID- 24769583 TI - [Award for excellent poster presentation in the 60th Annual JSV Meeting]. PMID- 24769584 TI - [Current discussion on dual use issues in microbiological research]. PMID- 24769585 TI - [Exploration for anti-enterovirus compounds and analysis on the mechanism of its inhibitory effect on virus infection]. AB - Poliovirus (PV) is a small non-enveloped virus belonging to the family Picornaviridae, and is the causative agent of poliomyelitis. With established vaccines, the global eradication program for poliomyelitis is ongoing by the World Health Organization since 1988. In the eradication program, antivirals are anticipated to have some roles in the endgame and post-eradication era of PV. During our search for potent anti-PV compounds, we identified candidate compounds that are associated with a common resistance mutation in viral protein 3A similar to enviroxime (designated as enviroxime-like compounds). Recently, PIK93, an inhibitor of host phosphatidylinositol 4-kinase III beta (PI4KB), was identified as a potent anti-enterovirus compound (Hsu et al., Cell 141:799-811). We found that PIK93 is an enviroxime-like compound, and showed that T-00127-HEV1, which is a novel enviroxime-like compound identified in high-throughput screening, is a specific PI4KB inhibitor. We also showed that PI4KB is an enterovirus-specific host factor required for its viral RNA replication. Analysis of anti-enterovirus compounds would unravel novel host factors that could serve as promising antiviral targets of prophylaxis and therapy of the infection. PMID- 24769586 TI - [Reverse genetics system of rotaviruses: development and application for analysis of VP4 spike protein]. AB - The rotavirus genome is composed of 11 gene segments of double-stranded (ds)RNA. Reverse genetics is the powerful and ideal methodology for the molecular analysis of virus biology, which enables the virus genome to be artificially manipulated. Although reverse genetics systems exist for nearly all major groups of RNA viruses, development of such a system for rotaviruses is more challenging owing in part to the technical complexity of manipulation of their multi-segmented genome. A breakthrough in the field of rotavirus reverse genetics came in 2006, when we established the first reverse genetics system for rotaviruses, which is a partially plasmid-based system that permits replacement of a viral gene segment with the aid of a helper virus. Although this helper virus-driven system is technically limited and gives low levels of recombinant viruses, it allows alteration of the rotavirus genome, thus contributing to our understanding of these medically important viruses. In this review, I describe the development and application of our rotavirus reverse genetics system, and its future perspectives. PMID- 24769587 TI - Lanthanide-doped NaGdF4 core-shell nanoparticles for non-contact self-referencing temperature sensors. AB - We report that non-contact self-referencing temperature sensors can be realized with the use of core-shell nanostructures. These lanthanide-based nanothermometers (NaGdF4:Yb(3+)/Tm(3+)@Tb(3+)/Eu(3+)) exhibit higher sensitivity in a wide range from 125 to 300 K based on two emissions of Tb(3+) at 545 nm and Eu(3+) at 615 nm under near-infrared laser excitation. PMID- 24769588 TI - The personification of cancer. AB - Facilitating a session recently at the C4YW conference in Orlando, FL, moved me in ways that I am still processing. This conference is for women who were diagnosed with breast cancer prior to the age of 45, and these survivors are encouraged to return to the conference for education, support, and fellowship for as long as they want. They can bring family members or friends with them and the meeting rooms and hallways are filled with laughter and tears. PMID- 24769589 TI - Symptom prevalence and physiologic biomarkers among adolescents using a mobile phone intervention following hematopoietic stem cell transplantation. AB - PURPOSE/OBJECTIVES: To examine symptom reports and physiologic parameters in adolescents using the Eating After Transplant (EAT!) intervention during recovery after hematopoietic stem cell transplantation (HSCT). DESIGN: Repeated measures design. SETTING: HSCT service at a pediatric teaching institution in the southern United States. SAMPLE: 16 adolescents recovering from a first-time allogeneic HSCT. METHODS: Use of EAT! was monitored electronically, symptom reports were obtained from a questionnaire, and physiologic parameters were obtained from the medical record at HSCT hospital discharge and 20, 40, and 60 days postdischarge. MAIN RESEARCH VARIABLES: EAT! use, symptom prevalence, symptom-related distress, and physiologic parameters including weight, body mass index (BMI), pre-albumin, and albumin. FINDINGS: Symptom prevalence was highest at hospital discharge and steadily declined; however, mean symptom distress scores remained stable. Mean weight and BMI significantly declined during the first 60 days postdischarge; pre albumin and albumin markers were unchanged. No correlation was noted among use of EAT! and any research variables. CONCLUSIONS: The most frequent symptoms were not always the most distressing symptoms. Weight and BMI significantly declined during HSCT recovery. IMPLICATIONS FOR NURSING: Nurses should assess symptom frequency and distress to fully understand patients' symptom experiences. Nurses should monitor weight and BMI throughout HSCT recovery. PMID- 24769590 TI - The impact of yoga on quality of life and psychological distress in caregivers for patients with cancer. AB - PURPOSE/OBJECTIVES: To assess the effects of a six-week Vinyasa yoga (VY) intervention on caregivers' overall quality of life (QOL) and psychological distress. DESIGN: A single-group, pre- and post-test pilot study. SETTING: University public recreational facility. SAMPLE: 12 informal caregivers for patients with cancer. METHODS: Caregivers participated in a six-week VY intervention and completed measures of QOL and psychological distress pre- and postintervention. Program satisfaction was measured with open-ended survey questions. MAIN RESEARCH VARIABLES: QOL, psychological distress, and program satisfaction. FINDINGS: Significant improvements were found in the mental component score of overall QOL and in overall psychological distress. Several subdomains of QOL and psychological distress were also improved significantly. Open-ended survey question responses revealed participants perceived physical and mental benefit from the intervention, highlighting improvements in flexibility, core and upper-body strength, balance, breathing, and energy. CONCLUSIONS: Informal caregivers may benefit mentally and physically from participating in VY. IMPLICATIONS FOR NURSING: Caregivers of patients with cancer characterize a group worthy of attention, research, and interventions focusing on their healthcare needs. PMID- 24769591 TI - Implementing survivorship care plans for colon cancer survivors. AB - PURPOSE/OBJECTIVES: To evaluate the feasibility, usability, and satisfaction of a survivorship care plan (SCP) and identify the optimum time for its delivery during the first 12 months after diagnosis. DESIGN: Prospective, descriptive, single-arm study. SETTING: A National Cancer Institute-designated cancer center in the southeastern United States. SAMPLE: 28 nonmetastatic colon cancer survivors within the first year of diagnosis and their primary care physicians (PCPs). METHODS: Regular screening identified potential participants who were followed until treatment ended. An oncology certified nurse developed the JourneyForwardTM SCP, which then was delivered to the patient by the oncology nurse practitioner (NP) during a routine follow-up visit and mailed to the PCP. MAIN RESEARCH VARIABLES: Time to complete, time to deliver, usability, and satisfaction with the SCP. FINDINGS: During one year, 75 patients were screened for eligibility, 34 SCPs were delivered, and 28 survivors and 15 PCPs participated in the study. It took an average of 49 minutes to complete a surgery SCP and 90 minutes to complete a surgery plus chemotherapy SCP. Most survivors identified that before treatment ended or within the first three months was the preferred time to receive an SCP. CONCLUSIONS: The SCPs were well received by the survivors and their PCPs, but were too time and labor intensive to track and complete. IMPLICATIONS FOR NURSING: More work needs to be done to streamline processes that identify eligible patients and to develop and implement SCPs. Measuring outcomes will be needed to demonstrate whether SCPs are useful or not. PMID- 24769593 TI - Physiologic and psychological symptoms experienced by adults with acute leukemia: an integrative literature review. AB - PURPOSE/OBJECTIVES: To evaluate the current knowledge of symptoms experienced by adults with acute leukemia (AL) and provide evidence to inform practice and research. DATA SOURCES: Literature review using an electronic search supplemented by a hand search of current literature reporting the physiologic and/or psychological symptoms of patients with AL was conducted. DATA SYNTHESIS: Because of the variability found in the methods and specific aims of the articles, a rating system was applied to score how strongly the findings contributed to meeting the aims of the research. This rating system was applied to assist the authors in analyzing the findings. Therefore, the articles that scored lower ultimately contributed less during the analysis phase. CONCLUSIONS: Knowledge regarding the symptoms experienced by adults undergoing treatment is being slowly evaluated. However, to better understand and subsequently manage these symptoms, longitudinal research examining the symptom trajectories in this population is needed. IMPLICATIONS FOR NURSING: Additional investigation into symptom characteristics will facilitate the development of tailored interventions to manage the temporal characteristics of symptoms for this population. PMID- 24769592 TI - Influence of patient and treatment factors on adherence to adjuvant endocrine therapy in breast cancer. AB - PURPOSE/OBJECTIVES: To comprehensively assess the patient and illness or treatment factors that may predict nonadherence to adjuvant endocrine therapy and to explore whether an interaction occurs between these factors in women with breast cancer. DESIGN: Repeated-measures design. SETTING: The Outpatient Services of the Women's Cancer Program at the University of Pittsburgh Cancer Institute and participants' homes. SAMPLE: 91 women with early-stage breast cancer who received endocrine therapy. METHODS: Adherence was assessed continuously for the first 18 months of endocrine therapy. Patient and illness or treatment factors were assessed at four time points (Time 1 to Time 4). Time 1 (baseline) was within two weeks prior to the initiation of endocrine therapy. Times 2-4 occurred at six-month intervals, as many as 18 months after Time 1. MAIN RESEARCH VARIABLES: Adherence, patient factors, and illness or treatment factors. FINDINGS: Adherence to endocrine therapy declined significantly during the first 18 months of treatment in women with breast cancer. The presence of negative mood and symptoms before starting treatment predicted nonadherence to endocrine therapy over time. Perceptions of financial hardship, symptoms, disease stage, and more complex medication regimens intensified the effect of negative mood on adherence over time. CONCLUSIONS: Women with breast cancer may be at risk for nonadherence to prescribed endocrine therapy if they experience depression or anxiety and symptoms prior to initiating therapy. IMPLICATIONS FOR NURSING: Oncology nurses should be alert to women with breast cancer who are depressed or anxious or who are experiencing symptoms. Management of negative mood and symptoms may result in better adherence. PMID- 24769594 TI - Supportive care needs after gynecologic cancer: where does sexual health fit in? AB - DESIGN: Descriptive, cross-sectional study. SETTING: Follow-up clinic of a gynecologic oncology program in a regional cancer center. SAMPLE: 113 women treated for gynecologic cancer. METHODS: Data were collected using standardized instruments and analyzed through descriptive and correlation statistics. MAIN RESEARCH VARIABLES: Supportive care needs, sexual health needs, vaginal changes, desire for help, and socio-demographic and medical factors. FINDINGS: Forty percent of the sample was worried about the status of their sex life and many wished to meet one-on-one with a health professional or to receive written information. Younger age, premenopausal status at diagnosis, and lower sexual satisfaction and more vaginal changes after treatment were associated with greater sexual health needs and desire for help. CONCLUSIONS: Several sexual health needs were among the highest reported supportive care needs. Certain subgroups may report higher needs and desire for help; this domain merits additional research. Needs were extremely diverse, reflecting the use of an individual approach to screening for and meeting survivor needs. IMPLICATIONS FOR NURSING: Personal perceptions of the implications and meaning of sexual health and vaginal changes create the subjective experience of a need. Discussions of the women's perceptions of their needs and their views of healthy sexuality will help develop effective treatment plans. PMID- 24769595 TI - Communication behaviors and patient and caregiver emotional concerns: a description of home hospice communication. AB - PURPOSE/OBJECTIVES: To identify and describe communication behaviors used by hospice nurses when eliciting and addressing concerns of patients with cancer and their caregivers. DESIGN: Secondary analysis. SETTING: Home hospice in Salt Lake City, UT. SAMPLE: Audio recordings from seven patient and caregiver dyads and five hospice nurses. METHODS: Audio recordings were coded using the Roter Interaction Analysis System for patient and caregiver concern statements indicating negative affect and distress and the surrounding nurse communication behaviors. Concern content was categorized using domains developed by the National Consensus Project for Quality Palliative Care. MAIN RESEARCH VARIABLES: Patient and caregiver concern statements and nurse communication behaviors. FINDINGS: 180 patient and caregiver speaking turns containing concerns were identified across 31 hospice visits. Patients and caregivers expressed at least one concern in the vast majority of visits. The most prevalent distress areas reflected psychological and physical issues. Nurses used proportionally more positive emotion statements before patient and caregiver concerns, compared to the visit overall. Nurses asked proportionally more physical questions after concern statements. Nurses also used more emotional responses before and after patient and caregiver concerns, relative to the entire visit. CONCLUSIONS: Patients with cancer and caregivers frequently talk about distressing issues. Hospice nurses use specific communication behaviors to elicit and address those issues. IMPLICATIONS FOR NURSING: Home hospice provides a venue to examine nurse communication behaviors used to elicit and respond to patient and caregiver distress. These strategies could be taught to nurses who encounter patient distress less frequently or are less comfortable with emotional conversations. PMID- 24769596 TI - Computer-assisted qualitative data analysis software. AB - Advances in technology have provided new approaches for data collection methods and analysis for researchers. Data collection is no longer limited to paper-and pencil format, and numerous methods are now available through Internet and electronic resources. With these techniques, researchers are not burdened with entering data manually and data analysis is facilitated by software programs. Quantitative research is supported by the use of computer software and provides ease in the management of large data sets and rapid analysis of numeric statistical methods. New technologies are emerging to support qualitative research with the availability of computer-assisted qualitative data analysis software (CAQDAS).CAQDAS will be presented with a discussion of advantages, limitations, controversial issues, and recommendations for this type of software use. PMID- 24769597 TI - Financial savvy: the value of business acumen in oncology nursing. AB - Have you given serious thought to your individual ability to affect the high cost of health care? If so, you may have determined that the opportunity to have any meaningful effect on cost of services for patients with cancer is limited. You may believe that budgets are the responsibility of nursing leadership. Indeed, the development of the unit or department budget is an activity that many of us have no direct (or even indirect) role in completing. Once the budget is finalized, we are frequently given directives to control our costs and improve the financial bottom line for our employers. One could argue that this is a particularly difficult missive for oncology nurses with the soaring costs of chemotherapy and biotherapy drugs, the expenses incurred to provide supportive care needed by patients with cancer, and the need to provide services to the increasing number of cancer survivors. PMID- 24769598 TI - Herpes simplex virus-related oral mucositis in patients with lymphoma. AB - A 58-year-old man named J.S. was diagnosed with non-Hodgkin lymphoma and underwent treatment with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. He presented to his local outpatient clinic for evaluation and laboratory tests on day 10 after cycle 3. During this visit, J.S. reported great difficulty opening his mouth with significant gingival and lingual pain when eating and drinking in spite of prophylactic oral care. Laboratory test results revealed a white blood cell count of 0.9 k/ul, hemoglobin level of 8.9 g/dl, platelets of 100 k/ul, serum creatinine level of 1 mg/dl, and blood urea nitrogen level of 29 mg/dl. PMID- 24769599 TI - Microsatellite testing in colon cancer. AB - Significant progress has been made in understanding the molecular genetic basis of colorectal cancer (CRC). That information is paving the way to understanding the genetic basis of other tumors, as well. Oncology nurses should anticipate the routine integration of this information and testing of CRC tumors to understand the molecular basis of the disease in clinical practice. Molecular testing can lead to the identification of families at risk for hereditary cancer syndromes, particularly Lynch syndrome, which sometimes is referred to as hereditary nonpolyposis colorectal cancer. Knowledge of the genetic basis of CRC also contributes valuable information aimed at selecting appropriate and effective targeted therapy. PMID- 24769600 TI - Patients with primary brain tumors. AB - The purpose of this prospective phase II/III trial was to study the effect of therapy intensification when combining procarbazine, lomustine, and vincristine (PCV) chemotherapy with a standard course of radiation therapy (RT) on cognitive functioning for patients with World Health Organization grade 2 low-grade gliomas (LGGs). Initial results of the trial demonstrated a progression-free survival benefit with adjuvant PCV, but no overall survival benefit in the intention-to treat analysis. Because patients with LGGs have favorable prognostic indicators, the five-year overall survival rates range from 60%-70%. The effect of cancer treatment on neurocognitive function is a topic of increasing interest to healthcare providers and patients. The negative effect is commonly called "chemobrain" and refers to diminished concentration and compromised short-term memory following treatment. Chemobrain has been studied in other populations of patients with cancer (e.g., breast cancer) with associated statistically significant chemotherapy-associated compromised cognitive function when chemotherapy was added to RT. PMID- 24769602 TI - A meta-analysis of the relationship among impaired taste and treatment, treatment type, and tumor site in head and neck cancer treatment survivors. AB - PROBLEM IDENTIFICATION: To understand how taste impairment caused by head and neck cancer treatment changes over time or varies with treatment site or type. LITERATURE SEARCH: Ovid MEDLINE(r) database was searched for reports of health related quality of life (HRQOL) in head and neck cancer treatment survivors (HNCTS), which included taste function in a HRQOL instrument from 1946-2013. Eligible studies compared taste scores from baseline to post-treatment, using two treatment types or two cancer sites. DATA EVALUATION: 247 reports were identified; 19 were suitable for meta-analysis. DATA ANALYSIS: A series of dichotomous meta-analyses were conducted using comprehensive meta-analysis software .PRESENTATION OF FINDINGS: Taste scores were statistically significantly worse after treatment; the summary effect for the standard measure difference between pretreatment and post-treatment taste scores was 0.353 (p < 0.001). Patients treated with radiation therapy (RT) reported statistically significant worse taste function post-treatment than those who received no RT; the summary effect for the standard mean differences in taste scores was 0.77 (p = 0.001). Differences in tumor site were not significant. IMPLICATIONS FOR NURSING: Taste dysfunction is a long-term complication for HNCTS, and nurses should screen survivors for this sensory dysfunction. PMID- 24769601 TI - The effect of a couples intervention to increase breast cancer screening among korean americans. AB - PURPOSE/OBJECTIVES: To assess the efficacy of Korean Immigrants and Mammography Culture-Specific Health Intervention (KIM-CHI), an educational program for Korean American (KA) couples designed to improve mammography uptake among KA women. DESIGN: A two-group cluster randomized, longitudinal, controlled design. SETTING: 50 KA religious organizations in the Chicago area. SAMPLE: 428 married KA women 40 years of age or older who had not had a mammogram in the past year. The women and their husbands were recruited from 50 KA religious organizations. METHODS: Couples were randomly assigned to intervention or attention control groups. Those in the KIM-CHI program (n = 211 couples) were compared to an attention control group (n = 217 couples) at baseline, as well as at 6 and 15 months postintervention on mammogram uptake. MAIN RESEARCH VARIABLES: Sociodemographic variables and mammography uptake were measured. Level of acculturation was measured using the Suinn-Lew Asian Self-Identity Acculturation Scale. Researchers asked questions about healthcare resources and use, health insurance status, usual source of care, physical examinations in the past two years, family history of breast cancer, and history of mammography. FINDINGS: The KIM-CHI group showed statistically significant increases in mammography uptake compared to the attention control group at 6 months and 15 months postintervention. CONCLUSIONS: The culturally targeted KIM-CHI program was effective in increasing mammogram uptake among nonadherent KA women. IMPLICATIONS FOR NURSING: Nurses and healthcare providers should consider specific health beliefs as well as inclusion of husbands or significant others. They also should target education to be culturally relevant for KA women to effectively improve frequency of breast cancer screening. PMID- 24769603 TI - Lung cancer stigma predicts timing of medical help-seeking behavior. AB - PURPOSE/OBJECTIVES: To examine relationships among demographic variables, healthcare system distrust, lung cancer stigma, smoking status, and timing of medical help-seeking behavior in individuals with symptoms suggestive of lung cancer after controlling for ethnicity, socioeconomic status, and social desirability. DESIGN: Descriptive, cross-sectional, correlational study. SETTING: Outpatient oncology clinics in Louisville, KY. SAMPLE: 94 patients diagnosed in the past three weeks to six years with all stages of lung cancer. METHODS: Self report, written survey packets were administered in person followed by a semistructured interview to assess symptoms and timing characteristics of practice-identified patients with lung cancer. MAIN RESEARCH VARIABLES: Timing of medical help-seeking behavior, healthcare system distrust, lung cancer stigma, and smoking status. FINDINGS: Lung cancer stigma was independently associated with timing of medical help-seeking behavior in patients with lung cancer. Healthcare system distrust and smoking status were not independently associated with timing of medical help-seeking behavior. CONCLUSIONS: FINDINGS suggest that stigma influences medical help-seeking behavior for lung cancer symptoms, serving as a barrier to prompt medical help-seeking behavior. IMPLICATIONS FOR NURSING: When designing interventions to promote early medical help-seeking behavior in individuals with symptoms suggestive of lung cancer, methods that consider lung cancer stigma as a barrier that can be addressed through public awareness and patient-targeted interventions should be included. PMID- 24769604 TI - Rural living as context: a study of disparities in long-term cancer survivors. AB - PURPOSE/OBJECTIVES: To explore the impact of rurality on health-related quality of-life (HRQOL) disparities in rural long-term cancer survivors. DESIGN: Cross sectional survey. SETTING: Rural-Urban Continuum Codes (RUCC) 7, 8, and 9. SAMPLE: 91 adults at least five years post-treatment. METHODS: Mailed surveys measured HRQOL, self-esteem, and social support. Regression models were estimated to isolate (from self-esteem and social support) the effect of level of rurality on HRQOL. MAIN RESEARCH VARIABLES: HRQOL, self-esteem, social support, and rurality. FINDINGS: No differences in demographic characteristics existed among RUCCs. Survivors residing in RUCCs 7 or 8 tended to be similar in several dimensions of HRQOL. Survivors living in RUCC 7 reported significantly lower social function and greater financial difficulty and number of symptoms compared to survivors in RUCC 9 (the most remote). Self-esteem and social support strongly correlated with HRQOL. CONCLUSIONS: The significant impact of rurality on HRQOL beyond self-esteem and social support suggests its role in explaining cancer survivorship disparities and directing practice. Until additional exploration can identify mechanisms behind rurality's impact, consideration of level of rurality as a potential factor in evaluating survivors' HRQOL outcomes is reasonable. IMPLICATIONS FOR NURSING: Survivor context (e.g., level of rurality) influences HRQOL outcomes. Context or culture-relevant risk minimization and HRQOL optimization nursing practices are indicated. PMID- 24769605 TI - Octahedral-shaped perovskite nanocrystals and their visible-light photocatalytic activity. AB - Octahedral-shaped perovskite PbTiO3 nanocrystals (PT OCT) with well-defined {111} facets exposed have been successfully synthesized via a facile hydrothermal method by using LiNO3 as an ion surfactant. The Li-O bond on the surface of PT OCT nanocrystals is essential to the stability of such nanocrystals and also results in a dramatic high visible-light photocatalytic activity. PMID- 24769606 TI - Video-laryngoscope difficult-airway blades: lower pressure and better glottic view? A preliminary in vitro study. PMID- 24769607 TI - Recent advances in surface functionalization techniques on polymethacrylate materials for optical biosensor applications. AB - Biosensor chips for immune-based assay systems have been investigated for their application in early diagnostics. The development of such systems strongly depends on the effective protein immobilization on polymer substrates. In order to achieve this complex heterogeneous interaction the polymer surface must be functionalized with chemical groups that are reactive towards proteins in a way that surface functional groups (such as carboxyl, -COOH; amine, -NH2; and hydroxyl, -OH) chemically or physically anchor the proteins to the polymer platform. Since the proteins are very sensitive towards their environment and can easily lose their activity when brought in close proximity to the solid surface, effective surface functionalization and high level of control over surface chemistry present the most important steps in the fabrication of biosensors. This paper reviews recent developments in surface functionalization and preparation of polymethacrylates for protein immobilization. Due to their versatility and cost effectiveness, this particular group of plastic polymers is widely used both in research and in industry. PMID- 24769608 TI - Early treatment of unilateral temporomandibular joint ankylosis: a multidisciplinary approach. AB - Ankylosis of temporomandibular joint is a condition in which partial or complete immobilization of mandible occurs because of fusion between mandibular condyle and skull base. This condition can be treated orthodontically, surgically, or therapeutically or by prosthodontic rehabilitation. A 10-year-old female patient presented to the Department of Oral and Maxillofacial Surgery, Gazi University Faculty of Dentistry, with limited mouth opening. She got injury in the face when she was 5 years old. Extraoral and intraoral examination findings were facial asymmetry on the left side, micrognathic mandible, and 19-mm mouth opening. After radiographic examination, ankylosis (Shawney type I) on the left side was revealed, and the patient was referred to Department of Orthodontics. After orthodontic clinical examination, we create following multidisciplinary treatment approach: (1) acrylic posterior bite block with spring application, (2) interpositional arthroplasty operation, and (3) physiotherapy (passive mouth opening exercises). After the follow-up of 9 months, significant improvement (5 mm) was noticed in the opening of the mouth, and we decided to remove appliance and operate on the patient. Surgical procedure was performed under general anesthesia via blinded nasotracheal intubation. To prevent postoperative relapse, temporal fascia was interpositioned and sutured. Passive mouth-opening exercises were started 10 days after the surgery. Thirty-one-millimeter mouth opening was reached after the surgery and passive mouth-opening exercises. Patient's routine controls have been continued for 2 years. PMID- 24769609 TI - Using endaural approach for temporomandibular joint access. PMID- 24769610 TI - Cutaneous angiomyolipoma in the forehead. PMID- 24769611 TI - Correlation of clinical predictions and surgical results in maxillary superior repositioning. AB - This is a prospective study to evaluate the accuracy of clinical predictions related to surgical results in subjects who underwent maxillary superior repositioning without anterior-posterior movement. Surgeons' predictions according to clinical (tooth show at rest and at the maximum smile) and cephalometric evaluation were documented for the amount of maxillary superior repositioning. Overcorrection or undercorrection was documented for every subject 1 year after the operations. Receiver operating characteristic curve test was used to find a cutoff point in prediction errors and to determine positive predictive value (PPV) and negative predictive value. Forty subjects (14 males and 26 females) were studied. Results showed a significant difference between changes in the tooth show at rest and at the maximum smile line before and after surgery. Analysis of the data demonstrated no correlation between the predictive data and the surgical results. The incidence of undercorrection (25%) was more common than overcorrection (7.5%). The cutoff point for errors in predictions was 5 mm for tooth show at rest and 15 mm at the maximum smile. When the amount of the presurgical tooth show at rest was more than 5 mm, 50.5% of clinical predictions did not match the clinical results (PPV), and 75% of clinical predictions showed the same results when the tooth show was less than 5 mm (negative predictive value). When the amount of presurgical tooth shown in the maximum smile line was more than 15 mm, 75% of clinical predictions did not match with clinical results (PPV), and 25% of the predictions had the same results because the tooth show at the maximum smile was lower than 15 mm. Clinical predictions according to the tooth show at rest and at the maximum smile have a poor correlation with clinical results in maxillary superior repositioning for vertical maxillary excess. The risk of errors in predictions increased when the amount of superior repositioning of the maxilla increased. Generally, surgeons have a tendency to undercorrect rather than overcorrect, although clinical prediction is an original guideline for surgeons, and it may be associated with variable clinical results. PMID- 24769612 TI - The distraction osteogenesis in midfacial hypoplasia. AB - Distraction osteogenesis (DO) can generate new bone in a gap between 2 vascularized bone surfaces in response to application of graduated tensile stress across the bone gap. The authors present the clinical result in a cleft patient with severe maxillary deficiency treated by a rigid external distraction (RED) device. A boy complained of both masticatory and psychological problems because of cleft with severe midfacial retrusion. The treatment aimed to create a well balanced facial profile, increase maxillary incisal display, create proper overjet and overbite, and align his dentition. By the RED system, the traction is applied to the maxilla through the dentition by an intraoral splint. A complete Le Fort I osteotomy was performed, including pterygomaxillary and septal disjunction, with mobilization. Once osteotomy was completed, the halo portion of the RED device was adjusted for the width of the neurocranium and was rigidly fixed around the head with 2 scalp screws on each side. A well-balanced facial profile and a good alignment of the dentition were obtained. The patients had considerable improvement in his self-esteem. Clinical reports have suggested that maxillary advancements achieved by distraction are more stable than those achieved with orthognathic surgery with a minimal influence on velopharyngeal competence. PMID- 24769614 TI - Treatment of unstable fractures of the zygomatic arch. PMID- 24769615 TI - Esthetic restoration in progressive hemifacial atrophy (Romberg disease): structural fat grafting versus local/free flaps. AB - BACKGROUND: Progressive hemifacial atrophy, also called Parry-Romberg disease, is a craniofacial disorder that typically involves the subcutaneous layer of 1 side of the face. Autologous reconstruction is achieved through various techniques, including autologous grafting of fatty tissue, the use of pedicled flaps, and free tissue transfer based on microvascular anastomoses. Thus far, a systematic literature review devoted to compare different surgical techniques has not been published. METHODS: The study selection process was adapted from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Data were identified by performing a systematic search on Medline, Ovid, Embase, the Cochrane Database, Current Contents, PubMed, Google, and Google Scholar. RESULTS: The initial search resulted in 871 articles through online access on July 2013. Sixty-six articles were included and fully reviewed for data extraction of the surgical procedures and divided into the following 4 groups: pedicled flaps, free flaps, structural fat grafting, and conjoint treatment (free flaps plus lipofilling). CONCLUSIONS: The therapeutic management of progressive hemifacial atrophy is based on the severity of the disease. Except for minor degrees of atrophy, for which lipofilling can satisfy the requirements, vascularized fatty tissue is essential for long-term contour correction. Microsurgical transfer of buried flaps can be considered the most effective surgical treatment of middle and severe Romberg disease in long-term correction, complication rate, and reoperative rate. PMID- 24769616 TI - The thickness of alveolar bone at the mandibular canine and premolar teeth in normal occlusion. AB - PURPOSE: The purpose of this study was to investigate the alveolar bone thickness on the buccal and lingual aspects of mandibular canines and premolars using cone beam computed tomography (CBCT). The differences between the left side and the right side and that in male and female measurements were reviewed. PATIENTS AND METHODS: Three-dimensional CBCT of 20 subjects with normal occlusion (9 males and 11 females; mean [SD] age, 21.9 [3.0] y) were used. The thickness of the buccal and lingual bone walls, perpendicular to the long axis of the root, was evaluated at 3 and 5 mm apical to the cementoenamel junction (CEJ) and at the root apex. RESULTS: The mean buccal bone thickness measured at 3 and 5 mm apical to the CEJ was less than 2 mm on the canines and the premolars. The buccal bone thickness of the second premolar at 3 and 5 mm from the CEJ was significantly greater than that of the canine and the first premolar. There were no significant differences between the left and right sides, and the overall measurements of the alveolar bone thickness did not show significant male/female differences. CONCLUSIONS: This study presented the thickness of the buccal and lingual bone in different locations apical to the CEJ in subjects with normal occlusion and the frequency distribution of thick buccal bone wall (>= 2 mm). The second premolar had the highest frequency distribution of thick buccal bone (>= 2 mm) when compared with canine and the first premolar. The teeth with thin buccal bone (< 2 mm) should be treated with care for the implant because a thin buccal bone may be damaged more easily and buccal bone resorption may occur. This study may provide estimated value for patients with normal occlusion during tooth extraction and implant installation in the canine and premolar area of the mandible. Preoperative radiographic analysis, with care in using CBCT, may be applied for tooth extraction and implant therapy. PMID- 24769617 TI - Amelioration of high salinity stress damage by plant growth-promoting bacterial endophytes that contain ACC deaminase. AB - Plant growth and productivity is negatively affected by soil salinity. However, it is predicted that plant growth-promoting bacterial (PGPB) endophytes that contain 1-aminocyclopropane-1-carboxylate (ACC) deaminase (E.C. 4.1.99.4) can facilitate plant growth and development in the presence of a number of different stresses. In present study, the ability of ACC deaminase containing PGPB endophytes Pseudomonas fluorescens YsS6, Pseudomonas migulae 8R6, and their ACC deaminase deficient mutants to promote tomato plant growth in the absence of salt and under two different levels of salt stress (165 mM and 185 mM) was assessed. It was evidence that wild-type bacterial endophytes (P. fluorescens YsS6 and P. migulae 8R6) promoted tomato plant growth significantly even in the absence of stress (salinity). Plants pretreated with wild-type ACC deaminase containing endophytic strains were healthier and grew to a much larger size under high salinity stress compared to plants pretreated with the ACC deaminase deficient mutants or no bacterial treatment (control). The plants pretreated with ACC deaminase containing bacterial endophytes exhibit higher fresh and dry biomass, higher chlorophyll contents, and a greater number of flowers and buds than the other treatments. Since the only difference between wild-type and mutant bacterial endophytes was ACC deaminase activity, it is concluded that this enzyme is directly responsible for the different behavior of tomato plants in response to salt stress. The use of PGPB endophytes with ACC deaminase activity has the potential to facilitate plant growth on land that is not normally suitable for the majority of crops due to their high salt contents. PMID- 24769618 TI - Density functional theory investigations of the trivalent lanthanide and actinide extraction complexes with diglycolamides. AB - At present, designing novel ligands for efficient actinide extraction in spent nuclear fuel reprocessing is extremely challenging due to the complicated chemical behaviors of actinides, the similar chemical properties of minor actinides (MA) and lanthanides, and the vulnerability of organic ligands in acidic radioactive solutions. In this work, a quantum chemical study on Am(III), Cm(III) and Eu(III) complexes with N,N,N',N'-tetraoctyl diglycolamide (TODGA) and N,N'-dimethyl-N,N'-diheptyl-3-oxapentanediamide (DMDHOPDA) has been carried out to explore the extraction behaviors of trivalent actinides (An) and lanthanides (Ln) with diglycolamides from acidic media. It has been found that in the 1 : 1 (ligand : metal) and 2 : 1 stoichiometric complexes, the carbonyl oxygen atoms have stronger coordination ability than the ether oxygen atoms, and the interactions between metal cations and organic ligands are substantially ionic. The neutral ML(NO3)3 (M = Am, Cm, Eu) complexes seem to be the most favorable species in the extraction process, and the predicted relative selectivities are in agreement with experimental results, i.e., the diglycolamide ligands have slightly higher selectivity for Am(III) over Eu(III). Such a thermodynamical priority is probably caused by the higher stabilities of Eu(III) hydration species and Eu(III)-L complexes in aqueous solution compared to their analogues. In addition, our thermodynamic analysis from water to organic medium confirms that DMDHOPDA has higher extraction ability for the trivalent actinides and lanthanides than TODGA, which may be due to the steric hindrance of the bulky alkyl groups of TODGA ligands. This work might provide an insight into understanding the origin of the actinide selectivity and a theoretical basis for designing highly efficient extractants for actinide separation. PMID- 24769619 TI - Single-photon quantum router with multiple output ports. AB - The routing capability is a requisite in quantum network. Although the quantum routing of signals has been investigated in various systems both in theory and experiment, the general form of quantum routing with many output terminals still needs to be explored. Here we propose a scheme to achieve the multi-channel quantum routing of the single photons in a waveguide-emitter system. The channels are composed by the waveguides and are connected by intermediate two-level emitters. By adjusting the intermediate emitters, the output channels of the input single photons can be controlled. This is demonstrated in the cases of one output channel, two output channels and the generic N output channels. The results show that the multi-channel quantum routing of single photons can be well achieved in the proposed system. This offers a scheme for the experimental realization of general quantum routing of single photons. PMID- 24769621 TI - A narrative review of the empirical evidence on public attitudes on brain death and vital organ transplantation: the need for better data to inform policy. AB - Vital organ transplantation is premised on 'the dead donor rule': donors must be declared dead according to medical and legal criteria prior to donation. However, it is controversial whether individuals diagnosed as 'brain dead' are really dead in accordance with the established biological conception of death-the irreversible cessation of the functioning of the organism as a whole. A basic understanding of brain death is also relevant for giving valid, informed consent to serve as an organ donor. There is therefore a need for reliable empirical data on public understanding of brain death and vital organ transplantation. We conducted a review of the empirical literature that identified 43 articles with approximately 18,603 study participants. These data demonstrate that participants generally do not understand three key issues: (1) uncontested biological facts about brain death, (2) the legal status of brain death and (3) that organs are procured from brain dead patients while their hearts are still beating and before their removal from ventilators. These data suggest that, despite scholarly claims of widespread public support for organ donation from brain dead patients, the existing data on public attitudes regarding brain death and organ transplantation reflect substantial public confusion. Our review raises questions about the validity of consent for vital organ transplantation and suggests that existing data are of little assistance in developing policy proposals for organ transplantation from brain dead patients. New approaches to rigorous empirical research with educational components and evaluations of understanding are urgently needed. PMID- 24769622 TI - KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps. AB - The functional properties of KCNQ1 channels are highly dependent on associated KCNE-beta subunits. Mutations in KCNQ1 or KCNE subunits can cause congenital channelopathies, such as deafness, cardiac arrhythmias and epilepsy. The mechanism by which KCNE1-beta subunits slow the kinetics of KCNQ1 channels is a matter of current controversy. Here we show that KCNQ1/KCNE1 channel activation occurs in two steps: first, mutually independent voltage sensor movements in the four KCNQ1 subunits generate the main gating charge movement and underlie the initial delay in the activation time course of KCNQ1/KCNE1 currents. Second, a slower and concerted conformational change of all four voltage sensors and the gate, which opens the KCNQ1/KCNE1 channel. Our data show that KCNE1 divides the voltage sensor movement into two steps with widely different voltage dependences and kinetics. The two voltage sensor steps in KCNQ1/KCNE1 channels can be pharmacologically isolated and further separated by a disease-causing mutation. PMID- 24769623 TI - Development of a 'mouse and human cross-reactive' affinity-matured exosite inhibitory human antibody specific to TACE (ADAM17) for cancer immunotherapy. AB - We previously showed that a human anti-TACE antibody, D1(A12), is a potent inhibitor of TNF-alpha converting enzyme (TACE) ectodomain proteolysis and has pharmacokinetic properties suitable for studies of the inhibition of TACE dependent growth factor shedding in relation to possible therapeutic applications. However, the lack of murine TACE immunoreactivity limits pre clinical in vivo studies to human xenograft models which are poor analogies to in situ pathology and are not considered clinically predictive. Here, to overcome these limitations, we set out to develop a 'mouse and human cross-reactive' specific anti-TACE antibody. We first re-investigated the originally selected anti-TACE ectodomain phage-display clones, and isolated a lead 'mouse-human cross reactive' anti-TACE scFv, clone A9. We reformatted scFv-A9 into an IgG2 framework for comprehensive biochemical and cellular characterization and further demonstrated that A9 is an exosite TACE inhibitor. However, surface plasmon resonance analysis and quenched-fluorescent (QF) peptide assay indicated that IgG reformatting of A9 caused low binding affinity and an 80-fold reduction in TACE ectodomain inhibition, severely limiting its efficacy. To address this, we constructed second generation phage-display randomization libraries focused on the complementarity-determining region 3, and carried out affinity selections shuffling between human and mouse TACE ectodomain as antigen in addition to an off-rate selection to increase the chance of affinity improvement. The bespoke 'three-step' selections enabled a 100-fold affinity enhancement of A9 IgG, and also improved its IC50 in a QF peptide assay to 0.2 nM. In human and mouse cancer cell assays, matured A9 IgG showed significant cell-surface TACE inhibition as a monotherapy or combination therapy with chemotherapeutic agent. Collectively, these data suggest that we successfully developed an exosite inhibitor of TACE with sub-nanomolar affinity, which possesses both murine and human immunoreactive properties that can be used for in vivo application in murine pre-clinical cancer models. PMID- 24769624 TI - The effects of physical exercise with music on cognitive function of elderly people: Mihama-Kiho project. AB - BACKGROUND: Physical exercise has positive effects on cognitive function in elderly people. It is unknown, however, if combinations of non-pharmaceutical interventions can produce more benefits than single ones. This study aimed to identify if physical exercise combined with music improves cognitive function in normal elderly people more than exercise alone. METHODS: We enrolled 119 subjects (age 65-84 years old). Forty subjects performed physical exercise (once a week for an hour with professional trainers) with musical accompaniment (ExM group), developed by YAMAHA Music Foundation; 40 subjects performed the same exercise without music (Ex group); 39 subjects were the control group (Cont group). Before and after the year-long intervention, each patient was assessed by neuropsychological batteries. MRIs were performed before and after intervention; the Voxel-based Specific Regional analysis system for Alzheimer's Disease (VSRAD) was used to assess medial temporal lobe atrophy. RESULTS: Analysis of variance (ANOVA) was significant only in visuospatial function. The multiple comparison (ExM vs. Ex, ExM vs. Cont, Ex vs. Cont) was significant between the ExM and Cont group. Intra-group analyses before and after intervention revealed significant improvement in visuospatial function in the ExM group, and significant improvements in other batteries in all three groups. The VSRAD score significantly worsened in the ExM and Ex groups. CONCLUSIONS: Physical exercise combined with music produced more positive effects on cognitive function in elderly people than exercise alone. We attributed this improvement to the multifaceted nature of combining physical exercise with music, which can act simultaneously as both cognitive and physical training. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR) UMIN000012148. PMID- 24769626 TI - Multi-level control of conductive nano-filament evolution in HfO2 ReRAM by pulse train operations. AB - Precise electrical manipulation of nanoscale defects such as vacancy nano filaments is highly desired for the multi-level control of ReRAM. In this paper we present a systematic investigation on the pulse-train operation scheme for reliable multi-level control of conductive filament evolution. By applying the pulse-train scheme to a 3 bit per cell HfO2 ReRAM, the relative standard deviations of resistance levels are improved up to 80% compared to the single pulse scheme. The observed exponential relationship between the saturated resistance and the pulse amplitude provides evidence for the gap-formation model of the filament-rupture process. PMID- 24769625 TI - The potential for elimination of racial-ethnic disparities in HIV treatment initiation in the Medicaid population among 14 southern states. AB - OBJECTIVES: The purpose of this study was to explore the racial and ethnic disparities in initiation of antiretroviral treatment (ARV treatment or ART) among HIV-infected Medicaid enrollees 18-64 years of age in 14 southern states which have high prevalence of HIV/AIDS and high racial disparities in HIV treatment access and mortality. METHODS: We used Medicaid claims data from 2005 to 2007 for a retrospective cohort study. We compared frequency variances of HIV treatment uptake among persons of different racial- ethnic groups using univariate and multivariate methods. The unadjusted odds ratio was estimated through multinomial logistic regression. The multinomial logistic regression model was repeated with adjustment for multiple covariates. RESULTS: Of the 23,801 Medicaid enrollees who met criteria for initiation of ARV treatment, only one third (34.6%) received ART consistent with national guideline treatment protocols, and 21.5% received some ARV medication, but with sub-optimal treatment profiles. There was no significant difference in the proportion of people who received ARV treatment between black (35.8%) and non-Hispanic whites (35.7%), but Hispanic/Latino persons (26%) were significantly less likely to receive ARV treatment. CONCLUSIONS: Overall ARV treatment levels for all segments of the population are less than optimal. Among the Medicaid population there are no racial HIV treatment disparities between Black and White persons living with HIV, which suggests the potential relevance of Medicaid to currently uninsured populations, and the potential to achieve similar levels of equality within Medicaid for Hispanic/Latino enrollees and other segments of the Medicaid population. PMID- 24769627 TI - Disruption of cerebrospinal fluid flow through the olfactory system may contribute to Alzheimer's disease pathogenesis. AB - Plaques and tangles may be manifestations of a more substantial underlying cause of Alzheimer's disease (AD). Disease-related changes in the clearance of amyloid beta (Abeta) and other metabolites suggest this cause may involve cerebrospinal fluid (CSF) flow through the interstitial spaces of the brain, including an archaic route through the olfactory system that predates neocortical expansion by three hundred million years. This olfactory CSF conduit (OCC) runs from the medial temporal lobe (MTL) along the lateral olfactory stria, through the olfactory trigone, and down the olfactory tract to the olfactory bulb, where CSF seeps through the cribriform plate to the nasal submucosa. Olfactory dysfunction is common in AD and could be related to alterations in CSF flow along the OCC. Further, reductions in OCC flow may impact CSF hydrodynamics upstream in the MTL and basal forebrain, resulting in less efficient Abeta removal from those areas among the first affected by neuritic plaques in AD. Factors that reduce CSF drainage across the cribriform plate and slow the clearance of metabolite-laden CSF could include aging-related bone changes, head trauma, inflammation of the nasal epithelium, and toxins that affect olfactory neuron survival and renewal, as well as vascular effects related to diabetes, obesity, and atherosclerosis-all of which have been linked to AD risk. Problems with CSF-mediated clearance could also provide a link between these seemingly disparate factors and familial AD mutations that induce plaque and tangle formation. I hypothesize that disruptions of CSF flow across the cribriform plate are important early events in AD, and I propose that restoring this flow will enhance the drainage of Abeta oligomers and other metabolites from the MTL. PMID- 24769628 TI - Utricular Dysfunction in Refractory Benign Paroxysmal Positional Vertigo. AB - OBJECTIVE: To determine the prevalence of otolith dysfunction in patients with refractory benign paroxysmal positional vertigo (BPPV). STUDY DESIGN: Unmatched case control. SETTING: Tertiary care institution. SUBJECTS AND METHODS: Patients included were diagnosed with BPPV, failed initial in-office canalith repositioning maneuvers (CRMs), and completed vestibular testing and vestibular rehabilitation (n = 40). Refractory BPPV (n = 19) was defined in patients whose symptoms did not resolve despite vestibular rehabilitation. These patients were compared with a control group of those with nonrefractory BPPV (n = 21) for results of a caloric test, cervical vestibular evoked myogenic potential (cVEMP), and subjective visual vertical (SVV). RESULTS: Forty-six of 251 patients failed initial treatment with in-office CRM. Forty patients met inclusion criteria. There was no significant difference between the cases (refractory BPPV) (n = 19) and controls (nonrefractory BPPV) (n = 21) in terms of age, duration of symptoms, laterality of BPPV, and BPPV symptoms. There was no difference in the prevalence of caloric weakness and cVEMP abnormalities (P > .05), with odds ratios (ORs [95% confidence interval (CI)]) of having abnormal results among cases vs controls of 1.1818 (0.3329-4.1954) and 4.3846 (0.7627-25.2048), for caloric and cVEMP, respectively. Abnormal eccentric SVV was more prevalent in refractory BPPV cases (58%) than in controls (14%) (P < .0072). The OR (95% CI) of having abnormal SVV was 8.25 (1.7967-37.8822) higher among patients with refractory BPPV than those with nonrefractory BPPV. CONCLUSION: Patients with refractory BPPV are more likely to have abnormal eccentric SVV and thus underlying utricular dysfunction. This finding is important to take into account when designing rehabilitation strategies for patients with BPPV who fail CRM. PMID- 24769629 TI - Renal corticomedullary differentiation by non-contrast-enhanced MR imaging with a spatially selective IR pulse at various inversion times: comparison with fast asymmetric spin echo (FASE) and steady-state free-precession (SSFP). AB - We compared visualization of corticomedullary differentiation between fast asymmetric spin echo (FASE) and steady-state free precession (SSFP) combined with spatially selective inversion recovery (IR) pulse and optimal inversion time (TI). Though the corticomedullary contrast ratio was higher in FASE than SSFP images, visualization of corticomedullary differentiation was significantly better in SSFP images than FASE images obtained with spatially selective IR pulses and optimal TI. PMID- 24769630 TI - Assessment of improved motion-sensitized driven equilibrium (iMSDE) for multi contrast vessel wall screening. AB - PURPOSE: We assessed the improved motion-sensitized driven equilibrium (iMSDE) technique for multiple contrast 3-dimensional vessel wall imaging at 3T. METHODS: Carotid images were obtained using iMSDE combined with turbo field echo (iMSDE TFE) and conventional double inversion-recovery turbo spin-echo (DIR-TSE) in 5 healthy adult subjects. The tissue signal-to-noise efficiency (SNReff), SNR divided by the square root of scan time, lumen-tissue contrast-to-noise efficiency (CNReff), CNR divided by the square root of scan time, and tissue signal intensity ratio (SIR) were measured in both techniques and compared. RESULTS: The iMSDE-TFE had higher SNReff and CNReff (P < 0.01) and strong correlation in SIR (R = 0.92) compared to DIR-TSE. CONCLUSION: The iMSDE-TFE sequence is an efficient technique for vessel wall screening. PMID- 24769631 TI - Clinical significance of mammillary body enhancement in Wernicke encephalopathy: report of 2 cases and review of the literature. AB - In 2 cases of Wernicke encephalopathy in which the initial symptom was double vision, the only abnormal finding on magnetic resonance (MR) imaging was abnormal enhancement of the mammillary bodies. The mammillary bodies are the region most vulnerable to abnormal enhancement. Because MR imaging with contrast enhancement can detect such abnormal enhancement at an early stage, it should be performed more often in patients with oculomotor disorders to avoid underdiagnosis of Wernicke encephalopathy. PMID- 24769632 TI - Interimager variability in ADC measurement of the human brain. AB - PURPOSE: Routine clinical practice involves the application of diverse scanning parameters that can affect apparent diffusion coefficient (ADC) values. We evaluated interimager variability in ADC values with respect to their potential effect in clinical applications. METHODS: In 7 healthy volunteers, we obtained diffusion-weighted (DW) images using routine clinical parameters and 1.5- (n = 9) and 3-tesla (n = 3) magnetic resonance (MR) imagers from 5 different vendors, performing 84 MR imaging studies. To evaluate the differences in ADC values among the imagers, vendors, and magnetic field strengths, we measured the mean pixel values of the frontal white matter and thalamus (gray matter) in both cerebral hemispheres of the 7 volunteers and used repeated-measures analysis of variance for multiple comparisons. RESULTS: The laterality of ADC values in the bilateral structures ranged from one to 3% for the 12 imagers. Although the relative difference in ADC values of white matter was 7% for scanners yielding the highest and lowest mean ADC values (P < 0.01), it was within 2 to 4% for instruments from the same vendors. For gray matter, the interimager difference was 4 to 12%, even among the same vendors (P < 0.05). Among the 3T imagers, the difference for white and gray matter was approximately 3%. CONCLUSIONS: There were significant interimager differences in ADC values, especially with respect to gray matter. Taking into consideration the existing laterality, however, the differences among our 3T imagers may be acceptable despite the use of diverse scanning parameters. In routine clinical practice, the existing variability must be considered imager by imager. PMID- 24769633 TI - MR imaging of carcinosarcoma of the liver using Gd-EOB-DTPA. AB - We present a case of a 69-year-old man with primary hepatic carcinosarcoma who underwent computed tomography that revealed a hypervascular hepatic tumor with local dense calcification. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging revealed hyperintense lesions in the hepatobiliary phase that indicated hepatocellular carcinoma with bile production. The patient underwent right lobectomy, and the presence of a sarcoma component within the tumor on histopathology confirmed liver carcinosarcoma that included hepatocellular carcinoma. In cases with atypical images that resemble this case, the hyperintensity of a lesion in the hepatobiliary phase aids differential diagnosis. PMID- 24769634 TI - Utility of apparent diffusion coefficients in the evaluation of solid renal tumors at 3T. AB - PURPOSE: We assessed the usefulness of apparent diffusion coefficients (ADCs) for solid renal tumor imaging using diffusion-weighted magnetic resonance imaging (DWI) at 3T. METHODS: This retrospective study assessed ADCs of 31 patients with renal tumors that were imaged using preoperative DWI. DWI was performed with the b values of 50, 500, and 1000 s/mm(2), using a 3T magnetic resonance imaging (MRI) system (MAGNETOM Trio, 3T, Siemens Healthcare, Erlangen, Germany). The ADC map was calculated using the b values of 50 and 1000 s/mm(2). ADCs of the different tumors were compared according to the Tukey-Kramer test. RESULTS: The tumors were diagnosed as clear cell renal cell carcinoma (RCC; n = 20), papillary RCC (n = 1), infiltrating urothelial carcinoma (UC) of the kidney (n = 4), cystic RCC (n = 1), poorly differentiated carcinoma (n = 1), and angiomyolipoma (AML; n = 4). The mean ADC of clear cell RCC was significantly higher than that of infiltrating UC of the kidney (1.423 vs. 0.931 * 10(-3) mm(2)/s; P < 0.05), and the mean ADC of AML was significantly lower than that of clear cell RCC (0.674 vs. 1.423 * 10(-3) mm(2)/s; P < 0.01). CONCLUSION: ADCs used in DWI at 3T may be useful for differentiation of different types of solid renal tumors. PMID- 24769635 TI - Optimization of inversion time for postmortem short-tau inversion recovery (STIR) MR imaging. AB - PURPOSE: Signal intensity and image contrast differ between postmortem magnetic resonance (PMMR) images and images acquired from the living body. We sought to achieve sufficient fat suppression with short-tau inversion recovery (STIR) PMMR imaging by optimizing inversion time (TI). MATERIAL AND METHODS: We subjected 37 deceased adult patients to PMMR imaging at 1.5 tesla 8 to 60 hours after confirmation of death and measured T1 values of areas of subcutaneous fat with relaxation time maps. Rectal temperature (RT) measured immediately after PMMR ranged from 6 to 31 degrees C. We used Pearson's correlation coefficient to analyze the relationship between T1 and relaxation time (RT). We compared STIR images from 4 cadavers acquired with a TI commonly used in the living body and another TI calculated from the linear regression of T1 and RT. RESULTS: T1 values of subcutaneous fat ranged from 89.4 to 182.2 ms. There was a strong, positive, and significant correlation between T1 and RT (r = 0.91, P < 0.0001). The regression expression for the relationship was T1 = 2.6*RT + 90 at a field strength of 1.5T. The subcutaneous fat signal was suppressed more effectively with the optimized TI. CONCLUSION: The T1 value of subcutaneous fat in PMMR correlates linearly with body temperature. Using this correlation to determine TI, fat suppression with PMMR STIR imaging can be easily improved. PMID- 24769636 TI - MR imaging of Meniere's disease after combined intratympanic and intravenous injection of gadolinium using HYDROPS2. AB - Endolymphatic hydrops (EH) in Meniere's disease is currently evaluated by 3 dimensional (3D)-real inversion recovery (IR) sequence after intratympanic (IT) administration of gadolinium (Gd) or by heavily T2-weighted (hT2W)-3D-fluid attenuated IR (FLAIR) sequence after intravenous (IV) injection of Gd. Unilateral IT injection is usually performed. We employed a method in which we simultaneously administered contrast into one ear intravenously (IV side) and into the other ear both intravenously and intratympanically (IT + IV side) to evaluate EH in 10 patients with Meniere's disease. We then compared a HYDROPS2 image obtained by subtracting magnetic resonance cisternography from hT2W-3D FLAIR with an image obtained by 3D-real IR and found that we could evaluate EH in all ears on the HYDROPS2 image but only in the IT + IV side on the 3D-real IR image. PMID- 24769637 TI - Time course for measuring endolymphatic size in healthy volunteers following intravenous administration of gadoteridol. AB - PURPOSE: We developed semi-quantitative methods to measure endolymphatic size on images obtained 4 hours after intravenous administration of single-dose gadolinium-based contrast medium (IV-SD-GBCM) and found little variation in results between observers. We used the methods to measure the size of the endolymph in healthy volunteers at various times after IV-SD-GBCM and attempted to determine the optimal timing for the evaluation. METHODS: In 8 healthy male volunteers, we obtained heavily T2-weighted 3-dimensional fluid-attenuated inversion recovery (hT2W-3D-FLAIR) images 1.5, 3, 4.5, and 6 hours after IV-SD GBCM as positive perilymph images (PPI) as well as acquiring positive endolymph images (PEI) and magnetic resonance cisternography (MRC). To evaluate the endolymph, we generated 2 kinds of processed images (HYDROPS-Mi2 and HYDROPS2 Mi2) by subtracting PEI or MRC from PPI as previously proposed. We semi quantitatively measured the ratio of the area of the endolymph (%EL) to that of total lymph on the 2 kinds of generated images for the cochlea and vestibule according to the previously proposed method. We analyzed statistics to evaluate the change in %EL over time and used analysis of variance (ANOVA) for a 2 * 4 repeated-measures design to assess difference in image type. We adopted 5% as a significance level. RESULTS: The %EL was significantly larger at 1.5 hours after IV-SD-GBCM than at 3, 4.5, and 6 hours in both the cochlea and vestibule for both kinds of generated images. Between 4.5 and 6 hours, the %EL plateaued for both the cochlea and vestibule, and the 2 kinds of generated images did not differ significantly. CONCLUSION: A delay of 1.5 hours after IV-SD-GBCM is not sufficient to evaluate endolymphatic size. The %EL plateaus between 4.5 and 6 hours. These data might be valuable for further clinical studies. PMID- 24769638 TI - Fast and robust estimation of diffusional kurtosis imaging (DKI) parameters by general closed-form expressions and their extensions. AB - Diffusional kurtosis imaging (DKI) for clinical imaging involves time-consuming computation and demonstrates low robustness. Standard estimation of DKI parameters is based on an extension of Stejskal-Tanner's signal model with squared b-value term and is a least-squares fitting problem. The use of numerical methods for computation requires time, and estimation of DKI parameters is noise sensitive and often produces noisy results, such as images with pepper noise.In this study, we propose general closed-form solutions for DKI parameters to avoid numerical computation for least-squares fitting, solutions that can be applied to diffusion weighted imaging (DWI) datasets with any number of b-values more than three. Solutions are obtained through stationary-point conditions of an objective function that are minimized for fitting. We use 3 techniques to extend the solutions to increase robustness-b-value-dependent weighting in fitting, removal of outliers, and addition of neighbor sampling. Based on synthetic datasets and clinical datasets that both consist of 6 b-value and 3 b-value datasets, we detail and compare the 3 methods including a method by Jensen et al. are compared and investigated in detail. The synthetic data consist of several combinations of DKI parameters and some Rician noise. In addition to visually assessing result images, we also performed quantitative evaluation using a range of estimated parameters, positive-definiteness of the objective function for fitting, and root mean-square error including estimation bias from the true value (synthetic data only). Methods that added neighbor sampling outperformed others in terms of low errors and visual smoothness. Though the solution by our method is to estimate DKI parameters in a single MPG direction, it can contribute to anisotropic analysis of diffusional kurtosis such as kurtosis tensor. More robust estimation is expected by combining techniques. PMID- 24769639 TI - Second-line chemotherapy in advanced biliary cancer: a systematic review. AB - The randomized NCRN phase III ABC-02 trial provided level-A evidence for first line chemotherapy with cisplatin and gemcitabine combination in advanced biliary cancer (ABC). This systematic literature review aims to evaluate the level of evidence for the use of second-line chemotherapy for patients with ABC in terms of overall survival (OS), response, toxicity and quality of life. Eligible studies were identified using Medline, ASCO, ESMO and the World Gastrointestinal Congress databases. Searches were last updated on 15 December 2013. Eligible studies reported survival and/or response data for patients with ABC receiving second-line systemic chemotherapy. This systematic review was registered in the PROSPERO database (No. CRD42013004205). Five hundred and fifty-eight studies were identified from the searches in Medline (n = 342), ASCO (n = 160), ESMO (n = 27) and World Gastrointestinal Congress (n = 29). Twenty-five studies were eligible: 14 phase II clinical trials, 9 retrospective analyses and 2 case reports. In total, data from 761 patients were reported with median number of patients included in each study of 22 (range 9-96). The mean OS was 7.2 months [95% confidence interval (CI) 6.2-8.2] [phase II: 6.6 (95% CI 5.1-8.1); retrospective analysis: 7.7 (95% CI 6.5-8.9)]. The mean progression-free survival (PFS), response rate (RR) and disease control rate were 3.2 months (95% CI 2.7-3.7), 7.7% (95% CI 4.6-10.9) and 49.5% (95% CI 41.4-57.7), respectively. The best correlations were between OS and PFS for all studies (r = 0.54; P = 0.01) and between OS and PFS (r = 0.61; P = 0.04) and OS and RR (r = 0.62; P = 0.03) for phase II studies, respectively. Biliary tract cancer is known to be a chemo responsive disease. There is insufficient evidence (level C) to recommend a second-line chemotherapy schedule in ABC, although the available data suggest that a cohort of patients may benefit. Further prospective and randomized studies are needed to clarify the relative value of second-line chemotherapy in this setting. PMID- 24769640 TI - Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine. AB - BACKGROUND: In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial. METHODS: The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits. RESULTS: For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks. CONCLUSIONS: This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient. ClinicalTrials.gov Identifier: NCT01227889. PMID- 24769641 TI - Polyoxoniobate-based 3D framework materials with photocatalytic hydrogen evolution activity. AB - Two phosphoniobate-based 3D frameworks were firstly constructed using the hexa capped Keggin polyoxoniobates [PNb12O40(VO)6](3-) and copper cations. Photocatalytic studies indicated that the hybrid materials exhibit photocatalytic hydrogen evolution activity. PMID- 24769643 TI - Electronic versus paper-based assessment of health-related quality of life specific to HIV disease: reliability study of the PROQOL-HIV questionnaire. AB - BACKGROUND: Electronic patient-reported outcomes (PRO) provide quick and usually reliable assessments of patients' health-related quality of life (HRQL). OBJECTIVE: An electronic version of the Patient-Reported Outcomes Quality of Life human immunodeficiency virus (PROQOL-HIV) questionnaire was developed, and its face validity and reliability were assessed using standard psychometric methods. METHODS: A sample of 80 French outpatients (66% male, 52/79; mean age 46.7 years, SD 10.9) were recruited. Paper-based and electronic questionnaires were completed in a randomized crossover design (2-7 day interval). Biomedical data were collected. Questionnaire version and order effects were tested on full-scale scores in a 2-way ANOVA with patients as random effects. Test-retest reliability was evaluated using Pearson and intraclass correlation coefficients (ICC, with 95% confidence interval) for each dimension. Usability testing was carried out from patients' survey reports, specifically, general satisfaction, ease of completion, quality and clarity of user interface, and motivation to participate in follow-up PROQOL-HIV electronic assessments. RESULTS: Questionnaire version and administration order effects (N=59 complete cases) were not significant at the 5% level, and no interaction was found between these 2 factors (P=.94). Reliability indexes were acceptable, with Pearson correlations greater than .7 and ICCs ranging from .708 to .939; scores were not statistically different between the two versions. A total of 63 (79%) complete patients' survey reports were available, and 55% of patients (30/55) reported being satisfied and interested in electronic assessment of their HRQL in clinical follow-up. Individual ratings of PROQOL-HIV user interface (85%-100% of positive responses) confirmed user interface clarity and usability. CONCLUSIONS: The electronic PROQOL-HIV introduces minor modifications to the original paper-based version, following International Society for Pharmacoeconomics and Outcomes Research (ISPOR) ePRO Task Force guidelines, and shows good reliability and face validity. Patients can complete the computerized PROQOL-HIV questionnaire and the scores from the paper or electronic versions share comparable accuracy and interpretation. PMID- 24769642 TI - Combined staurosporine and retinoic acid induces differentiation in retinoic acid resistant acute promyelocytic leukemia cell lines. AB - All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In ATRA resistant APL cell lines NB4-R1 and NB4-R2, the combination of staurosporine and ATRA synergized to trigger differentiation accompanied by significantly enhanced protein level of CCAAT/enhancer binding protein epsilon (C/EBPepsilon) and C/EBPbeta as well as the phosphorylation of mitogen-activated protein (MEK) and extracellular signal regulated kinase (ERK). Furthermore, attenuation of the MEK activation blocked not only the differentiation but also the increased protein level of C/EBPepsilon and C/EBPbeta. Taken together, we concluded that the combination of ATRA and staurosporine could overcome differentiation block via MEK/ERK signaling pathway in ATRA-resistant APL cell lines. PMID- 24769644 TI - The optimal use of PEG-asparaginase in relapsed ALL--lessons from the ALLR3 Clinical Trial. PMID- 24769645 TI - Distinct roles of class I PI3K isoforms in multiple myeloma cell survival and dissemination. PMID- 24769646 TI - Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is associated with the level of H3K4me2 in the RARalpha promoter region. AB - All-trans retinoic acid (ATRA) is well established as differentiation therapy for acute promyelocytic leukemia (APL) in which the PML-RARalpha (promyelocytic leukemia-retinoic acid receptor alpha) fusion protein causes blockade of the retinoic acid (RA) pathway; however, in types of acute myeloid leukemia (AML) other than APL, the mechanism of RA pathway inactivation is not fully understood. This study revealed the potential mechanism of high ATRA sensitivity of mixed lineage leukemia (MLL)-AF9-positive AML compared with MLL-AF4/5q31-positive AML. Treatment with ATRA induced significant myeloid differentiation accompanied by upregulation of RARalpha, C/EBPalpha, C/EBPE and PU.1 in MLL-AF9-positive but not in MLL-AF4/5q31-positive cells. Combining ATRA with cytarabine had a synergistic antileukemic effect in MLL-AF9-positive cells in vitro. The level of dimethyl histone H3 lysine 4 (H3K4me2) in the RARalpha gene-promoter region, PU.1 upstream regulatory region (URE) and RUNX1+24/+25 intronic enhancer was higher in MLL-AF9 positive cells than in MLL-AF4-positive cells, and inhibiting lysine-specific demethylase 1, which acts as a histone demethylase inhibitor, reactivated ATRA sensitivity in MLL-AF4-positive cells. These findings suggest that the level of H3K4me2 in the RARalpha gene-promoter region, PU.1 URE and RUNX1 intronic enhancer is determined by the MLL-fusion partner. Our findings provide insight into the mechanisms of ATRA sensitivity in AML and novel treatment strategies for ATRA-resistant AML. PMID- 24769648 TI - Organocatalytic cascade reactions: diversity-oriented synthesis for the construction of hydroisoquinoline scaffolds. AB - The organocatalytic enantioselective synthesis of highly functionalized hydroisoquinolines by trienamine-mediated [4+2]-cycloaddition/nucleophilic ring closing reaction cascade sequence of cyanoacrylamides with 2,4-dienals is presented. The corresponding cycloadducts are formed in high yields and excellent stereoselectivities. Moreover, a series of transformations demonstrate the synthetic application of the obtained hydroisoquinolines. PMID- 24769649 TI - Human papillomavirus vaccine uptake: what works and what can we do better? PMID- 24769647 TI - The emerging role of Twist proteins in hematopoietic cells and hematological malignancies. AB - Twist1 and Twist2 (Twist1-2) are two transcription factors, members of the basic helix-loop-helix family, that have been well established as master transcriptional regulators of embryogenesis and developmental programs of mesenchymal cell lineages. Their role in oncogenesis in epithelium-derived cancer and in epithelial-to-mesenchymal transition has also been thoroughly characterized. Recently, emerging evidence also suggests a key role for Twist1-2 in the function and development of hematopoietic cells, as well as in survival and development of numerous hematological malignancies. In this review, we summarize the latest data that depict the role of Twist1-2 in monocytes, T cells and B lymphocyte activation, and in associated hematological malignancies. PMID- 24769650 TI - Vulvovaginal pyoderma gangrenosum secondary to rituximab therapy. AB - Rituximab is being used increasingly for the treatment of B-cell malignancies and nonmalignant conditions. Pyoderma gangrenosum is a rare neutrophilic dermatosis, which can be either idiopathic or associated with underlying systemic inflammatory conditions. We present a series of 4 patients who presented with ulcerative pyoderma gangrenosum in the vulvovaginal area after treatment with rituximab. PMID- 24769651 TI - The effect of vaginal lubrication on unsatisfactory results of cervical smears. AB - OBJECTIVE: Speculum lubrication with water-based gels before cervical smear sampling has been investigated and commented on thoroughly during the last decade. The present meta-analysis was based on randomized and quasi-randomized control trials and evaluated its impact on unsatisfactory cytologic results. We also assessed its efficacy in producing lower pain scores during speculum insertion. MATERIALS AND METHODS: We searched MEDLINE (1966- 2013), Scopus (2004 2013), Clinicaltrials.org (1997-2013), Popline (1973-2013), Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2013), and Google Scholar (2004 2013) engines for published randomized control trials, as well as the reference lists from all the included studies. RESULTS: Five randomized trials and 2 quasi randomized trials were included in the present review involving 8,717 women. Unsatisfactory results based on conventional cytology did not statistically differ among procedures performed with lubricated speculums and those without (odds ratio = 0.94, 95% CI = 0.64-1.37). Consequently, pain scores also did not differ significantly among the 2 groups (odds ratio = -0.37, 95% CI = -1.10 to 0.36). Only 2 studies evaluated unsatisfactory results on liquid-based cytology, precluding firm results. CONCLUSIONS: It seems that speculum lubrication does not interfere with the rates of unsatisfactory results when examination is based on conventional cytology. Conversely, however, the limited number of studies evaluating speculum lubrication on liquid-based cytology precludes firm conclusions. PMID- 24769652 TI - Lesions of the mons pubis: a review. AB - The mons pubis may become involved in dermatologic conditions or gynecologic lesions affecting the vulva. There are also unusual lesions that have been reported arising from the mons specifically. A familiarity with these lesions will be helpful if a patient with a lesion of the mons is encountered. PMID- 24769653 TI - The utility of human papillomavirus testing in young women with atypical glandular cells on pap test. AB - OBJECTIVE: This study aimed to gain information regarding the follow-up diagnoses and human papillomavirus (HPV) status of women younger than 35 years diagnosed with atypical glandular cells (AGCs) on Pap test. MATERIALS AND METHODS: This is a retrospective observational study in which the cytopathology files at Fletcher Allen Health Care were reviewed from 2000 to 2013 for the diagnoses of AGC in women younger than 35 years. Subsequent pathology reports and HPV testing results were obtained. Significant lesions were defined as cervical intraepithelial neoplasia (CIN) 2 or 3, invasive squamous cell carcinoma, adenocarcinoma in situ, or adenocarcinoma. RESULTS: One hundred six women younger than 35 years with an AGC Pap diagnosis and subsequent follow-up were identified. Significant lesions were diagnosed in 44.3% of the women (47); the majority (55.3%, 26 patients) of which were classified as CIN 2 or 3. Adenocarcinoma in situ was diagnosed in 27.7% of the cases (13). A diagnosis of both CIN 2 or 3 and adenocarcinoma in situ was made in 14.9% of the cases (7). One patient (2.1%) was diagnosed with endometrial adenocarcinoma. The HPV status was identified in 36.8% of the women (39): 69.2% (27) was HPV positive, and 30.8% (12) was HPV negative. Fifty-five percent of HPV-positive women were diagnosed with a significant lesion upon follow-up. No known HPV-negative women were diagnosed with a significant lesion. CONCLUSIONS: Human papillomavirus testing may be useful in risk stratifying young women with AGC on Pap test because they are at risk of having an HPV-positive cervical lesion. PMID- 24769654 TI - Comment on "Vulvovaginal candidiasis as a chronic disease: diagnostic criteria and definition". PMID- 24769655 TI - Reply to Dr. Reichman's comments on "Vulvovaginal candidiasis as a chronic disease: diagnostic criteria and definition". PMID- 24769656 TI - Posttreatment assessment of women at risk of developing high-grade cervical disease: proposal for new guidelines based on data from the Netherlands. AB - OBJECTIVE: Women treated for high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or grade 3 [CIN2/3]) face a significant risk of developing post-treatment disease. Therefore, in most European countries, they are monitored by cytologic testing at 6, 12, and 24 months after treatment. Although testing for high-risk types of the human papillomavirus (hrHPV) in the follow-up seems to be a valuable supplementary method, its use is not yet fully explored. METHODS: Besides reviewing the literature, we completed a long-term follow-up study describing the cumulative risk for CIN2/3 or cancer (CIN2+) of different hrHPV and cytology test results after treatment. CONCLUSIONS: High-risk HPV testing improves the sensitivity to detect posttreatment CIN2/3 (relative sensitivity=1.15, 95% confidence interval [CI]=1.06-1.25), but the highest sensitivity (95%, 95% CI=91%-98%) is reached by performing cotesting (both cytology and hrHPV). The CIN2+ risk after a single negative cotesting result taken 6 months after treatments was similar to the risk after 3 consecutive negative cytologic test results (5-y CIN2+ risk being 3.0% [95% CI=1.5%-6.1%] and 2.9% [95% CI=1.2%-7.1%], respectively). Women who test negative for cotesting at both 6 and 24 months after treatment have a minimal risk of developing CIN3+ in the next 5 years (0.0%, 95% CI=0.0%-3.0%). RECOMMENDATIONS: We propose a new posttreatment surveillance protocol, consisting of combined testing with both cytology and hrHPV at 6 and 24 months after treatment. After 2 negative cotesting results, women should be retested after 5 years. PMID- 24769657 TI - Hydrogen evolution by a metal-free electrocatalyst. AB - Electrocatalytic reduction of water to molecular hydrogen via the hydrogen evolution reaction may provide a sustainable energy supply for the future, but its commercial application is hampered by the use of precious platinum catalysts. All alternatives to platinum thus far are based on nonprecious metals, and, to our knowledge, there is no report about a catalyst for electrocatalytic hydrogen evolution beyond metals. Here we couple graphitic-carbon nitride with nitrogen doped graphene to produce a metal-free hybrid catalyst, which shows an unexpected hydrogen evolution reaction activity with comparable overpotential and Tafel slope to some of well-developed metallic catalysts. Experimental observations in combination with density functional theory calculations reveal that its unusual electrocatalytic properties originate from an intrinsic chemical and electronic coupling that synergistically promotes the proton adsorption and reduction kinetics. PMID- 24769658 TI - Using haemoglobin A(1c) to diagnose type 2 diabetes or to identify people at high risk of diabetes. PMID- 24769659 TI - Dimeric 1,3-propanediaminetetraacetato lanthanides as the precursors of catalysts for the oxidative coupling of methane. AB - From neutral solutions, dimeric 1,3-propanediaminetetraacetato lanthanides (NH4)2[Ln2(1,3-pdta)2(H2O)4].8H2O [Ln = La, 1; Ce, 2] and K2[Ln2(1,3 pdta)2(H2O)4].11H2O [Ln = La, 3; Ce, 4] (1,3-H4pdta = 1,3 propanediaminetetraacetic acid, C11H18N2O8) were isolated in high yields. The reaction of excess strontium nitrate with 1 resulted in the formation of a two dimensional coordination polymer [La2(1,3-pdta)2(H2O)4]n.[Sr2(H2O)6]n.[La2(1,3 pdta)2(H2O)2]n.18nH2O (5) at 70 degrees C. Complexes 1-4 show a similar central molecular structure. The lanthanide ions are coordinated by two nitrogen atoms, four carboxy oxygen atoms from one 1,3-pdta ligand, two from the neighboring 1,3 pdta ligand forming a four-membered ring and two water molecules. Complex 5 has two kinds of dimeric lanthanum unit and extends into a 2D coordination polymer through strontium ions and bridged oxygen atoms, and forms a fourteen membered ring linked by oxygen atoms from carboxy groups of pdta. Complexes 1-4 are soluble in water. The (13)C{(1)H} NMR experiments for complex 1 were tested in solution. Thermal products from 1 and 5 show good catalytic activities towards the oxidative coupling reaction of methane (OCM). The conversion of methane and selectivity to C2 reached 29.7% and 51.7% at 750 degrees C for the product of 5. From TGA, XRD and SEM analyses, the thermal products from 1 and 5 are rod- and poly-shaped, which are assigned as lanthanum oxocarbonate and a mixture of La2O3, SrCO3 and La2O2CO3 for 1 and 5, respectively. The precursor method is favorable for the formation of regular shaped mixed oxides. PMID- 24769660 TI - Acute facial oedema post live-donor renal transplantation. AB - Facial oedema leading to airway compromise immediately after surgery is a rare event. We report a case of acute facial swelling sufficient to cause a significant obstruction of the patient's airway in recovery. We believe it was caused by partial obstruction of the venous drainage from the head associated with a sudden and large fluid load. A 35-year-old man underwent a live ABO incompatible renal transplantation during which a central line was inserted into the right subclavian vein and a large volume of fluid was given intraoperatively. He also had a longstanding permacatheter on the left side used for haemodialysis. In the recovery room he developed acute facial swelling which did not resolve with steroids or antihistamines. He was managed by intubation of his airway and ventilation in the intensive care unit overnight before he made a complete recovery with no further intervention. We hypothesise that this event was related to an impaired venous return from his head secondary to the central venous line and the permacatheter partially obstructing the venous drainage from his head and neck combined with an acute large venous fluid load. PMID- 24769661 TI - Wide complex ventricular tachycardia presenting sign of metastatic pleural mesothelioma. AB - Malignant mesothelioma is an uncommon neoplasm of serosal surfaces, such as the pleura, the peritoneum, less frequently pericardium and tunica vaginalis. It usually spreads locally to the lungs and mediastinum. We describe a case of malignant mesothelioma with metastasis to the heart. The patient presented with syncope, chest pain and light-headedness. He was found to have wide complex ventricular tachycardia (Vtach). He was cardioverted and then noted to have multiple (more than 20) similar episodes during the hospital course. He was treated with multiple antiarrhythmic medications. A CT scan of the chest revealed a circumferential rind of soft tissue in the right hemithorax and invasion of the pericardium. The repeated Vtach episodes were secondary to the metastasis of the pericardium. Oncology was involved and as there were no further treatment options available, the patient was discharged home with hospice care. The disease is a huge economic burden and early recognition can lead to better outcomes. PMID- 24769662 TI - Acute myocardial infarction due to coronary thrombosis caused by blunt chest trauma. AB - A 65-year-old man presented to the emergency department following an anterior chest trauma. He had significant chest pain and chest X-ray was significant for revealed multiple rib fractures and negative. CT scan of the chest ruled out pulmonary embolism or aortic dissection. However, few hours later he developed hypotension requiring admission to medical intensive care unit and intravenous vasopressors. Further workup showed ST elevation myocardial infarction involving the anterior ECG leads. Emergent coronary angiography was performed with intervention to the mid-left anterior descending occlusion. Cardiogenic shock resolved and patient was discharged few days later. One-year follow-up with echocardiogram showed stable ischaemic cardiomyopathy with improved left ventricular ejection fraction to 50%. PMID- 24769663 TI - Lead aVR: beyond 'No man's land'. AB - Coronary artery disease (CAD) is one of the leading causes of mortality in the world. Treadmill test is a very useful non-invasive test to diagnose and stratify the risk of CAD. Lead aVR is usually a neglected lead while reading the ECG. We describe a case demonstrating the importance of subtle changes in lead aVR that has got a direct angiographic correlation with left main CAD. Therefore picking up the subtle clues on ECG may help in stratifying the risk and optimal treatment of the patient in a timely fashion. PMID- 24769664 TI - Takotsubo cardiomyopathy with secondary coronary embolus. AB - We describe the case of a 65-year-old patient who was admitted to our tertiary centre with cardiac sounding chest pain and inferior ST elevation. Coronary angiography revealed mild plaque disease in the left anterior descending artery. The right coronary artery was smooth with no plaques with the exception of an occluded distal branch with no flow. The left ventriculogram revealed a ballooned and akinetic apex typical of Takotsubo syndrome (TS). We suspected a coronary embolus secondary to TS. A serial rise and fall in biomarkers of myocardial necrosis was noted. The patient was treated for acute coronary syndrome and discharged home 72 h from admission. Distal thromboembolism has been described in the literature before. On a search of PubMed there are no examples of coronary artery embolus in the context of TS. PMID- 24769665 TI - Graves' disease as an uncommon cause of acute pericarditis. AB - Acute pericarditis is either dry, fibrinous or effusive, independent of its aetiology. A case is presented involving a 44-year-old man with acute pericarditis. The cause was established to be an aggravation of Graves' disease due to non-compliance with treatment. Pericarditis is an uncommon cardiac complication of Graves' disease and is associated with more recurrent episodes when not detected. Pharmacological treatment should include anti-inflammatory drugs in combination with treatment for hyperthyroidism. The specific pathophysiological link between the two conditions is still to be elucidated. PMID- 24769666 TI - Cystic schwannoma of the recurrent laryngeal nerve: a rare finding posing diagnostic difficulties. AB - A 49-year-old woman with a painless mass in the neck was examined by the surgeon. Imaging and cytology prior to surgery suggested the mass to be either a thyroid cyst or a branchial cleft cyst. After surgery, the patient reported a hoarse voice and the pathologist confirmed the removed lesion to be a cystic schwannoma of the left recurrent laryngeal nerve. The inconclusive imaging results, combined with colloid-like material in the punctate should prompt the investigator to include cystic schwannoma in the differential diagnosis. With the probability of a neurogenic origin of the mass in mind, nerve-sparing surgery can be performed. As a future prospect, positron emission tomography scans are mentioned as a modality with possibilities to discriminate a cystic schwannoma from other common cystic lesions. PMID- 24769667 TI - Let sleeping dogs lie: a surprising chest X-ray in the paediatric emergency department. PMID- 24769668 TI - Bortezomib protects from varicose-like venous remodeling. AB - Despite the high prevalence of venous diseases that are associated with and based on the structural reorganization of the venous vessel wall, not much is known about their mechanistic causes. In this context, we demonstrated that the quantity of myocardin, a transcriptional regulator of the contractile and quiescent smooth muscle cell phenotype, was diminished in proliferating synthetic venous smooth muscle cells (VSMCs) of human and mouse varicose veins by 51 and 60%, respectively. On the basis of the relevance of proteasomal activity for such phenotypic changes, we hypothesized that the observed VSMC activation is attenuated by the proteasome inhibitor bortezomib. This drug fully abolished VSMC proliferation and loss of myocardin in perfused mouse veins and blocked VSMC invasion in collagen gels by almost 80%. In line with this, topical transdermal treatment with bortezomib diminished VSMC proliferation by 80%, rescued 90% of VSMC myocardin abundance, and inhibited varicose-like venous remodeling by 67 to 72% in a mouse model. Collectively, our data indicate that the proteasome plays a pivotal role in VSMC phenotype changes during venous remodeling processes. Its inhibition protects from varicose-like vein remodeling in mice and may thus serve as a putative therapeutic strategy to treat human varicose veins. PMID- 24769669 TI - Secretin receptor-knockout mice are resistant to high-fat diet-induced obesity and exhibit impaired intestinal lipid absorption. AB - Secretin, a classical gastrointestinal hormone released from S cells in response to acid and dietary lipid, regulates pleiotropic physiological functions, such as exocrine pancreatic secretion and gastric motility. Subsequent to recently proposed revisit on secretin's metabolic effects, we have confirmed lipolytic actions of secretin during starvation and discovered a hormone-sensitive lipase mediated mechanistic pathway behind. In this study, a 12 wk high-fat diet (HFD) feeding to secretin receptor-knockout (SCTR(-/-)) mice and their wild-type (SCTR(+/+)) littermates revealed that, despite similar food intake, SCTR(-/-) mice gained significantly less weight (SCTR(+/+): 49.6+/-0.9 g; SCTR(-/-): 44.7+/ 1.4 g; P<0.05) and exhibited lower body fat content. These SCTR(-/-) mice have corresponding alleviated HFD-associated hyperleptinemia and improved glucose/insulin tolerance. Further analyses indicate that SCTR(-/-) have impaired intestinal fatty acid absorption while having similar energy expenditure and locomotor activity. Reduced fat absorption in the intestine is further supported by lowered postprandial triglyceride concentrations in circulation in SCTR(-/-) mice. In jejunal cells, transcript and protein levels of a key fat absorption regulator, cluster of differentiation 36 (CD36), was reduced in knockout mice, while transcript of Cd36 and fatty-acid uptake in isolated enterocytes was stimulated by secretin. Based on our findings, a novel positive feedback pathway involving secretin and CD36 to enhance intestinal lipid absorption is being proposed. PMID- 24769670 TI - L-gulono-gamma-lactone oxidase expression and vitamin C synthesis in the brain and kidney of the African lungfish, Protopterus annectens. AB - This study aimed to test the hypothesis that the brain of Protopterus annectens expressed L-gulono-gamma-lactone oxidase (gulo/Gulo), the enzyme catalyzing the last step of ascorbate biosynthesis, and could maintain high concentrations of ascorbate during estivation. We cloned and sequenced gulo from the kidney of P. annectens and performed quantitative PCR to determine its mRNA expression in kidney and brain. Gulo activity was assayed and its protein abundance was determined by Western blot using custom-made anti-Gulo antibody. Effects of estivation on concentrations of ascorbate and dehydroascorbate in the kidney and brain were also determined. Both brain and kidney, but not liver, of P. annectens expressed gulo/Gulo. Desiccation induced P. annectens to estivate, and 6 mo of estivation led to drastic decreases in gulo/Gulo expression and ascorbate concentration in the kidney. However, high concentrations of ascorbate and ascorbate + dehydroascorbate were maintained in the brain during estivation, probably resulting from in situ ascorbate synthesis. Control fish were placed in freshwater, where they were fully active in a favorable environment unlike estivation on land. The ability to synthesize ascorbate to ameliorate oxidative stress directly in the brain might contribute to the ability of P. annectens to undergo prolonged estivation on land. PMID- 24769671 TI - Suppression of hepatocellular carcinoma proliferation and hepatitis B surface antigen secretion with interferon-lambda1 or PEG-interferon-lambda1. AB - Hepatocellular carcinoma (HCC) is a common cancer associated with chronic hepatitis B virus (HBV) infection. Conventional interferon-alpha (IFN-alpha) and pegylated IFNs (PEG-IFNs) approved for chronic HBV infection treatment can reduce the risk of HCC but are not suitable for the majority of patients and cause significant side effects. IFN-lambda1 is a type III IFN with antiviral, antiproliferative, and immunomodulatory functions similar to type I IFNs but with fewer side effects. However, the tolerability and antitumor activity of PEG-IFN lambda1 in HCC xenograft mice are unknown. In vitro IFN-lambda1 treatment of Hep3B and Huh7 human hepatoma cell lines increased MHC class I expression, activated JAK-STAT signaling pathways, induced IFN-stimulated gene expression, and inhibited hepatitis B surface antigen (HBsAg) expression. IFN-lambda1 treatment also caused 23.2 and 19.9% growth inhibition of Hep3B and Huh7 cells, respectively, and promoted cellular apoptosis. PEG-IFN-lambda1, but not IFN lambda1 treatment, significantly suppressed tumor growth (P=0.002) and induced tumor cell apoptosis in a Hep3B cell xenograft mouse model without significant weight loss or toxicity. PEG-IFN-lambda1 also significantly inhibited (P=0.000) serum HBsAg secretion from Hep3B xenograft tumors in vivo. Thus, PEG-IFN-lambda1 can suppress Hep3B xenograft tumor growth and inhibit HBsAg production and may be a potential treatment for HBV-related HCC. PMID- 24769672 TI - Interprofessional collaboration between residents and nurses in general internal medicine: a qualitative study on behaviours enhancing teamwork quality. AB - BACKGROUND: Effective teamwork is necessary for optimal patient care. There is insufficient understanding of interactions between physicians and nurses on internal medicine wards. OBJECTIVE: To describe resident physicians' and nurses' actual behaviours contributing to teamwork quality in the setting of a simulated internal medicine ward. METHODS: A volunteer sample of 14 pairs of residents and nurses in internal medicine was asked to manage one non-urgent and one urgent clinical case in a simulated ward, using a high-fidelity manikin. After the simulation, participants attended a stimulated-recall session during which they viewed the videotape of the simulation and explained their actions and perceptions. All simulations were transcribed, coded, and analyzed, using a qualitative method (template analysis). Quality of teamwork was assessed, based on patient management efficiency and presence of shared management goals and of team spirit. RESULTS: Most resident-nurse pairs tended to interact in a traditional way, with residents taking the leadership and nurses executing medical prescriptions and assuming their own specific role. They also demonstrated different types of interactions involving shared responsibilities and decision making, constructive suggestions, active communication and listening, and manifestations of positive team building. The presence of a leader in the pair or a truly shared leadership between resident and nurse contributed to teamwork quality only if both members of the pair demonstrated sufficient autonomy. In case of a lack of autonomy of one member, the other member could compensate for it, if his/her own autonomy was sufficiently strong and if there were demonstrations of mutual listening, information sharing, and positive team building. CONCLUSIONS: Although they often relied on traditional types of interaction, residents and nurses also demonstrated readiness for increased sharing of responsibilities. Interprofessional education should insist on better redefinition of respective roles and reinforce behaviours shown to enhance teamwork quality. PMID- 24769674 TI - A cationic iridium(III) complex with aggregation-induced emission (AIE) properties for highly selective detection of explosives. AB - A new cationic Ir(III) complex with AIE characteristics was designed and synthesized with the help of density functional theory calculations, which exhibits highly sensitive and selective detection of explosives (2,4,6 trinitrophenol, TNP). PMID- 24769673 TI - Rural villagers and urban residents exposure to poultry in China. AB - Patterns of poultry exposure in rural and urban areas in China have not been systematically evaluated and compared. The objective of our study is to investigate patterns in human exposure to poultry in rural and urban China. We conducted a two-stage household-based clustered survey on population exposure to live/sick/dead poultry in Xiuning and Shenzhen. Half of the rural households (51%) in Xiuning raised poultry, mostly (78%) free-range. Around half of those households (40%) allowed poultry to stay in their living areas. One quarter of villagers reported having contact with sick or dead poultry. In Shenzhen, 37% urban residents visited live poultry markets. Among these, 40% purchased live poultry and 16% touched the poultry or cages during purchase. Our findings indicated that human exposure to poultry was different in rural and urban areas in China. This discrepancy could contribute to the observed differences in epidemiologic characteristics between urban and rural cases of influenza A(H7N9) and A(H5N1) virus infection. PMID- 24769675 TI - [Epidemiology of bone and joint disease - the present and future - . Epidemiology of osteoporosis and osteoporotic fracture in Japan]. AB - Osteoporosis is a major burden on modern society because of its high prevalence and tragic consequences due to fractures. According to population-based epidemiologic studies, number of people with osteoporosis in Japan was estimated to be 13 million in 2005, and only 20% of them were under treatment. Osteoporosis is a highly undertreated disease. Number of hip fractures occurred in Japan in 2007 was approximately 130 thousands which were 2.8-fold greater than those in 1987. This increase can be explained by an increase in the elderly population. Prevalence rate of vertebral fracture was reported to be approximately 30% in women aged 70s and 40% in those aged 80s. Fracture risk assessment in individuals is essential for osteoporosis management. To improve prediction accuracy for major osteoporotic fractures, FRAX((r)) model including clinical risk factors was developed. Predicted risk of major osteoporotic fractures for Japanese women by FRAX((r)) were not significantly different from observed risk in the Japanese Population-based Osteoporosis (JPOS) Cohort Study, and FRAX((r)) model without bone mineral density (BMD) showed a similar validity to FRAX((r)) model with BMD. This suggests that FRAX((r)) without BMD may be used as a screening tool for people at increased risk of fractures in community. However, FRAX((r)) should be improved further in combination with new bone strength indices. Epidemiology should play a great role in developing and evaluating such improvement in fracture risk assessment. PMID- 24769676 TI - [Epidemiology of bone and joint disease - the present and future - . Epidemiology of lumbar spondylosis in Japan : the ROAD study]. AB - To clarify the prevalence and estimate the number of people with osteoarthritis, and osteoporosis in Japan, we established a large-scale population-based cohort study entitled Research on Osteoarthritis/osteoporosis Against Disability (ROAD). The prevalence of lumbar spondylosis (LS) in men and women was 80.6% and 61.5%, respectively with utilizing the ROAD baseline data. The cumulative incidence of LS in men and women was 15.2%/y and 10.4%/y, respectively with using the follow up data. The estimated number of prevalent cases and incident cases/y of LS in Japan was approximately 38 million and 9 million, respectively. Older age, male sex, and greater BMI were associated with the occurrence of LS. PMID- 24769677 TI - [Epidemiology of bone and joint disease - the present and future - . Epidemiology of sarcopenia]. AB - The prevalence of sarcopenia diagnosed only by muscle mass in the elderly ranged from 12% to 50%, when muscle mass was measured by DXA with high accuracy. In Japanese elderly, it was reportedly 12%, 24%, 40%, and 53% in the 50s, 60s, 70s, and 80s men, respectively, and 24%, 21%, 24%, and 25% in the 50s, 60s, 70s, and 80s women, respectively. Recently, as new criteria including physical performance such as gait speed, and muscle strength, two international consensuses were obtained in Europe and US. In addition, Asian criteria have also been decided most recently. The prevalence of sarcopenia in Japanese people aged 65 years or over diagnosed using European criteria, was reportedly 10% and 22% in men, and 15% and 22% in women. The future development of epidemiological studies for sarcopenia is awaited. PMID- 24769678 TI - [Epidemiology of bone and joint disease - the present and future - . Epidemiology of falls]. AB - A longitudinal analysis using a population-based cohort study known as Research on Osteoarthritis/osteoporosis Against Disability (ROAD) clarified the associations of physical performance and bone and joint diseases with falls. A total of 452 men and 896 women were analyzed in the present study (mean age, 63.9 years). A questionnaire was used to assess the number of falls during the 3-year follow-up. Grip strength, 6-m walking time, and chair stand time were measured at baseline. Knee osteoarthritis (OA) and lumbar spondylosis were defined as Kellgren Lawrence = 3 or 4. Vertebral fracture (VFx) was assessed with the Japanese Society of Bone and Mineral Research criteria. Knee and lower back pain were estimated by an interview. During a 3-year follow-up, 17.4% men and 24.1% women reported at least one fall. Multinomial logistic regression analysis after adjustment for age and BMI showed that a longer 6-m walking time was a risk factor for multiple falls in men and women. Knee pan was also a risk factor for multiple falls in women. Walking time and knee pain may be a simple and quick option for measuring the risk of falling. PMID- 24769679 TI - [Epidemiology of bone and joint disease - the present and future - . Molecular epidemiology of osteoporosis]. AB - Osteoporosis is a common skeletal disease characterized by low bone mineral density (BMD) and microarchitectural deterioration of bone tissue. Osteoporosis increases susceptibility to fracture. Over the last 10 years, genome-wide association studies (GWAS) have identified the single-nucleotide polymorphisms (SNPs) associated with low BMD, osteoporosis and osteoporotic fractures. These SNPs were mapped close to or within the genes, such as Wnt- and RANKL-related genes. In the future, molecular epidemiology of osteoporosis may provide novel candidates for therapeutic targets. PMID- 24769680 TI - [Epidemiology of bone and joint disease - the present and future - . Genetic epidemiology on osteoarthritis]. AB - Although a large number of studies have been made to identify genetic loci associated with osteoarthritis (OA), there are only a few that have been reported to be associated with OA in many regions and countries. One of the reasons for the lack of success may be small effect sizes. A sufficiently large sample size is required for the genetic epidemiology on OA to elucidate genetic influence regarding the occurrence and progression. PMID- 24769681 TI - [Epidemiology of bone and joint disease - the present and future - . The importance of study designs and statistical analysis in epidemiology]. AB - In epidemiological studies where researchers investigate the factors that can affect human health, the theory and methodology of the statistics are a powerful tool to assert findings the data indicate. On the other hand, study designs and data analyses that are made without fully understanding the statistics can easily make it difficult to achieve the study goals or lead to misleading results. In this article, some basics researchers should know in epidemiological studies and some issues they may often misunderstand are addressed, with a particular focus at study designing and data analysis. PMID- 24769682 TI - [Epidemiology of bone and joint disease - the present and future - . Health economics of osteoporosis and osteoporotic fractures]. AB - Osteoporotic fractures are associated with increased mortality, and impose a huge financial burden on healthcare systems. Preventing osteoporotic fractures in the elderly therefore represents an important issue in health economics. In recent years, it has also become increasingly important to consider the evidence on the cost-effectiveness of health technologies. Here we introduce the basic idea of health economic evaluation and study examples in the field of osteoporosis. PMID- 24769683 TI - [Epidemiology of bone and joint disease - the present and future - . The present situation and problems associated with medical screening systems for osteoporosis]. AB - The current low osteoporosis treatment rate (20%) in Japan is problematic. Osteoporosis screening is needed to ensure that asymptomatic osteoporosis patients are identified and treated. However, five problems are associated with osteoporosis screening in Japan. First, among 1,783 district municipalities, osteoporosis screening was performed in only 1,062 municipalities in 2011. The performance rate is approximately 60% every year. Often, screening was not performed because of financial reasons. Second, the screening participation rates are low and vary among districts (0 - 15%). Third, the bone mineral density measuring apparatus is not sufficiently and widely available for osteoporosis screening. Fourth, the screening results are mainly determined from bone mineral densities; therefore, fracture risk factors besides bone mineral density are not sufficiently reflected in the results. Finally, the screening interval is 5 years, which appears to be excessively longer than the interval of cancer screening. The Fracture Risk Assessment Tool (FRAX((r))) and locomotion check are useful methods for solving these problems. The addition of these two tools to the specific health check-ups increased the participation of patients from Asahi machi compared with that previously observed ; the use of these tools was inexpensive. Furthermore, education and enlightenment regarding osteoporosis are important to increase the osteoporosis medical treatment rate and to spread awareness regarding osteoporosis screening through osteoporosis liaison services. PMID- 24769684 TI - [Epidemiology of bone and joint disease - the present and future - . Diagnosis of sarcopenia : techniques for assessing muscle mass]. AB - Diagnosis of sarcopenia is operationally based on having a low skeletal muscle mass in combination with poor physical functioning. Currently, several techniques are available for assessing regional or whole-body muscle mass noninvasively. Among these techniques, dual-energy X-ray absorptiometry (DXA) is regarded as a most reliable and practical method for both clinical and research settings. This article will review the current understanding of techniques for assessing muscle mass, focusing on DXA technology. PMID- 24769685 TI - [Epidemiology of bone and joint disease - the present and future - . Risk and prevention/treatment of fractures associated with lifestyle-related diseases]. AB - The risk of osteoporotic fracture is greater in patients with lifestyle-related diseases such as poorly controlled type 2 diabetes mellitus and stage G3 chronic kidney disease (CKD). The Japanese 2011 Guidelines for the Prevention and Treatment of Osteoporosis covered osteoporosis secondary to lifestyle-related diseases as a typical example of secondary osteoporosis, but specific treatment methods for osteoporosis secondary to lifestyle-related diseases have yet to be established. Therefore, treatment currently follows the clinical guidelines for primary osteoporosis. However, reduced bone quality is common in osteoporosis secondary to lifestyle-related diseases and therapeutic intervention should be considered even in patients without bone fracture if bone density is less than 80% that of the young adult mean. It is generally considered that the effectiveness and safety of bisphosphonate and selective estrogen receptor modulators for patients with osteoporosis and type 2 diabetes mellitus or stage G3 CKD are equivalent to those for patients without such lifestyle-related diseases. PMID- 24769686 TI - [Epidemiology of bone and joint disease - the present and future - . Risk factors for fractures and treatment of osteoporosis in Japanese patients with rheumatoid arthritis]. AB - Patients with rheumatoid arthritis (RA) are at increased risk for developing osteoporosis and fractures compared to controls. This risk is further increased since a majority of patients with RA also receive concomitant corticosteroids, which have been shown to induce osteoporosis and increase the risk of fractures. Glucocorticoids use and physical disability as well as low bone mineral density and older age are recognized as significant risk factors for fractures in patients with RA. This article reviews the epidemiology and treatment for osteoporosis in Japanese patients with RA. PMID- 24769687 TI - [Epidemiology of bone and joint disease - the present and future - . Fracture risk and secondary prevention following fragility fracture]. AB - Incidences of fragility fractures, such as of the vertebral and hip, increase with age. Both the number and severity of prevalent vertebral fractures involve independent risk factors for future fractures. However, it has been reported that the vast majority of patients who experience fragility fractures do not receive anti-osteoporotic therapy. Among patients who begin anti- osteoporosis treatment after fracture, adherence to treatment remains suboptimal. The recent development of anti-osteoporosis drugs has revolutionized the field of fracture prevention by reducing risk more than 50%. A consensus of systematic and multidisciplinary approaches to secondary fragility fracture prevention, called the Fracture (Osteoporosis) Liaison Service, has been developed over the last decade. PMID- 24769688 TI - Low-temperature solution-processable Ni(OH)2 ultrathin nanosheet/N-graphene nanohybrids for high-performance supercapacitor electrodes. AB - A novel and facile strategy is developed to fabricate highly nitrogen-doped graphene (N-graphene) based layered, quasi-two-dimensional nanohybrids with ultrathin nanosheet nanocrystals using a low-temperature, solution processing method for high-performance supercapacitor electrodes. High N doping can be achieved together with one of the lowest oxygen content in chemically reduced graphene and related nanohybrids at low temperature by large-scale residue defects of chemically reduced graphene. The layered, quasi-two-dimensional nanohybrids or heterostructures of ultrathin Ni(OH)2 nanosheet nanocrystal/N graphene can be applied in supercapacitor electrodes with ultrahigh capacitances of ~1551 F g(-1), excellent rate performance in the scan measurements (from 2 mV s(-1) to 100 mV s(-1)) and in the discharge tests (from 1.5 A g(-1) to 30 A g( 1)) and good cycling stability. Moreover, the capacitance of Ni(OH)2 nanosheet/N graphene nanohybrids is two and one orders of magnitude higher than that for pure nanocrystals and for the physical mixture of nanocrystal/N-graphene, respectively. Electron transfer in supercapacitor electrodes based on nanohybrids is over 100 times faster than that in electrodes from pure nanocrystals and several tens of times faster than that in electrodes from nanocrystal/N-graphene mixtures. This low-temperature method may provide a low-cost, solution processable and easily scalable route to high-performance graphene nanohybrid electrodes for energy applications. PMID- 24769689 TI - A general strategy for hybrid thin film fabrication and transfer onto arbitrary substrates. AB - The development of thin film-based structures/devices often requires thin films to be transferred onto arbitrary substrates/surfaces. Controllable and non destructive transfer method, although highly desired, remains quite challenging. Here we report a general method for fabrication and transfer of hybrid (ultra)thin films. The proposed solution-based in-situ transfer method shows not only its robust ability for thin film transfer onto arbitrary substrates but also its highly controlled and non-destructive characteristic. With a hole structure as the support, fully-stretched free-standing thin film is prepared. The successful transfer to a curved surface demonstrates the possibility for production of thin film-coated complex optical components. Ultrathin (35 nm) hybrid film transferred onto PET (50 MUm thick) shows high transparency (>90% in visible range), conductivity (1.54 * 10(4) S/m), and flexibility (radius of curvature down to mm scale). The reported transfer method would provide a powerful route towards complex thin film-based structures/devices. PMID- 24769690 TI - Theoretical investigation on gas-phase reaction of CF3CH2OCH3 with OH radicals and fate of alkoxy radicals (CF3CH(O*)OCH3/CF3CH2OCH2O*). AB - Detailed theoretical investigation has been performed on the mechanism, kinetics and thermochemistry of the gas phase reactions of CF3CH2OCH3 (HFE-263fb2) with OH radicals using ab-initio and DFT methods. Reaction profiles are modeled including the formation of pre-reactive and post-reactive complexes at entrance and exit channels, respectively. Our calculations reveal that hydrogen abstraction from the CH2 group is thermodynamically and kinetically more facile than that from the CH3 group. Using group-balanced isodesmic reactions, the standard enthalpies of formation for CF3CH2OCH3 and radicals (CF3CHOCH3 and CF3CH2OCH2) are also reported for the first time. The calculated bond dissociation energies for the CH bonds are in good agreement with experimental results. At 298K, the calculated total rate coefficient for CF3CH2OCH3+OH reactions is found to be in good agreement with the experimental results. The atmospheric fate of the alkoxy radicals, CF3CH(O)OCH3 and CF3CH2OCH2O are also investigated for the first time using the same level of theory. Out of three plausible decomposition channels, our results clearly point out that reaction with O2 is not the dominant path leading to the formation of CF3C(O)OCH3 for the decomposition of CF3CH(O)OCH3 radical in the atmosphere. This is in accord with the recent report of Osterstrom et al. [CPL 524 (2012) 32] but found to be in contradiction with experimental finding of Oyaro et al. [JPCA 109 (2005) 337]. PMID- 24769691 TI - In silico design of small molecule inhibitors of CDK9/cyclin T1 interaction. AB - In order to design a small molecule which potentially may interfere with CDK9/cyclin T1 complex formation and therefore influence its physiological role, a computational study of dynamics and druggability of CDK9 binding surface was conducted. Druggability estimates and pocket opening analyses indicated binding regions of cyclin T1 residues, Phe 146 and Lys 6, as starting points for the design of small molecules with the potential to inhibit the CDK9/cyclin T1 association. A pharmacophore model was created, based on these two residues and used to select potential inhibitor structures. Binding energies of the inhibitors were estimated with MM-GBSA. A good correlation of MM-GBSA energies and FTMap druggability predictions was observed. Amongst studied compounds a derivative of 2-amino-8-hydroxyquinoline was identified as the best potential candidate to inhibit CDK9/cyclin T1 interactions. PMID- 24769693 TI - Monitoring of commitment, blocking, and continuation of nutrient germination of individual Bacillus subtilis spores. AB - Short exposures of Bacillus spores to nutrient germinants can commit spores to germinate when germinants are removed or their binding to the spores' nutrient germinant receptors (GRs) is inhibited. Bacillus subtilis spores were exposed to germinants for various periods, followed by germinant removal to prevent further commitment. Release of spore dipicolinic acid (DPA) was then measured by differential interference contrast microscopy to monitor germination of multiple individual spores, and spores did not release DPA after 1 to 2 min of germinant exposure until ~7 min after germinant removal. With longer germinant exposures, percentages of committed spores with times for completion of DPA release (Trelease) greater than the time of germinant removal (Tb) increased, while the time Tlag - Tb, where Tlag represents the time when rapid DPA release began, was decreased but rapid DPA release times (DeltaTrelease = Trelease - Tlag) were increased; Factors affecting average Trelease values and the percentages of committed spores were germinant exposure time, germinant concentration, sporulation conditions, and spore heat activation, as previously shown for commitment of spore populations. Surprisingly, germination of spores given a 2nd short germinant exposure 30 to 45 min after a 1st exposure of the same duration was significantly higher than after the 1st exposure, but the number of spores that germinated in the 2nd germinant exposure decreased as the interval between germinant exposures increased up to 12 h. The latter results indicate that spores have some memory, albeit transient, of their previous exposure to nutrient germinants. PMID- 24769692 TI - Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. AB - BACKGROUND: Positive association between obesity and survival after breast cancer was demonstrated in previous meta-analyses of published data, but only the results for the comparison of obese versus non-obese was summarised. METHODS: We systematically searched in MEDLINE and EMBASE for follow-up studies of breast cancer survivors with body mass index (BMI) before and after diagnosis, and total and cause-specific mortality until June 2013, as part of the World Cancer Research Fund Continuous Update Project. Random-effects meta-analyses were conducted to explore the magnitude and the shape of the associations. RESULTS: Eighty-two studies, including 213 075 breast cancer survivors with 41 477 deaths (23 182 from breast cancer) were identified. For BMI before diagnosis, compared with normal weight women, the summary relative risks (RRs) of total mortality were 1.41 [95% confidence interval (CI) 1.29-1.53] for obese (BMI >30.0), 1.07 (95 CI 1.02-1.12) for overweight (BMI 25.0-<30.0) and 1.10 (95% CI 0.92-1.31) for underweight (BMI <18.5) women. For obese women, the summary RRs were 1.75 (95% CI 1.26-2.41) for pre-menopausal and 1.34 (95% CI 1.18-1.53) for post-menopausal breast cancer. For each 5 kg/m(2) increment of BMI before, <12 months after, and >=12 months after diagnosis, increased risks of 17%, 11%, and 8% for total mortality, and 18%, 14%, and 29% for breast cancer mortality were observed, respectively. CONCLUSIONS: Obesity is associated with poorer overall and breast cancer survival in pre- and post-menopausal breast cancer, regardless of when BMI is ascertained. Being overweight is also related to a higher risk of mortality. Randomised clinical trials are needed to test interventions for weight loss and maintenance on survival in women with breast cancer. PMID- 24769694 TI - The transcription factor Mlc promotes Vibrio cholerae biofilm formation through repression of phosphotransferase system components. AB - The phosphoenol phosphotransferase system (PTS) is a multicomponent signal transduction cascade that regulates diverse aspects of bacterial cellular physiology in response to the availability of high-energy sugars in the environment. Many PTS components are repressed at the transcriptional level when the substrates they transport are not available. In Escherichia coli, the transcription factor Mlc (for makes large colonies) represses transcription of the genes encoding enzyme I (EI), histidine protein (HPr), and the glucose specific enzyme IIBC (EIIBC(Glc)) in defined media that lack PTS substrates. When glucose is present, the unphosphorylated form of EIIBC(Glc) sequesters Mlc to the cell membrane, preventing its interaction with DNA. Very little is known about Vibrio cholerae Mlc. We found that V. cholerae Mlc activates biofilm formation in LB broth but not in defined medium supplemented with either pyruvate or glucose. Therefore, we questioned whether V. cholerae Mlc functions differently than E. coli Mlc. Here we have shown that, like E. coli Mlc, V. cholerae Mlc represses transcription of PTS components in both defined medium and LB broth and that E. coli Mlc is able to rescue the biofilm defect of a V. cholerae Deltamlc mutant. Furthermore, we provide evidence that Mlc indirectly activates transcription of the vps genes by repressing expression of EI. Because activation of the vps genes by Mlc occurs under only a subset of the conditions in which repression of PTS components is observed, we conclude that additional inputs present in LB broth are required for activation of vps gene transcription by Mlc. PMID- 24769695 TI - Analysis of surface-exposed outer membrane proteins in Helicobacter pylori. AB - More than 50 Helicobacter pylori genes are predicted to encode outer membrane proteins (OMPs), but there has been relatively little experimental investigation of the H. pylori cell surface proteome. In this study, we used selective biotinylation to label proteins localized to the surface of H. pylori, along with differential detergent extraction procedures to isolate proteins localized to the outer membrane. Proteins that met multiple criteria for surface-exposed outer membrane localization included known adhesins, as well as Cag proteins required for activity of the cag type IV secretion system, putative lipoproteins, and other proteins not previously recognized as cell surface components. We identified sites of nontryptic cleavage consistent with signal sequence cleavage, as well as C-terminal motifs that may be important for protein localization. A subset of surface-exposed proteins were highly susceptible to proteolysis when intact bacteria were treated with proteinase K. Most Hop and Hom OMPs were susceptible to proteolysis, whereas Hor and Hof proteins were relatively resistant. Most of the protease-susceptible OMPs contain a large protease susceptible extracellular domain exported beyond the outer membrane and a protease-resistant domain at the C terminus with a predicted beta-barrel structure. These features suggest that, similar to the secretion of the VacA passenger domain, the N-terminal domains of protease-susceptible OMPs are exported through an autotransporter pathway. Collectively, these results provide new insights into the repertoire of surface-exposed H. pylori proteins that may mediate bacterium-host interactions, as well as the cell surface topology of these proteins. PMID- 24769696 TI - Pyruvate formate-lyase is essential for fumarate-independent anaerobic glycerol utilization in the Enterococcus faecalis strain W11. AB - Although anaerobic glycerol metabolism in Enterococcus faecalis requires exogenous fumarate for NADH oxidation, E. faecalis strain W11 can metabolize glycerol in the absence of oxygen without exogenous fumarate. In this study, metabolic end product analyses and reporter assays probing the expression of enzymes involved in pyruvate metabolism were performed to investigate this fumarate-independent anaerobic metabolism of glycerol in W11. Under aerobic conditions, the metabolic end products of W11 cultured with glycerol were similar to those of W11 cultured with glucose. However, when W11 was cultured anaerobically, most of the glucose was converted to l-lactate, but glycerol was converted to ethanol and formate. During anaerobic culture with glycerol, the expression of the l-lactate dehydrogenase and pyruvate dehydrogenase E1alphabeta genes in W11 was downregulated, whereas the expression of the pyruvate formate lyase (Pfl) and aldehyde/alcohol dehydrogenase genes was upregulated. These changes in the expression levels caused the change in the composition of end products. A pflB gene disruptant (Deltapfl mutant) of W11 could barely utilize glycerol under anaerobic conditions, but the growth of the Deltapfl mutant cultured with either glucose or dihydroxyacetone (DHA) under anaerobic conditions was the same as that of W11. Glucose metabolism and DHA generates one NADH molecule per pyruvate molecule, whereas glycerol metabolism in the dehydrogenation pathway generates two NADH molecules per pyruvate molecule. These findings demonstrate that NADH generated from anaerobic glycerol metabolism in the absence of fumarate is oxidized through the Pfl-ethanol fermentation pathway. Thus, Pfl is essential to avoid the accumulation of excess NADH during fumarate independent anaerobic glycerol metabolism. PMID- 24769697 TI - Mechanistic study of classical translocation-dead SpoIIIE36 reveals the functional importance of the hinge within the SpoIIIE motor. AB - SpoIIIE/FtsK ATPases are central players in bacterial chromosome segregation. It remains unclear how these DNA translocases harness chemical energy (ATP turnover) to perform mechanical work (DNA movement). Bacillus subtilis sporulation provides a dramatic example of intercompartmental DNA transport, in which SpoIIIE moves 70% of the chromosome across the division plane. To understand the mechanistic requirements for DNA translocation, we investigated the DNA translocation defect of a classical nontranslocating allele, spoIIIE36. We found that the translocation phenotype is caused by a single substitution, a change of valine to methionine at position 429 (V429M), within the motor of SpoIIIE. This substitution is located at the base of a hinge between the RecA-like beta domain and the alpha domain, which is a domain unique to the SpoIIIE/FtsK family and currently has no known function. V429M interferes with both protein-DNA interactions and oligomer assembly. These mechanistic defects disrupt coordination between ATP turnover and DNA interaction, effectively uncoupling ATP hydrolysis from DNA movement. Our data provide the first functional evidence for the importance of the hinge in DNA translocation. PMID- 24769698 TI - Steady-state hydrogen peroxide induces glycolysis in Staphylococcus aureus and Pseudomonas aeruginosa. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from human pathogens Staphylococcus aureus and Pseudomonas aeruginosa can be readily inhibited by reactive oxygen species (ROS)-mediated direct oxidation of their catalytic active cysteines. Because of the rapid degradation of H2O2 by bacterial catalase, only steady-state but not one-dose treatment with H2O2 rapidly induces glycolysis and the pentose phosphate pathway (PPP). We conducted transcriptome sequencing (RNA seq) analyses to globally profile the bacterial transcriptomes in response to a steady level of H2O2, which revealed profound transcriptional changes, including the induced expression of glycolytic genes in both bacteria. Our results revealed that the inactivation of GAPDH by H2O2 induces metabolic levels of glycolysis and the PPP; the elevated levels of fructose 1,6-biphosphate (FBP) and 2-keto-3-deoxy 6-phosphogluconate (KDPG) lead to dissociation of their corresponding glycolytic repressors (GapR and HexR, respectively) from their cognate promoters, thus resulting in derepression of the glycolytic genes to overcome H2O2-stalled glycolysis in S. aureus and P. aeruginosa, respectively. Both GapR and HexR may directly sense oxidative stresses, such as menadione. PMID- 24769699 TI - Elucidating the process of activation of methyl-coenzyme M reductase. AB - Methyl-coenzyme M reductase (MCR) catalyzes the reversible reduction of methyl coenzyme M (CH3-S-CoM) and coenzyme B (HS-CoB) to methane and heterodisulfide CoM S-S-CoB (HDS). MCR contains the hydroporphinoid nickel complex coenzyme F430 in its active site, and the Ni center has to be in its Ni(I) valence state for the enzyme to be active. Until now, no in vitro method that fully converted the inactive MCRsilent-Ni(II) form to the active MCRred1-Ni(I) form has been described. With the potential use of recombinant MCR in the production of biofuels and the need to better understand this enzyme and its activation process, we studied its activation under nonturnover conditions and achieved full MCR activation in the presence of dithiothreitol and protein components A2, an ATP carrier, and A3a. It was found that the presence of HDS promotes the inactivation of MCRred1, which makes it essential that the activation process is isolated from the methane formation assay, which tends to result in minimal activation rates. Component A3a is a multienzyme complex that includes the mcrC gene product, an Fe-protein homolog, an iron-sulfur flavoprotein, and protein components involved in electron bifurcation. A hypothetical model for the cellular activation process of MCR is presented. PMID- 24769701 TI - Wet- and dry-season steroid hormone profiles and stress reactivity of an insular dwarf snake, the Hog Island boa (Boa constrictor imperator). AB - Field endocrine studies providing new comparisons for inference into the evolutionary and ecological factors shaping organismal physiology are important, often yielding novel physiological insights. Here, we explored factors associated with the sex steroid hormone concentrations and adrenocortical response to capture stress in Hog Island boas (Boa constrictor imperator) in the Cayos Cochinos archipelago of Honduras to generate comparative field hormone data from a tropical reptile and test the island tameness hypothesis. Baseline concentrations of testosterone, corticosterone, estradiol, and progesterone were measured during the wet and dry seasons, and an acute stressor of 1 h in a cloth bag was used to assess the stress response. Plasma steroid concentrations in these snakes were generally low in comparison to other taxa. Higher testosterone concentrations in males and higher estradiol and corticosterone concentrations in females were observed during the wet season compared to the dry season, which may be indicative of mating activities and vitellogenesis during this period. Snakes displayed a 15-fold increase in corticosterone concentrations in response to capture stress, a rise that was not impacted by whether a snake had been captured during previous years. The adrenocortical stress response was greater in males and positively related to body temperature. We suggest that this system merits future inquiries into the physiology and behavior of B. c. imperator, particularly as a model for studying insular impacts on diverse life history characters. PMID- 24769700 TI - Two different rpf clusters distributed among a population of Stenotrophomonas maltophilia clinical strains display differential diffusible signal factor production and virulence regulation. AB - The quorum-sensing (QS) system present in the emerging nosocomial pathogen Stenotrophomonas maltophilia is based on the signaling molecule diffusible signal factor (DSF). Production and detection of DSF are governed by the rpf cluster, which encodes the synthase RpfF and the sensor RpfC, among other components. Despite a well-studied system, little is known about its implication in virulence regulation in S. maltophilia. Here, we have analyzed the rpfF gene from 82 S. maltophilia clinical isolates. Although rpfF was found to be present in all of the strains, it showed substantial variation, with two populations (rpfF-1 and rpfF-2) clearly distinguishable by the N-terminal region of the protein. Analysis of rpfC in seven complete genome sequences revealed a corresponding variability in the N-terminal transmembrane domain of its product, suggesting that each RpfF variant has an associated RpfC variant. We show that only RpfC-RpfF-1 variant strains display detectable DSF production. Heterologous rpfF complementation of DeltarpfF mutants of a representative strain of each variant suggests that RpfF-2 is, however, functional and that the observed DSF-deficient phenotype of RpfC RpfF-2 variant strains is due to permanent repression of RpfF-2 by RpfC-2. This is corroborated by the DeltarpfC mutant of the RpfC-RpfF-2 representative strain. In line with this observations, deletion of rpfF from the RpfC-RpfF-1 strain leads to an increase in biofilm formation, a decrease in swarming motility, and relative attenuation in the Caenorhabditis elegans and zebrafish infection models, whereas deletion of the same gene from the representative RpfC-RpfF-2 strain has no significant effect on these virulence-related phenotypes. PMID- 24769702 TI - Pulmonary compliance and lung volume are related to terrestriality in anuran amphibians. AB - Dehydration tolerance of anuran amphibians is directly related to their ability to mobilize lymphatic reserves, with more terrestrial species having more effective lymph mobilization dependent on specialized skeletal muscles acting directly on the lymph sacs and via pulmonary ventilation. Consequently, we tested the hypothesis that pulmonary compliance, lung volume, and femoral lymphatic sac volume were related to terrestriality-and, hence, lymph mobilization-for 18 species of aquatic, semiaquatic, or terrestrial anuran amphibians. Lung compliance and volume were significantly related to body mass, but there was no significant phylogenetic pattern. There were significant habitat-related patterns for mass-corrected and phylogenetically corrected residuals for these pulmonary variables. Femoral lymph volume was significantly related to body mass, with no significant phylogenetic pattern, and there was only a weak correlation for habitat with mass-corrected and phylogenetically corrected residuals. These results suggest that pulmonary volume and compliance are strongly related to terrestriality in anuran amphibians and are under significant selection pressure to enhance lymph mobilization, but lymph sac volume does not appear to have a major role in adaptation to terrestriality. PMID- 24769703 TI - Individual (co)variation in standard metabolic rate, feeding rate, and exploratory behavior in wild-caught semiaquatic salamanders. AB - Repeatability is an important concept in evolutionary analyses because it provides information regarding the benefit of repeated measurements and, in most cases, a putative upper limit to heritability estimates. Repeatability (R) of different aspects of energy metabolism and behavior has been demonstrated in a variety of organisms over short and long time intervals. Recent research suggests that consistent individual differences in behavior and energy metabolism might covary. Here we present new data on the repeatability of body mass, standard metabolic rate (SMR), voluntary exploratory behavior, and feeding rate in a semiaquatic salamander and ask whether individual variation in behavioral traits is correlated with individual variation in metabolism on a whole-animal basis and after conditioning on body mass. All measured traits were repeatable, but the repeatability estimates ranged from very high for body mass (R = 0.98), to intermediate for SMR (R = 0.39) and food intake (R = 0.58), to low for exploratory behavior (R = 0.25). Moreover, repeatability estimates for all traits except body mass declined over time (i.e., from 3 to 9 wk), although this pattern could be a consequence of the relatively low sample size used in this study. Despite significant repeatability in all traits, we find little evidence that behaviors are correlated with SMR at the phenotypic and among-individual levels when conditioned on body mass. Specifically, the phenotypic correlations between SMR and exploratory behavior were negative in all trials but significantly so in one trial only. Salamanders in this study showed individual variation in how their exploratory behavior changed across trials (but not body mass, SMR, and feed intake), which might have contributed to observed changing correlations across trials. PMID- 24769704 TI - The hormonal regulation of color changes in the sexually dichromatic frog Buergeria robusta. AB - During the breeding season, dynamic changes in body coloration are regularly observed in the male brown tree frog Buergeria robusta. This study investigated the hypothesis that this sexual dichromatism in male B. robusta is mediated through hormonal regulation. Frogs were exogenously injected with testosterone (T) or estradiol (E2). This manipulation revealed that the body coloration (hue, brightness, and saturation) of the male frog increased significantly (i.e., the brilliant yellow color developed) in response to T but not in response to E2. Concurrently, the levels of expression of brain-derived neurotrophic factor (BDNF) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the pituitary gland were reduced in frogs whose coloration was pale brown on a yellow background. In particular, the weakest expressions of BDNF, PACAP, and PACAP type II receptors (VPAC-1R) were found in male frogs with a brilliant yellow body color during the breeding season regardless of background color. These changes may decrease alpha-melanocyte-stimulating hormone production associated with the PACAP receptors (VPAC-1R), resulting in the aggregation of black pigment in melanophores and the production of a brilliant yellow body color. The effects of hormones on skin coloration were further examined in isolated skin in vitro. The results of this investigation showed that the dispersion of xanthophores was stimulated by T or prolactin (PRL) and that the melanophores were aggregated by melatonin (MEL) but not by E2. Furthermore, yellow pigments in the xanthophores were significantly dispersed following the PRL+T treatment. In the T+MEL, PRL+MEL, and T+PRL+MEL treatments, xanthophores were dispersed, and melanophores were aggregated and subsequently moved to the low spongiosum layer of the dorsal skin, causing the increase in yellow coloration. These results reveal that multiple hormones play major roles in the regulation of the brilliant yellow coloration of male B. robusta by high plasma T during the breeding season. PMID- 24769705 TI - Reproductive investment compromises maternal health in three species of freshwater turtle. AB - Life-history theory predicts that a trade-off in the allocation of resources between different physiological systems exists because resources are finite. As a result, females investing heavily in reproduction may compromise their future health. We used hematology, serum biochemistry, mass, and morphometric measurements as indicators of physiological health state to investigate whether reproductive investment altered subsequent maternal health in three Australian freshwater turtles: the oblong turtle (Chelodina oblonga; n = 12), the Macquarie turtle (Emydura macquarii; n = 9), and the eastern long-necked turtle (Chelodina longicollis; n = 8). Maternal health was impaired in turtles that produced larger and heavier eggs and clutches. In C. oblonga and E. macquarii, increased reproductive investment generally resulted in negative changes to the hematology and serum biochemistry profile of maternal blood. Generally, increases in heterophil/lymphocyte ratio, aspartate transaminase, creatine kinase, calcium/phosphorus ratio, and albumin/globulin ratio were observed following reproduction, in addition to a decrease in glucose and total protein. These findings agree with the physiological constraint hypothesis and highlight the connection between life-history evolution and animal physiology by documenting, for the first time, how measures of physiological health state relate to reproductive investment in Australian freshwater turtles. Additionally, our findings suggest that body condition, a readily used morphological biomarker, is a poor predictor of health in turtles. Our results emphasize the need to investigate how maternal health is influenced by the reproductive process in different species. PMID- 24769706 TI - Regulation of breeding behavior: do energy-demanding periods induce a change in prolactin or corticosterone baseline levels in the common tern (Sterna hirundo)? AB - Hormones are involved in reproductive decisions, linking environmental cues and body condition and adapting behavior. Mass loss is often accompanied by decreased prolactin and increased corticosterone concentrations, influencing incubation and brooding behavior and ultimately triggering nest desertion. Using blood-sucking bugs (Dipetalogaster maxima), we measured baseline prolactin, corticosterone, and ketone body values in incubating common terns (Sterna hirundo) between 2006 and 2009 during energy-demanding periods: 50 pairs were sampled hungry (after an incubation bout) and again fed (after foraging). In a second approach, we sampled 57 other pairs (experienced and inexperienced birds) three times over their individual breeding period, because reproduction, especially chick rearing, is a very energy-demanding process. In line with the common physiological pattern of fasting, we found significantly lower baseline prolactin values in hungry terns, which were negatively related to mass loss over the incubation bout, whereas corticosterone and ketone body levels were marginally increased. Compared to that in the incubation phase, the prolactin level dropped after hatching of chicks in inexperienced birds, perhaps indicating lower parental expenditure. Corticosterone, on the other hand, increased after hatching in males, probably linked to higher foraging activity, as males mainly deliver food during the first days. These energy-demanding periods clearly influenced hormones and ketone bodies, maybe reinforced by the low energy margin of this small seabird species, but energy reserves were not depleted to a level affecting behavior or reproductive success. PMID- 24769707 TI - Seasonal phenotypic flexibility of body mass, organ masses, and tissue oxidative capacity and their relationship to resting metabolic rate in Chinese bulbuls. AB - Survival of small birds in fluctuating environments is facilitated by seasonal metabolic and morphological flexibility. Chinese bulbuls Pycnonotus sinensis show winter increases in resting metabolic rate (RMR), nutritional organ masses, and liver and muscle cellular aerobic capacity relative to summer. In this study, we build on these findings from previous studies by measuring seasonal adjustments in body mass (Mb), RMR, nutritional and exercise organ masses, and several physiological, biochemical, and hormonal markers over the entire annual cycle in wild-trapped Chinese bulbuls from Wenzhou, China. Furthermore, we analyzed the relationships between variation in organ masses and cellular aerobic capacity and variation in RMR in individual birds. Mb and RMR were higher in spring (March May) and winter (December-February) than in summer (June-August). The dry masses of several nutritional organs and mitochondrial protein content, state 4 respiration, and cytochrome c oxidase (COX) activity in liver and muscle were all heightened in winter relative to other seasons. In addition, dry masses of heart and pectoral muscle, but not nutritional organs, and biochemical markers of cellular aerobic capacity in liver and muscle were positively correlated with RMR. Plasma triiodothyronine (T3) concentration was higher in winter and spring than in summer and autumn, and it was positively correlated with RMR, mitochondrial protein content, state 4 respiration, and COX activity in liver and muscle. These results suggest that seasonal changes in nutritional and exercise organ masses and liver and muscle cellular aerobic capacity interact to promote seasonal metabolic flexibility in Chinese bulbuls. T3 appears to promote these seasonal thermoregulatory adjustments. PMID- 24769708 TI - Mistletoebirds and xylose: Australian frugivores differ in their handling of dietary sugars. AB - Carbohydrate-rich mistletoe fruits are consumed by a wide range of avian species. Small birds absorb a large portion of water-soluble nutrients, such as glucose, via the paracellular pathway. d-xylose, a pentose monosaccharide, is abundant in some nectars and mistletoe fruits consumed by birds, and it has been suggested that it is most likely absorbed via the paracellular pathway in birds. We measured apparent assimilation efficiency ([Formula: see text]) and bioavailability (f) for d-xylose and d- and l-glucose in three frugivorous Australian bird species. Mistletoebirds, silvereyes, and singing honeyeaters showed significantly lower [Formula: see text] for d-xylose than for d-glucose. Across two diet sugar concentrations, silvereyes and singing honeyeaters significantly increased f of both l-glucose (a metabolically inert isomer of d glucose commonly used to quantify paracellular uptake) and d-xylose on the more concentrated diet, probably because of increased gut processing time. By contrast, mistletoebirds (mistletoe fruit specialists) did not vary f of either sugar with diet concentration. Mistletoebirds also showed higher f for d-xylose than l-glucose and eliminated d-xylose more slowly than silvereyes and singing honeyeaters, demonstrating differences in the handling of dietary xylose between these species. Our results suggest that d-xylose may be absorbed by both mediated and nonmediated mechanisms in mistletoebirds. PMID- 24769709 TI - The physiological responses of green sturgeon (Acipenser medirostris) to potential global climate change stressors. AB - The green sturgeon (Acipenser medirostris) is an anadromous species with a distinct population segment in the San Francisco Bay-Sacramento River Delta that is currently listed as threatened. Although this species is able to tolerate salinity challenges as soon as 6 mo posthatch, its ability to deal with unpredictable salinity fluctuations remains unknown. Global climate change is predicted to result in large freshwater (FW) flushes through the estuary during winter and greater tidal influence during the summer. We exposed green sturgeon acclimated to 15 (EST) or 24 (BAY) g/L salinity to a rapid FW influx, where salinity was reduced to 0 g/L in 3 h in order to simulate the effect of the "winter" scenario. Both groups survived, enduring a 10% plasma osmolality reduction after 3 h. BAY-acclimated sturgeon upregulated both Na(+), K(+)-ATPase (NKA) activity and caspase 3/7 activity, but no changes were observed in the EST acclimated fish. In addition, we exposed FW-acclimated sturgeon to a dual 12-h salinity fluctuation cycle (0-24-0 g/L) in order to simulate the effect of greater tidal influence. At 6 h, the sturgeon showed a significant increase in plasma osmolality, and branchial NKA and caspase 3/7 activities were increased, indicating an acclimation response. There was no acclimation at 18 h, and plasma osmolality was higher than the peak observed at 6 h. The second fluctuation elicited an upregulation of the stress proteins ubiquitin and heat shock 70-kDa protein (HSP 70). Sturgeon can acclimate to changes in salinity; however, salinity fluctuations resulted in substantial cellular stress. PMID- 24769710 TI - Control of breathing in in vitro brain stem preparation from goldfish (Carassius auratus; Linnaeus). AB - In vitro brain stem preparations from goldfish (Carassius auratus) were used to first determine whether this species possesses central chemoreceptors able to modulate respiratory activity. Preparations were superfused with an artificial cerebrospinal fluid (aCSF); fictive breathing was recorded extracellularly by placing a suction electrode on cranial nerve VII. Reducing the level of O2 in the gas mixture used to bubble the aCSF from a hyperoxic level (80% or 98.7% O2) to a relative hypoxic level (20% or 40% O2) increased the frequency of the fictive respiratory burst (P = 0.0002). Reducing the pH of the aCSF from 7.9 to 7.4 by increasing CO2 in the superfusate did not affect fictive breathing. Chloride mediated neurotransmission (GABA/glycine) is a major modulator of respiratory activity; however, its effect on the neural circuits that regulate breathing in teleosts remains unknown. Bath application of GABA (0.5, 5.0 mM) decreased burst frequency but not amplitude; this effect was dose dependent (drug * concentration: P = 0.01). Superfusion of the preparations with aCSF containing 1.25 MUM of bicuculline methochloride and 1.50 MUM of strychnine hydrochloride (GABAA and glycine receptor antagonists, respectively) increased burst frequency (P = 0.002) and amplitude (P < 0.001). We conclude that respiratory activity produced by the goldfish brain stem is not responsive to the moderate CO2 levels used in this study; it may contain O2 chemoreceptors, but the relatively small response could also reflect nonspecific effects of hypoxia on the central nervous system. Cl(-)-mediated neurotransmission inhibits fictive breathing; this aspect of respiratory regulation is similar to other groups of vertebrates. PMID- 24769711 TI - Partitioning of evaporative water loss into respiratory and cutaneous pathways in Wahlberg's epauletted fruit bats (Epomophorus wahlbergi). AB - The relative contributions of respiratory and cutaneous evaporation to total evaporative water loss (TEWL) and how the partitioning of these two avenues varies with environmental temperature has received little attention in bats. We trained Wahlberg's epauletted fruit bats (Epomophorus wahlbergi) captured in Pretoria, South Africa, to wear latex masks while hanging in respirometry chambers, and we measured respiratory evaporative water loss (REWL) and cutaneous evaporative water loss (CEWL) over air temperatures (Ta) from 10 degrees to 40 degrees C. The bats' normothermic body temperature (Tb) was approximately 36 degrees C, which increased at higher Ta to 40.5 degrees +/- 1.0 degrees C at Ta ~ 40 degrees C. Both TEWL and resting metabolic rate (RMR) increased sharply at Ta >35 degrees C, with a mean TEWL at 40 degrees C equivalent to 411% of that at 30 degrees C. The increase in TEWL was driven by large increases in both CEWL and REWL. CEWL comprised more than 50% of TEWL over the entire Ta range, with the exception of Ta ~ 40 degrees C, where REWL accounted for 58% of evaporative water loss. Surface area-specific CEWL increased approximately sixfold with increasing Ta. Thermoregulation at Ta approaching or exceeding Tb involved a considerable energetic cost, with RMR at Ta ~ 40 degrees C exceeding by 24% that measured at Ta ~ 10 degrees C. Our data do not support recent arguments that respiratory gas exchange across the wing membranes represents 5%-10% of the total in E. wahlbergi. PMID- 24769712 TI - Metabolomic and ecdysteroid variations in Anopheles gambiae s.l. mosquitoes exposed to the stressful conditions of the dry season in Burkina Faso, West Africa. AB - This study explored the metabolic adjustments prompted by a switch between the rainy and dry season conditions in the African malaria mosquitoes Anopheles gambiae (M and S molecular forms) and Anopheles arabiensis. Mosquitoes were reared in contrasted experimental conditions reflecting environmental variation in Burkina Faso. Thirty-five metabolites (including sugars, polyols, and amino acids) were monitored in newly emerged males and females, and their ecdysteroid titers were determined. Metabolomic signatures were remarkably similar across species, when specimens of same age and sex were reared under identical experimental conditions. In males and females, amino acids (including glycine, leucine, phenylanine, serine, threonine, and valine) were accumulated in 1-h-old mosquitoes, then decreased 24 h after emergence, probably reflecting adult maturation and the amino acid-consuming process of cuticle sclerotisation. In turn, elevated amounts of alanine and proline in 24-h-old mosquitoes may assist the development of flight ability. Lower concentration of tricarboxylic acid cycle intermediates and isoleucine characterized older females reared under dry season conditions, suggesting metabolic and reproduction depression. In all cases, ecdysteroid concentration was much higher in males than in females, with significant seasonal variation in males. This might reflect a unique role of these hormones in shaping reproductive strategies and population demography in the An. gambiae s.l. species complex, further contributing to local adaptation in a highly fluctuating environment. PMID- 24769714 TI - Effect of continuous positive airway pressure on lipid profile in patients with obstructive sleep apnea syndrome: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for development of dyslipidemia. Continuous positive airway pressure (CPAP) is the first-line treatment for OSAS. However, it is unclear whether CPAP improves lipid metabolism. OBJECTIVES: To review the effect of CPAP on lipid profile of patients with OSAS. METHODS: We searched PubMed, Embase, and the Cochrane Library to identify eligible articles published prior to October 30, 2013. Six randomized controlled trials (RCTs) were subjected to meta-analysis using Comprehensive Meta Analysis software. RESULTS: Six RCTs meeting the inclusion criteria were enrolled. The total numbers of measurements of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, in CPAP intervention patients and sham/control groups, were 370 and 371, 330 and 328, 276 and 274, and 269 and 266 respectively. The pooled estimate of the difference in the mean TC level between the CPAP and sham CPAP/control groups was significantly different (-0.15 [95% confidence interval, -0.27 to -0.03]; p = 0.01). Subgroup analysis revealed that OSAS patients of younger age, who were more obese, and who had been treated via CPAP for a longer duration, showed a significant decrease in TC levels (the differences in the means were -0.27, -0.24, and -0.20; and the p values 0.001, 0.01, and 0.04, respectively). CONCLUSION: We confirmed that CPAP decreases the TC level, especially in OSAS patients who are younger, more obese, and who use CPAP for a longer period. CPAP did not alter TG, LDL, or HDL levels, suggesting that CPAP may have no clinically important effect on lipid metabolism. PMID- 24769715 TI - Researching the researchers. PMID- 24769716 TI - MDA5 and autoimmune disease. PMID- 24769717 TI - TDP2 keeps the brain healthy. PMID- 24769718 TI - ACVR1 mutations and the genomic landscape of pediatric diffuse glioma. PMID- 24769724 TI - Elucidation of slow magnetic relaxation in a ferromagnetic 1D dysprosium chain through magnetic dilution. AB - A novel ferromagnetic 1D dysprosium chain was synthesized. It exhibits slow magnetic relaxation, originating from the single-ion behaviour of Dy(3+) as indicated by dc and ac magnetic data of both diluted and un-diluted samples. PMID- 24769725 TI - FDA moves to regulate e-cigarettes and pipe and hookah tobacco. PMID- 24769726 TI - Insulator-half metal transition driven by hole doping: a density functional study of Sr-doped La2VMnO6. AB - La2VMnO6 is an insulating ferrimagnet experimentally. By substituting La with Sr, La2-xSrxVMnO6 (x = 0.5, 1.0, 1.5, 2.0) was investigated using the density functional theory. Our results indicated that half metallic properties are obtained for x = 0.5, 1.5, 2.0. For x = 1.0, it is insulating. With the increase of hole doping, the holes initially go to V 3d orbitals for x = 0.5, 1.0, and after that, the holes go to the Mn 3d orbitals for x = 1.5, 2.0. Ferrimagnetic coupling between V and Mn is found to be the ground state for x = 0.5, 1.5, while for x = 1.0 and 2.0, ferromagnetic and antiferromagnetic couplings between Mn and Mn are competitive for the ground state. PMID- 24769727 TI - Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression. AB - Deregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell biology, little is known about their role in melanocyte homeostasis and melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit a melanoblast migration defect and, unexpectedly, a severe melanocyte differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a downregulation of the Microphthalmia-associated transcription factor (Mitf) and melanocyte differentiation markers concomitant with an upregulation of Zeb1. We identify a transcriptional signaling network in which the EMT transcription factor ZEB2 regulates MITF levels to control melanocyte differentiation. Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2 expression is associated with reduced patient survival. PMID- 24769728 TI - Programmed cell death during neuronal development: the sympathetic neuron model. AB - Developing sympathetic neurons of the superior cervical ganglion are one of the best studied models of neuronal apoptosis. These cells require nerve growth factor (NGF) for survival at the time that they innervate their final target tissues during late embryonic and early postnatal development. In the absence of NGF, developing sympathetic neurons die by apoptosis in a transcription-dependent manner. Molecular studies of sympathetic neuron apoptosis began in the 1980s. We now know that NGF withdrawal activates the mitochondrial (intrinsic) pathway of apoptosis in sympathetic neurons cultured in vitro, and the roles of caspases, Bcl-2 (B-cell CLL/lymphoma 2) family proteins and XIAP (X-linked inhibitor of apoptosis protein) have been extensively studied. Importantly, a considerable amount has also been learned about the intracellular signalling pathways and transcription factors that regulate programmed cell death in sympathetic neurons. In this article, we review the key papers published in the past few years, covering all aspects of apoptosis regulation in sympathetic neurons and focusing, in particular, on how signalling pathways and transcription factors regulate the cell death programme. We make some comparisons with other models of neuronal apoptosis and describe possible future directions for the field. PMID- 24769729 TI - ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. AB - The process of autophagy has been described in detail at the molecular level in normal cells, but less is known of its regulation in cancer cells. Aplasia Ras homolog member I (ARHI; DIRAS3) is an imprinted tumor suppressor gene that is downregulated in multiple malignancies including ovarian cancer. Re-expression of ARHI slows proliferation, inhibits motility, induces autophagy and produces tumor dormancy. Our previous studies have implicated autophagy in the survival of dormant ovarian cancer cells and have shown that ARHI is required for autophagy induced by starvation or rapamycin treatment. Re-expression of ARHI in ovarian cancer cells blocks signaling through the PI3K and Ras/MAP pathways, which, in turn, downregulates mTOR and initiates autophagy. Here we show that ARHI is required for autophagy-meditated cancer cell arrest and ARHI inhibits signaling through PI3K/AKT and Ras/MAP by enhancing internalization and degradation of the epidermal growth factor receptor. ARHI-mediated downregulation of PI3K/AKT and Ras/ERK signaling also decreases phosphorylation of FOXo3a, which sequesters this transcription factor in the nucleus. Nuclear retention of FOXo3a induces ATG4 and MAP-LC3-I, required for maturation of autophagosomes, and also increases the expression of Rab7, required for fusion of autophagosomes with lysosomes. Following the knockdown of FOXo3a or Rab7, autophagolysosome formation was observed but was markedly inhibited, resulting in numerous enlarged autophagosomes. ARHI expression correlates with LC3 expression and FOXo3a nuclear localization in surgical specimens of ovarian cancer. Thus, ARHI contributes to the induction of autophagy through multiple mechanisms in ovarian cancer cells. PMID- 24769730 TI - Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis. AB - Non-alcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte lipoapoptosis. This lipoapoptosis requires increased JNK phosphorylation and activation of the pro apoptotic BH3-only proteins Bim and PUMA. Kelch-like ECH-associated protein (Keap)-1 is a BTB/Kelch protein that can regulate the expression of Bcl-2 protein and control apoptotic cell death. Yet, the role of Keap1 in hepatocyte lipotoxicity is unclear. Here we demonstrate that Keap1 protein was rapidly degraded in hepatocytes, through autophagy in a p62-dependent manner, in response to the toxic saturated FFA palmitate, but not following incubation with the non toxic FFA oleic acid. Stable knockdown of Keap1 expression, using shRNA technology, in hepatocarcinoma cell lines induced spontaneous cell toxicity that was associated with JNK1-dependent upregulation of Bim and PUMA protein levels. Also, Keap1 knockdown further sensitized hepatocytes to lipoapoptosis by palmitate. Likewise, primary hepatocytes isolated from liver-specific Keap1(-/-) mice displayed higher Bim and PUMA protein levels and demonstrated increased sensitivity to palmitate-induced apoptosis than wild-type mouse hepatocytes. Finally, stable knockdown of Bim or PUMA expression prevented cell toxicity induced by loss of Keap1. These results implicate p62-dependent autophagic degradation of Keap1 by palmitate as a mechanism contributing to hepatocyte lipoapoptosis. PMID- 24769732 TI - Second EACR Conference on Cell Death in Cancer, Amsterdam, The Netherlands, 30 January-1 February 2014. PMID- 24769731 TI - Role of Ku70 in deubiquitination of Mcl-1 and suppression of apoptosis. AB - Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) cells or depletion from human lung cancer H1299 cells leads to the accumulation of polyubiquitinated Mcl-1 and a reduction in its half-life and protein expression. Conversely, expression of exogenous Ku70 in Ku70(-/-) MEF cells restores Mcl-1 expression. Subcellular fractionation indicates that Ku70 extensively colocalizes with Mcl-1 in mitochondria, endoplasmic reticulum and nucleus in H1299 cells. Ku70 directly interacts with Mcl-1 via its C terminus (that is, aa 536-609), which is required and sufficient for deubiquitination and stabilization of Mcl-1, leading to suppression of apoptosis. Purified Ku70 protein directly deubiquitinates Mcl-1 by removing K48-linked polyubiquitin chains. Ku70 knockdown not only promotes Mcl-1 turnover but also enhances antitumor efficacy of the BH3-mimetic ABT-737 in human lung cancer xenografts. These findings identify Ku70 as a novel Mcl-1 deubiquitinase that could be a potential target for cancer therapy by manipulating Mcl-1 deubiquitination. PMID- 24769733 TI - Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis. AB - Macrophages can be activated and regulated by high-mobility group box 1 (HMGB1), a highly conserved nuclear protein. Inflammatory functions of HMGB1 are mediated by binding to cell surface receptors, including the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, TLR4, and TLR9. Pyroptosis is a caspase-1-dependent programmed cell death, which features rapid plasma membrane rupture, DNA fragmentation, and release of proinflammatory intracellular contents. Pyroptosis can be triggered by various stimuli, however, the mechanism underlying pyroptosis remains unclear. In this study, we identify a novel pathway of HMGB1-induced macrophage pyroptosis. We demonstrate that HMGB1, acting through RAGE and dynamin-dependent signaling, initiates HMGB1endocytosis, which in turn induces cell pyroptosis. The endocytosis of HMGB1 triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. We further confirm that HMGB1-induced macrophage pyroptosis also occurs in vivo during endotoxemia, suggesting a pathophysiological significance for this form of pyroptosis in the development of inflammation. These findings shed light on the regulatory role of ligand-receptor internalization in directing cell fate, which may have an important role in the progress of inflammation following infection and injury. PMID- 24769734 TI - Dominant-negative function of the C-terminal fragments of NBR1 and SQSTM1 generated during enteroviral infection. AB - Coxsackievirus infection induces an abnormal accumulation of ubiquitin aggregates that are generally believed to be noxious to the cells and have a key role in viral pathogenesis. Selective autophagy mediated by autophagy adaptor proteins, including sequestosome 1 (SQSTM1/p62) and neighbor of BRCA1 gene 1 protein (NBR1), are an important pathway for disposing of misfolded/ubiquitin conjugates. We have recently demonstrated that SQSTM1 is cleaved after coxsackievirus infection, resulting in the disruption of SQSTM1 function in selective autophagy. NBR1 is a functional homolog of SQSTM1. In this study, we propose to test whether NBR1 can compensate for the compromise of SQSTM1 after viral infection. Of interest, we found that NBR1 was also cleaved after coxsackievirus infection. This cleavage took place at two sites mediated by virus-encoded protease 2A(pro) and 3C(pro), respectively. In addition to the loss-of-function, we further investigated whether cleavage of SQSTM1/NBR1 leads to the generation of toxic gain-of-function mutants. We showed that the C-terminal fragments of SQSTM1 and NBR1 exhibited a dominant-negative effect against native SQSTM1/NBR1, probably by competing for LC3 and ubiquitin chain binding. Finally, we demonstrated a positive, mutual regulatory relationship between SQSTM1 and NBR1 during viral infection. We showed that knockdown of SQSTM1 resulted in reduced expression of NBR1, whereas overexpression of SQSTM1 led to increased level of NBR1, and vice versa, further excluding the possible compensation of NBR1 for the loss of SQSTM1. Taken together, the findings in this study suggest a novel mechanism through which coxsackievirus infection induces increased accumulation of ubiquitin conjugates and subsequent viral damage. PMID- 24769736 TI - How Will "I" Versus "We" Perform? An Investigation of Future Outlooks and Self Construals. AB - Previous theory and research suggests that people generate predictions to prepare for an uncertain future, often basing predictions on task-relevant information like prior performance. Four studies test the hypothesis that preparation via prediction occurs more readily when interdependent (vs. independent) self construals are salient. This hypothesis was supported when examining chronic tendencies to generate negative predictions (Study 1) and spontaneous predictions in response to task-relevant information (Studies 2, 3, and 4), as well as when self-construals were measured (Studies 1, 2, and 4) and primed (Study 3). Moreover, performance prediction occurs in conjunction with increases in task persistence, but only for individuals with interdependent self-construals. Individuals with independent self-construals tend toward preparation via prediction only when preparation is urgent. Discussion centers on the applicability of within-cultural differences in self-construal on cross-cultural investigations, and implications for future research on predictive judgments. PMID- 24769735 TI - Can we identify non-stationary dynamics of trial-to-trial variability? AB - Identifying sources of the apparent variability in non-stationary scenarios is a fundamental problem in many biological data analysis settings. For instance, neurophysiological responses to the same task often vary from each repetition of the same experiment (trial) to the next. The origin and functional role of this observed variability is one of the fundamental questions in neuroscience. The nature of such trial-to-trial dynamics however remains largely elusive to current data analysis approaches. A range of strategies have been proposed in modalities such as electro-encephalography but gaining a fundamental insight into latent sources of trial-to-trial variability in neural recordings is still a major challenge. In this paper, we present a proof-of-concept study to the analysis of trial-to-trial variability dynamics founded on non-autonomous dynamical systems. At this initial stage, we evaluate the capacity of a simple statistic based on the behaviour of trajectories in classification settings, the trajectory coherence, in order to identify trial-to-trial dynamics. First, we derive the conditions leading to observable changes in datasets generated by a compact dynamical system (the Duffing equation). This canonical system plays the role of a ubiquitous model of non-stationary supervised classification problems. Second, we estimate the coherence of class-trajectories in empirically reconstructed space of system states. We show how this analysis can discern variations attributable to non-autonomous deterministic processes from stochastic fluctuations. The analyses are benchmarked using simulated and two different real datasets which have been shown to exhibit attractor dynamics. As an illustrative example, we focused on the analysis of the rat's frontal cortex ensemble dynamics during a decision-making task. Results suggest that, in line with recent hypotheses, rather than internal noise, it is the deterministic trend which most likely underlies the observed trial-to-trial variability. Thus, the empirical tool developed within this study potentially allows us to infer the source of variability in in-vivo neural recordings. PMID- 24769737 TI - Putting the Freeze on Priming: The Role of Need for Cognitive Closure on the Prime-Norm Dynamic. AB - Past research has indicated that individuals with a high need for cognitive closure (NFCC) are more susceptible to priming effects in norm-absent contexts. We proposed that in norm-present contexts, whereby normative information competes with priming in affecting individuals' understanding of the social environment, the opposite pattern would occur. In Study 1, low- rather than high-NFCC individuals showed greater prime-consistent behavior in a context with a strong norm to comply. In Study 2, when both priming and normative information were manipulated, priming dictated low-NFCC individuals' behaviors, whereas norms guided high-NFCC individuals' behavior. In Study 3, the effect of a single priming manipulation was observed in two consecutive contexts. While high-NFCC individuals, compared with low-NFCC ones, were less prime-consistent in the norm present context, they were more influenced by the same priming manipulation in the norm-absent context. Our findings underscore the importance of NFCC in people's selection of environmental cues to guide self-regulation. PMID- 24769738 TI - Prioritization of Potential Mates' History of Sexual Fidelity During a Conjoint Ranking Task. AB - This series of studies is the first to use conjoint analysis to examine how individuals make trade-offs during mate selection when provided information about a partner's history of sexual infidelity. Across three studies, participants ranked profiles of potential mates, with each profile varying across five attributes: financial stability, physical attractiveness, sexual fidelity, emotional investment, and similarity. They also rated each attribute separately for importance in an ideal mate. Overall, we found that for a long-term mate, participants prioritized a potential partner's history of sexual fidelity over other attributes when profiles were ranked conjointly. For a short-term mate, sexual fidelity, physical attractiveness, and financial stability were equally important, and each was more important than emotional investment and similarity. These patterns contrast with participants' self-reported importance ratings of each individual attribute. Our results are interpreted within the context of previous literature examining how making trade-offs affect mate selection. PMID- 24769739 TI - Social Interactions and Well-Being: The Surprising Power of Weak Ties. AB - Although we interact with a wide network of people on a daily basis, the social psychology literature has primarily focused on interactions with close friends and family. The present research tested whether subjective well-being is related not only to interactions with these strong ties but also to interactions with weak social ties (i.e., acquaintances). In Study 1, students experienced greater happiness and greater feelings of belonging on days when they interacted with more classmates than usual. Broadening the scope in Studies 2A and 2B to include all daily interactions (with both strong and weak ties), we again found that weak ties are related to social and emotional well-being. The current results highlight the power of weak ties, suggesting that even social interactions with the more peripheral members of our social networks contribute to our well-being. PMID- 24769740 TI - Diagnosis and prediction of neuroendocrine liver metastases: a protocol of six systematic reviews. PMID- 24769741 TI - Highly efficient conversion of biomass-derived glycolide to ethylene glycol over CuO in water. AB - The efficient conversion of biomass-derived glycolide into ethylene glycol over CuO in water was investigated. The reaction of glycolide was carried out with 25 mmol Zn and 6 mmol CuO with 25% water filling at 250 degrees C for 150 min, which yielded the desired ethylene glycol in 94% yield. PMID- 24769742 TI - Formation of hexagonal boron nitride nanoscrolls induced by inclusion and exclusion of self-assembling molecules in solution process. AB - Unlike nanoscrolls of 2D graphene, those of 2D h-BN have not been demonstrated, except for only a few experimental reports. Nanoscrolls of h-BN with high yields and reproducibility are first synthesized by a simple solution process. Inner tube diameters of BNSs including LCAs, N-(2-aminoethyl)-3alpha-hydroxy-5beta cholan-24-amide, a bile acid derivative and self-assembling material, can be controlled by adjusting the diameter of the LCA fiber which is grown by self assembly. TEM and SEM images show that BNSs have a tube-like morphology and the inner-tube diameter of BNSs can be controlled in the range from 20 to 60 nm for a smaller diameter, up to 300 nm for a larger diameter by LCA fiber growth inside the BNSs. Finally, open cylindrical BNSs with hollow cores were obtained by dissolving LCAs inside BNSs. PMID- 24769743 TI - Evolutionary biology redux. AB - This article offers a novel, enlightened concept for determining the mechanism of evolution. It is based on homeostasis, which distinguishes life from non-life and as such is the universal mechanism for the evolution of all living organisms. This view of evolution is logical, mechanistic, non-scalar, predictive, testable, and falsifiable, and it illuminates the epistemological relationships between physics and biology, ontogeny and phylogeny, development and aging, ultimate and proximate causation, health and disease. In addition to validating Haeckel's biogenetic law and Lamarckian epigenetics, reflecting the enabling value of the cellular approach, this perspective also expresses the evolutionary process at the cell-molecular level, since the mechanism of cell communication itself is universal in biology, in keeping with a Kuhnian paradigm shift. This approach may even elucidate the nature and evolution of consciousness as a manifestation of the cellular continuum from unicellular to multicellular life. We need such a functional genomic mechanism for the process of evolution if we are to make progress in biology and medicine. Like Copernican heliocentrism, a cellular approach to evolution may fundamentally change humankind's perceptions about our place in the universe. PMID- 24769744 TI - The role of genetic information in personalized medicine. AB - Personalized medicine is the latest promise of a gene-centered biomedicine to provide treatments custom-tailored to the specific needs of patients. Although surrounded by much hype, personalized medicine at present lacks the empirical and theoretical foundations necessary to render it a realistic long-term perspective. In particular, the role of genetic data and the relationship between causal understanding, prediction, prevention, and treatment of a disease need clarifying. This article critically examines the concept of information in genetics and its relation to modern-day genetic determinism, using pharmacogenetics, personalized medicine's core discipline, as a test case. The article concludes that: (1) genetic knowledge does not constitute a privileged basis for personalized medicine because there is an a priori complete causal parity of genetic and nongenetic resources of development; and (2) prediction, prevention, and treatment all depend on a causal-mechanistic understanding that will follow only from integrating data across the whole gamut of developmental factors-genetic and non-genetic. In a future successful personalized medicine, genes will have no special status, either as determinants of phenotype, markers of disease or as targets of treatment. PMID- 24769745 TI - When pigs could fly: influenza and the elusive nature of diagnosis. AB - Diagnosis plays an important role in how we understand disease, and how medicine confirms its status in contemporary society. However, diagnoses are far less concrete than their taxonomies suggest. This essay presents influenza as a case study in the elusive nature of the diagnosis, and in its complicated realities. Using the metaphor of boundary transgression, it reveals the fluidity of diagnosis and the paradoxes presented by the naturalization of diseases. In order to contain influenza, medicine commits other paradoxical transgressions of boundaries. Lay self-diagnosis, use of the lay expression "flu," and wide reliance upon the belief in the influenza-like syndrome are used to attempt to cement a concrete notion of influenza. PMID- 24769746 TI - Noninvasive prenatal testing for early sex identification: a few benefits and many concerns. AB - A new technology, noninvasive prenatal testing (NIPT), can identify fetal sex early in pregnancy, five weeks after conception, with a high degree of accuracy through analysis of maternal blood plasma. This article considers the possibility that NIPT will encourage greater sex selection in developed countries and discusses the implications. Sex selection raises serious social and ethical issues unless it is done for medical reasons. The article also assesses options to discourage sex-selective abortions, including the effectiveness of potential legal measures. PMID- 24769748 TI - Medical therapeutics: from induction to scientific evolution. AB - The field of medical therapeutics may be characterized as having suffered major scientific evolution in the last decades. The publication of landmark studies has been important enough to produce shifts in patient care. However, the scientific evolution in this field does not necessarily imply a progressively greater degree of certitude. In fact, it is not uncommon for new knowledge, when reflected in clinical practice, to weaken previous knowledge. In medical therapeutics, strict inductive reasoning implies the existence of empirical intervention data, typically clinical trial data. In many instances, however, such data does not exist-leaving room for a mixture of inductive and "pseudo-deductive" reasoning. It is often necessary to establish treatment on the basis of incomplete and inconclusive information, more so when the clinical situation is grave, but when no valid information exists, no treatment may be an option. In many instances, the rule "I wish not to impose on others" has superseded the concept "Do not impose on others what you yourself do not desire." PMID- 24769747 TI - The Stateville penitentiary malaria experiments: a case study in retrospective ethical assessment. AB - During World War II, malaria research was conducted in prisons. A notable example was the experiments at Stateville Penitentiary in Illinois, in which prisoner subjects were infected with malaria for the purpose of testing the safety and efficacy of novel anti-malaria drugs. Over time, commentators have shifted from viewing the malaria research at Stateville as a model of ethical clinical research to seeing the experiments as paradigmatic of abusive human experimentation. This essay undertakes a retrospective ethical assessment of the Stateville malaria research during the 1940s in light of basic ethical principles and the Nuremberg Code, as well as contemporary malaria research. In addition to its historical interest, this case study provides a rich context for addressing basic issues of research ethics, including the voluntariness of consent, the justification of risks, and the exploitation of vulnerable subjects. PMID- 24769749 TI - The medical ecoculture at work: the case of the metal-on-metal hip. AB - The United States has the most expensive, technologically intensive system of medical care in the world, but not the most effective. Reforming health care will require understanding the interactions among the many individuals and institutions that collectively constitute the health-care ecoculture, an ecosystem with a major human component. Because technology is a key driver of health-care costs and a critical component of the patient's experience of American medicine, it is fruitful to consider an example of a particular technology: why it was embraced, who benefited from its use, and the response of the ecoculture when a critical flaw in the technology emerged. The case of the introduction, diffusion, and withdrawal of metal-on-metal hip prostheses will be discussed from the perspective of patients, physicians, device manufacturers, regulators, and the legal system. Each of these groups responded to external stimuli by adaptation in an attempt to maximize its own interests. Interactions between the groups served as a further mechanism of maintaining the status quo within medicine. A single change, such as modification of the payment system or incentivizing patients, is thus unlikely to be effective in transforming health care; instead, a multi-pronged approach, along with reforms outside medicine, will likely be necessary. PMID- 24769750 TI - The hitchhiker's guide to global health blogging. AB - Social media use in modern medicine is fraught with ethical dilemmas and risks of unprofessional behavior. This essay surveys the existing literature on the possibilities and pitfalls of social media use by health-care professionals and concludes that non-engagement with social media is not an option. A mindful approach, not vague guidelines or long checklists, will foster a generation of physicians comfortable using online platforms for education and reflection. The use of social media during global health experiences abroad has been largely ignored in the literature and presents special challenges. With a view to starting a reflective dialogue on this subject, this essay identifies some ethically nebulous aspects of global health blogging. The discussion focuses on physician and student blogging, but these principles should apply to other online platforms as well and should prove valuable for health-care professionals who are engaged in developing guidelines, educating medical students and resident physicians, or in sharing their experiences and insights on the internet. PMID- 24769751 TI - Against narrative medicine. AB - This essay aims to provoke debate on how and what the medical humanities should teach. It argues that the field has been dominated (to its detriment) by two misguided movements, postmodernism and narrative medicine, and that it should be redirected from utilitarian aims towards the goal of exposing medical students to a climate of thought and reflection. PMID- 24769752 TI - Super-resolution microscopy of mitochondria. AB - Mitochondria, the powerhouses of the cell, are essential organelles in eukaryotic cells. With their complex inner architecture featuring a smooth outer and a highly convoluted inner membrane, they are challenging objects for microscopy. The diameter of mitochondria is generally close to the resolution limit of conventional light microscopy, rendering diffraction-unlimited super-resolution light microscopy (nanoscopy) for imaging submitochondrial protein distributions often mandatory. In this review, we discuss what can be expected when imaging mitochondria with conventional diffraction-limited and diffraction-unlimited microscopy. We provide an overview on recent studies using super-resolution microscopy to investigate mitochondria and discuss further developments and challenges in mitochondrial biology that might by addressed with these technologies in the future. PMID- 24769753 TI - Mitochondrial genome rearrangements in the scleractinia/corallimorpharia complex: implications for coral phylogeny. AB - Corallimorpharia is a small Order of skeleton-less animals that is closely related to the reef-building corals (Scleractinia) and of fundamental interest in the context of understanding the potential impacts of climate change in the future on coral reefs. The relationship between the nominal Orders Corallimorpharia and Scleractinia is controversial-the former is either the closest outgroup to the Scleractinia or alternatively is derived from corals via skeleton loss. This latter scenario, the "naked coral" hypothesis, is strongly supported by analyses based on mitochondrial (mt) protein sequences, whereas the former is equally strongly supported by analyses of mt nucleotide sequences. The "naked coral" hypothesis seeks to link skeleton loss in the putative ancestor of corallimorpharians with a period of elevated oceanic CO2 during the Cretaceous, leading to the idea that these skeleton-less animals may be harbingers for the fate of coral reefs under global climate change. In an attempt to better understand their evolutionary relationships, we examined mt genome organization in a representative range (12 species, representing 3 of the 4 extant families) of corallimorpharians and compared these patterns with other Hexacorallia. The most surprising finding was that mt genome organization in Corallimorphus profundus, a deep-water species that is the most scleractinian-like of all corallimorpharians on the basis of morphology, was much more similar to the common scleractinian pattern than to those of other corallimorpharians. This finding is consistent with the idea that C. profundus represents a key position in the coral <-> corallimorpharian transition. PMID- 24769754 TI - Primary malignancy in patients with nonmelanoma skin cancer-letter. PMID- 24769755 TI - Primary malignancy in patients with nonmelanoma skin cancer-response. PMID- 24769756 TI - Metastasis: understanding the prowess of mutant p53. PMID- 24769757 TI - Signalling: Inhibiting oncogenic BRAF signalling by copper depletion. PMID- 24769759 TI - BVA calls for 'significant changes' to pilot badger culls. PMID- 24769763 TI - Eli Lilly agrees to acquire Novartis Animal Health. PMID- 24769758 TI - The effect of inhibition of host MreB on the infection of thermophilic phage GVE2 in high temperature environment. AB - In eukaryotes, the manipulation of the host actin cytoskeleton is a necessary strategy for viral pathogens to invade host cells. Increasing evidence indicates that the actin homolog MreB of bacteria plays key roles in cell shape formation, cell polarity, cell wall biosynthesis, and chromosome segregation. However, the role of bacterial MreB in the bacteriophage infection is not extensively investigated. To address this issue, in this study, the MreB of thermophilic Geobacillus sp. E263 from a deep-sea hydrothermal field was characterized by inhibiting the MreB polymerization and subsequently evaluating the bacteriophage GVE2 infection. The results showed that the host MreB played important roles in the bacteriophage infection at high temperature. After the host cells were treated with small molecule drug A22 or MP265, the specific inhibitors of MreB polymerization, the adsorption of GVE2 and the replication of GVE2 genome were significantly repressed. The confocal microscopy data revealed that MreB facilitated the GVE2 infection by inducing the polar distribution of virions during the phage infection. Our study contributed novel information to understand the molecular events of the host in response to bacteriophage challenge and extended our knowledge about the host-virus interaction in deep-sea vent ecosystems. PMID- 24769764 TI - Prepubertal neutering key to tackling 'cat crisis', says RSPCA. PMID- 24769767 TI - VMD launches adverse events monitoring scheme for microchips. PMID- 24769768 TI - Shared ancestry: using embryology to discover human evolution. AB - This year's BSAVA lecture was given by Alice Roberts, a clinical anatomist and professor of public engagement in science at the University of Birmingham. Her talk focused around human beings as 'just another animal', and how a shared ancestry between humans and other animals can be shown through embryological development. Georgina Mills reports. PMID- 24769769 TI - The BSAVA presents its awards. AB - Inspiring work and exceptional contributions to veterinary medicine, surgery and practice were recognised at this year's BSAVA awards ceremony, held on April 3 as part of the association's congress in Birmingham. PMID- 24769770 TI - The Commonwealth Veterinary Association--what does it do? AB - Many UK vets may be aware that there is a Commonwealth Veterinary Association (CVA), but they may not be quite so sure about what it does. Karen Reed, the current CVA secretary, explains more. PMID- 24769771 TI - Scoring pododermatitis in pet rabbits. PMID- 24769772 TI - Removal of postnominals from the RCVS Register. PMID- 24769773 TI - Mycobacterial infections and vole bacillus vaccines. PMID- 24769775 TI - Cu(I)-mediated (18)F-trifluoromethylation of arenes: rapid synthesis of (18)F labeled trifluoromethyl arenes. AB - This report is concerned with an efficient, Cu(I)-mediated method for the radiosynthesis of [(18)F]trifluoromethyl arenes, abundant motifs in small molecule drug candidates and potential radiotracers for positron emission tomography. Three (18)F-labelled radiotracer candidates were synthesised from [(18)F]fluoride ions as proof of principle. The new protocol is widely applicable for the synthesis of novel radiotracers in high radiochemical yields. PMID- 24769774 TI - Responses of the metabolism of the larvae of Pocillopora damicornis to ocean acidification and warming. AB - Ocean acidification and warming are expected to threaten the persistence of tropical coral reef ecosystems. As coral reefs face multiple stressors, the distribution and abundance of corals will depend on the successful dispersal and settlement of coral larvae under changing environmental conditions. To explore this scenario, we used metabolic rate, at holobiont and molecular levels, as an index for assessing the physiological plasticity of Pocillopora damicornis larvae from this site to conditions of ocean acidity and warming. Larvae were incubated for 6 hours in seawater containing combinations of CO2 concentration (450 and 950 uatm) and temperature (28 and 30 degrees C). Rates of larval oxygen consumption were higher at elevated temperatures. In contrast, high CO2 levels elicited depressed metabolic rates, especially for larvae released later in the spawning period. Rates of citrate synthase, a rate-limiting enzyme in aerobic metabolism, suggested a biochemical limit for increasing oxidative capacity in coral larvae in a warming, acidifying ocean. Biological responses were also compared between larvae released from adult colonies on the same day (cohorts). The metabolic physiology of Pocillopora damicornis larvae varied significantly by day of release. Additionally, we used environmental data collected on a reef in Moorea, French Polynesia to provide information about what adult corals and larvae may currently experience in the field. An autonomous pH sensor provided a continuous time series of pH on the natal fringing reef. In February/March, 2011, pH values averaged 8.075 +/- 0.023. Our results suggest that without adaptation or acclimatization, only a portion of naive Pocillopora damicornis larvae may have suitable metabolic phenotypes for maintaining function and fitness in an end-of the century ocean. PMID- 24769776 TI - Radiological results of modified Dega osteotomy in Tonnis grade 3 and 4 developmental dysplasia of the hip. AB - Dega acetabuloplasty at the time of open reduction is effective in improving the acetabular coverage of the femoral head, hence improving the stability of reduction and preventing possible surgery in the future for residual acetabular dysplasia in older children with Tonnis grade 3 and 4 developmental dysplasia of the hip (DDH). The aim of this study was to assess the radiological results of open reduction combined with Dega osteotomy in DDH. Twenty-two children's 26 hips were operated on at a mean age of 38+/-20.4 SD months and followed up for an average of 42 (range 24-108) months. Thirteen hips (50%) were operated on with concomitant open reduction and capsulorrhaphy, and 13 hips (50%) were treated with concomitant open reduction, capsulorrhaphy and femoral shortening osteotomy. Radiological examination included acetabular index (AI) and centre edge angle measurements. The mean preoperative AI was 39.4+/-6.9 degrees SD, which improved to 18.3+/-4.5 degrees SD postoperatively, and AI was measured as 15+/-3.5 degrees SD at the latest follow-up. There was a significant difference in the mean AI values between the last follow-up and the preoperative measurements (P<0.05). The mean centre edge angle was 31+/-5.6 degrees SD postoperatively, and it was 31+/-6.2 degrees SD at follow-up. There was no significant difference between the two values. Two hips were noted to have lateralization of the femoral head due to coxa valga anteverta. One of them was operated with a femoral varus osteotomy. The Dega osteotomy combined with anterior open reduction and femoral osteotomies is a safe and effective acetabular osteotomy for surgical treatment of severe DDH such as Tonnis grade 3 and 4 dislocations. PMID- 24769777 TI - Unusual presentation of a type 1 Monteggia equivalent lesion: simultaneous medial humeral condyle fracture with ipsilateral anterior dislocation of the radial head and acute plastic bowing of the ulna. AB - The authors describe a case of simultaneous anterior dislocation of the radial head with plastic deformation of the ulna and an ipsilateral medial humeral condyle fracture in a 6-year-old boy after a fall on an outstretched hand. This rare combination of injuries has not been described previously in the literature. Closed reduction of the dislocated radial head and percutaneous K-wire fixation of the medial humeral condyle fracture achieved an excellent result with full function. This rare combination of injuries is considered to be an unusual subtype of the Bado type I Monteggia equivalent lesion. The case emphasizes that when a fracture is detected around an elbow, other injuries in the region should be suspected. PMID- 24769778 TI - Comment on the article 'The biomechanics of guided growth: does screw size, plate size, or screw configuration matter?' by Schoenleber et al. PMID- 24769779 TI - Effectively identifying the inpatient with hyperglycemia to increase patient care and lower costs. AB - Recent years have seen an increased focus on merging quality care and financial results. This focus not only extends to the inpatient setting but also is of major importance in assuring effective transitions of care from hospital to home. Inducements to meld the 2 factors include tying payment to quality standards, investing in patient safety, and offering new incentives for providers who deliver high-quality and coordinated care. Once seen as the purview of primary care or specific surgical screening programs, identification of patients with hyperglycemia or undiagnosed diabetes mellitus now presents providers with opportunities to improve care. Part of the new focus will need to address the length of stay for patients with diabetes mellitus. These patients are proven to require longer hospital stays regardless of the admission diagnosis. With reducing length of stay as a major objective, efficiency combined with improved quality is the desired outcome. Even with the mounting evidence supporting the benefits of improving glycemic control in the hospital setting, institutions continue to struggle with inpatient glycemic control. Multiple national groups have provided recommendations for blood glucose assessment and glycated hemoglobin testing. This article identifies the key benefits in identifying patients with hyperglycemia and reviews possible ways to identify, monitor, and treat this potential problem area and thereby increase the level of patient care and cost-effectiveness. PMID- 24769780 TI - Should guidelines for glycemic control of the critically ill be individualized?: Weighing the evidence from randomized and observational investigations. AB - The monitoring of blood glucose and treatment of hyperglycemia has been a standard of care in intensive care units since the publication of a single-center randomized controlled trial (RCT) of intensive insulin therapy in 2001 that demonstrated marked improvements in mortality. Professional societies created guidelines based on the results of this investigation, and revised them based on the results of a very small group of RCTs that followed. This commentary reviews the weight of evidence provided by the RCTs in comparison to the large body of evidence from observational studies regarding glycemic control of the critically ill, and suggests that the totality of evidence should be considered in the formulation of clinical practice paradigms. PMID- 24769781 TI - Insulin requirements in non-critically ill hospitalized patients with diabetes and steroid-induced hyperglycemia. AB - OBJECTIVE: Steroid-induced hyperglycemia is common in hospitalized patients with diabetes mellitus. Guidelines for glucose management in this setting are lacking. METHODS: We conducted a retrospective chart review of non-critically ill patients with diabetes receiving steroids, hospitalized from January 2009 to October 2012. Fifty-eight patients were identified from 247 consults. Multivariable linear regression was used to assess median daily insulin requirements of normoglycemic patients compared with hyperglycemic patients. RESULTS: Of the 58 total patients included in our study, 20 achieved normoglycemia during admission (patient-day weighted mean blood glucose [PDWMBG] level = 154 +/- 16 mg/dL) and 38 remained hyperglycemic (PDWMBG level = 243 +/- 39 mg/dL; P < 0.001). There were no differences between the 2 patient groups in age, sex, race, body weight, renal function, HbA1c level, glucose-altering medications, diabetes type, or disease duration. Following multivariable adjustment, compared with hyperglycemic patients, normoglycemic patients required similar units of basal insulin (median interquartile range [IQR])(23.6 [17.9, 31.2] vs 20.1 [16.5, 24.4]; P = 0.35); higher units of nutritional insulin (45.5 [34.2, 60.4] vs 20.1 [16.4, 24.5]; P < 0.001]; and lower units of correctional insulin (5.8 [4.1, 8.1] vs 13.0 [10.2, 16.5]; P < 0.001]). Patients achieving normoglycemia required a significantly lower percentage of correction insulin (total daily dose [TDD]: 7.4% vs 23.4%; P < 0.001) and a higher percentage of nutritional insulin (TDD: 58.1% vs 36.2%; P <0.001) than hyperglycemic patients. There was no difference in the TDD per kilogram, TDD per milligram hydrocortisone dose, or TDD per milligram hydrocortisone dose per kilogram weight between the 2 groups. CONCLUSION: The data suggest that non-critically ill patients with hyperglycemia receiving steroids require a higher percentage of TDD insulin therapy as nutritional insulin to achieve normoglycemia. PMID- 24769782 TI - Effect of continuous positive airway pressure on type 2 diabetes mellitus and glucose metabolism. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a prevalent condition that is associated with significant comorbidities, including obesity, hypertension, cardiovascular disease, and insulin resistance. Continuous positive airway pressure (CPAP) is an effective treatment for OSA. The effect of CPAP on glucose metabolism in patients with OSA has been controversial. This study evaluates the impact of CPAP on patients with OSA and type 2 diabetes mellitus (T2DM) or prediabetes. MATERIALS AND METHODS: PubMed, Ovid Medline, and EMBASE were searched for original English language studies performed on or after 2003. Subjects were aged > 18 years, were diagnosed with OSA via polysomnography, and had either T2DM or prediabetes according to laboratory evaluation. RESULTS: Of the 22 articles that met the selection criteria, 17 studies (77%) showed that a prolonged use of CPAP produced significant changes in glucose metabolism of patients who had T2DM and prediabetes. These changes were observed in studies measuring glycosylated hemoglobin (HbA1c), postprandial or nocturnal glucose, and insulin sensitivity or resistance. Of the 17 studies, 4 showed improvement in HbA1c levels or increased insulin sensitivity only after long-term use of CPAP for >= 3 months. CONCLUSION: This literature review shows that CPAP improves not only hypoxia while restoring normal breathing during sleep, but also glucose metabolism in patients with OSA and T2DM or prediabetes. A few studies have shown that patients can experience even better results with long-term CPAP treatment (>= 3 months of daily use) for > 4 hours a night. Therefore, this improvement in glucose metabolism with the use of CPAP may contribute to T2DM prevention and decrease further progression of the disease. However, additional studies are needed to confirm these findings. PMID- 24769783 TI - Time and labor costs associated with administration of intravenous bisphosphonates for breast or prostate cancer patients with metastatic bone disease: a time and motion study. AB - OBJECTIVES: To estimate, using a time and motion method, the time and labor costs associated with the administration of zoledronic acid and pamidronate in cancer patients with metastatic bone diseases. METHODS: During clinic visits for participating patients receiving intravenous zoledronic acid or pamidronate, all times and activities associated with the administration of bisphosphonates were recorded by a trained observer using a stopwatch and data recording forms. The total time associated with the administration of bisphosphonates was estimated and converted to labor costs by applying corresponding health care professional hourly wage rates plus the fringe-benefit rate. The costs were presented in 2011 Canadian dollars. RESULTS: A convenience sample of 37 patients from 2 hospital outpatient oncology clinics in Ontario and Quebec participated in the study. Nineteen patients were diagnosed with breast cancer and 18 with prostate cancer. The average patient age was 66 years, and patients had been diagnosed with cancer and metastatic bone disease for 8 years and 3 years, respectively. The times and costs associated with the administration of bisphosphonates for the 28 patients who did not receive concurrent chemotherapy during the scheduled clinic visits are also reported. The mean infusion time for patients receiving zoledronic acid was 20.6 minutes. With the use of ambulatory infusion devices, the mean infusion time of pamidronate was 23 minutes (limited to observations of patients who were seated during administration). In contrast, the mean infusion time using regular infusion devices was 162 minutes. The mean labor cost for administering zoledronic acid was $20. The mean labor cost for administering pamidronate was $10 using ambulatory infusion devices and $68 using regular infusion devices. CONCLUSION: The time burden to cancer patients with metastatic bone disease who receive intravenous bisphosphonates and the costs to the health care system are substantial, especially when regular infusion devices are used. PMID- 24769784 TI - Estimation of cardiac risk before noncardiac surgery: the evolution of cardiac risk indices. AB - Postoperative cardiac complications are among the most feared events in patients undergoing noncardiac surgery. Hospitalists, internists, cardiologists, and anesthesiologists are frequently asked to provide preoperative consultations to assess risk and optimize medical treatment for the patient. Over the years, numerous studies have attempted to define preoperative risk factors in an attempt to risk stratify patients and determine when interventions may be applied to reduce risk. These studies have proposed various risk indices and algorithms based on identification of different risk factors, related to variations in patient populations, types of surgery, definitions of comorbidities, and endpoints studied. This article reviews many of these risk indices, highlighting their findings, utilities, and limitations. PMID- 24769785 TI - Readmissions after hospital discharge with acute exacerbation of COPD: are we missing something? AB - Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is an important part of the disease's morbidity, mortality, and progression, and is associated with increasing utilization of health care resources. The concept of integrated care based on a chronic care model is relatively new to chronic obstructive pulmonary disease, but has proved successful in improving clinical outcomes and probably in decreasing health care utilization in other chronic conditions. A comprehensive approach is needed to target a change in behavioral patterns in patients, increase physician's awareness and adherence to evidence based recommendations, and address system related issues. This article discusses the evidence for various facets of nonpharmacological management of AECOPD and proposes a model of care that might be the missing link for reducing hospital readmissions for AECOPD. This model may decrease the morbidity, slow disease progression, and curb the increasing health care resource utilization without compromising patient care. PMID- 24769786 TI - Hospitalist management of vaso-occlusive pain crisis in patients with sickle cell disease using a pathway of care. AB - BACKGROUND: Patients with sickle cell disease (SCD) suffer from intermittent vaso occlusive pain crises (VOCs). These crises lead to frequent hospitalizations, significant morbidity, and increased mortality risk. Care pathways can enhance efficiency and quality of care. Our study sought to evaluate the development and implementation of a care pathway for patients with SCD experiencing VOCs. METHODS: The University of North Carolina (UNC) Comprehensive Sickle Cell Program provides all levels of care for a large population of patients with sickle cell anemia. All patients admitted to UNC Hospitals with SCD VOCs from January 2009 through June 2011 were evaluated. During this time period, we also assessed sequential prospective cohorts during progressive phases of developing and implementing a quality improvement and pathway of care program for this patient population in our study. The developed pathway entailed geographic localization for VOC patients, a single group of faculty physicians caring for these patients, and early use of patient-controlled analgesia (PCA) to achieve pain control. Physicians from the UNC Hospital Medicine Program were responsible for the initiatives. Cohorts were compared to a baseline historical control. Outcomes of interest included patient length of stay (LOS) in the hospital, 30-day readmission rate, need for transfusion, incidence of acute chest syndrome, use of naloxone, and use of PCA. RESULTS: Compared with an historical baseline cohort, the development and implementation of a VOC care pathway for patients with SCD led to reduction in average hospital LOS by 1.44 days (P < 0.05) and an increase in use of PCAs (P < 0.05). Patient readmission rates, number of transfusions, incidence of acute chest syndrome, and use of naloxone did not significantly change. CONCLUSIONS: Hospitalist-led management of patients with SCD VOCs using a care pathway that emphasizes early, aggressive PCA-based pain control is associated with reduced hospital LOS. The LOS reduction seen in our study is clinically meaningful. Notably, other measures of patient outcomes and quality of care metrics did not change significantly, and some trended towards improvement. PMID- 24769787 TI - Factors associated with therapeutic goal attainment in patients with concomitant hypertension and dyslipidemia. AB - BACKGROUND: Hypertension and dyslipidemia are the most prevalent cardiovascular risk factors, with approximately 30 million patients in the United States having these concomitant conditions. Further, the presence of high body mass index (BMI) has a negative effect on the achievement of blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) targets. OBJECTIVE: This study evaluates the demographic, diagnostic, and medication-related factors associated with BP and LDL-C goal attainment in patients with concomitant hypertension and dyslipidemia stratified by BMI. METHODS: This retrospective study utilized the GE Centricity Electronic Medical Records database (2004-2011) of a primary care physician group. Patients aged >= 18 years with concomitant hypertension and dyslipidemia were included. The attainment of BP and LDL-C targets were assessed based on Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines. Patients were classified into 3 cohorts based on their BMI: normal weight (<= 24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (>= 30.0 kg/m2). Multivariate logistic regression analysis was conducted to identify the predictors of goal attainment. RESULTS: A total of 9086 patients with concomitant hypertension and dyslipidemia were identified, of which 7723, 6724, and 5824 patients did not attain BP, LDL-C, and dual BP and LDL-C goals, respectively. Age was a significant predictor of BP and LDL-C goal attainment in those who were of normal weight or overweight, and obese women had a decreased likelihood of achieving these goals (P < 0.05). Failure to attain BP and LDL-C goals was more likely in patients with diabetes across all BMI groups (P < 0.001). Further, patients with stage 1 hypertension and higher baseline total cholesterol levels were less successful in attaining BP and LDL-C goals, respectively (P < 0.001). CONCLUSIONS: These variations in therapeutic goal attainment in patients with concomitant hypertension and dyslipidemia across different BMI groups suggest that future research is needed to determine the underlying reasons for these disparities. PMID- 24769788 TI - Bone health care for patients with prostate cancer receiving androgen deprivation therapy. AB - Patients with prostate cancer often receive androgen deprivation therapy (ADT) as part of their treatment regimen. However, treatment with ADT causes multiple side effects, including reduced bone mineral density (BMD), lower lean body mass, and a higher risk for fractures. Several organizations provide clinical practice guidelines for osteoporosis screening, prevention, and treatment in this population, but adherence to these guidelines remains low. Areas for improvement in provider adherence include baseline and follow-up BMD testing, as well as counseling regarding healthy bone behaviors such as calcium/vitamin D intake, lifestyle changes, and physical exercise. Comparison of osteoporosis care in breast cancer and non-oncology populations shows that suboptimal bone health care is not isolated to prostate cancer. A summary of the literature examining improvements in patient adherence and provider delivery of bone health care is included in this review, but high-quality studies are lacking. Patients may be the most receptive to written educational information delivered at or near the time of ADT initiation. Involvement of a primary care practitioner and oncologist in care delivery is associated with higher BMD test use. Institution-level programs that automatically initiate osteoporosis screening and management may be effective at reducing the incidence of hip fracture. Lastly, suggestions are provided for future approaches to knowledge translation and quality of care studies to improve bone health. PMID- 24769789 TI - Screening for prostate cancer: are digital rectal examinations being performed? AB - OBJECTIVE: Prostate cancer is common and prostate cancer screening is controversial; this retrospective observational study was conducted to determine the prevalence of digital rectal examination (DRE) in those in whom a prostate specific antigen (PSA) test was performed. METHODS: A manual review was performed of the electronic medical record for male veterans in the VA Connecticut Healthcare System without a history of known prostate cancer aged between 50 and 74 years who underwent PSA testing. MAIN OUTCOMES: Documentation of DRE (or refusal) within 12 months before or after the performance of a PSA test. RESULTS: Less than half (47.6%) of patients underwent DRE. An additional 6.9% were offered DRE and refused. Although the provider gender was not associated with DRE, resident physicians were less likely to perform DRE than nonresidents; P = 0.01. Patients whose PSA was > 4.0 ng/mL were more likely to undergo DRE than those whose PSA was <= 4.0 ng/mL; P = 0.002. Those with body mass index (BMI) > 40 kg/m 2 were less likely to undergo DRE than those with BMI < 30 kg/m 2 ; P = 0.04. CONCLUSIONS: Screening for prostate cancer remains controversial. We found a low rate of DRE among veterans in whom prostate cancer screening was entertained. Although the provider gender does not seem to influence DRE, resident physicians were less likely to perform DRE than other providers. Our finding that BMI > 40 kg/m 2 is associated with a lower rate of DRE than those with BMI < 30 kg/m 2 is consistent with screening for other cancers and should be explored further. PMID- 24769790 TI - Clinical focus: infections in pregnancy. AB - Pregnant women are particularly susceptible to a number of infectious diseases, such as influenza, hepatitis E, malaria, and tuberculosis. The management of many other infections-including urinary tract infections, human immunodeficiency virus, and sexually transmitted diseases-is also made more complex by pregnancy; even if some infections do not pose a great risk to the expectant mother, they can impact fetal and neonatal development, thus posing a treatment challenge to physicians. By focusing on the most important diseases that physicians may encounter in pregnant patients, this review outlines the challenges associated with managing important infectious diseases in the pregnant population and references the most recent evidence and international treatment guidelines. PMID- 24769791 TI - The information theoretic perspective on medical diagnostic inference. AB - The goal of this work is to present information theory, specifically Claude Shannon's mathematical theory of communication, in a clinical context and elucidate its potential contributions to understanding the process of diagnostic inference. We use probability theory, information theory, and clinical examples to develop information theory as a means to examine uncertainty in diagnostic testing situations. We begin our discussion with a brief review of probability theory as it relates to diagnostic testing. An outline of Shannon's theory of communication theory and how it directly translates to the medical diagnostic process serves as the essential justification for this article. Finally, we introduce the mathematical tools of information theory that allow for an understanding of diagnostic uncertainty and test effectiveness in a variety of contexts. We show that information theory provides a quantitative framework for understanding uncertainty that readily extends to medical diagnostic contexts. PMID- 24769792 TI - The not so independent tobacco experts. PMID- 24769794 TI - Intestinal-mucosa anti-transglutaminase antibody assays to test for genetic gluten intolerance. PMID- 24769793 TI - TLR2 and TLR4 signaling pathways are required for recombinant Brucella abortus BCSP31-induced cytokine production, functional upregulation of mouse macrophages, and the Th1 immune response in vivo and in vitro. AB - Brucella abortus is a zoonotic Gram-negative pathogen that causes brucelosis in ruminants and humans. Toll-like receptors (TLRs) recognize Brucella abortus and initiate antigen-presenting cell activities that affect both innate and adaptive immunity. In this study, we focused on recombinant Brucella cell-surface protein 31 (rBCSP31) to determine its effects on mouse macrophages. Our results demonstrated that rBCSP31 induced TNF-alpha, IL-6 and IL-12p40 production, which depended on the activation of mitogen-activated protein kinases (MAPKs) by stimulating the rapid phosphorylation of p38 and JNK and the activation of transcription factor NF-kappaB in macrophages. In addition, continuous exposure (>24 h) of RAW264.7 cells to rBCSP31 significantly enhanced IFN-gamma-induced expression of MHC-II and the ability to present rBCSP31 peptide to CD4(+) T cells. Furthermore, we found that rBCSP31 could interact with both TLR2 and TLR4. The rBCSP31-induced cytokine production by macrophages from TLR2(-/-) and TLR4(-/ ) mice was lower than that from C57BL/6 macrophages, and the activation of NF kappaB and MAPKs was attenuated in macrophages from TLR2(-/-) and TLR4(-/-) mice. In addition, CD4(+) T cells from C57BL/6 mice immunized with rBCSP31 produced higher levels of IFN-gamma and IL-2 compared with CD4(+) T cells from TLR2(-/-) and TLR4(-/-) mice. Macrophages from immunized C57BL/6 mice produced higher levels of IL-12p40 than those from TLR2(-/-) and TLR4(-/-) mice. Furthermore, immunization with rBCSP31 provided better protection in C57BL/6 mice than in TLR2(-/-) and TLR4(-/-) mice after B. abortus 2308 challenge. These results indicate that rBCSP31 is a TLR2 and TLR4 agonist that induces cytokine production, upregulates macrophage function and induces the Th1 immune response. PMID- 24769795 TI - Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling. AB - The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8(+) T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling. PMID- 24769796 TI - Linker-determined drug release mechanism of free camptothecin from self assembling drug amphiphiles. AB - We report here that the release mechanism of free camptothecin from self assembling drug amphiphiles can be regulated by use of different linker groups. Our results highlight the significance of the linker group of drug amphiphiles on the drug release efficiency and their consequent in vitro efficacy. PMID- 24769798 TI - Decision-Making Under Risk: Integrating Perspectives From Biology, Economics, and Psychology. AB - Decision-making under risk has been variably characterized and examined in many different disciplines. However, interdisciplinary integration has not been forthcoming. Classic theories of decision-making have not been amply revised in light of greater empirical data on actual patterns of decision-making behavior. Furthermore, the meta-theoretical framework of evolution by natural selection has been largely ignored in theories of decision-making under risk in the human behavioral sciences. In this review, I critically examine four of the most influential theories of decision-making from economics, psychology, and biology: expected utility theory, prospect theory, risk-sensitivity theory, and heuristic approaches. I focus especially on risk-sensitivity theory, which offers a framework for understanding decision-making under risk that explicitly involves evolutionary considerations. I also review robust empirical evidence for individual differences and environmental/situational factors that predict actual risky decision-making that any general theory must account for. Finally, I offer steps toward integrating various theoretical perspectives and empirical findings on risky decision-making. PMID- 24769797 TI - Total synthesis of an anticancer norsesquiterpene alkaloid isolated from the fungus Flammulina velutipes. AB - The first total synthesis of a norsesquiterpene alkaloid (R)-8-hydroxy-4,7,7 trimethyl-7,8-dihydrocyclopenta[e]isoindole-1,3(2H,6H)-dione, isolated from the mushroom-forming fungus Flammulina velutipes, in both racemic and enantiomeric pure forms, is reported. The (-)-enantiomer of the natural product has been synthesized from the D-(-)-pantolactone chiral pool. The synthesis features a one pot, three-step reaction sequence comprising an enyne RCM/Diels Alder/aromatization to construct the desired indane skeleton present in the natural product. Our synthesis further confirms the assigned structure and absolute configuration of the natural product. PMID- 24769799 TI - Protective role of sodium para-amino salicylic acid against manganese-induced hippocampal neurons damage. AB - Manganese (Mn) is an essential trace element of human. However, excessive Mn can cause manganism. Mn selectively accumulated in Mn-exposed workers' hippocampus which is crucial for higher brain functions such as learning, memory, and motivation during our postnatal life. Studies suggested sodium para aminosalicylic acid (PAS) appeared to be therapeutic for manganism. We aimed to explore whether PAS could block Mn-induced neuronal injury in hippocampus in vitro. Hippocampal neurons were exposed to 50 MUM manganese chloride (MnCl(2)) for 24 h, following by 50, 500, or 5000 MUM PAS treatment for 24 h. Cell viability, apoptosis rate, mean fluorescence intensity of mitochondrial and DNA damage were respectively performed. MnCl(2) significantly decreased neurons' viability and fluorescence intensity of comet head of DNA, while increasing the apoptosis rate, mean fluorescence intensity of mitochondrial, percentage of tail DNA, and Olive tail moment of DNA. PAS reduced the percentage of tail DNA and Olive tail moment of Mn-exposed neurons. These data suggested that Mn caused hippocampal neurons' injury, and 50-5000 MUM PAS could inhibit Mn-induced DNA damage. PMID- 24769801 TI - The Fielding H. Garrison lecture: the aesthetic grounding of modern medicine. AB - This article focuses on visual choices that American physicians made in representing their profession, their work, and themselves during the decades when modern medical culture was set in place, the 1880s through the 1940s. Historians have emphasized the role that image played in the formation of modern medicine, but the visual images they have explored in connection to this process have tended to take a reductionist aesthetic identified with experimental laboratory science as emblematic of medical modernity. Explored here instead are several counterexamples-genres of self-representation in which medical students and physicians did not seek to link their identity with the laboratory and in some ways distanced themselves from the image and ideals of experimental science. The cultivation of these images invites us to see the cultural grounding of modern medicine as vastly more complex than a story scripted around the biomedical embrace of a stripped down, reductionist aesthetic. PMID- 24769800 TI - Specific changes of serum proteins in Parkinson's disease patients. AB - The aim of this study is to identify and validate protein change in the serum from PD patients. We used serum samples from 21 PD patients and 20 age-matched normal people as control to conduct a comparative proteomic study. We performed 2 DE and analyzed the differentially expressed protein spots by LC-MS/MS. In PD group 13 spots were shown to be differentially expressed compared to control group. They were identified as 6 proteins. Among these, 3 proteins were confirmed by Western blot analysis. It showed that the frequency of fibrinogen gamma-chain (FGG) appeared 70% in PD, which could not be detected in control group. The protein of inter-alpha-trypsin inhibitor heavy chain H4 (ITI-H4) was found to exist two forms in serum. The full size (120 kDa) of the protein was increased and the fragmented ITI-H4 (35 kDa) was decreased in PD group. The ratio of full size ITI-H4 to fragmented ITI-H4 in PD patients was 3.85 +/- 0.29-fold higher than in control group. Furthermore, fragmented Apo A-IV (~ 26 kDa) was mainly detected in control group, while it was rare to be found in PD group. Above findings might be useful for diagnosis of PD. When the expressions of FGG and 120 kDa ITI-H4 are increase, as well as ~ 26 kDa Apo A-IV disappear would provide strong evidence for PD. PMID- 24769802 TI - Metaphors and images of cancer in early modern Europe. AB - Drawing on learned medical writing about cancer and on nonmedical texts that used cancer as a metaphor for hateful cultural, social, religious, or political phenomena that warranted drastic measures, this article traces the metaphors and images that framed the perception and experience of cancer in the early modern period. It finds that cancer was closely associated with notions of impurity and a visible destruction of the body's surface and was diagnosed primarily in women, as breast and uterine cancer. Putrid, corrosive cancerous humor was thought not only to accumulate and eat its way into the surrounding flesh but also to spread, like the seeds of a plant, "infecting" the whole body. This infectious quality, the putrid secretions, and the often horrendous smell emanating from cancer victims raised fears, in turn, of contagion and were taken to justify a separation of cancer patients from the rest of society. PMID- 24769803 TI - Cargo, "infection," and the logic of quarantine in the nineteenth century. AB - In the nineteenth century, maritime quarantine officials often paid more attention to ships' cargo than they did to the health of passengers or crew members. Based on a close reading of the everyday practice of quarantine at Philadelphia's Lazaretto (1801-1895), this article suggests that the historical significance of quarantine has been distorted by its association with the etiological debate over contagion and with xenophobic responses to immigration. In fact, the practice of quarantine rested neither on contagionist medical doctrine nor on nativism. Rather, it was based on the danger of infection, an elusive but fundamental concept in nineteenth-century public health. The concern about cargo rather than people-and the logic of infection it reflects-bespeak a widely shared set of perceptions of illness and public health in the first three quarters of the nineteenth century that is not captured by discussions of contagion or of anti-immigrant bias. PMID- 24769804 TI - Exercises in therapy--neurological gymnastics between Kurort and hospital medicine, 1880-1945. AB - This article focuses on the convergence of sports and medicine in the practice of neurological gymnastics (Ubungstherapie) in the German-speaking world at the turn of the twentieth century. It shows how Ubungstherapie first found receptive ground within the peripheral medical space of the spa town (Kurort). Ubungstherapie appealed to Kurort patients because, as a form of neurological gymnastics, it drew on the cultural capital of the broader German gymnastics movement. Only later did Ubungstherapie find a place in more mainstream medicine, recasting itself as an integral part of neurological practice. Recuperating the therapeutic aspects of neurology, this article suggests that the development of Ubungstherapie contributed to the formation of neurology as an independent specialty, distinct from psychiatry and internal medicine. It thus demonstrates the importance of expanding the scope of historical study beyond the traditional boundaries of the mainstream in order to understand clinical, institutional, and disciplinary change. PMID- 24769805 TI - Ex utero: live human fetal research and the films of Davenport Hooker. AB - Between 1932 and 1963 University of Pittsburgh anatomist Davenport Hooker, Ph.D., performed and filmed noninvasive studies of reflexive movement on more than 150 surgically aborted human fetuses. The resulting imagery and information would contribute substantially to new visual and biomedical conceptions of fetuses as baby-like, autonomous human entities that emerged in the 1960s and 1970s. Hooker's methods, though broadly conforming to contemporary research practices and views of fetuses, would not have been feasible later. But while Hooker and the 1930s medical and general public viewed live fetuses as acceptable materials for nontherapeutic research, they also shared a regard for fetuses as developing humans with some degree of social value. Hooker's research and the various reactions to his work demonstrate the varied and changing perspectives on fetuses and fetal experimentation, and the influence those views can have on biomedical research. PMID- 24769806 TI - "Patient Zero": the absence of a patient's view of the early North American AIDS epidemic. AB - This article contextualizes the production and reception of And the Band Played On, Randy Shilts's popular history of the initial recognition of the American AIDS epidemic. Published over twenty-five years ago, the book and its most notorious character, "Patient Zero," are in particular need of a critical historical treatment. The article presents a more balanced consideration-a "patient's view"-of Gaetan Dugas's experience of the early years of AIDS. I oppose the assertion that Dugas, the so-called Patient Zero, ignored incontrovertible information about the condition and was intent on spreading his infection. Instead I argue that scientific ideas in 1982 and 1983 about AIDS and the transmissibility of a causative agent were later portrayed to be more self evident than they were at the time. The article also traces how Shilts's highly selective-and highly readable-characterization of Dugas rapidly became embedded in discussions about the need to criminalize the reckless transmission of HIV. PMID- 24769808 TI - Banking (on) the brain: from consent to authorisation and the transformative potential of solidarity. AB - Modern technologies and biomedicine ambitions have given rise to new models of medical research, including population biobanking. One example of biobanking is brain banking, which refers to the collection and storage of brain and spinal cord samples for research into neurological diseases. Obviously, brain banking involves taking brains and tissue from deceased people, a fact which complicates the role of recruiters and makes consent a poor tool for stakeholders. After contextualising brain banking and considering the public health issues at stake, this article explores the legal definitions and demands of, and actual processes around, consent in England/Wales/Northern Ireland and authorisation in Scotland, articulating and evaluating their conceptual and practical differences. It then argues for an expanded but improved operation of 'authorisation' in the brain banking (and broader biobanking) setting, adopting 'solidarity' as our foundation and the improvement of the 'public good' our objective. PMID- 24769809 TI - Rapid and sensitive suspension array for multiplex detection of organophosphorus pesticides and carbamate pesticides based on silica-hydrogel hybrid microbeads. AB - A technique for multiplex detection of organophosphorus pesticides and carbamate pesticides has been developed using a suspension array based on silica-hydrogel hybrid microbeads (SHHMs). The main advantage of SHHMs, which consist of both silica and hydrogel materials, is that they not only could be distinguished by their characteristic reflection peak originating from the stop-band of the photonic crystal but also have low non-specific adsorption of proteins. Using fluorescent immunoassay, the LODs for fenitrothion, chlorpyrifos-methyl, fenthion, carbaryl and metolcarb were measured to be 0.02ng/mL, 0.012ng/mL, 0.04ng/mL, 0.05ng/mL and 0.1ng/mL, respectively, all of which are much lower than the maximum residue limits, as reported in the European Union pesticides database. All the determination coefficients for these five pesticides were greater than 0.99, demonstrating excellent correlations. The suspension array was specific and had no significant cross-reactivity with other chemicals. The results for the detection of pesticide residues collected from agricultural samples using this method agree well with those from liquid chromatography-tandem mass spectrometry. Our results showed that this simple method is suitable for simultaneous detection of these five pesticides residues in fruits and vegetables. PMID- 24769810 TI - Immobilization of BiOX (X = Cl, Br) on activated carbon fibers as recycled photocatalysts. AB - BiOX have been grown on the surface of activated carbon fibers (ACF) as recycled photocatalysts. The analysis results illustrate that electrostatic adsorption plays an important role in the formation of BiOX/ACF composites. The photocatalytic experimental results indicate that BiOX/ACF show excellent cyclic properties and stable performance. PMID- 24769811 TI - A hot start alternative for high-fidelity DNA polymerase amplification mediated by quantum dots. AB - Quantum dots (QDs) are of great interest due to their unique chemical and physical properties. Recently, a hot start (HS) polymerase chain reaction (PCR) amplification performance based on QDs with a high-fidelity Pfu DNA polymerase has been reported. However, whether QDs can trigger HS effects with other high fidelity or conventional DNA polymerases is yet to be understood. In the present study, we studied the QD-triggered HS effects with four high-fidelity and three conventional DNA polymerases, and the HS effect comparisons among them were also made. It was found that QDs could trigger a distinct HS PCR amplification performance with all the four tested high-fidelity DNA polymerases, and specific target DNA could be well amplified even if the PCR mixture was pre-incubated for 2 h at 50 degrees C. On the contrary, the HS effects were not prominent with all the three conventional Taq DNA polymerases. Specifically, the fidelity of Pfu is not sacrificed in the presence of QDs, even after a 1 h pre-incubation at 50 degrees C before PCR. Furthermore, the electrophoresis results preliminarily demonstrated that QDs prefer to adsorb high-fidelity polymerases rather than conventional ones, which might result in the QD-triggered HS effects on PCR performance by using high-fidelity DNA polymerases. PMID- 24769812 TI - H2 spillover enhanced hydrogenation capability of TiO2 used for photocatalytic splitting of water: a traditional phenomenon for new applications. AB - Black TiO2 was usually obtained via hydrogenation at high pressure and high temperature. Herein, we reported a facile hydrogenation of TiO2 in the presence of a small amount of Pt at relatively low temperature and atmospheric pressure. The hydrogen spillover from Pt to TiO2 accounts well for the greatly enhanced hydrogenation capability. The as-synthesized Pt/TiO2 exhibits remarkably improved photocatalytic activity for water splitting. PMID- 24769814 TI - Red cell distribution width is increased in patients with ascending aortic dilatation. AB - OBJECTIVES: The prognostic importance of red cell distribution width (RDW) and neutrophil/lymphocyte ratio (NLR) in cardiovascular diseases has been shown. Ascending aortic dilatation (AAD) is a common cardiovascular disease and is associated with aortic wall inflammation and cystic degeneration. In this study, we aimed to investigate the relationship between serum levels of RDW, NLR and the presence of AAD. STUDY DESIGN: Two-hundred consecutive patients with AAD diagnosed by transthoracic echocardiography were prospectively recruited and were compared to 170 age-gender- matched subjects with normal aortic diameters. Complete blood counts (CBCs) were analyzed for hemoglobin, RDW and NLR counts, as well as mean corpuscular volume (MCV). If possible, results of CBC tests within the previous two years were also included and the averages were used. RESULTS: RDW [median 13.9, interquartile range (IQR) 1.40 vs. median 13.3, IQR 1.05%, p=0.01], NLR (median 2.04, IQR 1.09 vs. median 1.78, IQR 0.90, p=0.01) and high sensitive C-reactive protein (hs-CRP) (median 0.60, IQR 0.80 vs. median 0.44, IQR 0.68 mg/L, p=0.01) levels were significantly higher in the AAD group compared to the control group. In univariate correlation analysis, ascending aortic diameters were correlated with RDW levels (r=0.31, p=0.01), NLR levels (r=0.15, p=0.01) and hs-CRP levels (r=0.12, p=0.03). In multivariate logistic regression analysis, increased levels of RDW and hs-CRP remained as the independent correlates of AAD in the study population. Receiver operating characteristic (ROC) curve analysis revealed that a RDW measurement higher than >13.8% predicted AAD with a sensitivity of 49.5% and a specificity of 82.8% (area under the curve [AUC] 0.681, p=0.01). CONCLUSION: In patients with AAD, RDW and hs-CRP levels are increased, which may indicate the role of inflammation in the pathogenesis of AAD. PMID- 24769813 TI - Association between phosphorylated AMP-activated protein kinase and acetyl-CoA carboxylase expression and outcome in patients with squamous cell carcinoma of the head and neck. AB - BACKGROUND: Epidemiological studies have indicated that impaired glucose metabolism may increase the risk of squamous cell carcinoma of the head and neck (SCCHN). AMP-activated protein kinase (AMPK) regulates glucose and lipid metabolism via the phosphorylation and subsequent inactivation of its downstream target acetyl-CoA carboxylase (ACC).Thus, we analyzed the expression of pAMPK and its downstream target phosphorylated acetyl-CoA carboxylase (pACC), as well as their impact on the survival of patients with resected SCCHN. METHODS: One hundred eighteen patients with surgically resected SCCHN were enrolled. Immunohistochemical (IHC) staining for pAMPK and pACC was performed using tissue microarrays of operative specimens of SCCHN. The expression was divided into two or three groups according to the IHC score [pAMPK: negative (0), positive (1-3); pACC: negative (0), low expression (1, 2), and high expression (3)]. Statistical analysis was performed to determine the association of pAMPK expression with clinicopathological features and pACC and pErk expression. RESULTS: The positive rates of pAMPK and pACC expression were 64.4% (76/118) and 68.6% (81/118), respectively. pAMPK was significantly higher in patients aged younger than 60 years (P = 0.024; chi2 test) and those with early-stage (T1/T2; P = 0.02; chi2 test) and oral cavity (P = 0.026; Fisher's exact test) tumors. In multivariate analysis, pAMPK expression was not significantly correlated with overall survival (OS) (adjusted hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.35-1.23), whereas high pACC expression was independently associated with worse OS in node positive patients (adjusted HR: 17.58; 95% CI: 3.50-88.18). CONCLUSIONS: Strong expression of pACC was found to be an independent prognostic marker for patients with node-positive SCCHN. Our results suggest that pACC may play a role in tumor progression of SCCHN and may help to identify patient subgroups at high risk for poor disease outcome. PMID- 24769815 TI - Usefulness of admission gamma-glutamyltransferase level for predicting new-onset heart failure in patients with acute coronary syndrome with left ventricular systolic dysfunction. AB - OBJECTIVES: Our aim was to determine whether there is a relationship between admission gamma-glutamyltransferase (GGT) and subsequent heart failure hospitalizations in patients with acute coronary syndrome. STUDY DESIGN: We selected 123 patients with newly diagnosed acute coronary syndrome of ejection fraction (EF) <45%. Patients were followed 15+/-10 months, and the relationship between admission GGT level and hospitalization because of heart failure during the follow-up was examined. RESULTS: Twenty-three (18.7%) patients were hospitalized during the follow-up of 15+/-10 months. Receiver operating characteristic (ROC) curve analysis showed that the cut-off point of admission GGT related to predict hospitalization was 49 IU/L, with a sensitivity of 81.7% and specificity of 65.2%. Increased GGT >49 IU/L on admission, presence of hypertension and hyperlipidemia, left ventricular ejection fraction (LVEF), right ventricular dysfunction, moderate-to-severe mitral regurgitation, alanine aminotransferase level, and antiplatelet agent usage were found to have prognostic significance in univariate Cox proportional hazards analysis. In multivariate Cox proportional-hazards model, increased GGT >49 IU/L on admission (hazard ratio [HR] 2.663, p=0.047), presence of hypertension (HR 4.107, p=0.007), and LVEF (HR 0.911, p=0.002) were found to be independent factors to predict new onset heart failure requiring hospitalization. CONCLUSION: Hospitalization in heart failure was associated with increased admission GGT levels. Increased admission GGT level in acute coronary syndrome with heart failure should be monitored closely and treated aggressively. PMID- 24769816 TI - [Coronary revascularization (Examples from the world and Turkey)]. AB - OBJECTIVES: In this article, our aims were to analyze and assess the data related to coronary revascularization rates, particularly in recent years. STUDY DESIGN: For this purpose, results of important studies, statistics of the Organisation for Economic Co-operation and Development (OECD) countries and data from Turkey's Social Security Agency (SSA) were analyzed for the first time. Until recently, there has been no healthy digital database regarding revascularization rates in Turkey. In the years following the establishment of SSA, it became possible to collect and analyze data obtained from the Medulla database of the Agency. Using the data from the Agency for the period 2009-2011, revascularization rates and cost analyses were performed. RESULTS: Between 2000 and 2010 in European countries as well as in other OECD countries, the percutaneous coronary intervention (PCI) rate was on average 75% of the total revascularization rate and neared 80%. In some countries, the rate has exceeded 85%. In our country, in 2009, 2010 and 2011, the number of coronary angiography procedures and as a result PCI has steadily increased. The rate for PCI was 66.8% in 2009, but it increased to 74% in 2011. At the same time, PCI accounted for 2/3-4/5 of all revascularization procedures. In the cost analysis, however, PCI constituted only 1/5-1/4 of the costs of all revascularization procedures. CONCLUSION: This report is the first analysis in this area and it gives an initial idea about the current situation of the numerical and financial aspects. This analysis has provided the opportunity to obtain more accurate information about coronary revascularization rates in Turkey and to compare the data to that of other countries. PMID- 24769817 TI - Lipids and leptin level in natives of Kyrgyzstan. AB - OBJECTIVES: A possible link between obesity and impaired lipid metabolism is leptin, the 167-amino acid protein, secreted by adipocytes. The content of leptin in the body is closely associated with body mass index (BMI). Data obtained from studies on the association of leptin with dyslipidemia are contradictory. The level of leptin has not been studied in the ethnic Kyrgyz population previously. The purpose of this study was to investigate the relationship between leptin and lipid parameters in a group of ethnic Kyrgyz. STUDY DESIGN: The study included 322 ethnic Kyrgyz (145 males, 177 females) aged >=30 years, living in Kyrgyzstan. Measurement of anthropometric parameters (height, weight, waist circumference [WC], hip circumference [HC]) and blood pressure (BP) was done. Laboratory tests included blood glucose (fasting) in plasma, lipid profile (total cholesterol [TC], triglycerides [TG], high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol), and serum leptin. RESULTS: Leptin was positively correlated with BMI, WC and TG in both sexes and with TC in males. CONCLUSION: Leptin is associated with BMI, WC and TG in both sexes of Kyrgyz and with TC in Kyrgyz males. PMID- 24769818 TI - [Correlation between Haller index and echocardiographic and spirometric findings in children with pectus excavatum]. AB - OBJECTIVES: In this study, we evaluated the correlation between severity of deformity and cardiopulmonary function with regards to echocardiographic and spirometric findings. STUDY DESIGN: Twenty-five children, mean age 13.6 years, presenting with pectus excavatum between August 2012 and May 2013, were included. Haller index (HI) was calculated for each patient. Patients with an index of <2.5 were accepted as Group 1, 2.5-3.6 as Group 2, and >3.6 as Group 3. Left ventricle dimension, ejection fraction, and shortening fraction were evaluated with echocardiography. Using spirometry, forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and FEV1/FVC ratio were calculated. Groups were compared using these parameters. RESULTS: There were 18 males and 7 females. The mean index was 3.48+/-0.78. Though there was no significant difference in the index with regards to sex, the index increased with age. Eight percent of patients were in Group 1, 52% in Group 2 and 40% in Group 3. A significant decrease in ejection and shortening fractions was evident as the index increased. A statistically significant relation between HI and cardiac dysfunction was evident (p<0.01). As the index increased, there was significant decrease in FEV1 and the FEV1/FVC ratio, while there was no significant difference in FVC. As the deformity worsened, incidence of pulmonary dysfunction was found to be higher. CONCLUSION: This study revealed that pectus excavatum leads to cardiac and pulmonary problems, and functions of the left ventricle may be affected by the deformity. Furthermore, the relation between the severity of the deformity and cardiovascular function is evident. PMID- 24769819 TI - Protective effect of melatonin on adriamycin-induced cardiotoxicity in rats. AB - OBJECTIVES: Adriamycin is one of the most widely used anticancer drugs. The major limiting factor of using this drug is the development of cardiotoxicity. However, melatonin (N-acetyl-5-methoxytryptamine) is a ubiquitous molecule as a good antioxidant that may protect the heart. We investigated whether or not pretreatment with melatonin can attenuate adriamycin-induced cardiotoxicity. STUDY DESIGN: All procedures and experiments were approved by the Animal Ethics Committee of Gazi Osman Pasa University (2012-HADYEK-022). Adult male Wistar Albino rats were randomly divided into four groups, namely control (CON, n=7), melatonin (MEL, n=7), adriamycin (ADR, n=7), and adriamycin+melatonin (ADR+MEL, n=7) groups. Cardiotoxicity in rats was induced by adriamycin injection (cumulative dose: 18 mg/kg, intraperitoneal [i.p.]) at an interval of 24 hours (h) on the 5th, 6th and 7th days. Rats receiving melatonin treatment in the adriamycin group received melatonin (10 mg/kg/day, i.p.) for 7 days and were injected with adriamycin (18 mg/kg, i.p.) on 5th, 6th and 7th days. On the 8th day, gravimetric, electrocardiography (ECG) and biochemical parameters were assessed. RESULTS: Adriamycin induction caused changes in the ECG pattern, including ST-segment elevation and decreased R-amplitude, increase in the serum levels of cardiac injury markers (creatine kinase [CK], CK-MB, aspartate transaminase, and lactate dehydrogenase), decrease in the antioxidant enzymes activity (superoxide dismutase, glutathione peroxidase), elevated lipid peroxidation (malondialdehyde), and altered lipid profile in the serum. Melatonin treatment prevented all the parameters of adriamycin-induced cardiotoxicity in rats. CONCLUSION: Melatonin has a protective effect on the heart against adriamycin-induced cardiotoxicity in rats. PMID- 24769820 TI - Anthracycline-induced cardiotoxicity. PMID- 24769821 TI - Recurrent pulmonary embolism in an asthmatic patient who had interrupted inferior vena cava with azygous continuation. AB - A 45-year-old woman with a history of recurrent pulmonary embolism was admitted to the emergency clinic with dyspnea, wheezing and tachypnea. Partial deep vein thrombosis of the popliteal vein was seen on Doppler sonography. On the contrast enhanced thorax computed tomography (CT) scan, a clot was detected in the right main pulmonary artery and its major descending branch. Moreover, the azygos vein was prominently dilated. Abdominal multi-slice computed tomography (MSCT) scan revealed absence of the hepatic segment of the inferior vena cava (IVC) with continuation of the IVC as a dilated right-sided azygos vein. The hepatic veins were draining directly into the right atrium. Thus, we discuss herein this rare anatomic variant presented with recurrent pulmonary embolism, together with the findings on MSCT. PMID- 24769822 TI - An unusual case of idiopathic hypereosinophilic syndrome presenting with myopericarditis and a polypoid cardiac mass. AB - Idiopathic hypereosinophilic syndrome (IHES) is a rare systemic disorder with blood eosinophilia and multiple system involvement. Commonly, there is endocardial fibrosis with overlying mural thrombus, and mitral and tricuspid valves can be involved concomitantly. Outflow tracts near the aortic and pulmonary valves are generally protected. We herein describe an atypical case of IHES with a mass on the left ventricular outflow tract (LVOT), which showed regression under steroid therapy. There are two features that make our case worthy of reporting: First, the mitral and tricuspid valves are expected to be involved in IHES, and outflow tracts near the aortic and pulmonary valves are generally protected. Second, within one month of steroid therapy, the vegetation had reduced dramatically in size and signs of myocarditis and pericarditis had also disappeared. PMID- 24769823 TI - Misdiagnosis of Behcet's disease presented with intracardiac mass as inflammatory myofibroblastic tumor. AB - Behcet's disease is a chronic multisystem inflammatory disorder. There are limited data about cardiac involvement, but it is seen rarely. Herein, we present a 33-year-old male patient with heart failure secondary to a right ventricular mass. It was first diagnosed as inflammatory myofibroblastic tumor (IMT) histopathologically. During the postoperative follow-up, a thrombus was detected at the interatrial septum, and the patient was reevaluated. The diagnosis was possible Behcet's disease, and the mass, previously reported as IMT, was determined to be an organizing thrombus with a mixture of granulation tissue and thrombotic material. PMID- 24769824 TI - Acute pulmonary embolism mimicking inferior myocardial infarction. AB - Pulmonary embolism (PE) is a potentially life-threatening emergency that is sometimes difficult to diagnose due to nonspecific symptoms and findings. A 69 year-old male was admitted to our hospital with new-onset chest pain and sweating. The electrocardiogram (ECG) revealed sinus rhythm with ST elevations in the inferior leads. His angiogram showed noncritical coronary artery disease with a few plaques. Right heart catheterization was made, which revealed an elevated pulmonary artery pressure of 45/23 mmHg. A pulmonary angiogram was then performed, at first from the pulmonary trunk and then the right pulmonary artery, which showed occlusion of the pulmonary artery to the right lower lobe. This report emphasizes that acute PE should be suspected in every patient with ST elevation myocardial infarction and normal coronary arteries. ST changes may be in the inferior as well as the anterior leads. PMID- 24769825 TI - The use of low molecular weight heparin during pregnancy in patients with mechanical heart valves carries potential risk for valve thrombosis: a report of three cases. AB - Pregnancy is associated with an increased risk of valve thrombosis, hemorrhagic complications, and offspring complications in patients with metallic prosthetic heart valve (MHV). Warfarin treatment is the best regimen against thromboembolic complications, but its use in the first trimester can result in embryopathy. Low molecular weight heparin (LMWH) does not cross the placenta and has some potential advantages. However, the pharmacokinetics of LMWHs change during pregnancy, and serial monitoring of anti-Xa levels is strongly recommended. Despite this recommendation, LMWH therapy in a fixed dose is still used in pregnant women with MHV without monitoring anti-Xa activity in clinical practice. We present three cases of MHV thrombosis occurring while on therapy with LMWH during pregnancy. One of these patients showed cerebrovascular event, one presented with pulmonary edema, and one underwent reoperation for MHV thrombosis. PMID- 24769826 TI - Transcatheter closure of ruptured sinus Valsalva aneurysm with retrograde approach. AB - A three-year-old girl with multiple heart malformations admitted to the pediatric cardiology unit because of excessive sweating and fatigue. Abnormal color Doppler flow was detected into the right atrium from the dilated coronary sinus on the echocardiographic examination, and ruptured sinus Valsalva aneurysm (SVA) was diagnosed. Although in most such cases, an antegrade transcatheter approach has been used, a retrograde approach can be used as a cost-effective treatment modality in those cases with selective high-risk surgery. In this report, we present a patient with ruptured SVA, which was closed via Amplatzer vascular plug 4 by retrograde approach. PMID- 24769827 TI - [A qualified weapon in the fight against challenging coronary artery lesions: Rotablator(r) device]. AB - Atherectomy is a procedure that clears blockages in the coronary arteries in order to improve blood flow to the heart and relieve symptoms of coronary artery disease. The procedure may be performed instead of or in addition to other procedures and can improve both the immediate and long-term success of balloon angioplasty and stenting. Although it is no longer a common procedure, it does play an important role in interventional cardiology. When the challenging atherosclerotic coronary artery lesions cannot be crossed by a balloon or cannot be adequately dilated even with non-compliant balloon, such lesions may be better treated by rota-ablation, which is carried out by operators who are experienced in rotational atherectomy. PMID- 24769828 TI - Case images: left ventricular "grape-shaped", mobile thrombi in an elderly patient. PMID- 24769829 TI - Case images: quadricuspid aortic valve with partial pulmonary venous return anomaly and atrial septal defect. PMID- 24769830 TI - Case images: a case of unusual coronary-cameral fistula. PMID- 24769831 TI - Case images: percutaneous transcatheter closure of atrial and ventricular septal defect in the same session. PMID- 24769832 TI - Case images: Himalayan P waves in a patient with ischemic cardiomyopathy - a new entity. PMID- 24769833 TI - [Letter to the editor]. PMID- 24769834 TI - [Authors reply]. PMID- 24769835 TI - MnO2 nanorods intercalating graphene oxide/polyaniline ternary composites for robust high-performance supercapacitors. AB - New ternary composites of MnO2 nanorods, polyaniline (PANI) and graphene oxide (GO) have been prepared by a two-step process. The 100 nm-long MnO2 nanorods with a diameter ~20 nm are conformably coated with PANI layers and fastened between GO layers. The MnO2 nanorods incorporated ternary composites electrode exhibits significantly increased specific capacitance than PANI/GO binary composite in supercapacitors. The ternary composite with 70% MnO2 exhibits a highest specific capacitance reaching 512 F/g and outstanding cycling performance, with ~97% capacitance retained over 5000 cycles. The ternary composite approach offers an effective solution to enhance the device performance of metal-oxide based supercapacitors for long cycling applications. PMID- 24769836 TI - Presenting the marvels of immunity. PMID- 24769837 TI - Moving the point of doctors' registration. PMID- 24769838 TI - Insight of the cytotoxicity of the aggregates of peptides or aberrant proteins: a meta-analysis. AB - Aberrant proteins or peptide aggregates form soluble oligomers or nanofibrils that can cause a wide range of amyloidosis diseases, including Alzheimer's disease (AD). The mechanisms of their cytotoxicity, however, remain controversial and poorly understood, greatly hindering the development of AD drugs. Here we report a comprehensive evaluation of the cytotoxicity of the aggregates by meta analysis. The analysis indicates that the cytotoxicity of the aggregates converges in a narrower range in the mass concentrations than in the molar concentrations, suggesting that it is the weight of the aggregates rather than the number of the molecules that dictates the cytotoxicity. This new perspective implies that these aggregates are likely to have non-specific interactions with cells to cause cell death. The comparison of several existing theories regarding cellular volumes supports that the aggregates may result in crowding effect and increase the free energy, thus resulting in instability of the cells. PMID- 24769839 TI - Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, alpha-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys. AB - Proteins aggregate in several slowly progressive neurodegenerative diseases called 'proteinopathies'. Studies with cell cultures and transgenic mice overexpressing mutated proteins suggested that aggregates of one protein induced misfolding and aggregation of other proteins as well - a possible common mechanism for some neurodegenerative diseases. However, most proteinopathies are 'sporadic', without gene mutation or overexpression. Thus, proteinopathies in WT animals genetically close to humans might be informative. Squirrel monkeys infected with the classical bovine spongiform encephalopathy agent developed an encephalopathy resembling variant Creutzfeldt-Jakob disease with accumulations not only of abnormal prion protein (PrP(TSE)), but also three other proteins: hyperphosphorylated tau (p-tau), alpha-synuclein and ubiquitin; beta-amyloid protein (Abeta) did not accumulate. Severity of brain lesions correlated with spongiform degeneration. No amyloid was detected. These results suggested that PrP(TSE) enhanced formation of p-tau and aggregation of alpha-synuclein and ubiquitin, but not Abeta, providing a new experimental model for neurodegenerative diseases associated with complex proteinopathies. PMID- 24769840 TI - Activated vitamin D3 and pro-activated vitamin D3 attenuate induction of permanent changes caused by neonatal estrogen exposure in the mouse vagina. AB - Exposure of mice to a high dose of estrogens including diethylstilbestrol (DES) during the neonatal period modifies the developmental plan of the genital tract, which leads to various permanent changes in physiology, morphology and gene expression. These changes include development of an abnormal vaginal epithelium lined with hyperplastic mucinous cells accompanied by Tff1 gene expression in mice. Here, the influence of vitamin D on the direct effect of estrogen on the developing mouse vagina was examined. The mid-vagina of neonatal mice was cultured in a serum-free medium containing estradiol-17beta (E2) and various concentrations of 1,25-dihydroxyvitamin D3 (1,25(OH)2D) ex vivo and then was transplanted under the renal capsule of ovariectomized host mice for 35 days. Exposure to E2 alone caused the vaginal tissue to develop estrogen-independent epithelial hyperplasia and to express TFF1 mRNA, while addition of a low nanomolar amount of 1,25(OH)2D added at the same time as E2 to the culture medium attenuated the effects of estrogen. Expression of vitamin D receptor was also evident in the neonatal mouse vagina. Interestingly, addition of 25 hydroxyvitamin D3, a pro-activated form of vitamin D, at the micromolar level was found to be potent in disrupting the developmental effects of E2, while cholecalciferol was not at least at the dose examined. Correspondingly, expression of Cyp27B1, a kidney-specific 25-hydroxyvitamin D hydroxylase, was evident in the neonatal mouse vagina when examined by RT-PCR. In addition, simultaneous administration of 1,25(OH)2D successfully attenuated DES-induced ovary-independent hyperplasia in the vagina in neonatal mice in vivo. Thus, manipulation of vitamin D influenced the harmful effects of estrogens on mouse vaginal development. PMID- 24769841 TI - Lipopolysaccharide (LPS) inhibits steroid production in theca cells of bovine follicles in vitro: distinct effect of LPS on theca cell function in pre- and post-selection follicles. AB - In postpartum dairy cows, lipopolysaccharide (LPS) derived from gram-negative bacteria such as Escherichia coli causes uterine inflammation and leads to ovarian dysfunction. The aim of this study was to determine the effect of LPS on steroid production in bovine theca cells at different stages of follicular development. Theca cells isolated from pre- and post-selection follicles (PRFs, <8.5 mm in diameter, and POFs, >8.5 mm in diameter, respectively) of bovine ovaries were exposed to LPS under luteinizing hormone (LH) conditions, estradiol (E2) conditions or both conditions in vitro. Bovine theca cells expressed the LPS receptor gene complex: Toll-like receptor 4 (TLR4), CD14 and MD2. LPS suppressed progesterone (P4) and androstenedione (A4) production with downregulation of steroidogenic enzyme transcripts when theca cells were stimulated with LH. By contrast, LPS did not affect P4 or A4 production when theca cells were stimulated with E2. P4 and A4 production in theca cells from PRFs was suppressed by LPS as early as at 48 h of culture, whereas the effect of LPS on theca cells from POFs was observed at 96 h of culture. The results demonstrate that LPS inhibits steroid production in theca cells under LH conditions. Moreover, theca cells from POFs showed a slower response to LPS compared with that of theca cells from PRFs, which might imply a distinct effect of LPS on follicles at different developmental stages. These findings suggest a possible mechanism of ovarian dysfunction and subsequent infertility in cows with endometritis. PMID- 24769842 TI - Decreased expression of NKG2D, NKp46, DNAM-1 receptors, and intracellular perforin and STAT-1 effector molecules in NK cells and their dim and bright subsets in metastatic melanoma patients. AB - Although natural killer (NK) cells play an important antitumor role, melanoma cells may affect their effector functions. In this study, we analyzed the expression of various receptors and effector molecules in NK cells and their subsets in metastatic melanoma (MM) patients compared with healthy controls (HCs). In HC and MM patients, we analyzed NK cell activity using a chromium release assay and the expression of CD107a degranulation marker, activating NKG2D, NKp46, DNAM-1, and inhibitory CD158a and CD158b receptors, IL-12R beta 1, IL-12R beta 2, intracellular interferon (IFN)-gamma, perforin, and STAT-1 in CD3 CD56+ NK cells, and cytotoxic CD3-CD56 and immunoregulatory CD3-CD56 subsets by flow cytometry. MM patients compared with HC not only had significantly decreased NK cell activity, lower expression of CD107a, and impaired IFN-gamma production but also had decreased expression of activating NKG2D, NKp46, and DNAM-1 receptors, which was followed by lower expression of perforin, STAT-1, and both IL-12R subunits in NK cells. In MM patients only, there was a positive correlation between NKG2D expression and degranulation capacity, as well as IFN gamma production in NK cells. Analysis of the expression of various parameters of NK cell effector functions between MM patients with different localization of distant metastases showed that patients in the unfavorable M1c subclass had decreased expression of NKG2D and NKp46 on NK cells compared with patients in the M1a+b group. Downregulated NKG2D, NKp46, and DNAM-1 receptors associated with impaired NK cell effector function are important biomarkers of advanced disease with a poor prognosis in melanoma patients. PMID- 24769843 TI - Asymmetric synthesis of 3,3,5,5-tetrasubstituted 1,2-dioxolanes: total synthesis of epiplakinic acid F. AB - The first enantioselective total synthesis of epiplakinic acid F (1) was achieved through a pivotal step involving a radical-mediated asymmetric peroxidation of vinylcyclopropanes with molecular oxygen to construct highly substituted 1,2 dioxolanes. Subsequent conversions of the chiral 1,2-dioxolanes led to total synthesis of epiplakinic acid F (1) and the confirmation of its absolute configuration. The enantiomer of epiplakinic acid F methyl ester (2) was also prepared. PMID- 24769844 TI - Regulation of the biosynthesis of thiopeptide antibiotic cyclothiazomycin by the transcriptional regulator SHJG8833 in Streptomyces hygroscopicus 5008. AB - Cyclothiazomycin is a member of the thiopeptide antibiotics, which are usually complicated derivatives of ribosomally synthesized peptides. A gene cluster containing 12 ORFs identical to the clt cluster encoding cyclothiazomycin from Streptomyces hygroscopicus 10-22 was revealed by genome sequencing in S. hygroscopicus 5008. Genes SHJG8833 and SHJG8837 of the cluster and flanking gene SHJG8838 were predicted to encode regulatory proteins from different families. In this study, we showed that the newly identified cluster is functional and we investigated the roles of these regulatory genes in the regulation of cyclothiazomycin biosynthesis. We determined that SHJG8833, but not SHJG8837 or SHJG8838, is critical for cyclothiazomycin biosynthesis. The transcriptional start point of SHJG8833 was located to a thymidine 54 nt upstream of the start codon. Inactivation of SHJG8833 abrogated the production of cyclothiazomycin, and synthesis could be restored by reintroducing SHJG8833 into the mutant strain. Gene expression analyses indicated that SHJG8833 regulates a consecutive set of seven genes from SHJG8826 to SHJG8832, whose products are predicted to be involved in different steps in the construction of the main framework of cyclothiazomycin. Transcriptional analysis indicated that these seven genes may form two operons, SHJG8826-27 and SHJG8828-32. Gel-shift analysis demonstrated that the DNA-binding domain of SHJG8833 binds the promoters of SHJG8826 and SHJG8828 and sequences internal to SHJG8826 and SHJG8829, and a conserved binding sequence was deduced. These results indicate that SHJG8833 is a positive regulator that controls cyclothiazomycin biosynthesis by activating structural genes in the clt cluster. PMID- 24769845 TI - Oxidation of aquatic pollutants by ferrous-oxalate complexes under dark aerobic conditions. AB - This study evaluates the ability of Fe(II)-oxalate complexes for the generation of OH through oxygen reduction and the oxidative degradation of aquatic pollutants under dark aerobic conditions (i.e., with oxygen but without light). The degradation of 4-chlorophenol (4-CP) was rapid in the mixture of Fe(2+) and oxalate prepared using ultrapure water, but was absent without either Fe(2+) or oxalate. The formation of Fe(II)-oxalate complexes enables two-electron reduction of oxygen to generate H2O2 and subsequent production of OH. The significant inhibition of 4-CP degradation in the presence of H2O2 and OH scavenger confirms such mechanisms. The degradation experiments with varying [Fe(2+)], [oxalate], and initial pH demonstrated that the degradation rate depends on [Fe(II)(Ox)2(2 )], but the degree of degradation is primarily determined by [Fe(II)(Ox)2(2 )]+[Fe(II)(Ox)(0)]. Efficient degradation of diverse aquatic pollutants, especially phenolic pollutants, was observed in the Fe(II)-oxalate complexes system, wherein the oxidation efficacy was primarily correlated with the reaction rate constant between pollutant and OH. The effect of various organic ligands (oxalate, citrate, EDTA, malonate, and acetate) on the degradation kinetics of 4 CP was investigated. The highest efficiency of oxalate for the oxidative degradation is attributed to its high capability to enhance the reducing power and low reactivity with OH. PMID- 24769846 TI - Microwave treatment of electric arc furnace dust with PVC: dielectric characterization and pyrolysis-leaching. AB - Microwave treatment of electric arc furnace dust (EAFD) with poly(vinyl chloride) (PVC) was studied in this work. A comprehensive characterization of the dust as well as assessing the suitability of using the thermal de-chlorination of the common plastic (PVC) under inert atmosphere was carried out to assess the possibility of Zn and other heavy metals extraction (Pb and Cd) from EAFD. The dielectric and thermal properties of EAFD, PVC and their mixtures were measured. Once combined and heated the metal oxides present in the dust reacted with HCl released from PVC during thermal de-chlorination, forming metal chlorides which were subsequently recovered by leaching with water. It was found that zinc chloride could be almost completely recovered in the leaching stage, with the overall recovery of Zn reaching 97% when the EAFD:PVC ratio was 1:2. The investigation highlighted that franklinite, the most refractory mineral to leaching, was completely destroyed. The leaching residue was found to compose mainly of magnetite and hematite. PMID- 24769847 TI - Transgenerational effects of traffic-related fine particulate matter (PM2.5) on nematode Caenorhabditis elegans. AB - Numerous studies have demonstrated the toxic effects of fine particle matter less than 2.5 MUm (PM2.5) on health of human. However, little information is available on PM2.5 ecotoxicity. We employed Caenorhabditis elegans to investigate the adverse effects of traffic-related PM2.5 on exposed animals and their progeny. Acute exposure to high concentrations of PM2.5 in the range of mg/L caused adverse effects on development, lifespan, reproduction, and locomotion behavior of nematodes. In contrast, prolonged exposure to low concentrations of PM2.5 in the range of MUg/L resulted in adverse effects on development, lifespan, reproduction, locomotion behavior, and intestinal development of nematodes. Prolonged exposure to PM2.5 could even cause adverse effects on lifespan, reproduction, locomotion behavior, and intestinal development in progeny of exposed nematodes. PM2.5 toxicity was only partially recovered in progeny of exposed nematodes. For the PM2.5 toxicity on nematodes and their progeny, we hypothesize that it might be the combinational effects of oxidative stress, damage on intestinal barrier, and abnormal defecation behavior. Our data here imply the potential toxic effects of long-term exposure to traffic-related PM2.5 on environmental organisms. Our results further highlight the possible crucial roles of biological barrier and defecation behavior in regulating the PM2.5 toxicity. PMID- 24769848 TI - Efficient removal of pathogenic bacteria and viruses by multifunctional amine modified magnetic nanoparticles. AB - A novel amine-functionalized magnetic Fe3O4-SiO2-NH2 nanoparticle was prepared by layer-by-layer method and used for rapid removal of both pathogenic bacteria and viruses from water. The nanoparticles were characterized by TEM, EDS, XRD, XPS, FT-IR, BET surface analysis, magnetic property tests and zeta-potential measurements, respectively, which demonstrated its well-defined core-shell structures and strong magnetic responsivity. Pathogenic bacteria and viruses are often needed to be removed conveniently because of a lot of co-existing conditions. The amine-modified nanoparticles we prepared were attractive for capturing a wide range of pathogens including not only bacteriophage f2 and virus (Poliovirus-1), but also various bacteria such as S. aureus, E. coli O157:H7, P. aeruginosa, Salmonella, and B. subtilis. Using as-prepared amine-functionalized MNPs as absorbent, the nonspecific removal efficiency of E. coli O157:H7 or virus was more than 97.39%, while it is only 29.8% with Fe3O4-SiO2 particles. From joint removal test of bacteria and virus, there are over 95.03% harmful E. coli O157:H7 that can be removed from mixed solution with polyclonal anti-E. coli O157:H7 antibody modified nanoparticles. Moreover, the synergy effective mechanism has also been suggested. PMID- 24769849 TI - Use of a La(III)-modified bentonite for effective phosphate removal from aqueous media. AB - A bentonite from the Northeast Brazilian region was modified with lanthanum (NT 25La) using an ion exchange process. Lanthanum incorporation in the natural clay, as well as the properties of the clay materials, were confirmed by X-ray diffraction, X-ray fluorescence, specific surface area and scanning electron microscopy (SEM/EDX). Phosphate adsorption equilibrium and kinetic tests were performed at different temperatures. The adsorption data have shown that NT-25La reaches equilibrium between modified clay and phosphate solution within 60 min of contact. The phosphate retention at room temperature reached 95%, when initial phosphate concentration in solution was 5 mg L(-1). A kinetic-order variable model provided satisfactory fitting of the kinetic data. Adsorption of phosphate was best described by a Langmuir isotherm, with maximum phosphate sorption capacity of 14.0 mg g(-1). Two distinct adsorption mechanisms were observed that may influence the adsorption processes. The investigation pointed out that the phosphate adsorption occurs via physisorption processes and that the use of NT 25La provides a maximum phosphate sorption capacity higher than many commercial adsorbents. PMID- 24769850 TI - Stacked stem cell sheets enhance cell-matrix interactions. AB - Cell sheet engineering has enabled the production of confluent cell sheets stacked together for use as a cardiac patch to increase cell survival rate and engraftment after transplantation, thereby providing a promising strategy for high density stem cell delivery for cardiac repair. One key challenge in using cell sheet technology is the difficulty of cell sheet handling due to its weak mechanical properties. A single-layer cell sheet is generally very fragile and tends to break or clump during harvest. Effective transfer and stacking methods are needed to move cell sheet technology into widespread clinical applications. In this study, we developed a simple and effective micropipette based method to aid cell sheet transfer and stacking. The cell viability after transfer was tested and multi-layer stem cell sheets were fabricated using the developed method. Furthermore, we examined the interactions between stacked stem cell sheets and fibrin matrix. Our results have shown that the preserved ECM associated with the detached cell sheet greatly facilitates its adherence to fibrin matrix and enhances the cell sheet-matrix interactions. Accelerated fibrin degradation caused by attached cell sheets was also observed. PMID- 24769851 TI - Tyrosine phosphorylation within the intrinsically disordered cytosolic domains of the B-cell receptor: an NMR-based structural analysis. AB - Intrinsically disordered proteins are found extensively in cell signaling pathways where they often are targets of posttranslational modifications e.g. phosphorylation. Such modifications can sometimes induce or disrupt secondary structure elements present in the modified protein. CD79a and CD79b are membrane spanning, signal-transducing components of the B-cell receptor. The cytosolic domains of these proteins are intrinsically disordered and each has an immunoreceptor tyrosine-based activation motif (ITAM). When an antigen binds to the receptor, conserved tyrosines located in the ITAMs are phosphorylated which initiate further downstream signaling. Here we use NMR spectroscopy to examine the secondary structure propensity of the cytosolic domains of CD79a and CD79b in vitro before and after phosphorylation. The phosphorylation patterns are identified through analysis of changes of backbone chemical shifts found for the affected tyrosines and neighboring residues. The number of the phosphorylated sites is confirmed by mass spectrometry. The secondary structure propensities are calculated using the method of intrinsic referencing, where the reference random coil chemical shifts are measured for the same protein under denaturing conditions. Our analysis revealed that CD79a and CD79b both have an overall propensity for alpha-helical structure that is greatest in the C-terminal region of the ITAM. Phosphorylation of CD79a caused a decrease in helical propensity in the C-terminal ITAM region. For CD79b, the opposite was observed and phosphorylation resulted in an increase of helical propensity in the C-terminal part. PMID- 24769852 TI - The special case of hepatocytes: unique tissue architecture calls for a distinct mode of cell division. AB - Columnar epithelia (e.g., kidney, intestine) and hepatocytes embody the two major organizational phenotypes of non-stratified epithelial cells. Columnar epithelia establish their apical and basal domains at opposing poles and organize in monolayered cysts and tubules, in which their apical surfaces form a single continuous lumen whereas hepatocytes establish their apical domains in the midst of their basolateral domains and organize a highly branched capillary luminal network, the bile canaliculi, in which a single hepatocyte can engage in lumen formation with multiple neighbors. To maintain their distinct tissue architectures, columnar epithelial cells bisect their luminal domains during symmetric cell divisions, while the cleavage furrow in dividing hepatocytes avoids bisecting the bile canalicular domains. We discuss recently discovered molecular mechanisms that underlie the different cell division phenotypes in columnar and hepatocytic model cell lines. The serine/threonine kinase Par1b determines both the epithelial lumen polarity and cell division phenotype via cell adhesion signaling that converges on the small GTPase RhoA. PMID- 24769853 TI - Phospholipid-derived fatty acids and quinones as markers for bacterial biomass and community structure in marine sediments. AB - Phospholipid-derived fatty acids (PLFA) and respiratory quinones (RQ) are microbial compounds that have been utilized as biomarkers to quantify bacterial biomass and to characterize microbial community structure in sediments, waters, and soils. While PLFAs have been widely used as quantitative bacterial biomarkers in marine sediments, applications of quinone analysis in marine sediments are very limited. In this study, we investigated the relation between both groups of bacterial biomarkers in a broad range of marine sediments from the intertidal zone to the deep sea. We found a good log-log correlation between concentrations of bacterial PLFA and RQ over several orders of magnitude. This relationship is probably due to metabolic variation in quinone concentrations in bacterial cells in different environments, whereas PLFA concentrations are relatively stable under different conditions. We also found a good agreement in the community structure classifications based on the bacterial PLFAs and RQs. These results strengthen the application of both compounds as quantitative bacterial biomarkers. Moreover, the bacterial PLFA- and RQ profiles revealed a comparable dissimilarity pattern of the sampled sediments, but with a higher level of dissimilarity for the RQs. This means that the quinone method has a higher resolution for resolving differences in bacterial community composition. Combining PLFA and quinone analysis as a complementary method is a good strategy to yield higher resolving power in bacterial community structure. PMID- 24769854 TI - The differences in homocysteine level between obstructive sleep apnea patients and controls: a meta-analysis. AB - BACKGROUND: Studies have reported inconsistent findings regarding the relationship between obstructive sleep apnea (OSA) and homocysteine (HCY) level. This study aimed to assess the difference in plasma HCY level between OSA patients and controls by conducting a meta-analysis of published studies. METHODS: Database of PubMed, SCI, and China National Knowledge Internet (CNKI) were comprehensively searched. Eligible studies regarding plasma HCY level in OSA patients were identified by two independent reviewers. RevMan (version 5.2) and STATA (version 12.0) were employed for data synthesis. RESULTS: A total of 10 studies involving 432 subjects were included. Meta-analysis showed that plasma HCY levels in OSA group were 3.11 umol/l higher than that in control group (95% confidence interval: 2.08 to 4.15, P<0.01). Subgroup analysis revealed a more significant differences between OSA patients and controls when average body mass index >= 30 (the total weighted mean difference (WMD) was 3.64), average age<50 (the total WMD was 3.96) and average apnea hypopnea index >= 35 (the total WMD was 4.54). CONCLUSIONS: In this meta-analysis, plasma HCY levels were found to be higher in OSA patients compared to control subjects. PMID- 24769856 TI - Medical and obstetric complications among pregnant women aged 45 and older. AB - OBJECTIVE: The number of women aged 45 and older who become pregnant is increasing. The objective of this study was to estimate the risk of medical and obstetric complications among women aged 45 and older. METHODS: The Nationwide Inpatient Sample was used to identify pregnant woman during admission for delivery. Deliveries were identified using International Classification of Diseases, Ninth Revision (ICD-9-CM) codes. Using ICD-9-CM codes, pre-existing medical conditions and medical and obstetric complications were identified in women at the time of delivery and were compared for women aged 45 years and older to women under age 35. Outcomes among women aged 35-44 were also compared to women under age 35 to determine if women in this group demonstrated intermediate risk between the older and younger groups. Logistic regression analyses were used to calculate odds ratios with 95% confidence intervals for pre-existing medical conditions and medical and obstetric complications for both older groups relative to women under 35. Multivariable logistic regression analyses were also developed for outcomes at delivery among older women, while controlling for pre-existing medical conditions, multiple gestation, and insurance status, to determine the effect of age on the studied outcomes. RESULTS: Women aged 45 and older had higher adjusted odds for death, transfusion, myocardial infarction/ischemia, cardiac arrest, acute heart failure, pulmonary embolism, deep vein thrombosis, acute renal failure, cesarean delivery, gestational diabetes, fetal demise, fetal chromosomal anomaly, and placenta previa compared to women under 35. CONCLUSION: Pregnant women aged 45 and older experience significantly more medical and obstetric complications and are more likely to die at the time of a delivery than women under age 35, though the absolute risks are low and these events are rare. Further research is needed to determine what associated factors among pregnant women aged 45 and older may contribute to these findings. PMID- 24769857 TI - Genetic variants in microRNA machinery genes are associated [corrected] with idiopathic recurrent pregnancy loss risk. AB - OBJECTIVE: Key molecules involved in microRNA (miRNA) biogenesis, such as DROSHA, XPO5, and DICER, have been identified in trophoblast cells, confirming that the miRNA biogenesis pathway is active in human placenta. In addition, miRNAs regulate uterine gene expression associated with inflammatory responses during the peri-implantation period and participate in maternal-fetal immune tolerance. The purpose of this study was to demonstrate whether genetic polymorphisms in miRNA machinery genes show an association with idiopathic recurrent pregnancy loss (RPL) in Korean women. STUDY DESIGN: We performed a case-control study with 238 controls and 338 women who had experienced at least two consecutive pregnancy losses between 1999 and 2010. Genotypes of miRNA machinery genes, including DICER rs3742330, DROSHA rs10719, RAN GTPase (RAN) rs14035, and exportin-5 (XPO5) rs11077 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The logistic odds ratios (ORs) of RPL were estimated with a 95% confidence interval (CI) in multivariate analysis after maternal age adjustment. Gene-gene interactions among the loci of the four gene polymorphisms were evaluated using the multifactor dimensionality reduction (MDR) method. RESULTS: The RAN rs14035 CC genotype and DICER rs3742330/DROSHA rs10719 GG/TC+CC, rs3742330/RAN rs14035 GG/CC, and DICER rs3742330/XPO5 rs11077 GG/AC+CC combinations were significantly associated with increased RPL risk, whereas the RAN rs14035 CT, DICER rs3742330/RAN rs14035 AA+AG/CT+TT, DROSHA rs10719/RAN rs14035 TC+CC/CT+TT, and RAN rs14035/XPO5 rs11077 CT+TT/AA combinations reduced RPL risk. The A-T-T-C and G-C-T-A allele combinations (DICER/DROSHA/RAN/XPO5) were 20 times more frequent in the RPL group than in the control group. CONCLUSION: Our study demonstrates the relationship between RPL development and the polymorphism of the miRNA machinery gene RAN and combined genotype of DROSHA/DICER. PMID- 24769858 TI - P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo. AB - High-density lipoprotein (HDL) is known to protect against atherosclerosis by promoting the reverse cholesterol transport. A new pathway for the regulation of HDL-cholesterol (HDL-c) removal involving F1-ATPase and P2Y13 receptor (P2Y13R) was described in vitro, and recently in mice. However, the physiological role of F1-ATPase/P2Y13R pathway in the modulation of vascular pathology i.e. in the development of atherosclerotic plaques is still unknown. We designed a specific novel agonist (CT1007900) of the P2Y13R that caused stimulation of bile acid secretion associated with an increased uptake of HDL-c in the liver after single dosing in mice. Repeated dose administration in mice, for 2 weeks, stimulated the apoA-I synthesis and formation of small HDL particles. Plasma samples from the agonist-treated mice had high efflux capacity for mobilization of cholesterol in vitro compared to placebo group. In apoE-/- mice this agonist induced a decrease of atherosclerotic plaques in aortas and carotids. The specificity of P2Y13R pathway in those mice was assessed using adenovirus encoding P2Y13R-shRNA. These results demonstrate that P2Y13R plays a pivotal role in the HDL metabolism and could also be a useful therapeutic agent to decrease atherosclerosis. In this study, the up-regulation of HDL-c metabolism via activation of the P2Y13R using agonists could promote reverse cholesterol transport and promote inhibition of atherosclerosis progression in mice. PMID- 24769860 TI - Mapping the hinterland: Data issues in open science. AB - Open science is a practice in which the scientific process is shared completely and in real time. It offers the potential to support information flow, collaboration and dialogue among professional and non-professional participants. Using semi-structured interviews and case studies, this research investigated the relationship between open science and public engagement. This article concentrates on three particular areas of concern that emerged: first, how to effectively contextualise and narrate information to render it accessible, as opposed to simply available; second, concerns about data quantity and quality; and third, concerns about the skills required for effective contextualisation, mapping and interpretation of information. PMID- 24769859 TI - Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair. AB - Efficient local monocyte/macrophage recruitment is critical for tissue repair. Recruited macrophages are polarized toward classical (proinflammatory) or alternative (prohealing) activation in response to cytokines, with tight temporal regulation crucial for efficient wound repair. Estrogen acts as a potent anti inflammatory regulator of cutaneous healing. However, an understanding of estrogen/estrogen receptor (ER) contribution to macrophage polarization and subsequent local effects on wound healing is lacking. Here we identify, to our knowledge previously unreported, a role whereby estrogen receptor alpha (ERalpha) signaling preferentially polarizes macrophages from a range of sources to an alternative phenotype. Cell-specific ER ablation studies confirm an in vivo role for inflammatory cell ERalpha, but not ERbeta, in poor healing associated with an altered cytokine profile and fewer alternatively activated macrophages. Furthermore, we reveal intrinsic changes in ERalpha-deficient macrophages, which are unable to respond to alternative activation signals in vitro. Collectively, our data reveal that inflammatory cell-expressed ERalpha promotes alternative macrophage polarization, which is beneficial for timely healing. Given the diverse physiological roles of ERs, these findings will likely be of relevance to many pathologies involving excessive inflammation. PMID- 24769861 TI - Synthesis, spectral and thermal studies of pyridyl adducts of Zn(II) and Cd(II) dithiocarbamates, and their use as single source precursors for ZnS and CdS nanoparticles. AB - The synthesis, spectroscopic characterisation, and thermal studies of pyridyl adducts of Zn(II) and Cd(II) complexes of N-ethyl-N-phenyl dithiocarbamate, represented as [ZnL2py] and [CdL2py2], are reported. Single-crystal X-ray structural analysis of the Zn compound showed that it is five-coordinate with four sulphurs from dithiocarbamate and one nitrogen from pyridine in a distorted square pyramidal geometry. The thermogravimetric studies indicate that the zinc and cadmium compounds undergo fast weight loss, and the temperature at maximum rate of decomposition is at 277 degrees C and 265 degrees C respectively, to give the metal (Zn or Cd) sulphide residues. These compounds were used as single molecule precursors to produce nanocrystalline MS (M = Zn, Cd) after thermolysis in hexadecylamine. The morphological and optical properties of the resulting MS nanocrystallites were investigated using transmission electron microscopy (TEM), scanning electron microscopy (SEM), UV-Vis absorption and photoluminescence (PL) spectroscopy, and powdered X-ray diffraction (XRD). By varying the growth time, the temporal evolution of the optical properties and morphology of the nanocrystals were investigated. PMID- 24769863 TI - Stereochemical aspects and the synthetic scope of the S(H)i at the sulfur atom. Preparation of enantiopure 3-substituted 2,3-dihydro-1,2-benzoisothiazole 1 oxides and 1,1-dioxides. AB - Intramolecular homolytic substitution (SHi) on the sulfur atom at acyclic N-(o bromobenzyl)sulfinamides takes place with a complete inversion of the configuration and provides an excellent tool to connect N-tert butanesulfinylimines with enantiopure 3-substituted benzo-fused sulfinamides (1,2 benzoisothiazoline 1-oxides) and the related pharmacologically relevant sulfonamides. PMID- 24769862 TI - Coffee induces autophagy in vivo. AB - Epidemiological studies and clinical trials revealed that chronic consumption coffee is associated with the inhibition of several metabolic diseases as well as reduction in overall and cause-specific mortality. We show that both natural and decaffeinated brands of coffee similarly rapidly trigger autophagy in mice. One to 4 h after coffee consumption, we observed an increase in autophagic flux in all investigated organs (liver, muscle, heart) in vivo, as indicated by the increased lipidation of LC3B and the reduction of the abundance of the autophagic substrate sequestosome 1 (p62/SQSTM1). These changes were accompanied by the inhibition of the enzymatic activity of mammalian target of rapamycin complex 1 (mTORC1), leading to the reduced phosphorylation of p70(S6K), as well as by the global deacetylation of cellular proteins detectable by immunoblot. Immunohistochemical analyses of transgenic mice expressing a GFP-LC3B fusion protein confirmed the coffee-induced relocation of LC3B to autophagosomes, as well as general protein deacetylation. Altogether, these results indicate that coffee triggers 2 phenomena that are also induced by nutrient depletion, namely a reduction of protein acetylation coupled to an increase in autophagy. We speculate that polyphenols contained in coffee promote health by stimulating autophagy. PMID- 24769864 TI - Hyperpolarized functional magnetic resonance of murine skeletal muscle enabled by multiple tracer-paradigm synchronizations. AB - Measuring metabolism's time- and space-dependent responses upon stimulation lies at the core of functional magnetic resonance imaging. While focusing on water's sole resonance, further insight could arise from monitoring the temporal responses arising from the metabolites themselves, in what is known as functional magnetic resonance spectroscopy. Performing these measurements in real time, however, is severely challenged by the short functional timescales and low concentrations of natural metabolites. Dissolution dynamic nuclear polarization is an emerging technique that can potentially alleviate this, as it provides a massive sensitivity enhancement allowing one to probe low-concentration tracers and products in a single-scan. Still, conventional implementations of this hyperpolarization approach are not immediately amenable to the repeated acquisitions needed in real-time functional settings. This work proposes a strategy for functional magnetic resonance of hyperpolarized metabolites that bypasses this limitation, and enables the observation of real-time metabolic changes through the synchronization of stimuli-triggered, multiple-bolus injections of the metabolic tracer 13C1-pyruvate. This new approach is demonstrated with paradigms tailored to reveal in vivo thresholds of murine hind limb skeletal muscle activation, involving the conversion of 13C1-pyruvate to 13C1-lactate and 13C1-alanine. These functional hind-limb studies revealed that graded skeletal muscle stimulation causes commensurate increases in glycolytic metabolism in a frequency- and amplitude-dependent fashion, that can be monitored on the seconds/minutes timescale using dissolution dynamic nuclear polarization. Spectroscopic imaging further allowed the in vivo visualization of uptake, transformation and distribution of the tracer and products, in fast-twitch glycolytic and in slow-twitch oxidative muscle fiber groups. While these studies open vistas in time and sensitivity for metabolic functional magnetic resonance studies in muscle, the simplicity of our approach makes this technique amenable to a wide range of functional metabolic tracer studies. PMID- 24769865 TI - Peptide-catalyzed consecutive 1,6- and 1,4-additions of thiols to alpha,beta,gamma,delta-unsaturated aldehydes. AB - Regio- and enantioselective addition of thiols to alpha,beta,gamma,delta unsaturated aldehydes was performed with a resin-supported peptide catalyst. It was shown that a 1,4-adduct was generated mainly at the initial stage of the reaction, and this was eventually converted to a thermodynamically stable 1,6- and 1,4-diadduct through retro-addition/addition reactions. PMID- 24769866 TI - Do students know the physical activity recommendations for health promotion? AB - BACKGROUND: Knowledge is required for people to make health decisions. It can be conjectured that knowledge of physical activity recommended levels can be a step to behavior change. This study examined the knowledge of physical activity guidelines of adolescents who were completing the secondary school. METHODS: A survey was conducted with 2718 students (1613 girls), aged 16 to 18 years (Mean = 17.2 +/- 0.2 years). Gender and age were self-reported and socioeconomic status was calculated based on parental occupation. Students were asked about frequency, duration, and intensity of physical activity to achieve the recommended level. Chi-square was applied to the results. RESULTS: 16.2% reported that physical activity should be practiced daily. For the duration component of the recommendation, 43.5% identified correctly that the minimum recommended is 60 min/day. The intensity component was correctly answered by 62.7%. Considering all the components of the recommendation, only 3.6% of the students were able to identify correctly the physical activity recommendation, with no differences between genders or among socioeconomic status. CONCLUSIONS: These results highlight the need for an effective communication strategy for disseminating the message to ensure that young people are aware of, and understand the physical activity guidelines. PMID- 24769867 TI - Bacterial pathogenesis: Pirate bacteria hijack efferocytosis. PMID- 24769868 TI - microRNAs suppress cellular phenotypic heterogeneity. PMID- 24769869 TI - Trapping photons on the line: controllable dynamics of a quantum walk. AB - Optical interferometers comprising birefringent-crystal beam displacers, wave plates, and phase shifters serve as stable devices for simulating quantum information processes such as heralded coined quantum walks. Quantum walks are important for quantum algorithms, universal quantum computing circuits, quantum transport in complex systems, and demonstrating intriguing nonlinear dynamical quantum phenomena. We introduce fully controllable polarization-independent phase shifters in optical pathes in order to realize site-dependent phase defects. The effectiveness of our interferometer is demonstrated through realizing single photon quantum-walk dynamics in one dimension. By applying site-dependent phase defects, the translational symmetry of an ideal standard quantum walk is broken resulting in localization effect in a quantum walk architecture. The walk is realized for different site-dependent phase defects and coin settings, indicating the strength of localization signature depends on the level of phase due to site dependent phase defects and coin settings and opening the way for the implementation of a quantum-walk-based algorithm. PMID- 24769871 TI - Fatty acid composition, oxidation status and volatile organic compounds in "Colonnata" lard from Large White or Cinta Senese pigs as affected by curing time. AB - The aim of the present paper was to evaluate the fatty acid composition, lipolysis, lipid oxidation and volatile organic compounds (VOCs) in Colonnata lard from Large White (LW) or Cinta Senese (CS) pigs during one-year of curing. CS lard contained higher amounts of unsaturated fatty acids than that from LW, due to the different rearing and feeding systems. Despite higher lipolysis in CS backfat during the curing period, the rate of fatty acid and cholesterol oxidation was higher in LW. The amount of cholesterol oxidation products (COPs) and thiobarbituric acid reactive substances (TBARs) significantly decreased after 3 months of curing, regardless of the type of lard. VOCs composition of lard was affected by curing time, but not by breed. While volatile fatty acid oxidation products (mainly aldehydes) were present at the beginning of curing, subsequently other volatile compounds (such as sulphur compounds and terpenes) that derived from ingredients used for lard production, increased in the samples. PMID- 24769870 TI - Real-time bidirectional pyrophosphorolysis-activated polymerization for quantitative detection of somatic mutations. AB - Detection of somatic mutations for targeted therapy is increasingly used in clinical settings. However, due to the difficulties of detecting rare mutations in excess of wild-type DNA, current methods often lack high sensitivity, require multiple procedural steps, or fail to be quantitative. We developed real-time bidirectional pyrophosphorolysis-activated polymerization (real-time Bi-PAP) that allows quantitative detection of somatic mutations. We applied the method to quantify seven mutations at codons 12 and 13 in KRAS, and 2 mutations (L858R, and T790M) in EGFR in clinical samples. The real-time Bi-PAP could detect 0.01% mutation in the presence of 100 ng template DNA. Of the 34 samples from the colon cancer patients, real-time Bi-PAP detected 14 KRAS mutant samples whereas the traditional real-time allele-specific PCR missed two samples with mutation abundance <1% and DNA sequencing missed nine samples with mutation abundance <10%. The detection results of the two EGFR mutations in 45 non-small cell lung cancer samples further supported the applicability of the real-time Bi-PAP. The real-time Bi-PAP also proved to be more efficient than the real-time allele specific PCR in the detection of templates prepared from formalin-fixed paraffin embedded samples. Thus, real-time Bi-PAP can be used for rapid and accurate quantification of somatic mutations. This flexible approach could be widely used for somatic mutation detection in clinical settings. PMID- 24769872 TI - The use of computer-assisted image analysis in the evaluation of the effect of management systems on changes in the color, chemical composition and texture of m. longissimus dorsi in pigs. AB - The effect of management systems on selected physical properties and chemical composition of m. longissimus dorsi was studied in pigs. Muscle texture parameters were determined by computer-assisted image analysis, and the color of muscle samples was evaluated using a spectrophotometer. Highly significant correlations were observed between chemical composition and selected texture variables in the analyzed images. Chemical composition was not correlated with color or spectral distribution. Subject to the applied classification methods and groups of variables included in the classification model, the experimental groups were identified correctly in 35-95%. No significant differences in the chemical composition of m. longissimus dorsi were observed between experimental groups. Significant differences were noted in color lightness (L*) and redness (a*). PMID- 24769873 TI - Shelf life of cooked goat blood sausage prepared with the addition of heart and kidney. AB - This study focused on the effect of two packaging formats (vacuum packaging and over-wrap packaging) on the shelf life of cooked sausage prepared with blood, heart, kidney and goat meat fragments under storage at 4+/-1 degrees C for a period of 90 days. The storage time and type of packaging significantly affected the chemical (pH, moisture, protein and TBARS number), physical (shear force) and microbial (mould and yeast) parameters of cooked sausage. Vacuum packaging maintained the microbiological and chemical qualities of cooked goat blood sausage for a longer period of time (63 days) compared to over-wrap packaging (41 days) and could be a viable alternative to refrigerated storage of the product for quality maintenance. PMID- 24769874 TI - Effects of packaging systems and fat concentrations on microbiology, sensory and physical properties of ground beef stored at 4+/-1 degrees C for 25 days. AB - This study evaluated effects of modified atmosphere (MAP, 0.4% carbon monoxide [CO], 30% carbon dioxide, and 69.6% nitrogen), vacuum (VP) and polyvinyl chloride (PVC) packaging systems and fat levels (10, 20 and 30% fat) on ground beef stored at 4 +/- 1 degrees C for 25 days for microbiology, sensory, pH, thiobarbituric acid reactive substances (TBARS), objective color, headspace and residual CO. As storage time increased, pH decreased (P< 0.05) for MAP and VP and increased (P < 0.05) for PVC. TBARS varied (P < 0.05) among MAP and VP treatments. Except for day 1, CO headspace concentrations were similar among fat concentrations, and residual CO absorption in meat increased (P < 0.05) for all MAP treatments. In all treatments, degree of lightness was similar, redness decreased and brown discoloration increased during storage. As psychrotrophic bacteria counts increased, panelists detected color and off-odor deterioration in all systems. The CO treatment had no effect on maintaining the carboxymyoglobin "cherry red" fresh meat color during meat spoilage. PMID- 24769875 TI - Investigation of persistence of infectious Toxoplasma gondii in raw sausages using in-house developed and validated real time-PCR. AB - The question, if and to what extent raw-sausage-products represent a possible source of infection for the globally distributed and potentially health threatening toxoplasmosis gave reason for this study. For this, the survival capability of Toxoplasma gondii in relation to the raw-sausage-manufacturing process including different ripening-processes was investigated. To enable a fast and reliable parasite-detection, a real time-PCR-system based on a specific 529 bp-fragment of T. gondii and an internal amplification control (IAC) was developed and established. The applicability was tested in various experiments where T. gondii-tachyzoites were mixed into different types of raw-sausages and then investigated by using the real time-PCR-system. The latter was also used to investigate the possible infection-risk of raw-sausages. For this, two pigs were intravenously infected with T. gondii-tachyzoites and after having reached the typical slaughtering age, their meat was manufactured to different raw-sausage products ("Mett"- and "Teewurst" as well as "Salami"). In order to prove the potential infectivity of these products under conditions close to reality, sausages in different ripening stages were fed to laboratory mice. The animals' organs (brain, heart and spleen) were examined employing the real time-PCR. T. gondii-DNA was detected in four out of 288 (1.4%) mice indicating that marketable raw-sausage-products generally bear a risk for consumers. However, the probability of an infection seems to be quite marginal. PMID- 24769876 TI - The protection of bovine skeletal myofibrils from proteolytic damage post mortem by small heat shock proteins. AB - This study aimed to determine how small heat shock proteins (sHSPs) protect myofibrillar proteins from MU-calpain degradation during ageing. Immunoprecipitation experiments with M. longissimus dorsi (LD) from Angus heifers (n = 14) examined the interaction between alphabeta-crystallin, desmin, titin, HSP20, HSP27 and MU-calpain. Results showed that alphabeta-crystallin associated with desmin, titin, HSP20, HSP27 and MU-calpain. Exogenous alphabeta-crystallin reduced desmin and titin degradations in myofibrillar extracts and attenuated MU calpain activity. In a second experiment, bull LD (n = 94) were aged at -1.5 degrees C for up to 28 days post mortem. MU-Calpain autolysed faster in high ultimate pH (pH(u)) meat (pH(u)>=6.2) and this was concomitant with the more rapid degradation of titin and filamin in this pH(u) group. Desmin stability in intermediate pH(u) meat (pH(u) 5.8 to 6.19) may be due to the protection of myofibril-bound sHSPs combined with the competitive inhibition of MU-calpain by sHSPs. PMID- 24769877 TI - Nutrient database improvement project: the influence of USDA quality and yield grade on the separable components and proximate composition of raw and cooked retail cuts from the beef chuck. AB - This study was designed to provide updated information on the separable components, cooking yields, and proximate composition of retail cuts from the beef chuck. Additionally, the impact the United States Department of Agriculture (USDA) Quality and Yield Grade may have on such factors was investigated. Ultimately, these data will be used in the USDA - Nutrient Data Laboratory's (NDL) National Nutrient Database for Standard Reference (SR). To represent the current United States beef supply, seventy-two carcasses were selected from six regions of the country based on USDA Yield Grade, USDA Quality Grade, gender, and genetic type. Whole beef chuck primals from selected carcasses were shipped to three university laboratories for subsequent retail cut fabrication, raw and cooked cut dissection, and proximate analyses. The incorporation of these data into the SR will improve dietary education, product labeling, and other applications both domestically and abroad, thus emphasizing the importance of accurate and relevant beef nutrient data. PMID- 24769878 TI - Investigating the control of Listeria monocytogenes on alternatively-cured frankfurters using natural antimicrobial ingredients or post-lethality interventions. AB - The objective of this study was to investigate natural antimicrobials including cranberry powder, dried vinegar and lemon juice/vinegar concentrate, and post lethality interventions (lauric arginate, octanoic acid, thermal treatment and high hydrostatic pressure) for the control of Listeria monocytogenes on alternatively-cured frankfurters. Lauric arginate, octanoic acid, and high hydrostatic pressure (400 MPa) reduced L. monocytogenes populations by 2.28, 2.03, and 1.88 log 10 CFU per g compared to the control. L. monocytogenes grew in all post-lethality intervention treatments, except after a 600 MPa high hydrostatic pressure treatment for 4 min. Cranberry powder did not inhibit the growth of L. monocytogenes, while a dried vinegar and a vinegar/lemon juice concentrate did. This study demonstrated the bactericidal properties of high hydrostatic pressure, octanoic acid and lauric arginate, and the bacteriostatic potential of natural antimicrobial ingredients such as dried vinegar and vinegar/lemon juice concentrate against L. monocytogenes. PMID- 24769879 TI - Effect of partial replacement of pork meat with an olive oil organogel on the physicochemical and sensory quality of dry-ripened venison sausages. AB - A venison salchichon was made using varying proportions of olive oil to replace the traditional pork meat and to obtain a healthier product. Six types of salchichon were produced. The control type contained 75% lean venison and 25% pork meat; in the other types, 15%, 25%, 35%, 45% and 55% of the pork meat were replaced by olive oil introduced in the form of an organogel (olive oil emulsified with soy protein and water). All types were satisfactory in terms of physicochemical characteristics (pH, a(w), moisture loss) and instrumental colour throughout ripening, and displayed acceptable levels of lipolysis (acidity index) and lipid oxidation (TBARS). Higher proportions of olive oil prompted an increase in monounsaturated fatty acid content (mainly C18:1). All six types of salchichon were judged acceptable by consumers, the highest scores being given to those in which no more than 25% of the pork meat was replaced by olive oil. PMID- 24769880 TI - The role of red and processed meat in colorectal cancer development: a perspective. AB - This paper is based on a workshop held in Oslo, Norway in November 2013, in which experts discussed how to reach consensus on the healthiness of red and processed meat. Recent nutritional recommendations include reducing intake of red and processed meat to reduce cancer risk, in particular colorectal cancer (CRC). Epidemiological and mechanistic data on associations between red and processed meat intake and CRC are inconsistent and underlying mechanisms are unclear. There is a need for further studies on differences between white and red meat, between processed and whole red meat and between different types of processed meats, as potential health risks may not be the same for all products. Better biomarkers of meat intake and of cancer occurrence and updated food composition databases are required for future studies. Modifying meat composition via animal feeding and breeding, improving meat processing by alternative methods such as adding phytochemicals and improving our diets in general are strategies that need to be followed up. PMID- 24769882 TI - Middle fossa vestibular neurectomy for refractory vertigo: less is more. AB - OBJECTIVE: This study aimed to evaluate outcomes of the middle fossa (MF) superior vestibular neurectomy in unilateral Meniere's disease. PATIENTS AND METHODS: Case series with preoperative and postoperative analysis of the 1995 American Academy of Otolaryngology hearing stage and vertigo class, gait instability, and results of vestibular-evoked myogenic potentials (VEMP). RESULTS: Four out of the 5 patients had total vertigo control (class A) and 1 had near total control (class B) by the last visit (mean follow-up, 23.6 months). There were no changes in hearing thresholds and hearing stage. Four patients had resolution of their gait instability by 2 months after surgery. Postoperative VEMP responses were preserved in all 3 patients with positive VEMP preoperatively. CONCLUSION: This is the first report of the anatomical and functional preservation of the inferior vestibular nerve in vestibular neurectomy for the treatment of refractory vertigo in unilateral Meniere's disease, with VEMP testing before and after vestibular neurectomy. The modified technique limits the surgical dissection and may help avoid complications such as postoperative hearing loss and persistent gait instability. This approach is indicated when other more conservative measures have failed, and patient selection is paramount to avoid long-term complications. PMID- 24769883 TI - A molecular link between distinct neuronal asymmetries. PMID- 24769884 TI - Systematic experimental charge density analysis of anion receptor complexes. AB - The first systematic electronic resolution study of a series of urea-based anion receptor complexes is presented. The hydrogen bonding in these multi-component systems was fully characterised using Bader's Quantum Theory of Atoms In Molecules (QTAIM) with the strength of the various N-H...anion hydrogen bonds quantified and the individual contributions of different intermolecular forces to the overall receptor: anion interaction derived by comparison of the charge densities in the related complexes. The strength of the N-Hanion hydrogen bonds was correlated to the basicity of the anion and related to the structure of the receptors. The geometric criteria used to identify hydrogen bonding interactions in standard resolution X-ray diffraction studies were shown to be valid for stronger interactions. However, these geometric criteria are less reliable and lead to assumptions that are not necessarily upheld when applied to weaker intermolecular interactions. The presence of these could only be confirmed by charge density studies. The effect that changes to the receptor substitution pattern have on the entire supramolecular system is illustrated by the differences in the electrostatic potential distributions and atomic charges across the series. The application of systematic high resolution studies to rationalise a variety of host-guest systems has been demonstrated. PMID- 24769885 TI - A device for performing automated balloon catheter inflation ischemia studies. AB - Coronary collateral growth (arteriogenesis) is a physiological adaptive response to transient and repetitive occlusion of major coronary arteries in which small arterioles (native collaterals) with minimal to no blood flow remodel into larger conduit arteries capable of supplying adequate perfusion to tissue distal to the site of occlusion. The ability to reliably and reproducibly mimic transient, repetitive coronary artery occlusion (ischemia) in animal models is critical to the development of therapies to restore coronary collateral development in type II diabetes and the metabolic syndrome. Current animal models for repetitive coronary artery occlusion implement a pneumatic occluder (balloon) that is secured onto the surface of the heart with the suture, which is inflated manually, via a catheter connected to syringe, to effect occlusion of the left anterior descending coronary artery (LAD). This method, although effective, presents complications in terms of reproducibility and practicality. To address these limitations, we have designed a device for automated, transient inflation of balloon catheters in coronary artery occlusion models. This device allows repeated, consistent inflation (to either specified pressure or volume) and the capability for implementing very complex, month-long protocols. This system has significantly increased the reproducibility of coronary collateral growth studies in our laboratory, resulting in a significant decrease in the numbers of animals needed to complete each study while relieving laboratory personnel from the burden of extra working hours and enabling us to continue studies over periods when we previously could not. In this paper, we present all details necessary for construction and operation of the inflator. In addition, all of the components for this device are commercially available and economical (Table S1). It is our hope that the adoption of automated balloon catheter inflation protocols will improve the experimental reliability of transient ischemia studies at many research institutions. PMID- 24769887 TI - False-positive rates associated with the use of multiple performance and symptom validity tests. AB - Performance validity test (PVT) error rates using Monte Carlo simulation reported by Berthelson and colleagues (in False positive diagnosis of malingering due to the use of multiple effort tests. Brain Injury, 27, 909-916, 2013) were compared with PVT and symptom validity test (SVT) failure rates in two nonmalingering clinical samples. At a per-test false-positive rate of 10%, Monte Carlo simulation overestimated error rates for: (i) failure of >=2 out of 5 PVTs/SVT for Larrabee (in Detection of malingering using atypical performance patterns on standard neuropsychological tests. The Clinical Neuropsychologist, 17, 410-425, 2003) and ACS (Pearson, Advanced clinical solutions for use with WAIS-IV and WMS IV. San Antonio: Pearson Education, 2009) and (ii) failure of >=2 out of 7 PVTs/SVT for Larrabee (Detection of malingering using atypical performance patterns on standard neuropsychological tests. The Clinical Neuropsychologist, 17, 410-425, 2003; Malingering scales for the Continuous Recognition Memory Test and Continuous Visual Memory Test. The Clinical Neuropsychologist, 23, 167-180, 2009 combined). Monte Carlo overestimation is likely because PVT performances are atypical in pattern or degree for what occurs in actual neurologic, psychiatric, or developmental disorders. Consequently, PVT scores form skewed distributions with performance at ceiling and restricted range, rather than forming a standard normal distribution with mean of 0 and standard deviation of 1.0. These results support the practice of using >=2 PVT/SVT failures as representing probable invalid clinical presentation. PMID- 24769888 TI - Clinical feasibility study to detect angiogenesis following bone marrow stem cell transplantation in chronic ischaemic heart failure. AB - BACKGROUND: Bone marrow stem cell (BMSC) therapy for cardiovascular disease has shown considerable preclinical and clinical promise, but there remains a need for mechanistic studies to help bridge the transition from bench to bedside. We have designed a substudy to our REGENERATE-IHD trial (ClinicalTrial.gov Identifier: NCT00747708) to assess the feasibility of a novel imaging technique to detect angiogenesis following BMSC therapy. METHODS AND RESULTS: Nine patients who had been randomized to receive intracoronary injection of G-CSF-mobilized BMSCs or control (serum) were included in this substudy. Patients underwent SPECT imaging using a novel radiolabelled peptide (Tc-NC100692), which has a high affinity for the alphavbeta3 integrin, an angiogenesis-related integrin. This was repeated 4 days after intracoronary injection of BMSCs/control to assess for neoangiogenesis. The imaging study was well tolerated with no adverse effects. Myocardial tracer uptake was detectable at baseline in all nine patients, with no myocardial uptake seen in two control patients used for comparison. Baseline uptake appeared to correlate with baseline ejection fraction but changes with therapy did not reach statistical significance. CONCLUSION: SPECT imaging with a Tc-NC100692 is feasible in patients with heart failure, with baseline activity suggesting persistent angiogenesis in patients with remote myocardial infarction. PMID- 24769889 TI - Circulating estrogen metabolites and risk of breast cancer in postmenopausal women. AB - BACKGROUND: It has been hypothesized that predominance of the 2-hydroxylation estrogen metabolism pathway over the 16alpha-hydroxylation pathway may be inversely associated with breast cancer risk. METHODS: We examined the associations of invasive breast cancer risk with circulating 2-hydroxyestrone (2 OHE1), 16alpha-hydroxyestrone (16alpha-OHE1), and the 2-OHE1:16alpha-OHE1 ratio in a case-control study of postmenopausal women nested within two prospective cohorts: the New York University Women's Health Study (NYUWHS) and the Northern Sweden Mammary Screening Cohort (NSMSC), with adjustment for circulating levels of estrone, and additional analyses by tumor estrogen receptor (ER) status. Levels of 2-OHE1 and 16alpha-OHE1 were measured using ESTRAMET 2/16 assay in stored serum or plasma samples from 499 incident breast cancer cases and 499 controls, who were matched on cohort, age, and date of blood donation. RESULTS: Overall, no significant associations were observed between breast cancer risk and circulating levels of 2-OHE1, 16alpha-OHE1, or their ratio in either cohort and in combined analyses. For 2-OHE1, there was evidence of heterogeneity by ER status in models adjusting for estrone (P <= 0.03). We observed a protective association of 2-OHE1 with ER+ breast cancer [multivariate-adjusted OR for a doubling of 2-OHE1, 0.67 (95% confidence interval [CI], 0.48-0.94; P = 0.02)]. CONCLUSIONS: In this study, higher levels of 2-OHE1 were associated with reduced risk of ER+ breast cancer in postmenopausal women after adjustment for circulating estrone. IMPACT: These results suggest that taking into account the levels of parent estrogens and ER status is important in studies of estrogen metabolites and breast cancer. PMID- 24769890 TI - Epstein-Barr virus serology as a potential screening marker for nasopharyngeal carcinoma among high-risk individuals from multiplex families in Taiwan. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated cancer that is highly treatable when diagnosed early, with 5-year disease-free survival of approximately 90%. However, NPC is typically diagnosed at advanced stages, in which disease-free survival is <50%. There is, therefore, a need for clinical tools to assist in early NPC detection, particularly among high-risk individuals. METHODS: We evaluated the ability of anti-EBV IgA antibodies to detect incident NPC among high-risk Taiwanese individuals. NPC cases (N = 21) and age- and sex-matched controls (N = 84) were selected. Serum collected before NPC diagnosis was tested for ELISA-based IgA antibodies against the following EBV peptides: EBNA1, VCAp18, EAp138, Ead_p47, and VCAp18 + EBNA1 peptide mixture. The sensitivity, specificity, and screening program parameters were calculated. RESULTS: EBNA1 IgA had the best performance characteristics. At an optimized threshold value, EBNA1 IgA measured at baseline identified 80% of the high-risk individuals who developed NPC during follow-up (80% sensitivity). However, approximately 40% of high-risk individuals who did not develop NPC also tested positive (false positives). Application of EBNA1 IgA as a biomarker to detect incident NPC in a previously unscreened, high-risk population revealed that 164 individuals needed to be screened to detect 1 NPC and that 69 individuals tested positive per case detected. CONCLUSIONS: EBNA1 IgA proved to be a sensitive biomarker for identifying incident NPC, but future work is warranted to develop more specific screening tools to decrease the number of false positives. IMPACT: Results from this study could inform decisions about screening biomarkers and referral thresholds for future NPC early-detection program evaluations. PMID- 24769892 TI - Synthesis of alkylidene pyrrolo[3,4-b]pyridin-7-one derivatives via Rh(III) catalyzed cascade oxidative alkenylation/annulation of picolinamides. AB - A practical Rh(III)-catalyzed cascade olefination/annulation of picolinamides leading to pyrrolo[3,4-b]pyridines has been developed. The reaction shows wide scope, complete regiocontrol and excellent stereoselectivity. PMID- 24769896 TI - Nucleostemin stabilizes ARF by inhibiting the ubiquitin ligase ULF. AB - Upregulated expression of nucleolar GTPase nucleostemin (NS) has been associated with increased cellular proliferation potential and tumor malignancy during cancer development. Recent reports attribute the growth regulatory effects of NS protein to its role in facilitating ribosome production. However, the oncogenic potential of NS remains unclear, as imbalanced levels of NS have been reported to exert growth inhibitory effect by modulating p53 tumor-suppressor activity. It also remains in questions if aberrant NS levels might have a p53-independent role in regulation of cell proliferation and growth. In this study, we performed affinity purification and mass spectrometry analysis to explore protein-protein interactions influencing NS growth regulatory properties independently of p53 tumor suppressor. We identified the alternative reading frame (ARF) protein as a key protein associating with NS and further verified the interaction through in vitro and in vivo assays. We demonstrated that NS is able to regulate cell cycle progression by regulating the stability of the ARF tumor suppressor. Furthermore, overexpression of NS suppressed ARF polyubiquitination by its E3 ligase Ubiquitin Ligase for ARF and elongated its half-life, whereas knockdown of NS led to the decrease of ARF levels. Also, we found that NS can enhance NPM stabilization of ARF. Thus, we propose that in the absence of p53, ARF can be stabilized by NS and nucleophosmin to serve as an alternative tumor-suppressor surveillance, preventing potential cellular transformation resulting from the growth-inducing effects of NS overexpression. PMID- 24769897 TI - The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis. AB - ORCTL3 is a member of a group of genes, the so-called anticancer genes, that cause tumour-specific cell death. We show that this activity is triggered in isogenic renal cells upon their transformation independently of the cells' proliferation status. For its cell death effect ORCTL3 targets the enzyme stearoyl-CoA desaturase-1 (SCD1) in fatty acid metabolism. This is caused by transmembrane domains 3 and 4, which are more efficacious in vitro than a low molecular weight drug against SCD1, and critically depend on their expression level. SCD1 is found upregulated upon renal cell transformation indicating that its activity, while not impacting proliferation, represents a critical bottleneck for tumourigenesis. An adenovirus expressing ORCTL3 leads to growth inhibition of renal tumours in vivo and to substantial destruction of patients' kidney tumour cells ex vivo. Our results indicate fatty acid metabolism as a target for tumour specific apoptosis in renal tumours and suggest ORCTL3 as a means to accomplish this. PMID- 24769898 TI - TACC3 deregulates the DNA damage response and confers sensitivity to radiation and PARP inhibition. AB - Deregulation of the transforming acidic coiled-coil protein 3 (TACC3), an important factor in the centrosome-microtubule system, has been linked to a variety of human cancer types. We have recently reported on the oncogenic potential of TACC3; however, the molecular mechanisms by which TACC3 mediates oncogenic function remain to be elucidated. In this study, we show that high levels of TACC3 lead to the accumulation of DNA double-strand breaks (DSBs) and disrupt the normal cellular response to DNA damage, at least in part, by negatively regulating the expression of ataxia telangiectasia mutated (ATM) and the subsequent DNA damage response (DDR) signaling cascade. Cells expressing high levels of TACC3 display defective checkpoints and DSB-mediated homologous recombination (HR) and non-homologous end joining (NHEJ) repair systems, leading to genomic instability. Importantly, high levels of TACC3 confer cellular sensitization to radiation and poly(ADP-ribose) polymerase (PARP) inhibition. Overall, our findings provide critical information regarding the mechanisms by which TACC3 contributes to genomic instability, potentially leading to cancer development, and suggest a novel prognostic, diagnostic and therapeutic strategy for the treatment of cancer types expressing high levels of TACC3. PMID- 24769899 TI - miR-615-5p is epigenetically inactivated and functions as a tumor suppressor in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis. Although microRNA (miRNA) transcripts have a crucial role in carcinogenesis and development, little information is known regarding the aberrant DNA methylation of miRNAs in PDAC. Using methylated DNA immunoprecipitation-chip analysis, we found that miR-615-5p was hypermethylated in its putative promoter region, which silenced its expression in PDAC cell lines. In addition, the overexpression of miR-615-5p in pancreatic cancer cells suppressed cell proliferation, migration and invasion. Insulin-like growth factor 2 (IGF2) is an imprinted gene, and its abnormal expression contributes to tumor growth. Here, we identified IGF2 as a target of miR-615-5p using a luciferase reporter assay. IGF2 upregulation in PDAC tissues was not correlated with a loss of imprinting but was inversely correlated with miR-615-5p downregulation. In addition, miR-615-5p suppressed pancreatic cancer cell proliferation, migration and invasion by directly targeting IGF2, and this effect could be reversed by co transfection with IGF2. Furthermore, the stable overexpression of miR-615-5p inhibited tumor growth in vivo and was correlated with IGF2 expression. Using RNA sequencing, we further identified miR-615-5p as potentially targeting other genes, such as the proto-oncogene JUNB, and interfering with the insulin signaling pathway. Taken together, our results demonstrate that miR-615-5p was abnormally downregulated in PDAC cells due to promoter hypermethylation, which limited its inhibition of IGF2 and other target genes, thereby contributing to tumor growth, invasion and migration. These data demonstrate a novel and important role of miR-615-5p as a tumor suppressor in PDAC. PMID- 24769900 TI - Evidence that the insertion events of IS2 transposition are biased towards abrupt compositional shifts in target DNA and modulated by a diverse set of culture parameters. AB - Insertion specificity of mobile genetic elements is a rather complex aspect of DNA transposition, which, despite much progress towards its elucidation, still remains incompletely understood. We report here the results of a meta-analysis of IS2 target sites from genomic, phage, and plasmid DNA and find that newly acquired IS2 elements are consistently inserted around abrupt DNA compositional shifts, particularly in the form of switch sites of GC skew. The results presented in this study not only corroborate our previous observations that both the insertion sequence (IS) minicircle junction and target region adopt intrinsically bent conformations in IS2, but most interestingly, extend this requirement to other families of IS elements. Using this information, we were able to pinpoint regions with high propensity for transposition and to predict and detect, de novo, a novel IS2 insertion event in the 3' region of the gfp gene of a reporter plasmid. We also found that during amplification of this plasmid, process parameters such as scale, culture growth phase, and medium composition exacerbate IS2 transposition, leading to contamination levels with potentially detrimental clinical effects. Overall, our findings provide new insights into the role of target DNA structure in the mechanism of transposition of IS elements and extend our understanding of how culture conditions are a relevant factor in the induction of genetic instability. PMID- 24769901 TI - Control of glycolytic flux in directed biosynthesis of uridine-phosphoryl compounds through the manipulation of ATP availability. AB - Adenosine triphosphate (ATP), the most important energy source for metabolic reactions and pathways, plays a vital role in control of metabolic flux. Considering the importance of ATP in regulation of the glycolytic pathway, the use of ATP-oriented manipulation is a rational and efficient route to regulate metabolic flux. In this paper, a series of efficient ATP-oriented regulation methods, such as changing ambient temperature and altering reduced nicotinamide adenine dinucleotide (NADH), was developed. To satisfy the different demand for ATP at different phases in directed biosynthesis of uridine-phosphoryl compounds, a multiphase ATP supply regulation strategy was also used to enhance to yield of target metabolites. PMID- 24769902 TI - Functions of poly-gamma-glutamic acid (gamma-PGA) degradation genes in gamma-PGA synthesis and cell morphology maintenance. AB - Poly-gamma-glutamic acid (gamma-PGA) is an important biopolymer with greatly potential in industrial and medical applications. In the present study, we constructed a metabolically engineered glutamate-independent Bacillus amyloliquefaciens LL3 strain with considerable gamma-PGA production, which was carried out by single, double, and triple markerless deletions of three degradation genes pgdS, ggt, and cwlO. The highest gamma-PGA production (7.12 g/L) was obtained from the pgdS and cwlO double-deletion strain NK-pc, which was 93 % higher than that of wild-type LL3 strain (3.69 g/L). The triple-gene deletion strain NK-pgc showed a 28 % decrease in gamma-PGA production, leading to a yield of 2.69 g/L. Furthermore, the cell morphologies of the mutant strains were also characterized. The cell length of cwlO deletion strains NK-c and NK-pc was shorter than that of the wild-type strain, while the ggt deletion strains NK g, NK-pg, NK-gc, and NK-pgc showed longer cell lengths. This is the first report concerning the markerless deletion of gamma-PGA degradation genes to improve gamma-PGA production in a glutamate-independent strain and the first observation that gamma-glutamyltranspeptidase (encoded by ggt) could be involved in the inhibition of cell elongation. PMID- 24769903 TI - Occurrence and diversity of nitrite-dependent anaerobic methane oxidation bacteria in the sediments of the South China Sea revealed by amplification of both 16S rRNA and pmoA genes. AB - Nitrite-dependent anaerobic methane oxidation (n-damo) process is unique in linking the microbial carbon and nitrogen cycles, but the presence of n-damo bacteria in marine ecosystem and the associated environmental factors are still poorly understood. In the present study, detection of n-damo bacteria using 16S rRNA and pmoA gene-based PCR primers was successfully employed to reveal their diversity and distribution in the surface and subsurface sediments of the South China Sea (SCS). The widespread occurrence of n-damo bacteria in both the surface and subsurface sediments with high diversity has been confirmed in this study. The pmoA gene-amplified sequences clustered within three newly erected subclusters, namely SCS-1, SCS-2, and SCS-3, suggesting the unique niche specificity of n-damo bacteria in the marine ecosystem. Results indicated the presence of n-damo bacteria in the west Pacific Ocean with a wide distribution from the continental shelf (E201S) to the deep abyss (E407S and E407B). Community structures of n-damo bacteria in SCS are clearly different from those of nonmarine ones known. It is also found that NO x (-) and NH4 (+) affected the community structures and distribution of n-damo bacteria in the SCS sediments differently. Salinity is another important factor identified, shaping the n-damo communities in marine environments. The community based on pmoA gene-amplified sequences, and community richness and diversity based on 16S rRNA gene-amplified sequences correlated with temperature. PMID- 24769904 TI - Atmospheric and room temperature plasma (ARTP) as a new powerful mutagenesis tool. AB - Developing rapid and diverse microbial mutation tool is of importance to strain modification. In this review, a new mutagenesis method for microbial mutation breeding using the radio-frequency atmospheric-pressure glow discharge (RF APGD) plasma jets is summarized. Based on the experimental study, the helium RF APGD plasma jet has been found to be able to change the DNA sequences significantly, indicating that the RF APGD plasma jet would be a powerful tool for the microbial mutagenesis with its outstanding features, such as the low and controllable gas temperatures, abundant chemically reactive species, rapid mutation, high operation flexibility, etc. Then, with the RF APGD plasma generator as the core component, a mutation machine named as atmospheric and room temperature plasma (ARTP) mutation system has been developed and successfully employed for the mutation breeding of more than 40 kinds of microorganisms including bacteria, fungi, and microalgae. Finally, the prospect of the ARTP mutagenesis is discussed. PMID- 24769905 TI - Reconstructing a Thauera genome from a hydrogenotrophic-denitrifying consortium using metagenomic sequence data. AB - Here, shotgun metagenomic sequencing was conducted to reveal the hydrogen oxidizing autotrophic-denitrifying metabolism in an enriched Thauera-dominated consortium. A draft genome named Thauera R4 of over 90 % completeness (3.8 Mb) was retrieved mainly by a coverage-defined binning method from 3.5 Gb paired-end Illumina reads. We identified 1,263 genes (accounting for 33 % of total genes in the finished genome of Thauera aminoaromatica MZ1T) with average nucleotide identity of 87.6 % shared between Thauera R4 and T. aminoaromatica MZ1T. Although Thauera R4 and T. aminoaromatica shared quite similar nitrogen metabolism and a high nucleotide similarity (98.8 %) in their 16S ribosomal RNA genes, they showed different functional potentials in several important environmentally relevant processes. Unlike T. aminoaromatica MZ1T, Thauera R4 carries an operon of [NiFe] hydrogenase (EC 1.12.99.6) catalyzing molecular hydrogen oxidation in nitrate rich solution. Moreover, Thauera R4 is a mixtrophic bacterium possessing key enzymes for autotrophic CO2-fixation and heterotrophic acetate assimilation metabolism. This Thauera R4 bin provides another genetic reference to better understand the niches of Thauera and demonstrates a model pipeline to reveal functional profiles and reconstruct novel and dominant genomes from a simplified mixed culture in environmental studies. PMID- 24769906 TI - Enhancement of free fatty acid production in Saccharomyces cerevisiae by control of fatty acyl-CoA metabolism. AB - Production of biofuels derived from microbial fatty acids has attracted great attention in recent years owing to their potential to replace petroleum-derived fuels. To be cost competitive with current petroleum fuel, flux toward the direct precursor fatty acids needs to be enhanced to approach high yields. Herein, fatty acyl-CoA metabolism in Saccharomyces cerevisiae was engineered to accumulate more free fatty acids (FFA). For this purpose, firstly, haploid S. cerevisiae double deletion strain ?faa1?faa4 was constructed, in which the genes FAA1 and FAA4 encoding two acyl-CoA synthetases were deleted. Then the truncated version of acyl-CoA thioesterase ACOT5 (Acot5s) encoding Mus musculus peroxisomal acyl-CoA thioesterase 5 was expressed in the cytoplasm of the strain ?faa1?faa4. The resulting strain ?faa1?faa4 [Acot5s] accumulated more extracellular FFA with higher unsaturated fatty acid (UFA) ratio as compared to the wild-type strain and double deletion strain ?faa1?faa4. The extracellular total fatty acids (TFA) in the strain ?faa1?faa4 [Acot5s] increased to 6.43-fold as compared to the wild type strain during the stationary phase. UFA accounted for 42 % of TFA in the strain ?faa1?faa4 [Acot5s], while no UFA was detected in the wild-type strain. In addition, the expression of Acot5s in ?faa1?faa4 restored the growth, which indicates that FFA may not be the reason for growth inhibition in the strain ?faa1?faa4. RT-PCR results demonstrated that the de-repression of fatty acid synthesis genes led to the increase of extracellular fatty acids. The study presented here showed that through control of the acyl-CoA metabolism by deleting acyl-CoA synthetase and expressing thioesterase, more FFA could be produced in S. cerevisiae, demonstrating great potential for exploitation in the platform of microbial fatty acid-derived biofuels. PMID- 24769907 TI - Comparative transcriptomic analysis of the heat stress response in the filamentous fungus Metarhizium anisopliae using RNA-Seq. AB - The entomopathogenic fungus Metarhizium anisopliae is widely used for biological control of a variety of insect pests. The effectiveness of the microbial pest control agent, however, is limited by poor thermotolerance. The molecular mechanism underlying the response to heat stress in the conidia of entomopathogenic fungi remains unclear. Here, we conducted high-throughput RNA Seq to analyze the differential gene expression between control and heat treated conidia of M. anisopliae at the transcriptome level. RNA-Seq analysis generated 6,284,262 and 5,826,934 clean reads in the control and heat treated groups, respectively. A total of 2,722 up-regulated and 788 down-regulated genes, with a cutoff of twofold change, were identified by expression analysis. Among these differentially expressed genes, many were related to metabolic processes, biological regulation, cellular processes and response to stimuli. The majority of genes involved in endocytic pathways, proteosome pathways and regulation of autophagy were up-regulated, while most genes involved in the ribosome pathway were down-regulated. These results suggest that these differentially expressed genes may be involved in the heat stress response in conidia. As expected, significant changes in expression levels of genes encoding heat shock proteins and proteins involved in trehalose accumulation were observed in conditions of heat stress. These results expand our understanding of the molecular mechanisms of the heat stress response of conidia and provide a foundation for future investigations. PMID- 24769908 TI - Evidence of the survival of ectopically transplanted oral mucosal epithelial stem cells after repeated wounding of cornea. AB - Tissue engineering has become an essential tool in the development of regenerative medicine. We have developed cell sheet-based techniques for use in regenerative medicine that have already been successfully used in clinical applications. Native corneal epithelium is produced from limbal stem cells located in the transition zone between the cornea and the bulbar conjunctiva. Limbal stem cell deficiency (LSCD) is a severe defect of the limbal stem cells leading to vision loss due to conjunctival epithelial invasion and neovascularization. Rabbit LSCD models were treated with transplantable autologous oral mucosal epithelial cell (OEC) sheets fabricated on temperature responsive cell culture surfaces, after which, the ocular surfaces were clear and smooth with no observable defects. The central part of the reconstructed ocular surface was scraped and wounded, after which proliferating epithelial cells covered the scraped area within a few days. The ocular surfaces were clear and smooth even after repeated scrapings and consisted of only OECs or heterogeneously mixed with corneal epithelial cells. This study demonstrates that transplanted cell sheets containing oral mucosal epithelial stem cells could reconstruct the ocular surface to maintain cornea homeostasis; moreover, they provide an ideal microenvironment to support the proliferation of remaining native limbal stem cells. PMID- 24769909 TI - Minimally invasive approach to the repair of injured skeletal muscle with a shape memory scaffold. AB - Repair of injured skeletal muscle by cell therapies has been limited by poor survival of injected cells. Use of a carrier scaffold delivering cells locally, may enhance in vivo cell survival, and promote skeletal muscle regeneration. Biomaterial scaffolds are often implanted into muscle tissue through invasive surgeries, which can result in trauma that delays healing. Minimally invasive approaches to scaffold implantation are thought to minimize these adverse effects. This hypothesis was addressed in the context of a severe mouse skeletal muscle injury model. A degradable, shape-memory alginate scaffold that was highly porous and compressible was delivered by minimally invasive surgical techniques to injured tibialis anterior muscle. The scaffold controlled was quickly rehydrated in situ with autologous myoblasts and growth factors (either insulin like growth factor-1 (IGF-1) alone or IGF-1 with vascular endothelial growth factor (VEGF)). The implanted scaffolds delivering myoblasts and IGF-1 significantly reduced scar formation, enhanced cell engraftment, and improved muscle contractile function. The addition of VEGF to the scaffold further improved functional recovery likely through increased angiogenesis. Thus, the delivery of myoblasts and dual local release of VEGF and IGF-1 from degradable scaffolds implanted through a minimally invasive procedure effectively promoted the functional regeneration of injured skeletal muscle. PMID- 24769911 TI - Formation of cyanates in low-valent uranium chemistry: a synergistic experimental/theoretical study. AB - Computational studies on the reductive activation of a mixture of CO and NO by the U(iii) complex [U(eta-C8H6{Si(i)Pr3-1,4}2)(eta-Cp*)], which affords a mixture of [U(eta-C8H6{Si(i)Pr3-1,4}2)(eta-Cp*)]2(MU-OCN)21 and [U(eta-C8H6{Si(i)Pr3 1,4}2)(eta-Cp*)]2(MU-O) 2, show that the reaction proceeds via an initial attack of CO on a MU-eta(2):eta(2) coordinated NO, side-on bridged between two uranium centres. This leads to the formation of the bridging oxo complex 2 and the cyanate radical; coordination of the latter to the starting complex and dimerisation affords 1. The DFT studies also predict the existence of the monocyanate-bridged, mixed valence species [U(eta-C8H6{Si(i)Pr3-1,4}2)(eta Cp*)]2(MU-OCN) 3, which has now been experimentally observed. PMID- 24769910 TI - Sustained delivery of VEGF maintains innervation and promotes reperfusion in ischemic skeletal muscles via NGF/GDNF signaling. AB - Tissue reinnervation following trauma, disease, or transplantation often presents a significant challenge. Here, we show that the delivery of vascular endothelial growth factor (VEGF) from alginate hydrogels ameliorates loss of skeletal muscle innervation after ischemic injury by promoting both maintenance and regrowth of damaged axons in mice. Nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) mediated VEGF-induced axonal regeneration, and the expression of both is induced by VEGF presentation. Using both in vitro and in vivo modeling approaches, we demonstrate that the activity of NGF and GDNF regulates VEGF driven angiogenesis, controlling endothelial cell sprouting and blood vessel maturation. Altogether, these studies produce evidence of new mechanisms of VEGF action, further broaden the understanding of the roles of NGF and GDNF in angiogenesis and axonal regeneration, and suggest approaches to improve axonal and ischemic tissue repair therapies. PMID- 24769912 TI - Analysis of UV-absorbing photoprotectant mycosporine-like amino acid (MAA) in the cyanobacterium Arthrospira sp. CU2556. AB - Mycosporine-like amino acids (MAAs) are ecologically important biomolecules with great photoprotective potential. The present study aimed to investigate the biosynthesis of MAAs in the cyanobacterium Arthrospira sp. CU2556. High performance liquid chromatography (HPLC) with photodiode-array detection studies revealed the presence of a UV-absorbing compound with an absorption maximum at 310 nm. Based on its UV absorption spectrum and ion trap liquid chromatography/mass spectrometry (LC/MS) analysis, the compound was identified as a primary MAA mycosporine-glycine (m/z: 246). To the best of our knowledge this is the first report on the occurrence of MAA mycosporine-glycine (M-Gly) in Arthrospira strains studied so far. In contrast to photosynthetic activity under UV-A radiation, the induction of the biosynthesis of M-Gly was significantly more prominent under UV-B radiation. The content of M-Gly was found to increase with the increase in exposure time under UV-B radiation. The MAA M-Gly was highly stable under UV radiation, heat, strongly acidic and alkaline conditions. It also exhibited good antioxidant activity and photoprotective ability by detoxifying the in vivo reactive oxygen species (ROS) generated by UV radiation. Our results indicate that the studied cyanobacterium may protect itself by synthesizing the UV-absorbing/screening compounds as important defense mechanisms, in their natural brightly-lit habitat with high solar UV-B fluxes. PMID- 24769913 TI - Effect of physical inactivity on major noncommunicable diseases and life expectancy in Brazil. AB - BACKGROUND: In Brazil, one-fifth of the population reports not doing any physical activity. This study aimed to assess the impact of physical inactivity on major noncommunicable diseases (NCDs), all-cause mortality and life expectancy in Brazil, by region and sociodemographic profile. METHODS: We estimated the population attributable fraction (PAF) for physical inactivity associated with coronary heart disease, type 2 diabetes, breast cancer, colon cancer, and all cause mortality. To calculate the PAF, we used the physical inactivity prevalence from the 2008 Brazilian Household Survey and relative risk data in the literature. RESULTS: In Brazil, physical inactivity is attributable to 3% to 5% of all major NCDs and 5.31% of all-cause mortality, ranging from 5.82% in the southeastern region to 2.83% in the southern region. Eliminating physical inactivity would increase the life expectancy by an average of 0.31 years. This reduction would affect mainly individuals with >= 15 years of schooling, male, Asian, elderly, residing in an urban area and earning >= 2 times the national minimum wage. CONCLUSIONS: In Brazil, physical inactivity has a major impact on NCDs and mortality, principally in the southeastern and central-west regions. Public policies and interventions promoting physical activity will significantly improve the health of the population. PMID- 24769914 TI - Hardening behavior after high-temperature solution treatment of Ag-20Pd-12Au-xCu alloys with different Cu contents for dental prosthetic restorations. AB - Ag-Pd-Au-Cu alloys have been used widely for dental prosthetic applications. Significant enhancement of the mechanical properties of the Ag-20Pd-12Au-14.5Cu alloy as a result of the precipitation of the beta' phase through high temperature solution treatment (ST), which is different from conventional aging treatment in these alloys, has been reported. The relationship between the unique hardening behavior and precipitation of the beta' phase in Ag-20Pd-12Au-xCu alloys (x=6.5, 13, 14.5, 17, and 20mass%) subjected to the high-temperature ST at 1123K for 3.6ks was investigated in this study. Unique hardening behavior after the high-temperature ST also occurs in Ag-20Pd-12Au-xCu alloys (x=13, 17, and 20) with precipitation of the beta' phase. However, hardening is not observed and the beta' phase does not precipitate in the Ag-20Pd-12Au-6.5Cu alloy after the same ST. The tensile strength and 0.2% proof stress also increase in Ag-20Pd-12Au-xCu alloys (x=13, 14.5, 17, and 20) after the high-temperature ST. In addition, these values after the high-temperature ST increase with increasing Cu content in Ag 20Pd-12Au-xCu alloys (x=14.5, 17, and 20). The formation process of the beta' phase can be explained in terms of diffusion of Ag and Cu atoms and precipitation of the beta' phase. Clarification of the relationship between hardening and precipitation of the beta' phase via high-temperature ST is expected to help the development of more effective heat treatments for hardening in Ag-20Pd-12Au-xCu alloys. PMID- 24769915 TI - Characterization of biomechanical properties of agar based tissue mimicking phantoms for ultrasound stiffness imaging techniques. AB - Pathological changes of the body have been observed to change the mechanical properties of soft tissue types which can be imaged by ultrasound elastography. Though initial clinical results using ultrasound elastography in detection of tumors are promising, quantification of signal to noise ratio, resolution and strain image patterns are the best achieved under a controlled study using phantoms with similar biomechanical properties of normal and abnormal tissues. The purpose of this work is to characterize the biomechanical properties of agar based tissue mimicking phantoms by varying the agar concentration from 1.7 to 6.6% by weight and identify the optimum property to be used in classification of cancerous tissues. We performed quasi-static uniaxial compression test under a strain rate of 0.5mm/min up to 15% strain and measured Young's modulus of phantom samples which are from 50kPa to 450kPa. Phantoms show nonlinear stress-strain characteristics at finite strain which were characterized using hyperelastic parameters by fitting Neo-Hookean, Mooney Rivlin, Ogden and Veronda Westmann models. We also investigated viscoelastic parameters of the samples by conducting oscillatory shear rheometry at various precompression levels (2-5%). Loss modulus values are always less than storage modulus which represents the behavior of soft tissues. The increase in agar concentration increases the shear modulus of the samples as well as decreases the linear viscoelastic region. The results suggest that dynamic shear modul are more promising than linear and nonlinear elastic modul in differentiation of various classes of abnormal tissues. PMID- 24769916 TI - Illness perceptions and psychological distress associated with physical health related quality of life in primary Sjogren's syndrome compared to systemic lupus erythematosus and rheumatoid arthritis. AB - Notwithstanding that psychological distress and illness perceptions are important in determining outcomes in rheumatic diseases, few studies investigated these variables in primary Sjogren's syndrome (pSS). We aimed to compare illness perceptions and psychological distress in patients with pSS, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and to test whether their associations with health-related quality of life (HRQoL) are similar in these groups of patients. In 57 patients with pSS, 75 with SLE and 199 with RA, we administered the Patient Health Questionnaire (PHQ-9), the Symptom Check-List and the Brief-Illness Perception Questionnaire to assess psychological variables and the World Health Organization Quality of Life Instrument, Short-Form to assess HRQoL. Hierarchical regression models determined the associations of psychological variables with HRQoL after adjusting for demographic variables and clinical parameters. The prevalence of clinically significant depressive symptoms (PHQ-9 >= 10) was 24.6 % in pSS, 29.3 % in SLE and 25.1 % in RA. Patients with pSS showed little understanding of their disease (comprehensibility) and attributed more symptoms to their illness (identity) compared with the other groups of patients. Illness perceptions and depressive symptoms were independently associated with physical HRQoL in a similar pattern in all three groups. In pSS, however, the patients' worries about the consequences of their illness was a stronger correlate of physical HRQoL than pain. These findings indicate that psychological factors are important correlates of HRQoL in these disease groups and encourage the design of psycho-educational therapies targeting disease-related cognitions in pSS in an attempt to improve patient's physical HRQoL. PMID- 24769918 TI - Transforming healthcare: necessary but difficult. PMID- 24769917 TI - Heterogeneous structure of stem cells dynamics: statistical models and quantitative predictions. AB - Understanding stem cell (SC) population dynamics is essential for developing models that can be used in basic science and medicine, to aid in predicting cells fate. These models can be used as tools e.g. in studying patho-physiological events at the cellular and tissue level, predicting (mal)functions along the developmental course, and personalized regenerative medicine. Using time-lapsed imaging and statistical tools, we show that the dynamics of SC populations involve a heterogeneous structure consisting of multiple sub-population behaviors. Using non-Gaussian statistical approaches, we identify the co existence of fast and slow dividing subpopulations, and quiescent cells, in stem cells from three species. The mathematical analysis also shows that, instead of developing independently, SCs exhibit a time-dependent fractal behavior as they interact with each other through molecular and tactile signals. These findings suggest that more sophisticated models of SC dynamics should view SC populations as a collective and avoid the simplifying homogeneity assumption by accounting for the presence of more than one dividing sub-population, and their multi fractal characteristics. PMID- 24769919 TI - Ionic mechanisms underlying tonic and phasic firing behaviors in retinal ganglion cells: a model study. AB - In the retina, the firing behaviors that ganglion cells exhibit when exposed to light stimuli are very important due to the significant roles they play in encoding the visual information. However, the detailed mechanisms, especially the intrinsic properties that generate and modulate these firing behaviors is not completely clear yet. In this study, 2 typical firing behaviors-i.e., tonic and phasic activities, which are widely observed in retinal ganglion cells (RGCs)-are investigated. A modified computational model was developed to explore the possible ionic mechanisms that underlie the generation of these 2 firing patterns. Computational results indicate that the generation of tonic and phasic activities may be attributed to the collective actions of 2 kinds of adaptation currents, i.e., an inactivating sodium current and a delayed-rectifier potassium current. The concentration of magnesium ions has crucial but differential effects in the modulation of tonic and phasic firings, when the model neuron is driven by N-methyl-D-aspartate (NMDA) -type synaptic input instead of constant current injections. The proposed model has robust features that account for the ionic mechanisms underlying the tonic and phasic firing behaviors, and it may also be used as a good candidate for modeling some other firing patterns in RGCs. PMID- 24769921 TI - Numerical study of purely viscous non-Newtonian flow in an abdominal aortic aneurysm. AB - It is well known that blood has non-Newtonian properties, but it is generally accepted that blood behaves as a Newtonian fluid at shear rates above 100 s-1. However, in transient conditions, there are times and locations where the shear rate is well below 100 s-1, and it is reasonable to infer that non-Newtonian effects could become important. In this study, purely viscous non-Newtonian (generalized Newtonian) properties of blood are incorporated into the simulation based framework for cardiovascular surgery planning developed by Taylor et al. (1999, "Predictive Medicine: Computational Techniques in Therapeutic Decision Making," Comput. Aided Surg., 4, pp. 231-247; 1998, "Finite Element Modeling of Blood Flow in Arteries," Comput. Methods Appl. Mech. Eng., 158, pp. 155-196). Equations describing blood flow are solved in a patient-based abdominal aortic aneurysm model under steady and physiological flow conditions. Direct numerical simulation (DNS) is used, and the complex flow is found to be constantly transitioning between laminar and turbulent in both the spatial and temporal sense. It is found for the case simulated that using the non-Newtonian viscosity modifies the solution in subtle ways that yield a mesh-independent solution with fewer degrees of freedom than the Newtonian counterpart. It appears that in regions of separated flow, the lower shear rate produces higher viscosity with the non-Newtonian model, which reduces the associated resolution needs. When considering the real case of pulsatile flow, high shear layers lead to greater unsteadiness in the Newtonian case relative to the non-Newtonian case. This, in turn, results in a tendency for the non-Newtonian model to need fewer computational resources even though it has to perform additional calculations for the viscosity. It is also shown that both viscosity models predict comparable wall shear stress distribution. This work suggests that the use of a non Newtonian viscosity models may be attractive to solve cardiovascular flows since it can provide simulation results that are presumably physically more realistic with at least comparable computational effort for a given level of accuracy. PMID- 24769920 TI - Cost-effectiveness of breast cancer control strategies in Central America: the cases of Costa Rica and Mexico. AB - This paper reports the most cost-effective policy options to support and improve breast cancer control in Costa Rica and Mexico. Total costs and effects of breast cancer interventions were estimated using the health care perspective and WHO CHOICE methodology. Effects were measured in disability-adjusted life years (DALYs) averted. Costs were assessed in 2009 United States Dollars (US$). To the extent available, analyses were based on locally obtained data. In Costa Rica, the current strategy of treating breast cancer in stages I to IV at a 80% coverage level seems to be the most cost-effective with an incremental cost effectiveness ratio (ICER) of US$4,739 per DALY averted. At a coverage level of 95%, biennial clinical breast examination (CBE) screening could improve Costa Rica's population health twofold, and can still be considered very cost-effective (ICER US$5,964/DALY). For Mexico, our results indicate that at 95% coverage a mass-media awareness raising program (MAR) could be the most cost-effective (ICER US$5,021/DALY). If more resources are available in Mexico, biennial mammography screening for women 50-70 yrs (ICER US$12,718/DALY), adding trastuzumab (ICER US$13,994/DALY) or screening women 40-70 yrs biennially plus trastuzumab (ICER US$17,115/DALY) are less cost-effective options. We recommend both Costa Rica and Mexico to engage in MAR, CBE or mammography screening programs, depending on their budget. The results of this study should be interpreted with caution however, as the evidence on the intervention effectiveness is uncertain. Also, these programs require several organizational, budgetary and human resources, and the accessibility of breast cancer diagnostic, referral, treatment and palliative care facilities should be improved simultaneously. A gradual implementation of early detection programs should give the respective Ministries of Health the time to negotiate the required budget, train the required human resources and understand possible socioeconomic barriers. PMID- 24769923 TI - De novo SOX10 nonsense mutation in a patient with Kallmann syndrome and hearing loss. PMID- 24770324 TI - Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. AB - Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and FokI nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites ~15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 'nickases', recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least fourfold higher than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the versatility of this approach for highly specific genome-wide editing. PMID- 24770326 TI - Conformation of the neurotransmitter gamma-aminobutyric acid in liquid water. AB - We study the conformation and reorientation dynamics of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) under neutral and acidic conditions using a combination of broadband dielectric relaxation spectroscopy and polarization-resolved femtosecond mid-infrared pump-probe spectroscopy. We find that both zwitterionic and cationic GABA adopt nearly linear conformations in aqueous solution, meaning that the two charged functional groups of the GABA zwitterion are hydrated separately. PMID- 24770325 TI - Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. AB - Monomeric CRISPR-Cas9 nucleases are widely used for targeted genome editing but can induce unwanted off-target mutations with high frequencies. Here we describe dimeric RNA-guided FokI nucleases (RFNs) that can recognize extended sequences and edit endogenous genes with high efficiencies in human cells. RFN cleavage activity depends strictly on the binding of two guide RNAs (gRNAs) to DNA with a defined spacing and orientation substantially reducing the likelihood that a suitable target site will occur more than once in the genome and therefore improving specificities relative to wild-type Cas9 monomers. RFNs guided by a single gRNA generally induce lower levels of unwanted mutations than matched monomeric Cas9 nickases. In addition, we describe a simple method for expressing multiple gRNAs bearing any 5' end nucleotide, which gives dimeric RFNs a broad targeting range. RFNs combine the ease of RNA-based targeting with the specificity enhancement inherent to dimerization and are likely to be useful in applications that require highly precise genome editing. PMID- 24770327 TI - White blood cell counts, leukocyte ratios, and eosinophils as inflammatory markers in patients with coronary artery disease. AB - Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count has emerged as a marker of inflammation that is widely available in clinical practice. Since inflammation plays a key role in atherosclerosis and its end results, discovering new biomarkers of inflammation becomes important in order to help diagnostic accuracy and provide prognostic information about coronary cardiac disease. In acute coronary syndromes and percutaneous coronary intervention, elevated levels of almost all subtypes of white blood cell counts, including eosinophils, monocytes, neutrophils, and lymphocytes, and neutrophil-lymphocyte ratio and eosinophil-leukocyte ratio constitute independent predictors of adverse outcomes. Eosinophil count and eosinophil-leukocyte ratio, in particular, emerge as novel biomarkers for risk stratification in patients with coronary artery disease. Since the presence of eosinophils denotes hypersensitivity inflammation and hypersensitivity associated with Kounis syndrome, this reality is essential for elucidating the etiology of inflammation in order to consider predictive and preventive measures and to apply the appropriate therapeutic methods. PMID- 24770328 TI - Plasma Levels of Plasminogen Activator Inhibitor Type 1 and Vitronectin in Children With Cancer. AB - BACKGROUND: The plasminogen activator system controls intravascular fibrin deposition; besides, it also participates in a wide variety of physiologic and pathologic processes, including cancer. PROCEDURE: In this study, we examined the levels of plasminogen activator inhibitor 1 (PAI-1) and vitronectin in 32 newly diagnosed pediatric patients with malignancies, determined by enzyme-linked immunosorbent assay between January 2009 and January 2010 and compared them to 35 age-matched healthy children, using SPSS 16.0 software. RESULTS: The mean level of PAI-1 was 23.02 +/- 15 (8.2-71.19) ng/mL and vitronectin was 83.10% +/- 23.77% (12%-126%) in the tumor group. Thirty-five healthy children in the same age range were enrolled in the control group. The levels of PAI-1 and vitronectin were 23.63 +/- 10.44 (11.67-58.85) ng/mL and 85% +/- 20.85% (39%-126%), respectively. No significant difference was found between the 2 groups by independent sample t test (P = .86 and P = .69). CONCLUSIONS: This is a preliminary study done in children with malignancies, investigating PAI-1 and vitronectin. Further study is needed, including larger trials and tumor tissue with histopathological examination as in adults. PMID- 24770329 TI - Benzyl-substituted metallocarbene antibiotics and anticancer drugs. AB - Benzyl-substituted metallocarbene compounds synthesised by our group and others during the past 5 years give a new perspective on their activity as antibiotic and antitumoral drugs. N-heterocyclic carbenes containing an imidazole core were functionalised and their transition metal complexes (M = Ag, Au, Cu, Ru) have shown promising antibacterial as well as anticancer activity in vitro and in vivo. IC50 values in the nanomolar region or antibacterial activity comparable to conventional antibiotics lead the way towards novel drug candidates. PMID- 24770330 TI - How to infer relative fitness from a sample of genomic sequences. AB - Mounting evidence suggests that natural populations can harbor extensive fitness diversity with numerous genomic loci under selection. It is also known that genealogical trees for populations under selection are quantifiably different from those expected under neutral evolution and described statistically by Kingman's coalescent. While differences in the statistical structure of genealogies have long been used as a test for the presence of selection, the full extent of the information that they contain has not been exploited. Here we demonstrate that the shape of the reconstructed genealogical tree for a moderately large number of random genomic samples taken from a fitness diverse, but otherwise unstructured, asexual population can be used to predict the relative fitness of individuals within the sample. To achieve this we define a heuristic algorithm, which we test in silico, using simulations of a Wright Fisher model for a realistic range of mutation rates and selection strength. Our inferred fitness ranking is based on a linear discriminator that identifies rapidly coalescing lineages in the reconstructed tree. Inferred fitness ranking correlates strongly with actual fitness, with a genome in the top 10% ranked being in the top 20% fittest with false discovery rate of 0.1-0.3, depending on the mutation/selection parameters. The ranking also enables us to predict the genotypes that future populations inherit from the present one. While the inference accuracy increases monotonically with sample size, samples of 200 nearly saturate the performance. We propose that our approach can be used for inferring relative fitness of genomes obtained in single-cell sequencing of tumors and in monitoring viral outbreaks. PMID- 24770331 TI - Chromosomal evolution and patterns of introgression in helianthus. AB - Knowledge of the nature and extent of karyotypic differences between species provides insight into the evolutionary history of the genomes in question and, in the case of closely related species, the potential for genetic exchange between taxa. We constructed high-density genetic maps of the silverleaf sunflower (Helianthus argophyllus) and Algodones Dune sunflower (H. niveus ssp. tephrodes) genomes and compared them to a consensus map of cultivated sunflower (H. annuus) to identify chromosomal rearrangements between species. The genetic maps of H. argophyllus and H. niveus ssp. tephrodes included 17 linkage groups each and spanned 1337 and 1478 cM, respectively. Comparative analyses revealed greater divergence between H. annuus and H. niveus ssp. tephrodes (13 inverted segments, 18 translocated segments) than between H. annuus and H. argophyllus (10 inverted segments, 8 translocated segments), consistent with their known phylogenetic relationships. Marker order was conserved across much of the genome, with 83 and 64% of the H. argophyllus and H. niveus ssp. tephrodes genomes, respectively, being syntenic with H. annuus. Population genomic analyses between H. annuus and H. argophyllus, which are sympatric across a portion of the natural range of H. annuus, revealed significantly elevated genetic structure in rearranged portions of the genome, indicating that such rearrangements are associated with restricted gene flow between these two species. PMID- 24770332 TI - The lengths of admixture tracts. AB - The distribution of admixture tract lengths has received considerable attention, in part because it can be used to infer the timing of past gene flow events between populations. It is commonly assumed that these lengths can be modeled as independently and identically distributed (iid) exponential random variables. This assumption is fundamental for many popular methods that analyze admixture using hidden Markov models. We compare the expected distribution of admixture tract lengths under a number of population-genetic models to the distribution predicted by the Wright-Fisher model with recombination. We show that under the latter model, the assumption of iid exponential tract lengths does not hold for recent or for ancient admixture events and that relying on this assumption can lead to false positives when inferring the number of admixture events. To further investigate the tract-length distribution, we develop a dyadic interval-based stochastic process for generating admixture tracts. This representation is useful for analyzing admixture tract-length distributions for populations with recent admixture, a scenario in which existing models perform poorly. PMID- 24770334 TI - Fate of atrioventricular valve function of the transplanted heart. AB - BACKGROUND: Long-term echocardiographic data on quantitative assessment of tricuspid and mitral regurgitation after heart transplantation are scarce. METHODS AND RESULTS: From November 1992 to December 2008, the medical records for 201 patients (mean age, 42.8+/-12.4 years, 47 females) who underwent heart transplantation were reviewed. Quantitative assessment of mitral and tricuspid valve function was performed using transthoracic echocardiography through long term follow-up. A total of 196 (97.5%) patients were evaluated with echocardiography for more than 6 months postoperatively. During a mean echocardiography follow-up duration of 89.9+/-54.3 months, 23 (11.4%) patients showed either tricuspid regurgitation (TR >mild; n=21, 10.4%) or mitral regurgitation (MR >mild; n=6, 3.0%); 4 (2.0%) patients experienced both significant TR and MR. Freedom from moderate-to-severe TR at 10 years was 85.5+/ 5.1% and 93.4+/-2.2% for the standard and bicaval techniques, respectively (P=0.531). Freedom from moderate-to-severe MR at 10 years was 96.0+/-2.7% and 98.6+/-1.0%, respectively, for the 2 techniques (P=0.252). In multivariate analysis, older-age donor emerged as the only independent predictor of significant TR (hazard ratio 1.06, 95% confidence interval 1.01-1.12, P=0.012). CONCLUSIONS: The long-term results of atrioventricular function after heart transplantation in adults were excellent regardless of anastomotic technique. Older-age donor was significantly associated with the development of postoperative TR. PMID- 24770333 TI - A small system--high-resolution study of metabolic adaptation in the central metabolic pathway to temperate climates in Drosophila melanogaster. AB - In this article, we couple the geographic variation in 127 single-nucleotide polymorphism (SNP) frequencies in genes of 46 enzymes of central metabolism with their associated cis-expression variation to predict latitudinal or climatic driven gene expression changes in the metabolic architecture of Drosophila melanogaster. Forty-two percent of the SNPs in 65% of the genes show statistically significant clines in frequency with latitude across the 20 local population samples collected from southern Florida to Ontario. A number of SNPs in the screened genes are also associated with significant expression variation within the Raleigh population from North Carolina. A principal component analysis of the full variance-covariance matrix of latitudinal changes in SNP-associated standardized gene expression allows us to identify those major genes in the pathway and its associated branches that are likely targets of natural selection. When embedded in a central metabolic context, we show that these apparent targets are concentrated in the genes of the upper glycolytic pathway and pentose shunt, those controlling glycerol shuttle activity, and finally those enzymes associated with the utilization of glutamate and pyruvate. These metabolites possess high connectivity and thus may be the points where flux balance can be best shifted. We also propose that these points are conserved points associated with coupling energy homeostasis and energy sensing in mammals. We speculate that the modulation of gene expression at specific points in central metabolism that are associated with shifting flux balance or possibly energy-state sensing plays a role in adaptation to climatic variation. PMID- 24770335 TI - Imaging of native high-density lipoprotein in human coronary plaques by color fluorescent angioscopy. AB - BACKGROUND: High-density lipoprotein (HDL) plays a key role in reverse cholesterol transport, and halts the progression of atherosclerosis. The aim of the present study was to visualize native HDL in the human coronary arterial wall. METHODS AND RESULTS: The fluorescence characteristics of HDL were investigated by color fluorescent microscopy (CFM) using excitation at 470 nm and emission at 515 nm with Fast green dye (FG) as the biomarker. HDL in 30 normal coronary segments, and in 25 white and 25 yellow plaques in excised human coronary arteries, was visualized by color fluorescent angioscopy (CFA) and CFM. Localization of HDL visualized by CFM was compared with that stained by immunostaining using an anti-HDL antibody. FG elicited a characteristic brown fluorescence of HDL. By CFA, the percent incidence of HDL in normal segments, white (early stage of plaque growth) and yellow (advanced stage of plaque growth) plaques was, respectively, 33%, 76% (P<0.05 vs. normal segments and yellow plaques) and 21%. Localization of HDL visualized by CFM did not differ from that stained by immunostaining. CONCLUSIONS: In the human coronary arterial wall, HDL deposits infrequently in normal segments, but increasingly deposits with plaque formation, and decreases in the advanced stage of plaque growth. PMID- 24770336 TI - Effects of leisure-time and occupational physical activity on total mortality risk in NHANES III according to sex, ethnicity, central obesity, and age. AB - BACKGROUND: Associations of physical activity with all-cause mortality seem to be quite strong, but little is known about potential effect modifiers as sex, race/ethnicity, age, and obesity. METHODS: Data of the Third National Health and Nutrition Examination Survey (NHANES III), conducted 1988-1994 with mortality follow-up until 2006, were used to compare mortality risk between different levels of leisure-time physical activity (LTPA) and occupational physical activity (OPA). Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: LTPA (n = 15,307) was inversely associated with all-cause mortality (HR 0.75, 95% CI 0.64-0.88 for regular vs. no LTPA). There was a statistically significant interaction with age (P = .03), with participants over 60 years of age benefitting more from regular or irregular LTPA. OPA was positively associated with all-cause mortality (HR 1.25, 95% CI 0.85-1.84 for high vs. low OPA), particularly among Mexican Americans (HR 2.28, 95% CI 1.23-4.22); statistically significant interactions were observed for obesity and gender. CONCLUSIONS: LTPA clearly predicts all cause mortality. However, associations between OPA and all-cause mortality are unclear and need further research with special regard to ethnic differences. PMID- 24770337 TI - Developments at the graft interface in homo- and hetero-grafts: Gene expression and histological changes during the first month after grafting. AB - Gene expression changes induced during graft union formation (the first month after grafting) in grapevine have been studied using whole genome microarrays. The genes differentially expressed between the rootstock and graft interface tissues of homo-grafts (Cabernet Sauvignon (CS) grafted onto CS) were compared at 3 and 28 days after grafting (dag). Graft union formation was associated with the upregulation of genes involved in secondary metabolism, cell wall, wound responses and hormone signaling. These gene expression differences were associated with the accumulation of lignin, cellulose and callose in the callus cells. Superimposed upon this, hetero-grafting between two different grapevine genotypes resulted in the further upregulation of stress and/or defense responses at the graft interface. Here we discuss the limitations of the techniques used to study the developments at the graft interface to date and future research directions to understand graft union formation in plants. PMID- 24770340 TI - How much sunlight is enough? AB - Living on a sun-drenched planet has necessitated adaption to and protection from the harmful effects of solar ultraviolet (UV) radiation, particularly skin cancer. However, convincing epidemiological and recent empirical evidence also supports a protective effect of UV against a range of diseases including multiple sclerosis, asthma and cardiovascular disease. Despite years of research attention into the biological effects of sunlight exposure, we are still far from being able to fully answer the question: How much sunlight is enough? This is probably because the answer is dependent on many complex and interacting variables. Many talented researchers are focused on exploring whether UV-induced vitamin D explains some of these effects. This perspectives article proposes an alternative hypothesis, namely that targeting UV-induced immune suppression by affecting the activation of regulatory cells and molecules will be of therapeutic benefit. PMID- 24770339 TI - Numb promotes cell proliferation and correlates with poor prognosis in hepatocellular carcinoma. AB - BACKGROUND: Numb is an evolutionary conserved protein that plays critical roles in cell fate determination, cell adhesion, cell migration and a number of signaling pathways, but evidence for a substantial involvement of Numb in HCC has remained unclear. The present study was aimed to investigate the clinical and prognostic significance of Numb and its role in hepatocellular carcinoma (HCC). METHODOLOGY: The expression of Numb was detected in 107 cases of clinical paraffin-embedded hepatocellular carcinoma tissues,5 matched paris of fresh tissues and six hepatocellular cell lines by immunohistochemistry with clinicopathological analyses,RT-PCR or Western blot. Moreover, loss of function and gain of function assays were performed to evaluate the effect of Numb on cell proliferation in vitro. CONCLUSIONS: We found that Numb was obviously up regulated in HCC tissues and cell lines (p<0.05). The Numb up-regulation correlated significantly with poor prognosis, and Numb status was identified as an independent prognostic factor. Over-expression of Numb increased proliferation in SMMC-7721 and BEL-7402 cells, while knock-down of Numb showed the opposite effect. Our study indicates that Numb up-regulation significantly correlates with cell proliferation and poor prognosis in hepatocellular carcinoma patients. It may be a useful biomarker for therapeutic strategy in hepatocellular carcinoma treatment. PMID- 24770341 TI - Correction: Two intense decades of 19th century whaling precipitated rapid decline of right whales around New Zealand and east Australia. AB - Right whales (Eubalaena spp.) were the focus of worldwide whaling activities from the 16th to the 20th century. During the first part of the 19th century, the southern right whale (E. australis) was heavily exploited on whaling grounds around New Zealand (NZ) and east Australia (EA). Here we build upon previous estimates of the total catch of NZ and EA right whales by improving and combining estimates from four different fisheries. Two fisheries have previously been considered: shore-based whaling in bays and ship-based whaling offshore. These were both improved by comparison with primary sources and the American offshore whaling catch record was improved by using a sample of logbooks to produce a more accurate catch record in terms of location and species composition. Two fisheries had not been previously integrated into the NZ and EA catch series: ship-based whaling in bays and whaling in the 20th century. To investigate the previously unaddressed problem of offshore whalers operating in bays, we identified a subset of vessels likely to be operating in bays and read available extant logbooks. This allowed us to estimate the total likely catch from bay-whaling by offshore whalers from the number of vessels seasons and whales killed per season: it ranged from 2,989 to 4,652 whales. The revised total estimate of 53,000 to 58,000 southern right whales killed is a considerable increase on the previous estimate of 26,000, partly because it applies fishery-specific estimates of struck and loss rates. Over 80% of kills were taken between 1830 and 1849, indicating a brief and intensive fishery that resulted in the commercial extinction of southern right whales in NZ and EA in just two decades. This conforms to the global trend of increasingly intense and destructive southern right whale fisheries over time. PMID- 24770342 TI - Using a statistically calibrated biphasic finite element model of the human knee joint to identify robust designs for a meniscal substitute. AB - This paper describes a methodology for selecting a set of biomechanical engineering design variables to optimize the performance of an engineered meniscal substitute when implanted in a population of subjects whose characteristics can be specified stochastically. For the meniscal design problem where engineering variables include aspects of meniscal geometry and meniscal material properties, this method shows that meniscal designs having simultaneously large radial modulus and large circumferential modulus provide both low mean peak contact stress and small variability in peak contact stress when used in the specified subject population. The method also shows that the mean peak contact stress is relatively insensitive to meniscal permeability, so the permeability used in the manufacture of a meniscal substitute can be selected on the basis of manufacturing ease or cost. This is a multiple objective problem with the mean peak contact stress over the population of subjects and its variability both desired to be small. The problem is solved by using a predictor of the mean peak contact stress across the tibial plateau that was developed from experimentally measured peak contact stresses from two modalities. The first experimental modality provided computed peak contact stresses using a finite element computational simulator of the dynamic tibial contact stress during axial dynamic loading. A small number of meniscal designs with specified subject environmental inputs were selected to make computational runs and to provide training data for the predictor developed below. The second experimental modality consisted of measured peak contact stress from a set of cadaver knees. The cadaver measurements were used to bias-correct and calibrate the simulator output. Because the finite element simulator is expensive to evaluate, a rapidly computable (calibrated) Kriging predictor was used to explore extensively the contact stresses for a wide range of meniscal engineering inputs and subject variables. The predicted values were used to determine the Pareto optimal set of engineering inputs to minimize peak contact stresses in the targeted population of subjects. PMID- 24770344 TI - Interaction between TRP and Ca2+-activated chloride channels. PMID- 24770345 TI - Water-soluble DNA minor groove binders as potential chemotherapeutic agents: synthesis, characterization, DNA binding and cleavage, antioxidation, cytotoxicity and HSA interactions. AB - Two new water-soluble copper(ii)-dipeptide complexes: [Cu(glygly)(PyTA)]ClO4.1.5H2O (1) and [Cu(glygly)(PzTA)]ClO4.1.5H2O (2) (glygly = glycylglycine anion, PyTA = 2,4-diamino-6-(2'-pyridyl)-1,3,5-triazine and PzTA = 2,4-diamino-6-(2'-pyrazino)-1,3,5-triazine), utilizing two interrelated DNA base like ligands (PyTA and PzTA), have been synthesized and characterized. The structure elucidation for 1 performed by single crystal X-ray diffraction showed a one dimensional chain conformation in which the central copper ions arrange in a five-coordinate distorted square-pyramidal geometry. Spectroscopic titration, viscosity and electrophoresis measurements revealed that the complexes bound to DNA via an outside groove binding mode, and cleaved pBR322 DNA efficiently in the presence of ascorbate, probably via an oxidative mechanism with the involvement of OH and O2(-). Notably, the complexes exhibited considerable in vitro cytotoxicity against four human carcinoma cell lines (HepG2, HeLa, A549 and U87) with IC50 values ranging from 41.68 to 159.17 MUM, in addition to their excellent SOD mimics (IC50 ~ 0.091 and 0.114 MUM). Besides, multispectroscopic evidence suggested their HSA-binding at the cavity containing Trp-214 in subdomain IIA with moderate affinity, mainly via hydrophobic interaction. Further, the molecular docking technique utilized for ascertaining the mechanism and mode of action towards DNA and HSA theoretically verified the experimental results. PMID- 24770347 TI - A luminescent ionogel based on an europium(III)-coordinated carboxyl functionalized ionic liquid and gelatin. AB - In this work, we report the preparation and luminescent properties of a novel luminescent ionogel consisting of a carboxyl-functionalized ionic liquid, Eu(3+) ions and gelatin. The obtained ionogel was investigated by FT-IR, SEM and photoluminescence spectroscopy. FT-IR spectra show that both the ionic liquid and the gelatin are coordinated to Eu(3+) ions through oxygen atoms. Luminescence data confirm that Eu(3+) ions are well-protected by the ionic liquid and gelatin from deleterious quenching interactions with water molecules. PMID- 24770346 TI - Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. AB - Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the alpha4beta1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the alpha4beta1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis. PMID- 24770348 TI - Arthroscopic medial capsular plication using the suture anchor technique. AB - PURPOSE: The suture anchor technique for medial capsular plication has been previously described. We present our technique and its medium-term results. METHODS: A single surgeon's experience (senior author) of the suture anchor technique for medial capsular plication was reviewed in 14 knees in 14 patients. All patients underwent arthroscopic stabilisation for patello-femoral instability. The method used was the suture anchor technique for medial capsular plication (full technique described in paper). The primary outcome measure used was further dislocation or instability. The validated Kujala score was used pre- and post-op to assess functional outcome. RESULTS: There were nine male and five female patients (M:F, 64%:34%). Median age was 25 (range 16-65). Mean follow-up was 52 months (95% CI 44-56 range 24-72). The mean pre-op Kujala score was 54.6 (SD 24.4). The mean post-op Kujala score was 78.2 (SD 20.5). The mean increase in Kujala score was 23.6 (95% CI 7.9-39.4). There was a statistically significant increase in Kujala score, P=0.006. Only 1 of 14 patients had a further dislocation (7%), and there were no further episodes of instability. CONCLUSION: This is the first paper to describe the results of this technique in the literature. There was a statistically significant improvement in the patients' functional outcome and 13/14 patients did not re-dislocate or experience instability. It was concluded that this technique is a successful mode of treatment for patello-femoral instability. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24770349 TI - Severe and morbid obesity (BMI >= 35 kg/m(2)) does not increase surgical time and length of hospital stay in total knee arthroplasty surgery. AB - PURPOSE: Certain aspects of total knee arthroplasty (TKA) in severely and morbidly obese (SMO) patients (BMI >= 35 kg/m(2)) remain controversial. This study aimed to assess the duration of TKA surgery and hospital stay in relation to patients' BMI. METHODS: Three operative times during TKA surgery were recorded: tourniquet time, to determine surgical difficulty, total surgical time, to assess the difficulty of achieving anaesthesia, and time in the surgical area, to assess patient management in the surgical area. Length of hospital stay was also calculated. Data were collected prospectively from consecutive patients and were recorded in a database for retrospective analysis. RESULTS: Data were obtained from 922 consecutive patients undergoing TKA. The non-obese group comprised 418 patients (45.3%), obese group Class I 331 (36%), and the SMO group (Class II-III) 173 (18.7%). Mean tourniquet time was 53 min, mean total surgical time was 84 min, and mean time in the surgical area was 132 min. There were no differences according to BMI group. Median length hospital stay (LHS) was 6 days in all patients regardless of BMI. Factors that significantly prolonged LHS were ASA III-IV and pre-operative haemoglobin between 12 and 13 g/dl. CONCLUSION: Severely and morbidly obese (SMO) patients (BMI >= 35 kg/m(2)) undergoing TKA surgery do not require longer operative time or hospital stay than non-obese or obese Class I patients. The fact that surgical time was not significantly different could be due to greater specialisation in the treatment of these patients, which may favour a lower incidence of post-operative complications. LEVEL OF EVIDENCE: Retrospective comparative study, Level IV. PMID- 24770352 TI - Contribution of reference bodies in diagnosis of keratoconus. AB - PURPOSE: To evaluate the contribution of reference bodies for elevation maps in diagnosis of keratoconus (KC) and forme fruste keratoconus (FFK). METHODS: Study groups included (1) 80 eyes with KC, (2) 55 eyes with FFK, and (3) 95 eyes as control eyes. The maximum elevation value at the central 5 mm of the posterior cornea (MEL) and the elevation value at thinnest corneal point (TEL) were evaluated for their diagnostic capacity using receiver operating characteristic curves under the following reference bodies: sphere, ellipsoid, toric ellipsoid, and torus, with autodiameter and fixed 8-mm-diameter settings. Moreover, characteristic parameters for each reference body and the root mean square (RMS) were evaluated for their diagnostic capacity. RESULTS: Significant differences were detected in TEL, MEL, and RMS parameters among groups, for almost all reference bodies. The highest predictive accuracy (KC group, >99.97%; FFK group, >90.9%) was estimated for the TEL and MEL parameters using the toric ellipsoid (8 mm) reference body with a fixed eccentricity of 0.4. Moreover, the RMS parameter demonstrated sufficient diagnostic capacity (KC group, 99.95%; FFK group, 85.1%). The cutoff points for the TEL parameter were found to be 7 and 3 MUm in the KC group and the FFK group, respectively; for the MEL parameter, they were 11 and 6 MUm, respectively; and for the RMS parameter, they were 6.87 and 7.19 MUm, respectively. CONCLUSIONS: The posterior corneal elevation values and the RMS parameter can effectively discriminate KC from normal corneas, although measured values and cutoff points depend on the selection of reference body. Moreover, the use of a toric ellipsoid reference body, with a fixed eccentricity of 0.4, seems to be an effective tool even in diagnosis of FFK. PMID- 24770350 TI - In vivo performance of a novel silk fibroin scaffold for partial meniscal replacement in a sheep model. AB - PURPOSE: Due to the negative effects of meniscectomy, there is a need for an adequate material to replace damaged meniscal tissue. To date, no material tested has been able to replace the meniscus sufficiently. Therefore, a new silk fibroin scaffold was investigated in an in vivo sheep model. METHODS: Partial meniscectomy was carried out to the medial meniscus of 28 sheep, and a scaffold was implanted in 19 menisci (3-month scaffold group, n = 9; 6-month scaffold group, n = 10). In 9 sheep, the defect remained empty (partial meniscectomy group). Sham operation was performed in 9 animals. RESULTS: The silk scaffold was able to withstand the loads experienced during the implantation period. It caused no inflammatory reaction in the joint 6 months postoperatively, and there were no significant differences in cartilage degeneration between the scaffold and sham groups. The compressive properties of the scaffold approached those of meniscal tissue. However, the scaffolds were not always stably fixed in the defect, leading to gapping between implant and host tissue or to total loss of the implant in 3 of 9 cases in each scaffold group. Hence, the fixation technique needs to be improved to achieve a better integration into the host tissue, and the long-term performance of the scaffolds should be further investigated. CONCLUSION: These first in vivo results on a new silk fibroin scaffold provide the basis for further meniscal implant development. Whilst more data are required, there is preliminary evidence of chondroprotective properties, and the compressive properties and biocompatibility are promising. PMID- 24770353 TI - Contrast sensitivity function after correcting residual wavefront aberrations during RGP lens wear. AB - PURPOSE: To investigate the effect on the contrast sensitivity function (CSF) of correcting the residual wavefront aberrations in myopic and keratoconic subjects wearing rigid gas permeable (RGP) contact lenses. METHODS: Seventeen eyes of 16 myopic subjects and 20 eyes of 19 keratoconic subjects were included in this study. All eyes were habitually corrected with RGP lenses. The residual aberrations of the RGP lens-wearing eyes were compensated by an adaptive optics (AO) system. The contrast sensitivities were measured through a 4-mm artificial pupil at spatial frequencies of 2, 4, 8, 16, and 32 cycles per degree (cpd) during RGP lens wear for the myopic and keratoconic groups, respectively. The CSF measurements were repeated with and without AO correction. Comparisons of contrast sensitivity at all spatial frequencies with and without AO correction were performed respectively for the myopic and keratoconic groups during RGP lens wear. RESULTS: In the myopic RGP lens-wearing group, the differences in contrast sensitivity at each spatial frequency, with and without AO correction, were not significant (all p values > 0.05). In the keratoconic RGP lens-wearing group, the contrast sensitivities at all spatial frequencies with AO correction were higher than those without AO correction, but differences only at the low (2 cpd) and intermediate (4, 8, and 16 cpd) spatial frequencies were significant (p = 0.039, 0.005, 0.001, and 0.007). CONCLUSIONS: The residual aberrations significantly reduced the contrast sensitivities at low and intermediate spatial frequencies for keratoconic RGP lens-wearing eyes but did not have any effect on the CSF for the myopic RGP lens-wearing eyes. Developing techniques that could more completely correct the wavefront aberrations may improve visual performance in keratoconus. PMID- 24770354 TI - Resonant bonding leads to low lattice thermal conductivity. AB - Understanding the lattice dynamics and low thermal conductivities of IV-VI, V2 VI3 and V materials is critical to the development of better thermoelectric and phase-change materials. Here we provide a link between chemical bonding and low thermal conductivity. Our first-principles calculations reveal that long-ranged interaction along the <100> direction of the rocksalt structure exist in lead chalcogenides, SnTe, Bi2Te3, Bi and Sb due to the resonant bonding that is common to all of them. This long-ranged interaction in lead chalcogenides and SnTe cause optical phonon softening, strong anharmonic scattering and large phase space for three-phonon scattering processes, which explain why rocksalt IV-VI compounds have much lower thermal conductivities than zincblende III-V compounds. The new insights on the relationship between resonant bonding and low thermal conductivity will help in the development of better thermoelectric and phase change materials. PMID- 24770355 TI - Which school- and home-based factors in elementary school-age children predict physical activity and sedentary behavior in secondary school-age children? A prospective cohort study. AB - BACKGROUND: To examine which school- and home-based factors at age 11 to 12 (6th grade, elementary school) predict physical activity (PA) and sedentary behavior (SB) at age 13 to 14 (8th grade, secondary school). METHODS: Data at both time points were collected from 472 children (mean age baseline = 10.97, SD age = 0.41) and their parents. Children and parents completed self-reported questionnaires. Children's height and weight were measured and children wore a pedometer for 7 days. RESULTS: Hierarchical regression analyses revealed that predominantly boys (beta = -.11), children with higher levels of pedometer determined PA (beta = .44) and more parental logistic support (beta = .11) at age 11 to 12 displayed higher levels of pedometer-determined PA at age 13 to 14 (R2 = 39.1%). Similar results emerged for self-reported moderate-to-vigorous PA (R2 = 36.7%). Finally, lower levels of screen-based SB at age 13 to 14 (R2 = 32.5%) were most strongly related to lower levels of screen-based SB (beta = .41), a medium/high socioeconomic status (beta = -.18), and higher levels of parental PA explicit modeling (beta = -.18) at age 11 to 12. CONCLUSIONS: Children's PA/SB and the supportive role of parents at age 11 to 12 are strong predictors of PA and screen-based SB at age 13 to 14. PMID- 24770356 TI - Utility of noninvasive endothelial function test for prediction of deep vein thrombosis after total hip or knee arthroplasty. AB - BACKGROUND: Venous thromboembolism (VTE) is a common and sometimes lethal postoperative complication of arthroplasty. Endothelial dysfunction is important in the pathogenesis of thrombus formation. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) can noninvasively evaluate endothelial function. This study investigated the predictive value of RH-PAT for deep vein thrombosis (DVT) after lower limb arthroplasty. METHODS AND RESULTS: A prospective observational study of 126 osteoarthritic patients who underwent total knee arthroplasty (TKA) or hip arthroplasty (THA) was conducted. The RH-PAT index (RHI) was measured on the day before surgery, and presence of DVT was checked by ultrasonography or phlebography before and after surgery. Following arthroplasty, DVT was diagnosed in 51 patients (40.5%). RHI in the DVT group (0.58+/-0.25) was significantly lower than in the non-DVT group (0.71+/-0.25, P=0.004). RHI was a significant and independent predictor of postoperative DVT in multivariate logistic regression analyses and improved a net reclassification index (23.8%, P=0.022). Subgroup analyses according to operation site with adjustment for Qthrombosis score demonstrated that RHI significantly predicted postoperative DVT in the THA group (odds ratio per 0.1, 0.77; 95% confidence interval 0.60-0.98; P=0.03), but did not reach statistical significance in the TKA group. CONCLUSIONS: Low RHI was significantly associated with DVT after lower limb arthroplasty. Endothelial dysfunction, as assessed by RH-PAT, is potentially useful for identifying patients at high risk for VTE especially after THA. PMID- 24770357 TI - Exercise preconditioning-induced early and late phase of cardioprotection is associated with protein kinase C epsilon translocation. AB - BACKGROUND: Exercise preconditioning (EP) can provide powerful protection to the heart. Evidence supports the contention that EP directly enhances myocardial tolerance to ischaemia through a protein kinase C (PKC)-mediated mechanism. However, studies investigating the role of isoform-specific PKC after EP are lacking. METHODS AND RESULTS: In this study, a male Sprague-Dawley rat model of EP was established (4 periods of 30 m/min for 10 min exercise then a 10 min rest at 0% grade treadmill exercise). Rats were subjected to exhaustive exercise to induce myocardial injury. Chelerythrine (5 mg/kg) was injected before EP to investigate the role of PKC in EP. EP was found to attenuate exhaustive exercise induced myocardial injury in both of EP's 2 protective phases, especially the latter phase. After EP, PKCepsilon was markedly upregulated, and PKCepsilon was translocated to myocardial intercalated disks, and p-PKCepsilon(Ser729) was translocated to the myocardial cytomembrane. Even though PKCepsilon was markedly upregulated and translocated to intercalated disks during exhaustive exercise, p PKCepsilon(Ser729) was mainly distributed in the cytoplasm. A chelerythrine injection before EP did not suppress the activation of PKC and the protection of EP. CONCLUSIONS: These results indicate that PKCepsilon plays an important role in EP-mediated protection of the myocardium during exhaustive exercise-induced myocardial injury, and that a chelerythrine injection during exercise is not suitable for demonstrating the role of PKCepsilon. PMID- 24770358 TI - Three-dimensional speckle tracking echocardiography. AB - Speckle tracking echocardiography (STE) was popularized in the first decade of this century. Analysis of cardiac mechanics has been the focus of ultrasonics, and the breakthrough came with STE. Beyond analysis solely of left ventricular ejection fraction, STE allows the assessment of various pathophysiologies, including myocardial layer-specific myocardial function, twist and rotation, and dyssynchrony. Recent developments in the technology have resulted in commercially available 3-dimensional (D)-STE systems. Through experimental studies and clinical investigations, the reliability and feasibility of 3D-STE-derived data have been validated, and the advantages of 3D-STE over 2D-STE have been revealed. In addition, because of the 3D nature of the technology, 3D-STE provides novel deformation parameters (ie, 3D-strain and area change ratio) that have the potential for more accurate assessment of overall and regional myocardial function. Recently, various preliminary studies using 3D-STE have reported on myocardial characteristics, novel mechanics in the left ventricle, prediction of therapeutic effects, observations of cardiac function through interventions, and challenges for left atrial and right ventricular functions. In this review, we focus on the features of the methodology, validation, and clinical application of 3D-ST. PMID- 24770359 TI - Measuring large-scale social networks with high resolution. AB - This paper describes the deployment of a large-scale study designed to measure human interactions across a variety of communication channels, with high temporal resolution and spanning multiple years-the Copenhagen Networks Study. Specifically, we collect data on face-to-face interactions, telecommunication, social networks, location, and background information (personality, demographics, health, politics) for a densely connected population of 1000 individuals, using state-of-the-art smartphones as social sensors. Here we provide an overview of the related work and describe the motivation and research agenda driving the study. Additionally, the paper details the data-types measured, and the technical infrastructure in terms of both backend and phone software, as well as an outline of the deployment procedures. We document the participant privacy procedures and their underlying principles. The paper is concluded with early results from data analysis, illustrating the importance of multi-channel high-resolution approach to data collection. PMID- 24770360 TI - Time-resolved double-slit interference pattern measurement with entangled photons. AB - The double-slit experiment strikingly demonstrates the wave-particle duality of quantum objects. In this famous experiment, particles pass one-by-one through a pair of slits and are detected on a distant screen. A distinct wave-like pattern emerges after many discrete particle impacts as if each particle is passing through both slits and interfering with itself. Here we present a temporally- and spatially-resolved measurement of the double-slit interference pattern using single photons. We send single photons through a birefringent double-slit apparatus and use a linear array of single-photon detectors to observe the developing interference pattern. The analysis of the buildup allows us to compare quantum mechanics and the corpuscular model, which aims to explain the mystery of single-particle interference. Finally, we send one photon from an entangled pair through our double-slit setup and show the dependence of the resulting interference pattern on the twin photon's measured state. Our results provide new insight into the dynamics of the buildup process in the double-slit experiment, and can be used as a valuable resource in quantum information applications. PMID- 24770361 TI - [The culture of public health and the nursing profession: an opportunity not to miss]. PMID- 24770362 TI - [Second victims of medical errors: a systematic review of the literature]. AB - "Second victims" are health care providers who remain traumatized and suffer at the psycho-physical level after being involved in a patient adverse event. A systematic review of the literature was conducted to: a) estimate the prevalence of second victims among healthcare workers, b) describe personal and work outcomes of second victims, c) identify coping strategies used by second victims to face their problems, and d) describe current support strategies. Findings reveal that the prevalence of "second victims" of medical errors is high, ranging in four studies from 10.4% to 43.3%. Medical errors have a negative impact on healthcare providers involved, leading to physical, cognitive and behavioural symptoms including the practice of defensive medicine. Managers of health organizations need to be aware of the "second victim" phenomenon and ensure adequate support is given to healthcare providers involved. The best strategy seems to be the creation of networks of support at both the individual and organizational levels. More research is needed to evaluate the efficacy of support structures for second victims and to quantify the extent of the practice of defensive medicine following medical error. PMID- 24770363 TI - [Voluntary mediation in healthcare disputes: the experience of the "Fondazione IRCCS Istituto Nazionale dei Tumori" in Milan (Italy)]. AB - The "Fondazione IRCCS Istituto Nazionale dei Tumori" ( National Tumour Institute) in Milan (Italy) offers mediation services aimed at restoring communication between patients and healthcare professionals, when their relationship has been altered by a conflict during the diagnosis or treatment process. A method derived from transformative mediation is used. The purpose of mediation is not to examine clinical aspects, nor to identify who is right and who is wrong. Individual sessions are often sufficient to reduce litigation. PMID- 24770364 TI - Epidemiology and screening of sickle cell anemia in the Mediterranean area and in developing countries. AB - This article reviews the epidemiology and screening of sickle cell anemia in the Mediterranean area and in developing countries. Its aim is to create awareness of the global health burden of this condition, which is one of the most common genetic diseases worldwide. The constantly growing incidence of this condition, also caused by recent migrations, has induced the World Health Organization to pressure national health systems to strengthen prevention programs and to recognize it as a public health problem. However, scarce financial resources hinder implementation of activities. PMID- 24770365 TI - [Day surgery: the role and training needs of nurses]. AB - Medicine and health care are increasingly directed towards the achievement of high quality standards and of costs reduction. It is in this framework that same day surgery finds its role, being able to satisfy both of the above needs. Despite its recognized benefits, in Italy this efficient model of hospitalization still meets several obstacles and the ratio of services provided in day hospital with respect to ordinary hospital admission is about 1 to 3. Day Surgery services depend on team work and the nurse's role is of utmost importance and responsibility since it involves both clinical care and managerial activities. Through a careful analysis of the skills required of a day surgery nurse, the authors discuss aspects of nurses' training in view of the pre- and post-graduate courses currently offered, including on-the-job training. PMID- 24770366 TI - ["Del governo tecnico sanitario degli Ospedali" (Italian) ("Hospital governance") by E. Ronzani (1877-1943)- Padua (Italy), 1910]. AB - This article describes the contents of the first edition of the Italian textbook "Del governo tecnico sanitario degli ospedali" ("Hospital Governance") written by Prof. Enrico Ronzani (1877- 1943) and published in Padua (Italy) in 1910. The textbook contains a a preface by Prof. A. Serafini. Prof. Ronzani, a lecturer in Hygiene and health in 1910, introduced the first university course in "Hygiene and hospital technique" in Italy, in Padua in the academic year 1910-1911. The book focuses principally on the duties and responsibilities inherent in the role of the medical director. PMID- 24770367 TI - [Herpes Zoster and its prevention in Italy. Scientific consensus statement]. AB - In this paper, an Italian group of experts presents a revision of the available data about epidemiology and prevention of Herpes Zoster (HZ). HZ is an acute viral diseases caused by the reactivation of Varicella Zoster Virus (VZV). HZ is characterized by neurological and dermatological symptoms with a dermatomeric localization. The reactivation of the virus from the latent status in the sensitive ganglia increases with age and failing cell mediated immunity. In Europe, more than 95% of adults presents antibodies against VZV. Incidence of HZ is similar all over the world, related to the age of the population: from 2 3/1000 persons/year in the age group 20 to 50 years to 5/1000 in the 60 years old, 6-7/1000 between 70 and 80 up to >1/100 in older than 80. In Italy, about 157,000 new cases of HZ are estimated every year with an incidence of 6.3/1000 persons/year mostly in older adults. Among the hospitalized cases, 60% are over 65 years of age. The more frequent and severe complication of HZ is post herpetic neuralgia (PHN), characterized by severe localized pain lasting at least 3 month after the beginning of the acute phase. The pain is responsible for a sharp decrease in the quality of life. In Europe, PHN is described in 2.6-27% of HZ cases. In Italy, data obtained by a network of General Practitioner show PHN in 20.6% of HZ patients, while 9.2% of the patients still presents PHN at 6 months. The more frequent localization is thoracic; when the virus reactivate at the level of the ophthalmic division of the trigeminal nerve most patients develop ocular complications. The clinical and therapeutical managements of HZ patients is difficult and the results are often poor. Prevention of HZ e PHN in the population over 50 years is possible using a live attenuated vaccine containing VZV (Oka/Merck strain, not less than 19.400 plaque forming units), available since 2006. Efficacy of anti-HZ vaccine was demonstrated in two large clinical trials that showed a 51% reduction in the incidence of HZ and a 61% decrease of the burden of illness. Incidence of PHN showed a reduction of 67% in immunized subjects. Long-term follow-up showed a persistence of the protection even if a decrease was noted in older subjects and with time. Effectiveness studies confirm the data of clinical trials and numerous pharmaco-economical evaluation show a favorable profile of HZ vaccine. The vaccine is recommended in USA, Canada and some European countries for people over 60. The expert group concluded that HZ and PHN represent an important clinical and Public Health problem in Italy and that the possibility to prevent them should be carefully evaluated. PMID- 24770368 TI - Modulation of peanut-induced allergic immune responses by oral lactic acid bacteria-based vaccines in mice. AB - Peanut allergy (PNA) has becoming a non-negligible health concern worldwide. Thus far, allergen-specific immunotherapy aimed at inducing mucosal tolerance has widely been regarded as a major management strategy for PNA. The safety profiles and the intrinsic probiotic properties of lactic acid bacteria (LAB) render them attractive delivery vehicles for mucosal vaccines. In the present study, we exploited genetically modified Lactococcus lactis to produce peanut allergen Ara h 2 via different protein-targeting systems and their immunomodulatory potency for allergic immune responses in mice were investigated. By comparison with the strain expressing the cytoplasmic form of Ara h 2 (LL1), the strains expressing the secreted and anchored forms of Ara h 2 (LL2 and LL3) were more potent in redirecting a Th2-polarized to a non-allergic Th1 immune responses. Induction of SIgA and regulatory T cells were also observed at the local levels by orally administration of recombinant L. lactis. Our results indicate that allergen producing L. lactis strains modulated allergic immune responses and may be developed as promising mucosal vaccines for managing allergic diseases. PMID- 24770369 TI - Breast cancer screening pamphlets mislead women. PMID- 24770370 TI - stepwiseCM: An R Package for Stepwise Classification of Cancer Samples Using Multiple Heterogeneous Data Sets. AB - This paper presents the R/Bioconductor package stepwiseCM, which classifies cancer samples using two heterogeneous data sets in an efficient way. The algorithm is able to capture the distinct classification power of two given data types without actually combining them. This package suits for classification problems where two different types of data sets on the same samples are available. One of these data types has measurements on all samples and the other one has measurements on some samples. One is easy to collect and/or relatively cheap (eg, clinical covariates) compared to the latter (high-dimensional data, eg, gene expression). One additional application for which stepwiseCM is proven to be useful as well is the combination of two high-dimensional data types, eg, DNA copy number and mRNA expression. The package includes functions to project the neighborhood information in one data space to the other to determine a potential group of samples that are likely to benefit most by measuring the second type of covariates. The two heterogeneous data spaces are connected by indirect mapping. The crucial difference between the stepwise classification strategy implemented in this package and the existing packages is that our approach aims to be cost-efficient by avoiding measuring additional covariates, which might be expensive or patient-unfriendly, for a potentially large subgroup of individuals. Moreover, in diagnosis for these individuals test, results would be quickly available, which may lead to reduced waiting times and hence lower the patients' distress. The improvement described remedies the key limitations of existing packages, and facilitates the use of the stepwiseCM package in diverse applications. PMID- 24770371 TI - The Dementia Severity Rating Scale predicts clinical dementia rating sum of boxes scores. PMID- 24770372 TI - Coexisting primary Sjogren's syndrome and sarcoidosis: coincidence, mutually exclusive conditions or syndrome? AB - Herein, we describe a 44-year-old female diagnosed with histologically proven coexistence of primary Sjogren's syndrome and sarcoidosis with pulmonary and muscular involvement. The differential diagnosis may be difficult, but this is not an exceptional case, which highlights the need to critically revise the consideration of sarcoidosis as an exclusion for primary Sjogren's syndrome, as established in current classification criteria. PMID- 24770374 TI - Tobacco and alcohol sales in community pharmacies: policy statements from U.S. professional pharmacy associations. AB - OBJECTIVE: To characterize the extent to which state and national professional pharmacy associations have implemented formal policies addressing the sale of tobacco and alcohol products in community pharmacies. METHODS: To determine existence of tobacco and alcohol policies, national professional pharmacy associations (n = 10) and state-level pharmacy associations (n = 86) affiliated with the American Pharmacists Association (APhA) and/or the American Society of Health-System Pharmacists (ASHP) were contacted via telephone and/or e-mail, and a search of the association websites was conducted. RESULTS: Of 95 responding associations (99%), 14% have a formal policy opposing the sale of tobacco products in pharmacies and 5% have a formal policy opposing the sale of alcohol in pharmacies. Of the associations representing major tobacco-producing states, 40% have a formal policy against tobacco sales in pharmacies, significantly more than the 8% of non-tobacco state associations with such policies. CONCLUSION: Among national professional pharmacy associations, only APhA and ASHP have formal policy statements opposing the sale of both tobacco and alcohol in pharmacies. Most state-level professional pharmacy associations affiliated with these two national organizations have no formal policy statement or position. PMID- 24770375 TI - [A study of the pharmacist work changes associated with dispensing unit-of-use packaging in community pharmacies]. AB - This study aimed to determine how much time can be saved with the use of unit-of use packaging for prescription drugs as compared with bulk packaging in community pharmacies as well as to determine the number of errors. In a simulation, mock prescriptions were dispensed either in unit-of-use packages or by transferring medication from a bulk container, and a time study was conducted to measure the time spent on dispensing and prescription auditing by pharmacists. Pharmacists' and patients' degree of satisfaction was also surveyed. The time saved with unit of-use packaging was 66.25 s per prescription. The sole dispensing error that was found in the study occurred with bulk dispensing. Among both pharmacists and patients, many were of the opinion that dispensing with unit-of-use packaging was preferable to bulk dispensing. Unit-of-use packaging shortens the time that pharmacists spend on dispensing activities and increases the efficiency of their work. Unit-of-use packaging is also thought to reduce the number of counting errors. PMID- 24770373 TI - Inflammation and prolonged QT time: results from the Cardiovascular Disease, Living and Ageing in Halle (CARLA) study. AB - BACKGROUND: Previous research found an association of CRP with QT time in population based samples. Even more, there is evidence of a substantial involvement of the tumor necrosis factor-alpha system in the pathophysiology of cardiac arrhythmia, while the role of Interleukin 6 remains inconclusive. OBJECTIVE: To determine the association between inflammation with an abnormally prolonged QT-time (APQT) in men and women of the elderly general population. METHODS: Data descend from the baseline examination of the prospective, population-based Cardiovascular Disease, Living and Ageing in Halle (CARLA) Study. After exclusion of subjects with atrial fibrillation and missing ECG recording the final study cohort consisted of 919 men and 797 women. Blood parameters of inflammation were the soluble TNF-Receptor 1 (sTNF-R1), the high sensitive C-reactive protein (hsCRP), and Interleukin 6 (IL-6). In accordance with major cardiologic societies we defined an APQT above a QT time of 460 ms in women and 450 ms in men. Effect sizes and the corresponding 95% confidence intervals (CI) were estimated by performing multiple linear and logistic regression analyses including the analysis of sex differences by interaction terms. RESULTS: After covariate adjustment we found an odds ratio (OR) of 1.89 (95% CI: 1.13, 3.17) per 1000 pg/mL increase of sTNF-R1 in women, and 0.74 (95% CI: 0.48, 1.15) in men. In the covariate adjusted linear regression sTNF-R1 was again positively associated with QT time in women (5.75 ms per 1000 pg/mL, 95% CI: 1.32, 10.18), but not in men. Taking possible confounders into account IL-6 and hsCRP were not significantly related to APQT in both sexes. CONCLUSION: Our findings from cross-sectional analyses give evidence for an involvement of TNF alpha in the pathology of APQT in women. PMID- 24770376 TI - Constructing a mixed pi-conjugated bridge to effectively enhance the nonlinear optical response in the Mobius cyclacene-based systems. AB - Using density functional theory computations, employing the concept of a mixed pi conjugated bridge can effectively improve the first hyperpolarizability (beta0) of Mobius cyclacene (MC)-based systems with a D-pi-A framework. This mixed pi conjugated bridge is constructed by applying a -(CH=CH)x-NH2 or -(CH=CH)x-NO2 chain to modify [8]MC, which can lead to a considerable beta0 value (e.g. [8]MC (CH=CH)12-NO2 (9.87 * 10(5) au) with only a certain chain length), much larger than the sole [8]MC (261 au) and the corresponding NH2/NO2-modified polyethylene chain with the same pi-conjugated length. It is revealed that the substituent sites and the chain length can play a crucial role in improving beta0 values of these MC-chain systems, where the beta0 value can monotonically increase with increasing -(CH=CH)x- length, and the substituent electron-withdrawing -(CH=CH)x NO2 chain is superior to the parallel electron-donating -(CH=CH)x-NH2. These appealing findings can provide valuable insights into the design of novel NLO materials based on MC. PMID- 24770377 TI - Use of online water quality monitoring for assessing the effects of WWTP overflows in rivers. AB - The effects on river water quality of sewer overflows are not well known. Since the duration of the overflow is in the order of magnitude of minutes to hours, continuous measurements of water quality are needed and traditional grab sampling is unable to quantify the pollution loads. The objective of this paper was to demonstrate the applicability of high frequency measurements for assessing the impacts of waste water treatment plants on the water quality of the receiving surface water. In our in situ water quality monitoring setup, two types of multiparameter sensors mounted on a floating fixed platform were used to determine the dynamics of dissolved oxygen, specific conductivity, ammonium-N, nitrate-N and dissolved organic carbon downstream of a waste water treatment plant (WWTP), in combination with data on rainfall, river discharge and WWTP overflow discharge. The monitoring data for water quantity and water quality were used to estimate the pollution load from waste water overflow events and to assess the impact of waste water overflows on the river water quality. The effect of sewer overflow on a small river in terms of N load was shown to be significant. The WWTP overflow events accounted for about 1/3 of the river discharge. The NH4-N loads during overflow events contributed 29% and 21% to the August 2010 and June 2011 load, respectively, in only 8% and 3% of the monthly time span. The results indicate that continuous monitoring is needed to accurately represent the effects of sewer overflows in river systems. PMID- 24770378 TI - Intensity-specific leisure-time physical activity and the built environment among Brazilian adults: a best-fit model. AB - BACKGROUND: There is little understanding about which sets of environmental features could simultaneously predict intensity-specific leisure-time physical activity (LTPA) among Brazilians. The objectives were to identify the environmental correlates for intensity-specific LTPA, and to build the best-fit linear models to predict intensity-specific LTPA among adults of Curitiba, Brazil. METHODS: Cross sectional study in Curitiba, Brazil (2009, n = 1461). The International Physical Activity Questionnaire and Abbreviated Neighborhood Environment Assessment Scale were used. Ninety-two perceived environment variables were categorized in 10 domains. LTPA was classified as walking for leisure (LWLK), moderate-intensity leisure-time PA (MLPA), vigorous-intensity leisure-time PA (VLPA), and moderate-to-vigorous intensity leisure-time PA (MVLPA). Best fitting linear predictive models were built. RESULTS: Forty environmental variables were correlated to at least 1 LTPA outcome. The variability explained by the 4 best-fit models ranged from 17% (MLPA) to 46% (MVLPA). All models contained recreation areas and aesthetics variables; none included residential density predictors. At least 1 neighborhood satisfaction variable was present in each of the intensity-specific models, but not for overall MVLPA. CONCLUSIONS: This study demonstrates the simultaneous effect of sets of perceived environmental features on intensity-specific LTPA among Brazilian adults. The differences found compared with high-income countries suggest caution in generalizing results across settings. PMID- 24770379 TI - Update: the search for the human cough receptor. AB - Despite the best efforts of basic and applied science, the identity of the human "cough receptor" remains elusive. The attraction of identifying a single "catch all" cough receptor is obvious, although such an objective is unlikely to be realised given the concept of "cough hypersensitivity," which is now considered the most clinically relevant description of what underlies problem coughing. One means of progressing this area is to join the thinking and experimental effort of basic science and clinical research in an effective manner. Some of the best examples of cooperative and translational research over the years together with an update on the most recent work will be discussed in this article. PMID- 24770380 TI - Quantifying rotator cuff atrophy and fatty degeneration at the supraspinatus origin in the scapular fossa. AB - PURPOSE: The aim of this study was to evaluate the location difference (distance) between the conventional Y-view (CYV) and the bony origin of the supraspinatus, and therefore, to suggest hypotrophy measurement in the CYV could be highly influenced by retraction of a torn tendon. METHODS: Ninety five arthroscopically repaired rotator cuff tears were retrospectively enrolled in this study. The most lateral portion of the osseous origin of the supraspinatus muscle [the Y-view at the level was newly defined as the supraspinatus origin-view (SOV)] and the CYV were determined on the MRI, and location discrepancy between the two levels was measured. Fatty degeneration and cross-sectional areas of rotator cuff muscles were measured on both views. Subgroup analyses were performed in partial thickness tears and full-thickness tears with tendon retraction. RESULTS: Distance between the SOV and CYV was 11.2 +/- 3.7 mm. Discrepancy of the supraspinatus areas at the two views was greater in full-thickness tears than it was in partial-thickness tears without retraction. In the full-thickness tear group, correlation analysis between retraction and cross-sectional areas of the supraspinatus in both views exhibited statistical significance [Pearson's correlation coefficients = 0.500 (P < 0.001) in the CYV and 0.283 (P = 0.017) in the SOV]; however, the correlation was stronger in the CYV. Ratings of fatty degeneration were similar in both views. CONCLUSIONS: There is considerable location discrepancy between the osseous origin of the supraspinatus at the suprascapular fossa and the CYV in which fatty degeneration and hypotrophy are routinely measured. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24770381 TI - Variable bone mineral density reductions post-unicompartmental knee arthroplasty. AB - PURPOSE: Radiolucencies are commonly observed in unicompartmental knee arthroplasty (UKA) patients within 1 year of arthroplasty. The objective of the study was to identify how the bone mineral density (BMD) changes up to 1 year post-arthroplasty. METHODS: Dual X-ray absorptiometry scans were obtained from 11 UKA patients at 10 days and 3, 6, and 12 months post-surgery. Patients were scanned in both anteroposterior and lateral knee orientations. RESULTS: Most subjects saw a large decline in BMD in the first 6 months following surgery, followed by some recovery in bone mass. The biggest change occurred under the tibial intercondylar eminence, which decreased significantly by an average of 18 % at 6 months and was 15 % at 1 year. The average bone loss under the tibial tray was low; however, the bone loss at the anterior portion was higher with a significant average decrease of 14 %. There was no change in BMD under the tibial keel. There was significant bone loss of 13 % under the femoral component; the regions anterior and posterior to the central femoral implant peg both had significant bone loss of 14 %. The bone response between patients was very variable, with some patients losing bone steadily, and others gaining it rapidly after an early fall. CONCLUSIONS: While the overall reduction in BMD under both components was low, it was significant and there was substantial individual variation superimposed on this. Improving our understanding of this response to surgery may impact on prosthesis survival. LEVEL OF EVIDENCE: Therapeutic study: case series with no comparison group, Level IV. PMID- 24770383 TI - Kinetic modeling of rhamnolipid production by Pseudomonas aeruginosa PAO1 including cell density-dependent regulation. AB - The production of rhamnolipid biosurfactants by Pseudomonas aeruginosa is under complex control of a quorum sensing-dependent regulatory network. Due to a lack of understanding of the kinetics applicable to the process and relevant interrelations of variables, current processes for rhamnolipid production are based on heuristic approaches. To systematically establish a knowledge-based process for rhamnolipid production, a deeper understanding of the time-course and coupling of process variables is required. By combining reaction kinetics, stoichiometry, and experimental data, a process model for rhamnolipid production with P. aeruginosa PAO1 on sunflower oil was developed as a system of coupled ordinary differential equations (ODEs). In addition, cell density-based quorum sensing dynamics were included in the model. The model comprises a total of 36 parameters, 14 of which are yield coefficients and 7 of which are substrate affinity and inhibition constants. Of all 36 parameters, 30 were derived from dedicated experimental results, literature, and databases and 6 of them were used as fitting parameters. The model is able to describe data on biomass growth, substrates, and products obtained from a reference batch process and other validation scenarios. The model presented describes the time-course and interrelation of biomass, relevant substrates, and products on a process level while including a kinetic representation of cell density-dependent regulatory mechanisms. PMID- 24770382 TI - Single-bundle modified patellar tendon versus double-bundle tibialis anterior allograft ACL reconstruction: a prospective randomized study. AB - PURPOSE: The purpose of this study was to prospectively compare the outcomes of single-bundle (SB) anterior cruciate ligament (ACL) reconstruction with modified bone-patellar tendon-bone (BPTB) allograft and double-bundle (DB) reconstruction with tibialis anterior allograft. METHODS: With 94 patients enroled in the study, 43 subjects who had SB ACL reconstruction with modified BPTB allograft (group S) and 41 subjects of DB ACL reconstruction with tibialis anterior allograft (group D) were followed up for a minimum of 2 years. Clinical outcomes including Lachman and pivot-shift tests, KT-1000 arthrometer measurements, and the International Knee Documentation Committee (IKDC) classification, Lysholm and Tegner activity scores were compared between the two groups at the last follow-up. RESULTS: The mean graft size of the group S, the anteromedial bundle and posterolateral bundle in group D were 9.9 +/- 0.2, 7.5 +/- 0.4 and 6.6 +/- 0.4 mm, with statistically significant difference between the group S graft to either bundle of group D grafts (p < 0.001). At the last follow-up, there was no statistical difference between the two groups for the Lachman test, pivot-shift test and side-to-side difference. Substantial improvements in the subjective knee function scores were achieved in both groups, but without significant difference between the two groups. CONCLUSIONS: After a 2-year minimum follow-up, SB ACL reconstruction based on modified BPTB allograft achieved similar clinical outcomes to DB reconstruction with tibialis anterior allograft in knee stability, both anterior posterior and rotational, as well as knee function. The modified BPTB allograft was recommended as an ideal graft option for the SB ACL reconstruction. LEVEL OF EVIDENCE: Therapeutic, randomized controlled study, Level II. PMID- 24770384 TI - Crystal structure of the novel haloalkane dehalogenase DatA from Agrobacterium tumefaciens C58 reveals a special halide-stabilizing pair and enantioselectivity mechanism. AB - A novel haloalkane dehalogenase DatA from Agrobacterium tumefaciens C58 belongs to the HLD-II subfamily and hydrolyzes brominated and iodinated compounds, leading to the generation of the corresponding alcohol, a halide ion, and a proton. Because DatA possesses a unique Asn-Tyr pair instead of the Asn-Trp pair conserved among the subfamily members, which was proposed to keep the released halide ion stable, the structural basis for its reaction mechanism should be elucidated. Here, we determined the crystal structures of DatA and its Y109W mutant at 1.70 and 1.95 A, respectively, and confirmed the location of the active site by using its novel competitive inhibitor. The structural information from these two crystal structures and the docking simulation suggested that (i) the replacement of the Asn-Tyr pair with the Asn-Trp pair increases the binding affinity for some halogenated compounds, such as 1,3-dibromopropane, mainly due to the electrostatic interaction between Trp109 and halogenated compounds and the change of substrate-binding mode caused by the interaction and (ii) the primary halide-stabilizing residue is only Asn43 in the wild-type DatA, while Tyr109 is a secondary halide-stabilizing residue. Furthermore, docking simulation using the crystal structures of DatA indicated that its enantioselectivity is determined by the large and small spaces around the halogen-binding site. PMID- 24770385 TI - Homologous yeast lipases/acyltransferases exhibit remarkable cold-active properties. AB - Lipases/acyltransferases catalyse acyltransfer to various nucleophiles preferentially to hydrolysis even in aqueous media with high thermodynamic activity of water (a w >0.9). Characterization of hydrolysis and acyltransfer activities in a large range of temperature (5 to 80 degrees C) of secreted recombinant homologous lipases of the Pseudozyma antarctica lipase A superfamily (CaLA) expressed in Pichia pastoris, enlighten the exceptional cold-activity of two remarkable lipases/acyltransferases: CpLIP2 from Candida parapsilosis and CtroL4 from Candida tropicalis. The activation energy of the reactions catalysed by CpLIP2 and CtroL4 was 18-23 kJ mol(-1) for hydrolysis and less than 15 kJ mol( 1) for transesterification between 5 and 35 degrees C, while it was respectively 43 and 47 kJ mol(-1) with the thermostable CaLA. A remarkable consequence is the high rate of the reactions catalysed by CpLIP2 and CtroL4 at very low temperatures, with CpLIP2 displaying at 5 degrees C 65 % of its alcoholysis activity and 45 % of its hydrolysis activity at 30 degrees C. These results suggest that, within the CaLA superfamily and its homologous subgroups, common structural determinants might allow both acyltransfer and cold-active properties. Such biocatalysts are of great interest for the efficient synthesis or functionalization of temperature-sensitive lipid derivatives, or more generally to lessen the environmental impact of biocatalytic processes. PMID- 24770386 TI - Biaxial mesophase behavior of amphiphilic anisometric colloids: a simulation study. AB - The phase behavior of amphiphilic anisometric particles is explored using Monte Carlo simulations. The particles are composed of two incompatible laterally attached units: a spherocylinder and a spheroplatelet. A liquid crystalline phase polymorphism is obtained including biaxial nematic, (quasi long range biaxial) calamitic smectic-A, biaxial lamellar and columnar phases. The simulation results demonstrate intriguing phase transitions such as nematic-nematic, discotic nematic to (quasi long range biaxial) calamitic smectic-A, biaxial nematic to uniaxial calamitic smectic-A, and isotropic or discotic nematic to biaxial lamellar phases that possess nematic ordering within the layers. These findings are rationalized in terms of molecular geometry and amphiphilicity of different molecular units. The molecular model can be used as a tool for the prediction of the complex phase behavior that is relevant to liquid crystalline colloids. PMID- 24770389 TI - Incorporating biomarkers of frailty and senescence in cancer therapeutic trials. AB - As the population ages, oncologists are faced with the quandary of how to efficiently identify frail individuals that may have more difficulty tolerating and recovering from systemic therapy for cancer. Recent advances have been made in recognizing frailty via clinical geriatric assessment of older patients with cancer. These advances appear to allow for better prediction of toxicity than physician-rated performance status. Although the development of these tools is a large step forward in geriatric oncology, we still lack an understanding of how the underlying biologic processes of aging affect tolerance of cancer treatment. Determining specific biologic causes underlying frailty may allow oncologists to become even more adept at identifying patients at risk for excessive toxicity and provide the opportunity to therapeutically target these processes to help improve tolerability and survival outcomes for older patients with cancer. This article provides a background on potential biologic factors that may identify frail individuals at increased risk for toxicity related to cancer treatment. Potential methods to incorporate these factors into cancer therapeutic trials are discussed. PMID- 24770390 TI - [Care, research, clinical experimentation. Many and diverse or just one question(s)/answer(s)?]. PMID- 24770388 TI - Photochemical generation and kinetic studies of a putative porphyrin-ruthenium(V) oxo species. AB - Photo-disproportionation of a bis-porphyrin-diruthenium(IV) MU-oxo dimer gave a porphyrin-ruthenium(III) species and a putative porphyrin-ruthenium(V)-oxo species that can be detected and studied in real time via laser flash photolysis methods. As determined by its spectral and kinetic behavior, the same oxo transient was also formed by photolysis of a porphyrin-ruthenium(III) N-oxide adduct. Second-order rate constants for reactions with several substrates at 22 degrees C were determined; representative values of rate constants were kox = 6.6 * 10(3) M(-1) s(-1) for diphenylmethanol, kox = 2.5 * 10(3) M(-1) s(-1) for styrene, and kox = 1.8 * 10(3) M(-1) s(-1) for cyclohexene. The putative porphyrin-ruthenium(V)-oxo transient reacted 5-6 orders of magnitude faster than the corresponding trans-dioxoruthenium(VI) porphyrins, and the rate constants obtained in this work were similar to those of the corrole-iron(V)-oxo derivative. The high reactivity for the photochemically generated ruthenium-oxo species in comparison to other porphyrin-metal-oxo intermediates suggests that it is a true ruthenium(V)-oxo species. PMID- 24770387 TI - Chromosomal DNA deletion confers phage resistance to Pseudomonas aeruginosa. AB - Bacteria develop a broad range of phage resistance mechanisms, such as prevention of phage adsorption and CRISPR/Cas system, to survive phage predation. In this study, Pseudomonas aeruginosa PA1 strain was infected with lytic phage PaP1, and phage-resistant mutants were selected. A high percentage (~30%) of these mutants displayed red pigmentation phenotype (Red mutant). Through comparative genomic analysis, one Red mutant PA1r was found to have a 219.6 kb genomic fragment deletion, which contains two key genes hmgA and galU related to the observed phenotypes. Deletion of hmgA resulted in the accumulation of a red compound homogentisic acid; while A galU mutant is devoid of O-antigen, which is required for phage adsorption. Intriguingly, while the loss of galU conferred phage resistance, it significantly attenuated PA1r in a mouse infection experiment. Our study revealed a novel phage resistance mechanism via chromosomal DNA deletion in P. aeruginosa. PMID- 24770391 TI - [Level of sedation level and modifications of vital signs during hygienic care in patients admitted to an intensive care unit]. AB - INTRODUCTION: Hygienic care practices may represent a source of stress for intensive care patients. AIM: To identify the hygienic care practices more involved in changes of vital signs and the association to the level of sedation. METHODS: Prospective observational study of eleven patients admitted to a general intensive care unit, observed for three consecutive hygiene care morning practices. A protocol for standardizing hygiene practices was adopted. Vital signs were recorded on an electronic database at the beginning of each of the following phase: before the start of hygiene, of mouth cleaning, of sponge bath, positioning of bedpan, first and second side rotation, change of position of endotracheal tube and replacement of tapes, and at the end of hygiene. RESULTS: 29 events of hygiene practices were observed in the 11 patients included in the study (the measurements of three events were discarded). Significant vital signs alterations were induced mainly by the rotation and change of position of the orotracheal tube. Significant correlations were observed between changes in Heart Rate and Bispectral Index (BIS) (coefficient of 0.345; P: 0.329), between BIS and systolic arterial blood pressure (0.774, P: 0.009), BIS and Tidal Volume (-0.569, P: 0.086), and BIS and Respiratory Rate (0.707, P: 0.022). CONCLUSIONS: The hygienic care in intensive care patients may negatively impact on vital signs. Some nursing manoeuvres cause variations of the vital signs also related to changes in the state of consciousness caused by possible defects or excesses of sedation. The sedation level, during hygienic care, should be constantly monitored. PMID- 24770392 TI - [The admission to Nursing Homes and Home care services of elderly patients: analysis of the trend from 2008 to 2011 in a North Italian district]. AB - INTRODUCTION: The effects of the economic crisis impact on several aspects, included the use of health and social services. AIM: To analyze the effects of the economic recession on the request of in-home and long run social-health services. METHODS: Retrospective research. The databases of a In-home Nursing Service, the Social Services and the Welfare area of a Social-Health Local Service in North of Italy have been consulted, with reference to the period between 31st December 2008 to 31st December 2011. RESULTS: From 2008 to 2011 the users supported by the In-Home Nursing Service increased by 30.3% while a decrease in the waiting lists for public and private nursing homes was observed. The users of In-Home Assistance Service decreased by 11%, as well as recipients of In-Home Meal Service (33%). Since 2008, the number of regional economic allowance beneficiaries dramatically increased; these allowances are dispensed as a support to In-Home Nursing Service and to social frailty. CONCLUSIONS: Profound changes of the offer and use of long term care services is evident. The endurance of this trend could impair the In-Home Nursing Services ability to answer to health needs of citizens. Health care professionals should strengthen the educational interventions to improve the level of patients'self care. PMID- 24770393 TI - [The assessment of the impact of education and support to nursing research on nurses' scientific production in an Emilia Romagna Hospital]. AB - INTRODUCTION: In Italy research conducted by non medical professions is scarce also for the lack of knowledge on methods. At Rizzoli hospital in Bologna in 2006 a Centre for research to educate and support health professionals was implemented. AIM: To assess the impact of the research centre on number of research articles and protocols produced by nurses. METHODS: Interrupted time series. In the five years before and after the implementation of the centre data on the number of protocols approved by Ethical Committee with a nurse as principal investigator and on the number of articles published on impacted journals with a nurse as first author were collected. The number of nurses authors of the publications was also collected. RESULTS: For all the variables an increasing trend, starting from 2006 was observed, with statistically significant differences from 2008 for the number of research protocols presented (p=0.037), the number of nurses authors of scientific articles (p=0.027). Although the number of publications on impacted journals increased from 2006, differences were not statistically significant after 2008. CONCLUSIONS: An hospital based Centre for education and support to research for health professionals may facilitate the scientific and research production. PMID- 24770394 TI - [Systematic review and meta-analysis of the accuracy of "impaired gas exchange" defining characteristics]. AB - INTRODUCTION: Nursing diagnoses share some common defining characteristics. OBJECTIVE: To identify key defining characteristics for the nursing diagnosis "Impaired gas exchange". METHOD: Systematic review with meta-analysis of three studies in samples with different clinical profiles. The relevance and quality of the studies were assessed according the QUADAS protocol. RESULTS: Two studies were on children with acute respiratory infection and one on adults with mechanical ventilation. The heterogeneity statistic test suggested that the studies are homogeneous. The defining characteristics with higher accuracy were: headaches upon waking, irritability and tachycardia. DISCUSSION: The clinical indicators headache, irritability and tachycardia are signals secondary to hypoxia. Although of different magnitudes according to the age, they are the body's physiological responses. CONCLUSIONS: A comparison of the defining characteristics of "Impaired gas exchange" showed their accuracy. Obtaining measures can contribute to a better identification of this nursing diagnosis. PMID- 24770395 TI - [Ethical principles for medical research on human subjects]. PMID- 24770396 TI - [Clinical trials in nursing journals]. AB - INTRODUCTION: Clinical trials are pivotal for the development of nursing knowledge. AIMS: To describe the clinical trials published in nursing journals in the last two years and propose some general reflections on nursing research. METHODS: A search with the key-word trial was done on PubMed (2009-2013) on Cancer Nursing, European Journal of Oncology Nursing, International Journal of Nursing Studies, Journal of Advanced Nursing, Journal of Clinical Nursing and Nursing Research. RESULTS: Of 228 trials identified, 104 (45.8%) were published in the last 2 years. Nurses from Asian countries published the larger number of trials. Educational and supportive interventions were the most studied (61/104 trials), followed by clinical interventions (33/104). Samples were limited and most trials are monocentric. CONCLUSIONS: A growing number of trials is published, on issues relevant for the nursing profession, however larger samples and multicentric studies would be necessary. PMID- 24770397 TI - [Clinical trials and patients' rights: the debate on the position of Veronesi Foundation]. AB - Clinical trials and patients' rights: the debate on the position of Veronesi Foundation. The ethical committee of Veronesi Foundation released a document casting doubts on the liceity and ethicity of randomization as the control group in clinical trials would be exposed to potentially ineffective or less effective treatments and strumentally used to obtain an increased knowledge and not with the aim of cure. These positions raised a lively debate whose main points are reported in this contribution. PMID- 24770399 TI - Emi2 mediates meiotic MII arrest by competitively inhibiting the binding of Ube2S to the APC/C. AB - In vertebrates, unfertilized eggs are arrested at metaphase of meiosis II by Emi2, a direct inhibitor of the APC/C ubiquitin ligase. Two different ubiquitin conjugating enzymes, UbcH10 and Ube2S, work with the APC/C to target APC/C substrates for degradation. However, their possible roles and regulations in unfertilized/fertilized eggs are not known. Here we use Xenopus egg extracts to show that both UbcH10 and Ube2S are required for rapid cyclin B degradation at fertilization, when APC/C binding of Ube2S, but not of UbcH10, increases several fold, coincidently with (SCF(beta-TrCP)-dependent) Emi2 degradation. Interestingly, before fertilization, Emi2 directly inhibits APC/C-Ube2S binding via the C-terminal tail, but on fertilization, its degradation allows the binding mediated by the Ube2S C-terminal tail. Significantly, Emi2 and Ube2S bind commonly to the APC/C catalytic subunit APC10 via their similar C-terminal tails. Thus, Emi2 competitively inhibits APC/C-Ube2S binding before fertilization, while its degradation on fertilization relieves the inhibition for APC/C activation. PMID- 24770400 TI - Patients with vestibular loss, tullio phenomenon, and pressure-induced nystagmus: vestibular atelectasis? AB - OBJECTIVE: To propose an etiology for a syndrome of bilateral vestibular hypofunction and sound and/or pressure-evoked eye movements with normal hearing thresholds. DESIGN: Retrospective case series. SETTING: Tertiary care referral center. PATIENTS: Four patients with bilateral vestibular hypofunction, sound and/or pressure-evoked nystagmus and normal hearing thresholds were identified over a 3-year period. No evidence of other known vestibular disorders was identified. None of these patients presented with a history of exposure to toxins, radiation, aminoglycosides or chemotherapy; head trauma; or a family history of inherited vestibular loss. MAIN OUTCOME MEASURE: All patients underwent high-resolution CT scan of the temporal bones to evaluate for labyrinthine dehiscence. Additionally, all individuals underwent audiometric testing to ANSI standards, vestibular-evoked myogenic potentials (VEMP) testing using either click stimulus cervical VEMPs (cVEMPs), or tone burst ocular VEMPs (oVEMPs). Bithermal caloric stimulation was used to measure horizontal semicircular canal function, with either videonystagmography (VNG) or electronystagmography (ENG) to record eye movements. Individual responses of each of the 6 semicircular canals (SCC) to rapid head rotations were tested with the bedside head impulse test. RESULTS: We identified 4 patients with a combination of bilateral vestibular hypofunction and sound and/or pressure-induced eye movements, normal-hearing thresholds and no evidence for any other vestibular disorder. CONCLUSION: We suggest that this unique combination of symptoms should be considered as the clinical presentation of vestibular atelectasis, which has been previously described histologically as collapse of the endolymph-containing portions of the labyrinth. PMID- 24770401 TI - Vestibular Calcification in a Case of Congenital Cytomegalovirus Infection. PMID- 24770402 TI - The effect of etanercept and methylprednisolone on functional recovery of the facial nerve after crush injury. AB - OBJECTIVE: To establish whether etanercept, a TNF-alpha antagonist, is an alternative and effective treatment on facial nerve after crush injury. METHOD: Fifty-four rats underwent exposure of the left main trunk of the facial nerve followed by a standard crush injury. Animals were randomly divided into 3 groups: control group, methylprednisolone-treated group, and etanercept-treated group. All these groups were divided into 2 subgroups; animals were sacrificed on the 4th day after facial crush injury in the first subgroup and on the 28th day in the second subgroup. Functional recovery of vibrissae movement, eye blink reflex, and vibrissae orientation was measured on a 3-point scale (1 = no recovery, 2 = partial recovery, and 3 = complete recovery) during the recovery process. Facial nerve, from the main trunk at the stylomastoid foramen to the zygomatic, buccal, and marginal branches, were dissected and postfixed in the same fixative. The paraffin sections were studied with macrophage marker, GAP-43 and T Cell Marker. RESULTS: Animals receiving etanercept demonstrated significantly better functional recovery compared with control and methylprednisolone-treated animals. The etanercept-treated group showed highest GAP-43 immunoreactivity in the nerves. After the macrophage marker and T cell marker staining, the etanercept and methylprednisolone groups demonstrated statistically significant difference compared with the control group (p < 0.001). CONCLUSION: The present study demonstrates accelerated functional recovery associated with etanercept treatment after facial nerve crush injury in rats. PMID- 24770403 TI - High-frequency involved hearing loss caused by novel mitochondrial DNA mutation in 16S ribosomal RNA gene. AB - OBJECTIVE: To clarify the responsible gene for a family associated with hearing loss but having no well-known mitochondrial mutations. SUBJECTS: A Japanese family showing late-onset, progressive, and ski-sloping sensorineural hearing loss. RESULTS: Whole mitochondrial genome sequencing identified the 1673T>C mutation, a novel mitochondrial DNA mutation in the 16S ribosomal RNA gene. CONCLUSION: Whole mitochondrial genome sequencing is a powerful tool to identify the responsible gene for plausible mitochondrially inherited families. This is additional evidence that mitochondrial gene mutations may cause late-onset, progressive, and ski-sloping sensorineural hearing loss. PMID- 24770404 TI - Pseudogout in the middle ear. PMID- 24770405 TI - Individual computer-assisted 3D planning for surgical placement of a new bone conduction hearing device. AB - OBJECTIVE: To evaluate the benefit of a preoperative three-dimensional (3D) planning tool for surgically placing the bone conduction floating mass transducer (BC-FMT) of the Bonebridge (BB) bone conduction implant. PATIENTS: Adult patients (n = 5) and one pediatric patient (n = 1) with conductive or mixed hearing loss caused by chronic ear disease, malformation, or single-sided deafness. INTERVENTION(S): Development of a preoperative planning tool that allowed free adjustment of the implant in an individual 3D model of the skull to evaluate completely fitting the BC-FMT into a bony bed and to identify an optimal implant position. Implantation of the BB with mastoid or retrosigmoid placement after individual preoperative planning and "virtual surgery". MAIN OUTCOME MEASURES: Feasibility of the preoperative 3D planning process, transfer into the intraoperative situation, and audiologic results after BB implantation. RESULTS: Individual preoperative planning was considered beneficial especially in cases of small mastoid bone volume, for example, because of previous canal wall down mastoidectomies, and in the case with malformation. CONCLUSION: For optimal placement of the BC-FMT of the BB, preoperative 3D planning is recommended especially in primarily small poorly pneumatized mastoids, hypoplastic mastoids in malformations, reduced bone volume after canal wall down mastoidectomy, or the small mastoids in children. Effort should be made to reduce segmentation and surgical planning time by means of automation. PMID- 24770406 TI - A five-year follow-up on the osseointegration of bone-anchored hearing device implantation without tissue reduction. AB - OBJECTIVE: To evaluate the outcome of the non-skin thinning technique as compared with the thinning technique 5 years after surgical implantation of bone-anchored hearing "devices." STUDY DESIGN: A single-center, 5-year retrospective follow-up study was designed to evaluate the novel surgical technique without skin thinning as compared to conventional techniques. Eligible patients were consecutively operated on 5 years earlier in a test group without thinning and in two control groups with thinning. In the first control group, a flap technique was used, whereas in the second control group a dermatome technique was used and age matched patients were selected. MATERIALS AND METHODS: Thirty-six patients were operated on with a single-step surgery under local anesthesia. In the test group (non-skin thinning technique), 12 patients were operated on with a linear incision using an 8.5-mm abutment. In the control groups (flap and dermatome techniques, 12 patients in each group), the standard protocol with skin thinning was used with a 5.5-mm abutment. RESULTS: Throughout the 5-year span under review, the non-skin thinning test group exhibited good preservation of tissue with decreased skin reactions and no adverse events. The time required for surgery without skin thinning was reduced to approximately 10 to 15 minutes and the cosmetic outcome after 5 years was improved. Numbness and peri-implant infections were minimal in the surrounding skin area for patients who underwent surgery without thinning. CONCLUSION: This 5-year follow-up study demonstrates that percutaneous osseointegrated implantation without skin thinning is safe and has a better outcome than implantation with skin thinning. PMID- 24770407 TI - Longitudinal assessment of endolymphatic hydrops with contrast-enhanced magnetic resonance imaging of the labyrinth. AB - OBJECTIVE: To visualize the progression of endolymphatic hydrops in a patient with Meniere's disease. PATIENT AND METHODS: A 53-year-old patient with definite Meniere's disease underwent locally enhanced inner ear magnetic resonance imaging (LEIM) for visualizing endolymphatic hydrops. Two years later, a second magnetic resonance imaging was performed for follow-up. RESULTS: The first magnetic resonance image confirmed the presence of endolymphatic hydrops and a treatment with betahistine was begun. Two years later, no more vertigo attacks occurred. The audiometry showed a deterioration of the hearing loss on both sides, whereas the caloric irrigation revealed normal results on both occasions. In comparison to the first examination, the second LEIM showed an augmented endolymphatic hydrops in both the cochlear and the vestibular compartments. CONCLUSION: For the first time, this case of Meniere's disease shows an enlargement of endolymphatic hydrops in 1 individual in the course of 2 years. A further development of the LEIM technique is desirable to enable the volumetric quantification of endolymphatic hydrops and to monitor the effect of therapies on the course of Meniere's disease. PMID- 24770408 TI - Electrically evoked auditory brainstem response-based evaluation of the spatial distribution of auditory neuronal tissue in common cavity deformities. AB - OBJECTIVE: In a common cavity (CC) deformity, the cochlea and vestibule are confluent to form a single cavity without internal architecture, and distribution of auditory neuronal tissue is unclear. The purposes of this study are to reveal the spatial distribution of auditory neuronal tissue in CC deformity using electrically evoked auditory brainstem response (EABR) during cochlear implantation. STUDY DESIGN: Retrospective case review. SETTING: Cochlear implant (CI) center at a tertiary referral hospital. PATIENTS: Five patients with CC deformity who underwent cochlear implantation and intraoperative EABR testing. MAIN OUTCOME MEASURES: Spatial distribution of electrodes that elicited an evoked wave V (eV) in EABR testing was evaluated in each CC deformity. RESULTS: Electrically evoked auditory brainstem response testing demonstrated that electrodes attached on the inner wall of the anteroinferior cavity of the CC deformity successfully elicited a reproducible eV in all cases, and the latency of each eV was an approximately 4 ms, which is similar to those reported in patients without an inner ear malformation. Interestingly, in Case 1 with the lowest percentage of eV-positive electrodes (31.8%), CI-aided audiometric thresholds were changed, depending on the frequency allocation to eV-positive electrodes in the programming. Cochlear implant-mediated facial nerve stimulation was observed in 3 of 5 cases, and results of EABR testing were useful for optimizing the device program to decrease facial nerve stimulation without sacrificing CI-mediated auditory performance. CONCLUSION: The results of EABR testing suggested that auditory neuronal elements are distributed to the anteroinferior part of CC deformity, mainly around or near the inner wall of the cavity. In cases with CC deformity, EABR testing is useful to achieve the optimal electrode array placement and to adjust programming parameters of the implanted device, which might be essential to maximize CI outcomes and to decrease facial nerve stimulation. PMID- 24770409 TI - Temporal bone histopathology case of the month. First branchial cleft anomaly with an orifice in the bony external auditory canal accompanied by contralateral middle ear cholesteatoma. PMID- 24770410 TI - Successful cochlear implantation in a case of Vogt-Koyanagi-Harada disease. AB - OBJECTIVE: To characterize the auditory phenotype of Vogt-Koyanagi-Harada disease (VKH) and highlight the potential for successful cochlear implantation (CI). PATIENTS: Single case report INTERVENTION(S): Therapeutic MAIN OUTCOME MEASURE(S): AzBio Sentences in quiet and noise, CNC Words, BKB-SIN RESULTS: VKH is a systemic autoimmune disorder characterized by granulomatous uveitis accompanied by neurologic and auditory-vestibular symptoms. Development is attributed to an autoimmune response against pigmented cells, with destruction of melanocytes by T lymphocytes directed against an unidentified antigen; accordingly, the disease typically affects races with darkly pigmented skin. VKH presents as blurring of vision and eye inflammation, severe headaches, and meningismis. Auditory symptoms include sensorineural hearing loss (SNHL), tinnitus, and imbalance. SNHL can persist despite immunosuppressant therapy.This report describes successful cochlear implantation in a 26-year-old female patient with VKH who presented with complaints of blurred vision and bilateral sudden SNHL. Oral steroids initially restored hearing, but benefit ceased upon discontinuation of oral steroids and was not restored following a series of intratympanic steroid injections. The patient underwent bilateral CI, which was fast-tracked because of the autoimmune nature of her hearing loss. After implantation, her speech understanding in both quiet and noise far exceeds her pre-implant scores. CONCLUSION: This unique case is the first to report successful CI in VKH. It is important for hearing health professionals to be aware of the signs and symptoms of this disease as patients may present initially with hearing loss, tinnitus, or imbalance, and may benefit from CI in cases of persistent, steroid-unresponsive, severe-to-profound SNHL. PMID- 24770411 TI - Results of myringoplasty in children with cleft palate: a patient-matched study. AB - OBJECTIVES: To assess the anatomic and functional outcome of underlay cartilage myringoplasty in children with cleft palate, at different postoperative periods compared with a patients-matched control group STUDY DESIGN: Case control study, tertiary referral center. METHODS: An otologic database was used to select children with cleft palate and perforated tympanic membrane who underwent myringoplasty between 1995 and 2012. These subjects were matched with control patients, without cleft palate, using the following criteria: age, size of perforation, status of contralateral ear, and status of middle ear mucosa. Charts were reviewed for the following: patients characteristics, preoperative findings, surgical data, postoperative anatomic and functional outcomes, and reinterventions. The postoperative findings were divided into 5 different periods. RESULTS: A group of 32 cleft palate patients as well as 32 control patients were included in this study, with a mean follow up of 63.6 +/- 41 months. There were no differences between the groups in anatomic success as it was achieved in 84% in both groups. No differences were seen in functional outcome when compared with each different postoperative period. Using the last available audiogram, the postoperative mean air conduction and the air-bone gap were significantly worse in the cleft group compared with the control group, respectively, 26.1 +/- 13.7 dB versus 18.4 +/- 10.1 dB, p = 0.042; and 16.5 +/- 9.4 dB and 11.3 +/- 6.4 dB, p = 0.046. Additionally, the functional success was significantly worse in the cleft group; 58% versus 87% in the control group (OR, 5.5 [95% CI, 1.22-24.81], p = 0.027). CONCLUSION: Children with cleft palate can benefit from cartilage underlay myringoplasty in terms of closure of tympanic membrane, although there is a worse functional outcome. PMID- 24770412 TI - Surgical anatomy of the basal turn of the human cochlea as pertaining to cochlear implantation. AB - HYPOTHESIS: To study the morphometry of the human cochlea with special emphasis on its basal and turn and their implications for cochlear implantation. BACKGROUND: Cochlear implantation is an established mode of treatment for patients with bilateral, profound sensorineural hearing loss. The intricate knowledge of the anatomy of the cochlea and its variations like unusual constriction of the cochlear lumen or dysmorphic cochlea is important for the success of cochlear implantation. DESIGN: Forty nonpathologic formalin-preserved human temporal bones were microdissected to expose the medial wall of the tympanic cavity. After exposure of the cochlea, its widest transverse and vertical diameters were measured. The internal diameter of the basal turn of the cochlea was measured on 13 sites at every 30-degree interval. The outer wall length of the basal turn was also measured. RESULTS: The mean +/- standard deviation transverse and vertical diameters of cochleae were 8.06 +/- 0.80 and 5.85 +/- 0.72 mm, respectively. The mean diameter of the basal turn gradually tapered from 1.98 +/- 0.34 mm at 0 degrees to 1.21 +/- 0.32 mm at 360 degrees. Unusual constrictions were observed in the basal turn of the cochlea in 3 cases (7.5%). A wide range was found in the outer wall length of the basal turn of the cochlea (range 15.6-24.6 mm). CONCLUSIONS: The cochleae differed significantly in their dimensions. Unusual constrictions found in the basal turn of the cochlea in 7.5% cases may explain the difficulties experienced by surgeons to reach full insertion in such cases. An extensive range (15.6-24.6 mm) of the length of the basal turn denotes significant variations of insertion degrees at constant surgical depths. The refined morphometric information of the cochlea may help in designing and selecting the electrode array for cochlear implantation. PMID- 24770413 TI - Reply to comment: Salzman et al,, Osteonecrosis of the external auditory canal associated with oral bisphosphonate therapy: case report and literature review. PMID- 24770414 TI - Cloning and functional characterization of three branch point oxidosqualene cyclases from Withania somnifera (L.) dunal. AB - Oxidosqualene cyclases (OSCs) positioned at a key metabolic subdividing junction execute indispensable enzymatic cyclization of 2,3-oxidosqualene for varied triterpenoid biosynthesis. Such branch points present favorable gene targets for redirecting metabolic flux toward specific secondary metabolites. However, detailed information regarding the candidate OSCs covering different branches and their regulation is necessary for the desired genetic manipulation. The aim of the present study, therefore, was to characterize members of OSC superfamily from Withania somnifera (Ws), a medicinal plant of immense repute known to synthesize a large array of biologically active steroidal lactone triterpenoids called withanolides. Three full-length OSC cDNAs, beta-amyrin synthase (WsOSC/BS), lupeol synthase (WsOSC/LS), and cycloartenol synthase (WsOSC/CS), having open reading frames of 2289, 2268, and 2277 bp, were isolated. Heterologous expression in Schizosaccharomyces pombe, LC-MS analyses, and kinetic studies confirmed their monofunctionality. The three WsOSCs were found to be spatially regulated at transcriptional level with WsOSC/CS being maximally expressed in leaf tissue. Promoter analysis of three WsOSCs genes resulted in identification of distinct cis-regulatory elements. Further, transcript profiling under methyl jasmonate, gibberellic acid, and yeast extract elicitations displayed differential transcriptional regulation of each of the OSCs. Changes were also observed in mRNA levels under elicitations and further substantiated with protein expression levels by Western blotting. Negative regulation by yeast extract resulted in significant increase in withanolide content. Empirical evidence suggests that repression of competitive branch OSCs like WsOSC/BS and WsOSC/LS possibly leads to diversion of substrate pool toward WsOSC/CS for increased withanolide production. PMID- 24770415 TI - Myeloid cell-specific disruption of Period1 and Period2 exacerbates diet-induced inflammation and insulin resistance. AB - The circadian clockworks gate macrophage inflammatory responses. Given the association between clock dysregulation and metabolic disorders, we conducted experiments to determine the extent to which over-nutrition modulates macrophage clock function and whether macrophage circadian dysregulation is a key factor linking over-nutrition to macrophage proinflammatory activation, adipose tissue inflammation, and systemic insulin resistance. Our results demonstrate that 1) macrophages from high fat diet-fed mice are marked by dysregulation of the molecular clockworks in conjunction with increased proinflammatory activation, 2) global disruption of the clock genes Period1 (Per1) and Per2 recapitulates this amplified macrophage proinflammatory activation, 3) adoptive transfer of Per1/2 disrupted bone marrow cells into wild-type mice potentiates high fat diet-induced adipose and liver tissue inflammation and systemic insulin resistance, and 4) Per1/2-disrupted macrophages similarly exacerbate inflammatory responses and decrease insulin sensitivity in co-cultured adipocytes in vitro. Furthermore, PPARgamma levels are decreased in Per1/2-disrupted macrophages and PPARgamma2 overexpression ameliorates Per1/2 disruption-associated macrophage proinflammatory activation, suggesting that this transcription factor may link the molecular clockworks to signaling pathways regulating macrophage polarization. Thus, macrophage circadian clock dysregulation is a key process in the physiological cascade by which diet-induced obesity triggers macrophage proinflammatory activation, adipose tissue inflammation, and insulin resistance. PMID- 24770416 TI - The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. AB - Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) has been previously proposed as a potential drug for use in substrate reduction therapy for mucopolysaccharidoses, a group of inherited metabolic diseases caused by mutations leading to inefficient degradation of glycosaminoglycans (GAGs) in lysosomes. It was demonstrated that this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases. So far, no comprehensive genomic analyses have been performed to elucidate the molecular mechanisms underlying the effect elicited by genistein. Therefore, the aim of this work was to identify the genistein-modulated gene network regulating GAG biosynthesis and degradation, taking into consideration the entire lysosomal metabolism. Our analyses identified over 60 genes with known roles in lysosomal biogenesis and/or function whose expression was enhanced by genistein. Moreover, 19 genes whose products are involved in both GAG synthesis and degradation pathways were found to be remarkably differentially regulated by genistein treatment. We found a regulatory network linking genistein-mediated control of transcription factor EB (TFEB) gene expression, TFEB nuclear translocation, and activation of TFEB-dependent lysosome biogenesis to lysosomal metabolism. Our data indicate that the molecular mechanism of genistein action involves not only impairment of GAG synthesis but more importantly lysosomal enhancement via TFEB. These findings contribute to explaining the beneficial effects of genistein in lysosomal storage diseases as well as envisage new therapeutic approaches to treat these devastating diseases. PMID- 24770417 TI - Helicase SUV3, polynucleotide phosphorylase, and mitochondrial polyadenylation polymerase form a transient complex to modulate mitochondrial mRNA polyadenylated tail lengths in response to energetic changes. AB - Mammalian mitochondrial mRNA (mt-mRNA) transcripts are polyadenylated at the 3' end with different lengths. The SUV3.PNPase complex and mtPAP have been shown to degrade and polyadenylate mt mRNA, respectively. How these two opposite actions are coordinated to modulate mt-mRNA poly(A) lengths is of interest to pursue. Here, we demonstrated that a fraction of the SUV3.PNPase complex interacts with mitochondrial polyadenylation polymerase (mtPAP) under low mitochondrial matrix inorganic phosphate (Pi) conditions. In vitro binding experiments using purified proteins suggested that SUV3 binds to mtPAP through the N-terminal region around amino acids 100-104, distinctive from the C-terminal region around amino acids 510-514 of SUV3 for PNPase binding. mtPAP does not interact with PNPase directly, and SUV3 served as a bridge capable of simultaneously binding with mtPAP and PNPase. The complex consists of a SUV3 dimer, a mtPAP dimer, and a PNPase trimer, based on the molecular sizing experiments. Mechanistically, SUV3 provides a robust single strand RNA binding domain to enhance the polyadenylation activity of mtPAP. Furthermore, purified SUV3.PNPase.mtPAP complex is capable of lengthening or shortening the RNA poly(A) tail lengths in low or high Pi/ATP ratios, respectively. Consistently, the poly(A) tail lengths of mt-mRNA transcripts can be lengthened or shortened by altering the mitochondrial matrix Pi levels via selective inhibition of the electron transport chain or ATP synthase, respectively. Taken together, these results suggested that SUV3.PNPase.mtPAP form a transient complex to modulate mt-mRNA poly(A) tail lengths in response to cellular energy changes. PMID- 24770418 TI - Molecular and cellular roles of PI31 (PSMF1) protein in regulation of proteasome function. AB - We investigated molecular features and cellular roles of PI31 (PSMF1) on regulation of proteasome function. PI31 has a C-terminal HbYX (where Hb is a hydrophobic amino acid, Y is tyrosine, and X is any amino acid) motif characteristic of several proteasome activators. Peptides corresponding to the PI31 C terminus also bind to and activate the 20 S proteasome in an HbYX dependent manner, but intact PI31protein inhibits in vitro 20 S activity. Binding to and inhibition of the proteasome by PI31 are conferred by the HbYX-containing proline-rich C-terminal domain but do not require HbYX residues. Thus, multiple regions of PI31 bind independently to the proteasome and collectively determine effects on activity. PI31 blocks the ATP-dependent in vitro assembly of 26 S proteasome from 20 S proteasome and PA700 subcomplexes but has no effect on in vitro activity of the intact 26 S proteasome. To determine the physiologic significance of these in vitro effects, we assessed multiple aspects of cellular proteasome content and function after altering PI31 levels. We detected no change in overall cellular proteasome content or function when PI31 levels were either increased by moderate ectopic overexpression or decreased by RNA interference (RNAi). We also failed to identify a role of PI31 ADP-ribosylation as a mechanism for regulation of overall 26 S proteasome content and function, as recently proposed. Thus, despite its in vitro effects on various proteasome activities and its structural relationship to established proteasome regulators, cellular roles and mechanisms of PI31 in regulation of proteasome function remain unclear and require future definition. PMID- 24770421 TI - A retrospective review of clopidogrel as primary therapy for migraineurs with right to left shunt lesions. AB - BACKGROUND: The association of patient foramen ovale (PFO) and migraine headache (migraine) with aura (MA) is well established. Current research suggests a mechanistic link between platelet activation, paradoxical embolization and migraine in some patients. METHODS: Clopidogrel, a platelet inhibitor, was added to existing migraine therapy, as a 4-week open-label trial in 15 women, aged 16 56 years, with severe migraine and documented right to left shunt (RLS). RESULTS: 13/15 had > 50% reduction or complete elimination of migraine symptoms. After completing the trial period, five responders remain on clopidogrel with ongoing benefit at 11.9 +/- 4.5 months (6.5-20), one stopped clopidogrel because of side effects. Nine other responders underwent PFO closure and clopidogrel discontinuation. Eight of nine have had ongoing benefit. CONCLUSIONS: Clopidogrel may have a primary prophylactic role in migraine/RLS patients, but may also help select candidates who would benefit from PFO closure. A randomized clinical trial is being established. PMID- 24770419 TI - Inefficient translocation of preproinsulin contributes to pancreatic beta cell failure and late-onset diabetes. AB - Among the defects in the early events of insulin biosynthesis, proinsulin misfolding and endoplasmic reticulum (ER) stress have drawn increasing attention as causes of beta cell failure. However, no studies have yet addressed potential defects at the cytosolic entry point of preproinsulin into the secretory pathway. Here, we provide the first evidence that inefficient translocation of preproinsulin (caused by loss of a positive charge in the n region of its signal sequence) contributes to beta cell failure and diabetes. Specifically, we find that, after targeting to the ER membrane, preproinsulin signal peptide (SP) mutants associated with autosomal dominant late-onset diabetes fail to be fully translocated across the ER membrane. The newly synthesized, untranslocated preproinsulin remains strongly associated with the ER membrane, exposing its proinsulin moiety to the cytosol. Rather than accumulating in the ER and inducing ER stress, untranslocated preproinsulin accumulates in a juxtanuclear compartment distinct from the Golgi complex, induces the expression of heat shock protein 70 (HSP70), and promotes beta cell death. Restoring an N-terminal positive charge to the mutant preproinsulin SP significantly improves the translocation defect. These findings not only reveal a novel molecular pathogenesis of beta cell failure and diabetes but also provide the first evidence of the physiological and pathological significance of the SP n region positive charge of secretory proteins. PMID- 24770420 TI - Interaction of branch migration translocases with the Holliday junction-resolving enzyme and their implications in Holliday junction resolution. AB - Double-strand break repair involves the formation of Holliday junction (HJ) structures that need to be resolved to promote correct replication and chromosomal segregation. The molecular mechanisms of HJ branch migration and/or resolution are poorly characterized in Firmicutes. Genetic evidence suggested that the absence of the RuvAB branch migration translocase and the RecU HJ resolvase is synthetically lethal in Bacillus subtilis, whereas a recU recG mutant was viable. In vitro RecU, which is restricted to bacteria of the Firmicutes phylum, binds HJs with high affinity. In this work we found that RecU does not bind simultaneously with RecG to a HJ. RuvB by interacting with RecU bound to the central region of HJ DNA, loses its nonspecific association with DNA, and re-localizes with RecU to form a ternary complex. RecU cannot stimulate the ATPase or branch migration activity of RuvB. The presence of RuvB.ATPgammaS greatly stimulates RecU-mediated HJ resolution, but the addition of ATP or RuvA abolishes this stimulatory effect. A RecU.HJ.RuvAB complex might be formed. RecU does not increase the RuvAB activities but slightly inhibits them. PMID- 24770422 TI - Allodynia is associated with a higher prevalence of depression in migraine patients. AB - INTRODUCTION: There is a strong association between migraine and depression. The aim of this study is to identify migraine-specific factors involved in this association. METHODS: We conducted a cross-sectional study in a large, well defined cohort of migraine patients (n=2533). We assessed lifetime depression using validated questionnaires, and diagnosed migraine based on the International Classification of Headache Disorders III-beta criteria. Multivariate regression analyses were conducted. RESULTS: Of the 2533 migraineurs that were eligible, 1137 (45%) suffered from lifetime depression. The following independent factors were associated with an increased depression prevalence: i) migraine-specific risk factors: high migraine attack frequency and the presence of allodynia, ii) general factors: being a bad sleeper, female gender, high BMI, being single, smoking, and a low alcohol consumption. CONCLUSION: This study identified allodynia, in addition to high migraine attack frequency, as a new migraine specific factor associated with depression. PMID- 24770424 TI - Pharmaceutical identifier confirmation via DART-TOF. AB - Pharmaceutical analysis comprises a large amount of the casework in forensic controlled substances laboratories. In order to reduce the time of analysis for pharmaceuticals, a Direct Analysis in Real Time ion source coupled with an accurate mass time-of-flight (DART-TOF) mass spectrometer was used to confirm identity. DART-TOF spectral data for pharmaceutical samples were analyzed and evaluated by comparison to standard spectra. Identical mass pharmaceuticals were differentiated using collision induced dissociation fragmentation, present/absent ions, and abundance comparison box plots; principal component analysis (PCA) and linear discriminant analysis (LDA) were used for differentiation of identical mass mixed drug spectra. Mass assignment reproducibility and robustness tests were performed on the DART-TOF spectra. Impacts on the forensic science community include a decrease in analysis time over the traditional gas chromatograph/mass spectrometry (GC/MS) confirmations, better laboratory efficiency, and simpler sample preparation. Using physical identifiers and the DART-TOF to confirm pharmaceutical identity will eliminate the use of GC/MS and effectively reduce analysis time while still complying with accepted analysis protocols. This will prove helpful in laboratories with large backlogs and will simplify the confirmation process. PMID- 24770423 TI - Effects of high intensity training and high volume training on endothelial microparticles and angiogenic growth factors. AB - AIMS: Endothelial microparticles (EMP) are complex vesicular structures shed from activated or apoptotic endothelial cells. As endurance exercise affects the endothelium, the objective of the study was to examine levels of EMP and angiogenic growth factors following different endurance exercise protocols. METHODS: 12 subjects performed 3 different endurance exercise protocols: 1. High volume training (HVT; 130 min at 55% peak power output (PPO); 2. 4 * 4 min at 95% PPO; 3. 4 * 30 sec all-out. EMPs were quantified using flow cytometry after staining platelet-poor-plasma. Events positive for Annexin-V and CD31, and negative for CD42b, were classified as EMPs. Vascular endothelial growth factor (VEGF), migratory inhibiting factor (MIF) and hepatocyte growth factor (HGF) were determined by ELISA technique. For all these measurements venous blood samples were taken pre, 0', 30', 60' and 180' after each intervention. Furthermore, in vitro experiments were performed to explore the effect of collected sera on target endothelial functions and MP uptake capacities. RESULTS: VEGF and HGF significantly increased after HIT interventions. All three interventions caused a significant decrease in EMP levels post exercise compared to pre values. The sera taken after exercise increased the uptake of EMP in target endothelial cells compared to sera taken under resting conditions, which was shown to be phosphatidylserin-dependent. Increased EMP uptake was associated with an improved protection of target cells against apoptosis. Sera taken prior and after exercise promoted target endothelial cell migration, which was abrogated after inhibition of VEGF. CONCLUSION: Physical exercise leads to decreased EMP levels and promotes a phosphatidylserin-dependent uptake of EMP into target endothelial cells, which is associated with a protection of target cells against apoptosis. PMID- 24770425 TI - [The IABP-SHOCK II study]. PMID- 24770426 TI - [Studies on the efficacy of post-cardiac arrest hypothermia]. PMID- 24770427 TI - [Surgical heart failure treatment program - the experience of Kazakhstan]. AB - In Kazakhstan, geographical and cultural reasons do not favor the development of heart transplant activity. Thus, a surgical program for treatment of advanced, refractory heart failure was implemented, focusing the efforts on ventricular assist device (VAD) therapy. The program, supported and funded by the national healthcare system, is based on a single, highly specialized surgical Center for the operation, and on a regional infrastructure for outpatient follow-up. Regional VAD coordinators are educated by the National Center. They are in charge of regular patient check, anticoagulant and antiplatelet treatment prescription, and continuing patients' and caregivers' education, mainly regarding driveline exit site dressing and driveline stabilization. From November 2011 to November 2013, 95 patients received 100 devices, mainly for left ventricular support (LVAD): HeartMate II, n=70, HeartWare, n=25. Mean age was 49.5 years, and 87.37% of the patients were males. Most patients had INTERMACS profile 4 (55%), followed by 3 and 2 (17% each). Symptomatic and functional improvement are testified by changes from baseline to month 3 of NYHA functional class (from III-IV to I-II), results of the 6-min walk test (from 152 to 440 m), and NT-proBNP levels (from 6997 to 1126 pg/ml). Overall 1-year survival was 69%, with a trend for outcome improvement over time and a relationship with preoperative INTERMACS profile (1 year survival of 60% in patients with INTERMACS profile 1-2 vs 75% in those with INTERMACS profile 3-4). In summary, where and when a heart transplant program cannot be implemented, LVAD represents a realistic therapeutic alternative. The key points for a successful VAD program are a dedicated, highly specialized multidisciplinary team at the Cardiac Surgery Center, an infrastructure throughout the country for coordinated outpatient follow-up, adequate reimbursement for this activity, and support by the healthcare system. PMID- 24770428 TI - [Dyslipidemias and statins: from guidelines to clinical practice. An updated review of the literature]. AB - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability not only in countries with a high degree of socio-economic development but also in low-middle income countries. The study of atherosclerosis and the strategies to control ASCVD are in progress. All strategies emphasize the need for lowering LDL cholesterol through appropriate lifestyle and use of lipid lowering drugs, mainly statins. The mode of approach is variable. Statin therapy is recommended in secondary prevention, whereas use in primary prevention is still a matter of debate. The guidelines provided by international panels serve as a reference in clinical practice but, as stated by the National Cholesterol Education Program (NCEP), do not replace the physician's clinical judgment. PMID- 24770429 TI - [Coronary artery ectasia: etiopathogenesis, diagnosis and treatment]. AB - Coronary ectasia is a dilation of coronary arteries, angiographically defined if the diameter of the artery is >= 1.5 times greater than that of the intact adjacent vascular segment. An association has been found between coronary artery ectasia and a broad spectrum of different diseases, first of all atherosclerotic coronary artery disease. The mechanisms that determine the abnormal dilatation of the vascular lumen and the etiology of coronary artery ectasia are still poorly understood. Various hypotheses have been formulated over the time, the most accredited between these recognizes as main responsible an uncontrolled activity of a particular family of enzymes that degrade the extracellular matrix, the metalloproteinases. This exaggerated activity can be due to an increase in the absolute sense of these enzymes and/or a reduction in the levels of their natural specific inhibitors. Coronary ectasia may have a variable clinical presentation. It is often an occasional finding detected at coronary angiography or following the occurrence of atypical chest pain, stable angina or even acute coronary syndrome. The frequent coexistence of coronary artery ectasia and atherosclerotic coronary artery disease and their common histopathological features have led to hypothesize that coronary ectasia may represent a variant of atherosclerosis. However, some significant differences between these two diseases leave open the hypothesis that coronary artery ectasia may be a pathological entity per se. PMID- 24770430 TI - [Use of sutureless prosthetic aortic valves in cardiac surgery]. AB - In the last years, an increasing proportion of high-risk patients undergo surgical aortic valve replacement. In order to reduce the risk associated with cross-clamp time or cardioplegic ischemic time, sutureless aortic prostheses have been developed. These bioprosthetic valves are not hand sewn, and this technological advance translates into reduced implantation times, thus improving outcome of patients referred for aortic valve replacement. At present, three sutureless bioprostheses are available on the market: 3f Enable (Medtronic Inc., Minneapolis, Minnesota, USA), Perceval (Sorin Group, Saluggia, Italy) and Intuity (Edwards Lifesciences, Irvine, California, USA). This article provides an overview of the available literature on sutureless aortic valves with the aim to better define current role and future perspectives of sutureless aortic bioprostheses for the treatment of aortic valve stenosis. PMID- 24770431 TI - [Results of the OBSERVANT study: clinical characteristics and short-term outcome of the enrolled population treated with transcatheter versus surgical aortic valve implantation]. AB - BACKGROUND: OBSERVANT represents the first national observational study on the comparative effectiveness of transcatheter aortic valve implantation (TAVI) vs surgical aortic valve replacement (SAVR) at short, medium and long term, in a patient population with severe aortic stenosis (AS). The aim of this paper is to describe patient characteristics and short-term outcomes of the enrolled population. METHODS: OBSERVANT is an observational prospective multicenter cohort study that enrolled AS patients undergoing SAVR or TAVI from December 2010 to June 2012 in the participating hospitals. Information on demographic characteristics, health status prior to intervention, therapeutic approach, intraprocedural and 30-day outcomes was collected. An administrative follow-up was set up to collect data on long-term outcomes. RESULTS: The enrolled population included 7618 patients undergoing transfemoral/transubclavian TAVI (TF/TS-TAVI, n=1652), transapical TAVI (TA-TAVI, n=259) or SAVR (n=5707). SAVR patients were younger and with a lower risk profile than TAVI patients (logistic EuroSCORE: SAVR 6.4 +/- 7.3%, TF/TS-TAVI 14.1 +/- 12.1%, TA-TAVI 15.5 +/- 11.0%; p<0.001). When 30-day mortality rates were stratified by logistic EuroSCORE, a statistically significant difference was found only in the patient subgroup with logistic EuroSCORE <=5% (SAVR 1.0%, TF/TS-TAVI 4.7%, TA-TAVI 0.0%; p=0.005). CONCLUSIONS: Findings from the OBSERVANT study confirm that patients undergoing TAVI are older and sicker than patients undergoing SAVR. Nevertheless, the logistic EuroSCORE shows that, in Italy, also patients at intermediate surgical risk are treated with TAVI. Stratifying by logistic EuroSCORE, SAVR seems to be superior to TAVI in the subgroup of patients at very low risk. More sophisticated analyses on patient subgroups with comparable risk profile and on long-term follow-up will allow to obtain valuable information on the effectiveness of TAVI and SAVR procedures. PMID- 24770432 TI - [Transcatheter aortic valve implantation between virtual and real data]. PMID- 24770433 TI - [Transcatheter treatment of aortic stenosis in Italy]. PMID- 24770434 TI - [Anomalous origin of the right coronary artery from the left sinus of Valsalva: essential role of computed tomography to clarify the coronary artery course and literature review on diagnostic and therapeutic management in 215 cases]. AB - Coronary artery anomalies are among the most confusing topics in cardiology. Although the medical community is increasingly aware that coronary anomalies can be fatal, the reasons for a sudden fatal event and the frequency with which it occurs are generally unclear. In addition, coronary anomalies are usually compatible with normal prenatal myocardial development and postnatal growth and function, even permitting intense athletic activity. Nevertheless, coronary anomalies may lead to a pathological state, which usually originates suddenly, and the diagnostic and therapeutic management remains controversial, as outlined in our review of 215 cases in the literature. We report the case of a 53-year-old female who presented with effort/stress angina. She underwent coronary angiography, which demonstrated no significant parietal lesions but an anomalous origin of the right coronary artery (RCA) from the left sinus of Valsalva: the RCA showed an anomalous course between the aorta and the pulmonary artery with systolic compression and potential myocardial ischemia. The patient was then referred for surgical treatment and, according to the surgeons, she underwent isolated coronary artery bypass with the right internal mammary artery on the RCA and ligature of the native RCA to prevent competitive flow. PMID- 24770435 TI - [Multi-imaging in Cardiology: anomalous origin of the left anterior descending coronary artery from the right coronary artery associated with type IV dual left anterior descending coronary artery]. PMID- 24770437 TI - Excitonic energy transfer in polymer wrapped carbon nanotubes in gradually grown nanoassemblies. AB - We investigate the exciton energy transfer (ET) in nanoassemblies (nanotube based aggregates) formed by polymer wrapped single-walled carbon nanotubes (SWNTs) using photoluminescence (PL) spectroscopy and simulation. The distinctive feature of this study is the gradual growth of such nanostructures in aqueous medium induced by increasing the concentration of porphyrin molecules stitching nanotube polymer complexes in densely packed assemblies. Experimental dependencies of PL intensity on the porphyrin concentration for different types of semiconducting SWNTs demonstrate step-like behavior controlled by the amount of bound nanotubes and are in good agreement with the simulating model. The simulation algorithm determines the criterion of the aggregate formation depending on the number of porphyrin molecules per tube and the cascade exciton energy transfer between neighboring semiconducting nanotubes of different chiralities. Aggregates of small sizes (up to six-eight individual tubes) contain mostly semiconducting species, while aggregates of a larger size (up to several tens of tubes) incorporate metallic SWNTs, inducing strong PL quenching. From the fitting procedure, an ET rate of 0.6 * 10(10) s(-1) has been determined which is consistent with the center to center distance (~2.3 nm) between adjacent tubes separated by polymer and porphyrin molecules. The threshold of the dimer formation corresponds to one porphyrin molecule per ~20 nm of tube lengths that was supported by molecular dynamics simulation. These findings provide insight into the ET mechanism in SWNT nanoassemblies of variable sizes, which can be gradually controlled by the external factor (the concentration of porphyrin molecules). PMID- 24770438 TI - Validation of the Fitbit wireless activity tracker for prediction of energy expenditure. AB - OBJECTIVE: The purpose of this study was to examine the accuracy of the Fitbit wireless activity tracker in assessing energy expenditure (EE) for different activities. METHODS: Twenty participants (10 males, 10 females) wore the Fitbit Classic wireless activity tracker on the hip and the Oxycon Mobile portable metabolic system (criterion). Participants performed walking and running trials on a treadmill and a simulated free-living activity routine. Paired t tests were used to test for differences between estimated (Fitbit) and criterion (Oxycon) kcals for each of the activities. RESULTS: Mean bias for estimated energy expenditure for all activities was -4.5 +/- 1.0 kcals/6 min (95% limits of agreement: -25.2 to 15.8 kcals/6 min). The Fitbit significantly underestimated EE for cycling, laundry, raking, treadmill (TM) 3 mph at 5% grade, ascent/descent stairs, and TM 4 mph at 5% grade, and significantly overestimated EE for carrying groceries. Energy expenditure estimated by the Fitbit was not significantly different than EE calculated from the Oxycon Mobile for 9 activities. CONCLUSION: The Fitbit worn on the hip significantly underestimates EE of activities. The variability in underestimation of EE for the different activities may be problematic for weight loss management applications since accurate EE estimates are important for tracking/monitoring energy deficit. PMID- 24770440 TI - Medicare star ratings: stakeholder proceedings on community pharmacy and managed care partnerships in quality. AB - OBJECTIVES: To describe the Medicare star rating system, created by the Centers for Medicare & Medicaid Services (CMS) in 2007; identify quality measures that can potentially be improved through collaboration between health plans and community pharmacy; provide examples of current collaboration between health plans and community pharmacy; and identify collaboration goals, challenges, components, and strategies. DATA SOURCES: National thought leaders at a conference titled CMS Star Ratings: A Stakeholder Discussion, held on March 21, 2013, supplemented with related information from the literature. SUMMARY: The Medicare star rating system is part of CMS's efforts to define, measure, and reward quality health care. Approximately one-half of the star rating performance measures can be influenced directly by community pharmacists working in conjunction with payers that must meet the quality measures. In 2012, a weighting system for star ratings was implemented. Of 10 triple-weighted ratings, 8 are related directly and indirectly to medication therapy and thus have the potential to be improved by pharmacist intervention. Plan ratings can have a substantial impact on beneficiary enrollment. Since very small improvements in performance measures can translate into large effects on star ratings, concerted efforts to improve pharmacy-related measures could move a plan to a higher star rating; conversely, inattention to areas such as high-risk medications, antidiabetic pharmacotherapy, and medication adherence could lower a plan's star rating. Topics discussed in this article include the Electronic Quality Improvement Platform for Plans and Pharmacies, or EQUIPP, the payer perspective on pharmacies, programs currently under way in community pharmacies, and ways plans and pharmacies can better collaborate with each other. CONCLUSION: The pharmacist's ability to work directly with patients to improve medication use is a critical factor in improving health plan Medicare star ratings. Health plans and community pharmacies must forge partnerships based on well-defined goals and innovative tactics to ensure care quality consistent with evolving public and private payment models. PMID- 24770439 TI - Evaluation of gene expression classification studies: factors associated with classification performance. AB - Classification methods used in microarray studies for gene expression are diverse in the way they deal with the underlying complexity of the data, as well as in the technique used to build the classification model. The MAQC II study on cancer classification problems has found that performance was affected by factors such as the classification algorithm, cross validation method, number of genes, and gene selection method. In this paper, we study the hypothesis that the disease under study significantly determines which method is optimal, and that additionally sample size, class imbalance, type of medical question (diagnostic, prognostic or treatment response), and microarray platform are potentially influential. A systematic literature review was used to extract the information from 48 published articles on non-cancer microarray classification studies. The impact of the various factors on the reported classification accuracy was analyzed through random-intercept logistic regression. The type of medical question and method of cross validation dominated the explained variation in accuracy among studies, followed by disease category and microarray platform. In total, 42% of the between study variation was explained by all the study specific and problem specific factors that we studied together. PMID- 24770441 TI - Proteomic analysis of salt stress and recovery in leaves of Vigna unguiculata cultivars differing in salt tolerance. AB - KEY MESSAGE: Cowpea cultivars differing in salt tolerance reveal differences in protein profiles and adopt different strategies to overcome salt stress. Salt tolerant cultivar shows induction of proteins related to photosynthesis and energy metabolism. Salinity is a major abiotic stress affecting plant cultivation and productivity. The objective of this study was to examine differential proteomic responses to salt stress in leaves of the cowpea cultivars Pitiuba (salt tolerant) and TVu 2331 (salt sensitive). Plants of both cultivars were subjected to salt stress (75 mM NaCl) followed by a recovery period of 5 days. Proteins extracted from leaves of both cultivars were analyzed by two-dimensional electrophoresis (2-DE) under salt stress and after recovery. In total, 22 proteins differentially regulated by both salt and recovery were identified by LC ESI-MS/MS. Our current proteome data revealed that cowpea cultivars adopted different strategies to overcome salt stress. For the salt-tolerant cultivar (Pitiuba), increase in abundance of proteins involved in photosynthesis and energy metabolism, such as rubisco activase, ribulose-5-phosphate kinase (Ru5PK) (EC 2.7.1.19), glycine decarboxylase (EC 1.4.4.2) and oxygen-evolving enhancer (OEE) protein 2, was observed. However, these vital metabolic processes were more profoundly affected in salt-sensitive cultivar (TVu), as indicated by the down regulation of OEE protein 1, Mn-stabilizing protein-II, carbonic anhydrase (EC 4.2.1.1) and Rubisco (EC 4.1.1.39), leading to energy reduction and a decline in plant growth. Other proteins differentially regulated in both cultivars corresponded to different physiological responses. Overall, our results provide information that could lead to a better understanding of the molecular basis of salt tolerance and sensitivity in cowpea plants. PMID- 24770442 TI - High-frequency generation and characterization of intergeneric hybrids and haploids from new wheat-barley crosses. AB - KEY MESSAGE: Hybrid plants and a high frequency of maternal haploids were obtained using an efficient wheat-barley hybridization system (with new genotype combinations) and confirmed by several cytological and molecular tools. An efficient hybridization system between wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.) is presented on the basis of three new genotype combinations. A particularly high, 14% frequency of plant regeneration per florets was achieved in the wheat-barley genotype combination of 'Sichuan' * 'Morex'. The genome composition in 42 of the 95 plants regenerated by embryo rescue was determined using ploidy analysis, genomic in situ hybridization and the application of chromosome arm-specific molecular markers (SSR and STS). A high overall frequency (76%) of maternal (wheat) haploids was observed in all the tests for all three cross combinations. A major implication of this observation is that this new hybridization system represents a useful tool to study the mechanism of uniparental chromosome elimination in cereals. PMID- 24770443 TI - Incidence of bacteremia following bronchoscopy with argon plasma coagulation: a prospective study. AB - BACKGROUND: This evaluation was undertaken to determine the incidence of bacteremia and infectious complications associated with argon plasma coagulation (APC) procedures. METHODS: Consecutive patients undergoing bronchoscopy with APC for treatment of endobronchial lesions were studied. Venesection was performed for blood cultures within 60 s of the APC procedure. APC catheter washings were cultured. Patients with positive blood cultures were reviewed immediately. All patients underwent clinical review 1 and 12 weeks after APC. RESULTS: Forty-two patients underwent 44 APC procedures. Their mean age was 66 +/- 12 years. One case (2.3 %) had bacteremia with Acinetobacter lwolfii. APC catheter washing culture was positive in 14 (31.8 %) procedures. No patient had clinical features suggesting infection and there were no complications. Phone review after 1 week revealed no complications. After 3 months, 8 (18 %) had died, all related to advanced lung malignancy and not to the APC procedure. CONCLUSIONS: APC does not appear to increase the risk of bacteremia compared to airway insertion of the bronchoscope. Although contamination of the APC catheter with oropharyngeal commensal bacteria is common, clinically significant infection following the APC procedure is rare. PMID- 24770444 TI - Correlations between anxiety and the stress responses of electrogastrography (EGG) induced by the mirror drawing test (MDT). AB - Electrogastrograms (EGGs) were recorded at 16 locations on the thoraco-abdominal surface at rest and then both during and after the acute stress of performing the mirror drawing test (MDT). A significant linear correlation with a negative slope was found between the anxiety scores and the ratio of the power content during MDT to the power content at rest (r) (MDTr(-1)) of the 3 cpm component from the epigastric channel 2 recording. In contrast, significant linear correlations with positive slopes were found between the anxiety scores and MDTr(-1) of the 6 cpm component of the recordings from the infraumbilical channels (channels 13, 15, and 16). The epigastric 3-cpm EGG activity reflects gastric myoelectric activity, while the infraumbilical 3- and 6-cpm activity reflects that of the colon. Therefore, these results seem to further support the previous report of the inhibition of gastric EGG by stress and the stress-mediated facilitation of colonic EGG (Homma S, J Smooth Muscle Res. 2012; 48(2-3): 47-57). PMID- 24770445 TI - Pathological function of Ca2+-sensing receptor in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is defined as an intractable disease characterized by a progressive elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP), leading to right heart failure and premature death. The five-year survival rate after diagnosis is approximately 57%. Although extensive research has identified some factors associated with the cause of PAH, the etiology and pathogenesis remain unclear. In addition to Ca(2+) channel blockers (nifedipine, diltiazem), three categories of drug have been developed for the treatment of PAH based on the pathological mechanisms: prostacyclin and its analogues (epoprostenol, treprostinil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). However, screening of novel types of drug acting on the signal pathway associated with the pathological mechanism underlying PAH is ongoing. We recently found that the extracellular Ca(2+) sensing receptor (CaSR), which belongs to family C of the G protein-coupled receptor (GPCR) superfamily, is upregulated in pulmonary arterial smooth muscle cells (PASMCs) from patients with idiopathic PAH (IPAH). The upregulated CaSR is necessary for the enhanced Ca(2+) signaling and the augmented cell proliferation in PASMCs from IPAH patients. Most importantly, blockage of CaSR with an antagonist, NPS2143, prevents the development of pulmonary hypertension and right ventricular hypertrophy in animal models of pulmonary hypertension. The use of calcilytics, antagonists of CaSR, may be a novel therapeutic approach for PAH patients. PMID- 24770446 TI - Involvement of myosin regulatory light chain diphosphorylation in sustained vasoconstriction under pathophysiological conditions. AB - Smooth muscle contraction is activated primarily by phosphorylation at Ser19 of the regulatory light chain subunits (LC20) of myosin II, catalysed by Ca(2+)/calmodulin-dependent myosin light chain kinase. Ca(2+)-independent contraction can be induced by inhibition of myosin light chain phosphatase, which correlates with diphosphorylation of LC20 at Ser19 and Thr18, catalysed by integrin-linked kinase (ILK) and zipper-interacting protein kinase (ZIPK). LC20 diphosphorylation at Ser19 and Thr18 has been detected in mammalian vascular smooth muscle tissues in response to specific contractile stimuli (e.g. endothelin-1 stimulation of rat renal afferent arterioles) and in pathophysiological situations associated with hypercontractility (e.g. cerebral vasospasm following subarachnoid hemorrhage). Comparison of the effects of LC 20 monophosphorylation at Ser19 and diphosphorylation at Ser19 and Thr18 on contraction and relaxation of Triton-skinned rat caudal arterial smooth muscle revealed that phosphorylation at Thr18 has no effect on steady-state force induced by Ser19 phosphorylation. On the other hand, the rates of dephosphorylation and relaxation are significantly slower following diphosphorylation at Thr18 and Ser19 compared to monophosphorylation at Ser19. We propose that this diphosphorylation mechanism underlies the prolonged contractile response of particular vascular smooth muscle tissues to specific stimuli, e.g. endothelin-1 stimulation of renal afferent arterioles, and the vasospastic behavior observed in pathological conditions such as cerebral vasospasm following subarachnoid hemorrhage and coronary arterial vasospasm. ILK and ZIPK may, therefore, be useful therapeutic targets for the treatment of such conditions. PMID- 24770448 TI - Reply to Letter: "Staging Laparoscopy Is Not the Best Option to Identify Unresectable Gallbladder Cancer With 100% of Accuracy". PMID- 24770447 TI - Fibrinogen plasma concentration is an independent marker of haemodynamic impairment in chronic thromboembolic pulmonary hypertension. AB - Fibrinogen has a crucial role in both inflammation and coagulation, two processes pivotal for the pathogenesis of pulmonary hypertension. We therefore aimed to investigate whether fibrinogen plasma concentrations a) are elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and b) may serve as a novel biomarker for haemodynamic impairment. In a dual-centre, retrospective analysis including 112 patients with PAH (n = 52), CTEPH (n = 49) and a control cohort of patients with suspected PAH ruled out by right heart catheterisation (n = 11), we found fibrinogen plasma concentrations to be increased in patients with PAH (4.1 +/- 1.4 g/l) and CTEPH (4.3 +/- 1.2 g/l) compared to control patients (3.4 +/- 0.5 g/l, p = 0.0035 and p = 0.0004, respectively). In CTEPH patients but not in PAH patients fibrinogen was associated with haemodynamics (p < 0.036) and functional parameters (p < 0.041). Furthermore, fibrinogen was linked to disease severity (WHO functional class, p = 0.017) and independently predicted haemodynamic impairment specifically in CTEPH (p < 0.016). Therefore, fibrinogen seems to represent an important factor in CTEPH pathophysiology and may have the potential to guide clinical diagnosis and therapy. PMID- 24770449 TI - No association of neurotensin receptor 1 gene polymorphisms with verbal and visual learning in healthy Chinese-Han individuals. PMID- 24770450 TI - DISC1 loci not associated with anhedonia in individuals with genetic liability for schizophrenia. PMID- 24770451 TI - A Framework for Content-based Retrieval of EEG with Applications to Neuroscience and Beyond. AB - This paper introduces a prototype framework for content-based EEG retrieval (CBER). Like content-based image retrieval, the proposed framework retrieves EEG segments similar to the query EEG segment in a large database. Such retrieval of EEG can be used to assist data mining of brain signals by allowing researchers to understand the association between brain patterns, responses, and the environment. Retrieval might also be used to enhance the accuracy of Brain Computer Interface (BCI) systems by providing related samples for training. We present key components of CBER and explain how to handle the distinctive characteristics of EEG. To demonstrate the feasibility of the framework, we implemented a simple EEG database of about 37,000 samples from more than 100 subjects. We ran two retrieval scenarios with a set of EEG features and evaluation metrics. The results of finding similar subjects clearly demonstrate the potential of CBER in many EEG applications. PMID- 24770452 TI - India must make cancer care more affordable and accessible, says commission. PMID- 24770453 TI - Activation of macrophages stimulated by the bengkoang fiber extract through toll like receptor 4. AB - Bengkoang (Pachyrhizus erosus (L.) Urban) is an edible root tuber containing fairly large amounts of carbohydrates and crude fibers. Our previous studies showed that the bengkoang fiber extract (BFE) stimulates activation of macrophages, leading to induction of phagocytotic activity and cytokine production. In the present study we investigated the mechanism underlying activation of murine macrophages by BFE. BFE increased production of TNF-alpha, IL-6, and nitric oxide by J774.1 cells. In addition BFE also facilitated the gene expression levels of inducible nitric oxide synthase. We examined the effect of a TLR4 inhibitor on cytokine production to investigate the membrane receptor of macrophage activation by BFE. Treatment of J774.1 cells with the TLR4 inhibitor significantly inhibited production of IL-6 and TNF-alpha, suggesting that TLR4 is the target membrane receptor for BFE. The main signal molecules located downstream of TLR4 such as JNK, p38, ERK, and NF-kappaB were activated by BFE treatment. The immunostimulatory effect of BFE was cancelled by the pectinase treatment, suggesting that the active ingredient in BFE is pectin-like molecules. Overall results suggested that BFE activates J774.1 cells via the MAPK and NF kappaB signaling pathways. PMID- 24770454 TI - Purification and identification of metabolites produced by Bacillus cereus and B. subtilis active against Meloidogyne exigua, and their in silico interaction with a putative phosphoribosyltransferase from M. incognita. AB - To contribute to the development of products to control Meloidogyne exigua, the bacteria Bacillus cereus and B. subtilis were cultivated in liquid medium to produce metabolites active against this plant-parasitic nematode. Fractionation of the crude dichloromethane extracts obtained from the cultures afforded uracil, 9H-purine and dihydrouracil. All compounds were active against M. exigua, the latter being the most efficient. This substance presented a LC50 of 204 ug/mL against the nematode, while a LC50 of 260 ug/mL was observed for the commercial nematicide carbofuran. A search for protein-ligand complexes in which the ligands were structurally similar to dihydrouracil resulted in the selection of phosphoribosyltransferases, the sequences of which were used in an in silico search in the genome of M. incognita for a similar sequence of amino acids. The resulting sequence was modelled and dihydrouracil and 9H-purine were inserted in the active site of this putative phosphoribosyltransferase resulting in protein ligand complexes that underwent molecular dynamics simulations. Calculation of the binding free-energies of these complexes revealed that the dissociation constant of dihydrouracil and 9H-purine to this protein is around 8.3 x 10-7 and 1.6 x 10-6 M, respectively. Consequently, these substances and the putative phosphoribosyltransferase are promising for the development of new products to control M. exigua. PMID- 24770455 TI - Seasonal, daily activity, and habitat use by three sympatric pit vipers (Serpentes, Viperidae) from southern Brazil. AB - Viperid snakes are widely distributed in the South America and the greater distribution range of the family is found at the Crotalinae subfamily. Despite the abundance of this snakes along their geographic distribution, some ecological aspects remain unknown, principally at subtropical areas. In the present study, we evaluated the activity (daily and seasonal) and the use of the habitat by Bothrops diporus, B. jararaca and B. jararacussu, in an Atlantic Forest area at southern Brazil. We observed higher incidence of viperid snakes during the months with higher temperatures, while no snakes were found during the months with lower temperatures. The data suggest the minimum temperature as environmental variable with the greatest influence on the seasonal activity of this species. Considering the daily activity, we observed a tendency of snakes to avoid the warmest hours. Bothrops jararacussu tend to avoid open areas, being registered only inside and at the edges of the forest. We compared our results with previous studies realized at tropical areas and we suggest the observed seasonal activity as an evolutive response, despite the influence of the different environmental variables, according to the occurence region. PMID- 24770456 TI - Common Deletion (CD) in mitochondrial DNA of irradiated rat heart. AB - The purpose of this study was to map the common deletion (CD) area in mtDNA and investigate the levels of this deletion in irradiated heart. The assays were developed in male Wistar rats that were irradiated with three different single doses (5, 10 or 15 Gy) delivered directly to the heart and the analyses were performed at various times post-irradiation (3, 15 or 120 days). The CDs area were sequenced and the CD quantified by real-time PCR. Our study demonstrated that the CD levels progressively decreased from the 3rd until the 15th day after irradiation, and then increased thereafter. Additionally, it was observed that the levels of CD are modulated differently according to the different categories of doses (moderate and high). This study demonstrated an immediate response to ionizing radiation, measured by the presence of mutations in the CD area and a decrease in the CD levels. PMID- 24770457 TI - Prolonged post-dural puncture headache in a patient during treatment with selective serotonin reuptake inhibitor: a case report and animal experiment. AB - We report a case of prolonged post-dural puncture headache (PDPH) in a patient with panic disorder. A 41-year-old woman received spinal anesthesia for interstitial cystitis. She noticed headache after surgery but did not report it to her doctor. As her headache worsened, she was readmitted to the hospital and diagnosed with PDPH 1 month after surgery. She had panic disorder, controlled by treatment with a selective serotonin reuptake inhibitor, sertraline. Conservative treatments were performed for 1 week, but her headache persisted. Successful resolution of PDPH was achieved following two epidural blood patch applications. A recent study showed that the duration of PDPH was prolonged with a history of depression. Therefore, we conducted a reverse translational experiment to investigate the effects of sertraline on the production of cerebrospinal fluid (CSF) in rats. Our results demonstrated that a clinically relevant dose of sertraline decreased the production of CSF. Our findings imply that treatment with sertraline may have contributed to the development of prolonged PDPH in this case. PMID- 24770458 TI - Monitoring the chemotherapeutic response in primary lung cancer using (99m)Tc MIBI SPET. AB - Prediction and evaluation of the response to chemotherapy (CTx) are important for the correct and cost-effective treatment of patients with primary lung cancer. Although fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) is accepted as the most useful and accurate nuclear medicine technique for this purpose, its expense and limited availability restrict its use. Compared with PET agents, technetium-99m methoxyisobutylisonitrile (MIBI), which is used in nuclear oncology, is cheaper and available in any nuclear medicine clinic. With this in mind, in this study we aimed to evaluate the role of (99m)Tc-MIBI in monitoring the chemotherapeutic response in primary lung cancer. Twenty patients with primary lung cancer underwent (99m)Tc-MIBI single-photon emission tomography (SPET) at 15 min (early) and 3-4 h (delayed) after injection of the tracer. All patients underwent (99m)Tc-MIBI SPET study twice: before and after the 3rd cycle of CTx. Patients were divided into two groups, responders [R(+), n=10] and non responders [R(-), n=10], according to the change in tumour size on CT scan taken 2 weeks after the last cycle of the CTx. From the SPET images early and delayed tumour/lung ratios (ER and DR) were obtained before and after CTx. In the R(+) group, ER and DR decreased significantly after CTx, from 3.28+/-1.55 to 1.78+/ 0.72 (P<0.04) and from 3.23+/-1.55 to 2.0+/-0.88 (P<0.05), respectively. However, in the R(-) group, while ER showed a slight and statistically insignificant increase after CTx (from 2.51+/-1.23 to 2.65+/-1.86), DR increased significantly, from 2.74+/-1.37 to 3.27+/-2.31 (P<0.03). The percentage decreases in ER and DR in the R(+) group after CTx was significantly higher than that in the R(-) group: 34.36%+/-26.7% vs -13.78%+/-27.58% (P<0.0002) and 29.45%+/-25.23% vs -18.58%+/ 20.51% (P<0.0005), respectively. Using a decrease of >=10% as a threshold for monitoring the chemotherapeutic response, (99m)Tc-MIBI had a sensitivity of 90% and a specificity of 100%. We found a positive correlation in 14 patients between ER and DR and survival: r=0.6754 and P=0.008, and r=0.5755 and P=0.031, respectively. Our results suggest that (99m)Tc-MIBI might be used in routine practice to monitor the chemotherapeutic response in patients with primary lung cancer, especially when PET is not available. PMID- 24770459 TI - Evaluation of head and neck cancer with (18)F-FDG PET: a comparison with conventional methods. AB - The aim of this study was to evaluate the usefulness of (18)F-FDG PET in the diagnosis and staging of primary and recurrent malignant head and neck tumours in comparison with conventional imaging methods [including ultrasonography, radiography, computed tomography (CT) and magnetic resonance imaging (MRI)], physical examination, panendoscopy and biopsies in clinical routine. A total of 54 patients (13 female, 41 male, age 61.3+/-12 years) were investigated retrospectively. Three groups were formed. In group I, (18)F-FDG PET was performed in 15 patients to detect unknown primary cancers. In group II, 24 studies were obtained for preoperative staging of proven head and neck cancer. In group III, (18)F-FDG PET was used in 15 patients to monitor tumour recurrence after radiotherapy and/or chemotherapy. In all patients, imaging was obtained at 70 min after the intravenous administration of 180 MBq (18)F-FDG. In 11 of the 15 patients in group I, the primary cancer could be found with (18)F-FDG, yielding a detection rate of 73.3%. In 4 of the 15 patients, CT findings were also suggestive of the primary cancer but were nonetheless equivocal. In these patients, (18)F-FDG showed increased (18)F-FDG uptake by the primary tumour, which was confirmed by histology. One patient had recurrence of breast carcinoma that could not be detected with (18)F-FDG PET, but was detected by CT. In three cases, the primary cancer could not be found with any imaging method. Among the 24 patients in group II investigated for staging purposes, (18)F-FDG PET detected a total of 13 local and three distant lymph node metastases, whereas the conventional imaging methods detected only nine local and one distant lymph node metastases. The results of (18)F-FDG PET led to an upstaging in 5/24 (20.8%) patients. The conventional imaging methods were false positive in 5/24 (20.8%). There was one false positive result using (18)F-FDG PET. Among the 15 patients of group III with suspected recurrence after radiotherapy and/or chemotherapy, (18)F FDG was true positive in 7/15 (46.6%) and true negative in 4/15 (26.6%). The conventional imaging methods were true positive in 5/15 (33.3%) and true negative in 4/15 (26.6%). One false negative (6.6%) and three false positive findings (20%) on (18)F-FDG PET were due to inflamed tissue. The conventional imaging methods were false positive in three (20%) and false negative in three cases (20%). It is concluded that in comparison to conventional diagnostic methods, (18)F-FDG PET provides additional and clinically relevant information in the detection of primary and metastatic carcinomas as well as in the early detection of recurrent or persistent head and neck cancer after radiotherapy and/or chemotherapy. (18)F-FDG PET should therefore be performed early in clinical routine, usually before CT or MRI. PMID- 24770460 TI - [Not Available]. PMID- 24770461 TI - Affective Response to Exercise and Preferred Exercise Intensity Among Adolescents. AB - BACKGROUND: Little information exists as to the exercise intensity that adolescents enjoy and whether identifiable subgroups of adolescents will choose higher-intensity exercise. METHODS: Healthy adolescents (N = 74; mean age = 11.09 years) completed a cardiorespiratory fitness test, a moderate-intensity exercise task, and an exercise task at an intensity that felt "good." Heart rate (HR), work rate (WR), and ratings of perceived exertion (RPE) were assessed every 3 minutes. RESULTS: During the "feels good" task, adolescents exercised at a HR recognized as beneficial for cardiovascular health (mean HR = 66% to 72% of HR at VO2peak). Adolescents who experienced a positive affective shift during the moderate-intensity task engaged in higher-intensity exercise during the feels good task as compared with those whose affective response to moderate-intensity exercise was neutral or negative (76% of peak HR vs. 70% of peak HR, P < .01).There was no difference between groups in RPE. CONCLUSIONS: Adolescents tend to select an exercise intensity associated with fitness benefits when afforded the opportunity to choose an intensity that feels good. An identified subgroup engaged in higher-intensity exercise without a commensurate perception of working harder. Encouraging adolescents to exercise at an intensity that feels good may increase future exercise without sacrificing fitness. PMID- 24770462 TI - Four-defect repair in women with symptomatic anterior compartment prolapse: a large cohort study. AB - INTRODUCTION AND HYPOTHESIS: We aimed to collect long-term follow-up data and report on both objective and subjective outcome, including morbidity, reinterventions, and sexual function following four-defect repair (FDR) as surgical correction of symptomatic anterior vaginal wall prolapse with or without stress urinary incontinence (SUI). METHODS: Consecutive patients who underwent FDR between 1999 and 2005 were included in this study. We performed a retrospective analysis to evaluate anatomical and functional outcome by reviewing medical charts and sending validated questionnaires (Urogenital Distress Inventory and Defecatory Distress Inventory) to all patients. We also sent a self developed, nonvalidated questionnaire to assess sexual function and inform the patient about reinterventions for pelvic floor dysfunction. RESULTS: Two hundred and twenty-nine (60 %) of the 381 patients who underwent FDR participated. At a median follow-up of 40 months (range 5-88), 21 % of patients reported bothersome prolapse symptoms, and 11 % reported bothersome SUI. Temporary postoperative urinary retention occurred in 23 %. During follow-up, posterior vaginal wall prolapse was observed in 14 % of patients. Overall surgical reintervention rates were 15 % and 4 % for (all types of) pelvic organ prolapse and SUI, respectively; dyspareunia was reported by 30 %. CONCLUSIONS: Functional cure rates of FDR as surgical treatment for anterior vaginal wall prolapse with or without SUI are satisfying. Nevertheless, given the negative side effects of FDR (urinary retention, high reintervention rate for posterior vaginal wall prolapse, high risk of sexual dysfunction), we question the superiority of FDR over standard anterior colporrhaphy in patients with anterior vaginal wall prolapse only. PMID- 24770463 TI - Does concomitant vaginal prolapse repair affect the outcomes of the transobturator tape procedure in the long term? AB - INTRODUCTION AND HYPOTHESIS: Little information is available on the effects of concomitant vaginal prolapse repair on the outcomes of the transobturator tape (TOT) procedure. The purpose of this study is to assess the results and complications of TOT when combined with vaginal prolapse repair with a long-term follow-up. METHODS: We conducted a retrospective cohort study of 232 female patients who underwent the TOT procedure at two institutions. There were two groups: group 1 consisted of patients who had undergone TOT alone and group 2 consisted of patients who had undergone concomitant vaginal prolapse repair. The outcomes were analyzed considering four postoperative parameters: objective cure, subjective cure, resolution of urgency urinary incontinence (UUI), and patient satisfaction. The mean follow-up was 66.3 months (range 60-85). RESULTS: A total of 117 patients in group 1 and 104 patients in group 2 were documented in this study. The subjective and objective cure rates were 87.17%, 64.95% in group 1 and 89.42%, 68.26% in group 2. Patient satisfaction rates (visual analog scale [VAS] score >=80) were 71.79 and 83.65% in groups 1 and 2 respectively (p = 0.035). Complications were reported according to the Clavien-Dindo classification with grade I 7.7%, grade II 69.2%, grade IIIa 7.7%, and grade IIIb 15.4%, and grade I 9.5%, grade II 47.6%, grade IIIa 42.8%, and grade IIIb 0% in groups 1 and 2 respectively. CONCLUSIONS: Concomitant vaginal prolapse repair with TOT does not have any negative effects on continence outcomes; on the contrary, it increases patient satisfaction. PMID- 24770464 TI - Pixel-by-pixel analysis of DCE-MRI curve shape patterns in knees of active and inactive juvenile idiopathic arthritis patients. AB - OBJECTIVES: To compare DCE-MRI parameters and the relative number of time intensity curve (TIC) shapes as derived from pixel-by-pixel DCE-MRI TIC shape analysis between knees of clinically active and inactive juvenile idiopathic arthritis (JIA) patients. METHODS: DCE-MRI data sets were prospectively obtained. Patients were classified into two clinical groups: active disease (n = 43) and inactive disease (n = 34). Parametric maps, showing seven different TIC shape types, were created per slice. Statistical measures of different TIC shapes, maximal enhancement (ME), maximal initial slope (MIS), initial area under the curve (iAUC), time-to-peak (TTP), enhancing volume (EV), volume transfer constant (K(trans)), extravascular space fractional volume (V(e)) and reverse volume transfer constant (k(ep)) of each voxel were calculated in a three-dimensional volume-of-interest of the synovial membrane. RESULTS: Imaging findings from 77 JIA patients were analysed. Significantly higher numbers of TIC shape 4 (P = 0.008), median ME (P = 0.015), MIS (P = 0.001) and iAUC (P = 0.002) were observed in clinically active compared with inactive patients. TIC shape 5 showed higher presence in the clinically inactive patients (P = 0.036). CONCLUSIONS: The pixel by-pixel DCE-MRI TIC shape analysis method proved capable of differentiating clinically active from inactive JIA patients by the difference in the number of TIC shapes, as well as the descriptive parameters ME, MIS and iAUC. KEY POINTS: * The pixel-by-pixel TIC shape method differentiates clinically active and inactive JIA patients * Significantly higher numbers of TIC shape 4 were observed in clinically active patients * DCE-MRI parameters ME, MIS and iAUC differ between active and inactive patients * The pixel-by-pixel analysis method allows direct visualization of the heterogeneously distributed disease * The DCE-MRI TIC shape method may serve as a quantitative outcome measure. PMID- 24770465 TI - Femoroacetabular impingement: normal values of the quantitative morphometric parameters in asymptomatic hips. AB - OBJECTIVE: To determine the means and the reference intervals of the quantitative morphometric parameters of femoroacetabular impingement (FAI) in normal hips with high-resolution computed tomography (CT). METHODS: We prospectively included 94 adult individuals who underwent CT for thoracic, abdominal or urologic pathologies. Patients with a clinical history of hip pathology and/or with osteoarthritis on CT were excluded. We calculated means and 95% reference intervals for imaging signs of cam-type (alpha angle at 90 degrees and 45 degrees and femoral head-neck offset) and pincer-type impingement (acetabular version angle, lateral centre-edge angle and acetabular index). RESULTS: The 95 % reference interval limits were all far beyond the abnormal thresholds found in the literature for cam-type and to a lesser extent for pincer-type FAI. The upper limits of the reference intervals for the alpha angles (at 90 degrees /45 degrees ) were 68 degrees /83 degrees (men) and 69 degrees /84 degrees (women), compared to thresholds from the literature (50 degrees , 55 degrees or 60 degrees ). Reference intervals were similar between genders for cam-type parameters, and slightly differed for pincer-type. CONCLUSION: The 95% reference intervals of morphometric measurements of FAI in asymptomatic hips were beyond the abnormal thresholds, which was especially true for cam-type FAI. Our results suggest the need for redefining the current morphometric parameters used in the diagnosis of FAI. KEY POINTS: * 95% reference intervals limits of FAI morphotype were beyond currently defined thresholds. * Reference intervals of pincer-type morphotype measurements were close to current definitions. * Reference intervals of cam-type morphotype measurements were far beyond the current definitions. * Current morphometric definitions of cam-type morphotype should be used with care. PMID- 24770466 TI - Hepatocellular carcinoma (HCC) in non-cirrhotic liver: clinical, radiological and pathological findings. AB - OBJECTIVES: Our aim was to evaluate the clinical and pathological findings, mutidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI) appearances, treatment and 1-year survival of patients with HCC in non-cirrhotic liver. METHODS: Histopathological and laboratory findings of 30 non-cirrhotic patients with 32 HCCs were reviewed retrospectively. MDCT and gadobenate dimeglumine-enhanced MR images were evaluated in consensus by two radiologists in terms of HCC size, presence of tumour capsule, necrosis, haemorrhage, fat and calcification, and vascular involvement. Imaging patterns were compared directly with HCC findings in a matched group of cirrhotic patients. RESULTS: No differences between non-cirrhotic and cirrhotic patients were noted in terms of serum alpha-fetoprotein levels (elevated in 11 [36.7%] and 21 [35%] patients, respectively). The imaging appearance at CT and contrast-enhanced MRI was typical in 27 (84.3%) and 28 (87.5%) cases respectively. Most lesions presented as a well differentiated large solitary mass, with well-defined margins, areas of necrosis and peripheral capsule. No significant differences in HCC pattern were observed between cirrhotic and non-cirrhotic liver. CONCLUSIONS: In non-cirrhotic patients, HCC is more likely to manifest as an asymptomatic mass with elevation of serum tumour markers similar to that seen in cirrhotic patients. HCC in cirrhotic and non-cirrhotic livers show similar enhancement patterns. KEY POINTS: HCC shows similar CT/MRI pattern in cirrhotic and non-cirrhotic livers. Non invasive diagnostic criteria for HCC should also be extended to non-cirrhotic livers. No differences were found between alpha-fetoprotein levels in non cirrhotic and cirrhotic patients. PMID- 24770468 TI - The effect of motor load on planning and inhibition in developmental coordination disorder. AB - Previous research has reported mixed findings regarding executive function (EF) abilities in developmental coordination disorder (DCD), which is diagnosed on the basis of significant impairments in motor skills. The current study aimed to assess whether these differences in study outcomes could result from the relative motor loads of the tasks used to assess EF in DCD. Children with DCD had significant difficulties on measures of inhibition and planning compared to a control group, although there were no significant correlations between motor skills and EF task performance in either group. The complexity of the response, as well as the component skills required in EF tasks, should be considered in future research to ensure easier comparison across studies and a better understanding of EF in DCD over development. PMID- 24770467 TI - Validity and reliability of the Mastication Observation and Evaluation (MOE) instrument. AB - The Mastication Observation and Evaluation (MOE) instrument was developed to allow objective assessment of a child's mastication process. It contains 14 items and was developed over three Delphi rounds. The present study concerns the further development of the MOE using the COSMIN (Consensus based Standard for the Selection of Measurement Instruments) and investigated the instrument's internal consistency, inter-observer reliability, construct validity and floor and ceiling effects. Consumption of three bites of bread and biscuit was evaluated using the MOE. Data of 59 healthy children (6-48 mths) and 38 children (bread) and 37 children (biscuit) with cerebral palsy (24-72 mths) were used. Four items were excluded before analysis due to zero variance. Principal Components Analysis showed one factor with 8 items. Internal consistency was >0.70 (Chronbach's alpha) for both food consistencies and for both groups of children. Inter observer reliability varied from 0.51 to 0.98 (weighted Gwet's agreement coefficient). The total MOE scores for both groups showed normal distribution for the population. There were no floor or ceiling effects. The revised MOE now contains 8 items that (a) have a consistent concept for mastication and can be scored on a 4-point scale with sufficient reliability and (b) are sensitive to stages of chewing development in young children. The removed items are retained as part of a criterion referenced list within the MOE. PMID- 24770469 TI - Investigating graph comprehension in students with dyslexia: an eye tracking study. AB - The purpose of this study was to examine graph comprehension in college students with developmental dyslexia. We investigated how graph types (line, vertical bar, and horizontal bar graphs), graphic patterns (single and double graphic patterns), and question types (point locating and comparison questions) differentially affect graph comprehension of students with and without dyslexia. Groups were compared for (1) reaction times for answering comprehension questions based on graphed data and (2) eye gaze times for specific graph subregions (x axis, y-axis, pattern, legend, question, and answer). Dyslexic readers were significantly slower in their graph comprehension than their peers with group differences becoming more robust with the increasing complexity of graphs and tasks. In addition, dyslexic readers' initial eye gaze viewing times for linguistic subregions (question and answer) and total viewing times for both linguistic (question and answer) and nonlinguistic (pattern) subregions were significantly longer than their control peers' times. In spite of using elementary-level paragraphs for comprehension and simple graph forms, young adults with dyslexia needed more time to process linguistic and nonlinguistic stimuli. These findings are discussed relative to theories proposed to address fundamental processing deficits in individuals with dyslexia. PMID- 24770470 TI - Family-centredness of professionals who support people with profound intellectual and multiple disabilities: validation of the Dutch 'Measure of Processes of Care for Service Providers' (MPOC-SP-PIMD). AB - A Dutch version of the 'Measure of Processes of Care for Service Providers' (MPOC SP) was developed to determine the extent to which professionals apply the principles of family-centred care in the rehabilitation of children with physical disabilities. However, no data were available on the reliability and construct validity of this instrument when it comes to supporting people with profound intellectual and multiple disabilities (PIMD). This study aimed to validate an adapted version of the Dutch MPOC-SP for assessing the family-centred behaviours of professionals who support this group (MPOC-SP-PIMD). A total of 105 professionals took part in the study. A Mokken scale analysis was conducted to determine whether the instrument satisfied the assumptions of both monotone homogeneity and double monotonicity. Loevinger's scalability coefficient (H) was used for the scalability of the entire scale and of each item separately. Rho was calculated as a measure of the internal consistency of the scales. The analyses resulted in two scales: a nine-item scale interpreted as 'Showing Interpersonal Sensitivity', with H=.39 and rho=.76, and a seven-item scale interpreted as 'Treating People Respectfully', with H=.49 and rho=.78. A validated version of the MPOC-SP-PIMD, suitable for supporting people with PIMD, consists of a subset of two scales from the original Dutch MPOC-SP. This instrument can be used to compare the family-centredness of professionals with parent's expectations and views. This information can be used in practice to match the support to the needs of the parents and family of the child with PIMD. PMID- 24770471 TI - The effect of computer-assisted therapeutic practice for children with handwriting deficit: a comparison with the effect of the traditional sensorimotor approach. AB - The objective of this study was to compare the effect of computer-assisted practice with the sensorimotor approach on the remediation of handwriting problems in children with dysgraphia. In a randomized controlled trial, experiments were conducted to verify the intervention effect. Forty two children with handwriting deficit were assigned to computer-assisted instruction, sensorimotor training, or a control group. Handwriting performance was measured using the elementary reading/writing test and computerized handwriting evaluation before and after 6 weeks of intervention. Repeated-measures ANOVA of changed scores were conducted to show whether statistically significant differences across the three groups were present. Significant differences in the elementary reading/writing test were found among the three groups. The computer group showed more significant improvements than the other two groups did. In the kinematic and kinetic analyses, the computer group showed promising results in the remediation of handwriting speed and fluency. This study provided clinical evidence for applying a computer-assisted handwriting program for children with dysgraphia. Clinicians and school teachers are provided with a systematic intervention for the improvement of handwriting difficulties. PMID- 24770472 TI - Sleep self-intoxication and sleep driving as rare zolpidem-induced complex behaviour. AB - INTRODUCTION: The GABA(A) receptor agonist zolpidem has been used for treatment of insomnia since years, but special side effects have been reported. These side effects were called zolpidem-induced sleep-related complex behaviour. Such complex behaviour is associated with somnambulism and includes sleepwalking, sleep eating, sleep conversation and sleep driving. CASE PRESENTATION: Two cases of zolpidem-induced sleep-related complex behaviour following self-intoxication, sleep driving and amnesia are presented. In both cases, the subjects reported the voluntary intake of only one zolpidem tablet of 10 mg and amnesia for the time afterwards. Shortly after the onset of the drug's action, both individuals drifted into a somnambulism-like state and toxicological blood analysis suggested the intake of the remaining zolpidem tablets which might be called "sleep intoxication". Later, the subjects were arrested by police after driving under drug influence and not realizing the situation. Retrospectively, both subjects suffered from psychiatric disorders and in case 2, the subject was treated for depression with doxepin. Consequently, these co-factors may have increased the risk for the occurrence of the sleep-related complex behaviour. DISCUSSION: Involuntary self-intoxication should be taken into account in addition to the known pattern of zolpidem-induced complex behaviour. In legal cases, the forensic expert has to assess the blood concentration of zolpidem in evaluating this strange behaviour. CONCLUSION: Amnesia and incoherence of speech, disorganization of behaviour, inability to realize the situation and mood changes may indicate a zolpidem-induced somnambulism-like state with sleep-related complex behaviour. PMID- 24770474 TI - Bis-tropolonate complexes of tungsten: scaffolds for selective side-on binding of nitriles, imines and ketones. AB - The chiral bis-tropolonate tungsten(ii) tricarbonyl compound, (trop)2W(CO)3 (1), has been synthesized and structurally characterized. This seven-coordinate compound readily loses two carbonyl ligands to preferentially bind a series of pi bonding substrates to form six-coordinate complexes of the type (trop)2W(CO)(L). Alkynes coordinate strongly to form (trop)2W(CO)(eta(2)-RCCR) (2) in which spectroscopic data is consistent with the alkyne serving as a 4-electron donor. Compound 1 will also preferentially coordinate organic nitriles in a side-on fashion through the CN triple bond. A dramatic shift in the nitrile carbon signals to greater than 210 ppm in the (13)C NMR confirms the nitriles are coordinated in an eta(2) 4-electron donating capacity. Aldehydes, ketones, and imines also react with 1 to form 4-electron donor eta(2) adducts. The imine adduct (trop)2W(CO)(eta(2)-MeN=C(H)(tol)) (5) was characterized crystallographically and the short 1.91 A W-N bond distance supports the postulation of 4-electron donation from the imine through C=N pi-bonding and N lone pair donation. Side-on coordination of ligands of this type is rare and may provide a means towards asymmetric functionalization of these substrates. All of the tropolonate compounds are prone to oxidation in air and the alkyne compounds will oxidize to stable W(IV) oxo alkyne species, (trop)2W(O)(eta(2)-RCCR) (6). This causes a 90 degrees rotation of the alkyne ligand and a reduction in alkyne donation to approximately 3 electrons, to maintain an optimal 18 electron configuration. PMID- 24770473 TI - The stimulus-evoked population response in visual cortex of awake monkey is a propagating wave. AB - Propagating waves occur in many excitable media and were recently found in neural systems from retina to neocortex. While propagating waves are clearly present under anaesthesia, whether they also appear during awake and conscious states remains unclear. One possibility is that these waves are systematically missed in trial-averaged data, due to variability. Here we present a method for detecting propagating waves in noisy multichannel recordings. Applying this method to single-trial voltage-sensitive dye imaging data, we show that the stimulus-evoked population response in primary visual cortex of the awake monkey propagates as a travelling wave, with consistent dynamics across trials. A network model suggests that this reliability is the hallmark of the horizontal fibre network of superficial cortical layers. Propagating waves with similar properties occur independently in secondary visual cortex, but maintain precise phase relations with the waves in primary visual cortex. These results show that, in response to a visual stimulus, propagating waves are systematically evoked in several visual areas, generating a consistent spatiotemporal frame for further neuronal interactions. PMID- 24770475 TI - Effect of sterol esters on lipid composition and antioxidant status of erythrocyte membrane of hypercholesterolemic rats. AB - Hypercholesterolemia is a major cause of coronary heart disease. Erythrocyte membrane is affected during hypercholesterolemia. The effect of EPA-DHA rich sterol ester and ALA rich sterol ester on erythrocyte membrane composition, osmotic fragility in normal and hypercholesterolemic rats and changes in antioxidant status of erythrocyte membrane were studied. Erythrocyte membrane composition, osmotic fragility of the membrane and antioxidant enzyme activities was analyzed. Osmotic fragility data suggested that the erythrocyte membrane of hypercholesterolemia was relatively more fragile than that of the normal rats' membrane which could be reversed with the addition of sterol esters in the diet. The increased plasma cholesterol in hypercholesterolemic rats could also be lowered by the sterol ester administration. There was also marked changes in the antioxidant enzyme activities of the erythrocyte membrane. Antioxidant enzyme levels decreased in the membrane of the hypercholesterolemic subjects were increased with the treatment of the sterol esters. The antioxidative activity of ALA rich sterol ester was better in comparison to EPA-DHA rich sterol ester. In conclusion, rat erythrocytes appear to be deformed and became more fragile in cholesterol rich blood. This deformity and fragility was partially reversed by sterol esters by virtue of their ability to lower the extent of hypercholesterolemia. PMID- 24770476 TI - Characterization of triacylglycerol composition of fish oils by using chromatographic techniques. AB - Triacylglycerols (TAG) of two different refined fish oils from sardine and a mixture of tuna and sardine oil were separated by reverse phase high performance liquid chromatography (RP-HPLC) with a binary solvent gradient of acetone/acetonitrile. Different fractions were observed in the chromatogram and TAG species were tentatively identified by subsequent analysis of the fatty acid (FA) profile in each fraction by capillary Gas Chromatography (GC). Peak identities were assigned on the basis of a multiple linear regression analysis by using factors such as carbon number, number of double bonds, number of monounsaturated fatty acids (MUFA) and number of polyunsaturated fatty acids (PUFA) in the molecule as predictors for TAG retention time. A successful correlation was obtained between retention times and the equivalent carbon number (ECN) of triacylglycerols. Regiospecific analysis of fatty acids in the TAG has been conducted by ethanolysis of the fish oil by using an immobilized lipase. The subsequent separation of 2-monoacylglycerol (2-MAG) by TLC (thin layer chromatography) analysis showed that ethanolysis system is effective for analysis of FA composition at the 2-position in oils containing PUFA. Principal components analysis (PCA) has been also applied to establish correlations between the different fatty acids in the TAG. PMID- 24770477 TI - Evolution of fatty alcohols in olive oils produced in Calabria (Southern Italy) during fruit ripening. AB - A study was conducted on olive oils extracted from olives collected in South West Calabria (Southern Italy) over three harvest years 2010-2011-2012. Three autochthonous cultivars were considered: Cassanese, Ottobratica and Sinopolese and seven allochtonous cultivars: Coratina, Itrana, Leccino, Nocellara Messinese, Nociara, Pendolino and Picholine. Thin Layer Chromatography - Gas Chromatograph (TLC-GC) technique permitted the separation and analysis of the fatty alcohol compounds. A general decline in fatty alcohol content was found during the three months of sampling, most evident in hexacosanol. Pendolino showed the greatest decline. A less evident decrease was measured in the odd chained fatty alcohols, mainly in heptacosanol. Both harvest date and cultivar significantly influenced the fatty alcohol content. This is the first report about the fatty alcohol variation during ripening in olive oil produced in South West Calabria (Southern Italy). PMID- 24770478 TI - Antioxidant and lipase inhibitory activities and essential oil composition of pomegranate peel extracts. AB - The chemical composition of essential oil, antioxidant and pancreatic lipase inhibitory activities of various solvent extracts obtained from pomegranate peelTunisian cultivar was evaluated. Gas chromatography/mass spectrometry was used to determine the composition of the PP essential oil. Nine-teen components were identified and the main compounds were the camphor (60.32%) and the benzaldehyde (20.98%). The phenolic and flavonoids content varied from 0 to 290.10 mg Gallic acid equivalent and from 5.2 to 20.43 mg catechin equivalent/g dried extract. The antioxidant activity of various solvent extracts from pomegranate peel was also investigated using various in vitro assays as the 1,1 diphenyl-2-picrylhydrazyl (DPPH) radical method, beta-carotene bleaching and reducing power assays.Methanol and ethanol extracts showed the most potent antioxidant activity in all assays tested followed by water and acetone extracts. The inhibitory effect of the pomegranate peelextracts on porcine pancreatic lipase was evaluated and the results showed that ethanol and methanol extracts markedly reduced lipase activity. Generally, the highestlipase activity inhibitory (100%) was observed at a concentration of 1 mg/ml after 30 min of incubation. LC-MS analysis of ethanol extract showed the presence of four components which are cholorogenic acid, mannogalloylhexoside, gallic acid and ellagic acid. Our findings demonstrate that the ethanol extract from pomegranate peel might be a good candidate for furtherinvestigations of new bioactive substances. PMID- 24770479 TI - Proportion of nervonic acid in serum lipids is associated with serum plasmalogen levels and metabolic syndrome. AB - An increase in serum plasmalogens (1-O-alk-1-enyl-2-acyl glycerophospholipids), which are endogenous anti-oxidative phospholipids, can potentially prevent age related diseases such as atherosclerosis and metabolic syndrome (MetS). Very long chain fatty acids (VLCFAs) in plasma may supply the materials for plasmalogen biosynthesis through peroxisomal beta-oxidation. On the other hand, elevated levels of saturated and monounsaturated VLCFAs in plasma appear to be associated with decreased peroxisomal function, and are a symptom of age-related diseases. To reconcile these contradictory findings, we attempted to investigate the relationship between the serum levels of saturated and monounsaturated VLCFAs, clinical and biochemical parameters, and serum levels of plasmalogens in subjects with MetS (n = 117), who were asymptomatic Japanese males over 40 years of age. Fatty acids in serum lipids were quantified using gas chromatography/mass spectrometry (GC/MS). Serum plasmalogen levels were determined by liquid chromatography using radioactive iodine (125I-HPLC), and the molecular composition of serum plasmalogens was analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). We found that MetS subjects showed a significant reduction in the proportion of specific saturated and monounsaturated VLCFAs such as behenic acid (C22:0), lignoceric acid (C24:0), and nervonic acid (C24:1) in serum lipids compared to non-MetS subjects. These VLCFAs were positively associated with serum levels of high density lipoprotein cholesterol (HDL-C) as well as plasmalogen-related parameters, and inversely with serum levels of triglyceride (TG) and small dense low density lipoprotein cholesterol (sdLDL-C). In conclusion, the proportion of nervonic acid in serum lipids is associated with serum levels of plasmalogens and with MetS, and probably reflects the peroxisomal dysfunction and enhancement of endoplasmic reticulum (ER) stress seen in common age-related diseases. PMID- 24770480 TI - Simple and convenient synthesis of esters from carboxylic acids and alkyl halides using tetrabutylammonium fluoride. AB - A simple and convenient method has been developed for the synthesis of esters from the corresponding carboxylic acids and alkyl halides by using a stoichiometric amount of tetrabutylammonium fluoride (Bu4NF) as the base. The reaction of carboxylic acids and a Bu4NF/THF solution in DMF or THF as the solvent generates carboxylate ions in situ. The carboxylate ions thus generated and accumulated are highly reactive. They are then allowed to react with alkyl halides as the electrophiles, and afford the corresponding esters in moderate to good yields. The reaction without Bu4NF does not afford any product; therefore, Bu4NF seems to play an important role as the base in these reactions. A bulky countercation such as the tetrabutylammonium cation seems to increase the reactivity of the carboxylate ions in the solution phase. PMID- 24770481 TI - Clusters in the adsorbates of vapours and gases: zeta isotherm approach. AB - A procedure for determining the structure of vapour and gas adsorbates that is based on the Zeta adsorption isotherm is reported. For vapours and for gases, this isotherm supposes that an adsorbate consists of particle clusters with the number of particles in a cluster denoted zeta, where zeta can be 1, 2, 3... up to a maximum of zetam, and predicts the isotherm constants are independent of pressure. For vapours, this allows the isotherm constants to be determined from isotherm measurements made at pressures less than the saturation-vapour pressure, Ps, but applied at pressures greater than Ps. Since zeta has an upper limit, we show that there are no singularities in the vapour or gas adsorption isotherms for any pressure. This allows the adsorption of vapours at pressures greater than Ps to be investigated: clusters with zetam molecules are predicted to increase in number as P(V) is increased, until they form an adsorbed film with each adsorption site occupied by a zetam-cluster. We apply the same procedure to determine the value of zetam for gas adsorption. For CO adsorbing on Ni(100), zetam is predicted to be unity for all the cases considered, indicating that the adsorbate consists of adsorbed molecules without any clustering. For H2 adsorption on the three different materials, zetam is found to be two: indicating the adsorbate consists of both adsorbed molecules and atoms. For each material considered, a pressure is predicted where the mole fractions of both are equal, and at higher pressure, the mole fraction of adsorbed molecules exceeds that of the adsorbed atoms. PMID- 24770482 TI - [Acute heart failure in Italy]. PMID- 24770483 TI - [Definition of acute heart failure]. AB - Acute heart failure (AHF) is a potentially life-threatening condition that may arise as a deterioration of a previous heart failure or may be the first presentation of heart failure. Several causes or precipitating factors have been listed, as well as different mechanisms have been described, thus leading to a broad spectrum of clinical presentations. Symptoms and signs of AHF have a strong clinical and prognostic significance and are kept into consideration to guide disease management. In particular, a higher clinical severity or a worse prognosis are associated with lower blood pressure levels, fluid overload, evidence of myocardial ischemia or renal impairment. Putatively, interventions addressed to restore these factors may play a role in the management of AHF. PMID- 24770484 TI - [Epidemiology of heart failure]. AB - Heart failure is a common and clinically relevant disease, whose prevalence is progressively increasing with the ageing of the population and the improvement in treatments. Within this condition, acute heart failure (AHF) has at present the higher burden on mortality and hospitalization rates. This results from both suboptimal management and difficulties in estimating the actual frequency of AHF. This paper is focused on AHF epidemiology based on reliable Italian national and regional data. PMID- 24770485 TI - [Hospitalization for acute heart failure]. AB - Background. Acute heart failure (AHF) is a common and clinically relevant condition that usually implies the need for hospitalization. The aim of this study was to provide data about hospital activity related to AHF at a national and regional level. Methods. The analysis describes acute hospitalization (year 2010) for AHF in both public and private accredited facilities in the Italian Regions and Autonomous Provinces, using as source the hospital discharge records collected by the Italian Ministry of Health. Results. Our findings are consistent with available data in the literature, although they show relevant outcome variability regarding hospitalization rates and mean length of hospital stay. Conclusions. Evaluation of hospitalization costs confirms that the burden of hospitalization is quite high, though characterized by a great variability. PMID- 24770486 TI - [Acute heart failure clinical pathways, hospital funding and accreditation standards]. AB - Background. The aim of this study was to analyze the formalization of hospital pathways for patients with acute heart failure (AHF) and to describe standards of accreditation and funding of the providers. Methods. This study was carried out in 10 Italian Regions, through the analysis of regional determination and grey literature. Results. Pathway standardization is mainly present for patients with chronic heart failure; only the Piedmont and Emilia Romagna Regions provide a formal standardization for patients with AHF. Among the analyzed Regions, there were no differences in the start of the management process for AHF, including hospital admission. Conversely, several differences were observed among Regions in the organization of Short Way Observation (both in terms of duration and supply), the possibility of alternative modality of admission (e.g. "home hospitalization") and the funding rules of emergency departments. Conclusions. These above stressed differences are likely to have a significant impact on the optimal management of patients with AHF. PMID- 24770488 TI - Children diagnosed with attention deficit disorder and their hospitalisations: population data linkage study. AB - Examine the hospital admission risk in young children who are subsequently diagnosed with attention deficit hyperactivity disorder (ADHD). We conducted a population-based, record linkage study. Records of all non-Aboriginal children under 18 years who met the DSMIV/ICD10 criteria for ADHD and prescribed stimulant medication in Western Australia between 2003 and 2007 (n = 11,902) were linked to two other health data systems-the hospital morbidity data system and the midwives notification system (MNS). The non-ADHD reference population (n = 27,304) was randomly selected from the MNS. Compared with controls, children under 4 years who subsequently were diagnosed and treated for ADHD were 70% [odds ratio (OR) 1.70; 95% confidence intervals (CI) 1.62-1.77] more likely to be admitted to hospital under 4 years of age. There was an increased risk for injury or poison (OR 1.73; 95% CI 1.59-1.88), respiratory disease (OR 1.49; 95% CI 1.40-1.59), ear disease (OR 2.03; 95% CI 1.86-2.21), infectious diseases (OR 1.68; 95% CI 1.53 1.85) and neurological conditions (OR 2.03; 95% CI 1.68-2.44). Admissions under 4 years of age for head injuries, burns, poisons, all other injuries, diseases of the tonsils and adenoids, asthma and early infections were all more common amongst children subsequently diagnosed with and treated for ADHD. There is significant early hospital morbidity for children subsequently diagnosed with ADHD. Multiple aetiologies and causal pathways need to be considered where some of these may include early infections, inflammatory conditions, epilepsy and injuries. Future studies should look at which of these conditions may be on the causal pathway or likely early markers for ADHD. PMID- 24770490 TI - Magnetic-assisted triboelectric nanogenerators as self-powered visualized omnidirectional tilt sensing system. AB - The triboelectric nanogenerator (TENG) is a promising device in energy harvesting and self-powered sensing. In this work, we demonstrate a magnetic-assisted TENG, utilizing the magnetic force for electric generation. Maximum power density of 541.1 mW/m(2) is obtained at 16.67 MOmega for the triboelectric part, while the electromagnetic part can provide power density of 649.4 mW/m(2) at 16 Omega. Through theoretical calculation and experimental measurement, linear relationship between the tilt angle and output voltage at large angles is observed. On this basis, a self-powered omnidirectional tilt sensor is realized by two magnetic assisted TENGs, which can measure the magnitude and direction of the tilt angle at the same time. For visualized sensing of the tilt angle, a sensing system is established, which is portable, intuitive, and self-powered. This visualized system greatly simplifies the measure process, and promotes the development of self-powered systems. PMID- 24770487 TI - Protein phosphatase 2A (PP2A) regulates low density lipoprotein uptake through regulating sterol response element-binding protein-2 (SREBP-2) DNA binding. AB - LDL-cholesterol (LDL-C) uptake by Ldlr is regulated at the transcriptional level by the cleavage-dependent activation of membrane-associated sterol response element-binding protein (SREBP-2). Activated SREBP-2 translocates to the nucleus, where it binds to an LDLR promoter sterol response element (SRE), increasing LDLR gene expression and LDL-C uptake. SREBP-2 cleavage and translocation steps are well established. Several SREBP-2 phosphorylation sites have been mapped and functionally characterized. The phosphatases dephosphorylating these sites remain elusive. The phosphatase(s) regulating SREBP-2 represents a novel pharmacological target for treating hypercholesterolemia. Here we show that protein phosphatase 2A (PP2A) promotes SREBP-2 LDLR promoter binding in response to cholesterol depletion. No binding to an LDLR SRE was observed in the presence of the HMG-CoA reductase inhibitor, lovastatin, when PP2A activity was inhibited by okadaic acid or depleted by siRNA methods. SREBP-2 cleavage and nuclear translocation were not affected by loss of PP2A. PP2A activity was required for SREBP-2 DNA binding. In response to cholesterol depletion, PP2A directly interacted with SREBP-2 and altered its phosphorylation state, causing an increase in SREBP-2 binding to an LDLR SRE site. Increased binding resulted in induced LDLR gene expression and increased LDL uptake. We conclude that PP2A activity regulates cholesterol homeostasis and LDL-C uptake. PMID- 24770491 TI - Chemoenzymatic synthesis and structural characterization of 2-O-sulfated glucuronic acid-containing heparan sulfate hexasaccharides. AB - Heparan sulfate and heparin are highly sulfated polysaccharides that consist of a repeating disaccharide unit of glucosamine and glucuronic or iduronic acid. The 2 O-sulfated iduronic acid (IdoA2S) residue is commonly found in heparan sulfate and heparin; however, 2-O-sulfated glucuronic acid (GlcA2S) is a less abundant monosaccharide (~<5% of total saccharides). Here, we report the synthesis of three GlcA2S-containing hexasaccharides using a chemoenzymatic approach. For comparison purposes, additional IdoA2S-containing hexasaccharides were synthesized. Nuclear magnetic resonance analyses were performed to obtain full chemical shift assignments for the GlcA2S- and IdoA2S-hexasaccharides. These data show that GlcA2S is a more structurally rigid saccharide residue than IdoA2S. The antithrombin (AT) binding affinities of a GlcA2S- and an IdoA2S-hexasaccharide were determined by affinity co-electrophoresis. In contrast to IdoA2S hexasaccharides, the GlcA2S-hexasaccharide does not bind to AT, confirming that the presence of IdoA2S is critically important for the anticoagulant activity. The availability of pure synthetic GlcA2S-containing oligosaccharides will allow the investigation of the structure and activity relationships of individual sites in heparin or heparan sulfate. PMID- 24770492 TI - Stacked Predictive Sparse Coding for Classification of Distinct Regions of Tumor Histopathology. AB - Image-based classification of tissue histology, in terms of distinct histopathology (e.g., tumor or necrosis regions), provides a series of indices for tumor composition. Furthermore, aggregation of these indices from each whole slide image (WSI) in a large cohort can provide predictive models of clinical outcome. However, the performance of the existing techniques is hindered as a result of large technical variations (e.g., fixation, staining) and biological heterogeneities (e.g., cell type, cell state) that are always present in a large cohort. We suggest that, compared with human engineered features widely adopted in existing systems, unsupervised feature learning is more tolerant to batch effect (e.g., technical variations associated with sample preparation) and pertinent features can be learned without user intervention. This leads to a novel approach for classification of tissue histology based on unsupervised feature learning and spatial pyramid matching (SPM), which utilize sparse tissue morphometric signatures at various locations and scales. This approach has been evaluated on two distinct datasets consisting of different tumor types collected from The Cancer Genome Atlas (TCGA), and the experimental results indicate that the proposed approach is (i) extensible to different tumor types; (ii) robust in the presence of wide technical variations and biological heterogeneities; and (iii) scalable with varying training sample sizes. PMID- 24770493 TI - Role of cytoskeletal proteins in cerebral cavernous malformation signaling pathways: a proteomic analysis. AB - Three genetic mutations were found to cause cerebral cavernous malformation (CCM), a vascular anomaly predisposing affected individuals to hemorrhagic stroke. These CCM proteins function together as a protein complex in the cell. Loss of expression of each CCM gene results in loss of in vitro endothelial tube formation. Label-free differential protein expression analysis using multidimensional liquid chromatography/tandem mass spectrometry (2D-LC-MS/MS) was applied to explore the proteomic profile for loss of each CCM gene expression in mouse endothelial stem cells (MEES) compared to mock shRNA and no shRNA control cell-lines. Differentially expressed proteins were identified (p < 0.05). 120 proteins were differentially expressed among the cell-lines. Principal component analysis and cluster analysis show the effects of individual knockdown. In all knockdown cell-lines, altered expression of cytoskeletal proteins is the most common. While all CCM mutations result in similar pathology, different CCM mutations have their own distinct pathogenesis in cell signaling. PMID- 24770494 TI - A meta-analysis of arbuscular mycorrhizal effects on plants grown under salt stress. AB - Salt stress limits crop yield and sustainable agriculture in most arid and semiarid regions of the world. Arbuscular mycorrhizal fungi (AMF) are considered bio-ameliorators of soil salinity tolerance in plants. In evaluating AMF as significant predictors of mycorrhizal ecology, precise quantifiable changes in plant biomass and nutrient uptake under salt stress are crucial factors. Therefore, the objective of the present study was to analyze the magnitude of the effects of AMF inoculation on growth and nutrient uptake of plants under salt stress through meta-analyses. For this, data were compared in the context of mycorrhizal host plant species, plant family and functional group, herbaceous vs. woody plants, annual vs. perennial plants, and the level of salinity across 43 studies. Results indicate that, under saline conditions, AMF inoculation significantly increased total, shoot, and root biomass as well as phosphorous (P), nitrogen (N), and potassium (K) uptake. Activities of the antioxidant enzymes superoxide dismutase, catalase, peroxidase, and ascorbate peroxidase also increased significantly in mycorrhizal compared to nonmycorrhizal plants growing under salt stress. In addition, sodium (Na) uptake decreased significantly in mycorrhizal plants, while changes in proline accumulation were not significant. Across most subsets of the data analysis, identities of AMF (Glomus fasciculatum) and host plants (Acacia nilotica, herbs, woody and perennial) were found to be essential in understanding plant responses to salinity stress. For the analyzed dataset, it is concluded that under salt stress, mycorrhizal plants have extensive root traits and mycorrhizal morphological traits which help the uptake of more P and K, together with the enhanced production of antioxidant enzymes resulting in salt stress alleviation and increased plant biomass. PMID- 24770495 TI - Leprosy: review of the epidemiological, clinical, and etiopathogenic aspects - part 1. AB - Leprosy is caused by Mycobacterium leprae and has been known since biblical times. It is still endemic in many regions of the world and a public health problem in Brazil. The prevalence rate in 2011 reached 1.54 cases per 10,000 inhabitants in Brazil. The mechanism of transmission of leprosy consists of prolonged close contact between susceptible and genetically predisposed individuals and untreated multibacillary patients. Transmission occurs through inhalation of bacilli present in upper airway secretion. The nasal mucosa is the main entry or exit route of M. leprae. The deeper understanding of the structural and biological characteristics of M. leprae, the sequencing of its genome, along with the advances in understanding the mechanisms of host immune response against the bacilli, dependent on genetic susceptibility, have contributed to the understanding of the pathogenesis, variations in the clinical characteristics, and progression of the disease. This article aims to update dermatologist on epidemiological, clinical, and etiopathogenic leprosy aspects. PMID- 24770496 TI - Cutaneous tuberculosis: epidemiologic, etiopathogenic and clinical aspects - part I. AB - Cutaneous tuberculosis (CTB) is the result of a chronic infection by Mycobacterium tuberculosis, M. ovis and occasionally by the Calmette-Guerin bacillus. The clinical manifestations are variable and depend on the interaction of several factors including the site of infection and the host's immunity. This article revises the current knowledge about this disease's physiopathology and immunology as well as detailing the possible clinical presentations. PMID- 24770497 TI - Evaluation of anxiety and depression prevalence in patients with primary severe hyperhidrosis. AB - BACKGROUND: Primary hyperhidrosis (PH) can lead to mood changes due to the inconveniences it causes. OBJECTIVE: This study aimed to examine the existence of anxiety and depression in patients with severe primary hyperhidrosis who sought treatment at a medical office. METHODS: The questionnaire "Hospital Anxiety and Depression Scale" was used for 197 individuals, in addition to the chi square test and Fisher exact test, p <0.05. RESULTS: There was an increased prevalence of anxiety (49.6%) but not of depression (11.2%) among patients with PH, with no link to gender, age or amount of affected areas. Palmar and plantar primary hyperhidrosis were the most frequent but when associated with the presence of anxiety, the most frequent were the axillary (p = 0.02) and craniofacial (p = 0.02) forms. There was an association between patients with depression and anxiety (p = 0.001). CONCLUSIONS: the involvement of Primary hyperhidrosis was responsible for a higher prevalence of anxiety than that described among the general population and patients with other chronic diseases. Depression had a low prevalence rate, while mild and moderate forms were the most common and frequently associated with anxiety. The degree of anxiety was higher in mild and moderate types than in the severe form. PMID- 24770498 TI - A prospective, open, comparative study of 5% potassium hydroxide solution versus cryotherapy in the treatment of genital warts in men. AB - BACKGROUND: Genital warts are caused by human papillomavirus infection and represent one of the most common sexually transmitted diseases. Many infections are transient but the virus may recur, persist, or become latent. To date, there is no effective antiviral treatment to eliminate HPV infection and most therapies are aimed at the destruction of visible lesions. Potassium hydroxide is a strong alkali that has been shown to be safe and effective for the treatment of genital warts and molluscum contagiosum. Cryotherapy is considered one of the most established treatments for genital warts. No comparative trials have been reported to date on the use of potassium hydroxide for genital warts. OBJECTIVE: A prospective, open-label, randomized clinical trial was conducted to compare topical potassium hydroxide versus cryotherapy in the treatment of genital warts affecting immunocompetent, sexually active men. METHODS: Over a period of 10 months, 48 patients were enrolled. They were randomly divided into two groups and selected on an alternative basis for either potassium hydroxide therapy or cryotherapy. While response to therapy did not differ substantially between both treatment modalities, side effects such as local pain and post-treatment hypopigmentation were considerably more prevalent in the groups treated using cryotherapy. RESULT: In our study, potassium hydroxide therapy proved to be at least as effective as cryotherapy and offered the benefit of a better safety profile. CONCLUSION: Topical 5% potassium hydroxide presents an effective, safe, and low-cost treatment modality for genital warts in men and should be included in the spectrum of therapies for genital warts. PMID- 24770499 TI - Lack of compliance: a challenge for digital dermoscopy follow-up. AB - BACKGROUND: Digital dermoscopy is the gold standard follow-up method for patients with high risk for developing cutaneous malignant melanoma. By comparing the same lesion at different moments, it allows early detection of subtle changes that could suggest the diagnosis of melanoma. Thus, it is clear that the test must be repeated after a period of time, according to time intervals determined by the evaluator. OBJECTIVES: To evaluate adherence of patients to follow-up examinations using digital dermoscopy. METHOD: Retrospective analysis of 36 patients who underwent digital dermoscopic examination and total-body photography in a private medical center between September 2010 and January 2013. RESULTS: Only 25% of the patients returned for followup evaluations. CONCLUSIONS: Low adherence to digital dermoscopy follow-up could compromise the efficacy of this valuable method. This lack of adherence represents a challenge for the evaluator. PMID- 24770500 TI - Tissue immunostaining for factor XIIIa in dermal dendrocytes of pityriasis alba skin lesions. AB - BACKGROUND: Pityriasis alba affects 1% of the world population and about 9.9% of the children in Brazil. However, its etiology remains uncertain. OBJECTIVE: The objective of the present study was to evaluate the immunoexpression of factor XIIIa in dermal dendrocytes of skin lesions of pityriasis alba. METHOD: Twenty patients with pityriasis alba and 20 patients with atopic dermatitis underwent biopsy. The dermal dendrocytes marked by factor XIIIa were counted by means of immunohistochemical analysis. RESULTS: The mean amount of dermal dendrocytes found in the patients with pityriasis alba was 2, whereas in the patients with atopic dermatitis it was 4, with a statistically significant difference between them. A cutoff point of 3 cells/square inch was established to differentiate pityriasis alba from atopic dermatitis, with 80% sensibility and 90% specificity. CONCLUSION: We believe that pityriasis alba and atopic dermatitis should be considered different clinical forms within the spectrum of atopic disease, in which sun radiation plays an important role by modulating the progression of the disease. PMID- 24770501 TI - Fractional Erbium laser in the treatment of photoaging: randomized comparative, clinical and histopathological study of ablative (2940nm) vs. non-ablative (1540nm) methods after 3 months. AB - BACKGROUND: Fractional non-ablative lasers keep the epidermis intact, while fractional ablative lasers remove it, making them theoretically more effective. OBJECTIVES: To evaluate the clinical and histological alterations induced by fractional photothermolysis for treating photoaging, comparing the possible equivalence of multiple sessions of 1540nm Erbium, to one session of 2940nm Erbium. METHODS: Eighteen patients (mean age 55.9) completed the treatment with three sessions of 1540nm fractional Erbium laser on one side of the face (50 mJ/mB, 15ms, 2 passes), and one session of 2940nm on the other side (5mJ/mB, 0.25ms, 2 passes). Biopsies were performed before and 3 months after treatment. Clinical, histological and morphometric evaluations were carried out. RESULTS: All patients presented clinical improvement with no statistically significant difference (p> 0.05) between the treated sides. Histopathology revealed a new organization of collagen and elastic fibers, accompanied by edema, which was more evident with the 2940nm laser. This finding was confirmed by morphometry, which showed a decrease in collagen density for both treatments, with a statistical significance for the 2940nm laser (p > 0.001). CONCLUSIONS: Three 1540nm sessions were clinically equivalent to one 2940nm session. The edema probably contributed to the positive results after three months, togheter with the new collagen and elastic fibers organization. The greater edema after the 2940nm session indicates that dermal remodeling takes longer than with 1540nm. It is possible that this histological superiority relates to a more prolonged effect, but a cohort longer than three months is needed to confirm that supposition. PMID- 24770502 TI - Clinical, epidemiological, and therapeutic profile of dermatophytosis. AB - BACKGROUND: The cutaneous mycoses, mainly caused by dermatophyte fungi, are among the most common fungal infections worldwide. It is estimated that 10% to 15% of the population will be infected by a dermatophyte at some point in their lives, thus making this a group of diseases with great public health importance. OBJECTIVE: To analyze the clinical, epidemiological, and therapeutic profile of dermatophytosis in patients enrolled at the Dermatology service of Universidade do Estado do Para, Brazil, from July 2010 to September 2012. METHOD: A total of 145 medical records of patients diagnosed with dermatophytosis were surveyed. Data were collected and subsequently recorded according to a protocol developed by the researchers. This protocol consisted of information regarding epidemiological and clinical aspects of the disease and the therapy employed. RESULTS: The main clinical form of dermatophyte infection was onychomycosis, followed by tinea corporis, tinea pedis, and tinea capitis. Furthermore, the female population and the age group of 51 to 60 years were the most affected. Regarding therapy, there was a preference for treatments that combine topical and systemic drugs, and the most widely used drugs were fluconazole (systemic) and ciclopirox olamine (topical). CONCLUSION: This study showed the importance of recurrent analysis of the epidemiological profile of dermatophytosis to enable correct therapeutic and preventive management of these conditions, which have significant clinical consequences, with chronic, difficult-totreat lesions that can decrease patient quality of life and cause disfigurement. PMID- 24770503 TI - Prevention of repeated episodes of type 2 reaction of leprosy with the use of thalidomide 100 mg/day. AB - BACKGROUND: Leprosy can have its course interrupted by type 1 and 2 reactional episodes, the last named of erythema nodosum leprosum (ENL). Thalidomide has been the medication of choice for the control of ENL episodes since 1965. OBJECTIVES: These episodes can repeat and cause damages to the patient. In order to prevent these episodes, an extra dose of 100 mg/day thalidomide was used during six months, followed by a follow-up period of six more months after thalidomide discontinuation. METHODS: We included 42 patients with multibacillary (MB) leprosy who had episodes of ENL. They were male and female patients aged between 18 and 84 years. RESULTS: Of the 42 patients, 39 (92.85%) had the lepromatous form and three (7.15%) had the borderline form. We found that 100% of patients had no reactional episode during the use of the drug. During the follow-up period after thalidomide discontinuation, 33 (78.57%) patients had no reactional episode and nine (21.43%), all of them with the lepromatous form, had mild episodes, which were controlled using non-steroidal anti-inflammatory. There were no thalidomide-related side effects. CONCLUSION: A maintenance dose of 100 mg/day of thalidomide showed to be effective to prevent repeated type 2 reactional episodes of ENL. PMID- 24770504 TI - Bullous pemphigoid and comorbidities: a case-control study in Portuguese patients. AB - BACKGROUND: Although rare, bullous pemphigoid (BP) is the most common autoimmune blistering disease. Recent studies have shown that patients with bullous pemphigoid are more likely to have neurological and psychiatric diseases, particularly prior to the diagnosis of bullous pemphigoid. OBJECTIVE: The aims were: (i) to evaluate the demographic and clinical features of bullous pemphigoid from a database of patients at a Portuguese university hospital and (ii) to compare the prevalence of comorbid conditions before the diagnosis of bullous pemphigoid with a control group. METHODS: Seventy-seven patients with bullous pemphigoid were enrolled in the study. They were compared with 176 age- and gender-matched controls, which also had the same inpatient to outpatient ratio, but no history of bullous or cutaneous malignant disease. Univariate and multivariate analyses were used to calculate odds ratios for specific comorbid diseases. RESULTS: At least one neurologic diagnosis was present in 55.8% of BP patients compared with 20.5% controls (p<0.001). Comparing cases to controls, stroke was seen in 35.1 vs. 6.8%, OR 8.10 (3.80-17.25); dementia in 37.7 vs. 11.9%, OR 5.25 (2.71-10.16); and Parkinson's disease in 5.2 vs. 1.1%, OR 4.91 (0.88-27.44). Using multivariate analysis, all diseases except Parkinson's retained their association with BP. Patients under systemic treatment were eight times more likely to have complications than those treated with topical steroids (p< 0.017). CONCLUSIONS: The results of this study substantiate the association between BP and neurological diseases. In addition, they highlight the potential complications associated with the treatment of BP. PMID- 24770505 TI - Presenting data in tables and charts. AB - The present paper aims to provide basic guidelines to present epidemiological data using tables and graphs in Dermatology. Although simple, the preparation of tables and graphs should follow basic recommendations, which make it much easier to understand the data under analysis and to promote accurate communication in science. Additionally, this paper deals with other basic concepts in epidemiology, such as variable, observation, and data, which are useful both in the exchange of information between researchers and in the planning and conception of a research project. PMID- 24770506 TI - Stem cells in dermatology. AB - Preclinical and clinical research have shown that stem cell therapy could be a promising therapeutic option for many diseases in which current medical treatments do not achieve satisfying results or cure. This article describes stem cells sources and their therapeutic applications in dermatology today. PMID- 24770507 TI - Impetigo - review. AB - Impetigo is a common cutaneous infection that is especially prevalent in children. Historically, impetigo is caused by either group A beta-hemolytic streptococci or Staphylococcus aureus. Currently, the most frequently isolated pathogen is S. aureus. This article discusses the microbiologic and virulence factors of group A beta-hemolytic streptococci and Staphylococcus aureus, clinical characteristics, complications, as well as the approach to diagnosis and management of impetigo. Topical agents for impetigo therapy are reviewed. PMID- 24770508 TI - Cutaneous melanoma: new advances in treatment. AB - Cutaneous melanoma is a challenge to treat. Over the last 30 years, no drug or combination of drugs demonstrated significant impact to improve patient survival. From 1995 to 2000, the use of cytokines such as interferon and interleukin become treatment options. In 2011, new drugs were approved by the U.S. Food and Drug Administration, including peginterferon alfa-2b for patients with stage III disease, vemurafenib for patients with metastatic melanoma with the BRAF V600E mutation, and ipilimumab, a monoclonal antibody directed to the CTLA-4 T lymphocyte receptor, to combat metastatic melanoma in patients who do not have the BRAF V600E mutation. Both ipilimumab and vemurafenib showed results in terms of overall survival. Other trials with inhibitors of other genes, such as the KIT gene and MEK, are underway in the search for new discoveries. The discovery of new treatments for advanced or metastatic disease aims to relieve symptoms and improve patient quality of life. PMID- 24770509 TI - Nail psoriasis: a review of the literature. AB - Nails are considered epidermal appendages, and as such, are commonly affected in patients with psoriasis, 80% of whom are likely to develop nail psoriasis as a result of their condition. Two patterns of nail disorders have been shown to be caused by psoriasis. Nail matrix involvement can result in features such as leukonychia, pitting (punctures or cupuliform depressions), red spots in the lunula and crumbling. Nail bed involvement, on the other hand, can cause onycholysis, salmon or oil-drop patches, subungual hyperkeratosis and splinter hemorrhages. Nail disease causes aesthetic and functional impairment, and is indicative of more severe forms of psoriasis as well as of joint involvement. The treatment for nail psoriasis involves behavioral interventions, topical medications, or systemic therapy in case of extensive skin or joint involvement. This article presents a review of the main features of nail psoriasis, its clinical presentation, diagnostic and assessment methods, clinical repercussions, and of its available treatment options. PMID- 24770510 TI - Psoriasiform keratosis - case report. AB - Psoriasiform Keratosis is a rare clinic entity. The etiopathogenesis remains unknown and the disease is characterized by a solitary, scaly or keratotic papule, or plaque mainly located on the extremities. Histopathological features closely resemble those of psoriasis. We report the case of a 70-year-old woman presenting a solitary and asymptomatic keratotic plaque, located on the back of the left leg, unresponsive to topical corticosteroids. We performed an excisional biopsy and histopathology was consistent with psoriasiform keratosis. PMID- 24770511 TI - Alopecia universalis during treatment with leflunomide and adalimumab - case report. AB - Alopecia areata is a non-scarring form of alopecia that can be localized or widespread. Its etiology is unknown, but immunological factors are implicated in its pathogenesis. With the more frequent use of anti TNFalpha biologic drugs, some alopecia areata cases during their use have been described. We report a case of universal alopecia in a patient with rheumatoid arthritis while using adalimumab and leflunomide. PMID- 24770512 TI - Arthritis and diagnosis of leprosy: a case report and review of the literature. AB - Leprosy is clinically characterized by involvement of peripheral nerves and skin. The immunological profile of the individual defines the diversity of clinical manifestations, from skin disorders to systemic manifestations, especially the articulation ones, common in multibacillary forms, which may mimic collagen diseases and often posing diagnostic difficulties in endemic areas. This is a case report of asymmetric polyarthritis of small and large articulations associated with skin lesions which had been treated by a rheumatologist for 2 years with initial clinical diagnosis of rheumatoid arthritis, and later, with the appearance of skin lesions, of systemic lupus erythematosus. PMID- 24770513 TI - Primary essential cutis verticis gyrata - case report. AB - Cutis verticis gyrata is characterized by excessive formation of scalp skin. It may be primary (essential and nonessential) or secondary. In the primary essential form it presents only folding skin formation on the scalp, mimicking cerebral gyri, without associated comorbidities. We report a rare case of a 28 year-old male patient with primary essential cutis verticis gyrata. PMID- 24770514 TI - Kissing nevus of the penis. Report of two cases and review of the literature. AB - Kissing nevus is a curious type of nevus that was first described on the eyelids and rarely described on the penis. We report two cases of kissing nevus of the penis and review previously reported cases. The lesions of the kissing nevus of the penis showed characteristic mirror-image symmetry relative to the coronal sulcus. On histopathology, the lesion showed a compound nevus. PMID- 24770515 TI - Cutaneous larva migrans on the scalp: atypical presentation of a common disease. AB - Cutaneous larva migrans is a pruritic dermatitis due to the inoculation of helminths larvae in the skin, and it often occurs in children in tropical and subtropical areas. The authors describe an atypical case of cutaneous larva migrans in a 11 year-old child with scalp involvement, an unusual topography for this lesion. PMID- 24770516 TI - Scanning electron microscopy of tinea nigra. AB - Tinea nigra is a rare superficial mycosis caused by Hortaea werneckii. This infection presents as asymptomatic brown to black maculae mostly in palmo-plantar regions. We performed scanning electron microscopy of a superficial shaving of a tinea nigra lesion. The examination of the outer surface of the sample showed the epidermis with corneocytes and hyphae and elimination of fungal filaments. The inner surface of the sample showed important aggregation of hyphae among keratinocytes, which formed small fungal colonies. The ultrastructural findings correlated with those of dermoscopic examination - the small fungal aggregations may be the dark spicules seen on dermoscopy - and also allowed to document the mode of dissemination of tinea nigra, showing how hyphae are eliminated on the surface of the lesion. PMID- 24770517 TI - Follicular mucinosis - case report. AB - Follicular mucinosis, also known as alopecia mucinosa, is a cutaneous mucinosis histologically characterized by accumulation of dermal type mucin in the pilosebaceous follicle and sebaceous glands. It presents in two forms, a primary or idiopathic form and a secondary form associated with various benign or malignant processes. Among the malignant processes, the main association is with mycosis fungoides. The frequent overlap of clinical, histopathological, immunohistochemical and molecular biology characteristics makes the correct classification of these conditions difficult, therefore a long follow-up of all cases is recommended. We report the case of an adolescent with disseminated lesions and discuss the difficulty of early identification of secondary follicular mucinosis associated with cutaneous lymphoma. PMID- 24770518 TI - Multiple lesions by vampire bat bites in a patient in Niteroi, Brazil - case report. AB - Over the last few centuries, the expansion of urbanization brought bats closer to urbanized areas, increasing the risk of accidents by bat bites. The morphology of bat bites can be varied, usually having an elliptical shape, about 0.5 cm along its greatest length, and the characteristic corkscrew bite pattern. The authors present the case of a patient who was repeatedly bitten by vampire bats for two months. A polymerase chain reaction was performed in the cutaneous nerves at the base of the hair follicles which showed negativity towards the rabies virus. The authors highlight the public health importance of this case, and discuss the morphological characteristics of these hematophagous bat bites. PMID- 24770519 TI - Comedo-like openings in melanoma. AB - We describe a case of melanoma with the presence of comedo-like openings at dermoscopy. These structures, typical of seborrheic keratosis, represent an uncommon finding in melanoma. We emphasize the importance of searching for specific dermoscopic criteria for melanocytic lesions during the examination of a pigmented lesion, despite possible observations of characteristic structures of non-melanocytic lesions, in order to increase the accuracy in the diagnosis of melanoma. PMID- 24770520 TI - Comparative scanning electron microscopy of bullous diseases. AB - The purpose of this study is to compare scanning electron microscopy findings of the blister roof in three distinct bullous diseases: one intraepidermal acantholytic (pemphigus foliaceus); one due to hemidesmosomal dysfunction (bullous pemphigoid); and one secondary to anchoring fibril dysfunction - type VII collagen (dystrophic epidermolysis bullosa). In pemphigus foliaceus, acantholytic phenomena were readily demonstrated. In bullous pemphigoid, the epidermis had a solid aspect. In dystrophic epidermolysis bullosa a net was seen in the blister roof. PMID- 24770521 TI - Chromoblastomycosis: an exuberant case. AB - Chromoblastomycosis is a chronic subcutaneous mycotic infection caused by dematiaceous saprophytic moulds. The most frequently isolated agent is Fonsecae pedrosoi. This article reports a case of a man from the Amazon region in Northern Brazil who presented with a lesion of 12 months' duration, which gradually increased in size until covering the majority of his right leg. A successful treatment with itraconazole was performed. PMID- 24770522 TI - Case for diagnosis. Alopecia areata and congenital triangular alopecia. AB - A 6 year-old patient began to experience localized hairloss in the right temporal region three years ago. During the first appointment, diagnoses of alopecia areata and congenital triangular alopecia were made. After one year, there was no change. Upon dermatological examination, non-scarring alopecia was noted in the right temporal region, revealing extremely fine and fair hair follicles. A dermoscopy revealed only thin vellus-type hairs. Congenital triangular alopecia is a condition commonly confused with alopecia areata and is thus underdiagnosed. However, well-established clinical parameters and dermoscopic criteria can be used to distinguish skin diseases that affect hair and define the diagnosis. PMID- 24770523 TI - Case for diagnosis. Dermatofibrosarcoma protuberans. AB - Dermatofibrosarcoma protuberans is a fibrohistiocytic tumor of intermediate malignancy with aggressive localized growth, high recurrence rate, but low metastatic potential. It appears as a hardened plaque, with slow growth, upon which the development of nodules occurs. It predominates in the trunk and is unusual in acral locations. Histopathology reveals spindle cells with storiform pattern and cartwheel-like or whirlwind-like aspect. Immunohistochemistry shows positivity for CD34. The treatment is surgical. We report a case of long evolution, with an unusual location, that relapsed after surgery, to emphasize the importance of early diagnosis and proper treatment, avoiding aggressive resections with increased morbidity. PMID- 24770524 TI - Case for diagnosis. Pachydermodactyly. AB - Pachydermodactyly is a rare and benign form of acquired digital fibromatosis characterized by the expansion of soft tissue around proximal phalanges and interphalangeal joints. The etiology remains unknown, although it is suggested that repetitive mechanic trauma like the interlacing or rubbing of the fingers can lead to skin thickening. We report a case of a young man with skin thickening around interphalangeal joints and compulsive finger manipulation habit. The histopathology disclosed hyperkeratosis, discrete papillomatosis, mild increase of fibroblasts and dermal mucinosis. The lesions regressed partially, after finger manipulation was stopped. PMID- 24770525 TI - Syndrome in question. Multiple autoimmune syndrome. AB - Multiple autoimmune syndrome is a rare condition, described by Humbert and Dupond in 1988. It is defined by the association of at least 3 autoimmune diseases in the same patient. Vitiligo is the most common skin condition in this syndrome. This article presents the case of a 31-year-old male with vitiligo, alopecia areata, Crohn's disease, psoriasis vulgaris and oral lichen planus. The rarity of this case is highlighted by the coexistence of four autoimmune skin diseases in association with Crohn's disease, never described in the literature. PMID- 24770526 TI - Syndrome in question. Hay-Wells syndrome. AB - Hay-Wells syndrome or AEC (Ankyloblepharon, Ectodermal dysplasia and Cleft lip and palate syndrome) is a rare ectodermal disorder. The treatment is aimed to prevent clinical complications. We describe the case of a four-month old male patient with erosions on the scalp, trunk and arms, trachyonychia, deformity of the ears, micropenis, cleft palate, decreased eyebrow and eyelash hairs, in addition to antecedents of surgical correction of ankyloblepharon. The importance of the correct diagnosis is emphasized, besides the investigation of the associated diseases, treatment of complications and genetic counseling of the parents. PMID- 24770527 TI - Biologic therapy for psoriasis - still searching for the best target. AB - Psoriasis is a chronic skin disease that results from the complex interaction between genetic and environmental factors. Over the last few decades, scientific evidence has redirected the focus of therapeutic studies to the immunologic pathways underlying its pathogenesis. This led to the biologic boom that we are currently experiencing, with the development and approval of targeted progressively more selective biological therapies and ongoing clinical trials of increasingly specific drugs, given their important implications for long-term efficacy and safety. Nevertheless, the search for the optimal biologic is still ongoing, and the best target has yet to be found. PMID- 24770528 TI - Retrospective analysis of melanocytic lesions in children at the National Cancer Institute-RJ. AB - Skin cancer is the most common neoplasm in Brazil. Melanoma accounts for 4% of these neoplasms. Although childhood melanoma is rare, there is evidence that its incidence is increasing, placing it among the most important public health problems for the future. This work sought to conduct a retrospective review of cases of suspected melanocytic skin lesions in children, their diagnosis and management, and evaluate the sentinel lymph node biopsy method in some cases of cutaneous melanoma. PMID- 24770529 TI - Lutzomyia whitmani is the main vector of American Cutaneous Leishmaniasis in the Brazilian Federal District and the most prevalent species in residential areas of the Administrative Region of Sobradinho. AB - Although cases of cutaneous Leishmaniasis have been reported in Brasilia - DF, its mode of transmission is still unknown. Center of Disease Control traps (CDC trap) placed around Sobradinho, a periurban area in the Brazilian Federal District, were able to capture a sample of phlebotomines composed of 89% Lutzomyia whitmani, 7% Lu. bacula, and 3% Lu. davisi specimens. Being of 77% of these specimens were captured in peridomiciliary. PCR analyses showed that the specimens were negative for Leishmania DNA. However, the high prevalence of Lu. Whitmani in the studied region suggests that it may be the main vector for the transmission of Leishmaniasis in peridomiciliary areas in the studied region. PMID- 24770530 TI - Thimerosal: current sources of contact in Brazil. AB - Thimerosal is an organic mercury derivative found in ophthalmic solutions and certain vaccines in Brazil. Although most studies suggest the prevalence of thimerosal sensitivity to be quite high, this condition does not currently have any clinical relevance. The present article surveyed 184 Brazilian products (151 topical medications and 33 vaccines) and found that thimerosal was only present in 3 ophthalmic solutions and 5 vaccines. PMID- 24770531 TI - The Quality of School Physical Activity Policies Within Maryland and Virginia. AB - BACKGROUND: Since the adoption of the Healthy, Hunger-Free Kids Act of 2010, many researchers have examined changes in the school nutrition environment; however, far less research has focused on the evaluation of physical activity (PA) policies within public schools. METHODS: School district wellness policies (n = 144) of Virginia and Maryland were coded using a previously validated audit tool with a scale of 0 (weakest, least comprehensive) to 1 (strongest, most comprehensive). RESULTS: Mean policy strength was weak (.20 +/- .15), and, on average, policies were moderately comprehensive (.40 +/- .22). The strongest (.73 +/- .44) and most comprehensive (.79 +/- .40) policy subgroup addressed daily recess in elementary schools. Virginia had significantly higher scores in 9 policy groups, while Maryland had higher significant policy scores in the 2 following groups: (1) the strength and comprehensiveness of a written physical education (PE) curriculum for each grade level (Ps < .05) and (2) the strength and comprehensiveness of addressing the use of PE waivers (Ps < .05). CONCLUSIONS: PA wellness policies in Maryland and Virginia are extremely weak and only moderately comprehensive; it is unlikely that these policies will significantly influence school-based PA. PMID- 24770536 TI - [Avastin-Lucentis: off-label and surroundings]. AB - In Italy, the debate on the off-label use of intravitreal bevacizumab in patients with age-related macular degeneration (AMD) has attracted a very wide coverage by the media. Our national regulation on the off-label uses of pharmacological agents was initially issued in 1999 to handle the case of the so-called "Di Bella therapy" in patients with cancer. Some changes to this regulation have been made thereafter, and the most recent law currently prohibits the use of off-label agents in cases where approved medicines are available. Bevacizumab and ranibizumab are thought to be equi-effective, and also their safety profiles are similar. Since the cost per intravitreal injection is much lower for off-label bevacizumab than for ranibizumab, in our National Health System the criterion of economic savings, that favours bevacizumab, conflicts with the criterion set by the current regulation that instead favours ranibizumab. Therefore, a lively debate has been started and is still ongoing to establish how the present regulation in this area can be revised. In devising the new regulation on this issue, one point deserving consideration is that the case of bevacizumab vs ranibizumab in patients with AMD is very atypical in the current scenario of in hospital drug treatments. Hence, the new regulation should be tailored to the therapeutic needs of all patients likely to receive an off-label treatment for any clinical indication rather than to the specific case of intravitreal treatments for patients with AMD. PMID- 24770532 TI - Novel use of 3T MRI in assessment of optic nerve volume in glaucoma. AB - PURPOSE: To measure optic nerve (ON) volume using 3 T magnetic resonance imaging (MRI), to correlate ON volume with retinal nerve fiber layer (RNFL) thickness, and to determine the viability of MRI as an objective tool in distinguishing glaucoma severity. METHODS: In this cross-sectional study, 30 severe glaucoma patients, 30 mild glaucoma patients and 30 age-matched controls were recruited. All subjects underwent standard automated perimetry, RNFL analysis and 3 T MRI examinations. Glaucoma patients were classified according to the Hodapp-Anderson Parish classification. Pearson's correlation coefficient was used to correlate ON volume with RNFL, and receiver operating curve (ROC) analysis was performed to determine the sensitivity and specificity of ON volume in detecting glaucoma severity. RESULTS: Optic nerve volume was significantly lower in both the left and right eyes of the severe glaucoma group (168.70 +/- 46.28 mm(3); 167.40 +/- 45.36 mm(3)) than in the mild glaucoma group (264.03 +/- 78.53 mm(3); 264.76 +/- 78.88 mm(3)) and the control group (297.80 +/- 71.45 mm(3); 296.56 +/- 71.02 mm(3)). Moderate correlation was observed between: RNFL thickness and ON volume (r = 0.51, p <0.001), and in mean deviation of visual field and optic nerve volume (r = 0.60, p < 0.001). ON volume below 236 mm(3) was 96 % sensitive and 80 % specific for the detection of severe glaucoma. CONCLUSIONS: MRI measured optic nerve volume is a reliable method of assessing glaucomatous damage beyond the optic nerve head. A value of 236 mm(3) and below can be used to define severe glaucoma. PMID- 24770537 TI - [The 5th revised edition of the DSM: a revolution half-accomplished]. AB - To date, the diagnosis of mental disorders has been based on clinical observation and the 5th revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published in May 2013, has confirmed this approach placing disorders in discrete statistical categories like the preceding editions. This has disappointed the expectations of those who hypothesized the revolution of a "neuroscience based DSM", where the psychiatric diagnoses are based on the identification of sensitive biological markers. Another controversial point is that, according to several authors, the DSM-5 does not provide a clear definition of the boundaries between mental disorders and the range of normality. However, in the new edition of the DSM, there are several interesting changes, such as the introduction of the "dimensions" that are aimed to bridge the gap between the historical categorical approach and the new research data and the reclassification and the redefinition of most categories. Purpose of this editorial is to provide a brief overview of these changes and critical aspects. PMID- 24770533 TI - GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development. AB - The embryonic vertebrate heart tube develops an atrioventricular canal that divides the atrial and ventricular chambers, forms atrioventricular conduction tissue and organizes valve development. Here we assess the transcriptional mechanism underlying this localized differentiation process. We show that atrioventricular canal-specific enhancers are GATA-binding site-dependent and act as switches that repress gene activity in the chambers. We find that atrioventricular canal-specific gene loci are enriched in H3K27ac, a marker of active enhancers, in atrioventricular canal tissue and depleted in H3K27ac in chamber tissue. In the atrioventricular canal, Gata4 activates the enhancers in synergy with Bmp2/Smad signalling, leading to H3K27 acetylation. In contrast, in chambers, Gata4 cooperates with pan-cardiac Hdac1 and Hdac2 and chamber-specific Hey1 and Hey2, leading to H3K27 deacetylation and repression. We conclude that atrioventricular canal-specific enhancers are platforms integrating cardiac transcription factors, broadly active histone modification enzymes and localized co-factors to drive atrioventricular canal-specific gene activity. PMID- 24770538 TI - [Alcohol, cardiovascular prevention and cancer]. AB - It is well known that light to moderate drinking (10-25 g/day) has a protective effect on ischaemic heart disease. This effect seems independent of the type of alcoholic beverage. Recently, the International Agency for Research on Cancer (World Health Organization) stated that alcoholic beverages are carcinogenic for human (oral cavity, pharynx, larynx, oesophagus, colorectum, liver and breast). There is a dose-response relationship between alcohol and cancer in that the risk of cancer increases proportionally with alcohol consumption. Low doses of alcohol (10 g/day) are associated with an increased risk for oral cavity, pharynx, larynx, oesophagus and breast cancer. Therefore, a physically active lifestyle and a healthy diet are more effective in preventing ischaemic heart disease than a low level of alcohol consumption. PMID- 24770539 TI - [The primary healthcare centres]. AB - The central attributes of primary care are: first contact (accessibility), longitudinality (person- focused preventive and curative care overtime), patient oriented comprehensiveness and coordination (including navigation towards secondary and tertiary care). Besides taking care of the needs of the individuals, primary health care teams are also looking at the community, especially when addressing social determinants of health. The rationale for the benefits for primary care for health has been found in: 1) greater access to needed services; 2) better quality of care; 3) a greater focus on prevention; 4) early management of health problems; 5) organizing and delivering high quality care for chronic non-communicable diseases. This paper describes the role of primary healthcare centres in strengthening community primary services and in reducing health inequalities. Furthemore, the experiences of Regional Health Services from Tuscany and Emilia-Romagna are discussed, with a brief overview of the literature. PMID- 24770540 TI - [Chronic pain in the obese: a quali-quantitative observational study]. AB - INTRODUCTION: Obesity (Ob) is one of the major issues for the public health care system with a constantly increasing prevalence. Chronic Pain (CP), on the other hand, is a pathological condition as severe and prevalent as the former. Ob and CP are not only pathological conditions, they also are important factors of risk for the onset of a number of morbid conditions. MATERIALS AND METHODS: In our study we have enrolled 182 patients with Ob, to whom we have asked to fill a brief questionnaire with the purpose of evaluating prevalence and characteristics of CP, therapeutic attitude and its results, as well as the knowledge of the Law n. 38 - 15/03/2010. RESULTS: From the analysis of gathered data, CP is present in the 39% of subjects with Ob (73.2% of females and 23.9% of males) and proportionally increases as BMI increases. The majority of patients (48%) shows pain at articular level, and a "pin" and a "gripping" pain are the two types of pain that are mostly described. Almost all the subjects enrolled (90%) suffer of a pain reported at a moderate to intense level. 15% circa of the patients do not take any therapy, while FANS have resulted to be the most used drugs among them (over 50% of the patients) and the 45% of the subjects have currently reported not to have a good control over the pain. The Law n. 38 has been reported unknown by the 8.2% of the investigated sample. CONCLUSIONS: The study has demonstrated a substantial association between the Ob and CP, particularly in the female gender, the clinical relevance of pain, its BMI-dependent tendency, the inadequacy of the therapy and the widespread lack of awareness and attention to the themes and issues of pain. PMID- 24770541 TI - [Chronic pain in the diabetic patient: a quali-quantitative observational study]. AB - AIM: The purpose of this study is to evaluate the prevalence and characteristics of pain in subjects affected by Diabetes Mellitus (DM), to assess approach and therapeutically valid outcomes as well as the knowledge of the Law n. 38/15/03/2010 of the Italian Government ("Dispositions to guarantee the access to the Palliative Cares and Pain Therapy"). MATERIALS AND METHODS: We have enrolled 462 patients affected by DM [242 (52.4%) males, 209 (42.5%) females; while in 11 (5.1%) cases the gender has not been specified], with characteristics as follows: 62 patients (13.4%) affected by T1DM (37 males and 25 females) e 400 patients (86.6%) affected by T2DM (224 males e 176 females). The average age was of 65.2 years old (range 20-91). All the patients have been presented with an original questionnaires based on 10 questions. RESULTS: 221 subjects (48%) have claimed to have experienced pain; 60% within the females, 38% within the males (p<0.001). 31% of these are to be included among the patients with T1DM, 50.5% among those with T2DM (p<0.01). The presence of chronic pain has been acknowledged by 162 subjects (35%). As per chronic pain, this has been described as articular pain by 128 patients (80%), while 63 (38%) located the pain through the spine and 29 (18%) throughout the muscles. Chronic pain was described as moderate by 73 subjects (45%), intense by 59 (36%), feeble by 15 (9%), utterly intense by 5 (3%), moderate/intense by 1 (1%). The drugs for treating the chronic pain used by the patients have been enlisted as follows: FANS (41%), paracetamol (30%), glucocorticoids (3%), weak opioids (2%); 27% of subjects have received no therapy. As for the Law 38/2010, only 8% have said they have had news of it. CONCLUSIONS: The data gathered in this study have drawn attention on the fact that the presence of pain is higher in female gender, with a prevalence of 60% compared to the 38% of the male gender. It has been observed no relation with the age range, in particular no proportional increase level of pain has been observed, although the higher peak of prevalence has been experienced in the age range between 70-79, both for pain in general and for chronic pain. Speaking about efficacy of the treatment, almost 50% of the subjects have received no improvement from the therapy. PMID- 24770542 TI - [Role of intensive medical training on Law 38 to improve pain management in primary care]. AB - The Italian Law no. 38/2010 requires that the physician reports in the medical record the type and the intensity of pain, analgesic therapies and clinical results. We developed a training model for 256 primary care physicians (GPs). After a period of intensive training on the content of the law no. 38, diagnostic and pharmacological approach of pain, we carried out a clinical audit by a web based clinical record to assess doctor's compliance to Law no. 38 and the use of opioids. 2631 patients were assessed (age 71,5+/-13,7 years; median 74). The mean of chronic non oncologic pain intesity was 5.41+/-2.0 (static) and 6.10+/-2.32 (dynamic). After a systematic measurement of pain, a better control of patients was achieved (2.22+/-2.12 points lower for static, 2.37+/-2.34 lower for dynamic pain (p<0.001 vs basal time). An increased use of opioids have been detected. GPs have also used strong opioids in opioid-naive patients, avoiding the first or the second step if intensity of pain detected was severe. In fact, a greater pain control was achieved with oxycodone compared to tramadol or codeine (all of them with normal release and combined with acetaminophen). Chronic non cancer pain remains one of the major clinical problems in the primary care setting, especially in the elderly. The standard measurement of parameters related to pain and the proper use of opioids depends on the scientific update and how this is delivered. GPs are crucial to implement the Law 38 and to increase the degree of complexity of the patient to be properly admitted to a SPOKE/HUB center. PMID- 24770543 TI - [The measurement of pain in patients with dementia: a review of the most appropriate tools]. AB - Pain is one of the most frequent symptom in elderly people with dementia and despite of this, it is still under-acknowledged and under-treated. The best approach to pain assessment is to evaluate it with the most appropriate scale. While in the elderly suffering mild-moderate cognitive impairment, it's possible to use self-report scales, in the elderly with severe cognitive impairment the use of observational scales is recommended. The objective of this review is to analyze the various types of pain assessment tools used in patients with cognitive impairment. Literature review was carried out through consultation of the most important bio-medical databases: Medline (PubMed), KT+, Trip Database, Cinahl, Cochrane Library, Embase. The keywords used were: "pain measurement", "pain assessment", "dementia", "validation study", "aged". All keywords were linked using AND and OR boolean operators. Altogether 5 self-report scales and 17 observational scales were retrieved, 7 of which available in Italian validated versions. The review analyzes potential and limitations of each assessment tool, in order to assist the clinician to make the most appropriate choice when using it in health care contexts. PMID- 24770545 TI - [Medicine and literature: an anthology]. PMID- 24770546 TI - Aarskog-Scott syndrome: a novel mutation in the FGD1 gene associated with severe craniofacial dysplasia. AB - Aarskog syndrome (AAS) is an X-linked human disease that affects the skeletal formation and embryonic morphogenesis and is caused by mutations in the FGD1 gene. Patients typically show distinctive skeletal and genital developmental abnormalities, but a broad spectrum of clinical phenotypes has been observed. We report here on the clinical and molecular analysis of a family that reveals a novel FGD1 mutation in a 9-year-old boy displaying extreme craniofacial dysplasia associated with attention deficit hyperactivity disorder. Sequencing of FGD1 revealed a novel mutation in exon 7 at position c.1468 C > T in the index patient, leading to a stop codon in the highly conserved RhoGEF gene domain. His mother and maternal grandmother were also found to be heterozygous for this FGD1 mutation. CONCLUSION: Our results identify a novel mutation of FDG1 in a family with Aarskog syndrome and underscore the phenotypical variability of this condition. PMID- 24770547 TI - Richard Gitzelmann (23rd February 1930--31st October 2013). PMID- 24770548 TI - Does cation break the cyano bond? A critical evaluation of nitrile-cation interaction. AB - DFT and G4 results reveal that cations display the following trends in imparting its positive charge to acrylonitrile; H+ > Li+ > Na+ > K+ for group I and Be2+ > Mg2+ > Ca2+ for group II. Solvation by water molecules and interaction with cation make the cyano bond more polarized and exhibits ketene-imine character. Bond order in nitrile-cation complexes has been predicted based on the s character of the covalent bond orbitals. Mulliken, CHELPG, and NPA charges are in good agreement in predicting positive charge buildup and GIAO nuclear deshileding on C1. G4 enthalpies show that Mg2+ is more strongly bound to acrylonitrile than to acetonitrile by 3 kcal mol-1, and the proton affinity of the former is higher by 0.8 kcal mol-1. G4 enthalpies of reductions support prior experimental observation that metalated conjugated nitriles show enhanced reactivity toward weak nucleophiles to afford Michael addition products. PMID- 24770550 TI - Lithium, sodium and potassium picolyl complexes: syntheses, structures and bonding. AB - Synthetically important for introducing a picolyl scaffold into a molecular construction, alkali metallated picoline (methylpyridine) complexes are also interesting in their own right for the diversity of their ligand-metal bonding possibilities. Here the syntheses of seven new such complexes are reported: namely three 4-picoline derivatives 4-picLi.Me6TREN, 1, 4-picNa.Me6TREN, 2, and [4-picK.2(4-picH)]infinity, 3; and four 2-picoline derivatives, 2-picLi.Me6TREN, 4, 2-picLi.PMDETA, 4', 2-picNa.Me6TREN, 5, and [2-picK.PMDETA]2, 6' [where pic = NC5H4(CH2); Me6TREN = tris(N,N-dimethyl-2-aminoethyl)amine, (Me2NCH2CH2)3N; PMDETA = N,N,N',N'',N''-pentamethyldiethylenetriamine, (Me2NCH2CH2)2NMe]. X-ray crystallographic studies establish that the lighter alkali metal complexes 1, 2, 4' and 5 adopt monomeric structures in contrast to the polymeric and dimeric arrangements adopted by potassium complexes 3 and 6' respectively. All complexes have also been characterized by solution NMR spectroscopy ((1)H, (13)C, and where relevant (7)Li). This study represents the first example of sodium and potassium picolyl complexes to be isolated and characterized. DOSY (Diffusion-Ordered Spectroscopy) experiments performed on 4 and 4' suggest both compounds retain their monomeric constitutions in C6D6 solution. Discussion focuses on the influence of the metal and neutral donor molecule on the structures and the nature of the ligand-metal (enamido versus aza-allylic) interactions. PMID- 24770549 TI - Fosfomycin induced structural change in fosfomycin resistance kinases FomA: molecular dynamics and molecular docking studies. AB - Fosfomycin resistance kinases FomA, one of the key enzymes responsible for bacterial resistances to fosfomycin, has gained much attention recently due to the raising public concern for multi-drug resistant bacteria. Using molecular docking followed by molecular dynamics simulations, our group illustrated the process of fosfomycin induced conformational change of FomA. The detailed roles of the catalytic residues (Lys18, His58 and Thr210) during the formation of the enzyme-substrate complex were shown in our research. The organization functions of Gly53, Gly54, Ile61 and Leu75 were also highlighted. Furthermore, the cation pi interaction between Arg62 and Trp207 was observed and speculated to play an auxiliary role in the conformation change process of the enzyme. This detailed molecular level illustration of the formation of FomA.ATP.Mg.Fosfomycin complex could provide insight for both anti-biotic discovery and improvement of fosfomycin in the future. PMID- 24770551 TI - Diclofenac toxicity in human intestine ex vivo is not related to the formation of intestinal metabolites. AB - The use of diclofenac (DCF), a nonsteroidal anti-inflammatory drug, is associated with a high prevalence of gastrointestinal side effects. In vivo studies in rodents suggested that reactive metabolites of DCF produced by the liver or the intestine might be responsible for this toxicity. In the present study, precision cut intestinal slices (PCIS) prepared from the jejunum of 18 human donors were used as an ex vivo model to investigate whether DCF intestinal metabolites are responsible for its intestinal toxicity in man. PCIS were incubated with a concentration range of DCF (0-600 uM) up to 24 h. DCF (>=400 uM) caused direct toxicity to the intestine as demonstrated by ATP depletion, morphological damage, caspase 3 activation, and lactate dehydrogenase leakage. Three main metabolites produced by PCIS (4'-hydroxy DCF, 5-hydroxy DCF, and DCF acyl glucuronide) were detected by HPLC. Protein adducts were detected by immunohistochemical staining and showed correlation with the intestinal metabolites. DCF induced similar toxicity to each of the samples regardless of the variation in metabolism among them. Less metabolites were produced by slices incubated with 400 uM DCF than with 100 uM DCF. The addition of the metabolic inhibitors such as ketoconazole, cimetidine, or borneol decreased the metabolite formation but increased the toxicity. The results suggest that DCF can induce intestinal toxicity in human PCIS directly at therapeutically relevant concentrations, independent of the reactive metabolites 4'-OH DCF, 5-OH DCF, or diclofenac acylglucuronide produced by the liver or formed in the intestine. PMID- 24770552 TI - Epidermal growth factor receptor signalling in keratinocyte biology: implications for skin toxicity of tyrosine kinase inhibitors. AB - The epidermal growth factor receptor (EGFR) and its ligands have been long recognized as centrally involved in the growth and repair process of epithelia, as well as in carcinogenesis. In addition, the EGFR has been demonstrated to be importantly involved in the control of inflammatory responses. During this last decade, a number of highly specific agents targeting this system have become an integral component of pharmacologic strategies against many solid malignancies. These drugs have led to increased patient survival and made therapy more tolerant when compared to conventional cytotoxic drugs. Nonetheless, their use is associated with a constellation of toxic effects on the skin, including follicular pustules, persistent inflammation, xerosis and pruritus, and enhanced susceptibility to infections. This dramatic impairment of skin homoeostasis underscores the centrality of the EGFR-ligand system in the whole skin immune system. So far, no mechanism-based approaches are available to specifically counteract the adverse effects of anti-EGFR drugs or any other class of tyrosine kinase inhibitors. Only the knowledge of the cellular and molecular events underlying these adverse effects in humans, combined with in vitro/in vivo models able to mimic these toxic responses, may guide the development of mechanism-based treatment or prevention strategies. PMID- 24770553 TI - Metformin aggravates immune-mediated liver injury in mice. AB - Hepatotoxicity of the antidiabetic drug metformin has been reported, but the underlying mechanisms remain unclear. We here investigated the effect of metformin in immune-mediated liver damage. While not hepatotoxic alone, metformin (200 mg/kg) aggravated concanavalin A (Con A, 12 mg/kg)-induced hepatitis, an experimental model of T cell-mediated liver injury, in both relatively resistant BALB/c and highly susceptible C57Bl/6 mice. Metformin + Con A-treated mice had elevated serum levels of pro-inflammatory cytokines TNF-alpha and IFN-gamma, accompanied by a massive mononuclear cell infiltration in the liver. This was associated with the higher numbers of CD4(+) T cells producing TNF-alpha, IFN gamma and IL-17, CD4(+) T cells expressing chemokine receptor CXCR3 and activation marker CD27, CD4(+)CD62L(-)CCR7(-) and CD8(+)CD62L(-)CCR7(-) effector memory cells, IFN-gamma producing NK cells, IL-4 and IL-17 producing NKT cells and IL-12 producing macrophages/dendritic cells. The percentage of CD4(+)CXCR3(+)Tbet(+)IL-10(+) and CD4(+)CD69(+)CD25(-) regulatory T cells was reduced. Metformin stimulated inducible nitric oxide synthase (iNOS) expression in the liver and spleen, and genetic deletion of iNOS attenuated the hepatotoxicity of metformin. Metformin increased the autophagic light chain 3 conversion and mRNA expression of important autophagy-inducing (beclin-1, Atg5 and GABARAP) and pro-apoptotic (p21, p27, Puma, Noxa, Bax, Bad, Bak1, Bim and Apaf1), but not anti-apoptotic molecules (Bcl-xL, survivin and XIAP), which correlated with the apoptotic caspase-3/PARP cleavage in the liver. The autophagy inhibitor chloroquine (20 mg/kg) prevented liver injury and apoptotic changes induced by metformin. Therefore, metformin aggravates immune-mediated hepatitis by promoting autophagy and activation of immune cells, affecting effector, as well as liver-specific regulatory T cells and iNOS expression. PMID- 24770554 TI - Hepatic magnetic resonance imaging with T2* mapping of ovariectomized rats: correlation between iron overload and postmenopausal osteoporosis. AB - OBJECTIVE: To explore the correlation between liver iron overload and bone mineral density (BMD) in an ovariectomy (OVX) rat model, using liver magnetic resonance (MR)-T2* and dual-energy X-ray absorptiometry (DEXA). METHODS: Sprague Dawley rats received deferoxamine (DFO) or phosphate-buffered saline 3 months after bilateral OVX. MRI and DEXA were performed pre- and postoperatively. Five rats per group were killed every month for micro-CT, histopathology and biochemical examinations. Statistical analysis was performed with independent samples t tests, box plots and Pearson's correlation analysis. RESULTS: At 2 months postoperatively, BMD was significantly lower in the OVX group than in the control group (P < 0.01), corresponding to the increased serum ferritin concentration (SFC; P < 0.01) and liver iron concentration (LIC; P < 0.01). Liver T2* values significantly differed between the two groups at 1 month postoperatively (P < 0.001) and improved 1 month after DFO injection (P < 0.05). These values were significantly and positively correlated with BMD in the control (r = 0.527, P < 0.001) and OVX (r = 0.456, P < 0.001) groups. CONCLUSION: Liver MRI T2* changed markedly earlier than BMD, LIC and SFC, and correlated well with osteoporosis; it may thus be a valuable early indicator of osteoporosis. KEY POINTS: * Iron overload plays a vital role in the pathogenesis of postmenopausal osteoporosis. * Liver T2* relaxation time is a sensitive value in reflecting iron overload. * Liver T2* mapping elucidates changes in postmenopausal osteoporosis earlier than BMD. * Iron chelation increases BMD in ovariectomized rats. * Liver T2* has a moderate positive correlation with BMD. PMID- 24770555 TI - Tailoring entanglement through domain engineering in a lithium niobate waveguide. AB - We propose to integrate the electro-optic (EO) tuning function into on-chip domain engineered lithium niobate (LN) waveguide. Due to the versatility of LN, both the spontaneously parametric down conversion (SPDC) and EO interaction could be realized simultaneously. Photon pairs are generated through SPDC, and the formation of entangled state is modulated by EO processes. An EO tunable polarization-entangled photon state is proposed. Orthogonally-polarized and parallel-polarized entanglements of photon pairs are instantly switchable by tuning the applied field. The characteristics of the source are theoretically investigated showing adjustable bandwidths and high entanglement degrees. Moreover, other kinds of reconfigurable entanglement are also achievable based on suitable domain-design. We believe tailoring entanglement based on domain engineering is a very promising solution for next generation function-integrated quantum circuits. PMID- 24770556 TI - Optimizing success with lumbar disc arthroplasty. AB - PURPOSE: This study aimed at determining the variables that may prove useful in predicting clinical outcomes following lumbar disc arthroplasty. METHODS: Pre- and post-operative imaging assessments were obtained for 99 single-level lumbar disc arthroplasty patients from a prospective IDE study. The assessments and patient demographics were tested to identify variables that were significantly associated with clinical outcomes. RESULTS: Clinical outcome data were available for 85 % of patients at the 5-year follow-up. Numerous assessments made from the pre-operative imaging were found to have statistically significant associations with clinical outcomes at 2 and 5 years. The most notable factors were related to the amount of degeneration at the index level, with patients achieving better outcome scores at 5 years if they have higher grades of degeneration preoperatively. CONCLUSIONS: Several variables may prove effective at optimizing clinical outcomes including a preoperative disc height <8 mm, Modic type 2 changes adjacent to the target disc, a low amount of lordosis present at the treatment level, low levels of fatty replacement of the paraspinal musculature, a prominent amount of facet joint or disc degeneration, and the presence of flat or convex vertebral endplates. There were also post-operative findings associated with better patient outcomes including a larger percent of the endplate covered with the implant, larger implant heights, greater increases in disc space heights, and a larger increase in index level lumbar lordosis. These variables could be explored in other clinical studies to facilitate meta-analyses that could identify effective strategies to optimize clinical outcomes with lumbar disc arthroplasty. PMID- 24770557 TI - Modified Augmented Renal Clearance score predicts rapid piperacillin and tazobactam clearance in critically ill surgery and trauma patients. AB - BACKGROUND: Recent evidence suggests that current antimicrobial dosing may be inadequate for some critically ill patients. A major contributor in patients with unimpaired renal function may be Augmented Renal Clearance (ARC), wherein urinary creatinine clearance exceeds that predicted by serum creatinine concentration. We used pharmacokinetic data to evaluate the diagnostic accuracy of a recently proposed ARC score. METHODS: Pharmacokinetic data from trauma/surgical intensive care unit patients receiving piperacillin/tazobactam were evaluated. We combined intermediate scores (4-6 points) into a single low score (<=6) group and compared pharmacokinetic parameters against the high (>=7) ARC score group. Diagnostic performance was evaluated using median clearance and volume of distribution, area under the antibiotic time-concentration curve (AUC), and achievement of free concentrations greater than a minimum inhibitory concentration (MIC) of 16 MUg/mL for at least 50% of the dose interval (fT > MIC >= 50%). Alternative dosing strategies were explored in silico. RESULTS: The ARC score was 100% sensitive and 71.4% specific for detecting increased clearance, increased volume of distribution, decreased AUC, and fT > MIC < 50% at an MIC of 16 MUg/mL. The area under the receiver operating characteristic curve was 0.86 for each, reflecting a high degree of diagnostic accuracy for the ARC score. Serum creatinine less than 0.6 mg/dL had comparable specificity (71.4%) but was less sensitive (66.7%) and accurate (area under the receiver operating characteristic curve, 0.69) for detecting higher clearance rates. Monte Carlo pharmacokinetic simulations demonstrated increased time at therapeutic drug levels with extended infusion dosing at a drug cost savings of up to 66.7% over multiple intermittent dosing regimens. CONCLUSION: Given its ability to predict antimicrobial clearance above population medians, which could compromise therapy, the ARC score should be considered as a means to identify patients at risk for subtherapeutic antibiotic levels. Adequately powered studies should prospectively confirm the utility of the ARC score and the role of antimicrobial therapeutic drug monitoring in such patients. LEVEL OF EVIDENCE: Diagnostic tests, level III. PMID- 24770558 TI - Hemoglobin-based oxygen carriers: an update on their continued potential for military application. PMID- 24770559 TI - Early identification of uncontrolled hemorrhage after trauma: current status and future direction. PMID- 24770560 TI - Evaluation of standard versus nonstandard vital signs monitors in the prehospital and emergency departments: results and lessons learned from a trauma patient care protocol. AB - BACKGROUND: This study aimed to determine the effectiveness of using a wireless, portable vital signs monitor (WVSM) for predicting the need for lifesaving interventions (LSIs) in the emergency department (ED) and use a multivariate logistic regression model to determine whether the WVSM was an improved predictor of LSIs in the ED over the standard of care monitor currently being used. METHODS: This study analyzed 305 consecutive patients transported from the scene via helicopter to a Level I trauma center. For 104 patients in the study, a WVSM was also attached to the patient's arm and used to record and display prehospital and hospital physiologic data in real time on a handheld computer and in the trauma bay. Multivariate logistic regression analyses were performed for accuracy in predicting needs for LSIs in control and WVSM subjects. In addition, receiver operating characteristic curves were obtained to examine the discriminating power of the models for the outcome of one or more LSIs in the ED. RESULTS: Of the 305 patients, 73 underwent 109 LSIs in the ED. Of these, 21 patients wore the WVSM during transport in addition to the standard monitor. Logistic regression analysis revealed that heart rate, respiratory rate, and systolic blood pressure were significantly associated with an increased risk for LSIs in the ED (p < 0.05). Receiver operating characteristic curve analysis also demonstrated better prediction for LSIs performed in the ED in WVSM subjects than in control subjects (area under the curve, 0.86 vs. 0.81, respectively). CONCLUSION: The WVSM system leads to improved LSI accuracy in the ED. In addition, many important lessons have been learned in preparation for this study. Adoption of nonstandard vital signs monitors into critical care/trauma medicine may require a new paradigm of personnel education, training, and practice. LEVEL OF EVIDENCE: Therapeutic/care management, level IV. PMID- 24770561 TI - Molecular structure and stability of dissolved lithium polysulfide species. AB - The ability to predict the solubility and stability of lithium polysulfide is vital in realizing longer lasting lithium-sulfur batteries. Herein we report combined experimental and computational analyses to understand the dissolution mechanism of lithium polysulfide species in an aprotic solvent medium. Multinuclear NMR, variable temperature ESR and sulfur K-edge XAS analyses reveal that the lithium exchange between polysulfide species and solvent molecules constitutes the first step in the dissolution process. Lithium exchange leads to de-lithiated polysulfide ions (Sn(2-)) which subsequently form highly reactive free radicals through dissociation reaction (Sn(2-) -> 2Sn/2(-)). The energy required for the dissociation and possible dimer formation reactions of the polysulfide species is analyzed using density functional theory (DFT) based calculations. Based on these findings, we discuss approaches to optimize the electrolyte in order to control the polysulfide solubility. PMID- 24770562 TI - Solubility and dissolution enhancement of tadalafil using self-nanoemulsifying drug delivery system. AB - The aim of this study was to develop and evaluate self-nanoemulsifying drug delivery system (SNEDDS) of tadalafil (TDL) in order to enhance its aqueous solubility and dissolution rate. TDL SNEDDS were developed by aqueous phase titration method via construction of pseudo-ternary phase diagrams. The formulations which passed thermodynamic stability and self-nanoemulsification tests were further characterized in terms of droplet size, viscosity, % transmittance and drug content. Selected SNEDDS and drug suspension were subjected to in vitro drug release studies via dialysis membrane in phosphate buffer (pH 6.8). In vitro drug release studies showed 96.6% release of TDL from optimized SNEDDS F5 as compared to only 12.4% from drug suspension after 24 h of study. The results of solubility studies showed 1434 folds enhancement in TDL solubility from optimized SNEDDS F5 as compared to its aqueous solubility. Overall, these results indicated that developed SNEDDS could be successfully used to enhance solubility and dissolution rate of poorly soluble drugs such as TDL. PMID- 24770563 TI - Fabrication of sub-20 nm nano-gap structures through the elastomeric nano-stamp assisted secondary sputtering phenomenon. AB - We describe a highly efficient method for fabricating controllable and reliable sub-20 nm scale nano-gap structures through an elastomeric nano-stamp with an embedded ultra-thin pattern. The stamp consists of ultrahigh resolution (approximately 10 nm) and high aspect ratio (ca. 15) metal nano-structures, which are obtained by secondary sputtering lithography (SSL). The nano-gap structures fabricated in this fashion achieve a high resolution and meet the requirements of minimal cost, high reliability, controllability, reproducibility, and applicability to different materials. Further, we demonstrate that this method enables the fabrication of SERS substrates for detection at the single-molecule level. PMID- 24770564 TI - Catalysis of diazoalkane-carbonyl homologation. How new developments in hydrazone oxidation enable the carbon insertion strategy for synthesis. AB - Diazo compounds continue both to challenge and to fascinate practitioners of chemical synthesis. The most strategically powerful and unique type of reactivity observed with these reagents is a formal insertion of the donor-acceptor carbon into C-C or C-H bonds alpha to carbonyl groups. Although the reaction does not involve discrete carbon-metal bonds, it can be catalyzed by metal-based Lewis acids. This chapter investigates both classical and modern developments in diazoalkyl carbon insertion with a special emphasis on nonstabilized nucleophiles. PMID- 24770565 TI - Synthetic molecular walkers. AB - In biological systems, molecular motors have been developed to harness Brownian motion and perform specific tasks. Among the cytoskeletal motor proteins, kinesins ensure directional transport of cargoes to the periphery of the cell by taking discrete steps along microtubular tracks. In the past decade there has been an increasing interest in the development of molecules that mimic aspects of the dynamics of biological systems and can became a starting point for the creation of artificial transport systems.To date, both DNA-based and small molecule walkers have been developed, each taking advantage of the different chemistries available to them. DNA strollers exploit orthogonal base pairing and utilize strand-displacement reactions to control the relative association of the component parts. Small-molecule walkers take advantage of the reversibility of weak noncovalent interactions as well as the robustness of dynamic covalent bonds in order to transport molecular fragments along surfaces and molecular tracks using both diffusional processes and ratchet mechanisms. Here we review both types of synthetic systems, including their designs, dynamics, and how they are being used to perform functions by controlled mechanical motion at the molecular level. PMID- 24770566 TI - Misinterpretation of trial evidence on statin adverse effects may harm patients. PMID- 24770567 TI - Successful domino liver transplantation in maple syrup urine disease using a related living donor. AB - Maple syrup urine disease (MSUD) is an autosomal recessive disease associated with high levels of branched-chain amino acids. Children with MSUD can present severe neurological damage, but liver transplantation (LT) allows the patient to resume a normal diet and avoid further neurological damage. The use of living related donors has been controversial because parents are obligatory heterozygotes. We report a case of a 2-year-old child with MSUD who underwent a living donor LT. The donor was the patient's mother, and his liver was then used as a domino graft. The postoperative course was uneventful in all three subjects. DNA analysis performed after the transplantation (sequencing of the coding regions of BCKDHA, BCKDHB, and DBT genes) showed that the MSUD patient was heterozygous for a pathogenic mutation in the BCKDHB gene. This mutation was not found in his mother, who is an obligatory carrier for MSUD according to the family history and, as expected, presented both normal clinical phenotype and levels of branched-chain amino acids. In conclusion, our data suggest that the use of a related donor in LT for MSUD was effective, and the liver of the MSUD patient was successfully used in domino transplantation. Routine donor genotyping may not be feasible, because the test is not widely available, and, most importantly, the disease is associated with both the presence of allelic and locus heterogeneity. Further studies with this population of patients are required to expand the use of related donors in MSUD. PMID- 24770568 TI - Liver cancer stem cells are selectively enriched by low-dose cisplatin. AB - Accumulating evidence has indicated the importance of cancer stem cells in carcinogenesis. The goal of the present study was to determine the effect of low dose cisplatin on enriched liver cancer stem cells (LCSCs). Human hepatoblastoma HepG2 cells were treated with concentrations of cisplatin ranging from 1 to 5 MUg/mL. Cell survival and proliferation were evaluated using a tetrazolium dye (MTT) assay. LCSCs were identified using specific markers, namely aldehyde dehydrogenase-1 (ALDH1) and CD133. The percentage of ALDH1+ or CD133+ cells was examined by flow cytometric analysis. The expression of ALDH1 and/or CD133 in HepG2 cells was determined by immunocytochemical analysis. Low-dose cisplatin treatment significantly decreased cell survival in HepG2 cells after 24 or 72 h. However, the percentage of LCSCs in the surviving cells was greatly increased. The percentage of ALDH1+ or CD133+ cells was increased in a time- and dose dependent manner after treatment with 1-4 MUg/mL cisplatin, whereas 5 MUg/mL cisplatin exposure slightly reduced the number of positive cells. These findings indicate that low-dose cisplatin treatment may efficiently enrich the LCSC population in HepG2 cells. PMID- 24770569 TI - Long-term (4 years) results of choroidal hemangioma treated with proton beam irradiation. AB - BACKGROUND: The aim of this retrospective study was to determine the efficacy of proton beam irradiation in choroidal hemangioma in a long-term follow-up. PATIENTS AND METHODS: A total dose of 20 Cobalt Gray equivalent (CGE) was administered to 50 eyes of 50 patients from September 1998 to September 2010. All treated patients presented with a symptomatic tumor. Nine patients were pre treated by photodynamic therapy (PDT). Visual outcome, tumor regression, and complications resulting from radiation were investigated. RESULTS: The mean follow-up was 55.4 months (range 13-132). Tumor thickness decreased in all patients. Retinal re-attachment was achieved without evidence of tumor leakage. Visual acuity improved by two lines after one year in 43.4 % of patients and after two years in 36.8 % of patients. During the 55.4 months of long-term follow up the visual acuity improved from 6/15 to 6/12 after proton therapy. Twenty three patients (46.0 %) developed radiation retinopathy. According to the Finger classification of 2004, 21 patients (42.0 %) showed a stage 1 or 2 (functionally not relevant) retinopathy, and two patients (4.0 %) presented a stage 3 or 4 (functionally relevant) retinopathy. Further complications included sicca syndrome in nine cases, cataract formation in 10 cases, and radiation optic neuropathy in four cases. CONCLUSION: Proton therapy with 20 CGE is an efficient primary therapy in choroidal hemangioma and is very effective as a secondary treatment after PDT. PMID- 24770570 TI - [The Italian edition of DSM-5]. PMID- 24770571 TI - [The Stendhal syndrome between psychoanalysis and neuroscience]. AB - The Stendhal Syndrome was proposed in 1977 by the Florentine psychiatrist Graziella Magherini who observed and described an acute and unexpected psychiatric breakdown among tourists exposed to artworks. AIM: The aim of the present study is to evaluate whether the Stendhal Syndrome has achieved a solid scientific validity any years after its first description. The relationship between art and psychopathology is evaluated within a modern neurobiological perspective, also taking into account the recent neuroaesthetic theories. METHOD: An updated review of the current literature was conducted in order to compare the psychological and neurobiological perspectives. RESULTS: There are suggestions that specific cerebral areas are activated while observing an artwork. CONCLUSIONS: There is no scientific evidence to define the Stendhal Syndrome as a specific psychiatric disorder; on the other hand there is evidence that the same cerebral areas involved in emotional reactions are activated during the exposure to artworks. PMID- 24770572 TI - [Can we draw an identikit of cannabis smokers who may be at higher risk of developing a psychosis?]. AB - PURPOSE: The purpose of this review is to identify somatic and environmental factors, which make some people more at risk of developing psychosis in connection with the use of cannabis. METHODS: Were selected in PubMed studies of the last 20 years that have assessed the main factors of vulnerability to psychosis (premorbid personality, family history of psychosis, gender, genetic predisposition, adolescence, childhood trauma, use of other substances, social context, use of internet) and the additive effect of cannabis use. RESULTS: From the literature the existence of a subgroup of subjects prone to the development of psychotic disorders emerges with good evidence, which is characterized by features such as: male gender, premorbid schizotypal personality traits, early use of cannabis in adolescence, family history of psychiatric illness, personal history of abuse and childhood trauma, tendency to social anxiety. The evidences about a genetic predisposition are scarce, and there are few studies in this regard; there is a growing interest in internet addiction and its relationship with drug addiction. CONCLUSIONS: Despite the paucity of studies on the vulnerability to psychosis and the additive effect of cannabis use, the topic is of considerable interest, especially for the purpose of sound clinical practice aimed at preventon of psychiatric disorders, and for the correct address of social policies on the use of substances. PMID- 24770573 TI - Cognitive functioning and insight in schizophrenia and in schizoaffective disorder. AB - AIM: The aim of this study was to investigate cognitive functioning and insight of illness in two groups of patients during their stable phases, one with schizophrenia and one with schizoaffective disorder. METHODS: We recruited 104 consecutive outpatients, 64 with schizophrenia, 40 with schizoaffective disorder, in the period between July 2010 and July 2011. They all fulfilled formal Diagnostic and Statistical Manual of Mental disorders (DSM-IV-TR) diagnostic criteria for schizophrenia and schizoaffective disorder. Psychiatric assessment included the Clinical Global Impression Scale-Severity (CGI-S), the Positive and Negative Sindrome Scale (PANSS), the Calgary Depression Scale for Schizophrenia (CDSS) and the Global Assessment of Functioning (GAF). Insight of illness was evaluated using SUMD. Neuropsychological assessment included Winsconsin Card Sorting Test (WCST), California Verbal Learning Test (CVLT), Stroop Test and Trail Making Test (TMT). Differences between the groups were tested using Chi square test for categorical variables and one-way analysis of variance (ANOVA) for continuous variables. All variables significantly different between the two groups of subjects were subsequently analysed using a logistic regression with a backward stepwise procedure using diagnosis (schizophrenia/schizoaffective disorder) as dependent variable. RESULTS: After backward selection of variables, four variables predicted a schizoaffective disorder diagnosis: marital status, a higher number of admission, better attentive functions and awareness of specific signs or symptoms of disease. The prediction model accounted for 55% of the variance of schizoaffective disorder diagnosis. DISCUSSION: With replication, our findings would allow higher diagnostic accuracy and have an impact on clinical decision making, in light of an amelioration of vocational functioning. PMID- 24770574 TI - Seizure threshold variations in ECT-treated chronic patients with schizophrenia: a brief report. AB - Seizure threshold (ST) is a parameter that differs in each person and can be modified both spontaneously and because of drug intake and/or other exogenous factors. A rise in ST during a course of electroconvulsive therapy (ECT) has been demonstrated in patients with depression and mania, but little information has been available as to whether the same result occurs in schizophrenia (SCZ). 11 male patients underwent estimation of the seizure threshold over a bilateral ECT course. Mean ST changed not significantly. No correlations were found between baseline ST and Positive and Negative Syndrome Scale (PANSS) scores. A significant positive correlation emerged between baseline ST and the variation of Hamilton Depression Rating Scale (HDRS) total and cognitive scores. The results suggest that ST in SCZ patients is not related to baseline psychopathological features, it is not related to clinical improvements of negative or positive SCZ symptoms and it does not change during the ECT course but it appears predictive of the improvement of affective and cognitive symptmos. PMID- 24770575 TI - Pathological gambling and impulsivity: an Italian study. AB - AIM: Although the precise nature of pathological gambling (PG) is still elusive, currently it is considered an impulse-control disorder that shares several features with substance dependence, such as deficit in self-regulation and impaired impulsivity. The aim of this study was to evaluate the impulsivity of PG patients by means of the Barratt Impulsivity Scale, version 11 (BIS-11), as compared with healthy control subjects, and to explore the possible correlations with gambling severity. METHODS: Thirty-five outpatients (all men) with a diagnosis of PG were recruited at their first psychiatric interview in a psychiatric outpatient ward, and compared with a similar group of healthy control subjects. The severity of PG was assessed by means of the South Oaks Gambling Screen (SOGS). RESULTS: The results showed that the BIS-11 total score, as well as the scores of different factors (motor impulsity and cognitive complexity) and subscales (motor and non-planning impulsivity) were significantly higher in PG patients than in control subjects. In addition, positive correlations were detected between the SOGS and the BIS-11 total scores, and the attention and cognitive instability factor scores, or the attentional and motor impulsivity (rs=0.459, p=.021) subscale scores. CONCLUSIONS: These findings support the notion that impulsivity represents a core element of PG linked to the severity of the clinical picture. PMID- 24770576 TI - Dandy-Walker syndrome with psychotic symptoms: a case report. AB - Here we report the case of a patient with psychotic symptoms apparently resistant to antipsychotic treatments. Since the last admission in a psychiatric division the patient was diagnosed with Bipolar Disorder type I and then referred to our Outpatients Unit of Treatment Resistant Psychosis, where she was subsequently re diagnosed with Dandy-Walker Syndrome. The Dandy Walker Complex is a congenital brain malformation involving the fourth ventricle and the cerebellum. We investigated the cognitive impairment of the patient and found deficits prominently in executive functions. This report may add further evidence on the importance of a correct diagnosis prior to defining a patient as treatment resistant and highlights cerebellar dysfunctions that may contribute to neuropsychiatric symptoms and cognitive impairment. PMID- 24770577 TI - "Legal highs": safe and legal "heavens"? A study on the diffusion, knowledge and risk awareness of novel psychoactive drugs among students in the UK. AB - BACKGROUND: The recent emergence of new recreational drugs, combined with the ability of the Internet to disseminate information quickly, have raised a number of concerns in the fields of drug policy, substance use research, and public health. METHODS: A semi-structured questionnaire was advertised on The Study Room's website from November to December 2010 to explore the awareness, the use and the perception of risks of "legal highs" among student population in the UK. RESULTS: One-third (31.40%) of the 446 participants reported use of these kinds of drugs. Respondents were more likely to have taken were: mephedrone (41.4%), Salvia divinorum (20%), "Spice drugs" (10.7%), methylone (1.4%), naphyrone (NRG) (2.1%) and benzylpiperazine (BZP) (2.1%), while 15.7% did not know what compounds they had ever consumed. The large majority (78.9%) considered these as legal substances, while 74.2% did not consider these safer than illicit drugs. Half (50.8%) of the respondents were aware of the presence of illegal agents in the products they had consumed. CONCLUSIONS: The study contributes to an initial assessment of the use and the risks awareness of novel psychoactive compounds among students in the UK. Further research is required, especially in terms of personality and lifestyle attitudes to better profile these new forms of abuse also in non-recreational settings. PMID- 24770578 TI - [Mental disorders and creativity]. PMID- 24770580 TI - Parental practices encouraging and discouraging physical activity in Hong Kong Chinese preschoolers. AB - BACKGROUND: Regular participation in physical activity (PA) can help reduce the risk of overweight/obesity. Parental practices related to PA are modifiable determinants of preschoolers' PA that are still not well understood, especially in non-Western cultures. This qualitative explorative study aimed to identify parental practices encouraging or discouraging PA in Hong Kong preschoolers. METHODS: Nominal Group Technique (NGT) sessions (n = 45; 6 to 9/group), complemented by a focus group (n = 6) and individual interviews (n = 12), were conducted with primary caregivers (mainly parents) of Hong Kong preschoolers to investigate what parents do to encourage (4 groups) and discourage (2 groups) PA in children. The groups were stratified by low and high neighborhood socioeconomic status. RESULTS: Participants generated 21 and 16 items describing practices encouraging and discouraging preschoolers' PA, respectively. Parental provision of instrumental, motivational, and conditional support were thought to encourage child's PA, while parental safety concerns, focus on academic achievement, lack of time and resources, and promotion of sedentary behaviors were thought to discourage child's PA. CONCLUSIONS: Several parental practices that were deemed to encourage or discourage Hong Kong preschoolers' PA were identified. These can assist with development of a culturally sensitive scale of PA parenting practices and inform future quantitative research. PMID- 24770581 TI - Process evaluation of European 'Healthy Stadia' program. AB - Healthy Stadia (HS) is a European public health pilot-program started in 2007 to support sports stadia in promoting the health of people who work and visit sports stadia, as well as inhabitants of the surrounding communities. The aim of this study is to describe the process evaluation of the program, from its beginning in July 2007 to December 2009, in order to assess the feasibility and sustainability of an HS network across Europe. The program involved nine associate partners involved in the coordination of activities at a local level, in the recruitment of stadia, in the development of specific program tasks and in the dissemination of the program at a national level. The activities of associate partners were evaluated through structured questionnaires administered every 6 months. The questionnaire response rate from associate partners was 77.8% for the first and third evaluations and 88.9% for the second and fourth evaluations. According to the evaluation's results, several good practices such as alcohol prevention policies and those supporting people with disabilities were implemented in stadia over the course of the program. Conversely, practices supporting mental health and green transport were generally not achieved. The implemented activities mainly involved staff and visitors. Lack of human and economic resources, especially toward the end of the program, was considered the principal challenge for program development. In conclusion, the process evaluation presented the feasibility of the HS program and the development of health promoting practices in sport stadia over time. PMID- 24770582 TI - Sorafenib enhances effects of transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis. AB - BACKGROUND AND AIM: Combination therapy of sorafenib and transarterial chemoembolization (TACE) showed benefits for hepatocellular carcinoma (HCC). This systematic review aims for evaluation of efficacy and safety between sorafenib plus TACE and TACE alone for HCC. METHODS: We systematically searched multi databases to identify eligible studies. Studies comparing sorafenib combined with TACE and TACE alone for HCC were included. RESULTS: Nine studies with 900 patients (sorafenib + TACE = 446, TACE = 454) were finally included. Sorafenib combined with TACE significantly reduced 6-month mortality [OR 0.24, 95 % confidential interval (CI) 0.09-0.68, P = 0.007] and 1-year mortality (OR 0.35, 95 % CI 0.21-0.56, P < 0.0001), but did not decrease 2-year mortality (OR 0.58, 95 % CI 0.14-2.46, P = 0.46). Although combination therapy tend to reduce 3-month (OR 0.76, 95 % CI 0.52-1.10, P = 0.15) and 6-month progression free rate (OR 0.27, 95 % CI 0.07-1.05, P = 0.06), the changes were not significant. Additionally, objective response ratio (OR 0.39, 95 % CI 0.19-0.78, P = 0.008) and clinical benefit ratio (OR 0.27, 95 % CI 0.15-0.50, P < 0.0001) also favored for combination therapy, which, however, caused higher morbidity, especially hand foot skin reaction (OR 53.71, 95 % CI 28.86-99.93, P < 0.00001), hematological events (OR 14.8, 95 % CI 6.07-36.07, P < 0.00001), diarrhea (OR 6.62, 95 % CI 3.82-11.45, P < 0.00001), hypertension (OR 5.03, 95 % CI 3.02-8.38, P < 0.00001), rash/desquamation (OR 5.67, 95 % CI 3.58-8.99, P < 0.00001), and fatigue (OR 2.5, 95 % CI 1.09-5.72, P = 0.03). CONCLUSION: Combination of sorafenib and TACE showed survival and clinical benefits in patients with HCC, though enhanced morbidity. PMID- 24770583 TI - Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity. AB - DNA damage recognition subunits such as DDB2 and XPC protect the human skin from ultraviolet (UV) light-induced genome instability and cancer, as demonstrated by the devastating inherited syndrome xeroderma pigmentosum. Here we show that the beneficial DNA repair response triggered by these two genome caretakers critically depends on a dynamic spatiotemporal regulation of their homeostasis. The prolonged retention of DDB2 and XPC in chromatin, because of a failure to readily remove both recognition subunits by the ubiquitin-dependent p97/VCP/Cdc48 segregase complex, leads to impaired DNA excision repair of UV lesions. Surprisingly, the ensuing chromosomal aberrations in p97-deficient cells are alleviated by a concomitant downregulation of DDB2 or XPC. Also, genome instability resulting from an excess of DDB2 persisting in UV-irradiated cells is prevented by concurrent p97 overexpression. Our findings demonstrate that DNA damage sensors and repair initiators acquire unexpected genotoxic properties if not controlled by timely extraction from chromatin. PMID- 24770584 TI - Sequencing and annotated analysis of full genome of Holstein breed bull. AB - In the present study, we describe the deep sequencing and structural analysis of the Holstein breed bull genome. Our aim was to receive a high-quality Holstein bull genome reference sequence and to describe different types of variations in its genome compared to Hereford breed as a reference. We generated four mate paired libraries and one fragment library from 30 MUg of genomic DNA. Colour space fasta were mapped and paired to the reference cow (Bos taurus) genome assembly from Oct. 2011 (Baylor 4.6.1/bosTau7). Initial sequencing resulted in the 4,864,054,296 of 50-bp reads. Average mapping efficiency was 71.7 % and altogether 3,494,534,136 reads and 157,928,163,086 bp were successfully mapped, resulting in 60 * coverage. This is the highest coverage for bovine genome published so far. Tertiary analysis found 6,362,988 SNPs in the bull's genome, 4,045,889 heterozygous and 2,317,099 homozygous variants. Annotation revealed that 4,330,337 of all discovered SNPs were annotated in the dbSNP database (build 137) and therefore 2,032,651 SNPs were novel. Large indel variations accounted for the 245,947,845 bp of the variation in entire genome and their number was 312,879. We also found that small indels (number was 633,310) accounted for the total variation of 2,542,552 nucleotides in the genome. Only 106,768 small indels were listed in the dbSNP. Finally, we identified 2,758 inversions in the genome of the bull covering in total 23,099,054 bp of genome's variation. The largest inversion was 87,440 bp in size. In conclusion, the present study discovered different types of novel variants in bull's genome after high-coverage sequencing. Better knowledge of the functions of these variations is needed. PMID- 24770586 TI - Improving population health one person at a time? Accountable care organisations: perceptions of population health--a qualitative interview study. AB - OBJECTIVE: This qualitative interview study explored perceptions of the phrases 'population health', 'public health' and 'community health'. SETTING: Accountable care organisations (ACOs), and public health or similar agencies in different parts of the USA. PARTICIPANTS: Purposive sample of 29 interviewees at four ACOs, and 10 interviewees at six public health or similar agencies. RESULTS: Interviewees working for ACOs most often viewed 'population health' as referring to a defined group of their organisation's patients, though a few applied the phrase to people living in a geographical area. In contrast, interviewees working for public health agencies were more likely to consider 'population health' from a geographical perspective. CONCLUSIONS: Conflating geographical population health with the health of ACOs' patients may divert attention and resources away from organisations that use non-medical means to improve the health of geographical populations. As ACOs battle to control costs of their population of patients, it would be more accurate to consider using a more specific phrase, such as 'population of attributed patients', to refer to ACOs' efforts to care for the health of their defined group of patients. PMID- 24770585 TI - Linking cellular zinc status to body weight and fat mass: mapping quantitative trait loci in Znt7 knockout mice. AB - Zinc transporter 7 (Znt7, Slc30a7) knockout (KO) mice display abnormalities in body weight gain and body adiposity. Regulation of body weight and body fat accumulation is complex, involving multiple genetic and environmental factors. To understand how zinc homeostasis influences body weight and fat deposit and to identify quantitative trait loci (QTLs) that link zinc metabolism to growth and adiposity, we conducted a genome-wide mapping study using male F2 Znt7 KO mice and wild-type (WT) littermates with a mixed 129P1/ReJ and C57BL/6J genetic background. The mice were fed a semi-purified diet containing 30-mg Zn/kg diet at weaning. Body weights and fat pad weights including epididymal, retroperitoneal, and femoral subcutaneous fat pads were measured at 16 weeks of age. We detected two significant QTLs (p < 0.05) for body weight and fat deposit. One was in the F2 Znt7 KO population and the other in the F2 WT population. In Znt7 KO mice, the body weight and fat deposit was significantly linked to a locus on chromosome 7 ranging from 64.3 to 78.3 Mb. In WT mice, a significant linkage of retroperitoneal fat mass was found on chromosome 8 between 14.5 and 63.5 Mb. In addition, several other suggestive QTLs (p < 0.63) for body weight and fat accumulation were detected in Znt7 KO and WT mice. In conclusion, the QTLs identified in this study may provide new hints to uncover the genes linking cellular zinc status to growth and body fat accumulation. PMID- 24770587 TI - The art of being healthy: a qualitative study to develop a thematic framework for understanding the relationship between health and the arts. AB - OBJECTIVE: In recent years the health-arts nexus has received increasing attention; however, the relationship is not well understood and the extent of possible positive, negative and unintended outcomes is unknown. Guided by the biopsychosocial model of health and theories of social epidemiology, the aim of this study was to develop a framework pertaining to the relationship between arts engagement and population health that included outcomes, confounders and effect modifiers. A health-arts framework is of value to researchers seeking to build the evidence base; health professionals interested in understanding the health arts relationship, especially those who use social prescribing for health promotion or to complement treatments; in teaching medical, nursing and health science students about arts outcomes, as well as artists and health professionals in the development of policy and programmes. DESIGN: A qualitative study was conducted. Semistructured interviews were analysed thematically. SETTING: Western Australia. PARTICIPANTS: 33 Western Australian adults (18+ years). Participants were randomly selected from a pool of general population nominees who engaged in the arts for enjoyment, entertainment or as a hobby (response rate=100%). RESULTS: A thematic analysis was conducted using QSR-NVivo10. The resulting framework contained seven outcome themes and 63 subthemes. Three themes specifically related to health, that is, mental, social and physical health, while economic, knowledge, art and identity outcomes were classified as health determinants. Within each theme, positive, negative and unintended outcomes (subthemes) were identified and categorised as relating to the individual and/or to the community. A list of confounding and/or effect modifying factors, related to both the arts and health, was identified. CONCLUSIONS: Given the increasing pressure on health resources, the arts have the potential to assist in the promotion of health and healing. This framework expands on current knowledge, further defines the health-arts relationship and is a step towards the conceptualisation of a causal health-arts model. PMID- 24770588 TI - Concealing of facial expressions by a wild Barbary macaque (Macaca sylvanus). AB - Behavioural research on non-vocal communication among non-human primates and its possible links to the origin of human language is a long-standing research topic. Because human language is under voluntary control, it is of interest whether this is also true for any communicative signals of other species. It has been argued that the behaviour of hiding a facial expression with one's hand supports the idea that gestures might be under more voluntary control than facial expressions among non-human primates, and it has also been interpreted as a sign of intentionality. So far, the behaviour has only been reported twice, for single gorilla and chimpanzee individuals, both in captivity. Here, we report the first observation of concealing of facial expressions by a monkey, a Barbary macaque (Macaca sylvanus), living in the wild. On eight separate occasions between 2009 and 2011 an adult male was filmed concealing two different facial expressions associated with play and aggression ("play face" and "scream face"), 22 times in total. The videos were analysed in detail, including gaze direction, hand usage, duration, and individuals present. This male was the only individual in his group to manifest this behaviour, which always occurred in the presence of a dominant male. Several possible interpretations of the function of the behaviour are discussed. The observations in this study indicate that the gestural communication and cognitive abilities of monkeys warrant more research attention. PMID- 24770589 TI - Comparison of the risk of breakage of two kinds of sacroiliac screws in the treatment of bilateral sacral fractures. AB - PURPOSE: This study aimed at comparing the risk of breakage of lengthened sacroiliac screw and ordinary sacroiliac screw for the treatment of bilateral vertical sacral fractures to provide reference for clinical application. METHODS: A finite element model of type C pelvic ring injury (bilateral type Denis II fracture of sacrum) was produced. The bilateral sacral fractures were fixed with lengthened sacroiliac screw and ordinary sacroiliac screw in seven types of models, respectively. The maximal Von Mises stresses and stress distribution of the two kinds of screws in the case of standing on both feet were measured and compared. RESULTS: (1) Whether in lengthened sacroiliac screw or ordinary sacroiliac screw, the maximal Von Mises stress of screw fixation only in S1 segment is the largest, and the maximal Von Mises stress of screw fixation only in S2 segment is minor, and the maximal Von Mises stress of screw fixation in S1 and S2 segments, respectively, is the least. (2) When S1 and S2 were both fixed with ordinary screws, the maximal Von Mises stress of screw in S1 segment is larger than that of S2. When S1 and S2 were both fixed with lengthened screws, the maximal Von Mises stress of screw in S1 segment is similar to that of S2. (3) The maximal Von Mises stresses of bilateral symmetrical screws are similar. (4) When only S1 was fixed, the maximal Von Mises stress of lengthened screw is less than that of ordinary screw. When only S2 was fixed, the maximal Von Mises stress of lengthened screw is larger than that of ordinary screw. When S1 and S2 were both fixed, the maximal Von Mises stress of lengthened screw is slightly less than that of ordinary screw. (5) Whether in lengthened screw or ordinary screw, the stress concentrations all exhibited at the regions of screws corresponding to the sacral fracture regions and the part between sacral bilateral fracture lines. Compared with ordinary screw, the stress distribution in lengthened screw is more homogeneous. Whether in lengthened screw or ordinary screw, the stress distribution of only one sacral segment fixation is more concentrated than that of two sacral segments' fixation. When S1 and S2 were both fixed, the stress distribution of upper screw is more concentrated and that of lower screw is more homogeneous. CONCLUSION: In a finite elements simulated type C pelvic ring disruption (bilateral type Denis II sacral fracture), the breakage risk of screws fixed in double-segment bilaterally symmetrically is low, and the breakage risk of screws fixed in S2 segment is lower than that of S1 segment. The bilaterally symmetrical screw fixation in double-segment is strongly recommended to reduce the breakage risk of screws. In addition, the breakage risk of lengthened screws is lower than that of ordinary screws except when screws are fixed in only S2 segment, which merits attention. PMID- 24770590 TI - CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver. AB - Overdose of acetaminophen (APAP) causes necrosis of centrilobular cells of the liver. Accumulating evidence suggests that innate immune system may contribute to APAP-induced hepatotoxicity. Interaction between RANTES and its receptor C-C chemokine receptor (CCR) 5 is related to recruitment of macrophages to sites of inflammation. In this study, we examined effects of CCR5 deficiency on APAP mediated liver injury by employing CCR5 knockout (KO) mice. CCR5 wild-type (WT) and KO mice received intraperitoneal injection of APAP (300 mg/kg) and were killed 24 h after the injection. Hepatic injury was determined by using histological and biochemical analyses. Intraperitoneal APAP caused the hepatocytic necrosis, as evidenced by hematoxylin and eosin staining and an increase in alanine transaminase and aspartate transaminase levels in serum. Hepatic damage appeared to be larger in CCR5 WT animals compared with KO animals. There were no differences in cytochrome P450 2E1 between CCR5 WT and KO animals suggesting that the resistance of CCR5 KO mice did not come from alterations in APAP metabolism. Infiltration of macrophages into the liver was reduced in CCR5 KO mice, and this was accompanied decreased inflammatory responses. Inhibition of macrophage activity by pretreatment of gadolinium chloride significantly blocked APAP-caused hepatotoxicity. These results indicate that recruitment of macrophage into the inflammatory sites significantly contributes to APAP-mediated hepatocytic death and CCR5 gene deletion protects from APAP-induced liver injury by alleviating macrophage recruitment and inflammatory responses. This study represents a critical role of CCR5 in macrophage infiltration into the liver and subsequent hepatotoxicity upon challenge of APAP. PMID- 24770591 TI - A meta-analysis of olanzapine for the prevention of chemotherapy-induced nausea and vomiting. AB - Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life and is one of the reasons for the discontinuation of treatment. Olanzapine is known as an atypical antipsychotic agent, but it has been reported to be effective in treating refractory CINV due to its broad and potent inhibitory activity at multiple receptors involved in the nausea and vomiting pathways. This study was conducted to assess the efficacy of olanzapine for the prevention of CINV after moderately or highly emetogenic chemotherapy. After a search of Medline (Ovid), PubMed, CNKI, Wanfang and Weipu from 1990 to October 2013, all randomised controlled trials of olanzapine for the prevention of CINV were included in this study. The meta-analysis was performed using RevMan 5.0.19 software. 6 studies involving 726 total patients were included, of which 441 were Chinese oncology patients. We found that for both general populations and Chinese populations, antiemetic regimens including olanzapine are more effective at reducing CINV than regimens that do not include olanzapine, especially in the delayed phase of CINV. PMID- 24770592 TI - Modulation of TMEM16A-channel activity as Ca2+ activated Cl- conductance via the interaction with actin cytoskeleton in murine portal vein. AB - TMEM16A is a major component of Ca(2+)-activated Cl(-) channel (CaCC) conductance in murine portal vein smooth muscle cells (mPVSMCs). Here, the regulation of CaCC activity by the actin cytoskeleton was examined in mPVSMCs. Actin disruption by cytochalasin D did not affect the current density, but increased the deactivation time constant in mPVSMCs. The elongated deactivation was recovered by jasplakinolide. When murine TMEM16A was transfected into HEK293 cells that have a poorly developed actin cytoskeleton, electrophysiological properties of CaCC currents were not changed by cytochalasin D. In conclusion, the CaCC activity in mPVSMCs is modified by the interaction of TMEM16A with abundant actin cytoskeleton. PMID- 24770593 TI - The influence of the Hubbard U parameter in simulating the catalytic behaviour of cerium oxide. AB - The seemingly unique redox and oxygen storage properties of cerium oxide (ceria) lead to broad practical application. However, the theoretical treatment of ceria can be troublesome due to the localised nature of the f-electrons and the self interaction error associated with Density Functional Theory (DFT). DFT + U has been a widely used method to correct for these errors when probing specific physical material properties. However, due to the empirical nature of the U correction it is not immediately obvious that correcting certain bulk properties leads to the correct description of catalytic reactivity at surfaces. We propose an approach to choosing the U parameter using adsorption properties that provides a consistent method to simulate catalytic properties of ceria. We go on to show that combining the derived ceria energetics with those of adsorption at metal surfaces, allow us to construct transition metal-oxide pairings to develop a redox screening model for catalysis. PMID- 24770594 TI - [Preface. Anemia]. PMID- 24770595 TI - Anemia is an important complication in patients with chronic kidney disease. Editorial. PMID- 24770596 TI - [Diagnosis of anemia in patients with chronic kidney disease]. PMID- 24770597 TI - [Monitoring of hematimetric parameters]. PMID- 24770598 TI - [Iron supplementation in anemia treatment]. PMID- 24770599 TI - [Use of erythropoiesis stimulating agents]. PMID- 24770600 TI - [Hemoglobin target range]. PMID- 24770601 TI - [Adjuvant therapy]. PMID- 24770602 TI - [Transfusion]. PMID- 24770603 TI - [Recommendations for anemia treatment in kidney transplant patients]. PMID- 24770604 TI - [Recommendations for anemia treatment in pediatric patients]. PMID- 24770605 TI - Kaempferol attenuates the glutamate-induced oxidative stress in mouse-derived hippocampal neuronal HT22 cells. AB - It is thought that the neuronal cell loss caused by oxidative stress is the primary mechanism underlying the pathogenesis of several neurodegenerative disorders. Glutamate is an endogenous neurotransmitter, but at high concentrations it can act as a neurotoxicant by increasing the intracellular levels of reactive oxygen species (ROS). Therefore, the development of factors that can attenuate glutamate-induced oxidative stress in neuronal cells is a good strategy by which new drugs could be discovered that may treat or prevent neurodegenerative diseases. Here, the neuroprotective effects of kaempferol (KF) isolated from the stems of butterbur (Petasites japonicus) were examined in glutamate-treated hippocampal neuronal cells (HT22). The administration of KF (25 MUM) resulted in a significant increase in cell viability (105.18 +/- 7.48%) compared with the control (100.00 +/- 3.05%), while glutamate (5 mM) reduced cell viability by 39.94 +/- 1.61%. The glutamate-induced calcium (Ca(2+)) influx (1.93 +/- 0.08-fold) was significantly reduced by 0.89 +/- 0.02-fold following the administration of 25 MUM KF. Additionally, when HT22 cells were stressed with excessive glutamate, there was a 3.70 +/- 0.01-fold increase in intracellular ROS generation, even though this was effectively attenuated by KF (25 MUM, 0.72 +/- 0.01-fold). The protective effects of KF in HT22 cells were later confirmed using a lactate dehydrogenase (LDH) assay and a FITC-annexin V/propidium iodide double staining procedure. These findings also revealed that the neuroprotective effects of KF are a result of the regulation of the expression levels of proteins, such as Bcl-2, Bid, apoptosis-inducing factor (AIF), and mitogen-activated protein kinase (MAPK). This is the first report to investigate the neuroprotective influence of KF in glutamate-treated HT22 cells. These data demonstrate that KF may be a useful candidate for pharmacological therapies that can prevent and treat neurodegenerative diseases such as Alzheimer's disease (AD). PMID- 24770606 TI - Primary diffuse leptomeningeal glioneuronal tumors. AB - Diffuse leptomeningeal disseminated glioneuronal tumor (DL-GNT) is a rare brain tumor that presents as a plaque-like subarachnoid tumor, commonly involving the basal cisterns and interhemispheric fissure of children but lacking intraparenchymal tumor. Histologically, the tumors are composed of sheets of monotonous rounded cells. Here, we report three cases of DL-GNTs, focusing on clinicopathologic features. Two patients were adult male, but one patient was child. The patients presented with seizures (n = 1) or headaches (n = 2). In all patients, radiography revealed characteristic leptomeningeal thickening and enhancement with minor superficial parenchymal lesions. All three cases were diffusely positive for both GFAP and synaptophysin, and scattered positive for OLIG2 and NeuN, but negative for IDH-1 (H09). Electron microscopic examination showed astrocytic and neuronal differentiation. The patient with the anaplastic tumor died due to aggressive progression of the tumor, but the remaining two patients were stable without tumor recurrence for 23 and 37 months. Thus, these findings suggest that DL-GNT can occur in both children and adult and both supra- and infra-tentorial leptomeninges. It has unique radiological and histopathological features and biological behavior. Further clinicopathological data with molecular genetic study are required for establishing DL-GNT as a unique entity. PMID- 24770607 TI - CT severity of post-ERCP pancreatitis: results from a single tertiary medical center. AB - PURPOSE: To evaluate the CT severity of post-ERCP pancreatitis (PEP) and determine the association between radiographic and clinical severity. METHODS: There were 1332 patients admitted to the hospital with suspicion for PEP after undergoing ERCP as outpatients over a 10-year period, of whom 84 (6.3%) patients underwent at least one contrast-enhanced CT scan while hospitalized were evaluated. All CT scans were evaluated by two radiologists, and the modified CT severity index (MCTSI) score was calculated. Demographic, clinical, and procedural data as well as clinical severity parameters including systemic inflammatory response syndrome, organ failure, need for ICU, need for intervention, length of hospital stay, and mortality were recorded. Statistical analysis was performed using the chi (2) and Student's t test or ANOVA and logistic regression analysis. RESULTS: Patients were predominantly females (70%) with a mean age of 46.5 years (range 20-86). The most common indication for ERCP was sphincter of Oddi dysfunction. MCTSI was graded as mild in 45 (53.6%), moderate in 36 (42.8%), and severe in 3 (3.6%) patients. The interobserver agreement was excellent (kappa: 0.91, p < 0.0001) for MCTSI. The duration of ERCP (p = 0.005) was the only risk factor for PEP that significantly correlated with the MCTSI score. Increasing MCTSI was significantly associated with hospital length of stay. CONCLUSIONS: PEP is typically a mild disease by radiologic and clinical criteria. Longer duration of ERCP is a risk factor for severe radiologic PEP. Severe radiographic PEP is associated with significantly longer hospital length of stay. PMID- 24770608 TI - Feasible and technical aspects of transcatheter arterial chemoembolization for non-resectable hepatocellular carcinoma using a 3.5-French catheter system. AB - PURPOSE: To evaluate the feasibility and technical aspects of transcatheter arterial chemoembolization (TACE) for non-resectable hepatocellular carcinoma (HCC) using a 3.5-French (Fr) catheter system. METHODS: This study included 328 consecutive cases of HCC among 232 patients who underwent TACE procedures using both a 3.5-Fr catheter system and a microcatheter fitted to a 3.5-Fr system between April 2009 and November 2011. We assessed the ability to reach the catheter into the proper hepatic artery (PHA), main hepatic branch, segmental artery, and subsegmental or sub-subsegmental artery. The feasibility was rated according to the following factors: (1) the number of arteries that could be used to reach the target artery/total number of procedures using the 3.5-Fr system, (2) the rate of successful completion of the procedures without changing over to the 4-Fr system and (3) the reasons for changing over the 4-Fr system. RESULTS: TACE of the PHA (27 sessions), RHA/LHA (103 sessions), segmental (31 sessions), or subsegmental/sub-subsegmental arteries (162 sessions) was performed. The rate of successfully reaching the target artery using the 3.5-Fr system was 93% (306/328 sessions). We were unable to reach the target artery in 22 sessions, including 11/8/3 procedures targeting the sub-subsegmental artery, subsegmental artery, and RHA/LHA, respectively. We changed over to the 4-Fr system in six sessions; therefore, the rate of successful completion of the procedures without changing over to the 4-Fr system was 98% (322/328 sessions). CONCLUSIONS: TACE of the target artery can be successfully performed using the 3.5-Fr system in most patients with HCC. PMID- 24770609 TI - Playground Safety is Associated With Playground, Park, and Neighborhood Characteristics. AB - BACKGROUND: More than 200,000 children each year are treated at emergency departments for injuries occurring on playgrounds. Empirically derived data are needed to elucidate factors associated with playground safety and reduce injury rates. OBJECTIVE: Determine if neighborhood, park and playground characteristics are significantly associated with playground safety. METHODS: A 24-item report card developed by the National Program for Playground Safety was used to assess playground safety at 41 public parks in a small to midsized, Midwestern city. Trained assessors evaluated the parks and playgrounds in June/July and used a standardized method to count the numbers of users. Data from the 2010 U.S. Census were used to describe the neighborhoods surrounding the parks. RESULTS: The average safety score for all playgrounds was 77.4% which denotes acceptable safety levels. However, 17.1% of the playgrounds were potentially hazardous and in need of corrective measures. Playgrounds were safer in neighborhoods with more youth (< 18 years of age) and educated adults and in parks with better quality features. Playgrounds with fewer amenities were relatively less safe. CONCLUSIONS: Park safety levels need to be improved to reduce the risk of physical injuries. Future studies examining cause-effect associations between environmental features and playground safety are warranted. PMID- 24770610 TI - Development of new risk score for pre-test probability of obstructive coronary artery disease based on coronary CT angiography. AB - Existing methods to calculate pre-test probability of obstructive coronary artery disease (CAD) have been established using selected high-risk patients who were referred to conventional coronary angiography. The purpose of this study is to develop and validate our new method for pre-test probability of obstructive CAD using patients who underwent coronary CT angiography (CTA), which could be applicable to a wider range of patient population. Using consecutive 4137 patients with suspected CAD who underwent coronary CTA at our institution, a multivariate logistic regression model including clinical factors as covariates calculated the pre-test probability (K-score) of obstructive CAD determined by coronary CTA. The K-score was compared with the Duke clinical score using the area under the curve (AUC) for the receiver-operating characteristic curve. External validation was performed by an independent sample of 319 patients. The final model included eight significant predictors: age, gender, coronary risk factor (hypertension, diabetes mellitus, dyslipidemia, smoking), history of cerebral infarction, and chest symptom. The AUC of the K-score was significantly greater than that of the Duke clinical score for both derivation (0.736 vs. 0.699) and validation (0.714 vs. 0.688) data sets. Among patients who underwent coronary CTA, newly developed K-score had better pre-test prediction ability of obstructive CAD compared to Duke clinical score in Japanese population. PMID- 24770611 TI - Addressing statin adverse effects in the clinic: the 5 Ms. AB - With the release of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, emphasis has been placed on using evidence-based intensity of therapy to reduce atherosclerotic cardiovascular disease (ASCVD) risk, rather than focusing on goal cholesterol levels. Before initiating therapy, however, it is critical that physicians and patients discuss 4 key topics: (1) the benefit of ASCVD risk reduction, (2) medication adverse effects, (3) drug-drug interactions, and (4) patient preferences. To facilitate discussion of statin adverse effects, we present here an evidence-based review of the 5 Ms of statin adverse effects: metabolism, muscle, medication interactions, major organ effects, and memory. "Metabolism" represents the small risk of new onset diabetes that comes with statins, which is highest in those with diabetes risk factors. "Muscle" requires discussion of the wide range of muscle symptoms that occur with statins but emphasizes that these have been no more prevalent than those experienced with placebo in randomized controlled trials (RCTs). "Medication interactions" emphasize that statins interact with numerous medications. Interaction profiles vary widely between statins, and patients should be made aware of the most common interactions with their prescription. "Major organ effects" prompt the physician to review the possibility of a transient transaminitis as well as the recent observation of rare acute kidney injury with statin use. Both are rare and do not require routine monitoring. Finally, "memory" references the recent observational data suggesting statins may contribute to memory loss and confusion, both of which have not been observed in RCTs and resolve with drug cessation. Reviewing these common effects has the possibility to strengthen the doctor-patient relationship and boost both medication adherence and patient satisfaction. PMID- 24770612 TI - Transport of DNA in hydrophobic microchannels: a dissipative particle dynamics simulation. AB - In this work, we numerically study a new means of manipulating single DNA chains in microchannels. The method is based on the effect of finite slip at hydrophobic walls on the hydrodynamics and, consequently, on the dynamics of the DNA in microchannels. We use dissipative particle dynamics to study DNA transport as a function of chain length and the Reynolds number in two dimensional parallel plate channels. We show how an asymmetric velocity profile in a channel with hydrophobic and hydrophilic walls can be used to manipulate the location of the DNA molecules. Using this effect, we propose a simple arrangement of hydrophobic and hydrophilic strips which can be exploited to separate long and short DNA chains. PMID- 24770614 TI - Early alteration of kidney function in nonuremic type 1 diabetic islet transplant recipients under tacrolimus-mycophenolate therapy. AB - BACKGROUND: Transplant patients on tacrolimus therapy exhibit a reduced glomerular filtration rate (GFR). The type of graft and immune treatment protocol may influence the extent and reversibility of this side effect. METHODS: The present single-center study is conducted in 48 nonuremic type 1 diabetic recipients of an intraportal islet-cell graft under maintenance immunosuppression (IS) with tacrolimus and mycophenolate mofetil. Estimated GFR (eGFR) and albuminuria were followed up to 5 years posttransplantation. RESULTS: Mean eGFR values decreased by 19 mL/min/1.73 m after 1 to 2 weeks of IS (P<0.0001) and then remained stable throughout the complete treatment period. The decrease was related to predose trough tacrolimus concentrations or doses and disappeared upon its discontinuation; it was also associated with the presence of albuminuria at the time of transplantation. Tacrolimus treatment resulted in a reduction of albuminuria; its discontinuation restored albuminuria to the initial levels. CONCLUSIONS: The use of tacrolimus in our islet-cell transplant protocol caused an initial 20% reduction in eGFR, which was reversible following its discontinuation, at least within the 5-year follow-up period. The associated reduction in albuminuria was also reversible, compatible with a tacrolimus induced preglomerular vasoconstriction. These observations support further use of our tacrolimus regimen in this patient population. PMID- 24770613 TI - Association of genetic variants with rapid fibrosis: progression after liver transplantation for hepatitis C. AB - BACKGROUND: Recurrence of hepatitis C, the main indication for liver transplantation in the United States, leads to rapid fibrosis progression and worse outcomes compared to other indications. While clinical variables play a role, they are insufficient to explain all inter-patient variability in posttransplant fibrosis progression. Genetic factors associated with hepatitis C virus (HCV) outcomes have been identified, but limited studies have been conducted in the context of HCV-related liver transplantation. Therefore, the purpose of this study was to examine candidate genes related to the immune response and rate of fibrosis in subjects undergoing liver transplantation for HCV. METHODS: One hundred twelve recipients with detailed posttransplant fibrosis and clinical information were genotyped using 25 single nucleotide variants (SNVs), including five SNVs within the IL28B gene region. Associations between SNVs and rapid fibrosis progression were performed controlling for pertinent clinical variables and haplotype analyses for the IL28B gene were completed. RESULTS: Significant multivariable associations were found for rs8099917 (IL28B), rs1991401 (DDX5), rs4969168 (SOC3), and rs7976497 (MLEC). The minor allele was protective against rapid fibrosis progression for the IL28B SNV (G allele), MLEC SNV (T allele), and DDX5 SNV (G allele). For the SOC3 SNV, the minor allele (A) increased the risk for rapid fibrosis progression. Additionally, two recipient haplotype structures for IL28B were significantly associated with rapid fibrosis progression. CONCLUSIONS: These findings indicate that recipient genetic factors play a role in posttransplant HCV-related fibrosis progression. Molecular studies of these pathways may elucidate the pathogenesis of posttransplant fibrosis progression and provide risk prediction markers. PMID- 24770615 TI - Hypervolemia and blood pressure in prevalent kidney transplant recipients. AB - BACKGROUND: The prevalence and consequences of hypervolemia in kidney transplant recipients (KTRs) have not been investigated. Specifically, its impact on blood pressure (BP) and relationship with N-terminal fragment of prohormone B-type natriuretic peptide (NT-proBNP) are unknown. The objectives of this study were to establish the prevalence of hypervolemia among clinically stable KTRs, investigate the predictors of posttransplant hypervolemia, assess its impact on blood pressure, and determine its relationship with NT-proBNP. METHODS: This single-center cross-sectional study enrolled 123 clinically stable KTRs. Extracellular volume status was determined by multifrequency bioimpedance analysis. Mild and severe hypervolemia were defined as percentage volume expansion of greater than 7% and greater than 15%, respectively. Systolic BP (SBP) and diastolic BP (DBP) were measured, with mean arterial pressure (MAP) calculated. Serum NT-proBNP was quantified using a noncompetitive immunoluminometric assay. Potential demographic, nutritional, and clinical predictors of extracellular volume status, BP, and NT-proBNP levels were assessed. RESULTS: Hypervolemia was present in 30% of KTRs, with 5% classified as severe hypervolemia. Significant predictors of volume expansion were increased sodium intake, advancing age, and reduced fat mass (P<0.01 for all associations). Hypervolemia was the only independent predictor of elevated MAP, SBP, and DBP (P<0.001 for all associations). Raised NT-proBNP levels were independently associated with both hypervolemia (P=0.01) and allograft dysfunction (P=0.03). CONCLUSIONS: Hypervolemia is unexpectedly common among clinically stable KTRs. It is closely associated with elevated BP. The relationship with increased sodium intake signals potential therapeutic focus. Further study is warranted to prospectively investigate objective measures of extracellular volume status among KTRs. PMID- 24770616 TI - The effect of remote ischemic postconditioning on graft function in patients undergoing living donor kidney transplantation. AB - BACKGROUND: We evaluated whether remote ischemic postconditioning (RiPoC) could improve initial graft function in living donor kidney transplantation (KT). METHODS: Patients undergoing living donor KT were randomly assigned to either RiPoC (n=30) or control group (n=30). Immediately after reperfusion in the RiPoC group, three cycles of ischemia and reperfusion, lasting 5 min each, were performed on one upper limb. Renal function was assessed before surgery, 2 hr after surgery, and at 12-hr intervals for 96 hr postsurgery by measuring serum creatinine (sCr) and the estimated glomerular filtration rate (eGFR). Urine output and urine creatinine were assessed until postoperative day 7, and hospital stay and complication rates were compared. RESULTS: The time for sCr to reach 50% of its preoperative level was significantly shorter in the RiPoC group than in the control group [12 (12-24) hr for RiPoC vs. 24 (21-36) hr for the control, P=0.005]. The number of patients whose sCr was reduced by 50% within 24 hr was significantly greater in the RiPoC group than in the control group [n=26 (87%) in RiPoC vs. n=18 (60%) in control, P=0.020]. However, there were no differences in sCr and eGFR thereafter, the incidence of graft dysfunction or complication rates between groups. CONCLUSION: In this study, RiPoC appeared to hasten the recovery of graft function within 24 hr but did not affect the graft function thereafter. However, considering most recipients had immediate graft function, further studies with deceased donors or studies powered to detect a smaller difference are needed. PMID- 24770617 TI - Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients. AB - BACKGROUND: Highly HLA-sensitized (HS) patients have difficulty accessing compatible donors, especially deceased donor (DD) transplants. Desensitization protocols (DES) have evolved, but rigorous evaluation is lacking. Here, we examined the efficacy of rituximab as a DES agent in a placebo-controlled trial. METHODS: Candidates were randomized to IVIG+placebo versus IVIG+rituximab. End points included rates of transplantation, antibody-mediated rejection (ABMR), and renal function. Protocol biopsies were performed at 1 year and analysis of patient and graft survival and donor-specific HLA antibodies (DSA) were performed. RESULTS: Initially, 15 HS DDs were randomized with 13 receiving transplants. However, we discontinued study entry after five serious adverse events were observed. The study was un-blinded and attribution of patients was noted (IVIG+placebo N=7, IVIG+rituximab N=6). No significant differences were seen in DSA levels at transplant. All ABMR episodes occurred in the IVIG+placebo arm and required intense therapy (P=0.06). The two graft losses were in the placebo group. DSA rebound associated with severe ABMR was seen in three patients in the IVIG+placebo group. No rebound was seen in the IVIG+rituximab group. Renal function at 6 and 12 months showed a significant benefit for IVIG+rituximab (P=0.04). CONCLUSIONS: Based on limited assessment with acknowledged limitations, both protocols appear effective in achieving levels of DSA allowable for transplantation. However, IVIG+rituximab appeared more effective in preventing DSA rebound and, more importantly, preventing ABMR and development of transplant glomerulopathy. PMID- 24770618 TI - Hypertension in chronic kidney disease: the influence of renal transplantation. AB - BACKGROUND: Hypertension is one of the most prevalent cardiovascular risk factors in chronic kidney disease (CKD) and kidney transplants. The contribution of transplantation to hypertension in comparison to patients with CKD and similar renal function has not been characterized. METHODS: Ninety-two transplants and 97 CKD patients with an estimated glomerular filtration rate less than 60 mL/min/1.73 m not receiving dialysis were enrolled. At entry, office blood pressure (BP) and 24-hr ambulatory blood pressure monitoring (ABPM) were obtained. RESULTS: Office BP was not different between transplants and CKD patients (139.5+/-14.3 vs. 135.2+/-19.3, P=1.00, respectively). ABPM 24-hr systolic blood pressure (SBP) (133.9+/-14.3 vs. 126.2+/-16.1, P=0.014), awake SBP (135.6+/-15.2 vs. 128.7+/-16.2, P=0.042), and sleep SBP (131.2+/-16.2 vs. 120.2 +/-17.9, P=0.0014) were higher in renal transplants. When patients were classified according to BP patterns associated with highest cardiovascular risk, the proportion of patients with both nocturnal hypertension and non-dipper pattern was higher in transplants (68.5% vs. 47.4%, P=0.03). In the multivariate regression analysis, transplantation was an independent predictor of 24-hr, awake, and sleep SBP. CONCLUSION: Office BP is similar in kidney transplants and CKD patients with similar renal function. On the contrary, hypertension is more severe in kidney transplants when evaluated with ABPM mainly as a result of increased sleep systolic BP. Thus, precise evaluation of hypertension in kidney transplants requires ABPM. PMID- 24770619 TI - Investigation of variant Creutzfeldt-Jakob disease implicated organ or tissue transplantation in the United Kingdom. AB - BACKGROUND: Person-to-person transmission of variant Creutzfeldt-Jakob disease (vCJD) has occurred through blood transfusion and could also theoretically occur as a result of the transplantation of organs or tissues. This study aimed to investigate whether there were transplant-associated vCJD cases in the United Kingdom (UK). METHODS: Medical histories were reviewed for 177 UK vCJD cases to identify situations where the transplantation of organs or tissues might have occurred. A "look-back" was then performed to trace the respective donors or recipients of the implicated organ or tissue. RESULTS: A single patient had undergone an organ (liver) transplant before vCJD onset, from a donor who had died of causes unrelated to vCJD. The look-back was able to trace six other organ or tissue donations made by the same donor. No other situations were identified where the receipt or donation of organs or tissues had occurred in people who went on to develop vCJD. There was considered no need, on this particular occasion, to implement public health measures associated with the organ transplantation, beyond those already in place. CONCLUSIONS: This study provides no evidence of transplant-associated vCJD in the UK. It is, however, important to continue to seek to identify individuals who might be at risk of vCJD by this route so that appropriate public health measures can be implemented. PMID- 24770620 TI - Reduced hepatic arterial perfusion impairs the recovery from focal hepatic venous outflow obstruction in liver-resected rats. AB - BACKGROUND: Extended partial hepatectomy (PH) in patients is leading to portal hyperperfusion but reduced hepatic arterial perfusion (HAP), and is invariably causing focal hepatic venous outflow obstruction (FHVOO). We observed in a rat model that PH in combination with right median hepatic vein ligation (RMHV-L) caused confluent parenchymal necrosis interspersed with viable portal tracts in the obstructed territory and large sinusoidal vascular canals in the border zone. Lack of HAP impaired the spontaneous course of recovery in terms of enlarged parenchymal necrosis, delayed regeneration, and the absence of draining vascular canals. We aimed to investigate whether pharmacological intervention modulates the imbalance between portal venous and hepatic arterial inflow, aggravates the liver damage, and delays the recovery process after FHVOO in liver-resected rats. METHODS: Male Lewis rats were subjected to 70% PH and RMHV-L. Molsidomine or NG nitro-L-arginine methyl ester (L-NAME) or saline were applied daily. Hepatic damage, microcirculation, regeneration, and vascular remodeling were evaluated at postoperative days 1, 2, and 7. Animals subjected to RMHV-L only were used as "no HAP" control. RESULTS: Significant increase of portal venous inflow with a concomitant decrease in HAP was observed in all groups after PH. Molsidomine treatment did neither affect hepatic hemodynamics nor the spontaneous recovery. In contrast, L-NAME treatment further decreased HAP which impaired hepatic microcirculation, aggravated parenchymal damage, decelerated recovery, and impaired the formation of sinusoidal canals. CONCLUSIONS: Reduction of HAP through inhibition of nitric oxide production worsened the recovery from FHVOO. Drugs increasing HAP need to be evaluated to reverse the hyperperfusion-induced impairment of the spontaneous course after FHVOO. PMID- 24770621 TI - Engraftment versus immunosuppression: cost-benefit analysis of immunosuppression after intrahepatic murine islet transplantation. AB - OBJECTIVE: Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects. METHODS: To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1 0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx. RESULTS: RAPA >=0.5 mg/Kg, FK506 >=0.5 mg/Kg, and MMF >=120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection. CONCLUSION: IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection. PMID- 24770622 TI - Regional perspective: developing organ transplantation in sub-saharan Africa. PMID- 24770624 TI - The acute effects of MDMA and ethanol administration on electrophysiological correlates of performance monitoring in healthy volunteers. AB - RATIONALE: Knowing how commonly used drugs affect performance monitoring is of great importance, because drug use is often associated with compromised behavioral control. Two of the most commonly used recreational drugs in the western world, 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and ethanol (alcohol), are also often used in combination. The error-related negativity (ERN), correct-related negativity (CRN), and N2 are electrophysiological indices of performance monitoring. OBJECTIVES: The present study aimed to investigate how ethanol, MDMA, and their co-administration affect performance monitoring as indexed by the electrophysiological correlates. METHODS: Behavioral and EEG data were obtained from 14 healthy volunteers during execution of a speeded choice reaction-time task after administration of ethanol, MDMA, and combined ethanol and MDMA, in a double-blind, placebo-controlled, randomized crossover design. RESULTS: Ethanol significantly reduced ERN amplitudes, while administration of MDMA did not affect the ERN. Co-administration of MDMA and ethanol did not further impair nor ameliorate the effect of ethanol alone. No drug effects on CRN nor N2 were observed. DISCUSSION: A decreased ERN following ethanol administration is in line with previous work and offers further support for the impairing effects of alcohol intoxication on performance monitoring. This impairment may underlie maladaptive behavior in people who are under influence. Moreover, these data demonstrate for the first time that MDMA does not affect performance monitoring nor does it interact with ethanol in this process. These findings corroborate the notion that MDMA leaves central executive functions relatively unaffected. PMID- 24770625 TI - Neuroendocrine and sympathetic responses to an orexin receptor antagonist, SB 649868, and alprazolam following insulin-induced hypoglycemia in humans. AB - RATIONALE: The orexin-hypocretin system is important for translating peripheral metabolic signals and central neuronal inputs to a diverse range of behaviors, from feeding, motivation and arousal, to sleep and wakefulness. Orexin signaling is thus an exciting potential therapeutic target for disorders of sleep, feeding, addiction, and stress. OBJECTIVES/METHODS: Here, we investigated the low dose pharmacology of orexin receptor antagonist, SB-649868, on neuroendocrine, sympathetic nervous system, and behavioral responses to insulin-induced hypoglycemic stress, in 24 healthy male subjects (aged 18-45 years; BMI 19.0-25.9 kg/m(2)), using a randomized, double-blind, placebo-controlled, within-subject crossover design. Alprazolam, a licensed benzodiazepine anxiolytic, was used as a positive comparator, as it has previously been validated using the insulin tolerance test (ITT) model in humans. RESULTS: Of the primary endpoints, ITT induced defined increases in pulse rate, plasma cortisol, and adrenocorticotropic hormone in the placebo condition, but these responses were not significantly impacted by alprazolam or SB-649868 pre-treatment. Of the secondary endpoints, ITT induced a defined increase in plasma concentrations of adrenaline, noradrenaline, growth hormone (GH), and prolactin in the placebo condition. Alprazolam pre-treatment significantly reduced the GH response to ITT (p < 0.003), the peak electromyography (p < 0.0001) and galvanic skin response (GSR, p = 0.04) to acoustic startle, the resting GSR (p = 0.01), and increased appetite following ITT (p < 0.0005). SB-649868 pre-treatment produced no significant results. CONCLUSION: We concluded that the ITT model may be informative for assessing the effects of drugs directly acting on the neuroendocrine or sympathetic nervous systems, but could not be validated for studying low dose orexin antagonist activity. PMID- 24770627 TI - Effects of systemic opioid receptor ligands on ethanol- and sucrose seeking and drinking in alcohol-preferring (P) and Long Evans rats. AB - The endogenous opioid system has been implicated in mediating the reinforcing effects of ethanol (EtOH). Naltrexone (NTX), an opioid antagonist with concentration-dependent selectivity for the mu receptor, naltrindole (NTI), a selective delta receptor antagonist, and U50,488H, a selective kappa receptor agonist were examined in both alcohol-preferring (P) and nonselected (Long Evans (LE)) rats to determine whether they differentially affected the seeking and consumption of EtOH and sucrose. Using the sipper-tube model, rats reinforced with either 2% sucrose or 10% EtOH were injected with vehicle and either NTI (2.5, 5.0, or 10.0 mg/kg), U50 (2.5, 5.0, or 10.0 mg/kg), low-dose NTX (0.1, 0.3, or 1.0 mg/kg), or high-dose NTX (1.0, 3.0, or 10.0 mg/kg). Subsequent intakes (consummatory) or lever responses (seeking) were assessed. Overall, NTI, U50, and NTX attenuated intake and responding for sucrose and EtOH, with EtOH-reinforced P rats being the most sensitive to the effects of NTI on intake and seeking. U50 treatment decreased intake and seeking in both P and LE rats but did not selectively reduce EtOH intake or seeking in either line. P rats were more sensitive than LE rats to lower doses of NTX, and these doses more selectively attenuated responding for EtOH than sucrose. Higher doses of NTX suppressed intake and responding across both lines and reinforcers. These results suggest that drugs selective for the opioid receptors may be good pharmacotherapeutic targets, particularly in those with an underlying genetic predisposition for greater EtOH preference/intake. PMID- 24770626 TI - Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies. AB - RATIONALE: Neuroactive steroids are endogenous or synthetic steroids that rapidly alter neuronal excitability via membrane receptors, primarily gamma-aminobutyric acid type A (GABAA) receptors. Neuroactive steroids regulate many physiological processes including hypothalamic-pituitary-adrenal (HPA) axis function, ovarian cycle, pregnancy, aging, and reward. Moreover, alterations in neuroactive steroid synthesis are implicated in several neuropsychiatric disorders. OBJECTIVES: This review will summarize the pharmacological properties and physiological regulation of neuroactive steroids, with a particular focus on divergent neuroactive steroid responses to stress and ethanol in rats, mice, and humans. RESULTS: GABAergic neuroactive steroids exert a homeostatic regulation of the HPA axis in rats and humans, whereby the increase in neuroactive steroid levels following acute stress counteracts HPA axis hyperactivity and restores homeostasis. In contrast, in C57BL/6J mice, acute stress decreases neurosteroidogenesis and neuroactive steroids exert paradoxical excitatory effects upon the HPA axis. Rats, mice, and humans also differ in the neuroactive steroid responses to ethanol. Genetic variation in neurosteroidogenesis may explain the different neuroactive steroid responses to stress or ethanol. CONCLUSIONS: Rats and mouse strains show divergent effects of stress and ethanol on neuroactive steroids in both plasma and brain. The study of genetic variation in the various processes that determine neuroactive steroids levels as well as their effects on cell signaling may underlie these differences and may play a relevant role for the potential therapeutic benefits of neuroactive steroids. PMID- 24770628 TI - Enriched environment prevents cognitive and motor deficits associated with postnatal MK-801 treatment. AB - RATIONALE: Previous studies have shown the beneficial effects of enriched environment (EE) in rescuing behavioral deficits such as pre-pulse inhibition and locomotor hyperactivity associated with N-methyl-D-aspartate (NMDA) receptor blockade; however, cognitive deficits remain unresponsive. OBJECTIVES: We designed experiments to determine the consequences of raising rat pups in an EE on several behavioral aberrations, mainly cognitive deficits, observed in rats postnatally exposed to MK-801 (NMDA receptor antagonist). METHODS: Male Wistar rats were injected with MK-801 (1 mg/kg) from postnatal day (P) 6-10. Rat pups were housed in an EE from birth up to the time of behavioral experiments at P28 34. The effects of EE in correcting MK-801-associated behaviors were assessed by rotarod, wire grip, open filed, and Morris water maze tests. RESULTS: We found that EE not only has beneficial effects on cognitive performance of normal rats but also prevents spatial learning and memory deficits in Morris water maze induced by MK-801. Postnatal MK-801 treatment also led to motor deficits both in wire grip and accelerating rotarod tests. These deficits were not observed in MK 801-treated rats raised in EE. In the open field test, EE prevented increase in "frequency of grooming" and decrease in "time spent in the center" associated with MK-801. CONCLUSIONS: Our results suggest that exposure to an EE would be strongly beneficial in correcting deficits, notably cognitive, associated with MK 801. Given that the postnatal MK-801 treatment represents an animal model of schizophrenia, we propose timely environmental interventions might be an effective strategy in the protection against schizophrenia. PMID- 24770629 TI - Alexander Rudolf Cools (1942-2013). PMID- 24770630 TI - Magnitude of change with antidepressants and placebo in antidepressant clinical trials using structured, taped and appraised rater interviews (SIGMA-RAPS) compared to trials using traditional semi-structured interviews. AB - RATIONALE: Although newer interview methods such as Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA; MADRS) with audiotaping and Rater Applied Performance Scale (RAPS) appraisal have been introduced to improve reliability of ratings in antidepressant clinical trials, there is limited evidence that these methods actually improve trial outcome. OBJECTIVE: The objective of this study uis to evaluate outcome in four similarly designed trials of two recently approved antidepressants: two trials randomly used taped SIGMA interviews with RAPS appraisal and two trials used traditional semi structured MADRS interviews. METHODS: We reviewed data from patients who were screened (N = 243) and randomized (N = 148), evaluating the magnitude of change with placebo and antidepressants on mean total MADRS score. RESULTS: Depressed patients assigned to placebo in trials using taped SIGMA interviews with RAPS appraisal had a significantly larger MADRS change score (M = -11.5 +/- 12.7) compared to patients assigned to placebo in trials using traditional semi structured interviews (-5.4 +/- 8.9; F(df = 1.57) = 5.58, p = 0.022). The error variance was also significantly larger in the placebo arm of trials using SIGMA interviews (F = 5.43, p = 0.023). Depressed patients assigned to antidepressants had similar outcome in all of the four trials. CONCLUSION: The recently suggested modifications in obtaining clinical data in antidepressant trials such as taped SIGMA interviews with RAPS rating appraisals may in fact result in a higher magnitude of placebo response and a lower magnitude of antidepressant-placebo differences compared to the traditional methods of collecting clinical data. These results were unexpected and indicate the necessity to test new methods prospectively, no matter how intuitively sensible they seem, prior to their implementation. PMID- 24770631 TI - Data quality in fMRI and simultaneous EEG-fMRI. AB - OBJECT: To evaluate functional magnetic resonance imaging (fMRI) and simultaneous electroencephalography (EEG)-fMRI data quality in an organization using several magnetic resonance imaging (MRI) systems. MATERIALS AND METHODS: Functional magnetic resonance imaging measurements were carried out twice with a uniform gel phantom on five different MRI systems with field strengths of 1.5 and 3.0 T. Several image quality parameters were measured with automatic analysis software. For simultaneous EEG-fMRI, data quality was evaluated on 3.0 T systems, and the phantom results were compared to data on human volunteers. RESULTS: The fMRI quality parameters measured with different MRI systems were on an acceptable level. The presence of the EEG equipment caused superficial artifacts on the phantom image. The typical artifact depth was 15 mm, and no artifacts were observed in the brain area in the images of volunteers. Average signal-to-noise ratio (SNR) reduction in the phantom measurements was 15 %, a reduction of SNR similar to that observed in the human data. We also detected minor changes in the noise of the EEG signal during the phantom measurement. CONCLUSION: The phantom proved valuable in the successful evaluation of the data quality of fMRI and EEG fMRI. The results fell within acceptable limits. This study demonstrated a repeatable method to measure and follow up on the data quality of simultaneous EEG-fMRI. PMID- 24770632 TI - Discovery of gigantic molecular nanostructures using a flow reaction array as a search engine. AB - The discovery of gigantic molecular nanostructures like coordination and polyoxometalate clusters is extremely time-consuming since a vast combinatorial space needs to be searched, and even a systematic and exhaustive exploration of the available synthetic parameters relies on a great deal of serendipity. Here we present a synthetic methodology that combines a flow reaction array and algorithmic control to give a chemical 'real-space' search engine leading to the discovery and isolation of a range of new molecular nanoclusters based on [Mo(2)O(2)S(2)](2+)-based building blocks with either fourfold (C4) or fivefold (C5) symmetry templates and linkers. This engine leads us to isolate six new nanoscale cluster compounds: 1, {Mo(10)(C5)}; 2, {Mo(14)(C4)4(C5)2}; 3, {Mo(60)(C4)10}; 4, {Mo(48)(C4)6}; 5, {Mo(34)(C4)4}; 6, {Mo(18)(C4)9}; in only 200 automated experiments from a parameter space spanning ~5 million possible combinations. PMID- 24770633 TI - The expression of Wnt-inhibitor DKK1 (Dickkopf 1) is determined by intercellular crosstalk and hypoxia in human malignant gliomas. AB - OBJECTIVE: Wnt signalling pathways regulate proliferation, motility and survival in a variety of human cell types. Dickkopf 1 (DKK1) gene codes for a secreted Wnt inhibitory factor. It functions as tumour suppressor gene in breast cancer and as a pro-apoptotic factor in glioma cells. In this study, we aimed to demonstrate whether the different expression of DKK1 in human glioma-derived cells is dependent on microenvironmental factors like hypoxia and regulated by the intercellular crosstalk with bone-marrow-derived mesenchymal stem cells (bmMSCs). METHODS: Glioma cell line U87-MG, three cell lines from human glioblastoma grade IV (glioma-derived mesenchymal stem cells) and three bmMSCs were selected for the experiment. The expression of DKK1 in cell lines under normoxic/hypoxic environment or co-culture condition was measured using real-time PCR and enzyme linked immunoadsorbent assay. The effect of DKK1 on cell migration and proliferation was evaluated by in vitro wound healing assays and sulphorhodamine assays, respectively. RESULTS: Glioma-derived cells U87-MG displayed lower DKK1 expression compared with bmMSCs. Hypoxia led to an overexpression of DKK1 in bmMSCs and U87-MG when compared to normoxic environment, whereas co-culture of U87-MG with bmMSCs induced the expression of DKK1 in both cell lines. Exogenous recombinant DKK1 inhibited cell migration on all cell lines, but did not have a significant effect on cell proliferation of bmMSCs and glioma cell lines. CONCLUSION: In this study, we showed for the first time that the expression of DKK1 was hypoxia dependent in human malignant glioma cell lines. The induction of DKK1 by intracellular crosstalk or hypoxia stimuli sheds light on the intense adaption of glial tumour cells to environmental alterations. PMID- 24770634 TI - Prognostic significance of ALDH1A1-positive cancer stem cells in patients with locally advanced, metastasized head and neck squamous cell carcinoma. AB - PURPOSE: Aldehyde dehydrogenase 1 (ALDH1A1) has now been recognized as a cancer stem(-like) cells (CSCs) marker in various tumors including head and neck squamous cell carcinoma (HNSCC). The objective of this study was to examine the expression of ALDH1A1 in patients with locally advanced, metastasized HNSCC and to determine its prognostic value. METHODS: Human papillomavirus genotypes and expression of ALDH1A1, Twist1, and p16 were analyzed in specimens of 81 patients with primary HNSCC and 49 lymph node metastases. Patient clinicopathologic and follow-up data were analyzed. RESULTS: Expression of ALDH1A1 was observed in 38 (46.9 %) of 81 primary tumors and 26 (53 %) of 49 lymph node metastases, respectively. Notably, the expression of ALDH1A1 was correlated significantly with poor tumor differentiation grade (p = 0.011). Interestingly, ALDH1A1 was observed co-expressed with Twist1 in primary tumor and lymph node metastases. Multivariate analysis showed that ALDH1A1 expression predicted poor prognosis in patients with HNSCC (p = 0.011) and the subgroup of oropharyngeal squamous cell carcinoma (p = 0.001). In the patient cohort with advanced, metastasized tumors, ALDH1A1 was identified as independent predictor of overall survival in both groups. CONCLUSIONS: Our results provide evidence for the prognostic value of ALDH1A1 as a CSC marker in patients with locally advanced, metastasized HNSCC. PMID- 24770635 TI - HDGF and ADAM9 are novel molecular staging biomarkers, prognostic biomarkers and predictive biomarkers for adjuvant chemotherapy in surgically resected stage I non-small cell lung cancer. AB - INTRODUCTION: This study was to investigate whether the expression of a disintegrin and metalloproteinase-9 (ADAM9) is correlated with the expression of hepatoma-derived growth factor (HDGF) in surgically resected non-small cell lung cancer (NSCLC), to evaluate the significance of HDGF and ADAM9 as novel molecular staging biomarkers, prognostic biomarkers and predictive biomarkers for postoperative adjuvant chemotherapy in surgically resected stage I NSCLC, to provide essential consistence proof to the possible novel pathway of HDGF-ADAM9 pathway. METHODS: Sixty-three cases of resected stage I NSCLC with mediastinal N2 lymph node dissection were immunohistochemically analyzed for HDGF and ADAM9 protein expression. Multivariate analysis and survival analysis were conducted. RESULTS: HDGF and ADAM9 were observed highly expressed in NSCLC compared with normal control lung tissues (P < 0.05). HDGF high expression cases showed significantly lower survival rate (55.6 vs. 84.7 %, P = 0.009). HDGF high expression was an independent factor of shortened survival time in resected stage I NSCLC (P = 0.015). ADAM9 high expression cases showed significantly lower survival rate (56.9 vs. 88.7 %, P = 0.015). ADAM9 high expression was an independent factor of shortened survival time in resected stage I NSCLC (P = 0.021). Pearson's correlation analysis revealed that ADAM9 expression was correlated positively and significantly with HDGF expression in 63 cases of stage I NSCLC (r = 0.547, P = 0.000). CONCLUSION: These results clearly demonstrate that ADAM9 high expression is correlated positively and significantly with HDGF high expression, which provides essential evidence for the novel HDGF-ADAM9 pathway, through which HDGF promotes invasion and metastasis of NSCLC cells; HDGF and ADAM9 are novel molecular staging biomarkers, prognostic biomarkers, which might become useful predictive biomarkers for the selection of postoperative adjuvant chemotherapy treatment in surgically resected stage I NSCLC. PMID- 24770636 TI - Dopamine dynamics and signaling in Drosophila: an overview of genes, drugs and behavioral paradigms. AB - Changes in dopamine (DA) signaling have been implicated in a number of human neurologic and psychiatric disorders. Similarly, defects in DA signaling in the fruit fly, Drosophila melanogaster, have also been associated with several behavioral defects. As most genes involved in DA synthesis, transport, secretion, and signaling are conserved between species, Drosophila is a powerful genetic model organism to study the regulation of DA signaling in vivo. In this review, we will provide an overview of the genes and drugs that regulate DA biology in Drosophila. Furthermore, we will discuss the behavioral paradigms that are regulated by DA signaling in flies. By analyzing the genes and neuronal circuits that govern such behaviors using sophisticated genetic, pharmacologic, electrophysiologic, and imaging approaches in Drosophila, we will likely gain a better understanding about how this neuromodulator regulates motor tasks and cognition in humans. PMID- 24770637 TI - Diabetic complications in obese type 2 diabetic rat models. AB - We overviewed the pathophysiological features of diabetes and its complications in obese type 2 diabetic rat models: Otsuka Long-Evans Tokushima fatty (OLETF) rat, Wistar fatty rat, Zucker diabetic fatty (ZDF) rat and Spontaneously diabetic Torii (SDT) fatty rat. Pancreatic changes with progression of diabetes were classified into early changes, such as islet hypertrophy and degranulation of beta cells, and degenerative changes, such as islet atrophy and fibrosis of islet with infiltration of inflammatory cells. Renal lesions in tubuli and glomeruli were observed, and nodular lesions in glomeruli were notable changes in OLETF and SDT fatty rats. Among retinal changes, folding and thickening were interesting findings in SDT fatty rats. A decrease of motor nerve conduction velocity with progression of diabetes was presented in obese diabetic rats. Other diabetic complications, osteoporosis and sexual dysfunction, were also observed. Observation of bone metabolic abnormalities, including decrease of osteogenesis and bone mineral density, and sexual dysfunction, including hypotestosteronemia and erectile dysfunction, in obese type 2 diabetic rats have been reported. PMID- 24770639 TI - Effect of weak acid hypochlorous solution on selected viruses and bacteria of laboratory rodents. AB - Weak acid hypochlorous solution (WAHS) is known to have efficacy for inactivating pathogens and to be relatively safe with respect to the live body. Based on these advantages, many animal facilities have recently been introducing WAHS for daily cleaning of animal houses. In this study, we determined the effect of WAHS in inactivating specific pathogens of laboratory rodents and pathogens of opportunistic infection. WAHS with an actual chloride concentration of 60 ppm and a pH value of 6.0 was generated using purpose-built equipment. One volume of mouse hepatitis virus (MHV), Sendai virus, lymphocytic choriomeningitis virus, Bordetella bronchiseptica, Pasteurella pneumotropica, Corynebacterium kutscheri, Staphylococcus aureus, and Pseudomonas aeruginosa was mixed with 9 or 99 volumes of WAHS (*10 and *100 reaction) for various periods (0.5, 1, and 5 min) at 25 degrees C. After incubation, the remaining infectious viruses and live bacteria were determined by plaque assay or culture. In the *100 reaction mixture, infectious viruses and live bacteria could not be detected for any of the pathogens examined even with the 0.5-min incubation. However, the effects for MHV, B. bronchiseptica, and P. aeruginosa were variable in the *10 reaction mixture with the 0.5- and 1-min incubations. Sufficient effects were obtained by elongation of the reaction time to 5 min. In the case of MHV, reducing organic substances in the virus stock resulted in the WAHS being completely effective. WAHS is recommended for daily cleaning in animal facilities but should be used properly in order to obtain a sufficient effect, which includes such things as using a large enough volume to reduce effects of organic substances. PMID- 24770638 TI - Overexpression of GATA-3 in T cells accelerates dextran sulfate sodium-induced colitis. AB - Ulcerative colitis (UC) is an inflammatory bowel disease, and its pathogenesis includes genetic, environmental, and immunological factors, such as T helper cells and their secreted cytokines. T helper cells are classified as Th1, Th2, and Th17 cells. However, it is unclear which T helper cells are important in UC. Dextran sulfate sodium (DSS)-induced colitis is a commonly used model of UC. In this study, we induced DSS colitis in Th1 dominant (T-bet transgenic (Tg)) mice, Th2 dominant (GATA-3 Tg) mice, and Th17 dominant (RORgammat Tg) mice to elucidate the roles of T helper cell in DSS colitis. The results showed that GATA-3 Tg mice developed the most severe DSS colitis compared with the other groups. GATA-3 Tg mice showed a significant decreased in weight from day 1 to day 7, and an increased high score for the disease activity index compared with the other groups. Furthermore, GATA-3 Tg mice developed many ulcers in the colon, and many neutrophils and macrophages were detected on day 4 after DSS treatment. Measurement of GATA-3-induced cytokines demonstrated that IL-13 was highly expressed in the colon from DSS-induced GATA-3 Tg mice. In conclusion, GATA-3 overexpression in T-cells and IL-13 might play important roles in the development of DSS colitis. PMID- 24770640 TI - Effects of cholesterol-loaded cyclodextrins on the rate and the quality of motility in frozen and thawed rabbit sperm. AB - The motility of sperm after freezing and thawing is critical for effective cryopreservation. It is known that supplementation with cholesterol-loaded cyclodextrin (CLC) improves cryosurvival of sperm in various animals. To clarify the effects of supplementation with CLC on rabbit sperm motility after freezing and thawing, rabbit sperm motility was analyzed using a computer-assisted sperm analysis system. Sperm motility with CLC supplementation was 29.4 +/- 9.6% (mean +/- SD), which was significantly higher than that of controls (20.8 +/- 7.1%, P<0.05). The curvilinear velocity of sperm with CLC exceeded that of controls, whereas the values for linearity and wobble were significantly lower in sperm with CLC compared with controls. After artificial insemination, 44.3% of recovered ova were fertilized in the CLC-supplemented group, which was higher than the percentage in the control group (36.4%). The results indicate that supplementation with CLC improves the rate and quality of motility in rabbit sperm after freezing and thawing, and would be advantageous for successful cryopreservation. PMID- 24770641 TI - Dominant trait linked to chromosome 1 in DBA/2 mice for the resistance to autoimmune gastritis appears in bone marrow cells. AB - Neonatal thymectomy (NTx) induces autoimmune gastritis (AIG) in BALB/c mice, a model for human type A chronic atrophic gastritis, but not in DBA/2 mice and rarely in CDF1 mice (a hybrid of BALB/c and DBA/2 mice). The aim of this study was to clarify the mechanisms of AIG-resistance in mice bearing the dominant trait of DBA/2. Linkage groups associated with, and cells related to AIG resistance were examined with CDF1-BALB/c backcrosses. Intracellular staining and flow-cytometric bead array for several cytokines were performed on NTx BALB/c mice and NTx DBA/2-chimeric BALB/c mice receiving DBA/2-bone marrow cells. In NTx BALB/c mice, IFN-gamma-secreting CD4(+) T cells were increased, but not in NTx DBA/2 mice. Because Vbeta6(+) T cell-bearing mice of half of their backcrosses developed AIG, but the other half of Vbeta6(+) T cell-negative mice developed scarcely, resistance for AIG generation is associated with the presence of the Mls-1a locus on chromosome 1 in DBA/2 mice, which deletes Vbeta6(+) T cells. NTx DBA/2-chimera BALB/c mice showed dominant production of IL-10 and resistance for AIG, although the deletion of Vbeta6(+) T cells was found not to be a cause of AIG-resistance from Mls-1a locus segregation experiments. Although NTx DBA/2 chimeric BALB/c mice did not suffer from AIG, they brought immediate precursors of T cells for AIG. It is concluded that DBA/2 mice generate bone marrow-derived cells that produce anti-inflammatory cytokines to prevent the activation of AIG-T cells. PMID- 24770642 TI - Prevalence of helicobacter in laboratory mice in Thailand. AB - Prevalence of Helicobacter is mostly unknown in laboratory animals in Thailand. The 221 mice feces/cecum from 8 universities, 2 pharmaceutical companies and 3 research institutions in Thailand were surveyed for the prevalence and distribution of Helicobacter species by using the Electrochemical DNA chip. Helicobacter were detected 23/46 samples in Specific Pathogen Free (SPF) and 168/175 in conventional condition. Prevalence of Helicobacter were 98%, 96%, 92% and 78% in South (n=40), Northeast (n=40), North (n=25) and Central area (n=116), respectively. Only Central area holds SPF facility resulting in Helicobacter prevalence that seems to be lower than other areas. Three species of Helicobacter were detected in feces/cecum samples by sequence analysis: H. rodentium (67.0%, 148 samples), Helicobacter sp. MIT 01-6451 (15.4%, 34 samples), and unidentified Helicobacter species (14.1%, 9 samples). The results suggested that H. rodentium is the most common species of Helicobacter in laboratory mice in Thailand. PMID- 24770643 TI - Fertilizability of Superovulated Eggs by Estrous Stage-independent PMSG/hCG Treatment in Adult Wistar-Imamichi Rats. AB - We investigated the fertilization and developmental ability of superovulated eggs obtained from adult Wistar-Imamichi (WI) rats, by using pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) treatment. Female WI rats, 11-13 weeks of age, were divided into four groups by estrous stage (metestrus [ME], diestrus [DE], proestrus [PE], or estrus [E]). PMSG (150 IU/kg) and hCG (75 IU/kg) were injected at an interval of 48 or 55 h and the female rats were mated with mature male rats. The ovulated eggs were collected 20, 24, and 27 h after hCG injection. Regardless of the estrous stage at the time of PMSG injection, the treated rats mated and ovulated similar to the untreated spontaneously ovulated rats (S group). Although the proportion of fertilized eggs in the E- and PE-treated groups was less than the S group 20 h after hCG injection, the proportion was not different among all treated and S groups 24 h after hCG injection. The proportion of fertilized eggs using in vitro fertilization and the proportion of offspring obtained from 2-cell stage embryo transfer did not differ among the treated and S groups. In comparison with PMSG/hCG-treated immature rats, mating and ovulation rate of adult rats were significantly higher. The proportion of fertilized eggs obtained from mated rats did not differ between immature and adult rats. These results demonstrate that adult WI rats are good egg donors for reproductive biotechnological studies using unfertilized or fertilized eggs. PMID- 24770644 TI - Generation and characterization of Ins1-cre-driver C57BL/6N for exclusive pancreatic beta cell-specific Cre-loxP recombination. AB - Cre/loxP system-mediated site-specific recombination is utilized to study gene function in vivo. Successful conditional knockout of genes of interest is dependent on the availability of Cre-driver mice. We produced and characterized pancreatic beta cell-specific Cre-driver mice for use in diabetes mellitus research. The gene encoding Cre was inserted into the second exon of mouse Ins1 in a bacterial artificial chromosome (BAC). Five founder mice were produced by microinjection of linearized BAC Ins1-cre. The transgene was integrated between Mafa and the telomere on chromosome 15 in one of the founders, BAC Ins1-cre25. To investigate Cre-loxP recombination, BAC Ins1-cre25 males were crossed with two different Cre-reporters, R26R and R26GRR females. On gross observation, reporter signal after Cre-loxP recombination was detected exclusively in the adult pancreatic islets in both F1 mice. Immunohistological analysis indicated that Cre loxP recombination-mediated reporter signal was colocalized with insulin in pancreatic islet cells of both F1 mice, but not with glucagon. Moreover, Cre-loxP recombination signal was already observed in the pancreatic islets at E13.5 in both F1 fetuses. Finally, we investigated ectopic Cre-loxP recombination for Ins1, because the ortholog Ins2 is also expressed in the brain, in addition to the pancreas. However, there was no Cre-loxP recombination-mediated reporter signal in the brain of both F1 mice. Our data suggest that BAC Ins1-cre25 mice are a useful Cre-driver C57BL/6N for pancreatic beta cell-specific Cre-loxP recombination, except for crossing with knock-in mice carrying floxed gene on chromosome 15. PMID- 24770645 TI - A new Enpp1 allele, Enpp1(ttw-Ham), identified in an ICR closed colony. AB - We recently have reported on a novel ankylosis gene that is closely linked to the Enpp1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene on chromosome 10. Here, we have discovered novel mutant mice in a Jcl:ICR closed colony with ankylosis in the toes of the forelimbs at about 3 weeks of age. The mutant mice exhibited rigidity in almost all joints, including the vertebral column, which increased with age. These mice also showed hypogrowth with age after 16 weeks due to a loss of visceral fat, which may have been caused by poor nutrition. Histological examination and soft X-ray imaging demonstrated the ectopic ossification of various joints in the mutant mice. In particular, increased calcium deposits were observed in the joints of the toes, the carpal bones and the vertebral column. We sequenced all exons and exon/intron boundaries of Enpp1 in the normal and mutant mice, and identified a G-to-T substitution (c.259+1G>T) in the 5' splice donor site of intron 2 in the Enpp1 gene of the mutant mice. This substitution led to the skipping of exon 2 (73 bp), which generated a stop codon at position 354 bp (amino acid 62) of the cDNA (p.V63Xfs). Nucleotide pyrophosphohydrolase (NPPH) activity of ENPP1 in the mutant mice was also decreased, suggesting that Enpp1 gene function is disrupted in this novel mutant. The mutant mice reported in this study will be a valuable animal model for future studies of human osteochondral diseases and malnutrition. PMID- 24770646 TI - Characteristics of sleep and wakefulness in wild-derived inbred mice. AB - Genetic variations in the wild-derived inbred mouse strains are more diverse than that of classical laboratory inbred mouse strains, including C57BL/6J (B6). The sleep/wake and monoamine properties of six wild-derived inbred mouse strains (PGN2, NJL, BLG2, KJR, MSM, HMI) were characterized and compared with those of B6 mice. All examined mice were nocturnal and had a polyphasic sleep pattern with a "main sleep period" identified during the light period. However, there were three sleep/wake phenotypic differences between the wild-derived mouse strains and B6 strain. First, the amount of sleep during the dark phase was comparable with that of B6 mice. However, the amount of sleep during the light phase was more varied among strains, in particular, NJL and HMI had significantly less sleep compared with that of B6 mice. Second, PGN2, NJL, BLG2, and KJR mice showed a "highly awake period" (in which the hourly total sleep time was <10%) immediately after the onset of the dark period, which was not seen in B6 mice. Third, relative to that of B6 mice, PGN2 and KJR mice showed longer duration of wakefulness episodes during the 12-h dark phase. Differences in whole brain noradrenaline, dopamine, and 5-hydroxy-tryptamine contents between the wild-derived mouse strains and B6 strain were also found. These identified phenotypes might be potentially under strong genetic control. Hence, wild-derived inbred mice could be useful for identifying the genetic factors underlying the regulation of sleep and wakefulness. PMID- 24770647 TI - Transcriptional and histological analyses of the thymic developmental process in the fetal pig. AB - The humanized pig model, in which human cells or tissues can be functionally maintained in pigs, can be an invaluable tool for human medical research. Although the recent development of immunodeficient pigs has opened the door for the development of such a model, the efficient engraftment and differentiation of human cells may be difficult to achieve. The transplantation of human cells into fetal pigs, whose immune system is immature, will ameliorate this problem. Therefore, we examined the development of porcine fetal thymus, which is critical for the establishment of the immune system. We first analyzed the levels of mRNA expression of genes that are relevant to the function of thymic epithelial cells or thymocytes in whole thymi from 35 to 85 days of gestation (DG) and at 2 days postpartum (DP) by quantitative RT-PCR. In addition, immunohistochemical analyses of thymic epithelial cells from DG35 to DG55 and DP2 were performed. These analyses showed that the thymic cortex was formed as early as DG35, and thymic medulla gradually developed from DG45 to DG55. These findings suggested that, at least before DG45, the thymus do not differentiate to form fully functional T cells. PMID- 24770648 TI - Lumbar intervertebral disc puncture under C-arm fluoroscopy: a new rat model of lumbar intervertebral disc degeneration. AB - To establish a minimally invasive rat model of lumbar intervertebral disc degeneration (IDD) to better understand the pathophysiology of the human condition. The annulus fibrosus of lumbar level 4-5 (L4-5) and L5-6 discs were punctured by 27-gauge needles using the posterior approach under C-arm fluoroscopic guidance. Magnetic resonance imaging (MRI), histological examination by hematoxylin and eosin (H&E) staining, and reverse transcription polymerase chain reaction (RT-PCR) were performed at baseline and 2, 4, and 8 weeks after disc puncture surgery to determine the degree of degeneration. All sixty discs (thirty rats) were punctured successfully. Only two of thirty rats subjected to the procedure exhibited immediate neurological symptoms. The MRI results indicated a gradual increase in Pfirrmann grade from 4 to 8 weeks post-surgery (P<0.05), and H&E staining demonstrated a parallel increase in histological grade (P<0.05). Expression levels of aggrecan, type II collagen (Col2), and Sox9 mRNAs, which encode disc components, decreased gradually post-surgery. In contrast, mRNA expression of type I collagen (Col1), an indicator of fibrosis, increased (P<0.05). The procedure of annular puncture using a 27-gauge needle under C-arm fluoroscopic guidance had a high success rate. Histological, MRI, and RT-PCR results revealed that the rat model of disc degeneration is a progressive pathological process that is similar to human IDD. PMID- 24770649 TI - Rag2-deficient IL-1 Receptor Antagonist-deficient Mice Are a Novel Colitis Model in Which Innate Lymphoid Cell-derived IL-17 Is Involved in the Pathogenesis. AB - Il1rn(-/-) mice spontaneously develop arthritis and aortitis by an autoimmune mechanism and also develop dermatitis by an autoinflammatory mechanism. Here, we show that Rag2(-/-)Il1rn(-/-) mice develop spontaneous colitis with high mortality, making a contrast to the suppression of arthritis in these mice. Enhanced IL-17A expression in group 3 innate lymphoid cells (ILC3s) was observed in the colon of Rag2(-/-)Il1rn(-/-) mice. IL-17A-deficiency prolonged the survival of Rag2(-/-)Il1rn(-/-) mice, suggesting a pathogenic role of this cytokine in the development of intestinal inflammation. Although IL-17A-producing T cells were increased in Il1rn(-/-) mice, these mice did not develop colitis, because CD4(+)Foxp3(+) regulatory T cell population was also expanded. Thus, excess IL-1 signaling and IL-1-induced IL-17A from ILC3s cause colitis in Rag2(-/ )Il1rn(-/-) mice in which Treg cells are absent. These observations suggest that the balance between IL-17A-producing cells and Treg cells is important to keep the immune homeostasis of the colon. PMID- 24770650 TI - Ubiquitin C-terminal hydrolase l1 is expressed in mouse pituitary gonadotropes in vivo and gonadotrope cell lines in vitro. AB - The ubiquitin-proteasome system (UPS) plays a fundamental role in regulating various biological activities. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme, belonging to the UPS. To date, it has been reported that UCH-L1 is highly and restrictedly expressed in neural and reproductive tissues and plays significant roles in these organs. Although the expression of UCH-L1 in the anterior pituitary gland has been reported, the detailed localization and the role of UCH-L1 remain obscure. In the present study, we detected UCH-L1 protein exclusively in hormone-producing cells, but not non-hormone producing folliculostellate cells in the anterior pituitary lobe. In addition, the cytoplasmic expression of UCH-L1 varied and was limited to gonadotropes and mammotropes. To investigate the role of UCH-L1 in anterior pituitary cells, we performed a comparative analysis using genetically UCH-L1-deficient gad mice. Significant decreases in the numbers of gonadotropes and mammotropes were observed in gad mice, suggesting a close involvement of UCH-L1 in these cells. Moreover, we also determined the expression of UCH-L1 in cultured gonadotropes. Taken together, this is the first report to definitely demonstrate the presence of UCH-L1 in mouse anterior pituitary gland, and our results might provide a novel insight for better understanding the role of UCH-L1 in the hypothalamic pituitary-gonadal axis and in the reproduction. PMID- 24770651 TI - Regulation of apelin and its receptor expression in adipose tissues of obesity rats with hypertension and cultured 3T3-L1 adipocytes. AB - The apelin/APJ system has been implicated in obesity-related hypertension. We investigated the mechanism responsible for the pathogenesis of obesity-related hypertension with a special focus on the crosstalk between AngII/its type 1 receptor (AT1R) signaling and apelin/APJ expression. Sprague-Dawley rats fed a high-fat (obesity-related hypertension, OH) or normal-fat diet (NF) for 15 weeks were randomly assigned to one of two groups and administered vehicle or perindopril for 4 weeks. Compared to the NF rats, the OH rats showed lower levels of plasma apelin and apelin/APJ mRNAs of perirenal adipose tissues, and these changes were restored by perindopril. Administration of the AT1R antagonist olmesartan resulted in the restoration of the reduction of apelin and APJ expressions induced by AngII for 48 h in 3T3-L1 adipocytes. Among several inhibitors for extracellular signal-regulated kinases 1/2 (ERK1/2) PD98059, p38 mitogen-activated protein kinase (p38MAPK) SB203580 and phosphatidylinositol 3 kinase (PI3K) LY294002, the latter showed an additive effect on AngII-mediated inhibitory effects. In addition, the levels of p-Akt, p-ERK and p38MAPK proteins were decreased by long-term treatment with AngII (120 min), and these changes were restored by Olmesartan. Apelin/APJ appears to be impaired in obesity-related hypertension. The AngII inhibition-mediated beneficial effects are likely attributable, at least in part, to restoration of p38/ERK-dependent apelin/APJ expression in diet-induced obesity-related hypertension. PMID- 24770652 TI - Spinal osteotomies to treat post-traumatic thoracolumbar deformity. AB - Fractures of the thoracolumbar junction can lead to regional kyphosis, this being a significant cause of pain and disability for the patients. After a traumatic fracture of the thoracolumbar spine, early or late regional kyphosis can be observed. This post-traumatic deformity can, however, be corrected with appropriate surgical methods. Posterior tricolumnar osteotomies are some of the most powerful methods of correction and are particularly indicated when sagittal and coronal deformities have to be simultaneously corrected or when anterior surgery is not possible. Anterior corpectomy and lengthening with posterior instrumentation are, however, an alternative technique to restore the anterior column support and to correct the regional kyphotic deformity and an option for appropriate sagittal balance restoration and control of symptoms. Proper surgical technique, evaluation of the bone quality and identification of eventual extension of the deformity to the thoracic spine are key aspects in prevention of failures. PMID- 24770653 TI - Perceived neighborhood size: implications for physical activity-environment research. AB - BACKGROUND: Nonsignificant findings are reported in approximately half of the studies examining correlations between environmental characteristics and walking. One reason could involve spatial incongruence in which environments examined are not necessarily the ones where the behavior occurred. PURPOSE: To study correlates of perceived neighborhood size and the congruence between perceived and investigator defined neighborhood areas. METHODS: Door-to-door surveys were conducted in 12 U.S. Census block groups with 18- to 87-year-old adults. Participants were asked about exercise participation and to draw a map representing their neighborhood. Geographical information software was used to construct maps, calculate neighborhood areas, and analyze congruence. RESULTS: Neighborhood sizes perceived by women were smaller than those perceived by men and positively related to min/wk of biking and education. Education and age were negatively and perceived neighborhood support for exercise was positively associated with perceived neighborhood size in men. Approximately 90% of perceived neighborhood areas overlapped with neighborhood areas defined by circles with 1200-m radii from participants' homes. CONCLUSIONS: Several individual characteristics including exercise are associated with perceptions of neighborhood size. Standard investigator-defined neighborhoods using a 1200-m radius (15 min walk) from a participant's home is sufficient to capture a majority of perceived neighborhood areas. PMID- 24770654 TI - Exposure to maltreatment and urban violence in children working on the streets in Sao Paulo, Brazil: factors associated with street work. AB - OBJECTIVE: To quantitatively study the exposure to childhood maltreatment and urban violence in children from families with at least one child working on the streets and to investigate the relationship between these factors and street work. METHODS: Families who participated in a nongovernmental organization (NGO) program to eliminate child labor were included. Data concerning sociodemographic characteristics, punishment methods used in the family environment against the children, five types of abuse and neglect perpetrated by the caregivers, urban violence exposure and family functioning were collected. RESULTS: The sample included 126 children who were working on the streets and 65 siblings who were not working on the streets. Caregivers reported high levels of severe physical punishment. The children reported high levels of abuse and neglect, and high levels of urban violence exposure. The families showed a predominance of dysfunctional and unsatisfactory relationships. A multiple logistic regression model showed that age older than 12 years and severe physical punishment at home were associated with street work. CONCLUSION: Interventions to decrease the risk of child street work should be family-focused and should aim to reduce violence in the family environment. PMID- 24770655 TI - Personality changes and return to work after severe traumatic brain injury: a prospective study. AB - OBJECTIVE: To evaluate predictors of non-return to work (nRTW) among social, demographic, clinical, and psychiatric variables after severe traumatic brain injury (TBI) in a cohort of Brazilian patients. METHODS: Prospective study. Forty three community-dwelling individuals treated at a Level I trauma center at the time of TBI were evaluated 18 months after trauma. Measures included DSM-IV-TR criteria for personality changes after TBI and Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to assess psychiatric diagnosis. Hospitalization variables included Glasgow Coma Scale scores, pupil examination findings, associated limb trauma, Marshall computed tomography classification, and blood glucose levels. RESULTS: After multiple logistic regression analysis, only the diagnosis of personality changes was found to be independently associated with nRTW, with an adjusted odds ratio of 10.92 (p = 0.02, 95% confidence interval 1.41-84.28). CONCLUSIONS: In this study, personality changes were an independent predictor of nRTW after severe TBI. Ways to predict risk factors associated with personality changes after severe brain injury could aid in identification of early and effective interventions that might ease the burden associated with this condition. PMID- 24770656 TI - Validity and screening properties of three depression rating scales in a prospective sample of patients with severe traumatic brain injury. AB - OBJECTIVE: To evaluate the validity and utility of the Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS) as screening tools for depression after severe traumatic brain injury (TBI). METHODS: Forty-six consecutive survivors of severe TBI were evaluated at a median of 15 months after injury. Receiver operating characteristic (ROC) analysis was performed using HAM-D, BDI, and HADS as predictors, and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) as gold standard. RESULTS: The area under the curve (AUC) for HAM-D was 0.89, and the optimal cutoff point was 7 (sensitivity 92.9%, specificity 78.1%); for the BDI, the AUC was 0.946 and the optimal cutoff point was 14 (sensitivity 92.3%, specificity 96.7%); for the HADS, the AUC was 0.947 and the optimal cutoff point was 9 (sensitivity 100%, specificity 80.7%); and for the HADS depression subscale, the AUC was 0.937 and the optimal cutoff point was 6 (sensitivity 92.9%, specificity 83.9%). There were no statistically significant differences among the AUCs. CONCLUSION: Our findings support a high validity and utility for the HAM-D, BDI, and HADS as screening tools for depression in patients with severe TBI, without major changes in standard cutoff points. PMID- 24770658 TI - Combined excitatory and inhibitory coupling in a 1-D array of Belousov Zhabotinsky droplets. AB - We study the dynamical behavior of one-dimensional arrays of ~100 MUm diameter aqueous droplets containing the oscillatory Belousov-Zhabotinsky (BZ) reaction, separated by narrow gaps of a fluorinated oil. In this closed system, the malonic acid concentration decreases as the reaction proceeds. Starting with a low initial malonic acid concentration, we observe a series of attractors as a function of time in the following order: anti-phase attractors; in-phase attractors, which evolve into traveling waves; and mixed modes that contain either regions of in-phase droplets separated by anti-phase oscillators, or in phase oscillators combined with non-oscillatory droplets. Most of the observations are consistent with numerical chemical models of the BZ reaction in which components that participate in the excitatory (bromine dioxide and bromous acid) and inhibitory (bromine) pathways diffuse between the droplets. The models are used to quantitatively assess the inter-drop coupling strength as a function of drop separation, drop size and malonic acid concentration. To experimentally establish the mechanism of excitatory coupling between the BZ droplets, we verify the transport through the fluorinated oil of chlorine dioxide and several weak acids, including malonic acid. PMID- 24770657 TI - Oxidative stress markers, cognitive functions, and psychosocial functioning in bipolar disorder: an empirical cross-sectional study. AB - OBJECTIVE: This study aimed to evaluate the relationship between oxidative stress markers and cognitive functions and domains of psychosocial functioning in bipolar disorder. METHODS: Oxidative stress markers, cognitive functions, and domains of psychosocial functioning were evaluated in 51 patients with bipolar disorder who were in remission. Correlation analyses between these parameters were calculated with data controlled for duration of illness and number of episodes. RESULTS: There was no statistically significant correlation between oxidative stress markers and cognitive functions. In terms of psychosocial functioning, significant correlations were found between malondialdehyde and sense of stigmatization (r = -0.502); household activities and superoxide dismutase (r = 0.501); participation in social activities and nitric oxide (r = 0.414); hobbies and leisure time activities and total glutathione (r = -0.567), superoxide dismutase (r = 0.667), and neurotrophin 4 (r = 0.450); and taking initiative and self-sufficiency and superoxide dismutase (r = 0.597). There was no correlation between other domains of psychosocial functioning and oxidative stress markers. CONCLUSION: These results imply that oxidative stress markers do not appear to correlate clearly with cognitive impairment and reduced psychosocial functioning. However, there were some associations between selected oxidative markers and activity-oriented functional markers. This may represent a true negative association, or may be an artifact of oxidative stress being a state rather than a trait marker. PMID- 24770659 TI - Consideration of dynamic photothermal effect for evaluation of scanning light sources in optical devices using pulsed source criteria. AB - Quantitative evaluation of the potential radiation hazards of scanning light sources in medical optical devices is critical. Currently, point scanning light sources of continuous radiation are treated as pulsed sources, where the dwell time at each point is equal to the pulse duration. This study compares the photothermal effects from scanning light and pulsed sources using numerical calculation for scanning without restricting aperture and with various spot sizes. The calculation results show that the thermal damage threshold of scanning source not restricted by measurement aperture does not significantly differ from that of pulsed source. Temporal temperature response and size-dependent photothermal effect also confirm the similarity between scanning and pulsed sources. PMID- 24770660 TI - Mueller matrix decomposition for determination of optical rotation of glucose molecules in turbid media. AB - The optical activity of glucose molecules is important for diagnosing and monitoring blood glucose of diabetes. In order to accurately detect the diabetes at an early stage, there is an urgent need to develop innovative detection methods. By use of Mueller matrix decomposition (MMD), we have studied the optical activity of glucose molecules in three types of turbid media--polystyrene (PST) sphere suspension, chicken blood, and the vein blood of diabetic patients. The experimental setup to obtain the Mueller matrix in the forward detection geometry has been used. The experimental results show that the rotation angle has linear relationship with the concentration of the glucose when the scattering coefficient of the PST sphere suspension remains unchanged, whereas the scattering effect enlarges the rotation angle. Furthermore, optical rotation abides by Drude's dispersion equation. The decomposition method has also been found useful applications in quantifying the optical rotations of blood glucose in diabetic patients. The diabetic severity status can be distinguished with the rotation angle of glucose and also is in accordance with the clinical diagnosis. Thus, the method of MMD has promising applications in diabetic diagnosis and monitoring. PMID- 24770661 TI - Limited-projection-angle hybrid fluorescence molecular tomography of multiple molecules. AB - An advantage of fluorescence methods over other imaging modalities is the ability to concurrently resolve multiple moieties using fluorochromes emitting at different spectral regions. Simultaneous imaging of spectrally separated agents is helpful in interrogating multiple functions or establishing internal controls for accurate measurements. Herein, we investigated multimoiety imaging in the context of a limited-projection-angle hybrid fluorescence molecular tomography (FMT), and x-ray computed tomography implementation and the further registration with positron emission tomography (PET) data. Multichannel FMT systems may image fluorescent probes of varying distribution patterns. Therefore, it is possible that different channels may require different use of priors and regularization parameters. We examined the performance of automatically estimating regularization factors implementing priors, using data-driven regularization specific for limited-projection-angle schemes. We were particularly interested in identifying the implementation variations between hybrid-FMT channels due to probe distribution variation. For this reason, initial validation of the data driven algorithm on a phantom was followed by imaging different agent distributions in animals, assuming superficial and deep seated activity. We further demonstrate the benefits of combining hybrid FMT with PET to gain multiple readings on the molecular composition of disease. PMID- 24770662 TI - Application of phasor plot and autofluorescence correction for study of heterogeneous cell population. AB - Protein-protein interactions in cells are often studied using fluorescence resonance energy transfer (FRET) phenomenon by fluorescence lifetime imaging microscopy (FLIM). Here, we demonstrate approaches to the quantitative analysis of FRET in cell population in a case complicated by a highly heterogeneous donor expression, multiexponential donor lifetime, large contribution of cell autofluorescence, and significant presence of unquenched donor molecules that do not interact with the acceptor due to low affinity of donor-acceptor binding. We applied a multifrequency phasor plot to visualize FRET FLIM data, developed a method for lifetime background correction, and performed a detailed time-resolved analysis using a biexponential model. These approaches were applied to study the interaction between the Toll Interleukin-1 receptor (TIR) domain of Toll-like receptor 4 (TLR4) and the decoy peptide 4BB. TLR4 was fused to Cerulean fluorescent protein (Cer) and 4BB peptide was labeled with Bodipy TMRX (BTX). Phasor displays for multifrequency FLIM data are presented. The analytical procedure for lifetime background correction is described and the effect of correction on FLIM data is demonstrated. The absolute FRET efficiency was determined based on the phasor plot display and multifrequency FLIM data analysis. The binding affinity between TLR4-Cer (donor) and decoy peptide 4BB-BTX (acceptor) was estimated in a heterogeneous HeLa cell population. PMID- 24770663 TI - Dynamic interplay of flow and collagen stabilizes primary hepatocytes culture in a microfluidic platform. AB - The creation of stable flow cultures of hepatocytes is highly desirable for the development of platforms for drug toxicity screening, bio-artificial liver support devices, and models for investigating liver physiology and pathophysiology. Given that hepatocytes cultured using the collagen overlay or in 'sandwich' configuration maintain a wide range of differentiated functions, we describe a simple method for adapting this culture configuration within a microfluidic device. The device design consists of a porous membrane sandwiched between two layers of PDMS resulting in a two-chambered device. In the bottom chamber, hepatocytes are cultured in the collagen sandwich configuration, while the top chamber is accessible for flow. We demonstrate that hepatocytes cultured under flow exhibit higher albumin and urea secretions and induce cytochrome P450 1A1 activity in comparison to static cultures. Furthermore, over two weeks, hepatocytes cultured under flow show a well-connected cellular network with bile canaliculi formation, whereas static cultures show formation of gaps in the cellular network that progressively increase over time. Although enhanced functional response of hepatocytes cultured under flow has been observed in multiple prior studies, the exact mechanism for this flow induced effect remains unknown. In our work, we identified that hepatocytes secrete a higher level of collagen in the flow cultures; inhibiting collagen secretion within the flow cultures reduced albumin secretion and restored the appearance of gaps in the cellular network similar to the static cultures. These results demonstrate the importance of the increased collagen secretion by hepatocytes cultured under flow as a mechanism to maintain a well-connected cellular network and a differentiated function. PMID- 24770664 TI - The surgical management of pediatric brain tumors causing epilepsy: consideration of the epileptogenic zone. AB - OBJECTIVE: Children suffering from epilepsy with suspected low-grade tumors may benefit from a surgical approach that considers the epileptogenic zone, which can be more extensive than the tumor region. This study aimed to determine the prevalence of epilepsy in children undergoing supratentorial tumor resection and the factors predictive of postoperative seizure freedom in children with low grade tumors. METHODS: Subjects 3 months to 21 years undergoing supratentorial brain tumor resection between 2007 and 2011 were included in this retrospective study. Children with supratentorial, cortically based tumors and a preoperative diagnosis of epilepsy were considered epilepsy surgery candidates. Pre- and postoperative MRI were reviewed and scored for extent of resection, adjacent dysplasia, and remaining abnormal cortex postoperatively. RESULTS: The prevalence of seizures in all cases of supratentorial tumors was 46/87 (53 %). Eighteen were epilepsy surgery candidates. Eight of 18 (44 %) were seizure-free postoperatively with a mean follow-up of 39 months. Children who were seizure free postoperatively had tried fewer anticonvulsants than those with continued seizures (1.7 v. 2.9, p = 0.01). Presurgical evaluation was nonstandardized, and a more extensive workup and resection were performed in children who continued to have seizures postoperatively. CONCLUSIONS: All epilepsy surgery candidates had low-grade tumors on histological evaluation, indicating that a surgical approach that takes into consideration the epileptogenic zone is reasonable in this population. Gross total resection should be the goal, with additional attention to resection of the epileptogenic zone when located in the noneloquent cortex. PMID- 24770665 TI - High-fat diet alters the oligosaccharide chains of colon mucins in mice. AB - Mucins are high molecular weight epithelial proteins, strongly glycosylated, and are the main component of the mucus. Since mucus secretion can be altered in diseases, colon mucins can be regarded as a biomarker of chronic inflammatory bowel diseases or preneoplastic changes. Conventional histochemistry and lectin histochemistry combined with chemical treatment and enzymatic digestion were carried out to analyze the colon mucins in mice fed a high-fat diet for 25 weeks, a period sufficient to induce simple liver steatosis, to check whether the carbohydrate features of mucus can be altered by an inadequate diet. An increase in the sialo/sulfomucins ratio with respect to control mice, assessed by computerized image analysis, was observed in the colon, although differences in sialic acid acetylation between control and mice fed a high-fat diet were not found. High-fat diet was also associated with altered lectin-binding pattern of the mucus, with a probable shortening of oligosaccharide chains of glycoproteins. This pattern was leading to over-expression of Galbeta1,3GalNAc terminal dimers (TF antigen) and GalNAc terminal residues (Tn antigen). This altered composition of mucins can be related to a defect in the process of glycosylation, or to incomplete maturation of goblet cells, and may be an early indication of preneoplastic and neoplastic changes. In conclusion, our findings confirm that a fatty-rich diet (Western-style diet) induces alteration of mucins and may be associated with colon diseases. Our investigation corroborates the usefulness of lectins histochemistry in the early diagnosis of prepathological states of the colon. PMID- 24770666 TI - IL-7 splicing variant IL-7delta5 induces EMT and metastasis of human breast cancer cell lines MCF-7 and BT-20 through activation of PI3K/Akt pathway. AB - Our previous study has confirmed that IL-7delta5 (an IL-7 variant lacking exon 5) promotes breast cancer growth. However, whether IL-7delta5 is involved in tumor cell EMT and metastasis remains unclear. In this study, we investigated the preclinical effects and molecular mechanisms of IL-7delta5 on EMT and metastasis in human MCF-7 and BT-20 breast cancer cells in vitro and in vivo. The results showed that IL-7delta5 induced EMT and invasion in tumor cells, associated with up-regulation of N-cadherin and the down-regulation of E-cadherin. Furthermore, we found that IL-7delta5 induced the activation of Akt. Inhibition of PI3K/Akt pathway by LY294002 reversed the EMT transition in breast cancer cell lines MCF-7 and BT-20 induced by IL-7delta5. In addition, IL-7delta5 enhanced cancer metastasis and shortened survival time, with increased level changes of activated Akt in nude mice with breast cancer. In conclusion, our findings demonstrate that IL-7delta5 induces human breast cancer cell lines EMT and metastasis via activation of PI3K/Akt pathway. Thus, IL-7delta5 may be a potential target against human breast cancer. PMID- 24770667 TI - Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non small cell lung cancer patients who have progressed following chemotherapy. AB - BACKGROUND: IMO-2055 is a Toll-like receptor 9 (TLR9) agonist that potentially enhances the efficacy of antitumor agents through immune stimulation. The objective of this phase Ib dose-escalation trial (3 + 3 design) was to determine the recommended phase II dose (RP2D) of IMO-2055 when combined with erlotinib and bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with stage 3/4 NSCLC and progressive disease (PD) following chemotherapy received IMO-2055 0.08, 0.16, 0.32, or 0.48 mg/kg once weekly plus erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients could receive treatment until PD or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled; 35 received at least one treatment dose. Two dose-limiting toxicities were observed across the dose range (Grade 3 dehydration and fatigue) with neither suggestive of a consistent toxicity pattern. IMO-2055 0.32 mg/kg was adopted as RP2D based on clinical and pharmacodynamic data. The most common treatment-emergent adverse events (TEAEs) were diarrhea (74 %), nausea (51 %), fatigue (51 %), rash (51 %), and injection-site reactions (49 %). Four patients experienced serious TEAEs considered to be study drug related. Five patients died, all due to PD. High-grade neutropenia and electrolyte disturbances previously reported with TLR9 agonists combined with platinum-based therapy were not observed in this study. Five of 33 patients evaluable for response (15 %) achieved partial response; another 20 (61 %) had stable disease, including 13 with stable disease >=4 months. CONCLUSIONS: IMO-2055 demonstrated good tolerability and possible antitumor activity in combination with erlotinib and bevacizumab in heavily pretreated patients with advanced NSCLC. PMID- 24770668 TI - Fabrication of enzyme-degradable and size-controlled protein nanowires using single particle nano-fabrication technique. AB - Protein nanowires exhibiting specific biological activities hold promise for interacting with living cells and controlling and predicting biological responses such as apoptosis, endocytosis and cell adhesion. Here we report the result of the interaction of a single high-energy charged particle with protein molecules, giving size-controlled protein nanowires with an ultra-high aspect ratio of over 1,000. Degradation of the human serum albumin nanowires was examined using trypsin. The biotinylated human serum albumin nanowires bound avidin, demonstrating the high affinity of the nanowires. Human serum albumin-avidin hybrid nanowires were also fabricated from a solid state mixture and exhibited good mechanical strength in phosphate-buffered saline. The biotinylated human serum albumin nanowires can be transformed into nanowires exhibiting a biological function such as avidin-biotinyl interactions and peroxidase activity. The present technique is a versatile platform for functionalizing the surface of any protein molecule with an extremely large surface area. PMID- 24770669 TI - Generation of electromagnetic waves with arbitrary orbital angular momentum modes. AB - Recently, much attention has been focused on beams carrying orbital angular momentum (OAM) for radio communication. Here we experimentally demonstrate a planar-spiral phase plate (planar-SPP) for generating arbitrary mixed OAM beams. This proposed planar-SPP uses the concept of transmit array antenna having a perforated substrate to control the outputting phase for generating beams carrying OAM with arbitrary modes. As demonstrations, three planar-SPPs with a single OAM mode and two mixed OAM modes around 94 GHz have been investigated with design and experiments in this paper, respectively. The typical experimental intensity and phase patterns show that the proposed method of generating OAM beams really works. PMID- 24770670 TI - Acetylcholinesterase biosensor based on a gold nanoparticle-polypyrrole-reduced graphene oxide nanocomposite modified electrode for the amperometric detection of organophosphorus pesticides. AB - A nanohybrid of gold nanoparticles, polypyrrole, and reduced graphene oxide sheets (named as Au-PPy-rGO) was achieved by electrochemical deposition of reduced graphene oxide with pyrrole and the introduction of gold nanoparticles. Acetylcholinesterase (AChE) was further encapsulated in a silica matrix and immobilized on the Au-PPy-rGO nanocomposite by co-deposition with (NH4)2SiF6. The presence of PPy helped to avoid the aggregation of rGO caused by van der Waals interactions between individual sheets and significantly increased the surface area of the modified electrode. The obtained Au-PPy-rGO nanocomposite not only showed excellent conductivity but also exhibited a high electrocatalytic activity and specific affinity for thiocholine, the hydrolysis product of the enzyme, and thus an improved detection sensitivity. Since AChE molecules were protected by the circumambient silica matrix, which provided a biocompatible environment and facilitated mass transport, the fabricated AChE biosensor displayed high stability and excellent activity together with a fast response to organophosphorus pesticides. Under optimum conditions, the biosensor led to the rapid and sensitive detection of paraoxon-ethyl from 1.0 nM to 5 MUM with a detection limit of 0.5 nM. PMID- 24770671 TI - Mosquito larvicidal properties of silver nanoparticles synthesized using Heliotropium indicum (Boraginaceae) against Aedes aegypti, Anopheles stephensi, and Culex quinquefasciatus (Diptera: Culicidae). AB - Mosquitoes transmit dreadful diseases to human beings wherein biological control of these vectors using plant-derived molecules would be an alternative to reduce mosquito population. In the present study activity of aqueous leaf extract and silver nanoparticles (AgNPs) synthesized using Helitropium indicum plant leaves against late third instar larvae of Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. The range of varying concentrations of synthesized AgNPs (8, 16, 24, 32, and 40 MUg/mL) and aqueous leaf extract (30, 60, 90, 120, and 150 MUg/mL) were tested against the larvae of Anopheles stephensi, Aedes aegypti, and Culex quinquefasciatus. The synthesized AgNPs from H. indicum were highly toxic than crude leaf aqueous extract in three important vector mosquito species. The results were recorded from UV-Vis spectrum, Fourier transform infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy analysis, transmission electron microscopy, and histogram. The synthesized AgNPs showed larvicidal effects after 24 h of exposure. Considerable mortality was evident after the treatment of H. indicum for all three important vector mosquitoes. The LC50 and LC90 values of H. indicum aqueous leaf extract appeared to be effective against A. stephensi (LC50, 68.73 MUg/mL; LC90, 121.07 MUg/mL) followed by A. aegypti (LC50, 72.72 MUg/mL; LC90, 126.86 MUg/mL) and C. quinquefasciatus (LC50, 78.74 MUg/mL; LC90, 134.39 MUg/mL). Synthesized AgNPs against the vector mosquitoes of A. stephensi, A. aegypti, and C. quinquefasciatus had the following LC50 and LC90 values: A. stephensi had LC50 and LC90 values of 18.40 and 32.45 MUg/mL, A. aegypti had LC50 and LC90 values of 20.10 and 35.97 MUg/mL, and C. quinquefasciatus had LC50 and LC90 values of 21.84 and 38.10 MUg/mL. No mortality was observed in the control. These results suggest that the leaf aqueous extracts of H. indicum and green synthesis of silver nanoparticles have the potential to be used as an ideal ecofriendly approach for the control of A. stephensi, A. aegypti, and C. quinquefasciatus. This is the first report on the mosquito larvicidal activity of the plant extracts and synthesized nanoparticles. PMID- 24770672 TI - Ultrastructural features of the spermatozoon and its differentiation in Brandesia turgida (Brandes, 1888) (Digenea, Microphalloidea, Pleurogenidae). AB - Spermatological characters of the digenean Brandesia turgida (Brandes, 1888), an intestinal parasite of the frog Pelophylax ridibundus (Pallas, 1771), have been investigated by means of transmission electron microscopy for the first time. The process of the spermatozoon formation begins with the appearance of the differentiation zone bordered by cortical microtubules and containing two centrioles associated with striated rootlets and with an intercentriolar body. The intercentriolar body is made up of seven distinct electron-dense plates, two less electron-dense, and four electron-lucent zones. The orthogonal development of the two flagella is followed by a flagellar rotation and their proximodistal fusion with the median cytoplasmic process. This process is accompanied by an extension of both the mitochondrion and nucleus into the median cytoplasmic process. The mature spermatozoon of B. turgida contains two parallel axonemes of unequal lengths with the 9 + "1" trepaxonematan pattern, mitochondrion, nucleus, parallel cortical microtubules, four electron-dense attachment zones, an external ornamentation of the plasma membrane, and electron-dense glycogen granules. The anterior extremity of the male gamete contains one complete centriole, a small component of the central element of the second centriole, and peripheral cortical microtubules (up to 45). The posterior extremity of the mature spematozoon exhibits tubular elements of the disorganized axoneme. The present study provides the first data on spermiogenesis within the family Pleurogenidae. Variations of the spermatozoa ultrastructural characters within Digenea, in particular, between different families of the superfamily Microphalloidea, are discussed. PMID- 24770673 TI - Geographic variation in caste ratio of trematode colonies with a division of labour reflect local adaptation. AB - Similarly to the division of labour in social insects, castes of morphologically distinct individuals exist within colonies of some species of parasitic trematodes. These colonies occur in the first intermediate host of the trematode's complex life cycle and are composed of clonal individuals. Individuals of the reproductive caste have significantly larger bodies while non reproductive individuals are small and appear to be specialised for defence against co-infecting trematode colonies. In parallel with colony organisation of social insects, demographic traits such as the proportion of the small, non reproducing individuals relative to the large, reproducing individuals and colony size are expected to vary and adjust to local conditions. In the case of colonies from geographically and potentially genetically distinct populations, this variation is hypothesised to become fixed by evolutionary divergence, as reported in social insect studies. In this study, the adaptive demography theory was further tested by looking at caste ratio and colony organisation of Philophthalmus sp. (a parasitic trematode with a recently discovered division of labour) colonies from geographically distinct populations. Results indicate that the caste ratio from geographically distinct Philophthalmus sp. colonies differs; the proportion of small, defensive individuals is higher in colonies from the location where the risk of competition is highest. This is suggestive of local adaptation, as caste ratios do not change over time under standardised laboratory conditions. This is the first evidence to support the adaptive demography theory in a species with a division of labour other than social insects. PMID- 24770674 TI - Field trials assessing deltamethrin (Butox(r)) treatments of sheep against Culicoides species. AB - Culicoides (Diptera: Ceratopogonidae) biting midges may transmit various diseases of economic importance, including bluetongue virus (BTV) and Schmallenberg (SV) virus, which affect ruminants. During the outbreak of BTV in central and northern Europe in 2006, and in the absence of BTV vaccines, many national veterinary services recommended the treatment of susceptible livestock with pyrethroids as a first-line defense against biting midges, although these insecticides were officially not registered and authorized for use against Culicoides midges. The efficacy of Butox(r) pour on (7.5 mg deltamethrin/mL) against biting midges was therefore evaluated in a double-blinded GCP field trial performed in Brandenburg, Germany. Forty female Merino sheep with an average body weight of 38 kg (+/-7 kg) were used for the study. Twenty randomly selected sheep were treated with 10 mL Butox(r) pour on. The remaining 20 sheep were left untreated and served as a control group. Midge collections took place in two separate drop traps covering two crush pens with three confined treated/untreated sheep standing inside, on weekdays at 1, 7, 14, 21, 28, and 35 days post treatment. A total of 19,057 midges were collected during this period. Midges were identified as belonging to the subgenus Avaritia, Fox (84.6%) and subgenus Culicoides, Latreille (15.4%). A total of 12,031 midges were collected inside the drop trap containing untreated sheep, in comparison to 7,026 midges collected from the vicinity of the treated sheep. Significantly, more midges had fed on control compared to treated sheep with 757 and 103 engorged midges, respectively. The results indicate that treatment of sheep with Butox(r) pour on provided a significant decrease in Culicoides feeding rates under field conditions for at least 35 days. PMID- 24770675 TI - Sexual reproduction and seasonality of the Alaskan red tree coral, Primnoa pacifica. AB - The red tree coral Primnoa pacifica is an important habitat forming octocoral in North Pacific waters. Given the prominence of this species in shelf and upper slope areas of the Gulf of Alaska where fishing disturbance can be high, it may be able to sustain healthy populations through adaptive reproductive processes. This study was designed to test this hypothesis, examining reproductive mode, seasonality and fecundity in both undamaged and simulated damaged colonies over the course of 16 months using a deepwater-emerged population in Tracy Arm Fjord. Females within the population developed asynchronously, though males showed trends of synchronicity, with production of immature spermatocysts heightened in December/January and maturation of gametes in the fall months. Periodicity of individuals varied from a single year reproductive event to some individuals taking more than the 16 months sampled to produce viable gametes. Multiple stages of gametes occurred in polyps of the same colony during most sampling periods. Mean oocyte size ranged from 50 to 200 um in any season, and maximum oocyte size (802 um) suggests a lecithotrophic larva. No brooding larvae were found during this study, though unfertilized oocytes were found adhered to the outside of polyps, where they are presumably fertilized. This species demonstrated size dependent reproduction, with gametes first forming in colonies over 42-cm length, and steady oocyte sizes being achieved after reaching 80-cm in length. The average fecundity was 86 (+/- 12) total oocytes per polyp, and 17 (+/- 12) potential per polyp fecundity. Sub-lethal injury by removing 21-40% of colony tissue had no significant reproductive response in males or females over the course of this study, except for a corresponding loss in overall colony fecundity. The reproductive patterns and long gamete generation times observed in this study indicate that recruitment events are likely to be highly sporadic in this species increasing its vulnerability to anthropogenic disturbances. PMID- 24770677 TI - New automated procedure to assess context recognition memory in mice. AB - RATIONALE AND OBJECTIVES: Recognition memory is an important aspect of human declarative memory and is one of the routine memory abilities altered in patients with amnestic syndrome and Alzheimer's disease. In rodents, recognition memory has been most widely assessed using the novel object preference paradigm, which exploits the spontaneous preference that animals display for novel objects. Here, we used nose-poke units instead of objects to design a simple automated method for assessing context recognition memory in mice. METHODS: In the acquisition trial, mice are exposed for the first time to an operant chamber with one blinking nose-poke unit. In the choice session, a novel nonblinking nose-poke unit is inserted into an empty spatial location and the number of nose poking dedicated to each set of nose-poke unit is used as an index of recognition memory. RESULTS: We report that recognition performance varies as a function of the length of the acquisition period and the retention delay and is sensitive to conventional amnestic treatments. By manipulating the features of the operant chamber during a brief retrieval episode (3-min long), we further demonstrate that reconsolidation of the original contextual memory depends on the magnitude and the type of environmental changes introduced into the familiar spatial environment. CONCLUSIONS: These results show that the nose-poke recognition task provides a rapid and reliable way for assessing context recognition memory in mice and offers new possibilities for the deciphering of the brain mechanisms governing the reconsolidation process. PMID- 24770676 TI - CB1 antagonism: interference with affective properties of acute naloxone precipitated morphine withdrawal in rats. AB - RATIONALE: Modulation of the endocannabinoid system has been found to interfere with opiate withdrawal. The potential of activation and blockade of the endocannabinoid system to prevent the aversive-affective state of naloxone precipitated morphine withdrawal (MWD) was investigated in a one-trial conditioned place aversion (CPA) paradigm. OBJECTIVE: CPA provides a sensitive measure of the motivational effects of acute MWD. The potential of the fatty acid amide hydrolase (FAAH) inhibitors, URB597 and PF-3845, the CB1 antagonist/inverse agonist, AM251, and the neutral CB1 antagonists, AM4113 and AM6527 (oral), to interfere with establishment of a MWD-induced CPA was investigated. As well, the potential of AM251 and AM4113 to interfere with reinstatement of a previously established MWD-induced CPA was investigated. MATERIALS AND METHODS: Using a one trial place conditioning paradigm, rats were administered naloxone (1 mg/kg, subcutaneous (s.c.)) 24 h after receiving a high dose of morphine (20 mg/kg, s.c.) and were placed on the conditioning floor. To determine the effect of each pretreatment drug on the establishment of the MWD-induced CPA, URB597 (0.3 mg/kg, intraperitoneally (i.p.)), PF-3845 (10 mg/kg, i.p.), AM251 (1 or 2.5 mg/kg, i.p.), AM4113 (1 or 2.5 mg/kg, i.p.), and AM6527 (5 mg/kg, oral) were administered prior to conditioning. RESULTS: AM251 (2.5, but not 1 mg/k), AM4113, and AM6527, but not URB597 or PF-3845, interfered with the establishment of the MWD-induced CPA. AM251 and AM4113 did not prevent reinstatement of the CPA. CONCLUSIONS: Neutral antagonism of the CB1 receptor reduces the aversive affective properties of morphine withdrawal. PMID- 24770678 TI - Association of miRNA-related genetic polymorphisms and prognosis in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly disease with a poor prognosis. The single nucleotide polymorphisms (SNPs) involved in microRNA (miRNA) functions are potential biomarkers for prognosis of various human cancers. We investigated the association of the miRNA-related SNPs with the prognosis of ESCC. METHODS: A total of 504 patients with ESCC were enrolled. The genotypes of 18 miRNA-related SNPs were analyzed from the genomic DNA of peripheral leukocytes and were correlated with the prognosis of patients randomly assigned to a training set (n = 129) or an independent replication set (n = 375). RESULTS: In the training group, only the rs4919510 SNP of the mir-608 gene was significantly associated with clinical outcome (CG vs. GG, hazard ratio [HR] 0.47, 95 % confidence interval [CI] 0.27-0.82, P = 0.008 for death, HR 0.47, 95 % CI 0.29-0.77, P = 0.002 for recurrence). The association for overall survival was confirmed in an independent replication group (CG vs. GG, HR 0.74, 95 % CI 0.56 0.97, P = 0.031 for death). Two other SNPs, rs14035 of RAN and rs7813 of GEMIN4, showed a borderline significant association with the prognosis of ESCC. In a combined analysis, we demonstrated the cumulative effect of the mir-608, RAN, and GEMIN4 polymorphisms on the clinical outcome of ESCC (HR 1.40, 95 % CI 1.18-1.67, P trend < 0.001 for mortality, HR 1.30, 95 % CI 1.10-1.53, P trend = 0.002 for recurrence). The cumulative effect was more evident in patients receiving concurrent chemoradiotherapy. CONCLUSIONS: The hereditary genetic polymorphisms of mir-608, RAN, and GEMIN4 can serve as predictors for clinical outcome in ESCC patients treated with concurrent chemoradiotherapy. PMID- 24770679 TI - Cytoplasmic YAP expression is associated with prolonged survival in patients with lung adenocarcinomas and epidermal growth factor receptor tyrosine kinase inhibitor treatment. AB - BACKGROUND: Yes-associated protein (YAP) has been reported to be associated with the prognosis of various cancers and also to affect epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) activity in ovarian cancer cell lines. However, few studies have evaluated YAP protein expression in lung cancer, and the results have lacked consistency. METHODS: YAP expression was evaluated in a total of 205 curatively resected lung adenocarcinomas and 36 cases of EGFR mutated TKI-treated patients. Correlations between the expression of YAP and clinicopathologic features, response to EGFR-TKI treatment, and prognostic significance were analyzed. RESULTS: High cytoplasmic YAP expression was positively correlated with the clinicopathologic parameters that have been associated with favorable prognosis. Multivariate analysis revealed that high cytoplasmic YAP expression was an independent prognostic factor in lung adenocarcinomas (progression-free survival: hazard ratio [HR] 0.659; 95 % confidence interval [CI] 0.431-1.010; p = 0.050; overall survival: HR, 0.474; 95 % CI 0.263-0.854; p = 0.013) and EGFR-TKI-treated patients with EGFR mutation (progression-free survival: HR, 0.346; 95 % CI 0.146-0.818; p = 0.016; overall survival: HR, 0.291; 95 % CI 0.125-0.676; p = 0.004). CONCLUSIONS: High cytoplasmic YAP expression predicted a good clinical outcome for patients with lung adenocarcinoma and in EGFR-TKI-treated patients. Therefore, YAP may play a role in EGFR-TKI-treated lung cancer, and YAP targeting may enhance therapeutic effects in combination with other cancer drugs. PMID- 24770681 TI - Does completion thyroidectomy improve the outcome of patients with minimally invasive follicular carcinoma of the thyroid? AB - BACKGROUND: The diagnosis of minimally invasive follicular thyroid carcinoma (MIFTC) is often made histologically after thyroid lobectomy. We attempted to determine whether completion thyroidectomy should be considered necessary for all patients diagnosed with MIFTC after thyroid lobectomy. METHODS: The subjects of this study were a total of 324 patients who underwent thyroid lobectomy as initial surgery at our institution between 1989 and 2010 and diagnosed histologically as MIFTC. Completion thyroidectomy was performed on 101 patients, and the other 223 patients were followed up without further treatments. Cumulative cause-specific survival (CSS) rates and distant-metastasis-free survival (DMFS) rates were calculated by the Kaplan-Meier method. Differences between groups were analyzed for statistical significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional hazards model. RESULTS: During the follow-up period, 39 patients were diagnosed with distant metastasis, and 7 patients died of their disease. Age at the initial surgery was found to be a significant factor related to DMFS in both the univariate and multivariate analysis and to also be related to CSS in the univariate analysis. Completion thyroidectomy did not have a significant effect on DMFS or CSS according to the results of the univariate analysis, but it had significant effect on DMFS according to the results of the multivariate analysis. CONCLUSIONS: Although we were unable to demonstrate sufficient statistical evidence that completion thyroidectomy improved the outcome of MIFTC patients, it is noteworthy none of the patient who underwent completion thyroidectomy died of the disease. PMID- 24770680 TI - The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy for adenocarcinoma. AB - BACKGROUND: The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy (PD) for adenocarcinoma is still unclear. METHODS: A retrospective review of all patients undergoing PD at our institution between 1995 and 2011 was performed. Clinicopathological data, including Clavien-Dindo complication grade, time to adjuvant therapy (TTA), and survival, were analyzed. RESULTS: A total of 1,144 patients underwent PD for adenocarcinoma between 1995 and 2011. The overall complication rate was 49.1 % and clinically severe complications (>=IIIb) occurred in 4.2 %. Overall, 621 patients (54.3 %) were known to have received adjuvant therapy. The median TTA was 60 days. Although the presence of a complication was associated with a delay in TTA (p = 0.002), the grade of complication was not (p = 0.112). On multivariate analysis, only age > 68 years (p < 0.001) and length of stay >9 days (p = 0.002) correlated with no adjuvant therapy. Patients with postoperative complications were more likely to receive single adjuvant chemotherapy or radiation therapy (31.4 %) than were patients without complications (17.1 %; p < 0.001). Patients without a complication had a longer median survival compared with patients who experienced complications (19.5 vs. 16.1 months; p = 0.001). Patients without complications who received adjuvant therapy had longer median survival than patients with complications who received no adjuvant therapy (22.5 vs. 10.7 months; p < 0.001). Multivariate analysis demonstrated that complications [hazard ratio (HR) 1.16; p = 0.023] and adjuvant therapy (HR 0.67; p < 0.001) were related to survival. CONCLUSION: Complications and no adjuvant therapy are common following PD for adenocarcinoma. Postoperative complications delay TTA and reduce the likelihood of multimodality adjuvant therapy. Identifying patients at increased risk for complications and those unlikely to receive adjuvant therapy warrants further investigation as they may benefit from a neoadjuvant approach. PMID- 24770682 TI - [Is the ICU staff satisfied with the computerized physician order entry? A cross sectional survey study]. AB - OBJECTIVE: To evaluate the satisfaction of the intensive care unit staff with a computerized physician order entry and to compare the concept of the computerized physician order entry relevance among intensive care unit healthcare workers. METHODS: We performed a cross-sectional survey to assess the satisfaction of the intensive care unit staff with the computerized physician order entry in a 30-bed medical/surgical adult intensive care unit using a self-administered questionnaire. The questions used for grading satisfaction levels were answered according to a numerical scale that ranged from 1 point (low satisfaction) to 10 points (high satisfaction). RESULTS: The majority of the respondents (n=250) were female (66%) between the ages of 30 and 35 years of age (69%). The overall satisfaction with the computerized physician order entry scored 5.74+/-2.14 points. The satisfaction was lower among physicians (n=42) than among nurses, nurse technicians, respiratory therapists, clinical pharmacists and diet specialists (4.62+/-1.79 versus 5.97+/-2.14, p<0.001); satisfaction decreased with age (p<0.001). Physicians scored lower concerning the potential of the computerized physician order entry for improving patient safety (5.45+/-2.20 versus 8.09+/-2.21, p<0.001) and the ease of using the computerized physician order entry (3.83+/-1.88 versus 6.44+/-2.31, p<0.001). The characteristics independently associated with satisfaction were the system's user-friendliness, accuracy, capacity to provide clear information, and fast response time. CONCLUSION: Six months after its implementation, healthcare workers were satisfied, albeit not entirely, with the computerized physician order entry. The overall users' satisfaction with computerized physician order entry was lower among physicians compared to other healthcare professionals. The factors associated with satisfaction included the belief that digitalization decreased the workload and contributed to the intensive care unit quality with a user friendly and accurate system and that digitalization provided concise information within a reasonable time frame. PMID- 24770683 TI - [Impact of a continuous education program on the quality of assistance offered by intensive care physiotherapy]. AB - OBJECTIVE: To evaluate the role of quality indicators and adverse events registering in the quality assessment of intensive care physiotherapy and to evaluate the impact of implementing protocolized care and professional training in the quality improvement process. METHODS: A prospective before-after study was designed to assess 15 indicators of the quality of care. Baseline compliance and adverse events were collected before and after the implementation of treatment protocols and staff training. RESULTS: Eighty-nine patients admitted, being 48 in the pre-intervention period and 41 in the post-intervention period with a total of 1246 and 1191 observations respectively. Among the indicators related to the global population, there was a significant improvement in chest x-ray control, multidisciplinary rounds and shift changes as well as in compliance with these decisions. Indicators related to the population under mechanical ventilation, obtained by direct observation at bedside, showed a significant improvement in the compliance with the tidal volume of 6-8 mL/Kg, plateau pressure <30 cmH2O, adequate mechanical ventilation alarm setting, mechanical ventilation humidification control, adequate humidification line exchange and orotracheal tube position. Among the mechanical ventilation indicators collected through the physiotherapy records, there was significantly improved compliance with the predicted tidal volume registry and cuff pressure registry. There was a significant reduction in the number of adverse events. There was no impact on intensive care unit mortality, length of stay, duration of mechanical ventilation and ventilator-free days. CONCLUSION: It is possible to measure the quality of physiotherapy care using indicators of quality control. The implementation of care protocols and training of the professionals can improve team performance. PMID- 24770684 TI - [Augmented renal clearance in critically ill patients: incidence, associated factors and effects on vancomycin treatment]. AB - OBJECTIVE: An augmented renal clearance has been described in some groups of critically ill patients, and it might induce sub-optimal concentrations of drugs eliminated by glomerular filtration, mainly antibiotics. Studies on its occurrence and determinants are lacking. Our goals were to determine the incidence and associated factors of augmented renal clearance and the effects on vancomycin concentrations and dosing in a series of intensive care unit patients. METHODS: We prospectively studied 363 patients admitted during 1 year to a clinical-surgical intensive care unit. Patients with serum creatinine >1.3 mg/dL were excluded. Creatinine clearance was calculated from a 24-hour urine collection. Patients were grouped according to the presence of augmented renal clearance (creatinine clearance >120 mL/min/1.73 m2), and possible risk factors were analyzed with bivariate and logistic regression analysis. In patients treated with vancomycin, dosage and plasma concentrations were registered. RESULTS: Augmented renal clearance was present in 103 patients (28%); they were younger (48+/-15 versus 65+/-17 years, p<0.0001), had more frequent obstetric (16 versus 7%, p=0.0006) and trauma admissions (10 versus 3%, p=0.016) and fewer comorbidities. The only independent determinants for the development of augmented renal clearance were age (OR 0.95; p<0.0001; 95%CI 0.93-0.96) and absence of diabetes (OR 0.34; p=0.03; 95%CI 0.12-0.92). Twelve of the 46 patients who received vancomycin had augmented renal clearance and despite higher doses, had lower concentrations. CONCLUSIONS: In this cohort of critically ill patients, augmented renal clearance was a common finding. Age and absence of diabetes were the only independent determinants. Therefore, younger and previously healthy patients might require larger vancomycin dosing. PMID- 24770685 TI - [Profile of effective donors from organ and tissue procurement services]. AB - OBJECTIVE: To characterize the profile of effective organ and tissue donors and to understand which organs and tissues were donated for transplantation. METHODS: This was a quantitative, descriptive, exploratory, retrospective study that analyzed clinical data from 305 donors between January 2006 to December 2010. The data were then analyzed using descriptive analyses, generating frequency tables, measures of position (mean, minimum and maximum) and measures of dispersion (standard deviation) for data that was social and clinical in nature. RESULTS: There was an overall predominance of white (72%) and male (55%) individuals between the ages of 41 and 60 years (44%). The primary cause of brain death was cerebrovascular accident (55%). In the patient history, 31% of the patients were classified as overweight, 27% as hypertensive and only 4.3% as having diabetes mellitus. Vasoactive drugs were used in 92.7% of the donors, and the main drug of choice was noradrenaline (81.6%). Hyperglycemia and hypernatremia were diagnosed in 78% and 71% of the donors, respectively. CONCLUSION: Significant hemodynamic changes were found, and the results indicate that the use of vasoactive drugs was the main strategy used to control these changes. Furthermore, most donors presented with hyperglycemia and hypernatremia, which were frequently reported in association with brain death. The persistent nature of these findings suggests that the organ donors were inadequately maintained. PMID- 24770686 TI - [Reaction time of a health care team to monitoring alarms in the intensive care unit: implications for the safety of seriously ill patients]. AB - OBJECTIVE: To define the characteristics and measure the reaction time of a health care team monitoring alarms in the intensive care unit. METHODS: A quantitative, observational, and descriptive study developed at the coronary care unit of a cardiology public hospital in Rio de Janeiro state (RJ). Data were obtained from the information collected on the patients, the monitoring used, and the measurement of the team's reaction time to the alarms of multi-parameter monitors during a non-participatory field observation. RESULTS: Eighty-eight patients were followed (49 during the day shift and 39 during the night shift). During the 40 hours of observation (20 hours during the day shift and 20 hours during the night shift), the total number of monitoring alarms was 227, with 106 alarms during the day shift and 121 during the night shift, an average of 5.7 alarms/hour. In total, 145 alarms unanswered by the team were observed, with 68 occurring during the day shift (64.15%) and 77 during the night shift (63.64%). This study demonstrated that the reaction time was longer than 10 minutes in more than 60% of the alarms, which were considered as unanswered alarms. The median reaction time of the answered alarms was 4 minutes and 54 seconds during the day shift and 4 minutes and 55 seconds during the night shift. The respiration monitoring was activated in only nine patients (23.07%) during the night shift. Regarding the alarm quality of these variables, the arrhythmia alarm was qualified in only 10 (20.40%) of the day-shift patients and the respiration alarm in four night-shift patients (44.44%). CONCLUSION: The programming and configuration of the physiological variables monitored and the parameters of alarms in the intensive care unit were inadequate; there was a delay and lack of response to the alarms, suggesting that relevant alarms may have been ignored by the health care team, thus compromising the patient safety. PMID- 24770687 TI - [Use of scores to calculate the nursing workload in a pediatric intensive care unit]. AB - OBJECTIVE: To assess the performance of the Nursing Activities Score in a pediatric intensive care unit, compare its scores expressed as time spent on nursing activities to the corresponding ones calculated using the Simplified Therapeutic Intervention Scoring System, and correlate the results obtained by both instruments with severity, morbidity and mortality. METHODS: Prospective, observational, and analytical cohort study conducted at a type III general pediatric intensive care unit. The study participants were all the children aged 29 days to 12 years admitted to the investigated pediatric intensive care unit from August 2008 to February 2009. RESULTS: A total of 545 patients were studied, which corresponded to 2,951 assessments. The average score of the Simplified Therapeutic Intervention Scoring System was 28.79+/-10.37 (915+/-330 minutes), and that of the Nursing Activities Score was 55.6+/-11.82 (802+/-161 minutes). The number of minutes that resulted from the conversion of the Simplified Therapeutic Intervention Scoring System score was higher compared to that resulting from the Nursing Activities Score for all the assessments (p<0.001). The correlation between the instruments was significant, direct, positive, and moderate (R=0.564). CONCLUSIONS: The agreement between the investigated instruments was satisfactory, and both instruments also exhibited satisfactory discrimination of mortality; for that purpose, the best cutoff point was 16 nursing hours/patient day. PMID- 24770688 TI - [Performance of the Pediatric Index of Mortality 2 in a pediatric intensive care unit]. AB - OBJECTIVE: To assess the discrimination and calibration of the Pediatric Index of Mortality 2 in patients admitted to a pediatric intensive care unit. METHODS: The study was conducted with a contemporary cohort from November 2005 to November 2006. Patients aged 29 days to 18 years were included in the study. Patients who died within 12 hours of admission and cases of readmission were excluded from the study. The performance of the Pediatric Index of Mortality 2 was assessed by means of the Hosmer-Lemeshow goodness-of-fit test, the standardized mortality ratio and the area under receiver operating characteristic (ROC) curve with 95% confidence interval. The significance level was established as 5%. RESULTS: A total of 276 admissions to the pediatric intensive care unit were included in the analysis. The mortality rate was 14.13%, and the efficiency of admission 0.88%. The median age of the sample was 42.22 months, and most participants were male (60.1%). Most admissions were referrals from the emergency department. The mean duration of stay in pediatric intensive care unit was 6.43+/-5.23 days. Approximately 72.46% of admissions were for clinical reasons and exhibited an association with the outcome death (odds ratio: 2.9; 95%CI: 1.09-7.74; p=0.017). Calibration of the Pediatric Index of Mortality 2 with the chi-square statistic was 12.2686 (p=0.1396) in the Hosmer-Lemeshow goodness-of-fit test, and the standardized mortality ratio was 1.0. The area under the ROC curve assessing model discrimination was 0.778. CONCLUSION: Pediatric Index of Mortality 2 exhibited satisfactory performance. PMID- 24770689 TI - [Predictors of extubation failure and reintubation in newborn infants subjected to mechanical ventilation]. AB - OBJECTIVE: To identify risk factors for extubation failure and reintubation in newborn infants subjected to mechanical ventilation and to establish whether ventilation parameters and blood gas analysis behave as predictors of those outcomes. METHODS: Prospective study conducted at a neonatal intensive care unit from May to November 2011. A total of 176 infants of both genders subjected to mechanical ventilation were assessed after extubation. Extubation failure was defined as the need to resume mechanical ventilation within less than 72 hours. Reintubation was defined as the need to reintubate the infants any time after the first 72 hours. RESULTS: Based on the univariate analysis, the variables gestational age <28 weeks, birth weight <1,000 g and low Apgar scores were associated with extubation failure and reintubation. Based on the multivariate analysis, the variables length of mechanical ventilation (days), potential of hydrogen (pH) and partial pressure of oxygen (pO2) remained associated with extubation failure, and the five-minute Apgar score and age at extubation were associated with reintubation. CONCLUSION: Low five-minute Apgar scores, age at extubation, length of mechanical ventilation, acid-base disorders and hyperoxia exhibited associations with the investigated outcomes of extubation failure and reintubation. PMID- 24770690 TI - [Availability of physical therapy assistance in neonatal intensive care units in the city of Sao Paulo, Brazil]. AB - OBJECTIVE: To describe the characteristics of physical therapy assistance to newborns and to provide a profile of physical therapists working in intensive care units in the city of Sao Paulo, Brazil. METHODS: This cross-sectional study was conducted in every hospital in Sao Paulo city that had at least one intensive care unit bed for newborns registered at the National Registry of Health Establishments in 2010. In each unit, three types of physical therapists were included: an executive who was responsible for the physical therapy service in that hospital (chief-physical therapists), a physical therapist who was responsible for the physical therapy assistance in the neonatal unit (reference physical therapists), and a randomly selected physical therapist who was directly involved in the neonatal care (care-physical therapists). RESULTS: Among the 67 hospitals eligible for the study, 63 (94.0%) had a physical therapy service. Of those hospitals, three (4.8%) refused to participate. Thus, 60 chief-PTs, 52 reference-physical therapists, and 44 care-physical therapists were interviewed. During day shifts, night shifts, and weekends/holidays, there were no physical therapists in 1.7%, 45.0%, and 13.3% of the intensive care units, respectively. Physical therapy assistance was available for 17.8+/-7.2 hours/day, and each physical therapist cared for 9.4+/-2.6 newborns during six working hours. Most professionals had completed at least one specialization course. CONCLUSION: Most neonatal intensive care units in the city of Sao Paulo had physical therapists working on the day shift. However, other shifts had incomplete staff with less than 18 hours of available physical therapy assistance per day. PMID- 24770691 TI - [Impact of hospitalization in an intensive care unit on range of motion of critically ill patients: a pilot study]. AB - OBJECTIVE: To evaluate the joint range of motion of critically ill patients during hospitalization in the intensive care unit. METHODS: This work was a prospective longitudinal study conducted in a critical care unit of a public hospital in the city of Salvador (BA) from September to November 2010. The main variable evaluated was the passive joint range of motion. A goniometer was used to measure the elbows, knees and ankles at the time of admission and at discharge. All patients admitted in the period were included other than patients with length of stay <72 hours and patients with reduced joint range of motion on admission. RESULTS: The sample consisted of 22 subjects with a mean age of 53.5+/ 17.6 years, duration of stay in the intensive care unit of 13.0+/-6.0 days and time on mechanical ventilation of 12.0+/-6.3 days. The APACHE II score was 28.5+/ 7.3, and the majority of patients had functional independence at admission with a prior Barthel index of 88.8+/-19. The losses of joint range of motion were 11.1+/ 2.1 degrees , 11.0+/-2.2 degrees , 8.4+/-1.7 degrees , 9.2+/-1.6 degrees , 5.8+/ 0.9 degrees and 5.1+/-1.0 degrees , for the right and left elbows, knees and ankles, respectively (p<0.001). CONCLUSION: There was a tendency towards decreased range of motion of large joints such as the ankle, knee and elbow during hospitalization in the intensive care unit. PMID- 24770692 TI - [Assessment and treatment of hyperglycemia in critically ill patients]. AB - Hyperglycemia is a commonly encountered issue in critically ill patients in the intensive care setting. The presence of hyperglycemia is associated with increased morbidity and mortality, regardless of the reason for admission (e.g., acute myocardial infarction, status post-cardiovascular surgery, stroke, sepsis). However, the pathophysiology and, in particular, the treatment of hyperglycemia in the critically ill patient remain controversial. In clinical practice, several aspects must be taken into account in the management of these patients, including blood glucose targets, history of diabetes mellitus, the route of nutrition (enteral or parenteral), and available monitoring equipment, which substantially increases the workload of providers involved in the patients' care. This review describes the epidemiology, pathophysiology, management, and monitoring of hyperglycemia in the critically ill adult patient. PMID- 24770693 TI - Distal tibia fractures and medial plating: factors influencing re-operation. AB - PURPOSE: We compared types of complications leading to re-operations in open and closed distal tibia fractures treated by locking or nonlocking medial plates. METHODS: Ninety-three patients from 2002 to 2012 who underwent open reduction and internal fixation (ORIF) and medial plating for distal extra-articular or partial articular tibia fractures were identified. Charts were retrospectively reviewed to determine the incidence of re-operation based on the type of complication that developed. Fisher's exact and chi-square tests were performed to analyze the incidence of complications based on injury and type of plate used. RESULTS: Thirty-three (35.5 %) patients required re-operations: 28.6 % (n = 16) with closed injuries had complications leading to re-operations compared with 45.9 % (n = 17) of patients with open injuries (p = 0.12). Patients with closed injuries were more likely to require re-operation due to hardware pain/prominence (p = 0.03), whereas patients with open injuries were more likely to require re operation due to nonunion (p = 0.04). There were no significant differences in infection (p = 0.66) or malunion (p = 0.99) between groups. Locking plates showed higher costs but were not associated with decreased risk of re-operation. CONCLUSIONS: There was a high re-operation rate associated with distal tibia medial plating, with significant differences in the reason for re-operation between open versus closed groups. Complication rates were not influenced by the use of locking plates. Results of this study suggest that methods be considered to reduce re-operation based on type of fracture, such as early bone grafting or the use of alternate implants for open fractures. PMID- 24770694 TI - Clinical relevance of neuroforaminal patency after anterior cervical discectomy and fusion. AB - BACKGROUND: We sought to investigate the clinical relevance of neuroforaminal patency and facet degeneration one year after anterior cervical discectomy and fusion (ACDF). Previous studies were characterized by imprecise techniques and fragmentary measurements, and most lacked reliable clinical data and correlation analyses. METHODS: Patients with cervical mono- or bi-level degenerative pathology were prospectively included. Neuroforaminal size and segmental height were determined quantitatively, and the degree of facet degeneration was assessed qualitatively before and one year after the operation, by computed tomography. Clinical data, such as the severity of neck and arm pain, were assessed on a visual analogue scale (VAS) from 0 to 10, and neck disability index (NDI) was recorded before and one year after the operation. Their correlation with radiological data was investigated. RESULTS: Seventy-nine patients aged 53.3 +/- 11.3 years were included. One year after surgery, median VAS pain intensity was still significantly improved (neck, from 5 to 1; right arm, from 2 to 1; left arm, from 4 to 1) as was NDI (from 40 to 20). Neuroforaminal size showed a reduction on both sides (left, 0.0289 +/- 0.09 cm(2); right, 0.0149 +/- 0.08 cm(2)). One year after the operation, segmental height decreased and facet degeneration increased from measures taken before the operation. No correlations were found between neuroforaminal stenosis or the degree of facet degeneration and various clinical outcome parameters. CONCLUSIONS: The decrease in segmental height one year after ACDF leads in turn to secondary neuroforaminal stenosis and progressive facet degeneration. Of the various neuroforaminal variables used, none revealed a threshold value indicative of the presence or severity of radicular arm pain. This absence of correlation between imaging and clinical information is important and should be considered when allocating patients for surgical interventions. PMID- 24770695 TI - Simple, low cost MHz-order acoustomicrofluidics using aluminium foil electrodes. AB - It is now possible to circumvent costly and complex cleanroom fabrication procedures to produce MHz-order acoustically-driven microfluidic platforms through the use of electrode strips cut simply from kitchen aluminium foil and pressed against piezoelectric substrates. Cleanroom deposition, lithographic patterning, and etching are entirely avoided in favor of this cut-and-place technique, which enables the generation of acoustic Lamb waves of sufficient amplitude to demonstrate rapid and efficient microfluidic transport and manipulation, microcentrifugation, and even nebulization of both sessile drops and paper-based substrates. Elimination of microfabrication processes typical of acoustic microfluidics brings us a significant step closer towards commercially viable consumer diagnostic devices, especially for use in the developing world. PMID- 24770696 TI - Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in embryonic stem cells. AB - Kruppel-like factors (Klf) 4 and 5 are two closely related members of the Klf family, known to play key roles in cell cycle regulation, somatic cell reprogramming and pluripotency. Here we focus on the functional divergence between Klf4 and Klf5 in the inhibition of mouse embryonic stem (ES) cell differentiation. Using microarrays and chromatin immunoprecipitation coupled to ultra-high-throughput DNA sequencing, we show that Klf4 negatively regulates the expression of endodermal markers in the undifferentiated ES cells, including transcription factors involved in the commitment of pluripotent stem cells to endoderm differentiation. Knockdown of Klf4 enhances differentiation towards visceral and definitive endoderm. In contrast, Klf5 negatively regulates the expression of mesodermal markers, some of which control commitment to the mesoderm lineage, and knockdown of Klf5 specifically enhances differentiation towards mesoderm. We conclude that Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in murine ES cells. PMID- 24770697 TI - Energy expenditure in individuals with spinal cord injury quantified by doubly labeled water and a multi-sensor armband. AB - BACKGROUND: The objective of this study was to determine whether doubly labeled water (DLW) and a multi-sensor armband (SWA) could detect the variation in energy expenditure incurred by a period of increased exercise (EXE) versus a period of high sedentary activity (SED), in individuals with spinal cord injury (SCI). METHODS: Eight participants with SCI were submitted to 2 testing periods of energy expenditure assessment: 1) a 14-day phase during which sedentary living conditions were imposed and 2) a 14-day phase during which an exercise training intervention was employed. For each phase, total daily energy expenditure (TDEE) and physical activity energy expenditure (PAEE) were measured by DLW and SWA. RESULTS: Mean TDEE assessed by DLW, was significantly higher during EXE versus SED (11,605 +/- 2151 kJ.day-1 and 10,069 +/- 2310 kJ.day-1). PAEE predicted by DLW was also significantly higher during EXE versus SED (5422 +/- 2240 kJ.day-1 and 3855 +/- 2496 kJ.day-1). SWA-predicted PAEE significantly underestimated PAEE measured by the DLW during SED and EXE. CONCLUSION: DLW is sensitive to detect variation in within-individual energy expenditure during voluntary increase in physical activity in individuals with SCI. SWA failed to detect statistically significant variations in energy expenditure between periods of high versus low activity in SCI. PMID- 24770698 TI - Competition between excited state proton and OH(-) transport via a short water wire: solvent effects open the gate. AB - We investigate the acid-base proton exchange reaction in a microsolvated bifunctional chromophore by means of quantum chemical calculations. The UV/vis spectroscopy shows that equilibrium of the keto- and enol-forms in the electronic ground state is shifted to the keto conformation in the excited state. A previously unknown mechanism involving a hydroxide ion transport along a short water wire is characterized energetically, which turns out to be competitive with the commonly assumed proton transport. Both mechanisms are shown to have a concerted character, as opposed to a step-wise mechanism. The alternative mechanism of a hydrogen atom transport is critically examined, and evidence for strong solvent dependence is presented. Specifically, we observe electrostatic destabilization of the corresponding pisigma* state by the aqueous solvent. As a consequence, no conical intersections are found along the reaction pathway. PMID- 24770699 TI - Exercise volume and intensity: a dose-response relationship with health benefits. AB - INTRODUCTION: The health benefits of exercise are well established. However, the relationship between exercise volume and intensity and health benefits remains unclear, particularly the benefits of low-volume and intensity exercise. PURPOSE: The primary purpose of this investigation was, therefore, to examine the dose response relationship between exercise volume and intensity with derived health benefits including volumes and intensity of activity well below international recommendations. METHODS: Generally healthy, active participants (n = 72; age = 44 +/- 13 years) were assigned randomly to control (n = 10) or one of five 13 week exercise programs: (1) 10-min brisk walking 1*/week (n = 10), (2) 10-min brisk walking 3*/week (n = 10), (3) 30-min brisk walking 3*/week (n = 18), (4) 60 min brisk walking 3*/week (n = 10), and (5) 30-min running 3*/week (n = 14), in addition to their regular physical activity. Health measures evaluated pre- and post-training including blood pressure, body composition, fasting lipids and glucose, and maximal aerobic power (VO2max). RESULTS: Health improvements were observed among programs at least 30 min in duration, including body composition and VO2max: 30-min walking 28.8-34.5 mL kg(-1) min(-1), 60-min walking 25.1-28.9 mL kg(-1) min(-1), and 30-min running 32.4-36.4 mL kg(-1) min(-1). The greater intensity running program also demonstrated improvements in triglycerides. CONCLUSION: In healthy active individuals, a physical activity program of at least 30 min in duration for three sessions/per week is associated with consistent improvements in health status. PMID- 24770700 TI - Relating significance and relations of differentially expressed genes in response to Aspergillus flavus infection in maize. AB - Aspergillus flavus is a pathogenic fungus infecting maize and producing aflatoxins that are health hazards to humans and animals. Characterizing host defense mechanism and prioritizing candidate resistance genes are important to the development of resistant maize germplasm. We investigated methods amenable for the analysis of the significance and relations among maize candidate genes based on the empirical gene expression data obtained by RT-qPCR technique from maize inbred lines. We optimized a pipeline of analysis tools chosen from various programs to provide rigorous statistical analysis and state of the art data visualization. A network-based method was also explored to construct the empirical gene expression relational structures. Maize genes at the centers in the network were considered as important candidate genes for maize DNA marker studies. The methods in this research can be used to analyze large RT-qPCR datasets and establish complex empirical gene relational structures across multiple experimental conditions. PMID- 24770701 TI - Inguinal hernia repair using a synthetic long-term resorbable mesh: results from a 3-year prospective safety and performance study. AB - PURPOSE: Conventional meshes for hernia repair and abdominal wall reinforcement are usually made from polypropylene, polyester or other synthetic plastic materials known to promote foreign body reactions and a state of chronic inflammation that may lead to long-term complications. A novel approach is to use long-term resorbable implants like TIGR((r)) Matrix Surgical Mesh. Preclinical studies have shown that this mesh maintains mechanical integrity beyond the point in time where newly formed tissue is capable of carrying the abdominal loads. METHODS: This was a first-in-man, prospective, pilot study performed during 2009, at two sites in Sweden. Forty patients with primary inguinal hernias were enrolled for Lichtenstein repair using TIGR((r)) Matrix Surgical Mesh. The primary endpoint was safety as assessed by monitoring the incidence of adverse events and serious adverse events (SAEs) both related and unrelated to the mesh. The secondary endpoint was pain or discomfort. Visual Analogue Scale (VAS) 0-10 and Inguinal Pain Questionnaire were used for scoring pain and discomfort. Included patients have been followed for 36 months using ultrasound in combination with clinical examination. RESULTS: All patients followed a normal early postoperative course. After 12 months no SAEs were reported. None of the patients with an isolated lateral inguinal hernia (LIH) had developed a recurrence but 4 (44 %) with medial and 4 (33 %) with combined hernias had recurred at 36-month follow-up. After 3-year follow-up none of the patients with LIH reported pain in the VAS-form and none of those patients could feel the sensation of a mesh in their groin. In the total study population 5 (16 %) patients experienced chronic pain in the form of mild sporadic pain and 3 (9.7 %) patients could feel the sensation of a mesh in their groin. CONCLUSION: The use of a synthetic long-term resorbable mesh (TIGR((r)) Matrix Surgical Mesh) in Lichtenstein repair was found to be safe, without recurrences, and promising regarding pain/discomfort at 3-year follow-up in patients with LIH. However, patients with medial and combined inguinal hernias had high recurrence rates. PMID- 24770702 TI - Is prior laparoscopy experience required for adaptation to robotic rectal surgery?: Feasibility of one-step transition from open to robotic surgery. AB - PURPOSE: The objective of this study is to ascertain the impact of laparoscopic colorectal surgery (LCS) experience on the learning curve of robotic rectal cancer surgery (RRS). Whether LCS experience is mandatory on overcoming the learning curve of RRS or not remains undetermined. METHODS: Before starting the robotic procedure, surgeon A had a limited experience of less than 30 LCS cases, whereas surgeon B had performed more than 300 cases of LCS. From the beginning, 100 consecutive, unselected RRS cases performed by each of the two surgeons were retrospectively analyzed (groups A and B). Perioperative surgical and oncologic outcomes were compared between the two groups. RESULTS: Clinicopathological characteristics between the two groups were similar. One case in group A was converted to open surgery. Mean operation time was shorter in group A than that of group B (272 vs. 344 min, p < 0.001). Overall perioperative morbidity rates were not different between the two groups (17.0 vs. 10.0 %, p = 0.214). There was no difference of circumferential resection margin positivity rate and retrieved lymph node numbers. In group A, the operation time decreased with a steep slope until 17 cases on the moving average curve. The slope in group B maintained a steady state and showed no remarkable changes throughout the study period. CONCLUSIONS: A one-step transition from open to robotic rectal cancer surgery can be achieved without having extensive prior laparoscopic experience. PMID- 24770703 TI - Evaluation of selected risk factors of cardiovascular diseases among patients after kidney transplantation, with particular focus on the role of 24-hour automatic blood pressure measurement in the diagnosis of hypertension: an introductory report. AB - BACKGROUND: Arterial hypertension is a donor-related and modifiable risk factor in a graft dysfunction. The aim of the study was to perform a multi-factor analysis describing the relations between arterial hypertension and clinical parameters of a graft recipient. MATERIAL AND METHODS: Fifty patients 3 months after a kidney transplant took part in the study. The following research tools were used: (1) 24-hour Ambulatory Blood Pressure Monitoring, ABPM; (2) traditional method - office BP; (3) the authors' questionnaire form, (4) Morisky Green test for self-evaluation of the compliance level; (5) disease history. The relevance level was p<0.05. RESULTS: ABPM results showed that only 8 (16%) renal transplant recipients are normotensive without any antihypertensive drugs. It was shown through ABPM that insufficient controlling of hypertension was observed in 22 patients (44%). It was shown that 9 patients (18%) had masked hypertension and 5 patients (10%) white-coat hypertension. Eight patients (16%) showed controlled daily rhythm of blood pressure ("dippers"). No statistically significant correlation between ABPM and office BP and creatinine level was observed. CONCLUSIONS: The results of the study show insufficient control of arterial hypertension and the occurrence of masked hypertension and the white-coat effect in patients after KTx. ABPM should be routinely performed in post-KTx patients. Nonadherence to regular taking of medication and improper lifestyle of patients in the third month after KTx are not a risk factor in higher values of arterial hypertension and higher level of creatinine. PMID- 24770704 TI - Pitch Memory in Nonmusicians and Musicians: Revealing Functional Differences Using Transcranial Direct Current Stimulation. AB - For music and language processing, memory for relative pitches is highly important. Functional imaging studies have shown activation of a complex neural system for pitch memory. One region that has been shown to be causally involved in the process for nonmusicians is the supramarginal gyrus (SMG). The present study aims at replicating this finding and at further examining the role of the SMG for pitch memory in musicians. Nonmusicians and musicians received cathodal transcranial direct current stimulation (tDCS) over the left SMG, right SMG, or sham stimulation, while completing a pitch recognition, pitch recall, and visual memory task. Cathodal tDCS over the left SMG led to a significant decrease in performance on both pitch memory tasks in nonmusicians. In musicians, cathodal stimulation over the left SMG had no effect, but stimulation over the right SMG impaired performance on the recognition task only. Furthermore, the results show a more pronounced deterioration effect for longer pitch sequences indicating that the SMG is involved in maintaining higher memory load. No stimulation effect was found in both groups on the visual control task. These findings provide evidence for a causal distinction of the left and right SMG function in musicians and nonmusicians. PMID- 24770705 TI - ADF/Cofilin Controls Synaptic Actin Dynamics and Regulates Synaptic Vesicle Mobilization and Exocytosis. AB - Actin is a regulator of synaptic vesicle mobilization and exocytosis, but little is known about the mechanisms that regulate actin at presynaptic terminals. Genetic data on LIMK1, a negative regulator of actin-depolymerizing proteins of the ADF/cofilin family, suggest a role for ADF/cofilin in presynaptic function. However, synapse physiology is fully preserved upon genetic ablation of ADF in mice, and n-cofilin mutant mice display defects in postsynaptic plasticity, but not in presynaptic function. One explanation for this phenomenon is overlapping functions of ADF and n-cofilin in presynaptic physiology. Here, we tested this hypothesis and genetically removed ADF together with n-cofilin from synapses. In double mutants for ADF and n-cofilin, synaptic actin dynamics was impaired and more severely affected than in single mutants. The resulting cytoskeletal defects heavily affected the organization, mobilization, and exocytosis of synaptic vesicles in hippocampal CA3-CA1 synapses. Our data for the first time identify overlapping functions for ADF and n-cofilin in presynaptic physiology and vesicle trafficking. We conclude that n-cofilin is a limiting factor in postsynaptic plasticity, a function which cannot be substituted by ADF. On the presynaptic side, the presence of either ADF or n-cofilin is sufficient to control actin remodeling during vesicle release. PMID- 24770706 TI - Widespread Monoaminergic Dysregulation of Both Motor and Non-Motor Circuits in Parkinsonism and Dyskinesia. AB - Beyond dopamine (DA) loss, Parkinson's disease is associated with many other monoamine alterations. While some monoaminergic systems benefit from l-3,4 dihydroxyphenylalanine (l-Dopa) treatment, others seem to be further altered, contributing to dyskinesia and nonmotor symptoms. Surprisingly, the different contributions of parkinsonism and l-Dopa treatment on monoaminergic changes remain largely unknown. Here, both the consequences of vehicle or 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure and the subsequent effects of acute or chronic l-Dopa treatment were evaluated in macaques. Monoamine levels were measured in the putamen, the motor and prefrontal cortices, the hippocampus, and the amygdala using postmortem high-pressure liquid chromatography. In normal monkeys, l-Dopa treatment increased DA in the prefrontal cortex and hippocampus, but decreased serotonin levels in motor domains. Chronic l-Dopa treatment elevated monoamine levels in the prefrontal cortex, hippocampus, and amygdala in both normal and MPTP-treated monkeys. A substantial increase in DA levels in these regions, paralleled by a decrease in serotonin concentrations were related with dyskinesia severity, demonstrating that major changes in monoamine release also occur in nonmotor regions. Such monoaminergic dysregulation in limbic domains may also directly contribute to the expression of motor complications, such as dyskinesia, by impairing integrative processes upstream from motor execution. PMID- 24770707 TI - Network Interactions Explain Sensitivity to Dynamic Faces in the Superior Temporal Sulcus. AB - The superior temporal sulcus (STS) in the human and monkey is sensitive to the motion of complex forms such as facial and bodily actions. We used functional magnetic resonance imaging (fMRI) to explore network-level explanations for how the form and motion information in dynamic facial expressions might be combined in the human STS. Ventral occipitotemporal areas selective for facial form were localized in occipital and fusiform face areas (OFA and FFA), and motion sensitivity was localized in the more dorsal temporal area V5. We then tested various connectivity models that modeled communication between the ventral form and dorsal motion pathways. We show that facial form information modulated transmission of motion information from V5 to the STS, and that this face selective modulation likely originated in OFA. This finding shows that form selective motion sensitivity in the STS can be explained in terms of modulation of gain control on information flow in the motion pathway, and provides a substantial constraint for theories of the perception of faces and biological motion. PMID- 24770708 TI - The Effects of X Chromosome Loss on Neuroanatomical and Cognitive Phenotypes During Adolescence: a Multi-modal Structural MRI and Diffusion Tensor Imaging Study. AB - The absence of all or part of one X chromosome in female humans causes Turner's syndrome (TS), providing a unique "knockout model" to investigate the role of the X chromosome in neuroanatomy and cognition. Previous studies have demonstrated TS associated brain differences; however, it remains largely unknown 1) how the brain structures are affected by the type of X chromosome loss and 2) how X chromosome loss influences the brain-cognition relationship. Here, we addressed these by investigating gray matter morphology and white matter connectivity using a multimodal MRI dataset from 34 adolescent TS patients (13 mosaic and 21 nonmosaic) and 21 controls. Intriguingly, the 2 TS groups exhibited significant differences in surface area in the right angular gyrus and in white matter integrity of the left tapetum of corpus callosum; these data support a link between these brain phenotypes and the type of X chromosome loss in TS. We further showed that the X chromosome modulates specific brain-cognition relationships: thickness and surface area in multiple cortical regions are positively correlated with working-memory performance in controls but negatively in TS. These findings provide novel insights into the X chromosome effect on neuroanatomical and cognitive phenotypes and highlight the role of genetic factors in brain-cognition relationships. PMID- 24770709 TI - Determinants of Global Color-Based Selection in Human Visual Cortex. AB - Feature attention operates in a spatially global way, with attended feature values being prioritized for selection outside the focus of attention. Accounts of global feature attention have emphasized feature competition as a determining factor. Here, we use magnetoencephalographic recordings in humans to test whether competition is critical for global feature selection to arise. Subjects performed a color/shape discrimination task in one visual field (VF), while irrelevant color probes were presented in the other unattended VF. Global effects of color attention were assessed by analyzing the response to the probe as a function of whether or not the probe's color was a target-defining color. We find that global color selection involves a sequence of modulations in extrastriate cortex, with an initial phase in higher tier areas (lateral occipital complex) followed by a later phase in lower tier retinotopic areas (V3/V4). Importantly, these modulations appeared with and without color competition in the focus of attention. Moreover, early parts of the modulation emerged for a task-relevant color not even present in the focus of attention. All modulations, however, were eliminated during simple onset-detection of the colored target. These results indicate that global color-based attention depends on target discrimination independent of feature competition in the focus of attention. PMID- 24770710 TI - Cortical Gray-White Matter Blurring and Cognitive Morbidity in Focal Cortical Dysplasia. AB - Focal cortical dysplasia (FCD) is a malformation of cortical development that is associated with high rates of cognitive morbidity. However, the degree to which specific irregularities of dysplastic tissue directly impact cognition remains unknown. This study investigates the relationship between blurring of the cortical gray and white matter boundary on magnetic resonance imaging (MRI) and global cognitive abilities in FCD. Gray-white blurring (GWB) is quantified by sampling the non-normalized T1 image intensity contrast above and below the gray and white matter interface along the cortical mantle. Spherical averaging is used to compare resulting GWB for patients with histopathologically verified FCD with matched controls. Whole-brain correlational analyses are used to investigate the relationship between blurring and general cognitive abilities, controlling for epilepsy duration. Results show that cognitive performance is reduced in patients with FCD relative to controls. Patients show increased GWB in bilateral temporal, parietal, and frontal regions. Furthermore, increased GWB in these regions is linearly related to decreased cognition and mediates group differences in cognitive performance. These findings demonstrate that GWB is a marker of reduced cognitive efficiency in FCD that can potentially be used to probe general and domain-specific cognitive functions in other neurological disorders. PMID- 24770711 TI - Functional Characterization of the Cingulo-Opercular Network in the Maintenance of Tonic Alertness. AB - The complex processing architecture underlying attentional control requires delineation of the functional role of different control-related brain networks. A key component is the cingulo-opercular (CO) network composed of anterior insula/operculum, dorsal anterior cingulate cortex, and thalamus. Its function has been particularly difficult to characterize due to the network's pervasive activity and frequent co-activation with other control-related networks. We previously suggested this network to underlie intrinsically maintained tonic alertness. Here, we tested this hypothesis by separately manipulating the demand for selective attention and for tonic alertness in a two-factorial, continuous pitch discrimination paradigm. The 2 factors had independent behavioral effects. Functional imaging revealed that activity as well as functional connectivity in the CO network increased when the task required more tonic alertness. Conversely, heightened selective attention to pitch increased activity in the dorsal attention (DAT) network but not in the CO network. Across participants, performance accuracy showed dissociable correlation patterns with activity in the CO, DAT, and fronto-parietal (FP) control networks. These results support tonic alertness as a fundamental function of the CO network. They further the characterization of this function as the effortful process of maintaining cognitive faculties available for current processing requirements. PMID- 24770712 TI - Neural Mechanism for Mirrored Self-face Recognition. AB - Self-face recognition in the mirror is considered to involve multiple processes that integrate 2 perceptual cues: temporal contingency of the visual feedback on one's action (contingency cue) and matching with self-face representation in long term memory (figurative cue). The aim of this study was to examine the neural bases of these processes by manipulating 2 perceptual cues using a "virtual mirror" system. This system allowed online dynamic presentations of real-time and delayed self- or other facial actions. Perception-level processes were identified as responses to only a single perceptual cue. The effect of the contingency cue was identified in the cuneus. The regions sensitive to the figurative cue were subdivided by the response to a static self-face, which was identified in the right temporal, parietal, and frontal regions, but not in the bilateral occipitoparietal regions. Semantic- or integration-level processes, including amodal self-representation and belief validation, which allow modality independent self-recognition and the resolution of potential conflicts between perceptual cues, respectively, were identified in distinct regions in the right frontal and insular cortices. The results are supportive of the multicomponent notion of self-recognition and suggest a critical role for contingency detection in the co-emergence of self-recognition and empathy in infants. PMID- 24770713 TI - Coordinated Information Generation and Mental Flexibility: Large-Scale Network Disruption in Children with Autism. AB - Autism spectrum disorder (ASD) includes deficits in social cognition, communication, and executive function. Recent neuroimaging studies suggest that ASD disrupts the structural and functional organization of brain networks and, presumably, how they generate information. Here, we relate deficits in an aspect of cognitive control to network-level disturbances in information processing. We recorded magnetoencephalography while children with ASD and typically developing controls performed a set-shifting task designed to test mental flexibility. We used multiscale entropy (MSE) to estimate the rate at which information was generated in a set of sources distributed across the brain. Multivariate partial least-squares analysis revealed 2 distributed networks, operating at fast and slow time scales, that respond completely differently to set shifting in ASD compared with control children, indicating disrupted temporal organization within these networks. Moreover, when typically developing children engaged these networks, they achieved faster reaction times. When children with ASD engaged these networks, there was no improvement in performance, suggesting that the networks were ineffective in children with ASD. Our data demonstrate that the coordination and temporal organization of large-scale neural assemblies during the performance of cognitive control tasks is disrupted in children with ASD, contributing to executive function deficits in this group. PMID- 24770714 TI - Accelerated evolution of morph-biased genes in pea aphids. AB - Phenotypic plasticity, the production of alternative phenotypes (or morphs) from the same genotype due to environmental factors, results in some genes being expressed in a morph-biased manner. Theoretically, these morph-biased genes experience relaxed selection, the consequence of which is the buildup of slightly deleterious mutations at these genes. Over time, this is expected to result in increased protein divergence at these genes between species and a signature of relaxed purifying selection within species. Here we test these theoretical expectations using morph-biased genes in the pea aphid, a species that produces multiple morphs via polyphenism. We find that morph-biased genes exhibit faster rates of evolution (in terms of dN/dS) relative to unbiased genes and that divergence generally increases with increasing morph bias. Further, genes with expression biased toward rarer morphs (sexual females and males) show faster rates of evolution than genes expressed in the more common morph (asexual females), demonstrating that the amount of time a gene spends being expressed in a morph is associated with its rate of evolution. And finally, we show that genes expressed in the rarer morphs experience decreased purifying selection relative to unbiased genes, suggesting that it is a relaxation of purifying selection that contributes to their faster rates of evolution. Our results provide an important empirical look at the impact of phenotypic plasticity on gene evolution. PMID- 24770715 TI - Origin and evolution of B chromosomes in the cichlid fish Astatotilapia latifasciata based on integrated genomic analyses. AB - Approximately 15% of eukaryotes contain supernumerary B chromosomes. When present, B chromosomes frequently represent as much as 5% of the genome. Despite thousands of reports describing the distribution of supernumeraries in various taxa, a comprehensive theory for the origin, maintenance, and evolution of B chromosomes has not emerged. Here, we sequence the complete genomes of individual cichlid fish (Astatotilapia latifasciata) with and without B chromosomes, as well as microdissected B chromosomes, to identify DNA sequences on the B. B sequences were further analyzed through quantitative polymerase chain reaction and in situ hybridization. We find that the B chromosome contains thousands of sequences duplicated from essentially every chromosome in the ancestral karyotype. Although most genes on the B chromosome are fragmented, a few are largely intact, and we detect evidence that at least three of them are transcriptionally active. We propose a model in which the B chromosome originated early in the evolutionary history of Lake Victoria cichlids from a small fragment of one autosome. DNA sequences originating from several autosomes, including protein-coding genes and transposable elements, subsequently inserted into this proto-B. We propose that intact B chromosome genes involved with microtubule organization, kinetochore structure, recombination and progression through the cell cycle may play a role in driving the transmission of the B chromosome. Furthermore, our work suggests that karyotyping is an essential step prior to genome sequencing to avoid problems in genome assembly and analytical biases created by the presence of high copy number sequences on the B chromosome. PMID- 24770716 TI - Quantum dots in diagnostics and detection: principles and paradigms. AB - Quantum dots are semiconductor nanocrystals that exhibit exceptional optical and electrical behaviors not found in their bulk counterparts. Following seminal work in the development of water-soluble quantum dots in the late 1990's, researchers have sought to develop interesting and novel ways of exploiting the extraordinary properties of quantum dots for biomedical applications. Since that time, over 10,000 articles have been published related to the use of quantum dots in biomedicine, many of which regard their use in detection and diagnostic bioassays. This review presents a didactic overview of fundamental physical phenomena associated with quantum dots and paradigm examples of how these phenomena can and have been readily exploited for manifold uses in nanobiotechnology with a specific focus on their implementation in in vitro diagnostic assays and biodetection. PMID- 24770717 TI - First report of Kudoa species in the somatic muscle of the Japanese parrotfish Calotomus japonicus (Scaridae) and a description of Kudoa igami, n. sp. (Myxozoa: Multivalvulida). AB - Three species of the Kudoid parasite (Myxozoa: Multivalvulida) were observed in the somatic muscle of Japanese parrotfish Calotomus japonicus caught off the coast of western Japan. All three species formed pseudocysts in myofibers and caused subclinical infections. The three Kudoa species were distinguished by spore morphology, as well as their 18S and 28S rDNA sequences. We identified a previously undescribed taxa Kudoa igami n. sp. with spores that were stellate with rounded peripheral edges and five to six polar capsules (prevalence 29.3%). Kudoa igami n. sp. were morphologically most similar to Kudoa neothunni but were distinguishable by a more rounded shape in the apical view. Molecular analyses demonstrated that the K. igami n. sp. is closely related to Kudoa thalassomi; however, the similarity in the 28S rDNA sequence was <96% and the spore morphology was different. We found Kudoa thalassomi in one sample (prevalence 2.4%), which is a new host and geographical record for this species. Kudoa lateolabracis, which causes postmortem myoliquefaction in Chinese sea bass Lateolabrax sp. and olive flounder Paralichthys olivaceus was found in Japanese parrotfish (prevalence 41.5%) for the first time, but did not cause myoliquefaction. We also expanded the host record for the brain-infecting Kudoa yasunagai (prevalence 94.1%). In addition, an unidentified microsporidia was observed in the somatic muscle (prevalence 23.3%). PMID- 24770718 TI - Acaricidal activity of usnic acid and sodium usnic acid against Psoroptes cuniculi in vitro. AB - Usnic acid, a major active compound in lichens, was first isolated in 1884. Since then, usnic acid and its sodium salt (sodium usnic acid) have been used in medicine, perfumery, cosmetics, and other industries due to its extensive biological activities. However, its acaricidal activity has not been studied. In this paper, we investigated the acaricidal activity of usnic acid and sodium usnic acid against Psoroptes cuniculi in vitro. After evaluating the acaricidal activity and toxicity of usnic acid and sodium usnic acid in vitro, the results showed that at doses of 250, 125, and 62.5 mg/ml, usnic acid and sodium usnic acid can kill mites with 91.67, 85.00, and 55.00% and 100, 100, and 60.00% mortality after treatment 24 h. The LT50 values were 4.208, 8.249, and 16.950 h and 3.712, 7.339, and 15.773 h for usnic acid and sodium usnic acid, respectively. Sodium usnic acid has a higher acaricidal activity than usnic acid, which may be related to the difference in their structures. PMID- 24770719 TI - Performance of a new gelled nested PCR test for the diagnosis of imported malaria: comparison with microscopy, rapid diagnostic test, and real-time PCR. AB - Microscopy and rapid diagnostic tests (RDTs) are the techniques commonly used for malaria diagnosis but they are usually insensitive at very low levels of parasitemia. Nested PCR is commonly used as a reference technique in the diagnosis of malaria due to its high sensitivity and specificity. However, it is a cumbersome assay only available in reference centers. We evaluated a new nested PCR-based assay, BIOMALAR kit (Biotools B&M Labs, Madrid, Spain) which employs ready-to-use gelled reagents and allows the identification of the main four species of Plasmodium. Blood samples were obtained from patients with clinical suspicion of malaria. A total of 94 subjects were studied. Fifty-two (55.3%) of them were malaria-infected subjects corresponding to 48 cases of Plasmodium falciparum, 1 Plasmodium malariae, 2 Plasmodium vivax, and 1 Plasmodium ovale. The performance of the BIOMALAR test was compared with microscopy, rapid diagnostic test (RDT) (BinaxNOW(r) Malaria) and real-time quantitative PCR (qPCR). The BIOMALAR test showed a sensitivity of 98.1% (95% confidence interval [CI], 89.7-100), superior to microscopy (82.7% [95% CI, 69.7-91.8]) and RDT (94.2% [95% CI, 84.1-98.8]) and similar to qPCR (100% [95% CI, 93.2-100]). In terms of specificity, the BIOMALAR assay showed the same value as microscopy and qPCR (100% [95% CI, 93.2-100]). Nine subjects were submicroscopic carriers of malaria. The BIOMALAR test identified almost all of them (8/9) in comparison with RDT (6/9) and microscopy (0/9). In conclusion, the BIOMALAR is a PCR-based assay easy to use with an excellent performance and especially useful for diagnosis submicroscopic malaria. PMID- 24770720 TI - The first genotype determination of Acanthamoeba potential threat to human health, isolated from natural water reservoirs in Poland. AB - Different species of amoebae belonging to the genus Acanthamoeba are widely distributed in many parts of the world and known as free-living organisms. Some strains of the protozoans may exist as parasites and cause risk to human health as causative agents of serious human diseases. Currently, in Poland, there is no sufficient information about the distribution of Acanthamoeba strains and their genotypes in the environment. Therefore, 20 environmental surface water samples were collected from different sites located at five water reservoirs in Gdynia, Sopot, and Gdansk (northern Poland). The material was cultured to obtain Acanthamoeba isolates that were then specifically analyzed with both PCR and real time PCR assays. Of the 20 samples examined, Acanthamoeba DNA was found in 13 samples tested with the use of real-time PCR; in 10 of them, DNA of the amoeba was also detected using PCR technique. The comparison with sequences available in the GenBank confirmed that the PCR products are fragments of Acanthamoeba 18S rRNA gene and that isolates represent T4 genotype, known as the most common strains related to AK cases. This is the first investigation in Poland describing Acanthamoeba detection in environmental water samples with molecular techniques and genotyping. The results indicate that surface water in Poland may be a source of acanthamoebic strains potentially pathogenic for humans. PMID- 24770721 TI - Dualistic classification of epithelial ovarian cancer: surgical and survival outcomes in a large retrospective series. AB - BACKGROUND: Ovarian cancers have been recently categorized into types I and II according to a dualistic model of tumorigenesis. Data on the correlation between this classification and clinical outcome are still scarce and controversial. METHODS: A retrospective analysis of patients with ovarian cancer treated from 1998 to 2013 and operated by the same surgeon was conducted. Patients were classified into two groups: type I (125 patients), including low-grade serous, mucinous, endometrioid, and clear cell tumors; and type II (286 patients), including high-grade serous tumors, unspecified adenocarcinomas, and undifferentiated carcinomas. RESULTS: Type II patients had a significantly higher incidence of advanced disease than type I (88.4 vs. 65.6 %, P = 0.0001) and required more aggressive surgical procedures. Rates of optimal tumor debulking were almost similar between groups (92.6 vs. 91.7 %, type I vs. II, P = NS). After a median follow-up of 41 months, 207 patients (50.4 %) were alive and 204 (49.6 %) were dead; 79 type I patients (63.8 %) and 237 type II patients (82.7 %) experienced relapse (P = 0.02). Progression-free survival was significantly different between groups: 25 months for type I vs. 17 months for type II (P = 0.023). Overall survival was not significantly different between groups, with a median overall survival of 75 months for type I vs. 62 months for type II (P = 0.116). CONCLUSIONS: The dualistic histotype-based classification into types I and II of ovarian cancer does not seem to correlate with prognosis. Different molecular characteristics of type I and II tumors may have therapeutic implications and should be deeply investigated. PMID- 24770722 TI - Genetic variations in STK11, PRKAA1, and TSC1 associated with prognosis for patients with colorectal cancer. AB - BACKGROUND: Assuming an association between cancer and metabolism, oncogene directed metabolic reprogramming in cancer has revealed new target strategies. For example, the LKB1-AMPK-mTOR signaling pathway genes are already known to alter the cell metabolism and to play a critical role in the malignant behavior of cancer. Accordingly, based on the assumption that genetic variations in the LKB1-AMPK-mTOR signaling pathway can change the intracellular signal in terms of metabolic reprogramming, the present study analyzed 18 single nucleotide polymorphisms (SNPs) of the STK11, PRKAA1, TSC1/2, and mTOR genes and their impact on the survival of patients with colorectal cancer. METHODS: Seven hundred seventy-two patients with surgically resected colorectal adenocarcinoma were enrolled in the present study. Eighteen SNPs were selected from an in silico analysis based on previous evidence of association. The SNP genotyping was performed using a SEQUENOM MassARRAY. RESULTS: Among the 18 polymorphisms, three SNPs (STK11 rs741765, PRKAA1 rs461404, and TSC1 rs13295634) were significantly associated with disease-free survival (DFS) or overall survival (OS). In a multivariate analysis, the GG genotype of STK11, TT genotype of PRKAA1, and TG or GG genotype of TSC1 were identified as independent prognostic factors for a worse DFS (hazard ratio = 1.398, 1.408, and 1.388; p = 0.030, 0.013, and 0.002, respectively) and OS (hazard ratio = 1.431, 1.680, and 1.394; p = 0.038, 0.001, and 0.009, respectively). CONCLUSIONS: The present results suggest that genetic variants of the STK11, PRKAA1, and TSC1 genes could be used as prognostic biomarkers for patients with surgically resected colorectal cancer. PMID- 24770723 TI - Inhibition of fungal plant pathogens by synergistic action of chito oligosaccharides and commercially available fungicides. AB - Chitosan is a linear heteropolymer consisting of beta 1,4-linked N-acetyl-D glucosamine (GlcNAc) and D-glucosamine (GlcN). We have compared the antifungal activity of chitosan with DPn (average degree of polymerization) 206 and FA (fraction of acetylation) 0.15 and of enzymatically produced chito oligosaccharides (CHOS) of different DPn alone and in combination with commercially available synthetic fungicides, against Botrytis cinerea, the causative agent of gray mold in numerous fruit and vegetable crops. CHOS with DPn in the range of 15-40 had the greatest anti-fungal activity. The combination of CHOS and low dosages of synthetic fungicides showed synergistic effects on antifungal activity in both in vitro and in vivo assays. Our study shows that CHOS enhance the activity of commercially available fungicides. Thus, addition of CHOS, available as a nontoxic byproduct of the shellfish industry, may reduce the amounts of fungicides that are needed to control plant diseases. PMID- 24770724 TI - Evaluation of social and demographic characteristics of incest cases in a university hospital in Turkey. AB - BACKGROUND: Incest is defined as any sexual activity between close blood relatives including step relatives and family members who are forbidden by law to marry. It is a problem that can be seen in all the social classes in developed and undeveloped societies. The World Health Organization classifies this problem as a silent health emergency. Father-daughter incest is reported to be the most common incest type followed by the other types like brother-sister, sister-sister and mother-son incest. MATERIAL AND METHODS: Subjects for this study were recruited from a sample of incest cases referred to Forensic Medicine Department of Gaziosmanpasa University Medical Faculty Hospital between 2008 and 2012. Data involved social and demographic characteristics and clinical features of victims, perpetrators and the families. The ethical committee of the faculty of medicine approved the study. RESULTS: The study sample consisted of 43 incest cases (36 females and 7 males) with an age rage 4-40 years. Two third of the victims were under 18 years old. All perpetrators were males. Father - daughter incest (34.9%) was found to be most common incest type followed by brother - sister incest (14%). 75% of the perpetrators were family members and relatives with consanguinity while 25% of them were not consanguineous but faithful and intimate relatives to victims. CONCLUSIONS: Increasing awareness about incest and its damaging effects is so important and clinicians should keep in mind sexual abuse or incest when examining the risky population. Multidisciplinary approach is necessary for determining short term or long term results and preventing the negative consequences of incest. PMID- 24770725 TI - Comment on Paolo et al. "Effect of pulsed electromagnetic field therapy in patients undergoing total knee arthroplasty: a randomized controlled trial". PMID- 24770726 TI - A radiographic and clinical comparison of reamer-irrigator-aspirator versus iliac crest bone graft in ankle arthrodesis. AB - PURPOSE: We evaluated radiographic fusion at follow-up and complication rates in patients who had either iliac crest (ICBG) or femoral reamer-irrigator-aspirator (RIA) bone graft for tibiotalar fusion. METHODS: We retrospectively reviewed charts and radiographs of all patients who had a tibiotalar fusion from August 2007 to February 2011. Records were analysed for patient demographics, complications, and clinical symptoms. Radiographs were reviewed in sequential order by two fellowship-trained foot and ankle surgeons and one orthopaedic surgeon who specialises in foot and ankle surgery to determine radiographic fusion at routine follow-up. Patients were contacted to determine current visual analog scores (VAS) at their graft site. RESULTS: Mean patient age was 49.4 +/- 12.1 years in the RIA group and 49.3 +/- 15.4 years in the ICBG group (p = .97). Pre-operative characteristics showed no significant differences between groups. The ICBG group had significantly more nonunions than the RIA group (six vs. one, p = 0.04). Two patients in the ICBG had chronic pain at their graft site based on their VAS score; there were none in the RIA group. Radiographic fusion at follow up was similar between groups, with no significant difference (12.48 +/- 3.85 weeks vs.12.21 +/- 3.19 weeks, p = .80). CONCLUSIONS: There was a significantly higher nonunion rate in the ICBG group, but both groups had a solid radiographic bony fusion at similar follow-up time points. Our results suggest RIA bone graft is a viable alternative to ICBG for tibiotalar fusion. PMID- 24770727 TI - Longitudinal investigation of training status and cardiopulmonary responses in pre- and early-pubertal children. AB - PURPOSE: The presence of a maturational threshold that modulates children's physiological responses to exercise training continues to be debated, not least due to a lack of longitudinal evidence to address this question. The purpose of this study was to investigate the interaction between swim-training status and maturity in nineteen trained (T, 10 +/- 1 years, -2.4 +/- 1.9 years pre-peak height velocity, 8 boys) and fifteen untrained (UT, 10 +/- 1 years, -2.3 +/- 0.9 years pre-peak height velocity, 5 boys) children, at three annual measurements. METHODS: In addition to pulmonary gas exchange measurements, stroke volume (SV) and cardiac output ([Formula: see text]) were estimated by thoracic bioelectrical impedance during incremental ramp exercise. RESULTS: At baseline and both subsequent measurement points, trained children had significantly (P < 0.05) higher peak oxygen uptake (year 1 T 1.75 +/- 0.34 vs. UT 1.49 +/- 0.22; year 2 T 2.01 +/- 0.31 vs. UT 1.65 +/- 0.08; year 3 T 2.07 +/- 0.30 vs. UT 1.77 +/- 0.16 l min(-1)) and [Formula: see text] (year 1 T 15.0 +/- 2.9 vs. UT 13.2 +/- 2.2; year 2 T 16.1 +/- 2.8 vs. UT 13.8 +/- 2.9; year 3 T 19.3 +/- 4.4 vs. UT 16.0 +/- 2.7 l min(-1)). Furthermore, the SV response pattern differed significantly with training status, demonstrating the conventional plateau in UT but a progressive increase in T. Multilevel modelling revealed that none of the measured pulmonary or cardiovascular parameters interacted with maturational status, and the magnitude of the difference between T and UT was similar, irrespective of maturational status. CONCLUSION: The results of this novel longitudinal study challenge the notion that differences in training status in young people are only evident once a maturational threshold has been exceeded. PMID- 24770728 TI - Spontaneous intracerebral hemorrhage with antiplatelets/anticoagulants/none: a comparison analysis. AB - BACKGROUND: Problems that the risk of using antiplatelet/anticoagulant may overwhelm its benefits have been raised. We analyzed patients with spontaneous intracerebral hemorrhage who had received antiplatelet/anticoagulant therapy. METHOD: A consecutive series of patients with spontaneous intracerebral hemorrhage who underwent brain computed tomographic (CT) scans within 48 h from attack. We analyzed the clinical manifestations and radiologic findings of the patients according to antiplatelet/anticoagulant therapy: Antiplatelet group, Anticoagulant group, and None group. RESULTS: A total of 338 patients were included in the study. The initial volume of hematoma was 46.8 ml in the Anticoagulant group, and 24.1 ml in the None group. There were significant differences among the groups in terms of intraventricular hemorrhage (Antiplatelet group: 45.6 %, Anticoagulant group: 20 %, None: 26.4 %, p = 0.008), and the proportion of hydrocephalus in the Antiplatelet group was higher than in another group (p = 0.017). Also, herniation and expansion of spontaneous intracerebral hemorrhage had significant differences among the groups. The prognoses of the None group were the best among the groups. There was also significant difference in the mortality among the groups. CONCLUSIONS: In comparison with the None group, the spontaneous intracerebral hemorrhages of the Antiplatelet/Anticoagulant group were a little more extensive and they had more intraventricular hemorrhage, hydrocephalus, herniation, and expansion of spontaneous intracerebral hemorrhage that would come to poor prognosis. Therefore, antiplatelets and anticoagulants should be used under strict indications. PMID- 24770729 TI - Microvascular decompression for trigeminal neuralgia using the 'Stitched Sling Retraction' technique in recurrent cases after previous microvascular decompression. AB - BACKGROUND: Microvascular decompression is a well-known therapeutic option for trigeminal neuralgia. It is considered safe and effective, and is the surgical treatment of choice for the malady. However, there is no standard technique for it and different authors have proposed different techniques of performing it. In this study, we observe the clinical results of the so-called 'stitched sling retraction' technique for recurrent cases of trigeminal neuralgia. METHODS: Twelve consecutive patients with recurrent trigeminal neuralgia after previous microvascular decompression(s) were admitted to our institution form February 2009 to February 2011 and underwent microvascular decompression of the trigeminal nerve using the 'stitched sling retraction' technique. In this technique, the offending loop of the superior cerebellar artery is retracted from the nerve and, using a silk thread loop around it, is suspended to the adjacent tentorium. RESULTS: All patients experienced pain resolution during the immediate post operative period or within the first 6 months after surgery. They were followed for 24 to 38 months. No recurrence occurred. CONCLUSIONS: The 'stitched sling retraction' technique shows promising preliminary results in recurrent cases of trigeminal neuralgia after previous microvascular decompression(s). Since it is a 'transposing' technique, it might be associated with less recurrence rates (due to resuming of the neurovascular conflict) than the classic interposing technique, which uses a prosthesis between the offending vessel and the trigeminal nerve. PMID- 24770730 TI - Analytical anatomy: quantifying surgical access with and without orbital bar removal--cadaver and surgical phantom studies. PMID- 24770731 TI - Mini-craniotomy and chronic subdural hematoma. PMID- 24770732 TI - Use of intraoperative fluorescein sodium fluorescence to improve the accuracy of tissue diagnosis during stereotactic needle biopsy of high-grade gliomas. AB - BACKGROUND: Stereotactic needle biopsy is valuable for tissue diagnosis of suspected high-grade gliomas, but limited by a sampling error that can lead to inappropriate grading of the tumor or failure to provide diagnosis. Increasing the number of biopsy attempts can increase morbidity. The authors designed a protocol to increase safety and efficiency of the procedure. METHODS: Six consecutive patients with suspected high-grade gliomas who were not candidates for cytoreductive surgery underwent fluorescein-guided stereotactic needle biopsy. All received an injection of 3 mg/kg fluorescein sodium during anesthesia induction. Samples were obtained and observed under a microscope-integrated fluorescent module. If the initial specimens were fluorescent, the procedure was complete if the pathologist confirmed diagnostic tissue. Additional specimens were obtained only at the pathologist's request. An independent neuropathologist later analyzed and graded samples for diagnostic value, tumor, and necrosis. This information was correlated to the degree of intraoperative fluorescent signal in biopsy samples. RESULTS: During six biopsy procedures, 26 specimens were obtained: 15 (58 %) fluorescent and 11 (42 %) nonfluorescent. All fluorescent specimens contained diagnostic tissue appropriate for tumor grading. Of 11 nonfluorescent specimens, four (36 %) did not contain tumor, three (27 %) contained minor hypercellularity or gliosis, and four (36 %) contained tumor with a high proportion of necrosis. All six tumors were diagnosed as glioblastoma multiforme. The sensitivity and specificity for fluorescein fluorescence was 79 % and 100 %, respectively. CONCLUSIONS: Fluorescein fluorescence may improve diagnostic accuracy and expedite stereotactic biopsy procedures. PMID- 24770733 TI - Use of the bovine pericardial patch and fibrin sealant in meningomyelocele closure. AB - BACKGROUND: Meningomyelocele is the most common and complex birth defect of the central nervous system. The operative principle of meningomyelocele repair consists of consecutive separate closures of the neural placode, dura mater, lumbar fascia, subcutaneous layer, and skin. While the neurosurgical techniques for the closure of the neural placode and dura mater have been well accepted, the most appropriate soft tissue closure technique has not yet been applied. METHODS: This study reviews a case series of eight meningomyelocele patients treated with the bovine pericardial patch and fibrin sealant. Following the reconstruction of the neural placode and the closure of the dura mater, soft tissue coverage was achieved using the bovine pericardial patch and fibrin sealant. RESULTS: In this series of eight patients, stable coverage was achieved with the application of a bovine pericardial patch and fibrin sealant technique. After the operations, none of the possible complications such as cerebrospinal fluid leak, seroma, hematoma, skin necrosis, deep or superficial infection, and wound breakdown was observed. CONCLUSIONS: The usage of the bovine pericardial patch and fibrin sealant technique at the fascial level-between the dural sac and the skin-provides adequate soft tissue coverage in meningomyelocele repair surgery. PMID- 24770734 TI - Unusual ultra-low-frequency fluctuations in freestanding graphene. AB - Intrinsic ripples in freestanding graphene have been exceedingly difficult to study. Individual ripple geometry was recently imaged using scanning tunnelling microscopy, but these measurements are limited to static configurations. Thermally-activated flexural phonon modes should generate dynamic changes in curvature. Here we show how to track the vertical movement of a one-square angstrom region of freestanding graphene using scanning tunnelling microscopy, thereby allowing measurement of the out-of-plane time trajectory and fluctuations over long time periods. We also present a model from elasticity theory to explain the very-low-frequency oscillations. Unexpectedly, we sometimes detect a sudden colossal jump, which we interpret as due to mirror buckling. This innovative technique provides a much needed atomic-scale probe for the time-dependent behaviours of intrinsic ripples. The discovery of this novel progenitor represents a fundamental advance in the use of scanning tunnelling microscopy, which together with the application of a thermal load provides a low-frequency nano-resonator. PMID- 24770735 TI - Proteomic study of rat hippocampus under conditions of emotional stress. AB - Proteomic differences in the hippocampus of stress-resistant and stress-sensitive rats were detected on the model of emotional stress. Differential expression of some proteins was detected in animals with different behavioral activity initially and after experimental stress exposure. Specific involvement of the hippocampus in the realization of stress response in animals with different sensitivity to emotional stress was demonstrated. PMID- 24770736 TI - Neurophysiological patterns of search and creative behavior in patients with psychoactive substance-induced disorders. AB - The correlation between search and creative behavior with parameters of bioelectric brain activity was observed in patients with addictive disorders. The prevalence of alpha- and theta-activities in the parietal-temporal-occipital areas of the cortex and increased theta-activity in the right hemisphere in addiction patients with high search and creative activities were associated with enhanced high-frequency activity in these brain areas. These changes can reflect the formation of a focus of pathologically increased excitation related to the pathogenic mechanisms of addictive disorders. PMID- 24770737 TI - Formation of spatial and nonspatial memory in different condensed versions of short-term learning in Morris water maze. AB - We studied the formation of spatial and nonspatial memory in mice during learning in three different condensed versions of Morris water maze task. Learning in combined version caused the formation of both spatial and nonspatial memory, whereas learning in condensed versions (spatial and nonspatial) led to memory formation specific for the version. PMID- 24770738 TI - Ultrastructural correlates of antidiuretic response of rat kidney. AB - We studied ultrastructural features of epithelial cells of the inner medullary collecting tubules in Brattleboro and Wistar under the action of desmopressin (dDAVP, 5 MUg/100 g body weight for 2 days). Intracellular reorganization of transepithelial barrier for osmotic water transport depended on the capacity of rats to the synthesis of endogenous vasopressin. PMID- 24770739 TI - Effect of activated peripheral kappa-opioid receptors on the action of nicotine and its withdrawal in nicotine-dependent rats. AB - We studied the possibilities of modulating the effects of nicotine and its withdrawal in nicotine-dependent rats by peripheral injection of kappa-opioid receptor agonist ICI 204,448. Injection of nicotine to rats previously treated with nicotine for 14 days reduced motor activity, suppressed metabolism, and increased food intake. In rats receiving ICI 204,448 after chronic administration of nicotine, food intake did not differ from that in control animals receiving isotonic NaCl solution. ICI 204,448 had virtually no effect on suppression of motor activity and metabolism. The rats receiving the last injection of nicotine 24 h prior to the experiment demonstrated an increase in metabolism, locomotor activity, and food intake. In these animals, ICI 204,448 completely abolished the effects of nicotine withdrawal. It was found that peripheral administration of compound ICI 204,448 did not significantly inhibit the effect of nicotine in nicotine-dependent rats, but abolished symptoms of nicotine withdrawal. It can be hypothesized that nicotine withdrawal syndrome is related to inhibition of dopamine release in the nucleus accumbens probably caused by enhanced kappa opioid activity in presynaptic terminals. Activation of peripheral kappa-opioid receptors apparently suppressed (via vagal afferent pathways) central kappa opioid activity and reduced nicotine withdrawal symptoms in nicotine-dependent subjects. PMID- 24770740 TI - Effects of SCH-23390 and sulpiride on active avoidance in ovariectomized rats treated with a low dose of 17beta-estradiol. AB - We studied the effects of dopamine D1/D2 receptor antagonists on the dynamics of acquisition and extinction of active avoidance responses and open field behavior in ovariectomized female rats. Dopamine D1 receptor antagonist SCH-23390 (0.1 mg/kg intraperitoneally) and dopamine D2 receptor antagonist sulpiride (10.0 mg/kg intraperitoneally) were administered chronically (14 days) either alone or in combination with a low dose of 17beta-estradiol (0.5 MUg per rat subcutaneously) to females after ovariectomy. It was found that SCH-23390 in combination with a low dose of 17beta-estradiol completely restored impaired conditioning and retention of a conditioned avoidance response in ovariectomized animals. Simultaneous correction of behavioral patterns in the open field test was also observed in ovariectomized females receiving SCH-23390. Sulpiride injected alone or in combination with low dose of 17beta-estradiol did not correct conditioning and reproduction of active avoidance response in females with estrogen deficiency and did not significantly affect animal behavior. The results indicate positive effect of dopamine D1 receptor blockade on active learning under conditions of estrogen deficiency. PMID- 24770741 TI - Dynamics of heart rhythm characteristics and efficiency of intellectual activity during computer work. AB - Heart rhythm variability characteristics were studied in volunteers with different stability of the results upon switching from one type of intellectual activity to another. Individuals with stable results differed from those with worse accuracy of information reproduction by high initial CV, total power of heart rhythm variability and power of VLF, LF, and HF spectra. Volunteers with stable results were characterized by high lability manifesting by changing values and proportions of heart rhythm variability characteristics at different stages of activity and by the absence of a relationship between these parameters at different stages of activity and initial status of the volunteer. VLF spectrum power decreased with impairing the accuracy of information reproduction. PMID- 24770742 TI - Administration of histone deacetylase inhibitor during neonatal period changes emotionality of adult male 129Sv mice. AB - Environmental factors acting during the neonatal period affected the formation of phenotype of adult animals via epigenetic modifications of the genome, e.g. histone acetylation. We studied the effects of blockage of histone deacetylases with sodium valproate on week 1 of life on the behavioral pattern of adult male 129Sv mice. The results of behavioral tests attest to long-term changes in emotional, but not cognitive pattern of adult animals after sodium valproate administration, which manifested in increased anxiety of animals. PMID- 24770743 TI - Analysis of the efficiency of osmotic concentration in Wistar and Brattleboro rats under the effect of desmopressin. AB - We studied the effect of vasopressin V2 receptor agonist (desmopressin, 5 MUg/100 g body weight for 2 days) on the efficiency of osmotic concentration in Wistar rats and homozygous Brattleboro rats defective by the synthesis of antidiuretic hormone. Specific differences in the reaction of the osmotic concentration system components (urine osmolality and urea, sodium, and potassium content in the renal tissue) involved in the realization of the hydroosmotic effect of the hormone depend on genetically determined capacity to vasopressin synthesis in these animals. PMID- 24770744 TI - Melatonin effects on serum cytokine profiles of rats with different behavioral parameters in acute emotional stress. AB - The effects of melatonin (epiphyseal neurohormone) on the serum cytokine profiles of rats with different behavioral characteristics were studied after acute emotional stress. One-hour immobilization of animals with simultaneous electrocutaneous stimulation of subthreshold intensity served as the stress model. Acute stress exposure of animals with active behavior led to reduction of the peripheral blood concentrations of pro-inflammatory (IL-1alpha, IL-1beta, IL 2, IFN-gamma, granulomonocytic CSF) and anti-inflammatory (IL-4, IL-10) cytokines. Passive rats exposed to emotional stress developed a pronounced increase of pro-inflammatory IL-1beta concentration. Reduction of pro inflammatory cytokine levels in active rats exposed to stress was less pronounced after intraperitoneal preinjection of melatonin (2 mg/kg). In passive animals, exogenous melatonin inverted the poststress changes in the serum levels of pro inflammatory IL-2 cytokine and of anti-inflammatory IL-4 and IL-10 cytokines. The modulatory effect of melatonin on the cytokine profiles of rats with different behavioral parameters seemed to contribute to adaptation of animals to emotional stress exposure. PMID- 24770745 TI - Pluronics suppress association of low-density lipoproteins inducing atherogenesis. AB - We studied the effect of pluronics P85, L61, and F68 with different hydrophilic lipophilic characteristics on association of LDL. It was found that pluronics with pronounced hydrophobic properties (P85 and L61) in concentrations close to or surpassing the critical concentration of micelle formation inhibited LDL association, while hydrophilic pluronic F68 in all concentrations had no effect on LDL association. PMID- 24770746 TI - System of matrix metalloproteinases and cytokine secretion in type 2 diabetes mellitus and impaired carbohydrate tolerance associated with arterial hypertension. AB - The study included patients with type 2 diabetes mellitus and impaired carbohydrate tolerance associated with arterial hypertension, patients with arterial hypertension, and healthy volunteers. We evaluated the levels of matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), tissue inhibitor of metalloproteinase type 1 (TIMP-1), glucose, insulin, C-peptide, glycated hemoglobin, and spontaneous and mitogen-activated cytokine secretion (IL-2, IL4, IL-6, IL-10, IL 17, TNF-alpha, and IFN-gamma). Patients with type 2 diabetes mellitus in combination with arterial hypertension exhibited maximum TIMP-1 levels and TIMP 1/MMP-2, TIMP-1/ MMP-9 ratios as well as enhanced secretion of TNF-alpha, IL-6, IL-17 and reduced secretion of IL-10 in comparison with healthy individuals. The observed shifts are probably determined the development of systemic hyperinsulinemia in patients suffering from type 2 diabetes mellitus coupled with arterial hypertension. PMID- 24770747 TI - High-calorie diet as a factor of prediabetes development in rats. AB - We studied the key parameters of the development of prediabetic state in rats maintained on a high-calorie diet. It was found that long-term feeding a high calorie diet increased blood concentration of glucose, glycosylated hemoglobin, and insulin and reduced the rate of glucose uptake in comparison with rats receiving standard ration. PMID- 24770748 TI - Neuroprotective effects of erythropoietin in focal brain ischemia in rats. AB - Neuroprotective effect of erythropoietin administered before ischemia has been previously demonstrated. The efficiency of erythropoietin administration after ischemia was not studied, though in case of success these protocols would be applied in clinical neurology. In our experiments on the model of transitory focal ischemia, erythropoietin was injected intraperitoneally during the early and delayed postischemic period (3 and 12 h). The size of the necrotic zone, neurological deficit, and the severity of brain edema were evaluated in 48 h. Injection of erythropoietin in 3 and 12 h after ischemia significantly reduced the size of necrosis (p = 0.0007 and p=0.0016, respectively), neurological deficit (p=0.0013 and p=0.0062, respectively), and brain edema (p=0.02 and p=0.0186, respectively). Injection of erythropoietin after transitory focal cerebral ischemia produced a pronounced neuroprotective effect. PMID- 24770749 TI - Functional state of myocardial mitochondria in ischemia reperfusion of the heart in rats adapted to hypoxia. AB - Parameters of respiration, transmembrane potential, and Ca(2+)-binding capacity of mitochondria isolated from Langendorff-perfused hearts of rats adapted to normobaric hypoxia were analyzed. Ischemia and reperfusion modeling in intact and adapted animals reduced Ca(2+)-binding capacity of mitochondria, which indicated increased sensitivity of mitochondrial permeability transition pores (MPTP) to calcium ions. These changes were accompanied by a decrease in transmembrane potential, ADP/O coefficient (ratio of added ADP to oxygen consumption in State 3), and inhibition of State 3 respiration. At the same time, adaptation attenuated the negative effect of ischemia and reperfusion on the functional state of mitochondria. PMID- 24770750 TI - Rats of hypertensive ISIAH strain are resistant to the development of metabolic syndrome induced by high-fat diet. AB - We studied the influence of high-fat diet on the development of metabolic syndrome in rats of hypertensive ISIAH strain and normotensive WAG strain. In contrast to ISIAH rats, high-fat diet in WAG rats led visceral obesity, glucose tolerance, and dyslipidemia. DNA-binding activity of the peroxisome proliferator activated receptor alpha (PPARalpha) decreased in the liver of WAG rats and increased in ISIAH rats. Blood levels of TNF-alpha, IL-6, and corticosterone increased more significantly in WAG rats. Corticosterone content in the adrenal glands was more markedly reduced in WAG rats. High-fat diet had no effect on BP in ISIAH and WAG rats. It was concluded that ISIAH rats can be used as a genetic model in studies of the mechanism of resistance to the metabolic syndrome. PMID- 24770751 TI - Manifestation of cystic fibrosis transmembrane regulator (CFTR) in hepatic ductal structures and renal tubules of female rats with experimental cholestasis of pregnancy. AB - Studies by the immunohistochemical method with semiquantitative analysis of images showed that hyperprolactinemia stimulated CFTR protein manifestation in the bile ducts of female rats, which was clearly expressed in experimental cholestasis of pregnancy. The expression of CFTR in the renal tubules was reduced in hyperprolactinemia under conditions of normal liver function and in cholestasis of pregnancy. Significant positive correlations between CFTR, prolactin receptor, and multiple drug resistance protein 3 were detected in the bile ducts, but not in the renal tubules. Presumably, prolactin has a direct effect on CFTR expression in the bile ducts and indirect effect in the renal tubules. Changes in CFTR protein manifestation in the hepatic ductal structures and renal tubules in experimental pregnancy cholestasis could aggravate the disease. PMID- 24770752 TI - Effect of peptides corresponding to extracellular domains of serotonin 1B/1D receptors and melanocortin 3 and 4 receptors on hormonal regulation of adenylate cyclase in rat brain. AB - The ligand-recognizing part of G protein-coupled receptors consists of their extracellular loops and N-terminal domain. Identification of these sites is essential for receptor mapping and for the development and testing of new hormone system regulators. The peptides corresponding by their structure to extracellular loop 2 of serotonin 1B/1D receptor (peptide 1), extracellular loop 3 of melanocortin 3 receptor (peptide 2), and N-terminal domain of melanocortin 4 (peptide 3) were synthesized by the solid-phase method. In synaptosomal membranes isolated from rat brain, peptide 1 (10(-5)-10(-4) M) attenuated the effects of 5 nonyloxytryptamine (selective agonist of serotonin 1B/1D receptor) and to a lesser extent serotonin and 5-methoxy-N,N-dimethyltryptamine acting on all the subtypes of serotonin receptor 1. Peptide 2 (10(-5)-10(-4) M) significantly reduced the adenylate cyclase-stimulating effect of gamma-melanocyte-stimulating hormone (agonist of melanocortin receptor 3), but had no effect on the adenylate cyclase effect of THIQ (agonist melanocortin receptor 4). Peptide 3 reduced the adenylate cyclase-stimulating effects of THIQ and alpha-melanocyte-stimulating hormone (non-selective agonist of melanocortin receptors 3 and 4), but did not modulate the effect of gamma-melanocyte-stimulating hormone. The effect of peptide 3 was weaker: it was observed at peptide 3 concentration of 10(-4) M. Peptides 1-3 did no change the adenylate cyclase-modulating effects of hormones acting through non-homologous receptors. Thus, the synthesized peptides specifically inhibited the regulatory effects of hormones acting through homologous receptors. This suggests that the corresponding extracellular domains are involved in ligand recognition and binding and determine functional activity of the receptor. PMID- 24770753 TI - Correction of aftereffects of ionizing radiation by exposure to low-intensity light. AB - Specific features of free radical oxidation were studied after experimental exposure to ionizing radiation. A decrease in the level of products of oxidative modification of proteins and LPO was observed after exposure of irradiated zone to low-intensity incoherent red light. It was suggested that low-intensity radiation of this spectrum produces a radioprotective effect and can be used for the correction of ionizing radiation-induced disturbances. PMID- 24770754 TI - Anti-inflammatory activity of diterpene alkaloids from Aconitum baikalense. AB - We compared anti-inflammatory activity of individual diterpene alkaloids isolated from Aconitum baikalense (napelline, songorine, hypaconitine, mesaconitine, 12 epinapelline N-oxide) under conditions of acute inflammation of different genesis. The tested substances showed high antiexudative activity comparable with that of sodium diclofenac. Unlike nonsteroidal anti-inflammatory drugs, diterpene alkaloids exerted no ulcerogenic effect. PMID- 24770755 TI - Effect of galectin-1 on apoptosis of CD4(+) lymphocytes differentiated in vitro towards regulatory T cells. AB - We studied the effect of galectin-1 on apoptosis of CD4(+) lymphocytes intact and in vitro differentiated towards regulatory T cells. An increase in the content of apoptotic CD4(+) lymphocytes was observed after exposure of intact cells with 15 ng/ml galectin-1 and after exposure of regulatory T cells with 10 and 15 ng/ml galectin-1. Apoptosis of regulatory T cells induced by galectin-1 was accompanied by an increase in the content of proapoptotic protein Bad. PMID- 24770756 TI - Biological characteristics of influenza A(H1N1)pdm09 virus circulating in West Siberia during pandemic and post-pandemic periods. AB - We studied biological characteristics of influenza A(H1N1)pdm09 virus circulating in Siberia during the 2009 pandemic and the post-pandemic period of 2011. BALB/c mice were chosen as the experimental model. Virus titers in the lungs were evaluated on days 1, 3, 6 and blood serum titers on day 15 after infection with different strains. Blood sera of convalescents after influenza of 2010-2011 epidemic season were analyzed. Influenza A(H1N1)pdm09 virus strains isolated during the post-pandemic period of 2011 were characterized by low epidemic activity and virulence in comparison with the strains isolated during 2009 pandemic period, which indicates completion of the pandemic cycle. PMID- 24770757 TI - Association of 5-HTR2A and 5-HTR2C serotonin receptor gene polymorphisms with depression risk in patients with coronary heart disease. AB - Associations between 5-HTR2A -1438A/G and 5-HTR2C Cys23Ser polymorphisms and depression and its severity were studied in CHD patients with consideration for the trigger factors, pathogenetic characteristics of CHD, and personal anxiety. The study was carried out in 169 men aged 31-84 (59.0 +/- 8.8) years with verified CHD. Depression was more severe (Hamilton score) if it was caused by manifestation or exacerbation of CHD (nosogenic factor) and in the presence of the painful syndrome caused by the cardiac disease, high personal anxiety, and presence of allele G polymorphism - 1438A/G in the genotype. The risk of medium severe and severe depression in allele G carriers was 2.4-fold higher than in AA genotype carriers. The nosogenic factor modulated the association between allele G and severity of depression symptoms. The risk of medium-severe and severe depression was almost 4-fold higher in carriers of this allele in the presence of this factor. PMID- 24770758 TI - Insulin-like growth factors (IGF), IGF-binding proteins (IGFBP), and vascular endothelial growth factor (VEGF) in blood serum of patients with colorectal cancer. AB - Serum levels of insulin-like growth factors (IGF-1 and IGF-2), IGF-binding proteins (IGFBP-1, IGFBP-2, and IGFBP-3) and vascular endothelial growth factor (VEGF) were measured by standard ELISA technique in 95 primary colorectal cancer patients and 48 healthy individuals. Significant increase in serum levels of IGF 1, IGFBP-2, and VEGF and decrease in IGFBP-3 level were demonstrated in patients in comparison with the control group; in male patients, serum level of IGF-2 was also increased. Sensitivity of IGF-1 as the prospective diagnostic marker of colorectal cancer was 80% and specificity was 75% at the threshold level of 140 ng/ml. Serum levels of IGF-1 significantly decreased with age in both patients and healthy donors, but in patients, this correlation was much weaker. These parameters did not correlate with the main clinical and morphological indices, such as dissemination, localization, and histological structure of colorectal cancer. PMID- 24770759 TI - Study of interactions between DNA and tetrapeptides using methods of molecular mechanics. AB - Tetrapeptide Lys-Glu-Asp-Trp is a mimetic of insulinotropic peptides and reduces the blood glucose level. This tetrapeptide increases the content of important factors of differentiation in endocrine pancreatic cells in vitro. Molecular modeling shows that this tetrapeptide can interact with not only minor, but also major groove of DNA molecule. The interaction with the major groove is more specific, because it depends on the primary sequences of the tetrapeptide and DNA. Sequence GGCAG is the putative binding site for the tetrapeptide. PMID- 24770760 TI - Effects of fullerene C60 on proteomic profile of Danio rerio fish embryos. AB - The effects of phosphatidylcholine-based phospholipid nanoparticles containing fullerene C60 on Danio rerio fish embryos were studied. Exposure of the embryos with the nanoparticles for 48 h did not lead to appreciable changes in the number of protein bands in SDS-PAGE in comparison with the control (exposure in medium with phosphatidylcholine). Mass spectrometric identification of proteins showed differences in the proteomic profiles of the samples. The content of vitellogenins changed after exposure with phosphatidylcholine-based nanoparticles with C60 fullerenes. This could indicate low toxicity of the nanoparticles towards D. rerio embryos under experimental conditions. PMID- 24770761 TI - Specific features of analgesic effect of docosahexaenoic acid in rats with neuropathic pain syndrome. AB - Experiments on white rats showed that sciatic nerve ligation induced the development of neuropathic pain syndrome: thermal pain threshold decreased, significant reduction in weight bearing of the injured limb, and degenerative changes in the foot tissues. Administration of docosahexaenoic acid reduces activity and duration neuropathic pain syndrome, promoted reversion of weight bearing asymmetry, and prevented the development of degenerative changes in the foot tissues. PMID- 24770762 TI - Express method for systemic psychophysiological analysis of human purposeful activity. AB - A psychophysiological sensorimotor test for systemic evaluation of human purposeful activity and detection of his/her mental strain are created and tested. The novelty and priority of the new test consists in the possibility for the subject to choose the situational and trigger signals for achieving the result. The algorithm of data analysis includes an important component: performance evaluation after errors. PMID- 24770763 TI - On the construction of medical test systems using greedy algorithm and support vector machine. AB - The paper presents a formalized statement of the problem of selecting parameters and construction of a genomic classifier for medical test systems with mathematical methods of machine learning without the use of biological and medical knowledge. A method is proposed to solve this problem. The results of testing the method using microarray datasets containing information on genome wide transcriptome of the samples of estrogen positive breast tumors are discussed. Testing showed that the quality of classification provided by the constructed test system and implemented on the basis of assessments of expression of 12 genes is not inferior to the quality of classification carried out by such test systems as OncotypeDX and MammaPrint. PMID- 24770764 TI - Takotsubo cardiomyopathy in complicated Pickering syndrome: endovascular therapy of an occluded renal artery. PMID- 24770765 TI - [The art of being a teacher]. PMID- 24770766 TI - Incidence of deep vein thrombosis and quality of venous thromboembolism prophylaxis. AB - OBJECTIVE: to determine the incidence of deep vein thrombosis and prophylaxis quality in hospitalized patients undergoing vascular and orthopedic surgical procedures. METHODS: we evaluated 296 patients, whose incidence of deep venous thrombosis was studied by vascular ultrasonography. Risk factors for venous thrombosis were stratified according the Caprini model. To assess the quality of prophylaxis we compared the adopted measures with the prophylaxis guidelines of the American College of Chest Physicians. RESULTS: the overall incidence of deep venous thrombosis was 7.5%. As for the risk groups, 10.8% were considered low risk, 14.9%moderate risk, 24.3% high risk and 50.5% very high risk. Prophylaxis of deep venous thrombosis was correct in 57.7%. In groups of high and very high risk, adequate prophylaxis rates were 72.2% and 71.6%, respectively. Excessive use of chemoprophylaxis was seen in 68.7% and 61.4% in the low and moderate-risk groups, respectively. CONCLUSION: although most patients are deemed to be at high and very high risk for deep vein thrombosis, deficiency in the application of prophylaxis persists in medical practice. PMID- 24770767 TI - Percutaneous core biopsy of palpable breast lesions: accuracy of frozen section histopathological exam in the diagnosis of breast cancer. AB - OBJECTIVE: to evaluate the accuracy of frozen section histopathology from fragments of tissue obtained by percutaneous core needle biopsy of palpable tumors in the diagnosis of breast cancer. METHODS: a cohort study was performed on 57 patients with palpable tumors and suspected breast cancer undergoing percutaneous thick needle core biopsy. The fragments were analyzed by the same pathologist. RESULTS: frozen section diagnosed 16 benign cases (28.6%) and 40 malignant (71.4%), whereas paraffin showed that 15 were benign (26.8%) and 41 malignant (73.2%). Histopathological examinations were concordant in 55 cases and there was one false-negative (6.2%). Statistics rates were: negative predictive value of 93.8%, positive predictive value of 100%, no false-positive (0%), one false negative (6.2%), specificity of 100%, sensitivity of 97 6%; observed agreement = 98.2%; expected agreement = 59.9%, Kappa = 0.955 [ 95% CI = 0.925 0.974, p < 0.01 ]. CONCLUSIONS: frozen section histopathological findings showed excellent correlation with the findings by the technique in paraffin in the fragments of palpable breast tumors obtained by thick needle percutaneous core biopsy (98.2% accuracy). Therefore, in these patients, it was possible to anticipate the diagnosis, staging and the breast cancer treatment planning. PMID- 24770768 TI - Lymph node metastasis in early gastric cancer. AB - OBJECTIVE: to evaluate the incidence of lymph node metastasis in early gastric cancer, identifying risk factors for its development. METHODS: we conducted a prospective study of patients with gastric cancer admitted to the Section of the Esophago-Gastric Surgery of the Surgery of Service HUCFF-UFRJ, from January 2006 to May 2012. RESULTS: the rate of early gastric cancer was 16.3%. The incidence of nodal metastases was 30.8% and occurred more frequently in patients with tumors with involvement of the submucosa (42.9%), in those poorly differentiated (36.4%), in tumors larger than 2 cm (33.3%) and in type III ulcerated lesions (43.8%). CONCLUSION: the incidence of lymph node metastases in patients was very high and suggests that one should keep the radicality of resection in early gastric cancer, particularly in relation to D2 lymphadenectomy, recommended for advanced gastric cancer. Conservative resections, with lymphadenectomies smaller than D2, should be performed only in selected cases, well-studied as for the risk factors of lymph node metastasis. Despite the small number of cases did not permit to relate the rate of lymph node metastasis to the risk factors considered, we noted a strong tendency for the occurrence of these metastases in the poorly differentiated, type III, larger than 2 cm tumors, and in the Lauren diffuse types. PMID- 24770769 TI - Results of surgical treatment of massive localized lymphedema in severely obese patients. AB - OBJECTIVE: to evaluate the importance of treatment of deformities caused by massive localized lymphedema (MLL) in the severely obese. METHODS: in a period of seven years, nine patients with morbid obesity and a mean age of 33 years underwent surgical resection of massive localized lymphedema with primary synthesis. This is a retrospective study on the surgical technique, complication rates and improved quality of life. RESULTS: all patients reported significant improvement after surgery, with greater range of motion, ambulation with ease and more effective hygiene. Histological analysis demonstrated the existence of a chronic inflammatory process marked by lymphomonocitary infiltrate and severe tissue edema. We observed foci of necrosis, formation of microabscesses, points of suppuration and local fibrosis organization, and pachydermia. The lymphatic vessels and some blood capillaries were increased, depicting a framework of linfangiectasias. CONCLUSION: surgical treatment of MLL proved to be important for improving patients' quality of life, functionally rehabilitating them and optimizing multidisciplinary follow-up of morbid obesity, with satisfactory surgical results and acceptable complication rates, demonstrating the importance of treatment and awareness about the disease. PMID- 24770770 TI - Immunohistochemical evaluation of fibrillar components of the extracellular matrix of transversalis fascia and anterior abdominal rectus sheath in men with inguinal hernia. AB - OBJECTIVE: to evaluate the role of fibrillar extracellular matrix components in the pathogenesis of inguinal hernias. METHODS: samples of the transverse fascia and of the anterior sheath of the rectus abdominis muscle were collected from 40 men aged between 20 and 60 years with type II and IIIA Nyhus inguinal hernia and from 10 fresh male cadavers (controls) without hernia in the same age range. The staining technique was immunohistochemistry for collagen I, collagen III and elastic fibers; quantification of fibrillar components was performed with an image analysis processing software. RESULTS: no statistically significant differences were found in the amount of elastic fibers, collagen I and collagen III, and the ratio of collagen I / III among patients with inguinal hernia when compared with subjects without hernia. CONCLUSION: the amount of fibrillar extracellular matrix components did not change in patients with and without inguinal hernia. PMID- 24770771 TI - Arthroscopic treatment of refractory adhesive capsulitis of the shoulder. AB - OBJECTIVE: to evaluate the results of arthroscopic treatment of refractory adhesive capsulitis of the shoulder associated as for improved range of motion after a minimum follow up of six years. METHODS: from August 2002 to December 2004, ten patients with adhesive capsulitis of the shoulder resistant to conservative treatment underwent arthroscopic surgery. One interscalene catheter was placed for postoperative analgesia before the procedure. All were in Phase II, with a minimum follow up of two years. The mean age was 52.9 years (39-66), predominantly female (90%), six on the left shoulder. The time between onset of symptoms and surgical treatment ranged from six to 20 months. Four adhesive capsulitis were found to be primary (40%) and six secondary (60%). RESULTS: the preoperative mean of active anterior elevation was 92 degrees , of external rotation was 10.5 degrees of the L5 level internal rotation; the postoperative ones were 149 degrees , 40 degrees and T12 level, respectively. Therefore, the average gain was 57 degrees for the anterior elevation, 29.5 degrees for external rotation in six spinous processes. There was a significant difference in movements' gains between the pre and post-operative periods (p<0.001). By the Constant Score (range of motion), there was an increase of 13.8 (average pre) to 32 points (average post). CONCLUSION: the arthroscopic treatment proved effective in refractory adhesive capsulitis of the shoulder resistant to conservative treatment, improving the range of joint movements of patients evaluated after a minimum follow up of six years. PMID- 24770772 TI - Prevalence of radiographic markers of femoroacetabular impingement in asymptomatic adults. AB - OBJECTIVE: to determine the prevalence of radiographic signs of femoroacetabular impingement (FAI) in asymptomatic adults and correlate them with data from physical examinations. METHODS: We conducted a cross-sectional study with 82 asymptomatic volunteers, 164 hips, between 40 and 60 years of age, selected by convenience. They were submitted to anamnesis and clinical examination of the hip, anteroposterior (AP) pelvis radiographs with three incidences, Dunn 45 degrees and Lequesne false profile of each hip, to measure the variables. We measured the alpha angle, anterior offset of the femoral neck, cervical diaphyseal angle, CE angle of Wiberg, acetabular index, Sharp angle, and the crossing, ischial spine and posterior wall signs. RESULTS: our sample consisted of 66% women, mean age of 50.4 years. The average alpha angle was 45.10 degrees , SD=8.6. One quarter of the hips showed alpha angle greater than or equal to 50 degrees ; among men the prevalence was 34%, and among women, 11%. We found indicative radiographic signs of femoroacetabular impingement in 42.6% of hips, whether femoral or acetabular, and the increased alpha angle was related to the decrease in hip internal rotation (p<0.001). CONCLUSION: the radiographic findings of femoroacetabular impingement in asymptomatic patients were frequent in the studied sample. The increase in alpha angle was associated with decreased internal rotation. PMID- 24770773 TI - Does a previous surgical experience interfere on psychic stress in patients submitted to major surgery? AB - OBJECTIVE: to evaluate the impact of stress in patients undergoing major surgeries under general anesthesia, relating their physical and psychic reactions to the different stages of stress. METHODS: we studied 100 adult patients of both genders, who were divided into two groups: Group 1 - 22 patients without experience with surgery; Group 2 - 78 patients previously submitted to medium and major surgery. To investigate the stress, we used the Inventory of Stress Symptoms for Adults, developed by Lipp, the day before the procedure and two days and seven days after the operation. The comparison of groups with respect to gender, pain, and percentage of stress were performed using the Chi-square test, and for the age variable the Student's t test was used. Differences were considered significant at p<0.05. RESULTS: the groups were not homogeneous as for the overall percentage of stress on the three measurements. G1 had decreased postoperative stress, whilst in G2 it increased. Psychological symptoms of stress prevailed in both groups. CONCLUSION: previous surgery reduced preoperative stress but did not affect postoperative emotional disorders. PMID- 24770774 TI - Effects of low intensity laser in in vitro bacterial culture and in vivo infected wounds. AB - OBJECTIVE: to compare the effects of low intensity laser therapy on in vitro bacterial growth and in vivo in infected wounds, and to analyze the effectiveness of the AsGa Laser technology in in vivo wound infections. METHODS: in vitro: Staphylococcus aureus were incubated on blood agar plates, half of them being irradiated with 904 nm wavelength laser and dose of 3J/cm2 daily for seven days. In vivo: 32 male Wistar rats were divided into control group (uninfected) and Experimental Group (Infected). Half of the animals had their wounds irradiated. RESULTS: in vitro: there was no statistically significant variation between the experimental groups as for the source plates and the derived ones (p>0.05). In vivo: there was a significant increase in the deposition of type I and III collagen in the wounds of the infected and irradiated animals when assessed on the fourth day of the experiment (p=0.034). CONCLUSION: low-intensity Laser Therapy applied with a wavelength of 904 nm and dose 3J/cm2 did not alter the in vitro growth of S. aureus in experimental groups; in vivo, however, it showed significant increase in the deposition of type I and III collagen in the wound of infected and irradiated animals on the fourth day of the experiment. PMID- 24770775 TI - Tobacco experimental model to induce urinary bladder neoplasms. AB - OBJECTIVE: to develop an experimental model of exposure to tobacco burning (cigarette) products to assess the effects of its chronic use in relation to cancers of the bladder. METHODS: the animals were chronically exposed to the burning tobacco products in a semi-open chamber to simulate smoking. Thirty young Wistar rats were divided into two groups: one with 20 animals simulating smoking for six months, and ten not exposed control animals for the same period. After exposure by inhalation of cigarette smoke, animals were euthanized and subjected to histopathological study of the bladder wall. RESULTS: no tumor was found but mild and non significant alterations. The studies of hemo-oximetry (carboxyhemoglobin and methemoglobin) and the concentration of carbon dioxide (CO2) confirm that the animals were exposed to high concentrations of tobacco smoke and its derivatives. CONCLUSION: no bladder mucosal neoplasia was found in the pathological study of animals. The developed experimental models were highly efficient, practical and easy to use and can be used in other similar studies to determine the harmful effects caused by smoking. PMID- 24770776 TI - Surgical techniques for maxillary bone grafting - literature review. AB - For oral rehabilitation with implant-supported prostheses, there are required procedures to create the bone volume needed for installation of the implants. Thus, bone grafts from intraoral or extraoral donor sites represent a very favorable opportunity. This study aimed to review the literature on the subject, seeking to discuss parameters for the indications, advantages and complications of techniques for autogenous bone grafts. PMID- 24770777 TI - Protecting the skin during thyroidectomy. AB - In this note we describe the standard technical maneuver used in our department to protect the skin during thyroidectomy in order to get the best aesthetic result. We use surgical gloves to protect the skin during these operations to reduce the negative impact of thermal trauma and mechanical retractors and energy delivery devices at the edges of the skin incised. This practice is effective, inexpensive, rapid, reproducible and showed no complication in our experience of over 2,500 thyroidectomies. PMID- 24770778 TI - An alternative experimental model for training in microsurgery. AB - OBJECTIVE: to describe a new model of training in microsurgery with pig spleen after splenectomy performed by undergraduate students of the Discipline of Operative Technique of the UFPR Medical School. METHODS: after the completion of splenectomy we performed dissection of the vascular pedicle, distal and proximal to the ligation performed for removal of the spleen. After complete dissection of the splenic artery and vein with microscope, clamps were placed and the vessels were cut. We then made the anastomosis of the vessels with 9.0 nylon. RESULT: the microsurgical training with a well-defined routine, qualified supervision and using low cost experimental materials proved to be effective in the practice of initial microvascular surgery. CONCLUSION: the use of pig spleen, which would be discarded after splenectomy, is an excellent model for microsurgical training, since besides having the consistency and sensitivity of a real model, it saves the sacrifice of a new animal model in the initial learning phase of this technique. PMID- 24770779 TI - Management of stab wounds to the anterior abdominal wall. AB - The meeting of the Publication "Evidence Based Telemedicine - Trauma and Emergency Surgery" (TBE-CiTE), through literature review, selected three recent articles on the treatment of victims stab wounds to the abdominal wall. The first study looked at the role of computed tomography (CT) in the treatment of patients with stab wounds to the abdominal wall. The second examined the use of laparoscopy over serial physical examinations to evaluate patients in need of laparotomy. The third did a review of surgical exploration of the abdominal wound, use of diagnostic peritoneal lavage and CT for the early identification of significant lesions and the best time for intervention. There was consensus to laparotomy in the presence of hemodynamic instability or signs of peritonitis, or evisceration. The wound should be explored under local anesthesia and if there is no injury to the aponeurosis the patient can be discharged. In the presence of penetration into the abdominal cavity, serial abdominal examinations are safe without CT. Laparoscopy is well indicated when there is doubt about any intracavitary lesion, in centers experienced in this method. PMID- 24770780 TI - Whole dystrophin gene analysis by next-generation sequencing: a comprehensive genetic diagnosis of Duchenne and Becker muscular dystrophy. AB - Duchenne/Becker muscular dystrophies are the most frequent inherited neuromuscular diseases caused by mutations of the dystrophin gene. However, approximately 30% of patients with the disease do not receive a molecular diagnosis because of the complex mutational spectrum and the large size of the gene. The introduction and use of next-generation sequencing have advanced clinical genetic research and might be a suitable method for the detection of various types of mutations in the dystrophin gene. To identify the mutational spectrum using a single platform, whole dystrophin gene sequencing was performed using next-generation sequencing. The entire dystrophin gene, including all exons, introns and promoter regions, was target enriched using a DMD whole gene enrichment kit. The enrichment libraries were sequenced on an Illumina HiSeq 2000 sequencer using paired read 100 bp sequencing. We studied 26 patients: 21 had known large deletion/duplications and 5 did not have detectable large deletion/duplications by multiplex ligation-dependent probe amplification technology (MLPA). We applied whole dystrophin gene analysis by next-generation sequencing to the five patients who did not have detectable large deletion/duplications and to five randomly chosen patients from the 21 who did have large deletion/duplications. The sequencing data covered almost 100% of the exonic region of the dystrophin gene by >=10 reads with a mean read depth of 147. Five small mutations were identified in the first five patients, of which four variants were unreported in the dmd.nl database. The deleted or duplicated exons and the breakpoints in the five large deletion/duplication patients were precisely identified. Whole dystrophin gene sequencing by next-generation sequencing may be a useful tool for the genetic diagnosis of Duchenne and Becker muscular dystrophies. PMID- 24770781 TI - Selection of reference genes for quantitative reverse-transcription polymerase chain reaction normalization in Brassica napus under various stress conditions. AB - Data normalization is essential for reliable output of quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) assays, as the unsuitable choice of reference gene(s), whose expression might be influenced by exogenous treatments in plant tissues, could cause misinterpretation of results. To date, no systematic studies on reference genes have been performed in stressed Brassica napus. In this study, we investigated the expression variations of nine candidate reference genes in 40 samples of B. napus leaves subjected to various exogenous treatments. Parallel analyses by geNorm and NormFinder revealed that optimal reference genes differed across the different sets of samples. The best ranked reference genes were PP2A and TIP41 for salt stress, TIP41 and ACT7 for heavy metal (Cr(6+)) stress, PP2A and UBC21 for drought stress, F-box and SAND for cold stress, F-box and ZNF for salicylic acid stress, TIP41, ACT7, and PP2A for methyl jasmonate stress, TIP41 and ACT7 for abscisic acid stress, and TIP41, UBC21, and PP2A for Sclerotinia sclerotiorum stress. Two newly employed reference genes, TIP41 and PP2A, showed better performances, suggesting their suitability in multiple conditions. To further validate the suitability of the reference genes, the expression patterns of BnWRKY40 and BnMKS1 were studied in parallel. This study is the first systematic analysis of reference gene selection for qRT PCR normalization in B. napus, an agriculturally important crop, under different stress conditions. The results will contribute toward more accurate and widespread use of qRT-PCR in gene analysis of the genus Brassica. PMID- 24770782 TI - Genomic localization of AtRE1 and AtRE2, copia-type retrotransposons, in natural variants of Arabidopsis thaliana. AB - Retrotransposons are ubiquitous components of plant genomes. They affect genome organization, and can also affect the expression patterns of neighboring genes. Retrotransposons are therefore important elements for changing genomic information. To understand the evolution of the Arabidopsis genome, we examined the distribution of certain retrotransposons, AtRE1s and AtRE2s, in the genomes of 12 natural variants (accessions) of Arabidopsis thaliana. AtRE1 and AtRE2 are copia-type retrotransposons that are potentially active. Their copy numbers are low, and they are absent from the genomes of some accessions. We detected four loci with AtRE1s inserted in six accessions, and one locus with an insertion of a solo-LTR-like sequence derived from AtRE1 in two accessions. Seven loci with AtRE2s inserted were detected on eight accessions. These loci were distributed in euchromatic regions of chromosomes 1, 2, 3, and 4. The AtRE1 and AtRE2 sequences at some loci identified in this study have not been recorded in the database of the 1001 Genome project. The sequences of AtRE1s and those of AtRE2s in different accessions and at different loci were highly conserved. There was a complete or almost complete conservation of sequences of both long terminal repeats in each AtRE1 and in each AtRE2. These results suggest that AtRE1 and AtRE2 appeared quite recently in the Arabidopsis genome. Furthermore, sequence comparisons of AtRE1 and AtRE2 loci among accessions revealed the possibility that large deletions containing entire sequences of AtRE1 and AtRE2 have occurred in some accessions. PMID- 24770783 TI - Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression. AB - Multiple sclerosis (MS) is a common demyelinating neurodegenerative disease with a strong genetic component. Previous studies have associated genetic variants in IL2RA and IL7R in the pathophysiology of the disease. In this study, we describe the association between IL2RA (rs2104286) and IL7R (rs6897932) in the Canadian population. Genotyping 1,978 MS patients and 830 controls failed to identify any significant association between these variants and disease risk. However, stratified analysis for family history of disease and disease course identified a trend towards association for IL2RA in patients without a family history (p = 0.05; odds ratio = 0.77) and a significant association between IL7R and patients who developed progressive MS (PrMS) (p = 0.002; odds ratio = 0.73). Although not statistically significant, the effect of IL2RA (rs2104286) in patients without a family history of MS indicates that the genetic components for familial and sporadic disease are perhaps distinct. This data suggests that the onset of sporadic disease is likely determined by a large number of variants of small effect, whereas MS in patients with a family history of disease is caused by a few deleterious variants. In addition, the significant association between PrMS and rs6897932 indicates that IL7R may not be disease-causing but a determinant of disease course. Further characterization of the effect of IL2RA and IL7R genetic variants in defined MS subtypes is warranted to evaluate the effect of these genes on specific clinical outcomes and to further elucidate the mechanisms of disease onset and progression. PMID- 24770784 TI - Overall mutational spectrum of SLC20A2, PDGFB and PDGFRB in idiopathic basal ganglia calcification. PMID- 24770785 TI - The role of omentectomy and random peritoneal biopsies as part of comprehensive surgical staging in apparent early-stage epithelial ovarian cancer. AB - BACKGROUND: Comprehensive surgical staging plays an important role in apparent early-stage epithelial ovarian cancer (eEOC). However, few studies have evaluated how often upstaging occurs solely as a result of microscopic metastases identified from omentectomy and random peritoneal biopsies. The purpose of this study was to evaluate the significance of omentectomy and random peritoneal biopsies for normal-appearing tissues in eEOC. METHODS: A retrospective study was performed of patients with eEOC [International Federation of Gynecology and Obstetrics (FIGO) Stages I-IIIA] between 1991 and 2010. The demographic characteristics, surgical findings, and pathologic variables were analyzed. RESULTS: In total, 324 patients were included in the study. Of 127 patients who underwent random peritoneal biopsies, 6 (4.7 %) were upstaged to IIB or IIC based solely on pelvic peritoneal biopsy findings and 3 (2.4 %) were upstaged to IIIA based on abdominal peritoneal biopsy findings. Of 256 patients who underwent omentectomy, 7 (2.7 %) were upstaged to IIIA based on microscopic metastases identified in the normal-appearing omentum. Following routine omentectomy and random peritoneal biopsies, only one patient in our cohort experienced a change in her adjuvant treatment recommendation. CONCLUSIONS: Although the rate of upstaging based on routine omentectomy and random peritoneal biopsies is not negligible, there is a low chance that the treatment plan will be altered to include chemotherapy after surgery as a result of the occult microscopic metastases identified. PMID- 24770786 TI - Multivalent chelators for spatially and temporally controlled protein functionalization. AB - Site-specific protein modification-e.g. for immobilization or labelling-is a key prerequisite for numerous bioanalytical applications. Although modification by use of short peptide tags is particularly attractive, efficient and bio orthogonal systems are still lacking. Here, we review the application of multivalent chelators (MCH) for high-affinity yet reversible recognition of oligohistidine (His)-tagged proteins. MCH are based on multiple nitrilotriacetic acid (NTA) moieties grafted on to molecular scaffolds suitable for conjugation to surfaces, probes or other biomolecules. Reversible interaction with the His-tag is mediated via transition metal ions chelated by the NTA moieties. The small size and biochemical compatibility of these recognition units and the possibility of rapid dissociation of the interaction with His-tagged proteins despite sub nanomolar binding affinity, enable distinct and versatile handling and modification of recombinant proteins. In this review, we briefly introduce the key principles and features of MCH-His-tag interactions and recapitulate the broad spectrum of bioanalytical applications with a focus on quantitative protein interaction analysis on micro or nano-patterned solid surfaces and specific protein labelling in living cells. PMID- 24770787 TI - Short-term effect of temperature on daily emergency visits for acute myocardial infarction with threshold temperatures. AB - BACKGROUND: The relationship between temperature and myocardial infarction has not been fully explained. In this study, we identified the threshold temperature and examined the relationship between temperature and emergency admissions due to MI in Korea. METHODS: Poisson generalized additive model analyses were used to assess the short-term effects of temperature (mean, maximum, minimum, diurnal) on MI emergency visits, after controlling for meteorological variable and air pollution (PM10, NO2). We defined the threshold temperature when the inflection point showed a statistically significant difference in the regression coefficients of the generalized additive models (GAMs) analysis. The analysis was performed on the following subgroups: geographical region, gender, age (<75 years or >= 75 years), and MI status (STEMI or non-STEMI). RESULTS: The threshold temperatures during heat exposure were for the maximum temperature as 25.5-31.5 degrees C and for the mean temperature as 27.5-28.5 degrees C. The threshold temperatures during cold exposure were for the minimum temperature as -2.5-1.5 degrees C. Relative risks (RRs) of emergency visits above hot temperature thresholds ranged from 1.02 to 1.30 and those below cold temperature thresholds ranged from 1.01 to 1.05. We also observed increased RRs ranged from 1.02 to 1.65 of emergency visits when temperatures changes on a single day or on successive days. CONCLUSIONS: We found a relationship between temperature and MI occurrence during both heat and cold exposure at the threshold temperature. Diurnal temperature or temperature change on successive days also increased MI risk. PMID- 24770788 TI - The fun integration theory: toward sustaining children and adolescents sport participation. AB - BACKGROUND: Children cite "fun" as the primary reason for participation in organized sport and its absence as the number-one reason for youth sport attrition. Therefore, the purpose of this study was to develop a theoretical framework of fun using a novel mixed-method assessment of participants in sport (FUN MAPS) via concept mapping. METHODS: Youth soccer players (n = 142), coaches (n = 37), and parents (n = 57) were stratified by age, sex, and competition level and contributed their ideas through (a) qualitative brainstorming, identifying all of the things that make playing sports fun for players; (b) sorting of ideas; and (c) rating each idea on its importance, frequency, and feasibility. RESULTS: The FUN MAPS identify the 4 fundamental tenets of fun in youth sport within 11 fun-dimensions composed of 81 specific fun-determinants, while also establishing the youth sport ethos. CONCLUSION: The FUN MAPS provide pictorial evidence-based blueprints for the fun integration theory (FIT), which is a multitheoretical, multidimensional, and stakeholder derived framework that can be used to maximize fun for children and adolescents to promote and sustain an active and healthy lifestyle through sport. PMID- 24770789 TI - Structural characterization of disease-causing mutations on SAP and the functional impact on the SLAM peptide: a molecular dynamics approach. AB - X-linked lymphoproliferative (XLP) syndrome is an extremely rare inherited immunodeficiency disease characterized by severe immune dysregulation caused by mutations in signaling lymphocyte activation molecule (SLAM) associated protein (SAP) gene. The XLP syndrome was manifested due to dysfunction of SAP as a result of amino acid substitution. Hence, to understand the molecular aspects of the XLP syndrome, we structurally characterized two observed mutations, R32Q and T53I on SAP through the systematic molecular dynamics (MD) approach. Our MD analysis showed that mutant structures elucidated an atomic level variation influenced by mutations that substantially altered the residual flexibility and more importantly the hot spot residues as well in unbound and bound systems. In addition, change in residual flexibility of mutant structures showed an unusual conformational behavior associated with their molecular recognition function compared to the wild-type SAP in both systems. Besides, both mutant structures established different secondary structural profiles during the course of the simulation period in both systems. Moreover, the docking analysis revealed that mutant R32Q and T53I structures displayed remarkably reduced levels of binding affinity to the unphosphorylated SLAM peptide with respect to their docking scores. Collectively, our findings provide knowledge to understand the structural and functional relationship of disease-causing mutations, R32Q and T53I on SAP as well as gain further insights into the molecular pathogenesis of the XLP syndrome. PMID- 24770790 TI - Long-term self-assembly of inorganic layered materials influenced by the local states of the interlayer cations. AB - A wide variety of parameters as, e.g., temperature, humidity, particle size, and cation state are known to influence the agglomeration process of two-dimensional (2D) nanosheets, called self-assembly, in inorganic layered materials. The detailed studies on which parameters are decisive and how they influence the self assembly, however, have not been performed yet. Here, the long-term self-assembly was studied for layered stevensite and hectorite, and compared with our previous data of saponite for elucidating an influence of local states of the interlayer cations. The results were analyzed with respect to a recently established rheological model, in which 2D nanosheets migrate parallel to the layer direction aided by water molecules as lubricants [K. Sato et al., J. Phys. Chem. C, 2012, 116, 22954]. With decreasing the strength of the local electric fields facing to the interlayer spaces, cation positions split into two or three, which makes the distribution of water molecules more uniformly. These water molecules enhance the rheological motion of the 2D nanosheets parallel to the layer direction, thus accelerating the self-assembly process. PMID- 24770791 TI - An unusual case of familial adenomatous polyposis with very early symptom occurrence. AB - We report the clinical case of a patient who showed an "accelerated" form of polyposis, with development of major lesions within the first decade of life. The patient belongs to a familial adenomatous polyposis family-already described in 2001-featured by profuse polyposis at an early age of onset and desmoid tumors in the majority of affected individuals (of both sexes). The family was characterized by an uncommon mutation of the APC gene (c.4391_4700del310insCACCTACTGCTGAAA, previously defined as c.4394ins15del310) consisting in a large deletion of 310 bp at codon 1,464 with duplication of the breakpoint leading to a stop codon at position 1,575. The proband was affected by desmoids tumors at the age of 3 years. In the same year (2004) numerous polyps in the large bowel and a hepatoblastoma developed. After several months new desmoids appeared in the surgical scar. In 2010, at age 9, the patient was operated of total colectomy and endorectal pull-through of the small intestine owing to profuse colorectal adenomatosis. New desmoids developed in 2011 and 2012, and required chemotherapy. Further analysis of the APC gene in the proband revealed several polymorphisms. One of these (c.398A>G) had not been previously reported, nor was present in two other affected members of the family. The clinical case, and the practical implications for therapy, are discussed according to the most recent theories of colorectal cancer development. Long-term treatment with Cox-2 inhibitors might represent a good option for this patient. PMID- 24770792 TI - A fluorescent molecular probe for the identification of zinc and cadmium salts by excited state charge transfer modulation. AB - A fluorescent probe for the identification of a given metal salt is not known. Herein we present a new fluorescent probe 1 for the identification of different zinc and cadmium salts by exploiting the effect of the charge density of counteranions to perturb the excited state solvatochromic behavior of the probe. PMID- 24770794 TI - Fewer fluctuations, higher maximum concentration and better motor response of levodopa with catechol-O-methyltransferase inhibition. AB - Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson's disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition. PMID- 24770793 TI - The phosphoinositide PI(3,5)P2 mediates activation of mammalian but not plant TPC proteins: functional expression of endolysosomal channels in yeast and plant cells. AB - Two-pore channel proteins (TPC) encode intracellular ion channels in both animals and plants. In mammalian cells, the two isoforms (TPC1 and TPC2) localize to the endo-lysosomal compartment, whereas the plant TPC1 protein is targeted to the membrane surrounding the large lytic vacuole. Although it is well established that plant TPC1 channels activate in a voltage- and calcium-dependent manner in vitro, there is still debate on their activation under physiological conditions. Likewise, the mode of animal TPC activation is heavily disputed between two camps favoring as activator either nicotinic acid adenine dinucleotide phosphate (NAADP) or the phosphoinositide PI(3,5)P2. Here, we investigated TPC current responses to either of these second messengers by whole-vacuole patch-clamp experiments on isolated vacuoles of Arabidopsis thaliana. After expression in mesophyll protoplasts from Arabidopsis tpc1 knock-out plants, we detected the Arabidopsis TPC1-EGFP and human TPC2-EGFP fusion proteins at the membrane of the large central vacuole. Bath (cytosolic) application of either NAADP or PI(3,5)P2 did not affect the voltage- and calcium-dependent characteristics of AtTPC1-EGFP. By contrast, PI(3,5)P2 elicited large sodium currents in hTPC2-EGFP-containing vacuoles, while NAADP had no such effect. Analogous results were obtained when PI(3,5)P2 was applied to hTPC2 expressed in baker's yeast giant vacuoles. Our results underscore the fundamental differences in the mode of current activation and ion selectivity between animal and plant TPC proteins and corroborate the PI(3,5)P2-mediated activation and Na(+) selectivity of mammalian TPC2. PMID- 24770795 TI - Performance of different criteria sets for inflammatory back pain in patients with axial spondyloarthritis with and without radiographic sacroiliitis. AB - It is important to recognize inflammatory back pain (IBP) for an early diagnosis of ankylosing spondylitis (AS). Assessment of Spondyloarthritis International Society (ASAS) has recently published new criteria set for diagnosing IBP. In the present study, we evaluated the performance of the new ASAS IBP criteria and to compare the performance of IBP criteria sets in axial spondyloarthritis (axSpA) patients with and without radiographic sacroiliitis. The study sample included a total of 274 patients with a diagnosis of axSpA and 50 patients with a diagnosis of chronic (>3 months) mechanical back pain (MBP). A face-to-face interview by using a standardized questionnaire addressing all the components of IBP was performed. Data about HLA-B27 status and C-reactive protein levels were obtained from the patients' charts. There were significantly more male patients (P < 0.001) in the AS group (68.6 %) than in the non-radiographic axSpA group (29.6 %) and also than in the MBP group (37.5 %). Among the criteria sets, the Calin criteria showed the best sensitivity (91.2 %), and the Berlin criteria showed the best specificity (82.4 %) in differentiation of IBP from MBP. If the morning stiffness item of the Calin criteria was defined as lasting >30 min (Calin 30), the specificity improved (72.9 %), but at a price of loss in sensitivity (82.4 %). In this study, new ASAS criteria for IBP performed almost as good as but not better than the existing criteria sets. Performances of the criteria sets were quite comparable in the differentiation of IBP from MBP in patients with and without radiographic sacroiliitis. PMID- 24770796 TI - Infliximab has no apparent effect in the inner ear hearing function of patients with rheumatoid arthritis and ankylosing spondylitis. AB - Animal studies suggest that tumor necrosis factor (TNF) alpha blockers may pass to the inner ear in adequate concentration. In this prospective study, we aimed to evaluate the effect of infliximab on the inner ear hearing function in patients with ankylosing spondylitis (AS) and rheumatoid arthritis (RA). The patients with high disease activity, who were planned to begin infliximab for therapy by physical medicine and rehabilitation department, were referred to ear nose-throat clinic for consultation. After physical and otoscopic examination, audiological tests were performed. Air conduction thresholds between 250 and 8,000 Hz, bone conduction thresholds between 500 and 4,000 Hz, pure tone average, speech discrimination scores, distortion product otoacoustic emission (DPOAE) were used to evaluate the hearing function. The tests were repeated 2 and 6 months after the initiation of the drug "infliximab." A total of 44 ears of 22 patients (17 males and 5 females) were evaluated. Fifteen patients had a diagnosis of AS, and seven patients had RA. After initiation of infliximab therapy, statistically significant improvement was observed in disease activity scores [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AS, Disease Activity Score 28 (DAS-28) for RA] after 2 and 6 months (p < 0.05). We did not find any statistically significant difference between the air conduction thresholds, bone conduction thresholds, pure tone average, speech discrimination scores, and measurements of DPOAE before the initiation of treatment and after 2 and 6 months (p > 0.05). Any problem about the balance, vertigo, or dizziness was not reported from the patients during the treatment period. As a result, our study showed that there was no notable change or deterioration in the hearing function of the patients with AS and RA who were treated with infliximab. Further studies with higher number of patients with AS and RA and also with different TNF alpha inhibitors are needed to make more valid conclusion. PMID- 24770797 TI - Serum growth arrest-specific protein 6 levels are elevated in adult-onset Still's disease. AB - We investigated the growth arrest-specific protein 6 in adult-onset Still's disease. Serums were collected from 52 adult-onset Still's disease patients with follow-up samples of 21 patients. The growth arrest-specific protein 6 levels in adult-onset Still's disease were higher compared to those in the normal controls (25.37+/-7.71 vs. 19.86+/-5.01 ng/mL, p<0.001). However, growth arrest-specific protein 6 did not correlate with disease activity. Also, growth arrest-specific protein 6 was not decreased after activity was resolved in the follow-up. The growth arrest-specific protein 6 in adult-onset Still's disease patients were higher than the normal controls. However, growth arrest-specific protein 6 was not correlated with disease activity. PMID- 24770798 TI - Uncommon cause of ST-segment elevation in V1-V3: incremental value of cardiac magnetic resonance imaging. PMID- 24770799 TI - A novel approach to abdominoplasty: TULUA modifications (transverse plication, no undermining, full liposuction, neoumbilicoplasty, and low transverse abdominal scar). AB - BACKGROUND: Lipoabdominoplasty can be associated with complications, particularly tissue necrosis, wound dehiscence, epigastric bulging, high transverse scar, low positioning of the umbilicus, and seroma. METHODS: Modified abdominoplasty characterized by (1) transverse elliptical plication of the lower abdominal wall, (2) no undermining of the flap above the navel, (3) unrestricted liposuction, (4) umbilical amputation and neoumbilicoplasty by skin graft, and (5) low transversely placed abdominal scar (TULUA) was performed for 42 patients. These procedures were elective and performed primarily to remedy epigastric skin redundancy associated with obesity or when supraumbilical undermining was considered inappropriate. RESULTS: The results were objectively scored as excellent for 20 patients, good for 21 patients, and fair for 1 patient. A normal appearing umbilicus was attained in all cases except one. The lower transverse scars were generally concealable (6.3 +/- 1.4 cm from the anterior vulvar commissure), and epigastric bulging was avoided. Although four patients experienced seromas at the tail ends of incisions, no skin necrosis, wound dehiscence, or other major complications such as venothromboembolism occurred, and there were no fatalities. In four patients, postoperative magnetic resonance imaging demonstrated measurable and significant changes attributable to plicature compared with equivalent control points (p < 0.000001), which persisted over time. CONCLUSIONS: The TULUA procedure offers potential advantages in terms of vascular safety, sensory recovery, position and quality of the umbilicus, and transverse scar location, with aesthetic outcomes that generally eliminate epigastric bulging. A sizeable patient population stands to benefit from this approach, especially when obesity, smoking, secondary revisions, umbilical or hypogastric hernias, and massive weight loss are clinical considerations for abdominoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24770800 TI - Suspension sutures for neck rejuvenation. PMID- 24770801 TI - Commentary on "ultrasonography: a useful tool for plastic surgeons". PMID- 24770802 TI - Inverted nipple correction with dermal flaps and traction. AB - BACKGROUND: Inverted nipple occurs when part of or the entire nipple is abnormally located below the areola. Surgical repair of severe cases involves suture or flap techniques. Complications include recurrence, lactation problems, hypopigmented scar formation in the areola, and loss of sensation. We describe an alternative repair technique using a dermal flap and traction, which leads to less apparent scarring and preserves lactation function and sensation. METHODS: Between January 2010 and January 2013, we treated 28 inverted nipples in 16 patients using two areola-based triangular dermal flaps and traction. The scar was aligned with the junction of the nipple and the areola. Postoperatively, traction was applied through an apparatus prepared from a 50-cc syringe. Patients were followed up for 8-24 months (mean = 16.5 months). RESULTS: Adequate projection was achieved in all patients and no wound dehiscence or complications such as infection occurred. Unilateral recurrence occurred in one patient on the 10th postoperative day. This patient was reoperated on successfully using the same method. No loss of sensation was observed in any of the patients during the postoperative period. CONCLUSIONS: This dermal flap technique for treating inverted nipple was effective and preserved lactation function. The alignment of the scar with the junction of the nipple and the areola led to a more aesthetic appearance with no apparent scarring. The traction method helped maintain traction for a longer period, which in our opinion increased the success rate of the surgery. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24770803 TI - Molecular dynamics simulations and principal component analysis on human laforin mutation W32G and W32G/K87A. AB - Mutations in human laforin lead to an autosomal neurodegenerative disorder Lafora disease. In N-terminal carbohydrate binding domain of laforin, two mutations W32G and K87A are reported as highly disease causing laforin mutants. Experimental studies reported that mutations are responsible for the abolishment of glycogen binding which is a critical function of laforin. Our current computational study focused on the role of conformational changes in human laforin structure due to existing single mutation W32G and prepared double mutation W32G/K87A related to loss of glycogen binding. We performed 10 ns molecular dynamics (MD) simulation studies in the Gromacs package for both mutations and analyzed the trajectories. From the results, the global properties like root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and hydrogen bonds showed structural changes in atomic level observed in W32G and W32G/K87A laforin mutants. The conformational change induced by mutants influenced the loss of the overall stability of the native laforin. Moreover, the change in overall motion of protein was analyzed by principal component analysis and results showed protein clusters expanded more than native and also change in direction in case of double mutant in conformational space. Overall, our report provides theoretical information on loss of structure-function relationship due to flexible nature of laforin mutants. In conclusion, comparative MD simulation studies support the experimental data on W32G and W32G/K87A related to the lafora disease mechanism on glycogen binding. PMID- 24770804 TI - QuEChERS sample preparation for the determination of pesticides and other organic residues in environmental matrices: a critical review. AB - Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) is an extraction and clean-up technique originally developed for recovering pesticide residues from fruits and vegetables. Since its introduction, and until December 2013, about 700 papers have been published using the QuEChERS technique, according to a literature overview carried out using SciFinder, Elsevier SciVerse, and Google search engines. Most of these papers were dedicated to pesticide multiresidue analysis in food matrices, and this topic has been thoroughly reviewed over recent years. The QuEChERS approach is now rapidly developing beyond its original field of application to analytes other than pesticides, and matrices other than food, such as biological fluids and non-edible plants, including Chinese medicinal plants. Recently, the QuEChERS concept has spread to environmental applications by analyzing not only pesticides but also other compounds of environmental concern in soil, sediments, and water. To the best of our knowledge, QuEChERS environmental applications have not been reviewed so far; therefore, in this contribution, after a general discussion on the evolution and changes of the original QuEChERS method, a critical survey of the literature regarding environmental applications of conventional and modified QuEChERS methodology is provided. The overall recoveries obtained with QuEChERS and other extraction approaches (e.g., accelerated solvent extraction, ultrasonic solvent extraction, liquid/solid extraction, and soxhlet extraction) were compared, providing evidence for QuEChERS higher recoveries for various classes of compounds, such as biopesticides, chloroalkanes, phenols, and perfluoroalkyl substances. The role of physicochemical properties of soil (i.e., clay and organic carbon content, as well as cation exchange capacity) and target analytes (i.e., log KOW, water solubility, and vapor pressure) were also evaluated in order to interpret recovery and matrix effect data. PMID- 24770805 TI - A "turn-on" and label-free fluorescent assay for the rapid detection of exonuclease III activity based on Tb(3+)-induced G-quadruplex conjugates. AB - A "turn-on" and label-free fluorescent assay for the specific, rapid, and sensitive detection of 3' -> 5' exonuclease III activity is reported in this study. The assay is based on the Tb(3+)-promoted G-quadruplex, which lead to the enhancement of Tb(3+) fluorescence due to the energy transfer from guanines. The proposed assay is highly simple, rapid, and cost-effective, and does not require sophisticated experimental techniques such as gel-based equipment or radioactive labels. It can be used for the rapid detection of exonuclease III activity with a detection limit of 0.8 U and a RSD (n = 6) <5 %. Notably, no dye was covalently conjugated to the DNA strands, which offers the advantages of low-cost and being interference-free. PMID- 24770806 TI - Surface chemical approach to single-step measurement of antibody in human serum using localized surface plasmon resonance biosensor on microtiter plate system. AB - In clinical settings, serum antibody levels serve as markers of pathology. For example, antibodies related to autoimmune diseases are among the conventional targets in laboratory tests. Simple clinical tests can improve the efficacy of laboratory practice. This study describes a single-step, wash-free technique for optically detecting antibodies in human serum through the localized surface plasmon resonance (LSPR) of gold nanoparticles. As a proof-of-concept experiment, the amount of antibiotin dissolved in human serum was measured with a LSPR-based biosensor in a wash-free manner using a conventional 96-well microtiter plate and a plate reader. For an efficient surface modification of biosensors, zwitterionic copolymer was used as a scaffold on the gold nanoparticle surface to immobilize antigen and blocking reagent. Single-step, wash-free measurement of antibiotin in human serum was successfully achieved. In addition, nonspecific responses from serum contents were significantly reduced because both the copolymer and hydrophilic antigen reagent that we employed were composed of poly(ethylene oxide) spacer. Comparative experiments of the antigen-antibody reaction in serum to that in buffered solution revealed that serum is a favorable environment for the biological reaction. In conclusion, our gold-nanoparticle-based LSPR method may provide a rapid and simple way to measure the amount of antibody in serum quantitatively in clinical practice. PMID- 24770807 TI - The investigation of the prognostic value of mean platelet volume in patients with sudden hearing loss. AB - OBJECTIVE: The study was aimed to observe the changes in mean platelet volume in patients with sudden hearing loss, taking the close relationship of vascular reasons and sudden hearing loss into account. MATERIALS AND METHODS: Patients who were admitted and treated with sudden hearing loss in the study. The control group was made up of healthy people. The hemoglobin values, mean platelet volumes, platelet counts of the groups were recorded. RESULTS: Forty sixth patients in the sudden hearing loss group and 45 patients in the control group were evaluated. No statistically significant difference between the two groups regarding mean platelet volume values and platelet counts were found. There was also no significant difference between the high mean platelet volumes and hearing loss levels. CONCLUSIONS: We think it would be beneficial to examine the mean platelet volume values in further studies with more patient series on patients with sudden hearing loss. PMID- 24770808 TI - Urinary bladder characteristics via ultrasound as predictors of acute urinary retention in men with benign prostatic hyperplasia. AB - OBJECTIVE: To determine the clinical utility of urinary bladder and prostate characteristics measured by ultrasound scan in predicting acute urinary retention (AUR) for men with bladder outlet obstruction with an underlying benign prostate hyperplasia (BPH). MATERIALS AND METHODS: Consecutive men aged >=50 years presenting with lower urinary tract symptoms (LUTS) or AUR were prospectively recruited in this cross-sectional study. International prostatic symptom score (IPSS) and serum prostate-specific antigen (PSA) were recorded. High-resolution ultrasound was used to measure bladder detrusor thickness (DT, mm), prostatic volume (PV, cm3), intravesical prostatic protrusion (IPP, mm), bladder wall thickness (BWT,mm), intravesical volume and bladder radius. The latter two parameters were used to estimate bladder weight (UEBW, g), assuming a spherical bladder. RESULTS: Among selected patients, thirty had AUR while 32 men presented with LUTS only. There were significant differences between those with and without AUR in their age (70.5 vs 66.0, p=0.017), IPSS (24.0 vs 18.5, p=0.009), serum PSA (6.18 vs 1.77, p=0.002), PV (56.7 vs 32.4, p=0.006), BWT (5.0 vs 4.4, p=0.034) and UEBW (39.1 vs 25.0, p=0.0003). Multivariate analysis revealed high IPSS and UEBW to be predictors for AUR. UEBW was the strongest predictor of AUR: area under ROC curve was 0.767, with sensitivity and specificity of 63.3% and 87.5%, respectively, at cut-off point of 35 g. The likelihood ratio for AUR was also best with UEBW>=35 g. CONCLUSIONS: Combined with IPSS, ultrasound determined bladder characteristic, particularly UEBW, is a useful tool in predicting AUR in men with BPH. PMID- 24770810 TI - High IgE levels in patients affected by psoriasis: review of the literature and personal observations. AB - OBJECTIVE: The concomitance of psoriasis and high IgE levels in the same patient, possibly associated to allergies, should not come as a surprise anymore, because both diseases are characterised by an immunological disorder, involving cytokines and other inflammatory mediators, with massive activation of the cell-mediated immunity. MATERIALS AND METHODS: During a period of 18 months, using a radio immunologic method, we assessed the level of IgE in patients with severe psoriasis who were not responding to the common therapy. RESULTS: Patients with severe psoriasis had high levels of IgE. CONCLUSIONS: IgEs have an important role in pathogenesis of psoriasis and atopic dermatitis, but the mechanism is not yet clear. PMID- 24770809 TI - Sexual dysfunction among postmenopausal women. AB - INTRODUCTION AND OBJECTIVE: Female sexual dysfunction (FSD) has a major impact on interpersonal relationships and quality of life. For many women it has been emotionally distressing, physically disconcerting, and socially disruptive. To determine the prevalence and factors that contribute to female sexual dysfunction (FSD) and to evaluate the different sexual domains that influence sexual function amongst post menopausal women. MATERIALS AND METHODS: This was a cross-sectional study among postmenopausal women attended the Menopause Clinic, Universiti Kebangsaan Malaysia Medical Centre (UKMMC). It was conducted over a period of one year. A validated English and Malay Version of the Female Sexual Function Index (FSFI) were used to assess female sexual function. RESULTS: The median age of menopause in this study population was 50 years and majority of these patients was on hormonal therapy (58.2%). The prevalence for sexual dysfunction was high (85.2%). The most affected sexual domains were: dissatisfaction (89.0%), arousal (67.0%) and desire (62.4%). Factors associated with sexual dysfunction among post menopausal women that were statistically significant were age more than 60 (p=0.033), lower educational level (p<0.001), and type of menopause (p=0.029). Women with naturally occurring menopause were found to be 2.5 times more likely to have sexual dysfunction. CONCLUSIONS: The prevalence of sexual dysfunction among post menopausal women was high. The most affected domains were satisfaction, desire and arousal. The associated factors were older age, lower education level, and type of menopause. PMID- 24770811 TI - Seroprevalence of serum HBsAg positivity and hepatitis delta virus infection among blood donors in Southeastern Turkey. AB - AIMS: HBV and HDV infection is still a serious health problem in Southeastern Turkey. In this study, we aim to investigate the prevalence serum HBsAg along with HDV infection among volunteer blood donors. MATERIALS AND METHODS: This single centre and prospective study was performed in 6200 consecutive volunteer blood donors admitted to the Central Blood Bank of Dicle University Hospital. All adult blood donors included males and females were screened for HBsAg positivity. The positive serum samples for HBsAg were assessed for total anti-delta antibodies using the micro-ELISA method. Serum samples of anti-delta antibody positive cases were then examined for the presence of serum HDV RNA by real time, reverse transcription PCR method. RESULTS: Six thousand two hundred adult volunteer blood donors were enrolled to the study. Of all analyzed blood donors, 6004 (96.8%) were men and 196 (3.2%) were women. Serum HBsAg positivity was found in 3% (186/6200) of 6200 blood donors. The mean age and female/male ratio of HBsAg positive cases (n=186) were 32.85+/-10.04 years and 12/174, respectively. Serum anti-delta antibodies were detected in 6.98% (13/186) of HBsAg positive cases. The mean age of anti-delta antibody positive cases (n=13) was 44.5+/-13.61 years and female/male ratio was 1/12. Moreover, 2 cases, (15.39%, 2/13) that were positive for anti-delta antibody, had serum HDV RNA positivity. CONCLUSIONS: It would be appropriate for HBsAg positive volunteer blood donors to be assessed regarding concurrent HDV infection as well. The magnitude of the contribution and benefit that this screening would provide to our region, which is endemic for HDV infection, is the early diagnosis and management of this devastating disease. The real viremia in these cases can be best shown by using sensitive real time PCR method for the presence of serum HDV RNA. PMID- 24770812 TI - [Adult-Onset Still's Disease, an improbable differential diagnosis: a case report]. AB - Juvenile idiopathic arthritides (JIA) comprehend a heterogeneous group of inflammatory diseases of the joints, with an unknown aetiology, arising within 16 years of age, and lasting more than six weeks. The systemic form, known as Still's disease, represents from 4 to 17% of all the JIA. AOSD (Adult Onset Still's Disease) is a variant of JIA affecting adults, with identical clinical manifestations. Here we describe the case of a 36 year old woman, with a symptomatology characterized by fever, skin rash, arthralgies and lymphadenopathy. The arise of the fever in this case has uncommonly preceded by several weeks the arise of the other signs; this has determined a considerable delay in the diagnosis: Still's disease diagnosis is made hard as it shares its signs and symptoms with several infectious, immunological as well as tumoral diseases. In this case, the blossoming of the laboratory parameters at the sixth day of hospitalization with leucocytosis and neutrophilia represented the solving clue. Still's disease, though a rare nosographic entity, must be kept into consideration in unclear cases occurring in an internal medicine department. PMID- 24770814 TI - Scrotal lump: do not forget tuberculosis! AB - Scrotal tuberculosis (TB) is rare. Lack of awareness may lead to a misdiagnosis and/or delayed diagnosis of scrotal TB. Clinicians should have a high suspicion index for scrotal TB when facing a patient with a chronic scrotal lump. Since scrotal TB can be medically cured, biopsy of the scrotal lump for pathology study and/or urine polymerase chain reaction (PCR) analysis for M. tuberculosis should be performed first for rapid diagnostic purposes, and therefore unnecessary surgery may thereby be circumvented. PMID- 24770813 TI - An unusual array of extensor musculature and tendons of the hand clinico anatomical insight. AB - Extensor tendon injury is a frequent finding in clinical practice. During a routine dissection class of undergraduate medical students examining the extensor aspect of the right hand, they found an interesting pattern of extensor tendons. The extensor digitorum (ED) exhibited three tendons for the middle and ring fingers. The intermediate tendon of the ED was found to pass to the junctura connecting the tendons of the ring and middle fingers. Additionally the Extensor carpi ulnaris displayed two tendinus slips. The lateral slip was inserted on the base of fifth metacarpal as usual, whereas the medial slip divided into two strands- proximal and distal. Apart from the above findings in the current case specimen, there was an accessory muscle belly for the index finger and the extensor digiti minimi bifurcated into two tendinus slips which gained attachment to the dorsal digital expansion of the little finger. These accessory muscle bellies and tendons could possibly be utilized for tendon reconstructions such as repairs, tenoplasties or tendon transfers. PMID- 24770815 TI - Multifaceted profile of an unusual paramedian occipital condyle-anatomical and computerised tomographic evaluation. AB - During extensive osteological study of 150 dry skulls in the Department of Anatomy, Vardhman Mahavir Medical college, an unusual Paramedian Occipital (POC) condyle was detected in the occipital bone of a cadaveric skull. The anatomical details of this unusual occipital condyle were carefully studied and its morphometric measurements taken. A coronal multiplanner reformatted image and a volume rendered image were taken to study radiological details and establish significant clinical correlation. Precise understanding of anatomy of craniovertebral junction and its anomalies have become immensely important for the present day surgeon during orthopaedic and neurosurgical procedures of this region . Technical advancements in imaging modalities such as CT and MRI scans further signify the importance of these anatomical variations ,which are often missed in routine examination. Osteological study combined with radiological details of the paramedian occipital condyle in the present case aims to emphasize the importance of bony anomalies in the craniovertebral region and their role in diagnosis and appropriate treatment of neurovascular compression syndromes of craniovertebral junction. The present study highlights anatomical details, clinical relevance and embryological basis of such a rare unusual paramedian occipital condyle. PMID- 24770816 TI - Validation of an original questionnaire for patients with psoriatic arthritis: the Psoriatic Arthritis Impact Profile (PAIP). AB - BACKGROUND AND AIMS: There is a wide evidence that Psoriatic Arthritis (PsA) as well as Psoriasis (Ps) lead to significant health problems and interfere with the patient quality of life (QoL). Even though a validated questionnaire for Ps is available, no questionnaire for PsA is currently present in literature. The aim of our work has been to confirm the efficacy of our original questionnaire as well as to validate it, through the comparison with other existing recognised and accepted questionnaires, such as MOF-SF36, HAQ, McGill Pain Questionnaire, and Zeung Self-Rating Depression and Anxiety Scales. MATERIALS AND METHODS: We have realized a questionnaire for PsA (Psoriatic Arthritis Impact Questionnaire, PAIP), in terms of psychological and rheumatological evaluation, QoL, social and economic assets. RESULTS: The statistical comparisons between PAIP and the accepted questionnaires (see above) confirm that PAIP is widely validated and represents a useful tool suitable for clinical evaluation and management of patients with PsA. CONCLUSIONS: The indexes of the correlation among the different parts of PAIP and the other questionnaires have shown positive correlations. Moreover, PAIP presents a dedicated unit for the economical and therapeutic parameters, The short time for compilation (15 minutes), the easy of comprehension of the questions, and - above all - the validation of PAIP, make our questionnaire a useful tool, suitable for the clinical management of the patients with PsA. PMID- 24770817 TI - The ethical and legal implications of nanotechnologies: a preliminary survey to picture the perceptions of law students and medical students. AB - PURPOSE: The aim of this preliminary survey was to picture the current knowledge and opinions of law students and medical students about nanotechnologies. MATERIALS AND METHODS: Data were collected in June 2012 by interviews with 60 students of the University of Camerino (Macerata, Italy) defined as "jurist population" and 159 medical students of the Universita Cattolica del Sacro Cuore (Rome, Italy) defined as "medical population". RESULTS: The Authors found that both law and medical students have some knowledge on what nanotechnologies are; with regards to the ethical issues and risks perception, both categories indicated that nanotechnologies generate bioethical issues. Nevertheless, a high percentage of respondents believed that neither existing technologies nor nanotechnologies pose risks for human health. Opinions on regulation of nanotechnologies are instead different. CONCLUSIONS: These preliminary findings underlined the ambiguity surrounding nanotechnologies both concerning the bioethical dimension and risks perception and their regulation. These early data therefore showed a need of additional reflection on these technologies that should be investigated more in detail; moving from students, future scientists and regulators, these data could contribute to clarify the debate on them. PMID- 24770819 TI - False accusations of sexual abuse as a mean of revenge in couple disputes. AB - OBJECTIVE: In forensic-psychiatric evaluations on a minor presumed victim of sexual abuse, one may come across "false positives" and "false negatives". The aim of this study was to examine the phenomenon of false sexual abuse as revenge by one ex-partner against the other, and to offer recommendations about how to avoid this risk. MATERIALS AND METHODS: The authors examined 75 technical consultations and expert testimonials in which intrafamilial sexual abuse of a minor was reported. RESULTS: Twenty two (30%) were found to be baseless and result of conflict, revenge of one partner upon the other. Of these 22, 5 involved men who accused their ex-wives and/or live-in partners. The remaining 17 cases involved charges by women against their ex- husbands, and/or live-in partners. CONCLUSIONS: Charges of abuse represent not only an instrument of protection of one's own children, but also a weapon of revenge against an ex partner, putting these minors into the role of victims. PMID- 24770818 TI - [The management of post-surgical pain in the patient treated for hallux valgus with percutaneous and minimally invasive technique]. AB - OBJECTIVE: In today's literature there are no defined guidelines for the treatment of postoperative pain in corrective surgery of hallux valgus. In this study we evaluated the use of a new treatment protocol designed to minimize the postoperative pain related to the surgical treatment of hallux valgus. MATERIALS AND METHODS: The study involved 20 female patients (20 feet) treated for moderate to severe hallux valgus between September 2011 and December of 2012 with a percutaneous technique (10 feet) and minimally invasive surgery (Endolog System) (10 feet). All patients received postoperative as analgesic therapy 1 cp etoricoxib 120 mg/ day for 5 days + oxycodone hydrochloride/naloxone 5mg 1cp * 2/day for 15 days. The evaluation forms of pain VAS/VRS have been used for the evaluation of pre and postoperative pain at 15 and 30 days. RESULTS: In both groups we found a significant reduction of pain in the days following surgery. At 30 days the VAS score was similar in between the two groups. Few and mild side effects were reported (1 case). CONCLUSIONS: The co-administration of an anti cox2 and an opioid in the first postoperative hours is useful to reduce soft tissue swelling and to control pain without causing significant side effects. The therapeutic protocol adopted, along with an adequate anesthesiological approach, has proved to be very effective for pain management in peri-and post-operative treatment of hallux valgus. PMID- 24770820 TI - Does gamma irradiation affect physicochemical properties of honey? AB - BACKGROUND AND AIMS: Honey is a supersaturated solution of sugars, enriched with proteins, minerals, vitamins, organic acids and polyphenols. Gamma irradiation is a physical technique of food preservation which protects the honey from insects' and microbial contamination during storage. We investigated the effect of gamma irradiation on physicochemical properties in two types of Malaysian honey, Gelam and Nenas. MATERIALS AND METHODS: Both honeys were irradiated at the dose 25 kGy in a cobalt-60 irradiator. The physicochemical properties pH, moisture, acidity, color, and sugar content as well as vitamins C and E, hydroxymethylfurfural (HMF) and mineral contents, for the irradiated and non-irradiated honeys were assessed. RESULTS: The results revealed that pH, acidity, minerals and sugar contents in both types of honey were not affected significantly by gamma irradiation, while moisture, vitamin E contents and HMF level decreased significantly with gamma irradiation. However, significant increased in color intensity and vitamin C were observed after gamma irradiation for both types of honey. DISCUSSION: In summary, gamma irradiation treatment of honey (in the dose mentioned above) did not cause significant changes in the physicochemical and mineral contents, except for significant alterations in color intensity, moisture, vitamins (C and E), and HMF contents. PMID- 24770821 TI - Intracranial lipomas: clinical and imaging findings. AB - PURPOSE: Intracranial lipomas are rare congenital malformations. The most common location of intracranial lipoma is the midline cerebral structures. The most frequently seen symptoms are headaches, seizures, psychomotor retardation and cranial nerve deficits. This study aimed to evaluate the clinical and radiological findings of 14 patients with intracranial lipoma. MATERIALS AND METHODS: The study comprised 14 patients diagnosed with intracranial lipoma from computed tomography and magnetic resonance imaging taken after presentation at our hospital with headaches or seizures between January 2008 and April 2012. The cranial CT and MR images were evaluated by two experienced specialist radiologists. The lipoma localisation, size, morphology, any concomitant anomalies and findings of compression were recorded. RESULTS: The study comprised 14 patients diagnosed with intracranial lipoma. The lipoma was observed to be located pericallosal, adjacent to the mamillary body and the optic chiasm, interhemispheric, in the quadrigeminal cistern and sylvian fissure. 3 patients had a history of seizures. The others had headaches. CONCLUSIONS: If there are no concomitant central nervous system (CNS) anomalies, there are no significant clinical or neurological findings apart from headaches. PMID- 24770822 TI - 131I therapy and Graves' disease in a long term observation: euthyroidism is a suitable goal. Our experience. AB - OBJECTIVE: The aim of the study was to verify early and definitive outcome of radioiodine therapy in patients with Graves' disease, administering 131I calculated dose to pursue euthyroidism. PATIENTS AND METHODS: We retrospectively analyzed 639 patients affected by Graves' disease and treated by one or more 131I calculated doses. Results dose by dose are reported. As to the first administration, outcome is related to parameters used to calculate dose and to patients' available features. Failures and hypothyroidism onset are evaluated. RESULTS: A mean dose of 10 mCi shows great effectiveness: 75% of patients were cured after one administration, 88% after two. Of the failures, 84.1% occurred in a mean time of 0.34+/-0.23 years and were more frequent for larger glands, accelerated intra-gland radioiodine turnover, ophtalmopathy, administration of antithyroid drugs until 131I therapy. Of hypothyroid patients, 39.8% were diagnosed within the first year. After a sharp initial rise, hypothyroidism occurred at a slower rate, with estimated yearly increases of 3.8% until 10 years and of 1.8% later. In still followed up patients, euthyroidism was observed in about half the population after 10 years and in a third after 25 years. CONCLUSIONS: 131I can be the first line treatment for Graves' disease in small medium thyroids. Calculated doses can achieve a high amount of long term euthyroid patients. Similar results could be expected by fixed doses of 10 mCi. PMID- 24770823 TI - The effect of feto-maternal blood type incompatibility on development of gestational diabetes mellitus. AB - OBJECTIVE: To assess the relation between fetal and maternal blood type (ABO, Rh) incompatibility and development of gestational diabetes mellitus (GDM). MATERIALS AND METHODS: A total of 500 pregnant women underwent diagnostic test for GDM by a 100-g oral glucose tolerance test (OGTT) after an 8 to 12-h overnight fast participated in this study. OGTT was performed between the 24-28 weeks of gestation, but participants who were at high risk for GDM were tested after the first prenatal visit. In the postpartum period, maternal and infant blood types were determined. Presence of GDM was evaluated in terms of matched and unmatched fetal and maternal ABO and Rh blood types separately. RESULTS: GDM was detected in 235 participants. Unmatched ABO blood types between the mother-infant pairs were present in 44.7% (n=105) of GDM (+) and 35.8 % (n=95) of GDM (-) patients. Incompatible feto-maternal ABO blood type was positively correlated with development of GDM which was marginally significant. (p=0.045; R=1.2;95% CL; 1.004-1.48). However, Rh feto-maternal blood type incompatibility was not related with development of GDM. CONCLUSIONS: Feto-maternal ABO blood type incompatibility may be a weak risk factor for the development of GDM. PMID- 24770824 TI - Effects of the inflammatory response on serum omentin levels in early acute and chronic pancreatitis. AB - BACKGROUND AND AIMS: Acute pancreatitis is an acute inflammation of the parenchyma of the pancreas. Several adipokines have been investigated in acute pancreatitis, and these cytokines contribute to inflammation in acute pancreatitis. However, not enough data exist regarding omentin in injuries of the pancreas. Because of a possible common pathogenesis, we aimed to study the association between pancreatic damage and serum omentin levels. MATERIALS AND METHODS: Twenty-four Sprague Dowley rats weighing 200-250 g were randomly placed into three groups: a sham group (n=8), an acute pancreatitis group (n=8), and a chronic pancreatitis group (n=8). Both rats in the sham group underwent laparotomy, and 0.1 cc of saline solution was injected through the pancreatic canal. On the seventh day, a blood sample was obtained by abdominal aorta puncture, and the pancreas was resected for histological examination. In the acute and chronic pancreatitis groups, 0.1 cc of 4.5% Sodium Taurocholote was injected through the pancreatic canal. Blood samples were obtained and pancreatic resection was performed after 24 hours for the acute pancreatitis group and after 7 days for the chronic pancreatitis group. RESULTS: Serum omentin levels of rats with chronic pancreatitis (49.37+/-2.82 ng/ml) were increased compared to both acute pancreatitis (37.79+/-1.24 ng/ml) (p<0.01) and sham rats (22.49+/-1.4 ng/ml) (p<0.01). In addition, the omentin level of rats with acute pancreatitis was significantly increased compared to the sham group (p<0.01). CONCLUSIONS: The elevation in omentin levels in rats in the early stage of pancreatitis was due to the anti-inflammatory effects of omentin; hence, elevated omentin levels improved insulin resistance and caused a significant reduction in glucose levels. PMID- 24770825 TI - Prognostic value of the Intermediate QRS prolongation in patients with acute myocardial infarction. AB - OBJECTIVE: Studies have shown different effect of intermediate QRS prolongation on major cardiovascular events in acute myocardial infarction (AMI) patients. The aim of this study was to investigate the predictive and prognostic value of intermediate QRS prolongation on in-hospital complication rate and long term mortality in patients with AMI. MATERIALS AND METHODS: We performed an observational study that enrolled 114 consecutive patients with AMI. Patient's admission electrocardiography (ECG) were enlarged two fold, and QRS duration (QRSd) was measured manually. Patients were divided into two groups according to the admission EKG QRSd. Group A defined as patient with QRSd between 90-120 msn and group B QRSd <90msn. Echocardiographic, angiographic, clinic and laboratory results were recorded for all patients. Patients were followed next twelve months. RESULTS: In-hospital follow-up period, major adverse cardiac events were higher in group A than group B (0.9 +/-0.9 vs. 0.5 +/-0.5 p=0.02). There were increased end-diastolic and end-systolic volume in group A (91+/-15 vs. 82+/-12 p=0.002; 50+/-10 vs. 44+/-9 p=0.002. respectively). Left ventricular ejection fraction (LVEF) was lower in group A. but it did not reach statistical significance (43.5+/-6.3 vs. 45.5+/-5.5 p=0.06). Angiographic evaluation was detected severe coronary artery disease (CAD) in group A than group B (1.9+/-0.8 vs. 1.5+/-0.7 p=0.013). During 12 months of follow-up period. five patients were died. Although these patients had longer QRSd on admission, it was not statistically significant (96+/-14 vs. 90+/-11 p=0.3). CONCLUSIONS: Intermediate QRS prolongation on admission EKG were found to be positively correlated with increased EDV, ESV, major in-hospital cardiovascular events, and multivessel coronary artery disease and inversely correlated with LVEF. Although deceased patients had prolonged QRSd it was not statistically significant. PMID- 24770826 TI - Treatment of permagna incisional hernia with skin necrosis and abscess: case report. AB - Ventral incisional hernia rate is decreasing due to the introduction of new clinical and surgery method. As a result, the complex incisional hernias, are less often described and rarely treated. We describe our experience in emergency case. We present the case of permagna incisional hernia with skin necrosis, subcutaneous abscess and bowel perforation which cause a long-lasting bedding. The successful management includes an emergency surgery applying hernia reduction, bowel resection and abdominal wall reconstruction through a biological mesh and positioning of VAC System. There is not a gold standard treatment that obtained an unanimous consensus, however we recommend the following procedure in that, in our patient, it shows no recurrences, infections and other post operative complications. PMID- 24770827 TI - Is HE4 serum level a valid screening test in women candidates for kidney transplant? A case report and a review of literature. AB - While studying a candidate for kidney transplant it is essential to exclude active malignant diseases. Serum biomarkers help to exclude specific cancers. Tumor markers are proteins secreted by neoplastic cells that can mark their activities. HE4 is a new tumor marker used in ovarian cancer. It is an epithelium protein that appears overexpressed in ovarian cancer, but it is also present in other normal human tissues. Often in patients with kidney failure serum biomarkers are increased compared to healthy people. We report a case of a Caucasian woman suffering from kidney failure examined by our team to be included on the kidney transplantation list. Patient had a known pelvic mass. Determination of serum biomarkers, CA125 and HE4, was performed to exclude pelvic tumor, and we found high levels of HE4 with normal levels of CA125. A new transvaginal ultrasound was performed on the patient and it showed a pelvic mass near the left ovary. This mass resulted bigger than in the previous ultrasound, performed about a month before. We decided to perform a pelvic CT for improved diagnostic accuracy. The reports of this exam showed that the mass was a hematoma correlated with a previous knee prosthetic surgery. Even tough many serum biomarkers are higher in patients with renal failure, there is no study to demonstrate that HE4 blood levels are modified in these patients. This case report shows how HE4 can be elevated in people in hemodialysis in a benign situation, also in a pelvic mass not from the genital tract. There is no similar case described in literature. PMID- 24770828 TI - Efficacy of ranolazine for rhythm control in an elderly patient with paroxysmal atrial fibrillation. AB - We report the case of an elderly woman with coronary heart disease and paroxysmal atrial fibrillation. It could be hypothesized that the predisposing anatomic substrate for arrhythmogenesis in this patient derived from both age-related left atrial dilation and coexistent ischaemic heart disease. Unfortunately the usual antiarrhythmic therapy was unsafe or not feasible for this subject. Ranolazine 750 mg twice daily completely suppressed atrial fibrillation recurrences. PMID- 24770829 TI - Large symptomatic simple hepatic cyst with gastric compression treated with percutaneous drainage. AB - Nonparasitic hepatic cysts consist of a heterogeneous group of disorders, which differ in etiology, prevalence, and manifestations. Simple hepatic cysts are considered nonparasitic ones. These are a result of congenital anomalies of the biliary system, and these may be single or multiple. Generally, hepatic cysts are incidentally found during occasional laparotomy or laparoscopy, necropsy, and even during routine ultrasound or computerized tomography (CT) scan. Nowadays, with improving diagnostic techniques, hepatic cysts are becoming more common. Generally these lesions are asymptomatic. However, if they grow, they may become symptomatic. Symptoms depend on the size and location. When symptoms developed, these must be treated. Compressive complications due to local "liver mass" effect include: portal hypertension, edema due to caval compression, jaundice and arrhythmia and duodenal obstruction. Gastric extrinsic compression by liver cysts has been poorly described. Herein, we present a case of a female in whom percutaneous drainage of a large simple hepatic cysts not complicated was performed in order to reduce signs of gastric compression. PMID- 24770830 TI - [The alpha chemokine "Interferon gamma-induced protein 10" (IP-10) in Graves' disease]. AB - The alpha chemokine Interferon gamma-induced protein 10 (IP-10) and its receptor, CXC receptor 3, appear to contribute to the pathogenesis of Graves' disease (GD) and Graves' ophthalmopathy (GO). Under the influence of Interferon-gamma, IP-10 is secreted by thyrocytes (in GD), fibroblasts and preadipocytes (in GO). Determination of high level of IP-10 in peripheral liquids is therefore a marker of a Th1 orientated immune response. Circulating IP-10 is associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients. Methimazole reduces IP-10 secretion by isolated thyrocytes, decreases serum IP-10 levels, and promotes a transition from Th1 to Th2 dominance in patients in GD active phase. In GD patients the decrease of IP-10 after thyroidectomy and radioiodine strongly suggests that this chemokine is mainly produced by the thyroid itself. In GO patients the increased concentrations of IP-10, at least in part, reflect the activity of orbital inflammation. A significant reductions in IP-10 serum concentrations during corticosteroids and or radiotherapy treatments, as compared both to control group and to basal values in GO patients, suggest that this chemokine could serve as a guideline in therapeutic decision-making in patients with GO. Further studies are needed to evaluate whether IP-10 is a novel therapeutic target in GD and GO. PMID- 24770832 TI - Some considerations on integrity in scientific research. AB - Some aspects of research integrity are presented and discussed, primarily through reference to institutional documents, particularly those published by the European Union. A scrupulous approach to scientific publications is emphasized as being crucial to integrity in research, while clinical trials are indicated as an area in which especially strict rules should be observed. The article comprises: an introduction, in which "integrity in research" is defined; some examples of violations of research integrity; an analysis of possible ways to implement general rules in particular contexts; a call for scrupulousness in scientific publications as a crucial factor in research integrity; a brief reference to ethics in clinical trials, where the observation of particularly severe rules is imperative. PMID- 24770831 TI - Type 1 diabetes and (C-X-C motif) ligand (CXCL) 10 chemokine. AB - The upregulation of (C-X-C motif) receptor 3 (CXCR3) and its ligand (C-X-C motif) ligand (CXCL)10 (CXCL10) has been documented in many autoimmune disorders. Many studies have suggested that the CXCL10/CXCR3 axis plays a critical role in the autoimmune process and in beta-cell destruction in Type 1 Diabetes (T1D). Serum CXCL10 level "Th1 chemokine" is high in T1D patients, and this suggests that CXCL10 may be a candidate for a predictive marker of T1D. Furthermore, serum CXCL10 levels measurement may be useful to assess the pathophysiology of the disease course in T1D. Blocking of the CXCL10 chemokine expression in newly onset of diabetes seems to be a possible approach for the therapy of T1D. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of T1D. PMID- 24770833 TI - Treatment of iron deficiency anemia induces weight loss and improves metabolic parameters. AB - BACKGROUND: The treatment of iron deficiency anemia is oral iron replacement which has side effects mostly related with gastrointestinal system. A significant rate of the patients that discontinuing the treatment complained of weight gain during treatment in our clinical practise, despite, oral iron preparations are not known to have such a side effect in adults. Therefore, we planned to investigate this myth whether iron preparations cause an increase in weight, waist circumference, body mass index and laboratory metabolic parameters that may accompany to weight gain. MATERIALS AND METHODS: Twenty-one women admitted to our out-patient clinics with iron deficiency anemia were enrolled to the study. Waist circumference, body weight, body mass index, systolic and diastolic blood pressures, hemogram and other laboratory parameters assessed and recorded at the first visit and repeated 4 to 6 moths after initiation of treatment. RESULTS: Waist circumference, body weight and BMI significantly reduced in patients after treatment compared to pre-treatment period. Moreover, HDL was increased and triglyceride was decreased significantly in after treatment compared to pre treatment period. CONCLUSIONS: We suggest that treatment of iron deficiency may improve not only haematological but also metabolic and anthropometric parameters. Due to the small study population of our cohort, larger prospective studies are needed to confirm our results. PMID- 24770834 TI - Anesthetic management in hydatid disease: a review of 435 cases. AB - BACKGROUND AND AIMS: Hydatid cyst diseases are still a problem in Turkey, especially in the east and southeast of Anatolian Region, as well as in many other places in the world. In this study a retrospective review was made of the anesthetic management for surgical and interventional treatment of 435 patients with hydatid cysts. The study data were collected between January 1997 and December 2012 at Harran University Hospital, Sanliurfa, Turkey. MATERIALS AND METHODS: Patients' demographics and localization of the cysts were recorded. Suitable anesthetic and surgical management were performed to the cysts according to their locations. Four hundred thirty-five patients had general anesthesia with a midazolam premedication and one of them was treated by sedation. RESULTS: Of the 435 patients, 251 were females (57.7%) and 184 males (42.3%) and ages ranged from 1 to 74 years (mean: 36.3 +/- 25.4). These include; preoperative using of steroids and antihistamines to prevent the allergy possibility, intraoperative hypotension and tachycardia and administration of colloids, and improvement of postoperative anaphylaxis. Anaphylaxis was observed in only two patients who undertook percutaneous aspiration. Also bronchospasm was developed in four patients during the postoperative period and successfully treated with standard bronchodilatators. CONCLUSIONS: Anaphylactic reaction during operation is a serious complication, but a very rare one. Prophylactic use of antihistamine and steroid drugs were reduced allergy and anaphylaxis. PMID- 24770835 TI - Workers exposed to urban stressors and the effects on antidiuretic hormone secretion. AB - BACKGROUND: The aim of this study was to evaluate whether urban pollutants can affect plasma levels of antidiuretic hormone (ADH) in outdoor workers. MATERIALS AND METHODS: We selected 208 subjects, 104 exposed to urban stressors and 104 non exposed to urban stressors. We divided these workers in 3 groups: Group 1 (non smokers and non-drinkers), Group 2 (smokers and not drinkers) and Group 3 (drinkers and not smokers). The means and standard deviations of ADH were calculated, and a Student's t-test was used to compare means. The data were considered significant at p <= 0.05. RESULTS: The outdoor workers in Group 1 had significantly reduced plasma levels of ADH. In contrast, the outdoor workers in Groups 2 and 3 had increased plasma levels of ADH. These results were consistent in both men and women. CONCLUSIONS: The results suggest that urban pollutants may influence the secretion of ADH. PMID- 24770836 TI - Selected metal ions protect Bacillus subtilis biofilms from erosion. AB - Many problems caused by bacterial biofilms can be traced back to their high resilience towards chemical perturbations and their extraordinary sturdiness towards mechanical forces. However, the molecular mechanisms that link the mechanical properties of a biofilm with the ability of bacteria to survive in different chemical environments remain enigmatic. Here, we study the erosion stability of Bacillus subtilis (B. subtilis) biofilms in the presence of different chemical environments. We find that these biofilms can utilize the absorption of certain metal ions such as Cu(2+), Zn(2+), Fe(2+), Fe(3+) and Al(3+) into the biofilm matrix to avoid erosion by shear forces. Interestingly, many of these metal ions are toxic for planktonic B. subtilis bacteria. However, their toxic activity is suppressed when the ions are absorbed into the biofilm matrix. Our experiments clearly demonstrate that the biofilm matrix has to fulfill a dual function, i.e. regulating both the mechanical properties of the biofilm and providing a selective barrier towards toxic chemicals. PMID- 24770837 TI - Thoracic endovascular aortic repair with left subclavian artery coverage without prophylactic revascularisation-early and midterm results. AB - BACKGROUND: The management of the left subclavian artery when coverage is necessary during thoracic aorta endografting remains a matter of debate. MATERIALS AND METHODS: A retrospective analysis of a single-centre experience with thoracic endovascular aorta repair (TEVAR) was performed. Between April 2004 and October 2012, 125 cases of TEVAR were performed. The analysis focused on patients who required coverage of the left subclavian artery (LSA). We analysed mortality and morbidity with special attention to the rates of cerebrovascular accidents (CVAs) and spinal cord ischaemia (SCI) in the early and midterm. RESULTS: Of the 125 patients, 53 (42 %, group A) required an intentional coverage of the LSA to obtain an adequate proximal seal for the endograft; the remaining patients constituted group B. None of the patients in group A had protective LSA revascularisation prior to TEVAR. The primary technical success rate was 79.2 vs. 90.3 % (group A vs. group B, p = 0.08), and the primary clinical success rate was 77.4 vs. 82 % (group A vs. group B, p = 0.53). The 30-day mortality rate was 11.3 vs. 11.1 % (group A vs. group B, p = 0.97). The 30-day morbidity was 7.5 vs. 13.9 % (group A vs. group B, p = 0.4). CVA occurred in 1.9 % of group A patients, compared to 1.4 % of patients from group B (p = 0.82). The SCI incidence rate was 0 vs. 1.4 % (p = 0.39). The mean follow-up of group A was 24.1 months (range 2 64.6 months, SD = 19). Additionally, the 1-year estimated survival was 85.5 %, and the 3-year estimated survival was 78 %. There were no midterm CVAs; one event of SCI occurred in the seventh post-operative month in group A. CONCLUSION: Our analysis, although retrospective and based on one institution experience, shows a realistic population of TEVAR patients. We prove that TEVAR with coverage of LSA origin can be accomplished with minimal neurological morbidity in this patient population. The study shows that LSA revascularisation is not mandatory before endograft deployment, especially in emergency settings. We also prove that although zone 2 TEVAR extends the proximal landing zone, it does not prevent type IA endoleaks from appearing. A multicentre randomised control trial with higher number of patients is necessary for proper, robust conclusion to be established. PMID- 24770838 TI - Effect of Persea americana (avocado) fruit extract on the level of expression of adiponectin and PPAR-gamma in rats subjected to experimental hyperlipidemia and obesity. AB - BACKGROUND: Persea americana, commonly known as avocado, is traditionally consumed fruit which possesses body fat lowering capacity. Adiponectin plays an important role in regulating obesity. In this study, the effect of hydro alcoholic fruit extract of P. americana (HAEPA) on the level of blood lipids, glutathione, lipid peroxidation products, adiponectin and peroxisome proliferator activated receptor (PPAR)-gamma expressions was investigated in rats fed a high fat diet (HFD). METHODS: Male Sprague Dawley rats were divided into four groups: groups 1 and 2 were fed normal rat chow (5% fat) and groups 3 and 4 were fed HFD (23% fat) for a period of 14 weeks. In addition, groups 2 and 4 rats were administered orally with 100 mg/kg body weight of HAEPA from third week. After 14 weeks, rats were sacrificed, and serum/plasma levels of total cholesterol, phospholipids, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and adiponectin were determined. The mRNA expression of adiponectin, PPAR-gamma and protein expression of PPAR-gamma were also evaluated. RESULTS: The body mass index (BMI), total fat pad mass and adiposity index were significantly decreased in HAEPA co-administered rats than in HFD-fed rats. The levels of LDL and lipid peroxides were significantly higher in HFD group than in HFD+HAEPA group. Levels of reduced glutathione, adiponectin, mRNA expression of adiponectin, PPAR-gamma and protein expression of PPAR-gamma were found to be increased in HFD+HAEPA group than in HFD group. The hypolipidemic effect of HAEPA is also evidenced by the histological observations in liver, heart and adipose tissue. CONCLUSIONS: The results indicate that HAEPA exhibits hypolipidemic activity probably by increasing the mRNA expression of adiponectin and PPAR gamma, which reduce the risk of hyperlipidemia and obesity. PMID- 24770841 TI - Pressure dependent OH yields in the reactions of CH3CO and HOCH2CO with O2. AB - OH-formation in the reactions of CH3CO (R1) and HOCH2CO (R4) with O2 was studied in He, N2 and air (27 to 400 mbar) using OH-detection by laser induced fluorescence (LIF). 248 nm laser photolysis of COCl2 in the presence of CH3CHO or HOCH2CHO was used as source of the acyl radicals CH3CO and HOCH2CO. The LIF system was calibrated in back-to-back experiments by the 248 nm laser photolysis of H2O2 as OH radical precursor. A straight-forward analytical expression was used to derive OH yields (alpha) for both reactions. A Stern-Volmer-analysis results in alpha1b(-1)(N2) = 1 + (9.4 +/- 1.7) * 10(-18) cm(3) molecule(-1) * [M], alpha1b(-1)(He) = 1 + (3.6 +/- 0.6) * 10(-18) cm(3) molecule(-1) * [M] and alpha4b(-1)(N2) = 1 + (1.85 +/- 0.38) * 10(-18) cm(3) molecule(-1) * [M]. Our results for CH3CO are compared to the previous (divergent) literature values whilst that for HOCH2CO, for which no previous data were available, provide some insight into the factors controlling the yield of OH in these reactions. PMID- 24770840 TI - Mycelial antineoplastic activity of Agaricus blazei. AB - Basidiocarp of Agaricus blazei (=Agaricus brasiliensis; =Agaricus subrufescens) is used as teas or capsules due to its antineoplastic effect but there are few reports of using mycelium for this purpose. The objective of this study was to evaluate the antineoplastic activity on sarcoma 180 cells implanted in mice of two forms of preparation of the mycelium from two A. blazei strains grown in culture medium with different concentrations of isolated soy protein. Mycelia were grown in Pontecorvo medium with different concentrations of isolated soybean protein (ISP). Mycelial hot water extract, moistened mycelial powder, hot water extract of green tea, Ifosfamida((r)) (ifosfamide drug), and saline solution were administered daily by gavage in mice with sarcoma 180 cells to evaluate antineoplastic activity. It was concluded that antineoplastic activity was the same for both strains, except when used as moistened mycelial powder, which rules out the use of mycelial powder in capsules. Mycelial hot water extract had high antineoplastic activity with lower metabolic demand on the spleen and maintenance of normal blood parameters. Mycelial growth in different ISP concentrations had the same antineoplastic activity. Also the vegetative mycelium was as effective as the basidiocarp for sarcoma 180 tumor inhibition. Green tea was as effective as mycelial hot water extract. PMID- 24770842 TI - Acquisition of aberrant DNA methylation is associated with frailty in the very old: findings from the Newcastle 85+ Study. AB - Frailty is a major health problem in older people and, as the population ages, identification of its underlying biological mechanisms will be increasingly important. DNA methylation patterns within genomic DNA change during ageing and alterations in DNA methylation, particularly at gene promoter regions, can lead to altered gene expression. However the importance of altered DNA methylation in frailty is largely unknown. Using cross-sectional data from the Newcastle 85+ Study (all participants aged 85 years) frailty was operationalized by the Fried model. DNA methylation levels were assessed by highly quantitative pyrosequencing at the gene promoter associated CpG islands from a panel of five age-related methylation marker loci and at LINE-1 repetitive elements (as a surrogate for genome-wide methylation). While genome-wide methylation (as assessed at LINE-1 elements) showed no association with frailty status, there was a clear association between CpG island methylation and frailty. When compared to participants with CpG island methylation levels in the combined middle two (referent) quartiles, those in the lowest quartile had significantly decreased odds of frailty [odds ratio 0.47 (95 % CI 0.26-0.85); n = 321, p = 0.013]. Overall this study suggests a potential role for age-related changes in CpG island methylation in the development of frailty. PMID- 24770844 TI - Hypoxic pulmonary vasoconstriction as a contributor to response in acute pulmonary embolism. AB - Hypoxic pulmonary vasoconstriction (HPV) is an adaptive response unique to the lung whereby blood flow is diverted away from areas of low alveolar oxygen to improve ventilation-perfusion matching and resultant gas exchange. Some previous experimental studies have suggested that the HPV response to hypoxia is blunted in acute pulmonary embolism (APE), while others have concluded that HPV contributes to elevated pulmonary blood pressures in APE. To understand these contradictory observations, we have used a structure-based computational model of integrated lung function in 10 subjects to study the impact of HPV on pulmonary hemodynamics and gas exchange in the presence of regional arterial occlusion. The integrated model includes an experimentally-derived model for HPV. Its function is validated against measurements of pulmonary vascular resistance in normal subjects at four levels of inspired oxygen. Our results show that the apparently disparate observations of previous studies can be explained within a single model: the model predicts that HPV increases mean pulmonary artery pressure in APE (by 8.2 +/- 7.0% in these subjects), and concurrently shows a reduction in response to hypoxia in the subjects who have high levels of occlusion and therefore maximal HPV in normoxia. PMID- 24770845 TI - Complete genome sequence of Tunisvirus, a new member of the proposed family Marseilleviridae. AB - Marseillevirus is the founding member of the proposed family Marseilleviridae, which is the second discovered family of giant viruses that infect amoebae. These viruses have been recovered from environmental water samples and, more recently, from humans. Tunisvirus was isolated from fountain water in Tunis, Tunisia, by culturing on Acanthamoeba spp. and is a new marseillevirus. We describe here its 380,011 base-pair genome. A total of 484 proteins were identified, among which 320 and 358 have an ortholog in Marseillevirus and Lausannevirus (e-value<1e-2), respectively, and 259 and 299 have best reciprocal hits with a Marseillevirus and a Lausannevirus protein, respectively. In addition, a significant hit was found in organisms other than marseilleviruses for 144 Tunisvirus proteins, indicating extensive lateral gene transfers, as has been demonstrated previously for Marseillevirus. Finally, a total of 21 ORFans were identified. Phylogeny reconstructions and analysis of the gene repertoires of marseilleviruses, including the proportion of orthologs and the mean amino acid identity between genes in pairs, suggest that the proposed family Marseilleviridae encompasses three lineages. Lineage A is composed of Marseillevirus, Cannes 8 virus and Senegalvirus; lineage B is represented by Lausannevirus alone; and lineage C has Tunisvirus as its first member. Taken together, these findings suggest that the marseilleviruses display a substantial level of diversity. PMID- 24770843 TI - Decreased proliferative capacity of aged dermal fibroblasts in a three dimensional matrix is associated with reduced IGF1R expression and activation. AB - Skin aging results in increased susceptibility to injury and impaired wound healing. Proliferation of fibroblasts is reduced in aged dermis, which contributes to delays in wound closure. Age-associated differences are regulated, in part, by local or systemic factors such as the IGF-1/IGF1R system. The aim of this study was to determine if expression and activation of IGF1R in aged human dermal fibroblasts, when compared to young fibroblasts, is associated with altered proliferative capacity in a 3D collagen matrix that better simulates the dermal extracellular matrix in vivo. The proliferation of young and aged human dermal fibroblasts in 3D collagen and its association with baseline levels of IGF1R expression were measured. The effect of stimulation and inhibition of Erk phosphorylation on the proliferative capacity of fibroblasts in a 3D collagen matrix was defined. Our results show that proliferation and Erk phosphorylation is reduced in aged dermal fibroblasts relative to young fibroblasts. Activation of Erk phosphorylation in aged fibroblasts is associated with a significant increase in fibroblast proliferation in 3D collagen. PMID- 24770846 TI - Analysis of the nucleocapsid gene brings new insights to the classification of Sigmodontinae-borne hantaviruses. AB - Hantaviruses, members of the family Bunyaviridae, are the causative agents of hantavirus cardiopulmonary syndrome in South America. Hantaviruses are currently classified into species based on the guidelines provided by the International Committee on Taxonomy of Viruses. However, a new taxonomic system was proposed recently to classify Sigmodontinae-borne hantaviruses, which are divided currently into three phylogenetic clades corresponding to Andes, Laguna Negra, and Rio Mamore. Analyzing complete nucleocapsid gene sequences of all Sigmodontinae-borne hantaviruses, we propose the addition of a new clade and a fourth group to the already established Andes clade, allowing a better classification of the Sigmodontinae-borne hantaviruses. PMID- 24770847 TI - One-pot synthesis of 2-substituted benzo[b]furans via Pd-tetraphosphine catalyzed coupling of 2-halophenols with alkynes. AB - A catalyst composed of [Pd(eta(3)-C3H5)Cl]2 and N,N,N',N' tetra(diphenylphosphinomethyl)pyridine-2,6-diamine (L) was found to be effective for one-pot synthesis of 2-substituted benzo[b]furans from 2-halophenols and alkynes. For 2-bromo-3-hydroxypyridine, the catalyst loading could be as low as 1 ppm and the turnover number (TON) was up to 870,000. PMID- 24770848 TI - Risk factor awareness in a coronary population and the association with health related quality of life outcomes. AB - OBJECTIVES: The purpose of this study was to investigate the risk factor level awareness in coronary patients and to assess its associations with health-related quality of life (HRQoL)/psychological distress. METHODS: Data on 8,743 coronary patients from 22 European countries, interviewed and examined at least 6 months after their acute event was available. RESULTS: 81.7% of patients indicated to be aware of their own blood pressure level, whereas only 46.6% of patients indicated to be aware of their cholesterol level. Furthermore, 43.7% of patients were aware of their blood glucose level, whereas in diabetes patients blood glucose level awareness reached 81.8%. Risk factor level awareness was significantly associated with HRQoL/psychological distress, with patients being unaware of their risk factor levels having worse outcomes. The relationship between awareness and HRQoL/psychological distress seemed to be partly mediated by the attempt of patients to adopt a healthier behaviour. CONCLUSIONS: Health care workers should be encouraged to inform their patients about the importance of their coronary risk factors, the actual level and their personal target. PMID- 24770849 TI - Explanatory models concerning the effects of small-area characteristics on individual health. AB - OBJECTIVES: Material and social living conditions at the small-area level are assumed to have an effect on individual health. We review existing explanatory models concerning the effects of small-area characteristics on health and describe the gaps future research should try to fill. METHODS: Systematic literature search for, and analysis of, studies that propose an explanatory model of the relationship between small-area characteristics and health. RESULTS: Fourteen studies met our inclusion criteria. Using various theoretical approaches, almost all of the models are based on a three-tier structure linking social inequalities (posited at the macro-level), small-area characteristics (posited at the meso-level) and individual health (micro-level). No study explicitly defines the geographical borders of the small-area context. The health impact of the small-area characteristics is explained by specific pathways involving mediating factors (psychological, behavioural, biological). These pathways tend to be seen as uni-directional; often, causality is implied. They may be modified by individual factors. CONCLUSIONS: A number of issues need more attention in research on explanatory models concerning small-area effects on health. Among them are the (geographical) definition of the small-area context; the systematic description of pathways comprising small-area contextual as well as compositional factors; questions of direction of association and causality; and the integration of a time dimension. PMID- 24770852 TI - Bounded influence function based inference in joint modelling of ordinal partial linear model and accelerated failure time model. AB - A common objective in longitudinal studies is to characterize the relationship between a longitudinal response process and a time-to-event data. Ordinal nature of the response and possible missing information on covariates add complications to the joint model. In such circumstances, some influential observations often present in the data may upset the analysis. In this paper, a joint model based on ordinal partial mixed model and an accelerated failure time model is used, to account for the repeated ordered response and time-to-event data, respectively. Here, we propose an influence function-based robust estimation method. Monte Carlo expectation maximization method-based algorithm is used for parameter estimation. A detailed simulation study has been done to evaluate the performance of the proposed method. As an application, a data on muscular dystrophy among children is used. Robust estimates are then compared with classical maximum likelihood estimates. PMID- 24770851 TI - Pharmacogenomics: novel loci identification via integrating gene differential analysis and eQTL analysis. AB - Nearly one-half of asthmatic patients do not respond to the most commonly prescribed controller therapy, inhaled corticosteroids (ICS). We conducted an expression quantitative trait loci (eQTL) analysis using >300 expression microarrays (from 117 lymphoblastoid cell lines) in corticosteroid (dexamethasone) treated and untreated cells derived from asthmatic subjects in the Childhood Asthma Management Program (CAMP) clinical trial. We then tested the associations of eQTL with longitudinal change in airway responsiveness to methacholine (LnPC20) on ICS. We identified 2484 cis-eQTL affecting 767 genes following dexamethasone treatment. A significant over-representation of lnPC20 associated cis-eQTL [190 single-nucleotide polymorphisms (SNPs)] among differentially expressed genes (odds ratio = 1.76, 95% confidence interval: 1.35 2.29) was noted in CAMP Caucasians. Forty-six of these 190 clinical associations were replicated in CAMP African Americans, including seven SNPs near six genes meeting criteria for genome-wide significance (P < 2 * 10(-7)). Notably, the majority of genome-wide findings would not have been uncovered via analysis of untreated samples. These results indicate that identifying eQTL after relevant environmental perturbation enables identification of true pharmacogenetic variants. PMID- 24770853 TI - Modelling life course blood pressure trajectories using Bayesian adaptive splines. AB - No single study has collected data over individuals' entire lifespans. To understand changes over the entire life course, it is necessary to combine data from various studies that cover the whole life course. Such combination may be methodologically challenging due to potential differences in study protocols, information available and instruments used to measure the outcome of interest. Motivated by our interest in modelling blood pressure changes over the life course, we propose the use of Bayesian adaptive splines within a hierarchical setting to combine data from several UK-based longitudinal studies where blood pressure measures were taken in different stages of life. Our method allowed us to obtain a realistic estimate of the mean life course trajectory, quantify the variability both within and between studies, and examine overall and study specific effects of relevant risk factors on life course blood pressure changes. PMID- 24770854 TI - Fabrication of large-scale single-crystal bismuth telluride (Bi2Te3) nanosheet arrays by a single-step electrolysis process. AB - Nanolizing of thermoelectric materials is one approach to reduce the thermal conductivity and hence enhance the figure of merit. Bismuth telluride (Bi2Te3) based materials have excellent figure of merit at room temperature. For device applications, precise control and rapid fabrication for the nanostructure of thermoelectric materials are essential issues. In the present study, we demonstrate a one-step electrolysis process to directly form Bi2Te3 nanosheet arrays (NSAs) on the surface of bulk Bi2Te3 with controllable spacing distance and depth by tuning the applied bias and duration. The single sheet of NSAs reveals that the average thickness and electrical resistivity of single crystalline Bi2Te3 in composition are 399.8 nm and 137.34 MUOmega m, respectively. The formation mechanism of NSAs has been proposed. A 1.12% efficiency of quantum dot-sensitized solar cells with Bi2Te3 NSAs for counter electrode has been demonstrated, indicating that Bi2Te3 NSAs from top-down processing with a high ratio of surface area to volume are a promising candidate for possible applications such as thermoelectrics, dye-sensitized solar cells (DSSCs), and lithium-ion batteries. PMID- 24770855 TI - Was Religiousness/Spirituality Divided into Typologies or Strata? : Comment on Article of Park NS et al.: Typologies of Religiousness/Spirituality: Implications for Health and Well-Being, JRH 52: 828-839. PMID- 24770850 TI - Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. AB - Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 * 10( 9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 * 10(-5)) and short adult stature (p = 7.5 * 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies. PMID- 24770856 TI - Reduction in parvalbumin-positive interneurons and inhibitory input in the cortex of mice with experimental autoimmune encephalomyelitis. AB - In multiple sclerosis (MS), inflammation leads to damage of central nervous system myelin and axons. Previous studies have postulated impaired GABA transmission in MS, and recent postmortem analysis has shown that GABAergic parvalbumin (PV)-positive interneurons are decreased in the primary motor cortex (M1) of patients with MS. In this report, we present evidence for the loss of a specific population of GABAergic interneurons in the experimental autoimmune encephalomyelitis mouse model of MS. Using experimental autoimmune encephalomyelitis, we evaluated the distribution of both PV-positive interneurons and of the inhibitory presynaptic input in the M1 of experimental autoimmune encephalomyelitis and control mice. Our results demonstrate a specific decrease in the number of PV-positive interneurons in the M1 of mice with experimental autoimmune encephalomyelitis. We detected a significant reduction in the number of PV-positive interneurons in the layers II and III of the M1 of diseased mice, while there was no difference in the number of calretinin (CR)-positive cells between animals with experimental autoimmune encephalomyelitis and control animals. Moreover, we observed a significant reduction in the inhibitory presynaptic input in the M1 of treated mice. These changes were specific for the mice with elevated clinical score, while they were not detectable in the mice with low clinical score. Our results support the hypothesis that reinforcing the action of the GABAergic network may represent a therapeutic alternative to limit the progression of the neuronal damage in MS patients. PMID- 24770857 TI - Segment interdependency and gaze anchoring during manual two-segment sequences. AB - This study examined two-segment pointing movements with various accuracy constraints to test whether there is segment interdependency in saccadic eye movements that accompany manual actions. The other purpose was to examine how planning of movement accuracy and amplitude for the second pointing influences the timing of gaze shift to the second target at the transition between two segments. Participants performed a rapid two-segment pointing task, in which the first segment had two target sizes, and the second segment had two target sizes and two movement distances. The results showed that duration and peak velocity of the initial pointing were influenced by altered kinematic characteristics of the second pointing due to task manipulations of the second segment, revealing segment interdependency in hand movements. In contrast, saccade duration and velocity did not show such segment interdependency. Thus, unlike hand movements, saccades are planned and organized independently for each segment during sequential manual actions. In terms of the timing of gaze shift to the second target, this was delayed when the initial pointing was made to the smaller first target, indicating that gaze anchoring to the initial target is used to verify the pointing termination. Importantly, the gaze shift was delayed when the second pointing was made to the smaller or farther second target. This suggests that visual information of the hand position at the initial target is important for the planning of movement distance and accuracy of the next pointing. Furthermore, timings of gaze shift and pointing initiation to the second target were highly correlated. Thus, at the transition between two segments, gazes and hand movements are highly coupled in time, which allows the sensorimotor system to process visual and proprioceptive information for the verification of pointing termination and planning of the next pointing. PMID- 24770858 TI - Effects of cause of pain on the processing of pain in others: an ERP study. AB - Determining how the perceived cause of pain influences the perception of pain in others has implications for prosocial behavior and moral reasoning. In this research, behavior and event-related potential (ERP) responses were recorded as 28 participants (12 men, 16 women) viewed images of painful situations said to be self-inflicted by the protagonist or caused by another person on the protagonist. As predicted, participants provided significantly higher pain intensity ratings for depictions featuring pain caused by another person than depictions of self inflicted pain. ERP analyses showed no significant differences between protagonist alone and protagonist with other images of pain in the early negative component (N1). However, contrary to initial hypotheses, more positive P3 amplitudes were induced by images of self-inflicted pain in protagonists than images of protagonist pain caused by another person. Salience was considered as a key influence that may help to account for this pattern of findings. PMID- 24770859 TI - Visual influences on postural and manual interpersonal coordination during a joint precision task. AB - We investigated whether the interpersonal postural coordination that occurs during a joint supra-postural, manual precision task is driven by the constraints of the task, or, instead results from visual entrainment to the movements of a co actor. Participants were instructed to coordinate their finger movements under conditions where participants could see others' whole-body movements or could only see the results of the other's actions. Participants' finger and torso movements were recorded. Coordination was quantified using cross-recurrence quantification analysis measures. Interpersonal coordination was enhanced by, although it did not depend entirely upon, visual information about the co-actor's body movements. PMID- 24770860 TI - Alcohol exposure inhibits adult neural stem cell proliferation. AB - Alcohol exposure can reduce adult proliferation and/or neurogenesis, but its impact on the ultimate neurogenic precursors, neural stem cells (NSCs), has been poorly addressed. Accordingly, the impact of voluntary consumption of alcohol on NSCs in the subventricular zone (SVZ) of the lateral ventricle was examined in this study. The NSC population in adult male C57BL/6J mice was measured after voluntary alcohol exposure in a two-bottle choice task using the neurosphere assay, while the number of NSCs that had proliferated 2 weeks prior to tissue collection was indexed using bromodeoxyuridine (BrdU) retention. There was a significant decrease in the number of BrdU-retaining cells in alcohol-consuming mice compared with controls, but no difference in the number of neurosphere forming cells that could be derived from the SVZ of alcohol-consuming mice compared with controls. Additionally, PCNA-labeled cells in the SVZ tended to be lower, but there was no difference in BrdU labeling in the dentate gyrus following alcohol exposure. To determine alcohol's direct impact on NSCs and their progeny, neurospheres derived from naive mice were treated with alcohol in vitro. Neurosphere formation was reduced by 100 mM alcohol without reducing cell viability. These findings are the first to assess the impact of moderate voluntary alcohol consumption on selective measures of adult NSCs and indicate that such exposure alters NSC proliferation dynamics in vivo and alcohol has direct but dissociable effects on the expansion and viability on NSCs and their progeny in vitro. PMID- 24770861 TI - Auditory deprivation affects biases of visuospatial attention as measured by line bisection. AB - In this study, we investigated whether early deafness affects the typical pattern of hemispheric lateralization [i.e., right hemisphere (RH) dominance] in the control of spatial attention. To this aim, deaf signers, deaf non-signers, hearing signers, and hearing non-signers were required to bisect a series of centrally presented visual lines. The directional bisection bias was found to be significantly different between hearing and deaf participants, irrespective of sign language use. Hearing participants (both signers and non-signers) showed a consistent leftward bias, reflecting RH dominance. Conversely, we observed no evidence of a clear directional bias in deaf signers or non-signers (deaf participants overall showing a non-significant tendency to deviate rightward), suggesting that deafness may be associated to a more bilateral hemispheric engagement in visuospatial tasks. PMID- 24770862 TI - Bilateral motor tasks involve more brain regions and higher neural activation than unilateral tasks: an fMRI study. AB - Movements that involve simultaneous coordination of muscles of the right and left lower limbs form a large part of our daily activities (e.g., standing, rising from a chair). This study used functional magnetic resonance imaging to determine which brain areas are used to control coordinated lower-limb movements, specifically comparing regions that are activated during bilateral exertions to those performed unilaterally. Plantarflexor exertions were produced at a target force level of 15% of the participants' maximum voluntary contraction, in three conditions, with their right (dominant) foot, with their left foot, and with both feet simultaneously. A voxel-wise analysis determined which regions were active in the bilateral, but not in the unilateral conditions. In addition, a region of interest (ROI) approach was used to determine differences in the percent signal change (PSC) between the conditions within motor areas. The voxel-wise analysis showed a large number of regions (cortical, subcortical, and cerebellar) that were active during the bilateral condition, but not during either unilateral condition. The ROI analysis showed several motor regions with higher activation in the bilateral condition than unilateral conditions; further, the magnitude of bilateral PSC was more than the sum of the two unilateral conditions in several of these regions. We postulate that the greater levels of activation during bilateral exertions may arise from interhemispheric inhibition, as well as from the greater need for motor coordination (e.g., synchronizing the two limbs to activate together) and visual processing (e.g., monitoring of two visual stimuli). PMID- 24770863 TI - Depressing effect of electroacupuncture on the spinal non-painful sensory input of the rat. AB - The aim of this study was to explore the effect of electroacupuncture (EA) applied in the Zusanli (ST36) and Sanyinjiao (SP6) points on the N1 component of the cord dorsum potential (CDP) evoked by electrical stimulation of the sural nerve (SU) in the rat. The experiments were performed in 44 Wistar rats (250-300 g) anesthetized with ketamine (100 mg/kg) and xylazine (2 mg/kg). A bilateral laminectomy was performed to expose the L3 to S2 segments of the spinal cord. The SU nerve was exposed and placed on pairs of hook electrodes for electrical stimulation. The N1-CDPs were recorded with three silver-ball electrodes located on the dorsal surface of the L5 to S1 segments. Ipsilateral high and low EA stimulation (100, 2 Hz, 6 mA, 30 min) induced a considerable reduction in the amplitude (45 +/- 5.6, 41 +/- 6.2%) of the N1-CDP recorded at the L6 segmental level. Recovery of the N1-CDP amplitude occurred approximately 1-3 s after EA. Sectioning of the saphenous and superficial peroneal nerves reduced the depressing effect provoked by the EA stimulation (18.7 +/- 1.3, 27 +/- 3.8%). Similarly, sectioning of the posterior and anterior tibial, deep peroneal and gastrocnemius nerves partially reduced the effect provoked by EA (11 +/- 1.5, 9.8 +/- 1.1, 12.6 +/- 1.9%). Intravenous picrotoxin (1 mg/kg) also reduced the action of low and high EA (23 +/- 4.8, 27 +/- 5.2%). It is suggested that EA stimulation depresses non-painful sensory pathways through the activation of specific inhibitory pathways that receive modulatory actions from other sensory and muscle afferent inputs in the rat spinal cord. PMID- 24770864 TI - YB-1 expression promotes epithelial-to-mesenchymal transition in prostate cancer that is inhibited by a small molecule fisetin. AB - Epithelial-to-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis. The transcription/translation regulatory Y-box binding protein-1 (YB-1) is known to be associated with cancer metastasis. We observed that YB-1 expression increased with tumor grade and showed an inverse relationship with E-cadherin in a human PCa tissue array. Forced YB-1 expression induced a mesenchymal morphology that was associated with down regulation of epithelial markers. Silencing of YB-1 reversed mesenchymal features and decreased cell proliferation, migration and invasion in PCa cells. YB-1 is activated directly via Akt mediated phosphorylation at Ser102 within the cold shock domain (CSD). We next identified fisetin as an inhibitor of YB-1 activation. Computational docking and molecular dynamics suggested that fisetin binds on the residues from beta1 - beta4 strands of CSD, hindering Akt's interaction with YB 1. Calculated free binding energy ranged from -11.9845 to -9.6273 kcal/mol. Plasmon Surface Resonance studies showed that fisetin binds to YB-1 with an affinity of approximately 35 uM, with both slow association and dissociation. Fisetin also inhibited EGF induced YB-1 phosphorylation and markers of EMT both in vitro and in vivo. Collectively our data suggest that YB-1 induces EMT in PCa and identify fisetin as an inhibitor of its activation. PMID- 24770865 TI - Evaluating the utilization of educational materials in communicating about Lynch syndrome to at-risk relatives. AB - Facilitating family communication about Lynch syndrome is a public health priority since following appropriate screening guidelines can decrease morbidity and mortality. The aims of this study were to (1) ascertain what educational materials individuals with Lynch syndrome provide to at-risk relatives, and (2) identify relationships between receiving educational materials and pursuing clinical follow-up. Seventy-four participants, recruited from the Stanford Cancer Institute and a support group, completed an online questionnaire; 50 were first to be diagnosed with a Lynch syndrome mutation in their family (probands) and 24 were first or second-degree relatives. Probands reported informing 88 % (184/209) of first-degree relatives and 64 % (161/252) of second-degree relatives of the mutation. Probands shared their genetic counseling note with 53 % of relatives; other resources, including family letters, personal notes, testing laboratory information, online resources, support group information, and genetics referrals, were given to 33 % or fewer relatives. Probands reported that female relatives (p = 0.028) and first-degree relatives (p <= 0.001) were more likely to be given materials. Relatives who received an educational material were more likely to follow up with a clinician (74 vs 22 %, p <=0.001) and attend a genetic counseling appointment (43 vs 16 %, p <= 0.001). First-degree relatives who received an educational material were more likely to have undergone genetic testing (51 vs 19 %, p = 0.012) and cancer screening (69 vs 29 %, p = 0.001). Facilitating information transmission in families with Lynch syndrome using educational materials may play a role in informed clinical decision-making and cascade screening of at-risk relatives. PMID- 24770866 TI - BRCA1 founder mutations compared to ovarian cancer in Belarus. AB - In Belarus and other Slavic countries, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases, but the data on contribution of these mutations to ovarian cancers are limited. To estimate the proportion of ovarian cancers in Belarus, which are dependent on BRCA1 Slavic founder mutations, we sought the presence of three most frequent mutations (BRCA1: 5382insC, C61G and, 4153delA) in 158 consecutive unselected cases of ovarian cancer. One of the three founder mutations was present in 25 of 158 unselected cases of ovarian cancer (15.8 %). We recommend that all cases of ovarian cancer in Belarus be offered genetic testing for these founder mutations. Furthermore, genetic testing of the Belarusian population will provide the opportunity to prevent a significant proportion of ovarian cancer. PMID- 24770867 TI - Relation of dietary glycemic load with ischemic and hemorrhagic stroke: a cohort study in Greece and a meta-analysis. AB - PURPOSE: High glycemic load (GL) has been associated with excess stroke risk. Data suggest a different role of diet in the etiology of ischemic and hemorrhagic stroke. METHODS: We analyzed data from 19,824 participants of the Greek cohort of the population-based European Prospective Investigation into Cancer and nutrition (EPIC), who were free of cardiovascular diseases, cancer, and diabetes at baseline and had not developed diabetes. Diet was assessed at enrollment through a validated, interviewer-administered semi-quantitative food frequency questionnaire. The average daily GL was derived using standard tables. We also conducted a meta-analysis on GL and stroke (overall, ischemic and hemorrhagic), using random-effects models. RESULTS: In the Greek EPIC cohort, 304 incident stroke cases were identified (67 ischemic, 49 hemorrhagic). Using Cox proportional hazards regression models adjusted for potential confounders, the hazard ratios for the highest versus the lowest GL tertiles were 1.07 [95 % confidence interval (CI) 0.74-1.54] for overall stroke, 1.55 (95 % CI 0.72-3.36) for ischemic and 0.48 (95 % CI 0.18-1.25) for hemorrhagic stroke (p-heterogeneity <0.01). The meta-analysis, including a total of 3,088 incident cases and 247 deaths from stroke (1,469 cases and 126 deaths ischemic; 576 cases and 94 deaths hemorrhagic), estimated pooled relative risks for the highest versus the lowest GL levels of 1.23 (95 % CI 1.07-1.41) for overall, 1.35 (95 % CI 1.06-1.72) for ischemic, and 1.09 (95 % CI 0.81-1.47) for hemorrhagic stroke (p-heterogeneity = 0.275). CONCLUSIONS: This study indicates that GL is an important determinant of the more common ischemic-though not of the hemorrhagic-stroke. PMID- 24770868 TI - BTEB2 prevents neuronal apoptosis via promoting bad phosphorylation in rat intracerebral hemorrhage model. AB - Kruppel-like zinc-finger transcription factor 5 (KLF5), known as BTEB2 or IKLF, has several biological functions that involve cell proliferation, development and apoptosis. Previous studies demonstrated that BTEB2 had anti-apoptotic effect in multiple diseases such as esophageal cancer and non-small cell lung cancers (NSCLCs). However, the distribution and function of BTEB2 in CNS diseases remain unknown. In this study, we show that BTEB2 down-regulates neuronal apoptosis during pathophysiological processes of intracerebral hemorrhage (ICH). A rat ICH model was established by behavioral tests. Western blot and immunohistochemistry revealed a remarkable up-regulation of BTEB2 expression surrounding the hematoma after ICH. Double-labeled immunofluorescence showed BTEB2 was mostly co-localized with neurons, rarely with activated astrocytes and microglia. Furthermore, we detected that neuronal apoptosis marker active caspase-3 had co-localizations with BTEB2. In addition, KLF5 knockdown in vitro specifically resulted in increasing neuronal apoptosis coupled with reduced Bad phosphorylation at both ser112 and ser136 residues. All our findings suggested that BTEB2 down-regulated neuronal apoptosis via promoting Bad phosphorylation after ICH. PMID- 24770869 TI - Activating BRAF and PIK3CA mutations cooperate to promote anaplastic thyroid carcinogenesis. AB - Thyroid malignancies are the most common type of endocrine tumors. Of the various histologic subtypes, anaplastic thyroid carcinoma (ATC) represents a subset of all cases but is responsible for a significant proportion of thyroid cancer related mortality. Indeed, ATC is regarded as one of the more aggressive and hard to treat forms of cancer. To date, there is a paucity of relevant model systems to critically evaluate how the signature genetic abnormalities detected in human ATC contribute to disease pathogenesis. Mutational activation of the BRAF protooncogene is detected in approximately 40% of papillary thyroid carcinoma (PTC) and in 25% of ATC. Moreover, in ATC, mutated BRAF is frequently found in combination with gain-of-function mutations in the p110 catalytic subunit of PI3' Kinase (PIK3CA) or loss-of-function alterations in either the p53 (TP53) or PTEN tumor suppressors. Using mice with conditional, thyrocyte-specific expression of BRAF(V600E), we previously developed a model of PTC. However, as in humans, BRAF(V600E)-induced mouse PTC is indolent and does not lead to rapid development of end-stage disease. Here, we use mice carrying a conditional allele of PIK3CA to demonstrate that, although mutationally activated PIK3CA(H1047R) is unable to drive transformation on its own, when combined with BRAF(V600E) in thyrocytes, this leads to development of lethal ATC in mice. Combined, these data demonstrate that the BRAF(V600E) cooperates with either PIK3CA(H1074R) or with silencing of the tumor-suppressor PTEN, to promote development of anaplastic thyroid carcinoma. IMPLICATIONS: This genetically relevant mouse model of ATC will be an invaluable platform for preclinical testing of pathway-targeted therapies for the prevention and treatment of thyroid carcinoma. PMID- 24770871 TI - Expression of a wolf spider toxin in tobacco inhibits the growth of microbes and insects. AB - Lycotoxin I, from the wolf spider (Lycosa carolinensis), is an amphipathic pore forming peptide that has antimicrobial and anti-insect activity. Constitutive expression of a lycotoxin I modified for oral toxicity to insects in tobacco (Nicotiana tabacum) conferred significantly enhanced resistance to larvae of the corn earworm (Helicoverpa zea) and cigarette beetle (Lasioderma serricorne). Gene expression levels of modified lycotoxin I were negatively correlated to the survival of corn earworm larvae. In addition, pathogenic symptoms caused by Pseudomonas syringae pathovar tabaci and Alternaria alternata on the modified lycotoxin I-expressing leaves were significantly less severe than on wild type leaves. These results indicate that modified lycotoxin I expression in tobacco can potentially protect leaf tissue from a broad spectrum of pests and pathogens. PMID- 24770870 TI - Base excision repair defects invoke hypersensitivity to PARP inhibition. AB - PARP-1 is important for the recognition of both endogenous and exogenous DNA damage, and binds to DNA strand breaks including intermediates of base excision repair (BER). Once DNA-bound, PARP-1 becomes catalytically activated synthesizing PAR polymers onto itself and other repair factors (PARylation). As a result, BER repair proteins such as XRCC1 and DNA polymerase beta (pol beta) are more efficiently and rapidly recruited to sites of DNA damage. In the presence of an inhibitor of PARP activity (PARPi), PARP-1 binds to sites of DNA damage, but PARylation is prevented. BER enzyme recruitment is hindered, but binding of PARP 1 to DNA is stabilized, impeding DNA repair and leading to double-strand DNA breaks (DSB). Deficiencies in pol beta(-/-) and Xrcc1(-/-) cells resulted in hypersensitivity to the PARP inhibitor 4-AN and reexpression of pol beta or XRCC1, in these contexts, reversed the 4-AN hypersensitivity phenotype. BER deficiencies also showed evidence of replication defects that lead to DSB-induced apoptosis upon PARPi treatment. Finally, the clinically relevant PARP inhibitors olaparib and veliparib also exhibited hypersensitivity in both pol beta(-/-) and Xrcc1(-/-) BER-deficient cells. These results reveal heightened sensitivity to PARPi as a function of BER deficiency. IMPLICATIONS: BER deficiency represents a new therapeutic opportunity to enhance PARPi efficacy. PMID- 24770872 TI - Characterization of a glutamate decarboxylase (GAD) gene from Lactobacillus zymae. AB - Lactic acid bacteria (LAB) were isolated from Kimchi, a Korean traditional fermented vegetable food. LAB accumulating GABA (gamma-aminobutyric acid) in the culture media were screened by TLC analysis. One isolate, GU240, produced the highest amount of GABA among the 3,000 isolates and identified as a Lactobacillus zymae strain. Glutamate decarboxylase (GAD) gene was cloned and over-expressed in E. coli BL21(DE3) using pET26b(+). The recombinant GAD was purified by using a Ni NTA column. Its size was 53 kDa by SDS-PAGE. Maximum GAD activity was at pH 4.5 and 41 degrees C and the activity was dependent on pyridoxal 5'-phosphate. Km and Vmax of LzGAD were 1.7 mM and 0.01 mM/min, respectively, when glutamate was used as a substrate. PMID- 24770873 TI - Biodegradation of aflatoxin B1 in contaminated rice straw by Pleurotus ostreatus MTCC 142 and Pleurotus ostreatus GHBBF10 in the presence of metal salts and surfactants. AB - Aflatoxin B1 (AFB1) is a highly toxic fungal metabolite having carcinogenic, mutagenic and teratogenic effects on human and animal health. Accidental feeding of aflatoxin-contaminated rice straw may be detrimental for ruminant livestock and can lead to transmission of this toxin or its metabolites into the milk of dairy cattle. White-rot basidiomycetous fungus Pleurotus ostreatus produces ligninolytic enzymes like laccase and manganese peroxidase (MnP). These extracellular enzymes have been reported to degrade many environmentally hazardous compounds. The present study examines the ability of P. ostreatus strains to degrade AFB1 in rice straw in the presence of metal salts and surfactants. Laccase and MnP activities were determined spectrophotometrically. The efficiency of AFB1 degradation was evaluated by high performance liquid chromatography. Highest degradation was recorded for both P. ostreatus MTCC 142 (89.14 %) and P. ostreatus GHBBF10 (91.76 %) at 0.5 ug mL(-1) initial concentration of AFB1. Enhanced degradation was noted for P. ostreatus MTCC 142 in the presence of Cu(2+) and Triton X-100, at toxin concentration of 5 ug mL( 1). P. ostreatus GHBBF10 showed highest degradation in the presence of Zn(2+) and Tween 80. Liquid chromatography-mass spectrometric analysis revealed the formation of hydrated, decarbonylated and O-dealkylated products. The present findings suggested that supplementation of AFB1-contaminated rice straw by certain metal salts and surfactants can improve the enzymatic degradation of this mycotoxin by P. ostreatus strains. PMID- 24770874 TI - Application of quantile regression to recent genetic and -omic studies. AB - This paper provides a review of recent applications of quantile regression to the fields of genetic and the emerging -omic studies. It begins with a general background about this statistical approach following the seminal paper of Koenker and Bassett (Econometrica 46:33-50, 1978). Applications are described, as diverse as genetic association studies, penetrance estimation, gene expression, CGH array experiments, RNAseq experiments, methylation data and proteomics. This paper also introduces recent extensions of quantile regression with a particular focus on the Copula-quantile regression, an approach we recently proposed for sib-pair analysis. A real data example from eQTL analysis is then presented and the [Formula: see text] codes, which run the analyses are provided. Finally, we conclude with some statistical software presentation and some general statements about the potential and interests of quantile regression in modern biological experiments. PMID- 24770876 TI - Dielectric spectra of ionic liquids and their conversion to solvation dynamics: a detailed computational analysis of polarizable systems. AB - For the three molecular ionic liquids 1-ethyl-3-methylimidazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium trifluoromethanesulfonate and 1 butyl-3-methylimidazolium tetrafluoroborate, dielectric spectra were calculated from molecular dynamics simulations based on polarizable force fields. Using the reaction field continuum model the dielectric spectra were converted to the solvation dynamics of coumarin 153. It is shown in detail that the inclusion of the static conductivity in this model is essential. When simplifying the dielectric spectrum to the static conductivity hyperbola, the solvation response function becomes mono-exponential. Taking into account the frequency dependence of the conductivity, the typical two time-regimes of the solvation response function in ionic liquids are already obtained. However, the mean relaxation time remains the same. When converting the complete dielectric spectrum, i.e. also including frequency-dependent dielectric permittivity, quantitative changes are observed, but the qualitative shape is conserved. In accordance with previous experimental studies, solvation dynamics in ionic liquids predicted by the reaction field continuum model is too fast for longer times. This correlates with the suppression of the fine structure of the dielectric spectrum at low frequencies by the static conductivity hyperbola. By scaling down the static conductivity this effect can be partially amended. In addition to the impact of the solvent dielectric spectrum on solvation dynamics, solute-specific effects, i.e. anisotropy in shape and charge distribution as well as polarizability, were also studied. PMID- 24770875 TI - Determining causality and consequence of expression quantitative trait loci. AB - Expression quantitative trait loci (eQTLs) are currently the most abundant and systematically-surveyed class of functional consequence for genetic variation. Recent genetic studies of gene expression have identified thousands of eQTLs in diverse tissue types for the majority of human genes. Application of this large eQTL catalog provides an important resource for understanding the molecular basis of common genetic diseases. However, only now has both the availability of individuals with full genomes and corresponding advances in functional genomics provided the opportunity to dissect eQTLs to identify causal regulatory variants. Resolving the properties of such causal regulatory variants is improving understanding of the molecular mechanisms that influence traits and guiding the development of new genome-scale approaches to variant interpretation. In this review, we provide an overview of current computational and experimental methods for identifying causal regulatory variants and predicting their phenotypic consequences. PMID- 24770878 TI - Adaptive evolution of defense ability leads to diversification of prey species. AB - In this paper, by using the adaptive dynamics approach, we investigate how the adaptive evolution of defense ability promotes the diversity of prey species in an initial one-prey-two-predator community. We assume that the prey species can evolve to a safer strategy such that it can reduce the predation risk, but a prey with a high defense ability for one predator may have a low defense ability for the other and vice versa. First, by using the method of critical function analysis, we find that if the trade-off is convex in the vicinity of the evolutionarily singular strategy, then this singular strategy is a continuously stable strategy. However, if the trade-off is weakly concave near the singular strategy and the competition between the two predators is relatively weak, then the singular strategy may be an evolutionary branching point. Second, we find that after the branching has occurred in the prey strategy, if the trade-off curve is globally concave, then the prey species might eventually evolve into two specialists, each caught by only one predator species. However, if the trade-off curve is convex-concave-convex, the prey species might eventually branch into two partial specialists, each being caught by both of the two predators and they can stably coexist on the much longer evolutionary timescale. PMID- 24770877 TI - Comparison of the laparoscopic versus open live donor nephrectomy: an overview of surgical complications and outcome. AB - BACKGROUND: Kidney transplantation (KTx) is considered to be the treatment of choice for end stage renal disease. One of the most challenging dilemmas in KTx is the shortage of suitable organs. The live donor nephrectomy is considered a unique operation performed on healthy donors, which provides a superior outcome in the recipients. Several surgical techniques have been developed so far to minimize donor postoperative complications as much as possible without compromising the quality of the kidney. The development of a minimally invasive surgery, laparoscopic live donor nephrectomy (LDN), was based on this concept. MATERIALS AND METHODS: By searching the pubmed, we reviewed the most evidence based clinical studies specifically randomized clinical trials and meta-analyses to give an overview of the efficacy and safety of LDN versus ODN. RESULTS: The advantages of a LDN vs. a conventional open donor nephrectomy (ODN) are a smaller incision, better wound cosmetics, a lower rate of incisional hernia and adhesion, less postoperative pain, shorter hospitalization, and earlier return to work. Some concerns are longer operative and warm ischemic times, long-term learning curve for surgeons, and the risk of more serious complications than during an ODN. CONCLUSION: Overall, the review of literature shows that a LDN provides less postoperative pain, a shorter hospital stay, a shorter period of rehabilitation, and earlier return to normal work and physical activities in comparison to the conventional open flank nephrectomy but is comparable to the mini muscle splitting approach. The complication rate is generally lower in centers accustomed to performing LDNs; however, complications can be life threatening and could impose significant costs to the health system. Weighing the longer operation and warm ischemic time, as well as the risk of more serious complications against the advantages of a LDN mandates a precise indication. The risk-benefit assessment for choosing one procedure should be done meticulously. Even though the short-term graft function in both techniques is comparable, there is a lack of enough long-term outcome analyses. Finally, in any transplant center, the cost of the laparoscopic procedure should be considered. PMID- 24770879 TI - A fast-response, highly sensitive and selective fluorescent probe for the ratiometric imaging of nitroxyl in living cells. AB - A fast-response, highly sensitive and selective fluorescent probe with the 2 (diphenylphosphino)benzoate moiety as a recognition receptor for the ratiometric imaging of nitroxyl in living cells was first developed. PMID- 24770880 TI - Cytochemical and ultrastructural aspects of aquatic carnivorous plant turions. AB - Turions, which are modified shoot apices, are vegetative, dormant overwintering organs produced by perennial aquatic plants. In this study, the turion cytochemistry and ultrastructure of Aldrovanda vesiculosa, Utricularia vulgaris and U. stygia were compared with particular emphasis placed on storage substances. These three aquatic, rootless carnivorous plant species were studied at the end of their winter dormancy. At this stage, the turions of all species had starch as their main storage material. In contrast with A. vesiculosa, Utricularia turions were rich in protein storage vacuoles, and proteins were also accumulated as crystalline inclusions in the nuclei. All examined species accumulated lipid droplets in cells of epidermal glands. PMID- 24770882 TI - Characterization and expression analysis of the transferrin gene in Nile tilapia (Oreochromis niloticus) and its upregulation in response to Streptococcus agalactiae infection. AB - In this study, full-length tilapia transferrin (OnTF) isolated from liver cDNA of Nile tilapia (Oreochromis niloticus) was found to have an open reading frame of 2,091-bp encoding 696 amino acid residues. Two additional amino acids: Gly(369) and Gly(370) were observed compared with the reported Nile tilapia transferrin protein sequence. Pre-mature protein has a predicted molecular weight of 78.2 kDa, while mature protein is 73.28 kDa in size. Comparative sequence analysis with transferrin from other species revealed two major putative iron-binding domains designated as the N-lobe and the C-lobe in accordance with the transferrin protein characteristics. The predicted tertiary structure of tilapia transferrin confirmed the presence of iron and anion-binding sites on both lobes that are conserved among transferrins from other species. Quantitative real-time PCR analysis showed significantly higher expression of tilapia transferrin gene in liver than in other tissues (p < 0.05). Transferrin expression in tilapia experimentally infected with 10(6) and 10(8) colony-forming units mL(-1) of Streptococcus agalactiae was significantly upregulated at 24 and 12 h post infection (hpi), respectively, and decreased afterward. Iron-deficiency in serum of bacterially infected fish was detected at 48 and 24 hpi, respectively. The expression pattern of the transferrin gene and the iron levels of infected tilapia in this study were consistent with the function of transferrin in innate immunity. PMID- 24770883 TI - Video-assisted thoracoscopic lobectomy with the patient in the semi-prone position: initial experience and benefits of lymph node dissection. AB - OBJECTIVES: Recently, the prone position has been used for thoracoscopic oesophagectomy for oesophageal cancer because it is known to facilitate mediastinal dissection. We hypothesized that this advantage of the prone position could apply to video-assisted thoracoscopic surgery, which has been commonly performed with the patient in the lateral position. METHODS: Forty-six patients with clinical stage I, right-sided, non-small cell lung cancer were enrolled in this study. They were classified into three groups: conventional thoracotomy using rib retractors (n = 17), and the lateral (n = 15) and semi-prone (n = 14) positions in video-assisted thoracoscopic surgery. Surgical parameters, such as operation time, the amount of blood loss, and the number of dissected lymph nodes, of each group of patients were compared. RESULTS: There were three (6.5 %) minor complications in this study, chylothorax and heart failure in the thoracotomy group and atelectasis with the video-assisted thoracoscopic surgery in the lateral position group. No complications were seen in the semi-prone group. The number of dissected lymph nodes was significantly higher in the video assisted thoracoscopic surgery in the semi-prone position group than in the conventional thoracotomy group for inferior mediastinal nodes (subcarinal, paraeosophageal, and pulmonary ligament, average 8.9 and 5.9 lymph nodes, p = 0.04). CONCLUSIONS: To the best of our knowledge, this is the first report that has described video-assisted thoracoscopic lobectomy with the patient in the semi prone position. Although the number of cases was limited, the results of this study show that the semi-prone position could be attempted especially for right lower lobe lung cancer. PMID- 24770884 TI - Helical metallic micro- and nanostructures: fabrication and application. AB - Metal elements occupy more than 70% of the positions in the periodic table, and their use has accelerated human civilization due to their invaluable chemical and physical characteristics. With the rapid development of metals, various structures of microscopic metal particles have been fabricated and investigated as functional materials in scientific research and practical applications. The phrase 'structure determines properties' has been widely acknowledged as a golden rule in chemistry and materials science, especially when the size of small particles is in the micro- or nanoscale dimension. Helical metallic micro- and nanostructures with complex shapes have recently emerged and may be used for various useful applications such as photonics, sensors, actuators, micro /nanorobotics, and micro-/nanoelectronics, based on their unique mechanical, electrical, and electromagnetic properties. This review paper specifically focuses on the fabrication and application of helical metallic structures with a size ranging from the micro- to nanoscale. The unusual spatial distribution of active atoms in helical metallic micro- and nanostructures and their helical morphology could offer new opportunities for applications beyond those of other conventional metallic and nonmetallic micro- and nanostructures. PMID- 24770881 TI - ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. AB - Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 * 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor. PMID- 24770885 TI - Wild robins (Petroica longipes) respond to human gaze. AB - Gaze following and awareness of attentional cues are hallmarks of human and non human social intelligence. Here, we show that the North Island robin (Petroica longipes), a food-hoarding songbird endemic to New Zealand, responds to human eyes. Robins were presented with six different conditions, in which two human experimenters altered the orientation or visibility of their body, head or eyes in relation to mealworm prey. One experimenter had visual access to the prey, and the second experimenter did not. Robins were then given the opportunity to 'steal' one of two mealworms presented by each experimenter. Robins responded by preferentially choosing the mealworm in front of the experimenter who could not see, in all conditions but one. Robins failed to discriminate between experimenters who were facing the mealworm and those who had their head turned 90 degrees to the side. This may suggest that robins do not make decisions using the same eye visibility cues that primates and corvids evince, whether for ecological, experiential or evolutionary reasons. PMID- 24770887 TI - [The art of treating multiorgan failure]. PMID- 24770886 TI - Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells. AB - The capacity of breast cancer cells to form mammospheres in non-adherent serum free culture is used as a functional characteristic of the self-renewing stem like cell population. The present studies demonstrate that silencing expression of the MUC1-C oncoprotein inhibits growth of luminal MCF-7 and HER2 overexpressing SKBR3 breast cancer cells as mammospheres. We also show that triple-negative MDA-MB-468 breast cancer cells are dependent on MUC1-C for growth as mammospheres and tumor xenografts. Similar results were obtained when MUC1-C function was inhibited by expression of a MUC1-C(CQC?AQA) mutant. Moreover, treatment with the MUC1-C inhibitor GO-203, a cell penetrating peptide that binds to the MUC1-C cytoplasmic domain and blocks MUC1-C function, confirmed the importance of this target for self-renewal. The mechanistic basis for these findings is supported by the demonstration that MUC1-C activates NF-kappaB, occupies the IL-8 promoter with NF-kappaB, and induces IL-8 transcription. MUC1-C also induces NF-kappaB-dependent expression of the IL-8 receptor, CXCR1. In concert with these results, targeting MUC1-C with GO-203 suppresses IL-8/CXCR1 expression and disrupts the formation of established mammospheres. Our findings indicate that MUC1-C contributes to the self-renewal of breast cancer cells by activating the NF-kappaB?IL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population. PMID- 24770888 TI - [Shock liver and cholestatic liver in critically ill patients]. AB - Liver dysfunction is frequently observed in critically ill patients. Its occurrence is associated with high morbidity and mortality. The most frequent entities of hepatic dysfunction in the intensive care unit are shock liver and cholestatic liver dysfunction with incidence rates up to 10 and 30 %, respectively.Both conditions are frequently triggered by hypoxic and/or ischemic events, most commonly cardiogenic shock and sepsis/septic shock. However, several other potential contributors have been identified especially for cholestatic liver dysfunction. Apart from chronic liver diseases and malignancies, iatrogenic factors such as total parenteral nutrition, high pressure ventilation, surgical procedures, drugs and blood transfusions promote its occurrence.In shock liver and in cholestatic liver disease, early detection and therapy of the underlying disease is the only established treatment. PMID- 24770889 TI - [Extracorporeal therapy of patients with liver disease in the intensive care unit]. AB - Acute and acute-on-chronic liver failure are often associated with development of organ failure. Its occurrence is associated with high morbidity and mortality. Extracorporeal replacement therapies are frequently necessary in these patient populations. Replacement therapies can be divided into renal replacement therapies and liver support therapies. These therapies consist of artificial liver support systems (i.e., MARS((r)) system, Prometheus((r))), which are able to remove water-soluble and albumin-bound toxins, and of bioartifical liver support systems. This manuscript provides a review of current practice in the extracorporeal support of patients with liver diseases in the intensive care unit. PMID- 24770890 TI - [Near fatal intoxication with the novel psychoactive substance 25C-NBOMe]. AB - BACKGROUND: Effects of overdosing 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2 methoxyphenyl)methyl]ethanamine (25C-NBOMe) have not been previously described. Currently the drug is legal in most parts of the world. CASE REPORT: The case of a 19-year-old man who had nasally administered 2 mg of 25C-NBOMe, a novel psychoactive drug, within 1 h is described. Two hours later, he experienced a generalized seizure. Due to loss of consciousness and low oxygen saturation, he required mechanical ventilation. On day 2, he could be extubated without need for supplemental oxygen and appeared to recover quickly. On day 3, he developed acute kidney failure requiring hemofiltration. His condition continued to deteriorate with development of acute lung failure on day 4. He again required non-invasive and subsequently invasive ventilation with high demands for oxygen and high supporting pressure. On days 7 and 8 his condition became life threatening due to difficulties to achieve sufficient oxygenation even with a FIO2 of 80 %. After 13 days in the intensive care unit, he finally recovered without sequelae. CONCLUSION: In summary, 2 mg of 25C-NBOMe placed a young healthy man in a critical situation both acutely a few hours after ingestion due to a generalized seizure and during the subsequent days due to multiple organ failure. PMID- 24770891 TI - Mesh fixation at laparoscopic inguinal hernia repair: a meta-analysis comparing tissue glue and tack fixation. AB - BACKGROUND: The aim of this study was to conduct a comprehensive systematic review comparing tissue glue (TG) against tacks/staples for mesh fixation in laparoscopic (totally extra-peritoneal and trans-abdominal pre-peritoneal) groin hernia repair with the incidence of post-operative chronic pain as the primary outcome measure. METHODS: A computerized search of MEDLINE, EMBASE, and Cochrane databases for the period from 1 January 1,990 to 30 June 2013 produced 39 reports. The quality of reports was assessed according to criteria reported by the Cochrane communication review group. RESULTS: Five randomized controlled trials (RCTs, 491 patients) and five non-RCTs (1,034 patients) fulfilled the selection criteria. A meta-analysis of chronic pain from the five RCTs gave a statistically significant Peto odds ratio (OR) of 0.40 (0.21-0.76; p = 0.005) indicating that the TG group experience less chronic pain. Although the studies are underpowered to detect recurrence, the meta-analysis of the recurrence rates from the RCTs identified no difference between tacks/staple and glue fixation (OR 2.36; 0.67-8.37). There were also no differences found in meta-analysis of seroma and hematoma formation between the two methods of fixation. The wide variation in time points regarding pain score meant it was not possible to combine the studies and perform analysis for pain score with earlier time points. CONCLUSIONS: Meta analysis of RCTs comparing TG with tack fixation in laparoscopic inguinal hernia surgery depicts a significant reduction in chronic pain with no increase in recurrence rates. Early post-operative outcome is similar after both methods of mesh fixation, although larger RCTs are required, with long-term pain as the primary endpoint. PMID- 24770892 TI - Measuring religiosity and its effects on personal well-being: a case study of Muslim female academicians in Malaysia. AB - This study seeks to measure religiosity in an Islamic context and to assess its effects on the personal well-being of Muslims. The determinants of religiosity included under this research are prayer, beliefs, and worship. This research also attempts to examine the coping strategies Muslims use to deal with life problems and changes such as prayer, supplication, trust and reliance on God, remembrance of death, and concept of life after death. Today, many scales of religiosity are being put into use among Muslims. This study measures religiosity and its effects on the well-being of Muslim academicians. The researchers used 315 Muslim female of academic staff as respondents, working in Research Universities in the Klang Valley such as University of Malaya, National University and Putra University area of Kuala Lumpur, Malaysia. Their ages ranged from 30 to 60 years. The results of this study show that there exists a positive yet significant correlation between personal well-being and religiosity. The well-being also shows significant positive correlations with beliefs and worship and prayer. PMID- 24770894 TI - Signaling molecules and transcription factors involved in the development of the sympathetic nervous system, with special emphasis on the superior cervical ganglion. AB - The cells that constitute the sympathetic nervous system originate from the neural crest. This review addresses the current understanding of sympathetic ganglion development viewed from molecular and morphological perspectives. Development of the sympathetic nervous system is categorized into three main steps, as follows: (1) differentiation and migration of cells in the neural crest lineage for formation of the primary sympathetic chain, (2) differentiation of sympathetic progenitors, and (3) growth and survival of sympathetic ganglia. The signaling molecules and transcription factors involved in each of these developmental stages are elaborated mostly on the basis of the results of targeted mutation of respective genes. Analyses in mutant mice revealed differences between the superior cervical ganglion (SCG) and the other posterior sympathetic ganglia. This review provides a summary of the similarities and differences in the development of the SCG and other posterior sympathetic ganglia. Relevant to the development of sympathetic ganglia is the demonstration that neuroendocrine cells, such as adrenal chromaffin cells and carotid body glomus cells, share a common origin with the sympathetic ganglia. Neural crest cells at the trunk level give rise to common sympathoadrenal progenitors of sympathetic neurons and chromaffin cells, while progenitors segregated from the SCG give rise to glomus cells. After separation from the sympathetic primordium, the progenitors of both chromaffin cells and glomus cells colonize the anlage of the adrenal gland and carotid body, respectively. This review highlights the biological properties of chromaffin cells and glomus cells, because, although both cell types are derivatives of sympathetic primordium, they are distinct in many respects. PMID- 24770893 TI - Effects of the chemokine CXCL12 and combined internalization of its receptors CXCR4 and CXCR7 in human MCF-7 breast cancer cells. AB - The chemokine CXCL12 (stromal cell-derived factor-1, SDF-1) and its receptor CXCR4 play a major role in tumor initiation, promotion, progression and metastasis, especially for breast cancer cells. Recently, CXCR7 has been identified as a second receptor for CXCL12; nevertheless, it also binds CXCL11 (interferon-inducible T cell alpha chemoattractant, I-TAC). However, little is known about the co-expression of the two receptors and their interactions. Quantitative reverse transcription plus the polymerase chain reaction has demonstrated that both receptors are frequently co-expressed in breast cancer cell lines, whereas other tumor cell lines often express only one of them. For interaction studies, we chose MCF-7 breast cancer cells, since they highly express CXCR4 and CXCR7 at the protein level but not CXCR3 (another target for CXCL11). Immunofluorescence and gold-labeling by light and electron microscopy, respectively, revealed that both receptors were localized at the cell surface in non-stimulated cells. After exposure to CXCL12 or CXCL11, the receptors were rapidly internalized alone or in close proximity. Stimulation with the CXCR4- or CXCR7-selective non-peptide antagonists AMD3100 and CCX733 resulted not only in single internalization but partly also in co-internalization of the two receptors. Furthermore, both chemokine ligands reduced staurosporine-induced apoptosis and caspase-3/7 activation; however, the selective inhibitors merely had partial inhibitory effects on these biological responses. Our findings suggest that CXCR4 and CXCR7 closely interact in breast cancer cells. Both are co internalized, transduce signals and induce further biological effects partly independently of a selective stimulus or antagonist. PMID- 24770895 TI - PRRX1 and PRRX2 distinctively participate in pituitary organogenesis and a cell supply system. AB - Paired-related homeobox transcription factors, PRRX1 and PRRX2, are known to be important factors for craniofacial and limb morphogenesis. We recently cloned Prrx2 from the porcine adult pituitary cDNA library and found that only PRRX1 is present in the rat embryonic pituitary. In this study, we re-investigated the temporospatial expression and localization of PRRX1 and PRRX2 in the rat pituitary throughout life. The persistent expression of Prrx1 was ascertained after the middle stage of embryonic development, whereas significant expression of Prrx2 was found only in the postnatal pituitary. Immunohistochemistry confirmed that PRRX1-positive cells appeared inside the pituitary on embryonic day 16.5 in the marginal cell layer (MCL), a pituitary stem/progenitor cell niche, and the expanding parenchyma of the anterior pituitary. In contrast, PRRX2 positive cells first appeared in the anterior lobe and intermediate lobe sides of the MCL around postnatal day 30 when the postnatal pituitary growth wave had almost terminated. Immunostaining for PRRX1 with a stem/progenitor cell marker SOX2, a pituitary progenitor marker PROP1, or pituitary hormones revealed that PRRX1 localized in cells in the transition process from the multipotent progenitor stage to the early stage of terminal differentiation throughout life. PRRX2 emerged in cells positive for SOX2 but negative for PROP1 in the anterior and intermediate lobe sides of the postnatal MCL. Thus, PRRX1 and PRRX2 might participate distinctly in pituitary organogenesis and the postnatal cell-supply system. PMID- 24770896 TI - The RNA editing enzymes ADARs: mechanism of action and human disease. AB - A-to-I RNA editing is a ubiquitous and crucial molecular mechanism able to convert adenosines into inosines (then read as guanosines by several intracellular proteins/enzymes) within RNA molecules, changing the genomic information. The A-to-I deaminase enzymes (ADARs), which modify the adenosine, can alter the splicing and translation machineries, the double-stranded RNA structures and the binding affinity between RNA and RNA-binding proteins. ADAR activity is an essential mechanism in mammals and altered editing has been associated with several human diseases. Many efforts are now being concentrated on modifying ADAR activity in vivo in an attempt to correct RNA editing dysfunction. Concomitantly, ongoing studies aim to show the way that the ADAR deaminase domain can be used as a possible new tool, an intracellular Trojan horse, for the correction of heritage diseases not related to RNA editing events. PMID- 24770897 TI - Expression of chemokine CXCL10 in dendritic-cell-like S100beta-positive cells in rat anterior pituitary gland. AB - Chemokines are mostly small secreted polypeptides whose signals are mediated by seven trans-membrane G-protein-coupled receptors. Their functions include the control of leukocytes and the intercellular mediation of cell migration, proliferation, and adhesion in several tissues. We have previously revealed that the CXC chemokine ligand 12 (CXCL12) and its receptor 4 (CXCR4) are expressed in the anterior pituitary gland, and that the CXCL12/CXCR4 axis evokes the migration and interconnection of S100beta-protein-positive cells (S100beta-positive cells), which do not produce classical anterior pituitary hormones. However, little is known of the cells producing the other CXCLs and CXCRs or of their characteristics in the anterior pituitary. We therefore examined whether CXCLs and CXCRs occurred in the rat anterior pituitary lobe. We used reverse transcription plus the polymerase chain reaction to analyze the expression of Cxcl and Cxcr and identified the cells that expressed Cxcl by in situ hybridization. Transcripts of Cxcl10 and its receptor (Cxcr3 and toll-like receptor 4, Tlr4) were clearly detected: cells expressing Cxcl10 and Tlr4 were identified amongst S100beta-positive cells and those expressing Cxcr3 amongst adrenocorticotropic hormone (ACTH)-producing cells. We also investigated Cxcl10 expression in subpopulations of S100beta-positive cells. We separated cultured S100beta-positive cells into the round-type (dendritic-cell-like) and process type (astrocyte- or epithelial-cell-like) by their adherent activity to laminin, a component of the extracellular matrix; CXCL10 was expressed only in round-type S100beta-positive cells. Thus, CXCL10 produced by a subpopulation of S100beta positive cells probably exerts an autocrine/paracrine effect on S100beta-positive cells and ACTH-producing cells in the anterior lobe. PMID- 24770898 TI - Carbon dioxide levels during polygraphy in children with sleep-disordered breathing. AB - PURPOSE: The recent scoring rules of the American Academy of Sleep Medicine (AASM) define hypoventilation in children as a carbon dioxide (CO2) level of >50 mmHg for >25 % of total sleep time (partial pressure of CO2 (PCO2) > 50[>25 %]). As there is no validated level of nocturnal hypoventilation with regard to end organ damage in children, we evaluated the prevalence of hypoventilation with the AASM definition but also with a lesser degree of elevated CO2 in children with sleep-disordered breathing (SDB). METHODS: Transcutaneous CO2 (PtcCO2) was recorded during overnight polygraphy (PG). Hypoventilation was defined according to four definitions: the AASM score (PCO2 > 50[>25 %]), the peak value of PtcCO2 > 50 mmHg (PtcCO2 > 50[peak]), a percentage of PtcCO2 > 50 mmHg > 2 % of nighttime recording (PtcCO2 > 50[>2 %]) or a nocturnal PtcCO2 > 10 mmHg above waking baseline level (PtcCO2[>10 mmHg]). PtcCO2 indices were correlated to the apnoea-hypopnoea index (AHI) and oxygenation indices. RESULTS: PGs from 221 children with suspicion of obstructive sleep apnoea (72 %), neuromuscular diseases (21 %), and lung diseases (7 %) were analysed. The prevalence of hypoventilation according to PCO2 > 50[>25 %], PtcCO2 > 50[peak], PtcCO2 > 50[>2 %] and PtcCO2[>10 mmHg] were 16, 27, 31 and 52 %, respectively, and did not differ between the three diagnostic groups. Significant but weak correlations were observed between hypoventilation and AHI and oxygenation indices. CONCLUSIONS: Nocturnal hypoventilation occurs in a large number of children referred for SDB, independent of the underlying disease, when more stringent criteria than those of the AASM are used. The poor correlation between hypoventilation and AHI or oxygenation indices is in favour of CO2 being a supplemental index of SDB. PMID- 24770899 TI - In vitro evaluation of a multispecies oral biofilm on different implant surfaces. AB - Biofilm accumulation on implant surfaces is one of the most important factors for early and late implant failure. Because of the related clinical implications, the aim of this in vitro study was to compare the bacterial cell attachment of a four species oral biofilm on titanium discs of purity grade 2 and 4, with machined surfaces and etched-thermochemically modified with Avantblast(r). The in vitro biofilm model was composed of early (Actinomyces naeslundii, Streptococcus gordonii), secondary (Veillonella parvula), and intermediate (Fusobacterium nucleatum ssp. polymorphum) colonizers of tooth surfaces. A total of 36 discs were divided into four groups: Tigr2-c (titanium grade 2, machined surface), Tigr2-t (titanium grade 2, modified surface with Avantblast(r)), Tigr4-c (titanium grade 4, machined surface), Tigr4-t (titanium grade 4, modified surface with Avantblast(r)). The experiment was repeated three times. Biofilm viability was tested with 1% 2, 3, 5-triphenyltetrazolium chloride solution and bacterial cell quantification by checkerboard DNA-DNA hybridization. Descriptive analysis was performed to evaluate biofilm composition and differences between groups were checked with the Mann-Whitney test (p < 0.05). After one week, multispecies biofilms showed a similar pattern of bacterial composition on all analyzed implant surfaces. The most prevalent bacterium was V. parvula (~50% of the total biomass), followed by S. gordonii (~30%), F. nucleatum ssp. polymorphum (~10%) and A. naeslundii (<5%). Total bacterial biomass was significantly higher in both grade-4-titanium surfaces (p < 0.05). The results demonstrated that not only implant surface treatment, but also titanium purity, influence early bacterial colonization. PMID- 24770900 TI - Mild thiamine deficiency and chronic ethanol consumption modulate acetylcholinesterase activity change and spatial memory performance in a water maze task. AB - Chronic thiamine deficiency may be responsible for pathologic changes in the brains of alcoholics, and subclinical episodes of this vitamin deficiency may cause cumulative brain damage. In the present work, the chronic effects of ethanol and its association to a mild thiamine deficiency episode (subclinical model) on neocortical and hippocampal acetylcholinesterase activity were assessed along with their possible association to spatial cognitive dysfunction. The results indicate that in the beginning of the neurodegenerative process, before the appearance of brain lesions, chronic ethanol consumption reverses the effects of mild thiamine deficiency on both spatial cognitive performance and acetylcholinesterase activity without having significant effects on any morphometric parameter. PMID- 24770902 TI - Biological conservation of a prey-predator system incorporating constant prey refuge through provision of alternative food to predators: a theoretical study. AB - We describe a prey-predator system incorporating constant prey refuge through provision of alternative food to predators. The proposed model deals with a problem of non-selective harvesting of a prey-predator system in which both the prey and the predator species obey logistic law of growth. The long-run sustainability of an exploited system is discussed through provision of alternative food to predators. We have analyzed the variability of the system in presence of constant prey refuge and examined the stabilizing effect on predator prey system. The steady states of the system are derived and dynamical behavior of the system is extensively analyzed around steady states. The optimal harvesting policy is formulated and solved with the help of Pontryagin's maximal principle. Our objective is to maximize the monetary social benefit through protecting the predator species from extinction, keeping the ecological balance. Results finally illustrated with the help of numerical examples. PMID- 24770901 TI - Poloxamer-188 can attenuate blood-brain barrier damage to exert neuroprotective effect in mice intracerebral hemorrhage model. AB - Blood-brain barrier (BBB) disruption and brain edema formation play important roles in the secondary neuronal death and neurological dysfunction induced by intracerebral hemorrhage (ICH). Poloxamer 188 (P188), a multiblock copolymer surfactant, has been shown to be capable of sealing damaged cell membranes and decrease neuronal cell death. In this study, we explored whether P188 had a protective effect against ICH and its underlying mechanisms. Male ICR mice were subjected to infusion of type IV collagenase (to induce ICH) of saline (for shams) into the left striatum. The results showed that P188-12 mg post-treatment by tail intravenous injection significantly ameliorated the neurological symptoms and brain edema, attenuated BBB permeability, and decreased cell insults and injury volume at 24 and 72 h after ICH. Furthermore, P188 maintained the protein levels of tight junction (TJ) proteins including claudin-5, occludin, and zonula occludens-1, and reversed the increases of nuclear factor-kappaB (NF-kappaB), matrix metalloproteinase (MMP)-2, and MMP-9 protein expression at 72 h post ICH. Immunofluorescence showed P188 treatment rearranged the structure of TJ proteins in a continuous and linear pattern. Therefore, the present study concludes that P188 can protect against ICH, and the protective effect was associated with preventing BBB disruption through NF-kappaB-MMPs-mediated TJ proteins degradation. PMID- 24770903 TI - Effects of physical activity and training programs on plasma homocysteine levels: a systematic review. AB - Homocysteine is an amino acid produced in the liver that, when present in high concentrations, is thought to contribute to plaque formation and, consequently, increased risk of cardiovascular disease. However, daily physical activity and training programs may contribute to controlling atherosclerosis. Given that physical exercise induces changes in protein and amino acid metabolism, it is important to understand whether homocysteine levels are also affected by exercise and to determine possible underlying mechanisms. Moreover, regarding the possible characteristics of different training programs (intensity, duration, repetition, volume), it becomes prudent to determine which types of exercise reduce homocysteine levels. To these ends, a systematic review was conducted to examine the effects of daily physical activity and different training programs on homocysteine levels. EndNote((r)) was used to locate articles on the PubMed database from 2002 to 2013 with the keyword combinations "physical activity and homocysteine", "training and homocysteine", and/or "exercise and homocysteine". After 34 studies were identified, correlative and comparative studies of homocysteine levels revealed lower levels in patients engaged in greater quantities of daily physical activity. Regarding the acute effects of exercise, all studies reported increased homocysteine levels. Concerning intervention studies with training programs, aerobic training programs used different methods and analyses that complicate making any conclusion, though resistance training programs induced decreased homocysteine levels. In conclusion, this review suggests that greater daily physical activity is associated with lower homocysteine levels and that exercise programs could positively affect homocysteine control. PMID- 24770904 TI - Solid-phase peptide synthesis (SPPS), C-terminal vs. side-chain anchoring: a reality or a myth. AB - Here we review the strategies for the solid-phase synthesis of peptides starting from the side chain of the C-terminal amino acid. Furthermore, we provide experimental data to support that C-terminal and side-chain syntheses give similar results in terms of purity. However, the stability of the two bonds that anchor the peptide to the polymer may determine the overall yield and this should be considered for the large-scale production of peptides. In addition, resins/linkers which do not subject to side reactions can be preferred for some peptides. PMID- 24770905 TI - Chiromers: conformation-driven mirror-image supramolecular chirality isomerism identified in a new class of helical rosette nanotubes. AB - Rosette nanotubes are biologically inspired nanostructures, formed through the hierarchical organization of a hybrid DNA base analogue (G?C), which features hydrogen-bonding arrays of guanine and cytosine. Several twin-G?C motifs functionalized with chiral moieties, which undergo a self-assembly process under methanolic and aqueous conditions to produce helical rosette nanotubes (RNTs), were synthesized and characterized. The built-in molecular chirality in the twin G?C building blocks led to the supramolecular chirality exhibited by the RNTs, as evidenced by the CD activity. Depending on the motifs and environmental conditions, mirror-image supramolecular chirality due to absolute molecular chirality, solvent-induced and structure-dependent supramolecular chirality inversion, and pH-controlled chiroptical switching were observed. PMID- 24770906 TI - Impact of ATLS training on preventable and potentially preventable deaths. AB - BACKGROUND: Multiple trauma continues to have a high incidence worldwide. Trauma is the leading cause of death among people between the ages of 10 and 40. The Advanced Trauma Life Support (ATLS) is the most widely accepted method for the initial control and treatment of multiple trauma patients. It is based on the following hypothesis: The application of the ATLS program may reduce preventable or potentially preventable deaths in trauma patients. MATERIALS AND METHODS: The present article reports a retrospective study based on the records of prospectively evaluated trauma patients between January 2007 and December 2012. Trauma patients over the age of 18 admitted to the critical care unit or patients who died before hospital admission were included. A multidisciplinary committee looked for errors in the management of each patient and classified deaths into preventable, potentially preventable, or nonpreventable. We recorded the number of specialists at our center who had received training in the ATLS program. RESULTS: A total of 898 trauma patients were registered. The mean injury severity score was 21 (SD 15), and the mortality rate was 10.7 % (96 cases). There were 14 cases (14.6 %) of preventable or potentially preventable death. The main errors were delay in initiating suitable treatment and performing a computed tomography scan in cases of hemodynamic instability, followed by initiation of incorrect treatment or omission of an essential procedure. As the number of ATLS-trained professionals increases, the rates of potentially preventable or preventable death fall. CONCLUSIONS: Well-founded protocols such as the ATLS can help provide the preparation health professionals need. In our hospital environment, ATLS training has helped to reduce preventable or potentially preventable mortality among trauma patients. PMID- 24770907 TI - Invited commentary: Promotion and prevention in youth development: two sides of the same coin? AB - This commentary uses the contributions of the 4-H Study of Positive Youth Development as a chance to reflect on the progress of the past two decades and suggest important tasks for the future. Meaningful advances in theory now set the stage for needed work on measurement, evaluation, and understanding of contextual processes. The commentary ends with a plea for an integration of the research and programmatic approaches of promotion and prevention in order to study youth development and implement youth programs. PMID- 24770908 TI - Oriented Gaussian mixture models for nonrigid 2D/3D coronary artery registration. AB - 2D/3D registration of patient vasculature from preinterventional computed tomography angiography (CTA) to interventional X-ray angiography is of interest to improve guidance in percutaneous coronary interventions. In this paper we present a novel feature based 2D/3D registration framework, that is based on probabilistic point correspondences, and show its usefulness on aligning 3D coronary artery centerlines derived from CTA images with their 2D projection derived from interventional X-ray angiography. The registration framework is an extension of the Gaussian mixture model (GMM) based point-set registration to the 2D/3D setting, with a modified distance metric. We also propose a way to incorporate orientation in the registration, and show its added value for artery registration on patient datasets as well as in simulation experiments. The oriented GMM registration achieved a median accuracy of 1.06 mm, with a convergence rate of 81% for nonrigid vessel centerline registration on 12 patient datasets, using a statistical shape model. The method thereby outperformed the iterative closest point algorithm, the GMM registration without orientation, and two recently published methods on 2D/3D coronary artery registration. PMID- 24770909 TI - Elastic shape analysis of cylindrical surfaces for 3D/2D registration in endometrial tissue characterization. AB - We study the problem of joint registration and deformation analysis of endometrial tissue using 3D magnetic resonance imaging (MRI) and 2D trans-vaginal ultrasound (TVUS) measurements. In addition to the different imaging techniques involved in the two modalities, this problem is complicated due to: 1) different patient pose during MRI and TVUS observations, 2) the 3D nature of MRI and 2D nature of TVUS measurements, 3) the unknown intersecting plane for TVUS in MRI volume, and 4) the potential deformation of endometrial tissue during TVUS measurement process. Focusing on the shape of the tissue, we use expert manual segmentation of its boundaries in the two modalities and apply, with modification, recent developments in shape analysis of parametric surfaces to this problem. First, we extend the 2D TVUS curves to generalized cylindrical surfaces through replication, and then we compare them with MRI surfaces using elastic shape analysis. This shape analysis provides a simultaneous registration (optimal reparameterization) and deformation (geodesic) between any two parametrized surfaces. Specifically, it provides optimal curves on MRI surfaces that match with the original TVUS curves. This framework results in an accurate quantification and localization of the deformable endometrial cells for radiologists, and growth characterization for gynecologists and obstetricians. We present experimental results using semi-synthetic data and real data from patients to illustrate these ideas. PMID- 24770910 TI - MRI-compatible device for examining brain activation related to stepping. AB - Repetitive and alternating lower limb movements are a specific component of human gait. Due to technical challenges, the neural mechanisms underlying such movements have not been previously studied with functional magnetic resonance imaging. In this study, we present a novel treadmill device employed to investigate the kinematics and the brain activation patterns involved in alternating and repetitive movements of the lower limbs. Once inside the scanner, 19 healthy subjects were guided by two visual cues and instructed to perform a motor task which involved repetitive and alternating movements of both lower limbs while selecting their individual comfortable amplitude on the treadmill. The device facilitated the performance of coordinated stepping while registering the concurrent lower-limb displacements, which allowed us to quantify some movement primary kinematic features such as amplitude and frequency. During stepping, significant blood oxygen level dependent signal increases were observed bilaterally in primary and secondary sensorimotor cortex, the supplementary motor area, premotor cortex, prefrontal cortex, superior and inferior parietal lobules, putamen and cerebellum, regions that are known to be involved in lower limb motor control. Brain activations related to individual adjustments during motor performance were identified in a right lateralized network including striatal, extrastriatal, and fronto-parietal areas. PMID- 24770911 TI - Automatic detection and measurement of structures in fetal head ultrasound volumes using sequential estimation and Integrated Detection Network (IDN). AB - Routine ultrasound exam in the second and third trimesters of pregnancy involves manually measuring fetal head and brain structures in 2-D scans. The procedure requires a sonographer to find the standardized visualization planes with a probe and manually place measurement calipers on the structures of interest. The process is tedious, time consuming, and introduces user variability into the measurements. This paper proposes an automatic fetal head and brain (AFHB) system for automatically measuring anatomical structures from 3-D ultrasound volumes. The system searches the 3-D volume in a hierarchy of resolutions and by focusing on regions that are likely to be the measured anatomy. The output is a standardized visualization of the plane with correct orientation and centering as well as the biometric measurement of the anatomy. The system is based on a novel framework for detecting multiple structures in 3-D volumes. Since a joint model is difficult to obtain in most practical situations, the structures are detected in a sequence, one-by-one. The detection relies on Sequential Estimation techniques, frequently applied to visual tracking. The interdependence of structure poses and strong prior information embedded in our domain yields faster and more accurate results than detecting the objects individually. The posterior distribution of the structure pose is approximated at each step by sequential Monte Carlo. The samples are propagated within the sequence across multiple structures and hierarchical levels. The probabilistic model helps solve many challenges present in the ultrasound images of the fetus such as speckle noise, signal drop-out, shadows caused by bones, and appearance variations caused by the differences in the fetus gestational age. This is possible by discriminative learning on an extensive database of scans comprising more than two thousand volumes and more than thirteen thousand annotations. The average difference between ground truth and automatic measurements is below 2 mm with a running time of 6.9 s (GPU) or 14.7 s (CPU). The accuracy of the AFHB system is within inter user variability and the running time is fast, which meets the requirements for clinical use. PMID- 24770912 TI - Automated aortic Doppler flow tracing for reproducible research and clinical measurements. AB - In clinical practice, echocardiographers are often unkeen to make the significant time investment to make additional multiple measurements of Doppler velocity. Main hurdle to obtaining multiple measurements is the time required to manually trace a series of Doppler traces. To make it easier to analyze more beats, we present the description of an application system for automated aortic Doppler envelope quantification, compatible with a range of hardware platforms. It analyses long Doppler strips, spanning many heartbeats, and does not require electrocardiogram to separate individual beats. We tested its measurement of velocity-time-integral and peak-velocity against the reference standard defined as the average of three experts who each made three separate measurements. The automated measurements of velocity-time-integral showed strong correspondence (R(2) = 0.94) and good Bland-Altman agreement (SD = 1.39 cm) with the reference consensus expert values, and indeed performed as well as the individual experts ( R(2) = 0.90 to 0.96, SD = 1.05 to 1.53 cm). The same performance was observed for peak-velocities; ( R(2) = 0.98, SD = 3.07 cm/s) and ( R(2) = 0.93 to 0.98, SD = 2.96 to 5.18 cm/s). This automated technology allows > 10 times as many beats to be analyzed compared to the conventional manual approach. This would make clinical and research protocols more precise for the same operator effort. PMID- 24770913 TI - Computer-aided detection of prostate cancer in MRI. AB - Prostate cancer is one of the major causes of cancer death for men in the western world. Magnetic resonance imaging (MRI) is being increasingly used as a modality to detect prostate cancer. Therefore, computer-aided detection of prostate cancer in MRI images has become an active area of research. In this paper we investigate a fully automated computer-aided detection system which consists of two stages. In the first stage, we detect initial candidates using multi-atlas-based prostate segmentation, voxel feature extraction, classification and local maxima detection. The second stage segments the candidate regions and using classification we obtain cancer likelihoods for each candidate. Features represent pharmacokinetic behavior, symmetry and appearance, among others. The system is evaluated on a large consecutive cohort of 347 patients with MR-guided biopsy as the reference standard. This set contained 165 patients with cancer and 182 patients without prostate cancer. Performance evaluation is based on lesion based free-response receiver operating characteristic curve and patient-based receiver operating characteristic analysis. The system is also compared to the prospective clinical performance of radiologists. Results show a sensitivity of 0.42, 0.75, and 0.89 at 0.1, 1, and 10 false positives per normal case. In clinical workflow the system could potentially be used to improve the sensitivity of the radiologist. At the high specificity reading setting, which is typical in screening situations, the system does not perform significantly different from the radiologist and could be used as an independent second reader instead of a second radiologist. Furthermore, the system has potential in a first-reader setting. PMID- 24770914 TI - An analysis of whole body tracer kinetics in dynamic PET studies with application to image-based blood input function extraction. AB - In a positron emission tomography (PET) study, the local uptake of the tracer is dependent on vascular delivery and retention. For dynamic studies the measured uptake time-course information can be best interpreted when knowledge of the time course of tracer in the blood is available. This is certainly true for the most established tracers such as 18F-Fluorodeoxyglucose (FDG) and 15O-Water (H2O). Since direct sampling of blood as part of PET studies is increasingly impractical, there is ongoing interest in image-extraction of blood time-course information. But analysis of PET-measured blood pool signals is complicated because they will typically involve a combination of arterial, venous and tissue information. Thus, a careful appreciation of these components is needed to interpret the available data. To facilitate this process, we propose a novel Markov chain model for representation of the circulation of a tracer atom in the body. The model represents both arterial and venous time-course patterns. Under reasonable conditions equilibration of tracer activity in arterial and venous blood is achieved by the end of the PET study-consistent with empirical measurement. Statistical inference for Markov model parameters is a challenge. A penalized nonlinear least squares process, incorporating a generalized cross validation score, is proposed. Random effects analysis is used to adaptively specify the structure of the penalty function based on historical samples of directly measured blood data. A collection of arterially sampled data from PET studies with FDG and H2O is used to illustrate the methodology. These data analyses are highly supportive of the overall modeling approach. An adaptation of the model to the problem of extraction of arterial blood signals from imaging data is also developed and promising preliminary results for cerebral and thoracic imaging studies with FDG and H2O are obtained. PMID- 24770915 TI - Reconstructing 3-D skin surface motion for the DIET breast cancer screening system. AB - Digital image-based elasto-tomography (DIET) is a prototype system for breast cancer screening. A breast is imaged while being vibrated, and the observed surface motion is used to infer the internal stiffness of the breast, hence identifying tumors. This paper describes a computer vision system for accurately measuring 3-D surface motion. A model-based segmentation is used to identify the profile of the breast in each image, and the 3-D surface is reconstructed by fitting a model to the profiles. The surface motion is measured using a modern optical flow implementation customized to the application, then trajectories of points on the 3-D surface are given by fusing the optical flow with the reconstructed surfaces. On data from human trials, the system is shown to exceed the performance of an earlier marker-based system at tracking skin surface motion. We demonstrate that the system can detect a 10 mm tumor in a silicone phantom breast. PMID- 24770916 TI - Order of magnitude sensitivity increase in X-ray Fluorescence Computed Tomography (XFCT) imaging with an optimized spectro-spatial detector configuration: theory and simulation. AB - The purpose of this study was to increase the sensitivity of XFCT imaging by optimizing the data acquisition geometry for reduced scatter X-rays. The placement of detectors and detector energy window were chosen to minimize scatter X-rays. We performed both theoretical calculations and Monte Carlo simulations of this optimized detector configuration on a mouse-sized phantom containing various gold concentrations. The sensitivity limits were determined for three different X ray spectra: a monoenergetic source, a Gaussian source, and a conventional X-ray tube source. Scatter X-rays were minimized using a backscatter detector orientation (scatter direction > 110( degrees ) to the primary X-ray beam). The optimized configuration simultaneously reduced the number of detectors and improved the image signal-to-noise ratio. The sensitivity of the optimized configuration was 10 MUg/mL (10 pM) at 2 mGy dose with the mono-energetic source, which is an order of magnitude improvement over the unoptimized configuration (102 pM without the optimization). Similar improvements were seen with the Gaussian spectrum source and conventional X-ray tube source. The optimization improvements were predicted in the theoretical model and also demonstrated in simulations. The sensitivity of XFCT imaging can be enhanced by an order of magnitude with the data acquisition optimization, greatly enhancing the potential of this modality for future use in clinical molecular imaging. PMID- 24770917 TI - Image-based quantitative analysis of gold immunochromatographic strip via cellular neural network approach. AB - Gold immunochromatographic strip assay provides a rapid, simple, single-copy and on-site way to detect the presence or absence of the target analyte. This paper aims to develop a method for accurately segmenting the test line and control line of the gold immunochromatographic strip (GICS) image for quantitatively determining the trace concentrations in the specimen, which can lead to more functional information than the traditional qualitative or semi-quantitative strip assay. The canny operator as well as the mathematical morphology method is used to detect and extract the GICS reading-window. Then, the test line and control line of the GICS reading-window are segmented by the cellular neural network (CNN) algorithm, where the template parameters of the CNN are designed by the switching particle swarm optimization (SPSO) algorithm for improving the performance of the CNN. It is shown that the SPSO-based CNN offers a robust method for accurately segmenting the test and control lines, and therefore serves as a novel image methodology for the interpretation of GICS. Furthermore, quantitative comparison is carried out among four algorithms in terms of the peak signal-to-noise ratio. It is concluded that the proposed CNN algorithm gives higher accuracy and the CNN is capable of parallelism and analog very-large-scale integration implementation within a remarkably efficient time. PMID- 24770918 TI - Model-based classification methods of global patterns in dermoscopic images. AB - In this paper different model-based methods of classification of global patterns in dermoscopic images are proposed. Global patterns identification is included in the pattern analysis framework, the melanoma diagnosis method most used among dermatologists. The modeling is performed in two senses: first a dermoscopic image is modeled by a finite symmetric conditional Markov model applied to L*a*b* color space and the estimated parameters of this model are treated as features. In turn, the distribution of these features are supposed that follow different models along a lesion: a Gaussian model, a Gaussian mixture model, and a bag-of features histogram model. For each case, the classification is carried out by an image retrieval approach with different distance metrics. The main objective is to classify a whole pigmented lesion into three possible patterns: globular, homogeneous, and reticular. An extensive evaluation of the performance of each method has been carried out on an image database extracted from a public Atlas of Dermoscopy. The best classification success rate is achieved by the Gaussian mixture model-based method with a 78.44% success rate in average. In a further evaluation the multicomponent pattern is analyzed obtaining a 72.91% success rate. PMID- 24770919 TI - A new technique for the estimation of cardiac motion in echocardiography based on transverse oscillations: a preliminary evaluation in silico and a feasibility demonstration in vivo. AB - Quantification of regional myocardial motion and deformation from cardiac ultrasound is fostering considerable research efforts. Despite the tremendous improvements done in the field, all existing approaches still face a common limitation which is intrinsically connected with the formation of the ultrasound images. Specifically, the reduced lateral resolution and the absence of phase information in the lateral direction highly limit the accuracy in the computation of lateral displacements. In this context, this paper introduces a novel setup for the estimation of cardiac motion with ultrasound. The framework includes an unconventional beamforming technique and a dedicated motion estimation algorithm. The beamformer aims at introducing phase information in the lateral direction by producing transverse oscillations. The estimator directly exploits the phase information in the two directions by decomposing the image into two 2-D single orthant analytic signals. An in silico evaluation of the proposed framework is presented on five ultra-realistic simulated echocardiographic sequences, where the proposed motion estimator is contrasted against other two phase-based solutions exploiting the presence of transverse oscillations and against block matching on standard images. An implementation of the new beamforming strategy on a research ultrasound platform is also shown along with a preliminary in vivo evaluation on one healthy subject. PMID- 24770920 TI - Simultaneous sparsity model for histopathological image representation and classification. AB - The multi-channel nature of digital histopathological images presents an opportunity to exploit the correlated color channel information for better image modeling. Inspired by recent work in sparsity for single channel image classification, we propose a new simultaneous sparsity model for multi-channel histopathological image representation and classification (SHIRC). Essentially, we represent a histopathological image as a sparse linear combination of training examples under suitable channel-wise constraints. Classification is performed by solving a newly formulated simultaneous sparsity-based optimization problem. A practical challenge is the correspondence of image objects (cellular and nuclear structures) at different spatial locations in the image. We propose a robust locally adaptive variant of SHIRC (LA-SHIRC) to tackle this issue. Experiments on two challenging real-world image data sets: 1) mammalian tissue images acquired by pathologists of the animal diagnostics lab (ADL) at Pennsylvania State University, and 2) human intraductal breast lesions, reveal the merits of our proposal over state-of-the-art alternatives. Further, we demonstrate that LA SHIRC exhibits a more graceful decay in classification accuracy against the number of training images which is highly desirable in practice where generous training per class is often not available. PMID- 24770921 TI - Discrete imaging models for three-dimensional optoacoustic tomography using radially symmetric expansion functions. AB - Optoacoustic tomography (OAT), also known as photoacoustic tomography, is an emerging computed biomedical imaging modality that exploits optical contrast and ultrasonic detection principles. Iterative image reconstruction algorithms that are based on discrete imaging models are actively being developed for OAT due to their ability to improve image quality by incorporating accurate models of the imaging physics, instrument response, and measurement noise. In this work, we investigate the use of discrete imaging models based on Kaiser-Bessel window functions for iterative image reconstruction in OAT. A closed-form expression for the pressure produced by a Kaiser-Bessel function is calculated, which facilitates accurate computation of the system matrix. Computer-simulation and experimental studies are employed to demonstrate the potential advantages of Kaiser-Bessel function-based iterative image reconstruction in OAT. PMID- 24770922 TI - Multiscale multispectral optoacoustic tomography by a stationary wavelet transform prior to unmixing. AB - Multispectral optoacoustic tomography (MSOT) utilizes broadband ultrasound detection for imaging biologically-relevant optical absorption features at a range of scales. Due to the multiscale and multispectral features of the technology, MSOT comes with distinct requirements in implementation and data analysis. In this work, we investigate the interplay between scale, which depends on ultrasonic detection frequency, and optical multispectral spectral analysis, two dimensions that are unique to MSOT and represent a previously unexplored challenge. We show that ultrasound frequency-dependent artifacts suppress multispectral features and complicate spectral analysis. In response, we employ a wavelet decomposition to perform spectral unmixing on a per-scale basis (or per ultrasound frequency band) and showcase imaging of fine-scale features otherwise hidden by low frequency components. We explain the proposed algorithm by means of simple simulations and demonstrate improved performance in imaging data of blood vessels in human subjects. PMID- 24770924 TI - Recycling of nickel smelter slag for arsenic remediation--an experimental study. AB - In this study, recycled Ni smelter slag has been used as a reactive medium for arsenic (As) removal from aqueous solutions. The results of the study showed that 10.16-11.43-cm long columns containing 451-550 g of slag operated for at least 65 days were able to remove 99-100 % As species from continuously flowing contaminated water at an initial As concentration of 10 mg/L. The removal capacities were found to be 1.039 to 1.054 mg As per g of slag. X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy data also showed that electrostatic attraction and oxidation-reduction reactions between As species and mixed iron oxides present in the slag were the main mechanisms for the removal of arsenic from aqueous solutions. Theoretical multiplet analysis of XPS data revealed that the amount of goethite in the slag increased from 22 to 60 % during arsenic removal by adsorption and the percentage of magnetite decreased from 50 to 40 %. These changes indicate that redox-mediated reactions occurred as part of the As(V) removal process. Raman spectroscopy studies confirmed that, in addition to surface reactions, internal interactions between the slag and arsenic also occurred. The findings of the study suggest that recycled Ni smelter slag could be an effective low-cost reactive medium for a subsurface remediation system, such as a permeable reactive barrier. Recycling of waste material (slag) for the removal of another waste (arsenic) can significantly reduce the environmental footprint of metallurgical operations and hence contribute to sustainable development. Such recycling also decreases slag disposal costs and eliminates the need to purchase commercial reactive material or obtain expensive natural material for remediation purposes. PMID- 24770925 TI - The effect of arsenic on some antioxidant enzyme activities and lipid peroxidation in various tissues of mirror carp (Cyprinus carpio carpio). AB - The effect of arsenic bioaccumulation in liver, kidney, skin, muscle, and intestinal tissues of mirror carp (Cyprinus carpio carpio) was investigated on lipid peroxidation and certain antioxidant enzyme activities. In this study, three aquarium groups were formed from mirror carp: control group, 0.5-, and 1 mg/L arsenic concentrations. The fish were dissected after 1 month. Arsenic bioaccumulation, malondialdehyde (MDA) levels, catalase (CAT), and superoxide dismutase (SOD) enzyme activities were determined in the tissues. Results showed that arsenic was accumulated in liver, kidney, muscle, skin, and intestinal tissues. As the final product of lipid peroxidation, MDA levels were determined to have increased in all tissues with the exception of muscle. On the other hand, CAT and SOD enzyme activities in the fish tissues were decreased as compared to the control group. In the muscle tissue, differences were observed in the enzyme activities depending on arsenic concentration. Considering the increases in enzyme inhibition and MDA levels, liver was observed to be the main tissue affected in response to the arsenic toxicity. PMID- 24770926 TI - Towards standardised evaluative measurement of nature impacts: two spatial planning case studies for major Dutch lakes. AB - In the assessment of complex spatial planning projects, the ecological impacts and socio-economic impacts are fundamental to the evaluation. The measurements of ecological impacts of spatial plans have to be integrated in a standardised way. In the present paper, we analyse two Dutch case studies and apply the standardised Threat-Weighted Ecological Quality Area measurement. This measurement is developed to evaluate projects with terrestrial impacts but has not yet been applied for water evaluations. We aim to show how the use of a common measurement tool incorporates both ecological quality and degree of threat on criteria in the EU Water Framework Directive and Nature 2000. The measurements discussed here derive from two cases of cost-benefit analysis: The first case is the Markermeer, the second largest lake of The Netherlands, and a study on water quality improvement and nature restoration; an artificial island will also be the setting for a new residential area. The second case study is on water level management carried out on the IJsselmeer, the largest lake in the country. Results of our analysis show the potential impacts with a standardised method to the spatial distribution and quality of the ecosystems. PMID- 24770927 TI - The capability of estuarine sediments to remove nitrogen: implications for drinking water resource in Yangtze Estuary. AB - Water in the Yangtze Estuary is fresh most of the year because of the large discharge of Yangtze River. The Qingcaosha Reservoir built on the Changxing Island in the Yangtze Estuary is an estuarine reservoir for drinking water. Denitrification rate in the top 10 cm sediment of the intertidal marshes and bare mudflat of Yangtze Estuarine islands was measured by the acetylene inhibition method. Annual denitrification rate in the top 10 cm of sediment was 23.1 MUmol m(-2) h(-1) in marshes (ranged from 7.5 to 42.1 MUmol m(-2) h(-1)) and 15.1 MUmol m(-2) h(-1) at the mudflat (ranged from 6.6 to 26.5 MUmol m(-2) h(-1)). Annual average denitrification rate is higher at mashes than at mudflat, but without a significant difference (p = 0.084, paired t test.). Taking into account the vegetation and water area of the reservoir, a total 1.42 * 10(8) g N could be converted into nitrogen gas (N2) annually by the sediment, which is 97.7 % of the dissolved inorganic nitrogen input through precipitation. Denitrification in reservoir sediment can control the bioavailable nitrogen level of the water body. At the Yangtze estuary, denitrification primarily took place in the top 4 cm of sediment, and there was no significant spatial or temporal variation of denitrification during the year at the marshes and mudflat, which led to no single factor determining the denitrification process but the combined effects of the environmental factors, hydrologic condition, and wetland vegetation. PMID- 24770929 TI - Low-molecular-mass gels responding to ultrasound and mechanical stress: towards self-healing materials. AB - In this review, we focus on the types of smart supramolecular gels whose self assembly processes are affected or even triggered by physical forces including sonication and mechanical stress (mechanical force). The types of gels that are responsive to sonication and mechanical stress are examined and summarised. The gels exhibit non-covalent interactions among the gelator molecules and show dynamic and reversible properties controlled by the stimuli. Upon stimulation, the gelators cause instant and in situ gelation of organic solvents or water with different modes and outcomes of self-assembly. On the other hand, sonication and mechanical stress, as external factors, can give rise to dynamic changes in microscopic morphology, optical properties, etc. Certain thixotropic supramolecular gels exhibit perfect self-healing characteristics. The driving forces and the mechanism of the self-assembly process and the responsive outcome of morphological and spectroscopic changes are discussed. Those supramolecular gels responding to sonication and mechanical stress offer a wide range of applications in fields such as smart and adaptive materials, switches, drug control and release, and tissue engineering. PMID- 24770928 TI - The influence of hospital drug formulary policies on the prescribing patterns of proton pump inhibitors in primary care. AB - AIM: This study had two aims: Firstly, to describe how prescriptions for proton pump inhibitor (PPI) in primary care were influenced by a change of the hospital drug policy, and secondly, to describe if a large discount on an expensive PPI (esomeprazole) to a hospital would influence prescribing patterns after discharge. METHODS: This register study was conducted at Odense University Hospital, Denmark, and by use of pharmacy dispensing data and a hospital-based pharmacoepidemiological database, the medication regimens of patients were followed across hospitalisation. The influence of hospital drug policy on prescribings in primary care was measured by the likelihood of having a high-cost PPI prescribed before and after change of drug policy. RESULTS: In total, 9,341 hospital stays in 2009 and 2010 were included. The probability of a patient to be prescribed an expensive PPI after discharge decreased from 33.5 to 9.4%, corresponding to a risk ratio of 0.28. In primary care after discharge, 13.4% of esomeprazole use was initiated in the hospital, and this was 8.4% for PPIs in general. After the change of hospital drug policy, this decreased to 6.5% for esomeprazole and increased for the recommended PPIs pantoprazole and lansoprazole to 14.6 and 26.1%, respectively. The effect of a large discount on expensive PPI to hospital was 14.7%, and this decreased to 2.6% when coordinating drug policy in hospital and primary care. CONCLUSION: The likelihood of having an expensive PPI prescribed after hospital stay decreased when coordinating drug policy and the influence of a large discount to hospital could be minimised. PMID- 24770930 TI - First-in-man results of a novel vascular graft coated with resorbable polymer for aortic reconstructions--a multicenter, non-randomized safety study. AB - OBJECTIVES: The purpose of this "first-in-man" study was to investigate the safety of a novel vascular polyester prosthesis coated with a resorbable polymer and free of any animal-based coating agents such as gelatin or collagen. METHODS: In a nonrandomized first-in-man multicenter safety study, the frequency of perigraft seroma (PGS) as the primary endpoint was studied in consecutive patients undergoing aortic reconstructions. The follow-up control to study the primary endpoint was intended at 3 months under routine clinical conditions. Pre- and postoperative white blood cell counts (WBC), C-reactive protein (CRP), and liver enzyme levels to characterize the systemic inflammation response and possible metabolic consequences were determined at different postoperative time points (secondary endpoints). Additionally, the primary unassisted patency rate, perioperative complications and serious adverse events, as well as intraoperative handling properties of the graft based on a semiquantitative scale were assessed. Magnetic resonance angiography (MRA) follow-up investigations were scheduled postoperatively at 3 months to determine graft tissue integration and the presence of PGS. RESULTS: A total of 24 patients with comorbidities such as coronary artery disease (8.3 %, 2/24), chronic occlusive pulmonary disease (COPD, 8.3 %, 2/24), Fontaine III/IV (20.8 %, 5/24), and diabetes (20.8 %, 5/24) were enrolled from June 2011 to September 2012. Due to two early nongraft-related deaths, there were 22 patients that had a follow-up. In these 22 patients, the freedom from PGS was 90.9 % (20/22) suggesting that the graft/tissue integration was comparable to other vascular grafts described in the relevant literature. WBC counts were not significantly different (pre (8.67 +/- 2.98 1/nl) vs. follow-up (7.97 +/- 2.24 1/nlI, p = 0.203). Likewise, preoperative CRP serum levels (6.47 +/- 11.59 mg/l) were not different from those at follow-up (7.87 +/- 12.81 mg/l, p = 0.769). There were two patients with a documented coagulation disorder and two premature deaths (cardiac failure, cerebral bleeding). The primary unassisted patency at follow-up was 77.3 % (17/22) in all patients who reached the follow-up (85.0 % or 17/20 if two cases with documented coagulation disorders are excluded). The reasons for occlusions were technical/surgical difficulties (2/5) and documented coagulation disorders (2/5). In one occlusion, the cause was unknown. There were no graft infections. Intraoperative graft handling properties were evaluated less favorable as compared to the routinely used gelatin- or collagen-coated polyester grafts in each investigator's clinical practice. CONCLUSIONS: Our results suggest that Uni-Graft(r) Synthetic is a promising prosthetic vascular graft to reduce PGS. Our findings should be interpreted with caution noting the limitation of the lack of a control group. PMID- 24770931 TI - TP53 status regulates ACSL5-induced expression of mitochondrial mortalin in enterocytes and colorectal adenocarcinomas. AB - Acyl-CoA synthetase 5 (ACSL5), a mitochondrially localized enzyme, catalyzes the synthesis of long-chain fatty acid thioesters and is physiologically involved in pro-apoptotic sensing of enterocytes. The aim of the present study is to identify an ACSL5-dependent regulation of mitochondrially expressed proteins and the characterization of related pathways in normal and diseased human intestinal mucosa. Proteomics of isolated mitochondria from ACSL5 transfectants and CaCo2 controls were performed. ACSL5-dependent protein synthesis was verified with quantitative reverse transcription plus the polymerase chain reaction, Western blotting, short-interfering-RNA-mediated gene silencing and additional cell culture experiments. Lipid changes were analyzed with tandem mass spectrometry. ACSL5-related pathways were characterized in normal mucosa and sporadic adenocarcinomas of the human intestine. In CaCo2 cells transfected with ACSL5, mortalin (HSPA9) was about two-fold increased in mitochondria, whereas cytoplasmic mortalin levels were unchanged. Disturbance of acyl-CoA/sphingolipid metabolism, induced by ACSL5 over-expression, was characterized as crucial. ACSL5 related over-expression of mitochondrial mortalin was found in HEK293 and Lovo (wild-type TP53 [tumor protein p53]) and CaCo2 (p53-negative; TP53 mutated) cells but not in Colo320DM cells (mutated TP53). In normal human intestinal mucosa, an increasing gradient of both ACSL5 and mortalin from bottom to top was observed, whereas p53 (wild-type TP53) decreased. In sporadic intestinal adenocarcinomas with strong p53 immunostaining (mutated TP53), ACSL5-related mortalin expression was heterogeneous. ACSL5-induced mitochondrial mortalin expression is assumed to be a stress response to ACSL5-related changes in lipid metabolism and is regulated by the TP53 status. Uncoupling of ACSL5 and mitochondrial mortalin by mutated TP53 could be important in colorectal carcinogenesis. PMID- 24770932 TI - Protein LUMA is a cytoplasmic plaque constituent of various epithelial adherens junctions and composite junctions of myocardial intercalated disks: a unifying finding for cell biology and cardiology. AB - In a series of recent reports, mutations in the gene encoding a protein called LUMA (or TMEM43), widely speculated to be a tetraspan transmembrane protein of the nuclear envelope, have been associated with a specific subtype of cardiomyopathy (arrhythmogenic cardiomyopathies) and cases of sudden death. However, using antibodies of high specificity in immunolocalization experiments, we have discovered that, in mammals, LUMA is a component of zonula adhaerens and punctum adhaerens plaques of diverse epithelia and epithelial cell cultures and is also located in (or in some species associated with) the plaques of composite junctions (CJs) in myocardiac intercalated disks (IDs). In CJs, LUMA often colocalizes with several other CJ marker proteins. In all these cells, LUMA has not been detected in the nuclear envelope. Surprisingly, under certain conditions, similar CJ localizations have also been seen with some antibodies commercially available for some time. The identification of LUMA as a plaque component of myocardiac CJs leads to reconsiderations of the molecular composition and architecture, the development, the functions, and the pathogenic states of CJs and IDs. These findings now also allow the general conclusion that LUMA has to be added to the list of mutations of cardiomyocyte junction proteins that may be involved in cardiomyopathies. PMID- 24770933 TI - Formation and cultivation of medaka primordial germ cells. AB - Primordial germ cell (PGC) formation is pivotal for fertility. Mammalian PGCs are epigenetically induced without the need for maternal factors and can also be derived in culture from pluripotent stem cells. In egg-laying animals such as Drosophila and zebrafish, PGCs are specified by maternal germ plasm factors without the need for inducing factors. In these organisms, PGC formation and cultivation in vitro from indeterminate embryonic cells have not been possible. Here, we report PGC formation and cultivation in vitro from blastomeres dissociated from midblastula embryos (MBEs) of the fish medaka (Oryzias latipes). PGCs were identified by using germ-cell-specific green fluorescent protein (GFP) expression from a transgene under the control of the vasa promoter. Embryo perturbation was exploited to study PGC formation in vivo, and dissociated MBE cells were cultivated under various conditions to study PGC formation in vitro. Perturbation of somatic development did not prevent PGC formation in live embryos. Dissociated MBE blastomeres formed PGCs in the absence of normal somatic structures and of known inducing factors. Most importantly, under culture conditions conducive to stem cell derivation, some dissociated MBE blastomeres produced GFP-positive PGC-like cells. These GFP-positive cells contained genuine PGCs, as they expressed PGC markers and migrated into the embryonic gonad to generate germline chimeras. Our data thus provide evidence for PGC preformation in medaka and demonstrate, for the first time, that PGC formation and derivation can be obtained in culture from early embryos of medaka as a lower vertebrate model. PMID- 24770934 TI - A novel TSC2 mutation in a Korean patient with tuberous sclerosis complex. PMID- 24770935 TI - Vertical gaze-evoked nystagmus and internuclear ophthalmoplegia as sole manifestations in paramedian pontine infarction. PMID- 24770936 TI - Safety screw fixation technique in a case of coracoid base fracture with acromioclavicular dislocation and coracoid base cross-sectional size data from a computed axial tomography study. AB - Coracoid base fracture accompanied by acromioclavicular joint dislocation with intact coracoclavicular ligaments is a rare injury. Generally, an open reduction with screw fixation is the first treatment choice, as it protects the important structures around the coracoid process. This report presents a new technique of screw fixation for coracoid base fracture and provides anatomic information on cross-sectional size of the coracoid base obtained by computed tomography (CT). An axial image of the coracoid base was visualized over the neck of the scapula, and a guidewire was inserted into this circle under fluoroscopic guidance. The wire was inserted easily into the neck of scapula across the coracoid base fracture with imaging in only 1 plane. In addition, 25 measurements of the coracoid base were made in 25 subjects on axial CT images. Average length of the long and short axes at the thinnest part of the coracoid base was 13.9 +/- 2.0 mm (range 10.6-17.0) and 10.5 +/- 2.2 mm (6.6-15.1), respectively. This new screw fixation technique and measurement data on the coracoid base may be beneficial for safety screw fixation of coracoid base fracture. PMID- 24770937 TI - Coexistence of urinary incontinence and major depressive disorder with health related quality of life in older Americans with and without cancer. AB - PURPOSE: This study evaluates the prevalence and factors associated with major depressive disorder (MDD) in a population of cancer survivors and the impact of co-occurring MDD and urinary incontinence (UI) on health-related quality of life (HRQOL). METHODS: The prevalence of MDD risk among cancer survivors (breast, prostate, bladder, colorectal, lung, and endometrial/uterine cancers) and those without cancer was estimated using the Surveillance, Epidemiology and End Results Program-Medicare Health Outcomes Survey (SEER-MHOS) linked database (n = 9,282 with cancer/n = 289,744 without cancer). Risk for MDD was measured using three items from the Diagnostic Interview Schedule, and HRQOL was measured by the SF 36. UI was defined as self-reported leakage of urine causing a problem in previous 6 months. Factors associated with MDD were investigated using logistic regression, and the impact of co-occurring MDD and UI on HRQOL scores was determined using linear regression. RESULTS: The prevalence of MDD risk ranged from 19.2 % for prostate to 34.1 % for lung. Lung cancer diagnosis was associated with risk of MDD. Being >=5 years from diagnosis was associated with decreased risk of MDD (prevalence odds ratio (POR) = 0.82, 95 % confidence interval (95 % CI) 0.71, 0.95). The coexistence of both UI and MDD was associated with a decrease across HRQOL subscales; including 40 points on role-emotional (RE) score. CONCLUSIONS: Cancer survivors reporting co-occurrence of UI and MDD experienced significant decrements in HRQOL. IMPLICATIONS OF CANCER SURVIVORS: Understanding the combined effect of UI and MDD may help clinicians to better recognize and alleviate their effects on cancer survivors' HRQOL. PMID- 24770938 TI - High-resolution analysis of DNA copy number alterations in rectal cancer: correlation with metastasis, survival, and mRNA expression. AB - BACKGROUND AND PURPOSE: This study aimed to determine the candidate genes and chromosomal imbalances capable of predicting occurrences of metastasis in patients with rectal cancer. PATIENTS AND METHODS: Fresh frozen tumor tissues from 80 patients with rectal cancer were prospectively collected and analyzed using Affymetrix HG-U133 Plus 2.0 gene expression arrays and high-resolution Illumina single-nucleotide polymorphism (SNP) arrays. Endpoints of the study were metastasis-free survival (MFS) and cancer-specific survival (CSS). RESULTS: The median follow-up was 102 months (1-146). Deletions of 8p and 1p36-35 correlated with worse MFS (p = 0.005 and p = 0.01, respectively) and CSS (p = 0.001 and p = 0.01, respectively). Multivariate analysis identified 8p deletion as an independent prognostic factor for MFS (p = 0.04) and CSS (p = 0.003); 97 genes located on the 8p chromosome were significantly underexpressed in tumors with 8p deletion. CONCLUSION: This study shows for the first time in rectal cancer an independent correlation of 8p deletion with MFS and CSS and highlights potential new tumor suppressor genes. PMID- 24770939 TI - [Non- inferior moderate hypofractionated irradiation of glottis T1/T2 laryngeal cancer ]. PMID- 24770942 TI - Ruptured ectopic pregnancy: the long and tortuous journey to the theatre. AB - Ectopic pregnancy is a common gynaecological emergency in Nigeria, West Africa. Here we present a case that brings to light some of the problems facing the health sector in reducing the high maternal mortality rate. PMID- 24770943 TI - Lactoferrin differently modulates the inflammatory response in epithelial models mimicking human inflammatory and infectious diseases. AB - Conflicting data are reported on pro- or anti-inflammatory activity of bovine lactoferrin (bLf) in different cell models as phagocytes or epithelial cell lines infected by bacteria. Here we evaluated the bLf effect on epithelial models mimicking two human pathologies characterized by inflammation and infection with specific bacterial species. Primary bronchial epithelium from a cystic fibrosis (CF) patient and differentiated intestinal epithelial cells were infected with Pseudomonas aeruginosa LESB58 isolated from a CF patient and Adherent-Invasive Escherichia coli LF82 isolated from a Crohn's disease patient. Surprisingly, bLf significantly reduced the intracellular bacterial survival, but differently modulated the inflammatory response. These data lead us to hypothesize that bLf differentially acts depending on the epithelial model and infecting pathogen. To verify this hypothesis, we explored whether bLf could modulate ferroportin (Fpn), the only known cellular iron exporter from cells, that, by lowering the intracellular iron level, determines a non permissive environment for intracellular pathogens. Here, for the first time, we describe the bLf ability to up-regulate Fpn protein in infected epithelial models. Our data suggest that the mechanism underlying the bLf modulating activity on inflammatory response in epithelial cells is complex and the bLf involvement in modulating cellular iron homeostasis should be taken into account. PMID- 24770944 TI - Directing chondrogenic differentiation of mesenchymal stem cells with a solid supported chitosan thermogel for cartilage tissue engineering. AB - Hydrogels are attractive for cartilage tissue engineering because of their high plasticity and similarity with the native cartilage matrix. However, one critical drawback of hydrogels for osteochondral repair is their inadequate mechanical strength. To address this limitation, we constructed a solid-supported thermogel comprising a chitosan hydrogel system and demineralized bone matrix. Scanning electron microscopy, the equilibrium scanning ratio, the biodegradation rate, biomechanical tests, biochemical assays, metabolic activity tests, immunostaining and cartilage-specific gene expression analysis were used to evaluate the solid supported thermogel. Compared with pure hydrogel or demineralized matrix, the hybrid biomaterial showed superior porosity, equilibrium swelling and degradation rate. The hybrid scaffolds exhibited an increased mechanical strength: 75% and 30% higher compared with pure hydrogels and demineralized matrix, respectively. After three days culture, bone-derived mesenchymal stem cells (BMSCs) maintained viability above 90% in all three materials; however, the cell retention of the hybrid scaffolds was more efficient and uniform than the other materials. Matrix production and chondrogenic differentiation of BMSCs in the hybrid scaffolds were superior to its precursors, based on glycosaminoglycan quantification and hyaline cartilage marker expression after three weeks in culture. Its easy preparation, favourable biophysical properties and chondrogenic capacity indicated that this solid-supported thermogel could be an attractive biomaterial framework for cartilage tissue engineering. PMID- 24770945 TI - Nursing interventions in cases of agitation and dementia. AB - This study had two objectives: firstly, to assess and compare the frequency and circumstances of agitation and, secondly, to generate decision-making aids for the treatment of agitation patients by applying a nursing intervention in cases of dementia and agitation. For that purpose, 1002 measurements of open nursing interventions in cases of agitation were obtained over a period of 11 weeks in two nursing homes in the city of Zurich and in the nursing home Sonnweid. Before, during and after two intervention periods of four weeks each, data were collected for 60 persons suffering from severe dementia. The results show that two-thirds of the residents were never agitated, one-quarter was moderately agitated and only very few suffered from medium-to-severe agitation. In almost half the cases, agitation occurred while the person was alone (46%), followed by cases of agitation as a constant state (26%). There was rarely any agitation while the residents were engaged in activities. After analysing 433 documented cases, it turned out that the most successful care interventions were avoiding noise, accompanying the person to the toilet, communication/validation, walking about/movement and administering beverages. Being based on newly translated observational methods and a unique longitudinal study design with combined intervention, this study provides important insights into how agitation in dementia can be influenced within the care context, as well as a practical evaluation of interventions specific to different institutions. PMID- 24770946 TI - How a creative storytelling intervention can improve medical student attitude towards persons with dementia: a mixed methods study. AB - BACKGROUND: The creative arts can integrate humanistic experiences into geriatric education. This experiential learning case study evaluated whether medical student participation in TimeSlips, a creative storytelling program with persons affected by dementia, would improve attitudes towards this patient population. METHODS: Twenty-two fourth-year medical students participated in TimeSlips for one month. The authors analyzed pre- and post-program scores of items, sub domains for comfort and knowledge, and overall scale from the Dementia Attitudes Scale using paired t-tests or Wilcoxon Signed-rank tests to evaluate mean change in students' self-reported attitudes towards persons with dementia. A case study approach using student reflective writing and focus group data was used to explain quantitative results. RESULTS: Twelve of the 20 items, the two sub domains, and the overall Dementia Attitudes Scale showed significant improvement post-intervention. Qualitative analysis identified four themes that added insight to quantitative results: (a) expressions of fear and discomfort felt before storytelling, (b) comfort experienced during storytelling, (c) creativity and openness achieved through storytelling, and (d) humanistic perspectives developed during storytelling can influence future patient care. CONCLUSIONS: This study provides preliminary evidence that participation in a creative storytelling program improves medical student attitudes towards persons with dementia, and suggests mechanisms for why attitudinal changes occurred. PMID- 24770947 TI - Drug use and sexual risk among gay and bisexual men who frequent party venues. AB - Research connecting club drug use to risky sex among gay/bisexual men (GBM) contains methodological issues that have limited knowledge about the relative risks of distinct drugs. This paper reports drug use and sexual behavior data from 197 GBM who frequented at least one party venue within 3 months of participating. Alarming rates of drug use and unprotected anal intercourse (UAI) with casual sex-partners were reported in connection with time spent at a bar, club or circuit party. Structural equation modeling revealed that use of methamphetamine, gammahydroxybutrate (GHB), and/or ketamine (K), but not use of ecstasy, at a party venue helped explain likelihood of UAI with a casual sex partner while under the influence of a drug during/following time partying (beta = 0.41, p < .01). Findings suggest use of methamphetamine, GHB and/or K at party venues increases risk for subsequent UAI with casual sex-partners. Study implications, limitations, and recommendations for future research are discussed. PMID- 24770948 TI - Improving the counselling skills of lay counsellors in antiretroviral adherence settings: a cluster randomised controlled trial in the Western Cape, South Africa. AB - Little research has investigated interventions to improve the delivery of counselling in health care settings. We determined the impact of training and supervision delivered as part of the Options: Western Cape project on lay antiretroviral adherence counsellors' practice. Four NGOs employing 39 adherence counsellors in the Western Cape were randomly allocated to receive 53 h of training and supervision in Options for Health, an intervention based on the approach of Motivational Interviewing. Five NGOs employing 52 adherence counsellors were randomly allocated to the standard care control condition. Counselling observations were analysed for 23 intervention and 32 control counsellors. Intervention counsellors' practice was more consistent with a client centred approach than control counsellors', and significantly more intervention counsellors engaged in problem-solving barriers to adherence (91 vs. 41 %). The Options: Western Cape training and supervision package enabled lay counsellors to deliver counselling for behaviour change in a manner consistent with evidence based approaches. PMID- 24770949 TI - Characterization of the human cumulus cell transcriptome during final follicular maturation and ovulation. AB - Cumulus expansion and oocyte maturation are central processes in ovulation. Knowledge gained from rodent and other mammalian models has revealed some of the molecular pathways associated with these processes. However, the equivalent pathways in humans have not been thoroughly studied and remain unidentified. Compact cumulus cells (CCs) from germinal vesicle cumulus oocyte complexes (COCs) were obtained from patients undergoing in vitro maturation (IVM) procedures. Expanded CCs from metaphase 2 COC were obtained from patients undergoing IVF/ICSI. Global transcriptome profiles of the samples were obtained using state of-the-art RNA sequencing techniques. We identified 1746 differentially expressed (DE) genes between compact and expanded CCs. Most of these genes were involved in cellular growth and proliferation, cellular movement, cell cycle, cell-to-cell signaling and interaction, extracellular matrix and steroidogenesis. Out of the DE genes, we found 89 long noncoding RNAs, of which 12 are encoded within introns of genes known to be involved in granulosa cell processes. This suggests that unique noncoding RNA transcripts may contribute to the regulation of cumulus expansion and oocyte maturation. Using global transcriptome sequencing, we were able to generate a library of genes regulated during cumulus expansion and oocyte maturation processes. Analysis of these genes allowed us to identify important new genes and noncoding RNAs potentially involved in COC maturation and cumulus expansion. These results may increase our understanding of the process of oocyte maturation and could ultimately improve the efficacy of IVM treatment. PMID- 24770951 TI - Use of a tracheal tube introducer guide to facilitate difficult intubation with a video laryngoscope. PMID- 24770950 TI - Uterine epithelial cell proliferation and endometrial hyperplasia: evidence from a mouse model. AB - In the uterus, epithelial cell proliferation changes during the estrous cycle and pregnancy. Uncontrolled epithelial cell proliferation results in implantation failure and/or cancer development. Transforming growth factor-beta (TGF-beta) signaling is a fundamental regulator of diverse biological processes and is indispensable for multiple reproductive functions. However, the in vivo role of TGF-beta signaling in uterine epithelial cells remains poorly defined. We have shown that in the uterus, conditional deletion of the Type 1 receptor for TGF beta (Tgfbr1) using anti-Mullerian hormone receptor type 2 (Amhr2) Cre leads to myometrial defects. Here, we describe enhanced epithelial cell proliferation by immunostaining of Ki67 in the uteri of these mice. The aberration culminated in endometrial hyperplasia in aged females. To exclude the potential influence of ovarian steroid hormones, the proliferative status of uterine epithelial cells was assessed following ovariectomy. Increased uterine epithelial cell proliferation was also revealed in ovariectomized Tgfbr1 Amhr2-Cre conditional knockout mice. We further demonstrated that transcript levels for fibroblast growth factor 10 (Fgf10) were markedly up-regulated in Tgfbr1 Amhr2-Cre conditional knockout uteri. Consistently, treatment of primary uterine stromal cells with TGF-beta1 significantly reduced Fgf10 mRNA expression. Thus, our findings suggest a potential involvement of TGFBR1-mediated signaling in the regulation of uterine epithelial cell proliferation, and provide genetic evidence supporting the role of uterine epithelial cell proliferation in the pathogenesis of endometrial hyperplasia. PMID- 24770952 TI - Prognostic factors that govern localized synovial sarcoma: a single institution retrospective study on 51 patients. AB - Synovial sarcoma is a rare type of sarcoma with poor prognosis. Data on relevant prognostic factors are inconsistent. The objective of this study was to determine the independent prognostic factors that govern local recurrence, distant metastasis and overall survival. A retrospective analysis of 51 patients treated for localized synovial sarcoma at a single institution by a multidisciplinary/multimodality approach over a period of 12 years. Patients, tumor and treatment characteristics were collected including age, sex, tumor site, location, depth, size, status of margins, histology subtype and involvement of bone or lymph nodes. Type of surgery, adjuvant chemotherapy and radiotherapy were also examined. The endpoints analyzed were local recurrence-free survival (LRFS), metastasis-free survival (MFS) and overall survival (OS). Median age of patients was 26 years (range 3-64 years) with 73 % above the age of 20 year. All patients received surgery, 57 % received adjuvant radiotherapy and 45 % adjuvant chemotherapy. The median survival was 111 months, and 5-year OS was 73 %. Deep seatedness of the tumor was linked to OS as the only independent risk factor. Twelve patients had local recurrence, and the 5-year LRFS was 61 %. Multivariate analysis determined negative margins and adjuvant radiotherapy as independent predicting factors for LRFS. Five-year MFS was 48 %; multivariate analysis identified monophasic subtype and site other than lower extremity as the only independent factors associated with inferior MFS. The most important factors that govern LRFS and MFS are negative margins and adjuvant radiotherapy for LRFS and tumor histology and site for MFS, while deep seatedness of the tumor is the sole independent factor that governs OS. PMID- 24770953 TI - Knowledge, perception and utilization of postnatal care of mothers in Gondar Zuria District, Ethiopia: a cross-sectional study. AB - Mothers and their newborns are vulnerable to illnesses and deaths during the postnatal period. More than half a million women each year die of causes related to pregnancy and childbirth. The majority of deaths occur in less developed countries. Utilization of postnatal care (PNC) service in Ethiopia is low due to various factors. These problems problem significantly hold back the goal of decreasing maternal and child mortality. To assess mothers' knowledge, perception and utilization of PNC in the Gondar Zuria District, Ethiopia. Our study is a community-based, cross-sectional study supported by a qualitative study conducted among 15-49 years mothers who gave birth during the last year. A multistage sampling technique was used to selected participants; structured questionnaires and focus group discussions were used to collect data. Data were entered into EPI info version 3.5.1 and exported into SPSS version 16.0 for the quantitative study and thematic framework analysis was applied to the qualitative portion. The majority of the women (84.39 %) were aware and considered PNC necessary (74.27 %); however, only 66.83 % of women obtained PNC. The most frequent reasons for not obtaining PNC were lack of time (30.47 %), long distance to a provider (19.25 %), lack of guardians for children care (16.07 %), and lack of service (8.60 %). Based on the multivariate analysis, place of residence (AOR 2.68; 95 % CI 1.45 4.98), distance from a health institution (AOR 2.21; 95 % CI 1.39-3.51), antenatal care visit (AOR 2.60; 95 % CI 1.40-5.06), and having decision-making authority for utilization (AOR 1.86; 95 % CI 1.30-2.65) were factors found to be significantly associated with PNC utilization. Mothers in the study area had a high level of awareness and perception about the necessity of PNC. Urban women and those who displayed higher levels of autonomy were more likely to use postnatal health services. PMID- 24770954 TI - Validation of self-reported maternal and infant health indicators in the Pregnancy Risk Assessment Monitoring System. AB - To assess the validity of self-reported maternal and infant health indicators reported by mothers an average of 4 months after delivery. Three validity measures-sensitivity, specificity and positive predictive value (PPV)-were calculated for pregnancy history, pregnancy complications, health care utilization, and infant health indicators self-reported on the Pregnancy Risk Assessment Monitoring System (PRAMS) questionnaire by a representative sample of mothers delivering live births in New York City (NYC) (n = 603) and Vermont (n = 664) in 2009. Data abstracted from hospital records served as gold standards. All data were weighted to be representative of women delivering live births in NYC or Vermont during the study period. Most PRAMS indicators had >90 % specificity. Indicators with >90 % sensitivity and PPV for both sites included prior live birth, any diabetes, and Medicaid insurance at delivery, and for Vermont only, infant admission to the NICU and breastfeeding in the hospital. Indicators with poor sensitivity and PPV (<70 %) for both sites (i.e., NYC and Vermont) included placenta previa and/or placental abruption, urinary tract infection or kidney infection, and for NYC only, preterm labor, prior low-birth-weight birth, and prior preterm birth. For Vermont only, receipt of an HIV test during pregnancy had poor sensitivity and PPV. Mothers accurately reported information on prior live births and Medicaid insurance at delivery; however, mothers' recall of certain pregnancy complications and pregnancy history was poor. These findings could be used to prioritize data collection of indicators with high validity. PMID- 24770955 TI - Determinants of cesarean delivery in the US: a lifecourse approach. AB - This study takes a lifecourse approach to understanding the factors contributing to delivery methods in the US by identifying preconception and pregnancy-related determinants of medically indicated and non-medically indicated cesarean section (C-section) deliveries. Data are from the Early Childhood Longitudinal Study Birth Cohort, a nationally representative, population-based survey of women delivering a live baby in 2001 (n = 9,350). Three delivery methods were examined: (1) vaginal delivery (reference); (2) medically indicated C-section; and (3) non medically indicated C-sections. Using multinomial logistic regression, we examined the role of sociodemographics, health, healthcare, stressful life events, pregnancy complications, and history of C-section on the odds of medically indicated and non-medically indicated C-sections, compared to vaginal delivery. 74.2 % of women had a vaginal delivery, 11.6 % had a non-medically indicated C-section, and 14.2 % had a medically indicated C-section. Multivariable analyses revealed that prior C-section was the strongest predictor of both medically indicated and non-medically indicated C-sections. However, we found salient differences between the risk factors for indicated and non indicated C-sections. Surgical deliveries continue to occur at a high rate in the US despite evidence that they increase the risk for morbidity and mortality among women and their children. Reducing the number of non-medically indicated C sections is warranted to lower the short- and long-term risks for deleterious health outcomes for women and their babies across the lifecourse. Healthcare providers should address the risk factors for medically indicated C-sections to optimize low-risk delivery methods and improve the survival, health, and well being of children and their mothers. PMID- 24770956 TI - Effects of maternity care coordination on pregnancy outcomes: propensity-weighted analyses. AB - Care coordination services that link pregnant women to health-promoting resources, avoid duplication of effort, and improve communication between families and providers have been endorsed as a strategy for reducing disparities in adverse pregnancy outcomes, however empirical evidence regarding the effects of these services is contradictory and incomplete. This study investigates the effects of maternity care coordination (MCC) on pregnancy outcomes in North Carolina. Birth certificate and Medicaid claims data were analyzed for 7,124 women delivering live infants in North Carolina from October 2008 through September 2010, of whom 2,255 received MCC services. Propensity-weighted analyses were conducted to reduce the influence of selection bias in evaluating program participation. Sensitivity analyses compared these results to conventional ordinary least squares analyses. The unadjusted preterm birth rate was lower among women who received MCC services (7.0 % compared to 8.3 % among controls). Propensity-weighted analyses demonstrated that women receiving services had a 1.8 % point reduction in preterm birth risk; p < 0.05). MCC services were also associated with lower pregnancy weight gain (p = 0.10). No effects of MCC were seen for birthweight. These findings suggest that coordination of care in pregnancy can significantly reduce the risk of preterm delivery among Medicaid enrolled women. Further research evaluating specific components of care coordination services and their effects on preterm birth risk among racial/ethnic and geographic subgroups of Medicaid enrolled mothers could inform efforts to reduce disparities in pregnancy outcome. PMID- 24770957 TI - Preparation of immobilized whole cell biocatalyst and biodiesel production using a packed-bed bioreactor. AB - Rhizopus oryzae NBRC 4697 was selected from among promising candidates as a biocatalyst for biodiesel production. This microorganism was immobilized on to polyurethane foam coated with activated carbon for reuse, and, for biodiesel production. Vacuum drying of the immobilized cells was found to be more efficient than natural or freeze-drying processes. Although the immobilized cells were severely inhibited by a molar ratio of methanol to soybean oil in excess of 2.0, stepwise methanol addition (3 aliquots at 24-h feeding intervals) significantly prevented methanol inhibition. A packed-bed bioreactor (PBB) containing the immobilized whole cell biocatalyst was then operated under circulating batch mode. Stepwise methanol feeding was used to mitigate methanol inhibition of the immobilized cells in the PBB. An increase in the feeding rate (circulating rate) of the reaction mixture barely affected biodiesel production, while an increase in the packing volume of the immobilized cells enhanced biodiesel production noticeably. Finally, repeated circulating batch operation of the PBB was carried out for five consecutive rounds without a noticeable decrease in the performance of the PBB for the three rounds. PMID- 24770958 TI - The Potential of the Imitation Game Method in Exploring Healthcare Professionals' Understanding of the Lived Experiences and Practical Challenges of Chronically Ill Patients. AB - This paper explores the potential and relevance of an innovative sociological research method known as the Imitation Game for research in health care. Whilst this method and its potential have until recently only been explored within sociology, there are many interesting and promising facets that may render this approach fruitful within the health care field, most notably to questions about the experiential knowledge or 'expertise' of chronically ill patients (and the extent to which different health care professionals are able to understand this experiential knowledge). The Imitation Game can be especially useful because it provides a way to map this experiential knowledge more systematically, without falling in the dual trap of either over-relying on in-depth, but highly specific phenomenological 'insider'-approaches that are hard to generalize, or, alternatively, problematically reducing the rich life-worlds of patients to a set of indicators in a questionnaire. The main focus of this paper is theoretical and conceptual: explaining the Imitation Game method, discussing its usefulness in the health care domain, and exploring the ways in which the approach can be utilized for chronic illness care. The paper presents both a conceptual and empirical exploration of how the Imitation Game method and its underlying theoretical concepts of 'contributory expertise' and 'interactional expertise' can be transferred from the sociological realm to the field of health care, what kinds of insights can be gained from the method, which methodological issues it may raise, and what potentially fruitful research routes can be explored. I argue that the Imitation Game can be thought of as a 'social learning experiment' that simultaneously enables the participants to learn from each other's perspectives, allows researchers to explore exciting new possibilities, and also offers the tools to intervene in the practice that is being studied. PMID- 24770960 TI - Alcohol percutaneous neurolysis of the sphenopalatine ganglion in the management of refractory cranio-facial pain. AB - INTRODUCTION: The sphenopalatine ganglion (SPN) has been proven to be involved in various types of facial pain syndromes. Management of these cranio-facial pain syndromes can be challenging, and existing specific treatments are sometimes inefficient and may fail. The purpose of this study is to describe and evaluate alcohol SPN in the management of cranio-facial pain. METHODS: Forty-two patients suffering from refractory facial pain who underwent 58 consecutive SPN were included in this study between 2000 and 2013. Patients were divided into three groups: group "cluster headache" (CH), group "persistent idiopathic facial pain" (PFIP), and group "Other". Pain was assessed using Visual Analogue Scale scores (measured immediately before and after procedure and at regular intervals following the procedure). Alcohol SPN was considered to be effective when pain relief was equal to or greater than 50 % and lasting for at least 1 month. All procedures were realized ambulatory under CT guidance and consisted of an injection of 1 ml of absolute alcohol. RESULTS: Overall efficacy rate of alcohol SPN was 67.2 %, with mean pain relief duration of 10.3 months. Procedure was graded either not painful or tolerable by patients in 64.2 %. Analysis showed a higher efficacy rate in the groups CH (76.5 %) and PFIP (85.7 %) compared to the group Other (40 %). No difference was found between groups regarding the recurrence rate. CONCLUSION: Alcohol SPN under CT guidance appears as a safe and effective treatment of refractory facial pain, especially in cases of cluster headache and persistent idiopathic facial pain. PMID- 24770961 TI - D-Aminoacylase-initiated cascade Aldol condensation/Robinson annulation for synthesis of substituted cyclohex-2-enones from simple aldehydes and acetone. AB - As an important building block, developing efficient and green synthesis strategy of cyclohex-2-enones is of great importance. In this present work, a general approach to the mild synthesis of substituted cyclohex-2-enones derivatives starting fro m simple aldehydes and acetone have been achieved via D-aminoacylase initiated Aldol condensation/Robinson annulation cascade reaction using imidazole as an additive in organic media. The influences of reaction conditions including solvents, enzyme concentration, additives type, molar ratio of enzyme to additive, and substrate scopes were systematically investigated. Furthermore, some experiments were designed to explore the catalytic roles of D-aminoacylase and imidazole in the multistep cascade process, and one possible mechanism was proposed. PMID- 24770963 TI - Endoscopic retrograde cholangiopancreatography using a cap-assisted highly flexible colonoscope in patients with Roux-en-Y anastomosis. AB - In this retrospective study of 10 patients with Roux-en-Y anastomosis, endoscopic retrograde cholangiopancreatography (ERCP) using a cap-assisted thin highly flexible colonoscope was done for treatment of bile duct stones. In five patients, the papilla of Vater was successfully reached using the colonoscope alone. However, in the other five patients, combination with an overtube was needed to reach the papilla. In all cases, complete removal of bile duct stones was accomplished. Procedure-related adverse events occurred in two cases. In conclusion, use of a cap-assisted thin highly flexible colonoscope for ERCP was successful in patients with a Roux-en-Y anastomosis. PMID- 24770965 TI - Esophageal submucosal dissection under steady pressure automatically controlled endoscopy (SPACE): a clinical feasibility study. AB - BACKGROUND AND STUDY AIMS: Steady pressure automatically controlled endoscopy (SPACE) is a new insufflation system that provides constant carbon dioxide (CO2) insufflation pressure during prolonged procedures. The system consists of an overtube, a surgical insufflator, and a newly developed leak-proof valve. The aims of this study were to validate the feasibility and safety of SPACE for esophageal endoscopic submucosal dissection (ESD). PATIENTS AND METHODS: This was a clinical phase I trial, involving 10 patients who underwent esophageal ESD. The primary end point was the rate of adverse events within 30 days (grade 0 to 4). Secondary end points were changes in partial pressure of carbon dioxide (PaCO2) and vital signs during ESD, completion rate of ESD, and degree of abdominal distension by patient assessment and radiographic grading. RESULTS: All adverse events were Grade 2 or less. Mild PaCO2 elevation after ESD was noted; however, no associated symptoms were reported. The procedure was completed under SPACE alone in 8 of 10 patients. Minimal post-procedural bowel distension was observed. CONCLUSIONS: In this small pilot study, SPACE was feasible and appeared to be safe. Further study with larger case numbers is required to demonstrate efficacy and safety. CLINICAL TRIAL REGISTRATION: UMIN000005434. PMID- 24770964 TI - Routine use of Hemospray for gastrointestinal bleeding: prospective two-center experience in Switzerland. AB - Hemospray (Cook Medical, Winston-Salem, North Carolina, USA) is a hemostatic agent recently introduced for the management of upper gastrointestinal bleeding (GIB). To date, there is little experience with this fairly new hemostatic tool. The aim of this case series was to reflect the use and effectiveness of Hemospray as a treatment option in GIB in everyday clinical practice at two tertiary referral centers. Consecutive patients (n = 16) with active GIB of various origins were treated with Hemospray. The rate of successful initial hemostasis was 93.75 % (15 /16; salvage therapy 92.85 % [13/14]; monotherapy 100 % [2 /2]). The rebleeding rate within 7 days was 12.5 % (2/16). One patient, in whom interventional radiology also failed, had to undergo surgery as salvage therapy. The effectiveness of Hemospray in the management of GIB in various clinical situations is promising. Future multicenter randomized prospective trials for clearly defined bleeding situations are needed for greater generalizability of case series findings. PMID- 24770966 TI - Suppression of stent-induced tissue hyperplasia in rats by using small interfering RNA to target matrix metalloproteinase-9. AB - BACKGROUND AND STUDY AIMS: We evaluated the efficacy of small interfering RNA (siRNA) in targeting matrix metalloproteinase (MMP-9) to suppress stent-induced tissue hyperplasia in a rat esophageal model. METHODS: The silencing effect of the candidate siRNA (termed (MMP-9 siRNA) was evaluated in 9 L rat glial cells. Four groups of rats (n = 10, each group) were used: Eso-S, stent insertion only, comparison; Eso-R, stent insertion plus treatment with MMP-9 siRNA complexed with Chol-R9 for delivery, experimental; Eso-P, stent insertion plus treatment with pCMV-luc complexed with Chol-R9, for confirmation of Chol-R9 delivery effect; and Eso-N, no stent insertion and no treatment, controls. All rats were sacrificed at 3 weeks. The therapeutic efficacy of the MMP-9 siRNA/Chol-R9 complex was assessed. RESULTS: The most potent MMP-9 siRNA was selected. Compared with the Eso-S group, the Eso-R group showed significantly less tissue hyperplasia with a lower percentage of granulation tissue and smaller granulation tissue area, and also significantly lower MMP-9 level. CONCLUSIONS: MMP-9 siRNA/Chol-R9 is effective for inhibiting stent-induced tissue hyperplasia in a rat esophageal model. PMID- 24770967 TI - A novel viscous dissecting gel for endoscopic submucosal dissection: a prospective survival study in a porcine model. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is a technically challenging procedure. A novel gel can facilitate ESD due to its submucosal dissecting properties. This prospective porcine survival study evaluated clinical and histologic parameters of hybrid ESD using the gel. PATIENTS AND METHODS: Gastric submucosal lesions were created in six pigs and hybrid ESD was performed. Healing was assessed weekly until necropsy at Day 28. RESULTS: En bloc resection was achieved in all lesions (mean size 40.7 mm). The mean total procedure time was 13.5 minutes and the mean resection time was 5.5 minutes. The mean total histologic injury score was 4. At necropsy, four ulcers had healed completely and two were < 6 mm in size. CONCLUSION: Hybrid ESD of large gastric lesions in a porcine model can be facilitated by the novel gel, dramatically reducing procedure and resection times by eliminating the need for time-consuming submucosal dissection. The novel gel is safe and easy to use, and has the potential to simplify ESD. Further prospective human studies are needed to validate these findings. PMID- 24770968 TI - Endoscopic removal of over-the-scope clips using a novel cutting device: a retrospective case series. AB - BACKGROUND AND STUDY AIMS: Over-the-scope clips (OTSCs; Ovesco Endoscopy, Tubingen, Germany) are extensively used for treatment of gastrointestinal perforations, leakages, fistulas, and bleeding. In this report, a new method of removing OTSCs using a prototype bipolar cutting device is described. PATIENTS AND METHODS: A total of 11 patients underwent endoscopic removal of an OTSC. The OTSC was cut at two opposing sites by a prototype device (DC ClipCutter; Ovesco Endoscopy). The remaining clip fragments were extracted using a standard forceps. RESULTS: Mean procedure time was 47 minutes (range 35 - 75 minutes). Cutting of the OTSC at two opposing sites was successful in all cases (100 %). Complete retrieval of all clip fragments was possible in 10 patients (91 %). The overall success rate for cutting and complete removal of the clip was 91 %. No major complications were observed. CONCLUSIONS: Removal of OTSCs with the prototype device was feasible and effective. The device may be valuable for OTSC removal in emergency as well as elective indications. PMID- 24770969 TI - Endoscopic submucosal dissection using a new scissors-type electrosurgical knife: a first-in-human feasibility study. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) is more difficult and has a higher rate of complications, such as perforation and bleeding, compared with conventional endoscopic resection. The aim of this study was to evaluate the feasibility of a new scissors-type electrosurgical knife for ESD, which was developed for improved durability and ease of use. MATERIALS AND METHODS: Initial ex vivo experiments and subsequent ESD procedures in live pigs were carried out. A human feasibility study was then performed in patients with early esophageal or gastric cancer. The primary end point was serious adverse events (SAE) related to ESD. RESULTS: In the ex vivo and live animal models, no mechanical errors occurred and only minor damage to surrounding tissue was observed. Four patients were enrolled in the human feasibility study; all ESD procedures were completed with a mean procedure time of 31 minutes. All specimens were resected completely without any SAEs. The device worked smoothly, with no electrical problems noted. CONCLUSION: ESD using a novel scissors-type knife for early esophageal or gastric cancer is feasible. CLINICAL TRIAL REGISTRATION: UMIN000004941. PMID- 24770970 TI - Acute renal failure following oral sodium phosphate bowel preparation: a nationwide case-crossover study. AB - BACKGROUND AND STUDY AIMS: Oral sodium phosphate (OSP) is a cleansing agent for colonoscopy. Recent reports have cited an increased risk of acute renal failure (ARF) in OSP bowel purgative users, but this risk remains under debate. This study was performed to evaluate the association between OSP and ARF in patients who underwent colonoscopy. PATIENTS AND METHODS: A population-based case crossover study was conducted using the Korean Health Insurance Review and Assessment Service (HIRA) claims data from 1 January 2005 to 31 December 2009. The study population consisted of patients aged >= 50 years who underwent colonoscopies after an OSP prescription prior to their first hospitalization for ARF. For each patient, one hazard and four control periods were matched at specified time windows. Conditional logistic regression analysis was used to estimate the odds ratio (OR) and 95 % confidence interval (CI), adjusting for concomitant medications that could induce ARF. RESULTS: A total of 1105 patients were included (54 % male). The adjusted ORs for ARF related to the use of OSP when applying the 1-, 2-, 4-, 8-, or 12-week time windows were 3.7 (95 %CI 2.37 - 5.67), 3.5 (95 %CI 2.45 - 4.89), 3.0 (95 %CI 2.30 - 3.95), 2.4 (95 %CI 1.93 - 2.96), and 2.0 (95 %CI 1.69 - 2.46), respectively. When adopting an 8-week time window, the adjusted OR was 2.5 (95 %CI 1.98 - 3.16) for the subgroup without chronic renal failure. CONCLUSIONS: The use of OSP was significantly associated with ARF both in patients with and without co-morbidities. PMID- 24770971 TI - Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel. AB - BACKGROUND AND STUDY AIMS: Endoscopic ultrasound (EUS)-guided ethanol lavage with paclitaxel injection has been shown to be effective for the treatment of pancreatic cystic neoplasms; however, the evidence for effectiveness is based primarily on cyst resolution on imaging. The aim of this study was to evaluate changes in pancreatic cyst fluid DNA following EUS-guided pancreatic cyst ablation (PCA) with ethanol and paclitaxel. PATIENTS AND METHODS: In a single center, prospective study, patients with suspected benign pancreatic cysts (15 - 50 mm in diameter; <= 5 compartments) underwent EUS-PCA with ethanol and paclitaxel followed 3 months later by repeat EUS-FNA, cyst aspiration for repeat DNA analysis, and possible repeat EUS-PCA. Abdominal imaging was repeated 3 - 4 months and 12 months after the second EUS. Changes in baseline pancreatic cyst fluid DNA, procedural complications, and radiographic changes in cyst volume were evaluated. RESULTS: A total of 22 patients (median age 67 years; 15 women) with cysts in the head or uncinate (n = 10), body or neck (n = 8), and tail (n = 4), measuring a median diameter of 25 mm (range 15 - 43 mm), underwent one (n = 22) or two (n = 9) EUS-PCA procedures. Baseline cyst DNA included mutations in 11 patients (50 %). Postablation cyst fluid (n = 19) showed elimination of all baseline mutations in eight patients, new mutations in three, and no changes in eight without a baseline mutation. The largest per-protocol postablation image defined volume change (n = 20) from either of the follow-up abdominal imaging studies (n = 20) demonstrated complete response ( < 5 % original volume) in 10 patients (50 %), partial response (5 % - 25 % original volume) in 5 (25 %), and a persistent cyst (> 25 % original volume) in 5 (25 %). During a median follow-up of 27 months (range 17 - 42 months), adverse events from all EUS-PCAs (n = 31) included abdominal pain alone in four patients (13 %), pancreatitis in three (10 %), peritonitis in one (3 %), and gastric wall cyst in one (3 %). The adverse events were classified as moderately severe in four patients (three with pancreatitis, one with peritonitis). CONCLUSION: EUS-PCA with ethanol and paclitaxel may possibly eliminate mutant DNA in neoplastic pancreatic cysts. This technique leads to complete or partial image-defined resolution in 75 % of cysts but may lead to rare adverse events. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT01643460). PMID- 24770972 TI - Development and initial validation of an endoscopic part-task training box. AB - BACKGROUND AND STUDY AIMS: There is currently no objective and validated methodology available to assess the progress of endoscopy trainees or to determine when technical competence has been achieved. The aims of the current study were to develop an endoscopic part-task simulator and to assess scoring system validity. METHODS: Fundamental endoscopic skills were determined via kinematic analysis, literature review, and expert interviews. Simulator prototypes and scoring systems were developed to reflect these skills. Validity evidence for content, internal structure, and response process was evaluated. RESULTS: The final training box consisted of five modules (knob control, torque, retroflexion, polypectomy, and navigation and loop reduction). A total of 5 minutes were permitted per module with extra points for early completion. Content validity index (CVI)-realism was 0.88, CVI-relevance was 1.00, and CVI representativeness was 0.88, giving a composite CVI of 0.92. Overall, 82 % of participants considered the simulator to be capable of differentiating between ability levels, and 93 % thought the simulator should be used to assess ability prior to performing procedures in patients. Inter-item assessment revealed correlations from 0.67 to 0.93, suggesting that tasks were sufficiently correlated to assess the same underlying construct, with each task remaining independent. Each module represented 16.0 % - 26.1 % of the total score, suggesting that no module contributed disproportionately to the composite score. Average box scores were 272.6 and 284.4 (P = 0.94) when performed sequentially, and average score for all participants with proctor 1 was 297.6 and 308.1 with proctor 2 (P = 0.94), suggesting reproducibility and minimal error associated with test administration. CONCLUSION: A part-task training box and scoring system were developed to assess fundamental endoscopic skills, and validity evidence regarding content, internal structure, and response process was demonstrated. PMID- 24770973 TI - Extracellular H+ induces Ca2+ signals in respiratory chemoreceptors of zebrafish. AB - Neuroepithelial cells (NECs) of the fish gill are respiratory chemoreceptors that detect changes in O2 and CO2/H(+) and are homologous to type I cells of the mammalian carotid body. In zebrafish (Danio rerio), stimulation of NECs by hypoxia or hypercapnia initiates inhibition of K(+) channels and subsequent membrane depolarisation. The goal of the present study was to further elucidate, in zebrafish NECs, the signalling pathways that underlie CO2/H(+) sensing and generate intracellular Ca(2+) ([Ca(2+)]i) signals. Breathing frequency was elevated maximally in fish exposed to 5 % CO2 (~37.5 mmHg). Measurement of [Ca(2+)]i in isolated NECs using Fura-2 imaging indicated that [Ca(2+)]i increased in response to acidic hypercapnia (5 % CO2, pH 6.6) and isocapnic acidosis (normocapnia, pH 6.6), but not to isohydric hypercapnia (5 % CO2, pH 7.6). Measurement of intracellular pH (pHi) using BCECF demonstrated a rapid decrease in pHi in response to acidic and isohydric hypercapnia, while isocapnic acidosis produced a smaller change in pHi. Intracellular acidification was reduced by the carbonic anhydrase inhibitor, acetazolamide, without affecting [Ca(2+)]i responses. Moreover, intracellular acidification using acetate (at constant extracellular pH) was without effect on [Ca(2+)]i. The acid-induced increase in [Ca(2+)]i persisted in the absence of extracellular Ca(2+) and was unaffected by Ca(2+) channel blockers (Cd(2+), Ni(2+) or nifedipine). The results of this study demonstrate that, unlike type I cells, extracellular H(+) is critical to the hypercapnia-induced increase in [Ca(2+)]i in NECs. The increase in [Ca(2+)]i occurs independently of pHi and appears to originate primarily from Ca(2+) derived from intracellular stores. PMID- 24770974 TI - The importance of nitric oxide and arginase in the pathogenesis of acute neuroinflammation: are those contra players with the same direction? AB - To investigate the concentrations of nitric oxide (NO) products (NOx) and arginase activity in acute neuroinflammation, we analyzed cerebrospinal fluid (CSF) and plasma of clinically isolated syndrome (CIS) and relapsing remitting multiple sclerosis (RRMS) patients, who were divided into groups on the basis of clinical and radiological disease activity. The NOx levels, in both, CSF and plasma, were increased in CIS (p = 0.0015, p = 0.0014, respectively) and RRMS group (p = 0.002, p = 0.0019, respectively), while arginase activity approached low levels, in CIS (p = 0.009, p = 0.02, respectively) and RRMS group (p = 0.018, p = 0.034, respectively) compared to controls. The NOx levels were higher in CSF and plasma of CIS than in RRMS group (p = 0.065, p = 0.037, respectively), inverse to arginase activity which was higher, in CSF and plasma, in RRMS than in CIS group (p = 0.031, p = 0.02, respectively). The CSF and plasma NOx values positively correlated with the clinical disease activity in CIS (r = 0.09, p = 0.81; r = 0.45, p = 0.023, respectively) and RRMS group (r = 0.311, p = 0.04; r = 0.512, p = 0.01, respectively). Also, CSF and plasma arginase activity showed negative correlation with clinical disease activity in CIS (r = 0.39, p = 0.03; r = 0.1, p = 0.65, respectively) and RRMS group (r = 0.43, p = 0.03; r = 0.62, p = 0.015, respectively). The CSF NOx levels showed positive correlation with volume of acute radiological lesions of CNS in CIS (r = 0.25, p = 0.045) and RRMS group (r = 0.31, p = 0.04), while arginase activity showed the negative correlations in CIS (r = 0.41; p = 0.035) and RRMS group (r = 0.52, p = 0.022). The results support NO and arginase involvement in the pathogenesis of acute neuroinflammation, which determination may be useful as surrogate markers for clinical and radiological disease activity. PMID- 24770975 TI - Validating the content of a brief informational intervention to empower patients and spouses facing breast cancer: perspectives of both couple members. AB - PURPOSE: The study objectives were to identify key information components that would be the basic content of a brief informational intervention, developed from a population perspective, to empower individual couple members facing breast cancer and to validate the relevance and acceptability of these components. METHODS: A review of information relevant to couples facing cancer presented in internet sites and documents of national cancer organizations was made to identify information components to include in a brief informational intervention. These information components were framed as messages, that is, very brief sentences or tips. To validate the relevance and acceptability of these messages, six focus groups were conducted in Quebec City and Montreal among women who had had breast cancer and their spouses. Reactions to the messages were synthesized by analyzing the verbatim transcripts. RESULTS: A total of 70 individuals (35 women with an average of 14 months since diagnosis and 35 spouses) participated in the groups. The content of almost all messages was seen as relevant, although nuances and improvements were discussed. However, the message format provoked irritation and will need improvement. CONCLUSIONS: Findings provide validation of the relevance, from the viewpoint of women and their spouses, of the message content to be part of a brief informational intervention intended to empower couples as they cope with breast cancer. IMPLICATIONS FOR CANCER SURVIVORS: Couples approved of the idea of being guided in their adjustment to breast cancer. However, the message format requires adaptation and further testing. PMID- 24770976 TI - [New direct oral anticoagulants : Many advantages, but open questions]. AB - In the past few years, the clinical field of anticoagulation has undergone dramatic changes due to the introduction of the new class of direct oral anticoagulants. All these agents share common features such as stable oral bioavailability, short half-life compared to vitamin K antagonists, paucity of drug-drug interactions, and fixed dosing without laboratory monitoring. However, the new agents differ regarding metabolism pathways, impact on routine clotting tests, availability of test systems for plasma concentration, and-of utmost clinical importance-dose regimens, clinical evidence, and approved indications.The present review outlines pharmacologic properties, clinical indications, different dose regimens, and preliminary clinical experience from their use in daily practice. Each of the four topics will be complemented by a compilation and in-depth discussion of open questions and lessons still to learn. The well-documented benefits of the direct oral anticoagulants as documented in clinical trials will translate to routine clinical practice only if all the rules regarding dosing and indications are obeyed, and if the experience with these agents is captured and communicated in a controlled manner. PMID- 24770977 TI - [Complications after allogeneic bone marrow and stem cell transplantation]. AB - Since the 1970s there has been an increase in the number of bone marrow and stem cell transplantations as well as a decrease in transplantation-associated fatalities due to improved transplantation techniques and supportive therapy. Annually nearly 50,000 transplantations are conducted worldwide with matched family grafts and matched or sometimes mismatched unrelated donor grafts. The number of long-term survivors is increasing and the late complications of this relatively aggressive therapy are now becoming apparent. This article is essentially concerned with the delayed complications of bone marrow and stem cell transplantations. Despite curing the malignant primary disease the total survival of transplantation patients is reduced. The main reasons are infection, organ dysfunction and therapy-associated secondary neoplasms. Among the high risk factors are total body irradiation, chronic graft versus host disease as well as treatment during childhood. Guidelines for the follow-up care of these long-term survivors were first published in 2006 and then updated in 2011. PMID- 24770978 TI - [Fever, atrial fibrillation, and angina pectoris in a 58-year-old man]. AB - Primary cardiac lymphoma (PCL) respresents a very rare type of cardiac tumour. This report illustrates a case of PCL in an immunocompetent 58-year-old man presenting with atrial fibrillation and febrile syndrome. Comprehensive imaging [computer tomography (CT), cardiac magnetic resonance imaging (cMRI), 3 dimensional transesophageal echocardiography (3D-TEE)] identified a large right atrial tumour, leading to pericardial effusion. Isolated cardiac involvement was confirmed by positron emission tomography (PET)-CT. A diffuse large B-cell lymphoma (DLBCL) was diagnosed based on the results of a TEE-guided biopsy. A normalized PET scan (PETAL study) indicated complete remission following R-CHOP 14 immunochemotherapy. Thus, an interdisciplinary and multimodal approach avoided unnecessary cardiac surgery. PMID- 24770979 TI - [New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk : Statement of the D*A*CH Society for Prevention of Cardiovascular Diseases, the Austrian Atherosclerosis Society and the Working Group on Lipids and Atherosclerosis (AGLA) of the Swiss Society for Cardiology]. AB - Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines. PMID- 24770981 TI - Insidious onset of Pisa syndrome after rasagiline therapy in a patient with Parkinson's disease. PMID- 24770980 TI - Therapeutic effect of taurine against aluminum-induced impairment on learning, memory and brain neurotransmitters in rats. AB - The aim of the study was to demonstrate the therapeutic effect of taurine against aluminum (Al)-induced neurological disorders in rats. Forty-two Wistar rats were randomly allotted into six groups: control (saline only), Al exposure (281.4 mg/kg/day for 1 month), Al + taurine (Al administration as previously plus taurine, doses were 200, 400 and 800 mg/kg/day, respectively, for the next 1 month) and prevention group (along with the Al administration as previously, 400 mg/kg/day taurine was treated for 1 month. During the next 1 month, rats were given taurine 400 mg/kg/day only). Starting from the sixth week, the body weight gain was significantly reduced in Al exposure group compared with saline (P < 0.05), and at the eighth week, the gain in prevention group was increased compared with Al (P < 0.05). Brain coefficient was gained in Al exposure compared with saline or prevention group (P < 0.05). Al exposure resulted in learning and memory impairment by increasing the escape latency and searching distance, meanwhile, decreasing the swimming time in the quadrant of platform and the numbers of crossing the platform (P < 0.05). Unsurprisingly, taurine treatment (400, 800 mg/kg/day and prevention) significantly protected against Al-induced brain dysfunction (P < 0.05). The Al exposure led to significant decreases in levels of gamma-GABA and Tau, meanwhile, increased in level of Asp and Glu compared with saline (P < 0.05). And yet, taurine treatment partially reversed the deteriorated changes. The results suggested that taurine probably has neuroprotective effect against Al-induced learning, memory and brain neurotransmitters dysfunction. PMID- 24770982 TI - A comparison of the anteromedial and transtibial drilling technique in ACL reconstruction after a short-term follow-up. AB - INTRODUCTION: The purpose of this study was to compare clinical and radiological outcomes of patients who underwent single-bundle anterior cruciate ligament (ACL) reconstruction with anteromedial portal (AMP) and transtibial (TT) techniques. MATERIALS AND METHODS: Arthroscopic single-bundle ACL reconstruction was performed using AMP technique in 34 patients and TT technique in 30 patients. The patients were evaluated retrospectively. Aperture fixation was used for femoral fixation, and absorbable screws and U staples were used for tibial fixation of the graft. Pivot shift test, Lachman test, Lysholm, Tegner, and International Knee Documentation Committee (IKDC-2000) scoring systems were used in the clinical and functional evaluation of patients before and after the surgery. Time to return sports and activity level were assessed. In the radiological evaluation of non-anatomic bone tunnel placement, the criteria developed by lllingworth et al. were used. The mean duration of follow-up was 20.4 and 24.6 months in the AMP and TT groups, respectively. RESULTS: There was a significant difference between the AMP group (86.7 %) and the TT (14.7 %) group in terms of anatomical placement of the femoral tunnels and grafts (p < 0.001). No significant difference was observed between the two groups in terms of the Pivot shift test, Lachman test, Lysholm, Tegner, and IKDC scores, and activity level (p > 0.05). The patients in the AMP group returned to sports 1.5 months earlier on average (p < 0.001). CONCLUSIONS: It was shown that AMP technique was superior to the TT technique in providing anatomical placement of the graft and in recovery time to return sports; however, there was no difference between groups in early periods in terms of the clinical and functional outcomes. PMID- 24770983 TI - The use of monitoring data in EU chemicals management--experiences and considerations from the German environmental specimen bank. AB - Since the 1970s, environmental specimen banks (ESB) have emerged in many countries. Their highly standardised sampling and archiving strategies make them a valuable tool in tracing time trends and spatial distributions of chemicals in ecosystem compartments. The present article intends to highlight the potential of ESBs for regulatory agencies in the European Union (EU). The arguments are supported by examples of retrospective monitoring studies conducted under the programme of the German ESB. These studies have evaluated the success of regulatory and industry provisions for substances of concern (i.e. PCB, polybrominated diphenyl ethers, perfluorinated compounds, alkylphenol compounds, organotin compounds, triclosan/methyl-triclosan, musk fragrances). Time trend studies revealed for example that levels of organotin compounds in marine biota from German coastal waters decreased significantly after the EU had decided on a total ban of organotin-based antifoulings in 2003. Similarly, concentrations of commercially relevant congeners of polybrominated diphenyl ethers decreased in herring gull eggs from the North Sea only after an EU-wide ban in 2004. The data presented demonstrate the usefulness of ESB samples for (retrospective) time trend monitoring and underline the benefit of a more intensive cooperation between chemicals management and specimen banking. PMID- 24770984 TI - The unique challenges facing HIV-positive patients who smoke cigarettes: HIV viremia, ART adherence, engagement in HIV care, and concurrent substance use. AB - Evidence suggests that smoking may have negative associations with HIV health outcomes. The smoking rate in our sample of people living with HIV (N = 333) was triple that of the general population (57 v. 19 %). Regression analyses revealed that (smokers v. non-smokers) reported lower medication adherence (unstandardized beta = 9.01) and were more likely to have a detectable viral load (OR = 2.85, 95 % CI [1.53-5.30]). Smokers attended fewer routine medical visits (beta = -0.16) and were more likely to report recent hospitalization (OR = 1.89, 95 % CI [0.99, 3.57]). Smokers ranked "health" as less important to their quality of life (beta = -0.13) and were more likely to report problematic alcohol (OR = 2.40, 95 % CI [1.35, 4.30]), cocaine (OR = 2.87, 95 % CI [1.48-5.58]), heroin (OR = 4.75, 95 % CI [1.01, 22.30]), or marijuana use (OR = 3.08, 95 % CI [1.76-5.38]). Findings underscore the need for integrated behavioral smoking cessation interventions and routine tobacco screenings in HIV primary care. PMID- 24770985 TI - A pilot RCT of an intervention to reduce HIV sexual risk and increase self acceptance among MSM in Chennai, India. AB - This is a 2-arm pilot randomized controlled trial (N = 96) of a behavioral intervention (4 group and 4 individual sessions) integrating risk reduction counseling with counseling to foster self-acceptance in MSM in India compared to enhanced standard of care (ESOC). Both conditions involved HIV and STI testing and counseling at baseline and 6-months, and assessments of condomless sex at baseline, 3-, and 6-months. A significant condition by time interaction suggested a difference in the rate of change in number of anal sex acts without condoms in the intervention versus ESOC (p < 0.0001). Post hoc contrasts suggested that the overall difference was due to intervention-response at 3-months. The incidence of bacterial STIs was 17.5 % in the intervention condition and a 28.6 % in ESOC. Addressing self-acceptance and related psychosocial concerns in the context sexual risk reduction counseling for MSM in India was feasible and acceptable. Testing the intervention for efficacy is justified. PMID- 24770986 TI - Acetylcholinesterase biosensor for carbaryl detection based on interdigitated array microelectrodes. AB - In this study, an acetylcholinesterase (AChE) biosensor with superior accuracy and sensitivity was successfully developed based on interdigitated array microelectrodes (IAMs). IAMs have a series of parallel microband electrodes with alternating microbands connected together. Chitosan was used as the enzyme immobilization material, and AChE was used as the model enzyme for carbaryl detection to fabricate AChE biosensor. Electrochemical impedance spectroscopy was used in conjunction with the fabricated biosensor to detect pesticide residues. Based on the inhibition of pesticides on the AChE activity, using carbaryl as model compounds, the biosensor exhibited a wide range, low detection limit, and high stability. Moreover, the biosensor can also be used as a new promising tool for pesticide residue analysis. PMID- 24770987 TI - Siderophore production by actinobacteria. AB - Produced by bacteria, fungi and plants, siderophores are low-molecular-weight chelating agents (200-2,000 Da) to facilitate uptake of iron (Fe). They play an important role in extracellular Fe solubilization from minerals to make it available to microorganisms. Siderophores have various chemical structures and form a family of at least 500 different compounds. Some antibiotics (i.e., albomycins, ferrimycins, danomycins, salmycins, and tetracyclines) can bind Fe and some siderophores showed diverse biological activities. Functions and applications of siderophores derived from actinobacteria were reviewed to better understand the diverse metabolites. PMID- 24770988 TI - Lactoferrin and bifidobacteria. AB - We herein summarized the effects of lactoferrin (LF) on bifidobacteria. Many in vitro studies previously reported the growth-promoting (bifidogenic) effects of LF on bifidobacteria. The involvement of bound iron, sugar chains, and LF peptides has been proposed in this bifidogenic mechanism. Peptides in the LF pepsin hydrolysate (LFH) showed stronger bifidogenic activity than natural LF; therefore, we speculated that peptides may be the bifidogenic active principle of LF. LF or its peptides may be recognized by LF-binding proteins on the surface of bifidobacterial cells, and the cationic nature or disulfide bonds of LF or its peptides may play a crucial role in its recognition by these proteins. Of the bifidobacterial species so far identified, human LF and peptides in human LFH were more likely to show bifidogenic activity especially to Bifidobacterium bifidum, and bovine LF (bLF) and peptides in bovine LFH (bLFH) to B. breve and B. infantis. In animal studies, the administration of LF to mice or piglets increased bifidobacteria levels in the intestine. In human trials, the administration of LF-containing formula to infants increased bifidobacteria levels in the feces; however, human milk achieved better results than LF containing formula. In the case of breast-fed infants, LF may show bifidogenic activity synergistically with other milk components such as human milk oligosaccharides. As bLFH showed stronger bifidogenic activity than natural bLF, especially to B. breve and B. infantis in vitro, and these species are known to be infant-specific species, bLFH may be a beneficial ingredient in formula. PMID- 24770989 TI - A plasma concentration of alpha-ketoglutarate influences the kinetic interaction of ligands with organic anion transporter 1. AB - The purpose of the present study was to determine whether a physiologic plasma concentration of alpha-ketoglutarate (alphaKG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular alphaKG on the kinetics of para-aminohippurate (PAH) and cidofovir transport was examined along with its effect on the potency of 10 drugs in five different classes (uricosuric, nonsteroidal anti-inflammatories, loop diuretics, angiotensin II receptor antagonists, and beta-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular alphaKG competitively inhibited PAH and cidofovir transport with Ki values (~5 MUM) approximating its unbound plasma concentration (determined by equilibrium dialysis). When PAH was the substrate, extracellular alphaKG (5 MUM) significantly increased IC50 values for some inhibitors (up to 4-fold), such as probenecid, but not for others (an inhibitor-dependent effect). For some inhibitors, a significant increase in IC50 value was observed when cidofovir was the substrate, but not PAH (a substrate dependent effect). A significant increase in IC50 value was also observed for inhibition of PAH transport by probenecid in renal basolateral membrane vesicles (5.2-fold). The substrate- and inhibitor-dependent effect of extracellular alphaKG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-binding surface. The effect of extracellular alphaKG on the potency of OAT1 inhibition should be considered when assessing drug-drug interaction potential at the transporter. PMID- 24770990 TI - Rapid bovine and caprine species identification in ruminant feeds by duplex real time PCR melting curve analysis using EvaGreen fluorescence dye. AB - A duplex real-time PCR assay with melting curve analysis, using the EvaGreen fluorescence dye, was developed for rapid and reliable identification of bovine and caprine in ruminant feeds. The method merges the use of bovine (Bos taurus) and caprine (Capra hircus) specific primers that amplify small fragments (bovine 96 bp and caprine 142 bp) of the mitochondrial 16S rRNA and 12S rRNA genes, respectively. DNA was isolated from heat-treated meats (133 degrees C/3 bar for 20 min) mixtures of bovine and caprine and was used to optimize the assay. Gene products of caprine and bovine produced two distinct melting peaks simultaneously at 82 and 86.8 degrees C, respectively. Duplex analysis of the reference samples showed that the detection limit of the assay was 0.003 % for bovine and 0.005 % for caprine species. The aim of this study was to develop a duplex real-time PCR assay followed by a melt curve step for sensitive, rapid, specific, and cost effective detection of bovine and caprine species based on the amplicon melting peak in ruminant feeds to prevent Transmissible Spongiform Encephalopathies. PMID- 24770991 TI - Small-for-gestational age and preterm birth across generations: a population based study of Illinois births. AB - Small for gestational age (weight for gestational age <10th percentile, SGA) and preterm birth (<37 weeks, PTB) are the major determinants of infant mortality rates and racial disparities therein. To determine the generational inheritance patterns of SGA and PTB among non-Hispanic Whites and African-Americans. Stratified and multivariable binominal regression analyses were performed on an Illinois transgenerational dataset of White and African-American infants (1989 1991) and their mothers (1956-1976) with appended US census income information. Former SGA White mothers (N = 8,993) had a twofold greater infant SGA frequency than former non-SGA White mothers (N = 101,312); 14.4 versus 6.9 %, RR = 2.1 (2.0 2.2). Former SGA African American (N = 4,861) mothers had a SGA birth frequency of 25.7 % compared to 16.1 % for former non-SGA mothers (N = 28,090); RR = 1.5 (1.5-1.6). The adjusted (controlling for maternal age, education, marital status, parity, prenatal care usage, cigarette smoking, and hypertension) RR (95 % CI) of infant SGA for former SGA (compared to non-SGA) White and African-American mothers equaled 2.0 (1.9-2.1 and 1.5 (1.5-1.6), respectively. The adjusted RR (95 % CI) of infant preterm birth for former preterm (compared to term) White and African-American mothers were 1.1 (1.0-1.2). The findings were minimally changed among mothers with a lifelong residence in impoverished or affluent neighborhoods. In both races, approximately 8 % of SGA births were attributable to maternal SGA. There is a transgenerational association of SGA but not preterm birth among non-Hispanic Whites and African-Americans. In both races, a similar proportion of SGA births are attributable to maternal SGA. PMID- 24770992 TI - Clinical needs of in-treatment pregnant women with co-occurring disorders: implications for primary care. AB - We investigated social vulnerability and behavioral health clinical profiles (symptom severity) of pregnant women with co-occurring disorders, defined as substance abuse, mental illness, and trauma at treatment entry compared to their nonpregnant counterparts and the role of interpersonal abuse in clinical presentation among pregnant women. Our objective was to provide primary health care providers with insight into the needs of pregnant patients with high behavioral health risks to serve them better during the critical window of opportunity for long-term impact. We conducted cross-sectional secondary analysis of baseline data from women enrolled in treatment programs in the Women, Co occurring Disorders and Violence Study from nine sites across the United States. We used analysis of variance and Cochran-Mantel-Haenszel statistical analyses to compare means and frequencies of social vulnerability indicators and baseline Addiction Severity Index, Brief Symptom Inventory of mental health, and Posttraumatic Stress Diagnostic Scale scores between 152 pregnant and 2,577 nonpregnant women, and between pregnant women with and without current interpersonal abuse. Compared to nonpregnant women, pregnant women evidenced more social vulnerability but better behavioral health clinical profiles at treatment entry. Current interpersonal abuse was associated with increased mental health and trauma symptomatology but not with alcohol or drug abuse severity among pregnant women. The prenatal period is an important time for screening and intervention for factors such as social vulnerability and co-occurring disorders, known to affect pregnancy and infant outcomes; social and behavioral health services are particularly essential among pregnant women with co-occurring disorders. PMID- 24770995 TI - Clinical and economic implications of early discharge following posterior spinal fusion for adolescent idiopathic scoliosis. AB - OBJECTIVE: To evaluate the clinical and economic impact of a novel postoperative pathway following posterior spinal fusion (PSF) in patients with adolescent idiopathic scoliosis (AIS). METHODS: Patient charts were reviewed for demographic data and to determine length of surgery, implant density, use of osteotomies, estimated blood loss, American Society of Anesthesiologists (ASA) score, length of hospital stay, and any subsequent complications. Hospital charges were divided by charge code to evaluate potential savings. RESULTS: Two hundred and seventy nine of 365 patients (76.4 %) treated with PSF carried a diagnosis of AIS and had completed 6 months of clinical and radiologic follow-up, a period of time deemed adequate to assess early complications. There was no difference between groups in age at surgery, sex, number of levels fused, or length of follow-up. Patients managed under the accelerated discharge (AD) pathway averaged 1.36 (31.7 %) fewer days of inpatient stay. Operative time was associated with a shorter length of stay. There was no difference in complications between groups. Hospital charges for room and board were significantly less in the AD group ($1.885 vs. $2,779, p < 0.001). CONCLUSIONS: A pathway aimed to expedite discharge following PSF for AIS decreased hospital stay by nearly one-third without any increase in early complication rate. A small but significant decrease in hospital charges was seen following early discharge. Early discharge following PSF for AIS may be achieved without increased risk of complications, while providing a small cost savings. PMID- 24770996 TI - Acclimation and deacclimation of brown trout (Salmo trutta) to zinc and copper singly and in combination with cadmium or copper. AB - Brown trout (Salmo trutta) were chronically exposed to low and high levels of zinc (Zn) alone, copper (Cu) alone, a Zn-Cu mixture, and a Zn-cadmium (Cd) mixture all starting with eyed eggs and continuing through to the fingerling stage. Exposure to the metals and metal mixtures resulted in acclimation as measured by greater median lethal concentrations (LC50) values relative to metal naive fry. The degree of acclimation was similar between the low and high exposures except for Cu, where acclimation was observed at the high but not the low acclimation level. The increases in tolerance relative to metal-naive controls were usually less than a factor of 2 and never exceeded a factor of 3. Acclimation exposures did not affect hatch or survival except for the high acclimation regime of Zn plus Cu. Acclimation came at an apparent metabolic cost because growth was decreased by most acclimation exposures. Deacclimation, as evidenced by a return of LC50 values to naive levels, occurred after 2-5 weeks in clean water. PMID- 24770997 TI - Specific targeting of neurotoxic side effects and pharmacological profile of the novel cancer stem cell drug salinomycin in mice. AB - Salinomycin is a polyether antibiotic which effectively eliminates a variety of cancer stem cells and chemotherapy-resistant tumor cells in vitro and in vivo. One important caveat for its clinical application is the paucity of preclinical pharmacological and safety data. In the present study, we thus aimed to elucidate pharmacokinetic properties of salinomycin and to assess the side effect profile of chronic treatment with this compound in C57Bl/6 mice. In addition, we tested whether neurotoxic side effects can be prevented by interference with the intracellular calcium homeostasis. We observed that salinomycin has a narrow therapeutic index; however, a dose of 5 mg/kg body weight was well tolerated, and analysis of blood parameters as well as organ histology of liver, kidney, skeletal muscle, and heart showed no abnormalities after daily salinomycin injection for 4 weeks. Pharmacokinetic evaluation revealed low micromolar peak concentrations and an almost complete systemic elimination within 5 h after injection. In contrast to low systemic toxicity, typical signs of a sensory polyneuropathy with mechanical and cold allodynia, distinct gait alterations, decreased sensory nerve action potential amplitudes, and loss of myelinated fibers in the sciatic nerve were observed in salinomycin-treated animals. Inhibition of the mitochondrial Na(+)/Ca(2+) exchanger partially prevented the development of salinomycin-induced neuropathy in vivo, an approach which did not reduce salinomycin's antineoplastic efficacy in vitro. Taken together, this study establishes a framework of pharmacokinetic data for future preclinical trials and safety data for translational trials. Furthermore, we established a strategy to reduce salinomycin's off-target neurotoxic effects. KEY MESSAGE: Salinomycin has a narrow therapeutic index; a dose of 5 mg/kg is tolerated in mice. Mice treated with salinomycin develop a painful sensory polyneuropathy. An optimized protocol was established to measure salinomycin in serum samples. Inhibition of Na(+)/Ca(2+) exchangers prevents salinomycin-induced neuropathy. Blocking mitochondrial Na(+)/Ca(2+) exchangers does not impair antineoplastic efficacy. PMID- 24770998 TI - Incidence of disability and its associated factors in Japanese men and women: the Longitudinal Cohorts of Motor System Organ (LOCOMO) study. AB - We investigated the incidence of disability and its risk factors in older Japanese adults to establish an evidence-based disability prevention strategy for this population. For this purpose, we used data from the Longitudinal Cohorts of Motor System Organ (LOCOMO) study, initiated in 2008 to integrate information from cohorts in nine communities across Japan: Tokyo (two regions), Wakayama (two regions), Hiroshima, Niigata, Mie, Akita, and Gunma prefectures. We examined the annual occurrence of disability from 8,454 individuals (2,705 men and 5,749 women) aged >=65 years. The estimated incidence of disability was 3.58/100 person years (p-y) (men: 3.17/100 p-y; women: 3.78/100 p-y). To determine factors associated with disability, Cox's proportional hazard model was used, with the occurrence of disability as an objective variable and age (+1 year), gender (vs. women), body build (0: normal/overweight range, BMI 18.5-27.5 kg/m(2); 1: emaciation, BMI <18.5 kg/m(2); 2: obesity, BMI >27.5 kg/m(2)), and regional differences (0: rural areas including Wakayama, Niigata, Mie, Akita, and Gunma vs. 1: urban areas including Tokyo and Hiroshima) as explanatory variables. Age, body build, and regional difference significantly influenced the occurrence of disability (age, +1 year: hazard ratio 1.13, 95% confidence interval 1.12-1.15, p < 0.001; body build, vs. emaciation: 1.24, 1.01-1.53, p = 0.041; body build, vs. obesity: 1.36, 1.08-1.71, p = 0.009; residence, vs. living in rural areas: 1.59, 1.37-1.85, p < 0.001). We concluded that higher age, both emaciation and obesity, and living in rural areas would be risk factors for the occurrence of disability. PMID- 24770999 TI - The role of AMH in anovulation associated with PCOS: a hypothesis. AB - Polycystic ovary syndrome (PCOS) is the most common cause of infertility due to anovulation. Despite its prevalence, the precise cause of the anovulation is yet to be clearly defined. There is an increased number of pre-antral and antral follicles in the polycystic ovary, many of which individually produce increased amounts of anti-Mullerian hormone (AMH) compared with those in the normal ovary. In this article, it is hypothesized that the high AMH concentrations present in women with PCOS play an integral role in causing anovulation due to its inhibitory influence on the actions of follicle-stimulating hormone, which normally promotes follicular development from the small antral to the ovulatory stage. PMID- 24771000 TI - Role of zinc trafficking in male fertility: from germ to sperm. AB - STUDY QUESTION: What are the dynamics of zinc (Zn) trafficking in sperm, at the testicular, epididymal and ejaculate levels? SUMMARY ANSWER: Zn transporters are peculiarly expressed in the cells of the germ line and Zn uptake is maximal at the post-epididymal phase, where Zn is involved in the regulation of sperm functions. WHAT IS KNOWN ALREADY: Zn is known to influence several phases of sperm life, from germ cell development to spermiation. Zn trafficking across the membrane is allowed by specific families of transporters known as the ZnTs, which are involved in effluent release, and the Zips, which mediate uptake. STUDY DESIGN, SIZE, DURATION: We enrolled 10 normozoospermic healthy participants in an infertility survey programme, as well as 5 patients affected by testicular germ cell cancer, and 18 patients presenting with obstructive azoospermia, without mutations of the CFTR gene, and undergoing assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: The research study was performed at our University Clinic. Semen samples, or biopsies or fine needle aspirates from the testis or epididymis, were obtained from each of the participants. Protein expression of main members of the ZnT and Zip families of Zn transporters was examined in human testis and epididymis samples by immunofluorescence. Quantification of sperm Zn content was performed by flow cytometry, atomic absorption spectrometry (AA) and autometallography. MAIN RESULTS AND THE ROLE OF CHANCE: Intratubular cells of the germ line displayed a high redundancy of Zip family members involved in Zn uptake, while ZnT transporters were more represented in epididymis. Testicular and epididymal spermatozoa contained less Zn than ejaculated spermatozoa (2.56 +/- 0.51 and 12.58 +/- 3.16 versus 40.48 +/- 12.71 ng Zn/10(6)cells, respectively). Gain of hypermotility and acrosomal reaction were significantly linked to the loss of Zn content in ejaculated spermatozoa. LIMITATIONS, REASONS FOR CAUTION: This was an ancillary study performed on a small cohort of normozoospermic subjects. Although these results clarify the Zn trafficking during different phases of sperm life, no conclusive information can be drawn about the fertilizing potential of sperm, and the overall pregnancy outcomes, after Zn supplementation. WIDER IMPLICATIONS OF THE FINDINGS: Our data disclose the dynamics of Zn trafficking during over the sperm lifespan. STUDY FUNDING/COMPETING INTEREST(S): No external funding was sought or obtained for this study. No conflict of interest is declared. PMID- 24771001 TI - Mitochondrial SIRT3 and its target glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age. AB - STUDY QUESTION: Is the activity of sirtuin 3 (SIRT3) altered in granulosa and cumulus cells from young women with reduced ovarian reserve or women of advanced maternal age? SUMMARY ANSWER: SIRT3 mRNA and active protein in granulosa and cumulus cells were decreased in women with reduced ovarian reserve and advanced maternal age. WHAT IS KNOWN ALREADY: Young women with reduced ovarian reserve or women of advanced maternal age have reduced oocyte viability, possibly due to altered granulosa and cumulus cell metabolism. The mitochondrial SIRT3 protein may be implicated in these processes as it is able to sense the metabolic state of the cell and alter mitochondrial protein function post-translationally. STUDY DESIGN, SIZE, DURATION: This is a prospective cohort study, in which women (n = 72) undergoing routine IVF/ICSI were recruited and allocated to one of three cohorts based on age and ovarian reserve (as assessed by serum anti-Mullerian hormone level). Women were classified as young (<=35 years) or of advanced maternal age (>=40 years). PARTICIPANTS/MATERIALS, SETTING, METHODS: Granulosa and cumulus cells were collected. SIRT3 mRNA and protein levels and protein activity was analysed in granulosa and cumulus cells via quantitative PCR, immunohistochemistry and western blotting, and deacetylation activity, respectively. Activity of the glutamate dehydrogenase (GDH) enzyme, a known target of SIRT3, was assessed, and acetylated proteins in mitochondria isolated from granulosa and cumulus cells were separated by immunoprecipitation and acetylation of GDH assessed by western blotting. Data for women with good prognosis (young women with normal ovarian reserve) were compared with those from young women with reduced ovarian reserve and those of advanced maternal age. MAIN RESULTS AND THE ROLE OF CHANCE: SIRT3 mRNA and active protein were present in granulosa and cumulus cells and co-localized to the mitochondria. SIRT3 mRNA in granulosa cells was decreased in young women with reduced ovarian reserve and advanced maternal age versus young women with normal ovarian reserve (P < 0.05). SIRT3 mRNA in cumulus cells was decreased in women of advanced maternal age versus young women with normal ovarian reserve only (P < 0.05). Granulosa cell GDH activity was decreased in young women with reduced ovarian reserve and in women of advanced maternal age (P < 0.05), whereas cumulus cell GDH activity was reduced in the advanced maternal age group only (P < 0.05). The acetylation profile of GDH in mitochondria revealed increased acetylation of GDH in granulosa and cumulus cells from women of advanced maternal age (P < 0.05) while young women with reduced ovarian reserve had increased GDH acetylation in granulosa cells only (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Although patients were allocated to groups based on maternal age and ovarian reserve and matched for BMI, other maternal factors may also alter the 'molecular health' of ovarian cells. WIDER IMPLICATIONS OF THE FINDINGS: Our data suggest that SIRT3 post translational modification of mitochondrial enzymes in human granulosa and cumulus cells may regulate GDH activity, thus altering the metabolic milieu surrounding the developing oocyte. Owing to the association between the decline in oocyte quality and pregnancy rates in women of advanced maternal age and the possible association with reduced ovarian reserve, knowledge of perturbed SIRT3 function in granulosa and cumulus cells may lead to novel therapies to improve mitochondrial metabolism in the oocyte and follicular cells in women undergoing IVF treatment. STUDY FUNDING/COMPETING INTEREST(S): No conflicts of interest to declare. Research was funded by an NHMRC project grant. PMID- 24771002 TI - Is gastric lymphoepithelioma-like carcinoma a special subtype of EBV-associated gastric carcinoma? New insight based on clinicopathological features and EBV genome polymorphisms. AB - BACKGROUND: Gastric lymphoepithelioma-like carcinoma (LELC) is a rare entity that is closely associated with Epstein-Barr virus (EBV). However, the EBV latency pattern and genome polymorphisms in gastric LELC have not been systematically explored. METHODS: The clinicopathological features, EBV latency pattern and genome polymorphisms of EBV-positive gastric LELC in Guangzhou, southern China were investigated and compared with those of ordinary EBV-associated gastric carcinoma (EBVaGC) in the same area. RESULTS: Ten (1.42%) of 702 gastric carcinoma cases were identified as gastric LELC, in which eight (80%) cases were EBV-positive. The clinicopathological characteristics and EBV latency pattern of EBV-positive gastric LELC were similar to those of ordinary EBVaGC. In EBV genotype analysis, type A strain, type F, I, mut-W1/I, XhoI- and del-LMP1 variants were predominant among EBV-positive gastric LELCs, accounting for eight (100%), six (75%), eight (100%), seven (87.5%), five (62.5%) and six (75%) cases, respectively, which are similar to those in ordinary EBVaGC. For EBNA1 polymorphisms, the V-leu and P-ala subtypes were predominant in EBV-positive gastric LELC, which is different from the predominant V-val subtype in ordinary EBVaGC. EBV-positive gastric LELC has a favorable prognosis when compared to ordinary EBVaGC (median survival time 43.0 vs. 18.0 months). CONCLUSIONS: Gastric LELC is strongly associated with EBV and EBV-positive gastric LELC should be regarded as a special subtype of EBVaGC. This, to our best knowledge, is the first time in the world that the EBV latency pattern and genome polymorphisms of EBV-positive gastric LELC are systematically revealed. PMID- 24771004 TI - Membrane-initiated estradiol signaling of epithelial-mesenchymal transition associated mechanisms through regulation of tight junctions in human breast cancer cells. AB - Tumor cells utilize inappropriate epithelial-mesenchymal transition (EMT) mechanisms during the invasive process. It is becoming increasingly clear that estradiol (E2) induces breast cancer cell progression and enhances EMT; however, the mechanisms associated with this are unclear. We investigated the role of E2 on the expression and intracellular localization of the tight junction (TJ) associated proteins, zonula occluden 1 (ZO-1), ZO-1-associated nucleic acid binding (ZONAB), and occludin, on the activation of c-Src and human epidermal growth factor receptor 2 (HER2) expression and cellular migration in the estrogen receptor (ER)-positive breast cancer cell lines, MCF-7 and T47D. We demonstrated that 1 nM E2 elicits c-Src activation after 15 min. The p-Src/ZO-1 complex led to ZO-1 and ZONAB disruption at the TJ and increased expression of HER2 mRNAs. These changes correlate with decreased expression of the epithelial markers occludin and CRB3 and increased synthesis of N-cadherin. This led to increased MCF-7 cell migration induced by E2, even in the presence of a cell proliferation inhibitor. Incubation with ICI 182,780 (Fulvestrant), an ER antagonist, precluded the effects of E2 on c-Src phosphorylation, p-Src/ZO-1 complex formation, ZO-1/ZONAB nuclear translocation, and migration of MCF-7 cells. Our findings suggest that E2 promotes TJ disruption during tumor progression and increases cell motility. We propose a novel pathway where estrogens promote EMT-associated mechanisms that possibly lead to metastasis. PMID- 24771005 TI - Diffusion tensor imaging analysis of optic radiation using readout-segmented echo planar imaging. AB - PURPOSE: To investigate the diffusion tensor imaging parameters of the optic radiation and surrounding structures using the high-resolution readout-segmented diffusion tensor imaging method. MATERIALS AND METHODS: Coronal readout-segmented diffusion tensor images were acquired in 15 healthy volunteers. On three slices of each image, eigenvalue 1, fractional anisotropy, radial diffusivity, apparent diffusion coefficient, and signal intensity on T2-weighted images were measured in the lateral inferior longitudinal fasciculus, external and internal layers of the optic radiation, and the tapetum within regions of interest delineated by two independent observers. Profile curve analysis of regions of interest across the optic radiation and surrounding structures was performed for a representative typical case. RESULTS: Significant differences in fractional anisotropy, radial diffusivity and apparent diffusion coefficient were observed between external and internal layers of the optic radiation, while there was no significant difference in eigenvalue 1. In fractional anisotropy maps, two low signal bands were observed between the inferior longitudinal fasciculus, the optic radiation and the tapetum. Profile curve analysis showed a minimum on the fractional anisotropy and eigenvalue 1 images and a maximum in the radial diffusivity image. CONCLUSION: Readout-segmented diffusion tensor imaging revealed significant differences in the diffusion tensor imaging parameters between internal and external layers of the optic radiation. PMID- 24771006 TI - Analyzing the auditory scene: neurophysiologic evidence of a dissociation between detection of regularity and detection of change. AB - Detecting regularity and change in the environment is crucial for survival, as it enables making predictions about the world and informing goal-directed behavior. In the auditory modality, the detection of regularity involves segregating incoming sounds into distinct perceptual objects (stream segregation). The detection of change from this within-stream regularity is associated with the mismatch negativity, a component of auditory event-related brain potentials (ERPs). A central unanswered question is how the detection of regularity and the detection of change are interrelated, and whether attention affects the former, the latter, or both. Here we show that the detection of regularity and the detection of change can be empirically dissociated, and that attention modulates the detection of change without precluding the detection of regularity, and the perceptual organization of the auditory background into distinct streams. By applying frequency spectra analysis on the EEG of subjects engaged in a selective listening task, we found distinct peaks of ERP synchronization, corresponding to the rhythm of the frequency streams, independently of whether the stream was attended or ignored. Our results provide direct neurophysiological evidence of regularity detection in the auditory background, and show that it can occur independently of change detection and in the absence of attention. PMID- 24771007 TI - Unscrambling the effect of C-terminal tail deletion on the stability of a cold adapted, organic solvent stable lipase from Staphylococcus epidermidis AT2. AB - Terminal moieties of most proteins are long known to be disordered and flexible. To unravel the functional role of these regions on the structural stability and biochemical properties of AT2 lipase, four C-terminal end residues, (Ile-Thr-Arg Lys) which formed a flexible, short tail-like random-coil segment were targeted for mutation. Swapping of the tail-like region had resulted in an improved crystallizability and anti-aggregation property along with a slight shift of the thermostability profile. The lipolytic activity of mutant (M386) retained by 43 % compared to its wild-type with 18 % of the remaining activity at 45 degrees C. In silico analysis conducted at 25 and 45 degrees C was found to be in accordance to the experimental findings in which the RMSD values of M386 were more stable throughout the total trajectory in comparison to its wild-type. Terminal moieties were also observed to exhibit large movement and flexibility as denoted by high RMSF values at both dynamics. Variation in organic solvent stability property was detected in M386 where the lipolytic activity was stimulated in the presence of 25 % (v/v) of DMSO, isopropanol, and diethyl ether. This may be worth due to changes in the surface charge residues at the mutation point which probably involve in protein-solvent interaction. PMID- 24771008 TI - Epidemiology of cardiovascular disease in patients with type 1 diabetes: European perspective. AB - The International Diabetes Federation estimated that 5.1 million people aged between 20 and 79 years died from diabetes in 2013, accounting for 8.4% of global all-cause mortality among people in this age group. Type 1 diabetes is associated with a 2- to 4-fold increased mortality risk compared with the general population. Before the onset of late complications, most of the excess mortality is from potentially preventable causes of death such as ketoacidosis, whereas the long-term excess mortality is largely due to cardiovascular disease. However, a wide geographic variation in mortality of type 1 diabetic patients has been evidenced and accurate estimates of mortality attributable to diabetes are difficult to obtain. The review provides an overview of currently available evidence and summarizes main problems in estimating early and long-term mortality by cause of death in type 1 diabetes, paying particular attention to European studies. PMID- 24771009 TI - Pharmacokinetics, pharmacodynamics, and cytotoxicity of recombinant orally administrated long-lasting GLP-1 and its therapeutic effect on db/db mice. AB - Recombinant orally long-acting glucagon-like peptide 1 (rolGLP-1), a novel analog of native GLP-1 that can stimulate insulin secretion, was constructed via site directed mutagenesis by our laboratory. This study was designed to investigate the pharmacokinetics, pharmacodynamics, and the cytotoxicity of rolGLP-1. Diabetic db/db mice were given 125I-rolGLP-1 through a single dose of oral administration to evaluate the pharmacokinetics of rolGLP-1 by trichloroacetic acid-Radioactive assay (TCA-RA). Separately, rolGLP-1 was orally administered to the db/db mice daily for 28 days to evaluate its therapeutic effect. In addition, the safety of rolGLP-1 was assessed based on cytotoxicity testing on the cell line SH-SY5Y by both the MTT assay and the cell counts method. The results showed that the half-life of rolGLP-1 in db/db mice was 68.2 h, which is longer than that of native GLP-1. Results after the 28 day treatment showed glucose homeostasis was improved. Furthermore, rolGLP-1 was also proved to mitigate insulin resistance, alleviate hyperinsulinemia and decreased glycosylated hemoglobin content. Lastly, no visible adverse events were observed in cytotoxicity treatments on SH-SY5Y. Our results revealed that oral administration of rolGLP-1 harbored a longer half-life and a good therapeutic effect for type 2 db/db mice. All the results suggest the capacity and safety of rolGLP-1 for further use as an anti-diabetic agent for type 2 diabetes.This study was supported by Project 863 of China (2008AA02Z205). PMID- 24771010 TI - The relationship between acute coronary syndrome and stress hyperglycemia. AB - BACKGROUND AND OBJECTIVE: Hyperglycemia on admission is associated with increased mortality and morbidity in acute coronary syndrome (ACS) irrespective of presence of diabetes mellitus. To the best of our knowledge, no evidence on the relationship between stress hyperglycemia (SH) and the extent of coronary artery disease is found in the literature. Our objective in this study is to assess the relationship of SH with the prognosis of acute coronary syndrome, extent of coronary artery disease (CAD), development of arrhythmia, and major adverse cardiac events. METHOD: 89 patients who were hospitalized in the coronary intensive care unit with diagnosis of ACS between January 2010 and June 2010 were enrolled in the study. The patients were separated into 2 groups as having stress hypergly-cemia or not, according to their blood glucose levels on admission. TIMI and GRACE risk scores were obtained and GENSINI scoring was performed to assess CAD extent for all the patients. Major adverse cardiac events (MACE) (death, MI, re-revascularization, stroke) were recorded for all patients while in the hospital and at 1st and 6th months. RESULTS: In our study, MACE, GENSINI scores at 6 months and development of in-hospital arrhythmia rates were statistically significantly higher and left ventricular ejection fractions were statistically significantly lower in the group with SH. The association of TIMI, GRACE, GENSINI, New York Heart Association (NYHA) and Killip classifications with blood glucose, fasting blood glucose and HbA1c on admission was confirmed. CONCLUSION: Prognostic course happens to be worse and CAD is more extensive in patients with SH. In addition, blood glucose values may have to be estimated lower compared to the samples in the literature, in order to diagnose SH. PMID- 24771011 TI - The influence of radioiodine therapy on the number of circulating epithelial cells (CEC) in patients with differentiated thyroid carcinoma - a pilot study. AB - GOAL: The aim of this pilot study was to investigate the changes of circulating epithelial cells in the blood of patients with differentiated thyroid cancer after radioiodine-therapy with I-131. METHODS: The cells were detected by fluorescence-microscopy via the epithelial-cell-adhesion-molecule (EpCAM), a molecule described to be over-expressed in most carcinoma tissues and also present on circulating cells deriving from primary site. Epithelial cells were assessed before radioiodine-therapy, as well as 2 days, 14 days, and 3 months after therapy. 2 patient groups were examined: 1) patients with thyroid cancer receiving a first radioiodine-therapy after thyroidectomy (RITfirst, n=13), and 2) patients with thyroid cancer in need of repeated radioiodine-therapy due to local or metastatic recurrences (RITrep, n=15). Circulating epithelial cell changes were correlated to changes of serum-thyroglobulin and to clinical response evaluated 3 months after therapy. RESULTS: Patients with an early decrease of cells after radioiodine-therapy (RITfirst 7/13; RITrep 2/15) showed an increase of serum-thyroglobulin in most of the cases (RITfirst 5/7; RITrep 2/2). In the RITrep group, a decrease in cell counts 2 days after radioiodine therapy indicated a clinical response in 90% of the cases. CONCLUSIONS: This study indicates that the number of circulating epithelial cells in differentiated thyroid cancer undergo changes in response to radioiodine-therapy. The destruction of cells through radioiodine-therapy may induce a short-term release of thyroglobulin in the blood. A clear relationship between the clinical outcome and the cell changes could not be found, but early cell decreases may help identifying patients more likely to respond to radioiodine-therapy. PMID- 24771012 TI - Relationship between autoantibody to the angiotensin II-1 receptor and cardiovascular manifestations of Graves' disease. AB - OBJECTIVE: To investigate the role of autoantibody against angiotensin II-1 receptor (AT1-AA) in patients with cardiovascular manifestations of Graves' disease (GD). METHODS: The epitope of the second extracellular loop of AT1 receptor (165-191) was synthesized and used as antigens to screen the autoantibody by enzyme linked immunosorbent assay (ELISA). The patients with GD were divided into the patients with cardiovascular manifestations associated to GD (Group A, n=58) and the patients with GD not complicated by heart disease (Group B, n=60). 40 healthy subjects were included in the study (Group C, n=40). Echocardiography was performed and the differences of echocardiography parameters were compared between AT1-AA positive and negative groups in group A. Factors related to left heart enlargement were analyzed by multiple logistic regression. RESULTS: (1) The frequency of AT1-AA in Group A (52.2%, 32/58) were significantly higher than those in Group B (16.7%, 10/60) and Group C (12.5%, 5/40) (all p<0.001). (2) There were no differences in the level of TGAb, TPOAb and TRAb between AT1-AA positive and negative groups in patients with GD (all p>0.05). (3) In patients with cardiovascular manifestations of GD, the ratios between left atrial and ventricular enlargement (LAE and LVE) were significantly higher in the AT1-AA positive group than in the AT1-AA negative group (68.8% vs. 26.9%, 62.5% vs. 23.1%, all p<0.01); the frequency of atrial fibrillation differed significantly between these 2 groups (53.1% vs. 19.2%, p<0.01). (4) Regression analysis demonstrated that the positive AT1-AA and course of GD were significantly correlated to the presence of LAE and LVE. CONCLUSIONS: AT1-AA plays an important role in the pathogenesis of cardiovascular manifestations associated to GD. Especially, AT1-AA is involved in left cardiac dilatation of GD complicated by heart disease, which represents a cardio-vascular risk factor for GD patients. PMID- 24771013 TI - Polymorphisms in the vitamin D receptor (VDR) genes and skin cancer risk in European population: a meta-analysis. AB - There have been a few epidemiological studies reporting VDR polymorphisms including Fok1, Bsm1, Apa1 and Taq1 with skin cancer incidence and, therefore, risk. The results, however, are controversial, often due to smaller sample size. Concerning most of the studies were performed on Caucasian population, we conducted this comprehensive analysis to better understand roles of the polymorphisms in skin cancer development among Caucasian population. The results showed that Fok1 polymorphism was associated with an overall significantly increased risk of skin cancer (Ff vs. FF: OR = 1.20, 95 % CI = 1.01-1.44; ff vs. FF: OR = 1.41, 95 % CI = 1.08-1.84; Ff + ff vs. FF: OR = 1.26, 95 % CI = 1.04 1.53). Besides, we found that Taq1 polymorphism could contribute to non-melanoma skin cancer susceptibility (Tt vs. TT: OR = 1.88, 95 % CI = 1.29-2.74; tt vs. TT: OR = 2.00, 95 % CI = 1.22-3.28; Tt + tt vs. TT: OR = 1.92, 95 % CI = 1.35-2.73). We also found that the Apa1 polymorphism is associated with skin cancer development (Aa vs. AA: OR = 1.27, 95 % CI = 1.05-1.53; Aa + aa vs. AA: OR = 1.23, 95 % CI = 1.04-1.47) and NMSC subgroup (Aa vs. AA: OR = 1.72, 95 % CI = 1.51-2.57; Aa + aa vs. AA: OR = 1.50, 95 % CI = 1.03-2.17). No significant association was observed between the Bsm1 polymorphism and skin cancer risk. The current meta-analysis shows that Fok1, Taq1 and Apa1 may be the susceptibility biomarker for skin cancer in Caucasians. PMID- 24771014 TI - Age-related learning and memory deficits in rats: role of altered brain neurotransmitters, acetylcholinesterase activity and changes in antioxidant defense system. AB - Oxidative stress from generation of increased reactive oxygen species or free radicals of oxygen has been reported to play an important role in the aging. To investigate the relationship between the oxidative stress and memory decline during aging, we have determined the level of lipid peroxidation, activities of antioxidant enzymes, and activity of acetylcholine esterase (AChE) in brain and plasma as well as biogenic amine levels in brain from Albino-Wistar rats at age of 4 and 24 months. The results showed that the level of lipid peroxidation in the brain and plasma was significantly higher in older than that in the young rats. The activities of antioxidant enzymes displayed an age-dependent decline in both brain and plasma. Glutathione peroxidase and catalase activities were found to be significantly decreased in brain and plasma of aged rats. Superoxide dismutase (SOD) was also significantly decreased in plasma of aged rats; however, a decreased tendency (non-significant) of SOD in brain was also observed. AChE activity in brain and plasma was significantly decreased in aged rats. Learning and memory of rats in the present study was assessed by Morris Water Maze (MWM) and Elevated plus Maze (EPM) test. Short-term memory and long-term memory was impaired significantly in older rats, which was evident by a significant increase in the latency time in MWM and increase in transfer latency in EPM. Moreover, a marked decrease in biogenic amines (NA, DA, and 5-HT) was also found in the brain of aged rats. In conclusion, our data suggest that increased oxidative stress, decline of antioxidant enzyme activities, altered AChE activity, and decreased biogenic amines level in the brain of aged rats may potentially be involved in diminished memory function. PMID- 24771015 TI - Effects of zinc-fortified drinking skim milk (as functional food) on cytokine release and thymic hormone activity in very old persons: a pilot study. AB - Zinc is a relevant nutritional factor for the whole life of an organism because it affects the inflammatory/immune response and antioxidant activity, leading to a healthy state. Despite its important function, the dietary intake of zinc is inadequate in elderly. Possible interventions include food fortification because it does not require changes in dietary patterns, the cost is low and it can reach a large portion of the elderly population, including very old subjects. Studies evaluating the impact of Zn-fortified foods on functional parameters in elderly, in particular, in very old individuals, are missing. The objective of this study was to evaluate the efficacy of consumption of a zinc-fortified drinking skim milk (Zn-FMilk) for a period of 2 months in comparison to standard non-fortified milk (No-FMilk) on some biochemical parameters, zinc status, inflammatory/immune response and on a key parameter of the T cell-mediated immunity (thymulin hormone) in healthy very old subjects. The treatment with zinc-fortified milk (Zn FMilk) is a good omen to increase the cell-mediated immunity in very old age represented by thymulin activity and some cytokine (IL-12p70, IFN-gamma) release. At clinical level, a good healthy state occurs in 70 % of the subjects with no hospitalization after 1 year of the follow-up in comparison to very old control subjects that did not participate to crossover design. In conclusion, the Zn FMilk can be considered a good functional food for elderly, including older people. It might be a good replacement to the zinc tablets or lozenges taking into account the attitude of old people to uptake milk as a preferential food. PMID- 24771018 TI - Performing elective surgery on the breastfeeding patient: a review of the literature. AB - The prevalence of breastfeeding among women in the United States is increasing along with the understanding of the importance of continually and exclusively breastfeeding an infant in the first half year of life. Modern necessities and problems evoke questions about what medications can be safely utilized by a breastfeeding mother and which procedures she may safely undergo. Planning elective surgery for a patient who is breastfeeding is a challenge because of insufficient studies regarding medication safety, apprehension among patients, and inadequate information from care providers. Nonetheless, information on the pharmacokinetics of drugs in the maternal system, the possible adverse effects to the infant, and how to minimize drug exposure to the infant is easily accessible to both patients and their surgeons. Positively informed providers and breastfeeding mothers who elect to undergo surgery, willing to take the proper steps and precautions, ensure healthy outcomes postoperatively. PMID- 24771016 TI - Triiodothyronine regulates distribution of thyroid hormone receptors by activating AMP-activated protein kinase in 3T3-L1 adipocytes and induces uncoupling protein-1 expression. AB - The purposes of this study were to examine whether thermogenesis in 3T3-L1 adipocytes is related to variations in thyroid hormone receptors (TRs) that are differently regulated by triiodothyronine (T3), and the possible role of AMP activated protein (AMPK) in thermogenesis after cell differentiation. Differentiated 3T3-L1 adipocytes were maintained under four conditions: normal control group, T3 treatment group, AMPK agonist (5-aminoimidazole-4-carboxamide-1 beta-D-ribofuranoside) treatment group, and T3 and AMPK inhibitor (Compound C) treatment group. Real-time polymerase chain reaction was then performed to evaluate the changes in TRalpha and TRbeta mRNA levels in the cells, as well as marker genes for brown adipose tissue including uncoupling protein (UCP)-1 and Cidea. Western blotting was carried out for the cells to detect the expressions of TRalpha, TRbeta, and AMPK protein levels. After T3 treatment, the mRNA and protein levels of TRalpha decreased compared with the control group, while TRbeta mRNA and protein levels increased markedly at the same time. We also found elevated mRNA levels of UCP-1 and Cidea after exposure to T3. However, the distribution of TRs was reversed by Compound C. AMPK protein levels were clearly activated by T3. Our results suggest that the distribution of TRs is related to thermogenesis, and AMPK may participate in the alterations. PMID- 24771017 TI - Positive choices: outcomes of a brief risk reduction intervention for newly HIV diagnosed men who have sex with men. AB - Positive choices (PC), a brief sexual risk reduction intervention conducted with newly HIV-diagnosed men who have sex with men (MSM), was evaluated for preliminary efficacy. Participants were enrolled if they reported unprotected anal intercourse (UAI) in the three months prior to HIV diagnosis (n = 102). Three months after diagnosis, participants completed baseline assessments and were randomly assigned to receive the 3-session PC intervention or the comprehensive standard of care (C-SoC) at a community health center. Participants completed assessments at 3- (post intervention), 6-, and 9- months after baseline. Compared to C-SoC participants, PC participants significantly reduced the frequency of UAI with HIV serodiscordant (HIV negative or status unknown) partners over the 9-month follow-up period. No differences by condition were found in the frequency of UAI with all partners. The findings from this trial suggest that brief risk reduction approaches for newly-diagnosed MSM integrated into HIV care can benefit secondary HIV prevention efforts. PMID- 24771019 TI - A single platelet-rich plasma injection for chronic midsubstance achilles tendinopathy: a retrospective preliminary analysis. AB - The purpose of this study was to evaluate a series of patients undergoing a single platelet-rich plasma (PRP) injection for the treatment of chronic midsubstance Achilles tendinopathy, in whom conservative treatment had failed. Thirty-two patients underwent a single PRP injection for the treatment of chronic midsubstance Achilles tendinopathy and were evaluated at a 6-month final follow up using the Foot and Ankle Outcome Score and Short Form 12 general health questionnaire. Magnetic resonance imaging was performed on all patients prior to and 6 months after injection. Twenty-five of 32 patients (78%) reported that they were asymptomatic at the 6-month follow-up visit and were able to participate in their respective sports and daily activities. The remaining 7 patients (22%) who reported symptoms that did not improve after 6 months ultimately required surgery. Four patients went on to have an Achilles tendoscopy, while the other 3 had an open debridement via a tendon splitting approach. A retrospective evaluation of patients receiving a single PRP injection for chronic midsubstance Achilles tendinopathy revealed that 78% had experienced clinical improvement and had avoided surgical intervention at 6-month follow-up. LEVELS OF EVIDENCE: Therapeutic, Level IV: Retrospective case series. PMID- 24771020 TI - Evolutionary Asiacentrism, Peking man, and the origins of sinocentric ethno nationalism. AB - This paper discusses how the theory of evolutionary Asiacentrism and the Peking Man findings at the Zhoukoudian site stimulated Chinese intellectuals to construct Sinocentric ethno-nationalism during the period from the late 1920s to the early 1940s. It shows that the theory was first popularized by foreign scientists in Beijing, and the Peking man discoveries further provided strong evidence for the idea that Central Asia, or to be more specific, Tibet, Xinjiang, and Mongolia, was the original cradle of humans. Chinese scholars in the late 1930s and 1940s appropriated the findings to construct the monogenesis theory of the Chinese, which designated that all the diverse ethnic groups within the territory of China shared a common ancestor back to antiquity. PMID- 24771021 TI - Natural variation and genetic analysis of the tiller angle gene MsTAC1 in Miscanthus sinensis. AB - Biomass yield is an important target trait in Miscanthus breeding for desirable energy crops. Tiller angle is a key trait of plant architecture because it determines planting density and further influences biomass yield through affecting photosynthesis efficiency. TAC1, a major gene involved in tiller and leaf angle control in rice and maize, respectively, has been extensively studied. Nucleotide variation at this gene, MsTAC1, was investigated in 33 Miscanthus sinensis accessions collected from different areas in China, and one genotype of Miscanthus * giganteus. A total of 136 loci, including 129 single base substitutions and seven InDels, occurred within the MsTAC1 gene of 1,874 bp. The genetic diversity at MsTAC1 is characterized by high nucleotide diversity (pi value) and high heterozygosity. Clustering analysis indicated that the phylogenetic tree of the 33 M. sinensis accessions was correlated with their geographical sites of origin. The neutrality test revealed no strong selection pressure on coding and non-coding region variations of the MsTAC1 gene in the accessions. Phenotype evaluations were conducted for tiller angle and five other traits in the Miscanthus panels in the first two growth years of 2009 and 2010. Analysis of variance showed significant phenotypic variations in the examined traits. Association analysis using 246 markers detected 88 loci associated with all the test traits in either 1 or 2 years, and 11 of the 88 were year reproducible and thus reliable. These associations indicate that the variation of MsTAC1 affects the phenotypic value of the tiller angle, tiller number and biomass yield, suggesting that allelic variation in MsTAC1 affects multiple traits and demonstrates its significance in Miscanthus breeding programs. PMID- 24771022 TI - Structural and functional characteristics of S-like ribonucleases from carnivorous plants. AB - Although the S-like ribonucleases (RNases) share sequence homology with the S RNases involved in the self-incompatibility mechanism in plants, they are not associated with this mechanism. They usually function in stress responses in non carnivorous plants and in carnivory in carnivorous plants. In this study, we clarified the structures of the S-like RNases of Aldrovanda vesiculosa, Nepenthes bicalcarata and Sarracenia leucophylla, and compared them with those of other plants. At ten positions, amino acid residues are conserved or almost conserved only for carnivorous plants (six in total). In contrast, two positions are specific to non-carnivorous plants. A phylogenetic analysis revealed that the S like RNases of the carnivorous plants form a group beyond the phylogenetic relationships of the plants. We also prepared and characterized recombinant S like RNases of Dionaea muscipula, Cephalotus follicularis, A. vesiculosa, N. bicalcarata and S. leucophylla, and RNS1 of Arabidopsis thaliana. The recombinant carnivorous plant enzymes showed optimum activities at about pH 4.0. Generally, poly(C) was digested less efficiently than poly(A), poly(I) and poly(U). The kinetic parameters of the recombinant D. muscipula enzyme (DM-I) and A. thaliana enzyme RNS1 were similar. The k cat/K m of recombinant RNS1 was the highest among the enzymes, followed closely by that of recombinant DM-I. On the other hand, the k cat/K m of the recombinant S. leucophylla enzyme was the lowest, and was ~1/30 of that for recombinant RNS1. The magnitudes of the k cat/K m values or k cat values for carnivorous plant S-like RNases seem to correlate negatively with the dependency on symbionts for prey digestion. PMID- 24771023 TI - Elicitation of jasmonate-mediated host defense in Brassica juncea (L.) attenuates population growth of mustard aphid Lipaphis erysimi (Kalt.). AB - The productivity of Brassica oilseeds is severely affected by its major pest: aphids. Unavailability of resistance source within the crossable germplasms has stalled the breeding efforts to derive aphid resistant cultivars. In this study, jasmonate-mediated host defense in Indian mustard Brassica juncea (L.) Czern. was evaluated and compared with regard to its elicitation in response to mustard aphid Lipaphis erysimi (Kalt.) and the defense elicitor methyl jasmonate (MeJ). Identification of jasmonate-induced unigenes in B. juncea revealed that most are orthologous to aphid-responsive genes, identified in taxonomically diverse plant aphid interactions. The unigenes largely represented genes related to signal transduction, response to biotic and abiotic stimuli and homeostasis of reactive oxygen species (ROS), in addition to genes related to cellular and metabolic processes involved in cell organization, biogenesis, and development. Gene expression studies revealed induction of the key jasmonate biosynthetic genes (LOX, AOC, 12-OPDR), redox genes (CAT3 and GST6), and other downstream defense genes (PAL, ELI3, MYR, and TPI) by several folds, both in response to MeJ and plant-wounding. However, interestingly aphid infestation even after 24 h did not elicit any activation of these genes. In contrast, when the jasmonate-mediated host defense was elicited by exogenous application of MeJ the treated B. juncea plants showed a strong antibiosis effect on the infesting aphids and reduced the growth of aphid populations. The level of redox enzymes CAT, APX, and SOD, involved in ROS homeostasis in defense signaling, and several defense enzymes viz. POD, PPO, and PAL, remained high in treated plants. We conclude that in B. juncea, the jasmonate activated endogenous-defense, which is not effectively activated in response to mustard aphids, has the potential to reduce population growth of mustard aphids. PMID- 24771024 TI - Evaluation of amphotericin B and chloramphenicol as alternative drugs for treatment of chytridiomycosis and their impacts on innate skin defenses. AB - Chytridiomycosis, an amphibian skin disease caused by the emerging fungal pathogen Batrachochytrium dendrobatidis, has been implicated in catastrophic global amphibian declines. The result is an alarming decrease in amphibian diversity that is a great concern for the scientific community. Clinical trials testing potential antifungal drugs are needed to identify alternative treatments for amphibians infected with this pathogen. In this study, we quantified the MICs of chloramphenicol (800 MUg/ml), amphotericin B (0.8 to 1.6 MUg/ml), and itraconazole (Sporanox) (20 ng/ml) against B. dendrobatidis. Both chloramphenicol and amphotericin B significantly reduced B. dendrobatidis infection in naturally infected southern leopard frogs (Rana [Lithobates] sphenocephala), although neither drug was capable of complete fungal clearance. Long-term exposure of R. sphenocephala to these drugs did not inhibit antimicrobial peptide (AMP) synthesis, indicating that neither drug is detrimental to this important innate skin defense. However, we observed that chloramphenicol, but not amphotericin B or itraconazole, inhibited the growth of multiple R. sphenocephala skin bacterial isolates in vitro at concentrations below the MIC against B. dendrobatidis. These results indicate that treatment with chloramphenicol might dramatically alter the protective natural skin microbiome when used as an antifungal agent. This study represents the first examination of the effects of alternative antifungal drug treatments on amphibian innate skin defenses, a crucial step to validating these treatments for practical applications. PMID- 24771025 TI - 300-Fold increase in production of the Zn2+-dependent dechlorinase TrzN in soluble form via apoenzyme stabilization. AB - Microbial metalloenzymes constitute a large library of biocatalysts, a number of which have already been shown to catalyze the breakdown of toxic chemicals or industrially relevant chemical transformations. However, while there is considerable interest in harnessing these catalysts for biotechnology, for many of the enzymes, their large-scale production in active, soluble form in recombinant systems is a significant barrier to their use. In this work, we demonstrate that as few as three mutations can result in a 300-fold increase in the expression of soluble TrzN, an enzyme from Arthrobacter aurescens with environmental applications that catalyzes the hydrolysis of triazine herbicides, in Escherichia coli. Using a combination of X-ray crystallography, kinetic analysis, and computational simulation, we show that the majority of the improvement in expression is due to stabilization of the apoenzyme rather than the metal ion-bound holoenzyme. This provides a structural and mechanistic explanation for the observation that many compensatory mutations can increase levels of soluble-protein production without increasing the stability of the final, active form of the enzyme. This study provides a molecular understanding of the importance of the stability of metal ion free states to the accumulation of soluble protein and shows that differences between apoenzyme and holoenzyme structures can result in mutations affecting the stability of either state differently. PMID- 24771026 TI - Benzoate metabolism intermediate benzoyl coenzyme A affects gentisate pathway regulation in Comamonas testosteroni. AB - A previous study showed that benzoate was catabolized via a coenzyme A (CoA) dependent epoxide pathway in Azoarcus evansii (R. Niemetz, U. Altenschmidt, S. Brucker, and G. Fuchs, Eur. J. Biochem. 227:161-168, 1995), but gentisate 1,2 dioxygenase was induced. Similarly, we found that the Comamonas testosteroni strain CNB-1 degraded benzoate via a CoA-dependent epoxide pathway and that gentisate 1,2-dioxygenase (GenA) was also induced when benzoate or 3 hydroxybenzoate served as a carbon source for growth. Genes encoding the CoA dependent epoxide (box genes) and gentisate (gen genes) pathways were identified. Genetic disruption revealed that the gen genes were not involved in benzoate and 3-hydroxybenzoate degradation. Hence, we investigated gen gene regulation in the CNB-1 strain. The PgenA promoter, a MarR-type regulator (GenR), and the GenR binding site were identified. We found that GenR took gentisate, 3 hydroxybenzoate, and benzoyl-CoA as effectors and that binding of GenR to its target DNA sequence was prohibited when these effectors were present. In vivo studies showed that the CNB-1 mutant that lost benzoyl-CoA synthesis was not able to activate PgenA promoter, while transcription of genA was upregulated in another CNB-1 mutant that lost the ability to degrade benzoyl-CoA. The finding that benzoyl-CoA (a metabolic intermediate of benzoate degradation) and 3 hydroxybenzoate function as GenR effectors explains why GenA was induced when CNB 1 grew on benzoate or 3-hydroxybenzoate. Regulation of gentisate pathways by MarR , LysR-, and IclR-type regulators in diverse bacterial groups is discussed in detail. PMID- 24771027 TI - Shifts in abundance and diversity of mobile genetic elements after the introduction of diverse pesticides into an on-farm biopurification system over the course of a year. AB - Biopurification systems (BPS) are used on farms to control pollution by treating pesticide-contaminated water. It is assumed that mobile genetic elements (MGEs) carrying genes coding for enzymes involved in degradation might contribute to the degradation of pesticides. Therefore, the composition and shifts of MGEs, in particular, of IncP-1 plasmids carried by BPS bacterial communities exposed to various pesticides, were monitored over the course of an agricultural season. PCR amplification of total community DNA using primers targeting genes specific to different plasmid groups combined with Southern blot hybridization indicated a high abundance of plasmids belonging to IncP-1, IncP-7, IncP-9, IncQ, and IncW, while IncU and IncN plasmids were less abundant or not detected. Furthermore, the integrase genes of class 1 and 2 integrons (intI1, intI2) and genes encoding resistance to sulfonamides (sul1, sul2) and streptomycin (aadA) were detected and seasonality was revealed. Amplicon pyrosequencing of the IncP-1 trfA gene coding for the replication initiation protein revealed high IncP-1 plasmid diversity and an increase in the abundance of IncP-1beta and a decrease in the abundance of IncP-1epsilon over time. The data of the chemical analysis showed increasing concentrations of various pesticides over the course of the agricultural season. As an increase in the relative abundances of bacteria carrying IncP-1beta plasmids also occurred, this might point to a role of these plasmids in the degradation of many different pesticides. PMID- 24771028 TI - Bacterial targets as potential indicators of diesel fuel toxicity in subantarctic soils. AB - Appropriate remediation targets or universal guidelines for polar regions do not currently exist, and a comprehensive understanding of the effects of diesel fuel on the natural microbial populations in polar and subpolar soils is lacking. Our aim was to investigate the response of the bacterial community to diesel fuel and to evaluate if these responses have the potential to be used as indicators of soil toxicity thresholds. We set up short- and long-exposure tests across a soil organic carbon gradient. Utilizing broad and targeted community indices, as well as functional genes involved in the nitrogen cycle, we investigated the bacterial community structure and its potential functioning in response to special Antarctic blend (SAB) diesel fuel. We found the primary effect of diesel fuel toxicity was a reduction in species richness, evenness, and phylogenetic diversity, with the resulting community heavily dominated by a few species, principally Pseudomonas. The decline in richness and phylogenetic diversity was linked to disruption of the nitrogen cycle, with species and functional genes involved in nitrification significantly reduced. Of the 11 targets we evaluated, we found the bacterial amoA gene indicative of potential ammonium oxidation, the most suitable indicator of toxicity. Dose-response modeling for this target generated an average effective concentration responsible for 20% change (EC20) of 155 mg kg(-1), which is consistent with previous Macquarie Island ecotoxicology assays. Unlike traditional single-species tolerance testing, bacterial targets allowed us to simultaneously evaluate more than 1,700 species from 39 phyla, inclusive of rare, sensitive, and functionally relevant portions of the community. PMID- 24771029 TI - Mechanism of algal aggregation by Bacillus sp. strain RP1137. AB - Alga-derived biofuels are one of the best alternatives for economically replacing liquid fossil fuels with a fungible renewable energy source. Production of fuel from algae is technically feasible but not yet economically viable. Harvest of dilute algal biomass from the surrounding water remains one of the largest barriers to economic production of algal biofuel. We identified Bacillus sp. strain RP1137 in a previous study and showed that this strain can rapidly aggregate several biofuel-producing algae in a pH- and divalent-cation-dependent manner. In this study, we further characterized the mechanism of algal aggregation by RP1137. We show that aggregation of both algae and bacteria is optimal in the exponential phase of growth and that the density of ionizable residues on the RP1137 cell surface changes with growth stage. Aggregation likely occurs via charge neutralization with calcium ions at the cell surface of both algae and bacteria. We show that charge neutralization occurs at least in part through binding of calcium to negatively charged teichoic acid residues. The addition of calcium also renders both algae and bacteria more able to bind to hydrophobic beads, suggesting that aggregation may occur through hydrophobic interactions. Knowledge of the aggregation mechanism may enable engineering of RP1137 to obtain more efficient algal harvesting. PMID- 24771030 TI - Molecular method for detection of total coliforms in drinking water samples. AB - This work demonstrates the ability of a bacterial concentration and recovery procedure combined with three different PCR assays targeting the lacZ, wecG, and 16S rRNA genes, respectively, to detect the presence of total coliforms in 100-ml samples of potable water (presence/absence test). PCR assays were first compared to the culture-based Colilert and MI agar methods to determine their ability to detect 147 coliform strains representing 76 species of Enterobacteriaceae encountered in fecal and environmental settings. Results showed that 86 (58.5%) and 109 (74.1%) strains yielded a positive signal with Colilert and MI agar methods, respectively, whereas the lacZ, wecG, and 16S rRNA PCR assays detected 133 (90.5%), 111 (75.5%), and 146 (99.3%) of the 147 total coliform strains tested. These assays were then assessed by testing 122 well water samples collected in the Quebec City region of Canada. Results showed that 97 (79.5%) of the samples tested by culture-based methods and 95 (77.9%), 82 (67.2%), and 98 (80.3%) of samples tested using PCR-based methods contained total coliforms, respectively. Consequently, despite the high genetic variability of the total coliform group, this study demonstrated that it is possible to use molecular assays to detect total coliforms in potable water: the 16S rRNA molecular assay was shown to be as efficient as recommended culture-based methods. This assay might be used in combination with an Escherichia coli molecular assay to assess drinking water quality. PMID- 24771031 TI - Protective effects of Lactobacillus plantarum CCFM8610 against chronic cadmium toxicity in mice indicate routes of protection besides intestinal sequestration. AB - Our previous study confirmed the ability of Lactobacillus plantarum CCFM8610 to protect against acute cadmium (Cd) toxicity in mice. This study was designed to evaluate the protective effects of CCFM8610 against chronic Cd toxicity in mice and to gain insights into the protection mode of this strain. Experimental mice were divided into two groups and exposed to Cd for 8 weeks via drinking water or intraperitoneal injection. Both groups were further divided into four subgroups, control, Cd only, CCFM8610 only, and Cd plus CCFM8610. Levels of Cd were measured in the feces, liver, and kidneys, and alterations of several biomarkers of Cd toxicity were noted. The results showed that when Cd was introduced orally, cotreatment with Cd and CCFM8610 effectively decreased intestinal Cd absorption, reduced Cd accumulation in tissue, alleviated tissue oxidative stress, reversed hepatic and renal damage, and ameliorated the corresponding histopathological changes. When Cd was introduced intraperitoneally, administration of CCFM8610 did not have an impact on tissue Cd accumulation or reverse the activities of antioxidant enzymes. However, CCFM8610 still offered protection against oxidative stress and reversed the alterations of Cd toxicity biomarkers and tissue histopathology. These results suggest that CCFM8610 is effective against chronic cadmium toxicity in mice. Besides intestinal Cd sequestration, CCFM8610 treatment offers direct protection against Cd-induced oxidative stress. We also provide evidence that the latter is unlikely to be mediated via protection against Cd induced alteration of antioxidant enzyme activities. PMID- 24771032 TI - Causal relationship between microbial ecology dynamics and proteolysis during manufacture and ripening of protected designation of origin (PDO) cheese Canestrato Pugliese. AB - Pyrosequencing of the 16S rRNA gene, community-level physiological profiles determined by the use of Biolog EcoPlates, and proteolysis analyses were used to characterize Canestrato Pugliese Protected Designation of Origin (PDO) cheese. The number of presumptive mesophilic lactococci in raw ewes' milk was higher than that of presumptive mesophilic lactobacilli. The numbers of these microbial groups increased during ripening, showing temporal and numerical differences. Urea-PAGE showed limited primary proteolysis, whereas the analysis of the pH 4.6 soluble fraction of the cheese revealed that secondary proteolysis increased mainly from 45 to 75 days of ripening. This agreed with the concentration of free amino acids. Raw ewes' milk was contaminated by several bacterial phyla: Proteobacteria (68%; mainly Pseudomonas), Firmicutes (30%; mainly Carnobacterium and Lactococcus), Bacteroidetes (0.05%), and Actinobacteria (0.02%). Almost the same microbial composition persisted in the curd after molding. From day 1 of ripening onwards, the phylum Firmicutes dominated. Lactococcus dominated throughout ripening, and most of the Lactobacillus species appeared only at 7 or 15 days. At 90 days, Lactococcus (87.2%), Lactobacillus (4.8%; mainly Lactobacillus plantarum and Lactobacillus sakei), and Leuconostoc (3.9%) dominated. The relative utilization of carbon sources by the bacterial community reflected the succession. This study identified strategic phases that characterized the manufacture and ripening of Canestrato Pugliese cheese and established a causal relationship between mesophilic lactobacilli and proteolysis. PMID- 24771033 TI - An international smoking ban-how many lives will be saved? AB - Multicomponent tobacco control strategies are crucial to combat the ongoing global smoking challenge. In the twenty-first century, many countries have signed up to the World Health Organization Framework Convention on Tobacco Control, and in recent years a mounting number of countries and regions have implemented partial or complete smoking bans to protect the general public from passive smoke exposure. There is substantial evidence that workers, particularly in the hospitality sector, benefit from reduced exposure. More recently, several reports have appeared from different countries showing a temporal relationship between the introduction of a smoking ban and reduced hospital admissions for cardiovascular, respiratory and maternity outcomes. This will have a measurable benefit for public health, saving many lives. Multicomponent strategies could also reduce active smoking significantly if successfully implemented worldwide. PMID- 24771034 TI - Thoraco-abdominal CT examinations for evaluating cause of cardiac arrest and complications of chest compression in resuscitated patients. AB - The objective of the study is to describe the causes of cardiac arrest and complications of cardiopulmonary resuscitation (CPR) on thoraco-abdominal CT examinations for resuscitated patients in our institution. We evaluated the causes of cardiac arrest on thoraco-abdominal CT scans, which was compared with the final diagnosis (determined by consensus of two emergency physicians based on the clinical, imaging, and laboratory findings). Additionally, we evaluated the complications of CPR on thoraco-abdominal CT scans. From March 2005 to August 2011, 82 patients underwent CT of the thorax (n=77) and abdomen (n=23) within 24 h after CPR. Final diagnosis was as follows: cardiac (n=29), respiratory (n=28), metabolic (n=11), exsanguination (n=5), cerebral (n=2), sepsis (n=1), and indeterminate (n=6). In 25 patients (30 %), thoraco-abdominal CT scans made the role either as a definitive study (n=22) or as a supportive test (n=3) for the diagnosis. In particular, CT was critical in diagnosis of many respiratory causes (64 %) and all exsanguinations. The most common complications following CPR were skeletal chest injuries (n=48), followed by lung contusion (n=45). Thoraco abdominal CT examinations are helpful for the diagnosis of cause of cardiac arrest and complications of CPR. PMID- 24771035 TI - ASER core curriculum illustration project-volvulus: a rare cause of small bowel obstruction. AB - This is the ninth installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at http://www.aseronline.org/curriculum/toc.htm . PMID- 24771037 TI - [Diagnosis, prognosis, prediction]. PMID- 24771038 TI - [Paradigm shift in the so-called "certification of medical fitness" for the recruitment of new civil servants]. AB - In actual jurisdiction the Federal Administrative Court has substantially reduced the standard of "health ability" for civil servants who shall be newly employed. That means for the regulated official pre-employment medical examination that in critical cases a recommendation for non-employment will be more rarely considered in the lack of valid, i. e., selective scientific principles. Thereby the formerly pursued selection effect based on civil service law mainly will not apply in the future. Even though the widely opened approach to the civil servant status might be a favour for interested handicapped persons, the following impacts on official-organisational as well as fiscal aspects (governmental aid, pension- burden) can be difficultly foreseen. Hence, in the future the official pre-employment medical -examination will develop an increasing focus on advices about restrictions of assignment possibly having to be considered for admitted candidates. PMID- 24771036 TI - Assembly of nonheme Mn/Fe active sites in heterodinuclear metalloproteins. AB - The ferritin superfamily contains several protein groups that share a common fold and metal coordinating ligands. The different groups utilize different dinuclear cofactors to perform a diverse set of reactions. Several groups use an oxygen activating di-iron cluster, while others use di-manganese or heterodinuclear Mn/Fe cofactors. Given the similar primary ligand preferences of Mn and Fe as well as the similarities between the binding sites, the basis for metal specificity in these systems remains enigmatic. Recent data for the heterodinuclear cluster show that the protein scaffold per se is capable of discriminating between Mn and Fe and can assemble the Mn/Fe center in the absence of any potential assembly machineries or metal chaperones. Here we review the current understanding of the assembly of the heterodinuclear cofactor in the two different protein groups in which it has been identified, ribonucleotide reductase R2c proteins and R2-like ligand-binding oxidases. Interestingly, although the two groups form the same metal cluster they appear to employ partly different mechanisms to assemble it. In addition, it seems that both the thermodynamics of metal binding and the kinetics of oxygen activation play a role in achieving metal specificity. PMID- 24771039 TI - Disparities in knowledge and willingness to donate research biospecimens: a mixed methods study in an underserved urban community. AB - Although research involving biospecimens is essential in advancing cancer research, minorities, especially African-Americans, are underrepresented in such research. We conducted a mixed-method (qualitative focus groups among African Americans and quantitative cross-sectional surveys) study on factors associated with biospecimen knowledge and donation intent in the medically underserved urban communities in Southeast and Southwest Washington, DC. Focus groups were conducted among 41 African-Americans and survey data was available from 302 community residents of different races/ethnicities using convenience sampling. We used logistic regression to model the association between biospecimen knowledge and donation intent with selected sociodemographic variables using survey data. Only 47 % of the participants had knowledge of the different types of biospecimens. In multivariate logistic regression models, male gender, African American race, and low education levels were significantly associated with lower knowledge about biospecimens. Compared to Whites (79 %), fewer African-Americans (39 %) and Hispanics (57 %) had knowledge of biospecimens but the difference was significant for African-Americans only. Positive intent to donate biospecimens for research was observed among 36 % of the survey respondents. After multivariate adjustment, only biospecimen knowledge was associated with donation intent (odds ratio = 1.91, 95 % confidence interval 1.12, 3.27). Contrary to popular opinion, "mistrust of the medical community" was not the most commonly reported barrier for biospecimen donation among African-Americans. "Not knowing how biospecimens will be used" and "lack of knowledge of biospecimens" were the most common barriers. Our study highlights the importance of education on biospecimens among community residents to increase minority participation in biospecimen research. PMID- 24771040 TI - Morphological change and phenotypic plasticity in native and non-native pumpkinseed sunfish in response to competition. AB - Non-indigenous species are oftentimes exposed to ecosystems with unfamiliar species, and organisms that exhibit a high degree of phenotypic plasticity may be better able to contend with the novel competitors that they may encounter during range expansion. In this study, differences in morphological plasticity were investigated using young-of-year pumpkinseed sunfish (Lepomis gibbosus) from native North American and non-native European populations. Two Canadian populations, isolated from bluegill sunfish (L. macrochirus) since the last glaciation, and two Spanish populations, isolated from bluegill since their introduction in Europe, were reared in a common environment using artificial enclosures. Fish were subjected to allopatric (without bluegill) or sympatric (with bluegill) conditions, and differences in plasticity were tested through a MANOVA of discriminant function scores. All pumpkinseed populations exhibited dietary shifts towards more benthivorous prey when held with bluegill. Differences between North American and European populations were observed in body dimensions, gill raker length and pelvic fin position. Sympatric treatments induced an increase in body width and a decrease in caudal peduncle length in native fish; non-native fish exhibited longer caudal peduncle lengths when held in sympatry with bluegill. Overall, phenotypic plasticity influenced morphological divergence less than genetic factors, regardless of population. Contrary to predictions, pumpkinseeds from Europe exhibited lower levels of phenotypic plasticity than Canadian populations, suggesting that European pumpkinseeds are more canalized than their North American counterparts. PMID- 24771041 TI - Uracil excision by endogenous SMUG1 glycosylase promotes efficient Ig class switching and impacts on A:T substitutions during somatic mutation. AB - Excision of uracil introduced into the immunoglobulin loci by AID is central to antibody diversification. While predominantly carried out by the UNG uracil-DNA glycosylase as reflected by deficiency in immunoglobulin class switching in Ung( /-) mice, the deficiency is incomplete, as evidenced by the emergence of switched IgG in the serum of Ung(-/-) mice. Lack of switching in mice deficient in both UNG and MSH2 suggested that mismatch repair initiated a backup pathway. We now show that most of the residual class switching in Ung(-/-) mice depends upon the endogenous SMUG1 uracil-DNA glycosylase, with in vitro switching to IgG1 as well as serum IgG3, IgG2b, and IgA greatly diminished in Ung(-/-) Smug1(-/-) mice, and that Smug1 partially compensates for Ung deficiency over time. Nonetheless, using a highly MSH2-dependent mechanism, Ung(-/-) Smug1(-/-) mice can still produce detectable levels of switched isotypes, especially IgG1. While not affecting the pattern of base substitutions, SMUG1 deficiency in an Ung(-/-) background further reduces somatic hypermutation at A:T base pairs. Our data reveal an essential requirement for uracil excision in class switching and in facilitating noncanonical mismatch repair for the A:T phase of hypermutation presumably by creating nicks near the U:G lesion recognized by MSH2. PMID- 24771042 TI - Association between matrix metalloproteinase family gene polymorphisms and ischemic stroke: a meta-analysis. AB - Numerous studies have studied the relationships between matrix metalloproteinase (MMP) family gene polymorphisms and ischemic stroke. However, findings remain controversial. The objective of this study was to evaluate the relationships between MMP gene polymorphisms and ischemic stroke by using a meta-analysis. The PubMed, Embase, and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers, and pooled odds ratio (OR) with 95 % confidence interval (CI) were calculated. Eleven studies were enrolled, including a total of 589 cases and 494 controls of MMP-1 -1607 1G/2G; 1,817 cases and 1,731 controls of MMP-3 -1612 5A/6A; and 540 cases and 547 controls of MMP-9 -1562C/T. Under the dominant and recessive models, respectively, the overall ORs and 95 % CIs of -1607 2G were 1.54, 1.16-2.04 (P = 0.005) and 1.25, 0.95-1.65 (P = 0.457); the overall ORs and 95 % CIs of -1612 6A were 1.01, 0.84-1.21 (P = 0.003) and 0.88, 0.75-1.03 (P = 0.057); and the overall ORs and 95 % CIs of -1562T were 0.78, 0.59-1.02 (P = 0.460) and 1.65, 0.73-3.75 (P = 0.340). No publication bias was found in this meta-analysis. This meta-analysis showed that MMP-1 -1607 1G/2G and MMP-3 -1612 5A/6A were risk factors for ischemic stroke, while MMP-9 -1562C/T was not associated with ischemic stroke. PMID- 24771043 TI - Apparent reduction of ADAM10 in scrapie-infected cultured cells and in the brains of scrapie-infected rodents. AB - It has been described that A disintegrin and metalloproteinase (ADAM10) may involve in the physiopathology of prion diseases, but the direct molecular basis still remains unsolved. In this study, we confirmed that ADAM10 was able to cleave recombinant human prion protein in vitro. Using immunoprecipitation tests (IP) and immunofluorescent assays (IFA), reliable molecular interaction between the native cellular form of PrP (PrP(C)) and ADAM10 was observed not only in various cultured neuronal cell lines but also in brain homogenates of healthy hamsters and mice. Only mature ADAM10 (after removal of its prodomain) molecules showed the binding activity with the native PrP(C). Remarkably more prion protein (PrP)-ADAM10 complexes were detected in the membrane fraction of cultured cells. In the scrapie-infected SMB cell model, the endogenous ADAM10 levels, especially the mature ADAM10, were significantly decreased in the fraction of cell membrane. IP and IFA tests of prion-infected SMB-S15 cells confirmed no detectable PrP ADAM10 complex in the cellular lysates and PrP-ADAM10 co-localization on the cell surface. Furthermore, we demonstrated that the levels of ADAM10 in the brain homogenates of scrapie agent 263K-infected hamsters and agent ME7-infected mice were also almost diminished at the terminal stage, showing time-dependent decreases during the incubation period. Our data here provide the solid molecular basis for the endoproteolysis of ADAM10 on PrP molecules and interaction between ADAM10 and PrP(C). Obvious loss of ADAM10 during prion infection in vitro and in vivo highlights that ADAM10 may play essential pathophysiological roles in prion replication and accumulation. PMID- 24771044 TI - Novel link of anti-apoptotic ATF3 with pro-apoptotic CTMP in the ischemic brain. AB - Activating transcription factor 3 (ATF3) is a stress-induced transcription factor with diverse functions under disease states in multiple cell types. ATF3 has neuroprotective action against cerebral ischemia, which may involve caspase 3. However, the molecular mechanisms underlying ATF3 regulation of apoptosis are largely unknown. Here, we used gain- and loss-of-function and rescue approaches to demonstrate ATF3 attenuating hypoxic neuronal apoptosis. As well, the protective effect of ATF3 was mediated by downregulation of carboxyl-terminal modulator protein (CTMP), a pro-apoptotic factor that inhibits the anti-apoptotic Akt/PKB cascade. ATF3 (1) downregulated the mRNA and protein levels of CTMP; (2) its temporal expression pattern was reciprocal to that of CTMP; and (3) nuclear localization suggested that ATF3 may regulate CTMP transcription following hypoxic insult. Reporter assays demonstrated that ATF3 suppressed CTMP transcription, whereas ATF3 fusion with VP16, converting ATF3 to transcriptional activator, boosted CTMP transcription. By contrast, NF-kappaB increased CTMP transcription, and degradation-resistant IkappaBalpha decreased CTMP transcription. ChIP assays further confirmed that binding of ATF3 to the ATF/CREB site hindered NF-kappaB binding to the CTMP promoter, which repressed CTMP expression. Furthermore, CTMP siRNA treatment reduced hypoxic neuronal apoptosis by increasing p-Akt (Ser473) levels and leaving the upstream ATF3 level unchanged. We have identified an endogenous neuroprotective ATF3->CTMP signal cascade that may be a therapeutic target for reducing ischemic brain injury. PMID- 24771046 TI - Self-reported fertility in long-term survivors of acute myeloid leukemia. AB - Acute myeloid leukemia (AML) survival rates in younger patients have improved considerably since the 1970s. In order to evaluate the impact of AML and its treatment on fertility and family situation in adult long-term survivors, we used the Swedish population-based registries to identify 161 adult patients diagnosed with AML within the Leukemia Group of Middle Sweden (LGMS) 1973-2003, who survived for more than 5 years and were alive in 2010. Ninety-eight patients (61 %) completed a questionnaire including items on reproductive concerns, family situation, and infertility-related distress. After excluding women >45 years and/or postmenopausal women and men >55 years, 22 women and 38 men were included in the final analysis. Nine of the women (41 %) tried to conceive after treatment, but only three succeeded. Five (83 %) of the unwillingly childless women reported "a moderate" or "a lot" of distress caused by this. Among men in the same age group, all six who wanted children after treatment succeeded. None of the men 46-55 years old cryopreserved their sperm or tried to father a child. Among patients who wanted children after AML treatment, 46 % of the women and 40 % of the younger men reported that they were not, or not fully, informed about fertility-related issues. In contrast, among men 46-55 years, none reported they would have wanted more information. Infertility among young female AML survivors thus remains an important clinical issue, and there is a need for improved clinical counseling and education in this area. PMID- 24771045 TI - KIR haplotype B donors but not KIR-ligand mismatch result in a reduced incidence of relapse after haploidentical transplantation using reduced intensity conditioning and CD3/CD19-depleted grafts. AB - Natural killer (NK)-cell alloreactivity after allogeneic hematopoietic cell transplantation (HCT) is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and human leukocyte antigen (HLA) class I ligands on recipient cells. We investigated the influence of donor KIR haplotype and KIR-ligand mismatch (MM) on relapse in 57 patients with hematologic malignancies receiving haploidentical HCT after reduced intensity conditioning and graft CD3/CD19 depletion. Of the 57 donors, 17 had KIR haplotype A (29.8 %) and 40 had KIR haplotype B (70.2 %). A KIR-ligand MM was found in 34 of 57 patients (59.6 %). There was no difference between donor KIR haplotypes in non-relapse mortality (NRM, p = 0.200) but had a significantly reduced incidence of relapse for patients with a haplotype B donor (p = 0.001). In particular, patients in partial remission (PR) benefited more from a haplotype B graft (p = 0.008) than patients in complete remission (CR, p = 0.297). Evaluating KIR-ligand MM cumulative incidences of relapse (p = 0.680) or NRM (p = 0.579), we found no significant difference. In conclusion, in the setting of reduced intensity conditioning (RIC) and CD3/CD19-depleted haploidentical HCT, we could not confirm the positive data with KIR-ligand MM but observed a significant lower risk of relapse with a KIR haplotype B donor. PMID- 24771047 TI - Epithelial mesenchymal transition in early invasive breast cancer: an immunohistochemical and reverse phase protein array study. AB - Epithelial mesenchymal transition (EMT), as defined by loss of epithelial characteristics and gain of a mesenchymal phenotype, has been reported in vivo although the occurrence of events remains unclear. This study aims at exploration of EMT portraits of breast cancer (BC) with relevance to different molecular pathways, especially potential EMT triggers and BC molecular subtypes. Immunohistochemical (IHC) expression of markers/triggers of EMT was studied on a well-defined cohort of invasive non-lobular BC (n = 1,035), prepared as tissue microarrays. IHC panel of biomarkers included cadherins (cad; E-cad and N-cad), TGFbeta1, PIK3CA, pAkt, and others. Reverse phase protein array (RPPA) was performed for quantitative analysis of proteins extracted from formalin fixed paraffin embedded tissues of a subset of cases from this cohort. Four combinatorial phenotypic groups representing cadherin switch were defined, including E-cad(+)/N-cad(-), E-cad(-)/N-cad(-), E-cad(+)/N-cad(+), and E-cad(-)/N cad(+). Statistically significant association was noticed between these phenotypes and histological tumour grade, tumour type and size and NPI staging classes. The E-cad/N-cad switch occurred more frequently in the triple negative molecular class, both basal and non-basal, and in the HER2(+) subtype than in luminal BC. Significant outcome differences were observed between cadherin switch combinatorial groups regarding BCSS and DMFS (p < 0.001). Results of RPPA confirm those observed using IHC regarding differential expressions of EMT markers/triggers. EMT/cadherin switch programs in BC appear to occur in synergy with TGFbeta1 and PIK3/Akt pathways activation. These data explain, at translational proteomic level, the molecular heterogeneity and in turn the varied clinical behaviour of BC molecular subtypes. RPPA is a promising high-throughput technique in monitoring subtle quantitative changes in protein expression in archival material. PMID- 24771048 TI - Cost-effectiveness analysis of extended adjuvant endocrine therapy in the treatment of post-menopausal women with hormone receptor positive breast cancer. AB - Five years of Tamoxifen (Standard TAM) is a common treatment option for early stage, hormone receptor positive (HR+) breast cancer (BC). Extending Standard TAM by 5 additional years (Extended TAM) can improve survival and BC recurrences. In postmenopausal women, the use of extended aromatase inhibitors (Extended AI) after Standard TAM is an alternative to Extended TAM. This study examines the cost-effectiveness (CE) of extending Standard TAM with Extended TAM vs. Extended AI in postmenopausal HR+ early-stage BC patients. Three treatments were assessed: (1) Standard TAM; (2) Extended TAM; (3) Extended AI through a Markov model using a Canadian health system perspective, lifetime time-horizon, quality adjusted life years (QALYs), and a 5 % discount rate for future costs and utilities. Incremental cost-effectiveness ratios (ICERs) were calculated, and the impact of parameter uncertainty was assessed through probabilistic sensitivity analyses (SA) using conventional CE thresholds. The estimated total per person costs in 2012 Canadian dollars [$1.00 CAD = $0.99 US 2012] were the least for Extended TAM ($8,623 CAD) and most for Extended AI ($9,432 CAD). Extended AI was the most effective regimen, while Standard TAM was the least. Extended AI was cost effective at conventional thresholds vs. Extended TAM (ICER: $3,402 CAD/QALY) which was robust to the SA. This study suggests that Extended AI and Extended TAM result in improved QALYs and lower healthcare costs vs Standard TAM. Extended AI results in the greatest improvement in QALYs and is the most cost-effective treatment alternative despite its higher drug costs. PMID- 24771050 TI - Rapid determination of glutamine in human plasma by high-performance liquid chromatographic-tandem mass spectrometry and its application in pharmacokinetic studies. AB - A rapid and accurate high-performance liquid chromatographic-tandem mass spectrometric method was developed and validated for the determination of glutamine in human plasma. Phenomenex EZ: faast(TM) amino acid analysis kit was used for sample pretreatment. Chromatographic separation was conducted on an EZ: faast amino acid analysis-mass spectrometry column (250 * 3.0 mm i.d., 4 MUm). A binary gradient elution of mobile phases A (0.2% formic acid containing 5 mM ammonium acetate) and B (methanol, containing 0.2% formic acid and 5 mM ammonium acetate) was programmed at 0.4 mL/min. Multiple reaction monitoring was used for quantification by monitoring ion transitions of m/z 275.3/172.1 for derivatized glutamine and 317.3/84.1 for internal standard in the electrospray positive ionization mode. The standard curve was linear (r(2) > 0.99) over the concentration range of 3.14-157.20 MUg/mL. The intra- and inter-day precision values were <8.70% and the accuracy within -4.35 to 8.91% at three concentrations. The method was successfully applied to the pharmacokinetic study in Chinese healthy male subjects following oral administration of glutamine with doses of 2 and 4 g. PMID- 24771049 TI - Prognostic factors for survival in metastatic breast cancer by hormone receptor status. AB - Hormone receptor (HR) status is an important prognostic factor for patients with metastatic breast cancer (MBC) and is also correlated with other prognostic factors, such as initial lymph node status, HER2-Neu status and age. The prognostic value of these other factors, however, is unknown when stratified by HR positive versus HR negative patients. The aim of this study was to evaluate prognostic factors for MBC survival in relation to HR status. Dutch women diagnosed with breast cancer in 2003-2006 treated with curative intent who developed MBC within 5 years of follow-up were selected from the Netherlands cancer registry (N = 2,001). Independent prognostic factors for survival after metastatic occurrence were determined by multivariable Cox survival analyses stratified by HR status. Interactions between HR status and prognostic factors were determined. Median survival for MBC patients with HR negative (HR-) tumours was 8 months, compared to 19 months for HR positive (HR+) patients. The prognostic value of lymph node status, HER2-Neu status, adjuvant endocrine treatment and first-line palliative chemotherapy was dependent on HR status. Initial lymph node status was independently associated with survival in HR- patients, but not in HR+ patients. HER2-Neu positive status was associated with better survival in both HR+ and HR- patients, although the association was stronger in HR- patients. Similarly, patients treated with first-line palliative chemotherapy fared better, especially HR- patients. HR+ patients had worse survival if they had received adjuvant endocrine treatment. This study shows that the prognostic value of various factors depends on HR status in MBC. This information may help physicians to determine individual prognostic profiles and therapeutic strategies for MBC patients. PMID- 24771051 TI - Simultaneous determination of enalapril and hydrochlorothiazide in pharmaceutical preparations using microemulsion liquid chromatography. AB - A rapid high-performance liquid chromatography procedure for analytical quality control of mixture containing enalapril maleate (ENM) and hydrochlorothiazide (HCT) in their pharmaceutical preparations was developed using a microemulsion as an eluent. The separation was performed on a column packed with cyano-bonded stationary phase adopting UV detection at 210 nm using a flow rate of 1 mL/min. The optimized microemulsion mobile phase consisted of 0.2 M sodium dodecyl sulfate, 1% octanol, 10% n-propanol and 0.3% triethylamine in 0.02 M phosphoric acid, and pH was adjusted at 3.5. The proposed method was found to be linear over the concentration ranges 1-100 and 0.05-5 MUg/mL for ENM and HCT, respectively with a correlation coefficient of 0.9999 for both drugs. The developed method was validated in terms of specificity, linearity, lower limit of quantification, lower limit of detection, precision and accuracy. The proposed method is rapid (5 min), reproducible (relative standard deviation <2.0%) and achieves a satisfactory resolution between ENM and HCT (resolution factor = 3.62). The mean recoveries of the analytes in tablets were in agreement with those obtained from a comparison method, as revealed by statistical analysis of the obtained results using Student's t-test and the variance ratio F-test. PMID- 24771052 TI - Development and validation of a sensitive method for simultaneous determination of eight beta2-agonists in pork by ultrasonic-assisted extraction and liquid chromatography/tandem mass spectrometry. AB - A simple and sensitive ultrasonic-assisted extraction coupled with liquid chromatography-tandem quadrupole mass spectrometry was developed for the simultaneous determination of eight beta2-agonists (i.e., phenylethanolamine, fenoterol, formoterol, clenbuterol, ractopamine, salbutamol, terbutaline and tulobuterol) in pork. The recovery rate of ultrasonic-assisted extraction was compared with that of enzymolysis. Results showed that ultrasonic-assisted extraction is a satisfactory method for the treatment of pork samples, yielding beta2-agonist recovery rates of 82.0-114.0%. In contrast, most of the recovery rates obtained by enzymolysis were <80%. Linearities obtained ranged from 0.1 to 16.0 MUg kg(-1) for terbutaline, formoterol, tulobuterol and phenylethanolamine, 0.2 to 16.0 MUg kg(-1) for salbutamol, fenoterol and ractopamine, and 0.2 to 40.0 MUg kg(-1) for clenbuterol. The correlation coefficients were >0.9945 for all analytes. The lower limits of quantification were between 0.086 and 0.20 MUg kg( 1). The applicability of the proposed method for detecting and quantifying beta2 agonists was demonstrated in the analysis of 50 pork samples. PMID- 24771053 TI - Simultaneous determination of hydrochlorothiazide and benazepril hydrochloride or amiloride hydrochloride in presence of hydrochlorothiazide impurities: chlorothiazide and salamide by HPTLC method. AB - Simple, selective and sensitive high-performance thin layer chromatographic (HPTLC) method has been developed and validated for the simultaneous determination of hydrochlorothiazide (HCZ) in the presence of its impurities (chlorothiazide (CT) and salamide (DSA)), in two quaternary mixtures with benazepril hydrochloride (BZ) or amiloride hydrochloride (AM). The separation was carried out on HPTLC silica gel 60 F254 using ethyl acetate-methanol-glacial acetic acid (85:2:0.3 v/v/v) followed by densitometric measurement of bands at 240 nm for the first mixture containing HCZ, CT, DSA, BZ and by using ethyl acetate-methanol-water-ammonia (90:10:5:3 v/v/v) followed by densitometric measurement at 278 nm for the second mixture containing HCZ, CT, DSA, AM. Calibration curves were constructed in the range of (0.2-1.8 ug/band) and (0.4 2.2 ug/band) with good accuracy for HCZ and BZ, respectively, for the first mixture and in the range of (0.6-1.8 ug/band) and (0.4-2.4 ug/band) with good accuracy for HCZ and AM, respectively, for the second mixture. The developed method was validated according to ICH guidelines and demonstrated good accuracy and precision. Moreover, the methods were successfully applied for the determination of HCZ and BZ and AM in pure form and pharmaceutical dosage forms. The results were statically compared with the reported methods with no significant difference, indicating the ability of the proposed method to be used for routine analysis of drug product. PMID- 24771054 TI - A rapid and simple UPLC-MS-MS method for determination of glipizide in human plasma and its application to bioequivalence study. AB - In this study, a simple, rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry method is described for the determination of glipizide in human plasma samples using carbamazepine as the internal standard (IS) from bioequivalence assays. Sample preparation was accomplished through protein precipitation with methanol, and chromatographic separation was performed on an Acquity BEH C18 column (2.1 mm * 50 mm, 1.7 MUm) with gradient profile at a flow rate of 0.4 mL/min. Mass spectrometric analysis was performed using an QTrap5500 mass spectrometer coupled with an electrospray ionization source in the positive ion mode. The multiple reaction monitoring transitions of m/z 446.1 -> 321.0 and m/z 237.1 -> 194.2 were used to quantify for glipizide and IS. The linearity of this method was found to be within the concentration range of 10 1,500 ng/mL for glipizide in human plasma. Only 1.0 min was needed for an analytical run. The method was applied to a bioequivalence study of two drug products containing glipizide in human plasma samples. PMID- 24771055 TI - Brain tissue distribution of spinosin in rats determined by a new high performance liquid chromatography-electrospray ionization-mass/mass spectrometry method. AB - Spinosin, a flavone-C-glycoside, is a bioactive ingredient isolated from a traditional Chinese herb Zizyphi Spinosi Semen. In this study, a new high performance liquid chromatography-electrospray ionization-mass/mass spectrometry method was developed and validated to determine spinosin in brain tissues including olfactory region, hippocampus, corpus striatum, cerebrum (cerebral cortex) and cerebellum, after intravenous administration with the dose of 5 mg/kg. The tissue homogenate samples were pretreated and extracted with acetonitrile by a simple protein precipitation method. The separation was performed on a YMC ODS-AQ(TM) column (250 * 2.0 mm, 3.5 MUm) with the mobile phase of acetonitrile-aqueous phase (0.1% formic acid) (25 : 75, v/v) at a flow rate of 0.3 mL/min. The retention times of spinosin and naringin (internal standard) were 3.3 and 5.1 min, respectively. Multiple reaction monitoring mode was used to monitor precursor/product ion transitions of m/z 607.2 -> 427.0 for spinosin and m/z 579.2 -> 271.0 for naringin. The proposed method was successfully applied to the preclinical brain tissue distribution of spinosin in rats. The results showed that there was a wide brain regional tissue distribution of spinosin. The concentrations of spinosin in corpus striatum and hippocampus were higher than that in other areas. PMID- 24771056 TI - Simultaneous determination of 11 alkaloids in crude and wine-processed Rhizoma Coptidis by HPLC-PAD. AB - A high-performance liquid chromatography method coupled with photo array diode detector has been developed and validated for simultaneous quantification of 11 active alkaloids in Rhizoma Coptidis (R.C.). The analysis was performed on a Benetnach-C18 column (250 * 4.6 mm, i.d., 5 MUm) using binary gradient elution with 30 mmol/L ammonium bicarbonate water containing 0.7% ammonia solution and 0.1% triethylamine (A) and acetonitrile (B) at a flow rate of 1 mL/min, a column temperature of 35 degrees C and UV detection at 275 nm. All calibration curves showed good linear regression (r > 0.9993) in the range of 6.94-111.03, 0.625 10.10, 6.27-100.14, 31.88-510.50, 16.25-260.70, 19.88-18.20, 3.13-50.70, 0.125 2.14, 16.44-263, 62.5-1,000, 0.125-2.14 MUg/mL for magnoflorine, noroxyhydrastinine, jatrorrhizine, columbamine, epiberberine, coptisine, berberubine, worenine, palmatine, berberine, oxyberberine, respectively. It also showed good precision, repeatability and stability for quantification of these 11 alkaloids. The limit of detections and limit of quantitations for the analytes ranged from 0.031 to 0.423 MUg/mL and from 0.094 to 1.27 MUg/mL, respectively. This method was effective and rapid. The optimized method, which was applied to the determination of alkaloids in crude and wine-processed R.C. samples, was found to be feasible, reliable and suitable for their routine quality control. PMID- 24771057 TI - Determination of aflatoxins in rice samples by ultrasound-assisted matrix solid phase dispersion. AB - This work describes the application of ultrasound-assisted matrix solid-phase dispersion as an extraction and sample preparation approach for aflatoxins (B1, B2, G1 and G2) and subsequent determination of them by high-performance liquid chromatography-fluorescence detection. A Box-Behnken design in combination with response surface methodology was used to determine the affecting parameters on the extraction procedure. The influence of different variables including type of dispersing phase, sample-to-dispersing phase ratio, type and quantity of clean-up phase, ultrasonication time, ultrasonication temperature, nature and volume of the elution solvent was investigated in the optimization study. C18, primary secondary amine (PSA) and acetonitrile were selected as dispersing phase, clean up phase and elution solvent, respectively. The obtained optimized values were sample-to-dispersing phase ratio of 1 : 1, 60 mg of PSA, 11 min ultrasonication time, 30 degrees C ultrasonication temperature and 4 mL acetonitrile. Under the optimal conditions, the limits of detection were ranged from 0.09 to 0.14 ng g( 1) and the precisions [relative standard deviation (RSD%)] were <8.6%. The recoveries of the matrix solid-phase dispersion process ranged from 78 to 83% with RSD <10% in all cases. Finally, this method was successfully applied to the extraction of trace amounts of aflatoxins in rice samples. PMID- 24771059 TI - Crossmodal encoding of motor sequence memories. AB - In this study, we tested the hypothesis that exposure to specific auditory sequences could lead to the crossmodal induction of new motor memories. Twenty young, healthy participants memorized a melody without moving. Each tone in the memorized melody had previously been associated with a particular finger movement. For ten of the participants, the contour of the melody memorized was congruent to a subsequently performed, but never practiced, finger movement sequence (C group, n = 10). For the other ten participants, the melody memorized was incongruent to the subsequent finger movement sequence (InC group, n = 10). Results showed faster performance of the movement sequence in the C group than in the InC group. This difference in motor performance was most pronounced 6 h after melody learning and then dissipated over 30 days. These results provide evidence of a specific, crossmodal encoding of a movement sequence representation through an auditory sequence with the effect on motor performance lasting for several hours. The findings of this study are significant, as the formation of new motor memories through exposure to auditory stimuli may be useful in rehabilitation settings where the initial encoding of motor memories through physical training is disrupted. PMID- 24771058 TI - Control of blood pressure in hypertensive neurological emergencies. AB - Neurological hypertensive emergencies cause significant morbidity and mortality. Most occur in the setting of ischaemic stroke, spontaneous intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH), but other causes relate to hypertensive encephalopathy and reversible cerebral vasoconstriction syndrome (RCVS). Prompt and controlled reduction of blood pressure (BP) is necessary, although there remains uncertainty as to the optimal rate of decline and ideal antihypertensive agent. There is probably no single treatment strategy that covers all neurological hypertensive emergencies. Prompt diagnosis of the underlying disorder, recognition of its severity, and appropriate targeted treatment are required. Lack of comparative-effectiveness data leaves clinicians with limited evidence-based guidance in management, although significant developments have occurred recently in the field. In this article, we review the management of specific neurological hypertensive emergencies, with particular emphasis on recent evidence. PMID- 24771060 TI - Assessment of longitudinal systolic ventricular dysfunction and asynchrony using velocity vector imaging in children with a single right ventricle. AB - Assessment of ventricular dysfunction and asynchrony is very important in predicting the outcome for children with a single right ventricle. However, the assessment is inaccurate and subjective because of the unusual ventricular shape. This study aimed to evaluate the feasibility and clinical value of velocity vector imaging for assessing longitudinal systolic ventricular dysfunction and intraventricular asynchrony in children with a single right ventricle. The study enrolled 36 children with a single right ventricle and 36 age-matched children with a normal heart. Peak systolic velocity, peak displacement, strain, strain rate, time to peak systolic velocity, and time to peak systolic strain were measured via velocity vector imaging using the Siemens Sequoia C512 echocardiography instrument. The maximum positive rate of ventricular pressure change (Max [dp/dt]) was obtained by cardiac catheterization for all the children with a single right ventricle. In the children with a single right ventricle, the maximal temporal differences and the standard deviations of the times to peak systolic velocity and peak systolic strain were higher (P < 0.01) than in the children with a normal heart. Moreover, the strain and strain rate values were significantly lower in all six segments (P < 0.05). The strain rate of the basal segment adjacent to the rudimentary chamber correlated best with Max (dp/dt) (r = 0.86; P < 0.01). Longitudinal systolic dysfunction and intraventricular asynchrony could be assessed accurately using velocity vector imaging in children with a single right ventricle. PMID- 24771061 TI - Establishment of an efficient transformation protocol and its application in marine-derived Bacillus strain. AB - Marine-derived Bacillus strains have been proved to be a very promising source for natural product leads. However, transformation of environmental strains is much more difficult than that of domesticated strains. Here, we report the development of an efficient and robust electroporation-based transformation system for marine-derived Bacillus marinus B-9987, which is a macrolactin antibiotics producer and a very promising biological control agent against fungal plant diseases. The transformation efficiency was greatly enhanced 10(3)-fold by using unmethylated plasmid to bypass modification-restriction barrier, and using glycine betaine to protect cells from electrical damages during electroporation. Addition of HEPES and 2 mmol L(-1) MgCl2 further improved the efficiency by additional 2-fold, with a maximum value of 7.1*10(4) cfu/MUg pHT3101. To demonstrate the feasibility and efficiency of the protocol, a green fluorescent protein reporter system was constructed; furthermore, phosphopantetheinyl transferase gene sfp, which is essential to the biosynthesis of polyketides and nonribosomal peptides, was overexpressed in B-9987, leading to increased production of macrolactin A by about 1.6-fold. In addition, this protocol is also applicable to marine-derived Bacillus licheniforms EI-34-6, indicating it could be a reference for other undomesticated Bacillus strains. To our knowledge, this is the first report regarding the transformation of marine-derived Bacillus strain. PMID- 24771062 TI - Determination of delay time in individual transfer function for central aortic pressure reconstruction. AB - In previous research, time-delay (Deltat) was a more important parameter than the reflection coefficient in the individual transfer function of central aortic pressure reconstruction. The Deltat can be obtained by electrocardiography (ECG) or phonocardiography (PCG). Because the pre-ejection period remains an uncertain factor, the present study used ECG and PCG to define the delay time and analyzed the accuracy of the reconstruction results. The Deltat pre is the actual delay time derived from the aorta to the carotid pressure wave, Deltat PCG is the time delay between the aortic valve component of the second heart sound and the dicrotic incisura of the carotid pressure wave, and Deltat ECG represents the delay from the interval of the ECG R-peak to the foot of the carotid pressure wave. Compared with the measured aortic pressure, the reconstruction result obtained by Deltat=Deltat PCG slightly differed from the best result estimated by Deltat=Deltat pre. However, the differences between the result obtained by Deltat=Deltat ECG and the best result were significant in terms of the diastolic blood pressure, and pulse pressure, and especially in terms of the augmentation index and root-mean-square-error. Thus, the Deltat should be determined by PCG for central aortic pressure reconstruction in practice. PMID- 24771064 TI - TIKI2 suppresses growth of osteosarcoma by targeting Wnt/beta-catenin pathway. AB - Osteosarcoma is the most bone-associated malignancy with high lethality. The current therapeutic strategy benefits little on the survival of patients. Studies have shown that aberrant activation of Wnt/beta-catenin pathway is essential for the progression of osteosarcoma, implying that targeting this signaling may be an effective way of therapeutics. Recently, TIKI family has been identified as a new class of negative regulators for Wnt/beta-catenin pathway. However, the implication of TIKIs with osteosarcoma has not been explored. Here, we constructed an adenoviral vector that expresses TIKI2 in osteosarcoma cells (Ad TIKI2). TIKI2 expression was found to be reduced in osteosarcoma specimens and cell lines. In tested osteosarcoma cells, the activation of Wnt/beta-catenin pathway was found to be inhibited by TIKI2 expression. Furthermore, the proliferation, colony formation ability, and invasion were all significantly suppressed in osteosarcoma cells infected with Ad-TIKI2. Finally, animal experiments further confirmed that TIKI2 restoration was able to inhibit the growth of osteosarcoma in vivo. Taken together, we provided evidence that reduced expression of TIKI family protein in osteosarcoma may participate in the progression of osteosarcoma and restoring its expression was able to impair the growth of osteosarcoma. PMID- 24771066 TI - ZNF580 mediates eNOS expression and endothelial cell migration/proliferation via the TGF-beta1/ALK5/Smad2 pathway. AB - ZNF580 is a novel C2H2 zinc-finger nuclear transcription factor with potential involvement in the transforming growth factor-beta1 (TGF-beta1) signal transduction pathway. Emerging evidence suggests that TGF-beta1 can regulate endothelial nitric oxide synthase (eNOS) expression in endothelial cells. This study aimed to determine if ZNF580 mediated eNOS expression and participated in endothelial cell migration and proliferation via the TGF-beta1/Smad2/ZNF580/eNOS signaling pathway. Overexpression/downexpression of ZNF580 in EAhy926 cells leads to the enhancement/decrease of eNOS expression. TGF-beta1 downregulated both ZNF580 and eNOS at the mRNA and protein levels in concentration- and time dependent manners. ZNF580 and eNOS downregulation induced by TGF-beta1 was blocked by the specific TGF-beta1 type I receptor ALK5 inhibitor, SB431542. Overexpression of ZNF580 attenuated TGF-beta1-induced inhibition of EAhy926 cell growth and mobility, and vice versa. These results suggest that ZNF580 mediates eNOS expression and endothelial cell migration/proliferation via the TGF beta1/ALK5/Smad2 pathway, and thus plays a crucial role in vascular endothelial cells. PMID- 24771065 TI - Lipid metabolites and their differential pro-arrhythmic profiles: of importance in the development of a new anti-arrhythmic pharmacology. AB - Arrhythmias have been treated for a long time with drugs that mainly target the ionic pumps and channels. These anti-arrhythmic regimens per se introduce new arrhythmias, which can be detrimental to patients. Advances in development of novel pharmacology without introduction of iatrogenic arrhythmias are thus favorable for an effective treatment of arrhythmias. Electrophysiological stability of the heart has been shown to be closely associated with cardiac metabolism. The present effective anti-arrhythmic drugs such as beta-blockers and amiodarone have profound beneficial effects in regulating myocardial metabolism. Aiming at decreasing production of toxic metabolites or preventing accumulation of arrhythmogenic lipids perhaps is a good strategy to effectively control arrhythmias. Therefore, a better understanding of the pro-arrhythmic profiles of cardiac metabolites helps to explore a new generation of metabolically oriented anti-arrhythmic medications. In this review, we present several lipid metabolites and summarize their arrhythmogenic characteristics. PMID- 24771067 TI - CYP2E1-mediated oxidative stress regulates HO-1 and GST expression in maneb- and paraquat-treated rat polymorphonuclear leukocytes. AB - Cytochrome P4502E1 (CYP2E1), glutathione-S-transferase A4-4 (GSTA4-4), and inducible nitric oxide synthase (iNOS) are implicated in maneb- and paraquat induced toxicity leading to various pathological conditions. The study aimed to investigate the role of CYP2E1 in maneb- and paraquat-induced oxidative stress in rat polymorphonuclear leukocytes (PMNs) and its crosstalk with iNOS-mediated nitrosative stress and GSTA4-4-linked protective effect, if any and their consequent links with the nuclear factor erythoid 2-related factor 2 (Nrf2) activation and heme oxygenase-1 (HO-1) expression. Rats were treated with/without maneb and/or paraquat for 1, 2, and 3 weeks along with vehicle controls. Subsets of rats were also treated with diallyl sulfide (DAS) or aminoguanidine (AG) along with the respective controls. Maneb and paraquat augmented the reactive oxygen species (ROS), lipid peroxidation (LPO) and 4-hydroxy nonenal (4-HNE) contents, and superoxide dismutase (SOD) activity in the PMNs. However, maneb and paraquat attenuated the reduced glutathione (GSH) level and the expression/activity of total GST and GST-pi. Maneb and paraquat increased the expression/activity of CYP2E1, GSTA4-4, iNOS, Nrf2 and HO-1, and nitrite content. CYP2E1 inhibitor, DAS noticeably alleviated maneb- and paraquat-induced ROS, LPO, 4-HNE, SOD, Nrf2 and HO-1, GST, GSH, and GST-pi while iNOS, nitrite content and GSTA4-4 levels were unchanged. Conversely, AG, an iNOS inhibitor, attenuated maneb- and paraquat directed changes in nitrite, LPO, iNOS but it did not alter ROS, GSH, SOD, GST, GST-pi, Nrf2, HO-1, CYP2E1, and GSTA4-4. The results demonstrate that CYP2E1 induces iNOS-independent free radical generation and subsequently modulates the Nrf2-dependent HO-1 and 4-HNE-mediated GST expression in maneb- and paraquat treated PMNs. PMID- 24771068 TI - Protective effect of pioglitazone, a PPARgamma agonist against acetaminophen induced hepatotoxicity in rats. AB - Acetaminophen has a reasonable safety profile when consumed in therapeutic doses. However, it could induce hepatotoxicity and even acute liver failure when taken at an overdose. Pioglitazone, PPARgamma ligand, is clinically tested and used in treatment of diabetes. PPARgamma is a key nuclear hormone receptor of lipid metabolisms and regulates several gene transcriptions associated with differentiation, growth arrest, and apoptosis. The aim of our study was to evaluate the hepatoprotective activity of pioglitazone on acetaminophen-induced hepatotoxicity and to understand the relationship between the PPARgamma and acetaminophen-induced hepato injury. For the experiment, Sprague-Dawley rats (160 180 g) were used and divided into four groups. Groups I and II were normal and experimental controls, respectively. Groups III and IV received the pioglitazone 20 mg/kg for 10 days. Hepatotoxicity was induced in Groups II and III on the eighth day with acetaminophen (i.p. 350 mg/kg body weight). The hepatoprotective effect was evaluated by performing an assay of the total protein, total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and alpha-fetoprotein as well as glutathione peroxidase, lipid peroxidation, catalase, superoxide dismutase, and glutathione transferase and liver histopathology. The assay results were presented as mean and standard error of mean for each group. The study group was compared with the control group by one-way ANOVA test. A p value of <0.05 was considered significant. Pioglitazone significantly reduced the elevated level of above serum marker enzymes and also inhibits the free radical formation by scavenging hydroxyl ions. It also restored the level of LPO and significantly elevated the levels of endogenous antioxidant enzymes in acetaminophen-challenged hepatotoxicity. Liver histopathological examination showed that pioglitazone administration antagonized acetaminophen induced liver pathological damage. Various biochemical estimations of different hepatic markers and antioxidant enzymes and histopathological studies of liver tissues glimpse a support to its significant hepatoprotective activity on acetaminophen -induced hepatotoxicity. PMID- 24771069 TI - D-penicillamine-induced granulomatous hepatitis in brown Norway rats. AB - The mechanism of idiosyncratic drug reactions (IDRs) remains poorly understood. D penicillamine treatment is associated with a wide range of autoimmune reactions including liver injury. An animal model which utilizes brown Norway (BN) rats has been used to investigate the mechanism of D-penicillamine-induced IDRs because it mimics the autoimmune reactions that occur in humans. The purpose of this study was to investigate the type of liver injury that results from D-penicillamine treatment in BN rats. We had previously noted that D-penicillamine caused histological changes in the liver, but there was no increase in alanine transaminase (ALT), and we assumed that there was no significant injury. However, we subsequently discovered that D-penicillamine inhibits the ALT assay. In the present study, we found that treatment of BN rats with a low doses of D penicillamine (10 or 15 mg/day) resulted in a mild increases in glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities; however, this was not associated with histological changes. A higher dose of D-penicillamine (20 mg/day) resulted in 63% of the rats developing a skin rash, and these rats had elevated serum GLDH and SDH levels with histopathological changes characteristic of granulomatous hepatitis. This included large clusters of leukocytes in the form of granulomas that contained neutrophils, macrophages, and CD8 T cells. These changes did not occur in the rats that did not get sick. This model may be a good model to investigate the characteristics of drug-induced granulomatous hepatitis. PMID- 24771070 TI - Nitric oxide mediates cell aggregation and mesenchymal to epithelial transition in anoikis-resistant lung cancer cells. AB - Cancer cell aggregation has been long known to facilitate metastatic potential of cancer cells. In addition, the presence of nitric oxide (NO) in cancer area may have a significant impact on aggregation behavior of the cells. We show herein that lung cancer H460 cells possessing high ability of anoikis resistance formed loose aggregates in detached condition. Importantly, NO treatment tightened the aggregates by enhancing cell-cell interaction via E-cadherin-dependent mechanism, and such E-cadherin contact increased anoikis resistance potential by up regulating pro-survival signals of the cells including active ATP-dependent tyrosine kinase and extracellular-regulated protein kinases (ERK1/2). Since an increase of E-cadherin was frequently found in mesenchymal to epithelial transition (MET) process, we further tested the cells for MET markers and found that NO treatment of these cells significantly enhanced MET. As aggregation and MET of cancer cells may facilitate cancer metastasis by many means, the insights gained from the present study could benefit the deep understanding in the biology of cancer cell metastasis. PMID- 24771071 TI - Geniposide plays an anti-inflammatory role via regulating TLR4 and downstream signaling pathways in lipopolysaccharide-induced mastitis in mice. AB - Geniposide is a medicine isolated from Gardenia jasminoides Ellis, which is a traditional Chinese herb that is widely used in Asia for the treatment of inflammation, brain diseases, and hepatic disorders. Mastitis is a highly prevalent and important infectious disease. In this study, we used a lipopolysaccharide (LPS)-induced mouse mastitis model and LPS-stimulated primary mouse mammary epithelial cells (mMECs) to explore the anti-inflammatory effect and the mechanism of action of geniposide. Using intraductal injection of LPS as a mouse model of mastitis, we found that geniposide significantly reduced the infiltration of inflammatory cells and downregulated the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin 6 (IL-6). To further investigate the anti-inflammatory mechanism, we used LPS stimulated mMECs as an in vitro mastitis model. The results of enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR) showed that geniposide inhibited the expression of TNF-alpha, IL-1beta, and IL-6 in a dose-dependent manner. Western blot analysis demonstrated that geniposide could suppress the phosphorylation of inhibitory kappa B (IkappaBalpha), nuclear factor-kappaB (NF-kappaB), p38, extracellular signal regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Geniposide also inhibited the expression of toll-like receptor 4 (TLR4) in the LPS-stimulated mMECs. In conclusion, geniposide exerted its anti-inflammatory effect by regulating TLR4 expression, which affected the downstream NF-kappaB and mitogen activated protein kinase (MAPK) signaling pathways. Thus, geniposide may be a potential drug for mastitis therapy. PMID- 24771072 TI - Anti-inflammatory effect of B-type natriuretic peptide postconditioning during myocardial ischemia-reperfusion: involvement of PI3K/Akt signaling pathway. AB - High mobility group box 1 protein (HMGB1) plays an important role in myocardial ischemia-reperfusion (I/R) injury. B-type natriuretic peptide (BNP) postconditioning has been reported to reduce myocardial I/R injury. The present study investigated whether postconditioning of BNP could reduce myocardial I/R injury by inhibiting HMGB1 expression and the potential mechanisms in rats. The left anterior descending coronary arteries of rats were occluded to induce ischemia for 30 min and reopened to imitate reperfusion for 4 h. The rats were treated with BNP (0.03 MUg/kg min, i.v.) 15 min before reperfusion until the end of the procedure, with or without treatment of LY294002 (an inhibitor of phosphoinositide 3-kinase (PI3K), 0.3 mg/kg, i.v.), which was injected 20 min before reperfusion. Lactate dehydrogenase (LDH), creatine kinase (CK), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and infarct size were measured. Phospho-Akt, total Akt, and HMGB1 expression were assessed by immunoblotting. The results showed that treatment of BNP postconditioning could significantly decrease the infarct size and the levels of LDH and CK after 4-h reperfusion (all p<0.05). BNP postconditioning could also significantly inhibit the increases of TNF-alpha and IL-6 (both p<0.05). In addition, BNP postconditioning could significantly inhibit HMGB1 expression induced by I/R (p<0.05). Administration of LY294002 abolished the effects of BNP postconditioning on myocardial I/R injury and the expressions of phospho-Akt and HMGB1 (all p<0.05). The present study suggests that postconditioning of BNP could protect against myocardial I/R injury which may be associated with inhibiting HMGB1 expression, while PI3K/Akt signaling pathway may be involved in the expression of HMGB1 and the protective effect of BNP postconditioning. PMID- 24771073 TI - CRP gene (1059G>C) polymorphism and its plasma levels in ischemic stroke and hemorrhagic stroke in a south Indian population. AB - In the present study, we evaluated the association of 1059G>C polymorphism in C reactive protein (CRP) gene with the risk of ischemic and hemorrhagic strokes. We did not find a significant association of this polymorphism with stroke. However, 2 % of mutants were observed in hemorrhagic stroke patients with a 0.01 frequency for the C allele. We also estimated the high-sensitivity C-reactive protein (hsCRP) levels in hemorrhagic stroke and compared the levels with our already published data on ischemic stroke. The hsCRP level in hemorrhagic stroke was found to be significantly elevated in comparison with that in controls (p<0.001). However, there was no difference in the mean value of hsCRP levels between types of stroke. In conclusion, the G>C polymorphism in the promoter region of the CRP gene is not abundant in the population and cannot be connected with different hsCRP levels and stroke prediction. The CRP level is a useful marker in stroke, but cannot help in differentiating between types of stroke. PMID- 24771074 TI - Orientin inhibits HMGB1-induced inflammatory responses in HUVECs and in murine polymicrobial sepsis. AB - High mobility group box-1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. Orientin has been known to have anxiolytic and antioxidative activities. However, the effect of orientin on HMGB1-induced inflammatory response has not been studied. We assessed this question by monitoring the effects of post-treatment orientin and its derivatives on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of pro-inflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Post-treatment orientin was found to suppress LPS-mediated release of HMGB1 and HMGB1-mediated cytoskeletal rearrangements. Orientin inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. Orientin also induced down-regulation of CLP-induced release of HMGB1 and mortality. Collectively, these results suggest that orientin may be regarded as a candidate therapeutic agent for treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. PMID- 24771075 TI - Yup'ik culture and context in Southwest Alaska: community member perspectives of tradition, social change, and prevention. AB - This paper provides an introduction to key aspects of Yup'ik Inuit culture and context from both historical and contemporary community member perspectives. Its purpose is to provide a framework for understanding the development and implementation of a prevention initiative centered on youth in two communities in Southwest Alaska as part of collaboration with the University of Alaska Fairbanks and the National Institutes of Health. This paper is written from the perspective of elders and local prevention workers from each of the two prevention communities. The co-authors discuss their culture and their community from their own perspectives, drawing from direct experience and from ancestral knowledge gained through learning and living the Yuuyaraq or the Yup'ik way of life. The authors of this paper identity key aspects of traditional Yup'ik culture that once contributed to the adaptability and survivability of their ancestors, particularly through times of hardship and social disruption. These key processes and practices represent dimensions of culture in a Yup'ik context that contribute to personal and collective growth, protection and wellbeing. Intervention development in Yup'ik communities requires bridging historical cultural frames with contemporary contexts and shifting focus from reviving cultural activities to repairing and revitalizing cultural systems that structure community. PMID- 24771076 TI - Metabolic responses of CHO cells to limitation of key amino acids. AB - Chinese hamster ovary (CHO) cells are the predominant host for production of therapeutic glycoproteins. In particular, the glutamine-synthetase (GS) expression system has been widely used in the biopharmaceutical industry for efficient selection of high-yielding clones. However, much remains unclear on how metabolic wiring affects culture performance. For instance, asparagine and serine have been observed to be the largest nitrogen sources taken up by GS-CHO cells, but their roles in biosynthesis and energy generation are poorly understood. In this work, a comprehensive profiling of extracellular metabolites coupled with an analysis of intracellular label distributions after 1-(13) C-pyruvate supplementation were used to trace metabolic rearrangements in different scenarios of asparagine and serine availability. The absence of asparagine in the medium caused growth arrest, and was associated with a dramatic increase in pyruvate uptake, a higher ratio of pyruvate carboxylation to dehydrogenation and an inability for de novo asparagine synthesis. The release of ammonia and amino acids such as aspartate, glutamate, and alanine were deeply impacted. This confirms asparagine to be essential for these GS-CHO cells as the main source of intracellular nitrogen as well as having an important anaplerotic role in TCA cycle activity. In turn, serine unavailability also negatively affected culture growth while triggering its de novo synthesis, confirmed by label incorporation coming from pyruvate, and reduced glycine and formate secretion congruent with its role as a precursor in the metabolism of one-carbon units. Overall, these results unfold important insights into GS-CHO cells metabolism that lay a clearer basis for fine-tuning bioprocess optimization. PMID- 24771079 TI - Prostate-specific antigen density predicts extracapsular extension and increased risk of biochemical recurrence in patients with high-risk prostate cancer who underwent radical prostatectomy. AB - BACKGROUND: Patients with advanced local-stage, high-grade prostate cancer (Pca) and high pretreatment prostate-specific antigen (PSA) levels have inferior outcomes compared to their counterparts with more favorable clinical characteristics. However, some patients exhibit favorable pathological features or experience long-term PSA-free survival after radical prostatectomy (RP). We retrospectively examined the ability of preoperative characteristics to predict pathological and oncological outcomes in high-risk Pca patients who underwent RP. METHODS: We examined data of 1,268 consecutive Pca patients treated with RP alone at 4 hospitals from the Michinoku Urological Cancer Study Group database. Preoperative predictors included age, PSA level, biopsy Gleason score, clinical T stage, and PSA density (PSAD). The outcome measures pathological T stage and PSA free survival were evaluated by multivariate analysis. RESULTS: We identified 380 high-risk Pca patients, of which 44 % patients had extracapsular extension. Logistic regression analysis indicated that PSAD was an independent predictor of adverse pathologic stage. The 5-year PSA-free survival rates were 82.9 % for patients with PSAD <=0.468 ng mL(-1) cm(-2) and 50.7 % for those with PSAD >0.468 ng mL(-1) cm(-2) (P < 0.0001). Multivariate analyses revealed that PSAD, cT, and the number of preoperative high-risk Pca criteria were independent predictors of PSA-free survival. CONCLUSIONS: PSAD may be an independent predictor of advanced pathological features and biochemical recurrence in high-risk Pca patients treated with RP alone. PSAD may be used for further risk stratification of high risk Pca patients. PMID- 24771080 TI - The relationship of glucokinase activator-induced hypoglycemia with arteriopathy, neuronal necrosis, and peripheral neuropathy in nonclinical studies. AB - Glucokinase activators (GKAs) are being developed for the treatment of type 2 diabetes. The toxicity of 4 GKAs (PF-04279405, PF-04651887, piragliatin, and PF 04937319) was assessed in mice, rats, dogs, and/or monkeys. GKAs were administered for 2 to 8 weeks. Standard endpoints, glucose, and insulin were assessed. All compounds produced varying degrees of hypoglycemia in all species. Brain neuronal necrosis and/or peripheral neuropathy were observed with most compounds. These findings are consistent with literature reports linking hypoglycemia with nervous system effects. Arteriopathy, mainly of cardiac vessels, was observed at a low frequency in monkey and/or dog. Arteriopathy occurred only at doses that produced severe and prolonged periods of repeated hypoglycemia. Since this lesion occurred in multiple studies with structurally distinct GKAs, these results suggested arteriopathy was related to GKA pharmacology. The morphological characteristics of the arteriopathy were consistent with that produced by experimental catecholamine administration. We hypothesize that the prolonged periods of hypoglycemia resulted in increased local and/or systemic concentrations of catecholamines via a counterregulatory and/or stress-related mechanism. Alternatively, prolonged hypoglycemia may have resulted in endothelial dysfunction leading to arteriopathy. This risk can be managed in human patients in clinical studies by careful glucose monitoring and intervention to avoid prolonged episodes of hypoglycemia. PMID- 24771081 TI - Spontaneous nonneoplastic lesions in control Syrian hamsters in three 24-month long-term carcinogenicity studies. AB - Information about the incidence of spontaneously occurring, nonneoplastic background findings in Syrian hamsters is essential if Syrian hamsters are to be used for toxicity studies. Male and female Syrian hamsters of the strain Han:AURA from the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) breeding colony were maintained as control animals for carcinogenicity studies and were examined for the presence of nonneoplastic background findings either when they died or when the study was terminated. The nonneoplastic background lesions observed at an incidence of >50% (high), >25% (moderate), and >10% (low) in either male or female animals or in both sexes in one or more long-term studies are detailed. The results are compared to previous published reports of nonneoplastic, spontaneous background lesions in Syrian hamsters. Background information about the incidence of background lesions in Syrian hamsters on short and long-term studies is useful to both toxicologists and toxicological pathologists. PMID- 24771082 TI - Translation strategy for the qualification of drug-induced vascular injury biomarkers. AB - Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commission's Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes. PMID- 24771083 TI - Treatment-associated changes in body composition, health behaviors, and mood as predictors of change in body satisfaction in obese women: effects of age and race/ethnicity. AB - A lack of satisfaction with one's body is common among women with obesity, often prompting unhealthy "dieting." Beyond typically slow improvements in weight and body composition, behavioral factors might also affect change in body satisfaction. Age and race/ethnicity (African American vs. White) might moderate such change. Obese women (N = 246; M(age) = 43 years; M BMI = 39 kg/m(2)) initiating a 6-month cognitive-behaviorally based physical activity and nutrition treatment were assessed on possible predictors of body satisfaction change. At baseline, African American and younger women had significantly higher body satisfaction. The treatment was associated with significant within-group improvements in mood, health behaviors (physical activity and fruit/vegetable intake), and body composition (waist circumference). A multiple regression analysis indicated that mood, health behavior, and body composition changes explained a significant 27% of the variance in body satisfaction change. Of these predictors, changes in mood (beta = -.36, p < .001) and health behaviors (beta = .18, p = .01) made significant, unique contributions to the variance in change in body satisfaction that was accounted for, while only the measure of actual physiological change (body composition) did not. Neither age nor race/ethnicity was a significant moderator when each was entered separately into the multiple regression equation. Practical implications for leveraging manageable changes in behavioral factors for improving body satisfaction were discussed. PMID- 24771086 TI - Prebiotic metabolic networks? AB - A prebiotic origin of metabolism has been proposed as one of several scenarios for the origin of life. In their recent work, Ralser and colleagues (Keller et al, 2014) observe an enzyme-free, metabolism-like reaction network under conditions reproducing a possible prebiotic environment. PMID- 24771084 TI - Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean. AB - The reaction sequences of central metabolism, glycolysis and the pentose phosphate pathway provide essential precursors for nucleic acids, amino acids and lipids. However, their evolutionary origins are not yet understood. Here, we provide evidence that their structure could have been fundamentally shaped by the general chemical environments in earth's earliest oceans. We reconstructed potential scenarios for oceans of the prebiotic Archean based on the composition of early sediments. We report that the resultant reaction milieu catalyses the interconversion of metabolites that in modern organisms constitute glycolysis and the pentose phosphate pathway. The 29 observed reactions include the formation and/or interconversion of glucose, pyruvate, the nucleic acid precursor ribose-5 phosphate and the amino acid precursor erythrose-4-phosphate, antedating reactions sequences similar to that used by the metabolic pathways. Moreover, the Archean ocean mimetic increased the stability of the phosphorylated intermediates and accelerated the rate of intermediate reactions and pyruvate production. The catalytic capacity of the reconstructed ocean milieu was attributable to its metal content. The reactions were particularly sensitive to ferrous iron Fe(II), which is understood to have had high concentrations in the Archean oceans. These observations reveal that reaction sequences that constitute central carbon metabolism could have been constrained by the iron-rich oceanic environment of the early Archean. The origin of metabolism could thus date back to the prebiotic world. PMID- 24771088 TI - Parasitic manipulation of hosts' phenotype, or how to make a zombie--an introduction to the symposium. AB - Nearly all animals in nature are infected by at least one parasite, and many of those parasites can significantly change the phenotype of their hosts, often in ways that increase the parasite's likelihood of transmission. Hosts' phenotypic changes are multidimensional, and manipulated traits include behavior, neurotransmission, coloration, morphology, and hormone levels. The field of parasitic manipulation of hosts' phenotype has now accrued many examples of systems where parasites manipulate the phenotypes of their hosts and focus has shifted to answering three main questions. First, through what mechanisms do parasites manipulate the hosts' phenotype? Parasites often induce changes in the hosts' phenotypes that neuroscientists are unable to recreate under laboratory conditions, suggesting that parasites may have much to teach us about links between the brain, immune system, and the expression of phenotype. Second, what are the ecological implications of phenotypic manipulation? Manipulated hosts are often abundant, and changes in their phenotype may have important population, community, and ecosystem-level implications. Finally, how did parasitic manipulation of hosts' phenotype evolve? The selective pressures faced by parasites are extremely complex, often with multiple hosts that are actively resisting infection, both in physiological and evolutionary time-scales. Here, we provide an overview of how the work presented in this special issue contributes to tackling these three main questions. Studies on parasites' manipulation of their hosts' phenotype are undertaken largely by parasitologists, and a major goal of this symposium is to recruit researchers from other fields to the study of these phenomena. Our ability to answer the three questions outlined above would be greatly enhanced by participation from individuals trained in the fields of, for example, neurobiology, physiology, immunology, ecology, evolutionary biology, and invertebrate biology. Conversely, because parasites that alter their hosts' phenotype are widespread, these fields will benefit from such study. PMID- 24771087 TI - Old cell, new trick? Cnidocytes as a model for the evolution of novelty. AB - Understanding how new cell types arise is critical for understanding the evolution of organismal complexity. Questions of this nature, however, can be difficult to answer due to the challenge associated with defining the identity of a truly novel cell. Cnidarians (anemones, jellies, and their allies) provide a unique opportunity to investigate the molecular regulation and development of cell-novelty because they possess a cell that is unique to the cnidarian lineage and that also has a very well-characterized phenotype: the cnidocyte (stinging cell). Because cnidocytes are thought to differentiate from the cell lineage that also gives rise to neurons, cnidocytes can be expected to express many of the same genes expressed in their neural "sister" cells. Conversely, only cnidocytes posses a cnidocyst (the explosive organelle that gives cnidocytes their sting); therefore, those genes or gene-regulatory relationships required for the development of the cnidocyst can be expected to be expressed uniquely (or in unique combination) in cnidocytes. This system provides an important opportunity to: (1) construct the gene-regulatory network (GRN) underlying the differentiation of cnidocytes, (2) assess the relative contributions of both conserved and derived genes in the cnidocyte GRN, and (3) test hypotheses about the role of novel regulatory relationships in the generation of novel cell types. In this review, we summarize common challenges to studying the evolution of novelty, introduce the utility of cnidocyte differentiation in the model cnidarian, Nematostella vectensis, as a means of overcoming these challenges, and describe an experimental approach that leverages comparative tissue-specific transcriptomics to generate hypotheses about the GRNs underlying the acquisition of the cnidocyte identity. PMID- 24771089 TI - Changes in coffee intake and subsequent risk of type 2 diabetes: three large cohorts of US men and women. AB - AIMS/HYPOTHESIS: Coffee and tea consumption has been associated with a lower type 2 diabetes risk but little is known about how changes in coffee and tea consumption influence subsequent type 2 diabetes risk. We examined the associations between 4 year changes in coffee and tea consumption and risk of type 2 diabetes in the subsequent 4 years. METHODS: We prospectively followed 48,464 women in the Nurses' Health Study (NHS; 1986-2006), 47,510 women in NHS II (1991-2007) and 27,759 men in the Health Professionals Follow-up Study (HPFS; 1986-2006). Diet was assessed every 4 years using a validated food-frequency questionnaire. Self-reported cases of incident type 2 diabetes were validated by supplementary questionnaires. RESULTS: During 1,663,319 person-years of follow up, we documented 7,269 cases of incident type 2 diabetes. Participants who increased their coffee consumption by more than 1 cup/day (median change = 1.69 cups/day) over a 4 year period had an 11% (95% CI 3%, 18%) lower risk of type 2 diabetes in the subsequent 4 years compared with those who made no changes in consumption. Participants who decreased their coffee intake by more than 1 cup/day (median change = -2 cups/day) had a 17% (95% CI 8%, 26%) higher risk for type 2 diabetes. Changes in tea consumption were not associated with type 2 diabetes risk. CONCLUSIONS/INTERPRETATION: Our data provide novel evidence that increasing coffee consumption over a 4 year period is associated with a lower risk of type 2 diabetes, while decreasing coffee consumption is associated with a higher risk of type 2 diabetes in subsequent years. PMID- 24771090 TI - Basal insulin glargine and microvascular outcomes in dysglycaemic individuals: results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial. AB - AIMS/HYPOTHESIS: As glycaemia and the incidence of microvascular diabetes complications follow a log-linear relationship, it becomes increasingly difficult to demonstrate a microvascular benefit of glucose-lowering when the HbA1c level is close to normal. METHODS: The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomised 12,537 people with diabetes, impaired glucose tolerance or impaired fasting glucose to receive standard glycaemic care or standard care with the addition of basal insulin glargine (A21Gly,B31Arg,B32Arg human insulin), targeting a fasting plasma glucose level <=5.3 mmol/l. Microvascular outcomes during a median follow-up of 6.2 years were examined in participants whose baseline HbA1c was above or below the median of 6.4% (46.4 mmol/mol). RESULTS: Allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA1c level was >=6.4% (46.4 mmol/mol; HR 0.90 [95% CI 0.81, 0.99]) but not in participants with a lower baseline HbA1c (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). In people whose baseline HbA1c level was >=6.4% (46.4 mmol/mol), the median post-randomisation change in HbA1c was -0.65% (interquartile range -0.16, -0.91%) after allocation to insulin glargine and -0.33% (-0.83, 0.13%) after allocation to standard care (median HbA1c difference 0.33%; p < 0.0001). A smaller median difference of 0.22% was noted in people whose baseline HbA1c was <6.4% (p < 0.0001). CONCLUSIONS/INTERPRETATION: In patients with dysglycaemia, intervention targeting normal fasting glucose levels reduced HbA1c and attenuated the risk of microvascular outcomes in participants with a baseline HbA1c level >=6.4% (46.4 mmol/mol). A neutral effect was seen in those with a lower baseline HbA1c level. TRIAL REGISTRATION: ClinicalTrials.gov NCT00069784. PMID- 24771091 TI - Hepatic 11beta-hydroxysteroid dehydrogenase type 1 activity in obesity and type 2 diabetes using a novel triple tracer cortisol technique. AB - AIMS/HYPOTHESIS: Dysregulation of 11beta-hydroxysteroid dehydrogenase (11beta HSD) enzyme activities are implicated in the pathogenesis of obesity and insulin resistance. The aim of the study was to determine whether hepatic 11beta-HSD type 1 (11beta-HSD-1) enzyme activity differs in people with and without obesity and type 2 diabetes. METHODS: We measured hepatic 11beta-HSD-1 activity in the overnight fasted state in 20 lean non-diabetic participants (LND), 21 overweight/obese non-diabetic participants (OND) and 20 overweight/obese participants with type 2 diabetes (ODM) using a non-invasive approach. One mg doses of [9,12,12-(2)H3]cortisol (D cortisol) and [4-(13)C]cortisone ([(13)C]cortisone) were ingested, while [1,2,6,7-(3)H]cortisol ([(3)H] cortisol) was infused intravenously to enable concurrent measurements of first-pass hepatic extraction of ingested D cortisol and hepatic conversion of ingested [(13)C]cortisone to C13 cortisol derived from the ingested cortisone (a measure of 11beta-HSD-1 activity in the liver) using an isotope dilution technique. One way ANOVA models and Kruskal-Wallis tests were used to test the hypothesis. RESULTS: Plasma D cortisol and C13 cortisol concentrations were lower in OND than in LND (p < 0.05) over 6 h of the study. There was no difference (p = 0.15) in C13 and D cortisol concentrations between OND and ODM and between LND and ODM for the same study period. Hepatic conversion of [(13)C]cortisone to C13 cortisol was similar between groups. CONCLUSIONS/INTERPRETATION: Hepatic conversion of [(13)C]cortisone to C13 cortisol did not differ between the groups studied. We conclude that hepatic 11beta-HSD-1 activity is similar in individuals who are overweight/obese or who have type 2 diabetes. PMID- 24771092 TI - The CCR5Delta32 polymorphism as a pre-eclampsia susceptibility marker: an evaluation in Brazilian women. PMID- 24771093 TI - Chemical shift assignments of a reduced N-terminal truncation mutant of the disulfide bond isomerase TrbB from plasmid F, TrbBDelta29. AB - TrbB from the conjugative plasmid F is a 181-residue disulfide bond isomerase that plays a role in the correct folding and maintenance of disulfide bonds within F plasmid encoded proteins in the bacterial periplasm. As a member of the thioredoxin-like superfamily, TrbB has a predicted thioredoxin-like fold that contains a C-X-X-C active site required for performing specific redox chemistries on protein substrates. Here we report the sequence-specific assignments of the reduced form of the N-terminally truncated TrbB construct, TrbBDelta29. PMID- 24771094 TI - Gadobenate-dimeglumine-enhanced magnetic resonance imaging for hepatic lesions in children. AB - BACKGROUND: Magnetic resonance imaging enhanced by hepatocyte-specific contrast media has been found useful to characterize liver lesions in adults and children. OBJECTIVE: To present our experience with gadobenate dimeglumine (Gd-BOPTA) enhanced MRI for evaluation of focal liver lesions in children. MATERIALS AND METHODS: We retrospectively reviewed gadobenate-dimeglumine-enhanced MR images obtained for evaluation of suspected hepatic lesions in 30 children. Signal characteristics on various sequences including 45- to 60-min hepatobiliary phase images were noted by two radiologists. Chart review identified relevant clinical details including history of cancer treatment, available pathology and stability of lesion size on follow-up imaging. RESULTS: Of the 30 children who had gadobenate-enhanced MRI, 26 showed focal lesions. Diagnoses in 26 children were focal nodular hyperplasia (FNH) in 15, hemangiomas in 3, regenerating nodules in 3, focal fatty infiltration in 2, indeterminate lesions in 3, and one patient each with adenomas, hepatoblastoma and metastasis. Two patients had multiple diagnoses. All FNH lesions (39), all regenerative nodules (19) and an indeterminate lesion were iso- or hyperintense on hepatobiliary-phase images while all other lesions (28) were hypointense to hepatic parenchyma. The average follow-up period was 21.7 months. CONCLUSION: Our experience with gadobenate enhanced MRI indicates potential utility of gadobenate in the evaluation of pediatric hepatic lesions in differentiating FNH and regenerating nodules from other lesions. PMID- 24771095 TI - Frequency of intrathoracic injuries in children younger than 3 years with rib fractures. AB - BACKGROUND: Research documents that among children admitted to trauma intensive care units the number of rib fractures sustained indicates the child's likelihood of having and severity of intrathoracic injury. This has been misused in court to argue that children with multiple rib fractures who lack intrathoracic injury have abnormal bone fragility rather than inflicted injury. OBJECTIVE: To determine frequency of intrathoracic injuries in children younger than 3 years with rib fractures in cases of child abuse and accidental trauma. MATERIALS AND METHODS: We conducted a retrospective review of rib fractures caused by documented abuse or accidents from 2003 to 2010 in children treated at Seattle Children's Hospital and Harborview Medical Center. A senior pediatric radiologist and radiology fellow independently reviewed the imaging. Children with bone demineralization were excluded. Descriptive and simple comparative statistics were used. RESULTS: Seventy-two percent (47/65) of infants and toddlers with rib fractures were abused. Abused children had more rib fractures than accidentally injured children (5.55 vs. 3.11, P = 0.012). However intrathoracic injuries as a whole (55.6% vs. 12.8%, P < 0.001) and individual types of intrathoracic injuries were more common with accidents. Rates of other thoracic cage injuries did not differ substantially (27.8% accidents vs. 12.8% abuse, P = 0.064). Intracranial and intra-abdominal injuries and skull fractures were equally frequent, but other extrathoracic fractures were more common with abuse (70.2% vs. 16.7%, P < 0.001). CONCLUSIONS: Abused infants and toddlers have fewer intrathoracic injuries but more rib fractures than accidentally injured peers. This likely reflects different injury mechanics. Lack of intrathoracic injuries in abused children with rib fractures does not imply bone fragility. PMID- 24771096 TI - Additional imaging features of intramuscular capillary-type hemangioma: the importance of ultrasound. PMID- 24771097 TI - Reply to Merrow et al. regarding additional imaging features of intramuscular capillary-type hemangioma and the importance of ultrasound. PMID- 24771098 TI - Neurofibromatosis 1 vasculopathy manifesting as a peripheral aneurysm in an adolescent. AB - Arterial vasculopathy is a well-recognized but uncommon manifestation of neurofibromatosis type 1 (NF-1). It can manifest as stenoses, aneurysms or arteriovenous malformations. NF-1 vasculopathy typically involves the aorta, visceral arteries or carotid-vertebral circulation. Aortic and visceral vasculopathy typically presents as stenotic lesions, while aneurysms have been reported primarily in the subclavian/vertebral arteries. Aneurysms of the peripheral/extremity arteries are an extremely rare complication of NF-1 that may present as a mass or spontaneous rupture. We present the case of a teenage boy with an arm mass secondary to an aneurysm. We hope this case will increase recognition of the variable clinical manifestations of NF-1 vasculopathy among radiologists. PMID- 24771099 TI - [The use and benefit of the 'children with special health care needs screener' in the paediatric school entrance examinations 2004/2005 in Cologne]. AB - The aim of this study was to provide an assessment of the usefulness of the questionnaire "Children with Special Health Care Needs Screener" (CSHCN Screener) as a screening instrument to identify children with special needs in the context of paediatric school entrance examinations (SEE).In a retrospective cross sectional study of the years 2004 and 2005 in Cologne, Germany, the sum variables were derived from the results of the SEE in accordance to the 7 questions of the CSHCN Screener. The correlations of the SEE sum variables and the CSHCN Screener results were analysed and tested for correlations with sociodemographic factors.Of the 18 402 children of the cohorts 2004/2005, corresponding SEE findings and results of the CSHCN Screener were available for 13 076 children. The prevalence of children with special needs was only 6% according to the results of the CSHCN Screener. According to the SEE, however, 26% of the children showed diseases or developmental problems. Out of this group, only one in 8 children was identified by the CSHCN Screener (sensitivity 13%). The sensitivity of the screener was also 13% for children who had been diagnosed to be in need of special support by school physicians. In the case of girls and of children with migration family backgrounds, the sensitivity of the screener was even lower. The CSHCN Screener also could not detect the higher rate of special needs determined by school physicians in children from areas with high quotas of state family support payments.The results of the CSHCN Screener are not convincing, due to his low sensitivity. This is true with regard to its use as a diagnostic tool for the individual child at the beginning of school age as well for its use as an instrument to assess an increased need for support in cohorts of school entry students. PMID- 24771100 TI - [Psychosocial situation of families with chronically ill children: a survey of parent initiatives]. AB - Children with chronic illness or disabilities and their families require more support than healthy families. The working group "custodial and psychosocial supply" defined 4 theses to figure out deficits and targets of family support: 1) my child is different; 2) my child is not devisable; 3) my child needs strong helpers; and 4) my child needs safety.Based on these theses, a questionnaire for parents was designed of which 20 were sent to 34 parent initiatives in Germany each, for distribution to a random sample of member families.499/680 questionnaires were returned of which 419 could be included in the analysis. Less than 50% of the parents felt adequately and timely informed about their child's condition, and support for coping with the child's diagnosis was rarely given. Less than half of the parents reported to have been informed about the options for support within the German social system, and less than 15% were aware of instructions for clearing houses on care and support. About a third of the parents reported needs for managing family, siblings or household, but only a third of these had been offered organised and structured family support. More than 50% of the families reported restraints in participating in social life: such restraints were associated with problems in partnership and loss of friends. Half of the parents felt restraints of the family income because of their child's condition.There is need for improvement of the psychosocial condition of families with chronically ill or disabled children by better, more and timely information about the child's clinical condition, access to the social support system and availability of support services. PMID- 24771102 TI - [Are health inequalities increasing with time? Results of a literature review and recommendations for further research]. AB - It has been shown that socio-economic status (SES) and health are closely linked to one another. Now we focus on further questions, and one of the most important ones is whether these "health inequalities" increase with time. In Germany, there is little discussion about this question and no review summarising the empirical evidence is available.This review focuses on 4 dimensions: time trends of health inequalities concerning mortality (or, respectively, life expectancy), self-rated health, smoking and obesity. First we included all empirical analyses from Germany, and all analyses from other European countries published between 2008 and 2012. Then, step-wise, 44 studies (including 5 from Germany) were selected by predefined criteria for a detailed -description of empirical results and methods.The number of publications has strong-ly increased in recent years, illustrating the growing interest in time trends of health inequalities. The empirical results of the 44 studies could be summarised in the following way: All in all, 184 empirical results are reported about time trends in health inequalities and 112 of them show increasing inequalities; decreasing inequalities are shown in 13 reports. The studies from Germany point in the same direction (i. e., most results indicate increasing health inequalities). It is also important to stress that there is great -heterogeneity concerning the methodical approaches. Some studies analyse health inequalities by individual socio-economic status (e. g., educational level), others by regional deprivation. Sometimes changes in the extent of health inequalities over time are not calculated explicitly. Some papers do not include absolute and relative measures of inequalities, but just one of them.In Germany, there is a need for more empirical studies looking at time trends of health inequalities; the available datasets should be used more often for this type of analysis. If possible, further studies should include individual SES and regional deprivation, measures of absolute and relative inequality (stratified by sex, with significance tests for time trend), and they should cover as many points in time as possible. Also, it would be important to relate the chang-es in health inequalities to the other changes in the society. PMID- 24771101 TI - [Nursing tasks left undone in German acute care hospitals - results from the international study RN4Cast]. AB - BACKGROUND: Implicit rationing of nursing care - likewise as in medical care - has never been empirically measured in German hospitals. Thus, little is known about prevalence and patterns of nursing care left undone as well as its association with nurse work environment and staffing. METHODOLOGY: We surveyed 1,511 registered nurses from 49 German acute hospitals participating in the multi country cross-sectional study RN4CAST. Analyses were made by descriptive statistics as well as multilevel regression analysis to calculate predictors from the nurse work environment and staffing. RESULTS: On average 4.7 out of 13 nursing tasks were rationed. The range was between 82% for "comfort/talk with patients" and 15% for "treatments and procedures". The analysis revealed that hospital work environments and staffing ratios were significantly associated with the level of nursing care left undone. Further significant associations were found between poor leadership, inadequate organisation of nursing work as well as high emotional exhaustion and rationing. DISCUSSION: The phenomenon of nursing care left undone was prevalent in German hospitals. Those tasks which are most likely to have negative consequences for patients (e. g., pain management and medication on time) seem to receive higher priority than tasks whose potential effects are less immediate or direct (e. g., psychosocial care). With regard to the measured correlation with the nurse work environment, it is recommend to invest in a good environment before (or simultaneously) investing in nurse staffing. PMID- 24771104 TI - Exoelectrogenic biofilm as a template for sustainable formation of a catalytic mesoporous structure. AB - Mesoporous structures can increase catalytic activity by maximizing the ratio of surface area to volume, but current synthesis techniques utilize expensive polymers and toxic chemicals. A Geobacter sulfurreducens biofilm was used as a sustainable template to form mesoporous Pd structures while eliminating the need for synthetic chemicals. The bulk of the biofilm material was removed by thermal treatments after nanoparticle formation, producing a catalytic Pd mesoporous (pore size 9.7 +/- 0.1 nm) structure attached to the graphite electrode with a 1.5-2 um thick backbone composed of nanoparticles (~200 nm). A control electrode electrochemically plated with Pd in the absence of a biofilm exhibited a variable planar Pd base (~0.5-3 um thick) with sporadic Pd extrusions (~2 um across, 1-5 um tall) from the surface. The biotemplated mesoporous structure produced 15-20% higher stable current densities during H2 oxidation tests than the electrochemically plated control electrode, even though 30% less Pd was present in the biotemplated catalyst. These results indicate that electroactive biofilms can be used as a sustainable base material to produce nanoporous structures without the need for synthetic polymers. Biotechnol. Bioeng. 2014;111: 2349-2354. (c) 2014 Wiley Periodicals, Inc. PMID- 24771103 TI - Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase. AB - PURPOSE: Asparaginase is an essential component of pediatric acute lymphoblastic leukemia (ALL) therapy. However, asparaginase-induced hypersensitivity reactions can compromise its efficacy either by directly influencing the pharmacokinetics of asparaginase or by leading to a discontinuation of asparaginase treatment. Here, we report successful challenges using native Escherichia coli asparaginase after previous hypersensitivity reactions to both PEGylated E. coli asparaginase and Erwinia asparaginase. PATIENTS AND METHODS: The two patients included in this case report were diagnosed with B-precursor ALL at St. Jude Children's Research Hospital and were treated with a common regimen. Both patients developed hypersensitivity reactions to PEGylated E. coli asparaginase and Erwinia asparaginase early in treatment, and they were challenged with native E. coli asparaginase. Serum samples were collected for estimating the pharmacokinetic parameters of each patient during native E. coli asparaginase therapy. RESULTS: Challenges with native E. coli asparaginase were successful, and asparaginase serum concentrations above therapeutic levels were attained in both patients. CONCLUSIONS: These two cases suggest that some patients can be given native E. coli asparaginase after hypersensitivity reactions to PEGylated asparaginase and achieve therapeutic concentrations of the drug in serum. PMID- 24771106 TI - What causes breast cancer? A systematic review of causal attributions among breast cancer survivors and how these compare to expert-endorsed risk factors. AB - PURPOSE: The aim of this paper was to review published research that analyzed causal attributions for breast cancer among women previously diagnosed with breast cancer. These attributions were compared with risk factors identified by published scientific evidence in order to determine the level of agreement between cancer survivors' attributions and expert opinion. METHODS: A comprehensive search for articles, published between 1982 and 2012, reporting studies on causal attributions for breast cancer among patients and survivors was undertaken. Of 5,135 potentially relevant articles, 22 studies met the inclusion criteria. Two additional articles were sourced from reference lists of included studies. RESULTS: Results indicated a consistent belief among survivors that their own breast cancer could be attributed to family history, environmental factors, stress, fate, or chance. Lifestyle factors were less frequently identified, despite expert health information highlighting the importance of these factors in controlling and modifying cancer risk. This review demonstrated that misperceptions about the contribution of modifiable lifestyle factors to the risk of breast cancer have remained largely unchanged over the past 30 years. CONCLUSIONS: The findings of this review indicate that beliefs about the causes of breast cancer among affected women are not always consistent with the judgement of experts. Breast cancer survivors did not regularly identify causal factors supported by expert consensus such as age, physical inactivity, breast density, alcohol consumption, and reproductive history. Further research examining psychological predictors of attributions and the impact of cancer prevention messages on adjustment and well-being of cancer survivors is warranted. PMID- 24771105 TI - Treatment and physiology in Parkinson's disease and dystonia: using transcranial magnetic stimulation to uncover the mechanisms of action. AB - Transcranial magnetic stimulation (TMS) has served as an important technological breakthrough in the field of the physiology of movement disorders over the last three decades. TMS has grown popular owing to the ease of application as well as its painless and noninvasive character. The technique has provide important insights into understanding the pathophysiology of movement disorders, particularly Parkinson's disease and dystonia. The basic applications have included the study of motor cortex excitability, functioning of excitatory and inhibitory circuits, study of interactions between sensory and motor systems, and the plasticity response of the brain. TMS has also made important contributions to understanding the response to treatments such as dopaminergic medications, botulinum toxin injections, and deep brain stimulation surgery. This review summarizes the knowledge gained to date with TMS in Parkinson's disease and dystonia, and highlights the current challenges in the use of TMS technology. PMID- 24771107 TI - Assessing oral cancer knowledge in Romanian undergraduate dental students. AB - The aim of this study is to investigate the level of Romanian dental students' knowledge regarding the oral cancer risk and non-risk factors as well as oral cancer signs, symptoms, and diagnostic signs. A total of 192 first- to sixth-year undergraduate dental students (mean age 22.20 +/- 2.94 years) who consented to participate in the study filled in a questionnaire enquiring about their knowledge of oral cancer. A score of the oral cancer knowledge was calculated for each participant based on their correct answers. Regarding the knowledge of oral cancer risk factors, the vast majority of the students correctly recognized tobacco (96.8 %), having a prior oral cancer lesion (85.1 %), the consumption of alcohol (77.7 %), and older age (64.2 %). Respectively, 87.7 and 54.3 % knew the tongue and the floor of mouth to be the most common oral cancer sites. Of the students, 71.3 % agreed that oral cancer examinations for those 20 years of age and older should be provided during regular periodic health examinations, 92.9 % considered that patients with suspicious oral lesions should be referred to specialists, and 84.6 % agreed that oral cancer examinations should be a routine part of a comprehensive oral examination. A significant association was found between the year of study in the dental school, age, and knowledge of the oral cancer knowledge scores. Although students' knowledge increased with academic year, there is a clear need to enhance the dental curricula in oral cancer clinical training in oral cancer prevention and examination for dental students. PMID- 24771108 TI - Tim-3 cell signaling and iNOS are involved in the protective effects of ischemic postconditioning against focal ischemia in rats. AB - The protective effect of ischemic postconditioning (IPostC) against stroke has been well-established, and the underlying mechanisms are known to involve inhibited-inflammation and free radical production. Nevertheless, how IPostC affects protein expression of iNOS, nitrotyrosine, and COX-2 has not been characterized. In addition, the role of the galectin-9/Tim-3 cell signaling pathway--a novel inflammatory pathway--in IPostC has not been studied. We examined whether iNOS, nitrotyrosine, and COX-2, as well as galectin-9/Tim-3 are involved in the protective effects of IpostC in a rat focal ischemia model. Western blot and confocal immunofluoresent staining results indicate that IPostC significantly inhibited Tim-3 expression, and that galectin-9 expression was also inhibited. In addition, IPostC attenuated production of iNOS and nitrotyrosine, but not COX-2, suggesting that IPostC has distinct effects on these inflammatory factors. Furthermore, the inflammation inhibitor minocycline blocked Tim-3 and iNOS expression induced by stroke. Taken together, we show that the galectin 9/Tim-3 cell signaling pathway is involved in inflammation induced by stroke, and IPostC may reduce infarction by attenuating this novel pathway as well as the inflammatory factors iNOS and nitrotyrosine, but not COX-2. PMID- 24771109 TI - Effects of diabetes on brain metabolism--is brain glycogen a significant player? AB - Brain glycogen, being an intracellular glucose reservoir, contributes to maintain energy and neurotransmitter homeostasis under physiological as well as pathological conditions. Under conditions with a disturbance in systemic glucose metabolism such as in diabetes, the supply of glucose to the brain may be affected and have important impacts on brain metabolism and neurotransmission. This also implies that brain glycogen may serve an essential role in the diabetic state to sustain appropriate brain function. There are two main types of diabetes; type 1 and type 2 diabetes and both types may be associated with brain impairments e.g. cognitive decline and dementia. It is however, not clear how these impairments on brain function are linked to alterations in brain energy and neurotransmitter metabolism. In this review, we will illuminate how rodent diabetes models have contributed to a better understanding of how brain energy and neurotransmitter metabolism is affected in diabetes. There will be a particular focus on the role of brain glycogen to support glycolytic and TCA cycle activity as well as glutamate-glutamine cycle in type 1 and type 2 diabetes. PMID- 24771111 TI - Fluorescence in situ hybridization and qPCR to detect Merkel cell polyomavirus physical status and load in Merkel cell carcinomas. AB - The Merkel cell polyomavirus (MCPyV) is detected in 80% of Merkel cell carcinomas (MCC). Clonal integration and tumor-specific mutations in the large T antigen are strong arguments that MCPyV is a human tumor virus. However, the relationship between viral presence and cancer induction remains discussed controversially. Since almost all studies on virus prevalence are based on PCR techniques, we performed MCPyV fluorescence in situ hybridization (FISH) on MCC to gain information about the quality of the viral presence on the single cell level. MCPyV-FISH was performed on tissue microarrays containing 62 formalin-fixed and paraffin-embedded tissue samples including all tumor grades of 42 patients. The hybridization patterns were correlated to the qPCR data determined on corresponding whole tissue sections. Indeed, MCPyV-FISH and qPCR data were highly correlated, i.e. 83% for FISH-positive and 93% for FISH-negative cores. Accordingly, the mean of the qPCR values of all MCPyV-positive cores differed significantly from the mean of the negative cores (p = 0.0076). Importantly, two hybridization patterns were definable in the MCPyV-FISH: a punctate pattern (85%) indicating viral integration, which correlated with a moderate viral abundance and a combination of the punctate with a diffuse pattern (15%), suggesting a possible coexistence of integrated and episomal virus which was associated with very high viral load and VP1 expression. Thus, MCPyV-FISH adds important information on the single cell level within the histomorphological context and could therefore be an important tool to further elucidate MCPyV related carcinogenesis. PMID- 24771110 TI - Ablation of matrix metalloproteinase-9 gene decreases cerebrovascular permeability and fibrinogen deposition post traumatic brain injury in mice. AB - Traumatic brain injury (TBI) is accompanied with enhanced matrix metalloproteinase-9 (MMP-9) activity and elevated levels of plasma fibrinogen (Fg), which is a known inflammatory agent. Activation of MMP-9 and increase in blood content of Fg (i.e. hyperfibrinogenemia, HFg) both contribute to cerebrovascular disorders leading to blood brain barrier disruption. It is well known that activation of MMP-9 contributes to vascular permeability. It has been shown that at an elevated level (i.e. HFg) Fg disrupts blood brain barrier. However, mechanisms of their actions during TBI are not known. Mild TBI was induced in wild type (WT, C57BL/6 J) and MMP-9 gene knockout (Mmp9(-/-)) homozygous, mice. Pial venular permeability to fluorescein isothiocyanate conjugated bovine serum albumin in pericontusional area was observed 14 days after injury. Mice memory was tested with a novel object recognition test. Increased expression of Fg endothelial receptor intercellular adhesion protein-1 and formation of caveolae were associated with enhanced activity of MMP-9 causing an increase in pial venular permeability. As a result, an enhanced deposition of Fg and cellular prion protein (PrP(C)) were found in pericontusional area. These changes were attenuated in Mmp9(-/-) mice and were associated with lesser loss of short-term memory in these mice than in WT mice. Our data suggest that mild TBI induced increased cerebrovascular permeability enhances deposition of Fg-PrP(C) and loss of memory, which is ameliorated in the absence of MMP-9 activity. Thus, targeting MMP-9 activity and blood level of Fg can be a possible therapeutic remedy to diminish vasculo-neuronal damage after TBI. PMID- 24771112 TI - Cost-effectiveness of treatment strategies using combination disease-modifying anti-rheumatic drugs and glucocorticoids in early rheumatoid arthritis. AB - OBJECTIVE: The aim of this study was to estimate the cost-effectiveness of combination DMARDs with short-term glucocorticoids in early active RA using data from the 2-year Combination of Anti-Rheumatic Drugs in Early RA (CARDERA) trial. METHODS: CARDERA enrolled 467 patients with active RA of <24-months duration. All patients received MTX; half received step-down prednisolone and half ciclosporin in a placebo-controlled factorial design. Differences in mean costs and quality adjusted life-years (QALYs) over 24-months follow-up were estimated using patient level data from a UK health service perspective and 2011-12 costs. RESULTS: Two year costs for each treatment strategy showed primary care costs were negligible across all groups. Drug costs were lowest with MTX/ciclosporin and triple therapy. Hospital costs were lowest with MTX/prednisolone and triple therapy. Triple therapy was least costly and most effective; it dominated all other strategies. At positive values for a QALY in the typical UK range (L20 000-30 000) the probability that triple therapy was the most cost-effective strategy was 0.9. Results were robust to methods used to impute missing data. CONCLUSION: Intensive treatment of early RA with triple therapy (two DMARDs and short-term glucocorticoids) is both clinically effective and cost effective. PMID- 24771116 TI - Two different microarray technologies for preimplantation genetic diagnosis and screening, due to reciprocal translocation imbalances, demonstrate equivalent euploidy and clinical pregnancy rates. AB - PURPOSE: To compare single nucleotide polymorphism (SNP) and comparative genomic hybridization (aCGH) microarray platforms to evaluate embryos for parental translocation imbalances and aneuploidy. METHODS: A retrospective review of preimplantation genetic diagnosis and screening (PGD/PGS) results of 498 embryos from 63 couples undergoing 75 in vitro fertilization cycles due to parental carriers of a reciprocal translocation. RESULTS: There was no significant difference between SNP and aCGH microarrays when comparing the prevalence of embryos that were euploid with no translocation imbalance, euploidy with a parental translocation imbalance or aneuploid with or without the parental chromosome imbalance. The clinical pregnancy rates were also equivalent for SNP (60 %) versus aCGH (65 %) microarrays. Of 498 diagnosed embryos, 45 % (226/498) were chromosomally normal without translocation errors or aneuploidy, 22 % (112/498) were euploid but had a parentally derived unbalanced chromosomal segregant, 8 % (42/498) harbored both a translocation imbalance and aneuploidy and 24 % (118/498) of embryos were genetically balanced for the parental reciprocal translocation but were aneuploid for other chromosomes. The overall clinical pregnancy rate per IVF cycle following SNP or aCGH microarray analysis was 61 % and was higher if the biopsy was done on blastocysts (65 %) versus cleavage stage embryos (59 %), although not statistically significant. CONCLUSIONS: SNP or aCGH microarray technologies demonstrate equivalent clinical findings that maximize the pregnancy potential in patients with known parental reciprocal chromosomal translocations. PMID- 24771117 TI - Confronting the fissions and fusions of human fertilization. PMID- 24771118 TI - CFS-SMO based classification of breast density using multiple texture models. AB - It is highly acknowledged in the medical profession that density of breast tissue is a major cause for the growth of breast cancer. Increased breast density was found to be linked with an increased risk of breast cancer growth, as high density makes it difficult for radiologists to see an abnormality which leads to false negative results. Therefore, there is need for the development of highly efficient techniques for breast tissue classification based on density. This paper presents a hybrid scheme for classification of fatty and dense mammograms using correlation-based feature selection (CFS) and sequential minimal optimization (SMO). In this work, texture analysis is done on a region of interest selected from the mammogram. Various texture models have been used to quantify the texture of parenchymal patterns of breast. To reduce the dimensionality and to identify the features which differentiate between breast tissue densities, CFS is used. Finally, classification is performed using SMO. The performance is evaluated using 322 images of mini-MIAS database. Highest accuracy of 96.46% is obtained for two-class problem (fatty and dense) using proposed approach. Performance of selected features by CFS is also evaluated by Naive Bayes, Multilayer Perceptron, RBF Network, J48 and kNN classifier. The proposed CFS-SMO method outperforms all other classifiers giving a sensitivity of 100%. This makes it suitable to be taken as a second opinion in classifying breast tissue density. PMID- 24771119 TI - Poorly differentiated clusters (PDCs) as a novel histological predictor of nodal metastases in pT1 colorectal cancer. AB - The practical use of histological factors such as submucosal (SM) invasion depth, poor differentiation, presence of lymphovascular invasion (LVI) and tumour budding to establish the risk of nodal dissemination in pT1 colorectal cancer (CRC) is limited by their low standardization and high inter-observer variability. It was recently suggested that the presence in CRC histological sections of poorly differentiated clusters (PDCs), defined as >=5 cancer cells with no gland formation, may predict the metastatic potential of CRC. In addition, PDC assessment was shown to be more reproducible than the evaluation of the other aforementioned histological predictors. Hence, in this study, we investigated and compared the predictive value of PDC and other histological parameters on the risk of nodal involvement in pT1 CRC. The presence of PDC, SM invasion depth >=1,000 MUm and LVI was significantly associated with N+ status in pT1 CRC (P < 0.0001). Among these parameters, SM invasion depth had the highest sensitivity to identify N+ pT1 CRC but with the lowest specificity. When the analysis was restricted to CRCs with SM invasion depth >=1,000 MUm, the presence of PDC was the only independent risk factor for nodal metastases and allowed the identification of 87.5 % of N+ cancers. In conclusion, in this study, we demonstrate that the presence of PDC is associated with the metastatic potential of pT1 CRC. The combination of this parameter with SM invasion depth may allow identifying most of the pT1 CRC with nodal metastases. PMID- 24771120 TI - Clear cell papillary renal cell carcinoma with angiomyomatous stroma: a histological, immunohistochemical, and fluorescence in situ hybridization study. AB - Clear cell papillary renal cell carcinoma (CCPRCC) is a novel tumor entity that was recently recognized as a new distinct epithelial tumor within the current classification system. Nonclassic morphologic variants have rarely been reported. We present six challenging cases of CCPRCC with prominent (>75 %) tubular, acinar, and/or solid component and angioleiomyomatous stroma. The tumors lacked well-organized papillary architecture. All tumors had a variously thick capsule formed by a layer of bands of smooth muscle. The leiomyomatous tissue often entirely encased patches of tubular structures, or it formed only small leiomyomatous islands within the epithelial component. There was a remarkable relationship between the vascular network and the epithelial component in the sense that every single tubule or acinus was associated with a fine capillary network, with the capillaries intimately surrounding the tubular or acinar circumference. CCPRCC with variant morphology expressed carbonic anhydrase IX (CA IX) in cup-shaped distribution. In addition, the tumor cells stained positive for cytokeratin 34betaE12, CK7, and vimentin. Renal cell carcinoma (RCC), P504s/AMACR, Melan A, and HMB45 were negative in tumor cells in all cases examined. Fluorescence in situ hybridization studies showed the presence of a normal copy number for chromosomes 7, 17, 3q, and 3p. CCPRCC with variant morphology seems to have a favorable prognosis. In the current series, tumor stage was low at presentation, and none of the patients had local recurrence or metastatic disease. The distinction between CCPRCC with variant morphology and clear cell RCC is critical because no case of CCPRCC has behaved aggressively. PMID- 24771125 TI - Native flagellin does not protect mice against an experimental Proteus mirabilis ascending urinary tract infection and neutralizes the protective effect of MrpA fimbrial protein. AB - Proteus mirabilis expresses several virulence factors including MR/P fimbriae and flagella. Bacterial flagellin has frequently shown interesting adjuvant and protective properties in vaccine formulations. However, native P. mirabilis flagellin has not been analyzed so far. Native P. mirabilis flagellin was evaluated as a protective antigen and as an adjuvant in co-immunizations with MrpA (structural subunit of MR/P fimbriae) using an ascending UTI model in the mouse. Four groups of mice were intranasally treated with either MrpA, native flagellin, both proteins and PBS. Urine and blood samples were collected before and after immunization for specific antibodies determination. Cytokine production was assessed in immunized mice splenocytes cultures. Mice were challenged with P. mirabilis, and bacteria quantified in kidneys and bladders. MrpA immunization induced serum and urine specific anti-MrpA antibodies while MrpA coadministered with native flagellin did not. None of the animals developed significant anti flagellin antibodies. Only MrpA-immunized mice showed a significant decrease of P. mirabilis in bladders and kidneys. Instead, infection levels in MrpA-flagellin or flagellin-treated mice showed no significant differences with the control group. IL-10 was significantly induced in splenocytes of mice that received native flagellin or MrpA-flagellin. Native P. mirabilis flagellin did not protect mice against an ascending UTI. Moreover, it showed an immunomodulatory effect, neutralizing the protective role of MrpA. P. mirabilis flagellin exhibits particular immunological properties compared to other bacterial flagellins. PMID- 24771126 TI - Description of Niveispirillum fermenti gen. nov., sp. nov., isolated from a fermentor in Taiwan, transfer of Azospirillum irakense (1989) as Niveispirillum irakense comb. nov., and reclassification of Azospirillum amazonense (1983) as Nitrospirillum amazonense gen. nov. AB - A taxonomic study was carried out on a novel aerobic bacterial strain (designated CC-LY736(T)) isolated from a fermentor in Taiwan. Cells of strain CC-LY736(T) were Gram-stain negative, spiral-shaped and motile by means of a monopolar flagellum. Strain CC-LY736(T) shared the greatest degree of 16S rRNA gene sequence similarity to Azospirillum irakense DSM 11586(T) (97.2 %), Rhodocista centenaria JCM 21060(T) (96.3 %) and Rhodocista pekingensis JCM 11669(T) (96.1 %). The major fatty acids were C16:0, C16:1 omega5c, C19:0 cyclo omega8c, C18:1 omega7c/C18:1 omega6c, C16:0 3-OH and C18:1 2-OH. The predominant polar lipids included phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidyldimethylethanolamine and two unidentified glycolipids. The common major respiratory quinone was ubiquinone Q-10 and predominant polyamines were sym homospermidine and putrescine. The DNA G+C content of strain CC-LY736(T) was 67.6 +/- 0.1 mol %. During phylogenetic analysis, strain CC-LY736(T) formed a unique phyletic lineage associated with Rhodocista species. However, the combination of genetic, chemotaxonomic and physiological data clearly indicated that strain CC LY736(T) was a novel representative of the family Rhodospirillaceae. Based on the polyphasic comparison, the name Niveispirillum fermenti gen. nov., sp. nov. is proposed; the type strain of the type species is CC-LY736(T) (= BCRC 80504(T) = LMG 27263(T)). In addition, the reclassifications of Azospirillum irakense as Niveispirillum irakense comb. nov. (type strain KBC1(T) = ATCC 51182(T) = BCRC 15764(T) = CIP 103311(T)), and Azospirillum amazonense as Nitrospirillum amazonense gen. nov., sp. nov. (type strain Am14(T) = ATCC 35119(T) = BCRC 14279(T) = DSM 3787(T)) are proposed based on the polyphasic taxonomic data obtained in this study. PMID- 24771127 TI - OX40 controls effector CD4+ T-cell expansion, not follicular T helper cell generation in acute Listeria infection. AB - To investigate the importance of OX40 signals for physiological CD4(+) T-cell responses, an endogenous antigen-specific population of CD4(+) T cells that recognise the 2W1S peptide was assessed and temporal control of OX40 signals was achieved using blocking or agonistic antibodies (Abs) in vivo. Following infection with Listeria monocytogenes expressing 2W1S peptide, OX40 was briefly expressed by the responding 2W1S-specific CD4(+) T cells, but only on a subset that co-expressed effector cell markers. This population was specifically expanded by Ab-ligation of OX40 during priming, which also caused skewing of the memory response towards effector memory cells. Strikingly, this greatly enhanced effector response was accompanied by the loss of T follicular helper (TFH) cells and germinal centres. Mice deficient in OX40 and CD30 showed normal generation of TFH cells but impaired numbers of 2W1S-specific effector cells. OX40 was not expressed by 2W1S-specific memory cells, although it was rapidly up-regulated upon challenge whereupon Ab-ligation of OX40 specifically affected the effector subset. In summary, these data indicate that for CD4(+) T cells, OX40 signals are important for generation of effector T cells rather than TFH cells in this response to acute bacterial infection. PMID- 24771128 TI - Attrition in Chronic Disease Self-Management Programs and self-efficacy at enrollment. AB - Among other goals, the Chronic Disease Self-Management Program (CDSMP) is designed to improve self-efficacy of the chronically ill. However, a substantial proportion of the enrollees often leave CDSMPs before completing the program curriculum. This study examines factors associated with program attrition in a CDSMP implemented in a community setting. We used data from the Our Pathways to Health program, implemented in Humboldt County, California, from 2008 to 2011. Our conceptual framework is based on Bandura's self-efficacy theory, and we used logistic regression to investigate whether baseline self-efficacy and other members' efficacy are associated with participants dropping out of the CDSMP. Twenty-three percent of the participants did not complete the program similar to previous studies. Lower baseline self-efficacy increased the odds of dropout, but other members' efficacy was not associated with differential odds of dropout. Age, educational difference between the individual and the group, weekday sessions, and social/role activity limitations are also found to be associated with program attrition. Our results suggest that participants with low starting self-efficacy may need extra help to complete the program. Further research is needed to understand how to effectively provide additional support to this group. PMID- 24771129 TI - Perineal stapled prolapse resection (PSPR) in elderly patients for external rectal prolapse: early experience. AB - BACKGROUND: Full-thickness rectal prolapse in frail elderly patients is often treated by a perineal approach with considerable attendant morbidity. We report our preliminary results of the perineal stapled prolapse resection (PSPR) technique for resection of full-thickness external rectal prolapse using a new reloadable Contour((r)) TranstarTM stapler (Ethicon Endo-Surgery) device. METHODS: Fourteen elderly high-risk patients with an external prolapse up to 10 cm in length were treated between April 2010 and October 2011, and operative factors, outcome and recurrence rates were assessed. RESULTS: There were no intraoperative difficulties and no perioperative morbidity. The median operating time was 35 min (range 25-45 min) with a median hospital stay of 3 days (range 3 5 days). Four patients developed early recurrence over a median follow-up of 32 months (range 25-41 months). CONCLUSIONS: PSPR is safer, faster and easier to perform than other conventional perineal prolapse procedures and is suitable for elderly, high-risk patients for whom an abdominal approach under general anesthesia is not advisable. PMID- 24771130 TI - Gender- and age-related differences in rest and post-stress left ventricular cardiac function determined by gated SPECT. AB - Gender- and age-related changes of left ventricular (LV) function and dimensions have not been elucidated in a large population by gated SPECT. Thus, the aim of this study was to derive male and female reference limits for left ventricular functional parameters, and determine the effect of age on LV dimensions and systolic function for this imaging modality. 1,639 (53% males) subjects without cardiovascular disease who underwent cardiac SPECT between January 2002 and June 2012 were included in this study. Mean age at presentation was 61 +/- 12 years (range 18-92 years). A significant effect of age (p = 0.011) and gender (p < 0.0001) on resting LV ejection fraction (LVEF) was observed, with an increase in LVEF with age being more pronounced in women (DeltaB-coefficient: -0.088, p = 0.011). Overall, mean LVEF was higher in women compared to men (70.3 +/- 8.6% vs. 64.4 +/- 7.5%, p < 0.0001). LVEF after pharmacological stress with adenosine was significantly lower than at rest in both women and men (?LVEF = 1.1% in males and ?LVEF = 1.6% in females, p = 0.01), which was the result of a significant increase in end-systolic volume after stress (p = 0.0001). With advancing age an increase in LVEF was observed that was more pronounced in women than in men. These findings indicate that the evaluation of cardiac function and volumes of patients by gated SPECT should consider age- and gender-matched normative values. PMID- 24771131 TI - Cardiac autonomic control in high level Brazilian power and endurance track-and field athletes. AB - The autonomic nervous system (ANS) has an important role in physical performance. However, the cardiac ANS activity in high-level track and field athletes has been poorly explored. Thus, we tested the hypothesis that endurance and power athletes would present a markedly different cardiac autonomic control at rest. We analyzed the cardiac ANS by means of time and frequency domains heart rate variability (HRV) analyses and by symbolic analysis. Endurance athletes showed higher pulse interval than power athletes (1,265+/-126 vs. 1,031+/-98 ms respectively; p<0.05). No differences were found in time and frequency domains between the groups. However, the LF%, HF% and LF/HF ratio presented high effect sizes (1.46, 1.46 and 1.30, respectively). The symbolic analysis revealed that endurance athletes had higher 2V parasympathetic modulation (36+/-6.5) than power athletes (24+/-9.3; p<0.05). A reduced 0V sympathetic modulation was observed in endurance athletes (21+/-9.9) compared to power athletes (33+/-11; p<0.05 and ES=1.30). Our results suggest greater parasympathetic modulation and less sympathetic modulation in endurance athletes compared to power athletes. Additionally, the type of HRV analysis needs to be chosen with well-defined criteria and caution because their use in assessing cardiac autonomic modulation can interfere with the interpretation of results. In practical terms, symbolic analysis appears to better discriminate between cardiac autonomic activities of athletes with different training backgrounds than frequency domain analysis. PMID- 24771132 TI - Cooling during exercise in temperate conditions: impact on performance and thermoregulation. AB - Exercise-induced increase in core body temperature may lead to the development of hyperthermia (>40.0 degrees C) and/or decreased performance levels. This study examined the effects of wearing a cooling vest during a 5-km time trial on thermoregulatory responses and performance. 10 male masters athletes (42+/-10 years) performed a 5-km time trial on a motorized treadmill in a climate chamber (25 degrees C, 55% relative humidity) with and without a cooling vest. Split times, heart rate, core-, skin- and cooling vest temperature were measured every 500 m. Subjects also rated thermal comfort and level of perceived exertion. The cooling vest significantly decreased heart rate (p<0.05), decreased skin temperature (p<0.001) and improved thermal comfort (p<0.005) during the time trial. Time to finish the 5-km time trial and pacing strategy did not differ between the control (1 246+/-96 s) and cooling vest condition (1 254+/-98 s, p=0.85). Additionally, thermoregulatory responses, maximum core body temperature and level of perceived exertion were not different across conditions (p=0.85, p=0.49, p=0.11, respectively). In conclusion, we demonstrated that wearing a cooling vest during exercise improves thermal comfort but does not enhance performance or decrease core body temperature in male masters athletes under temperate ambient conditions. PMID- 24771133 TI - Assessment of microcystin concentration in carp and catfish: a case study from Lakshmikund pond, Varanasi, India. AB - The present study was conducted to analyse microcystin concentrations in Lakshmikund pond, Varanasi, India, as well as in carp and catfish of the pond. The concentrations of microcystin were found well above the WHO guidelines (1 ug/L) both for the dissolved and particulate fractions of bloom samples. The microcystin concentrations in different organs of carp and catfish were in the following sequence; liver > gut > kidney > gall bladder > gills > muscles and gut > liver > kidney > gall bladder > gills > muscles, respectively. The bioaccumulation of microcystin in carp and catfish was negatively correlated with body weight, and showed species specificity. The higher bioaccumulation of microcystin in muscles of catfish (>tenfold) over carp indicates a possible threat to human beings on consumption of catfish. Therefore, to avoid animal and human intoxication, routine analyses of microcystin in pond water as well as fishes are strongly recommended. PMID- 24771134 TI - Addition of citrate to Acidithiobacillus ferrooxidans cultures enables precipitate-free growth at elevated pH and reduces ferric inhibition. AB - Acidithiobacillus ferrooxidans is an acidophilic chemolithoautotroph that is important in biomining and other biotechnological operations. The cells are able to oxidize inorganic iron, but the insolubility and product inhibition by Fe(3+) complicates characterization of these cultures. Here we explore the growth kinetics of A. ferrooxidans in iron-based medium in a pH range from 1.6 to 2.2. It was found that as the pH was increased from 1.6 to 2.0, the maintenance coefficient decreased while both the growth kinetics and maximum cell yield increased in the precipitate-free, low Fe(2+) concentration medium. In higher iron media a similar trend was observed at low pH, but the formation of precipitates at higher pH (2.0) hampered cell growth and lowered the specific growth rate and maximum cell yield. In order to eliminate ferric precipitates, chelating agents were introduced into the medium. Citric acid was found to be relatively non-toxic and did not appear to interfere with iron oxidation at a maximum concentration of 70 mM. Inclusion of citric acid prevented precipitation and A. ferrooxidans growth parameters resumed their trends as a function of pH. The addition of citrate also decreased the apparent substrate saturation constant (KS ) indicating a reduction in the competitive inhibition of growth by ferric ions. These results indicate that continuous cultures of A. ferrooxidans in the presence of citrate at elevated pH will enable enhanced cell yields and productivities. This will be critical as these cells are used in the development of new biotechnological applications such as electrofuel production. PMID- 24771135 TI - CD40-independent natural killer-cell help promotes dendritic cell vaccine-induced T-cell immunity against endogenous B-cell lymphoma. AB - It is well established that an interplay between natural killer (NK) cells and dendritic cells (DCs) gives rise to their reciprocal activation and provides a Th1-biased cytokine milieu that fosters antitumor T-cell responses. Ex vivo differentiated DCs transferred into mice strongly stimulate endogenous NK cells to produce interferon (IFN)-gamma and initiate a cascade that eventually leads to cytotoxic T-lymphocyte responses. We show that the ability of exogenous DCs to trigger this pathway obviates CD40 signaling and CD4(+) T-cell help and depends on a preceding maturation step. Importantly, this mechanism was also effective in endogenously arising tumors where IFN-gamma production is compromised in contrast to transplantable tumors. In c-myc-transgenic mice developing spontaneous lymphomas, injection of unpulsed DCs caused NK-cell activation and induced CD8(+) T cells capable of recognizing the lymphoma cells. Animals treated with unpulsed DCs showed a survival benefit compared to untreated myc mice. Hence, tumor immunity induced by DC-based vaccines not only depends on specific antigens loaded on the DCs. Rather, DC vaccines generate broader immune responses, because endogenous DCs presenting tumor antigens may also become stimulated by NK cells that were activated by exogenous DCs. Thus, the DC/NK-cell/cytotoxic T lymphocyte axis may commonly have relevance for DC-based vaccination protocols in clinical settings. PMID- 24771136 TI - Direct interaction of a CFTR potentiator and a CFTR corrector with phospholipid bilayers. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors are new drugs that target the basic CFTR protein defect and are expected to benefit cystic fibrosis patients. To optimize the substances so far proposed for human use, and to minimise unwanted side effects, it is essential to investigate possible interactions between the drugs and cell components. We used small-angle X-ray scattering with synchrotron radiation to analyse the effects of two representative drugs, the potentiator VX-770 (Ivacaftor), approved for human use, and the corrector VX-809 (Lumacaftor), on a model phospholipid membrane. By reconstruction of the electron density profile of unilamellar vesicles treated with VX-770 or VX-809 we found that these drugs penetrate the phospholipid bilayer. VX-809 becomes homogeneously distributed throughout the bilayer whereas VX-770 accumulates predominantly in the internal leaflet, behaviour probably favoured by the asymmetry of the bilayer, because of vesicle curvature. Penetration of the bilayer by these drugs, probably as part of the mechanisms of permeation, causes destabilization of the membrane; this must be taken into account during future drug development. PMID- 24771137 TI - Ligament reconstruction/advancement for management of instability due to ligament insufficiency during total knee arthroplasty: a viable alternative to constrained implant. AB - BACKGROUND: We aimed to assess the results of ligament reconstruction/advancement for the management of ligament insufficiency during total knee arthroplasty. METHOD: We retrospectively reviewed the results of ligament reconstruction/advancement for management of instability due to ligament insufficiency during total knee arthroplasty (TKA). Between January 2001 and January 2008 collateral ligament reconstruction/advancement was done in 15 patients. Wherever ligament advancement was not possible (mid-substance tear) ligament reconstruction was done using the hamstring tendon. Knee society scores were calculated and Kaplan-Meier survival analysis was done. RESULTS: Average follow-up was 6.2 years. No patient developed instability until the last follow up, except one patient who required revision due to instability at six years after primary surgery. CONCLUSION: We concluded from this study that ligament reconstruction/advancement during TKA is a viable option to address instability due to ligament insufficiency. PMID- 24771138 TI - Radiolucent zone of the patella following total knee arthroplasty without patellar resurfacing. AB - BACKGROUND: The radiolucent zones in the patella are sometimes observed in patients who have undergone total knee arthroplasty (TKA) without patellar resurfacing. On the basis of radiological findings from our clinical experience, we hypothesize that the pathogenesis of this lesion may be similar to that of the lesions of spontaneous osteonecrosis, and this lesion may be due to both osteoporosis and stress concentration. The present study aimed to determine the incidence of the radiolucent zone after TKA without patellar resurfacing. Moreover, the roles of osteoporosis and patellar morphology, which are related to the stress distribution in the patella, were also investigated. METHODS: We studied 48 knees of 38 patients who underwent primary TKA using the Genesis II prosthesis. Axial radiographs taken 1 year postoperatively were used to assess the incidence of the radiolucent zone. The World Health Organization fracture risk assessment tool (FRAX) score and the preoperative patellar facet angle were compared between patients with and without the radiolucent zones. RESULTS: Five patellae (10.4%) showed the radiolucent zones postoperatively (the radiolucent group), whereas no such lesions were found in the remaining 43 patellae (the normal group). The major osteoporotic fracture risk of the radiolucent group calculated using the FRAX was 24.8% and significantly higher than that in the normal group (14.7%; p = 0.01). The average patellar facet angle in the radiolucent group was 123.6 degrees , which was significantly smaller than that in the normal group (133.6 degrees ; p = 0.003). DISCUSSION AND CONCLUSIONS: The results of the present study suggest that both underlying osteoporosis and a steep patellar facet angle may play an important role in the pathogenesis of the radiolucent zones in patellae after TKA without patellar resurfacing. Patellar resurfacing may be considered, particularly in osteoporotic patients who have a steep patellar facet angle, to avoid the appearance of the postoperative radiolucent zone in the patella. PMID- 24771139 TI - Evaluation of PAX2 and PAX8 expression in salivary gland neoplasms. AB - PAX2 and PAX8 are transcription factors involved in embryogenesis that have been utilized as immunohistochemical indicators of tumor origin. Specifically, PAX2 is a marker of neoplasms of renal and mullerian origin, while PAX8 is expressed by renal, mullerian, and thyroid tumors. While studies examining these transcription factors in a variety of tumors have been published, data regarding their expression in salivary gland neoplasms are limited. The goal of this study was to assess expression of PAX2 and PAX8 in a large cohort of salivary gland tumors. Utilizing tissue microarrays, samples of normal salivary glands (n = 68) and benign and malignant salivary gland neoplasms (n = 442) were evaluated for nuclear immunoreactivity with PAX2 and PAX8. No expression was observed with either marker in the normal salivary glands, and PAX8 was negative in all neoplasms. Focal expression of PAX2 was observed in one example each of oncocytoma and acinic cell carcinoma. These results indicate that evaluation of PAX2 and/or PAX8 expression would be valuable in differentiating primary salivary gland tumors from metastases known to express PAX2 and/or PAX8. PMID- 24771141 TI - Jugular bulb abnormalities in patients with Meniere's disease using high resolution computed tomography. PMID- 24771142 TI - Computer-assisted segmentation of CT images by statistical region merging for the production of voxel models of anatomy for CT dosimetry. AB - The segmentation of CT images to produce a computational model of anatomy is a time-consuming and laborious process. Here we report a time saving semi-automatic approach. The image-processing technique known as "statistical region merging" (SRM) was used to pre-segment the 54 original CT images of the ADELAIDE data set into regions of related pixels. These regions were amalgamated into organs and tissues by a program operated through a graphical user interface. This combination of SRM and GUI was used to build a voxel computational model of anatomy. The "new" version of ADELAIDE was compared to the "old" version by simulating an abdominal CT procedure on both models and comparing the Monte Carlo calculated organ doses. Seventeen of the 21 SRM-GUI segmented tissues received doses that were within 18 % of the doses received by the manually segmented tissues. Hence the SRM-GUI segmentation technique can produce a computational model that is not functionally different from a manually segmented computational model. The SRM-GUI segmentation technique is able to reduce the time taken to construct a voxel tomographic model from CT images. PMID- 24771140 TI - Salivary mucoepidermoid carcinoma revisited. AB - Clinicopathological features, prognosis and therapeutic strategies for mucoepidermoid carcinoma originating in salivary and salivary-type glands of the head and neck are reviewed. We emphasise histopathological aspects, appraise the value of histochemistry, electron microscopy, immunohistochemistry and cytophotometry, and discuss histogenesis and characteristic gene translocations. We additionally consider possible diagnostic difficulties, problems related to histological grading and accuracy of existing literature, and areas of controversy or uncertainty which may benefit from further investigations. PMID- 24771143 TI - Functional analyses of a putative plasma membrane Na+/H+ antiporter gene isolated from salt tolerant Helianthus tuberosus. AB - Jerusalem artichokes (Helianthus tuberosus L.) can tolerate relatively higher salinity, drought and heat stress. In this paper, we report the cloning of a Salt Overly Sensitive 1 (SOS1) gene encoding a plasma membrane Na(+)/H(+) antiporter from a highly salt-tolerant genotype of H. tuberosus, NY1, named HtSOS1 and characterization of its function in yeast and rice. The amino acid sequence of HtSOS1 showed 83.4% identity with the previously isolated SOS1 gene from the Chrysanthemum crassum. The mRNA level in the leaves of H. tuberosus was significantly up-regulated by presence of high concentrations of NaCl. Localization analysis using rice protoplast expression showed that the protein encoded by HtSOS1 was located in the plasma membrane. HtSOS1 partially suppressed the salt sensitive phenotypes of a salt sensitive yeast strain. In comparison with wild type (Oryza sativa L., ssp. Japonica. cv. Nipponbare), the transgenic rice expressed with HtSOS1 could exclude more Na(+) and accumulate more K(+). Expression of HtSOS1 decreased Na(+) content much larger in the shoot than in the roots, resulting in more water content in the transgenic rice than WT. These data suggested that HtSOS1 may be useful in transgenic approaches to improving the salinity tolerance of glycophyte. PMID- 24771144 TI - Computational chemogenomics: is it more than inductive transfer? AB - High-throughput assays challenge us to extract knowledge from multi-ligand, multi target activity data. In QSAR, weights are statically fitted to each ligand descriptor with respect to a single endpoint or target. However, computational chemogenomics (CG) has demonstrated benefits of learning from entire grids of data at once, rather than building target-specific QSARs. A possible reason for this is the emergence of inductive knowledge transfer (IT) between targets, providing statistical robustness to the model, with no assumption about the structure of the targets. Relevant protein descriptors in CG should allow one to learn how to dynamically adjust ligand attribute weights with respect to protein structure. Hence, models built through explicit learning (EL) by including protein information, while benefitting from IT enhancement, should provide additional predictive capability, notably for protein deorphanization. This interplay between IT and EL in CG modeling is not sufficiently studied. While IT is likely to occur irrespective of the injected target information, it is not clear whether and when boosting due to EL may occur. EL is only possible if protein description is appropriate to the target set under investigation. The key issue here is the search for evidence of genuine EL exceeding expectations based on pure IT. We explore the problem in the context of Support Vector Regression, using more than 9,400 pKi values of 31 GPCRs, where compound-protein interactions are represented by the concatenation of vectorial descriptions of compounds and proteins. This provides a unified framework to generate both IT-enhanced and potentially EL-enabled models, where the difference is toggled by supplied protein information. For EL-enabled models, protein information includes genuine protein descriptors such as typical sequence-based terms, but also the experimentally determined affinity cross-correlation fingerprints. These latter benchmark the expected behavior of a quasi-ideal descriptor capturing the actual functional protein-protein relatedness, and therefore thought to be the most likely to enable EL. EL- and IT-based methods were benchmarked alongside classical QSAR, with respect to cross-validation and deorphanization challenges. A rational method for projecting benchmarked methodologies into a strategy space is given, in the aims that the projection will provide directions for the types of molecule designs possible using a given methodology. While EL-enabled strategies outperform classical QSARs and favorably compare to similar published results, they are, in all respects evaluated herein, not strongly distinguished from IT-enhanced models. Moreover, EL-enabled strategies failed to prove superior in deorphanization challenges. Therefore, this paper raises caution that, contrary to common belief and intuitive expectation, the benefits of chemogenomics models over classical QSAR are quite possibly due less to the injection of protein-related information, and rather impacted more by the effect of inductive transfer, due to simultaneous learning from all of the modeled endpoints. These results show that the field of protein descriptor research needs further improvements to truly realize the expected benefit of EL. PMID- 24771145 TI - Structure-based design, synthesis and biological evaluation of beta-glucuronidase inhibitors. AB - Using structure-based virtual screening approach, a coumarin derivative (1) was identified as beta-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of beta-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against beta-glucuronidase, however, their potency varied substantially from IC50 = 9.9 352.6 uM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 uM, respectively. We further studied their dose responses and also checked our results by using detergent Triton *-100. We found that our results are true and not affected by detergent. PMID- 24771147 TI - Efficacy of cyclosporine combination therapy for new-onset minimal change nephrotic syndrome in adults. AB - BACKGROUND: Cyclosporine and prednisolone combination therapy has been used in the treatment of minimal change nephrotic syndrome (MCNS). However, few studies have evaluated the efficacy of cyclosporine combined with intravenous methylprednisolone pulse therapy (MPT) as a first-line treatment for new-onset MCNS. We conducted a retrospective clinical study to evaluate the efficacy and safety of cyclosporine combined with MPT and oral prednisolone for new-onset MCNS in adults. METHODS: Forty-six adult patients with biopsy-proven MCNS were analyzed retrospectively. This study included three groups. Group 1 (n = 17) was treated with intravenous MPT (0.5 or 1.0 g/day for 3 days) followed by oral cyclosporine (2-3 mg/kg/day) and prednisolone (30 mg/day). Group 2 (n = 15) was treated with intravenous MPT followed by oral prednisolone (0.4-0.8 mg/kg/day). Group 3 (n = 14) was treated with oral prednisolone (0.6-1.0 mg/kg/day) alone. RESULTS: The length of hospital stay was the shortest in Group 1 (P < 0.001). The mean duration to achieve <20 mg/day of prednisolone was also the shortest in Group 1 (P < 0.05). Complete remission rates were 100 % in Group 1, 85.7 % in Group 2, and 69.2 % in Group 3 during the 9-month follow-up (P = 0.073). The rate of adverse effects caused by prednisolone was less in Group 1 (P < 0.05). Multivariate analysis revealed that the independent determinants of durations of remission were the selectivity index (P = 0.004), eGFR (P = 0.001) and the use of cyclosporine (P = 0.045). CONCLUSIONS: Combination therapy with cyclosporine may be a beneficial treatment option for new-onset MCNS in adults because of its clinical efficacy and safety. PMID- 24771149 TI - Mimicking breast cancer-induced bone metastasis in vivo: current transplantation models and advanced humanized strategies. AB - Bone metastasis is a complication that occurs in 80 % of women with advanced breast cancer. Despite the prevalence of bone metastatic disease, the avenues for its clinical management are still restricted to palliative treatment options. In fact, the underlying mechanisms of breast cancer osteotropism have not yet been fully elucidated due to a lack of suitable in vivo models that are able to recapitulate the human disease. In this work, we review the current transplantation-based models to investigate breast cancer-induced bone metastasis and delineate the strengths and limitations of the use of different grafting techniques, tissue sources, and hosts. We further show that humanized xenograft models incorporating human cells or tissue grafts at the primary tumor site or the metastatic site mimic more closely the human disease. Tissue-engineered constructs are emerging as a reproducible alternative to recapitulate functional humanized tissues in these murine models. The development of advanced humanized animal models may provide better platforms to investigate the mutual interactions between human cancer cells and their microenvironment and ultimately improve the translation of preclinical drug trials to the clinic. PMID- 24771148 TI - Selective antigen-specific CD4(+) T-cell, but not CD8(+) T- or B-cell, tolerance corrupts cancer immunotherapy. AB - Self-tolerance, presumably through lineage-unbiased elimination of self-antigen specific lymphocytes (CD4(+) T, CD8(+) T, and B cells), creates a formidable barrier to cancer immunotherapy. In contrast to this prevailing paradigm, we demonstrate that for some antigens, self-tolerance reflects selective elimination of antigen-specific CD4(+) T cells, but preservation of CD8(+) T- and B-cell populations. In mice, antigen-specific CD4(+) T-cell tolerance restricted CD8(+) T- and B-cell responses targeting the endogenous self-antigen guanylyl cyclase c (GUCY2C) in colorectal cancer. Although selective CD4(+) T-cell tolerance blocked GUCY2C-specific antitumor immunity and memory responses, it offered a unique solution to the inefficacy of GUCY2C vaccines through recruitment of self-antigen independent CD4(+) T-cell help. Incorporating CD4(+) T-cell epitopes from foreign antigens into vaccines against GUCY2C reconstituted CD4(+) T-cell help, revealing the latent functional capacity of GUCY2C-specific CD8(+) T- and B-cell pools, producing durable antitumor immunity without autoimmunity. Incorporating CD4(+) T cell epitopes from foreign antigens into vaccines targeting self-antigens in melanoma (Trp2) and breast cancer (Her2) produced similar results, suggesting selective CD4(+) T-cell tolerance underlies ineffective vaccination against many cancer antigens. Thus, identification of self-antigens characterized by selective CD4(+) T-cell tolerance and abrogation of such tolerance through self-antigen independent T-cell help is essential for future immunotherapeutics. PMID- 24771150 TI - Uveitis masquerade syndrome and orbital lymphoma: two challenging diagnosis. PMID- 24771151 TI - [Biodegradable nano-polymer agent, an analogue of heparan sulfate, in therapy refractory varicella keratitis]. PMID- 24771152 TI - Diffuse lamellar keratitis induced by a corneal foreign body six months after Femto-LASIK. PMID- 24771153 TI - [DMEK in corneal endothelial disorders: first Swiss consecutive series]. AB - PURPOSE: The aim of this study was to analyse clinical and functional results after Descemet membrane endothelial keratoplasty (DMEK) as preferred technique in patients with Fuchs dystrophy and endothelial decompensation in a consecutive series. HISTORY AND SIGNS: In 12 eyes of 11 patients with Fuchs dystrophy or postoperative corneal decompensation a Descemet membrane endothelial keratoplasty as sole technique was indicated. All eyes were pseudophakic. Mean preoperative visual acuity was 0.25. Corneal stromal edema was observed since 18 months in mean. THERAPY AND OUTCOME: There were neither postoperative complications nor graft loss due to preparation. Mean follow-up time was 7 months. Stromal edema vanished within 4 weeks in mean. Postoperative visual acuity improved in all cases to 0.6 in mean. Neither immune reaction nor endophthalmitis nor primary graft failure were observed so far. Endothelial cell loss was 20% in mean. CONCLUSION: Descemet membrane endothelial keratoplasty seems to be a promising procedure. Long-term follow-up will show the real value of this exciting technique. PMID- 24771154 TI - [Dysphotopsia due to a manufacturing error in an intraocular lens]. PMID- 24771155 TI - [Opacification of a hydrophilic intraocular lens due to calcification after silicone oil surgery]. PMID- 24771156 TI - Minimally invasive surgery technique for re-enclavation of prepupillary iris-claw IOLs. AB - BACKGROUND: Disenclavation is a common complication of prepupillary iris-claw intraocular lenses (IOL). We present a new minimally invasive revision surgery technique for reenclavation of prepupillary iris-claw IOLs using standard 23 Gauge (G) vitrectomy instruments. HISTORY AND SIGNS: Three cases of revision surgery by unilaterally dislocated prepupillary iris-claw IOLs are presented. THERAPY AND OUTCOME: Two 20 G sideports 90 degrees apart were constructed. Healon 10(r) was injected to maintain the anterior chamber. A standard enclavation needle was introduced to rotate the optic into correct position and a 23 G endgrasping forceps was used to grasp and stabilize the IOL for enclavation. The reenclavation was successful in all three cases and the mean visual acuity improved from preoperatively 0.1 (range counting fingers [CF] to 0.25) to 0.6 (range 0.4 to 0.8) with no significant induction of astigmatism. CONCLUSIONS: This minimally invasive reenclavation technique for repositioning of the prepupillary iris claw IOL appears to lead to successful and rapid visual rehabilitation. PMID- 24771157 TI - A new IOL with labeled accurate dioptric powers reduces the postoperative refractive error. AB - BACKGROUND: There is a need for improved predictability in cataract surgery. The aim of this study was to investigate whether implantation of intraocular lenses (IOLs) with accurately labeled dioptric power could improve the postoperative results and allow better predictability. PATIENTS AND METHODS: 113 eyes were implanted with Crystal Evolution(r) (MTO) IOLs and 261 eyes with AF-1 iMics1(r) (Hoya) IOLs. The predictability of the postoperative spherical equivalence (SE) and the best-corrected visual acuity (BCVA) were compared between both groups. The predictability was also compared to 2 previous studies. RESULTS: With Crystal Evolution(r), the predictability was significantly better than with AF-1 iMics1(r) (p<0.0001). The results were also better than those described in the 2 studies. Although the BCVA obtained with Crystal Evolution(r) were better than with AF-1 iMics1(r), the difference were not significant. CONCLUSIONS: Our data indicate that accurate dioptric labeling of IOLs may improve the postoperative refraction outcome. PMID- 24771158 TI - [Salzmann's nodular corneal degeneration - a case report]. PMID- 24771159 TI - Severe chemical burn to the eye after pepper spray attack. PMID- 24771160 TI - Topography-guided transepithelial photorefractive keratektomy (cTEN) for treatment of Thiel-Behnke dystrophy. PMID- 24771161 TI - Control of ocular disease in mucous membrane pemphigoid. AB - BACKGROUND: Mucous membrane pemphigoid is a rare immune-mediated disease. It is characterised by an abnormal binding of immunoglobulins to the basement membrane zone of mucous membranes and the skin. Conjunctival involvement in mucous membrane pemphigoid may lead to cicatrising conjunctivitis and eventually to corneal blindness. The factors that determine mild or progressive disease are not fully understood and need to be clarified. This study examines the features, progression and risk factors of patients with ocular involvement in mucous membrane pemphigoid. METHODS: 36 eyes of 18 patients with the diagnosis of ocular disease associated with MMP were identified. Fornix depth and keratopathy were repeatedly assessed using a standardised protocol to identify progression. MMP was diagnosed based on the characteristic clinical and laboratory features. Endpoints of the study were the incidence of progressive disease and the development of keratopathy with and without systemic immunomodulatory therapy. RESULTS: 12 eyes of 6 patients (33%) showed progressive conjunctival cicatrisation. Obvious progression was observed in 2 patients who had refused systemic treatment at an early stage. 10 eyes showed progression while on systemic treatment. In these patients, however, systemic treatment was started at an advanced stage of the ocular disease. None of the patients receiving systemic treatment developed persistent keratopathy. CONCLUSION: Systemic treatment with diaminodiphenyl sulfone and/or cyclophosphamide allows one to control the further progression of cicatrising conjunctivitis. It prevents keratopathy. To be efficient, however, treatment has to be started at an early stage of the ocular disease. PMID- 24771162 TI - Analysis of risk factors for long-term glaucomatous damage development. AB - PURPOSE: The aim of this study was to analyze predictors of long-term glaucoma progression. PATIENTS AND METHODS: We followed 17 primary open angle glaucoma patients (POAG) and 25 ocular hypertensives (OHT) over three years, with regular follow-up examinations of both eyes every 6 months. Glaucoma damage was quantified by optical coherence tomography (retinal nerve fiber layer - OCT RNFL) and by perimetry. Corneal and hand temperature (infrared thermometer), corneal hysteresis, pachymetry and ocular pulse amplitude (OPA) readings were taken at baseline, and applanatory intraocular pressure and retinal vessel analysis recordings were made at baseline and follow-up visits. Forward-stepwise multiple regression analysis was performed. RESULTS: With OCT-RNFL progression as the dependent variable, the model selected initial diagnosis (OHT less probable of progressing), baseline RNFL thickness, retinal arterial and venous diameter and arterial flicker response as significant damage predictors. For visual field damage progression, these were: corneal temperature, OPA, initial diagnosis and venous flicker response (all p<0.05). CONCLUSION: Initial damage and vascular factors are strong predictors of future glaucoma progression. PMID- 24771163 TI - Do optic nerve head and visual field parameters in patients with obstructive sleep apnea syndrome differ from those in control individuals? AB - BACKGROUND: It has been suggested that sleep apnea syndrome may play a role in normal-tension glaucoma contributing to optic nerve damage. The purpose of this study was to evaluate if optic nerve and visual field parameters in individuals with sleep apnea syndrome differ from those in controls. PATIENTS AND METHODS: From the records of the sleep laboratory at the University Hospital in Bern, Switzerland, we recruited consecutive patients with severe sleep apnea syndrome proven by polysomnography, apnea-hypopnea index >20, as well as no sleep apnea controls with apnea-hypopnea index <10. Participants had to be unknown to the ophtalmology department and had to have no recent eye examination in the medical history. All participants underwent a comprehensive eye examination, scanning laser polarimetry (GDx VCC, Carl Zeiss Meditec, Dublin, California), scanning laser ophthalmoscopy (Heidelberg Retina Tomograph II, HRT II), and automated perimetry (Octopus 101 Programm G2, Haag-Streit Diagnostics, Koeniz, Switzerland). Mean values of the parameters of the two groups were compared by t test. RESULTS: The sleep apnea group consisted of 69 eyes of 35 patients; age 52.7 +/- 9.7 years, apnea-hypopnea index 46.1 +/- 24.8. As controls served 38 eyes of 19 patients; age 45.8 +/- 11.2 years, apnea-hypopnea index 4.8 +/- 1.9. A difference was found in mean intraocular pressure, although in a fully overlapping range, sleep apnea group: 15.2 +/- 3.1, range 8-22 mmHg, controls: 13.6 +/- 2.3, range 9-18 mmHg; p<0.01. None of the extended visual field, optic nerve head (HRT) and retinal nerve fiber layer (GDx VCC) parameters showed a significant difference between the groups. CONCLUSION: Visual field, optic nerve head, and retinal nerve fiber layer parameters in patients with sleep apnea did not differ from those in the control group. Our results do not support a pathogenic relationship between sleep apnea syndrome and glaucoma. PMID- 24771164 TI - Frequency of symptoms and signs of primary vascular dysregulation in Swiss and Korean populations. AB - BACKGROUND: Primary vascular dysregulation syndrome (also called Flammer syndrome) is related to certain eye diseases, particularly normal tension glaucoma. Primary vascular dysregulation is characterized by a number of symptoms and signs (e.g., cold hands and/or feet, low blood pressure), that occur more frequently in subjects with primary vascular dysregulation compared to the general population. The aim of the present study was to test and compare the relative frequency of symptoms and signs related to primary vascular dysregulation in unselected populations in Switzerland and Korea. SUBJECTS AND METHODS: Swiss (n=259) and Korean (n=1116) subjects filled out our questionnaire containing 15 questions related to symptoms and signs of primary vascular dysregulation. RESULTS: In the populations studied, seven of 15 symptoms and signs of primary vascular dysregulation (increased smell perception, increased pain sensation, increased response to certain drugs, low body mass index, feeling cold, cold hands and/or feet, and headaches) occurred significantly more often in the Swiss population than in the Korean population, whereas five symptoms and signs (reversible skin blotches, tendency toward perfectionism, long sleep onset time, tinnitus, and dizziness) occurred significantly more often in the Korean population. CONCLUSION: The relative frequency of these symptoms and signs of primary vascular dysregulation in an unselected average population differs between Switzerland and Korea. Therefore, if a diagnosis of primary vascular dysregulation is based on the self-reported symptoms and signs of the patient, they must be compared with the frequency of symptoms and signs in the corresponding local population. PMID- 24771165 TI - Hemorrhagic descemet membrane detachment after classic canaloplasty. AB - PURPOSE: Canaloplasty is a safe and effective alternative in glaucoma surgery, avoiding the risk for hypotony and bleb-related complications. Two cases of hemorrhagic Descemet membrane detachment (DMD) after canaloplasty are reported in patients who did not have previous surgery. RESULTS: Two patients with primary open-angle glaucoma underwent canaloplasty because of medically uncontrolled intraocular pressure (IOP). Canaloplasty was performed using a flexible microcatheter, viscoelastic material and a tensioning suture. The day after surgery, hemorrhagic DMD was observed in the inferior quadrants in both patients on slit-lamp biomicroscopy. THERAPY: For the size and location (occlusion of the visual axis), aspiration of blood and descemetopexy with air tamponade were performed promptly. In both cases, a small translucent scar remained. CONCLUSIONS: Circumferential cannulation and viscodilation of the Schlemm canal increases the risk for DMD, which may be aggravated by blood reflux resulting from the tensioning suture and low postoperative IOP. Surgeons should be aware of this specific and potentially sight-threatening complication in classic canaloplasty. Immediate intervention is recommended for good visual prognosis. PMID- 24771166 TI - Long-term efficacy of selective laser trabeculoplasty in patients on prostaglandin therapy. AB - BACKGROUND: The aim of the study was to analyse the efficacy of selective laser trabeculoplasty in patients on medical therapy and to evaluate a possible influence of prostaglandin therapy on intraocular pressure reduction. PATIENTS AND METHODS: A retrospective chart review was undertaken of patients with ocular hypertension or open angle glaucoma who underwent selective laser trabeculoplasty between 3/2008 and 12/2010. Data were collected preoperatively, on the day of intervention, 1 day, 1 month and then every 3 months post selective laser trabeculoplasty. The main outcome measure was mean intraocular pressure reduction. RESULTS: 109 eyes (76 on prostaglandins) were included. Mean preoperative intraocular pressure was 22.3 +/- 4.5 mmHg (prostaglandin naive) and 19.2 +/- 4.8 mmHg (on prostaglandin) (p=0.003). Up to 1 year follow-up, intraocular pressure was statistically significantly reduced in both groups (p <= 0.019). Eyes with a higher preoperative intraocular pressure had a greater pressure reduction (Spearman rho=0.387, p=0.002). Eyes naive to prostaglandins initially had a greater reduction in intraocular pressure, although after 1 year of follow-up the difference was no longer statistically significant. CONCLUSIONS: Selective laser trabeculoplasty significantly reduces intraocular pressure in patients already on medical therapy. A sustained influence of prostaglandin therapy on the efficacy of selective laser trabeculoplasty was not found. PMID- 24771167 TI - Long-term efficacy of selective laser trabeculoplasty in pseudophakic patients - a "real-life" analysis. AB - BACKGROUND: The aim of this study was to report on the course and long-term effect of selective laser trabeculoplasty on intraocular pressure of pseudophakic patients suffering from open angle glaucoma or ocular hypertension with insufficient intraocular pressure lowering despite maximally tolerated topical and systemic intraocular pressure lowering medication. PATIENTS AND METHODS: A retrospective chart review of patients who underwent selective laser trabeculoplasty (360 degrees ) between 2008 and 2010 at the University hospital Zurich was undertaken. Intraocular pressure values before intervention, on the day of the intervention, 1 day, 1 month, 3 months and every 3 months up to 43 months after the intervention were analysed with respect to lens status. RESULTS: Out of 153 treated eyes of 111 patients (mean age 70.6 years +/- 11.13 SD) 40 were pseudophakic. Mean baseline intraocular pressures were 19.00 mmHg +/- 4.61 in the pseudophakic group and 20.12 mmHg +/- 4.89 in the phakic group. One month after selective laser trabeculoplasty intraocular pressure reduction measured between -0.33 and -4.10 mmHg (CI 95%) in the pseudophakic group and between -3.64 and -5.58 mmHg (CI 95%) in the phakic group, the difference at this time point was significant (p=0.01). Beyond one month after selective laser trabeculoplasty there was no statistically significant difference in intraocular pressure reduction between pseudophakic and phakic patients. The mean decrease in intraocular pressure from baseline to the last follow-up of 43 months was 0.67 mmHg in the pseudophakic group and 0.25 mmHg in the phakic group (p=0.72). CONCLUSIONS: One month after selective laser trabeculoplasty pseudophakic patients showed a statistically significant diminished reduction of intraocular pressure compared to phakic patients. Later on there was no statistically significant difference in intraocular pressure reduction between pseudophakic and phakic patients. Therefore we conclude that there was no clinically relevant influence of pseudophakia on the long-term effect of selective laser trabeculoplasty. PMID- 24771168 TI - Ocular pulse amplitude measurement using pascal dynamic contour tonometer in glaucoma patients. AB - AIM: This study aims to measure and compare the ocular pulse amplitude using Pascal dynamic contour tonometry in normal persons and in glaucoma patients. PATIENTS AND METHODS: 20 patients (40 eyes) with primary open angle glaucoma (Group A), 8 patients (16 eyes) with normal tension glaucoma (Group B), and 12 patients (24 eyes) with ocular hypertension (Group C) were included in the study. Control group (Group D) comprised 25 normal volunteers (50 eyes). Intraocular pressure was measured using both Goldmann applanation tonometry in the slit-lamp and Pascal dynamic contour tonometry. Ocular pulse amplitude was evaluated with Pascal dynamic contour tonometry. Statistical evaluation of the differences in ocular pulse amplitude and intraocular pressure among the different groups was performed using Student's t-test. RESULTS: Mean ocular pulse amplitude values expressed in mmHg were 3.66 +/- 1.00, 2.46 +/- 0.60, 4.04 +/- 1.47, and 2.52 +/- 0.52, for Groups A, B, C, and D, respectively. The ocular pulse amplitude was significantly higher in Group A (primary open angle glaucoma) and Group C (ocular hypertension) when compared with Group D (control group) and Group B (normal tension glaucoma). No statistically significant difference was detected between Group D (control group) and Group B (normal tension glaucoma). CONCLUSIONS: Although we can measure the intraocular pressure with Goldmann applanation tonometry, no information can be derived regarding the ocular pulse amplitude. The use of Pascal dynamic contour tonometry in intraocular pressure estimation provides useful clinical information also about the magnitude of the ocular pulse amplitude in different types of glaucoma. Pascal dynamic contour tonometry discloses an elevation of ocular pulse amplitude in primary open angle glaucoma and ocular hypertension patients. On the contrary, the ocular pulse amplitude is within normal limits in normal tension glaucoma patients. PMID- 24771169 TI - Posterior pole asymmetry analysis with optical coherence tomography. AB - BACKGROUND: The aim of this study was to evaluate the reproducibility of the posterior pole asymmetry analysis (PPAA) in glaucomatous eyes and healthy controls in comparison to retinal nerve fiber layer measurements (RNFL) with spectral domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: Prospectively, in a single session by one operator, three measurements were taken of the retinal thickness with the PPAA and three measurements of the RNFL with the eye-tracker function of the Heidelberg Spectralis SD-OCT. RESULTS: The mean intraclass correlation coefficient (ICC) and lower confidence intervals (in parentheses) for PPAA were 0.98 (0.96) in both healthy (36 eyes) and glaucomatous eyes (26 eyes). Global coefficients of variation (COVs) were between 0.0 and 1.1% in healthy controls and between 0.0 and 1.9% in glaucoma eyes. Global ICCs for RNFL were 0.98 (0.96) in healthy controls and 0.98 (0.97) in glaucoma eyes and global COVs were between 0.0 and 6.8% in healthy controls and between 0.0 and 3.0% in glaucoma eyes. CONCLUSION: Reproducibility of the PPAA was good and exceeds that of established RNFL measurements. Thus, PPAA is an additional useful tool in management of glaucoma. PMID- 24771170 TI - Transient hypotony caused by traumatic ciliary body tear without cyclodialysis cleft. PMID- 24771172 TI - Abnormal extraocular muscle insertion in Williams Beuren syndrome (WBS). PMID- 24771171 TI - Two-year clinical experience with the CyPass micro-stent: safety and surgical outcomes of a novel supraciliary micro-stent. AB - PURPOSE: The aim of this study was to evaluate through 2 postoperative years the clinical outcomes associated with a novel supraciliary micro-stent for the surgical treatment of open-angle glaucoma (OAG) when implanted in conjunction with cataract surgery. PATIENTS AND METHOD: In a multicenter, prospective, consecutive case series, 136 subjects (136 eyes) with OAG and requiring cataract surgery with 24-month postoperative data were included. A combined phacoemulsification procedure, with intraocular lens insertion and CyPass Micro Stent implantation into the supraciliary space of the study eye, was performed. At baseline, all subjects were on glaucoma medication with either uncontrolled intraocular pressure (IOP; >= 21 mmHg, Cohort 1, n=51) or controlled IOP (<21 mmHg, Cohort 2, n=85). Glaucoma medications were stopped postoperatively, but could be restarted if needed, at the investigator's discretion. Device-related adverse events, postoperative IOP, best corrected distance visual acuity (BCDVA), and number of IOP-lowering medications were recorded. RESULTS: The micro-stent was successfully implanted in all eyes. At 24 months, 82 subjects remained in the study. No sight-threatening adverse events occurred. The most common adverse events were transient hypotony (15.4%) and micro-stent obstruction (8.8%), typically due to iris tissue overgrowth. Fifteen subjects (11%) required secondary incisional glaucoma surgery. For Cohort 1 (n=23), mean +/- SD IOP was 15.8 +/- 3.8 mmHg after 24 months (change, -37% +/- 19%). Mean IOP decrease from baseline was statistically significant (p<0.0001) at months 6, 12, and 24. For Cohort 2 (n=59), mean +/- SD IOP at 24 months was 16.1 +/- 3.2 mmHg (change, 0% +/- 28%). Mean decrease from baseline was statistically significant at months 6 (p=0.0188) and 12 (p=0.0356). At 24 months, the mean +/- SD number of medications was 1.0 +/- 1.1 in Cohort 1 and 1.1 +/- 1.1 in Cohort 2. Mean decrease from baseline medication use was statistically significant at months 6 (p<0.001), 12 (p<0.001), and 24 (p=0.0265) in Cohort 1, and at months 6, 12, and 24 (all p<0.0001) in Cohort 2. CONCLUSIONS: CyPass Micro-Stent implantation, in combination with cataract surgery, was associated with minimal complications while substantially lowering IOP and/or use of IOP-lowering medications. PMID- 24771173 TI - [Confirmation of the diagnosis of optic disc pit in a child with the use of 3-D OCT visualisation]. PMID- 24771174 TI - Inferior oblique muscle anteriorization in congenital superior oblique palsy. AB - BACKGROUND: Inferior oblique muscle overaction of variable amounts is usually present with congenital superior oblique palsy. Inferior oblique muscle anteriorization has been described as a suitable surgical procedure in this entity. The aim of this study was to investigate the effect of inferior oblique muscle anteriorization in patients with congenital superior oblique palsy on vertical, torsional and horizontal alignment. PATIENTS AND METHODS: The study was designed as an institutional retrospective cohort study. 45 patients with congenital superior oblique palsy (15 female, 30 male; mean age 36 years +/- 19.2 SD, ranging from 6 to 75 years) underwent inferior oblique muscle anteriorization between 2000 and 2010. Preoperative amounts of vertical, torsional and horizontal deviation (using Harms tangent screen), measurements of Bielschowsky head tilt phenomenon as well as stereopsis (Lang test) were compared with findings three months and one year postoperatively. RESULTS: Preoperative vertical deviation in primary position measured 10.1 degrees (mean; range 0-19). Three months postoperatively vertical deviation was significantly reduced (p<0.001) to 4 degrees (mean; range 0-20). After one year vertical deviation measured 3.5 degrees (mean; range 0-15). The values three months postoperatively did not significantly differ from those one year postoperatively (p=0.46). CONCLUSIONS: Inferior oblique muscle anteriorization leads to a significant and sustained improvement of ocular alignment in patients with congenital superior oblique palsy of various degrees of severity. Thus the procedure is recommendable as a first line treatment in this clinical situation. PMID- 24771175 TI - Ischemic optic neuropathy after a long airplane flight: coincidence or rare economy class syndrome manifestation? PMID- 24771176 TI - [Chronic eye redness and ipsilateral oculomotor nerve palsy - does it fit together?]. PMID- 24771177 TI - Lymphoma of the ocular adnexa. AB - BACKGROUND: Over the last decades, the incidence of ocular adnexal lymphomas has been increasing. Over the last decade advances in the imaging of ocular adnexal lymphomas have enabled precise biopsies of the tumors. Biopsies are necessary for immunophenotyping, correct molecular classification and the immediate start of the appropriate treatment. PATIENTS AND METHODS: In a retrospective study, we collected data from 16 patients (19 eyes) treated for lymphoma of the ocular adnexa between 2006 and 2011 with various tumor sites. We evaluated ocular symptoms of the patients in correlation to the tumor localization on imaging and determined the access of biopsy. Follow-up period (13.7 +/- 15.4 months) and therapy were analyzed. RESULTS: The mean age of study patients was 67.4 +/- 13.6 years. Seven patients presented with exophthalmos, 6 with upper lid swelling, 5 with double vision, 5 with reduced visual acuity and one patient with retinal detachment. None of the patients complained of pain. In 7 cases the location of the OAL was superior, in 6 retrobulbar, in 4 patients in the lacrimal gland (1 bilaterally affected), one case with lacrimal sac infiltration and another with isolated subconjunctival lymphoma. Patients with retrobulbar tumors complained of visual loss, whereas patients with anterior orbital tumors showed localized nodular swelling. In 11 cases (58%) the diagnosis was marginal zone B-cell lymphoma (MALT), in 5 (26%) follicular lymphoma. 11 patients (69%) received curative and one HIV-positive patient palliative radiation. Three patients were treated with systemic rituximab due to generalized lymphoma and one of them was complemented with CHOP therapy. One patient received chemotherapy alone (CHOP). During the follow-up the HIV-positive patient died. CONCLUSIONS: All our lymphoma patients showed full tumor regression, without side effects from radiotherapy. In this study we emphasize the need to perform a diagnostic biopsy. The risk of biopsy by a trained surgeon is small. Early and accurate diagnosis is crucial for proper treatment. In unclear situations repeated biopsies might be necessary. PMID- 24771178 TI - Cone-rod dystrophy caused by a novel homozygous RPE65 mutation in Leber congenital amaurosis. AB - BACKGROUND: The aim of this study was to describe an unexpected phenotype in a family with Leber congenital amaurosis (LCA) due to a retinal pigment epithelium specific protein 65 kDa (RPE65) homozygous mutation. HISTORY AND SIGNS: We analyzed a family from Yemen in which 3 individuals were affected with LCA. Linkage analysis using markers flanking the known LCA genes was done, followed by direct sequencing of RPE65. THERAPY AND OUTCOME: Severe visual impairment and night blindness were observed during infancy. We observed photophobia only in the 8-year-old patient. The youngest affected had bilateral hyperopia of +3.50 and visual acuity of 1/60. The oldest two had visual acuity limited to hand movements in the right eye (OD) and counting fingers in the left eye (OS) for the oldest and of 5/60 OD, 6/60 OS for the other. They showed disc pallor, attenuated vessels, white flecks in the retina mid-periphery and bull's eye maculopathy. ERGs of the oldest child were completely unresponsive. Genomic sequencing identified a novel homozygous missense mutation, IVS2-3C>G, in the second RPE65 intron. CONCLUSIONS: We identified a novel LCA-related homozygous RPE65 mutation associated with a severe clinical presentation including an early and severe cone dysfunction. This is in contrast with the presentation associated with other RPE65 mutations predominantly causing rod-cone dystrophy with residual visual function. PMID- 24771179 TI - RPE adenocarcinoma arising from a congenital hypertrophy of the RPE (CHRPE) treated with proton therapy. PMID- 24771180 TI - [Intravitreal anti-VEGF treatment of choroidal neovascularization (CNV) in pathological myopia (PM): a review]. AB - Anti-VEGF injections are widely used "off-label" for the treatment of choroidal neovascularization secondary to pathological myopia based on data generated by multiple case series with small sample sizes. In this review we have analyzed the results of case series with at least 20 patients and a follow-up of >= 12 months. 18 case series were identified in Medline meeting these demands. The mean gain of visual acuity after 12 months was 2.2 +/- 0.7 (mean +/- 1 standard deviation, case number weighted: 2.0) lines with a mean of 3.0 +/- 1.7 injections (case number weighted 2.7). There was no significant difference between bevacizumab and ranibizumab. The mean gain of visual acuity in the first year could be stabilized in the second year with a visual acuity of a mean of 2.2 +/- 1.0 lines at the end of follow-up. The mean age of patients at the beginning was 56.0 +/- 6.0 (case number weighted: 56.2). The results of this analysis indicate very clearly that a favourable long-term outcome can be achieved with a relatively small number of injections in cases of choroidal neovascularization secondary to pathological myopia. PMID- 24771181 TI - Modified McCannel iridoplasty simulating basal iridectomy for silicone oil tamponade in aphakia and partial aniridia. PMID- 24771182 TI - [Ophthalmological findings in Menkes syndrome]. PMID- 24771183 TI - Preliminary results of aflibercept in treatment-naive choroidal neovascularization of wet age-related macular degeneration. AB - BACKGROUND: The aim of this study was to evaluate the early response of aflibercept as first-line therapy in treatment-naive patients with newly diagnosed choroidal neovascularization (CNV) in age-related macular degeneration (AMD). PATIENTS AND METHODS: An analysis of 35 eyes (35 patients, 28 female, 7 male) with treatment-naive active CNV was undertaken. Lesion activity was determined based on fluorescein angiography, clinical and optical coherence tomography (OCT) findings, including the presence of sub-, intraretinal fluid, retinal pigment epithelial (RPE) detachment and hemorrhage. Logarithm of the minimum angle of resolution (LogMAR) charts were used for testing best corrected or best available visual acuity (BCVA). Treatment response was evaluated based on changes in BCVA and lesion activity. RESULTS: Classic or predominantly classic CNV was diagnosed in 7 eyes (20.0%), occult or minimally classic in 21 eyes (60.0%), retinal angiomatous proliferation in 5 eyes (14.3%) and polypoidal choroidal vasculopathy in 2 eyes (5.7%). Lesion activity was evaluated as unchanged in only one eye. In all other eyes, a definite treatment response was observed with complete resolution of fluid in 20 eyes after a single injection. Three eyes did not show improved sub-RPE fluid with smaller pigment epithelial detachments. A rip of the RPE was seen in 3 eyes. All patients maintained vision, 7 patients (7 eyes) gained >15 letters from baseline to month 2 follow-up, of whom 4 reached this level of visual acuity after one injection. The visual acuity gains in this study were maintained through 6 months. CONCLUSION: There seems to be a rapid treatment response to aflibercept independent of the underlying CNV. Aflibercept may be beneficial even in eyes with large pigment epithelial detachments due to exudative AMD. PMID- 24771184 TI - Ranibizumab treatment in age-related macular degeneration: a meta-analysis of one year results. AB - BACKGROUND: Although ranibizumab is widely used in age-related macular degeneration there is no systematic data available on the relation between treatment frequency and functional efficacy within the first 12 months of follow up. MATERIAL AND METHODS: A meta-analysis was performed on available MEDLINE literature. 47 relevant clinical studies (54 case series) could be identified covering 11706 treated eyes. Non-linear and linear regressions were calculated for the relation between treatment frequency and functional outcome (average gain in visual acuity, % of eyes losing less than 15 letters of visual acuity, % of eyes gaining >= 15 letters) within the first year of care. RESULTS: Mean improvement of average visual gain was +4.9 +/- 3.6 (mean +/- 1 standard deviation) letters (case-weighted: 3.3 letters). The average number of ranibizumab injections until month 12 was 6.3 +/- 2.0 (case-weighted: 5.9). 92.4 +/- 3.9% of eyes (case-weighted: 91.9%) lost less than three lines of visual acuity and 24.5 +/- 8.2% (case-weighted: 23.3) gained more than 3 lines within the first year. Analysis of the relation between the number of injections and functional improvement indicated best fit for non-linear equations. A nearly stepwise improvement of functional gain occurred between 6.8 and 7.2 injections/year. A saturation effect of treatment occurred at higher injection frequency. CONCLUSIONS: The results of this meta-analysis clearly indicate a non linear relation between the number of injections and functional gain of ranibizumab within the first 12 months of treatment. Treatment saturation seems to occur at a treatment frequency >7.2 injections within the first 12 months. PMID- 24771185 TI - Retinal pigment epithelium rips after ranibizumab in neovascular age-related macular degeneration: incidence, risk factors and long-term outcome. AB - BACKGROUND: Retinal pigment epithelium (RPE) rips after ranibizumab for wet age related macular degeneration (AMD) with a pigment epithelial detachments (PED) are a dreaded complication. Aim of this study was to analyse the incidence, the risk factors and long-term outcome after a PED tear. PATIENTS AND METHODS: 401 patients with wet AMD were analysed. A total of 33 eyes with PED were identified. Mean follow up time was 635 days (SD +/- 311). RESULTS: PED tears occurred in 8 (24%) patients. Most RPE rips (40%) occurred within the first three months. Mean visual loss was 13 letters (range -57-9). The PED tear group had a mean PED height of 521 um. The PED group without a tear had a mean height of 300 um (p <= 0.001). Patients with a PED height over 300 um had more than twice the risk to develop a RPE rip compared to patients with PED height smaller than 300 um (p <= 0.001). CONCLUSIONS: PED height is a relevant factor for the incidence of RPE rips after treatment with ranibizumab. Owing to the close time relationship with the therapy, this complication must be taken into account before treatment as it may lead to significant vision loss. PMID- 24771186 TI - [Unusual presentation of a racemose haemangioma of the retina with involution after central retinal vein occlusion]. PMID- 24771187 TI - Bilateral severe anterior uveitis and acute angle-closure glaucoma following topiramate use for migraine crisis. PMID- 24771188 TI - Retinal vessel oxygen saturation in giant cell arteritis patients without ocular symptoms. AB - BACKGROUND: The aim of this study was to determine subclinical ocular ischemia related to giant cell arteritis (GCA) by means of retinal oximetry (RO) measurements. PATIENTS AND METHODS: Four test-retest RO images per eye were taken with the retinal vessel analyser (IMEDOS Systems UG, Jena). RO measurements in arterial (A-SO2) and venous (V-SO2) retinal vessels and their difference (A-V SO2) were calculated in GCA patients and compared to those of age-matched controls. RESULTS: GCA biopsy and duplex sonography positive patients (n=8, 13 eyes) from the Basler Riesenzellarteriitis Kohorte study (BARK) were recruited. In controls (n=6, 10 eyes), the mean (+/- SD) A-SO2 and V-SO2 were measured at 93.89% (+/- 3.0) and at 55.60% (+/- 3.4), respectively. In the GCAs, a reduction in the A-SO2 to 93.37% (+/- 3.3) and an increase in V-SO2 to 61.13% (+/- 3.6) were found. The A-V SO2 difference was reduced in the GCAs to 32.24% (+/- 3.8) whereas in the controls the difference was 38.31% (+/- 2.8). CONCLUSIONS: Oxygen metabolism is affected in cases with GCA. Thus, RO may provide additional data in the diagnosis of GCA, even when no ophthalmic symptoms have been reported. PMID- 24771189 TI - Retinal vessel oxygen saturation in patients suffering from inherited diseases of the retina. AB - PURPOSE: The aim of this study was to evaluate the oxygen saturation in patients with inherited diseases of the retina. METHODS: Fundus oximetry images were taken using a retinal vessel analyser (IMEDOS Systems UG, Jena, Germany). Retinal vessel oximetry was performed in 53 eyes of 27 patients suffering from inherited retinal diseases and compared to 22 eyes of 11 healthy controls. The oxygen saturation in all four major retinal arterioles (A-SO2) and venules (V-SO2) were measured and their difference (A-V SO2) was calculated. The data were compared within groups and to controls. RESULTS: Based on V-SO2 values, the rod-cone dystrophy group (66.46%; SD, +/- 5.09) could well be differentiated from controls 54.02% (SD, +/- 3.04), from cone-rod dystrophies 57.56% (SD, +/- 5.66), as well as from inherited maculopathies 58.42% (SD, +/- 4.74). The mean A-SO2 in the rod cone dystrophy group was increased to 98.96% (SD, +/- 6.06, p<0.014), while in the cone-rod group and in the maculopathy group it was 92.75% (SD, +/- 3.75), respectively 94.44% (SD +/- 4.85), closer to the normal values (92.68%; SD, +/- 3.53, p>0.05). The A-V SO2 difference, as an indirect indicator for retinal oxygen use, was reduced in the rod-cone patients, however only when the controls were taken into account (p=0.01). CONCLUSION: This is to our knowledge the first study which proposes the retinal vessel oximetry to be a sensitive measure for differentiating rod-cone dystrophy patients not only from controls, but also from patients with other inherited retinal dystrophies. PMID- 24771190 TI - Small-cell lung carcinoma presenting as paraneoplastic autoimmune optic neuritis with retinitis. PMID- 24771191 TI - [Imitation of tumor progression by peripheral proliferation of lens epithelial cells - a diagnostic challenge]. PMID- 24771192 TI - [Posterior uveitis. Part 1: diagnostics and basic concepts of therapy]. PMID- 24771193 TI - [Treatment of bleeding in patients undergoing oral anticoagulant therapy]. PMID- 24771194 TI - Bedside colonoscopy in intensive care units: indications, techniques, and outcomes. AB - BACKGROUND: Colonoscopy performed in critically ill patients is poorly documented in the literature. The clinical setting is completely different from routine outpatient colonoscopy with different aims and techniques. We proposed to examine the role of urgent colonoscopy in critically ill patients. METHODS: This was a retrospective review of patients in a prospectively recorded database. All patients undergoing colonoscopy in an intensive care unit were identified from a colonoscopy database. A chart review yielded indications, diagnoses, co morbidities, depth of intubation, and outcome. Main outcome measures were indications for colonoscopy, type and dose of sedation, bowel preparation, completion rate, findings, treatment, and complications. RESULTS: Forty one patients underwent 49 bedside colonoscopies (31 men (79 percent), 10 women, mean age of 68.1 years). The most common indications were to exclude ischemic colitis in 25 (confirmed in 19, operated in 14), decompression of colonic distension in 7 (all decompressed, 0 operated), and diagnosis of lower gastrointestinal hemorrhage in 7 (cause found in 7, 0 operated). All patients had major co morbidities and 28 were being ventilated at the time of the colonoscopy. A minority of patients received sedation. 14 (36 %) of the patients died. Colonoscopy reached the cecum in 16 patients (41 %), the hepatic flexure in 25 (64 %), and the splenic flexure in 36 (92 %). Prep was poor in 15 patients and stool prevented completion in 13. In 30 % of patients, colonoscopy was not pursued to the cecum. CONCLUSION: Bedside colonoscopy is helpful in the diagnosis and management of acute lower gastrointestinal disease in intensive care patients. PMID- 24771195 TI - Prospective cohort study on surgeons' response to equipment failure in the laparoscopic environment. AB - BACKGROUND: Equipment malfunction accounts for approximately one-fourth of surgical errors in the operating room. A serious game was developed to train surgeons in recognizing and responding to equipment failure in minimally invasive surgery (MIS) adequately. This study determined the baseline performance of surgeons, surgical residents, surgical novices, and MIS equipment technicians in solving MIS equipment failure. METHODS: The serious game included 37 problem scenarios on the subjects lighting and imaging, insufflation and gas transport, electrosurgery, and pathophysiological disturbances. The scenarios were validated by laparoscopic surgeons and MIS equipment specialists. Forty-nine licensed surgeons, surgical residents, medical students, and MIS equipment specialists played four sessions on the serious game at a surgical convention. Scores on different outcome parameters were compared between groups of a different MIS experience. RESULTS: Laparoscopic equipment specialists solved significantly more MIS equipment-related problems than surgical novices, intermediates, and experts (68.9 vs. 51.0 %, 51.4, and 45.0 %, respectively, p = 0.01). Laparoscopic equipment specialists required significantly fewer steps to solve a problem accurately (median of 1.0 vs. 2.0 for the other groups). Most notably, experienced surgeons were unable to outperform novice and intermediate groups. Experienced surgeons took less time to solve the problems, but made more mistakes in doing so. CONCLUSIONS: Experienced surgeons did not outperform inexperienced surgeons in dealing with laparoscopic equipment failure. These results are worrying and need to be addressed by the surgical community. PMID- 24771196 TI - Robotic surgery for primary hyperparathyroidism. AB - BACKGROUND: Open cervical parathyroidectomy is the standard of care for the treatment of primary hyperparathyroidism (PHP). However, in patients with a history of keloid or hypertrophic scar formation, the cosmetic result may sometimes be unsatisfactory. Furthermore, in the presence of mediastinal glands, a more morbid approach is sometimes necessary, involving a sternal split or thoracotomy. Robotic parathyroidectomy, either transaxillary or transthoracic, could be an alternative in both settings. METHODS: Between 2008 and 2013, 14 patients with PHP and a well-localized single adenoma underwent robotic transaxillary cervical (TAC) (n = 8) or transthoracic mediastinal (TTM) (n = 6) parathyroidectomy at an academic tertiary medical center and their outcomes were analyzed. RESULTS: All 14 operations were completed successfully as planned. For TAC and TTM parathyroidectomies, mean operative time was 184 and 168 min, respectively. With the exception of one TTM patient, intraoperative PTH determination indicated a >50 % drop in all patients 10 min after excision and no patients presented with recurrent disease on follow-up. Average length of hospital stay was 1 day after TAC parathyroidectomy and 2.2 days after TTM. On a visual analog pain scale (0-10), average pain scores after TAC were 6/10 on postoperative day 1 and 1/10 on day 14, compared to 7.7/10 and 1.5/10, respectively, after TTM. Complications included development of seroma in 1 patient in the TAC group and pericardial and pleural effusion in 1 patient in the TTM cohort. CONCLUSIONS: This initial study shows that robotic TAC and TTM parathyroidectomy are feasible in selected PHP patients with preoperatively well localized disease. Although the TAC approach offers a potential cosmetic benefit in patients with a history of keloid or hypertrophic scar formation, a more generalized use cannot be recommended based on current evidence. The robotic TTM approach presents a minimally invasive alternative to resections previously performed through thoracotomy and sternotomy. PMID- 24771197 TI - Validation of the VBLaST peg transfer task: a first step toward an alternate training standard. AB - BACKGROUND: The FLS trainer lacks objective and automated assessments of laparoscopic performance and requires a large supply of relatively expensive consumables. Virtual reality simulation has a great potential as a training and assessment tool of laparoscopic skills and can overcome some limitations of the FLS trainer. This study was carried out to assess the value of our Virtual Basic Laparoscopic Surgical Trainer (VBLaST((c))) in the peg transfer task compared to the FLS trainer and its ability to differentiate performance between novice, intermediate, and expert groups. METHODS: Thirty subjects were divided into three groups: novices (PGY1-2, n = 10), intermediates (PGY3-4, n = 10), and experts (PGY5, surgical fellows and attendings, n = 10). All subjects performed ten trials of the peg transfer task on each simulator. Assessment of laparoscopic performance was based on FLS scoring while a questionnaire was used for subjective evaluation. RESULTS: The performance scores in the two simulators were correlated, though subjects performed significantly better in the FLS trainer. Experts performed better than novices only on the FLS trainer while no significant differences were observed between the other groups. Moreover, a significant learning effect was found on both trainers, with a greater improvement of performance on the VBLaST((c)). Finally, 82.6% of the subjects preferred the FLS over the VBLaST((c)) for surgical training which could be attributed to the novelty of the VR technology and existing deficiencies of the user interface for the VBLaST((c)). CONCLUSION: This study demonstrated that the VBLaST((c)) reproduced faithfully some aspects of the FLS peg transfer task (such as color, size, and shape of the peg board, etc.) while other aspects require additional development. Future improvement of the user interface and haptic feedback will enhance the value of the system as an alternative to the FLS as the standard training tool for laparoscopic surgery skills. PMID- 24771200 TI - The role of pH on the resistance of resting- and active anammox bacteria to NO2- inhibition. AB - The anaerobic oxidation of ammonium (anammox) uses nitrite as terminal electron acceptor. The nitrite can cause inhibition to the bacteria that catalyze the anammox reaction. The literature shows a great divergence on the levels of NO2 ( ) causing inhibition. Moreover, the conditions influencing the resistance of anammox bacteria to NO2 (-) inhibitory effect are not well understood. This work investigated the effect of the pH and the concentration of nitrite on the activity and metabolism of anammox granular sludge under different physiological conditions. Batch activity tests in a range of pH values were carried out in which either actively metabolizing cells or resting cells were exposed to nitrite in the presence or absence of the electron donating substrate ammonium, respectively. The response of the bacteria was evaluated by analyzing the specific anammox activity, the accumulation of nitric oxide, and the evolution of the ATP content in the biomass. Additionally, the effect of the pH on the tolerance of the biomass to single substrate feeding interruptions was evaluated in continuous anammox bioreactors. The results show that the influence of the pH on the NO2 (-) inhibition of anammox bacteria is greater under non-metabolizing conditions than during active metabolism. The exposure of resting cells to NO2 ( ) (100 mg N L(-1) ) at pH values below 7.2 caused complete inhibition of the anammox activity. The inhibition was accompanied by accumulation of the intermediate, nitric oxide, in the gas phase. In contrast, just mild inhibition was observed for resting cells exposed to the same NO2 (-) concentration at pH values higher than 7.5 or any of the pH values tested in assays with actively metabolizing cells. ATP initially increased and subsequently decreased in time after resting cells were exposed to NO2 (-) suggesting an active response of the cells to nitrite stress. Furthermore, bioreactors operated at pH lower than 6.8 had greater sensitivity to NO2 (-) during an ammonium feed interruption than a bioreactor operated at pH 7.1. The results suggest that the ability of resting cells to tolerate NO2 (-) inhibition is seriously impeded at mildly acidic pH values; whereas actively metabolizing biomass is resistant to NO2 (-) toxicity over a wide range of pH values. PMID- 24771201 TI - The functional and aesthetic reconstruction of midfacial and orbital defects by combining free flap transfer and craniofacial prosthesis. AB - OBJECTIVES: The reconstruction of complex facial defects should satisfy both aesthetic and functional requirements. In the midfacial area, the nasal passage should be sufficiently separated from the orbit and the oral cavity to avoid both dysphagia and articulation disorders and to allow unimpaired nasal breathing. In the case of large defects, the use of craniofacial prostheses alone is ineffective in the restoration of functional units in the majority of patients. Therefore, we evaluated the combination of microvascular tissue transfer and episthetic constructions in a series of patients. MATERIAL AND METHODS: Our case series included ten patients requiring one or more free flaps in combination with extraoral implants and episthetic work. RESULTS: Four women and six men with a mean age of 68 years were included. All patients were treated because of tumours in the midface area. Eight patients were free of recurrence, one patient died during the follow-up. For the reconstructions, we used anterolateral thigh flaps, radial forearm flaps, fibular flaps and iliac crest bone flaps. On average, we inserted four extraoral implants in the periorbital region. Seven implants of four patients did not osseointegrate and had to be removed. CONCLUSIONS: For complex reconstructions of extensive defects in the midfacial area, microvascular free tissue transfer in combination with extraoral implants and craniofacial prosthetic work yields reasonable functional and aesthetic outcomes and noticeably improves the quality of life. CLINICAL RELEVANCE: This work investigates patient cases with extensive defects in which free flap or episthetic work alone proved ineffective for reconstruction. PMID- 24771202 TI - Computer methods for follow-up study of hemodynamic and disease progression in the stented coronary artery by fusing IVUS and X-ray angiography. AB - Despite a lot of progress in the fields of medical imaging and modeling, problem of estimating the risk of in-stent restenosis and monitoring the progress of the therapy following stenting still remains. The principal aim of this paper was to propose architecture and implementation details of state of the art of computer methods for a follow-up study of disease progression in coronary arteries stented with bare-metal stents. The 3D reconstruction of coronary arteries was performed by fusing X-ray angiography and intravascular ultrasound (IVUS) as the most dominant modalities in interventional cardiology. The finite element simulation of plaque progression was performed by coupling the flow equations with the reaction-diffusion equation applying realistic boundary conditions at the wall. The alignment of baseline and follow-up data was performed automatically by temporal alignment of IVUS electrocardiogram-gated frames. The assessment was performed using three six-month follow-ups of right coronary artery. Simulation results were compared with the ground truth data measured by clinicians. In all three data sets, simulation results indicated the right places as critical. With the obtained difference of 5.89 +/- ~4.5% between the clinical measurements and the results of computer simulations, we showed that presented framework is suitable for tracking the progress of coronary disease, especially for comparing face-to-face results and data of the same artery from distinct time periods. PMID- 24771203 TI - Comparison of spinal cord stimulation profiles from intra- and extradural electrode arrangements by finite element modelling. AB - Spinal cord stimulation currently relies on extradural electrode arrays that are separated from the spinal cord surface by a highly conducting layer of cerebrospinal fluid. It has recently been suggested that intradural placement of the electrodes in direct contact with the pial surface could greatly enhance the specificity and efficiency of stimulation. The present computational study aims at quantifying and comparing the electrical current distributions as well as the spatial recruitment profiles resulting from extra- and intra-dural electrode arrangements. The electrical potential distribution is calculated using a 3D finite element model of the human thoracic spinal canal. The likely recruitment areas are then obtained using the potential as input to an equivalent circuit model of the pre-threshold axonal response. The results show that the current threshold to recruitment of axons in the dorsal column is more than an order of magnitude smaller for intradural than extradural stimulation. Intradural placement of the electrodes also leads to much higher contrast between the stimulation thresholds for the dorsal root entry zone and the dorsal column, allowing better focusing of the stimulus. PMID- 24771204 TI - Coronary artery disease associated with severe mitral and tricuspid valve regurgitation after left pneumonectomy: report of a successful hybrid procedure. AB - The literature concerning heart surgery after pneumonectomy is still poor. Moreover, there is still a lack of a standardized approach to such a patient in the decision-making process. Here, we report a case of a patient who had previously had left pneumonectomy for malignancy and who had coronary artery disease and mitral and tricuspid regurgitation treated with a hybrid procedure. PMID- 24771205 TI - Beneficial effect of fenoldopam mesylate in preventing peak blood lactate level during cardiopulmonary bypass for paediatric cardiac surgery. AB - OBJECTIVES: To evaluate the efficacy of fenoldopam mesylate (dose 0.2 ug/kg/min) in reducing the occurrence of hyperlactataemia (i.e. peak level of blood lactate >2.0 mM/l) during cardiopulmonary bypass (CPB) in paediatric cardiac surgery. Hyperlactataemia occurring during CPB for paediatric cardiac surgery is considered an early biomarker of an increased risk of poor outcome. METHODS: This was a dose/effectiveness clinical study applying Simon's two-stage optimal design with 5% type I error rate and 90% statistical power. Following parents' written informed consent, 53 children undergoing elective cardiac surgery with CPB between March 2009 and February 2012 were enrolled. Inclusion criteria were children weighing 3-15 kg scheduled for elective cardiac surgery and with expected CPB time of 60-180 min. Patients requiring surgery with total circulatory arrest were excluded. All patients received fenoldopam infusion at a dose of 0.2 ug/kg/min from the beginning of surgery until the end of CPB. RESULTS: The primary end-point was the evaluation of response to fenoldopam, i.e., blood lactate levels <=2.0 mM/l. A total of 53 children, median age 5.7 months (range 11 days to 48 months) were enrolled. In the first stage, 18 of 19 (95%) children achieved normalization of lactate values. Then the study was continued to stage II by enrolling an additional 34 patients. At study conclusion, 96.2% of patients showed normalized lactate values. Fenoldopam infusion was well tolerated in all patients. No adverse events were observed. CONCLUSIONS: In this study, fenoldopam at a dose of 0.2 ug/kg/min was well tolerated in paediatric patients undergoing elective cardiac surgery with CPB. In 96.2% of patients, infusion of fenoldopam was associated with intraoperative blood lactate <2.0 mM/l. PMID- 24771206 TI - Understanding placebo and nocebo responses for pain management. AB - Placebo analgesia makes individuals experience relief of their pain simply by virtue of the anticipation of a benefit. A reduction of pain can occur also when placebos follow the administration of active and effective painkillers. In fact, studies indicate that placebos mimic the action of active treatments and promote the endogenous release of opioids in both humans and animals. Finally, social support and observational learning also lead to analgesic effects. Thus, different psychological factors and situations induce expectations of analgesia facilitating the activation of the top-down systems for pain control along with the release of endogenous mediators crucially involved in placebo-induced benefits. Recent scientific investigation in the field of brain imaging is opening new avenues to understanding the cognitive mechanisms and neurobiological substrates of expectation-induced pain modulation. Gaining deeper knowledge of top-down mechanisms of pain modulation has enormous implications for personalizing and optimizing pain management. PMID- 24771207 TI - Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models. AB - Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. 3'-Deoxy-3'-(18) F-fluorothymidine ((18) F-FLT) positron emission tomography (PET) scans showed a remarkable decrease in (18) F-FLT signal in TC- and TB-treated OS-1 tumors, which was already noticeable after 1 week of treatment. No baseline uptake was observed in the OS-33 model. Both immunohistochemistry and (18) F-FLT-PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although (18) F FLT-PET could be used for accurate and early response monitoring for temsirolimus based therapies in the OS-1 model, we could not evaluate OS-33 tumors with this molecular imaging technique. Further research on the value of the use of (18) F FLT-PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients. PMID- 24771210 TI - Comparative analysis between radiation doses obtained by EPR dosimetry using tooth enamel and established analytical methods for the population of radioactively contaminated territories. AB - A comparative analysis of radiation doses determined by tooth enamel electron paramagnetic resonance (EPR) spectroscopy and by an acknowledged analytical method is performed for individual doses and for average doses in population of some settlements of the Bryansk region (Russia), which have been contaminated after the Chernobyl nuclear accident. The analysis is performed for doses in the range of 0-200 mGy for individuals and in the range of 0-50 mGy for the averaged populations. The method of orthogonal distance linear regression is used for the analysis. For both data sets the slopes of the regression line close to unity and the intercept close to zero are obtained, which indicates that doses determined by these two methods agree with each other. The root-mean-square difference between the results of EPR and analytical methods is estimated to be 35 mGy for individual doses and 15 mGy for averaged doses, which is consistent with uncertainty of these methods. PMID- 24771209 TI - Unusual evolutionary conservation and further species-specific adaptations of a large family of nonclassical MHC class Ib genes across different degrees of genome ploidy in the amphibian subfamily Xenopodinae. AB - Nonclassical MHC class Ib (class Ib) genes are a family of highly diverse and rapidly evolving genes wherein gene numbers, organization, and expression markedly differ even among closely related species rendering class Ib phylogeny difficult to establish. Whereas among mammals there are few unambiguous class Ib gene orthologs, different amphibian species belonging to the anuran subfamily Xenopodinae exhibit an unusually high degree of conservation among multiple class Ib gene lineages. Comparative genomic analysis of class Ib gene loci of two divergent (~65 million years) Xenopodinae subfamily members Xenopus laevis (allotetraploid) and Xenopus tropicalis (diploid) shows that both species possess a large cluster of class Ib genes denoted as Xenopus/Silurana nonclassical (XNC/SNC). Our study reveals two distinct phylogenetic patterns among these genes: some gene lineages display a high degree of flexibility, as demonstrated by species-specific expansion and contractions, whereas other class Ib gene lineages have been maintained as monogenic subfamilies with very few changes in their nucleotide sequence across divergent species. In this second category, we further investigated the XNC/SNC10 gene lineage that in X. laevis is required for the development of a distinct semi-invariant T cell population. We report compelling evidence of the remarkable high degree of conservation of this gene lineage that is present in all 12 species of the Xenopodinae examined, including species with different degrees of ploidy ranging from 2, 4, 8 to 12 N. This suggests that the critical role of XNC10 during early T cell development is conserved in amphibians. PMID- 24771211 TI - Dosimetric analysis of the use of CBCT in diagnostic radiology: sinus and middle ear. AB - The use of cone beam computed tomography (CBCT) in diagnostic radiology departments is increasing. Several discussions arise whether with the CBCT application, some multi-slice CT (MSCT) examinations can be replaced by it. High hopes are set regarding the dosimetric aspects of CBCT: are patient doses in between those of conventional X-rays and MSCT? In this study, effective dose and organ doses were evaluated for two non-dental CBCT examinations: sinus and middle ear. A comparison with the dose obtained with a MSCT protocol was performed. Moreover, the sinus examination was also compared with the dose obtained by projection radiography (RX). Effective doses were estimated from thermoluminescent detector dose measurements in an anthropomorphic phantom and were compared against Monte Carlo simulations. Results show that the effective dose for the sinus examination is more than three times higher with MSCT than with CBCT and about five times lower with RX compared with CBCT, whereas for the middle ear examination, the effective dose obtained with MSCT is almost six times higher than that of CBCT. Finally, a sensitivity study on the size and position of the CBCT field of view showed the influence of these two factors on the dose received by the patient. PMID- 24771212 TI - The fencing problem and Coleochaete cell division. AB - The findings in this study suggest that the solution of a boundary value problem for differential equation system can be used to discuss the fencing problem in mathematics and Coleochaete, a green algae, cell division. This differential equation model in parametric expression is used to simulate the two kinds of cell division process, one is for the usual case and the case with a "dead" daughter cell. PMID- 24771213 TI - Naso-oropharyngeal choristoma (hairy polyps): an overview and current update on presentation, management, origin and related controversies. AB - This review presents a comprehensive and updated overview of bigerminal choristomas (hairy polyps) of naso-oropharynx/oral cavity, and discusses the controversies related to nosology and origin from a clinico-embryologic perspective. English-language texts of the last 25 years (January 1989-January 2014) were collected from the PubMed/MEDLINE database using the given keywords. Of the 330 records, 64 full-text articles (mostly case reports/series) were selected, incorporating clinical data from 78 patients, after screening through duplicates and the given exclusion criteria. With the available evidence, hairy polyps appear more common than generally believed, and are increasingly being recognized as an important, often-missed cause of respiratory distress and feeding difficulty in neonates and infants. Such a child without any apparent cause should be examined with flexible nasopharyngoscope to specifically look for hairy polyps which might be life-threatening, especially when small. The female preponderance as believed today has been found to be an overestimation in this review. These lesions are characteristically composed of mature ectodermal and mesodermal tissue derivatives presenting as heterotopic masses, hence termed choristoma. However, little is known about their origin, and whether they are developmental malformations or primitive teratomas is debatable. Involvement of Eustachian tube and tonsils as predominant subsites and the speculated molecular embryogenesis link hairy polyps to the development of the first and second pharyngeal arches. They are exceptionally rare in adults, but form a distinct entity in this age-group and could be explained as delayed pluripotent cell morphogenesis or focal neoplastic malformations, keeping with the present-day understandings of the expanded "teratoma family". PMID- 24771214 TI - The significance of osteitis in rhinosinusitis. AB - Rhinosinusitis is a disease of multifactorial aetiology. As a profession our insight into this pathological process has progressed enormously over the last few decades. The contribution from environmental, host immunity, microbiology and anatomical factors is well recognised, if not completely understood. The involvement of underlying bone in rhinosinusitis was first recognised experimentally in animals and has subsequently been highlighted as a potentially significant finding in humans with CRS. In this review, the role of bone in chronic rhinosinusitis and the evidence behind that role are discussed. Both histological and radiological findings are presented and the subsequent potential clinical impact and relevance of osteitis in rhinosinusitis patients. Future pathways for research to add to the current knowledge of the impact of bony involvement are also discussed. PMID- 24771215 TI - [Alfred Gutgemann (1907-1985). Pioneer, criminally authorised!]. PMID- 24771216 TI - ["Mastering surgical biology" - a retrospective view of the 17th surgical research days in Frankfurt]. PMID- 24771217 TI - [Use of Reusable Textile Undergloves for Medical Procedures: A Feasibility Study]. AB - OBJECTIVE: Undergloves are a way to reduce moisture-related skin damage. The aim of this feasibility study was to gain experience with logistics, applicability, acceptability and cost of the routine use of reusable textile undergloves in a hospital setting. METHODS: Undergloves were tested with 18 health-care workers on an intensive care unit over three months. Data on usage as well as logistics were recorded. At baseline, personal data and knowledge and use of cotton undergloves, existing skin problems and the nursing behaviour of the hands by the subjects were determined by means of an input questionnaire. After each wearing, data on usage were collected by a questionnaire. Participants were interviewed by means of a questionnaire with respect to their experience with the use of the undergloves. RESULTS: Acceptance and compliance with the use of undergloves was remarkably good. This was partly due to the properties of the gloves, and partly to the reduction of sweating and very positive effect on the skin of the hands. In the study period 2165 underglove uses were documented, resulting in an average daily consumption of four pairs per person per day. The average wearing time was 28.6 min. The undergloves were suitable for application as well as reprocessing. Reprocessment-related fatigue was relatively low and did not lead to the loss of the properties, only few gloves had to be sorted out. Even if one assumes a complete write-off of the gloves with end of the study, costs for reprocessing were about 0.46 ? or 64 % less than the single use. CONCLUSION: The routine use of textile, reprocessable undergloves is feasible. Major challenges for broad usage are within logistics and acceptance by the user. PMID- 24771218 TI - [What do general, abdominal and vascular surgeons need to know on plastic surgery - aspects of plastic surgery in the field of general, abdominal and vascular surgery]. AB - There is overlap between general, abdominal and vascular surgery on one hand and plastic surgery on the other hand, e.g., in hernia surgery, in particular, recurrent hernia, reconstruction of the abdominal wall or defect closure after abdominal or vascular surgery. Bariatric operations involve both special fields too. Plastic surgeons sometimes use skin and muscle compartments of the abdominal wall for reconstruction at other regions of the body. This article aims to i) give an overview about functional, anatomic and clinical aspects as well as the potential of surgical interventions in plastic surgery. General/abdominal/vascular surgeons can benefit from this in their surgical planning and competent execution of their own surgical interventions with limited morbidity/lethality and an optimal, in particular, functional as well as aesthetic outcome, ii) support the interdisciplinary work of general/abdominal/vascular and plastic surgery, and iii) provide a better understanding of plastic surgery and its profile of surgical interventions and options. PMID- 24771219 TI - [Component separation for closing large abdominal wall defects: evolution of a method from 1990 to present day]. AB - BACKGROUND: The separation of autologous and functional active components of the lateral abdominal wall for closing large midline defects was introduced in 1990. The original components separation technique (CS) has undergone numerous modifications. The aim of this work is to summarise the essential steps of the development. METHODS: Based on a literature review, the original technique, the modifications and advancements are presented and evaluated regarding indication, techniques and results. RESULTS: The original technique still has a high status, because of the large extent of rectus complex medialisation. Numerous modifications of the anterior conventional component separation with different clinical results were described. The development of a minimally invasive technique with balloon dilatation trocars was an essential step and decreased wound morbidity. The modified posterior component separation by transverse abdominis release currently seems to be an encouraging alternative to be regarded as a widening of the sublay technique. All methods can be combined with implantation of prosthetic or biological implants in intraperitoneal, sublay or onlay technique, whereby the recurrence rate can be decreased. CONCLUSION: From where we stand today no single technique can generally be recommended. The latest methods aim for decreasing complications and recurrences by means of minimally invasive procedures. The surgical strategy still depends on the complexity and extent of abdominal wall defect and has to be determined according to individual aspects and sometimes requires an interdisciplinary approach. PMID- 24771220 TI - Cyclin-dependent kinase 4 overexpression is mostly independent of gene amplification and constitutes an independent prognosticator for nasopharyngeal carcinoma. AB - Data mining in the public domain demonstrates that cyclin-dependent kinase 4 (CDK4) is highly expressed in nasopharyngeal carcinomas (NPC). Associated with cyclin-D, CDK4 phosphorylates and inactivates retinoblastoma (Rb) protein family members and mediates progression through the G1- to the S-phase of the cell cycle. Amplification and overexpression of CDK4 has been identified in various human malignancies. However, its expression and amplification has never been systemically evaluated in NPC. This study aimed to evaluate the amplification and expression status, correlation with clinicopathological features, and prognostic implications of CDK4 based on public domain dataset and in our well-defined cohort of NPC patients. The association between CDK4 transcript level and gene dosage was explored by analysis of an independent public domain dataset. We retrospectively assessed CDK4 immunoexpression in biopsies of 124 consecutive NPC patients devoid of initial distant metastasis and treated according to consistent guidelines. The results were correlated with clinicopathological features, local recurrence-free survival (LRFS), distant metastasis-free survival (DMeFS), and disease-specific survival (DSS). High levels of CDK4 protein were positively correlated with the T 3, 4 status (p = 0.024); N 2, 3 status (p < 0.001); and the American Joint Committee on Cancer stage 3, 4 (p < 0.001). Multivariate analysis suggested high CDK4 expression was an independent prognostic indicator of worse DMeFS (p = 0.001, hazard ratio (HR) = 3.226) and DSS (p = 0.037, HR = 1.838). Although CDK4 is frequently upregulated, its gene locus is very uncommonly amplified in NPC. CDK4 overexpression is mostly independent with gene amplification and represents a potential prognostic biomarker in NPC and may indicate tumor aggressiveness through cell cycle dysregulation. PMID- 24771221 TI - Inhibition of FoxO1 nuclear exclusion prevents metastasis of glioblastoma. AB - Glioblastoma is the most aggressive malignant primary brain tumor in humans, with extremely poor patient survival. Although previous studies have demonstrated that expression of matrix metalloproteinase-9 (MMP9) in glioblastoma promotes cancer metastasis, the upstream molecular signaling cascades that control activation of MMP9 remain largely unknown. Here, we used a human glioblastoma line, A-172, to examine molecular signaling to activate MMP9. We found that epidermal growth factor (EGF)-induced activation of epidermal growth factor receptor (EGFR) in A 172 cells activated MMP9, resulting in an increase in cancer invasiveness. A specific inhibitor for EGFR efficiently blocked EGF-induced activation of MMP9 and then cancer invasiveness. Moreover, an inhibitor for phosphatidylinositol 3 kinase (PI-3 K)/protein kinase B (Akt) significantly inhibited the EGF-induced activation of MMP9. Furthermore, nuclear exclusion of a major Akt downstream target, Forkhead box protein O1 (FoxO1), was induced by Akt activation, which could be inhibited by either an EGFR inhibitor or by PI-3 K/Akt inhibitor. An expression of a constitutive nuclear form of FoxO1 significantly inhibited MMP9 activation induced by EGF. Taken together, these findings suggest that EGF/EGFR signaling activates downstream PI-3 K/Akt to induce FoxO1 nuclear exclusion, which activates MMP9 to promote glioblastoma invasiveness. Thus, FoxO1 appears to be a novel therapeutic target for inhibiting metastasis of glioblastoma. PMID- 24771222 TI - The ABO blood group predicts survival in esophageal squamous cell carcinoma in patients who ever smoked: a retrospective study from China. AB - The association between clinical characteristics, prognosis, and the ABO blood group of esophageal squamous cell carcinoma (ESCC) is rarely discussed. The aims of the current study were to investigate the correlation of the ABO blood group with the clinicopathological characteristics in a consecutive cohort of patients with ESCC and to assess whether the ABO blood group was associated with prognosis. A total of 511 patients with locoregional ESCC who underwent curative treatment were retrospectively analyzed at a single institution between January 2007 and December 2008. The relationship between the ABO blood group and clinicopathological variables was assessed by chi-squared analysis. The Kaplan Meier method was used to estimate the 5-year overall survival (OS). The Cox proportional hazards model was used in univariate and multivariate analyses of OS. There were no significant differences in the clinicopathological characteristics among patients with different ABO blood groups. The 5-year OS rates were 50.0 % for patients with blood type A, 45.4 % for type B, 50.8 % for type O, and 60.7 % for type AB. In a subgroup analysis of 321 patients who ever smoked, the B/O group had a poorer OS compared with the A/AB group (p = 0.0245). Multivariate analysis revealed an unfavorable and independent impact of the B/O group on patient survival with ESCC who ever smoked (p = 0.011). Findings suggest the B/O blood type as a predictor of mortality in ESCC patients who ever smoked. Future studies conducted prospectively are warranted to confirm this work and to better understand the underlying biological mechanisms. PMID- 24771223 TI - Cardiac complications of chemotherapy: role of biomarkers. AB - OPINION STATEMENT: Both conventional and novel antineoplastic drugs may cause damage to the heart, ultimately affecting patients' survival and quality of life. In fact, the most frequent and typical clinical manifestation of cardiotoxicity, asymptomatic or symptomatic left ventricular dysfunction, may be induced not only by conventional cancer therapy, like anthracyclines, but also by new antitumoral targeted therapy such as trastuzumab. At present, left ventricular ejection fraction assessment represents the main standard practice for cardiac monitoring during cancer therapy, but it detects myocardial damage only when a functional impairment has already occurred, not allowing for early preventive strategies. In the last decade, a newer approach based on the measurement of cardiospecific biomarkers has been proposed, proving to have higher prognostic value than imaging modalities. In particular, cardiac troponin elevation during chemotherapy allows us to identify patients who are more prone to develop myocardial dysfunction and cardiac events during follow up. In these patients, the use of an angiotensin-converting enzyme inhibitor, such as enalapril, has shown to be effective in improving clinical outcome, giving the chance for a cardioprotective strategy in a selected population. PMID- 24771224 TI - Granulocyte-colony stimulating factor reduces cardiomyocyte apoptosis and ameliorates diastolic dysfunction in Otsuka Long-Evans Tokushima Fatty rats. AB - BACKGROUND: In recent studies, granulocyte-colony stimulating factor (G-CSF) was shown to improve cardiac function in myocardial infarction and non-ischemic cardiomyopathies. The mechanisms of these beneficial effects of G-CSF in diabetic cardiomyopathy are not yet fully understood. Therefore, we investigated the mechanisms of action of G-CSF on diabetic cardiomyopathy in a rat model of type 2 diabetes. METHODS: Seventeen-week-old OLETF (Otsuka Long Evans Tokushima Fatty) diabetic rats and LETO (Long Evans Tokushima Otuska) rats were randomized to treatment with 5 days of G-CSF (100 MUg/kg/day) or with saline. Cardiac function was evaluated by serial echocardiography performed before and 4 weeks after treatment. We measured expression of the G-CSF receptor (GCSFR) and Bcl-2, as well as the extent of apoptosis in the myocardium. RESULTS: G-CSF treatment significantly improved cardiac diastolic function in the serial echocardiography assessments. Expression of G-CSFR was down-regulated in the diabetic myocardium (0.03 +/- 0.12 % vs. 1 +/- 0.15 %, p < 0.05), and its expression was stimulated by G-CSF treatment (0.03 +/- 0.12 % vs. 0.42 +/- 0.06 %, p < 0.05). In addition, G-CSF treatment increased the expression of Bcl-2 in the diabetic myocardium (0.69 +/- 0.06 % vs. 0.26 +/- 0.11 %, p < 0.05), consistent with the reduced cardiomyocyte apoptosis (9.38 +/- 0.67 % vs. 17.28 +/- 2.16 %, p < 0.05). CONCLUSIONS: Our results suggest that G-CSF might have a cardioprotective effect in diabetic cardiomyopathy through up-regulation of G-CSFR, attenuation of apoptosis by up-regulation of Bcl-2 expression, and glucose-lowering effect. Our findings support the therapeutic potential of G-CSF in diabetic cardiomyopathy. PMID- 24771225 TI - Monocyte-based microrobot with chemotactic motility for tumor theragnosis. AB - Biocompatibility, sensing, and self-actuation are very important features for a therapeutic biomedical microrobot. As a new concept for tumor theragnosis, this paper proposes a monocyte-based microrobots, which are combining the phagocytosis and engulfment activities containing human acute monocytic leukemia cell line (THP-1) with various sized polystyrene microbeads are engulfed instead of a therapeutic drug. For the validation of the blood vessel barrier-penetrating activity of the monocyte-based microrobot, we fabricate a new cell migration assay with monolayer-cultured endothelial cell (HUVEC), similar with the blood vessels. We perform the penetrating chemotactic motility of the monocyte-based microrobot using various types of the chemo-attractants, such as monocyte chemotactic protein (MCP)-1, human breast cancer cell lines (MCF7)-cell lysates, and -contained alginate spheroids. The monocyte-based microrobot show chemotactic transmigrating motilities similar with what an actual monocyte does. This new paradigm of a monocyte-based microrobot having various useful properties such as biocompatibility, sensing, and self-actuation can become the basis of a biomedical microrobot using monocytes for diagnosis and therapy of various diseases. PMID- 24771226 TI - Implanted endocardial lead characteristics and risk of stroke or transient ischemic attack. AB - INTRODUCTION: Patent foramen ovale (PFO) has been recently implicated as a strong predictor of stroke or transient ischemic attack (TIA) in patients with implanted pacemaker or defibrillation leads. Leads in the right heart can form thrombi that embolize to the pulmonary circulation and raise pulmonary pressure. This increases right-to-left shunting through PFO or intrapulmonary shunts and can result in paradoxical embolism. We sought to determine whether certain lead characteristics confer a higher thrombogenic risk resulting in stroke/TIAs in patients either with or without a PFO. METHODS: We retrospectively analyzed 5,646 patients (mean age 67.3 +/- 16.3 years, 64 % male) who had endocardial device leads implanted in 2000-2010. We performed univariate and multivariate-adjusted proportional hazards models to determine association of lead characteristics with stroke/TIA during follow-up. RESULTS: On univariate analysis, passively fixated tined leads were associated with more stroke/TIAs (HR 1.77, 95 % CI 1.27, 2.47; p<0.001), whereas presence of defibrillation coil was associated with fewer stroke/TIAs (HR 0.59, 95 % CI 0.42-0.84; p=0.003). Number of leads per patient, presence of atrial lead, maximum lead size, tip shape, and type of insulating material were not associated with stoke/TIA. On multivariate analyses adjusting for age, sex, diagnosis of PFO, and prior history of stroke/TIA, the presence of tined leads was associated with stroke/TIA (HR 1.41, 95 % CI 1.00-1.97; p=0.049). Defibrillation coils were no longer associated with lower stroke/TIA on multivariate analysis. CONCLUSIONS: Most physical characteristics of contemporary leads do not impact rate of stroke/TIA among patients receiving implantable devices. The presence of a PFO is a major risk factor for stroke/TIA in patients with endovascular leads. PMID- 24771228 TI - Five-year results of vital pulp therapy in permanent molars with irreversible pulpitis: a non-inferiority multicenter randomized clinical trial. AB - OBJECTIVES: Previous reported results of up to 12 months as well as 24-month follow-ups revealed superior and equivalent treatment outcomes for vital pulp therapy (VPT) using calcium-enriched mixture cement (CEM) in comparison with root canal therapy (RCT) for mature molars with established irreversible pulpitis, respectively. Present non-inferiority multicenter randomized clinical trial assesses the final long-term (5-year) results as well as the effects of patients' age/gender and the presence of preoperative periapical lesion on the treatment outcomes. MATERIALS AND METHODS: A total number of 407 patients were blindly allocated into two treatment groups [group 1 (VPT/CEM, n = 205) and group 2 (RCT, n = 202)] treated in 23 health-care centers by calibrated dentists. The treatment outcomes were assessed after 60 months. RESULTS: The 5-year results revealed no significant differences in the successes of both study arms (P = 0.29); a total number of 271 patients were available (~33 % were lost to follow-up). The patients' age/gender did not affect the outcomes; the presence of preoperative periapical lesion also did not implement a significant effect in both groups (P > 0.05). CONCLUSIONS: As an alternative for RCT, VPT/CEM can be considered as a valid treatment for vital mature permanent molars clinically diagnosed with irreversible pulpitis. CLINICAL RELEVANCE: Considering the favorable outcomes of 6- to 60-month follow-ups, as an evidence based/simple/affordable/effective/biologic approach in cases of irreversible pulpitis, VPT/CEM is highly recommended for universal clinical practice. PMID- 24771227 TI - Reduced folate carrier-1 G80a gene polymorphism is associated with neuroblastoma's development. AB - Neuroblastoma is a malignant embryonal tumor of neural crest cells that give rise to the sympathetic nervous system, responsible for 10-70% of all cases of childhood cancer. Because of its early appearance, it has been suggested that risk factors active in the prenatal can be associated with the pathogenesis of neuroblastoma. The aim of this study was to investigate whether the genetic polymorphisms MTHFR C677T and A1298C, MTR A2756G, TYMS 2R/3R and SLC19A1 G80A, involved in folate metabolism, increase the risk of neuroblastoma in Brazilian children. This study comprised 31 Brazilian children (0-14 years old) diagnosed with neuroblastoma compared with 92 controls. Investigation of polymorphisms MTHFR C677T, MTR A2756G and SLC19A1 A80G was performed using PCR-RFLP, the TYMS 2R/3R using PCR and MTHFR A1298C using AS-PCR. The SLC19A1 A80A genotype was significantly associated with the development of neuroblastoma, compared with the control group (Williams G-Test = 0.0286; OR = 5.1667; 95% CI = 1.4481-18.4338; p = 0.0175). When analyzed together, the 80AG+AA genotypes showed a trend toward association (OR = 3.3033; 95% CI = 1.0586-10.3080; p = 0.0563). Our results suggest that individuals carriers of genotype AA for the SLC19A1 gene present risk for the development of neuroblastoma and possibly have difficulty in absorption of folic acid by the cells, and this may adversely affect the metabolism of folate causing genomic instability and promoting the development of cancer. This is the first retrospective/prospective study to examine the relationship between polymorphisms of folate pathway genes and risk of neuroblastoma. PMID- 24771229 TI - Transient abnormal myelopoiesis in a phenotypically normal newborn with polyclonal trisomy 21. AB - We report a rare case of transient abnormal myelopoiesis (TAM) in a phenotypically normal neonate. The presence of a palpable hepatomegaly prompted in-depth laboratory tests, which revealed the presence of severe hyperleukocytosis, with blast cells present in a peripheral blood smear. Although no signs of Down syndrome were present, we suspected TAM. Further analysis identified a mutation in GATA1 along with the unique finding of two different trisomic cell lines, detected upon karyotyping; one with trisomy 21 only, and one with trisomies 21 and 22, which was present in a subpopulation of peripheral blood cells. These genetic abnormalities disappeared by the age of 6 months. The presence of two different trisomic clones may be an evidence of the polyclonal nature of TAM in this patient. PMID- 24771231 TI - Amnion: a versatile tissue and cell source in tissue repair and regeneration. PMID- 24771230 TI - Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study. AB - Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B-cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case-control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p = 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2-4, respectively, p-trend = 0.001], diffuse large B-cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2 4, respectively, p-trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2-4, respectively, p-trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL. PMID- 24771232 TI - Massively parallel implementation of 3D-RISM calculation with volumetric 3D-FFT. AB - A new three-dimensional reference interaction site model (3D-RISM) program for massively parallel machines combined with the volumetric 3D fast Fourier transform (3D-FFT) was developed, and tested on the RIKEN K supercomputer. The ordinary parallel 3D-RISM program has a limitation on the number of parallelizations because of the limitations of the slab-type 3D-FFT. The volumetric 3D-FFT relieves this limitation drastically. We tested the 3D-RISM calculation on the large and fine calculation cell (2048(3) grid points) on 16,384 nodes, each having eight CPU cores. The new 3D-RISM program achieved excellent scalability to the parallelization, running on the RIKEN K supercomputer. As a benchmark application, we employed the program, combined with molecular dynamics simulation, to analyze the oligomerization process of chymotrypsin Inhibitor 2 mutant. The results demonstrate that the massive parallel 3D-RISM program is effective to analyze the hydration properties of the large biomolecular systems. PMID- 24771233 TI - Spatio-temporal dynamics of an active, polar, viscoelastic ring. AB - Constitutive equations for a one-dimensional, active, polar, viscoelastic liquid are derived by treating the strain field as a slow hydrodynamic variable. Taking into account the couplings between strain and polarity allowed by symmetry, the hydrodynamics of an active, polar, viscoelastic body include an evolution equation for the polarity field that generalizes the damped Kuramoto-Sivashinsky equation. Beyond thresholds of the active coupling coefficients between the polarity and the stress or the strain rate, bifurcations of the homogeneous state lead first to stationary waves, then to propagating waves of the strain, stress and polarity fields. I argue that these results are relevant to living matter, and may explain rotating actomyosin rings in cells and mechanical waves in epithelial cell monolayers. PMID- 24771234 TI - Fusion plasma turbulence described by modified sandpile dynamics. AB - Transport in fusion plasmas is investigated with modified sandpile models. Based on results from more complete simulations, the sandpile model is modified in steps. Models with a constant source are obtained by coupling two sandpiles. Decoupling the mean field from the bursts allows one to develop a reduced model which captures some of the key features of flux-driven simulations. In the latter sandpile model, turbulent transport is mediated by the burst field while the mean field gradient governs the transfer to the bursts. This allows one to investigate spreading, namely turbulent transport into stable regions, and transport barriers, regions where the transfer from the mean field to turbulence is reduced. Both cases are found to exhibit intermittent behaviors when the system undergoes spontaneous transitions between different transport regimes. Finally, one couples to the sandpile algorithm a species evolution algorithm that assigns a quality factor to each site. The latter appears to self-generate corrugations, or micro-barriers. These are found to naturally cluster radially in structures that are large enough to impact confinement. The mechanisms introduced to alleviate the clustering, destabilization of the corrugation by overloading and by secondary instabilities at critical radial extents, are shown to generate long range relaxation events in space and in time with quasiperiodic reorganization of the corrugation pattern. PMID- 24771235 TI - Dynamics of falling liquid films. AB - Falling liquid films are examples of open flows which undergo a sequence of supercritical instabilities giving way to a spatio-temporal weak disorder organized around interfacial waves in interaction. The long-wave nature of the waves and the laminar state of the flow enable to derive reduced sets of equations or models that are amenable to thorough analytic investigations. This paper reviews the phenomenology of falling film flows and discusses recent low dimensional modeling attempts. Some open questions and perspectives are also considered. PMID- 24771236 TI - Supernovae: an example of complexity in the physics of compressible fluids. AB - Because the collapse of massive stars occurs in a few seconds, while the stars evolve on billions of years, the supernovae are typical complex phenomena in fluid mechanics with multiple time scales. We describe them in the light of catastrophe theory, assuming that successive equilibria between pressure and gravity present a saddle-center bifurcation. In the early stage we show that the loss of equilibrium may be described by a generic equation of the Painleve I form. This is confirmed by two approaches, first by the full numerical solutions of the Euler-Poisson equations for a particular pressure-density relation, secondly by a derivation of the normal form of the solutions close to the saddle center. In the final stage of the collapse, just before the divergence of the central density, we show that the existence of a self-similar collapsing solution compatible with the numerical observations imposes that the gravity forces are stronger than the pressure ones. This situation differs drastically in its principle from the one generally admitted where pressure and gravity forces are assumed to be of the same order. Moreover it leads to different scaling laws for the density and the velocity of the collapsing material. The new self-similar solution (based on the hypothesis of dominant gravity forces) which matches the smooth solution of the outer core solution, agrees globally well with our numerical results, except a delay in the very central part of the star, as discussed. Whereas some differences with the earlier self-similar solutions are minor, others are very important. For example, we find that the velocity field becomes singular at the collapse time, diverging at the center, and decreasing slowly outside the core, whereas previous works described a finite velocity field in the core which tends to a supersonic constant value at large distances. This discrepancy should be important for explaining the emission of remnants in the post-collapse regime. Finally we describe the post-collapse dynamics, when mass begins to accumulate in the center, also within the hypothesis that gravity forces are dominant. PMID- 24771237 TI - Reversibility of crumpling on compressed thin sheets: reversibility of crumpling. AB - Compressing thin sheets usually yields the formation of singularities which focus curvature and stretching on points or lines. In particular, following the common experience of crumpled paper where a paper sheet is crushed in a paper ball, one might guess that elastic singularities should be the rule beyond some compression level. In contrast, we show here that, somewhat surprisingly, compressing a sheet between cylinders make singularities spontaneously disappear at large compression. This "stress defocusing" phenomenon is qualitatively explained from scale-invariance and further linked to a criterion based on a balance between stretching and curvature energies on defocused states. This criterion is made quantitative using the scalings relevant to sheet elasticity and compared to experiment. These results are synthesized in a phase diagram completed with plastic transitions and buckling saturation. They provide a renewed vision of elastic singularities as a thermodynamic condensed phase where stress is focused, in competition with a regular diluted phase where stress is defocused. The physical differences between phases is emphasized by determining experimentally the mechanical response when stress is focused or defocused and by recovering the corresponding scaling laws. In this phase diagram, different compression routes may be followed by constraining differently the two principal curvatures of a sheet. As evidenced here, this may provide an efficient way of compressing a sheet that avoids the occurrence of plastic damages by inducing a spontaneous regularization of geometry and stress. PMID- 24771238 TI - Turbulent spots in channel flow: an experimental study: large-scale flow, inner structure and low-order model. AB - We present new experimental results on the development of turbulent spots in channel flow. The internal structure of a turbulent spot is measured, with Time Resolved Stereoscopic Particle Image Velocimetry. We report the observation of travelling-wave-like structures at the trailing edge of the turbulent spot. Special attention is paid to the large-scale flow surrounding the spot. We show that this large-scale flow is an asymmetric quadrupole centred on the spot. We measure the time evolution of the turbulent fluctuations and the mean flow distortions and compare these with the predictions of a nonlinear reduced order model predicting the main features of subcritical transition to turbulence. PMID- 24771240 TI - Heat transfer in the thermo-electro-hydrodynamic convection under microgravity conditions. AB - This article deals with the thermal convection in a dielectric fluid confined in a finite-length plane capacitor with a temperature gradient under microgravity conditions. The dielectrophoretic force resulting from differential polarization of the fluid plays the role of buoyancy force associated with an electric effective gravity. It induces the convection when the Rayleigh number based on this electric gravity exceeds a critical value. Two-dimensional numerical simulation for a geometry with a large aspect ratio is used to determine the convective flow in the saturated state. The Nusselt number Nu is computed for a wide range of Prandtl number (0.01 <= Pr <= 10(3)) and its dependence on the distance from the critical condition is determined. A correlation between Nu and Pr in the vicinity of criticality is obtained and compared with that of the Rayleigh-Benard convection. The behavior of the convection is analyzed in detail from an energetic viewpoint: electrostatic energy, power inputs by different components of the electric gravity and viscous and thermal dissipations are computed. PMID- 24771239 TI - Unstable flow structures in the Blasius boundary layer. AB - Finite amplitude coherent structures with a reflection symmetry in the spanwise direction of a parallel boundary layer flow are reported together with a preliminary analysis of their stability. The search for the solutions is based on the self-sustaining process originally described by Waleffe (Phys. Fluids 9, 883 (1997)). This requires adding a body force to the Navier-Stokes equations; to locate a relevant nonlinear solution it is necessary to perform a continuation in the nonlinear regime and parameter space in order to render the body force of vanishing amplitude. Some states computed display a spanwise spacing between streaks of the same length scale as turbulence flow structures observed in experiments (S.K. Robinson, Ann. Rev. Fluid Mech. 23, 601 (1991)), and are found to be situated within the buffer layer. The exact coherent structures are unstable to small amplitude perturbations and thus may be part of a set of unstable nonlinear states of possible use to describe the turbulent transition. The nonlinear solutions survive down to a displacement thickness Reynolds number Re * = 496 , displaying a 4-vortex structure and an amplitude of the streamwise root-mean-square velocity of 6% scaled with the free-stream velocity. At this Re* the exact coherent structure bifurcates supercritically and this is the point where the laminar Blasius flow starts to cohabit the phase space with alternative simple exact solutions of the Navier-Stokes equations. PMID- 24771241 TI - Collapsed heteroclinic snaking near a heteroclinic chain in dragged meniscus problems. AB - A liquid film is studied that is deposited onto a flat plate that is inclined at a constant angle to the horizontal and is extracted from a liquid bath at a constant speed. We analyse steady-state solutions of a long-wave evolution equation for the film thickness. Using centre manifold theory, we first obtain an asymptotic expansion of solutions in the bath region. The presence of an additional temperature gradient along the plate that induces a Marangoni shear stress significantly changes these expansions and leads to the presence of logarithmic terms that are absent otherwise. Next, we numerically obtain steady solutions and analyse their behaviour as the plate velocity is changed. We observe that the bifurcation curve exhibits collapsed (or exponential) heteroclinic snaking when the plate inclination angle is above a certain critical value. Otherwise, the bifurcation curve is monotonic. The steady profiles along these curves are characterised by a foot-like structure that is formed close to the meniscus and is preceded by a thin precursor film further up the plate. The length of the foot increases along the bifurcation curve. Finally, we prove with a Shilnikov-type method that the snaking behaviour of the bifurcation curves is caused by the existence of an infinite number of heteroclinic orbits close to a heteroclinic chain that connects in an appropriate three-dimensional phase space the fixed point corresponding to the precursor film with the fixed point corresponding to the foot and then with the fixed point corresponding to the bath. PMID- 24771242 TI - The glass transition in a nutshell: a source of inspiration to describe the subcritical transition to turbulence. AB - The starting point of the present work is the observation of possible analogies, both at the phenomenological and at the methodological level, between the subcritical transition to turbulence and the glass transition. Having recalled the phenomenology of the subcritical transition to turbulence, we review the theories of the glass transition at a very basic level, focusing on the history of their development as well as on the concepts they have elaborated. Doing so, we aim at attracting the attention on the above-mentioned analogies, which we believe could inspire new developments in the theory of the subcritical transition to turbulence. We then briefly describe a model inspired by one of the simplest and most inspiring models of the glass transition, the so-called Random Energy Model, as a first step in that direction. PMID- 24771243 TI - Complexity of localised coherent structures in a boundary-layer flow. AB - We study numerically transitional coherent structures in a boundary-layer flow with homogeneous suction at the wall (the so-called asymptotic suction boundary layer ASBL). The dynamics restricted to the laminar-turbulent separatrix is investigated in a spanwise-extended domain that allows for robust localisation of all edge states. We work at fixed Reynolds number and study the edge states as a function of the streamwise period. We demonstrate the complex spatio-temporal dynamics of these localised states, which exhibits multistability and undergoes complex bifurcations leading from periodic to chaotic regimes. It is argued that in all regimes the dynamics restricted to the edge is essentially low-dimensional and non-extensive. PMID- 24771245 TI - NADPH-dependent reductive biotransformation with Escherichia coli and its pfkA deletion mutant: influence on global gene expression and role of oxygen supply. AB - An Escherichia coli DeltapfkA mutant lacking the major phosphofructokinase possesses a partially cyclized pentose phosphate pathway leading to an increased NADPH per glucose ratio. This effect decreases the amount of glucose required for NADPH regeneration in reductive biotransformations, such as the conversion of methyl acetoacetate (MAA) to (R)-methyl 3-hydroxybutyrate (MHB) by an alcohol dehydrogenase from Lactobacillus brevis. Here, global transcriptional analyses were performed to study regulatory responses during reductive biotransformation. DNA microarray analysis revealed amongst other things increased expression of soxS, supporting previous results indicating that a high NADPH demand contributes to the activation of SoxR, the transcriptional activator of soxS. Furthermore, several target genes of the ArcAB two-component system showed a lower mRNA level in the reference strain than in the DeltapfkA mutant, pointing to an increased QH2 /Q ratio in the reference strain. This prompted us to analyze yields and productivities of MAA reduction to MHB under different oxygen regimes in a bioreactor. Under anaerobic conditions, the specific MHB production rates of both strains were comparable (7.4 +/- 0.2 mmolMHB h(-1) gcdw (-1) ) and lower than under conditions of 15% dissolved oxygen, where those of the reference strain (12.8 mmol h(-1) gcdw (-1) ) and of the DeltapfkA mutant (11.0 mmol h(-1) gcdw (-1) ) were 73% and 49% higher. While the oxygen transfer rate (OTR) of the reference strain increased after the addition of MAA, presumably due to the oxidation of the acetate accumulated before MAA addition, the OTR of the DeltapfkA strain strongly decreased, indicating a very low respiration rate despite sufficient oxygen supply. The latter effect can likely be attributed to a restricted conversion of NADPH into NADH via the soluble transhydrogenase SthA, as the enzyme is outcompeted in the presence of MAA by the recombinant NADPH dependent alcohol dehydrogenase. The differences in respiration rates can explain the suggested higher ArcAB activity in the reference strain. PMID- 24771244 TI - Associations of neighborhood concentrated poverty, neighborhood racial/ethnic composition, and indoor allergen exposures: a cross-sectional analysis of los angeles households, 2006-2008. AB - Although racial/ethnic, socioeconomic, and neighborhood factors have been linked to asthma, and the association between indoor allergens and asthma is well documented, few studies have examined the relationship between these factors and indoor allergens. We examined the frequency of reported indoor allergens and differences by racial/ethnic, socioeconomic, and neighborhood characteristics among a diverse sample of Los Angeles households. Multilevel logistic regression models were used to analyze the data from 723 households from wave 2 of the Los Angeles Family and Neighborhood Survey. The reported presence of rats, mice, cockroaches, mold, pets, and tobacco smoke were the primary outcomes of interest. Hispanic and Asian households had a nearly threefold increase in the odds of reporting cockroaches compared to non-Hispanic Whites (OR, 2.85; 95 % CI 1.38 5.88 and OR, 2.62; 95 % CI 1.02-6.73, respectively) even after adjusting for socioeconomic factors. Primary caregivers who had obtained a high school degree were significantly less likely to report the presence of mice and cockroaches compared to primary caregivers with less than a high school degree (OR, 0.19; 95 % CI 0.08-0.46 and OR, 0.39; 95 % CI 0.23-0.68, respectively). Primary caregivers with more than a high school degree were also less likely to report the presence of rats, mice, and cockroaches within their households, compared to those with less than a high school degree. Compared to renters, home owners were less likely to report the presence of mice, cockroaches, and mold within their households. At the neighborhood level, households located within neighborhoods of high concentrated poverty (where the average poverty rate is at least 50 %) were more likely to report the presence of mice and cockroaches compared to households in low concentrated poverty neighborhoods (average poverty rate is 10 % or less), after adjusting for individual race/ethnicity and socioeconomic characteristics. Our study found evidence in support of neighborhood-level racial/ethnic and socioeconomic influences on indoor allergen exposure, above and beyond individual factors. Future studies should continue to explore individual and neighborhood level racial/ethnic and socioeconomic differences in household allergen exposures across diverse contexts. PMID- 24771246 TI - White matter tracts for the trafficking of neural progenitor cells characterized by cellular MRI and immunohistology: the role of CXCL12/CXCR4 signaling. AB - White matter tracts are important for the trafficking of neural progenitor cells (NPCs) in both normal and pathological conditions, but the underlying mechanism is not clear. The directionality of white matter is advantageous for molecules or cells to distribute over a long distance, but this feature is unlikely solely responsible for efficient migration. The present study hypothesizes that the efficient migration of NPCs into white matter is under the influences of neurochemical attraction-CXCL12/CXCR4 signaling, a major mechanism underlying the targeted migration of NPCs. To test this view, the present study investigated the effects of CXCL12 administration into the corpus callosum (CC) on the migratory behavior of transplanted NPCs. A living animal tracking platform based on MRI and a magnetic cell labeling technique was employed. The NPCs were magnetically labeled and then transplanted at the right end of the CC. CXCL12 was infused continuously at the left end. Migration of NPCs was monitored repeatedly over a 7 day course using 3D gradient echo T2*-weighted imaging. It was found that, CXCL12 induced NPCs to migrate up to 1,881 MUm from the graft whereas the spontaneous migration was mere 200 MUm. CXCL12 induced migration that was nine times as efficient in the speed. The results indicate that the CXCL12/CXCR4 signaling may be a mechanism via which NPCs efficiently migrate along the white matter tracts. The study also presents a potential strategy for facilitating the targeted migration in NPC therapy for brain disorders. PMID- 24771248 TI - Unusual inflammation in gynecologic pathology associated with defective endometrial receptivity. AB - Human cycling endometrium displays a series of periodic transitions unique to this mucosal tissue, which includes rapid proliferation, secretory transformation, physiological angiogenesis, interstitial edema, and menstrual shedding. Among these properties of the endometrium are the inflammatory changes that occur dynamically across the menstrual cycle. Immunocompetent cell composition and inflammatory gene expression pattern in the human endometrium drastically fluctuate from the proliferative phase to the secretory phase, particularly at the time of ovulation. These local immune responses are fine tuned by the direct or indirect action of two representative ovarian steroids, estradiol and progesterone, and are essential for successful blastocyst implantation. Meanwhile, studies have been accumulating the evidence that such physiological endometrial inflammatory status is altered in the presence of certain gynecologic pathologies. Given that blastocysts are semi-allografts for maternal tissue, even subtle alterations in endometrial immunity potentially have a negative impact on implantation process. In this article, we aimed to review and discuss the physiological and pathological mucosal inflammatory conditions that can affect endometrial receptivity. PMID- 24771247 TI - Abnormalities in structural covariance of cortical gyrification in schizophrenia. AB - The highly convoluted shape of the adult human brain results from several well coordinated maturational events that start from embryonic development and extend through the adult life span. Disturbances in these maturational events can result in various neurological and psychiatric disorders, resulting in abnormal patterns of morphological relationship among cortical structures (structural covariance). Structural covariance can be studied using graph theory-based approaches that evaluate topological properties of brain networks. Covariance-based graph metrics allow cross-sectional study of coordinated maturational relationship among brain regions. Disrupted gyrification of focal brain regions is a consistent feature of schizophrenia. However, it is unclear if these localized disturbances result from a failure of coordinated development of brain regions in schizophrenia. We studied the structural covariance of gyrification in a sample of 41 patients with schizophrenia and 40 healthy controls by constructing gyrification-based networks using a 3-dimensional index. We found that several key regions including anterior insula and dorsolateral prefrontal cortex show increased segregation in schizophrenia, alongside reduced segregation in somato-sensory and occipital regions. Patients also showed a lack of prominence of the distributed covariance (hubness) of cingulate cortex. The abnormal segregated folding pattern in the right peri-sylvian regions (insula and fronto-temporal cortex) was associated with greater severity of illness. The study of structural covariance in cortical folding supports the presence of subtle deviation in the coordinated development of cortical convolutions in schizophrenia. The heterogeneity in the severity of schizophrenia could be explained in part by aberrant trajectories of neurodevelopment. PMID- 24771249 TI - Glioblastoma at progression: therapy of a challenging problem addressed candidly with evidence-based techniques. PMID- 24771250 TI - Proteomic analyses of CSF aimed at biomarker development for pediatric brain tumors. AB - Primary brain tumors cumulatively represent the most common solid tumors of childhood and are the leading cause of cancer related death in this age group. Traditionally, molecular findings and histological analyses from biopsies of resected tumor tissue have been used for diagnosis and classification of these diseases. However, there is a dearth of useful biomarkers that have been validated and clinically implemented for pediatric brain tumors. Notably, diseases of the central nervous system (CNS) can be assayed through analysis of cerebrospinal fluid (CSF) and as such, CSF represents an appropriate medium to obtain liquid biopsies that can be informative for diagnosis, disease classification and risk stratification. Proteomic profiling of pediatric CNS malignancies has identified putative protein markers of disease, yet few effective biomarkers have been clinically validated or implemented. Advances in protein quantification techniques have made it possible to conduct such investigations rapidly and accurately through proteome-wide analyses. This review summarizes the current literature on proteomics in pediatric neuro-oncology and discusses the implications for clinical applications of proteomics research. We also outline strategies for translating effective CSF proteomic studies into clinical applications to optimize the care of this patient population. PMID- 24771251 TI - MGMT promoter methylation status in clival chordoma. AB - Chordomas are rare, slow-growing neoplasms, characterized by locally aggressive growth patterns and high local recurrence rates. To the best of our knowledge, the MGMT promoter methylation status has not been studied in a population of patients with chordomas to determine if a biologic rationale exists to support the use of temozolomide. We here show for the first time that methylation of MGMT promoter is present in a significant portion or recurring clival chordomas; on the contrary in clival chordomas without recurrence MGMT promoter was always unmethylated (p = 0.0317). Although these observations need to be confirmed in a larger study population, our results (1) indicate that methylation of MGMT promoter is present in a significant portion of recurring chordomas, and (2) prompt further investigation into the potential role of temozolomide as an adjuvant treatment of these tumors. PMID- 24771253 TI - Neurobiological measures to classify ADHD: a critical appraisal. PMID- 24771255 TI - Florid Cystic Endosalpingiosis. PMID- 24771252 TI - The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods. AB - Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive-compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarified fully. There is now mounting evidence that the genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene. Based on recent progress in many other common disorders with apparently similar genetic architectures, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA) are part of a sharing repository located within the National Institute for Mental Health Center for Collaborative Genomics Research on Mental Disorders, USA, and will be made available to the broad scientific community. This resource will ultimately facilitate better understanding of the pathophysiology of TS and related disorders and the development of novel therapies. Here, we describe the objectives and methods of the TIC Genetics study as a reference for future studies from our group and to facilitate collaboration between genetics consortia in the field of TS. PMID- 24771254 TI - Eupalopsellidae and Stigmaeidae (Acari: Prostigmata) within citrus orchards in Florida: species distribution, relative and seasonal abundance within trees, associated vines, and ground cover plants. AB - Seven citrus orchards on reduced- to no-pesticide spray programs were sampled for predacious mites in the families Eupalopsellidae and Stigmaeidae (Acari: Prostigmata) in central and south central Florida. Inner and outer canopy leaves, fruit, twigs, and trunk scrapings were sampled monthly between August 1994 and January 1996. Open flowers were sampled in March from five of the sites. Two species of eupalopsellid mites (Exothorhis caudata Summers and Saniosulus harteni (van-Dis and Ueckermann)) were identified from 252 specimens collected within citrus tree canopies within the seven citrus orchards of which 249 were E. caudata. Only two E. caudata were collected from ground cover plants within five of the seven orchards. Eight species of Stigmaeidae were identified from 5,637 specimens: Agistemus floridanus Gonzalez, A. terminalis Gonzalez, Eustigmaeus arcuata (Chandhri), E. sp. near arcuata, E. segnis (Koch), Mediostigmaeus citri (Rakha and McCoy), Stigmaeus seminudus Wood, and Zetzellia languida Gonzalez were collected from within citrus tree canopies from seven orchard sites. Agistemus floridanus was the only species in either family that was abundant with 5,483 collected from within citrus tree canopies compared with only 39 from vine or ground cover plants. A total of 431 samples from one or more of 82 vines and ground cover plants were sampled monthly between September 1994 and January 1996 in five of these orchards and one or more eupalopsellids or stigmaeids were collected from 19 of these plants. Richardia brasiliensis (Meg.) Gomez had nine A. floridanus from 5 of 25 samples collected from this plant. Solanum sp. had five A. floridanus from three samples taken. Both eupalopsellid and stigmaeid species numbers represented <1 % of the total numbers of phytoseiid species taken from the same plants. The two remaining orchards were on full herbicide programs and ground cover plants were absent. Agistemus floridanus was more abundant in the citrus orchards with on-going or recent herbicide programs compared with orchards having well-developed ground cover plants. Agistemus floridanus was most abundant on inner leaves between January and April and again during September through November. Additional collection records of E. caudata, S. harteni, A. terminalis, M. citri, Z. languida, and Zetzellia sp. near silvicola within Florida citrus orchards between 1989 and 2004 are included. Four species of Eupalopsellidae and ten species of Stigmaeidae occur within Florida citrus orchards. PMID- 24771256 TI - Gestational lung adenocarcinoma: case report. AB - Gestational cancer is a dramatic situation, with a deep impact on the patient and family, with an overall incidence of 1 per 100 pregnancies. Lung cancers are extremely rare during pregnancy but have become more frequent in past years, as the mean age of pregnancy has increased. The purpose of this case report is to present a gestational lung adenocarcinoma, with metastasis in the liver and ovaries, diagnosed in the third trimester, with a fatal outcome in days after birth through cesarean section. PMID- 24771257 TI - Pediatric plasmablastic lymphoma: a clinicopathologic study. AB - Plasmablastic lymphoma (PBL) is reported rarely in children. To date, 10 cases are documented in the English-language literature. This study, based on 13 biopsies from 11 HIV-positive children (9 males, 2 females), documents the clinicopathologic features of PBL. The CD4 count ranged from 9 to 800 cells/mm(3). All biopsies demonstrated exclusive plasmablastic morphology; CD20 immunonegativity; and VS38c, EMA, CD31, MUM-1, CD45, and CD79a immunopositivity. B-cell monoclonality was confirmed in all biopsies. Of 3 biopsies subjected to FISH investigation, 2 had a t(8,14) translocation. Nine patients with follow-up details were treated exclusively with HAART (highly active antiretroviral therapy) or with combinations of HAART, chemotherapy, and radiotherapy. Seven patients died. PBL histomorphology, disease stage, and treatment modalities employed were not predictive of outcome. The survival of 2 stage 4 patients for 3 and 8 years each, managed on HAART, chemotherapy, and radiotherapy, however, may justify a role for combined therapeutic modalities for PBL. PMID- 24771258 TI - Epithelioid angiosarcoma arising in an adrenal cortical adenoma: a case report and review of the literature. AB - Adrenal masses are common incidental imaging findings, with the majority comprising benign adrenal cortical adenomas. However, the differential diagnosis is extensive and includes both primary and secondary malignant lesions. Primary adrenal angiosarcomas are rare and often exhibit epithelioid morphology, which can present a diagnostic pitfall. We report an exceptional "incidentaloma" in a 60-year-old lady, which showed the features of a primary epithelioid angiosarcoma arising within an adrenal cortical adenoma. No other primary tumor was identified on extensive imaging. This unusual combined tumor has been reported only once before, to the best of our knowledge. The pattern of infiltration of the malignant endothelial cells raises the suggestion that the angiosarcoma arose from vascular elements of the adenoma. PMID- 24771259 TI - [Importance of pathology for therapy planning of testicular germ cell tumors]. AB - Testicular tumors can be divided into germ cell tumors and sex cord stromal tumors. Malignant testicular germ cell tumors (TGCT) represent about 90-95 % of all testicular tumors and are the most common solid neoplasms in young men aged 20-40 years with an increasing incidence in industrialized countries. Treatment of TGCT is performed by an individual and risk-adapted approach taking primary tumor histology, histopathlogical and molecular prognostic risk factors, tumor stage and for metastasized tumors the response to systemic chemotherapy into consideration. Knowledge of the specific histopathology of the primary tumor and the prognostic factors is of utmost importance for the treating urologist and oncologist in order to avoid undertreatment or overtreatment. Established risk factors which have been validated in retrospective and prospective studies for clinical stage I non-seminomatous TGCT are the presence of vascular invasion and the percentage of embryonal carcinoma. In clinical stage I seminomas tumor size (> 4 cm) and presence of rete testis infiltration have been identified as risk factors in retrospective but not in prospective studies. Quantitative histopathology of the primary tumor is also important for the management of small residual masses following chemotherapy: if the masses are <= 1 cm, postchemotherapy retroperitoneal lymph node dissection is only indicated if the primary tumor contains >= 50 % teratoma. Quantitative pathohistology of the resected residual masses is of importance for the decision-making process of a consolidating chemotherapy which is only of benefit if the amount of vital cancer tissue is > 10 %. Resection of residual hepatic and thoracic masses is indispensable. For gonadal stromal tumors knowledge of atypical nuclear forms, increased rate of mitosis and increased growth fractions are important for therapy planning. PMID- 24771260 TI - High early failure rate after cementless hip replacement in the octogenarian. AB - BACKGROUND: Use of cementless hip replacements is increasing in many countries, but the best method for fixation for octogenarian patients remains unknown. QUESTIONS/PURPOSES: We studied how fixation method (cemented, cementless, hybrid) affects the survival of primary hip replacements and mortality in patients 80 years or older. Specifically, we asked if fixation method affects (1) the risk of revision; (2) the reasons for revision; and (3) the mortality after contemporary primary hip replacement in octogenarian patients. METHODS: A total of 4777 primary total hip replacements were performed in 4509 octogenarian patients with primary osteoarthritis in Finland between 1998 and 2009 and were registered in the Finnish Arthroplasty Register. Comorbidity data were collected from a nationwide quality register. Survival of hip replacements, using any revision as the end point, and mortality were analyzed using competing risks survival analysis and Cox regression analysis. The average followup was 4 years (range, 1 13 years). RESULTS: Cementless hip replacements were associated with a higher rate of early (within 1 year) revision compared with cemented hip replacements (hazard ratio, 2.9; 95% CI, 1.7-5.1), particularly in women. The difference was not explained by comorbidity or provider-related factors. Periprosthetic fracture was the leading mode of failure of cementless hip replacements. After 1 year, there were no differences in the survival rates although 10-year survival was slightly lower for cementless than cemented and hybrid hip replacements (93.9% [95% CI, 91.1%-96.7%] versus 97.4% [95% CI, 96.9%-98.0%] and 98.1% [95% CI, 96.9% 99.4%], respectively). Fixation method was not associated with mortality. CONCLUSIONS: Cementless fixation was associated with an increased risk of revision and did not provide any benefit in terms of lower mortality in octogenarian patients. LEVEL OF EVIDENCE: Level II, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24771261 TI - Confirmation of long-term in vivo bearing mobility in eight rotating-platform TKAs. AB - BACKGROUND: Posterior-stabilized rotating-platform prostheses for TKAs were designed to improve contact mechanics at the femoral-polyethylene (PE) interface. Short-term followup studies have shown that the PE bearings rotate with respect to the tibia but might not necessarily track with the femur. It is important to know how kinematics in these designs change owing to long-term in vivo use. QUESTIONS/PURPOSES: We asked whether there is a significant change in the in vivo kinematic performance of a posterior-stabilized rotating-platform prosthesis at as much as 10 years postoperative. We specifically examined (1) relative femoral component-PE bearing and relative PE bearing-tibial tray motion; (2) relative AP motion of the femoral condyles with respect to the tibial tray; and (3) relative femorotibial condylar translations. METHODS: In vivo three-dimensional kinematics were evaluated for eight patients at 3 months, 15 months, 5 years, and 10 years after TKA with primary implantation of a posterior-stabilized rotating-platform prosthesis. Each patient performed deep knee bend activity, and three-dimensional kinematics were reconstructed from multiple fluoroscopic images using a three dimensional to two-dimensional registration technique. Once complete, relative component axial rotation patterns, medial and lateral condyle motions throughout flexion, and the presence of femoral condylar lift-off were analyzed. RESULTS: Overall, tibial bearing rotation was maintained at 10 years postoperatively. There was no statistical difference between postoperative periods for any kinematic parameter except for femoral component-PE bearing axial rotation, which was reduced at the 10-year evaluation versus other assessment periods (p = 0.0006). The lack of statistical difference between postoperative evaluation periods indicates sustained overall implant kinematic performance. CONCLUSIONS: Our study showed that PE bearing-tibial tray mobility was maintained and that femoral component-PE bearing rotation was reduced at the 10-year followup. This suggests that the overall kinematic performance of this mobile-bearing implant is not negatively affected 10 years postoperatively. LEVEL OF EVIDENCE: Level III, retrospective study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24771262 TI - Robotic ablation of atrial fibrillation with a new remote catheter system. AB - PURPOSE: Pulmonary vein isolation (PVI) is widely established as a curative treatment option for atrial fibrillation (AF). A wide range of techniques to improve catheter manipulation and steerability has been developed over the past years. A new remote catheter system (RCS) has recently become available (Amigo Remote Catheter System, Catheter Robotics, Budd Lake, NJ, USA). Here, we present a dual-center study on the RCS for left atrial mapping and PVI in patients with paroxysmal AF compared to a control group undergoing conventional PVI. METHODS: One hundred nineteen patients who underwent PVI for paroxysmal AF were studied. Forty patients underwent PVI with the use of the RCS. Seventy-nine patients, who underwent conventional PVI, served as control group. Procedural data were compared between the two groups. RESULTS: PVI was achieved in all patients. In the RCS group compared to standard ablation group, there were no significant differences in procedure duration (159.1 +/- 45.4 vs. 146 +/- 30.1 min, p = 0.19), total energy delivery (78,146.3 +/- 26,992.4 vs. 87,963.9 +/- 79,202.1 Ws, p = 0.57), and total fluoroscopy time (21.2 +/- 8.6 vs. 23.9 +/- 5.4 min, p = 0.15). Operator fluoroscopy exposure was significantly reduced in the RCS group (13.4 +/- 6.1 vs. 23.9 +/- 5.4 min, p < 0.001). CONCLUSIONS: These initial results suggest that left atrial mapping and PVI are feasible with the use of the Amigo RCS. Acute procedural efficacy is comparable to the standard approach. The use of the Amigo RCS leads to a significant reduction of operator fluoroscopy exposure. PMID- 24771263 TI - Quantitation of rare circulating tumor cells by folate receptor alpha ligand targeted PCR in bladder transitional cell carcinoma and its potential diagnostic significance. AB - Numerous attempts for detection of circulating tumor cells (CTC) have been made to develop reliable assays for early diagnosis of cancers. In this study, we validated the application of folate receptor alpha (FRalpha) as the tumor marker to detect CTC through tumor-specific ligand PCR (LT-PCR) and assessed its utility for diagnosis of bladder transitional cell carcinoma (TCC). Immunohistochemistry for FRalpha was performed on ten bladder TCC tissues. Enzyme-linked immunosorbent assay (ELISA) for FRalpha was performed on both urine and serum specimens from bladder TCC patients (n = 64 and n = 20, respectively) and healthy volunteers (n = 20 and n = 23, respectively). Western blot analysis and qRT-PCR were performed to confirm the expression of FRalpha in bladder TCC cells. CTC values in 3-mL peripheral blood were measured in 57 bladder TCC patients, 48 healthy volunteers, and 15 subjects with benign urologic pathologies by the folate receptor alpha ligand-targeted PCR. We found that FRalpha protein was overexpressed in both bladder TCC cells and tissues. The levels of FRalpha mRNA were also much higher in bladder cancer cell lines 5637 and SW780 than those of leukocyte. Values of FRalpha were higher in both serum and urine specimens of bladder TCC patients than those of control. CTC values were also higher in 3-mL peripheral blood of bladder TCC patients than those of control (median 26.5 Cu/3 mL vs 14.0 Cu/3 mL). Area under the receiver operating characteristic (ROC) curve for bladder TCC detection was 0.819, 95 % CI (0.738-0.883). At the cutoff value of 15.43 Cu/3 mL, the sensitivity and the specificity for detecting bladder cancer are 82.14 and 61.9 %, respectively. We concluded that quantitation of CTCs through FRalpha ligand-PCR could be a promising method for noninvasive diagnosis of bladder TCC. PMID- 24771264 TI - HE4, Ca125 and ROMA algorithm for differential diagnosis between benign gynaecological diseases and ovarian cancer. AB - The aim of this study is to evaluate the diagnostic performance of human epididymis protein 4 (HE4), cancer antigen 125 (Ca125) and the risk of ovarian malignancy algorithm (ROMA) in discriminating ovarian cancer from other benign gynaecological diseases. Serum levels of HE4 and Ca125 were measured in 119 women with benign gynaecological diseases, 29 patients with primary ovarian cancer, 32 patients with ovarian cancer on chemotherapy treatment (18 of them with progressive disease), 6 patients treated and free of disease and 32 healthy women. Sensitivity, specificity, positive and negative predictive values and positive and negative likelihood ratios (LR +/-) were calculated. Receiver operator characteristic (ROC) curves were constructed, and the areas under the curve (AUC) were calculated. High serum levels for HE4, Ca125 and ROMA were observed in cancer patients. HE4 was elevated in 12.6 %, Ca125 in 21 % and ROMA in 9.2 % in the benign group, but HE4 was not elevated in endometriosis. The AUC values for HE4, Ca125 and ROMA were 0.92, 0.911 and 0.945 respectively. The sensitivity for discriminating ovarian cancer from benign gynaecological diseases was 86.2 % for HE4 and Ca125 and 93.1 % for ROMA. The specificity was 87.4, 78.9 and 90.7 % for HE4, Ca125 and ROMA. The overall positive likelihood ratio (LR+) was 6.84 for HE4, 4.1 for Ca125 and 10.01 for ROMA. In premenopausal women, LR + was 11.86 for HE4, 5.11 for ROMA and 2.02 for Ca125. HE4 might be significant in the differential diagnosis of ovarian cancer. HE4 seems to be superior to Ca125 in terms of diagnostic performance of all premenopausal women. ROMA could help to discriminate in cases with any doubt with a high diagnostic accuracy. PMID- 24771265 TI - EZH2-specific microRNA-98 inhibits human ovarian cancer stem cell proliferation via regulating the pRb-E2F pathway. AB - The Polycomb group protein, enhancer of zeste homolog 2 (EZH2), plays an important role in transcriptional regulation through chromatin remodeling and interactions with other transcription factors to control cell proliferation and embryonic development. Previous study has shown that EZH2 is important for cell cycle regulation and is highly expressed in human ovarian cancer. Loss of EZH2 inhibits growth of ovarian cancer as well as other human carcinomas. In this study, an expression plasmid of EZH2-targeted microRNA-98 was constructed and transfected into human ovarian cancer stem cells (OCSCs). Seventy-two hours after transfection, cell growth was inhibited and arrested at the G0/G1 transition. p21(CIPI/WAF1) was up-regulated, while the CDK2/cyclin E complex and c-Myc were down-regulated. Most importantly, expression levels of E2F1, retinoblastoma protein (pRb), and histone deacetylase 1 (HDAC1) in the pRb-E2F signaling pathway had changed. Furthermore, microRNA-98 suppressed the growth of OCSCs xenograft tumors. Our findings suggest that EZH2-specific microRNA-98 can effectively inhibit cell proliferation in vitro and regulate the pRb-E2F pathway in human OCSCs. PMID- 24771266 TI - Down-regulation of EphB4 phosphorylation is necessary for esophageal squamous cell carcinoma tumorigenecity. AB - Eph/ephrin signaling system plays a very important role in the tumorigenesis and the formation of blood vessel. However, the function of EphB4 and its ligand ephrin B2 in the carcinogenesis of esophageal squamous cell carcinoma (ESCC) is not fully understood. Here, it was found that the expression of EphB4 was up regulated in ESCC tissues compared with the paired normal tissues, while ephrin B2 was down-regulated in ESCC samples. Phosphorylation of EphB4 induced by its ligand ephrin B2-Fc inhibited the growth, migration and colony formation of ESCC cells. Moreover, over-expression of EphB4 or EphB4 kinase dead mutant (EphB4 KD) in ESCC cells promoted cell growth and migration, suggesting EphB4 promoted cell growth and migration independent of its kinase activity. Furthermore, we found that EphB4 interacted with the adaptor protein RACK1 and RACK1 decreased the phosphorylation level of EphB4. Taken together, our study revealed the important function and regulation of EphB4 in the progression of ESCC and suggested EphB4 as a novel target for the treatment of ESCC. PMID- 24771267 TI - Serum transforming growth factor-beta 1 (TGF-beta1) levels have diagnostic, predictive, and possible prognostic roles in patients with melanoma. AB - Transforming growth factor-beta 1 (TGF-beta1) plays an important role in the pathogenesis of multiple malignancies, and its expression also strongly affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of TGF-beta1 in melanoma patients. A total of 60 patients with a pathologically confirmed diagnosis of melanoma were enrolled into this study. Serum TGF-beta1 concentrations were determined by the solid-phase sandwich ELISA method. Thirty age- and sex-matched healthy controls were included in the analysis. The median age at diagnosis was 53.5 years (range 16 to 88 years). The baseline serum TGF-beta1 levels of the melanoma patients were significantly higher than those in the control group (median values 171.85 vs. 19.95 pg/mL, respectively; p < 0.001). The known clinical variables including age of patient, gender, site of lesion, histology, stage of disease, and serum LDH levels were not found to be correlated with serum TGF-beta1 concentrations (p > 0.05). However, the chemotherapy-responsive patients had higher serum TGF-beta1 levels compared with chemotherapy-unresponsive ones (p = 0.05). Additionally, serum TGF-beta1 concentration was a trend to have a prognostic role on survival (p = 0.07). Patients with elevated serum TGF-beta1 concentrations had close to significantly favorable overall survival compared to those with lower levels (median 30.1 vs. 20.9 months, respectively). In conclusion, serum levels of TGF beta1 have diagnostic, predictive, and possible prognostic roles in melanoma patients. PMID- 24771268 TI - Amelioration of colorectal cancer using negative lipidoid nanoparticles to encapsulate siRNA against APRIL by enema delivery mode. AB - A proliferation-inducing ligand (APRIL) is a key cell proliferation-regulatory molecule and have been investigated well enough in immunity regulation and a few of immune diseases. APRIL can stimulate tumor cell growth and is up-expressed in cancer tissues, especially in CRC (colorectal cancer). However, whether inhibition of APRIL can regulate tumor-relative genes expression in vivo and subsequently ameliorate the pathological progress of CRC remains obscure. To address this question, we developed a novel negative lipidoid nanoparticles (NLNs) encapsulating small interference RNA (siRNA) for selectively silencing APRIL in the parenchyma of CRC focus in vivo, which uptake proceeded through a lipid raft endocytotic pathway. Local enema delivery of APRIL-NLNs silenced APRIL in CRC cells and animal models, and then ameliorated experimentally the progress of CRC by suppressing CRC cell proliferation, metastasis, and apoptosis-related cytokine expression and did not affect the function of liver and kidneys and not trigger the immune response of CRC models. This study reveals APRIL to be a potential anti-CRC target by in vivo experiments, and suggests that the application of similar modes of siRNA delivery may be feasible in other therapeutic settings. PMID- 24771269 TI - Oncogenic PTPN11 mutations are rare in solid tumors. PMID- 24771270 TI - Mental health predicts better academic outcomes: a longitudinal study of elementary school students in Chile. AB - The world's largest school-based mental health program, Habilidades para la Vida [Skills for Life (SFL)], has been operating on a national scale in Chile for 15 years. SFL's activities include using standardized measures to screen elementary school students and providing preventive workshops to students at risk for mental health problems. This paper used SFL's data on 37,397 students who were in first grade in 2009 and third grade in 2011 to ascertain whether first grade mental health predicted subsequent academic achievement and whether remission of mental health problems predicted improved academic outcomes. Results showed that mental health was a significant predictor of future academic performance and that, overall, students whose mental health improved between first and third grade made better academic progress than students whose mental health did not improve or worsened. Our findings suggest that school-based mental health programs like SFL may help improve students' academic outcomes. PMID- 24771271 TI - Gene co-expression analysis identifies common modules related to prognosis and drug resistance in cancer cell lines. AB - To discover a common gene co-expression network in cancer cell, we applied weighted gene co-expression network analysis to transcriptional profiles of 917 cancer cell lines. Fourteen biologically meaningful modules were identified, including cytoskeleton, cell cycle, RNA splicing, signaling pathway, transcription, translation and others. These modules were robust in an independent human cancer microarray dataset. Furthermore, we collected 11 independent cancer microarray datasets, and correlated these modules with clinical outcome. Most of these modules could predict patient survival in one or more cancer types. Some modules were predictive of relapse, metastasis and drug resistance. Novel regulatory mechanisms were also implicated. In summary, our findings, for the first time, provide a modular map for cancer cell lines, new targets for therapy and modules for regulatory mechanism of cancer development and drug resistance. PMID- 24771272 TI - Moving of fullerene between potential wells in the external icosahedral shell. AB - The results of the theoretical investigation of the behavior of fullerenes C20 and C60 inside the icosahedral external shell on example of carbon nanoclusters, C20@S240 and C60@S540, are presented in this article. The multiwell potential of interaction between fullerenes in investigated nanoclusters is calculated to reveal the regularities of moving for internal fullerene in the field of holding potential of the external shell. The possible variants of fullerenes C20 and C60 moving between the potential wells are predicted on base of topology data of the fullerenes relative positioning in nanoparticle and analysis of relief of the energy surface of interaction between fullerenes. The formulated prediction is confirmed by the data of the numerical experiment. The investigation of two-shell fullerenes allows to conclude that the light fullerene S20 will probably jump between the potential wells already at small temperatures (139-400 K) if the external shell is slightly bigger. PMID- 24771273 TI - Stochastic simulations of normal aging and Werner's syndrome. AB - Human cells typically consist of 23 pairs of chromosomes. Telomeres are repetitive sequences of DNA located at the ends of chromosomes. During cell replication, a number of basepairs are lost from the end of the chromosome and this shortening restricts the number of divisions that a cell can complete before it becomes senescent, or non-replicative. In this paper, we use Monte Carlo simulations to form a stochastic model of telomere shortening to investigate how telomere shortening affects normal aging. Using this model, we study various hypotheses for the way in which shortening occurs by comparing their impact on aging at the chromosome and cell levels. We consider different types of length dependent loss and replication probabilities to describe these processes. After analyzing a simple model for a population of independent chromosomes, we simulate a population of cells in which each cell has 46 chromosomes and the shortest telomere governs the replicative potential of the cell. We generalize these simulations to Werner's syndrome, a condition in which large sections of DNA are removed during cell division and, amongst other conditions, results in rapid aging. Since the mechanisms governing the loss of additional basepairs are not known, we use our model to simulate a variety of possible forms for the rate at which additional telomeres are lost per replication and several expressions for how the probability of cell division depends on telomere length. As well as the evolution of the mean telomere length, we consider the standard deviation and the shape of the distribution. We compare our results with a variety of data from the literature, covering both experimental data and previous models. We find good agreement for the evolution of telomere length when plotted against population doubling. PMID- 24771274 TI - A stuctured discrete model for dengue fever infections and the determination of R0 from age-stratified serological data. AB - A time discrete age-structured model for modeling the spread of Dengue fever is built. The demographic dynamics is introduced trough the Leslie model. The basic reproductive number is introduced, and an approximation for it is built. The final age distributions for the susceptibles, infected and removed are obtained, and we show how they can be used to produce an actual estimate for R0 from stratified serological data. An application is made using data from Recife, Brazil, and explicit estimates for R0 are given. PMID- 24771275 TI - Data resource profile: the Australian early development index (AEDI). AB - Every 3 years, the Australian Government conducts a developmental census across the entire population of children in their first year of full-time schooling (median age 5 years). The first developmental census was conducted in 2009, including 261,147 children, and in 2012 data were collected on 289,973 children representing 97.5% and 96.5% of the estimated eligible population, respectively. The questionnaire is completed by teachers on the basis of at least 1 month's knowledge of the child, including aspects of physical, social, emotional, language and cognitive development, as well as data on special needs. Teachers are also asked to include details of the child's care arrangements and attendance in early education programmes in the years preceding school. Demographic and geographical data are recorded at the individual and area levels. PMID- 24771276 TI - Cohort Profile: Recruitment cohorts in the neuropsychological substudy of the Multicenter AIDS Cohort Study. AB - The Multicenter AIDS Cohort Study (MACS) is one of the largest and longest running studies of the natural and treated history of HIV disease. The Neuropsychological (NP) substudy was begun in 1988 following reports of significant adverse neurological consequences of HIV disease, including dementia. The goal was to characterize the neuropsychological deficits among individuals with HIV disease, and track the natural history of the neurological complications over time. There were three distinct MACS recruitment stages that focused on different groups of HIV-infected men, or men at risk for infection. Initially, a subcohort was evaluated semi-annually with NP tests but, beginning in 2005, the entire group of MACS participants have had NP examinations biannually, unless closer follow-up was warranted. The participants complete a battery of NP tests, and are classified as either normal, mildly or severely impaired using the Antinori criteria for HIV-Associated Neurocognitive Disorder (HAND). Additional behavioural data, including mood state and psychoactive substance use, are recorded as part of the main MACS data collection. The MACS public data set (PDS) has been available since 1994 and includes baseline and 6-monthly follow-up data. Beginning in October 1995, the PDS has been released annually with new releases superseding previous versions. PMID- 24771277 TI - Rescue stem cell mobilization with plerixafor economizes leukapheresis in patients with multiple myeloma. AB - While extensive data demonstrated that plerixafor improves stem cell harvest in difficult-to-mobilize patients, economic concerns limit a broader application. We retrospectively assessed the effect of an early plerixafor rescue regimen for mobilization in patients with multiple myeloma. Patients were intended for high dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ABSCT) and therefore received cyclophosphamide-based mobilization chemotherapy and consecutive stimulation with granulocyte colony stimulating factor (G-CSF). Fifteen patients with poor stem cell harvest in the first leukapheresis session received plerixafor. Data were compared with a matched historic control group of 45 patients who also had a poor stem cell yield in the first apheresis session, but continued mobilization with G-CSF alone. Patients in the plerixafor group collected significantly more CD34+ cells in total (median 4.9 vs. 3.7 [range 1.6-14.1 vs. 1.1-8.0] * 10(6) CD34+ cells /kg bw; P < 0.05), and also more CD34+ cells per leukapheresis procedure (P < 0.001). Consequently, they required a significantly lower number of leukapheresis procedures to achieve the collection goal (median 2.0 vs. 4.0 [range 2-3 vs. 2-9] procedures; P < 0.001). The efficiency of the collected stem cells in terms of hematologic engraftment after ABSCT was found to be equal in both groups. These data demonstrate that rescue mobilization with plerixafor triggered by a low stem cell yield in the first leukapheresis session is effective. Although the actual economic benefit may vary depending on the local leukapheresis costs, the median saving of two leukapheresis procedures offsets most of the expenses for the substance in this setting. An exemplary cost calculation is provided to illustrate this effect. PMID- 24771278 TI - Switching a newly discovered lactonase into an efficient and thermostable phosphotriesterase by simple double mutations His250Ile/Ile263Trp. AB - OPHC2 is a thermostable organophosphate (OP) hydrolase in the beta-lactamase superfamily. OPs are highly toxic synthetic chemicals with no natural analogs. How did OPHC2 acquire phosphotriesterase (PTE) activity remained unclear. In this study, an OPHC2 analogue, PoOPH was discovered from Pseudomonas oleovorans exhibiting high lactonase and esterase activities and latent PTE activity. Sequence analysis revealed conserved His250 and Ile263 and site-directed mutagenesis at these crucial residues enhanced PTE activity. The best variant PoOPHM2 carrying H250I/I263W mutations displayed 6,962- and 106-fold improvements in catalytic efficiency for methyl-parathion and ethyl-paraoxon degradation, whereas the original lactonase and esterase activities decreased dramatically. A 1.4 * 10(7) -fold of specificity inversion was achieved by only two residue substitutions. Significantly, thermostability of the variants was not compromised. Crystal structure of PoOPHM2 was determined at 2.25 A resolution and docking studies suggested that the two residues in the binding pocket determine substrate recognition. Lastly, new organophosphorus hydrolases (OPHs) were discovered using simple double mutations. Among them, PpOPHM2 from Pseudomonas putida emerged as a new promising OPH with very high activity (41.0 U mg(-1) ) toward methyl-parathion. Our results offer a first scrutiny to PTE activity evolution of OPHs in beta-lactamase superfamily and provide efficient and robust enzymes for OP detoxification. PMID- 24771279 TI - Dioscin induces caspase-independent apoptosis through activation of apoptosis inducing factor in breast cancer cells. AB - Dioscin, a saponin extracted from the roots of Polygonatum zanlanscianense, shows several bioactivities such as antitumor, antifungal, and antiviral properties. Although, dioscin is already known to induce cell death in variety cancer cells, the molecular basis for dioscin-induced cell death was not definitely known in cancer cells. In this study, we found that dioscin treatment induced cell death in dose-dependent manner in breast cancer cells such as MDA-MB-231, MDA-MB-453, and T47D cells. Dioscin decreased expressions of Bcl-2 and cIAP-1 proteins, which were down-regulated at the transcriptional level. Conversely, Mcl-1 protein level was down-regulated by facilitating ubiquitin/proteasome-mediated Mcl-1 degradation in dioscin-treated cells. Pretreatment with z-VAD fails to attenuate dioscin-induced cell death as well as caspase-mediated events such as cleavages of procaspase-3 and PARP. In addition, dioscin treatment increased the population of annexin V positive cells and induced DNA fragmentation in a dose-dependent manner in MDA-MB-231 cells. Furthermore, apoptosis inducing factor (AIF) was released from the mitochondria and translocated to the nucleus. Suppression in AIF expression by siRNA reduced dioscin-induced apoptosis in MDA-MB-231 cells. Taken together, our results demonstrate that dioscin-induced cell death was mediated via AIF-facilitating caspase-independent pathway as well as down regulating anti-apoptotic proteins such as Bcl-2, cIAP-1, and Mcl-1 in breast cancer cells. PMID- 24771280 TI - Evaluation of thermal bioclimate based on observational data and numerical simulations: an application to Greece. AB - The evaluation of thermal bioclimate can be conducted employing either observational or modeling techniques. The advantage of the numerical modeling approach lies in that it can be applied in areas where there is lack of observational data, providing a detailed insight on the prevailing thermal bioclimatic conditions. However, this approach should be exploited carefully since model simulations can be frequently biased. The aim of this paper is to examine the suitability of a mesoscale atmospheric model in terms of evaluating thermal bioclimate. For this, the numerical weather prediction Weather Research and Forecasting (WRF) model and the radiation RayMan model are employed for simulating thermal bioclimatic conditions in Greece during a 1-year time period. The physiologically equivalent temperature (PET) is selected as an index for evaluating thermal bioclimate, while synoptic weather station data are exploited for verifying model performance. The results of the present study shed light on the strengths and weaknesses of the numerical modeling approach. Overall, it is shown that model simulations can provide a useful alternative tool for studying thermal bioclimate. Specifically for Greece, the WRF/RayMan modeling system was found to perform adequately well in reproducing the spatial and temporal variations of PET. PMID- 24771281 TI - Age-related differences in function and structure of rSMG and reduced functional connectivity with DLPFC explains heightened emotional egocentricity bias in childhood. AB - Humans often judge others egocentrically, assuming that they feel or think similarly to themselves. Emotional egocentricity bias (EEB) occurs in situations when others feel differently to oneself. Using a novel paradigm, we investigated the neurocognitive mechanisms underlying the developmental capacity to overcome such EEB in children compared with adults. We showed that children display a stronger EEB than adults and that this correlates with reduced activation in right supramarginal gyrus (rSMG) as well as reduced coupling between rSMG and left dorsolateral prefrontal cortex (lDLPFC) in children compared with adults. Crucially, functional recruitment of rSMG was associated with age-related differences in cortical thickness of this region. Although in adults the mere presence of emotional conflict occurs between self and other recruited rSMG, rSMG lDLPFC coupling was only observed when implementing empathic judgements. Finally, resting state analyses comparing connectivity patterns of rSMG with that of right temporoparietal junction suggested a unique role of rSMG for self-other distinction in the emotional domain for adults as well as for children. Thus, children's difficulties in overcoming EEB may be due to late maturation of regions distinguishing between conflicting socio-affective information and relaying this information to regions necessary for implementing accurate judgments. PMID- 24771282 TI - Neural underpinnings of superior action prediction abilities in soccer players. AB - The ability to form anticipatory representations of ongoing actions is crucial for effective interactions in dynamic environments. In sports, elite athletes exhibit greater ability than novices in predicting other players' actions, mainly based on reading their body kinematics. This superior perceptual ability has been associated with a modulation of visual and motor areas by visual and motor expertise. Here, we investigated the causative role of visual and motor action representations in experts' ability to predict the outcome of soccer actions. We asked expert soccer players (outfield players and goalkeepers) and novices to predict the direction of the ball after perceiving the initial phases of penalty kicks that contained or not incongruent body kinematics. During the task, we applied repetitive transcranial magnetic stimulation (rTMS) over the superior temporal sulcus (STS) and the dorsal premotor cortex (PMd). Results showed that STS-rTMS disrupted performance in both experts and novices, especially in those with greater visual expertise (i.e. goalkeepers). Conversely, PMd-rTMS impaired performance only in expert players (i.e. outfield players and goalkeepers), who exhibit strong motor expertise into facing domain-specific actions in soccer games. These results provide causative evidence of the complimentary functional role of visual and motor action representations in experts' action prediction. PMID- 24771283 TI - A transition-metal-free synthesis of fluorinated naphthols. AB - Herein, we describe a transition-metal-free protocol for the conversion of simple 2-allyl-3-(trifluoromethyl)phenols into substituted 5-fluoronaphthalen-1-ols. The key events of this reaction include the selective activation of two C-F bonds and formation of an intermediate hexatriene system, which undergoes a 6pi electrocyclization, followed by rearomatization. This concept enables the rapid conversion (three steps) of various commercially available 3 (trifluoromethyl)phenols into novel fluorine-containing naphthols, which are difficult to prepare by previous methods. The reported sequence was also extended to a one-pot transformation of 3-(trifluoromethyl)phenols into 5-fluoronaphthalen 1-ols. PMID- 24771284 TI - Stapled anopexy and STARR in surgical treatment of haemorrhoidal disease. AB - The treatment of hemorrhoidal disease using stapled anopexy (SA) is still burdened by a high incidence of recurrence. Probably this condition is secondary to inadequate removal of the prolapsed tissue due to the reduced capacity of resection from the adopted device. In order to limit the incidence of failures by providing a removal of a greater amount of prolapsed tissue was considered the opportunity to use the STARR technique even in the presence of haemorrhoidal disease not burdened by symptoms of obstructed defecation. We evaluated the early and at a distance results of 285 patients who had undergone in 2007-2011 surgical resection with trans-anal circular stapler for symptomatic III-IV degree haemorrhoids without obstructed defecation disorders. 237 patients were subjected to SA, while in the remaining 48, since on intervention prolapse committed the CAD more than half of the device, we performed a STARR. adopted the Chi square test (C) considering significant p-values less than 0.05. The anamnestic preoperative evaluation allowed to put the correct indication for surgical treatment in 80% of patients. Mean operative times, hospital stay, incidence of early and more important complications, the symptomatic recurrence of disease (5%) were not dissimilar in the two groups under consideration. Conversely (p < 0.05) the relief of residual asymptomatic disease (24 vs. 10%) was significant . The overall satisfaction was significantly higher in the ST group (73.5 vs 58.6%). The STARR in case of massive prolapse who express themselves with only haemorrhoidal disease is a safe technique, able to optimize the long-term effectiveness of trans-anal resection surgery, limiting the incidence of symptomatic recurrences. The information offered to the patient at the time of the consent to surgery must be extensive and detailed, always considering the possibility of adopting the two techniques alternately and that, at completion of the intervention, could be necessary also the removal of persistent skin tags. PMID- 24771285 TI - A new sheep model with automatized analysis of biomaterial-induced bone tissue regeneration. AB - Presently, several bone graft substitutes are being developed or already available for clinical use. However, the limited number of clinical and in vivo trials for direct comparison between these products may complicate this choice. One of the main reasons for this scarcity it is the use of models that do not readily allow the direct comparison of multiple bone graft substitutes, due especially to the small number of implantation sites. Although sheep cancellous bone models are now well established for these purposes, the limited availability of cancellous bone makes it difficult to find multiple comparable sites within a same animal. These limitations can be overcome by the monocortical model here proposed as it consists in 5-6 holes (5 mm O), in the femoral diaphysis, with similar bone structure, overlying soft tissue and loading pattern for all defects. Associated to this model, it is also described a fast histomorphometric analysis method using a computer image segmentation test (Threshold method) to assess bone regeneration parameters. The information compiled through the experimental use of 45 sheep in several studies allowed determining that this ovine model has the potential to demonstrate differences in bone-forming performance between various scaffolds. Additionally, the described histomorphometric method is fast, accurate and reproducible. PMID- 24771287 TI - Intracranial ganglioglioma WHO I: results in a series of eight patients treated with stereotactic interstitial brachytherapy. AB - In this retrospective study we evaluated the efficacy of interstitial brachytherapy (IBT) using (125)Iodine seeds ((125)I) for intracranial ganglioglioma WHO I. Between October 1994 and March 2010, eight patients (m/f = 5/3, median age 30.4 years, age range 7-42.5 years) with intracranial ganglioglioma WHO I were treated with IBT using stereotactically implanted (125)I seeds. The median follow-up time was 41.5 months (range 16.7-140.1 months). Prior to interstitial brachytherapy one patient underwent microsurgical resection for three times; seven patients were treated with IBT primarily. In all patients we implanted the (125)I seeds stereotactically guided. The cumulative tumor surface dose ranged between 50 and 65 Gy (permanent implantation) and the median tumor volume was 5.6 ml (range 0.9-26 ml). After brachytherapy, follow-up MR imaging revealed complete remission in one patient, partial remission in three and stable disease in the remaining four patients. Five of eight patients presented with seizures were either seizure-free (1/5) or improved (4/5). Temporary treatment related morbidity occurred in one patient only (headache, nausea/vomiting) and resolved completely under steroid medication after 4 weeks. No treatment-related mortality was observed. This study indicates that interstitial brachytherapy for the treatment of intracranial ganglioglioma WHO I is safe and provides a high rate of local tumor control. Due to the limited number of cases, it is not possible to conduct a rigorous statistical evaluation. Thus, larger numbers of patients are required. PMID- 24771286 TI - Recommendations for the radiological diagnosis and follow-up of neuropathological abnormalities associated with tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is a genetic condition with multisystem involvement, characterized by the development of tumors and other abnormalities in organs such as the brain, retina, skin, heart, kidneys, and lungs. Most patients have neuropathological abnormalities such as cortical tubers, white matter radial migration lines, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs). These lesions are associated with different neurological manifestations that are frequently associated with TSC. These manifestations consist of epilepsy, intellectual disability, and neurobehavioral and psychiatric problems, including autism spectrum disorder. Hydrocephalus may also develop in patients with SEGAs due to ventricular obstruction, when this usually slow growing tumor reaches sufficient size. Surgery has been the classical approach to treat SEGAs, although this treatment is associated with substantial morbidity and does not completely prevent tumor recurrence. Recently, the mammalian target of rapamycin (mTOR) inhibitor, everolimus, has been approved by the Food and Drug Administration and the European Medicines Agency for the treatment of patients with SEGAs associated with TSC. However, the treatment of SEGAs with these agents requires the development of guidelines that establish a differential diagnosis between SENs and SEGAs, in which neuroradiological examinations play an essential role. With the aim of improving the neuroradiological diagnosis and follow-up of the neuropathological abnormalities associated with TSC, a group of experts in this field has reviewed different aspects related to these issues and put together, a series of statements and recommendations intended to provide guidance to specialists involved in the management of TSC. PMID- 24771288 TI - Assessment of acrylamide degradation potential of Pseudomonas aeruginosa BAC-6 isolated from industrial effluent. AB - Acrylamide finds diverse industrial applications but is considered an environmental threat because of its neurotoxic, carcinogenic, and teratogenic effects. Certain bacteria enzymatically degrade acrylamide to acrylic acid and ammonia. The present investigation was carried out to isolate and identify an acrylamide-degrading bacterium from industrial effluent. Bacterial growth and extent of acrylamide degradation in the presence of different acrylamide concentrations, nutrients, varied range of pH, and temperature were analyzed. Among the eight acrylamide-degrading isolates, isolate BAC-6 demonstrated the highest degradation, and based upon the partial 16S rDNA sequencing, it was identified as Pseudomonas aeruginosa. P. aeruginosa BAC-6 grew over a wide range of acrylamide concentrations, but the highest degradation was recorded at 500 mg/L concentration with concomitant cell growth. Among the carbon supplements, mannitol supported the highest growth and degradation. Maximum degradation was reported at neutral pH. A mesophilic temperature range (25-40 degrees C) facilitated conducive bacterial growth followed by degradation. The highest degradation and bacterial growth were observed at 30 and 35 degrees C, respectively. Thus, it could be inferred from the present investigation that cultural conditions strongly affected the degradation potential of P. aeruginosa BAC-6 and advocated the utilization of the isolate in bioremediation of sites polluted with acrylamide. PMID- 24771289 TI - Psychological changes in melanoma patients during ipilimumab treatment compared to low-dose interferon alpha therapy-a follow-up study of first experiences. AB - Immuntherapies are frequently accompanied by psychological side effects. Our goals were to detect the changes of psychological factors (depression, anxiety) among melanoma patients during ipilimumab treatment. Ten ipilimumab treated melanoma patients (Group 1.) and 18 low-dose interferon-alpha treated patients (Group 2.) were compared. In our longitudinal study we measured depression (Zung Self-Rating Depression Scale) and anxiety (State-Trait Anxiety Inventory, STAI). Psychological status was tested four times: in every 3 week during ipilimumab treatment according to the relevant treatment protocol and at baseline, 1st, 3rd and 6th month of interferon therapy. No significant differences were detected at different timepoints in the level of depression or in the anxiety scale in Group 1. However significant increase of depression was found in Group 2 during the 6 months of the study. Increased levels of anxiety were found in the second timepoint in both treatment groups. This increase was only temporary and the level of anxiety returned to the baseline. In our sample no measurable psychological differences were detectable during the 12 weeks treatment period of ipilimumab. Ipilimumab seems to have fewer psychological side-effects compared to other immune therapies. PMID- 24771290 TI - Anthropometric measures and bladder cancer risk: a prospective study in the EPIC cohort. AB - Anthropometric measures have been related to risk of several cancers. For bladder cancer, however, evidence is sparse. Comparability of existing studies is hampered by use of different obesity-measures, inadequate control for smoking, and few female cases. This study examined associations between height, weight, waist and hip circumference, waist-hip ratio, waist-height ratio, body mass index (BMI), recalled weight at age 20 and bladder cancer, and investigated effect modification by age, tumor aggressiveness and smoking. The study was conducted in the European Prospective Investigation into Cancer and Nutrition cohort, in 390,878 participants. Associations were calculated using Cox Proportional Hazards Models. During follow-up, 1,391 bladder cancers (1,018 male; 373 female) occurred. Height was unrelated to bladder cancer in both genders. We found a small but significant positive association with weight [1.04 (1.01-1.07) per 5 kilo], BMI [1.05 (1.02-1.08) per 2 units], waist circumference [1.04 (1.01-1.08) per 5 cm], waist-hip ratio (1.07 (1.02-1.13) per 0.05 unit] and waist-height ratio [1.07 (1.01-1.13) per 0.05 unit] in men. Stratification by smoking status confined associations in men to former smokers. In never smokers, we found no significant associations, suggesting residual confounding by smoking. Results did not differ with tumor aggressiveness and age. Residual analyses on BMI/waist circumference showed a significantly higher disease risk with BMI in men (p = 0.01), but no association with waist circumference. In conclusion, in this large study, height was unrelated to bladder cancer, whereas overweight was associated with a slightly higher bladder cancer risk in men. This association may, however, be distorted by residual confounding by smoking. PMID- 24771291 TI - Interaction of aromatic units of amino acids with guanidinium cation: The interplay of pi...pi, X-H...pi, and M+ ...pi contacts. AB - Complexes formed by guanidinium cation and a pair of aromatic molecules among benzene, phenol, or indole have been computationally studied to determine the characteristics of the cation...pi interaction in ternary systems modeling amino acid side chains. Guanidinium coordinates to the aromatic units preferentially in the following order: indole, phenol, and benzene. Complexes containing two different aromatic units show an intermediate behavior between that observed for complexes with only one kind of aromatic unit. Most stable structures correspond to doubly-T shaped arrangements with the two aromatic units coordinating guanidinium by its NH2 groups. Other structures with only one aromatic unit coordinated to guanidinium, such as T-shaped or parallel-stacked ones, are less favorable but still showing significant stabilization. In indole and phenol complexes, the formation of hydrogen bonds between the aromatic molecules introduces extra stabilization in T-shaped structures. Three body effects are small and repulsive in doubly T-shaped minima. Only when hydrogen bonds involving the aromatic molecules are formed in T-shaped structures a cooperative effect can be observed. In most complexes the interaction is controlled by electrostatics, with induction and dispersion also contributing significantly depending on the nature and orientation of the aromatic species forming the complex. Although the stability in these systems is mainly controlled by the intensity of the interaction between guanidinium and the aromatic molecules coordinated to it, interactions between aromatic molecules can modulate the characteristics of the complex, especially when hydrogen bonds are formed. PMID- 24771292 TI - DIEP flap sentinel skin paddle positioning algorithm. AB - Although clinical examination alone or in combination with other techniques is the only ubiquitous method for flap monitoring, it becomes problematic with buried free-tissue transfer. We present a DIEP flap sentinel skin paddle (SSP) positioning algorithm and its reliability is also investigated using a standardized monitoring protocol. All DIEP flaps were monitored with hand-held Doppler examination and clinical observation beginning immediately after surgery in recovery room and continued postoperatively at the ward. Skin paddle (SP) position was preoperatively drawn following mastectomy type incisions; in skin sparing mastectomies types I-III a small SP (sSP) replaces nipple-areola complex; in skin-sparing mastectomy type IV, SSP is positioned between wise-pattern branches while in type V between medial/lateral branches. In case of nipple sparing mastectomy SSP is positioned at inframammary fold or in lateral/medial branches of omega/inverted omega incision if used. Three hundred forty-seven DIEP flap breast reconstructions were reviewed and stratified according to SP type into group A including 216 flaps with large SP and group B including 131 flaps with SSP and sSP. Sixteen flaps (4.6%) were taken back for pedicle compromise, 13 of which were salvaged (81.25%), 11 among 13 from group A and 2 among 3 from group B. There was no statistical difference between the groups concerning microvascular complication rate (P = 0.108), and time until take-back (P = 0.521) and flap salvage rate (P = 0.473) resulted independent of SP type. Our results suggest that early detection of perfusion impairment and successful flaps salvage could be achieved using SSP for buried DIEP flap monitoring, without adjunctive expensive monitoring tests. PMID- 24771293 TI - Room-temperature hydrohydrazination of terminal alkynes catalyzed by saturated abnormal N-heterocyclic carbene-gold(I) complexes. AB - A number of saturated abnormal N-heterocyclic carbene (NHC) complexes of gold, in combination with KBAr(F) 4 as activator, were successfully applied in the chemoselective addition of hydrazine to alkynes. The reaction proceeds even at room temperature, which was not possible to date with gold catalysts. The reaction can be applied to a number of substituted arylalkynes. With alkylalkynes the yields are low. The saturated abnormal NHC ligands are resistant to isomerization to the saturated normal NHC coordination mode under basic reaction conditions. Under acidic conditions, a simple protonation at the nitrogen atom not neighboring the carbene center was observed and unambiguously characterized by an X-ray crystal-structure analysis. Computational studies confirm that such an isomerization would be highly exothermic, the observed kinetic stability probably results from the need to shift two protons in such a process. PMID- 24771294 TI - Psychosocial well-being construct in people with severe mental disorders enrolled in supported employment programs. AB - The main purpose of this prospective study is to validate the construct of psychosocial well-being (PSWB) for people with severe mental disorders enrolled in Supported Employment (SE) programs. This paper also aims to assess the impact of job acquisition on PSWB after obtaining competitive employment. A two-phase study approach was used and 231 individuals with severe mental disorders enrolled in SE programs who took part in both phases. The shortened versions of the Psychological Well-Being Scale (Keyes et al. in J Personal Soc Psychol, 82(6):1007-1022, 2002; Ryff and Keyes in J Personal Soc Psychol 69(4):719-727, 1995) and the Social Well-Being Scale (Keyes in Soc Psychol Q 61(2):121-140, 1998) were used. The PSWB's multidimensionality construct was confirmed. The results of repeated measure ANOVA analyses revealed that job acquisition, as well as, being involved in a work-seeking process increase the PSWB of people with severe mental disorders. Employment specialists might find clinical utility in using this validated tool for assessing PSWB in their clients with severe mental disorders. In a recovery oriented approach to psychiatric services and SE programs, clinicians and employment specialists should continue to encourage their clients in their work integration process even though they may not all obtain competitive employment quickly. PMID- 24771295 TI - Down-regulation of miRNA-30a alleviates cerebral ischemic injury through enhancing beclin 1-mediated autophagy. AB - The understanding of molecular mechanism underlying ischemia/reperfusion-induced neuronal death and neurological dysfunction may provide therapeutic targets for ischemic stroke. The up-regulated miRNA-30a among our previous identified 19 MicroRNAs (miRNAs) in mouse brain after 6 h middle cerebral artery occlusion (MCAO) could negatively regulate Beclin 1 messenger RNA (mRNA) resulting in decreased autophagic activity in tumor cells and cardiomyocytes, but its role in ischemic stroke is unclear. In this study, the effects of miRNA-30a on ischemic injury in N2A cells and cultured cortical neurons after oxygen glucose deprivation (OGD), and mouse brain with MCAO-induced ischemic stroke were evaluated. The results showed that miRNA-30a expression levels were up regulated in the brain of mice after 6 h MCAO without reperfusion, but significantly down regulated in the peri-infarct region of mice with 1 h MCAO/24 h reperfusion and in N2A cells after 1 h OGD/6-48 h reoxygenation. Both the conversion ratio of microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I and Beclin 1 protein level increased in N2A cells and cultured cortical neurons following 1 h OGD/24 h reoxygenation. The down-regulated miRNA-30a could attenuate 1 h OGD/24 h reoxygenation-induced ischemic injury in N2A cells and cultured cortical neurons through enhancing Beclin 1-mediated autophagy, as miRNA-30a recognized the 3' untranslated region of beclin 1 mRNA to negatively regulate Beclin 1-protein level via promoting beclin 1 messenger RNA (mRNA) degradation, and Beclin 1 siRNA abolished anti-miR-30a-induced neuroprotection in 1 h OGD/24 h reoxygenation treated N2A cells. In addition, anti-miR-30a attenuated the neural cell loss and improved behavioral outcome of mice with ischemic stroke. These results suggested that down-regulation of miRNA-30a alleviates ischemic injury through enhancing beclin 1-mediated autophagy, providing a potential therapeutic target for ischemic stroke. PMID- 24771296 TI - NMR structure analysis of uniformly 13C-labeled carbohydrates. AB - In this study, a set of nuclear magnetic resonance experiments, some of them commonly used in the study of (13)C-labeled proteins and/or nucleic acids, is applied for the structure determination of uniformly (13)C-enriched carbohydrates. Two model substances were employed: one compound of low molecular weight [(UL-(13)C)-sucrose, 342 Da] and one compound of medium molecular weight ((13)C-enriched O-antigenic polysaccharide isolated from Escherichia coli O142, ~10 kDa). The first step in this approach involves the assignment of the carbon resonances in each monosaccharide spin system using the anomeric carbon signal as the starting point. The (13)C resonances are traced using (13)C-(13)C correlations from homonuclear experiments, such as (H)CC-CT-COSY, (H)CC-NOESY, CC CT-TOCSY and/or virtually decoupled (H)CC-TOCSY. Based on the assignment of the (13)C resonances, the (1)H chemical shifts are derived in a straightforward manner using one-bond (1)H-(13)C correlations from heteronuclear experiments (HC CT-HSQC). In order to avoid the (1) J CC splitting of the (13)C resonances and to improve the resolution, either constant-time (CT) in the indirect dimension or virtual decoupling in the direct dimension were used. The monosaccharide sequence and linkage positions in oligosaccharides were determined using either (13)C or (1)H detected experiments, namely CC-CT-COSY, band-selective (H)CC-TOCSY, HC-CT HSQC-NOESY or long-range HC-CT-HSQC. However, due to the short T2 relaxation time associated with larger polysaccharides, the sequential information in the O antigen polysaccharide from E. coli O142 could only be elucidated using the (1)H detected experiments. Exchanging protons of hydroxyl groups and N-acetyl amides in the (13)C-enriched polysaccharide were assigned by using HC-H2BC spectra. The assignment of the N-acetyl groups with (15)N at natural abundance was completed by using HN-SOFAST-HMQC, HNCA, HNCO and (13)C-detected (H)CACO spectra. PMID- 24771297 TI - Protocol for aerosol-free recombinant production and NMR analysis of prion proteins. AB - The central hallmark of prion diseases is the misfolding of cellular prion protein (PrP(C)) into a disease-associated aggregated isoform known as scrapie prion protein (PrP(Sc)). NMR spectroscopy has made many essential contributions to the characterization of recombinant PrP in its folded, unfolded and aggregated states. Recent studies reporting on de novo generation of prions from recombinant PrP and infection of animals using prion aerosols suggest that adjustment of current biosafety measures may be necessary, particularly given the relatively high protein concentrations required for NMR applications that favor aggregation. We here present a protocol for the production of recombinant PrP under biosafety level 2 conditions that avoids entirely exposure of the experimenter to aerosols that might contain harmful PrP aggregates. In addition, we introduce an NMR sample tube setup that allows for safe handling of PrP samples at the spectrometer that usually is not part of a dedicated biosafety level 2 laboratory. PMID- 24771298 TI - Five-year monitoring of considerable changes in tyrosine phosphorylation motifs of the Helicobacter pylori cagA gene in Iran. AB - CagA is a major virulence factor of Helicobacter pylori involved in host cell modulation. The C-terminal part of CagA containing the EPIYA motifs is highly variable and is important for the biological activity of the protein. The aim of this study was consideration of the changes in cagA tyrosine phosphorylation motifs (TPMs) of H. pylori. A set of 302 H. pylori DNA samples from the Iranian population from 2006 to 2011 was selected for the proposed study. The cagA gene and its TPMs were assessed by using polymerase chain reaction (PCR) and specific primers. The prevalence of the cagA gene in our study ranged from 91.43% to 97.06% (with an average of 95.03%). Out of the cagA-positive samples, the prevalence of TPMs A and B increased from 12.5% and 23.44% to 71.2% and 63.63%, respectively. Also, the prevalence of samples infected with Western and East Asian types of H. pylori ranged from 64.06% to 5.73% for the Western type and 17.19% to 51.59% for the East Asian type. Overall, our results showed a high prevalence of the cagA gene. Also, it seems that cagA TPMs of H. pylori is undergoing a change from the Western type to the East Asian type in Iran. PMID- 24771299 TI - A pilot study: dose adaptation of capecitabine using mobile phone toxicity monitoring - supporting patients in their homes. AB - PURPOSE: Real-time symptom monitoring using a mobile phone is potentially advantageous for patients receiving oral chemotherapy. We therefore conducted a pilot study of patient dose adaptation using mobile phone monitoring of specific symptoms to investigate relative dose intensity of capecitabine, level of toxicity and perceived supportive care. METHODS: Patients with breast or colorectal cancer receiving capecitabine completed a symptom, temperature and dose diary twice a day using a mobile phone application. This information was encrypted and automatically transmitted in real time to a secure server, with moderate levels of toxicity automatically prompting self-care symptom management messages on the screen of the patient's mobile phone or in severe cases, a call from a specialist nurse to advise on care according to an agreed protocol. RESULTS: Patients (n = 26) completed the mobile phone diary on 92.6 % of occasions. Twelve patients had a maximum toxicity grade of 3 (46.2 %). The average dose intensity for all patients as a percentage of standard dose was 90 %. In eight patients, the dose of capecitabine was reduced, and in eight patients, the dose of capecitabine was increased. Patients and healthcare professionals involved felt reassured by the novel monitoring system, in particular, during out of hours. CONCLUSION: It is possible to optimise the individual dose of oral chemotherapy safely including dose increase and to manage chemotherapy side effects effectively using real-time mobile phone monitoring of toxicity parameters entered by the patient. PMID- 24771301 TI - Characteristics and outcomes of advanced cancer patients who miss outpatient supportive care consult appointments. AB - BACKGROUND: Missed appointments (MA) are frequent, but there are no studies on the effects of the first MA at supportive care outpatient clinics on clinical outcomes. METHODS: We determined the frequency of MA among all patients referred to our clinic from January-December 2011 and recorded the clinical and demographic data and outcomes of 218 MA patients and 217 consecutive patients who kept their first appointments (KA). RESULTS: Of 1,352 advanced-cancer patients referred to our clinic, 218 (16 %) had an MA. The MA patients' median age was 57 years (interquartile range, 49-67). The mean time between referral and appointment was 7.4 days (range, 0-71) for KA patients vs. 9.1 days (range, 0-89) for MA patients (P = 0.006). Reasons for missing included admission to the hospital (17/218 [8 %]), death (4/218 [2 %]), appointments with primary oncologists (37/218 [18 %]), other appointments (19/218 [9 %]), visits to the emergency room (ER) (9/218 [9 %]), and unknown (111/218 [54 %]). MA patients visited the ER more at 2 weeks (16/214 [7 %] vs. 5/217 [2 %], P = 0.010) and 4 weeks (17/205 [8 %] vs. 8/217 [4 %], P = 0.060). Median-survival duration for MA patients was 177 days (range, 127-215) vs. 253 days (range, 192-347) for KA patients (P = 0.013). Multivariate analysis showed that MAs were associated with longer time between referral and scheduled appointment (odds ratio [OR], 1.026/day, P = 0.030), referral from targeted therapy services (OR, 2.177, P = 0.004), living in Texas/Louisiana regions (OR, 2.345, P = 0.002), having an advanced directive (OR, 0.154, P < 0.0001), and being referred for symptom control (OR, 0.024, P = 0.0003). CONCLUSION: MA patients with advanced cancer have worse survival and increased ER utilization than KA patients. Patients at higher risk for MA should undergo more aggressive follow-up. More research is needed. PMID- 24771302 TI - Impact of dose modification on intravenous bortezomib-induced peripheral neuropathy in multiple myeloma patients. AB - PURPOSE: Patients discontinue bortezomib treatment despite good response to the therapy because of bortezomib-induced neuropathy. Early and active dose reduction is recommended for efficacy of treatment. This study evaluates patterns of bortezomib-associated neuropathy and examines the effectiveness of dose modification on symptom management and treatment compliance. METHODS: This is a retrospective cohort study of multiple myeloma patients who received bortezomib intravenously from 2009 to 2012 at Samsung Medical Center, Seoul, Korea. Peripheral neuropathy was assessed using neurotoxicity subscale of the FACT/GOG Ntx at daily clinical practice; physicians modified the dosage and schedule of bortezomib treatment. Mixed-effect models were used for evaluating changes of neuropathy symptoms over time. Linear spline models and multivariate logistic regression were used for testing the effectiveness of interventions. RESULTS: There were 1,060 visits of 55 multiple myeloma patients during the study period. Patients were most likely to have numbness of feet, painful burning in feet, muscle weakness, and the symptoms worsened over time (P < 0.05). For patients who received intervention (n = 32, 58.1 %), neuropathy symptoms were significantly decreased after the intervention (coefficient, -0.1 (95 % confidence interval (CI), -0.8, 0.6)). The intervention group had on average 5.19 (95 % CI, 3.79, 6.59) more bortezomib administrations and was 1.4 times more likely to complete the treatment (odds ratio, 1.40 (95 % CI, 0.31, 6.32)) than the nonintervention group. CONCLUSION: Close monitoring of peripheral neuropathy in patients receiving bortezomib is a feasible and useful way to manage neuropathy in the real world. PMID- 24771303 TI - Active relearning for robust supervised training of emphysema patterns. AB - Radiologists are adept at recognizing the character and extent of lung parenchymal abnormalities in computed tomography (CT) scans. However, the inconsistent differential diagnosis due to subjective aggregation necessitates the exploration of automated classification based on supervised or unsupervised learning. The robustness of supervised learning depends on the training samples. Towards optimizing emphysema classification, we introduce a physician-in-the-loop feedback approach to minimize ambiguity in the selected training samples. An experienced thoracic radiologist selected 412 regions of interest (ROIs) across 15 datasets to represent 124, 129, 139 and 20 training samples of mild, moderate, severe emphysema and normal appearance, respectively. Using multi-view (multiple metrics to capture complementary features) inductive learning, an ensemble of seven un-optimized support vector models (SVM) each based on a specific metric was constructed in less than 6 s. The training samples were classified using seven SVM models and consensus labels were created using majority voting. In the active relearning phase, the ensemble-expert label conflicts were resolved by the expert. The efficacy and generality of active relearning feedback was assessed in the optimized parameter space of six general purpose classifiers across the seven dissimilarity metrics. The proposed just-in-time active relearning feedback with un-optimized SVMs yielded 15 % increase in classification accuracy and 25 % reduction in the number of support vectors. The average improvement in accuracy of six classifiers in their optimized parameter space was 21 %. The proposed cooperative feedback method enhances the quality of training samples used to construct automated classification of emphysematous CT scans. Such an approach could lead to substantial improvement in quantification of emphysema. PMID- 24771305 TI - Question 2: Should steroids be used in the treatment of septic arthritis? PMID- 24771304 TI - Personality compensates for impaired quality of life and social functioning in patients with psychotic disorders who experienced traumatic events. AB - BACKGROUND: Patients with psychotic disorders who experienced childhood trauma show more social dysfunction than patients without traumatic experiences. However, this may not hold for all patients with traumatic experiences. Little is known about the potential compensating role of Five-Factor Model personality traits within this group, despite their strong predictive value for social functioning and well-being in the general population. METHODS: Our sample consisted of 195 patients with psychotic disorders (74% diagnosed with schizophrenia) and 132 controls. Cluster analyses were conducted to identify and validate distinct personality profiles. General linear model analyses were conducted to examine whether patients with different profiles differed in social functioning and quality of life (QoL), while controlling for possible confounders. Mediation models were tested to assess potential causal links. RESULTS: In general, patients with higher levels of self-reported traumatic experiences (PT+) showed lower QoL and more social withdrawal compared with patients with lower traumatic experiences (PT-). Two clusters reflecting personality profiles were identified. PT+ with the first profile (lower neuroticism and higher extraversion, openness, agreeableness, and conscientiousness) presented higher levels of QoL and better social functioning in several areas, including less withdrawal, compared with both PT+ and PT- with the second profile. PT+ and PT- with the first personality profile did not differ in QoL and social functioning. Mediation analyses suggested that personality traits mediate the relation between traumatic experiences and QoL and social withdrawal. CONCLUSIONS: Our findings indicate that personality may "buffer" the impact of childhood traumatic experiences on functional outcome in patients with psychotic disorders. PMID- 24771306 TI - A giant sialolith in a 16-year-old boy presenting to the emergency room. PMID- 24771307 TI - Gonorrhoea, chlamydia, syphilis and trichomonas in children under 13 years of age: national surveillance in the UK and Republic of Ireland. AB - BACKGROUND: Sexually transmitted infections in children ought to raise concerns about sexual abuse. It is not known how frequently they are identified in the UK and Ireland, nor how well they are investigated. AIMS: To measure the incidence, mode of presentation, investigations and child protection procedures among children under 13 years and over 12 months of age presenting with infections of Neisseria gonorrhoea, Treponema pallidum, Chlamydia trachomatis or Trichomonas vaginalis in the UK and Republic of Ireland. METHODS: National surveillance study over 25 months through the British Paediatric Surveillance Unit. All consultant paediatricians in the UK and Republic of Ireland reported laboratory confirmed infections followed by a confidential questionnaire covering clinical details, investigation results and child protection outcomes. RESULTS: Fifteen cases were reported, giving an overall incidence of these infections of 0.075 cases per 100,000 children per year. Most were identified because they presented with symptoms. Five cases presented with ophthalmic infection. Laboratory investigation and screening for other infections was adequate in most cases. Although only three cases of sexual abuse were confirmed in court or case conference, abuse was suspected in a further seven cases based on clinical factors, family or social history. CONCLUSIONS: Sexually transmitted infections in children, although rare, are generally well investigated. The findings support current guidance on the management of sexually transmitted infection in young children and the need to maintain a high index of suspicion for sexual abuse. Isolated ophthalmic infection with N gonorrhoeae and C trachomatis occurs beyond infancy, but the mode of transmission is unclear. PMID- 24771308 TI - Fear of oxygen therapy for children in Malawi. AB - BACKGROUND: Although pneumonia is a common cause of death in children in Malawi, healthcare staff frequently encounter patients or carers who refuse oxygen therapy. This qualitative study documents factors that influence acceptance or refusal of oxygen therapy for children in Malawi. METHODS: Nine group interviews involving 86 participants were held in community and hospital settings in rural and urban Malawi. Eleven in-depth interviews of healthcare staff providing oxygen were held in a central hospital. Thematic analysis of transcripts of the audio recordings was carried out to identify recurring themes. RESULTS: Similar ideas were identified in the group interviews and in-depth staff interviews. Past experiences of oxygen use (direct and indirect, positive and negative) had a strong influence on views of oxygen. A recurrent theme was fear of oxygen, often due to a perceived association between death and recent oxygen use. Fears were intensified by a lack of familiarity with equipment used to deliver oxygen, distrust of medical staff and concerns about cost of oxygen. CONCLUSIONS: This study identifies reasons for refusal of oxygen therapy for children in a low income country. Findings from the study suggest that training of healthcare staff to address fears of parents, and information, education and communication (IEC) approaches that improve public understanding of oxygen and provide positive examples of its use are likely to be helpful in improving uptake of oxygen therapy in Malawi. PMID- 24771310 TI - Zinc supplement modulates oxidative stress and antioxidant values in rats with severe acute pancreatitis. AB - Oxidative stress is a main factor in the pathogenesis of severe acute pancreatitis (SAP). The ability of zinc (Zn) to retard oxidative processes has been recognized for many years. This study aims to examine the levels of free oxygen radicals and antioxidant enzyme in SAP rats and know the effect of Zn supplementation on free oxygen radicals and antioxidant system in rats with SAP. Forty-five male Wistar rats were divided into three groups-the SAP group (n=15), the Zn-treated group (n=15), and the controlled group (n=15). For the SAP group, sodium taurocholate is injected into the pancreatic duct to induce SAP; for the Zn-treated group, Zn (5 mg/kg) is subcutaneously injected immediately after injection of 5% sodium taurocholate. Firstly, the activity of erythrocyte glutathione peroxidase (GSH-Px), erythrocyte superoxide dismutase (SOD), and the content of plasma malondialdehyde (MDA), which are the toxic products of oxidative stress, is measured. Secondly, the levels of free oxygen radicals in the liver and kidney are detected. The result showed that the activity of GSH-Px and SOD was lower in the SAP group than that in the controlled group, although the content of plasma MDA increased. However, the activity of SOD and GSH-Px in the Zn-treated group was not significantly decreased after comparing with the controlled group; in the mean time, the content of MDA was not significantly increased either. Moreover, the content of free radical in liver and kidney was higher in the SAP group compared with the controlled group, but the content of free radical in the Zn-treated group was not higher than that in the controlled group (p>0.05). All of the above indicated that Zn may recover the activity of free radical-scavenging enzymes and decrease the content of free radical for the SAP group rats. In conclusion, the content of free radical increase may be one of the reasons that SAP rats are injured, and it is possible for Zn to be used to treat SAP through scavenging free radical and increasing the activity of SOD and GSH-Px of erythrocyte. PMID- 24771309 TI - Diagnosis and management of primary ciliary dyskinesia. AB - Primary ciliary dyskinesia (PCD) is an inherited autosomal-recessive disorder of motile cilia characterised by chronic lung disease, rhinosinusitis, hearing impairment and subfertility. Nasal symptoms and respiratory distress usually start soon after birth, and by adulthood bronchiectasis is invariable. Organ laterality defects, usually situs inversus, occur in ~50% of cases. The estimated prevalence of PCD is up to ~1 per 10,000 births, but it is more common in populations where consanguinity is common. This review examines who to refer for diagnostic testing. It describes the limitations surrounding diagnosis using currently available techniques and considers whether recent advances to genotype patients with PCD will lead to genetic testing and screening to aid diagnosis in the near future. It discusses the challenges of monitoring and treating respiratory and ENT disease in children with PCD. PMID- 24771311 TI - Environmental cadmium exposure impacts physiological responses in Manila clams. AB - The physiological responses of marine bivalves to chronic cadmium (Cd) exposure at sub-lethal concentrations have been well documented. As of now, few studies have examined the effect of Cd exposure and subsequent recovery period at environmentally realistic concentrations. In this study, environmentally, Cd exposures were performed to assess the physiological responses of the Manila clam Ruditapes philippinarum. The clams were exposed to waterborne Cd at two environmentally realistic concentrations (4 and 40 MUg L(-1)) for 35 days and then allowed to recover for another 35 days. The accumulation and elimination of Cd in R. philippinarum were tissue-specific and dose- and time-dependent. Cd accumulation increased sharply in the digestive gland, and Cd elimination was rapid in the gill. Major physiological responses, including clearance rate, absorption efficiency, respiration rate, excretion rate, oxygen to nitrogen ratio, and scope for growth, were significantly affected by Cd exposure. Yet, the clams exposed to 4-MUg L(-1) Cd were able to quickly recover their normal physiological processes and clearly exhibited catch-up growth once they were transferred to clean seawater. Hence, R. philippinarum can exhibit good physiological plasticity when confronted with moderately environmental Cd exposure. All physiological responses measured exhibited a highly significant and generally predictable correlation with tissue Cd concentration, which in turn, reflected environmentally realistic exposure conditions. Our results further confirm that the measurement of physiological responses is a sensitive method for assessing stress at environmentally realistic metal concentrations. PMID- 24771312 TI - A versatile approach to the generation of fluid supported lipid bilayers and its applications. AB - Establishing supported lipid bilayers with biologically relevant composition, including transmembrane proteins and various classes of lipids, presents a significant challenge. We describe a generic and facile approach to the production of fluid polymer-supported lipid bilayers that allows for the incorporation of a wide variety of lipids and transmembrane proteins. The method is based on the formation of a polymer brush displaying lipid groups, followed by spin-coating of membrane lipids. Subsequentially, transmembrane proteins are incorporated by the fusion of proteoliposomes with the bilayer. Several applications, including the incorporation and single-molecule tracking of transmembrane proteins in a bilayer and the visualization of the fusion of individual, membrane-enveloped viruses with a supported membrane, are demonstrated. Our results suggest that the membrane properties are consistent with those found in physiologically relevant conditions and underscore the wide applicability of our approach to synthetic biology, lab-on-a-chip applications, biophysical and pharmaceutical studies. PMID- 24771313 TI - Swine model of chronic postcapillary pulmonary hypertension with right ventricular remodeling: long-term characterization by cardiac catheterization, magnetic resonance, and pathology. AB - Pulmonary hypertension (PH) is prevalent and carries high morbidity and mortality, mostly due to right ventricular (RV) dysfunction. Postcapillary PH is the most frequent form but there are no large-animal models available. We developed and characterized a porcine model of postcapillary PH by non restrictive banding of the confluent of both inferior pulmonary veins (n = 10; sham controls n = 3). Right heart catheterization and magnetic resonance were performed before the procedure and monthly during 4 months. All banded animals developed PH. Compared to controls, banded animals presented higher mean pulmonary artery pressure [median (first to third quartile) 30 mmHg (25-37) vs. 20 mmHg (18-23); p = 0.018] and higher pulmonary vascular resistance [5.2 WU (3.8 7.1) vs. 2.3 WU (2.1-3.5); p = 0.028] after 2 months. Differences in indexed RV end-systolic volume [42 mL/m(2) (36-53) vs. 24 mL/m(2) (24-33); p = 0.028] and RV ejection fraction [59 % (54-63) vs. 66 % (64-68); p = 0.028] were also significant after 2 months. Differences remained significant throughout the study. Histopathology revealed increased lung weight and fibrosis but no increase in average water content. Also, remodeling on pulmonary arteries including increased medial and intimal thickness and fibrosis and RV myocardial disarray and fibrosis was demonstrated. Lung remodeling findings were similar in all pulmonary lobes. PMID- 24771315 TI - A system for context-aware intraoperative augmented reality in dental implant surgery. AB - PURPOSE: Large volumes of information in the OR are ignored by surgeons when the amount outpaces human mental processing abilities. We developed an augmented reality (AR) system for dental implant surgery that acts as an automatic information filter, selectively displaying only relevant information. The purpose is to reduce information overflow and offer intuitive image guidance. The system was evaluated in a pig cadaver experiment. METHODS: Information filtering is implemented via rule-based situation interpretation with description logics. The interpretation is based on intraoperative distances measurement between anatomical structures and the dental drill with optical tracking. For AR, a head mounted display is used, which was calibrated with a novel method based on SPAAM. To adapt to surgeon specific preferences, we offer two alternative display formats: one with static and another with contact analog AR. RESULTS: The system made the surgery easier and showed ergonomical benefits, as assessed by a questionnaire. All relevant phases were recognized reliably. The new calibration showed significant improvements, while the deviation of the realized implants was <2.5 mm. CONCLUSION: The system allowed the surgeon to fully concentrate on the surgery itself. It offered greater flexibility since the surgeon received all relevant information, but was free to deviate from it. Accuracy of the realized implants remains an open issue and part of future work. PMID- 24771314 TI - State of the art in carotid artery stenting: trial data, technical aspects, and limitations. AB - The volume of carotid artery stenting (CAS) safety and efficacy data has grown exponentially over the last decade. Recent comparative data with carotid endarterectomy, the utility of embolic protection devices, peri-procedural medications, basic technical aspects of CAS, developments in carotid stent design, potential complications of CAS, and complication risk factors are discussed in this review. PMID- 24771316 TI - Diazoxide pretreatment prevents Abeta1-42 induced oxidative stress in cholinergic neurons via alleviating NOX2 expression. AB - The aggregation and accumulation of amyloid-beta (Abeta) plays a significant role in the pathogenesis of Alzheimer's disease. Abeta is known to increase free radical production in neuronal cells, leading to oxidative stress and cell death. Diazoxide (DZ), a highly selective drug capable of opening mitochondrial ATP sensitive potassium channels, has neuroprotective effects against neuronal cell death. However, the mechanism through which DZ protects cholinergic neurons against Abeta-induced oxidative injury is still unclear. The present study was designed to investigate the effects of DZ pretreatment against Abeta1-42 induced oxidative damage and cytotoxicity. Through measures of DZ effects on Abeta1-42 induced cellular damage, reactive oxygen species (ROS) and MDA generation and expressions of gp91phox and p47phox in cholinergic neurons, new insights into the neuroprotective mechanisms can be derived. Abeta1-42 significantly decreased 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide levels and increased ROS and MDA production; all effects were attenuated by pretreatment with DZ or diphenyleneiodonium chloride (a NOX2 inhibitor). Pretreatment with DZ also attenuated the upregulation of NOX2 subunits (gp91phox and p47phox) induced by Abeta1-42. Since NOX2 is one of the main sources of free radicals, these results suggest that DZ can counteract Abeta1-42 induced oxidative stress and associated cell death by reducing the level of ROS and MDA, in part, by alleviating NOX2 expression. PMID- 24771317 TI - Lorentz sphere versus generalized Lorentzian approach: What would lorentz say about it? PMID- 24771318 TI - Chloride-induced aufbau of perchlorinated cyclohexasilanes from Si2Cl6: a mechanistic scenario. AB - A surprisingly simple preparative procedure, addition of Si2Cl6 to a solution of [nBu4N]Cl in CH2Cl2, leads to the formation of the chloride-complexed cyclic dianions [Si6Cl12?2Cl](2-), [(SiCl3)Si6Cl11?2Cl](2-), or [1,y (SiCl3)2Si6Cl10?2Cl](2-) (y = 1, 3, 4), depending on the stoichiometric ratio of the reactants and the reaction temperature (25-85 degrees C). Below -40 degrees C the open-chain oligosilane chloride adducts [Si3Cl9](-), [Si3Cl10](2-), [Si4Cl11](-), and [Si6Cl15](-) are formed, again depending on the reaction conditions chosen. All species were characterized by X-ray crystallography. The underlying reaction mechanism is elucidated by DFT calculations. It incorporates all experimental findings and involves a few key elementary steps: 1) chloride induced liberation of SiCl3(-) or higher silanides, 2) their addition to neutral silanes yielding larger oligosilane chloride adducts, 3) dimerization of larger silanides to (substituted) cyclohexasilane dichloride adducts with inverse sandwich structure. PMID- 24771319 TI - Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization. AB - BACKGROUND: Immobilization of the lower leg is associated with venous thromboembolism (VTE). Low molecular weight heparin (LMWH) is an anticoagulant treatment which might be used in adult patients with lower-leg immobilization to prevent deep venous thrombosis (DVT) and its complications. This is an update of the review first published in 2008. OBJECTIVES: To assess the effectiveness of low molecular weight heparin for the prevention of venous thromboembolism in patients with lower-leg immobilization in an ambulant setting. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co ordinator searched the Specialised Register (last searched June 2013) and CENTRAL (2013, Issue 5). SELECTION CRITERIA: Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that described thromboprophylaxis by means of LMWH compared with no prophylaxis or placebo in adult patients with lower-leg immobilization. Immobilization was by means of a plaster cast or brace. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. The review authors contacted the trial authors for additional information if required. Statistical analysis was carried out using Review Manager (RevMan 5). MAIN RESULTS: We included six RCTs fulfilling the above criteria with a total of 1490 patients. We found an incidence of VTE ranging from 4.3% to 40% in patients who had a leg injury that had been immobilized in a plaster cast or a brace for at least one week and who received no prophylaxis, or placebo. This number was significantly lower in patients who received daily subcutaneous injections of LMWH during immobilization (event rates ranging from 0% to 37%; odds ratio (OR) 0.49; fixed 95% confidence interval (CI) 0.34 to 0.72; with minimal evidence of heterogeneity with an I(2) of 20%, P = 0. 29). Comparable results were seen in the following subcategories: operated patients, conservatively treated patients, patients with fractures, patients with soft tissue injuries, patients with proximal thrombosis, patients with distal thrombosis and patients with below-knee casts. Complications of major bleeding events were extremely rare (0.3%) and there were no reports of heparin-induced thrombocytopenia. AUTHORS' CONCLUSIONS: Use of LMWH in outpatients significantly reduces VTE when immobilization of the lower leg is required. PMID- 24771321 TI - Identification of individuals with ADHD using the Dean-Woodcock sensory motor battery and a boosted tree algorithm. AB - The accurate and early identification of individuals with pervasive conditions such as attention deficit hyperactivity disorder (ADHD) is crucial to ensuring that they receive appropriate and timely assistance and treatment. Heretofore, identification of such individuals has proven somewhat difficult, typically involving clinical decision making based on descriptions and observations of behavior, in conjunction with the administration of cognitive assessments. The present study reports on the use of a sensory motor battery in conjunction with a recursive partitioning computer algorithm, boosted trees, to develop a prediction heuristic for identifying individuals with ADHD. Results of the study demonstrate that this method is able to do so with accuracy rates of over 95 %, much higher than the popular logistic regression model against which it was compared. Implications of these results for practice are provided. PMID- 24771320 TI - Efficacy and safety of endoscopic papillary large balloon dilation for large bile duct stones in elderly patients. AB - BACKGROUND: Minimally invasive interventions for choledocholithiasis are preferable in elderly patients because they tend to have multiple underlying disorders or a decreased activity of daily living. Endoscopic sphincterotomy and endoscopic papillary balloon dilation have been recognized as first-line treatments for choledocholithiasis excluding difficult cases such as large stones or multiple stones. Recently, the safety and efficacy of endoscopic papillary large balloon dilation (EPLBD) for difficult choledocholithiasis cases have been reported, although scarcely in elderly patients. AIMS: To investigate whether EPLBD can be safety and effectively performed in patients aged 75 years or older. METHODS: The medical records of 165 patients who underwent EPLBD from November 2006 to August 2013 were analyzed retrospectively. The patients were divided into 2 groups: Group A (>= 75 years); Group B (<75 years). RESULTS: Some underlying diseases were significantly more common in Group A than in Group B (P < 0.05). However, there was no significant difference in the success rates in the first session (96.2 vs 95.0 %, P = 0.970) and in the final success rates (100 % in both groups) between Group A and Group B. The adverse event rates (2.9 vs 5.0 %, P = 0.783) and recurrence rates of choledocholithiasis (6.7 vs 10.0 %, P = 0.444) were not significantly different. Regarding patients with an altered anatomy, the EPLBD outcome was not significantly different. CONCLUSION: EPLBD can be safely performed for elderly patients similarly to younger patients. PMID- 24771322 TI - Validity and reliability of an online visual-spatial working memory task for self reliant administration in school-aged children. AB - Working memory is an important predictor of academic performance, and of math performance in particular. Most working memory tasks depend on one-to-one administration by a testing assistant, which makes the use of such tasks in large scale studies time-consuming and costly. Therefore, an online, self-reliant visual-spatial working memory task (the Lion game) was developed for primary school children (6-12 years of age). In two studies, the validity and reliability of the Lion game were investigated. The results from Study 1 (n = 442) indicated satisfactory six-week test-retest reliability, excellent internal consistency, and good concurrent and predictive validity. The results from Study 2 (n = 5,059) confirmed the results on the internal consistency and predictive validity of the Lion game. In addition, multilevel analysis revealed that classroom membership influenced Lion game scores. We concluded that the Lion game is a valid and reliable instrument for the online computerized and self-reliant measurement of visual-spatial working memory (i.e., updating). PMID- 24771323 TI - Ad hominen or ad rem? Good autocorrelation or bad? PMID- 24771325 TI - Authors' response: politicization with misrepresentation: on de-trending in time series analysis. PMID- 24771324 TI - Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents. AB - BACKGROUND: Age at natural menopause (ANM) is considered a marker of biological ageing and is increasingly recognized as a sentinel for chronic disease risk in later life. Socioeconomic position (SEP) and lifestyle factors are thought to be associated with ANM. METHODS: We performed a systematic review and meta-analyses to determine the overall mean ANM, and the effect of SEP and lifestyle factors on ANM by calculating the weighted mean difference (WMD) and pooling adjusted hazard ratios. We explored heterogeneity using meta-regression and also included unpublished findings from the Australian Longitudinal Study on Women's Health. RESULTS: We identified 46 studies across 24 countries. Mean ANM was 48.8 years [95% confidence interval (CI): 48.3, 49.2], with between-study heterogeneity partly explained by geographical region. ANM was lowest among African, Latin American, Asian and Middle Eastern countries and highest in Europe and Australia, followed by the USA. Education was associated with later ANM (WMD middle vs low education 0.30, 95% CI: 0.10, 0.51; high vs low education 0.64, 95% CI 0.26, 1.02). A similar dose-response relationship was also observed for occupation. Smoking was associated with a 1-year reduction of ANM (WMD: -0.91, 95% CI: -1.34, -0.48). Being overweight and moderate/high physical activity were modestly associated with later ANM, but findings were less conclusive. CONCLUSIONS: ANM varies across populations, partly due to differences across geographical regions. SEP and some lifestyle factors are associated with ANM, but further research is needed to examine the impact of the associations between risk factors and ANM on future health outcomes. PMID- 24771326 TI - Automated NMR resonance assignment strategy for RNA via the phosphodiester backbone based on high-dimensional through-bond APSY experiments. AB - A fast, robust and reliable strategy for automated sequential resonance assignment for uniformly [(13)C, (15)N]-labeled RNA via its phosphodiester backbone is presented. It is based on a series of high-dimensional through-bond APSY experiments: a 5D HCP-CCH COSY, a 4D H1'C1'CH TOCSY for ribose resonances, a 5D HCNCH for ribose-to-base connection, a 4D H6C6C5H5 TOCSY for pyrimidine resonances, and a 4D H8C8(C)C2H2 TOCSY for adenine resonances. The utilized pulse sequences are partially novel, and optimized to enable long evolution times in all dimensions. The highly precise APSY peak lists derived with these experiments could be used directly for reliable automated resonance assignment with the FLYA algorithm. This approach resulted in 98 % assignment completeness for all (13)C (1)H, (15)N1/9 and (31)P resonances of a stem-loop with 14 nucleotides. PMID- 24771327 TI - Crystal structures of acyl carrier protein in complex with two catalytic partners show a dynamic role in cellular metabolism. AB - ACP captured in action: Two recently reported crystal structures are the first to capture ACP-mediated substrate delivery to a catalytic partner at high resolution. These studies highlight key interactions of transient ACP-partner complexes and define the dynamic movements of ACP that facilitate substrate delivery and trigger complex dissociation. PMID- 24771328 TI - Selective targeting of Toll-like receptors and OX40 inhibit regulatory T-cell function in follicular lymphoma. AB - Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin-containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression-free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD-1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll-like receptors (TLR) with TLR ligands Pam3 CSK4 (TLR 1/2), flagellin (TLR 5), and CpG-B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor-specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients. PMID- 24771330 TI - Breastfeeding and HIV-infected women in the United States: harm reduction counseling strategies. AB - Social and cultural forces have led some human immunodeficiency virus (HIV) infected women to question the recommendation in the United States not to breastfeed. Without an open dialogue, women may choose to breastfeed exclusively or intermittently and not disclose this to their provider. We review the evidence from global studies of the risks of breastfeeding among HIV-infected mothers and propose a harm reduction model for women considering breastfeeding. PMID- 24771329 TI - Severe malarial anemia is associated with long-term neurocognitive impairment. AB - BACKGROUND: Cerebral malaria (CM) is associated with long-term neurocognitive impairment in children >=5 years of age. No prospective studies to date have assessed neurocognitive impairment in children with CM <5 years of age, or in children with severe malarial anemia (SMA), a form of severe malaria estimated to affect as many as 5 million children annually. METHODS: Children <5 years of age presenting to Mulago Hospital, Kampala, Uganda, with CM (n = 80) or SMA (n = 86) were assessed for overall cognitive ability, attention, and associative memory 1 week after discharge and 6 and 12 months later. The z scores for each domain were computed based on scores of 61 healthy community children (CC), who were also tested at enrollment and 6 and 12 months later. Groups were compared using mixed linear models, adjusted for age, weight for age, and child's education. RESULTS: At 12 months, children with CM had lower adjusted scores than CC in cognitive ability (P < .001), attention (P = .02), and associative memory, (P = .002). Children with SMA had lower scores than CC in cognitive ability (P = .01) but not attention or associative memory. Cognitive ability scores in children with CM and SMA did not differ significantly. CONCLUSIONS: In children <5 years of age, SMA is associated with long-term impairment in cognitive ability, whereas CM is associated with additional impairment in the areas of attention and associative memory. SMA may be a major contributor to long-term neurocognitive impairment in children in sub-Saharan Africa. PMID- 24771331 TI - Proposed clinical case definition for cytomegalovirus-immune recovery retinitis. AB - BACKGROUND: Cytomegalovirus (CMV) retinitis has been extensively described in patients with advanced or late human immunodeficiency virus (HIV) disease under ineffective treatment of opportunistic infection and antiretroviral therapy (ART) failure. However, there is limited information about patients who develop active cytomegalovirus retinitis as an immune reconstitution inflammatory syndrome (IRIS) after successful initiation of ART. Therefore, a case definition of cytomegalovirus-immune recovery retinitis (CMV-IRR) is proposed here. METHODS: We reviewed medical records of 116 HIV-infected patients with CMV retinitis attending our institution during January 2003-June 2012. We retrospectively studied HIV-infected patients who had CMV retinitis on ART initiation or during the subsequent 6 months. Clinical and immunological characteristics of patients with active CMV retinitis were described. RESULTS: Of the 75 patients under successful ART included in the study, 20 had improvement of CMV retinitis. The remaining 55 patients experienced CMV-IRR; 35 of those developed CMV-IRR after ART initiation (unmasking CMV-IRR) and 20 experienced paradoxical clinical worsening of retinitis (paradoxical CMV-IRR). Nineteen patients with CMV-IRR had a CD4 count of >=50 cells/uL. Six patients with CMV-IRR subsequently developed immune recovery uveitis. CONCLUSIONS: There is no case definition for CMV-IRR, although this condition is likely to occur after successful initiation of ART, even in patients with high CD4 T-cell counts. By consequence, we propose the case definitions for paradoxical and unmasking CMV-IRR. We recommend close follow-up of HIV-infected patients following ART initiation. PMID- 24771332 TI - Emerging technologies for rapid identification of bloodstream pathogens. AB - Technologies for rapid microbial identification are poised to revolutionize clinical microbiology and enable informed decision making for patients with life threatening bloodstream infections. Species identification of microorganisms in positive blood cultures can be performed in minutes using commercial fluorescence in situ hybridization tests or mass spectroscopy. Microorganisms in positive blood cultures can also be identified within 1-2.5 hours using automated polymerase chain reaction-based systems that can also detect selected antibiotic resistance markers, such as methicillin resistance. When combined with antibiotic stewardship programs, these approaches improve clinical outcomes and reduce healthcare expenditures. Tests for direct detection in whole blood samples are highly desirable because of their potential to identify bloodstream pathogens without waiting 1-2 days for blood cultures to become positive. However, results for pathogen detection in whole blood do not overlap with those of conventional blood culture techniques and we are still learning how best to use these approaches. PMID- 24771334 TI - Mannose-binding lectin gene, MBL2, polymorphisms are not associated with susceptibility to invasive pneumococcal disease in children. AB - BACKGROUND: Most children are transiently colonized with Streptococcus pneumoniae, but very few develop invasive pneumococcal disease (IPD). Host genetic variation of innate immunity may predispose to IPD. We investigated the effect of genetic variation in the mannose-binding lectin gene, MBL2, on susceptibility and disease severity of IPD in previously healthy children aged <5 years. METHODS: IPD cases were identified through national registries. DNA was obtained from the Danish Neonatal Screening Biobank. Pneumococcal serotypes were determined by Quellung reaction. The associations between MBL2 diplotypes and IPD susceptibility, serotypes, and outcome were investigated using logistic regression analysis. RESULTS: We included 372 cases with meningitis, 907 with bacteremia, and 1263 age- and sex-matched controls; 2372 individuals were successfully genotyped and assigned MBL2 diplotypes. The median age in our combined case series was 13 months. Children with defective diplotypes were not at higher risk for meningitis than children with other diplotypes (odds ratio [OR], 0.85; 95% confidence interval [CI], .56-1.28). Similar results were found for bacteremia (OR, 0.89; 95% CI, .68-1.15) as well as for all cases (OR, 0.87; 95% CI, .70-1.09). There was no association with susceptibility to recurrent IPD (n = 12) for children with defective diplotypes compared with cases with a single episode (OR, 0.53; 95% CI, .07-4.13) and with all controls (OR, 0.46; 95% CI, .06 3.56). There was no association between diplotypes and mortality or between diplotypes and pneumococcal serotypes. CONCLUSIONS: Defective MBL2 polymorphisms did not predict increased IPD susceptibility in children born in Northern Europe. PMID- 24771336 TI - An early aggressive strategy for the treatment of Hanta virus cardiopulmonary syndrome: a perspective from an extracorporeal membrane oxygenation center. PMID- 24771335 TI - Healthcare-associated Klebsiella pneumoniae carbapenemase producing K. pneumoniae bloodstream infection: the time has come. PMID- 24771333 TI - Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. AB - BACKGROUND: Patterns of cause-specific mortality in individuals infected with human immunodeficiency virus type 1 (HIV-1) are changing dramatically in the era of antiretroviral therapy (ART). METHODS: Sixteen cohorts from Europe and North America contributed data on adult patients followed from the start of ART. Procedures for coding causes of death were standardized. Estimated hazard ratios (HRs) were adjusted for transmission risk group, sex, age, year of ART initiation, baseline CD4 count, viral load, and AIDS status, before and after the first year of ART. RESULTS: A total of 4237 of 65 121 (6.5%) patients died (median, 4.5 years follow-up). Rates of AIDS death decreased substantially with time since starting ART, but mortality from non-AIDS malignancy increased (rate ratio, 1.04 per year; 95% confidence interval [CI], 1.0-1.1). Higher mortality in men than women during the first year of ART was mostly due to non-AIDS malignancy and liver-related deaths. Associations with age were strongest for cardiovascular disease, heart/vascular, and malignancy deaths. Patients with presumed transmission through injection drug use had higher rates of all causes of death, particularly for liver-related causes (HRs compared with men who have sex with men: 18.1 [95% CI, 6.2-52.7] during the first year of ART and 9.1 [95% CI, 5.8 14.2] thereafter). There was a persistent role of CD4 count at baseline and at 12 months in predicting AIDS, non-AIDS infection, and non-AIDS malignancy deaths. Lack of viral suppression on ART was associated with AIDS, non-AIDS infection, and other causes of death. CONCLUSIONS: Better understanding of patterns of and risk factors for cause-specific mortality in the ART era can aid in development of appropriate care for HIV-infected individuals and inform guidelines for risk factor management. PMID- 24771337 TI - Increased expression of angiogenic factors in cultured human brain arteriovenous malformation endothelial cells. AB - To compare the mRNA level of angiogenic factor vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2, and MMP-9 in cultured human brain arteriovenous malformation (AVM) endothelial cells (ECs) and normal brain endothelial cells (BECs). Tissue explants both from deformed vessels of AVM and normal microvessel were put into culture for endothelial cells. After the monolayer adherent ECs reached confluence, they were tested with endothelial specific marker CD34 and von Willebrand factor (vWF) by immunochemical assay. mRNA levels of VEGF-A, MMP-2, and MMP-9 in AVM endothelial cells (AVMECs) and BECs were measured by PCR. Immunostaining confirmed that more than 95 % of the cultured cells were CD34 (Fig. 1b) and/or vWF positive. Expression levels of VEGF A and MMP-2 mRNAs were significantly higher in AVMECs than in BECs. The MMP-9 level was also increased in AVMECs, but the difference was not statistically significant. Vascular tissue explants adherent method is a better approach for isolation and culture of AVMECs. Cultured AVMECs expressed higher angiogenic factors (VEGF, MMP-2) than the controlled BECs, implicating angiogenesis plays an important role in the pathogenesis of AVM. PMID- 24771338 TI - Nucleosome regulatory dynamics in response to TGFbeta. AB - Nucleosomes play important roles in a cell beyond their basal functionality in chromatin compaction. Their placement affects all steps in transcriptional regulation, from transcription factor (TF) binding to messenger ribonucleic acid (mRNA) synthesis. Careful profiling of their locations and dynamics in response to stimuli is important to further our understanding of transcriptional regulation by the state of chromatin. We measured nucleosome occupancy in human hepatic cells before and after treatment with transforming growth factor beta 1 (TGFbeta1), using massively parallel sequencing. With a newly developed method, SuMMIt, for precise positioning of nucleosomes we inferred dynamics of the nucleosomal landscape. Distinct nucleosome positioning has previously been described at transcription start site and flanking TF binding sites. We found that the average pattern is present at very few sites and, in case of TF binding, the double peak surrounding the sites is just an artifact of averaging over many loci. We systematically searched for depleted nucleosomes in stimulated cells compared to unstimulated cells and identified 24 318 loci. Depending on genomic annotation, 44-78% of them were over-represented in binding motifs for TFs. Changes in binding affinity were verified for HNF4alpha by qPCR. Strikingly many of these loci were associated with expression changes, as measured by RNA sequencing. PMID- 24771339 TI - RNApdbee--a webserver to derive secondary structures from pdb files of knotted and unknotted RNAs. AB - In RNA structural biology and bioinformatics an access to correct RNA secondary structure and its proper representation is of crucial importance. This is true especially in the field of secondary and 3D RNA structure prediction. Here, we introduce RNApdbee-a new tool that allows to extract RNA secondary structure from the pdb file, and presents it in both textual and graphical form. RNApdbee supports processing of knotted and unknotted structures of large RNAs, also within protein complexes. The method works not only for first but also for high order pseudoknots, and gives an information about canonical and non-canonical base pairs. A combination of these features is unique among existing applications for RNA structure analysis. Additionally, a function of converting between the text notations, i.e. BPSEQ, CT and extended dot-bracket, is provided. In order to facilitate a more comprehensive study, the webserver integrates the functionality of RNAView, MC-Annotate and 3DNA/DSSR, being the most common tools used for automated identification and classification of RNA base pairs. RNApdbee is implemented as a publicly available webserver with an intuitive interface and can be freely accessed at http://rnapdbee.cs.put.poznan.pl/. PMID- 24771340 TI - NetVenn: an integrated network analysis web platform for gene lists. AB - Many lists containing biological identifiers, such as gene lists, have been generated in various genomics projects. Identifying the overlap among gene lists can enable us to understand the similarities and differences between the data sets. Here, we present an interactome network-based web application platform named NetVenn for comparing and mining the relationships among gene lists. NetVenn contains interactome network data publically available for several species and supports a user upload of customized interactome network data. It has an efficient and interactive graphic tool that provides a Venn diagram view for comparing two to four lists in the context of an interactome network. NetVenn also provides a comprehensive annotation of genes in the gene lists by using enriched terms from multiple functional databases. In addition, it allows for mapping the gene expression data, providing information of transcription status of genes in the network. The power graph analysis tool is integrated in NetVenn for simplified visualization of gene relationships in the network. NetVenn is freely available at http://probes.pw.usda.gov/NetVenn or http://wheat.pw.usda.gov/NetVenn. PMID- 24771341 TI - iMODS: internal coordinates normal mode analysis server. AB - Normal mode analysis (NMA) in internal (dihedral) coordinates naturally reproduces the collective functional motions of biological macromolecules. iMODS facilitates the exploration of such modes and generates feasible transition pathways between two homologous structures, even with large macromolecules. The distinctive internal coordinate formulation improves the efficiency of NMA and extends its applicability while implicitly maintaining stereochemistry. Vibrational analysis, motion animations and morphing trajectories can be easily carried out at different resolution scales almost interactively. The server is versatile; non-specialists can rapidly characterize potential conformational changes, whereas advanced users can customize the model resolution with multiple coarse-grained atomic representations and elastic network potentials. iMODS supports advanced visualization capabilities for illustrating collective motions, including an improved affine-model-based arrow representation of domain dynamics. The generated all-heavy-atoms conformations can be used to introduce flexibility for more advanced modeling or sampling strategies. The server is free and open to all users with no login requirement at http://imods.chaconlab.org. PMID- 24771342 TI - CANOES: detecting rare copy number variants from whole exome sequencing data. AB - We present CANOES, an algorithm for the detection of rare copy number variants from exome sequencing data. CANOES models read counts using a negative binomial distribution and estimates variance of the read counts using a regression-based approach based on selected reference samples in a given dataset. We test CANOES on a family-based exome sequencing dataset, and show that its sensitivity and specificity is comparable to that of XHMM. Moreover, the method is complementary to Gaussian approximation-based methods (e.g. XHMM or CoNIFER). When CANOES is used in combination with these methods, it will be possible to produce high accuracy calls, as demonstrated by a much reduced and more realistic de novo rate in results from trio data. PMID- 24771343 TI - Absence/presence calling in microarray-based CGH experiments with non-model organisms. AB - Structural variations in genomes are commonly studied by (micro)array-based comparative genomic hybridization. The data analysis methods to infer copy number variation in model organisms (human, mouse) are established. In principle, the procedures are based on signal ratios between test and reference samples and the order of the probe targets in the genome. These procedures are less applicable to experiments with non-model organisms, which frequently comprise non-sequenced genomes with an unknown order of probe targets. We therefore present an additional analysis approach, which does not depend on the structural information of a reference genome, and quantifies the presence or absence of a probe target in an unknown genome. The principle is that intensity values of target probes are compared with the intensities of negative-control probes and positive-control probes from a control hybridization, to determine if a probe target is absent or present. In a test, analyzing the genome content of a known bacterial strain: Staphylococcus aureus MRSA252, this approach proved to be successful, demonstrated by receiver operating characteristic area under the curve values larger than 0.9995. We show its usability in various applications, such as comparing genome content and validating next-generation sequencing reads from eukaryotic non-model organisms. PMID- 24771344 TI - Identification of non-coding RNAs with a new composite feature in the Hybrid Random Forest Ensemble algorithm. AB - To identify non-coding RNA (ncRNA) signals within genomic regions, a classification tool was developed based on a hybrid random forest (RF) with a logistic regression model to efficiently discriminate short ncRNA sequences as well as long complex ncRNA sequences. This RF-based classifier was trained on a well-balanced dataset with a discriminative set of features and achieved an accuracy, sensitivity and specificity of 92.11%, 90.7% and 93.5%, respectively. The selected feature set includes a new proposed feature, SCORE. This feature is generated based on a logistic regression function that combines five significant features-structure, sequence, modularity, structural robustness and coding potential-to enable improved characterization of long ncRNA (lncRNA) elements. The use of SCORE improved the performance of the RF-based classifier in the identification of Rfam lncRNA families. A genome-wide ncRNA classification framework was applied to a wide variety of organisms, with an emphasis on those of economic, social, public health, environmental and agricultural significance, such as various bacteria genomes, the Arthrospira (Spirulina) genome, and rice and human genomic regions. Our framework was able to identify known ncRNAs with sensitivities of greater than 90% and 77.7% for prokaryotic and eukaryotic sequences, respectively. Our classifier is available at http://ncrna pred.com/HLRF.htm. PMID- 24771345 TI - Identification and characterization of RNA guanine-quadruplex binding proteins. AB - Guanine quadruplex (G-quadruplex) motifs in the 5' untranslated region (5'-UTR) of mRNAs were recently shown to influence the efficiency of translation. In the present study, we investigate the interaction between cellular proteins and the G quadruplexes located in two mRNAs (MMP16 and ARPC2). Formation of the G quadruplexes was confirmed by biophysical characterization and the inhibitory activity on translation was shown by luciferase reporter assays. In experiments with whole cell extracts from different eukaryotic cell lines, G-quadruplex binding proteins were isolated by pull-down assays and subsequently identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. The binding partners of the RNA G-quadruplexes we discovered included several heterogeneous nuclear ribonucleoproteins, ribosomal proteins, and splicing factors, as well as other proteins that have previously not been described to interact with nucleic acids. While most of the proteins were specific for either of the investigated G-quadruplexes, some of them bound to both motifs. Selected candidate proteins were subsequently produced by recombinant expression and dissociation constants for the interaction between the proteins and RNA G quadruplexes in the low nanomolar range were determined by surface plasmon resonance spectroscopy. The present study may thus help to increase our understanding of the mechanisms by which G-quadruplexes regulate translation. PMID- 24771346 TI - SIP1/NHERF2 enhances estrogen receptor alpha transactivation in breast cancer cells. AB - The estrogen receptor alpha (ERalpha) is a ligand-activated transcription factor that possesses two activating domains designated AF-1 and AF-2 that mediate its transcriptional activity. The role of AF-2 is to recruit coregulator protein complexes capable of modifying chromatin condensation status. In contrast, the mechanism responsible for the ligand-independent AF-1 activity and for its synergistic functional interaction with AF-2 is unclear. In this study, we have identified the protein Na+/H+ Exchanger RegulatoryFactor 2 (NHERF2) as an ERalpha associated coactivator that interacts predominantly with the AF-1 domain of the nuclear receptor. Overexpression of NHERF2 in breast cancer MCF7 cells produced an increase in ERalpha transactivation. Interestingly, the presence of SRC-1 in NHERF2 stably overexpressing MCF7 cells produced a synergistic increase in ERalpha activity. We show further that NHERF2 interacts with ERalpha and SRC-1 in the promoter region of ERalpha target genes. The binding of NHERF2 to ERalpha in MCF7 cells increased cell proliferation and the ability of MCF7 cells to form tumors in a mouse model. We analyzed the expression of NHERF2 in breast cancer tumors finding a 2- to 17-fold increase in its mRNA levels in 50% of the tumor samples compared to normal breast tissue. These results indicate that NHERF2 is a coactivator of ERalpha that may participate in the development of estrogen dependent breast cancer tumors. PMID- 24771348 TI - Model-based cell number quantification using online single-oxygen sensor data for tissue engineering perfusion bioreactors. AB - Online and non-invasive quantification of critical tissue engineering (TE) construct quality attributes in TE bioreactors is indispensable for the cost effective up-scaling and automation of cellular construct manufacturing. However, appropriate monitoring techniques for cellular constructs in bioreactors are still lacking. This study presents a generic and robust approach to determine cell number and metabolic activity of cell-based TE constructs in perfusion bioreactors based on single oxygen sensor data in dynamic perfusion conditions. A data-based mechanistic modeling technique was used that is able to correlate the number of cells within the scaffold (R(2) = 0.80) and the metabolic activity of the cells (R(2) = 0.82) to the dynamics of the oxygen response to step changes in the perfusion rate. This generic non-destructive measurement technique is effective for a large range of cells, from as low as 1.0 * 10(5) cells to potentially multiple millions of cells, and can open-up new possibilities for effective bioprocess monitoring. PMID- 24771347 TI - Suicidal cross-linking of PARP-1 to AP site intermediates in cells undergoing base excision repair. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme in mammalian cells. The enzyme synthesizes polymers of ADP-ribose from the coenzyme NAD(+) and plays multifaceted roles in cellular responses to genotoxic stress, including DNA repair. It had been shown that mouse fibroblasts treated with a DNA methylating agent in combination with a PARP inhibitor exhibit higher cytotoxicity than cells treated with methylating agent alone. This lethality of the PARP inhibitor is dependent on apurinic/apyrimidinic (AP) sites in the DNA and the presence of PARP 1. Here, we show that purified PARP-1 is capable of forming a DNA-protein cross link (DPC) by covalently attaching to the AP site. This DPC formation is specific to the presence of the natural AP site in DNA and is accompanied by a single strand DNA incision. Cellular studies confirm the formation of PARP-1 DPCs during alkylating agent-induced base excision repair (BER) and formation of DPCs is enhanced by a PARP inhibitor. Using an N-terminal and C-terminal truncated PARP-1 we show that a polypeptide fragment comprising the zinc 3 and BRCT sub-domains is sufficient for DPC formation. The covalent attachment of PARP-1 to AP site containing DNA appears to be a suicidal event when BER is overwhelmed or disrupted. PMID- 24771349 TI - Rare variants and cardiovascular disease. AB - Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the Western world. Large genome-wide association studies (GWASs) of coronary artery disease, myocardial infarction, stroke and dilated cardiomyopathy have identified a number of common genetic variants with modest effects on disease risk. Similarly, studies of important modifiable risk factors of CVD have identified a large number of predominantly common variant associations, for example, with blood pressure and blood lipid levels. In each case, despite the often large numbers of loci identified, only a small proportion of the phenotypic variance is explained. It has been hypothesised that rare variants with large effects may account for some of the missing variance but large-scale studies of rare variation are in their infancy for cardiovascular traits and have yet to produce fruitful results. Studies of monogenic CVDs, inherited disorders believed to be entirely driven by individual rare mutations, have highlighted genes that play a key role in disease aetiology. In this review, we discuss how findings from studies of rare variants in monogenic disease and GWAS of predominantly common variants are converging to provide further insight into biological disease mechanisms. PMID- 24771351 TI - Treatment for peritoneal dialysis-associated peritonitis. AB - BACKGROUND: Peritonitis is a common complication of peritoneal dialysis (PD) that is associated with significant morbidity including death, hospitalisation, and need to change from PD to haemodialysis. Treatment is aimed to reduce morbidity and recurrence. This is an update of a review first published in 2008. OBJECTIVES: To evaluate the benefits and harms of treatments for PD-associated peritonitis. SEARCH METHODS: For this review update we searched the Cochrane Renal Group's Specialised Register to March 2014 through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE, and handsearching conference proceedings. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs assessing the treatment of peritonitis in PD patients (adults and children). We included any study that evaluated: administration of an antibiotic by different routes (e.g. oral, intraperitoneal (IP), intravenous (IV)); dose of an antibiotic agent; different schedules of administration of antimicrobial agents; comparisons of different regimens of antimicrobial agents; any other intervention including fibrinolytic agents, peritoneal lavage and early catheter removal. DATA COLLECTION AND ANALYSIS: Multiple authors independently extracted data on study risk of bias and outcomes. Statistical analyses were performed using the random effects model. We expressed summarised treatment estimates as a risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. MAIN RESULTS: We identified 42 eligible studies in 2433 participants: antimicrobial agents (36 studies); urokinase (4 studies), peritoneal lavage (1 study), and IP immunoglobulin (1 study). We did not identify any optimal antibiotic agent or combination of agents. IP glycopeptides (vancomycin or teicoplanin) had uncertain effects on primary treatment response, relapse rates, and need for catheter removal compared to first generation cephalosporins, although glycopeptide regimens were more likely to achieve a complete cure (3 studies, 370 episodes: RR 1.66, 95% CI 1.01 to 2.72). For relapsing or persistent peritonitis, simultaneous catheter removal and replacement was better than urokinase at reducing treatment failure rates (RR 2.35, 95% CI 1.13 to 4.91) although evidence was limited to a single small study. Continuous and intermittent IP antibiotic dosing schedules had similar treatment failure and relapse rates. IP antibiotics were superior to IV antibiotics in reducing treatment failure in one small study (RR 3.52, 95% CI 1.26 to 9.81). Longer duration treatment (21 days of IV vancomycin and IP gentamicin) had uncertain effects on risk of treatment relapse compared with 10 days treatment (1 study, 49 patients: RR 1.56, 95% CI 0.60 to 3.95) although may have increased ototoxicity.In general, review conclusions were based on a small number of studies with few events in which risk of bias was generally high; interventions were heterogeneous, and outcome definitions were often inconsistent. There were no RCTs evaluating optimal timing of catheter removal and data for automated PD were absent. AUTHORS' CONCLUSIONS: Many of the studies evaluating treatment of PD-related peritonitis are small, out-dated, of poor quality, and had inconsistent definitions and dosing regimens. IP administration of antibiotics was superior to IV administration for treating PD-associated peritonitis and glycopeptides appear optimal for complete cure of peritonitis, although evidence for this finding was assessed as low quality. PD catheter removal may be the best treatment for relapsing or persistent peritonitis.Evidence was insufficient to identify the optimal agent, route or duration of antibiotics to treat peritonitis. No specific antibiotic appears to have superior efficacy for preventing treatment failure or relapse of peritonitis, but evidence is limited to few trials. The role of routine peritoneal lavage or urokinase is uncertain. PMID- 24771350 TI - Safety, tolerability and anti-tumour activity of the androgen biosynthesis inhibitor ASP9521 in patients with metastatic castration-resistant prostate cancer: multi-centre phase I/II study. AB - BACKGROUND: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 beta-hydroxysteroid dehydrogenase type 5 (17 betaHSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumour activity in in vitro and in vivo preclinical models. MATERIAL AND METHODS: This first-in-man phase I/II study utilised a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed. RESULTS: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part. CONCLUSIONS: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity. PMID- 24771352 TI - Terpenes and sterols from the fruits of Prunus mume and their inhibitory effects on osteoclast differentiation by suppressing tartrate-resistant acid phosphatase activity. AB - The fruits of Prunus mume are a common commercial product and a valuable source of food and medicinal material in Eastern Asian countries. Our phytochemical investigation of the P. mume fruit led to the isolation of nine terpenes, including three ursane-type triterpenes (1-3), two cycloartane-type triterpenes (4 and 5), and four tocopherols (10-13), as well as four sterols (6-9). Their structures were elucidated based on extensive spectroscopic analysis, including 1D and 2D NMR and ESI-MS, and the majority of these compounds were isolated from this plant for the first time. The anti-osteoporosis activities of 1-13 were evaluated by measuring their inhibitory effects on tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor kappaB ligand induced osteoclastic RAW 264.7 macrophage cells. Compounds 2-7 and 9-12 significantly suppressed TRAP activity down to 47.96 +/- 2.45-86.45 +/- 3.07 % relative to the control at a concentration of 1 MUM. These results suggest that the fruits of P. mume could be an excellent source of anti-osteoporosis phytochemicals that may be developed as natural nutraceuticals and functional foods. PMID- 24771353 TI - Inhibitors of Alzheimer's BACE-1 with 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4 aryl-1,4-dihydropyridine structure. AB - beta-site amyloid precursor protein cleaving enzyme (BACE-1) is a validated target for Alzheimer therapy due to its distinctive role in pathogenesis of AD. In the present contribution, a series of new 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine structures were synthesized as BACE-1 inhibitors (6a-6n). In vitro BACE-1 inhibitory activities were determined by enzymatic fluorescence resonance energy transfer assay. Synthesized dihydropyridine (DHP) analogues exhibited weak to good inhibitory activities while 6i, 6n and 6a were found to be the most potent molecules with 83.76, 79.45 and 72.47 % BACE-1 inhibition at 10 MUM, respectively. Structure binding/activity relationship elucidations revealed that superior BACE-1 inhibitory activities were observed for DHP derivatives bearing fused/non-fused thiazole groups and particularly 3,5-bis-N-(6-ethoxy-2-benzothiazolyl) moiety. Binding maps showed that enhanced activity may be attributed to the additional H-bond and hydrophobic interactions with S2-S3 subpockets of BACE-1. PMID- 24771354 TI - SMAC-armed vaccinia virus induces both apoptosis and necroptosis and synergizes the efficiency of vinblastine in HCC. AB - Hepatocellular carcinoma (HCC) has particularly high incidence rate in Asia and its resistance to the chemotherapeutic drugs and cell death make it intractable. Vaccinia virus (VV) is a potential vehicle and has been widely used in cancer therapy. SMAC/DIABLO is a critical factor in activating caspases and eliminating inhibition of IAPs when the programmed cell death is promoted. In this study, we constructed a tumor-targeted vaccinia virus carrying SMAC/DIABLO gene that was knocked in the region of viral thymidine kinase gene (VV-SMAC). Our results showed that VV-SMAC efficiently infected and destroyed HCC cells via triggering both caspase-dependent apoptosis and necroptosis with depletion of IAPs. Furthermore, ripoptosome, a prerequisite complex of necroptosis, was assembled and induced by VV-SMAC. In addition, the combination of VV-SMAC and vinblastine represented a synergistic effect on HCC cells. In summary, our data suggest that VV-SMAC is a potential candidate and combination of VV-SMAC and vinblastine may provide a new avenue in treatment of HCC. PMID- 24771355 TI - Pediatric surgical care in Lilongwe, Malawi: outcomes and opportunities for improvement. AB - BACKGROUND: One of the objectives of the Millennium Development Goals is to improve child health. We describe the burden of pediatric surgical disease at a tertiary hospital in Malawi. METHODS: We conducted a retrospective analysis of a pediatric surgery database at Kamuzu Central Hospital in Malawi for the calendar year 2012. Variables included patient demographics, admission diagnosis, primary surgery and outcome. RESULTS: A total of 1170 pediatric patients aged 0-17 years were admitted to the surgical service during the study period. The mean age was 6.9 years, and 62% were male. Trauma was the most common indication for admission (51%, n = 596), and 67% (n = 779) of all patients were managed non-operatively. Neonates and patients managed non-operatively had a significantly increased risk of mortality. CONCLUSION: Only a third of patients admitted to the pediatric surgery service underwent surgery. More than half of patients with congenital anomalies did not undergo surgical intervention. Importantly, patients who underwent surgery had a survival advantage. PMID- 24771356 TI - A perinatal cytomegalovirus infection in an immunocompetent patient with chorioretinitis. AB - Cytomegalovirus (CMV) infection is the most common viral infection of newborns in all periods worldwide. Perinatal form of infection is usually less severe than the congenital form because of having a lower rate for serious organ involvement like central nervous system. In this article, we report a 3-month-old immunocompetent patient who was diagnosed as having perinatal CMV infection with a scar of chorioretinitis after presenting with gastroenteritis and hepatitis. PMID- 24771357 TI - Optimization of scanning parameters for MR elastography at 3.0 T clinical unit: volunteer study. AB - PURPOSE: We sought to optimize scanning parameters for MR elastography at 3.0 T clinical unit. MATERIALS AND METHODS: 10 volunteers were scanned with various magnetization encoding gradient (MEG) frequencies from 60 to 120 Hz at every 10 Hz, with otherwise fixed parameters (external driver frequency/amplitude = 60 Hz/50 %, 10 mm slice thickness, etc.). Images were qualitatively assessed for the degree of image defects, and also quantitatively for the areas without cross hatching. After determining optimal MEG frequency, external driver amplitudes of 70 % (vs 50 %) and slice thickness of 8 mm (vs 10 mm) were also tested. With the optimized parameters, scans were repeated 1 week after the initial scan, and the repeatability of the liver stiffness measurement was validated. RESULTS: 80 or 90 Hz was shown to be the best MEG frequency. There were no significant differences in the qualitative and quantitative assessment between the two amplitudes and two slice thicknesses; however, 70 % amplitude resulted in discomfort at the chest wall beneath the external acoustic driver. Thus, MEG 80 (or 90) Hz, amplitude 50 %, and thickness 10 (or 8) mm were considered optimal. Repeatability of the liver stiffness measurement was +/-10 % (95 % confidence interval). CONCLUSIONS: With the optimized parameters, repeatability of +/-10 % in liver stiffness measurement was obtained. PMID- 24771358 TI - Minimizing the acquisition phase in coronary CT angiography using the second generation 320-row CT. AB - PURPOSE: We aimed to compare the radiation dose and image quality of a minimal phase window centered at 77 % compared with a wide phase window in coronary CT angiography using the second-generation 320-row CT. MATERIALS AND METHODS: Eighty patients with heart rate <=75 bpm were retrospectively included. The first 40 patients underwent scanning with a wide phase window (65-85 %), while the last 40 patients underwent scanning with a minimal phase window centered at 77 %. Subjective image quality was graded using a 4-point scale (4 = excellent). Image noise and contrast-to-noise ratio at the proximal segments were also analyzed. The mean effective dose was derived from the dose length product multiplied by a chest conversion coefficient (kappa = 0.014 mSv mGy(-1) cm(-1)). RESULTS: Minimal phase window scanning centered at 77 % reduced the radiation dose by 30 % compared with wide phase window scanning (1.7 vs 2.4 mSv, p = 0.0009). The subjective image quality showed no significant difference (3.75 vs 3.76, p = 0.77). No significant difference was observed in the image noise, CT number, and contrast-to-noise ratio. CONCLUSIONS: Radiation dose could be reduced while maintaining image quality by use of a minimal phase window centered at 77 % compared with a wide phase window in coronary CT angiography using the second generation 320-row CT. PMID- 24771359 TI - Characterization of the effect of Cr(VI) on humoral innate immunity using Drosophila melanogaster. AB - With the advancement of human race, different anthropogenic activities have heaped the environment with chemicals that can cause alteration in the immune system of exposed organism. As a first line of barrier, the evolutionary conserved innate immunity is crucial for the health of an organism. However, there is paucity of information regarding in vivo assessment of the effect of environmental chemicals on innate immunity. Therefore, we examined the effect of a widely used environmental chemical, Cr(VI), on humoral innate immune response using Drosophila melanogaster. The adverse effect of Cr(VI) on host humoral response was characterized by decreased gene expression of antimicrobial peptides (AMPs) in the exposed organism. Concurrently, a significantly decreased transcription of humoral pathway receptors (Toll and PGRP) and triglyceride level along with inhibition of antioxidant enzyme activities were observed in exposed organism. This in turn weakened the immune response of exposed organism that was manifested by their reduced resistance against bacterial infection. In addition, overexpression of the components of humoral immunity particularly Diptericin benefits Drosophila from Cr(VI)-induced humoral immune-suppressive effect. To our knowledge, this is the first report regarding negative impact of an environmental chemical on humoral innate immune response of Drosophila along with subsequent protection by AMPs, which may provide novel insight into host-chemical interactions. Also, our data validate the utility and sensitivity of Drosophila as a model that could be used for screening the possible risk of environmental chemicals on innate immunity with minimum ethical concern that can be further extrapolated to higher organisms. PMID- 24771360 TI - Gamma oscillations in the somatosensory cortex of newborn rats. AB - Here we addressed a question of whether gamma oscillations previously described in the whisker-related barrel cortex are a universal pattern of activity in the somatosensory cortex of newborn rats. Intracortical recording of local field potentials and action potentials in neurons using multisite silicon electrodes in 2-7-day-old rats showed that mechanical stimulation of single fingers or specific areas on the plantar or back side of the foot evoked early gamma oscillations followed by spindle-burst oscillations in the corresponding regions of the somatosensory cortex. Early gamma oscillations had maximum amplitude in layer IV of the somatosensory cortex and effectively synchronized action potentials in layer IV neurons. It was concluded that early gamma oscillations evoked by activation of the topographic sensory input are a universal activity pattern of the entire somatosensory cortex of newborn rats. PMID- 24771361 TI - Involvement of P2Y(2,4) receptors in the regulation of myocardial contractility in growing rats. AB - Experiments with R2Y receptor blockers allowed identification of R2Y subtypes mediating the inhibitory effects of uridine triphosphate on myocardial contractility. In 100-day-old animals, the myocardial inotropic response to the administration of uridine triphosphate was mediated by R2Y2 receptors. R2Y4 receptors took part in the realization of negative inotropic response to uridine triphosphate in all age groups, but the most pronounced effects of this substance on myocardial contractility were found in 100-day-old rats. It was found that R2Y receptor blockers PPADS and reagent blue-2 affect amplitude-time parameters of myocardial contractility in rats of various ages. PMID- 24771362 TI - Metabolic role of lipid peroxidation processes and antioxidant defense system in the pathogenesis of hypothalamic syndrome. AB - LPO processes and blood antioxidant status were studied in reproductive-age women with the hypothalamic syndrome. The control group consisted of somatically healthy women without reproductive disorders. Female patients with the hypothalamic syndrome were characterized by an imbalance in the LPO-antioxidant defense system, which aggravated the course of the underlying disease. PMID- 24771363 TI - Adaptogenic effects of dihydroquercetin-chitosan composition during modeling of acute hypoxia. AB - The course of preventive oral treatment with a dihydroquercetin-chitosan composition produced a strong antihypoxic effect under conditions of experimental hypobaric hypoxia (arbitrary altitude 12,000 m). The lactate/pyruvate ratio in composition-receiving rats was much lower than in hypoxic animals (by 83%), but higher than in intact specimens (by 29%). The composition of chitosan and dihydroquercetin also possessed a strong antioxidant activity. PMID- 24771364 TI - Functional activity of BK(Ca) channels in coronary vascular smooth muscle cells during combined exposure to hyperglycemia and stress. AB - The effect of tetraethylammonium in a dose of 1 mM (inhibiting functional activity and preventing opening of BKCa channels) was least pronounced during restraint stress. The influence of this agent was more significant in animals exposed to 14-day hyperglycemia alone or in combination with restraint stress. Therefore, hyperglycemia and stress (individual or combined exposure) significantly inhibit functional activity of BKCa channels in smooth muscles of the coronary vessels. Our results suggest that the development of hyperglycemia is realized via pathogenetic mechanisms of vascular injury in the heart (similarly to stress conditions). Permanent increase in blood glucose level and 6 h immobilization probably induces nonspecific post-stress abnormalities in channel function. PMID- 24771365 TI - Expression of genes encoding serotonin receptors and SERT in various brain structures of stressed rats after chronic exposure to ultrasound. AB - The expression of genes encoding serotonin receptors and serotonin transporter in emotiogenic structures of rat brain was shown to change after chronic stress with ultrasonic waves of varying frequencies. A QPCR-RT study revealed the increased expression of genes for SERT and 5-HT1B receptor and decreased expression of the 5-HT2A receptor in the prefrontal cortex of rats after chronic exposure to ultrasonic waves of varying frequencies. Gene expression was increased for SERT, but decreased for 5-HT1B, 5-HT2A, and 5-HT2B receptors in the midbrain of animals. The hippocampus was characterized by an increased expression of genes encoding SERT and 5-HT1A, 5-HT2A, and 5-HT2B receptors. Our results indicate that the exposure to this type of stress is followed by dysregulation in the serotoninergic system of the brain. PMID- 24771366 TI - Proliferation and local manifestations of oxidative stress in mucous membrane of the ileum in patients at early stages of hemorrhagic fever with renal syndrome. AB - Activation of proliferative processes (Ki-67 proliferation index) and local oxidative stress was found in biopsy material from the mucosa of the large intestine of patients at the early stages of hemorrhagic fever with renal syndrome on days 5-10 after disease onset. Analysis of data of rectosigmoidoscopy and clinical examination refl ected the presence of colitis. It can be suggested that activation of proliferation is typically associated with local oxidative stress during various pathological processes. PMID- 24771367 TI - Effect of protein synthesis rhythm-organizing signal persists for a day after single administration of melatonin to rat. AB - Melatonin administered to rat intraperitoneally organizes ultradian rhythm of protein synthesis in hepatocytes that persists for 1 day after exposure to the synchronizing signal. Hepatocytes were isolated 1 day after melatonin administration and cultured on coverslips in a serum-free medium. In 24 h in culture, the kinetics of protein synthesis was analyzed. In our previous experiments, we detected a rhythm in cells isolated in 1.5 h, but not in 3 days after melatonin administration to the rat. We have found that synchronization of oscillations of the protein synthesis intensity in vivo persists over 1 day after rat exposure to melatonin. Phenylephrine, an efficient synchronizer of protein synthesis in vitro, does not organize the rhythm in vivo. PMID- 24771368 TI - Effect of polyunsaturated fatty acids omega-3 on the induction of activity and expression of CYP1A1 and CYP1A2 genes in the liver of rats under the influence of indole-3-carbinol. AB - Supplementation of the ration with eicosapentaenoic and docosahexaenoic omega-3 polyunsaturated fatty acids (PUFA) in doses of 0.3 and 1 g/kg body weight for 4 weeks had no effect on ethoxyresorufin O-dealkylase (EROD) activity and expression of the CYP1A1 gene in male Wistar rats, but caused a dose-dependent increase in methoxyresorufin O-dealkylase (MROD) activity of CYP1A2 (by 28 and 73%, respectively) without significant changes in CYP1A2 mRNA expression. omega-3 PUFA had no effect on the indole-3-carbinol-induced (20 mg/kg body weight over the last 7 days of the experiment) EROD activity and expression of CYP1A1 mRNA. The indole-3-carbinol-induced MROD activity was shown to increase by 6.2 times in rats not receiving omega-3 PUFA and only by 3.9 and 2.7 times in animals receiving omega-3 PUFA. The indole-3-carbinol-induced expression of CYP1A2 mRNA slightly increased in animals receiving omega-3 PUFA. Our results suggest that the effect of omega-3 PUFA on the induced and basal activity of CYP1A2 is not related to modulation of CYP1A2 gene expression. PMID- 24771369 TI - Effect of ions of potassium and lithium on NO synthase expression in the human adrenal cortex. AB - The expression of endothelial and inducible NO synthase in the human adrenal glands was studied under a change in the concentration of K(+), which plays a regulatory role in aldosterone secretion. K(+) ions stimulated the expression of both isoforms of NO synthase in the human adrenal cortex. A stimulatory effect of K(+) on NO synthase is probably related to activation of the calmodulin system and potassium-induced translocation of protein kinase C. Lithium produced n inhibitory effect on both isoforms of NO synthase, which suggests that protein kinase C serves a major regulator of expression in the human adrenal glands. PMID- 24771370 TI - Correcting effect of ladasten on variations in the subpopulation composition of T lymphocytes in C57BL/6 mice on the experimental model of an anxious-depressive state. AB - We studied the effect of Ladasten (30 mg/kg intraperitoneally for 5 days) on the subpopulation composition of T cells in immunocompetent organs of male C57Bl/6 mice during modeling of an anxious-depressive state (chronic zoosocial stress). Stress exposure of animals for 30 days was followed by a decrease in the relative weight of the thymus, increase in the weight of the spleen, reduction of the percentage of T cell populations, and shift in the CD4(+)/CD8(+) ratio toward cytotoxic T cells. Administration of Ladasten had a normalizing effect on the relative weights of study organs and subpopulation composition of T cells in immunocompetent organs, which returned to the control level. PMID- 24771371 TI - Hypolipidemic and hypoglycemic effect of peptide Lys-Glu-Trp-NH(2) in rats with associated metabolic disorders. AB - The effect of peptide Lys-Glu-Trp-NH2 in doses of 0.2, 20, and 2000 MUg/kg on lipid and carbohydrate metabolism was studied in Wistar rats with experimental hyperlipidemia and diabetes mellitus. This tripeptide in a dose of 2000 MUg/kg produced a hypolipidemic effect on atherogenic lipoproteins, decreased the intensity of LPO, improved the state of the antioxidant system, and normalized the content of HDL. Treatment with this tripeptide had a hypolipidemic effect and reduced the severity of specifi c morphofunctional changes in the pancreatic and hepatic tissue. PMID- 24771372 TI - Comparative activity of proline-containing dipeptide noopept and inhibitor of dipeptidyl peptidase-4 sitagliptin in a rat model of developing diabetes. AB - Developing diabetes was modeled on adult male Wistar rats by repeated intraperitoneal injections of streptozotocin in a subdiabetogenic dose of 30 mg/kg for 3 days. Proline-containing dipeptide drug Noopept or a standard diabetic drug dipeptidyl peptidase-4 inhibitor sitagliptin was administered per os in a dose of 5 mg/kg before each injection of the toxin and then for 16 days after streptozotocin course. In active control group, spontaneously increase glucose level and reduced tolerance to glucose load (1000 mg/kg intraperitoneally) were observed on the next day after the third administration of toxin. Basal glucose level decreased by day 16, but glucose tolerance remained impaired. Noopept normalized the basal blood glucose level and tolerance to glucose load on the next day after administration of streptozotocin. The effect of Noopept persisted to the end of the experiment. At early terms of the experiment, sitagliptin was somewhat superior to Noopept by the effect on baseline glucose level, but was inferior by the influence on glucose tolerance.. By the end of the experiment, Noopept significantly (by 2 times) surpassed sitagliptin by its effect on glucose tolerance. PMID- 24771373 TI - Effects of 3-hydroxypyridine derivatives and succinic acid on endometrial leukocyte infiltration, cytokinemia and related affective symptoms during exacerbation of the chronic inflammation of the uterus and adnexa. AB - We studied the effects of original Russian derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) on the time course of endometrial leukocyte infiltration, blood levels of inflammatory cytokines (IL 1beta and TNF-alpha), and indicators of affective status in women with exacerbation of the chronic inflammation of the uterus and adnexa. It was found that emoxipine, reamberin, and mexidol included in the complex therapy corrects anxiety and depressive disorders depending on the degree of reduction of endometrial leukocyte infiltration and blood levels of inflammatory cytokines. Derivatives of 3-hydroxypyridine (emoxipine and mexidol) exhibited efficiency, which were superior to derivative of succinic acid (reamberin) in the degree of reduction in endometrial leukocyte and neutrophyl infiltration and in severity of anxiety and depressive disorders. Mexidol, a 3-hydroxypyridine and succinic acid derivative, was most effective and surpassed emoxipine by the degree of reduction of inflammatory cytokine level in the blood and the severity of affective anxiety symptoms in women with exacerbation of the chronic inflammation of the uterus and adnexa. PMID- 24771374 TI - Possibility of usage of aminostigmine structural analogue for the treatment of toxic cognitive disorders. AB - We studied the effects of 2-(hexyl(methyl)amino)methyl)pyridyl-3-dimethyl carbamate (OPDC), a structural analogue of aminostigmine oxalate, on memory formation in rats with toxic scopolamine-induced amnesia. It was shown that OPDC in non-toxic doses ((1)/215 LD50) has significant anti-amnesic action. Ipidacrine and galantamine in the doses similar to toxic doses ((1)/17 and (1)/6 of LD50, respectively) induced the retention of memory trace. Administration of aminostigmine ((1)/11 of LD50) induced unstable anti-amnesic effect in the model of scopolamine-induced amnesia. PMID- 24771375 TI - Generation of recombinant extracellular fragment of vascular endothelial growth factor receptor 2 and specific monoclonal antibodies to this receptor. AB - cDNA extracellular Ig-like domains I-III of vascular endothelial growth factor receptor 2 (VEGFR2) was cloned in an expressing vector pET_32a. Western blotting showed immunochemical identity of recombinant VEGFR2I-III produced by prokaryotic expression system to the native receptor. BALB/c mice were immunized with VEGFR2I III for obtaining specific antibodies to VEGFR2. Hybridomas producing monoclonal antibodies were selected by ELISA, Western blotting, and immunocytochemical assay. Thus, we obtained hybridoma producing monoclonal antibodies to VEGFR2 that selectively interact with both recombinant and native extracellular fragment of the receptor. PMID- 24771376 TI - Comparative evaluation of opioid-induced changes in immune reactivity of CBA mice. AB - Comparison of IgM and IgG-humoral immune response of CBA mice immunized with SE (5 * 10(8) cells) to activation of MU- (DAGO, 100 MUg/kg) and delta2- (DSLET, 100 MUg/kg) opioid receptors was studied. Different effects of opioids on IgM and IgG antibody production and peripheral blood and spleen levels of CD4(+) and CD8(+) subpopulations were detected at the peak of immune response under these conditions. PMID- 24771377 TI - Effects of S. officinalis L. radix triterpene glycosides on innate immunity factors. AB - The effects of triterpene glycosides (saponins) extracted from Saponaria officinalis L. radices, on the cellular and humoral innate immunity factors were studied. Saponins stimulated the phagocytic, bactericidal, and adhesion activities of polymorphonuclear leukocytes. Optimal conditions of saponin treatment (dose and duration) were determined for mice. Saponins promoted the maturation of human peripheral blood dendritic cells, which was proven by high expression of CD83 (terminal differentiation marker) and CD86 (bone-stimulating molecule) and of HLA-DR and HLA-ABC molecules on the cell membrane. Saponins modulated the production of TNF-alpha, IL-1beta, IL-4, IL-6, and IFN-gamma in cultured peripheral blood intact cells. The results help to understand some mechanisms of the effects of saponins extracted from Saponaria officinalis L. radix on the cellular and humoral factors of innate immunity and demonstrate good prospects of their practical use. PMID- 24771378 TI - Transplanted tumor growth inhibition by functionalized short single-walled carbon nanotubules. AB - The effects of short single-walled carbon nanotubules functionalized by COOH- and NH2- containing groups (NT-COOH and NT-NH2), on the dynamics of transplanted Pliss lymphosarcoma growth were studied after tumor cell preincubation with nanotubules and after injection of nanotubules into the developing tumor. Tumor growth was inhibited and the lifespan of rats with tumors was prolonged by 1.7 times after transplantation of tumor preincubated with NT-NH2, while NT-COOH caused no effect of this kind. Intratumor injection of NT-NH2 inhibited tumor growth over 3 weeks and prolonged animal lifespan. PMID- 24771379 TI - Pacemakers in extrahepatic biliary ducts. AB - Pacemaker cells in the biliary system were studied by using electromyographic and histological methods. The pacemaker cells of the duodenal-biliary complex are located in the bile duct (predominantly, in its proximal part). They are characterized with enhanced spontaneous spike and slow-wave electrical activity. The pacemaker cells organize the sequential motor activity of the proximal and distal portions of ductus choledochus, with subsequent involvement of the duodenum into this activity. PMID- 24771380 TI - Apoptosis regulator proteins: basis for the development of innovation strategies for the treatment of rheumatoid arthritis in patients of different age. AB - Apoptosis markers (p53, PUMA, p21, and Mdm2) were studied in patients with rheumatoid arthritis at the early and late stages of disease on bone marrow smears and frozen sections of the articular synovial membrane. The target molecules were found in all patients. The early stage was characterized by maximum expression of antiapoptotic (Mdm2) molecule and the minimum expression of proapoptotic molecules (p53, PUMA, and p21). The proapoptotic proteins predominated in patients with the late stage of rheumatoid arthritis, while the antiapoptotic factor (Mdm2) was depressed significantly. These data suggested total suppression of apoptosis at the early stage of rheumatoid arthritis and recommended the Mdm2 molecule as a prospective target for the development of new drugs. PMID- 24771381 TI - Bioimpedancemetry in the diagnostics of inflammatory process in the mammary gland. AB - The changes in mammary gland bioimpedance were examined in the dynamics of the inflammatory process. Bioimpedance of affected gland was 2-3-fold lower than that of the contralateral one; normally, this difference did not exceed 10%. The phases of inflammation development were paralleled by changes in bioimpedance. During wound epithelization, impedance increased and approximated the normal level. Further increase of bioimpedance by more than 30% and its stabilization at this level attested to recurrence of inflammation, while its irreversible drop indicated devitalization the tissues. The diagnostic criterion attesting to the development of local inflammatory reaction is deviation of bioimpedance in the impaired area by more than 15% from that of the adjacent intact site. PMID- 24771382 TI - Interactions of quantum dots with donor blood erythrocytes in vitro. AB - The effects of quantum dots CdSe/ZnS-mercaptopropionic acid, (CdSe/CdZnS)ZnS polyT, and CdSeCdSZnS/polyT/SiO2-NH2 on human erythrocytes were studied. The nanomaterials reduced signifi cantly the erythrocyte sedimentation rate and modified the erythrocyte membrane resistance to induced (acid and hypo-osmotic) hemolysis. Evaluation of the erythrocyte morphology by atomic force microscopy in the control and after exposure to quantum dots showed significant differences in erythrocyte size and changes in their morphology as a result of exposure to the nanomaterials. PMID- 24771383 TI - Antiproliferative activity of zinc and metal alloy nanoparticles in transplanted sarcomas. AB - The effects of zinc and metal alloy (Cu, Zn, and Fe) nanoparticles on transplantation capacity of tumors (mouse sarcoma 37, rat sarcoma 45 and Pliss lymphosarcoma) and the levels of exogenous Zn in tumor and non-tumor tissues of mice were studied. Preincubation (30 min, 37 degrees C) of sarcoma 37 cells with zinc nanoparticles and sarcoma 45 with alloy nanoparticles before transplantation completely prevented the tumor development in animals. Preincubation of Pliss lymphosarcoma cells with nanoparticles led to tumor growth inhibition and prolongation of the animal lifespan. The effect of metal nanoparticles was presumably explained by their local destructive effect on tumor cells. Zinc nanoparticles injected into the tumor concentrated in it after 4 days and were not detected in the adjacent normal tissue. Selective accumulation of metal nanoparticles in tumor tissue and their antiproliferative effect suggested their use as antitumor drugs. PMID- 24771384 TI - Morphological and phenotypical characteristics of human osteoblasts after short term space mission. AB - Morphological and phenotypical signs of cultured readaptation osteoblasts were studied after a short-term space mission. The ultrastructure and phenotype of human osteoblasts after Soyuz TMA-11 space flight (2007) were evaluated by scanning electron microscopy, laser confocal microscopy, and ELISA. The morphofunctional changes in cell cultures persisted after 12 passages. Osteoblasts retained the drastic changes in their shape and size, contour deformation, disorganization of the microtubular network, redistribution of organelles and specialized structures of the plasmalemma in comparison with the ground control cells. On the other hand, the expression of osteoprotegerin and osteocalcin (bone metabolism markers) increased; the expression of bone resorption markers ICAM-1 and IL-6 also increased, while the expression of VCAM-1 decreased. Hence, space flight led to the development of persistent shifts in cultured osteoblasts indicating injuries to the cytoskeleton and the phenotype changes, indicating modulation of bone metabolism biomarkers. PMID- 24771385 TI - Microcirculation and structural reorganization of the bladder mucosa in chronic cystitis under conditions of ozone therapy. AB - Structural reorganization of the bladder mucosa in chronic cystitis and its correction by ozone therapy were studied. A relationship between the epithelial layer restructuring of different kinds (dystrophy, metaplasia, and degeneration), level of cell proliferation, and ultrastructural organization of urotheliocytes was detected. This complex of structural reactions was combined with dysregulation of tissue bloodflow in the bladder mucosa, shown by laser Doppler flowmetry. Positive structural changes were most marked in intravesical and less so in parenteral ozone therapy added to the therapeutic complex and manifested in reduction of inflammation and alteration in parallel with more intense reparative reactions. A special feature of parenteral ozone therapy was a significant improvement of microcirculation in the bladder mucosa. PMID- 24771386 TI - Perfusion scintigraphy method for the diagnosis of pulmonary circulation disorders in rats during disease simulation. AB - We proposed a modified method for radiological studies of the lungs in small laboratory animals applicable for studies of vascular dysfunctions at different stages of experimental disease formation - chronic obstructive disease of the lungs and pulmonary artery thromboembolism. PMID- 24771387 TI - Morphofunctional analysis of human platelets by vital staining. AB - We developed a method for differential staining of human platelets preserving their functional activity based on vital fl uorochrome stains trypafl avin and acridine orange. Platelets stained with trypafl avin and acridine orange exhibited under a fl uorescent microscope green fl uorescence of the cytoplasm and red-orange fl uorescence of the granules. Morphofunctional analysis of platelets was carried out on the cells from donor blood, donor concentrated platelets, and cells from hematological patients and patients with thromboembolic complications. Populations with low (16 %) and high (2 %) morphofunctional activities of platelets were detected among donors. The morphofunctional parameters of platelets were sharply reduced in hematological patients with the hemorrhagic syndrome and elevated signifi cantly in patients with thromboembolic complications in comparison with donors. The method seemed to be effective for evaluating the platelet quality in donor and patients' blood components. PMID- 24771388 TI - Experimental model of rat aorta angioplasty with a Paclitaxel releasing balloon catheter. AB - We present an original and safe experimental model of the rat aorta angioplasty with a paclitaxel-releasing balloon catheter. No toxic effects of the drug on experimental animals were detected. PMID- 24771391 TI - Sharp intense line in the bioluminescence emission of the firefly. AB - Numerous investigations have been carried out on the spectral distribution of the light of different species of fireflies. Here we record the emission spectrum of the Indian species of the firefly Luciola praeusta Kiesenwetter 1874 (Coleoptera : Lampyridae : Luciolinae) on a color film. Green and red color-sectors, with an intense yellow one in between, appear in this spectrum. Intensity profile of this spectrum reveals a hitherto undetected strong narrow yellow line, which lies within the full-width-at-half maximum (FWHM) of the intensity profile. The spectrum recorded in a high-resolution spectrometer confirms the presence of this sharp intense line. This finding lends support to an earlier drawn analogy between the in vivo emission of the firefly and laser light. PMID- 24771392 TI - Plasma and dietary carotenoids and vitamins A, C and E and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition. AB - Carotenoids and vitamins A, C and E are possibly associated with a reduced colorectal cancer (CRC) risk through antioxidative properties. The association of prediagnostic plasma concentrations and dietary consumption of carotenoids and vitamins A, C and E with the risk of colon and rectal cancer was examined in this case-control study, nested within the European Prospective Investigation into Cancer and Nutrition study. Plasma concentrations of carotenoids (alpha- and beta carotene, canthaxanthin, beta-cryptoxanthin, lutein, lycopene, zeaxanthin) and vitamins A (retinol), C and E (alpha-, beta- and gamma- and delta-tocopherol) and dietary consumption of beta-carotene and vitamins A, C and E were determined in 898 colon cancer cases, 501 rectal cancer cases and 1,399 matched controls. Multivariable conditional logistic regression models were performed to estimate incidence rate ratios (IRR) and corresponding 95% confidence intervals (CIs). An association was observed between higher prediagnostic plasma retinol concentration and a lower risk of colon cancer (IRR for highest quartile = 0.63, 95% CI: 0.46, 0.87, p for trend = 0.01), most notably proximal colon cancer (IRR for highest quartile = 0.46, 95% CI: 0.27, 0.77, p for trend = 0.01). Additionally, inverse associations for dietary beta-carotene and dietary vitamins C and E with (distal) colon cancer were observed. Although other associations were suggested, there seems little evidence for a role of these selected compounds in preventing CRC through their antioxidative properties. PMID- 24771393 TI - Increased susceptibility of Staphylococcus aureus small colony variant to tea tree oil: comment on Cuaron et al. 2014. PMID- 24771394 TI - The proceedings of the California Stem Cell Agency. PMID- 24771395 TI - How California Institute for Regenerative Medicine research programs support science and regulatory policy. PMID- 24771396 TI - Brain. Editorial. PMID- 24771397 TI - Magic shotgun for Parkinson's disease? PMID- 24771398 TI - To know or not to know: does EEG monitoring in the paediatric intensive care unit add anything besides cost? PMID- 24771399 TI - Enabling motor control in chronic spinal cord injury: found in translation. PMID- 24771400 TI - Predictors of early-onset cognitive impairment. PMID- 24771401 TI - Effects of patient-, environment- and medication-related factors on high-alert medication incidents. AB - OBJECTIVE: To measure the rate of medication incidents associated with the prescription and administration of high-alert medications and to identify patient , environment- and medication-related factors associated with these incidents. DESIGN: A retrospective chart audit design was conducted of medical records for patient admissions from 1 January 2010 to 31 December 2010. SETTING: Five practice settings (cardiac care, emergency care, intensive care, oncology care and perioperative care) at a public teaching hospital in Melbourne, Australia. PARTICIPANTS: Patients were considered for inclusion if they were prescribed at least one high-alert medication and if they were admitted to one of five practice settings. MAIN OUTCOME MEASURES: High-alert prescribing and administering incidents were measured in each of the five practice settings. Generalized linear mixed modeling was used for data analysis. RESULTS: There were 6984 opportunities for high-alert medication incidents across the five clinical settings. The overall medication incident rate was 1934/6984 (27.69%). There were 1176 prescribing incidents (16.84%) and 758 administering incidents (10.85%). Statistical modeling showed that, in each of the five clinical settings, an increased number of ward transfers was associated with increased odds of prescribing incidents. In addition, statistical modeling demonstrated that an increased number of ward transfers was associated with increased odds of administering incidents in emergency care and perioperative care. CONCLUSIONS: Complex relationships were found in managing high-alert medications in specialty clinical settings. Employing measures to address patients' movements across ward settings can reduce high-alert medication incidents and improve quality of care. PMID- 24771402 TI - Improved incident reporting following the implementation of a standardized emergency department peer review process. AB - OBJECTIVE: Incident reporting is an important component of health care quality improvement. The objective of this investigation was to evaluate the effectiveness of an emergency department (ED) peer review process in promoting incident reporting. DESIGN: An observational, interrupted time-series analysis of health care provider (HCP) incident reporting to the ED during a 30-month study period prior to and following the peer review process implementation and a survey based assessment of physician perceptions of the peer review process' educational value and its effectiveness in identifying errors. SETTING: Large, urban, academic ED. PARTICIPANTS AND INTERVENTIONS: HCPs were invited to participate in a standardized, non-punitive, non-anonymous peer review process that involved analysis and structured discussion of incident reports submitted to ED physician leadership. MAIN OUTCOME MEASURES: Monthly frequency of incident reporting by HCPs and physician perceptions of the peer review process. RESULTS: HCPs submitted 314 incident reports to the ED over the study period. Following the intervention, frequency of reporting by HCPs within the hospital increased over time. The frequencies of self-reporting, reporting by other ED practitioners and reporting by non-ED practitioners within the hospital increased compared with a control group of outside HCPs (P = 0.0019, P = 0.0025 and P < 0.0001). Physicians perceived the peer review process to be educational and highly effective in identifying errors. CONCLUSIONS: The implementation of a non-punitive peer review process that provides timely feedback and is perceived as being valuable for error identification and education can lead to increased incident reporting by HCPs. PMID- 24771403 TI - Dosing of chemotherapy in obese and cachectic patients: results of a national survey. AB - BACKGROUND: It is not unusual to find obese and cachectic patients in the hematology oncology setting. However, information on dosage in these groups is scarce. OBJECTIVE: The objectives of our study were to explore the dosing strategies applied in the treatment of obese and cachectic cancer patients and to determine whether these strategies are applied in clinical trials. SETTING: Members of the Spanish Group for the Development of Hematology-Oncology Pharmacy (GEDEFO). METHODS: We invited all cancer hospital pharmacists to participate in a survey. MAIN OUTCOME MEASURE: Descriptive statistics of the dosing strategies approaches. RESULTS: We invited 159 eligible hospitals to participate, and 38 responded to the survey. A total of 50 surveys were received: different strategies were applied by different physicians from the same hospital and by hematology and oncology departments. Body mass index was used to define obesity and cachexia in 40 and 30 % of the cases, respectively. Capping the body surface area (BSA) was the approach most commonly followed (64.1 %) in obese patients, whereas no specific approach was adopted in cachectic patients. In hematology patients, the BSA calculation was based on ideal body weight or adjusted body weight in 16.0 % of cases (n = 2) and 50.0 % of cases (n = 6), respectively; in oncology patients, use of adjusted or ideal body weight was negligible. Actual body weight was the main approach in obese patients (35 surveys) and cachectic patients (48 surveys). Creatinine clearance was assessed mainly using the Cockcroft and Gault equation (around 76.0 % of responses). As for clinical trials, 64.1 % of the respondents (n = 25 hospitals) considered the criteria from each clinical trial individually. CONCLUSIONS: Dose adjustments are more frequent in obese patients than in cachectic patients. In cancer oncology patients, dose is adjusted mainly by hematology and hematopoietic cell transplant teams. Capping BSA is the most frequent strategy, followed by calculating actual body weight. PMID- 24771404 TI - Incorporating reference in parallel imaging and compressed sensing. AB - PURPOSE: To develop a new compressed sensing parallel imaging technique called READ-PICS that can effectively incorporate prior information from a reference scan for MR image reconstruction from highly undersampled multichannel measurements. METHODS: READ-PICS incorporates information from a high-spatial resolution reference prior using the generalized series model, to achieve increased image sparsity and mitigated noise amplification simultaneously. To further improve the ill-conditioning of the parallel imaging system, an annular area in the central residual k-space is used for calibration. Additionally, the mixed L1-L2 norm of the coefficients from the prior component and residual component is used to enforce joint sparsity. RESULTS: The evaluations on parametric imaging and multiscan experiment demonstrate superior performance of READ-PICS in terms of detail preservation and noise suppression compared to state of-the-art technique, L1-Iterative self-consistent parallel imaging reconstruction, and prescan required method, correlation imaging. CONCLUSIONS: The proposed method can significantly increase signal sparsity and improve the ill-conditioning of the parallel imaging system using reference adaptive regularization. This technique can be easily adapted to other imaging applications where multiple images need to be acquired sequentially and a reference prior is also available. PMID- 24771405 TI - Knockdown of LYRM1 rescues insulin resistance and mitochondrial dysfunction induced by FCCP in 3T3-L1 adipocytes. AB - LYR motif-containing 1 (LYRM1) was recently discovered to be involved in adipose tissue homeostasis and obesity-associated insulin resistance. We previously demonstrated that LYRM1 overexpression might contribute to insulin resistance and mitochondrial dysfunction. Additionally, knockdown of LYRM1 enhanced insulin sensitivity and mitochondrial function in 3T3-L1 adipocytes. We investigated whether knockdown of LYRM1 in 3T3-L1 adipocytes could rescue insulin resistance and mitochondrial dysfunction induced by the cyanide p-trifluoromethoxyphenyl hydrazone (FCCP), a mitochondrion uncoupler, to further ascertain the mechanism by which LYRM1 is involved in obesity-associated insulin resistance. Incubation of 3T3-L1 adipocytes with 1 uM FCCP for 12 h decreased insulin-stimulated glucose uptake, reduced intracellular ATP synthesis, increased intracellular reactive oxygen species (ROS) production, impaired insulin-stimulated Glucose transporter type 4 (GLUT4) translocation, and diminished insulin-stimulated tyrosine phosphorylation of Insulin receptor substrate-1 (IRS-1) and serine phosphorylation of Protein Kinase B (Akt). Knockdown of LYRM1 restored insulin stimulated glucose uptake, rescued intracellular ATP synthesis, reduced intracellular ROS production, restored insulin-stimulated GLUT4 translocation, and rescued insulin-stimulated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt in FCCP-treated 3T3-L1 adipocytes. This study indicates that FCCP-induced mitochondrial dysfunction and insulin resistance are ameliorated by knockdown of LYRM1. PMID- 24771406 TI - TNF-alpha, IL-6, and leptin increase the expression of miR-378, an adipogenesis related microRNA in human adipocytes. AB - Obesity has become a global public health problem associated with complications including type 2 diabetes, cardiovascular disease, and several cancers. Adipocyte differentiation (adipogenesis) plays an important role in obesity and energy homeostasis. Adipose tissue secretes multiple cytokines and adipokines which can cause the complications of obesity, especially insulin resistance. TNF-alpha, IL 6, leptin, and resistin have been identified as the main regulators of obesity and insulin activity. miR-378 is highly induced during adipogenesis and has been reported to be positively regulated in adipogenesis. In the current study, matured human adipocytes were treated with TNF-alpha, IL-6, leptin, or resistin on the 15th day after the induction of human pre-adipocyte differentiation. We demonstrated that TNF-alpha, IL-6, and leptin upregulated miR-378 expression indicating that miR-378 probably is a novel mediator in the development of insulin resistance related to obesity. PMID- 24771407 TI - Bioinformatics approach to evaluate differential gene expression of M1/M2 macrophage phenotypes and antioxidant genes in atherosclerosis. AB - Atherosclerosis is a pro-inflammatory process intrinsically related to systemic redox impairments. Macrophages play a major role on disease development. The specific involvement of classically activated, M1 (pro-inflammatory), or the alternatively activated, M2 (anti-inflammatory), on plaque formation and disease progression are still not established. Thus, based on meta-data analysis of public micro-array datasets, we compared differential gene expression levels of the human antioxidant genes (HAG) and M1/M2 genes between early and advanced human atherosclerotic plaques, and among peripheric macrophages (with or without foam cells induction by oxidized low density lipoprotein, oxLDL) from healthy and atherosclerotic subjects. Two independent datasets, GSE28829 and GSE9874, were selected from gene expression omnibus (http://www.ncbi.nlm.nih.gov/geo/) repository. Functional interactions were obtained with STRING (http://string db.org/) and Medusa (http://coot.embl.de/medusa/). Statistical analysis was performed with ViaComplex((r)) (http://lief.if.ufrgs.br/pub/biosoftwares/viacomplex/) and gene score enrichment analysis (http://www.broadinstitute.org/gsea/index.jsp). Bootstrap analysis demonstrated that the activity (expression) of HAG and M1 gene sets were significantly increased in advance compared to early atherosclerotic plaque. Increased expressions of HAG, M1, and M2 gene sets were found in peripheric macrophages from atherosclerotic subjects compared to peripheric macrophages from healthy subjects, while only M1 gene set was increased in foam cells from atherosclerotic subjects compared to foam cells from healthy subjects. However, M1 gene set was decreased in foam cells from healthy subjects compared to peripheric macrophages from healthy subjects, while no differences were found in foam cells from atherosclerotic subjects compared to peripheric macrophages from atherosclerotic subjects. Our data suggest that, different to cancer, in atherosclerosis there is no M1 or M2 polarization of macrophages. Actually, M1 and M2 phenotype are equally induced, what is an important aspect to better understand the disease progression, and can help to develop new therapeutic approaches. PMID- 24771408 TI - Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. AB - BACKGROUND: Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. OBJECTIVES: To assess the effectiveness and safety of early initiation of EPO or darepoetin (initiated before eight days after birth) in reducing red blood cell (RBC) transfusions in preterm and/orlow birth weight infants. SEARCH METHODS: The Cochrane Library, MEDLINE, EMBASE, CINAHL, reference lists of identified trials and reviews, Pediatric Academic Societies Annual meetings 2000 to 2013 (Abstracts2View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp) were searched in July 2013. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of early (< eight days of age) initiation of EPO treatment versus placebo or no intervention in preterm and/or low birth weightinfants. DATA COLLECTION AND ANALYSIS: The methods of the Neonatal Cochrane Review Group were used. MAIN RESULTS: The updated review includes 27 studies enrolling 2209 infants. One study enrolling infants at a mean age of > eight days and one duplicate publication were excluded. One new study using darepoetin was identified.Early EPO reduced the risk of the 'use of one or more RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.73 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I(2) = 54% for both; number needed to treat to benefit (NNTB) 7, 95% CI 6 to 10; 16 studies, 1661 infants).The total volume of RBCs transfused per infant was reduced (typical mean difference (MD) 7 mL/kg, 95% CI -12 to - 2; I(2) = 63%; 7 studies, 581 infants). The number of RBC transfusions per infant was minimally reduced (typical MD -0.27, 95% CI -0.42 to -0.12; I(2) = 64%; 13 studies, 951 infants). The number of donors to whom the infants were exposed was significantly reduced (MD-0.54, 95% CI -0.89 to -0.20; I(2) = 0%; 3 studies, 254 infants).There was a non-significant increase in the risk of stage >= 3 retinopathy of prematurity (ROP) with early EPO (typical RR 1.37, 95% CI 0.87 to 2.17; I(2) = 0%; typical RD 0.03, 95% CI -0.01 to 0.06; I(2) = 29%; 7 studies, 801 infants). A post hoc analysis including all studies that reported on ROP stage >= 3, regardless of the age of the infant when EPO treatment was started, showed a significantly increased typical RR of 1.48 (95% CI 1.02 to 2.13; P = 0.04; I(2) = 0%) and typical RD of 0.03 (95% CI 0.00 to 0.06; P = 0.03; I(2) = 50%; 10 studies, 1303 infants) with a number needed to treat to harm (NNTH) of 33 (95% CI 17 to infinity). In an Italian study in which the authors compared the use of early intravenous EPO with subcutaneous EPO the overall incidence of stage >= 3 was 15%, similar to the incidence of 17% in the study by Romagnoli and co-workers.The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months varied. AUTHORS' CONCLUSIONS: Early administration of EPO reduces the use of RBC transfusions, the volume of RBCs transfused, and donor exposure after study entry. The small reductions are likely to be of limited clinical importance. Donor exposure is probably not avoided since all but one study included infants who had received RBC transfusions prior to trial entry. In this update there was no significant increase in the rate of ROP (stage >= 3) for studies that initiated EPO treatment at less than eight days of age. In a post hoc analysis including all studies that reported on ROP stage >= 3 regardless of age at initiation of treatment there was an increased risk of ROP. The rates for mortality and morbidities including intraventricular haemorrhage and necrotizing enterocolitis were not significantly changed by early EPO treatment. Neurodevelopmental outcomes at 18 to 22 months vary in the studies published to date. Ongoing research should deal with the issue of ROP and evaluate current clinical practice that will limit donor exposure. Due to the limited benefits and the possibly increased risk of ROP, administration of EPO is not recommended. Darbepoetin requires further study. The possible neuroprotective role of EPO in neonates will be reviewed in separate Cochrane reviews. PMID- 24771409 TI - Does the metal content in soil around a pregnant woman's home increase the risk of low birth weight for her infant? AB - Low birth weight (LBW) is associated with a number of maternal environmental exposures during pregnancy. This study explored the association between soil metal concentrations around the home where the mother lived during pregnancy and the outcome of LBW. We used a retrospective cohort of 9,920 mother-child pairs who were insured by Medicaid during pregnancy and lived in ten residential areas, where we conducted soil sampling. We used a grid that overlaid the residential areas and collected soil samples at the grid intersections. The soil was analyzed for the concentration of eight metals [arsenic (As), barium (Ba), chromium (Cr), copper (Cu), lead (Pb), manganese (Mn), nickel (Ni), and mercury (Hg)], and we then used Bayesian Kriging to estimate the concentration at the actual maternal addresses, since we had the GIS coordinates of the homes. We used generalized additive modeling, because the metal concentrations had nonlinear associations with LBW, to develop the best fitting multivariable model for estimating the risk of LBW. The final model showed significant associations for female infants, maternal smoking during pregnancy, non-white mothers, Cu, and As with LBW. The As variable was nonlinear in relation to LBW, and the association between higher concentrations of As with LBW was strong (p = 0.002). We identified a statistically significant association between soil concentrations of arsenic around the home of pregnant women and an increased risk of LBW for her infant. PMID- 24771410 TI - Estimated risk of cancer transmission from organ donor to graft recipient in a national transplantation registry. AB - BACKGROUND: Transplanted organs carry the risk of inadvertent donor cancer transmission. Some cancers in organ donors have been classified as being associated with a high or unacceptable risk, but the evidence for such recommendations is scanty. METHODS: The risk of cancer transmission from donors characterized as high or unacceptable risk was studied by analysing transplant and cancer registry data. Donors and recipients from England (1990-2008) were identified from the UK Transplant Registry. Cancer details were obtained from cancer registries and classified using guidelines from the Council of Europe and Organ Procurement and Transplantation Network/United Network for Organ Sharing. RESULTS: Of 17,639 donors, 202 (1.1 per cent) had a history of cancer, including 61 donors with cancers classed as having an unacceptable/high risk of transmission. No cancer transmission was noted in 133 recipients of organs from these 61 donors. At 10 years after transplantation, the additional survival benefit gained by transplanting organs from donors with unacceptable/high-risk cancer was 944 (95 per cent confidence interval (c.i.) 851 to 1037) life-years, with a mean survival of 7.1 (95 per cent c.i. 6.4 to 7.8) years per recipient. CONCLUSION: Strict implementation of present guidelines is likely to result in overestimation of cancer transmission risk in some donors. Organs from some donors with cancers defined as unacceptable/high risk can be used safely. PMID- 24771411 TI - Impact of chiasma opticum malformations on the organization of the human ventral visual cortex. AB - Congenital malformations of the optic chiasm, such as enhanced and reduced crossing of the optic nerve fibers, are evident in albinism and achiasma, respectively. In early visual cortex the resulting additional visual input from the ipsilateral visual hemifield is superimposed onto the normal retinotopic representation of the contralateral visual field, which is likely due to conservative geniculo-striate projections. Counterintuitively, this organization in early visual cortex does not have profound consequences on visual function. Here we ask, whether higher stages of visual processing provide a correction to the abnormal representation allowing for largely normal perception. To this end we assessed the organization patterns of early and ventral visual cortex in five albinotic, one achiasmic, and five control participants. In albinism and achiasma the mirror-symmetrical superposition of the ipsilateral and contalateral visual fields was evident not only in early visual cortex, but also in the higher areas of the ventral processing stream. Specifically, in the visual areas VO1/2 and PHC1/2 no differences in the extent, the degree of superposition, and the magnitude of the responses were evident in comparison to the early visual areas. Consequently, the highly atypical organization of the primary visual cortex was propagated downstream to highly specialized processing stages in an undiminished and unchanged manner. This indicates largely unaltered cortico-cortical connections in both types of misrouting, i.e., enhanced and reduced crossing of the optic nerves. It is concluded that main aspects of visual function are preserved despite sizable representation abnormalities in the ventral visual processing stream. PMID- 24771412 TI - Development of an easy method to test for HER2 in breast cancer using dual-color in situ hybridization. AB - BACKGROUND: Although human epidermal growth factor receptor 2 (HER2) is a significant clinical biomarker for breast cancer, the HER2 testing involves a complicated evaluation process. We devised an easy method for HER2 gene testing and investigated its utility. METHODS: HER2 testing was performed by immunohistochemistry (IHC) and dual-color in situ hybridization (DISH) on surgical specimens from 50 patients with invasive breast cancer. DISH was evaluated by two methods. One was the DISH count method in which the HER2 and CEP17 signals were counted and the HER2/CEP17 signal ratio was calculated. The other was the DISH-easy method in which pathologists only observed slices without counting the signals. The DISH-easy method was performed by two pathologists. We analyzed the correlations between the DISH-easy method and the DISH count method by each pathologist and calculated the inter-observer concordance rate of the DISH-easy method. RESULTS: The results from two pathologists using the DISH-easy method corresponded to the IHC results (P < 0.01) and the DISH count method results (P < 0.01). All cases determined to be negative using the DISH-easy method were also negative via the DISH count method with a corresponding rate of 100 % for both pathologist A (34/34) and B (32/32). Most of the results for the positive cases also corresponded; the correspondence rate of pathologist A was 100 % (8/8) and 89 % for B (8/9). The inter-observer concordance rate was 81 % (kappa = 0.65). CONCLUSIONS: The DISH-easy method is simple and useful for HER2 testing regardless of proficiency of the evaluators. PMID- 24771413 TI - Functions of volume-sensitive and calcium-activated chloride channels. AB - The review describes molecular and functional properties of the volume regulated anion channel and Ca(2+)-dependent Cl(-) channels belonging to the anoctamin family with emphasis on physiological importance of these channels in regulation of cell volume, cell migration, cell proliferation, and programmed cell death. Finally, we discuss the role of Cl(-) channels in various diseases. PMID- 24771414 TI - Evaluation of a Danish pharmacist student-physician medication review collaboration model. AB - BACKGROUND: Interprofessional collaboration between pharmacists and physicians to conduct joint home medication reviews (HMR) is important for optimizing the medical treatment of patients suffering from chronic illnesses. However, collaboration has proved difficult to achieve. The HMR programme "Medisam" was launched in 2009 at the University of Copenhagen with the aim of "developing, implementing and evaluating a collaboration model for HMRs and medicine reconciliations in Denmark". The Medisam programme involves patients, pharmacy internship students, the (pharmacist) supervisor of the pharmacy students and physicians. OBJECTIVE: To explore if it was possible through the Medisam programme to obtain a fruitful HMR collaboration between pharmacy internship students and physicians as a means to develop HMR collaboration between trained pharmacists and physicians further. SETTING: Ten matching pairs of student physician collaboration were studied across Denmark. METHOD: Semi-structured interviews about existing collaboration were conducted with pharmacy internship students in the HMR programme, their supervisors and physicians partners. The theoretical framework forming the analyses was derived especially from works of Bradley et al. (Res Soc Adm Pharm 8:36-46, 2012), and Snyder et al. (Res Soc Adm Pharm 6:307-23, 2010) on pharmacists/physician collaboration. MAIN OUTCOME MEASURE: The development of inter-professional collaboration between students and physicians according to the three collaboration drivers: trustworthiness, role specification and professional interaction. RESULTS: Full collaboration was not achieved. Physicians found collaboration satisfactory, students however expressed the need of more interaction with physicians. The written collaboration contracts did not ensure a possible need of students to re-negotiate roles and tasks, and did therefore not entirely ensure role specification. Developing mutual professional interdependence through students being recognized by physicians to contribute to improved patient outcomes was also limited. CONCLUSION: Some challenges to fruitful collaboration were identified. Solutions to these challenges include students and their pharmacist supervisors to find ways to present their collaborative needs to physicians and for students to illustrate more explicitly the benefits patient achieve if physicians implement the recommendations of students. PMID- 24771415 TI - An imported case of acute pulmonary coccidioidomycosis in an Italian traveller. AB - Coccidioidomycosis is a fungal infection caused by the Coccidioides species, which is endemic in the deserts of the southwestern region of the United States, northern Mexico, and in some areas of Central and South America. We describe a case of pulmonary coccidioidomycosis in a 49-year-old Italian man who came to our hospital with fever and joint and muscle pain 10 days after his return to Italy from Venezuela. Computer Tomography revealed multiple bilateral pulmonary nodules with mediastinal lymphadenopathy. Pulmonary coccidioidomycosis was diagnosed by a serological test, and fluconazole was immediately started. The patient improved within 2 weeks, with complete clinical recovery after 6 months of therapy. This case appears to be part of a large serologically unconfirmed outbreak. In order to provide early diagnosis and treatment, healthcare providers should be aware of coccidioidomycosis, even in travellers returning home from short trips to endemic areas. PMID- 24771416 TI - Staphylococcus aureus infection of the feet following fish pedicure. AB - We report a case of Staphylococcus aureus infection of the feet that appeared after a "fish pedicure" (immersion of the feet in a tank with the fish Garra rufa, that nibbles off dead skin). Clinical picture was characterized by maceration, purulent discharge, scales, crusts, itching and burning sensation. Bacteriological examinations were positive for Staphylococcus aureus. Mycological examinations were negative. The patient was successfully treated with ciprofloxacin. Only one case of skin foot infection after fish pedicure was reported so far. Fish pedicure can be a potentially dangerous procedure in immunocompromised or diabetic patients. PMID- 24771417 TI - Comparative study of the effects of free bound and carrier protein angiotensin II in experimental hypoglycemia and hyperglycemia. AB - Experimental hypoglycemia and hyperglycemia eliminated the differences in the regulatory functions of free angiotensin II and its complexes with carrier proteins (transport protein BSA and neurospecific protein S100b) in rats. Under these conditions, free and protein-bound angiotensin II primarily suppressed operant drinking behavior and reduced the hypertensive and tachyarrhythmic effects in comparison with control rats. These changes were most pronounced during acute hyperglycemia. We hypothesized that complexes of angiotensin II with functionally different proteins are differentially and simultaneously involved in not only compensation of behavioral and hemodynamic disturbances during acute and/or chronic hypoglycemia and hyperglycemia, but also their transformation into pathological processes mediated by the so-called metabolic memory mechanisms. PMID- 24771418 TI - Changes in feeding behavior, locomotor activity, and metabolism in rats upon modulation of opioid receptors in the gastrointestinal tract. AB - We studied the role of MU-, delta-, and kappa-opioid receptors of the stomach in the regulation of natural feeding behavior, metabolism, and locomotor activity of rats. Locomotor activity (number of crossed squares), food and water intake, oxygen consumption, and carbon dioxide release in animals were estimated in the standard home cage using a Phenomaster device (TSE) for 24 h at 40-min intervals. Administration of a MU-opioid receptor agonist DAMGO suppressed feeding behavior of animals in the light phase, but had little effect on locomotor activity and metabolism. Treatment with a delta-opioid receptor agonist DADLE was followed by the increase in metabolism over 24 h. These changes were accompanied by a decrease in locomotor activity during the light phase and activation of feeding behavior in the transition period. Intragastric administration of a kappa-opioid receptor agonist ICI-204,448 inhibited feeding behavior, metabolism, and locomotor activity of rats only in the nighttime. These data suggest that opioid peptides produced in the stomach during food digestion play an important role in the regulation of food motivation and metabolism in rats. Various subtypes of opioid receptors probably regulate feeding behavior and metabolism of animals in different phases of vital activity. PMID- 24771419 TI - Content of S100b protein, HLDF24 peptide and autoantibodies to these factors as potential biomarkers for arterial hypertension in blood serum of healthy people. AB - The content of S100b protein, HLDF24 peptide, and autoantibodies to these factors in blood serum was measured in healthy individuals (35-64-year-old men and women) with various levels of "normal" BP. Significant differences in the amount of these molecular factors were found in individuals with various categories of BP. We revealed age-related and gender differences in the content of molecular factors in the serum. Our results indicate that variations in the concentration of S100b, HLDF24, and autoantibodies to these factors in blood serum from adult people can serve as a reliable criterion for the risk of arterial hypertension. PMID- 24771420 TI - Processes of DNA methylation are involved in the mechanisms of amnesia induction and conditioned food aversion memory reconsolidation. AB - We studied the role of DNA methylation in the mechanisms of amnesia in edible snails, which was induced by impairment of conditioned food aversion memory reconsolidation with NMDA glutamate receptor antagonist. The effects of DNA methyltransferase inhibitors were shown to depend on the stage of amnesia. At the early stage of amnesia (day 3 after induction), injections of methyltransferase inhibitors in combination with conditioned food stimulus (reminder) were followed by memory recovery. Application of inhibitors in the absence of the reminder was ineffective. Methyltransferase inhibitors were ineffective at the late stage of amnesia (day 10). Our results suggest that the presentation of reminding conditioned stimuli is followed by reactivation of amnesia. Methylation or demethylation of DNA in nerve cells serves as one of the key mechanisms for amnesia. PMID- 24771421 TI - Effect of interleukin-1beta on peripheral blood leukocytes in rats with various behavioral characteristics during acute stress. AB - We studied the effect of a pro-inflammatory cytokine IL-1beta (5 MUg/kg intraperitoneally) on blood leukocytes in Wistar rats various behavioral characteristics during acute emotional stress (1-h immobilization with simultaneous delivery of subthreshold electrocutaneous stimulation). Stress exposure was accompanied by a decrease in the total number of peripheral blood leukocytes in rats. Active animals were characterized by the increase in neutrophil count during stress. The number of eosinophils in passive specimens was shown to decrease under these conditions. Emotional stress was followed by a decrease in the lymphocyte index (by Shaganin) of active rats and increase in the leukocyte intoxication index (according to Kalf-Kalif) of passive specimens. Stress-induced changes in leukocytes differed after pretreatment with IL-1beta. The number of blood leukocytes increased in animals receiving a cytokine injection before stress exposure. Exogenous IL-1beta inverted (in active rats) or prevented (in passive specimens) a change in the percentage of various types of blood leukocytes, which was found after stress exposure. These data contribute to the understanding of peripheral mechanisms for the involvement of immunomodulatory cytokines in the systemic organization of physiological functions in specimens with different prognostic resistance to a similar stress exposure. PMID- 24771422 TI - Cytokine profile of peripheral blood in rats with various behavioral characteristics during acute emotional stress. AB - The cytokine profile of peripheral blood plasma was studied in rats with various behavioral characteristics after acute emotional stress (1-hour immobilization with simultaneous electrocutaneous stimulation). Under basal conditions the concentrations of pro-inflammatory (IL-1alpha, IL-1beta, IL-2, IFN-gamma, and granulocyte-monocyte CSF) and anti-inflammatory cytokines (IL-4 and IL-10) in the blood of active animals were higher than in passive specimens. Acute stress was accompanied by a decrease in the level of plasma cytokines in behaviorally active rats. Stressed passive specimens were characterized by the accumulation of a pro inflammatory cytokine IL-1beta and anti-inflammatory cytokine IL-4 in the peripheral blood. The observed differences in the cytokine profile of the blood in behaviorally passive and active rats under basal conditions and after a negative emotiogenic exposure can be related to the specifics of immune reactions and metabolic processes in animals with different prognostic resistance to similar stress factors. PMID- 24771423 TI - Lipid peroxidation and state of the erythron in newborn rats under normal conditions and impairment of sensorimotor reflexes. AB - Specimens with a stereotypic sensorimotor deficit were revealed among newborn rats due to abnormalities in prenatal ontogeny and birth stress. Genetically determined differences in the total lipid content of blood plasma were found in Wistar and August rat pups. Hence, LPO processes were shown to differ in these animals. August rats with intense lipid metabolism were characterized by higher activity of LPO in comparison with Wistar rats. The increase in LPO was associated with a relatively low activity of antioxidant enzymes. Impairment of sensorimotor reflexes in newborn Wistar and August rats was accompanied by suppression of the erythron and activation of extravascular hemolysis. PMID- 24771424 TI - Structural signs of dynamic state of synaptic contacts between neurotransplant and brain. AB - We studied ultrastructure of synaptic connections between long-living dentate fascia transplants and somatosensory area of the neocortex in rats. Giant synaptic terminals of granular neurons upon contact with unusual neuronal targets in the neocortex reproduced their specific constitutive morphological features. At the same time, developing synapses with signs of active structural and metabolic reorganization were revealed. This is indicative of a dynamic state and instability of functional connections between the transplant and brain despite long time after transplantation. PMID- 24771425 TI - Systemic effects of TRAIL (TNF-related apoptosis-inducing ligand) during acute gamma-irradiation. AB - The effects of TRAIL at various physiological levels were studied on 101/Hf and C3H/Sn mice during acute gamma-irradiation with 750 R. An intravenous injection of TRAIL attenuated the effects of gamma-irradiation on the body weight, subfractions of blood plasma, horizontal and vertical activity in the open-field test, tissue injury in the small intestine and liver, and content of Hassall's corpuscles in the thymus. The degree of these changes differed in mice of study strains. PMID- 24771426 TI - Expression of metabotropic glutamate receptors after hippocampal injury. AB - The expression of metabotropic glutamate receptors (mGluR2, mGluR3, mGluR4, and mGluR5) and dendritic cytoplasmic BC1 RNA in the hippocampus and frontal neocortex of Wistar rats was studied 1 and 4 weeks after intrahippocampal microinjection of kainic acid. The efficiency of glutamatergic transmission was shown to change not only in the injured hippocampus, but also in the neocortex. It was associated with variations in the expression of presynaptic (mGluR2, mGluR3, and mGluR4) and postsynaptic receptors (mGluR5). PMID- 24771427 TI - Effect of N-arachidonoyl dopamine on activity of neuronal network in primary hippocampus culture upon hypoxia modelling. AB - We studied the effect of endocannabinoid N-arachidonoyl dopamine on spontaneous bioelectric activity of cultured hippocampal neurons in a model of hypoxia/reoxygenation. Incubation under hypoxic conditions induced irreversible decrease in spontaneous bioelectric activity of neurons and their death. Application of N-arachidonoyl dopamine during hypoxia and in the post-hypoxic period preserved bioelectric activity and viability of neurons. The protective effect of N-arachidonoyl dopamine was primarily mediated by type I cannabinoid receptors. PMID- 24771428 TI - Signaling events during macrophage activation with Betula pendula roth pectic polysaccharides. AB - We studied the effect of two pectic polysaccharides PS-B1-AG and PS-B2-RG that were contained in total polysaccharides extracted from Betula pendula leaves on NO production by mouse macrophages and the contribution of signaling molecules to macrophage activation by the test substances. Unlike the total sample, pectins produced a NO-stimulating effect on macrophages. The effect of PS-B2-RG (10 MUg/ml) did not differ from the effect of LPS, while PS-B1-AG produced this effect only in a concentration of 20 MUg/ml, which was probably due to differences in the chemical structure of the test substances. The studied pectin polysaccharides activated transcription factor NF-kappaB, kinases p38 and PI3, and cAMP as a negative regulator. These results indicate that Betula pendula polysaccharides are promising substances for creation of immunomodulating drugs. PMID- 24771429 TI - Effects of gonadoliberin analogue triptorelin on the pituitary-testicular complex in neonatal rats. AB - Triptorelin, a synthetic analogue of neurohormone gonadoliberin (gonadotropin releasing hormone, GnRH) administered daily to rats on postnatal days 5-7 suppressed the expression of GnRH receptor in the pituitary gland, but did not change functioning of the pituitary-testicular complex. Administration of triptorelin on postnatal days 12-14 (i.e. during the formation of pulsatile pattern of GnRH secretion and increasing levels of its mRNA receptor in the pituitary gland) had no effect on receptor expression, but increased the levels of luteinizing hormone mRNA in the pituitary gland and the weight of testes. At that time, blood levels of testosterone were lowered, which indicated disturbed pulsatile pattern of GnRH secretion. PMID- 24771430 TI - Parameters of cellular and humoral immunity in experimental hyperthyroidism and its correction. AB - We demonstrate changes in cellular and humoral immunity in animals with experimental hyperthyroidism induced by chronic administration of potassium iodide (KI) solution. KI increased the weight and cellularity of the thymus and spleen and number of antibody-forming cells to sheep red blood cells and modified the relative content of T cell subpopulations. Phytosorption complex LimfoFit modifying cellular and humoral immunity affected only its individual parameters in hyperthyroid animals. PMID- 24771431 TI - Role of the distal fragment of chromosome 13 in the regulation of IL-6-induced effect on the behavior of mice. AB - We studied the effect of IL-6 on the open-field behavior and degree of cataleptic freezing in male AKR/J mice and AKR.CBA-D13Mit76 congenic animals (differing from CBA/Lac mice in the chromosome 13 fragment of 111.35-116.14 Mbp). IL-6 in both doses significantly increased the time of cataleptic freezing. IL-6 in a dose of 3 MUg/kg had a strong inhibitory effect on locomotor activity of AKR.CBA-D13Mit76 males in the open-field test. However, IL-6 in both doses did not modulate locomotor activity and severity of catalepsy in AKR/J males. Our results indicate that the distal fragment of chromosome 13 is involved in the effect of IL-6 on the locomotor activity of mice. PMID- 24771432 TI - Experimental study of combined therapy for malignant glioma. AB - The efficiency of photodynamic therapy with photosensitizer Tiosens (Russia) was evaluated in mono- and combined therapy of rats with malignant gliomas (glioblastoma 101/8, oligodendroglioma 14-4-9, and C6 glioma). The efficiency of photodynamic monotherapy was not high: the animals died from brain edema developing in tumor tissue and in the adjacent normal cerebral tissue. Pathomorphological studies of tumor tissue detected necrosis and apoptosis, destruction of vessels with hemorrhages, and vascular thrombosis. Combined therapy for malignant gliomas including Tiosens photodynamic therapy and subsequent temodal or lysomustine chemotherapy, was the most effective. In glioblastoma 101/8, combined therapy with lysomustine or temodal led to prolongation of the lifespan by 127 %; 62.5 and 50 % rats were cured, respectively; in oligodendroglioma 14-4-9, animal lifespan was prolonged by 80 and 60 %, with 43 and 45 % rats cured, respectively. Glioma C6 was least sensitive to therapy. PMID- 24771433 TI - Mechanisms of reparative regeneration of rat testis after injection of paclitaxel. AB - Population of spermatogonia was reduced in 2, 3, and 6 months after single intravenous injection of antitumor drug paclitaxel in maximum tolerated dose (MTD). The count of Sertoli cell increased in 3 months after the start of the experiment. The maturity of the seminiferous tubule epithelium was lower than in intact rats. Spermatogenesis productivity did not differ from that in intact animals 6 months after start of the experiment. These data indicate that regeneration of the spermatogenous tissue after paclitaxel treatment is realized via renewal of the spermatogenic epithelium, but considering the amount of spermatogonial cell population, the recovery rate would be low. PMID- 24771434 TI - Comparison of the results of PCR analysis of gene expression in breast cancer tissue specimens stabilized in formalin and RNAlater. AB - We compared the results of real-time PCR analysis of gene expression in paired specimens breast cancer tissue fixed in RNAlater (Qiagen) stabilization reagent (FF samples) and in formalin (FFPE samples). A clear-cut linear relationship (correlation coefficient 0.76 +/- 0.07) was detected between the gene expression logarithm values in FF and FFPE samples. This fact suggests that collections of paraffin blocks with formalin-fixed tissue specimens from patients with a many year disease history can be effectively used in modern studies. PMID- 24771435 TI - Reaction of dermal structures to subcutaneous injection of gold nanoparticles to CBA mice. AB - The reactions of dermal structures to subcutaneous injections of gold nanoparticles were studied in CBA mice. Routes of the nanoparticles migration after injection and the mechanisms of their effects on the adjacent tissues were studied. Injected nanoparticles were phagocytosed by macrophages; some of them migrated to lymphoid follicles of the lymph node, while others migrated into blood vessels, where the particles were released from the macrophage cytoplasm into circulating blood. The endothelium was destroyed as a result of the toxic activity of macrophages loaded with nanoparticles. Two mechanisms of angiogenesis inhibition and death of blood vessels in tissues after injection of nanoparticles were distinguished. One mechanism consisted in deactivation of macrophages producing vascular endothelium growth factor inducing the formation of endothelium in the growing blood vessels, but not in direct inhibition of this factor. The other mechanism was realized through direct death of the endothelium in migration of macrophages through the vascular wall. PMID- 24771436 TI - Effects of gold nanoparticles on erythrocyte hemolysis. AB - We studied hemolytic activity of gold nanoparticles added to the whole blood (ex vivo) and of nanoparticles coated and not coated with plasma components on erythrocytes in hypotonic medium (osmotic hemolysis) in vitro. Gold nanoparticles did not stimulate erythrocyte hemolysis after 4-h incubation with the whole blood ex vivo. Hemolysis tended to increase in the presence of small gold nanoparticles (5, 10, 20 nm) at the maximum concentration of 20 MUM (by gold content) used in our study in comparison with the control. This tendency was detected during the 1st hour of the nanoparticles incubation with blood. Gold nanoparticles in the used concentrations (up to 20 MUM of gold) coated with plasma components after preincubation with autologous plasma and nanoparticles without coating caused no osmotic hemolysis of erythrocytes in vitro. PMID- 24771437 TI - Circadian changes in cardiac rhythm structure in decompensated chronic heart failure. AB - Circadian changes in heart rhythm structure were studied in rats with decompensated heart failure (experimental group) using the telemetric system for ECG recording and analysis. Analysis of many-day ECG records showed the predominance of various mechanisms of heart rhythm regulation in experimental and control rats throughout 24 h. More severe dysfunction of neuroautonomic mechanisms of regulation in experimental rats was characterized by a circadian dynamics. Many-fold increase in the number of QTc intervals longer than 220 msec and the Tpeak-Tend, most pronounced in experimental animals at night and in the morning, indicated the maximally high risk of fatal ventricular arrhythmias, leading to sudden cardiac death. PMID- 24771438 TI - Scleractinium coral aquaculture skeleton: a possible 3D scaffold for cell cultures and bone tissue engineering. AB - Cytocompatibility of 5 coral aquaculture skeleton species derived from two families (Acroporidae and Pocilloporidae) was studied over the course of in vitro culturing in continuous human fibroblast culture by the MMT test. Biocompatibility and capacity of scaffold to "transfer" cell cultures (specifically, multipotent mesenchymal stromal cells) to sites of implantation were studied in vivo by subcutaneous implantation of skeletal fragments to rats. All coral skeleton aquaculture specimens were cytocompatible (nontoxic and with surface matrix characteristics satisfactory for cells), biocompatible, and could be tried as 3D matrices for bone tissue engineering. PMID- 24771439 TI - Morphological and functional changes in the spleen of mice offspring at different stages of postnatal development after a single immunostimulating impact on maternal organism in early pregnancy. AB - We studied the effect of short-term activation of the maternal immune system with T-cell mitogen concanavalin A at the early terms of pregnancy on the postnatal development of the spleen in the offspring. It was found that single immunostimulatory exposure prior to the formation of the fetal immune system delays the postnatal development of the spleen until the beginning of puberty and impairs the formation of splenic lymphatic nodules with the predominant development of germinal centers as well as increases the number of mast cells in this organ. PMID- 24771440 TI - Immunotropic effects of hexavalent chromium soluble compounds on the thymus and peripheral blood values in a subacute experiment. AB - Intraperitoneal injections of hexavalent chromium (sodium bichromate) in the concentrations of 0.025 MUg/kg (10-fold lower than MAC; group 1) and 2.5 MUg/kg (10-fold higher than MAC; group 2) to rats in a subacute experiment caused dose dependent morphological changes in the thymus: increased the counts of cells in a state of destruction, macrophages, and plasmocytes and impairs interactions between epithelial reticular cells and lymphocytes with formation of cystic cavities. Proliferation of lymphoblasts and large lymphocytes of the glandular cortical matter was detected in groups 1 and 2, of medium-sized and minor lymphocytes in group 1. Lymph node-like zones with Hassall's corpuscles, pigment foci in the cortical matter, and plasmocytes in the medulla were detected throughout the entire study in controls and in group 1 animals and on days 1 and 7 in group 2. Histiocytes, macrophages, cells in a state of destruction, and siderophages were detected in dilated lymph sinuses. Normal tissue of the gland left lobe in group 2 was completely replaced by lymph node-like zones on days 15 and 30, while the right lobe retained the structure characteristic of the gland. A dose-dependent reduction of the peripheral blood erythrocyte and platelet counts and a decrease in hemoglobin level were observed in experimental animals. On day 30 peripheral blood lympho- and leukocytosis developed at the expense of higher counts of B (CD20) and T lymphocytes (CD3) and their subpopulations - T helpers (CD4), T suppressors (CD8), and immature lymphocytes in group 1 and at the expense of higher counts of only B lymphocytes (CD20) and immature lymphocytes in group 2. PMID- 24771441 TI - Pacemakers of the upper divisions of the digestive tract. AB - Pacemaker cells of the upper portion of the digestive tract were studied by electromyography of various parts of the stomach and duodenum. Pacemaker cells of the stomach were located mainly at the interface between the lesser curvature and cardia and in the proximal part of the antrum and were characterized by high spontaneous slow-wave and spike activities. Antroduodenal coordination contributes to sequential motor activity of the stomach and duodenum. Pacemaker cells were characterized by a specific shape and a lesser number of myofibrils. PMID- 24771442 TI - Objective method for registration of the sniffing component of the search behavior in rabbits subjected to food deprivation. AB - A method for registration of the sniffing component of the search behavior in rabbits subjected to food deprivation is suggested. Pulsed activities of the muscles controlling the movements of the wings of the nostrils and the pressure in the nasal cavity are recorded simultaneously. The method allows accurate artifact-free registration of the time and amplitude parameters of the sniffing component of the search behavior. The registration is realized on an MP150 programmed complex, consisting of EMG 100C biopotential amplifiers and Samba 202 intracavitary pressure recorder. The method allows synchronous real-time registration of pulsed activities of the muscles setting in motion the wings of the nostrils and the changes in the intranasal pressure in the course of search behavior of animals under conditions of food deprivation without limiting their locomotor activity. PMID- 24771443 TI - Mathematical description of human body constitution and fatness. AB - Using mathematical modeling of human body, we demonstrated logical drawbacks of body mass index (BMI1 = M/H(2); A. Quetelet, 1832) and proposed more precise body mass index (BMI2 = M/H(3)) as well as body constitution index (BCI = (M/H(3))(1/2)) and fatness index (FI = M/HC(2)), where M, H, and C are body weight, height, and wrist circumference of the individual. PMID- 24771444 TI - Effects of polypropylene and polytetrafluoroethylene prostheses for abdominal plasty on local and systemic cytokine production. AB - We studied the effects of Esphyl polypropylene mesh and Ecoflon polytetrafluoroethylene endoprostheses on local and systemic production of cytokines. Polytetrafluoroethylene is a more reactogenic material than polypropylene; it stimulates mainly the local production of pro-inflammatory cytokines. The local anti-inflammatory effect of polypropylene was less pronounced, but persisted for longer time. PMID- 24771445 TI - Mechanisms of therapeutic activity of multipotent cells in heart diseases. AB - Analysis of our findings and published reports on possible mechanisms of therapeutic activity of stem/progenitor cell transplantation in cardiovascular pathologies is presented. PMID- 24771446 TI - Specific effects of chondroitin sulfate-modified hyaluronidase on the function of progenitor cells. AB - We have demonstrated the possibility of stimulation of the function of various types of precursor cells with hyaluronidase modified with chondroitin sulfate. Parenteral administration of modified hyaluronidase increased the number of fibroblast, granulomonocyte, and erythroid CFU in the hemopoietic tissue. The changes in the pool of mesenchymal progenitor cells were more pronounced in comparison with those induced by native enzyme. PMID- 24771447 TI - Effect of 3D chondrocyte culturing conditions on the formation of extracellular matrix in cartilage tissue-engineering constructs. AB - We studied biochemical, morphological, and histological parameters of the extracellular matrix in scaffold-free tissue engineering chondrotransplants prepared from chondrocytes isolated from knee joint cartilage biopsy specimens of Haflinger horses (age 3.5-14 years) and in transplants prepared on the basis of commercial matrixes of Ethisorb(r) and Chondro-Gide((r)). A total of 50 tissue engineering constructs were designed and analyzed. Passage 2 cells populations were used. Mechanical stimulation during culturing of scaffold-free constructs considerably activated synthesis of the basic components of the cartilage matrix (proteoglycan concentration was 35% of the content in the native tissue, and the content of collagen-specific amino acids hydroxyproline and hydroxylysine attained 29.3 and 12.7%, respectively). The architecture of these cartilage constructs was morphologically and histologically similar to the native cartilage tissue. Insufficient support of the chondrogenesis by scaffold-based chondrotransplants and no differences between these constructs by the studied parameters were noted despite different chemical nature and structure of these scaffolds. PMID- 24771448 TI - Participation of PI3K, MAPK ERK1/2, and p38 in the realization of growth potential of mesenchymal precursor cells under in vitro conditions. AB - We studied the role of intracellular signal molecules PI3K, MAPK ERK1/2, and p38 in the realization of the growth potential of mesenchymal progenitor elements. Under in vitro conditions, PI3K i ERK1/2 specifi c inhibitors reduced fi broblastic colony- and cluster-formation and considerably suppressed proliferative activity of mesenchymal precursors. Blocker of p38 and protein kinase B had no effect on the function of fi broblast CFU. PMID- 24771449 TI - Effect of platelet releasate on osteogenic differentiation of human mesenchymal bone marrow stem cells. AB - We studied the effect of platelet releasate on osteogenic differentiation of human mesenchymal BM stem cells. Histological staining and reverse transcription PCR analysis showed that addition of platelet releasate to osteogenic differentiation medium stimulated the formation of calcium ossificates and alkaline phosphatase and increased expression of osteopontin and alkaline phosphatase genes. PMID- 24771450 TI - Effect of factors produced by the placenta on cytokine secretion by THP-1 cells cultured on a 3D scaffold. AB - We compared the effects of soluble products from the placenta obtained from women with normal pregnancy and pregnancy complicated by preeclampsia on cytokine secretion by THP-1 cells cultured on a 3D Matrigel scaffold. In the presence of soluble products from all placentas, the cells actively secreted IL-8, MCP-1, and soluble forms of CD14, TNFRI, and TNFRII receptors. Secretion of VEGF was below the spontaneous level. Secretion of IL-6 by THP-1 cells after incubation with soluble products of the placentas obtained during weeks 9-11 of physiological pregnancy and 38-39 of pregnancy complicated by preeclampsia surpassed the spontaneous level. In the presence of soluble factors of trimester I placentas, secretion of IL-6 and soluble form of TNFRI receptor was higher than in the presence of trimester III placental factors. Secretion of IL-6 by THP-1 cells was higher, while secretion of soluble TNFRII receptor was lower in the presence of placentas from women with preeclampsia in comparison with physiological pregnancy. PMID- 24771451 TI - Mesenchymal stromal cells of rat spleen during pre-and postnatal ontogeny: Comparative analysis of clonal growth, phenotype and differentiation potencies. AB - Comparison of mesenchymal stromal cells of embryonic and adult rat spleen showed that splenic cells from 20-day rat fetuses exhibit the capacity for clonal growth, express surface antigens CD73, CD90, and CD106, and have weak osteogenic and adipogenic potencies, while splenic cells from adult animals are characterized by lower cloning efficiency, rapid decrease of proliferative activity during passaging, the absence of CD73 and CD90 expression, and are incapable of osteogenesis The observed changes are probably related to extinction of myelopoiesis in the spleen during the postnatal ontogeny. PMID- 24771452 TI - Proliferative activity of cadriomyocytes in chronic hypercholesterolemia. AB - We studied proliferative activity of cardiomyocytes (using proliferation marker Ki-67) and compared it with their total number in the heart under conditions of experimental chronic hypercholesterolemia and its combination with hypothyroidism. It was found that Ki-67-positive cells are primarily located in the subepicardial layer near the heart base in both intact and experimental animals. Replicative cardiomyocyte pool in intact rats constituted 1.67 +/- 0.330/00 of the total cardiomyocyte population; after 68-day atherogenic diet with exogenous cholesterol alone, the replicative cardiomyocyte pool decreased by 16 % (to 1.40 +/- 0.240/00). Treatment with mercazolil against the background of exogenous cholesterol increased this parameter by 40 % (to 2.33 +/- 0.880/00). Changes in replicative activity of cardiomyocytes correlated with their total number in the heart and organ weight. We conclude that replicative cardiomyocyte pool primarily includes non-terminally differentiated cardiomyocytes (small mononuclear cardiomyocytes) and their proliferation maintains the total number of cardiomyocytes in the heart under conditions of cytopathic influences and provides the basis for physiological and reparative regeneration of the myocardium. PMID- 24771453 TI - Enrichment of umbilical cord blood mononuclears with hemopoietic precursors in co culture with mesenchymal stromal cells from human adipose tissue. AB - We demonstrated the possibility of enrichment of umbilical cord blood mononuclear fraction with early non-differentiated precursors under conditions of co culturing with mesenchymal stromal cells from the human adipose tissue. It was established that umbilical cord blood mononuclear cells adhered to mesenchymal stromal cell feeder and then proliferate and differentiate into hemopoietic cells. In comparison with the initial umbilical cord blood mononuclear fraction, the cell population obtained after 7-day expansion contained 2-fold more CFU and 33.4 +/- 9.5 and 24.2 +/- 11.2% CD34(+) and CD133(+) cells, respectively, which corresponds to enrichment of precursor cell population by 148 +/- 60. The proposed scheme of expansion of hemopoietic cells from umbilical cord blood is economically expedient and can widely used in biology and medicine. PMID- 24771454 TI - Effect of immobilized hyaluronidase on stem and progenitor cells in pulmonary fibrosis. AB - The effect of immobilized hyaluronidase on stem and progenitor cells of the lungs was studied on the model of partially reversible toxic bleomycin-induced pulmonary fibrosis in C57Bl/6 mice. During the inflammation phase, immobilized hyaluronidase reduced infiltration of alveolar interstitium with hemopoietic stem cells Sca-1(+), c-Kit(+), CD34(-), (CD3, CD45R (B220), Ly6C, Ly6G (Gr1), CD11b (Mac1), TER-119)(-). Improvement of histological parameters of bleomycin lungs during the phase of collagen fiber deposition after the treatment was accompanied by accumulation of mesenchymal multipotent stromal cells (CD31(-), CD34(-), CD45( ), CD44(+), CD73(+), CD90(+), CD106(+)decrease in the population of pan hemopoietic cells (CD45(+)), accelerated restoration of the content of endothelial cells, and inhibition of clonal activity of fibroblast precursors (CD45(-)). PMID- 24771455 TI - Xenon NMR of phase biaxiality in liquid crystals. AB - Biaxial thermotropic nematic liquid crystals would be of great importance in liquid crystal display technology. Less than a decade ago, such liquid crystals were suggested. The biaxiality of the phases was confirmed using (2)H NMR spectroscopy of deuterated probe molecules. The spectra were collected from a sample rotating around an axis perpendicular to the external magnetic field, resulting in a two-dimensional powder pattern. We have proposed an alternate technique that is based on the second order quadrupole shift detectable in (131)Xe NMR spectra of dissolved xenon. The method has many advantages, such as the NMR spectra are taken from a static sample and the (131)Xe quadrupole coupling tensor is extremely sensitive to the symmetry of the phase. In the present study, we report results obtained on a 600-MHz NMR spectrometer. Together with the data of our earlier study, they confirm that the asymmetry parameter of the (131)Xe quadrupole coupling tensor in the nematic phase of a ferroelectric liquid crystal is 0.85 and in the smectic A phase ca 0.62, indicating significant phase biaxiality. PMID- 24771456 TI - Regulation of mitochondrial morphology by lipids. AB - Although great progress has been made in identifying key protein factors that regulate mitochondrial morphology through mediating fission and fusion, signaling lipids are increasingly being recognized as important in the process as well. We review here roles that have been proposed for the signaling and bulk lipids cardiolipin, phosphatidic acid, lysophosphatidic acid, diacylglycerol, and phosphatidylethanolamine and the enzymes that generate or catabolize them in the regulation of mitochondrial morphology in yeast and mammals. Mutations in some of these enzymes are causal in a number of disease settings, highlighting the significance of controlling the lipid environment in this setting. PMID- 24771457 TI - Expression of G proteins in the olfactory receptor neurons of the newt Cynops pyrrhogaster: their unique projection into the olfactory bulbs. AB - We analyzed the expression of G protein alpha subunits and the axonal projection into the brain in the olfactory system of the semiaquatic newt Cynops pyrrhogaster by immunostaining with antibodies against Galphaolf and Galphao , by in situ hybridization using probes for Galphaolf , Galphao , and Galphai2 , and by neuronal tracing with DiI and DiA. The main olfactory epithelium (OE) consists of two parts, the ventral OE and dorsal OE. In the ventral OE, the Galphaolf - and Galphao -expressing neurons are located in the apical and basal zone of the OE, respectively. This zonal expression was similar to that of the OE in the middle cavity of the fully aquatic toad Xenopus laevis. However, the Galphaolf - and Galphao -expressing neurons in the newt ventral OE project their axons toward the main olfactory bulb (MOB) and the accessory olfactory bulb (AOB), respectively, whereas in Xenopus, the axons of both neurons project solely toward the MOB. In the dorsal OE of the newt, as in the principal cavity of Xenopus, the majority of the neurons express Galphaolf and extend their axons into the MOB. In the vomeronasal organ (VNO), the neurons mostly express Galphao . These neurons and quite a few Galphaolf -expressing neurons project their axons toward the AOB. This feature is similar to that in the terrestrial toad Bufo japonicus and is different from that in Xenopus, in which VNO neurons express solely Galphao , although their axons invariably project toward the AOB. We discuss the findings in the light of diversification and evolution of the vertebrate olfactory system. PMID- 24771458 TI - The effects of Bruton tyrosine kinase inhibition on chemotaxis and superoxide generation in human neutrophils. AB - PURPOSE: The role of the Bruton tyrosine kinase (Btk) protein in neutrophil function has been evaluated using neutrophils from healthy volunteers after incubation with a Btk inhibitor, leflunomide metabolite analog (LFM-A13), suggesting an important role for Btk in neutrophil function. We sought to determine the role of Btk protein on neutrophil superoxide generation and chemotaxis stimulated by N-formyl-methionine-leucine-phenylalanine (fMLP). METHODS: Chemotaxis was assayed on agarose gel and superoxide generation by cytochrome C reduction. The affects of LFM-A13 on chemotaxis and superoxide generation in unstimulated and fMLP stimulated neutrophils were studied in Btk deficient neutrophils from XLA patients compared with matched controls analyzed simultaneously. RESULTS: Chemotaxis and stimulated superoxide production were similar in the normal and Btk deficient neutrophils and were similarly inhibited by LFM-A13. In one patient, LFMA13 had no effect on superoxide generation in Btk deficient neutrophils up to a concentration of 25 microM, while inhibited superoxide production by control neutrophils. CONCLUSIONS: Our results suggest that Btk does not have a specific role in neutrophil fMLP-stimulated superoxide generation and chemotaxis since these activities were similarly inhibited by LFM A13 in Btk deficient and normal neutrophils. The lack of superoxide generation following Btk inhibition by LFM-A13 in Btk deficient neutrophils from one patient may suggest some heterogeneity in the role of Btk in fMLP induced neutrophil superoxide generation. PMID- 24771459 TI - Comparison of energy metabolism in liver grafts from donors after circulatory death and donors after brain death during cold storage and reperfusion. AB - BACKGROUND: Donation after circulatory death (DCD) liver grafts have supplemented the donor organ pool, but certain adverse outcomes have prevented exploration of the full potential of such organs. The aim of this study was to determine key differences in basic energy metabolism between DCD and donation after brainstem death (DBD) grafts. METHODS: Microdialysis samples from DCD and DBD allograft parenchyma from cold storage to 48 h after reperfusion were analysed by colorimetric methods. Interstitial lactate, pyruvate and glycerol levels were measured and the lactate/pyruvate ratio was calculated to estimate energy depletion of the grafts. Histological features of ischaemia and reperfusion injury were assessed. RESULTS: Donor age, extent of steatosis and cold ischaemia time were comparable between ten DCD and 20 DBD organs. DCD grafts had higher levels of interstitial lactate (median 11.6 versus 1.2 mmol/l; P = 0.015) and increased lactate/pyruvate ratio (792 versus 38; P = 0.001) during cold storage. There was no significant difference in glycerol levels between DCD and DBD grafts (225.1 versus 127.5 umol/l respectively; P = 0.700). Rapid restoration of energy levels with lactate clearance, increased pyruvate levels and reduced lactate/pyruvate ratio was seen following reperfusion of functioning DCD grafts, parallel with levels in DBD grafts. Histology revealed more pronounced glycogen depletion in DCD grafts. Three allografts that failed owing to primary non function showed energy exhaustion with severe glycogen depletion. CONCLUSION: Liver grafts from DCD donors exhibited depletion of intracellular energy reserves during cold storage. Failed allografts showed severe energy depletion. Modified organ preservation techniques to minimize organ injury related to altered energy metabolism may enable better utilization of donor organs after circulatory death. PMID- 24771460 TI - Exercise-based rehabilitation for heart failure. AB - BACKGROUND: Previous systematic reviews and meta-analyses consistently show the positive effect of exercise-based rehabilitation for heart failure (HF) on exercise capacity; however, the direction and magnitude of effects on health related quality of life, mortality and hospital admissions in HF remain less certain. This is an update of a Cochrane systematic review previously published in 2010. OBJECTIVES: To determine the effectiveness of exercise-based rehabilitation on the mortality, hospitalisation admissions, morbidity and health related quality of life for people with HF. Review inclusion criteria were extended to consider not only HF due to reduced ejection fraction (HFREF or 'systolic HF') but also HF due to preserved ejection fraction (HFPEF or 'diastolic HF'). SEARCH METHODS: We updated searches from the previous Cochrane review. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue1, 2013) from January 2008 to January 2013. We also searched MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCO) and PsycINFO (Ovid) (January 2008 to January 2013). We handsearched Web of Science, bibliographies of systematic reviews and trial registers (Controlled-trials.com and Clinicaltrials.gov). SELECTION CRITERIA: Randomised controlled trials of exercise-based interventions with six months' follow-up or longer compared with a no exercise control that could include usual medical care. The study population comprised adults over 18 years and were broadened to include individuals with HFPEF in addition to HFREF. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references and rejected those that were clearly ineligible. We obtained full-text papers of potentially relevant trials. One review author independently extracted data from the included trials and assessed their risk of bias; a second review author checked data. MAIN RESULTS: We included 33 trials with 4740 people with HF predominantly with HFREF and New York Heart Association classes II and III. This latest update identified a further 14 trials. The overall risk of bias of included trials was moderate. There was no difference in pooled mortality between exercise-based rehabilitation versus no exercise control in trials with up to one-year follow-up (25 trials, 1871 participants: risk ratio (RR) 0.93; 95% confidence interval (CI) 0.69 to 1.27, fixed-effect analysis). However, there was trend towards a reduction in mortality with exercise in trials with more than one year of follow-up (6 trials, 2845 participants: RR 0.88; 95% CI 0.75 to 1.02, fixed-effect analysis). Compared with control, exercise training reduced the rate of overall (15 trials, 1328 participants: RR 0.75; 95% CI 0.62 to 0.92, fixed-effect analysis) and HF specific hospitalisation (12 trials, 1036 participants: RR 0.61; 95% CI 0.46 to 0.80, fixed-effect analysis). Exercise also resulted in a clinically important improvement superior in the Minnesota Living with Heart Failure questionnaire (13 trials, 1270 participants: mean difference: 5.8 points; 95% CI -9.2 to -2.4, random-effects analysis) - a disease specific health-related quality of life measure. However, levels of statistical heterogeneity across studies in this outcome were substantial. Univariate meta regression analysis showed that these benefits were independent of the participant's age, gender, degree of left ventricular dysfunction, type of cardiac rehabilitation (exercise only vs. comprehensive rehabilitation), mean dose of exercise intervention, length of follow-up, overall risk of bias and trial publication date. Within these included studies, a small body of evidence supported exercise-based rehabilitation for HFPEF (three trials, undefined participant number) and when exclusively delivered in a home-based setting (5 trials, 521 participants). One study reported an additional mean healthcare cost in the training group compared with control of USD3227/person. Two studies indicated exercise-based rehabilitation to be a potentially cost-effective use of resources in terms of gain in quality-adjusted life years (QALYs) and life-years saved. AUTHORS' CONCLUSIONS: This updated Cochrane review supports the conclusions of the previous version of this review that, compared with no exercise control, exercise-based rehabilitation does not increase or decrease the risk of all-cause mortality in the short term (up to 12-months' follow-up) but reduces the risk of hospital admissions and confers important improvements in health-related quality of life. This update provides further evidence that exercise training may reduce mortality in the longer term and that the benefits of exercise training on appear to be consistent across participant characteristics including age, gender and HF severity. Further randomised controlled trials are needed to confirm the small body of evidence seen in this review for the benefit of exercise in HFPEF and when exercise rehabilitation is exclusively delivered in a home-based setting. PMID- 24771461 TI - Left paraduodenal hernia causing small bowel obstruction. AB - A case of small bowel obstruction secondary to a left paraduodenal hernia is illustrated together with its radiological features and intra-operative appearance. Paraduodenal hernias are rare congenital causes of small bowel obstruction, and various approaches to surgical treatment are available including conventional open and minimally invasive laparoscopic techniques. This case presents one possible option for surgical management and briefly reviews the literature for the various surgical techniques and strategies available to the surgeon when faced with a left paraduodenal hernia. PMID- 24771463 TI - Transport of dissolved nutrients and chlorophyll a in a tropical estuary, southwest coast of India. AB - Intra-tidal variability in the transport of materials through the Cochin estuary was studied over successive spring and neap tides to estimate the export fluxes of nutrients and chlorophyll a into the adjoining coastal zone. The results showed that there was a substantial increase in the freshwater flow into the estuary following heavy rains (~126 mm) prior to the spring tide observations. The estuary responded accordingly with a relatively larger export through the Cochin inlet during spring tide over neap tide. Despite an increased freshwater discharge during spring tide, the export fluxes of phosphate and ammonia were high during neap tide due to their input into the estuary through anthropogenic activities. The significance of this study is that the export fluxes from the Cochin estuary could be a major factor sustaining the spectacular monsoon fishery along the southwest coast of India. PMID- 24771462 TI - Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. AB - Currently, grading in lung neuroendocrine tumors (NETs) is inherently defined by the histological classification based on cell features, mitosis count, and necrosis, for which typical carcinoids (TC) are low-grade malignant tumors with long life expectation, atypical carcinoids (AC) intermediate-grade malignant tumors with more aggressive clinical behavior, and large cell NE carcinomas (LCNEC) and small cell lung carcinomas (SCLC) high-grade malignant tumors with dismal prognosis. While Ki-67 antigen labeling index, highlighting the proportion of proliferating tumor cells, has largely been used in digestive NETs for assessing prognosis and assisting therapy decisions, the same marker does not play an established role in the diagnosis, grading, and prognosis of lung NETs. Next generation sequencing techniques (NGS), thanks to their astonishing ability to process in a shorter timeframe up to billions of DNA strands, are radically revolutionizing our approach to diagnosis and therapy of tumors, including lung cancer. When applied to single genes, panels of genes, exome, or the whole genome by using either frozen or paraffin tissues, NGS techniques increase our understanding of cancer, thus realizing the bases of precision medicine. Data are emerging that TC and AC are mainly altered in chromatin remodeling genes, whereas LCNEC and SCLC are also mutated in cell cycle checkpoint and cell differentiation regulators. A common denominator to all lung NETs is a deregulation of cell proliferation, which represents a biological rationale for morphologic (mitoses and necrosis) and molecular (Ki-67 antigen) parameters to successfully serve as predictors of tumor behavior (i.e., identification of pathological entities with clinical correlation). It is envisaged that a novel grading system in lung NETs based on the combined assessment of mitoses, necrosis, and Ki-67 LI may offer a better stratification of prognostic classes, realizing a bridge between molecular alterations, morphological features, and clinical behavior. PMID- 24771464 TI - Evaluation of optimal conditions for determination of low selenium content in shellfish samples collected at Todos os Santos Bay, Bahia, Brazil using HG-AFS. AB - This work proposes a procedure for the determination of total selenium content in shellfish after digestion of samples in block using cold finger system and detection using atomic fluorescent spectrometry coupled hydride generation (HG AFS). The optimal conditions for HG such as effect and volume of prereduction KBr 10 % (m/v) (1.0 and 2.0 ml) and concentration of hydrochloric acid (3.0 and 6.0 mol L(-1)) were evaluated. The best results were obtained using 3 mL of HCl (6 mol L(-1)) and 1 mL of KBr 10 % (m/v), followed by 30 min of prereduction for the volume of 1 mL of the digested sample. The precision and accuracy were assessed by the analysis of the Certified Reference Material NIST 1566b. Under the optimized conditions, the detection and quantification limits were 6.06 and 21.21 MUg kg(-1), respectively. The developed method was applied to samples of shellfish (oysters, clams, and mussels) collected at Todos os Santos Bay, Bahia, Brazil. Selenium concentrations ranged from 0.23 +/- 0.02 to 3.70 +/- 0.27 mg kg( 1) for Mytella guyanensis and Anomalocardia brasiliana, respectively. The developed method proved to be accurate, precise, cheap, fast, and could be used for monitoring Se in shellfish samples. PMID- 24771465 TI - Ornithokinin (avian bradykinin) from the skin of the Chinese bamboo odorous frog, Odorrana versabilis. AB - One of the most widespread and abundant families of pharmacologically active peptides in amphibian defensive skin secretions is the bradykinins and related peptides. Despite retaining certain primary structural attributes that assign them to this peptide family, bradykinins and related peptides are unique among amphibian skin peptides in that they exhibit a wide range of primary structural variations, post-translational modifications and/or N-terminal or C-terminal extensions. Initially it was believed that their high degree of primary structural heterogeneity was reflective of random gene mutations within species, but latterly, there is an increasing body of evidence that the spectrum of structural modifications found within this peptide family is reflective of the vertebrate predator spectrum of individual species. Here we report the discovery of ornithokinin (avian bradykinin - Thr(6) , Leu(8) -bradykinin) in the skin secretion of the Chinese bamboo odorous frog, Odorrana versabilis. Molecular cloning of its biosynthetic precursor-encoding cDNA from a skin secretion-derived cDNA library revealed a deduced open-reading frame of 86 amino acid residues, encoding a single copy of ornithokinin towards its C-terminus. The domain architecture of this ornithokinin precursor protein was consistent with that of a typical amphibian skin peptide and quite different to that of the ornithokininogen from chicken plasma. Ornithokinin was reported to induce hypotension in the chicken and to contract the chicken oviduct but to have no obvious effect on the rat uterus. However, in this study, synthetic ornithokinin was found to contract the rat ileum (EC50 = 539 nM) and to increase contraction frequency in the rat uterus (EC50 = 1.87 MUM). PMID- 24771466 TI - Macrophage Infiltration in Tumor Stroma is Related to Tumor Cell Expression of CD163 in Colorectal Cancer. AB - The scavenger receptor, CD163, is a macrophage-specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression as a macrophage trait in cancer cells, and macrophage infiltration and its clinical significance in colorectal cancer. Immunostaining of CD163 and macrophage infiltration were evaluated in paraffin-embedded specimens, earlier analyzed for CD31, D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 75 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data. CD163 expression was positive in cancer cells in 20 % of colorectal cancer patients and was related to advanced tumor stages (P = 0.008) and unfavorable prognosis (p = 0.001). High macrophage infiltration was related to shorter survival and positive CD163 expression in tumor cells. The prognostic impact of macrophage infiltration was independent of tumor stage and CD163 expression in cancer cells (p = 0.034). The expression of macrophage phenotype in colorectal cancer cells is associated with macrophage density in tumor stroma and lower survival rates. Macrophage infiltration has an independent prognostic impact on mortality in colorectal cancer. In accordance with previous experimental studies, these findings provide new insights into the role of macrophages in colorectal cancer. PMID- 24771467 TI - Delivery of BMP-2 by two clinically available apatite materials: in vitro and in vivo comparison. AB - Bone morphogenetic proteins (BMPs) are deposited in bone and responsible for osteoinduction. The interplay between delivery system and BMP, resulting in a characteristic release profile, is crucial for clinical success. We here report on two apatite based commercially available granules which could potentially be used in a combination product with recombinant human BMP-2 (rhBMP-2). Regardless of their similar chemistry, their interaction with rhBMP-2 differs. Deproteinized bovine bone matrix (DBBM), a clinically well-established bone substitute, has a high affinity to rhBMP-2 and releases only 50% of the growth factor during the first 2 weeks in vitro. Activity of the physio-adsorbed rhBMP-2 is indicated by an enhanced bone augmentation in vivo. In contrast, all rhBMP-2 delivered in combination with synthetic hydroxyapatite/beta-tricalcium phosphate (HA/TCP) granules is released during the first 24 h. For both HA/TCP and DBBM, the released rhBMP-2 is active in vitro. Our results suggest that the different release behavior from these two apatite granules is due to the 1000-fold higher specific surface area of DBBM compared to HA/TCP. PMID- 24771468 TI - Synthesis and spectral investigations of Cu(II) ion-doped NaCaAlPO4 F3 phosphor. AB - Cu(II) ion-doped NaCaAlPO(4)F(3) phosphor has been synthesized using a solid state reaction method. The prepared sample is characterized by powder X-ray diffraction, scanning electron microscope, optical absorption, electron paramagnetic resonance photoluminescence and Fourier transform infrared spectroscopy techniques. The crystallite size evaluated from x-ray diffraction data is in nanometers. Scanning electron microscopy micrographs showed the presence of several irregular shaped particles. From optical absorption and electron paramagnetic resonance spectral data the doped Cu(II) ions are ascribed to distorted octahedral site symmetry. The synthesized phosphor exhibits emission bands in ultraviolet, blue and green regions under the excitation wavelength of 335 nm. The CIE chromaticity coordinates (x = 0.159, y = 0.204) also calculated for the prepared sample from the emission spectrum. The Fourier transform infrared spectroscopy spectrum revealed the characteristic vibrational bands of the prepared phosphor material. PMID- 24771469 TI - Recent advances in sports nutrition. PMID- 24771471 TI - Induced neuronal reprogramming. AB - Cellular differentiation processes during normal embryonic development are guided by extracellular soluble factors such as morphogen gradients and cell contact signals, eventually resulting in induction of specific combinations of lineage determining transcription factors. The young field of epigenetic reprogramming takes advantage of this knowledge and uses cell fate determination factors to convert one lineage into another such as the conversion of fibroblasts into pluripotent stem cells or neurons. These induced cell fate conversions open up new avenues for studying disease processes, generating cell material for therapeutic intervention such as drug screening and potentially also for cell based therapies. However, there are still limitations that have to be overcome to fulfill these promises, centering on reprogramming efficiencies, cell identity, and maturation. In this review, we discuss the discovery of induced neuronal reprogramming, ways to improve the conversion process, and finally how to define properly the identity of those converted neuronal cells. PMID- 24771473 TI - Should screening of renal markers be recommended in a working population? AB - INTRODUCTION: It is debated whether the general population should be screened for kidney disease. This study evaluated whether screening of albuminuria and estimated glomerular filtration rate (eGFR) in a working population should be recommended to detect subjects with chronic kidney disease. METHODS: The unreferred renal insufficiency study is a cross-sectional study in 1,398 workers aged 17-65. Markers of cardiovascular and renal disease were measured. Cardiovascular risk (CVR) was defined by hypertension (n = 416), diabetes (n = 45), dyslipidemia (n = 159) and/or history of a cardiovascular event (n = 10). RESULTS: In our population, 5 % of the workers had microalbuminuria, 0.5 % had macroalbuminuria and <0.1 % had eGFR <60 ml/min/1.73 m(2). All workers with an eGFR <60 ml/min/1.73 m(2) and/or macroalbuminuria (8/8) had at least one CVR factor, whereas this was the case in only half of workers with microalbuminuria (36/73, p = 0.007). In workers without CVR factors, the presence of microalbuminuria was associated with low body mass index (BMI, p < 0.001) or physiochemical exposure risk (p < 0.001). CONCLUSIONS: Screening of renal markers in a working population, identified only a few subjects with an eGFR <60 ml/min/1.73 m(2) or macroalbuminuria. Although microalbuminuria was more prevalent, it might not necessarily indicate kidney disease, as it may have a completely different meanings depending of the phenotype of the screened subjects. Besides underlying CVR factors, microalbuminuria was also associated with low BMI in absence of any risk factor, suggesting presence of benign postural proteinuria. In addition, microalbuminuria also seemed to be related to physicochemical exposure. In view of the impossibility to further analyze this finding in the present study, the meaning of this observation needs to be further investigated. PMID- 24771472 TI - A translational medicine appraisal of specialized andrology testing in unexplained male infertility. AB - The diagnostic and prognostic validity of sperm function biomarkers is particularly relevant for males with unexplained infertility in which routine semen analysis fails to detect subcellular sperm dysfunctions. In this general review, we examine the role and significance of specialized andrology laboratory tests from past to present and provide a glance toward the future. We concluded that the assessment of sperm DNA damage and oxidative stress provide a relatively independent measure of fertility that yields diagnostic and prognostic information complementary to, but distinct and more significant than, standard sperm parameters. Since none of the available methods for such testing have been fully translated, further research is necessary to evaluate their cost effectiveness when applied in large scale to daily medical practice. Application of translational medicine concepts would also be useful to accelerate the clinical application of recent discoveries in the fields of genomics, proteomics and metabolomics. PMID- 24771474 TI - Copper-catalyzed N-H insertion and oxidative aromatization cascade: facile synthesis of 2-arylaminophenols. AB - A copper-catalyzed cascade reaction of N-H insertion and oxidative aromatization has been developed. 2-Arylaminophenols have been prepared in moderate to high yields from the diazo substrates. Moreover, this newly established methodology allows efficient access to natural 1-oxygenated carbazole alkaloids, such as glycozolicine and murrayafoline A. PMID- 24771475 TI - Donor age as a risk factor in donation after circulatory death liver transplantation in a controlled withdrawal protocol programme. AB - BACKGROUND: Results of donation after circulatory death (DCD) liver transplantation are impaired by graft loss, resulting mainly from non-anastomotic biliary stricture. Donor age is a risk factor in deceased donor liver transplantation, and particularly in DCD liver transplantation. At the authors' institute, age is not an absolute exclusion criterion for discarding DCD liver grafts, DCD donors receive comfort therapy before withdrawal, and cold ischaemia is minimized. METHODS: All consecutive DCD liver transplantations performed from 2003 to 2012 were studied retrospectively. Three age groups were compared in terms of donor and recipient demographics, procurement and transplantation conditions, peak laboratory values during the first post-transplant 72 h, and results at 1 and 3 years. RESULTS: A total of 70 DCD liver transplants were performed, including 32 liver grafts from donors aged 55 years or less, 20 aged 56-69 years, and 18 aged 70 years or more. The overall graft survival rate at 1 month, 1 and 3 years was 99, 91 and 72 per cent respectively, with no graft lost secondary to non-anastomotic stricture. No difference other than age was noted between the three groups for donor or recipient characteristics, or procurement conditions. No primary non-function occurred, but one patient needed retransplantation for artery thrombosis. Biliary complications were similar in the three groups. Graft and patient survival rates were no different at 1 and 3 years between the three groups (P = 0.605). CONCLUSION: Results for DCD liver transplantation from younger and older donors were similar. Donor age above 50 years should not be a contraindication to DCD liver transplantation if other donor risk factors (such as warm and cold ischaemia time) are minimized. PMID- 24771476 TI - Cerebellar cytokine expression in a rat model for fetal asphyctic preconditioning and perinatal asphyxia. AB - Asphyctic brain injury is a major cause of neuronal inflammation in the perinatal period. Fetal asphyctic preconditioning has been shown to modulate the cerebral inflammatory cytokine response, hereby protecting the brain against asphyctic injury at birth. This study was designated to examine the effects of perinatal asphyxia and fetal asphyctic preconditioning on the inflammatory cytokine response in the cerebellum. Fetal asphyxia was induced at embryonic day 17 by clamping the uterine vasculature for 30 min. At term birth, global perinatal asphyxia was induced by placing the uterine horns in saline for 19 min. Pro- and anti-inflammatory cytokine expression were assessed by real-time PCR and immunohistochemistry in cerebella of newborn rats. We found that tumor necrosis factor alpha and interleukin-10 mRNA were increased 12 h after fetal asphyxia, while the inflammatory cytokine response was decreased 96 h postfetal asphyxia. When applied as preconditioning stimulus, fetal asphyxia attenuates the cerebellar cytokine response. These results indicate that sublethal fetal asphyxia may protect the cerebellum from perinatal asphyxia-induced damage via inhibition of inflammation. PMID- 24771477 TI - Survival and development of the forensically important blow fly, Calliphora varifrons (Diptera: Calliphoridae) at constant temperatures. AB - The influence of temperature on the development of the forensically important blow fly, Calliphora varifrons Malloch 1932 (Diptera: Calliphoridae), was investigated at seven constant temperatures ranging from 12 to 30 degrees C. C. varifrons completed development between 12 and 27 degrees C. At 30 degrees C larvae formed pupae but did not successfully emerge. Temperature significantly influenced development time, mortality, maximum larval length, and adult body size. Development time (larviposition to adult emergence) ranged from 16.65 +/- 0.17 days at 27 degrees C to 49.93 +/- 0.26 days at 12 degrees C. Development rate was essentially linear throughout the 12-27 degrees C temperature range. Linear estimates of lower developmental threshold and thermal requirement (K) for development of C. varifrons were 4.20 degrees C and 368.46 +/- 26.38 K. At 30 degrees C, a slight inhibitory effect of high temperature on third instar development rate was observed followed by a rapid decline when subsequent development and survival ceased. Nonlinear estimates of lower developmental threshold for third instar development were comparatively higher (6.29 degrees C). Nonlinear estimates of optimal developmental temperature and upper lethal developmental threshold were 25.94 and 32.13 degrees C respectively. Mortality was high at both temperature extremes (12 and 27 degrees C) and lowest between 18 and 24 degrees C. Maximum larval length was inversely related to temperature. Adult body size was significantly smaller at 12 degrees C, peaked at 18 degrees C, and declined as temperatures increased. The species-specific development data presented are the first available for C. varifrons for use by forensic practitioners for estimation of minimum time since death. PMID- 24771478 TI - Seizure disorder secondary to remote gunshot wound of the head: a case of sudden unexpected death in epilepsy. PMID- 24771479 TI - A case of suicide by ingestion of caffeine. AB - Intentional or unintentional caffeine abuse due to excessive intake of beverages or energy drinks containing caffeine is relatively frequent. However, death due to caffeine intoxication is rare and case reports of fatalities from caffeine toxicity are relatively infrequent. In this report, we describe an autopsy case involving a 31 year-old man who intentionally took a large amount of caffeine tablets in the form of a weight loss supplement as part of a suicide plan. Caffeine femoral blood concentration (170 mg/l) was within the toxic and potentially lethal ranges reported in the literature in similar cases. Postmortem biochemistry results suggested depressed glomerular filtration rate and pre-renal failure at the time of death but failed to reveal myoglobinuria, glycosuria, ketonuria or ketonemia. Based on the absence of pathological findings at autopsy and the high blood caffeine level, death was attributed to acute caffeine toxicity. The case emphasizes the usefulness of performing exhaustive toxicology and searching for all potentially relevant information in order to formulate appropriate hypotheses concerning the cause and manner of death. PMID- 24771480 TI - Gabapentin for chronic neuropathic pain and fibromyalgia in adults. AB - BACKGROUND: This review is an update of a review published in 2011, itself a major update of previous reviews published in 2005 and 2000, investigating the effects of gabapentin in chronic neuropathic pain (pain due to nerve damage). Antiepileptic drugs are used to manage chronic neuropathic pain and fibromyalgia. OBJECTIVES: To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain and fibromyalgia. SEARCH METHODS: We identified randomised trials of gabapentin for chronic neuropathic pain or fibromyalgia by searching the databases MEDLINE (1966 to March 2014), EMBASE (1980 to 2014 week 10), and CENTRAL in The Cochrane Library (Issue 3 of 12, 2014). We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched Clinicaltrials.gov. Searches were run originally in 2011 and the date of the most recent search was 17 March 2014. SELECTION CRITERIA: Randomised, double-blind studies reporting the analgesic and adverse effects of gabapentin in neuropathic pain or fibromyalgia with assessment of pain intensity, pain relief, or both, using validated scales. Participants were adults. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.For efficacy, we calculated the number needed to treat to benefit (NNT), concentrating on at least 50% pain intensity reduction, and Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) definitions of at least moderate and substantial benefit. For harm we calculated number needed to treat for harm (NNH) for adverse effects and withdrawal. Meta-analysis was undertaken using a fixed-effect model. We emphasised differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, complex regional painsyndrome type 1 (CRPS-1), and fibromyalgia. MAIN RESULTS: Seven new studies with 1919 participants were added. Another report (147 participants) provided results for a study already included, but which previously had no usable data. A further report (170 participants) used an experimental formulation of intrathecal gabapentin. Thirty-seven studies (5633 participants) studied oral gabapentin at daily doses of 1200 mg or more in 12 chronic pain conditions; 84% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy or mixed neuropathic pain. There was no first tier evidence.Second tier evidence for the outcome of at least 50% pain intensity reduction, considered valuable by patients with chronic pain, showed that gabapentin was significantly better than placebo in postherpetic neuralgia (34% gabapentin versus 21% placebo; NNT 8.0, 95% CI 6.0 to 12) and painful diabetic neuropathy (38% versus 21%, NNT 5.9, 95% CI 4.6 to 8.3). There was insufficient information in other pain conditions to reach any reliable conclusion. There was no obvious difference between standard gabapentin formulations and recently introduced extended-release or gastro-retentive formulations, or between different doses of gabapentin.Adverse events occurred significantly more often with gabapentin. Persons taking gabapentin could expect to have at least one adverse event (62%), withdraw because of an adverse event (11%), suffer dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (9%). Serious adverse events (3%) were no more common than with placebo.There were insufficient data for direct comparisons with other active treatments, and only third tier evidence for other painful conditions. AUTHORS' CONCLUSIONS: There was no top tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with some painful neuropathic pain conditions. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. About 35% achieved this degree of pain relief with gabapentin, compared with 21% for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in neuropathic pain conditions except postherpetic neuralgia and painful diabetic neuropathy, and in fibromyalgia, is very limited.The levels of efficacy found for gabapentin are consistent with those found for other drug therapies in postherpetic neuralgia and painful diabetic neuropathy. PMID- 24771481 TI - Altered bone material properties in HLA-B27 rats include reduced mineral to matrix ratio and altered collagen cross-links. AB - Spondyloarthropathy and inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease, are often associated with severe osteopenia/osteoporosis in both children and adults. HLA-B27 transgenic rats present a phenotype that includes severe colitis and severely accelerated alveolar bone loss. The purpose of this study was to evaluate long bone density status, systemic bone metabolic markers, and intrinsic bone material properties in HLA-B27 transgenic (TG) rats, and compare them with those of age- and sex matched wild-type (WT) animals. The results indicate that in the HLA-B27 rat, an animal susceptible to both alveolar bone loss (ABL) and long bone osteopenia, there is a statistically significant negative correlation between ABL and long bone bone mineral density (BMD), as well as mineral/matrix ratio at active bone forming trabecular surfaces. The TG animals had a lower mineral/matrix ratio and higher relative proteoglycan and advanced glycation end product (epsilon-N Carboxymethyl-L-lysine) content and pyridinoline/divalent collagen cross-link ratio compared with WT. These results may provide better understanding of the interrelationship between osteoporosis and oral bone loss, the underlying causes of the inferior bone strength in the HLA-B27 transgenic animals, and could prove to be a useful model in the elucidation of the pathophysiology of spondyloarthropathy and IBD-associated osteopenia/osteoporosis and in the evaluation of pharmacological intervention(s) against such conditions. PMID- 24771482 TI - Structural changes of human serum albumin induced by cadmium acetate. AB - The structural changes of human serum albumin (HSA) induced by the addition of cadmium acetate were systematically investigated using UV-vis absorption, circular dichroism (CD), synchronous, and three-dimentional (3D) fluorescence methods. The fluorescence spectra suggested the formation of cadmium acetate-HSA complex. UV absorption result indicated that the interaction between cadmium acetate and HSA could lead to the alteration of the protein skeleton. The structural analysis according to CD method showed that the cadmium acetate binding altered HSA conformation with a major reduction of alpha-helix, inducing a partial protein unfolding. Synchronous fluorescence spectra suggested that cadmium acetate was situated closer to tryptophan residue compared to tyrosine residues, making tryptophan residue locate in a more hydrophobic environment. 3D fluorescence demonstrated that cadmium acetate could induce the HSA aggregation and cause a slight unfolding of the polypeptide backbone of the protein. PMID- 24771483 TI - Development of therapies for autoimmune disease at Stanford: a tale of multiple shots and one goal. AB - The title of this contribution on Immunology at Stanford is purposely ambiguous. One goal is the development of safe and effective therapy for autoimmune diseases. Another definition of goal is to score, and this would ultimately mean the development of an approved drug. Indeed, the efforts in my four decades at Stanford, have included the discovery and subsequent development of a monoclonal antibody to block homing to the inflamed brain, leading to natalizumab, an approved therapeutic for two autoimmune diseases: relapsing-remitting MS and for inflammatory bowel disease. Multiple attempts to develop new therapies for autoimmune disease are described here: The trimolecular complex and the immune synapse serve as one major set of targets, with attempts to inhibit particular major histocompatibility molecules, the variable regions of the T cell receptor, and CD4. Other approaches focusing on antigen-specific tolerance include ongoing attempts with tolerizing DNA vaccines in type 1 diabetes. Finally, the repurposing of popular drugs approved for other indications, including statins and inhibitors of angiotensin converting enzyme is under development and showing promise in the clinic, particularly for secondary progressive multiple sclerosis. The milieu within Stanford Immunology has helped to nurture these efforts to translate discoveries in immunology and to take them from bench to bedside. PMID- 24771484 TI - Security enhancement of a biometric based authentication scheme for telecare medicine information systems with nonce. AB - Telecare medicine information systems (TMIS) present the platform to deliver clinical service door to door. The technological advances in mobile computing are enhancing the quality of healthcare and a user can access these services using its mobile device. However, user and Telecare system communicate via public channels in these online services which increase the security risk. Therefore, it is required to ensure that only authorized user is accessing the system and user is interacting with the correct system. The mutual authentication provides the way to achieve this. Although existing schemes are either vulnerable to attacks or they have higher computational cost while an scalable authentication scheme for mobile devices should be secure and efficient. Recently, Awasthi and Srivastava presented a biometric based authentication scheme for TMIS with nonce. Their scheme only requires the computation of the hash and XOR functions.pagebreak Thus, this scheme fits for TMIS. However, we observe that Awasthi and Srivastava's scheme does not achieve efficient password change phase. Moreover, their scheme does not resist off-line password guessing attack. Further, we propose an improvement of Awasthi and Srivastava's scheme with the aim to remove the drawbacks of their scheme. PMID- 24771485 TI - Oriented bone formation using biomimetic fibrin hydrogels with three-dimensional patterned bone matrices. AB - Cortical bone exerts its biological properties through internal orientations of hydroxyapatite. Recently, we succeeded in fabricating three-dimensional (3D) patterns of bone matrices using fibrin gels. We hypothesized that these fibrin gels would induce cortical bone-like tissue in vivo and offer promising prospects for biomimetic materials. The purposes of this study were to assess the characteristics of osteoblastic-induced fibrin gels in vitro and evaluate whether fibrin gels with biomimetic matrices formed cortical bone-like tissue in vivo. When bone marrow stromal cell (BMSC)-containing fibrin gels were uniaxially fixed and cultured, BMSCs became aligned parallel to the fixed direction. The tensile strengths of the gels increased dramatically from 1.5 to 218 kPa after 50 days in culture. Furthermore, Fourier-transform infrared spectroscopy revealed that the fibrin gel constituents changed into those of native bone. Quantitative analyses of specific components demonstrated that the amounts of calcium and osteopontin in the gels increased with prolonged culture. After subcutaneous implantation into immunodeficient mice, cortical bone-like tissues that possessed layered structures were formed. The results indicated that 3D patterned bone matrices induced 3D patterned cortical bone formation in vivo. These biomimetic materials containing 3D patterned bone matrices are promising tools for the field of bone regenerative medicine. PMID- 24771486 TI - Movement of cyantraniliprole in plants after foliar applications and its impact on the control of sucking and chewing insects. AB - BACKGROUND: Given the physical properties of insecticides, there is often some movement of these compounds within crop plants following foliar application. In this context, movement of two formulations of cyantraniliprole, an anthranilic diamide, was characterized for translocation to new growth, distribution within a leaf and penetration through the leaf cuticle. RESULTS: Upward movement of cyantraniliprole to new plant growth via the xylem was confirmed using (14) C radiolabeled cyantraniliprole and from Helicoverpa zea mortality on tomato leaves that had not been directly treated. Within a leaf there was significant acropetal movement (base to apex) of cyantraniliprole, but no significant basipetal movement (apex to base). Translaminar movement, the ability of a compound to penetrate the leaf cuticle, was demonstrated in a variety of plants, both with and without the use of adjuvants, by treating only the adaxial surface of the leaf and measuring control of diamondback moth (Plutella xylostella), green peach aphid (Myzus persicae) and sweetpotato whitefly (Bemisia tabaci) exposed in clip cages to the untreated abaxial surface. CONCLUSION: The plant mobility and plant protection of cyantraniliprole is discussed with implications for use in insect resistance management and integrated pest management programs. PMID- 24771487 TI - Synthesis and characterization of two-photon chromophores based on a tetrasubstituted tetraethynylethylene scaffold. AB - A new series of model dye molecules composed of three multibranched analogues based on the tetrasubstituted tetraethynylethylene structural motif have been synthesized and experimentally shown to possess strong and widely dispersed two photon absorption (2PA) in the near-IR region. It was found that the spectral position of the major 2PA band could be tuned by the electronic nature of the selected substitution units. The studied model fluorophores also exhibited fairly low photodegradation of their fluorescence intensity even under prolonged UV light irradiation, which is beneficial for the development of fluorescence probes that are needed for long-term light exposure. Furthermore, representative chromophores were selected to demonstrate the power-control properties within the femtosecond and nanosecond time domains. PMID- 24771488 TI - Late-onset obsessive-compulsive disorder associated with left cerebellar lesion. AB - The onset of obsessive-compulsive disorder (OCD) after age 50 is rare and generally related to an organic etiology. An involvement of fronto-striatal circuits has been strongly suggested, whereas cerebellum remains so far scarcely explored. We present here the description of a "pure" late-onset OCD associated with a cerebellar lesion, neither comorbid with other mental disorders nor with neurological syndromes. To our knowledge, this condition was not previously described in literature. The patient is a 62-year-old woman who developed a late onset OCD associated with a left cerebellar lesion due to an arachnoid cyst in the left posterior fossa. We debate the possible role of the cerebellar lesion in favoring a transition from a predisposing liability (namely an obsessive compulsive personality disorder and a depressive status) to the onset of OCD in this woman. PMID- 24771489 TI - Undecussated superior cerebellar peduncles and absence of the dorsal transverse pontine fibers: a new axonal guidance disorder? AB - Axonal guidance disorders are a newly recognized group of diseases of the human central nervous system. These disorders are characterized by white matter tracts with abnormal course and failure to cross the midline or presence of ectopic white matter tracts. Diffusion tensor imaging (DTI) and fiber tractography are suitable neuroimaging tools to detect morphological abnormalities in the course, decussation, and location of white matter tracts. We report on a 6.5-year-old child with significant global developmental delay. Axial color-coded fractional anisotropy (FA)-maps revealed absence of (1) the midline "focal red dot" at the level of the pontomesencephalic junction representing absence of decussation of the superior cerebellar peduncles and (2) the dorsal component of the transverse pontine fibers. These findings are highly suggestive of an axonal guidance disorders. The complete neuroimaging phenotype of this child does not match well known diseases with similar DTI findings. We show how DTI reveals important information of microstructural brain malformations that may go undetected or remains underestimated and consequently DTI may suggest the possible pathomechanism. We conclude that this child may be suffering from a not yet described subtype of an axonal guidance disorder. PMID- 24771490 TI - A novel cell migratory zone in the developing hippocampal formation. AB - The hippocampal formation (HF) is a unique structure in the mammalian brain and is subdivided into the dentate gyrus, Ammon's horn, and subiculum by their functions and connectivity in the neuronal circuit. Because behaviors of the neural stem cells, neuronal progenitors, and the differentiating neurons are complex during hippocampal morphogenesis, the differentiation of these subdivisions has not been well understood. In this study, we investigated embryonic and postnatal expression of the proteins Prox1, Math2, and Ctip2, which clearly indicate principal cells of the dentate gyrus (Prox1 positive) and Ammon's horn (Math2 and Ctip2 positive). Expression patterns of Prox1 and Math2 were consistent with previously suggested localization of migratory pathways of the dentate granule cells and hippocampal pyramidal cells. Interestingly, we found intermingling of Prox1-expressing cells and Math2-expressing cells in a cell migratory stream, suggesting previously unknown behaviors of differentiating cells of the HF. PMID- 24771491 TI - KSHV-associated multicentric Castleman disease: A tangle of different entities requiring multitarget treatment strategies. AB - Multicentric Castleman Disease (MCD) is a lymphoproliferative disorder presenting with heterogeneous pathological and clinical features. It comprises disease entities with a complex aetiology and overlapping pathogenesis. MCD can be found in association with HIV infection, plasma-cell dyscrasias, Kaposi sarcoma (KS), B cell lymphomas including primary effusion lymphoma (PEL) and its solid variant, and Hodgkin lymphoma. In KSHV-associated MCD cases, a common association is KS and a specific variant of lymphoma referred to as "plasmablastic lymphoma," also called "large B-cell lymphoma arising in KSHV-associated MCD" lacking EBV infection. MCD is often referred to as human interleukin-6 (hIL-6) syndrome, since an overproduction of IL-6 occurs in MCD-associated diseases as well as in MCD itself. hIL-6 and a viral IL-6 (vIL-6) homolog encoded by KSHV can independently or together lead to flares of KSHV-associated MCD. Recently, a new clinical entity was proposed to describe a severe systemic infection/reactivation of KSHV: KSHV inflammatory syndrome (KICS). KICS may contribute in inducing the inflammatory symptoms seen in some patients with severe KS or PEL. The precise relationship of KICS to KSHV-associated MCD is unclear and it is possible that KICS may be prodromal symptoms to frank KSHV-associated MCD. Options for treatment of KSHV-associated MCD and related diseases include monoclonal antibodies, chemotherapy, immune modulators, virus-activated cytotoxic therapy and antiviral therapies. A comprehensive understanding of the intricacies of the HIV-KSHV coinfection will probably lead to additional advances in therapy and managements for these disorders. PMID- 24771492 TI - The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. AB - The goal of our study was to estimate the prevalence of osteoporosis and low bone mass based on bone mineral density (BMD) at the femoral neck and the lumbar spine in adults 50 years and older in the United States (US). We applied prevalence estimates of osteoporosis or low bone mass at the femoral neck or lumbar spine (adjusted by age, sex, and race/ethnicity to the 2010 Census) for the noninstitutionalized population aged 50 years and older from the National Health and Nutrition Examination Survey 2005-2010 to 2010 US Census population counts to determine the total number of older US residents with osteoporosis and low bone mass. There were more than 99 million adults aged 50 years and older in the US in 2010. Based on an overall 10.3% prevalence of osteoporosis, we estimated that in 2010, 10.2 million older adults had osteoporosis. The overall low bone mass prevalence was 43.9%, from which we estimated that 43.4 million older adults had low bone mass. We estimated that 7.7 million non-Hispanic white, 0.5 million non Hispanic black, and 0.6 million Mexican American adults had osteoporosis, and another 33.8, 2.9, and 2.0 million had low bone mass, respectively. When combined, osteoporosis and low bone mass at the femoral neck or lumbar spine affected an estimated 53.6 million older US adults in 2010. Although most of the individuals with osteoporosis or low bone mass were non-Hispanic white women, a substantial number of men and women from other racial/ethnic groups also had osteoporotic BMD or low bone mass. PMID- 24771493 TI - Anticoagulant treatment for subsegmental pulmonary embolism. AB - BACKGROUND: Acute pulmonary embolism (PE) is a common cause of death, accounting for 50,000 to 200,000 deaths annually. It is the third most common cause of mortality among the cardiovascular diseases, after coronary artery disease and stroke.The advent of multi-detector computed tomographic pulmonary angiography (CTPA) has allowed better assessment of PE regarding visualisation of the peripheral pulmonary arteries, increasing its rate of diagnosis. More cases of peripheral PEs, such as isolated subsegmental PE (SSPE) and incidental PE, have thereby been identified. These two conditions are usually found in patients with few or none of the classic PE symptoms such as haemoptysis or pleuritic pain, acute dyspnoea or circulatory collapse. However, in patients with reduced cardio pulmonary (C/P) reserve the classic PE symptoms can be found with isolated SSPEs. Incidental SSPE is found casually in asymptomatic patients, usually by diagnostic imaging performed for other reasons (for example routine CT for cancer staging in oncologic patients).Traditionally, all PEs are anticoagulated in a similar manner independent of the location, number and size of the thrombi. It has been suggested that many patients with SSPE may be treated without benefit, increasing adverse events by possible unnecessary use of anticoagulants.Patients with isolated SSPE or incidental PE may have a more benign clinical presentation compared with those with proximal PEs. However, the clinical significance in patients and their prognosis have to be studied to evaluate whether anticoagulation therapy is required. OBJECTIVES: To assess the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co ordinator searched the Specialised Register (last searched October 2013) and CENTRAL (2013, Issue 9). MEDLINE, EMBASE, LILACS and clinical trials databases were also searched (October 2013). SELECTION CRITERIA: Randomised controlled trials of anticoagulation therapy versus no intervention in patients with SSPE or incidental SSPE. DATA COLLECTION AND ANALYSIS: Two review authors inspected all citations to ensure reliable selection. We planned for two review authors to independently extract data and to assess the methodological quality of identified trials using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: No studies were identified that met the inclusion criteria. AUTHORS' CONCLUSIONS: There is no randomised controlled trial evidence for the effectiveness and safety of anticoagulation therapy versus no intervention in patients with isolated subsegmental pulmonary embolism (SSPE) or incidental SSPE, and therefore we can not draw any conclusions. Well-conducted research is required before informed practice decisions can be made. PMID- 24771494 TI - AAML0523: a report from the Children's Oncology Group on the efficacy of clofarabine in combination with cytarabine in pediatric patients with recurrent acute myeloid leukemia. AB - BACKGROUND: The discovery of new, effective non-anthracycline-based reinduction regimens for children with recurrent acute myeloid leukemia (AML) is critical. In this phase 1/2 study, the tolerability and overall response rate of clofarabine in combination with cytarabine was investigated in children with recurrent/refractory AML. METHODS: AAML0523 enrolled 49 children with AML in first recurrence or who were refractory to induction therapy. The study consisted of a dose-finding phase (9 patients) and an efficacy phase (40 patients). Two children received clofarabine at a dose of 40 mg/m(2)/day and 47 children at a dose of 52 mg/m(2)/day. RESULTS: Toxicities typical for intensive chemotherapy regimens were observed at all doses of clofarabine. The recommended pediatric phase 2 dose of clofarabine in combination with cytarabine was 52 mg/m(2)/day for 5 days. Of 48 evaluable patients, the overall response rate (complete remission plus complete remission with partial platelet recovery) was 48%. Four patients met conventional criteria for complete remission with incomplete count recovery. Twenty-one of 23 responders subsequently underwent hematopoietic stem cell transplantation. The overall survival rate at 3 years was 46% for responders compared with 16% for nonresponders (P < .001). Patients found to have no minimal residual disease at the end of the first cycle by flow cytometric analysis had superior overall survival after 1 year (100% vs 38%; P = .01). CONCLUSIONS: The combination of clofarabine and cytarabine yielded an acceptable response rate without excess toxicity in children with recurrent AML. The nearly 50% survival rate reported in responders is highly encouraging in these high-risk patients and suggests that this combination is an effective bridge to hematopoietic stem cell transplantation. PMID- 24771495 TI - Bioinformatics insight into the spike glycoprotein gene of field porcine epidemic diarrhea strains during 2011-2013 in Guangdong, China. AB - Three strains of porcine epidemic diarrhea virus (PEDV) were isolated from dead or diseased pigs at different swine farms in Guangdong during 2011-2013, and their S genes were sequenced. In the same period, seven PEDV strains were also isolated in Guangdong by other laboratories. The spike sequences of 10 Guangdong isolates were compared with vaccine strains and reference pathogenic isolates using six bioinformatics tools. The results revealed that 10 Guangdong strains, excluding strain GDS03, had distinct characteristics in terms of primary structure, secondary structure, high-specificity N-glycosylation sites, potential phosphorylation sites, and palmitoylation sites. Phylogenetic analysis also confirmed these findings and revealed that all PEDV strains were clustered into three distinct groups. Ten Guangdong strains, not including GDS03, belong to Group 1, whereas four vaccine strains and GDS03 belong to Group 3, which is evolutionarily distant from Group 1. Alignment analysis of the neutralizing region amino acid sequences indicated that the amino acid substitutions of Y/D766S, T549S, and G594S that are present in the Guangdong strains, not including GDS03, were a sign of predominant genetic changes among the isolated strains. GDS03 is closely related to the 83P-5 vaccine strain, which suggests that it might represent re-isolation of the vaccine strain or vaccine variants. Taken together, these results indicate that there have been predominant new strains circulating in Guangdong from 2011 to 2013, and the circulating PEDV strains have a genetic composition that is distant from reference strains, especially the vaccine strains; however, the vaccinations might also provide some level of cross-protection, as there have been no changes in the neutralizing epitopes of SS2 and 2C10. This explains why there have been constant but infrequent outbreaks recently in comparison to late 2010 in which PEDV outbreaks were more frequent and severe. In addition, the USA-Colorado-2013 strain had the same amino acid substitutions in the neutralizing regions as the Guangdong strains except GDS03, which suggests that the information and strategies in this study may play role in PEDV variant research in other countries. PMID- 24771498 TI - Tacrolimus therapy in adult-onset steroid-resistant nephrotic syndrome due to a focal segmental glomerulosclerosis single-center experience. AB - INTRODUCTION: Management of adults with steroid-resistant (SR) nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) is a challenging task. Is tacrolimus (TAC) effective in this situation without serious adverse effects? This prospective study was done to answer this question. MATERIALS AND METHODS: In patients with SR nephrotic syndrome due to FSGS, oral TAC (0.1 mg/kg/day) was started targeting a trough level of 5-10 ng/mL along with oral prednisolone (0.15 mg/kg/day) for 48 weeks. In patients with complete remission (CR), TAC dose was reduced to a target of 3-6 ng/mL whereas in partial responders, TAC trough levels were kept at 5-10 ng/mL. TAC was discontinued in those with no remission at 24 weeks and was deemed TAC resistant. Outcome, namely CR and partial remission (PR), was assessed at the end of 24 and 48 weeks. All patients were prospectively followed for 60 weeks. Relapses after CR or PR were recorded; adverse effects, namely nephrotoxicity (>25% rise in creatinine), cosmetic effects, infections and hyperglycemia, were recorded every month. RESULTS: A total of 44 SR-FSGS [not otherwise specified 33 (75%), tip lesion 03 (6.8%) and cellular variant 8 (18.1%)] were analyzed. Mean age was 25.16 +/- 8.26 (18-51) years. Of 44 patients, CR and PR were achieved in 17 (38.6%) and 06 (13.6%) patients, respectively. TAC resistance was seen in 21 (47.7%) patients. Time taken to achieve remission was 15.2 +/- 6 weeks. Five (21.7%) patients with CR had relapse on tapering the dose and seven (30.4%) after stopping TAC. Reversible nephrotoxicity was seen in seven (15.9%) and irreversible in four patients (9%). TAC-related diarrhea was the problem in 10 (22.7%), and infections were seen in 19 patients (43.1%). Impaired fasting glucose and diabetes mellitus were seen in 10 patients (22.7%). CONCLUSION: TAC is an effective agent in the management of SR-FSGS. However, strict renal function and blood sugar monitoring is required due to its potential nephrotoxicity and diabetogenic potential. PMID- 24771497 TI - Agenesis of the corpus callosum and autism: a comprehensive comparison. AB - The corpus callosum, with its ~200 million axons, remains enigmatic in its contribution to cognition and behaviour. Agenesis of the corpus callosum is a congenital condition in which the corpus callosum fails to develop; such individuals exhibit localized deficits in non-literal language comprehension, humour, theory of mind and social reasoning. These findings together with parent reports suggest that behavioural and cognitive impairments in subjects with callosal agenesis may overlap with the profile of autism spectrum disorders, particularly with respect to impairments in social interaction and communication. To provide a comprehensive test of this hypothesis, we directly compared a group of 26 adults with callosal agenesis to a group of 28 adults with a diagnosis of autism spectrum disorder but no neurological abnormality. All participants had full-scale intelligence quotient scores >78 and groups were matched on age, handedness, and gender ratio. Using the Autism Diagnostic Observation Schedule together with current clinical presentation to assess autistic symptomatology, we found that 8/26 (about a third) of agenesis subjects presented with autism. However, more formal diagnosis additionally involving recollective parent-report measures regarding childhood behaviour showed that only 3/22 met complete formal criteria for an autism spectrum disorder (parent reports were unavailable for four subjects). We found no relationship between intelligence quotient and autism symptomatology in callosal agenesis, nor evidence that the presence of any residual corpus callosum differentiated those who exhibited current autism spectrum symptoms from those who did not. Relative to the autism spectrum comparison group, parent ratings of childhood behaviour indicated children with agenesis were less likely to meet diagnostic criteria for autism, even for those who met autism spectrum criteria as adults, and even though there was no group difference in parent report of current behaviours. The findings suggest two broad conclusions. First, they support the hypothesis that congenital disruption of the corpus callosum constitutes a major risk factor for developing autism. Second, they quantify specific features that distinguish autistic behaviour associated with callosal agenesis from autism more generally. Taken together, these two findings also leverage specific questions for future investigation: what are the distal causes (genetic and environmental) determining both callosal agenesis and its autistic features, and what are the proximal mechanisms by which absence of the callosum might generate autistic symptomatology? PMID- 24771499 TI - The impact of induction therapy on the homeostasis and function of regulatory T cells in kidney transplant patients. AB - BACKGROUND: To evaluate the influence of induction therapy on Tregs we investigated their origin, kinetics and function in kidney transplant patients after treatment with T-cell depleting rabbit antithymocyte globulin (rATG) or IL 2 receptor antagonist basiliximab. METHODS: Flow cytometry was used to study thymopoiesis by CD31+ naive Tregs, homeostatic proliferation by Ki-67+ Tregs and Treg origin by the expression of Helios (nTreg-marker). FACSsorted Tregs were analysed for the demethylation status of the Treg-specific demethylated region (TSDR) of the FoxP3 gene, and Treg-suppressive function. RESULTS: Differential effects of rATG and basiliximab induction therapies were measured on the repopulation kinetics of Tregs. While decreased absolute numbers of Tregs were found in both study arms, increased percentages of Tregs were found in rATG treated patients and decreased percentages in basiliximab treated patients. In both groups, Treg repopulation was the result of homeostatic proliferation and not of thymopoiesis. At 1 month after rATG and 6 months after basiliximab therapy, high percentages of Ki-67+ Treg were measured, which in the rATG group, was accompanied by low percentages of Ki-67+Helios+ Treg, and by cells with a demethylated TSDR in the FoxP3 gene. After both rATG and basiliximab therapy, repopulated Tregs inhibited proliferation of allo-antigen activated T effector cells (Teff). CONCLUSIONS: In kidney transplant patients, repopulation of Treg after rATG and basiliximab therapy is the result of homeostatic proliferation and not of thymopoiesis. These repopulated Treg were functional after both induction strategies; however only after rATG therapy, were increased proportions of Helios(-) methylated FoxP3 Treg found. PMID- 24771500 TI - Identifying the interacting roles of stressors in driving the global loss of canopy-forming to mat-forming algae in marine ecosystems. AB - Identifying the type and strength of interactions between local anthropogenic and other stressors can help to set achievable management targets for degraded marine ecosystems and support their resilience by identifying local actions. We undertook a meta-analysis, using data from 118 studies to test the hypothesis that ongoing global declines in the dominant habitat along temperate rocky coastlines, forests of canopy-forming algae and/or their replacement by mat forming algae are driven by the nonadditive interactions between local anthropogenic stressors that can be addressed through management actions (fishing, heavy metal pollution, nutrient enrichment and high sediment loads) and other stressors (presence of competitors or grazers, removal of canopy algae, limiting or excessive light, low or high salinity, increasing temperature, high wave exposure and high UV or CO2 ), not as easily amenable to management actions. In general, the cumulative effects of local anthropogenic and other stressors had negative effects on the growth and survival of canopy-forming algae. Conversely, the growth or survival of mat-forming algae was either unaffected or significantly enhanced by the same pairs of stressors. Contrary to our predictions, the majority of interactions between stressors were additive. There were however synergistic interactions between nutrient enrichment and heavy metals, the presence of competitors, low light and increasing temperature, leading to amplified negative effects on canopy-forming algae. There were also synergistic interactions between nutrient enrichment and increasing CO2 and temperature leading to amplified positive effects on mat-forming algae. Our review of the current literature shows that management of nutrient levels, rather than fishing, heavy metal pollution or high sediment loads, would provide the greatest opportunity for preventing the shift from canopy to mat-forming algae, particularly in enclosed bays or estuaries because of the higher prevalence of synergistic interactions between nutrient enrichment with other local and global stressors, and as such it should be prioritized. PMID- 24771501 TI - Reply to Denoeud-Ndam et al. PMID- 24771502 TI - Is cotrimoxazole prophylaxis effective to prevent malaria in HIV-infected pregnant women? PMID- 24771504 TI - Mother-to-child transmission of Trypanosoma cruzi infection (Chagas disease): a neglected problem. AB - Congenital Chagas disease may be considered a global health problem and the underdiagnosis of congenital infections should be a matter of concern. Vertical transmission is an important mode of transmission of Trypanosoma cruzi infection in non-endemic areas. Treatment in the early phases of the infection can prevent progression of the disease and is curative in the majority of cases. Prevention strategies should focus on early detection and treatment of congenital cases, screening at-risk women during pregnancy and treatment of non-pregnant women of childbearing age. Management of congenital Chagas disease and T. cruzi infection during pregnancy is discussed. PMID- 24771503 TI - Mitochondrial PCR-based malaria detection in saliva and urine of symptomatic patients. AB - BACKGROUND: Malaria can be diagnosed in saliva and urine using mitochondrial PCR detection of Plasmodium DNA. METHODS: Blood, saliva and urine were collected from 99 febrile patients referred to health centers in Sistan and Baluchestan Province, southeastern Iran, from May to November 2011. The mitochondrial cytochrome b gene of Plasmodium falciparum and Plasmodium vivax was targeted in saliva, urine and blood samples using nested PCR. RESULTS: Nested PCR proved to be more sensitive than microscopy for the diagnosis of sub-microscopic and mixed species infections. The results of nested PCR amplifications of saliva and urine samples showed the same specificity of 97% and sensitivity of 91% and 70%, respectively. Nested PCR amplifications of saliva samples and microscopy showed the greatest area under the receiver operating characteristic (ROC) curve and were more accurate than nested PCR amplifications of urine samples. CONCLUSION: Nested PCR amplification of saliva samples showed good levels of detection of mitochondrial Plasmodium DNA as compared to nested PCR of blood (k=0.84; AUC=0.94), which was used as a reference standard. Based on the results of nested PCR as well as the advantages of saliva sampling, we suggest that saliva could be an alternative to blood, in malaria diagnosis, in cases where repeat sampling is required. Further studies are needed to validate these findings. PMID- 24771505 TI - Effects of pulsed ultrasound on Escherichia coli and Staphylococcus aureus. AB - BACKGROUND: Common disinfection methods like biocides, ultraviolet light and heat treatment are not efficient enough to succeed in bacterial inactivation for some microorganisms have become resistant to them. The aim of this study was to obtain information about the effect of pulsed ultrasound sonication with 30 kHz frequency and 100 W power on the inactivation capability of two bacteria groups, namely Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923, in physiological water samples. METHODS: The ultrasonic irradiation of bacterial samples with different populations of 5*10(3), 1.5*10(4) and 3*10(4) cfu/ml was performed at constant frequency with various treatment times. The specific energies (gamma) were calculated for these different concentrations of E. coli and S. aureus. The rate constant of ultrasonic inactivation was estimated in the linear region of the plot representing survival ratio logarithm vs sonication time. RESULTS: While a significant death rate for E. coli was observed by ultrasonic treatment, contrary to expectation, an increase in S. aureus populations was observed. CONCLUSIONS: Considering the widespread use of ultrasound for the sterilization of tools and equipment used in hospitals, the obtained results indicate that ultrasound sonication is not a suitable method for the elimination of S. aureus, a major hospital pathogen. PMID- 24771506 TI - Establishment of endogenous human tympanic membrane-derived somatic stem cells for stem cell therapy. AB - We examined whether somatic stem cells (SSCs) exist in human tympanis membrane (hTM) and whether they could be differentiated into neural lineage cells. The hTM SSCs could generate neurospheres, which could differentiate into specific neural linage cells under specific differentiation conditions. Also, we conducted another experiment that led to differentiation into neurospheres and neuronal lineage cells, which occurred independent of each other. Independent of each other condition, hTM-SSCs could differentiate into neurospheres, and subsequently, into neuronal lineage cells. However, NS-NR neural differentiation rates are higher than independent of each other culture system. PMID- 24771507 TI - A novel approach: Beauveria bassiana granules applied to nursery soil for management of rice water weevils in paddy fields. AB - BACKGROUND: Spraying of entomopathogenic fungi formulated as wettable powders and suspension concentrates based on oils or water has been used for the management of crop pests. However, the use of fungal granules to control paddy field pests has not been fully explored. Herein, several Beauveria bassiana isolates (ERL1170, ERL1578 and ERL836) were produced as granules using a millet-based solid culture. The granules were applied to the rice nursery 3 days before transplanting, and their control efficacy against rice water weevils was determined in paddy fields. RESULTS: The solid cultures produced ~1 * 10(8) conidia g(-1) of millet grains 10 days after the inoculation. The granules were applied to the soil in the rice nursery 3 days before the rice seedlings were transplanted in the paddy fields. Rice in plots with granules of ERL1578 had 17.3% leaf damage (74% control efficacy) 14 days post-application, whereas rice plants in the untreated control had 66.5% damage. Rice plants treated in the nursery with ERL1170 and ERL836 had 52-54% damage. In the rice plots previously treated with ERL1578, the smallest numbers of larvae and adults were observed 38 days post-application. In laboratory conditions, ERL1578-treated larvae turned pink and were covered with mycelial mass. CONCLUSION: Applications of millet based B. bassiana granules on rice nursery soil can be an effective and efficient biological control strategy for the management of rice water weevils. This method can be relatively inexpensive and requires less labor than practices involving the spraying of fungi directly on rice in paddy fields. PMID- 24771508 TI - Oxidative-induction time as a measure of vitamin E concentration in ultra-high molecular weight polyethylene. AB - A novel, sensitive method for quantifying an equivalent antioxidant concentration, specifically vitamin E (VE), in postprocessed ultra-high molecular weight polyethylene (UHMWPE) for orthopedic implants is presented. This method correlates oxidative-induction time (OIT) determined from differential scanning calorimetry with starting VE weight percent in solvent blended samples using a nonlinear power law fit. The generated calibration curve reliably determined the equivalent VE concentration down to blended concentrations lower than 0.007 wt %, with a measurement uncertainty of 0.0009 wt %. This measurement uncertainty implies a detection limit that is significantly lower than currently achievable with the established method using Fourier transform infrared spectroscopy to calculate a VE index. However, exact processes that are influencing the OIT in irradiated materials are unclear at this time. UHMWPE blended with VE in powder, consolidated and irradiated form were investigated. In addition, intralaboratory results give support that this technique may lend itself to standardization in quality control and verification. PMID- 24771510 TI - Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism. AB - The current paradigm stipulates that inhibition of histone deacetylase (HDAC) 6 is essential for the combinatorial effect of proteasome and HDAC inhibitors for the treatment of cancers. Our study aims to investigate the effect of combining different class I HDAC inhibitors (without HDAC6 action) with a proteasome inhibitor on apoptosis of nasopharyngeal carcinoma (NPC). We found that combination of a proteasome inhibitor, bortezomib, and several class I HDAC inhibitors, including MS-275, apicidin and romidepsin, potently induced killing of NPC cells both in vitro and in vivo. Among the drug pairs, combination of bortezomib and romidepsin (bort/romidepsin) was the most potent and could induce apoptosis at low nanomolar concentrations. The apoptosis of NPC cells was reactive oxygen species (ROS)- and caspase-dependent but was independent of HDAC6 inhibition. Of note, bort/romidepsin might directly suppress the formation of aggresome through the downregulation of c-myc. In addition, two markers of endoplasmic reticulum (ER) stress-induced apoptosis, ATF-4 and CHOP/GADD153, were upregulated, whereas a specific inhibitor of caspase-4 (an initiator of ER stress induced apoptosis) could suppress the apoptosis. When ROS level in the NPC cells was reduced to the untreated level, ER stress-induced caspase activation was abrogated. Collectively, our data demonstrate a model of synergism between proteasome and class I HDAC inhibitors in the induction of ROS-dependent ER stress-induced apoptosis of NPC cells, independent of HDAC6 inhibition, and provide the rationale to combine the more specific and potent class I HDAC inhibitors with proteasome inhibitors for the treatment of cancers. PMID- 24771511 TI - Digitalis for treatment of heart failure in patients in sinus rhythm. AB - BACKGROUND: Digitalis glycosides have been in clinical use for the treatment of heart failure (HF) for longer than 200 years. In recent years, several trials have been conducted to address concerns about their efficacy and toxicity. OBJECTIVES: To examine the effectiveness of digitalis glycosides in treating HF in patients with normal sinus rhythm. To examine the effects of digitalis in patients taking diuretics and angiotensin-converting enzyme inhibitors; in patients with varying severity and duration of disease; in patients with prior exposure to digitalis versus no prior exposure; and in patients with "HF due to systolic dysfunction" versus "HF with preserved ejection fraction." SEARCH METHODS: Searches on the following databases were updated in May 2013: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Dissertation Abstracts. Annual meeting abstracts of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology were searched from 1996 to March 2013. In addition, reference lists provided by the pharmaceutical industry (GlaxoSmithKline and Covis Pharma) were searched. SELECTION CRITERIA: Included were randomized placebo-controlled trials of 20 or more adult participants of either sex with symptomatic HF who were studied for seven weeks or longer. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of HF such as acute ischemic heart disease or myocarditis was present. DATA COLLECTION AND ANALYSIS: Articles selected from the searches described above were evaluated in a joint effort of the review authors. The staff of the Cochrane Heart Group ran searches on the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. MAIN RESULTS: No new studies were identified in the updated searches. Thirteen studies (7896 participants) are included, and major endpoints of mortality, hospitalization, and clinical status, based respectively on 8, 4, and 12 of these selected studies, were recorded and analyzed. The data show no evidence of a difference in mortality between treatment and control groups, whereas digitalis therapy is associated with lower rates of both hospitalization and clinical deterioration. The largest study, in which most participants were taking angiotensin-converting enzyme inhibitors, showed a significant rise in "other cardiac" deaths, possibly due to arrhythmias. However collectively, these findings were based on studies done before beta-blockers, as well as angiotensin receptor blockers and aldosterone antagonists, became widely used to treat HF. AUTHORS' CONCLUSIONS: The literature indicates that digitalis may have a useful role in the treatment of patients with HF who are in normal sinus rhythm. New trials are needed to elucidate the importance of the dosage of digitalis and its usefulness in the era of beta-blockers and other agents shown to be effective in treating HF. PMID- 24771509 TI - Mixed-species biofilm compromises wound healing by disrupting epidermal barrier function. AB - In chronic wounds, biofilm infects host tissue for extended periods of time. This work establishes the first chronic preclinical model of wound biofilm infection aimed at addressing the long-term host response. Although biofilm-infected wounds did not show marked differences in wound closure, the repaired skin demonstrated compromised barrier function. This observation is clinically significant, because it leads to the notion that even if a biofilm infected wound is closed, as observed visually, it may be complicated by the presence of failed skin, which is likely to be infected and/or further complicated postclosure. Study of the underlying mechanisms recognized for the first time biofilm-inducible miR-146a and miR-106b in the host skin wound-edge tissue. These miRs silenced ZO-1 and ZO 2 to compromise tight junction function, resulting in leaky skin as measured by transepidermal water loss (TEWL). Intervention strategies aimed at inhibiting biofilm-inducible miRNAs may be productive in restoring the barrier function of host skin. PMID- 24771512 TI - Surface-grafted semiconductor layer prepared by surface initiated ring-opening polymerization of L-lysine NCA derivatives. AB - Asymmetric and symmetric L-lysine N-carboxylic anhydrides based on perylene bisimide derivatives were successfully synthesized and grafted onto silicon wafers via surface-initiated ring-opening polymerization. The grafted n-type semiconductor film was flat and compact, and its thickness could be tuned by variation of the polymerization conditions. PMID- 24771513 TI - Cortical interneuron loss and symptom heterogeneity in Huntington disease. AB - OBJECTIVE: The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons. METHODS: We undertook a double-blind study using stereological cell counting methods to quantify the 3 major types of gamma-aminobutyric acidergic interneurons (calbindin-D28k, calretinin, parvalbumin) in 13 HD cases of variable motor/mood symptomatology and 15 matched control cases in the primary motor and anterior cingulate cortices. RESULTS: In the primary motor cortex, there was a significant loss (57% reduction) of only calbindin interneurons (p=0.022) in HD cases dominated by motor symptoms, but no significant interneuron loss in cases with a dominant mood phenotype. In contrast, the anterior cingulate cortex showed a major significant loss in all 3 interneuron populations, with 71% loss of calbindin (p=0.001), 60% loss of calretinin (p=0.001), and 80% loss of parvalbumin interneurons (p=0.005) in HD cases with major mood disorder, and no interneuron loss was observed in cases with major motor dysfunction. INTERPRETATION: These findings suggest that region-specific degeneration of cortical interneurons is a key component in understanding the neural basis of symptom heterogeneity in HD. PMID- 24771514 TI - Photoinduced bending behavior of cross-linked azobenzene liquid-crystalline polymer films with a poly(oxyethylene) backbone. AB - Cross-linked azobenzene liquid-crystalline polymer films with a poly(oxyethylene) backbone are synthesized by photoinitiated cationic copolymerization. Azobenzene moieties in the film surface toward the light source are simultaneously photoaligned during photopolymerization with unpolarized 436 nm light and thus form a splayed alignment in the whole film. The prepared films show reversible photoinduced bending behavior with opposite bending directions when different surfaces of one film face to ultraviolet light irradiation. PMID- 24771516 TI - ThunderSTORM: a comprehensive ImageJ plug-in for PALM and STORM data analysis and super-resolution imaging. AB - ThunderSTORM is an open-source, interactive and modular plug-in for ImageJ designed for automated processing, analysis and visualization of data acquired by single-molecule localization microscopy methods such as photo-activated localization microscopy and stochastic optical reconstruction microscopy. ThunderSTORM offers an extensive collection of processing and post-processing methods so that users can easily adapt the process of analysis to their data. ThunderSTORM also offers a set of tools for creation of simulated data and quantitative performance evaluation of localization algorithms using Monte Carlo simulations. AVAILABILITY AND IMPLEMENTATION: ThunderSTORM and the online documentation are both freely accessible at https://code.google.com/p/thunder storm/. PMID- 24771515 TI - Concept and viability of androgen annihilation for advanced prostate cancer. AB - There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5alpha-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. PMID- 24771517 TI - Redundancy-weighting for better inference of protein structural features. AB - MOTIVATION: Structural knowledge, extracted from the Protein Data Bank (PDB), underlies numerous potential functions and prediction methods. The PDB, however, is highly biased: many proteins have more than one entry, while entire protein families are represented by a single structure, or even not at all. The standard solution to this problem is to limit the studies to non-redundant subsets of the PDB. While alleviating biases, this solution hides the many-to-many relations between sequences and structures. That is, non-redundant datasets conceal the diversity of sequences that share the same fold and the existence of multiple conformations for the same protein. A particularly disturbing aspect of non redundant subsets is that they hardly benefit from the rapid pace of protein structure determination, as most newly solved structures fall within existing families. RESULTS: In this study we explore the concept of redundancy-weighted datasets, originally suggested by Miyazawa and Jernigan. Redundancy-weighted datasets include all available structures and associate them (or features thereof) with weights that are inversely proportional to the number of their homologs. Here, we provide the first systematic comparison of redundancy-weighted datasets with non-redundant ones. We test three weighting schemes and show that the distributions of structural features that they produce are smoother (having higher entropy) compared with the distributions inferred from non-redundant datasets. We further show that these smoothed distributions are both more robust and more correct than their non-redundant counterparts. We suggest that the better distributions, inferred using redundancy-weighting, may improve the accuracy of knowledge-based potentials and increase the power of protein structure prediction methods. Consequently, they may enhance model-driven molecular biology. PMID- 24771518 TI - Modeling disease progression using dynamics of pathway connectivity. AB - MOTIVATION: Disease progression is driven by dynamic changes in both the activity and connectivity of molecular pathways. Understanding these dynamic events is critical for disease prognosis and effective treatment. Compared with activity dynamics, connectivity dynamics is poorly explored. RESULTS: We describe the M module algorithm to identify gene modules with common members but varied connectivity across multiple gene co-expression networks (aka M-modules). We introduce a novel metric to capture the connectivity dynamics of an entire M module. We find that M-modules with dynamic connectivity have distinct topological and biochemical properties compared with static M-modules and hub genes. We demonstrate that incorporation of module connectivity dynamics significantly improves disease stage prediction. We identify different sets of M modules that are important for specific disease stage transitions and offer new insights into the molecular events underlying disease progression. Besides modeling disease progression, the algorithm and metric introduced here are broadly applicable to modeling dynamics of molecular pathways. AVAILABILITY AND IMPLEMENTATION: M-module is implemented in R. The source code is freely available at http://www.healthcare.uiowa.edu/labs/tan/M-module.zip. PMID- 24771520 TI - Clinical and pathogenetic implications of occipital bending in depression. PMID- 24771519 TI - Within-patient correspondence of amyloid-beta and intrinsic network connectivity in Alzheimer's disease. AB - There is striking overlap between the spatial distribution of amyloid-beta pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-beta and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-beta plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-beta exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-beta on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-beta and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-beta on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-beta distributions. Here we compared spatial patterns of amyloid-beta-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-beta and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-beta aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-beta-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-beta pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-beta-plaque concentration. The local negative association between amyloid-beta and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-beta on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-beta and intrinsic connectivity, with the distribution of amyloid-beta pathology following functional connectivity gradients within and across intrinsic networks. PMID- 24771521 TI - Soil respiration under climate warming: differential response of heterotrophic and autotrophic respiration. AB - Despite decades of research, how climate warming alters the global flux of soil respiration is still poorly characterized. Here, we use meta-analysis to synthesize 202 soil respiration datasets from 50 ecosystem warming experiments across multiple terrestrial ecosystems. We found that, on average, warming by 2 degrees C increased soil respiration by 12% during the early warming years, but warming-induced drought partially offset this effect. More significantly, the two components of soil respiration, heterotrophic respiration and autotrophic respiration showed distinct responses. The warming effect on autotrophic respiration was not statistically detectable during the early warming years, but nonetheless decreased with treatment duration. In contrast, warming by 2 degrees C increased heterotrophic respiration by an average of 21%, and this stimulation remained stable over the warming duration. This result challenged the assumption that microbial activity would acclimate to the rising temperature. Together, our findings demonstrate that distinguishing heterotrophic respiration and autotrophic respiration would allow us better understand and predict the long term response of soil respiration to warming. The dependence of soil respiration on soil moisture condition also underscores the importance of incorporating warming-induced soil hydrological changes when modeling soil respiration under climate change. PMID- 24771522 TI - Duties to kin through a tragi-comic lens. AB - Euripides' Alcestis (1959) raises the issue of ethical duties within families and exposes the romantic postures and rhetoric that can dominate such discussions. Should anybody be asked to sacrifice themselves or even undergo significant health risks for members of their own family? (An issue that is also relevant in considering our duties to future generations in terms of the earth we leave to them.) The issue that is dramatized to a heroic level in Alcestis arises in live organ and tissue donation within a family and challenges the idea that families should be trusted to sort out solutions that they can all live with. Alcestis intensifies the debate because the sacrifice of one life for another is its topic but, in doing so, it exposes many traps lying in wait for ethicists and medical jurists who boldly enter such debates (where emotions create shifting ground on which angels fear to tread). PMID- 24771523 TI - Privacy in the context of "re-emergent" infectious diseases. PMID- 24771524 TI - Ultraviolet light-treated zirconia with different roughness affects function of human gingival fibroblasts in vitro: the potential surface modification developed from implant to abutment. AB - OBJECTIVES: To evaluate whether ultraviolet (UV) light irradiation of smooth and rough zirconia disks enhances its biocompatibility with human gingival fibroblasts (HGFs). MATERIALS AND METHODS: Zirconia disks were divided into four groups: smooth control (S-C), smooth with UV light treatment (S-UV), rough control (R-C), and rough with UV light treatment (R-UV). The surface morphology and wettability were analyzed, and X-ray photoelectron spectroscopy was carried out. The cultured HGFs' adhesive density, morphology, proliferation, and collagen synthesis were measured on different time points from 3 h to 7 days. RESULTS: After 24-h UV light treatment, contact angles decreased from 51.98 degrees (S-C) and 63.87 degrees (R-C) to 33.76 degrees (S-UV) and 36.15 degrees (R-UV). X ray photoelectron spectroscopy analysis showed that surface C/O ratio reduced from 1.86 and 2.39 to 1.33 and 1.19. After UV light treatment, cells initial spreading areas and perimeters were doubled on S-UV disks and nearly tripled on R UV disks. Three hours cell adhesion was enhanced on S-UV disks, and 24-h cell density was increased on R-UV. Cell proliferation of 48 or 72 h was all significantly changed on UV-treated disks. Cells on R-UV also released highest level of Col-1 after 3 and 7 days, whereas those on S-UV produced less levels compared with control. CONCLUSION: Our study demonstrated for the first time that UV light treatment on rough (Ra = 0.19 +/- 0.03 MUm) zirconia had a positive effect on behavior of HGFs, including 24-h cell adhesion, proliferation, and collagen release. The effect varied with surface roughness and time point. Surface morphology and hydrophilicity, as two interacted factors, both are governed on HGFs behavior. PMID- 24771525 TI - Development and application of a quantitative loop-mediated isothermal amplification method for detecting genetically modified maize MON863. AB - BACKGROUND: A SYBR Green I-based quantitative loop-mediated isothermal amplification (LAMP) assay was developed for the rapid detection of genetically modified maize MON863. A set of primers was designed based on the integration region of the Cry3Bb1 and tahsp17 genes. RESULTS: The qualitative and quantitative reaction conditions (dNTPs, betaine, primers, Mg(2+), Bst polymerase, temperature, reaction time) were optimized. The concentrations of Mg(2+) and betaine were found to be important to the LAMP assay. The detection limits of both qualitative and quantitative LAMP for MON863 were as low as 4 haploid genomic DNA, and the LAMP reactions can be completed within 1 h at an isothermal temperature of 65 degrees C. CONCLUSION: The results of this study demonstrate that this new SYBR Green I-based quantitative LAMP assay system is reliable, sensitive and accurate. PMID- 24771530 TI - Generation of a Magoh conditional allele in mice. AB - Magoh encodes a core component of the exon junction complex (EJC), which binds mRNA and regulates mRNA metabolism. Magoh is highly expressed in proliferative tissues during development. EJC components have been implicated in several developmental disorders including TAR syndrome, Richieri-Costa-Pereira syndrome, and intellectual disability. Existing germline null Magoh mice are embryonic lethal as homozygotes and perinatal lethal as heterozygotes, precluding detailed analysis of embryonic and postnatal functions. Here, we report the generation of a new genetic tool to dissect temporal and tissue-specific roles for Magoh in development and adult homeostasis. This Magoh conditional allele has two loxP sites flanking the second exon. Ubiquitous Cre-mediated deletion of the floxed allele in a heterozygous mouse (Magoh(del/+) ) causes 50% reduction of both Magoh mRNA and protein. Magoh(del/+) mice exhibit both microcephaly and hypopigmentation, thus phenocopying germline haploinsufficient Magoh mice. Using Emx1-Cre, we further show that conditional Magoh deletion in neural progenitors during embryonic development also causes microcephaly. We anticipate this novel conditional allele will be a valuable tool for assessing tissue-specific roles for Magoh in mammalian development and postnatal processes. PMID- 24771531 TI - The neglected role of resource manager in residency training. AB - OBJECTIVE: The goal of this study was to investigate residency training in the four roles of systems-based practice: patient care advocate, team member, information integrator, and resource manager. METHODS: The authors surveyed 457 psychiatry residents and fellows across 12 programs from April 2009 to November 2010. Residents were asked to rate the extent in which they were encouraged to perform behaviors consistent with systems-based practice. RESULTS: Approximately 52% residents (n=237) completed the survey. Differences in the average Likert ratings for the four roles were significant [F (3, 4,021)=122.152, p<0.001]. Residents were more likely to report routine encouragement to function as a team member (82%, OR=7.2, 95% CI=4.7-11.0), information integrator (77%, OR=5.4, 95% CI=3.6-8.1), or patient care advocate (74%, OR=4.6, 95% CI=3.1-6.8) compared to resource manager (38%). CONCLUSIONS: Based upon this study, residency training in resource management is relatively limited compared to other aspects of systems based practice. PMID- 24771532 TI - Efficacy of amitraz plus inactivated parapoxvirus ovis in the treatment of canine generalised demodicosis. AB - Canine generalised demodicosis (CGD) is a challenging disease to treat effectively. Inactivated parapoxvirus ovis (iPPVO) could help to accelerate treatment with acaricidial therapy by altering the immune response. This study was designed to investigate the effects of treating CGD with amitraz plus iPPVO in terms of clinical outcomes and blood parameters. The study involved 16 dogs ranging in age from eight months to six years and weighing between 10 and 40 kg. Eight dogs were treated with amitraz and eight with amitraz plus iPPVO. Biochemical analysis of whole blood and serum, including serum C reactive protein (CRP) and serum amyloid A (SAA), was performed. Skin scrapings were conducted on days 0, 10, 40, 80 and 120 of treatment, and mite numbers were recorded. Clinical remission was determined according to mite numbers and clinical scores. The difference in mean whole remission days between the amitraz group (104.3 days) and the amitraz+iPPVO group (84.5 days) was statistically significant (P<0.05). Mean clinical scores were also significantly better in the amitraz+iPPVO (5.60) group when compared with the amitraz group (7.65). No adverse reactions were observed in either group. In view of these findings, the use of iPPVO in conjunction with amitraz can be recommended for treating CGD. PMID- 24771533 TI - Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project. AB - BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate that was approved in 2011 for the treatment of patients with anaplastic large cell and Hodgkin lymphomas. The product label indicates that 3 patients who were treated with BV developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC virus-induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. In the current study, the authors reported 5 patients who developed BV associated PML, including 2 immunocompetent patients. METHODS: Case information was obtained from clinicians (4 patients) or a US Food and Drug Administration database (1 patient). RESULTS: All 5 patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of 3 BV doses (range, 2 doses-6 doses) and within a median of 7 weeks after BV initiation (range, 3 weeks-34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in the cerebrospinal fluid (2 patients) or central nervous system biopsy (3 patients); and brain magnetic resonance imaging scans with white matter abnormalities (5 patients). Four patients died at a median of 8 weeks (range, 6 weeks-16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. CONCLUSIONS: PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop after the initiation of BV treatment. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options. PMID- 24771534 TI - Hierarchically porous nickel oxide nanosheets grown on nickel foam prepared by one-step in situ anodization for high-performance supercapacitors. AB - Porous NiO nanosheets are successfully grown on nickel foam substrate through an in situ anodization by using molten KOH as the electrolyte. High-purity NiO is directly obtained by this one-step method without any subsequent treatment. The obtained NiO supported on nickel foam is used as a binder-free electrode for a supercapacitor and its pseudocapacitive behavior has been investigated by cyclic voltammetry and galvanostatic charge-discharge tests in a 6 M aqueous solution of KOH. Electrochemical data demonstrates that this binder-free electrode possesses ultrahigh capacitance (4.74 F cm(-2) at 4 mA cm(-2)), excellent rate capability, and cycling stability. After 1000 cycles, the areal capacitance value is 9.4 % lower than the initial value and maintains 85.4 % of the maximum capacitance value. PMID- 24771536 TI - Association of pial venous reflux with hemorrhage or edema in dural arteriovenous fistula. AB - OBJECTIVE: We investigated whether pial venous reflux (PVR) is associated with hemorrhage or edema in dural arteriovenous fistula (DAVF). METHODS: We evaluated the association of hemorrhage or edema with the occurrence of PVR or cortical venous reflux (CVR) in 222 patients with DAVF. We determined whether angiographic findings of PVR or CVR (more than Borden I or Cognard IIa) were associated with symptoms, lesion location, or brain lesion (hemorrhage or edema). We evaluated the lesion progression or the follow-up results after obliteration of the DAVF. RESULTS: Hemorrhage or edema developed in 18% (40/222) of the patients with DAVF and 55% (40/72) of the patients with PVR. There were 2 patterns of PVR associated with hemorrhage or edema: (1) PVR in any particular CVR territory (75%), and (2) direct PVR not via CVR (25%). The presence of brain lesion increased the odds of presence of PVR by 4.09 times compared to the group without brain lesion (95% confidence interval = 1.570-11.394, p = 0.004). Brain edema caused by PVR was reversible after obliteration of the fistula and may have progressed to hemorrhage without proper patient management performed within several weeks after the initial presentation. CONCLUSIONS: Our results show that PVR is more closely associated with the hemorrhage or edema than CVR in patients with DAVF. PVR can occur not only as a part of CVR but also directly in certain types of DAVF. PMID- 24771535 TI - Pathologic heterogeneity persists in early active multiple sclerosis lesions. AB - OBJECTIVE: Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross-sectional studies reported immunopatterns of demyelination were identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time-dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient. METHODS: Archival tissue samples derived from patients with pathologically confirmed central nervous system inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy were analyzed immunohistochemically. The inclusion criteria consisted of the presence of early active demyelinating lesions--required for immunopattern classification--obtained from the same patient at 2 or more time points. RESULTS: Among 1,321 surgical biopsies consistent with MS, 22 cases met the study inclusion criteria. Twenty-one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy. INTERPRETATION: These findings continue to support the concept of patient-dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized therapeutic approaches. PMID- 24771537 TI - Effects of insulin resistance on white matter microstructure in middle-aged and older adults. AB - OBJECTIVE: To investigate the potential relationship between insulin resistance (IR) and white matter (WM) microstructure using diffusion tensor imaging in cognitively healthy middle-aged and older adults. METHODS: Diffusion tensor imaging was acquired from 127 individuals (age range 41-86 years). IR was evaluated by the homeostasis model assessment of IR (HOMA-IR). Participants were divided into 2 groups based on HOMA-IR values: "high HOMA-IR" (>=2.5, n = 27) and "low HOMA-IR" (<2.5, n = 100). Cross-sectional voxel-based comparisons were performed using Tract-Based Spatial Statistics and anatomically defined regions of interest analysis. RESULTS: The high HOMA-IR group demonstrated decreased axial diffusivity broadly throughout the cerebral WM in areas such as the corpus callosum, corona radiata, cerebral peduncle, posterior thalamic radiation, and right superior longitudinal fasciculus, and WM underlying the frontal, parietal, and temporal lobes, as well as decreased fractional anisotropy in the body and genu of corpus callosum and parts of the superior and anterior corona radiata, compared with the low HOMA-IR group, independent of age, WM signal abnormality volume, and antihypertensive medication status. These regions additionally demonstrated linear associations between diffusion measures and HOMA-IR across all subjects, with higher HOMA-IR values being correlated with lower axial diffusivity. CONCLUSIONS: In generally healthy adults, greater IR is associated with alterations in WM tissue integrity. These cross-sectional findings suggest that IR contributes to WM microstructural alterations in middle-aged and older adults. PMID- 24771539 TI - Correlation between motor function and axonal morphology in neonatally sciatic nerve-injured rats. AB - The present study was conducted to investigate the correlation between motor function and axonal morphology in neonatally sciatic nerve-injured rats. The left sciatic nerve of newborn rats was transected or crushed, and functionality of the sciatic nerve was assessed by the static sciatic index after 8 weeks. After functional assessment, the common peroneal nerves in the control, nerve transected, and nerve-crushed rats were removed and prepared for morphometric examinations. The cross-sectional area of the nerve, total number of myelinated axons, and size of each myelinated axon were analyzed for each group. The control rats showed normal motor function, whereas the nerve-transected rats showed severe motor dysfunction. The cross-sectional area of the nerve and total number of myelinated axons were reduced after nerve transection. Moreover, the percentage per size class of myelinated axons was almost uniform in the control rats, while the distribution was shifted to the left in the nerve-transected rats. Furthermore, no large myelinated axons were observed in the nerve transected rats. The nerve-crushed rats showed various gait functions with various distribution patterns of axonal size, and the rats were divided into two groups with and without uninjured residual large axons. The results showed that the importance of regenerated medium-sized axons in cases without large axons and of residual large axons in cases with large axons in motor function. It was revealed that motor function was related closely to axonal size in neonatally nerve-injured rats. PMID- 24771538 TI - Progranulin protein levels are differently regulated in plasma and CSF. AB - OBJECTIVE: We aimed to investigate the relationship between plasma and CSF progranulin (PGRN) levels. METHODS: Plasma and CSF PGRN were measured in a cohort of 345 subjects from the Mayo Clinic Study of Aging by ELISA. Single nucleotide polymorphism genotyping was performed using TaqMan assays. Associations between PGRN and sex, age at sample collection, diagnosis, single nucleotide polymorphism genotypes (GRN, SORT1, and APOE), and Pittsburgh compound B score were explored separately in CSF and plasma using single variable linear regression models. Pearson partial correlation coefficient was used to estimate the correlation of PGRN in CSF and plasma. RESULTS: Plasma (p = 0.0031) and CSF (p = 0.0044) PGRN significantly increased with age, whereas plasma PGRN levels were 7% lower (p = 0.0025) and CSF PGRN levels 5% higher (p = 0.0024) in male compared with female participants. Correcting for age and sex, higher plasma PGRN was associated with higher CSF PGRN (partial r = 0.17, p = 0.004). In plasma, both rs5848 (GRN; p = 0.002) and rs646776 (SORT1; p = 3.56E-7) were associated with PGRN, while only rs5848 showed highly significant association in CSF (p = 5.59E-14). Age, sex, rs5848 genotype, and plasma PGRN together accounted for only 18% of the variability observed in CSF PGRN. CONCLUSIONS: While some correlation exists between plasma and CSF PGRN, age, sex, and genetic factors differently affect PGRN levels. Therefore, caution should be taken when using plasma PGRN to predict PGRN changes in the brain. These findings further highlight that plasma PGRN levels may not accurately predict clinical features or response to future frontotemporal lobar degeneration therapies. PMID- 24771540 TI - Epithelial phenotype as a predictive marker for response to EGFR-TKIs in non small cell lung cancer patients with wild-type EGFR. AB - Epithelial-to-mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Nowadays, there is still no predictive biomarker identified for the use of EGFR-TKIs in non-small cell lung cancer (NSCLC) patients with wild-type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR-TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from June 2008 to September 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E-cadherin, fibronectin, N-cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (p = 0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5 vs. 11.1 vs. 0.0 vs. 2.4%, p = 0.011), longer progression-free survival (4.4 vs. 1.9 vs. 1.7 vs. 1.0 months, p < 0.001) and longer overall survival (11.5 vs. 8.9 vs. 4.5 vs. 4.9 months, p < 0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild-type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR TKI therapy in this population. PMID- 24771542 TI - Effect of the restitution properties of cardiac tissue on the repeatability of entrainment mapping response. AB - BACKGROUND: The difference between the postpacing interval (PPI) and the tachycardia cycle length (TCL; PPI-TCL) is a useful tool in mapping macro reentrant tachycardias. However, entrainment pacing causes some perturbation of the conduction velocity within the tachycardia circuit, which may affect the repeatability and consequently the accuracy of the measurement of PPI-TCL. The aim of this study was to assess PPI-TCL repeatability both in vivo and in silico. METHODS AND RESULTS: In the experimental part, entrainment pacing was performed twice at each of the 124 tested sites for 30 patients undergoing radiofrequency ablation of atrial and ventricular re-entrant arrhythmias. A similar protocol was used in a simplified computer model of the cardiac tachycardia circuit in a 2 dimensional tissue strip using a Fenton-Karma model of cardiac tissue. In vivo, in the case of fast tachycardias (<350 ms), PPI-TCL variability observed was doubled compared with slow tachycardias (>350 ms; 95% Limits of Agreement ranged from -21.4 to 21.6 ms for TCL<350 ms and from -10.8 to 11.5 ms for TCL>350 ms). Simulations show that this increase of variability may be because of the oscillations of the conduction velocity inside the tachycardia circuits. The effect of the restitution properties of cardiac tissue on the outcome of entrainment pacing is discussed. CONCLUSIONS: PPI-TCL is characterized by a high repeatability with the differences between the results for individual stimulations of <=20 ms. The variability of this parameter is significantly lower in the case of slow tachycardias. PMID- 24771541 TI - The recognition of membrane-bound PtdIns3P by PX domains. AB - Phox-homology (PX) domains target proteins to the organelles of the secretary and endocytic systems by binding to phosphatidylinositol phospholipids (PIPs). Among all the structures of PX domains that have been solved, only three have been solved in a complex with the main physiological ligand: PtdIns3P. In this work, molecular dynamic simulations have been used to explore the structure and dynamics of the p40(phox) -PX domain and the SNX17-PX domain and their interaction with membrane-bound PtdIns3P. In the simulations, both PX domains associated spontaneously with the membrane-bound PtdIns3P and formed stable complexes. The interaction between the p40(phox) -PX domain and PtdIns3P in the membrane was found to be similar to the crystal structure of the p40(phox) -PX PtdIns3P complex that is available. The interaction between the SNX17-PX domain and PtdIns3P was similar to that observed in the p40(phox) -PX-PtdIns3P complex; however, some residues adopted different orientations. The simulations also showed that nonspecific interactions between the beta1-beta2 loop and the membrane play an important role in the interaction of membrane bound PtdIns3P and different PX domains. The behaviour of unbound PtdIns3P within a 2-oleoyl-1 palmitoyl-sn-glycero-3-phosphocholine (POPC) membrane environment was also examined and compared to the available experimental data and simulation studies of related molecules. PMID- 24771543 TI - Prevalence and prognostic value of concealed structural abnormalities in patients with apparently idiopathic ventricular arrhythmias of left versus right ventricular origin: a magnetic resonance imaging study. AB - BACKGROUND: Routine diagnostic work-up occasionally does not identify any abnormality among patients with monomorphic ventricular arrhythmias (VAs) of left ventricular (LV) origin. Aim of this study was to investigate the value of cardiac MRI (cMRI) for the diagnostic work-up and prognostication of these patients. METHODS AND RESULTS: Forty-six consecutive patients (65% males; mean age, 44+/-15 years) with monomorphic VAs of LV origin and negative routine diagnostic work-up were included. Seventy-four consecutive patients (60% males; mean age, 40+/-17 years) with apparently idiopathic monomorphic VAs of right ventricular origin served as control group. Both groups underwent comprehensive cMRI study and were followed-up for a median of 14 months (25th-75th percentiles, 7-37 months). The outcome event was an arrhythmic composite end point of sudden cardiac death or nonfatal episode of ventricular fibrillation or sustained ventricular tachycardia requiring external cardioversion or appropriate implantable cardioverter defibrillator therapy. The 2 groups of patients did not differ in age (P=0.14) and sex (P=0.57). No significant difference was observed between patients with VAs of LV origin and VAs of right ventricular origin about biventricular volumes and systolic function. cMRI demonstrated myocardial structural abnormalities in 19 (41%) patients with VAs of LV origin versus 4 (5%) patients with VAs of right ventricular origin (P<0.001). The outcome event occurred in 9 patients; myocardial structural abnormalities on cMRI were significantly related to the outcome event (hazard ratio, 41.6; 95% confidence interval, 5.2-225.0; P<0.001). CONCLUSIONS: Myocardial structural changes are detected by cMRI in a non-negligible proportion of patients with apparently idiopathic monomorphic VAs of LV origin and are associated with worse outcome. PMID- 24771545 TI - Effects of drought after pollination on grain yield and quality of fresh waxy maize. AB - BACKGROUND: Waxy maize is consumed as a vegetable when harvested at fresh stage (23-26 days after pollination) in China. Fresh waxy maize is normally grown under rain-fed conditions and suffers drought frequently during plant growth. The effect of drought on grain development of fresh waxy maize is not known. RESULTS: Two years of pot trials showed that drought decreased fresh grain number and weight, which consequently reduced fresh ear and grain yields, especially in Yunuo7. Moisture and starch contents in grains were not affected but protein content was increased under drought treatment in both varieties. Grain soluble sugar content response to drought was not affected in Suyunuo5 but was decreased in Yunuo7. Pasting and gelatinization temperatures, trough viscosity, final viscosity, setback viscosity, gelatinization enthalpy and springiness of grain were little affected by drought. Drought decreased peak viscosity, breakdown viscosity and adhesiveness (absolute value), whereas it increased hardness. The retrogradation percentage was increased in both varieties in both years. CONCLUSION: Drought after pollination decreased the fresh waxy maize yield. Grain quality was reduced through decreased peak viscosity and adhesiveness (absolute value), while its hardness and retrogradation percentage were increased, which might be due to the increased protein content. PMID- 24771544 TI - Ocean cleaning stations under a changing climate: biological responses of tropical and temperate fish-cleaner shrimp to global warming. AB - Cleaning symbioses play an important role in the health of certain coastal marine communities. These interspecific associations often occur at specific sites (cleaning stations) where a cleaner organism (commonly a fish or shrimp) removes ectoparasites/damaged tissue from a 'client' (a larger cooperating fish). At present, the potential impact of climate change on the fitness of cleaner organisms remains unknown. This study investigated the physiological and biochemical responses of tropical (Lysmata amboinensis) and temperate (L. seticaudata) cleaner shrimp to global warming. Specifically, thermal limits (CTMax), metabolic rates, thermal sensitivity, heat shock response (HSR), lipid peroxidation [malondialdehyde (MDA) concentration], lactate levels, antioxidant (GST, SOD and catalase) and digestive enzyme activities (trypsin and alkaline phosphatase) at current and warming (+3 degrees C) temperature conditions. In contrast to the temperate species, CTMax values decreased significantly from current (24-27 degrees C) to warming temperature conditions (30 degrees C) for the tropical shrimp, where metabolic thermal sensitivity was affected and the HSR was significantly reduced. MDA levels in tropical shrimp increased dramatically, indicating extreme cellular lipid peroxidation, which was not observed in the temperate shrimp. Lactate levels, GST and SOD activities were significantly enhanced within the muscle tissue of the tropical species. Digestive enzyme activities in the hepatopancreas of both species were significantly decreased by warmer temperatures. Our data suggest that the tropical cleaner shrimp will be more vulnerable to global warming than the temperate Lysmata seticaudata; the latter evolved in a relatively unstable environment with seasonal thermal variations that may have conferred greater adaptive plasticity. Thus, tropical cleaning symbioses may be challenged at a greater degree by warming-related anthropogenic forcing, with potential cascading effects on the health and structuring of tropical coastal communities (e.g. coral reefs). PMID- 24771546 TI - Anthranilic acid analogs as diamagnetic CEST MRI contrast agents that feature an intramolecular-bond shifted hydrogen. AB - Diamagnetic chemical exchange saturation transfer (diaCEST) agents are a new class of imaging agents, which have unique magnetic resonance (MR) properties similar to agents used for optical imaging. Here we present a series of anthranilic acid analogs as examples of diaCEST agents that feature an exchangeable proton shifted downfield, namely, an intramolecular-bond shifted hydrogen (IM-SHY), which produces significant and tunable contrast at frequencies of 4.8-9.3 ppm from water. Five analogs of N-sulfonyl anthranilic acids are all highly soluble and produced similar CEST contrast at ~6-8 ppm. We also discovered that flufenamic acid, a commercial nonsteroidal anti-inflammatory drug, displayed CEST contrast at 4.8 ppm. For these N-H IM-SHY agents, the contrast produced was insensitive to pH, making them complementary to existing diaCEST probes. This initial IM-SHY library includes the largest reported shifts for N-H protons on small organic diaCEST agents, and should find use as multifrequency MR agents for in vivo applications. PMID- 24771547 TI - Production of allitol from D-psicose by a novel isolated strain of Klebsiella oxytoca G4A4. AB - A novel bacterium capable of producing allitol from D-psicose was isolated from soil and identified as Klebsiella oxytoca G4A4. An efficient method for the transformation of D-psicose to allitol was achieved through the resting cell reaction. Ribitol as an inducer is suitable for cell cultivation, and cells are most active in Tris-HCl buffer (pH 8.0) at 37 degrees C with a density of 40 (OD600 nm ). After the reaction, the final conversion rates of the washed cells were approximately 87, 83, and 55% at D-psicose concentrations of 0.25, 0.5, and 1%, respectively. The product from D-psicose was purified and determined to be allitol by high-performance liquid chromatography and nuclear magnetic resonance spectroscopy. PMID- 24771548 TI - UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. AB - We report a 5-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X linked inheritance in all studied affected individuals. As ubiquilin-2-positive inclusions were identified in brain, we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations. PMID- 24771550 TI - Liver graft allocation for hepatocellular carcinoma patients: is a forced ablate and-wait protocol nationally applicable? PMID- 24771549 TI - Development of the analysis of fecal stanols in the oyster Crassostrea gigas and identification of fecal contamination in shellfish harvesting areas. AB - The objective of this work was to study the effects of washing and purification steps on qualitative and quantitative analysis of fecal stanols in the oyster Crassostrea gigas using either single or a combination of lipid purification steps on silica gel or aminopropyl bonded silica gel (NH2) or a washing step. Among the three analytical pathways compared, the two including water extraction or NH2 purification did not lead to higher recoveries and decreased repeatabilities of extractions compared to the single purification on silica gel. This latter led to similar recoveries (ca. 80%) and repeatabilities (ca. 10%) for both spiked standards (coprostanol and sitostanol). This analytical pathway has been applied to oysters collected in a harvesting area in Brittany (France) where fecal contaminations are important and allowed to quantify eight stanols in oysters. The relative proportions of fecal stanols of these oysters were combined with principal component analysis in order to investigate the usefulness of their stanol fingerprints to record a fecal contamination and to distinguish its source between human, porcine and bovine contaminations. Oysters non-fecally contaminated by Escherichia coli did not present specific stanol fingerprints while oysters fecally contaminated had a bovine fingerprint, suggesting a contamination of these samples by bovine sources. As a consequence, the method developed here allows the use of stanol fingerprints of oysters as a microbial source tracking tool that can be applied to shellfish harvesting areas subjected to fecal contaminations in order to identify the different sources of contamination and improve watershed management. PMID- 24771551 TI - Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study. AB - Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40-50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category ( 0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83-4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3 : 1.09, 95% CI: 1.01-1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3 : 1.37, 95% CI: 1.02-1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood. PMID- 24771552 TI - Gastroenteropancreatic high-grade neuroendocrine carcinoma. AB - Gastroenteropancreatic (GEP) neuroendocrine neoplasms are classified as low grade, intermediate-grade, and high-grade tumors based on morphologic criteria and the proliferation rate. Most studies have been conducted in patients with well differentiated (low-grade to intermediate-grade) neuroendocrine tumors. Data are substantially scarcer on poorly differentiated, high-grade neuroendocrine carcinoma (NEC), which includes the entities of small cell carcinoma and large cell NEC. A literature search of GEP-NEC was performed. Long-term survival was poor even among patients who presented with localized disease. Several studies highlighted heterogeneity within the high-grade NEC category and a need for the further identification of discreet prognostic and predictive groups. Tumors with a Ki-67 proliferation index <55% were less responsive to platinum-based chemotherapy, and patients with such tumors or with well differentiated morphology had better survival than patients who had tumors with poorly differentiated morphology or a higher Ki-67 index. Treatment options beyond platinum-based chemotherapy are emerging. A revision of the World Health Organization high-grade NEC classification seems to be necessary based on recent data. Platinum-based chemotherapy may not be the optimal treatment for patients who have GEP-NEC with a moderately high proliferation rate. Adequate diagnostic and prognostic stratifications constitute the basis for future progress. PMID- 24771553 TI - Occurrence and implications of voltage reversal in stacked microbial fuel cells. AB - Voltage reversal in stacked microbial fuel cells (MFCs) is a significant challenge that must be addressed, and the information on its definite cause and occurrence process is still obscure. In this work, we first demonstrated that different anodic reaction rates caused voltage reversal in a stacked MFC. Sluggish reaction rates on the anode in unit 1 of the stacked MFC resulted in a significantly increased anode overpotential of up to 0.132 V, as compared to negligible anode overpotential (0.0247 V) in unit 2. This work clearly verified the process of voltage reversal in the stacked MFC. As the current was gradually increased in the stacked MFC, the voltage in the stacked unit 1 decreased to 0 V prior to that of the stacked unit 2. Then, when the voltage in unit 1 became 0 V, it was converted from a galvanic cell to an electrochemical cell powered by unit 2. We found that the stacked unit 2 provided electrical energy for the stacked unit 1 as a power supply. Finally, the anode potential of the stacked unit 1 significantly increased over cathode potential as current increased further, which caused voltage reversal in unit 1. Voltage reversal occurs in stacked MFCs as a result of non-spontaneous anode overpotential in a unit MFC that has sluggish anode kinetics compared to the other unit MFCs. PMID- 24771554 TI - The p66 immature precursor of HIV-1 reverse transcriptase. AB - In contrast to the wealth of structural data available for the mature p66/p51 heterodimeric human immunodeficiency virus type 1 reverse transcriptase (RT), the structure of the homodimeric p66 precursor remains unknown. In all X-ray structures of mature RT, free or complexed, the processing site in the p66 subunit, for generating the p51 subunit, is sequestered into a beta-strand within the folded ribonuclease H (RNH) domain and is not readily accessible to proteolysis, rendering it difficult to propose a simple and straightforward mechanism of the maturation step. Here, we investigated, by solution NMR, the conformation of the RT p66 homodimer. Our data demonstrate that the RNH and Thumb domains in the p66 homodimer are folded and possess conformations very similar to those in mature RT. This finding suggests that maturation models which invoke a complete or predominantly unfolded RNH domain are unlikely. The present study lays the foundation for further in-depth mechanistic investigations at the atomic level. PMID- 24771555 TI - Real-time magnetic resonance assessment of septal curvature accurately tracks acute hemodynamic changes in pediatric pulmonary hypertension. AB - BACKGROUND: This study assesses the relationship between septal curvature and mean pulmonary artery pressure and indexed pulmonary vascular resistance in children with pulmonary hypertension. We hypothesized that septal curvature could be used to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics. METHODS AND RESULTS: Fifty patients with a median age of 6.7 years (range, 0.45-16.5 years) underwent combined cardiac catheterization and cardiovascular magnetic resonance. The majority had idiopathic pulmonary arterial hypertension (n=30); the remaining patients had pulmonary hypertension associated with repaired congenital heart disease (n=17) or lung disease (n=3). Mean pulmonary artery pressure and pulmonary vascular resistance were acquired at baseline and during vasodilation. Septal curvature was measured using real-time cardiovascular magnetic resonance. There was a strong correlation between mean pulmonary artery pressure and SCmin at baseline and during vasodilator testing (r=-0.81 and -0.85, respectively; P<0.01). A strong linear relationship also existed between pulmonary vascular resistance and minimum septal curvature indexed to cardiac output both at baseline and during vasodilator testing (r= 0.88 and -0.87, respectively; P<0.01). Change in septal curvature metrics moderately correlated with absolute change in mean pulmonary artery pressure and pulmonary vascular resistance, respectively (r=0.58 and -0.74; P<0.01). Septal curvature metrics were able to identify vasoresponders with a sensitivity of 83% (95% confidence interval, 0.36-0.99) and a specificity of 91% (95% confidence interval, 0.77-0.97), using the Sitbon criteria. Idiopathic pulmonary arterial hypertension subgroup analysis revealed 3 responders with DeltaSCmin values of 0.523, 0.551, and 0.568. If the middle value of 0.551 is taken as a cutoff, the approximate sensitivity would be 67% and the specificity would be 93%. CONCLUSIONS: Septal curvature metrics are able to estimate right ventricular afterload and track acute changes in pulmonary hemodynamics during vasodilator testing. This suggests that septal curvature could be used for continuing assessment of load in pulmonary hypertension. PMID- 24771556 TI - Effects of dietary polysaccharides from the submerged fermentation concentrate of Hericium caput-medusae (Bull.:Fr.) Pers. on fat deposition in broilers. AB - BACKGROUND: The present study was conducted to investigate the lipid-lowering effect of polysaccharides from the submerged fermentation concentrate of Hericium caput-medusae (Bull.:Fr.) Pers. (HFCP) in broilers. A total of 480 female Arbor Acres broilers were randomly divided into four dietary treatments, each consisting of six pens as replicates, and fed diets containing 0 (control), 1, 3 or 5 g kg(-1) HFCP. RESULTS: The results revealed that the average daily gain of broilers increased (linear (L), P < 0.01; quadratic (Q), P < 0.01) when the HFCP levels increased. The serum cholesterol, triglyceride and low-density lipoprotein cholesterol levels decreased (Q, P < 0.05) while the high-density lipoprotein cholesterol level increased (Q, P < 0.05) when the HFCP levels increased. The caecum Escherichia coli count and pH decreased (Q, P < 0.01) while the lactobacilli count and bifidobacteria count increased (L, P < 0.05; Q, P < 0.05) when the HFCP levels increased. The propionic acid and butyric acid concentrations increased (L, P < 0.001; Q, P < 0.001) while the abdominal fat rate and liver fat content decreased (L, P < 0.01; Q, P < 0.05) when the HFCP levels increased. CONCLUSION: Dietary supplementation with HFCP may lead to the development of low abdominal fat of broilers as demanded by health-conscious consumers. PMID- 24771557 TI - Dendritic Au/Pt and Au/PtCu nanowires with enhanced electrocatalytic activity for methanol electrooxidation. AB - The high-yield synthesis of dendritic Au/Pt and Au/PtCu nanowires is achieved through an effective heterogeneous, epitaxial growth strategy conducted in the water-phase to grow dendritic Pt and PtCu nanoshells on Au nanowires. The synthesized products exhibit excellent electrocatalytic activity towards methanol electrooxidation. PMID- 24771558 TI - Wood production response to climate change will depend critically on forest composition and structure. AB - Established forests currently function as a major carbon sink, sequestering as woody biomass about 26% of global fossil fuel emissions. Whether forests continue to act as a global sink will depend on many factors, including the response of aboveground wood production (AWP; MgC ha(-1 ) yr(-1) ) to climate change. Here, we explore how AWP in New Zealand's natural forests is likely to change. We start by statistically modelling the present-day growth of 97 199 individual trees within 1070 permanently marked inventory plots as a function of tree size, competitive neighbourhood and climate. We then use these growth models to identify the factors that most influence present-day AWP and to predict responses to medium-term climate change under different assumptions. We find that if the composition and structure of New Zealand's forests were to remain unchanged over the next 30 years, then AWP would increase by 6-23%, primarily as a result of physiological responses to warmer temperatures (with no appreciable effect of changing rainfall). However, if warmth-requiring trees were able to migrate into currently cooler areas and if denser canopies were able to form, then a different AWP response is likely: forests growing in the cool mountain environments would show a 30% increase in AWP, while those in the lowland would hardly respond (on average, -3% when mean annual temperature exceeds 8.0 degrees C). We conclude that response of wood production to anthropogenic climate change is not only dependent on the physiological responses of individual trees, but is highly contingent on whether forests adjust in composition and structure. PMID- 24771559 TI - The role of metals in production and scavenging of reactive oxygen species in photosystem II. AB - Metal ions play a crucial role in enzymatic reactions in all photosynthetic organisms such as cyanobacteria, algae and plants. It well known that metal ions maintain the binding of substrate in the active site of the metalloenzymes and control the redox activity of the metalloenzyme in the enzymatic reaction. A large pigment-protein complex, PSII, known to serve as a water-plastoquinone oxidoreductase, contains three metal centers comprising non-heme iron, heme iron of Cyt b559 and the water-splitting manganese complex. Metal ions bound to PSII proteins maintain the electron transport from water to plastoquinone and regulate the pro-oxidant and antioxidant activity in PSII. In this review, attention is focused on the role of PSII metal centers in (i) the formation of superoxide anion and hydroxyl radicals by sequential one-electron reduction of molecular oxygen and the formation of hydrogen peroxide by incomplete two-electron oxidation of water; and (ii) the elimination of superoxide anion radical by one electron oxidation and reduction (superoxide dismutase activity) and of hydrogen peroxide by two-electron oxidation and reduction (catalase activity). The balance between the formation and elimination of reactive oxygen species by PSII metal centers is discussed as an important aspect in the prevention of photo-oxidative damage of PSII proteins and lipids. PMID- 24771560 TI - WebProtege: a collaborative Web-based platform for editing biomedical ontologies. AB - WebProtege is an open-source Web application for editing OWL 2 ontologies. It contains several features to aid collaboration, including support for the discussion of issues, change notification and revision-based change tracking. WebProtege also features a simple user interface, which is geared towards editing the kinds of class descriptions and annotations that are prevalent throughout biomedical ontologies. Moreover, it is possible to configure the user interface using views that are optimized for editing Open Biomedical Ontology (OBO) class descriptions and metadata. Some of these views are shown in the Supplementary Material and can be seen in WebProtege itself by configuring the project as an OBO project. AVAILABILITY AND IMPLEMENTATION: WebProtege is freely available for use on the Web at http://webprotege.stanford.edu. It is implemented in Java and JavaScript using the OWL API and the Google Web Toolkit. All major browsers are supported. For users who do not wish to host their ontologies on the Stanford servers, WebProtege is available as a Web app that can be run locally using a Servlet container such as Tomcat. Binaries, source code and documentation are available under an open-source license at http://protegewiki.stanford.edu/wiki/WebProtege. PMID- 24771561 TI - EnsembleGASVR: a novel ensemble method for classifying missense single nucleotide polymorphisms. AB - MOTIVATION: Single nucleotide polymorphisms (SNPs) are considered the most frequently occurring DNA sequence variations. Several computational methods have been proposed for the classification of missense SNPs to neutral and disease associated. However, existing computational approaches fail to select relevant features by choosing them arbitrarily without sufficient documentation. Moreover, they are limited to the problem of missing values, imbalance between the learning datasets and most of them do not support their predictions with confidence scores. RESULTS: To overcome these limitations, a novel ensemble computational methodology is proposed. EnsembleGASVR facilitates a two-step algorithm, which in its first step applies a novel evolutionary embedded algorithm to locate close to optimal Support Vector Regression models. In its second step, these models are combined to extract a universal predictor, which is less prone to overfitting issues, systematizes the rebalancing of the learning sets and uses an internal approach for solving the missing values problem without loss of information. Confidence scores support all the predictions and the model becomes tunable by modifying the classification thresholds. An extensive study was performed for collecting the most relevant features for the problem of classifying SNPs, and a superset of 88 features was constructed. Experimental results show that the proposed framework outperforms well-known algorithms in terms of classification performance in the examined datasets. Finally, the proposed algorithmic framework was able to uncover the significant role of certain features such as the solvent accessibility feature, and the top-scored predictions were further validated by linking them with disease phenotypes. AVAILABILITY AND IMPLEMENTATION: Datasets and codes are freely available on the Web at http://prlab.ceid.upatras.gr/EnsembleGASVR/dataset-codes.zip. All the required information about the article is available through http://prlab.ceid.upatras.gr/EnsembleGASVR/site.html. PMID- 24771562 TI - Quantifying spatiotemporal properties of vocal fold dynamics based on a multiscale analysis of phonovibrograms. AB - In order to objectively assess the laryngeal vibratory behavior, endoscopic high speed cameras capture several thousand frames per second of the vocal folds during phonation. However, judging all inherent clinically relevant features is a challenging task and requires well-founded expert knowledge. In this study, an automated wavelet-based analysis of laryngeal high-speed videos based on phonovibrograms is presented. The phonovibrogram is an image representation of the spatiotemporal pattern of vocal fold vibration and constitutes the basis for a computer-based analysis of laryngeal dynamics. The features extracted from the wavelet transform are shown to be closely related to a basic set of video-based measurements categorized by the European Laryngological Society for a subjective assessment of pathologic voices. The wavelet-based analysis further offers information about irregularity and lateral asymmetry and asynchrony. It is demonstrated in healthy and pathologic subjects as well as for a surgical group that was examined before and after the removal of a vocal fold polyp. The features were found to not only classify glottal closure characteristics but also quantify the impact of pathologies on the vibratory behavior. The interpretability and the discriminative power of the proposed feature set show promising relevance for a computer-assisted diagnosis and classification of voice disorders. PMID- 24771563 TI - Combining multiobjective optimization and cluster analysis to study vocal fold functional morphology. AB - Morphological design and the relationship between form and function have great influence on the functionality of a biological organ. However, the simultaneous investigation of morphological diversity and function is difficult in complex natural systems. We have developed a multiobjective optimization (MOO) approach in association with cluster analysis to study the form-function relation in vocal folds. An evolutionary algorithm (NSGA-II) was used to integrate MOO with an existing finite element model of the laryngeal sound source. Vocal fold morphology parameters served as decision variables and acoustic requirements (fundamental frequency, sound pressure level) as objective functions. A two-layer and a three-layer vocal fold configuration were explored to produce the targeted acoustic requirements. The mutation and crossover parameters of the NSGA-II algorithm were chosen to maximize a hypervolume indicator. The results were expressed using cluster analysis and were validated against a brute force method. Results from the MOO and the brute force approaches were comparable. The MOO approach demonstrated greater resolution in the exploration of the morphological space. In association with cluster analysis, MOO can efficiently explore vocal fold functional morphology. PMID- 24771564 TI - Tracking epithelial cell junctions in C. elegans embryogenesis with active contours guided by SIFT flow. AB - Quantitative analysis of cell shape in live samples is an important goal in developmental biology. Automated or semi-automated segmentation and tracking of cell nuclei has been successfully implemented in several biological systems. Segmentation and tracking of cell surfaces has been more challenging. Here, we present a new approach to tracking cell junctions in the developing epidermis of C. elegans embryos. Epithelial junctions as visualized with DLG-1::GFP form lines at the subapical circumference of differentiated epidermal cells and delineate changes in epidermal cell shape and position. We develop and compare two approaches for junction segmentation. For the first method (projection approach), 3-D cell boundaries are projected into 2D for segmentation using active contours with a nonintersecting force, and subsequently tracked using scale-invariant feature transform (SIFT) flow. The resulting 2-D tracked boundaries are then back projected into 3-D space. The second method (volumetric approach) uses a 3-D extended version of active contours guided by SIFT flow in 3-D space. In both methods, cell junctions are manually located at the first time point and tracked in a fully automated way for the remainder of the video. Using these methods, we have generated the first quantitative description of ventral epidermal cell movements and shape changes during epidermal enclosure. PMID- 24771565 TI - An EEMD-IVA framework for concurrent multidimensional EEG and unidimensional kinematic data analysis. AB - Joint blind source separation (JBSS) is a means to extract common sources simultaneously found across multiple datasets, e.g., electroencephalogram (EEG) and kinematic data jointly recorded during reaching movements. Existing JBSS approaches are designed to handle multidimensional datasets, yet to our knowledge, there is no existing means to examine common components that may be found across a unidimensional dataset and a multidimensional one. In this paper, we propose a simple, yet effective method to achieve the goal of JBSS when concurrent multidimensional EEG and unidimensional kinematic datasets are available, by combining ensemble empirical mode decomposition (EEMD) with independent vector analysis (IVA). We demonstrate the performance of the proposed method through numerical simulations and application to data collected from reaching movements in Parkinson's disease. The proposed method is a promising JBSS tool for real-world biomedical signal processing applications. PMID- 24771566 TI - Quantitative gait measurement with pulse-Doppler radar for passive in-home gait assessment. AB - In this paper, we propose a pulse-Doppler radar system for in-home gait assessment of older adults. A methodology has been developed to extract gait parameters including walking speed and step time using Doppler radar. The gait parameters have been validated with a Vicon motion capture system in the lab with 13 participants and 158 test runs. The study revealed that for an optimal step recognition and walking speed estimation, a dual radar set up with one radar placed at foot level and the other at torso level is necessary. An excellent absolute agreement with intraclass correlation coefficients of 0.97 was found for step time estimation with the foot level radar. For walking speed, although both radars show excellent consistency they all have a system offset compared to the ground truth due to walking direction with respect to the radar beam. The torso level radar has a better performance (9% offset on average) in the speed estimation compared to the foot level radar (13%-18% offset). Quantitative analysis has been performed to compute the angles causing the systematic error. These lab results demonstrate the capability of the system to be used as a daily gait assessment tool in home environments, useful for fall risk assessment and other health care applications. The system is currently being tested in an unstructured home environment. PMID- 24771567 TI - Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. AB - OBJECTIVE: Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity. METHODS: Effects of UVB light were analyzed in a murine model of CNS autoimmunity (experimental autoimmune encephalomyelitis). Additionally, patients with relapsing-remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples, and immune cells of the peripheral blood. RESULTS: Regulatory T cells (Tregs), which are induced locally in the skin-draining lymph nodes in response to UVB exposure, connect the cutaneous immune response to CNS immunity by migration to the sites of inflammation (blood, spleen, CNS). Here, they attenuate the inflammatory response and ameliorate disease symptoms. Treg-inducing tolerogenic dendritic cells (DCs) were further necessary for induction of this systemic immune regulation by UVB radiation, because ablation of Langerhans cells abolished the UVB-induced phenotype. MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T-cell effector cytokine interleukin 21. The treatment further induced elevated serum levels of vitamin D. INTERPRETATION: Local UVB radiation of the skin influences systemic immune reactions and attenuates systemic autoimmunity via the induction of skin-derived tolerogenic DCs and Tregs. Our data could have implications for the understanding or therapeutic modulation of environmental factors that influence immune tolerance. PMID- 24771569 TI - Clinical dilemma in the surgical treatment of organ malperfusion caused by acute type A aortic dissection. AB - The malperfusion syndrome associated with acute aortic dissection draws attention because the clinical picture is very dramatic, and patients with malperfusion have poorer clinical outcomes. To improve surgical outcomes, the ischemic damages associated with organ malperfusion should be minimized by restoring perfusion as early as possible, which occasionally can hardly coexist with central repair. This paper reviews the current evidence, problems, and dilemma related to the diagnosis and treatment of the malperfusion syndrome caused by acute type A aortic dissection. PMID- 24771570 TI - Paratrechina longicornis ants in a tropical dry forest harbor specific Actinobacteria diversity. AB - The diversity of Actinobacteria associated with Paratrechina longicornis, an ant species that prefers a high protein diet, in a subtropical dry forest (Guanica, Puerto Rico) was determined by culture methods and by 16S rDNA clone libraries. The results of both methodologies were integrated to obtain a broader view of the diversity. Streptomyces, Actinomadura, Nocardia, Ornithinimicrobium, Tsukamurella, Brevibacterium, Saccharopolyspora, Nocardioides, Microbacterium, Leifsonia, Pseudonocardia, Corynebacterium, Geodermatophilus, Amycolatopsis, and Nonomuraea were found associated with the ants. The genera Streptomyces and Actinomadura were the most abundant. Also, the diversity of Actinobacteria associated with the soil surrounding the nest was determined using 16S rDNA clone libraries. In total, 27 genera of Actinobacteria were associated with the nest soils. A dominant genus was not observed in any of the soil samples. We compared statistically the Actinobacteria communities among P. longicornis nests and each nest with its surrounding soil using the clone libraries data. We established that the communities associated with the ants were consistent and significantly different from those found in the soil in which the ants live. PMID- 24771571 TI - Spatially-resolved hydraulic conductivity estimation via poroelastic magnetic resonance elastography. AB - Poroelastic magnetic resonance elastography is an imaging technique that could recover mechanical and hydrodynamical material properties of in vivo tissue. To date, mechanical properties have been estimated while hydrodynamical parameters have been assumed homogeneous with literature-based values. Estimating spatially varying hydraulic conductivity would likely improve model accuracy and provide new image information related to a tissue's interstitial fluid compartment. A poroelastic model was reformulated to recover hydraulic conductivity with more appropriate fluid-flow boundary conditions. Simulated and physical experiments were conducted to evaluate the accuracy and stability of the inversion algorithm. Simulations were accurate (property errors were < 2%) even in the presence of Gaussian measurement noise up to 3%. The reformulated model significantly decreased variation in the shear modulus estimate (p << 0.001) and eliminated the homogeneity assumption and the need to assign hydraulic conductivity values from literature. Material property contrast was recovered experimentally in three different tofu phantoms and the accuracy was improved through soft-prior regularization. A frequency-dependence in hydraulic conductivity contrast was observed suggesting that fluid-solid interactions may be more prominent at low frequency. In vivo recovery of both structural and hydrodynamical characteristics of tissue could improve detection and diagnosis of neurological disorders such as hydrocephalus and brain tumors. PMID- 24771572 TI - Accurate high-resolution measurements of 3-D tissue dynamics with registration enhanced displacement encoded MRI. AB - Displacement fields are important to analyze deformation, which is associated with functional and material tissue properties often used as indicators of health. Magnetic resonance imaging (MRI) techniques like DENSE and image registration methods like Hyperelastic Warping have been used to produce pixel level deformation fields that are desirable in high-resolution analysis. However, DENSE can be complicated by challenges associated with image phase unwrapping, in particular offset determination. On the other hand, Hyperelastic Warping can be hampered by low local image contrast. The current work proposes a novel approach for measuring tissue displacement with both DENSE and Hyperelastic Warping, incorporating physically accurate displacements obtained by the latter to improve phase characterization in DENSE. The validity of the proposed technique is demonstrated using numerical and physical phantoms, and in vivo small animal cardiac MRI. PMID- 24771573 TI - A unified graphical models framework for automated mitosis detection in human embryos. AB - Time lapse microscopy has emerged as an important modality for studying human embryo development, as mitosis events can provide insight into embryo health and fate. Mitosis detection can happen through tracking of embryonic cells (tracking based), or from low level image features and classifiers (tracking free). Tracking based approaches are challenged by high dimensional search space, weak features, outliers, missing data, multiple deformable targets, and weak motion model. Tracking free approaches are data driven and complement tracking based approaches. We pose mitosis detection as augmented simultaneous segmentation and classification in a conditional random field (CRF) framework that combines both approaches. It uses a rich set of discriminative features and their spatiotemporal context. It performs a dual pass approximate inference that addresses the high dimensionality of tracking and combines results from both components. For 312 clinical sequences we measured division events to within 30 min and observed an improvement of 25.6% and a 32.9% improvement over purely tracking based and tracking free approach respectively, and close to an order of magnitude over a traditional particle filter. While our work was motivated by human embryo development, it can be extended to other detection problems in image sequences of evolving cell populations. PMID- 24771574 TI - Cine cone beam CT reconstruction using low-rank matrix factorization: algorithm and a proof-of-principle study. AB - Respiration-correlated CBCT, commonly called 4DCBCT, provides respiratory phase resolved CBCT images. A typical 4DCBCT represents averaged patient images over one breathing cycle and the fourth dimension is actually breathing phase instead of time. In many clinical applications, it is desirable to obtain true 4DCBCT with the fourth dimension being time, i.e., each constituent CBCT image corresponds to an instantaneous projection. Theoretically it is impossible to reconstruct a CBCT image from a single projection. However, if all the constituent CBCT images of a 4DCBCT scan share a lot of redundant information, it might be possible to make a good reconstruction of these images by exploring their sparsity and coherence/redundancy. Though these CBCT images are not completely time resolved, they can exploit both local and global temporal coherence of the patient anatomy automatically and contain much more temporal variation information of the patient geometry than the conventional 4DCBCT. We propose in this work a computational model and algorithms for the reconstruction of this type of semi-time-resolved CBCT, called cine-CBCT, based on low rank approximation that can utilize the underlying temporal coherence both locally and globally, such as slow variation, periodicity or repetition, in those cine-CBCT images. PMID- 24771575 TI - Local metric learning in 2D/3D deformable registration with application in the abdomen. AB - In image-guided radiotherapy (IGRT) of disease sites subject to respiratory motion, soft tissue deformations can affect localization accuracy. We describe the application of a method of 2D/3D deformable registration to soft tissue localization in abdomen. The method, called registration efficiency and accuracy through learning a metric on shape (REALMS), is designed to support real-time IGRT. In a previously developed version of REALMS, the method interpolated 3D deformation parameters for any credible deformation in a deformation space using a single globally-trained Riemannian metric for each parameter. We propose a refinement of the method in which the metric is trained over a particular region of the deformation space, such that interpolation accuracy within that region is improved. We report on the application of the proposed algorithm to IGRT in abdominal disease sites, which is more challenging than in lung because of low intensity contrast and nonrespiratory deformation. We introduce a rigid translation vector to compensate for nonrespiratory deformation, and design a special region-of-interest around fiducial markers implanted near the tumor to produce a more reliable registration. Both synthetic data and actual data tests on abdominal datasets show that the localized approach achieves more accurate 2D/3D deformable registration than the global approach. PMID- 24771576 TI - Registration of whole-mount histology and volumetric imaging of the prostate using particle filtering. AB - Registration of histological slices to volumetric imaging of the prostate is an important task that can be used to optimize imaging for cancer detection. Such registration is challenging due to physical changes of the specimen during excision and fixation, and misalignment of the histological slices during preparation and digital scanning. In this work, we consider a multi-slice to volume registration method in which a stack of sparse, unaligned 2-D whole-mount histological slices is registered to a 3-D volumetric imaging of the prostate. We propose a particle filtering framework to contend with the high dimensionality of the search space and multimodal nature of the optimization. Such framework allows modeling of the uncertainty in the pose of the slices and in the imaged information, in order to derive optimal registration parameters in a Bayesian approach. Intensity-, region-, and point-based similarity metrics were incorporated into the registration algorithm to account for different imaging modalities. We demonstrate and evaluate our method on a diverse set of data that includes a synthetic volume, ex vivo and in vivo magnetic resonance imaging, and in vivo ultrasound. PMID- 24771578 TI - A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with Prader Willi syndrome. AB - In recent years, it has been suggested that defects in energy metabolism may accompany Prader Willi syndrome. Mutations in the mitochondrial cytochrome b gene have been commonly associated isolated mitochondrial myopathy and exercise intolerance, rarely with multisystem disorders. The authors describe a novel mutation (mt. 15209T>C) in mitochondrial cytochrome b gene in a 2-year-old girl with Prader-Willi syndrome with a clinical history of lactic acidosis attacks, renal sodium loss, hepatopathy, progressive cerebral atrophy, and sudden death. The authors suggest that atypical clinical findings in patients with Prader-Willi syndrome should direct the physician to search for a mitochondrial disease. PMID- 24771579 TI - On scanning linear barcodes from out-of-focus blurred images: a spatial domain dynamic template matching approach. AB - Because of the lack of disciplined and efficient mechanisms, most modern area charge-coupled device-based barcode scanning technologies are not capable of handling out-of-focus (OOF) image blur and rely heavily on camera systems for capturing good quality, well-focused barcode images. In this paper, we present a novel linear barcode scanning system based on a dynamic template matching scheme. The proposed system works entirely in the spatial domain, and is capable of reading linear barcodes from low-resolution images containing severe OOF blur. This paper treats linear barcode scanning under the perspective of deformed binary waveform analysis and classification. A directed graphical model is designed to characterize the relationship between the blurred barcode waveform and its corresponding symbol value at any specific blur level. Under this model, linear barcode scanning is cast to find the optimal state sequence associated with the deformed barcode waveform segments. A dynamic programming-based inference algorithm is designed to retrieve the optimal state sequence, enabling real-time decoding on mobile devices of limited processing power. PMID- 24771580 TI - Hyperspectral image classification through bilayer graph-based learning. AB - Hyperspectral image classification with limited number of labeled pixels is a challenging task. In this paper, we propose a bilayer graph-based learning framework to address this problem. For graph-based classification, how to establish the neighboring relationship among the pixels from the high dimensional features is the key toward a successful classification. Our graph learning algorithm contains two layers. The first-layer constructs a simple graph, where each vertex denotes one pixel and the edge weight encodes the similarity between two pixels. Unsupervised learning is then conducted to estimate the grouping relations among different pixels. These relations are subsequently fed into the second layer to form a hypergraph structure, on top of which, semisupervised transductive learning is conducted to obtain the final classification results. Our experiments on three data sets demonstrate the merits of our proposed approach, which compares favorably with state of the art. PMID- 24771581 TI - Patch-ordering-based wavelet frame and its use in inverse problems. AB - In our previous work [1] we have introduced a redundant tree-based wavelet transform (RTBWT), originally designed to represent functions defined on high dimensional data clouds and graphs. We have further shown that RTBWT can be used as a highly effective image-adaptive redundant transform that operates on an image using orderings of its overlapped patches. The resulting transform is robust to corruptions in the image, and thus able to efficiently represent the unknown target image even when it is calculated from its corrupted version. In this paper, we utilize this redundant transform as a powerful sparsity-promoting regularizer in inverse problems in image processing. We show that the image representation obtained with this transform is a frame expansion, and derive the analysis and synthesis operators associated with it. We explore the use of this frame operators to image denoising and deblurring, and demonstrate in both these cases state-of-the-art results. PMID- 24771582 TI - Vascular cell adhesion molecule-1 (VCAM-1)--an increasing insight into its role in tumorigenicity and metastasis. AB - Vascular cell adhesion molecule-1 (VCAM-1) first attracted attention more than two decades ago as endothelial adhesion receptor with key function for leukocyte recruitment in term of cellular immune response. The early finding of VCAM-1 binding to melanoma cells, and thus a suggested mechanistic contribution to metastatic spread, was the first and for a long time the only link of VCAM-1 to cancer sciences. In the last few years, hallmarked by a growing insight into the molecular understanding of tumorigenicity and metastasis, an impressive variety of VCAM-1 functionalities in cancer have been elucidated. The present review aims to provide a current overview of VCAM-1 relevance for tumor growth, metastasis, angiogenesis, and related processes. By illustrating the intriguing role of VCAM 1 in cancer disease, VCAM-1 is suggested as a new and up to now underestimated target in cancer treatment and in clinical diagnosis of malignancies. PMID- 24771583 TI - Effects of processing sorghum and millets on their phenolic phytochemicals and the implications of this to the health-enhancing properties of sorghum and millet food and beverage products. AB - Sorghum and millet grains are generally rich in phytochemicals, particularly various types of phenolics. However, the types and amounts vary greatly between and within species. The food-processing operations applied to these grains, i.e. dehulling and decortication, malting, fermentation and thermal processing, dramatically affect the quantity of phenolics present, most generally reducing them. Thus the levels of phytochemicals in sorghum and millet foods and beverages are usually considerably lower than in the grains. Notwithstanding this, there is considerable evidence that sorghum and millet foods and beverages have important functional and health-promoting effects, specifically antidiabetic, cardiovascular disease and cancer prevention, due to the actions of these phytochemicals. Also their lactic acid bacteria-fermented products may have probiotic effects related to their unique microflora. However, direct proof of these health-enhancing effects is lacking as most studies have been carried out on the grains or grain extracts and not the food and beverage products themselves, and also most research work has been in vitro or ex vivo and not in vivo. To provide the required evidence, better designed studies are needed. The sorghum and millet products should be fully characterised, especially their phytochemical composition. Most importantly, well-controlled human clinical studies and intervention trials are required. PMID- 24771584 TI - Mutant IDH1 inhibits PI3K/Akt signaling in human glioma. AB - BACKGROUND: Recently, isocitrate dehydrogenase 1 (IDH1) was identified as a major participant in glioma pathogenesis. At present, the enzymatic activity of the protein has been the main topic in investigating its physiological function, but its signaling pathway allocation was unsuccessful. Interestingly, proteins regulated by phosphoinositide 3-kinase (PI3K)/Akt signaling, are among the top downregulated genes in gliomas associated with high percentage of IDH1 and IDH2 mutations. The aim of this study was to investigate a hypothetical relation between IDH1 and PI3K signaling. METHODS: The presence of mutant IDH1 and markers for active PI3K/Akt signaling, present as phosphorylated Akt and podoplanin (PDPN), were investigated in a discovery cohort of 354 patients with glioma. In vitro experiments were used to confirm functional links. RESULTS: This study shows an inverse correlation between mutant IDH1 and markers for active PI3K/Akt signaling. In support of a functional link between these molecules, in vitro expression of mutant IDH1 inhibited Akt phosphorylation in a 2-hydroxyglutarate dependent manner. CONCLUSIONS: This study provides patient tumor and in vitro evidence suggesting that mutant IDH1 inhibits PI3K/Akt signaling. PMID- 24771585 TI - Tricks of light on helices: transformation of helical polymers by photoirradiation. AB - The following polymer structural transitions were achieved using light: preferred handed helix formation for poly(9,9-di-n-octylfluoren-2,7-diyl), helix racemization (helix-helix transition) for poly(2,7-bis(4-t-butylphenyl)fluoren-9 yl acrylate) and poly(2,5-bis[4-((S)-2-methylbutyloxy)phenyl]styrene), and helix decomposition for poly(2,7-bis(4-t-butylphenyl)-9-methylfluoren-9-yl acrylate) and poly(2,7-bis(4-t-butylphenyl)fluoren-9-ylmethyl methacrylate). Although these types of transitions and chemical transformations have been studied mainly using heat or chemicals as stimuli, light can also cause these structural alterations. In the helix construction and the helix-helix transition, a key transition is a twist-coplanar conformational change of a biphenyl or an aryl-aryl unit in the side chain or the main chain of the polymer. Furthermore, the helix-helix transition was caused only by light and not by heat. The examples discussed in this review are expected to trigger off a new direction in synthesis and reaction of chiral polymers. PMID- 24771586 TI - Experimental performance evaluation of human balance control models. AB - Two factors commonly differentiate proposed balance control models for quiet human standing: 1) intermittent muscle activation and 2) prediction that overcomes sensorimotor time delays. In this experiment we assessed the viability and performance of intermittent activation and prediction in a balance control loop that included the neuromuscular dynamics of human calf muscles. Muscles were driven by functional electrical stimulation (FES). The performance of the different controllers was compared based on sway patterns and mechanical effort required to balance a human body load on a robotic balance simulator. All evaluated controllers balanced subjects with and without a neural block applied to their common peroneal and tibial nerves, showing that the models can produce stable balance in the absence of natural activation. Intermittent activation required less stimulation energy than continuous control but predisposed the system to increased sway. Relative to intermittent control, continuous control reproduced the sway size of natural standing better. Prediction was not necessary for stable balance control but did improve stability when control was intermittent, suggesting a possible benefit of a predictor for intermittent activation. Further application of intermittent activation and predictive control models may drive prolonged, stable FES-controlled standing that improves quality of life for people with balance impairments. PMID- 24771587 TI - Solid-phase extraction with the metal-organic framework MIL-101(Cr) combined with direct analysis in real time mass spectrometry for the fast analysis of triazine herbicides. AB - MIL-101(Cr) is an excellent metal-organic framework with high surface area and nanoscale cavities, making it promising in solid-phase extraction. Herein, we used MIL-101(Cr) as a solid-phase extraction packing material combined with fast detection of direct analysis in real time mass spectrometry (DART-MS) for the analysis of triazine herbicides. After systematic optimization of the operation parameters, including the gas temperature of DART, the moving speed of the 1D platform, solvent for desorption, amount of MIL-101(Cr) extraction time, eluent volume and salt concentration, this method can realize the simultaneous detection of five kinds of triazine herbicides. The limits of detection were 0.1~0.2 ng/mL and the linear ranges covered more than two orders of magnitude with the quantitation limits of 0.5~1 ng/mL. Moreover, the developed method has been applied for the analysis of lake water samples and the recoveries for spiked analytes were in the range of 85~110%. These results showed that solid-phase extraction with metal-organic frameworks is an efficient sample preparation approach for DART-MS analysis and could find more applications in environmental analysis. PMID- 24771588 TI - Decision-making, sensitivity to reward and attrition in weight management. AB - OBJECTIVE: Attrition is a common problem in weight management. Understanding the risk factors for attrition should enhance professionals' ability to increase completion rates and improve health outcomes for more individuals. A model that draws upon neuropsychological knowledge on reward-sensitivity in obesity and overeating to predict attrition is proposed. METHODS: A total of 52 participants in a weight-management program completed a complex decision-making task. Decision making characteristics-including sensitivity to reward-were further estimated using a quantitative model. Impulsivity and risk-taking measures were also administered. RESULTS: Consistent with the hypothesis that sensitivity to reward predicted attrition, program dropouts had higher sensitivity to reward than completers (P < 0.03). No differences were observed between completers and dropouts in initial BMI, age, employment status, or the number of prior weight loss attempts (P >= 0.07). Completers had a slightly higher education level than dropouts, but its inclusion in the model did not increase predictive power. Impulsivity, delay of gratification, and risk taking did not predict attrition, either. CONCLUSIONS: Findings link attrition in weight management to the neural mechanisms associated with reward-seeking and related influences on decision making. Individual differences in the magnitude of response elicited by rewards may account for the relative difficulty experienced by dieters in adhering to treatment. PMID- 24771590 TI - Acute physical stress induces the alteration of the serotonin 1A receptor density in the hippocampus. AB - Stress affects the serotonergic system, which is associated with depression. Previous research has showed that chronic stress causes the deactivation of the limbic system. However, the influence of the acute physical stress on the serotonergic system in vivo was primarily unclear. The purpose of this research is to elucidate the effects of the acute physical stress in vivo using PET. For quantification of the 5-HT1A receptors in the brain, we measured [(18)F]Mefway uptake in the two experiment groups (control and despair rats). The despair group was subjected to the external stressful situation (i.e., forced swimming) and total duration time of immobility, refers to the despair severity, and was analyzed. In the intercomparison experiment, the resulting PET images of [(18)F]Mefway in the despair rat displayed a significant reduction of radioactivity in the hippocampus (HP) compared with the control. The nondisplaceable binding potential (BPND ) refers to the ratio of the concentration of radioligand in the receptor-rich region (i.e., HP) to the concentration of that in the receptor-free region (i.e., cerebellum). The hippocampal uptake and the BPND in the despair group were respectively about 25 and 18% lower than those of the control group. The ratio of specific binding to nonspecific binding in the despair group was 18% lower than that of the control. In the intracomparison experiments, the BPND and immobility in the despair group showed a strong negative correlation. Taken together, the data illustrates that an acute physical stress induces the change in the serotonergic system that correlates with the behavioral despair. PMID- 24771589 TI - Nonconvulsive seizures in subarachnoid hemorrhage link inflammation and outcome. AB - OBJECTIVE: Nonconvulsive seizures (NCSz) are frequent following acute brain injury and have been implicated as a cause of secondary brain injury, but mechanisms that cause NCSz are controversial. Proinflammatory states are common after many brain injuries, and inflammation-mediated changes in blood-brain barrier permeability have been experimentally linked to seizures. METHODS: In this prospective observational study of aneurysmal subarachnoid hemorrhage (SAH) patients, we explored the link between the inflammatory response following SAH and in-hospital NCSz studying clinical (systemic inflammatory response syndrome [SIRS]) and laboratory (tumor necrosis factor receptor 1 [TNF-R1], high sensitivity C-reactive protein [hsCRP]) markers of inflammation. Logistic regression, Cox proportional hazards regression, and mediation analyses were performed to investigate temporal and causal relationships. RESULTS: Among 479 SAH patients, 53 (11%) had in-hospital NCSz. Patients with in-hospital NCSz had a more pronounced SIRS response (odds ratio [OR]=1.9 per point increase in SIRS, 95% confidence interval [CI]=1.3-2.9), inflammatory surges were more likely immediately preceding NCSz onset, and the negative impact of SIRS on functional outcome at 3 months was mediated in part through in-hospital NCSz. In a subset with inflammatory serum biomarkers, we confirmed these findings linking higher serum TNF-R1 and hsCRP to in-hospital NCSz (OR=1.2 per 20-point hsCRP increase, 95% CI=1.1-1.4; OR=2.5 per 100-point TNF-R1 increase, 95% CI=2.1-2.9). The association of inflammatory biomarkers with poor outcome was mediated in part through NCSz. INTERPRETATION: In-hospital NCSz were independently associated with a proinflammatory state following SAH as reflected in clinical symptoms and serum biomarkers of inflammation. Our findings suggest that inflammation following SAH is associated with poor outcome and that this effect is at least in part mediated through in-hospital NCSz. PMID- 24771591 TI - NovoHCD: de novo peptide sequencing from HCD spectra. AB - In recent years, de novo peptide sequencing from mass spectrometry data has developed as one of the major peptide identification methods with the emergence of new instruments and advanced computational methods. However, there are still limitations to this method; for example, the typically used spectrum graph model cannot represent all the information and relationships inherent in tandem mass spectra (MS/MS spectra). Here, we present a new method named NovoHCD which applies a spectrum graph model with multiple types of edges (called a multi-edge graph), and integrates into it amino acid combination (AAC) information and peptide tags. In addition, information on immonium ions observed particularly in higher-energy collisional dissociation (HCD) spectra is incorporated. Comparisons between NovoHCD and another successful de novo peptide sequencing method for HCD spectra, pNovo, were performed. Experiments were conducted on five HCD spectral datasets. Results show that NovoHCD outperforms pNovo in terms of full length peptide identification accuracy; specifically, the accuracy increases 13%-21% over the five datasets. PMID- 24771592 TI - Molecular communication among biological nanomachines: a layered architecture and research issues. AB - Molecular communication is an emerging communication paradigm for biological nanomachines. It allows biological nanomachines to communicate through exchanging molecules in an aqueous environment and to perform collaborative tasks through integrating functionalities of individual biological nanomachines. This paper develops the layered architecture of molecular communication and describes research issues that molecular communication faces at each layer of the architecture. Specifically, this paper applies a layered architecture approach, traditionally used in communication networks, to molecular communication, decomposes complex molecular communication functionality into a set of manageable layers, identifies basic functionalities of each layer, and develops a descriptive model consisting of key components of the layer for each layer. This paper also discusses open research issues that need to be addressed at each layer. In addition, this paper provides an example design of targeted drug delivery, a nanomedical application, to illustrate how the layered architecture helps design an application of molecular communication. The primary contribution of this paper is to provide an in-depth architectural view of molecular communication. Establishing a layered architecture of molecular communication helps organize various research issues and design concerns into layers that are relatively independent of each other, and thus accelerates research in each layer and facilitates the design and development of applications of molecular communication. PMID- 24771594 TI - A new strategy for protein interface identification using manifold learning method. AB - Protein interactions play vital roles in biological processes. The study for protein interface will allow people to elucidate the mechanism of protein interaction. However, a large portion of protein interface data is incorrectly collected in current studies. In this paper, a novel strategy of dataset reconstruction using manifold learning method has been proposed for dealing with the noises in the interaction interface data whose definition is based on the residue distances among the different chains within protein complexes. Three support vector machine-based predictors are constructed using different protein features to identify the functional sites involved in the formation of protein interface. The experimental results achieved in this work demonstrate that our strategy can remove noises, and therefore improve the ability for identification of protein interfaces with 77.8% accuracy. PMID- 24771593 TI - Hybrid method inference for the construction of cooperative regulatory network in human. AB - Reconstruction of large scale gene regulatory networks (GRNs in the following) is an important step for understanding the complex regulatory mechanisms within the cell. Many modeling approaches have been introduced to find the causal relationship between genes using expression data. However, they have been suffering from high dimensionality-large number of genes but a small number of samples, overfitting, heavy computation time and low interpretability. We have previously proposed an original Data Mining algorithm Licorn, that infers cooperative regulation network from expression datasets. In this work, we present an extension of Licorn to a hybrid inference method h-Licorn that uses search in both discrete and real valued spaces. Licorn's algorithm, using the discrete space to find cooperative regulation relationships fitting the target gene expression, has been shown to be powerful in identifying cooperative regulation relationships that are out of the scope of most GRN inference methods. Still, as many of related GRN inference techniques, Licorn suffers from a large number of false positives. We propose here an extension of Licorn with a numerical selection step, expressed as a linear regression problem, that effectively complements the discrete search of Licorn. We evaluate a bootstrapped version of h-Licorn on the in silico Dream5 dataset and show that h-Licorn has significantly higher performance than Licorn, and is competitive or outperforms state of the art GRN inference algorithms, especially when operating on small data sets. We also applied h-Licorn on a real dataset of human bladder cancer and show that it performs better than other methods in finding candidate regulatory interactions. In particular, solely based on gene expression data, h-Licorn is able to identify experimentally validated regulator cooperative relationships involved in cancer. PMID- 24771595 TI - Optical detection of lead and potassium ions using a quantum-dot-based aptamer nanosensor. AB - Quantum-dot (QD) based nanosensors can be used to detect a wide range of molecules. This study examined a nanosensor comprised of thrombin binding aptamer (TBA) with 700NC InGaP QD on the 5 (') terminus and an Au nanoparticle quencher on the 3 (') terminus. Both K(+) and Pb(2+) bind to TBA, resulting in a conformational change that brings the Au quencher closer to the QD. Photoluminescence measurements indicated a decrease in fluorescence corresponding to an increase in either K(+) or Pb(2+) concentration. For healthy blood serum K(+) concentrations (3.5-5 mM), the beacon exhibited 15-17% quenching efficiency. Pb(2+) concentration of 0.48 MUM, the threshold for toxicity in serum, yielded 14% quenching. The beacon's ability to detect changes in ion levels in a critical range of concentrations can make it an effective diagnostic tool. PMID- 24771596 TI - Factors predicting outcome after salvage treatment for stage IV oral squamous cell carcinoma: Evidence of the potential importance of the cyclooxygenase-2 prostaglandin E2 pathway. AB - BACKGROUND: We determined the clinicopathological factors that predicted outcome after salvage treatment for stage IV oral squamous cell carcinoma (OSCC). Additionally, the prognostic significance of the cyclooxygenase-2 (COX 2)/microsomal prostaglandin-E synthase-1 (mPGES-1) pathway was evaluated. METHODS: Thirty-one patients who underwent salvage surgery were included. COX-2 and mPGES-1 levels were quantified by real time polymerase chain reaction (PCR). RESULTS: The 2-year disease-free and overall survival rates were 46% and 53%, respectively. Adequacy of initial treatment, tobacco smoking, and the presence of pathological risk factors were predictive of mortality. In patients who had not received chemotherapy before salvage surgery, high levels of intratumoral COX-2 and mPGES-1 were associated with poor prognosis. By contrast, high intratumoral COX-2 and mPGES-1 after chemotherapy were associated with improved outcomes. CONCLUSION: Clinicopathological factors may inform treatment decisions in patients with stage IV OSCC. Expression patterns of COX-2 and mPGES-1 correlated with outcome and warrant further investigation. (c) 2014 Wiley Periodicals, Inc. Head Neck 37: 1142-1149, 2015. PMID- 24771597 TI - Effects of chitosan and oligochitosan on development and mitochondrial function of Rhizopus stolonifer. AB - The antifungal activities of chitosan and oligochitosan have been used to control postharvest decay of the fruits. The effect of chitosan and oligochitosan on mycelium growth, spore germination, and mitochondrial function of Rhizopus stolonifer was evaluated in order to establish a connection between fungus development and the main organelle in charge to provide energy to the cell. The mycelium growth of R. stolonifer was significantly reduced on minimum media amended with chitosan or oligochitosan. The highest antifungal indexes were obtained on media containing chitosan or oligochitosan at 2.0 mg ml(-1). Microscopic observation showed that chitosan and oligochitosan affected the spore germination and hyphae morphology. Both polymers increased oxygen consumption of R. stolonifer. Respiratory activity was restored with NADH in permeabilized treated and untreated cells, and was inhibited with rotenone and flavones. Complex III and IV were inhibited by antimycin A and cyanide, respectively, in treated and untreated cells. Chitosan and oligochitosan increased NADH dehydrogenase activity in isolated mitochondria. However, there were not changes in the cytochrome c oxidase and ATPase activities by effect of these polymers. These results suggest that both chitosan and oligochitosan affect the development of R. stolonifer and might be implicated in the mitochondrial dysfunction. PMID- 24771598 TI - Stroke parameters identification algorithm in handwriting movements analysis by synthesis. AB - This paper presents a new approach to identify the stroke parameters in handwriting movement data understanding. A two-step analysis by synthesis paradigm is employed to facilitate the coarse-to-fine parameter identification for all strokes. One is the stroke data extraction, the other is the coarse-to fine stroke parameter identification. The new consideration of using this two step paradigm is that the nonnegative primitive factorization technique is incorporated to decouple the overlapped strokes from the measurement data. In comparison to the existing paradigms of using the heuristic stroke data decoupling techniques, our paradigm presented here contributes to alleviating the difficulty of local optimum traps with the well-shaped initializations in the global optimization for jointly identifying stroke parameters. Moreover, our paradigm excludes the iteration between two steps, which contributes to the enhancement of computational efficiency. Experimental results are reported to validate the proposed approach. PMID- 24771599 TI - Genetic algorithm-based classifiers fusion for multisensor activity recognition of elderly people. AB - Activity recognition of an elderly person can be used to provide information and intelligent services to health care professionals, carers, elderly people, and their families so that the elderly people can remain at homes independently. This study investigates the use and contribution of wrist-worn multisensors for activity recognition. We found that accelerometers are the most important sensors and heart rate data can be used to boost classification of activities with diverse heart rates. We propose a genetic algorithm-based fusion weight selection (GAFW) approach which utilizes GA to find fusion weights. For all possible classifier combinations and fusion methods, the study shows that 98% of times GAFW can achieve equal or higher accuracy than the best classifier within the group. PMID- 24771600 TI - A MDP model for breast and ovarian cancer intervention strategies for BRCA1/2 mutation carriers. AB - PURPOSE: Women with BRCA1/2 mutations have higher risk for breast and ovarian cancers. Available intervention actions include prophylactic surgeries and breast screening, which vary significantly in cost, cancer prevention, and in resulting death from other causes. We present a model designed to yield optimal intervention strategies for mutation carriers between the ages of 30 and 65 and any prior intervention history. METHODS: A Markov decision process (MDP) model is developed that considers yearly state transitions for the mutation carriers and state dependent intervention actions. State is defined as a vector comprising mutation type, health states, prior intervention actions, and age. A discounted value iteration algorithm is used to obtain optimal strategies from the MDP model using both cost and quality-adjusted life years (QALYs) as rewards. RESULTS: The results from MDP model show that for 30-year-old women with BRCA1 mutation and no prior intervention history, the cost-optimal strategy is a combination of prophylactic mastectomy (PM) and prophylactic oophorectomy (PO) at age 30 with no screening afterwards. Whereas, the QALYs-optimal strategy suggests PO at age 30 and PM at age 50 with screening afterwards. For BRCA2 mutation carriers at age 30, the cost-optimal strategy is PO at age 30, PM at age 40, and yearly screening only after age 56. Corresponding QALYs-optimal strategy is PM at age 40 with screening. Strategies for all other ages (31 to 65) are obtained and presented. It is also demonstrated that the cost-optimal strategies offer near maximum survival rate and near minimum cancer incidence rates by age 70, when compared to other ad hoc strategies. PMID- 24771601 TI - Fall detection based on body part tracking using a depth camera. AB - The elderly population is increasing rapidly all over the world. One major risk for elderly people is fall accidents, especially for those living alone. In this paper, we propose a robust fall detection approach by analyzing the tracked key joints of the human body using a single depth camera. Compared to the rivals that rely on the RGB inputs, the proposed scheme is independent of illumination of the lights and can work even in a dark room. In our scheme, a pose-invariant randomized decision tree algorithm is proposed for the key joint extraction, which requires low computational cost during the training and test. Then, the support vector machine classifier is employed to determine whether a fall motion occurs, whose input is the 3-D trajectory of the head joint. The experimental results demonstrate that the proposed fall detection method is more accurate and robust compared with the state-of-the-art methods. PMID- 24771602 TI - Validation of the 10/66 Dementia Research Group diagnostic assessment for dementia in Arabic: a study in Lebanon. AB - OBJECTIVES: In the North Africa and Middle East region, the illiteracy rates among older people are high, posing a great challenge to cognitive assessment. Validated diagnostic instruments for dementia in Arabic are lacking, hampering the development of dementia research in the region. The study aimed at validating the Arabic version of the 10/66 Dementia Research Group (DRG) diagnostic assessment for dementia to determine whether it is suitable for case ascertainment in epidemiological research. METHODS: A total of 244 participants older than 65 years were included, 100 with normal cognition and 144 with mild to moderate dementia. Dementia was diagnosed by clinicians according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. Depression was diagnosed using the Geriatric Mental State. Trained interviewers blind to the cognitive status of the participants administered the 10/66 DRG diagnostic assessment to the participants and interviewed the caregivers. The discriminatory ability of the 10/66 DRG assessment and its subcomponents were evaluated against the clinical diagnoses. RESULTS: Half of the participants had no formal education and 49% of them were depressed. The 10/66 DRG diagnostic assessment showed excellent sensitivity (92.0%), specificity (95.1%), positive predictive value (PPV, 92.9%), and low false-positive rates among controls with no formal education (8.1%) and depression (5.6%). Each subcomponent of the 10/66 DRG diagnostic assessment independently predicted dementia diagnosis. The predictive ability of the 10/66 DRG assessment was superior to that of its subcomponents. CONCLUSION: The 10/66 DRG diagnostic assessment for dementia is well suited for case ascertainment in epidemiological studies among Arabic-speaking older population with high prevalence of illiteracy. PMID- 24771603 TI - Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. AB - Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose independent, three-compartment model with allometric relationship for body weight, was similar for all tumor types. Inter-individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulin's effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure-efficacy relationships to inform physicians treating patients with MBC. PMID- 24771604 TI - Automated adjustment of region-based active contour parameters using local image geometry. AB - A principled method for active contour (AC) parameterization remains a challenging issue in segmentation research, with a potential impact on the quality, objectivity, and robustness of the segmentation results. This paper introduces a novel framework for automated adjustment of region-based AC regularization and data fidelity parameters. Motivated by an isomorphism between the weighting factors of AC energy terms and the eigenvalues of structure tensors, we encode local geometry information by mining the orientation coherence in edge regions. In this light, the AC is repelled from regions of randomly oriented edges and guided toward structured edge regions. Experiments are performed on four state-of-the-art AC models, which are automatically adjusted and applied on benchmark datasets of natural, textured and biomedical images and two image restoration models. The experimental results demonstrate that the obtained segmentation quality is comparable to the one obtained by empirical parameter adjustment, without the cumbersome and time-consuming process of trial and error. PMID- 24771606 TI - Adaptive synchronization for neutral-type neural networks with stochastic perturbation and Markovian switching parameters. AB - In this paper, the problem of adaptive synchronization is investigated for stochastic neural networks of neutral-type with Markovian switching parameters. Using the M-matrix approach and the stochastic analysis method, some sufficient conditions are obtained to ensure three kinds of adaptive synchronization for the stochastic neutral-type neural networks. These three kinds of adaptive synchronization include the almost sure asymptotical synchronization, exponential synchronization in p th moment and almost sure exponential synchronization. Some numerical examples are provided to illustrate the effectiveness and potential of the proposed design techniques. PMID- 24771605 TI - NCC-RANSAC: a fast plane extraction method for 3-D range data segmentation. AB - This paper presents a new plane extraction (PE) method based on the random sample consensus (RANSAC) approach. The generic RANSAC-based PE algorithm may over extract a plane, and it may fail in case of a multistep scene where the RANSAC procedure results in multiple inlier patches that form a slant plane straddling the steps. The CC-RANSAC PE algorithm successfully overcomes the latter limitation if the inlier patches are separate. However, it fails if the inlier patches are connected. A typical scenario is a stairway with a stair wall where the RANSAC plane-fitting procedure results in inliers patches in the tread, riser, and stair wall planes. They connect together and form a plane. The proposed method, called normal-coherence CC-RANSAC (NCC-RANSAC), performs a normal coherence check to all data points of the inlier patches and removes the data points whose normal directions are contradictory to that of the fitted plane. This process results in separate inlier patches, each of which is treated as a candidate plane. A recursive plane clustering process is then executed to grow each of the candidate planes until all planes are extracted in their entireties. The RANSAC plane-fitting and the recursive plane clustering processes are repeated until no more planes are found. A probabilistic model is introduced to predict the success probability of the NCC-RANSAC algorithm and validated with real data of a 3-D time-of-flight camera-SwissRanger SR4000. Experimental results demonstrate that the proposed method extracts more accurate planes with less computational time than the existing RANSAC-based methods. PMID- 24771607 TI - Simultaneous analysis of metformin and cyanoguanidine by capillary zone electrophoresis and its application in a stability study. AB - A capillary zone electrophoresis method was established for stability study of metformin (MET). MET and cyanoguanidine (CGN; a major degradation product) were well separated (with a resolution of 38.9) in 40 mM citrate buffer (pH 6.7) using a fused-silica capillary with an effective length of 60 cm and an inner diameter of 50 MUm, injection at 50 mbar for 5 s at 30 degrees C with an applied voltage of 15 kV and diode array detection at 214 nm. Method validation showed good linearity (r(2) > 0.99), precision (%RSDs < 1.98%), and accuracy (%recovery between 98.3 and 100.9%). Limits of detection and quantification were <30 and 100 MUg/mL, respectively. The method was robust upon alteration of pH and voltage (%RSDs < 1.99%). Stability profiles of metformin from 11 stress conditions and the degradation kinetics could be established, using the simple capillary zone electrophoresis system. A mechanism for the degradation of MET was also proposed. MET was stable in neutral hydrolysis, but degraded under alkaline hydrolysis and oxidation. Under both conditions, CGN was quantified as the degradation product. An assay of MET in raw material and tablets showed that content of the drugs in all samples met the requirements of pharmacopeias and CGN was not detected. PMID- 24771608 TI - Green and blue areas as predictors of overweight and obesity in an 8-year follow up study. AB - OBJECTIVE: To longitudinally examine associations between proximity of urban green or blue areas and BMI. METHODS: The study population consisted of the Finnish Public Sector study participants who responded to surveys in 2000 and 2008 and lived in an urban area; 15,621 of them did not move residence (nonmovers) during the follow-up, and 9696 did (movers). The associations for objectively measured distance and change in distance to blue area and usable green area with self-reported BMI were assessed (normal weight/overweight/obese). RESULTS: Among the nonmovers, living >750 versus <250 m from usable green area increased the odds of overweight (odds ratio [OR] 1.50; 95% confidence interval [CI] 1.07-2.11), and living 500-750 versus <250 m from the nearest blue area increased the odds of overweight (OR 1.24; 95% CI 1.01-1.52). No significant associations were observed for obesity. Moving away from the proximity of green, but not blue, area (from <250 to >250m) increased the odds of obesity (OR 1.49; 95% CI 1.08-2.06). CONCLUSIONS: These longitudinal population level findings suggest that living far from usable green areas or waterfront in urban areas increases the risk of overweight. PMID- 24771609 TI - International differences in clinical characteristics, management, and outcomes in acute heart failure patients: better short-term outcomes in patients enrolled in Eastern Europe and Russia in the PROTECT trial. AB - AIMS: The implications of geographical variation are unknown following adjustment for hospital length of stay (LOS) in heart failure (HF) trials that included patients whether or not they had systolic dysfunction. We investigated regional differences in an international acute HF trial. METHODS AND RESULTS: The PROTECT trial investigated 2033 patients with acute HF and renal dysfunction hospitalized at 173 sites in 17 countries with randomization to rolofylline or placebo. We grouped enrolling countries into six regions. Baseline characteristics, in hospital management, and outcomes were explored by region. The primary study outcome was 60-day mortality or cardiovascular/renal hospitalization. Secondary outcomes included 180-day mortality. Of 2033 patients, 33% were from Eastern Europe, 19% from Western Europe, 16% from Israel, 15% from North America, 14% from Russia, and 3% from Argentina. Marked differences in baseline characteristics, HF phenotype, in-hospital diuretic and vasodilator strategies, and LOS were observed by region. LOS was shortest in North America and Israel (median 5 days) and longest in Russia (median 15 days). Regional event rates varied significantly. Following multivariable adjustment, region was an independent predictor of the risk of mortality/hospitalization at 60 days, with the lowest risk in Russia (hazard ratio 0.39, 95% confidence interval 0.23-0.64 vs. Western Europe) due to lower rehospitalization; mortality differences were attenuated by 180 days. CONCLUSIONS: In an international HF trial, there were differences in baseline characteristics, treatments, LOS, and rehospitalization amongst regions, but little difference in longer term mortality. Rehospitalization differences exist independent of LOS. This analysis may help inform future trial design and should be externally validated. PMID- 24771610 TI - Neurobiology of attachment to an abusive caregiver: short-term benefits and long term costs. AB - Childhood maltreatment is associated with adverse brain development and later life psychiatric disorders, with maltreatment from the caregiver inducing a particular vulnerability to later life psychopathologies. Here we review two complementary rodent models of early life abuse, which are used to examine the infant response to trauma within attachment and the developmental trajectories that lead to later life neurobehavioral deficits. These rodent models include being reared with an abusive mother, and a more controlled attachment-learning paradigm using odor-shock conditioning to produce a new maternal odor. In both of these rodent models, pups learn a strong attachment and preference to the maternal odor. However, both models produce similar enduring neurobehavioral deficits, which emerge with maturation. Importantly, cues associated with our models of abuse serve as paradoxical safety signals, by normalizing enduring neurobehavioral deficits following abuse. Here we review these models and explore implications for human interventions for early life maltreatment. PMID- 24771612 TI - Gelsolin regulates cisplatin sensitivity in human head-and-neck cancer. AB - Chemoresistance is a major challenge in cancer therapy. Cisplatin is commonly used for chemotherapy in patients with head-and-neck cancer (HNC), but it increases control of the disease by only 10-15%. Downregulation of proapoptotic pathways is a key determinant for chemoresistance in which gelsolin (GSN) is critically involved. We analyzed the association between GSN expression and cisplatin resistance in HNC cell lines, animals with HNC and cancer tissue samples from 58 cisplatin-treated patients with HNC. GSN expression levels were positively associated with chemoresistance in vitro and in vivo. Cisplatin induced GSN downregulation was associated with the cleavage of GSN and the promotion of apoptosis. GSN silencing facilitated cisplatin-induced apoptosis in chemoresistant cells. In contrast, intact gelsolin was prosurvival in the presence of cisplatin by interacting with X-linked inhibitor of apoptosis protein (XIAP). In chemosensitive cells, cisplatin suppressed GSN-XIAP interaction, promoted translocation of XIAP from the perinuclear region to the nucleus and induced apoptosis. In chemoresistant cells, GSN was highly expressed, and cisplatin had no significant effect on GSN-XIAP interaction and apoptosis. We conclude that GSN is important for chemoresistance in HNC and may be an appropriate therapeutic target in chemoresistant cancers. PMID- 24771613 TI - Incorporation of primary patient-derived glycoproteins into authentic infectious hepatitis C virus particles. AB - The Japanese fulminant hepatitis-1 (JFH1)-based hepatitis C virus (HCV) infection system has permitted analysis of the complete viral replication cycle in vitro. However, lack of robust infection systems for primary, patient-derived isolates limits systematic functional studies of viral intrahost variation and vaccine development. Therefore, we aimed at developing cell culture models for incorporation of primary patient-derived glycoproteins into infectious HCV particles for in-depth mechanistic studies of envelope gene function. To this end, we first constructed a packaging cell line expressing core, p7, and NS2 based on the highly infectious Jc1 genotype (GT) 2a chimeric genome. We show that this packaging cell line can be transfected with HCV replicons encoding cognate Jc1-derived glycoprotein genes for production of single-round infectious particles by way of trans-complementation. Testing replicons expressing representative envelope protein genes from all major HCV genotypes, we observed that virus production occurred in a genotype- and isolate-dependent fashion. Importantly, primary GT 2 patient-derived glycoproteins were efficiently incorporated into infectious particles. Moreover, replacement of J6 (GT 2a) core, p7, and NS2 with GT 1a-derived H77 proteins allowed production of infectious HCV particles with GT 1 patient-derived glycoproteins. Notably, adaptive mutations known to enhance virus production from GT 1a-2a chimeric genomes further increased virus release. Finally, virus particles with primary patient-derived E1 E2 proteins possessed biophysical properties comparable to Jc1 HCVcc particles, used CD81 for cell entry, were associated with ApoE and could be neutralized by immune sera. CONCLUSION: This work describes cell culture systems for production of infectious HCV particles with primary envelope protein genes from GT 1 and GT 2-infected patients, thus opening up new opportunities to dissect envelope gene function in an individualized fashion. PMID- 24771611 TI - A protease storm cleaves a cell-cell adhesion molecule in cancer: multiple proteases converge to regulate PTPmu in glioma cells. AB - Cleavage of the cell-cell adhesion molecule, PTPu, occurs in human glioblastoma multiforme brain tumor tissue and glioma cell lines. PTPu cleavage is linked to increased cell motility and growth factor independent survival of glioma cells in vitro. Previously, PTPu was shown to be cleaved by furin in the endoplasmic reticulum to generate membrane associated E- (extracellular) and P- (phosphatase) subunits, and by ADAMs and the gamma secretase complex at the plasma membrane. We also identified the presence of additional extracellular and intracellular PTPu fragments in brain tumors. We set out to biochemically analyze PTPu cleavage in cancer cells. We determined that, in addition to the furin-processed form of PTPu, a pool of 200 kDa full-length PTPu exists at the plasma membrane that is cleaved directly by ADAM to generate a larger shed form of the PTPu extracellular segment. Notably, in glioma cells, full-length PTPu is also subject to calpain cleavage, which generates novel PTPu fragments not found in other immortalized cells. We also observed glycosylation and phosphorylation differences in the cancer cells. Our data suggest that an additional serine protease also contributes to PTPu shedding in glioma cells. We hypothesize that a "protease storm" occurs in cancer cells whereby multiple proteases converge to reduce the presence of cell-cell adhesion molecules at the plasma membrane and to generate protein fragments with unique biological functions. As a consequence, the "protease storm" could promote the migration and invasion of tumor cells. PMID- 24771614 TI - Thc6 protein, isolated from Trichoderma harzianum, can induce maize defense response against Curvularia lunata. AB - Mutant T66 was isolated from 450 mutants (constructed with Agrobacterium tumefaciens-mediated transformation method) of Trichoderma harzianum. Maize seeds coated with T66 were more susceptible to Curvularia lunata when compared with those coated with wild-type (WT) strain. The disease index of maize treated with T66 and WT were 62.5 and 42.1%, respectively. Further research showed T-DNA has inserted into the ORF of one gene, which resulted in the functional difference between WT and T66. The gene was cloned and named Thc6, which encodes a novel 327 amino acid protein. To investigate its function, we obtained knockout, complementation, and overexpression mutants of Thc6. Challenge inoculation studies suggested that the Thc6 overexpression mutant can reduce the disease index of maize inbred line Huangzao 4 against the leaf spot pathogen (C. lunata). Meanwhile, The Thc6 mutants were found to affect the resistance of maize inbred line Huangzao 4 against C. lunata by enhancing the activation of jasmonate responsive genes expression. Liquid chromatography-mass spectrometry (LC-MS) data further confirmed that the concentration of jasmonate in the induced maize exhibits a parallel change tendency with the expression level of defense-related genes. Hence, the Thc6 gene could be participated in the induced resistance of maize inbred line Huangzao 4 against C. lunata infection through a jasmonic acid dependent pathway. PMID- 24771615 TI - Left ventricular systolic dysfunction in outpatients with peripheral atherosclerotic vascular disease: prevalence and association with location of arterial disease. AB - AIMS: We aimed to determine the prevalence of left ventricular systolic dysfunction (LVSD) in outpatients with peripheral atherosclerotic vascular disease (PAVD). Further, the associations of stenotic internal carotid artery disease (SICAD) and lower extremity artery disease (LEAD) with LVSD were evaluated. METHODS AND RESULTS: In the Peripheral Artery Disease in Vastmanland study, consecutive outpatients with ultrasonographically identified mild to severe stenosis in the internal carotid artery or symptoms of claudication combined with either ankle brachial index of <=0.90 or ultrasonographic occlusive findings were included (n = 437). Population-based control subjects were matched to the patients (n = 395). LVSD was defined as echocardiographically determined left ventricular ejection fraction (LVEF) <55%, and moderate or greater LVSD was defined as LVEF <45%. The prevalence of LVSD was significantly greater in patients than in controls (13.7% vs. 6.1%, P < 0.001). The prevalence of moderate or greater LVSD in participants not on treatment with a combination of angiotensin-converting enzyme inhibitor and beta-blocker was 2.3% in patients and 1.3% in controls (P = 0.31). When LEAD and SICAD were analysed together, adjusted for potential confounders, SICAD [odds ratio (OR) 2.54, 95% confidence interval (CI) 1.03-6.32], but not LEAD (OR 1.59, 95% CI 0.80-3.18), was independently associated with LVSD. CONCLUSIONS: In outpatients with PAVD, we found a 13.7% prevalence of LVSD. However, the prevalence of at least moderate LVSD in patients not on treatment with angiotensin-converting enzyme inhibitor and a beta-blocker was only 2.3% and not significantly different from controls. Stenotic artery disease in the internal carotid artery, but not in the lower extremities, was independently associated with LVSD. PMID- 24771616 TI - The association of proton pump inhibitors and hypomagnesemia in the community setting. AB - Evidence for the association between hypomagnesemia and proton pump inhibitors (PPIs), highlighted by the 2011 FDA Drug Safety Communication, rests mainly on studies in hospitalized patients. Our objectives were to determine the prevalence of hypomagnesemia and its association with PPIs in the community setting. We performed a retrospective cross-sectional analysis of a large health maintenance organization administrative database, including ambulatory patients with >=1 serum magnesium concentrations between 2008 and 2011, the lowest referred to as "index magnesium." In cases with any (index magnesium <=0.7 mmol/L) or severe (<=0.55 mmol/L) hypomagnesemia, we analyzed (vs. controls, >0.7 mmol/L) the association with PPI or H2 -blocker use during the 4-12 months preceding the index magnesium by logistic regression analysis, adjusting for confounders. Among 95,205 subjects, 5,696 (6.0%) had any hypomagnesemia, which was severe in 454 (0.5%), with twofold higher prevalences in those with established risk factors. PPI use during the 4 months preceding the index magnesium was more common in cases of any hypomagnesemia (adjusted OR = 1.66; 95% CI, 1.55-1.78) and severe hypomagnesemia (adjusted OR = 3.79; 2.99-4.82) than in controls without acid suppression. Hypomagnesemia remained significantly associated with PPI use when using H2 -blocker-users as reference (adjusted OR = 1.25 [P = 0.003] and 2.65 [P < 0.001] for any and severe hypomagnesemia, respectively). We conclude that hypomagnesemia is associated with PPI use in ambulatory patients. PMID- 24771617 TI - Fosb gene products contribute to excitotoxic microglial activation by regulating the expression of complement C5a receptors in microglia. AB - The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and DeltaFosb, encoding full-length FOSB and DeltaFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored. In this study, we found that microglia express equivalent levels of Fosb and DeltaFosb mRNAs to hippocampal neurons and, using microarray analysis, we identified six microglial genes whose expression is dependent on Fosb products. Of these genes, we focused on C5ar1 and C5ar2, which encode receptors for complement C5a. In isolated Fosb-null microglia, chemotactic responsiveness toward the truncated form of C5a was significantly lower than that in wild-type cells. Fosb-null mice were significantly resistant to kainate induced seizures compared with wild-type mice. C5ar1 mRNA levels and C5aR1 immunoreactivity were increased in wild-type hippocampus 24 hours after kainate administration; however, such induction was significantly reduced in Fosb-null hippocampus. Furthermore, microglial activation after kainate administration was significantly diminished in Fosb-null hippocampus, as shown by significant reductions in CD68 immunoreactivity, morphological change and reduced levels of Il6 and Tnf mRNAs, although no change in the number of Iba-1-positive cells was observed. These findings demonstrate that, under excitotoxicity, Fosb products contribute to a neuroinflammatory response in the hippocampus through regulation of microglial C5ar1 and C5ar2 expression. PMID- 24771619 TI - Aldehyde dehydrogenase, Ald4p, is a major component of mitochondrial fluorescent inclusion bodies in the yeast Saccharomyces cerevisiae. AB - When Saccharomyces cerevisiae strain 3626 was cultured to the stationary phase in a medium that contained glucose, needle-like structures that emitted autofluorescence were observed in almost all cells by fluorescence microscopy under UV excitation. The needle-like structures completely overlapped with the profile of straight elongated mitochondria. Therefore, these structures were designated as mitochondrial fluorescent inclusion bodies (MFIBs). The MFIB enriched mitochondrial fractions were successfully isolated and 2D-gel electrophoresis revealed that a protein of 54 kDa was only highly concentrated in the fractions. Determination of the N-terminal amino acid sequence of the 54-kDa protein identified it as a mitochondrial aldehyde dehydrogenase, Ald4p. Immunofluorescence microscopy showed that anti-Ald4p antibody specifically stained MFIBs. Freeze-substitution electron microscopy demonstrated that cells that retained MFIBs had electron-dense filamentous structures with a diameter of 10 nm in straight elongated mitochondria. Immunoelectron microscopy showed that Ald4p was localized to the electron-dense filamentous structures in mitochondria. These results together showed that a major component of MFIBs is Ald4p. In addition, we demonstrate that MFIBs are common features that appear in mitochondria of many species of yeast. PMID- 24771620 TI - Drag, but not buoyancy, affects swim speed in captive Steller sea lions. AB - Swimming at an optimal speed is critical for breath-hold divers seeking to maximize the time they can spend foraging underwater. Theoretical studies have predicted that the optimal swim speed for an animal while transiting to and from depth is independent of buoyancy, but is dependent on drag and metabolic rate. However, this prediction has never been experimentally tested. Our study assessed the effects of buoyancy and drag on the swim speed of three captive Steller sea lions (Eumetopias jubatus) that made 186 dives. Our study animals were trained to dive to feed at fixed depths (10-50 m) under artificially controlled buoyancy and drag conditions. Buoyancy and drag were manipulated using a pair of polyvinyl chloride (PVC) tubes attached to harnesses worn by the sea lions, and buoyancy conditions were designed to fall within the natural range of wild animals (~12 26% subcutaneous fat). Drag conditions were changed with and without the PVC tubes, and swim speeds were recorded and compared during descent and ascent phases using an accelerometer attached to the harnesses. Generalized linear mixed effect models with the animal as the random variable and five explanatory variables (body mass, buoyancy, dive depth, dive phase, and drag) showed that swim speed was best predicted by two variables, drag and dive phase (AIC = -139). Consistent with a previous theoretical prediction, the results of our study suggest that the optimal swim speed of Steller sea lions is a function of drag, and is independent of dive depth and buoyancy. PMID- 24771621 TI - Hydra myc2, a unique pre-bilaterian member of the myc gene family, is activated in cell proliferation and gametogenesis. AB - The myc protooncogene encodes the Myc transcription factor which is the essential part of the Myc-Max network controlling fundamental cellular processes. Deregulation of myc leads to tumorigenesis and is a hallmark of many human cancers. We have recently identified homologs of myc (myc1, myc2) and max in the early diploblastic cnidarian Hydra and have characterized myc1 in detail. Here we show that myc2 is transcriptionally activated in the interstitial stem cell system. Furthermore, in contrast to myc1, myc2 expression is also detectable in proliferating epithelial stem cells throughout the gastric region. myc2 but not myc1 is activated in cycling precursor cells during early oogenesis and spermatogenesis, suggesting that the Hydra Myc2 protein has a possible non redundant function in cell cycle progression. The Myc2 protein displays the principal design and properties of vertebrate Myc proteins. In complex with Max, Myc2 binds to DNA with similar affinity as Myc1-Max heterodimers. Immunoprecipitation of Hydra chromatin revealed that both Myc1 and Myc2 bind to the enhancer region of CAD, a classical Myc target gene in mammals. Luciferase reporter gene assays showed that Myc1 but not Myc2 transcriptionally activates the CAD promoter. Myc2 has oncogenic potential when tested in primary avian fibroblasts but to a lower degree as compared to Myc1. The identification of an additional myc gene in Cnidaria, a phylum that diverged prior to bilaterians, with characteristic expression patterns in tissue homeostasis and developmental processes suggests that principle functions of myc genes have arisen very early in metazoan evolution. PMID- 24771622 TI - Combination of dispersive solid-phase extraction and salting-out homogeneous liquid-liquid extraction for the determination of organophosphorus pesticides in cereal grains. AB - A new analytical method for the determination of organophosphorus pesticides in cereal samples was developed by combining dispersive SPE (d-SPE) and salting-out homogeneous liquid-liquid extraction (SHLLE). The pesticides were first extracted from cereal grains with acetonitrile, followed by d-SPE cleanup. A 2 mL aliquot of the extract was then added to a centrifuge tube containing 9.2 mL water and 3.3 g NaCl for SHLLE. Analysis of the extract was carried out by gas chromatography coupled with flame photometric detection. The d-SPE procedure effectively provides the necessary cleanup of the extract while SHLLE is used as an efficient concentration technique. Experimental parameters influencing the extraction efficiency including amounts of added water and salt were investigated. Recovery studies were carried out at three fortification levels, yielding recoveries in the range of 57.7-98.1% with the RSD from 3.7 to 10.9%. The reported limits of determination obtained from this study were 1 MUg/kg, which is better than the conventional methods. In the analysis of 40 wheat and corn samples taken from Beijing suburbs, only two wheat samples have chlorpyrifos residue over the limits of determination. PMID- 24771624 TI - B cells in multiple sclerosis: good or bad guys?: An article for 28 May 2014 - World MS Day 2014. PMID- 24771629 TI - Implementation of integrated heterogeneous electronic electrocardiography data into Maharaj Nakorn Chiang Mai Hospital Information System. AB - Electrocardiography is one of the most important non-invasive diagnostic tools for diagnosing coronary heart disease. The electrocardiography information system in Maharaj Nakorn Chiang Mai Hospital required a massive manual labor effort. In this article, we propose an approach toward the integration of heterogeneous electrocardiography data and the implementation of an integrated electrocardiography information system into the existing Hospital Information System. The system integrates different electrocardiography formats into a consistent electrocardiography rendering by using Java software. The interface acts as middleware to seamlessly integrate different electrocardiography formats. Instead of using a common electrocardiography protocol, we applied a central format based on Java classes for mapping different electrocardiography formats which contains a specific parser for each electrocardiography format to acquire the same information. Our observations showed that the new system improved the effectiveness of data management, work flow, and data quality; increased the availability of information; and finally improved quality of care. PMID- 24771630 TI - Differentiating soft tissue leiomyosarcoma and undifferentiated pleomorphic sarcoma: A miRNA analysis. AB - The rare and highly aggressive adult soft tissue sarcomas leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) contain complex genomes characterized by a multitude of rearrangements, amplifications, and deletions. Differential diagnosis remains a challenge. MicroRNA (miRNA) profiling was conducted on a series of LMS and UPS samples to initially investigate the differential expression and to identify specific signatures useful for improving the differential diagnosis. Initially, 10 high-grade LMS and 10 high-grade UPS were profiled with a miRNA microarray. Two cultured human mesenchymal stem cell samples were used as controls. 38 and 46 miRNAs classified UPS and LMS samples, respectively, into separate groups compared to control samples. When comparing the two profiles, miR-199b-5p, miR-320a, miR-199a-3p, miR-126, miR-22 were differentially expressed. These were validated by RT-PCR on a further series of 27 UPS and 21 LMS for a total of 68 cases. The levels of miR-199-5p and miR-320a, in particular, confirmed the microarray data, the former highly expressed in UPS and the latter in LMS. Immunohistochemistry was performed on all 68 cases to confirm original diagnosis. Recently reported LMS- and UPS-associated genes were correlated with miRNA targets based on target algorithms of three databases. Several genes including IMP3, ROR2, MDM2, CDK4, and UPA, are targets of differentially expressed miRNAs. We identified miRNA expression patterns in LMS and UPS, linking them to chromosomal regions and mRNA targets known to be involved in tumor development/progression of LMS and UPS. PMID- 24771631 TI - Twenty years of workers' compensation costs due to falls from height among union carpenters, Washington state. AB - BACKGROUND: Falls from height (FFH) are a longstanding, serious problem in construction. METHODS: We report workers' compensation (WC) payments associated with FFH among a cohort (n = 24,830; 1989-2008) of carpenters. Mean/median payments, cost rates, and adjusted rate ratios based on hours worked were calculated using negative-binomial regression. RESULTS: Over the 20-year period FFH accounted for $66.6 million in WC payments or $700 per year for each full time equivalent (2,000 hr of work). FFH were responsible for 5.5% of injuries but 15.1% of costs. Cost declines were observed, but not monotonically. Reductions were more pronounced for indemnity than medical care. Mean costs were 2.3 times greater among carpenters over 50 than those under 30; cost rates were only modestly higher. CONCLUSIONS: Significant progress has been made in reducing WC payments associated with FFH in this cohort particularly through 1996; primary gains reflect reduction in frequency of falls. FFH that occur remain costly. PMID- 24771632 TI - From environmental signals to regulators: modulation of biofilm development in Gram-positive bacteria. AB - Bacterial lifestyle is influenced by environmental signals, and many differentiation processes in bacteria are governed by the threshold concentrations of molecules present in their niche. Biofilm is one such example where bacteria in their sessile state adapt to a lifestyle that causes several adaptive alterations in the population. Here, a brief overview is given on a variety of environmental signals that bias biofilm development in Gram-positive bacteria, including nutrient conditions, self- and heterologously produced substances, like quorum sensing and host produced molecules. The Gram-positive model organism, Bacillus subtilis is a superb example to illustrate how distinct signals activate sensor proteins that integrate the environmental signals towards global regulators related to biofilm formation. The role of reduced oxygen level, polyketides, antimicrobials, plant secreted carbohydrates, plant cell derived polymers, glycerol, and osmotic conditions are discussed during the transcriptional activation of biofilm related genes in B. subtilis. PMID- 24771633 TI - Synthesis of a nano-sized chiral imprinted polymer and its use as an (S)-atenolol carrier in the bulk liquid membrane. AB - In this work, nanosized chiral imprinted polymers containing (S)-atenolol ((S) ATN) selective sites were synthesized by using suspension polymerization in silicon oil. (S)-ATN, methacrylic acid, and ethylene glycol dimethacrylate were used as enantiomerically pure template, functional monomer, and cross-linker, respectively. The prepared chiral imprinted polymers were used as the carrier elements in a bulk liquid membrane (BLM). (S)-ATN transport capability of the chiral imprinted polymers was compared with that of the nonimprinted polymer. It was shown that chiral imprinted polymers could transport (S)-ATN through the BLM more effectively than (R)-ATN, whereas no difference in the facilitated transport was observed between (R)-ATN and (S)-ATN when using nonimprinted polymer particles as the carrier element in the BLM. A kinetic model was proposed for the transportation of (S)-ATN through the chiral imprinted polymers based BLM. It was found that the extraction of ATN from the source to the membrane controls the chiral separation process. It was also found that the pH of source and receiving phases as well as the racemic ATN concentration in source phase had very crucial effect on the chiral separation efficiency. PMID- 24771618 TI - Evaluation of early weight loss thresholds for identifying nonresponders to an intensive lifestyle intervention. AB - OBJECTIVE: Weight losses in lifestyle interventions are variable, yet prediction of long-term success is difficult. The utility of using various weight loss thresholds in the first 2 months of treatment for predicting 1-year outcomes was examined. METHODS: Participants included 2327 adults with type 2 diabetes (BMI:35.8 +/- 6.0) randomized to the intensive lifestyle intervention (ILI) of the Look AHEAD trial. ILI included weekly behavioral sessions designed to increase physical activity and reduce caloric intake. 1-month, 2-month, and 1 year weight changes were calculated. RESULTS: Participants failing to achieve a >=2% weight loss at Month 1 were 5.6 (95% CI:4.5, 7.0) times more likely to also not achieve a >=10% weight loss at Year 1, compared to those losing >=2% initially. These odds were increased to 11.6 (95% CI:8.6, 15.6) when using a 3% weight loss threshold at Month 2. Only 15.2% and 8.2% of individuals failing to achieve the >=2% and >=3% thresholds at Months 1 and 2, respectively, go on to achieve a >=10% weight loss at Year 1. CONCLUSIONS: Given the association between initial and 1-year weight loss, the first few months of treatment may be an opportune time to identify those who are unsuccessful and utilize rescue efforts. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00017953. PMID- 24771635 TI - Saxitoxin. AB - The paralytic agent (+)-saxitoxin (STX), most commonly associated with oceanic red tides and shellfish poisoning, is a potent inhibitor of electrical conduction in cells. Its nefarious effects result from inhibition of voltage-gated sodium channels (Na(V)s), the obligatory proteins responsible for the initiation and propagation of action potentials. In the annals of ion channel research, the identification and characterization of Na(V)s trace to the availability of STX and an allied guanidinium derivative, tetrodotoxin. The mystique of STX is expressed in both its function and form, as this uniquely compact dication boasts more heteroatoms than carbon centers. This Review highlights both the chemistry and chemical biology of this fascinating natural product, and offers a perspective as to how molecular design and synthesis may be used to explore Na(V) structure and function. PMID- 24771634 TI - Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis. AB - The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25 minutes) every 12 hours of either: placebo and placebo; 2 g ceftriaxone and placebo; or 2 g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14 L (0.17 L/kg); elimination half-life, 8-9 h; total clearance, 17-21 mL/min (0.22-0.25 mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34 hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0 uM (0.55 ug/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS. PMID- 24771636 TI - Optimizing a spontaneously contracting heart tissue patch with rat neonatal cardiac cells on fibrin gel. AB - Engineered cardiac tissues have been constructed with primary or stem cell derived cardiac cells on natural or synthetic scaffolds. They represent a tremendous potential for the treatment of injured areas through the addition of tensional support and delivery of sufficient cells. In this study, 1-6 million (M) neonatal cardiac cells were seeded on fibrin gels to fabricate cardiac tissue patches, and the effects of culture time and cell density on spontaneous contraction rates, twitch forces and paced response frequencies were measured. Electrocardiograms and signal volume index of connexin 43 were also analysed. Patches of 1-6 M cell densities exhibited maximal contraction rates in the range 305-410 beats/min (bpm) within the first 4 days after plating; low cell density (1-3 M) patches sustained rhythmic contraction longer than high cell density patches (4-6 M). Patches with 1-6 M cell densities generated contractile forces in the range 2.245-14.065 mN/mm3 on days 4-6. Upon patch formation, a paced response frequency of approximately 6 Hz was obtained, and decreased to approximately 3 Hz after 6 days of culture. High cell density patches contained a thicker real cardiac tissue layer, which generated higher R-wave amplitudes; however, low-density patches had a greater signal volume index of connexin 43. In addition, all patches manifested endothelial cell growth and robust nuclear division. The present study demonstrates that the proper time for in vivo implantation of this cardiac construct is just at patch formation, and patches with 3-4 M cell densities are the best candidates. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24771637 TI - Enantioselective acute toxicity effects and bioaccumulation of furalaxyl in the earthworm (Eisenia foetida). AB - The enantioselectivities of individual enantiomers of furalaxyl in acute toxicity and bioaccumulation in the earthworm (Eisenia foetida) were studied. The acute toxicity was tested by filter paper contact test. After 48 h of exposure, the calculated LC50 values of the R-form, rac-form, and S-form were 2.27, 2.08, and 1.22 ug cm(-2), respectively. After 72 h of exposure, the calculated LC50 values were 1.90, 1.54, and 1.00 ug cm(-2), respectively. Therefore, the acute toxicity of furalaxyl enantiomers was enantioselective. During the bioaccumulation experiment, the enantiomer fraction of furalaxyl in earthworm tissue was observed to deviate from 0.50 and maintained a range of 0.55-0.60; in other words, the bioaccumulation of furalaxyl was enantioselective in earthworm tissue with a preferential accumulation of S-furalaxyl. The uptake kinetic of furalaxyl enantiomers fitted the first-order kinetics well and the calculated kinetic parameters were consistent with the low accumulation efficiency. PMID- 24771638 TI - Quantitative proteome profiling of lymph node-positive vs. -negative colorectal carcinomas pinpoints MX1 as a marker for lymph node metastasis. AB - We used high-resolution mass spectrometry to measure the abundance of more than 9,000 proteins in 19 individually dissected colorectal tumors representing lymph node metastatic (n = 10) and nonmetastatic (n = 9) phenotypes. Statistical analysis identified MX1 and several other proteins as overexpressed in lymph node positive tumors. MX1, IGF1-R and IRF2BP1 showed significantly different expression in immunohistochemical validation (Wilcoxon test p = 0.007 for IGF1-R, p = 0.04 for IRF2BP1 and p = 0.02 for MX1 at the invasion front) in the validation cohort. Knockout of MX1 by siRNA in cell cultures and wound healing assays provided additional evidence for the involvement of this protein in tumor invasion. The collection of identified and quantified proteins to our knowledge is the largest tumor proteome dataset available at the present. The identified proteins can give insights into the mechanisms of lymphatic metastasis in colorectal carcinoma and may act as prognostic markers and therapeutic targets after further prospective validation. PMID- 24771639 TI - MicroRNA-340-mediated degradation of microphthalmia-associated transcription factor mRNA is inhibited by the coding region determinant-binding protein. PMID- 24771642 TI - RNAi screen identifies a synthetic lethal interaction between PIM1 overexpression and PLK1 inhibition. AB - PURPOSE: To identify genes whose depletion is detrimental to Pim1-overexpressing prostate cancer cells and to validate this finding in vitro and in vivo. EXPERIMENTAL DESIGN: RNAi screening was used to identify genes whose depletion is detrimental to Pim1-overexpressing cells. Our finding was validated using shRNA or PLK1-specific inhibitor BI 2536. Xenograft studies were performed using both PLK1-knockdown cells and BI 2536 to investigate the effects of PLK1 inhibition on tumorigenesis in Pim1-overexpressing cells. Finally, PLK1 and PIM1 expression patterns in human prostate tumors were examined by immunohistochemistry using tissue microarrays. RESULTS: We identified the mitotic regulator polo-like kinase (PLK1) as a gene whose depletion is particularly detrimental to the viability of Pim1-overexpressing prostate cancer. Inhibition of PLK1 by shRNA or BI 2536 in Pim1-overexpressing prostate cancer xenograft models resulted in a dramatic inhibition of tumor progression. Notably, Pim1-overexpressing cells were more prone to mitotic arrest followed by apoptosis due to PLK1 inhibition than control cells. Furthermore, inhibition of PLK1 led to the reduction of MYC protein levels both in vitro and in vivo. Our data also suggest that PIM1 and PLK1 physically interact and PIM1 might phosphorylate PLK1. Finally, PLK1 and PIM1 are frequently co-expressed in human prostate tumors, and co-expression of PLK1 and PIM1 was significantly correlated to higher Gleason grades. CONCLUSIONS: Our findings demonstrate that PIM1-overexpressing cancer cells are particularly sensitive to PLK1 inhibition, suggesting that PIM1 might be used as a marker for identifying patients who will benefit from PLK1 inhibitor treatment. PMID- 24771643 TI - Overexpression of sirt7 exhibits oncogenic property and serves as a prognostic factor in colorectal cancer. AB - PURPOSE: Sirtuins play an important role in cancer development. Sirt7, as a member of this family, is frequently overexpressed in certain carcinomas, but the oncogenic mechanism is seldom reported. In this study, Sirt7 was characterized for its role in colorectal cancer aggressiveness and underlying molecular mechanisms. EXPERIMENTAL DESIGN: Quantitative PCR, Western blotting, and immunohistochemistry were performed to study Sirt7 expression in a cohort of colorectal cancer tissues and non-tumor tissues and cells. A series of in vitro and in vivo assays was performed to elucidate the function of Sirt7 in colorectal cancer and its underlying mechanisms. Association between the Sirt7 signature and survival was examined using Kaplan-Meier analysis and log-rank tests. RESULTS: The Sirt7 protein level significantly correlated with tumor stage (P = 0.029), lymph node metastasis (P = 0.046), and poor patient survival (P < 0.05). Sirt7 knockdown significantly inhibited colorectal cancer cell proliferation, colony formation, and motility. Ectopic Sirt7 expression promoted colony formation, induced a more invasive phenotype, and accelerated cell growth both in vitro and in vivo. Moreover, Sirt7 enhanced MAPK pathway activity concomitantly with p-ERK and p-MEK upregulation. In Sirt7-overexpressing cells, the mesenchymal markers vimentin and fibronectin were upregulated, and the epithelial markers E-cadherin and beta-catenin were downregulated, which was linked to enhanced invasion by colorectal cancer cells. CONCLUSION: Our findings suggest that Sirt7 plays an important role in the development and progression of human colorectal cancer and functions as a valuable marker of colorectal cancer prognosis. PMID- 24771644 TI - Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer. AB - PURPOSE: It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone naive and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression. EXPERIMENTAL DESIGN: Freshly harvested prostate tissue [benign, hormone-naive, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset. RESULTS: Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naive cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-alpha dione" pathway. CONCLUSIONS: Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC. PMID- 24771646 TI - Immunotherapy for brain cancer: recent progress and future promise. AB - Immunotherapy is emerging as the newest pillar of cancer treatment, with the potential to assume a place alongside surgical debulking, radiotherapy, and chemotherapy. Early experiences with antitumor vaccines demonstrated the feasibility and potential efficacy of this approach, and newer agents, such as immune checkpoint blocking antibodies and modern vaccine platforms, have ushered in a new era. These efforts are headlined by work in melanoma, prostate cancer, and renal cell carcinoma; however, substantial progress has been achieved in a variety of other cancers, including high-grade gliomas. A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiotherapy and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also use an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas, and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology. PMID- 24771648 TI - Characterization of the chemical constituents in Da-Huang-Gan-Cao-Tang by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and liquid chromatography coupled with ion trap mass spectrometry. AB - In this work, the chemical constituents in Da-Huang-Gan-Cao-Tang, a traditional Chinese formula, were studied by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and liquid chromatography coupled with ion trap mass spectrometry for the first time. Among the 146 compounds detected in Da-Huang-Gan-Cao-Tang, 104 compounds were identified unambiguously or tentatively based on their accurate molecular weight and multistage MS data, including one potential novel compound and two reported in Glycyrrhiza genus for the first time. The possible fragmentation pathways were proposed and fragmentation rules of the major types of compounds were concluded. This study provided an example to facilitate the tedious identification of chemical composition in traditional Chinese medicine, and maybe a promising reference approach to research the analogous formulae. PMID- 24771645 TI - FGFR1 mRNA and protein expression, not gene copy number, predict FGFR TKI sensitivity across all lung cancer histologies. AB - PURPOSE: FGFR1 gene copy number (GCN) is being evaluated as a biomarker for FGFR tyrosine kinase inhibitor (TKI) response in squamous cell lung cancers (SCC). The exclusive use of FGFR1 GCN for predicting FGFR TKI sensitivity assumes increased GCN is the only mechanism for biologically relevant increases in FGFR1 signaling. Herein, we tested whether FGFR1 mRNA and protein expression may serve as better biomarkers of FGFR TKI sensitivity in lung cancer. EXPERIMENTAL DESIGN: Histologically diverse lung cancer cell lines were submitted to assays for ponatinib sensitivity, a potent FGFR TKI. A tissue microarray composed of resected lung tumors was submitted to FGFR1 GCN, and mRNA analyses and the results were validated with The Cancer Genome Atlas (TCGA) lung cancer data. RESULTS: Among 58 cell lines, 14 exhibited ponatinib sensitivity (IC50 values <= 50 nmol/L) that correlated with FGFR1 mRNA and protein expression, but not with FGFR1 GCN or histology. Moreover, ponatinib sensitivity associated with mRNA expression of the ligands, FGF2 and FGF9. In resected tumors, 22% of adenocarcinomas and 28% of SCCs expressed high FGFR1 mRNA. Importantly, only 46% of SCCs with increased FGFR1 GCN expressed high mRNA. Lung cancer TCGA data validated these findings and unveiled overlap of FGFR1 mRNA positivity with KRAS and PIK3CA mutations. CONCLUSIONS: FGFR1 dependency is frequent across various lung cancer histologies, and FGFR1 mRNA may serve as a better biomarker of FGFR TKI response in lung cancer than FGFR1 GCN. The study provides important and timely insight into clinical testing of FGFR TKIs in lung cancer and other solid tumor types. PMID- 24771647 TI - Hsa-miR-31-3p expression is linked to progression-free survival in patients with KRAS wild-type metastatic colorectal cancer treated with anti-EGFR therapy. AB - PURPOSE: To identify microRNAs (miRNA) that predict response to anti-EGFR antibodies in patients with wild-type KRAS metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: miRNA profiling was performed in a training set of 87 patients with mCRC refractory to chemotherapy treated with anti-EGFR antibodies. This included 33 fresh-frozen (FF) and 35 formalin-fixed paraffin-embedded (FFPE) samples retrospectively collected and 19 prospectively collected FF samples. An independent validation cohort consisting of 19 FF and 26 FFPE prospectively collected samples from patients with mCRC treated with anti-EGFR antibodies was used to confirm our findings. RESULTS: After screening the expression of 1,145 miRNAs in FF samples from the training set, we identified that hsa-miR-31-3p expression level was significantly associated with progression-free survival (PFS). Statistical models based on miRNA expression discriminated between high and low risk of progression for both FF and FFPE samples. These models were confirmed in the validation cohort for both FF [HR, 4.1; 95% confidence interval (CI), 1.1-15.3; P < 0.04] and FFPE samples (HR, 2.44; 95% CI, 1.1-5.4; P = 0.028). The percentage of variation of RECIST criteria in the validation series was significantly associated with the expression level of hsa-miR-31-3p (r(2) = 0.49; P = 0.0035) and risk status determined by hsa-miR-31-3p expression level (P = 0.02, Kruskal-Wallis rank test). Nomograms were built and validated to predict PFS-depending on hsa-miR-31-3p expression level. Following in vitro studies, we identified 47 genes regulated by hsa-miR-31-3p. CONCLUSION: Hsa-miR-31-3p seems to be a new mCRC biomarker whose expression level allows for the identification of patients with wild-type KRAS mCRC who are more likely to respond to anti-EGFR therapy. PMID- 24771649 TI - Photopolymerizable chitosan-collagen hydrogels for bone tissue engineering. AB - Photopolymerizable hydrogels derived from naturally occurring polymers have attracted significant interest in tissue-engineering applications due to their excellent biocompatibility, hydrophilic nature favourable for cell ingrowth and ability to be cured in situ through a minimally invasive procedure. In this study, we developed a composite hydrogel consisting of photocrosslinkable methacrylated glycol chitosan (MeGC) and semi-interpenetrating collagen (Col) with a riboflavin photoinitiator under blue light. The incorporation of Col in MeGC hydrogels enhanced the compressive modulus and slowed the degradation rate of the hydrogels. MeGC-Col composite hydrogels significantly enhanced cellular attachment, spreading, proliferation and osteogenic differentiation of mouse bone marrow stromal cells (BMSCs) seeded on the hydrogels compared with pure MeGC hydrogels, as observed by upregulated alkaline phosphatase (ALP) activity as well as increased mineralization. Similarly, when cells were encapsulated within hydrogels, BMSCs exhibited greater proliferation, ALP activity and mineral deposits in the presence of Col. These findings demonstrate that MeGC-Col composite hydrogels may be useful in promoting bone regeneration. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24771653 TI - Biosynthesis and chemical synthesis of presilphiperfolanol natural products. AB - Presilphiperfolanols constitute a family of biosynthetically important sesquiterpenes which can rearrange to diverse sesquiterpenoid skeletons. While the origin of these natural products can be traced to simple linear terpene precursors, the details of the enzymatic cyclization mechanism that forms the stereochemically dense tricyclic skeleton has required extensive biochemical, computational, and synthetic investigation. Parallel efforts to prepare the unique and intriguing structures of these compounds by total synthesis have also inspired novel strategies, thus resulting in four synthetic approaches and two completed syntheses. While the biosynthesis and chemical synthesis studies performed to date have provided much insight into the role and properties of these molecules, emerging questions regarding the biosynthesis of newer members of the family and subtle details of rearrangement mechanisms have yet to be explored. PMID- 24771655 TI - An approximate approach to sample size determination in bioequivalence testing with multiple pharmacokinetic responses. AB - The approval of generic drugs requires the evidence of average bioequivalence (ABE) on both the area under the concentration-time curve and the peak concentration Cmax . The bioequivalence (BE) hypothesis can be decomposed into the non-inferiority (NI) and non-superiority (NS) hypothesis. Most of regulatory agencies employ the two one-sided tests (TOST) procedure to test ABE between two formulations. As it is based on the intersection-union principle, the TOST procedure is conservative in terms of the type I error rate. However, the type II error rate is the sum of the type II error rates with respect to each null hypothesis of NI and NS hypotheses. When the difference in population means between two treatments is not 0, no close-form solution for the sample size for the BE hypothesis is available. Current methods provide the sample sizes with either insufficient power or unnecessarily excessive power. We suggest an approximate method for sample size determination, which can also provide the type II rate for each of NI and NS hypotheses. In addition, the proposed method is flexible to allow extension from one pharmacokinetic (PK) response to determination of the sample size required for multiple PK responses. We report the results of a numerical study. An R code is provided to calculate the sample size for BE testing based on the proposed methods. PMID- 24771654 TI - Body mass index at early adulthood, subsequent weight change and cancer incidence and mortality. AB - Obesity later in adulthood is associated with increased risks of many cancers. However, the effect of body fatness in early adulthood, and change in weight from early to later adulthood on cancer risk later in life is less clear. We used data from 13,901 people aged 45-64 in the Atherosclerosis Risk in Communities cohort who at baseline (1987-1989) self-reported their weight at the age of 25 and had weight and height measured. Incident cancers were identified through 2006 and cancer deaths were ascertained through 2009. Multivariable Cox proportional hazard models were used to relate body mass index (BMI) at age 25 and percent weight change from age 25 to baseline to cancer incidence and mortality. After adjusting for weight change from age 25 until baseline, a 5 kg/m(2) increment in BMI at age 25 was associated with a greater risk of incidence of all cancers in women [hazard ratio (95% confidence interval): 1.10 (1.02-1.20)], but not in men. Associations with incident endometrial cancer were strong [1.83 (1.47-2.26)]. After adjusting for BMI at age 25, a 5% increment in weight from age 25 to baseline was associated with a greater risk of incident postmenopausal breast cancer [1.05 (1.02-1.07)] and endometrial cancer [1.09 (1.04-1.14)] in women and incident colorectal cancer [1.05 (1.00-1.10)] in men. Excess weight during young adulthood and weight gain from young to older adulthood may be independently associated with subsequent cancer risk. Excess weight and weight gain in early adulthood should be avoided. PMID- 24771656 TI - Chiral ligand-exchange resolution of underivatized amino acids on a dynamically modified stationary phase for RP-HPTLC. AB - The synthesis of Spi(tau-dec), derived from the selective alkylation of L spinacine (4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid) at the tau-nitrogen of its heteroaromatic ring, with a linear hydrocarbon chain of 10 carbon atoms, is described here for the first time. Spi(tau-dec) was successfully employed in the past to prepare home-made chiral columns for chiral ligand exchange high-performance liquid chromatography. In the present article a new method is described, using Spi(tau-dec) as a chiral selector in high-performance thin-layer chromatography (HPTLC): commercial hydrophobic plates were first coated with Spi(tau-dec) and then treated with copper sulfate. The performance of this new chiral stationary phase was tested against racemic mixtures of aromatic amino acids, after appropriate optimization of both the conditions of preparation of the plates and the mobile phase composition. The enantioselectivity values obtained for the studied compounds were higher than those reported in the literature for similar systems. The method employed here for the preparation of chiral HPTLC plates proved practical, efficient, and inexpensive. PMID- 24771657 TI - Mutational analysis of charged residues in the cytoplasmic loops of MotA and MotP in the Bacillus subtilis flagellar motor. AB - Bacterial flagellar motors are energized by a proton (H(+)) or sodium ion (Na(+)) motive force. The motor torque is generated by the interactions between a rotor and about a dozen stators at the interface. MotAB-type stators use H(+), whereas MotPS- and PomAB-type stators use Na(+) as the coupling ion. In Escherichia coli, the cytoplasmic loop of MotA contains charged residues that interact with conserved charged residues in a rotor protein FliG. Bacillus subtilis has two distinct stator elements MotAB and MotPS. Both stator elements contribute to torque generation by the flagellar motor. To clarify the roles of conserved charged residues in the cytoplasmic loops of MotA and MotP in flagellar rotation, we performed site-directed mutagenesis and analysed motility as well as the relative expression levels of mutant Mot proteins. The motility of the majority of these mutants was reduced compared with that of the wild-type, but was observed at a significant level compared with that of a DeltamotAB DeltamotPS mutant. From the expression levels and the decrease in the motility, we propose that MotA-E98, MotA-E102, MotP-R94, MotP-K95 and MotP-E107 may be responsible for flagellar rotation. PMID- 24771658 TI - RegPhos 2.0: an updated resource to explore protein kinase-substrate phosphorylation networks in mammals. AB - Protein phosphorylation catalyzed by kinases plays crucial roles in regulating a variety of intracellular processes. Owing to an increasing number of in vivo phosphorylation sites that have been identified by mass spectrometry (MS)-based proteomics, the RegPhos, available online at http://csb.cse.yzu.edu.tw/RegPhos2/, was developed to explore protein phosphorylation networks in human. In this update, we not only enhance the data content in human but also investigate kinase substrate phosphorylation networks in mouse and rat. The experimentally validated phosphorylation sites as well as their catalytic kinases were extracted from public resources, and MS/MS phosphopeptides were manually curated from research articles. RegPhos 2.0 aims to provide a more comprehensive view of intracellular signaling networks by integrating the information of metabolic pathways and protein-protein interactions. A case study shows that analyzing the phosphoproteome profile of time-dependent cell activation obtained from Liquid chromatography-mass spectrometry (LC-MS/MS) analysis, the RegPhos deciphered not only the consistent scheme in B cell receptor (BCR) signaling pathway but also novel regulatory molecules that may involve in it. With an attempt to help users efficiently identify the candidate biomarkers in cancers, 30 microarray experiments, including 39 cancerous versus normal cells, were analyzed for detecting cancer-specific expressed genes coding for kinases and their substrates. Furthermore, this update features an improved web interface to facilitate convenient access to the exploration of phosphorylation networks for a group of genes/proteins. Database URL: http://csb.cse.yzu.edu.tw/RegPhos2/ PMID- 24771660 TI - A new golden age for donor-acceptor cyclopropanes. AB - The effective use of ring strain has been applied to considerable advantage for the construction of complex systems. The focus here is directed towards cyclopropanes as building blocks for organic synthesis. Although thermodynamics should take the side of synthetic chemists, only a specific substitution pattern at the cyclopropane ring allows for particularly mild, efficient, and selective transformations. The required decrease in the activation barrier is achieved by the combined effects of vicinal electron-donating and electron-accepting moieties. This Review highlights the appropriate tools for successfully employing donor-acceptor cyclopropanes in ring-opening reactions, cycloadditions, and rearrangements. PMID- 24771659 TI - High-resolution high-performance liquid chromatography with electrospray ionization mass spectrometry and tandem mass spectrometry characterization of a new isoform of human salivary acidic proline-rich proteins named Roma-Boston Ser22 (Phos) -> Phe variant. AB - During a survey of human saliva by a top-down reversed-phase high-performance liquid chromatography with electrospray ionization mass spectrometry approach, two proteins eluting at 27.4 and 28.4 min, with average masses of 15 494 +/- 1 and 11 142 +/- 1 Da, were detected in a subject from Boston. The Deltamass value (4352 Da) of the two proteins was similar to the difference in mass values between intact (150 amino acids, [a.a.]) and truncated acidic proline-rich proteins (aPRPs; 106 a.a.) suggesting an a.a. substitution in the first 106 residues resulting in a strong reduction in polarity, since under the same experimental conditions aPRPs eluted at ~22.5 min (intact) and 23.5 min (truncated forms). Manual inspection of the high-resolution high-performance liquid chromatography with electrospray ionization tandem mass spectra of the truncated isoform showed the replacement of the phosphorylated Ser-22 in PRP-3 with a Phe residue. Inspection of the tandem mass spectra of the intact isoform confirmed the substitution, which is allowed by the code transition TCT->TTT and is in agreement with the dramatic increase in elution time. The isoform was also detected in two other subjects, one from Boston (unrelated to the previous) and one from Rome. For this reason we propose to name this variant PRP-1 (PRP-3) RB (Roma-Boston) Ser22 (phos)->Phe. PMID- 24771661 TI - Validation of LC-MS/MS method applied to evaluation of free tissue concentrations of vildagliptin in diabetic rats by microdialysis. AB - A novel LC-MS/MS method was developed for the quantification of vildagliptin in an aqueous matrix. The method was successfully validated, meeting all the requisites of US Food and Drug Administration guide for a bioanalytical method. The developed method presented a limit of quantification of 10 ng/mL and the range of concentration achieved was 10-1875 ng/mL. The injection volume necessary was only 10 MUL, and retention time was 4.60 min. The mobile phase employed was methanol-ammonium acetate 5 mm (95:5). The stability of the drug was evaluated in the different conditions through which the samples passed. A pharmacokinetic experiment was conducted with diabetic male Wistar rats, and the concentration of drug in liver was evaluated through a microdialysis technique. The perfusion fluid employed was ultrapure water. The dose administrated was 50 mg/kg and the method allowed the quantification of vildagliptin for more than three half lives, successfully characterizing the pharmacokinetic profile when the developed method was applied. This is the first report on the tissue pharmacokinetics of a DPP-4 inhibitor and could contribute to drug dosage optimization in the future. PMID- 24771662 TI - Propensity score methods for estimating relative risks in cluster randomized trials with low-incidence binary outcomes and selection bias. AB - Despite randomization, selection bias may occur in cluster randomized trials. Classical multivariable regression usually allows for adjusting treatment effect estimates with unbalanced covariates. However, for binary outcomes with low incidence, such a method may fail because of separation problems. This simulation study focused on the performance of propensity score (PS)-based methods to estimate relative risks from cluster randomized trials with binary outcomes with low incidence. The results suggested that among the different approaches used (multivariable regression, direct adjustment on PS, inverse weighting on PS, and stratification on PS), only direct adjustment on the PS fully corrected the bias and moreover had the best statistical properties. PMID- 24771663 TI - Touch massage, a rewarding experience. AB - This study aims to describe and analyze healthy individuals' expressed experiences of touch massage (TM). Fifteen healthy participants received whole body touch massage during 60 minutes for two separate occasions. Interviews were analyzed by narrative analysis. Four identifiable storyline was found, Touch massage as an essential need, in this storyline the participants talked about a desire and need for human touch and TM. Another storyline was about, Touch massage as a pleasurable experience and the participants talked about the pleasure of having had TM. In the third storyline Touch massage as a dynamic experience, the informants talked about things that could modulate the experience of receiving TM. In the last storyline, Touch massage influences self-awareness, the participants described how TM affected some of their psychological and physical experiences. Experiences of touch massage was in general described as pleasant sensations and the different storylines could be seen in the light of rewarding experiences. PMID- 24771664 TI - "Not just a theory": the relationship between Jin Shin Jyutsu(r) self-care training for nurses and stress, physical health, emotional health, and caring efficacy. AB - PURPOSE: The purpose of this study was to evaluate the effect of training nurses in Jin Shin Jyutsu(r) self-care methods and to correlate the training with measurement of the nurses' personal and organizational stress and their perceptions of their caring efficacy for patients. DESIGN: A quasi-experimental, pretest, posttest, and 30- to 40-day posttest design was used. METHOD: In all, 20 participants received three 2-hour Jin Shin Jyutsu self-care training sessions from a certified Jin Shin Jyutsu self-care trainer (who was also a registered nurse). The training took place over a 1-month period, and participants agreed to practice the self-care daily. Two study instruments, one measuring organizational and personal stress and the second measuring caring efficacy, were completed before the first training, after the last training, and 1 month after the trainings had been completed. FINDINGS: Analysis of data from the Personal and Organizational Quality Assessment-Revised by paired t tests showed significant increases in positive outlook, gratitude, motivation, calmness, and communication effectiveness and significant decreases in anger, resentfulness, depression, stress symptoms, time pressure, and morale issues. Nurses reported less muscle aches, sleeplessness, and headaches. Analysis of the Coates Caring Efficacy Scale measures showed statistically significant increases in nurses' caring efficacy in areas of serenity in giving care, tuning in to patients, relating to patients, providing culturally congruent care, individualization of patient care, ability to decrease stressful situations, planning for multiple needs, and creativity in care. CONCLUSIONS: This small study suggests that Jin Shin Jyutsu self-care may be a valuable tool for nurses, to decrease stress, both emotional and physical, and increase caring efficacy. Administrators may wish to invest in such a program, which may improve quality of care delivered. The Watson caring model, which reminds us that nurses who care for themselves and feel good about their work can better care for others, proved an accurate framework for this study. PMID- 24771666 TI - Self-transcendence in Alzheimer's disease: the application of theory to practice. AB - The middle-range nursing theory of self-transcendence may be applicable to individuals in the early stages of Alzheimer's disease. Full cognitive ability may not be necessary for the essential principles of this theory to be implemented. The theory can offer guidance to families and health care providers in attempting to facilitate a meaningful aging process. A case scenario of an elderly woman with Alzheimer's disease demonstrates how family and caregivers can initiate interventions based on the theoretical concepts. PMID- 24771665 TI - Strategies to support spirituality in health care communication: a home hospice cancer caregiver case study. AB - BACKGROUND: Although there is growing recognition of the importance of integrating spirituality within health care, there is little evidence to guide clinicians in how to best communicate with patients and family about their spiritual or existential concerns. METHODS: Using an audio-recorded home hospice nurse visit immediately following the death of a patient as a case-study, we identify spiritually-sensitive communication strategies. RESULTS: The nurse incorporates spirituality in her support of the family by 1) creating space to allow for the expression of emotions and spiritual beliefs and 2) encouraging meaning-based coping, including emphasizing the caregivers' strengths and reframing negative experiences. DISCUSSION: Hospice provides an excellent venue for modeling successful examples of spiritual communication. Health care professionals can learn these techniques to support patients and families in their own holistic practice. IMPLICATIONS FOR PRACTICE: All health care professionals benefit from proficiency in spiritual communication skills. Attention to spiritual concerns ultimately improves care. PMID- 24771667 TI - Influence of central metalloligand geometry on electronic communication between metals: syntheses, crystal structures, MMCT properties of isomeric cyanido bridged Fe2Ru complexes, and TDDFT calculations. AB - To investigate how the central metalloligand geometry influences distant or vicinal metal-to-metal charge-transfer (MMCT) properties of polynuclear complexes, cis- and trans-isomeric heterotrimetallic complexes, and their one- and two-electron oxidation products, cis/trans-[Cp(dppe)Fe(II)NCRu(II)(phen)2CN Fe(II)(dppe)Cp][PF6]2 (cis/trans-1[PF6]2), cis/trans [Cp(dppe)Fe(II)NCRu(II)(phen)2CNFe(III)-(dppe)Cp][PF6]3 (cis/trans-1[PF6]3) and cis/trans-[Cp(dppe)Fe(III)NCRu(II)(phen)2CN-Fe(III)(dppe)Cp][PF6]4 (cis/trans 1[PF6]4) have been synthesized and characterized. Electrochemical measurements show the presence of electronic interactions between the two external Fe(II) atoms of the cis- and trans-isomeric complexes cis/trans-1[PF6]2. The electronic properties of all these complexes were studied and compared by spectroscopic techniques and TDDFT//DFT calculations. As expected, both mixed valence complexes cis/trans-1[PF6]3 exhibited different strong absorption signals in the NIR region, which should mainly be attributed to a transition from an MO that is delocalized over the Ru(II)-CN-Fe(II) subunit to a Fe(III) d orbital with some contributions from the co-ligands. Moreover, the NIR transition energy in trans 1[PF6]3 is lower than that in cis-1[PF6]3, which is related to the symmetry of their molecular orbitals on the basis of the molecular orbital analysis. Also, the electronic spectra of the two-electron oxidized complexes show that trans 1[PF6]4 possesses lower vicinal Ru(II) -> Fe(III) MMCT transition energy than cis 1[PF6]4. Moreover, the assignment of MMCT transition of the oxidized products and the differences of the electronic properties between the cis and trans complexes can be well rationalized using TDDFT//DFT calculations. PMID- 24771668 TI - Fully automatic exposed and in-syringe dynamic single-drop microextraction with online agitation for the determination of polycyclic musks in surface waters of the Pearl River Estuary and South China Sea. AB - An automatic exposed and in-syringe dynamic single-drop microextraction method (SDME) for the determination of five polycyclic musks in natural waters was developed using gas chromatography with mass spectrometry. Online agitation was first introduced to the automatic SDME with a magnetic mixer fixed to the bottom of the sample tray of the autosampler. A high enrichment factor (110 ~182) for the target analytes could be achieved after several parameters that affected the microextraction were optimized. The recoveries were between 84.9 and 119.5%, while the limit of detection ranged from 3.4 to 11 ng/L with relative standard deviation < 11.1% for the polycyclic musks. This new SDME mode is fully automatic with great convenience, high enrichment and good reproducibility, and no human intervention. The proposed method was, therefore, successfully applied to determine the polycyclic musks in 31 surface sea waters that were collected from the Pearl River Estuary and the South China Sea. Most polycyclic musks could be detected with the total concentrations ranging from 58.9 to 528.5 ng/L. By using spatial interpolation method of ordinary kriging, the most contaminated area was found near the cities of Dongguan and Guangzhou with local discharge via the major rivers. PMID- 24771669 TI - PhylOPDb: a 16S rRNA oligonucleotide probe database for prokaryotic identification. AB - In recent years, high-throughput molecular tools have led to an exponential growth of available 16S rRNA gene sequences. Incorporating such data, molecular tools based on target-probe hybridization were developed to monitor microbial communities within complex environments. Unfortunately, only a few 16S rRNA gene targeted probe collections were described. Here, we present PhylOPDb, an online resource for a comprehensive phylogenetic oligonucleotide probe database. PhylOPDb provides a convivial and easy-to-use web interface to browse both regular and explorative 16S rRNA-targeted probes. Such probes set or subset could be used to globally monitor known and unknown prokaryotic communities through various techniques including DNA microarrays, polymerase chain reaction (PCR), fluorescent in situ hybridization (FISH), targeted gene capture or in silico rapid sequence identification. PhylOPDb contains 74 003 25-mer probes targeting 2178 genera including Bacteria and Archaea. Database URL: http://g2im.u clermont1.fr/phylopdb/ PMID- 24771670 TI - The use of silyl ketene acetals and enol ethers in the catalytic enantioselective alkylative ring opening of oxa/aza bicyclic alkenes. AB - Silyl ketene acetals and enol ethers are employed as reactive and functional group tolerant nucleophiles in the enantioselective rhodium-catalyzed alkylative ring opening of a diverse class of oxa/azabicyclic alkenes. This method provides access to enantioenriched dihydronaphthalene and cyclohexene scaffolds, which have the potential to be derivatized toward core motifs of naphthoquinone and sesquiterpene natural products. PMID- 24771671 TI - General protocol for the synthesis of functionalized magnetic nanoparticles for magnetic resonance imaging from protected metal-organic precursors. AB - The development of magnetic nanoparticles (MNPs) with functional groups has been intensively pursued in recent years. Herein, a simple, versatile, and cost effective strategy to synthesize water-soluble and amino-functionalized MNPs, based on the thermal decomposition of phthalimide-protected metal-organic precursors followed by deprotection, was developed. The resulting amino functionalized Fe3O4, MnFe2O4, and Mn3O4 MNPs with particle sizes of about 14.3, 7.5, and 6.6 nm, respectively, had narrow size distributions and good dispersibility in water. These MNPs also exhibited high magnetism and relaxivities of r2 = 107.25 mM(-1) s(-1) for Fe3O4, r2 = 245.75 mM(-1) s(-1) for MnFe2O4, and r1 = 2.74 mM(-1) s(-1) for Mn3O4. The amino-functionalized MNPs were further conjugated with a fluorescent dye (rhodamine B) and a targeting ligand (folic acid: FA) and used as multifunctional probes. Magnetic resonance imaging and flow-cytometric studies showed that these probes could specifically target cancer cells overexpressing FA receptors. This new protocol opens a new way for the synthesis and design of water-soluble and amino-functionalized MNPs by an easy and versatile route. PMID- 24771672 TI - Age-related differences in diffusion tensor indices and fiber architecture in the medial and lateral gastrocnemius. AB - PURPOSE: To investigate age related changes in diffusion tensor indices and fiber architecture of the medial and lateral gastrocnemius (MG and LG) muscles using diffusion tensor imaging (DTI). MATERIALS AND METHODS: The lower leg of five young and five senior subjects was scanned at 3 Tesla and DTI indices extracted using three methods: region of interest, histogram, and tract based. Tracked fibers were automatically edited to ensure physiologically relevant tracks. Pennation angles were measured with respect to the deep and superficial aponeuroses of both muscles. RESULTS: The three methods provided internally consistent measures of the DTI indices (correlation coefficient in the range of 0.90-0.99). The primary, secondary, and tertiary eigenvalues in the MG and LG increased significantly in the senior cohort (P < 0.05), while the small increase in fractional anisotropy with age was not significant (MG/LG: P = 0.39/0.85; 95% confidence interval: [-0.059/-0.056, 0.116/0.064]). Fiber lengths of MG fibers originating distally were significantly decreased in seniors (P < 0.05) while pennation angles decreased with age in the MG and LG but this was not significant. CONCLUSION: Fiber atrophy and increased fibrosis have opposing effects on the diffusion indices resulting in a complicated dependence with aging. Fiber architectural changes could play a role in determining aging muscle function. PMID- 24771673 TI - Urinary metabolomic study of non-small cell lung carcinoma based on ultra high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - Metabolic profiles from human urine reveal the significant difference of carnitine and acylcarnitines levels between non-small cell lung carcinoma patients and healthy controls. Urine samples from cancer patients and healthy individuals were assayed in this metabolomic study using ultra high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. The data were normalized by the sum of all intensities and creatinine calibration, respectively, before orthogonal partial least squares discriminant analysis. Twenty differential metabolites were identified based on standard compounds or tandem mass spectrometry fragments. Among them, some medium-/long-chain acylcarnitines, for example, cis-3,4-methylene heptanoylcarnitine, were found to be downregulated while carnitine was upregulated in urine samples from the cancer group compared to the control group. Receiver operating characteristic analysis of the two groups showed that the area under curve for the combination of carnitine and 11 selected acylcarnitines was 0.958. This study suggests that the developed carnitine and acylcarnitines profiling method has the potential to be used for screening non-small cell lung carcinoma. PMID- 24771674 TI - Does nerve repair influence the outcome of reconstruction of a digital nail defect using a free composite flap taken from the great toe? AB - We describe reconstruction of a nail unit defect in the finger using a free composite flap taken from the great toe, comparing the outcome in patients in whom neurorrhaphy between the dorsal digital nerve of the great toe and the dorsal branch of the proper digital nerve of the injured finger was performed to those in which no nerve repair was made. From January 2002 to March 2009, 47 patients with traumatic fingernail defects were treated. Twenty-two patients before February 2005 had no nerve repair and subsequently 25 patients had nerve repair. The mean size of the germinal matrix and sterile matrix defects was 9 * 8 mm, and the mean size of the nail bed flaps was 9 * 9 mm. The mean length of the arteries used for the flap was 2.2 cm. Outcomes were rated. In the nerve repair group, full flap survival was achieved in 24 patients. At the mean follow-up period of 25 months, there were 12 excellent, seven very good, four good, and two fair results. In the comparison group without nerve repair, there were seven excellent, four very good, four good, five fair, and two poor results. Donor site morbidities were similar in both groups. The use of a free composite flap taken from the great toe is a useful technique for reconstructing nail unit defects in the finger. Innervated nail flap reconstructions tended to show better outcomes than those in which no nerve repair was performed. There is no difference in function or donor site between those in whom the nerve was repaired compared with those in whom it was not repaired. PMID- 24771680 TI - Introducing deep eutectic solvents to polar organometallic chemistry: chemoselective addition of organolithium and Grignard reagents to ketones in air. AB - Despite their enormous synthetic relevance, the use of polar organolithium and Grignard reagents is greatly limited by their requirements of low temperatures in order to control their reactivity as well as the need of dry organic solvents and inert atmosphere protocols to avoid their fast decomposition. Breaking new ground on the applications of these commodity organometallics in synthesis under more environmentally friendly conditions, this work introduces deep eutetic solvents (DESs) as a green alternative media to carry out chemoselective additions of ketones in air at room temperature. Comparing their reactivities in DES with those observed in pure water suggest that a kinetic activation of the alkylating reagents is taking place, favoring nucleophilic addition over the competitive hydrolysis, which can be rationalized through formation of halide-rich magnesiate or lithiate species. PMID- 24771681 TI - Metal-free reduction of CO2 with hydroboranes: two efficient pathways at play for the reduction of CO2 to methanol. AB - Guanidines and amidines prove to be highly efficient metal-free catalysts for the reduction of CO2 to methanol with hydroboranes such as 9-borabicyclo[3.3.1]nonane (9-BBN) and catecholborane (catBH). Nitrogen bases, such as 1,5,7 triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (Me-TBD), and 1,8-diazabicycloundec-7-ene (DBU), are active catalysts for this transformation and Me-TBD can catalyze the reduction of CO2 to methoxyborane at room temperature with TONs and TOFs of up to 648 and 33 h(-1) (25 degrees C), respectively. Formate HCOOBR2 and acetal H2C(OBR2)2 derivatives have been identified as reaction intermediates in the reduction of CO2 with R2BH, and the first C-H-bond formation is rate determining. Experimental and computational investigations show that TBD and Me-TBD follow distinct mechanisms. The N-H bond of TBD is reactive toward dehydrocoupling with 9-BBN and affords a novel frustrated Lewis pair (FLP) that can activate a CO2 molecule and form the stable adduct 2, which is the catalytically active species and can facilitate the hydride transfer from the boron to the carbon atoms. In contrast, Me-TBD promotes the reduction of CO2 through the activation of the hydroborane reagent. Detailed DFT calculations have shown that the computed energy barriers for the two mechanisms are consistent with the experimental findings and account for the reactivity of the different boron reductants. PMID- 24771675 TI - Cell microencapsulation with synthetic polymers. AB - The encapsulation of cells into polymeric microspheres or microcapsules has permitted the transplantation of cells into human and animal subjects without the need for immunosuppressants. Cell-based therapies use donor cells to provide sustained release of a therapeutic product, such as insulin, and have shown promise in treating a variety of diseases. Immunoisolation of these cells via microencapsulation is a hotly investigated field, and the preferred material of choice has been alginate, a natural polymer derived from seaweed due to its gelling conditions. Although many natural polymers tend to gel in conditions favorable to mammalian cell encapsulation, there remain challenges such as batch to batch variability and residual components from the original source that can lead to an immune response when implanted into a recipient. Synthetic materials have the potential to avoid these issues; however, historically they have required harsh polymerization conditions that are not favorable to mammalian cells. As research into microencapsulation grows, more investigators are exploring methods to microencapsulate cells into synthetic polymers. This review describes a variety of synthetic polymers used to microencapsulate cells. PMID- 24771682 TI - Overcoming cancer multidrug resistance by codelivery of doxorubicin and verapamil with hydrogel nanoparticles. AB - The efficacy of chemotherapy is often inhibited by multidrug resistance (MDR). A highly engineerable hydrogel nanoparticle (NP) serves as a carrier for the optimal codelivery to tumor cells of the chemodrug, doxorubicin (Dox) and the chemosensitizer, verapamil (Vera), aiming at alleviating tumor MDR. The hydrogel NPs are prepared via the copolymerization of acrylamide and 2-carboxyethyl acrylate. Dox and Vera are post-loaded into the respective NPs, with drug loading around 7.7 wt% and 8.0 wt%, respectively. The codelivery of Dox-NPs and Vera-NPs increases the intracellular accumulation of Dox, and significantly enhances the cell killing ability of Dox with respect to NCI/ADR-RES cells in vitro. These findings suggest that such codelivery nanoplatforms provide a promising route for overcoming tumor MDR. PMID- 24771683 TI - Long-term consequences of neonatal fluoxetine exposure in adult rats. AB - Serotonin (5-HT) plays important roles during neural development. Administration of selective serotonin reuptake inhibitor (SSRI)-type medication during gestation may influence the maturation of the fetal brain and subsequent brain functions. To mimic the condition of late-gestation SSRI exposure, we administered fluoxetine (FLX) in neonatal rats during the first postnatal week, which roughly corresponds to the third trimester period of human gestation. FLX-exposed adult male rats exhibited reduced locomotor activity and depression-like behaviors. Furthermore, sensorimotor gating capacity was also impaired. Interestingly, increased social interaction was noticed in FLX-exposed rats. When the levels of 5-HT and tryptophan hydroxylase were examined, no significant changes were found in FLX rats compared to control (CON) rats. The behavioral phenotypes of FLX rats suggested malfunction of the limbic system. Dendritic architectures of neurons in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) were examined. Layer II/III mPFC pyramidal neurons in FLX rats had exuberant dendritic branches with elongated terminal segments compared to those in CON rats. In BLA pyramidal neurons, the dendritic profiles were comparable between the two groups. However, in FLX rats, the density of dendritic spines was reduced in both mPFC and BLA. Together, our results demonstrated the long-lasting effects of early FLX treatment on emotional and social behaviors in adult rats in which impaired neuronal structure in the limbic system was also noticed. The risk of taking SSRI type antidepressants during pregnancy should be considered. PMID- 24771684 TI - Association of patient characteristics with chemotherapy receipt among depressed and non-depressed patients with non-small cell lung cancer. PMID- 24771685 TI - N-terminal modification of VEGF-A C terminus-derived peptides delineates structural features involved in neuropilin-1 binding and functional activity. AB - The interaction between VEGF-A and its neuropilin (NRP) receptors mediates a number of important biological effects. NRP1 and the related molecule NRP2 are widely expressed on multiple tumour types and throughout the tumour vasculature, and are emerging as critical molecules required for the progression of angiogenic diseases. Given the increasing evidence supporting a role for NRP1 in tumour development, there is growing interest in developing inhibitors of NRP1 interactions with VEGF and its other ligands. In order to probe the interaction we synthesised a number of exon 7- and 8-derived bicyclic peptides with N terminal lipophilic groups and found a simple N-octanoyl derivative (EG00086) to be the most potent and functionally active. Detailed modelling studies indicated that new intramolecular hydrogen bonds were formed, stabilising the structure and possibly contributing to the potency. Removal of a salt bridge between D142 and R164 implicated in VEGF-A binding to neuropilin-1 had a minor effect on potency. Isothermal calorimetry was used to assess binding of EG00086 to NRP1 and NRP2, and the stability of the peptide in serum and in vivo was investigated. EG00086 is a potent blocker of VEGF-promoted cellular adhesion to extracellular matrices, and phosphorylation of p130Cas contributes to this effect. PMID- 24771686 TI - Osteochondral regeneration using an oriented nanofiber yarn-collagen type I/hyaluronate hybrid/TCP biphasic scaffold. AB - Osteochondral defects affect both the articular cartilage and the underlying subchondral bone, but poor osteochondral regeneration is still a daunting challenge. Although the tissue engineering technology provides a promising approach for osteochondral repair, an ideal biphasic scaffold is in high demand with regards to proper biomechanical strength. In this study, an oriented poly(l lacticacid)-co-poly(epsilon-caprolactone) P(LLA-CL)/collagen type I(Col-I) nanofiber yarn mesh, fabricated by dynamic liquid electrospinning served as a skeleton for a freeze-dried Col-I/Hhyaluronate (HA) chondral phase (SPONGE) to enhance the mechanical strength of the scaffold. In vitro results show that the Yarn Col-I/HA hybrid scaffold (Yarn-CH) can allow the cell infiltration like sponge scaffolds. Using porous beta-tricalcium phosphate (TCP) as the osseous phase, the Yarn-CH/TCP biphasic scaffold was then assembled by freeze drying. After combination of bone marrow mesenchymal stem cells, the biphasic complex was successfully used to repair the osteochondral defects in a rabbit model with greatly improved repairing scores and compressive modulus. PMID- 24771687 TI - Cerebral, subcortical, and cerebellar activation evoked by selective stimulation of muscle and cutaneous afferents: an fMRI study. AB - Abstract We compared the brain areas that showed significant flow changes induced by selective stimulation of muscle and cutaneous afferents using fMRI BOLD imaging. Afferents arising from the right hand were studied in eight volunteers with electrical stimulation of the digital nerve of the index finger and over the motor point of the FDI muscle. Both methods evoked areas of significant activation cortically, subcortically, and in the cerebellum. Selective muscle afferent stimulation caused significant activation in motor-related areas. It also caused significantly greater activation within the contralateral precentral gyrus, insula, and within the ipsilateral cerebellum as well as greater areas of reduced blood flow when compared to the cutaneous stimuli. We demonstrated separate precentral and postcentral foci of excitation with muscle afferent stimulation. We conclude, contrary to the findings with evoked potentials, that muscle afferents evoke more widespread cortical, subcortical, and cerebellar activation than do cutaneous afferents. This emphasizes the importance, for studies of movement, of matching the kinematic aspects in order to avoid the results being confounded by alterations in muscle afferent activation. The findings are consistent with clinical observations of the movement consequences of sensory loss and may also be the basis for the contribution of disturbed sensorimotor processing to disorders of movement. PMID- 24771688 TI - Regulating hippocampal hyperexcitability through GABAB Receptors. AB - Abstract Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein-coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 MUmol/L nor the GABAB receptor agonist baclofen at 0.1 MUmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 MUmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure-related hyperexcitability. PMID- 24771689 TI - Small intestinal permeability in older adults. AB - Abstract It is not yet clear whether intestinal mucosal permeability changes with advancing age in humans. This question is of high importance for drug and nutrition approaches for older adults. Our main objective was to answer the question if small intestinal barrier integrity deteriorates with healthy aging. We conducted a cross-sectional study including the pooled data of 215 nonsmoking healthy adults (93 female/122 male), 84 of whom were aged between 60 and 82 years. After a 12-h fast, all participants ingested 10 g of lactulose and 5 g of mannitol. Urine was collected for 5 h afterwards and analyzed for test sugars. The permeability index (PI = lactulose/mannitol) was used to assess small intestinal permeability. Low-grade inflammation defined by high-sensitivity C reactive protein >=1 mL/L and kidney function (estimated glomerular filtration rate) were determined in the older age group. The PI was similar in older compared to younger adults (P = 0.887). However, the urinary recovery of lactulose and mannitol was lower in the older adults and this change was neither associated with urinary volume nor glomerular filtration rate. The PI was not significantly correlated with low-grade inflammation or presence of noninsulin dependent type 2 diabetes. However, it significantly deteriorated in the copresence of both conditions compared to low-grade inflammation alone (P = 0.043) or type 2 diabetes alone (P = 0.015). Small intestinal mucosal barrier does not deteriorate with age per se. But low-grade inflammation coupled with minor disease challenges, such as type 2 diabetes, can compromise the small intestinal barrier. PMID- 24771690 TI - Female rats are more susceptible to central nervous system oxygen toxicity than male rats. AB - Abstract Tonic-clonic seizures typify central nervous system oxygen toxicity (CNS OT) in humans and animals exposed to high levels of oxygen, as are encountered during scuba diving. We previously demonstrated that high doses of pseudoephedrine (PSE) decrease the latency to seizure (LS) for CNS-OT in young male rats. This study investigated whether female rats respond similarly to PSE and hyperbaric oxygen (HBO). We implanted 60 virgin stock (VS) and 54 former breeder (FB) female rats with radio-telemetry devices that measured brain electrical activity. One week later, rats were gavaged with saline or PSE in saline (40, 80, 120, 160, or 320 mg/kg) before diving to five atmospheres absolute in 100% oxygen. The time between reaching maximum pressure and exhibiting seizure was LS. Vaginal smears identified estrus cycle phase. PSE did not decrease LS for VS or FB, primarily because they exhibited low LS for all conditions tested. VS had shorter LS than males at 0, 40, and 80 mg/kg (-42, -49, and -57%, respectively). FB also had shorter LS than males at 0, 40, and 80 mg/kg (-60, -86, and -73%, respectively). FB were older than VS (286 +/- 10 days vs. 128 +/- 5 days) and weighed more than VS (299 +/- 2.7 g vs. 272 +/- 2.1 g). Males tested were younger (88 +/- 2 days), heavier (340 +/- 4.5 g), and gained more weight postoperatively (7.2 +/- 1.6 g) than either VS (-0.4 +/- 1.5 g) or FB ( 1.6 +/- 1.5 g); however, LS correlated poorly with age, body mass, change in body mass, and estrus cycle phase. We hypothesize that differences in sex hormones underlie females' higher susceptibility to CNS-OT than males. PMID- 24771691 TI - Mitochondrial mitophagy in mesenteric artery remodeling in hyperhomocysteinemia. AB - Abstract Although high levels of homocysteine also termed as hyperhomocysteinemia (HHcy) has been associated with inflammatory bowel disease and mesenteric artery occlusion, the mitochondrial mechanisms behind endothelial dysfunction that lead to mesenteric artery remodeling are largely unknown. We hypothesize that in HHcy there is increased mitochondrial fission due to altered Mfn-2/Drp-1 ratio, which leads to endothelial dysfunction and collagen deposition in the mesenteric artery inducing vascular remodeling. To test this hypothesis, we used four groups of mice: (i) WT (C57BL/6J); (ii) mice with HHcy (CBS+/-); (iii) oxidative stress resistant mice (C3H) and (iv) mice with HHcy and oxidative stress resistance (CBS+/-/C3H). For mitochondrial dynamics, we studied the expression of Mfn-2 which is a mitochondrial fusion protein and Drp-1 which is a mitochondrial fission protein by western blots, real-time PCR and immunohistochemistry. We also examined oxidative stress markers, endothelial cell, and gap junction proteins that play an important role in endothelial dysfunction. Our data showed increase in oxidative stress, mitochondrial fission (Drp-1), and collagen deposition in CBS+/- compared to WT and C3H mice. We also observed significant down regulation of Mfn-2 (mitochondrial fusion marker), CD31, eNOS and connexin 40 (gap junction protein) in CBS+/- mice as compared to WT and C3H mice. In conclusion, our data suggested that HHcy increased mitochondrial fission (i.e., decreased Mfn-2/Drp-1 ratio, causing mitophagy) that leads to endothelial cell damage and collagen deposition in the mesenteric artery. This is a novel report on the role of mitochondrial dynamics alteration defining mesenteric artery remodeling. PMID- 24771692 TI - Ex vivo, microelectrode analysis of conduction through the AV node of wild-type and Nkx2-5 mutant mouse hearts as guided by a Cx40-eGFP transgenic reporter. AB - Abstract Mutations of the cardiac transcription factor NKX2-5 cause hypoplastic development of the AV node and conduction block. How the anatomy of the mutant AV node relates to its function is unknown. We thus studied conduction through the AV nodal region in ex vivo preparations of wild-type and Nkx2-5(+/-) mouse hearts in which the central conduction system was highlighted by a transgenic Cx40-eGFP reporter. Fluorescence imaging guided electrode placement and pacing of the inferior and superior approaches to the AV node. Nkx2-5(+/-) hearts had a prolonged atrio-His interval compared to the wild type, consistent with previous in vivo observations. The conduction time to the His bundle from the Cx40(-) AV nodal region that is superior to and immediately adjacent to the Cx40(+) lower node is slightly, but not significantly greater in Nkx2-5(+/-) than wild-type hearts. A novel phenotype was also observed. Pacing the Cx40(-) inferior approach to the AV node with increasing stimulus strength led to progressive shortening of the stimulus-to-His conduction interval in wild-type but not Nkx2-5(+/-) hearts. The strength of pacing at the Cx40(-) superior approach had no effect on the conduction interval in either group. The prolonged AV delay in the Nkx2-5(+/-) heart appears to arise before the Cx40(+) lower node. Whether the pacing phenotype explains the mutant's conduction defect is uncertain, but the observation adds to a number of unique properties of the inferior approach to the AV node. PMID- 24771693 TI - Admittance-based pressure-volume loops versus gold standard cardiac magnetic resonance imaging in a porcine model of myocardial infarction. AB - Abstract A novel admittance-based pressure-volume system (AS) has recently been developed and introduced. Thus far, the new technique has been validated predominantly in small animals. In large animals it has only been compared to three-dimensional echocardiography (3DE) where the AS showed to overestimate left ventricular (LV) volumes. To fully determine the accuracy of this device, we compared the AS with gold standard cardiac magnetic resonance imaging (CMRI) in a porcine model of chronic myocardial infarction (MI). Fourteen pigs were subjected to 90 min closed chest balloon occlusion of the left anterior descending artery. After 8 weeks of follow up, pigs were consecutively subjected to LV volume measurements by the AS, CMRI, and 3DE under general anesthesia. The AS overestimated end diastolic volume (EDV; +20.9 +/- 30.6 mL, P = 0.024) and end systolic volume (ESV; +17.7 +/- 29.4 mL, P = 0.042) but not ejection fraction (EF; +2.46 +/- 6.16%, P = NS) compared to CMRI. Good correlations of EDV (R = 0.626, P = 0.017) and EF (R = 0.704, P = 0.005) between the AS and CMRI were observed. EF measured by the AS and 3DE also correlated significantly (R = 0.624, P = 0.030). After subjection of pigs to MI, the AS very moderately overestimates LV volumes and shows accurate measurements for EF compared to CMRI. This makes the AS a useful tool to determine cardiac function and dynamic changes in large animal models of cardiac disease. PMID- 24771694 TI - 14-3-3-beta and -{varepsilon} contribute to activation of the osmoprotective transcription factor NFAT5 by increasing its protein abundance and its transactivating activity. AB - Abstract Having previously found that high NaCl causes rapid exit of 14-3-3 isoforms from the nucleus, we used siRNA-mediated knockdown to test whether 14-3 3s contribute to the high NaCl-induced increase in the activity of the osmoprotective transcription factor NFAT5. We find that, when NaCl is elevated, knockdown of 14-3-3-beta and/or 14-3-3-epsilon decreases NFAT5 transcriptional activity, as assayed both by luciferase reporter and by the mRNA abundance of the NFAT5 target genes aldose reductase and the sodium- and chloride-dependent betaine transporter, BGT1. Knockdown of other 14-3-3 isoforms does not significantly affect NFAT5 activity. 14-3-3-beta and/or 14-3-3-epsilon do not act by affecting the nuclear localization of NFAT5, but by at least two other mechanisms: (1) 14-3-3-beta and 14-3-3-epsilon increase protein abundance of NFAT5 and (2) they increase NFAT5 transactivating activity. When NaCl is elevated, knockdown of 14-3-3-beta and/or 14-3-3-epsilon reduces the protein abundance of NFAT5, as measured by Western blot, without affecting the level of NFAT5 mRNA, and the knockdown also decreases NFAT5 transactivating activity, as measured by luciferase reporter. The 14-3-3s increase NFAT5 protein, not by increasing its translation, but by decreasing the rate at which it is degraded, as measured by cycloheximide chase. It is not clear at this point whether the 14 3-3s affect NFAT5 directly or indirectly through their effects on other proteins that signal activation of NFAT5. PMID- 24771695 TI - The impact of obesity and hypoxia on left ventricular function and glycolytic metabolism. AB - Abstract We have previously reported that 4 weeks of intermittent hypoxia (IH) exposure, mimicking the hypoxic stress of obstructive sleep apnea, produces compensatory increases in left ventricular (LV) contractility in lean C57BL/6J mice. In this study we compared the effects of 4 weeks IH to 4 weeks of sustained hypoxia (SH) on LV function and cardiac glycolysis in lean C57BL/6J mice and obese ob/ob mice at 10-12 weeks of age. The four exposure conditions were IH (nadir O2 [5-6%] at 60 cycles/h during the 12 h light period), SH (24 h inspired O2 [10%]), and control groups of intermittent air (IA) or room air. Cardiac function was assessed under isoflurane anesthesia (1-2%) by echocardiography and pressure-volume loop analysis and myocardial glycolytic rates were determined ex vivo using radiolabeled (3)H-glucose. Lean mice exposed to IH exhibited increases in contractile parameters which were associated with elevated glycolytic rates (3.4 vs. 5.7 MUg/MUL.g; P < 0.05). Ob/ob mice did not show any improvements in contractility after IH. Moreover, cardiac glycolytic rates and LV systolic and diastolic function did not differ from IA ob/ob controls. Following SH exposure, lean mice exhibited increased contractility and glycolytic rates (3.8 vs. 5.7 MUg/MUL.g; P < 0.05), however, LV lumen dimensions were reduced. In contrast, ob/ob mice exposed to SH show compromised systolic and diastolic function associated with unchanging glycolytic rates. These findings demonstrate that, in a murine model of obesity, an inability to increase glycolysis is associated with an absence of an adaptive cardiac response to IH and marked systolic and diastolic dysfunction in response to SH. PMID- 24771697 TI - Erratum. PMID- 24771696 TI - Epithelial monolayer culture system for real-time single-cell analyses. AB - Abstract Many epithelial cells form polarized monolayers under in vivo and in vitro conditions. Typically, epithelial cells are cultured for differentiation on insert systems where cells are plated on a porous filter membrane. Although the cultured monolayers have been a standard system to study epithelial physiology, there are some limits: The epithelial cells growing inside the commercial inserts are not optimal to visualize directly through lenses on inverted microscopes. The cell images are optically distorted and background fluorescence is bright due to the filter membrane positioned between the cells and the lens. In addition, the cells are not easily accessible by electrodes due to the presence of tall side walls. Here, we present the design, fabrication, and practical applications of an improved system for analysis of polarized epithelial monolayers. This new system allows (1) direct imaging of cells without an interfering filter membrane, (2) electrophysiological measurements, and (3) detection of apical secretion with minimal dilution. Therefore, our culture method is optimized to study differentiated epithelial cells at the single-cell and subcellular levels, and can be extended to other cell types with minor modifications. PMID- 24771698 TI - Highly efficient gold-catalyzed synthesis of dibenzocycloheptatrienes. AB - Dibenzocycloheptatrienes are obtained by a gold-catalyzed 7-exo-dig hydroarylation protocol in a highly efficient manner. The gold-catalyzed reaction usually gives the products in high yields and excellent selectivity. This procedure provides an easy and efficient access to dibenzocycloheptanoids, which are an interesting and unique class of natural products. This was underlined by the first total synthesis of reticuol. PMID- 24771699 TI - Standard error estimation using the EM algorithm for the joint modeling of survival and longitudinal data. AB - Joint modeling of survival and longitudinal data has been studied extensively in the recent literature. The likelihood approach is one of the most popular estimation methods employed within the joint modeling framework. Typically, the parameters are estimated using maximum likelihood, with computation performed by the expectation maximization (EM) algorithm. However, one drawback of this approach is that standard error (SE) estimates are not automatically produced when using the EM algorithm. Many different procedures have been proposed to obtain the asymptotic covariance matrix for the parameters when the number of parameters is typically small. In the joint modeling context, however, there may be an infinite-dimensional parameter, the baseline hazard function, which greatly complicates the problem, so that the existing methods cannot be readily applied. The profile likelihood and the bootstrap methods overcome the difficulty to some extent; however, they can be computationally intensive. In this paper, we propose two new methods for SE estimation using the EM algorithm that allow for more efficient computation of the SE of a subset of parametric components in a semiparametric or high-dimensional parametric model. The precision and computation time are evaluated through a thorough simulation study. We conclude with an application of our SE estimation method to analyze an HIV clinical trial dataset. PMID- 24771700 TI - Response of fish tissue mercury in a freshwater lake to local, regional, and global changes in mercury emissions. AB - A suite of mechanistic atmospheric and mercury (Hg) cycling and bioaccumulation models is applied to simulate atmospheric Hg deposition and Hg concentrations in the water column and in fish in a Hg-impaired freshwater lake located in the northeastern United States that receives its Hg loading primarily through deposition. Two future-year scenarios evaluate the long-term response of fish tissue Hg concentrations to reductions in local and nationwide coal-fired electric-generating utility and other Hg emissions and an increase or decrease in global (non-US) Hg emissions. Results indicate that fish tissue Hg concentrations in this ecosystem could require approximately 3 yr to 8 yr to begin to respond to declines in US emissions and deposition with a fish Hg reduction proportional to deposition reduction requiring over 50 yr. Furthermore, recovery could potentially be partially or completely offset by growth in non-US Hg emissions. PMID- 24771701 TI - Rostral-caudal distribution of Emx1-lineage stem/transit amplifying cells and lineage progression in embryonic cortex depend on Hedgehog signaling. AB - Lineage progression of neural precursors to an EGF-responsive state can be promoted by several extrinsic signals, including fibroblast growth factor 2 (FGF2) and Hedgehog (Hh). It has been suggested that EGF-responsive precursors in the embryonic cerebral cortex originate in the ventral telencephalon in an FGF dependent manner and migrate dorsally. To determine whether cortical EGF responsive cells originate locally from dorsal precursors, we marked these precursors using Emx1-cre and the cre reporter Z/EG and observed a local origin for EGF-responsive cells. We also found a rostral-caudal difference in the abundance of self-renewing, neurogenic Emx1-lineage precursors, with more present rostrally. Deleting the Hh receptor smoothened in Emx-1 lineage cells impaired their progression to an EGF-responsive state. Moreover, loss of smoothened increased the proportion of neurogenic, self-renewing Emx1-lineage cells in caudal regions of cortex, eliminating their asymmetric distribution. Our results support the idea that Hh signaling promotes lineage progression of stem/transit amplifying cells, particularly in caudal regions of the embryonic cortex, leading to rostral-caudal differences in the abundance of neurogenic, self-renewing precursors. PMID- 24771702 TI - Ultrastructural aspects of Cystoisospora belli (syn. Isospora belli) in continuous cell lines. AB - Cystoisospora belli is an opportunistic protozoan that causes human cystoisosporiasis, an infection characterized by diarrhea, steatorrhea, abdominal pain, fever, and weight loss. The lack of animal models susceptible to C. belli, and the difficulty in obtaining clinical samples with fair amounts of oocysts have limited the research pertaining to the basic biology of this parasite. This study aimed to describe the ultrastructure of endogenous stages of C. belli in Monkey Rhesus Kidney Cells (MK2) and Human Ileocecal Adenocarcinoma cells (HCT 8). Zoites of C. belli exhibited typical morphological features of coccidia, which included a trilaminar pellicle, an apical complex formed by a conoid, polar rings, rhoptries, and micronemes, in addition to dense granules and the endoplasmic reticulum. No crystalloid body was observed but various lipid and amylopectin granules were usually present in the cytoplasm of zoites. We observed a tendency of the endoplasmic reticulum of the host cell to be located near the parasitophorous vacuole membrane. Merozoites were formed by endodyogeny and during replication, the apical complex of the mother cell remained intact. The formation of gametes or oocysts was not observed. The ultrastructural findings of C. belli are further evidence of its proximity to Sarcocystidae family members and corroborate their reclassification as Cystoisospora spp. PMID- 24771703 TI - Redox-responsive nanoparticles with Aggregation-Induced Emission (AIE) characteristic for fluorescence imaging. AB - The redox environment between intracellular compartments and extracellular matrix is significantly different, and the cellular redox homeostasis determines many physiological functions. Here, redox-responsive nanoparticles with aggregation induced emission (AIE) characteristic for fluorescence imaging are developed by encapsulation of fluorophore with redox "turn-on" AIE characteristic, TPE-MI, into the micelles of poly(ethylene glycol) (PEG)- and cholesterol (CE)-conjugated disulfide containing poly(amido amine)s. The redox-responsive fluorescence profiles of the nanoparticles are investigated after reaction with glutathione (GSH). The encapsulation of TPE-MI in micelles leads to a higher efficiency and red shift in emission, and the fluorescence intensity of the nanoparticles increases with the concentration of GSH. Confocal microscopy imaging shows that the nanoparticles can provide obvious contrast between the intracellular compartments and the extracellular matrix in MCF-7 and HepG2 cells. So the nanoparticles with PEG shells and low cytotoxicity are promising to provide fluorescence bioimaging with a high contrast and for differentiation of cellular redox environment. PMID- 24771704 TI - Electrospinning of unidirectionally and orthogonally aligned thermoplastic polyurethane nanofibers: fiber orientation and cell migration. AB - Unidirectionally and orthogonally aligned thermoplastic polyurethane (TPU) nanofibers were electrospun using a custom-built electrospinning device. The unidirectionally aligned fibers were collected using two parallel copper plates, and the orthogonally aligned fibers were collected using two orthogonal sets of parallel copper plates with alternate negative connections. Carbon nanotubes (CNT) and polyacrylic acid (PAA) were added to modify the polymer solution. It was found that both CNT and PAA were capable of increasing solution conductivity. The TPU/PAA fiber showed the highest degree of fiber orientation with more than 90% of the fibers having an orientation angle between -10 degrees and 10 degrees for unidirectionally aligned fibers, and for orthogonally aligned fibers, the orientation angle of 50% fibers located between -10 degrees and 10 degrees and 48% fibers located between 80 degrees and 100 degrees . Viability assessment of 3T3 fibroblasts cultured on TPU/PAA fibers suggested that the material was cytocompatible. The cells' orientation and migration direction closely matched the fibers' orientation. The cell migration velocity and distance were both enhanced with the guidance of fibers compared with cells cultured on random fibers and common tissue culture plastic. Controlling cell migration velocity and directionality may provide ways to influence differentiation and gene expression and systems that would allow further exploration of wound repair and metastatic cell behavior. PMID- 24771705 TI - Expanding the binding envelope of CYP51 inhibitors targeting Trypanosoma cruzi with 4-aminopyridyl-based sulfonamide derivatives. AB - Chagas disease is a chronic infection caused by the protozoan parasite Trypanosoma cruzi, manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Therapeutic options to prevent or treat Chagas disease are limited. CYP51, the enzyme key to the biosynthesis of eukaryotic membrane sterols, is a validated drug target in both fungi and T. cruzi. Sulfonamide derivatives of 4-aminopyridyl-based inhibitors of T. cruzi CYP51 (TcCYP51), including the sub-nanomolar compound 3, have molecular structures distinct from other validated CYP51 inhibitors. They augment the biologically relevant chemical space of molecules targeting TcCYP51. In a 2.08 A X-ray structure, TcCYP51 is in a conformation that has been influenced by compound 3 and is distinct from the previously characterized ground-state conformation of CYP51 drug-target complexes. That the binding site was modulated in response to an incoming inhibitor for the first time characterizes TcCYP51 as a flexible target rather than a rigid template. PMID- 24771707 TI - Palladium-catalyzed/norbornene-mediated C-H activation/N-tosylhydrazone insertion reaction: a route to highly functionalized vinylarenes. AB - A straightforward method for the synthesis of highly functionalized vinylarenes through palladium-catalyzed, norbornene-mediated C-H activation/carbene migratory insertion is described. Extension to a one-pot procedure is also developed. Furthermore, this method can also be used to generate polysubstituted bicyclic molecules. The reaction proceeds under mild conditions to give the products in satisfactory yields using readily available starting materials. This is a Catellani-Lautens reaction that incorporates different types of coupling partners. Additionally, this reaction is the first to demonstrate the possibility of combining Pd-catalyzed insertion of diazo compounds and Pd-catalyzed C-H activation. PMID- 24771706 TI - Self-monitoring of blood pressure for improving adherence to antihypertensive medicines and blood pressure control: a randomized controlled trial. AB - BACKGROUND: Self-monitoring is reported to have limited efficacy for hypertension management in high-income countries. In this study, we aimed to evaluate the effect of self-monitoring on blood pressure (BP) control in an Iranian population. METHODS: A randomized controlled trial was conducted on 196 mild to moderate hypertensive patients in an outpatient cardiovascular clinic. Patients in the intervention group received a wrist self-monitoring device and were educated to measure and document their BP daily during the study period (24 weeks). Patients in the control group received usual care. Three follow-up visits with the physician were scheduled for all patients (weeks 4, 12, and 24), and the investigator assessed adherence to medications after each visit (pill counting). The primary outcome (BP) was compared between groups using repeated-measure analysis of variance. RESULTS: One hundred ninety patients completed the study. Systolic BP (144.4+/-7.4 vs 145.9+/-6.4mm Hg) and diastolic BP (85.5+/-6.9 vs. 85.1+/-7.7mm Hg) were similar between groups at baseline. The trend of BP was not significantly different between groups during the study period. Systolic and diastolic BP decreased significantly in both groups at the first follow-up visit (systolic BP: 132.6 vs. 133.4mm Hg; diastolic BP: 77.4 vs. 77.2mm Hg). In the intervention group, we observed a small continued decrease in diastolic BP up to week 24 BP (P = 0.01). Both groups showed adherence rates >95% during the study period. CONCLUSIONS: Our study could not confirm that self-monitoring can improve BP control in patients with frequent medical visits. PMID- 24771710 TI - Validation of a measure of alliance for an adolescent inpatient setting. AB - The link between alliance and treatment outcome is robust. Nevertheless, few, if any, self-report measures exist to assess the alliance between hospitalized adolescents and their treatment team as a whole. The present study looks to extend the use of a brief self-report measure of inpatient treatment alliance designed for adult inpatients to be used with adolescents. The scale is designed incorporating items that tap the three factors of alliance (bond, goals and collaboration) to assess the alliance that the patient has with his or her treatment team. Our results show that the Inpatient-Treatment Alliance Scale is unifactoral, shows good psychometrics and is linked in theoretically meaningful ways to global clinician ratings of engagement in individual psychotherapy. KEY PRACTITIONER MESSAGE: Inpatient treatment of adolescents requires the assessment of alliance to be between the patient and his or her treatment team rather than an individual clinician. Assessment of the alliance can benefit clinicians treating hospitalized adolescents especially because these patients are difficult to engage with in treatment. This study shows that the Inpatient-Treatment Alliance Scale is a promising measure for assessing treatment alliance on an adolescent inpatient setting. PMID- 24771711 TI - Effects of food quality on trade-offs among growth, immunity and survival in the greater wax moth Galleria mellonella. AB - The resources available to an individual in any given environment are finite, and variation in life history traits reflect differential allocation of these resources to competing life functions. Nutritional quality of food is of particular importance in these life history decisions. In this study, we tested trade-offs among growth, immunity and survival in 3 groups of greater wax moth (Galleria mellonella) larvae fed on diets of high and average nutritional quality. We found rapid growth and weak immunity (as measured by encapsulation response) in the larvae of the high-energy food group. It took longer to develop on food of average nutritional quality. However, encapsulation response was stronger in this group. The larvae grew longer in the low-energy food group, and had the strongest encapsulation response. We observed the highest survival rates in larvae of the low-energy food group, while the highest mortality rates were observed in the high-energy food group. A significant negative correlation between body mass and the strength of encapsulation response was found only in the high-energy food group revealing significant competition between growth and immunity only at the highest rates of growth. The results of this study help to establish relationships between types of food, its nutritional value and life history traits of G. mellonella larvae. PMID- 24771712 TI - Polyethlyene glycol microgels to deliver bioactive nerve growth factor. AB - Delivery of bioactive molecules is a critical step in fabricating materials for regenerative medicine, yet, this step is particularly challenging in hydrated scaffolds such as hydrogels. Although bulk photocrosslinked poly(ethylene glycol) (PEG) hydrogels have been used for a variety of tissue engineering applications, their capability as drug delivery scaffolds has been limited due to undesirable release profiles and reduction in bioactivity of molecules. To solve these problems, this article presents the fabrication of degradable PEG microgels, which are micron-sized spherical hydrogels, to deliver bioactive nerve growth factor (NGF). NGF release and activity was measured after encapsulation in microgels formed from either 3 kDa or 6 kDa PEG to determine the role of hydrogel mesh size on release. Microgels formed from 6 kDa PEG were statistically larger and had a higher swelling ratio than 3 kDa PEG. The 6 kDa PEG microgels provided a Fickian release with a reduced burst effect and 3 kDa microgels provided anomalous release over >=20 days. Regardless of molecular weight of PEG, NGF bioactivity was not significantly reduced compared to unprocessed NGF. These results demonstrate that microgels provide easy mechanisms to control the release while retaining the activity of growth factors. As this microgel-based delivery system can be injected at the site of nerve injury to promote nerve repair, the potential to deliver active growth factors in a controlled manner may reduce healing time for neural tissue engineering applications. PMID- 24771713 TI - Evaluation of the interaction between phosphohistidine analogues and phosphotyrosine binding domains. AB - We have investigated the interaction of peptides containing phosphohistidine analogues and their homologues with the prototypical phosphotyrosine binding SH2 domain from the eukaryotic cell signalling protein Grb2 by using a combination of isothermal titration calorimetry and a fluorescence anisotropy competition assay. These investigations demonstrated that the triazole class of phosphohistidine analogues are capable of binding too, suggesting that phosphohistidine could potentially be detected by this class of proteins in vivo. PMID- 24771715 TI - Crosslinked fibrin gels for tissue engineering: two approaches to improve their properties. AB - Fibrin is a protein that can be used as an ideal scaffolding material to promote tissue regeneration. In order to enhance its physical properties in this study a natural crosslinker, genipin (GP), was employed with the aim to obtain a hydrogel with tuneable properties for tissue engineering applications. The fibrin gel was crosslinked by two different methods using four concentrations of GP to get a stable hydrogel network. Crosslinking density, mechanical properties, swelling, and enzymatic degradation of the hydrogels were tested for each GP content and method employed. The method I: Crosslinking after gel formation promotes a high crosslinking and retains the gel shape for long term whilst the method II: Simultaneous gel formation and crosslinking improves the mechanical properties of the gel. This study confirms the use of GP at different concentrations as a suitable crosslinker of fibrin that promotes the cellular viability of L929 for 21 days of in vitro culture. PMID- 24771714 TI - Air toxics and epigenetic effects: ozone altered microRNAs in the sputum of human subjects. AB - Ozone (O3) is a criteria air pollutant that is associated with numerous adverse health effects, including altered respiratory immune responses. Despite its deleterious health effects, possible epigenetic mechanisms underlying O3-induced health effects remain understudied. MicroRNAs (miRNAs) are epigenetic regulators of genomic response to environmental insults and unstudied in relationship to O3 inhalation exposure. Our objective was to test whether O3 inhalation exposure significantly alters miRNA expression profiles within the human bronchial airways. Twenty healthy adult human volunteers were exposed to 0.4 ppm O3 for 2 h. Induced sputum samples were collected from each subject 48 h preexposure and 6 h postexposure for evaluation of miRNA expression and markers of inflammation in the airways. Genomewide miRNA expression profiles were evaluated by microarray analysis, and in silico predicted mRNA targets of the O3-responsive miRNAs were identified and validated against previously measured O3-induced changes in mRNA targets. Biological network analysis was performed on the O3-associated miRNAs and mRNA targets to reveal potential associated response signaling and functional enrichment. Expression analysis of the sputum samples revealed that O3 exposure significantly increased the expression levels of 10 miRNAs, namely miR-132, miR 143, miR-145, miR-199a*, miR-199b-5p, miR-222, miR-223, miR-25, miR-424, and miR 582-5p. The miRNAs and their predicted targets were associated with a diverse range of biological functions and disease signatures, noted among them inflammation and immune-related disease. The present study shows that O3 inhalation exposure disrupts select miRNA expression profiles that are associated with inflammatory and immune response signaling. These findings provide novel insight into epigenetic regulation of responses to O3 exposure. PMID- 24771716 TI - Homicidal/violent thoughts, suicidal ideation and violent behavior in adolescents with social phobia in Metropolitan Lima, Peru. AB - INTRODUCTION: Social phobia and violent behavior are both important mental health problems among adolescent populations in different parts of the world. This study attempts to evaluate possible connections between social phobia, homicidal/violent thoughts, suicidal ideation, and subsequent violent behavior among adolescents living in the metropolitan area of Lima, Peru. METHODS: A sample of 991 adolescents, part of the 2002 Epidemiological Study in Metropolitan Lima, conducted by the National Institute of Mental Health "Honorio Delgado Hideyo Noguchi" (INSM "HD-HN") was studied. Social phobia was diagnosed on the basis of clinical assessment and the use of MINI, and suicidal ideation, homicidal/violent thoughts, and violent behavior were identified through the Mental Health Questionnaire. Odds ratio (OR) statistical analyses adjusted by logistic regression controlling for age and gender were performed. RESULTS: Variables associated with social phobia were homicidal thoughts in the last month (OR: 5.19, confidence interval [CI] at 95% 4.95-5.40), an impulse to hit known (OR: 1.56; 95% CI, 1.53-1.59) and unknown (OR: 3.98, 95% CI,3.89-4.07) persons, the wish to take revenge for a past offense (OR: 2.60, 95% CI 2.54-2.64), getting involved in fights with different kinds of weapons (OR: 1,78, 95% CI 1.70-1.87), suicidal ideation throughout lifetime (OR: 4.74, 95% CI 4.65-4.83), and life prevalence of suicidal attempt (OR: 5.39, 95% CI 5.23-5.55). DISCUSSION: Social phobia in adolescents of this Peruvian sample seems to be closely associated with both homicidal/violent thoughts, violent behavior, and suicidal ideation. PMID- 24771717 TI - Identification and characterization by LC-UV-MS/MS of melanotan II skin-tanning products sold illegally on the Internet. AB - New methods were developed and validated to determine the identity, contents, and purity of samples of melanotan II, a synthetic melanocortin receptor agonist, sold in vials as injectable skin-tanning products that were purchased from three online shops. Methods were based on liquid chromatography with ultra-violet detection (LC-UV) at wavelength 218 nm, and tandem mass spectrometric detection (MS/MS) after collision-induced fragmentation of the double charged [M+2H](2+) precursor ion (m/z 513). Identification of melanotan II was verified by correct chromatographic retention time, and relative abundance ratios of five qualifying fragment ions. LC-UV was used to quantify melanotan II as well as impurities. Method validation was performed with reference to guidelines for assessing active substances in authorized medicinal products to reach acceptable accuracy and precision. Vials from two shops contained unknown impurities ranging from 4.1 to 5.9%; impurities from one shop were below the quantification limit. The total amount of melanotan II in vials ranged between 4.32 and 8.84 mg, although each shop claimed that vials contained 10 mg melanotan II. A broad range of drugs used for enhancement purposes can be obtained from the illicit market. However, users of these drugs may be exposed to a range of potential harms, as shown in this study, given that these products are manufactured, distributed and supplied from an illicit market. PMID- 24771718 TI - A hierarchical nanostructured carbon nanofiber-In2S3 photocatalyst with high photodegradation and disinfection abilities under visible light. AB - Photocatalytic degradation of pollutants under visible light provides a new door to solve the water contamination problem by utilizing free and renewable sunlight. The search for highly efficient photocatalysts with hierarchical nanostructures remains crucial for accessing this new door. In this work, a new hierarchical nanostructured photocatalyst is designed and synthesized, for the first time, by anchoring In2S3 flower-like nanostructures on non-woven carbon nanofiber (CNF). The nanostructures of these CNF-In2S3 composites were fine tuned, with the aim of achieving the highest photocatalytic activity under visible light. The formation mechanism of the hierarchical nanostructure is also investigated. The results indicate that the optimized hierarchical CNF-In2S3 photocatalyst is superior in photodegradation and disinfection efficiency to that of pure In2S3 under visible-light irradiation. The prominent photocatalytic activities of these hierarchical CNF-In2S3 photocatalysts can be attributed to the excellent properties of enhanced light absorption, large surface area, and efficient charge separation, which are all derived from the special three dimensional hierarchical nanostructures. Therefore, this work presents the great potential of this hierarchical nanostructured CNF-In2S3 photocatalyst in practical environmental remediation fields. PMID- 24771719 TI - Surprising effect of smoking on allergies and chronic rhinosinusitis. Editorial. PMID- 24771722 TI - Strong antiferromagnetic coupling of spins in the (MDABCO+)(C60.-) salt with 3D close packing of the C60.- radical anions (MDABCO+: N-methyldiazabicyclooctanium cation). AB - A new salt, (MDABCO(+))(C60(.-)) (1; MDABCO(+) = N-methyldiazabicyclooctanium cation), was obtained as single crystals. The crystal structure of 1 determined at 250 and 100 K showed 3D close packing of fullerenes with eight fullerene neighbors for each C60(.-). These neighbors are located at 10.01-10.11 A center to-center distances (250 K) and van der Waals interfullerene C???C contacts are formed with four fullerene neighbors arranged in the bc plane. Fullerene ordering observed below 160 K is accompanied by the appearance of one and a half independent C60(.-) and trebling of the unit cell along the b axis. Fullerenes are packed closer to each other at 100 K. As a result, fullerenes are located in the three-dimensional packing at 9.91-10.12 A center-to-center distances and 18 short interfullerene C???C contacts are formed for each C60(.-). Although they are closed packed, fullerenes are not dimerized down to 1.9 K. Magnetic data indicate strong antiferromagnetic coupling of spins in the 70-300 K range with a Weiss temperature of Theta = -118 K. Magnetic susceptibility shows a round maximum at 46 K. Such behavior can be described well by the Heisenberg model for square two-dimensional antiferromagnetic coupling of spins with an exchange interaction of J/kB = -25.3 K. This magnetic coupling is one of the strongest observed for C60(.-) salts. PMID- 24771721 TI - Atrial antitachycardia pacing and managed ventricular pacing in bradycardia patients with paroxysmal or persistent atrial tachyarrhythmias: the MINERVA randomized multicentre international trial. AB - AIMS: Atrial fibrillation (AF) is a common comorbidity in bradycardia patients. Advanced pacemakers feature atrial preventive pacing and atrial antitachycardia pacing (DDDRP) and managed ventricular pacing (MVP), which minimizes unnecessary right ventricular pacing. We evaluated whether DDDRP and MVP might reduce mortality, morbidity, or progression to permanent AF when compared with standard dual-chamber pacing (Control DDDR). METHODS AND RESULTS: In a randomized, parallel, single-blind, multi-centre trial we enrolled 1300 patients with bradycardia and previous atrial tachyarrhythmias, in whom a DDDRP pacemaker had recently been implanted. History of permanent AF and third-degree atrioventricular block were exclusion criteria. After a 1-month run-in period, 1166 eligible patients, aged 74 +/- 9 years, 50% females, were randomized to Control DDDR, DDDRP + MVP, or MVP. Analysis was intention-to-treat. The primary outcome, i.e. the 2-year incidence of a combined endpoint composed of death, cardiovascular hospitalizations, or permanent AF, occurred in 102/385 (26.5%) Control DDDR patients, in 76/383 (19.8%) DDDRP + MVP patients [hazard ratio (HR) = 0.74, 95% confidence interval 0.55-0.99, P = 0.04 vs. Control DDDR] and in 85/398 (21.4%) MVP patients (HR = 0.89, 95% confidence interval 0.77-1.03, P = 0.125 vs. Control DDDR). When compared with Control DDDR, DDDRP + MVP reduced the risk for AF longer than 1 day (HR = 0.66, 95% CI 0.52-0.85, P < 0.001), AF longer than 7 days (HR = 0.52, 95% CI 0.36-0.73, P < 0.001), and permanent AF (HR = 0.39, 95% CI 0.21-0.75, P = 0.004). CONCLUSION: In patients with bradycardia and atrial tachyarrhythmias, DDDRP + MVP is superior to standard dual-chamber pacing. The primary endpoint was significantly lowered through the reduction of the progression of atrial tachyarrhythmias to permanent AF. CLINICALTRIALSGOV IDENTIFIER: NCT00262119. PMID- 24771723 TI - Honey bee colonies act as reservoirs for two Spiroplasma facultative symbionts and incur complex, multiyear infection dynamics. AB - Two species of Spiroplasma (Mollicutes) bacteria were isolated from and described as pathogens of the European honey bee, Apis mellifera, ~30 years ago but recent information on them is lacking despite global concern to understand bee population declines. Here we provide a comprehensive survey for the prevalence of these two Spiroplasma species in current populations of honey bees using improved molecular diagnostic techniques to assay multiyear colony samples from North America (U.S.A.) and South America (Brazil). Significant annual and seasonal fluctuations of Spiroplasma apis and Spiroplasma melliferum prevalence in colonies from the U.S.A. (n = 616) and Brazil (n = 139) occurred during surveys from 2011 through 2013. Overall, 33% of U.S.A. colonies and 54% of Brazil colonies were infected by Spiroplasma spp., where S. melliferum predominated over S. apis in both countries (25% vs. 14% and 44% vs. 38% frequency, respectively). Colonies were co-infected by both species more frequently than expected in both countries and at a much higher rate in Brazil (52%) compared to the U.S.A. (16.5%). U.S.A. samples showed that both species were prevalent not only during spring, as expected from prior research, but also during other seasons. These findings demonstrate that the model of honey bee spiroplasmas as springtime restricted pathogens needs to be broadened and their role as occasional pathogens considered in current contexts. PMID- 24771725 TI - Patent ductus arteriosus in preterm infants: benefits of early surgical closure. AB - BACKGROUND: Patent ductus arteriosus in preterm neonates leads to significant morbidity. Surgery is indicated when pharmacological treatment fails or is contraindicated, but the optimal timing remains unclear. METHODS: We retrospectively studied all 41 preterm neonates with symptomatic ductus arteriosus who underwent ligation between 1988 and 2009. We compared early complications rates and late neurological outcomes of patients operated on before 21 days of age with these operated on later. RESULTS: The median gestational age at birth was 26 weeks (range 23-31 weeks) and median weight at birth was 930 g (range 510-1500 g); 34 (82.9%) received pharmacological treatment before surgery. Fourteen (34.1%) patients underwent surgical closure before 21 days of age and 27 (65.9%) after 21 days. The 2 groups did not differ significantly in gestational age and weight at birth, but those operated on after 21 days received significantly more pharmacological treatment cycles. Patients in the early closure group had shorter intubation times: median 23 days (range 13-35 days) vs. 43 days (range 27-84 days; p < 0.001) and shorter neonatal intensive care unit stay: median 44 days (range 31-66 days) vs. 76 days (range 41-97 days; p < 0.001), with significantly lower rates of bronchopulmonary dysplasia, intraventricular hemorrhage, and acute renal failure, and significantly better neurological outcomes. DISCUSSION: Performing early ligation of symptomatic ductus arteriosus after unsuccessful pharmacological therapy in preterm neonates might lower complication rates and improve neurological outcome. Prospective randomized studies are needed to determine the optimal treatment. PMID- 24771724 TI - Fibrosis-related biomarkers and risk of total and cause-specific mortality: the cardiovascular health study. AB - Fibrosis has been implicated in diverse diseases of the liver, kidney, lungs, and heart, but its importance as a risk factor for mortality remains unconfirmed. We determined the prospective associations of 2 complementary biomarkers of fibrosis, transforming growth factor-beta (TGF-beta) and procollagen type III N terminal propeptide (PIIINP), with total and cause-specific mortality risks among community-living older adults in the Cardiovascular Health Study (1996-2010). We measured circulating TGF-beta and PIIINP levels in plasma samples collected in 1996 and ascertained the number of deaths through 2010. Both TGF-beta and PIIINP were associated with elevated risks of total and pulmonary mortality after adjustment for sociodemographic, clinical, and biochemical risk factors. For total mortality, the hazard ratios per doubling of TGF-beta and PIIINP were 1.09 (95% confidence interval (CI): 1.01, 1.17; P = 0.02) and 1.14 (CI: 1.03, 1.27; P = 0.01), respectively. The corresponding hazard ratios for pulmonary mortality were 1.27 (CI: 1.01, 1.60; P = 0.04) for TGF-beta and 1.52 (CI: 1.11, 2.10; P = 0.01) for PIIINP. Associations of TGF-beta and PIIINP with total and pulmonary mortality were strongest among individuals with higher C-reactive protein concentrations (P for interaction < 0.05). Our findings provide some of the first large-scale prospective evidence that circulating biomarkers of fibrosis measured late in life are associated with death. PMID- 24771726 TI - Myocardial infarction false alarm: initial electrocardiogram and cardiac enzymes. AB - OBJECTIVE: The objectives of this study were to determine the incidence of a myocardial infarction "false alarm" and evaluate the efficacy of the initial electrocardiogram and cardiac enzymes in diagnosing myocardial infarction in Malaysia. METHODS: We recruited patients who were admitted with suspected myocardial infarction from June to August 2008. The medical records of these patients were reviewed for the initial electrocardiogram, initial cardiac enzyme levels (creatinine kinase-MB and troponin T), and the final diagnosis upon discharge. The subjects were stratified into 2 groups: true myocardial infarction, and false alarm. RESULTS: 125 patients were enrolled in this study. Following admission and further evaluation, the diagnosis was revised from myocardial infarction to other medical conditions in 48 (38.4%) patients. The sensitivity and specificity of the initial ischemic electrocardiographic changes were 54.5% and 70.8%, respectively. Raised cardiac enzymes had a sensitivity of 44.3% and specificity of 95.8%. CONCLUSION: A significant proportion of patients in Malaysia are admitted with a false-alarm myocardial infarction. The efficacy of the electrocardiogram in diagnosing myocardial infarction in Malaysia was comparable to the findings of Western studies, but the cardiac enzymes had a much lower sensitivity. PMID- 24771727 TI - Heart rate variability in patients undergoing univentricular heart repair. AB - OBJECTIVE: Altered cardiac autonomic control may play a role in the long-term outcome of patients undergoing univentricular heart repair. This study was undertaken to compare bidirectional superior cavopulmonary anastomosis with preserved antegrade pulmonary blood flow and total cavopulmonary connection, with regard to their effects on cardiac autonomic activity, as measured by heart rate variability indices, prior to and early after surgery. METHODS: This prospective study included 46 patients (27 with bidirectional superior cavopulmonary anastomosis and 19 with total cavopulmonary connection. Heart rate variability was measured preoperatively and at 2 and 9 months postoperatively. The heart rate variability was measured by a 900-s electrocardiogram recording. Comparisons were drawn between and within groups, using standard statistical methods. RESULTS: All heart rate variability parameters were comparable in the 2 groups preoperatively. At the first follow-up, all heart rate variability parameters had decreased in both groups, but the decreases were not statistically significant. Between-group comparisons showed significantly higher parasympathetic and lower sympathetic tone in the bidirectional superior cavopulmonary anastomosis group. At the second follow-up, the bidirectional superior cavopulmonary anastomosis group had a significant increase in overall cardiac autonomic tone, and the total cavopulmonary connection group had a significant increase in parasympathetic tone, compared to the first follow-up. Between-group comparisons showed higher cardiac autonomic tone in the bidirectional superior cavopulmonary anastomosis group. CONCLUSION: Total cavopulmonary connection leads to a significant reduction in overall cardiac autonomic tone, compared to bidirectional superior cavopulmonary anastomosis with antegrade pulmonary blood flow. PMID- 24771728 TI - Is steel wire closure of sternotomy better than polyester suture closure? AB - INTRODUCTION: Median sternotomy is the preferred approach for open heart surgeries. The sternotomy incision is predominantly closed with either steel wire or polyester suture. The type of material used is primarily based on the surgeon's choice, and both materials achieve a good result. No prospective clinical study has been undertaken to evaluate differences in the incidence of wound infection and the degree of pain associated with both techniques. PATIENTS AND METHODS: Our randomized controlled double-blind study included 200 adults undergoing single-valve replacement. The technique of surgery, apart from the material used for sternal closure, was the same in both groups. Postoperatively, patients were analyzed for wound infection and wound pain based on the ASEPSIS score and Numeric Pain Rating Score, respectively. RESULTS: The polyester suture group had a significantly higher mean ASEPSIS score, indicating a higher incidence of wound infection, and more late wound complications. The polyester suture group also had a significantly higher mean pain score. The steel wire group had significantly higher mediastinal drain output in the first 48 h after surgery. CONCLUSION: The use of polyester suture for sternal closure in adult patients results in increased wound infection, wound pain, and late wound complications, but lower mediastinal drain output. PMID- 24771729 TI - Radial artery compression in incomplete palmar arch for radial artery harvesting. AB - BACKGROUND: incomplete palmar arch causing inadequate collateral flow is considered a contraindication for harvesting radial artery as a conduit for coronary artery bypass grafting. The objective of this pilot study was to assess whether iatrogenic radial artery compression could improve collateral circulation in the nondominant hand in such patients. METHODS: 5 patients scheduled for coronary artery bypass, with incomplete palmar arch suspected by an abnormal modified Allen's test and confirmed by dynamic color Doppler sonography, were included in the study. The flow in branches of the radial artery (superficial palmar branch and dorsal digital artery of the thumb) was measured by dynamic color Doppler sonography. Intermittent radial artery compression was applied to the nondominant hand, using a radial compression device for 15 days, and the tests were repeated to assess changes in radial artery branch flow. RESULTS: flow in the superficial palmar branch was increased in 3 patients, with a significant increase in 2 of them. The 3 patients in whom the dorsal digital artery of the thumb could be seen on precompression Doppler, all had substantially increased flow. The increase in flow assessed by the modified Allen's test was statistically significant, but the flow change measured by Doppler sonography did not reach statistical significance. CONCLUSIONS: collaterals developed during 15 days of intermittent radial artery compression. The collateral development led to increased flow in the radial artery branches. A larger sample is required to confirm the results. PMID- 24771730 TI - Left atrial reduction in modified maze procedure with concomitant mitral surgery. AB - BACKGROUND: An association between mitral valve disease and atrial fibrillation is common. Modifications of energy sources have simplified surgical ablation. Left atrial size reduction should improve outcomes of the maze operation. METHODS: Between 2004 and 2011, 236 patients with permanent atrial fibrillation and mitral valve disease underwent mitral valve surgery and modified biatrial radiofrequency ablation. The study evaluated cardiac rhythm, atrial size, atrial contractility, and survival. RESULTS: The mitral valve was repaired in 88 (37.3%) patients and replaced in 148 (62.7%). The left atrium was reduced in 192 (81.4%) patients: 31 (13.1%) had posterior wall reduction and 161 (68.2%) had right lateral and posterior wall resection. The 30-day mortality was 4.2% (10/236). The median follow-up was 41 months. Actuarial freedom from atrial fibrillation at 1 year and last follow-up was 87.7% and 84.9%, respectively. Predictors of recurrence were preoperative left atrial diameter >60 mm (p = 0.002), postoperative diameter >50 mm (p < 0.001), atrial fibrillation on day 7 (p < 0.001), and technique of reduction (posterolateral/posterior) in patients with atrial size >60 mm (p = 0.017). Atrial fibrillation during follow-up (p = 0.002) and age >60 years (p = 0.003) were significant predictors of poorer survival. During 5-year follow-up, non-atrial fibrillation patients survived significantly longer than atrial fibrillation patients (p = 0.002). CONCLUSIONS: Radiofrequency ablation is an effective option for treatment of permanent atrial fibrillation concomitant with mitral valve surgery. Atrial reduction to <50 mm improves success. Elimination of atrial fibrillation significantly prolongs patient survival. PMID- 24771731 TI - Does discharge hemoglobin affect medium-term survival after coronary bypass? AB - BACKGROUND: the effect of discharge hemoglobin on survival of patients undergoing isolated coronary artery bypass grafting is unknown. Blood transfusion frequently confounds the issue. METHODS: 4682 consecutive patients undergoing isolated coronary artery bypass were studied. Univariate and multivariate analyses were performed to identify whether discharge hemoglobin was an independent risk factor determining survival after isolated coronary artery bypass. The analysis was complemented with a neuronal network. RESULTS: univariate analysis identified discharge hemoglobin (p = 0.01) and blood transfusion (p < 0.0001) as significant factors affecting survival. Multivariate analysis identified age (p < 0.0001) ejection fraction (p < 0.0001), dialysis (p < 0.0001), peripheral vascular disease (p = 0.001), preoperative hemoglobin (p = 0.01), and blood transfusion (p = 0.0002) as significant factors determining survival. Neuronal network analysis confirmed the lack of importance of hemoglobin on discharge as a factor determining survival. CONCLUSIONS: the discharge hemoglobin level does not affect medium-term survival. PMID- 24771732 TI - Prosthetic reconstruction of bicuspid pulmonary valve in tetralogy of Fallot. AB - BACKGROUND: Various techniques have been described for preserving pulmonary valve function in tetralogy of Fallot repair. In selected substrates, the pulmonary valve can be bicuspidized and preserved using polytetrafluoroethylene pericardial membrane. METHODS: This study was a retrospective review of 20 patients aged 11 months to 31 years with tetralogy of Fallot and a bicuspid pulmonary valve (with anteroposterior cusps) who underwent intracardiac repair from August 2010 to January 2013. The anterior cusp was augmented using polytetrafluoroethylene pericardial membrane to preserve the valve hinge. A transannular patch was used in all cases. Data relating to surgical outcome, intensive care unit course, pulmonary regurgitation, and right ventricular outflow tract gradient were collected. RESULTS: There was no mortality. Predischarge pulmonary regurgitation was <=grade 2 in 18 (90%) patients. One patient had an outflow gradient >40 mm Hg. On follow-up of 3-24 months, there was no increase in outflow gradient; 18.7% had progression of pulmonary regurgitation. CONCLUSION: In selected substrates, this technique is associated with minimization of pulmonary regurgitation and an excellent functional outcome. The utility of this technique needs to be validated over a longer time scale in a larger series. PMID- 24771733 TI - Treatment outcomes of pneumothorax with chronic obstructive pulmonary disease. AB - BACKGROUND: Coexisting pulmonary fibrosis and emphysema in the same individual has received increased attention. We retrospectively investigated treatment outcomes of secondary spontaneous pneumothorax in chronic obstructive pulmonary disease patients with both pulmonary fibrosis and emphysema. METHODS: Among 362 consecutive secondary spontaneous pneumothorax patients treated at our hospital from 2003 to 2012, 58 with emphysema-dominant chronic obstructive pulmonary disease (all elderly men with a smoking history) were enrolled and divided into 2 groups based on computed tomography images: emphysema alone (n = 51) and coexisting emphysema and pulmonary fibrosis (n = 7). The clinical characteristics and mortality were compared between the 2 groups. RESULTS: There was no significant difference in the recurrence rate after nonsurgical treatment. No patient died of pneumothorax-related complications, but one of 2 with pulmonary fibrosis who underwent surgery died of a postoperative respiratory complication. The mortality rate from respiratory failure during follow-up was significantly higher in the group with pulmonary fibrosis (6/7) than in the group without pulmonary fibrosis (11/51, p = 0.002). The median survival was 0.8 years in the group with pulmonary fibrosis vs. and 5.4 years in the group without pulmonary fibrosis. CONCLUSIONS: The coexistence of pulmonary fibrosis and emphysema on computed tomography images may represent a predictor of respiratory mortality in elderly chronic obstructive pulmonary disease patients with secondary spontaneous pneumothorax. Because of the potential risk of respiratory failure, we recommend nonsurgical treatment for secondary spontaneous pneumothorax in chronic obstructive pulmonary disease patients with these radiological features. PMID- 24771734 TI - Trends and practice patterns in the management of thoracic empyema. AB - BACKGROUND: This study explored the modern treatment of thoracic empyema. We evaluated outcomes of various operative approaches in both academic and nonacademic institutions. METHODS: We queried the Society of Thoracic Surgeons National Database for patients undergoing thoracic procedures with a primary diagnosis of empyema between 2009 and 2011. We compared treatment outcomes of patients having procedures at academic (n = 1101, 28.3%) and nonacademic (n = 2790, 71.7%) medical centers. RESULTS: Empyema treatments recorded in the database included tube thoracostomy (n = 325, 8.4%), video-assisted thoracic surgery (n = 1992, 51.2%), and thoracotomy (n = 1574, 40.5%). Academic centers had higher rates of treatment by thoracostomy (13.8% vs. 6.2%), similar treatment rates of video-assisted thoracic surgery (49.9% vs. 51.7%), and lower rates of thoracotomy (36.3% vs. 42.1%) compared to nonacademic centers (p < 0.001). Academic centers treated almost twice as many complicated empyemas with fistulas (11.4% vs. 6.5%, p < 0.001). Postoperative length of stay was higher in the academic centers (interquartile range 5-13 vs. 4-11 days, p = 0.001), while mechanical ventilation >48 h was more frequent in the nonacademic centers (7.6% vs. 4.4%, p = 0.013). CONCLUSION: Surgeons in both academic and nonacademic centers use selective surgical approaches for treatment of thoracic empyema, depending on the clinical condition of the patient, with fairly equivalent results across all procedure types. PMID- 24771735 TI - Aspergillus colonization in patients with bronchogenic carcinoma. AB - BACKGROUND: Aspergillus antigens such as galactomannan antigen, a cell wall polysaccharide, can be detected in patient's serum or bronchoalveolar lavage. To study the prevalence of Aspergillus infection in patients with bronchogenic carcinoma, we measured galactomannan antigen in serum and bronchoalveolar lavage samples of patients with bronchogenic carcinoma. METHODS: The study was conducted on 45 bronchogenic carcinoma patients. The diagnosis of lung cancer was confirmed by bronchoscopy, histopathological and radiological examinations. Bronchoalveolar lavage fluid collected from each patient by fiberoptic bronchoscopy was subjected to direct microscopy and culture on Sabouraud's dextrose agar and Czapek-Dox agar, and Aspergillus galactomannan antigen was measured in serum and bronchoalveolar lavage samples. RESULTS: The majority of patients were male (93.3%) in the age group 51-60 years, 88.9% were addicted to gutka chewing, and 82.1% were addicted to smoking. Most patients complained of cough (73%) and shortness of breath (51.1%). Squamous cell carcinoma (64.4%) was the most common malignancy, followed by adenocarcinoma (13.3%). On culture of bronchoalveolar lavage samples, 35.5% showed growth of Aspergillus spp. (Aspergillus fumigatus in 17.8%, Aspergillus flavus in 13.3%, and Aspergillus niger in 4.4%). Galactomannan antigen was detected in 58.3% of bronchoalveolar lavage samples and 47.2% of serum samples. CONCLUSIONS: There is a high prevalence of aspergillosis in patients with lung carcinoma, especially among smokers and gutka chewers. PMID- 24771736 TI - Right atrial obstruction due to cardiac extension of hepatocellular carcinoma. AB - Hepatocellular carcinoma is fatal and has a marked propensity for vascular invasion. However, tumor thrombi rarely occur in the right atrium. A 72-year-old man was admitted with dyspnea and disturbed consciousness. Abdominal computed tomography and echocardiography showed a huge tumor thrombus in the inferior vena cava and the right atrium. The tumor thrombus was surgically removed to treat the hemodynamic compromise. The patient underwent transcatheter arterial chemoembolization postoperatively and survived for 6 months. PMID- 24771737 TI - Single coronary artery anomaly causing ischemic mitral insufficiency. AB - Single coronary artery anomaly is rarely seen, and although it can present with sudden death, chest pain, arrhythmia, myocardial infarction, or congestive heart failure, it can also be asymptomatic. We describe the case of a 58-year-old man with single coronary artery anomaly in whom the coronary artery stemmed from the left coronary sinus and caused ischemic mitral insufficiency due to left anterior descending artery stenosis. He underwent successful mitral valve repair and coronary bypass. PMID- 24771738 TI - Tailor-made approach for quadricuspid aortic valve repair. AB - We describe the successful repair of a quadricuspid aortic valve in a 64-year-old man after attempted tricuspidization via detachment of a commissure of the accessory cusp failed. Bicuspidization via detachment of another commissure was successful. Quadricuspid aortic valve repair by bicuspidization, which surgically transforms 3 cusps into 1, may be a simple and reproducible technique if tricuspidization repair has failed. PMID- 24771739 TI - Nondilated abdominal aortic rupture caused by acute type B aortic dissection. AB - A 31-year-old man presented with sudden abdominal pain. Computed tomography showed type B aortic dissection and a huge retroperitoneal hematoma. Accordingly, we diagnosed rupture of the abdominal aorta which was of almost normal caliber. Emergency open abdominal aortic repair was performed successfully. Pathology of the aortic wall revealed diffuse medial degeneration with severe elastin fragmentation, but gene analysis found no gene mutation that could lead to a connective tissue disorder. PMID- 24771740 TI - Acquired coronary-to-bronchial artery fistula after two valve surgeries. AB - A 62-year-old woman with Takayasu arteritis and 2 prior aortic valve replacements, was admitted with unstable angina. Computed tomographic angiography showed a newly developed right coronary artery-to-right bronchial artery fistula. Because of dense aortic calcification, catheter embolization was undertaken, which was successful. We believe the acquired coronary artery fistula developed after her uneventful second aortic valve surgery, due to inevitable trauma to the mediastinum and ascending aorta, and partly due to her underlying Takayasu arteritis. PMID- 24771741 TI - Infected pseudoaneurysm following a modified Blalock-Taussig shunt procedure. AB - A 3-year-old boy with pulmonary atresia with ventricular septal defect, who had undergone placement of a modified Blalock-Taussig shunt, presented with a 1-week history of high fever. Computed tomography showed a pseudoaneurysm at the anastomosis between the right brachiocephalic artery and the graft. After intravenous antibiotic therapy, the pseudoaneurysm and infected graft were resected through a median sternotomy. This report describes successful management of a potentially fatal complication following placement of a modified Blalock Taussig shunt. PMID- 24771742 TI - Successful surgical outcome of infected aneurysmal drug-coated stent endocarditis. AB - A 52-year-old man developed pyrexia after primary angioplasty following anterior myocardial infarction Noninvasive evaluation revealed staphylococcal septicemia with suspicion of an aneurysm or abscess at the stented segment. Coronary angiography confirmed the presence of a large aneurysm. The infected left anterior descending artery aneurysm was de-roofed and ligated, and a saphenous vein bypass graft was placed, with an excellent outcome. PMID- 24771743 TI - Pulmonary embolism and tuberculosis. AB - Tuberculosis has a high prevalence in Tunisia, but pulmonary embolism is rarely reported in Mycobacterium tuberculosis infection. We describe 3 cases of pulmonary embolism associated with severe pulmonary tuberculosis. Pulmonary embolism occurred within 2 to 13 days of pulmonary tuberculosis diagnosis. Clinical, bacteriological, and radiological evolutions were noted within 6 months for pulmonary tuberculosis, but controlling the international normalized ratio was difficult in 2 cases, and low-molecular-weight heparin was prescribed for 6 months in one case. The association between tuberculosis and pulmonary embolism is rare, but it should be systematically investigated, particularly in those with severe pulmonary or disseminated tuberculosis. PMID- 24771744 TI - Second relapse of solitary fibrous tumor within 20 years of initial resection. AB - A 64-year-old woman presented with a sessile solitary fibrous tumor in the right thoracic cavity. She had undergone 2 solitary fibrous tumor resections 7 and 20 years previously. The latest histological findings were identical to the previous, and pathologically benign. However, we clinically classified the tumors as malignant because of repeated relapse. The tumor and extrapulmonary structures should be resected at the time of recurrence. PMID- 24771745 TI - Discoid lupus and pulmonary blastoma in an elderly patient. AB - Discoid lupus is an autosomal disease that has not been found to predispose to cancer. Pulmonary blastoma is a rare primary lung tumor with a poor prognosis, which commonly presents at a younger age than non-small-cell lung carcinoma. We report a rare case of pulmonary blastoma in a 62-year-old man with discoid lupus who presented with chronic cough and pleuritic pain. The 5.3-cm tumor was located in the left upper lobe, invaded the visceral pleura, and adhered to the parietal pleura. The patient underwent a left upper lobectomy and chest wall excision, with adjuvant chemotherapy and radiotherapy. PMID- 24771746 TI - Huge intrathoracic goiter in an asymptomatic patient. PMID- 24771747 TI - Ascending aortic aneurysm in adult with patent ductus arteriosus. PMID- 24771748 TI - Four lobes of the right lung. PMID- 24771749 TI - Delayed aortic injury caused by sharp rib fracture. PMID- 24771750 TI - Gossypiboma. PMID- 24771751 TI - Effort angina with coronary-pulmonary and bronchial-pulmonary artery fistulae. PMID- 24771753 TI - The role of the emphysema multidisciplinary team in a successful lung volume reduction surgery programme?. AB - OBJECTIVES: Lung volume reduction surgery (LVRS) for advanced emphysema is well established, with strong evidence from the National Emphysema Treatment Trial. However, there is still reluctance to offer the procedure, and many have looked for alternative, unproven treatments. The multidisciplinary approach has been well established in treatment of lung cancer and, more recently, in coronary artery surgery. We reviewed our practice to validate the role of our multidisciplinary team approach in our LVRS programme. METHODS: Our multidisciplinary approach employs respiratory physicians, radiologists and surgeons involved in case selection, who meet on a regular basis. Cases are selected on the basis of clinical presentation, imaging (radionuclide lung perfusion and computerized tomography) and respiratory physiology. Retrospective analysis of prospectively collected data on 633 patients referred for lung volume reduction surgery between July 1995 and July 2013. RESULTS: Six hundred and thirty-three patients (422 male) were referred for LVRS, of whom 253 [178 male; median age 61 years (range 37-79 years)] underwent 292 LVRS procedures.There were 268 video-assisted thoracoscopic surgical procedures, of which 13 were one-stage bilateral procedures and 37 required a staged second side. Overall median hospital stay was 13 (4-197) days, during which 11 patients died. Prolonged hospital stay was associated with increasing age and with duration of air leak, which in turn was associated with diffusion capacity and forced expiratory volume in 1 s. CONCLUSIONS: The outcomes of a successful LVRS programme are not only dependent on good surgical technique and post-operative care. Case selection and work-up by a dedicated multidisciplinary approach for emphysema patients plays an invaluable and integral part in an LVRS programme. PMID- 24771754 TI - Splenic haematoma complicating infective endocarditis: role of preoperative splenic artery embolization. AB - Splenic involvement is not uncommon among patients with infective endocarditis (IE). These patients are susceptible to massive intra-abdominal haemorrhage resulting either from splenic rupture complicating endocarditis or from complication of major splenectomy. We report a patient with splenic haematoma complicating IE with progressive cardiac decompensation and valve destruction warranting early surgery. Preoperative splenic artery embolization was successfully performed and the patient subsequently received life-saving cardiac valvular replacement surgery. The favourable outcome of our patient depicts a pivotal role of preoperative splenic artery embolization in haemodynamically compromised patients undergoing cardiac valvular surgery for IE. PMID- 24771755 TI - A volume buffer capacity device dynamically reduces excessive venous line pressure and arterial gaseous embolic load during minimized cardiopulmonary bypass. PMID- 24771756 TI - Reply to Simons and Weerwind. PMID- 24771757 TI - Ross procedure: is the root replacement technique superior to the sub-coronary implantation technique? Long-term results. AB - There is controversy over the use of the Ross procedure with regard to the sub coronary and root replacement technique and its long-term durability. A systematic review of the literature may provide insight into the outcomes of these two surgical subvariants. A systematic review of reports between 1967 and February 2013 on sub-coronary and root replacement Ross procedures was undertaken. Twenty-four articles were included and divided into (i) sub-coronary technique and (ii) root replacement technique. The 10-year survival rate for a mixed-patient population in the sub-coronary procedure was 87.3% with a 95% confidence interval (CI) of 79.7-93.4 and 89.1% (95% CI, 85.3-92.1) in the root replacement technique category. For adults, it was 94 vs 95.3% (CI, 88.9-98.1) and in the paediatric series it was 90 vs 92.7% (CI, 86.9-96.0), respectively. Freedom from reoperation at 10 years was, in the mixed population, 83.3% (95% CI, 69.9-93.4) and 93.3% (95% CI, 89.4-95.9) for sub-coronary versus root replacement technique, respectively. In adults, it was 98 vs 91.2% (95% CI, 82.4-295.8), and in the paediatric series 93.3 vs 92.0% (95% CI, 86.1-96.5) for sub-coronary versus root replacement technique, respectively. The Ross procedure arguably has satisfactory results over 5 and 10 years for both adults and children. The results do not support the advantages of the sub-coronary technique over the root replacement technique. Root replacement was of benefit to patients undergoing reoperations on neoaorta and for long-term survival in mixed series. PMID- 24771758 TI - Right and left ventricular mechanics and interaction late after balloon valvoplasty for pulmonary stenosis. AB - AIMS: This study sought to explore right (RV) and left ventricular (LV) mechanics and ventricular-ventricular interaction in adolescents and young adults late after percutaneous balloon pulmonary valvoplasty (PBPV) for valvar pulmonary stenosis (PS). METHODS AND RESULTS: Potential late effects of PS despite PBPV on cardiac mechanics have not been well defined. Thirty-one patients aged 20.2 +/- 7.6 years were studied at 18 +/- 6 years after PBPV. Ventricular myocardial deformation was determined using speckle tracking echocardiography, while RV and LV volumes and ejection fraction as well as LV systolic dyssynchrony index were assessed by three-dimensional echocardiography. The results were compared with those of 30 controls. Pulmonary regurgitation, mostly trivial to mild, was present in 90% (28/31) of patients. Compared with controls, patients had significantly greater RV end-diastolic (P < 0.001), RV end-systolic (P < 0.001), and LV end-systolic (P = 0.04) volumes as well as lower LV ejection fraction (P < 0.001). For deformation, patients had significantly reduced RV longitudinal systolic strain (P = 0.004), decreased LV circumferential systolic strain (P < 0.001), and strain rate (P = 0.001) as well as greater LV mechanical dyssynchrony (P < 0.001). In patients, RV end-diastolic and end-systolic volumes correlated with LV circumferential strain (r = -0.47, P = 0.008 and r = -0.36, P = 0.049, respectively) and dyssynchrony (r = 0.53, P = 0.002 and r = 0.49, P = 0.005, respectively). Patients who had PBPV at age <=1 year had ventricular deformation indices similar to those who had interventions beyond 1 year. CONCLUSION: Impaired RV and LV mechanics and adverse ventricular-ventricular interaction occur in adolescents and young adults late after balloon valvoplasty for isolated valvar PS. PMID- 24771759 TI - Comparison of outcomes using diced cartilage with or without tensor fascia latae wrapping in rabbits. AB - BACKGROUND: Diced cartilage has been associated with several advantages and rewarding results, leading to its widespread application in various forms in rhinoplasty, but the outcomes of diced cartilage with and without tensor fascia latae wrapping have not been widely reported in evidence-based articles. OBJECTIVES: The authors compared changes in weight, size, and histology of both bare and fascia-wrapped diced cartilage in rabbits as a model for human surgical outcomes. METHODS: One auricle from each of 15 rabbits was divided into 2 pieces, and both samples were diced. The tensor fascia latae of the rabbit was wrapped around 1 cartilage specimen from each rabbit (group A specimen); the other specimen received no wrapping (group B specimen). A group A specimen and a group B specimen were implanted into separate subcutaneous pockets in each rabbit. After 3 months, samples were removed from the recipient beds and weighed to compare pre- and postoperative weights. All specimens were examined for evidence of cartilage viability by histologic methods. RESULTS: There was a significant decrease in the weight of cartilage in group A. A nonsignificant weight increase was observed in group B. Histologic analyses of 5 parameters revealed no significant differences between the 2 groups, except for a significantly greater amount of new cartilage formation in group B. CONCLUSIONS: Any type of wrapping around diced cartilage may inhibit its access to surrounding nutrients. Dicing increases the absorption surface, which may result in some overgrowth, but wrapping may have a negative impact on the viability of the diced cartilage. LEVEL OF EVIDENCE: 4. PMID- 24771762 TI - The rehabilitation engineering research center for the advancement of cognitive technologies. AB - Barring few exceptions, allied health professionals, engineers, manufacturers of assistive technologies (ATs), and consumer product manufacturers have developed few technologies for individuals with cognitive impairments (CIs). In 2004, the National Institute on Disability Rehabilitation Research (NIDRR) recognized the need to support research in this emergent field. They funded the first Rehabilitation Engineering Research Center for the Advancement of Cognitive Technologies (RERC-ACT). The RERC-ACT has since designed and evaluated existing and emerging technologies through rigorous research, improving upon existing AT devices, and creating new technologies for individuals with CIs. The RERC-ACT has contributed to the development and testing of AT products that assist persons with CIs to actively engage in tasks of daily living at home, school, work, and in the community. This article highlights the RERC-ACT's engineering development and research projects and discusses how current research may impact the quality of life for an aging population. PMID- 24771763 TI - Dementia and cognitive impairment in patients with Parkinson's disease from India: a 7-year prospective study. AB - Depression and cognitive impairment are frequent manifestations in Parkinson's disease (PD). Although a few longitudinal studies have reported on depression and dementia in PD, there is a yet a lack of such studies in India. This 7-year longitudinal study is a hospital-based prospective case (n = 250)-control (n = 280) study. In all, 36.8% had PD with no cognitive impairment (PD-Normal), 27.2% of the patients with PD were affected by dementia (PDD), and 36% of the remaining patients with PD had mild cognitive impairment (PD-MCI) at baseline. After 7 years of evaluation, 32 new patients, 12 patients from the PD-MCI group and 9 patients from the PD-Normal group, were diagnosed with dementia. The 7-year prevalence rate for dementia was estimated to be 49.28%. In the Indian population, an early onset of dementia is noted among patients with PD, with the age of onset being less than 55 years. Patients with early-onset PDD showed depression symptoms that differed significantly from the controls of the same age group. There was a major difference in verbal fluency, word list recall, constructional praxis and recall, word list recognition, abridged Boston Naming Test, word list memory with repetition, and Mini-Mental State Examination between PD-MCI and PDD groups. Hallucinations before baseline (odds ratio [OR] = 4.427, 95% confidence interval [CI] = 2.122-9.373), akinetic/tremor dominancy (OR = 0.380, 95%CI = 0.149-0.953), and asymmetrical disease onset (OR = 0.3285, 95%CI = 0.1576-0.685) can be considered as risk factors for patients with dementia. Patients with early-onset PD might be more prone to complex depression and dementia. As the disease progresses, akinetic-dominant PD, early hallucinations, and asymmetrical disease onset are the potential risk factors for the development of dementia in patients with PD. PMID- 24771764 TI - Effects of tracking technology on daily life of persons with dementia: three experimental single-case studies. AB - OBJECTIVES: To investigate the effects of using tracking technology on independent outdoor activities and psychological well-being in 3 persons with dementia (PwDs) and their spouses. METHODS: Three experimental single-case studies with an A1B1A2B2 design. The intervention entailed access to a passive positioning alarm and technical support. Continual daily measures of independent outdoor activities among PwDs' and spouses' worries about these activities were made during all phases. RESULTS: Access to a tracking technology consistently increased the independent outdoor activities of 2 PwDs. One of the spouses consistently reported decreased worry during B phases, another's worry decreased only in B2, and the third showed little variability in worrying across all phases. CONCLUSION: Tracking technology may support PwDs to engage in independent outdoor activities and decrease spouses' worries; however, randomized controlled group studies are needed to investigate whether these results can be replicated on a group level. PMID- 24771765 TI - Brassinosteroids control root epidermal cell fate via direct regulation of a MYB bHLH-WD40 complex by GSK3-like kinases. AB - In Arabidopsis, root hair and non-hair cell fates are determined by a MYB-bHLH WD40 transcription factor complex and are regulated by many internal and environmental cues. Brassinosteroids play important roles in regulating root hair specification by unknown mechanisms. Here, we systematically examined root hair phenotypes in brassinosteroid-related mutants, and found that brassinosteroid signaling inhibits root hair formation through GSK3-like kinases or upstream components. We found that with enhanced brassinosteroid signaling, GL2, a cell fate marker for non-hair cells, is ectopically expressed in hair cells, while its expression in non-hair cells is suppressed when BR signaling is reduced. Genetic analysis demonstrated that brassinosteroid-regulated root epidermal cell patterning is dependent on the WER-GL3/EGL3-TTG1 transcription factor complex. One of the GSK3-like kinases, BIN2, interacted with and phosphorylated EGL3, and EGL3s mutated at phosphorylation siteswere retained in hair cell nuclei. BIN2 phosphorylated TTG1 to inhibit the activity of the WER-GL3/EGL3-TTG1 complex. Thus, our study provides insights into the mechanism of brassinosteroid regulation of root hair patterning. PMID- 24771766 TI - Filament formation by metabolic enzymes is a specific adaptation to an advanced state of cellular starvation. AB - One of the key questions in biology is how the metabolism of a cell responds to changes in the environment. In budding yeast, starvation causes a drop in intracellular pH, but the functional role of this pH change is not well understood. Here, we show that the enzyme glutamine synthetase (Gln1) forms filaments at low pH and that filament formation leads to enzymatic inactivation. Filament formation by Gln1 is a highly cooperative process, strongly dependent on macromolecular crowding, and involves back-to-back stacking of cylindrical homo decamers into filaments that associate laterally to form higher order fibrils. Other metabolic enzymes also assemble into filaments at low pH. Hence, we propose that filament formation is a general mechanism to inactivate and store key metabolic enzymes during a state of advanced cellular starvation. These findings have broad implications for understanding the interplay between nutritional stress, the metabolism and the physical organization of a cell. PMID- 24771767 TI - Genetic interactions affecting human gene expression identified by variance association mapping. AB - Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ~70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits.DOI: http://dx.doi.org/10.7554/eLife.01381.001. PMID- 24771769 TI - In defense of qualitative research. PMID- 24771770 TI - Periodontal and general health: clinical recommendations. AB - The purpose of Linking Research to Clinical Practice is to present evidence based information to clinical dental hygienists so that they can make informed decisions regarding patient treatment and recommendations. Each issue will feature a different topic area of importance to clinical dental hygienists with A BOTTOM LINE to translate the research findings into clinical application. PMID- 24771771 TI - Preventive services program: a model engaging volunteers to expand community based oral health services for children. AB - PURPOSE: This paper describes the Preventive Services Program (PSP), a community based oral health program model which engages volunteers to provide preventive services and education for underserved children in Missouri. In 2006, the Missouri Department of Health and Senior Services created a program for children designed to use a systems approach for population-based prevention of oral disease. Currently, 5 part-time dental hygienists serve as Oral Health Program Consultants to work with the citizens of a community to engage dentists, dental hygienists, parents and other interested stakeholders in the activities of the program. Dental volunteers evaluate oral health and disease in the community's children and facilitate referrals for dental care. Other volunteers apply fluoride varnish and provide educational services to the children. PROGRAM OUTCOMES: In 2006, 273 volunteer dentists and dental hygienists and 415 community volunteers provided oral screenings, oral health education, 2 fluoride varnish applications and referral for unmet dental care for 8,529 children. In 2011, 775 volunteer dentists and dental hygienists and 1,837 other community volunteers provided by PSP services to nearly 65,000 children. CONCLUSION: It has been demonstrated that when the local citizens take responsibility for their own needs that a sustainable and evidence-based program like PSP is possible. Guidelines which provide criteria for matching models with the specific community characteristics need to be generated. Furthermore, a national review of successful program models would be helpful to those endeavoring to implement community oral health program. PMID- 24771772 TI - Adjunctive use of the diode laser in non-surgical periodontal therapy: exploring the controversy. AB - PURPOSE: Despite the controversy regarding clinical efficacy, dental hygienists use the diode laser as an adjunct to non-surgical periodontal therapy. The technique to maximize successful laser therapy outcome is controversial as well. The purpose of this review is to explore the scientific foundation of the controversy surrounding the use of the diode laser as an adjunct to non-surgical periodontal therapy. Further, this paper addresses the weaknesses in study design, the heterogeneity of methodology in the published clinical studies, especially the laser parameters, and how these issues impact the collective clinical and microbial data, and thus conclusions regarding clinical efficacy. Evaluation of the literature identifies possible mechanisms that could contribute to the varied, often conflicting results among laser studies that are the foundation of the controversy surrounding clinical efficacy. These mechanisms include current paradigms of periodontal biofilm behavior, tissue response to laser therapy being dependent on tissue type and health, and that the successful therapeutic treatment window is specific to the target tissue, biofilm composition, laser wavelength, and laser energy delivered. Lastly, this paper discusses laser parameters used in the various clinical studies, and how their diversity contributes to the controversy. Although this review does not establish clinical efficacy, it does reveal the scientific foundation of the controversy and the need for standardized, well designed randomized controlled clinical trials to develop specific guidelines for using the laser as an adjunct to non surgical periodontal therapy. Using evidence-based laser guidelines would allow dental hygienists to provide more effective non-surgical periodontal care. PMID- 24771768 TI - Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. AB - Resveratrol has beneficial effects on aging, inflammation and metabolism, which are thought to result from activation of the lysine deacetylase, sirtuin 1 (SIRT1), the cAMP pathway, or AMP-activated protein kinase. In this study, we report that resveratrol acts as a pathway-selective estrogen receptor-alpha (ERalpha) ligand to modulate the inflammatory response but not cell proliferation. A crystal structure of the ERalpha ligand-binding domain (LBD) as a complex with resveratrol revealed a unique perturbation of the coactivator binding surface, consistent with an altered coregulator recruitment profile. Gene expression analyses revealed significant overlap of TNFalpha genes modulated by resveratrol and estradiol. Furthermore, the ability of resveratrol to suppress interleukin-6 transcription was shown to require ERalpha and several ERalpha coregulators, suggesting that ERalpha functions as a primary conduit for resveratrol activity.DOI: http://dx.doi.org/10.7554/eLife.02057.001. PMID- 24771773 TI - Analysis of patient factors impacting duration of periodontal maintenance appointments: an exploratory study. AB - PURPOSE: The periodontal maintenance (PM) appointment requires varying amounts of time and is absolutely essential for long-term successful periodontal therapy. This study assessed time requirements for PM and relative contribution of patient level factors such as oral health status, complex medical history, maintenance compliance and demographics. METHODS: One hundred patients receiving PM in a graduate periodontal program at a dental school participated in this cross sectional, observational study and components of their PM were timed in minutes/seconds. Descriptive data were obtained for average total-time required for PM and relative time for each treatment component. Hierarchical multiple linear regression determined what patient-level factors demonstrated the greatest impact on total-time to complete PM. RESULTS: The average PM appointment interval, with radiographs, was 1 hour, 16 minutes, 23 seconds (SD 19:25 minutes). When cubicle preparation and disinfection was included, the total-time was 1 hour, 24 minutes, 31 seconds (+/-19:32 minutes). Multiple regression showed that BOP, dentist examinations, number of carious lesions and/or restorative defects, number of teeth/implants, taking radiographs, female gender and deposit aggregate (supragingival and subgingival calculus and stain) were significant predictors of total PM duration and explained 57% variance (p<0.05, R2=0.569). CONCLUSION: Based on the average comprehensive PM appointment time of 1:16 minutes, the typical appointment of 60 minutes is insufficient to achieve the goals of a comprehensive PM in this academic clinic setting. These findings suggest the need to utilize more customized models for scheduling PM in order to achieve time allocations that are individualized to address specific patients' needs. PMID- 24771775 TI - Subjective pain perception during calculus detection with use of a periodontal endoscope. AB - PURPOSE: Periodontal endoscopes are relatively new to the dental field. The purpose of this study was to determine the amount of pain reported by subjects with periodontal disease after experiencing the use of a periodontal endoscope compared with the use of a periodontal probe during calculus detection. METHODS: A total of 30 subjects with at least 4 sites of 5 to 8 mm pocket depths were treated with scaling and root planing therapy in a split-mouth design. The 2 quadrants were randomly assigned to either S/RP with tactile determination of calculus using an 11/12 explorer, or S/RP treatment with endoscopic detection of calculus. Each subject's pain experience was determined by via a Heft-Parker Visual Analogue Scale (VAS), which measured perceived pain level during periodontal probing and during subgingival visualization via endoscopy. Since subjects expressing some level of dental anxiety generally express increased levels of pain, a pre-treatment survey was also given to determine each subject's level of dental anxiety in order to eliminate dental anxiety as a confounding factor in determining the expressed level of pain. RESULTS: The level of perceived pain was significantly lower with the periodontal endoscope versus the probe (mean VAS 33.0 mm versus 60.2 mm, p<0.0001). Subjects who indicated some level of dental anxiety did express increased pain levels, but these levels were not statistically significant. CONCLUSION: Subjects did not find the periodontal endoscope to elicit significant anxiety or pain during subgingival visualization. PMID- 24771776 TI - Evaluation of resources for an interactive infection control instructional program. AB - PURPOSE: To evaluate educational resources used in developing and implementing an interactive infection control instructional program for first year (n=26) and second year (n=26) dental hygiene students in a baccalaureate program. METHODS: An educator's toolkit was used to develop online and interactive learning modalities for teaching infection control content. Descriptive statistics were used to evaluate responses on a post instruction opinion survey on a 5-point Likert-type scale. RESULTS: Following the instructional program, most students reported on an opinion survey that they understood infection control principles (92% first year, 100% second year), felt prepared to work safely in clinic (96% first year, 100% second year) and liked working at their own pace (88% first year, 100% second year). First year students valued the online learning components and were less favorable toward supplemental textbook readings and the limited time to complete all 10 modules. Most second year students valued the interactive workshop but did not take the time to complete the online videos and did not watch all of them. Seventy-nine percent of second year students (n=20) preferred the interactive workshop method over traditional lecture instruction completed during their first year. CONCLUSION: This paper describes 1 institution's process of developing and implementing an infection control instructional program utilizing an educator's toolkit. PMID- 24771774 TI - Oral health-related complications of breast cancer treatment: assessing dental hygienists' knowledge and professional practice. AB - PURPOSE: Approximately 200,000 women are diagnosed with breast cancer in the U.S. every year. These patients commonly suffer from oral complications of their cancer therapy. The purpose of this study was to assess dental hygienists' knowledge and professional practice related to providing care for breast cancer patients. METHODS: A pre-tested 43-item survey was mailed to a random sample of 10% of all licensed dental hygienists in the state of Michigan (n=962). The survey assessed the respondents' knowledge of potential oral complications of breast cancer treatments as well as their professional practices when treating patients with breast cancer. After 2 mailings, the response rate was 37% (n=331). Descriptive and inferential analyses were conducted using SAS. RESULTS: Many dental hygienists were unaware of the recommended clinical guidelines for treating breast cancer patients and lacked specific knowledge concerning the commonly prescribed anti-estrogen medications for pre-and postmenopausal breast cancer patients. Over 70% of the respondents indicated they were unfamiliar with the AI class of medications. Only 13% of dental hygienists correctly identified the mechanism of action of anti-estrogen therapy. Dental hygienists reported increased gingival inflammation, gingival bleeding, periodontal pocketing, xerostomia and burning tissues in patients receiving anti-estrogen therapies. Less than 10% believed that their knowledge of breast cancer treatments and the potential oral side effects is up to date. CONCLUSION: Results indicate a need for more education about the oral effects of breast cancer therapies and about providing the best possible care for patients undergoing breast cancer treatment. PMID- 24771777 TI - Oral health promotion: knowledge, confidence, and practices in preventing early severe childhood caries of Virginia WIC program personnel. AB - PURPOSE: This study assessed the oral health knowledge, confidence and practices of Virginia personnel in the Special Supplemental Food Program for Women, Infants and Children (WIC). METHODS: In 2009, 257 WIC personnel were electronically emailed via an investigator-designed 22-item Survey Monkey(r) questionnaire. Descriptive statistics, Chi-square and Fishers Exact tests compared personnel demographics and oral health knowledge, confidence and practices at the p<=0.01 and 0.05 significance level. RESULTS: Response rate was 68%. WIC personnel were knowledgeable about basic oral health concepts. More than half of those reporting were not confident assessing for visual signs of dental decay and do not routinely assess for visual signs of decay. Only 4% of personnel apply fluoride therapy. CONCLUSION: Findings support the need for health promotion/disease prevention at WIC. PMID- 24771778 TI - V. 'For now we see through a glass, darkly': the anaesthesia syndrome. PMID- 24771779 TI - Analgesia/nociception index for the assessment of acute postoperative pain. PMID- 24771780 TI - Analgesia-nociception index. PMID- 24771781 TI - Endobronchial intubation technique and airway morbidity. PMID- 24771782 TI - 180 degrees rotation of double-lumen endobronchial tube during intubation. PMID- 24771783 TI - In pursuit of interscalene safety. PMID- 24771784 TI - Journal club response. PMID- 24771785 TI - Procedural sedation: it is not what you do, it is how you do it. PMID- 24771786 TI - Tracheostomy care: it is not just about the training. PMID- 24771787 TI - Haemodialysis before emergency surgery in a patient treated with dabigatran. PMID- 24771788 TI - Bioreactance for estimating cardiac output and the effects of passive leg raising in critically ill patients. PMID- 24771789 TI - Reply from the authors to Dr Squara. PMID- 24771790 TI - Bioreactance is not reliable for estimating cardiac output and the effects of passive leg raising in critically ill patients. PMID- 24771791 TI - Contribution of oxycodone and its metabolites to the analgesic effect. PMID- 24771792 TI - Spinal catheter observer effect and surgical technique. PMID- 24771793 TI - Ventilation with the Ventrain through a small lumen catheter in the failed paediatric airway: two case reports. PMID- 24771794 TI - Miosis with dexmedetomidine: every little helps, every picture tells a story. PMID- 24771795 TI - Efficacy of ventilation through a customized novel cuffed airway exchange catheter: a tracheal/lung model study. PMID- 24771796 TI - Sugammadex after magnesium sulphate administration in a morbidly obese patient undergoing general anaesthesia. PMID- 24771797 TI - Prolonged diaphragm dysfunction after interscalene brachial plexus block and shoulder surgery: a prospective observational pilot study. PMID- 24771798 TI - Proposal for a surrogate surgical invasiveness score to obtain a 'post hoc' quantification of surgical stress and tissue trauma in the context of postoperative outcome assessments. PMID- 24771805 TI - Dexmedetomidine reduces intestinal and hepatic injury after hepatectomy with inflow occlusion under general anaesthesia: a randomized controlled trial. AB - BACKGROUND: We compared intestinal, hepatic, and other organ function after hepatic portal occlusion with or without dexmedetomidine administration under general anaesthesia. METHODS: In this prospective, randomized double-blind investigation, 44 patients undergoing elective hepatectomy with inflow occlusion were randomized into a dexmedetomidine group or a control group. The dexmedetomidine group received an initial dexmedetomidine loading dose of 1 MUg kg(-1) over 10 min followed by a maintenance dose of 0.3 MUg kg(-1) h(-1). In the control group, 0.9% sodium chloride was administered. The primary outcome was serum diamine oxidase (DAO) activity reflecting intestinal injury. The secondary outcomes included variables reflecting intestinal, hepatic, kidney, and cardiopulmonary function, and biomarkers of oxidative stress and systemic inflammatory response. RESULTS: DAO activity was lower in the dexmedetomidine group than in the control group at 6 and 24 h after liver reperfusion [9.77 (1.07) vs14.29 (1.43) units ml(-1), P=0.021; 9.67 (0.98) vs 13.97 (1.31) units ml(-1), P=0.017]. d-lactate acid levels were lower during 1-72 h after liver reperfusion compared with the control group (all P<0.05). Also, the intestinal injury severity grade was decreased by dexmedetomidine (P=0.038). The biomarkers reflecting liver injury increased over time, but were lower in the dexmedetomidine group (all P<0.05), while the variables reflecting cardiopulmonary and renal function showed no differences between the groups (all P>0.05). CONCLUSIONS: Dexmedetomidine administered perioperatively attenuates intestinal and hepatic injury in patients undergoing elective liver resection with inflow occlusion without any potential risk. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-11001530, September 2011. PMID- 24771806 TI - Use of the NexfinTM device to detect acute arterial pressure variations during anaesthesia induction. AB - BACKGROUND: Standard non-invasive arterial pressure (AP) measurements are discontinuous. By providing non-invasive beat-to-beat AP measurements, NexfinTM might limit duration of intraoperative hypotension and hypertension. We assessed the ability of NexfinTM to detect AP variations by comparing its trending ability with invasive AP monitoring. METHODS: Thirty-one subjects undergoing elective surgery under general anaesthesia were included. During induction, simultaneous pairs of AP measurements were collected every 5 s from the NexfinTM finger sensor and a homolateral radial artery catheter. Magnitude and time lags of AP variations from baseline to nadir and peak were calculated for both methods. Concordance analysis was performed by the Bland-Altman method (for comparison of repeated measures when appropriate). RESULTS: NexfinTM detected 100% of AP changes with the median delays of 0 s (-13 to 7) and 0 s (-5 to 12) for nadir and peak, respectively. Bias [limits of agreement (LOA)] of systolic AP (SAP) variations was -0.5 mm Hg (-31.2 to 30.2) and -9.4 mm Hg (-31.3 to 12.6) from baseline to nadir and from baseline to peak, respectively. For 3479 analysed paired measurements, bias was -3.8 and -8.8 mm Hg for SAP and diastolic AP, with LOA of (-36.0 to 28.5) and (-29.8 to 12.3), respectively. CONCLUSIONS: NexfinTM detects AP variations accurately and can be a useful warning device during anaesthesia. However, it is not interchangeable with invasive monitoring, given the large LOA between the two measurements. CLINICAL TRIAL REGISTRATION: NCT01658631. PMID- 24771807 TI - The best of times ... PMID- 24771808 TI - Making research matter. PMID- 24771809 TI - Academic primary care: at a tipping point? PMID- 24771810 TI - Improving the care of adolescents in general practice. PMID- 24771811 TI - A landmark study of collective action by general practices. PMID- 24771813 TI - Five cards. PMID- 24771814 TI - Author's response. PMID- 24771815 TI - Author's response. PMID- 24771816 TI - Incorrect inclusion of individual studies and methodological flaws in systematic review and meta-analysis. PMID- 24771817 TI - Authors' response. PMID- 24771818 TI - Patient experience and GP trainees. PMID- 24771819 TI - Knowledge and attitudes of waterpipe tobacco smoking among GPs in England. PMID- 24771820 TI - Impact of training location on the workforce crisis. PMID- 24771821 TI - Only 50 shades of grey? PMID- 24771822 TI - Death's worsening taboo: is hampering the provision of high quality palliative care. PMID- 24771823 TI - Finance, fibromyalgia, caring, & communication. PMID- 24771824 TI - Do our consultation models meet our patients' needs? PMID- 24771825 TI - Degas' 'exercise of circumvention'. PMID- 24771826 TI - Q is for Qualia. PMID- 24771827 TI - Female GPs and family life -- still taboo. PMID- 24771831 TI - Dyslexia, dyspraxia, and ADHD in adults: what you need to know. PMID- 24771832 TI - What's the opposite of efficiency? PMID- 24771834 TI - Is the NHS a business? PMID- 24771833 TI - What can science contribute to quality improvement in general practice? PMID- 24771835 TI - Research into practice: safe prescribing. PMID- 24771836 TI - Diagnosing and managing carpal tunnel syndrome in primary care. PMID- 24771837 TI - Patterns of engagement between GPs and adolescents presenting with psychological difficulties: a qualitative study. AB - BACKGROUND: Psychological difficulties are common in adolescence with general practice attendees having higher rates than reported in community surveys. Yet GP identification of common mental health problems in this age group is limited. Anxiety and uncertainty around professional practice have been found among GPs and they vary in their degree of engagement with adolescents presenting with psychological difficulties. AIM: To explore which factors influence the degree of GP engagement. DESIGN AND SETTING: Qualitative study based in 18 practices in the north east of England. The practices recruited included rural, urban, and mixed populations of patients predominantly living in socioeconomically disadvantaged communities. METHOD: Theoretical sampling was used to guide recruitment of GP participants continuing until theoretical saturation was reached. Data were analysed using the constant comparative method of grounded theory and situational analysis. RESULTS: In total 19 GPs were recruited: 10 were female, the age range was 29-59 years, with a modal range of 40-49 years. The participants collectively described a sense of their professional competence being challenged, yet reacted with varying degrees of engagement. Three themes appeared to shape a GP's response: performance in the clinical encounter; view of adolescents and their health needs; and the GP's own preferred epistemological framework. CONCLUSION: The findings suggest that better patterns of engagement between GPs and adolescents are supported by medical education which includes input and feedback from adolescents; education about the science and psychology of adolescence; more effective working across disciplinary boundaries; and recognition of the importance of addressing psychological difficulties early. PMID- 24771838 TI - GPs' responses to adolescents presenting with psychological difficulties: a conceptual model of fixers, future planners, and collaborators. AB - BACKGROUND: Psychological difficulties are common in adolescents yet are not often addressed by GPs. Anxiety and uncertainty about professional practice, with a reluctance to medicalise distress, have been found among GPs. GP involvement in this clinical area has been shown to be influenced by how GPs respond to the challenges of the clinical consultation, how they view young people and their perception of their health needs, and a GP's knowledge framework. AIM: To explore the relationship between the above three influences to develop an overarching conceptual model. DESIGN AND SETTING: Qualitative study based in 18 practices in the north east of England. The practices recruited included rural, urban, and mixed populations of patients predominantly living in socioeconomically disadvantaged communities. METHOD: Theoretical sampling was used to guide recruitment of GP participants continuing until theoretical saturation was reached. Data were analysed using the constant comparative method of grounded theory and situational analysis. RESULTS: In total 19 GPs were recruited: 10 were female, the age range was 29-59 years, with a modal range of 40-49 years. Three levels of analysis were undertaken. This study presents the final stage of analysis. GP 'enactment of role' was found to be the key to explaining the relationship between the three influencing factors. Three role archetypes were supported by the data: 'fixers', 'future planners', and 'collaborators'. CONCLUSION: The role of GPs in managing adolescent psychological difficulties is unclear. Policy advocates a direct role but this is unsupported by education and service delivery. GPs adopt their own position along a continuum, resulting in different educational needs. Better preparation for GPs is required with exploration of new, more collaborative models of care for troubled adolescents. PMID- 24771839 TI - Encouraging adolescents to contact their GP: a community-based trial. AB - BACKGROUND: Adolescents, especially males, often fail to see their GP. AIM: To determine whether an informative letter could enhance the accessibility and utilisation of healthcare facilities and services. DESIGN AND SETTING: A community-based trial in one town in Oslo, using a retrospective control group. METHOD: GPs in one town in Oslo sent a personal, informative letter at the beginning of 2008 and 2009 to individuals in their practice population who were turning 16 years of age that year. The pooled data for the same year for each surgery were collected. Retrospective data from 1990 and 1991 served as controls for the intervention groups of data collected in 2006 and 2007 respectively. An International Classification of Primary Care-2 diagnosis was given for each contact. RESULTS: The proportion of adolescents in contact with a GP increased from 59% in the control group to 69% in the intervention group (P<0.001). For the males, the increase was from 54% to 72% (P<0.001). This reduced sex differences in healthcare seeking. For diagnoses mentioned in the informative letter the incidence rose from 38% in the control group to 55% in the intervention group (P<0.001). For the females, there was a non-significant increase in the proportion in contact with the GP, from 63% to 66% in control and intervention groups, respectively. The most frequent contact reasons were respiratory disorders, followed by general and unspecified complaints, skin disorders, musculoskeletal disorders, and psychological disorders. This pattern did not change because of the intervention. CONCLUSION: An information letter about health problems and health rights (such as the protection of the adolescent's privacy) seems to enhance the accessibility and utilisation of GPs, as measured by contact rate, particularly for males. PMID- 24771840 TI - Improving cardiovascular disease using managed networks in general practice: an observational study in inner London. AB - BACKGROUND: System redesign is described in one primary care trust (PCT)/clinical commissioning group (CCG) resulting in improved cardiovascular disease (CVD) management. AIM: To evaluate CVD managed practice networks in one entire local health economy using practice networks, compared with PCTs in London, England, and local PCTs. DESIGN AND SETTING: Observational study of 34 general practices in Tower Hamlets, a socially disadvantaged inner-London borough. METHOD: In 2009, all 34 practices were allocated to eight geographical networks of four to five practices, each serving 30 000-50 000 patients. Each network had a network manager, administrative support, and an educational budget to deliver financially incentivised attainment targets in four care packages of which CVD comprised one. RESULTS: In 2009/11, Tower Hamlets increased total statin prescribing (ADQ-STAR PU) by 17.9% compared with 5.5% in England (P<0.001). Key CVD indicators improved faster in Tower Hamlets than in England, London, or local PCTs, and in 2012/13, Tower Hamlets ranked top in the national Quality and Outcomes Framework for blood pressure and cholesterol control in coronary heart disease (CHD) and diabetes, top five for stroke and top in London for all these measures. Male mortality from CHD was fourth highest in England in 2008 and reduced more than any other PCT in the next 3 years; reducing by 43% compared with an average fall of 25% for the top 10 PCTs in 2008 ranked by mortality. CONCLUSION: Managed geographical practice networks delivered a step-change in key CVD performance indicators in comparison with England, London, or similar PCT/CCGs. PMID- 24771841 TI - Improving anticoagulation in atrial fibrillation: observational study in three primary care trusts. AB - BACKGROUND: Atrial fibrillation (AF) is a cause of stroke, and undertreatment with anticoagulants is a persistent issue despite their effectiveness. AIM: To increase the proportion of people with AF treated appropriately using anticoagulants, and reduce inappropriate antiplatelet therapy. DESIGN OF STUDY: Cross-sectional analysis. SETTING: Electronic patient health records on 4604 patients with AF obtained from general practices in three inner London primary care trusts between April 2011 and 2013. METHOD: The Anticoagulant Programme East London (APEL) sought to achieve its aims through an intervention with three components: altering professional beliefs using new clinical guidance and related education; facilitating change using computer software to support clinical decisions and patient review optimising anticoagulation; motivating change through evaluative feedback showing individual practice performance relative to peers. RESULTS: From April 2011 to April 2013, the proportion of people with CHA2DS2-VASc >=1 on anticoagulants increased from 52.6% to 59.8% (trend difference P<0.001). The proportion of people with CHA2DS2-VASc >=1 on aspirin declined from 37.7% to 30.3% (trend difference P<0.001). Comparing the 2 years before the intervention with the 2 years after, numbers of new people on the AF register almost doubled from 108 to 204. CONCLUSIONS: The APEL programme supports improvement in clinical managing AF by a combined programme of education around agreed guidance, computer aids to facilitate decision-making and patient review and feedback of locally identifiable results. If replicated nationally over 3 years, such a programme could result in approximately 1600 fewer strokes every year. PMID- 24771842 TI - Introducing genetic testing for cardiovascular disease in primary care: a qualitative study. AB - BACKGROUND: While primary care systematically offers conventional cardiovascular risk assessment, genetic tests for coronary heart disease (CHD) are increasingly commercially available to patients. It is unclear how individuals may respond to these new sources of risk information. AIM: To explore how patients who have had a recent conventional cardiovascular risk assessment, perceive additional information from genetic testing for CHD. DESIGN AND SETTING: Qualitative interview study in 12 practices in Nottinghamshire from both urban and rural settings. METHOD: Interviews were conducted with 29 adults, who consented to genetic testing after having had a conventional cardiovascular risk assessment. RESULTS: Individuals' principal motivation for genetic testing was their family history of CHD and a desire to convey the results to their children. After testing, however, there was limited recall of genetic test results and scepticism about the value of informing their children. Participants dealt with conflicting findings from the genetic test, family history, and conventional assessment by either focusing on genetic risk or environmental lifestyle factors. In some participants, genetic test results appeared to reinforce healthy behaviour but others were falsely reassured, despite having an 'above-average' conventional cardiovascular risk score. CONCLUSION: Although genetic testing was acceptable, participants were unclear how to interpret genetic risk results. To facilitate healthy behaviour, health professionals should explore patients' understanding of genetic test results in light of their family history and conventional risk assessment. PMID- 24771843 TI - Patient-initiated camera phone images in general practice: a qualitative study of illustrated narratives. AB - BACKGROUND: Camera phones have become ubiquitous in the digital age. Patients are beginning to bring images recorded on their mobile phones to share with their GP during medical consultations. AIM: To explore GP perceptions about the effect of patient-initiated camera phone images on the consultation. DESIGN AND SETTING: An interview study of GPs based in rural and urban locations in Australia. METHODS: Semi-structured telephone interviews with nine GPs about their experiences with patient-initiated camera phone images. RESULTS: GPs described how patient initiated camera phone photos and videos contributed to the diagnostic process, management and continuity of care. These images gave GPs in the study additional insight into the patient's world. Potential harm resulting from inappropriate use of camera phones by patients was also identified. CONCLUSION: Patient-initiated camera phone images can empower patients by illustrating their narratives, thus contributing to improved communication in general practice. Potential harm could result from inappropriate use of these images. GPs shown images on patients' camera phones should make the most of this opportunity for improved understanding of the patient's world. There are however, potential medicolegal implications such as informed consent, protection of patient and doctor privacy, and the risk of misdiagnosis. PMID- 24771844 TI - Evaluating pancreatitis in primary care: a population-based cohort study. AB - BACKGROUND: Pancreatitis is an important condition with significant mortality. Primary care may have an important role to play in its prevention, early diagnosis, and ongoing management. AIM: To evaluate incidence, case fatality, and clinical features of acute and chronic pancreatitis in a large population. DESIGN AND SETTING: Population-based cohort study using a primary care database in the UK from 1990 to 2013. METHOD: Use of general practice records from 16 491 patients diagnosed with pancreatitis. Age-standardised incidence rates and case fatality were estimated. Clinical features, aetiology, and patterns of recurrence were evaluated. RESULTS: Incidence of pancreatitis increased from 14.8 in 100 000 (1990-1994) to 31.2 in 100 000 (2010-2013) in males, and from 14.5 to 28.3 in 100 000 in females (2010-2013). Overall case fatality after diagnosis was 4.3% (95% CI = 4.0% to 4.6%) at 90 days and 7.9% (95% CI = 7.5% to 8.4%) at 365 days. In 1990-1994, 10% of patients with acute pancreatitis were recorded as heavy drinkers, increasing to 12% in 2010-2012; for patients with chronic pancreatitis the proportions were 13%, rising to 21%. Among patients who died in the 90 days after diagnosis, 92% consulted with their general practice in the 2 months before first diagnosis. CONCLUSION: The incidence of pancreatitis is increasing over time. Alcohol abuse may now account for at least one in eight cases of acute, and one in five cases of chronic pancreatitis. Consultations among those who subsequently died may have offered potential for earlier diagnosis and intervention. PMID- 24771845 TI - The influence of children's day care on antibiotic seeking: a mixed methods study. AB - BACKGROUND: Preschool-aged children are the highest consumers of antibiotics, but consult mainly for viral infections. Little is known about how day care, which is common in this age group, influences primary care consulting and treatment seeking behaviours. AIM: To investigate daycare providers' approaches to excluding and/or readmitting children with infections, and the consequences for parents' consulting and antibiotic-seeking behaviours. DESIGN AND SETTING: Cross sectional survey, document analysis, and qualitative interviews of daycare providers and parents in South East Wales, UK. METHOD: A total of 328 daycare providers were asked to complete a survey about infection exclusion practices and to provide a copy of their sickness exclusion policy. Next, 52 semi-structured interviews were conducted with purposively selected questionnaire responders and parents using their services. Questionnaire responses underwent bivariate analysis, policies underwent document analysis, and interviews were thematically analysed using constant comparison methods. RESULTS: In total 217 out of 328 (66%) daycare providers responded; 82 out of 199 (41%) reported advising parents that their child may need antibiotics and 199 out of 214 (93%) reported advising general practice consultations. Interviews confirmed that such advice was routine, and beliefs about antibiotic indications often went against clinical guidelines: 24% (n = 136) of sickness exclusion policies mentioning infections made at least one non-evidence-based indication for 'treatment' or antibiotics. Parent interviews revealed that negotiating daycare requirements lowered thresholds for consulting and encouraged antibiotic seeking. CONCLUSION: Daycare providers encourage parents to consult general practice and seek antibiotics through non-evidence-based policies and practices. Parents' perceptions of daycare providers' requirements override their own beliefs of when it is appropriate to consult and seek treatment. PMID- 24771846 TI - A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. AB - Most melanomas harbor oncogenic BRAF(V600) mutations, which constitutively activate the MAPK pathway. Although MAPK pathway inhibitors show clinical benefit in BRAF(V600)-mutant melanoma, it remains incompletely understood why 10% to 20% of patients fail to respond. Here, we show that RAF inhibitor-sensitive and inhibitor-resistant BRAF(V600)-mutant melanomas display distinct transcriptional profiles. Whereas most drug-sensitive cell lines and patient biopsies showed high expression and activity of the melanocytic lineage transcription factor MITF, intrinsically resistant cell lines and biopsies displayed low MITF expression but higher levels of NF-kappaB signaling and the receptor tyrosine kinase AXL. In vitro, these MITF-low/NF-kappaB-high melanomas were resistant to inhibition of RAF and MEK, singly or in combination, and ERK. Moreover, in cell lines, NF kappaB activation antagonized MITF expression and induced both resistance marker genes and drug resistance. Thus, distinct cell states characterized by MITF or NF kappaB activity may influence intrinsic resistance to MAPK pathway inhibitors in BRAF(V600)-mutant melanoma. SIGNIFICANCE: Although most BRAF(V600)-mutant melanomas are sensitive to RAF and/or MEK inhibitors, a subset fails to respond to such treatment. This study characterizes a transcriptional cell state distinction linked to MITF and NF-kappaB that may modulate intrinsic sensitivity of melanomas to MAPK pathway inhibitors. PMID- 24771848 TI - TLR costimulation causes oxidative stress with unbalance of proinflammatory and anti-inflammatory cytokine production. AB - IL-1beta acts in concert with anti-inflammatory cytokines, in particular, IL-1R antagonist (IL-1Ra), to ensure the correct development and outcome of the inflammation: imbalance in the IL-1beta/IL-1Ra ratio is implicated in many human diseases and may lead to dramatic consequences. In this article, we show that single TLR engagement induces IL-1beta and, with a little delay, IL-1Ra. Differently, costimulation of TLR2, TLR4, and TLR7/8 enhances IL-1beta secretion but severely inhibits IL-1Ra production. The IL-1beta/IL-1Ra unbalance after activation of multiple TLRs depends on the insurgence of oxidative stress, because of enhanced production of reactive oxygen species and failure of the antioxidant systems. Increased reactive oxygen species levels increase ATP externalization by monocytes, resulting in enhanced inflammasome activation and IL-1beta secretion. Oxidative stress then induces cell responses to stress, including inhibition of protein synthesis, which, in turn, is responsible for the impaired production of IL-1Ra. IL-1Ra secretion is restored by exogenous antioxidants that oppose oxidative stress. Similar effects are evident also on other cytokines: TNF-alpha is induced, whereas IL-6 is inhibited by costimulation. Our findings provide a molecular basis to the imbalance between proinflammatory and regulatory cytokine circuits that occur in various pathologic conditions, and suggest new strategies for controlling inflammation. PMID- 24771847 TI - Evaluation of clinical criteria for the identification of Lynch syndrome among unselected patients with endometrial cancer. AB - Clinical criteria, primarily young age of cancer onset and family history of signature cancers, have been developed to identify individuals at elevated risk for Lynch syndrome with the goals of early identification and cancer prevention. In 2007, the Society of Gynecologic Oncology (SGO)-codified criteria for women presenting with gynecologic cancers. These criteria have not been validated in a population-based setting. For 412 unselected endometrial cancers, immunohistochemical expression of DNA mismatch repair proteins and MLH1 methylation were assessed to classify tumors as sporadic or probable Lynch syndrome (PLS). In this cohort, 10.5% of patients were designated as PLS based on tumor testing. The sensitivity and specificity of the SGO criteria to identify these same cases were 32.6% [95% confidence interval (CI), 19.2-48.5] and 77% (95% CI, 72.7-81.8), respectively. With the exception of tumor location in the lower uterine segment, multivariate analysis of clinical features, family history, and pathologic variables failed to identify significant differences between the sporadic and PLS groups. A simplified cost-effectiveness analysis demonstrated that the SGO clinical criteria and universal tissue testing strategies had comparable costs per patient with PLS identified. In conclusion, the SGO criteria successfully identify PLS cases among women with endometrial cancer who are young or have significant family history of signature tumors. However, a larger proportion of patients with PLS who are older and have less significant family history are not detected by this screening strategy. Universal tissue testing may be necessary to capture more individuals at risk for having Lynch syndrome. PMID- 24771850 TI - NADPH oxidase-independent formation of extracellular DNA traps by basophils. AB - Basophils are primarily associated with a proinflammatory and immunoregulatory role in allergic diseases and parasitic infections. Recent studies have shown that basophils can also bind various bacteria both in the presence and the absence of opsonizing Abs. In this report, we show that both human and mouse basophils are able to produce mitochondrial reactive oxygen species and to form extracellular DNA traps upon IL-3 priming and subsequent activation of the complement factor 5 a receptor or FcepsilonRI. Such basophil extracellular traps (BETs) contain mitochondrial, but not nuclear DNA, as well as the granule proteins basogranulin and mouse mast cell protease 8. BET formation occurs despite the absence of any functional NADPH oxidase in basophils. BETs can be found in both human and mouse inflamed tissues, suggesting that they also play a role under in vivo inflammatory conditions. Taken together, these findings suggest that basophils exert direct innate immune effector functions in the extracellular space. PMID- 24771849 TI - Human lymphoid development in the absence of common gamma-chain receptor signaling. AB - Despite the power of model systems to reveal basic immunologic mechanisms, critical differences exist between species that necessitate the direct study of human cells. Illustrating this point is the difference in phenotype between patients with SCID caused by mutations affecting the common gamma-chain (gammac) cytokine signaling pathway and mice with similar mutations. Although in both species, null mutations in either IL-2RG (which encodes gammac), or its direct downstream signaling partner JAK3, result in T and NK cell deficiency, an associated B cell deficiency is seen in mice but not in humans with these genetic defects. In this study, we applied recent data that have revised our understanding of the earliest stages of lymphoid commitment in human bone marrow (BM) to determine the requirement for signaling through IL-2RG and JAK3 in normal development of human lymphoid progenitors. BM samples from SCID patients with IL 2RG (n = 3) or JAK3 deficiency (n = 2), which produce similar "T-NK-B+" clinical phenotypes, were compared with normal BM and umbilical cord blood as well as BM from children on enzyme treatment for adenosine deaminase-deficient SCID (n = 2). In both IL-2RG- and JAK3-SCID patients, the early stages of lymphoid commitment from hematopoietic stem cells were present with development of lymphoid-primed multipotent progenitors, common lymphoid progenitors and B cell progenitors, normal expression patterns of IL-7RA and TLSPR, and the DNA recombination genes DNTT and RAG1. Thus, in humans, signaling through the gammac pathway is not required for prethymic lymphoid commitment or for DNA rearrangement. PMID- 24771851 TI - Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins. AB - Killer lymphocyte granzyme (Gzm) serine proteases induce apoptosis of pathogen infected cells and tumor cells. Many known Gzm substrates are nucleic acid binding proteins, and the Gzms accumulate in the target cell nucleus by an unknown mechanism. In this study, we show that human Gzms bind to DNA and RNA with nanomolar affinity. Gzms cleave their substrates most efficiently when both are bound to nucleic acids. RNase treatment of cell lysates reduces Gzm cleavage of RNA binding protein targets, whereas adding RNA to recombinant RNA binding protein substrates increases in vitro cleavage. Binding to nucleic acids also influences Gzm trafficking within target cells. Preincubation with competitor DNA and DNase treatment both reduce Gzm nuclear localization. The Gzms are closely related to neutrophil proteases, including neutrophil elastase (NE) and cathepsin G. During neutrophil activation, NE translocates to the nucleus to initiate DNA extrusion into neutrophil extracellular traps, which bind NE and cathepsin G. These myeloid cell proteases, but not digestive serine proteases, also bind DNA strongly and localize to nuclei and neutrophil extracellular traps in a DNA dependent manner. Thus, high-affinity nucleic acid binding is a conserved and functionally important property specific to leukocyte serine proteases. Furthermore, nucleic acid binding provides an elegant and simple mechanism to confer specificity of these proteases for cleavage of nucleic acid binding protein substrates that play essential roles in cellular gene expression and cell proliferation. PMID- 24771852 TI - A soluble form of IL-27Ralpha is a natural IL-27 antagonist. AB - IL-27 is a cytokine of the IL-12 family that plays a key role in the regulation of inflammatory and T cell responses. Its receptor is composed of IL-27Ralpha and gp130 and activates the STAT pathway. We show in this study, using an ELISA that we developed, that a naturally occurring soluble form of IL-27Ralpha (sIL 27Ralpha) is produced by human activated CD4(+) and CD8(+) T cells, B cells, myeloid cells, and various cell lines. sIL-27Ralpha is present at a mean concentration of 10,344 +/- 1,274 pg/ml in the sera from healthy individuals. Biochemical studies showed that sIL-27Ralpha is released as two N-glycosylated variants of ~ 90 and ~ 70 kDa. In IL-27Ralpha-transfected COS7 cells, primary cells, and cell lines, production of sIL-27Ralpha is inhibited by the metalloprotease inhibitors GM6001 and TAPI-0. Importantly, natural sIL-27Ralpha binds rIL-27, inhibits IL-27 binding to its cell surface receptor, and is a potent inhibitor of IL-27 signaling, as shown by its ability to specifically block IL-27-mediated STAT activation, at low molar excess over IL-27. Also, we found that serum levels of sIL-27Ralpha were elevated in patients with Crohn's disease, a Th1-mediated disease. These findings suggest that sIL-27Ralpha may play important immunoregulatory functions under normal and pathological conditions. PMID- 24771853 TI - Overlapping and asymmetric functions of TCR signaling during thymic selection of CD4 and CD8 lineages. AB - TCR signaling plays a central role in directing developmental fates of thymocytes. Current models suggest TCR signal duration directs CD4 versus CD8 lineage development. To investigate the role of TCR signaling during positive selection directly, we switched signaling off in a cohort of selecting thymocytes and followed, in time, their subsequent fate. We did this using an inducible Zap70 transgenic mouse model that allowed Zap70-dependent signaling to be turned on and then off again. Surprisingly, loss of TCR signaling in CD4(+)CD8(lo) thymocytes did not prevent their development into committed CD4 single positives (SPs), nor their continued maturation to HSA(lo) SPs. However, numbers of CD4 SPs underwent a substantial decline following loss of Zap70 expression, suggesting an essential survival role for the kinase. Termination of TCR signaling is considered an essential step in CD8 lineage development. Loss of Zap70 expression, however, resulted in the rapid death of CD8 lineage precursor thymocytes and a failure to generate CD8 SPs. Significantly, extending the window of Zap70 expression was sufficient for generation and export of both CD4 and CD8 T cells. These data reveal a parallel requirement for TCR-mediated survival signaling, but an asymmetric requirement for TCR-mediated maturation signals. PMID- 24771854 TI - Citrullination alters immunomodulatory function of LL-37 essential for prevention of endotoxin-induced sepsis. AB - Cathelicidin LL-37 plays an essential role in innate immunity by killing invading microorganisms and regulating the inflammatory response. These activities depend on the cationic character of the peptide, which is conferred by arginine and lysine residues. At inflammatory foci in vivo, LL-37 is exposed to peptidyl arginine deiminase (PAD), an enzyme released by inflammatory cells. Therefore, we hypothesized that PAD-mediated citrullination of the arginine residues within LL 37 will abrogate its immunomodulatory functions. We found that, when citrullinated, LL-37 was at least 40 times less efficient at neutralizing the proinflammatory activity of LPS due to a marked decrease in its affinity for endotoxin. Also, the ability of citrullinated LL-37 to quench macrophage responses to lipoteichoic acid and poly(I:C) signaling via TLR2 and TLR3, respectively, was significantly reduced. Furthermore, in stark contrast to native LL-37, the modified peptide completely lost the ability to prevent morbidity and mortality in a mouse model of d-galactosamine-sensitized endotoxin shock. In fact, administration of citrullinated LL-37 plus endotoxin actually exacerbated sepsis due to the inability of LL-37 to neutralize LPS and the subsequent enhancement of systemic inflammation due to increased serum levels of IL-6. Importantly, serum from septic mice showed increased PAD activity, which strongly correlated with the level of citrullination, indicating that PAD-driven protein modification occurs in vivo. Because LL-37 is a potential treatment for sepsis, its administration should be preceded by a careful analysis to ensure that the citrullinated peptide is not generated in treated patients. PMID- 24771855 TI - Role of leukotriene A4 hydrolase aminopeptidase in the pathogenesis of emphysema. AB - The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme with epoxy hydrolase and aminopeptidase activities. We hypothesize that the LTA4H aminopeptidase activity alleviates neutrophilic inflammation, which contributes to cigarette smoke (CS)-induced emphysema by clearing proline-glycine-proline (PGP), a triamino acid chemokine known to induce chemotaxis of neutrophils. To investigate the biological contributions made by the LTA4H aminopeptidase activity in CS-induced emphysema, we exposed wild-type mice to CS over 5 mo while treating them with a vehicle or a pharmaceutical agent (4MDM) that selectively augments the LTA4H aminopeptidase without affecting the bioproduction of leukotriene B4. Emphysematous phenotypes were assessed by premortem lung physiology with a small animal ventilator and by postmortem histologic morphometry. CS exposure acidified the airspaces and induced localization of the LTA4H protein into the nuclei of the epithelial cells. This resulted in accumulation of PGP in the airspaces by suppressing the LTA4H aminopeptidase activity. When the LTA4H aminopeptidase activity was selectively augmented by 4MDM, the levels of PGP in the bronchoalveolar lavage fluid and infiltration of neutrophils into the lungs were significantly reduced without affecting the levels of leukotriene B4. This protected murine lungs from CS-induced emphysematous alveolar remodeling. In conclusion, CS exposure promotes the development of CS-induced emphysema by suppressing the enzymatic activities of the LTA4H aminopeptidase in lung tissues and accumulating PGP and neutrophils in the airspaces. However, restoring the leukotriene A4 aminopeptidase activity with a pharmaceutical agent protected murine lungs from developing CS-induced emphysema. PMID- 24771856 TI - An increase in tolerogenic dendritic cell and natural regulatory T cell numbers during experimental autoimmune encephalomyelitis in Rras-/- mice results in attenuated disease. AB - R-Ras is a member of the Ras superfamily of small GTPases, which are regulators of various cellular processes, including adhesion, survival, proliferation, trafficking, and cytokine production. R-Ras is expressed by immune cells and has been shown to modulate dendritic cell (DC) function in vitro and has been associated with liver autoimmunity. We used Rras-deficient mice to study the mechanism whereby R-Ras contributes to autoimmunity using experimental autoimmune encephalomyelitis (EAE), a mouse model of the CNS autoimmune disease multiple sclerosis. We found that a lack of R-Ras in peripheral immune cells resulted in attenuated EAE disease. Further investigation revealed that, during EAE, absence of R-Ras promoted the formation of MHC II(low) DC concomitant with a significant increase in proliferation of natural regulatory T cells, resulting in an increase in their cell numbers in the periphery. Our study suggests a novel role for R-Ras in promoting autoimmunity through negative regulation of natural regulatory T cell numbers by inhibiting the development of MHCII(low) DC with tolerogenic potential. PMID- 24771857 TI - Myeloid PTEN deficiency protects livers from ischemia reperfusion injury by facilitating M2 macrophage differentiation. AB - Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-alpha and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation. PMID- 24771858 TI - The thromboprotective effect of bortezomib is dependent on the transcription factor Kruppel-like factor 2 (KLF2). AB - Multiple myeloma confers a high risk for vascular thrombosis, a risk that is increased by treatment with immunomodulatory agents. Strikingly, inclusion of the proteasome inhibitor bortezomib reduces thrombotic risk, yet the molecular basis for this observation remains unknown. Here, we show that bortezomib prolongs thrombosis times in the carotid artery photochemical injury assay in normal mice. Cell-based studies show that bortezomib increases expression of the transcription factor Kruppel-like factor 2 (KLF2) in multiple cell types. Global postnatal overexpression of KLF2 (GL-K2-TG) increased time to thrombosis, and global postnatal deletion of KLF2 (GL-K2-KO) conferred an antiparallel effect. Finally, studies in GL-K2-KO mice showed that the thromboprotective effect of bortezomib is KLF2 dependent. These findings identify a transcriptional basis for the antithrombotic effects of bortezomib. PMID- 24771860 TI - Store doping samples for 10 years to stop sports cheats, say anti-doping bodies. PMID- 24771861 TI - Demand for family caregivers will exceed supply by 2017, think tank predicts. PMID- 24771859 TI - Runx1 exon 6-related alternative splicing isoforms differentially regulate hematopoiesis in mice. AB - RUNX1 is an important transcription factor for hematopoiesis. There are multiple alternatively spliced isoforms of RUNX1. The best known isoforms are RUNX1a from use of exon 7A and RUNX1b and c from use of exon 7B. RUNX1a has unique functions due to its lack of C-terminal regions common to RUNX1b and c. Here, we report that the ortholog of human RUNX1a was only found in primates. Furthermore, we characterized 3 Runx1 isoforms generated by exon 6 alternative splicing. Runx1bEx6(-) (Runx1b without exon 6) and a unique mouse Runx1bEx6e showed higher colony-forming activity than the full-length Runx1b (Runx1bEx6(+)). They also facilitated the transactivation of Runx1bEx6(+). To gain insight into in vivo functions, we analyzed a knock-in (KI) mouse model that lacks isoforms Runx1b/cEx6(-) and Runx1bEx6e. KI mice had significantly fewer lineage-Sca1(+)c Kit(+) cells, short-term hematopoietic stem cells (HSCs) and multipotent progenitors than controls. In vivo competitive repopulation assays demonstrated a sevenfold difference of functional HSCs between wild-type and KI mice. Together, our results show that Runx1 isoforms involving exon 6 support high self-renewal capacity in vitro, and their loss results in reduction of the HSC pool in vivo, which underscore the importance of fine-tuning RNA splicing in hematopoiesis. PMID- 24771862 TI - Novel genotyping tools for investigating transmission dynamics of Plasmodium falciparum. AB - BACKGROUND: Differentiation between gametocyte-producing Plasmodium falciparum clones depends on both high levels of stage-specific transcripts and high genetic diversity of the selected genotyping marker obtained by a high-resolution typing method. By analyzing consecutive samples of one host, the contribution of each infecting clone to transmission and the dynamics of gametocyte production in multiclone infections can be studied. METHODS: We have evaluated capillary electrophoresis based differentiation of 6 length-polymorphic gametocyte genes. RNA and DNA of 25 uL whole blood from 46 individuals from Burkina Faso were simultaneously genotyped. RESULTS: Highest discrimination power was achieved by pfs230 with 18 alleles, followed by pfg377 with 15 alleles. When assays were performed in parallel on RNA and DNA, 85.7% of all pfs230 samples and 59.5% of all pfg377 samples contained at least one matching genotype in DNA and RNA. CONCLUSIONS: The imperfect detection in both, DNA and RNA, was identified as major limitation for investigating transmission dynamics, owing primarily to the volume of blood processed and the incomplete representation of all clones in the sample tested. Abundant low-density gametocyte carriers impede clone detectability, which may be improved by analyzing larger volumes and detecting initially sequestered gametocyte clones in follow-up samples. PMID- 24771863 TI - Outer membrane protein OlpA contributes to Moraxella catarrhalis serum resistance via interaction with factor H and the alternative pathway. AB - Factor H is an important complement regulator of the alternative pathway commonly recruited by pathogens to achieve increased rates of survival in the human host. The respiratory pathogen Moraxella catarrhalis, which resides in the mucosa, is highly resistant to the bactericidal activity of serum and causes otitis media in children and respiratory tract infections in individuals with underlying diseases. In this study, we show that M. catarrhalis binds factor H via the outer membrane protein OlpA. M. catarrhalis serum resistance was dramatically decreased in the absence of either OlpA or factor H, demonstrating that this inhibition of the alternative pathway significantly contributes to the virulence of M. catarrhalis. PMID- 24771864 TI - Severe infusion reactions to cetuximab occur within 1 h in patients with metastatic colorectal cancer: results of a nationwide, multicenter, prospective registry study of 2126 patients in Japan. AB - OBJECTIVE: Infusion reactions are common adverse reactions associated with antibody preparations. However, no studies have examined the time to onset of serious infusion reactions after administering cetuximab. We aimed to investigate the timing and severity of IRs affecting Japanese patients after administration of cetuximab. METHODS: Study subjects were identified from a nationwide prospective registry of 2126 metastatic colorectal cancer patients scheduled to receive cetuximab. Infusion reactions were examined in 2006 patients with adequate safety data. RESULTS: Infusion reactions of any grade occurred in 114 patients (5.7%), including Grade 3-4 infusion reactions in 22 patients (1.1%). Premedications were antihistamine plus corticosteroid (88.9% of patients with infusion reactions), antihistamine alone (9.2%) or corticosteroid alone (1.1%). In 95 patients (83.3%), infusion reactions occurred after the first dose. Twenty of the 22 Grade 3-4 infusion reactions occurred within 1 h of the first dose (the timing of the infusion reaction was unknown in one patient while another infusion reaction occurred after the fourth dose). Infusion reactions resolved in 111/114 patients (97.4%) while one patient recovered with sequelae, one patient died and one patient failed to recover within the follow-up period. Thirteen patients (15.7% of patients with infusion reactions) with Grade 1-2 infusion reactions showed recurrence after readministration of cetuximab; the recurrent infusion reactions were less severe than the initial reactions. CONCLUSIONS: Grade 3-4 infusion reactions occurred in 1.1% of colorectal cancer patients, and most occurred within 1 h of receiving the first dose of cetuximab. Therefore, patients should be carefully observed following cetuximab infusion, especially during the first hour after the first infusion. PMID- 24771865 TI - High-dose versus standard-dose radiotherapy with concurrent chemotherapy in stages II-III esophageal cancer. AB - OBJECTIVE: In this study, we investigated the effects of radiotherapy >=60 Gy in the setting of concurrent chemo-radiotherapy for treating patients with Stages II III esophageal cancer. METHODS: A total of 126 patients treated with 5 fluorouracilbased concurrent chemo-radiotherapy between January 1998 and February 2008 were retrospectively reviewed. Among these patients, 49 received a total radiation dose of <60 Gy (standard-dose group), while 77 received a total radiation dose of >=60 Gy (high-dose group). The median doses in the standard- and high-dose groups were 54 Gy (range, 45-59.4 Gy) and 63 Gy (range, 60-81 Gy), respectively. RESULTS: The high-dose group showed significantly improved locoregional control (2-year locoregional control rate, 69 versus 32%, P < 0.01) and progression-free survival (2-year progression-free survival, 47 versus 20%, P = 0.01) than the standard-dose group. Median overall survival in the high- and the standard-dose groups was 28 and 18 months, respectively (P = 0.26). In multivariate analysis, 60 Gy or higher radiotherapy was a significant prognostic factor for improved locoregional control, progression-free survival and overall survival. No significant differences were found in frequencies of late radiation pneumonitis, post-treatment esophageal stricture or treatment-related mortality between the two groups. CONCLUSIONS: High-dose radiotherapy of 60 Gy or higher with concurrent chemotherapy improved locoregional control and progression-free survival without a significant increase of in treatment-related toxicity in patients with Stages II-III esophageal cancer. Our study could provide the basis for future randomized clinical trials. PMID- 24771866 TI - On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO. AB - A new mechanism for formation of 7-ketocholesterol was recently described involving cytochrome P-450 (CYP)7A1-catalyzed conversion of 7-dehydrocholesterol into 7-ketocholesterol with cholesterol-7,8-epoxide as a side product. Some patients with cerebrotendinous xanthomatosis (CTX) and all patients with Smith Lemli-Opitz syndrome (SLO) have markedly increased levels of 7-dehydrocholesterol in plasma and tissues. In addition, the former patients have markedly upregulated CYP7A1. We hypothesized that these patients may produce 7-ketocholesterol from 7 dehydrocholesterol with formation of cholesterol-7,8-epoxide as a side product. In accord with this hypothesis, two patients with CTX were found to have increased levels of 7-ketocholesterol and 7-dehydrocholesterol, as well as a significant level of cholesterol-7,8-epoxide. The latter steroid was not detectable in plasma from healthy volunteers. Downregulation of CYP7A1 activity by treatment with chenodeoxycholic acid reduced the levels of 7-ketocholesterol in parallel with decreased levels of 7-dehydrocholesterol and cholesterol-7,8 epoxide. Three patients with SLO were found to have markedly elevated levels of 7 ketocholesterol as well as high levels of cholesterol-7,8-epoxide. The results support the hypothesis that 7-dehydrocholesterol is a precursor to 7 ketocholesterol in SLO and some patients with CTX. PMID- 24771867 TI - Thyroid hormone responsive protein Spot14 enhances catalysis of fatty acid synthase in lactating mammary epithelium. AB - Thyroid hormone responsive protein Spot 14 has been consistently associated with de novo fatty acid synthesis activity in multiple tissues, including the lactating mammary gland, which synthesizes large quantities of medium chain fatty acids (MCFAs) exclusively via FASN. However, the molecular function of Spot14 remains undefined during lactation. Spot14-null mice produce milk deficient in total triglyceride and de novo MCFA that does not sustain optimal neonatal growth. The lactation defect was rescued by provision of a high fat diet to the lactating dam. Transgenic mice overexpressing Spot14 in mammary epithelium produced total milk fat equivalent to controls, but with significantly greater MCFA. Spot14-null dams have no diminution of metabolic gene expression, enzyme protein levels, or intermediate metabolites that accounts for impaired de novo MCFA. When [(13)C] fatty acid products were quantified in vitro using crude cytosolic lysates, native FASN activity was 1.6-fold greater in control relative to Spot14-null lysates, and add back of Spot14 partially restored activity. Recombinant FASN catalysis increased 1.4-fold and C = 14:0 yield was enhanced 4 fold in vitro following addition of Spot14. These findings implicate Spot14 as a direct protein enhancer of FASN catalysis in the mammary gland during lactation when maximal MCFA production is needed. PMID- 24771869 TI - Erratum. PMID- 24771870 TI - Nano-palpation AFM and its quantitative mechanical property mapping. AB - We review nano-palpation atomic force microscopy, which offers quantitative mechanical property mapping especially for soft materials. The method measures force-deformation curves on the surfaces of soft materials. The emphasis is placed on how both Hertzian and Derjaguin-Muller-Toporov contact mechanics fail to reproduce the experimental curves and, alternatively, how the Johnson-Kendall Roberts model does. We also describe the force-volume technique for obtaining a two-dimensional map of mechanical properties, such as the elastic modulus and adhesive energy, based on the above-mentioned analysis. Finally, we conclude with several counterpart measurements, which describe the viscoelastic nature of soft materials, and give examples, including vulcanized isoprene rubber and the current status of ISO standardization. PMID- 24771868 TI - Effect of soluble epoxide hydrolase polymorphism on substrate and inhibitor selectivity and dimer formation. AB - Epoxy FAs (EpFAs) are important lipid mediators that are mainly metabolized by soluble epoxide hydrolase (sEH). Thus, sEH inhibition is a promising therapeutic target to treat numerous ailments. Several sEH polymorphisms result in amino acid substitutions and alter enzyme activity. K55R and R287Q are associated with inflammatory, cardiovascular, and metabolic diseases. R287Q seems to affect sEH activity through reducing formation of a catalytically active dimer. Thus, understanding how these SNPs affect the selectivity of sEH for substrates and inhibitors is of potential clinical importance. We investigated the selectivity of four sEH SNPs toward a series of EpFAs and inhibitors. We found that the SNPs alter the catalytic activity of the enzyme but do not alter the relative substrate and inhibitor selectivity. We also determined their dimer/monomer constants (KD/M). The WT sEH formed a very tight dimer, with a KD/M in the low picomolar range. Only R287Q resulted in a large change of the KD/M However, human tissue concentrations of sEH suggest that it is always in its dimer form independently of the SNP. These results suggest that the different biologies associated with K55R and R287Q are not explained by alteration in dimer formation or substrate selectivity. PMID- 24771871 TI - In situ observation of structural transformation of gold nanorods under pulsed laser irradiation in an HVEM. AB - A pulsed laser light illumination system was attached to a high-voltage electron microscope (HVEM) for in situ observation of light-induced behaviors of nano objects. The wavelength lambda of emitted laser pulses was 1064, 532 or 266 nm, and the pulse duration was 6-8 ns. Using this combined HVEM system, we observed the deformation behavior of gold nanorods irradiated by a pulsed laser (lambda = 1064 nm) at an intensity of 310 J m(-2) pulse or higher. A single shot of pulsed laser reduced the aspect ratio of the gold nanorods from 5 to a much smaller value. The extent of the reduction increased at higher laser intensities. However, at 310 J m(-2) pulse(-1), additional pulsed shots induced limited further deformation. The mean aspect ratio approximated to 2.5 even after irradiation with 7 pulses (total fluence exceeding 2 MJ m(-2)). In situ high resolution transmission electron microscopy (HRTEM) observation revealed that deformation was accompanied by total atomic restructuring of the nanorod interiors. PMID- 24771873 TI - Response. PMID- 24771874 TI - RE: Prostate-specific antigen screening trials and prostate cancer deaths: the androgen deprivation connection. PMID- 24771875 TI - Re: Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis. PMID- 24771876 TI - Response. PMID- 24771877 TI - Proton CT for Improved Stopping Power Determination in Proton Therapy, invited. PMID- 24771878 TI - Overview of the LLUMC/UCSC/CSUSB Phase 2 Proton CT Project. PMID- 24771879 TI - The Dropout Learning Algorithm. AB - Dropout is a recently introduced algorithm for training neural network by randomly dropping units during training to prevent their co-adaptation. A mathematical analysis of some of the static and dynamic properties of dropout is provided using Bernoulli gating variables, general enough to accommodate dropout on units or connections, and with variable rates. The framework allows a complete analysis of the ensemble averaging properties of dropout in linear networks, which is useful to understand the non-linear case. The ensemble averaging properties of dropout in non-linear logistic networks result from three fundamental equations: (1) the approximation of the expectations of logistic functions by normalized geometric means, for which bounds and estimates are derived; (2) the algebraic equality between normalized geometric means of logistic functions with the logistic of the means, which mathematically characterizes logistic functions; and (3) the linearity of the means with respect to sums, as well as products of independent variables. The results are also extended to other classes of transfer functions, including rectified linear functions. Approximation errors tend to cancel each other and do not accumulate. Dropout can also be connected to stochastic neurons and used to predict firing rates, and to backpropagation by viewing the backward propagation as ensemble averaging in a dropout linear network. Moreover, the convergence properties of dropout can be understood in terms of stochastic gradient descent. Finally, for the regularization properties of dropout, the expectation of the dropout gradient is the gradient of the corresponding approximation ensemble, regularized by an adaptive weight decay term with a propensity for self-consistent variance minimization and sparse representations. PMID- 24771880 TI - An open-label pilot study of divalproex sodium for posttraumatic stress disorder related to childhood abuse. AB - BACKGROUND: Few effective pharmacotherapeutic strategies have been established for the treatment of symptoms associated with posttraumatic stress disorder (PTSD). Preliminary evidence supports the efficacy of serotonergic agents and anticonvulsants, such as divalproex sodium, for the treatment of PTSD symptoms, particularly in military populations. OBJECTIVE: The aim of this study was to obtain pilot data on the use of divalproex sodium for the treatment of PTSD among adult civilian outpatients with a history of childhood physical and/or sexual abuse. METHODS: Outpatients with a primary psychiatric diagnosis of PTSD received open-label, flexibly dosed divalproex sodium as adjuvant therapy or monotherapy for 8 weeks. Overall and subcluster PTSD features, as well as affective symptoms and clinical global improvement, were monitored using standardized assessment scales. RESULTS: A total of 7 patients (5 women, 2 men; mean age, 44.1 years [range, 29-57 years]) were enrolled. At a mean (SD) peak dosage of 1500 (661) mg/d, significant improvement occurred in overall PTSD symptom severity (P<0.02) and in the diagnostic subclusters of hyperarousal and avoidance (P<0.02 for both). Depressive symptoms also were significantly improved from baseline (P<0.02). Divalproex sodium was well tolerated, except in 1 patient who prematurely discontinued treatment due to cognitive adverse events. CONCLUSIONS: These provisional findings support the possible utility of divalproex sodium therapy for adult outpatients with PTSD related to physical and/or sexual abuse during childhood. Controlled trials with larger sample sizes powered to show safety and efficacy are needed to substantiate these initial findings. PMID- 24771881 TI - Improved Bi Film Wrapped Single Walled Carbon Nanotubes for Ultrasensitive Electrochemical Detection of Trace Cr(VI). AB - We report here the successful fabrication of an improved Bi film wrapped single walled carbon nanotubes modified glassy carbon electrode (Bi/SWNTs/GCE) as a highly sensitive platform for ultratrace Cr(VI) detection through catalytic adsorptive cathodic stripping voltammetry (AdCSV). The introduction of negatively charged SWNTs extraordinarily decreased the size of Bi particles to nanoscale due to electrostatic interaction which made Bi(III) cations easily attracted onto the surface of SWNTs in good order, leading to higher quality of Bi film deposition. The obtained Bi/SWNTs composite was well characterized with electrochemical impedance spectroscopy (EIS), scanning electron microscopy (SEM), the static water contact angle and the voltammetric measurements. The results demonstrates the improvements in the quality of Bi film deposited on the surface of SWNTs such as faster speed of electron transfer, more uniform and smoother morphology, better hydrophilicity and higher stripping signal. Using diethylene triaminepentaacetic acid (DTPA) as complexing ligand, the fabricated electrode displays a well-defined and highly sensitive peak for the reduction of Cr(III) DTPA complex at -1.06 V (vs. Ag/AgCl) with a linear concentration range of 0-25 nM and a fairly low detection limit of 0.036 nM. No interference was found in the presence of coexisting ions, and good recoveries were achieved for the analysis of a river sample. In comparison to previous approaches using Bi film modified GCE, the newly designed electrode exhibits better reproducibility and repeatability towards aqueous detection of trace Cr(VI) and appears to be very promising as the basis of a highly sensitive and selective voltammetric procedure for Cr(VI) detection at trace level in real samples. PMID- 24771882 TI - Differential Growth Trajectories for Achievement Among Children Retained in First Grade: A Growth Mixture Model. AB - The authors investigated the differential effect of retention on the development of academic achievement from grade one to five on children retained in first grade over six years. Growth Mixture Model (GMM) analyses supported the existence of two distinct trajectory groups of retained children for both reading and math among 125 ethnically and linguistically diverse retained children. For each achievement domain, a low intercept/higher growth group (Class 1) and a high intercept/slower growth group (Class 2) were identified. Furthermore, Class 1 children were found to score lower on several measures of learning related skills (LRS) variables and were characterized by having poorer self-regulation and less prosocial behaviors, compared to the other group. Findings suggest that some children appear to benefit more from retention, in terms of higher reading and math growth, than others. Study findings have implications for selecting children into retention intervention and early intervention. PMID- 24771883 TI - Hypertensive Disorders of Pregnancy - A Life-Long Risk?! AB - Background: Arterial hypertension is one of the most important causes of cardiovascular diseases, and the latter are responsible for almost half of the deaths in the industrialised nations. Hypertensive disorders of pregnancy constitute one of the most frequent causes of feto-maternal morbidity and mortality; on the other hand the occurrence of a hypertensive disorder of pregnancy represents a risk for the later development of hypertension and the cardiovascular risks resulting therefrom. The aim of this article is to demonstrate the association of hypertensive disorders of pregnancy with consecutive cardiovascular diseases. Materials and Methods: Specific selective literature research. Results: After the occurrence of a hypertensive disorder of pregnancy the relative risks for hypertension are 3.7 (2.70-5.05), for ischaemic heart disease 2.2 (1.86-2.52), for cerebral insult 1.8 (1.45-2.27) and for mortality resulting from cardiovascular causes 1.5 (1.05-2.14) and are thus significant. According to a recent study 56 % of internal specialists and 23 % of gynecologists do not know about the association of preeclampsia with ischemic heart disease, 48 % and 38 % respectively are not aware of the link with stroke and 79 % and 77 % respectively are not aware of the association with a reduced life expectancy after preeclampsia. The presence of hypertension is not known by many of the patients, merely 28-38 % receive an appropriate therapy. Conclusion: Adequate follow-up after hypertensive disorders of pregnancy and the early recognition of and therapy for hypertension represent the cornerstones in the prevention of late cardiovascular sequelae. General practitioners, specialist for internal medicine and gynaecologists have a special responsibility with regard to the reduction of later complications. PMID- 24771884 TI - Male and Female Physicians in Hospital Gynaecology Departments - Analysis of the Impact of "Feminisation" from the Viewpoint of Medical Directors. AB - Introduction: At present the topic "feminisation" in medicine, in other words the increasing number of female staff members is under heavy discussion; however, there are only few data upon the basis of which a scientific discussion can be held. The question arises as to the possibility of problems arising therefrom for the specialty gynaecology and obstetrics. Methods: With the help of a questionnaire the directors of departments of gynaecology and obstetrics were questioned about the various aspects of the topic feminisation in gynaecology and obstetrics. Results: Among current applications the proportion of female applicants is estimated to be 84.2 %. Reasons given most frequently for the feminisation in the specialty include low income, loss of face of the medical profession and the poor career chances. Among the spontaneously mentioned reasons were the increasingly female dominated image of gynaecology and the working conditions in hospitals. Whereas the taking on of surgical duties and of directing functions was less markedly desired by women than by men, the questioned directors found that male and female staff members were equally motivated to take on duties outside of their working hours or to engage in research work. Discussion: Feminisation in medicine represents a challenge. It seems to be important to evaluate and investigate the motivation of staff members with regard to their wishes in professional life and thus to be able to offer an appropriate working environment based on the survey results. PMID- 24771885 TI - Prevalence, Spectrum and Antibiotic Susceptibility of Bacterial and Candida Colonization between the 21st and 33rd Week of Gestation in Women with PPROM - 5 Years' Experience in 1 Perinatal Center. AB - Objective: The aim of this study was to evaluate the prevalence, spectrum and antibiotic susceptibility of bacterial and Candida colonization of the vagina between the 21st and the 33rd week of gestation in women who had preterm premature rupture of membranes (PPROM). Study design: High vaginal swabs from 245 subjects with PPROM were analyzed in a retrospective cohort study using cultivation-dependent methods. Patients were additionally divided into two groups: women with PPROM between the 21st and 27th week of gestation (group A) and women with PPROM between the 28th and 33rd week of gestation (group B). A subgroup analysis comparing the two groups was done. Results: The prevalence of pathological bacterial colonization was similar in both study groups (40.8 vs. 41.4 %; p > 0.05), however, a difference in antibiotic susceptibility was noted, which did not reach statistical significance (resistance to ampicillin 71.4 vs. 52.5 %; cefuroxime 9.5 vs. 11.7 %; gentamicin 28.6 vs. 16.4 %; ciprofloxacin 5.0 vs. 5.4 %). In group A there was a statistically significant lower rate of Candida colonization (11.1 vs. 24.3 %; p = 0.04). Conclusion: In patients with early PPROM, the rate of Candida colonization (group A) is lower and there are indications of a difference in antibiotic susceptibility of the colonizing bacteria depending on gestational age. Larger study groups are required to confirm these preliminary results. PMID- 24771886 TI - Participation in the SUCCESS-A Trial Improves Intensity and Quality of Care for Patients with Primary Breast Cancer. AB - The SUCCESS-A trial is a prospective, multicenter, phase III clinical trial for high-risk primary breast cancer. It compares disease-free survival after randomization in patients treated with fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel (FEC-D) with that of patients treated with 3 cycles of FEC followed by 3 cycles of gemcitabine and docetaxel (FEC-DG). After a second randomization patients were treated with zoledronate for 2 or 5 years. A total of 251 centers took part in the trial and 3754 patients were recruited over a period of 18 months which ended in March 2007. In a questionnaire-based survey we investigated the impact of enrollment in the trial on patient care, the choice of chemotherapy protocol and access to current oncologic information as well as overall satisfaction in the respective centers. Analysis of the 78 questionnaires returned showed that 40 % of the centers had never previously enrolled patients with these indications in clinical studies. Prior to participating in the study, 4 % of the centers prescribed CMF or other protocols in patients with high-primary breast cancer risk, 46 % administered anthracycline-based chemotherapy and 50 % gave taxane-based chemotherapy. Around half of the participating centers noted that intensity of care and overall quality of care became even better and that access to breast cancer-specific information improved through participation in the trial. After their experience with the SUCCESS-A trial, all of the centers stated that they were prepared to enroll patients in clinical phase III trials again in the future. These data indicate that both patients and physicians benefit from clinical trials, as enrollment improves treatment strategies and individual patient care, irrespective of study endpoints. PMID- 24771888 TI - Position Paper on the Necessity for Inpatient Primary Treatment of Breast Cancer. PMID- 24771887 TI - Gastrointestinal Stromal Tumor (GIST) Presenting as a Huge Pelvic Mass. AB - Gastrointestinal stromal tumors (GISTs) are rare tumors that can arise anywhere in the tubular gastrointestinal tract. These tumors occasionally present as a pelvic mass, leading to a misdiagnosis of gynecological disease. A 47-year-old woman presented with a pelvic mass measuring 30 cm in diameter and highly elevated CA-125 levels. She underwent exploratory laparotomy with resection of the pelvic mass. The mass mimicking ovarian malignancy was found in the sigmoid colon and was correctly diagnosed as a GIST at surgery. It should be noted that preoperative diagnosis of GIST is uncommon, due to its rarity and the varying clinical presentation. However, non-gynecological tumors should be included in the differential diagnosis of a pelvic mass with atypical presentation. Gynecologists need to be cognizant of extra-ovarian pathology in patients presenting with an atypical pelvic mass. PMID- 24771889 TI - Mammography Screening - as of 2013. AB - Introduction: Since 2008 the German Mammography Screening Programme has been available throughout Germany to all women aged between 50 and 69. The programme strictly follows the European Guidelines. There are controversial discussions in the media as well as in the specialised press. Materials and Methods: Overview of the available data with regard to an evaluation of randomised studies and with regard to quality-assured screening programmes in accordance with EU Guidelines (including data from 18 screening countries). Results: Positive effects of screening: reduction in mortality, less invasive treatment. Negative effects: False-positive diagnoses and biopsy recommendations, so-called overdiagnoses, radiation dose. Limits of screening: Interval carcinomas, incomplete reduction in mortality. A mathematical synopsis of the latest publications from the European screening programmes with the diagnosis rates in Germany determined from > 4.6 million screening examinations produces the following: a total of 10 000 mammograms are created for 1000 women (P) taking part in the Mammography Screening Programme (each of whom undergoes 10 mammograms in 20 years). Overall, the risk of triggering breast cancer through a mammogram is very clearly below the annual natural risk of suffering from breast cancer. In the German screening, of these 1000 women, an average of 288 women are called back once in 20 years as a result of changes that are ultimately benign (< 3 % per cycle). Of these, 74 of the 288 women undergo a biopsy due to a benign change (false-positive biopsy recommendations, usually punch or vacuum biopsies). According to EUROSCREEN, 71 carcinomas develop among participants (56 are discovered in the screening, 15 in the interval), and 67 carcinomas among non-participants (N-P) (in some cases, several years later) during this period. The 4 additional diagnoses among the Ps are referred to as overdiagnoses, as they do not contribute to a reduction in mortality (these participants die beforehand from other causes of death). With regard to the carcinomas that concern the screening periods, 11 women out of 1000 die among the Ps; there are 19 deaths among the N-Ps (within the observation period plus follow-up period). Discussion: The false-positive rate is unavoidable, but is far lower with mammography screening than with other methods. Overdiagnoses are to be expected with any early detection. All calculations require assumptions and are therefore highly discrepant. They have very low evidence levels. The radiation dose should not be an argument against screening when applied correctly due to the very low risk and significant benefits. Interval carcinomas indicate the limits of a mammography screening programme. False-negatives only represent a subset of the interval carcinomas and are not to be equated with them. There is a very high evidence level for a significant reduction in mortality through mammography screening. For the first time, an independent expert commission has confirmed the results of the randomised studies and the statement of the WHO from 2002 and their further validity. Participants can expect a reduction in mortality of 30 %. Data from the current European screening programmes confirm a mortality reduction of 43 %, corresponding to 8/19 saved lives among 71 women with breast cancer or 1000 asymptomatic Ps. Many additional Ps benefit from less invasive treatment due to the early detection. Conclusions: As a result of the risk/benefit ratio, mammography screening should absolutely be recommended to asymptomatic women aged between 50-69. High importance is given to the provision of education for women by the treating gynaecologists as regards the opportunities for quality-assured early detection available to them in the healthcare system. PMID- 24771890 TI - Vaginal Estrogen Therapy for Patients with Breast Cancer. AB - On account of the good prognosis for patients with breast cancer, improving or maintaining the quality of life in the aftercare period is becoming more and more important. In particular, the increasing usage of aromatase inhibitors in the past few years has led to an increased incidence of vaginal atrophy with symptoms such as vaginal dryness, petechial bleeding, dyspareunia and recurrent cystitis. And just these symptoms have a detrimental impact on the quality of life of breast cancer patients. Application of a topical estrogen therapy represents the most effective means to treat vaginal atrophy. The use of a systemic or, respectively, topical hormone therapy is, however, contraindicated for breast cancer patients. Further clinical trials are needed in order to assess the safety of vaginal estrogen therapy. PMID- 24771891 TI - Health Literacy Requires Empowerment - Results of an Analysis of Patient Needs and the Demand for Qualification over a 10-Year Period. AB - Patients are expected to be increasingly competent about health issues, and patient self-determination is on the rise. This makes it ever more necessary to provide high quality information which is increasingly being offered to patients at all levels of the healthcare system. One example of a regionally available information service offered to patients is the Women's Academy, created 10 years ago, at the University Women's Hospital Tubingen in association with the Institute for Women's Health. The Women's Academy also serves as a forum and an outreach hub for the (cancer) centres of the Women's Hospital. The topics addressed include problematic areas in medicine and problems in coping with health and disease and additionally reflect the emergence of various patient interests and needs over time. The communication between physician and patient is central to the promotion of health literacy and individualised medicine. Regionally available services like the Women's Academy offer complementary benefits and are able to reach vulnerable groups of women who have little or no access to online information. PMID- 24771892 TI - Intraoperative Ultrasound in the Treatment of Breast Cancer. AB - Purpose: The aim of this study was to investigate the value of intraoperative ultrasound in breast-conserving operations and to compare it with standard procedures. Methods: For this purpose 307 women with palpable breast cancers and 116 patients with non-palpable breast cancers were compared retrospectively. In the group with palpable breast cancers 177 patients were treated by US-guided operations and 130 patients underwent palpation-guided breast-conserving operations. As primary outcomes, the resection margins and the rate of re operations were evaluated. Results: With regard to disease-free resection margins, intraoperative ultrasound was significantly superior to palpation alone. In the group of patients in whom the tumours were extirpated with the help of palpation, R1 resections were observed almost twice as often (16.9 %) as in the US-guided group (8.5 %). In the group with non-palpable breast cancers, intraoperative ultrasound was employed in 61 patients. As a control, 43 cases were evaluated in whom the breast-conserving operation was performed after wire marking. In this group US-guided tumour removal proved to be superior to that after wire marking for tumours that did not exhibit any intraductal components. Otherwise the redo resection rate was reduced by use of ultrasound. Furthermore, the surgeon was able by means of intraoperative ultrasound to identify "problematic" margins and to excise them in the same sitting. Conclusions: The US guided, breast-conserving operations led to a lower rate of R1 resections and redo operations in comparison to operations with palpation alone or those after wire marking. PMID- 24771893 TI - Anatomical Position of Four Different Transobturator Mesh Implants for Female Anterior Prolapse Repair. AB - Purpose: Polypropylene mesh implants are frequently used for pelvic floor reconstruction in women. Yet they vary in size and fixation. The purpose of this study is to compare four mesh products with regard to their anatomical positioning and functionality within the pelvic floor, to determine whether each mesh fits equally well in a female cadaver. Methods: One female pelvis was dissected, opening the retropubic space exposing the endopelvic fascia and demonstrating the arcus tendineus fasciae pelvis (ATFP). Anatomical parameters were measured before and after implanting four meshes via the transobturator approach. Results: The anterior fixation of the ATFP was found to be 5 mm lateral to the symphysis in this cadaver. The endopelvic fascia covered 54.6 cm2. The obturator nerve was located 35 mm from the white line. The distance of the proximal and lateral points of mesh fixation from the ischial spine or ATFP varied from 0 to 25 mm. The meshes varied in size and anatomical positioning. Conclusion: These observations demonstrate the necessity of developing optimally sized meshes and appropriate introducer techniques that can provide sufficient vaginal support. Surgeons, furthermore, need profound knowledge of anatomy, the patient's pelvic floor defect and the meshes available on the market. PMID- 24771894 TI - Cytotoxic T-Cells in Peripheral Blood in Women with Endometriosis. AB - Aim: The etiology of endometriosis remains unknown, but increasing evidence suggests that immune regulation may be important. Our study aimed to evaluate peripheral blood lymphocyte subpopulations during the menstrual cycle in women with peritoneal and ovarian endometriosis relative to healthy women. Methods: In this study, 65 women with endometriosis (37 in the follicular phase and 28 in the luteal phase of the menstrual cycle) and 61 healthy women (33 in the follicular phase and 28 in the luteal phase) were enrolled. Flow cytometric analysis measured peripheral blood lymphocyte subpopulations. The serum levels of cortisol were also determined. Results: In healthy controls, we detected an increased concentration of cytotoxic (CD8+) T cells and activated (HLA-DR) T cells in the luteal phase compared with the follicular phase of the menstrual cycle (p = 0.020 and p = 0.045), whereas no such fluctuation was detected in endometriosis. However, a marked increase in regulatory T-cell concentration in the luteal phase was detected only in endometriosis patients (p = 0.005). Women with endometriosis had higher levels of serum cortisol (p = 0.022), which correlated with the concentration of regulatory T cells (p = 0.048). Conclusions: Women with endometriosis do not exhibit fluctuations in the concentrations of cytotoxic and activated peripheral blood lymphocytes during the menstrual cycle. The marked fluctuation of regulatory T cells detected in endometriosis could be attributed to altered immune response. PMID- 24771895 TI - Biological Matrices and Synthetic Meshes Used in Implant-based Breast Reconstruction - a Review of Products Available in Germany. AB - While autologous breast reconstruction was considered the procedure of choice for immediate breast reconstruction, there has been a shift towards implant-based breast reconstruction (IBBR) in recent years. The proven safety of silicone breast implants and the development of biological matrices and synthetic meshes have contributed to the growing popularity of this approach. Although these different products are widely used, only limited clinical data are available with regard to breast surgery. The aim of this review was to give an overview of available biological matrices and synthetic meshes and discuss their use in clinical practice. PMID- 24771896 TI - Regulation of Endothelial Permeability in the Corpus Luteum: A Review of the Literature. AB - The development of the human corpus luteum (yellow body) is dictated by a strictly controlled system of mutually communicating cells, the luteal steroid hormone-producing cells and endothelial cells. This cell-to-cell communication facilitates control of neoangiogenesis which is a prerequisite for the development of the corpus luteum and its function, the rapid release of large amounts of progesterone into the blood-vascular system. Preconditions for this process are the hormonal regulation of endothelial cell proliferation as well as of vascular permeability through LH and hCG. The morphological correlates of endothelial permeability are cell-to-cell adhesion molecules such as adherens junctions (AJ) and tight junctions (TJ) that open and close the gaps between mutually interacting, neighbouring endothelial cells like a "zip fastener". Various types of cell adhesion molecules have been detected in the corpus luteum such as occludin, claudin 1 and claudin 5 as well as VE-cadherin. It may be assumed that the regulation of AJ and TJ proteins is of particular importance for the permeability and thus for the function of the corpus luteum in early pregnancy since hCG treatment leads to a down-regulation of cell adhesion molecules in the luteal vessels. This effect is apparently mediated by VEGF. From a functional point of view, the hCG-dependent and VEGF-mediated down-regulation of cell adhesion molecules leads to a reduced transmissibility of cell-to-cell contacts and thus to an increased endothelial permeability. In this process the various cell adhesion molecules are not only directly regulated by VEGF but they also mutually interact and thus influence one another. PMID- 24771897 TI - Living with Kallmann Syndrome - Analysis of Subjective Experience Reports from Women. AB - Five women were questioned on their experiences with Kallmann Syndrome (KS) in thematically focused, open interviews. This investigation complements the study of the experiences of men with KS 1. The results show that the consequences and pressures of KS extend beyond the somato-medical field and that those affected are also burdened by mental and psycho-social impacts. The pressures experienced by those affected include a distorted body image resulting from the lack of physical development, which in turn leads to difficulties in developing a healthy feeling of self-worth. Furthermore, particular attention should be paid to the influence of hormone therapy on mood and libido during medical treatment. Some of the affected women reported experiencing depressive moods and low libido, and pressures in their relationship associated with this. The affected women wanted KS to be viewed as a whole in order to achieve better handling. In particular, attentive handling of issues relating to fertility was important to them. Additional relevant support included offers of confidential discussions, and offers of psychotherapy and, where required, sex education or sex therapy. PMID- 24771898 TI - Cervical Detachment Using Monopolar SupraLoopTM Electrode versus Monopolar Needle in Laparoscopic Supracervical Hysterectomy (LSH): An Interventional, Comparative Cohort Study. AB - Objective: Currently available monopolar loop electrodes are difficult to handle in laparoscopic supracervical hysterectomy (LSH) and are entirely disposable devices, generating additional operating costs. The aim of this interventional study was the comparison of the efficiency and safety of cervical detachment with a newly developed monopolar loop electrode (SupraLoopTM) with a conventional method of cervical detachment in LSH. Material and Methods: Our study sample included 1598 patients; 1070 patients that underwent LSH with cervical detachment using the monopolar SupraLoopTM (study group) and 528 patients that underwent LSH with cervical detachment using the monopolar needle (control group). We also assessed cervical detachment time and total device application and cutting time in a subgroup of 49 patients (23 patients from the study group and 26 patients from the control group). Results: Total operation time for LSH was significantly shorter among SupraLoopTM patients (93 +/- 41 minutes) when compared to patients in whom cervical detachment was performed with the needle (105 +/- 44 minutes) (p < 0.001). Cervical detachment time and total device application including cutting time was significantly shorter for the SupraLoopTM group (SupraLoop vs. needle; 0.12 +/- 0.21 min vs. 5.1 +/- 4.4 min [p < 0.001]; 2.3 +/- 1.8 min vs. 5.4 +/- 2.4 min [p < 0.001]). There were no major or minor complications directly related to the use of the SupraLoopTM device, whereas two intraoperative complications were directly related to the application of the monopolar needle. Conclusion: The newly developed monopolar loop electrode (SupraLoopTM) is both an effective and safe instrument for cervical detachment in laparoscopic supracervical hysterectomy, and performed better than the needle, offering a significantly shorter operating time and less complications for the hysterectomy compared to the conventional method. PMID- 24771899 TI - Does Non-Placement of a Drain in Breast Surgery Increase the Rate of Complications and Revisions? AB - Purpose: Although surgical therapy for breast cancer has become less radical, intrasurgical placement of drains and the use of compression bandages is still standard practice. However, evidence for the clinical benefit of wound drains is controversial, and use of drains is associated with increased pain and longer hospital stays. This raises the question whether, given the latest surgical techniques, wound drainage is still medically necessary. Material and Method: A retrospective analysis was done of patients with breast cancer treated surgically between January 2009 and April 2012 in the Breast Centre Hohenlohe (n = 573). Complication rates and revision following surgery with and without placement of wound drains were compared for patients who had breast-conserving surgery (n = 425) and patients who underwent mastectomy (n = 148). Results: The baseline characteristics (age, number of resected lymph nodes, numbers of patients who had sentinel lymph node resection, tumour characteristics, receptor status and affected side) were comparable for the investigated patient groups. The overall rate of complications was 4 %. There was no significant difference with regard to complication rates after surgery with and without placement of wound drains between the group of patients with breast-conserving surgery and the group of patients with mastectomy (p = 0.68 and p = 0.54, respectively). Conclusion: Our data indicate that non-placement of a wound drain does not influence complication or revision rates after breast-conserving surgery or mastectomy. PMID- 24771900 TI - Evaluation of Newly Adapted Clip Marker System in Ultrasound-Guided Core Needle Biopsy for Suspicion of Breast Cancer. AB - Introduction: A newly adapted clip system for intramammary marking during ultrasound-guided core needle biopsy for suspicion of breast cancer is described and evaluated here. Material and Method: Fifty patients with suspicion of breast cancer (cT2) had ultrasound-guided core needle biopsy using a newly adapted clip marker system (HistoCoreTM and O-Twist MarkerTM). Subsequently, ultrasound follow up and tomosynthesis scans were done to determine the location of the marker clips. Results: No dislocation of the marker clip was detected on ultrasound in 45 of 50 patients (90 %), and 5 patients (10 %) had a maximum dislocation of 5 mm along the x-, y- or z-axis. Tomosynthesis scans demonstrated precise placement without dislocation of the clip markers in 48 patients (96 %); 2 patients (4 %) had a maximum dislocation of 3 mm along the x-, y- or z-axis. Conclusion: The newly developed clip marker system, a combination of a single-use breast biopsy needle and a precise, length-adapted intramammary marker clip, represents a further improvement in oncological therapy. This is of particular importance for patients requiring subsequent neoadjuvant chemotherapy, as in cases with complete tumour remission, there is no target point for preoperative, ultrasound-guided wire marking. PMID- 24771901 TI - S3-Guidelines for the Treatment of Inflammatory Breast Disease during the Lactation Period: AWMF Guidelines, Registry No. 015/071 (short version) AWMF Leitlinien-Register Nr. 015/071 (Kurzfassung). AB - Breastfeeding is widely acknowledged to be the best and most complete form of nutrition for healthy infants born at term and is associated with numerous benefits in terms of infants' health, growth, immunity and development. However, breastfeeding problems often result in early weaning. Standardized treatment recommendations for breastfeeding-related diseases are necessary to optimize the care offered to breastfeeding women. Evidence and consensus based guidelines for the treatment of puerperal mastitis, sore nipples, engorgement and blocked ducts were developed on the initiative of the National Breastfeeding Committee. These guidelines were developed in accordance with the criteria set up by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF), the Association of Scientific Medical Societies in Germany. The recommendations were drawn up by an interdisciplinary group of experts and were based on a systematic search and evaluation of the literature but also took clinical experience into account. Additionally good clinical practice (GCP) in terms of expert opinion was formulated in cases where scientific investigations could not be performed or were not aimed for. This article presents a summary of the recommendations of the S3-guidelines. PMID- 24771902 TI - Antibiotic Therapy for Premature Rupture of Membranes and Preterm Labor and Effect on Fetal Outcome. AB - In Germany almost 10 % of children are born before the end of 37th week of gestation. In at least one quarter of these cases, ascending infection of the vagina plays a causative role, particularly during the early weeks of gestation. If, in addition to the decidua, the amniotic membrane, amniotic fluid and the umbilical cord are also affected, infection not only triggers uterine contractions and premature rupture of membranes but also initiates a systemic inflammatory reaction on the part of the fetus, which can increase neonatal morbidity. Numerous studies and meta-analyses have found that antibiotic therapy prolongs pregnancy and reduces neonatal morbidity. No general benefit of antibiotic treatment was found for premature uterine contractions. But it is conceivable that a subgroup of pregnant women would benefit from antibiotic treatment. It is important to identify this subgroup of women and offer them targeted treatment. This overview summarizes the current body of evidence on antibiotic treatment for impending preterm birth and the effect on neonatal outcomes. PMID- 24771903 TI - Breast Cancer Risk - From Genetics to Molecular Understanding of Pathogenesis. AB - Several advancements over the last decade have triggered the developments in the field of breast cancer risk research. One of them is the availability of the human genome sequence along with cheap genotyping possibilities. Another is the globalization of research, which has led to the growth of research collaboration into large international consortia that facilitate the pooling of clinical and genotype data of hundreds of thousands of patients and healthy control individuals. This review concerns with the recent developments in breast cancer risk research and focuses on the discovery of new genetic breast cancer risk factors and their meaning in the context of established non-genetic risk factors. Finally the clinical application is highly dependent on the accuracy of breast cancer risk prediction models, not only for all breast cancer patients, but also for molecular subtypes, preferably for those which are associated with an unfavorable prognosis. Recently risk prediction incorporates all possible risk factors, which include epidemiological risk factors, mammographic density and genetic risk factors. PMID- 24771904 TI - New Insights into the Pathogenesis of Preeclampsia - The Role of Nrf2 Activators and their Potential Therapeutic Impact. AB - Preeclampsia (PE), characterized by proteinuric hypertension and occurring in 2-3 % of all pregnancies, is one of the leading causes of maternal, fetal and neonatal morbidity and mortality. The etiology of PE still remains unclear and current treatments for this devastating disorder are still limited to symptomatic therapies. Placental oxidative stress may be a key intermediate step in the pathogenesis of PE; it has been related to excessive secretion of multiple antiangiogenic factors, mainly soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). The nuclear factor-erythroid 2-like 2 (Nrf2) pathway is one of the most important systems that enhance cellular protection against oxidative stress. Nrf2 serves as a master transcriptional regulator of the basal and inducible expression of a multitude of genes encoding detoxification enzymes and antioxidative proteins. Evidence for a link between Nrf2 and restoring the balance between pro- and antiangiogenic factors mainly through its downstream target protein heme oxygenase-1 (HO-1) has lately been discussed. HO-1 metabolizes heme to biliverdin, iron and carbon monoxide (CO). CO enhances vascular endothelial growth factor (VEGF) synthesis in vascular smooth muscle and promotes its relaxation and hence vasodilatation. In addition, HO-1 has been shown in vitro to inhibit the production of sFlt-1. A recent animal study demonstrated that the induction of HO-1 in a mouse model of PE attenuates the induced hypertension in pregnant mice. This provides compelling evidence for the protective role of Nrf2/HO-1 in pregnancy and identifies this pathway as a target to treat women with PE. We summarize the recent findings on the involvement of Nrf2 in the pathogenesis of PE, and provide an overview of the possible beneficial effects of Nrf2 inducers in PE. PMID- 24771906 TI - Analysis of the German Perinatal Survey of the Years 2007-2011 and Comparison with Data From 1995-1997: Maternal Characteristics. AB - Background and Aim: We have previously presented analyses of data obtained from the German Perinatal Survey for the years 1995-1997. Here we present an analysis of data from the years 2007-2011 and compare the data to the previous data from the 1990s. Material and Methods: For the years 1995-1997, the data on 1 815 318 singleton pregnancies were provided by the Chambers of Physicians of all the states of Germany except Baden-Wurttemberg. For the years 2007-2011, the data on 3 187 920 singleton pregnancies from the German Perinatal Survey (all states of Germany) were obtained from the AQUA Institute in Gottingen, Germany. SPSS was used for data analysis. Plausibility checks were performed on the data. Results: Mean maternal age has increased over the years, from 28.7 years in 1995 to 30.2 years in 2011. We observed a decrease in smoking. While not all cases included data on maternal smoking after the pregnancy was known, when the cases with data on smoking were analysed, in 1995-1997 23.5 % of pregnant women were smokers compared to 11.2 % smokers in 2007-2011. Maternal body mass index (BMI) also changed; 8.2 % of women were obese (BMI: 30-40 kg/m2), while 13.0 % were obese in 2011. In 1995, 0.6 % of women were morbidly obese (BMI >= 40 kg/m2) compared to 1.8 % of women in 2011. The mean maternal body weight at the time of the first obstetric consultation also increased from 65.9 kg in 1995 to 68.7 kg in 2011. Conclusions: While the decrease in the number of women smoking over time is clearly a positive development, increasing maternal age and obesity present challenges in clinical practice. PMID- 24771905 TI - Polyhydramnios: Causes, Diagnosis and Therapy. AB - Polyhydramnios is defined as a pathological increase of amniotic fluid volume in pregnancy and is associated with increased perinatal morbidity and mortality. Common causes of polyhydramnios include gestational diabetes, fetal anomalies with disturbed fetal swallowing of amniotic fluid, fetal infections and other, rarer causes. The diagnosis is obtained by ultrasound. The prognosis of polyhydramnios depends on its cause and severity. Typical symptoms of polyhydramnios include maternal dyspnea, preterm labor, premature rupture of membranes (PPROM), abnormal fetal presentation, cord prolapse and postpartum hemorrhage. Due to its common etiology with gestational diabetes, polyhydramnios is often associated with fetal macrosomia. To prevent the above complications, there are two methods of prenatal treatment: amnioreduction and pharmacological treatment with non-steroidal anti-inflammatory drugs (NSAIDs). However, prenatal administration of NSAIDs to reduce amniotic fluid volumes has not been approved in Germany. In addition to conventional management, experimental therapies which would alter fetal diuresis are being considered. PMID- 24771907 TI - Severe Case of Autoimmune Thrombocytopenia First Diagnosed in Pregnancy. AB - We report on a 28-year old primigravida who presented in the second trimester with sudden onset of bleeding tendencies and thrombocytopenia of 2/nL during the first manifestation of autoimmune thrombocytopenia (ITP). Therapy with intravenous immunoglobulins (IVIG) and steroids was initiated but could not prevent renewed bleeding incidents and recurrent thrombocytopenia in the long term, thus premature delivery by Caesarean section in the 32 + 3 week of pregnancy could not be avoided. The bleeding complications could only be mastered by multiple thrombocyte transfusions. Because the ITP remained refractory to therapy in the postpartum period a thrombopoietin receptor agonist (TPO-RA) was administered. This led to an increase in the thrombocyte count which was later stabilised by prednisolone alone. PMID- 24771908 TI - Epidemiology of Malignant Cervical, Corpus Uteri and Ovarian Tumours - Current Data and Epidemiological Trends. AB - Cervical, uterine and ovarian cancers are the most common malignancies of the female genital tract. Using current data from population-based cancer registries in Germany, we present the recent figures for the incidence, prevalence, associated mortality and survival for these cancers. In 2009, a total of 23 800 women were newly diagnosed with one of the three gynaecological cancers (cervical cancer: 20.3 %, endometrial cancer: 48.5 %, ovarian cancer: 31.2 %). This figure equals approximately one third of the number of women newly diagnosed with breast cancer in the same year. The relative 5-year survival for carcinomas of the corpus uteri is 79 % and is higher that those for cervical cancer (68 %) and ovarian cancer (40 %). Ovarian cancer in particular is often diagnosed at a later stage and has a high risk of recurrence. Due to the favourable prognosis for endometrial tumours and the unfavourable prognosis for ovarian malignancies, the incidence of various gynaecological tumours is ranked differently compared to the 5-year prevalence of these same tumours. Currently, the 5-year prevalence in Germany for patients with cervical, endometrial or ovarian cancer is estimated to be around 80 000 women. Slightly more than half of these women were diagnosed with cancer of the corpus uteri. Around 25 % of women have ovarian and 21 % have cervical cancer. PMID- 24771909 TI - Epidemiology of Breast Cancer - Current Figures and Trends. AB - The epidemiology of breast cancer has clearly changed in the past few years. On the basis of current data from population-based cancer registries characteristic numbers for incidence, prevalence, mortality and survival after breast cancer are presented. The number of incident cases has increased to around 72 000 in 2009 (+ 23 % since 2003). It is estimated that at present 250 000 women with a prevalent breast cancer (5-year prevalence) are living in Germany. The most frequent localisation is the outer upper quadrant of the breast. Poorly differentiated or undifferentiated tumour tissue is found in every third patient. Since 2003 the age-standardised mortality has declined slightly (- 9 %) whereas the relative survival has improved from 79 to 86 %. Changes in the epidemiology of breast cancer can most probably be attributed to the introduction of early detection programmes such as mammography screening as well as to improved treatment options. To what extent mammography screening will lead to a further reduction of mortality remains to be seen. PMID- 24771911 TI - Use of the Sentinel Lymph Node Technique Compared to Complete Inguino-femoral Lymph Node Removal in Patients with Invasive Vulvar Cancer in Germany. AB - In the current S2 guidelines, the standard surgical therapy for patients with vulvar cancer also includes inguino-femoral lymphadenectomy. However, in view of the severe side-effects associated with this approach such as problems with wound healing, lymphoceles and lymphoedema, the search is on for alternative treatments that could decrease treatment-associated morbidity and improve patients' quality of life, particularly for node-negative patients. The sentinel lymph node technique is currently the gold standard in the treatment of unifocal breast cancer (clinically negative axilla), and studies on the use of this technique in the treatment of vulvar cancer are promising. To date, the diagnostic accuracy of this method in vulvar cancer has only been evaluated in a single, one-arm, non randomised, multicentre study. In preparation for a multicentre study, in 2010 we surveyed 41 German hospitals to investigate how often they used the sentinel lymph node technique compared to inguino-femoral lymphadenectomy. The hospitals were grouped according to hospital size and number of patients treated for vulvar cancer. The decision criteria to determine the type of procedure performed were also investigated. Finally, the hospitals were asked whether they would be willing to participate in a prospective clinical study to evaluate the sentinel lymph node technique in patients with vulvar cancer. The majority of surgeons questioned (73 %) already had some experience with this technique in patients with vulvar cancer. In our survey, 27 % of hospitals carried out inguino-femoral lymphadenectomy, 10 % used the sentinel lymph node technique, and 63 % used both methods. In 24 % of hospitals, the standard procedure consisted of the sentinel lymph node technique supplemented by inguino-femoral lymphadenectomy. Only 20 % of the institutions surveyed in our study carried out sentinel lymph node biopsy alone in accordance with the criteria of the consensus recommendations. The majority of the investigated institutions were willing to participate in a randomised prospective clinical study to evaluate the effectiveness of sentinel lymph node sampling in patients with vulvar cancer. PMID- 24771910 TI - Mammographic Density and Prediction of Nodal Status in Breast Cancer Patients. AB - Aim: Nodal status remains one of the most important prognostic factors in breast cancer. The cellular and molecular reasons for the spread of tumor cells to the lymph nodes are not well understood and there are only few predictors in addition to tumor size and multifocality that give an insight into additional mechanisms of lymphatic spread. Aim of our study was therefore to investigate whether breast characteristics such as mammographic density (MD) add to the predictive value of the presence of lymph node metastases in patients with primary breast cancer. Methods: In this retrospective study we analyzed primary, metastasis-free breast cancer patients from one breast center for whom data on MD and staging information were available. A total of 1831 patients were included into this study. MD was assessed as percentage MD (PMD) using a semiautomated method and two readers for every patient. Multiple logistic regression analyses with nodal status as outcome were used to investigate the predictive value of PMD in addition to age, tumor size, Ki-67, estrogen receptor (ER), progesterone receptor (PR), grading, histology, and multi-focality. Results: Multifocality, tumor size, Ki-67 and grading were relevant predictors for nodal status. Adding PMD to a prediction model which included these factors did not significantly improve the prediction of nodal status (p = 0.24, likelihood ratio test). Conclusion: Nodal status could be predicted quite well with the factors multifocality, tumor size, Ki-67 and grading. PMD does not seem to play a role in the lymphatic spread of tumor cells. It could be concluded that the amount of extracellular matrix and stromal cell content of the breast which is reflected by MD does not influence the probability of malignant breast cells spreading from the primary tumor to the lymph nodes. PMID- 24771912 TI - Fat Necrosis of the Breast Following Folinic Acid Extravasation. AB - Case Report: We report here on a 58-year-old patient with abnormal findings in the left breast on screening mammography (October 2012). In May 2008 the patient was diagnosed with rectal cancer, subsequently treated by surgical resection followed by radiochemotherapy. In September 2011 the patient was diagnosed with peritoneal cancer. Extravasation of folinic acid occurred during palliative chemotherapy, which was delivered through a surgically implanted port, placed prepectorally on the left side. The patient had not previously undergone breast surgery. The abnormal finding in the left breast was located at the 1-2 o'clock position. The mammogram showed extensive hyperdense nodules with predominantly round, fine granular calcifications. On sonography, the findings presented as a hypoechogenic, inhomogenous, partially diffuse, partly solid, partly cystic mass with individual calcifications and reduced echogenicity in the dorsal aspect. Strong densification of the left breast was found at the corresponding position on palpation. On computed tomography (CT) done during follow-up for rectal cancer, new streaky/pitted densifications were noted in the left breast. Based on the patient's previous history and the results of the breast diagnostics a diagnosis of extensive fat necrosis after folinic acid extravasation was made. No further measures were taken. The patient will continue to be screened using mammography. Conclusion: A good knowledge of the mammographic and sonographic features of fat necrosis can reduce the number of unnecessary biopsies. Careful consideration of the patient's prior medical history is very important in breast diagnostics and may often be decisive for the correct diagnosis. PMID- 24771913 TI - Statement by the Kommission OVAR of the AGO Study Group on the Use of HIPEC (Hyperthermic Intraperitoneal Chemotherapy) to Treat Primary and Recurrent Ovarian Cancer. AB - HIPEC is offered to patients with ovarian, fallopian tube or primary peritoneal cancer at some hospitals. Altogether, there is still no evidence that HIPEC leads to an improvement of prognosis in any gynecologic tumor, neither in primary therapy nor in treatment of relapse. The available data indicate an increased complication rate which might negatively impact the benefit-risk balance of this procedure. In addition, standard treatment with proven efficacy might be withheld due to application of unproven methods. The use of HIPEC outside of well designed, prospective and controlled clinical trials is therefore disregarded. PMID- 24771914 TI - S3 Guideline "Management of Patients with Non-Specific, Functional and Somatoform Physical Complaints" - What is Important for Gynaecological Practice? AB - When the guideline was compiled, the available evidence was heterogeneous; the evidence varied depending on the subject addressed and was often of only moderate quality. Nevertheless, a strong consensus was reached on almost all subjects. It is recommended that physicians develop a collaborative working relationship with the patient, focus on symptoms and coping strategies and avoid making stigmatising comments. A biopsychosocial diagnostic evaluation with a sensitive discussion of the signs of psychosocial stress allows problems of this type and co-morbid conditions to be recognised early on and reduces the risk of iatrogenic somatisation. In uncomplicated cases, establishing a biopsychosocial explanatory model and physical/social activation are recommended. More serious cases call for collaborative, coordinated management with regular appointments (as opposed to ad hoc appointments when the patient feels worse), gradual activation and psychotherapy. The comprehensive treatment plan can be multimodal and can potentially include physical management strategies, relaxation techniques and antidepressants. PMID- 24771916 TI - Yoga for Patients with Early Breast Cancer and its Impact on Quality of Life - a Randomized Controlled Trial. AB - The aim of this prospective, randomized, controlled trial was to investigate the impact of yoga on newly diagnosed patients with early breast cancer in the immediate postoperative phase. 93 women newly diagnosed with early breast cancer were randomized into an intervention group (IG) and a control group (waiting group, WG). The IG started yoga immediately after the operation. The WG started yoga 5 weeks after surgery. Both groups attended yoga classes twice weekly for 5 weeks. Quality of life (QoL) was evaluated using the EORTC QLQ-C30 and EORTC QLQ BR23 questionnaires before the intervention, immediately after the operation and after 3 months. After 3 months the patients were asked whether yoga improved their physical activity and whether they wished to continue with yoga. The overall QoL (p = 0.002) and the functional status (p = 0.005) increased significantly in the IG, while physical symptoms decreased over time in both groups. 86 % of patients in the IG and only 59 % of patients in the WG (p = 0.04) confirmed a positive change in their physical activity through yoga. More women in the IG intended to continue with yoga (p = 0.03). Early initiation of yoga as a supportive treatment in cancer had a positive impact on QoL. Teaching yoga allowed patients to practice yoga by themselves, enhanced the patients' QoL and was found to improve physical activity. PMID- 24771915 TI - Aspects of Therapy for Cervical Cancer in Germany 2012 - Results from a Survey of German Gynaecological Hospitals. AB - Introduction: In spite of the existence of guidelines and international recommendations, many aspects in the diagnosis, therapy and follow-up of patients with cervical cancer are not based on validated data. A broad spectrum of different opinions and procedures concerning the therapy for patients with cervical cancer is under controversial discussion by the responsible gynaecologists in German hospitals. Methods: The present study is intended to picture the current treatment situation for cervical cancer in Germany. For this purpose a specially developed questionnaire with questions divided into 19 subsections was sent to all 688 gynaecological hospitals in Germany. Results: The response rate to the questionnaire was 34 %. 91 % of the hospitals treated between 0 and 25 patients with cervical cancer per year. 7.5 % treated between 26 and 50 and 1.4 % of the hospitals more than 50 patients per year. The bimanual examination was the most frequently used staging method (98 %); PET-CT was the least used staging method (2.3 %). Interestingly 48 % of the hospitals used surgical staging. The great majority of the hospitals (71 %) used abdominal radical hysterectomy (Wertheim-Meigs operation) to treat their patients. TMMR via laparotomy was used by 13 %. 16 % of the hospitals performed laparoscopic or robot-assisted radical hysterectomies. The sentinel concept was hardly used even in the early stages. It must be emphasised that in 74 % of the hospitals radical hysterectomies were performed even in cases with positive pelvic lymph nodes and in 43 % also in cases with positive paraaortic lymph nodes. The therapy of choice for FIGO IIB cancers is primary radiochemotherapy (RCTX) in 21 % of the hospitals; operative staging followed by radiochemotherapy in 24 % and treatment by radical hysterectomy followed by adjuvant RCTX was employed in this situation by 46 % of the hospitals. In 15-97 % of the hospitals for node-negative and in sano resected patients in stage pT1B1/1B2 after radical hysterectomy, an adjuvant RCTX is recommended when further risk factors exist (LVSI, tumour > 4 cm, age < 40 years, adenocarcinoma, S3). Conclusion: A broad spectrum of differing staging and therapy concepts is in use for patients with cervical cancer in Germany. A standardisation of therapy is needed. An update of national guidelines could help to achieve more transparency and a standardisation of treatment for patients with cervical cancer. PMID- 24771917 TI - Maternal Weight Gain during Pregnancy and Somatic Classification of Neonates According to Birth Weight and Duration of Pregnancy Taking Account of Maternal Body Weight and Height. AB - Background and Aim: The classification of weight gain during pregnancy and the somatic classification of neonates according to birth weight and duration of pregnancy can be done using percentile values. We aimed to compare such classifications using percentiles of the overall study population with classifications using percentiles that were calculated taking account of maternal height and weight. Material and Methods: Using data from the German Perinatal Survey (1995-2000, over 2.2 million singleton pregnancies) we classified weight gain during pregnancy as low (< 10th percentile), high (> 90th percentile), or medium (10th-90th percentile). Neonates were classified by birth weight as small for gestational age (SGA, < 10th percentile), large for gestational age (LGA, > 90th percentile), or appropriate for gestational age (AGA, 10th-90th percentile). Classifications were performed for 12 groups of women and their neonates formed according to maternal height and weight, either with the percentiles calculated from the total study population or with group-specific percentiles. Results: Using percentiles of the total study population there was large variability between the 12 groups in the proportions with low and high weight gain and in the proportions of SGA and LGA neonates. The variability was much lower when group specific percentiles were used. Conclusions: Classifications of maternal weight gain during pregnancy and birth weight differ substantially, depending on whether percentiles calculated from the total study population or group-specific percentiles are used. The impact of using percentiles that take account of maternal anthropometric parameters for the medical care and health of neonates needs to be elucidated in future research. PMID- 24771918 TI - Neonatal Transfer Rate and Mode of Delivery from 37th Week of Gestation in a German Perinatal Center Level 1. AB - Introduction: Rates for caesarean section are on the rise and the reasons for this are being discussed worldwide. As the data is unclear, the identification of additional predictive factors for caesarean section is important as caesarean sections are closely linked to maternal and neonatal morbidity. The aim of the study was to identify predictive factors for the transfer of the neonate to a neonatal intensive care unit (NICU) depending on the mode of delivery. The study investigated the neonatal transfer rates for singleton and twin pregnancies delivered at >= 36 + 0 weeks of gestation. Material and Methods: The data of all singleton (n = 4181) and twin pregnancies (n = 305 neonates), delivered between 1 January 2009 and 31 March 2012 in the OB/Gyn Department of the University Hospital Frankfurt/M, Germany, (perinatal center level 1) were evaluated. The indications for transfer to the NICU and possible predictive factors were evaluated. Results: Our study found a two times lower neonatal transfer rate for vaginal deliveries of pregnant women without risk factors compared to women with risk factors. The following neonatal transfer rates to the NICU were noted for singleton pregnancies: 4.7 % without risk factors, 8.3 % high-risk pregnancy, 6.2 % vaginal breech delivery, 9.3 % forceps delivery, 10 % elective primary caesarean section and 14 % secondary caesarean section. There was a statistically signific. PMID- 24771919 TI - Surgical and Conservative Management of Symptomatic Leiomyomas during Pregnancy: a Retrospective Pilot Study. AB - Purpose: Evidence regarding distinguishing characteristics of women with symptomatic leiomyomas during pregnancy who undergo myomectomy during pregnancy and those who respond to conservative treatment is sparse because it mostly derives from case reports and small patient series. As the first of its type, the present study analyzed the characteristics of women with symptomatic leiomyomas treated with myomectomy during pregnancy and those treated conservatively. Methods: We performed a computer search of medical records from 1 January 2001 to 31 March 2011 using the International Classification of Diseases Codes for pregnancy, myomectomy and leiomyomas during pregnancy. Results: 27 patients were admitted during pregnancy directly related to leiomyomas; 17 of the 27 patients received conservative treatment for symptomatic leiomyomas, and 10 patients had surgery during pregnancy: 3 had undergone diagnostic surgical procedures and 7 myomectomy. Perioperative and postoperative morbidity was low in all women in our sample. Conclusion: In our pilot study, myomectomy during pregnancy was safely performed in carefully selected patients, with subserosal or pedunculated leiomyomas that failed to respond to conservative treatment, with low perioperative and postoperative morbidity. PMID- 24771920 TI - Bisphosphonates and their Role in Therapy for Breast Cancer - Results from the PATH Biobank. AB - Introduction: Bisphosphonates are well known above all for their use in the treatment of osteoporosis. They also play an important role as accompanying therapy for advanced tumour diseases with extensive spread into the skeletal system. Their adjuvant use in the treatment of breast cancer without bony metastases is currently a subject of controversial discussion. The objective of the present evaluation is to describe the use of bisphosphonates in the therapy for breast cancer. We will show how frequently bisphosphonates are used, which bisphosphonates are preferred and what specific features patients under bisphosphonate therapy exhibit. Methods and Materials: The pseudonymous data set from the biobank of the German PATH foundation was used for the evaluation. From the total collective, 2492 patients were selected after consideration of the inclusion and exclusion criteria. The selected patient collective was divided into two groups (with and without bisphosphonate therapy) and the two groups compared with one another with the help of descriptive statistics. Results: 17.5 % of the 2492 patients had prescriptions for a bisphosphonate as part of their therapy. The most frequently administered bisphosphonate was zoledronate. Pathological (induced by tumour therapy) osteoporosis was the most frequently stated indication among the bisphosphonate patients, followed by consumption starting prior to the breast cancer therapy and treatment of bony metastases. Patients under bisphosphonate and antihormonal therapy frequently received an aromatase inhibitor as the active principle in the antihormonal therapy whereas patients under antihormonal therapy but without bisphosphonates more frequently received tamoxifen as active principle. Ten of the 2492 patients reported receiving bisphosphonate therapy as prophylaxis for bony metastases without a documented and approved indication. Use of bisphosphonates in the course of the GAIN, ICE, SUCCESS or, respectively, NATAN trials was reported by 29 of the 2492 patients. Conclusions: In the PATH collective, bisphosphonates were employed above all for the treatment of (tumour therapy-induced) osteoporosis and bony metastases. Off-label use and participation in clinical trials played only a minor role in this patient collective. Against the background of the uncertain data status for the adjuvant use of bisphosphonates, the development (and use) of standardised, validated questionnaires to record the indications for and frequency of use of bisphosphonate therapy is recommended. PMID- 24771921 TI - Full Field Digital Mammography (FFDM) versus CMOS Technology, Specimen Radiography System (SRS) and Tomosynthesis (DBT) - Which System Can Optimise Surgical Therapy? AB - Aim: This prospective clinical study aimed to evaluate whether it would be possible to reduce the rate of re-excisions using CMOS technology, a specimen radiography system (SRS) or digital breast tomosynthesis (DBT) compared to a conventional full field digital mammography (FFDM) system. Material and Method: Between 12/2012 and 2/2013 50 patients were diagnosed with invasive breast cancer (BI-RADSTM 5). After histological verification, all patients underwent breast conserving therapy with intraoperative imaging using 4 different systems and differing magnifications: 1. InspirationTM (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 um pixel pitch, 8 lp/mm; 2. BioVisionTM (Bioptics, Tucson, AZ, USA), CMOS technology, photodiode array, flat panel, tungsten source, focus 0.05, resolution 50 um pixel pitch, 12 lp/mm; 3. the TridentTM specimen radiography system (SRS) (Hologic, Bedford, MA, USA), amorphous selenium, tungsten source, focus 0.05, resolution 70 um pixel pitch, 7.1 lp/mm; 4. tomosynthesis (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 um pixel pitch, 8 lp/mm, angular range 50 degrees, 25 projections, scan time > 20 s, geometry: uniform scanning, reconstruction: filtered back projection. The 600 radiographs were prospectively shown to 3 radiologists. Results: Of the 50 patients with histologically proven breast cancer (BI-RADSTM 6), 39 patients required no further surgical therapy (re-excision) after breast-conserving surgery. A retrospective analysis (n = 11) showed a significant (p < 0.05) increase of sensitivity with the BioVisionTM, the TridentTM and tomosynthesis compared to the InspirationTM at a magnification of 1.0 : 2.0 or 1.0 : 1.0 (tomosynthesis) (2.6, 3.3 or 3.6 %), i.e. re-excision would not have been necessary in 2, 3 or 4 patients, respectively, compared to findings obtained with a standard magnification of 1.0 : 1.0. Conclusion: The sensitivity of the BioVisionTM, the TridentTM and tomosynthesis was significantly (p < 0.05) higher and the rate of re-excisions was reduced compared to FFDM using a conventional detector at a magnification of 2.0 but without zooming. PMID- 24771922 TI - Sexual Function, Sexual Activity and Quality of Life in Women with Ovarian and Endometrial Cancer. AB - Background: Gynecological cancer (GC) is assumed to have an impact on sexual function and activity, but pertinent evidence is currently limited. Patients and Methods: Sexual function and activity were investigated in patients with gynecological cancer (GC) and in a control group (C), using the "Sexual Activity Questionnaire" (SAQ), the "Female Sexual Function Index" (FSFI), and parts of the EORTC QLQ-C30. Results: 727 women (335 GC and 392 C) were given a questionnaire and 22.8 % of them responded. Response rates were equivalent for both groups (23.6 % [GC] and 22.2 % [C]). 51.5 % (C) and 59.5 % (GC) were not sexually active, mainly owing to lack of a partner (37 %) or lack of interest (21 %) (C group), and lack of interest (40 %, p < 0.05), physical problems (31.9 %, p < 0.05), and physical problems suffered by their partner (21 %, p < 0.05) (GC group). There were significant differences between both groups in the SAQ discomfort score (p < 0.05), but no significant differences in quality of life or other scores for sexuality. Conclusion: The quality of sexuality tends to be impaired in GC patients, but this does not appear to influence quality of life. A shift in priorities caused by the considerable anxiety about surviving the cancer might explain our findings. PMID- 24771923 TI - Chemotherapy for 70-Year-Old Women with Breast Cancer in Germany: A Survey by the German Breast Group. AB - Aim: Around half of all women in Germany with breast cancer are older than 65 and approximately one third of them is older than 70 years of age. In theory, the preferred therapeutic management of women with breast cancer aged 65 and above corresponds to that formulated for younger patients and complies with the S3 Guidelines and the therapy recommendations formulated by AGO. To study the current therapies used to treat women with breast cancer aged 70 and above in Germany, a survey of the clinics of the German Breast Group (GBG) was done. Method: An online survey was carried out with requests sent to 599 physicians registered as principal investigators in the database of the GBG. The 12-item questionnaire was used to investigate the systematic therapeutic management of 70 year-old patients in different settings. The indication for chemotherapy was taken as a given. Results: In a neoadjuvant setting, 62 % of physicians opted for anthracycline and taxane-based therapy as did 56.6 % of physicians in an adjuvant setting. One third of physicians preferred a taxane-based therapy with the anti angiogenesis inhibitor bevacizumab as first-line therapy for primary metastatic cancer and after anthracycline-based therapy. Capecitabine (around 30 %) and navelbine (around 20 %) were proposed as second-line neoadjuvant and adjuvant therapies after prior anthracycline- and taxane-based therapy. Conclusion: The chemotherapy regimen prescribed for women with breast cancer aged 70 and above in Germany appears to be relatively standardised and corresponds to the recommendations given in the S3 Guidelines and by the AGO Breast Committee. PMID- 24771924 TI - Prenatal Clinical Assessment of sFlt-1 (Soluble fms-like Tyrosine Kinase-1)/PlGF (Placental Growth Factor) Ratio as a Diagnostic Tool for Preeclampsia, Pregnancy induced Hypertension, and Proteinuria. AB - Background: Aim of the study was a critical assessment of the clinical validity of the prenatal determination of sFlt-1/PlGF for preeclampsia (PE), pregnancy induced hypertension (PIH), and proteinuria. Our analysis was based on a specificity of 95 % and a sensitivity of 82 % for the prediction of preeclampsia, as described by Elecsys (Roche). Methods: In this retrospective study the ratio of the prenatal antiangiogenic factor sFlt-1 (soluble fms-like tyrosine kinase-1) to the proangiogenic factor PIGF (placental growth factor) was analyzed using the electrochemiluminescence immunoassay of Elecsys (Roche Diagnostics, Mannheim, Germany) in 173 pregnant women. Sixty-three women with PE, 34 women with PIH and 6 women with proteinuria were compared to 72 controls. On average, the sFlt 1/PlGF ratio was determined 8 (controls), 2.4 (PE), 3.2 (PIH) and 4.1 (proteinuria) weeks before delivery. The PE and PIH cases were further subdivided into early (< 34 weeks of gestation) and late (>= 34 weeks of gestation) onset groups. Statistical data analysis was done using the usual descriptive statistics and logistic regression analysis. ROC curves were calculated, and the sensitivity, specificity, and negative and positive predictive value (NPV, PPV) were estimated for a threshold of 85. Results: Although the specificity of the sFlt-1/PlGF ratio was high for PE, the sensitivity was low (only 59.4 %), thus giving unsatisfying results for PE. The sensitivity only increased to 62.5 % for the early-onset PE group. Intriguingly, a high ratio was detected for the combination of IUGR (intrauterine growth restriction) and PE in the early-onset PE group (8 cases). In the control group, 4 cases exceeded the cut-off value of 85 but showed no clinical signs of PE and the birth was unremarkable. In summary, we found that the sFlt-1/PIGF ratio could not be used as a predictive test for preeclampsia but rather as an indicator for the development and estimation of the severity of PE. Thus, the test is less suitable for the reliable exclusion of PE in routine clinical practice. Recommendation: The determination of the sFlT 1/PlGF ratio is only one element for PE diagnosis in addition to the measurement of blood pressure, proteinuria, ultrasound and Doppler. PMID- 24771927 TI - Assessment of University Gynaecology Clinics Based on Quality Reports. AB - Introduction: Quality reporting was initially implemented to offer a better means of assessing hospitals and to provide patients with information to help them when choosing their hospital. Quality reports are published every 2 years and include parameters describing the hospital's structure and general infrastructure together with specific data on individual specialised departments or clinics. Method: This study investigated the 2010 quality reports of German university hospitals published online, focussing on the following data: number of inpatients treated by the hospital, focus of care provided by the unit/department, range of medical services and care provided by the unit/department, non-medical services provided by the unit/department, number of cases treated in the unit/department, ICD diagnoses, OPS procedures, number of outpatient procedures, day surgeries as defined by Section 115b SGB V, presence of an accident insurance consultant and number of staff employed. Results: University gynaecology clinics (UGCs) treat 10 % (range: 6-17 %) of all inpatients of their respective university hospital. There were no important differences in infrastructure between clinics. All UGCs offered full medical care and were specialist clinics for gynaecology (surgery, breast centres, genital cancer, urogynaecology, endoscopy), obstetrics (prenatal diagnostics, high-risk obstetrics); many were also specialist clinics for endocrinology and reproductive medicine. On average, each clinic employs 32 physicians (range: 16-78). Half of them (30-77 %) are specialists. Around 171 (117-289) inpatients are treated on average per physician. The most common ICD coded treatments were deliveries and treatment of infants. Gynaecological diagnoses are underrepresented. Summary: UGCs treat 10 % of all inpatients treated in university hospitals, making them important ports of entry for their respective university hospital. Around half of the physicians are specialists. Quality reports offer little information on the differences in competencies or medical specialties. The statutory quality reports are not useful for patients and referring physicians when choosing a clinic. PMID- 24771926 TI - Small Cell Ovarian Carcinomas - Characterisation of Two Rare Tumor Entities. AB - Objective: Small cell ovarian carcinomas (SCOC) are differentiated into two types: hypercalcaemic (SCOCHT) and pulmonary (SCOCPT). Unfortunately, little is known about pulmonary-type small cell ovarian carcinoma. Study Design: We carried out a systematic analysis of all available reports in the literature on individual cases of SCOCHT and SCOCPT. Results: We found that patients with SCOCPT were significantly older than those with SCOCHT. Vimentin and chromogranin detection by immunohistochemistry allow good differentiation between the two types. Interestingly, SCOCPT but not SCOCHT was found to be associated with other benign and malignant ovarian tumours in about 44 % of cases. Although the percentage of R0/R1 resections was high (~ 74 %), survival was poor; even in patients with disease limited to the ovaries (stage Ia and Ib) the recurrence rate was 40 %. Chemotherapy with etoposide or anthracyclines could be useful. Conclusion: Taking the limitations of our study such as its retrospective nature into account and based on the results from studies of small cell carcinomas originating from other tumour sites, we conclude that treatment of SCOCPT should be based on the therapies used to treat other small cell carcinomas. Surgery is appropriate, especially in very early stages of disease, but chemotherapy should not be omitted. Newer concepts such as treatment with somatostatin analogues could help to control symptoms and stabilise some slow-growing tumours. PMID- 24771928 TI - Impact of New Shift Models for Doctors Working at a German University Hospital for Gynaecology and Obstetrics Four Years After Implementation. Can They Meet the European Working Time Directive Without Increasing Costs? AB - Background: The impact of the European Working Time Directive and subsequent collective wage agreements for doctors from 2006 onwards were substantial. So far, no systematic evaluation of their application in Germany has been performed. We evaluated the impact four years after implementation of new shift models in a University Hospital for Gynaecology and Obstetrics (UHGO). Methods: A new shift model was created together with doctors of Tubingen UHOG in 2007 and implemented in 2008. Documentation of working hours has hence been done electronically. Adherence to the average weekly working time limit (AWTL) and the maximum of 10 h daily working time (10 h-dwt) was evaluated, as well as staffing costs in relation to case-weight points gathered within the German DRG (diagnosis related groups) System. Results: Staff increased from a mean of 44.7 full time equivalent (FTE) doctors in 2007 to 52.5 FTE in 2009, 50.8 in 2010, and 54.5 in 2011. There was no statistically significant difference of the monthly staff expenditures per case-weight between the years 2009 or 2010 vs. 2007. 2011, however, was significantly more expensive than 2007 (p = 0.02). The internal control group (five other departments of the university hospital) did not show an increase during the same period. AWTL were respected by 90, 96, and 98 % in 2009, 2010, and 2011, respectively. Of all shifts 10 h-dwt was exceeded by 7.4 % in 2009, 1.3 % in 2010, and 2.6 % in 2011, with significant differences between 2009 and both, 2010 and 2011 (p < 0.001), and between 2010 and 2011 (p = 0.02). Discussion: AWTL and 10 h-dwt could be continuously respected quite well after implementation of the new shift model without increasing the cost/earnings ratio for the first two years. However, in 2011 the ratio increased significantly (p = 0.02). PMID- 24771929 TI - Upper Blepharoplasty for Areola Reconstruction. AB - Blepharoplasty is one of the most common rejuvenating facial plastic surgery procedures. The procedure has been described many times and has very few complications. The tissue removed from the upper eyelid during blepharoplasty can be used as a skin graft for areola reconstruction due to the tissue's similarity to the areola's natural skin. The present study investigated the use of upper blepharoplasty for areola reconstruction. Criteria were patient satisfaction, objective measurements and the assessment of cosmesis by a panel of physicians. All eight patients included in the study were very satisfied with the cosmetic result. Objective measurements and assessment by a panel of physicians using photographs of the reconstructed nipple-areola complex showed very good aesthetic results. PMID- 24771925 TI - Interdisciplinary GoR level III Guidelines for the Diagnosis, Therapy and Follow up Care of Breast Cancer: Short version - AWMF Registry No.: 032-045OL AWMF Register-Nummer: 032-045OL - Kurzversion 3.0, Juli 2012. PMID- 24771930 TI - Vaginal Removal of Very Large Nascent Uterine Myoma - Case Report and Literature Review. AB - This report shows that even extremely large nascent uterine myomas can be removed vaginally. A 25-year-old nulligravid and nulliparous patient with malaise, hypermenorrhea, and intermittent cramping pain in the lower abdomen was referred to our clinic. Gynecological examination revealed a round cauliflower-like tumor, 7 cm in diameter, originating from the external cervical os with a rough surface and without a palpable stalk or base. Ultrasound scan showed a hyperechogenic mass within the uterine cavity with two distinct subunits: one (55 * 44 mm) well demarcated from the surrounding structures and the other (43 * 38 mm) in close proximity to the lower part of the anterior uterine wall and in continuity with the myometrium. At surgery, the myoma was completely removed vaginally. Recovery was prompt, complete, and uneventful. Follow-up at one and three months confirmed normal gynecological and sonographic findings. In conclusion, vaginal myomectomy is the treatment of choice for prolapsed pedunculated submucous myoma; even extremely large nascent myomas can be efficiently removed vaginally. PMID- 24771931 TI - Shaping the System - The DRG Evaluation Project of the German Society for Gynaecology and Obstetrics (Deutsche Gesellschaft fur Gynakologie und Geburtshilfe, DGGG). AB - Introduction: The German DRG system is annually adapted to the changing services provided. For the further development, the self-governing body and its DRG Institute (InEK) depend on participation of the users. Methods: For one of the DRG evaluation projects initiated by DGGG, cost and performance data for the year 2011 from 16 hospitals were available. After plausibility checks and corrections, analyses for service and cost homogeneity were performed. In cases of inadequate DRG-representation attributes were sought that would make an appropriate reimbursement possible. Conspicuities and potential solutions were checked for clinical plausibility. Results: 44 concrete modification proposals for further development of the G-DRG system were formulated and submitted in due time to the InEK. In addition, 3 modification proposals were addressed to the German Institute for Medical Documentation and Information (Deutsches Institut fur Medizinische Dokumentation und Information, DIMDI) for further development of the diagnosis classification ICD-10-GM. For all modification proposals care was taken to minimise misdirected incentives and to reduce the potential for disputes with the cost bearers and their auditors services in settlements. Discussion: The publication of the G-DRG system 2014 shows which modification proposals have been realised. Essentially, an appropriate redistribution of the resources among the gynaecological and obstetrics departments is to be expected. The financial pressure that is caused by the generally inadequate financing of hospitals will not be reduced by a further development of the G-DRG system. PMID- 24771932 TI - Impact of Patient and Procedure Mix on Finances of Perinatal Centres - Theoretical Models for Economic Strategies in Perinatal Centres. AB - Introduction: In Germany, cost and revenue structures of hospitals with defined treatment priorities are currently being discussed to identify uneconomic services. This discussion has also affected perinatal centres (PNCs) and represents a new economic challenge for PNCs. In addition to optimising the time spent in hospital, the hospital management needs to define the "best" patient mix based on costs and revenues. Method: Different theoretical models were proposed based on the cost and revenue structures of the University Perinatal Centre for Franconia (UPF). Multi-step marginal costing was then used to show the impact on operating profits of changes in services and bed occupancy rates. The current contribution margin accounting used by the UPF served as the basis for the calculations. The models demonstrated the impact of changes in services on costs and revenues of a level 1 PNC. Results: Contribution margin analysis was used to calculate profitable and unprofitable DRGs based on average inpatient cost per day. Nineteen theoretical models were created. The current direct costing used by the UPF and a theoretical model with a 100 % bed occupancy rate were used as reference models. Significantly higher operating profits could be achieved by doubling the number of profitable DRGs and halving the number of less profitable DRGs. Operating profits could be increased even more by changing the rates of profitable DRGs per bed occupancy. The exclusive specialisation on pathological and high-risk pregnancies resulted in operating losses. All models which increased the numbers of caesarean sections or focused exclusively on c-sections resulted in operating losses. Conclusion: These theoretical models offer a basis for economic planning. They illustrate the enormous impact potential changes can have on the operating profits of PNCs. Level 1 PNCs require high bed occupancy rates and a profitable patient mix to cover the extremely high costs incurred due to the services they are legally required to offer. Based on our theoretical models it must be stated that spontaneous vaginal births (not caesarean sections) were the most profitable procedures in the current DRG system. Overall, it currently makes economic sense for level I PNCs to treat as many low-risk pregnancies and neonates as possible to cover costs. PMID- 24771933 TI - Children and Employment - Resource or Stressors after Breast Cancer? AB - Introduction: Breast cancer patients suffer clinically relevant levels of psychological stress because of their disease. Various factors can affect the level of stress experienced. This study aimed to investigate the relationship between the level of psychological stress and employment and children, including time since diagnosis. Material and Methods: A randomised clinical study was done of 724 breast cancer patients aged between 18 and 65 years; all were in the curative stage of disease and had been diagnosed 0-12 months previously. Patients were investigated for their levels of psychological stress (anxiety and depression) using the Hospital Anxiety and Depression Scale (HADS). The relationship between anxiety and depression and the variables "employment", "parenthood" and "time since diagnosis" were investigated, using univariate and multivariate analysis. Results: Patients with a longer time since diagnosis (4-12 months) were found to have lower levels of anxiety (6.28) compared to patients who had been diagnosed only 0-3 months previously (7.24; p < 0.01). There was no unambiguous relation between parenthood and anxiety. The age of the children was crucial. Even when results were controlled for patient age, the anxiety levels of women with children below the age of 16 years were significantly higher (7.84) compared to patients without children (6.42) or patients whose children were older than 16 years (6.87; p = 0.04). Women who were not employed had significantly higher levels of depression compared to all other participants in the study (p = 0.02). No reciprocal effects were found between investigated variables. Conclusion: We found a differentiated relationship between the variables "time since diagnosis", "employment" and "children" and the level of psychological stress experienced by breast cancer patients. When determining the level of psychological stress in the 1st year after diagnosis, particular attention should be paid to patients who are not employed and patients with children below the age of 16 years. PMID- 24771934 TI - Knowledge and Behaviour of Young People Concerning Fertility Risks - Results of a Questionnaire. AB - Purpose: The aim of this study was, in the light of the increasing number of involuntarily childless couples, to investigate the state of knowledge of young people of fertile age about the risks for fertility disorders and their own risk behaviour. In addition, we wanted to check for a relationship between these aspects and the motives for wanting children, individual personality traits and psychological status. Materials and Methods: 498 women and men between the ages of 18 and 30 years participated in an anonymous survey. The sample consisted of 153 medical students, 190 students from other faculties and 155 vocational trainees. Their knowledge was tested by way of open questions on reproduction. The sum total from relevant life-style factors was used to estimate their risk taking behaviour. Their psychic states were examined using the Health Questionnaire for Patients "Gesundheitsfragebogen fur Patienten" PHQ-D, in addition the Leipzig Questionnaire on Motives for Wanting Children "Der Leipziger Fragebogen zu Kinderwunschmotiven" and the short version of the "Big Five Inventory" BFI-K were used. Results: The participants were aware of the risks for fertility disorders but did not always correctly assess their influence on fertility. Their knowledge about reproduction was rather low (on average 6.3 from 16 points). Medical students had a significantly higher state of knowledge and exhibited less risky behaviour as compared to the other two groups. Depressiveness and risky behaviour correlated positively and emotional aspects played the major role in attitudes towards having children. Risk behaviour was best predicted by the variables depressiveness, low level of knowledge and the feeling of being restricted in personal life by children. Discussion: Lack of knowledge on the topics fertility and reproduction could be a reason for risky behaviour and thus have a negative impact on lifestyle factors relating to fertility. Young people are aware of the risk factors that may affect fertility but do not always act accordingly. Primary prevention or, respectively, health promotion is thus necessary to prevent further increases in the number of infertile couples. PMID- 24771935 TI - Success Rate of Inseminations Dependent on Maternal Age? An Analysis of 4246 Insemination Cycles. AB - Intrauterine insemination (IUI) has latterly become less important in reproductive medicine. The aim of this retrospective analysis was to identify and evaluate the success rates of repeated insemination cycles in women of different ages. All women who underwent intrauterine insemination in the Wiesbaden Fertility Clinic between 1998 and 2010 were included in the analysis. Additional inclusion criteria were: not more than 45 years old, previous FSH stimulation and slight to moderate subfertility of the male partner. A total of 4246 insemination cycles in 1612 patients were included in the analysis. The average number of IUI cycles per patient was 2.24 (1-14). Patient age ranged from 19 to 45 years (mean: 33.9 years). Logistic regression analysis showed a drop in pregnancy rates with increasing age (p = 0.000). However, for the first three cycles the pregnancy rates for women aged 40 and 41 did not differ from those of women aged between 35 and 39 years. Overall pregnancy rates were stable in women up to the age of 40, even after several insemination cycles (7.5 and 10 %). Insemination is therefore still an effective procedure in selected patients. Stable pregnancy rates were recorded even after more than 3 cycles. After 3 cycles, the success rates for women aged 40 and 41 did not differ from those of women below the age of 40. PMID- 24771936 TI - Pregnancy and Birth After a Two-Step PGD: Polar Body Diagnosis for Hemophilia A and Array CGH on Trophectoderm Cells for Chromosomal Aberrations. AB - Objective: To demonstrate that a PGD program can be successfully established after the 2011 verdict of the German Bundestag concerning PGD. Material and Method: Eight years previously, the couple had had a daughter who suffered from clinically manifest hemophilia A due to an unbalanced X-inactivation, as well as microdeletion syndrome resulting in severe physical and mental disability. The couple wished to have a second child but refused the idea of a "trial" pregnancy. Given the indications for both, it was necessary to carry out polar body diagnosis (PBD) to rule out hemophilia A and, during the same cycle, a subsequent PGD on the blastocysts to rule out genetic aberrations. The PBD and PGD (trophectoderm biopsy, TEB) were performed after high-dosage ovarian stimulation and ICSI fertilization of the oocytes. A blastocyst was successfully transferred on day 6. Results: The patient conceived immediately. The pregnancy developed normally and the patient gave birth to a girl in the 40th week of pregnancy. Post natal examinations showed that the baby is free from hemophilia A and is developing normally both physically and mentally. Conclusion: Establishment of a PGD program is now possible after legalization of PGD in Germany. It is possible to apply two investigative techniques in a single treatment cycle if multifactorial diagnosis is required. PMID- 24771939 TI - Interdisciplinary S2e Guideline for the Diagnosis and Treatment of Stress Urinary Incontinence in Women: Short version - AWMF Registry No. 015-005, July 2013. PMID- 24771940 TI - Explanation and Use of the Colposcopy Terminology of the IFCPC (International Federation for Cervical Pathology and Colposcopy) Rio 2011. AB - In July 2012 a revised terminology on colposcopic examinations of the cervix uteri was adopted by IFCPC. Central aspect is a description of characteristics that should aid in the definition of the disease entity cervix uteri. The nomenclature is built up in such a way that the examiner can evaluate colposcopic criteria according to a specific scheme. Firstly it is assessed whether the colposcopy is representative. Then it should be clarified whether or not the findings are normal. If the findings are not normal but rather abnormal the severity of the lesion is classified according to the so-called grade 1 (minor change) and grade 2 findings (major change). Specific abnormal findings such as leukoplakia, erosion and Lugol's finding are also not defined at this point. Characteristics suspicious for an invasion are described separately, in particular, atypical vessel patterns are mentioned here. As already held in the previous revised nomenclature (Barcelona), various findings are described in a last group: congenital transformation zones (CTZ), congenital anomalies, condylomas (papillomas), endometriosis, polyps (ectocervical, endocervical), inflammation, stenosis, postoperative changes (scarred portio, vaginal stump). PMID- 24771938 TI - Interdisciplinary S2k Guidelines for the Diagnosis and Treatment of Endometriosis: Short Version - AWMF Registry No. 015-045, August 2013. PMID- 24771941 TI - Innovations in Cervical and Endometrial Cancer. AB - The S2k guideline "Diagnostics and Therapy for Cervical Cancer" published in 2008 is currently being revised to the S3 level. Current developments in epidemiology, surgical therapy, radiochemotherapy and drug therapy will be presented. The S2k guideline "Diagnostics and Therapy for Endometrial Cancer" will also be up-dated this year. The revised recommendations on early diagnosis and diagnostics, therapy for precursors, surgical therapy, adjuvant therapy and therapy for recurrences and metastases will be presented. PMID- 24771937 TI - S3-Guideline on Diagnostics, Therapy and Follow-up of Malignant Ovarian Tumours: Short version 1.0 - AWMF registration number: 032/035OL, June 2013. PMID- 24771942 TI - Use of Laparoscopy in the Treatment of Endometrial and Cervical Cancer - Results of a 2012 Germany-wide Survey. AB - Introduction: Endoscopy has begun to play an increasingly important role in the surgical therapy of uterine cancers. To date, there is no data on the use of laparoscopy to treat endometrial cancer (EC) and cervical cancer (CC). Method: A Germany-wide, anonymised survey was done of all gynaecological clinics/endoscopy clinics, using a standardised questionnaire. Results: A total of 128 clinics responded: 16 university clinics (12.5 %), 30 hospitals offering maximum care (23.4 %), 66 general hospitals (51.5 %), 5 outpatient clinics (3,9 %), 4 physicians in private practice affiliated to hospitals (3.1 %) and 7 hospitals (5.4 %) which did not indicate status. Laparoscopy was used in the treatment of 82 % of all EC and 54 % of CC. Surgery for EC was done completely laparoscopically in 58 % of cases and with laparoscopic assistance using a vaginal approach in 32 % of cases. If lymphadenectomy (LNE) was additionally performed, this was done abdominally in 42 % of cases and laparoscopically in 53 %. Cervical cancer was treated by laparoscopic radical hysterectomy (HE) in 44 % of cases and by radical HE using a vaginal approach in 14 %. 4 % of hospitals reported the use of other endoscopic methods (e.g. DaVinci). While the majority of hospitals (43.3 %) treated more than 75 % of EC patients using laparoscopy, in many clinics (38.3 %) less than 25 % of CC patients were treated using endoscopy. Discussion: Laparoscopy is used more often in EC surgery as compared to surgery for CC. However, there are still major differences between hospitals with regard to case numbers, the number of uterine cancers treated using endoscopic surgery, and the type of endoscopic surgery. PMID- 24771943 TI - Surgical Therapy of Endometriosis: Challenges and Controversies. AB - Endometriosis is one of the most common disorders encountered in surgical gynaecology. The laparoscopic technique, the planning of the surgical intervention, the extent of information provided to patients and the interdisciplinary coordination make it a challenging intervention. Complete resection of all visible foci of disease offers the best control of symptoms. However, the possibility of achieving this goal is limited by the difficulty of detecting all foci and the risks associated with radical surgical strategies. Thus, the excision of ovarian endometrioma can result in a significant impairment of ovarian function, while damage to nerve structures during resection of the uterosacral ligaments, the parametrium, the rectovaginal septum or the vaginal cuff to treat deep infiltrating endometriosis can lead to serious functional impairments such as voiding disorders. A detailed risk-benefit analysis is therefore necessary, and patients must be treated using an individual approach. PMID- 24771944 TI - Adenomyosis: Epidemiology, Risk Factors, Clinical Phenotype and Surgical and Interventional Alternatives to Hysterectomy. AB - Adenomyosis is an important clinical challenge in gynecology and healthcare economics; in its fully developed form, hysterectomy is often used to treat it in premenopausal and perimenopausal women. Symptoms of adenomyosis typically include menorrhagia, pelvic pain and dysmenorrhea. Moreover, adenomyosis and leiomyomas commonly coexist in the same uterus, and differentiating the symptoms for each pathological process can be problematic. Although it has been recognized for over a century, reliable epidemiological studies on this condition are limited, because only postoperative diagnoses were possible in the past. Minimally invasive surgical techniques (endometrial ablation/resection, myometrial excision/reduction, myometrial electrocoagulation, uterine artery ligation) have had limited success in the treatment of adenomyosis, and the reported data for these procedures have been obtained from case reports or small case series with only short follow-up times. However, newer techniques including uterine artery embolization (UAE) and magnetic resonance imaging guided focused ultrasound (MRgFUS) show promise in treating adenomyosis. The data is strongest for UAE; these studies have the largest patient cohorts. However, none of the UAE studies were randomized or controlled. Thus, despite the clinical importance of adenomyosis, there is little evidence on which to base treatment decisions. The objective of this review is to summarize the epidemiology, risk factors, clinical phenotype and to evaluate the accrued experience with surgical and interventional alternatives to hysterectomy. PMID- 24771946 TI - Rapid Characterization of Magnetic Moment of Cells for Magnetic Separation. AB - NCI-H1650 lung cancer cell lines labeled with magnetic nanoparticles via the Epithelial Cell Adhesion Molecule (EpCAM) antigen were previously shown to be captured at high efficiencies by a microfabricated magnetic sifter. If fine control and optimization of the magnetic separation process is to be achieved, it is vital to be able to characterize the labeled cells' magnetic moment rapidly. We have thus adapted a rapid prototyping method to obtain the saturation magnetic moment of these cells. This method utilizes a cross-correlation algorithm to analyze the cells' motion in a simple fluidic channel to obtain their magnetophoretic velocity, and is effective even when the magnetic moments of cells are small. This rapid characterization is proven useful in optimizing our microfabricated magnetic sifter procedures for magnetic cell capture. PMID- 24771947 TI - Legislating Change? Responses to Criminalizing Female Genital Cutting in Senegal. AB - Although the international community has recently promoted legislation as an important reform strategy for ending female genital cutting (FGC), there exist divergent views on its potential effects. Supporters argue that legal prohibition of FGC has a general deterrent effect, while others argue legislation can be perceived as coercive, and derail local efforts to end the practice. This study examines the range of responses observed in rural Senegal, where a 1999 anti-FGC law was imposed on communities in which the practice was being actively contested and targeted for elimination. Drawing on data from a mixed-methods study, we analyze responses in relation to two leading theories on social regulation, the law and economics and law and society paradigms, which make divergent predictions on the interplay between social norms and legal norms. Among supporters of FGC, legal norms ran counter to social norms, and did little to deter the practice, and in some instances incited reactance or drove the practice underground. Conversely, where FGC was being contested, legislation served to strengthen the stance of those contemplating or favoring abandonment. We conclude that legislation can complement other reform strategies by creating an "enabling environment" that supports those who have or wish to abandon FGC. PMID- 24771945 TI - Multigene Assays for Classification, Prognosis, and Prediction in Breast Cancer: a Critical Review on the Background and Clinical Utility. AB - Gene signatures which are based on multigene profiling assays have been developed for the purpose to better define the prognosis and prediction of therapy results in early-stage breast cancer. These assays were designed to be more specific than conventional clinico-pathologic parameters in the selection of patients for (neo )adjuvant treatment and in effect help to avoid unnecessary cytotoxic treatment. In this review we describe molecular risk scores, for which tests are commercially available (PAM50(r), MammaTyper(r), MammaPrint(r), Oncotype DX(r), Endopredict(r), Genomic Grade Index(r)) and IHC risk scores (Mammostrat(r) and IHC4), and discuss the current evidence of their clinical use. PMID- 24771948 TI - Species-specific bioluminescence facilitates speciation in the deep sea. AB - The vast darkness of the deep sea is an environment with few obvious genetic isolating barriers, and little is known regarding the macroevolutionary processes that have shaped present-day biodiversity in this habitat. Bioluminescence, the production and emission of light from a living organism through a chemical reaction, is thought to occur in approximately 80 % of the eukaryotic life that inhabits the deep sea (water depth greater than 200 m). In this study, we show, for the first time, that deep-sea fishes that possess species-specific bioluminescent structures (e.g., lanternfishes, dragonfishes) are diversifying into new species at a more rapid rate than deep-sea fishes that utilize bioluminescence in ways that would not promote isolation of populations (e.g., camouflage, predation). This work adds to our understanding of how life thrives and evolution shaped present-day biodiversity in the deep sea, the largest and arguably least explored habitat on earth. PMID- 24771949 TI - ANALYSIS OF A NUMERICAL SOLVER FOR RADIATIVE TRANSPORT EQUATION. AB - We analyze a numerical algorithm for solving radiative transport equation with vacuum or reflection boundary condition that was proposed in [4] with angular discretization by finite element method and spatial discretization by discontinuous Galerkin or finite difference method. PMID- 24771950 TI - Modeling Time-Dependent Association in Longitudinal Data: A Lag as Moderator Approach. AB - We describe a straightforward, yet novel, approach to examine time-dependent association between variables. The approach relies on a measurement-lag research design in conjunction with statistical interaction models. We base arguments in favor of this approach on the potential for better understanding the associations between variables by describing how the association changes with time. We introduce a number of different functional forms for describing these lag moderated associations, each with a different substantive meaning. Finally, we use empirical data to demonstrate methods for exploring functional forms and model fitting based on this approach. PMID- 24771951 TI - Total Synthesis of (+/-)-Hibiscone C. AB - A total synthesis of (+/-)- hibiscone C, one member of the furanosteroid family of natural products that also includes viridin and wortmannin, is reported. Two new pathways for formation of the key diacyl furan subunit are described. PMID- 24771953 TI - From the Consulting Room to the Court Room? Taking the Clinical Model of Responsibility Without Blame into the Legal Realm. AB - Within contemporary penal philosophy, the view that punishment can only be justified if the offender is a moral agent who is responsible and hence blameworthy for their offence is one of the few areas on which a consensus prevails. In recent literature, this precept is associated with the retributive tradition, in the modern form of 'just deserts'. Turning its back on the rehabilitative ideal, this tradition forges a strong association between the justification of punishment, the attribution of responsible agency in relation to the offence, and the appropriateness of blame. By contrast, effective clinical treatment of disorders of agency employs a conceptual framework in which ideas of responsibility and blameworthiness are clearly separated from what we call 'affective blame': the range of hostile, negative attitudes and emotions that are typical human responses to criminal or immoral conduct. We argue that taking this clinical model of 'responsibility without blame' into the legal realm offers new possibilities. Theoretically, it allows for the reconciliation of the idea of 'just deserts' with a rehabilitative ideal in penal philosophy. Punishment can be reconceived as consequences-typically negative but occasionally not, so long as they are serious and appropriate to the crime and the context-imposed in response to, by reason of, and in proportion to responsibility and blameworthiness, but without the hard treatment and stigma typical of affective blame. Practically, it suggests how sentencing and punishment can better avoid affective blame and instead further rehabilitative and related ends, while yet serving the demands of justice. PMID- 24771952 TI - The emergence of intention attribution in infancy. AB - Perception of the social world in terms of agents and their intentional relations is fundamental to human experience. In this chapter, we review recent investigations into the origins of this fundamental ability that trace its roots to the first year of life. These studies show that infants represent others' actions not as purely physical motions, but rather as actions directed at goals and objects of attention. Infants are able to recover intentional relations at varying levels of analysis, including concrete action goals, higher-order plans, acts of attention, and collaborative goals. There is mounting evidence that these early competencies are strongly influenced by infants' own experience as intentional agents. Action experience shapes infants' action perception. PMID- 24771954 TI - Effects of lexical status and morphological complexity in masked priming: An ERP study. AB - Two masked priming experiments examined behavioural and event-related potential responses to simplex target words (e.g., flex) preceded by briefly presented, masked, derived word primes (flexible-flex), complex nonword primes formed by an illegal combination of the target word and a real suffix (flexify-flex), and simplex nonword primes formed by adding a nonsuffix word ending to the target (flexint-flex). Subjects performed a lexical decision task. Behavioural results showed that all prime types significantly facilitated target recognition. Priming effects were reflected in the electrophysiological data by reduced N250 and N400 amplitudes, and these priming effects were statistically equivalent for the three types of prime. The strong priming effects found with simplex primes in the present study, compared with prior research, are thought to be due to the combination of targets always being completely embedded in prime stimuli plus the reduced lexical inhibition that arises with nonword primes. In line with prior behavioural research, however, there was evidence for differential priming effects as a function of prime type in the N400 ERP component in Experiment 2, with greater priming effects for derived and pseudocomplex primes relative to simplex primes at lateral posterior electrode sites. PMID- 24771955 TI - Referential choice across the lifespan: why children and elderly adults produce ambiguous pronouns. AB - In this study, children, young adults and elderly adults were tested in production and comprehension tasks assessing referential choice. Our aims were (1) to determine whether speakers egocentrically base their referential choice on the preceding linguistic discourse or also take into account the perspective of a hypothetical listener and (2) whether the possible impact of perspective taking on referential choice changes with increasing age, with its associated changes in cognitive capacity. In the production task, participants described picture-based stories featuring two characters of the same gender, making it necessary to use unambiguous forms; in the comprehension task, participants interpreted potentially ambiguous pronouns at the end of similar orally presented stories. Young adults (aged 18-35) were highly sensitive to the informational needs of hypothetical conversational partners in their production and comprehension of referring expressions. In contrast, children (aged 4-7) did not take into account possible conversational partners and tended to use pronouns for all given referents, leading to the production of ambiguous pronouns that are unrecoverable for a listener. This was mirrored in the outcome of the comprehension task, where children were insensitive to the shift of discourse topic marked by the speaker. The elderly adults (aged 69-87) behaved differently from both young adults and children. They showed a clear sensitivity to the other person's perspective in both production and comprehension, but appeared to lack the necessary cognitive capacities to keep track of the prominence of discourse referents, producing more potentially ambiguous pronouns than young adults, though fewer than children. In conclusion then, referential choice seems to depend on perspective taking in language, which develops with increasing linguistic experience and cognitive capacity, but also on the ability to keep track of the prominence of discourse referents, which is gradually lost with older age. PMID- 24771956 TI - Potential novel biomarkers for diabetic testicular damage in streptozotocin induced diabetic rats: nerve growth factor Beta and vascular endothelial growth factor. AB - BACKGROUND: It is well known that diabetes mellitus may cause testicular damage. Vascular endothelial growth factor (VEGF) and nerve growth factor beta (NGF-beta) are important neurotrophic factors for male reproductive system. OBJECTIVE: We aimed to investigate the correlation between testicular damage and testicular VEGF and NGF-beta levels in diabetic rats. METHODS: Diabetes was induced by streptozotocin (STZ, 45 mg/kg/i.p.) in adult rats. Five weeks later testicular tissue was removed; testicular VEGF and NGF-beta levels were measured by ELISA. Testicular damage was detected by using hematoxylin and eosin staining and periodic acid-Schiff staining, and apoptosis was identified by terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL). Seminiferous tubular sperm formation was evaluated using Johnsen's score. RESULTS: In diabetic rats, seminiferous tubule diameter was found to be decreased; basement membrane was found to be thickened in seminiferous tubules and degenerated germ cells. Additionally, TUNEL-positive cells were increased in number of VEGF+ cells and levels of VEGF and NGF-beta were decreased in diabetic testes. Correlation between VEGF and NGF-beta levels was strong. CONCLUSION: These results suggest that the decrease of VEGF and NGF-beta levels is associated with the increase of the apoptosis and testicular damage in diabetic rats. Testis VEGF and NGF-beta levels could be potential novel biomarkers for diabetes induced testicular damage. PMID- 24771958 TI - Arsenic(V) Removal in Wetland Filters Treating Drinking Water with Different Substrates and Plants. AB - Constructed wetlands are an attractive choice for removing arsenic (As) within water resources used for drinking water production. The role of substrate and vegetation in As removal processes is still poorly understood. In this study, gravel, zeolite (microporous aluminosilicate mineral), ceramsite (lightweight expanded clay aggregate) and manganese sand were tested as prospective substrates while aquatic Juncus effuses (Soft Rush or Common Rush) and terrestrial Pteris vittata L. (Chinese Ladder Brake; known as As hyperaccumulator) were tested as potential wetland plants. Indoor batch adsorption experiments combined with outdoor column experiments were conducted to assess the As removal performances and process mechanisms. Batch adsorption results indicated that manganese sand had the maximum As(V) adsorption rate of 4.55 h-1 and an adsorption capacity of 42.37 MUg/g compared to the other three aggregates. The adsorption process followed the pseudo-first-order kinetic model and Freundlich isotherm equations better than other kinetic and isotherm models. Film-diffusion was the rate limiting step. Mean adsorption energy calculation results indicated that chemical forces, particle diffusion and physical processes dominated As adsorption to manganese sand, zeolite and gravel, respectively. During the whole running period, manganese sand-packed wetland filters were associated with constantly 90% higher As(V) reduction of approximate 500 MUg/L influent loads regardless if planted or not. The presence of P. vittata contributed to no more than 13.5% of the total As removal. In contrast, J. effuses was associated with a 24% As removal efficiency. PMID- 24771957 TI - The use of functional genomics in conjunction with metabolomics for Mycobacterium tuberculosis research. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a fatal infectious disease, resulting in 1.4 million deaths globally per annum. Over the past three decades, genomic studies have been conducted in an attempt to elucidate the functionality of the genome of the pathogen. However, many aspects of this complex genome remain largely unexplored, as approaches like genomics, proteomics, and transcriptomics have failed to characterize them successfully. In turn, metabolomics, which is relatively new to the "omics" revolution, has shown great potential for investigating biological systems or their modifications. Furthermore, when these data are interpreted in combination with previously acquired genomics, proteomics and transcriptomics data, using what is termed a systems biology approach, a more holistic understanding of these systems can be achieved. In this review we discuss how metabolomics has contributed so far to characterizing TB, with emphasis on the resulting improved elucidation of M. tuberculosis in terms of (1) metabolism, (2) growth and replication, (3) pathogenicity, and (4) drug resistance, from the perspective of systems biology. PMID- 24771959 TI - The effect of female mating status on male offspring traits. AB - In haplodiploid insects, males develop from unfertilized eggs; consequently, unmated females can reproduce. In a patchy, highly structured population, where brothers compete for mates and the reproductive return through sons is lower, females should minimize the number of male offspring. Consequently, unmated females are likely to have a reduced fitness compared to mated females. Here, we tested the oviposition behaviour of the haplodiploid beetle Coccotrypes dactyliperda. In this species, the unmated female can mate with her son to produce daughters. We predicted that unmated females could increase their fitness by (1) producing only few and small sons sufficient for mother-son mating and (2) dispersing to a patch occupied by conspecific females in order to increase their or their sons' chance of mating. We demonstrate that (1) unmated females are common (23 % of all females), (2) they oviposit more frequently than mated females in occupied patches, (3) unmated females oviposit more eggs than mated females-this is in spite of the trade-offs, evident in this study, between the number of sons and the number of the mother's future offspring after mating, (4) unmated females have a higher proportion of dispersing sons, and (5) sons of unmated females are smaller than sons of mated females. We conclude that the incidence of unmated females in the structured populations of C. dactyliperda is explained by plasticity in their oviposition behaviour. We discuss conditions where a high incidence of unmated females can persist as a successful strategy in structured populations. PMID- 24771960 TI - Limited geographic variation in the acoustic structure of and responses to adult male alarm barks of African green monkeys. AB - The global diversity of human languages is a remarkable feature of our species, which requires a capacity for rapid vocal learning. Given that primate alarm calling systems have played an important role in the language origin debate, identifying geographic variation in primate alarm calls and understanding the underlying causal mechanisms are important steps to help uncover evolutionary precursors to language. This study investigates geographic variation in the alarm bark of the widely distributed African green monkey (Chlorocebus). To quantify geographic variation in spectral and temporal call structure, acoustic analysis was used to compare the adult male barks of green monkeys (Chlorocebus sabaeus) and two subspecies of vervet (Chlorocebus pygerythrus pygerythrus and Chlorocebus pygerythrus hilgerti). Playback experiments were also carried out to test whether adult male vervets would distinguish between the barks of own-group males, unknown conspecific males and green monkey males. Acoustic analysis showed that, whilst similar in overall structure, the barks of green monkeys could be distinguished from vervet barks with a high degree of accuracy; the barks of vervet subspecies could also be discriminated, although to a lesser degree. Males responded most strongly to unknown conspecific males' barks, and exhibited responses typical of leopard-avoidance and territorial defence. Taken together, these findings indicate that variation in alarm calls can be best explained by phylogenetic distance, and that intra- and inter-species differences are relevant during social interactions. Moreover, barks may function as an alarm and display call, which could explain the observed sexual dimorphism in barks in this genus. PMID- 24771961 TI - Evolution of within-colony distribution patterns of birds in response to habitat structure. AB - It has long been suggested that habitat structure affects how colonial birds are distributed within their nesting aggregations, but this hypothesis has never been formally tested. The aim of this study was to test for a correlated evolution between habitat heterogeneity and within-colony distributions of Ciconiiformes by using Pagel's general method of comparative analysis for discrete variables. The analysis indicated that central-periphery gradients of distribution (high-quality individuals occupying central nesting locations) prevail in species breeding in homogeneous habitats. These were mainly ground-nesting larids and spheniscids, where clear central-periphery patterns were recorded in ca. 80 % of the taxa. Since homogeneous habitats provide little variation in the physical quality of nest sites, central nesting locations should be largely preferred because they give better protection against predators by means of more efficient predator detection and deterrence. By contrast, central-periphery gradients tended to be disrupted in heterogeneous habitats, where 75 % of colonial Ciconiiform species showed uniform patterns of distribution. Under this model of distribution, edge nest sites of high physical quality confer higher fitness benefits in comparison to low-quality central sites, and thus, high-quality pairs are likely to choose nest sites irrespectively of their within-colony location. Breeding in homogeneous habitats and uniform distribution patterns were identified as probable ancestral states in Ciconiiformes, but there was a significant transition rate from uniform to central-periphery distributions in species occupying homogeneous habitats. PMID- 24771962 TI - THE DIABETES EPIDEMIC: Environmental Chemical Exposure in Etiology and Treatment. PMID- 24771963 TI - Effect of Intervention with the Self-Determined Learning Model of Instruction on Access and Goal Attainment. AB - Promoting student self-determination has been identified as best practice in special education and transition services and as a means to promote access to the general education curriculum for students with disabilities. There have been, however, limited evaluations of the effects of interventions to promote self determination on outcomes related to access to the general education curriculum. This article reports finding from a cluster or group-randomized trial control group study examining the impact of intervention using the Self-Determined Learning Model of Instruction on student academic and transition goal attainment and on access to the general education curriculum for students with intellectual disability and learning disabilities Findings support the efficacy of the model for both goal attainment and access to the general education curriculum, though students varied in the patterns of goal attainment as a function of type of disability. PMID- 24771965 TI - Awards galore ... the results are in! PMID- 24771964 TI - Culturally-Driven Biases in Preschoolers' Spatial Search Strategies for Ordinal and Non-Ordinal Dimensions. AB - Culturally-driven spatial biases affect the way people interact with and think about the world. We examine the ways in which spatial presentation of stimuli affects learning and memory in preschool-aged children in the USA and Israel. In Experiment 1, preschoolers in both cultures were given a spatial search task in which they were asked to utilize verbal labels (letters of the alphabet) to match the hiding locations of two monkeys. The labels were taught to the children in either a left-to-right or right-to-left fashion to assess whether performance on this task is affected by directionality of labeling. English-speaking children performed better on the spatial search task when locations were labeled in a left to-right fashion, while Hebrew-speaking children exhibited higher performance when labels were taught in a right-to-left fashion. In Experiment 2, English speaking preschoolers were given a modified task in which the verbal label was a non-ordinal stimulus type (colors). These children showed no subsequent advantage on the task for spatial presentations which were culturally-consistent (left-to right) relative to culturally-inconsistent (right-to-left). These findings support the hypothesis that culturally-consistent spatial layout improves learning and memory, and that this benefit is reduced or absent when information lacks ordinal properties. PMID- 24771966 TI - Effect of Stress-free Therapy on Cerebral Blood Flow: Comparisons among patients with metabolic cardiovascular disease, healthy subjects and placebo-treated subjects. AB - BACKGROUND AND AIMS: We have developed a Stress-free Therapy((r)) device wherein "Pinpoint Plantar Long-wavelength Infrared Light Irradiation (PP-LILI)" increases peripheral-deep body temperature and blood flow volume and stabilizes blood pressure as well as significantly reduces stress hormones such as adrenocorticotrophic hormone and cortisol without using drugs. Moreover, we have found this therapy to significantly improve blood glucose and insulin resistance in patients with type 2 diabetes. Based on this background of clinical efficacy, we validated changes in cerebral blood flow in patients with metabolic cardiovascular disease and examined the efficacy of Stress-free Therapy((r)) on cerebral blood flow as compared to that in healthy control subjects and placebo treated patients. RESULTS: The change in cerebral blood flow volume during 15 minute PP-LILI was 5.1 +/- 1.8 mL/min in patients with metabolic cardiovascular disease, showing a significant increase (P<0.05) of 3.1 mL/min as compared with the mean blood flow value after resting for 15 minutes. CONCLUSIONS: Our results suggested Stress-free Therapy((r)) to significantly increase cerebral blood flow, possibly leading to the prevention of metabolic cardiovascular disease. PMID- 24771967 TI - Efficacy and safety of a topical carbon suspension photoenhancer adjunctive to intense pulsed light treatment for pigmented lesions in Japanese patients: A pilot study. AB - BACKGROUND AND AIMS: Pigmented lesions, e.g., senile lentigo and seborrheic keratosis are commonly seen in photodamaged skin in the Japanese general population. The use of the laser to treat such lesions is often painful, and intense pulsed light (IPL) systems have become widely used. Clearly demarcated pigmented lesions may be identified easily and treated with IPL. Less well demarcated lesions, however, which are very difficult to identify or thick melanogesic lesions like seborrheic keratosis represent one of the most challenging conditions to be treated using IPL. This pilot study evaluated carbon suspension-assisted IPL treatment of such lesions. SUBJECTS AND METHODS: Three female Japanese patients, Fitzpatrick skin type III-IV, comprised the subjects, aged 58, 78 and 85, with indistinct senile lentigines or thick seborrheic keratoses. The lesions were painted or demarcated with a carbon-based ink from a commercially-available Japanese writing instrument (Fude-penTM, Pentel, Japan) consisting of a brush-like pen nib with a refillable or replaceable ink reservoir, and then treated with a broadband (560 - 1200 nm) IPL system. RESULTS: The poorly-demarcated lesions were quickly and easily marked with the pen, and the IPL treatments were well-tolerated. All patients had good improvement in their painted pigmented lesions based on the overall evaluation, compared with unpainted ones. Side effects after treatment, such as hyperpigmentation, persistent erythema, and scarring, were minimal. CONCLUSIONS: Topical carbon suspension-assisted IPL treatment could be a good option for patients with indistinct pigmented or thick melanogenesic lesions. Adverse reactions to this treatment were minimal and the results acceptable, though appropriate lesions need to be chosen carefully. PMID- 24771968 TI - The bleaching efficiency of KTP and diode 810 nm lasers on teeth stained with different substances: An in vitro study. AB - BACKGROUND AND AIMS: The purpose of this study was to evaluate the bleaching efficiency of two different lasers (KTP and diode 810 nm) on teeth, randomly divided by means an Excel function (Microsoft Excel 2010 "Fx causale") and stored in physiological solution, that were previously stained with different substances commonly considered as a cause of tooth discoloration, such as coffee, tea and red fruits and to investigate the role of laser irradiation in an experimental model, during the dental bleaching process. METHODS: Three groups of 45 bovine teeth were created and immersed for one week in a solution of tea, coffee or red fruits respectively. Each group was divided into three sub-groups of fifteen teeth. One was bleached with a 30% hydrogen peroxide gel for 30 min only as control, another 15 teeth group was bleached with the gel plus 810 nm diode laser irradiation and the last group was bleached with the gel plus KTP irradiation. The lasers were applied in three cycles of 30 sec each with a power of 1.5 W localized on a 10 mm spot on the teeth. The temperature of the gel was checked during the bleaching procedure using a thermometer and the colour of each tooth was measured by a spectrophotometer. RESULTS: Statistical analysis of the collected data was performed using Graph Pad Prism, version 6.01 software, Kruskal-Wallis test and Dunn's multiple comparison test and Mann-Whitney test. P value <0.0001 was considered extremely significant (***), P value between 0.001 to 0.01 very significant (**), P value between 0.01 to 0.05 significant (*) and P value >0.05 not significant (ns). By these tests diode laser was effective only at bleaching teeth stained with coffee meanwhile the KTP laser was efficient at bleaching teeth with coffee, tea and red fruits stains. CONCLUSION: This study suggests that a relation between the laser wavelength and the type of staining on the dental enamel and the efficacy of the whitening treatment exists. PMID- 24771969 TI - Adjusting the light in the limit conditions of consciousness by the means of ascending reticular activating system (ARAS) and of subordinated systems Part 1: Introduction and Aims. AB - BACKGROUND: In our activity in the Ambulance Service of Bucharest Municipality during March 2002 - March 2003 we studied a casuistry of patients who had fallen in a coma of varying degrees. To aid better understanding of coma, the concept of "pre-coma stage" or diencephalic "0 stage" was introduced. This concept complements the Arseni classification already used in medical practice, because some doctors alternatively use the term of "inaugural coma" for the same condition that we call diencephalic "0 stage". In the median hypothalamus and on the retino-hypothalamic path (SCN - AN) optical waves are transmitted, probably in the near infrared spectral range (800-1000 nm). These waves would constitute a means of transmitting information about the infradian biorhythm of coordination (frequencies below 1 cycle/28 hours), essential for the modulation and pre processing of the consciousness and wakefulness, a fact which has already been demonstrated in animals. METHODS: The current work is based on observations made on a group of 51 patients with the precoma and coma conditions, and on a thorough study of the specialized (especially Romanian) literature. Also, we used validated scientific proof of torture in conditions of lack of light. RESULTS: We found a perfect interpenetration between the ARAS and the following two complementary subsystems: 1. The hypothalamic suprachiasmatic nucleus, that has the role of coordinating the periodicity of some biological functions depending on the circadian rhythm; and 2. The main photoperiodic organ, the pineal gland (epiphysis), which together with the ARAS has a role in the photoperiodicity modulation of some biological functions during the state of vigilance. CONCLUSION: From the above mentioned one may conclude that the consciousness condition is the unitary result of action of all human brain systems and especially sub-systems, which are controlled and led by a psycho-neurological process of integration at the cortex level. "Everyone knows what the consciousness is, until one tries to define it" (William James: The Stream of Consciousness", 1892). PMID- 24771970 TI - Comparative evaluation of Ferric Sulfate, Electrosurgical and Diode Laser on human primary molars pulpotomy: an "in-vivo" study. AB - BACKGROUND AND AIMS: Despite modern advances in the prevention of dental caries and increased understanding of the importance of maintaining the natural primary dentition, many teeth are still lost prematurely. This can lead to malocclusion with aesthetic, phonetic and functional problems that may be transient or permanent. Therefore, maintaining the integrity and health of the oral tissues is the primary objective of pulp treatment. Pulpotomy has remained an acceptable and mainstay treatment in preserving the vitality of primary tooth and prolonging its life till the permanent successor erupts. Various materials and techniques are available for pulpotomy on primary molars; all with some advantages and disadvantages. The present study was carried out on 45 primary molars to evaluate and compare the clinical and radiographic success of diode laser, electrosurgical and ferric sulfate pulpotomy over a period of 9 months. Materials (Subjects) and Methods: The forty five primary molars were randomly and equally divided into three treatment groups which were as follows: Group A: 15 primary molars treated with 15.5% Ferric sulfate Group B: 15 primary molars treated with electrosurgical unit and Group C: 15 primary molars treated with diode laser. All teeth in three categories were followed up clinically and radiographically at 1, 3, 6 and 9 months post treatment and the findings were recorded on the prepared proforma RESULTS: Clinically, 86.6% success rate was found in ferric sulfate group whereas 100% success rate was found in electrosurgical and diode laser groups. Radiographically, 80% success rate was found in all the three groups at the end of 9 months with internal resorption being the most common cause of failure after pulpotomy. CONCLUSIONS: Thus, electrosurgery and diode lasers appear to be acceptable alternative to pharmacotherapeutic pulpotomy agents. PMID- 24771971 TI - The Role of the CO2 Laser and Fractional CO2 Laser in Dermatology. AB - BACKGROUND: Tremendous advances have been made in the medical application of the laser in the past few decades. Many diseases in the dermatological field are now indications for laser treatment that qualify for reimbursement by many national health insurance systems. Among laser types, the carbon dioxide (CO2) laser remains an important system for the dermatologist. RATIONALE: The lasers used in photosurgery have wavelengths that differ according to their intended use and are of various types, but the CO2 laser is one of the most widely used lasers in the dermatology field. With its wavelength in the mid-infrared at 10,600 nm, CO2 laser energy is wellabsorbed in water. As skin contains a very high water percentage, this makes the CO2 laser ideal for precise, safe ablation with good hemostasis. In addition to its efficacy in ablating benign raised lesions, the CO2 laser has been reported to be effective in the field of esthetic dermatology in the revision of acne scars as well as in photorejuvenation. With the addition of fractionation of the beam of energy into myriad microbeams, the fractional CO2 laser has offered a bridge between the frankly full ablative indications and the nonablative skin rejuvenation systems of the 2000s in the rejuvenation of photoaged skin on and off the face. CONCLUSIONS: The CO2 laser remains an efficient, precise and safe system for the dermatologist. Technological advances in CO2 laser construction have meant smaller spot sizes and greater precision for laser surgery, and more flexibility in tip sizes and protocols for fractional CO2 laser treatment. The range of dermatological applications of the CO2 laser is expected to continue to increase in the future. PMID- 24771972 TI - Supply chain and marketing of sea grapes, Caulerpa racemosa (Forsskal) J. Agardh (Chlorophyta: Caulerpaceae) in Fiji, Samoa and Tonga. AB - This report describes for the first time the supply chain of Caulerpa racemosa in three Pacific Island countries. The harvesting and marketing of C. racemosa are important subsistence activities for villagers in Fiji and Samoa, less so in Tonga. At least 150 harvesters are involved in Fiji, some 100 in Samoa and only a handful in Tonga. The annual combined crop is of some 123 t valued at around US$266,492. In Fiji, it is projected that supply does not meet local demand and there is a potential export market that is currently operating at a pilot project level. In Samoa, the supply is considered adequate for the current market. In Tonga, harvesting is carried out by a few families and supplies a niche market in that country. The possibilities of field cultivation of Caulerpa have been explored but, at present, with only limited success in Samoa. The supply chain is simple in all three countries, and only in Fiji are middlemen involved in the distribution process. The limitations for marketing include the fact that only a few sites supply most of the crop in all the three countries, that all sites need to be conserved through sustainable harvesting methods, the short shelf life of the crop and a lack of information on the carrying capacity of harvest sites. Caulerpa remains a crop that fulfils a niche market but has the potential to be scaled up for additional livelihood development in the future. PMID- 24771973 TI - Spatial distributions of floating seaweeds in the East China Sea from late winter to early spring. AB - Floating seaweeds play an important role as a habitat for many animals accompanying or attaching to them in offshore waters. It was in 2000 that the first report described abundant distributions of floating seaweeds in offshore waters in the East China Sea in spring. Young individuals of the yellowtail Seriola quinqueradiata are captured for aquaculture purposes from floating seaweeds in the East China Sea. Therefore, a sound understanding of the distributions of floating seaweeds in the East China Sea is needed. Detailed information is especially important during the late winter to early spring, which corresponds to the juvenile period of the yellowtail. Thus, field surveys using R/V Tansei-Maru were conducted in the Japanese Exclusive Economic Zone in the East China Sea from late winter to early spring in 2010 and 2011. We obtained positions of the vessel by GPS and transversal distances from the vessel to a raft by visual observation. Distance sampling method (Thomas et al. 2010) was applied to estimation of floating seaweed densities (rafts km-2). Seaweed rafts were also randomly sampled using nets during the research cruises. In the East China Sea, seaweed rafts were distributed mainly on the continental shelf west of the Kuroshio, especially in waters between 26 degrees N and 30 degrees N. Collected rafts consisted of only one species, Sargassum horneri (Turner) C. Agardh. Taking into account surface currents and geographical distribution of S. horneri, it is estimated that these floating seaweeds originated from natural beds along the coast between mid and south China. Considering the approximate travel times, it is suggested that floating patches are colonized by yellowtails early on during their trips, i.e., close to the Chinese coast. PMID- 24771974 TI - Unusual distribution of floating seaweeds in the East China Sea in the early spring of 2012. AB - Floating seaweeds play important ecological roles in offshore waters. Recently, large amounts of rafting seaweed have been observed in the East China Sea. In early spring, juveniles of commercially important fish such as yellowtail accompany these seaweed rafts. Because the spatial distributions of seaweed rafts in the spring are poorly understood, research cruises were undertaken to investigate them in 2010, 2011, and 2012. Floating seaweed samples collected from the East China Sea during the three surveys contained only Sargassum horneri. In 2010 and 2011, seaweed rafts were distributed only in the continental shelf and the Kuroshio Front because they had become trapped in the convergence zone of the Kuroshio Front. However, in 2012, seaweed was also distributed in the Kuroshio Current and its outer waters, and massive strandings of seaweed rafts were observed on the northern coast of Taiwan and on Tarama Island in the Ryukyu Archipelago. Environmental data (wind, currents, and sea surface height) were compared among the surveys of 2010, 2011, and 2012. Two factors are speculated to have caused the unusual distribution in 2012. First, a continuous strong north wind produced an Ekman drift current that transported seaweed southwestward to the continental shelf and eventually stranded seaweed rafts on the coast of Taiwan. Second, an anticyclonic eddy covering northeast Taiwan and the Kuroshio Current west of Taiwan generated a geostrophic current that crossed the Kuroshio Current and transported the rafts to the Kuroshio Current and its outer waters. Such unusual seaweed distributions may influence the distribution of fauna accompanying the rafts. PMID- 24771975 TI - Refuse and the 'Risk Society': The Political Ecology of Risk in Inter-war Britain. AB - This article responds to current critiques of Ulrich Beck's 'risk society' thesis by historians of science and medicine. Those who have engaged with the concept of risk society have been content to accept the fundamental categories of Beck's analysis. In contrast, we argue that Beck's risk society thesis underplays two key themes. First, the role of capitalist social relations as the driver of technological change and the transformation of everyday life; and second, the ways in which hegemonic discourses of risk can be appropriated and transformed by counter-hegemonic forces. In place of 'risk society', we propose an approach based upon a 'political ecology of risk', which emphasises the social relations that are fundamental to the everyday politics of environmental health. PMID- 24771976 TI - The Complexities of 'Consumerism': Choice, Collectivism and Participation within Britain's National Health Service, c.1961-c.1979. AB - This article explores the overlapping and conflicting points of contact between 'consumerism', collectivism and participation in Britain's National Health Service during a period of relatively well-funded expansion during the economic 'golden age' of the 1960s and 1970s. Despite recent neo-liberal attempts to define 'consumerism' around the wishes and choices of the individual, and to conceptualise areas such as individual hospital referrals as particularly 'consumerist', this article demonstrates that collective provision, the protection of disadvantaged groups and the concept of 'participatory' citizen involvement were all alternative meanings of the concept during this period, co existing uneasily with the competitive concepts that have become more familiar since the late 1980s. This insight is then utilised to show how health care debates today might become better informed, ignoring extreme claims for all three concepts and focusing instead on a theoretically informed but ultimately empirical grasp of constant flux in any health care system. PMID- 24771977 TI - Erratum: Beyond the Medical Text: Health and Illness in Early Medieval Italian Sources. AB - [This corrects the article DOI: 10.1093/shm/hkq115.]. PMID- 24771978 TI - Erratum: The 'Miracle of Childbirth': the Portrayal of Parturient Women in Medieval Miracle Narratives. AB - [This corrects the article DOI: 10.1093/shm/hks019.]. PMID- 24771979 TI - 'The dangers attending these conditions are evident': Public Health and the Working Environment of Lancashire Textile Communities, c.1870-1939. AB - This article examines the position of the working environment within public health priorities and as a contributor to the health of a community. Using two Lancashire textile towns (Burnley and Blackburn) as case studies and drawing on a variety of sources, it highlights how, while legislation set the industry parameters for legal enforcement of working conditions, local public health priorities were pivotal in setting codes of practice. The complexities entwined with identifying the working environment as a cause of ill health and with improving it were entangled within the local community health context. In addition, the multiple understandings of Medical Officers of Health surrounding the remit of their responsibilities impacted the local health context. These did not always parallel national regulations. Indeed, it was these local, community specific forces that set the public health agenda, determined its path and the place of the working environment within this. PMID- 24771980 TI - Appealing to the Republic of Letters: An Autopsy of Anti-venereal Trials in Eighteenth-century Mexico. AB - This study analyses the narrative elements of a little-known report into anti venereal trials written by an Irish military physician-surgeon, Daniel O'Sullivan (1760-c.1797). It explores the way in which O'Sullivan as the narrator of the Historico-critical report creates medical heroes and anti-heroes as a means to criticise procedures initiated by staff in the Hospital General de San Andres, Mexico City. The resulting work depicts a much less positive picture of medical trials and hospital authorities in this period than has been recorded to date, and provides a critical and complicated assessment of one of Spain's leading physicians of the nineteenth century, Francisco Javier Balmis (1753-1819). PMID- 24771981 TI - SELF ALIGNED TIP DEINSULATION OF ATOMIC LAYER DEPOSITED AL2O3 AND PARYLENE C COATED UTAH ELECTRODE ARRAY BASED NEURAL INTERFACES. AB - The recently developed alumina and Parylene C bi-layer encapsulation improved the lifetime of neural interfaces. Tip deinsulation of Utah electrode array based neural interfaces is challenging due to the complex 3D geometries and high aspect ratios of the devices. A three-step self-aligned process was developed for tip deinsulation of bilayer encapsulated arrays. The deinsulation process utilizes laser ablation to remove Parylene C, O2 reactive ion etching to remove carbon and Parylene residues, and buffered oxide etch to remove alumina deposited by atomic layer deposition, and expose the IrOx tip metallization. The deinsulated iridium oxide area was characterized by scanning electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, and electrochemical impedance spectroscopy to determine the morphology, surface morphology, composition, and electrical properties of the deposited layers and deinsulated tips. The alumina layer was found to prevent the formation of micro cracks on iridium oxide during the laser ablation process, which has been previously reported as a challenge for laser deinsulation of Parylene films. The charge injection capacity, charge storage capacity, and impedance of deinsulated iridium oxide were characterized to determine the deinsulation efficacy compared to Parylene-only insulation. Deinsulated iridium oxide with bilayer encapsulation had higher charge injection capacity (240 vs 320 nC) and similar electrochemical impedance (2.5 vs 2.5 kOmega) compared to deinsulated iridium oxide with only Parylene coating for an area of 2 * 10-4 cm2. Tip impedances were in the ranges of 20 to 50 kOmega, with median of 32 KOmega and standard deviation of 30 kOmega, showing the effectiveness of the self-aligned deinsulation process for alumina and Parylene C bi-layer encapsulation. The relatively uniform tip impedance values demonstrated the consistency of tip exposures. PMID- 24771983 TI - CD80 and CD86 costimulatory molecules differentially regulate OT-II CD4+ T lymphocyte proliferation and cytokine response in cocultures with antigen presenting cells derived from pregnant and pseudopregnant mice. AB - Immune phenomena during the preimplantation period of pregnancy are poorly understood. The aim of our study was to assess the capacity for antigen presentation of splenic antigen-presenting cells (APCs) derived from pregnant and pseudopregnant mice in in vitro conditions. Therefore, sorted CD11c(+) dendritic cells and macrophages F4/80(+) and CD11b(+) presenting ovalbumin (OVA) were cocultured with CD4(+) T cells derived from OT-II mice's (C57BL6/J Tg(TcraTcrb)1100Mjb/J) spleen. After 132 hours of cell culture, proliferation of lymphocytes (ELISA-BrdU), activation of these cells (flow cytometry), cytokine profile (ELISA), and influence of costimulatory molecules blocking on these parameters were measured. We did not detect any differences in regulation of Th1/Th2 cytokine balance. CD86 seems to be the main costimulatory molecule involved in the proliferation response but CD80 is the main costimulatory molecule influencing cytokine secretion in pregnant mice. In conclusion, this study showed that CD80 and CD86 costimulatory molecules regulate OT-II CD4(+) T lymphocyte proliferation and cytokine response in cocultures with antigen presenting cells derived from pregnant and pseudopregnant mice. The implications of these changes still remain unclear. PMID- 24771982 TI - Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses. AB - Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs) are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases. PMID- 24771984 TI - Metalloprotease dependent release of placenta derived fractalkine. AB - The chemokine fractalkine is considered as unique since it exists both as membrane-bound adhesion molecule and as shed soluble chemoattractant. Here the hypothesis was tested whether placental fractalkine can be shed and released into the maternal circulation. Immunohistochemical staining of human first trimester and term placenta sections localized fractalkine at the apical microvillous plasma membrane of the syncytiotrophoblast. Gene expression analysis revealed abundant upregulation in placental fractalkine at term, compared to first trimester. Fractalkine expression and release were detected in the trophoblast cell line BeWo, in primary term trophoblasts and placental explants. Incubation of BeWo cells and placental explants with metalloprotease inhibitor Batimastat inhibited the release of soluble fractalkine and at the same time increased the membrane-bound form. These results demonstrate that human placenta is a source for fractalkine, which is expressed in the syncytiotrophoblast and can be released into the maternal circulation by constitutive metalloprotease dependent shedding. Increased expression and release of placental fractalkine may contribute to low grade systemic inflammatory responses in third trimester of normal pregnancy. Aberrant placental metalloprotease activity may not only affect the release of placenta derived fractalkine but may at the same time affect the abundance of the membrane-bound form of the chemokine. PMID- 24771985 TI - Total adiponectin is inversely associated with platelet activation and CHA2DS2 VASc score in anticoagulated patients with atrial fibrillation. AB - BACKGROUND: Adiponectin (APN) possesses anti-inflammatory and antiatherogenic effects. Atrial fibrillation (AF) is burdened by enhanced systemic inflammation and platelet activation, as documented by increased blood levels of soluble CD40L (sCD40L). The interplay between APN and platelet activation in AF is still undefined. MATERIALS AND METHODS: Circulating levels of APN and sCD40L were measured in 257 anticoagulated nonvalvular AF patients. Exclusion criteria were as follows: prosthetic heart valves, cardiac revascularization in the previous year, severe cognitive impairment, chronic infectious or autoimmune diseases, and active cancer. RESULTS: Mean age was 72.9 (+/-8.7) years and 41.6% were female. Serum APN and plasmatic sCD40L were inversely correlated (R -0.626, P < 0.001). A progressive increase of sCD40L across tertiles of CHA2DS2-VASc score was observed (rS 0.473, P < 0.001), whilst APN was inversely correlated (rS -0.463, P < 0.001). A multivariable linear regression analysis showed that CHA2DS2-VASc score (B -0.227, P < 0.001) and sCD40L (B -0.524, P < 0.001) correlated to APN. CONCLUSIONS: AF patients at high risk of stroke disclose low and high levels of APN and sCD40L, respectively, suggesting a role for APN if it favors platelet activation in vivo in this clinical setting. Enhancing APN levels may be a future goal to reduce the risk of vascular outcomes in AF patients. PMID- 24771987 TI - Taking Wishes and Feelings Seriously: The Views of People Lacking Capacity in Court of Protection Decision-Making. AB - The Mental Capacity Act requires that where a person (P) lacks capacity to make a decision her wishes and feelings be taken into account when deciding what is in her best interests. This article considers how the Court of Protection evaluates evidence from P concerning her wishes and feelings. It finds that the Court ignores evidence regarding current wishes and fails to engage with more ambiguous evidence where P desires conflicting outcomes or may be concealing her true feelings. This is unhelpful since it makes the resulting judgment unconvincing to observers. It is legally problematic, since the Court should be following the practices of other decision-makers under the Mental Capacity Act (MCA). And it is ethically problematic since it undermines P's dignity and does not treat P as an actor whose evidence regarding her wishes and feelings has intrinsic status which the Court must make active efforts to engage with or discount rather than ignore. PMID- 24771988 TI - Paternal care and the evolution of exaggerated sexual swellings in primates. AB - The exaggerated sexual swellings exhibited by females of some primate species have been of interest to evolutionary biologists since the time of Darwin. We summarize existing hypotheses for their function and evolution and categorize these hypotheses within the context of 3 types of variation in sexual swelling size: 1) variation within a single sexual cycle, 2) variation between the sexual cycles of a single female, and 3) differences between females. We then propose the Paternal Care Hypothesis for the function of sexual swellings, which posits that exaggerated sexual swellings function to elicit the right quantity and quality of male care for a female's infant. As others have noted, swellings may allow females to engender paternity confusion, or they may allow females to confer relative paternal certainty on one male. Key to our hypothesis is that both of these scenarios create an incentive for one or more males to provide care. This hypothesis builds on previous hypotheses but differs from them by highlighting the elicitation of paternal care as a key function of swellings. Our hypothesis predicts that true paternal care (in which males accurately differentiate and provide assistance to their own offspring) will be most common in species in which exaggerated swellings accurately signal the probability of conception, and males can monopolize females during the window of highest conception probability. Our hypothesis also predicts that females will experience selection to behave in ways that either augment paternity confusion or enhance paternal certainty depending on their social and demographic contexts. PMID- 24771986 TI - Advanced glycation end products play adverse proinflammatory activities in osteoporosis. AB - Osteoporosis is a major public health burden that is expected to further increase as the global population ages. In the last twenty years, advanced glycation end products (AGEs) have been shown to be critical mediators both in the pathogenesis and development of osteoporosis and other chronic degenerative diseases related to aging. The accumulation of AGEs within the bone induces the formation of covalent cross-links with collagen and other bone proteins which affects the mechanical properties of tissue and disturbs bone remodelling and deterioration, underlying osteoporosis. On the other hand, the gradual deterioration of the immune system during aging (defined as immunosenescence) is also characterized by the generation of a high level of oxidants and AGEs. The synthesis and accumulation of AGEs (both localized within the bone or in the systemic circulation) might trigger a vicious circle (in which inflammation and aging merged in the word "Inflammaging") which can establish and sustain the development of osteoporosis. This narrative review will update the molecular mechanisms/pathways by which AGEs induce the functional and structural bone impairment typical of osteoporosis. PMID- 24771989 TI - Knowledge Mapping for Climate Change and Food- and Waterborne Diseases. AB - The authors extracted from the PubMed and ScienceDirect bibliographic databases all articles published between 1998 and 2009 that were relevant to climate change and food- and waterborne diseases. Any material within each article that provided information about a relevant pathogen and its relationship with climate and climate change was summarized as a key fact, entered into a relational knowledge base, and tagged with the terminology (predefined terms) used in the field. These terms were organized, quantified, and mapped according to predefined hierarchical categories. For noncholera Vibrio sp. and Cryptosporidium sp., data on climatic and environmental influences (52% and 49% of the total number of key facts, respectively) pertained to specific weather phenomena (as opposed to climate change phenomena) and environmental determinants, whereas information on the potential effects of food-related determinants that might be related to climate or climate change were virtually absent. This proportion was lower for the other pathogens studied (Campylobacter sp. 40%, Salmonella sp. 27%, Norovirus 25%, Listeria sp. 8%), but they all displayed a distinct concentration of information on general food-and water-related determinants or effects, albeit with little detail. Almost no information was available concerning the potential effects of changes in climatic variables on the pathogens evaluated, such as changes in air or water temperature, precipitation, humidity, UV radiation, wind, cloud coverage, sunshine hours, or seasonality. Frequency profiles revealed an abundance of data on weather and food-specific determinants, but also exposed extensive data deficiencies, particularly with regard to the potential effects of climate change on the pathogens evaluated. A reprioritization of public health research is warranted to ensure that funding is dedicated to explicitly studying the effects of changes in climate variables on food- and waterborne diseases. PMID- 24771990 TI - Is it possible to predict the presence of intestinal angioectasias? AB - Background and Aim. Angioectasias are the most common vascular anomalies found in the gastrointestinal tract. In small bowel (SB), they can cause obscure gastrointestinal bleeding (OGIB) and in this setting, small bowel capsule endoscopy (SBCE) is an important diagnostic tool. This study aimed to identify predictive factors for the presence of SB angioectasias, detected by SBCE. Methods. We retrospectively analyzed the results of 284 consecutive SBCE procedures between April 2006 and December 2012, whose indication was OGIB, of which 47 cases with SB angioectasias and 53 controls without vascular lesions were selected to enter the study. Demographic and clinical data were collected. Results. The mean age of subjects with angioectasias (70.9 +/- 14.7) was significantly higher than in controls (53.1 +/- 18.6; P < 0.001). The presence of SB angioectasias was significantly higher when the indication for the exam was overt OGIB versus occult OGIB (13/19 versus 34/81, P = 0.044). Hypertension and hypercholesterolemia were significantly associated with the presence of SB angioectasias (38/62 versus 9/38, P < 0.001 and 28/47 versus 19/53, P = 0.027, resp.). Other studied factors were not associated with small bowel angioectasias. Conclusions. In patients with OGIB, overt bleeding, older age, hypercholesterolemia, and hypertension are predictive of the presence of SB angioectasias detected by SBCE, which may be used to increase the diagnostic yield of the SBCE procedure and to reduce the proportion of nondiagnostic examinations. PMID- 24771991 TI - Supervisor Health and Safety Support: Scale Development and Validation. AB - Two studies were conducted to develop a psychometrically sound measure of supervisor health and safety support (SHSS). We identified three dimensions of supervisor support (physical health, psychological health, safety) and used Study 1 to develop items and establish content validity. Study 2 was used to establish the dimensionality of the new measure and provide criterion-related and discriminant validity evidence of the measure using supervisor and subordinate data. The measure had incremental validity in predicting employee performance and psychological strain outcomes above and beyond general work support variables. Implications of these findings and for workplace support theory and practice are discussed. PMID- 24771992 TI - Integrated IVUS-OCT Imaging for Atherosclerotic Plaque Characterization. AB - For the diagnosis of atherosclerosis, biomedical imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have been developed. The combined use of IVUS and OCT is hypothesized to remarkably increase diagnostic accuracy of vulnerable plaques. We have developed an integrated IVUS-OCT imaging apparatus, which includes the integrated catheter, motor drive unit, and imaging system. The dual-function imaging catheter has the same diameter of current clinical standard. The imaging system is capable for simultaneous IVUS and OCT imaging in real time. Ex vivo and in vivo experiments on rabbits with atherosclerosis were conducted to demonstrate the feasibility and superiority of the integrated intravascular imaging modality. PMID- 24771993 TI - Social Determinants of Health in Environmental Justice Communities: Examining Cumulative Risk in Terms of Environmental Exposures and Social Determinants of Health. AB - Residents of environmental justice (EJ) communities may bear a disproportionate burden of environmental health risk, and often face additional burdens from social determinants of health. Accounting for cumulative risk should include measures of risk from both environmental sources and social determinants. This study sought to better understand cumulative health risk from both social and environmental sources in a disadvantaged community in Texas. Key outcomes were determining what data are currently available for this assessment, clarifying data needs, identifying data gaps, and considering how those gaps could be filled. Analyses suggested that the traditionally defined EJ community in Port Arthur may have a lower environmental risk from air toxics than the rest of the City of Port Arthur (although the entire city has a higher risk than the average for the state), but may have a larger burden from social determinants of health. However, the results should be interpreted in light of the availability of data, the definitions of community boundaries, and the areal unit utilized. Continued focus on environmental justice communities and the cumulative risks faced by their residents is critical to protecting these residents and, ultimately, moving towards a more equitable distribution and acceptable level of risk throughout society. PMID- 24771994 TI - Using an Evidence-Based Approach to EMR Implementation to Optimize Outcomes and Avoid Unintended Consequences. AB - Implementation of an electronic medical record (EMR) with computerized physician order entry (CPOE) can provide an important foundation for preventing harm and improving outcomes. Incentivized by the recent economic stimulus initiative, healthcare systems are implementing vendor-based EMR systems at an unprecedented rate. Accumulating evidence suggests that local implementation decisions, rather than the specific EMR product or technology selected, are the primary drivers of the quality improvement performance of these systems. However, limited attention has been paid to effective approaches to EMR implementation. In this case report, we outline the evidence-based approach we used to make EMR implementation decisions in a pragmatic structure intended for replication at other sites. PMID- 24771995 TI - Metastatic Renal Cancer: What Role for Everolimus? AB - Metastatic renal cell carcinoma is uncommon (only 3% of cancers worldwide) but of poor prognosis. Renal cell carcinoma has traditionally been treated with cytokines (interferon-alpha or interleukin-2). More recently, a more clear understanding of the molecular and cellular mechanisms of the disease, involving the VEGF receptor and mTOR, has led to the discovery of novel therapies. Therapeutic options in patients with advanced RCC include the VEGF receptor inhibitors Sunitinib and Sorafenib, the anti-VEGF monoclonal antibody Bevacizumab and the mTORC1 inhibitors Temsirolimus and Everolimus. In 2009, Everolimus was FDA-approved for the treatment of patients with advanced clear cell RCC which had progressed within 6 months of stopping treatment with Sunitinib or sorafenib, or both drugs. Everolimus resulted in a 70% reduction in the risk of disease recurrence or death. The purpose of this review is to update on the current knowledge of the role of Everolimus in metastatic renal cell carcinoma. PMID- 24771996 TI - A Theoretical Analysis of the Perceptual Span based on SWIFT Simulations of the n + 2 Boundary Paradigm. AB - Eye-movement experiments suggest that the perceptual span during reading is larger than the fixated word, asymmetric around the fixation position, and shrinks in size contingent on the foveal processing load. We used the SWIFT model of eye-movement control during reading to test these hypotheses and their implications under the assumption of graded parallel processing of all words inside the perceptual span. Specifically, we simulated reading in the boundary paradigm and analysed the effects of denying the model to have valid preview of a parafoveal word n + 2 two words to the right of fixation. Optimizing the model parameters for the valid preview condition only, we obtained span parameters with remarkably realistic estimates conforming to the empirical findings on the size of the perceptual span. More importantly, the SWIFT model generated parafoveal processing up to word n + 2 without fitting the model to such preview effects. Our results suggest that asymmetry and dynamic modulation are plausible properties of the perceptual span in a parallel word-processing model such as SWIFT. Moreover, they seem to guide the flexible distribution of processing resources during reading between foveal and parafoveal words. PMID- 24771997 TI - Blur Detection is Unaffected by Cognitive Load. AB - Blur detection is affected by retinal eccentricity, but is it also affected by attentional resources? Research showing effects of selective attention on acuity and contrast sensitivity suggests that allocating attention should increase blur detection. However, research showing that blur affects selection of saccade targets suggests that blur detection may be pre-attentive. To investigate this question, we carried out experiments in which viewers detected blur in real-world scenes under varying levels of cognitive load manipulated by the N-back task. We used adaptive threshold estimation to measure blur detection thresholds at 0°, 3°, 6°, and 9° eccentricity. Participants carried out blur detection as a single task, a single task with to-be-ignored letters, or an N back task with four levels of cognitive load (0, 1, 2, or 3-back). In Experiment 1, blur was presented gaze-contingently for occasional single eye fixations while participants viewed scenes in preparation for an easy picture recognition memory task, and the N-back stimuli were presented auditorily. The results for three participants showed a large effect of retinal eccentricity on blur thresholds, significant effects of N-back level on N-back performance, scene recognition memory, and gaze dispersion, but no effect of N-back level on blur thresholds. In Experiment 2, we replicated Experiment 1 but presented the images tachistoscopically for 200 ms (half with, half without blur), to determine whether gaze-contingent blur presentation in Experiment 1 had produced attentional capture by blur onset during a fixation, thus eliminating any effect of cognitive load on blur detection. The results with three new participants replicated those of Experiment 1, indicating that the use of gaze-contingent blur presentation could not explain the lack of effect of cognitive load on blur detection. Thus, apparently blur detection in real-world scene images is unaffected by attentional resources, as manipulated by the cognitive load produced by the N-back task. PMID- 24771998 TI - Eye Tracking Research and Technology: Towards Objective Measurement of Data Quality. AB - Two methods for objectively measuring eye tracking data quality are explored. The first method works by tricking the eye tracker to detect an abrupt change in the gaze position of an artificial eye that in actuality does not move. Such a device, referred to as an artificial saccade generator, is shown to be extremely useful for measuring the temporal accuracy and precision of eye tracking systems and for validating the latency to display change in gaze contingent display paradigms. The second method involves an artificial pupil that is mounted on a computer controlled moving platform. This device is designed to be able to provide the eye tracker with motion sequences that closely resemble biological eye movements. The main advantage of using artificial motion for testing eye tracking data quality is the fact that the spatiotemporal signal is fully specified in a manner independent of the eye tracker that is being evaluated and that nearly identical motion sequence can be reproduced multiple times with great precision. The results of the present study demonstrate that the equipment described has the potential to become an important tool in the comprehensive evaluation of data quality. PMID- 24771999 TI - Validation of the SF-6D Health State Utilities Measure in Lower Extremity Sarcoma. AB - Aim. Health state utilities measures are preference-weighted patient-reported outcome (PRO) instruments that facilitate comparative effectiveness research. One such measure, the SF-6D, is generated from the Short Form 36 (SF-36). This report describes a psychometric evaluation of the SF-6D in a cross-sectional population of lower extremity sarcoma patients. Methods. Patients with lower extremity sarcoma from a prospective database who had completed the SF-36 and Toronto Extremity Salvage Score (TESS) were eligible for inclusion. Computed SF-6D health states were given preference weights based on a prior valuation. The primary outcome was correlation between the SF-6D and TESS. Results. In 63 pairs of surveys in a lower extremity sarcoma population, the mean preference-weighted SF 6D score was 0.59 (95% CI 0.4-0.81). The distribution of SF-6D scores approximated a normal curve (skewness = 0.11). There was a positive correlation between the SF-6D and TESS (r = 0.75, P < 0.01). Respondents who reported walking aid use had lower SF-6D scores (0.53 versus 0.61, P = 0.03). Five respondents underwent amputation, with lower SF-6D scores that approached significance (0.48 versus 0.6, P = 0.06). Conclusions. The SF-6D health state utilities measure demonstrated convergent validity without evidence of ceiling or floor effects. The SF-6D is a health state utilities measure suitable for further research in sarcoma patients. PMID- 24772000 TI - In Situ TEM Studies of Nanoparticle Growth in a Fluorozirconate (ZBLAN) Glass Matrix. PMID- 24772001 TI - Generation of Trityl Radicals by Nucleophilic Quenching of Tris(2,3,5,6 tetrathiaaryl)methyl Cations and Practical and Convenient Large-Scale Synthesis of Persistent Tris(4-carboxy-2,3,5,6-tetrathiaaryl)methyl Radical. AB - Tris(2,3,5,6-tetrathiaaryl)methyl cations, which were generated from the corresponding triarylmethanols in the presence of strong acids, underwent reaction with nucleophiles to give trityl radicals, as the product of a one electron reduction of the carbocation. Depending on the nature of the nucleophile, the only byproducts were either diamagnetic quinone methides or asymmetrical monosubstituted trityl radicals. Herein, we report a protocol for the large-scale synthesis of the Finland trityl, which has the advantage of high overall yield and reproducibility. PMID- 24772002 TI - An examination of black/white differences in the rate of age-related mortality increase. AB - BACKGROUND: The rate of mortality increase with age among adults is typically used as a measure of the rate of functional decline associated with aging or senescence. While black and white populations differ in the level of mortality, mortality also rises less rapidly with age for blacks than for whites, leading to the well-known black/white mortality "crossover". OBJECTIVE: This paper investigates black/white differences in the rate of mortality increase with age for major causes of death in order to examine the factors responsible for the black/white crossover. METHODS: The analysis considers two explanations for the crossover: selective survival and age misreporting. Mortality is modeled using a Gompertz model for 11 causes of death from ages 50-84 among blacks and whites by sex. RESULTS: Mortality increases more rapidly with age for whites than for blacks for nearly all causes of death considered. The all-cause mortality rate of mortality increase is nearly two percentage points higher for whites. The analysis finds evidence for both selective survival and age misreporting, although age misreporting is a more prominent explanation among women. CONCLUSIONS: The black/white mortality crossover reflects large differences in the rate of age-related mortality increase. Instead of reflecting the impact of specific causes of death, this pattern exists across many disparate disease conditions, indicating the need for a broad explanation. PMID- 24772003 TI - Autobiologies on YouTube: Narratives of Direct-to-Consumer Genetic Testing. AB - Despite a growing personal genomics market, little is known about how people engage with the possibilities offered by direct-to-consumer (DTC) genetic testing. In order to help address this gap, this study deploys narrative analysis of YouTube videos posted by individuals who have purchased DTC genetic testing for disease. Genetic testing is said to be contributing to new states of illness, where individuals may become "patients-in-waiting." In the videos analyzed, we found a new form of storytelling about this ambiguous state of illness, which we refer to as autobiology. Autobiology - the study of, and story about, one's own biology - concerns narratives of sense-making through forms of biological practice, as well as wayfaring narratives which interweave genetic markers and family histories of disease. These autobiologies - part of a broader shift toward public stories about genetics and other healthcare technologies - exhibit playfulness, as well as being bound with consumerist practices. PMID- 24772004 TI - What Matters When Children Play: Influence of Social Cognitive Theory and Perceived Environment on Levels of Physical Activity Among Elementary-Aged Youth. AB - OBJECTIVES: Social Cognitive Theory (SCT) has often been used as a guide to predict and modify physical activity (PA) behavior. We assessed the ability of commonly investigated SCT variables and perceived school environment variables to predict PA among elementary students. We also examined differences in influences between Hispanic and non-Hispanic students. DESIGN: This analysis used baseline data collected from eight schools who participated in a four-year study of a combined school-day curriculum and environmental intervention. METHODS: Data were collected from 393 students. A 3-step linear regression was used to measure associations between PA level, SCT variables (self-efficacy, social support, enjoyment), and perceived environment variables (schoolyard structures, condition, equipment/supervision). Logistic regression assessed associations between variables and whether students met PA recommendations. RESULTS: School and sex explained 6% of the moderate-to-vigorous PA models' variation. SCT variables explained an additional 15% of the models' variation, with much of the model's predictive ability coming from self-efficacy and social support. Sex was more strongly associated with PA level among Hispanic students, while self efficacy was more strongly associated among non-Hispanic students. Perceived environment variables contributed little to the models. CONCLUSIONS: Our findings add to the literature on the influences of PA among elementary-aged students. The differences seen in the influence of sex and self-efficacy among non-Hispanic and Hispanic students suggests these are areas where PA interventions could be tailored to improve efficacy. Additional research is needed to understand if different measures of perceived environment or perceptions at different ages may better predict PA. PMID- 24772005 TI - Perspectives: Microvascular endothelial dysfunction and gender. PMID- 24772006 TI - The Trial of Mid-Urethral Slings (TOMUS): Design and Methodology. AB - OBJECTIVE: Mid-urethral slings (MUS) are increasingly common surgical procedures for the treatment of stress urinary incontinence (SUI) in women. There are currently no adequately powered trials with sufficient length of follow-up comparing the efficacy or safety of the transobturator and retropubic MUS. As a result, no selection criteria are available to guide surgeons or patients. This article describes the methodology and rationale for the Trial Of Mid-Urethral Slings (TOMUS). PATIENTS AND METHODS: The primary aims of this randomized controlled trial is to compare subjective and objective success rates for urinary incontinence (UI) at 12 and 24 months following retropubic and transobturator MUS procedures. Secondary aims are to compare the resolution of overall and stress specific UI, morbidity, the time to adequate voiding, satisfaction, and quality of life in the two groups. TOMUS will also assess the clinical utility of pre operative urodynamics in women undergoing MUS procedures. The primary outcome will be obtained at 12 months and 24 months. The definition of treatment success is two-fold. Objective treatment success is defined by a negative stress test, a negative 24-hour pad test and no retreatment for SUI. Subjective treatment success is defined by no self-reported leakage on 3-day diary and no self reported SUI symptoms. Enrollment began April 2006 and is expected to be complete in 2 years. CONCLUSIONS: The TOMUS trial is designed to provide outcome and safety information to pelvic surgeons and their patients on the two most commonly performed MUS techniques. PMID- 24772007 TI - Computer-aided modelling and analysis of PV systems: a comparative study. AB - Modern scientific advances have enabled remarkable efficacy for photovoltaic systems with regard to the exploitation of solar energy, boosting them into having a rapidly growing position among the systems developed for the production of renewable energy. However, in many cases the design, analysis, and control of photovoltaic systems are tasks which are quite complex and thus difficult to be carried out. In order to cope with this kind of problems, appropriate software tools have been developed either as standalone products or parts of general purpose software platforms used to model and simulate the generation, transmission, and distribution of solar energy. The utilization of this kind of software tools may be extremely helpful to the successful performance evaluation of energy systems with maximum accuracy and minimum cost in time and effort. The work presented in this paper aims on a first level at the performance analysis of various configurations of photovoltaic systems through computer-aided modelling. On a second level, it provides a comparative evaluation of the credibility of two of the most advanced graphical programming environments, namely, Simulink and LabVIEW, with regard to their application in photovoltaic systems. PMID- 24772008 TI - Measurement and analysis of P2P IPTV program resource. AB - With the rapid development of P2P technology, P2P IPTV applications have received more and more attention. And program resource distribution is very important to P2P IPTV applications. In order to collect IPTV program resources, a distributed multi-protocol crawler is proposed. And the crawler has collected more than 13 million pieces of information of IPTV programs from 2009 to 2012. In addition, the distribution of IPTV programs is independent and incompact, resulting in chaos of program names, which obstructs searching and organizing programs. Thus, we focus on characteristic analysis of program resources, including the distributions of length of program names, the entropy of the character types, and hierarchy depth of programs. These analyses reveal the disorderly naming conventions of P2P IPTV programs. The analysis results can help to purify and extract useful information from chaotic names for better retrieval and accelerate automatic sorting of program and establishment of IPTV repository. In order to represent popularity of programs and to predict user behavior and popularity of hot programs over a period, we also put forward an analytical model of hot programs. PMID- 24772009 TI - Optical frequency upconversion technique for transmission of wireless MIMO-type signals over optical fiber. AB - The optical fiber is well adapted to pass multiple wireless signals having different carrier frequencies by using radio-over-fiber (ROF) technique. However, multiple wireless signals which have the same carrier frequency cannot propagate over a single optical fiber, such as wireless multi-input multi-output (MIMO) signals feeding multiple antennas in the fiber wireless (FiWi) system. A novel optical frequency upconversion (OFU) technique is proposed to solve this problem. In this paper, the novel OFU approach is used to transmit three wireless MIMO signals over a 20 km standard single mode fiber (SMF). The OFU technique exploits one optical source to produce multiple wavelengths by delivering it to a LiNbO3 external optical modulator. The wireless MIMO signals are then modulated by LiNbO3 optical intensity modulators separately using the generated optical carriers from the OFU process. These modulators use the optical single-sideband with carrier (OSSB+C) modulation scheme to optimize the system performance against the fiber dispersion effect. Each wireless MIMO signal is with a 2.4 GHz or 5 GHz carrier frequency, 1 Gb/s data rate, and 16-quadrature amplitude modulation (QAM). The crosstalk between the wireless MIMO signals is highly suppressed, since each wireless MIMO signal is carried on a specific optical wavelength. PMID- 24772010 TI - The development of sex reassignment surgery in Thailand: a social perspective. AB - This paper reviews the development of gender reassignment in Thailand during the period of 1975-2012, in terms of social attitude, epidemiology, surgical patients' profile, law and regulation, religion, and patients' path from psychiatric assessment to surgery. Thailand healthcare for transsexual patients is described. Figures related to the number of sex reassignment surgeries performed in Thailand over the past 30 years are reported. Transsexual individuals are only apparently integrated within the Thail society: the law system of Thailand in fact, does not guarantee to transsexuals the same rights as in other Western countries; the governmental healthcare does not offer free treatments for transsexual patients. In favor of the transsexual healthcare, instead, the Medical Council of Thailand recently published a policy entitled "Criteria for the treatment of sex change, Census 2009." The goal of this policy was to improve the care of transsexual patients in Thailand, by implementing the Standards of Care of the World Professional Association of Transgender Health. Currently, in Thailand, there are 6 major private groups performing sex reassignment surgery, and mostly performing surgery to patients coming from abroad. Particularly, the largest of these (Preecha's group) has performed nearly 3000 vaginoplasties for male-to-female transsexuals in the last 30 years. PMID- 24772011 TI - Analysis of the impact of fault mechanism radiation patterns on macroseismic fields in the epicentral area of 1998 and 2004 Krn Mountains earthquakes (NW Slovenia). AB - Two moderate magnitude (Mw = 5.6 and 5.2) earthquakes in Krn Mountains occurred in 1998 and 2004 which had maximum intensity VII-VIII and VI-VII EMS-98, respectively. Comparison of both macroseismic fields showed unexpected differences in the epicentral area which cannot be explained by site effects. Considerably, different distribution of the highest intensities can be noticed with respect to the strike of the seismogenic fault and in some localities even higher intensities have been estimated for the smaller earthquake. Although hypocentres of both earthquakes were only 2 km apart and were located on the same seismogenic Ravne fault, their focal mechanisms showed a slight difference: almost pure dextral strike-slip for the first event and a strike-slip with small reverse component on a steep fault plane for the second one. Seismotectonically the difference is explained as an active growth of the Ravne fault at its NW end. The radiation patterns of both events were studied to explain their possible impact on the observed variations in macroseismic fields and damage distribution. Radiation amplitude lobes were computed for three orthogonal directions: radial P, SV, and SH. The highest intensities of both earthquakes were systematically observed in directions of four (1998) or two (2004) large amplitude lobes in SH component (which corresponds mainly to Love waves), which have significantly different orientation for both events. On the other hand, radial P direction, which is almost purely symmetrical for the strike-slip mechanism of 1998 event, showed for the 2004 event that its small reverse component of movement has resulted in a very pronounced amplitude lobe in SW direction where two settlements are located which expressed higher intensities in the case of the 2004 event with respect to the 1998 one. Although both macroseismic fields are very complex due to influences of multiple earthquakes, retrofitting activity after 1998, site effects, and sparse distribution of settlements, unusual differences in observed intensities can be explained with different radiation patterns. PMID- 24772012 TI - Continuous-time SigmaDelta ADC with implicit variable gain amplifier for CMOS image sensor. AB - This paper presents a column-parallel continuous-time sigma delta (CTSD) ADC for mega-pixel resolution CMOS image sensor (CIS). The sigma delta modulator is implemented with a 2nd order resistor/capacitor-based loop filter. The first integrator uses a conventional operational transconductance amplifier (OTA), for the concern of a high power noise rejection. The second integrator is realized with a single-ended inverter-based amplifier, instead of a standard OTA. As a result, the power consumption is reduced, without sacrificing the noise performance. Moreover, the variable gain amplifier in the traditional column parallel read-out circuit is merged into the front-end of the CTSD modulator. By programming the input resistance, the amplitude range of the input current can be tuned with 8 scales, which is equivalent to a traditional 2-bit preamplification function without consuming extra power and chip area. The test chip prototype is fabricated using 0.18 MUm CMOS process and the measurement result shows an ADC power consumption lower than 63.5 MUW under 1.4 V power supply and 50 MHz clock frequency. PMID- 24772013 TI - Effect of Vetiveria zizanioides essential oil on melanogenesis in melanoma cells: downregulation of tyrosinase expression and suppression of oxidative stress. AB - The major objective of this study was to estimate the hypopigmentation function of the essential oil from Vetiveria zizanioides (VZ-EO). Our results indicated that VZ-EO exhibits potent lipid peroxidation inhibitory activity to moderate the bleaching of beta-carotene and to maintain the cellular glutathione (GSH) levels. VZ-EO can markedly decrease melanin production and tyrosinase activity in alpha melanin-stimulating-hormone- (alpha-MSH-) stimulated B16 cells. The effect of VZ EO on melanogenesis is achieved by the suppression of cellular tyrosinase expression. The results demonstrated that the activity of VZ-EO on melanogenesis might be the result of its potent antioxidative ability, which was reflected in the decreased cellular oxidant and malondialdehyde (MDA) levels and the recovered activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) in alpha-MSH-stimulated B16 cells. The most abundant compound in VZ-EO is cedr-8-en-13-ol (12.4%), which has a strong capability to inhibit lipid peroxidation. Therefore, VZ-EO has the potential to become an ingredient in future hypopigmentation drugs, foods, and cosmetics. PMID- 24772014 TI - Using fuzzy multiple criteria decision-making approach for assessing the risk of railway reconstruction project in Taiwan. AB - This study investigates the risk factors in railway reconstruction project through complete literature reviews on construction project risks and scrutinizing experiences and challenges of railway reconstructions in Taiwan. Based on the identified risk factors, an assessing framework based on the fuzzy multicriteria decision-making (fuzzy MCDM) approach to help construction agencies build awareness of the critical risk factors on the execution of railway reconstruction project, measure the impact and occurrence likelihood for these risk factors. Subjectivity, uncertainty and vagueness within the assessment process are dealt with using linguistic variables parameterized by trapezoid fuzzy numbers. By multiplying the degree of impact and the occurrence likelihood of risk factors, estimated severity values of each identified risk factor are determined. Based on the assessment results, the construction agencies were informed of what risks should be noticed and what they should do to avoid the risks. That is, it enables construction agencies of railway reconstruction to plan the appropriate risk responses/strategies to increase the opportunity of project success and effectiveness. PMID- 24772015 TI - Biogeographical variation and population genetic structure of Sporisorium scitamineum in Mainland China: insights from ISSR and SP-SRAP markers. AB - A total of 100 Sporisorium scitamineum isolates were investigated by inter simple sequence repeat (ISSR) and single primer-sequence related amplified polymorphism (SP-SRAP) markers. These isolates were clearly assorted into three distinct clusters regardless of method used: either cluster analysis or by principal component analysis (PCA) of the ISSR, SP-SRAP, or ISSR + SP-SRAP data set. The total gene diversity (H t) and gene diversity between subpopulations (H s) were estimated to be 0.34 to 0.38 and 0.22 to 0.29, respectively, by analyzing separately the ISSR and SP-SRAP data sets, and to be 0.26-0.36 by analyzing ISSR + SP-SRAP data set. The gene diversity attributable to differentiation among populations (G st) was estimated to be 0.35 and 0.22, and the gene flow (Nm) was 0.94 and 1.78, respectively, when analyzing separately ISSR and SP-SRAP data set, and was 0.27 and 1.33, respectively, when analyzing ISSR + SP-SRAP data set. Our study showed that there is considerable genetic variation in the analyzed 100 isolates, and the environmental heterogeneity has played an important role for this observed high degree of variation. The genetic differentiation of sugarcane smut fungus depends to a large extent on the heterogeneity of their habitats and is the result of long-term adaptations of pathogens to their ecological environments. PMID- 24772016 TI - On the shape of limit cycles that bifurcate from isochronous center. AB - New idea and algorithm are proposed to compute asymptotic expression of limit cycles bifurcated from the isochronous center. Compared with known inverse integrating factor method, new algorithm to analytically computing shape of limit cycle proposed in this paper is simple and easy to apply. The applications of new algorithm to some examples are also given. PMID- 24772017 TI - Unsupervised chunking based on graph propagation from bilingual corpus. AB - This paper presents a novel approach for unsupervised shallow parsing model trained on the unannotated Chinese text of parallel Chinese-English corpus. In this approach, no information of the Chinese side is applied. The exploitation of graph-based label propagation for bilingual knowledge transfer, along with an application of using the projected labels as features in unsupervised model, contributes to a better performance. The experimental comparisons with the state of-the-art algorithms show that the proposed approach is able to achieve impressive higher accuracy in terms of F-score. PMID- 24772018 TI - Microwave assisted synthesis, spectral and antifungal studies of 2-phenyl-N,N' bis(pyridin-4-ylcarbonyl)butanediamide ligand and its metal complexes. AB - 2-Phenyl-N,N'-bis(pyridin-4-ylcarbonyl)butanediamide ligand with a series of transition metal complexes has been synthesized via two routes: microwave irradiation and conventional heating method. Microwave irritation method happened to be the efficient and versatile route for the synthesis of these metal complexes. These complexes were found to have the general composition M(L)Cl2/M(L)(CH3COO)2 (where M = Cu(II), Co(II), Ni(II), and L = ligand). Different physical and spectroscopic techniques were used to investigate the structural features of the synthesized compounds, which supported an octahedral geometry for these complexes. In vitro antifungal activity of the ligand and its metal complexes revealed that the metal complexes are highly active compared to the standard drug. Metal complexes showed enhanced activity compared to the ligand, which is an important step towards the designing of antifungal drug candidates. PMID- 24772019 TI - Research on universal combinatorial coding. AB - The conception of universal combinatorial coding is proposed. Relations exist more or less in many coding methods. It means that a kind of universal coding method is objectively existent. It can be a bridge connecting many coding methods. Universal combinatorial coding is lossless and it is based on the combinatorics theory. The combinational and exhaustive property make it closely related with the existing code methods. Universal combinatorial coding does not depend on the probability statistic characteristic of information source, and it has the characteristics across three coding branches. It has analyzed the relationship between the universal combinatorial coding and the variety of coding method and has researched many applications technologies of this coding method. In addition, the efficiency of universal combinatorial coding is analyzed theoretically. The multicharacteristic and multiapplication of universal combinatorial coding are unique in the existing coding methods. Universal combinatorial coding has theoretical research and practical application value. PMID- 24772020 TI - A component prediction method for flue gas of natural gas combustion based on nonlinear partial least squares method. AB - Quantitative analysis for the flue gas of natural gas-fired generator is significant for energy conservation and emission reduction. The traditional partial least squares method may not deal with the nonlinear problems effectively. In the paper, a nonlinear partial least squares method with extended input based on radial basis function neural network (RBFNN) is used for components prediction of flue gas. For the proposed method, the original independent input matrix is the input of RBFNN and the outputs of hidden layer nodes of RBFNN are the extension term of the original independent input matrix. Then, the partial least squares regression is performed on the extended input matrix and the output matrix to establish the components prediction model of flue gas. A near-infrared spectral dataset of flue gas of natural gas combustion is used for estimating the effectiveness of the proposed method compared with PLS. The experiments results show that the root-mean-square errors of prediction values of the proposed method for methane, carbon monoxide, and carbon dioxide are, respectively, reduced by 4.74%, 21.76%, and 5.32% compared to those of PLS. Hence, the proposed method has higher predictive capabilities and better robustness. PMID- 24772021 TI - Evaluation of groundwater recharge estimates in a partially metamorphosed sedimentary basin in a tropical environment: application of natural tracers. AB - This study tests the representativeness of groundwater recharge estimates through the chloride mass balance (CMB) method in a tropical environment. The representativeness of recharge estimates using this methodology is tested using evaporation estimates from isotope data, the general spatial distribution of the potential field, and the topographical variations in the area. This study suggests that annual groundwater recharge rates in the area ranges between 0.9% and 21% of annual precipitation. These estimates are consistent with evaporation rates computed from stable isotope data of groundwater and surface water in the Voltaian Basin. Moreover, estimates of groundwater recharge through numerical model calibration in other parts of the terrain appear to be consistent with the current data in this study. A spatial distribution of groundwater recharge in the area based on the estimated data takes a pattern akin to the spatial pattern of distribution of the hydraulic head, the local topography, and geology of the terrain. This suggests that the estimates at least qualitatively predicts the local recharge and discharge locations in the terrain. PMID- 24772022 TI - Control problems for semilinear neutral differential equations in Hilbert spaces. AB - We construct some results on the regularity of solutions and the approximate controllability for neutral functional differential equations with unbounded principal operators in Hilbert spaces. In order to establish the controllability of the neutral equations, we first consider the existence and regularity of solutions of the neutral control system by using fractional power of operators and the local Lipschitz continuity of nonlinear term. Our purpose is to obtain the existence of solutions and the approximate controllability for neutral functional differential control systems without using many of the strong restrictions considered in the previous literature. Finally we give a simple example to which our main result can be applied. PMID- 24772023 TI - Enhancing artificial bee colony algorithm with self-adaptive searching strategy and artificial immune network operators for global optimization. AB - Artificial bee colony (ABC) algorithm, inspired by the intelligent foraging behavior of honey bees, was proposed by Karaboga. It has been shown to be superior to some conventional intelligent algorithms such as genetic algorithm (GA), artificial colony optimization (ACO), and particle swarm optimization (PSO). However, the ABC still has some limitations. For example, ABC can easily get trapped in the local optimum when handing in functions that have a narrow curving valley, a high eccentric ellipse, or complex multimodal functions. As a result, we proposed an enhanced ABC algorithm called EABC by introducing self adaptive searching strategy and artificial immune network operators to improve the exploitation and exploration. The simulation results tested on a suite of unimodal or multimodal benchmark functions illustrate that the EABC algorithm outperforms ACO, PSO, and the basic ABC in most of the experiments. PMID- 24772024 TI - Prediction of the wall factor of arbitrary particle settling through various fluid media in a cylindrical tube using artificial intelligence. AB - Considering the influence of particle shape and the rheological properties of fluid, two artificial intelligence methods (Artificial Neural Network and Support Vector Machine) were used to predict the wall factor which is widely introduced to deduce the net hydrodynamic drag force of confining boundaries on settling particles. 513 data points were culled from the experimental data of previous studies, which were divided into training set and test set. Particles with various shapes were divided into three kinds: sphere, cylinder, and rectangular prism; feature parameters of each kind of particle were extracted; prediction models of sphere and cylinder using artificial neural network were established. Due to the little number of rectangular prism sample, support vector machine was used to predict the wall factor, which is more suitable for addressing the problem of small samples. The characteristic dimension was presented to describe the shape and size of the diverse particles and a comprehensive prediction model of particles with arbitrary shapes was established to cover all types of conditions. Comparisons were conducted between the predicted values and the experimental results. PMID- 24772025 TI - A real-time and closed-loop control algorithm for cascaded multilevel inverter based on artificial neural network. AB - In order to control the cascaded H-bridges (CHB) converter with staircase modulation strategy in a real-time manner, a real-time and closed-loop control algorithm based on artificial neural network (ANN) for three-phase CHB converter is proposed in this paper. It costs little computation time and memory. It has two steps. In the first step, hierarchical particle swarm optimizer with time varying acceleration coefficient (HPSO-TVAC) algorithm is employed to minimize the total harmonic distortion (THD) and generate the optimal switching angles offline. In the second step, part of optimal switching angles are used to train an ANN and the well-designed ANN can generate optimal switching angles in a real time manner. Compared with previous real-time algorithm, the proposed algorithm is suitable for a wider range of modulation index and results in a smaller THD and a lower calculation time. Furthermore, the well-designed ANN is embedded into a closed-loop control algorithm for CHB converter with variable direct voltage (DC) sources. Simulation results demonstrate that the proposed closed-loop control algorithm is able to quickly stabilize load voltage and minimize the line current's THD (<5%) when subjecting the DC sources disturbance or load disturbance. In real design stage, a switching angle pulse generation scheme is proposed and experiment results verify its correctness. PMID- 24772026 TI - Designing a multistage supply chain in cross-stage reverse logistics environments: application of particle swarm optimization algorithms. AB - This study designed a cross-stage reverse logistics course for defective products so that damaged products generated in downstream partners can be directly returned to upstream partners throughout the stages of a supply chain for rework and maintenance. To solve this reverse supply chain design problem, an optimal cross-stage reverse logistics mathematical model was developed. In addition, we developed a genetic algorithm (GA) and three particle swarm optimization (PSO) algorithms: the inertia weight method (PSOA_IWM), V(Max) method (PSOA_VMM), and constriction factor method (PSOA_CFM), which we employed to find solutions to support this mathematical model. Finally, a real case and five simulative cases with different scopes were used to compare the execution times, convergence times, and objective function values of the four algorithms used to validate the model proposed in this study. Regarding system execution time, the GA consumed more time than the other three PSOs did. Regarding objective function value, the GA, PSOA_IWM, and PSOA_CFM could obtain a lower convergence value than PSOA_VMM could. Finally, PSOA_IWM demonstrated a faster convergence speed than PSOA_VMM, PSOA_CFM, and the GA did. PMID- 24772027 TI - Some refinements and generalizations of I. Schur type inequalities. AB - Recently, extensive researches on estimating the value of e have been studied. In this paper, the structural characteristics of I. Schur type inequalities are exploited to generalize the corresponding inequalities by variable parameter techniques. Some novel upper and lower bounds for the I. Schur inequality have also been obtained and the upper bounds may be obtained with the help of Maple and automated proving package (Bottema). Numerical examples are employed to demonstrate the reliability of the approximation of these new upper and lower bounds, which improve some known results in the recent literature. PMID- 24772028 TI - An embedded laser marking controller based on ARM and FPGA processors. AB - Laser marking is an important branch of the laser information processing technology. The existing laser marking machine based on PC and WINDOWS operating system, are large and inconvenient to move. Still, it cannot work outdoors or in other harsh environments. In order to compensate for the above mentioned disadvantages, this paper proposed an embedded laser marking controller based on ARM and FPGA processors. Based on the principle of laser galvanometer scanning marking, the hardware and software were designed for the application. Experiments showed that this new embedded laser marking controller controls the galvanometers synchronously and could achieve precise marking. PMID- 24772029 TI - Summary on several key techniques in 3D geological modeling. AB - Several key techniques in 3D geological modeling including planar mesh generation, spatial interpolation, and surface intersection are summarized in this paper. Note that these techniques are generic and widely used in various applications but play a key role in 3D geological modeling. There are two essential procedures in 3D geological modeling: the first is the simulation of geological interfaces using geometric surfaces and the second is the building of geological objects by means of various geometric computations such as the intersection of surfaces. Discrete geometric surfaces that represent geological interfaces can be generated by creating planar meshes first and then spatially interpolating; those surfaces intersect and then form volumes that represent three-dimensional geological objects such as rock bodies. In this paper, the most commonly used algorithms of the key techniques in 3D geological modeling are summarized. PMID- 24772030 TI - Modelling soil water retention using support vector machines with genetic algorithm optimisation. AB - This work presents point pedotransfer function (PTF) models of the soil water retention curve. The developed models allowed for estimation of the soil water content for the specified soil water potentials: -0.98, -3.10, -9.81, -31.02, 491.66, and -1554.78 kPa, based on the following soil characteristics: soil granulometric composition, total porosity, and bulk density. Support Vector Machines (SVM) methodology was used for model development. A new methodology for elaboration of retention function models is proposed. Alternative to previous attempts known from literature, the nu-SVM method was used for model development and the results were compared with the formerly used the C-SVM method. For the purpose of models' parameters search, genetic algorithms were used as an optimisation framework. A new form of the aim function used for models parameters search is proposed which allowed for development of models with better prediction capabilities. This new aim function avoids overestimation of models which is typically encountered when root mean squared error is used as an aim function. Elaborated models showed good agreement with measured soil water retention data. Achieved coefficients of determination values were in the range 0.67-0.92. Studies demonstrated usability of nu-SVM methodology together with genetic algorithm optimisation for retention modelling which gave better performing models than other tested approaches. PMID- 24772031 TI - A novel algorithm combining finite state method and genetic algorithm for solving crude oil scheduling problem. AB - A hybrid optimization algorithm combining finite state method (FSM) and genetic algorithm (GA) is proposed to solve the crude oil scheduling problem. The FSM and GA are combined to take the advantage of each method and compensate deficiencies of individual methods. In the proposed algorithm, the finite state method makes up for the weakness of GA which is poor at local searching ability. The heuristic returned by the FSM can guide the GA algorithm towards good solutions. The idea behind this is that we can generate promising substructure or partial solution by using FSM. Furthermore, the FSM can guarantee that the entire solution space is uniformly covered. Therefore, the combination of the two algorithms has better global performance than the existing GA or FSM which is operated individually. Finally, a real-life crude oil scheduling problem from the literature is used for conducting simulation. The experimental results validate that the proposed method outperforms the state-of-art GA method. PMID- 24772032 TI - Scheduling IT staff at a bank: a mathematical programming approach. AB - We address a real-world optimization problem: the scheduling of a Bank Information Technologies (IT) staff. This problem can be defined as the process of constructing optimized work schedules for staff. In a general sense, it requires the allocation of suitably qualified staff to specific shifts to meet the demands for services of an organization while observing workplace regulations and attempting to satisfy individual work preferences. A monthly shift schedule is prepared to determine the shift duties of each staff considering shift coverage requirements, seniority-based workload rules, and staff work preferences. Due to the large number of conflicting constraints, a multiobjective programming model has been proposed to automate the schedule generation process. The suggested mathematical model has been implemented using Lingo software. The results indicate that high quality solutions can be obtained within a few seconds compared to the manually prepared schedules. PMID- 24772033 TI - Dynamic and quantitative method of analyzing service consistency evolution based on extended hierarchical finite state automata. AB - This paper is concerned with the dynamic evolution analysis and quantitative measurement of primary factors that cause service inconsistency in service oriented distributed simulation applications (SODSA). Traditional methods are mostly qualitative and empirical, and they do not consider the dynamic disturbances among factors in service's evolution behaviors such as producing, publishing, calling, and maintenance. Moreover, SODSA are rapidly evolving in terms of large-scale, reusable, compositional, pervasive, and flexible features, which presents difficulties in the usage of traditional analysis methods. To resolve these problems, a novel dynamic evolution model extended hierarchical service-finite state automata (EHS-FSA) is constructed based on finite state automata (FSA), which formally depict overall changing processes of service consistency states. And also the service consistency evolution algorithms (SCEAs) based on EHS-FSA are developed to quantitatively assess these impact factors. Experimental results show that the bad reusability (17.93% on average) is the biggest influential factor, the noncomposition of atomic services (13.12%) is the second biggest one, and the service version's confusion (1.2%) is the smallest one. Compared with previous qualitative analysis, SCEAs present good effectiveness and feasibility. This research can guide the engineers of service consistency technologies toward obtaining a higher level of consistency in SODSA. PMID- 24772034 TI - Echocardiographic parameters as predictors of in-hospital mortality in patients with acute coronary syndrome undergoing percutaneous coronary intervention. AB - Different ways have been used to stratify risk in acute coronary syndrome (ACS) patients. The aim of the study was to examine the usefulness of echocardiographic parameters as predictors of in-hospital outcome in patients with ACS after percutaneous coronary intervention (PCI). A data of 2030 patients with diagnosis of ACS hospitalized from December 2008 to December 2011 was used to develop a risk model based on echocardiographic parameters using the binary logistic regression. This model was independently evaluated in validation cohort prospectively (954 patients admitted during 2012). In-hospital mortality in derivation cohort was 7.73%, and 6.28% in validation cohort. Developed model has been designed with 4 independent echocardiographic predictors of in-hospital mortality: left ventricular ejection fraction (LVEF RR = 0.892; 95%CI = 0.854 0.932, P < 0.0005), aortic leaflet separation diameter (AOvs RR = 0.131; 95%CI = 0.027-0.627, P = 0.011), right ventricle diameter (RV RR = 2.675; 95%CI = 1.109 6.448, P = 0.028) and right ventricle systolic pressure (RVSP RR = 1.036; 95%CI = 1.000-1.074, P = 0.048). Model has good prognostic accuracy (AUROC = 0.84) and it retains good (AUROC = 0.78) when testing on the validation cohort. Risks for in hospital mortality after PCI in ACS patients using echocardiographic measurements could be accurately predicted in contemporary practice. Incorporation of such developed model should facilitate research, clinical decisions, and optimizing treatment strategy in selected high risk ACS patients. PMID- 24772036 TI - Adaptive random testing with combinatorial input domain. AB - Random testing (RT) is a fundamental testing technique to assess software reliability, by simply selecting test cases in a random manner from the whole input domain. As an enhancement of RT, adaptive random testing (ART) has better failure-detection capability and has been widely applied in different scenarios, such as numerical programs, some object-oriented programs, and mobile applications. However, not much work has been done on the effectiveness of ART for the programs with combinatorial input domain (i.e., the set of categorical data). To extend the ideas to the testing for combinatorial input domain, we have adopted different similarity measures that are widely used for categorical data in data mining and have proposed two similarity measures based on interaction coverage. Then, we propose a new version named ART-CID as an extension of ART in combinatorial input domain, which selects an element from categorical data as the next test case such that it has the lowest similarity against already generated test cases. Experimental results show that ART-CID generally performs better than RT, with respect to different evaluation metrics. PMID- 24772035 TI - Evaluation the surface antigen of the Salmonella typhimurium ATCC 14028 ghosts prepared by "SLRP". AB - Recently, bacterial ghosts (BGs) were prepared using a protocol based on critical chemical concentrations. It has been given the name "sponge like" (SL) protocol and used in its reduced form "sponge like reduced protocol" (SLRP). While specific antibody for Salmonella is available on the market under the commercial names (of some kits) such as Febrile Antigen Kit (N.S. BIO-TEC), we used the described Kit to investigate the validity of the SLRP. In this study, using SLRP we succeeded to prepare STGs with correct surface antigens could interact with their specific antibodies. Additionally the study has included oral vaccination with STGs with challenge test. The rats serums have been evaluated against both of the O and H antigens. The antigen-antibody interaction (agglutination) results of both the SLRP and the animal experiments prove that we have correct STGs able to immunize the rats against viable Salmonella. STGs could be used as vaccine and as adjuvant and in the antibodies and in the diagnostic kits production. This study is an additional step for the establishment of correct BGs for immunological purposes. PMID- 24772037 TI - Fraction reduction in membrane systems. AB - Fraction reduction is a basic computation for rational numbers. P system is a new computing model, while the current methods for fraction reductions are not available in these systems. In this paper, we propose a method of fraction reduction and discuss how to carry it out in cell-like P systems with the membrane structure and the rules with priority designed. During the application of fraction reduction rules, synchronization is guaranteed by arranging some special objects in these rules. Our work contributes to performing the rational computation in P systems since the rational operands can be given in the form of fraction. PMID- 24772039 TI - A hybrid monkey search algorithm for clustering analysis. AB - Clustering is a popular data analysis and data mining technique. The k-means clustering algorithm is one of the most commonly used methods. However, it highly depends on the initial solution and is easy to fall into local optimum solution. In view of the disadvantages of the k-means method, this paper proposed a hybrid monkey algorithm based on search operator of artificial bee colony algorithm for clustering analysis and experiment on synthetic and real life datasets to show that the algorithm has a good performance than that of the basic monkey algorithm for clustering analysis. PMID- 24772038 TI - Ophthalmic drug dosage forms: characterisation and research methods. AB - This paper describes hitherto developed drug forms for topical ocular administration, that is, eye drops, ointments, in situ gels, inserts, multicompartment drug delivery systems, and ophthalmic drug forms with bioadhesive properties. Heretofore, many studies have demonstrated that new and more complex ophthalmic drug forms exhibit advantage over traditional ones and are able to increase the bioavailability of the active substance by, among others, reducing the susceptibility of drug forms to defense mechanisms of the human eye, extending contact time of drug with the cornea, increasing the penetration through the complex anatomical structure of the eye, and providing controlled release of drugs into the eye tissues, which allows reducing the drug application frequency. The rest of the paper describes recommended in vitro and in vivo studies to be performed for various ophthalmic drugs forms in order to assess whether the form is acceptable from the perspective of desired properties and patient's compliance. PMID- 24772040 TI - Use and diversity of palm (Arecaceae) resources in Central Western Brazil. AB - Arecaceae Schultz-Sch. (Palmae Juss.), a member of the monocotyledon group, is considered one of the oldest extant angiosperm families on Earth. This family is highly valuable because of its species diversity, its occurrence in a wide range of habitats, and its status as an integral part of the culture and the family based economy of many traditional and nontraditional communities. The main objectives of this study were to perform an ethnobotanical study involving these palms and a "Quilombola" (Maroon) community in the municipality of Cavalcante, GO, Brazil. The variables gender, age, and formal schooling had no influence on the number of species recognized and used by the Kalungas. Ethnobotanical studies based on traditional knowledge in addition to use and management of palms are fundamental aspects for planning and appliance of public policies directed to the use of natural resources and improvement of life quality. PMID- 24772041 TI - Characterization of metabolites of leonurine (SCM-198) in rats after oral administration by liquid chromatography/tandem mass spectrometry and NMR spectrometry. AB - Leonurine, a major bioactive component from Herba Leonuri, shows therapeutic potential for cardiovascular disease and stroke prevention in some preclinical experiments. The aim of this study is to characterize metabolites of leonurine in rats using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS). The chromatographic separation was performed on an Agilent ZORBAX SB-C18 column using a gradient elution with acetonitrile/ammonium acetate buffer (10 mM, pH 4.0) solvent system. An information dependent acquisition (IDA) method was developed for screening and identifying metabolites of leonurine under positive ion mode. Compared with control, the interesting compound in the extracted ion chromatogram (XIC) of the in vivo samples was chosen and further identified by analyzing their retention times, changes in observed mass (Deltam/z), and spectral patterns of product ion utilizing advanced software tool. For the first time, a total of three metabolites were identified, including two phase II metabolites generated by glucuronidation (M1) and sulfation (M2) and one phase I metabolite formed by O-demethylation (M3). Finally, the lead metabolite M1 was isolated from urine and its structure was characterized as leonurine-10-O- beta-D-glucuronide by NMR spectroscopy (1H, 13C, HMBC, and HSQC). PMID- 24772043 TI - Letter from the editor. PMID- 24772042 TI - On-the-fly Numerical Surface Integration for Finite-Difference Poisson-Boltzmann Methods. AB - Most implicit solvation models require the definition of a molecular surface as the interface that separates the solute in atomic detail from the solvent approximated as a continuous medium. Commonly used surface definitions include the solvent accessible surface (SAS), the solvent excluded surface (SES), and the van der Waals surface. In this study, we present an efficient numerical algorithm to compute the SES and SAS areas to facilitate the applications of finite difference Poisson-Boltzmann methods in biomolecular simulations. Different from previous numerical approaches, our algorithm is physics-inspired and intimately coupled to the finite-difference Poisson-Boltzmann methods to fully take advantage of its existing data structures. Our analysis shows that the algorithm can achieve very good agreement with the analytical method in the calculation of the SES and SAS areas. Specifically, in our comprehensive test of 1,555 molecules, the average unsigned relative error is 0.27% in the SES area calculations and 1.05% in the SAS area calculations at the grid spacing of 1/2A. In addition, a systematic correction analysis can be used to improve the accuracy for the coarse-grid SES area calculations, with the average unsigned relative error in the SES areas reduced to 0.13%. These validation studies indicate that the proposed algorithm can be applied to biomolecules over a broad range of sizes and structures. Finally, the numerical algorithm can also be adapted to evaluate the surface integral of either a vector field or a scalar field defined on the molecular surface for additional solvation energetics and force calculations. PMID- 24772044 TI - In the pipeline: updates on promising agents in development for gastroenterology & hepatology. PMID- 24772047 TI - The use of cryotherapy for treatment of barrett esophagus. PMID- 24772045 TI - Dysphagia in the elderly. AB - Elderly patients are inherently predisposed to dysphagia predominately because of comorbid health conditions. With the aging of the population in the United States, along with the increased prevalence of obesity and gastroesophageal reflux disease, healthcare providers will increasingly encounter older patients with either oropharyngeal or esophageal disease and complaints of dysphagia. Useful tests to evaluate dysphagia include the videofluoroscopic swallowing study and the fiberoptic endoscopic evaluation of swallowing. Swallow rehabilitation is useful to help patients compensate for swallowing difficulty and ultimately help strengthen the neuromusculature involved in swallowing. PMID- 24772048 TI - Endoscopic ultrasound: common challenging scenarios. PMID- 24772049 TI - Hepatitis C virus infection in special populations. PMID- 24772050 TI - Advances in the treatment of ulcerative colitis. PMID- 24772046 TI - Environmental influences on the onset and clinical course of Crohn's disease-part 2: infections and medication use. AB - The pathogenesis of Crohn's disease (CD) involves host, genetic, and environmental factors. These factors result in disturbances in the innate and adaptive immune systems and composition of the intestinal microbiota. Epidemiologic and migration studies support an environmental component in the development of CD. Environmental risk factors include childhood hygiene, air pollution, breastfeeding, smoking, diet, stress, exercise, seasonal variation, appendectomy, medications, and infections. This 2-part series provides an overview of these external contributors to the development or exacerbation of CD. Part 1, which was published in a previous issue, focused on childhood factors, perinatal influences, and lifestyle choices. Part 2, presented here, details the effects of infections, antibiotics, nonsteroidal anti-inflammatory drugs, and oral contraceptives. PMID- 24772051 TI - Acute renal dysfunction in liver cirrhosis. PMID- 24772052 TI - Highlights from AASLD 2013. PMID- 24772053 TI - Alternative approaches to treatment of Central Sleep Apnea. AB - Divergent approaches to treatment of hypocapnic central sleep apnea syndromes reflect the difficulties in taming a hyperactive respiratory chemoreflex. As both sleep fragmentation and a narrow CO2 reserve or increased loop gain drive the disease, sedatives (to induce longer periods of stable non-rapid eye movement (NREM) sleep and reduce the destabilizing effects of arousals in NREM sleep) and CO2-based stabilization approaches are logical. Adaptive ventilation reduces mean hyperventilation yet can induce ventilator-patient dyssynchrony, while enhanced expiratory rebreathing space (EERS, dead space during positive pressure therapy) and CO2 manipulation directly stabilize respiratory control by moving CO2 above the apnea threshold. Carbonic anhydrase inhibition can provide further adjunctive benefits. Provent and Winx may be less likely to trigger central apneas or periodic breathing in those with a narrow CO2 reserve. An oral appliance can meaningfully reduce positive pressure requirements and thus enable treatment of complex apnea. Novel pharmacological approaches may target mediators of carotid body glomus cell excitation, such as the balance between gas neurotransmitters. In complex apnea patients, single mode therapy is not always successful, and multi-modality therapy might need to be considered. Phenotyping of sleep apnea beyond conventional scoring approaches is the key to optimal management. PMID- 24772055 TI - Degradation of methylene blue using biologically synthesized silver nanoparticles. AB - Nowadays plant mediated synthesis of nanoparticles has great interest and achievement due to its eco-benign and low time consuming properties. In this study silver nanoparticles were successfully synthesized by using Morinda tinctoria leaf extract under different pH. The aqueous leaf extract was added to silver nitrate solution; the color of the reaction medium was changed from pale yellow to brown and that indicates reduction of silver ions to silver nanoparticles. Thus synthesized silver nanoparticles were characterized by UV-Vis spectrophotometer. Dispersity and morphology was characterized by scanning electron microscope (SEM); crystalline nature and purity of synthesized silver nanoparticles were revealed by X-ray diffraction (XRD) and energy dispersive X ray spectroscopy (EDX). FTIR spectrum was examined to identify the effective functional molecules responsible for the reduction and stabilization of silver nanoparticles synthesized by leaf extract. The photocatalytic activity of the synthesized silver nanoparticles was examined by degradation of methylene blue under sunlight irradiation. Green synthesized silver nanoparticles were effectively degrading the dye nearly 95% at 72 h of exposure time. PMID- 24772054 TI - Brain: normal variations and benign findings in fluorodeoxyglucose-PET/computed tomography imaging. AB - Brain 18F-fluorodeoxyglucose (18F-FDG) PET allows the in vivo study of cerebral glucose metabolism, reflecting neuronal and synaptic activity. 18F-FDG-PET has been extensively used to detect metabolic alterations in several neurologic diseases compared with normal aging. However, healthy subjects have variants of 18F-FDG distribution, especially as associated with aging. This article focuses on 18F-FDG-PET findings in so-called normal brain aging, and in particular on metabolic differences occurring with aging and as a function of people's gender. The effect of different substances, medications, and therapy procedures are discussed, as well as common artifacts. PMID- 24772056 TI - Changes in metabolite profiles caused by genetically determined obesity in mice. AB - The Berlin Fat Mouse Inbred (BFMI) line harbors a major recessive gene defect on chromosome 3 (jobes1) leading to juvenile obesity and metabolic syndrome. The present study aimed at the identification of metabolites that might be linked to recessively acting genes in the obesity locus. Firstly, serum metabolites were analyzed between obese BFMI and lean B6 and BFMI * B6 F1 mice to identify metabolites that are different. In a second step, a metabolite-protein network analysis was performed linking metabolites typical for BFMI mice with genes of the jobes1 region. The levels of 22 diacyl-phosphatidylcholines (PC aa), two lyso PC and three carnitines were found to be significantly lower in obese mice compared with lean mice, while serine, glycine, arginine and hydroxysphingomyelin were higher for the same comparison. The network analysis identified PC aa C42:1 as functionally linked with the genes Ccna2 and Trpc3 via the enzymes choline kinase alpha and phospholipase A2 group 1B (PLA2G1B), respectively. Gene expression analysis revealed elevated Ccna2 expression in adipose tissue of BFMI mice. Furthermore, unique mutations were found in the Ccna2 promoter of BFMI mice which are located in binding sites for transcription factors or micro RNAs and could cause differential Ccna2 mRNA levels between BFMI and B6 mice. Increased expression of Ccna2 was consistent with higher mitotic activity of adipose tissue in BFMI mice. Therefore, we suggest a higher demand for PC necessary for adipose tissue growth and remodeling. This study highlights the relationship between metabolite profiles and the underlying genetics of obesity in the BFMI line. PMID- 24772057 TI - Integrated MALDI-MS imaging and LC-MS techniques for visualizing spatiotemporal metabolomic dynamics in a rat stroke model. AB - Spatiotemporal information about biomolecules is indispensable for precise pathological analysis, but it remains largely unclear. Here we show a novel analytical platform combing mass spectrometry imaging (MSI) with its complementary technique, liquid chromatography-mass spectrometry (LC-MS), to elucidate more comprehensive metabolic behaviors, with spatiotemporal information, in tissues. Analysis of a rat transient middle cerebral artery occlusion (MCAO) brain tissue after ischemia-reperfusion was performed to characterize the detailed metabolomic response to pathological alterations. To compare the spatially resolved metabolic state between ischemic and contralateral hemispheres of the MCAO brain, coronally sliced tissues were subjected to MSI. We also measured the metabolites extracted from three different cerebral regions, including whole cortex (CTX), hippocampus (HI) and corpus striatum (CPu), by LC MS. In the ischemic hemisphere, significant metabolic changes at the CTX and CPu were observed after reperfusion, while not at the HI. A region-specific metabolic behavior was observed in amino acid and nucleotide metabolism, as well as in the TCA cycle. Correlation between MSI and LC-MS data was relatively high in the CTX and CPu. Combination of both MS platforms visualized the diverse spatiotemporal metabolic dynamics during pathological progress. Thus, our proposed strategy will contribute to the understanding of the complex pathogenesis of ischemia reperfusion. PMID- 24772058 TI - Comparative structural profiling of trichome specialized metabolites in tomato (Solanumlycopersicum) and S. habrochaites: acylsugar profiles revealed by UHPLC/MS and NMR. AB - Many plants accumulate large quantities of specialized metabolites in secretory glandular trichomes (SGTs), which are specialized epidermal cells. In the genus Solanum, SGTs store a diverse collection of glucose and sucrose esters. Profiling of extracts from two accessions (LA1777 and LA1392) of Solanum habrochaites using ultra-high performance liquid chromatography-mass spectrometry (UHPLC/MS) revealed wide acylsugar diversity, with up to 11 isomers annotated for each individual elemental formula. These isomers arise from differences in ester chain lengths and their positions of substitution or branching. Since fragment ion masses were not sufficient to distinguish all isomers, 24 acylsucroses were purified from S. habrochaites accessions and cultivated tomato (Solanum lycopersicum M82) and characterized using NMR spectroscopy. Two-dimensional NMR spectra yielded assignments of positions of substitution of specific acyl groups, and locations of branching. The range of substitution was wider than reported earlier, and in contrast to previous reports, tetra- and penta-acylsucroses were substituted at position 2 with acyl groups other than acetate. Because UHPLC/MS fails to yield sufficient information about structure diversity, and quantitative NMR of acylsugar mixtures is confounded by structural redundancy, the strategic combination of NMR and UHPLC/MS provides a powerful approach for profiling a class of metabolites with great structural diversity across genotypes. PMID- 24772061 TI - Palladium-Catalyzed Decarbonylative Dehydration of Fatty Acids for the Production of Linear Alpha Olefins. AB - A highly efficient palladium-catalyzed decarbonylative dehydration reaction of carboxylic acids is reported. This method transforms abundant and renewable even numbered natural fatty acids into valuable and expensive odd-numbered alpha olefins. Additionally, the chemistry displays a high functional group tolerance. The process employs low loading of palladium catalyst and proceeds under solvent free and relatively mild conditions. PMID- 24772059 TI - Alternatively Activated Macrophages Revisited: New Insights into the Regulation of Immunity, Inflammation and Metabolic Function following Parasite Infection. AB - The role of macrophages in homeostatic conditions and the immune system range from clearing debris to recognizing and killing pathogens. While classically activated macrophages (CAMacs) are induced by T helper type 1 (Th1) cytokines and exhibit microbicidal properties, Th2 cytokines promote alternative activation of macrophages (AAMacs). AAMacs contribute to the killing of helminth parasites and mediate additional host-protective processes such as regulating inflammation and wound healing. Yet, other parasites susceptible to Th1 type responses can exploit alternative activation of macrophages to diminish Th1 immune responses and prolong infection. In this review, we will delineate the factors that mediate alternative activation (e.g. Th2 cytokines and chitin) and the resulting downstream signaling events (e.g. STAT6 signaling). Next, the specific AAMac derived factors (e.g. Arginase1) that contribute to resistance or susceptibility to parasitic infections will be summarized. Finally, we will conclude with the discussion of additional AAMac functions beyond immunity to parasites, including the regulation of inflammation, wound healing and the regulation of metabolic disorders. PMID- 24772060 TI - Acoustic Inversion in Optoacoustic Tomography: A Review. AB - Optoacoustic tomography enables volumetric imaging with optical contrast in biological tissue at depths beyond the optical mean free path by the use of optical excitation and acoustic detection. The hybrid nature of optoacoustic tomography gives rise to two distinct inverse problems: The optical inverse problem, related to the propagation of the excitation light in tissue, and the acoustic inverse problem, which deals with the propagation and detection of the generated acoustic waves. Since the two inverse problems have different physical underpinnings and are governed by different types of equations, they are often treated independently as unrelated problems. From an imaging standpoint, the acoustic inverse problem relates to forming an image from the measured acoustic data, whereas the optical inverse problem relates to quantifying the formed image. This review focuses on the acoustic aspects of optoacoustic tomography, specifically acoustic reconstruction algorithms and imaging-system practicalities. As these two aspects are intimately linked, and no silver bullet exists in the path towards high-performance imaging, we adopt a holistic approach in our review and discuss the many links between the two aspects. Four classes of reconstruction algorithms are reviewed: time-domain (so called back-projection) formulae, frequency-domain formulae, time-reversal algorithms, and model-based algorithms. These algorithms are discussed in the context of the various acoustic detectors and detection surfaces which are commonly used in experimental studies. We further discuss the effects of non-ideal imaging scenarios on the quality of reconstruction and review methods that can mitigate these effects. Namely, we consider the cases of finite detector aperture, limited-view tomography, spatial under-sampling of the acoustic signals, and acoustic heterogeneities and losses. PMID- 24772062 TI - A comparative study of calcium absorption following a single serving administration of calcium carbonate powder versus calcium citrate tablets in healthy premenopausal women. AB - BACKGROUND: Calcium is an essential mineral often taken as a daily, long-term nutritional supplement. Data suggests that once-daily dosing is important with regard to long-term compliance of both drugs and nutritional supplements. OBJECTIVE: This study was undertaken to compare the bioavailability of a single serving of two calcium supplements in healthy, premenopausal women. DESIGN: A two period, crossover bioavailability study of a single serving of calcium citrate tablets (two tablets=500 mg calcium) versus a single serving of calcium carbonate powder (one packet of powder=1,000 mg calcium) was performed in healthy women aged between 25 and 45. All subjects were on a calcium-restricted diet 7 days prior to testing and fasted for 12 h before being evaluated at 0, 1, 2, and 4 h after oral administration of the test agents. Blood measurements for total and ionized calcium and parathyroid hormone were performed and adverse events were monitored. RESULTS: Twenty-three women were evaluable with a mean age of 33.2+/ 8.71. Results showed that administration of a single serving of a calcium carbonate powder resulted in greater absorption in total and ionized calcium versus a single serving of calcium citrate tablets at 4 h (4.25+/-0.21 vs. 4.16+/ 0.16, p=0.001). There were minimal side effects and no reported serious adverse events. CONCLUSIONS: This study shows that a single serving of a calcium carbonate powder is more bioavailable than a single serving of calcium citrate tablets. This may be beneficial for long-term compliance. PMID- 24772063 TI - mTOR signaling contributes to motor skill learning in mice. AB - The mammalian target of rapamycin (mTOR) kinase is a critical regulator of mRNA translation and is suspected to be involved in various long-lasting forms of synaptic and behavioral plasticity. However, its role in motor learning and control has never been examined. This study investigated, in mice, the implication of mTOR in the learning processes associated with the accelerating rotarod task. We first observed that the rotarod learning did not alter the levels of total mTOR in the striatum, hippocampus, cerebellum, and anterior cortex of trained mice. However, it increased the levels of phosphorylated mTOR in the striatum and hippocampus exclusively during the first session of training; no change was observed at the second and third sessions. In order to further investigate the potential role of mTOR during motor skill learning, we performed systemic and intrastriatal inhibitions of mTOR using the pharmacological inhibitor rapamycin, as well as a genetic knockdown of striatal mTOR using intrastriatal infusion of mTOR siRNA. These three independent approaches were all associated with a significant reduction in rotarod performances that were reminiscent of impaired consolidation processes. Notably, these treatments did not affect the capacity of mice to execute the pole test, suggesting that mTOR activity was mainly controlling motor learning rather than motor abilities. Moreover, all treatments decreased the levels of phosphorylated 4EBP1 and P70S6K, two molecular downstream targets of mTORC1. Our findings demonstrate that striatal mTOR kinase, via the phosphorylation of 4EBP1 and P70S6K, plays an important role in the cellular and molecular processes involved in motor skill learning. PMID- 24772065 TI - Benefits of exercise intervention in reducing neuropathic pain. AB - Peripheral neuropathy is a widespread and potentially incapacitating pathological condition that encompasses more than 100 different forms and manifestations of nerve damage. The diverse pathogenesis of peripheral neuropathy affects autonomic, motor and/or sensory neurons, and the symptoms that typify the condition are abnormal cutaneous sensation, muscle dysfunction and, most notably, chronic pain. Chronic neuropathic pain is difficult to treat and is often characterized by either exaggerated responses to painful stimuli (hyperalgesia) or pain resulting from stimuli that would not normally provoke pain (allodynia). The objective of this review is to provide an overview of some pathways associated with the development of peripheral neuropathy and then discuss the benefits of exercise interventions. The development of neuropathic pain is a highly complex and multifactorial process, but recent evidence indicates that the activation of spinal glial cells via the enzyme glycogen synthase kinase 3 and increases in the production of both pro-inflammatory cytokines and brain derived neurotropic factor are crucial steps. Since many of the most common causes of peripheral neuropathy cannot be fully treated, it is critical to understand that routine exercise may not only help prevent some of those causes, but that it has also proven to be an effective means of alleviating some of the condition's most distressing symptoms. More research is required to elucidate the typical mechanisms of injury associated with peripheral neuropathy and the exercise induced benefits to those mechanisms. PMID- 24772066 TI - Simultaneous imaging of neural activity in three dimensions. AB - We introduce a scanless optical method to image neuronal activity in three dimensions simultaneously. Using a spatial light modulator and a custom-designed phase mask, we illuminate and collect light simultaneously from different focal planes and perform calcium imaging of neuronal activity in vitro and in vivo. This method, combining structured illumination with volume projection imaging, could be used as a technological platform for brain activity mapping. PMID- 24772064 TI - Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment. AB - Recent studies on environmental enrichment (EE) have shown cytokines, cellular immune components [e.g., T lymphocytes, natural killer (NK) cells], and glial cells in causal relationship to EE in bringing out changes to neurobiology and behavior. The purpose of this review is to evaluate these neuroimmune mechanisms associated with neurobiological and behavioral changes in response to different EE methods. We systematically reviewed common research databases. After applying all inclusion and exclusion criteria, 328 articles remained for this review. Physical exercise (PE), a form of EE, elicits anti-inflammatory and neuromodulatory effects through interaction with several immune pathways including interleukin (IL)-6 secretion from muscle fibers, reduced expression of Toll-like receptors on monocytes and macrophages, reduced secretion of adipokines, modulation of hippocampal T cells, priming of microglia, and upregulation of mitogen-activated protein kinase phosphatase-1 in central nervous system. In contrast, immunomodulatory roles of other enrichment methods are not studied extensively. Nonetheless, studies showing reduction in the expression of IL-1beta and tumor necrosis factor-alpha in response to enrichment with novel objects and accessories suggest anti-inflammatory effects of novel environment. Likewise, social enrichment, though considered a necessity for healthy behavior, results in immunosuppression in socially defeated animals. This has been attributed to reduction in T lymphocytes, NK cells and IL-10 in subordinate animals. EE through sensory stimuli has been investigated to a lesser extent and the effect on immune factors has not been evaluated yet. Discovery of this multidimensional relationship between immune system, brain functioning, and EE has paved a way toward formulating environ-immuno therapies for treating psychiatric illnesses with minimal use of pharmacotherapy. While the immunomodulatory role of PE has been evaluated extensively, more research is required to investigate neuroimmune changes associated with other enrichment methods. PMID- 24772067 TI - Brain-wide imaging of neurons in action. PMID- 24772068 TI - The contribution of electrical synapses to field potential oscillations in the hippocampal formation. AB - Electrical synapses are a type of cellular membrane junction referred to as gap junctions (GJs). They provide a direct way to exchange ions between coupled cells and have been proposed as a structural basis for fast transmission of electrical potentials between neurons in the brain. For this reason GJs have been regarded as an important component within the neuronal networks that underlie synchronous neuronal activity and field potential oscillations. Initially, GJs appeared to play a particularly key role in the generation of high frequency oscillatory patterns in field potentials. In order to assess the scale of neuronal GJs contribution to field potential oscillations in the hippocampal formation, in vivo and in vitro studies are reviewed here. These investigations have shown that blocking the main neuronal GJs, those containing connexin 36 (Cx36-GJs), or knocking out the Cx36 gene affect field potential oscillatory patterns related to awake active behavior (gamma and theta rhythm) but have no effect on high frequency oscillations occurring during silent wake and sleep. Precisely how Cx36 GJs influence population activity of neurons is more complex than previously thought. Analysis of studies on the properties of transmission through GJ channels as well as Cx36-GJs functioning in pairs of coupled neurons provides some explanations of the specific influence of Cx36-GJs on field potential oscillations. It is proposed here that GJ transmission is strongly modulated by the level of neuronal network activity and changing behavioral states. Therefore, contribution of GJs to field potential oscillatory patterns depends on the behavioral state. I propose here a model, based on large body of experimental data gathered in this field by several authors, in which Cx36-GJ transmission especially contributes to oscillations related to active behavior, where it plays a role in filtering and enhancing coherent signals in the network under high noise conditions. In contrast, oscillations related to silent wake or sleep, especially high frequency oscillations, do not require transmission by neuronal GJs. The reliability of neuronal discharges during those oscillations could be assured by conditions of higher signal-to-noise ratio and some synaptic changes taking place during active behavior. PMID- 24772069 TI - A role of the claustrum in auditory scene analysis by reflecting sensory change. AB - The biological function of the claustrum remains speculative, despite many years of research. On the basis of its widespread connections it is often hypothesized that the claustrum may have an integrative function mainly reflecting objects rather than the details of sensory stimuli. Given the absence of a clear demonstration of any sensory integration in claustral neurons, however, we propose an alternative, data-driven, hypothesis: namely that the claustrum detects the occurrence of novel or salient sensory events. The detection of new events is critical for behavior and survival, as suddenly appearing objects may require rapid and coordinated reactions. Sounds are of particular relevance in this regard, and our conclusions are based on the analysis of neurons in the auditory zone of the primate claustrum. Specifically, we studied the responses to natural sounds, their preference to various sound categories, and to changes in the auditory scene. In a test for sound-category preference claustral neurons responded to but displayed a clear lack of selectivity between monkey vocalizations, other animal vocalizations or environmental sounds (Esnd). Claustral neurons were however able to detect target sounds embedded in a noisy background and their responses scaled with target signal to noise ratio (SNR). The single trial responses of individual neurons suggest that these neurons detected and reflected the occurrence of a change in the auditory scene. Given its widespread connectivity with sensory, motor and limbic structures the claustrum could play the essential role of identifying the occurrence of important sensory changes and notifying other brain areas-hence contributing to sensory awareness. PMID- 24772071 TI - Auditory training during development mitigates a hearing loss-induced perceptual deficit. AB - Sensory experience during early development can shape the central nervous system and this is thought to influence adult perceptual skills. In the auditory system, early induction of conductive hearing loss (CHL) leads to deficits in central auditory coding properties in adult animals, and this is accompanied by diminished perceptual thresholds. In contrast, a brief regimen of auditory training during development can enhance the perceptual skills of animals when tested in adulthood. Here, we asked whether a brief period of training during development could compensate for the perceptual deficits displayed by adult animals reared with CHL. Juvenile gerbils with CHL, and age-matched controls, were trained on a frequency modulation (FM) detection task for 4 or 10 days. The performance of each group was subsequently assessed in adulthood, and compared to adults with normal hearing (NH) or adults raised with CHL that did not receive juvenile training. We show that as juveniles, both CHL and NH animals display similar FM detection thresholds that are not immediately impacted by the perceptual training. However, as adults, detection thresholds and psychometric function slopes of these animals were significantly improved. Importantly, CHL adults with juvenile training displayed thresholds that approached NH adults. Additionally, we found that hearing impaired animals trained for 10 days displayed adult thresholds closer to untrained adults than those trained for 4 days. Thus, a relatively brief period of auditory training may compensate for the deleterious impact of hearing deprivation on auditory perception on the trained task. PMID- 24772070 TI - The claustrum in review. AB - The claustrum is among the most enigmatic of all prominent mammalian brain structures. Since the 19th century, a wealth of data has amassed on this forebrain nucleus. However, much of this data is disparate and contentious; conflicting views regarding the claustrum's structural definitions and possible functions abound. This review synthesizes historical and recent claustrum studies with the purpose of formulating an acceptable description of its structural properties. Integrating extant anatomical and functional literature with theorized functions of the claustrum, new visions of how this structure may be contributing to cognition and action are discussed. PMID- 24772072 TI - CCL2-ethanol interactions and hippocampal synaptic protein expression in a transgenic mouse model. AB - Chronic exposure to ethanol produces a number of detrimental effects on behavior. Neuroadaptive changes in brain structure or function underlie these behavioral effects and may be transient or persistent in nature. Central to the functional changes are alterations in the biology of neuronal and glial cells of the brain. Recent data show that ethanol induces glial cells of the brain to produce elevated levels of neuroimmune factors including CCL2, a key innate immune chemokine. Depending on the conditions of ethanol exposure, the upregulated levels of CCL2 can be transient or persistent and outlast the period of ethanol exposure. Importantly, results indicate that the upregulated levels of CCL2 may lead to CCL2-ethanol interactions that mediate or regulate the effects of ethanol on the brain. Glial cells are in close association with neurons and regulate many neuronal functions. Therefore, effects of ethanol on glial cells may underlie some of the effects of ethanol on neurons. To investigate this possibility, we are studying effects of chronic ethanol on hippocampal synaptic function in a transgenic mouse model that expresses elevated levels of CCL2 in the brain through enhanced glial expression, a situation know to occur in alcoholics. Both CCL2 and ethanol have been reported to alter synaptic function in the hippocampus. In the current study, we determined if interactions are evident between CCL2 and ethanol at the level of hippocampal synaptic proteins. Two ethanol exposure paradigms were used; the first involved ethanol exposure by drinking and the second involved ethanol exposure in a paradigm that combines drinking plus ethanol vapor. The first paradigm does not produce dependence on ethanol, whereas the second paradigm is commonly used to produce ethanol dependence. Results show modest effects of both ethanol exposure paradigms on the level of synaptic proteins in the hippocampus of CCL2 transgenic mice compared with their non-transgenic littermate controls, consistent with ethanol-CCL2 interactions. No evidence of toxic effects of CCL2 or CCL2-ethanol interactions was observed. Taken together, these results support the idea that ethanol induced astrocyte production of CCL2 can result in neuroadaptive changes that interact with the actions of ethanol. PMID- 24772073 TI - Recombineering strategies for developing next generation BAC transgenic tools for optogenetics and beyond. AB - The development and application of diverse BAC transgenic rodent lines has enabled rapid progress for precise molecular targeting of genetically-defined cell types in the mammalian central nervous system. These transgenic tools have played a central role in the optogenetic revolution in neuroscience. Indeed, an overwhelming proportion of studies in this field have made use of BAC transgenic Cre driver lines to achieve targeted expression of optogenetic probes in the brain. In addition, several BAC transgenic mouse lines have been established for direct cell-type specific expression of Channelrhodopsin-2 (ChR2). While the benefits of these new tools largely outweigh any accompanying challenges, many available BAC transgenic lines may suffer from confounds due in part to increased gene dosage of one or more "extra" genes contained within the large BAC DNA sequences. Here we discuss this under-appreciated issue and propose strategies for developing the next generation of BAC transgenic lines that are devoid of extra genes. Furthermore, we provide evidence that these strategies are simple, reproducible, and do not disrupt the intended cell-type specific transgene expression patterns for several distinct BAC clones. These strategies may be widely implemented for improved BAC transgenesis across diverse disciplines. PMID- 24772074 TI - Residual neural processing of musical sound features in adult cochlear implant users. AB - Auditory processing in general and music perception in particular are hampered in adult cochlear implant (CI) users. To examine the residual music perception skills and their underlying neural correlates in CI users implanted in adolescence or adulthood, we conducted an electrophysiological and behavioral study comparing adult CI users with normal-hearing age-matched controls (NH controls). We used a newly developed musical multi-feature paradigm, which makes it possible to test automatic auditory discrimination of six different types of sound feature changes inserted within a musical enriched setting lasting only 20 min. The presentation of stimuli did not require the participants' attention, allowing the study of the early automatic stage of feature processing in the auditory cortex. For the CI users, we obtained mismatch negativity (MMN) brain responses to five feature changes but not to changes of rhythm, whereas we obtained MMNs for all the feature changes in the NH controls. Furthermore, the MMNs to deviants of pitch of CI users were reduced in amplitude and later than those of NH controls for changes of pitch and guitar timber. No other group differences in MMN parameters were found to changes in intensity and saxophone timber. Furthermore, the MMNs in CI users reflected the behavioral scores from a respective discrimination task and were correlated with patients' age and speech intelligibility. Our results suggest that even though CI users are not performing at the same level as NH controls in neural discrimination of pitch-based features, they do possess potential neural abilities for music processing. However, CI users showed a disrupted ability to automatically discriminate rhythmic changes compared with controls. The current behavioral and MMN findings highlight the residual neural skills for music processing even in CI users who have been implanted in adolescence or adulthood. HIGHLIGHTS: -Automatic brain responses to musical feature changes reflect the limitations of central auditory processing in adult Cochlear Implant users.-The brains of adult CI users automatically process sound features changes even when inserted in a musical context.-CI users show disrupted automatic discriminatory abilities for rhythm in the brain.-Our fast paradigm demonstrate residual musical abilities in the brains of adult CI users giving hope for their future rehabilitation. PMID- 24772075 TI - Cultural influences on social feedback processing of character traits. AB - Cultural differences are generally explained by how people see themselves in relation to social interaction partners. While Western culture emphasizes independence, East Asian culture emphasizes interdependence. Despite this focus on social interactions, it remains elusive how people from different cultures process feedback on their own (and on others') character traits. Here, participants of either German or Chinese origin engaged in a face-to-face interaction. Consequently, they updated their self- and other-ratings of 80 character traits (e.g., polite, pedantic) after receiving feedback from their interaction partners. To exclude potential confounds, we obtained data from German and Chinese participants in Berlin [functional magnetic resonance imaging (fMRI)] and in Beijing (behavior). We tested cultural influences on social conformity, positivity biases, and self-related neural activity. First, Chinese conformed more to social feedback than Germans (i.e., Chinese updated their trait ratings more). Second, regardless of culture, participants processed self- and other-related feedback in a positively biased way (i.e., they updated more toward desirable than toward undesirable feedback). Third, changes in self-related medial prefrontal cortex activity were greater in Germans than in Chinese during feedback processing. By investigating conformity, positivity biases, and self related activity in relation to feedback obtained in a real-life interaction, we provide an essential step toward a unifying framework for understanding the diversity of human culture. PMID- 24772076 TI - Neural correlates of own and close-other's name recognition: ERP evidence. AB - One's own name seems to have a special status in the processing of incoming information. In event-related potential (ERP) studies this preferential status has mainly been associated with higher P300 to one's own name than to other names. Some studies showed preferential responses to own name even for earlier ERP components. However, instead of just being self-specific, these effects could be related to the processing of any highly relevant and/or frequently encountered stimuli. If this is the case: (1) processing of other highly relevant and highly familiar names (e.g., names of friends, partners, siblings, etc.) should be associated with similar ERP responses as processing of one's own name and (2) processing of own and close others' names should result in larger amplitudes of early and late ERP components than processing of less relevant and less familiar names (e.g., names of famous people, names of strangers, etc.). To test this hypothesis we measured and analyzed ERPs from 62 scalp electrodes in 22 subjects. Subjects performed a speeded two-choice recognition task-familiar vs. unfamiliar with one's own name being treated as one of the familiar names. All stimuli were presented visually. We found that amplitudes of P200, N250 and P300 did not differ between one's own and close-other's names. Crucially, they were significantly larger to own and close-other's names than to other names (unknown and famous for P300 and unknown for P200 and N250). Our findings suggest that preferential processing of one's own name is due to its personal-relevance and/or familiarity factors. This pattern of results speaks for a common preference in processing of different kinds of socially relevant stimuli. PMID- 24772078 TI - Stochastic variational learning in recurrent spiking networks. AB - The ability to learn and perform statistical inference with biologically plausible recurrent networks of spiking neurons is an important step toward understanding perception and reasoning. Here we derive and investigate a new learning rule for recurrent spiking networks with hidden neurons, combining principles from variational learning and reinforcement learning. Our network defines a generative model over spike train histories and the derived learning rule has the form of a local Spike Timing Dependent Plasticity rule modulated by global factors (neuromodulators) conveying information about "novelty" on a statistically rigorous ground. Simulations show that our model is able to learn both stationary and non-stationary patterns of spike trains. We also propose one experiment that could potentially be performed with animals in order to test the dynamics of the predicted novelty signal. PMID- 24772079 TI - Graph-based active learning of agglomeration (GALA): a Python library to segment 2D and 3D neuroimages. AB - The aim in high-resolution connectomics is to reconstruct complete neuronal connectivity in a tissue. Currently, the only technology capable of resolving the smallest neuronal processes is electron microscopy (EM). Thus, a common approach to network reconstruction is to perform (error-prone) automatic segmentation of EM images, followed by manual proofreading by experts to fix errors. We have developed an algorithm and software library to not only improve the accuracy of the initial automatic segmentation, but also point out the image coordinates where it is likely to have made errors. Our software, called gala (graph-based active learning of agglomeration), improves the state of the art in agglomerative image segmentation. It is implemented in Python and makes extensive use of the scientific Python stack (numpy, scipy, networkx, scikit-learn, scikit-image, and others). We present here the software architecture of the gala library, and discuss several designs that we consider would be generally useful for other segmentation packages. We also discuss the current limitations of the gala library and how we intend to address them. PMID- 24772077 TI - The role of alpha-rhythm states in perceptual learning: insights from experiments and computational models. AB - During the past two decades growing evidence indicates that brain oscillations in the alpha band (~10 Hz) not only reflect an "idle" state of cortical activity, but also take a more active role in the generation of complex cognitive functions. A recent study shows that more than 60% of the observed inter-subject variability in perceptual learning can be ascribed to ongoing alpha activity. This evidence indicates a significant role of alpha oscillations for perceptual learning and hence motivates to explore the potential underlying mechanisms. Hence, it is the purpose of this review to highlight existent evidence that ascribes intrinsic alpha oscillations a role in shaping our ability to learn. In the review, we disentangle the alpha rhythm into different neural signatures that control information processing within individual functional building blocks of perceptual learning. We further highlight computational studies that shed light on potential mechanisms regarding how alpha oscillations may modulate information transfer and connectivity changes relevant for learning. To enable testing of those model based hypotheses, we emphasize the need for multidisciplinary approaches combining assessment of behavior and multi-scale neuronal activity, active modulation of ongoing brain states and computational modeling to reveal the mathematical principles of the complex neuronal interactions. In particular we highlight the relevance of multi-scale modeling frameworks such as the one currently being developed by "The Virtual Brain" project. PMID- 24772080 TI - Preserved fine-tuning of face perception and memory: evidence from the own-race bias in high- and low-performing older adults. AB - Previous research suggests specific deficits in face perception and memory in older adults, which could reflect a dedifferentiation in the context of a general broadening of cognitive architecture with advanced age. Such dedifferentiation could manifest in a less specialized face processing system. A promising tool to investigate the fine-tuning of face processing in older age is the own-race bias (ORB), a phenomenon reflecting more accurate memory for own-relative to other race faces, which is related to an expertise-based specialization of early perceptual stages. To investigate whether poor face memory in older age is accompanied by reduced expertise-based specialization of face processing, we assessed event-related brain potential correlates of the ORB in high- vs. low performing older adults (mean age = 69 years; N = 24 per group). Intriguingly, both older groups demonstrated an equivalent pattern of a behavioral ORB, and a parallel increase in N170 for other-race faces, reflecting less efficient early perceptual processing for this face category. Group differences only emerged independent of face ethnicity: whereas low-performers exhibited a right lateralized N170, high-performers showed a more bilateral response. This finding may suggest a compensatory mechanism counteracting age-related decline in face perception enabling more efficient encoding into memory in high performers. Overall, our results demonstrate that even a less efficient face processing system in older adults can exhibit preserved expertise-related specialization toward own-race faces. PMID- 24772081 TI - Biophysics, pathophysiology, and pharmacology of ion channel gating pores. AB - Voltage sensor domains (VSDs) are a feature of voltage gated ion channels (VGICs) and voltage sensitive proteins. They are composed of four transmembrane (TM) segments (S1-S4). Currents leaking through VSDs are called omega or gating pore currents. Gating pores are caused by mutations of the highly conserved positively charged amino acids in the S4 segment that disrupt interactions between the S4 segment and the gating charge transfer center (GCTC). The GCTC separates the intracellular and extracellular water crevices. The disruption of S4-GCTC interactions allows these crevices to communicate and create a fast activating and non-inactivating alternative cation-selective permeation pathway of low conductance, or a gating pore. Gating pore currents have recently been shown to cause periodic paralysis phenotypes. There is also increasing evidence that gating pores are linked to several other familial diseases. For example, gating pores in Nav1.5 and Kv7.2 channels may underlie mixed arrhythmias associated with dilated cardiomyopathy (DCM) phenotypes and peripheral nerve hyperexcitability (PNH), respectively. There is little evidence for the existence of gating pore blockers. Moreover, it is known that a number of toxins bind to the VSD of a specific domain of Na(+) channels. These toxins may thus modulate gating pore currents. This focus on the VSD motif opens up a new area of research centered on developing molecules to treat a number of cell excitability disorders such as epilepsy, cardiac arrhythmias, and pain. The purpose of the present review is to summarize existing knowledge of the pathophysiology, biophysics, and pharmacology of gating pore currents and to serve as a guide for future studies aimed at improving our understanding of gating pores and their pathophysiological roles. PMID- 24772083 TI - Physiologic and pharmacokinetic changes in pregnancy. AB - Physiologic changes in pregnancy induce profound alterations to the pharmacokinetic properties of many medications. These changes affect distribution, absorption, metabolism, and excretion of drugs, and thus may impact their pharmacodynamic properties during pregnancy. Pregnant women undergo several adaptations in many organ systems. Some adaptations are secondary to hormonal changes in pregnancy, while others occur to support the gravid woman and her developing fetus. Some of the changes in maternal physiology during pregnancy include, for example, increased maternal fat and total body water, decreased plasma protein concentrations, especially albumin, increased maternal blood volume, cardiac output, and blood flow to the kidneys and uteroplacental unit, and decreased blood pressure. The maternal blood volume expansion occurs at a larger proportion than the increase in red blood cell mass, which results in physiologic anemia and hemodilution. Other physiologic changes include increased tidal volume, partially compensated respiratory alkalosis, delayed gastric emptying and gastrointestinal motility, and altered activity of hepatic drug metabolizing enzymes. Understating these changes and their profound impact on the pharmacokinetic properties of drugs in pregnancy is essential to optimize maternal and fetal health. PMID- 24772084 TI - Behavioral decline and premature lethality upon pan-neuronal ferritin overexpression in Drosophila infected with a virulent form of Wolbachia. AB - Iron is required for organismal growth. Therefore, limiting iron availability may be a key part of the host's innate immune response to various pathogens, for example, in Drosophila infected with Zygomycetes. One way the host can transiently reduce iron bioavailability is by ferritin overexpression. To study the effects of neuronal-specific ferritin overexpression on survival and neurodegeneration we generated flies simultaneously over-expressing transgenes for both ferritin subunits in all neurons. We used two independent recombinant chromosomes bearing UAS-Fer1HCH, UAS-Fer2LCH transgenes and obtained qualitatively different levels of late-onset behavioral and lifespan declines. We subsequently discovered that one parental strain had been infected with a virulent form of the bacterial endosymbiont Wolbachia, causing widespread neuronal apoptosis and premature death. This phenotype was exacerbated by ferritin overexpression and was curable by antibiotic treatment. Neuronal ferritin overexpression in uninfected flies did not cause evident neurodegeneration but resulted in a late-onset behavioral decline, as previously reported for ferritin overexpression in glia. The results suggest that ferritin overexpression in the central nervous system of flies is tolerated well in young individuals with adverse manifestations appearing only late in life or under unrelated pathophysiological conditions. PMID- 24772082 TI - Modeling CaMKII-mediated regulation of L-type Ca(2+) channels and ryanodine receptors in the heart. AB - Excitation-contraction coupling (ECC) in the cardiac myocyte is mediated by a number of highly integrated mechanisms of intracellular Ca(2+) transport. Voltage and Ca(2+)-dependent L-type Ca(2+) channels (LCCs) allow for Ca(2+) entry into the myocyte, which then binds to nearby ryanodine receptors (RyRs) and triggers Ca(2+) release from the sarcoplasmic reticulum in a process known as Ca(2+) induced Ca(2+) release. The highly coordinated Ca(2+)-mediated interaction between LCCs and RyRs is further regulated by the cardiac isoform of the Ca(2+)/calmodulin-dependent protein kinase (CaMKII). Because CaMKII targets and modulates the function of many ECC proteins, elucidation of its role in ECC and integrative cellular function is challenging and much insight has been gained through the use of detailed computational models. Multiscale models that can both reconstruct the detailed nature of local signaling events within the cardiac dyad and predict their functional consequences at the level of the whole cell have played an important role in advancing our understanding of CaMKII function in ECC. Here, we review experimentally based models of CaMKII function with a focus on LCC and RyR regulation, and the mechanistic insights that have been gained through their application. PMID- 24772085 TI - External and circadian inputs modulate synaptic protein expression in the visual system of Drosophila melanogaster. AB - In the visual system of Drosophila melanogaster the retina photoreceptors form tetrad synapses with the first order interneurons, amacrine cells and glial cells in the first optic neuropil (lamina), in order to transmit photic and visual information to the brain. Using the specific antibodies against synaptic proteins; Bruchpilot (BRP), Synapsin (SYN), and Disc Large (DLG), the synapses in the distal lamina were specifically labeled. Then their abundance was measured as immunofluorescence intensity in flies held in light/dark (LD 12:12), constant darkness (DD), and after locomotor and light stimulation. Moreover, the levels of proteins (SYN and DLG), and mRNAs of the brp, syn, and dlg genes, were measured in the fly's head and brain, respectively. In the head we did not detect SYN and DLG oscillations. We found, however, that in the lamina, DLG oscillates in LD 12:12 and DD but SYN cycles only in DD. The abundance of all synaptic proteins was also changed in the lamina after locomotor and light stimulation. One hour locomotor stimulations at different time points in LD 12:12 affected the pattern of the daily rhythm of synaptic proteins. In turn, light stimulations in DD increased the level of all proteins studied. In the case of SYN, however, this effect was observed only after a short light pulse (15 min). In contrast to proteins studied in the lamina, the mRNA of brp, syn, and dlg genes in the brain was not cycling in LD 12:12 and DD, except the mRNA of dlg in LD 12:12. Our earlier results and obtained in the present study showed that the abundance of BRP, SYN and DLG in the distal lamina, at the tetrad synapses, is regulated by light and a circadian clock while locomotor stimulation affects their daily pattern of expression. The observed changes in the level of synaptic markers reflect the circadian plasticity of tetrad synapses regulated by the circadian clock and external inputs, both specific and unspecific for the visual system. PMID- 24772086 TI - Cardiac looping may be driven by compressive loads resulting from unequal growth of the heart and pericardial cavity. Observations on a physical simulation model. AB - The transformation of the straight embryonic heart tube into a helically wound loop is named cardiac looping. Such looping is regarded as an essential process in cardiac morphogenesis since it brings the building blocks of the developing heart into an approximation of their definitive topographical relationships. During the past two decades, a large number of genes have been identified which play important roles in cardiac looping. However, how genetic information is physically translated into the dynamic form changes of the looping heart is still poorly understood. The oldest hypothesis of cardiac looping mechanics attributes the form changes of the heart loop (ventral bending -> simple helical coiling -> complex helical coiling) to compressive loads resulting from growth differences between the heart and the pericardial cavity. In the present study, we have tested the physical plausibility of this hypothesis, which we call the growth induced buckling hypothesis, for the first time. Using a physical simulation model, we show that growth-induced buckling of a straight elastic rod within the confined space of a hemispherical cavity can generate the same sequence of form changes as observed in the looping embryonic heart. Our simulation experiments have furthermore shown that, under bilaterally symmetric conditions, growth induced buckling generates left- and right-handed helices (D-/L-loops) in a 1:1 ratio, while even subtle left- or rightward displacements of the caudal end of the elastic rod at the pre-buckling state are sufficient to direct the buckling process toward the generation of only D- or L-loops, respectively. Our data are discussed with respect to observations made in biological "models." We conclude that compressive loads resulting from unequal growth of the heart and pericardial cavity play important roles in cardiac looping. Asymmetric positioning of the venous heart pole may direct these forces toward a biased generation of D- or L loops. PMID- 24772088 TI - Focal adhesion kinase regulates the activity of the osmosensitive transcription factor TonEBP/NFAT5 under hypertonic conditions. AB - TonEBP/NFAT5 is a major regulator of the urinary concentrating process and is essential for the osmoadaptation of renal medullary cells. Focal adhesion kinase (FAK) is a mechanosensitive non-receptor protein tyrosine kinase expressed abundantly in the renal medulla. Since osmotic stress causes cell shrinkage, the present study investigated the contribution of FAK on TonEBP/NFAT5 activation. Osmotic stress induced time-dependent activation of FAK as evidenced by phosphorylation at Tyr-397, and furosemide reduces FAK Tyr-397 phosphorylation in the rat renal medulla. Both pharmacological inhibition of FAK and siRNA-mediated knockdown of FAK drastically reduced TonEBP/NFAT5 transcriptional activity and target gene expression in HEK293 cells. This effect was not mediated by impaired nuclear translocation or by reduced transactivating activity of TonEBP/NFAT5. However, TonEBP/NFAT5 abundance under hypertonic conditions was diminished by 50% by FAK inhibition or siRNA knockdown of FAK. FAK inhibition only marginally reduced transcription of the TonEBP/NFAT5 gene. Rather, TonEBP/NFAT5 mRNA stability was diminished significantly by FAK inhibition, which correlated with reduced reporter activity of the TonEBP/NFAT5 mRNA 3' untranslated region (3' UTR). In conclusion, FAK is a major regulator of TonEBP/NFAT5 activity by increasing its abundance via stabilization of the mRNA. This in turn, depends on the presence of the TonEBP/NFAT5 3'-UTR. PMID- 24772087 TI - The future of vitamin D analogs. AB - The active form of vitamin D3, 1,25-dihydroxyvitamin D3, is a major regulator of bone and calcium homeostasis. In addition, this hormone also inhibits the proliferation and stimulates the differentiation of normal as well as malignant cells. Supraphysiological doses of 1,25-dihydroxyvitamin D3 are required to reduce cancer cell proliferation. However, these doses will lead in vivo to calcemic side effects such as hypercalcemia and hypercalciuria. During the last 25 years, many structural analogs of 1,25-dihydroxyvitamin D3 have been synthesized by the introduction of chemical modifications in the A-ring, central CD-ring region or side chain of 1,25-dihydroxyvitamin D3 in the hope to find molecules with a clear dissociation between the beneficial antiproliferative effects and adverse calcemic side effects. One example of such an analog with a good dissociation ratio is calcipotriol (Daivonex(r)), which is clinically used to treat the hyperproliferative skin disease psoriasis. Other vitamin D analogs were clinically approved for the treatment of osteoporosis or secondary hyperparathyroidism. No vitamin D analog is currently used in the clinic for the treatment of cancer although several analogs have been shown to be potent drugs in animal models of cancer. Transcriptomics studies as well as in vitro cell biological experiments unraveled basic mechanisms involved in the antineoplastic effects of vitamin D and its analogs. 1,25-dihydroxyvitamin D3 and analogs act in a cell type- and tissue-specific manner. Moreover, a blockade in the transition of the G0/1 toward S phase of the cell cycle, induction of apoptosis, inhibition of migration and invasion of tumor cells together with effects on angiogenesis and inflammation have been implicated in the pleiotropic effects of 1,25 dihydroxyvitamin D3 and its analogs. In this review we will give an overview of the action of vitamin D analogs in tumor cells and look forward how these compounds could be introduced in the clinical practice. PMID- 24772089 TI - Assessing uncertainty in model parameters based on sparse and noisy experimental data. AB - To perform parametric identification of mathematical models of biological events, experimental data are rare to be sufficient to estimate target behaviors produced by complex non-linear systems. We performed parameter fitting to a cell cycle model with experimental data as an in silico experiment. We calibrated model parameters with the generalized least squares method with randomized initial values and checked local and global sensitivity of the model. Sensitivity analyses showed that parameter optimization induced less sensitivity except for those related to the metabolism of the transcription factors c-Myc and E2F, which are required to overcome a restriction point (R-point). We performed bifurcation analyses with the optimized parameters and found the bimodality was lost. This result suggests that accumulation of c-Myc and E2F induced dysfunction of R point. We performed a second parameter optimization based on the results of sensitivity analyses and incorporating additional derived from recent in vivo data. This optimization returned the bimodal characteristics of the model with a narrower range of hysteresis than the original. This result suggests that the optimized model can more easily go through R-point and come back to the gap phase after once having overcome it. Two parameter space analyses showed metabolism of c-Myc is transformed as it can allow cell bimodal behavior with weak stimuli of growth factors. This result is compatible with the character of the cell line used in our experiments. At the same time, Rb, an inhibitor of E2F, can allow cell bimodal behavior with only a limited range of stimuli when it is activated, but with a wider range of stimuli when it is inactive. These results provide two insights; biologically, the two transcription factors play an essential role in malignant cells to overcome R-point with weaker growth factor stimuli, and theoretically, sparse time-course data can be used to change a model to a biologically expected state. PMID- 24772090 TI - Connexin 43 hemichannels and intracellular signaling in bone cells. AB - Cell function and survival are controlled by intracellular signals, and modulated by surrounding cells and the extracellular environment. Connexin channels participate in these processes by mediating cell-to-cell communication. In bone cells, gap junction channels were detected in the early 1970s, and are present among bone resorbing osteoclasts, bone forming osteoblasts, and osteocytes - mature osteoblasts embedded in the mineralized matrix. These channels are composed mainly by Cx43, although the expression of other connexins (45, 46, and 37) has also been reported. It is now believed that undocked Cx43 hemichannels (connexons) formed in unopposed cell membranes facing the extracellular environment participate in the interaction of bone cells with the extracellular environment, and in their communication with neighboring cells. Thus, we and others demonstrated the presence of active hemichannels in osteoblastic and osteocytic cells. These hemichannels open in response to pharmacological and mechanical stimulation. In particular, preservation of the viability of osteoblasts and osteocytes by the anti-osteoporotic drugs bisphosphonates depends on Cx43 expression in vitro and in vivo, and is mediated by undocked hemichannels. Cx43 hemichannels are also required for the release of prostaglandins and ATP by osteocytes, and for cell survival induced by mechanical stimulation in vitro. Moreover, they are required for the anti-apoptotic effect of parathyroid hormone in osteoblastic cells. This review summarizes the current knowledge on the presence and function of undocked connexons, and the role of hemichannel regulation for the maintenance of bone cell viability and, potentially, bone health. PMID- 24772091 TI - Membrane transport systems and the biodegradation potential and pathogenicity of genus Rhodococcus. AB - The Rhodococcus genus contains species with remarkable ability to tolerate toxic compounds and to degrade a myriad of substrates. These substrates have to cross a distinctive cell envelope dominated by mycolic acids anchored in a scaffold of arabinogalactan covalently attached to the cell wall peptidoglycan, and a cellular membrane with phospholipids, whose composition in fatty acids can be rapidly altered in response to environmental conditions. The hydrophobic nature of the cell envelope facilitates the entrance of hydrophobic molecules but some substrates require active transport systems. Additionally, toxic compounds may also be extruded by energy spending efflux systems. In this review, physiological evidences of the use of transport systems by Rhodococcus strains and genomic studies that corroborate their existence are presented and discussed. The recently released complete genomes of several Rhodococcus strains will be the basis for an in silico correlation analysis between the efflux pumps present in the genome and their role on active transport of substrates. These transport systems will be placed on an integrative perspective of the impact of this important genus on biotechnology and health, ranging from bioremediation to antibiotic and biocide resistance. PMID- 24772093 TI - Inconsistent Condom Use among Iranian Male Drug Injectors. AB - OBJECTIVES: The aim of this study was to determine the prevalence and associated factors of inconsistent condom use among Iranian male injecting drug users (IDUs). MATERIALS AND METHODS: Data came from the national Iranian behavioral survey of drug dependence, which sampled 7743 individuals with drug dependence, from medical centers, prisons, and streets in 29 provinces in Iran, in 2007. This study included all individuals who were male, IDUs, and were sexually active (n = 1131). The main outcome was inconsistent condom use which was assessed using a single item. A logistic regression was used to determine the association between socio-economic data, drug use data, and high risk injection behaviors with inconsistent condom use. RESULT: 83.3% of sexually active IDUs (n = 965) reported inconsistent condom use. Based on the logistic regression, likelihood of inconsistent condom use was higher among those with a history of syringe sharing [Odds Ratio (OR); 1.63, 95% Confidence Interval (CI); 1.13-2.34], but lower among those with higher education levels (OR; 0.34, 95% CI; 0.14-0.82), those who mostly inject at home (OR; 0.09, 95% CI; 0.02-0.47), and those with a history of treatment (OR; 0.54, 95% CI; 0.31-0.94). CONCLUSION: Because of the link between unsafe sex and risky injecting behaviors among Iranian IDUs, combined programs targeting both sexual and injection behavior may be more appropriate than programs that target sexual or injection behavior. The efficacy of combined programs should be, however, compared with traditional programs that only target sexual or injection behavior of IDUs. PMID- 24772092 TI - Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow. AB - Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions. PMID- 24772095 TI - Was it a vision or a waking dream? PMID- 24772096 TI - Brain networks supporting perceptual grouping and contour selection. AB - The human visual system groups local elements into global objects seemingly without effort. Using a contour integration task and EEG source level analyses, we tested the hypothesis that perceptual grouping requires a top-down selection, rather than a passive pooling, of neural information that codes local elements in the visual image. The participants were presented visual displays with or without a hidden contour. Two tasks were performed: a central luminance-change detection task and a peripheral contour detection task. Only in the contour-detection task could we find differential brain activity between contour and non-contour conditions, within a distributed brain network including parietal, lateral occipital and primary visual areas. Contour processing was associated with an inflow of information from lateral occipital into primary visual regions, as revealed from the slope of phase differences between source level oscillations within these areas. The findings suggest that contour integration results from a selection of neural information from lower visual areas, and that this selection is driven by the lateral occipital cortex. PMID- 24772097 TI - The ARSQ 2.0 reveals age and personality effects on mind-wandering experiences. AB - The human brain frequently generates thoughts and feelings detached from environmental demands. Investigating the rich repertoire of these mind-wandering experiences is challenging, as it depends on introspection and mapping its content requires an unknown number of dimensions. We recently developed a retrospective self-report questionnaire-the Amsterdam Resting-State Questionnaire (ARSQ)-which quantifies mind wandering along seven dimensions: "Discontinuity of Mind," "Theory of Mind," "Self," "Planning," "Sleepiness," "Comfort," and "Somatic Awareness." Here, we show using confirmatory factor analysis that the ARSQ can be simplified by standardizing the number of items per factor and extending it to a 10-dimensional model, adding "Health Concern," "Visual Thought," and "Verbal Thought." We will refer to this extended ARSQ as the "ARSQ 2.0." Testing for effects of age and gender revealed no main effect for gender, yet a moderate and significant negative effect for age on the dimensions of "Self," "Planning," and "Visual Thought." Interestingly, we observed stable and significant test-retest correlations across measurement intervals of 3-32 months except for "Sleepiness" and "Health Concern." To investigate whether this stability could be related to personality traits, we correlated ARSQ scores to proxy measures of Cloninger's Temperament and Character Inventory, revealing multiple significant associations for the trait "Self-Directedness." Other traits correlated to specific ARSQ dimensions, e.g., a negative association between "Harm Avoidance" and "Comfort." Together, our results suggest that the ARSQ 2.0 is a promising instrument for quantitative studies on mind wandering and its relation to other psychological or physiological phenomena. PMID- 24772094 TI - Posttraumatic stress disorder: a theoretical model of the hyperarousal subtype. AB - Posttraumatic stress disorder (PTSD) is a frequent and distressing mental disorder, about which much remains to be learned. It is a heterogeneous disorder; the hyperarousal subtype (about 70% of occurrences and simply termed PTSD in this paper) is the topic of this article, but the dissociative subtype (about 30% of occurrences and likely involving quite different brain mechanisms) is outside its scope. A theoretical model is presented that integrates neuroscience data on diverse brain regions known to be involved in PTSD, and extensive psychiatric findings on the disorder. Specifically, the amygdala is a multifunctional brain region that is crucial to PTSD, and processes peritraumatic hyperarousal on grounded cognition principles to produce hyperarousal symptoms. Amygdala activity also modulates hippocampal function, which is supported by a large body of evidence, and likewise amygdala activity modulates several brainstem regions, visual cortex, rostral anterior cingulate cortex (rACC), and medial orbitofrontal cortex (mOFC), to produce diverse startle, visual, memory, numbing, anger, and recklessness symptoms. Additional brain regions process other aspects of peritraumatic responses to produce further symptoms. These contentions are supported by neuroimaging, neuropsychological, neuroanatomical, physiological, cognitive, and behavioral evidence. Collectively, the model offers an account of how responses at the time of trauma are transformed into an extensive array of the 20 PTSD symptoms that are specified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition. It elucidates the neural mechanisms of a specific form of psychopathology, and accords with the Research Domain Criteria framework. PMID- 24772100 TI - Peripheral global neglect in high vs. low autistic tendency. AB - In addition to its core social deficits, autism is characterized by altered visual perception, with a preference for local percept in those high in autistic tendency. Here, the balance of global vs. local percepts for the perceptually rivalrous diamond illusion was assessed between groups scoring high and low on the Autism Spectrum Quotient (AQ). The global percept of a diamond shape oscillating horizontally behind three occluders can as easily be interpreted as the local percept of four line elements, each moving vertically. Increasing the luminance contrast of the occluders with respect to background resulted in an increase of initial global percept in both groups, with no difference in sensitivity between groups. Presenting the target further into the periphery resulted in a marked increase in the percentage of global perception with visual field eccentricity. However, while the performance for centrally presented diamond targets was not different between AQ groups, the peripheral global performance of the High AQ group was significantly reduced compared with the Low AQ group. On the basis of other imaging studies, this peripheral but not foveal global perceptual neglect may indicate an abnormal interaction between striate cortex and the Lateral Occipital Complex (LOC), or to differences in the deployment of attention between the two groups. PMID- 24772098 TI - Predicting first-grade mathematics achievement: the contributions of domain general cognitive abilities, nonverbal number sense, and early number competence. AB - Early number competence, grounded in number-specific and domain-general cognitive abilities, is theorized to lay the foundation for later math achievement. Few longitudinal studies have tested a comprehensive model for early math development. Using structural equation modeling and mediation analyses, the present work examined the influence of kindergarteners' nonverbal number sense and domain-general abilities (i.e., working memory, fluid intelligence, and receptive vocabulary) and their early number competence (i.e., symbolic number skills) on first grade math achievement (i.e., arithmetic, shape and space skills, and number line estimation) assessed 1 year later. Latent regression models revealed that nonverbal number sense and working memory are central building blocks for developing early number competence in kindergarten and that early number competence is key for first grade math achievement. After controlling for early number competence, fluid intelligence significantly predicted arithmetic and number line estimation while receptive vocabulary significantly predicted shape and space skills. In sum we suggest that early math achievement draws on different constellations of number-specific and domain general mechanisms. PMID- 24772101 TI - Retrieval practice enhances new learning: the forward effect of testing. AB - In the last couple of years, there has been a dramatic increase in laboratory research examining the benefits of recall testing on long-term learning and retention. This work was largely on the backward effect of testing, which shows that retrieval practice on previously studied information, compared to restudy of the same material, renders the information more likely to be remembered in the future. Going beyond this prominent work, more recent laboratory research provided evidence that there is also a forward effect of testing, which shows that recall testing of previously studied information can enhance learning of subsequently presented new information. Here, we provide a review of research on this forward effect of testing. The review shows that the effect is a well replicated phenomenon in laboratory studies that has been observed for both veridical information and misinformation. In particular, the review demonstrates that the effect may be applied to educational and clinical settings, enhancing learning in students and reducing memory deficits in clinical populations. The review discusses current theoretical explanations of the forward effect of testing and provides suggestions for future research directions. PMID- 24772099 TI - The shape of the human language-ready brain. AB - Our core hypothesis is that the emergence of our species-specific language-ready brain ought to be understood in light of the developmental changes expressed at the levels of brain morphology and neural connectivity that occurred in our species after the split from Neanderthals-Denisovans and that gave us a more globular braincase configuration. In addition to changes at the cortical level, we hypothesize that the anatomical shift that led to globularity also entailed significant changes at the subcortical level. We claim that the functional consequences of such changes must also be taken into account to gain a fuller understanding of our linguistic capacity. Here we focus on the thalamus, which we argue is central to language and human cognition, as it modulates fronto-parietal activity. With this new neurobiological perspective in place, we examine its possible molecular basis. We construct a candidate gene set whose members are involved in the development and connectivity of the thalamus, in the evolution of the human head, and are known to give rise to language-associated cognitive disorders. We submit that the new gene candidate set opens up new windows into our understanding of the genetic basis of our linguistic capacity. Thus, our hypothesis aims at generating new testing grounds concerning core aspects of language ontogeny and phylogeny. PMID- 24772102 TI - Vasovagal oscillations and vasovagal responses produced by the vestibulo sympathetic reflex in the rat. AB - Sinusoidal galvanic vestibular stimulation (sGVS) induces oscillations in blood pressure (BP) and heart rate (HR), i.e., vasovagal oscillations, as well as transient decreases in BP and HR, i.e., vasovagal responses, in isoflurane anesthetized rats. We determined the characteristics of the vasovagal oscillations, assessed their role in the generation of vasovagal responses, and determined whether they could be induced by monaural as well as by binaural sGVS and by oscillation in pitch. Wavelet analyses were used to determine the power distributions of the waveforms. Monaural and binaural sGVS and pitch generated vasovagal oscillations at the frequency and at twice the frequency of stimulation. Vasovagal oscillations and vasovagal responses were maximally induced at low stimulus frequencies (0.025-0.05 Hz). The oscillations were attenuated and the responses were rarely induced at higher stimulus frequencies. Vasovagal oscillations could occur without induction of vasovagal responses, but vasovagal responses were always associated with a vasovagal oscillation. We posit that the vasovagal oscillations originate in a low frequency band that, when appropriately activated by strong sympathetic stimulation, can generate vasovagal oscillations as a precursor for vasovagal responses and syncope. We further suggest that the activity responsible for the vasovagal oscillations arises in low frequency, otolith neurons with orientation vectors close to the vertical axis of the head. These neurons are likely to provide critical input to the vestibulo-sympathetic reflex to increase BP and HR upon changes in head position relative to gravity, and to contribute to the production of vasovagal oscillations and vasovagal responses and syncope when the baroreflex is inactivated. PMID- 24772103 TI - The gastrointestinal tract microbiome and potential link to Alzheimer's disease. PMID- 24772105 TI - Neuropeptide GPCRs in Neuroendocrinology. PMID- 24772106 TI - Astrocytic-Neuronal-Astrocytic Pathway Selection for Formation and Degradation of Glutamate/GABA. PMID- 24772107 TI - Assessment of the Deepwater Horizon oil spill impact on Gulf coast microbial communities. AB - One of the major environmental concerns of the Deepwater Horizon oil spill in the Gulf of Mexico was the ecological impact of the oil that reached shorelines of the Gulf Coast. Here we investigated the impact of the oil on the microbial composition in beach samples collected in June 2010 along a heavily impacted shoreline near Grand Isle, Louisiana. Successional changes in the microbial community structure due to the oil contamination were determined by deep sequencing of 16S rRNA genes. Metatranscriptomics was used to determine expression of functional genes involved in hydrocarbon degradation processes. In addition, potential hydrocarbon-degrading Bacteria were obtained in culture. The 16S data revealed that highly contaminated samples had higher abundances of Alpha and Gammaproteobacteria sequences. Successional changes in these classes were observed over time, during which the oil was partially degraded. The metatranscriptome data revealed that PAH, n-alkane, and toluene degradation genes were expressed in the contaminated samples, with high homology to genes from Alteromonadales, Rhodobacterales, and Pseudomonales. Notably, Marinobacter (Gammaproteobacteria) had the highest representation of expressed genes in the samples. A Marinobacter isolated from this beach was shown to have potential for transformation of hydrocarbons in incubation experiments with oil obtained from the Mississippi Canyon Block 252 (MC252) well; collected during the Deepwater Horizon spill. The combined data revealed a response of the beach microbial community to oil contaminants, including prevalence of Bacteria endowed with the functional capacity to degrade oil. PMID- 24772104 TI - Pleiotropic Activities of HGF/c-Met System in Testicular Physiology: Paracrine and Endocrine Implications. AB - In the last decades, a growing body of evidence has been reported concerning the expression and functional role of hepatocyte growth factor (HGF) on different aspects of testicular physiology. This review has the aim to summarize what is currently known regarding this topic. From early embryonic development to adult age, HGF and its receptor c-Met appeared to be clearly detectable in the testis. These molecules acquire different distribution patterns and roles depending on the developmental stage or the post-natal age considered. HGF acts as a paracrine modulator of testicular functions promoting the epithelium-mesenchyme cross-talk as described even in other organs. Interestingly, it has been reported that testicular HGF acts even as an autocrine factor and that its receptor might be modulated by endocrine signals that change at puberty: HGF receptor expressed by Sertoli cells, in fact, is up-regulated by FSH administration. HGF is in turn able to modify endocrine state of the organism being able to increase testosterone secretion of both fetal and adult Leydig cells. Moreover, c-Met is expressed in mitotic and meiotic male germ cells as well as in spermatozoa. The distribution pattern of c-Met on sperm cell membrane changes in the caput and cauda epididymal sperms and HGF is able to maintain epididymal sperm motility in vitro suggesting a physiological role of this growth factor in the acquisition of sperm motility. Noteworthy changes in HGF concentration in seminal plasma have been reported in different andrological diseases. All together these data indicate that HGF has a role in the control of spermatogenesis and sperm quality either directly, acting on male germ cells, or indirectly acting on tubular and interstitial somatic cells of the testis. PMID- 24772108 TI - Outbreak of Achromobacter xylosoxidans in an Italian Cystic fibrosis center: genome variability, biofilm production, antibiotic resistance, and motility in isolated strains. AB - Cystic fibrosis (CF) patients have chronic airway infection and frequent exposure to antibiotics, which often leads to the emergence of resistant organisms. Achromobacter xylosoxidans is a new emergent pathogen in CF spectrum. From 2005 to 2010 we had an outbreak in A. xylosoxidans prevalence in our CF center, thus, the present study was aimed at deeply investigating virulence traits of A. xylosoxidans strains isolated from infected CF patients. To this purpose, we assessed A. xylosoxidans genome variability by randomly amplified polymorphic DNA (RAPD), biofilm production, antibiotic resistances, and motility. All A. xylosoxidans strains resulted to be biofilm producers, and were resistant to antibiotics usually employed in CF treatment. Hodge Test showed the ability to produce carbapenemase in some strains. Strains who were resistant to beta lactamics antibiotics, showed the specific band related to metal beta-lactamase (blaIMP-1), and some of them showed to possess the integron1. Around 81% of A. xylosoxidans strains were motile. Multivariate analysis showed that RAPD profiles were able to predict Forced Expiratory Volume (FEV1%) and biofilm classes. A significant prevalence of strong biofilm producers strains was found in CF patients with severely impaired lung functions (FEV1% class 1). The outbreak we had in our center (prevalence from 8.9 to 16%) could be explained by an enhanced adaptation of A. xylosoxidans in the nosocomial environment, despite of aggressive antibiotic regimens that CF patients usually undergo. PMID- 24772109 TI - Salmonella enterica induces and subverts the plant immune system. AB - Infections with Salmonella enterica belong to the most prominent causes of food poisoning and infected fruits and vegetables represent important vectors for salmonellosis. Although it was shown that plants raise defense responses against Salmonella, these bacteria persist and proliferate in various plant tissues. Recent reports shed light into the molecular interaction between plants and Salmonella, highlighting the defense pathways induced and the means used by the bacteria to escape the plant immune system and accomplish colonization. It was recently shown that plants detect Salmonella pathogen-associated molecular patterns (PAMPs), such as the flagellin peptide flg22, and activate hallmarks of the defense program known as PAMP-triggered immunity (PTI). Interestingly, certain Salmonella strains carry mutations in the flg22 domain triggering PTI, suggesting that a strategy of Salmonella is to escape plant detection by mutating PAMP motifs. Another strategy may rely on the type III secretion system (T3SS) as T3SS mutants were found to induce stronger plant defense responses than wild type bacteria. Although Salmonella effector delivery into plant cells has not been shown, expression of Salmonella effectors in plant tissues shows that these bacteria also possess powerful means to manipulate the plant immune system. Altogether, these data suggest that Salmonella triggers PTI in plants and evolved strategies to avoid or subvert plant immunity. PMID- 24772110 TI - Glass-forming property of hydroxyectoine is the cause of its superior function as a desiccation protectant. AB - We were able to demonstrate that hydroxyectoine, in contrast to ectoine, is a good glass-forming compound. Fourier transform infrared and spin label electron spin resonance studies of dry ectoine and hydroxyectoine have shown that the superior glass-forming properties of hydroxyectoine result from stronger intermolecular H-bonds with the OH group of hydroxyectoine. Spin probe experiments have also shown that better molecular immobilization in dry hydroxyectoine provides better redox stability of the molecules embedded in this dry matrix. With a glass transition temperature of 87 degrees C (vs. 47 degrees C for ectoine) hydroxyectoine displays remarkable desiccation protection properties, on a par with sucrose and trehalose. This explains its accumulation in response to increased salinity and elevated temperature by halophiles such as Halomonas elongata and its successful application in ''anhydrobiotic engineering'' of both enzymes and whole cells. PMID- 24772111 TI - Cancer Vaccines in the World of Immune Suppressive Monocytes (CD14(+)HLA DR(lo/neg) Cells): The Gateway to Improved Responses. AB - Dendritic cells are an important target in cancer immunotherapy based on their critical role in antigen presentation and response to tumor development. The capacity of dendritic cells to stimulate anti-tumor immunity has led investigators to use these cells to mediate anti-tumor responses in a number of clinical trials. However, these trials have had mixed results. The typical method for generation of ex vivo dendritic cells starts with the purification of CD14(+) cells. Our studies identified a deficiency in the ability to generate mature dendritic cell using CD14(+) cells from cancer patients that corresponded with an increased population of monocytes with altered surface marker expression (CD14(+)HLA-DR(lo/neg)). Further studies identified systemic immune suppression and increased concentrations of CD14(+)HLA-DR(lo/neg) monocytes capable of inhibiting T-cell proliferation and DC maturation. Together, these findings strongly suggest that protocols aimed at immune stimulation via monocytes/dendritic cells, if optimized on normal monocytes or in systems without these suppressive monocytes, are unlikely to engender effective DC maturation in vitro or efficiently trigger DC maturation in vivo. This highlights the importance of developing optimal protocols for stimulating DCs in the context of significantly altered monocyte phenotypes often seen in cancer patients. PMID- 24772112 TI - Arrest chemokines. PMID- 24772113 TI - Mitochondrial RNA editing PPR proteins can tolerate protein tags at E as well as at DYW domain termini. PMID- 24772114 TI - Plasma membrane partitioning: from macro-domains to new views on plasmodesmata. AB - Compartmentalization of cellular functions relies on partitioning of domains of diverse sizes within the plasma membrane (PM). Macro-domains measure several micrometers and contain specific proteins concentrated to specific sides (apical, basal, and lateral) of the PM conferring a polarity to the cell. Cell polarity is one of the driving forces in tissue and growth patterning. To maintain macro domains within the PM, eukaryotic cells exert diverse mechanisms to counteract the free lateral diffusion of proteins. Protein activation/inactivation, endocytosis, PM recycling of transmembrane proteins and the role of diffusion barriers in macro-domains partitioning at PM will be discussed. Moreover, as plasmodesmata (PDs) are domains inserted within the PM which also mediate tissue and growth patterning, it is essential to understand how segregation of specific set of proteins is maintained at PDs while PDs domains are smaller in size compared to macro-domains. Here, we will present mechanisms allowing restriction of proteins at PM macro-domains, but for which molecular components have been found in PDs proteome. We will explore the hypothesis that partitioning of macro domains and PDs may be ruled by similar mechanisms. PMID- 24772115 TI - Nuclei in motion: movement and positioning of plant nuclei in development, signaling, symbiosis, and disease. AB - While textbook figures imply nuclei as resting spheres at the center of idealized cells, this picture fits few real situations. Plant nuclei come in many shapes and sizes, and can be actively transported within the cell. In several contexts, this nuclear movement is tightly coupled to a developmental program, the response to an abiotic signal, or a cellular reprogramming during either mutualistic or parasitic plant-microbe interactions. While many such phenomena have been observed and carefully described, the underlying molecular mechanism and the functional significance of the nuclear movement are typically unknown. Here, we survey recent as well as older literature to provide a concise starting point for applying contemporary molecular, genetic and biochemical approaches to this fascinating, yet poorly understood phenomenon. PMID- 24772117 TI - A Comprehensive, Multi-modal Evaluation of the Assessment System of an Undergraduate Research Methodology Course: Translating Theory into Practice. AB - OBJECTIVE: To evaluate assessment system of the 'Research Methodology Course' using utility criteria (i.e. validity, reliability, acceptability, educational impact, and cost-effectiveness). This study demonstrates comprehensive evaluation of assessment system and suggests a framework for similar courses. METHODS: Qualitative and quantitative methods used for evaluation of the course assessment components (50 MCQ, 3 Short Answer Questions (SAQ) and research project) using the utility criteria. RESULTS of multiple evaluation methods for all the assessment components were collected and interpreted together to arrive at holistic judgments, rather than judgments based on individual methods or individual assessment. RESULTS: Face validity, evaluated using a self administered questionnaire (response rate-88.7%) disclosed that the students perceived that there was an imbalance in the contents covered by the assessment. This was confirmed by the assessment blueprint. Construct validity was affected by the low correlation between MCQ and SAQ scores (r=0.326). There was a higher correlation between the project and MCQ (r=0.466)/SAQ (r=0.463) scores. Construct validity was also affected by the presence of recall type of MCQs (70%; 35/50), item construction flaws and non-functioning distractors. High discriminating indices (>0.35) were found in MCQs with moderate difficulty indices (0.3-0.7). Reliability of the MCQs was 0.75 which could be improved up to 0.8 by increasing the number of MCQs to at least 70. A positive educational impact was found in the form of the research project assessment driving students to present/publish their work in conferences/peer reviewed journals. Cost per student to complete the course was US$164.50. CONCLUSIONS: The multi-modal evaluation of an assessment system is feasible and provides thorough and diagnostic information. Utility of the assessment system could be further improved by modifying the psychometrically inappropriate assessment items. PMID- 24772118 TI - Factors associated with non-adherence to insulin in patients with type 1 diabetes. AB - OBJECTIVES: To find out the various factors associated with non-adherence to diet, physical activity and insulin among patients with type 1 diabetes. (T1DM). METHODS: This cross sectional study was conducted among T1DM subjects attending the Baqai Institute of Diabetology & Endocrinology (BIDE) and Diabetic Association of Pakistan (DAP), from July 2011 to June 2012.Clinical characteristics, anthropometric measurements, knowledge regarding type 1 diabetes along with adherence to dietary advice, physical activity and insulin were noted on a predesigned questionnaire and score was assigned to each question. Patients were categorized as adherent or non-adherent on the basis of scores obtained. Statistical Package for Social Sciences (SPSS) for windows version 17.0 was used to analyze the data. RESULTS: A total of 194 patients (Male 94, Female 100), with mean age of 17.9+/- 6.4 years, mean duration of diabetes 5.37+/-4.96 years (38.1% >5 yrs, 61.9% <5 yrs) were included in the study. One hundred and fourteen (58.5%) patients were non adherent to dietary advice, 82(42.3%) non adherent to physical activity while 88.1% respondents were non adherent to their prescribed insulin regimen. Factors associated with non-compliance were family type, occupation & educational level of respondent's parents, duration of T1DM, family history of diabetes, frequency of visits to diabetic clinic, knowledge regarding diabetes, lack of family support and fear of hypoglycemia. CONCLUSION: Non adherence to prescribed treatment regimen in patient with TIDM is quite high. There is need to design strategies to help patients and their family members understand their treatment regimen in order to improve their adherence. PMID- 24772119 TI - Effects of insulin on placental, fetal and maternal outcomes in gestational diabetes mellitus. AB - OBJECTIVE: To observe the effects of exogenous insulin on placental, fetal and maternal outcomes in Gestational Diabetes Mellitus (GDM). METHODS: After screening and diagnoses(WHO criteria) 30 GDM patients(Group A) were kept on diet control and 39 GDM (Group B) who did not achieve glycemic targets were added subcutaneous insulin. Term placental weight, size, shape, consistency, fibrinoid necrosis, hemorrhages, cord color, length of the cord, completeness of membranes, weight and condition of baby and mode of delivery were assessed in 25 patients in each group. RESULT: Placental weight, cord width and baby weight were found to be more in Group B, than Group A and were statistically significant with p value 0.005, 0.02 and 0.003 respectively. Ten patients in group A and 17 patients in group B had cesarean deliveries. CONCLUSION: Exogenous insulin produces significant effects on the placental, fetal and maternal outcomes in patients with GDM. PMID- 24772120 TI - Factors associated with preoperative and postoperative epileptic seizure in patients with cerebral ganglioglioma. AB - OBJECTIVE: To explore the factors associated with preoperative epileptic seizure and surgical outcome in patients with cerebral gangliolioma (GG). METHODS: A total of 31 consecutive patients with pathologically confirmed ganglioglioma and surgically treated from January 2003 to June 2011 in West China Hospital of Sichuan University were retrospectively reviewed. Clinical data, surgical procedure and follow-up information were collected and analyzed. RESULTS: Nineteen patients presented with epileptic seizure, of which 63.2% were males. The mean age at epilepsy surgery and mean seizure duration were 25.6 years and 2.3 years respectively. Factors associated with preoperative epileptic seizure were supratentorial lesion and temporal lobe involvement (p=0.016 and 0.008). Intraoperative electrocorticography (ECoG) was applied in 8 out of 19 epilepsy patients. Eighteen achieved total tumor excision. After a mean follow up of 2.8 (1.3-6.3) years, 11 (68.8%, 11/16) achieved seizure free (Engel class I). Early surgery (seizure duration <3 years) was a significant predictor of favorable seizure outcome (p=0.013). None of the factors including seizure type, tumor location, neuroimaging characteristics and application of intraoperative ECoG or surgical strategy were found to be significantly associated with postoperative seizure outcome. Postoperative combination of AEDs was unnecessary for seizure control. CONCLUSIONS: Ganglioglioma with temporal lobe involvement usually associated with intractable epilepsy. Early surgical resection is strongly suggested to achieve favorable outcome. Intraoperative ECoG is not inevitable and simple lesionectomy is sufficient for satisfactory seizure control. Early accurate diagnosis of ganglioglioma should be established on comprehensive consideration and plays an important role in dealing with these patients. PMID- 24772116 TI - Dietary interactions with the bacterial sensing machinery in the intestine: the plant polyphenol case. AB - There are millions of microbes that live in the human gut. These are important in digestion as well as defense. The host immune system needs to be able to distinguish between the harmless bacteria and pathogens. The initial interaction between bacteria and the host happen through the pattern recognition receptors (PRRs). As these receptors are in direct contact with the external environment, this makes them important candidates for regulation by dietary components and therefore potential targets for therapy. In this review, we introduce some of the main PRRs including a cellular process known as autophagy, and how they function. Additionally we review dietary phytochemicals from plants which are believed to be beneficial for humans. The purpose of this review was to give a better understanding of how these components work in order to create better awareness on how they could be explored in the future. PMID- 24772121 TI - Exploring the transition to DRGs in Developing Countries: A case study in Shanghai, China. AB - OBJECTIVE: With the success of DRGs (Diagnosis Related Groups) in developing countries, this prospective payment system has been imported into China from the early 21(st) century. However, DRGs has been struggling and has made little progress since (its adoption in) 2004. This study contributes to the debate on how to bridge the pay-for-service (system/scheme) and DRGs (Diagnosis Related Groups) during the transitional period of payment reform in China. METHODS: From 2008 to 2012, sixty regional general hospitals in Shanghai were divided into three groups according to their economic level, and one hospital was picked from each group randomly. After ranking of morbidity, 22130 patients with hypertension or coronary heart disease were chosen as sample. Using multiple linear regression analysis, the inter relationships between the total medical expenses of the inpatients, and age, gender of the inpatients, length of stay, region and economic level of the hospitals were examined. RESULTS: The main findings were (1) Age, LOS and the economic level of treatment location had a statistically significant impact on patients with hypertension or coronary heart disease. However, gender is only a significant factor to patients with coronary heart disease. The results suggested that age, LOS and the economic level of treatment location should be considered in formulating pricing standards for the hypertension patient group. Besides the above mentioned factors, gender should also be considered in formulating pricing standards for the coronary heart disease patient group. (2) Under the premise of limited resources, developing countries should first narrow down to screen for common and frequently occurring diseases, then study the key factors which affect the treatment cost of the diseases. CONCLUSION: Simplification of the DRGs standard- setting process based on standardized clinical pathways and accurate costing will greatly increase the efficiency of implementing DRGs in the developing world. PMID- 24772122 TI - Parental Psychological Abuse toward children and Mental Health Problems in adolescence. AB - OBJECTIVE: Present study was conducted to explore the relationship between parental psychological abuse toward their children and mental health problems in adolescence. METHOD: Three hundred participants age range 13-17 years, (57% boys and 43% girls) participated in the study from both public and private high schools of Lahore. Psychological maltreatment experience scale (PMES) and Youth Self-Report(YSR) were used for assessment and diagnosis. RESULTS: Findings revealed that psychological abuse by parents significantly related with mental health problems in adolescents, for mother abuse (r= .24 to.67, p< .05) and father abuse (r= .20 to.70, p< .05). Adolescents who perceived their parents as more abusive exhibited greater problems. Regression analysis indicated that hypothesized factors of parental psychological abuse predicted the mental health problems in adolescents (contributed from 10% to 49% of variance). CONCLUSION: Psychological abuse by parents is related with mental health problems in adolescents. These findings will contribute to a better understanding of non injurious psychological abuse and its impact on adolescents. Findings of the study can be used to bring the attention of parents, public and professionals' towards damaging effects of psychological abuse on adolescents. PMID- 24772123 TI - Ameliorative effect of melatonin against contrast media induced renal tubular cell injury. AB - BACKGROUND AND OBJECTIVE: Reactive oxygen species (ROS) is a mediator of renal damage. Melatonin is a potent-free radical scavenger. Our objective was to test whether melatonin would protect against the nephrotoxicity of contrast media. METHODS: In an experimental study 40 adult male Wistar rats were randomly divided into four equal groups including: 1) Control group (No drug), 2) Contrast media group (10 ml/kg iodixanol i.v. single dose), 3) Contrast media and melatonin (first 10 ml/kg iodixanol then 10 ml/kg/day melatonin by i.p. injection on days 3, 4 and 5) and 4) Contrast media and melatonin pretreatment group (melatonin 10 ml/ kg/day by i.p. injection on 1, 2 and 3 days, then 10 ml/kg iodixanol by i.v. injection on third day. The blood creatinine and BUN as well as the histological changes were evaluated for severity of renal injury (degeneration, vacuolization of tubular renal cells, dilatation of tubular lumen and presence of debris in the lumens), by scoring from one to four. RESULTS: Contrast media significantly increased the creatinine and BUN and renal injury (p<0.05). Melatonin prevented and reversed the injury induced by contrast media (P<0.05). Pretreatment with melatonin reduced the renal injury induced by contrast media (P<0.05). CONCLUSION: Melatonin is an effective drug to prevent contrast-induced renal injury. Therefore its usage (especially pretreatment) might be beneficial in patients who are planning to use contrast media agents. PMID- 24772124 TI - QT dispersion increases with low glomerular filtration rate in patients with coronary artery disease. AB - OBJECTIVE: We aimed to evaluate the relationship between estimated glomerular filtration rate (eGFR) and QT dispersion (QTd) in patients with coronary artery disease (CAD). METHODS: Sixty patients(mean age 62.72 +/- 12.48 years) included 46 male, (mean age 60.89 +/- 12.70 years)and 14 female (mean age 68.71+/- 9.86 years) were enrolled in this study. Patients were divided into 2 groups according to their eGFR using the 6 variable MDRD equation. Group 1 consisted of patients with estimated eGFR<60 ml/min/1.73m(2) and Group 2 consisted of patients witheGFR >= 60 ml/min/1.73m(2). RESULTS: Baseline patient characteristics were homogeneous in both groups except for age, gender and smoking.Also, the extent of CAD was similar in both groups (p > 0.05) QTd values were found higher in group 1 than those of group 2 (57.23 +/- 40.65 ms vs. 31.23 +/- 14.47 ms, p = 0.002). After adjustment for age, gender and smoking using one-way ANCOVA test, statistically significant difference in QTd still existedbetween the groups (p=0.038). CONCLUSION: QTd tends to be higher in patients with poor renal function independent of severity of angiographical CAD. QTd may be a potentially useful non-invasive test in the management of patients with poor renal function, especially those with CAD. PMID- 24772125 TI - To determine the effect of wearing shoe covers by medical staff and visitors on infection rates, mortality and length of stay in Intensive Care Unit. AB - OBJECTIVE: Intensive Care Units (ICUs) experience higher infection rates due to the severity of illness and frequent use of invasive devices. Use of personal protective equipment reduces the risk of acquiring an infection. This study has been conducted to determine the role of using shoe covers by medical staff and visitors on infection rates, mortality and length of stay in ICU. METHODS: It is a descriptive study, performed in Shifa International Hospital, Islamabad from January 2012 to July 2012. The rates of infection (by checking patients for common ICU pathogens), mortality and length of stay of patients admitted in MICU and SICU from January 2012 to March 2012 were measured. Use of shoe covers was abandoned during this period. The same parameters were measured for the patients admitted from May, 2012 to July, 2012; the period during which shoe covers were strictly used by all the staff members and visitors. The data was then analyzed and compared using chi-square test with significance value at p< 0.05. RESULTS: A total of 1151 patients were studied in 06 months period. Among the two groups of patients, managed with and without using shoe covers in ICU, statistically significant decrease was seen in terms of length of ICU stay(as P value is less than 0.05) in patients managed in duration of shoe covers. However, the time period in which shoe covers were used the infections with three common ICU pathogens MRSA, VRE and acinetobacter were statistically significant more than the periods in which shoe covers were not used. There was no significant difference in mortality for both groups (P value = 0.146). CONCLUSION: Use of shoe covers in critical care area is not helpful in preventing infections of common ICU pathogens and length of stay in ICU patients; nor has it decreased the mortality. PMID- 24772126 TI - The correlation between the first heart sound and cardiac output as measured by using digital esophageal stethoscope under anaesthesia. AB - OBJECTIVE: The use of an esophageal stethoscope is a basic heart sounds monitoring procedure performed in patients under general anesthesia. As the size of the first heart sound can express the left ventricle function, its correlation with cardiac output should be investigated. The aim of this study was to investigate the effects of cardiac output (CO) on the first heart sound (S1) amplitude. Methods : Six male beagles were chosen. The S1 was obtained with the newly developed esophageal stethoscope system. CO was measured using NICOM, a non invasive CO measuring device. Ephedrine and beta blockers were administered to the subjects to compare changes in figures, and the change from using an inhalation anesthetic was also compared. RESULTS: The S1 amplitude displayed positive correlation with the change rate of CO (r = 0.935, p < 0.001). The heart rate measured using the esophageal stethoscope and ECG showed considerably close figures through the Bland-Altman plot and showed a high positive correlation (r = 0.988, p < 0,001). CONCLUSION: In beagles, the amplitude of S1 had a significant correlation with changes in CO in a variety of situations. PMID- 24772127 TI - Effects of two genes coding squamous cell carcinoma antigen on the diagnosis and treatment of cervical squamous cell carcinoma. AB - OBJECTIVE: To study the effects of expressions of SCCA1 and SCCA2 in cervical squamous cell carcinoma on its diagnosis, treatment evaluation and prognosis analysis. M ethod s : Seventy-six cervical squamous cell carcinoma patients enrolled in our hospital from October 2011 to April 2013 were selected, and another 76 healthy females (without cervical tissue lesions) were enrolled as the control. SCCA1 and SCCA2 expressions in the two groups were compared by RT-PCR. The serodiagnosis results before and after chemotherapy were compared to clarify the effects of SCCA2 expression. RESULTS: The two groups had similar relative SCCA1 expression rates that were not significantly correlated with pathological factors. Before chemotherapy, the relative expression rates of SCCA2 were significantly higher in the patients with later stage (t=6.018, P=0.00082<0.05) and lymphatic metastasis (t=6.281, P=0.00192<0.05). After treatment, relative SCCA2 expression rate was decreased more significantly in the effective group than that in the ineffective group (t=10.27893, P=0.02815<0.05). CONCLUSION: The expression of SCCA1 failed to indicate the onset, diagnosis and prevention of cervical squamous cell carcinoma, whereas that of SCCA2 worked as one of the tumor markers. PMID- 24772128 TI - Clinical presentations and biochemical profile in adult celiac disease patients in Hyderabad: Pakistan. AB - OBJECTIVE: To see the various clinical presentations and biochemical profile in adult celiac disease patients of Hyderabad Sindh. METHODS: A total 60 suspected cases of adult celiac disease, both males and females were screened out from Liaquat University of Medical and Health Sciences hospital and private clinics at Sadar Hyderabad Sind by non probability purposive sampling during a period from July 2011 to December 2012.Age ranged between 18 to 55 Years. A detailed history and clinical examination was done. Patients already on gluten free diet, age <12years, tuberculosis or cancer of intestine/colon and patients of diabetes and thyroid disorder were excluded, while patients having positive ant tTG (value >15 iu/ml detected by ELISA) were included. The biochemical profile including serum albumin, calcium ,ferritin, SGPT, Alkaline phosphatase and Haemoglobin were estimated in central Diagnostic laboratory LUMHS by taking 10 cc centrifuged blood sample. The data was plotted on SPSS 16, mean and percentages were calculated. RESULTS: All patients were divided in to three groups according to age. The most common group was 18-30 years; (mean, 23.5+/-5.6) comprised 56.6%. The commonest clinical presentation was diarrhoea in 50%, menstrual irregularity in 21%, walking problems 21%, undue fatigue in 15% and edema in 15%. P values calculated in quantitative variable of males and females. The p value was significant in between serum calcium (p 0.004), haemoglobin (p 0,004), serum ferritin (<0.005) and alkaline phosphatise (<0.005). CONCLUSION: This study showed that Adult celiac disease was present with entirely different clinical and biochemical profile in patients in this region. PMID- 24772129 TI - Effects of low-dose amiodarone and Betaloc on the treatment of hypertrophic cardiomyopathy complicated with malignant ventricular arrhythmias. AB - OBJECTIVE: To study the therapeutic effects of low-dose amiodarone and Betaloc on hypertrophic cardiomyopathy complicated by malignant ventricular arrhythmias. METHODS: Eighty-two such patients were selected and divided into a treatment group and a control group by the random number method (n=41), which were administered with low-dose amiodarone plus Betaloc and individual Betaloc respectively. RESULTS: The treatment group had a significantly higher overall effective rate (85.4%) than the control group (65.9%) did. Based on the New York Heart Association's classification of cardiovascular disease, the treatment group mainly comprised Class III and IV patients before treatment, which were significantly relieved after treatment (P<0.05). The heart rate was evidently decreased from (119.99+/-18.91) bpm to (80.98+/-12.34) bpm, and the incidences of premature ventricular contraction and tachycardia were significantly reduced (P<0.05). The longest QT intervals after and before treatment were (421+/-32) ms and (411+/-35) ms respectively. The shortest QT interval after treatment [(350+/ 36) ms] was significantly longer than that before [(307+/-31) ms]. The QT dispersion before treatment [(96+/-29) ms] was significantly higher that after [(64+/-17) ms] (P<0.05). Six out of eighty two patients in the treatment group succumbed to adverse reactions (14.63%). CONCLUSION: Hypertrophic cardiomyopathy complicated with malignant ventricular arrhythmias can be well treated with low dose amiodarone and Betaloc, with mitigated symptoms, improved prognosis and few adverse reactions. PMID- 24772130 TI - Prevalence and associated risk factors for syphilis in women with recurrent miscarriages. AB - OBJECTIVE: A Cross Sectional population based serological studies was conducted to determine the prevalence and associated risk factors for syphilis women with recurrent miscarriages. METHODS: Patient's 5ml whole blood was collected through venepuncture technique. Data were collected by all women answered a questionnaire and by investigating blood sample VDRL test and FTA-ABS test. The study was conducted in a confidential manner and numbers were used to identify the participant. RESULTS: Total 256 women were included in the present study. Mean age of women was 29.4 years while range was 21 to 38 years (206/256). Out of the 256 samples, 05 (1.9%) were positive for active syphilis. Majority belonged to low socioeconomic group, uneducated and had previous congenital anomaly. CONCLUSION: Active infection with Treponema pallidum (T.P) in women belonging to low socioeconomic level were disquieting. This is probably due to illiteracy and high proportion of unsafe sexual behavior. It is also suggestive that seropositive status is often discovered in routine serological studies during pregnancy. PMID- 24772131 TI - Impact of Omega-3 and Omega-9 fatty acids enriched total parenteral nutrition on blood chemistry and inflammatory markers in septic patients. AB - OBJECTIVE: Lipid emulsions containing omega-3 are known to have positive effects on patient's prognosis due to anti-inflammatory properties. The aim of this study was to investigate the effects of omega-3 enriched total parenteral nutrition (TPN) emulsion containing omega-9 on biochemical parameters, inflammatory mediators in septic patients. METHODS: Thirty-two participants who were not fed orally for over five days and needing TPN support were included in this prospective, randomized and double-blind clinical study. Patients were randomly divided into control (n=16), treatment (n=16) groups. The treatment group received TPN containing 80% olive oil+20% soy oil additionally 10 g fish oil enriched TPN. Control group received only olive oil containing standard lipid emulsion (1.3+/-0.1 g/kg/day). Blood samples were collected for biochemical analysis on the 1(st) and 6(th) days of study. RESULTS: The serum albumin levels significantly increased (p<0.05) in both groups whereas total protein and prealbumin levels did not show any significant changes. In treatment group, significant decreases were determined in LTB4 and CRP levels (p<0.05) while decreases in IL-6, TNF-alpha and leukocyte levels were not significant. No statistically significant changes were found in LTB4, CRP, IL-6, TNF-alpha and leukocyte levels of controls. CONCLUSION: RESULTS of the study have shown that omega-3 enriched TPN solution containing omega-9 contributes to decrease in the levels of inflammatory mediators and to improvement in the biochemical parameters in septic patients. PMID- 24772132 TI - Effect of a workshop in rational pharmacotherapy for interns during family medicine clerkship in Samsun- Turkey. AB - OBJECTIVE: We aimed to investigate the effect of rational pharmacotherapy workshop for interns on the rationality, cost and number of drugs prescribed. METHODS: The participants were asked to prescribe a medication for acute noninflammatory osteoarthritis (ANOA), acute bacterial rhinosinusitis (ARS), acute otitis media (AOM), acute uncomplicated cystitis (AC), and acute bacterial tonsillopharyngitis (ABT) before and after workshop. Total 3000 prescriptions were scored regarding rationality of the drug choice (0-10), format (0-5), instructions (0-4), legibility (0-1) and total (0-20 points). The mean number of drug(s) and total costs per prescription were calculated. Paired samples t-test was used to compare the pre- and post score means. RESULTS: Total pre- and post prescribing scores (0-20) were significantly different (p=0.00 for each): ANOA (13.59+/-0.27, 18.33+/-0.18), ARS (13.26 +/-0.18, 15.15 +/-0.17), AOM (12.58 +/- 0.26, 14.66+/-0.27), AC (13.53+/-0.17, 15.76+/-0.20), ABT (13.54+/-0.24, 15.49 +/ 0.28). Mean number of drugs per prescription for the indications in the pre-test and post-test were: ANOA (1.24 +/-0.29, 1.02+/-0.01, p=0.00), ARS (2.08+/-0.04, 2.00+/-0.04, p=0.16), AOM (1.66+/-0.04 and 1.69+/-0.03, p=0.54), AC (1.55+/-0.04, 1.39+/-0.03, p=0.00) and ABT (2.10+/-0.05, 1.81+/-0.05, p=0.00). Mean costs per prescription in Turkish Liras: ANOA (6.31+/-0.29, 4.60+/-0.05, p=0.00), ARS (13.80+/-0.38, 4.63+/-0.04, p=0.00), AOM (10.18+/-0.28, 4.41+/-0.07, p=0.00), AC (11.33+/-0.21, 10.68+/-0.18, p=0.01) and ABT (12.03+/-0.34 and 10.41+/-0.35, p=0.00). CONCLUSION: Training produced a significant improvement in rational prescribing. PMID- 24772133 TI - The relationship between inferior vena cava diameter measured by bedside ultrasonography and central venous pressure value. AB - OBJECTIVE: We aimed to present inferior vena cava (IVC) diameter as a guiding method for detection of relationship between IVC diameter measured noninvasively with the help of ultrasonography (USG) and central venous pressure (CVP) and evaluation of patient's intravascular volume status. METHODS: Patients over the age of 18, to whom a central venous catheter was inserted to their subclavian vein or internal jugular vein were included in our study. IVC diameter measurements were recorded in millimeters following measurement by the same clinician with the help of USG both at the end-inspiratory and end-expiratory phase. CVP measurements were viewed on the monitor by means of piezoelectric transducer and recorded in mmHg. SPSS 18.0 package program was used for statistical analysis of data. RESULTS: Forty five patients were included in the study. The patients had the diagnosis of malignancy (35.6%), sepsis (13.3%), pneumonia, asthma, chronic obstructive pulmonary disease (11.1%). 11 patients (24.4%) required mechanical ventilation while 34 (75.6%) patients had spontaneous respiration. In patients with spontaneous respiration, a significant relationship was found between IVC diameters measured by ultrasonography at the end of expiratory and inspiratory phases and measured CVP values at the same phases (for expiratory p = 0.002, for inspiratory p= 0.001). There was no statistically significant association between IVC diameters measured by ultrasonography at the end of expiration and inspiration and measured CVP values at the same phases in mechanically ventilated patients. CONCLUSIONS: IVC diameter measured by bedside ultrasonography can be used for determination of the intravascular volume status of the patients with spontaneous respiration. PMID- 24772134 TI - Further exploration during open appendicectomy; assessment of some common intraoperative findings. AB - OBJECTIVE: Very few studies are available to relate the final histology of excised appendix with the detailed intra-operative findings during appendectomy, both open and laparoscopic. This study was aimed to correlate the histological features of appendix specimen with the intra operative findings at open appendicectomy (OA) in a bid to determine when to change the planned procedure to include further exploration. Methods : A prospective study that observes the condition of the greater omentum (GO), the vermiform appendix and peritoneal exudates at all OA done for uncomplicated appendicitis. Histological examination of the appendices done using the H&E stain. Results : Eighty-five patients had emergency open OA, their(') ages range from 6 to 62 yrs (median = 23yrs). Histology showed 7 normal appendix (HNA), 56 acute (HAA) and 22 "non acute" appendicitis (HNAA). Negative appendicectomy rate was 8.2%. The GO was sighted more in patients with HAA than HNAA (p=0.00015) and also significantly more inflamed in the former (p=0.00028). It is not significantly inflamed in those with HNAA (p=0.945). The negative predictive value (NPV) of absent GO is 35.7% while the positive predictive value (PPV) of sighted normal GO and inflamed GO are 92.8% and 100% respectively. The PPV and NPV of presence of pus for diseased appendix are 95.8% and 9.8% respectively while those of excess fluid are 94.8% and 10.8%. The PPV and NPV of macroscopic assessment of the appendix for inflammation are 97% and 45.5% respectively giving the diagnostic accuracy of 90.6%. A significant trend of increasing probability of histologically inflamed appendix with increasing severity of macroscopic feature was seen (X(2) = 004 df=1, p<0.005). CONCLUSION: High positive and low negative predictive values are similar for all the three parameters assessed. The macroscopic appearance of the appendix has a predictive likelihood ratio for further exploration. PMID- 24772135 TI - Atrial septal defect repair; our early and mid-phase results. AB - OBJECTIVE: Atrial septal defect is one of the most commonly encountered congenital heart diseases in adults. The effect of age of the patient to the surgery is disputable. The purpose of this report was to evaluate surgical repair in patients with ASD who are operated in our clinic. METHODS: Total 40 patients were subjected to surgical repair due to ASD in Van Yuksek Ihtisas Education and Research Hospital between February 2006 and April 2009. Twenty seven of the patients were female and 13 were male, their ages differed between 8 and 71 and mean age of the patients was 33.70+/-14.04. RESULT: Operative mortality did not occur. Two of our patients had coronary arterial disease in addition to ASD. ASD repair was performed together with coronary bypass surgery. Closing of ASD resulted in an increase in left ventricular ejection fraction, and a decrease in pulmonary arterial pressure and cardiothoracic ratio. Recovery in the functional capacity was observed post-surgery according to NYHA. CONCLUSION: In this series, surgical results of the patients of various ages, with ASD closed were positive. PMID- 24772136 TI - Factors effecting recurrence and progression of high grade non invasive bladder cancer treated by intravesical BCG. AB - OBJECTIVE: The rate of recurrence in high grade non muscle invasive bladder cancer (NMIBC) is 70% with progression rate of 15-40% at 5 years. The treatment of high grade NMIBC is intravesical BCG therapy, however for high risk cases radical cystectomy is recommended. In this study we determined the response of high grade NMIBC to BCG therapy and the factors affecting it in south Asian population. METHODS: This retrospective cohort study was conducted on 64 patients treated with intravesical BCG for high grade NMIBC from Dec 2008 to July 2012. Smoking, tumor size, location and multiplicity were taken as prognostic factors. Recurrence and progression were determined by cystoscopy and upper tract imaging according to European Association of Urology guidelines. The association of prognostic factors with recurrence and progression was determined. RESULTS: The rate of recurrence and progression was found to 45.8% and 27.1% respectively after a mean follow up 28.36 months. Smokers had 4 times greater odds of progression of tumor as compared to non-smokers. Patients with large tumors had 6.7 times greater odds of progression as compared to patients with small tumors. CONCLUSION: Smokers with large and multiple high grade NMIBC constitute the high risk group. These patients may be offered early radical cystectomy and advised to stop smoking. PMID- 24772137 TI - Predictors of microvascular invasion in patients with solitary small hepatitis B related hepatocellular carcinoma. AB - OBJECTIVE: To identify the risk factors for the presence of microvascular invasion (MVI) in patients with solitary small hepatitis B related hepatocellular carcinoma (HCC). METHODS: The data of 215 patients who underwent liver resection between 2008 and 2011 at our hospital were reviewed. MVI was confirmed on pathological examination in 41 patients. Preoperative risk factors for MVI were analyzed using uni- and multi-variate analyses. RESULTS: In the multivariate analysis, alpha-fetoprotein (AFP) greater than 400 ng/mL, tumor size and hypersplenism were independently associated with MVI. Receiver operating curve (ROC) analysis suggested the best cut-off value for tumor size was greater than 3.1 cm. The ROC curve analysis further identified patients with more than one above-mentioned risk factor may suffer from MVI with 75.6% sensitivity and 75.3% specificity. The recurrence-free and long-term survival rates of patients with MVI were significantly lower than patients without MVI. CONCLUSIONS: Patients with MVI may suffer from poor outcomes. AFP greater than 400 ng/mL, tumor size and hypersplenism were preoperative predictors of MVI in patients with solitary small hepatitis B related HCC. PMID- 24772138 TI - A method of percutaneous vertebroplasty under the guidance of two C-arm fluoroscopes. AB - OBJECTIVE: To compare the clinical application in the percutaneous vertebroplasty under the guidance of one or two C-arm fluoroscopes. METHODS: One hundred forty three elderly patients with Osteoporotic vertebral compression fractures (OVCFs) underwent percutaneous vertebroplasty under the guidance of one or two C-arm fluoroscopes. The number of pulsed imagings, the time of operation and the incidence of cement leakage were recorded. RESULTS: The average number of pulsed imagings was 16.00+/-1.58 vs 13.07+/-2.00 per patient under the guidance of one vs two C-arm fluoroscopes. The average time of operation was 48.42+/-5.00 minutes vs 39.70+/-7.42 minutes per patient under the guidance of one vs two C-arm fluoroscopes. The incidence of cement leakage was 20% vs 15.7% of the patients under the guidance of one vs two C-arm fluoroscopes. The differences in the number of pulsed imagings and the time of operation were statistically significant. The difference in incidence of cement leakage was not statistically significant. CONCLUSION: The two-fluoroscopic technique reduce the labor cost, the radiation, the time of operation and the operation risk. PMID- 24772139 TI - Management of Macular Pre-Retinal Subhyaloid hemorrhage by Nd:Yag laser hyaloidotomy. AB - OBJECTIVE: To evaluate the efficacy, visual outcome and complication following Nd:Yag laser hyaloidtomy for subhyaloid hemorrhage. METHODS: This interventional case series was managed at LRBT, Free Base Eye Hospital Karachi from January 2010 to December 2010. It included 30 eyes of 30 patients with subhyaloid hemorrhage due to different causes which underwent Nd: Yag laser sublyaloidotomy Results: Out of thirty patients, eighteen (60%) were male and twelve (40%) were females. Mean age was 32.57 years. Males pre-dominated the study. Pre laser visual acuity was between counting finger at one meter in 22 patients (73.33%) and between counting finger one meter to hand movement in 8 patients (26.66%). Vision improved to 6/6 in 10 patients (33%), 6/9 - 6/12 in 17 patients (56.66%) and between 6/24 - 6/60 in 3 patients (9.99%) at the end of follow up. Complications were persistent vitreous hemorrhage in one (3.33%) patient, failed drainage in one (3.33%) patient and metamorphopsia in one (3.33%) patient. CONCLUSION: Nd: Yag laser hyloidotomy is an excellent technique for management of Subhyaloid hemorrhage with early visual recovery provided there is no macular pathology. PMID- 24772140 TI - Finite element analysis of a bone healing model: 1-year follow-up after internal fixation surgery for femoral fracture. AB - OBJECTIVE: Finite element analysis was used to compare preoperative and postoperative stress distribution of a bone healing model of femur fracture, to identify whether broken ends of fractured bone would break or not after fixation dislodgement one year after intramedullary nailing. Method s: Using fast, personalized imaging, bone healing models of femur fracture were constructed based on data from multi-slice spiral computed tomography using Mimics, Geomagic Studio, and Abaqus software packages. The intramedullary pin was removed by Boolean operations before fixation was dislodged. Loads were applied on each model to simulate a person standing on one leg. The von Mises stress distribution, maximum stress, and its location was observed. Results : According to 10 kinds of display groups based on material assignment, the nodes of maximum and minimum von Mises stress were the same before and after dislodgement, and all nodes of maximum von Mises stress were outside the fracture line. The maximum von Mises stress node was situated at the bottom quarter of the femur. The von Mises stress distribution was identical before and after surgery. Conclusion : Fast, personalized model establishment can simulate fixation dislodgement before operation, and personalized finite element analysis was performed to successfully predict whether nail dislodgement would disrupt femur fracture or not. PMID- 24772141 TI - The morphology of medial malleolus and its clinical relevance. AB - OBJECTIVE: To provide morphological data of medial malleolus to decrease the possibility of posterior tibial tendon injury and inadvertent ankle penetration. METHODS: Computed tomography scans of the ankle in 215 patients were reviewed. Then parameters in the 3-D reconstruction images were measured by three independent, qualified observers on two separate occasions. RESULTS: The average angle between tibia plafond and the articular facet of the medial malleolus was 55.88+/-4.11 degrees . The distance from the most anterior point of the anterior colliculus to the center of the intercollicular groove was 11.68+/-1.13 mm. And the average angle between the bimalleolar axis and the articular facet of the medial malleolus was 76.61+/-2.04 degrees . Significant differences were observed in the distance from the most anterior point of the anterior colliculus to the center of the intercollicular groove between males and females. (P<0.05) All of the parameters exhibited moderate to excellent intra-class correlation coefficient (ICC). CONCLUSIONS: According to this study, the insertion angle is much smaller than previously believed, and adequate space only exists for two 4.0 mm screws in some large cases. The second screw will probably be near the posterior tibial tendon, especially in some small cases. PMID- 24772142 TI - Can Mean Platelet Volume and Platelet Distrubition Width be Possible Markers for Ectopic Pregnancy and Tubal Rupture? (MPV and PDW in Ectopic Pregnancy). AB - OBJECTIVE: We aimed to evaluate the alterations in serum levels of platelet indices such as mean platelet volume (MPV) and platelet distribution width (PDW) in ectopic pregnancy (EP) and discuss the mechanism of the alterations in MPV and PDW. METHODS: This retrospective evaluation of 153 tubal EP patients (39 ruptured and 114 non-ruptured) admitted to our clinic between 2009 and 2013 and 67 healthy pregnancies was conducted. The data regarding the maternal age, hemoglobin level, platelet level, MPV, PDW was analyzed. RESULTS: MPV was lower in the EP, especially in ruptured EP, compared to control group. However, no significant difference could be found between the groups (p=0.616). PDW was higher in the EP, especially in ruptured EP, compared to control group, however there was no statistical difference between the three groups (p=0.451). Platelet counts were significantly lower in ruptured EP compared to non-ruptured ectopic pregnancies and control groups (p=0.005). CONCLUSIONS: MPV seems to be lower in ruptured EP suggesting the possible high grade inflammation in pathology. Platelet counts tend to be lower in ruptured EP suggesting the consumption of the platelets at the inflammation site. However, further studies are needed to describe the usefulness of the platelet indices in the diagnosis and clinical follow-up of EP. Our preliminary results show that MPV levels may decrease in the ruptured EP cases. At the same time, PDW levels may increase. PMID- 24772143 TI - The effects of 21 and 23 milimeter aortic valve prosthesis on hemodynamic performance and functional capacity in young adults. AB - OBJECTIVE: Early and medium-term improvement of functional capacity and regression of left ventricular hypertrophy was evaluated in the young adult patient group following application of 21 mm or 23 mm bileaflet aortic mechanical valve prosthesis due to aortic stenosis. Methods : Twenty two patients (10 male, 12 female; mean age 27+-8.2 (19-43)) who underwent isolated aortic valve replacement due to rheumatic aortic stenosis, were included in the study. 21 mm and 23 mm bileaflet mechanical prosthesis was used respectively in eight and fourteen patients. The mean body surface area was 1.86 m(2) and 1.68 m(2) respectively in 23 mm and 21 mm prosthesis while 1.73 +/-0.25 m(2) for the whole group. Functional capacity was New York Heart Association (NYHA) class II in 9 patients and class III in thirteen patients. Implantation was performed without enlarging the aortic root in all except four patients. In all patients transvalvular gradients, effective orifice area and the diameter of left ventricle were measured with transthoracic echocardiography during rest and after maximal exercise. Mean follow-up was 34+/-12 months (range 11-57 months). RESULTS: There were no postoperative complications or deaths. All the patients were assessed as NYHA class I with regards to functional capacity (p=0.01). Significant improvements were determined in postoperative mean transvalvular gradient (p=0.005) and left ventricular mass index (p=0.01) when compared with preoperative values. CONCLUSION: Our findings show that replacement with 21 mm and 23 mm mechanical prosthesis provides a significant improvement in regression of symptoms and increase of functional capacity in young adults in early and mid period without increasing mortality and morbidity. PMID- 24772144 TI - The effect of erectile dysfunction on quality of life in male kidney transplant recipients. AB - Objective : To assess how erectile dysfunction (ED) affects the quality of life in male kidney transplant recipients. METHODS: We randomly selected 150 cases of married male kidney transplant recipients. Using the International Index of Erectile Function (IIEF-5) Questionnaire, we divided our research subjects into ED group (n=63) and non-ED group (n = 87). The Short-Form health survey (SF-36) was used to evaluate the quality of life of the recipients. Hamilton Anxiety Rating Scale was used to compare the mental health status of the two groups. RESULTS: No significant differences (P > 0.05) were observed between the ED and non-ED groups in physical functioning (PF), role-physical (RP), or bodily pain (BP). However, the ED group exhibited a lower score (P < 0.05) than the non-ED group in general health (GH), vitality, social functioning (SF), role emotional (RE) and mental health (MH). There were 13 cases in the ED group with anxiety disorders (20.6%), which was clearly more than in the non-ED group (3.4%, P < 0.05). CONCLUSION: Erectile dysfunction is an important factor in the quality of life of male kidney transplant recipients. PMID- 24772145 TI - Frequency, severity and risk indicators of retinopathy in patients with diabetes screened by fundus photographs: a study from primary health care. AB - OBJECTIVE: To determine the frequency, severity and risk indicators of diabetic retinopathy (DR) in patients with diabetes attending a primary care diabetes centre. METHODS: This observational study was conducted at Diabetic Association of Pakistan - a World Health Organization collaborating center in Karachi, from March 2009 to December 2011. Registered patients with diabetes were screened by two field fundus photographs. Retina specialists graded the signs of retinopathy according to diabetic retinopathy disease severity scale. RESULTS: Of total registered diabetic patients (n=11,158), 10,768 (96.5 %) were screened for DR. Overall DR was found in 2661 (24.7%) patients. DR was found in decreasing order of frequency in patients with type 2 (n= 2555, 23.7%) followed by patients with type 1 diabetes (n=101, 0.93% ) and patients with gestational diabetes mellitus (GDM) (n=5, 0.46%). Among patients with DR, signs of non-sight threatening retinopathy was dominant. Females and patients of working age group predominantly had retinopathy. Type 1 patients >16 years and type 2 patients < 5 years of history of diabetes had sign of retinopathy in increased frequency. CONCLUSION: Every forth patient with diabetes in this large cohort had signs of diabetic retinopathy. Females and patients in working age group predominantly had retinopathy. Type 2 patients with short while type 1 patients with long history of diabetes most frequently had DR. Dissemination of the present study findings may help in increasing the awareness of this serious complication of diabetes. PMID- 24772146 TI - Spectrum of pathologies in cases of intestinal obstruction & perforation based on histopathological examination of resected intestine - Report from a third world country. AB - BACKGROUND AND OBJECTIVE: Cases presenting with intestinal perforation and obstruction constitute a substantial work load on our surgical service. Etiologies vary in underdeveloped and developed countries. Histopathological examination of resected intestine is expected to provide the definite evidence of the underlying etiology- guiding a better health care planning for preventive measures. Our objective was to study the spectrum of histopathological findings in resected intestines from cases of intestinal obstruction and perforation in our local population to document the underlying etiology. METHODS: A total of 120 cases of intestinal resection were included. Detailed gross and microscopic examination with routine stains was performed. Definite evidence of any specific etiology on the basis of morphology was documented. RESULTS: A total of 95 cases with clinical/radiological diagnosis of obstruction (79.2%) and 25 of intestinal, perforation (20.8%) were included. Tuberculous enteritis was the commonest etiology (n=41; 43.1%) in cases of intestinal obstruction followed by malignant tumours (n=30; 31.5%). ischemic infarct/gangrene, post op illeal adhesions, polyps and ulcerative colitis followed. In cases of perforation, Typhoid enteritis (n=15; 60%), was the commonest pathology followed by idiopathic perforation (n=5; 20%), tuberculous enteritis (n=3;12%), carcinoma (4%) and ulcerative coliti (4%). Conclusion : In developing countries infective etiology remains a dominant cause of intestinal obstruction and perforation. Its presentation in younger age leading to intestinal resection demands effective preventive measures in this part of the world to prevent morbidity and mortality. PMID- 24772147 TI - Determination of Anti-nuclear Antibody Pattern Distribution and Clinical Relationship. AB - BACKGROUND AND OBJECTIVES: Autoantibodies are immunglobulins occurred directly against autoantigens that are known as endogen antigens. Autoimmune disease is an occasion that the body begins a fight against its own cells and tissues. The antibodies that are created by the body against its own cell nuclei are called as anti-nuclear antibodies (ANA), and one of the methods used for detection and pattern of ANA is indirect immunofluorescence test (IIF). In the present study, it was aimed to determine the rate of ANA positivity and patterns of the positive specimens, and to investigate the relationship between ANA positivity and diseases in patients. METHODS: ANA test results of a total of 3127 patients admitted during March 2010 to December 2012 were evaluated retrospectively. ANA test (HEp 20-10, EUROIMMUN, Germany) was used in dilution of 1:100 in IIF test. RESULTS: A total of 494 (15.8%) resulted as ANA positive. ANA positivity rate was significantly higher in female patients than the male ones (p<0.001). The most frequent ANA patterns were coarse speckled pattern (154 patients, 31.2%), nucleolar pattern (89 patients, 18.0%), fine speckled pattern (57 patients, 11.5%), and speckled pattern (48 patients, 9.7%). ANA positivity was most commonly determined in rheumatoid arthritis (RA) (42 patients, 8.5%), systemic lupus erythematosus (SLE) (29 patients, 5.9%), and rheumatoid vasculitis (RV) (28 patients, 5.7%). The most frequent symptoms or findings were joint pain (127 patients, 26.0%) and anemia (28 patients, 5.7%). ANA positivity rates were found to be significantly higher in patients with RA (p<0.001), with SLE (p<0.001), and with Raynaud phenomenon (p=0.001) in comparison to the controls. Amongst the most frequent diseases evaluated, no significant differences were found between the control groups and the groups of RV (p=0.089), multiple sclerosis (p=0.374), and Sjogren syndrome (p=0.311) in terms of ANA positivity rates. CONCLUSIONS: The present study is the first study reporting the positivity rate and distribution of ANA in Bolu located in northwestern Turkey. Information about the pattern types and the distribution of the patterns according to the diseases and symptoms contribute in diagnosis of autoimmune diseases. It is observed that clinical diagnosis has been supported significantly by ANA test according to data of our study. PMID- 24772148 TI - Impact of anthropometrical parameters on portal vein diameter and liver size in a subset of Karachi based population. AB - OBJECTIVE: The purpose was to study the impact of anthropometrical parameters on portal vein diameter and liver size by ultrasound in a subset of Karachi population. METHODS: Four hundred and fifty nine apparently healthy subjects were included in this cross sectional study. After recording weight and height of each subject, Portal vein diameter and both liver lobes were measured by gray scale ultrasonography. Students T test and ANOVA were applied for statistical analyses. RESULTS: With increasing age, portal vein diameter and right lobe of liver increased significantly (p value < 0.001). Increase in portal vein diameter was also observed with rise in body mass index (0.8 cm in underweight - 1.1 cm in obese subjects). Sizes of right and left liver lobes also increased with a rise in body mass index (p value < 0.001 and 0.001). Gender, however, did not have any effect on portal vein diameter and liver size. CONCLUSION: Age and body mass index are reliable parameters to consider for avoiding false positive diagnosis of hepatomegaly and portal hypertension. Knowing the right and left liver size with respect to anthropometrical measurements also assist a clinician in selecting a subject for liver transplantation. PMID- 24772149 TI - Isolation and antibiotic susceptibility of E. coli from urinary tract infections in a tertiary care hospital. AB - OBJECTIVE: The study was conducted to isolate and determine the antibiotic resistance in E. coli from urinary tract infections in a tertiary care hospital, Lahore. METHODS: Urine samples (n=500) were collected from patients with signs and symptoms of Urinary tract infections. Bacteria were isolated and identified by conventional biochemical profile. Antibiotic resistance pattern of E. coli against different antibiotic was determined by Kirby-Baur method. RESULTS: Bacterial etiological agent was isolated from 402 samples with highest prevalence of E. coli (321, 80%) followed by Staphylococcus aureus (9.4%), Proteus species (5.4%) and Pseudomonas species (5.2%). The E. coli were highly resistant to penicillin (100%), amoxicillin (100%) and cefotaxime (89.7%), followed by intermediate level of resistance to ceftazidime (73.8%), cephradine (73.8%), tetracycline (69.4%), doxycycline (66.6%), augmentin (62.6%), gentamycin (59.8%), cefuroxime (58.2%), ciprofloxacin (54.2%), cefaclor (50%), aztreonam (44.8%), ceftriaxone (43.3%), imipenem (43.3%), and low level of resistance to streptomycin (30%), kanamycin (19.9%), tazocin (14%), amikacin (12.7%) and lowest to norfloxacin (11.2%). Out of 321 E. coli isolates, 261 (81%) were declared as multiple drug resistant and 5 (1.5%) were extensive drug resistant. CONCLUSION: It is concluded that most of the urinary tract infections in human are caused by multiple drug resistant E. coli. PMID- 24772150 TI - Association of the use of bacterial cell wall synthesis Inhibitor drugs in early childhood with the Developmental Defects of Enamel. AB - OBJECTIVE: Our objective of the study was to determine the association between frequent use of Penicillins and Cephalosporins with developmental defects of enamel in pediatric age group. METHODS: This is a cross sectional study, conducted at Ziauddin University. A total of 367 children, having the history of either Penicillin or Cephalosporin exposure were included. The parents of children were asked to complete a questionnaire related to disease and drug history. Dental examination was carried out to assess the hypomineralization in tooth enamel based on modified Developmental Defects of Enamel (DDE) index. RESULTS: Out of 367 children, 124 (34%) were males and females were 243(66%). In the study group 22.6% (n= 83) of children were found to be hypomineralized. The maximum type of teeth defects were diffused opacities that was 12.0% (n=44). The statistically significant association (p-value < 0.05) was found between frequency of antibiotic use and hypomineralization for most teeth. Children who were exposed to either Penicillins or Cephalosporin in early childhood showed significant (p-value < 0.002) hypomineralized enamel. CONCLUSION: This study concludes that frequent use of antibiotics such as penicillins and cephalosporins has positive association with enamel hypomineralization in developing tooth structure. PMID- 24772151 TI - In vitro evaluation of antimicrobial effect of miswak against common oral pathogens. AB - BACKGROUND AND OBJECTIVE: Miswak is a natural tooth cleaning tool which is being used in many parts of the world since ancient times. It is known to be useful in prevention of dental caries. But still it is not used as frequently as other oral hygiene tools. This research was designed to scientifically establish antimicrobial effect of miswak in vitro against common oral pathogens. METHODS: This was a cross-sectional study involving 100 health care workers. This research was carried out in Microbiology section of Dow Diagnostic Research & Reference Laboratory. A questionnaire was designed to test oral hygiene habits of study subjects. Oral swabs were taken and microorganisms were identified by standard bacteriological methods. Test material included four different types of miswaks i.e. (1) root of the peelu (Salvadora persica) tree (in packing) (2) root of the peelu tree (without packing) (3) stem of the peelu tree & (4) stem of the neem (Azadirechta indica) tree. These miswaks were tested against three different types of microorganisms isolated from oral swabs: Staphylococcus aureus, Streptococcus mutans & Candida albicans by agar diffusion method. Inhibition zone was measured after 24 hrs of incubation at 37(o)C. RESULTS: Among the miswaks used, root of the peelu tree in both packing and without packing exhibited strong antimicrobial effect against all three tested microorganisms. However miswak taken from the stem of the peelu and neem tree did not show any antimicrobial activity against all three types of the tested microorganisms. CONCLUSION: Miswak taken from the root of the peelu tree exhibited antimicrobial activity against all the common oral pathogens and could be a good oral hygiene tool in combating dental caries. PMID- 24772152 TI - High fluoride and low pH level have been detected in popular flavoured beverages in Malaysia. AB - OBJECTIVE: In children, excessive ingestion of fluoride from different sources including bottled drinking water and flavoured beverages or soft drinks can lead to the development of dental fluorosis. In addition, the pH level of beverages is important. Low pH can cause dental erosion. In this study we explore the fluoride content and pH level of certain popular beverages available in Malaysian supermarkets and hawkers' stalls. METHODS: Bottled drinking water and selected popular flavoured packet drinks were purchased from a supermarket and the corresponding flavoured hawkers' drinks, from a hawker's stall in Kuala Lumpur. Fluoride and pH of the beverages were determined using digital fluoride meter and digital pH meter respectively. RESULTS: It was found that fluoride content and pH level vary among the beverages. The mean fluoride content in both packet and hawkers' drinks (7.64+/-1.88 mg/L, 7.51+/-1.60 mg/L, respectively) was approximately 7 times higher than the bottled drinking water (1.05+/-0.35 mg/L). Among the beverages, the tea packet drink was found to contain the highest amount of fluoride (13.02+/-0.23 mg/L). The mean pH of bottled-drinking water was near neutral (6.96+/-0.17), but acidic for both supermarket (4.78.00+/-0.49) and hawkers' drinks (5.73+/-0.24). The lychee packet drink had the lowest pH level (2.97+/-0.03). CONCLUSIONS: Due to the wide variation of the fluoride content and pH level of the drinks tested in this study, it is recommended that steps should be taken to control the fluoride concentration and pH level in beverages if dental fluorosis and erosion are to be prevented. PMID- 24772153 TI - The applicability of the Greulich & Pyle Atlas for bone age assessment in primary school-going children of Karachi, Pakistan. AB - OBJECTIVE: To assess the degree of applicability of bone age calculated by Greulich & Pyle Atlas in estimation of chronological age for therapeutic and medico legal purposes. METHODS: Two Hundred and Twenty children (139 males, 81 females) between ages of 56 and 113 months (4.5 to 9.5 years) were randomly selected from 4 primary schools of Shireen Jinnah & Clifton, Karachi. Digital images of hand and wrist radiographs were obtained by a computed radiography at Ziauddin Hospital Clifton. Bone ages were computed using Greulich & Pyle Atlas by radiologists at Ziauddin Hospital, North Nazimabad, Karachi. RESULTS: On average, the Greulich & Pyle Atlas underestimates chronological age by 6.65 +/- 13.47 months in females and 15.78 +/- 12.83 months in males (p-values < 0.001). High correlation was found between chronological age and bone age in both genders (Females r=0.778; p-value< 0.001, Males r=0.816; p-value < 0.001). CONCLUSION: Bone age calculated by Greulich & Pyle Atlas should not be used for estimating chronological age in children of ages 56-113 months in situations where high accuracy is required (e.g. medicolegal cases). However, serial measurements of bone age by this atlas can be used in management of growth related endocrine disorders in these children. PMID- 24772154 TI - Diagnostic efficacy of sonography for diagnosis of ovarian torsion. AB - OBJECTIVES: Misdiagnosing ovarian torsion is now suggested as an important issue in clinical setting. The aim of this study was to determine the diagnostic accuracy of sonography for ovarian torsion. Methods : In this study 323 women with acute pelvic pain with highly suspected ovarian torsion signs and symptoms attending Imam Reza Medical Center in Kermanshah between 2011 through 2012 were included and underwent a transabdominal sonography (2-5 MHz probes). Then findings of sonography were compared with laparatomy. Results : The ultrasound correctly diagnosed 72.1% of ovarian torsion and missed 27.9% of them (false negatives). However, one free subject (0.4%) was misclassified as ovarian torsion (false positive). There was a strong correlation between sonography and laparatomy with a kappa value of 84.0%. The sensitivity and specificity of sonography were 72.1% and 99.6%, respectively. Sonography had a positive predictive value of 96.9%, a negative predictive value of 95.9%, and a total accuracy of 96.0% for detection of ovarian torsion. CONCLUSION: Sonography appears to be an excellent method to evaluate patients with suspected ovarian torsion. Abnormal blood flow detected by sonography is highly predictive of ovarian torsion and is therefore useful in the diagnosis of this phenomenon. PMID- 24772155 TI - The effect of low and moderate intensity aerobic exercises on sleep quality in men older adults. AB - OBJECTIVE: Sleep is an active and complex rhythmic state that may be affected by the aging process. The purpose of present research was to investigate the effect of low and moderate intensity aerobic exercises on sleep quality in older adults. METHODS: The research method is quasi-experimental with pre-test and post-test design. The statistical sample included 45 volunteer elderly men with age range of 60-70 years-old that divided randomly in two experimental groups (aerobic exercise with low and moderate intensity) and one control group. In each group selected 15 older adults based on inclusion and exclusion criteria (such as, without sleep apnea, not smoking, and no taking hypnotic drugs). First, all subjects were evaluated by a doctor to confirm their physical and mental health. Also, the maximum heart rate (MaxHR) of subjects was obtained by subtracting one's age from 220. Furthermore, based on aerobic exercise type (40-50% MaxHR for low intensity group and 60-70% MaxHR for moderate intensity group) the target MaxHR was calculated for each subject. The exercise protocol consisted of 8 weeks aerobic exercises (2 sessions in per-week) based on Rockport one-mile walking/running test and the control group continued their daily activities. All subjects in per-test and post-test stages completed the Petersburg Sleep Quality Index (PSQI). RESULTS: In pre-test stage, results showed that there were no significant differences between control and experimental groups in sleep quality and its components (P>0.05). On the other hand, results in post-test stage showed that there were significant differences between control and experimental groups in these variables (P<0.05). Also, the Tukey Post Hoc showed that the moderate intensity group scores in total sleep quality and its components were better than other groups (P<0.05). Finally, the low intensity group scores in total sleep quality and its components were better than control group (P<0.05). CONCLUSION: Generally, the present research showed that the aerobic exercises with moderate intensity (60-70% MaxHR) have a positive and significant effect on sleep quality and its components. Thus, based on these findings, the aerobic exercises with moderate intensity is a useful to improve the sleep quality and its components among community older adults were recommended. PMID- 24772156 TI - Women Health in Saudi Arabia: A review of non-communicable diseases and their risk factors. AB - This is a review of the changing pattern of chronic diseases among women in the Kingdom of Saudi Arabia (KSA). Data from national surveys conducted in KSA, whose results were published between 1996 and 2011 were used. The results showed that over a period of ten years the prevalence of obesity increased in Saudi women from 23.6% to 44.0% and in men from 14.2% to 26.2%; self-reported physical inactivity worsened in both women (from 84.7% to 98.1%) and men (from 43.3% to 93.9%); prevalence of smoking in women increased (from 0.9% to 7.6%), while it declined in men (from 21.0% to 18.7%). The prevalence of metabolic syndrome was significantly greater in women than men (42.0% versus 37.2%; p <0.01). In conclusion, Saudi women are potentially at a greater risk than a decade ago to develop cardiovascular diseases and diabetes mellitus, with a notable increase in obesity compared to men. PMID- 24772157 TI - Frequent loss expression of dab2 and promotor hypermethylation in human cancers: a meta-analysis and systematic review. AB - Objective : Disabled-2 (Dab2) is an important endocytic adaptor which plays an inhibition role in cancer cell growth. The objective of this study was to systematically review expressions of Dab2 in human cancers. Methods : Eligible studies about Dab2 in human cancers were retrieved from databases of PubMed, Embase, Web of Science. Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated using Review Manager 5.0 software and statistical analyses were performed by the SPSS 13.0 software. Results : Fourteen case-control studies with a total of 689 human tumor tissues, 332 control tissues and 32 cancer cell lines were included in the meta-analysis study. The results indicated loss expressions of Dab2 were observed in 74.9% and 46.9% in human malignant cancer tissues and cancer cell lines, respectively. The ratio of Dab2 promotor hypermethylation is 34.54% in cancer tissues which Dab2 expression are lost, but none in the control tissues or cells by Methylation-specific PCR (MSP). Conclusions : The expressions of Dab2 are frequently lost in human malignant cancer tissues, and promotor hypermethylation of Dab2 are common in human malignant cancer tissues, which is an important factor for the loss expression of Dab2 in human cancers tissues. PMID- 24772158 TI - Actigraphy in post traumatic stress disorder. AB - Patients with posttraumatic stress disorder (PTSD) frequently complain of sleep disturbances such as insomnia and nightmares. Evaluation of sleep disturbances is often difficult due to the subjective nature of the complaints. Polysomnography (PSG) and other sleep studies are generally not indicated in the evaluation of insomnia or nightmares associated with PTSD. Actigraphy, (electronic activity monitoring) has been used in research to evaluate sleep disturbances in patients with PTSD. We reviewed the literature on the use of actigraphy in evaluation of sleep problems in patients with PTSD. METHODS: A literature search for articles on the topic was conducted on PubMed using the search algorithm (actigraphy[Title/Abstract] OR actigraphic[Title/Abstract]) AND PTSD[Title/Abstract]. Out of 11 search results, 9 studies in which application of actigraphy had relevance to the primary objective and outcome in PTSD patients with sleep problems were selected for review. We also handpicked one additional article from personal communication with our colleagues who have done some of these studies. CONCLUSION: Actigraphy has been used to evaluate circadian rhythm sleep disorders. Use of actigraphy in psychiatry clinics is uncommon. There is no data to support that there are specific actigraphic sleep related findings in PTSD patients. However, it can be a useful tool to complement the use of sleep diaries when assessing sleep and wake patterns in patients with PTSD. PMID- 24772159 TI - Severe anemia and melena caused by pyeloduodenal fistula due to renal stone associated squamous cell carcinoma. AB - Pyeloduodenal fistula is a rare condition and its association with malignancy is even rarer. Herein we report the case of a 66-year-old man who was admitted to the hospital with a three-month history of intermittent melena and a more than 20 year history of right-side renal stones. Computed tomography showed a heterogeneous right renal mass with a staghorn stone that had invaded the duodenum and caused an internal fistula. An upper gastrointestinal series showed pyeloduodenal fistula. The patient underwent an exploratory operation and a biopsy was taken at the peripelvic region. Pathological examination verified the existence of squamous cell carcinoma. To our knowledge, this is the first case of pyeloduodenal fistula associated with renal stones, squamous cell carcinoma and upper urinary tract calculus presenting on melena. We report on the features of this rare entity but also review and summarize the etiology, diagnosis and treatment options that can be extrapolated from the existing literature. PMID- 24772160 TI - Lupus catatonia in a young girl who presented with fever and altered sensorium. AB - We report a case of 20 Years old girl who presented with catatonia resulting from cerebral lupus. There are few cases of catatonia being described in Systemic Lupus Erythmatoses (SLE). The patient presented to us with fever and altered sensorium. She was initially treated on lines of Acute Bacterial Meningitis/encephalitis but lumbar puncture examination and CT scan showed no evidence of these conditions. Patient's behavior was also not improved after this treatment and she further deteriorated in the sense that she exhibited mutism, negativism and psychosocial withdrawal. Psychiatric analysis was done and she was found to be having catatonia and on further investigation came out to be a case of SLE. Keeping in mind her previous history of joint pains, oral ulcers and alopecia her autoimmune profile such as ANA and dsDNA was done that came out to be positive. Patient responded to treatment with steroids, Hyroxychloroquine and azathioprine in addition to clonazepam and fluoxetine for her catatonic behavior. Thus this case history illustrates the importance of considering organic disease in patients presenting with catatonia. PMID- 24772161 TI - Systemic lupus erythematosis with severe aplastic anemia successfully treated with rituximab and antithymocyte globulin. AB - Hematologic disorders are very common in Systmic lupus erythematosus (SLE).First presentation of SLE with severe aplastic anemia (SAA) is extremely rare. We report a patient with the diagnosis of secondary SAA associated with SLE. Conventional therapy was not effective. She received Rituximab (RTX) and Antithymocyte globulin (ATG) therapy, her response was satisfactory finally. Her hematologic parameters were within normal ranges until last follow-up, eight months and six months after therapy was initiated with RTX and ATG, respectively. This is the first time RTX and ATG were successfully used in the treatment of SAA secondary to SLE. PMID- 24772162 TI - Diagnostic dilemma in Broad Ligament Leiomyoma with Cystic Degeneration. AB - Fibroids are smooth muscle benign tumors; most commonly arise from uterus but may also rise from extra uterine sites like broad ligament. This case report of broad ligament myoma with extensive cystic degeneration is presented for its rarity and diagnostic challenges as they mimic pelvic adenexal tumors. Mrs. X, 43 years old p5+2, asymptomatic women with no co-morbids presented with mass in abdomen. The MRI showed mix attenuation mass of 19.7 x 16.8 x 13.7cms arising from right side of uterus extending up to epigastrium, with cystic and solid components and ascitic fluid. Resection of mass with abdominal hysterectomy with bilateral salphingo oophrectomy was done. No local or abdominal organ metastases were seen. Histopathology showed left broad ligament leiomyoma weighing 4000 grams with cystic degeneration. CONCLUSION: Huge broad ligament leiomyoma with cystic degeneration and abdominal ascites may cause diagnostic dilemma with ovarian malignancy. This differential diagnosis must be considered before surgery. PMID- 24772163 TI - A case report of an unusual complication from bee sting: acute brachial plexopathy. AB - Brachial plexopathy is usually related to trauma like direct injury to the nerve and stretching injuries. Neurological complications following bee sting are uncommon. Here, we describe a rare case of acute brachial plexopathy as a neurological complication following bee sting. A23-year-old maleinitially presented with angioedema and anaphylactic shock one hour after a bee stung at his neck. Twenty four hours after the incidence, he presented with sudden onset of left upper limb weakness. Nerve conduction study and electromyography had shown evidence of left brachial plexopathy. PMID- 24772164 TI - Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPAR gamma Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease. AB - Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP) of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD) are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPAR gamma ligand-dependent dysregulation as a key molecular initiating event (MIE) for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPAR gamma . Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPAR gamma -dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPAR gamma -mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPAR gamma ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPAR gamma activation in hepatocytes and (ii) PPAR gamma inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details. PMID- 24772165 TI - Dermatology residency selection criteria with an emphasis on program characteristics: a national program director survey. AB - Background. Dermatology residency programs are relatively diverse in their resident selection process. The authors investigated the importance of 25 dermatology residency selection criteria focusing on differences in program directors' (PDs') perception based on specific program demographics. Methods. This cross-sectional nationwide observational survey utilized a 41-item questionnaire that was developed by literature search, brainstorming sessions, and online expert reviews. The data were analyzed utilizing the reliability test, two-step clustering, and K-means methods as well as other methods. The main purpose of this study was to investigate the differences in PDs' perception regarding the importance of the selection criteria based on program demographics. Results. Ninety-five out of 114 PDs (83.3%) responded to the survey. The top five criteria for dermatology residency selection were interview, letters of recommendation, United States Medical Licensing Examination Step I scores, medical school transcripts, and clinical rotations. The following criteria were preferentially ranked based on different program characteristics: "advanced degrees," "interest in academics," "reputation of undergraduate and medical school," "prior unsuccessful attempts to match," and "number of publications." Conclusions. Our survey provides up-to-date factual data on dermatology PDs' perception in this regard. Dermatology residency programs may find the reported data useful in further optimizing their residency selection process. PMID- 24772166 TI - Delayed laparoscopic cholecystectomy is safe and effective for acute severe calculous cholecystitis in patients with advanced cirrhosis: a single center experience. AB - Acute calculous cholecystitis is a common disease in cirrhotic patients. Laparoscopic cholecystectomy can resolve this problem but is performed based on the premise that the local inflammation must been controlled. An Initial ultrasound guided percutaneous transhepatic cholecystostomy may reduce the local inflammation and provide advantages in subsequent surgery. In this paper, we detailed our experience of treating acute severe calculous cholecystitis in patients with advanced cirrhosis by delayed laparoscopic cholecystectomy plus initiated ultrasound guided percutaneous transhepatic cholecystostomy and provided the analysis of the treatment effect. We hope this paper can provided a kind of standard procedure for this special disease; however, further prospective comparative randomized trials are needed to assess this treatment in cirrhotic patients with acute cholecystitis. PMID- 24772167 TI - Helicobacter pylori and Systemic Disease. PMID- 24772168 TI - Common bile duct dilatations in asymptomatic neonates: incidence and prognosis. AB - Background. This retrospective study reviewed 213 asymptomatic neonates with common bile duct (CBD) dilatations diagnosed via ultrasound to evaluate their incidence and outcomes. Materials and Methods. From August 2001 to July 2010, 18,230 abdominal ultrasound scans were performed as newborn screening. There were 213 (1.17%) cases of CBD dilatation. Dilatation of neonatal CBD was defined when its diameter was >=2 mm. The neonates' birth history, CBD size, and follow-up results were analyzed. Results. In the 213 infants, four cystic dilatations (1.88%, 4/213) that were eventually diagnosed as choledochal cysts (CC). Among 209 neonates with fusiform dilatations (size 2.0-6.7 mm), 77 had ultrasound follow-up and 87% of them resolved spontaneously which were diagnosed as transient CBD dilatation (TCBDD). Eighty percent of TCBDDs resolved within 6 months. Patients with initial CBD size >=3 mm had significantly lower resolution rate and neonates whose mothers are older than 35 years took longer time to resolve. Conclusion. The incidence of CBD dilatation in asymptomatic neonates was 1.17%. Eighty percent of TCBDDs resolved within 6 months. Regular ultrasound follow-up every 6 months may be appropriate for asymptomatic neonates with fusiform CBD dilatations to ensure resolution or progression. PMID- 24772170 TI - Comment on "emergence of hepatitis B virus genotype f in aligarh region of north India". PMID- 24772171 TI - Trace analysis in end-exhaled air using direct solvent extraction in gas sampling tubes: tetrachloroethene in workers as an example. AB - Simple and cost-effective analytical methods are required to overcome the barriers preventing the use of exhaled air in routine occupational biological monitoring. Against this background, a new method is proposed that simplifies the automation and calibration of the analytical measurements. End-exhaled air is sampled using valveless gas sampling tubes made of glass. Gaseous analytes are transferred to a liquid phase using a microscale solvent extraction performed directly inside the gas sampling tubes. The liquid extracts are analysed using a gas chromatograph equipped, as usual, with a liquid autosampler, and liquid standards are used for calibration. For demonstration purposes, the method's concept was applied to the determination of tetrachloroethene in end-exhaled air, which is a biomarker for occupational tetrachloroethene exposure. The method's performance was investigated in the concentration range 2 to 20 MU g tetrachloroethene/L, which corresponds to today's exposure levels. The calibration curve was linear, and the intra-assay repeatability and recovery rate were sufficient. Analysis of real samples from dry-cleaning workers occupationally exposed to tetrachloroethene and from nonexposed subjects demonstrated the method's utility. In the case of tetrachloroethene, the method can be deployed quickly, requires no previous experiences in gas analysis, provides sufficient analytical reliability, and addresses typical end-exhaled air concentrations from exposed workers. PMID- 24772169 TI - Senescent remodeling of the innate and adaptive immune system in the elderly men with prostate cancer. AB - Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer. PMID- 24772172 TI - Branchial anomalies: diagnosis and management. AB - Objective. To find out the incidence of involvement of individual arches, anatomical types of lesions, the age and sex incidence, the site and side of predilection, the common clinical features, the common investigations, treatment, and complications of the different anomalies. Setting. Academic Department of Otolaryngology, Head and Neck Surgery. Design. A 10 year retrospective study. Participants. 30 patients with clinically proven branchial anomalies including patients with bilateral disease totaling 34 lesions. Main Outcome Measures. The demographical data, clinical features, type of branchial anomalies, and the management details were recorded and analyzed. Results and Observations. The mean age of presentation was 18.67 years. Male to female sex ratio was 1.27 : 1 with a male preponderance. Of the 34 lesions, maximum incidence was of second arch anomalies (50%) followed by first arch. We had two cases each of third and fourth arch anomalies. Only 1 (3.3%) patients of the 30 presented with lesion at birth. The most common pathological type of lesions was fistula (58.82%) followed by cyst. 41.18% of the lesions occurred on the right side. All the patients underwent surgical excision. None of our patients had involvement of facial nerve in first branchial anomaly. All patients had tracts going superficial to the facial nerve. Conclusion. Confirming the extent of the tract is mandatory before any surgery as these lesions pass in relation to some of the most vital structures of the neck. Surgery should always be the treatment option. injection of dye, microscopic removal and inclusion of surrounding tissue while excising the tract leads to a decreased incidence of recurrence. PMID- 24772173 TI - Bilateral renal tumour as indicator for birt-hogg-dube syndrome. AB - Birt-Hogg-Dube (BHD) syndrome is a cancer disorder caused by a pathogenic FLCN mutation characterized by fibrofolliculomas, lung cysts, pneumothorax, benign renal cyst, and renal cell carcinoma (RCC). In this case we describe a patient with bilateral renal tumour and a positive familial history for pneumothorax and renal cancer. Based on this clinical presentation, the patient was suspected for BHD syndrome, which was confirmed after molecular testing. We discuss the importance of recognizing this autosomal dominant cancer disorder when a patient is presented at the urologist with a positive family history of chromophobe renal cell cancer or a positive familial history for renal cell cancer and pneumothorax. PMID- 24772174 TI - Fingertips ischemia, nephroangiosclerosis, and focal segmental glomerulosclerosis: is genetic thrombophilia the unique explanation? AB - Case Presentation. 53-years-old-man with essential hypertension and nonnephrotic proteinuria (1.3 gr/24 h) and with normal renal function (eGFR-MDRD 123 mL/min/1.73 m(2)) was admitted to nephrology department; kidney biopsy showed FSGS; two years later the patient presented with ulceration and ischemic gangrene of the IV and V right-hand fingertips; genetic analysis demonstrated polymorphism of the methylenetetrahydrofolate reductase genes C677T (heterozygote C677T/1298AC with normal value of homocysteine) and mutations of prothrombin gene G20210A and of plasminogen activator inhibitor-1 4G/5G 675 with slight increase of its value. After five years from biopsy, 24-hours proteinuria was still around 1-1.3 g/die; renal function was still normal (eGFR 107 ml/min/1.73 m(2)). These data are against the previous diagnosis of primary FSGS. We hypothesize that genetic thrombophilia may explain all the clinical signs of our patient. Conclusions. Alterations in genes of thrombophilia should be ruled out in patients with bioptic diagnosis of "primary" FSGS, in particular if clinically atypical. PMID- 24772175 TI - Viral Aetiology of Acute Flaccid Paralysis Surveillance Cases, before and after Vaccine Policy Change from Oral Polio Vaccine to Inactivated Polio Vaccine. AB - Since 1992, surveillance for acute flaccid paralysis (AFP) cases was introduced in Malaysia along with the establishment of the National Poliovirus Laboratory at the Institute for Medical Research. In 2008, the Ministry of Health, Malaysia, approved a vaccine policy change from oral polio vaccine to inactivated polio vaccine (IPV). Eight states started using IPV in the Expanded Immunization Programme, followed by the remaining states in January 2010. The objective of this study was to determine the viral aetiology of AFP cases below 15 years of age, before and after vaccine policy change from oral polio vaccine to inactivated polio vaccine. One hundred and seventy-nine enteroviruses were isolated from the 3394 stool specimens investigated between 1992 and December 2012. Fifty-six out of 107 virus isolates were polioviruses and the remaining were non-polio enteroviruses. Since 2009 after the sequential introduction of IPV in the childhood immunization programme, no Sabin polioviruses were isolated from AFP cases. In 2012, the laboratory AFP surveillance was supplemented with environmental surveillance with sewage sampling. Thirteen Sabin polioviruses were also isolated from sewage in the same year, but no vaccine-derived poliovirus was detected during this period. PMID- 24772176 TI - The prophylactic use of C1 inhibitor in hereditary angioedema patients undergoing invasive surgical procedures: a retrospective study. AB - BACKGROUND: Hereditary Angioedema (HAE) is a rare autosomal dominant condition characterized by episodic angioedema, which may be triggered by invasive procedures and surgery. C1 inhibitor (C1 INH) was approved in the United States and Canada in 2009 and 2010, respectively, for the treatment of acute attacks. Most recently in April 2013, it was approved in Europe for short-term prophylaxis (STP), prior to medical, dental, or surgical procedures, to prevent HAE attacks in both children and adults. Currently, C1 INH is not approved in Canada or the United States for STP of HAE attacks. Our objective was to demonstrate the effectiveness of C1 INH as a short-term prophylactic treatment for patients with Type I HAE undergoing invasive surgical procedures. METHODS: A retrospective chart review between 1997-2013 was performed at one Canadian Tertiary Care Allergy and Asthma Clinic affiliated with The Ottawa Hospital, in Ottawa, Canada. The standard dose of C1 INH for STP was 10 or 20 U/kg. RESULTS: In all 24 procedures, there were no post-procedure HAE attacks after short-term prophylactic administration of C1 INH. CONCLUSIONS: In this retrospective chart review at one tertiary care Allergy and Clinical Immunology Clinic, short-term prophylactic use of C1 INH was found to be effective at preventing post-procedure HAE attacks, in patients diagnosed with Type I HAE. PMID- 24772177 TI - Antioxidant Capacity and Proanthocyanidin Composition of the Bark of Metasequoia glyptostroboides. AB - Metasequoia glyptostroboides Hu et Cheng is the only living species in the genus Metasequoia Miki ex Hu et Cheng (Taxodiaceae), which is well known as a "living fossil" species. In the Chinese folk medicine, the leaves and bark of M. glyptostroboides are used as antimicrobic, analgesic, and anti-inflammatory drug for dermatic diseases. This study is the first to report the free radical scavenging capacity, antioxidant activity, and proanthocyanidin composition of the bark of M. glyptostroboides. We observed total of six extracts and fractions, which were easily obtained by water-ethanol extraction and followed by a further separation with D101 resin column chromatography, had significant DPPH radical, superoxide anion radical, and hydroxyl radical scavenging capacity, total antioxidative capacity (T-AOC), lipid peroxidation inhibitory activity, and metal ions chelating capacity. The fraction MGEB, which was obtained by 60% ethanol extraction and followed by a further separation with D101 resin column chromatograph, possessed the highest proanthocyanidin content and the highest free radical scavenging and antioxidant activities. Furthermore, MGEB could significantly protect against CCl4 induced acute liver injury through inhibition of oxidative stress in mice. In addition, ten proanthocyanidins were isolated from MGEB, and six of them were firstly reported from this plant. PMID- 24772178 TI - Protective effect of danhong injection on acute hepatic failure induced by lipopolysaccharide and d-galactosamine in mice. AB - Acute hepatic failure (AHF), which leads to an extremely high mortality rate, has become the focus of attention in clinic. In this study, Danhong injection (DHI) was investigated to evaluate the preventive and protective effect on AHF induced by lipopolysaccharide (LPS) and D-galactosamine (GalN) in mice. For AHF induction, ICR mice were intraperitoneally injected with D-GalN (700 mg/kg) and LPS (20 MU g/kg). DHI was administrated twice, at 12 and 1 h, respectively, before D-GalN/LPS injection. After stimulation with D-GalN/LPS for 1 and 6 h, serum and livers were collected for analysis. We found that mice administrated with DHI displayed a higher survival rate, lower serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), glutathione S-transferase (GST), and tumor necrosis factor (TNF)- alpha . DHI inhibited the elevations of hepatic lipid peroxidation (malondialdehyde), caspase 8 activity, and mRNA expression levels of inflammatory cytokines (interleukin-1 beta and interleukin-6) increased by D-GalN/LPS in the liver. Furthermore, liver histopathological analysis indicated that the DHI group showed markedly fewer apoptotic (TUNEL positive) cells and less pathological changes than those in the AHF model group. These results provide a novel insight into the pharmacological actions of DHI as a potential candidate for treating AHF. PMID- 24772180 TI - New Perspectives on Specific Immune-Depletion Technique Using Monoclonal Antibodies against Small Active Molecules in Herbs. AB - One of the main focuses in Chinese Medicine research is the identification of efficacious components in Chinese herbal medicine (CHM). Studies in such area are difficult due to the complexity and the synergistic characteristics of CHM. Current methods to track and separate active components are not adequate to meet the needs of revealing effects and identify substances and pharmacological mechanisms, which directly restrict the modernization and globalization of CHM. In this paper, a new methodology to deplete a single active component via immunoassay was introduced. The specific active component in a CHM mixture can then be identified and studied through comparative analyses of the pharmacological effects before and after immune depletion. With this new methodology, degree of contribution of a particular component to the whole complex herbal mixture can be elucidated, and its synergistic property with other components can be determined. The new method can reflect not only the overall combined pharmacological effects of CHM but also the effect of individual component. It is an effective way to explain the degree of contribution of one specific component to the overall activity of a CHM prescription. PMID- 24772179 TI - Polyphenols as key players for the antileukaemic effects of propolis. AB - Propolis (a bee product) which has a long history of medicinal use by humans has attracted a great deal of research interest in the recent time; this is due to its widely reported biological activities such as antiviral, antifungal, antibacterial, anti-inflammatory, antioxidant, and anticarcinogenic properties. Crude form of propolis and its phenolic contents have both been reported to exhibit antileukaemic effects in various leukaemia cell lines. The ability of the polyphenols found in propolis to arrest cell cycle and induce apoptosis and differentiation in addition to inhibition of cell growth and proliferation makes them promising antileukaemic agents, and hence, they are believed to be a key to the antileukaemic effects of propolis in different types of leukaemia. This paper reviews the molecular bases of antileukaemic activity of both crude propolis and individual polyphenols on various leukaemia cell lines, and it indicates that propolis has the potential to be used in both treatment and prevention of leukaemia. This however needs further evaluation by in vitro, in vivo, and epidemiological studies as well as clinical trials. PMID- 24772181 TI - Electroacupuncture reduces hyperalgesia after injections of acidic saline in rats. AB - Background. Injections of acidic saline into the gastrocnemius muscle in rats produce a bilateral long-lasting hyperalgesia similar to fibromyalgia in humans. No previous study investigated the effect of electroacupuncture (EA) on this acidic saline model. This study aimed to identify the effects of EA in the hyperalgesia produced by repeated intramuscular injections of acidic saline. Methods. Rats were divided into four groups (n = 6, each group): control, acupuncture, EA 15 Hz, and 100 Hz. Left gastrocnemius muscle was injected with 100 MU L of pH 4.0 sterile saline twice five days apart. EA, acupuncture, or control therapy was daily administered (20 min) for 5 consecutive days under anesthesia. Needles were placed in the St36 and Sp6 acupoints. The assessment of secondary mechanical hyperalgesia, thermal hyperalgesia, and motor performance was performed before injections and before and after the treatment performed on each day. The paw withdrawal threshold was tested using the nonparametric Kruskal Wallis test and differences within the group Wilcoxon Matched Pairs. The latency and motor performance were tested for ANOVA parametric test for independent measures, and for differences in the group, we used t-test for paired samples. Post hoc Tukey test was used for multiple corrections. P values less than 0.05 were considered statistically significant. Results. Indicate that there was a significant reduction of mechanical withdrawal threshold and paw withdrawal latency 24 hours following the second injection. Moreover, mechanical and thermal hyperalgesia were significantly reversed by EA 15, 100 Hz, and acupuncture. Conclusions. The results suggest that EA high and low frequency as well as acupuncture are effective in reducing hyperalgesia in chronic muscle pain model. PMID- 24772182 TI - Synergetic antimicrobial effects of mixtures of ethiopian honeys and ginger powder extracts on standard and resistant clinical bacteria isolates. AB - Purpose. To evaluate antimicrobial effects of mixtures of Ethiopian honeys and ginger rhizome powder extracts on Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Staphylococcus aureus (MRSA), Escherichia coli (R), and Klebsiella pneumoniae (R). Methods. Agar diffusion and broth assays were performed to determine susceptibility of these standard and resistant clinical bacteria isolates using honey-ginger powder extract mixtures. Results. Honey ginger powder extract mixtures produced the highest mean inhibition (25.62 mm +/- 2.55) compared to the use of honeys (21.63 mm +/- 3.30) or ginger extracts (19.23 mm +/- 3.42) individually. The ranges of inhibitions produced by honey-ginger extract mixtures on susceptible test organisms (26-30 mm) and resistant strains (range: 19-27 mm) were higher compared to 7-22 mm and 0-14 mm by standard antibiotic discs. Minimum inhibitory concentrations (MIC) of mixture of honeys ginger extracts were 6.25% (0.625 v/mL) on the susceptible bacteria compared to 75% for resistant clinical isolates. Minimum bactericidal concentration (MBC) of honey-ginger extracts was 12.5% (0.125 g/mL) for all the test organisms. Conclusion. The result of this study showed that honey-ginger powder extract mixtures have the potential to serve as cheap source of antibacterial agents especially for the drug resistant bacteria strains. PMID- 24772183 TI - Phytochemistry and Preliminary Assessment of the Antibacterial Activity of Chloroform Extract of Amburana cearensis (Allemao) A.C. Sm. against Klebsiella pneumoniae Carbapenemase-Producing Strains. AB - The chloroform extract of the stem bark of Amburana cearensis was chemically characterized and tested for antibacterial activity.The extract was analyzed by gas chromatography and mass spectrometry. The main compounds identified were 4 methoxy-3-methylphenol (76.7%), triciclene (3.9%), alpha -pinene (1.0%), beta pinene (2.2%), and 4-hydroxybenzoic acid (3.1%). Preliminary antibacterial tests were carried out against species of distinct morphophysiological characteristics: Escherichia coli, Salmonella enterica Serotype Typhimurium, Pseudomonas aeruginosa, Staphylococcus aureus, Listeria monocytogenes, and Bacillus cereus. The minimum inhibitory concentration (MIC) was determinate in 96-well microplates for the chloroform extract and an analogue of themain compound identified, which was purchased commercially.We have shown that plant's extract was only inhibitory (but not bactericidal) at the maximum concentration of 6900 MU g/mL against Pseudomonas aeruginosa and Bacillus cereus. Conversely, the analogue 2-methoxy-4 methylphenol produced MICs ranging from215 to 431 MU g/mL against all bacterial species.New antibacterial assays conducted with such chemical compound against Klebsiella pneumoniae carbapenemase-producing strains have shown similarMICresults and minimumbactericidal concentration (MBC) of 431 MU g/mL.We conclude that A. cearensis is a good source of methoxy-methylphenol compounds,which could be screened for antibacterial activity againstmultiresistant bacteria fromdifferent species. PMID- 24772184 TI - Combination of paeoniae radix and cnidii rhizoma prolonged survival of fully mismatched cardiac allografts and generated regulatory cells in mice. AB - In previous studies, we have demonstrated that Tokishakuyakusan (TJ-23) can prolong the survival of allogeneic cardiac grafts and induce regulatory T cells. In this study we investigated the effects of Paeoniae radix and Cnidii rhizoma, two components of TJ-23, on alloimmune responses in a murine cardiac transplantation model and whether the two agents have synergistic effect. CBA mice underwent transplantation of a C57BL/6 heart and received oral administration of 2 g/kg/day of Paeoniae radix, Cnidii rhizoma, or the mixture of two agents from the day of transplantation until 7 days afterward. Naive CBA mice rejected C57BL/6 cardiac graft acutely (median survival time (MST): 7 days). Paeoniae radix and Cnidii rhizoma prolonged C57BL/6 allograft survival (MSTs: 13.5 and 15.5 days, resp.). However, the mixture of two agents prolonged C57BL/6 allograft survival indefinitely (MST > 100 days). Secondary CBA recipients given whole splenocytes from primary combination-treated CBA recipients with B6 cardiac allografts 30 days after grafting had prolonged survival of B6 hearts (MST: 33 days). Flow cytometry studies showed that the CD4(+)CD25(+)Foxp3(+) regulatory cell population was increased in combination-treated recipients. Combination of Paeoniae radix and Cnidii rhizoma induced hyporesponsiveness to fully allogeneic cardiac allografts and may generate CD4(+)CD25(+)Foxp3(+) regulatory cells in our model. PMID- 24772185 TI - Ficus deltoidea Jack: A Review on Its Phytochemical and Pharmacological Importance. AB - Ficus deltoidea Jack (Moraceae) has had a long history of use in traditional medicine among the Malays to alleviate and heal ailments such as sores, wounds, and rheumatism and as an after-birth tonic and an antidiabetic drug. Modern pharmacological studies demonstrated that this plant has a wide variety of beneficial attributes for human health. Despite its importance, a review of this species has not been published in the scientific literature to date. Here, we review and summarize the historic and current literature concerning the botany, traditional uses, phytochemistry, pharmacological effects, and toxicity of this wonder plant. This summary could be beneficial for future research aiming to exploit the therapeutic potential of this useful, medicinal species. PMID- 24772186 TI - Shen Song Yang Xin Capsule Combined with Antiarrhythmic Drugs, a New Integrative Medicine Therapy, for the Treatment of Frequent Premature Ventricular Contractions (FPVC): A Meta-Analysis of Randomized Controlled Trials. AB - Objective. To evaluate the beneficial and adverse effects of Shen Song Yang Xin Capsule (SSYX Capsule) combined with antiarrhythmic drugs for the treatment of frequent premature ventricular contractions (FPVC). Methods. Seven electronic databases were searched to retrieve any potential randomized controlled trials (RCTs) designed to evaluate the clinical efficacy of SSYX Capsule combined with Antiarrhythmic Drugs for FPVC reported in any language, with total effect for FPVC and number of ventricular premature contraction as the main outcome measure. The methodological quality of the included studies was assessed using criteria from the Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0, and analysed using RevMan 5.1.0 software. Results. Sixteen RCTs of SSYX Capsule were included. The methodological quality of the trials was generally evaluated as low. The results of meta-analysis showed that SSYX Capsule combined with antiarrhythmic drugs was more effective in total effect for FPVC and number of ventricular premature contraction compared with Antiarrhythmic Drugs in patients with FPVC or FPVC complicated by other diseases. Ten of the trials reported adverse events, indicating that the safety of SSYX Capsule is still uncertain. Conclusions. There is some but weak evidence about SSYX Capsule combined with antiarrhythmic drugs appearing to be more effective in total effect for FPVC and number of ventricular premature contraction in patients with FPVC and its complications. PMID- 24772187 TI - Alcohol use disorders and antiretroviral therapy among prisoners in Argentina. AB - PURPOSE: While Argentina has significantly improved access to HIV care and antiretroviral therapy (ART) for both the general population and prisoners, the prevalence of alcohol use disorders (AUDs) among HIV-infected prisoners and their relationship to accessing ART in Argentina is currently unknown. This study aims to characterize the substance abuse patterns of HIV-infected prisoners in Argentina and to assess the independent correlates of receipt of pre incarceration ART. DESIGN/METHODOLOGY/APPROACH: An anonymous, cross-sectional survey of 100 HIV-infected federal prisoners was conducted in the Buenos Aires municipality from July-December 2010. AUDs were assessed using the AUDIT scale. FINDINGS: A majority (63 per cent) of participants met criteria for AUDs, 45 per cent of subjects were diagnosed with HIV in prison and one-quarter had initiated ART during the current incarceration. In addition, over one-third (35 per cent) of participants did not receive ART during the pre-incarceration period despite receiving it upon incarceration. This correlated significantly with the presence of having an AUD (AOR 0.20, 95 per cent CI 0.06-0.74, p = 0.016). PRACTICAL IMPLICATIONS: AUDs are prevalent among HIV-infected prisoners in Argentina and are significantly related to negative secondary HIV prevention and treatment outcomes. While Argentina has provided an exemplary model of HIV-related health care reform within its prisons, future efforts to provide screening and treatment for AUDs are needed to improve the health of the nation's incarcerated population. ORIGINALITY/VALUE: This paper is the first to describe pre incarceration drug and alcohol use disorders and issues related to access to ART among prisoners in Argentina. PMID- 24772188 TI - Screening for cervical cancer using automated analysis of PAP-smears. AB - Cervical cancer is one of the most deadly and common forms of cancer among women if no action is taken to prevent it, yet it is preventable through a simple screening test, the so-called PAP-smear. This is the most effective cancer prevention measure developed so far. But the visual examination of the smears is time consuming and expensive and there have been numerous attempts at automating the analysis ever since the test was introduced more than 60 years ago. The first commercial systems for automated analysis of the cell samples appeared around the turn of the millennium but they have had limited impact on the screening costs. In this paper we examine the key issues that need to be addressed when an automated analysis system is developed and discuss how these challenges have been met over the years. The lessons learned may be useful in the efforts to create a cost-effective screening system that could make affordable screening for cervical cancer available for all women globally, thus preventing most of the quarter million annual unnecessary deaths still caused by this disease. PMID- 24772189 TI - BioTCM-SE: a semantic search engine for the information retrieval of modern biology and traditional Chinese medicine. AB - Understanding the functional mechanisms of the complex biological system as a whole is drawing more and more attention in global health care management. Traditional Chinese Medicine (TCM), essentially different from Western Medicine (WM), is gaining increasing attention due to its emphasis on individual wellness and natural herbal medicine, which satisfies the goal of integrative medicine. However, with the explosive growth of biomedical data on the Web, biomedical researchers are now confronted with the problem of large-scale data analysis and data query. Besides that, biomedical data also has a wide coverage which usually comes from multiple heterogeneous data sources and has different taxonomies, making it hard to integrate and query the big biomedical data. Embedded with domain knowledge from different disciplines all regarding human biological systems, the heterogeneous data repositories are implicitly connected by human expert knowledge. Traditional search engines cannot provide accurate and comprehensive search results for the semantically associated knowledge since they only support keywords-based searches. In this paper, we present BioTCM-SE, a semantic search engine for the information retrieval of modern biology and TCM, which provides biologists with a comprehensive and accurate associated knowledge query platform to greatly facilitate the implicit knowledge discovery between WM and TCM. PMID- 24772190 TI - Activation of a water molecule using a mononuclear Mn complex: from Mn-aquo, to Mn-hydroxo, to Mn-oxyl via charge compensation. AB - Activation of a water molecule by the electrochemical oxidation of a Mn-aquo complex accompanied by the loss of protons is reported. The sequential (2 * 1 electron/1 proton) and direct (2 electron/2 proton) proton-coupled electrochemical oxidation of a non-porphyrinic six-coordinated Mn(II)OH2 complex into a mononuclear Mn(O) complex is described. The intermediate Mn(III)OH2 and Mn(III)OH complexes are electrochemically prepared and analysed. Complete deprotonation of the coordinated water molecule in the Mn(O) complex is confirmed by electrochemical data while the analysis of EXAFS data reveals a gradual shortening of an Mn-O bond upon oxidation from Mn(II)OH2 to Mn(III)OH and Mn(O). Reactivity experiments, DFT calculations and XANES pre-edge features provide strong evidence that the bonding in Mn(O) is best characterized by a Mn(III)-oxyl description. Such oxyl species could play a crucial role in natural and artificial water splitting reactions. We provide here a synthetic example for such species, obtained by electrochemical activation of a water ligand. PMID- 24772192 TI - ANALYSIS OF DENDRITIC CELL STIMULATION UTILIZING A MULTI-FACETED NANOPOLYMER DELIVERY SYSTEM AND THE IMMUNE MODULATOR 1-METHYL TRYPTOPHAN. AB - Dendritic cells (DCs) play a pivotal role in immune modulation. Therefore, understanding and regulating the mechanism of DC activation is paramount for functional optimization of any immunotherapy strategy. In particular, the paradoxical ability of DCs to secrete the immune suppressive enzyme indoleamine 2, 3-dioxygenase (IDO) and the suppressive cytokine IL-10 during the course of, and in response to, stimulation is of great interest. 1-Methyl-Tryptophan (1 MT) is a known inhibitor of IDO and has thus been administered in numerous in vitro and in vivo systems to block IDO activity. However, the effect 1 MT has on DCs beyond inhibiting IDO, especially in therapeutic models, has rarely been analyzed. In the current study, we have administered 1 MT via a nanopolymer-based delivery system in conjunction with an antigen (ovalbumin, OVA) and an adjuvant (CpG motif DNA) to determine both the effects of 1 MT on DCs and the resulting efficacy of the polymer-based treatments. 1 MT delivery alone, either via the polymer-based delivery vehicle or dissolved in solution, induced no significant change in DC activation as measured by surface expression of CD80, CD86, and MHCII and several secreted products such as IL-12. These same factors were upregulated however, when 1 MT was delivered in conjunction with OVA and CpG. Although soluble delivery of these components increased the levels of expression and secretion of key proteins, a differential effect of DC stimulation was seen as a result of the polymer delivery system. The T cell suppressive IL-10 secretion was lower with the polymer-based treatments and IL-12 immune-enhancing secretion was increased when 1 MT was supplemented into the polymer system. As a result, including 1 MT in the polymers along with OVA and CpG was seen to have additional effects on DC stimulation and was able to shift DCs to a state more indicative of inducing a Th1-type response. PMID- 24772193 TI - A Simplified Approach for Simultaneous Measurements of Wavefront Velocity and Curvature in the Heart Using Activation Times. AB - The velocity and curvature of a wave front are important factors governing the propagation of electrical activity through cardiac tissue, particularly during heart arrhythmias of clinical importance such as fibrillation. Presently, no simple computational model exists to determine these values simultaneously. The proposed model uses the arrival times at four or five sites to determine the wave front speed (v), direction (theta), and radius of curvature (ROC) (r0). If the arrival times are measured, then v, theta, and r0 can be found from differences in arrival times and the distance between these sites. During isotropic conduction, we found good correlation between measured values of the ROC r0 and the distance from the unipolar stimulus (r = 0.9043 and p < 0.0001). The conduction velocity (m/s) was correlated (r = 0.998, p < 0.0001) using our method (mean = 0.2403, SD = 0.0533) and an empirical method (mean = 0.2352, SD = 0.0560). The model was applied to a condition of anisotropy and a complex case of reentry with a high voltage extra stimulus. Again, results show good correlation between our simplified approach and established methods for multiple wavefront morphologies. In conclusion, insignificant measurement errors were observed between this simplified approach and an approach that was more computationally demanding. Accuracy was maintained when the requirement that epsilon (epsilon = b/r0, ratio of recording site spacing over wave fronts ROC) was between 0.001 and 0.5. The present simplified model can be applied to a variety of clinical conditions to predict behavior of planar, elliptical, and reentrant wave fronts. It may be used to study the genesis and propagation of rotors in human arrhythmias and could lead to rotor mapping using low density endocardial recording electrodes. PMID- 24772194 TI - A Novel Approach to Simulate a Charge Transfer in DNA Repair by an Anacystis nidulans Photolyase. AB - An Anacystis nidulans photolyase enzyme containing two chromophore cofactors was simulated for a photoreaction DNA repairing process via molecular dynamics (MD) method. A novel approach has been introduced for the electron transfer between the FAD (flavin adenine dinucleotide; flavin) molecule and CPD (cyclobutane pyrimidine dimer). This approach involves four simulation stages with different charges for the FAD and CPD fragments and a role of a charged state of the active cofactor was qualified during the MD modeling. Observations show that flavin has actively participated in a charge transfer process, thereby involving the conformational changes of the DNA and CPD substrate fragment. The DNA conformation behavior has shown to correlate with the electron transfer from flavin to CPD. This is manifested on the similarities of the DNA repairing process by excision repair of the UV photoproducts. PMID- 24772195 TI - A combination method for electrocardiogram rejection from surface electromyogram. AB - The electrocardiogram signal which represents the electrical activity of the heart provides interference in the recording of the electromyogram signal, when the electromyogram signal is recorded from muscles close to the heart. Therefore, due to impurities, electromyogram signals recorded from this area cannot be used. In this paper, a new method was developed using a combination of artificial neural network and wavelet transform approaches, to eliminate the electrocardiogram artifact from electromyogram signals and improve results. For this purpose, contaminated signal is initially cleaned using the neural network. With this process, a large amount of noise can be removed. However, low-frequency noise components remain in the signal that can be removed using wavelet. Finally, the result of the proposed method is compared with other methods that were used in different papers to remove electrocardiogram from electromyogram. In this paper in order to compare methods, qualitative and quantitative criteria such as signal to noise ratio, relative error, power spectrum density and coherence have been investigated for evaluation and comparison. The results of signal to noise ratio and relative error are equal to 15.6015 and 0.0139, respectively. PMID- 24772196 TI - Characterization of Hybrid Bioactive Glass-polyvinyl Alcohol Scaffolds Containing a PTHrP-derived Pentapeptide as Implants for Tissue Engineering Applications. AB - Hybrid foam (BG-PVA) with 50 % Bioactive glass (BG) and 50 % polyvinyl alcohol (PVA) was prepared by sol-gel process to produce scaffolds for bone tissue engineering. The pore structure of hydrated foams was evaluated by 3-D confocal microscopy, confirming 70% porosity and interconnected macroporous network. In this study, we assessed the putative advantage of coating with osteostatin pentapeptide into BG-PVA hybrid scaffolds to improve their bioactivity. In vitro cell culture experiments were performed using mouse pre-osteoblastic MC3T3-E1 cell line. The exposure to osteostatin loaded-BG-PVA scaffolds increase cell proliferation in contrast with the unloaded scaffolds. An in vivo study was selected to implant BG-PVA scaffolds, non-coated (Group A) or coated (Group B) with osteostatin into non critical bone defect at rabbit femur. Both groups showed new compact bone formation on implant surface, with lamellae disposed around a haversian canal forming osteons-like structure. We observed signs of inflammation around the implanted unloaded scaffold at one month, but resolved at 3 months. This early inflammation did not occur in Group B; supporting the notion that osteostatin may act as anti-inflammatory inhibitor. On the other hand, Group B showed increased bone formation, as depicted by many new trabeculae partly mineralized in the implant regenerating area, incipient at 1 month and more evident at 3 months after implantation. PVA/BG hybrid scaffolds present a porous structure suitable to support osteoblast proliferation and differentiation. Our in vitro and in vivo findings indicate that osteostatin coating improves the osteogenic features of these scaffolds. PMID- 24772197 TI - HISTORICAL CONTAMINATION OF GROUNDWATER RESOURCES IN THE NORTH COAST KARST AQUIFERS OF PUERTO RICO. AB - The North Coast Karst Aquifer System of Puerto Rico is the island's most productive aquifer. The characteristics that make it highly productive also make it vulnerable to contamination. This research, which addresses the historical contamination of groundwater resources in the northern karst region was conducted through integration of spatial hydrogeologic and contaminant concentration data in the La Plata-Arecibo area. The study used GIS technologies and focused on phthalates and chlorinated volatile organic compounds (CVOCs) and phthalates due to their ubiquitous presence in the environment as well as their presence in listed and potential superfund sites in Puerto Rico and U.S. and potential for exposure and health impacts. Results show an extensive historical contamination of the groundwater resources in the northern karst aquifers. Long-term contamination indicates the aquifers' large capacity for storing and releasing contaminants and reflects a long-term potential for exposure. The degradation of this important water resource has resulted in a subsequent reduction of the extraction capacity and an increase in the cost of use. PMID- 24772198 TI - A Bayesian Approach for the Cox Proportional Hazards Model with Covariates Subject to Detection Limit. AB - The research on biomarkers has been limited in its effectiveness because biomarker levels can only be measured within the thresholds of assays and laboratory instruments, a challenge referred to as a detection limit (DL) problem. In this paper, we propose a Bayesian approach to the Cox proportional hazards model with explanatory variables subject to lower, upper, or interval DLs. We demonstrate that by formulating the time-to-event outcome using the Poisson density with counting process notation, implementing the proposed approach in the OpenBUGS and JAGS is straightforward. We have conducted extensive simulations to compare the proposed Bayesian approach to the other four commonly used methods and to evaluate its robustness with respect to the distribution assumption of the biomarkers. The proposed Bayesian approach and other methods were applied to an acute lung injury study, in which a panel of cytokine biomarkers was studied for the biomarkers' association with ventilation-free survival. PMID- 24772199 TI - A class of covariate-dependent spatiotemporal covariance functions. AB - In geostatistics, it is common to model spatially distributed phenomena through an underlying stationary and isotropic spatial process. However, these assumptions are often untenable in practice because of the influence of local effects in the correlation structure. Therefore, it has been of prolonged interest in the literature to provide flexible and effective ways to model non stationarity in the spatial effects. Arguably, due to the local nature of the problem, we might envision that the correlation structure would be highly dependent on local characteristics of the domain of study, namely the latitude, longitude and altitude of the observation sites, as well as other locally defined covariate information. In this work, we provide a flexible and computationally feasible way for allowing the correlation structure of the underlying processes to depend on local covariate information. We discuss the properties of the induced covariance functions and discuss methods to assess its dependence on local covariate information by means of a simulation study and the analysis of data observed at ozone-monitoring stations in the Southeast United States. PMID- 24772200 TI - Surface-Enhanced Raman Scattering Study on Graphene-Coated Metallic Nanostructure Substrates. AB - Graphene, which has a linear electronic band structure, is widely considered as a semimetal. In the present study, we combine graphene with conventional metallic surface-enhanced Raman scattering (SERS) substrates to achieve higher sensitivity of SERS detection. We synthesize high-quality, single-layer graphene sheets by chemical vapor deposition (CVD) and transfer them from copper foils to gold nanostructures, i.e., nanoparticle or nanohole arrays. SERS measurements are carried out on methylene blue (MB) molecules. The combined graphene nanostructure substrates show about threefold or ninefold enhancement in the Raman signal of MB, compared with the bare nanohole or nanoparticle substrates, respectively. The difference in the enhancement factors is explained by the different morphologies of graphene on the two substrates with the aid of numerical simulations. Our study indicates that applying graphene to SERS substrates can be an effective way to improve the sensitivity of conventional metallic SERS substrates. PMID- 24772201 TI - The Quantitative Imaging Network: NCI's Historical Perspective and Planned Goals. AB - The purpose of this editorial is to provide a brief history of National Institutes of Health National Cancer Institute (NCI) workshops as related to quantitative imaging within the oncology setting. The editorial will then focus on the recently supported NCI initiatives, including the Quantitative Imaging Network (QIN) initiative and its organizational structure, including planned research goals and deliverables. The publications in this issue of Translational Oncology come from many of the current members of this QIN research network. PMID- 24772202 TI - Radiologically defined ecological dynamics and clinical outcomes in glioblastoma multiforme: preliminary results. AB - MATERIALS AND METHODS: We examined pretreatment magnetic resonance imaging (MRI) examinations from 32 patients with glioblastoma multiforme (GBM) enrolled in The Cancer Genome Atlas (TCGA). Spatial variations in T1 post-gadolinium and either T2-weighted or fluid attenuated inversion recovery sequences from each tumor MRI study were used to characterize each small region of the tumor by its local contrast enhancement and edema/cellularity ("habitat"). The patient cohort was divided into group 1 (survival < 400 days, n = 16) and group 2 (survival > 400 days, n = 16). RESULTS: Histograms of relative values in each sequence demonstrated that the tumor regions were consistently divided into high and low blood contrast enhancement, each of which could be subdivided into regions of high, low, and intermediate cell density/interstitial edema. Group 1 tumors contained greater volumes of habitats with low contrast enhancement but intermediate and high cell density (not fully necrotic) than group 2. Both leave one-out and 10-fold cross-validation schemes demonstrated that individual patients could be correctly assigned to the short or long survival group with 81.25% accuracy. CONCLUSION: We demonstrate that novel image analytic techniques can characterize regional habitat variations in GBMs using combinations of MRI sequences. A preliminary study of 32 patients from the TCGA database found that the distribution of MRI-defined habitats varied significantly among the different survival groups. Radiologically defined ecological tumor analysis may provide valuable prognostic and predictive biomarkers in GBM and other tumors. PMID- 24772203 TI - Analyzing Spatial Heterogeneity in DCE- and DW-MRI Parametric Maps to Optimize Prediction of Pathologic Response to Neoadjuvant Chemotherapy in Breast Cancer. AB - The purpose of this study is to investigate the ability of multivariate analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted MRI (DW-MRI) parametric maps, obtained early in the course of therapy, to predict which patients will achieve pathologic complete response (pCR) at the time of surgery. Thirty-three patients underwent DCE-MRI (to estimate K (trans), v e, k ep, and v p) and DW-MRI [to estimate the apparent diffusion coefficient (ADC)] at baseline (t 1) and after the first cycle of neoadjuvant chemotherapy (t 2). Four analyses were performed and evaluated using receiver-operating characteristic (ROC) analysis to test their ability to predict pCR. First, a region of interest (ROI) level analysis input the mean K (trans), v e, k ep, v p, and ADC into the logistic model. Second, a voxel-based analysis was performed in which a longitudinal registration algorithm aligned serial parameters to a common space for each patient. The voxels with an increase in k ep, K (trans), and v p or a decrease in ADC or v e were then detected and input into the regression model. In the third analysis, both the ROI and voxel level data were included in the regression model. In the fourth analysis, the ROI and voxel level data were combined with selected clinical data in the regression model. The overfitting corrected area under the ROC curve (AUC) with 95% confidence intervals (CIs) was then calculated to evaluate the performance of the four analyses. The combination of k ep, ADC ROI, and voxel level data achieved the best AUC (95% CI) of 0.87 (0.77-0.98). PMID- 24772205 TI - Multisite Image Data Collection and Management Using the RSNA Image Sharing Network. AB - The execution of a multisite trial frequently includes image collection. The Clinical Trials Processor (CTP) makes removal of protected health information highly reliable. It also provides reliable transfer of images to a central review site. Trials using central review of imaging should consider using CTP for handling image data when a multisite trial is being designed. PMID- 24772204 TI - Automated tracking of quantitative assessments of tumor burden in clinical trials. AB - THERE ARE TWO KEY CHALLENGES HINDERING EFFECTIVE USE OF QUANTITATIVE ASSESSMENT OF IMAGING IN CANCER RESPONSE ASSESSMENT: 1) Radiologists usually describe the cancer lesions in imaging studies subjectively and sometimes ambiguously, and 2) it is difficult to repurpose imaging data, because lesion measurements are not recorded in a format that permits machine interpretation and interoperability. We have developed a freely available software platform on the basis of open standards, the electronic Physician Annotation Device (ePAD), to tackle these challenges in two ways. First, ePAD facilitates the radiologist in carrying out cancer lesion measurements as part of routine clinical trial image interpretation workflow. Second, ePAD records all image measurements and annotations in a data format that permits repurposing image data for analyses of alternative imaging biomarkers of treatment response. To determine the impact of ePAD on radiologist efficiency in quantitative assessment of imaging studies, a radiologist evaluated computed tomography (CT) imaging studies from 20 subjects having one baseline and three consecutive follow-up imaging studies with and without ePAD. The radiologist made measurements of target lesions in each imaging study using Response Evaluation Criteria in Solid Tumors 1.1 criteria, initially with the aid of ePAD, and then after a 30-day washout period, the exams were reread without ePAD. The mean total time required to review the images and summarize measurements of target lesions was 15% (P < .039) shorter using ePAD than without using this tool. In addition, it was possible to rapidly reanalyze the images to explore lesion cross-sectional area as an alternative imaging biomarker to linear measure. We conclude that ePAD appears promising to potentially improve reader efficiency for quantitative assessment of CT examinations, and it may enable discovery of future novel image-based biomarkers of cancer treatment response. PMID- 24772206 TI - Quantitative tumor segmentation for evaluation of extent of glioblastoma resection to facilitate multisite clinical trials. AB - Standard-of-care therapy for glioblastomas, the most common and aggressive primary adult brain neoplasm, is maximal safe resection, followed by radiation and chemotherapy. Because maximizing resection may be beneficial for these patients, improving tumor extent of resection (EOR) with methods such as intraoperative 5-aminolevulinic acid fluorescence-guided surgery (FGS) is currently under evaluation. However, it is difficult to reproducibly judge EOR in these studies due to the lack of reliable tumor segmentation methods, especially for postoperative magnetic resonance imaging (MRI) scans. Therefore, a reliable, easily distributable segmentation method is needed to permit valid comparison, especially across multiple sites. We report a segmentation method that combines versatile region-of-interest blob generation with automated clustering methods. We applied this to glioblastoma cases undergoing FGS and matched controls to illustrate the method's reliability and accuracy. Agreement and interrater variability between segmentations were assessed using the concordance correlation coefficient, and spatial accuracy was determined using the Dice similarity index and mean Euclidean distance. Fuzzy C-means clustering with three classes was the best performing method, generating volumes with high agreement with manual contouring and high interrater agreement preoperatively and postoperatively. The proposed segmentation method allows tumor volume measurements of contrast enhanced T 1-weighted images in the unbiased, reproducible fashion necessary for quantifying EOR in multicenter trials. PMID- 24772207 TI - Biases in Multicenter Longitudinal PET Standardized Uptake Value Measurements. AB - This study investigates measurement biases in longitudinal positron-emission tomography/computed tomography (PET/CT) studies that are due to instrumentation variability including human error. Improved estimation of variability between patient scans is of particular importance for assessing response to therapy and multicenter trials. We used National Institute of Standards and Technology traceable calibration methodology for solid germanium-68/gallium-68 ((68)Ge/(68)Ga) sources used as surrogates for fluorine-18 ((18)F) in radionuclide activity calibrators. One cross-calibration kit was constructed for both dose calibrators and PET scanners using the same 9-month half-life batch of (68)Ge/(68)Ga in epoxy. Repeat measurements occurred in a local network of PET imaging sites to assess standardized uptake value (SUV) errors over time for six dose calibrators from two major manufacturers and for six PET/CT scanners from three major manufacturers. Bias in activity measures by dose calibrators ranged from -50% to 9% and was relatively stable over time except at one site that modified settings between measurements. Bias in activity concentration measures by PET scanners ranged from -27% to 13% with a median of 174 days between the six repeat scans (range, 29 to 226 days). Corresponding errors in SUV measurements ranged from -20% to 47%. SUV biases were not stable over time with longitudinal differences for individual scanners ranging from -11% to 59%. Bias in SUV measurements varied over time and between scanner sites. These results suggest that attention should be paid to PET scanner calibration for longitudinal studies and use of dose calibrator and scanner cross-calibration kits could be helpful for quality assurance and control. PMID- 24772208 TI - Phase II Trial of Cetuximab and Conformal Radiotherapy Only in Locally Advanced Pancreatic Cancer with Concurrent Tissue Sampling Feasibility Study. AB - BACKGROUND: Preclinical data have indicated the anti-epidermal growth factor receptor (EGFR) agent cetuximab (Erbitux) as a radiosensitizer in pancreatic cancer, but this has not been specifically addressed in a clinical study. We report the results of an original study initiated in 2007, where cetuximab was tested with radiotherapy (RT) alone in locally advanced pancreatic cancer in a phase II trial (PACER). METHODS: Patients (n = 21) received cetuximab loading dose (400 mg/m(2)) and weekly dose (250 mg/m(2)) during RT (50.4 Gy in 28 fractions). Toxicity and disease response end point data were prospectively assessed. A feasibility study of on-trial patient blood and skin sampling was incorporated. RESULTS: Treatment was well tolerated, and toxicity was low; most patients (71%) experienced acute toxicities of grade 2 or less. Six months posttreatment, stable local disease was achieved in 90% of evaluable patients, but only 33% were free from metastatic progression. Median overall survival was 7.5 months, and actuarial survival was 33% at 1 year and 11% at 3 years, reflecting swift metastatic progression in some patients but good long-term control of localized disease in others. High-grade acneiform rash (P = .0027), posttreatment stable disease (P = .0059), and pretreatment cancer antigen 19.9 (CA19.9) level (P = .0042) associated with extended survival. Patient skin and blood samples yielded sufficient RNA and good quality protein, respectively. CONCLUSIONS: The results indicate that cetuximab inhibits EGFR-mediated radioresistance to achieve excellent local control with minimal toxicity but does not sufficiently control metastatic progression in all patients. Translational studies of patient tissue samples may yield molecular information that may enable individual treatment response prediction. PMID- 24772209 TI - Errors in Quantitative Image Analysis due to Platform-Dependent Image Scaling. AB - PURPOSE: To evaluate the ability of various software (SW) tools used for quantitative image analysis to properly account for source-specific image scaling employed by magnetic resonance imaging manufacturers. METHODS: A series of gadoteridol-doped distilled water solutions (0%, 0.5%, 1%, and 2% volume concentrations) was prepared for manual substitution into one (of three) phantom compartments to create "variable signal," whereas the other two compartments (containing mineral oil and 0.25% gadoteriol) were held unchanged. Pseudodynamic images were acquired over multiple series using four scanners such that the histogram of pixel intensities varied enough to provoke variable image scaling from series to series. Additional diffusion-weighted images were acquired of an ice-water phantom to generate scanner-specific apparent diffusion coefficient (ADC) maps. The resulting pseudodynamic images and ADC maps were analyzed by eight centers of the Quantitative Imaging Network using 16 different SW tools to measure compartment-specific region-of-interest intensity. RESULTS: Images generated by one of the scanners appeared to have additional intensity scaling that was not accounted for by the majority of tested quantitative image analysis SW tools. Incorrect image scaling leads to intensity measurement bias near 100%, compared to nonscaled images. CONCLUSION: Corrective actions for image scaling are suggested for manufacturers and quantitative imaging community. PMID- 24772210 TI - Reproducibility and Prognosis of Quantitative Features Extracted from CT Images. AB - We study the reproducibility of quantitative imaging features that are used to describe tumor shape, size, and texture from computed tomography (CT) scans of non-small cell lung cancer (NSCLC). CT images are dependent on various scanning factors. We focus on characterizing image features that are reproducible in the presence of variations due to patient factors and segmentation methods. Thirty two NSCLC nonenhanced lung CT scans were obtained from the Reference Image Database to Evaluate Response data set. The tumors were segmented using both manual (radiologist expert) and ensemble (software-automated) methods. A set of features (219 three-dimensional and 110 two-dimensional) was computed, and quantitative image features were statistically filtered to identify a subset of reproducible and nonredundant features. The variability in the repeated experiment was measured by the test-retest concordance correlation coefficient (CCCTreT). The natural range in the features, normalized to variance, was measured by the dynamic range (DR). In this study, there were 29 features across segmentation methods found with CCCTreT and DR >= 0.9 and R(2) Bet >= 0.95. These reproducible features were tested for predicting radiologist prognostic score; some texture features (run-length and Laws kernels) had an area under the curve of 0.9. The representative features were tested for their prognostic capabilities using an independent NSCLC data set (59 lung adenocarcinomas), where one of the texture features, run-length gray-level nonuniformity, was statistically significant in separating the samples into survival groups (P <= .046). PMID- 24772211 TI - Exploring Variability in CT Characterization of Tumors: A Preliminary Phantom Study. AB - PURPOSE: To explore the effects of computed tomography (CT) slice thickness and reconstruction algorithm on quantification of image features to characterize tumors using a chest phantom. MATERIALS AND METHODS: Twenty-two phantom lesions of known sizes (10 and 20 mm), shapes (spherical, elliptical, lobulated, and spiculated), and densities [-630, -10, and +100 Hounsfield Unit (HU)] were inserted into an anthropomorphic thorax phantom and scanned three times with relocations. The raw data were reconstructed using six imaging settings, i.e., a combination of three slice thicknesses of 1.25, 2.5, and 5 mm and two reconstruction kernels of lung and standard. Lesions were segmented and 14 image features representing lesion size, shape, and texture were calculated. Differences in the measured image features due to slice thickness and reconstruction algorithm were compared using linear regression method by adjusting three confounding variables (size, density, and shape). RESULTS: All 14 features were significantly different between 1.25 and 5 mm slice images. The 1.25 and 2.5 mm slice thicknesses were better than 5 mm for volume, density mean, density SD gray-level co-occurrence matrix (GLCM) energy and homogeneity. As for the reconstruction algorithm, there was no significant difference in uni dimension, volume, shape index 9, and compactness. Lung reconstruction was better for density mean, whereas standard reconstruction was better for density SD. CONCLUSIONS: CT slice thickness and reconstruction algorithm can significantly affect the quantification of image features. Thinner (1.25 and 2.5 mm) and thicker (5 mm) slice images should not be used interchangeably. Sharper and smoother reconstructions significantly affect the density-based features. PMID- 24772212 TI - Real-Time Measurement of Functional Tumor Volume by MRI to Assess Treatment Response in Breast Cancer Neoadjuvant Clinical Trials: Validation of the Aegis SER Software Platform. AB - PURPOSE: To evaluate the Aegis software implementation for real-time calculation of functional tumor volume (FTV) in the neoadjuvant breast cancer treatment trial setting. METHODS: The validation data set consisted of 689 contrast-enhanced magnetic resonance imaging (MRI) examinations from the multicenter American College of Radiology Imaging Network 6657 study. Subjects had stage III tumors >=3 cm in diameter and underwent MRI before, during, and after receiving anthracycline-cyclophosphamide chemotherapy. Studies were previously analyzed by the University of California San Francisco core laboratory using the three timepoint signal enhancement ratio (SER) FTV algorithm; FTV measurement was subsequently implemented on the Hologic (formerly Sentinelle Medical Inc) Aegis platform. All cases were processed using predefined volumes of interest with no user interaction. Spearman rank correlation was evaluated for all study sites and visits. Cox proportional hazards analysis was used to compare predictive performance of the platforms for recurrence-free survival (RFS) time. RESULTS: Overall agreement between platforms was good; rho varied from 0.96 to 0.98 for different study visits. Site-by-site analysis showed considerable variation, from rho = 0.54 to near perfect agreement (rho = 1.000) for several sites. Mean absolute difference between platforms ranged from 1.67 cm(3) pretreatment to 0.2 cm(3) posttreatment. The two platforms showed essentially identical performance for predicting RFS using pretreatment or posttreatment FTV. CONCLUSION: Implementation of the SER FTV algorithm on a commercial platform for real-time MRI volume assessments showed very good agreement with the reference core laboratory system, but variations by site and outlier analysis point out sensitivities to implementation-specific differences. PMID- 24772213 TI - Image registration for quantitative parametric response mapping of cancer treatment response. AB - Imaging biomarkers capable of early quantification of tumor response to therapy would provide an opportunity to individualize patient care. Image registration of longitudinal scans provides a method of detecting treatment associated changes within heterogeneous tumors by monitoring alterations in the quantitative value of individual voxels over time, which is unattainable by traditional volumetric based histogram methods. The concepts involved in the use of image registration for tracking and quantifying breast cancer treatment response using parametric response mapping (PRM), a voxel-based analysis of diffusion-weighted magnetic resonance imaging (DW-MRI) scans, are presented. Application of PRM to breast tumor response detection is described, wherein robust registration solutions for tracking small changes in water diffusivity in breast tumors during therapy are required. Methodologies that employ simulations are presented for measuring expected statistical accuracy of PRM for response assessment. Test-retest clinical scans are used to yield estimates of system noise to indicate significant changes in voxel-based changes in water diffusivity. Overall, registration-based PRM image analysis provides significant opportunities for voxel-based image analysis to provide the required accuracy for early assessment of response to treatment in breast cancer patients receiving neoadjuvant chemotherapy. PMID- 24772214 TI - Challenges and Approaches to Quantitative Therapy Response Assessment in Glioblastoma Multiforme Using the Novel Apoptosis Positron Emission Tomography Tracer F-18 ML-10. AB - Evaluation of cancer-therapy efficacy at early time points is necessary for realizing the goal of delivering maximally effective treatment. Molecular imaging with carefully selected tracers and methodologies can provide the means for realizing this ability. Many therapies are aimed at inducing apoptosis in malignant tissue; thus, the ability to quantify apoptosis in vivo may be a fruitful approach. Apoptosis rate changes occur on a fast time scale, potentially allowing correspondingly rapid decisions regarding therapy value. However, quantification of tissue status based on apoptosis imaging is complicated by this time scale and by the spatial heterogeneity of the process. Using the positron emission tomography (PET) tracer 2-(5-fluoro-pentyl)-2-methyl-malonic acid (F-18 ML-10), we present methods of voxelwise analysis yielding quantitative measures of apoptosis changes, parametric apoptosis change images, and graphical representation of apoptotic features. A method of deformable registration to account for anatomic changes between scan time points is also demonstrated. Overall apoptotic rates deduced from imaging depend on tumor density and the specific rate of apoptosis, a situation resulting in an ambiguity in the source of observed image-based changes. The ambiguity may be resolved through multimodality imaging. An example of intracellular sodium magnetic resonance imaging coupled with F-18 ML-10 PET is provided. PMID- 24772215 TI - Dynamic contrast-enhanced magnetic resonance imaging in prostate cancer clinical trials: potential roles and possible pitfalls. AB - Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluates the tissue microvasculature and may have a role in assessing and predicting therapeutic response in prostate cancer (PCa). In this review, we review principles of DCE-MRI and present the potential quantitative information that can be obtained. We discuss how it may be used as a biomarker for treatment with antiangiogenic and antivascular agents and potentially identify patients with PCa who may benefit from this form of therapy. Likewise, DCE-MRI may play a role in assessing response to combined androgen deprivation therapy and radiation therapy and theoretically could be a prognostic biomarker in evaluating second-generation hormone therapies. We also address the challenges of using DCE-MRI in PCa clinical trials and discuss the difficulties with standardization of this methodology to allow for biomarker validation, with particular reference to PCa. PMID- 24772216 TI - Repeatability of quantitative MRI measurements in normal breast tissue. AB - PURPOSE: To evaluate the variability and repeatability of repeated magnetic resonance imaging (MRI) measurements in normal breast tissues between and within subjects. METHODS: Eighteen normal premenopausal subjects underwent two contrast enhanced MRI scans within 72 hours or during the same menstrual phase in two consecutive months. A subset of nine women also completed diffusion-weighted imaging (DWI). Fibroglandular tissue (FGT) density and FGT enhancement were measured on the contrast-enhanced MRI. Apparent diffusion coefficient (ADC) values were computed from DWI. Between- and within-subject coefficients of variation (bCV and wCV, respectively) were assessed. Repeatability of all measurements was assessed by the coefficient of repeatability (CR) and Bland Altman plots. RESULTS: The bCV of FGT density and FGT enhancement at visit 1 and visit 2 ranged from 47% to 63%. The wCV was 13% for FGT density, 22% for FGT enhancement, and 11% for ADC. The CRs of FGT density and FGT enhancement were 0.15 and 0.19, respectively, and for ADC, it was 6.1 x 10(-4) mm(2)/s. CONCLUSIONS: We present an estimate of the variability and repeatability of MR measurements in normal breasts. These estimates provide the basis for understanding the normal variation of healthy breast tissue in MRI and establishing thresholds for agreement between measurements. PMID- 24772217 TI - A Virtual Clinical Trial of FDG-PET Imaging of Breast Cancer: Effect of Variability on Response Assessment. AB - INTRODUCTION: There is growing interest in using positron emission tomography (PET) standardized uptake values (SUVs) to assess tumor response to therapy. However, many error sources compromise the ability to detect SUV changes. We explore relationships between these errors and overall SUV variability. METHODS: We used simulations in a virtual clinical trial framework to study impacts of error sources from scanning and analysis effects on assessment of SUV changes. We varied tumor diameter, scan duration, pretherapy SUV, magnitude of change in SUV, image reconstruction filter, and SUV metric. Poisson noise was added to the raw data before image reconstruction. Variance from global sources of error, e.g., scanner calibration, was incorporated. Two thousand independent noisy sinograms per scenario were generated and reconstructed. We used SUVs to create receiver operating characteristic (ROC) curves to quantify ability to assess response. Integrating area under the ROC curve summarized ability to detect SUV changes. RESULTS: Scan duration and image reconstruction method had relatively little impact on ability to measure response. SUVMAX is nearly as effective as SUVMEAN, especially with increased image smoothing and despite size-matched region of interest placement. For an effective variability of 15%, we found the Positron Emission Tomography Response Criteria in Solid Tumors criteria for measuring response (+/-30%) similar to the European Organization for Research and Treatment of Cancer criteria (+/-25%). CONCLUSIONS: For typical PET variance levels, tumor response must be 30% to 40% to be reliably determined using SUVs. PET scan duration and image reconstruction method had relatively little effect. PMID- 24772218 TI - Quantitative Imaging Network: Data Sharing and Competitive AlgorithmValidation Leveraging The Cancer Imaging Archive. AB - The Quantitative Imaging Network (QIN), supported by the National Cancer Institute, is designed to promote research and development of quantitative imaging methods and candidate biomarkers for the measurement of tumor response in clinical trial settings. An integral aspect of the QIN mission is to facilitate collaborative activities that seek to develop best practices for the analysis of cancer imaging data. The QIN working groups and teams are developing new algorithms for image analysis and novel biomarkers for the assessment of response to therapy. To validate these algorithms and biomarkers and translate them into clinical practice, algorithms need to be compared and evaluated on large and diverse data sets. Analysis competitions, or "challenges," are being conducted within the QIN as a means to accomplish this goal. The QIN has demonstrated, through its leveraging of The Cancer Imaging Archive (TCIA), that data sharing of clinical images across multiple sites is feasible and that it can enable and support these challenges. In addition to Digital Imaging and Communications in Medicine (DICOM) imaging data, many TCIA collections provide linked clinical, pathology, and "ground truth" data generated by readers that could be used for further challenges. The TCIA-QIN partnership is a successful model that provides resources for multisite sharing of clinical imaging data and the implementation of challenges to support algorithm and biomarker validation. PMID- 24772220 TI - [Clinical and biological aspects of pediatric anemia in a urban district hospital in Cameroon]. PMID- 24772219 TI - Variations of dynamic contrast-enhanced magnetic resonance imaging in evaluation of breast cancer therapy response: a multicenter data analysis challenge. AB - Pharmacokinetic analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) time-course data allows estimation of quantitative parameters such as K (trans) (rate constant for plasma/interstitium contrast agent transfer), v e (extravascular extracellular volume fraction), and v p (plasma volume fraction). A plethora of factors in DCE-MRI data acquisition and analysis can affect accuracy and precision of these parameters and, consequently, the utility of quantitative DCE-MRI for assessing therapy response. In this multicenter data analysis challenge, DCE-MRI data acquired at one center from 10 patients with breast cancer before and after the first cycle of neoadjuvant chemotherapy were shared and processed with 12 software tools based on the Tofts model (TM), extended TM, and Shutter-Speed model. Inputs of tumor region of interest definition, pre-contrast T1, and arterial input function were controlled to focus on the variations in parameter value and response prediction capability caused by differences in models and associated algorithms. Considerable parameter variations were observed with the within-subject coefficient of variation (wCV) values for K (trans) and v p being as high as 0.59 and 0.82, respectively. Parameter agreement improved when only algorithms based on the same model were compared, e.g., the K (trans) intraclass correlation coefficient increased to as high as 0.84. Agreement in parameter percentage change was much better than that in absolute parameter value, e.g., the pairwise concordance correlation coefficient improved from 0.047 (for K (trans)) to 0.92 (for K (trans) percentage change) in comparing two TM algorithms. Nearly all algorithms provided good to excellent (univariate logistic regression c-statistic value ranging from 0.8 to 1.0) early prediction of therapy response using the metrics of mean tumor K (trans) and k ep (=K (trans)/v e, intravasation rate constant) after the first therapy cycle and the corresponding percentage changes. The results suggest that the interalgorithm parameter variations are largely systematic, which are not likely to significantly affect the utility of DCE-MRI for assessment of therapy response. PMID- 24772221 TI - [Primitive mammary neuroendocrine tumor: about a rare case]. PMID- 24772222 TI - [Colloid carcinoma of the breast: about a case]. PMID- 24772223 TI - [Tuberculous endometritis: about a case and review of the literature]. PMID- 24772224 TI - [Ilium honeycomb]. PMID- 24772225 TI - Pemphigus: use of the Japanese severity index in 56 Moroccan patients. AB - INTRODUCTION: In pemphigus, there still is no consensus on parameters mesuring clinically the disease severity. The aim of this study is to use the Japanese severity index in Moroccan patients with pemphigus. METHODS: Multicenter prospective study from September 2007 to September 2009 including consecutive patients with confirmed pemphigus. We used the Japenese severity index for pemphigus. For each patient, the score was calculated at diagnosis and at 6 months of follow-up and correlated to type of pemphigus; mean dosage of corticosteroids and clinical statuts at 6 months: dead or not. RESULTS: Fifty six patients were included, 20 men and 36 women, mean age 46.62 +/- 15.9 years. At diagnosis, the mean initial score was 7.7 + 2.36; at six months, it was 1.61 + 1.83. The score variation at 6 months and inclusion was 6.19 +/- 2.18 for deep pemphigus and 5.43 +/- 2.85 for superficial pemphigus (p = 0,3 non significant). At six months, 4 patients were dead: their initial score was 11 + 1.41 while the initial score in the 52 patients was 7.4+/-2.03 (p = 0,001, significant). Data showed no correlation between initial severity scores and cumulative dosage of corticosteroids at 6 months (Pearson coefficient of correlation 0.144; p = 0.580). CONCLUSION: In this study, initial severity scores for pemphigus were high and decreased at 6 months of treatment. Both deep pemphigus and superficial pemphigus were severe as their score variation was similar. Japenese severity score is useful for Moroccan patients with pemphigus. PMID- 24772226 TI - [Isolated fracture of the lesser trochanter in an adult, and if it was a metastasis: a case report and literature review]. PMID- 24772227 TI - Severe varicella in adult. PMID- 24772228 TI - Successful management of pregnancy in an African woman with Klippel Trenaunay syndrome. AB - Klippel Trenaunay syndrome (KTS) is a rare congenital disease characterized by a triad of cutaneous hemangioma, varicose veins and bone or soft tissue hypertrophy. Cases of pregnancy complicated by KTS are rare. There is an increased risk of thrombo-embolic disease and hemorrhage during pregnancy. Both obstetric and anesthetic management of KTS in pregnancy can be rather complicated. We present a successful management of pregnancy in an African woman with KTS at Yaounde General Hospital, Cameroon. PMID- 24772229 TI - [Heart failure with preserved ejection fraction in sub-Saharan Africa: about 32 cases]. PMID- 24772232 TI - Review: the autistic brain: thinking across the spectrum. PMID- 24772230 TI - The effect of patient and injury factors on long-term outcome after anterior cruciate ligament reconstruction. AB - BACKGROUND: Long-term follow-up is required for accurate assessment of results after anterior cruciate ligament (ACL) reconstruction and recent years have witnessed the publication of numerous papers detailing long-term outcomes. The primary aim of this systematic review was to determine which patient factors affect long-term clinical and radiographic outcomes based on the current literature. METHODS: A comprehensive literature review yielded 18 prospective manuscripts with minimum follow-up ranging from 5-12 years after ACL reconstruction. RESULTS: Longer follow-up was associated with increased radiographic evidence of osteoarthritis. Increased meniscal or articular cartilage pathology at ACL reconstruction were found to be associated with increased prevalence of radiographic evidence of osteoarthritis at long-term follow-up in most studies. There is currently insufficient evidence to correlate these intra-articular findings with decreases in clinical outcome measures. Further research is needed to determine the effect of body mass index (BMI) on long-term outcome after ACL reconstruction. CONCLUSIONS: Intra-articular injuries noted at the time of ACL reconstruction affect long-term results. The effect of BMI and other patient factors is unclear. Long-term follow-up of large multicenter cohorts will provide definitive data on the relative importance of different factors in determining results of ACL reconstruction. PMID- 24772231 TI - ADHD: 10 Years Later. AB - Estimates of children struggling with attention-deficit/hyperactivity disorder (ADHD) vary, but the Centers for Disease Control puts the number at a stunningly high 25 percent. Whatever the number, ADHD affects too many children at school, at home, and with their peers, and often persists into adulthood. The cause is as yet unknown, although genetic factors and their interaction with the environment are known to be pivotal. Ten years ago a landmark study showed that the structure of the brains of children with ADHD differs from that of unaffected children. Since that study, enhancements in imaging have given researchers a better look at key hubs in the brain and how they network-advances that could prove useful in the control and treatment of ADHD in both children and adults. PMID- 24772233 TI - Lewy Body Dementia: The Under-Recognized but Common FOE. AB - After Alzheimer's disease, Lewy body dementia (LBD) is the most prevalent progressive dementia of the many cognitive disorders wreaking unspeakable havoc on millions of lives. LBD is characterized by the presence of Lewy bodies, which are abnormal aggregates of a protein called alpha-synuclein, and are found in regions of the brain that regulate behavior, memory, movement, and personality. Many of the symptoms of Alzheimer's, Parkinson's, and LBD overlap, but LBD is more difficult to diagnose. Underdiagnosis is just part of the reason why LBD is unknown to the public and many health-care providers, and why funding for research lags far behind that for almost every other cognitive disorder. PMID- 24772234 TI - The Great Equalizer: Health Care Access and Infant Mortality in Thailand. AB - This paper analyzes Thailand's 2001 healthcare reform, "30 Baht". The program increased funding available to hospitals to care for the poor and reduced copays to 30 Baht (~$0.75). Our estimates suggest the supply-side funding of the program increased healthcare utilization, especially amongst the poor. Moreover, we find significant impacts on infant mortality: prior to 30 Baht poorer provinces had significantly higher infant mortality rates than richer provinces. After 30 Baht this correlation evaporates to zero. The results suggest that increased access to healthcare among the poor can significantly reduce their infant mortality rates. PMID- 24772235 TI - Allogeneic hematopoietic cell transplant for acute myeloid leukemia: Current state in 2013 and future directions. AB - Acute myeloid leukemia (AML) represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes. Though remission induction is an important first step in the management of AML, additional treatment strategies are essential to ensure long-term disease-free survival. Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse risk. Allogeneic hematopoietic cell transplantation (allo-HCT) represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions, with a demonstrable survival advantage in younger patients with intermediate- or poor-risk cytogenetics. Herein we review the published data regarding the role of allo-HCT in adults with AML. We searched MEDLINE/PubMed and EMBASE/Ovid. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. We discuss the role of allo-HCT in AML patients stratified by cytogenetic- and molecular risk in first complete remission, as well as allo-HCT as an option in relapsed/refractory AML. Besides the conventional sibling and unrelated donor allografts, we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood. We also discuss conditioning regimens, including reduced intensity conditioning which has broadened the applicability of allo-HCT. Finally we explore recent advances and future possibilities and directions of allo-HCT in AML. Practical therapeutic recommendations have been made where possible based on available data and expert opinion. PMID- 24772236 TI - Enhancing the efficacy of mesenchymal stem cell therapy. AB - Mesenchymal stem cell (MSC) therapy is entering a challenging phase after completion of many preclinical and clinical trials. Among the major hurdles encountered in MSC therapy are inconsistent stem cell potency, poor cell engraftment and survival, and age/disease-related host tissue impairment. The recognition that MSCs primarily mediate therapeutic benefits through paracrine mechanisms independent of cell differentiation provides a promising framework for enhancing stem cell potency and therapeutic benefits. Several MSC priming approaches are highlighted, which will likely allow us to harness the full potential of adult stem cells for their future routine clinical use. PMID- 24772237 TI - "Ins" and "Outs" of mesenchymal stem cell osteogenesis in regenerative medicine. AB - Repair and regeneration of bone requires mesenchymal stem cells that by self renewal, are able to generate a critical mass of cells with the ability to differentiate into osteoblasts that can produce bone protein matrix (osteoid) and enable its mineralization. The number of human mesenchymal stem cells (hMSCs) diminishes with age and ex vivo replication of hMSCs has limited potential. While propagating hMSCs under hypoxic conditions may maintain their ability to self renew, the strategy of using human telomerase reverse transcriptase (hTERT) to allow for hMSCs to prolong their replicative lifespan is an attractive means of ensuring a critical mass of cells with the potential to differentiate into various mesodermal structural tissues including bone. However, this strategy must be tempered by the oncogenic potential of TERT-transformed cells, or their ability to enhance already established cancers, the unknown differentiating potential of high population doubling hMSCs and the source of hMSCs (e.g., bone marrow, adipose-derived, muscle-derived, umbilical cord blood, etc.) that may provide peculiarities to self-renewal, differentiation, and physiologic function that may differ from non-transformed native cells. Tissue engineering approaches to use hMSCs to repair bone defects utilize the growth of hMSCs on three dimensional scaffolds that can either be a base on which hMSCs can attach and grow or as a means of sequestering growth factors to assist in the chemoattraction and differentiation of native hMSCs. The use of whole native extracellular matrix (ECM) produced by hMSCs, rather than individual ECM components, appear to be advantageous in not only being utilized as a three dimensional attachment base but also in appropriate orientation of cells and their differentiation through the growth factors that native ECM harbor or in simulating growth factor motifs. The origin of native ECM, whether from hMSCs from young or old individuals is a critical factor in "rejuvenating" hMSCs from older individuals grown on ECM from younger individuals. PMID- 24772238 TI - Progress of mesenchymal stem cell therapy for neural and retinal diseases. AB - Complex circuitry and limited regenerative power make central nervous system (CNS) disorders the most challenging and difficult for functional repair. With elusive disease mechanisms, traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases. However, the number of neurons still diminishes in many patients. Recently, stem cell therapy has been proposed as a viable option. Mesenchymal stem cells (MSCs), a widely-studied human adult stem cell population, have been discovered for more than 20 years. MSCs have been found all over the body and can be conveniently obtained from different accessible tissues: bone marrow, blood, and adipose and dental tissue. MSCs have high proliferative and differentiation abilities, providing an inexhaustible source of neurons and glia for cell replacement therapy. Moreover, MSCs also show neuroprotective effects without any genetic modification or reprogramming. In addition, the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation. These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders. Here, we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases. This review article will focus on multiple sclerosis, spinal cord injury, autism, glaucoma, retinitis pigmentosa and age-related macular degeneration. PMID- 24772239 TI - Mesenchymal stem cells in the treatment of spinal cord injuries: A review. AB - With technological advances in basic research, the intricate mechanism of secondary delayed spinal cord injury (SCI) continues to unravel at a rapid pace. However, despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord, the cure for paralysis remains elusive. Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI. Recent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results. An array of mesenchymal stem cells (MSCs) from various sources with novel and promising strategies are being developed to improve function after SCI. In this review, we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI. We will discuss the progress of MSCs application in research, focusing on the neuroprotective properties of MSCs. Finally, we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI. PMID- 24772240 TI - Brain mesenchymal stem cells: The other stem cells of the brain? AB - Multipotent mesenchymal stromal cells (MSC), have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation. The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair. However, some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist. In brain, perivascular MSCs like pericytes and adventitial cells, could constitute another stem cell population distinct to the neural stem cell pool. The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes, the demonstration of neural biomarkers expression, electrophysiological recordings, and the absence of cell fusion. The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells. It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression. PMID- 24772241 TI - Adipose mesenchymal stem cells in the field of bone tissue engineering. AB - Bone tissue engineering represents one of the most challenging emergent fields for scientists and clinicians. Current failures of autografts and allografts in many pathological conditions have prompted researchers to find new biomaterials able to promote bone repair or regeneration with specific characteristics of biocompatibility, biodegradability and osteoinductivity. Recent advancements for tissue regeneration in bone defects have occurred by following the diamond concept and combining the use of growth factors and mesenchymal stem cells (MSCs). In particular, a more abundant and easily accessible source of MSCs was recently discovered in adipose tissue. These adipose stem cells (ASCs) can be obtained in large quantities with little donor site morbidity or patient discomfort, in contrast to the invasive and painful isolation of bone marrow MSCs. The osteogenic potential of ASCs on scaffolds has been examined in cell cultures and animal models, with only a few cases reporting the use of ASCs for successful reconstruction or accelerated healing of defects of the skull and jaw in patients. Although these reports extend our limited knowledge concerning the use of ASCs for osseous tissue repair and regeneration, the lack of standardization in applied techniques makes the comparison between studies difficult. Additional clinical trials are needed to assess ASC therapy and address potential ethical and safety concerns, which must be resolved to permit application in regenerative medicine. PMID- 24772242 TI - Purinergic receptors and nucleotide processing ectoenzymes: Their roles in regulating mesenchymal stem cell functions. AB - Human mesenchymal stem cells (MSCs) are a rare population of non-hematopoietic stem cells with multilineage potential, originally identified in the bone marrow. Due to the lack of a single specific marker, MSCs can be recognized and isolated by a series of features such as plastic adherence, a panel of surface markers, the clonogenic and the differentiation abilities. The recognized role of MSCs in the regulation of hemopoiesis, in cell-degeneration protection and in the homeostasis of mesodermal tissues through their differentiation properties, justifies the current interest in identifying the biochemical signals produced by MSCs and their active crosstalk in tissue environments. Only recently have extracellular nucleotides (eNTPs) and their metabolites been included among the molecular signals produced by MSCs. These molecules are active on both ionotropic and metabotropic receptors present in most cell types. MSCs possess a significant display of these receptors and of nucleotide processing ectoenzymes on their plasma membrane. Thus, from their niche, MSCs give a significant contribution to the complex signaling network of eNTPs and its derivatives. Recent studies have demonstrated the multifaceted aspects of eNTP metabolism and their signal transduction in MSCs and revealed important roles in specifying differentiation lineages and modulating MSC physiology and communication with other cells. This review discusses the roles of eNTPs, their receptors and ectoenzymes, and the relevance of the signaling network and MSC functions, and also focuses on the importance of this emerging area of interest for future MSC-based cell therapies. PMID- 24772243 TI - Mesenchymal stem cells help pancreatic islet transplantation to control type 1 diabetes. AB - Islet cell transplantation has therapeutic potential to treat type 1 diabetes, which is characterized by autoimmune destruction of insulin-producing pancreatic islet beta cells. It represents a minimal invasive approach for beta cell replacement, but long-term blood control is still largely unachievable. This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia. Moreover, graft failures continue to occur because of immunological rejection, despite the use of potent immunosuppressive agents. Mesenchymal stem cells (MSCs) have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection. In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack. PMID- 24772244 TI - Mesenchymal stem cells in treating autism: Novel insights. AB - Autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, abnormal to absent verbal communication, restricted interests, and repetitive stereotypic verbal and non verbal behaviors, influencing the ability to relate to and communicate. The core symptoms of ASDs concern the cognitive, emotional, and neurobehavioural domains. The prevalence of autism appears to be increasing at an alarming rate, yet there is a lack of effective and definitive pharmacological options. This has created an increased sense of urgency, and the need to identify novel therapies. Given the growing awareness of immune dysregulation in a significant portion of the autistic population, cell therapies have been proposed and applied to ASDs. In particular, mesenchymal stem cells (MSCs) possess the immunological properties which make them promising candidates in regenerative medicine. MSC therapy may be applicable to several diseases associated with inflammation and tissue damage, where subsequent regeneration and repair is necessary. MSCs could exert a positive effect in ASDs through the following mechanisms: stimulation of repair in the damaged tissue, e.g., inflammatory bowel disease; synthesizing and releasing anti-inflammatory cytokines and survival-promoting growth factors; integrating into existing neural and synaptic network, and restoring plasticity. The paracrine mechanisms of MSCs show interesting potential in ASD treatment. Promising and impressive results have been reported from the few clinical studies published to date, although the exact mechanisms of action of MSCs in ASDs to restore functions are still largely unknown. The potential role of MSCs in mediating ASD recovery is discussed in light of the newest findings from recent clinical studies. PMID- 24772246 TI - Umbilical cord-derived mesenchymal stem cells: Their advantages and potential clinical utility. AB - Human umbilical cord (UC) is a promising source of mesenchymal stem cells (MSCs). Apart from their prominent advantages, such as a painless collection procedure and faster self-renewal, UC-MSCs have shown the ability to differentiate into three germ layers, to accumulate in damaged tissue or inflamed regions, to promote tissue repair, and to modulate immune response. There are diverse protocols and culture methods for the isolation of MSCs from the various compartments of UC, such as Wharton's jelly, vein, arteries, UC lining and subamnion and perivascular regions. In this review, we give a brief introduction to various compartments of UC as a source of MSCs and emphasize the potential clinical utility of UC-MSCs for regenerative medicine and immunotherapy. PMID- 24772245 TI - Neurotrauma and mesenchymal stem cells treatment: From experimental studies to clinical trials. AB - Mesenchymal stem cell (MSC) therapy has attracted the attention of scientists and clinicians around the world. Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury. These effects are believed to be due to their ability to differentiate into other cell lineages, modulate inflammatory and immunomodulatory responses, reduce cell apoptosis, secrete several neurotrophic factors and respond to tissue injury, among others. There are many pre-clinical studies on MSC treatment for spinal cord injury (SCI) and peripheral nerve injuries. However, the same is not true for clinical trials, particularly those concerned with nerve trauma, indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions. As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies. For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes. This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now. At the time of writing this article there were 43 and 36 pre clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves, respectively. PMID- 24772247 TI - Differentiation of mesenchymal stem cells into gonad and adrenal steroidogenic cells. AB - Hormone replacement therapy is necessary for patients with adrenal and gonadal failure. Steroid hormone treatment is also employed in aging people for sex hormone deficiency. These patients undergo such therapies, which have associated risks, for their entire life. Stem cells represent an innovative tool for tissue regeneration and the possibility of solving these problems. Among various stem cell types, mesenchymal stem cells have the potential to differentiate into steroidogenic cells both in vivo and in vitro. In particular, they can effectively be differentiated into steroidogenic cells by expressing nuclear receptor 5A subfamily proteins (steroidogenic factor-1 and liver receptor homolog 1) with the aid of cAMP. This approach will provide a source of cells for future regenerative medicine for the treatment of diseases caused by steroidogenesis deficiencies. It can also represent a useful tool for studying the molecular mechanisms of steroidogenesis and its related diseases. PMID- 24772249 TI - Glioblastoma stem cells: Molecular characteristics and therapeutic implications. AB - Glioblastoma Multiforme (GBM) is a grade IV astrocytoma, with a median survival of 14.6 mo. Within GBM, stem-like cells, namely glioblastoma stem cells (GSCs), have the ability to self-renew, differentiate into distinct lineages within the tumor and initiate tumor xenografts in immunocompromised animal models. More importantly, GSCs utilize cell-autonomous and tumor microenvironment-mediated mechanisms to overcome current therapeutic approaches. They are, therefore, very important therapeutic targets. Although the functional criteria defining GSCs are well defined, their molecular characteristics, the mechanisms whereby they establish the cellular hierarchy within tumors, and their contribution to tumor heterogeneity are not well understood. This review is aimed at summarizing current findings about GSCs and their therapeutic importance from a molecular and cellular point of view. A better characterization of GSCs is crucial for designing effective GSC-targeted therapies. PMID- 24772250 TI - Familial Alzheimer's disease modelling using induced pluripotent stem cell technology. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks. Diagnosis of AD is difficult, particularly in early stages of the disease, and largely consists of cognitive assessments, with only one in four patients being correctly diagnosed. Development of novel therapeutics for the treatment of AD has proved to be a lengthy, costly and relatively unproductive process with attrition rates of > 90%. As a result, there are no cures for AD and few treatment options available for patients. Therefore, there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications. Here, we discuss the use of induced pluripotent stem cells (iPSCs), which can be derived from adult cells, as a method of recapitulation of AD phenotype in vitro. We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy, toxicology and disease modelling. At present, a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications. However, whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field, it is one with immense potential that is likely to reach fruition within the next few years. PMID- 24772248 TI - Intestinal stem cells and celiac disease. AB - Stem cells (SCs) are the key to tissue genesis and regeneration. Given their central role in homeostasis, dysfunctions of the SC compartment play a pivotal role in the development of cancers, degenerative disorders, chronic inflammatory pathologies and organ failure. The gastrointestinal tract is constantly exposed to harsh mechanical and chemical conditions and most of the epithelial cells are replaced every 3 to 5 d. According to the so-called Unitarian hypothesis, this renewal is driven by a common intestinal stem cell (ISC) residing within the crypt base at the origin of the crypt-to-villus hierarchical migratory pattern. Celiac disease (CD) can be defined as a chronic immune-mediated disease that is triggered and maintained by dietary proteins (gluten) in genetically predisposed individuals. Many advances have been achieved over the last years in understanding of the pathogenic interactions among genetic, immunological and environmental factors in CD, with a particular emphasis on intestinal barrier and gut microbiota. Conversely, little is known about ISC modulation and deregulation in active celiac disease and upon a gluten-free diet. Nonetheless, bone marrow derived SC transplantation has become an option for celiac patients with complicated or refractory disease. This manuscript summarizes the "state of the art" regarding CD and ISCs, their niche and potential role in the development and treatment of the disease. PMID- 24772251 TI - Embryonic stem cell-derived neural progenitors as non-tumorigenic source for dopaminergic neurons. AB - AIM: To find a safe source for dopaminergic neurons, we generated neural progenitor cell lines from human embryonic stem cells. METHODS: The human embryonic stem (hES) cell line H9 was used to generate human neural progenitor (HNP) cell lines. The resulting HNP cell lines were differentiated into dopaminergic neurons and analyzed by quantitative real-time polymerase chain reaction and immunofluorescence for the expression of neuronal differentiation markers, including beta-III tubulin (TUJ1) and tyrosine hydroxylase (TH). To assess the risk of teratoma or other tumor formation, HNP cell lines and mouse neuronal progenitor (MNP) cell lines were injected subcutaneously into immunodeficient SCID/beige mice. RESULTS: We developed a fairly simple and fast protocol to obtain HNP cell lines from hES cells. These cell lines, which can be stored in liquid nitrogen for several years, have the potential to differentiate in vitro into dopaminergic neurons. Following day 30 of differentiation culture, the majority of the cells analyzed expressed the neuronal marker TUJ1 and a high proportion of these cells were positive for TH, indicating differentiation into dopaminergic neurons. In contrast to H9 ES cells, the HNP cell lines did not form tumors in immunodeficient SCID/beige mice within 6 mo after subcutaneous injection. Similarly, no tumors developed after injection of MNP cells. Notably, mouse ES cells or neuronal cells directly differentiated from mouse ES cells formed teratomas in more than 90% of the recipients. CONCLUSION: Our findings indicate that neural progenitor cell lines can differentiate into dopaminergic neurons and bear no risk of generating teratomas or other tumors in immunodeficient mice. PMID- 24772252 TI - Coronary artery calcification in chronic kidney disease: An update. AB - Arterial calcification is a well-recognized complication of advanced atherosclerosis. Chronic kidney disease (CKD) is characterized by significantly more pronounced, disseminated and fast-progressing calcification of the vascular system, including the coronary arteries. New computed tomography-based imaging techniques allow for the noninvasive assessment and monitoring of calcification in different vascular sites. Coronary artery calcification (CAC) develops early in the course of CKD and is tightly associated with mineral and bone disorders, which include but are not limited to secondary hyperparathyroidism. In this review, recent data on the pathogenesis of CAC development and progression are discussed, with a special emphasis on fibroblast growth factor 23 and its co receptor, klotho. The prevalence, progression and prognostic significance of CAC are reviewed separately for patients with end-stage renal disease treated with dialysis, kidney transplant recipients and patients with earlier stages of CKD. In the last section, therapeutic considerations are discussed, with special attention paid to the importance of treatment that addresses mineral and bone disorders of CKD. PMID- 24772253 TI - Myocardial ischemia is a key factor in the management of stable coronary artery disease. AB - Previous studies demonstrated that coronary revascularization, especially percutaneous coronary intervention (PCI), does not significantly decrease the incidence of cardiac death or myocardial infarction in patients with stable coronary artery disease. Many studies using myocardial perfusion imaging (MPI) showed that, for patients with moderate to severe ischemia, revascularization is the preferred therapy for survival benefit, whereas for patients with no to mild ischemia, medical therapy is the main choice, and revascularization is associated with increased mortality. There is some evidence that revascularization in patients with no or mild ischemia is likely to result in worsened ischemia, which is associated with increased mortality. Studies using fractional flow reserve (FFR) demonstrate that ischemia-guided PCI is superior to angiography-guided PCI, and the presence of ischemia is the key to decision-making for PCI. Complementary use of noninvasive MPI and invasive FFR would be important to compensate for each method's limitations. Recent studies of appropriateness criteria showed that, although PCI in the acute setting and coronary bypass surgery are properly performed in most patients, PCI in the non-acute setting is often inappropriate, and stress testing to identify myocardial ischemia is performed in less than half of patients. Also, some studies suggested that revascularization in an inappropriate setting is not associated with improved prognosis. Taken together, the presence and the extent of myocardial ischemia is a key factor in the management of patients with stable coronary artery disease, and coronary revascularization in the absence of myocardial ischemia is associated with worsened prognosis. PMID- 24772255 TI - Duration of dual antiplatelet treatment in the era of next generation drug eluting stents. AB - Current percutaneous coronary intervention guidelines recommend dual antiplatelets (aspirin 100 mg + clopidogrel 75 mg daily) for at least 12 mo following drug-eluting stent (DES) implantation if patients are not at high risk of bleeding. Several reports have tried to shorten the dual antiplatelet therapy to 3-6 mo, especially following next-generation DES implantation, for cost effectiveness. However, the clinical results are inconsistent and the data regarding next-generation DESs limited. In this report, recently published important pivotal reports regarding the optimal duration of dual antiplatelets following DES implantation are summarized. PMID- 24772254 TI - Clinical significance of glycated hemoglobin in the acute phase of ST elevation myocardial infarction. AB - In population-based studies, including diabetic and nondiabetic cohorts, glycated hemoglobin A1c (HbA1c) has been reported as an independent predictor of all-cause and cardiovascular disease mortality. Data on the prognostic role of HbA1c in patients with acute myocardial infarction (MI) are not univocal since they stem from studies which mainly differ in patients' selection criteria, therapy (thrombolysis vs mechanical revascularization) and number consistency. The present review is focused on available evidence on the prognostic significance of HbA1c measured in the acute phase in patients with ST-elevation myocardial infarction (STEMI) submitted to primary percutaneous coronary intervention (PCI). We furthermore highlighted the role of HbA1c as a screening tool for glucose intolerance in patients with STEMI. According to available evidence, in contemporary cohorts of STEMI patients submitted to mechanical revascularization, HbA1c does not seem to be associated with short and long term mortality rates. However, HbA1c may represent a screening tool for glucose intolerance from the early phase on in STEMI patients. On a pragmatic ground, an HbA1c test has several advantages over fasting plasma glucose or an oral glucose tolerance test in an acute setting. The test can be performed in the non-fasting state and reflects average glucose concentration over the preceding 2-3 mo. We therefore proposed an algorithm based on pragmatic grounds which could be applied in STEMI patients without known diabetes in order to detect glucose intolerance abnormalities from the early phase. The main advantage of this algorithm is that it may help in tailoring the follow-up program, by helping in identifying patients at risk for the development of glucose intolerance after MI. Further validation of this algorithm in prospective studies may be required in the contemporary STEMI population to resolve some of these uncertainties around HbA1c screening cutoff points. PMID- 24772257 TI - High-sensitivity cardiac troponins in everyday clinical practice. AB - High-sensitivity cardiac troponin (hs-cTn) assays are increasingly being used in many countries worldwide, however, a generally accepted definition of high sensitivity is still pending. These assays enable cTn measurement with a high degree of analytical sensitivity with a low analytical imprecision at the low measuring range of cTn assays (coefficient of variation of < 10% at the 99(th) percentile upper reference limit). One of the most important advantages of these new assays is that they allow novel, more rapid approaches to rule in or rule out acute coronary syndromes (ACSs) than with previous cTn assay generations which are still more commonly used in practice worldwide. hs-cTn is also more sensitive for the detection of myocardial damage unrelated to acute myocardial ischemia. Therefore, the increase in early diagnostic sensitivity of hs-cTn assays for ACS comes at the cost of a reduced ACS specificity, because more patients with other causes of acute or chronic myocardial injury without overt myocardial ischemia are detected than with previous cTn assays. As hs-cTn assays are increasingly being adopted in clinical practice and more hs-cTn assays are being developed, this review attempts to synthesize the available clinical data to make recommendations for their everyday clinical routine use. PMID- 24772258 TI - Molecular phenotypes of human parvovirus B19 in patients with myocarditis. AB - AIM: To investigate molecular phenotypes of myocardial B19V-infection to determine the role of B19V in myocarditis and dilated cardiomyopathy (DCM). METHODS: Endomyocardial biopsies (EMBs) from 498 B19V-positive patients with myocarditis and DCM were analyzed using molecular methods and functional experiments. EMBs were obtained from the University Hospitals of Greifswald and Tuebingen and additionally from 36 German cardiology centers. Control tissues were obtained at autopsy from 34 victims of accidents, crime or suicide. Identification of mononuclear cell infiltrates in EMBs was performed using immunohistological staining. Anti-B19V-IgM and anti-B19V-IgG were analyzed by enzyme-linked immunosorbent assay (ELISA). B19V viral loads were determined using in-house quantitative real-time polymerase chain reaction (PCR). For B19V genotyping a new B19V-genotype-specific restriction fragment length polymorphism (RFLP)-PCR was established. B19V-genotyping was verified by direct DNA-sequencing and sequences were aligned using BLAST and BioEdit software. B19V P6-promoter and HHV6-U94-transactivator constructs were generated for cell culture experiments. Transfection experiments were conducted using human endothelial cells 1. Luciferase reporter assays were performed to determine B19V-replication activity. Statistical analysis and graphical representation were calculated using SPSS and Prism5 software. RESULTS: The prevalence of B19V was significantly more likely to be associated with inflammatory cardiomyopathy (iCMP) compared to uninflamed DCM (59.6% vs 35.3%) (P < 0.0001). The detection of B19V-mRNA replication intermediates proved that replication of B19V was present. RFLP-PCR assays showed that B19V-genotype 1 (57.4%) and B19V-genotype 2 (36.7%) were the most prevalent viral genotypes. B19V-genotype 2 was observed more frequently in EMBs with iCMP (65.0%) compared to DCM (35%) (P = 0.049). Although there was no significant difference in gender-specific B19V-loads, women were more frequently infected with B19V-genotype 2 (44.6%) than men (36.0%) (P = 0.0448). Coinfection with B19V and other cardiotropic viruses was found in 19.2% of tissue samples and was associated with higher B19V viral load compared to B19V-monoinfected tissue (P = 0.0012). The most frequent coinfecting virus was human herpes virus 6 (HHV6, 16.5%). B19V-coinfection with HHV6 showed higher B19V-loads compared to B19V monoinfected EMBs (P = 0.0033), suggesting that HHV6 had transactivated B19V. In vitro experiments confirmed a 2.4-fold increased B19V P6-promoter activity by the HHV6 U94-transactivator. CONCLUSION: The finding of significantly increased B19V loads in patients with histologically proven cardiac inflammation suggests a crucial role of B19V-genotypes and reactivation of B19V-infection by HHV6 coinfection in B19V-associated iCMP. Our findings suggest that B19V-infection of the human heart can be a causative event for the development of an endothelial cell-mediated inflammatory disease and that this is related to both viral load and genotype. PMID- 24772256 TI - Arrhythmogenic ventricular cardiomyopathy: A paradigm shift from right to biventricular disease. AB - Arrhythmogenic ventricular cardiomyopathy (AVC) is generally referred to as arrhythmogenic right ventricular (RV) cardiomyopathy/dysplasia and constitutes an inherited cardiomyopathy. Affected patients may succumb to sudden cardiac death (SCD), ventricular tachyarrhythmias (VTA) and heart failure. Genetic studies have identified causative mutations in genes encoding proteins of the intercalated disk that lead to reduced myocardial electro-mechanical stability. The term arrhythmogenic RV cardiomyopathy is somewhat misleading as biventricular involvement or isolated left ventricular (LV) involvement may be present and thus a broader term such as AVC should be preferred. The diagnosis is established on a point score basis according to the revised 2010 task force criteria utilizing imaging modalities, demonstrating fibrous replacement through biopsy, electrocardiographic abnormalities, ventricular arrhythmias and a positive family history including identification of genetic mutations. Although several risk factors for SCD such as previous cardiac arrest, syncope, documented VTA, severe RV/LV dysfunction and young age at manifestation have been identified, risk stratification still needs improvement, especially in asymptomatic family members. Particularly, the role of genetic testing and environmental factors has to be further elucidated. Therapeutic interventions include restriction from physical exercise, beta-blockers, sotalol, amiodarone, implantable cardioverter defibrillators and catheter ablation. Life-long follow-up is warranted in symptomatic patients, but also asymptomatic carriers of pathogenic mutations. PMID- 24772259 TI - Coronary artery disease in congenital single coronary artery in adults: A Dutch case series. AB - AIM: To assess the current diagnostic and therapeutic management and the clinical implications of congenital single coronary artery (SCA) in adults. METHODS: We identified 15 patients with a SCA detected from four Dutch angiography centers in the period between 2010 and 2013. Symptomatic patients who underwent routine diagnostic coronary angiography (CAG) for suspected coronary artery disease and who incidentally were found to have isolated SCA were analyzed. RESULTS: Fifteen (7 females) with a mean age of 58.5 +/- 13.78 years (range 43-86) had a SCA. Conventional CAG demonstrated congenital isolated SCA originating as a single ostium from the right sinus of Valsalva in 6 patients and originating from the left in 9 patients. Minimal to moderate coronary atherosclerotic changes were found in 4, and severe stenotic lesions in another 4 patients. Seven patients were free of coronary atherosclerosis. Runs of non-sustained ventricular tachycardia were documented in 2 patients, one of whom demonstrated transmural ischemic changes on presentation. Myocardial perfusion scintigraphic evidence of transmural myocardial ischemia was found in 1 patient due to kinking and squeezing of the SCA with an interarterial course between the aorta and pulmonary artery. Multi-slice computed tomography (MSCT) was helpful to delineate the course of the anomalous artery relative to the aorta and pulmonary artery. Percutaneous coronary intervention was successfully performed in 3 patients. Eight patients were managed medically. Arterial bypass graft was performed in 4 patients with the squeezed SCA. CONCLUSION: SCA may be associated with transient transmural myocardial ischemia and aborted sudden death in the absence of coronary atherosclerosis. The availability and sophistication of MSCT facilitates the delineation of the course of a SCA. We present a Dutch case series and review of the literature. PMID- 24772260 TI - Prognostic value of increased carbohydrate antigen in patients with heart failure. AB - AIM: To study the prognostic value of carbohydrate antigen 125 (CA125) and whether it adds prognostic information to N-terminal pro-brain natriuretic peptide (NT-proBNP) in stable heart failure (HF) patients. METHODS: The predictive value of CA125 was retrospectively assessed in 156 patients with stable HF remitted to the outpatient HF unit for monitoring from 2009 to 2011. Patients were included in the study if they had a previous documented episode of HF and received HF treatment. CA125 and NT-proBNP concentrations were measured. The independent association between NT-proBNP or CA125 and mortality was assessed with Cox regression analysis, and their combined predictive ability was tested by the integrated discrimination improvement (IDI) index. RESULTS: The mean age of the 156 patients was 72 +/- 12 years. During follow-up (17 +/- 8 mo), 27 patients died, 1 received an urgent heart transplantation and 106 required hospitalization for HF. Higher CA125 values were correlated with outcomes: 58 +/- 85 KU/L if hospitalized vs 34 +/- 61 KU/L if not (P < 0.05), and 94 +/- 121 KU/L in those who died or needed urgent heart transplantation vs 45 +/- 78 KU/L in survivors (P < 0.01). After adjusting for propensity scores, the highest risk was observed when both biomarkers were elevated vs not elevated (HR = 8.95, 95%CI: 3.11-25.73; P < 0.001) and intermediate when only NT-proBNP was elevated vs not elevated (HR = 4.15, 95%CI: 1.41-12.24; P < 0.01). Moreover, when CA125 was added to the clinical model with NT-proBNP, a 4% (P < 0.05) improvement in the IDI was found. CONCLUSION: CA125 > 60 KU/L identified patients in stable HF with poor survival. Circulating CA125 level adds prognostic value to NT-proBNP level in predicting HF outcomes. PMID- 24772261 TI - Cardiac embolism after implantable cardiac defibrillator shock in non anticoagulated atrial fibrillation: The role of left atrial appendage occlusion. AB - Cardioembolic events are one of the most feared complications in patients with non-valvular atrial fibrillation (NVAF) and a formal contraindication to oral anticoagulation (OAC). The present case report describes a case of massive peripheral embolism after an implantable cardiac defibrillator (ICD) shock in a patient with NVAF and a formal contraindication to OAC due to previous intracranial hemorrhage. In order to reduce the risk of future cardioembolic events, the patient underwent percutaneous left atrial appendage (LAA) occlusion. A 25 mm AmplatzerTM Amulet was implanted and the patient was discharged the following day without complications. The potential risk of thrombus dislodgement after an electrical shock in patients with NVAF and no anticoagulation constitutes a particular scenario that might be associated with an additional cardioembolic risk. Although LAA occlusion is a relatively new technique, its usage is rapidly expanding worldwide and constitutes a very valid alternative for patients with NVAF and a formal contraindication to OAC. PMID- 24772262 TI - Mechanical evaluation and fem analysis of stress in fixed partial dentures zirconium-ceramic. AB - OBJECTIVE: Over the last several years, the Finite Element Analysis (FEM) has been widely recognized as a reference method in different fields of study, to simulate the distribution of mechanical stress, in order to evaluate the relative distribution of loads of different nature. The aim of this study is to investigate through the FEM analysis the stress distribution in fixed prostheses that have a core in Zirconia and a ceramic veneer supported by implants. MATERIALS AND METHODS: In this work we investigated the mechanical flexural strength of a ceramic material (Noritake((r))) and a of zirconium framework (Zircodent((r))) and the effects of the manufacturing processes of the material commonly performed during the production of fixed prostheses with CAD/CAM technology. Specifically three point bending mechanical tests were performed (three-point-bending) (1-3), using a machine from Test Equipment Instron 5566((r)), on two structures in zirconium framework-ceramic (structures supported by two implant abutments with pontic elements 1 and 2). A further in-depth analysis on the mechanical behavior in flexure of the specimens was conducted carrying out FEM studies in order to compare analog and digital data. RESULTS: The analysis of the data obtained showed that the stresses are distributed in a different way according to the intrinsic elasticity of the structure. The analysis of FPD with four elements, the stresses are mainly concentrated on the surface of the load, while, in the FPD of three elements, much more rigid, the stresses are concentrated near the inner margins of the abutments. The concentration of many stresses in this point could be correlated to chipping (4) that is found in the outer edges of the structure, as a direct result of the ceramic brittleness which opposes the resilience of the structure subjected to bending. CONCLUSIONS: The analysis of the UY linear displacement confirms previous data, showing, in a numerical way, that the presence of the ceramic is related to the lowering of the structure. So, the reference values are those of the linear lowering obtained in the Mechanical Test and in our FEM analysis. zirconium framework with four elements 4,227 10(-2)mm.zirconium framework with ceramic structure with four elements 2,266 10(-2) mm.That suggests that the presence of ceramics halves the flexion capabilities of the prosthetic materials. PMID- 24772263 TI - Diagnosis and treatment of paranasal sinus fungus ball of odontogenic origin: case report. AB - In recent years the incidence of fungal sinusitis has increased considerably, due both to increased survival of patients at risk and to improved diagnostic equipment. The pathogen responsible in most cases is the Aspergillus in its forms Fumigatus, Flavus and Niger. The diagnosis is often delayed because the symptoms, characterized by headache, cough, and facial algia, are generally similar to that of chronic bacterial rhinosinusitis. It can be divided into invasive and non invasive forms based on the clinical evolution and extent of the lesion. We report a case of non-invasive fungal rhinosinusitis in a patient with recurrent sinusitis and pain in the left maxillary region, resistant to antibiotic therapy. PMID- 24772264 TI - Sealants in dentistry: a systematic review of the literature. AB - The occlusal surface is the most affected area by dental caries and the sealing of the pits and of the fissures has been found, in time, the preventive method most effective trying to counteract the onset. Currently, the WHO considers it as a primary preventive measure, in other words one of the most effective and least invasive available to ensure the complete protection and the total preservation of the occlusal carious by the phenomenon. PURPOSE: THE AIM OF THIS WORK HAS BEEN TO PERFORM A SYSTEMATIC REVIEW OF THE LITERATURE ON CLINICAL TRIALS OF DIFFERENT SEALING MATERIALS, IN ORDER TO: compare their individual characteristics, highlight the reliability and the long-term efficacy and identify the most significant variables, both technological and clinics, in order to declare whether or not the success of this method prior. MATERIALS AND METHODS: The research has been carried out in the MEDLINE database by choosing keywords as "sealants" and "follow up". Only studies published in the last thirteen years have been considered and have been evaluated only types of scientific articles that fall within the definition of Anglo-Saxon "Clinical Trial" and "Controlled Clinical Trial", excluding all experimental works in vitro, case-reports, meta analyzes and literature reviews. Have been also considered only scientific papers on patients between the ages of 0 and 18 years. RESULTS: Out of 29 studies, evaluating a total of 2900 individuals (aged between 2.5 and 17 years), 7411 seals made by using resin-based sealants (RB Sealants), modified glass ionomer sealants (RMGI) and compomer sealants have been analyzed. The best retention capacity of the material in time has been obtained from the use of RB Sealants compared to RMGI, demonstrating retention values much lower with partial loss of material at a distance of one year from the clinic. The compomers demonstrate retention values intermediates. The incidence of caries in a year is negligible for all sealants application. CONCLUSIONS: In terms of retention, resin-based sealants (RB Sealants) are the materials that give more guarantees of success at 12 months, while in the same period there haven't been significant differences in caries prevention of disease among the various classes sealing materials analyzed. PMID- 24772265 TI - A patient with meningeal melanomatosis treated for periodontal disease with a bone regeneration procedure and dental implants: clinical and behavioral management to support medical compliance. AB - BACKGROUND: During the last three decades dental implants have become increasingly used in partially edentulous periodontally compromised patients. The type of bacteria in the peri-implant sulcus is influenced by the periodontal bacteria present on the surfaces of the remaining teeth. Peri-implant sulci of partially edentulous individuals harbour more motile rods and spirochetes than those of fully edentulous individuals. If Peri-implantitis arises, it may lead to implant failure. This complication occurs more frequently in patients with poor oral hygiene. This is a site-specific bacterial infection similar to that caused by periodontal bacteria around teeth and it should be prevented. AIM: This study was conducted to radiographically evaluate hard tissue response around 6 implants, over a 2-year period, in a previously surgically treated patient affected by severe chronic periodontitis. Psychological considerations and behavioral management of the patient are described. MATERIALS AND METHODS: A complex implant-perio-prosthodontic case of a 54-year-old man affected by meningeal melanomatosis with a history of generalized severe chronic periodontitis was recruited. A comprehensive periodontal examination around teeth was accomplished before periodontal and implant treatment. After diagnostic work up, compromised teeth from 1.3 to 2.3 and from 3.2 to 4.2 were extracted. Tooth 1.7 was also extracted. Afterwards fixed provisional restoration rehabilitated all the natural dentition and the missing teeth. Endodonthic therapies were conducted on all the teeth due to high dentinal sensitivity and pre-prosthodontic crown reconstructions performed. Periodontal surgery with modified Widman flaps were then accomplished on all the teeth. Three months later four maxillary implants in position 1.3,1.1,2.1,2.3 and two mandibular implants in position 4.2,3.2 were inserted. During mandibular implants positioning, the mental mussels were isolated and detached to achieve proper guided bone regeneration. During implant surgery, due to systemic conditions concern, the patient underwent intravenous sedation. Five months later the implants and the teeth were rehabilitated with fixed metal-ceramic bridges. Regarding the upper prosthetic rehabilitation, the incisors marginal edges were kept vertical to the nasal spine, due to lack of previous reference points. According to the reference points previously determined, the difference in bone level between radiographs taken at implants insertion and at the maintenance appointments was calculated. RESULTS: The health of the periodontally treated teeth resulted greatly enhanced. The mean alveolar bore loss was 0,30 mm after a 2-year observation period. CONCLUSIONS: The control of the periodontal disease before implant insertion in patients with severe chronic periodontitis is of paramount importance, as well as a regular maintenance program is essential for the health of the periodontal and peri-implant tissues. The management of patients with complex needs requires a multidisciplinary team designed to meet all the patient's needs on various levels. PMID- 24772267 TI - Guidelines for a priori grouping of species in hierarchical community models. AB - Recent methodological advances permit the estimation of species richness and occurrences for rare species by linking species-level occurrence models at the community level. The value of such methods is underscored by the ability to examine the influence of landscape heterogeneity on species assemblages at large spatial scales. A salient advantage of community-level approaches is that parameter estimates for data-poor species are more precise as the estimation process "borrows" from data-rich species. However, this analytical benefit raises a question about the degree to which inferences are dependent on the implicit assumption of relatedness among species. Here, we assess the sensitivity of community/group-level metrics, and individual-level species inferences given various classification schemes for grouping species assemblages using multispecies occurrence models. We explore the implications of these groupings on parameter estimates for avian communities in two ecosystems: tropical forests in Puerto Rico and temperate forests in northeastern United States. We report on the classification performance and extent of variability in occurrence probabilities and species richness estimates that can be observed depending on the classification scheme used. We found estimates of species richness to be most precise and to have the best predictive performance when all of the data were grouped at a single community level. Community/group-level parameters appear to be heavily influenced by the grouping criteria, but were not driven strictly by total number of detections for species. We found different grouping schemes can provide an opportunity to identify unique assemblage responses that would not have been found if all of the species were analyzed together. We suggest three guidelines: (1) classification schemes should be determined based on study objectives; (2) model selection should be used to quantitatively compare different classification approaches; and (3) sensitivity of results to different classification approaches should be assessed. These guidelines should help researchers apply hierarchical community models in the most effective manner. PMID- 24772266 TI - A perspective on molecular therapy in cholangiocarcinoma: present status and future directions. AB - Cholangiocarcinoma (CCA) is an orphan cancer with limited understanding of its genetic and genomic pathogenesis. Typically, it is highly treatment-refractory and patient outcome is dismal. Currently, there are no approved therapeutics for CCA and surgical resection remains the only option with curative intent. Clinical trials are currently being performed in a mixed cohort of biliary tract cancers that includes intrahepatic CCA, extrahepatic/perihilar CCA, distal extrahepatic CCA, gallbladder carcinoma and, in rare cases, even pancreatic cancers. Today, clinical trials fail primarily because they are underpowered mixed cohorts and designed without intent to enrich for markers to optimize success for targeted therapy. This review aims to emphasize current clinical attempts for targeted therapy of CCA, as well as highlight promising new candidate pathways revealed by translational genomics. PMID- 24772268 TI - Does seasonality drive spatial patterns in demography? Variation in survival in African reed warblers Acrocephalus baeticatus across southern Africa does not reflect global patterns. AB - Among birds, northern temperate species generally have larger clutches, shorter development periods and lower adult survival than similarly-sized southern and tropical species. Even though this global pattern is well accepted, the driving mechanism is still not fully understood. The main theories are founded on the differing environmental seasonality of these zones (higher seasonality in the North). These patterns arise in cross-species comparisons, but we hypothesized that the same patterns should arise among populations within a species if different types of seasonality select for different life histories. Few studies have examined this. We estimated survival of an azonal habitat specialist, the African reed warbler, across the environmentally diverse African subcontinent, and related survival to latitude and to the seasonality of the different environments of their breeding habitats. Data (1998-2010) collected through a public ringing scheme were analyzed with hierarchical capture-mark-recapture models to determine resident adult survival and its spatial variance across sixteen vegetation units spread across four biomes. The models were defined as state-space multi-state models to account for transience and implemented in a Bayesian framework. We did not find a latitudinal trend in survival or a clear link between seasonality and survival. Spatial variation in survival was substantial across the sixteen sites (spatial standard deviation of the logit mean survival: 0.70, 95% credible interval (CRI): 0.33-1.27). Mean site survival ranged from 0.49 (95% CRI: 0.18-0.80) to 0.83 (95% CRI: 0.62-0.97) with an overall mean of 0.67 (95% CRI: 0.47-0.85). A hierarchical modeling approach enabled us to estimate spatial variation in survival of the African reed warbler across the African subcontinent from sparse data. Although we could not confirm the global pattern of higher survival in less seasonal environments, our findings from a poorly studied region contribute to the study of life-history strategies. PMID- 24772269 TI - Human-aided admixture may fuel ecosystem transformation during biological invasions: theoretical and experimental evidence. AB - Biological invasions can transform our understanding of how the interplay of historical isolation and contemporary (human-aided) dispersal affects the structure of intraspecific diversity in functional traits, and in turn, how changes in functional traits affect other scales of biological organization such as communities and ecosystems. Because biological invasions frequently involve the admixture of previously isolated lineages as a result of human-aided dispersal, studies of invasive populations can reveal how admixture results in novel genotypes and shifts in functional trait variation within populations. Further, because invasive species can be ecosystem engineers within invaded ecosystems, admixture-induced shifts in the functional traits of invaders can affect the composition of native biodiversity and alter the flow of resources through the system. Thus, invasions represent promising yet under-investigated examples of how the effects of short-term evolutionary changes can cascade across biological scales of diversity. Here, we propose a conceptual framework that admixture between divergent source populations during biological invasions can reorganize the genetic variation underlying key functional traits, leading to shifts in the mean and variance of functional traits within invasive populations. Changes in the mean or variance of key traits can initiate new ecological feedback mechanisms that result in a critical transition from a native ecosystem to a novel invasive ecosystem. We illustrate the application of this framework with reference to a well-studied plant model system in invasion biology and show how a combination of quantitative genetic experiments, functional trait studies, whole ecosystem field studies and modeling can be used to explore the dynamics predicted to trigger these critical transitions. PMID- 24772270 TI - Divergent warning patterns contribute to assortative mating between incipient Heliconius species. AB - Theoretical models suggest that traits under divergent ecological selection, which also contribute to assortative mating, will facilitate speciation with gene flow. Evidence for these so-called "magic traits" now exists across a range of taxa. However, their importance during speciation will depend on the extent to which they contribute to reproductive isolation. Addressing this requires experiments to determine the exact cues involved as well as estimates of assortative mating in the wild. Heliconius butterflies are well known for their diversity of bright warning color patterns, and their amenability to experimental manipulation has provided an excellent opportunity to test their role in reproductive isolation. Here, we reveal that divergent color patterns contribute to mate recognition between the incipient species Heliconius himera and H. erato, a taxon pair for which assortative mating by color pattern has been demonstrated among wild individuals: First, we demonstrate that males are more likely to attempt to mate conspecific females; second, we show that males are more likely to approach pinned females that share their own warning pattern. These data are valuable as these taxa likely represent the early stages of speciation, but unusually also allow comparisons with rates of interbreeding between divergent ecologically relevant phenotypes measured in the wild. PMID- 24772271 TI - Phytoplankton chlorophyte structure as related to ENSO events in a saline lowland river (Salado River, Buenos Aires, Argentina). AB - We analyzed the phytoplankton present in the lower sector of the Salado River (Buenos Aires, Argentina) for 10 years (1995-2005) and detected significant changes occurring in chlorophyte abundance and species richness during La Nina event (1998-1999), which period was analyzed throughout the entire basin (main stream and tributaries). We compared the physicochemical and biologic variables between two El Nino-La Nina-Southern Oscillation (ENSO) periods - El Nino (March 1997-January 1998) and La Nina (May 1998-May 1999) - to identify possible indicators of a relationship between climatic anomalies and chlorophyte performance. Chlorophyte density increased during the La Nina. Under normal or extreme hydrologic conditions, mobile (Chlamydomonas spp.) and nonmobile (Monoraphidium spp.) chlorophytes codominated. These species belonged to Reynolds's functional groups X1 and X2, those typical of nutrient-enriched environments. Comparative analyses between El Nino and La Nina periods indicated significant differences in physicochemical (K(+), dissolved polyphenols, particulate reactive phosphorus, alkalinity, pH) and biologic (species diversity and richness, phytoplankton and chlorophyte total densities) variables between the two periods at all basin sites. During the La Nina condition, species richness was greater owing to interconnected shallow lakes and drainage-channel inputs, while the Shannon diversity index was lower because of the high abundance values of Monoraphidium minutum. A detailed analysis of the chlorophytes in the entire basin, indicated that changes in density and species dominance occurred on a regional scale although diverse chlorophyte assemblages were identified in the different sectors of the Salado River basin. After La Nina event, the entire basin had the potential to revert to the previous density values, showing the resilience to global environmental changes and the ability to reestablish the general conditions of stability. PMID- 24772272 TI - Testing the consistency of wildlife data types before combining them: the case of camera traps and telemetry. AB - Wildlife data gathered by different monitoring techniques are often combined to estimate animal density. However, methods to check whether different types of data provide consistent information (i.e., can information from one data type be used to predict responses in the other?) before combining them are lacking. We used generalized linear models and generalized linear mixed-effects models to relate camera trap probabilities for marked animals to independent space use from telemetry relocations using 2 years of data for fishers (Pekania pennanti) as a case study. We evaluated (1) camera trap efficacy by estimating how camera detection probabilities are related to nearby telemetry relocations and (2) whether home range utilization density estimated from telemetry data adequately predicts camera detection probabilities, which would indicate consistency of the two data types. The number of telemetry relocations within 250 and 500 m from camera traps predicted detection probability well. For the same number of relocations, females were more likely to be detected during the first year. During the second year, all fishers were more likely to be detected during the fall/winter season. Models predicting camera detection probability and photo counts solely from telemetry utilization density had the best or nearly best Akaike Information Criterion (AIC), suggesting that telemetry and camera traps provide consistent information on space use. Given the same utilization density, males were more likely to be photo-captured due to larger home ranges and higher movement rates. Although methods that combine data types (spatially explicit capture-recapture) make simple assumptions about home range shapes, it is reasonable to conclude that in our case, camera trap data do reflect space use in a manner consistent with telemetry data. However, differences between the 2 years of data suggest that camera efficacy is not fully consistent across ecological conditions and make the case for integrating other sources of space-use data. PMID- 24772273 TI - Filling the gap in functional trait databases: use of ecological hypotheses to replace missing data. AB - Functional trait databases are powerful tools in ecology, though most of them contain large amounts of missing values. The goal of this study was to test the effect of imputation methods on the evaluation of trait values at species level and on the subsequent calculation of functional diversity indices at community level using functional trait databases. Two simple imputation methods (average and median), two methods based on ecological hypotheses, and one multiple imputation method were tested using a large plant trait database, together with the influence of the percentage of missing data and differences between functional traits. At community level, the complete-case approach and three functional diversity indices calculated from grassland plant communities were included. At the species level, one of the methods based on ecological hypothesis was for all traits more accurate than imputation with average or median values, but the multiple imputation method was superior for most of the traits. The method based on functional proximity between species was the best method for traits with an unbalanced distribution, while the method based on the existence of relationships between traits was the best for traits with a balanced distribution. The ranking of the grassland communities for their functional diversity indices was not robust with the complete-case approach, even for low percentages of missing data. With the imputation methods based on ecological hypotheses, functional diversity indices could be computed with a maximum of 30% of missing data, without affecting the ranking between grassland communities. The multiple imputation method performed well, but not better than single imputation based on ecological hypothesis and adapted to the distribution of the trait values for the functional identity and range of the communities. Ecological studies using functional trait databases have to deal with missing data using imputation methods corresponding to their specific needs and making the most out of the information available in the databases. Within this framework, this study indicates the possibilities and limits of single imputation methods based on ecological hypothesis and concludes that they could be useful when studying the ranking of communities for their functional diversity indices. PMID- 24772274 TI - Revising traditional theory on the link between plant body size and fitness under competition: evidence from old-field vegetation. AB - The selection consequences of competition in plants have been traditionally interpreted based on a "size-advantage" hypothesis - that is, under intense crowding/competition from neighbors, natural selection generally favors capacity for a relatively large plant body size. However, this conflicts with abundant data, showing that resident species body size distributions are usually strongly right-skewed at virtually all scales within vegetation. Using surveys within sample plots and a neighbor-removal experiment, we tested: (1) whether resident species that have a larger maximum potential body size (MAX) generally have more successful local individual recruitment, and thus greater local abundance/density (as predicted by the traditional size-advantage hypothesis); and (2) whether there is a general between-species trade-off relationship between MAX and capacity to produce offspring when body size is severely suppressed by crowding/competition - that is, whether resident species with a larger MAX generally also need to reach a larger minimum reproductive threshold size (MIN) before they can reproduce at all. The results showed that MIN had a positive relationship with MAX across resident species, and local density - as well as local density of just reproductive individuals - was generally greater for species with smaller MIN (and hence smaller MAX). In addition, the cleared neighborhoods of larger target species (which had relatively large MIN) generally had - in the following growing season - a lower ratio of conspecific recruitment within these neighborhoods relative to recruitment of other (i.e., smaller) species (which had generally smaller MIN). These data are consistent with an alternative hypothesis based on a 'reproductive-economy-advantage' - that is, superior fitness under competition in plants generally requires not larger potential body size, but rather superior capacity to recruit offspring that are in turn capable of producing grand-offspring - and hence transmitting genes to future generations - despite intense and persistent (cross-generational) crowding/competition from near neighbors. Selection for the latter is expected to favor relatively small minimum reproductive threshold size and hence - as a tradeoff - relatively small (not large) potential body size. PMID- 24772275 TI - Biologic interactions determining geographic range size: a one species response to phylogenetic community structure. AB - Range size variation in closely related species suggests different responses to biotic and abiotic heterogeneity across large geographic regions. Species turnover generates a wide spectrum of species assemblages, resulting in different competition intensities among taxa, creating restrictions as important as environmental constraints. We chose to adopt the widely used phylogenetic relatedness (NRI) measurement to define a metric that depicts competition strength (via phylogenetic similarity), which one focal species confronts in its environment. This new approach (NRIfocal) measures the potential of the community structure effect over performance of a single species. We chose two ecologically similar Peucaea sparrows, which co-occur and have highly dissimilar range size to test whether the population response to competition intensity is different between species. We analyzed the correlation between both Peucaea species population sizes and NRIfocal using data from point counts. Results indicated that the widespread species population size was not associated with NRIfocal, whereas the population of restricted-sized species exhibited a negative relationship with competition intensity. Consequently, a species' sensitivity to competition might be a limiting factor to range expansion, which provides new insights into geographic range analysis and community ecology. PMID- 24772276 TI - Deep phylogeographic divergence of a migratory passerine in Sino-Himalayan and Siberian forests: the Red-flanked Bluetail (Tarsiger cyanurus) complex. AB - Enormous mountainous forests in Sino-Himalayans and Siberia harbor important avian biodiversity in the Northern Hemisphere. Numerous studies in last two decades have been contributed to systematics and taxonomy of passerines birds in these regions and have revealed various and complex phylogeographic patterns. A passerine species Red-flanked Bluetail Tarsiger cyanurus provided a good system to manifest such evolutionary complexity. The subspecies T. c. cyanurus and T. c. rufilatus (or/and T. c. pallidior), divergent in morphology, acoustics, and migratory strategies are allopatric in Siberia and Sino-Himalayan forests, respectively. The two taxa most likely deserve full species status but rigorous genetic analysis is missing. In this study, multilocus phylogeography based on mitochondrial DNA and Z-linked DNA reveals that T. c. cyanurus and T. c. rufilatus are reciprocally monophyletic with significant statistical support and differ with a large number of diagnostic nucleotide sites resulting substantial genetic divergence. Our finding supports the proposed split of Tarsiger cyanurus s.l. that T. cyanurus and T. rufilatus should be treated as two full species. Whether "pallidior" is a subspecies or geographical form of T. rufilatus is still uncertain. Additionally, these two forest passerine species may have diverged 1.88 (3.25-1.30) Mya, which might be shaped by geographical vicariance due to grassland and desert steppe on the central Loess Plateau during the Pliocene. Taken together, this study and further suggests another independent example of North Palearctic-Sino-Himalayan phylogeographic pattern in Palearctic birds. PMID- 24772277 TI - Modeling the role of the close-range effect and environmental variables in the occurrence and spread of Phragmites australis in four sites on the Finnish coast of the Gulf of Finland and the Archipelago Sea. AB - Phragmites australis, a native helophyte in coastal areas of the Baltic Sea, has significantly spread on the Finnish coast in the last decades raising ecological questions and social interest and concern due to the important role it plays in the ecosystem dynamics of shallow coastal areas. Despite its important implications on the planning and management of the area, predictive modeling of Phragmites distribution is not well studied. We examined the prevalence and progression of Phragmites in four sites along the Southern Finnish coast in multiple time frames in relation to a number of predictors. We also analyzed patterns of neighborhood effect on the expansion and disappearance of Phragmites in a cellular data model. We developed boosted regression trees models to predict Phragmites occurrences and produce maps of habitat suitability. Various Phragmites spread figures were observed in different areas and time periods, with a minimum annual expansion rate of 1% and a maximum of 8%. The water depth, shore openness, and proximity to river mouths were found influential in Phragmites distribution. The neighborhood configuration partially explained the dynamics of Phragmites colonies. The boosted regression trees method was successfully used to interpolate and extrapolate Phragmites distributions in the study sites highlighting its potential for assessing habitat suitability for Phragmites along the Finnish coast. Our findings are useful for a number of applications. With variables easily available, delineation of areas susceptible for Phragmites colonization allows early management plans to be made. Given the influence of reed beds on the littoral species and ecosystem, these results can be useful for the ecological studies of coastal areas. We provide estimates of habitat suitability and quantification of Phragmites expansion in a form suitable for dynamic modeling, which would be useful for predicting future Phragmites distribution under different scenarios of land cover change and Phragmites spatial configuration. PMID- 24772278 TI - A quantitative life history of endangered humpback chub that spawn in the Little Colorado River: variation in movement, growth, and survival. AB - While the ecology and evolution of partial migratory systems (defined broadly to include skip spawning) have been well studied, we are only beginning to understand how partial migratory populations are responding to ongoing environmental change. Environmental change can lead to differences in the fitness of residents and migrants, which could eventually lead to changes in the frequency of the strategies in the overall population. Here, we address questions concerning the life history of the endangered Gila cypha (humpback chub) in the regulated Colorado River and the unregulated tributary and primary spawning area, the Little Colorado River. We develop eight multistate models for the population based on three movement hypotheses, in which states are defined in terms of fish size classes and river locations. We fit these models to mark-recapture data collected in 2009-2012. We compare survival and growth estimates between the Colorado River and Little Colorado River and calculate abundances for all size classes. The best model supports the hypotheses that larger adults spawn more frequently than smaller adults, that there are residents in the spawning grounds, and that juveniles move out of the Little Colorado River in large numbers during the monsoon season (July-September). Monthly survival rates for G. cypha in the Colorado River are higher than in the Little Colorado River in all size classes; however, growth is slower. While the hypothetical life histories of life-long residents in the Little Colorado River and partial migrants spending most of its time in the Colorado River are very different, they lead to roughly similar fitness expectations when we used expected number of spawns as a proxy. However, more research is needed because our study period covers a period of years when conditions in the Colorado River for G. cypha are likely to have been better than has been typical over the last few decades. PMID- 24772279 TI - Increased genetic divergence between two closely related fir species in areas of range overlap. AB - Because of introgressive hybridization, closely related species can be more similar to each other in areas of range overlap (parapatry or sympatry) than in areas where they are geographically isolated from each other (allopatry). Here, we report the reverse situation based on nuclear genetic divergence between two fir species, Abies chensiensis and Abies fargesii, in China, at sites where they are parapatric relative to where they are allopatric. We examined genetic divergence across 126 amplified fragment length polymorphism (AFLP) markers in a set of 172 individuals sampled from both allopatric and parapatric populations of the two species. Our analyses demonstrated that AFLP divergence was much greater between the species when comparisons were made between parapatric populations than between allopatric populations. We suggest that selection in parapatry may have largely contributed to this increased divergence. PMID- 24772281 TI - Temporal changes of soil physic-chemical properties at different soil depths during larch afforestation by multivariate analysis of covariance. AB - Soil physic-chemical properties differ at different depths; however, differences in afforestation-induced temporal changes at different soil depths are seldom reported. By examining 19 parameters, the temporal changes and their interactions with soil depth in a large chronosequence dataset (159 plots; 636 profiles; 2544 samples) of larch plantations were checked by multivariate analysis of covariance (MANCOVA). No linear temporal changes were found in 9 parameters (N, K, N:P, available forms of N, P, K and ratios of N: available N, P: available P and K: available K), while marked linear changes were found in the rest 10 parameters. Four of them showed divergent temporal changes between surface and deep soils. At surface soils, changing rates were 262.1 g.kg(-1).year(-1) for SOM, 438.9 mg.g( 1).year(-1) for C:P, 5.3 mg.g(-1).year(-1) for C:K, and -3.23 mg.cm(-3).year(-1) for bulk density, while contrary tendencies were found in deeper soils. These divergences resulted in much moderated or no changes in the overall 80-cm soil profile. The other six parameters showed significant temporal changes for overall 0-80-cm soil profile (P: -4.10 mg.kg(-1).year(-1); pH: -0.0061 unit.year(-1); C:N: 167.1 mg.g(-1).year(-1); K:P: 371.5 mg.g(-1) year(-1); N:K: -0.242 mg.g( 1).year(-1); EC: 0.169 MUS.cm(-1).year(-1)), but without significant differences at different soil depths (P > 0.05). Our findings highlight the importance of deep soils in studying physic-chemical changes of soil properties, and the temporal changes occurred in both surface and deep soils should be fully considered for forest management and soil nutrient balance. PMID- 24772280 TI - Risk-sensitive reproductive allocation: fitness consequences of body mass losses in two contrasting environments. AB - For long-lived organisms, the fitness value of survival is greater than that of current reproduction. Asymmetric fitness rewards suggest that organisms inhabiting unpredictable environments should adopt a risk-sensitive life history, predicting that it is adaptive to allocate resources to increase their own body reserves at the expense of reproduction. We tested this using data from reindeer populations inhabiting contrasting environments and using winter body mass development as a proxy for the combined effect of winter severity and density dependence. Individuals in good and harsh environments responded similarly: Females who lost large amounts of winter body mass gained more body mass the coming summer compared with females losing less mass during winter. Additionally, females experienced a cost of reproduction: On average, barren females gained more body mass than lactating females. Winter body mass development positively affected both the females' reproductive success and offspring body mass. Finally, we discuss the relevance of our findings with respect to scenarios for future climate change. PMID- 24772282 TI - Do riparian reserves support dung beetle biodiversity and ecosystem services in oil palm-dominated tropical landscapes? AB - Agricultural expansion and intensification are major threats to global biodiversity, ecological functions, and ecosystem services. The rapid expansion of oil palm in forested tropical landscapes is of particular concern given their high biodiversity. Identifying management approaches that maintain native species and associated ecological processes within oil palm plantations is therefore a priority. Riparian reserves are strips of forest retained alongside rivers in cultivated areas, primarily for their positive hydrological impact. However, they can also support a range of forest-dependent species or ecosystem services. We surveyed communities of dung beetles and measured dung removal activity in an oil palm-dominated landscape in Sabah, Malaysian Borneo. The species richness, diversity, and functional group richness of dung beetles in riparian reserves were significantly higher than in oil palm, but lower than in adjacent logged forests. The community composition of the riparian reserves was more similar to logged forest than oil palm. Despite the pronounced differences in biodiversity, we did not find significant differences in dung removal rates among land uses. We also found no evidence that riparian reserves enhance dung removal rates within surrounding oil palm. These results contrast previous studies showing positive relationships between dung beetle species richness and dung removal in tropical forests. We found weak but significant positive relationships between riparian reserve width and dung beetle diversity, and between reserve vegetation complexity and dung beetle abundance, suggesting that these features may increase the conservation value of riparian reserves. Synthesis and applications: The similarity between riparian reserves and logged forest demonstrates that retaining riparian reserves increases biodiversity within oil palm landscapes. However, the lack of correlation between dung beetle community characteristics and dung removal highlights the need for further research into spatial variation in biodiversity-ecosystem function relationships and how the results of such studies are affected by methodological choices. PMID- 24772283 TI - Soil moisture variations affect short-term plant-microbial competition for ammonium, glycine, and glutamate. AB - We tested whether the presence of plant roots would impair the uptake of ammonium ([Formula: see text]), glycine, and glutamate by microorganisms in a deciduous forest soil exposed to constant or variable moisture in a short-term (24-h) experiment. The uptake of (15)NH4 and dual labeled amino acids by the grass Festuca gigantea L. and soil microorganisms was determined in planted and unplanted soils maintained at 60% WHC (water holding capacity) or subject to drying and rewetting. The experiment used a design by which competition was tested in soils that were primed by plant roots to the same extent in the planted and unplanted treatments. Festuca gigantea had no effect on microbial N uptake in the constant moist soil, but its presence doubled the microbial [Formula: see text] uptake in the dried and rewetted soil compared with the constant moist. The drying and rewetting reduced by half or more the [Formula: see text] uptake by F. gigantea, despite more than 60% increase in the soil concentration of [Formula: see text]. At the same time, the amino acid and [Formula: see text]-N became equally valued in the plant uptake, suggesting that plants used amino acids to compensate for the lower [Formula: see text] acquisition. Our results demonstrate the flexibility in plant-microbial use of different N sources in response to soil moisture fluctuations and emphasize the importance of including transient soil conditions in experiments on resource competition between plants and soil microorganisms. Competition between plants and microorganisms for N is demonstrated by a combination of removal of one of the potential competitors, the plant, and subsequent observations of the uptake of N in the organisms in soils that differ only in the physical presence and absence of the plant during a short assay. Those conditions are necessary to unequivocally test for competition. PMID- 24772284 TI - A long-term field experiment of soil transplantation demonstrating the role of contemporary geographic separation in shaping soil microbial community structure. AB - The spatial patterns of microbial communities are largely determined by the combined effects of historical contingencies and contemporary environmental disturbances, but their relative importance remains poorly understood. Empirical biogeographic data currently available are mostly based on the traditional method of observational survey, which typically involves comparing indigenous microbial communities across spatial scales. Here, we report a long-term soil transplantation experiment, whereby the same two soils (red Acrisol and purple Cambisol from Yingtan) were placed into two geographic locations of ~1000 km apart (i.e., Yingtan in the mid-subtropical region and Fengqiu in warm-temperate region; both located in China). Twenty years after the transplantation, the resulting soil microbial communities were subject to high-throughput 454 pyrosequencing analysis of 16S and 18S rRNA genes. Additionally, bacteria and archaea involved in nitrogen cycling were estimated using clone library analysis of four genes: archaeal amoA, bacterial amoA,nirK, and nifH. Data of subsequent phylogenetic analysis show that bacteria, fungi, and other microbial eukaryotes, as well as the nitrogen cycling genes, are grouped primarily by the factor of geographic location rather than soil type. Moreover, a shift of microbial communities toward those in local soil (i.e., Chao soil in Fengqiu) has been observed. The results thus suggest that the historical effects persistent in the soil microbial communities can be largely erased by contemporary disturbance within a short period of 20 years, implicating weak effects of historical contingencies on the structure and composition of microbial communities in the soil. PMID- 24772285 TI - Exposure of trees to drought-induced die-off is defined by a common climatic threshold across different vegetation types. AB - Increases in drought and temperature stress in forest and woodland ecosystems are thought to be responsible for the rise in episodic mortality events observed globally. However, key climatic drivers common to mortality events and the impacts of future extreme droughts on tree survival have not been evaluated. Here, we characterize climatic drivers associated with documented tree die-off events across Australia using standardized climatic indices to represent the key dimensions of drought stress for a range of vegetation types. We identify a common probabilistic threshold associated with an increased risk of die-off across all the sites that we examined. We show that observed die-off events occur when water deficits and maximum temperatures are high and exist outside 98% of the observed range in drought intensity; this threshold was evident at all sites regardless of vegetation type and climate. The observed die-off events also coincided with at least one heat wave (three consecutive days above the 90th percentile for maximum temperature), emphasizing a pivotal role of heat stress in amplifying tree die-off and mortality processes. The joint drought intensity and maximum temperature distributions were modeled for each site to describe the co occurrence of both hot and dry conditions and evaluate future shifts in climatic thresholds associated with the die-off events. Under a relatively dry and moderate warming scenario, the frequency of droughts capable of inducing significant tree die-off across Australia could increase from 1 in 24 years to 1 in 15 years by 2050, accompanied by a doubling in the occurrence of associated heat waves. By defining commonalities in drought conditions capable of inducing tree die-off, we show a strong interactive effect of water and high temperature stress and provide a consistent approach for assessing changes in the exposure of ecosystems to extreme drought events. PMID- 24772286 TI - Three divergent lineages within an Australian marsupial (Petrogale penicillata) suggest multiple major refugia for mesic taxa in southeast Australia. AB - Mesic southeastern Australia represents the continent's ancestral biome and is highly biodiverse, yet its phylogeographic history remains poorly understood. Here, we examine mitochondrial DNA (mtDNA) control region and microsatellite diversity in the brush-tailed rock-wallaby (Petrogale penicillata;n = 279 from 31 sites), to assess historic evolutionary and biogeographic processes in southeastern Australia. Our results (mtDNA, microsatellites) confirmed three geographically discrete and genetically divergent lineages within brush-tailed rock-wallabies, whose divergence appears to date to the mid-Pleistocene. These three lineages had been hypothesized previously but data were limited. While the Northern and Central lineages were separated by a known biogeographic barrier (Hunter Valley), the boundary between the Central and Southern lineages was not. We propose that during particularly cool glacial cycles, the high peaks of the Great Dividing Range and the narrow adjacent coastal plain resulted in a more significant north-south barrier for mesic taxa in southeastern Australia than has been previously appreciated. Similarly, located phylogeographic breaks in codistributed species highlight the importance of these regions in shaping the distribution of biodiversity in southeastern Australia and suggest the existence of three major refuge areas during the Pleistocene. Substructuring within the northern lineage also suggests the occurrence of multiple local refugia during some glacial cycles. Within the three major lineages, most brush-tailed rock wallaby populations were locally highly structured, indicating limited dispersal by both sexes. The three identified lineages represent evolutionarily significant units and should be managed to maximize the retention of genetic diversity within this threatened species. PMID- 24772287 TI - Genetic diversity of a successful colonizer: isolated populations of Metrioptera roeselii regain variation at an unusually rapid rate. AB - Newly founded isolated populations need to overcome detrimental effects of low genetic diversity. The establishment success of a population may therefore depend on various mechanisms such as assortative mating, purging of deleterious alleles, creation of new mutations and/or repeated inflow of new genotypes to reduce the effects of inbreeding and further loss of genetic variation. We compared the level of genetic variation in introduced populations of an insect species (Metrioptera roeselii) far beyond its natural distribution with levels found in their respective founder populations and coupled the data with timing since establishment. This allowed us to analyze if the introduced populations showed signs of temporal changes in genetic variation and have made it possible to evaluate underlying mechanisms. For this, we used neutral genetic markers, seven microsatellite loci and a 676-bp-long sequence of the mtDNA COI gene. All tested indices (allelic richness, unbiased expected heterozygosity, effective size, haplotype diversity, and nucleotide diversity) except inbreeding coefficient had significantly higher values in populations within the founding populations inside the continuous area of the species distribution compared with the introduced populations. A logarithmic model showed a significant correlation of both allelic richness and unbiased expected heterozygosity with age of the isolated populations. Considering the species' inferred colonization history and likely introduction pathways, we suggest that multiple introductions are the main mechanism behind the temporal pattern observed. However, we argue that influences of assortative mating, directional selection, and effects of an exceptional high intrapopulation mutation rate may have impacts. The ability to regain genetic diversity at this level may be one of the main reasons why M. roeselii successfully continue to colonize northern Europe. PMID- 24772288 TI - Crater lake cichlids individually specialize along the benthic-limnetic axis. AB - A common pattern of adaptive diversification in freshwater fishes is the repeated evolution of elongated open water (limnetic) species and high-bodied shore (benthic) species from generalist ancestors. Studies on phenotype-diet correlations have suggested that population-wide individual specialization occurs at an early evolutionary and ecological stage of divergence and niche partitioning. This variable restricted niche use across individuals can provide the raw material for earliest stages of sympatric divergence. We investigated variation in morphology and diet as well as their correlations along the benthic limnetic axis in an extremely young Midas cichlid species, Amphilophus tolteca, endemic to the Nicaraguan crater lake Asososca Managua. We found that A. tolteca varied continuously in ecologically relevant traits such as body shape and lower pharyngeal jaw morphology. The correlation of these phenotypes with niche suggested that individuals are specialized along the benthic-limnetic axis. No genetic differentiation within the crater lake was detected based on genotypes from 13 microsatellite loci. Overall, we found that individual specialization in this young crater lake species encompasses the limnetic-as well as the benthic macro-habitat. Yet there is no evidence for any diversification within the species, making this a candidate system for studying what might be the early stages preceding sympatric divergence. A common pattern of adaptive diversification in freshwater fishes is the repeated evolution of open water (limnetic) species and of shore (benthic) species. Individual specialization can reflect earliest stages of evolutionary and ecological divergence. We here demonstrate individual specialization along the benthic-limnetic axis in a young adaptive radiation of crater lake cichlid fishes. PMID- 24772289 TI - Dynamics of bacterial and fungal communities associated with eggshells during incubation. AB - Microorganisms are closely associated with eggs and may play a determinant role in embryo survival. Yet, the majority of studies focusing on this association relied on culture-based methodology, eventually leading to a skewed assessment of microbial communities. By targeting the 16S rRNA gene and internal transcribed spacer (ITS) region, we, respectively, described bacterial and fungal communities on eggshells of the homing pigeon Columba livia. We explored their structure, abundance, and composition. Firstly, we showed that sampling technique affected the outcome of the results. While broadly used, the egg swabbing procedure led to a lower DNA extraction efficiency and provided different profiles of bacterial communities than those based on crushed eggshell pieces. Secondly, we observed shifts in bacterial and fungal communities during incubation. At late incubation, bacterial communities showed a reduction in diversity, while their abundance increased, possibly due to the competitive advantage of some species. When compared to their bacterial counterparts, fungal communities also decreased in diversity at late incubation. In that case, however, the decline was associated with a diminution of their overall abundance. Conclusively, our results showed that although incubation might inhibit microbial growth when compared to unincubated eggs, we observed the selective growth of specific bacterial species during incubation. Moreover, we showed that fungi are a substantial component of the microbial communities associated with eggshells and require further investigations in avian ecology. Identifying the functional roles of these microorganisms is likely to provide news insights into the evolutionary strategies that control embryo survival. We aimed to describe the dynamics of bacterial and fungal communities on homing pigeon eggshell surfaces. We investigated these communities at early and late incubation stages. PMID- 24772290 TI - Estimation of capture probabilities using generalized estimating equations and mixed effects approaches. AB - Modeling individual heterogeneity in capture probabilities has been one of the most challenging tasks in capture-recapture studies. Heterogeneity in capture probabilities can be modeled as a function of individual covariates, but correlation structure among capture occasions should be taking into account. A proposed generalized estimating equations (GEE) and generalized linear mixed modeling (GLMM) approaches can be used to estimate capture probabilities and population size for capture-recapture closed population models. An example is used for an illustrative application and for comparison with currently used methodology. A simulation study is also conducted to show the performance of the estimation procedures. Our simulation results show that the proposed quasi likelihood based on GEE approach provides lower SE than partial likelihood based on either generalized linear models (GLM) or GLMM approaches for estimating population size in a closed capture-recapture experiment. Estimator performance is good if a large proportion of individuals are captured. For cases where only a small proportion of individuals are captured, the estimates become unstable, but the GEE approach outperforms the other methods. PMID- 24772291 TI - Asymmetric reproductive barriers and mosaic reproductive isolation: insights from Misty lake-stream stickleback. AB - Ecological speciation seems to occur readily but is clearly not ubiquitous - and the relative contributions of different reproductive barriers remain unclear in most systems. We here investigate the potential importance of selection against migrants in lake/stream stickleback (Gasterosteus aculeatus) from the Misty Lake system, Canada. This system is of particular interest because one population contrast (Lake vs. Outlet stream) shows very low genetic and morphological divergence, whereas another population contrast (Lake vs. Inlet stream) shows dramatic genetic and morphological divergence apparently without strong and symmetric reproductive barriers. To test whether selection against migrants might solve this "conundrum of missing reproductive isolation", we performed a fully factorial reciprocal transplant experiment using 225 individually marked stickleback collected from the wild. Relative fitness of the different ecotypes (Lake, Inlet, and Outlet) was assessed based on survival and mass change in experimental enclosures. We found that Inlet fish performed poorly in the lake (selection against migrants in that direction), whereas Lake fish outperformed Inlet fish in all environments (no selection against migrants in the opposite direction). As predicted from their phenotypic and genetic similarity, Outlet and Lake fish performed similarly in all environments. These results suggest that selection against migrants is asymmetric and, together with previous work, indicates that multiple reproductive barriers contribute to reproductive isolation. Similar mosaic patterns of reproductive isolation are likely in other natural systems. PMID- 24772292 TI - Stressful environments can indirectly select for increased longevity. AB - Longevity is modulated by a range of conserved genes in eukaryotes, but it is unclear how variation in these genes contributes to the evolution of longevity in nature. Mutations that increase life span in model organisms typically induce trade-offs which lead to a net reduction in fitness, suggesting that such mutations are unlikely to become established in natural populations. However, the fitness consequences of manipulating longevity have rarely been assessed in heterogeneous environments, in which stressful conditions are encountered. Using laboratory selection experiments, we demonstrate that long-lived, stress resistant Caenorhabditis elegans age-1(hx546) mutants have higher fitness than the wild-type genotype if mixed genotype populations are periodically exposed to high temperatures when food is not limited. We further establish, using stochastic population projection models, that the age-1(hx546) mutant allele can confer a selective advantage if temperature stress is encountered when food availability also varies over time. Our results indicate that heterogeneity in environmental stress may lead to altered allele frequencies over ecological timescales and indirectly drive the evolution of longevity. This has important implications for understanding the evolution of life-history strategies. PMID- 24772293 TI - Climate of origin affects tick (Ixodes ricinus) host-seeking behavior in response to temperature: implications for resilience to climate change? AB - Climate warming is changing distributions and phenologies of many organisms and may also impact on vectors of disease-causing pathogens. In Europe, the tick Ixodes ricinus is the primary vector of medically important pathogens (e.g., Borrelia burgdorferi sensu lato, the causative agent of Lyme borreliosis). How might climate change affect I. ricinus host-seeking behavior (questing)? We hypothesize that, in order to maximize survival, I. ricinus have adapted their questing in response to temperature in accordance with local climates. We predicted that ticks from cooler climates quest at cooler temperatures than those from warmer climates. This would suggest that I. ricinus can adapt and therefore have the potential to be resilient to climate change. I. ricinus were collected from a cline of climates using a latitudinal gradient (northeast Scotland, North Wales, South England, and central France). Under laboratory conditions, ticks were subjected to temperature increases of 1 degrees C per day, from 6 to 15 degrees C. The proportion of ticks questing was recorded five times per temperature (i.e., per day). The theoretical potential to quest was then estimated for each population over the year for future climate change projections. As predicted, more ticks from cooler climates quested at lower temperatures than did ticks from warmer climates. The proportion of ticks questing was strongly associated with key climate parameters from each location. Our projections, based on temperature alone, suggested that populations could advance their activity season by a month under climate change, which has implications for exposure periods of hosts to tick-borne pathogens. Our findings suggest that I. ricinus have adapted their behavior in response to climate, implying some potential to adapt to climate change. Predictive models of I. ricinus dynamics and disease risk over continental scales would benefit from knowledge of these differences between populations. PMID- 24772295 TI - Identifying Distal cis-acting Gene-Regulatory Sequences by Expressing BACs Functionalized with loxP-Tn10 Transposons in Zebrafish. AB - Bacterial Artificial Chromosomes (BACs) are large pieces of DNA from the chromosomes of organisms propagated faithfully in bacteria as large extra chromosomal plasmids. Expression of genes contained in BACs can be monitored after functionalizing the BAC DNA with reporter genes and other sequences that allow stable maintenance and propagation of the DNA in the new host organism. The DNA in BACs can be altered within its bacterial host in several ways. Here we discuss one such approach, using Tn10 mini-transposons, to introduce exogenous sequences into BACs for a variety of purposes. The largely random insertions of Tn10 transposons carrying lox sites have been used to position mammalian cell selectable antibiotic resistance genes, enhancer-traps and inverted repeat ends of the vertebrate transposon Tol2 precisely at the ends of the genomic DNA insert in BACs. These modified BACs are suitable for expression in zebrafish or mouse, and have been used to functionally identify important long-range gene regulatory sequences in both species. Enhancer-trapping using BACs should prove uniquely useful in analyzing multiple discontinuous DNA domains that act in concert to regulate expression of a gene, and is not limited by genome accessibility issues of traditional enhancer-trapping methods. PMID- 24772296 TI - Second malignancies after breast cancer: The impact of adjuvant therapy. AB - Second malignant neoplasms (SMNs) are potentially life-threatening late sequelae of the adjuvant therapy for breast cancer (BC). The increased risk of SMNs is associated with adjuvant chemotherapy (development of secondary acute myeloid leukemia and myelodysplastic syndrome) and hormonal therapy (risk of uterine cancer secondary to tamoxifen treatment). Previous studies have demonstrated an increased risk of SMNs associated with alkylating agents, topoisomerase-II inhibitors, granulocyte-stimulating factors and estrogen receptor modulators. Furthermore, analytical investigations have demonstrated that BC patients may be at an increased risk of leukemia following chemotherapy. In addition, correlations between an increased dose of hormonal therapy and solid tumor risk have been identified. Considering the ongoing alterations in the treatment of BC, with respect to lowering the daily as well as the cumulative dose of chemo therapeutic agents, it is anticipated that leukemias will have a considerably lower impact on BC survivors in the future. However, diligent follow-up is required to accurately evaluate the long-term risks associated with chemotherapy. PMID- 24772297 TI - Oral mucositis in cancer treatment: Natural history, prevention and treatment. AB - Oral mucositis is a condition that is characterized by ulcerative lesions in the mucosa of patients undergoing radiotherapy or chemotherapy. Oral mucositis is currently considered to be the most severe complication of anticancer therapy, affecting 40-80% of patients undergoing chemotherapy and almost all those undergoing radiotherapy of the head and neck. Although they do not prevent lesions from appearing, drugs for the treatment of oral mucositis are required to minimize its clinical aggressiveness and improve the nutritional status, hydration and quality of life of the affected patients. Furthermore, the prevention and control of oral ulcers is crucial for cancer prognosis, since the establishment of severe lesions may lead to temporary or permanent treatment discontinuation and compromise cancer control. The objective of this study was to present a review on this condition, its causes and its treatment to professional clinical dentists, in order to help minimize patient suffering. A search was conducted through PubMed, Lilacs and MedLine, to retrieve related articles published between 1994 and 2013. PMID- 24772299 TI - Contribution of diuretic therapy with human serum albumin to the management of ascites in patients with advanced liver cirrhosis: A prospective cohort study. AB - The number of available studies on the role of human serum albumin (HSA) in the treatment of cirrhotic ascites is currently limited. In this study, we aimed to investigated the parameters associated with diuretic therapy with HSA in patients with advanced cirrhotic ascites. The patient inclusion criteria were cirrhotic ascites and a serum albumin (Alb) concentration of <3.5 g/dl. A total of 49 patients registered and 38 patients were ultimately included in this study. The enrolled patients were mainly treated with oral spironolactone and furosemide, which were not specified; the HSA amount was also not specified, although the administration period was set to a maximum of 7 days. Our results demonstrated that the administration of HSA significantly increased the serum levels of Alb [0.97 g/dl; two-sided 95% confidence interval (CI): 0.83-1.11 g/dl] and decreased body weight (-2.24 kg; 95% CI: -3.06 to -1.43 kg), hematocrit ratio (0.96; 95% CI: 0.94-0.98) and plasma renin concentration (day 4; geometric mean fold change, -0.1528; 95% CI: -0.2510 to -0.0545; log-transformed data) in patients with advanced cirrhotic ascites. The observed weight loss was found to be correlated with the total amount of HSA administered (P=0.0012), as indicated by the results of the multiple linear regression analysis. In conclusion, this study confirmed the efficacy of HSA in patients with advanced cirrhotic ascites. PMID- 24772298 TI - Clinical applications of nucleic acid aptamers in cancer. AB - Nucleic acid aptamers are small single-stranded DNA or RNA oligonucleotide segments, which bind to their targets with high affinity and specificity via unique three-dimensional structures. Aptamers are generated by an iterative in vitro selection process, termed as systematic evolution of ligands by exponential enrichment. Owing to their specificity, non-immunogenicity, non-toxicity, easily modified chemical structure and wide range of targets, aptamers appear to be ideal candidates for various clinical applications (diagnosis or treatment), such as cell detection, target diagnosis, molecular imaging and drug delivery. Several aptamers have entered the clinical pipeline for applications in diseases such as macular degeneration, coronary artery bypass graft surgery and various types of cancer. The aim of this review was to summarize and highlight the clinical applications of aptamers in cancer diagnosis and treatment. PMID- 24772300 TI - KRAS mutation in patients with metastatic colorectal cancer does not preclude benefit from oxaliplatin-or irinotecan-based treatment. AB - Fluoropyrimidine-based chemotherapy plus antibody therapy is currently the standard first-line treatment for metastatic colorectal cancer (mCRC). In this study, we investigated the hypothesis that mutations in several of the targeted oncogenes are correlated with treatment outcomes in mCRC patients receiving different first-line regimens. Our study included a total of 194 patients who had undergone various forms of first-line chemotherapy. The KRAS, BRAF, PIK3CA, NRAS and AKT1 mutational status of the tumors was assessed and the association between mutational status and treatment outcome was evaluated. The median progression free survival (mPFS) of the wild-type and mutated KRAS subgroups that had received oxaliplatin-based treatment was 8.6 and 6.8 months, respectively (P=0.41), whereas the mPFS of the wild-type KRAS, BRAF, PIK3CA, NRAS and AKT1 subgroups and that of their respective mutant subgroups was 9.7 and 7.2 months, respectively (P=0.10). The mPFS of the wild-type and mutated KRAS subgroups that had received irinotecan-based treatments was 7.7 and 9.7 months, respectively (P= 0.43). The mPFS of the wild-type KRAS, BRAF, PIK3CA, NRAS and AKT1 subgroups and that of their respective mutant subgroups was 7.1 and 10.0 months, respectively (P=0.76). Our data indicated that mCRC patients with activation of KRAS, BRAF, PIK3CA, NRAS and AKT1 mutations, even those being treated with oxaliplatin- and irinotecan-based regimens as first-line treatment, may benefit from cytotoxic drug therapy. PMID- 24772301 TI - Clinicopathological characteristics of vascular endothelial growth factor expression in uveal melanoma: A meta-analysis. AB - Angiogenesis is a potential prognostic factor that has been extensively investigated in patients with uveal melanoma (UM). Vascular endothelial growth factor (VEGF) expression is crucial in angiogenesis. However, there have been conflicting data regarding the clinicopathological data in UM. A meta-analysis was performed of all the germane literature to assess the clinicopathological characteristics of VEGF expression by combining separately estimated odds ratio (OR) values. Our combined results demonstrated that, according to the available studies, the expression of VEGF in UM was significantly higher compared to normal tissue [338 patients and 99 controls; OR=16.15, 95% confidence interval (CI): 8.65-30.12, P<0.00001]. When stratifying the studies by age (315 patients; OR=2.08, 95% CI: 1.19-3.62, P=0.01), cell type (423 patients; OR=0.54, 95% CI: 0.32-0.90, P=0.02), tumor size (222 patients; OR=0.30, 95% CI: 0.14-0.68, P=0.004) and scleral invasion (248 patients; OR=0.34, 95% CI: 0.15-0.78, P=0.01), significant clinicopathological information was provided. Our results indicated that VEGF expression in UM patients was significantly higher compared to that observed in controls. It was also significantly higher in patients who presented with scleral invasion and those who were aged <50 years. In addition, VEGF expression was higher in mixed-cell type and epithelioid-cell type UM and in patients with large-sized tumors. PMID- 24772302 TI - En bloc vascular resection for the treatment of borderline resectable pancreatic head carcinoma. AB - Borderline resectable (BR) pancreatic head carcinoma (PhC) is an advanced disease, presenting with infiltration of major vessels. Major vascular resection (VR), particularly arterial resection, to achieve microscopic no residual tumor (R0) is a controversial approach, due to the potential complications. In this study, we aimed to clarify the benefit of en bloc R0 resection with VR for PhC by retrospectively evaluating 78 PhC patients who underwent pancreatoduodenectomy at our institute. The patients were divided into 4 groups as follows: R, resectable (n=20); BR-V, BR involving the superior mesenteric vein or portal vein (PV) (n=28); BR-SMA, BR involving the superior mesenteric artery (n=21); and BR-HA, BR involving the hepatic artery (n=9). In total, 65 patients underwent VR, with 63, 21 and 9 patients undergoing PV, SMA and HA resection, respectively. The R0 rates were as follows: R group, 85%; BR-V, 82%; BR-SMA, 71%; and BR-HA, 33%. The median survival time and 5-year survival rate for R0 resection were 31 months and 25% in the R group, 22 months and 28% in the BR-V group, 17 months and 27% in the BR-SMA group and 10 months and 0% in the BR-HA group, respectively. The prognosis was comparable among the BR-V, BR-SMA and R groups, but was significantly poorer in the BR-HA group. In total, 5 patients (6.4%) died perioperatively (4 from postoperative hemorrhage and 1 from suffocation due to failure of expectoration, without pneumonia or asthma). Of the 4 patients who succumbed to hemorrhage, 3 had undergone arterial resection. Therefore, en bloc resection with major VR for R0 may be suitable for BR-V and BR-SMA PhC patients. PMID- 24772303 TI - Palonosetron exhibits higher total control rate compared to first-generation serotonin antagonists and improves appetite in delayed-phase chemotherapy-induced nausea and vomiting. AB - In order to ensure the continuity of chemotherapy, it is crucial to provide appropriate supportive care to prevent chemotherapy-induced nausea and vomiting (CINV). The frequency of CINV is greatly affected by the type and combination of chemotherapy employed, which requires further investigation. With the use of patient diaries, a prospective study on the efficacy of antiemetic regimens for nausea and vomiting was conducted in 103 patients receiving highly or moderately emetogenic chemotherapy in the Ambulatory Therapy Center of our institution between August, 2010 and March, 2011. In this study, the efficacy of palonosetron in the delayed phase was affirmed. On days 4 and 5, in particular, palonosetron exhibited a significantly higher efficacy compared to that of other conventional serotonin (5-HT3) receptor antagonists (5-HT3RAs). When the effects of chemotherapy on food intake were assessed by switching granisetron to palonosetron, an improvement in appetite was observed in one-quarter of the cases in the delayed phase. In addition, palonosetron has not been associated with any severe adverse drug reactions. It was therefore suggested that the use of palonosetron be recommended as a 5-HT3RA. In conclusion, our data suggested that palonosetron is effective and may be used as a 5-HT3RA, since it is crucial that we take adequate measures against CINV in order to maintain the patients' quality of life and to develop antiemetic regimens that ensure the continuity of chemotherapy without dose reduction. PMID- 24772304 TI - Combined therapeutic efficacy of 188Re-liposomes and sorafenib in an experimental colorectal cancer liver metastasis model by intrasplenic injection of C26-luc murine colon cancer cells. AB - Rhenium-188 (188Re) displays abundant intermediate energy beta emission and possesses a physical half-life of 16.9 h. Sorafenib is an orally available multikinase inhibitor that targets Raf kinases and vascular endothelial growth factor receptors (VEGFRs). Sorafenib has demonstrated preclinical and clinical activity against several types of tumors, such as renal cell and colorectal carcinoma. In this study, we investigated the efficacy of radiotherapeutics of 188Re-liposomes combined with sorafenib in a C26-luc metastatic colorectal liver tumour mouse model. Liver metastases were established by intrasplenic injection of C26-luc murine colon cancer cells. Based on the results of the toxicity assessment, an administration dose of 80% the maximum tolerated dose was selected. 188Re-liposomes were administered on day 1, when metastases of several hundred micrometers in diameter were observed. In the combination therapy group, 10 mg/kg sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar) was administered every other day for 1 week and the survival of mice was assessed. The tumor growth was more significantly inhibited in the 188Re-liposome plus sorafenib group compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). Furthermore, 188Re-liposomes combined with sorafenib achieved higher survival rates compared with the 188Re-liposome alone, sorafenib alone and untreated normal saline groups (P=0.0000). These results support the use of combined radio chemotherapy with 188Re-liposomes plus sorafenib as a viable treatment option in the adjuvant setting for liver metastases of colorectal cancer. PMID- 24772305 TI - Alternative endpoints to the 5-year overall survival and locoregional control for nasopharyngeal carcinoma: A retrospective analysis of 2,450 patients. AB - The purpose of the present study was to investigate alternative endpoints to the 5-year overall survival (OS) and locoregional control (LRC) for nasopharyngeal carcinoma (NPC). A total of 2,450 NPC patients were enrolled in this study, including 1,842 patients treated with two-dimensional (2D) radiotherapy (RT), 451 treated with 3D conformal RT (CRT) and 157 treated with intensity-modulated RT (IMRT). We sequentially calculated the 1-, 2-, 3- and 4-year survival rates using a life table and compared these with the 5-year survival rate using the McNemar method, with the survival rate of the last indifferent comparison being considered as the alternative endpoint. For 2D RT, stage I patients exhibited similar survival rates at 1 and 5 years (98.9 vs. 94.4%, respectively; P=0.125 for both OS and LRC); stage N3 patients exhibited similar 4-year OS (55.2 vs. 53.5%; P=1.000) and 2-year LRC (78.3 vs. 71.2%; P=0.125) to the 5-year OS and LRC. For IMRT, the 1-, 2-, 3-, 4- and 5-year OS and LRC rates in stage I/II NPC patients were 100, 98, 96, 94 and 94% for OS and 100, 98, 96, 96 and 96% for LRC, respectively. No significant differences were observed for all the comparisons. For stage III/IV NPC patients treated with IMRT, the 1-, 2-, 3-, 4- and 5-year rates were 99.1, 96.3, 92.5, 88.8 and 85.0% for OS and 98.1, 97.2, 95.3, 90.7 and 89.7% for LRC, respectively. Only the 4-year OS and LRC rates were indifferent from those at 5 years (P=0.125 for OS and P=1.00 for LRC). In conclusion, the 1 year OS and LRC for stage I NPC patients treated with 2D RT or stage I/II NPC patients treated with IMRT, the 4-year OS and 2-year LRC for stage N3 NPC patients treated with 2D RT and the 4-year OS and LRC for stage III/IV NPC patients treated with IMRT were determined as the alternative endpoints to the 5 year OS and LRC for NPC patients. PMID- 24772306 TI - Clinical characteristics and prognostic factors for advanced hepatocellular carcinoma with extrahepatic metastasis. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The aim of this study was to evaluate whether there are differences in the clinical characteristics and survival between patients with advanced HCC with extrahepatic metastasis who received and those who did not receive previous treatment. Between April, 1998 and April, 2012, a total of 419 HCC patients with extrahepatic metastasis (81 previously untreated and 338 previously treated) were enrolled in this study. The differences in the clinical characteristics, including metastatic sites, were compared between the two groups. In addition, the prognostic predictors among all the patients and among the 81 previously untreated patients were analyzed. The distribution of the major metastatic sites was similar in the two groups; the most frequent site of extrahepatic metastasis was the lungs, followed by the bones, lymph nodes and adrenal glands. The median survival time (MST) among the 419 patients was 6.8 months. The 1-, 2-, 3- and 5 year survival rates were 31.6, 15.3, 9.5 and 2.3%, respectively. No significant differences in survival were observed between patients who received and those who did not receive previous treatment. The multivariate analysis revealed that the Child-Pugh classification, white blood cell count, neutrophil-lymphocyte ratio (NLR) and primary tumor stage were independent predictors of survival for all the patients and for the 81 previously untreated patients. Differences in the clinical characteristics of patients with advanced HCC with extrahepatic metastasis were identified between patients who received and those who did not receive previous treatment. Furthermore, intrahepatic tumor status, Child-Pugh classification, white blood cell count and NLR were demonstrated to be independent predictors of survival in HCC patients with extrahepatic metastasis. PMID- 24772307 TI - Hyperthermic intraperitoneal chemotherapy with mitomycin C and 5-fluorouracil in patients at high risk of peritoneal metastasis from colorectal cancer: A preliminary clinical study. AB - Although hyperthermic intraperitoneal chemotherapy (HIPEC) has been extensively used to treat patients with peritoneal metastases (PM) from colorectal cancer (CRC), a standard protocol has not yet been established. The aim of this preliminary clinical study was to confirm in vitro the efficacy of mitomycin C combined with 5-fluorouracil (MMC-5FU) under hyperthermic conditions in CRC and investigate the pharmacokinetics and feasibility of HIPEC with MMC-5FU for patients at high risk of PM from CRC. To simulate HIPEC in vitro, we used the collagen gel droplet-embedded culture drug sensitivity test with the HCT166 colorectal cell line to assess the antitumor efficacy of MMC and 5FU as single agent and combination treatments following incubation with HCT116 cells for 30 min at either 37 or 42 degrees C. In addition, five patients at high risk of PM from CRC underwent surgical tumor resection followed by HIPEC with MMC-5FU. Our results demonstrated that the combined administration of MMC-5FU suppressed tumor cell proliferation more efficiently compared to either agent used alone. In addition, hyperthermia at 42 degrees C significantly enhanced drug sensitivity. During the clinical application of HIPEC with MMC-5FU, no grade 4 hematological toxicities or surgical adverse events were recorded. In addition, there was no evidence of peritoneal recurrence during a median observational period of 38 months. Of note, two patients with positive intraoperative peritoneal cytology at the first surgery developed no peritoneal recurrence and exhibited negative peritoneal cytology at the second surgery. In conclusion, HIPEC using MMC-5FU was shown to be a feasible therapeutic option, with an acceptable toxicity profile, for patients at high risk of PM from CRC. Therefore, HIPEC with MMC-5FU may be a promising novel therapeutic option for such patients, which merits further verification of its safety and efficacy in large-scale clinical trials. PMID- 24772308 TI - Phase II study of concurrent chemoradiotherapy with carboplatin and vinorelbine for locally advanced non-small-cell lung cancer. AB - Patients with non-small cell lung cancer (NSCLC) have locally advanced disease with poor prognosis. Although concurrent chemoradiotherapy is the standard treatment, more effective regimens are required. The aim of this study was to assess the safety and efficacy of concurrent chemoradiotherapy with a divided schedule of carboplatin and vinorelbine in patients with locally advanced NSCLC. Patients with unresectable, stage IIIA or IIIB NSCLC were eligible for enrollment if they exhibited a performance status of 0-2 and were <=75 years of age. Patients were treated with carboplatin at an area under the plasma concentration vs. time curve of 2.5 mg/ml/min and vinorelbine at 20 mg/m2 on days 1 and 8 every 3 weeks. Thoracic radiotherapy at a total dose of 60 Gy was concurrently administered (2 Gy per fraction). Twenty-eight patients (23 men and 5 women; median age, 67 years; range 47-75 years) were enrolled in the present study. The overall response rate was 85.7% [95% confidence interval (CI), 67.3-96.0%] and the disease control rate was 96.4% (95% CI, 81.7-99.9%). The median survival time (MST) was 23 months and the median progression-free survival (PFS) time was 8 months. Grade 3-4 toxicities included neutropenia, thrombocytopenia, anemia and infection in 100, 14, 46 and 36% of patients, respectively. One patient (4%) developed grade 3 radiation esophagitis that resolved completely without residual dilation. Grade 3 radiation pneumonitis occurred in 2 patients (7%); however, the symptoms and radiographic abnormalities subsided with corticosteroid therapy. In conclusion, concurrent chemoradiotherapy with a divided schedule of carboplatin and vinorelbine is well-tolerated and effective in patients with locally advanced NSCLC. PMID- 24772309 TI - Prognostic significance of B-cell lymphoma 2 expression in acute leukemia: A systematic review and meta-analysis. AB - A number of studies have provided estimates of the correlation between B-cell lymphoma 2 (Bcl-2) expression and its clinical significance in acute leukemia (AL); however, the results have been heterogeneous. In order to clarify the prognostic significance of Bcl-2 status in patients with AL, a systematic review and meta-analysis of 5 published studies including a total of 665 subjects was performed. The reported frequency of Bcl-2 expression was 0-99.00%. Bcl-2 positive patients had a higher median white blood cell count compared to Bcl-2 negative patients. Additionally, Bcl-2-negative patients had >2-fold higher odds of achieving complete remission (CR) compared to Bcl-2-positive patients. The summary hazard ratio of Bcl-2 negativity/positivity for CR was 0.62 [95% confidence interval: 0.53-0.81, P<0.001]. Although this meta-analysis was based on data abstracted from observational studies, our results may justify the use of risk-adapted therapeutic strategies for AL according to the Bcl-2 expression status. PMID- 24772310 TI - Magnetic resonance characteristics of adult-onset Lhermitte-Duclos disease: An indicator for active cancer surveillance? AB - Lhermitte-Duclos disease (LDD) is a rare, non-cancerous entity characterized by enlarged, abnormally developed cerebellar folia containing dysplastic cells. Symptomatic LDD is commonly observed in adults (adult-onset LDD, aLDD) as an isolated condition or associated with Cowden's disease (CD). The present study aimed to investigate the magnetic resonance imaging (MRI) characteristics and the underlying pathological findings in 7 cases of aLDD, with emphasis on the association with CD and the need for active cancer surveillance once the diagnosis of LDD is confirmed. The MRI findings along with the clinical and histopathological data collected from 7 patients with aLDD were retrospectively reviewed. The diagnosis of CD was based on a range of clinical characteristics, according to the International Cowden Consortium Criteria. A thorough review of the published data was conducted and our results indicated that all 7 cases shared similar MRI characteristics, whether the aLDD was sporadic (2 cases) or associated with CD (5 cases), including a highly typical non-enhancing striated MRI appearance of thickened folia, consisting of alternating bands on T1- and T2 weighted images. On gross examination, the involved cerebellar folia were distorted and enlarged, whereas the histopathological examination revealed that the molecular layer was widened and occupied by abnormal ganglion cells. Moreover, a reduction in the number or absence of the Purkinje cells and hypertrophy of the granular cell layer were observed. Our findings were consistent with the diagnosis of LDD. Variable levels of vacuolization of the white matter and the molecular layer were observed in all the cases. Notably, CD34 immunohistochemical analysis revealed the presence of angiogenesis within the lesions. aLDD associated with CD exhibited no pathological or immunohistochemical characteristics that were distinct from those of isolated aLDD. Of the 7 cases of aLDD, 5 presented with symptoms suggestive of CD, which is a syndrome associated with a high risk of multiple benign and malignant neoplasms. In conclusion, aLDD exhibits characteristic MRI and histopathological findings and displays a strong association with CD. Therefore, we recommend that the MRI diagnosis of aLDD triggers active cancer surveillance and preventive care. PMID- 24772311 TI - Elastofibroma dorsi: Surgical indications and complications of a rare soft tissue tumor. AB - Elastofibroma dorsi (ED) is a tumor that develops in the space between the lower angle of the scapula and the posterior thoracic wall. Due to the rarity of this type of tumor, the number of reported consecutive series is limited. Surgical excision, usually recommended for symptomatic cases to confirm diagnosis and relieve symptoms, has been associated with a high complication rate. To analyze the clinical characteristics and outcomes of surgical treatment, we retrospectively reviewed 20 consecutive cases of surgically resected ED. Of the 20 patients, 14 (70%) exhibited preoperative symptoms associated with the tumor. The mean diameter of the resected tumors averaged 72 mm (range, 45-110 mm). The surgical outcomes were satisfactory, except for the development of hematoma or seroma in 9 cases (43%), 8 of which achieved a complete resolution with conservative treatment. Age, hypertension, the presence of preoperative tumor related symptoms and intraoperative bleeding were not found to be significantly associated with the incidence of hematoma. However, tumor diameter and the duration of postoperative drainage were significantly associated with occurrence of hematoma (P=0.02 and P=0.01, respectively). Surgical resection should only be recommended for symptomatic patients, due to the high incidence of postoperative complications. To prevent the development of postoperative hematoma or seroma, careful observation of the wound, with suction drainage for >7 days and additional surgical procedures to facilitate adhesion of the wound margins, are recommended. PMID- 24772312 TI - Expression and clinical significance of girdin in gastric cancer. AB - Gastric cancer is one of the most common malignant tumors and the second leading cause of cancer-related mortality. Elucidating the molecular mechanism underlying the development of gastric cancer is crucial in identifying gastric cancer susceptible populations, screening for tumor markers and in the application of gene therapy. This study was conducted to investigate girdin expression in gastric cancer and para-cancer tissues and to elucidate the role of girdin in the development of gastric cancer. Tissue micro-array and streptavidin-peroxidase immunohistochemical staining were used to detect girdin expression in 105 gastric cancer and 72 para-cancer tissue samples. Analyses of the patients' clinical and pathological data were also performed. The expression ratio of girdin was 40.0% in gastric cancer and 11.1% in the para-cancer tissues and the difference was statistically significant (P<0.05). Girdin expression was found to be positively correlated (P<0.05) with tumor invasion depth and lymph node metastasis, while no significant associations were found between girdin expression and gender, age, tumor size, pathological grade and clinical stage (P>0.05). In conclusion, the upregulation of girdin expression in gastric cancer may contribute to tumor metastasis and cancer development, suggesting that girdin may be a novel indicator for evaluating lymph node metastasis and gastric cancer outcome. PMID- 24772313 TI - Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma. AB - Lifestyle, particularly smoking and alcohol consumption, may induce and/or inhibit drug metabolism. In order to reveal the effects of smoking and alcohol consumption on the 5-fluorouracil (5-FU)-related metabolic enzymes, namely thymidylate synthase, dihydropyrimidine dehydrogenase (DPD; a sole catabolic enzyme of 5-FU), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase, in oral squamous cell carcinomas, the mRNA expression of these enzymes was investigated in 29 surgical specimens and compared by the Brinkman index and drinking years. The surgical specimens were divided into normal and tumor regions and were independently analyzed using quantitative reverse transcription-polymerase chain reaction. There was a significantly positive correlation between DPD mRNA expression in these tissues and Brinkman index/drinking years, with OPRT mRNA expression being significantly correlated to the Brinkman index in tumor tissues. These results revealed that lifestyle habits, including smoking and alcohol consumption, may vary the activity of the 5 FU-related metabolic enzymes. DPD is the initial and rate-limiting enzyme in the catabolic pathway of 5-FU. Therefore, smoking and alcohol consumption may reduce the anticancer activity of 5-FU, possibly through the induction of DPD activity. PMID- 24772315 TI - Results on efficacy and safety of cancer treatment with or without tumor necrosis factor-related apoptosis-inducing ligand-related agents: A meta-analysis. AB - This meta-analysis aimed to evaluate the currently available evidence on the efficacy and safety of cancer treatment with or without tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-related agents. We conducted a systematic search through Medline, Cochrane Library and EMBASE electronic databases and manually searched the Journal of Clinical Oncology to identify randomized controlled trials (RCTs) conducted between 1995 and 2013 comparing the efficacy and safety results of cancer treatment with and without TRAIL-related agents. The methodological quality of the included RCTs was assessed by the Cochrane Risk of Bias assessment tool. The outcome measurements included objective response rate (ORR), clinical benefit rate (CBR)/disease control rate (DCR) and adverse events (AEs). The relevant data were analyzed using Review Manager 5.2 software. Grading of Recommendations Assessment Development and Evaluation was used to assess the quality of evidence and grade of recommendation. Four RCTs, including a total of 596 patients, were ultimately selected and analyzed. There were no statistically significant differences among the 4 RCTs regarding ORR [relative risk (RR)=0.92, 95% confidence interval (CI): 0.73-1.15, P=0.45], CBR/DCR (RR=0.92, 95% CI: 0.81-1.05, P=0.21), progression free survival [hazard ratio (HR)=0.89, 95% CI: 0.75-1.05, P=0.16], overall survival (HR=0.90, 95% CI: 0.74-1.09, P=0.27), number of patients with any AEs (RR=0.99, 95% CI: 0.96-1.03, P=0.77), number of patients with any severe AEs (RR=0.95, 95% CI: 0.78-1.55, P=0.58), number of patients with >=grade 3 AEs (RR=1.13, 95% CI: 0.93-1.38, P=0.22) and number of fatal AEs (RR=1.14, 95% CI: 0.71-1.81, P=0.59). The quality of evidence was considered to be moderate and the recommendation grades were weak. In conclusion, the benefits of TRAIL-related agents in the treatment of cancer patients remain uncertain and further clinical trials are required. PMID- 24772314 TI - Next-generation sequencing of BRCA1 and BRCA2 in breast cancer patients and control subjects. AB - Breast cancer is currently the most common type of cancer in females. The majority of the hereditary forms of breast cancer are caused by mutations in the BRCA1 and BRCA2 genes, whose main function is the DNA repair of double-strand breaks. Genetic testing of females with a family history of breast cancer is recommended to determine their hereditary predisposition for this type of cancer. The variants with no clear clinical significance may represent a diagnostic challenge when performing targeted resequencing. In this study, DNA samples were obtained from 24 breast cancer patients (mean age, 35+/-10 years) with a positive family history and from 71 age-matched healthy controls. Informed consent was obtained from all the subjects. Sequence-targeted BRCA1 and BRCA2 libraries were prepared using the TruSeq Custom Amplicon method and sequenced on the Illumina MiSeq system. A wide range of variants were identified in the BRCA1 and BRCA2 genes. Two pathological/presumably pathological variants were detected in the breast cancer patient group: a mutation in BRCA2 at the chromosomal (chr) position chr13:32890665, which affected the first position of the 5' splice region following exon 2; and a mutation in BRCA1 at chr17:41219635, causing an in frame triple nucleotide deletion of valine 1688 (8.3%). In the patient and control groups, 7 likely polymorphic variants and 13 common variants were detected in the BRCA1 and BRCA2 genes. To the best of our knowledge, this study was the first to identify 3 common polymorphisms in BRCA2, characteristic solely of the Bulgarian population, including chr13:32973737, T/-, a single-nucleotide polymorphism (SNP) within the 3'-UTR of exon 27; chr13:32973280, A/-, a mononucleotide deletion within the 5'-UTR of exon 27; and chr13:32973924, T/-, a mononucleotide deletion downstream of the gene sequence. To the best of our knowledge, this study was the first to apply next-generation sequencing of the BRCA1 and BRCA2 genes in a Bulgarian population, prompting further investigation for local founder mutations and variants characteristic for this particular region. PMID- 24772316 TI - Erlotinib with pemetrexed/cisplatin for patients with EGFR wild-type lung adenocarcinoma with brain metastases. AB - Erlotinib and pemetrexed have been approved for the second-line treatment of non small cell lung cancer. Recent reports indicated that erlotinib and pemetrexed exerted synergistic effects against lung adenocarcinoma. The available treatment options for lung cancer with brain metastases (BM) are currently limited. In the present study, we investigated the efficacy of the combined administration of erlotinib and pemetrexed in 9 patients with epidermal growth factor receptor (EGFR) wild-type lung adenocarcinoma with BM. Pemetrexed (500 mg/m2) and cisplatin (20 mg/m2) were administered on day 1 and days 1-3, respectively. Erlotinib (150 mg) was administered daily on days 4-20. The 9 patients harbored EGFR wild-type mutation in the primary tumor tissues. With regard to the BM, no patients achieved complete remission, 7 patients exhibited a partial response (PR), 1 had stable disease (SD) and 1 had progressive disease (PD). As regards the extracranial tumors, 3 patients exhibited a PR, 2 had SD, 3 had PD and 1 was not applicable. The performance status and the symptoms improved in 3 patients following treatment. The median progression-free survival for intracranial and extracranial disease control was 179 and 146.5 days, respectively. The median overall survival was 197.4 days. Therefore, erlotinib combined with pemetrexed/cisplatin, was found to be effective in the treatment of patients with EGFR wild-type lung adenocarcinoma. PMID- 24772318 TI - Experimental study on Qizhu formula for modulating survivin, an inhibitor of apoptosis, in MGC-803 gastric cancer cells. AB - The aim of this study was to investigate the mechanism of action of Qizhu formula, a Chinese medicinal empirical formula, in modulating the action of survivin, an inhibitor of apoptosis, in MGC-803 gastric cancer cells. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) were applied to detect the effect of varying concentrations of Qizhu formula in the modulation of the expression of survivin in MGC-803 human gastric adenocarcinoma cells. The western blot analysis results demonstrated that Qizhu formula exerted no significant effects on the protein expression of the beta-actin housekeeping gene, whereas it exerted a significant inhibitory effect on the protein expression of the apoptosis-related survivin gene at concentrations of 250 MUg/ml and, particularly, 500 MUg/ml. RT-PCR was used to detect the effect of Qizhu formula on survivin mRNA in MGC-803 human gastric adenocarcinoma cells. The ratio of survivin/beta-actin in the 0.1% dimethylsulfoxide and the 125, 250 and 500 MUg/ml groups of Qizhu formula was 0.4543, 0.4025, 0.2415 and 0.2235, respectively. Therefore, Qizhu formula exerted a distinct inhibitory effect on the mRNA expression of survivin in MGC-803 cells in a dose-dependent manner. In conclusion, Qizhu formula may modulate the apoptosis of MGC-803 human gastric adenocarcinoma cells, which is associated with the downregulation of survivin mRNA and protein expression. PMID- 24772317 TI - Weekly administration of paclitaxel and carboplatin with concurrent thoracic radiation in previously untreated elderly patients with locally advanced non small-cell lung cancer: A case series of 20 patients. AB - Elderly patients with stage III non-small-cell lung cancer (NSCLC) are frequently underrepresented in clinical trials that evaluate chemoradiotherapy, due to their poor functional status, coexisting illnesses and limited life expectancy. The Japan Clinical Oncology Group 0301 trial (JCOG0301) was the first study to demonstrate that thoracic radiation therapy (TRT) with daily low-dose carboplatin may improve the outcome of elderly patients with stage III NSCLC. However, the efficacy and safety profiles of chemoradiotherapy, including platinum doublets, have not been clearly determined in this patient population. We retrospectively assessed the efficacy and toxicity of weekly paclitaxel in combination with carboplatin and concurrent TRT in patients aged >=75 years with previously untreated locally advanced NSCLC. Between February, 2004 and July, 2013, we collected the data of 20 patients treated with weekly paclitaxel and carboplatin for 6 weeks and concurrent TRT. The objective response rate was 90%, the disease control rate was 95%, the median progression-free survival was 8.63 months [95% confidence interval (CI): 5.7-16.7] and the median overall survival (OS) was 16.1 months (95% CI: 10.7-41.6). There were no grade 4 hematological or non hematological toxicities and no reported treatment-related deaths. Therefore, platinum doublet therapy in combination with TRT did not provide a clinically significant survival benefit in our population of elderly patients with locally advanced NSCLC. However, the present study demonstrated the good feasibility and safety of this regimen. Further prospective clinical trials are required to evaluate the efficacy and safety of platinum doublet with TRT in elderly patients. PMID- 24772319 TI - Safety and continuity of second- and third-line therapy with paclitaxel or irinotecan for advanced and recurrent gastric cancer. AB - In the treatment of advanced or recurrent gastric cancer, the prolongation of survival depends on the use of second-line therapy, with paclitaxel (PTX) or irinotecan (CPT-11) as the key agents. The present study aimed to retrospectively investigate the safety and continuity of weekly PTX and CPT-11 monotherapy as second- or third-line treatment for advanced or recurrent gastric cancer. A total of 62 patients who had received PTX or CPT-11 for gastric cancer at the Ogaki Municipal Hospital (Ogaki, Japan) were retrospectively reviewed. Of the 47 patients who received PTX as second-line therapy, 13 (27.7%) received third-line therapy with CPT-11. Second-line PTX and third-line CPT-11 were discontinued due to progressive disease (PD) in 27 and 7 cases, respectively, and deterioration in the performance status (PS) in 20 and 4 cases, respectively. Only 1 case of discontinuation due to adverse events (AEs) was reported for third-line CPT-11. Furthermore, of the 15 patients who received CPT-11 as second-line treatment, 11 (73.3%) then received PTX as third-line treatment. Second-line CPT-11 and third line PTX were discontinued due to PD in 9 and 6 cases, respectively, and deterioration in the PS in 4 and 5 cases, respectively, whereas there was only 1 case of discontinuation due to AEs for second-line CPT-11. Severe AEs for PTX and CPT-11 were infrequent; however, the frequency of diarrhea was high when PTX was administered as third-line therapy (63.6%), whereas the frequency of malaise was high when CPT-11 was administered as second- (73.3%) and third-line (76.9%) therapy. In conclusion, severe AEs due to PTX and CPT-11 as second- and third line treatment for advanced or recurrent gastric cancer are infrequent and patients are generally able to continue treatment. However, the possibility of diarrhea with third-line PTX and malaise with second- and third-line CPT-11 treatment should be considered when planning chemotherapy. PMID- 24772320 TI - Anthracycline-based induction chemotherapy followed by concurrent cyclophosphamide, methotrexate and 5-fluorouracil and radiation therapy in surgically resected axillary node-positive breast cancer. AB - The present study aimed to determine the toxicity and efficacy of 4 courses of anthracyclines-taxane (AT) chemotherapy followed by radiation therapy (XRT) concurrent with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in surgically resected axillary node-positive (N+) breast cancer. A total of 200 women with N+ breast cancer were treated with adriamycin and docetaxel followed by XRT concurrent with six courses of CMF. Two courses of dose-dense chemotherapy with ifosfamide, carboplatin and etoposide, supported by pegfilgrastim, were administered to patients with >5 histologically confirmed axillary lymph node metastases and patients with triple-negative disease. Additional treatments included 1 year of trastuzumab in human epidermal growth factor receptor 2 positive patients, 5 years of a luteinizing hormone-releasing hormone analogue in premenopausal women and 5 years of an aromatase inhibitor (AI) in estrogen receptor-positive (ER+) patients. The mean number of positive axillary lymph nodes was 4.4 (range, 2-37), 52% of the patients were premenopausal, 74% were ER+ and 26% had triple-negative disease. After a median follow-up of 73 months, grade 2 and 3 hematological toxicity was observed in 20% of the patients. The 10-year disease-free survival (DFS) and overall survival (OS) rates were 73 and 77%, respectively. There was no significant difference in DFS between ER+ and estrogen receptor-negative (ER-) patients (P>0.05), whereas the OS was better in ER+ vs. ER- patients (P<0.05) and in premenopausal vs. postmenopausal patients (P<0.005). In conclusion, induction AT concurrent CMF and XRT and dose-dense chemotherapy followed by AI in N+ high-risk breast cancer was associated with a low level of systemic and late cardiac toxicity and excellent local control, DFS and OS. PMID- 24772321 TI - Expression of ribonucleoside reductase subunit M1, but not excision repair cross complementation group 1, is predictive in muscle-invasive bladder cancer treated with chemotherapy and radiation. AB - The aim of this study was to determine the prognostic and predictive values of ribonucleoside reductase subunit M1 (RRM1) and excision repair cross complementation group 1 (ERCC1) expression in patients with muscle-invasive bladder cancer treated with chemoradiotherapy. The expression of RRM1 and ERCC1 in pretreatment tumor samples of retrospectively identified patients was determined by immunohistochemical analysis. A total of 39 patients were included in this study; 49% were treated with neoadjuvant chemotherapy and 67% with concomitant chemoradiotherapy; 56% were treated with gemcitabine-based and 51% with platinum-based chemoradiotherapy. The median follow-up was 19 months (interquartile range, 11-50 months). Based on the immunohistochemical analysis, 44 and 32% of the tumors exhibited increased expression of RRM1 and ERCC1, respectively. The complete response (CR) and local recurrence rates following chemoradiotherapy were 79 and 21%, respectively. A low expression of RRM1 was associated with a higher rate of CR to chemoradiotherapy (95 vs. 57%, P=0.012); however, there was no such association with low ERCC1 expression (67 vs. 84%, P=0.39). RRM1 expression predicted an improved CR in patients treated with gemcitabine-based chemoradiotherapy (57 vs. 100%, P=0.036), but not in those treated with other agents (56 vs. 88%, P=0.29). ERCC1 expression was not found to be correlated with CR (67 vs. 84%, P=0.39), even when restricted to patients treated with platinum agents (71 vs. 75%, P=1.0). In the univariate analysis, RRM1 expression, but not ERCC1 expression, was identified as a prognostic marker for worse cancer-specific survival in all the patients and in those treated with gemcitabine-based regimens. No independent prognostic factor was identified in the multivariate model, which included tumor stage, vascular invasion, hydronephrosis and RRM1 status. Although these findings require further validation, they suggest that RRM1 may be a beneficial stratification variable for the selection of chemotherapy regimens for chemoradiotherapy, with patients with low RRM1 expression being considered suitable for gemcitabine treatment. PMID- 24772322 TI - Microbiota, intestinal immunity, and mouse bustle. AB - The composition of the intestinal microbiota is regulated by the immune system. This paper discusses the role of cytokines and innate immunity lymphoid cells in the intestinal immune regulation by means of IgA. PMID- 24772323 TI - Williams syndrome as a model for elucidation of the pathway genes - the brain - cognitive functions: genetics and epigenetics. AB - Genomic diseases or syndromes with multiple manifestations arise spontaneously and unpredictably as a result of contiguous deletions and duplications generated by unequal recombination in chromosomal regions with a specific architecture. The Williams syndrome is believed to be one of the most attractive models for linking genes, the brain, behavior and cognitive functions. It is a neurogenetic disorder resulting from a 1.5 Mb deletion at 7q11.23 which covers more than 20 genes; the hemizigosity of these genes leads to multiple manifestations, with the behavioral ones comprising three distinct domains: 1) visuo-spatial orientation; 2) verbal and linguistic defect; and 3) hypersocialisation. The shortest observed deletion leads to hemizigosity in only two genes: eln and limk1. Therefore, the first gene is supposed to be responsible for cardiovascular pathology; and the second one, for cognitive pathology. Since cognitive pathology diminishes with a patient's age, the original idea of the crucial role of genes straightforwardly determining the brain's morphology and behavior was substituted by ideas of the brain's plasticity and the necessity of finding epigenetic factors that affect brain development and the functions manifested as behavioral changes. Recently, non coding microRNAs (miRs) began to be considered as the main players in these epigenetic events. This review tackles the following problems: is it possible to develop relatively simple model systems to analyze the contribution of both a single gene and the consequences of its epigenetic regulation in the formation of the Williams syndrome's cognitive phenotype? Is it possible to use Drosophila as a simple model system? PMID- 24772324 TI - Molecular mechanism of global genome nucleotide excision repair. AB - Nucleotide excision repair (NER) is a multistep process that recognizes and eliminates a wide spectrum of damage causing significant distortions in the DNA structure, such as UV-induced damage and bulky chemical adducts. The consequences of defective NER are apparent in the clinical symptoms of individuals affected by three disorders associated with reduced NER capacities: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). These disorders have in common increased sensitivity to UV irradiation, greatly elevated cancer incidence (XP), and multi-system immunological and neurological disorders. The eucaryotic NER system eliminates DNA damage by the excision of 24-32 nt single strand oligonucleotides from a damaged strand, followed by restoration of an intact double helix by DNA repair synthesis and DNA ligation. About 30 core polypeptides are involved in the entire repair process. NER consists of two pathways distinct in initial damage sensor proteins: transcription-coupled repair (TC-NER) and global genome repair (GG-NER). The article reviews current knowledge on the molecular mechanisms underlying damage recognition and its elimination from mammalian DNA. PMID- 24772325 TI - "Green" nanotechnologies: synthesis of metal nanoparticles using plants. AB - While metal nanoparticles are being increasingly used in many sectors of the economy, there is growing interest in the biological and environmental safety of their production. The main methods for nanoparticle production are chemical and physical approaches that are often costly and potentially harmful to the environment. The present review is devoted to the possibility of metal nanoparticle synthesis using plant extracts. This approach has been actively pursued in recent years as an alternative, efficient, inexpensive, and environmentally safe method for producing nanoparticles with specified properties. This review provides a detailed analysis of the various factors affecting the morphology, size, and yield of metal nanoparticles. The main focus is on the role of the natural plant biomolecules involved in the bioreduction of metal salts during the nanoparticle synthesis. Examples of effective use of exogenous biomatrices (peptides, proteins, and viral particles) to obtain nanoparticles in plant extracts are discussed. PMID- 24772326 TI - Generation of iPS Cells from Human Hair Follice Dermal Papilla Cells. AB - Dermal papilla (DP) cells are unique regional stem cells of the skin that induce formation of a hair follicle and its regeneration cycle. DP are multipotent stem cells; therefore we supposed that the efficiency of DPC reprogramming could exceed that of dermal fibroblasts reprogramming. We generated induced pluripotent stem cells from human DP cells using lentiviral transfection with Oct4, Sox2, Klf4, and c-Myc, and cultivation of cells both in a medium supplemented with valproic acid and at a physiological level of oxygen (5%). The efficiency of DP cells reprogramming was ~0.03%, while the efficiency of dermal fibroblast reprogramming under the same conditions was ~0.01%. Therefore, we demonstrated the suitability of DP cells as an alternative source of iPS cells. PMID- 24772327 TI - Patient-Specific Induced Pluripotent Stem Cells for SOD1-Associated Amyotrophic Lateral Sclerosis Pathogenesis Studies. AB - The genetic reprogramming technology allows one to generate pluripotent stem cells for individual patients. These cells, called induced pluripotent stem cells (iPSCs), can be an unlimited source of specialized cell types for the body. Thus, autologous somatic cell replacement therapy becomes possible, as well as the generation of in vitro cell models for studying the mechanisms of disease pathogenesis and drug discovery. Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder that leads to a loss of upper and lower motor neurons. About 10% of cases are genetically inherited, and the most common familial form of ALS is associated with mutations in the SOD1 gene. We used the reprogramming technology to generate induced pluripotent stem cells with patients with familial ALS. Patient-specific iPS cells were obtained by both integration and transgene-free delivery methods of reprogramming transcription factors. These iPS cells have the properties of pluripotent cells and are capable of direct differentiation into motor neurons. PMID- 24772328 TI - Fusion to the Lysosome Targeting Signal of the Invariant Chain Alters the Processing and Enhances the Immunogenicity of HIV-1 Reverse Transcriptase. AB - Intracellular processing of the antigen encoded by a DNA vaccine is one of the key steps in generating an immune response. Immunization with DNA constructs targeted to the endosomal-lysosomal compartments and to the MHC class II pathway can elicit a strong immune response. Herein, the weakly immunogenic reverse transcriptase of HIV-1 was fused to the minimal lysosomal targeting motif of the human MHC class II invariant chain. The motif fused to the N-terminus shifted the enzyme intracellular localization and accelerated its degradation. Degradation of the chimeric protein occurred predominantly in the lysosomal compartment. BALB/c mice immunized with the plasmid encoding the chimeric protein demonstrated an enhanced immune response, in the form of an increased antigen-specific production of Th1 cytokines, INF-gamma and IL-2, by mouse splenocytes. Moreover, the majority of the splenocytes secreted both cytokines; i.e., were polyfunctional. These findings suggest that retargeting of the antigen to the lysosomes enhances the immune response to DNA vaccine candidates with low intrinsic immunogenicity. PMID- 24772329 TI - The Role of Dihydroorotate Dehydrogenase in Apoptosis Induction in Response to Inhibition of the Mitochondrial Respiratory Chain Complex III. AB - A mechanism for the induction of programmed cell death (apoptosis) upon dysfunction of the mitochondrial respiratory chain has been studied. Previously, we had found that inhibition of mitochondrial cytochrome bc1, a component of the electron transport chain complex III, leads to activation of tumor suppressor p53, followed by apoptosis induction. The mitochondrial respiratory chain is coupled to the de novo pyrimidine biosynthesis pathway via the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). The p53 activation induced in response to the inhibition of the electron transport chain complex III has been shown to be triggered by the impairment of the de novo pyrimidine biosynthesis due to the suppression of DHODH. However, it remained unclear whether the suppression of the DHODH function is the main cause of the observed apoptotic cell death. Here, we show that apoptosis in human colon carcinoma cells induced by the mitochondrial respiratory chain complex III inhibition can be prevented by supplementation with uridine or orotate (products of the reaction catalyzed by DHODH) rather than with dihydroorotate (a DHODH substrate). We conclude that apoptosis is induced in response to the impairment of the de novo pyrimidine biosynthesis caused by the inhibition of DHODH. The conclusion is supported by the experiment showing that downregulation of DHODH by RNA interference leads to accumulation of the p53 tumor suppressor and to apoptotic cell death. PMID- 24772330 TI - Protective Immune Response against Bacillus anthracis Induced by Intranasal Introduction of a Recombinant Adenovirus Expressing the Protective Antigen Fused to the Fc-fragment of IgG2a. AB - Anthrax is a particularly dangerous infectious disease that affects humans and livestock. It is characterized by intoxication, serosanguineous skin lesions, development of lymph nodes and internal organs, and may manifest itsself in either a cutaneous or septic form. The pathogenic agent is Bacillus anthracis, a grampositive, endospore-forming, rod-shaped aerobic bacterium. Efficacious vaccines that can rapidly induce a long-term immune response are required to prevent anthrax infection in humans. In this study, we designed three recombinant human adenovirus serotype-5-based vectors containing various modifications of the fourth domain of the B. anthracis protective antigen (PA). Three PA modifications were constructed: a secretable form (Ad-sPA), a non-secretable form (Ad-cPA), and a form with the protective antigen fused to the Fc fragment of immunoglobulin G2a (Ad-PA-Fc). All these forms exhibited protective properties against Bacillus anthracis. The highest level of protection was induced by the Ad-PA-Fc recombinant adenovirus. Our findings indicate that the introduction of the Fc antibody fragment into the protective antigen significantly improves the protective properties of the Ad-PA-Fc adenovirus against B. anthracis. PMID- 24772331 TI - Development of immunoassays using interferometric real-time registration of their kinetics. AB - A method for effective development of solid-phase immunoassays on a glass surface and for optimization of related protocols by highly sensitive quantitative monitoring of each assay step has been proposed and experimentally implemented. The method is based on the spectral correlation interferometry (SCI) that allows real-time measuring of the thickness of a biomolecular layer bound to the recognition molecular receptors on the sensor chip surface. The method is realized with compact 3-channel SCI-biosensors that employ as the sensor chips standard cover glass slips without deposition of any additional films. Different schemes for antibody immobilization on a glass surface have been experimentally compared and optimized toward a higher sorption capacity of the sensor chips. Comparative characterization of the kinetics of each immunoassay stage has been implemented with the optimized protocols: i) covalent immobilization of antibody on an epoxylated surface and ii) biotinylated antibody sorption on a biotinylated surface via a high-affinity biotin-streptavidin bond. We have shown that magnetic nanoparticles employed as labels with model detection of cardiac troponin I further amplify the SCI signal, resulting in 100-fold improvement of the detection limit. The developed protocols can also be used with the alternative immunoassay platforms, including the label methods based on registration of only the final assay result, which is the quantity of bound labels. PMID- 24772332 TI - Composite Scaffolds Containing Silk Fibroin, Gelatin, and Hydroxyapatite for Bone Tissue Regeneration and 3D Cell Culturing. AB - Three-dimensional (3D) silk fibroin scaffolds were modified with one of the major bone tissue derivatives (nano-hydroxyapatite) and/or a collagen derivative (gelatin). Adhesion and proliferation of mouse embryonic fibroblasts (MEF) within the scaffold were increased after modification with either nano-hydroxyapatite or gelatin. However, a significant increase in MEF adhesion and proliferation was observed when both additives were introduced into the scaffold. Such modified composite scaffolds provide a new and better platform to study wound healing, bone and other tissue regeneration, as well as artificial organ bioengineering. This system can further be applied to establish experimental models to study cell substrate interactions, cell migration and other complex processes, which may be difficult to address using the conventional two-dimensional culture systems. PMID- 24772333 TI - Impact of surface modification with gold nanoparticles on the bioelectrocatalytic parameters of immobilized bilirubin oxidase. AB - We unveil experimental evidence that put into question the widely held notion concerning the impact of nanoparticles on the bioelectrocatalytic parameters of enzymatic electrodes. Comparative studies of the bioelectrocatalytic properties of fungal bilirubin oxidase from Myrothecium verrucaria adsorbed on gold electrodes, modified with gold nanoparticles of different diameters, clearly indicate that neither the direct electron transfer rate (standard heterogeneous electron transfer rate constants were calculated to be 31+/-9 s(-1)) nor the biocatalytic activity of the adsorbed enzyme (bioelectrocatalytic constants were calculated to be 34+/-11 s(-1)) depends on the size of the nanoparticles, which had diameters close to or larger than those of the enzyme molecules. PMID- 24772334 TI - The influence of radiation therapy dose escalation on overall survival in unresectable pancreatic adenocarcinoma. AB - PURPOSE: Radiation therapy (RT) dose escalation in unresectable pancreatic adenocarcinoma (PAC) remains investigational. We examined the association between total RT dose and overall survival (OS) in patients with unresectable PAC. METHODS AND MATERIALS: National cancer data base (NCDB) data were obtained for patients who underwent definitive chemotherapy and RT (chemo-RT) for unresectable PAC. Univariate (UV) and multivariate (MV) survival analysis were performed along with Kaplan-Meier (KM) estimates for incremental RT dose levels. RESULTS: A total of 977 analyzable patients met inclusion criteria. Median tumor size was 4.0 cm (0.3-40 cm) and median RT dose was 45 Gy. Median OS was 10 months (95% CI, 9-10 months). On MV analysis RT dose <30 Gy [HR, 2.38 (95% CI, 1.85-3.07); P<0.001] and RT dose >=30 to <40 Gy [HR, 1.41 (95% CI, 1.04-1.91); P=0.026] were associated with lower OS when compared with dose >=55 Gy. Patients receiving RT doses from 40 to <45, 45 to <50, 50 to <55, and >=55 Gy did not differ in OS. CONCLUSIONS: Lack of benefit to OS with conventionally delivered RT above 40 Gy is shown. Optimal RT dose escalation methods in unresectable PAC remain an important subject for investigation in prospective clinical trials. PMID- 24772335 TI - Overall survival analysis of neoadjuvant chemoradiotherapy and esophagectomy for esophageal cancer. AB - BACKGROUND: Patients treated with neoadjuvant chemoradiotherapy (NAC) followed by esophagectomy are more likely to have negative margins at resection, be downstaged, and have improved overall survival (OS). The specific aim of this study was to analyze OS outcomes using NAC followed by esophagectomy at a single, tertiary care academic medical center. METHODS: We retrospectively analyzed 106 patients that underwent NAC with platinum-based chemotherapy plus 5-fluorouracil (5-FU) or capecitabine followed by esophagectomy from September 1996 to May 2011. OS was analyzed by the Kaplan Meier method. RESULTS: Initial staging determined that of 106 patients, 62% had stage III (n=66), 31% stage II (n=33), and 7% had stage I disease (n=7). Following NAC, 92.5% (n=98) were resected with negative (R0) margins and pathologic staging revealed 59% (n=62) were downstaged, 9% (n=10) were upstaged, and 32% (n=34) remained at the same stage. A pathologic complete response (pCR) was achieved in 29% (n=31) of the cohort. Median OS was 35.2 months for all patients, 42 months for downstaged patients, 13 months when upstaged, and 17 months for those who remained at the same stage (P=0.08). OS by histological type was 30 months for adenocarcinoma and 71 months for squamous cell carcinoma (P=0.06). CONCLUSIONS: NAC was effective in downstaging 59% of patients and effectively increased the chance for an R0 resection. These patients, in turn, had improved OS compared to the median OS. Patients with squamous cell carcinoma showed a trend towards more favorable OS. PMID- 24772336 TI - Endoscopic stenting versus operative gastrojejunostomy for malignant gastric outlet obstruction-a systematic review and meta-analysis of randomized and non randomized trials. AB - BACKGROUND: Open surgical gastrojejunostomy (GJ) has been the treatment of choice, but it has high morbidity and mortality rates. During the last decade, endoscopic self-expandable metal stents (SEMS) have been used. This meta-analysis aimed to compare surgical GJ and endoscopic stenting in palliation of malignant gastric outlet obstruction (GOO). METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. The search identified 3 randomized controlled trials (RCTs) and 14 non-RCTs reporting on patients who underwent surgical GJ or endoscopic stenting for malignant gastroduodenal outflow obstruction. RESULTS: THE RESULTS OF THE THREE RCTS DEMONSTRATED THAT SEMS RESULTED IN COMPARABLE MAJOR [ODDS RATIO (OR): 0.62, 95% confidence intervals (CI): 0.021-18.371] and minor (OR: 0.32, 95% CI: 0.049-2.089) complications in a shorter time to tolerating an oral intake (SEMS: 3.55 days and GJ: 7.15 days) and shorter hospital stay (SEMS: 5.1 days and GJ: 12.13 days, however, statistical insignificant P value =0.11). Among the non RCTs: SEMS resulted in a shorter time to tolerating an oral intake (SEMS: 1.48 days and GJ: 8.07 days, P value <0.01), similar rate of complications (OR: 0.33, 95% CI: 0.1-1.08), lower mortality (OR: 0.5, 95% CI: 0.21-1.20, P value <0.01) and a shorter hospital stay (SEMS: 7.61 days and GJ: 19.04 days, P value <0.0001). There was no significant difference between median survival times among RCTs and non RCTs. CONCLUSIONS: These findings suggest that stent placement is associated with better short-term outcomes and hence, duodenal stenting is a safe means of palliating malignant gastric outflow obstruction. However, a large RCT is needed to systematically compare stent placement with GJ with regard to medical effects, quality of life and costs. PMID- 24772337 TI - Should we move beyond VEGF inhibition in metastatic colorectal cancer? Lessons from early phase clinical trials. AB - Data from recent clinical trials utilizing bevacizumab or other anti-VEGF agents in patients with metastatic colorectal cancer (mCRC) show improvements in progression-free survival (PFS) but modest, if any, improvements in overall survival (OS). Despite modest improvements, use of bevacizumab beyond first and second progression is routinely done in clinical practice. Recently, the CORRECT trial using regorafenib, a multi-kinase inhibitor with VEGF inhibitory properties, reported modest improvements in PFS and OS when compared to placebo, leading to FDA approval in the third-line setting. Prior to regorafenib, heavily pre-treated patients were often enrolled onto early phase clinical trials with many of these studies reporting efficacy amongst patients with mCRC; however, a collective efficacy analysis of mCRC patients enrolled into early phase clinical trials stratified by class of agents and their mechanism of action has not been done. To assess this, we performed an analysis of efficacy and stratified these findings based on VEGF inhibition versus non-VEGF inhibition in mCRC patients enrolled onto phase I trials at our institution from 3/2004-9/2012. Similar to many reported clinical studies, our data showed that VEGF inhibitors have a statistically significant improvement in PFS when compared to non-VEGF targeting agents; however, no differences in OS were observed between these two different classes of agents. We were not able to identify predictive biomarkers that correlate with efficacy of VEGF inhibitors. This should be further explored in prospective studies in order to identify active agents in this heavily pre treated population that improve efficacy while minimizing cost and toxicity. PMID- 24772338 TI - Tumor response assessment in locally advanced colon cancer after neoadjuvant chemotherapy. AB - BACKGROUND: Preoperative chemotherapy followed by radical surgery is a novel therapeutic approach for locally advanced colon cancer (LACC). Neoadjuvant strategies require highly accurate diagnostic tests for a proper selection of candidate patients, allowing a low risk of overtreatment. This paper assesses the radiological, metabolic and pathological findings induced by preoperative oxaliplatin and fluoropyrimidines-based chemotherapy in LACC. METHODS: Forty-four consecutive patients with a confirmed diagnosis of LACC who received neoadjuvant chemotherapy and colon surgery were included. All patients were staged at baseline and before surgery. Clinical diagnosis consisted of physical examination, endoscopy with biopsy and computed tomography (CT) scan. In selected cases, a positron emission tomography/CT (PET/CT) scan was also performed. Accuracy and correlations between CT scan findings and pathologic report was assayed for T stage, N stage and TN stage. This study is retrospective in design. RESULTS: After chemotherapy, a statistical significant tumor volume reduction of 62.5% was achieved by CT-scan (P<0.001; Wilcoxon test) and a 38.9% decrease of standard uptake value (SUVmax) was observed on PET/CT (P=0.004). No progressive disease was reported during neoadjuvant treatment. Accuracy for T and N classification was 62% and 87%, respectively. Accuracy for TN stage was 77%, with 13.6% and 9.1% of the patients being under or overstaged, respectively. Pathologic stage II and III disease was observed in 29/44 (65.9%) and 15/44 (34.1%) of the patients, respectively. Pathologic complete response was achieved in three patients. CONCLUSIONS: Oxaliplatin/fluorpyrimidine neoadjuvant chemotherapy induces major tumour shrinkage at both the pathological and radiological levels. The CT scan shows a high accuracy and a low overstaged rate in LACC patients treated by means of a neoadjuvant approach. PMID- 24772339 TI - Ethnic disparities in the risk of colorectal adenomas associated with aspirin and statin use: a retrospective multiethnic study. AB - BACKGROUND: Although data on the inverse association between colorectal adenomas (CRA) and daily aspirin or statin therapy exists in white and black patients, scarce data exists on these associations in the Hispanic population. With a rapidly increasing Hispanic population in the United States, defining the association in Hispanics is crucial. METHODS: The study sample included 1,843 consecutive patients who underwent a colonoscopy (screening or diagnostic) from 2009 to 2011 at a community hospital in East Meadow, New York. Data was then extracted from patient charts regarding aspirin and/or statin use. Adjusted odds ratios (OR) and their 95% confidence intervals (CI) were calculated to assess the association between colonoscopy findings and aspirin, statin, or aspirin/statin use. RESULTS: In our total population including all races, aspirin user had an increased risk for having two or more adenomas (OR =1.73, 95% CI: 1.00, 2.99, P=0.05) and presence of an adenoma in the proximal colon (OR =1.66, 95% CI: 1.07, 2.58, P=0.02). In the total study population, those who used both statin and aspirin had an increased risk for having two or more adenomas (OR =2.56, 95% CI: 1.21, 5.39, P=0.01). In the Hispanic population, users of both medications had an increased risk for having two or more adenomas (OR =19.04, 95% CI: 1.30, 280.09, P=0.03), adenoma present in the distal colon (OR =5.75, 95% CI: 1.64, 20.21, P=0.01) and largest adenoma in distal colon (OR =5.75, 95% CI: 1.64, 20.21, P=0.01). CONCLUSIONS: Aspirin use and aspirin/statin use was associated with abnormal colonoscopy findings, particularly in the Hispanic population. These findings may be due to environmental factors such as dietary, colonic flora, or genetic susceptibility. The findings warrant further investigational research, particularly in Hispanics. PMID- 24772340 TI - Safety and efficacy of esophageal stents preceding or during neoadjuvant chemotherapy for esophageal cancer: a systematic review and meta-analysis. AB - BACKGROUND: Patients with locally advanced esophageal cancer who require neoadjuvant therapy have significant dysphagia and may severely impair nutritional status. We conducted a meta-analysis to assess the efficacy of self expandable metal stents prior to neoadjuvant therapy. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. Original data was abstracted from each study and used to calculate a pooled odd ratio (OR) and 95% confidence interval (95% CI). RESULTS: Only nine studies comprising of 180 patients were included for analysis. The overall procedural success rate was 95% (95% CI, 0.895-0.977). There was a substantial decrease in the dysphagia scores standard difference in means (SDM) -0.81 [standard error (SE) 0.15, 95% CI, -1.1 to -0.51], similar increase in weight SDM 0.591 (SE 0.434, 95% CI, 0.261 to 1.442) and serum albumin SDM 0.35 (SE 0.271, 95% CI, -0.181 to 0.881). The incidence of major adverse events included stent migration 32% (95% CI, 0.258 0.395) and chest discomfort 51.4% (95% CI, 0.206-0.812). CONCLUSIONS: Placement of stents in patients with locally advanced esophageal cancer significantly improves dysphagia and allows for oral nutrition during neoadjuvant therapy. Stents appear to be effective for palliating dysphagia. Stent migration was a common occurrence; however, migration may be a sign of tumor response to neoadjuvant therapy. PMID- 24772341 TI - Sentinel lymph node in oesophageal cancer-a systematic review and meta-analysis. AB - BACKGROUND: Sentinel lymph nodes (SLNs) have been used to predict regional lymph node metastasis in patients with melanoma and breast cancer. However, the validity of the SLN hypothesis is still controversial for oesophageal cancer. We performed this meta-analysis to evaluate the feasibility and accuracy of radio guided SLN mapping for oesophageal cancer. METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google scholar, Science Direct, and Web of Science. Original data was abstracted from each study and used to calculate a pooled event rates and 95% confidence interval (95% CI). RESULTS: The search identified 23 relevant articles. The overall detection rate was 0.93 (95% CI: 0.894-0.950), sensitivity 0.87 (95% CI: 0.811-0.908), negative predictive value 0.77 (95% CI: 0.568-0.890) and the accuracy was 0.88 (95% CI: 0.817-0.921). In the adenocarcinoma cohort, detection rate was 0.98 (95% CI: 0.923-0.992), sensitivity 0.84 (95% CI: 0.743 0.911) and the accuracy was 0.87(95% CI: 0.796-0.913). In the squamous cell carcinoma group, detection rate was 0.89 (95% CI: 00.792-0.943), sensitivity 0.91 (95% CI: 0.754-0.972) and the accuracy was 0.84 (95% CI: 0.732-0.914). CONCLUSIONS: It is possible to identify and obtain a SLN before neoadjuvant therapy in oesophageal cancer. However, further work is needed to optimize radiocolloid type, refine the technique and develop a quick and accurate way to determine SLN status intraoperatively. This technique has to be further evaluated before it can be applied widely. PMID- 24772342 TI - Gastric cancer-a clinicopathological study in a tertiary care centre of North eastern India. AB - BACKGROUND: The incidence of gastric cancer varies in different parts of the world and among various ethnic groups. It remains the fifth most common cancer among males and seventh most common cancer among females in India. MATERIALS AND METHODS: We conducted a retrospective study using the data base of 158 patients of primary gastric cancer diagnosed in the Department of Surgery at Regional Cancer Centre, RIMS, Manipur, India from July 2009 to June 2013. RESULTS: Our study revealed a male to female ratio of 2.16(:)1, distribution of age varied from 28 to 91 years. Majority of the men were in the age group of more than 60 years (45.37%) and majority of females were of 51-60 years (44%). Nearly 7.6% patients had a positive family history. Dietary history of intake salted, fermented fish was present in 67.7% of patients, whereas history of consumption of smoked meat was found in 77.8% of patients. Only 27.8% of patients in our study had history of regular consumption of fresh fruits. About 35.4% of the patients had poor drinking water source. Nearly, 67.6% of males and 44% of females had smoking history. Combined consumption of alcohol and smoking was present in 33.5% of patients. Vague abdominal discomfort was the most common presenting symptom in 61.4% of patients. The most common site of gastric cancer in our study was antrum (50.6%) followed by cardia (17.1%). The most common histological type was adenocarcinoma (95.6%). Most of our patients presented in locally advanced stage (62.7%). CONCLUSIONS: Our analysis suggests that poor dietary habits such as smoked mead, dried fish and excessive use of tobacco are associated with high occurrence of gastric cancer in this part of the India. Increasing the awareness regarding the aetiology and varied clinical presentation among general population and health providers is needed for prevention and early detection. PMID- 24772343 TI - Analysis of surgical complications of primary tumor resection after neoadjuvant treatment in stage IV colon cancer. AB - PURPOSE: Assess the surgical complications of primary tumor resection in stage IV colon cancer patients previously treated with neoadjuvant chemotherapy. METHODS: Between July 2001 and September 2010, 67 consecutive patients received preoperative chemotherapy. Clinical and surgical complications were obtained from the medical records. This study was retrospective in design. RESULTS: All patients were affected with liver metastasis, and 29.8% had metastasis in additional organs. Three different schemes of preoperative chemotherapy were employed, based on FOLFIRI, XELOXIRI or XELOX plus cetuximab. Eighteen patients (26.8%) reported some side effects to the chemotherapy, without contraindicating any intervention. All patients underwent colon surgery and within those, eight patients (11.9%), underwent liver surgery simultaneously. Median hospital admission was 8 [3-29] days. The perioperative complication rate was 16.2%, when the estimated physiological and operative severity score for the enumeration of mortality and morbidity (POSSUM) was 58.3%. There was not perioperative mortality, despite the mortality prediction for Portsmouth-POSSUM (P-POSSUM) being 5.07%. No differences were observed between the chemotherapy regimen (P=0.72) or the kind of the surgery-simple or combined (P=0.58). CONCLUSIONS: Neoadjuvant chemotherapy as a systemic treatment for stage IV colon cancer does not indicate surgery contraindication nor increases postoperative morbimortality by a significant amount. PMID- 24772344 TI - A case of esophageal squamous cell intraepithelial neoplasia with positivity for type 16 human papillomavirus successfully treated with radiofrequency ablation. AB - Esophageal cancer is the eight most common cancer worldwide and the sixth cause of cancer related death with squamous cell carcinoma (SCC) accounting for almost half of all esophageal cancers. Persistent human papilloma virus (HPV) infection has been suspected to play an active role in esophageal carcinogenesis but a clear association has not still been proven and no specific indications or guidelines for possible endoscopic and surgical therapeutic approaches to this clinical scenario are available. We report a case of a 62-year-old woman with histological diagnosis of high-grade intraepithelial squamous neoplasia of distal esophagus associated with cytological modifications resembling cervical HPV infection and with a positive INNO-LiPA assay for genotype 16 HPV. A single session of radiofrequency ablation (RFA) was performed on the dysplastic esophageal area with complete endoscopic eradication as confirmed by the following endoscopic, histologic and microbiologic examinations. Our report might give further strength to the hypothesis of an etiological role of HPV in selected cases of esophageal carcinogenesis and opens a discussion on the possible use of Radio Frequency Ablation as an effective and safe endoscopic treatment for both early squamous cell neoplasia and HPV esophageal colonization. PMID- 24772345 TI - Carcinoma transverse colon masquerading as carcinoma gall bladder. AB - Colorectal cancer is one of the most common cancer worldwide .Its incidence is reported to be increasing in developing countries. It commonly presents with weight loss, anaemia, lump abdomen, change of bowel habit, obstruction or fresh rectal bleeding. Beside these common modes of presentations, there are some rare manifestations which masqueraded as different disease like obstructive jaundice, empyema gall bladder or cholecystitis. A 60-year-old male presented to hospital with right sided pain abdomen. On abdominal examination mild tenderness was present in right hypochondrium. Intra operatively gall bladder was separated from the adjoining gut, peritoneum and liver bed and was removed. On further exploration, there was a large mass in the vicinity of the gall bladder related to transverse colon. Extended right hemicolectomy was done. Histopathological examination of gut mass revealed adenocarcinoma of transverse colon with free margins and gall bladder showed cholecystitis with no evidence of malignancy. We present an interesting case of colon cancer colon that caused diagnostic confusion by mimicking as cholecystitis. Colorectal cancer constitutes a major public health issue globally. Therefore, public awareness, screening of high-risk populations, early diagnosis and effective treatment and follow-up will help to reduce its occurance and further complications. PMID- 24772346 TI - Posterior reversible leukoencephalopathy syndrome secondary to hepatic transarterial chemoembolization with doxorubicin drug eluting beads. AB - Posterior reversible encephalopathy syndrome (PRES) is a rare complication of transarterial chemoembolization (TACE) used to treat liver metastases and has never been reported in a patient with metastatic uveal melanoma (UM) to the liver. We report the first case of PRES secondary to TACE with drug eluting beads (DEBs) loaded with doxorubicin in a 56-year-old woman with metastatic UM to the liver. PMID- 24772347 TI - Spontaneous tumor lysis syndrome in a patient with cholangiocarcinoma. AB - Tumor lysis syndrome (TLS) is a potentially deadly complication of tumors or their treatment. This syndrome consists of a constellation of laboratory parameters such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia and clinical complications such as seizures, acute renal insult, cardiac dysrhythmias and death. TLS is especially common in patients with hematological malignancies with rapid cellular turnover rates such as acute lymphocytic leukemia and Burkitt lymphoma, but is very rare in patients with solid tumors. However, it is essential to keep in mind that solid tumors can also lead to TLS. We present a case of a 66-year-old African American male with metastatic cholangiocarcinoma complicated by the development of spontaneous TLS. TLS has never been reported in a patient with cholangiocarcinoma. PMID- 24772348 TI - Biliary and gastric drainage in advanced pancreatic serous cystadenoma and portal hypertension in Von Hippel-Lindau syndrome. AB - Von Hippel-Lindau is a genetic syndrome, comprising several variant mutations on chromosome 3, that predisposes patients to the development of benign and malignant tumors. Tough relatively common, Von Hippel-Lindau syndrome (VHL) with associated hepato-biliary and gastric outlet obstruction, and portal hypertension consequent to the mass effect of a pancreatic serous cystadenoma is a rare scenario. This manuscript reports a 41-year-old female with the aforementioned presentation who successfully underwent a palliative cholecysto- and a gastro jejunostomy. To the knowledge of the authors, this is the only report, describing a palliative biliary decompression for VHL-related pancreatic serous cystadenoma and portal hypertension. PMID- 24772349 TI - Management of the large upper eyelid defects with cutler-beard flap. AB - Background. To assess Cutler-Beard procedure results in patients after wide excision of malignant eyelid tumours. Materials and Methods. The records of two women and two men (four patients) referred to our clinic with eyelid mass complaints and malign eyelid tumour diagnosis according to the histopathological examination were examined retrospectively. Results. The patients were 60-73 years old and their average age was 66 +/- 11.10. The follow-up period of the cases was 16 (6-25) months. Total excisional biopsy was applied to all patients and then Cutler-Beard full thickness lid reconstruction was done because of the wide localization of the tumour. The patients' diagnoses were consistent with basal cell carcinoma, sebaceous gland carcinoma, eyelid lymphoma, and squamous cell carcinoma. The patients' eyelids were separated from each other 1 month postoperatively with a second operation. Superior eyelid entropium and blepharochalasis were seen in one patient during followup. Conclusions. Cutler Beard flap is a successful procedure for superior eyelid tumours accompanied by wide tissue loss. The long-time closure of the eyelids and the need for secondary surgery are the major disadvantages of this procedure. Our experience with this procedure will reveal better results with large case series. PMID- 24772350 TI - A patient-centered electronic tool for weight loss outcomes after Roux-en-Y gastric bypass. AB - BACKGROUND. Current patient education and informed consent regarding weight loss expectations for bariatric surgery candidates are largely based on averages from large patient cohorts. The variation in weight loss outcomes illustrates the need for establishing more realistic weight loss goals for individual patients. This study was designed to develop a simple web-based tool which provides patient specific weight loss expectations. METHODS. Postoperative weight measurements after Roux-en-Y gastric bypass (RYGB) were collected and analyzed with patient characteristics known to influence weight loss outcomes. Quantile regression was used to create expected weight loss curves (25th, 50th, and 75th %tile) for the 24 months after RYGB. The resulting equations were validated and used to develop web-based tool for predicting weight loss outcomes. RESULTS. Weight loss data from 2986 patients (2608 in the primary cohort and 378 in the validation cohort) were included. Preoperative body mass index (BMI) and age were found to have a high correlation with weight loss accomplishment (P < 0.0001 for each). An electronic tool was created that provides easy access to patient-specific, 24 month weight loss trajectories based on initial BMI and age. CONCLUSIONS. This validated, patient-centered electronic tool will assist patients and providers in patient teaching, informed consent, and postoperative weight loss management. PMID- 24772351 TI - Pomaglumetad Methionil (LY2140023 Monohydrate) and Aripiprazole in Patients with Schizophrenia: A Phase 3, Multicenter, Double-Blind Comparison. AB - We tested the hypothesis that long-term treatment with pomaglumetad methionil would demonstrate significantly less weight gain than aripiprazole in patients with schizophrenia. In this 24-week, multicenter, randomized, double-blind, Phase 3 study, 678 schizophrenia patients were randomized to either pomaglumetad methionil (n = 516) or aripiprazole (n = 162). Treatment groups were also compared on efficacy and various safety measures, including serious adverse events (SAEs), discontinuation due to adverse events (AEs), treatment-emergent adverse events (TEAEs), extrapyramidal symptoms (EPS), and suicide-related thoughts and behaviors. The pomaglumetad methionil group showed significantly greater weight loss at Week 24 (Visit 12) compared with the aripiprazole group ( 2.8 +/- 0.4 versus 0.4 +/- 0.6; P < 0.001). However, change in Positive and Negative Syndrome Scale (PANSS) total scores for aripiprazole was significantly greater than for pomaglumetad methionil (-15.58 +/- 1.58 versus -12.03 +/- 0.99; P = 0.045). The incidences of SAEs (8.2% versus 3.1%; P = 0.032) and discontinuation due to AEs (16.2% versus 8.7%; P = 0.020) were significantly higher for pomaglumetad methionil compared with aripiprazole. No statistically significant differences in the incidence of TEAEs, EPS, or suicidal ideation or behavior were noted between treatment groups. In conclusion, long-term treatment with pomaglumetad methionil resulted in significantly less weight gain than aripiprazole. This trial is registered with ClinicalTrials.gov NCT01328093. PMID- 24772352 TI - Sources of life strengths appraisal scale: a multidimensional approach to assessing older adults' perceived sources of life strengths. AB - Both cognitive and psychosocial theories of adult development stress the fundamental role of older adults' appraisals of the diverse sources of cognitive and social-emotional strengths. This study reports the development of a new self appraisal measure that incorporates key theoretical dimensions of internal and external sources of life strengths, as identified in the gerontological literature. Using a pilot study sample and three other independent samples to examine older adults' appraisals of their sources of life strengths which helped them in their daily functioning and to combat life challenges, adversity, and losses, a psychometric instrument having appropriate reliability and validity properties was developed. A 24-month followup of a randomly selected sample confirmed that the nine-scale appraisal measure (SLSAS) is a promising instrument for appraising older adults' sources of life strengths in dealing with stresses of daily life's functioning and also a robust measure for predicting outcomes of resilience, autonomy, and well-being for this age group. A unique strength of the appraisal instrument is its critically relevant features of brevity, simplicity of language, and ease of administration to frail older adults. Dedicated to the memory of Shanta Khurana whose assistance in the pilot work for the study was invaluable. PMID- 24772354 TI - Anaesthetic management of two patients with pompe disease for caesarean section. AB - The introduction of enzyme replacement therapy and the resultant stabilisation or improvement in mobility and respiratory muscle function afforded to patients with late-onset Pompe may lead to an increased number of Pompe patients prepared to accept the challenges of parenthood. In this case report, we describe our anaesthetic management of two patients with Pompe disease for a caesarean section. PMID- 24772355 TI - Endoscopic Removal of a Supernumerary Premolar in the Mandible during a Dental Implant Placement. AB - The surgical removal of supernumerary teeth is necessary in some cases, especially before the commencement of any orthodontic or implant treatment procedure. In the mandibular supernumerary premolar, a more conservative approach is required because of the presence of complications associated with conventional surgery due to the close proximity of the said premolar to the alveolar inferior and mental nerves, and the need for bone conservation for implant placement. The endoscopic surgical approach has been used for the removal of the maxillary supernumerary tooth, impacted third molar, and implants. In this case report, we present an endoscopically assisted surgical technique for the removal of an unerupted supernumerary premolar in the mandible associated with a dental implant placement procedure. PMID- 24772356 TI - Eosinophilic ascites and duodenal obstruction in a patient with liver cirrhosis. AB - Eosinophilic gastroenteritis (EG) is a rare disease characterized by eosinophilic infiltration of portions of the gastrointestinal tract. Eosinophilic ascites is probably the most unusual and rare presentation of EG and is generally associated with the serosal form of EG. Hereby, we report a case of eosinophilic ascites with duodenal obstruction in a patient with liver cirrhosis. A 50-year-old woman was admitted to our hospital because of abdominal pain, nausea, bloating, and constipation. She had a history of laparotomy because of duodenal obstruction 2 years ago. Based on clinical, radiological, endoscopic, and pathological findings, and given the excluding the other causes of peripheral eosinophilia, the diagnosis of eosinophilic gastroenteritis along with liver cirrhosis and spontaneous bacterial peritonitis was established. Based on the findings of the present case, it is highly recommended that, in the patients presented with liver cirrhosis associated with peripheral blood or ascitic fluid eosinophilia, performing gastrointestinal endoscopy and biopsy can probably reveal this rare disorder of EG. PMID- 24772353 TI - Surveillance, phagocytosis, and inflammation: how never-resting microglia influence adult hippocampal neurogenesis. AB - Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory. PMID- 24772357 TI - Open questions in the management of nodular lymphocyte predominant hodgkin lymphoma. AB - Localized Nodular Lymphocyte Predominant Hodgkin Lymphoma is a rare disease with an overall good prognosis but frequent late relapses. Due to it's rarity there is no standard therapeutic approach and pathological diagnosis may be hard. In this paper we discuss the technical aspects of the radiation therapy and histological issues. The new fields reductions proposed for classical Hodgkin lymphoma cannot be applied to early stages Nodular Lymphocyte Predominant Hodgkin lymphomas which are usually treated with radiation therapy without systemic chemotherapy. PMID- 24772358 TI - A case of mucinous cystadenofibroma of the ovary. AB - Ovarian adenofibroma is a rare benign tumour originating from the germinal lining and stroma of the ovary. We describe here the case of a 36-year-old woman with an ovarian mucinous cystadenofibroma that was diagnosed as a benign cystic mass of the ovary before surgery. The tumour was a cystic lesion composed of 2 regions: one filled with mucinous fluid and the other with yellowish solid components. The patient successfully underwent a left oophorectomy. PMID- 24772359 TI - LMN Facial Palsy in Pregnancy: An Opportunity to Predict Preeclampsia-Report and Review. AB - Facial paralysis is the most frequent unilateral cranial nerve pathology affecting pregnant population 2 to 4 times more often than the nonpregnant population. There exists an association with preeclampsia but this has largely been overlooked. Clinicians often dismiss it for idiopathic palsy as seen in the present case. A 30-year-old woman, Gravida 4, Para 3, presented at 26 weeks pregnancy with complaints of facial weakness, blurring of vision, altered taste sensation, increased noise sensitivity for 1 month, headache since 18 days, and vomiting since 2-3 days. Her pulse was 90/min, BP was 170/120, and RR was 18/min. Uterus was 18 weeks size and proteinuria++ was present. Ultrasonography revealed a 26 weeks fetus, severe bradycardia, and absent liquor. HELLP syndrome was diagnosed after investigations. Six units of fresh frozen plasma were transfused. An informed decision for termination of pregnancy was made. She delivered a 450 gram stillborn. The third stage was complicated with postpartum hemorrhage but it was managed successfully. Women with Bell's palsy during pregnancy should be evaluated critically as in some it may precede preeclampsia which has serious maternal and fetal implications. Therefore, these women should be in regular followup of the obstetrician. PMID- 24772360 TI - Upper extremity thrombosis presenting as medial elbow pain after shoulder arthroscopy. AB - Deep vein thrombosis of the upper extremity is believed to be an uncommon complication of arthroscopic shoulder surgery. It most commonly presents with significant swelling and pain throughout the upper extremity. However the diagnosis can be easily missed when findings are more subtle and unrelated or the patient asymptomatic. In this study we report on 5 cases of postoperative upper extremity deep vein thrombosis (UEDVT). Each case was performed in the lateral decubitus position with an interscalene block and postoperative sling immobilization. All patients presented with a primary complaint of medial elbow pain and went on to require anticoagulation. Only one patient was found to have a heritable coagulopathy. The true incidence of thromboembolic phenomena after shoulder arthroscopy may be higher than that reported in the current literature. Therefore a high index of suspicion must be maintained when evaluating patients postoperatively to avoid misdiagnosis. Symptoms of medial elbow pain after immobilization in a sling should be considered an indication for duplex ultrasound evaluation. Ultimately, further prospective study is needed to better understand the prevalence, prevention, and management of this entity. PMID- 24772361 TI - Swellings over the Limbs as the Earliest Feature in a Patient with Osteogenesis Imperfecta Type V. AB - Swellings over the upper and lower limbs were encountered in a one-year-old child. Skeletal survey showed a constellation of distinctive radiographic abnormalities of osteoporosis, hyperplastic callus and ossification of the interosseous membrane of the forearm, femora, and to lesser extent the tibiae. Neither wormian bones of the skull nor dentinogenesis imperfecta was present. Genetic tests revealed absence of mutation in COL1A1 or COL1A2 genes, respectively. The overall phenotypic features were consistent with the diagnosis of osteogenesis imperfecta type V (OI-V). The aim of this paper is to distinguish between swellings because of intrinsic bone disorders and these due to child physical abuse. PMID- 24772363 TI - Medial radial head dislocation associated with a proximal olecranon fracture: a bado type v? AB - The Monteggia fracture is relatively rare. We present an unreported configuration of a traumatic olecranon fracture with a concomitant medial radial head dislocation in a 3-year-old male. This injury was initially missed and required a subsequent operative intervention. Following surgery, there was evident fracture union, articular congruency, and a full functional recovery. Medial radial head dislocation is not accounted for in the Bado (1967) classification of the Monteggia lesion and hence we propose the addition of a Bado V category. PMID- 24772364 TI - Leptin Receptor Gene Gln223Arg Polymorphism Is Not Associated with Hypertension: A Preliminary Population-Based Cross-Sectional Study. AB - Hypertension is responsible for high morbidity and mortality as one of the most important cardiometabolic risk factors. The aim of the study was to investigate whether the Gln223Arg in the leptin receptor (LEPR) influences the prevalence of hypertension. A cross-sectional study was carried out in individuals aged >= 18 years. Polymorphism identification was performed using PCR-RFLP analysis. Participants with blood pressure >= 140/90 mmHg or medication use were considered hypertensive. Frequencies, means, cross-tabulations, and multivariate models were produced to study differences in hypertension prevalence by genotypes. The study includes 470 participants. The frequency of GG polymorphism variant was 10.43%, 46.81% AG, and 42.77% AA. The distribution of hypertension frequency by LEPR genotypes was the following: AA 43.8%, AG 40.4%, and GG 40.8%; there were no significant differences between groups. Comparative analysis which used multivariate Poisson regression adjusted by many potential confounders (age, sex, schooling, smoking, alcohol intake, obesity, and family history of parental obesity) did not modify this result. In this large sample of population-based study, the association of the LEPR Gln223Arg gene polymorphism with hypertension was not observed. PMID- 24772365 TI - Long-term mortality analysis in Parkinson's disease treated with deep brain stimulation. AB - Background. Few data have been published regarding long-term mortality in patients with Parkinson's disease treated with DBS. Methods. This study analyzed long-term mortality rates, causes, and correlates in PD patients treated with DBS. Results. 184 consecutive patients were included; mean follow-up was 50 months. Fifteen deaths occurred (total 8.15%, annual mortality rate 1.94%). Mean age at disease onset and at surgery was 48 +/- 2.4 and 63 +/- 1.6 years, respectively. Mean disease duration until death was 21 +/- 7.8 years. Most deaths related to stroke, myocardial infarction, other vascular/heart disorders, or severe infection; one suicide was recorded. Deceased PD patients were mostly male and had lower motor benefit after DBS, but univariate analysis failed to show significant differences regarding gender and motor benefit. Survival was 99% and 94% at 3 and 5 years. Conclusions. Long-term survival is to be expected in PD patients treated with DBS, possibly higher than previously expected. Death usually supervenes due to vascular events or infection. PMID- 24772366 TI - Pathology of Experimental Encephalitozoon cuniculi Infection in Immunocompetent and Immunosuppressed Mice in Iraq. AB - This study was performed to evaluate pathology of experimental Encephalitozoon cuniculi (Iraqi isolate) infection in normal and immunosuppressed mice. Pathological changes were not seen in negative control mice while secondary bacterial infections were noted in the lungs, kidneys, and heart of mice given dexamethasone. Typical E. cuniculi infection lesions were found in brain, livers, lungs, and kidneys of mice given 10(7) E. cuniculi spores/mouse orally. These lesions were in the form of nonsuppurative meningoencephalitis with vasculitis in brain, interstitial inflammation with infiltration of both lymphocytes and plasma cells in lung tissue, and nonsuppurative interstitial (focal and diffuse) nephritis, presence of vacuole containing mature and immature spores in enterocytes within the tips of villi, and lymphoiod hyperplasia of the white pulp and vasculitis of the intratrabecular vessels. Mice that were given 10(7) E. cuniculi spores/mouse orally showed lesions similar to those observed in the previous group (vasculitis and granulomas) but the lesions were more severe and widespread. In conclusion, this is the first report of experimental E. cuniculi infection induced by E. cuniculi isolated from a naturally infected rabbit in Iraq and that infection became more severe and widespread upon the administration of dexaethasone. PMID- 24772367 TI - Stroke Survivors Scoring Zero on the NIH Stroke Scale Score Still Exhibit Significant Motor Impairment and Functional Limitation. AB - Objective. To determine the National Institutes of Health Stroke Scale's (NIHSS's) association with upper extremity (UE) impairment and functional outcomes. Design. Secondary, retrospective analysis of randomized controlled trial data. Setting. Not applicable. Participants. 146 subjects with stable, chronic stroke-induced hemiparesis. Intervention. The NIHSS, the UE Fugl-Meyer (FM), and the Arm Motor Ability Test (AMAT) were administered prior to their participation in a multicenter randomized controlled trial. Main Outcome Measures. The NIHSS, FM, and AMAT. Results. The association between the NIHSS and UE impairment was statistically significant (P = -0.204; p = 0.014) but explained less than 4% of the variance among UE FM scores. The association between NIHSS total score and function as measured by the AMAT was not statistically significant (P = -0.141; p = 0.089). Subjects scoring a "zero" on the NIHSS exhibited discernible UE motor deficits and varied scores on the UE FM and AMAT. Conclusion. While being used in stroke trials, the NIHSS may have limited ability to discriminate between treatment responses, even when only a relatively narrow array of impairment levels exists among patients. Given these findings, NIHSS use should be restricted to acute stroke studies and clinical settings with the goal of reporting stroke severity. PMID- 24772368 TI - Sedentary behaviour and physical activity of people with stroke in rehabilitation hospitals. AB - Background. Sedentary behaviour is associated with health risks, independent of physical activity. This study aimed to investigate patterns of sedentary behaviour and physical activity among stroke survivors in rehabilitation hospitals. Methods. Stroke survivors admitted to four Swedish hospital-based rehabilitation units were recruited >=7 days since stroke onset and their activity was measured using behavioural mapping. Sedentary behaviour was defined as lying down or sitting supported. Results. 104 patients were observed (53% men). Participants spent an average of 74% (standard deviation, SD 21%) of the observed day in sedentary activities. Continuous sedentary bouts of >=1 hour represented 44% (SD 32%) of the observed day. A higher proportion (30%, SD 7%) of participants were physically active between 9:00 AM and 12:30 PM, compared to the rest of the observed day (23%, SD 6%, P < 0.0005). Patients had higher odds of being physically active in the hall (odds ratio, OR 1.7, P = 0.001) than in the therapy area. Conclusions. The time stroke survivors spend in stroke rehabilitation units may not be used in the most efficient way to promote maximal recovery. Interventions to promote reduced sedentary time could help improve outcome and these should be tested in clinical trials. PMID- 24772369 TI - Association of genotypes with infection types and antifungal susceptibilities in Candida albicans as revealed by recent molecular typing strategies. AB - Candida albicans is a commensal microorganism in the mucosa of healthy individuals, but is also the most common opportunistic fungal pathogen of humans. It causes from benign infections such as oral and vaginal candidiasis to fatal, systematic diseases in immunocompromised or critically ill patients. In addition to improved therapy, the rapid and accurate identification of the disease-causing strains is crucial for diagnosis, clinical treatment and epidemiological studies of candidiasis. A variety of methods for strain typing of C. albicans have been developed. The most commonly used methods with the focus on recently developed molecular typing or DNA-fingerprinting strategies and the recent findings in the association of specific and genetically similar genotypes with certain infection types and the correlation between azole susceptibilities and certain genotypes of C. albicans from China are reviewed. PMID- 24772370 TI - Assessment of aflatoxigenic Aspergillus and other fungi in millet and sesame from Plateau State, Nigeria. AB - Sixteen fonio millet and 17 sesame samples were analysed for incidence of moulds, especially aflatoxigenic Aspergillus species, in order to determine the safety of both crops to consumers, and to correlate aflatoxin levels in the crops with levels produced by toxigenic isolates on laboratory medium. Diverse moulds including Alternaria, Aspergillus, Cercospora, Fusarium, Mucor, Penicillium, Rhizopus and Trichoderma were isolated. Aspergillus was predominantly present in both crops (46-48%), and amongst the potentially aflatoxigenic Aspergillus species, A. flavus recorded the highest incidence (68% in fonio millet; 86% in sesame kernels). All A. parvisclerotigenus isolates produced B and G aflatoxins in culture while B aflatoxins were produced by only 39% and 20% of A. flavus strains isolated from the fonio millet and sesame kernels, respectively. Aflatoxin concentrations in fonio millet correlated inversely (r = -0.55; p = 0.02) with aflatoxin levels produced by toxigenic isolates on laboratory medium, but no correlation was observed in the case of the sesame samples. Both crops, especially sesame, may not be suitable substrates for aflatoxin biosynthesis. This is the first report on A. parvisclerotigenus in sesame. PMID- 24772371 TI - Helvolic acid, an antibacterial nortriterpenoid from a fungal endophyte, Xylaria sp. of orchid Anoectochilus setaceus endemic to Sri Lanka. AB - An endophytic fungus was isolated from surface sterilized leaf segments of Anoectochilus setaceus, an orchid endemic to Sri Lanka, and was identified as Xylaria sp. by morphological characters and DNA sequencing. Bioassay-guided chromatographic fractionation of the organic extract of a laboratory culture of this fungus led to the isolation of the known antibacterial helvolic acid. Helvolic acid was active against the Gram-positive bacteria, Bacillus subtilis [minimal inhibitory concentrations (MIC), 2 MUg mL-1] and methicillin-resistant Staphylococcus aureus (MIC, 4 MUg mL-1). PMID- 24772372 TI - Phylogenetic analysis of ligninolytic peroxidases: preliminary insights into the alternation of white-rot and brown-rot fungi in their lineage. AB - White-rot and brown-rot fungi employ different mechanisms to degrade lignocellulose. These fungi are not monophyletic and even alternate in their common lineage. To explore the reason for this, seventy-six ligninolytic peroxidases (LPs), including 14 sequences newly identified from available basidiomycetous whole-genome and EST databases in this study, were utilized for phylogenetic and selective pressure analyses. We demonstrate that LPs were subjected to the mixed process of concerted and birth-and-death evolution. After the duplication events of original LPs, various LP types may originate from mutation events of several key residues driven by positive selection, which may change LP types and even rot types in a small fraction of wood-decaying fungi. Our findings provide preliminary insights into the cause for the alternation of the two fungal rot types within the same lineage. PMID- 24772373 TI - Teaching Confirmatory Factor Analysis to Non-Statisticians: A Case Study for Estimating Composite Reliability of Psychometric Instruments. AB - Texts and software that we are currently using for teaching multivariate analysis to non-statisticians lack in the delivery of confirmatory factor analysis (CFA). The purpose of this paper is to provide educators with a complement to these resources that includes CFA and its computation. We focus on how to use CFA to estimate a "composite reliability" of a psychometric instrument. This paper provides guidance for introducing, via a case-study, the non-statistician to CFA. As a complement to our instruction about the more traditional SPSS, we successfully piloted the software R for estimating CFA on nine non-statisticians. This approach can be used with healthcare graduate students taking a multivariate course, as well as modified for community stakeholders of our Center for American Indian Community Health (e.g. community advisory boards, summer interns, & research team members). The placement of CFA at the end of the class is strategic and gives us an opportunity to do some innovative teaching: (1) build ideas for understanding the case study using previous course work (such as ANOVA); (2) incorporate multi-dimensional scaling (that students already learned) into the selection of a factor structure (new concept); (3) use interactive data from the students (active learning); (4) review matrix algebra and its importance to psychometric evaluation; (5) show students how to do the calculation on their own; and (6) give students access to an actual recent research project. PMID- 24772375 TI - R-PASS: A Fast Structure-based RNA Sequence Alignment Algorithm. AB - We present a fast pairwise RNA sequence alignment method using structural information, named R-PASS (RNA Pairwise Alignment of Structure and Sequence), which shows good accuracy on sequences with low sequence identity and significantly faster than alternative methods. The method begins by representing RNA secondary structure as a set of structure motifs. The motifs from two RNAs are then used as input into a bipartite graph-matching algorithm, which determines the structure matches. The matches are then used as constraints in a constrained dynamic programming sequence alignment procedure. The R-PASS method has an O(nm) complexity. We compare our method with two other structure-based alignment methods, LARA and ExpaLoc, and with a sequence-based alignment method, MAFFT, across three benchmarks and obtain favorable results in accuracy and orders of magnitude faster in speed. PMID- 24772374 TI - Treating Diabetes with Exercise - Focus on the Microvasculature. AB - The rising incidence of diabetes and the associated metabolic diseases including obesity, cardiovascular disease and hypertension have led to investigation of a number of drugs to treat these diseases. However, lifestyle interventions including diet and exercise remain the first line of defense. The benefits of exercise are typically presented in terms of weight loss, improved body composition and reduced fat mass, but exercise can have many other beneficial effects. Acute effects of exercise include major changes in blood flow through active muscle, an active hyperemia that increases the delivery of oxygen to the working muscle fibers. Longer term exercise training can affect the vasculature, improving endothelial health and possibly basal metabolic rates. Further, insulin sensitivity is improved both acutely after a single bout of exercise and shows chronic effects with exercise training, effectively reducing diabetes risk. Exercise-mediated improvements in endothelial function may also reduce complications associated with both diabetes and other metabolic disease. Thus, while drugs to improve microvascular function in diabetes continue to be investigated, exercise can also provide many similar benefits on endothelial function and should remain the first prescription when treating insulin resistance and diabetes. This review will investigate the effects of exercise on the blood vessel and the potential benefits of exercise on cardiovascular disease and diabetes. PMID- 24772376 TI - An Accurate Scalable Template-based Alignment Algorithm. AB - The rapid determination of nucleic acid sequences is increasing the number of sequences that are available. Inherent in a template or seed alignment is the culmination of structural and functional constraints that are selecting those mutations that are viable during the evolution of the RNA. While we might not understand these structural and functional, template-based alignment programs utilize the patterns of sequence conservation to encapsulate the characteristics of viable RNA sequences that are aligned properly. We have developed a program that utilizes the different dimensions of information in rCAD, a large RNA informatics resource, to establish a profile for each position in an alignment. The most significant include sequence identity and column composition in different phylogenetic taxa. We have compared our methods with a maximum of eight alternative alignment methods on different sets of 16S and 23S rRNA sequences with sequence percent identities ranging from 50% to 100%. The results showed that CRWAlign outperformed the other alignment methods in both speed and accuracy. A web-based alignment server is available at http://www.rna.ccbb.utexas.edu/SAE/2F/CRWAlign. PMID- 24772377 TI - Apolipoprotein Gene Polymorphisms (APOB, APOC111, APOE) in the Development of Coronary Heart Disease in Ethnic Groups of Kazakhstan. AB - BACKGROUND: Previous Analysis of polymorphism of genes associated with the development of coronary heart disease (CHD) reveals that the frequency distribution of genotypes and alleles depends on the ethnic characteristics of the populations under study. Further impetus is derived from the well established links between alcoholism (high prevalence in Kazakhstan region) and cardiovascular disorders. OBJECTIVES: The purpose of this study was to examine a number of apolipoprotein gene polymorphisms and correlate these alleles with changes of lipid profile in CHD patients of Kazakh and Uyghur nationalities. METHODS: Four-Hundred Forty Eight (448) males of Kazakh and Uyghur nationalities residing in Kazakhstan were evaluated and genotyped. The age range of these subjects was 30-55 years which included both afflicted and controls. Specifically, 161- Kazakhs suffered from myocardial infarction compared to 112 health controls; 80- Uyghurs suffered from CHD compared to 95 health controls. Blood lipid profiles were examined in the total cohort. Genotyping was performed by polymerase chain reaction (PCR) using oligonucleotide primers identifying; ApoB; ApoC111; and APOE gene polymorphisms. RESULTS: Initial screening revealed a significant inter-ethnic difference on the frequency of alleles associated with both the ApoB and APOE genes. We found that the X1 ApoB gene polymorphism is overrepresented in healthy Kazakhs relative to Uyghurs [86.4% in Kazakhs vs. 69.4% in Uyghurs]. Moreover, we found that the E4APOE allele was also overrepresented in healthy Kazakhs relative to Uyghurs [16.8% in Kazakhs vs. 9.5% in Uyghurs]. There was a significant relationship of polymorphisms of APOE such as ApoB and ApoC 111 with the value of lipid indices in Kazakhs. Additionally, we found that the E4 allele of the APOE gene also correlated with the value of lipid indices in Kazakhs. Further evaluation showed that the X2 allele of the ApoB and the S2 allele of the ApoCIII gene significantly associated with the lipid indices of Uyghurs. CONCLUSION: This systematic investigation confirms the association of various alleles of Apolipoprotein gene polymorphisms and contribution to aberrant lipid metabolism. Putatively at least in our population we are proposing that certain gene polymorphisms of Apolipoprotein genes such as ApoB; ApoC111; APOE ; X2 of ApoB; and S2 of ApoCIII differentially represented in either Kazakhs or Uyghurs are genetic markers of hypertriglyceridemia. PMID- 24772378 TI - Bridging Diversity and Family Systems: Culturally Informed and Flexible Family Based Treatment for Hispanic Adolescents. AB - There is growing interest in identifying interventions that have been tested and found efficacious with minority families. This interest is fueled in part by the growth of Hispanics in the U.S. as well as by research findings that suggest that Hispanics have better outcomes when treatments are adapted to their unique experiences, and risk and protective factors. Family-based treatments for culturally diverse populations require the integration of advances from both the cultural and family systems domains. Current intervention research has begun to move towards developing and advancing individualized interventions for patients/clients. Adaptive interventions, tailored interventions, adapted interventions, and targeted interventions have all been identified in the literature as appropriate for addressing distinct cultural characteristics which generic interventions may not address effectively. To date, research has focused less on tailored or adaptive interventions partly due to the fact that they require decision rules, more careful implementation, and measurement of individualized outcomes. In this article we present evidence for the usefulness of adaptive interventions that can address not only subgroup variability but within group variability as well. Culturally Informed and Flexible Family-Based Treatment for Adolescents is presented as an adaptive treatment that allows for the tailoring of treatment to the unique clinical and cultural variations of individual adolescents and families, but that does so in a systematic and replicable fashion. By building decision-making processes into the manualized treatment, the transportability of the treatment may be enhanced as family therapists appreciate it's flexibility to address the complexity of clinical work. PMID- 24772379 TI - Performance of commonly used respiratory questionnaire items in a cohort of infants born preterm. AB - BACKGROUND: Items from respiratory questionnaires validated in older children are often used in research studies of preterm infants, although they have not been validated in this population. We aimed to assess both test-retest reliability and convergent validity of a group of commonly used respiratory questionnaire items in a cohort of preterm infants. METHODS: The health status of 300 preterm infants was assessed by telephone questionnaire as part of a prospective cohort study. The questionnaire items analyzed in this study included six commonly used respiratory questions. The questionnaire responses used in this analysis were from the telephone follow-up in this cohort at six months of age adjusted for prematurity. A repeat interview one to two weeks after this interview was performed in a subset of subjects to assess test-retest reliability. The convergent validity of the respiratory items was also assessed by calculating the associations among the responses to the respiratory questions. RESULTS: A total of 43 infants were singletons that met the criteria for test-retest reliability analysis. All of the respiratory questions demonstrated fair to strong test retest reliability. Among 206 respondents, respiratory questionnaire items also demonstrated strong convergent validity, in that caretakers reporting wheezing or whistling in the chest were significantly more likely to also report other respiratory events. CONCLUSIONS: This selection of standard respiratory questionnaire items performed well for research purposes in this population. PMID- 24772380 TI - Monocarboxylate Transporter Inhibition with Osmotic Diuresis Increases gamma Hydroxybutyrate Renal Elimination in Humans: A Proof-of-Concept Study. AB - BACKGROUND AND OBJECTIVE: The purpose of the current study was to demonstrate proof-of-concept that monocarboxylate transporter (MCT) inhibition with L-lactate combined with osmotic diuresis increases renal clearance of gamma-hydroxybutyrate (GHB) in human subjects. GHB is a substrate for human and rodent MCTs, which are responsible for GHB renal reabsorption, and this therapy increases GHB renal clearance in rats. METHODS: Ten healthy volunteers were administered GHB orally as sodium oxybate 50 mg/kg (4.5 gm maximum dose) on two different study days. On study day 1, GHB was administered alone. On study day 2, treatment of L-lactate 0.125 mmol/kg and mannitol 200 mg/kg followed by L-lactate 0.75 mmol/kg/hr was administered intravenously 30 minutes after GHB ingestion. Blood and urine were collected for 6 hours, analyzed for GHB, and pharmacokinetic and statistical analyses performed. RESULTS: L-lactate/mannitol administration significantly increased GHB renal clearance compared to GHB alone, 439 vs. 615 mL/hr (P=0.001), and increased the percentage of GHB dose excreted in the urine, 2.2 vs. 3.3% (P=0.021). Total clearance was unchanged. CONCLUSIONS: MCT inhibition with L lactate combined with osmotic diuresis increases GHB renal elimination in humans. No effect on total clearance was observed in this study due to the negligible contribution of renal clearance to total clearance at this low GHB dose. Considering the nonlinear renal elimination of GHB, further research in overdose cases is warranted to assess the efficacy of this treatment strategy for increasing renal and total clearance at high GHB doses. PMID- 24772381 TI - 759C/T Variants of the Serotonin (5-HT2C) Receptor Gene and Weight Gain in Children and Adolescents in Long-Term Risperidone Treatment. AB - BACKGROUND: Great inter-individual variability exists in the susceptibility to gain weight during antipsychotic treatment. Thus, we examined whether the -759C/T variants in the promoter region of the 5HT2C receptor gene were differentially associated with weight gain in children and adolescents in long-term risperidone treatment. METHODS: Medically healthy 7 to 17 year-olds, treated with risperidone for >= six months, were enrolled. Anthropometric measurements, laboratory tests, and treatment history were obtained upon enrollment and from medical records. The effect of the genotype on the trajectory of age-sex-adjusted weight and body mass index (BMI) z scores before and after the onset of risperidone treatment was investigated. RESULTS: In 124 subjects (90% males, mean age: 11.8 years) treated with risperidone for a mean of 2.8 years, weight and BMI z scores significantly increased after starting risperidone. This change was similar across the two genotype groups as were changes in several cardiometabolic variables. CONCLUSION: In contrast to other reports, the T allele failed to confer protection against excessive weight gain or cardiometabolic abnormalities in this group of children and adolescents chronically treated with risperidone. PMID- 24772383 TI - Adolescent Medication Misuse: Results from the MUSC Inventory of Medication Experiences (MIME). AB - OBJECTIVES: To survey a diverse high school population on current prescription and over-the-counter medication misuse behaviors and attitudes. METHODS: We administered the MUSC Inventory of Medication Experiences (MIME), a newly developed self-report instrument, in demographically diverse high schools in Charleston, SC, to assess the feasibility of its administration and determine characteristics associated with medication misuse among high school students. RESULTS: A total of 3182 students completed the MIME (93% completion rate). Nearly one-third (31%) reported misuse of a medication more than once a month. Analysis was conducted to evaluate associations between misuse and age (<15=33%, 15=32%, 16=33%, 17=30%, 18=26%, >18=34%; p=.35), grade (9=29%, 10=32%, 11=33%, 12=30%; p=.22), race (White 34%, African-American 26%, others 30%; p<.001), gender (M=32%, F=28%; p=.01), parent/guardian level of education (college=30%; p=.12), if a participant was prescribed medication (yes=46%, no=21%; p<.001), if a family member was prescribed medication (yes=40%, no=26%; p<.001), and if a family member had ever offered their prescribed medication to the student (yes=91%, no=29%; p<.001). CONCLUSION: Medication misuse may be more pervasive than originally thought, with a notably high level among those most familiar with medications. PMID- 24772382 TI - Addictions and Personality Traits: Impulsivity and Related Constructs. AB - Behavioral tendencies that might be captured through self-report measures may provide insight into personality features that are associated with substance addictions. Recently, impulsivity and related constructs, such as sensation seeking, have been examined to help better understand their relationships with addictions. Here, we review recent findings that show links over developmental epochs between addictive behaviors and impulsivity, sensation-seeking, and other constructs that are theoretically linked. These findings have significant implications for generating improved treatments and interventions aimed at preventing the development of addictive disorders. PMID- 24772384 TI - Participant-Centric Initiatives: Tools to Facilitate Engagement In Research. AB - Clinical genomic research faces increasing challenges in establishing participant privacy and consent processes that facilitate meaningful choice and communication capacity for longitudinal and secondary research uses. There are an evolving range of participant-centric initiatives that combine web-based informatics tools with new models of engagement and research collaboration. These emerging initiatives may become valuable approaches to support large-scale and longitudinal research studies. We highlight and discuss four types of emerging initiatives for engaging and sustaining participation in research. PMID- 24772385 TI - Global Budgets and Technology-Intensive Medical Services. AB - BACKGROUND: In 2009-2010, Blue Cross Blue Shield of Massachusetts entered into global payment contracts (the Alternative Quality contract, AQC) with 11 provider organizations. We evaluated the impact of the AQC on spending and utilization of several categories of medical technologies, including one considered high value (colonoscopies) and three that include services that may be overused in some situations (cardiovascular, imaging, and orthopedic services). METHODS: Approximately 420,000 unique enrollees in 2009 and 180,000 in 2010 were linked to primary care physicians whose organizations joined the AQC. Using three years of pre-intervention data and a large control group, we analyzed changes in utilization and spending associated with the AQC with a propensity-weighted difference-in-differences approach adjusting for enrollee demographics, health status, secular trends, and cost-sharing. RESULTS: In the 2009 AQC cohort, total volume of colonoscopies increased 5.2 percent (p=0.04) in the first two years of the contract relative to control. The contract was associated with varied changes in volume for cardiovascular and imaging services, but total spending on cardiovascular services in the first two years decreased by 7.4% (p=0.02) while total spending on imaging services decreased by 6.1% (p<0.001) relative to control. In addition to lower utilization of higher-priced services, these decreases were also attributable to shifting care to lower-priced providers. No effect was found in orthopedics. CONCLUSIONS: As one example of a large-scale global payment initiative, the AQC was associated with higher use of colonoscopies. Among several categories of services whose value may be controversial, the contract generally shifted volume to lower-priced facilities or services. PMID- 24772386 TI - Detection and Treatment of Long-Chain Omega-3 Fatty Acid Deficiency in Adolescents with SSRI-Resistant Major Depressive Disorder. AB - Residual depressive symptoms are commonly observed in adolescents with major depressive disorder (MDD) following treatment with selective serotonin reuptake inhibitors (SSRIs). This study combined a case-control analysis and an open-label fish oil (FO) trial to investigate the relationship between long-chain omega-3 (LCn-3) fatty acid status and residual depressive symptoms in SSRI-resistant adolescent MDD patients. Baseline erythrocyte docosahexaenoic acid (DHA)(-28%, p=0.0003), but not eicosapentaenoic acid (EPA)(-18%, p=0.2), was significantly lower in patients (n=20) compared with healthy controls (n=20). Patients receiving 10-week low-dose (2.4 g/d, n=7) and high-dose (16.2 g/d, n=7) FO exhibited significant increases in erythrocyte EPA and DHA composition. In the intent-to-treat sample, depressive symptoms decreased significantly in the high dose group (n=7, -40%, p<0.0001), and there was a trend in the low-dose group (n=10, -20%, p=0.06). Symptom remission was observed in 40% of patients in the low-dose group and 100% of patients in the high-dose group. There were no significant changes in vital signs and adverse events were rated as mild or moderate in severity. These preliminary findings demonstrate that adolescents with SSRI-resistant depression exhibit robust DHA deficits, and suggest that adjunctive FO supplementation is well-tolerated and effective for increasing LCn 3 fatty acid status and augmenting SSRI antidepressant effects. PMID- 24772387 TI - Identification of thyroid hormone receptor active compounds using a quantitative high-throughput screening platform. AB - To adapt the use of GH3.TRE-Luc reporter gene cell line for a quantitative high throughput screening (qHTS) platform, we miniaturized the reporter gene assay to a 1536-well plate format. 1280 chemicals from the Library of Pharmacologically Active Compounds (LOPAC) and the National Toxicology Program (NTP) 1408 compound collection were analyzed to identify potential thyroid hormone receptor (TR) agonists and antagonists. Of the 2688 compounds tested, eight scored as potential TR agonists when the positive hit cut-off was defined at >=10% efficacy, relative to maximal triiodothyronine (T3) induction, and with only one of those compounds reaching >=20% efficacy. One common class of compounds positive in the agonist assays were retinoids such as all-trans retinoic acid, which are likely acting via the retinoid-X receptor, the heterodimer partner with the TR. Five potential TR antagonists were identified, including the antiallergy drug tranilast and the anxiolytic drug SB 205384 but also some cytotoxic compounds like 5-fluorouracil. None of the inactive compounds were structurally related to T3, nor had been reported elsewhere to be thyroid hormone disruptors, so false negatives were not detected. None of the low potency (>100uM) TR agonists resembled T3 or T4, thus these may not bind directly in the ligand-binding pocket of the receptor. For TR agonists, in the qHTS, a hit cut-off of >=20% efficacy at 100 uM may avoid identification of positives with low or no physiological relevance. The miniaturized GH3.TRE-Luc assay offers a promising addition to the in vitro test battery for endocrine disruption, and given the low percentage of compounds testing positive, its high-throughput nature is an important advantage for future toxicological screening. PMID- 24772388 TI - Spatially-Explicit Simulation Modeling of Ecological Response to Climate Change: Methodological Considerations in Predicting Shifting Population Dynamics of Infectious Disease Vectors. AB - Poikilothermic disease vectors can respond to altered climates through spatial changes in both population size and phenology. Quantitative descriptors to characterize, analyze and visualize these dynamic responses are lacking, particularly across large spatial domains. In order to demonstrate the value of a spatially explicit, dynamic modeling approach, we assessed spatial changes in the population dynamics of Ixodes scapularis, the Lyme disease vector, using a temperature-forced population model simulated across a grid of 4 * 4 km cells covering the eastern United States, using both modeled (Weather Research and Forecasting (WRF) 3.2.1) baseline/current (2001-2004) and projected (Representative Concentration Pathway (RCP) 4.5 and RCP 8.5; 2057-2059) climate data. Ten dynamic population features (DPFs) were derived from simulated populations and analyzed spatially to characterize the regional population response to current and future climate across the domain. Each DPF under the current climate was assessed for its ability to discriminate observed Lyme disease risk and known vector presence/absence, using data from the US Centers for Disease Control and Prevention. Peak vector population and month of peak vector population were the DPFs that performed best as predictors of current Lyme disease risk. When examined under baseline and projected climate scenarios, the spatial and temporal distributions of DPFs shift and the seasonal cycle of key questing life stages is compressed under some scenarios. Our results demonstrate the utility of spatial characterization, analysis and visualization of dynamic population responses-including altered phenology-of disease vectors to altered climate. PMID- 24772389 TI - Label-Free LC-MS Profiling of Skeletal Muscle Reveals Heart-Type Fatty Acid Binding Protein as a Candidate Biomarker of Aerobic Capacity. AB - Two-dimensional gel electrophoresis provides robust comparative analysis of skeletal muscle, but this technique is laborious and limited by its inability to resolve all proteins. In contrast, orthogonal separation by SDS-PAGE and reverse phase liquid chromatography (RPLC) coupled to mass spectrometry (MS) affords deep mining of the muscle proteome, but differential analysis between samples is challenging due to the greater level of fractionation and the complexities of quantifying proteins based on the abundances of their tryptic peptides. Here we report simple, semi-automated and time efficient (i.e., 3 h per sample) proteome profiling of skeletal muscle by 1-dimensional RPLC electrospray ionisation tandem MS. Solei were analysed from rats (n = 5, in each group) bred as either high- or low-capacity runners (HCR and LCR, respectively) that exhibited a 6.4-fold difference (1,625 +/- 112 m vs. 252 +/- 43 m, p < 0.0001) in running capacity during a standardized treadmill test. Soluble muscle proteins were extracted, digested with trypsin and individual biological replicates (50 ng of tryptic peptides) subjected to LC-MS profiling. Proteins were identified by triplicate LC MS/MS analysis of a pooled sample of each biological replicate. Differential expression profiling was performed on relative abundances (RA) of parent ions, which spanned three orders of magnitude. In total, 207 proteins were analysed, which encompassed almost all enzymes of the major metabolic pathways in skeletal muscle. The most abundant protein detected was type I myosin heavy chain (RA = 5,843 +/- 897) and the least abundant protein detected was heat shock 70 kDa protein (RA = 2 +/- 0.5). Sixteen proteins were significantly (p < 0.05) more abundant in HCR muscle and hierarchal clustering of the profiling data highlighted two protein subgroups, which encompassed proteins associated with either the respiratory chain or fatty acid oxidation. Heart-type fatty acid binding protein (FABPH) was 1.54-fold (p = 0.0064) more abundant in HCR than LCR soleus. This discovery was verified using selective reaction monitoring (SRM) of the y5 ion (551.21 m/z) of the doubly-charged peptide SLGVGFATR (454.19 m/z) of residues 23-31 of FABPH. SRM was conducted on technical replicates of each biological sample and exhibited a coefficient of variation of 20%. The abundance of FABPH measured by SRM was 2.84-fold greater (p = 0.0095) in HCR muscle. In addition, SRM of FABPH was performed in vastus lateralis samples of young and elderly humans with different habitual activity levels (collected during a previous study) finding FABPH abundance was 2.23-fold greater (p = 0.0396) in endurance-trained individuals regardless of differences in age. In summary, our findings in HCR/LCR rats provide protein-level confirmation for earlier transcriptome profiling work and show LC-MS is a viable means of profiling the abundance of almost all major metabolic enzymes of skeletal muscle in a highly parallel manner. Moreover, our approach is relatively more time efficient than techniques relying on orthogonal separations, and we demonstrate LC-MS profiling of the HCR/LCR selection model was able to highlight biomarkers that also exhibit differences in trained and untrained human muscle. PMID- 24772390 TI - Marrow Hematopoietic Stem Cells Revisited: They Exist in a Continuum and are Not Defined by Standard Purification Approaches; Then There are the Microvesicles. AB - Current concepts of hematopoiesis are encompassed in a hierarchical stem cell model. This developed initially from studies of colony-forming unit spleen and in vitro progenitors for different cell lineages, but then evolved into a comprehensive model of cells with different in vivo differentiative and proliferative potential. These cells were characterized and purified based largely on expression of a variety of lineage-specific and stem cell-specific surface epitopes. Monoclonal antibodies were bound to these epitopes and then used to physically and fluorescently separate different classes of these cells. The gold standard for the most primitive marrow stem cells was long-term multilineage repopulation and renewal in lethally irradiated mice. Progressive work seemed to have clonally defined a Lineage negative (Lin-), Sca-1+, c-kit+, CD150+ stem cell with great proliferative, differentiative, and renewal potential. This cell was stable and in the G0 phase of cell cycle. However, continued work in our laboratory indicated that the engraftment, differentiation, homing, and gene expression phenotype of the murine marrow stem cells continuously and reversibly changes with passage through cell cycle. Most recently, using cycle-defining supravital dyes and fluorescent-activated cell sorting and S-phase-specific tritiated thymidine suicide, we have established that the long-term repopulating hematopoietic stem cell is a rapidly proliferating, and thus a continually changing cell; as a corollary it cannot be purified or defined on a clonal single cell basis. Further in vivo studies employing injected and ingested 5-Bromodeoxyuridine (BrdU), showed that the G0 Lin-Sca-1, c-kit+ Flt3- cell was rapidly passing through cell cycle. These data are explained by considering the separative process: the proliferating stem cells are eliminated through the selective separations leaving non-representative dormant G0 stem cells. In other words, they throw out the real stem cells with the purification. This system, where the marrow stem cell continuously and reversibly changes with obligate cell cycle transit, is further complicated by the consideration of the impact of tissue microvesicles on the cell phenotypes. Tissue microvesicles have been found to alter the phenotype of marrow cells, possibly explaining the observations of "stem cell plasticity." These alterations, short-term, are due to transfer of originator cell mRNA and as yet undefined transcription factors. Long-term phenotype change is due to transcriptional modulation; a stable epigenetic change. Thus, the stem cell system is characterized by continuous cycle and microvesicle-related change. The challenge of the future is to define the stem cell population. PMID- 24772391 TI - CRISPR-Cas systems: new players in gene regulation and bacterial physiology. AB - CRISPR-Cas systems are bacterial defenses against foreign nucleic acids derived from bacteriophages, plasmids or other sources. These systems are targeted in an RNA-dependent, sequence-specific manner, and are also adaptive, providing protection against previously encountered foreign elements. In addition to their canonical function in defense against foreign nucleic acid, their roles in various aspects of bacterial physiology are now being uncovered. We recently revealed a role for a Cas9-based Type II CRISPR-Cas system in the control of endogenous gene expression, a novel form of prokaryotic gene regulation. Cas9 functions in association with two small RNAs to target and alter the stability of an endogenous transcript encoding a bacterial lipoprotein (BLP). Since BLPs are recognized by the host innate immune protein Toll-like Receptor 2 (TLR2), CRISPR Cas-mediated repression of BLP expression facilitates evasion of TLR2 by the intracellular bacterial pathogen Francisella novicida, and is essential for its virulence. Here we describe the Cas9 regulatory system in detail, as well as data on its role in controlling virulence traits of Neisseria meningitidis and Campylobacter jejuni. We also discuss potential roles of CRISPR-Cas systems in the response to envelope stress and other aspects of bacterial physiology. Since ~45% of bacteria and ~83% of Archaea encode these machineries, the newly appreciated regulatory functions of CRISPR-Cas systems are likely to play broad roles in controlling the pathogenesis and physiology of diverse prokaryotes. PMID- 24772394 TI - The effects of vitamin D on the renin-angiotensin system. AB - Implication for health policy/practice/research/medical education: The current literature indicates that maintaining adequate vitamin D levels may be an important consideration in the treatment of hypertension, especially in individuals with vitamin D insufficiency and deficiency. PMID- 24772393 TI - Bioaerosols from composting facilities--a review. AB - Bioaerosols generated at composting plants are released during processes that involve the vigorous movement of material such as shredding, compost pile turning, or compost screening. Such bioaerosols are a cause of concern because of their potential impact on both occupational health and the public living in close proximity to such facilities. The biological hazards potentially associated with bioaerosol emissions from composting activities include fungi, bacteria, endotoxin, and 1-3 beta-glucans. There is a major lack of knowledge concerning the dispersal of airborne microorganisms emitted by composting plants as well as the potential exposure of nearby residents. This is due in part to the difficulty of tracing specifically these microorganisms in air. In recent years, molecular tools have been used to develop new tracers which should help in risk assessments. This review summarizes current knowledge of microbial diversity in composting aerosols and of the associated risks to health. It also considers methodologies introduced recently to enhance understanding of bioaerosol dispersal, including new molecular indicators and modeling. PMID- 24772395 TI - Acute renal failure in a young female with vaginal bleeding with partial recovery. AB - Implication for health policy/practice/research/medical education: Glomerular collapse is one of the morphological patterns of response of kidney parenchyma to a variety of noxious agents. As such, it is commonly observed on renal biopsies showing a variety of diseases. It is important to report this lesion in the context of underlying major pathology so as not to confuse it with idiopathic collapsing glomerulopathy. The prognosis of this lesion is determined in such cases by the underlying pathology. PMID- 24772396 TI - Black kidney in Albinism. AB - Implication for health policy/practice/research/medical education: Oculocutaneous albinism may be similar to two related syndromes (Hermansky-Pudlak and Chediak Higashi) and could lead to more widespread lysosome excretory defects. These defects could lead to accumulation of some intracellular material, leading to the gross discoloration of the kidney. PMID- 24772392 TI - That's my story, and I'm sticking to it--an update on B. burgdorferi adhesins. AB - Adhesion is the initial event in the establishment of any infection. Borrelia burgdorferi, the etiological agent of Lyme disease, possesses myriad proteins termed adhesins that facilitate contact with its vertebrate hosts. B. burgdorferi adheres to host tissues through interactions with host cells and extracellular matrix, as well as other molecules present in serum and extracellular fluids. These interactions, both general and specific, are critical in the establishment of infection. Modulation of borrelial adhesion to host tissues affects the microorganisms's ability to colonize, disseminate, and persist. In this review, we update the current knowledge on structure, function, and role in pathogenesis of these "sticky" B. burgdorferi infection-associated proteins. PMID- 24772397 TI - Contrast-induced nephropathy; A literature review. AB - CONTEXT: Contrast-induced nephropathy (CIN) is a common cause of acute kidney dysfunction. EVIDENCE ACQUISITIONS: Directory of Open Access Journals, Google Scholar, PubMed, EBSCO and Web of Science have been searched. RESULTS: It is necessary to identify at risk patients at early stages to implement preventive strategies to decrease the incidence of this nephropathy. However, mechanisms of CIN have not fully explained yet. It seems that mechanisms which mediated by nitric oxide and prostaglandin-induced vasodilatation have been played a crucial role in the CIN. Hemodynamic changes of renal blood flow, which causes hypoxia in the renal medulla and direct toxic effects of contrast media on renal cells, are thought to contribute to the pathogenesis of CIN. Contrast media is normally divided into iso-osmolar, low-osmolar, and high-osmolar. N-acetylcysteine is considered as one of the best choices to prevent CIN in high-risk groups. CONCLUSIONS: The first aim to prevent CIN is identifying high-risk subjects and controlling associate risk factors. As significant differences existed between contrasts agents due to their physicochemical properties, low-osmolar or iso osmolar contrast media should be used to prevent CIN in at-risk patients. The volume of contrast media should be as low as possible. PMID- 24772398 TI - Dengue-associated kidney disease. AB - CONTEXT: A mosquito-borne viral illness highly prevalent in the tropics and subtropics, dengue is considered a major global health threat by the World Health Organization. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: An RNA virus from the genus Flavivirus, dengue virus is transmitted by Aedes aegypti,the yellow fever mosquito. Dengue is asymptomatic in as many as one half of infected individuals. Dengue fever is an acute febrile illness accompanied by constitutional symptoms. Dengue hemorrhagic fever and dengue shock syndrome are the severe forms of dengue infection.Dengue infection has been associated with a variety of renal disorders. Acute renal failure is a potential complication of severe dengue infection and is typically associated with hypotension, rhabdomyolysis, or hemolysis. Acute renal failure complicates severe dengue infection in 2-5% of the cases and carries a high mortality rate. Proteinuria has been detected in as high as 74% of patients with severe dengue infection. Hematuria has been reported in up to 12.5% of patients. Various types of glomerulonephritis have been reported during or shortly after dengue infection in humans and mouse models of dengue infection. Mesangial proliferation and immune complex deposition are the dominant histologic features of dengue associated glomerulonephritis. On a rare occasion, dengue infection is associated with systemic autoimmune disorders involving the kidneys. CONCLUSIONS: In the vast majority of cases, dengue infection and associated renal disorders are self limited. PMID- 24772399 TI - Hypertension, renal failure, and edema in a 38-year-old man: light chain deposition disease; a case report and review of the literature. AB - BACKGROUND: Monoclonal immunoglobulin deposition disease (MIDD) is a rare disease, usually manifesting between the 5(th) and 6(th) decades of life but can also occur earlier. Characteristic feature of MIDD is a non-fibrillar, Congo red negative deposition of monoclonal immunoglobulins in various organs, including the kidneys. Depending on the composition of the deposits, MIDD is classified into 3 types; light chain deposition disease (LCDD), which is the most common form, heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD). Kidney involvement is common in MIDD. Renal biopsy reveals nodular sclerosing glomerulopathy on light microscopy and diffuse linear staining of glomerular and tubular basement membranes on immunofluorescence (IF) microscopy. CASE PRESENTATION: A 38-year-old male patient recently diagnosed with hypertension presented with lower extremity edema, shortness of breath, and fatigue. The workup that was performed in a different hospital prior to this admission, demonstrated the presence of significant proteinuria and renal failure. He was intermittently dialyzed and a renal biopsy was obtained, which showed LCDD. Further laboratory workup revealed an increase of IgM, kappa chain and beta2 microglobulin chain, in addition to proteinuria and renal insufficiency. Bone marrow biopsy demonstrated an involvement of 30% with plasma cells. The flow cytometry test showed monotypic plasma cells expressing intracytoplasmic kappa light chain restriction with kappa to lambda ratio of 35/1. The diagnosis of LCDD was established. Treatment with steroids and bortezomib was initiated. CONCLUSIONS: MIDD is an unusual disease and LCDD is the most common form of MIDD. The peak incidence is around the 5(th) and 6(th) decade of life, however, LCDD can also be found in younger patients. Renal involvement, proteinuria, hematuria, and hypertension are markers of the initial clinical presentation. Nodular sclerosing glomerulopathy is found in about 60% of the affected patients. Early diagnosis and early treatment improve the prognostic course of LCDD. PMID- 24772400 TI - Prevalence and risk factors for early chronic allograft nephropathy in a live related renal transplant program. AB - BACKGROUND: Chronic allograft nephropathy (CAN) is a common cause of delayed allograft failure throughout the world. Its prevalence and risk factors vary depending on a number of factors. There is little information on the prevalence and risk factors for early CAN in live related renal transplant patients. OBJECTIVES: We aimed to determine the prevalence and the risk factors of early CAN in our setup. PATIENTS AND METHODS: The study was conducted at Sindh Institute of Urology & Transplantation (SIUT), Karachi, from 2002 to 2005 on patients who had live related kidney transplantation and underwent at least one allograft biopsy within 18 months of transplantation. The biopsies were performed and prepared in accordance with established indications and guidelines. The Banff 97 classification and its updates were used to diagnose and categorize the biopsy pathology. Patients were divided into two groups depending on the presence or absence of CAN on biopsies. Following parameters were compared among the groups: age, sex, human leukocyte antigen (HLA) match, immunosuppression used, acute rejection (AR) episodes, urinary tract infections (UTIs), viral infections, cyclosporine levels, early and late graft function monitored by serum creatinine. RESULTS: A total of 164 patients fulfilled the study inclusion criteria. The mean age of recipients and donors was relatively young. The majority of the donors were siblings. The overall prevalence of CAN was 25.6% (42/164), between 3 and 18 months post transplantation. The median time to the appearance of CAN was 9 months post-transplant. The prevalence of CAN increased as post-transplant duration increased. In 39 (92.8%) subjects, CAN was detected on the second or subsequent graft biopsy. Only 3 (7.2%) patients showed CAN on the first graft biopsy. The majority of cases belonged to moderate degree or grade II CAN. The mean serum creatinine values were higher in the CAN group at the time of discharge and all times post-transplantation. CONCLUSIONS: In conclusion, the results show that serum creatinine at the time of discharge is a useful predictor of later development of chronic changes in the allograft. Further studies are needed to identify the risk factors for the early development of chronic changes in living related renal transplant program. PMID- 24772401 TI - Nephrotoxicity and hepatotoxicity evaluation of Crocus sativus stigmas in neonates of nursing mice. AB - BACKGROUND: Crocus sativus, known as saffron crocus, is best known for the spice saffron. Saffron use spans more than 3500 years, however, its toxicity on neonates during lactation has not yet evaluated. OBJECTIVES: This study was aimed to examine the acute toxicity of saffron on adult mice and its nephrotoxicity and hepatotoxicity on neonates of lactating mothers that used saffron during lactation. MATERIALS AND METHODS: In this experimental study, following acute toxicity evaluation, 32 pregnant mice were randomly designated into four equal groups. Following delivery, the mothers of groups 1 to 4 were administered orally (by gavage) normal saline (control group), 500, 1000 or 2000 mg/kg/day of saffron for three weeks, respectively. The newborn's kidney and liver parameters were assessed at the end of the study for possible nephrotoxicity and hepatotoxicity evaluation. The kidney and liver tissue samples of newborns were histopathologically studied after staining with Hematoxylin & Eosin. Data were analyzed using ANOVA and Scheffe's tests Results: The LD50 value of saffron was calculated to be 4120±556 mg/kg in mice. To evaluate lactating toxicity, saffron was administered orally to the mothers once daily for 21 days, after delivery, during lactating period. Saffron increased serum urea nitrogen (p< 0.05). Histological studies indicated that saffron did not have any toxic effect on liver, however, histopathology changes were seen in the kidney of neonates. CONCLUSIONS: From the results of present study, it might be concluded that saffron is a nearly safe spice, however, nursing mothers should avoid high doses of this spice. PMID- 24772402 TI - Enhancement of Alcohol Metabolism by Sprouted Peanut Extract in SD Rats. AB - Excessive ethanol intake is known to induce a number of physiological symptoms, including headache, dizziness and vertigo. In this study, we investigated the attenuation effect of sprouted peanut extract (SPE) on ethanol-induced hangover in male Sprague-Dawley rats. The animals were divided into five groups: the control group, which was administered ethanol only; the ethanol plus SPE experimental groups, which were administered ethanol and 100, 200, or 400 mg SPE/kg b.w.; and the positive control group, which was administered ethanol plus DAWN808((r)), a commercial product. SPE-suspended water was delivered to rats via gavage 15 h and 30 min before the administration of ethanol. Blood was collected from the tail 0, 1, 3, and 5 h after ethanol administration. The results showed that serum ethanol concentrations were significantly lower in SPE treated groups than in the control group. Furthermore, hepatic alcohol and acetaldehyde dehydrogenase activities were enhanced by SPE in a dose dependent manner. These results suggest that SPE could be useful in attenuating hangover after alcohol consumption. PMID- 24772403 TI - Polyopes lancifolia Extract, a Potent alpha-Glucosidase Inhibitor, Alleviates Postprandial Hyperglycemia in Diabetic Mice. AB - This study was designed to investigate the inhibitory effects of Polyopes lancifolia extract (PLE) on alpha-glucosidase activity, alpha-amylase activitiy, and postprandial hyperglycemia in streptozotocin (STZ)-induced diabetic mice. The results of this study revealed a marked inhibitory effect of PLE on alpha glucosidase and alpha-amylase activities. The IC50s of PLE against alpha glucosidase and alpha-amylase were 0.20 mg/mL and 0.35 mg/mL, respectively. PLE was a more effective inhibitor of alpha-glucosidase and alpha-amylase activities than acarbose, the positive control. The postprandial blood glucose levels of STZ induced diabetic mice were significantly lower in the PLE treated group than in the control group. Moreover, PLE administration was associated with a decreased area under the curve for the glucose response in diabetic mice. These results indicate that PLE may be a potent inhibitor of alpha-glucosidase and alpha amylase activities and may suppress postprandial hyperglycemia. PMID- 24772404 TI - Immunostimulatory effect of fermented red ginseng in the mouse model. AB - In this study, Woongjin fermented red ginseng extract (WFRG) was evaluated for its potential ability to act as an adjuvant for the immune response of mice. For the in vitro study, macrophages were treated with serial concentrations (1 MUg/mL, 10 MUg/mL, and 100 MUg/mL) of WFRG. For in vivo studies, mice were administered different concentrations (10 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day) of WFRG orally for 21 days. In vitro, the production of nitric oxide and TNF-alpha by RAW 264.7 cells increased in a dose-dependent manner. In vivo, WFRG enhanced the proliferation of splenocytes induced by two mitogens (i.e., concanavalin A and lipopolysaccharide [LPS]) and increased LPS-induced production of TNF-alpha and IL-6, but not IL-1beta. In conclusion, WFRG has the potential to modulate immune function and should be further investigated as an immunostimulatory agent. PMID- 24772406 TI - In vitro Antioxidant Activities of Trianthema portulacastrum L. Hydrolysates. AB - Hydrolysates of Trianthema portulacastrum in acidified methanol were evaluated for their total phenolic (TP) constituents and respective antioxidant activities using in vitro assays (i.e., 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, percent inhibition of linoleic acid peroxidation, and ferric reducing power). The observed results indicate that root, shoot, and leaf fractions of T. portulacastrum contain 50.75~98.09 mg gallic acid equivalents/g dry weight of TP. In addition, these fractions have substantial reducing potentials (0.10~0.59), abilities to inhibit peroxidation (43.26~89.98%), and DPPH radical scavenging capabilities (6.98~311.61 MUg/mL IC50). The experimental data not only reveal T. portulacastrum as potential source of valuable antioxidants, but also indicate that acidified methanol may be an ideal choice for the enhanced recovery of phenolic compounds with retained biological potential for the food and pharmaceutical industry. PMID- 24772405 TI - Antioxidant Effects of Spinach (Spinacia oleracea L.) Supplementation in Hyperlipidemic Rats. AB - Increased consumption of fresh vegetables that are high in polyphenols has been associated with a reduced risk of oxidative stress-induced disease. The present study aimed to evaluate the antioxidant effects of spinach in vitro and in vivo in hyperlipidemic rats. For measurement of in vitro antioxidant activity, spinach was subjected to hot water extraction (WE) or ethanol extraction (EE) and examined for total polyphenol content (TPC), oxygen radical absorbance capacity (ORAC), cellular antioxidant activity (CAA), and antigenotoxic activity. The in vivo antioxidant activity of spinach was assessed using blood and liver lipid profiles and antioxidant status in rats fed a high fat-cholesterol diet (HFCD) for 6 weeks. The TPC of WE and EE were shown as 1.5+/-0.0 and 0.5+/-0.0 mg GAE/g, respectively. Increasing the concentration of the extracts resulted in increased ORAC value, CAA, and antigenotoxic activity for all extracts tested. HFCD-fed rats displayed hyperlipidemia and increased oxidative stress, as indicated by a significant rise in blood and liver lipid profiles, an increase in plasma conjugated diene concentration, an increase in liver thiobarbituric acid reactive substances (TBARS) level, and a significant decrease in manganese superoxide dismutase (Mn-SOD) activity compared with rats fed normal diet. However, administration of 5% spinach showed a beneficial effect in HFCD rats, as indicated by decreased liver TBARS level and DNA damage in leukocyte and increased plasma conjugated dienes and Mn-SOD activity. Thus, the antioxidant activity of spinach may be an effective way to ameliorate high fat and cholesterol diet-induced oxidative stress. PMID- 24772407 TI - Evaluation of the Antioxidant Activity of Cooked Gomchwi (Ligularia fischeri) Using the Myoglobin Methods. AB - This study evaluated the influence of cooking methods (blanching, pan-frying, and microwaving) on the antioxidant activity of Ligularia fischeri (LF) using myoglobin methods against five different reactive oxygen species (ROS) (i.e., 2,2 diphenyl-1-picrylhydrazyl (DPPH), hypochlorite ions, hydroxyl radicals, peroxyl radicals, and peroxynitrite ions). With respect to DPPH scavenging activity, the antioxidant activities of blanched LF and pan-fried LF were significantly higher (P<0.05) than that of fresh LF for all cooking times. Pan-fried LF and microwaved LF showed higher antioxidant activities against hydroxyl radicals and peroxyl radicals than uncooked LF, while the protective effect of blanched LF was low, except for the at the 3 min cooking time point. Microwaved LF showed high antioxidant activity against all ROS at the 2 min cooking time point. Interestingly, LF that had been microwaved for 2 min and 3 min had high antioxidant values, whereas blanched LF and pan-fried LF had low antioxidant values. The activities of cooked LF against five different ROS were characterized comprehensively by 5-axe cobweb charts. PMID- 24772408 TI - Effects of Extraction and Processing Methods on Antioxidant Compound Contents and Radical Scavenging Activities of Laver (Porphyra tenera). AB - Laver is one of the most consumed edible red algae seaweeds in the genus Porphyra. Laver is primarily prepared in the form of dried, roasted, and seasoned products. We investigated the total polyphenol and flavonoid contents of laver products, and evaluated the in vitro antioxidant properties of solvent extracts from commercially processed laver products. Significant differences in the concentration of phenolic compounds were found among differently processed laver. The total phenolic content for laver extracts ranged from 10.81 mg gallic acid equivalent (GAE)/g extract to 32.14 mg GAE/g extract, depending on extraction solvent and temperature. Laver extracts contained very few flavonoids (0.55 mg catechin equivalent/g extracts to 1.75 mg catechin equivalent/g extracts). 2,2 Diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis-3-ethylbenzothiazoline-6 sulphonic acid (ABTS), hydroxyl radical, and superoxide anion scavenging assays were used to determine the radical scavenging capacities of laver extracts. These assays revealed that the processing method and extraction condition affected the antioxidant potentials of laver. Antioxidant activity of dried laver, roasted laver, and seasoned laver increased in a concentration-dependent manner (100~1,000 MUg/mL). The radical scavenging activities of 37 degrees C and 100 degrees C water extracts were lower than that of a 37 degrees C 70% ethanol extract. The highest radical scavenging capacity was observed in the 37 degrees C 70% ethanol extracts of dried laver, roasted laver, and seasoned laver. Overall, these results support that notion that laver contains bioactive compounds, such as polyphenols and flavonoids, which may have a positive effect on health. PMID- 24772409 TI - Effects of cultured wild-ginseng root and xylitol on fermentation of kimchi. AB - This study evaluates the effects of cultured wild ginseng root (0.05%, 0.1% v/w) and xylitol in kimchi. The fermented characteristics of kimchi were investigated during 28 days of fermentation at 4 degrees C. The pH value in the sample with the cultured wild ginseng root was higher than that of control group. The total acidity in the sugar groups (SG groups) was higher than that of xylitol groups (XG groups). Comparing total bacterial count, XG groups were lower than SG groups, regardless of the additional ratio of the cultured wild ginseng root. Reducing sugar of XG groups decreased more slowly than SG groups for seven days; glucose and fructose of XG groups were lower than the control group. DPPH radical scavenging activity was higher in groups with cultured wild ginseng root than in control. In the result of sensory evaluation, XG groups were more preferred than other groups. In conclusion, our results indicate that cultured wild-ginseng root and xylitol have a positive effect on the quality of kimchi, such as antimicrobial and antioxidant functions. PMID- 24772410 TI - Clinical dilemma of positive histologic chorioamnionitis in term newborn. AB - BACKGROUND: Although histologic chorioamnionitis (HCA) is known to be associated with poor outcomes in preterm infants, its clinical significance among term infants is not clearly known. OBJECTIVES: To investigate the utility of HCA in determining early onset clinical sepsis (EOCS) among term newborns. METHODS: The incidence of HCA and EOCS in term infants born during 2008-2009 was evaluated in a single center retrospective study (n = 3417). The predictive value of HCA for determining EOCS in term infants admitted to the neonatal intensive care unit (NICU) for suspected sepsis (n = 388) was quantified. Outcome of otherwise healthy term infants in the nursery with HCA was also investigated. RESULTS: Overall, 11% of term infants with HCA also had EOCS. HCA was associated with increased risk for EOCS (OR 2.6, 95% confidence interval 1.6-4.2, P < 0.001) among term infants admitted to the NICU for suspected sepsis. No cases of EOCS were found among otherwise well-appearing infants in the nursery with HCA. Multiple logistic regression analysis indicated that addition of HCA does not increase the power of a model combining C-reactive protein (CRP) and immature to total neutrophil ratio in determining EOCS. CONCLUSION: Although HCA in term infants is associated with EOCS, it did not improve the ability of CRP and immature to total neutrophil ratio to predict EOCS. Routine placental examination may not contribute to the diagnosis of EOCS in term infants. PMID- 24772411 TI - Organizational factors influencing implementation of evidence-based practices for integrated treatment in behavioral health agencies. AB - Objective. In recent years, New Mexico has prioritized integrated treatment for cooccurring mental health and substance use disorders within its public behavioral health system. This report describes factors likely to be important when implementing evidence-based practices (EBPs) in community agencies. Methods. Our mixed-method research design consisted of observations, semistructured interviews, and surveys undertaken with employees at 14 agencies at baseline and after 18 months. We developed four-agency typologies based on iterative coding and analysis of observations and interviews. We then examined survey data from employees at the four exemplar agencies to validate qualitative findings. Results. Financial resources and strong leadership impacted agency capacity to train providers and implement EBPs. Quantitative analysis of service provider survey responses from these agencies (N = 38) supported qualitative findings and demonstrated significant mean score differences in leadership, organizational climate, and attitudes toward EBPs in anticipated directions. Conclusion. The availability of strong leadership and financial resources were key components to initial implementation success in this study of community agencies in New Mexico. Reliance only on external funding poses risks for sustainment when demoralizing work climates precipitate employee turnover. Strong agency leadership does not always compensate for deficient financial resources in vulnerable communities. PMID- 24772412 TI - The effects on sensorial block, motor block, and haemodynamics of levobupivacaine at different temperatures applied in the subarachnoid space. AB - AIM: To evaluate the effects of 0.5% levobupivacaine at 37 degrees C preheated from room temperature, on sensorial block, motor block, and haemodynamics in patients undergoing transurethral prostate resection (TUR-P). MATERIAL AND METHOD: The patients were randomly allocated to two groups: Group I patients were injected with 3 mL 0.5% levobupivacaine solution which had been kept at room temperature for at least 24 hours and Group II patients were injected with 3 mL 0.5% levobupivacaine solution which had been kept at 37 degrees C for at least 24 hours. The patients were examined in terms of sensorial block, motor block, haemodynamic profile, and incidence of side effects. RESULTS: No significant difference was found between the groups in terms of demographic data. The time to reach T 10 sensory block and the time of starting motor block were found to be significantly shorter in Group II. The duration of sensory block over T 10 and T 6, the duration of L 1 regression, the duration of the sensory block, and the regression time of the motor blocks from 3 to 2 were found to be longer in Group II. CONCLUSION: The use of 0.5% levobupivacaine spinal anaesthesia heated to 37 degrees C accelerated the start of sensory and motor block. PMID- 24772413 TI - Association of single nucleotide polymorphisms in estrogen receptor alpha gene with susceptibility to knee osteoarthritis: a case-control study in a Chinese Han population. AB - Osteoarthritis (OA) is the most prevalent form of arthritis and its multifactorial nature has been increasingly recognized. Genetic factors play an important role in OA etiology and estrogen receptor alpha (ESR1) gene polymorphisms may be involved. This study tried to explore whether the ESR1 gene single nucleotide polymorphisms (SNPs) were associated with primary knee OA in the Chinese Han population. Two SNPs, rs2234693 and rs9340799, were genotyped in 469 cases and 522 controls. Rs2234693 was associated with knee OA in the dominant genetic model (TT + TC versus CC) (P = 0.025) and a higher T allele frequency existed (P = 0.047) among females. The combined genotype (TT + TC) (P = 0.025) and T allele (P = 0.016) were related with mild knee OA only. For rs9340799, A allele was associated with knee OA in all subjects (P = 0.031) and females (P = 0.046). Statistical differences were detected in the dominant genetic model (AA + AG versus GG) among females (P = 0.030). The combined genotype (AA + AG) (P = 0.036) and A allele (P = 0.039) were merely correlated with mild knee OA. ESR1 gene is considerably associated with knee OA etiology in the Chinese Han population. PMID- 24772414 TI - Protein nanoparticles as drug delivery carriers for cancer therapy. AB - Nanoparticles have increasingly been used for a variety of applications, most notably for the delivery of therapeutic and diagnostic agents. A large number of nanoparticle drug delivery systems have been developed for cancer treatment and various materials have been explored as drug delivery agents to improve the therapeutic efficacy and safety of anticancer drugs. Natural biomolecules such as proteins are an attractive alternative to synthetic polymers which are commonly used in drug formulations because of their safety. In general, protein nanoparticles offer a number of advantages including biocompatibility and biodegradability. They can be prepared under mild conditions without the use of toxic chemicals or organic solvents. Moreover, due to their defined primary structure, protein-based nanoparticles offer various possibilities for surface modifications including covalent attachment of drugs and targeting ligands. In this paper, we review the most significant advancements in protein nanoparticle technology and their use in drug delivery arena. We then examine the various sources of protein materials that have been used successfully for the construction of protein nanoparticles as well as their methods of preparation. Finally, we discuss the applications of protein nanoparticles in cancer therapy. PMID- 24772415 TI - The effect of intravenous magnesium sulfate infusion on sensory spinal block and postoperative pain score in abdominal hysterectomy. AB - AIM: The aim of this study was to investigate the effect of i.v. infusion of magnesium sulphate during spinal anesthesia on duration of spinal block and postoperative pain. METHODS: Forty ASA physical status I and status II, aged between 18 and 65, female patients undergoing abdominal hysterectomy under spinal anesthesia were enrolled in this study. Patients in the magnesium group (Group M, n = 20) received magnesium sulphate 65 mg kg(-1) infusion in 250 mL 5% dextrose at 3.5 mL/min rate, and control group (Group C, n = 20) received at the same volume of saline during operation in a double-blind randomized manner. Duration of sensory and motor block, systolic, diastolic, and mean arterial blood pressures, heart rates, pain scores (VAS values), and side effects were recorded for each patient. Blood and CSF samples were taken for analysis of magnesium concentrations. RESULTS: Regression of sensorial block was longer in Group M when compared with that in Group C (175 +/- 39 versus 136 +/- 32 min) (P < 0.01). The VAS scores were lower in Group M than those in Group C at the 2 time points postoperatively (P < 0.01). CONCLUSION: 65 mg kg(-1) of magnesium sulphate i.v. infusion under spinal anesthesia prolongs spinal sensorial block duration and decreases pain VAS scores without complication in patients undergoing abdominal hysterectomy. PMID- 24772416 TI - Proteomic profiling of the dystrophin-deficient mdx phenocopy of dystrophinopathy associated cardiomyopathy. AB - Cardiorespiratory complications are frequent symptoms of Duchenne muscular dystrophy, a neuromuscular disorder caused by primary abnormalities in the dystrophin gene. Loss of cardiac dystrophin initially leads to changes in dystrophin-associated glycoproteins and subsequently triggers secondarily sarcolemmal disintegration, fibre necrosis, fibrosis, fatty tissue replacement, and interstitial inflammation. This results in progressive cardiac disease, which is the cause of death in a considerable number of patients afflicted with X linked muscular dystrophy. In order to better define the molecular pathogenesis of this type of cardiomyopathy, several studies have applied mass spectrometry based proteomics to determine proteome-wide alterations in dystrophinopathy associated cardiomyopathy. Proteomic studies included both gel-based and label free mass spectrometric surveys of dystrophin-deficient heart muscle from the established mdx animal model of dystrophinopathy. Comparative cardiac proteomics revealed novel changes in proteins associated with mitochondrial energy metabolism, glycolysis, signaling, iron binding, antibody response, fibre contraction, basal lamina stabilisation, and cytoskeletal organisation. This review summarizes the importance of studying cardiomyopathy within the field of muscular dystrophy research, outlines key features of the mdx heart and its suitability as a model system for studying cardiac pathogenesis, and discusses the impact of recent proteomic findings for exploring molecular and cellular aspects of cardiac abnormalities in inherited muscular dystrophies. PMID- 24772417 TI - Effects of mixture of pharmaceuticals on early life stages of tench (Tinca tinca). AB - Ubiquitous occurrence of pharmaceuticals in aquatic environment results in concern about potential adverse the effects on nontarget organisms. In water, drugs are present in complex mixtures, in which complicated interactions affect toxicity of single components. The purpose of this study was to examine effect of 35-day-long exposure to mixture of ibuprofen, diclofenac, and carbamazepine on the mortality, growth, early ontogeny, and histopathological changes in tench (Tinca tinca). Early life stage toxicity test was carried out using a modified protocol according to OECD guideline 210. Exposure to mixture of pharmaceuticals at concentration of 60 MUg . L(-1) for each substance was associated with significant increase in mortality, as well as significant increase in growth and elevated incidence of malformations. Any of the tested concentrations resulted in histopathological changes of liver, kidney, skin, or gill. After fourteen days of exposure there was short-term delay of development related to increased concentrations of pharmaceuticals in the mixture (2, 20, and 60 MUg . L(-1)). Environmentally relevant concentrations (0.02; and 0.2 MUg . L(-1)) used in this experiment did not result in toxic impairment of tench. PMID- 24772419 TI - Prooxidant mechanisms in toxicology. PMID- 24772418 TI - Biomarkers for sepsis: a review with special attention to India. AB - Sepsis is a serious infection and still a common cause of morbidity and mortality in resource-limited settings such as India. Even when microbiologic diagnostics are available, bacteremia is only identified in a proportion of patients who present with sepsis and bloodstream infections. Biomarkers have been used in a variety of disease processes and can help aid in diagnosing bacterial infections. There have been numerous biomarkers investigated to aid with diagnosis and prognostication in sepsis with the majority suffering from lack of sensitivity or specificity. Procalcitonin has been heralded as the biomarker that holds the most promise for bloodstream infections. Data are emerging in India, and in this review, we focus on the current data of biomarkers in sepsis with particular attention to how biomarkers could be used to augment diagnosis and treatment in India. PMID- 24772420 TI - Phytoremediation potential of Mana-Cubiu (Solanum sessiliflorum Dunal) for the deleterious effects of methylmercury on the reproductive system of rats. AB - Methylmercury, organic form of mercury, can increase the number of abnormal sperm and decrease sperm concentration and testosterone levels possibly due to the damage caused by reactive species to germ and Leydig cells. Mana-cubiu (Solanum sessiliflorum Dunal) is a native fruit from Amazon rich in iron, zinc, niacin, pectin, and citric acid, used in foods, beverages, and medicinal purposes, since it has been useful for treatment of various diseases caused by oxidative stress or nutritional deficiency. Therefore, this study evaluated the phytoremediation potential of this fruit on damages caused by exposure to MeHg on sperm quantity and quality and the histological aspect of the testis and epididymis. Wistar male rats (n = 20) were randomly allocated into four groups: Control group (received distilled water), MeHg group (140 MUg/Kg), Solanum group (1% of fruit Mana-cubiu on chow), and Solanum plus MeHg group (same treatment as MeHg and Solanum group). The organs were weighted, histopathology; sperm morphology and counts were obtained. The results showed reduction in body weight gain, testis weights, reduced sperm production, and increased histopathological abnormalities in the MeHg-treated group. However, treatment with Solanum plus MeHg revealed a protective effect of this fruit on damages caused by MeHg. PMID- 24772421 TI - Endothelial function increases after a 16-week diet and exercise intervention in overweight and obese young women. AB - Weight loss improves endothelial function in overweight individuals. The effects of weight loss through combined aerobic and resistance training and caloric restriction on in vivo vascular measures and blood markers associated with the regulation of endothelial function have not been comprehensively examined. Therefore, we investigated brachial artery endothelial function and potential regulatory blood markers in twenty overweight women (30.3 +/- 2.0 years) who participated in 16 weeks of aerobic (5 d/wk) and resistance training (2 d/wk) (combined: >= 250 kcal/d) and caloric restriction (-500 kcal/d versus requirement). Resting brachial artery flow mediated dilation (FMD) and circulating endothelin-1 (ET-1) and interleukin-6 (IL-6) were assessed at baseline and following the intervention. Relative and absolute FMD increased (before: 4.0 +/- 0.5% versus after: 6.9 +/- 0.6%, P < 0.05, and before: 0.14 +/- 0.02 mm versus after: 0.23 +/- 0.02 mm, P < 0.05, resp.), while body mass decreased (before: 86.9 +/- 2.4 kg versus after: 81.1 +/- 2.4 kg, P < 0.05) following the intervention. There were no changes in either blood marker (IL-6: before: 1.5 +/- 0.2 pg/mL versus after: 1.5 +/- 0.1 pg/mL, P > 0.05, and ET-1: before: 0.55 +/- 0.05 pg/mL versus after: 0.59 +/- 0.09 pg/mL, P > 0.05). 16 weeks of combined aerobic/resistance training and diet-induced weight loss improved endothelial function in overweight and obese young women, but this increase was not associated with changes in blood markers of vasoconstriction or inflammation. PMID- 24772422 TI - Supplementation with sodium selenite and selenium-enriched microalgae biomass show varying effects on blood enzymes activities, antioxidant response, and accumulation in common barbel (Barbus barbus). AB - Yearling common barbel (Barbus barbus L.) were fed four purified casein-based diets for 6 weeks in outdoor cages. Besides control diet, these were supplemented with 0.3 mg kg(-1) dw selenium (Se) from sodium selenite, or 0.3 and 1.0 mg kg( 1) from Se-enriched microalgae biomass (Chlorella), a previously untested Se source for fish. Fish mortality, growth, Se accumulation in muscle and liver, and activity of selected enzymes in blood plasma, muscle, liver, and intestine were evaluated. There was no mortality, and no differences in fish growth, among groups. Se concentrations in muscle and liver, activity of alanine aminotransferase and creatine kinase in blood plasma, glutathione reductase (GR) in muscle, and GR and catalase in muscle and liver suggested that selenium from Se-enriched Chlorella is more readily accumulated and biologically active while being less toxic than sodium selenite. PMID- 24772423 TI - Catechol-O-methyltransferase (COMT) genotype affects age-related changes in plasticity in working memory: a pilot study. AB - OBJECTIVES: Recent work suggests that a genetic variation associated with increased dopamine metabolism in the prefrontal cortex (catechol-O methyltransferase Val158Met; COMT) amplifies age-related changes in working memory performance. Research on younger adults indicates that the influence of dopamine-related genetic polymorphisms on working memory performance increases when testing the cognitive limits through training. To date, this has not been studied in older adults. METHOD: Here we investigate the effect of COMT genotype on plasticity in working memory in a sample of 14 younger (aged 24-30 years) and 25 older (aged 60-75 years) healthy adults. Participants underwent adaptive training in the n-back working memory task over 12 sessions under increasing difficulty conditions. RESULTS: Both younger and older adults exhibited sizeable behavioral plasticity through training (P < .001), which was larger in younger as compared to older adults (P < .001). Age-related differences were qualified by an interaction with COMT genotype (P < .001), and this interaction was due to decreased behavioral plasticity in older adults carrying the Val/Val genotype, while there was no effect of genotype in younger adults. DISCUSSION: Our findings indicate that age-related changes in plasticity in working memory are critically affected by genetic variation in prefrontal dopamine metabolism. PMID- 24772424 TI - Investigation of an intelligent system for fiber optic-based epidural anesthesia. AB - Even though there have been many approaches to assist the anesthesiologists in performing regional anesthesia, none of the prior arts may be said as an unrestricted technique. The lack of a design that is with sufficient sensitivity to the targets of interest and automatic indication of needle placement makes it difficult to all-round implementation of field usage of objectiveness. In addition, light-weight easy-to-use realization is the key point of portability. This paper reports on an intelligent system of epidural space identification using optical technique, with particular emphasis on efficiency-enhanced aspects. Statistical algorithms, implemented in a dedicated field-programmable hardware platform along with an on-platform application-specific integrated chip, used to advance real-time self decision making in needle advancement are discussed together with the feedback results. Clinicians' viewpoint of improving the correct rate of our technique is explained in detail. Our study demonstrates not only that the improved system is able to behave as if it is a skillful anesthesiologist but also it has potential to bring promising assist into clinical use under varied conditions and small amount of sample, provided that several concerns are addressed. PMID- 24772425 TI - A 3'UTR polymorphism of IL-6R is associated with Chinese pediatric tuberculosis. AB - BACKGROUND: IL-6 is a proinflammatory cytokine that plays a critical role in host defense against tuberculosis (TB). Genetic polymorphisms of IL-6 and its receptor IL-6R had been discussed in adult TB recently. However, their role in pediatric TB is still unclear. Due to the obvious differences in TB pathophysiology in children, which may also reflect differences in genetic background, further association studies in pediatric populations are needed. METHODS: A case-control study was carried out in a Chinese pediatric population including 353 TB patients and 400 healthy controls. Tag-SNPs of IL-6 and IL-6R genes were selected by Haploview software, genotyped using MassArray, and analyzed statistically. RESULTS: One polymorphism, rs2229238, in the 3'UTR region of IL-6R was observed to be associated with increased resistance to TB (adjusted P = 0.03). The rs2229238 T allele contributed to a reduced risk to TB in recessive heritable model (OR, 0.53; 95% CI, 0.35-0.78). CONCLUSIONS: By tag-SNP genotyping based case-control study, we identified a genetic polymorphism in the IL-6R 3'UTR that regulates host resistance to pediatric TB in a Chinese population. PMID- 24772426 TI - Film coating of nifedipine extended release pellets in a fluid bed coater with a Wurster insert. AB - The objective of this work was to study the coating process of nifedipine extended release pellets using Opadry and Opadry II, in a fluid bed coater with a Wurster insert. The coating process was studied using a complete experimental design of two factors at two levels for each polymer. The variables studied were the inlet air temperature and the coating suspension flow rate. The agglomerate fraction and coating efficiency were the analyzed response variables. The air temperature was the variable that most influenced the coating efficiency for both polymers. In addition, a study of the dissolution profiles of coated and uncoated pellets using 0.5% sodium lauryl sulfate in simulated gastric fluid without enzymes (pH 1.2) was conducted. The results showed a prolonged release profile for the coated and uncoated pellets that was very similar to the standards established by the U.S. Pharmacopoeia. The drug content and the release profiles were not significantly affected by storage at 40 degrees C and 75% relative humidity. However, when exposed to direct sunlight and fluorescent light (light from fluorescent bulbs), the coated pellets lost only 5% of the drug content, while the uncoated ones lost more than 35%; furthermore, the dissolution profile of the uncoated pellets was faster. PMID- 24772427 TI - Survey of network-based approaches to research of cardiovascular diseases. AB - Cardiovascular diseases (CVDs) are the leading health problem worldwide. Investigating causes and mechanisms of CVDs calls for an integrative approach that would take into account its complex etiology. Biological networks generated from available data on biomolecular interactions are an excellent platform for understanding interconnectedness of all processes within a living cell, including processes that underlie diseases. Consequently, topology of biological networks has successfully been used for identifying genes, pathways, and modules that govern molecular actions underlying various complex diseases. Here, we review approaches that explore and use relationships between topological properties of biological networks and mechanisms underlying CVDs. PMID- 24772428 TI - Detection and antibiotic treatment of Mycoplasma arginini contamination in a mouse epithelial cell line restore normal cell physiology. AB - Mycoplasma contamination of cultured cell lines is difficult to detect by routine observation. Infected cells can display normal morphology and the slow growth rate of mycoplasma can delay detection for extended periods of time, compromising experimental results. Positive identification of mycoplasma typically requires cells to be either fixed and stained for DNA or processed with PCR. We present a method to detect mycoplasma using live-cell optical microscopy typically used for routine observation of cell cultures. Images of untreated mycoplasma-infected epithelial cells alongside images of infected cells treated with Plasmocin, a commercially available antibiotic targeted to mycoplasma, are shown. We found that optical imaging is an effective screening tool for detection of mycoplasma contamination. Importantly, we found that cells regained normal function after the contamination was cleared. In conclusion, we present a technique to diagnose probable mycoplasma infections in live cultures without fixation, resulting in faster response times and decreased loss of cell material. PMID- 24772429 TI - Cerebrovascular and neuroprotective effects of adamantane derivative. AB - OBJECTIVES: The influence of 5-hydroxyadamantane-2-on was studied on the rats' brain blood flow and on morphological state of brain tissue under the condition of brain ischemia. The interaction of the substance with NMDA receptors was also studied. METHODS: Study has been implemented using the methods of local blood flow registration by laser flowmeter, [(3)H]-MK-801binding, and morphological examination of the brain tissue. We used the models of global transient ischemia of the brain, occlusion of middle cerebral artery, and hypergravity ischemia of the brain. RESULTS: Unlike memantine, antagonist of glutamatergic receptors, the 5-hydroxyadamantane-2-on does not block NMDA receptors but enhances the cerebral blood flow of rats with brain ischemia. This effect is eliminated by bicuculline. Under conditions of permanent occlusion of middle cerebral artery, 5 hydroxyadamantane-2-on has recovered compensatory regeneration in neural cells, axons, and glial cells, and the number of microcirculatory vessels was increased. 5-Hydroxyadamantane-2-on was increasing the survival rate of animals with hypergravity ischemia. CONCLUSIONS: 5-Hydroxyadamantane-2-on, an adamantane derivative, which is not NMDA receptors antagonist, demonstrates significant cerebrovascular and neuroprotective activity in conditions of brain ischemia. Presumably, the GABA-ergic system of brain vessels is involved in mechanisms of cerebrovascular and neuroprotective activity of 5-hydroxyadamantane-2-on. PMID- 24772430 TI - Topical application of retinyl palmitate-loaded nanotechnology-based drug delivery systems for the treatment of skin aging. AB - The objective of this study was to perform a structural characterization and evaluate the in vitro safety profile and in vitro antioxidant activity of liquid crystalline systems (LCS) with and without retinyl palmitate (RP). LCS containing polyether functional siloxane (PFS) as a surfactant, silicon glycol copolymer (SGC) as oil phase, and water in the ratios 30 : 25 : 45 and 40 : 50 : 10 with (OLS(v) = RP-loaded opaque liquid system and TLS(v) = RP-loaded transparent liquid system, respectively) and without (OLS and TLS, respectively) RP were studied. Samples were characterized using polarized light microscopy (PLM) and rheology analysis. In vitro safety profile was evaluated using red cell hemolysis and in vitro cytotoxicity assays. In vitro antioxidant activity was performed by the DPPH method. PLM analysis showed the presence of lamellar LCS just to TLS. Regardless of the presence of RP, the rheological studies showed the pseudoplastic behavior of the formulations. The results showed that the incorporation of RP in LCS improved the safety profile of the drug. In vitro antioxidant activity suggests that LCS presented a higher capacity to maintain the antioxidant activity of RP. PFS-based systems may be a promising platform for RP topical application for the treatment of skin aging. PMID- 24772431 TI - Age-related alterations in endothelial function of femoral artery in young SHR and WKY rats. AB - The present study was designed to evaluate the effects of vascular aging in juvenescence on endothelial function in femoral arteries and to assess differences between normotensive and hypertensive rats. The aim of the study was to determine if age affected nitric oxide- (NO-) mediated relaxations in normotensive and hypertensive rats. Juvenile (7-week-old) and young adult (22 week-old) male Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were used in this study. Femoral artery (FA) reactivity was determined by wire myograph and NO synthase activity by conversion of [(3)H]-L-arginine. During juvenescence systolic blood pressure (tail-cuff) increased significantly only in SHR, while NO synthesis decreased significantly in both strains. Endothelium dependent relaxations to acetylcholine were reduced in the FA of SHR compared to age-matched WKY at both ages, yet these parameters were unchanged in adult rats compared with juvenile animals. The NO-dependent component of vasorelaxation was markedly reduced, whereas the NO-independent component was increased in adult compared to juvenile rats in both strains. The endothelial dysfunction in SHR at both ages was associated with reduction of NO-independent mechanisms. In conclusion, aging in early periods of life was associated with reduction of vascular NO production and bioavailability in both strains investigated. This reduction was however fully compensated by accentuation of NO-independent mechanisms. PMID- 24772432 TI - Mitogenic effects of phosphatidylcholine nanoparticles on MCF-7 breast cancer cells. AB - Lecithins, mainly composed of the phospholipids phosphatidylcholines (PC), have many different uses in the pharmaceutical and clinical field. PC are involved in structural and biological functions as membrane trafficking processes and cellular signaling. Considering the increasing applications of lecithin-based nanosystems for the delivery of therapeutic agents, the aim of the present work was to determine the effects of phosphatidylcholine nanoparticles over breast cancer cellular proliferation and signaling. PC dispersions at 0.01 and 0.1% (w/v) prepared in buffer pH 7.0 and 5.0 were studied in the MCF-7 breast cancer cell line. Neutral 0.1% PC-derived nanoparticles induced the activation of the MEK-ERK1/2 pathway, increased cell viability and induced a 1.2 fold raise in proliferation. These biological effects correlated with the increase of epidermal growth factor receptor (EGFR) content and its altered cellular localization. Results suggest that nanoparticles derived from PC dispersion prepared in buffer pH 7.0 may induce physicochemical changes in the plasma membrane of cancer cells which may affect EGFR cellular localization and/or activity, increasing activation of the MEK-ERK1/2 pathway and inducing proliferation. Results from the present study suggest that possible biological effects of delivery systems based on lecithin nanoparticles should be taken into account in pharmaceutical formulation design. PMID- 24772433 TI - Cardiac electrophysiological alterations in heart/muscle-specific manganese superoxide dismutase-deficient mice: prevention by a dietary antioxidant polyphenol. AB - Cardiac electrophysiological alterations induced by chronic exposure to reactive oxygen species and protective effects of dietary antioxidant have not been thoroughly examined. We recorded surface electrocardiograms (ECG) and evaluated cellular electrophysiological abnormalities in enzymatically-dissociated left ventricular (LV) myocytes in heart/muscle-specific manganese-superoxide dismutase deficient (H/M-Sod2(-/-)) mice, which exhibit dilated cardiomyopathy due to increased oxidative stress. We also investigated the influences of intake of apple polyphenols (AP) containing mainly procyanidins with potent antioxidant activity. The QRS and QT intervals of ECG recorded in H/M-Sod2(-/-) mice were prolonged. The effective refractory period in the LV myocardium of H/M-Sod2(-/-) mice was prolonged, and susceptibility to ventricular tachycardia or fibrillation induced by rapid ventricular pacing was increased. Action potential duration in H/M-Sod2(-/-) LV myocytes was prolonged, and automaticity was enhanced. The density of the inwardly rectifier K(+) current (I K1) was decreased in the LV cells of H/M-Sod2(-/-) mice. The AP intake partially improved these electrophysiological alterations and extended the lifespan in H/M-Sod2(-/-) mice. Thus, chronic exposure of the heart to oxidative stress produces a variety of electrophysiological abnormalities, increased susceptibility to ventricular arrhythmias, and action potential changes associated with the reduced density of I K1. Dietary intake of antioxidant nutrients may prevent oxidative stress induced electrophysiological disturbances. PMID- 24772434 TI - Resistance to erythropoiesis-stimulating agents is associated with arterial microcalcification in early hemodialysis patients. AB - The aim of this study was to evaluate the relationship between arterial microcalcification (AMiC) and erythropoiesis-stimulating agents (ESA) hyporesponsiveness in hemodialysis patients. The presence of AMiC was confirmed by pathologic examination of von Kossa-stained arterial specimens acquired during vascular access surgery. We assessed the ESA hyporesponsiveness index (EHRI), defined as the weekly ESA dose per kilogram body weight divided by the hemoglobin level. AMiC was detected in 33 (40.2%) of 82 patients. Patients with diabetes had a higher incidence of AMiC than patients without diabetes. The serum levels of albumin and cholesterol were higher in patients without AMiC than in patients with AMiC. The serum levels of intact parathyroid hormone were lower in patients with AMiC than in patients without AMiC. The serum levels of phosphate and calcium-phosphorus product did not differ between the two groups. The mean EHRI value was higher in patients with AMiC than in patients without AMiC. In multivariate analyses, ESA hyporesponsiveness and diabetes showed a significant association with AMiC. In conclusion, ESA hyporesponsiveness may be a clinical relevant parameters related to AMiC in hemodialysis patients. PMID- 24772435 TI - The role of the extracellular matrix components in cutaneous wound healing. AB - Wound healing is the physiologic response to tissue trauma proceeding as a complex pathway of biochemical reactions and cellular events, secreted growth factors, and cytokines. Extracellular matrix constituents are essential components of the wound repair phenomenon. Firstly, they create a provisional matrix, providing a structural integrity of matrix during each stage of healing process. Secondly, matrix molecules regulate cellular functions, mediate the cell cell and cell-matrix interactions, and serve as a reservoir and modulator of cytokines and growth factors' action. Currently known mechanisms, by which extracellular matrix components modulate each stage of the process of soft tissue remodeling after injury, have been discussed. PMID- 24772436 TI - Association between circulating endothelial cells and carotid atherosclerosis in patients receiving maintenance hemodialysis. AB - Accelerated atherosclerosis is the major cause of mortality in maintenance hemodialysis (MHD) patients, and endothelial injury associated with MHD might contribute strongly to pathogenesis. The current study was designed to explore possible associations between circulating endothelial cells (CECs) and intima media thickness of common carotid artery (CCA-IMT) as an indicator of carotid atherosclerosis. Sixty-two MHD patients and 26 age- and sex-matched healthy volunteers were recruited. The number of CECs was determined in peripheral blood using multiparametric flow cytometry. CCA-IMT and presence of plaques in the common carotid arteries were assessed with ultrasound. Laboratory tests results and the demographics were recorded. The finding indicated that numbers of CECs were higher in patients before hemodialysis (predialysis) compared with numbers in controls (P = 0.045). CCA-IMT was also significantly higher in patients than in controls (P < 0.01). A positive relationship was observed between predialysis CECs numbers and CCA-IMT (P < 0.01) in MHD patients. In multiple linear regression analysis, the relationship between the predialysis CECs level and CCA IMT remained the same even if adjusting for confounding effects. Accordingly, the investigation indicates that the CECs level is positively associated with CCA-IMT in our hemodialysis patients. CECs might be an important marker to the severity of carotid atherosclerosis in MHD patients. PMID- 24772437 TI - A survey of FDG- and amyloid-PET imaging in dementia and GRADE analysis. AB - PET based tools can improve the early diagnosis of Alzheimer's disease (AD) and differential diagnosis of dementia. The importance of identifying individuals at risk of developing dementia among people with subjective cognitive complaints or mild cognitive impairment has clinical, social, and therapeutic implications. Within the two major classes of AD biomarkers currently identified, that is, markers of pathology and neurodegeneration, amyloid- and FDG-PET imaging represent decisive tools for their measurement. As a consequence, the PET tools have been recognized to be of crucial value in the recent guidelines for the early diagnosis of AD and other dementia conditions. The references based recommendations, however, include large PET imaging literature based on visual methods that greatly reduces sensitivity and specificity and lacks a clear cut off between normal and pathological findings. PET imaging can be assessed using parametric or voxel-wise analyses by comparing the subject's scan with a normative data set, significantly increasing the diagnostic accuracy. This paper is a survey of the relevant literature on FDG and amyloid-PET imaging aimed at providing the value of quantification for the early and differential diagnosis of AD. This allowed a meta-analysis and GRADE analysis revealing high values for PET imaging that might be useful in considering recommendations. PMID- 24772438 TI - Hypothalamus-anchored resting brain network changes before and after sertraline treatment in major depression. AB - Sertraline, one of the oldest antidepressants, remains to be the most efficacious treatment for depression. However, major depression disorder (MDD) is characterized by altered emotion processing and deficits in cognitive control. In cognitive interference tasks, patients with MDD have shown excessive hypothalamus activity. The purpose of this study was to examine the effects of antidepressant treatment (sertraline) on hypothalamus-anchored resting brain circuitry. Functional magnetic resonance imaging was conducted on depressed patients (n = 12) both before and after antidepressant treatment. After eight weeks of antidepressant treatment, patients with depression showed significantly increased connectivity between the hypothalamus and dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, insula, putamen, caudate, and claustrum. By contrast, decreased connectivity of the hypothalamus-related areas was primarily located in the inferior frontal gyrus, medial frontal gyrus, cingulated gyrus, precuneus, thalamus, and cerebellum. After eight weeks of antidepressant therapy, 8 out of the 12 depressed subjects achieved 70% reduction or better in depressive symptoms, as measured on the Hamilton depression rating scale. Our findings may infer that antidepressant treatment can alter the functional connectivity of the hypothalamus resting brain to achieve its therapeutic effect. PMID- 24772439 TI - Estimating glomerular filtration rate in older people. AB - We aimed at reviewing age-related changes in kidney structure and function, methods for estimating kidney function, and impact of reduced kidney function on geriatric outcomes, as well as the reliability and applicability of equations for estimating glomerular filtration rate (eGFR) in older patients. CKD is associated with different comorbidities and adverse outcomes such as disability and premature death in older populations. Creatinine clearance and other methods for estimating kidney function are not easy to apply in older subjects. Thus, an accurate and reliable method for calculating eGFR would be highly desirable for early detection and management of CKD in this vulnerable population. Equations based on serum creatinine, age, race, and gender have been widely used. However, these equations have their own limitations, and no equation seems better than the other ones in older people. New equations specifically developed for use in older populations, especially those based on serum cystatin C, hold promises. However, further studies are needed to definitely accept them as the reference method to estimate kidney function in older patients in the clinical setting. PMID- 24772441 TI - Awareness about a life-threatening condition: ectopic pregnancy in a network for surveillance of severe maternal morbidity in Brazil. AB - OBJECTIVE: To assess occurrence of severe maternal complications associated with ectopic pregnancy (EP). METHOD: A multicenter cross-sectional study was conducted, with prospective surveillance of potentially life-threatening conditions (PLTC), maternal near miss (MNM), and maternal death (MD). EP complications, patient sociodemographic/obstetric characteristics, and conditions of severity management were assessed, estimating prevalence ratios with respective 95% CI. Factors independently associated with greater severity were identified using multiple regression analysis. RESULTS: Of the 9.555 severe maternal morbidity patients, 312 women (3.3%) had complications after EP: 286 (91.7%) PLTC, 25 (8.0%) MNM, and 1 (0.3%) MD. Severe maternal outcome ratio (SMOR) was 0.3/1000 LB among EP cases and 10.8/1000 LB among other causes. Complicated EP patients faced a higher risk of blood transfusion, laparotomy, and lower risk of ICU admission and prolonged hospitalization than women developing complications resulting from other causes. Substandard care was the most common in more severe maternal morbidity and EP cases (22.7% MNM and MD versus 15% PLTC), although not significant. CONCLUSION: Increased maternal morbidity due to EP raised awareness about the condition and its impact on female reproductive life. No important risk factors for greater severity were identified. Care providers should develop specific guidelines and interventions to prevent severe maternal morbidity. PMID- 24772440 TI - MicroRNAs: new regulators of Toll-like receptor signalling pathways. AB - Toll-like receptors (TLRs), a critical family of pattern recognition receptors (PRRs), are responsible for the innate immune responses via signalling pathways to provide effective host defence against pathogen infections. However, TLR signalling pathways are also likely to stringently regulate tissue maintenance and homeostasis by elaborate modulatory mechanisms. MicroRNAs (miRNAs) have emerged as key regulators and as an essential part of the networks involved in regulating TLR-signalling pathways. In this review, we highlight our understanding of the regulation of miRNA expression profiles by TLR-signalling pathways and the regulation of TLR-signalling pathways by miRNAs. We focus on the roles of miRNAs in regulating TLR-signalling pathways by targeting multiple molecules, including TLRs themselves, their associated signalling proteins and regulatory molecules, and transcription factors and functional cytokines induced by them, at multiple levels. PMID- 24772442 TI - Prognostic utility of coronary computed tomographic angiography: a 5-year follow up in type 2 diabetes patients with suspected coronary artery disease. AB - OBJECTIVES: To analyze the predictive value of coronary computed tomography angiography on acute coronary artery events in patients with type 2 diabetes. METHODS: Coronary computed tomography angiography was performed in 250 type 2 diabetic patients. After a follow-up for 5 years, 145 patients were excluded as they did not have any coronary events. The remaining 95 patients were divided into study group and control group. According to their density and shape, the coronary artery plaques were classified into 3 types and 4 types, respectively. RESULTS: There is no statistically significant difference in the degree of stenosis between two groups. The proportion of calcified plaques in the study group was lower than in the control group. The proportion of mixed-calcified plaques in the study group was higher than in the other. Type III plaques have a 76.2% sensitivity and negative predictive value was 64.5% for acute coronary events; type IV plaques have a sensitivity of 52.6% and positive predictive value of 63% for chronic coronary events. CONCLUSIONS: CCTA may be used as a non invasive modality for evaluating and predicting vulnerable coronary atherosclerosis plaques in patients with type 2 diabetes. PMID- 24772443 TI - Association and predictive value analysis for resting heart rate and diabetes mellitus on cardiovascular autonomic neuropathy in general population. AB - BACKGROUND: The purpose of this study was to evaluate the predictive value of DM and resting HR on CAN in a large sample derived from a Chinese population. MATERIALS AND METHODS: We conducted a large-scale, population-based, cross sectional study to explore the relationships of CAN with DM and resting HR. A total of 387 subjects were diagnosed with CAN in our dataset. The associations of CAN with DM and resting HR were assessed by a multivariate logistic regression (MLR) analysis (using subjects without CAN as a reference group) after controlling for potential confounding factors. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive performance of resting HR and DM. RESULTS: A tendency toward increased CAN prevalence with increasing resting HR was reported (P for trend <0.001). MLR analysis showed that DM and resting HR were very significantly and independently associated with CAN (P < 0.001 for both). Resting HR alone or combined with DM (DM-HR) both strongly predicted CAN (AUC = 0.719, 95% CI 0.690-0.748 for resting HR and AUC = 0.738, 95% CI 0.710-0.766 for DM-HR). CONCLUSION: Our findings signify that resting HR and DM-HR have a high value in predicting CAN in the general population. PMID- 24772444 TI - Low protein diet inhibits uric acid synthesis and attenuates renal damage in streptozotocin-induced diabetic rats. AB - AIM: Several studies indicated that hyperuricemia may link to the worsening of diabetic nephropathy (DN). Meanwhile, low protein diet (LPD) retards exacerbation of renal damage in chronic kidney disease. We then assessed whether LPD influences uric acid metabolism and benefits the progression of DN in streptozotocin- (STZ-) induced diabetic rats. METHODS: STZ-induced and control rats were both fed with LPD (5%) and normal protein diet (18%), respectively, for 12 weeks. Vital signs, blood and urinary samples for UA metabolism were taken and analyzed every 3 weeks. Kidneys were removed at the end of the experiment. RESULTS: Diabetic rats developed into constantly high levels of serum UA (SUA), creatinine (SCr) and 24 h amounts of urinary albumin excretion (UAE), creatinine (UCr), urea nitrogen (UUN), and uric acid (UUA). LPD significantly decreased SUA, UAE, and blood glucose, yet left SCr, UCr, and UUN unchanged. A stepwise regression showed that high UUA is an independent risk factor for DN. LPD remarkably ameliorated degrees of enlarged glomeruli, proliferated mesangial cells, and hyaline-degenerated tubular epithelial cells in diabetic rats. Expression of TNF-alpha in tubulointerstitium significantly decreased in LPD-fed diabetic rats. CONCLUSION: LPD inhibits endogenous uric acid synthesis and might accordingly attenuate renal damage in STZ-induced diabetic rats. PMID- 24772445 TI - Comparison of metformin and repaglinide monotherapy in the treatment of new onset type 2 diabetes mellitus in China. AB - OBJECTIVE: This study was designed to compare the effects of metformin and repaglinide on the fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) in newly diagnosed type 2 diabetes in China. METHODS: A total of 107 newly diagnosed type 2 diabetic patients (46 women and 61 men) participated in the study. All patients received 3-month treatment of metformin or repaglinide. Fasting blood glucose and HbA1c were determined at baseline and at the end of the 3-month of treatment. RESULTS: FPG and HbA1c decreased in both metformin and repaglinide groups after 3 months treatment (P < 0.01). The reduction of HbA1c was significantly greater in the repaglinide group (P < 0.01). Metformin decreases fasting insulin concentration and HOMA-IR (P < 0.01), and repaglinide improves HOMA-beta(P < 0.01). Triglycerides (TG) were reduced in both groups (P < 0.01 in metformin group; P < 0.05 in repaglinide group), but total cholesterol (TC) and low-density lipoprotein (LDL) were decreased only after metformin treatment (P < 0.05). CONCLUSIONS: Both repaglinide and metformin were effective in glycaemic control in new onset patients with type 2 diabetes in China. Repaglinide had no effect on insulin sensitivity, but it improved beta-cell function. PMID- 24772446 TI - Proinflammatory and prothrombotic state in subjects with different glucose tolerance status before cardiovascular disease. AB - BACKGROUND: Inflammation has been associated with insulin resistance, type 2 diabetes mellitus (T2DM), and atherothrombosis. AIM: To determine differences in levels of proinflammatory and prothrombotic markers such as high sensitivity C reactive protein (hs-CRP) and fibrinogen in subjects with normal glucose tolerance (NGT), prediabetes, and T2DM and to establish their relationship with other cardiovascular risk factors before clinical manifestations of cardiovascular disease. METHODS: We conducted a nonrandomized, cross-sectional assay in a hospital at Mexico City. The levels of hs-CRP and fibrinogen were measured and compared according to glucose tolerance status. RESULTS: We enrolled 1047 individuals and they were distributed into NGT n = 473, pre-DM n = 250, and T2DM n = 216. There was a statistical difference between NGT and T2DM groups for fibrinogen (P = 0.01) and hs-CRP (P = 0.05). Fibrinogen and hs-CRP showed a significant positive correlation coefficient (r = 0.53, P<0.0001). In a multiple stepwise regression analysis, the variability in fibrinogen levels was explained by age, HbA1c, and hs-CRP (adjusted R2 = 0.31, P<0.0001), and for hs-CRP it was explained by BMI and fibrinogen (adjusted R2 = 0.33, P<0.0001). CONCLUSION: Inflammation and prothrombotic state are present in people with T2DM lacking cardiovascular disease. Fibrinogen and Hs-CRP are positively correlated. Fibrinogen and hs-CRP concentrations are predominantly determined by BMI rather than glucose levels. PMID- 24772448 TI - Altered expression profile of renal alpha(1D)-adrenergic receptor in diabetes and its modulation by PPAR agonists. AB - Alpha(1D)-adrenergic receptor (alpha(1D)-AR) plays important roles in regulating physiological and pathological responses mediated by catecholamines, particularly in the cardiovascular and urinary systems. The present study was designed to investigate the expression profile of alpha(1D)-AR in the diabetic kidneys and its modulation by activation of peroxisome proliferator-activated receptors (PPARs). 12-week-old Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with fenofibrate or rosiglitazone for 8-10 weeks. Gene microarray, real time PCR, and confocal immunofluorescence microscopy were performed to assess mRNA and protein expression of alpha(1D)-AR in rat kidney tissue. Using microarray, we found that alpha(1D)-AR gene was dramatically upregulated in 22 week-old ZD rats compared to ZL controls. Quantitative PCR analysis verified a 16 fold increase in alpha(1D)-AR mRNA in renal cortex from ZD animals compared to normal controls. Chronic treatment with fenofibrate or rosiglitazone reduced renal cortical alpha(1D)-AR gene. Immunofluorescence staining confirmed that alpha(1D)-AR protein was induced in the glomeruli and tubules of diabetic rats. Moreover, dual immunostaining for alpha(1D)-AR and kidney injury molecule-1 indicated that alpha(1D)-AR was expressed in dedifferentiated proximal tubules of diabetic Zucker rats. Taken together, our results show that alpha(1D)-AR expression is upregulated in the diabetic kidneys. PPAR activation suppressed renal expression of alpha(1D)-AR in diabetic nephropathy. PMID- 24772449 TI - Tracing fasting glucose fluxes with unstressed catheter approach in streptozotocin induced diabetic rats. AB - OBJECTIVE: Blood glucose concentrations of type 1 diabetic rats are vulnerable, especially to stress and trauma. The present study aimed to investigate the fasting endogenous glucose production and skeletal muscle glucose uptake of Streptozotocin induced type 1 diabetic rats using an unstressed vein and artery implantation of catheters at the tails of the rats as a platform. RESEARCH DESIGN AND METHODS: Streptozotocin (65 mg.kg-1) was administered to induce type 1 diabetic state. The unstressed approach of catheters of vein and artery at the tails of the rats was established before the isotope tracer injection. Dynamic measurement of fasting endogenous glucose production was assessed by continuously infusing stable isotope [6, 6-2H2] glucose, while skeletal muscle glucose uptake by bolus injecting radioactively labeled [1-14C]-2-deoxy-glucose. RESULTS: Streptozotocin induced type 1 diabetic rats displayed polydipsia, polyphagia, and polyuria along with overt hyperglycemia and hypoinsulinemia. They also had enhanced fasting endogenous glucose production and reduced glucose uptake in skeletal muscle compared to nondiabetic rats. CONCLUSIONS: The dual catheters implantation at the tails of the rats together with isotope tracers injection is a save time, unstressed, and feasible approach to explore the glucose metabolism in animal models in vivo. PMID- 24772447 TI - The cytotoxic role of intermittent high glucose on apoptosis and cell viability in pancreatic beta cells. AB - OBJECTIVES: Glucose fluctuations are both strong predictor of diabetic complications and crucial factor for beta cell damages. Here we investigated the effect of intermittent high glucose (IHG) on both cell apoptosis and proliferation activity in INS-1 cells and the potential mechanisms. METHODS: Cells were treated with normal glucose (5.5 mmol/L), constant high glucose (CHG) (25 mmol/L), and IHG (rotation per 24 h in 11.1 or 25 mmol/L) for 7 days. Reactive oxygen species (ROS), xanthine oxidase (XOD) level, apoptosis, cell viability, cell cycle, and expression of cyclinD1, p21, p27, and Skp2 were determined. RESULTS: We found that IHG induced more significant apoptosis than CHG and normal glucose; intracellular ROS and XOD levels were more markedly increased in cells exposed to IHG. Cells treated with IHG showed significant decreased cell viability and increased cell proportion in G0/G1 phase. Cell cycle related proteins such as cyclinD1 and Skp2 were decreased significantly, but expressions of p27 and p21 were increased markedly. CONCLUSIONS: This study suggested that IHG plays a more toxic effect including both apoptosis-inducing and antiproliferative effects on INS-1 cells. Excessive activation of cellular stress and regulation of cyclins might be potential mechanism of impairment in INS-1 cells induced by IHG. PMID- 24772450 TI - Combination therapy of an intestine-specific inhibitor of microsomal triglyceride transfer protein and peroxisome proliferator-activated receptor gamma agonist in diabetic rat. AB - We investigated effects on glucose and lipid metabolism in combination of JTT 130, a novel intestine-specific microsomal triglyceride transfer protein (MTP) inhibitor, and pioglitazone, peroxisome proliferator-activated receptor (PPAR) gamma agonist. Male Zucker diabetic fatty rats were divided into 4 groups: control group, JTT-130 treatment group, pioglitazone treatment group, and combination group. The Zucker diabetic fatty rats were fed a regular powdered diet with JTT-130 and/or pioglitazone as a food admixture for 6 weeks. Effects on glucose and lipid metabolism were compared mainly between JTT-130 treatment group and combination group. JTT-130 treatment showed good glycemic control, while the plasma glucose and glycated hemoglobin levels in combination group were significantly decreased as compared with those JTT-130 treatment group. The reduction in the plasma triglyceride and free fatty acid levels in combination group was higher than that in JTT-130 treatment group, and glucose utilization was significantly elevated in adipose tissues. In Zucker diabetic fatty rats, combination treatment of JTT-130 and pioglitazone showed better glycemic control and a strong hypolipidemic action with an enhancement of insulin sensitivity. Combination therapy of MTP inhibitor and PPAR gamma agonist might be more useful in the treatment of type 2 diabetes accompanied with obesity and insulin resistance. PMID- 24772451 TI - Acute Hemorrhage Following Gamma Knife Radiosurgery to a Clival Meningioma. AB - BACKGROUND: Gamma Knife radiosurgery (GKS) is a primary treatment modality for small, surgically-challenging meningiomas of the skull base in carefully selected patients. Despite the overall low incidence of complications from this procedure, rare instances of hemorrhagic events following GKS have been reported. In fact, only a single, probable case of acute hemorrhage after GKS for a meningioma exists in the literature. CASE DESCRIPTION: The authors present the case of a 59 year-old female treated with GKS to a clival meningioma who suffered an acute intra- and peritumoral hemorrhage within three hours after the procedure. The patient also had an ST-elevation myocardial infarction associated with the hemorrhage. At the time of her GKS she was taking aspirin and clopidogrel for treatment of coronary artery disease with multiple cardiac stents. Cerebral catheter angiography failed to reveal a source for the hemorrhage. CONCLUSION: Acute hemorrhage following GKS to a meningioma is a rare, but potentially serious, complication and consideration should be given to counseling patients of this risk prior to treatment. We hypothesize that acute change to the structural integrity of the vascular endothelium after GKS may have precipitated cerebrovascular dysfunction resulting in hemorrhage. While the administration of anti-platelet therapy may have been a contributing factor to his event, it appears that the low incidence of acute tumoral bleeding after GKS does not justify routinely discontinuing anti-platelet and/or anti-coagulation in patients with severe associated medical co-morbidities. PMID- 24772453 TI - Feasibility and Findings from a Novel Working Memory fMRI Paradigm in Multiple Sclerosis. AB - BACKGROUND: Functional MRI (fMRI) basic cognitive paradigms such as the n-back have been shown to detect cognitive impairment (CI) in Multiple Sclerosis (MS). The immediate memory task/delayed memory task (IMT/DMT) detects varying degrees of working memory (WM) by alternating three levels of complexity and two levels of WM delay. This paradigm has not been evaluated in MS nor validated against standard neuropsychological (NP) testing. OBJECTIVE: To evaluate the correlation between WM function and blood oxygen level dependent (BOLD) activation on fMRI in MS patients undergoing the IMT/DMT. To compare IMT/DMT behavioral scores to NP scores. METHODS: 10 MS patients with no history of CI underwent the Minimal Assessment of Cognitive Function in MS (MACFIMS) and an fMRI session where they performed the IMT/DMT. Working-memory ("wmem") activation was defined as the BOLD signal during DMT blocks for a particular condition (3, 5, or 7 digits per stimuli) minus the BOLD signal during IMT blocks for that condition. Areas of statistically significant Family Wise Error (FWE) -corrected cluster-level BOLD activation were identified using SPM8 Random Effects t-test. IMT/DMT behavioral data and MACFIMS scores were compared. RESULTS: The 3-digit as well as the 5 digit wmem showed significant fMRI BOLD activation. The 3-digit wmem, activation was found in portions of the bilateral superior and mid frontal cortex, supplementary motor area, pre and post central gyrus, bilateral superior and inferior parietal lobule, inferolateral pre-frontal cortex, cuneus, insula and cingulate regions. The 5 digit wmen activation was seen in the inferior medial frontal and medial orbitofrontal cortex. IMT/DMT behavioral scores were within normal range and consistent with MACFIMS. CONCLUSION: IMT/DMT, a novel fMRI working memory paradigm, is associated with BOLD activation in areas of the brain related to cognitive function in patients with MS. Both MACFIMS and IMT/DMT scores were in agreement and supported intact cognitive function. PMID- 24772452 TI - Genomic Analysis of Invasive Human Bone Marrow Derived Mesenchymal Stem Cells. AB - BACKGROUND: Human bone marrow derived mesenchymal stem cells (hMSCs) are capable of differentiation into multiple cell lineages and demonstrate a wide variety of use in various therapeutic applications. Only recently has research begun to understand the gene expression profiles of hMSCs and their differentiated counterparts in vivo and ex vivo. PURPOSE: The research presented here aimed at gaining a better understanding of gene expression patterns present during hMSC invasion through a basement membrane. METHODS: Changes in gene expression were evaluated between invasive and non-invasive cells using Agilent's gene expression arrays and Matrigel invasion chambers. The cells were specifically attracted to a defined stem cell media called SCM. RESULTS: A total 435 genes were up-regulated by 2- fold or more in the invasive population of cells and classified into developmental programs and immunological/inflammatory signaling pathways determined by Ingenuity Pathway Analysis (IPA). This list included a variety of regulators of growth and differentiation including NANOG, STAT3 and STAT5A and members of the polycomb repressive complex-2 (PCRC2) EZH2 and SUZ12. The known regulator of inflammation and hypoxia HIF-1alpha was also increased suggesting that regulation of the microenvironment is important during this process. Finally, the invasion process could be reversed using the STAT3 inhibitor Static. CONCLUSIONS: Overall these data will increase the understanding of the genetic pathways functioning during hMSC invasion and aid in the development of their therapeutic applications. PMID- 24772454 TI - rCAD: A Novel Database Schema for the Comparative Analysis of RNA. AB - Beyond its direct involvement in protein synthesis with mRNA, tRNA, and rRNA, RNA is now being appreciated for its significance in the overall metabolism and regulation of the cell. Comparative analysis has been very effective in the identification and characterization of RNA molecules, including the accurate prediction of their secondary structure. We are developing an integrative scalable data management and analysis system, the RNA Comparative Analysis Database (rCAD), implemented with SQL Server to support RNA comparative analysis. The platformagnostic database schema of rCAD captures the essential relationships between the different dimensions of information for RNA comparative analysis datasets. The rCAD implementation enables a variety of comparative analysis manipulations with multiple integrated data dimensions for advanced RNA comparative analysis workflows. In this paper, we describe details of the rCAD schema design and illustrate its usefulness with two usage scenarios. PMID- 24772455 TI - Measures of Cardiovascular Health and Physical Function after an Aerobic Exercise Intervention in a Patient Fifteen Days Post-Stroke. AB - Study Design: Case Study Background: Changes in cardiorespiratory (CR) fitness post-stroke severely impact an individual's quality of life. The purpose of this case study was to demonstrate whether a moderate to high intensity aerobic exercise program would improve cardiovascular fitness, and physical performance measures in a participant following discharge from acute stroke rehabilitation. The participant is a 58 year-old female who experienced an ischemic stroke 15 days prior to beginning the exercise intervention. Case Description: The participant was provided a supervised 8-week exercise intervention on a Total Body Recumbent Stepper (TBRS). The exercise intervention consisted of three sessions per week; the first 4 weeks the participant exercised at a moderate intensity of 50-59% heart rate reserve (HRR) calculated from the baseline exercise test; the last 4 weeks the intensity was increased to 60-69% HRR. Exercise duration began at 20 minutes with the goal of reaching 30 minutes of continuous exercise at a specified workload. Outcomes: Following 8-weeks of intervention, the participant showed improvement in cardiovascular measures including: resting blood pressure (BP), resting heart rate (HR), VO2 peak, and the maximum distance walked (6-MWT). Conclusion: The use of a moderate to high intensity aerobic exercise intervention may be effective for participants in the sub-acute phase of stroke recovery in order to improve cardiovascular health and physical function. PMID- 24772456 TI - Separation and purification of steroidal saponins from Paris polyphylla by microwave-assisted extraction coupled with countercurrent chromatography using evaporative light scattering detection. AB - A method of microwave-assisted extraction coupled with countercurrent chromatography using evaporative light scattering detection was successfully developed for the separation and purification of steroidal saponins from Paris polyphylla. The main extraction conditions including microwave power, liquid/solid ratio, irradiation time, and extraction temperature were optimized using an orthogonal array design method. A suitable two-phase solvent system consisting of n-heptane/n-butanol/acetonitrile/water (10:19:6:20, v/v/v/v) was employed in the separation and purification of the extracts of P. polyphylla. A total of 7.1 mg polyphyllin VII, 4.3 mg gracillin, 9.2 mg dioscin, and 10.2 mg polyphyllin I were obtained from 1.5 g P. polyphylla in less than 300 min, the purities of which determined by HPLC were 96.7, 97.3, 98.7, and 98.6%, respectively. The identification and characterization of these compounds were performed by LC-ESI-MS and 1H NMR spectroscopy. The results demonstrated that the proposed method is feasible, economical and efficient for the extraction, separation and purification of effective compounds from natural products. PMID- 24772457 TI - An important attempt to improve the outcome of congenital heart disease in Europe. AB - New recommendations for the organization of care for adults with congenital heart disease and for physician training in the subspecialty of 'Grown-up Congenital Heart Disease' in Europe. PMID- 24772458 TI - GUCH/ACHD: what is required of the newest field in medicine? AB - Cardiologists from the USA provide information from earlier experiences in this emerging specialty. PMID- 24772459 TI - Landmarks in the history of cardiology I. From pre-historic times to Galen's medical authority. PMID- 24772460 TI - Retraction: "Expression of angiotensin II and its receptors in cyclosporine induced gingival overgrowth" by T. Subramani,K. Senthilkumar, S. Periasamy, S. Rao. PMID- 24772461 TI - Surveillance systems to track progress towards global polio eradication,2012 2013. PMID- 24772462 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis, 2014. PMID- 24772463 TI - Retraction notice to "The human placenta is a hematopoietic organ during the embryonic and fetal periods of development" [Dev. Biol. 327 (2009) 24-33]. PMID- 24772464 TI - Receptor-ligand interactions: binding affinities studied by single-molecule and super-resolution microscopy on intact cells. AB - Protein-ligand interactions play an important role in many biological processes. Notably, membrane receptors are the starting point for a huge variety of cellular signal transduction pathways. Quantifying the binding affinity of a ligand for its transmembrane receptor is of great importance as it provides information on the potency of the ligand. We developed a new experimental procedure to determine binding affinities of ligands for their membrane receptors directly on intact single cells using super-resolution imaging. Dissociation constants were determined by titrating fluorophore-labelled ligand against cells expressing the target protein and applying single-molecule imaging. PMID- 24772466 TI - Comment on "Direct comparison of cardiac magnetic resonance and multidetector computed tomography stress-rest perfusion imaging for detection of coronary artery disease". PMID- 24772465 TI - Epigenetic and pharmacological regulation of 5HT3 receptors controls compulsive ethanol seeking in mice. AB - Factors underlying individual vulnerability to develop alcoholism are largely unknown. In humans, the risk for alcoholism is associated with elevated cue reactivity. Recent evidence suggests that in animal models, reactivity to reward paired cues is predictive of addictive behaviors. To model cue reactivity in mice, we used a Pavlovian approach (PA) paradigm in which mice were trained to associate a cue with delivery of a food reinforcer. We then investigated the relationship between PA status with habitual and compulsive-like ethanol seeking. After training mice to respond for 10% ethanol, habitual behavior was investigated using both an outcome devaluation paradigm, in which ethanol was devalued via association with lithium chloride-induced malaise, and a contingency degradation paradigm in which the relationship between action and outcome was disrupted. Compulsive-like behavior was investigated in a modified conditioned place preference paradigm in which footshock was paired with the reward-paired chamber. PA was found to be predictive of habitual and compulsive-like ethanol seeking. Additionally, innate risk status was related to epigenetic changes in the gene encoding the requisite subunit of the 5HT3 receptor, Htr3a, as well as 5HT3A protein expression in the amygdala. We then used pharmacological tools to demonstrate that risk status determines the ability of a 5HT3 antagonist to reduce compulsive ethanol seeking. These data indicate that risk status can be identified prior to any alcohol exposure by assessment of cue reactivity, and further that this endophenotype may be predictive of response to pharmacological treatment for components of alcoholism. PMID- 24772467 TI - [Not Available]. PMID- 24772468 TI - [Retina-therapy]. PMID- 24772469 TI - [Not Available]. PMID- 24772470 TI - [Not Available]. PMID- 24772471 TI - [Inverse corneal opacity in degenerative myopia]. PMID- 24772472 TI - [Rapid decrease in arterial pressure in patients with acute intracerebral hemorrhage]. PMID- 24772473 TI - [Cardiovascular effects of an intensive intervention on lifestyle in type 2 diabetes]. PMID- 24772474 TI - Physical and material properties of an emulsion-based lipstick produced via a continuous process. AB - OBJECTIVES: Water-in-oil emulsions in lipsticks could have the potential to improve moisturizing properties and deliver hydrophilic molecules to the lips. The aim of this work was to investigate the effect of a continuous process (scraped surface heat exchanger (SSHE) and pin stirrer (PS)) on the physical and material properties of an emulsion-based lipstick by altering the processing conditions of both the SSHE and PS. METHODS: Emulsion formation was achieved using a SSHE and PS. Emulsions were analysed using nuclear magnetic resonance restricted diffusion (droplet size), texture analysis and rheology (mechanical properties). RESULTS: Results showed that a higher impeller rotational velocity (IRV) (1500 r.p.m.) and a lower exit temperature (52 degrees C) produce the smallest droplets (~ 4 MUm), due to greater disruptive forces and a higher viscosity of the continuous phase. The addition of a PS reduces the droplet size (14-6 MUm) if the SSHE has a low IRV (500 r.p.m.), due to greater droplet disruption as the emulsion passes through the PS unit. Results also show that if the jacket temperature of a SSHE is 65 degrees C, so that crystallization occurs in both process and post-production, droplets can be integrated into the network resulting in a stiffer wax network (G' - 0.12, in comparison to 0.02 MPa). This is due to small crystals creating a shell around water droplets which can form connections with the continuous network forming a structured network. The addition of a pin stirrer can disrupt a formed network reducing the stiffness of the emulsion (0.3-0.05 MPa). CONCLUSION: This work suggests the potential use of a continuous process in producing an emulsion-based lipstick, particularly when wax crystals are produced in the process. Future work should consider the moisturizing or lubricating properties of wax continuous emulsions and the release of hydrophilic compounds from the aqueous phase. PMID- 24772475 TI - [Effectiveness of regimens of remission-induction on vasculitis associated with antineutrophil cytoplasmic antibodies]. PMID- 24772476 TI - Characterization, sensorial evaluation and moisturizing efficacy of nanolipidgel formulations. AB - BACKGROUND: Nanostructured lipid carriers (NLC) have been widely studied for cosmetic and dermatological applications due to their favourable properties that include the formation of an occlusive film on the skin surface that reduces the transepidermal water loss (TEWL) and increase in water content in the skin which improves the appearance on healthy human skin and reduces symptoms of some skin disorders like eczema. OBJECTIVE: The main objective of this study was the development of semisolid formulations based NLC with argan oil or jojoba oil as liquid lipids, by addition of Carbopol(r)934 or Carbopol(r)980 as gelling agents, followed by comparison between instrumental analysis and sensorial evaluation and in vivo efficacy evaluation. METHODS: Nanostructured lipid carriers dispersions were produced by the ultrasound technique, and to obtain a semisolid formulation, gelling agents were dispersed in the aqueous dispersion. Particle size, polydispersity index and zeta potential were determined. Instrumental characterization was performed by rheological and textural analysis; the sensorial evaluation was also performed. Finally, skin hydration and TEWL were studied by capacitance and evaporimetry evaluation, respectively. RESULTS: Particles showed a nanometric size in all the analysed formulations. All the gels present pseudoplastic behaviour. There is a correspondence between the properties firmness and adhesiveness as determined by textural analysis and the sensory evaluation. The formulations that showed a greater increase in skin hydration also presented appropriate technological and sensorial attributes for skin application. CONCLUSIONS: Nanolipidgel formulations with the addition of humectants are promising systems for cosmetic application with good sensory and instrumental attributes and moisturizing efficacy. PMID- 24772477 TI - Medicalization, wish-fulfilling medicine, and disease mongering: toward a brave new world? AB - Western societies are characterized by a growing medicalization of life events, such as pregnancy, aging, or even death. Three concepts -medicalization, wish fulfilling medicine, and disease mongering- are key in understanding the current practise of Medicine. Quite surprisingly, not a single study has addressed the relationship between all three of these concepts. The term medicalization expanded under the open-ended concept of health developed by the World Health Organization in 1946. One of the consequences of medicalization is the transition from patients to clients. Physicians are under increasing pressure to meet the insatiable demands of their clients. The term wish-fulfilling medicine refers to the increasing tendency of medicine to be used to fulfill personal wishes (i.e. enhanced work performance). The insatiable demand for healthcare is troublesome, particularly in Europe, where the welfare states are more and more under pressure. Finally, the term disease mongering refers to attempts by pharmaceutical companies to artificially enlarge their "markets" by convincing people that they suffer from some sickness and thus need medical treatment. Typical examples of disease mongering are social anxiety disorder, low bone mineral density, and premature ejaculation. Currently, some Public Health Services could be on the brink of collapse as they "navigate" between the scarce resources available and the users' insatiable health demands. Therefore, it appears necessary to generate clear-cut Public Health Services Port-folios. PMID- 24772478 TI - A critical role of hypocretin deficiency in pregnancy. AB - Hypocretin/orexin peptides are known for their role in the control of the wake sleep cycle and narcolepsy-cataplexy pathophysiology. Recent studies suggested that hypocretin peptides also have a role in pregnancy. We tested this hypothesis by conducting a retrospective analysis on pregnancy complications in two different mouse models of hypocretin deficiency. We recorded 85 pregnancies of mice lacking either hypocretin peptides (knockout) or hypocretin-releasing neurons (transgenic) and their wild-type controls. Pregnancy was associated with unexplained dam death before delivery in 3/15 pregnancies in knockout mice, and in 3/23 pregnancies in transgenic mice. No casualties occurred in wild-type pregnant dams (P < 0.007 versus hypocretin-deficient mice as a whole). Hypocretin deficiency did not impact either on litter size or the number of weaned pups per litter. These data provide preliminary evidence of a critical role of hypocretin deficiency in pregnancy. PMID- 24772479 TI - Identification and functional characterization of imatinib-sensitive DTD1-PDGFRB and CCDC88C-PDGFRB fusion genes in eosinophilia-associated myeloid/lymphoid neoplasms. AB - Eosinophilia-associated myeloid neoplasms with rearrangement of chromosome bands 5q31-33 are frequently associated with PDGFRB fusion genes, which are exquisitely sensitive to treatment with imatinib. In search for novel fusion partners of PDGFRB, we analyzed three cases with translocation t(5;20)(q33;p11), t(5;14)(q33;q32), and t(5;17;14)(q33;q11;q32) by 5'-rapid amplification of cDNA ends polymerase chain reaction (5'-RACE-PCR) and DNA-based long-distance inverse PCR (LDI-PCR) with primers derived from PDGFRB. LDI-PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11 in the case with t(5;17;14)(q33;q11;q32) while 5'-RACE-PCR identified fusions between CCDC88C exon 10 and PDGFRB exon 12 and between DTD1 exon 4 and PDGFRB exon 12 in the cases with t(5;14)(q33;q32) and t(5;20)(q33;p11), respectively. The PDGFRB tyrosine-kinase domain is predicted to be retained in all three fusion proteins. The partner proteins contained coiled coil domains or other domains, which putatively lead to constitutive activation of the PDGFRB fusion protein. In vitro functional analyses confirmed transforming activity and imatinib-sensitivity of the fusion proteins. All three patients achieved rapid and durable complete hematologic remissions on imatinib. PMID- 24772481 TI - Determining the etiology of cardiac arrest. A challenging part of diagnosis. Reply. PMID- 24772480 TI - Neovascularization is prominent in the chronic inflammatory lesions of Sjogren's syndrome. AB - Angiogenesis is a common finding in chronic inflammatory diseases; however, its role in Sjogren's syndrome (SS) remains to be elucidated. Previous SS studies have demonstrated an increase in VEGF-A/VEGFR-2 system expression in minor salivary gland (MSG) biopsies from patients with SS, but differences in the new blood vessel formation between the different grades of disease severity have not been reported. Therefore, experiments were performed to demonstrate angiogenesis during different phases of primary SS (pSS) and to define the relationship between the microvessel density (MVD), macrophage infiltration and histiocyte distribution in SS MSG inflammatory lesions. In this series of experiments, immunohistochemistry was used to examine angiogenesis in serial sections of pSS MSG. Patients with pSS were classified accordingly with the grade of inflammatory lesions as I = low-grade (low focus score of 1 or 2), II = intermediate-grade (focus score of 3-6) and III = extensive inflammation in the MSG (high focus score of 12). Histological examination demonstrated that the MVD increased with the severity of the inflammatory lesions, and in addition, we found an increased infiltration of inflammatory and pro-angiogenic cells.These findings reveal that angiogenesis is intimately involved in the progression of pSS, may be central to the propagation of the chronic immune response observed in pSS and could represent a novel potential biomarker of pSS disease activity. PMID- 24772482 TI - Anatomist and the pioneer of radiology Etienne Destot--95th anniversary of his death. AB - Destot was a leading pioneer in radiology, a pupil of Ollier, an anatomist, and researcher who followed in the experimental medicine tradition of Claude Bernard. This work is an extensive, in depth, look at the life and work of Etienne Destot. On February 5, 1896, he began performing X-ray examinations, less than two months after Roentgen's discovery! His pioneering work described a space bordered by the hamate, capitate, triquetrum, and lunate; this space is now known as Destot's space. Tanton stated that Destot was the first to reveal the mechanism of fractures of the posterior margin of the distal tibia and to emphasize their clinical relevance; in honor of this contribution, Tanton named such a fracture the "fracture of Destot." Moreover, Destot is credited with being the first physician to use the term "pilon" in the orthopedic literature. He first described fractures of the scaphoid in 1905. He also described superficial hematomas, Destot's sign, located above the inguinal ligament or in the scrotum or thigh. Such hematomas are indicative of pelvic fractures. Destot is credited with inventing or improving many pieces of medical equipment (e.g., Lambotte's screw plates, anastomotic boutons for the digestive tube, monopolar endocavital radiological tubes). He was also active in developing technical aspects of equipment (e.g., radioscopic examination of the heart, a prototype of the mobile radiological laboratory). Etienne Destot is best known as a radiologist; however, his influence extends well beyond this field. He was an anatomist and surgeon, the founder of radiology in Lyon, prosector, physician, electrician, researcher, and artist. PMID- 24772483 TI - Characterization of the heterozygous glucokinase knockout mouse as a translational disease model for glucose control in type 2 diabetes. AB - BACKGROUND AND PURPOSE: The global heterozygous glucokinase (GK) knockout (gk(wt/del)) male mouse, fed on a high-fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes (T2D). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose-lowering potential of novel glucokinase activators (GKAs) in this model. EXPERIMENTAL APPROACH: We measured the ability of insulin, metformin, glipizide, exendin-4 and sitagliptin, after acute or repeat dose administration, to lower free-feeding glucose levels in gk(wt/del) mice. Further, we measured the ability of novel GKAs, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents. KEY RESULTS: A single dose of insulin (1 unit.kg(-1)), metformin (150, 300 mg.kg(-1)), glipizide (0.1, 0.3 mg.kg(-1)), exendin-4 (2, 20 MUg.kg(-1)) and GKAs reduced free-feeding glucose levels. Sitagliptin (10 mg.kg(-1)), metformin (300 mg.kg(-1)) and AZD6370 (30, 400 mg.kg(-1)) reduced glucose excursions on repeat dosing. At a supra-therapeutic dose (400 mg.kg(-1)), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia. CONCLUSION AND IMPLICATIONS: Standard glucose-lowering therapeutic agents demonstrated significant acute glucose lowering in male gk(wt/del) mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D. Novel GKAs also lowered glucose in this mouse model. PMID- 24772485 TI - Differential expression of interleukin-2 by anti-CD3-stimulated peripheral blood mononuclear cells in patients with psoriatic arthritis and patients with cutaneous psoriasis. AB - The differences in systemic T-cell responses between patients with psoriatic arthritis (PsA) and patients with cutaneous psoriasis (Ps) are still largely unknown. To determine differential features that could be used to distinguish PsA from Ps, we compared the cytokine secretion profile of circulating T cells in patients with PsA, patients with cutaneous Ps and control subjects. We determined Th1, Th2 and Th17 cytokine secretion of anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) using a cytokine bead array. Normality of data distribution was assessed by the Shapiro-Wilk test, and statistical significance was calculated by the Mann-Whitney test. Phenotypic characterization of circulating T cells was performed by fluorescence-activated cell sorting analysis. We found that the major systemic differences distinguishing PsA from cutaneous Ps were the increased secretion of interleukin (IL)-2 by alpha-CD3 stimulated PBMCs and a higher percentage of circulating CD3+ T cells expressing the proliferation marker CD71 in PsA. These results indicate IL-2 as a possible biomarker of PsA, and suggest a role of circulating T cells with high proliferative capacity in the pathogenesis of PsA. PMID- 24772484 TI - Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes. AB - BACKGROUND AND PURPOSE: Pharmacological activation of glucokinase (GK) lowers blood glucose in animal models and humans, confirming proof of concept for this mechanism. However, recent clinical evidence from chronic studies suggests that the glucose-lowering effects mediated by glucokinase activators (GKAs) are not maintained in patients with type 2 diabetes (T2D). Existing preclinical data with GKAs do not explain this loss of sustained glucose-lowering efficacy in patients. Here, we have assessed the effects of chronic (up to 11 months) treatment with two different GKAs in two models of T2D. EXPERIMENTAL APPROACH: Two validated animal models of T2D, insulin-resistant obese Zucker rats and hyperglycaemic gk(wt/del) mice, were treated with two different GKAs for 1 or 11 months respectively at exposures that translate to clinical exposures in humans. Blood glucose, cholesterol, triglycerides and insulin were measured. GKA pharmacokinetics were also determined. KEY RESULTS: Treatment with either GKA provided sustained lowering of blood glucose for up to 1 month in the Zucker rat and up to 11 months in hyperglycaemic gk(wt/del) mice, with maintained compound exposures. This efficacy was achieved without increases in plasma or hepatic triglycerides, accumulation of hepatic glycogen or impairment of glucose stimulated insulin secretion. CONCLUSIONS AND IMPLICATIONS: Chronic treatment with two GKAs in two animal models of diabetes provided sustained lowering of blood glucose, in marked contrast to clinical findings. Therefore, either these animal models of T2D are not good predictors of responses in human T2D or we need a better understanding of the consequences of GK activation in humans. PMID- 24772486 TI - Linear IgA bullous dermatosis of childhood: good response to antibiotic treatment. PMID- 24772487 TI - Retraction. PMID- 24772488 TI - Discovery of new sites for drug binding to the hypertension-related renin angiotensinogen complex. AB - Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ~ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small druglike molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension. PMID- 24772489 TI - Molecular modeling of 5HT2A receptor - arylpiperazine ligands interactions. AB - In this paper, we report the molecular modeling of the 5HT2A receptor and the molecular docking of arylpiperazine-like ligands. The focus of the research was on explaining the effects the ligand structure has on the binding properties of the 5HT2A receptor and on the key interactions between the ligands and the receptor-binding site. To see what the receptor-ligand interactions were, various substituents were introduced in one part of the ligand, keeping the rest unchanged. In this way, using a docking analysis on the proposed 5HT2A receptor model, we identified key receptor-ligand interactions and determined their properties. Those properties were correlated with experimentally determined binding affinities in order to determine the structure to activity relationship of the examined compounds. PMID- 24772490 TI - In response. PMID- 24772491 TI - HIV treatment guidelines. PMID- 24772492 TI - Tetanus toxin reduces local and descending regulation of the H-reflex. AB - INTRODUCTION: Skeletal muscles that are under the influence of tetanus toxin show an exaggerated reflex response to stretch. We examined which changes in the stretch reflex may underlie the exaggerated response. METHODS: H-reflexes were obtained from the tibialis anterior (TA) and flexor digitorum brevis (FDB) muscles in rats 7 days after intramuscular injection of tetanus toxin into the TA. RESULTS: We found effects of the toxin on the threshold, amplitude, and duration of H-waves from the TA. The toxin inhibited rate-dependent depression in the FDB between the stimulation frequencies of 0.5-50 HZ and when a conditioning magnetic stimulus applied to the brain preceded a test electrical stimulus delivered to the plantar nerve. CONCLUSIONS: Tetanus toxin increased the amplitude of the Hwave and reduced the normal depression of H-wave amplitude that is associated with closely timed stimuli, two phenomena that could contribute to hyperactivity of the stretch reflex. PMID- 24772493 TI - A cross-sectional study on the prevalence of metabolic syndrome in psoriasis compared to psoriatic arthritis. AB - BACKGROUND: Increasing epidemiological evidence suggests associations between psoriasis, psoriatic arthritis (PsA) and metabolic disease. Elucidating the complex relationship between these comorbidities may have important management implications. OBJECTIVE: The aim of this study was to examine the difference in prevalence of metabolic disease burden between patients with psoriasis who lack arthritic manifestations (PsO) and PsA patients. METHODS: We performed a cross sectional study in 123 patients with PsO and PsA. Metabolic syndrome was defined using the new criteria developed by the International Diabetes Foundation (IDF) in 2004. Therefore, clinical examination and standard survey were performed and fasting blood samples were collected. RESULTS: One hundred and four patients were analysed, of which 49 were PsO and 55 were PsA patients. We found that prevalence of the metabolic syndrome according to the IDF criteria was significantly higher in the PsO (44.9%) compared with the PsA group (25.5%) (P = 0.037). Looking closer at the individual components of the metabolic syndrome, this difference can mainly be attributed to the significantly higher prevalence of abdominal obesity in PsO (83.7%) vs. PsA (65.5%) (P = 0.034). For other individual components of the metabolic syndrome such as triglycerides, high-density lipoproteins, hypertension and plasma glucose, we could not show statistically significant differences between the groups. CONCLUSION: Metabolic syndrome is more prevalent in patients with PsO than in PsA patients, mainly determined by the higher prevalence of abdominal obesity in PsO compared with PsA group. PMID- 24772494 TI - Industry involvement in publicly funded biobanks. PMID- 24772495 TI - Author response. PMID- 24772496 TI - Evidence of empowerment. PMID- 24772497 TI - The Health of Healthcare, Part III: Dissolving (curing) the cancer in healthcare. AB - In a previous part of this "The Health of Healthcare" series, the etiology of sickness in our healthcare system was established as cancer. This article offers a method to "cure" healthcare, taken from strategic management thinking called VOSIE. In this article, the use of VOSIE is described as well as who needs to apply this cure: the public. A unifying mantra is suggested: Think and decide. PMID- 24772498 TI - Benefit and formulary options appear in specialty pharmacy. Management tactic borrowed from traditional pharmacy. PMID- 24772499 TI - Bariatric surgery called cure for some diabetes patients. PMID- 24772500 TI - [Current approaches to the diagnosis and treatment for enteropathies]. AB - Enteropathies (EP) are the common name for pathological (inflammatory, hemorrhagic, erosive-ulcerative, and atrophic) changes in the small bowel. The paper describes the nosological entities of EP and the significance of laboratory and instrumental methods used for their diagnosis. It outlines the principles of etiotropic and pathogenetic therapies. PMID- 24772501 TI - [Value of the calcium-regulating system in the development of microcirculatory and hemostatic disorders in recurrent peptic ulcer disease]. AB - AIM: To elucidate the state and importance of the calcium-regulating system, calcium and phosphorus balances, their impact on ulcer activity, regional microcirculation, and hemostasis during recurrent peptic ulcer disease (PUD). SUBJECTS AND METHODS: Sixty patients with recurrent PUD were examined. They underwent determinations of blood parathyrin and calcitonin and blood and urinary calcium and phosphorus levels and studies of regional microcirculation in the gastroduodenal mucosa and systemic hemostatic parameters in addition to clinical and endoscopic examinations. RESULTS: Recurrent PUD is accompanied by a significant blood parathyrin rise and some calcitonin increase and by calcium phosphorus imbalance. Impaired calcium-regulating system functions attend significant microcirculatory disorders in the gastroduodenal mucosa and hemostatic changes characteristic of consumptive coagulopathy. CONCLUSION: A clear relationship between calcium-regulating hormone impairments, calcium and phosphorus metabolism with ulcer activity and microcirculatory and hemostatic changes may suggest the found shifts in ulcerogenesis and the pathogenetic substantiation of correction of these disorders may be of importance for the treatment of a disease recurrence. PMID- 24772502 TI - [Gastroesophageal reflux disease associated with duodenogastroesophageal reflux in patients with biliary pathology: the specific features of the course and esophagogastroduodenal microbial biocenosis]. AB - AIM: To study the specific features of the clinical course of gastroesophageal reflux disease (GERD) associated with duodenogastroesophageal reflux (DGER) in patients with chronic acalculous cholecystitis (CAC) and cholelithiasis (CL), as well as qualitative and quantitative characteristics. SUBJECTS AND METHODS: The clinical, morphological, motor tonic characteristics of the esophagogastroduodenal area, mucosal microbial biocenosis in the esophagus, stomach, and duodenum were studied in detail in 83 patients with GERD that was associated with DGER and ran concurrently with CAC or CL. RESULTS: Impaired duodenal propulsive activity as a concomitance of the signs of gastrostasis and duodenal dyskinesia with dyscoordination of both anthroduodenal and duodenojejunal propulsion and with the development of duodenogastric reflux and DGER, which in turn determine esophageal and gastric pH values is shown to be of importance in CAC and CL, which match GERD. Abnormal microbiocenosis in the upper digestive tract is characterized by the higher quantitative and qualitative content of the mucous microflora. Opportunistic microorganisms exhibit cytotoxic, hemolytic, lecithinase, caseinolytic, urease, and RNAase activities. CONCLUSION: The found specific features of the course of GERD associated with DGER in patients with biliary tract abnormalities lead us to search for novel therapeutic approaches based on the correction of digestive motor tonic disorders and abnormal microbiocenoses of the mucous flora in the esophagus, stomach, and duodenum. PMID- 24772503 TI - [Clinical aspects of gastroesophageal reflux disease in elderly patients: results of a 5-year prospective study]. AB - AIM: To evaluate the clinical manifestations and changes of non-erosive reflux disease, erosive reflux disease, and Barrett's esophagus (BE) in a cohort of elderly patients during a 5-year follow-up. SUBJECTS AND METHODS: A continuous method was used to compare the clinical manifestations of gastroesophageal reflux disease (GERD) in 950 patients aged 60 to 75 years and 453 patients aged 36 to 60 years. All the patients underwent clinical examination using the Mayo clinic questionnaire and fibroesophagogastroduodenoscopy. A prospective cohort study was performed in 950 patients aged 60 to 75 years for an average of 5 years. GERD was diagnosed on the basis of the Montreal Consensus guidelines (2006); the degree of esophageal mucosal injury was evaluated according to the Los-Angeles classification (1999). The diagnosis of BE was morphologically verified. RESULTS: The frequency of weekly heartburn was 10% higher in the mature-aged patients; but that of nocturnal heartburn, belching, and BE prevailed in the elderly patients. The 5-year prospective follow-up revealed a significant increase in the rate of erosive esophagitis and BE in the elderly patients with GERD. The risk factors of the latter were no maintenance therapy with proton pump inhibitors, as well as obesity and hiatal hernia. CONCLUSION: GERD shows clinical features and progression in the elderly patients. PMID- 24772504 TI - [Patient compliance as one of the factors determining the efficiency of eradication therapy]. AB - AIM: To improve the quality of eradication therapy (ET), by increasing patient compliance. SUBJECTS AND METHODS: An open-label cohort multicenter randomized study was conducted. A total of 350 patients with Helicobacter pylori infection associated diseases and indications for ET were examined. Work was done to improve compliance in a study patient group before treatment. RESULTS: In the study group of patients motivated for treatment, the efficiency of ET was significantly higher than in the control group. The factors influencing treatment adherence were identified and methods to optimize compliance during H. pylori eradication were developed. CONCLUSION: Awareness of the essence of the disease in a patient and his higher motivation for compliance are one of the components of successful H. pylori eradication. PMID- 24772505 TI - [Value of adhesion molecules for evaluating the efficiency of therapy for ulcerative colitis and Crohn's disease]. AB - AIM: To define the value of adhesion molecules (sVCAM-1 integrin, P-selectin, E selectin, and L-selectin) for the prediction and evaluation of the efficiency of treatment in patients with ulcerative colitis (UC) and Crohn's disease. SUBJECTS AND METHODS: Twenty-six patients with UC and 14 patients with CD were examined. Of them, 16 patients took infliximab (INF) in a dose of 5 mg/kg of body weight according to the standard scheme; 14 patients received cultured mesenchymal stem stromal cells (MSSCs) in a quantity of 150 x 10(8) cells, and 10 had azathioprine (AZA) 2 mg/kg and glucocorticosteroids (GCS) 1 mg/kg of body weight. Enzyme immunoassay was used to determine the serum concentration of the adhesion molecules (L-selectin, E-selectin, P-selectin, and sVCAM-1 integrin) before and 2 months after treatment. RESULTS: The signs of bowel inflammatory disease activity and the elevated levels of adhesion molecules whose synthesis did not occur under normal conditions remained in the patients receiving GCS and AZA. INF treatment caused a decrease in P-selectin, E-selectin, and sVCAM-1 levels to 8.9 +/- 1.0, 5.5 +/- 1.7, and 9.5 +/- 4.4 ng/ml, respectively (p < 0.001). Incorporation of MSSCs was followed by a reduction of the concentrations of P-selectin and E selectin to 6.9 +/- 1.1 and 5.7 +/- 1.3 ng/ml, respectively (p < 0.001). The level of integrin (cVCAM-1) fell to 12.2 +/- 2.2 ng/ml (p > 0.1); that of L selectin did not drop after MSSC administration and INF induction therapy. CONCLUSION: P-selectin, E-selectin, L-selectin, and sVCAM-1 integrin are current inflammatory markers and may be used to evaluate the efficiency of standard and biological therapies for inflammatory bowel diseases and to predict disease course. PMID- 24772506 TI - [Significance of a method for determination of deamidated gliadin peptide in the diagnosis of celiac disease]. AB - AIM: To define the value of a new enzyme immunoassay in determining the level of anti-deamidated gliadin peptide (DGP) antibodies (Abs) in the diagnosis of celiac disease. SUBJECTS AND METHODS: One hundred and twenty-four patients treated at the Department of Intestinal Pathology, Central Research Institute of Gastroenterology, were examined. Enzyme-linked immunosorbent assay (ELISA) was employed to determine Abs to tissue transglutaminase (tTG) and DGP of the IgA and IgG classes in the sera of all the patients. The diagnosis of celiac disease was verified by the histological examination of small bowel mucosa biopsy specimens. RESULTS: The examinees were divided into 3 groups: 1) 27 patients first diagnosed with celiac disease; 2) 40 patients keeping a gluten-free diet (GFD); 3) 57 patients with other gastrointestinal diseases (a comparison group). In the patients first diagnosed with celiac disease, the detection rate of elevated titers of anti-tTG and anti-DGP Abs in the IgA class was equal and constituted 92.5%; that in the IgG class was 96.2 and 55.5%, respectively. The comparison group showed an increase in the DGP levels in the IgA and IgG classes in 4 (7%) patients and a rise in tTG concentrations in the IgA and IgG classes was seen in only 2 (3.5%) patients. CONCLUSION: In the patents first diagnosed with celiac disease, the detection rate of elevated levels of anti-DGP Abs in the IgA and IgG classes is 92.5 and 96.2%, respectively, and significantly indifferent from that of IgA and IgG anti-tTG Abs. The patients keeping GFD displayed a reduction in anti-DGP Abs. The high detection rate of IgA anti-DGP Abs in the patients first diagnosed with celiac disease allows this method to be recommended for immunological diagnosis of this disease in adults. PMID- 24772507 TI - [Role of transforming growth factor-beta in the development of some liver diseases]. AB - AIM: To investigate the expression of transforming growth factor-beta 1 (TGF beta1) in the liver tissue of patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and chronic hepatitis C (CHC). MATERIALS AND METHODS: Liver biopsy specimens were histologically and immunohistologically examined in 37 patients with verified liver diseases (12 with AIH, 15 with PBC, and 10 with CHC). RESULTS: The expression of TGF-beta1 in the non-parenchymal liver cells of the patients with AIH and PBC with liver cirrhosis was statistically significantly higher than in those without the latter (p = 0.01 and p = 0.04, respectively). There was a positive relationship between the stage of fibrosis and the absolute content TGF-beta1 and CD68+ cells in the portal tracts (r = 0.51). The higher expression of TGF-beta1 was found in the patients with HCV and AIH than in those with PBC (p = 0.03 and p < 0.05, respectively). There were no differences in the expression of TGF-beta1 in the patients with AIH as compared to those with CHC (p = 0.55). The number of CD68-positive macrophages was higher in CHC than in AIH and PBC (p = 0.004 and p = 0.01, respectively). In autoimmune liver diseases, TGF-beta1 was mainly expressed by the macrophages located in the portal tracts and, in CHC, within the hepatic lobules. CONCLUSION: The enhanced TGF-beta1 expression in the nonparenchymal liver cells in AIH and PBC with liver cirrhosis confirms the role of this cytokine in development of fibrosis in autoimmune liver diseases. That in hepatitis of various etiologies versus PBC suggests that the TGF-beta1 signaling pathway may play an important role in an inappropriate immune response in hepatitides; and the variations found in the location of the macrophages expressing TGF-beta1 reflect a difference in the mechanisms of lesions. PMID- 24772508 TI - [Polymorphism of ethanol metabolism genes in alcoholic chronic pancreatitis]. AB - AIM: To study the gene polymorphisms of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome CYP2E1 in patients with alcoholic chronic pancreatitis (ACP) and to compare them with laboratory and instrumental findings. SUBJECTS AND METHODS: Seventy-two patients with ACP and 80 healthy individuals were examined. Polymorphic DNA loci were analyzed by polymerase chain reaction of DNA synthesis, followed by electrophoretic detection. Polymorphism in genes involved in ethanol metabolism was studied. RESULTS: The patents with ACP had mutations in the genes involved in ethanol metabolism. The study results of the rate of the alleles and genotypes of ADH, ALDH, and CYP2E1 genes were controversial. However, investigating the combinations of the genotypes of ADH and ALDH revealed that the patients having ADH1 B*47His and ALDH2*2 genotypes had a much higher risk for ACP and constituted more than 50% of the ACP patients. With this combination, ACP took its course with more evident structural and functional disorders of the pancreas. The CYP2E1 C/C homozygotes had an especially high risk of ACP. CONCLUSION: The investigation perspectives are to increase the number of examined patients and apparently healthy individuals and to find correlations between clinical, laboratory, and instrumental parameters and genotyping findings. The results of these investigations can define the possible strategy of prevention of CAP. PMID- 24772509 TI - [Blood lipid parameters in combat veterans with posttraumatic stress disorders]. AB - AIM: To study the specific features of blood lipid composition in combat veterans (CVs) with posttraumatic stress disorder (PTSD). SUBJECTS AND METHODS: One hundred and sixty-one CVs were examined; their mean age was 42.8 +/- 0.7 years. All the patients underwent a clinical and neurological examination using additional studies. I.O. Kotenev's trauma stress questionnaire was used. The mean intensity of PTSD was 65.5 +/- 0.95 scores. Fasting biochemical blood tests were carried out using clinical chemical analyzers. RESULTS: Dyslipidemias characterized mainly by elevated levels of total cholesterol and low-density lipoproteins are identified in the majority of present-day CVs. Higher triglyceride levels and lower high-density lipoproteins are encountered 2 and 1.5 times more frequently, respectively. A tendency has been found towards an inverse correlation between the degree of PTSD and the levels of total cholesterol and low-density lipoproteins. CONCLUSION: Neuroendocrine changes accompanying PTSD and leading to intensified adrenergic influences are an important trigger of accelerated hyperlipidemia development in CVs. Age-related changes and metabolic hepatic disorders associated with alcohol abuse and consequences of prior infectious diseases have become to play an important role in the pathogenesis of dyslipidemias in patients over 40-45 years of age. PMID- 24772510 TI - [Use of fendivia transdermal therapeutic system in Russian patients with malignant neoplasms during palliative care: pharmacoeconomic aspects]. AB - AIM: To make a comparative clinical and economic assessment of a transdermal therapeutic system (TTS) for fendivia and traditional opioid analgesics in patients with malignant neoplasms (MN) during palliative care. MATERIALS AND METHODS: Pharmacoeconomic analysis of opioid analgesics used in patients with MN during analgesic therapy was made using the cost-effectiveness analysis in the framework of a budget impact analysis (BIA). RESULTS: The assessment of the medical cost structure in the fendivia and morphine groups (100 patients in each group), which was made in the framework of BIA, demonstrated that the cost of pharmacotherapy in the fendivia group was comparable with that of an ambulance call for additional analgesia and correction of the side effects of performed therapy (615,804.00 and 645,337.60 rbl. monthly, respectively). At the same time, in the morphine group the cost of an ambulance call was more than 20 times that of pharmacotherapy (2,117,514.00 and 93,120.00 rbl. monthly, respectively). Thus, the total savings from applying the fendivia TTS in the group of 100 patients ranged up to 949,492.40 rbl. monthly. CONCLUSION: The application of the fendivia TTS is clinically and pharmacoeconomically valid and leads to a considerable reduction in public health care costs. PMID- 24772511 TI - [Whipple's disease in a patient with infantile cerebral palsy and hepatitis B virus cirrhosis]. AB - The paper describes a patient who has developed Whipple's disease in the presence of infantile cerebral palsy and hepatitis B virus cirrhosis. After 5-year treatment with co-trimoxazole (480 mg b.i.d.), the clinical manifestations subsided and PAS-positive macrophages were no longer detectable in the small intestinal mucosal biopsy specimens. Subsequent worsening of the patient's condition was associated with the progression of liver cirrhosis. PMID- 24772512 TI - [Shwachman-Diamond syndrome]. AB - Shwachman-Diamond syndrome is an inherited autosomal recessive disease that appears as exocrine pancreatic insufficiency, neutropenia, impaired neutrophil chemotaxis, aplastic anemia, thrombocytopenia, metaphyseal dysplasia, and physical retardation. Its worldwide prevalence is 1:10,000 to 1:20,000 live births depending on the region. The SBDS gene and a few mutations, which lead to this syndrome, have been found in the past decade. The paper describes a case of this rare disease in a 28-year-old male patient who has all characteristic manifestations as lipomatosis and severe exocrine pancreatic insufficiency, neutropenia with bone marrow hypoplasia, physical retardation, glucose intolerance, secondary osteopenia, and minor cardiac anomalies. Its clinical diagnosis was verified by molecular genetic testing. PMID- 24772513 TI - [The acid pocket as the pathogenic basis and therapeutic target in gastroesophageal reflux disease]. AB - Gastroesophageal reflux is the leading factor of the pathogenesis of gastroesophageal reflux disease (GERD). A number of mechanisms (decreased pressure and transient relaxation of the lower esophageal sphincter, increased intraabdominal pressure, hiatal hernia) for its development are described. At the same time, the acid pocket occurring after meals is a source of reflux. The data available in the literature on the clinical relevance of the acid pocket in GERD and on the factors influencing its size and location are given. The efficacy of drugs used to treat GERD in terms of their effect on the acid pocket is shown. Proton pump inhibitors reduce the volume of the acid pocket and increase its pH, by affecting gastric acid production. Prokinetic agents are able to displace the acid pocket from the gastroesophageal junction. An alginate-antacid formulation combines the physical antireflux effect of alginate and the acid-induced neutralization of the acid pocket. PMID- 24772514 TI - [Evolution of clinical ideas about Zollinger-Ellison syndrome]. AB - The paper gives the current views of the diagnosis and treatment of Zollinger Ellison syndrome (ZES). It underlines the importance of including ZES in differential diagnosis in patient with frequently recurrent and standard-dose proton pump inhibitor therapy-resistant erosive and ulcerative lesions of the upper gastrointestinal tract. It provides the current stepwise algorithm for the diagnosis of the pathology in question. Relevant and promising treatments in patients with ZES are considered. PMID- 24772515 TI - [Morphofunctional rearrangement of the hepatic vasculature in the pathogenesis of portal hypertension in liver cirrhosis]. AB - The paper presents an update on the mechanisms for enhanced hepatic vascular resistance to the portal circulation underlying the pathogenesis of portal hypertension in liver cirrhosis. In addition to gross hepatic structural disorders related to diffuse fibrosis and formation of regenerative nodules, the morphofunctional rearrangement of the hepatic vasculature is shown to play an important role in this process. It is characterized by endothelial dysfunction and impaired paracrine interaction between activated stellate hepatocytes and sinusoidal endotheliocytes, sinusoidal remodeling and capillarization, as well as intrahepatic angiogenesis. PMID- 24772516 TI - [Promising immunonutrients in general medical practice]. AB - The review gives data on prospects for using agents based on probiotics and trace elements for immunomodulation. It presents information on that a Lactobacillus casei rhamnosus 35-based probiotic is able to reduce the incidence and severity of viral and bacterial infections. The potential of zinc and selenium as immunotropic agents is shown. PMID- 24772517 TI - [Combination biological therapy for fistular Crohn's disease: clinical demonstration]. AB - Perianal fistulas are the most common and frequently encountered types of fistulas in Crohn's disease (CD). They are incurable, may worsen quality of life in a patient and increase the risk of total bowel resection. Despite the significant impact of biological (anticytokine) therapy for fistular CD, treatment in this category of patients remains a difficult task with the high risk of recurrent CD. Mesenchymal stromal cells (MSCs) having immunomodulatory properties and a great regenerative potential are currently also used to treat fistulas in CD and perianal fistulas of another etiology. The given clinical case demonstrates that complete fistula healing could be achieved only after a few local administrations of MSCs in combination with infliximab and azathioprine. World and our experiences indicate that there is a need for randomized controlled trials with a sufficient number of patients to prove the efficacy of MSCs in the combination therapy of fistulas in CD. PMID- 24772518 TI - [Q & A. Pancreatic tumor incidentally found at abdominal CT examination]. PMID- 24772519 TI - Transforming health in tribal communities. AB - (1) Chronic diseases account for 75 percent of the $2.5 trillion spent annually for health care in the United States. (2) Nearly half of American adults have at least one chronic disease. (3) A new federal program, Community Prevention Grants, will award grants of $100,000 or more to tribes, local governments and nonprofits to fight chronic disease. PMID- 24772520 TI - The association of albuminuria with tubular reabsorption of uric acid: results from a general population cohort. AB - BACKGROUND: Elevated albuminuria as well as an increased serum uric acid concentration is associated with poor cardiovascular outcome. We questioned whether these 2 variables (albuminuria and serum uric concentration) may be interrelated via tubular uric acid reabsorption. METHODS AND RESULTS: Included were 7688 participants of the PREVEND Study, an observational, general population based cohort study. Linear regression analyses were used to test associations of baseline albuminuria with baseline serum uric acid concentration and tubular uric acid reabsorption (calculated as [100-fractional uric acid excretion]%). Cox regression analyses were used to study the association of baseline serum uric acid and albuminuria with incident cardiovascular morbidity and mortality. In cross-sectional analyses, albuminuria was associated positively with serum uric acid concentration, both crude and after adjustment for potential confounders (both P<0.001). Albuminuria was found to be associated positively with tubular uric acid reabsorption, again both crude and after adjustment for potential confounders (both P<0.001). In longitudinal analyses during a median follow-up of 10.5 years, 702 cardiovascular events occurred. After adjusting for cardiovascular risk factors, both albuminuria and serum uric acid were associated with incident cardiovascular events (Hazard Ratios 1.09 [1.03 to 1.17], P=0.01 and 1.19 [1.09 to 1.30], P<0.001, respectively). A significant interaction between these variables was present (P<0.001), consistent with high serum uric acid being less predictive for cardiovascular morbidity and mortality in the presence of high albuminuria and vice versa. CONCLUSIONS: Albuminuria is strongly associated with tubular uric acid reabsorption, and consequently with serum uric acid concentration. This phenomenon may explain in part why albuminuria is associated with cardiovascular outcome. PMID- 24772521 TI - The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) observational follow-up study: benefits of RAS blockade with olmesartan treatment are sustained after study discontinuation. AB - BACKGROUND: The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study showed that 40 mg Olmesartan medoxomil (OM) versus placebo delayed microalbuminuria onset in patients with type 2 diabetes and normoalbuminuria. METHODS AND RESULTS: One thousand seven hundred and fifty-eight ROADMAP patients (placebo arm: 877; OM arm: 881) participated in the observational follow up (OFU) with an average of 3.3 years. They received standard medical care and micro- and macrovascular events were documented. During observational follow-up 62.9% and 60.1% in the former OM and placebo group, respectively, received treatment with a RAS blocking agent. During the OFU period the systolic blood pressure (SBP) increased to mean values of 135 mm Hg in both groups. Patients who had developed microalbuminuria during ROADMAP had a higher incidence of cardio- and cerebrovascular events (OR 1.77, CI 1.03 to 3.03, P=0.039) during the OFU period compared with patients in whom this was not the case. Diabetic retinopathy was significantly reduced in the former OM group (8 [0.9%] versus 23 [2.6%], OR: 0.34, CI 0.15 to 0.78, P=0.011) and the rate of microalbuminuria was numerically reduced. Congestive heart failure requiring hospitalization (3 [0.3%] versus 12 [1.4%], OR: 0.23, CI 0.06 to 0.85, P=0.027) was reduced and there was a trend of reduced cardio-/cerebrovascular events (OM versus Pb: 73 [8.3%] versus 86 [9.8%] patients). Seven (0.8%) deaths (including 2 CV events) were reported in former placebo patients versus 3 (0.3%) (non-CV events) in former OM patients. CONCLUSIONS: Development of microalbuminuria is a valid marker for future CV events. RAS blockade with Olmesartan might cause sustained reduction (legacy effect) of micro- and macrovascular events. PMID- 24772522 TI - Nuclear localization of a1A-adrenergic receptors is required for signaling in cardiac myocytes: an "inside-out" a1-AR signaling pathway. AB - BACKGROUND: Recent studies indicate that a1-adrenergic receptors (a1-ARs) are cardioprotective by preventing cardiac myocyte death and augmenting contractility in heart failure. Although G-protein-coupled receptors are assumed to localize to and signal at the plasma membrane, we previously demonstrated that endogenous a1 ARs localize to the nuclei in adult cardiac myocytes. However, the functional consequence of this nuclear localization remains unclear. Here, we attempted to reconcile nuclear localization of a1-ARs with their physiologic function by examining a1-AR-induced contractility in adult cardiac myocytes. METHODS AND RESULTS: By measuring shortening in unloaded, cultured adult cardiac myocytes, we found that the a1A-subtype regulated contractility through phosphorylation of cardiac troponin I (cTnI) at the protein kinase C (PKC) site, threonine 144. Reconstitution of an a1A-subtype nuclear localization mutant in cardiac myocytes lacking a1-ARs failed to rescue nuclear a1A-mediated phosphorylation of cTnI and myocyte contractility. Leptomycin B, the nuclear export inhibitor, also blocked a1A-mediated phosphorylation of cTnI. These data indicate that a1-AR signaling originates in the nucleus. Consistent with these observations, we localized the a1A-subtype to the inner nuclear membrane, identified PKCa, d, and e in the nucleus, and found that a1-ARs activate PKCd in nuclei isolated from adult cardiac myocytes. Finally, we found that a PKCd nuclear localization mutant blunted a1-induced phosphorylation of cTnI. CONCLUSIONS: Together, our data identify a novel, "inside-out" nuclear a1A-subtype/PKCd/cTnI-signaling pathway that regulates contractile function in adult cardiac myocytes. Importantly, these data help resolve the discrepancy between nuclear localization of a1-ARs and a1 AR-mediated physiologic function. PMID- 24772524 TI - Letter to the editor. Reply. PMID- 24772523 TI - Door-to-puncture: a practical metric for capturing and enhancing system processes associated with endovascular stroke care, preliminary results from the rapid reperfusion registry. AB - BACKGROUND: In 2011, the Brain Attack Coalition proposed door-to-treatment times of 2 hours as a benchmark for patients undergoing intra-arterial therapy (IAT). We designed the Rapid Reperfusion Registry to capture the percentage of stroke patients who meet the target and its impact on outcomes. METHODS AND RESULTS: This is a retrospective analysis of anterior circulation patients treated with IAT within 9 hours of symptom onset. Data was collected from December 31, 2011 to December 31, 2012 at 2 centers and from July 1, 2012 to December 31, 2012 at 7 centers. Short "Door-to-Puncture" (D2P) time was hypothesized to be associated with good patient outcomes. A total of 478 patients with a mean age of 68+/-14 years and median National Institutes of Health Stroke Scale (NIHSS) of 18 (IQR 14 to 21) were analyzed. The median times for IAT delivery were 234 minutes (IQR 163 to 304) for "last known normal-to-groin puncture" time (LKN-to-GP) and 112 minutes (IQR 68 to 176) for D2P time. The overall good outcome rate was 39.7% for the entire cohort. In a multivariable model adjusting for age, NIHSS, hypertension, diabetes, reperfusion status, and symptomatic hemorrhage, both short LKN-to-GP (OR 0.996; 95% CI [0.993 to 0.998]; P<0.001) and short D2P times (OR 0.993, 95% CI [0.990 to 0.996]; P<0.001) were associated with good outcomes. Only 52% of all patients in the registry achieved the targeted D2P time of 2 hours. CONCLUSIONS: The time interval of D2P presents a clinically relevant time frame by which system processes can be targeted to streamline the delivery of IAT care nationally. At present, there is much opportunity to enhance outcomes through reducing D2P. PMID- 24772525 TI - [Johana Filipa Neumanna]. AB - Johann Philipp Neumann's work is put into the limelight. He was the very first professor of physics with chemistry, who was not previously a Jesuit. The textbooks for chemistry which Neumann used for his lectures in Ljubljana are discussed. The paragraphs about chemistry of his own textbook published soon after he left Ljubljana for Graz Lyceum are analyzed. The chemical ideas in his paper on measurement of heat and temperature published a decade later are presented. The archival documents of Neumann's work in Ljubljana are published for the first time. PMID- 24772526 TI - Can neutral molecular markers be used to determine the success of an introduction of a "better" strain into an established population of a biocontrol parasitoid? AB - Neutral molecular markers are gene sequences where variants are considered to confer no fitness advantage, such as microsatellites and mitochondrial haplotypes. Several types of neutral marker are easy to develop, cheap to use, and have found extensive application for addressing ecological questions. In biocontrol, these markers are used to simplify identification of cryptic species and of prey remains in predators. Here, we address the potential of neutral molecular markers for determining the relative performance of a "superior" strain of a species after release into an already established conspecific population. We used modeling to show that only under very limited conditions can traditional neutral markers be used to demonstrate that beneficial genetic variation was successfully introgressed into the existing population. However, new population genomic methods do make it possible to track alleles at a large number of loci and consequently make it possible to show if alleles from a superior strain spread in an already established conspecific population. PMID- 24772527 TI - Defining terms for proactive management of resistance to Bt crops and pesticides. AB - Evolution of pest resistance to pesticides is an urgent global problem with resistance recorded in at least 954 species of pests, including 546 arthropods, 218 weeds, and 190 plant pathogens. To facilitate understanding and management of resistance, we provide definitions of 50 key terms related to resistance. We confirm the broad, long-standing definition of resistance, which is a genetically based decrease in susceptibility to a pesticide, and the definition of "field evolved resistance," which is a genetically based decrease in susceptibility to a pesticide in a population caused by exposure to the pesticide in the field. The impact of field-evolved resistance on pest control can vary from none to severe. We define "practical resistance" as field-evolved resistance that reduces pesticide efficacy and has practical consequences for pest control. Recognizing that resistance is not "all or none" and that intermediate levels of resistance can have a continuum of effects on pest control, we describe five categories of field-evolved resistance and use them to classify 13 cases of field-evolved resistance to five Bacillus thuringiensis (Bt) toxins in transgenic corn and cotton based on monitoring data from five continents for nine major pest species. We urge researchers to publish and analyze their resistance monitoring data in conjunction with data on management practices to accelerate progress in determining which actions will be most useful in response to specific data on the magnitude, distribution, and impact of resistance. PMID- 24772528 TI - Autumn invasion rates of Varroa destructor (Mesostigmata: Varroidae) into honey bee (Hymenoptera: Apidae) colonies and the resulting increase in mite populations. AB - The honey bee parasite Varroa destructor Anderson & Trueman can disperse and invade honey bee colonies by attaching to "drifting" and "robbing" honey bees that move into nonnatal colonies. We quantified the weekly invasion rates and the subsequent mite population growth from the end of July to November 2011 in 28 honey bee colonies kept in two apiaries that had high (HBD) and low (LBD) densities of neighboring colonies. At each apiary, half (seven) of the colonies were continuously treated with acaricides to kill all Varroa mites and thereby determine the invasion rates. The other group of colonies was only treated before the beginning of the experiment and then left untreated to record Varroa population growth until a final treatment in November. The numbers of bees and brood cells of all colonies were estimated according to the Liebefeld evaluation method. The invasion rates varied among individual colonies but revealed highly significant differences between the study sites. The average invasion rate per colony over the entire 3.5-mo period ranged from 266 to 1,171 mites at the HBD site compared with only 72 to 248 mites at the LBD apiary. In the untreated colonies, the Varroa population reached an average final infestation in November of 2,082 mites per colony (HBD) and 340 mites per colony (LBD). All colonies survived the winter; however, the higher infested colonies lost about three times more bees compared with the lower infested colonies. Therefore, mite invasion and late-year population growth must be considered more carefully for future treatment concepts in temperate regions. PMID- 24772529 TI - An evaluation of the associations of parameters related to the fall of Varroa destructor (Acari: Varroidae) from commercial honey bee (Hymenoptera: Apidae) colonies as tools for selective breeding for mite resistance. AB - Varroa destructor (Anderson and Trueman) trapped on bottom boards were assessed as indirect measurements of colony mite population differences and potential indicators of mite resistance in commercial colonies of Russian and Italian honey bees (Apis mellifera L.) by using 35 candidate measurements. Measurements included numbers of damaged and nondamaged younger mites, nymphs, damaged and nondamaged older mites, fresh mites, and all mites, each as a proportion of total mites in the colonies and as a proportion of all trapped mites or all trapped fresh mites. Several measurements differed strongly between the stocks, suggesting that the detailed characteristics of trapped mites may reflect the operation of resistance mechanisms in the Russian honey bees. Regression analyses were used to determine the relationships of these candidate measurements with the number of mites in the colonies. The largest positive regressions differed for the two stocks (Italian honey bees: trapped mites and trapped younger mites; Russian honey bees: trapped younger mites and trapped fresh mites). Also, the regressions for Italian honey bees were substantially stronger. The largest negative regressions with colony mites for both stocks were for the proportion of older mites out of all trapped mites. Although these regressions were statistically significant and consistent with those previously reported, they were weaker than those previously reported. The numbers of mites in the colonies were low, especially in the Russian honey bee colonies, which may have negatively influenced the precision of the regressions. PMID- 24772530 TI - Functionality of Varroa-resistant honey bees (Hymenoptera: Apidae) when used for western U.S. honey production and almond pollination. AB - Two types of honey bees, Apis mellifera L., bred for resistance to Varroa destructor Anderson & Trueman, were evaluated for performance when used for honey production in Montana, and for almond pollination the following winter. Colonies of Russian honey bees and outcrossed honey bees with Varroa-sensitive hygiene (VSH) were compared with control colonies of Italian honey bees. All colonies were managed without miticide treatments. In total, 185 and 175 colonies were established for trials in 2010-2011 and 2011-2012, respectively. Survival of colonies with original queens or with supersedure queens was similar among stocks for both years. Colony sizes of the Varroa-resistant stocks were as large as or larger than the control colonies during periods critical to honey production and almond pollination. Honey production varied among stocks. In the first year, all stocks produced similar amounts of honey. In the second year, Russian honey bees colonies produced less honey than the control colonies. V. destructor infestations also varied among stocks. In the first year, control colonies had more infesting mites than either of the Varroa-resistant stocks, especially later in the year. In the second year, the control and outcrossed Varroa-sensitive hygiene colonies had high and damaging levels of infestation while the Russian honey bees colonies maintained lower levels of infestation. Infestations of Acarapis woodi (Rennie) were generally infrequent and low. All the stocks had similarly high Nosema ceranae infections in the spring and following winter of both years. Overall, the two Varroa-resistant stocks functioned adequately in this model beekeeping system. PMID- 24772531 TI - Pupal development of Aethina tumida (Coleoptera: Nitidulidae) in thermo hygrometric soil conditions encountered in temperate climates. AB - The pupal development of Aethina tumida Murray (Coleoptera: Nitidulidae) was studied at various combinations of thermo-hygrometric soil conditions (temperatures of 16, 18, and 20 degrees C and soil water content levels of 0.37, 0.56, and 0.73 m3 water per cubic meter of dry soil) representative of southeastern Canada. Survivorship and development duration of A. tumida pupae, as well as sex ratio and life span of emerging adults, were assessed. Assays were conducted in growth chambers on an average of 50 third-instar larvae per thermo hygrometric combination. Results show that survivorship of pupae decreased with lower temperature and higher soil water content. Pupal development time shortened as temperature increased (69-78 d at 16 degrees C, 47-54 d at 18 degrees C, and 36-39 d at 20 degrees C), but was longer in dryer soil. Optimal soil water content for pupal development was 0.56 m3 water per cubic meter of soil. We estimated that the minimum development temperature for pupae is between 10.2 and 13.2 degrees C, depending on soil water content. The sex ratio of emerging adults was influenced by soil water content. We measured one female to one male for dry and intermediately wet soils and three females to one male for wet soils. Higher soil water content reduced the life span of emerging adults by half. This study contributes to a better understanding of A. tumida population dynamics in eastern Canada. PMID- 24772532 TI - Stylet penetration behaviors of Myzus persicae (Hemiptera: Aphididae) on four Ipomoea spp. infected or noninfected with sweet potato potyviruses. AB - Myzus persicae (Sulzer) is an efficient vector of potyviruses in sweet potato, Ipomoea batatas (L.). These potyviruses also infect members of the morning glory family Ipomoea cordatotriloba Dennstedt and Ipomoea hederacea Jacqin commonly found within or around sweet potato fields. Infection of sweet potato with potyviruses increases the intrinsic rate of increase of M. persicae. Thus, from the epidemiological stand point, virus infection can modify vector population dynamics, and therefore increase virus spread. To better understand this, stylet penetration behaviors of M. persicae on virus infected and noninfected sweet potato cvs. 'Beauregard' and 'Evangeline', as well as morning glory plants I. cordatotriloba and I. hederacea were monitored. Stylet penetration behaviors associated with nonpersistent virus transmission such as time to first intracellular puncture (potential drop), number of potential drops, duration of potential drop, duration of potential drop subphase II-3, and number of potential drops with subphase II-3 pulses were significantly increased on virus-infected compared with noninfected Beauregard, but greatly reduced on virus-infected compared with noninfected I. hederacea plants. Stylet penetration behaviors associated with host acceptance such as reduced nonprobing duration and nonprobing events were greater on virus-infected compared with noninfected Beauregard plants. In contrast, on Evangeline, I. cordatotriloba and I. hederacea stylet penetration behaviors by M. persicae indicate it had less preference for virus-infected compared with noninfected plants. PMID- 24772533 TI - Use of honeydew production to determine reduction in feeding by Bemisia tabaci (Hemiptera: Aleyrodidae) adults when exposed to cyantraniliprole and imidacloprid treatments. AB - Bemisia tabaci (Gennadius) whitefly populations produce economically important damage to crops by their direct feeding and also by transmitting plant viruses. Although there are several methods to reduce B. tabaci damage, most growers rely on the use of insecticides to decrease populations of this pest. Insecticides that reduce feeding of whitefly adults may also reduce the transmission of viruses that are harmful to crop plants. However, demonstrating the feeding reduction has proved challenging. In this study, water-sensitive paper was used to determine whitefly adult feeding, indirectly through honeydew production, when insects were placed on insecticide-treated and untreated plants. Plant treatments with two formulations of cyantraniliprole (Cyazypyr) showed a reduction in the amount of honeydew produced by B. tabaci adults equivalent to imidacloprid. The reduction in the amount of honeydew produced indicates reduced insect feeding and the possibility for a reduction in virus transmission. Plant treatments with two formulations of cyantraniliprole also resulted in higher mortality than imidacloprid. PMID- 24772534 TI - Biological activity of Bacillus thuringiensis (Bacillales: Bacillaceae) chitinase against Caenorhabditis elegans (Rhabditida: Rhabditidae). AB - In addition to being used increasingly as a model system in modern molecular biology studies, the free-living nematode Caenorhabditis elegans (Maupas, 1900) is an important pathogen in fungi and straw mushrooms. In this study, Bacillus thuringiensis strain 010 was found to have significantly detrimental activity against C. elegans. To further characterize this activity, the toxicological mechanism was elucidated at molecular level. Genes encoding for crystal protein and chitinase were isolated, cloned, and sequenced. However, the toxicity was detected only in the chitinase. Under transmission electron microscopy, change in the body wall and gut structures of C. elegans was observed, and thus degeneration of body wall and gut in the worms was also investigated. Further bioassay also confirmed the mortality of C. elegans fed with Escherichia coli TB1 strain. These observations suggest great potential for B. thuringiensis 010 as a biocontrol agent against C. elegans and other nematodes. PMID- 24772535 TI - Priming Galleria mellonella (Lepidoptera: Pyralidae) larvae with heat-killed bacterial cells induced an enhanced immune protection against Photorhabdus luminescens TT01 and the role of innate immunity in the process. AB - The current study investigated the characteristics and mechanism of the invertebrate immune priming using Galleria mellonella (L.) (Lepidoptera: Pyralidae) larvae (host) and Photorhabdus luminescens TT01 (pathogen) as a model. The following parameters of the G. mellonella larvae primed by hemocoel injection of heat-killed cells of TT01 or Bacillus thuringiensis HD-1 were determined at designated times after priming and then compared and analyzed systematically: mortality of the primed larvae against TT01 infection (immune protection level), hemocyte density, phagocytosis and encapsulation abilities ofhemocyte, and antibacterial activity of cell free hemolymph (major innate parameters). The results showed that 1) immune priming increased survival of the larvae against a lethal infection of TT01 and the levels and periods of protection correlated positively to the priming dose; 2) the changes on the levels of protection and the major innate parameters of the larvae primed with either TT01 or HD-1 followed a similar pattern of the convex curve, although the levels and the timing of changes differed significantly among the four innate immune parameters and between two priming bacteria; and 3) the immune protection level at a time after priming was correlated to the overall level of four innate immune parameters of the primed larvae. The current study demonstrated that the immune priming phenomenon of G. mellonella larvae has low level of specificity, and it was achieved mainly by the regulation on the quantity and activity of major innate immune parameters, such as hemocytes, antimicrobial peptides, and enzymes. PMID- 24772536 TI - Development of biological control of Tetranychus urticae (Acari: Tetranychidae) and Phorodon humuli (Hemiptera: Aphididae) in Oregon hop yards. AB - The temporal development of biological control of arthropod pests in perennial cropping systems is largely unreported. In this study, the development of biological control of twospotted spider mite, Tetranychus urticae Koch, and hop aphid, Phorodon humuli (Schrank), in a new planting of hop in Oregon is described over a period of 9 yr (2005-2013). Both the abundance and diversity of natural enemies increased over time. Known predators of hop aphid (Coccinellidae and Anthocoridae) were present in all years; however, stable biological control of hop aphid was not achieved in most years and aphicides were required to suppress populations at commercially acceptable levels in 5 of 9 yr. Populations of aphidophagous coccinellids developed synchronously with hop aphid populations, and temporal correlations indicated these are the primary predatory insect associated with hop aphid regulation. However, sampling methods did not assess levels of aphid parasitoids and hyperparasitoids and their contribution to biological control was unquantified. Spider mite biological control was associated primarily with predatory mites (Phytoseiidae) and Stethorus spp. (Coccinellidae). The magnitude of temporal correlations of abundance of these predators with spider mites was found to be greatest on the same sampling dates and at lags of 7-14 d. Stable biological control of spider mites occurred after four field seasons, suppressing spider mites to levels similar to those commonly achieved with chemical control. A survey of 11 commercial hop yards in Oregon documented pest and natural enemy densities under commercial management practices over a period of 4 yr (2008-2011). Natural enemy abundance in commercial hop yards was similar to that of a 2- to 3-yr-old hop yard with limited disturbance. Whereas total reliance on biological control for hop aphid is unlikely to be successful, there appears to be unrealized potential for biological control of spider mites in commercial production. Dynamic action thresholds that consider the value of natural enemies are needed for both pests. PMID- 24772537 TI - Effect of fermentation media on the production, efficacy, and storage stability of Metarhizium brunneum microsclerotia formulated as a prototype granule. AB - New liquid fermentation techniques for the production of the bioinsecticidal fungus Metarhizium brunneum strain F-52 have resulted in the formation of microsclerotia (MS), a compact, melonized-hyphal structure capable of surviving desiccation and formulation as dry granules. When rehydrated, these MS granules germinate to produce conidia that can infect susceptible insects. Fermentation media containing cottonseed or soy flours as nitrogen sources and formulated at two carbon to nitrogen ratios (C:N), 30:1 or 50:1, were evaluated forproduction of microsclerotia. Dry MS granule samples were compared for storage stability based on conidia production, and insecticidal activity against larvae of the lesser mealworm, Alphitobius diaperinus (Panzer), using a potting soil bioassay. Cottonseed and soy flours were equivalent for production, MS granule viability, and insecticidal activity. Fermentation media containing higher nitrogen concentrations (30:1 C:N) resulted in greater biomass accumulation and greater production of conidia from granules regardless of the nitrogen source. MS granules made with M. brunneum cultures grown in media with 30:1 C:N produced 8.5 x 10(9) conidia per gram of granules after 8-d incubation, significantly higher than MS granules made using fungus produced using 50:1 C:N media (5.5 x 10(9) conidia per gram dry MS granules). The LC50 for larval mortality was 8.05 x 10(5) conidia per cup, equivalent to applications of 94 or 147 microg granules per cup for granules made from high and low nitrogen media, respectively. Measurements of water activity were not significantly different among granule samples (0.28-0.29) even though granules made from high nitrogen media had higher moisture content (> 5.2%) compared with granules made from low nitrogen media (< 4.6%). Higher initial conidial production was reflected in longer storage stability at 25 degrees C, with half-lives estimated at 3.7 and 1.7 wk for 30:1 and 50:1 C:N ratios, respectively. These results support further evaluation of MS granule formulations for the control of soil-inhabiting insect pests. PMID- 24772538 TI - Comparison of torula yeast and various grape juice products as attractants for Mexican fruit fly (Diptera: Tephritidae). AB - Early research investigating attractants for the Mexican fruit fly, Anastrepha ludens Loew, during the 1930s indicated that fermentation products were effective attractants for Mexican fruit flies and other tropical Tephritidae, but that attraction to fruit components was only of academic interest. Tests reported here were carried out on populations of Mexican fruit flies from 2004 to 2011. Trapping experiments carried out at sites in the states Nuevo Leon and San Luis Potosi compared grape juice, reconstituted grape concentrate and powdered grape mixes, and torula yeast extract in orchards at each site. The Nuevo Leon orchard was mixed with alternate rows of pears and surrounded by alternate hosts. The San Luis Potosi site was surrounded by other orange orchards or nonhosts. Each test was run for at least 10 mo and included highest and lowest trapping periods. Results showed that grape juice captured the most total flies and had the fewest samples with zero flies. However, in the series of experiments, each product had the most captures in at least one experiment. Hydrolyzed torula was superior in one of the six experiments. In five of the tests, polyethylene glycol was tested as an additive to the grape products but never improved capture rate compared with the product without the additive. These results indicate that grape juice is superior to grape concentrate or powder and grape juice is at least equal to torula yeast hydrolysate for trapping pest populations of Mexican fruit flies in commercial citrus orchards. PMID- 24772539 TI - Toxicity of phosphine fumigation against Bactrocera tau at low temperature. AB - Bactrocera tau (Walker) is one of the most harmful pests to fruits and vegetables. To counteract this pest, the development of phytosanitary treatment is required to comply with the pest regulation requirements of certain countries. This study investigated the toxicity of phosphine fumigation against B. tau under low temperature conditions. Different growth stages (eggs and instars) of B. tau were exposed to 1.07 mg/liter phosphine for 1-10 d at 5 degrees C, and compared with unfumigated flies at 5 degrees C. The results showed that tolerance to cold treatment alone or phosphine fumigation at low temperatures generally increased with the stage of insect development. However, eggs incubated for 12 h at 25 degrees C represented the most tolerant growth stage to phosphine fumigation at 5 degrees C. Furthermore, 8.56- to 2.18-d exposure periods were required to achieve 99% mortality with a range of phosphine concentrations from 0.46 to 3.81 mg/liter. C0.62 t = k expression was obtained from the LT99 values, indicating that the exposure time was more important than the phosphine concentration. PMID- 24772540 TI - Precooling treatments induce resistance of Anastrepha ludens eggs to quarantine treatments of high-pressure processing combined with cold. AB - High-pressure processing (HPP) combined with heat or cold has been proposed as an alternative quarantine process for Mexican fruit fly Anastrepha ludens Loew (Diptera: Tephritidae). HPP conditions at levels higher than 100 MPa applied to destroy eggs and larvae can also affect the postharvest physiology of the fruits. HPP at pressure levels in the range of 50-100 MPa is recommended. Eggs have been reported as being more resistant to HPP than larvae. Therefore, the objective of this study was to assess the effect of a precooling treatment on the biological viability of A. ludens eggs treated by HPP at 0 degrees C. The capability of nondestroyed eggs to develop and reproduce was also evaluated. One-, 2-, 3-, and 4-d-old eggs were precooled in ice water for 0 (control) 3, 6, 12, or 24 h and then pressurized at 50, 70, or 90 MPa for 0, 3, 6, or 9 min at 0 degrees C. The hatching capability of pressurized eggs was evaluated. The most lethal effect of HPP on nonprecooled eggs (0 h) was obtained at 90 MPa for 9 min, destroying all eggs except for the 3-d-old ones, which showed an 11.8% hatch rate. Precooling treatment improved the hatch rate of eggs ranging from 4 to 50% depending on precooling conditions. The main effect was observed after 6 h. These results suggest that precooling modified the biochemistry and physiology of eggs, improving their resistance to HPP treatments. PMID- 24772541 TI - Life parameters of Tetranychus urticae (Acari: Tetranychidae) on six common bean cultivars. AB - It is well recognized that the quality of host plants affects the development and survival of twospotted spider mite Tetranychus urticae Koch. The life table parameters of T. urticae, on six cultivars of common bean (Phaseolus vulgaris L.) (chiti Khomein, chiti Ks21189, red Akhtar, red Ks31169, white Pak, and white G11867) were studied at constant laboratory conditions (27 +/- 2 degrees C, 70 +/ 5% RH and 16:8 L:D). Total development times of immature males and females were significantly influenced by bean cultivar. T. urticae laid significantly more eggs per day on red Akhtar (16.16) than on the other cultivars. The mean generation time ranged from 23.37 to 34.82 d, and a significant varietal effect was seen. Percentage of egg hatchability oftwospotted spider mite ranged from 88.25 to 94.20%. The highest intrinsic rate of increase, was recorded on red Akhtar (0.269 +/- 0.031) and the lowest value was obtained on white Pak (0.129 +/ 0.048). In addition, net reproductive rate and finite rate of increase of the twospotted spider mite had the highest value on red Akhtar: 62.38 +/- 1.05 and 1.30 +/- 1.02, respectively. The lowest values of these parameters were recorded on white Pak as 26.11 +/- 1.40 and 1.13 +/- 1.10, respectively. Doubling time varied significantly on different cultivars and the lowest and highest values were obtained on red Akhtar and white Pak, respectively. Our findings revealed that white beans (Pak and G11867) were less suitable cultivars, suggesting that they are more resistant to the twospotted spider mite than the other cultivars. PMID- 24772542 TI - Mating compatibility between Bactrocera invadens and Bactrocera dorsalis (Diptera: Tephritidae). AB - The invasive fruit fly, Bactrocera invadens Drew, Tsuruta & White, is a highly polyphagous fruit pest that occurs predominantly in Africa yet has its origins in the Indian subcontinent. It is extremely morphologically and genetically similar to the Oriental fruit fly, Bactrocera dorsalis (Hendel); as such the specific relationship between these two species is unresolved. We assessed prezygotic compatibility between B. dorsalis and B. invadens using standardized field cage mating tests, which have proven effectiveness in tephritid cryptic species studies. These tests were followed by an assessment of postzygotic compatibility by examining egg viability, larval and pupal survival, and sex ratios of offspring produced from parental and subsequent F1 crosses to examine for hybrid breakdown as predicted under a two-species hypothesis. B. dorsalis was sourced from two countries (Pakistan and China), and each population was compared with B. invadens from its type locality of Kenya. B. invadens mated randomly with B. dorsalis from both localities, and there were generally high levels of hybrid viability and survival resulting from parental and F1 crosses. Furthermore, all but one hybrid cross resulted in equal sex ratios, with the single deviation in favor of males and contrary to expectations under Haldane's rule. These data support the hypothesis that B. dorsalis and B. invadens represent the same biological species, an outcome that poses significant implications for pest management and international trade for sub-Saharan Africa. PMID- 24772543 TI - Responses of cereal aphids and their parasitic wasps to landscape complexity. AB - The intensification of agriculture has caused a decline in the complexity of agricultural landscapes because of the expansion of arable lands and the removal of natural habitats. These landscape changes, which have substantial effects on natural enemies (e.g., parasitoids) and on biological control services, have received considerable attention recently. In the current study, we analyzed the effects of landscape complexity on cereal aphids and their parasitic wasps in 24 sites during a period of 3 yr. In total, 11 primary parasitoid species and 6 hyperparasitoid species, comprising 5,220 individuals, were collected in our experiments. With the exception of two primary parasitic wasps (Trioxys asiaticus Telenga and Toxares sp.) and one hyperparasitic wasp (Dendrocerus carpenteri [Curtis]), most species were sensitive to landscape complexity after > or = 1 yr. Species diversity, primary parasitism, and hyperparasitism increased with increasing landscape complexity. However, the relationship between the population density of active primary parasitoids (effective primary parasitoids) and landscape complexity was indicated by a quadratic function, not a linear function. The effective population density of primary parasitoids was maximal (2.04 individuals per 100 wheat stems) if the percentage of noncrop habitat was 38%. The hypothesis that landscape complexity may enhance the activity or higher diversity of primary parasitoids and hyperparasitoids was well-supported by our study. However, the hyperparasitoids had a more sensitive response to landscape complexity than the primary parasitoids. Further studies should aim to enhance the biological pest control of primary parasitoids and suppress hyperparasitoids by habitat manipulation. This technique could be used effectively for pest management in mosaic landscapes through habitat rearrangement and reorganization. PMID- 24772544 TI - Lethal and sublethal effects of azadirachtin and cypermethrin on Habrobracon hebetor (Hymenoptera: Braconidae). AB - Habrobracon hebetor Say is an ectoparasitoid of larval stage of various lepidopteran pests. Lethal and sublethal effects of azadirachtin and cypermethrin were evaluated on adult and preimaginal stages of H. hebetor under laboratory conditions. Contact exposure bioassays with adults indicated that the lethal concentration (LC50) of two commercial azadirachtin-containing formulations, NeemGuard and BioNeem, were 43.5 and 10.2 microg a.i./ml, respectively. The LC50 of cypermethrin was 5.4 microg a.i./ml. When larval stage of H. hebetor was exposed to these insecticides with a field recommended concentration of NeemGuard, BioNeem, or cypermethrin by a dip protocol, the emergence rate was reduced by 39.0, 36.6, and 97.6%, respectively. To assay the sublethal effects of these insecticides, adult wasps were exposed to an LC30 concentration of the insecticides, and then demographic parameters of the surviving wasps were determined. Fecundity, fertility, and parameters including the intrinsic rate of increase (r(m)) were affected negatively. The r(m) values following exposure to NeemGuard, BioNeem, cypermethrin, or mock treatment were 0.143, 0.149, 0.160, and 0.179, respectively, female offspring per female per day, respectively. The current study showed that cypermethrin had more acute toxicity on larval and adult stages of H. hebetor compared with azadirachin. The commercial formulations of azadirachtin and cypermethrin negatively affected most of the life table parameters of the parasitoid. Semifield and field studies are needed for obtaining more applicable results on combining H. hebetor and the tested insecticides for an integrated pest management-based strategy for crop protection. PMID- 24772545 TI - Influence of planting date on stink bug injury, yield, fiber quality, and economic returns in Georgia cotton. AB - Phytophagous stink bugs are economically important pests of annual and perennial crops in the southeastern United States. Because of insecticide resistance and risk of secondary pest outbreaks, there is interest in identifying cultural practices that could lead to reduced insecticide applications. The objective of this project was to assess the importance of cotton planting date on stink bug damage to cotton. Unsprayed cotton plots with biweekly planting dates were established at three locations in southern Georgia in each of two crop years. During the bloom cycle, stink bug-induced boll injury was estimated weekly in each plot. Plots were subsequently defoliated, mechanically harvested, and ginned to assess differences in fiber yield and quality attributable to stink bug injury. Results show that the rate of boll damage generally increased more rapidly through the bloom cycle for planting dates in June compared with May. Similarly, estimates of boll damage from June-planted cotton more frequently exceeded the stink bug treatment threshold compared with May-planted cotton. In 2011, mean lint yield and economic returns from May planting dates were significantly greater than June planting dates. In 2012, lint yield and economic returns were greater in plots established in early May compared with later planting dates. Estimates of HVI color + b, a measure of fiber yellowness, were lower in early May-planted cotton compared with June planting. These data show that growers need to be aware of increased stink bug damage potential when planting late. PMID- 24772546 TI - Attraction of the orange mint moth and false celery leaftier moth (Lepidoptera: Crambidae) to floral chemical lures. AB - Orange mint moths, Pyrausta orphisalis (Walker) (Crambidae), were initially trapped in a study of noctuid moth attraction to floral volatiles. A subsequent series of trapping experiments in commercial mint fields determined that phenylacetaldehyde and 4-oxoisophorone were attractive to P. orphisalis, whereas benzyl acetate, eugenol, cis-jasmone, limonene, linalool, methyl-2 methoxybenzoate, methyl salicylate, beta-myrcene, and 2-phenylethanol were not. When used in combination with phenylacetaldehyde, 4-oxoisophorone and methyl-2 methoxybenzoate increased catches of P. orphisalis in traps by -50%, and beta myrcene tripled the trap catch. A second crambid species, the false celery leaftier moth, Udea profundalis Packard, was also attracted to phenylacetaldehyde, but was not attracted to any other single-chemical lure. Cis jasmone, limonene, and 4-oxoisophorone increased catches of U. profundalis by 50% when presented in traps with phenylacetaldehyde, while linalool increased the catch 2.5-fold, and beta-myrcene tripled the trap catch. Both sexes of each species were similarly attracted to most of these lures. These findings provide chemical lures for trapping males and females of both P. orphisalis and U. profundalis. PMID- 24772547 TI - Sustainable management tactics for control of Phyllotreta cruciferae (Coleoptera: Chrysomelidae) on canola in Montana. AB - The crucifer flea beetle, Phyllotreta cruciferae (Goeze) (Coleoptera: Chrysomelidae), has recently emerged as a serious pest of canola (Brassica napus L.) in Montana. The adult beetles feed on canola leaves, causing many small holes that stunt growth and reduce yield. In 2013, damage to canola seedlings was high (approximately 80%) in many parts of Montana, evidence that when flea beetles emerge in large numbers, they can quickly destroy a young canola crop. In the current study, the effectiveness of several biopesticides was evaluated and compared with two insecticides (deltamethrin and bifenthrin) commonly used as foliar sprays as well as seed treatment with an imidacloprid insecticide for the control of P. cruciferae under field conditions in 2013. The biopesticides used included an entomopathogenic nematode (Steinernema carpocapsae), two entomopathogenic fungi (Beauveria bassiana and Metarhizium brunneum), neem, and petroleum spray oils. The control agents were delivered in combination or alone in a single or repeated applications at different times. The plant-derived compound neem (azadirachtin), petroleum spray oil, and fatty acids (M-Pede) only showed moderate effect, although they significantly reduced leaf injuries caused by P. cruciferae and resulted in higher canola yield than the untreated control. Combined use of B. bassiana and M. brunneum in two repeated applications and bifenthrin in five applications were most effective in reducing feeding injuries and improving yield levels at both trial locations. This indicates that entomopathogenic fungi are effective against P. cruciferae, and may serve as alternatives to conventional insecticides or seed treatments in managing this pest. PMID- 24772548 TI - A comparison of electrophysiologically determined spectral responses in six subspecies of Lymantria. AB - The spectral sensitivity of the compound eye in three gypsy moth species from six different geographical regions (Lymantria dispar asiatica Vnukovskij [Asian gypsy moth], Lymantria dispar japonica Motschulsky [Japanese gypsy moth], and Lymantria dispar dispar L. [North American gypsy moth]) was tested electrophysiologically in the wavelength region 300-700 nm. For all moths examined, a maximum response occurred in the 480-520-nm range (blue-green region) with a shoulder peak occurring at 460 nm. A smaller, secondary peak was observed for both sexes at the 340-380-nm range, which is in the region considered behaviorally maximal in night flying insects. No peaks in sensitivity were observed between 520 and 700 nm (red region) for any of the moths tested. Based on our retinal recording data, a short wavelength blocking filter with a transition wavelength near 500 nm should reduce gypsy moth attraction to artificial lighting sources. This would help reduce the number of Lymantria-infested ships traveling to and from foreign ports. PMID- 24772549 TI - Coptoborus ochromactonus, n. sp. (Coleoptera: Curculionidae: Scolytinae), an emerging pest of cultivated balsa (Malvales: Malvaceae) in Ecuador. AB - A new species of xyleborine ambrosia beetle has been found to attack balsa, Ochroma pyramidale (Cavanilles ex Lamarck) Urban, in Ecuador. Coptoborus ochromactonus Smith & Cognato is described and its biology is reported. Large scale surveys were conducted between 2006 and 2009, and observational studies were carried out between 2010 and 2013 in Ecuadorian commercial plantations to determine life history and host preference characteristics. C. ochromactonus attacked balsa between 1.5 and 3 yr in age. Successful attacks were more prevalent in smaller diameter trees and unhealthy trees. In general, attacks and beetle-caused mortality were more prevalent during the dry summer months when trees were under more moisture and light stress. Fungal mycelia were consistently observed coating beetle galleries and are likely the true damaging agent to balsa trees. PMID- 24772550 TI - Repellent effect of alphacypermethrin-treated netting against Bemisia tabaci (Hemiptera: Aleyrodidae). AB - For > 20 yr, Bemisia tabaci Gennadius persists as a begomovirus vector and is a serious problem in tomato production in many parts of the world. In tropical countries, the use of netting to protect horticultural crops has proven to be an effective and sustainable tool against Lepidoptera but not against small insects. This study evaluated the repellent effect of AgroNet 0.9T, a 0.9-mm pore diameter and 40-mesh size netting treated with alphacypermethrin insecticide against B. tabaci. This pyrethroid insecticide is known to have toxic and repellent effects against mosquitoes and has been used for treatment of mosquito nets. Two nontreated netting materials were used as control: AgroNet 0.9NT with 0.9-mm pore diameter and 40-mesh size and AgroNet 0.4NT with 0.4-mm pore diameter and 80-mesh size. The behavior of B. tabaci and its parasitoid Encarsia formosa Gahan as they progressed through the treated netting was studied in the laboratory in choice and no-choice tests. The development of wild B. tabaci population on tomato plants protected by the same nets was followed in two field trials implemented in Njoro, Kenya. Results obtained with the no-choice tests showed a significant reduction of movement on the treated net with 40-mesh (19%) compared with nontreated netting (35 and 46% with 80- and 40-mesh, respectively). The mortality of B. tabaci was significantly higher (two-fold) in the test tube containing only the treated netting compared with the nontreated one. The repellent effect of the treated netting was also demonstrated against E. formosa, but it did not have this toxic effect. Unlike for B. tabaci, the treated and nontreated nets appeared to have a similar repellent effect on E. formosa in the choice test, which suggests a learning behavior of the parasitoid. In both field tests, B. tabaci population was significantly lower on tomato protected by the treated net compared with the same nontreated net. However there was no significant difference in B. tabaci population between the treated 0.9-pore diameter and the nontreated 0.4-pore diameter. We discussed these findings and their implications for the use of repellent netting in integrated pest management in horticulture and more specifically in vegetable production. PMID- 24772551 TI - Biology of the Huanglongbing vector Diaphorina citri (Hemiptera: Liviidae) on different host plants. AB - Although many studies have been conducted on the development and reproductive potential of Diaphorina citri Kuwayama, 1908 (Hemiptera: Liviidae) in different host species, few have evaluated these parameters on different varieties of the same host species. This study evaluated the influence of five commercial varieties of citrus (Citrus spp. L.)--Hamlin, Natal, Pera, Ponkan, and Valencia and orange jasmine [Murraya exotica (L.) Jack] on the development of D. citri. Survival rates for the egg stage were highest on orange jasmine (85.7%) and on Valencia (83.3%). The lowest viability of the nymphal stage was also observed on Hamlin, averaging 57.4%. Values for total viability ranged from 65.9 to 32.6%, and were highest on Valencia. The longest egg-adult development time was on Natal, with a mean of 18.4 d; the shortest total development time was on orange jasmine, with a mean of 17.3 d. Based on the fertility life table, the net reproductive rate (Ro) of D. citri was 2.5 times higher when reared on Valencia than on Hamlin. The other parameters (duration of each generation [T], finite rate of increase [lambda], and innate capacity to increase in number [r(m)]) also demonstrated that Valencia is best suited to this insect. The results obtained for the biological parameters and the fertility life table indicate that Valencia and orange jasmine were the most suitable hosts, whereas Hamlin was least suitable for the development of D. citri. These results provide information for the installation of new citrus groves, especially in the choice of varieties to be planted and the location of different varieties within the groves, with a view toward the management of Huanglongbing or HLB. PMID- 24772552 TI - Within-plant distribution of Aulacorthum solani (Hemiptera: Aphididae), on various greenhouse plants with implications for control. AB - Foxglove aphid, Aulacorthum solani (Kaltenbach) (Hemiptera: Aphididae), has recently undergone a status change from an occasional pest to a serious pest in greenhouses of North America and the United Kingdom. Little nonanecdotal information exists on the ecology of this insect in greenhouse crops. To help improve integrated pest management decisions for A. solani, the within-plant distribution of this pest was explored on a variety of common greenhouse plants in both the vegetative and flowering stage. This aphid generally was found on lower leaves of vegetative plants, but was found higher in the canopy on reproductive plants (on flowers, flower buds, or upper leaves). Aphid numbers were not consistently positively correlated with total leaf surface areas within plant strata across plant species. Thus, the observed differences in preferred feeding sites on vegetative versus flowering plants are possibly a response to differences in nutritional quality of the various host-plant tissues. Despite being anecdotally described as a "stem-feeding aphid," A. solani was rarely found feeding on stems at the population densities established in our tests, with the exception of racemes of scarlet sage (Salvia splendans). Although some previous reports suggested that A. solani prefers to feed on new growth of plants, our results indicate that mature leaves are preferred over growing tips and young leaves. The implications of the within-plant feeding preferences of A. solani populations with respect to both biological and chemical control are discussed. PMID- 24772553 TI - Effects of pesticide application on arthropod pests of nursery-grown maples. AB - Insecticides used against potato leafhopper, Empoasca fabae (Harris) (Homoptera: Cicadellidae), have been reported to cause problems with maple spider mite, Oligonychus aceris (Shimer) (Acarina: Tetranychidae), on nursery-grown 'Red Sunset' red maple and 'Autumn Blaze' Freeman maple. To test this, we conducted two experiments on field-grown trees in nurseries. In the first, the effects of early-season pesticide applications were examined during 2009. The second experiment was conducted in 2010 to compare effects of using threshold levels of one, three, or six leafhoppers per branch to time applications. Pesticide applications reduced abundance and damage by leafhoppers in both cultivars, but increased populations of O. aceris on Autumn Blaze during 2009. In contrast, on Red Sunset, populations of O. aceris did not increase after insecticide applications. In 2010, insecticide applications did not increase abundance of O. aceris on Autumn Blaze because use of treatment thresholds to manage leafhoppers greatly reduced numbers of trees requiring treatment for leafhoppers. Two phytoseiid mites, Neoseiulus fallacis (Garman) and Typhlodromus caudiglans (Schuster), and one stigmaeid, Zetzellia mali (Ewing), were identified as the principal predators of O. aceris on maple leaves. Insecticide applications had no significant effects on the total abundance of predatory mites on either Red Sunset or Autumn Blaze maples in 2009 or 2010. However, populations of predator Z. mali were higher during both years on Red Sunset than on Autumn Blaze. These results suggest that both early-season pesticide use and cultivar can affect the likelihood of secondary outbreaks of spider mites on maples. PMID- 24772554 TI - Intentional coverage gaps reduce cost of mating disruption for Phyllocnistis citrella (Lepidoptera: Gracillariidae) in citrus. AB - The leafminer, Phyllocnistis citrella Stainton (Lepidoptera: Gracillariidae), is a global pest of citrus and contributes to the incidence and severity of citrus bacterial canker. SPLAT CLM (ISCA Technologies, Riverside, CA) is an emulsified wax that provides sustained release of (Z,Z,E)-7,11,13-hexadecatrienal, the major component of P. citrella sex pheromone. Trials in commercial orchards demonstrated that SPLAT CLM applied to plots of varying width resulted in disruption of trap catch of male P. citrella within treated rows and across untreated rows adjacent to treated rows. SPLAT CLM applied to plots of constant width (10 rows) disrupted trap catch across an untreated gap as the square of the width of the gap. Similarly, the ability of the pheromone source in treated rows to disrupt trap catch across untreated gaps of constant size declined as the square of the width of adjacent treated areas. A coverage pattern of 4 rows skipped for every 10 treated rows resulted in a 4% reduction of trap shutdown, and reduced the product and application costs by 29%. Mining incidence by P. citrella in treated rows was reduced by 53% compared with untreated areas. Intentional coverage gaps can significantly reduce the cost of mating disruption. Commercial lures for P. citrella used in this study were highly potent with respect to attracting males. Each lure was approximately 10(3) times as attractive as an individual P. citrella female. Disruption of trap catch using commercial lures may underestimate actual mating disruption achieved in the field. PMID- 24772555 TI - Effects of a fipronil spot treatment on field colonies of Coptotermes formosanus (Isoptera: Rhinotermitidae). AB - This field study investigated the colony effect of a fipronil spot treatment applied to active infestations of Formosan subterranean termite, Coptotermes formosanus Shiraki. Spot treatments were applied to a single active independent monitor from each of four colonies in which multiple independent monitors were established. All treated monitors were abandoned, and the contents of the treated monitors were replaced with untreated wood at the approximately 30-d posttreatment inspection. All colonies survived treatment and only one colony exhibited long-term effects, which included significant reductions in termite collections and increased worker size. The affected colony was treated within 1 m of its primary nest. Two colonies exhibited a correlation between monitor termite production and distance from treatment. Distance appears to be a factor limiting fipronil's colony effects. The Formosan subterranean termite may not be a good candidate for the exterior perimeter and localized interior treatment label option because of the large range and size of the colony. PMID- 24772556 TI - Behavioral and histological changes in the Formosan subterranean termite (Isoptera: Rhinotermitidae) induced by the chitin synthesis inhibitor noviflumuron. AB - This study describes the behavioral and histological changes of the molting process in Coptotermes formosanus Shiraki caused by the chitin synthesis inhibitor noviflumuron. Termites exposed to noviflumuron initiated ecdysis as untreated individuals did; however, peristalsis contractions were weak and the expansion of the dorsal breach of the exoskeleton did not occur. Treated termites could not complete their molting process and died after the initiation of the ecdysis. Histological observations showed that the process of voiding the gut protozoa during premolting was not affected by the noviflumuron treatment. However, the formation of the new cuticle was disrupted resulting in the loss of integrity of the cuticle. The alteration of the cuticle was visible in the gizzard (foregut), the thoracic pleurons, and most of the exoskeleton. Muscles were partially able to reattach to the incompletely formed new cuticle, and muscle contractions resulted in tearing off the cuticle. Because the integrity of the newly formed cuticle was compromised by the noviflumuron treatment, we concluded that termites' death was caused primarily by the loss of hemolymph as a result of the damage done by the muscle contractions on the exoskeleton during the peristalsis. As the physiological homeostasis was disrupted, termites were too weak to shed their old cuticle, ultimately resulting in termite dying during the molting process. PMID- 24772557 TI - Polyacrylamide hydrogels: an effective tool for delivering liquid baits to pest ants (Hymenoptera: Formicidae). AB - Ant management in urban and natural areas often relies on toxic baits. Liquid baits are highly attractive to pest ants because they mimic natural food sources such as honeydew and nectar, the principal dietary components of many ants. However, liquid bait use has been limited owing to the lack of bait dispensers that are effective, inexpensive, and easy to service. The current study evaluated the potential of water-storing crystals (polyacrylamide spheres) to effectively deliver liquid thiamethoxam baits to laboratory colonies of Argentine ants, Linepithema humile Mayr. Results of laboratory trials show that bait crystals saturated in 25% sucrose solution containing 0.007% thiamethoxam are highly attractive to Argentine ants and highly effective against all castes and life stages, including workers, queens, and brood. Fresh bait crystals were highly effective and required approximately 2 d to kill all workers and approximately 6 d to achieve complete mortality in queens and brood. Results of bait aging tests show that the crystals lose approximately 70% of moisture in 8 h and the duration of outdoor exposure has a significant effect on moisture loss and subsequently bait acceptance and bait efficacy. A gradual decrease in mortality was observed for all castes and life stages as bait age increased. In general, fresh baits and those aged for < 8 h retained their efficacy and caused substantial mortality. Baits aged longer than 8 h were substantially less attractive and less effective. Horizontal transfer tests examined the transfer of thiamethoxam from live treated donors to live untreated recipients. The results show that donor ants that obtain thiamethoxam by feeding on bait crystals effectively transfer it to untreated recipient ants. The level of secondary mortality depended on the donor:recipient ratio, with approximately 40% recipient worker mortality with the 1:5 ratio and 15% recipient worker mortality with 1:10 or 1:20 ratios. However, no queens died in any transfer tests, suggesting that multiple feedings from multiple donors may be necessary to produce queen mortality. The results of the transfer tests demonstrate the role of trophallaxis in the distribution of thiamethoxam and confirm that thiamethoxam is effectively transferred in Argentine ant colonies. The distribution of thiamethoxam within Argentine ant colonies was further examined using protein marking coupled with an enzyme-linked immunosorbent assay to detect the marker. The distribution of thiamethoxam was highly efficient, with 79 +/- 13% of workers testing positive at 15 min and 100 +/- 0% of workers testing positive at 6 h. In summary, the results of this study demonstrate that water-storing crystals effectively deliver thiamethoxam to all castes and life stages of Argentine ants and may offer an effective tool for Argentine ant management. PMID- 24772558 TI - Topical and vapor toxicity of saturated fatty acids to the German cockroach (Dictyoptera: Blattellidae). AB - Topical and fumigant toxicity of saturated aliphatic fatty acids with chain lengths of C1 through C14 were determined against the German cockroach, Blattella germanica (L.). In the C1 to C11 series, topical toxicity (LD50 in milligram per adult male) ranged from 0.145 (C1) to 0.322 mg (C2). Toxicity declined dramatically with C12 and C14 acids whose LD50 values could not be calculated. The relative fumigation toxicity (LC50 in microliter per liter) of C1 through C5 acids was positively correlated with topical toxicity with values ranging from 6.159 (C3) to 12.302 microl/liter (C2). Fumigant toxicity decreased sharply with C6 (LC50 = 37.691 microl/liter) and there was no mortality of cockroaches exposed to vapors from C7 to C14 acids. The low fumigant toxicity of the C6 to C11 acids was correlated with their relatively low vapor pressure, but differences in diffusion of the vapors into the spiracles and subsequent passage to the target sites may have also been involved. PMID- 24772559 TI - Effect of maize lines on larval fitness costs of Cry1F resistance in the European corn borer (Lepidoptera: Crambidae). AB - Crops producing insecticidal toxins from the bacterium Bacillus thuringiensis (Bt) are widely planted and enable management of key insect pests while reducing the use of conventional insecticides. However, the evolution of Bt resistance could diminish these benefits. Fitness costs of Bt resistance occur in the absence of Bt toxin when individuals with resistance alleles show a reduction in fitness relative to susceptible individuals, and they can delay the evolution of resistance. Ecological factors including host-plant variety can affect the magnitude of fitness costs, and consequently, the degree to which fitness costs delay resistance. In this study, we measured fitness costs of resistance to Bt toxin Cry1F in the European corn borer Ostrinia nubilalis Hubner (Lepidoptera: Crambidae) using Cry1F-resistant and Cry1F-susceptible strains sharing a similar genetic background. Fitness costs were tested on three lines of maize, Zea mays L., by measuring larval survival and development in two greenhouse experiments with plants in either the vegetative or reproductive stage. Both experiments showed that maize line significantly affected larval survival and developmental rate. However, larval survival, mass, and developmental rate did not differ between the Cry1F-resistant and susceptible strains, indicating a lack of fitness costs of resistance to Cry1F for the larval fitness components measured in this experiment. Future experiments should test for fitness costs of Cry1F resistance affecting survival to adulthood and adult life-history parameters. PMID- 24772560 TI - Baseline susceptibility of Bemisia tabaci B biotype (Hemiptera: Aleyrodidae) populations from California and Arizona to spirotetramat. AB - Baseline toxicity levels to foliarly applied spirotetramat were established for 19 field populations of whiteflies, Bemisia tabaci (Gennadius) B biotype (=Bemisia argentifolii Bellows & Perring) (Hemiptera: Aleyrodidae) from Arizona and California in 2008 and 2009. The susceptibility data were determined against the second instar of B. tabaci field collections before the registration and widespread use of spirotetramat in California. Three strains of whitefly, resistant to either bifenthrin, imidacloprid, or pyriproxyfen, were also tested to determine the potential for cross-resistance to spirotetramat. No significant geographic variation in susceptibility to spirotetramat was observed among regions within Arizona. The LC50 values for the Arizona populations spanned a 14 fold range between populations during the 2 yr sampling tests including a low LC50 of 0.91 (micrg [AI] ml(-1)) and a high LC50 of 13.47 (microg [AI] ml(-1)), while the LC90 values showed a seven-fold range. The field populations from California exhibited limited variation in susceptibility to spirotetramat in general (1.02-7.02 microg [AI] ml(-1)) with one exception (27.98 microg [AI] ml( 1)). Variation in susceptibility among the resistant strains was about eight-fold at the LC50 level with the PYR-strain, showing the highest susceptibility to spirotetramat at 3.79 (microg [AI] ml(-1)). In addition, comparisons of relative susceptibilities among three older immature instars of two field populations showed no significant differences. These results establish a regional baseline that can serve as a reference for future monitoring and management of B. tabaci resistance to spirotetramat. PMID- 24772561 TI - Baseline susceptibility and monitoring of Brazilian populations of Spodoptera frugiperda (Lepidoptera: Noctuidae) and Diatraea saccharalis (Lepidoptera: Crambidae) to Vip3Aa20 insecticidal protein. AB - The genetically modified maize expressing Vip3Aa20 insecticidal protein from Bacillus thuringiensis Berliner is abiotechnological option for the control of Spodoptera frugiperda (J.E. Smith) and Diatraea saccharalis (F.) in Brazil. To support an Insect Resistance Management program, we conducted studies of baseline susceptibility and monitoring of Brazilian populations of S. frugiperda and D. saccharalis to the Vip3Aa20 insecticidal protein. Neonates were exposed to Vip3Aa20 applied on artificial diet surface. Mortality and growth inhibition were assessed after 7 d. All populations were susceptible to Vip3Aa20. The LC50 ranged from 92.38 to 611.65 ng Vip3Aa20/cm2 for 16 populations of S. frugiperda (6.6 fold variation), and between 61.18 and 367.86 ng Vip3Aa20/cm2 for 6 populations of D. saccharalis (sixfold variation). The EC50 ranged from 21.76 to 70.09 and 48.65 to 163.60 ng Vip3Aa20/cm2 for S. frugiperda and D. saccharalis, respectively. There was a low interpopulation variation in susceptibility to Vip3Aa20, which represents the natural geographic variation in the response, and not the variation caused by previous exposure to selection pressure. For these two pests, the diagnostic concentrations of 2,000 and 3,600 ng of Vip3Aa20/cm2 caused high mortality. These diagnostic concentrations will be used in resistance monitoring programs in Brazil. PMID- 24772562 TI - Effect of synergists on susceptibility to chlorantraniliprole in field populations of Chilo suppressalis (Lepidoptera: Pyralidae). AB - The Asiatice stem borer, Chilo suppressalis (Walker), an important rice insect pest in China, has developed resistances to several classes of insecticides. To control C. suppressalis, chlorantraniliprole has been introduced as a novel insecticide in rice field since 2008. It is an anthranilic diamide insecticide that binds and activates ryanodine receptors (RyR). The susceptibility of field populations of C. suppressalis to chlorantraniliprole was determined in this study. The hypotheses of equality and parallelism showed that regression lines in the tested five populations were neither equal nor parallel. The Ruian, Cangnan, and Liangyungang populations (RA12, CN12, and LYG12) collected in 2012 had lower LD50 values, whereas the Zhuji populations (ZJ12 and ZJ13) collected in 2012 and 2013 were approximately 15 times more tolerant than the RA12 population. To determine the potential mechanisms involved in this tolerance variation, synergism bioassays were performed. Significant differences in susceptibility were found between without synergist and with synergist for the three populations (RA12, LYG12, and ZJ13), based on the tests for the hypotheses of equality. In RA12 and LYG12 populations with chlorantraniliprole, the addition of piperonyl butoxide (PBO) significantly synergized the activity, with synergism ratios of 2.68- and 2.33-fold, respectively, whereas addition of S,S,S-tributyl phosphorotrithioate (DEF) and diethyl maleate (DEM) had no synergist effect. In ZJ13 population with chlorantraniliprole, the addition of PBO and DEF increased synergism ratios by 12.43- and 6.31-fold, respectively, whereas addition of DEM had no significant effect on the toxicity against ZJ13 larvae. These susceptibility and synergism data suggested that detoxification enzymes might be involved in the tolerance variation to chlorantraniliprole in field populations of C. suppressalis. PMID- 24772563 TI - Dillapiol: a pyrethrum synergist for control of the Colorado potato beetle. AB - Dillapiol, the main constituent in dill Anethum sowa Roxb. ex Fleming (Apiaceae) oil and wild pepper, Piper aduncum L. (Piperaceae), is an effective cytochrome P450 inhibitor similar to piperonylbutoxide (PBO). Laboratory and field trials with pyrethrum Chrysanthemum cinerariifolium (Trevir.) vis. extracts combined with dillapiol (1:5 and 1:16 ratio) were effective against both insecticide susceptible and -resistant Colorado potato beetle Leptinotarsa decemlineata (Say). In the laboratory, pyrethrum efficacy was increased 2.2-fold with the SS strain and 9.1-fold with the RS strains by using pyrethrum + dillapiol. Two field trials with the pyrethrum + dillapiol formulation demonstrated efficacy > or = 10 times than that of pyrethrum alone. The residual activity (half-life) of the combination exposed to direct sunlight was 3 h but it increased to 10.7 h by adding 2% of the sunscreen octylmethoxycinnamate. PMID- 24772564 TI - Chlorantraniliprole resistance in the diamondback moth (Lepidoptera: Plutellidae). AB - The wide application of chlorantraniliprole, which selectively targets insect ryanodine receptors (RyR), for control of the diamondback moth, Plutella xylostella (L.), has led to increasingly prominent development of resistance to this insecticide. Although much work has been carried out on the structure and function of RyR, the molecular mechanisms of resistance to chlorantraniliprole in diamondback moth still needs further investigation. P. xylostella strains with medium and high resistance to chlorantraniliprole were obtained by laboratory selection and field collection. The biological activity of chlorantraniliprole against the third-instar larvae of susceptible and resistant strains was tested, and resistance development and biological fitness were investigated. The realized heritability (h2) of resistance showed the diamondback moth has a high risk of resistance to chlorantraniliprole. RyR transcript levels were lower in resistant strains than in susceptible strains, indicating that decreased expression of PxRyR may be associated with chlorantraniliprole resistance in P. xylostella. A 4,400 bp fragment of the RyR cDNA, which encodes most of the functional domains of RyR, was cloned and characterized from four strains (S, F18, BY, and ZC). A 14 amino acid (Q4546-S4559) deletion was found in three resistant strains (F18, BY, and ZC). A point mutation resulting in a glycine to glutamate substitution, as reported in a previously published article, was also found in the carboxyl terminal region of two resistant strains (BY and ZC). These results indicated that decreased transcriptional level of RyR mRNA and combined with the site mutation might be related to chlorantraniliprole resistance in P. xylostella. PMID- 24772565 TI - Resistance in Cnaphalocrocis medinalis (Lepidoptera: Pyralidae) to new chemistry insecticides. AB - The control of rice leaffolder, Cnaphalocrocis medinalis (Guenee), depended mainly on the insecticide application in China for a long time, and the resistance development impacted the effects of insecticide application. In this study, 13 conventional and new chemistry insecticides were assayed for the toxicities to the larvae of rice leaffolder collected from Nanning, Changsha, and Nanjing, China, with rice seedling dip method during 2011-2013. Among the tested chemicals, macrolide insecticides spinetoram, spinosad, abamectin, and emanectin benzoate have the highest toxicities, whereas monosultap and Bt have the least toxicities to this insect. Comparing with the baseline data established in 2010, the susceptibilities of rice leaffolder to chlorantraniliprole, metaflumizone, and tebufenozide are declining simultaneously and gradually in the three regions from 2011 to 2013, and C. medinalis are becoming resistance to chlorantraniliprole, metaflumizone, and tebufenozide. The synchronous decreases of susceptibility in three geographic populations were not observed for macrolide insecticides, indoxacarb, chlorpyrifos, monosultap, and Bt. The synchronous insecticide susceptibility declines in field populations of the migratory insect collected from different areas indicated resistance evolution, and the sequence application patterns of different insecticides should be scheduled to delay the further development of resistance along the migratory pathway of the rice leaffolder in China. PMID- 24772566 TI - Shift in phenotypic variation coupled with rapid loss of genetic diversity in captive populations of Eristalis tenax (Diptera: Syrphidae): consequences for rearing and potential commercial use. AB - Because of its importance as a pollinator and its potential economic usefulness for the biodegradation of organic animal waste, the genetic and phenotypic diversity of the drone fly, Eristalis tenax L. (Diptera: Syrphidae), was studied in both wild and captive populations from southeastern Europe. Wild specimens from a natural protected habitat (with low human impact), field crop habitat (semisynanthropic condition), and intensive pig farming habitat (synanthropic condition) were compared with a laboratory colony reared on artificial media An integrative approach was applied based on allozyme loci, cytochrome c oxidase I mitochondrial DNA, wing traits (size and shape), and abdominal color patterns. Our results indicate that the fourth and eighth generations of the laboratory colony show a severe lack of genetic diversity compared with natural populations. Reduced genetic diversity in subsequent generations (F4 and F8) of the laboratory colony was found to be linked with phenotypic divergence. Loss of genetic variability associated with phenotypic differentiation in laboratory samples suggests a founder effect, followed by stochastic genetic processes and inbreeding. Hence, our results have implications for captive bred Eristalis flies, which have been used in crop pollination and biodegradation of organic waste under synanthropic conditions. PMID- 24772567 TI - Tolerance of wheat (Poales: Poaceae) seedlings to wireworm (Coleoptera: Elateridae). AB - Wireworms (Coleoptera: Elateridae), the subterranean larval stage of the click beetle, are becoming more prevalent in many cropping systems and posing an increasing economic threat to wheat growers in the Pacific Northwest following the cancellation of the insecticide lindane in 2006. Current insecticide seed treatments alone are not adequate for wireworm control. The objective of this study was to evaluate a diverse set of 163 wheat genotypes for tolerance to wireworm feeding. Entries were planted in replicated field trials over 3 yr and evaluated for their performance when grown in the presence of wireworms. Entries were rated based on survival and given a tolerance score. Results indicated that differences exist among wheat genotypes in their level of tolerance to wireworm feeding. In particular, consistently high-ranking genotypes of interest may be 'BR 18', 'Sonalika', 'Safed Lerma', and 'Hollis'. These genotypes, used in conjunction with other cultural or chemical control methods, may help provide an economic means of controlling wireworms. PMID- 24772568 TI - A binomial sequential sampling plan for Bactericera cockerelli (Hemiptera: Triozidae) in Solanum lycopersicum (Solanales: Solanacea). AB - The tomato-potato psyllid Bactericera cockerelli (Sulc) (Hemiptera: Triozidae) is a pest of many solanaceous plants, including tomato (Solanum lycopersicum L.) and potato (Solanum tuberosum L.). In tomato, feeding by nymphs is associated with "psyllid yellows." B. cockerelli also vectors "Candidatus Liberibacter psyllaurous," an infectious bacterium that causes "vein greening" disease. Decisions about management action are much more effective when guided by robust sampling. However, there are few previous studies of potato psyllid spatial distribution in tomato fields, and no published sequential sampling plans for the pest in tomato. We studied B. cockerelli in various tomato fields in California and used these data to generate a sequential sampling plan. We found that juvenile B. cockerelli in tomato fields exhibit an edge effect, an aggregated distribution, and individuals are primarily located on the bottom of leaves. Psyllids were concentrated in the upper segments of plants, but this changed over time. Finally, we present three binominal sequential sampling plans for managing tomato psyllids in tomato fields. These plans differed from both those for bell pepper (Capsicum annum L.) and potato, indicating that B. cockerelli needs to be sampled using crop-specific sampling plans. PMID- 24772569 TI - Sequential sampling for panicle caterpillars (Lepidoptera: Noctuidae) in sorghum. AB - Panicle caterpillars comprise an economically important insect pest complex of sorghum throughout the Great Plains of the United States, particularly in Kansas, Oklahoma, and Texas. The sorghum panicle caterpillar complex consists of larvae of two polyphagous lepidopteran species: the corn earworm, Helicoverpa zea (Boddie), and fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae). Sampling for panicle caterpillars in sorghum fields is usually accomplished by the beat bucket sampling technique with a fixed sample size of 30 beat bucket samples of one sorghum panicle each per 16.2 ha of field. We used Wald's sequential probability ratio test for a negative binomial distribution to develop a sequential sampling plan for panicle caterpillars. In total, 115 sorghum fields were sampled in Kansas, Oklahoma, and Texas from June to August 2010. Panicle caterpillars had an aggregated distribution of counts confirmed by Pearson's chi-square statistic for lack of fit to the negative binomial distribution for each sampled field. A sequential sampling plan was developed using a high threshold (an economic threshold) of 0.5 caterpillars per sorghum panicle, a low threshold (a safe level) of 0.20 caterpillars per panicle, and fixed error rates (alpha = 0.10 and beta = 0.05). At caterpillar densities > 0.45 and < 0.12 per panicle, the average number of panicles inspected to make a decision was less than the current recommendation of 30. In a 2013 validation test of 25 fields, the expected number of samples taken from average sample number curve was in close agreement with the number of samples required using the sequential plan (r2 = 0.93), and all fields were correctly classified when compared with a fixed sample size result. The plan improved upon current sampling recommendations for panicle caterpillars in sorghum because at known acceptable fixed error rates fewer samples were required when caterpillars are scarce or abundant, whereas more samples were required to make decisions with the same acceptable error rates when densities were near the economic thresholds. PMID- 24772570 TI - Residual efficacy of chlorfenapyr for control of stored-product psocids (Psocoptera). AB - The residual effect of chlorfenapyr (Phantom) was evaluated for residual control of three stored-product psocid species: Liposcelis bostrychophila Badonnel, Liposcelis entomophila (Enderlein), and Liposcelis paeta Pearman (Psocoptera: Liposcelididae). Chlorfenapyr was applied to individual arenas with a concrete surface at rates of 0, 2.8, 13.8, 20.6, 27.5, 55, and 110 mg active ingredient (AI)/m2. Adults were exposed on the treated arenas and mortality assessed after 1, 2, and 3 d. The procedures were repeated weekly on the same treated arenas for 3 wk to assess residual efficacy. At each week, mortality of all species was low after 1 d of exposure but notably increased after 2 or 3 d. L. entomophila was the most susceptible species, with 99-100% mortality at rates of 13.8 mg/m2 or higher. Similarly, mortality of L. paeta after 3 d of exposure at the same concentration ranged from 92 to 100%. L. bostrychophila was the least susceptible species, with mortality of < 60% during the third week after application at rates < or = 27.5 mg/m2. However, even for this species, mortality after 3 wk was 90% or higher at rates > 27.5 mg/m2. Complete mortality of all species occurred after 3 d exposure at the highest rate tested of 110 mg/m2. Thus, our results show that chlorfenapyr is effective against major psocid species at the application rates evaluated in this study. PMID- 24772571 TI - Azadirachtin-induced hormesis mediating shift in fecundity-longevity trade-off in the Mexican bean weevil (Chrysomelidae: Bruchinae). AB - Insecticides can have lethal or sublethal effects upon targeted pest species, and sublethal effects may even favor pest outbreaks if insecticide-induced hormesis occurs. Hormesis is a biphasic dose-response of a given chemical compound that is stimulatory at low doses and toxic at high doses. The former response may result from the disruption of animal homeostasis leading to trade-off shifts between basic ecophysiological processes. A growing interest in the use of biorational insecticides, such as azadirachtin to control stored-product pests, raises concerns about potential sublethal effects. In this study, we explored the hypothesis that azadirachtin can negatively impact the reproductive capacity of the Mexican bean weevil, Zabrotes subfasciatus (Boheman) (Chrysomelidae: Bruchinae), a key pest of stored beans. In addition, we investigated whether adults of this species could compensate for any sublethal effect that might have affected any of their reproductive parameters by adjusting the allocation of its reproductive efforts. The results showed that females of Z. subfasciatus increased fecundity daily to compensate for azadirachtin-induced decreased longevity. In addition, a stage-structured matrix study revealed that populations of Z. subfasciatus engendered from females exposed to azadirachtin exhibited a higher rate of population increase (r) and a higher net reproductive rate (R(o)). Finally, a projection matrix analysis showed notably higher densities along the generations for azadirachtin-exposed Z. subfasciatus populations. Thus, our study provides empirical evidence for the capacity of Z. subfasciatus to adapt to sublethal effects caused by biorational insecticides; consequently, this study highlights the importance of understanding this phenomenon when devising pest management strategies. PMID- 24772572 TI - Evaluation of potential attractants for Liposcelis bostrychophila (Psocoptera: Liposcelididae). AB - The psocid, Liposcelis bostrychophila Badonnel (Psocoptera: Liposcelididae), can cause significant damage to stored commodities, and its pest status in the United States has been increasing over the last decade. Because L. bostrychophila is difficult to control with conventional methods, it is critical to explore alternative approaches such as the use of attractants that can be incorporated into integrated pest management programs for monitoring psocids. The orientation response of several L. bostrychophila life stages (first and second instars, third and fourth instars, 0- to 7-d-old adults, 21- to 28-d-old adults, and adults of mixed ages) to a range of potential attractants (including whole and cracked grains, grain-based oils, wheat germ, brewer's yeast, and commercially available kairomone lures) was studied using a two-choice pitfall test to identify candidates for further development as lures in traps. Among the potential attractants evaluated, the strongest response by all stages of L. bostrychophila was to brewer's yeast. Other materials for which there was consistently a strong response were psocid diet, wheat germ, and wheat germ oil. These results show the potential for developing monitoring tools for integrated pest management programs for L. bostrychophila and other psocid species. PMID- 24772573 TI - Suppression of hop looper (Lepidoptera: Noctuidae) by the fungicide pyraclostrobin. AB - The hop looper, Hypena humuli Harris, is a reemergent pest of hop that often requires treatment to mitigate crop damage. In 4 yr of field trials, plots treated with fungicides were observed to sustain less hop looper defoliation compared with nontreated plots. Further investigation revealed that abundance of hop looper and associated defoliation were reduced when the fungicide pyraclostrobin was applied in late July to early August. Two other fungicides possessing active ingredients in the same chemical family (quinone outside inhibitor) did not reduce abundance of hop looper or its defoliation. Pyraclostrobin is efficacious against powdery mildew diseases, and the application timing evaluated in these studies corresponds with a period of juvenile susceptibility of hop cones to the disease. Use of fungicides containing pyraclostrobin at this time may have the ancillary benefit of reducing hop looper damage, potentially obviating the need for broad-spectrum insecticides later in the season. Follow-up studies are warranted to determine whether pyraclostrobin may inhibit other lepidopteran species. PMID- 24772574 TI - In vitro activity of colistin plus sulbactam against extensive-drug-resistant Acinetobacter baumannii by checkerboard method. AB - OBJECTIVE: To determine in vitro activity of colistin plus sulbactam against extensive-drug-resistant (XDR) Acinetobacter baumannii. MATERIAL AND METHOD: Checkerboard method was used to determine in vitro activity of colistin plus sulbactam against 11 clinical isolates of XDR A. baumannii. The concentrations of colistin and sulbactam used in the study were 0.025 to 128 mg/ 1 and 4 to 256 mg/l, respectively. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of colistin, sulbactam and colistin plus sulbactam at various concentrations were determined. Fractional inhibitory concentration index (FICI) was calculated. The antibiotic combination is considered synergistic if FICI < 0.5, indifferent if FICI 0.5 to 4.0, and antagonistic if FICI > 4.0. RESULTS: Ten isolates of XDR A. baumannii were susceptible to colistin (MIC < 2 mg/l) and one isolate was resistant to colistin (MIC 8 mg/l). There were no antagonistic effects of colistin plus sulbactam against all study isolates. For 10 isolates of colistin-susceptible XDR A. baumannii, some MIC values of the combinations were lower than those of single antibiotics. However no synergistic effect of colistin and sulbactam was observed in colistin-susceptible XDR A. baumannii isolates. The synergistic effect of colistin and sulbactam was detected in some concentrations of colistin and sulbactam against colistin-resistant XDR A. baumannii isolate. CONCLUSION: The combination of colistin and sulbactam showed an indifferent effect against colistin-susceptible XDR A. baumannii. The combination of colistin and sulbactam showed synergistic effect at some concentrations of colistin and sulbactam against a clinical isolate of colistin-resistant XDR A. baumannii. In vitro time kill method should be performed to confirm the aforementioned observations. PMID- 24772575 TI - In vitro susceptibility test of sitafloxacin against resistant gram-negative bacilli isolated from Thai patients by disk diffusion method. AB - OBJECTIVE: To determine a correlation of minimum inhibitory concentration (MIC) of sitafloxacin determined by agar dilution method with inhibition zone diameter of sitafloxacin determined by disk diffusion method, and to determine inhibition zone, diameter breakpoints of sitafloxacin against resistant gram-negative bacilli isolated from Thai patients. MATERIAL AND METHOD: The study bacteria were 332 clinical isolates of gram-negative bacilli including ESBL-producing E. coli, ESBL-producing K. pneumoniae, P. aeruginosa andA. baumannii. Each isolate of the present study bacteria was tested for minimum inhibitory concentration (MIC) of sitafloxacin by agar dilution method and inhibition zone diameter of sitafloxacin by disk diffusion method. RESULTS: The MICs and inhibition zone diameters of sitafloxacin against gram-negative bacilli were well correlated (correlation coefficient -0.926, p-value < 0.001). The inhibition zone diameter > or = 15 mm had the least total error for determining susceptibility to sitafloxacin based on MIC value of sitafloxacin but the inhibition zone diameter > or = 16 mm had less false susceptibility than that of > or = 15 mm when compared with sitafloxacin MIC < or = 2 mg/l that was considered susceptible. The inhibition zone diameter > or = 19 mm had the least total error for determining susceptibility to sitafloxacin based on MIC value of sitafloxacin but the inhibition zone diameter > or = 18 mm had less false susceptibility than that of > or = 19 mm when compared with sitafloxacin MIC < or = 1 mg/l that was considered susceptible. CONCLUSION: For the susceptibility test of sitafloxacin against resistant gram negative bacilli by disk diffusion method, the inhibition zone diameter > or = 16 mm and > or = 18 mm seem to be the appropriate breakpoints for susceptibility for resistant gram-negative bacilli isolated from urine and blood, respectively, since the serum concentration of sitafloxacin is rather low whereas the urinary concentration of sitafloxacin is much higher. PMID- 24772576 TI - Effectiveness of multifaceted interventions on rational use of antibiotics for patients with upper respiratory tract infections and acute diarrhea. AB - OBJECTIVE: To implement multifaceted interventions to promote rational use of antibiotics for out-patients with upper respiratory tract infection (URI) and acute diarrhea. MATERIAL AND METHOD: The present study was conducted at ambulatory care facility for patients under Social Security Healthcare Benefit Scheme and Universal Health Coverage Scheme of Siriraj Hospital from January to April 2012. Multifaceted interventions were: Training responsible healthcare personnel on rational use of antibiotics, Clinical practice guidelines, Preprinted medical record forms for patients, Throat swab or stool culture to be taken from the patients (if responsible physicians needed these); and provision of brochures containing causes, necessity and harm of antibiotics for URI and acute diarrhea to patients as well as their relatives while waiting for receiving care. Pre-printed medical records were collected every day. Each patient was called on day 3 after receiving care by an investigator to determine clinical responses. RESULTS: There were 1,241 episodes of URI and 210 episodes of acute diarrhea during the study period. Rates of antibiotic prescriptions were 13.0% for URI and 19.1% for acute diarrhea. Throat swab cultures recovered group A beta hemolytic streptococci in 3.8% of URI patients and non-typhoidal Salmonella spp. in 14.6% of acute diarrhea patients. Clinical responses of the patients on day 3 after receiving care revealed that more than 97% of the patients who received antibiotics and who did not receive antibiotics were cured or improved. CONCLUSION: Multifaceted interventions are very effective for promoting rational use of antibiotics for out-patients with URI and acute diarrhea at Siriraj Hospital. PMID- 24772577 TI - Bacterial contamination of fresh traumatic wounds at Trauma Center, Siriraj Hospital, Bangkok, Thailand. AB - BACKGROUND: Fresh traumatic wound is a common health problem in patients attending Trauma Center at Siriraj Hospital in Bangkok, Thailand. Antibiotic prophylaxis was given to nearly 90% of such patients. A contributing factor to a high prevalence of antibiotic prophylaxis is a lack of data on bacterial contamination at fresh traumatic wounds in Thai patients. OBJECTIVE: To determine prevalence and characters of bacterial contamination, and incidence of wound infection in adult patients with fresh traumatic wounds attending Siriraj Trauma Center. MATERIAL AND METHOD: Prospective study was conducted in 330 adult patients with fresh traumatic wounds from March 2012 and September 2012. All patients received wound care and antibiotic prophylaxis according to the judgment of their responsible physicians. A wound swab culture was taken from all patients. The patients were either called by telephone or asked to have follow-up visits in order to determine incidence of wound infection. The infected patient received regular care. RESULTS: Sixty-three percent and 8% of the patients had lacerated wounds and bite wounds, respectively. Ninety-one percent of them received antibiotics of which dicloxacillin and co-amoxiclav accounted for 80.3% and 11.4%, respectively. Wound swab cultures revealed that potential pathogenic bacteria i.e. S. aureus, streptococci, Enterobacteriaceae, Aeromonas spp., Acinetobacter spp. and non-fermentative gram-negative rods (NF GNR) were recovered from 7% of wounds. Incidence of wound infection was 1.2%, and all infected wounds were found in patients who had a contaminated wound and received antibiotic prophylaxis. Bacterial contaminations of infected patients were NF GNR, E. cloacae, and mixed organisms. All wound infections were successfully treated with appropriate wound care. CONCLUSION: More than 90% of adult patients with fresh traumatic wound at Siriraj Trauma Center received prophylactic antibiotics. Less than 10% of these wounds were contaminated with potentially pathogenic bacteria. Incidence of wound infection in fresh traumatic wounds was low. PMID- 24772578 TI - Clinical characteristics and outcomes of patients with cryptococcal meningoencephalitis in a resource-limited setting. AB - BACKGROUND: Cryptococcosis is a potentially lethal opportunistic infection among human immunodeficiency virus (HIV)-infected individuals. The mortality rate of patient with cryptococcal meningoencephalitis (CM) in Thailand is high. Studying the factors associated with treatment failure is important to improve outcome. MATERIAL AND METHOD: A retrospective study of patients with cryptococcosis in Siriraj Hospital, Thailand, during 2005-2008 was conducted. Treatment options, outcomes, survival and factors associated with outcomes and mortality were analyzed. RESULTS: A total of 143 patients with cryptococcosis were enrolled. Mean age was 39 years old and 58.7% were male. There were 124 HIV-infected patients (86.7%) and 116 of those had CM. Favorable clinical response in HIV associated CM was 55.2% and 6-month survival was 67.2%. Relapse was found in 21 patients (18.1%). Factors associated with favorable clinical response included lower opening and closing pressures and a higher white blood cell in cerebrospinal fluid (CSF). Favorable mycological response was 56.8% and factors associated with favorable mycological response were a lower CD4+ T-lymphocyte count and a longer amphotericin B treatment. The median time to achieve CSF sterilization was 30 days. Factors associated with survival were a longer course of amphotericin B, a lower CSF opening pressure and a higher white blood cell in CSF. CONCLUSION: High mortality rate of HIV-associated CM was demonstrated and most likely linked to inadequate induction antifungal therapy resulting in inability to sterilize CSF. New strategies and/or guidelines are suggested to improve survival. PMID- 24772579 TI - Epidemiology of infections caused by multidrug-resistant gram-negative bacteria in adult hospitalized patients at Siriraj Hospital. AB - OBJECTIVE: To investigate the clinical characteristics, risk factors, outcomes, antibiotic treatment and complications of hospitalized patients infected with multi-drug resistant (MDR) gram-negative bacteria in Siriraj Hospital. MATERIAL AND METHOD: A cross sectional study was performed in all hospitalized patients at Siriraj Hospital who had positive culture for Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii during February to May 2012. Clinical characteristics, risk factors and outcomes of MDR gram-negative bacteria were analyzed. RESULTS: The prevalence of overall MDR gram-negative bacteria was 48.8%. The percentage of MDR organism was 37.8% for Extended Spectrum Beta Lactamase (ESBL)-producing Enterobactericeae, 39.3% for carbapenem-resistant P. aeruginosa and 88.7% for MDR A. baumannii. Infections caused by MDR organisms were associated with admission to medical wards, respiratory tract origin and hospital onset of infection. The significant risk factor of overall MDR organism infection was previous antibiotic use within 1 year (adjusted odd ratio 6.818, 95% CI = 1.337-34.770). Rate of inappropriate antibiotic use was 56.7% for initial empirical regimen and under treatment was significantly higher in MDR group. The 30-day and 90-day survival rates of MDR group were significant lower than non-MDR group (58.8% vs. 75.0%, p = 0.013 at 30th day and 43% vs. 63%, p = 0.012 at 90th day). Antibiotic associated adverse effect found 42.9% in MDR group and 20.0% in non-MDR group (p < 0.001). CONCLUSION: The strongest risk factor for acquiring MDR gram-negative infection was previous antibiotic use. Inadequate empirical antimicrobial treatment was common in patients infected with MDR pathogens, resulting in unfavorable outcome and mortality. PMID- 24772580 TI - Reliability and validity of a Thai version of the Berlin questionnaire in patients with sleep disordered breathing. AB - OBJECTIVE: To assess the validity and test-retest reliability of a Thai version of the Berlin Questionnaire in patients with sleep disorder breathing. MARTIAL AND METHOD: Patients who were suspected of sleep disordered breathing attending the outpatient department of Siriraj Hospital and who had undergone polysomnography were recruited and asked to complete a Thai version of the Berlin questionnaire. Each participant was asked to repeat the same questionnaire over the next 2-4 weeks for test-retest reliability. RESULTS: One hundred and thirty two patients completed the present study. The age range of the patients was 26-72 years (mean, 48.15 ++/- .80 years). All 10 items of the Thai version of the Berlin questionnaire were moderately correlated in internal consistency (Cronbach's alpha correlation coefficient = 0.68). The test-retest reliability of the Thai version of the Berlin questionnaire was investigated in 98 patients and demonstrated a high degree of reliability in intra class correlation (ICC = 0.97). CONCLUSION: The present study reveals, for the first time, that the Thai version of the Berlin questionnaire has satisfactory validity and reliability when compared to the original English version. PMID- 24772581 TI - Reliability and validity of the Thai version of the Pittsburgh Sleep Quality Index. AB - OBJECTIVE: To assess the internal consistency, test-retest reliability, and validity of the Thai version of the Pittsburgh Sleep Quality Index (Thai-PSQI), which was recently translated using a standardized method, in Thai patients with major sleep disorders. MATERIAL AND METHOD: The Thai-PSQI was developed under a standard translation protocol and administered to "bad" sleepers (i.e. patients with suspected obstructive sleep apnea [OSA], depression, or insomnia) and "good" sleepers in an academic tertiary care setting. All participants were asked to complete the same questionnaire after 2-4 weeks. RESULTS: A total of 138 participants consisting of 69 patients with OSA, 28 with major depression, 11 with primary insomnia, and 30 controls completed the questionnaire. The global scores of the Thai-PSQI revealed that it had excellent internal consistency (Cronbach's alpha = 0.837) and test-retest reliability (intraclass correlation coefficient = 0.89). An analysis of covariance demonstrated a significant difference in Thai-PSQI global score between good sleepers and bad sleepers (p < 0.001). A cut-off point of 5 out of 6 on the global score resulted in a sensitivity of 77.78% and specificity of 93.33%. CONCLUSION: The Thai-PSQI is a valid and reliable tool for screening and identifying the presence of significant sleep disturbances, and is comparable to the original English version. PMID- 24772582 TI - Evaluation of sleep disorders in Parkinson's disease: a comparison between physician diagnosis and self-administered questionnaires. AB - OBJECTIVE: The objective of the present study was to compare a physician's diagnosis of sleep disorders in patients with Parkinson's disease (PD) during clinical evaluation of sleep disorders diagnosed by validated questionnaires. MATERIAL AND METHOD: Patients with PD at the Parkinson's clinic at Siriraj Hospital were included in this prospective cross-sectional study. Patients completed the Modified Parkinson's Disease Sleep Scale (MPDSS), Thai Epworth Sleepiness Scale (Thai-ESS), Scales for Outcomes in Parkinson's Disease-Sleep Scale questionnaire (SCOPA), Berlin questionnaire (Thai version), and Siriraj sleep questionnaire (SSQ). Thereafter, attending physicians diagnosed sleep disorders based on patient evaluation. RESULTS: One hundred twenty patients with PD participated in the present study. Among them, 73 (60.8%) were males, the mean age was 61.5 +/- 12.0 years, and the mean body mass index (BMI) was 22.7 +/- 3.5 kg/m2 (BMI > or = 30 kg/m2 in 1.7% of patients). The study demonstrated a prevalence of overall sleep disorders in 59.2% of patients based on physician diagnosis and 81.7% of patients based on the MPDSS questionnaire. The ESS was > 10 in 29.2% of the patients. High risk for obstructive sleep apnea was observed in 28.3% (Berlin) and 42% (MPDSS) of patients (15% by both). SSQ detected all sleep disorders in 86.7% of the population, and its results correlated with the MPDSS. CONCLUSION: Sleep disorders are common in patients with PD but remain underestimated because they are not routinely screened in clinical practice. This study demonstrates the use of validated questionnaires to efficiently detect and classify patients with PD at risk for common sleep disorders. PMID- 24772583 TI - Efficacy of quantitative capillary beta-hydroxybutyrate measurement in the diagnosis of diabetic ketoacidosis: a comparison to quantitative serum ketone measurement by nitroprusside reaction. AB - OBJECTIVE: To examine the efficacy of using capillary beta-hydroxy butyrate (beta OHB) levels in comparison with serum ketone levels in distinguishing diabetic ketoacidosis (DKA) from non-DKA states in patients who had severe hyperglycemia and to determine a cut-off level of capillary beta-OHB that is best for the diagnosis of DKA. MATERIAL AND METHOD: Diabetic patients who presented with capillary blood glucose of > or = 400 mg/dL were studied. Capillary beta-OHB levels were measured by using a ketometer (OptiumXceed) at the same time as blood sample collection for biochemical tests and serum ketone measurement using nitroprusside reaction. The American Diabetes Association (ADA) criteria 2012 were used as the gold standard in the diagnosed of DKA. RESULTS: There were 13 cases (34.2%) with DKA (DKA group) and 25 cases (65.8%) without DKA (non-DKA group). There was no difference in plasma glucose levels between both groups. (DKA group = 714.2 +/- 367.6 mg/dl vs. non-DKA group = 589.4 +/- 220.2 mg/dl). The DKA group had significantly higher serum ketone (7.2 +/- 3.6 vs. 0.28 +/- 0.05 mmol/L, p < 0.001) and capillary beta-OHB levels (4.3 +/- 0.7 vs. 1.0 +/- 1.1 mmol/L, p < 0.001) than did the non-DKA group. Capillary beta-OHB levels significantly correlated to serum anion gap values (r = 0.828, p < 0.001), serum bicarbonate (r = 0.715, p < 0.001), and ketone (r = 0.72, p < 0.001) levels. ROC analyses showed that a capillary beta-OHB level of > 3.1 mmol/L was the best cut off level for the diagnosis of DKA, and yielded a sensitivity of 100% (95% CI = 75.1-100) with a specificity of 96% (95% CI = 79.6-99.3). CONCLUSION: Using a cut off capillary beta-OHB level of > 3.1 mmol/L is highly effective in the diagnosis of DKA in patients who presented with hyperglycemia. Quantitative measurement of capillary beta-OHB levels using a ketometer offers an immediate result that is useful for a reliable triage of screening for DKA in patients presented with severe hyperglycemia. PMID- 24772584 TI - Clinical features and outcomes of isoniazid mono-resistant pulmonary tuberculosis. AB - OBJECTIVE: To determine the characteristics of pulmonary tuberculosis (TB) patients harbored organisms with isoniazid mono-resistant drug susceptibility pattern. MATERIAL AND METHOD: A retrospective review of medical records for all culture-proven adult pulmonary TB patients in Siriraj Hospital between July 2009 and July 2011 was conducted. Demographic data, clinical presentations, and radiological characteristics were recorded and compared between isoniazid mono resistant and other-resistant groups. Treatment regimens with outcome determination of patients infected with isoniazid mono-resistant strains were also verified. RESULTS: Among 489 patients during the present study period, 28 were infected with isoniazid mono-resistant strain (5.7%). The mean age was 53 +/ 18 years, and 8% of them had a history of previous treatment in the past. When compared with those infected with any other form of resistant strains, isoniazid mono-resistant pulmonary TB patients tended to have less radiographic cavitary lesion (8.3% vs. 26.7%, p = 0.006) but no significant difference was seen in term of demographic data and clinical presentations. All of them who had completed the treatment were cured. No difference in cure rate and relapse rate among patients treated with quinolone or non-quinolone containing regimens. CONCLUSION: Isoniazid mono-resistance shares common clinical features with other resistances pulmonary TB, except for less cavitary lesion from initial chest radiograph. Appropriate drug susceptibility testing with prompt regimen adjustment can lead to a favorable treatment outcome. PMID- 24772585 TI - Comparison between the effects of generic and original salmeterol/fluticasone combination (SFC) treatment on airway inflammation in stable asthmatic patients. AB - BACKGROUND: Little is known about the effect of inhaled corticosteroids (ICS)/long-acting beta2 agonists (LABA) in combination on inflammatory markers in asthma. In addition, therapeutic equivalence of generic salmeterol/fluticasone combination (SFC) and original SFC is as yet unknown. OBJECTIVE: To determine the effects of SFC and the effects of generic and original SFC on airway inflammation in patients with mild-to moderate stable asthma. MATERIAL AND METHOD: A randomized double-blinded, crossover non-inferiority study was conducted to compare the antiinflammatory effects of generic SFC and original SFC on sputum eosinophils as a primary outcome and fractional exhaled nitric oxide (FENO) as a secondary outcome. PATIENTS: The authors studied 51 mild-to-moderate asthmatic patients who ranged from 18 to 80 years of age and were treated with ICS or ICS/LABA of any dose, and whose asthma was stable without an exacerbation episode for at least 3 months prior to study entry. RESULTS: Both sputum eosinophils percentage and absolute eosinophil counts well correlated with FENO levels at baseline prior to the initiation of study medications. Significant reduction in sputum eosinophil percentage was observed following generic SFC and original SFC treatment. The degree of sputum eosinophil suppression by generic SFC was not inferior to original SFC, and this was not affected by treatments with the sequence of generic SFC first vs. original SFC second or original SFC first vs. generic SFC. In addition, there was no significant difference between treatments in terms of normalized gain in asthma control scores, including the number of patients found to have improved asthma control, irrespective of sequence, as change from baseline. However, this was not the case for the magnitude of FENO reduction that occurred after generic SFC treatment to a significantly larger extent than original SFC treatment. CONCLUSION: This short-term study demonstrated that there was no significant difference between generic SFC and original SFC in terms of anti-inflammatory activity and the control of asthma symptoms. However, it is completely unknown whether generic SFC could effectively prevent the development of asthma exacerbations on a long-term basis. Therefore, longer-term studies are indicated to evaluate generic SFC's relative efficacy on asthma exacerbations. PMID- 24772586 TI - Role of meditation in reducing sympathetic hyperactivity and improving quality of life in lupus nephritis patients with chronic kidney disease. AB - BACKGROUND: Lupus nephritis is an important leading cause of chronic kidney disease (CKD) among the young population in Thailand. Systemic lupus erythematosus (SLE) is often characterized by the presence of sympathetic hyperactivity, which results in a perishing outcome. Some physiological studies reveal that meditation may reduce this autonomic dysfunction. The authors hypothesized that meditation could be beneficial in alleviating the sympathetic hyperactivity and improving quality of life in lupus nephritis patients with CKD. MATERIAL AND METHOD: The authors performed a prospective pilot study, which enrolled lupus nephritis patients and categorized enrollees into meditation group and control group. Method of meditation was instructed by an expert in Buddhist studies for a duration of 60 minutes every month. Participants in the intervention group were advised to meditate every day for 24 weeks. To evaluate change in sympathetic activity, normetanephrine level was measured at beginning and the end of study and compared between both groups. Quality of life was determined by SF-36. Heart rate variability was also assessed in meditation group. RESULTS: Thirty eligible patients were recruited into the study. Fifteen patients were stratified in the meditation group and 15 patients in the control group. After meditation for 6 months, serum normetanephrine level decreased, but without statistical significance (0.105 vs. 0.059, p = 0.28). The reduction in normetanephrine level was also observed in the control group (p = 0.11). In the aspect of quality of life, scores of physical and mental components improved significantly. In meditation group, physical component score increased from 21.4 (5.0-50.2) to 62.2 (51.8-88.4) points (p < 0.01) and mental score increased from 16.9 (4.4-46.0) to 72.4 (45.1-81.6) points (p < 0.01). Quality of life score in the meditation group significantly increased more than in control group (p < 0.01). The parameter of heart rate variability in time and frequency domain also improved in the meditation group. CONCLUSION: In lupus nephritis patients with CKD, meditation shows a trend of benefits in reducing sympathetic overactivity and improving quality of life. Our results support the important role of meditation as a valuable adjunctive treatment of lupus nephritis with CKD. PMID- 24772587 TI - The quality of life in implantable cardioverter defibrillator patients. AB - BACKGROUND: Implantable cardioverter defibrillators (ICD) are effective for reducing mortality in patients at high risk for sudden cardiac death (SCD). The effects of the devices on psychological status and quality of life were poor especially in the patients who received ICD shocks. This study compared quality of life (QOL) in a group who received an ICD shock with a group who did not receive an ICD shock. MATERIAL AND METHOD: A prospective study enrolled patients with implantable cardioverter defibrillator who came for followup at Siriraj's device clinic between June and December 2010. These patients completed the Medical Outcomes Study Short Form-36 Questionnaire (SF-36) to assess QOL. RESULTS: There were 138 patients, 105 men and 33 women with a mean age of 59 completed the Medical Outcomes Study Short Form-36 Questionnaire. Sixty-seven (48.55%) patients received an ICD shock. Patients who received the shock had worse general health on the Short Form-36 Questionnaire compared with patients who had no shock (Mean 57.2 +/- 21 in shock group vs. 66.1 +/- 18 in non-shock group, p = 0.011). There was no statistically significant difference in mental health between two groups (p = 0.63). In shock group, there was no statistically significant difference in health status between appropriate, inappropriate, and appropriate-inappropriate shock groups. CONCLUSION: General health in patients who had ICD shock was significantly affected in a negative manner when compared to those who had no shock. PMID- 24772588 TI - Recent onset atrial fibrillation: baseline data from Thai subset of RECORD AF study. AB - BACKGROUND: The RECORD AF study is the first worldwide, prospective, observational 1-year longitudinal survey of real-life management of patients with recently diagnosed atrial fibrillation (AF). The authors present here the baseline data of Thai subset of the study. MATERIAL AND METHOD: The study enrolled consecutive patients of age > or = 18 years, presenting with and treated for AF (< or = 1 year from diagnosis), visiting office- or hospital-based cardiologists. The main primary objectives were to assess therapeutic success and clinical outcomes in rhythm- and rate-control strategies. RESULTS: Of 209 patients recruited between July and December 2007, 200 were eligible for evaluation (mean age: 62.8 years, SD 12.4; 51% males). Hypertension (49%) and dyslipidemia (36%) were the most common underlying cardiovascular diseases (CVDs). Thirty-six point nine percent of patients were at high risk of stroke (CHADS, score > or = 2). In the previous year 93 (52%) patients were diagnosed with paroxysmal AF and 86 (48%) patients with persistent AF. Rate-control was the main treatment strategy used in 151 (75.50%) of the patients, and was more frequently used in persistent AF (94.20%) than paroxysmal AF (61.3%). The most frequent medication used for rhythm-control strategy was amiodarone (83.7%) and, for rate-control strategy, it was beta-blockers (57%). For antithrombotic medication, antiplatelet agents were used in 92 (46%) patients and oral anticoagulation in 86 (43%) patients. CONCLUSION: For Thai patients with AF, hypertension and dyslipidemia were the most common underlying CVDs, and rate control was the preferred treatment strategy. The prospective 1-year data will provide insights on current AF treatment strategies. PMID- 24772589 TI - Prevalence and characters of anomalous coronary artery from coronary magnetic resonance angiography. AB - BACKGROUND: Many types of anomalous coronary artery have been reported. Some forms of the anomaly are potentially malignant and can lead to sudden death. OBJECTIVE: To determine the prevalence and characters of anomalous coronary artery, including the associations of myocardial ischemia. MATERIAL AND METHOD: This is a retrospective study. The authors enrolled patients who were referred for cardiac magnetic resonance (CMR) and had magnetic resonance coronary angiography (MRCA) images. Imaging of the coronary arteries was acquired. The presence and patterns of anomalous coronary artery and the presence of myocardial ischemia was recorded. Myocardial perfusion study was also performed in most patients using adenosine stress test. RESULTS: Anomalous coronary artery was detected in 56 out of 3,703 patients (1.51%). There were 24 men (42.9%). Average age was 62.1 +/- 15.0 years. Most common type was right coronary artery (RCA) from left coronary cusp. Malignant form was demonstrated in 31 patients (55.4%) and myocardial ischemia was detected in 10 patients (23.3%). CONCLUSION: Prevalence of anomalous coronary artery was 1.5%. Most common types were RCA from left coronary cusp (30%) and high take-off RCA (30%). PMID- 24772590 TI - Accuracy of left atrial enlargement diagnosed by electrocardiography as compared to cardiac magnetic resonance in hypertensive patients. AB - BACKGROUND: Anatomical left atrial enlargement is associated with significant cardiovascular morbidity and mortality, heart failure, stroke, atrial fibrillation and diastolic dysfunction. This concept is more pronounced in hypertensive population, who have an especially increased risk of LA enlargement from diastolic dysfunction when compared to the general population. However left atrial enlargement may not be correlated with basic investigation such as electrocardiographic (ECG) criteria. In the past, studies usually correlating ECG criteria with anatomic measures mainly used an inferior M-mode or two-dimensional echocardiography; moreover, these were applied in the general population, not hypertensive patients. In the present study it was sought to determine the accuracy of the ECG criteria to diagnose anatomical left atrial enlargement in a hypertensive population, as determined by volumetric cardiovascular magnetic resonance imaging (CMR). MATERIAL AND METHOD: A total of 230 consecutive hypertensive patients referring for CMR (46.2% males, mean age 71.5 +/- 10.44 years) were enrolled. The ECG criteria for left atrial enlargement (LAE) was analyzed as well as left atrial volume index using the biplane area-length method from CMR. ECG criteria for LAE were assessed by investigator blinded to CMR data. RESULTS: Mean SBP/DBP at the time of CMR was 140/67 +/- 18.5/9.7 mmHg. Mean BMI was 26.8 +/- 4.7 kg/m2, co-morbid diseases were as follows; DM, 68 patients (57.1%) and dyslipidemia 67 patients (56.3%). Mean LA volume index was 59.77 +/- 17.93 ml/m2 and mean LVEF was 63.18 +/- 7.16%. The prevalence of CMR (with the cut-off point of 28 ml/m2) LAE was 98% and by any ECG criteria, was 47%. Sensitivity of individual ECG criteria for LAE, p > 120 ms was 49.6%, biphasic P wave in V1 was 30.8%, and P notch > 40 ms was 9.7%. If combined, ECG criteria p > 120 ms and biphasic P wave in V1, sensitivity increased to 58.1%, that was higher than individual criteria. Specificity of individual ECG criteria for LAE was 100%. CONCLUSION: In the LAE from ECG criteria, at least one criteria is not sensitive for anatomical LAE but for specificity in hypertensive population. For individual criteria, p > 120 ms had the highest sensitivity. These findings from our study emphasized the lack of sensitivity of LAE by ECG criteria in hypertensive patients. Therefore, LAE by ECG criteria might be discovered too late to be the prognosticator in hypertensive patients. PMID- 24772591 TI - One-year clinical outcomes of ST segment elevation myocardial infarction patients treated with emergent percutaneous coronary intervention: the impact of thrombus burden. AB - OBJECTIVE: To investigate the impact of thrombus burden on 1-year clinical outcomes in patients who underwent emergent percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI). MATERIAL AND METHOD: Angiographic evidence of intracoronary thrombus adversely affects the outcome of PCI in STEMI. Large thrombus burden (> or = 2 times vessel diameter) has been shown to be a significant predictor of major adverse cardiac events (MACE). The impact of thrombus burden in Asian patients who undergo PCI in STEMI has not been described. This is an observational cohort of patients with STEMI from June 1, 2008 through May 31, 2011, who underwent emergent PCI (primary or rescue). The patients were categorized into two groups according to the angiographic thrombus burden, large thrombus burden (> or = 2X vessel diameter size, LTB) and small thrombus burden (< 2X vessel diameter size, STB). MACE was defined as the composite of death, repeat myocardial infarction, target vessel revascularization and stent thrombosis. RESULTS: 202 patients were enrolled, 72% were male and the mean age was 60 years old. 134 patients (66%) presented with an occluded infarct related artery. Primary PCI was performed in 90.6% of the patients and the remainder underwent rescue PCI. One hundred eleven (55%) patients were categorized into the STB group and 91 patients (45%) into the LTB group. The use of aspiration thrombectomy was significant higher in the LTB group (LTB 80.2% vs. STB 60.44%, p = 0.002). A higher proportion of patients in the STB group underwent direct stenting strategy (STB 32.4% vs. LTB 18.7%, p = 0.027). There were no significant differences in final TIMI grade 3 flows and procedural success between the groups. Overall, in hospital, mortality was 13.4% and there were no significant differences among the groups. At 1-year follow-up, there was no significant difference in cumulative MACE-free survival in the LTB vs. STB group (82.4% vs. 79.3%, 95% confidence interval for the difference: -8.0% to 13.8%, p = 0.59). CONCLUSION: In the current study, large thrombus burden is not an independent predictor of 1-year cumulative MACE in STEMI patients who were treated with emergent PCI. PMID- 24772592 TI - Low-density lipoprotein cholesterol goal attainment among post myocardial infarction patients on lipid lowering therapy at Siriraj outpatient clinic. AB - BACKGROUND: Cardiovascular disease is leading cause of death in the world and third order in Thailand. A number of large-scale clinical trials have demonstrated that statins reduce cardiovascular morbidity and mortality. Nevertheless, in clinical practice less than 50% of these patients could achieve the LDL-C goal based on NCEP ATP III treatment goal. The objective of this study is to assess the percentages of post myocardial infarction patients who attained LDL-C goal in Siriraj Hospital. MATERIAL AND METHOD: This is a retrospective review of all adult patients diagnosed with first event myocardial infarction (STEMI and NSTEMI) at Siriraj Hospital between 2007 and 2009. Patients were included if they were 18-75 years-old, received statins therapy before discharge and followed-up regularly at least 1 year at OPD. Patients were excluded if triglyceride > 400 mg/dL. Patient demographics, type of reimbursement and discharge medication data were collected. The goal attainment was assessed and result was demonstrated in percentages of patients who achieved LDL goal compare with all patients meeting exclusion and inclusion criteria. This goal is based on NCEP ATP III 2004 for the management of dyslipidemias treatment goal of LDL-C < 100 mg/dL. RESULTS: Eight hundred and eighty eight patients were diagnosed with myocardial infarction from 2007 to 2009. One hundred seventy-nine patients meet inclusion and exclusion criteria. Seventy-three percent are male with mean age 58.64 +/- 10.21 year-old. Civil servant reimbursement is most common type of reimbursement, for about half of patients. LDL-C goal achievement based on NCEP ATP III 2004 for the management of dyslipidemia was 84.9%. The majority of prescribed lipid lowering agent was simvastatin 72.1%, and then atorvastatin 20.7% and rosuvastatin 7.3%, respectively. LDL-C goal achievement did not depend on type of statin, type of reimbursement or type of specialist follow-up at OPD. CONCLUSION: Patients who were diagnosed first event of myocardial infarction (STEMI and NSTEMI) admitted in Siriraj hospital from 2007 and 2009, 84.9% of them could achieve LDL-C goal based on NCEP ATP III 2004. PMID- 24772593 TI - Effect of renal nerve denervation for resistant hypertension in Thai patients: a report of the first cases series in Thailand. AB - BACKGROUND: Hypertension is a major contributor to death. A significant portion of the patients is still in resistant hypertension with current medical treatment. Renal nerve denervation can reduce sympathetic activity, and subsequently reduce BP in western population. OBJECTIVE: To evaluate the effect of renal nerve denervation in treatment of resistant hypertension in Thai patients. MATERIAL AND METHOD: The present study is a case series of the first four Thai patients who underwent renal nerve denervation at Faculty of Medicine Siriraj Hospital. All patients had resistant hypertension. Baseline medical records, including demographic data, baseline systolic and diastolic blood pressure (BP), ambulatory BP monitoring, number and dose of anti-hypertensive medications before and after renal nerve denervation, were recorded. Patients were followed-up at 1 month, 3 month and 6 months after the procedure. RESULTS: Patients were taking antihypertensive medications ranging from 5 to 8 types of drug classes, but in all cases, their blood pressure was still not under control at baseline range from 160-190 of systolic BP and 100-120 mean BP. One of the patients had a history of hemorrhagic stroke as a consequence of un-control hypertension. All of them had blood pressure reduction immediately at the end of the first 24 hrs, and this was sustained until follow-up at 3-6 months. The mean of systolic BP reduction is 35.2 +/- 9.9 mmHg at 3-months follow-up. The mean reduction of the number of anti-hypertensive medications was 3.5 +/- 3.0 at 3 month follow-up. CONCLUSION: The authors found that the percutaneous renal nerve denervation was very effective in blood pressure reduction in these first four cases of Thai patients with resistant hypertension. PMID- 24772594 TI - G-suited for prevention of syncope in patients with vasovagal syncope: a pilot study. AB - BACKGROUND: Vasovagal syncope (VVS) represents by far the most common cause of syncope as it is diagnosed in around 50% of all patients that come to an emergency department. Although VVS is not fatal, it can cause an injury. Even serious injuries are not common, but there are reports of serious injuries of up to 5%. There are no current studies that demonstrate the effectiveness of any treatment. Past studies found that an Anti-Gravity suit (G-suit) can increase blood pressure and has been reported to prevent orthostatic hypotension effectively in patients with diabetes. It is possible that the G-suit can prevent VVS. OBJECTIVE: In the present study, the authors assessed the efficacy of G-suit for vasovagal syncope prevention. MATERIAL AND METHOD: In this open-label, randomized controlled study, we used the Italian tilt protocol, namely 60 degree passive tilting followed by 0.4 mg nitroglycerin challenge when the passive phase fails to induce syncope. If test was positive, then patient was enrolled. Tilt table test was repeated to compare G-suited and no G-suited to assess efficacy of G-suit for vasovagal syncope prevention. RESULTS: 10 patients were enrolled. There is no difference between the control group and an experimental group. In this study there is no cardio-inhibition vasovagal syncope. Positive tilt table test occurred in 50% of the patients receiving G-suited and 100% in control group (p 0.133). CONCLUSION: G-suit is unable to prevent syncope in patients with positive tilt table test but the result is not statistically significant. However, the number of patients may be too small. PMID- 24772595 TI - The temporal changes of tissue oxygen saturation (StO2) and central venous oxygen saturation (ScvO2) during sepsis/septic shock resuscitation. AB - BACKGROUND: Restoration of adequate tissue oxygenation is the goal of shock resuscitation. Commonly, central venous oxygen saturation and lactate clearance are used to monitor this therapeutic endpoint in sepsis. Tissue oxygen saturation (StO2) obtained by near-infrared spectroscopy (NIRS) has been introduced as an alternative. OBJECTIVE: To determine the temporal changes of tissue oxygen saturation and central venous oxygen saturation (ScvO2) in severe sepsis/septic shock patients from initial resuscitation to 72 hours after treatment, and to explore the relationship between both parameters including the association with outcomes. MATERIAL AND METHOD: A prospective, observational study was performed in a single center 14-bed university hospital, Medical Intensive Care Unit. The present study enrolled severe sepsis/septic shock patients aged > 18 years. Central venous oxygen saturation and tissue oxygen saturation were measured at 0 1st hour (right after central venous catheter was placed), 1st-6th hour (the point when hemodynamic goal was achieved), 6th-9th hour 9th-12th hour 24th hour, 48th hour, and 72th hour in simultaneous fashion. RESULTS: Thirty-five patients were enrolled and 170 paired-measurements were made. During the first 24 hours, both tissue and central venous oxygen saturation gradually increased in the same direction. However only fair correlation was observed (r = 0.253, p = 0.01) and the agreement was not satisfactory. Mean StO2 during the first 24 hours was higher in survived patients ((82.6 +/- 9.3 vs. 74.3 +/- 16.0, p = 0.016). When partitioned ScvO2 into ranges, namely ScvO2 < 60%, 60-64%, 65-69%, 70-74%, 75 79%, 80-84% and > 85%, the corresponding StO2 values were found randomly throughout the ScvO2 ranges, without specific predilection. CONCLUSION: The temporal changes of StO2 and ScvO2 during sepsis/septic shock resuscitation were demonstrated. Their correlation and agreement were not satisfactory. No specific StO2 value for the reversal of tissue hypoxia was observed. More studies are needed to explore the benefit of StO2 as a bedside tool for tissue perfusion monitoring. PMID- 24772596 TI - Therapeutic goal achievements during severe sepsis and septic shock resuscitation and their association with patients' outcomes. AB - BACKGROUND: Severe sepsis and septic shock are associated with high mortality. "Early goal-directed therapy" (EGDT) has been shown to improve survival. The authors report here the goal achievements in the protocol and their association with patients' outcomes. MATERIAL AND METHOD: A prospective cohort study of patients with severe sepsis and septic shock who were admitted from the Emergency Department from April 2011 to September 2012. All underwent the resuscitation protocol aimed to achieve hemodynamic goals within 6 hours after diagnosis. These goals included: 1) mean arterial > 65 mmHg, 2) urine output > 0.5 ml/kg/hour and 3) superior vena cava O2 saturation > 70% or serum lactate clearance > 10%. The primary outcome was 28-day mortality RESULTS: Of the 175 enrolled patients, 23 (13.1%) achieved all 3 goals at 6 hour while 75 (42.8%) achieved 2 goals and 52 (29.8%) achieved only 1 goal. The 28-day mortality of these patients was 8.7%, 16% and 35.5%, respectively while 44% of those who did not achieve any goal died. A central venous catheter was placed in 79 patients, 46 of whom had it inserted during the first 6 hours, and 42 of whom had a CVP of 8-12 mmHg. Only 13 patients had their ScvO2 measured. Mean arterial pressure target was achieved in 129 patients, who had lower initial APACHE II score, lower initial lactate level and higher initial blood pressures than those who did not. These patients received less fluid at 6 hours, at 24 hours and at 3 days, respectively; they also received less norepinephrine. This group had lower mortality (28-day mortality 19.4% vs. 34.86%, p = 0.043). Of 119 patients who had achieved the urine output goal, 21 reached this goal alone and their survival was better than those who did not achieve any target goal. Serum lactate was monitored in 51 patients and a clearance of > 10% was noted in 23 of them. These patients were divided into 3 groups.: group 1 consisted of patients with initial lactate < 2; group 2 were patients with initial lactate > 2, which decreased during resuscitation; group 3 consisted of patients with initial lactate > 2, which increased after wards. The mortalities were 7.7%, 14.3% and 43.6%, respectively, p = 0.011. CONCLUSION: The achievement of therapeutic targets at 6 hours after sepsis/septic shock resuscitation was associated with improved survival, especially when more goals were reached. Although the achievement of adequate tissue oxygenation was proved beneficial, only one-third of the patients were monitored. PMID- 24772597 TI - Non-invasive estimated continuous cardiac output (escCO) during severe sepsis and septic shock resuscitation. AB - BACKGROUND: Cardiac output (CO) is an important hemodynamic parameter during sepsis and septic shock resuscitation. Conventionally, this value is obtained at bedside by the thermodilution technique, which requires a pulmonary artery catheter (PAC). Estimated Continuous Cardiac Output (esCCO, Nihon Kohden, Japan) calculated from pulse-wave transit time (PWTT) was examined here as an alternative. MATERIAL AND METHOD: A prospective study was performed in a 14-bed ICU facility. Patients with severe sepsis and septic shock who had PAC placed were included. Serial thermodilution cardiac outputs (CO(IBT)) and esCCO (COesCCO) were obtained at the beginning of resuscitation (t0), at 48 hours (t48), and at 72 hours (t72). Other parameters from the tested device; namely, estimated continuous cardiac index (esCCI), estimated stroke volume (esSV), and estimated stroke volume index (esSVI), were also achieved. RESULTS: A total of 90 paired readings from ten ICU patients were collected. The overall correlation coefficient (R) between COesCCO and CO(IBT) was 0.76. When focusing on the correlation from each time point, we found R at t0 = 0.65, t48 = 0.74, and t72 = 0.84 (all p < 0.001). Bland and Altman analysis corrected for repeated measures showed a bias of 1.2 liter/min and limits of agreement from -2.8 to +5.2 liter/min. Results also showed fair to poor correlation with other parameters that derived from this device (esCCI, esSV esSVI). CONCLUSION: The estimated continuous cardiac output (esCCO) correlated well with the cardiac output obtained by thermodilution techniques, especially when patients were out of shock. PMID- 24772598 TI - Factors associated with consumption of caffeinated-beverage among Siriraj pre clinical year medical students, A 2-year consecutive survey. AB - BACKGROUND: Previous studies showed that significant proportion of medical students consumed caffeine to face sleep-deprived daily schedules. OBJECTIVE: To monitor the trend of caffeinated-beverage consumption among Siriraj medical students as well as to study possible factors associated with caffeine dependency. MATERIAL AND METHOD: The questionnaire was distributed to a class of medical students for 2 consecutive years. Statistical analysis was performed for descriptive purpose. RESULTS: 269 (89.7%) and 225 (74.5%) questionnaires were returned in year 1 and year 2, respectively 16.2% refused to take caffeine beverages totally. 13% of those who consumed caffeinated-beverages developed caffeine dependence. From logistical analysis, positive history of smoking-family member and female sex were the only other two factors associated with caffeine dependency (OR 2.19, 95% CI 1.04-4.61 and 1.76, 95% CI 1.01-3.07, respectively). Other investigated factors included: exercise (p = 0.08); sleep hours (p = 0.24); reading beverage labels (p = 0.87); alcohol consumption (p = 0.59); class performance (p = 0.87); family member coffee-drinking habits (p = 0.66);family member alcohol-drinking habits (p = 0.18); and family income (p = 0.06). CONCLUSION: Caffeinated-beverage consumption was common among Siriraj medical students. No significant change was detected in the pattern of caffeinated beverage consumption within the study period. Positive history of smoking family members and female sex were found as the only other two factors correlated with caffeine dependency. PMID- 24772599 TI - The effectiveness of holistic diabetic management between Siriraj Continuity of Care clinic and medical out-patient department. AB - BACKGROUND: Diabetes mellitus is one of the most common diseases in the Thai population, and it is well known that diabetic complications could be prevented with appropriate management. Despite published guidelines, most Thai patients with diabetes do not achieve treatment goals. Siriraj Continuity of Care clinic (CC clinic) was recently established in order to provide training for medical students and internal medicine residents. It is possible that the training component in the CC clinic may contribute to better overall outcomes in type 2 diabetes mellitus (type 2 DM) patients when compared with usual care at the medical out-patient department (OPD). OBJECTIVE: To compare the effectiveness of diabetic management in type 2 diabetes mellitus patients who attended the CC clinic and the medical OPD. MATERIAL AND METHOD: Retrospective chart review was performed in type 2 diabetes mellitus patients who were treated at either clinic at Siriraj Hospital in 2007-2011. Baseline demographics, treatment strategies and outcomes, and participation in an appropriate health maintenance program were assessed in both groups. RESULTS: Seven hundred and fifty seven medical records were reviewed, including 383 patients in the CC clinic group and 374 in the OPD group. Mean HbA1c was significantly lower in the CC clinic group compared with the OPD group (7.3 +/- 0.9% and 7.8 +/- 1.3%, respectively, < 0.001). The number of patients who achieved goal HbA1c of less than 7% in CC clinic group was 123 (32.1%) compared with 91 (24.3%) in the OPD group (p = 0.039). More patients were screened for diabetic complications in the CC clinic group compared with the OPD group, including screening for diabetic neuropathy (57.4% vs. 2.1%, p < 0.001), diabetic retinopathy (56.7% vs. 36.6%, p < 0.001), and diabetic nephropathy (80.9% vs. 36.9%, p < 0.001). Patients in the CC clinic group had a higher rate of age-appropriate cancer screening than those in the OPD group (54.2% vs. 13.3%, p < 0.001 for breast cancer; 24.0% vs. 0.9%, p < 0.001 for cervical cancer; and 23.0% vs. 7.4%, p < 0.001 for colon cancer). Moreover, significantly more patients in the CC clinic group received recommended immunization (influenza, diphtheria tetanus and pneumococcal vaccine) compared with the control group (p < or = 0.001). CONCLUSION: Diabetic patients treated at the CC clinic had better clinical outcomes and healthcare maintenance compared with those who received usual care at the medical OPD. Continuity of care and integrated training component may have contributed to the improved outcomes. PMID- 24772600 TI - Causes of prolonged hospitalization among general internal medicine patients of a tertiary care center. AB - BACKGROUND: Unnecessary days of prolonged hospitalization may lead to the increase in hospital-related complications and costs, especially in tertiary care center Currently, there have not been many studies about the causes of prolonged hospitalization. Some identified causes could, however, be prevented and improved. OBJECTIVE: To identify the prevalence, causes, predictive factors, prognosis, and economic burden of prolonged hospitalization in patients who had been in general internal medicine wards of the tertiary care center for 7 days or more. MATERIAL AND METHOD: Retrospective chart review study was conducted among all patients who were admitted for 7 days or more in general internal medicine wards of Siriraj Hospital, the largest tertiary care center in Thailand. The period of this study was from 1 August 2012 to 30 September 2012. Demographic data, principle diagnosis, comorbid diseases, complications, discharge status, total costs of admission and percentage of reimbursement were collected. The causes of prolonged hospitalization at day 7, 14, 30, and 90 were assessed. RESULTS: Five hundred and sixty-two charts were reviewed. The average length of stay was 25.9 days. The two most common causes of prolonged admission at day 7 were treatment of main diagnosed disease with stable condition (27.6%) and waiting for completion of intravenous antibiotics administration with stable condition (19.5%). The causes of prolonged hospitalization at day 14 were unstable condition from complications (22.6%) and those waiting for completion of intravenous antibiotics administration with stable condition (15.8%). The causes of prolonged admission at day 30 were unstable conditions from complications (25.6%), difficulty weaning or ventilator dependence (17.6%), and caregiver problems (15.2%). The causes of prolonged hospitalization at day 90 were unstable condition from complications (30.0%), caregiver problems (30.0%), and palliative care (25.0%). Poor outcomes were shown in the patients admitted more than 90 days. Percentage of death, being bedridden, and re-admission were 55, 40, and 22, respectively. The goal of treatment was only palliative care in 80 percent of this patient group. Respiratory failure among the hospitalized was the strongest predictive factors of death (Odds ratio = 7.5, p < 0.001). The average costs of admission per patient was 163,870 THB and the percentage of reimbursement was only 72%. For total costs of admission in these two months, Siriraj Hospital lost a large amount of money (about 26 million THB) for patients admitted for 7 days or more and almost 50% of this was spent on the patients admitted for 90 days or more. The average cost of admission per patient in the latter group was 1,073,004 THB. CONCLUSION: Prolonged hospitalization had adverse outcomes for the patients and the hospital, such as high complications, poor outcomes, high costs of treatment and low reimbursement ratio that created an enormous economic burden for the hospital. Therefore possible preventable causes of prolonged admission must be identified, prevented and managed by improving quality of multidisciplinary health care system and ancillary services. PMID- 24772601 TI - A survey of opinions regarding wishes toward the end-of-life among Thai elderly. AB - BACKGROUND: Knowledge of wishes toward the end-of-life is crucial for carrying out high quality palliative care. However, advance directive is not commonly available among Thais, particularly for non-cancerous older patients. OBJECTIVE: The present study aimed to explore Thai older person's wishes toward cares needed at the end-of-life. MATERIAL AND METHOD: A convenience sample of 100 older patients, who attended geriatric clinic at a university hospital in Thailand, was recruited. A 3-page questionnaire developed to suit Thai culture was utilized to elicit opinions concerning circumstances around end-of-life period. RESULTS: All participants were Buddhists with mean age of 75.9 (8.2). Toward the end-of-life, the majority wanted to know the truth about their illnesses and to be free from uncomfortable symptoms. Seventy-five percent did not want "prolong-life" treatments when chance of surviving is slim. Age less than 70 and having education of no more than 6 years were factors associated with being unwilling to prolong suffering with OR of 9.88 (1.20-81.57, p = 0.03) and 3.15 (1.11-8.95, p = 0.03), respectively. Interestingly, fifty-six percent of elderly did not want to die at home. Age less than 70 was the only factor significantly associated with being unwilling to die at home with OR of 2.80 (95% CI = 1.05-7.47, p = 0.04). CONCLUSION: The present study illustrated older persons' opinions in relation to cares at the end-of-life from a Thai perspective, which showed some similarities and differences when compared to western countries. These opinions should be crucial for carrying out optimal and qualitative end-of-life care for older people when advanced care planning is not in place for the individual. PMID- 24772602 TI - Interaction between physicians and pharmaceutical representatives, an insight from Thailand. AB - BACKGROUND: Evidence from Western countries has shown that informal relationships between the pharmaceutical industry and physicians could have some effect on physicians' prescribing behavior Many countries have, therefore, developed conflict-of-interest policies to mitigate the effects of such interactions. Interactions between pharmaceutical representatives and physicians, one among those relationships, have never been systematically studied in Thailand. OBJECTIVE: To measure, for the first time, interaction between pharmaceutical industry representatives and resident physicians in Thailand and to assess physicians' attitudes toward this interaction, and factors which determined their frequency. MATERIAL AND METHOD: The authors surveyed 970 residentphysicians in May 2009 at a university hospital in Thailand using 3-page anonymous, self administered questionnaire and analyzed their responses. RESULTS: Overall response rate was 71.6%. Three-fourth of trainees had weekly conversations with pharmaceutical representatives. Nearly 90% of physicians receive at least one gift per month. Residents in one of the specialties with the highest prescribing costs were most likely to have such interaction with an adjusted odds ratio (OR) of 7.91 (4.61-13.58)for having conversations and 5.18 (3.28-8.17) for receiving non-educational gifts. Those residents who perceived that it is impolite to decline gifts were more likely to accept non-educational gifts: adjusted OR of 1.68 (1.04-2.71). CONCLUSION: Frequency of interaction could have only been a marker for level of exposure, not a genuine influence on physicians' prescribing behavior Nevertheless, given that resident physicians in Thailand have frequent interaction with pharmaceutical industry representatives, guidance on managing conflict-of-interest should be included in medical training. PMID- 24772603 TI - Erysipelothrix rhusiopathiae bacteremia without endocarditis associated with psoas abscess: the first case report in Thailand. AB - The authors report a patient with a rare manifestation of invasive septic Erysipelothrix rhusiopathiae infection without endocardial involvement. Our patient presented with progressive paraparesis and subacute fever for ten days. He had underlying diabetes mellitus and alcoholic cirrhosis. Magnetic resonance imaging (MRI) of the lumbosacral spine showed a psoas abscess with vertebral osteomyelitis and discitis at level of L23 of the lumbar spine. His blood culture grew E. rhusiopathiae. Transthoracic echocardiography demonstrated normal endocardium. Surgical drainage and debridement with concomitant intravenous antibiotics administration resulted in clinical improvement, including neurological status. MRI showed resolution of the psoas abscess and osteomyelitis. Erysipelothrix infection should be considered as a causative pathogen of musculoskeletal infection in immunocompromised patients. To our knowledge, this is the first case report of psoas abscess caused by E. rhusiopathiae in Thailand. PMID- 24772604 TI - The underemphasized value of advancing scientific method. PMID- 24772605 TI - Levels, grades, and strength of evidence: "What's it all about, Alfie?". PMID- 24772606 TI - Developing a measure of cultural-, maturity-, or esteem-driven modesty among Jewish women. AB - Understanding modesty and how it relates to religiosity among Jewish women was relatively unexplained, and as part of a larger study, a measure was needed. The purpose of this article is to report on three studies which represent the three stages of instrument development of a measure of modesty among Jewish women, "Your Views of Modesty": (a) content/concept definition; (b) instrument development; and (c) evaluation of the psychometric properties of the instrument: reliability and validity. In Study I, Q methodology was used to define the domain and results suggesting that modesty has multidimensions. In Study II, an instrument was developed based on distinctive perspectives from each group or what was important and not so important. This formed a 25-item Likert scale. In Study III, a survey of 300 Jewish women revealed internal consistency estimates with Cronbach's alpha 0.92, indicating high degree of internal consistency reliability for "Your Views of Modesty." For construct validity, four factors were found explaining 55% of the variance of modesty: (a) religion-driven, (b) maturity-driven, (c) esteem-driven, and (d) public-based modesty was identified. "Your Views of Modesty" shows good evidence for reliability and validity in this Jewish population. PMID- 24772607 TI - A biobehavioral framework of worry for nursing application. AB - Worry, characterized by repetitive and involuntary aversive thoughts about perceived concerns, is a central mental health complaint known to negatively impact quality of life of individuals facing perceived threats to health or well being. Although empirical focus on worry has escalated over the past three decades, there has been less attention to current research trends and knowledge development related to this important phenomenon in nursing. This article presents a biobehavioral conceptual framework of worry for nursing application that is derived from a concept synthesis of biological, behavioral, clinical, and cognitive psychology sources. Databases including CINAHL, EBM Review, Health & Wellness Resource Center, PsycINFO, and PubMed were systematically reviewed for the years 2000-2012. The adapted conceptual framework describes relationships among perceived threat; process, structure, and content worry attributes; and outcomes of worry. The framework may be applied in clinical environments as a resource to better understand and care for patients facing perceived threats to health and well-being. The framework contributes a foundation to build empirical knowledge for nursing practice, theory, and research that has potential to improve patient well-being and health-related quality of life outcomes. PMID- 24772608 TI - Living with an implantable cardiac defibrillator: a model of chronic uncertainty. AB - Over the last two decades, the number of patients receiving implantable cardiac defibrillators (ICDs) for the prevention of sudden cardiac death has grown significantly. This growth is largely the result of broadened indication for ICD use because of the success of trials demonstrating efficacy. Early ICD indication centered on secondary prevention, which then advanced to primary prevention in high-risk patients. Nurses delivering care to these patients not only manage this complex technology but also patients' uncertainty about their survival and related psychosocial adjustment to receiving an ICD. To inform practice, theoretical models such as Mishel's (1988) uncertainty in illness model provide insight into such acute phases of illness. This article proposes expansion of the uncertainty in illness model to advance knowledge in this field for nurses caring for patients with ICD. PMID- 24772609 TI - Successful aging from the viewpoint of older adults. AB - The purpose of this study was to investigate older adults' perceptions of successful aging within the context of the theory of successful aging to validate and further inform this theory. This research was a secondary, qualitative analysis of data from two earlier studies in which participants were asked to provide a response to the open-ended question, "What does successful aging mean to you?" Content analysis using multiple coding was independently conducted by the investigators. Eight broad themes emerged: active independence, relationships with people, relationship with God, comfort resources, health, beneficial contribution, positive perspective/coping, and freedom. Differences and similarities of themes by study subgroups were also explored. The coping processes, functional performance mechanisms, and intrapsychic factors from the theory of successful aging were well represented in the findings of this study. The coping process of spirituality was less frequently represented, whereas that of gerotranscendence was slightly more often described. Interventions that enhance these factors associated with successful aging have the potential to improve quality of life and provide appealing, meaningful activities for older adults. PMID- 24772610 TI - [Role of transthoracic biopsy in the modern diagnosis of tumors of organs in the thoracic cavity]. AB - This review summarizes data of publications and meta-analyses devoted ton the use of transthoracic biopsy. It is showed that the method continues to be one of the main ways to diagnose pathological processes in the thoracic cavity's organs, especially tumors of the lungs, pleura, mediastinum and chest wall. Modern methods of navigation trepan-needles can receive sufficient volume of pathological tissue samples for subsequent full morphological study to individualize and optimize treatment algorithms. PMID- 24772611 TI - [Epidemiology and molecular pathogenesis of tumors of the oral cavity and pharynx]. AB - Tumors of the oral cavity and pharynx make up the majority of so-called tumors of the head and neck and represent a heterogeneous group of tumors of different origin. Since 90% of these tumors are squamous cell carcinomas of the mucosa, literature often refers to this position. Except squamous cell carcinomas, different types of sarcomas, lymphomas, melanomas of the mucous membranes, benign tumors, etc. and pharynx may develop there. PMID- 24772612 TI - [Neoadjuvant chemotherapy for colorectal cancer--time to learn a new treatment strategy?]. AB - The article discusses the possibility of neoadjuvant chemotherapy in colon cancer patients and rectal cancer patients without the additional use of radiation therapy. The possible risks and benefits of such approach are analyzed and the data of available clinical studies are provided. PMID- 24772613 TI - [Diabetes mellitus as a modifier of the course of tumors of the female reproductive system]. AB - Frequency of separate malignancies and diabetes tends to an increase. This is one of the reasons that diabetes is more often attracting attention as a potential risk factor for cancer. At the same time, in general, relatively less attention is paid to the analysis of the question of whether the presence of diabetes is able to influence on features of neoplasm, inherent at the diagnosis, as well as on the clinical course of the tumor process and its outcomes. In this paper, exactly this aspect of the problem is considered on example of such common and characterized by undoubted specificity of tumors of the female reproductive system as breast cancer and uterine cancer. PMID- 24772614 TI - [Epidemiology of malignant tumors of the brain and other parts of the CNS in the North-West Federal District of Russia]. AB - For the first time in Russia the dynamics of morbidity and mortality from malignant tumors of the brain and other parts of the CNS in the North-West Federal District of Russia is presented. A precise elaboration of data on cases is performed according to the database of the Population-based Cancer Registries of St. Petersburg and Arkhangelsk region. PMID- 24772615 TI - [Mortality from cancer of the population living close to a large nuclear power plant]. AB - There was analyzed cancer mortality of residents of Seversk, located close to the world's largest complex of enterprises of the nuclear industry - the Siberian Chemical Enterprise (the period from 01.01.1970 till 31.12.2005 For comparison there were used rates of cancer mortality in the nearest town (Tomsk), similar in climate-geographical, economic and social conditions. The study found that cancer mortality of Seversk residents during the period 1970-2005 increased in 3.2 times (from 70.2 to 223.5 per 100,000). Among the causes of cancer mortality in men there were prevailed tumors of the digestive system as well as blood and lymphatic tissues. In women, the leading causes of death were tumors of the digestive system, the genitals and the breast. Standardized rates of cancer mortality in the Seversk population were lower than in residents of Tomsk, except female mortality due to hematological malignancies and malignant tumors of the urinary tract and genitals. PMID- 24772616 TI - [Proliferation of cancer stem cells in colorectal adenocarcinoma]. AB - Correlation between level of ALDH1 expression and metastases development in patients with colorectal adenocarcinoma was not revealed. Proliferation of stem cancer cells (ALDH1-positive) was significantly lower comparatively ALDH-1 negative tumor cells (p < 0.001). Proliferation of stem cancer cells vary from 0,1% to 10%. PMID- 24772617 TI - [Cytogenetic status of patients with cancer of the gastrointestinal tract before and after treatment]. AB - Aim of this study was to analyze the karyological indicators in exfoliated cells in patients with cancer of the gastrointestinal tract. There was revealed statistically significant (p < 0.01) increase of all parameters in buccal and nasal epithelium in such kind of patients compared to healthy persons. These changes were systemic in nature and reflected the general state of the organism. PMID- 24772618 TI - [SPECT-CT in the diagnosis of metastatic skeletal lesion]. AB - The aim of this study was to compare the diagnostic capabilities of SPECT-CT and planar osteoscintigraphy with 99m-Tc-labeled phosphates in cancer patients. There were examined 227 patients with various primary malignancies (mean age 57 years). Depending on the identified changes in the planar study patients were divided into four groups: I--no abnormalities (n = 62), II--benign changes (n = 67), III- suspected metastatic lesion (n = 41), IV--metastatic lesion (n = 57). The use of SPECT-CT in group I revealed metastatic lesion in 7 (11%) patients, in 15 (24%) patients there were additionally found benign focal changes in the skeleton. In group II metastases were found in 4 (6%) patients; it was not possible to exclude secondary lesion in 3 (4%) patients. In group III suspected metastatic lesion was excluded in 29 (71%) and confirmed in 7 (17%) patients. In group IV in 14 (25%) patients there were found non-tumor changes, the nature of the changes has not been found in 2 (4%) patients. As a result, SPECT-CT with 99m-Tc-labeled phosphates is more informative method of diagnosis of metastatic skeletal lesion than planar osteoscintigraphy. SPECT-CT application resulted in changes of conclusions of the planar scintigraphy about the nature of bone pathology in 67 (30%) cancer patients. However, in 4% the recognition of the nature of changes in the skeleton has failed. PMID- 24772619 TI - [Effect of intraoperative intrapelvic chemotherapy with hyperthermia on the incidence of rectal cancer recurrences]. AB - Often due to a severe somatic condition of the patient, the presence of perifocal inflammation, anemia, age, it is not possible to perform neoadjuvant chemoradiotherapy for rectal cancer. To improve cancer treatment outcomes in these patients intraoperative intrapelvic chemotherapy with hyperthermia is used at the Centre. In the present study there included 120 patients with rectal cancer at stage T3-4N0-2M0, while 60 patients underwent intraoperative intrapelvic chemotherapy with hyperthermia (cisplatin at a dose of 150 mg, the time of the procedure--60 minutes, the temperature of the perfusate--44-45 degrees C). Conducting of intraoperative intrapelvic chemotherapy with hyperthermia allowed reducing the frequency of local recurrence in 2 times from 16.7% to 8.3% and increasing a 3-year overall survival by 10%--from 63% to 73%, which shows intraoperative intrapelvic chemotherapy with hyperthermia as an effective method in the prevention of local recurrences. PMID- 24772620 TI - [Experimental technology of chemoperfusion treatment for abdominal carcinomatosis in ovarian cancer]. AB - An experimental technology of normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet has been elaborated to treat abdominal carcinomatosis in ovarian cancer. Antitumor effects of the treatment were evaluated for the duration of animal life. Normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet in comparison with the standard intraperitoneal administration significantly increased the median life expectancy by 75-92%. Hyperthermic intraperitoneal chemoperfusion with dioxadet demonstrated potentiation of antitumor effect of hyperthermia and dioxadet. Experimental technology is recommended for testing new drugs and methods of chemoperfusion for malignant tumors affecting the peritoneum. PMID- 24772621 TI - [The evaluation of metastatic damage of the liver of the Wistar rats under conditions of spontaneous development of the Walker 256 carcinosarcoma]. AB - There was held micro- and ultrastructural study of the liver of the Wistar rats in the dynamics of development of transplantable Walker 256 carcinosarcoma. The regularities of the progression of the tumor process in the form of liver metastases with appearance of intralobular metastases. In the early stages of tumor development it was marked activation of cytotoxic function of the liver with necrosis of tumor lesions accompanied by a decrease of the structural density of metastases. In advanced stages of development of the Walker 256 carcinosarcoma an estimation of parameters of tumor invasion in the liver showed an intensification of these processes with increased severity of inflammatory reactions. PMID- 24772622 TI - [Experimental study of the effect of benzidinsulfon, included in the group of diaminodifenils, with potential carcinogenic effects]. AB - There was performed a study of carcinogenicity of benzidinsulfon (4.4' diaminodiphenil sulfone) in rats and mice. Experimental animals (99 mice and 99 rats, approximately equally divided by sex) received the drug throughout the life by subcutaneous injections (once a week) or addition to food (5 times a week). A single dose per animal in rats was: subcutaneous administration--50 mg (in females it was reduced due to the toxicity after beginning of the experiment to 25 mg) in 0.5 ml of oil, while feeding--20 mg in 0 5 ml of oil; in mice- respectively 5 mg in 0.2 ml of oil, and 2 mg in 0, 2 ml of oil. The maximum amount of a substance when administered subcutaneously to male rats was 5.65 g, to female rats--2, 68 g, when fed to rats 12.44 g, when injected subcutaneously in mice--380 mg, when fed--737 mg. The survival of experimental animals was significantly reduced as compared to the intact control because of the toxic effect of the drug, preferably chronic nephrosis with nephritic component and secondary nephrosclerosis and as well as miocardiosclerosis and aortic sclerosis. Frequency and timing of detection of tumors in experimental animals was not significantly different from that observed in the control that indicated the absence of carcinogenic features of benzidinsulfon. PMID- 24772623 TI - [Experimental evaluation of synergism of cisplatin with L-lysine-alpha-oxidase]. AB - Synergism effects of cisplatin and L-lysine-alpha-oxidase (LO), while sequential (no interval) administration of drugs depends on the tumor model and duration of treatment. Synergism is identified at intraperitoneal daily (during 3 days) administration of cisplatin to experimental animals in single doses of 1.5 or 3.0 mg/kg and intravenously 5-fold after 48 h administration of LO and also administered intravenously in cumulative doses of 300-600 E / kg discretely, the first dose--doubled. Synergism of cisplatin and LO is showed by significant (p < 0.05) therapeutic gain against cisplatin at such indicators as increased survival of mice with P388 tumor and increased inhibition of primary tumor melanoma B16. PMID- 24772624 TI - [Effect of epsilon-aminocaproic acid, cyclophosphamide and their combination on the growth of autochthonous sarcomas of mice induced by benzo(a)pyrene]. AB - Antifibrinolytic drug epsilon-aminocaproic acid as a therapeutic form (5% solution in saline) was tested for antitumor activity in the autochthonous subcutaneous tumors of mice, induced by benzo (a) pyrene, in monotherapy mode (instead animals received drinking water) and in combination with cyclophosphamide, which was administered once intraperitoneally in the dose of 200 mg/kg. In the control groups, treated with drinking water and saline solution instead of water, there was no stabilization and reduction in tumor volume, while in the groups receiving epsilon-aminocaproic acid, cyclophosphamide and their combination statistically significantly in comparison with the control groups there was increased the proportion of tumors with not changed or reduced volume; epsilon-aminocaproic acid enhanced the antitumor effect of cyclophosphamide. The data obtained are for further study of the antitumor effect of epsilon aminocaproic acid. PMID- 24772625 TI - [Anticancer propaganda: myth or reality?]. AB - The authors raise a very important problem of anticancer propaganda aimed at the early detection of cancer to be solved nowadays by means of screening and constructive interaction between oncologists and the public. To increase the level of knowledge of the population in this area it is necessary to expand the range of its adequate awareness of tumor diseases. Only joint efforts can limit the destructive effect of cancer on people's minds, so that every person would be responsible for his own health, clearly understanding the advantages of early visit to a doctor. This once again highlights the need of educational work with the public, motivational nature of which allows strengthening the value of screening in the whole complex of measures to fight cancer. PMID- 24772626 TI - [Adjuvant chemotherapy for breast cancer: search for new ways of planning]. AB - A decision regarding adjuvant chemotherapy in early (operable) breast cancer in the past was made entirely on the basis of clinical and pathological features. However with the growing awareness of tumor biology and the possibility of the genomic analysis to determine the molecular subtypes of breast cancer it is getting real to identify patients whose tumors are resistant to chemotherapy or vice versa benefit from its addition. Despite the fact that genomic analysis allows some patients avoiding chemotherapy (especially patients with localized breast cancer), such studies do not indicate the most appropriate chemotherapy regimens. Therefore treatment decisions should be based on a combination of biological features of the tumor, its stage and signs that characterize the patient such as age and tolerance to the side effects of therapy. PMID- 24772627 TI - [Pulmonary histiocytosis from Langerhans cells as the problem of clinical morphology]. AB - There are discussed modern views on one of the most difficult diagnosed forms of pulmonary dissemination. They relate to the dynamics of granulomatous changes in the lung tissue at the cellular and subcellular level as well as a characteristic of the immunophenotype of Langerhans cells. At present the frequency of this disease increases, which improves the responsibility for the timely diagnosis based on performing explicit clinical and morphological studies. PMID- 24772628 TI - [Immunological studies at the N.N. Petrov Research Institute of Oncology (100th anniversary of birth of Prof. T.A. Korosteleva)]. AB - Historical essay devoted to the life and work of Professor Tamara Alexandrovna Korosteleva (1913-1991), the former Head of the Laboratory of Oncoimmunology at the N.N. Petrov Research Institute of Oncology, St. Petersburg. PMID- 24772629 TI - Driven by doctors. A unique board committee adds physician leaders to the strategic decision-making process. PMID- 24772630 TI - Harnessing the power of sustainability. Energy-efficient hospitals generate big savings and healthier communities. AB - Hospitals are taking advantage of low-cost, high-impact ways to reduce energy expenses. PMID- 24772631 TI - Hospitals whacked by RAC. The audit program imposes a crushing burden on hospitals. Can it be fixed? AB - The audit program's growing burdens are siphoning resources from patient care. Can it be fixed? PMID- 24772632 TI - Tomorrow's health care workplace. PMID- 24772633 TI - A matter of perspective. The best boards respect the line between governing and managing. AB - Is your board governing or managing? Learn how to spot the difference. PMID- 24772634 TI - What to say, when to say it. Set the tone for a successful merger with five strategies for communication. AB - Boards and executives can take control of the merger conversation with these five strategies. PMID- 24772635 TI - New goals, new roles. Producing wellness instead of treating illness calls for different skills in the C-suite. AB - Catholic Health Initiatives redefines its leadership positions to align with today's market realities. PMID- 24772636 TI - IT as a strategic resource. Information technology can be the catalyst in transforming the health care delivery system. AB - Key questions from the board ensure health IT value realization. PMID- 24772637 TI - Taking the transformational path. AB - A new report suggests several paths to delivery system transformation. PMID- 24772638 TI - Strategy: shifting leadership competencies. PMID- 24772639 TI - [High level of efficacy and safety of antiviral vaccines and unsubstantiated critique]. AB - To counterbalance the unsubstantial declarations of some vaccinologists that vaccines and vaccination are not only useless, but also injurious to the health, this work represents the evidence that vaccines and vaccination not only reduce the morbidity of viral infection, but also allow some viral diseases to be eradicated and eliminated. The work also adduces the data about reducing economic impact of viral infections with the help of vaccination, as well as the data, which clearly show that serious reactions to vaccination are thousands of times less frequent than reactions and complications caused by infectious diseases. PMID- 24772640 TI - [Bovine viral diarrhea control in Russian Federation]. AB - Bovine viral diarrhea (BVD) is one of the greatest challenges for breeding and commercial livestock. It is characterized by lesions of the respiratory and gastrointestinal tract, abortion, infertility, immune deficiency, and persistence of the pathogen. In this work, a set of measures for the rehabilitation and prevention of BVD in cattle is described. It includes the data of the literature, guidance documents for the diagnosis and control of BVD adopted by OIE, EU countries, USA, as well as the results of this research. PMID- 24772641 TI - [Genetic characterization of new Komandory virus (KOMV; Bunyaviridae, Phlebovirus) isolated from the ticks Ixodes uriae, collected in guillemot (Uria aalge) nesting sites on Komandorski islands, the Bering sea]. AB - Unclassified virus named Komandory virus (KOMV) isolated in Komandorski islands from the ticks Ixodes uriae in 1986 was partially sequenced. The KOMV nucleocapsid (N) protein sequence shows 30-40% identity level with the mosquito borne phleboviruses and 43% with the Uukuniemi virus (UUKV) group (Phlebovirus, Bunyaviridae). The maximum identity (65%) for the KOMV N protein is observed for the Manawa virus. The KOMV glycoprotein identity with the UUKV group viruses ranges from 45% to 59%. The KOMV RdRp identity with the Manawa virus reaches 74%, while showing 63% level at average with the other UUKV group viruses. According to the results of molecular-genetic and phylogenetic analysis, the KOMV is a new member of the UUKV group (Phlebovirus, Bunyaviridae). PMID- 24772642 TI - [The taxonomy of the Baku virus (BAKV; Reoviridae, Orbivirus) isolated from the birds obligate parasites Argasidae ticks in Azerbaijan, Turkmenistan, and Uzbekistan]. AB - The Baku virus (BAKV) was originally isolated from the ticks Ornithodoros capensis Neumann, 1901 (Acari: Argasidae) collected from the seagull (Larus argentatus) seating nests on the islands of the Baku archipelago, the Caspian sea. BAKV was assigned to Kemerovo group (KEMV) (Orbivirus, Reoviridae). The BAKV was frequently isolated from the ticks O. coniceps Canestrini, 1980, collected from L. argentatus and tern (Sterna hirundo) nests in Turkmenia and pigeon (Columba livia neglecta) nests in Uzbekistan. In this work, the genome of the BAKV was sequenced using the next-generation sequencing technology. The BAKV Pol protein has 48.6% identity level with the viruses of the Great Island Virus group and at average 41% with non-tick orbiviruses. The BAKV T2 protein level identity with the orbiviruses ranges from 23.7% to 64.8%. The maximum identity level of the T2 protein (64.8%) is observed for the tick-borne viruses of the GIV (KEMV) group. According to the conducted molecular-genetic and phylogenetic analysis, the BAKV is a novel species of the genus Orbivirus. It forms a phylogenetic group distinctly related to the GIV group. PMID- 24772643 TI - [Evolution of influenza A(H3N2) virus from 2007 to 2012]. AB - The results of the genetic studies of influenza viruses make it possible to understand their evolution and recommendations for vaccine strains content. In this work, the data of complete sequence of the HA, NA, and M2-protein for 34 strains of influenza A(H3N2) virus circulating in Russia during 2007-2012 are presented. The influenza strains were isolated in Ivanovsky Institute of Virology, Moscow, and some collaborating Russian centers. The results of the phylogenetic analysis showed the differences among strains, which were observed during the analyzed period; the evolution had direction from A/Brisbane/10/2007 to A/Perth/16/2009 and A/ Victoria/208/2009. Hemagglutinin of the influenza A(H3N2) virus strains had differences between strains of last two seasons and strains circulating before, in the antigenic sites A, B, D, and, to a lesser extent, C, and E. In the neuraminidase gene the mutations responsible for the resistance to oseltamivir (E119V, R292K, N294S) and zanamivir (Q136K) were not found. All isolates carry the S31N mutation in the M2 gene responsible for resistance to amantadine. PMID- 24772644 TI - [Evaluation of the anti-neuraminidase antibodies in clinical trials of the live influenza vaccine of the A(H5N2) subtype]. AB - In the current study, we evaluated the neuraminidase-inhibition (NI) antibodies among volunteers during the phase I and phase II of the clinical trials of a monovalent live attenuated influenza vaccine (LAIV) A/17/duck/ Potsdam/86/92(H5N2). The reassortant influenza virus RN2/57-human A(H7N2) containing neuraminidase (NA) from the A/Leningrad/134/17/57(H2N2) was used in NI test. It was shown that two doses of the monovalent LAIV A(H5N2) led to a statistically significant increase in the NI antibodies to vaccine strain NA. More than twofold increase in antibodies was obtained among 19.5-33.3% of vaccinated. The microneutralization test and NI assay results coincidence in the same pairs of sera of the vaccinated volunteers was 73.2%, suggesting thus a statistically significant interdependence between the values of increase in antibodies revealed in both tests (p = 0.04). PMID- 24772645 TI - [Immunization with live attenuated A/H5N1 vaccine protects guinea pigs from reinfection]. AB - Cold-adapted influenza virus A/HK/1/68/162/35(H3N2) was developed as unified donor of attenuation and high reproductive capacity forvaccine strains. The reassortant of this donor with surface antigens of highly pathogenic strain Alchicken/Astana/6/05 (H5N1) was tested in guinea pigs as a live or inactivated preparation. Immunization with both formulations induced equal levels of serum virus specific antibodies, while the level of mucosal antibodies was significantly higher in animals immunized with live virus. The challenge with the homologous virus demonstrated complete virus clearance only in this group, thereby indicating a direct correlation of the protection level with the level of mucosal antibodies. PMID- 24772646 TI - [Analysis of the prevalence of HIV resistant strains to antiretroviral drug in Privolzhsky Federal District]. AB - Prevalence of the primary drug resistance mutations and resistance developed in patients receiving highly active antiretroviral therapies in the HIV-infected persons in the Privolzhsky federal district was studied. It was demonstrated that among the ART-naive HIV-positive patients there were no mutations leading to the development of resistance. A high level of the resistance to lamivudin, nevirapin, efavirenz was revealed among the persons receiving the antiretroviral therapy. As a whole, the frequency of mutations of resistance to nucleoside reverse transcriptase inhibitors (23.8%) and nonnucleoside reverse transcriptase inhibitors (26.9%) was much higher than to protease inhibitors (1.2%). PMID- 24772647 TI - [Mumps vaccine virus transmission]. AB - In this work we report the mumps vaccine virus shedding based on the laboratory confirmed cases of the mumps virus (MuV) infection. The likely epidemiological sources of the transmitted mumps virus were children who were recently vaccinated with the mumps vaccine containing Leningrad-Zagreb or Leningrad-3 MuV. The etiology of the described cases of the horizontal transmission of both mumps vaccine viruses was confirmed by PCR with the sequential restriction analysis. PMID- 24772648 TI - [The prevalence of behavioral risk factors and diseases of blood circulation system]. AB - The article is based on the data of "The study on global aging and adult health" (SAGE), a WHO international project carried out in 2007-2010. The sampling included respondents aged from 50 to 79 years old. The analysis covered such behavioral risk factors as tobacco smoking, physical activity, fruits consumption, etc. The results of measurement of blood pressure, body weight and body height were included into analysis. The prevalence of hypertension, angina pectoris and stroke was estimated The characteristics of prevalence of behavioral risk factors and types of their combination were established. The conclusion is made that in conditions of different status area and various degrees of physical exercises there is no possibility to make definite conclusion about real level of prevalence of diseases of blood circulation system in aged population. PMID- 24772649 TI - [The dispensarization of population and the content of prevention activities of physicians in primary health care system]. AB - Nowadays, positive trends in the development of priority principle of public health organization in Russia are observed. The dispensarization of large groups of population, declared by Minzdrav of Russia, made it possible to detect a large percentage of diseases. The implemented measures produced incontestable positive effect, though necessity is obvious to intensify involvement of citizen and families in health promoting activities. The article presents the study results providing important information concerning awareness of population and families about health and necessity to be concerned about health status. The means to enhance population health are in the areas of motivation of personal responsibility and public support from the state. PMID- 24772650 TI - [The analysis of structure of alcohol consumption in Russia in professional groups]. AB - The article presents the results of study of character of consumption of alcohol products by representatives of different professional groups. The research data was obtained from representative sampling of working population of Russia. On the basis of probit-modeling estimates of possibility of even if once consumption of alcohol were calculated. On the basis of tobit-modeling relative volume of consumed alcohol was evaluated. The results of analysis indicate that professional membership exerts significant but not determining influence on the character of alcohol consumption. The clear-cut age structure of volume consumption of particular alcohol beverages was established. The stable decrease of consumption of alcohol beverages during last years is mainly determined by financial economic crisis and not by measures of antialcoholic campaign. PMID- 24772651 TI - [The structural functional analysis of beds stock of curative preventive organizations of the state public health system of the Russian Federation]. AB - The article presents the results of comprehensive scientific analysis of size and structure of beds stock of medical curative preventive organizations of state and municipal health care systems of the Russian Federation. The issues of beds support of population on national, federal okrugs and federation subjects' levels including differentiation on different medical specialties are considered. The main indicators of functioning of hospitals, per capita consumption of hospital medical care and territorial characteristics and differences of these indicators are analyzed In conditions of on-going decrease of size of beds stock and amount of medical care in hospitals and against the background of stability of main indicators of beds use the expressed but not always objectively conditioned differences continue to be present concerning both population support with beds stock and indicators of consumption of medical care in hospitals. All these occurrences undoubtedly impact accessibility of this type of medical care to population and its resource capacity for the government. In 2012, beds support of population decreased from 85.7 to 84.1 beds per 10 000 of population. The value of indicator in federal subjects differs up to 2.9 times. In the structure of beds stock are prevailing specialized beds or groups of beds on such medical specialties as psychiatry, surgery, obstetrics and gynecology and therapy. The per capita use of medical care in hospitals decreased up to 2.609 beds-per-day that is 6.2% lower than standard value from the program of state guarantees of free-of-charge medical care support of citizen. The end values of indicator in federal subjects differ in 2.7 times. In federal subjects indicators of mean number of work of bed per year differ up to 1.2 times, of mean duration of treatment--up to 1.6 times, turn-over of bed--up to 1.6 times, hospital lethality -up to 5.9 times. The results of study confirm necessity of structural functional optimization of national beds stock and development of interaction between hospitals and out-patient services. PMID- 24772652 TI - [The mandatory medical insurance through eyes of medical personnel]. AB - The article considers the results of sociological survey carries out among medical personnel of the Moscowskaya oblast in August-September 2013. The purpose of the study was to examine opinions of medical personnel about system of mandatory insurance in conditions of implementation of the new law regulating system of mandatory medical insurance during last three years. The sampling included 932 respondents that corresponds approximately 1% of all medical personnel in the oblast. It is established that even 20 years later after the moment of organization of the system of mandatory medical insurance not all medical personnel is oriented in it. More than 70% of respondents consider this system too convoluted and over bureaucratized and only 22.2% of respondents assume that medical insurance organizations defense interests of patient and 25.8% feel no impact of mandatory medical insurance funds on functioning of medical organizations. Most of respondents consider functions of mandatory medical insurance organizations and mandatory medical insurance funds as controlling only. Only 31% of respondents support the actual system of mandatory medical insurance. PMID- 24772653 TI - [The actual issues and means of development of oncological service of the Krasnodarskiy kraiy]. AB - The article presents substantiation of actuality of oncological diseases. The results of the regional preventive program "Oncopatrol" are presented. The actual issues of oncological service of the Krasnodarskiy kraiy are emphasized. PMID- 24772654 TI - [The scientometric analysis of dissertation studies in the field of specialty public health and health care concerning children population]. AB - The article considers trends and priority directions of research studies of the field of public health and health care of children population. The interpretative content analysis was applied to study dissertations in the field of public health and health care in 1991-2012. The sampling included 4194 units of information. The first stage of study established that problems of children population are considered in 14.8% dissertations defended on the mentioned specialty. The next stage the categories of content-analysis were examined. They were divided on the following axes: axis I "Main problem of study", axis II "Localization of study", axis III "Examined age groups", axis IV "Distribution of studies on gender of examined contingent", axis V "Examined contingent", axis VI "Additional medical specialty". It is established that in dissertations on public health and health care of children population on axis I prevails organizational subject matter (27.2%). The health condition of various contingents of children population (16.8%), preventive aspects of pediatrics (12.2%), examination of particular conditions/diseases/classes of diseases (10.8%) are fixed as priority directions. In the most dissertations the regional character of studies is presented (98.2%). The prevailing age group in studies is the adolescent group (19.9%). The inter disciplinary relationships of dissertations on problems of public health and health care of children population are revealed with such specialties as "Pediatrics" (16.2%), "Obstetrics and gynecology" (3.8%) and "Hygiene" (3.4%). With consideration for recognition of health promotion and optimization of health care of children population as priority directions of public health policy amount of research studies in this field is to be admitted as inadequate. With purpose of optimization of scientific knowledge and development of system of medical social care to children population it is needed to promote research studies of problems of public health and health care of children and adolescents. PMID- 24772655 TI - [The medical social factors determining effectiveness of functioning of nephrology department]. AB - The article testifies that study and analysis of the results of medical and social effectiveness of functioning of department of nephrology department is a foundation of for optimization of curative preventive activities and adjustment of pharmaceutical therapy and promotes development of tactics of positive changes in attitude of patients to treatment. The recommendations developed for this department are applied in education process of training of manpower on specialty "Nursing business". PMID- 24772656 TI - [The analysis of opinion of physicians about their own professional qualification]. AB - The sociological questionnaire was applied to physicians and paramedical personnel of two large multitype hospitals to explore awareness of actual approaches to evaluation of quality of medical care. Only 49.2% of respondents consider themselves competent in this issue, 20.3% assume they are not enough competent and 5.1% gave negative answer to this question. About 25.4% were uncertain about this issue. In most cases, the respondents manifested minimal awareness concerning criteria of evaluation of quality of medical care, subjects and means of control. The hospital conferences are indicated as the major source of information. This choice indicates the necessity of corresponding correction of programs of pre-graduate and post-graduate training of specialists. PMID- 24772657 TI - [The Galenizm in the light of modern concepts of the structure of scientific knowledge]. AB - The article considers the foundation and characteristics of medical science of period of dominance of Galenizm in medicine. On the basis of analysis of available original sources the philosophical (ontological, epistemological, logical methodological and axiological) foundations, cognitive ideals and norms are presented. The pattern of the considered reality is discussed. PMID- 24772658 TI - [To the history of Tretiyakov almshouse of the A.I. Vishnevskiy Institute of Surgery]. AB - The article deals with reconstruction of history of building and functioning of Tretiyakov almshouse in the A.I. Vishnevskiy institute of surgery. The archive documents were used for exploration. The input of architect S.I. Soloviyev into formation of architectural complex is demonstrated. The significance of this object in the history of national architecture is established. PMID- 24772659 TI - [S.G. Levit Moscow School of Medical Genetics]. AB - The article considers medical genetic studies carried out by S.G. Levit scientific School. The workers of the Medical biologic institute studied geographical prevalence of different forms of colorblindness, early canities and surdomutism. The hospital examination of twins was another direction of research studies of Levit School. The organization of the mentioned research was clear-cut planned. The groups of researchers were organized to study normal and pathologic characteristics. The special research program was developed. The institute permanently carried out active workshops and conferences, published scientific transactions. The consolidation of various specialists around the scientific school made it possible to resolve many inter-disciplinary problems in the field of inherent pathology. PMID- 24772660 TI - [The formation of scientific anatomy in Europe of XVII century: to the 375th anniversary of Nicolas Steno (1638-1686)]. AB - The article, on the biography basis, systematizes the scientific directions in the activity of Nicolas Steno as one of leading creators of first scientific revolution in medicine (XVII century) which overwhelmed anatomical physiological Galen concept. The works of Nicolas Steno considering anatomy of excretory glands, cardiac and skeletal muscles and brain white substance are presented in the context of antecedent development of anatomy, content of anatomical physiological Galen concept and in interrelationship with underlying works of number European anatomist of XVII century (William Harvey, Thomas Bartholin, Jan Swammerdam, Marcello Malpighi, Willis, etc.). PMID- 24772661 TI - [The gladiators of the Ancient Rome: social status and medical care]. AB - The article considers issues of history of fights of gladiators in relation with life and daily shores of gladiators of the Ancient Rome, their medical care and their status in society and customs. PMID- 24772662 TI - Non-ionizing radiation, Part 2: Radiofrequency electromagnetic fields. PMID- 24772663 TI - Some chemicals present in industrial and consumer products, food and drinking water. PMID- 24772664 TI - Myeloperoxidase in cardiovascular disease. AB - Myeloperoxidase (MPO) plays a central role in the innate immune system by generating leukocyte-derived oxidants to combat invading pathogens. These reactive intermediates have been increasingly recognized to be potentially deleterious, causing oxidative injury in inflammatory disease states such as cardiovascular disease. Recent evidence now suggests that circulating MPO can act as a clinical prognostic indicator for patients with cardiovascular disease. PMID- 24772665 TI - Biomarkers of liver fibrosis. AB - Liver fibrosis is the final common pathway for almost all causes of chronic liver injury. Liver fibrosis is now known to be a dynamic process having significant potential for resolution. Therefore, fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. As such, there is strong demand for reliable liver biomarkers that provide insight into disease etiology, diagnosis, therapy, and prognosis in lieu of more invasive approaches such as liver biopsy. Current diagnostic strategies range from use of serum biomarkers to more advanced imaging techniques including transient elastography and magnetic resonance imaging. In addition to these modalities, there are other approaches including the use of novel, but yet to be validated, biomarkers. In this chapter, we discuss the biomarkers of liver fibrosis including the use of invasive and noninvasive biomarkers and disease-specific biomarkers in various chronic liver diseases. PMID- 24772666 TI - Keratin 18 and heat-shock protein in chronic kidney disease. AB - Chronic kidney disease (CKD) is an affliction associated with increased systemic stress and cell death. We will review the role of keratin 18 (K-18) and caspase cleaved CK-18 (ccK-18) as markers for increased apoptosis and necrosis during renal failure progression. The importance of preventative expression of heat shock proteins (HSPs) in response to cell stress will also be discussed. The frequent development of CKD leads to serious complications. The potential of use of K-18 and HSP as early biomarkers of renal failure will be reviewed. Also, the role of these proteins with respect to dialysis regimes and in acute ischemic kidney injury following renal transplantation will be discussed. PMID- 24772667 TI - Tear fluid protein biomarkers. AB - The tear film covers and protects the ocular surface. It contains various molecules including a large variety of proteins. The protein composition of the tear fluid can change with respect to various local and systemic diseases. Prior to the advent of the proteomic era, tear protein analysis was limited to a few analytical techniques, the most common of which was immunoelectrophoresis, an approach dependent on antibody availability. Using proteomics, hundreds of tear proteins could potentially be identified and subsequently studied. Although detection of low-abundance proteins in the complex tear proteome remains a challenge, advances in sample fractionation and mass spectrometry have greatly enhanced our ability to detect these proteins. With increasing proteomic applications, tears show great potential as biomarkers in the development of clinical assays for various human diseases. In this chapter, we discuss the structure and functions of the tear film and methods for its collection. We also summarize potential tear protein biomarkers identified using proteomic techniques for both ocular and systemic diseases. Finally, modern proteomic techniques for tear biomarker research and future challenges are explored. PMID- 24772668 TI - Urinary mRNA in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease with clinical manifestations that affect multiple organ systems. Lupus nephritis is recognized as one of the most severe organ involvements in SLE and affects half of the lupus patients. Notably, lupus nephritis is characterized by intrarenal lymphocyte activation and inflammation. Since most of the cytokines exert their effects in a paracrine fashion, measuring their expression at the site of pathology should be of biological relevance. Although kidney biopsy is widely used to determine the histology and severity of lupus nephritis, this invasive procedure has its own risk and is not practical for serial monitoring. In the past decade, extraction and quantification of messenger RNA (mRNA) from urinary sediment has emerged as a robust laboratory technique. Quantification of mRNA expression in urinary sediment has been tested as a noninvasive means to assess the disease activity of SLE patients. Available published evidence, however, is limited to small-scale studies. Based on the result of these studies, a number of cytokine and transcript factor genes have been found to have potential for the differentiation between active and inactive SLE, between proliferative and membranous types of lupus nephritis, assessment of the systemic lupus activity or histological activity of kidney biopsy specimen, monitoring of treatment response in active lupus nephritis, or detection of lupus disease flare in clinically quiescent patients. Being a simple and noninvasive method, urinary mRNA level deserves further studies to validate its role in risk stratification and monitoring of therapeutic response in patients with lupus nephritis. PMID- 24772669 TI - MicroRNA in gastrointestinal cancer: a step closer to reality. AB - Despite significant strides in understanding molecular pathogenesis of cancer, gastrointestinal malignancy (gastric, colorectal, pancreatic, and liver) still ranks among the leading causes of cancer-related mortality and morbidity worldwide. One of the key clinical challenges in effectively reducing disease burden associated with gastrointestinal neoplasia stems from late diagnosis, underscoring the need for early detection, risk assessment, and intervention. Currently available screening approaches are inadequate, and the development of accurate noninvasive molecular biomarkers is very much needed, microRNAs (miRNAs) are short (20-24 nucleotides in length) noncoding RNAs that have emerged as important translational gene regulators in cancer cells. In contrast to genetic markers, miRNAs have a cancer-specific expression pattern. They are present in a remarkably stable form and can be detected in a wide variety of body fluids including blood and feces. These properties make them attractive cancer biomarker targets. Although development of miRNA biomarkers is still in its early stages, burgeoning evidence supports their potential use for development as markers for early detection, prognosis, and prediction of disease recurrence and therapeutic outcome in gastrointestinal cancers. In the future, it is likely that miRNA biomarkers will revolutionize personalized medicine and mitigate disease burden associated with gastrointestinal cancers. PMID- 24772670 TI - Marine sulfated glycans with serpin-unrelated anticoagulant properties. AB - Marine organisms are a rich source of sulfated polysaccharides with unique structures. Fucosylated chondroitin sulfate (FucCS) from the sea cucumber Ludwigothurea grisea and sulfated galactan from the red alga Botryocladia occidentalis are one of these unusual molecules. Besides their uncommon structures, they also exhibit high anticoagulant and antithrombotic effects. Earlier, it was considered that the anticoagulant activities of these two marine glycans were driven mainly by a catalytic serpin-dependent mechanism likewise the mammalian heparins. Its serpin-dependent anticoagulant action relies on promoting thrombin and/or factor Xa inhibition by their specific natural inhibitors (the serpins antithrombin and heparin cofactor II). However, as opposed to heparins, these two previously mentioned marine glycans were proved still capable in promoting coagulation inhibition using serpin-free plasmas. This puzzle observation was further investigated and clearly demonstrated that the cucumber FucCS and the red algal sulfated galactan have an unusual serpin-independent anticoagulant effect by inhibiting the formation of factor Xa and/or thrombin through the procoagulants tenase and prothrombinase complexes, respectively. These marine polysaccharides with unusual anticoagulant effects open clearly new perspectives for the development of new antithrombotic drugs as well as push the glycomics project. PMID- 24772671 TI - Colonization and maintenance of Anopheles kleini and Anopheles sinensis from the Republic of Korea. AB - Colonization of members of the Anopheles Hyrcanus Group is required to facilitate a better understanding of their roles in the epidemiology, vector competence, transmission potential, and maintenance of vivax malaria in the Republic of Korea (ROK). A total of 158 resting blood-fed wild caught Anopheles species were collected on August 26, 2011 at Tongilchon, near the demilitarized zone, in the ROK and shipped on August 28, 2011 to the Entomology Department, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand. Four of the 5 species of the Anopheles Hyrcanus Group (Anopheles kleini, An. sinensis, An. pullus, and An. belenrae) were identified by polymerase chain reaction. Eggs were obtained from parent populations, and F, progeny provided blood meals using membrane feeding techniques. The mean numbers of eggs/female for An. sinensis and An. kleini were 157 and 146, respectively. Membrane blood feeding rates for An. sinensis (90.6%) and An. kleini (89.0%) were similar for F1-F30 generations. Colonies of An. kleini and An. sinensis were established by force mating techniques and maintained by the Insectary Section, Entomology Department, AFRIMS, to date. This is the 1st report of successful laboratory colonization of An. kleini collected from a vivax malaria high-risk area in the ROK. PMID- 24772672 TI - Modeling Culex tarsalis abundance on the northern Colorado front range using a landscape-level approach. AB - Remote sensing and Geographic Information System (GIS) data can be used to identify larval mosquito habitats and predict species distribution and abundance across a landscape. An understanding of the landscape features that impact abundance and dispersal can then be applied operationally in mosquito control efforts to reduce the transmission of mosquito-borne pathogens. In an effort to better understand the effects of landscape heterogeneity on the abundance of the West Nile virus (WNV) vector Culex tarsalis, we determined associations between GIS-based environmental data at multiple spatial extents and monthly abundance of adult Cx. tarsalis in Larimer County and Weld County, CO. Mosquito data were collected from Centers for Disease Control and Prevention miniature light traps operated as part of local WNV surveillance efforts. Multiple regression models were developed for prediction of monthly Cx. tarsalis abundance for June, July, and August using 4 years of data collected over 2007-10. The models explained monthly adult mosquito abundance with accuracies ranging from 51-61% in Fort Collins and 57-88% in Loveland-Johnstown. Models derived using landscape-level predictors indicated that adult Cx. tarsalis abundance is negatively correlated with elevation. In this case, low-elevation areas likely more abundantly include habitats for Cx. tarsalis. Model output indicated that the perimeter of larval sites is a significant predictor of Cx. tarsalis abundance at a spatial extent of 500 m in Loveland-Johnstown in all months examined. The contribution of irrigated crops at a spatial extent of 500 m improved model fit in August in both Fort Collins and Loveland-Johnstown. These results emphasize the significance of irrigation and the manual control of water across the landscape to provide viable larval habitats for Cx. tarsalis in the study area. Results from multiple regression models can be applied operationally to identify areas of larval Cx. tarsalis production (irrigated crops lands and standing water) and assign priority in larval treatments to areas with a high density of larval sites at relevant spatial extents around urban locations. PMID- 24772673 TI - Evaluation of a rapid analyte measurement platform and real-time reverse transcriptase polymerase chain reaction assay West Nile virus detection system in mosquito pools. AB - We evaluated the commercially available Rapid Analyte Measurement Platform (RAMP) West Nile virus (WNV) antigen detection test for sensitivity and consistency with real-time reverse transcriptase polymerase chain reaction (RT-PCR) confirmation testing. Panels of samples consisting of WNV-spiked mosquito pools and negative control pools were sent to 20 mosquito abatement districts (MADs) that processed the pools using the RAMP assay. The samples were then sent to the reference laboratories used by the MADs for confirmation by real-time RT-PCR. Positive pools with virus titers of roughly 1-3 log10 PFU/ml had RAMP scores above the RAMP test positive cutoff score of 30 RAMP units, but these virus-positive samples could not be reliably confirmed by real-time RT-PCR testing. Pools with virus titers > or =4 log10 PFU/ml scored > or =50 RAMP units. Real-time RT-PCR results varied among the confirmation laboratories. With few exceptions, pools returning a RAMP score of > or =100 were confirmed with real-time RT-PCR, while pools returning a RAMP score of 50-99 appeared to be at the limit of real-time RT PCR detection. Therefore, we recommend using a positive cutoff of 50 RAMP units with no real-time RT-PCR confirmation to maximize speed, efficiency, and economy of the RAMP assay. A more conservative approach would be to implement a "gray zone" range of 50-100 RAMP units. Pools scoring within the gray zone could be submitted for real-time RT-PCR confirmation with the understanding that positive pools may not confirm due to the inhibitory effect of the RAMP buffer on the real time RT-PCR assay. We also conducted a series of experiments using laboratory prepared mosquito pools spiked with WNV to compare mosquito homogenization buffers, pool sizes, and grinding methods in order to determine how these variables affect the RAMP and real-time RT-PCR assay results. PMID- 24772674 TI - Field evaluation of four spatial repellent devices against Arkansas rice-land mosquitoes. AB - Four commercially available spatial repellent devices were tested in a rice-land habitat near Stuttgart, AR, after semi-field level assessments had been made at the Center for Medical, Agricultural, and Veterinary Entomology, Agricultural Research Service, US Department of Agriculture in Gainesville, FL. OFF! Clip On(metofluthrin), Mosquito Cognito (linalool), No-Pest Strip (dichlorvos), and ThermaCELL (d-cisltrans allethrin) were selected for this study from >20 candidate products. The units based on metofluthrin, linalool, or d-cisltrans allethrin significantly reduced captures of 1 or more of the mosquito species at surrogate human sites (unlit Centers for Disease Control and Prevention traps with CO2 and octenol). Among the mosquito species analyzed statistically (Anopheles quadrimaculatus, Culex erraticus, and Psorophora columbiae), there were significantly different responses (up to 84% reduction) to individual products, suggesting that combinations of certain spatial repellents might provide significantly greater protection. PMID- 24772675 TI - Preliminary evaluation of a nonanal lure for collection of gravid Culex quinquefasciatus. AB - Gravid traps are important tools for disease monitoring and for research on mosquito ovipositional behavior. Two experiments were conducted to evaluate a 2% nonanal lure in gravid mosquito traps in Ifakara, Tanzania. The 1st experiment focused on whether water was needed in the pan below the trap for the nonanal lure to be effective. There was no significant difference between the numbers of gravid females of Culex quinquefasciatus collected in traps using a nonanal lure either with or without water. The 2nd experiment compared the lure, without water, to a grass infusion and a blank trap, without water or attractant. Significantly more mosquitoes were collected in traps with grass infusion than in traps with the other attractants, which were not significantly different from each other. Although more mosquitoes were collected in traps with grass infusion, substantial numbers were also collected in traps with the nonanal lure and unbaited traps. PMID- 24772676 TI - Ground ultra-low volume adulticiding field trials using pyrethroids against Aedes albopictus in the Baix Llobregat region, Spain. AB - Ground ultra-low volume (ULV) application against Aedes albopictus is a challenging methodology as its efficacy is strongly related to environmental conditions, insect behavior, and the pesticide formulation. Such operations are very relevant in many control programs, although their real efficacy is often unknown. Trials were carried out as part of real-world applications in urban scenarios in the Baix Llobregat region to evaluate the efficacy of 2 active ingredients, delatamethrin and alpha-cypermethrin. Both pyrethroids were tested against caged mosquitoes placed at a range of distances and under varying environmental conditions. Additionally, persistence on plants placed at the same distances was evaluated after 5 h, as well as droplet distribution using water sensitive papers. The deltamethrin formulation used yielded significantly higher 24-h mortality than alpha-cypermethrin (100% direct mortality up to 25 m versus 10 m; and 73.9% residual 5-h mortality at 20 m compared to <50% at 5 m). The influence of environmental factors, a comparison with other field tests, and the real effect on uncaged mosquitoes is discussed. PMID- 24772677 TI - First records of Armigeres malayi and Armigeres milnensis in Timor-Leste. AB - Larval Armigeres malayi and larval Ar. milnensis were first collected from rainwater-filled broken coconut shells in the district of Manufahi, subdistrict Same, in southwest Timor-Leste in September 2010. In subsequent surveys, Ar. malayi and Ar. milnensis were frequently observed in water-filled coconut shells either as the sole culicid species, or coexisting with each other, or with larval Aedes albopictus or Culex spp. Although there have been a number of published surveys of Culicidae in Timor-Leste, these Armigeres species have not previously been recorded in this country. Little is known about the status of these species as potential vectors of human or animal disease; however, it has been suggested that Ar. milnensis is a potential vector of Dirofilaria immitis and other filariae, so they may merit further study from a human and veterinary health perspective, as well as for their role in local ecosystems, particularly their competitive impact on other mosquito species that oviposit in the same container habitats. PMID- 24772678 TI - First collection records of Culiseta (Culicella) nipponica in the Republic of Korea. AB - The 1st confirmed record of Culiseta nipponica for the Republic of Korea was made at Osan Air Base and Tongilchon, Gyeonggi Province, and at the Incheon International Airport, Incheon metropolitan area, using carbon dioxide-baited light and Mosquito Magnet traps. Larval surveys near adult collection sites during June and August 2013 were negative for Culiseta nipponica. PMID- 24772679 TI - Notes on the occurrence and habitats of Sabethes purpureus in Salta Province, Argentina. AB - The finding of Sabethes purpureus larvae and pupae in tree holes both in urban and forest environments in San Ramon de la Nueva Oran, Salta Province, Argentina, is reported, together with information on the larval habitat. Tree holes were sampled monthly from January to March or April of 2011, 2012, and 2013 along sidewalks, in public access areas, and in 3 sites within forested areas outside the city, selected along an urban gradient in Oran. Sabathes purpureus was most frequently found in low numbers and with other mosquito species. A higher proportion of tree holes was positive in the urban compared to the forest environment, although there were no significant differences in abundances or densities per hole. To our best knowledge, this paper reports the species for the first time breeding in an urban environment, and extends its geographical distribution from the Atlantic and Paranaense forests to the Southern Andean Yungas in northwestern Argentina. PMID- 24772680 TI - Molecular survey for mosquito-transmitted viruses: detection of Tensaw virus in north central Florida mosquito populations. AB - A bunyavirus surveillance was performed in 2,600 pools consisting of 45,728 mosquitoes collected in north-central Florida from May 2006 to April 2007. Fifteen mosquito pools were found to be virus-positive from the total 2,600 mosquito pools tested (0.6% infection rate), which resulted in a minimum infection rate of 0.33 per 1,000 mosquitoes. Sequence data identified the virus to be Tensaw virus, a member of the Bunyaviridae family. All the virus-positive samples were obtained from pools collected from May to October 2006, in 3 of the 4 major locations studied, revealing the presence of Tensaw virus in north central Florida mosquito populations in 2006. PMID- 24772681 TI - Comparative laboratory and field evaluation of repellent formulations containing deet and lemon eucalyptus oil against mosquitoes in Queensland, Australia. AB - A field trial comparing a formulation containing 40% deet (N,N-diethyl-3-methyl benzamide) in ethanol (Bushman) and 32% lemon eucalyptus oil (LEO; Mosi-guard) as protection against mosquitoes at Redcliffe, Queensland, Australia, was conducted in February 2012 and February 2013. The 40% deet formulation provided 100% protection against mosquitoes for 7 h, while the 32% LEO provided >95% protection for 3 h. PMID- 24772682 TI - A comparison of FourStarTM Briquets and natularTM XRT tablets in a North Shore suburb of Chicago, Il. AB - Stormwater catch basins are the primary source of mosquitoes targeted by the North Shore Mosquito Abatement District, in the northern suburbs of Chicago. Over a 17-wk period (June to September 2011), 3 clusters of catch basins located within a 0.7-km2 area were monitored weekly with dipper samples of immature mosquitoes. During the 2nd week of monitoring, Natular XRT tablets (6.25% spinosad) were applied to northernmost cluster and FourStar Briquets (6% Bacillus u, 1% Bacillus thuringiensis israelensis) were applied to the southernmost cluster; the remaining middle cluster was kept untreated. Following 15 wk of monitoring in 20 basins in each cluster, both Natular and FourStar reduced immature numbers in treated catch basins for 8 consecutive weeks. These results suggest, if effectively timed, a single application of either larvicide may last an entire season. PMID- 24772683 TI - Ensuring medical device effectiveness and safety: a cross--national comparison of approaches to regulation. AB - Regulatory bodies weighing market approval for novel medical devices must balance the benefits and potential hazards carefully. We performed a legal and policy review of appraoches in the US, EU, Japan, and China to device regulation with a focus on postmarket surveillance. These markets share broad features such as a heavy reliance on passive adverse event collection, reflected by growing enthusiasm for more active and dynamic mechanisms such as unique device identification. More immediately, US and EU systems might benefit from scheduled, compulsory, and consequential re-examination of select devices, as is done in Japan and China, in order to strengthen post-market protection of patients and bolster public health. PMID- 24772684 TI - Challenging an immediate suspension of a DEA registration: is it time for a new tact? AB - A Drug Enforcement Administration ("DEA") registration is not only a necessity, but also an invaluable commodity for doctors, pharmacists, hospitals and drug wholesalers who prescribe, stock, and distribute controlled substances. While the DEA may only suspend a registration by issuing an immediate suspension order ("ISO) after an ex parte finding of "imminent danger to the public health or safety," the law fails to explicitly protect the registrant by way of a post suspension hearing on the ISO, despite the registrant's constitutionally protected property interest in the registration. A registrant has only two procedural options--which are often unsuccessful--to challenge the ISO: endure a long and arduous administrative review proceeding or petition the court for a "not-so-easily proven" injunction, all the while the suspension remains in effect and the controlled substance business operations cease. Accordingly, a suspension of the registration may be certain death to doctors and pharmacists without the financial means to operate the business in the absence of the registration. Because the DEA registration is a constitutionally-protected interest, there is a better way to challenge the suspension. The Supreme Court has held that once a license is issued, the continued possession of it is essential to the registrant's livelihood. Therefore suspension or revocation of such a protected interest requires due process. Due-process hearings, while varied, will provide the necessary avenues of review to provide a fair review of the justification of the suspension and its continuance, i.e., whether there truly is imminent danger to public health or safety and whether the suspension is overbroad and should be limited. To date, this thesis remains to be tested and awaits a petitioner with a justiciable claim and the financial resources to challenge the DEA in court. But in the field of DEA ISO challenges, it is time for a new tact! PMID- 24772685 TI - Legal considerations for social media marketing by pharmaceutical industry. AB - Social media marketing is the next frontier for direct-to-consumer advertising of pharmaceutical products, but represents an unchartered territory for regulatory action. With explosive growth in the use of social media, along with pharmaceutical companies' increasing adeptness at taking advantage of opportunities for social media marketing, the Food and Drug Administration (FDA) faces an urgent need to develop its own capacities to monitor and engage with social media marketing. In response to potential FDA action, pharmaceutical companies' marketing, regulatory compliance and legal staffs must work closely to design initiatives that are sensitive to FDA concerns. This article will address the current status of FDA regulations on social media advertising, their historical origins, challenges to implementation, and their likely future direction. PMID- 24772686 TI - Implementing the IOM's recommendations for reducing sodium in the U.S. food supply: considerations and approaches. AB - In 2010, the Institute of Medicine (IOM) recommended that the Food and Drug Administration modify the generally recognized as safe status of sodium by setting gradually decreasing limits on sodium amounts allowed in processed and prepared foods. Establishing limits on sodium uses would lead to a decrease in sodium intake, which, on average, far exceeds dietary recommendations. This article discusses the historical and regulatory context surrounding the IOM's recommendation, analyzes its potential, offers various strategies for implementing it, and concludes that the IOM's recommendation is likely the best tool currently available to achieve widespread sodium reductions in the food supply. PMID- 24772687 TI - The FDA's risk/benefit calculus in the approvals of Qsymia and Belviq: treating an obesity epidemic while avoiding another fen-phen. AB - As obesity rates continue to rise in the United States, both physicians and patients have demanded more safe and effective drug treatment options. However, following the fen-phen/Redux and sibutramine failures, the FDA has been hesitant to approve any anti-obesity drugs, despite the magnitude of the epidemic. Some have argued that these public embarrassments have led the FDA to overestimate the risks and underestimate the benefits when deciding whether to approve new anti obesity drugs. On June 27, 2012, the FDA approved Belviq for chronic weight management, making it the first anti-obesity drug approved by the FDA in thirteen years. Less than one month later, the FDA approved Qsymia for the treatment of obesity. Both drugs had been denied FDA approval less than two years earlier. In this paper, I will first review the obesity crisis and discuss the high-profile market withdrawals of fenfluramine, dexfenfluramine, and sibutramine. Second, I will explain the FDA's drug approval process with a focus on the FDA's risk/benefit calculus. Third, I will compare the FDA's risk/benefit analysis for Qsymia and Belviq in 2010 with the agency's risk/benefit analysis in 2012 to determine what caused the agency to grant approval in 2012 while denying it in 2010. Finally, I will analyze what these drug approvals may mean for the future of other anti-obesity drugs. PMID- 24772688 TI - Buckman extended: federal preemption of state fraud-on-the-FDA statutes. AB - A number of states have enacted statutes that provide protection to drug manufacturers in product liability actions. Additionally, several of these states have enacted "fraud-on-the-FDA" statutory provisions, which remove statutory protection afforded to drug manufacturers in product liability actions if plaintiffs can provide evidence that the drug manufacturer made misrepresentations to the FDA during the process of obtaining marketing approval for the drug. Currently, the federal circuits are in disagreement over whether these state "fraud-on-the-FDA" statutes should be federally preempted. This issue warrants resolution for drug manufacturers, private citizens, and state legislatures. This Comment will discuss the history and role of the FDA's authority in drug and medical device regulation; federal preemption generally and the Supreme Court's decisions that considered whether state law failure to warn claims are federally preempted in the context of drugs and medical devices; the Supreme Court's decision in Buckman v. Plaintiffs' Legal Committee, where the Court held that claims that a medical device manufacturer made fraudulent representations to the FDA were federally preempted because such claims interfered with the relationship between the FDA and the entities it regulated, state fraud-on-the-FDA statutory provisions, and the existing circuit split regarding whether those statutes should be federally preempted; the potential resolutions to the circuit split; and will conclude and advocate that the Supreme Court's Buckman holding be applied to federally preempt state fraud-on-the-FDA statutes because such statutes involve the relationship between a federal agency and the entity it regulates and thus undermine the FDA's authority. PMID- 24772689 TI - Who pays? How reimbursement impacts the emergency department. AB - BACKGROUND: Nationwide from 1996 to 2004, the overall proportion of Emergency Department (ED) reimbursement ratios for outpatient ED visits decreased from 57% to 42%. The continued falling of ED reimbursement ratios, which is the share of ED charges that are ultimately paid, is an indicator of the financial pressures facing the ED. Once the healthcare reforms are put in place what will the impact be on reimbursement rates of overburdened and underfunded emergency departments. PURPOSE: The purpose of this study is to examine if there is a declining disparity in payment rates for ED care based on payment sources in a safety net ED provider. Findings of this study could indicate how the healthcare reforms might impact these types of ED reimbursement ratios in the upcoming years. METHODS: This was a retrospective study that examined randomly selected charts of all ED visits charts from May 2002 to May 2008 at a level one adult and pediatric emergency trauma center with 45,000 annual visits. This study was IRB approved. RESULTS: A regression model was used to predict if there was a relationship between amount received and types of insurance payers within the ED. A significant relationship was found between types of insurance (payers) as the independent variable, and the dependent variables of charges (p = .00), payments (p = .00), amount of adjustments (p= .00), and balance remaining after 90 days (p = .00). CONCLUSIONS: Who pays for the ED services does impact the ED's bottom line. The privately funded patients will provide an ED with a higher reimbursement ratio per year as compared to those patients who are publicly or self pay. This explains why EDs that provide care for 40% or more publicly or self pay patients have seen a decline in reimbursement ratios. Healthcare reform has the potential to change and possibly improve safety net ED rate of reimbursement depending on how private, public and self pay patients pay for ED services. PMID- 24772690 TI - Linkages between organization climate and work outcomes: perceptual differences among health service professionals as a function of customer contact intensity. AB - The delivery of high-quality service, rendered by health service professionals who interact with customers (patients), increases the likelihood that customers will form positive evaluations of the quality of their service encounters as well as high levels of customer satisfaction. Using linkage theory to develop our conceptual framework, we identify four clusters of variables which contribute to a chain of sequential events that connect organization climate to personal and operational work outcomes. We then examine the perceptual differences of service professionals, grouped by intensity of customer contact, with respect to these variables. National data for this project were obtained from multiple sources made available by the Veterans Healthcare Administration (VHA). Cross-group differences were tested using a series of variance analyses. The results indicate that level of customer-contact intensity plays a significant role in explaining variation in perceptions of support staff, clinical practitioners, and nurses at the multivariate and univariate levels of analysis. Contact intensity appears to be a core determinant of the nature of work performed by health service professionals as well as their psychological responses to organizational and customer-related dynamics. Health service professionals are important resources because of their specialized knowledge, labor expense, and scarcity. Based on findings from our research, managers are advised to survey employees' perceptions of their organizational environment and design practices that respond to the unique viewpoints of each of the professional groups identified in this study. Such tailoring should help executives maximize the value of investments in human resources by underwriting patient satisfaction and financial sustainability. PMID- 24772691 TI - Organizational restructuring, government control and loss of legitimacy following an organizational crisis: the case of Israel's nonprofit human services. AB - The study explores organizational restructuring following the occurrence of a crisis. Restructuring activities following an intervention are considered here to be indicators of an organization's loss of legitimacy because they have lost their independent status, a basic characteristic of nonprofit human settings. The study shows that according to the Resource Based View of organization restructuring--experienced as downsizing, neglecting and abandoning of projects- organizations are affected by (a) government intervention in decision making; (b) higher demands for accountability; and (c) higher evaluations of performance gaps. On the basis of the study of a sample of 138 Nonprofit Human Services in Israel, the results show that the higher the level of restructuring, the higher the level of legitimacy. However, organization location in metropolitan areas moderates the link between restructuring and legitimacy loss. We conclude that Israel's nonprofit human services being overly dependent on goverhment funding are more prone to restructuring and losing legitimacy following organizational crisis. PMID- 24772693 TI - Relying on radiological findings in critically ill H1N1 infected patients-how logical? PMID- 24772692 TI - Medical service use among individuals receiving HIV prevention services in Los Angeles County. AB - Timely provision of medical services among communities at increased risk of HIV infection is crucial to detect the infection and to further prevent the spread of HIV. In the US, about one third of HIV cases were identified in the later stage of infection. The current study utilized the Gelberg-Andersen behavioral model for predicting medical service use among people who were at risk of HIV infection. The candidate variables included: social support, attitudinal, and behavioral variables. The data were collected from clients of HIV prevention agencies in Los Angeles County in 2004 who participated in the Countywide Risk Assessment Survey (CRAS). Using a logistic regression model, the study suggested that factors that were positively associated with use of medical services included living in a treatment center/halfway house or mission/shelter, experience of physical/sexual abuse, and ever receiving HIV testing/counseling. Factors inversely associated with medical service use were male gender, education, and consumption of alcohol. Analysis was conducted using SAS 9.3. Most of the findings are consistent with the Gelberg-Andersen model. The exception was that victims of physical or sexual abuse were more likely to use services instead of less likely as predicted by the model. PMID- 24772694 TI - Clinicoradiologic correlation in adult patients diagnosed with novel influenza A (H1N1). AB - BACKGROUND: Influenza A(H1N1) infection affected Indian population in 2009. Patients needed ICU admission and monitoring. OBJECTIVES: To describe and correlate clinical and radiographic features of Influenza A(H1N1) infection in patients hospitalised in Intensive care unit. MATERIAL AND METHODS: Retrospective study of records of 100 RT-PCR confirmed patients with Influenza A(H1N1) infection from August 2009 to March 2010 was done. Each patient underwent an evaluation to determine clinical and radiographic features. RESULTS: Mean age of the patients was 33.43 years (+/- 12.152) with maximum patients between 18-40 years, with 53% males and 43% females. Cough (96%), Fever (95%), breathlessness (83%), throat pain (34%), crepitations (69%), Tachypnoea (59%)were the prominent symptoms and signs. 61% (n = 63) had comorbid condition like pregnancy (n = 13,20.63%), Diabetes Mellitus (DM) (n = 12,19.05%), HT (n = 11,17.60%), Obesity (n = 10, 15.87%) and Rheumatic Valvular Heart Disease (RVHD) (n = 6,09.52%). Chest X ray was abnormal in 91% patients and normal in 09% pts. Bilateral findings were seen in 61.53% cases. Most common zones affected were lower zones (77.46%), then middle zones (71.42%), followed by upper zones (42.7%). Most common patterns were consolidation (64.83%), reticulonodular (24.17%) and nodular (10.98%). 27.47% had two, 21.97% had four, 19.78% had three,12.08% had six, 7.69% had five and 10.98% had single zone involvement. Fever, cough and tachypnoea were present in all 100% pts with nodular pattern while crepitations were observed in 79.66% cases of consolidation. Patchy consolidation was seen in comorbidities like pregnancy (n = 10) and obesity (n = 06), while reticulonodular pattern was observed in hypertensive patients (n = 06). Maximum number of deaths were between 21 and 30 years of age (60.71%). Total number of deaths were 28 with 60.71% (n = 17) deaths between 21 and 30 years of age. Deaths were more in presence of comorbidities like Pregnancy (n = 5, 17.85%), Hypertension (n = 4,14.28%), Diabetes (n = 3 10.21%) and RVHD (n = 3,10.71%), in presence of RLZ involvement (92.85%), RMZ (89.28%), LMZ (85.21%) and RUZ involvement (71.42%), with consolidation pattern (57.14%) followed by reticulonodular pattern (21.42%) and in presence of six zone involvement (36.37%) followed by four zone (35%) and then by three(33%) and two (32%) zone involvement. Mean duration of hospital stay was 9.1 days. 23% patients stayed for less than 5 days, 41% stayed between 9 and 14 days while only 7% required to stay for more than 15 days. 37% pts showed normal Xray at the time of discharge or death. 38% patients showed persistence of radiological lesion at discharge or death. CONCLUSIONS: Young to middle age patients were commonly affected. Common comorbidities were Pregnancy, Diabetes, Hypertension, and Obesity and patients had fever, cough, breathlessness, tachypnoea, crepitations as common clinical features. Radiologically it was multizonal, bilateral disease with predominant lower zone involvement and common patterns were consolidation followed by reticulonodular and nodular. Patchy consolidation was more common in pregnancy and obesity while reticulonodular pattern was more in hypertensive patients. Fever, cough and tachypnoea were present in all 100% pts with nodular pattern. Crepitations were common in pts with consolidation. Clinical recovery preceded radiological recovery. Young to middle aged individuals died more. Deaths were more in presence of comorbidities like Pregnancy, HT, DM and RVHD, also with RLZ, RMZ, LMZ involvement and with consolidation pattern and with six zone involvement. PMID- 24772695 TI - Utility of SOFA and APACHE II score in sepsis in rural set up MICU. AB - AIMS AND OBJECTIVES: To assess morbidity and mortality as well as to prognosticate the patients by using SOFA and APACHE II scores of patients with sepsis, severe sepsis and multi-organ dysfunction syndrome (MODS) in rural setup ICU. MATERIAL AND METHODOLOGY: We carried out prospective study on patients with sepsis as per ACCP guidelines and analysed their clinical and microbiological profile. We calculated SOFA score on day 1, 3 and 7. APACHE II score was also calculated on day of admission. We used both the scores for predicting the outcome. RESULTS: The mortality rate was 48% in our study group which had alarming proportion of MODS patients (78%). The most common organ involved was lung and the most common organism causing sepsis was Klebseilla. On day 3, the mortality rate of patients with SOFA score less than nine was 9.1%, while the mortality rate of patients with score more than nine was 78%. The trend of mean SOFA score was progressively declining in survivor group. The mean APACHE II score was marginally higher in non-survivor group compared to survivor group, however the difference was not statistically significant. CONCLUSIONS: Serial measurement of SOFA score during first week is very useful tool in predicting the outcome. The APACHE II score on day of admission was not reliable in predicting the mortality rate in this study and we believe that it may need modification in set up like ours. PMID- 24772696 TI - Melioidosis :an emerging infection in India. AB - BACKGROUND: Melioidosis caused by the gram-negative bacterium Burkholderia pseudomallei is endemic in Southeast Asia but may be under-diagnosed and under reported in the Indian subcontinent. This study was undertaken to analyse the clinical presentation and epidemiological risk factors for melioidosis in India. METHODS: We carried out a retrospective study of 32 culture proven cases of melioidosis at a tertiary care hospital in South India between 2005 and 2010. RESULTS: Thirty two culture confirmed cases of melioidosis were included in the study. Patient age varied from 4 to 60 years with a median age of 42.5 years. Males constituted 75% of cases and 78.12% of cases were from rural areas. Three fourth (24 of 32) had at least one risk factor that predisposed to melioidosis: diabetes (43.75%) followed by alcoholism (21.87%) were the commonest. Fever was the most common symptom (68.75%) and mean duration of symptoms was 2.34 months before diagnosis. More than half of the cases (56.25%) presented as disseminated disease with the remainder having localised disease, usually septic arthritis or abscesses. Three fourth of patients (75%) were treated successfully on follow-up, with a regimen of parenteral ceftazidime followed by oral doxycycline and cotrimoxazole. CONCLUSION: Melioidosis is an emerging infection in India especially in males from rural areas, with diabetes and alcoholism being the commonest risk factors. Both sepsis with bacteraemia and localised disease involving joints or focal abscess were common presentations. Diagnosis is readily made by culturing the organism from appropriate clinical specimens and identifying non-fermenting Gram negative bacteria to the species level. As there was an excellent response in 75% of patients, early suspicion, culture confirmation and therapy is warranted in India. PMID- 24772697 TI - Obstructive sleep apnoea and atopy among middle aged chronic obstructive pulmonary disease and bronchial asthma patients. AB - BACKGROUND: Obstructive sleep apnoea syndrome is associated with significant morbidity. A high prevalence of obstructive sleep apnoea (OSA) symptoms has been reported in patients with asthma and chronic obstructive pulmonary disease (COPD). There are limited studies regarding relationship between atopy and OSA. OBJECTIVE: To study the risk of obstructive sleep apnoea among middle aged chronic obstructive pulmonary disease and asthma patients by a home based sleep study and its association with atopy. METHODS: Patients with asthma and COPD were evaluated for OSA symptoms by Epworth sleepiness scale (ESS) and Berlin questionnaire (BQ). ESS score > or = 9 was considered as high risk for OSA. Patients having high risk for OSA by ESS and BQ were further evaluated for OSA by home based sleep study. Skin prick test against common allergens was done to diagnose atopy in these patients. RESULTS: Among 400 patients (229, 57.25% male and 171, 42.75% female) 328 were asthmatics and 72 were COPD patients. ESS and BQ was positive in 11.25% (45/400) and 18.25% (73/400) patients respectively. ESS was positive in 10.67% (35/328) of asthma and 13.88% (10/72) of COPD patients. BQ was positive in 18.29% (60/328) of asthmatic and 18.05% (13/72) of COPD patients. Skin prick test was positive in 74.16% patients. The maximum positivity was found in asthmatics (139/155, 89.68%) compared to COPD patients (16/155, 10.32%). Skin prick test was done for 40 patients out of 73 of Asthma and COPD patients who were found positive by ESS and BQ. 72.5% patients were found to be atopic. Out of 19 patients in whom home polysomnography was done, 13 patients consented for skin prick test with common aeroallergens and 9 (69.23%) patients were found to be atopic. CONCLUSIONS: There is an increased risk of obstructive sleep apnoea among middle aged chronic obstructive pulmonary disease and asthma patients. Atopy could be associated with OSA. The association needs to be proved in a larger study. PMID- 24772698 TI - Prevalence of depression among type 2 diabetes compared to healthy non diabetic controls. AB - AIMS: Successful diabetes management depends on patient behaviour. Diabetes is a significant risk factor for depression which itself is a risk factor for poor metabolic control. Data on this association is scarce from India--which is fast becoming the diabetes capital of the world. This study was done to see the prevalence of depression in adult patients with type 2 diabetes diagnosed within the previous 5 years and treated with oral hypoglycaemic agents compared to healthy persons without diabetes. Also, to evaluate Becks depression inventory (BDI) in terms of Mini International Neuropsychiatric Interview (MINI) as a tool to assess depression in diabetes. METHODS: Patients with diabetes within 5 year of diagnosis and on oral anti-diabetic drugs were included. Controls were healthy relatives of these patients without diabetes. These patients underwent clinical examination, biochemical tests, assessment of depression by BDI and MINI BDI and MINI were used to assess depression in controls as well. Prevalence of depression was found in both groups and compared. BDI was evaluated considering the MINI as gold standard in detecting depression in diabetes. RESULTS: The prevalence of co morbid depression was 27.05% according to the MINI. In the non-diabetic healthy patient relatives, this was 11.11%. Those having depression had a lower educational attainment and a higher prevalence of retinopathy, compared to subjects without depression. The relative risk for the diabetics to have co morbid depression was 2.97 (95% confidence interval 1.41-6.24). The BDI score with best sensitivity and specificity for diagnosing depression in diabetes was > or = 21. For healthy controls, a score of > or = 14 had best sensitivity and specificity. Diabetic patients had a higher score of BDI even without a diagnosis of depression on the MINI. CONCLUSION: Prevalence of depression was 27.05% diabetic patients and 11.11% healthy controls. A BDI score of 21 had the best sensitivity and specificity for diagnosing depression in adult type 2 diabetic patients. BDI can be used as a simple screening tool for the detection of depression in diabetic patients. PMID- 24772699 TI - Prevalence and pattern of antiphospholipid antibody syndrome in a hospital based longitudinal study of 193 patients of systemic lupus erythematosus. AB - BACKGROUND: Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disease characterised by thrombophilic state and obstetrical complications. Prevalence of APS varies in different parts of the world. So this study was conducted to find out the prevalence and pattern of APS in systemic lupus erythematosus (SLE) in this region. MATERIAL AND METHODS: In this hospital based longitudinal study from 2004 to 2011, we studied 193 patients of systemic lupus erythematosus (SLE) for prevalence of APS and its different characteristics. The diagnosis of SLE was made according to American College of Rheumatology (ACR) criteria and diagnosis of APS was made according to Sapporo criteria. RESULTS: Prevalence of APS in SLE was 25.38%. Mean age at study entry was 25.5 +/- 6.9 years and majority of APS patients were in the age group 21-30 yrs (44.89%). The most common clinical manifestation in both SLE with APS and SLE without APS was musuloskeletal involvement (79.59% and 84.72% respectively). Among 49 patients of SLE having APS, multisystem involvement was present in 16 patients and life threatening complications were present in 12 patients. Late foetal loss was the most common obstetrical manifestation of APS (26.53%) and deep vein thrombosis was most common thrombotic manifestation (16.32%). Anticardiolipin antibodies(IgG aCL) were the most common antibody (85.71%) detected. Lupus anticoagulant was present in 71.42% cases of SLE having APS. ANA and anti-dsDNA antibodies were present in 97.95% and 77.55% cases of SLE having APS. CONCLUSION: APS is a major cause of morbidity and mortality in patients of SLE. The incidence of secondary APS in SLE varies in different geographical regions and it was 25.38% in our study. Pregnancy morbidity and deep vein thrombosis were the most common complications of APS. IgG aCL was the most common antibody in APS patients. Screening for the presence of aPL antibodies in SLE patients and timely initiation of prophylactic treatment can prevent many of the complications. PMID- 24772700 TI - Clinical profile and mortality among novel influenza A (H1N1) infected patients: 2009-2010 Jodhpur, Rajasthan pandemic. AB - OBJECTIVES: Influenza causes annual seasonal epidemics around the world. Periodically, a genetically novel strain of influenza circulates worldwide, causing an influenza pandemic. The present study aims to assess the clinical profile, factors determining the response, prognosis of the disease and outcome in H1N1 positive patients during 2009-2010 H1N1 pandemic, so that epidemiology of the disease could be known and high risk groups can be identified. METHODS: Medical records of the H1N1 positive patients, confirmed by RT-PCR method, admitted in ICU/Isolation ward in M.D.M. Hospital, Jodhpur during pandemic of H1N1 influenza (2009-2010) were retrieved and retrospectively studied, the data collected was analysed. RESULTS: During the study period there were 221 H1N1 positive admissions. The age group most affected was 21-40 years in both males (52%) and females (67%). There were 80 deaths; mortality was high in rural population (64%) and pregnant women particularly in third trimester (80%). Common presenting symptoms were Cough, Fever, Breathlessness, Sore throat, Nasal Discharge, Expectoration and Body aches, other less common symptoms were Headache, Vomiting, Diarrhoea and Fatigue. CONCLUSION: Swine flu influenza infection took its heaviest toll in terms of human lives and economy because the young and productive population was mostly affected. Pregnant women and the patients with co-morbid conditions were the susceptible population and thus preventive and therapeutic interventions should be directed to them. Early vaccination of high risk groups and high index of suspicion in the symptomatic patients and chemoprophylaxis accordingly can save many human lives. PMID- 24772701 TI - A prospective clinical study of myocarditis in cases of acute ingestion of paraphenylene diamine (hair dye) poisoning in northern India. AB - BACKGROUND: Myocarditis is a unheard and unreported dangerous complication of hair dye ingestion which contains paraphenylene diamine. So a prospective study was planned to assess myocardial damage in regard to clinical profile and outcome with different treatment approaches in patients with oral ingestion of Hair dye. METHODS AND RESULTS: The material comprised of 1595 cases admitted in Medicine Department of Maharani Laxmi Bai Medical College, Jhansi, Uttar Pradesh-INDIA, from July 2004 to Jan 2011. Out of 1595 cases 1060 cases were of stone hair dye poisoning and 535 cases were of other branded hair dyes (powdered form containing less amount of Paraphenylene diamine). Diagnosis of myocarditis was made solely on the basis of the clinical signs/symptoms suggestive of myocardial damage, electrocardiography changes, elevated cardiac biomarkers and abnormalities on trans thoracic echocardiography. The cases were thoroughly studied for cardiac complications. Myocarditis was reported in 15% of total cases with mortality rate of 29%. Occurrence of myocarditis was directly related to amount of Hair dye ingested. In patients affected from myocarditis 9% develop life threatening Ventricular tachycardia/ventricular fibrillation. CONCLUSION: Hair dye (Paraphenylene di amine) is highly toxic. In cases who consumed more than 10 gram of Paraphenylene diamine, myocarditis is a dangerous complication. Proper management includes continuous cardiac monitoring to prevent sudden cardiac death. PMID- 24772702 TI - Clinical review of sitagliptin: a DPP-4 inhibitor. AB - Type 2 Diabetes Mellitus is most common form of diabetes. Oral agents are the main stay of pharmacological treatment for type 2 diabetes mellitus. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a new therapeutic approach for type 2 diabetes. Sitagliptin is highly selective DPP-4 inhibitor that has been approved for type 2 diabetes therapy. It acts by increasing the levels of incretins by inhibiting their degradation by DPP-4. Sitagliptin has been shown to be effective, well tolerated and safe in the treatment of type 2 diabetes in monotherapy or in combination with metformin or thiozolidinediones with minimal side effects. PMID- 24772703 TI - Lead aVR--the neglected lead. AB - The aVR is often neglected lead. It is an unipolar lead facing the right superior surface. As all the depolarisations are going away from lead aVR, all waves are negative in aVR (P, QRS, T) in normal sinus rhythm. In dextrocardia, (True and technical) the p is upright in aVR. The lead aVR is a very important lead in localisation of Coronary Artery Disease. In the presence of anterior ST elevation, ST elevation in lead aVR and V1 denotes proximal LAD obstruction where ST elevation is more in lead V1, than in aVR. In the presence of anterior ST depression, ST elevation in lead aVR indicates Left Main Coronary Artery (LMCA) Disease where ST elevation is more in aVR than in V1. In wide QRS tachycardia, tall R wave in aVR indicates Ventricular Tachycardia rather than SVT with aberrancy. In the presence of QS complexes in inferior leads, the lead aVR helps to differentiate between inferior wall MI (IWMI) and left anterior fascicular block (LAFB). Initial R in aVR is suggestive of IWMI and terminal R is suggestive of LAFB. In pericarditis, lead aVR is most often the only lead which shows reciprocal ST depression where as in Acute Infarction, usually a group of leads shows reciprocal depression. In the presence of persistent ST elevation in anterior chest leads, the R in aVR is suggestive of left ventricular aneurysm (Goldburger's sign). In acute pulmonary embolism, ST elevation in lead aVR is a bad prognostic sign. In Tricyclic antidepressant toxicity, R in aVR more than 3 mm is an adverse prognostic sign. So in variety of conditions, the aVR is proved to be a valuable lead not only in diagnosis but also in predicting the prognosis. PMID- 24772704 TI - Sinus of valsalva aneurysm. PMID- 24772705 TI - Forme fruste of Heerfordt syndrome. PMID- 24772706 TI - Inflammatory pseudotumour. AB - A 29 year old female patient with submandibular swelling, anaemia, fever was diagnosed to have inflammatory pseudotumour of neck. We are reporting this case as it can affect diverse locations in body with varied clinical manifestations mimicking malignancy and posing a diagnostic challenge. PMID- 24772707 TI - Congenital hypothyroidism presenting as menorrhagia in adulthood. AB - Although hypothyroidism is a common cause of menorrhagia, it is an uncommon presentation of congenital hypothyroidism. We report a case of congenital hypothyroidism presenting in adulthood with severe menorrhagia. Despite the late presentation, she had features to suggest hypothyroidism since birth. PMID- 24772708 TI - Malignant peripheral nerve sheath tumour presenting with Horner's syndrome. AB - A young male presented with clinical and radiological features of right apical lung mass and Horner's syndrome. Subsequently the patient was diagnosed as a case of malignant peripheral nerve sheath tumour (MPNST) at the apex of right lung originating from an intercostal nerve and compressing ipsilateral cervical sympathetic plexus and lower cord of brachial plexus, in a case of neurofibromatosis type 1. PMID- 24772709 TI - Chorea as a rare manifestation of hyperglycaemia. AB - INTRODUCTION: We present a case of chorea presenting as a clinical manifestation of hyperglycaemia.The purpose of presenting this case is to highlight the fact that movement disorder may be the clinical presentation of hyperglycaemia and it reverts on treatment of hyperglycaemia. CASE PRESENTATION: A 66-year-old female known case of type 2 diabetes mellitus and on oral hypoglycaemic drugs presented with abnormal and involuntary movements of the whole body and face since 7 days and high plasma glucose (446 mg/dl) and without ketosis. On controlling the blood sugar, there has been significant decrease in choreiform movements within 48 hrs and complete resolution of involuntary movements found at discharge at 1 week. CONCLUSION: Movement disorder like chorea may be the clinical presentation of the hyperglycaemia which could completely recover on rapid detection and correction of hyperglycaemia. PMID- 24772710 TI - Acute myocardial infarction in a 20 year pregnant female with prosthetic mitral valve. AB - Myocardial infarction is very uncommon in young females. We are reporting a case of acute myocardial infarction in a 20 year pregnant female with prosthetic mitral valve. Embolism from mitral valve prosthesis, in-situ thrombosis due to hypercoagulable state of pregnancy or coronary spasm could be responsible. PMID- 24772711 TI - Empyema with pleuropulmonary mucormycosis. AB - Pleuropulmonary mucormycosis is relatively rare disease and that too localised disease is very rare but has got better prognosis. Maintaining a high level of suspicion is important in right clinical setting with pleuropulmonary involvement that fails to antibacterial agent either clinically or radiologically. PMID- 24772712 TI - H1N1 encephalopathy. AB - The 2009 pandemic influenza A (H1N1) has been recognised to cause neurological complications including seizures and encephalopathy. Reporting a 16 year old girl admitted to Bidar Institute of Medical Sciences Hospital (BRIMS), with H1N1 encephalopathy, during pandemic H1N1 2009. PMID- 24772713 TI - Intrabronchial neurofibromatosis. AB - Thoracic manifestations of Neurofibromatosis include intrathoracic posterior mediastinal tumours, meningocoeles, kyphoscoliosis and interstitial fibrosis. Even though mediastinal neurofibromas are common, intrapulmonary neurofibromas are very rare. In this paper, we present a case of intrathoracic neurofibroma with intrabronchial extension. Lesions extending into the bronchial lumen making bronchoscopic diagnosis possible, as in this case is extremely rare. The case is presented because of its rarity. PMID- 24772714 TI - Hydatid cyst of the liver causing inferior vena caval obstruction. AB - Hydatid disease (cystic echinococcosis) is a zoonotic infection caused by larval forms of the tapeworm Echinococcus granulosus. Most common site for cysts is liver and hepatic hydatidosis has a diverse clinical spectrum. Mostly they remain asymptomatic and uncomplicated. Here we report a case of a 50 yr old farmer admitted for renal disease, who was incidentally found to have inferior vena caval obstruction. Ultrasound abdomen and CT abdomen were done and a 10 x 7 cms hepatic hydatid cyst compressing the vena cava was found. PMID- 24772715 TI - Refractory anaemia in an immunocompromised patient--what is it? AB - Anaemia is common among human immunodeficiency virus (HIV)-infected patients. It may be directly attributable to the virus or may be caused by opportunistic infections, neoplasms or drugs that cause either bone marrow suppression or haemolysis. Pure red cell aplasia (PRCA) is an uncommon haematological disorder that causes severe transfusion dependant anaemia. We report a 36 year-old female with HIV infection who developed anaemia which did not improve even after discontinuing the offending drug, namely Zidovudine. Routine investigations were unhelpful but her bone marrow study was consistent with pure red cell aplasia. She showed dramatic improvement with steroids with subsequent transfusion independence. PMID- 24772716 TI - Addison's disease presenting with muscle spasm. AB - Primary hypoadrenalism has various causes and protean manifestation. We report a young female patient who presented with severe muscle spasm as her primary complaint. On evaluation she was found to be a case of Addison's disease secondary to adrenal tuberculosis. Her muscle spasm disappeared rapidly with replacement dose of glucocorticoid. PMID- 24772717 TI - Madhavacharya. PMID- 24772718 TI - Medical philately. Robert Barany, father of otoneurology and vestibular functions. PMID- 24772719 TI - Occupational podoconiosis. PMID- 24772720 TI - Epidemiological study of blood pressure distribution and prevalence of hypertension in Spiti Valley of Himachal Pradesh. PMID- 24772721 TI - Carotid intima media thickness in type-2 diabetes mellitus with cardiac autonomic neuropathy. PMID- 24772722 TI - Reply from author. PMID- 24772723 TI - Stroke epidemic in India - time to prioritize prevention strategies. PMID- 24772724 TI - A study on stroke victims in Rajiv Gandhi Government General Hospital, Chennai. AB - OBJECTIVES: Stroke is a devastating and disabling cerebrovascular disease with some amount of residual deficit leading onto economic loss. Recent Indian studies have shown a stroke prevalence rate of 471.58 / 1,00,000 population. This study was undertaken to analyse the clinical profile and to arrive at important facts contributing to stroke in both the sexes. METHODS: This is a descriptive, retrospective cross-sectional study carried out on acute stroke patients, admitted to the I.I.M., RGGGH, Chennai. 150 patients were studied over a period of 3 months in the year 2011. RESULTS: 58% males and 42% females constituted our study population. Among males 18.4% and among females 22.2% were young stroke patients. Only 33.3% of patients were brought to the hospital within 6 hours. 90% patients had mild GCS score(> or =13/15) and presented with hemiplegia. 76% and 18% had infarct and intracerebral haemorrhage (ICH) respectively. RISK FACTORS: Type A personality (70.7%), Tobacco (60.7%) and Alcohol (44.7%) abuse, Systemic Hypertension (60.7%), Diabetes Mellitus (33.3%), Cardiac disorders (14%). CONCLUSION: Significant proportion of Cerebrovascular accidents(CVA) was seen in the young females. Type A personality was seen in large number of study subjects. Personal habits in males and chronic comorbid illness in females had a strong association with occurrence of stroke. A holistic approach encompassing public awareness, behavioural modification and comorbid medical illness management is the need of the hour. PMID- 24772725 TI - Multiple drug resistant bacterial biofilms on implanted catheters - a reservoir of infection. AB - BACKGROUND: Medical devices are an essential part of modern health-care, but its usage has led to the emergence of medical device associated infections otherwise known as Foreign-Body related infections (FBRIs). This is caused by bacterial adhesion and biofilm formation on their surfaces which act as a nidus of infection. These biofilms are resistant to antibacterial agents and host immune response. The antibiotics which are useful in treating planktonic forms cannot clear the biofilm and the device must usually be removed to resolve the infection. OBJECTIVE: The main objective of the study was to identify the prevalence of bacterial biofilms on retrieved catheters which included vascular catheters (141) and Foley catheters (86) from patients and understand the nature of antibiotic resistant strains in these biofilms. MATERIALS USED :227 numbers of retrieved catheters which included vascular catheters (141nos) and Foley catheters (86 nos) were used in the study.These retrieved implants were from patients from neurosurgery ward of SCTIMST who had undergone selective neurosurgical procedures. Patients with pre-existing infections including brain abscess were not included in the study.These patients had no clinical infection or pyrexia. Skin swabs were taken from patients using intravascular devices after retrieval of catheter. RESULTS AND CONCLUSIONS: Among vascular catheters Staphylococcus species were the major isolate and among the isolates many of the strains were Methicillin and some were Vancomycin resistant. Among the Foley catheter isolates E. faecalis was the major isolate followed by E. coli, Staphylococcus species, Klebsiella species, Pseudomonas species, Citrobacter etc. Most of the strains were resistant to multiple antibiotics. Although the patients selected did not have any clinical symptoms of infection, the presence of multiple-drug resistant organisms as biofilm points to this niche which can constitute a threat for HAls and its resultant complications. This suggests that catheters should be removed as early as possible to prevent Biofilm development on them. PMID- 24772726 TI - Randomised placebo-controlled double blind multicentric trial on efficacy and safety of Lactobacillus acidophilus LA-5 and Bifidobacterium BB-12 for prevention of antibiotic-associated diarrhoea. AB - AIMS: To evaluate the effectiveness, safety and tolerability of a probiotic formulation containing Lactobacillus acidophilus LA-5 and Bifidobacterium BB-12 in the prevention of antibiotic associated diarrhoea (AAD). METHODS AND MATERIAL: A double-blind randomised placebo controlled multicentric trial was conducted in adults who were prescribed a seven-day course of oral antibiotic (either cefadroxil or amoxycillin) for a documented indication. The effectiveness of a 14 day therapy (concomitant with antibiotic course and seven days thereafter) of the probiotic formulation in preventing AAD was evaluated. Safety profile was assessed by monitoring of all treatment emergent adverse events and tolerability on a global well being scale. RESULTS: The incidence of AAD in the probiotic group was 10.8% compared to 15.6% in the placebo group, the difference being statistically non-significant (p = 0.19). The relative risk for AAD was 0.7 with the 95% CI being 0.4 to 1.2. The diarrhoea duration in the probiotic group was two days with an interquartile range of 1- 3 days and was significantly less (p = 0.01) than the placebo group which was four days with an interquartile range of 3 - 5.5 days. Subgroup analysis of subjects with AAD showed that the incidence of severe diarrhoea (watery stools) was 96% in the placebo group (25 out of 26) compared to 31.6% (6 out of 19) in the probiotic group and this difference was significant statistically (p < 0.001). Four mild, non-serious, adverse events were detected (2.0%) in the probiotic group but there were none in the placebo group. CONCLUSION: This randomised controlled trial shows that prophylactic administration of the probiotic formulation containing Lactobacillus acidophilus LA-5 and Bifidobacterium BB-12, did not effectively lower the incidence of AAD in adults. However, compared to placebo the duration of diarrhoea in the probiotic group was significantly reduced. Its tolerability and safety profile were good. PMID- 24772727 TI - Mean arterial pressure may affect LV mass even when clinic BP is 120/80 mmHg or less. AB - Detailed echocardiographic evaluation was performed on sixty-four normal persons without any cardiovascular risk factor and clinic blood pressure of 120/80 mm of Hg or less with an aim to find, if there are subclinical echocardiographic changes even in this population. There was significant positive linear correlation between mean arterial pressure and LV mass index. On dividing the patients according to mean arterial pressure, those with mean arterial pressure of more than 85 had significantly higher LV mass index (P <0.01).There may be a relationship between mean arterial pressure and LV mass index in this population, but this needs to be further explored in a larger study. PMID- 24772728 TI - Glycaemic index (GI) of an Indian branded thermally treated basmati rice variety: a multi centric study. AB - BACKGROUND: Glycaemic Index (GI) is the classification of carbohydrates based on their ability to raise blood glucose levels and evidence shows that its usage has beneficial health implications. Rice forms a part of the Indian staple diet and one of the major energy contributors. Hence, it is important to establish the Glycaemic Index (GI) value of rice. However, due to availability of different varieties of rice it is important first to identify a lower GI variety and to make it available to the Indian population. Subjecting rice to thermal processing is also known to reduce the GI of rice. OBJECTIVE: An Indian thermally treated basmati rice variety was hypothesised to be low in GI. This multi centric study was conducted to test this hypothesis in healthy volunteers. STUDY DESIGN: In this study, out of 83 participants, data points of 70 healthy volunteers were taken into consideration for arriving at the final GI value. The study procedure was similar to the recommendations by FAO/WHO. A multi centric trial was conducted to nullify any regional or genetic variability. RESULTS: It was observed that reference glucose curve had the maximum average peak of 166.37 mg/dL while the basmati sample had a lower peak (136.22 mg/dL). The mean blood glucose incremental area under the curve for reference food was 5969.64 mins.mg/dL (SEM 95.94) and for rice it was 3267.81 mins. mg/dL (SEM 76.21). CONCLUSION: In this studyThe GI of Indian branded basmati rice was found to < 55 thus, placing it in lower GI category. The Indian basmati rice because of its lower GI can prove to be a healthier rice alternative. PMID- 24772729 TI - Efficacy of rosuvastatin in achieving target HDL, LDL, triglycerides and total cholesterol levels in type 2 diabetes mellitus (T2DM) with newly diagnosed dyslipidaemia: an open label, nonrandomised, non-interventional and observational study in India. AB - Asian Indians with dyslipidaemia should be treated as aggressively as if they had a CHD risk equivalent-similar to the treatment of patients with diabetes or heart disease. OBJECTIVE: To evaluate efficacy of Rosuvastatin in achieving target HDL, LDL, triglycerides and total cholesterol levels in type 2 diabetes mellitus (T2DM) patients with newly diagnosed dyslipidaemia, but without known coronary artery disease. METHODS: The study was an open label, nonrandomised, non interventional, observational study in India involving T2DM patients who require statin therapy to control dyslipidaemia. Data were collected at baseline, interim (8 weeks) and subsequently at 16 weeks of Rosuvastatin (10 and 20 mg) therapy. Efficacy of the treatment was assessed by evaluating whether subjects reached target LDL and total cholesterol levels according to NCEP ATP III guidelines. RESULTS: Four thousand three hundred and sixty-nine patients completed the study. Out of 4369, 1115 (25.52%) have achieved a target LDL level of < 100 mg/dL and 2930 (67.06%) falls under HDL level of 40-60 mg/dL.The mean change in HDL levels was 5.56 mg/dL in females and 4.59 mg/dL in males. Overall 63.95% of patients had achieved the total cholesterol target and 50.06% achieved triglyceride target. The adverse events reported were generally mild. CONCLUSION: On the basis of the above results, it can be concluded that Rosuvastatin safely and beneficially alters the entire spectrum of lipoproteins in Indian patients. PMID- 24772730 TI - How to ascertain drug related deaths during clinical trials ? AB - Recent guidelines by the Drug Controller General of India require extra care by Investigators & Sponsors of Clinical Trials in India. The author, an eminent member & Chairman of various Independent Ethics Committees in Mumbai, proposes various concrete solutions for adherence to these guidelines. Insurance cover to the subjects, use of Internet databanks for drug interactions, active involvement by the pharmacologists in Ethics Committee, review of data from animal studies, being amongst them. In case of death due to trial, autopsies, or at least verbal autopsies, are essential in the interest of Science and Law. More importantly Anticipation and prevention of ADEs can be done by exclusion of subjects from trials by using newer technologies like cDNA in microarrays to determine several polygenic quantitative trait loci (QTLs) and tests for Single Nucleotide Polymorphisms (SNPs). Drug manufacturers must provide prototypes of Affymetrix chips to clinicians and bear the cost in their own enlightened self-interest. PMID- 24772731 TI - Beck's syndrome. PMID- 24772732 TI - Dural arteriovenous fistula. PMID- 24772733 TI - Post renal transplant posterior reversible encephalopathy syndrome. AB - Posterior reversible encephalopathy syndrome is commonly associated with factors like hypertension, immunosuppression, uraemia, volume overload and electrolyte disturbances in post renal transplant patients. We report a case of (posterior reverssible encephalopathy syndrome) PRES in young post renal transplant patient where all these common associations were absent. High index of suspicion, clinical course and characteristic MRI finding was the key to the diagnosis. PMID- 24772734 TI - Reactive thrombocytosis leading to acute myocardial infarction. AB - Thrombocytosis is defined as platelet count of > 600000. An elevated platelet count may be primarily (essential) or secondary (reactive). Acute myocardial infarction and other vaso-occlusive phenomenon are seen in less than 5% of the patients of reactive thrombocytosis. Here we report such a case. A 49 yr old lady presented with chest pain and had isolated right ventricular infarction that progressed to anteroseptal wall STEMI. Her platelet count was 11 lac; the triggering factor in this case was reactive thrombocytosis secondary to lower respiratory tract infection and iron-deficiency anaemia confirmed after investigations. The clinical diagnosis was confirmed through IL6 levels. The patient was managed aggressively in ICCU, she had an uneventful recovery and was discharged with a normal platelet count. PMID- 24772735 TI - Protein losing enteropathy in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic immunologic disorder that may affect multiple organ systems and present with myriad of clinical features. Gastro-intestinal (GI) manifestations are oral ulcers, dysphagia and abdominal pain caused by autoimmune peritonitis/intestinal vasculitis. Hypoalbuminaemia due to GI loss is uncommon. Protein losing enteropathy (PLE) is a group of clinical entities where there is loss of protein through GI tract. PLE due to SLE is rare but it can be the initial manifestation. Patients usually present with pedal oedema mimicking nephrotic syndrome clinically. It is diagnosed by excluding other causes of hypoalbuminaemia. Radio nucleotide labelled albumin scan is useful in confirming albumin loss through GI tract. Often there is a good response to corticosteroids and immunosuppressive drugs. Here we present two SLE patients whose presenting manifestation was protein losing enteropathy and both improved with corticosteroids. PMID- 24772736 TI - Acute acalculus cholecystitis in dengue fever. AB - Atypical manifestations of dengue fever (DF) and dengue haemorrhagic fever (DHF) involving different organs are being increasingly recognised, especially in the dengue endemic areas. We report an atypical presentation of DF in a 22 year old lady presenting with fever and acute pain in the right hypochondrium, diagnosed to be acute acalculus cholecystitis (AAC). PMID- 24772737 TI - External iliac artery pseudoaneurysm complicating renal transplantation. AB - Pseudoaneurysms at donor renal-external iliac artery anastomosis is rare, multifactorial and more often leads to transplant nephrectomy.The incidence of such false aneurysms is less than 1%. With a few series of case reports in literature, the management, aetiology and indications for repair always remain very controversial and debatable. PMID- 24772738 TI - The 'forgotten disease' (or the never known). AB - Lemierre's syndrome is an acute oropharyngeal infection with secondary septic thrombophlebitis of the internal jugular vein and frequent metastatic infections. Despite its rarity, it is important to have a high degree of clinical suspicion to recognise it early. A history of sore throat followed by metastatic infections and abscesses should alert the clinician to the possibility of this unusual infection. We present a case of Lemierre's syndrome presenting with meningitis in a previously healthy young adult along with a review of the pathophysiology of necrobacillosis and its diagnosis, diagnostic difficulty and treatment. PMID- 24772739 TI - Fatal nitrofurantoin lung. AB - Nitrofurantoin is a drug commonly used for urinary tract infections. It acts by damaging bacterial DNA. It is given in dose of 50-100 mg orally and is generally considered a safe drug but has occasionally been known to cause pulmonary toxicity which is usually reversible and only rarely fatal. We present a case of an elderly lady receiving nitrofurantoin for her urinary tract infection who developed sudden acute lung injury to which she finally succumbed within a few weeks. PMID- 24772740 TI - Leukemoid reaction, a rare manifestation of autoimmune hemolytic anemia in a case of small duct primary sclerosing cholangitis. AB - A 48 year old lady presented with jaundice and exertional breathlesness. Her laboratory reports showed anaemia, reticulocytosis, leucocytosis, elevated Lactate Dehydrogenase (LDH), alkaline phosphatase levels, hyperbillirubinemia and positive direct Coomb's test. After ruling out all the other causes of autoimmunity and hemolytic anemia, she was diagnosed as leukemoid reaction due to autoimmune hemolytic anemia with primary sclerosing cholangitis. Patient showed immediate improvement after corticosteroids. PMID- 24772741 TI - Chakradatta. PMID- 24772742 TI - Hideyo Noguchi: syphilis, oraya fever and leptospira. PMID- 24772743 TI - Clinical profile and prognostic factors of severe falciparum malaria in a tertiary care hospital. PMID- 24772744 TI - Dengue masquerading as upper respiratory tract infection : a report of two cases. PMID- 24772745 TI - Emergence of non-alcoholic fatty liver disease (NAFLD). PMID- 24772746 TI - Study of prevalence of nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes patients in India (SPRINT). AB - Non-alcoholic fatty liver disease (NAFLD) is a distinct hepatic condition and one of the most common causes of chronic liver disease globally. Prevalence of the disease is estimated to be around 9-32% in the general Indian population, with a higher incidence rate amongst obese and diabetic patients. We conducted this study to determine frequency and risk factors of NAFLD in nonalcoholic Indian type 2 diabetic (T2DM) patients, based on elevated aminotransferase levels, defined as per NHANES III criteria. Out of 924 patients (355 female/569 male), in age group of 25-84 years, enrolled at 189 centers across 101 cities in India, a cohort of 522(56.5%) T2DM patients were identified as having NAFLD. Prevalence of the disease was found to be higher in females (60%) than in males (54.3%) T2DM patients; with prevalence of NAFLD varying from 44.1% in western India to 72.4% in northern states. In our study the prevalence of NAFLD increased with increasing age, with 239(45.8%) identified patients in age group of 25-50 years and 283(54.2%) among those aged 51 years (OR:0.71, 95%CI: 0.54-0.92, p=0.005); with highest prevalence recorded in 61-70 year age group, at 61.8%. The results from the study reinforced the well established clinical association of NAFLD with elements of metabolic syndrome (MetS) including dyslipidemia, hypertension and obesity; as T2DM population with these co-morbid conditions had 38%, 17% and 14% higher risk respectively, for NAFLD. The mean AST and ALT levels were 54.8+/-36.1 IU/L and 55.6+/-39.8 IU/L, respectively in NAFLD population and highest in age group of 25-40 years and lowest in 71-84 years age group. Mean ALT levels were found to be higher than mean AST levels across all age groups in identified T2DM NAFLD cohort, with 340(65.3%) patients having elevation of both AST and ALT levels. The results from this study besides demonstrating the prevalence pattern of NAFLD and associated risk factors in Indian T2DM patients, also point out that even mild elevation in aminotransferase levels warrants attention, since it might more often than not point to previously unsuspected liver disease. PMID- 24772747 TI - Isolation and survey of antibiotic sensitivity in nosocomial infections in north Maharashtra region. AB - BACKGROUND: The present work was aimed to study the prevalence of the drug resistance among Gram positive and Gram negative organisms isolated from clinical samples obtained from various private nursing homes of Jalgaon city and surrounding areas in the state of Maharashtra. MATERIALS AND METHODS: Different pathogenic organisms were isolated from one thousand seven hundred and ninety clinical samples obtained from various nursing homes of Jalgaon region of North Maharashtra, MS, India during the period of August, 2010 to July, 2011. Antibiotic sensitivity testing of isolated pathogenic organisms was done with fifty different antibiotics of 13 different groups by the disk diffusion technique using Mueller Hinton Agar Plates according to CLSI (formerly NCCLS) guidelines. RESULTS: Out of total samples analyzed 1171 samples showed the presence of infection while in 619 samples no growth of organisms was seen on culture medium. Microbial growth revealed presence of 11 different organisms (E. coli, Klebsiella spp., Proteus spp., Pseudomonas spp., Enterobacter spp., Salmonella spp., Acinetobater spp., Streptococccus spp., Staphylococcus aureus (MRSA and MSSA)) including Candida spp. Sensitivity profile of these organisms towards different antibiotics is reported here. CONCLUSION: The study resulted in generation of representative status of the antibiotic sensitivity pattern of commonly found organisms in nosocomial infections in the region. This could be useful for the clinicians to choose correct antibiotic and ensure the judicious use of the same for their patients. PMID- 24772748 TI - A study of hepatic dysfunction in dengue. AB - Dengue is a major international health concern that is prevalent in tropical and sub tropical countries. There are certain clinical features that are associated with Dengue in addition to the classical features. An analysis of 70 patients suffering from dengue showed liver dysfunction was present in all patients. Vomiting was an important symptom. SGOT levels were higher than SGPT levels. Hepatosplenomegaly and ascitis were also present in significant number of patients. One should be aware of these presentations when dealing with suspected cases of Dengue. PMID- 24772749 TI - Role of blood C - reactive protein levels in upper urinary tract infection and lower urinary tract infection in adult patients (>16 years). AB - AIM: Role of blood C - reactive protein levels in upper urinary tract infection and lower urinary tract infection in adult patients (>16 years). MATERIAL AND METHODS: Study included 2 groups of patients -Test group (n=58). Control group (n=28).Test group further classified into 2 groups- a). Patients having upper urinary tract infection b). Patients having lower urinary tract infection. Patients were subjected to following tests - complete hemogram, blood C-reactive protein levels, urinalysis. RESULTS: The mean value of C-reactive protein in the cases of upper urinary tract infection 127.33 mg/L which is statistically significantly raised when compared to control(t-value 12.370 and p-value<0.01). C reactive protein was significantly raised in upper urinary tract infection in comparison to control group( p<0.01), while in lower urinary tract infection this difference was insignificant (p<0.05). CONCLUSION: C-reactive protein has a good diagnostic role in differentiating upper and lower urinary tract infection. The simple size of our study is very small to say these authentically, hence, further studies of large number of cases is required. PMID- 24772750 TI - Angiotensin receptor blockers - advantages of the new sartans. AB - Advantages of the new angiotensin receptor blockers (ARBs) include once daily dosing, an absence of significant adverse reactions, well tolerated side effect profile and cost effectiveness. A growing realization is their beneficial pleotropic effects. Antihypertensive agents are widely used to reduce the risk of cardiovascular events partly beyond that of blood pressure-lowering. The RAAS, and its primary mediator Ang II, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. For patients at high cardiovascular risk based on the results of the ONTARGET and TRANSCEND studies, telmisartan is indicated for cardiovascular prevention. Studies have shown that olmesartan medoxomil treatment may slow the progression of atherosclerosis and postpone albuminuria thereby potentially improving CV outcomes. PMID- 24772751 TI - Chorea. AB - Chorea is an involuntary movement disorder characterised by flowing and rhythmic in nature. Hyperkinetic movement disorders such as myoclonus may be mistaken for chorea. Pathogenes of chorea is complex and results from dysfunction of network between motor nucleus of thalamus and subcortical nuclei including globus pallidus interna. There are genetic and non genetic causes of chorea. Huntington's disease is most common genetic cause of chorea. Clinical manifestations of Huntington's disease are mainly neurological and psychiatric. Recently non neurological clinical manifestations of this disease have been described. Genetic test for Huntington's disease is available which may be done for diagnosis and detection of family members at risk of developing disease. Other genetic causes of chorea are neuroacanthocytosis and Wilson's disease. Treatment of genetic causes of chore is usually symptomatic with exception of Wilson's disease. Sydenham's chorea is a neurological manifestation of acute rheumatic fever and most important cause of chorea seen in paediatric population. Treatment includes penicillin prophylaxis and drugs such as sodium valproate and carbamazepine. Diagnosis of chorea is mainly clinical. Family history is very important in diagnosis of genetic causes of chorea. In other patients a detailed work up is required before a final diagnosis is made. Hematological and blood chemistry investigations are helpful in diagnosis of some of the patients. Neuro imaging may also be useful mainly in Huntington's disease patients. Metabolic disorders and drugs are very important causes of non genetic chorea. Early diagnosis is important because majority of the patients respond to the treatment. PMID- 24772752 TI - Bardet-Biedl syndrome with seizures -a rare association. PMID- 24772753 TI - Metronidazole encephalopathy. PMID- 24772754 TI - Filariasis, with chyluria and nephrotic range proteinuria. AB - 28 yr female presented with (grade III) chyluria, with nephrotic range proteinuria and Ig M mesangial deposition in immunofluorescence, secondary to filariasis which was confirmed by serology and microfilaria in glomerulus,and successfully treated by Renal Pelvic instillation sclerotherapy with 0.2% povidine and medical treatment (Diethylcarbamazine). She was asymptomatic with follow up period of 19 months. PMID- 24772755 TI - Giant aneurysm of left main coronary artery, presenting as acute myocardial infarction in a young man. AB - We present a case of a young male, who presented with acute extensive myocardial infarction and later was found to have giant aneurysm of left main coronary artery. PMID- 24772756 TI - An unusual complication of a common gynaecological procedure. AB - A case of bilateral, but more of massive right sided transudative pleural effusion associated with bilateral ureteric trauma following laparoscopy for endometriosis is reported. The diagnosis of urinothorax was confirmed by demonstrating a pleural fluid to serum creatinine ratio of greater than one. Management of ureteric injury by insertion of Double J (DJ) stents on both sides resulted in resolution of the pleural effusion. PMID- 24772757 TI - Autoimmune hemolytic anaemia in Hodgkin's lymphoma. AB - Autoimmune hemolytic anaemia is a rare presentation of Hodgkin's lymphoma though its association with Non- Hodgkin's lymphoma is well known. It is usually detected at the time of diagnosis when it accompanies Hodgkin's and rarely precedes it. It is a warm immune hemolytic anemia which is responsive to steroids and rituximab. We hereby report a case of advanced Hodgkin's disease who presented as AIHA. PMID- 24772758 TI - Primary sclerosing cholangitis : an atypical presentation. AB - Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of bile ducts..Patients with PSC usually presents with fatigue, jaundice and pruritus. Ultimately it leads to cirrhosis of liver and portal hypertension. But it rarely presents with decompensated liver disease without any previous symptoms. Here we report a case of PSC which presented with features of decompensated liver disease with K-F rings in the eyes. PMID- 24772759 TI - Primary thyroid lymphoma: a series of two cases and review of literature. AB - Primary Thyroid Lymphoma (PTL) is lymphomatous process involving the thyroid gland without contiguous spread or distant metastases from other areas of involvement at diagnosis. It is a rare tumor usually presenting in 60s with rapidly enlarging thyroid mass. Proper evaluation of FNAC specimens is essential in diagnosis as they may be confused with Hashimoto's Thyroiditis or Anaplastic Carcinomas. With the advent of rituximab (monoclonal antibodies binding B lymphocytes), chemotherapy is the mainstay therapy- CHOP + rituximab. However, there may still be some role of local therapies. We present here two cases which had presented at our OPD in last year. Both our patients had presented with rapidly enlarging neck masses with compressive features. Both were reported as Hashimoto's Thyroiditis on initial FNAC. Both underwent thyroidectomy followed by chemotherapy with CHOP + rituximab and are now doing well with no recurrence till date. PMID- 24772760 TI - Primary cutaneous histoplasmosis simulating Molluscum contagiosum. AB - Primary cutaneous histoplasmosis in a HIV positive patient ie isolated cutaneous involvement without any deeper structures is a very rare entity. Only a handful cases have been reported worldwide. This patient presented with cutaneous lesion simulating Molluscum but histopathology revealed Histoplasma capsulatum. The patient had no deep organ involvement. The patient was put on Itraconazole which caused rapid dissolution of the lesions. He was subsequently put on HAART and discharged. PMID- 24772761 TI - The common, less common and uncommon examples of exercise ECG. AB - We present three interesting and representative cases of exercise ECGs which were done as part of Stress Myocardial Perfusion study. Aim is to emphasize the point that the stress part of the test should be conducted by an expert in the field and recovery phase ECG records should be analyzed carefully for maximum benefit from this test. PMID- 24772762 TI - Miliary sarcoidosis with secondary Sjogren's syndrome. AB - We report a case of miliary sarcoidosis with secondary Sjogren's in a 45-year-old male who presented with symptoms of sicca syndrome in the form of dryness of eyes and mouth with parotid swelling. Computed tomography thorax showed mediastinal and hilar lymphadenopathy, bilateral miliary opacities in lung parenchyma. Whole body FDG PET/CT showed involvement of both parotids, liver, diffuse uptake in lungs, mediastinal and retroperitoneal lymph nodes. Patient is on treatment with prednisolone and has responded well. PMID- 24772763 TI - Large pericardial effusion :a clinical dilemma! AB - A 55yr old gentleman known diabetic and hypertensive presented with breathlessness and tingling sensation of both upper and lower limbs with strong family history of similar neurological problems. On extensive evaluation he was found to have amyloidic peripheral neuropathy with large pericardial effusion. Tubercular etiology was confirmed by pericardial fluid PCR and culture. Here the diagnostic dilemma was whether Amloidosis is primary, secondary to Tubercular pericardial effusion or Hereditary Amyloidosis. In the end, how we have arrived at the diagnosis of Hereditary Amyloidosis based upon the strong family history and nerve biopsy is interestingly presented in the following case report. PMID- 24772764 TI - Medical philately. Georg von Bekesy - visualization of hearing. PMID- 24772765 TI - Low gradient severe aortic stenosis with normal ejection fraction. PMID- 24772766 TI - Wilson's disease unmasked by antitubercular therapy induced liver injury. PMID- 24772767 TI - [On the 90th anniversary of Nikolai Alekseevich Lopatkin]. PMID- 24772768 TI - [Potential biochemical factors for the development of urolithiasis in patients with spinal cord injuries]. AB - A comparative analysis of biochemical parameters of blood serum and daily urine in patients with urolithiasis developed after spinal cord injury (study group--35 patients) and patients without development of the disease (comparison group--20 patients) was performed. It was found that patients after spinal cord injury have developed productive azotemia, which led to the disruption of renal excretory function (accumulation of urea and creatinine in blood, and lowering their clearance). Against this background, there is violation of excretion of uric acid, magnesium, decreased sensitivity of the renal tubules to aldosterone (in patients with nephrolithiasis K/Na ratio in urine was lower). As a result, patients have decreased reabsorption of sodium and water retention, increased urine osmolality; against the background of electrolyte imbalance in urine, this leads to the formation of stones. In patients with spinal cord injuries, main trigger mechanism of formation of urinary stones was excessive posttraumatic azotemia. The high concentration of the products of protein-nitrogen catabolism in the serum of patients in the acute and early periods of spinal cord injury may be unfavorable criterion determining the significant risk of developing of kidney stones. PMID- 24772769 TI - [Impact of plasmapheresis on intraorgan blood flow of the transplanted kidney in the early postoperative period]. AB - Kidney transplant is inevitably subjected to ischemic and reperfusion injury. In many cases, this is due to a violation of intraorgan hemodynamics. Severity of such damage can be reduced using different methods of extracorporeal hemocorrection. The aim of the study was to examine the intraorgan blood flow of kidney transplant and assess the impact of plasmapheresis on its primary function in the early postoperative period. Plasmapheresis with replacement from 1,25 to 3,5 liters of plasma was applied in 40 recipients of the Group 1; in 40 recipients of Group 2 plasmapheresis was not performed. High resistance index (Ri > 0,9) at low flow velocities in the interlobular arteries at the first day after surgery is an informative criterion for the diagnosis of acute tubular necrosis and indicates the inadequate blood supply of kidney. Plasmapheresis has promoted the normalization of renal hemodynamics. Immediate graft function in patients of Group 1 was observed in 36 patients, whereas only in 19 patients of Group 2. In the Group 1, there were no patients with primary non-functioning graft, while there were three such patients in Group 2. Thus, plasmapheresis in the early postoperative period, no later than 3-5 h after reperfusion of the graft, has a positive effect on the functional status of the transplanted kidney. PMID- 24772770 TI - [Urination disorders. Do we know all about them?]. AB - The article presents the results of the pilot questionnaire survey of doctors of various specialties, living in some cities in the Southern Federal District, in the diagnosis and treatment of various urination disorders. The survey involved 101 urologists, 33 obstetricians, 37 internists, 35 surgeons, 9 neurologists and 1 infectiologist. Inadequate training of doctors of various specialties regarding the diagnosis and treatment of various disorders of urination of inflammatory and non-inflammatory nature should be noted. Misunderstanding of differential diagnosis of various forms of urinary incontinence and tactics of management of each of them come under notice. Most urologists (95.46%), obstetricians (92.3%), physicians (100%), neurologists (66.6%), and surgeons (88.58%) did not have a thorough knowledge about the symptoms of overactive bladder (OB). Only 63.37 % of the entire group of respondents, and 81% of urologists using conservative therapies, has prescribed M-anticholinergics for the treatment of OB. In the treatment of urgent forms of urinary incontinence, only 64.5% of urologists use M anticholinergics. Excessive use of M-anticholinergics for the treatment of stress urinary incontinence still persists--38% of urologists. alpha-blockers are the main group of drugs (96.6%) used in medical treatment of LUTS in benign prostatic hyperplasia. However, there is reduced (14.8%) understanding of the need to designate combination therapy with M-cholinergic antagonists when indicated. The issues of therapy of patients with lower urinary tract infections, namely the choice of antibiotics without considering antibiotic sensitivity and antibiotic resistance and knowledge of Russian and national guidelines and recommendations of the European Association of Urology are of particular concern. Curiously enough, there is underestimation of this issue by urologists (23%) compared to obstetricians (45%) and physicians (40.7%). These findings can determine the need for education programs for professionals in different areas of medicine, because patients with urination disorders occur in practice of doctors of various related specialties. PMID- 24772771 TI - [Positional changes of the magistral blood flow of the left kidney in men with varicocele and infertility]. AB - This paper proves the correlation between characteristics of blood flow rate in the renal veins and resistance indices of the renal arteries. As a result of polypositional assessment of venous blood flow, it was found that the violations of magistral venous blood flow in the left kidney can affect the formation and progression of varicocele, and the severity of disorders of spermatogenesis. The necessity of assessment of testicular veins and the pressure in left renal vein not only in clin- and orthostasis or Valsalva maneuver, but in the six static positions is discussed; this can allow to register the violations of magistral renal blood flow at the early stages important for fertility disorders, improve the efficiency of diagnosis and treatment of patients with varicocele. PMID- 24772772 TI - [Perineal saturation biopsy of the prostate]. AB - The effectiveness of perineal biopsy for the detection of prostate cancer (PC) using an array for brachytherapy/cryotherapy was evaluated. It is shown that perineal saturation biopsy provides high detection rate of prostate cancer in patients with suspected cancer after negative transrectal biopsies, does not increase the detection of clinically insignificant cancer and incidence of complications, but requires a lot of time and cost. PMID- 24772773 TI - [Three-year results of the treatment of localized prostate cancer using high intensity focused ultrasound]. AB - The study was aimed to the assessment of the effectiveness of treatment for prostate cancer using high-intensity focused ultrasound on the basis of clinical, radiation, laboratory data, and results of morphometric and immunohistochemical study of postoperative prostate biopsies. 112 sessions of HIFU-ablation of the prostate in 112 patients with localized prostate cancer were performed. Average number of impulses of action--634 +/- 176, the average volume of tissue exposed- 34.6 +/- 15.2 cm3 per 1 session. The operative time ranged from 90 to 165 min (mean 125 min). The postoperative hospital stay ranged from 7 to 14 days (average 10 +/- 0.8 days). Intraoperative complications during HIFU-ablation were not observed. The average level of prostate-specific antigen 1,5 months after surgery was 0.7 (0.12-3.67) ng/ml. Minimum level of prostate-specific antigen was reached 20 +/- 2 weeks after treatment, and the average level was 0.26 +/- 0.01 ng/ml. 6 months after, prostate volume decreased by an average of 49%; 10-12 months after intervention, prostate volume was 6.5 +/- 2.2 cm3. Morphological analysis after treatment included studies with standard and immunohistochemical staining using the following antibodies: PCNA, Bcl2, AMACR, E-cadherin, ANDR. Recurrence-free course was observed in 96 (85.8%) patients. Recurrences were detected in 16 (14.2%) patients, with biochemical progression in 11 (9.82%) patients. Local recurrence (morphologically confirmed) was diagnosed in 5 (4.46%) patients. PMID- 24772774 TI - [Scanning electron microscopy of resected ureters in children with ureterohydronephrosis]. AB - Using scanning electron microscopy, various portions of the ureter in reflux and obstructive ureterohydronephrosis in children were evaluated. In the first case, architectonics of the distal portions is preserved, while in the second case connective tissue is proliferated. Differences in the structure of proximal and distal portions in both forms of ureterohydronephrosis consist in inflammatory changes and violation of the integrity of the epithelial lining, edema and infiltration of the underlying layers, especially the inner muscle layer of the distal portion. The wall of the ureter in proximal part is much thinner, especially the muscular and mucous layers. PMID- 24772775 TI - [Lower urinary tract symptoms in men]. AB - Lower urinary tract symptoms (LUTS) are frequently encountered in clinical practice, especially in older men. The main focus in the primary treatment of men with complaints of violation of urination should be paid to assessing their severity on the basis of IPSS questionnaire. It is important to identify the predominant symptoms that determine treatment. In the absence of absolute indications for surgical treatment of clinical forms of benign prostatic hyperplasia (BPH), the drug treatment should be used. In cases of the prevalence of obstructive LUTS, first-line treatment is the use of alpha-adrenoblockers. In case of progression of BPH (prostate volume > or = 40 cm3, PSA > 1,5 ng/ml), it is useful to combine the alpha-adrenoblockers with 5alpha-reductase inhibitors. Combined medication in the form of alpha-adrenoblockers and M- cholinergic antagonists is justified in irritative LUTS in men with BPH. PMID- 24772776 TI - [Topical issues of antibiotic therapy of prostatitis]. AB - The first part of the review presents the results of the most interesting and major studies on the problem of the treatment of bacterial prostatitis and published after 2010. The second part represents the key provisions of current clinical recommendations of European Association of Urology on the antibacterial treatment of prostatitis, published in 2011 and based on studies up to 2010 inclusive. PMID- 24772777 TI - [The use of vitaprost in the treatment of patients with prostate diseases]. AB - Inflammatory diseases of the prostate are common among men. These diseases are frequently characterized by long-term course and relapses. Prostatitis-associated symptoms significantly reduce the quality of life of patients. Due to the lack of generally accepted criteria for the diagnosis of prostatitis, the frequency of inflammatory diseases of the prostate is difficult to establish. Inflammatory diseases of the prostate should be differentiated from chronic pelvic pain syndrome. The mainstay of treatment of infectious and inflammatory processes in the prostate are antibacterial drugs (generations III and IV fluoroquinolones). The recommended course of treatment includes 4-6 weeks. Prostate peptides from bovine (cytomedines) have proven efficacy in the treatment of patients with prostatitis; cytomedines influence the differentiation and proliferation of prostate cells, have anti-inflammatory and immunomodulatory properties. In clinical trials, high efficiency of cytomedines in prostatitis and prostate adenoma, as well as long-term remission of the diseases is demonstrated. PMID- 24772778 TI - [An 18-year follow-up of a patient with four asynchronous malignant tumors of the urogenital system]. PMID- 24772779 TI - [Comparative characteristics of the results of current surgical treatments in patients with prostate adenoma]. PMID- 24772780 TI - [Laparoscopic pyeloplasty]. PMID- 24772781 TI - [Effect of Chlamydia trachomatis lipopolysaccharides on sperm apoptosis and development of male infertility]. PMID- 24772782 TI - [Modern hypotheses of development of bladder cancer]. PMID- 24772783 TI - [Neonatal sepsis]. AB - Many newborns are exposed to diagnostic or treatment procedures due to a suspicion of sepsis. Since non-specific signs of neonatal sepsis can quickly proceed to a life-threatening condition, it is essential to have a low threshold to diagnostic procedures and to provide antimicrobial therapy while waiting for the test results. After sepsis has been ruled out, antimicrobial therapy should be discontinued without delay. Good clinical practice includes avoiding unnecessarily broad-spectrum antibiotics. The future challenge is to develop a sensitive and specific marker for early detection of the disease and for avoiding unnecessary antibiotics, hospital care days and mother-infant separation. PMID- 24772784 TI - [Food additives and healthiness]. AB - Additives are used for improving food structure or preventing its spoilage, for example. Many substances used as additives are also naturally present in food. The safety of additives is evaluated according to commonly agreed principles. If high concentrations of an additive cause adverse health effects for humans, a limit of acceptable daily intake (ADI) is set for it. An additive is a risk only when ADI is exceeded. The healthiness of food is measured on the basis of nutrient density and scientifically proven effects. PMID- 24772785 TI - [Removal of osteosynthesis material in children and young people]. AB - Metallic osteosynthesis materials, i.e. implants used in the treatment of fractures and correction of bone position in children have traditionally been subsequently removed in a further operation. The necessity for the removal of orthopedic implants left completely under the skin is arguable and research-based evidence is scarce. Treatment practices vary. We present our literature- and experience-based recommendation on the removal of implants or leaving them in position. The removal of an implant should, however, always be decided on an individual basis. PMID- 24772786 TI - [Pepmhigus of the mucous membrane of the mouth]. AB - Pemphigus is a rare autoimmune disease of the skin and mucous membranes. It is characterized by autoantibodies directed against the desmosomal adhesion proteins of epithelial cells (desmoglein type I and III) resulting in acantholysis of the epithelium. Painful blisters or erosions are typical clinical findings. Pemphigus is a severe disease that may be fatal. Early diagnosis of pemphigus is important in order to be able to start the treatment as soon as possible and to halt the progression of the disease and avoid serious secondary infections. PMID- 24772787 TI - [Diagnostics of non-small cell lung carcinoma]. AB - ALK inhibitor therapy is individual cancer treatment, in which the targeted drug therapy is directed to a patient group that is likely to benefit from the therapy. The detection in the tumor of ALK gene (anaplastic lymphoma kinase) rearrangement is a prerequisite for the ALK inhibitor therapy for non-small cell lung carcinoma. The ALK assay should be performed for non-squamous cellular non small cell lung carcinomas, especially adenocarcinomas. It is not recommended to be based on the patients' clinical features. The immunohistochemical method is well suited for screening of ALK positivity. The present recommendation is to ascertain the ALK gene rearrangement from immunopositive specimens by using the FISH procedure. PMID- 24772788 TI - [Esophageal varices and dyspnea. A clinicopathological conference report]. AB - A young man who had moved from India to Finland was extensively examined for abdominal complaints. The findings included large esophageal varices, open portal vein and enlarged lymph nodes. The large spleen was excised. The diagnosis did not become clear from laboratory investigations. After ten years the patient was repeatedly examined to reveal the cause of esophageal varices and abdominal complaints. Autoimmune pancreatitis and cholangitis were suspected after 23 years from the initial symptoms. In the end, the most plausible explanation for the patient's mixed disease was tuberculosis. Sarcoidosis was another disease that came into question. PMID- 24772789 TI - [Adult acute lymphoblastic leukemia - 20-year treatment results at TYKS]. AB - Approximately 30 cases of adult acute lymphoblastic leukemia (ALL) emerge in Finland yearly. In literature 35 to 40% of those under the age of 60 are reported to recover from their illness. Of the 67 adult ALL patients treated at the Turku University Hospital from 1990 to 2010, 96% achieved remission. The five-year survival rate was 53%. After remission, an allogeneic stem cell transplant was performed for 22 patients (37%), with 38 patients (63%) continuing on cytotoxic drugs. There was no difference in survival between modes of treatment or risk groups. PMID- 24772790 TI - [Antenatal and postnatal growth and 5-year cognitive outcome in very preterm infants]. PMID- 24772791 TI - [Update on Current Care Guideline: epilepsies (adult]. AB - First epileptic seizure is an indication for an urgent referral to a neurology care unit. Diagnosis of epilepsy is based on medical history and clinical examination, supplemented with MRI, EEG and laboratory tests. Exact diagnosis of the epilepsy type and etiology are the basis of the treatment. Patient education improves outcomes. The goal is complete long-term seizure control without significant adverse effects. Antiepileptic medication is usually initiated after the second epileptic seizure. If the patient does not respond to two appropriate drug schedules, patient should be evaluated for surgical treatment options. PMID- 24772792 TI - "It's time for the NMC to put its house in order". PMID- 24772793 TI - NMC criticised for "wrong decisions". PMID- 24772794 TI - "Can you explain the friends and family test results to patients?". PMID- 24772795 TI - "Engaged, empowered staff are the key to better patient care". PMID- 24772796 TI - Assessing and managing primary hypertension. AB - Hypertension is a major risk factor for coronary heart disease, stroke and heart failure. This article discusses treatments for primary hypertension, including lifestyle interventions and drug therapy, and blood pressure measurement. PMID- 24772797 TI - Rabies: risk, prognosis and prevention. AB - While the UK was declared free from rabies over 100 years ago, the disease remains a significant cause of death in many other countries around the world. It is hoped that eradication programmes in affected countries will succeed in the long term but, until then, prompt and thorough treatment can prevent people who have potentially been in contact with the rabies virus from developing this infection. This article provides a review of the disease and its prevention. PMID- 24772798 TI - Advising pregnant women on miminising travel risks. AB - Pregnant women may face additional risks when travelling overseas, which must be considered with assessment and travel health advice before they decide to travel. A careful risk assessment should be completed to identify the key risks and strategies for staying safe while travelling. PMID- 24772799 TI - A new college focusing on contemporary health issues. PMID- 24772801 TI - 60 seconds with Caroline Knott. PMID- 24772800 TI - Treatment for early-onset neonatal sepsis. AB - Up to one in 10 neonates are investigated and treated for neonatal sepsis, although most are later found to be uninfected. This review discusses identifying and treating this emergency condition and how implementing NICE guidance could reduce treatment time in well babies and saveonatal sepsis resources without compromising care. PMID- 24772802 TI - From patient to princess. PMID- 24772803 TI - How to get people dancing to your tune. PMID- 24772804 TI - [100 years of Dermatology in French-speaking Switzerland]. PMID- 24772805 TI - [Comorbidities in psoriasic arthritis]. AB - Psoriatic arthritis occurs almost exclusively together with psoriasis of the skin. It seems useful therefore for the practitioner to consider the two of them as manifestations of one "psoriatic disease". This pragmatic approach is more contemporary, particularly since it is increasingly clear that the "psoriatic disease" goes beyond damage to the skin and joints. The most important "comorbidities" associated with psoriatic disease are presented here; especially the cardiovascular diseases as well as their risk factors, namely smoking, obesity, and the metabolic syndrome. Moreover, infections, osteoporosis and neoplasia are to be considered. PMID- 24772806 TI - [Cutaneous B-cell lymphoma]. AB - Primary cutaneous B-cell lymphomas (PCBCL) present as skin lesions without evidence of extracutaneous involvement at diagnosis. This article summarizes clinical and histopathological features of the three main types of PCBCL: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma and primary cutaneous diffuse large B-cell lymphoma, leg type. It will discuss initial staging procedures, necessary to differentiate PCBCL from systemic lymphoma with secondary skin involvement. Finally, we will review the main treatments, local therapy (radiotherapy, surgical excision) for indolent PCBCL and multiagent chemotherapy for primary cutaneous diffuse large B-cell lymphoma, leg type. PMID- 24772807 TI - [Case report: unusual clinical presentation of a follicular lymphoma]. AB - Follicular lymphoma is an indolent B-cell lymphoma. Fluctuant asymptomatic lymphadenopathies are their usual clinical manifestation. B-cell neoplasms can sometimes involve the skin. In this case, it is important to distinguish a systemic B-cell lymphoma with secondary skin involvement from primary cutaneous lymphoma. Immunohistochemical stainings and staging usually allow to make the difference. Here we report the first case of a systemic follicular lymphoma with secondary cutaneous involvement presented with papular lesions on the face mimicking a rosacea. PMID- 24772808 TI - [Dermatophytes transmitted by pets and cattle]. AB - Most inflammatory skin and hair dermatophytoses are caused by one of four zoophilic dermatophyte species: Microsporum canis (from cats and dogs), Trichophyton verrucosum (from cattle), Arthroderma benhamiae (from Guinea-pigs) and Arthrodermna vanbreuseghemii (generally from cats and dogs). In cases of highly inflammatory tinea corporis, tinea faciae and tinea capitis in humans, it is important to identify with certainty the precise etiologic agent and to examine pets as the possible source of infection. The recurrence of infections or new infections can be prevented by adequately treating incriminated domestic animals and their environments. Cooperation between the medical and veterinary professions is required in this situation. PMID- 24772809 TI - [New light on skin photodynamic therapy]. AB - Photodynamic therapy (PDT) relies on the cellular toxicity of an exogenous porphyrin that is activated by light rays. Its specificity depends on its cellular uptake, which is typically high in cells with a high metabolism, such as cancer cells and several microbial pathogens. Both the diffusion of the substrate and the penetration of the light in the tissue limit its efficiency to the first few millimeters of the skin. This explains why this technique is used for the treatment of superficial skin cancers (actinic keratosis and basal cell carcinomas), but also for selected skin inflammatory diseases (psoriasis) or infections (leishmaniosis). However, at the bedside, the limitations of PDT are rather the complexity and the pain associated with the treatment. Herein, we present the new developments, in particular concerning the new light sources, which make PDT a better option for our patients. PMID- 24772810 TI - [Laser treatments in pediatric dermatology]. AB - Lasers in pediatric dermatology were developed as a result of the treatment of port-wine stains. Infantile hemangiomas may benefit, in some cases, from laser treatment as well as venous and lymphatic malformations. For certain pigmented lesions, as well as some hamartomas, laser treatments are a credible alternative to surgical resection. Bum scars are improved by lasers which stimulate collagen remodeling. Furthermore, hair removal of congenital and acquired hypertrichosis can relieve psychosocial discomfort and improve quality of life. The management of pain and fear of children undergoing laser treatment, using either topical or general anesthesia, remains of central importance. PMID- 24772811 TI - [Osteoporotic fractures: not only in females]. PMID- 24772812 TI - [Cannabis must not be considered as a mild drug]. PMID- 24772813 TI - [What medals and patriotic speeches don't tell- crisis in soldiers back home]. PMID- 24772814 TI - [100 years later, what to know about Maillard reaction and French fries toxicity?]. PMID- 24772815 TI - ["Golden Holocaust", then safety matches' time came]. PMID- 24772816 TI - [Medical confidentiality in prison and disintermediation]. PMID- 24772817 TI - Anti-inflammatory activity of selected plants from Saudi Arabia. AB - Thirteen selected Saudi Arabian plants, belonging to seven different families, were tested for possible anti-inflammatory activity using the carrageenin-induced paw edema model in rats. The methanolic extracts of Vernonia schimperi, Trichodesma trichodesmoides var. tomentosum, and Anabasis articulata exhibited the highest anti-inflammatory activity. The active extracts were further subjected to fractionation with chloroform, ethyl acetate, and n-butanol and tested together with their mother liquor for their anti-inflammatory activity in the same rat model. The most potent fractions were the n-butanol fractions of Anabasis articulata and Vernonia shimperi and the aqueous mother liquor of Trichodesma trichodesmoides. Nevertheless, the three potent methanolic extracts showed higher anti-inflammatory activities than their individual fractions. The antioxidant properties were assessed by their in vitro 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging activities. It was concluded that the anti inflammatory activity is dependent, at least in part, on the reduction of prostaglandin (PGE2) and tumour necrosis factor-alpha (TNF-alpha) levels and cyclooxygenase-2 (COX-2) activity. PMID- 24772818 TI - Propolis from northern California and Oregon: chemical composition, botanical origin, and content of allergens. AB - Propolis is a beehive product that bees manufacture by mixing their own wax with vegetable resins collected from different species of trees and bushes. The chemical composition of propolis is very variable because it depends on the flora locally available, and specimens from different geographical and climatic areas display unique properties. In this paper, the results of the chemical characterization of some propolis specimens collected in northern California and in Oregon are presented. Their chemical compositions show that all specimens contain resins from poplars of the Tacamahaca section (balsam poplars)- characteristic of the western part of the North American continent. Nevertheless, some of the specimens are of mixed origin because they also contain resins from poplars of the Aigeiros section (cottonwoods)--also present in this part of the world. Propolis causes allergies in sensitive human individuals, which are due to the presence of certain esters. The contents of known propolis allergenic esters- phenylethyl caffeate, 1,1-dimethylallyl caffeate, benzyl cinnamate, and benzyl salicylate--have been investigated in these specimens and found to depend on the botanical origin. PMID- 24772819 TI - Synthesis and pharmacological evaluation of novel unsubstituted indole anthraquinone carboxamide derivatives as potent antihyperlipidemic agents. AB - Five novel derivatives of N-(9,10-dihydro-9,10-dioxoanthracenyl)-1H-indole-2 carboxamide were synthesized and their lipid-lowering effects studied in hyperlipidemic rats. Fusion of the anthraquinone derivatives at high temperature with 5-indole-2-carbonyl chloride, followed by recrystallization from chloroform/methanol gave the desired compounds in excellent yields. Compounds 1 to 5 at a non-toxic dose (1 ml of 57 microM solutions) and bezafibrate as positive control were administered to rats that were hyperlipidemic due to treatment with Triton WR-1339. A decrease in the plasma levels of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) and an increase in the plasma level of high-density lipoprotein-cholesterol (HDL-C) were observed with compounds 1, 3, 4, and 5. Compounds 1, 4, and 5 significantly reduced total cholesterol (TC) levels as well. These compounds may provide agents for targeting dyslipidemia and cardiovascular disease. PMID- 24772820 TI - Anthraquinones from Vismia mexicana. AB - Vismia mexicana (Clusiaceae) is a small tropical tree found from Mexico to Honduras. The CH2Cl2/MeOH extract from the leaves has been reported to have inhibitory properties against reverse transcriptase of human immunodeficiency virus type 1 (HIV-1 RT). In order to characterize some of its chemical constituents, the EtOAc-soluble fraction of this extract was subjected to column chromatography. A new natural product was isolated and designated vismiaquinone D [1-hydroxy-6-methoxy-7,8-(3',3'-dimethyl-pyrano) anthraquinone]. In addition, vismiaquinone was obtained. The structures of vismiaquinone and vismiaquinone D were determined by 1H and 13C NMR spectroscopy, unambiguous assignments were achieved with DEPT, HSQC, and HMBC experiments, and corroborated by X-ray diffraction studies. The isolated anthraquinones were tested against HIV-1 RT. However, none showed relevant activity, suggesting that other compounds in this extract may be responsible for its HIV-1 RT inhibitory properties. PMID- 24772821 TI - Vascular and antioxidant effects of an aqueous Mentha cordifolia extract in experimental N(G)-nitro-L-arginine methyl ester-induced hypertension. AB - The effect of an aqueous Mentha cordifolia (MC) extract on the haemodynamic status, vascular remodeling, function, and oxidative status in NG-nitro-L arginine methyl ester (L-NAME)-induced hypertension was investigated. Male Sprague-Dawley rats were given L-NAME [50 mg/(kg body weight (BW) d)] in their drinking water for 5 weeks and were treated by intragastric administration with the MC extract [200 mg/(kgBWd)] for 2 consecutive weeks. Quercetin [25 mg/(kg BW d)] was used as a positive control. The effects of the MC extract on the haemodynamic status, thoracic aortic wall thickness, and oxidative stress markers were determined, and the vasorelaxant activity of the MC extract was tested in isolated mesenteric vascular beds in rats. Significant increases in the mean arterial pressure (MAP), heart rate (HR), hind limb vascular resistance (HVR), wall thickness, and cross-sectional area of the thoracic aorta, as well as oxidative stress markers were found in the L-NAME-treated group compared to the control (P < 0.05). MAP, HVR, wall thickness, cross-sectional area of the thoracic aorta, plasma malondialdehyde (MDA), and vascular superoxide anion production were significantly reduced in L-NAME hypersensitive rats treated with the MC extract or quercetin. Furthermore, the MC extract induced vasorelaxation in the pre-constricted mesenteric vascular bed with intact and denuded endothelium of normotensive and hypertensive rats. Our results suggest that the MC extract exhibits an antihypertensive effect via its antioxidant capacity, vasodilator property, and reduced vascular remodeling. PMID- 24772822 TI - Bioguided identification of antifungal and antiproliferative compounds from the Brazilian orchid Miltonia flavescens Lindl. AB - The Orchidaceae family is appreciated worldwide for the beauty of its flowers, and hundreds of species of this family occur in Brazil. Yet little is known about the potential of orchids for therapeutic application. We have investigated bioactive compounds produced by the South Brazilian orchid Miltonia flavescens Lindl. Bioguided studies with the fungus Cladosporium herbarum allowed the identification of hydrocinnamic acid as the active antifungal compound. In addition, the chloroform fraction exhibited an interesting activity against human cancer cells, and 5,7-dihydroxy-6,4'-dimethoxyflavone isolated from this fraction was found to be active against seven human cancer cell lines, including NCI/ADR RES ovary sarcoma, with an IC50 value of 2.6 microg/mL. This is the first report on the cytostatic activity of this flavone against human ovary sarcoma. PMID- 24772823 TI - Interspecific competition between Microcystis aeruginosa and Anabaena flos-aquae from Taihu Lake, China. AB - Microcystis and Anabaena are the main cyanobacteria that cause cyanobacterial blooms in Taihu Lake, China. The mechanism of population competition between M. aeruginosa and A. flos-aquae was studied by co-cultivation in the laboratory. The growth of M. aeruginosa was inhibited, while the growth of A. flos-aquae was promoted. The degree of inhibition or promotion was related to the ratio of the initial cell densities. Both cell-free filtrates of A. flos-aquae and co-culture inhibited M. aeruginosa growth, while both cell-free filtrates of M. aeruginosa and co-culture promoted A. flos-aquae growth. Analysis of the cell-free filtrate by gas chromatography-mass spectrometry indicated that M. aeruginosa and A. flos aquae may secrete some extracellular allelochemicals that inhibit (promote) the growth of M. aeruginosa (A. flos-aquae) in co-culture. These compounds included sulfur compounds, naphthalene derivatives, cedrene derivatives, quinones, phenol derivatives, diphenyl derivatives, anthracene derivatives, and phthalate esters. This study can help to understand the characteristics of M. aeruginosa and A. flos-aquae and to provide new concepts for the control of cyanobacterial blooms in Taihu Lake. PMID- 24772824 TI - Influence of culture conditions on the biotransformation of (+)-limonene by Aspergillus niger. AB - The influence of the cultivation system and of the culture medium on the biotransformation of (+)-limonene by a strain of Aspergillus niger was investigated. Biooxidation products were obtained in all conditions tested. Using a laboratory bioreactor, six terpenes were identified in every medium, predominantly terpineols and carveols, whereas terpinen-4-ol and perillyl alcohol were the only terpenes found when flasks were used for culture. Perillyl alcohol and carveols predominated when the medium was tryptic soy broth (TSB), whereas the formation of terpineols was clearly favoured in malt broth (MB). Thus, there was a marked influence of the culture conditions on the results of the biotransformation. Changes in the conditions led to variations both in the type and relative amount of products obtained. PMID- 24772825 TI - Low-dose radiation suppresses Pokemon expression under hypoxic conditions. AB - Our previous data demonstrated that CoCl2-induced hypoxia controls endoplasmic reticulum (ER) stress-associated and other intracellular factors. One of them, the transcription factor Pokemon, was differentially regulated by low-dose radiation (LDR). There are limited data regarding how this transcription factor is involved in expression of the unfolded protein response (UPR) under hypoxic conditions. The purpose of this study was to obtain clues on how Pokemon is involved in the UPR. Pokemon was selected as a differentially expressed gene under hypoxic conditions; however, its regulation was clearly repressed by LDR. It was also demonstrated that both expression of ER chaperones and ER stress sensors were affected by hypoxic conditions, and the same results were obtained when cells in which Pokemon was up- or down-regulated were used. The current state of UPR and LDR research associated with the Pokemon pathway offers an important opportunity to understand the oncogenesis, senescence, and differentiation of cells, as well as to facilitate introduction of new therapeutic radiopharmaceuticals. PMID- 24772826 TI - Polyamines in cell walls of chlorococcalean microalgae. AB - Biotechnology of microalgae represents a very attractive alternative as a source of energy and substances of high value when compared with plant cultivation. Cell walls of green microalgae have an extraordinary chemical and mechanical resistance and may impede some steps in the biotechnological/industrial exploitation of algae. The aim of the present contribution was to check the presence of polyamines in the cell walls of chlorococcalean green microalgae. Polyamines are nitrogenous compounds synthesized normally in cells and may affect the properties of the cell wall. Our work included strains either forming or not forming the polymer algaenan, allowing us to conclude that algaenan is not a prerequisite for the presence of polyamines in the cell walls. Polyamines were detected in isolated cell walls of Scenedesmus obliquus, Chlorella fusca, Chlorella saccharophila, and Chlorella vulgaris. Their concentration in isolated cell walls ranged between 0.4 and 8.4 nmol/mg dry weight. PMID- 24772827 TI - Identification of an endoplasmic reticulum membrane protein interacting with DNA polymerase beta by a yeast two-hybrid screen. AB - Base excision repair (BER) is a key pathway for maintaining genomic stability. A key enzyme in the BER pathway is DNA polymerase beta (polbeta). It has been shown that more than 11% of breast, bladder, esophageal, colon, and gastric cancer samples studied so far exhibit polbeta mutation. A truncated form of polbeta, polbetadelta (exon 11 deletion), identified in a colon tumour sample, exhibited dominant negative activity. Using this polbetadelta as bait, we screened a HeLa cDNA library for any interacting protein(s) in the yeast two-hybrid (Y2H) system. Polbetadelta was cloned into a pGBKT7 vector (pGBKT7-polbetadelta). pGBKT7 polbetadelta was transformed into the yeast strain AH109. Then the cDNA library was co-transformed into AH109/pGBKT7-polbetadelta and screened by the selection procedure. The yeast-purified plasmids were transformed into Escherichia coli. Plasmid DNA was isolated from the colonies, purified, digested with Sma I and Sal I, and the fragments were sequenced. Four positive clones were obtained. Out of these, three proteins were already known to interact with polbeta (XRCC1, MGC5306, and AP endonuclease 1). The only member previously not known to interact with polbeta was phosphatidylinositol glycosylase type S (PIGS). PIGS is a 64-kDa membrane protein, encoded in chromosome 17. The PIGS protein interacts also with wild-type polbeta which was confirmed by co-immunoprecipitation and Western blot analysis. The role of the newly identified protein in the dominant negative function of the variant form of polbeta remains to be seen. PMID- 24772828 TI - Prospective chest pain evaluation in the emergency department with use of high sensitivity C-reactive protein (PROCEED-CRP study). AB - We evaluated the clinical value of a single measurement of high-sensitivity C reactive protein (hs- CRP) in patients presenting to the emergency department with chest pain. We screened 408 consecutive patients of whom 292 comprised the final cohort for this study. Hs-CRP measured in the emergency department (ED) in patients presenting with chest pain and admitted for evaluation of acute myocardial infarction was neither sensitive nor specific in predicting acute myocardial infarction, myocardial ischemia on SPECT imaging, need for coronary revascularization, or cardiovascular or all-cause rehospitalization at 30 days. In addition, use of a specific CRP cut off >1 was not associated with an increase in all-cause rehospitalization at 30 days. PMID- 24772829 TI - Respiratory failure due to lung involvement with adult T-cell leukemia/lymphoma: case report and review of literature. AB - Acute adult T-cellleukemia/lymphoma (ATLL) is a hematologic malignancy that usually entails a poor prognosis; median survival is only six months. Significant immunosuppression is commonly seen in these patients. Lung involvement in ATLL is usually documented either radiographically or as an autopsy finding. Few proven cases of ante mortem extensive lung infiltration have been described in the scientific literature. We present a fatal case of acute respiratory failure as a result of histologically proven lung infiltration by malignant lymphocytes in a patientwith acuteATLL. Although the most common cause of death i n patients with ATLL is respiratory failure in the setting of an infectious process, it should be kept in mind that patients with ATLL with acute respiratory failure may have malignant lung infiltration as a potential cause. PMID- 24772830 TI - The perfect storm: hemophagocytic lymphohistiocytosis complicating disseminated yersiniosis. AB - Hemophagocytic lymphohistio-cytosis (HLH) is a rare but serious medical condition with variable clinical outcome. HLH presents real diagnostic and therapeutic challenges to the treating physician despite the major advances in molecular laboratory testing and the immune-chemotherapeutic interventions. Here we present a unique case ofHLH in the setting of hemoglobin H disease provoked by disseminated Yersinia enterocolitica infection. The hemoglobinopathy led to an iron overload state, which provided an optimal milieu for the siderophilic bacterium, Y. enterocolitica, to disseminate. This over whelming infection triggered an uncontrolled and dysregulated inflammatory cytokine cascade with resulting clinical sequelae. The patient was treated conservatively without immunosuppressive therapy and recovered quickly. The long-term outcome of such cases needs further definition. PMID- 24772831 TI - Large pleural effusions causing cardiac tamponade: a case report and review of the literature. AB - Hemodynamically significant cardiac tamponade physiology is an uncommon complication of a large pleural effusion. Previous reports have shown that this physiology can be reversed with thoracentesis. We describe a case of a 69-year old man with multiple cardiac risk factors presenting with decompensated congestive heart failure and unstable angina. A coronary stent was placed in the left anterior descending artery. Two days postprocedure, he became unresponsive and hemodynamically unstable. A chest x-ray (CXR) revealed bilateral large-sized pleural effusions with transthoracic echocardiography demonstrating a small pericardial effusion, large right pleural effusion, and evidence of cardiac tamponade. A right thoracentesis was performed, draining almost 1,000ml of fluid and resulting in a rapid improvement of his hemodynamic profile. PMID- 24772832 TI - Trends in sacral colpopexy for the management of apical prolapse. AB - OBJECTIVE: To evaluate trends in surgical approach for sacral colpopexy since the advent of robotic technology for gynecologic procedures. STUDY DESIGN: Women who underwent surgery for uterovaginal prolapse, cystocele, and/orvaginalvault prolapse were included in this study. The number of patients undergoing a vaginal approach for prolapse was compared to the number of patients receiving sacral colpopexy. Descriptive statistics comprised means and standard deviations, while categorical data were reported as frequencies. Inferential statistics comprised Student's t-test for assessing two-group differences between means ofcontinuous, normally distributed data and chi-squared tests for comparisons of equality of distribution between categorical variables. RESULTS: Patients undergoing sacral colpopexy were younger than their vaginal surgery counterparts (P< 0.001). When stage ofprolapsewas dichotomized, among those with stage 1-2 prolapse, a greater percentage of patients received colpopexy in favor of vaginal surgery in 2010 than in 2007 (P=0.001). CONCLUSION: There is an increasing trend towards robotic assisted sacralcolpopexyforthe management of apical prolapse. PMID- 24772833 TI - Surgical management of rhinophyma: a case report and review of literature. AB - As surgeons, we are often faced with treating many dermatologic and facial lesions. We present a case ofrhinophyma as well as review the medical and surgical management of such a condition. PMID- 24772834 TI - Isolated brain metastasis in cholangiocarcinoma: a case report and review of literature. AB - Cholangiocarcinoma is a rare malignancyinvolvingthe epithelium of the intrahepatic and extrahepatic bile ducts associated with high mortality usually from systemic recurrence. Isolated brain metastases occur rarely in this malignancy. We found three previous reports on this subject in our review of literature which had a varied presentation. We present the case report of a patient presenting with an isolated brain metastases and we present a review of the literature concerning this diagnosis. PMID- 24772835 TI - Cardiac tamponade complicating purulent pericarditis due to community acquired methicilin resistant Staphylococcus aureus (CA-MRSA). AB - Community acquired methicillin resistant Staphylococcus aureus(CA-MRSA) is a global pathogen capable of causing life-threatening infections with increasing prevalence since the 1990s. Purulentpericarditis, characterized by accumulation of purulent fluid in the pericardial space was historically a disease of the pediatric and early adult population, but through the years the median age of diagnosis has increased from 21 to 49. Mortality rates are as high as 40% even in the treated population. We report a case of purulent pericarditis due to CA-MRSA that was complicated by cardiac tamponade. Early diagnosis and intervention proved to be life-saving. A brief review of the literature and current management options are discussed. PMID- 24772837 TI - Transforming patient to partner: the e-patient movement is a call to action. PMID- 24772836 TI - Prostate biopsy volume predicts final tumor volume. AB - AIM: To assess the ability of prostate biopsy volume to effectively predict actual tumor volume, and whether increasing the number of prostate biopsy cores improves the ability to forecast actual tumor volume. METHODS: 765 patients who underwent robotic radical prostatectomy (2009-2010) were identified. Of these, 663 had complete demographics, biopsy, and final pathology data available. The number ofbiopsy samples, biopsy tumor volume, and actual tumor volume were calculated from pathology reports. RESULTS: Data from 663 radical prostatectomy specimens indicated a positive linearrelationship between biopsy tumor volume and actual tumor volume (R=0.524, P< 0.0001). The number ofbiopsy samples collected (i.e., < or =6, 7-8, 9-10, 11-12, 13-14, or > or =15) did not affect the ability of biopsy tumor volume to predict final tumor volume. CONCLUSIONS: The routine collection of biopsy tumor volume may prove useful in predicting actual tumor volume and the construction of more effective preoperative nomograms. PMID- 24772838 TI - The president's page. 1964. PMID- 24772839 TI - The blueprints of life's architecture. PMID- 24772840 TI - C for Connecticut. PMID- 24772841 TI - A slight twist. PMID- 24772842 TI - [The Ryazan University School of Gastroenterology]. PMID- 24772843 TI - [Transplantation of mesenchymal bone marrow stromal cells as new opportunity to overcome ineffectiveness of primary anti-cytokine therapy in Crohn's disease]. AB - Clinical observations and studies have shown that among 34 patients with Crohn's disease (CD) under infliximab (INFX) therapy in 8.8% cases was observed the loss of response to anticytokine therapy (so-called primary ineffectiveness of anti cytokine therapy (ACT)). The increasing of INFX dosage up to 10 mg/kg of body weight failed to achieve clinical and endoscopic remission. It should be noted that, despite the long anticytokine therapy in these patients the antibodies to INFX were not observed and INFX concentration in blood serum practically was not determined. In CD patients with primary ineffectiveness of anti-cytokine therapy (ACT) was detected clinical deterioration of CD: increase of WR Best Index (CDAI), appearance of pain, fever, increase of stool frequency with blood and mucus, improving performance of acute phase of inflammation. Transplantation of mesenchymal bone marrow stromal cells (MSC) enhanced the level of INFX in the serum and overcoming the primary ineffectiveness of anti-cytokine therapy (ACT) and increase in sensitivity to Infliximab. PMID- 24772844 TI - [Disturbances in motor function of the digestive system in celiac disease]. PMID- 24772845 TI - [Comparative analysis of quality of life and psychological features of patients with ulcerative colitis and Crohn's disease]. PMID- 24772846 TI - [Experimental investigation of efficacy and safety of different methods of endoscopic hemostasis]. AB - Treatment of ulcerative gastroduodenal bleedings remains one of the most pressing problems in urgent surgery. Available methods of endoscopic hemostasis are not fully eligible to safety requirements, effectiveness and reliability. In this connection persist high levels of general and postoperative mortality in our country and around the world. The aim of this study is to identify the advantages and disadvantages of endoscopic radiofrequency effects in comparison with standard techniques of hemostasis, used in the treatment of ulcer bleeding in the world practice. PMID- 24772847 TI - [Proteolysis in digestive system regulation]. AB - Signal enzymes with direct and indirect hormone releasing action are formed by means of proteolysis from exogenic and endogenic proteins. The proteolysis is the basis of hormone processing. The limited proteolysis forms hormones from pro hormones, ligand proteolysis excludes or reduces their stimulated or inhibited effects. The existence of polipotent proteinaso-activated receptors with regulative and modulated role in norm and pathology was proved. PMID- 24772848 TI - [Osteochondrosis painful form of the thoracic spine as a disease masking chronic cholecystitis exacerbations]. PMID- 24772849 TI - [Report about symposium "Colon diverticular disease", held on the 25th of October, 2013 at the State Research Center of Coloproctology Department of Healthcare, City of Moscow]. PMID- 24772850 TI - [Materials of the outbound plenary session of Gastroenterological Scientific Society of Russia, "Prevention of digestive diseases and interdisciplinary gastroenterology"]. PMID- 24772851 TI - [Hepatobiliary lesions in Crohn's disease and conservative methods of treatment]. PMID- 24772852 TI - [Comparative evaluation of various methods of conservative therapy of early stage of cholelithiasis]. AB - THE AIM OF INVESTIGATION: To explore the possibilities of use of conservative therapy in the early stage of cholelithiasis. MATERIALS AND METHODS: In the treatment of patients with early stage of gallstone disease in 103 patients was used mineral water Uvinskaya, in 96--Ursosan and in 118--Ursosan combined with mineral water Uvinskaya. RESULTS: The comparative evaluation of different variants of therapy showed that combined use of Ursosan and mineral water Uvinsky was the most effective to eliminate the clinical symptoms of the disease and reduce the lithogenic properties of bile. PMID- 24772853 TI - [Gaseous disorders and their role in the development of hepatopulmonary syndrome in liver cirrhosis associated with COPD]. AB - OBJECTIVE: To evaluate the indicators of arterial blood gasometry and levels of nitric oxide (NO) in exhaled breath of patients with liver cirrhosis (LC) in combination with COPD, and determine frequency of occurrence of hepatopulmonary syndrome (HPS). The comparison group consisted of 20 patients with COPD, control 15 volunteers. Gas measurement was estimated by ABL 725 radiometer (Denmark). MATERIAL AND METHODS: We examined 57 patients with liver cirrhosis. The patients were divided into 2 groups: 1st--Patients with liver cirrhosis (n = 48), 2nd group--the CPU and COPD (n = 9). Comparison group consisted of 20 patients with COPD, control - 15 volunteers. The gasometry was evaluated by ABL 725 radiometer (Denmark). NO levels in exhaled air was estimated using the NIOX MINO (Sweden). Contrast electrocardiography was performed on ATL HDI 5000 (Bothell, WA, USA). RESULTS: We found that the PaO2 was lower in the 2nd group compared with the control and with the 1st group (81.4 +/- 5.2; 95.5 +/- 5.3 and 94.5 +/- 5.1 mm Hg; p < 0.05), but the lowest PaO2 was in the group with COPD (68.4 mm Hg). AaDO2 was higher in the group with COPD (37.7 mm Hg). In the 2nd group this indicator was higher as compared with the control and with the 1st group (26.8 +/- 5.4; 8.2 +/- 4.5 and 14.9 +/- 5.2 mm Hg; p < 0.05). A strong negative correlation in the 1st and the 2nd groups between AaDO2 and PaO2 (r = -0.67 and r = -0.93; p < 0.05) was obtained. Content of NO in exhaled air was higher in the 1st and 2nd groups compared with control (18.7 +/- 4.1; 18,9 +/- 4.5 and 11.0 +/- 3.3 ppb; p < 0.05). Intrapulmonary shunts were detected in 3 patients in the 1st and 2nd groups. CONCLUSION: The relationship between measures of blood gas composition showed the leading role of hypoxemia in increasing the risk of formation of HPS in the LC, especially when combined with COPD. PMID- 24772854 TI - [Ways to improve efficiency of patient clinical examinations during early stage of cholelithiasis]. AB - PURPOSE: The aim of the work was to improve the organization and conduct of clinical examination of patients with gallstone disease (GSD). MATERIALS AND METHODS: An integrated study of 396 patients with different pathologies of the hepatobiliary system and the medical check-up for three years for 101 patients. RESULTS: Built logistic model to predict the likelihood of developing gallstone disease and developed a predictive scoring table it possible to distinguish patients at risk of developing gall stones. The result of follow-up of the proposed method was prevented economic losses due to the lack of need for a cholecystectomy, which is made up of one patient 6766.22 rubles., The entire group of 1,004,966.63 rubles. CONCLUSION: Obtained to diagnose cholelithiasis at an early stage dokamennoy. Developed a screening questionnaire, predictive scoring table, the scheme of follow-up also improves clinical examination of patients with cholelithiasis dokamennoy stage. PMID- 24772855 TI - [Serum interleukin-18 level in precancerous conditions and gastric cancer]. AB - The purpose of the study--to determine the serum concentration and the pathogenetic significance of changes of interleukin-18 in patients with chronic atrophic gastritis, peptic ulcer disease and gastric cancer. MATERIAL AND METHODS.:A comprehensive survey of 192 patients with diseases gastroduodenal zone. Diagnostic emphasis was placed on ELISA method as defined in the serum of IL-18, --1beta, interferon-gamma, kantsernogo antigen 19-9, vascular endothelial growth factor, total antibodies to CagA Helicobacter pylori. RESULTS: We examined patients revealed an increase in the concentration of interleukin-18, which correlated with tumor stage, the level of vascular endothelial growth factor, total antibodies to CagA Helicobacter pylori. CONCLUSION: The data obtained allow to recommend the use of interleukin-18 in serum for diagnostic of atrophic gastritis, peptic ulcer diseases and gastric cancer. PMID- 24772856 TI - [Protein-energy malnutrition in patients with connective tissue dysplasia]. AB - In the conditions of the specialized Center of a dysplasia of a connecting tissue the assessment of an protein--energy malnutrition at 121 patients with signs of a dysplasia of a connecting tissue is carried out. High frequency of an oligotrophy at patients with a dysplasia of a connecting tissue is registered. The I degree of a gipotorofiya is taped at 26.21% of the patients, II degree--at 18.44%, the III degree--at 3.88% of patients. PMID- 24772857 TI - [Individualization of antiviral treatment of chronic hepatitis]. PMID- 24772858 TI - [Calprotectin concentration in stool samples as a determinant of the activity degree of inflammatory process in inflammatory bowel diseases]. AB - At IBD in the exacerbation phase was detected the increase of fecal calprotectin (FC) level in 98% of patients. With increasing of clinical disease activity in patients with UC as well as CD was marked a significantly increased content of calprotectin in stool samples, which was accompanied by increase of indicators of inflammation acute phase: rising RRF, leukocytosis, an increase of frequency of stool with blood and mucus, fever and abdominal pain. In the phase of exacerbation the increase in concentration of CRP depends on the degree of inflammatory activity, rather than on lesion localization. The highest concentration of CRP was revealed at a high degree of IBD activity with stool frequency up to 8-10 times/day with impurity of blood and abdominal pain. At moderate activity of IBD, it is less expressed diarrhea (stool frequency 2-3 times a day), without blood, detected lower lever of PCF concentration--from 250 to 380 ug/g. A study of calprotectin concentrations in stool samples is considered to be reliable and sensitive method for evaluation of inflammatory activity in patients with inflammatory bowel disease. PMID- 24772859 TI - [Abdominal hemodynamic syndrome in patients with connective tissue dysplasia]. AB - Implications of an protein-energy malnutrition are diagnosed for patients with a dysplasia of a connecting tissue more often than in population (in 69.9% of cases). One of mechanisms is depression of a volume abdominal blood flow against the structural changes of vascular system associated with a dysplasia of a connecting tissue. PMID- 24772860 TI - [Serological tests of functional activity of the digestive system (gastrin, pepsinogen-I, trypsin), general IgE and serum cortisol levels in children with hepatitis A and B]. AB - The mild form of hepatitis A and B with children is attended by a functional activity of pancreatic gland (tripsin), mucous coats of stomach and duodenum (gastrin) which permits to consider them as a factor of the risk of digestive organs combined pathology starting with the disease acuity. Differences in gastrin levels with children depending on hepatitis etiology were specified. Highest levels of gastrin were observed with persons suffering from hepatitis B. PMID- 24772861 TI - [The role of clinical recommendations (protocols), medical assistance and health care standards to ensure the quality of care for patients with gastrointestinal diseases]. AB - The purpose of this article is studying of a role of clinical recommendations (protocols), orders of rendering medical care and standards of medical care in ensuring quality of medical care to patients with gastroenterology diseases. During work on article the existing normative legal acts regulating use of clinical recommendations (protocols), orders of rendering medical care and standards of medical care were studied. Contents of clinical recommendations (protocols), orders of rendering medical care and standards of medical care are analysed by the patients with gastroenterology diseases. Possibilities of clinical recommendations (protocols), orders of rendering medical care and standards of medical care are defined when ensuring quality of medical care to patients with gastroenterology diseases. PMID- 24772862 TI - [Nervous regulation of the esophagus motor activity]. PMID- 24772863 TI - [Endoscopic therapy of chronic pancreatitis]. AB - In article the main indications and conditions for the most successful endoscopic treatment of patients with chronic pancreatitis, especially in the presence of the burdened anamnesis, based on data of the world literature and own experience are formulated. PMID- 24772864 TI - [Colonoscopy in the diagosis and treatment of the colon polypoid formations]. AB - AIM OF THE STUDY: the estimation of endoscopic methods efficacy in diagnostics and treatment of colon polypoid neoplasm. The study was carried out in versatile city hospital. METHODS AND MATERIALS: 5811 colonoscopies (CS) were executed in endoscopic department of versatile city hospital Nr. 2, Krasnodar during the period of 01.01.2011 -01.01.2012 years. There were 332 endoscopic loop polypectomies, and 12 endoscopic mucosal resections among 5811 CS. RESULTS: The choice of endoscopic extraction method depended on neoplasm microscopic type and its histological structure according to pre-operated histological investigation. In the most cases the neoplasm Ip and Is types were extracted by loop polypectomy. In cases of III grade or more dysplasia in the neoplasm Ip and Is types had revealed the endoscopic mucosal resection was performed. The neoplasm IIa and IIb were extracted by the endoscopic mucosal resection. The presence of IIc component was assessed as a bad prognostic feature and only the dilatated loop biopsy was carried out. During the endoscopic extraction of 32 villous tumors of the colon (size of 17 ones was more than 3.0 cm, and 3 ones was more 5.0 cm) 2 complications occurred and an urgent surgery was carried out in 1 case. The following periods of endoscopic control were determined according to extracted polypoid neoplasm histological data: 1, 3, 6 and 12 months. The relapse absence was assessed not only visually, but by biopsy from colon mucosal scars. CONCLUSION: patients with the colon polypoid neoplasm need the dynamic clinic endoscopic supervision because of increased risk of oncotransformation. PMID- 24772865 TI - [Influence of pancreatic segment graft autotransplantation on its exocrine function]. AB - In experiments on dogs the exocrine secretion of pancreatic segment graft after its autotransplantation and of pancreatic stamps after proximal resection of the pancreas was investigated. More significant impairment of the exocrine secretion of the pancreas was revealed in animals after pancreatic graft autotransplantation in comparison with animals after the proximal resection of the pancreas. Maintenance of the adaptation of pancreatic exocrine secretion to the nutritional composition of the intestinal contents and "generalized inhibition" of pancreatic exocrine secretion caused by duodenal trypsin infusion was revealed in all groups. PMID- 24772866 TI - [Peptidergic and serotoninergic regulation of the pancreas]. AB - The paper contain the literature and own experimental data on peptid/serotoninergic regulation of pancreatic activity. Peptid- and serotoninergic mechanisms of regulation of pancreas activity are described. The experimental data on serotonin influence on pancreatic duct motility under pancreatitis are given. PMID- 24772867 TI - [Non-invasive techniques in diagnosis of steatosis and fibrosis in nonalcoholic fatty liver disease]. AB - Diagnosis and treatment of nonalcoholic fatty liver disease (NAFLD) is one of the most actual problems of modern hepatology. Ultrasound elastometry is alternative method to determine the density of the liver tissue. The efficiency of the method was confirmed by a large amount of data in patients with viral hepatitis. However, the diagnostic value of elastometry was not studied enough in patients with NAFLD. THE AIM OF THE RESEARCH: to study the possibility of non-invasive diagnostic methods of examination in a complex assessment of the liver in patients with NAFLD. MATERIALS AND METHODS: We studied 24 patients with signs of NAFLD and a long persistent elevation of liver enzymes. All patients underwent a needle biopsy of the liver. We conducted a comparative analysis of the results of the morphological study of the liver tissue with ultrasound elastometry, computed tomography of the liver, biochemical blood tests. RESULTS AND DISCUSSION: Among biochemical liver enzymes ALT was a marker of NAFLD which characterized the transformation of steatosis to steatohepatitis. The combined ALT and GGT increase reflected the high activity of inflammation in the liver tissue. Elastometry results were comparable to the histological features in all liver fibrosis stages, but the maximum diagnostic accuracy was observed at the late stages. The area under the ROC-curves showed the highest precision in the F2-F3 stages, the lowest value - in the F1 stage. Imprecision of the method in the early stages of fibrosis may be due to the hepatic steatosis in NAFLD and high biochemical activity with cholestasis signs. Patients with early-stage liver fibrosis diagnosed with elastometry need additional examination using other methods of noninvasive diagnostic tools. PMID- 24772868 TI - [Criteria of diagnostics of pancreatitis at children's age according to ultrasound research]. AB - In the article new criteria of diagnostics of chronic and reactive pancreatitis due to sonography data are described. Among symptoms of reactive pancreatitis are as follows: presence of pancreatic edema, appearance of hyper echogenic lineal admixtures (visualization of connective tissues jumpers). Among criteria of reactive pancreatitis due to ultrasonography belong all as follows: local (59.7%) or diffuse hyper echogenic (18.8%) parenchyma comparatively to parenchyma of parotic gland, as well as small dots or triangle-like formations - marker of fibrosis. At the same time among signs of long-lasting pancreatitis these symptoms are also characteristic areas of hypoechogenic parenchyma which mimic areas of hyperechogenic structure of pancreas (44.0% of incidences). Widening of pancreatic duct like prominent symptom of chronic pancreatitis they noticed in 1/3 cases of reactive pancreatitis together with local edema of pancreas. PMID- 24772869 TI - [Functional diseases of the digestive organs in patients with the connective tissue dysplasia]. AB - Research objective was studying of features of functional diseases of digestive organs at patients with a dysplasia of a connecting tissue. In the conditions of the specialized Center of a dysplasia of a connecting tissue the assessment of a functional condition of digestive organs at 121 patients with signs of a dysplasia of a connecting tissue is carried out. High frequency of functional disorders of digestive organs at patients with a dysplasia of a connecting tissue (74-75%) is registered. Overlapping of syndromes of functional diseases (functional dyspepsia and syndrome of the angry intestine) it is registered at 73 +/- 3.9% of patients with DST, in group of comparison - at 9 +/- 2.3% (p &It; 0.001). Syndromes demonstrated against a wide range of changes of the digestive organs associated with a dysplasia of a connecting tissue. Existence of a dysplasia of a connecting tissue defines variety and features of a course of functional diseases of digestive organs, development of a syndrome of a maldigestiya and advance of an protein-energy malnutrition at this category of patients. PMID- 24772870 TI - [Level of adalimumab and its antibody titers define the effectiveness of the biological (anticytokine) therapy in Crohn's disease]. AB - Formation of immune antibodies to adalimumab (ADM) in patients with Crohn's disease currently has high clinical value, as antibodies (AT) influence on bioavailability, pharmacokinetic, pharmacodynamic indicators, that eventually affects expression of clinical response to treatment. The results of this study indicate that after treatment with adalimumab in 12-14 weeks in any case there was not an increase of antibodies to adalimumab. Synchronous study of concentration of adalimumab (ADA) and antibodies to ADA in serum to determine the effectiveness of anti-cytokine therapy with adalimumab in Crohn's disease. PMID- 24772871 TI - [Protein-energy malnutrition in clinical practice]. AB - The analysis of the reasons and mechanisms of development of an protein-energy malnutrition, communication of fetal pathology and development of an protein energy malnutrition at mature age is submitted. Systemic character of a syndrome is marked out. Importance of a problem of an protein-energy malnutrition at patients with a dysplasia of a connecting tissue is bound to high prevalence of a syndrome at this pathology. PMID- 24772872 TI - [X-ray diagnostic of partial intestinal obstruction in small intestine diseases: a glance on the problem of radiologist-gastroenterologist]. AB - The article is devoted to special features of X-ray examining of patients suffering from acute abdomen pain and X-ray paradigma of some intestine diseases as a cause of partial bowel obstruction. Own clinical data are presented. Long term experience of our X-ray department is summarized. The possibilities of X-ray examining of abdomen with and without contrast in patients with partial bowel obstruction are described. PMID- 24772873 TI - [Application of direct electric current and intravenous ozone therapy in the complex treatment of destructive forms of acute pancreatitis in experiment]. AB - The results of experimental study which have carried out on 40 outbread dogs were analyzed in this thesis. Modeling of destructive pancreatitis in animals has been achieved via canalicular-hypertensive model by S.A. Shalimov. 4 series of experimental study were made to achieve the targeted goal. The first series 10 dogs without treatment, the second series 10 dogs in which conventional conservative therapy was used for the treatment of acute experimental destructive pancreatitis in animals, the third series 10 dogs that underwent intravenous ozone therapy in the complex together with medication therapy, the forth series the effectiveness of combined administration of intravenous ozone therapy and small doses of direct current in 10 dogs was evaluated. Combined administration of small doses of DC and intravenous ozone therapy in the complex treatment of destructive pancreatitis shows antiphlogistic action, favors accelerated rejection of necrotic tissue, remits inflammatory process as well as encourages regeneration process in pancreas whereby allows to decrease the mortality in experimental animals from 60% to 20%. PMID- 24772874 TI - [Adenomyomatosis of the gall bladder in rabbits]. AB - Possibility of the adenomiomatosis development of the gallbladder in rabbits of different age is studied. Adenomiomatosis appeared in one of 10 animals of older age animal group. The role of serotonin in the development of adenomiomatosis is discussed. PMID- 24772875 TI - [Tertiary syphilis of the pancreas and liver in 82-year-old patient: case study]. AB - It has been described a clinical case of late diagnosis of syphilis of the pancreas and liver of elderly patients. Two years before that it was wrongly diagnosed with cancer of the pancreas with liver metastases, and the patient was operated on with the imposition of cholecystostomy. It was conducted appropriate therapy and reconstructive surgery after verification of the diagnosis of syphilis of the pancreas and liver. PMID- 24772876 TI - [Concurrent development of non-Hodgkin lymphoma and hepatocellular carcinoma in patient with chronic hepatitis C]. PMID- 24772877 TI - [Diagnostic methods of liver fibrosis]. PMID- 24772878 TI - [Founders of domestic military medicine (to the 260 anniversary since the birth of E.T. Belopol'skii and to the 205 anniversary of introduction of the course of military medicine at the Moscow university)]. PMID- 24772879 TI - [The 45th meeting of the European Pancreatic Club, 2013]. PMID- 24772880 TI - Preface. Leading in health care organizations: improving safety, satisfaction and financial performance. PMID- 24772881 TI - A review on leadership of head nurses and patient safety and quality of care. AB - PURPOSE: The purpose of the study was to explore in literature what different leadership styles and behaviors of head nurses have a positive influence on the outcomes of patient safety or quality of care. DESIGN/METHODOLOGY/APPROACH: We reviewed the literature from January 2000 until September 2011. We searched Pubmed, Embase, Cinahl, Psychlit, and Econlit. FINDINGS: We found 10 studies addressing the relationship between head nurse leadership and safety and quality. A wide array of styles and practices were associated with different patient outcomes. Transformational leadership was the most used concept in the studies. A trend can be observed over these studies suggesting that a trustful relationship between the head nurse and subordinates is an important driving force for the achievement of positive patient outcomes. Furthermore, the effects of these trustful relationships seem to be amplified by supporting mechanisms, often objective conditions like clinical pathways and, especially, staffing level. VALUE/ORIGINALITY: This study offers an up-to-date review of the limited number of studies on the relationship between nurse leadership and patient outcomes. Although mostly transformational leadership was found to be responsible for positive associations with outcomes, also contingent reward had positive influence on outcomes. We formulated some comments on the predominance of the transformational leadership concept and suggested the application of complexity theory and political leadership for the current context of care. We formulated some implications for practice and further research, mainly the need for more systematic empirical and cross cultural studies and the urgent need for the development of a validated set of nurse-sensitive patient outcome indicators. PMID- 24772882 TI - "What you see depends on where you stand" exploring the relationship between leadership behavior and job type in health care. AB - PURPOSE: This chapter seeks to increase our understanding of health care employees' perceptions of effective and ineffective leadership behavior within their organization. DESIGN/METHODOLOGY/APPROACH: Interviews were conducted with 59 employees working in a diversity of positions within the case study hospital. Interviewees were asked to cite behaviors of both an effective and an ineffective leader in their organization. They were also asked to clarify whether their example described the behavior of a formal or informal leader. Grounded theory data analysis techniques were used and findings were interpreting using existing leadership behavior theories. FINDINGS: (1) There was a consistent link between effective leadership and relationally oriented behaviors. (2) Employees identified both formal and informal leadership within their hospital. (3) There were both similarities and differences with respect to the types of behaviors attributed to informal versus formal leaders. (4) Informants cited a number of leadership behaviors not yet accounted for in the leadership behavior literature (e.g., 'hands on', 'professional', 'knows organization'). (5) Ineffective leadership behavior is not simply the opposite of effective leadership. RESEARCH IMPLICATIONS: Findings support the following ideas: (1) there may be a relationship between the type of job held by employees in health care organizations and their perceptions of leader behavior, and (2) leadership behavior theories are not yet comprehensive enough to account for the varieties of leadership behavior in a health care organization. This study is limited by the fact that it focused on only those leadership theories that considered leader behavior. PRACTICAL IMPLICATIONS: There are two practical implications for health care organizations. (1) leaders should recognize that the type of behavior an employee prefers from a leader may vary by follower job group (e.g., nurses may prefer relational behavior more than managerial staff do), and (2) organizations could improve leader development programs and evaluation tools by identifying ineffective leadership behaviors that they want to see reduced within their workplace. SOCIAL IMPLICATIONS: Health care organizations could use these findings to identify informal leaders in their organization and invest in training and development for them in hopes that these individuals will have positive direct or indirect impacts on patient, staff, and organizational outcomes through their informal leadership role. VALUE/ORIGINALITY: This study contributes to research and practice on leadership behavior in health care organizations by explicitly considering effective and ineffective leader behavior preferences across multiple job types in a health care organization. Such a study has not previously been done despite the multi-professional nature of health care organizations. PMID- 24772883 TI - The role of leadership in eliminating health care-associated infections: a qualitative study of eight hospitals. AB - PURPOSE: Despite hospitals' efforts to reduce health care-associated infections (HAIs), success rates vary. We studied how leadership practices might impact these efforts. DESIGN/METHODOLOGY/APPROACH: We conducted eight case studies at hospitals pursuing central line-associated blood stream infection (CLABSI) prevention initiatives. At each hospital, we interviewed senior leaders, clinical leaders, and line clinicians (n = 194) using a semistructured interview protocol. All interviews were transcribed and iteratively analyzed. FINDINGS: We found that the presence of local clinical champions was perceived across organizations and interviewees as a key factor contributing to HAI-prevention efforts, with champions playing important roles as coordinators, cheerleaders, and advocates for the initiatives. Top-level support was also critical, with elements such as visibility, commitment, and clear expectations valued across interviewees. VALUE/ORGINALITY: Results suggest that leadership plays an important role in the successful implementation of HAI-prevention interventions. Improving our understanding of nonclinical differences across health systems may contribute to efforts to eliminate HAIs. PMID- 24772884 TI - Walk the talk: leaders' enacted priority of safety, incident reporting, and error management. AB - PURPOSE: The main goal of the current research was to investigate whether and how leaders in health care organizations can stimulate incident reporting and error management by "walking the safety talk" (enacted priority of safety). DESIGN/METHODOLOGY/APPROACH: Open interviews (N = 26) and a cross-sectional questionnaire (N = 183) were conducted at the Rotterdam Eye Hospital (REH) in The Netherlands. FINDINGS: As hypothesized, leaders' enacted priority of safety was positively related to incident reporting and error management, and the relation between leaders' enacted priority of safety and error management was mediated by incident reporting. The interviews yielded rich data on (near) incidents, the leaders' role in (non)reporting, and error management, grounding quantitative findings in concrete case descriptions. RESEARCH IMPLICATIONS: We support previous theorizing by providing empirical evidence showing that (1) enacted priority of safety has a stronger relationship with incident reporting than espoused priority of safety and (2) the previously implied positive link between incident reporting and error management indeed exists. Moreover, our findings extend our understanding of behavioral integrity for safety and the mechanisms through which it operates in medical settings. PRACTICAL IMPLICATIONS: Our findings indicate that for the promotion of incident reporting and error management, active reinforcement of priority of safety by leaders is crucial. VALUE/ORIGINALITY: Social sciences researchers, health care researchers and health care practitioners can utilize the findings of the current paper in order to help leaders create health care systems characterized by higher incident reporting and more constructive error handling. PMID- 24772885 TI - Exploring interpersonal behavior and team sensemaking during health information technology implementation. AB - PURPOSE: We examine how interpersonal behavior and social interaction influence team sensemaking and subsequent team actions during a hospital-based health information technology (HIT) implementation project. DESIGN/METHODOLOGY/APPROACH: Over the course of 18 months, we directly observed the interpersonal interactions of HIT implementation teams using a sensemaking lens. FINDINGS: We identified three voice-promoting strategies enacted by team leaders that fostered team member voice and sensemaking; communicating a vision; connecting goals to team member values; and seeking team member input. However, infrequent leader expressions of anger quickly undermined team sensemaking, halting dialog essential to problem solving. By seeking team member opinions, team leaders overcame the negative effects of anger. PRACTICAL IMPLICATIONS: Leaders must enact voice-promoting behaviors and use them throughout a team's engagement. Further, training teams in how to use conflict to achieve greater innovation may improve sensemaking essential to project risk mitigation. SOCIAL IMPLICATIONS: Health care work processes are complex; teams involved in implementing improvements must be prepared to deal with conflicting, contentious issues, which will arise during change. Therefore, team conflict training may be essential to sustaining sensemaking. RESEARCH IMPLICATIONS: Future research should seek to identify team interactions that foster sensemaking, especially when topics are difficult or unwelcome, then determine the association between staff sensemaking and the impact on HIT implementation outcomes. VALUE/ORIGINALITY: We are among the first to focus on project teams tasked with HIT implementation. This research extends our understanding of how leaders' behaviors might facilitate or impeded speaking up among project teams in health care settings. PMID- 24772886 TI - Exploring the relationship between nursing home financial performance and management entrepreneurial attributes. AB - PURPOSE: This paper explores the relationship between entrepreneurial orientation (EO) (i.e., their innovativeness, proactiveness and risk-taking) and financial performance in nursing homes. We hypothesize that nursing homes that are more proactive will report better short-term financial performance, while when firms with higher propensities for innovativeness and risk-taking will experience poorer financial performance in the short period due to the high costs associated with the initial adoption of innovation and with pursuing high-risks ventures. DESIGN/METHODOLOGY/APPROACH: In 2004, a survey was developed and mailed to a population of 670 nursing homes in the state of Florida who were listed in the Florida Nursing Home Guide of the Agency for Health Care Administration. The final sample for this study included 104 respondents. The data from these surveys were merged with additional variables gathered from the 2004 Online Survey Certification and Reporting (OSCAR) system and the 2004/2005 Medicare Cost Reports (MCR). EO was operationalized using a nine-item scale adapted from Covin and Slevin (1989), and financial performance was assessed using total profit margin. FINDINGS: The overall findings suggest partial support for the hypotheses. Support was found for the negative relationship between innovativeness and short-term financial performance, but only partial support was found for the relationship between performance and risk-taking. Our results demonstrated that the various aspects of entrepreneurial behaviors have a differential effect on firm performance. PRACTICAL IMPLICATIONS: From a managerial perspective, nursing home administrators may continue to seek ways to be entrepreneurial while understanding that some activities may only lead to short-term profitability. These findings should not dissuade administrators from innovative behaviors. They do suggest, however, that innovative administrators should prepare for some initial decrease in profitability following new service implementation. SOCIAL IMPLICATIONS: Findings suggest that to varying degrees, nursing home administrators may view themselves as being entrepreneurial despite the intense pressures from governments, poor public perceptions, decreasing reimbursement, more impaired residents, and increasing competition from substitute providers. Further administrators may need to manage the expectations of key stakeholders when they undertake innovative programs that will support social outcomes but which may not enhance short term financial performance. VALUE/ORIGINALITY: This paper demonstrates the complex relationship between entrepreneurial activities and firm performance in nursing homes and has implications for the broader health care setting. PMID- 24772887 TI - Leading toward value: the role of strategic human resource management in health system adaptability. AB - PURPOSE: Personnel costs typically account for 60% or more of total operating expenses in health systems, and as such become a necessary focus in most if not all substantive health reform adaptations. This study sought to assess whether strategic alignment of the human resource (HR) and learning functions was associated with greater adaptive capacity in U.S. health systems. DESIGN/METHODOLOGY/APPROACH: Data were gathered using a survey that was distributed electronically to chief human resource officers from two U.S.-based associations. The survey included questions about organizational structure, strategic human resource management, strategic learning, and organizational response to health reform. FINDINGS: Significant correlations were found between strategic alignment of HR and HR's involvement in responses related to cost control (r = 0.46, p < 0.01); quality improvement (r = 0.45, p < 0.01), and patient access (r = 0.39, p < 0.01). However, no significant relationships were found between strategic alignment of organizational learning and HR involvement with these responses. VALUE/ORIGINALITY: Results suggest that HR structure may affect an organization's capacity for adaptive response. Top-management teams in health systems should consider positioning HR as part of the core leadership team, with a reporting relationship that allows HR to maximally participate in formulating and implementing organizational adaptation. PMID- 24772888 TI - Safety leadership: extending workplace safety climate best practices across health care workforces. AB - PURPOSE: Hospitals within the United States consistently have injury rates that are over twice the national employee injury rate. Hospital safety studies typically investigate care providers rather than support service employees. Compounding the lack of evidence for this understudied population is the scant evidence that is available to examine the relationship of support service employees'perceptions of safety and work-related injuries. To examine this phenomenon, the purpose of this study was to investigate support service employees' perceptions of safety leadership and social support as well as the relationship of safety perception to levels of reported injuries. DESIGN/METHODOLOGY/APPROACH: A nonexperimental survey was conducted with the data collected from hospital support service employees (n = 1,272) and examined. (1) relationships between safety leadership (supervisor and organization) and individual and unit safety perceptions; (2) the moderating effect of social support (supervisor and coworker) on individual and unit safety perceptions; and (3) the relationship of safety perception to reported injury rates. The survey items in this study were based on the items from the AHRQ Patient Safety Culture Survey and the U.S. National Health Care Surveys. FINDINGS: Safety leadership (supervisor and organization) was found to be positively related to individual safety perceptions and unit safety grade as was supervisor and coworker support. Coworker support was found to positively moderate the following relationships: supervisor safety leadership and safety perceptions, supervisor safety leadership and unit safety grade, and senior management safety leadership and safety perceptions. Positive employee safety perceptions were found to have a significant relationship with lower reported injury rates. VALUE/ORIGINALITY: These findings suggest that safety leadership from supervisors and senior management as well as coworker support has positive implications for support service employees' perceptions of safety, which, in turn, are negatively related to lower odds of reporting injuries. PMID- 24772889 TI - Issues in researching leadership in health care organizations. AB - PURPOSE: We provide a review of the research in this volume and suggest avenues for future research. DESIGN/METHODOLOGY/APPROACH: Review of the research in this volume and unstructured interviews with health care executives. FINDINGS: We identified the three central themes: (1) trust in leadership, (2) leading by example, and (3) multi-level leadership. For each of these themes, we highlight the shared concerns and findings, and provide commentary about the contribution to the literature on leadership. RESEARCH IMPLICATIONS: While relation-oriented leadership is important in health care, there is a danger of too much emphasis on relations in an already caring profession. Moreover, in most health care organizations, leadership is distributed and scholars need to adopt the appropriate methods to investigate these multi-level phenomena. PRACTICAL IMPLICATIONS: In health care organizations, hands-on leadership, through role modeling, may be necessary to promote change. However, practicing what you preach is not as easy as it may seem. VALUE/ORIGINALITY: We provide a framework for understanding current research on leadership in health care organizations. PMID- 24772890 TI - [Rapid detection of novel avian influenza virus subtype H7N9 by multiplex real time RT-PCR]. AB - In order to develop a rapid detection kit for novel avian influenza virus (AIV) subtype H7N9, two sets of specific primers and probes were designed based on the nucleotide sequences of hemagglutinin antigen (HA) and neuraminidase antigen (NA) of novel H7N9 virus (2013) available in GenBank to establish the method of TaqMan probe-based multiplex real-time RT-PCR for rapid detection of AIV subtype H7N9. The primer and probe of HA were for all H7 subtype AIVs, while the primer and probe of NA were only for novel N9 subtype AIVs. The results showed that this method had high sensitivity and specificity. This method was applicable to the testing of positive standard sample with a minimum concentration of 10 copies/microL; it not only distinguished H7 subtype from H1, H3, H5, H6, and H9 subtypes, but also distinguished novel N9 subtype from traditional N9 subtype. A total of 2700 samples from Zhuhai, China were tested by this method, and the results were as expected. For the advantages of sensitivity and specificity, the method holds promise for wide application. PMID- 24772891 TI - [Characterization of BZLF1 gene and its promoter Zp of EBV strains in children with EBV-associated diseases in recent 5 years in Beijing area]. AB - This study aims to investigate the genetic characteristics of BZLF1 gene and its promoter Zp of the epidemic strains in children with primary Epstein-Barr virus (EBV)-associated diseases. Total DNA was extracted from the peripheral blood of 134 children with EBV-associated infectious mononucleosis (EBV-IM) and 32 children with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) who were admitted to Beijing Children's Hospital from 2006 to 2011. The EBNA3C, BZLF1, and Zp genes were amplified by PCR assay. Typing of EBV was performed according to the size of the amplification product of EBNA3C gene; the amplification products of BZLF1 and Zp genes were subjected to direct sequencing, and sequence analysis was performed using BioEdit 7. 0. 9. The results were as follows: (1) EBV-1 was present in 140 samples (97.2%, 140/144) and EBV-II in 4 samples (2.8%, 4/144). (2) Three BZLF1 genotypes and their 12 subtypes (including 6 newly found subtypes) were detected in this study; there were no significant differences in the frequencies of BZLF1-A and BZLF1-B between the children with EBV-IM and EBV-HLH (P = 0.083); BZLF1-A1 was the dominant genotype in children with EBV-associated diseases; t BZLF1-A mostly had three 29-bp repeats in the first intron of BZLF1 gene, and BZLF1-B mostly had 30-bp repeats (P = 0.000), with the number of repeats varying from 1 to 13. (3) Four Zp genotypes were detected in this study, including Zp-P, Zp-V3, Zp-V4, and Zp-V1; there were no significant differences in the frequencies of these Zp genotypes between children with EBV-IM and EBV-HLH (P = 0.272, 0.252, 1.0, and 1.0, respectively). (4) The linkage analysis of BZLF1 gene and its promoter Zp showed that BZLF1-A1 was highly associated with Zp-V3 (P = 0.000), while BZLF1-B4 with Zp-P (P = 0.000); EBV-I + BZLF1 A1 was highly associated with Zp-V3 (P = 0.000), while EBV-I+BZLF1 B4 with Zp-P (P = 0.000). The conclusions are as follows: (1) BZLF1-A1 is the dominant genotype in children with EBV-associated diseases; there are mostly 29 bp repeats in the first intron of BZLF1 gene for BZLF1-A genotype and 30-bp repeats for BZLF1-B genotype. (2) Zp-P and Zp-V3 are dominant Zp genotypes of EBV in children, which shared similar detection rates. (3) BZLF1-A1 is highly associated with Zp-V3, while BZLF1-B4 with Zp-P; EBV-I+BZLF1-A1 is highly associated with Zp-V3, while EBV-I+BZLF1-B4 with Zp-P. PMID- 24772892 TI - [A primary study of evolution of hepatitis B virus based on motif discovery]. AB - Hepatitis B is a serious infectious disease worldwide, and hepatitis B virus (HBV) is the direct cause of this disease. In recent years, as an essential part of its evolutionary process, HBV mutation has been extensively studied domestically and globally. However, the study on the conserved sequences in HBV sequences is still in its infancy. In this study, we applied multiple EM for motif elicitation (MEME) algorithm to discover HBV motif and proposed a new metric, conservative index (CI), to carry out phylogenetic analysis based on HBV sequences. Then, the constructed phylogenetic tree was subjected to reliability assessment. The results demonstrated that the new metric CI combined with the MEME algorithm can effectively help to discover motifs in HBV sequences and construct a phylogenetic tree based on them and to analyze the evolutionary relationship between HBV sequences; in addition, the possible ancestral sequences of samples may be obtained by conservative analysis. The proposed method is valuable for the exploratory study on large HBV sequence data sets. PMID- 24772893 TI - [Analysis of B/C recombinant structure of C gene in a newly found HBV subtype]. AB - Hepatitis B is one of the most serious global threats to human health. Phylogenetic analysis of hepatitis B virus (HBV) can reveal the evolutionary relationship between HBV sequences and thus provide a basis for the prediction and treatment of hepatitis B and other aspects. In this study, we performed sequence analyses on the HBV sequences of five clinical HBV samples and the HBV sequences retrieved from the GenBank, EMBL, and DDBJ to construct a phylogenetic tree and analyze sequence structures. The experimental results revealed that the C gene of one cloned sequence had a recombinant structure of HBV B/ C subtype. Moreover, the phylogenetic results proved the existence of a newly found subtype HBV/B6 in Xishuangbanna of Yunnan Province, China. The experimental conclusion represents certain value for phylogenetic studies of HBV in Yunnan ethnic minority groups. PMID- 24772894 TI - [Epidemiological features and pathogenic characteristics of hand, foot and mouth disease in Gansu Province, China during 2008-2012]. AB - This study aims to analyze the epidemiological features and pathogenic characteristics of hand, foot and mouth disease (HFMD) in Gansu Province, China and to provide a basis for the development of effective prevention and control measures. The descriptive epidemiological analysis was used to analyse the data of HFMD cases in Gansu. The specimens collected from hospitals were subjected to RT-PCR or real-time PCR to detect human enterovirus (HEV) nucleic acid, and HEV strains were isolated using human rhabdomyosarcoma cells and human laryngeal carcinoma cells. The complete VP1-encoding region of several identified enterovirus A71 (EV71) and coxsackievirus A16 (CVA16) was subjected to full length amplification by RT-PCR and then to sequencing and analysis. A total of 52 550 HFMD cases were reported in Gansu from 2008 to 2012, including 205 severe cases and 27 deaths. The incidence rates in the whole province from 2008 to 2012 were 22.42/10(5), 49.29/10(5), 47.20/10(5), 27.27/10(5), and 55.84/10(5), respectively. There were cases in all the 14 cities or prefectures in Gansu, and Lanzhou had the largest number of cases (16 001 cases), accounting for 30.45% of all cases in the province. HFMD cases were mostly reported during May to July, accounting for 51.69% of all cases throughout the year. The male-to-female ratio was 1.69:1. Of all the cases, 87.59% were under the age of five. Of the 5 416 cases for laboratory tests, 3 322 (61.34%) were positive for HEV nucleic acid, including EV71 (46.96%), CVA16 (41.57%), and other HEVs (11.47%). Among the 186 severe cases, 114 (61.29%) were positive for HEV nucleic acid, and 82.46% of the positive cases for EV71. All the 25 dead cases were infected with EV71. A total of 402 strains were isolated from 3 111 specimens collected from hospitals (2 123 throat swab specimens, 705 stool specimens, and 705 herpes specimens), including EV71 (70.15%), CVA16 (27.11), other coxsackievirus A (3.98%), coxsackievirus B (2.49%), echovirus (1.74%), and adenovirus (1.99%). The genotyping of VP1- encoding region showed that all the 194 EV71 strains isolated during 2008-2012 belonged to the C4a evolutionary branch of C4 subtype; among the 45 CVA16 strains, 12 belonged to the Bla evolutionary branch of B1 subtype and 33 to the B1b evolutionary branch, and B1b became the predominant subtype in 2012. In conclusion, in Gansu Province, HFMD occurs mostly in children under the age of five; EV71 and CVA16 are the main pathogens of this disease, and the two are predominant alternately from 2008 to 2012; the severe and dead cases of HFMD are closely related to infection with EV71; the types of pathogens varied across different regions in the same year during 2008-2012. PMID- 24772895 TI - [Serotype distribution of non-polio enterovirus in patients with acute flaccid paralysis during 2011-2012 in Hebei Province, China]. AB - This study aims to investigate the serotype distribution of non-polio enterovirus (NPEV) isolated from patients with acute flaccid paralysis (AFP) during 2011-2012 in Hebei Province, China and to analyze the relationship between these viruses and AFP. NPEV strains were isolated from the stool specimens from AFP cases in Hebei using human rhabdomyosarcoma cells (RD) and the mouse cell line expressing the gene for the human cellular receptor for poliovirus (L20B) according to the WHO requirements. The nucleotide sequence of VP1 region was determined, and the serotypes of NPEV were identified by molecular typing. The results showed that among the 82 strains of NPEV isolated from the AFP cases during 2011-2012, 42 isolates (55.3%) were identified as human enterovirus A (HEV-A), which were classified into 4 serotypes, 34 (44.7%) as human enterovirus B (HEV-B), which were classified into 13 serotypes, 2 as adenovirus, and 4 were untyped; human enteroviruses C and D were not found in these cases. Enterovirus A71 (EV-A71) was the main type of HEV-A, accounting for 85.7% of all HEV-A strains. HEV-A, especially EV-A71, was predominant among the NPEV strains isolated from AFP patients during 2011-2012 in Hebei Province. PMID- 24772896 TI - [Characteristics of complete genome of pandemic A/H1N1/2009 influenza virus isolated in Fujian Province, China]. AB - This study aims to investigate the characteristics of genomic variation of pandemic A/H1N1/2009 influenza virus isolated in Fujian Province, China. Complete genome sequence analysis was performed on 14 strains of pandemic A/H1N1/2009 influenza virus isolated from Fujian during 2009-2012. All virus strains were typical low-pathogenic influenza viruses, with resistance to amantadine and sensitivity to neuraminidase inhibitors. Eight genome fragments of all strains were closely related to those of A/California/07/2009 (H1N1) vaccine strain, with > or = 98.2% homology. Compared with the vaccine strain, the influenza strains from Fujian had relatively large variation, and variation was identified at 11 amino acid sites of the HA gene of A/Fujiangulou/SWL1155/2012 strain, including 4 sites (H138R, L161I, S185T, and S203T) involved inthree antigen determinants (Ca, Sa, and Sb). In conclusion, the influenza vaccine has a satisfactory protective effect on Fujian population, but the influenza strains from Fujian in 2012 has antigenic drift compared with the vaccine strain, more attention should therefore be paid to the surveillance of mutations of pandemic A/H1N1/2009 influenza virus. PMID- 24772897 TI - [Evolutionary analysis of neuraminidase gene of A/H7N9 influenza virus]. AB - In 2013, the World Health Organization reported the first case of human infection with a new influenza A (H7N9) virus in China. This has caused damage and panic within certain areas in China. Therefore, analysis of this virus with bioinformatics technology is very necessary. Neuraminidase (NA) is one of the most important antigens of the influenza virus and an important target for anti flu drugs. In this study, the nucleotide and protein sequences of NA gene of A/H7N9 influenza viruses were retrieved from the NCBI database, and MEGA 5.0 software was employed to construct a phylogenetic tree based on the nucleotide coding sequence; BioEdit software was used to align the nucleotide and protein sequences of NA and calculate the homologies of nucleotides and amino acids and then to analyze the important mutation sites of NA gene. The results demonstrated that the spread of influenza virus H7N9 showed certain geographical and temporal relations. The H7N9 virus isolated from China in 2013 belonged to Euroasiatic serotype, and its NA stalk region hadobvious variation, which may be one of the reasons that this virus infects human. These analyses may be very helpful for understanding the evolutionary relationship and mutation trend of A/H7N9 influenza viruses. PMID- 24772898 TI - [Comparative analysis of variable region of white spot syndrome virus genome in Penaeus vannamei in Guangxi, China]. AB - Comparative analysis of variable region ORF14/15 genes of white spot syndrome virus (WSSV) genome in Guangxi Penaeus vannamei (P. vannamei) could provide useful information for the evaluation of genetic diversity and genetic evolutionary relationship among WSSV isolates from Guangxi, China and other places. Based on geographical and temporal considerations, 40 WSSV-positive P. vannamei samples were collected during the period between May 2010 and July 2013 from Beihai, Qinzhou, and Fangchenggang, which were the main P. vannamei production areas in Guangxi, and the variable region ORF14/15 genes of the WSSV genome from all infected samples were amplified by PCR and then subjected to cloning and sequence analysis. Pairwise and multiple alignment analysis was then conducted to evaluate the degree of genetic divergence between different strains. The variable region ORF14/15 genes from 25 of 40 WSSV positive samples were successfully cloned and sequenced; among the ORF14/15 genes of 25 WSSV-positive strains, 22 was 619 bp in length and 3 was 620 bp. All the 25 Guangxi strains carried a 5949-bp deletion in the ORF14/15 region relative to TH-96-II, which has the longest nucleotide sequence in this region; the deletion of Guangxi strains occurred in the middle region of ORF14/15 gene, with only 190 bp and 429 bp/ 430 bp at 5' and 3' ends, respectively, which were coincident with WSSV-IN-05-I in deletion length and position. Sixteen of 25 Guangxi strains had completely identical nucleotide sequences in the variable re gion, and the homology between other strains also exceeded 97.9%. There were single nucleotide substi tution, deletion, and insertion in the ORF14/15 region of Guangxi strains compared with other strains in GenBank. In the phylogenetic tree based on WSSV variable region ORF14/15, the Guangxi strains were closely related and formed a separate branch with Indian strain IN-05-I, but far from other strains in GenBank. The ORF14/15 gene of WSSV isolates in cultured P. vannamei in Guangxi has a large deletion in the middle of the variable region, and the Guangxi WSSV strains show no significant spatio-temporal differences; the Guangxi strains are closer in genetics to Indian strain IN-05-I than other strains in GenBank. PMID- 24772899 TI - [First isolation of quang binh-like virus from mosquitoes in China]. AB - This study aims to investigate the distribution patterns of mosquito-borne viruses in Menghai County, Xishuangbanna Prefecture, Yunnan Province, China and to provide evidence for the prevention and control of mosquito-borne diseases. Mosquito samples were collected using mosquito lamps. Viruses were isolated from the samples by cell culture, and the isolates were identified by RT-PCR. The genomes of isolates were sequenced for phylogenetic analysis. In July 2012, a total of 1468 mosquitoes were captured in Daluo Town of Menghai County; they were divided into 32 pools, including Culex tritaeniorhynchus (28 pools, 1383 mosquitoes), Culex quinquefasciatus (2 pools, 66 mosquitoes), and Anopheles (2 pools, 19 mosquitoes). Golden hamster kidney cells (BHK-21) and Aedes albopictus cells (C6/36) were used for virus isolation. The results showed that C6/36 cells were susceptible to two isolates recovered from Culex tritaeniorhynchus (BNDL1205 and BNDL1227), with marked cytopathic effect (CPE) of cell fusion. By contrast, the two isolates could not cause CPE in BHK-21 cells. RT-PCR was performed for the two isolates using the flavivirus-specific primers FU2/cFD3, and a 800-bp amplicon was obtained from both of them. Phylogenetic analysis showed that the two isolates shared the same evolutionary branch with the Quang Binh virus (QBV) strain VN180, which had been isolated from Vietnam, with nucleotide sequence homologies of 83.4% and 82.9%, respectively. However, there existed relatively large differences in nucleotide sequence between them and other Culex flavivirus strains previously isolated in China and other regions. In light of the similarity between the two isolates and QBV, BNDL1205 and BNDL122 were referred to as Quang Binh-like virus, which were first reported in China. PMID- 24772900 TI - [IL15 DNA adjuvant enhances cellular and humoral immune responses induced by DNA and adenoviral vectors encoding HIV-1 subtype B gp160 gene]. AB - To enhance the immunogenicity of DNA and adenoviral vector vaccines expressing HIV-1 subtype B gp160, human interleukin 15 (hIL15) DNA adjuvant (pVR-hIL15) was constructed. BALB/c mice received DNA prime/protein boost immunization with pVR HIVgp160/Ad5-HIVgp160 alone or combined with pVR-hIL15. Cellular and humoral immune responses were evaluated by IFN-gamma enzyme-linked immunosorbent spot assay and enzyme-linked immunosorbent assay, respectively. Compared with those immunized with vaccines alone, the mice immunized with vaccines combined with pVR hIL15 had significantly increased specific cellular response and antibody titer (P < 0.05). It suggests that the IL15 DNA adjuvant can enhance the immune responses induced by prime-boost regimen using DNA and adenoviral vector encoding HIV-1 subtype B gp160. PMID- 24772901 TI - [Molecular epidemiological analysis of ECHO7 virus isolated from sewage water in Yunnan Province, China]. AB - To investigate the epidemic and evolutionary trends of enterovirus (EV) in the external environment of Yunnan Province, China, molecular typing was performed on 4 EV strains that were isolated from environmental sewage in Yunnan. The VP1 region of isolates was amplified by RT-PCR using universal enterovirus primers, and the amplified VP1 region was sequenced for GenBank BLAST search and genotype analysis. The 4 EV strains were identified as ECHO7. Their nucleotide and amino acid homologies with the VP1 sequences of 68 ECHO7 strains retrieved from GenBank were measured by Mega software analysis. Our findings showed that ECHO7 strains from environmental sewage and population samples were in different evolutionary branches. These strains showed typical geographical and temporal differences; In addition, there were different transmission chains at the same time and in the same area. ECHO7 strains isolated from sewage water and patients with acute flaccid paralysis during the same period in Yunnan belonged to different clusters and evolved at different speeds. Special concerns are needed for this problem. Continuous molecular biological surveillance of human EV in the external environment of Yunnan will provide strong support for early warning of EV diseases. PMID- 24772902 TI - [Advances in research and development of universal influenza vaccines]. AB - Vaccination is the primary strategy for the prevention and control of pandemic influenza. Because influenza virus is highly variable across strains, universal influenza vaccines need to be developed to address this problem. This review describes the research progress in conserved epitopes of influenza virus, the advances in the research and development of universal influenza vaccines based on the relatively conserved sequences of NP, M2e, HA2, and headless HA, the mechanisms of cross-protection, and the methods to improve cross-protection. PMID- 24772903 TI - [Research progress on chemokine receptor 5-targeted therapy for HIV-1]. AB - Along with the spread of human immunodeficiency virus 1 (HIV-1) infection in the world and the emergence of drug-resistant viral strains, it is urgent to seek the novel potent therapies. Chemokine receptor 5 (CCR5) is one of the main coreceptors involved in the entry of HIV-1 into target cells. Nowadays, a number of CCR5 antagonists have been developed and some of them have progressed to clinical trials or been approved. Research progress has also been made in the CCR5-targeted gene therapy. This review summarizes the recent research progress on the CCR5-targeted drug and gene therapy. PMID- 24772904 TI - [Research progress in HIV auxiliary proteins counteracting host restriction factors]. AB - Identification and functional analyses of antiviral restriction factors in hosts have become hot research topics. Four HIV restriction factors, APOBEC3G, Trim5alpha, Tetherin, and SAMHD1, have been identified in recent years. By encoding auxiliary proteins, lentiviruses can counteract host restriction factors. For example, the auxiliary proteins Vif, Vpu, and Vpx of HIV antagonize APOBEC3G, Tetherin, and SAMHD1, respectively. Furthermore, these auxiliary proteins enable the entry of HIV into host cells and influence the replication and pathogenicity of HIV. In this paper, we review the research progress in the functions of the three HIV auxiliary proteins that can antagonize the host restriction factors. PMID- 24772905 TI - [Roles of lipid droplets in hepatitis C virus life cycle]. AB - Lipid droplets are the main storage organelles for intracellular neutral lipids. Many recent studies have found that lipid droplets are closely related to hepatitis C virus (HCV). Lipid droplets play important roles in the multiple processes of HCV life cycle, such as infection, replication, assembly, and secretion. In this review, we summarize the recent research progress in the roles of lipid droplets in HCV life cycle. PMID- 24772906 TI - [Pathogenic significance and possible pathogenic mechanism of human endogenous viruses in development of schizophrenia]. AB - The association between psychogenic illness and human endogenous viruses (HEVs), including human endogenous retrovirus and Borna disease virus, remains unclear. As the component of human genome, HEVs may become the joint of various pathogenic factors of schizophrenia (SZ), such as heredity, environment, and immunity. In this review, we strive to uncover the clinical and laboratory evidence for the roles and possible pathogenic mechanism of HEVs in the development of SZ. PMID- 24772907 TI - [Progress on development and research of human bocavirus 1]. AB - Human bocavirus 1 (HBoV1) is a novel virus that mainly causes respiratory tract infection, and it has the characteristic of genome of Parvovirus, containing three open reading frames that encode non-structural proteins NS1 and NP1 and structural proteins VP1 and VP2. Circular episome is present during the rolling circle replication of HBoV1, which provides the possibility of full genome amplification and infectious clone construction to save HBoV1. The recombination between HBoV1 and HBoV2-4 occurs frequently. With the three-dimensional culture, in vitro culture of HBoV1 provides a powerful tool for research on the pathogenesis of HBoV1. This review focuses on the molecular characteristics, association with diseases, in vitro culture, diagnosis and treatment of HBoV1. PMID- 24772908 TI - Tumour markers, ultrasonography, and ovarian cancer diagnosis. PMID- 24772909 TI - Reply from M. Bozkurt, A E. Yumru1, I. Aral. PMID- 24772910 TI - Single port access (SPA) robot-assisted laparoscopic posterior pelvic exenteration for patients with advanced and recurrent ovarian cancer: Farghaly's technique. PMID- 24772911 TI - Cervical atypical glandular cells and false negative HPV testing: a dramatic reality of the wrong test at the right place. AB - BACKGROUND: Due to cervical cancer screening the number of squamous cancer have declined. The number of adenocarcinomas (ADCs) does appear to be rising. ADCs are often missed and human papillomavirus (HPV) testing could be helpful in detecting these abnormalities earlier. CASE: A 36-year-old woman, who had a normal smear three years earlier, had a pap smear with atypical glandular cells. The L1 HPV test showed that there was no HPV infection. Other HPV tests which looked at E6 and E7 showed an infection with HPV 16. Due to unknown reasons, no action was taken regarding the atypical glandular cells. Two years later the patient was diagnosed with a FIGO Stage IVb ADC of the cervix. The L1 HPV test was still negative and the E6/E7 HPV test was still positive. Despite several multiple treatment modalities she succumbed of her disease two years later leaving behind a young family. CONCLUSION: HPV test looking only at L1 can give false negative results if the virus is integrated in the human genome. PMID- 24772912 TI - Survival and toxicity of radical radiotherapy (with or without brachytherapy) for FIGO stage I and II cervical cancer: a mono-institutional analysis. AB - PURPOSE OF INVESTIGATION: To add to the existing outcome data regarding radical radiotherapy (RT) for FIGO Stage I and II cervical cancer in a mono-institutional series and to evaluate the cost-benefit ratio of the addition of brachytherapy (BRA) to external-beam radiotherapy (EBRT). MATERIALS AND METHODS: The authors report on 240 patients (pts) with FIGO Stage I and II cervical cancer, consecutively treated with radical RT from 1990 through 2009 at the Istituto del Radio "O. Alberti" (EBRT alone, 32, EBRT and BRA, 189, BRA alone, 19). BRA was delivered with low dose rate (LDR, 133.64%) until 2003 and then with high dose rate (HDR, 75.36%). RT was associated with concomitant chemotherapy (CHT), mainly weekly cisplatin 40 mg/m2, in 87 pts, mostly after 2000. The Chi-square test was used to compare the different variables, the Log-Rank test to compare the actuarial survival values, and the Cox-model for the multivariate analysis. RESULTS: Five-year actuarial overall survival (OS) equalled 65%, disease specific survival (DSS) 77%. Regardless of disease stage, better DSS was evident in pts treated with EBRT and BRA compared with those treated with EBRT alone (82% and 58% respectively, p = 0.005); pts treated with concomitant CHT (dose intensity > or = 50%) and higher RT doses (RT cumulative EQD2 > or = 75 Gy) obtained better DSS. Complete response (CR) rate approached 88.4% (206/233 evaluable pts) and more than half of the subsequent failures (21/36) were in distant sites. Older patients and those given BRA had better OS and DSS, while BRA dose rate did not result related with these outcomes. Chronic G3/G4 toxicity involved more frequently the intestinal/rectal tract than other organs at risk. Rectal and vaginal serious chronic sequelae developed mainly in pts treated with EBRT and BRA and suggest the need for more advanced treatment techniques. CONCLUSIONS: the present mono-institutional analysis confirms the efficacy of radical RT for the treatment of cervical cancer and provides support to the role of BRA to obtain better outcomes. An effort to reduce long-term toxicity of the treatment is needed. PMID- 24772913 TI - Adjuvant radiotherapy for endometrial cancer--a comparative review of radiotherapy technique with acute toxicity. AB - OBJECTIVES: The addition of pelvic radiotherapy to brachytherapy (EBRT-BT) in early-stage endometrial cancer is controversial and may cause unnecessary toxicity. The incidence of acute toxicity of EBRT-BT will have an impact on clinical decision and patient compliance but is currently poorly understood. This study compares the acute toxicities of EBRT-BT versus BT alone. MATERIALS AND METHODS: Seventy-nine patients with FIGO Stage IA-II endometrial cancer who underwent adjuvant radiotherapy, (EBRT-BT or BT alone) from 2001 to 2011 were included in the study. Medical records of these patients were reviewed retrospectively and toxicity graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients were followed up for at least three months post-treatment to assess resolution of toxicity. RESULTS: The mean age of the study group was 60.6 years. Median follow-up was four years. Forty patients received EBRT-BT. There was a 37% increase in Grade 1-3 diarrhea with the addition of pelvic radiotherapy (OR 18.67, p < 0.0005) and a 34% increase in lethargy (p < 0.0005). There was also an increased occurrence of genitourinary and skin toxicities. Two patients in the EBRT-BT group required hospitalisation for severe diarrhea and three patients were unable to complete the treatment. All acute toxicities had resolved by three months post treatment. CONCLUSION: EBRT-BT causes significantly more acute toxicities compared to BT alone. Patients should be informed of this during counselling. PMID- 24772914 TI - Maspin expression in endometrial hyperplasia and carcinoma, and its relation with angiogenesis. AB - AIM: The purpose of this study was to evaluate the maspin expression in endometrial hyperplasia and cancer, and also to investigate its relation with angiogenesis. MATERIALS AND METHODS: A total of 19 women with complex atypical hyperplasia, 44 patients with simple hyperplasia without atypia, and 67 patients with endometrial carcinoma were included. Maspin expression was assessed by immunohistochemistry (IHC), and tested for possible significant relation with age, FIGO stage, histologic type, grade, depth of myometrial invasion (MI), lymphovascular space involvement (LVSI), lymph node metastasis, and overall survival (OS). Angiogenesis was determined by vascular endothelial growth factor (VEGF) staining. RESULTS: Maspin expression was detected in only three patients with endometrial hyperplasia (5%). In patients with endometrial cancer, cytoplasmic and nuclear maspin expressions were detected in 36 (53.7%) and 18 (26.9%) patients, respectively. No significant relation was noted between staining localizations and prognostic variables. The five-year OS rate for patients with cytoplasmic staining was 91%, compared to 87% for patients without staining (p = 0.31). These values for nuclear expression were 100% and 87%, respectively (p = 0.16). The cytoplasmic and nuclear maspin expressions were found to be significantly correlated with VEGF (r = 0.278, p = 0.02 and r = 0.295, p = 0.01, respectively). DISCUSSION: This is the first study to demonstrate the relation between maspin expression and angiogenesis in endometrial cancer. Although no survival difference was noted for cytoplasmic or nuclear maspin expressions, a tendency was detected for nuclear staining. Further series will clarify the exact prognostic role of maspin expression in gynecological malignancies including endometrial cancer. PMID- 24772915 TI - Radiosensitization of cervical cancer cells with epigenetic drugs hydralazine and valproate. AB - PURPOSE: To evaluate the radiosensitizing effects of the DNA methylation inhibitor hydralazine in combination with valproic acid, a histone deacetylase inhibitor in cervical cancer cells. MATERIALS AND METHODS: Cell viability assays were performed in the SiHa cervical cancer cell line treated with hydralazine and valproic acid for five days with and without cisplatin. Cell irradiation was performed using teletherapy (1.25 MV). RESULTS: Neither hydralazine, valproic acid or cisplatin as single agents increased the cytotoxicity from radiation, however, the combination of hydralazine with valproic acid at ten microM and one mM, respectively, did induce radiosensitization (p = 0.046). Interestingly, this effect was further increased with the triple combination of hydralazine, valproic acid, and cisplatin (p = 0.041), where cell viability decreased more than 50% as compared to radiation alone. CONCLUSIONS: The present results demonstrate that epigenetic drugs increase the efficacy of cisplatin chemoradiation in cervical cancer cells. PMID- 24772916 TI - Appendectomy with cytoreductive surgery for ovarian and type 2 endometrial carcinoma. AB - There is considerable variation within and between cancer centers in the practice of appendectomy as part of cytoreductive surgery for ovarian carcinoma and in the surgical staging of endometrial carcinoma. The purpose of this study was to determine the prevalence and the type of appendiceal pathology, the morbidity associated with appendectomy in gynaecologic cancer surgery. MATERIALS AND METHODS: This is a retrospective review of all cytoreductive surgery for ovarian carcinoma and surgical staging for endometrial carcinoma with appendectomy over a four year period. RESULTS: Two hundred and fifty-one patients (38 patients for endometrial carcinoma surgery and 213 patients for ovarian cytoreduction) had an appendectomy performed. Metastases to the appendix was present in 46 (23.2%) of primary ovarian carcinoma and one (2.6%) primary endometrial carcinosarcoma. The appendix was more likely to be involved in advanced stage ovarian cancer with positive peritoneal washings, omental deposits, grade 3 differentiation, and papillary serous histology. Sixteen (6.4%) co-incidental primary appendiceal tumours were detected. No postoperative morbidity specific to appendectomy was identified. One case of ovarian carcinoma was upstaged from IC to IIIA by the appendiceal metastases. There was no upstaging of disease in the endometrial carcinoma group. DISCUSSION: Appendectomy is an integral part of ovarian cytoreductive surgery but the authors found it did not upstage the disease in a clinically significant manner. The incidence of co-incidental appendiceal primary tumours was high in this series and may add value to the procedure in preventing further surgeries. The absence of procedure related morbidity is reassuring. The authors recommend appendectomy for all ovarian staging surgery and its consideration in type 2 endometrial cancer. PMID- 24772917 TI - Contraception after breast cancer: a retrospective review of the practice among French gynecologists in the 2000's. AB - PURPOSE OF INVESTIGATION: To describe the French practices regarding contraception after breast cancer in the 2000's. MATERIALS AND METHODS: A total of 2,500 forms were sent to gynecologists practicing in France. Inclusion criteria were premenopausal patients who had a history of breast cancer and who had been prescribed contraception after diagnosis. Between June 1, 2002 and January 1, 2003, 197 evaluable responses were retrieved. RESULTS: The median age of the sample was 38.5 years. The most commonly used form of contraception was an intrauterine device (n = 144, 73.1%). Hormonal contraception was prescribed for 42 patients (21.3%), and other methods were used in 29 patients (14.7%) (Condoms n = 14, tubal sterilization n = 7, and others n = 8). Recurrence occurred in 27 patients (13%); 2.9% in the progestin group, 16.3% in the IUD group, and 14.8% with the other methods). CONCLUSIONS: It is necessary to evaluate current contraception practices after breast cancer to evaluate the efficacy and safety of contraception in these patients. PMID- 24772918 TI - Borderline ovarian tumors: outcomes of fertility sparing surgery. AB - AIM: Borderline ovarian tumors(BOT) account for ten to 20 percent of all epitelial ovarian carcinomas and often occur in reproductive ages. The aim of this study was to evaluate the clinical and reproductive outcomes of patients who were diagnosed with BOT and underwent fertility sparing surgery. MATERIALS AND METHODS: Patients younger than 40 years who underwent fertility sparing surgery for BOT from 2004 to 2012 were reviewed retrospectively and were evaluated according to the reproductive and clinical outcomes. RESULTS: Twenty-eight patients younger than 40 years with BOT underwent fertility sparing surgery. Median follow up time was 42 +/- 28.1 months. During the follow up period, two patients (7.1%) developed recurrence at 35 and 36 months, respectively. Five (17.9%) out of 28 patients became pregnant during the follow up period. CONCLUSION: Fertility sparing surgery should be the first choice for the treatment of BOT in patients who wish to preserve fertility. PMID- 24772919 TI - Management of breast lobular carcinoma in situ: radio-pathological correlation, clinical implications, and follow-up. AB - PURPOSE OF INVESTIGATION: To show management of patients with breast lobular carcinoma in situ (LCIS). MATERIALS AND METHODS: This study is the retrospective review of 65 patients, between 1996 and 2012, with isolated LCIS of the breast, evaluated through clinical examination, ultrasound, and mammography at the first examination and follow-up. RESULTS: In 53 patients (81.54%), clinical examination was negative. In 14/65 (21.54%) cases, ultrasound was positive and led to biopsy. The clusters of tiny calcifications were the predominant mammographic pattern (45 cases, 69.23%). Forty-six patients (70.77%) underwent surgical biopsy after guided stereotactic placement of metallic marker (hook-wire), 12 (18.46%) by stereotactic vacuum biopsy (SVB), 5 (7.69%) by core needle biopsy (CNB) under ultrasound guidance, two (3.08%) patients CNB with clinically palpable nodules. Fourteen (21.54%) women underwent a quadrantectomy or total mastectomy after the first diagnosis; in this latter group follow-up was negative. Among the 51 patients (78.46%) who did not undergo quadrantectomy or total mastectomy, five relapses occurred, respectively, three LCIS and two infiltrating ductal carcinomas (IDC). Follow-up ranged from 12 to 144 months. CONCLUSION: LCIS is a risk factor for invasive carcinoma and should be managed with careful follow-up, but if there is a discrepancy between pathology and imaging, surgical excision is mandatory. PMID- 24772920 TI - Management of a primary retroperitoneal mucinous cystadenocarcinoma: case report. AB - PURPOSE: To review the treatment of primary retroperitoneal mucinous cystadenocarcinoma (PRMC). CASE REPORT: A 30-year-old woman had a large retroperitoneal mucinous adenocarcinoma treated with conservative laparoscopic surgery. Two years later, she was found to have bilateral ovarian cysts at the time of cesarean section. Since cystectomies revealed mucinous adenocarcinoma, she underwent complete surgical staging and adjuvant chemotherapy at this time. CONCLUSION: A rare case of similar cancer in the ovary following treatment for PRMC was described. It is unclear whether the prognosis is improved by oophorectomy. Further cases and long-term follow-up are necessary. PMID- 24772921 TI - Transection of the obturator nerve by an electrosurgical instrument and its immediate repair during laparoscopic pelvic lymphadenectomy: a case report. AB - Obturator nerve injury seldom occurs in gynecologic surgery. However, gynecologic oncologic surgery, including pelvic lymph node dissection, increases the risk of this type of injury. Microsurgical techniques are usually performed for the repair of the nerve injury. Herein the authors report a case of obturator nerve injury caused by an electrosurgical instrument during laparoscopic pelvic lymphadenectomy, and its prompt repair by laparoscopic procedure in a 44-year-old patient with cervical cancer. PMID- 24772922 TI - Axillary lymph node metastasis as first presentation of peritoneal carcinomatosis from serous papillary ovarian cancer: case report and review of the literature. AB - Ovarian cancer usually spreads into abdominal cavity and to the loco-regional lymph nodes. Extra-abdominal metastases are less frequent and isolated axillary metastases are very rare. The authors describe the case of a 49-year-old woman who was diagnosed with a peritoneal carcinomatosis from ovarian cancer by mean of an enlarged axillary lymph node biopsy, whose histological examination identified as a ovarian cancer metastasis. Patient was treated by peritonectomy and intraperitoneal chemohyperthermic perfusion (HIPEC). Although patients with axillary lymph node metastasis from ovarian cancer are though to be metastatic (FIGO Stage IV), surgical radical treatment and adjuvant systemic chemotherapy can achieve the same prognosis of Stage IIIb-c patients, suggesting they could be a particularly good prognosis subset of patients. Early differential diagnosis between ovarian or breast cancer in axillary lymph node metastasis is crucial but not always very simple, because of the very different course and treatment of these tumours. PMID- 24772924 TI - Chylous ascites after retroperitoneal aortocava lymphadenectomy for endometrial cancer: a case report. AB - This is a case report of chylous ascites after retroperitoneal aortocava lymphadenectomy for endometrial cancer. There are few reports of chylous ascites in gynecologic surgery. Treatment is primarily conservative. The present case was resolved with a low fat diet with medium-chain triglyceride (MCT) supplements and somatostatin IV. PMID- 24772923 TI - Leiomyosarcoma of the broad ligament: a case report with CT and MRI images. AB - Primary leiomyosarcoma of the broad ligament is a very rare and highly malignant gynecological tumor. The authors report a 61-year-old postmenopausal woman with signs and symptoms of malignant ovarian tumor. Preoperative magnetic resonance imaging (MRI) was interpreted as being suspicious for malignant tumors, such as an ovarian cancer or a leiomyosarcoma of the broad ligament, so laparotomy was performed. Macroscopically, the tumor was revealed with a 18 x 13.7 x 9.5 cm degenerated, multiple cystic part and solid whitish part arising from broad ligament which on histopathology proved to be leiomyosarcoma. To the best of the authors' knowledge, primary leiomyosarcoma of the broad ligament has been documented in 21 reports or so, and no imaging findings are available. Here the authors present the MRI findings of primary leiomyosarcoma of the broad ligament. PMID- 24772925 TI - Malignant mixed Mullerian tumor with small cell neuroendocrine differentiation: a case report and review of the literature. AB - INTRODUCTION: Small cell neuroendocrine differentiation (NE) in malignant mixed Mullerian tumors (MMMTs) is a rare and unusual occurrence with very few previously reported cases. There is no consensus regarding its diagnosis, classification, and optimal treatment options. CASE: The authors report a patient with endometrial MMMT and NE differentiation who initially received comprehensive surgery followed by adjuvant chemotherapy containing cisplatin and etoposide. She further underwent metastasectomy and received carboplatin and paclitaxel for the relapse. She is still alive 12 months after the diagnosis. The authors performed a review of literature in order to characterize the clinical phenotype. These patients have a very aggressive disease. Median life expectancy seems to be less than a year. CONCLUSIONS: It is reasonable to perform comprehensive staging surgery followed by adjuvant chemotherapy irrespective to stage of the disease. PMID- 24772926 TI - Minimal deviation endometrioid adenocarcinoma of the endometrium and its MRI findings. AB - Minimal deviation endometrioid adenocarcinoma (MDA-E) of the endometrium is a rare pathological entity, and its radiological features are rarely documented. A 73-year-old Japanese woman was referred to the authors when an endometrial biopsy revealed moderately differentiated endometrioid adenocarcinoma. Preoperative radiological examinations, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) showed no evidence of cancer nests. In the hysterectomy specimen, mildly atypical glands were scattered throughout the entire depth of the myometrium, without stromal desmoplastic reaction, and a tiny focus of typical, ruptured, endometrioid adenocarcinoma glands was found in the atrophic endometrium. MRI had not been able to identify this unusual, scattered, myometrial invasion. It should be kept in mind that in cases showing Stage IA endometrial carcinoma without endometrial thickening on MRI, this rare form of invasion may be present. PMID- 24772927 TI - Leiomyomatosis peritonealis disseminata: an additional case. AB - Leiomyomatosis peritonealis disseminata (PPD) is a rare smooth muscle tumour of women in the reproductive age. It is characterized by multiple small nodules on the peritoneal surface, mimicking a metastatic process. To date, about 100 cases have been reported in literature. The authors herein present an additional case consisting of multiple nodules located on the surface of the omentum, parietal peritoneum, as well as colon and rectum wall in a patient without signs of excess of estrogen, progesterone, or steroid hormones nor treated with hormones for any reason. The patient has been submitted to laparoscopic myomectomy few years ago. Microscopically, these nodules consisted of bundles of spindle-shaped smooth muscle cells (positive for smooth muscle actin, desmin, estrogen, and progesterone receptor). A brief review of the literature on the pathogenesis of the disease is also added. PMID- 24772928 TI - A large pedunculated leiomyoma with two-sided cystic degenerations mimicking a bilateral ovarian malignancy: a case report. AB - The authors present an unusual case of a large, pedunculated uterine leiomyoma with two-sided cystic degenerations, which mimicked a bilateral malignant ovarian tumor on ultrasonography and magnetic resonance imaging (MRI). A 32-year-old unmarried female patient presented to our outpatient clinic with complaints of abdominal distention and a palpable abdominal mass extending into the upper abdomen. Ultrasonography and MRI revealed a large solid mass with bilateral cystic areas extending into both uterine adnexa. The patient then underwent a laparotomy. Gross examination revealed normal ovaries and a pedunculated mass with two-sided prominent cystic structures originating from the uterine fundus. The tumor was excised through the peduncle and pathologic evaluation revealed a uterine leiomyoma with cystic degenerations. In conclusion, a large, pedunculated leiomyoma with two-sided cystic degenerations can mimic a bilateral malignant ovarian neoplasm on imaging studies. Therefore, uterine leiomyomas with bilateral cystic degenerations should be considered during the differential diagnosis of malignant ovarian masses. PMID- 24772929 TI - Benign pulmonary metastasizing leiomyomatosis: case report. AB - The authors report a rare case of leiomyomatosis of the lung diagnosed in a 43 year-old woman, with uterine intravenous leiomyomatosis. Benign metastasizing leiomyoma (BML) is an extremely rare lesion characterized by usually multiple, benign-appearing smooth muscle tumors of the lung in females with coexisting uterine leiomyoma. On the basis of their histological and immunohistological features, a unified histogenetic view of leiomyomas with vascular invasion (LWVI) and BML of the uterus is proposed. LWVI and BML may be the same pathological entity and microscopic vascular invasion may represent the metastatic mechanism of BML. LWVI seems to be the precursor of BML. PMID- 24772930 TI - Ovary-preserving tumorectomy for immature teratoma in an adolescent--case report. AB - The authors present a case of a 14-year-old premenarchal girl with a large solid tumor of the left ovary. The rim of normal ovarian tissue was visible around the tumor on ultrasonography scan. Although the levels of two tumor markers, LDH and CA125, were elevated, the authors performed an organ-sparing tumorectomy. The final pathology report revealed foci of immature neural tissue, with a final diagnosis immature teratoma Stage Ia. PMID- 24772931 TI - Analysis of rapamycin induced autophagy in Dictyostelium discoideum. AB - Natural autophagy and autophagic cell death is being studied in the model system, D. discoideum, which has well known genetic and experimental advantages over the other known systems. There is no apoptotic machinery present in this organism which could interfere with the non-apoptotic cell death. The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway which when inhibited by the drug rapamycin induces autophagy. Rapamycin was originally discovered as an anti fungal agent but its use was abandoned when it was discovered to have potent immunosuppressive and anti-proliferative properties. It is a known drug used today for various cancer treatments and also for increasing longevity in many model organisms. It has a wide usage but its effects on other pathways or molecules are not known. This model system was used to study the action of rapamycin on autophagy induction. Using the GFP-Atg8, an autophagosome marker, it was shown that rapamycin treatment can induce autophagy by an accumulation of reactive oxygen species and intracellular free calcium. Rapamycin suppresses proliferation by induction of cell cycle arrest in the G1 phase. Taken together, the results suggest that the core machinery for autophagy is conserved in D. discoideum and it can serve as a good model system to delineate the action of rapamycin induced autophagy. PMID- 24772932 TI - Neuronal differentiation of PC12 and embryonic stem cells in two- and three dimensional in vitro culture. AB - The quality of neuronal differentiation and reduction in apoptosis that occurred in two-dimensional (2D) and three-dimensional (3D) culture conditions is compared. PC12 and embryonic stem cells are two commonly utilized cell lines for the study of neuronal regeneration. These cells were induced to neuronally differentiate by adding NGF and retinoic acid respectively. Total neurite length and expression of neuronal markers (MAP-2 and beta-tubulin) was assessed by morphometry and immunocytochemistry. Also, TUNEL assay was used to detect apoptosis. Upon exposure to a differentiation media in the 3D fibrin gel, PC12 and embryonic stem cells stopped dividing, had increased adhesion to the substratum, extended neurite processes and expressed neuronal markers. The same results, however, were not observedwith the 2D culture. Also, the apoptosis index performed by TUNEL a ss ay demonstrated a reduction in th e degree of apoptosis in the 3D culture compared to 2D culture. Fibrin matrix supports growth and n euronal differentiation of PC12 andembryonic stem cells. In addition, the 3D culture enhanced cellular resistance to apoptosis when compared to the 2D culture. It appears as if a 3D culture system may offer a better technique for future neuronal tissue engineering investigations. PMID- 24772933 TI - Epigallocatechin gallate induces the steady state mRNA levels of pS2 and PR genes in MCF-7 breast cancer cells. AB - Investigations using in vitro and in vivo models of breast carcinogenesis have demonstrated anti-neoplastic activity of the green tea polyphenol, epigallocatechin gallate (EGCG). Although a number of molecular targets of EGCG have been identified, its impact on the expression of estrogen target genes is not completely understood. Here, we examined the mRNA expression levels of two estrogen target genes, namely Trefoil Factor 1 (pS2) and Progesterone Receptor (PR) in MCF-7 cells treated with EGCG. We observed that treatment with 40 microM EGCG, which caused only 20% decrease in cell viability, resulted in increased steady state expression levels of pS2 and PR mRNA. This suggests that EGCG may exert its biological activities, at least in part, by influencing the expression of estrogen target genes. PMID- 24772934 TI - Chronic spinal infusion of loperamide alleviates postsurgical pain in rats. AB - Plantar incision in rat generates spontaneous pain behaviour. The opioid drug, morphine used to treat postsurgical pain produces tolerance after long-term administration. Loperamide, a potent mu-opioid agonist, has documented analgesic action in various pain conditions. However, loperamide analgesia and associated tolerance following continuous spinal administration in postsurgical pain has not been reported. Chronic spinal infusion of drugs was achieved using intrathecal catheters connected to osmotic minipump. Coinciding with the onset of spinal infusion of loperamide or morphine, rats were subjected to plantar incision. Pain related behaviour was assessed by Hargreaves apparatus (thermal hyperalgesia) and von Frey filaments (mechanical allodynia). Morphine and loperamide (0.5, 1 and 2 microL/h) induced analgesia was observed until 7th day post-plantar incision in Sprague-Dawley rats. Morphine and loperamide produced dose-dependent analgesia. Loperamide, in the highest dose, produced analgesia till 7th day. However, the highest dose of morphine produced inhibition of thermal hyperalgesia till 5th day and mechanical allodynia only till 3rd day post-plantar incision. Morphine and loperamide produced analgesia in postsurgical pain, which may be mediated through different mechanisms. Longer duration of analgesia with loperamide could probably be due sustained blockade of calcium channels. PMID- 24772935 TI - Protective effect of Azadirachta indica a. Juss against doxorubicin-induced cardiac toxicity in tumour bearing mice. AB - Doxorubicin (DOX) treatment (12 microg/g body weight, once a week for 2 weeks) resulted in a significant decrease in the heart rate along with an increase in QRS, ST, and QT intervals. Histopathological studies showed cardiomyocyte degeneration, cytoplasmic vacuolation and macrophage infiltration in cardiac tissue. A marked increase in the rate of apoptosis was also observed. An increased oxidative stress was evidenced by significantly higher levels of lipid peroxidation (LPO) and depletion of reduced glutathione. A decrease in the activity of cellular antioxidant defence enzymes was also observed. The decrease in the heart rate and ECG alterations were prevented significantly by AAILE (100 microg/g body weight, po) co-treatment, started two weeks prior to DOX treatment and continued till the termination of the experiment. The cardioprotection was also evident from histopathology and decrease in the rate of apoptosis in cardiomyocytes. AAILE co-treatment also prevented DOX-induced increase in LPO and decrease in antioxidant defence enzymes. The results suggest that AAILE administration prevents DOX-induced cardiotoxicity. PMID- 24772936 TI - Impairment of renal structure and function following heterogeneous chemical mixture exposure in rats. AB - Renal structural and functional alterations following an exposure to a heterogeneous chemical mixture (HCM) of phthalic acid di butyl ester, 1, 2 dichlorobenzene, cadmium chloride and chromium trioxide, administered through oral gavage in low doses (1/100 and 1/1000 of LD50 value of individual chemical) for 60 days, followed by withdrawal till 120 days resulted in significant rise in kidney lipid peroxidation and fall in the activities of enzymatic antioxidants. However, withdrawal of HCM treatment restored most of these altered parameters. Degenerative changes in the kidney included proximal convoluted tubules devoid of brush boarder with cytoplasmic blebbing, dissolution and sloughing of nuclei. Cortical glomeruli were also affected with epithelial disintegration, pyknosis of podocyte nuclei and mesengial cell hyperplasia. The morphological alterations recovered fully in the low dose compared to the high dose treatment group. PMID- 24772937 TI - Phenotypic plasticity and ecotypic variations in growth and flowering time of Arabidopsis thaliana (L.) under different light and temperature conditions. AB - Four ecotypes of A. thaliana (L.) (Ct-1, Pf-0, Old-1 and Per-i) from low to high latitudes were grown under different light (300 micro mol photon m-2s-1 and 150 micromol photon m-2s') and temperature (22 and 14 degreesC) conditions to investigate their effects on phenotypic plasticity and ecotypic variations in plant growth and first flowering time. The results suggest that in A. thaliana low temperature decreases both phenotypic plasticity and ecotypic variations in first flowering time and total dry matter at final harvest under different light intensities. Relative growth rate is the most stable parameter of A. thaliana that is hardly affected by ecotype (no effect), light (no effect) or temperature (small effect) and this may one of the reason why A. thaliana is widely distributed on earth as a result of adaptations to different environments. PMID- 24772938 TI - Regulation of nitrogen metabolism in salt tolerant and salt sensitive Frankia strains. AB - Effect of salinity (0, 50, 100, 250, 500 and 750 mM NaCI) was observed on some important physiological parameters of nitrogen metabolism such as nitrate uptake, intracellular and extracellular ammonium status and activities of nitrogenase, nitrate reductase, nitrite reductase and glutamine synthetase among Frankia strains differing in their salt tolerance capacity. Nitrogenase activity closely followed the growth pattern with regular decline on NaCI supplementation. All the other enzymes showed optimum activity at 100 mM and declined further. Co regulation of the nitrate uptake system and sequential enzyme activities plays a crucial role in governing the nitrogen status of strains during salt stress. HsIil0 experiencing minimum decline in enzyme activities and best possible nitrogen regulation under NaC1 replete condition showed adequate nutritional management. Among all the strains, HsIil0 proved to be salt tolerant on account of above features while the salt sensitive strain HsIi8 lacked the ability to regulate various steps of nitrogen metabolism during salinity, and thus Frankia strain HsIil0 can potentially serve as a potential biofertilizer in the saline soil. PMID- 24772939 TI - Biosynthesis of silver nanoparticles using fresh extracts of Tridax procumbens linn. AB - A simple and eco-friendly method for the synthesis of biogenic nanoparticles (NP's) using an aqueous solution of T. procumbens fresh plant extract (leaf and stem) as a bioreductant is reported. The prepared biogenic nanoparticles were well characterized using U.V. visible spectroscopy, scanning electron microscopy, X-ray diffraction and Fourier-transform infrared spectroscopy. The particles were confirmed to be elemental crystal by X-ray diffraction. The potential applications of biosynthesized nanoparticles as antimicrobial (antibacterial and antifungal) against pathogens Escherichia coli, Vibrio cholerae, Aspergillus niger and Aspergillusflavus were demonstrated. PMID- 24772940 TI - Efficacy of Spodoptera litura multiple nucleopolyhedrovirus after serial passage through the homologous insect larval host. AB - An originally isolated baculovirus, Spodoptera litura multiple nucleopolyhedrovirus (SpltMNPV) was serially passed through the S. litura larvae for upto four generations to determine the mean number of occlusion bodies (OBs) harvested per larva and their efficacy in terms of infectivity, feeding cessation and speed of kill of host larvae. The results revealed that the mean number of OBs harvested per larva increased significantly with increase in the dose of SpltMNPV at each passage and the yield was significantly lower in original stock wild-type SpltMNPV (P0) as compared to serially passed SpltMNPV (P1, P2, P3 and P4). Laboratory bioassays indicate that median lethal doses (LD50), median times to feeding cessation (FT50) and median survival times (ST50) of P0, P1, P2, P3 and P4 were significantly different from each other. The OBs of each passage when tested for their cross-infectivity against Spodoptera exigua and Spilarctia obliqua revealed significant reduction in their mortality. These results indicate that serially passed SpltMNPV is more host specific and more effective biocontrol agent than the original stock wild-type virus and can be adopted for mass production as a viral pesticide for control of the S. litura. PMID- 24772941 TI - Pharmacophore based approach to design inhibitors in crustaceans: an insight into the molt inhibition response to the receptor guanylyl cyclase. AB - The first set of competitive inhibitors of molt inhibiting hormone (MIH) has been developed using the effective approaches such as Hip-Hop, virtual screening and manual alterations. Moreover, the conserved residues at 71 and 72 positions in the molt inhibiting hormone is known to be significant for selective inhibition of ecdysteroidogenesis; thus, the information from mutation and solution structure were used to generate common pharmacophore features. The geometry of the final six-feature pharmacophore was also found to be consistent with the homology-modeled MIH structures from various other decapod crustaceans. The Hypo 1, comprising six features hypothesis was carefully selected as a best pharmacophore model for virtual screening created on the basis of rank score and cluster processes. The hypothesis was validated and the database was virtually screened using this 3D query and the compounds were then manually altered to enhance the fit value. The hits obtained were further filtered for drug-likeness, which is expressed as physicochemical properties that contribute to favorable ADME/Tox profiles to eliminate the molecules exhibit toxicity and poor pharmacokinetics. In conclusion, the higher fit values of CI-1 (4.6), CI-4 (4.9) and CI-7 (4.2) in conjunction with better pharmacokinetic profile made these molecules practically helpful tool to increase production by accelerating molt in crustaceans. The use of feeding sub-therapeutic dosages of these growth enhancers can be very effectively implemented and certainly turn out to be a vital part of emerging nutritional strategies for economically important crustacean livestock. PMID- 24772942 TI - Identification of a GJA3 mutation in a Chinese family with congenital nuclear cataract using exome sequencing. AB - Congenital cataract, a clinically and genetically heterogeneous lens disorder is defined as any opacity of the lens presented from birth and is responsible for approximately 10% of worldwide childhood poor vision or blindness. To identify the genetic defect responsible for congenital nuclear cataract in a four generation Chinese Han family, exome and direct Sanger sequencings were conducted and a missense variant c.139G>A (p.D47N) in the gap junction protein-alpha 3 gene (GJA3) was identified. The variant co-segregated with patients of the family and was not observed in unaffected family members or normal controls. The above findings indicated that the variant was a pathogenic mutation. The mutation p.D47N was found in the first extracellular loop (El) domain of GJA3 protein. Our data suggest that exome sequencing is a powerful tool to discover mutation(s) in cataract, a disorder with high genetic heterogeneity. Our findings may also provide new insights into the cause and diagnosis of congenital nuclear cataract and have implications for genetic counseling. PMID- 24772943 TI - Critical time delay of the pineal melatonin rhythm in humans due to weak electromagnetic exposure. AB - Electromagnetic fields (EMFs) can increase free radicals, activate the stress response and alter enzyme reactions. Intracellular signalling is mediated by free radicals and enzyme kinetics is affected by radical pair recombination rates. The magnetic field component of an external EMF can delay the "recombination rate" of free radical pairs. Magnetic fields thus increase radical life-times in biological systems. Although measured in nanoseconds, this extra time increases the potential to do more damage. Melatonin regulates the body's sleep-wake cycle or circadian rhythm. The World Health Organization (WHO) has confirmed that prolonged alterations in sleep patterns suppress the body's ability to make melatonin. Considerable cancer rates have been attributed to the reduction of melatonin production as a result of jet lag and night shift work. In this study, changes in circadian rhythm and melatonin concentration are observed due to the external perturbation of chemical reaction rates. We further analyze the pineal melatonin rhythm and investigate the critical time delay or maturation time of radical pair recombination rates, exploring the impact of the mRNA degradation rate on the critical time delay. The results show that significant melatonin interruption and changes to the circadian rhythm occur due to the perturbation of chemical reaction rates, as also reported in previous studies. The results also show the influence of the mRNA degradation rate on the circadian rhythm's critical time delay or maturation time. The results support the hypothesis that exposure to weak EMFs via melatonin disruption can adversely affect human health. PMID- 24772944 TI - Evaluation of leptin and insulin resistance in patients with cholelithiasis. AB - The association between insulin resistance, lipoproteins and leptin was evaluated in cholelithiasis. The study group included 55 women (68.8%) and 25 men (31.3%) with a mean age and SD of 50.56 +/- 14.28 yrs. The control group included 25 women (62.5%) and 15 men (37.5%) with a mean age of 50.93 +/- 11.73 yrs. Serum leptin levels were measured by the enzyme immunoassay method. HOMA-IR was determined by using fasting glucose and insulin levels. Insulin, total cholesterol (TC), LDL-C, HOMA-IR (p < 0.01) and leptin (p < 0.001) were significantly higher in the cholelithiasis group, compared to the controls. In patients with a HOMA-IR >2.2, age, body mass index (BMI), glucose, insulin, triglycerides (TG), TC and leptin levels were higher than in patients with a HOMA IR < 2.2. In patients with glucose levels >100 mg/dl, mean BMI, HOMA-IR, insulin, TG, TC and leptin levels were significantly higher than in patients with glucose levels <100 mg/dl. In patients with TG levels >150 mg/dl, mean age, BMI, glucose, insulin, TC, leptin and HOMA-IR were significantly higher than in patients with TG levels < 150 mg/dl. In patients with BMI > 25 kg/m2, mean age, glucose, insulin, TG, TC, leptin, HOMA-IR were significantly higher than in patients with BMI < 25. In cholelithiasis group, there was a positive correlation between leptin and age, BMI, glucose, insulin, TG, TC, LDL-C or HOMA-IR. In conclusion, we found a positive association between increased leptin levels and abnormal lipoprotein metabolism in cholelithiasis. Cholelithiasis subjects with insulin resistance showed higher cardiometabolic risk factors than those without it. PMID- 24772945 TI - Identification of three novel myeloid cathelicidin cDNAs and their predicted peptides in buffalo (Bubalus bubalis). AB - Antimicrobial peptides (AMPs) are broad spectrum antibiotics, which mostly act without specific receptors. Identification of AMPs is important in the current scenario of emerging multi-drug resistant bacteria. In the present study, in an attempt to identify new AMPs, myeloid cathelicidin cDNAs were synthesized from buffalo (Bubalus bubalis) bone marrow and were amplified using specific primers. Sequence analysis of cloned cDNAs revealed three novel myeloid cathelicidins. They were named based on the number of active amino acids in the C-terminal region of their predicted peptide sequences as BuMAP-28 (having an additional Gly at position 22nd), BuMAP-29 (having an additional IIe at position 27) and BuMAP 34, compared to BMAP-27, BMAP-28 and BMAP-34 of cattle. The BuMAPs showed 93%, 95% and 87% homology respectively with that of its cattle counterpart. Predicted number of amino acids of the cDNAs was 159, 155 and 157 residues, with cationic C terminal sequences of 28, 29 and 34, respectively, which correspond to putative antimicrobial domains. Several amino acid substitutions were observed in all the three cathelicidins. The conformation of the peptides was predicted to be alpha helical, having total net positive charge and hydrophobicity, similar to that of BMAPs in cattle. Comparative analysis of the predicted peptides suggested potential antimicrobial activity and the sequence variations detected might enable the peptides to act as effective broad spectrum antimicrobial agents. PMID- 24772946 TI - A QSAR study on a series of thiourea derivatives acting as anti-hepatitis C virus agents. AB - A quantitative structure-activity relationship (QSAR) study was performed on a large series of thiourea derivatives reported by Kang et al. [Bioorg Med Chem Lett (2009), 19, 1950-55 & 6063-68], acting as anti-hepatitis C virus (anti-HCV) agents. The activity of the compounds was found to be significantly correlated with their hydrophobic property and three indicator variables I1, I2 and I3, the first two specifying a negative effect of an alkyl and an aromatic group, respectively on their R-moiety and the third one specifying a negative effect of their Ar-moiety having a nitrogen-containing heterocyclic ring. The whole set containing 85 compounds was divided into two subsets: the training set and the test set containing 61 and 24 compounds, respectively. For the training set, the correlation coefficient (r) and the square of cross-validated correlation coefficient (r2cv) were found to be 0.926 and 0.83, respectively. The correlation obtained suggested that anti-HCV activity of the compounds would depend on their hydrophobic property, conformational flexibility and the steric effects of an alkyl or an aromatic group on the R-moiety. This suggested that the molecules might have significant hydrophobic interactions with the receptor which might be aided by their conformational flexibility, but hindered sterically by an alkyl or an aromatic group on their R-moiety. Using the correlation obtained, some new compounds having activity higher (> 8.0) than the most active compound in the existing series were predicted. PMID- 24772947 TI - Effect of near field ultrasound on carboplatin treatment of ovarian carcinoma cells. AB - It has long been shown that therapeutic ultrasound has the potential to affect cells surfaces and membranes. In this study, the effects of ultrasound in near field mode, the anti-cancer drug carboplatin and their combined application were studied on human carcinoma cells A2780. Four modes of treatment were used: exposure to ultrasonic field, application of carboplatin, exposure to ultrasound followed by carboplatin and carboplatin treatment followed by exposure to near field ultrasound. The value of viability was measured by standard MTT test. The value of ultrasound intensity was set 1 W x cm(-2) and 1 MHz frequency was used. The real value of acoustic pressure during in vitro experiments was assessed by hydrophone. The results showed that a combined effect of ultrasound and carboplatin influenced the viability of human carcinoma cells A2780 more than the application of ultrasound or carboplatin alone. It could be assumed that exposure of cells to ultrasonic field had an immediate effect on the structure of cell surface and consequently on the entry of carboplatin into the cell. The results of our experiments demonstrated possibility of using therapeutic ultrasound in potentiating the cytostatic treatment of human carcinoma cells. PMID- 24772948 TI - Protective effect of some amino acids synthesized derivatives and their chelates on Escherichia coli under X-ray irradiation. AB - The protective effects of novel synthesized derivatives of some amino acids- nicotinyl-L-tyrosinate and nicotinyl-L-tryptophanate schiff bases and their Cu(II) and Mn(II) chelates on growth, survival and membrane-associated ATPase activity of E. coli under X-ray irradiation were investigated. The specific growth rate and survival of E. coli were decreased at 10, 20 and 30 Gy doses. However, as 30 Gy was found to be the most effective irradiation dose, it was chosen for studying the radio-protective properties of different compounds. These compounds could increase the bacterial cell protection against X-ray irradiation in concentration-dependent manner. They had a role in stimulation of synthesis or regulation of activity of metal-dependent enzymes, required for reversing the X ray irradiation damage. The study may prove useful for further estimation of the effectiveness of different compounds as radio-protectors on bacteria and other cells, especially mammalian cells under X-ray irradiation. PMID- 24772949 TI - Wound healing potential of flowers extracts of Woodfordia fruticosa Kurz. AB - Wound healing or repair is the body's natural process of regenerating dermal and epidermal tissue. Woodfordia fruticosa Kurz (Family: Lythraceae) is used traditionally in wound healing by the tribals of Chhattisgarh district. However, there is a paucity of scientific data in support. In this study, we evaluated antimicrobial activity of petroleum ether, chloroform, ethanolic and aqueous extracts against a diverse range of gram +ve and gram -ve bacteria along with pathogenic fungi. The wound healing activity of ethanolic extract was also evaluated at dose levels of 250 and 500 mg/kg body wt in rats by excision, incision and dead space wound healing models along with histopathology of wound area of skin. The ethanolic extract showed potent wound healing activity, as evident from the increase in the wound contraction and breaking strength in dose dependent manner. Treatment with ethanolic extract (250 and 500 mg/kg body wt) showed significant dose-dependently decrease in epithelization period and scar area. Hydroxyproline, hexuronic acid and hexosamine contents, the important constituents of extracellular matrix of healing were also correlated with the observed healing pattern. During early wound healing phase, pro-inflammatory cytokines TNF-alpha, IL-6 and anti-inflammatory cytokine IL-10 levels were found to be upregulated by the ethanolic extract treatment. The ethanolic extract exhibited a strong and broad spectrum antimicrobial activity, as compared to other extracts. It showed very low Minimum inhibitory concentration (MIC) values and inhibited the growth of E. coli, Staphylococcus aureus and Candida albicans in concentration of 2.5 microg/disc. Thus, the results of the present study demonstrated the strong wound healing potential and antimicrobial activities of W. fruticosa, flowers, supporting the folklore use of the plant by the tribal people of Chhattisgarh district. PMID- 24772950 TI - Partial purification and characterization of extracellular protease from a halophilic and thermotolerant strain Streptomyces pseudogrisiolus NRC-15. AB - An alkaline protease was purified from a halophilic and thermotolerant potent alkaline protease-producing strain Streptomyces pseudogrisiolus NRC-15 using ammonium sulphate precipitation and Sephadex G-100 column chromatography. The enzyme was purified to 77.24-folds with a yield of 91.8% and the specific activity was 112 U/mg of protein. The protease showed a single band on SDS-PAGE with its molecular mass at 20 kDa and exhibited a maximum relative activity of 100% using casein as a substrate and. The enzyme had an optimum pH of 9.5 and displayed optimum activity at 50 degrees C. The enzyme activity was completely inhibited by the serine protease inhibitor PMSF, suggesting the presence of serine residue in the active site. The enzyme activity was increased by the metal ions Ca2+, Co2+, K+ and Mg2+. The enzyme significantly enhanced the removal of stains when used with wheel detergent, indicating the potential of the enzyme for using as a laundry detergent additive to improve the performance of heavy-duty laundry detergent. PMID- 24772951 TI - Influence of pulsed magnetic field on soybean (Glycine max L.) seed germination, seedling growth and soil microbial population. AB - The effects of pulsed magnetic field (PMF) treatment of soybean (Glycine max L. cv CO3) seeds were investigated on rate of seed germination, seedling growth, physico-chemical properties of seed leachates and soil microbial population under laboratory conditions. Seeds were exposed to PMF of 1500 nT at 0.1, 1.0 10.0 and 100.0 Hz for 5 h per day for 20 days, induced by enclosure coil systems. Non treated seeds were considered as controls. All PMF treatments significantly increased the rate of seed germination, while 10 and 100 Hz PMFs showed the most effective response. The 1.0 and 10 Hz PMFs remarkably improved the fresh weight of shoots and roots, leaf area and plant height from seedlings from magnetically exposed seeds compared to the control, while 10 Hz PMF increased the total soluble sugar, total protein and phenol contents. The leaf chlorophyll a, b and total chlorophyll were higher in PMF (10 and 100 Hz) pretreated plants, as compared to other treatments. In addition, activities of alpha-amylase, acid phosphatase, alkaline phosphatase, nitrate reductase, peroxidase and polyphenoloxidase were increased, while beta-amylase and protease activities were declined in PMF (10 Hz)-exposed soybean plants. Similarly, the capacity of absorbance of water by seeds and electrical conductivity of seed leachates were significantly enhanced by 10 Hz PMF exposure, whereas PMF (10 Hz) pretreated plants did not affect the microbial population in rhizosphere soil. The results suggested the potential of 10 Hz PMF treatment to enhance the germination and seedling growth of soybean. PMID- 24772952 TI - Evaluation of changes in lipid peroxidation, ROS production, surface structures, secondary metabolites and yield of linseed (Linum usitatissimum L.) under individual and combined stress of ultraviolet-B and ozone using open top chambers. AB - The individual and interactive effects of supplemental UV-B (sUV-B) (ambient + 7.2 kJ m(-2) d(-1)) and elevated O3 (ambient + 10 ppb) were evaluated under field conditions using open top chambers on two cultivars, Padmini and T-397 of linseed (Linum usitatissimum L.). Mean monthly surface level of O3 concentrations varied from 27.7 ppb to 59.0 ppb during the experimental period. Both UV-B and O03 induced the production of ROS (H2O2 and O2*-), resulting in significant damage of membranes due to lipid peroxidation and electrolyte leakage. Synthesis of secondary metabolites (flavonoids, anthocyanin, lignin and wax) was also enhanced in all the treatments, whereas biomass and yield were reduced. Alterations in frequency of stomata and wax distribution were also observed through scanning electron microscopy (SEM). Cultivar Padmini was found to be more sensitive because of higher damage of membrane vis-a-vis reduction in biomass and seed yield. However, concentrations of flavonoids, anthocyanin, lignin and wax were higher in T-397, suggesting its relative resistance against applied stress. Combined exposure of sUV-B and O3 was less harmful, as compared to their individual treatment. Among the three treatments, O3 was found to be more detrimental for overall growth and sUV-B for economic yield. PMID- 24772953 TI - In vivo anti-fatigue activity of total flavonoids from sweetpotato [Ipomoea batatas (L.) Lam.] leaf in mice. AB - The in vivo anti-fatigue activity of the total flavonoids from sweet potato [Ipomoea batatas (L.) Lam.] leaf was investigated in male Kunming mice. The total flavonoids from sweet potato leaf (TFSL) were orally administered at doses of 50, 100 and 200 mg/kg for 4 weeks and the anti-fatigue effect was studied using a weight-loaded swimming test, along with the determination of serum urea nitrogen (SUN), blood lactic acid (BLA) and hepatic and muscle glycogen contents. The results showed that TFSL had significant anti-fatigue effects. TFSL extended the exhaustive swimming time, effectively inhibited the increase of BLA, decreased the level of SUN and increased the hepatic and muscle glycogen content of mice. Thus, TFSL may have potential as an anti-fatigue agent. PMID- 24772954 TI - Inborn errors of metabolism and metabolic disorders: disease processes. Preface. PMID- 24772955 TI - Alkaptonuria: a very rare metabolic disorder. AB - Alkaptonuria (AKU) is a very rare autosomal recessive disorder of tyrosine metabolism in the liver due to deficiency of homogentisate 1,2 dioxygenase (HGD) activity, resulting in the accumulation of homogentisic acid (HGA). Circulating HGA pass into various tissues through-out the body, mainly in cartilage and connective tissues, where its oxidation products polymerize and deposit as a melanin-like pigment. Gram quantities of HGA are excreted in the urine. AKU is a progressive disease and the three main features, according the chronology of appearance, are: darkening of the urine at birth, then ochronosis (blue-dark pigmentation of the connective tissue) clinically visible at around 30 yrs in the ear and eye, and finally a severe ochronotic arthropathy at around 50 yrs with spine and large joints involvements. Cardiovascular and renal complications have been described in numerous case report studies. A treatment now is available in the form of a drug nitisinone, which decreases the production of HGA. The enzymatic defect in AKU is caused by the homozygous or compound heterozygous mutations within the HGD gene. This disease has a very low prevalence (1:100,000 250,000) in most of the ethnic groups, except Slovakia and Dominican Republic, where the incidence has shown increase up to 1:19,000. This review highlights classical and recent findings on this very rare disease. PMID- 24772957 TI - Molecular diagnosis of urea cycle disorders: current global scenario. AB - Urea cycle disorders are a group of inborn error of metabolism, characterized by hyperammonemia, metabolic alkalosis and clinical features of encephalopathy. These are among the commonest types of inborn errors of metabolism with a frequency of 1 in 8,000 to 1 in 30,000 in different population. This encompasses 5 major disorders, corresponding with deficiency of each step in the urea cycle, namely ornithine transcarbamoylase (OTC) deficiency, argininosuccinate lyase (ASL) deficiency, carbamoyl phosphate synthetase (CPS) deficiency, citrullinemia and argininemia. The most important clinical presentation is neurological abnormalities. The severity of UCD is correlated to extent of hyperammonemia. Early diagnosis and treatment are essential for successful patient outcome. Various modalities of treatment have been recommended; namely, treatment aimed at reducing ammonia level, including drugs like sodium benzoate and sodium phenyl butyrate, neuroprotective strategies, low protein diet, liver transplantation and hepatocyte transplantation. Molecular diagnosis is important to identify the pathogenesis of these disorders as well as it helps in prognosis. This review intends to summarize the important aspects of molecular diagnostic studies on urea cycle disorders. PMID- 24772956 TI - Genetic and biochemical consequences of adenosine deaminase deficiency in humans. AB - Adenosine deaminase deficiency accounts for approximately 15-20% of severe combined immunodeficiency in humans. The gene for adenosine deaminase is located on chromosome 20q12-q13.11 and codes for an aminohydrolase that catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. Absence of the enzyme causes a build-up of the substrates in addition to excess deoxyadenosine triphosphate, thereby compromising the regenerative capacity of the immune system. Due to underlying allelic heterogeneity, the disorder manifests as a spectrum, ranging from neonatal onset severe combined immunodeficiency to apparently normal partial adenosine deaminase deficiency. Tandem mass spectrometry coupled with high efficiency separation systems enables postnatal diagnosis of the disorder, while prenatal diagnosis relies on assaying enzyme activity in cultured amniotic fibroblasts or chorionic villi sampling. Screening of adenosine deaminase deficiency for relatives-at-risk may reduce costs of treatment and ensure timely medical intervention as applicable. This article reviews the genetic, biochemical and clinical aspects of adenosine deaminase deficiency. PMID- 24772958 TI - Protease inhibitors in potential drug development for Leishmaniasis. AB - Leishmaniasis is a deadly protozoan parasitic disease affecting millions of people worldwide. The treatment strategy of Leishmania infection depends exclusively on chemotherapy till date. But the treatment of the disease is greatly hampered due to high cost, toxicity of the available drugs and more importantly emergence of drug resistance. Hence the potential new drugs are highly needed to combat this disease. The first and foremost step of the drug discovery process is to search and select the putative target in a specific biological pathway in the parasite that should be either unambiguously absent in the host or considerably different from the host homolog. Importantly, Leishmania genome sequences enrich our knowledge about Leishmania and simultaneously reinforce us to identify the ideal drug targets that distinctly exist in the parasite as well as to develop the effective drugs for leishmaniasis. Though the leishmanial research has significantly progressed during the past two decades, the identification of suitable drug targets or development of effective drugs to combat leishmaniasis is far from satisfactory. Enzymatic systems of Leishmania metabolic and biochemical pathways are essential for their survival and infection. Concurrently, it is noteworthy that Leishmania proteases, especially the cysteine proteases, metalloproteases and serine proteases have been extensively investigated and found to be indispensable for the survival of the parasites and disease pathogenesis. Herein, we have discussed the importance of few enzymes, particularly the Leishmania proteases and their inhibitors as promising candidates for potential development of anti-leishmanial drugs. PMID- 24772959 TI - Inflammation and MMPs in alcohol-induced liver diseases and protective action of antioxidants. AB - The consumption of alcohol causes several liver-associated diseases all over the world. Alcoholic liver diseases (ALD) include hepatic inflammation, fatty liver, hepatitis, liver cirrhosis and fibrosis and finally hepatocellular carcinoma. Although the cellular, metabolic and biochemical mechanisms for these diseases are quite explicable, the roles of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) are still under investigation. The present review describes the roles and regulation of MMPs and TIMPs in different ALDs along with the involvement of other pathways. This review also summarizes the present knowledge on clinical and experimental trials with different antioxidants that help against alcohol associated liver diseases. PMID- 24772960 TI - Airborne agricultural particulate matter induces inflammatory cytokine secretion by respiratory epithelial cells: mechanisms of regulation by eicosanoid lipid signal mediators. AB - The purpose of this study was to elucidate the mechanism of the airborne poultry dust (particulate matter, PM)-induced respiratory tract inflammation, a common symptom in agricultural respiratory diseases. The study was based on the hypothesis that poultry PM would induce the release of inflammatory cytokine interleukin-8 (IL-8) by respiratory epithelial cells under the upstream regulation by cytosolic phospholipase A2 (cPLA2) activation and subsequent formation of cyclooxygenase (COX)- and lipoxygenase (LOX)-catalyzed arachidonic acid (AA) metabolites (eicosanoids). Human lung epithelial cells (A549) in culture were treated with the poultry PM (0.1-1.0 mg) for different lengths of time, following which PLA2 activity, release of eicosanoids and secretion of IL-8 in cells were determined. Poultry PM (1.0 mg/ml) caused a significant activation of PLA2 in a time-dependent manner (15-60 min), which was significantly attenuated by the calcium-chelating agents, cPLA2-specific inhibitor (AACOCF3) and antioxidant (vitamin C) in A549 cells. Poultry PM also significantly induced the release of COX- and LOX-catalyzed eicosanoids (prostaglandins, thromboxane A2 and leukotrienes B4 and C4) and upstream activation of AA LOX in the cells. Poultry PM also significantly induced release of IL-8 by the cells in a dose- and time-dependent manner, which was significantly attenuated by the calcium chelating agents, antioxidants and COX- and LOX-specific inhibitors. The current study for the first time revealed that the poultry PM-induced IL-8 release from the respiratory epithelial cells was regulated upstream by reactive oxygen species, cPLA2-, COX- and LOX-derived eicosanoid lipid signal mediators. PMID- 24772961 TI - Aluminum and ethanol induce alterations in superoxide and peroxide handling capacity (SPHC) in frontal and temporal cortex. AB - Aluminum is an omnipresent neurotoxicant and has been associated with several neuropathological disorders. Cerebrum and cerebellum have been shown to face augmented oxidative stress when animals are exposed to aluminum and high doses of ethanol. To establish the link between oxidative stress and neurobehavioral alterations, the present study was conducted to determine the extent of oxidative stress in low levels of pro-oxidant (ethanol exposure) status of the functionally discrete regions of the cerebrum. Male Wistar rats were exposed to aluminum (10 mg/kg body wt) and ethanol (0.2-0.6 g/kg body wt) for 4 weeks. Spontaneous motor activity (SMA) and Rota-Rod performances (RRP) were recorded weekly during the period of exposure. At the end of 4th week, oxidative stress parameters were determined from the homogenized cerebral tissue. GSH-independent superoxide peroxide handling capacity (GI-SPHC) and GSH-dependent superoxide peroxide handling capacity (GD-SPHC) were determined for FC and TC upon exposure to ethanol in the absence and presence of aluminum exposure. Aluminum was found to augment the oxidative stress at higher doses (0.6 g Ethanol/kg body wt) of ethanol, particularly in FC. The SPHC of FC was also found to be compromised significantly in aluminum-ethanol co-exposed animals. It was concluded that even though the manifestation of oxidative stress was not observed as revealed by assaying the widely used oxidative stress biochemical markers (indices), aluminum and ethanol (low doses) exposure induced alterations in the handling capacity of oxidant imbalance that could be recognized by studying the SPHC of FC. Comparison of GD-SPHC and GI-SPHC offered a possible mechanism of compromised SPHC in FC. This observation is likely to offer insights into the mechanism of association between aluminium exposure and behavioral changes in neurodegenerative disorders towards therapeutic strategies for these disorders. PMID- 24772962 TI - Analysis of osmotic stress induced Ca2+ spark termination in mammalian skeletal muscle. AB - Ca2+ sparks represent synchronous opening of the ryanodine receptor (RyR) Ca2+ release channels located at the sarcoplasmic reticulum (SR) membrane. Whereas a quantal nature of Ca2+ sparks has been defined in cardiac muscle, the regulation of Ca2+ sparks in skeletal muscle has not been well-studied. Osmotic-stress applied to an intact skeletal muscle fiber can produce brief Ca2+ sparks and prolonged Ca2+ burst events. Here, we show that termination of Ca2+ bursts occurs in a step wise and quantal manner. Ca2+ burst events display kinetic features that are consistent with the involvement of both stochastic attrition and coordinated closure of RyR channels in the termination of SR Ca2+ release. Elemental unitary transition steps could be defined with a mean deltaF/F0 of approximately 0.28. corresponding to the gating of 1-2 RyR channels. Moreover, the amplitude of the elemental transition steps declines at the later stage of the burst event. In tandem Ca2+ burst events where two Ca2+ bursts occur at the same position within a fiber in rapid succession, the trailing event is consistently of lower amplitude than the initial event. These two complementary results suggest that SR Ca2+ release may be associated with local depletion of SR Ca2+ stores in mammalian skeletal muscle. PMID- 24772963 TI - Effect of m-calpain in PKCalpha-mediated proliferation of pulmonary artery smooth muscle cells by low dose of ouabain. AB - There is growing evidence that ouabain, a cardiotonic steroid may promote growth of cardiac and vascular myocytes, indicating its novel role in cell growth and proliferation, without appreciable inhibition of the sodium pump. The mechanism(s) by which low dose of ouabain produces pulmonary artery smooth muscle cell proliferation, a prerequisite for right ventricular hypertrophy, is currently unknown. Here, we analyzed the effects of low dose of ouabain (10 nM) on increase in [Ca2+]i, m-calpain and protein kinase C (PKC) activities on pulmonary artery smooth muscle cell proliferation and determined their sequential involvement in this scenario. We treated bovine pulmonary artery smooth muscle cells with a low dose of ouabain (10 nM) and determined [Ca2+]i in the cells by fluorometric assay using fura2-AM, m-calpain activity by fluorometric assay using SLLVY-AMC as the substrate. PKC activity using an assay kit and assay of Na+/K+ ATPase activity spectrophotometrically. We purified m-calpain and PKCalpha by standard chromatographic procedure by HPLC and then studied cleavage of the purified PKCalpha by m-calpain using Western immunoblot method. Subsequently, we performed cell proliferation assay utilizing the redox dye resazunin. We used selective inhibitors of [Ca2+]i (BAPTA-AM), m-calpain (MDL28170), PKCalpha (Go6976) and determined their involvement in ouabain (10 nM)-mediated smooth muscle cell proliferation. Our results suggested that treatment of bovine pulmonary artery smooth muscle cells with a low dose of ouabain (10 nM) increased [Ca2+]i and subsequently stimulated m-calpain activity and proteolytically activated PKCalpha in caveolae (signaling microdomain also known as signalosomes) of the cells. Upon activation, PKCalpha increased the smooth muscle cell proliferation via Go/G1 to S/G2-M phase transition. Thus, [Ca2]i-mCalpain PKCalpha signaling axis plays a crucial role during low dose of ouabain-mediated pulmonary artery smooth muscle cell proliferation. PMID- 24772965 TI - Impact of COMT H108L, MAOB int 13 A>G and DRD2 haplotype on the susceptibility to Parkinson's disease in South Indian subjects. AB - In view of documented evidence demonstrating the association of dopaminergic metabolism and neurotransmission with Parkinson's disease (PD), a case-control study was conducted to investigate the impact of particular polymorphisms in the catechol O-methyl transferase (COMT) H108L, monoamine oxidase B (MAOB) int 13 A>G, dopamine transporter 1 (DAT1) A1215G, dopamine receptor D2 (DRD2) Taq1A, DRD2 Taq1B and DRD2 Taq1D genes on the susceptibility to PD. PCR-RFLP method was used for the genetic analysis. The COMT H108L polymorphism increased PD risk by 1.4-fold (95%CI: 1.02-1.98), whereas reduced risk was observed with MAOB int 13 A>G polymorphism (OR: 0.77, 95%CI: 0.51-0.99). Multifactor dimensionality reduction analysis showed gene-gene interactions between these two loci that resulted in loss of the protective role of MAOB G-allele in the presence of COMT L-allele. DAT1A1215G polymorphism in the exon 9 was not associated with PD. Individually, DRD2 polymorphisms showed null association. However, all-variant haplotype of DRD2 locus i.e. T-G-T haplotype showed 29.8-fold risk for PD compared to all-wild haplotype i.e., C-A-C haplotype (95%CI: 6.85-130.4). To conclude, genetic variants of COMT, MAOB and DRD2 loci modulate susceptibility to PD in South Indian subjects. PMID- 24772964 TI - Expression levels of sarcolemmal membrane repair proteins following prolonged exercise training in mice. AB - Membrane repair is a conserved cellular process, where intracellular vesicles translocate to sites of plasma membrane injury to actively reseal membrane disruptions. Such membrane disruptions commonly occur in the course of normal physiology, particularly in skeletal muscles due to repeated contraction producing small tears in the sarcolemmal membrane. Here, we investigated whether prolonged exercise could produce adaptive changes in expression levels of proteins associated with the membrane repair process, including mitsugumin 53/tripartite motif-containing protein 72 (MG53/TRIM72), dysferlin and caveolin-3 (cav3). Mice were exercised using a treadmill running protocol and protein levels were measured by immunoblotting. The specificity of the antibodies used was established by immunoblot testing of various tissue lysates from both mice and rats. We found that MG53/TRIM72 immunostaining on isolated mouse skeletal muscle fibers showed protein localization at sites of membrane disruption created by the isolation of these muscle fibers. However, no significant changes in the expression levels of the tested membrane repair proteins were observed following prolonged treadmill running for eight weeks (30 to 80 min/day). These findings suggest that any compensation occurring in the membrane repair process in skeletal muscle following prolonged exercise does not affect the expression levels of these three key membrane repair proteins. PMID- 24772966 TI - Analysis of gene mutations among South Indian patients with maple syrup urine disease: identification of four novel mutations. AB - Maple syrup urine disease (MSUD) is predominantly caused by mutations in the BCKDHA, BCKDHB and DBT genes, which encode for the E1alpha, E1beta and E2 subunits of the branched-chain alpha-keto acid dehydrogenase complex, respectively. Because disease causing mutations play a major role in the development of the disease, prenatal diagnosis at gestational level may have significance in making decisions by parents. Thus, this study was aimed to screen South Indian MSUD patients for mutations and assess the genotype-phenotype correlation. Thirteen patients diagnosed with MSUD by conventional biochemical screening such as urine analysis by DNPH test, thin layer chromatography for amino acids and blood amino acid quantification by HPLC were selected for mutation analysis. The entire coding regions of the BCKDHA, BCKDHB and DBT genes were analyzed for mutations by PCR-based direct DNA sequencing. BCKDHA and BCKDHB mutations were seen in 43% of the total ten patients, while disease-causing DBT gene mutation was observed only in 14%. Three patients displayed no mutations. Novel mutations were c.130C>T in BCKDHA gene, c. 599C>T and c.121_122delAC in BCKDHB gene and c.190G>A in DBT gene. Notably, patients harbouring these mutations were non-responsive to thiamine supplementation and other treatment regimens and might have a worse prognosis as compared to the patients not having such mutations. Thus, identification of these mutations may have a crucial role in the treatment as well as understanding the molecular mechanisms in MSUD. PMID- 24772967 TI - Association of genetic variants of xenobiotic metabolic pathway with systemic lupus erythematosus. AB - In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 ml, m2 and m4 variants (D': 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 ml variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L x GSTT1 null x GSTM1 null (p < 0.0001) and also between the phase II and I variants i.e. COMT H108L x GSTTI null x CYP1A1 ml x CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77 5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to ml and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE. PMID- 24772968 TI - Cardiac risk factors in descendants of parents with history of coronary artery disease (CAD): an evaluation focusing on small dense low density lipoprotein cholesterol (sdLDLc) and high density lipoprotein cholesterol (HDLc). AB - The risk of coronary artery disease (CAD) in descendants with positive family history of CAD was evaluated in either one of or both the parents among 71 selected families. Subjects were grouped as parents and descendants without and with CAD and descendants spouses without CAD or family history of CAD. All subjects were examined for anthropometric characteristics, fasting blood sugar, serum lipids, lipoprotein sub-fractions, insulin, insulin resistance and pancreatic beta cell function. The results were subjected to statistical analysis by using the analysis of variance (ANOVA). Metabolic syndrome (MetS) was prevalent in the 83% descendants with CAD and 54.6% parents with CAD. The traditional risk factors were observed in both parents and descendants with CAD. Metabolic risk factors, including hypertriglyceridemia, low HDLc levels and hyperglycaemia had a higher frequency in the descendants with CAD. ANOVA showed significant 'F' ratio for the anthropometric characteristics, hypertension, serum lipids, small dense (sd) LDLc levels, HDL2c levels and HDL3c levels in the descendants parents with CAD and CAD + diabetes mellitus (DM), as compared to those without CAD. The descendants without CAD, but with a positive family history had central adiposity, hypertension and had lower HDL levels and elevated sdLDLc levels. Multiple analyses of variance showed that sdLDLc and waist circumference were the most potent risk factors for prevalence of CAD. Thus, we conclude that a positive family history of CAD along with central adiposity and elevation of sdLDLc levels appear to be important factors in the assessment of CAD risk in humans. PMID- 24772969 TI - Role of nitric oxide, angiogenic growth factors and biochemical analysis in preeclampsia. AB - Preeclampsia, a pregnancy-related hypertensive disorder, is one of the leading causes of fetal and maternal mortality and morbidity globally. Angiogenic growth factors, including vascular endothelial growth factor (VEGF) and placental growth factor (P1GF) are involved in the generation of new blood vessels required for placental development and physiological functions, while nitric oxide (NO) acts as vasodilator and also plays a role in angiogenesis. The objective of this study was to evaluate the role of NO, angiogenic growth factors (VEGF and PIGF) and other biochemical parameters in the development of preeclampsia among pregnant mothers. A complete clinical history, including anthropometric measurements and biochemical investigations, including renal function tests, liver function tests and lipid profile were performed among twenty preeclampsia patients aged 19 to 32 yrs. Results were compared with age-matched normotensive pregnant mothers. The body weight, body mass index (BMI), blood pressure, concentrations of urea, uric acid and triglyceride and activities of transaminase enzymes (aspartate transaminase, AST and alanine transaminase, ALT) in serum were significantly higher (p < 0.05) than normotensive subjects. Serum concentrations of VEGF, P1GF and NO were significantly decreased (p < 0.005) in preeclamptic patients. NO was found negatively correlated with body weight (r = -0.369, p < 0.05), systolic blood pressure (r = -0.822, p < 0.005), diastolic blood pressure (r = -0.714, p < 0.005) and was positively correlated with VEGF (r = 0.464, p < 0.005) and P1GF (r = 0.546, p < 0.005). VEGF and P1GF showed significant (p < 0.005) negative correlation with systolic and diastolic blood pressure and PIGF was significantly correlated with triglyceride (r = -0.379). However, no significant correlation was observed between the VEGF and P1GF. In conclusion, the results indicated that body weight, triglyceride, angiogenic growth factors and NO might associate with preeclampsia development. PMID- 24772970 TI - Association of dietary caloric intake with blood pressure, serum lipids and anthropometric indices in patients with hypertension. AB - The influence of dietary caloric intake was studied on blood pressure (BP), serum lipids, body mass index (BMI) and waist-hip-ratio (WHR) according to age and gender. The study population consisted of 400 healthy individuals as controls and 746 first time detected untreated hypertensive (HTN) subjects. The subjects were regrouped according to amount of calorie intake per day i.e. high and low calorie intake diet within two age-groups: 30-50 years and 51-80 yrs. Blood samples were drawn from all the subjects, following an overnight fast and serum total cholesterol (TC), triglycerides (TG) and HDL-C were measured by standard methods. Serum LDL-C was calculated by Fredrickson-Friedwald formula. BP and anthropometric measurements were measured by a standardized protocol. Highly significant increases in TC, TG, LDL-C, anthropometric and atherogenic indices were seen. While a decrease in HDL-C was observed in high calorie HTN, as compared to low calorie controls. Gender-wise, men had increased values compared to women, except, HDL-C and BMI. With increase in age, all parameters increased in both the subject categories, except atherogenic and anthropometric indices. Hypertensive subjects with high calorie intake diet showed an increase in BP, serum lipids and BMI which might be the major contributor in precipitation of hypertension and also in increasing risk of cardiovascular morbidity and mortality. PMID- 24772971 TI - Autistic children exhibit distinct plasma amino acid profile. AB - In order to ascertain whether autistic children display characteristic metabolic signatures that are of diagnostic value, plasma amino acid analyses were carried out on a cohort of 138 autistic children and 138 normal controls using reverse phase HPLC. Pre-column derivatization of amino acids with phenyl isothiocyanate forms phenyl thio-carbamate derivates that have a lamba(max) of 254 nm, enabling their detection using photodiode array. Autistic children showed elevated levels of glutamic acid (120 +/- 89 vs. 83 +/- 35 micromol/L) and asparagine (85 +/- 37 vs. 47 +/- 19 micromol/L); lower levels of phenylalanine (45 +/- 20 vs. 59 +/- 18 micromol/L), tryptophan (24 +/- 11 vs. 41 +/- 16 micromol/L), methionine (22 +/- 9 vs. 28 +/- 9 micromol/L) and histidine (45 +/- 21 vs. 58 +/- 15 micromol/L). A low molar ratio of (tryptophan/large neutral amino acids) x 100 was observed in autism (5.4 vs 9.2), indicating lesser availability of tryptophan for neurotransmitter serotonin synthesis. To conclude, elevated levels of excitatory amino acids (glutamate and asparagine), decreased essential amino acids (phenylalanine, tryptophan and methionine) and decreased precursors of neurotransmitters (tyrosine and tryptophan) are the distinct characteristics of plasma amino acid profile of autistic children. Thus, such metabolic signatures might be useful tools for early diagnosis of autism. PMID- 24772972 TI - Triptolide induces apoptosis through extrinsic and intrinsic pathways in human osteosarcoma U2OS cells. AB - Triptolide, a diterpene derived from Tripterygium wilfordii Hook f., a Chinese medicinal herb, has been reported to inhibit cell proliferation and induce apoptosis in various human cancer cells, but its anticancer effects on human osteosarcoma cells have not yet been elucidated. In this study, we investigated whether triptolide induces apoptosis in human osteosarcoma cells and the underlying molecular mechanisms. We firstly demonstrated that triptolide inhibited cell growth and induced apoptosis in U2OS cells. Western blot analysis showed that the levels of procaspase-8, -9, Bcl-2, Bid and mitochondrial cytochrome c were downregulated in triptolide-treated U2OS cells, whereas the levels of Fas, FasL, Bax, cytosolic cytochrome c, cleaved caspase-3 and cleaved PARP were upregulated. These results suggest that triptolide induces apoptosis in U2OS cells by activating both death receptor and mitochondrial apoptotic pathways. PMID- 24772973 TI - Lipid peroxidation and large-scale deletions of mitochondrial DNA in asthenoteratozoospermic patients. AB - The correlation between malondialdehyde (MDA) an index of lipid peroxidation (LPO) with large-scale deletion mitochondrial DNA (mtDNA) was investigated in a case-control study with a total of 50 semen samples from infertile men, including 25 normozoospermic donor as the control group and 25 asthenoteratozoospermic (AT) patients as the case group. Routine semen analysis was performed according to World Health Organization (WHO, 1999) guidelines. MDA levels of the seminal plasma and spermatozoa were measured by TBARS method. A long-range polymerase chain reaction (PCR) method was used for the analysis of multiple large-scale mtDNA deletions based in two areas of mtDNA. The results showed that mean concentration of MDA in seminal plasma (nmol/ml) and spermatozoa (nmol/10 x 10(6) sperm) of AT men was higher than in normozoospermic patients, but the differences were not statistically significant. The products of PCR analysis showed multiple deletions of approximately 4.7, 4.8, 7.2, 7.3 and 7.4-kb in mtDNA of the spermatozoa in both AT and control groups. Multiple deletions were also observed in 64% of AT patients and 44% of the control group. Moreover, MDA level of the spermatozoa in deleted mtDNA samples group was significantly higher than in non deleted mtDNA group (p = 0.01). Our findings indicated a positive correlation between increased MDA levels and large-scale mtDNA deletions in human spermatozoa. It is suggested that LPO or other oxidative stress factors might be causative elements in mtDNA damage, effect on sperm motility and morphology, resulting in decline of fertility in men. PMID- 24772974 TI - Effect of garlic extract on some serum biochemical parameters and expression of npc1l1, abca1, abcg5 and abcg8 genes in the intestine of hypercholesterolemic mice. AB - Some compounds in the garlic inhibit cholesterol synthesis, resulting in lowering of serum cholesterol and triglycerides and increase in HDL level. However, the mechanism of this specific effect is not fully understood. In the small intestine, ATP-binding cassette transporters G5, G8 and A1 (ABCG5, ABCG8 and ABCA1), as well as Niemann-Pick C1 like 1 (NPC1L1) protein have important roles in cholesterol metabolism. In this study, we evaluated the beneficial effect of aqueous extract of garlic on lipid profile and also expression of npc1l1, abca1, abcg5 and abcg8 genes in the intestine of N-Marry mice fed a high cholesterol diet as a possible mechanism of garlic effect. Twenty-four mice were randomly divided into three groups: Group 1: hypercholesterolmic (received chow + 2% cholesterol + 0.5% cholic acid); Group 2: garlic (received chow + 4% (w/w) garlic extract + 2% cholesterol + 0.5% cholic acid); and Group 3: received chow only. After one month, mice were anesthetized and blood was collected from their heart. The jejunum was removed, washed with PBS and entrocytes were scraped and used for the experiments. Serum lipids were measured enzymatically and expression of mRNA levels for the above-mentioned proteins was determined by semi-quantitative RT PCR. Garlic extract significantly reduced serum lipids (p < 0.05), compared with the hypercholesterolemic group. Expression of the intestinal npc1l1 was significantly decreased (p < 0.01) in the garlic group, compared with the chow group, while abcg5 (p < 0.01), abcg8 (p < 0.01) and abca1 (p < 0.05) expressions were significantly increased. In conclusion, this study reveals a possible mechanism for the beneficial effects of the garlic in lowering serum lipids by decreasing the intestinal lipid absorption and increasing excretion of cholesterol back into the intestinal lumen. PMID- 24772975 TI - Effect of dexamethasone on unfolded protein response genes (MTJ1, Grp78, Grp94, CHOP, HMOX-1) in HEp2 cell line. AB - The endoplasmic reticulum (ER) is related to the various signal routes that are activated in unfolded protein response (UPR). The Grp78, Grp94, CHOP, MTJ1 and HMOX1 genes expressions demonstrate UPR activity. In this study, we investigated the UPR gene expressions in larynx epidermoid carcinoma (HEp2) to which dexamethasone (dex) was applied. HEp2 cells were administered for 48 h with different combinations using 0.1 microM and 1 microM dex, 1 mM phenyl butyric acid (PBA) and 100 ng/ml lipopolysaccharide (LPS). The Grp78, Grp94, CHOP, MTJ1 and HMOX1 genes expression was determined using quantitative RT-PCR. The Grp78, MTJ1 and HMOX1 gene expression increased with the administration of 1 microM dex. CHOP expression, on the other hand, decreased with 0.1 microM dex. When dex was combined with LPS, nearly all gene expressions decreased. The increase in Grp78, Grp94, HMOX1 and MTJ1 gene expression was greater in groups in which dex was administered in combination with PBA than in groups in which dex was administered alone. Dex in low dose (0.1 microM) caused a decrease in CHOP expression in HEp2 cells and an increase in Grp78 expression, in particular. The changes in UPR genes expressions may lead to the extended survival of the cells. PMID- 24772976 TI - Binding chemistry and molecular heterogeneity of neurotensin binding protein(s)/receptor in adult chicken tissues. AB - The study focuses on the importance of Tyr11 amino acid (AA) and subsequent stereochemistry involved in the binding process of neurotensin (NT) with its receptor (NTR)/binding protein(s) as well as the size heterogeneity. Using the binding of 125I-NT with several chicken tissues, it is identified that one of the crucial factors behind all high affinity (Kd -10 pM) interactions is due to phenolic-OH (D-OH) at the para (p) position of Tyr11 within RRPYIL-CO2H (NT8-13) sequence. Replacing the p-OH only in Tyr11 by substituting with p-C1, p-F and p NH2 results in significant change of the binding affinity (Kd); p-OH approximately equal p-NH2 (approximately 10 pM), p-Cl (approximately 100 pM), p-F (approximately 120 pM). Interestingly, p-NH2 equals to p-OH displaying the highest affinity. Experiments conducted by binding several of the 125I-azido-NT analogs having azido group attached at different positions within the NT molecule have further confirmed the necessity of RRPYIL sequence for high affinity ligand receptor interaction. The role of Tryp11 in place of Tyr11 in addition to the results above establishes a significant possibility of H-bonding occurring between p-OH of NT and NTR inside the docking space. Photo labeling of the liver tissue by substituted 125I-Y3-azido-NT analogs shows several specifically labeled bands with considerable range of molecular weight (Mr approximately 90-30 kDa) variations. These results indicate the existence of molecular heterogeneity concerning the sizes of NTR or else any NT binding proteins in the avian tissues. Further, the study has revealed that besides liver, several other chicken tissues also express similar specific high affinity binding (Kd approximately 20 pM) with varying capacities (Bmax). The order for Bmax is: liver (1.2 pMol/mg) > or = gall bladder (1.03 pMol/mg) > spleen (0.43 pMol/mg) > brain (0.3 pMol/mg) > colon > or = lung (0.15 pMol/mg). In all cases, the binding was reduced by GTPgammaS (ED50 to approximately 0.05 nM), NEM (ED50 to approximately 0.50 mM) and NaCl (ED50 to approximately 30 mM), indicating the existence of NTR identical to the mammalian type-1. PMID- 24772977 TI - Anti-carcinogenic potential of Euphorbia neriifolia leaves and isolated flavonoid against N-nitrosodiethylamine-induced renal carcinogenesis in mice. AB - Anti-carcinogenic potential of hydro-ethanolic extract of Euphorbia neriifolia (EN) leaves and an isolated flavonoid (ENF) was investigated against N Nitrosodiethylamine (DENA)-induced renal carcinogenesis in mice. Experimental mice were pretreated with 150 and 400 mg/kg body wt of EN, 0.5% and 1% mg/kg body wt of butylated hydroxylanisole (BHA) as a standard antioxidant and 50 mg/kg body wt of ENF for 21 days prior to the administration of a single dose of 50 mg/kg body wt of DENA. Levels of renal markers (urea and creatinine), xenobiotic metabolic enzymes (Cyt P450 and Cyt b5), lipid peroxidation (LPO), antioxidants (SOD, CAT, GST and GSH) and other biochemical parameters--AST, ALT, ALP, total protein (TP), and total cholesterol (TC) were measured to determine the renal carcinogenesis caused by DENA. DENA administration significantly (p < 0.001) decreased the body weight and increased the tissue weight. It significantly (p < 0.001) enhanced the levels of Cyt P450, Cyt b5 and LPO and decreased the levels of SOD, CAT, GST and GSH content. The activities of AST, ALT and ALP and the TP content and renal markers were also significantly decreased (p < 0.001), while TC level was markedly increased after DENA administration, as compared with the normal control group (p < 0.001). Pretreatment with EN and ENF counteracted DENA induced oxidative stress (LPO) and exerted its protective effects by restoring the levels of antioxidants (SOD, CAT, GST and GSH), biochemical parameters (AST, ALT, ALP, TP and TC), renal markers (urea and creatinine) and xenobiotic enzymes (Cyt P450 and Cyt b5) in renal tissue. In conclusion, the present study showed significant anti-carcinogenic potential of the hydro-ethanolic extract of E. neriifolia and ENF against DENA-induced renal carcinogenicity. PMID- 24772978 TI - Inhibitory effect of Piper betle Linn. leaf extract on protein glycation- quantification and characterization of the antiglycation components. AB - Piper betle Linn. is a Pan-Asiatic plant having several beneficial properties. Protein glycation and advanced glycation end products (AGEs) formation are associated with different pathophysiological conditions, including diabetes mellitus. Our study aims to find the effect of methanolic extract of P. betle leaves on in vitro protein glycation in bovine serum albumin (BSA)-glucose model. The extract inhibits glucose-induced glycation, thiol group modification and carbonyl formation in BSA in dose-dependent manner. It inhibits different stages of protein glycation, as demonstrated by using glycation models: hemoglobin-delta gluconolactone (for early stage, Amadori product formation), BSA-methylglyoxal (for middle stage, formation of oxidative cleavage products) and BSA-glucose (for last stage, formation of AGEs) systems. Several phenolic compounds are isolated from the extract. Considering their relative amounts present in the extract, rutin appears to be the most active antiglycating agent. The extract of P. betle leaf may thus have beneficial effect in preventing protein glycation and associated complications in pathological conditions. PMID- 24772979 TI - Characterization and expression of codon optimized soybean phytase gene in E. coli. AB - Phytic acid, the major storage form of phosphorus in plant seeds is degraded by the phytases to yield inositol and free phosphate, contributing thereby to the improved bioavailability of phytate phosphorus and essential minerals in plant foods and simultaneous reduction in phosphorus pollution of the terrestrial and aquatic ecosystems. As a possible strategy for altering seed phytate levels, the approach involving reduction of phytate content by ectopically expressing endogenous phytase gene during seed development of soybean (Glycine max L. cv. Pusa-20) was attempted in the present study. Semi-quantitative RT-PCR revealed the maximum expression of phytase gene transcripts in germinating cotyledons (approximately 10 days after germinations), compared to other vegetative tissues. A full-length phytase cDNA was amplified from the germinating seedlings by splicing by overlap extension (SOE)-PCR and its sequence analysis revealed an open-reading-frame of 1644 bp, including an N terminal signal peptide of 28 amino acids. Predicted amino acid sequence (547-aa) of molecular mass 62 kDa on alignment with related purple acid phosphatases in other plants shared five conserved domains and seven invariant amino acids involved in coordination of the metals in the binuclear center of purple acid phosphatases. Owing to a large number of E. coli low-usage codons in soybean phytase gene, the modified gene was cloned into a prokaryotic expression vector pET-28a (+) and its expression in E. coli was confirmed by SDS-PAGE and Western blot analysis. Bioassay of the crude expression product in E. coli revealed a functional phytase gene, showing a great potential for developing low phytate transgenic soybean through its seed-specific overexpression in the early stages of seed development. PMID- 24772980 TI - Carotenoid genes transcriptional regulation for astaxanthin accumulation in fresh water unicellular alga Haematococcus pluvialis by gibberellin A3 (GA3). AB - The fresh water unicellular alga Haematococcus pluvialis is a promising natural source of astaxanthin. The present study investigated the transcriptional expression of carotenoid genes for astaxanthin accumulation in H. pluvialis using real-time fluorescence quantitative PCR (qRT-PCR). With treatments of 20 and 40 mg/L of gibberllin A3 (GA3), five genes ipi-1, ipi-2, psy, pds and bkt2 were up regulated with different expression profiles. GA20 (20 mg/L of GA3) treatment had a greater effect on transcriptional expression of bkt2 than on ipi-1 ipi-2, psy and pds (> 4-fold up-regulation). However, GA40 (40 mg/L of GA3) induced more transcriptional expression of ipi-2, psy and bkt2 than both ipi-1 and pds. The expression of lyc, crtR-B and crtO for astaxanthin biosynthesis was not affected by GA3 in H. piuvialis. In the presence of GA3, astaxanthin biosynthesis genes of ipi-1, pds and bkt2 were up-regulated at transcriptional level, psy at post transcriptional level, whereas ipi-2 was up-regulated at both levels. The study could potentially lead to a scale application of exogenous GA3 in astaxanthin production with H. pluvialis just like GAs perform in increasing crops production and it would provide new insight about the multifunctional roles of carotenogenesis in response to GA3. PMID- 24772981 TI - Purification and characterization of 6-phosphogluconate dehydrogenase (6-PGD) from grass carp (Ctenopharyngodon idella) hepatopancreas. AB - 6-Phosphogluconate dehydrogenase (6-PGD, E.C.: 1.1.1.44) was purified and characterized from the hepatopancreas of grass carp (Ctenopharyngodon idella) for the first time. Grass carp represents the second largest aquaculture industry in the world after silver carp, constituting 14.7% of the world aquaculture production, with an average annual increase of 14% in China, mainly as a source of food. The purification procedure involved a single 2', 5'-ADP-Sepharose 4B affinity chromatographic step by using different elution buffers. The enzyme was purified 309-fold with a specific activity of 5.259 U/mg protein and yield of 68%. The purity and subunit molecular weights of the 6-PGD were checked on SDS PAGE and purified enzyme showed a single band on the gel. The subunit molecular mass was 57 kDa, with an optimum pH, temperature and ionic strength at 7.96, 50 degrees C and 100 mM Tris-HCl, respectively. The Km values of 6-PGA and NADP+ were 0.019 and 0.0052 mM, respectively, while Vm of 6-PGA and NADP+ was 0.69 U/ml. Dissociation constants (Ki) for 6-PGA and NADP+ were 2.05 and 0.12 mM, respectively. NADPH inhibited the enzyme in a competitive manner and its Ki value was 0.032 mM. The Cu2+, Zn2+, Cd2+ and Al3+ showed inhibitory effects on the enzyme with IC50 values of 0.293, 0.099, 0.045 and 1.526 mM, respectively. All tested metals inhibited the enzyme in a competitive manner, indicating that these metals might be toxic even at low concentrations for the 6-PGD. As the fish is one of valuable foodstuff of animal sources for human consumption, under certain environmental conditions, metal ions accumulated in fish up to a lethal concentration may be harmful for human health. Therefore, it is impending to reduce the concentration of metal ions in contaminated lakes and rivers for fishery and also for human health. PMID- 24772982 TI - Purification and characterization of structural and functional properties of two lectins from a marine sponge Spheciospongia vesparia. AB - The purification, structural and functional characterization of two different lectins (named Svl-1 and Svl-2) has been reported from the marine sponge Spheciospongia vesparia. Purification procedure includes ammonium sulfate precipitation, combined with chromatography including Octyl-Sepharose-(NH4)SO4 hydrophobic column and DEAE-Toyopearl anion-exchange column using a high performance liquid chromatography. The similarities in function, specificity for saccharides, molecular weight, amino acid content and the N-terminal sequence of two lectins suggest that these proteins are isolectins. Amino acid composition and fluorescence analyses reveal that they contain an intrachain disulfide bridge, which might contribute to their high thermal stability. Furthermore, the purified lectins exhibit antibacterial activity against the gram-negative bacteria Pseudomonas aeruginosa and E. coli, indicating that they may be involved in a recognition strategy and may play a role in the defense response function of the sponge. This is the first report on the isolation of lectins from the S. vesparia. The purified lectins represent a potential possible candidate for future application in the recognition or treatment of cancer cells. PMID- 24772983 TI - Study of reaction parameters and kinetics of esterification of lauric acid with butanol by immobilized Candida antarctica lipase. AB - Esterification of lauric acid with n-butanol, catalyzed by immobilized Candida antarctica lipase (CAL) in aqueous-organic biphasic solvent system was studied. Effects of various reaction parameters on esterification were investigated, such as type and amount of solvent, amount of buffer, pH, temperature, speed of agitation, amount of enzyme, butanol and lauric acid. The most suitable reaction conditions for esterification were observed at 50 degrees C and pH 7.0 using 5000 micromoles of lauric acid, 7000 pmoles of butanol, 0.25 ml phosphate buffer, 1 ml of isooctane as the solvent and 50 mg of immobilized enzyme in the reaction medium at agitation speed of 150 rpm. Maximum esterification of 96.36% was acheived in 600 min of reaction time at n-butanol to lauric acid molar ratio of 1: 0.7. Kinetic study for the esterification of lauric acid with n-butanol using immobilized CAL was carried out and the kinetic constants were estimated by using non-linear regression method. The estimated value of Michaelis kinetic constants for butanol (KmBt) and acid (KmAc) were 451.56 (M) and 4.7 x 10(-7)(M), respectively and the value of dissociation constant (KBt) of the butanol-lipase complex was 9.41 x 10(7)(M). The estimated constants agreed fairly well with literature data. PMID- 24772984 TI - It is more than cosmetric: why accuracy counts with post-nominal. PMID- 24772985 TI - 'eSimulation'. Part 2: Evaluation of an interactive multimedia mental health education program for generalist nurses. AB - This paper reports on an evaluation of an eSimulation mental health education program for generalist nurses; developed using the following five key attributes of simulation: (1) creating a hypothetical opportunity; (2) authentic representation; (3) active participation; (4) integration; (5) repetition, evaluation and reflection. Four themes emerged from a qualitative thematic analysis of semi-structured interview data involving fourteen generalist nurses. The following four themes: (1) authenticity; (2) participation; (3) clinical reasoning; (4) control of learning provide supporting evidence that these attributes are positioned within the learning resource. Participants found the scenarios within the resource realistic, engaging and relevant to their scope of practice. This type of learning resource may help in developing the knowledge, skills and confidence of generalist nurses in delivering safe and competent mental health care in the generalist setting, when access to specialist services and appropriate means of training are unavailable. PMID- 24772986 TI - Factors influencing the stages of breast cancer at the time of diagnosis in Thai women. AB - BACKGROUND: Early diagnosis of breast cancer leads to early treatment therefore improving women's health. However, most Thai women are diagnosed at a late stage. OBJECTIVE: This cross-sectional correlational study was designed to explore factors influencing the diagnosis of early stage breast cancer in Thai women. METHOD: Thai women (n = 400) newly diagnosed breast cancer at all clinical stages from public hospitals in Bangkok Metropolitan completed a questionnaire about knowledge of breast cancer and screening. The questionnaire addressed pre diagnosis data about: (1) health care provider's recommendations to undertake breast screening, (2) health coverage for mammography (MM) costs and (3) regularity of breast screening behaviors in terms of breast self-examination (BSE), clinical breast examination (CBE) and MM including stage breast cancer at diagnosis. Data analysis was determined by PASW Statistics version 18 as univariate and multivariate logistic regression. RESULTS: Health coverage for MM costs and all three behaviors were significantly related to and could predict the early stages breast cancer at diagnosis (p < 0.05): health coverage for MM costs (OR = 0.32, 95% confidence interval [CI], 0.17-0.63), BSE (OR = 8.08, CI 95%, 3.93-16.63), CBE (OR = 12.54, CI 95%, 2.29-68.65) and MM (OR = 5.89, CL 95%, 1.13 30.73). CONCLUSIONS: All three behaviors are essential and related to one another. CBE on a regular basis is the best predictor for early stages breast cancer at diagnosis in Thai context. Nurses should provide information and teach including re-check the woman's skills to perform BSE regularly. PMID- 24772987 TI - The foster carer's experience: an integrative review. AB - BACKGROUND: Foster carers have a significant responsibility in caring for children who are unable to live with their birth families and represent a key determinant in child outcomes. Difficulties in recruiting and retaining quality foster carers have resulted in an increase in research investigating foster carers and their experiences in recent years. AIM: To synthesise current literature investigating foster carers and their experiences to enable a better understanding of their unique care-giving context. METHOD: The electronic databases CINAHL, Health Source, MEDLINE, Pscyh-articles, PsycINFO and socilNDEX were searched using the key terms; 'foster carer', 'foster parent', 'foster mother' and 'foster father'. Articles were included if they reported primary data about foster carers experiences in the English language. Papers published prior to 2000 were excluded in order to provide a contemporary perspective of the foster carer experience. Data was extracted, tabulated and thematically analysed. FINDINGS: The findings from this review revealed the provision of foster care to have both positive and negative effects on foster carers personal well-being. These effects are largely reliant of foster carers perception of their role as either parental or professional, the nature of their relationships with child welfare personnel, and their ability to manage children's difficult behaviours. CONCLUSION: It is important for nurses to understand caregiving as it occurs in a variety of contexts. Nurses need to have an awareness and understanding of the value and role foster carers have in the lives of vulnerable children. In so doing, nurses are well positioned to assist foster carers to identify and express their needs in relation to their important caregiving role. PMID- 24772988 TI - Asthma self management in adults: a review of current literature. AB - Self management programs for chronic conditions, such as asthma, have an important place in healthcare delivery. When properly implemented, they can curb the impact of disease and reduce both the high personal costs for individuals and significant financial costs for health care systems. The purpose of this review was to establish an understanding of current published literature on asthma self management programs in adults and to identify any reported attributes or components which serve to either assist or obstruct the uptake of self management strategies. Electronic data sources including Scopus, Proquest 5000, CINAHL, PubMed and Web of Science were accessed and literature searches were conducted using the key terms: asthma, chronic disease, self management, morbidity, quality of life, health outcomes, patient education and best practice. Inclusion criteria for the search included journal articles relating to adults with asthma published in English in peer reviewed journals from 1995 to 2011. Exclusion criteria included research targeting children, parents of children or families; and articles examining Asthma and COPD (or any other co-morbidity). Sixty four articles were included in this review due to their relevance to the major components of asthma self management, as defined by the Australian Asthma Management Handbook. A major conclusion from this review was that the uptake of asthma self management strategies is poor despite global recommendations for over twenty years; and that a likely reason for this is that generic asthma self management advice does not engage the individual with asthma. PMID- 24772989 TI - Cluster randomised controlled trial: educational self-care intervention with older Taiwanese patients with type 2 diabetes mellitus--impact on blood glucose levels and diabetic complications. AB - AIMS: To investigate whether self care behaviours, medical outcomes and quality of life of Taiwanese elderly with Type 2 diabetes mellitus (DM) can be improved by delivery of an educational health care package. BACKGROUND: DM is a major health problem in developed and developing countries, with older adults constituting about half of the diabetic population. Type 2 DM is the most rapidly increasing chronic disease in Taiwan. METHODS: During 2005 and 2006, Taiwanese elderly with Type 2 DM (n = 500) were randomly allocated to either an intervention or control group. Data collection using validated instruments occurred at baseline and 6 months follow-up. Main outcome measures were blood glucose levels and diabetic complications. RESULTS: At baseline, 88.4% participants in the control and 78.8% in the experimental group had a blood glucose level above normal range (p = 0.076); respective results at 6 months were 92.4% for the control group and 60.4% for the experimental group (p < 0.001). The multivariate adjusted result showed that the intervention group was 11.1 times less likely to have blood glucose levels above normal (p = 0.002) at 6 months follow-up compared to the control group. Occurrence of complications was significantly fewer in the intervention group at baseline and at 6 month follow up compared to the control group (baseline: 42.0% versus 82.1%, p = 0.003; 6 month follow-up: 48.4% versus 87.0%; p = 0.006). CONCLUSION: Although overall occurrence of complications remained unchanged, the educational health care package specifically developed for Taiwanese elderly with Type 2 DM improved blood glucose levels. PMID- 24772990 TI - Professional regulation, public protection and nurse migration. AB - Nurse mobility, developments such as health tourism and the rapid expansion of health systems have increased the need for regulatory bodies to reach beyond their normal stakeholder groups so as to familiarize themselves with the legislation of other jurisdictions. PURPOSE: A systematic examination of a cross section of nursing legislation, to ascertain the degree of consistency in the number of definitions specified as well as their underlying structure, was conducted to identify opportunities to strengthen public protection and reduce barriers to freedom of movement. METHOD: A purposeful sample of legislation, drawn to maximize differences, was subjected to documentary analysis to identify possible relationships between the variables of interest and the way terms and processes were defined in fourteen nurse practice acts. RESULTS: Potential relationships were identified between factors such as geographic region, legal tradition, administrative approach, regulatory model and economic status and the number and approaches used to specify definitions. A major weakness in the precision of definitions was discovered. DISCUSSION: Several international organizations have started to develop lexicons but all have weaknesses. By drawing upon these lexicons a more comprehensive and precise dictionary could be formulated to support the development of next-generation nurse practice acts. CONCLUSIONS: Current legislation lacks precision and, within the context of increased mobility of nurses, there is an urgent need to develop an authoritative source of definitions that can contribute to increasing public safety as well as reducing delays in the freedom of movement of nurses from one jurisdiction to another. PMID- 24772991 TI - Looking up to the sky! An exploration of new graduate nurses' perceptions of remote area nursing. AB - Remote area nursing is characterised by two known realities: health inequalities and nursing challenges. The health inequalities are complex consequences of social determinants and health care access. Remote area nurses must negotiate these realities that powerfully interact. Yet we, as new graduate nurses, contemplate a remote area nursing career pathway with additional points of view, including a strong attraction to the long-lasting image of the 'Flying Nurse' within aero medical remote health services. This image holds for us the possibilities of excitement, drama, vital service, and intensive care. This paper explores the realities of this career attraction, and consequently explores the aspirations of contemplative new graduate nurses, as they assimilate their knowledge of remote area nursing with their plans for their future transitions into nursing practice. PMID- 24772992 TI - Cues that predict violence in the hospital setting: findings from an observational study. AB - BACKGROUND: The prevalence of violent acts in the health care environment has been the cause of increasing concern. Several cues associated with violence towards nurses in the acute care setting have been identified qualitatively. However, larger scale observational studies to determine the potential of these cues to predict physical violence, are lacking in the acute health setting. PURPOSE: To report an observational study determining whether particular behavioural cues are predictive of patient-to-nurse physical violence. METHOD: Non-participant structured observations. DISCUSSION: Clinical observation (n = 1150 h) resulted in 1501 observed cues for violence in 220 patients; 36 of whom were observed to become violent. Five (5) behavioural cues were found to predict violent acts. CONCLUSIONS: Findings suggest five behavioural cues could be used to assess potential physical violence. Additional research needs to be undertaken to further validate the efficacy of these cues in the acute hospital setting. PMID- 24772993 TI - Physical and psychosocial wellbeing of nurses in a regional Queensland hospital. AB - Occupational stress is common among nurses. Two factors that may influence stress levels are diet and physical activity. The purpose of this study was to investigate the diets and physical activity levels of nurses and to quantify the relationships between these behaviours and anxiety, depressed mood, stress, and burnout. Nurses (N = 52) from one regional hospital completed a survey assessing physical activity, nutrition, and psychological functioning. Almost two-thirds (65%) of participants had met recommended levels of both moderate and vigorous physical activity in the week prior. Participants met recommended levels for fruit, but not vegetable, consumption. Burnout and stress levels were close to norms for physicians and nurses. Scores for depressed mood, anxiety, and stress symptoms were within one standard deviation of norms for the Australian adult population. Several moderately sized correlations were found between the psychological constructs measured and both physical activity and nutrition. Although most of the participants were physically active and seemed to be consuming nutritious diets, some nurses may need encouragement to adopt similarly healthy behaviours. PMID- 24772994 TI - Development and application of 3-chloro-1,2-propandiol electrochemical sensor based on a polyaminothiophenol modified molecularly imprinted film. AB - In this work, a novel electrochemical sensor for 3-chloro-1,2-propandiol (3-MCPD) detection based on a gold nanoparticle-modified glassy carbon electrode (AuNP/GCE) coated with a molecular imprinted polymer (MIP) film was constructed. p-Aminothiophenol (p-ATP) and 3-MCPD were self-assembled on a AuNP/GCE surface, and then a MIP film was formed by electropolymerization. The 3-MCPD template combined with p-ATP during self-assembly and electropolymerization, and the cavities matching 3-MCPD remained after the removal of the template. The MIP sensor was characterized by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and scanning electron microscopy (SEM). Many factors that affected the performance of the MIP membrane were discussed and optimized. Under optimal conditions, the DPV current was linear with the log of the 3-MCPD concentration in the range from 1.0 * 10(-17) to 1.0 * 10(-13) mol L(-1) (R(2) = 0.9939), and the detection limit was 3.8 * 10(-18) mol L(-1) (S/N = 3). The average recovery rate of 3-MCPD from spiked soy sauce samples ranged from 95.0% to 106.4% (RSD < 3.49%). Practically, the sensor showed high sensitivity, good selectivity, excellent reproducibility, and stability during the quantitative determination of 3-MCPD. PMID- 24772995 TI - A 3D analysis of the joint torques developed during driver's ingress-egress motion. AB - Providing an easy ingress-egress (I/E) movement remains a challenge for car designers. I/E has been largely studied in kinematics, but not in dynamics. This study proposes: (1) to evaluate and describe the motor torques developed in the lower limbs and lumbar joints during I/E motions and (2) to analyse the influence of the car geometry and subject anthropometry. An experiment was performed to observe 15 subjects of three anthropometrical groups getting in and out of a car mock-up simulating three different vehicle configurations. Motor torques were extracted using an inverse dynamics analysis. Both ingress and egress motions were primarily characterised by large torques. Overall, the taller a subject and the lower the seat of the vehicle were, the larger the peak torques were. Moreover, peak torques were higher for egress than ingress. These results are discussed in regard to the current knowledge on I/E ergonomics. PRACTITIONER SUMMARY: Car ingress-egress (I/E) is an ergonomics challenge. Little is known about the physical efforts developed in this motion. Developed motor torques were experimentally assessed for three anthropometrical groups and vehicle configurations. Results obtained were discussed in regard to the current knowledge on I/E ergonomics. PMID- 24772996 TI - Nanomechanical molecular devices made of DNA origami. AB - CONSPECTUS: Eight years have passed since the striking debut of the DNA origami technique ( Rothemund, P. W. K. Nature 2006 , 440 , 297 - 302 ), in which long single-stranded DNA is folded into a designed nanostructure, in either 2D or 3D, with the aid of many short staple strands. The number of proposals for new design principles for DNA origami structures seems to have already reached a peak. It is apparent that DNA origami study is now entering the second phase of creating practical applications. The development of functional nanomechanical molecular devices using the DNA origami technique is one such application attracting significant interest from researchers in the field. Nanomechanical DNA origami devices, which maintain the characteristics of DNA origami structures, have various advantages over conventional DNA nanomachines. Comparatively high assembly yield, relatively large size visible via atomic force microscopy (AFM) or transmission electron microscopy (TEM), and the capability to assemble multiple functional groups with precision using multiple staple strands are some of the advantages of the DNA origami technique for constructing sophisticated molecular devices. This Account describes the recent developments of such nanomechanical DNA origami devices and reviews the emerging target of DNA origami studies. First, simple "dynamic" DNA origami structures with transformation capability, such as DNA origami boxes and a DNA origami hatch with structure control, are briefly summarized. More elaborate nanomechanical DNA origami devices are then reviewed. The first example describes DNA origami pinching devices that can be used as "single-molecule" beacons to detect a variety of biorelated molecules, from metal ions at the size of a few tens of atomic mass number units to relatively gigantic proteins with a molecular mass greater than a hundred kilodaltons, all on a single platform. Clamshell-like DNA nanorobots equipped with logic gates can discriminate different cell lines, open their shell, and bind to their target. An intelligent DNA origami "sheath" can mimic the function of suppressors in a transcription regulation system to control the expression of a loaded gene. DNA origami "rolls" are created to construct precisely arranged plasmonic devices with metal nanoparticles. All of their functions are derived from their nanomechanical movement, which is programmable by designing the DNA sequence or by using the significant repository of technical achievements in nucleic acid chemistry. Finally, some studies on detailed structural parameters of DNA origami or their mechanical properties in nanoscale are discussed, which may be useful and inspiring for readers who intend to design new nanomechanical DNA origami devices. PMID- 24772997 TI - A multicriteria decision analysis model and risk assessment framework for carbon capture and storage. AB - Multicriteria decision analysis (MCDA) has been applied to various energy problems to incorporate a variety of qualitative and quantitative criteria, usually spanning environmental, social, engineering, and economic fields. MCDA and associated methods such as life-cycle assessments and cost-benefit analysis can also include risk analysis to address uncertainties in criteria estimates. One technology now being assessed to help mitigate climate change is carbon capture and storage (CCS). CCS is a new process that captures CO2 emissions from fossil-fueled power plants and injects them into geological reservoirs for storage. It presents a unique challenge to decisionmakers (DMs) due to its technical complexity, range of environmental, social, and economic impacts, variety of stakeholders, and long time spans. The authors have developed a risk assessment model using a MCDA approach for CCS decisions such as selecting between CO2 storage locations and choosing among different mitigation actions for reducing risks. The model includes uncertainty measures for several factors, utility curve representations of all variables, Monte Carlo simulation, and sensitivity analysis. This article uses a CCS scenario example to demonstrate the development and application of the model based on data derived from published articles and publicly available sources. The model allows high-level DMs to better understand project risks and the tradeoffs inherent in modern, complex energy decisions. PMID- 24772998 TI - Genetic polymorphisms in the ESR1 gene and cerebral infarction risk: a meta analysis. AB - A number of studies have documented that estrogen receptor alpha (ESR1) may play an important role in the development and progression of cerebral infarction, but many existing studies have yielded inconclusive results. This meta-analysis was performed to evaluate the relationships between ESR1 genetic polymorphisms and cerebral infarction risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before October 1, 2013, without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Seven case-control studies were included with a total of 1471 patients with cerebral infarction and 4688 healthy control subjects. Two common single-nucleotide polymorphisms (SNPs) in the ESR1 gene (rs2234693 T>C and rs9340799 A>G) were assessed. Our meta analysis results revealed that ESR1 genetic polymorphisms might increase the risk of cerebral infarction. Subgroup analysis by SNP type indicated that both rs2234693 and rs9340799 polymorphisms in the ESR1 gene were strongly associated with an increased risk of cerebral infarction. Further subgroup analysis by ethnicity showed significant associations between ESR1 genetic polymorphisms and increased risk of cerebral infarction among both Asians and Caucasians. In the stratified subgroup analysis by gender, the results suggested that ESR1 genetic polymorphisms were associated with an increased risk of cerebral infarction in the female population. However, there were no statistically significant associations between ESR1 genetic polymorphisms and cerebral infarction risk in the male population. Meta-regression analyses also confirmed that gender might be a main source of heterogeneity. Our findings indicate that ESR1 genetic polymorphisms may contribute to the development of cerebral infarction, especially in the female population. PMID- 24772999 TI - Rhodium-catalyzed asymmetric tandem cyclization for efficient and rapid access to underexplored heterocyclic tertiary allylic alcohols containing a tetrasubstituted olefin. AB - The first Rh-catalyzed asymmetric tandem cyclization of nitrogen- or oxygen bridged 5-alkynones with arylboronic acids was achieved. The simple catalytic system involving a rhodium(I) complex with readily available chiral BINAP ligand promotes the reaction to proceed in a highly stereocontrolled manner. This protocol provides a very reliable and practical access to a variety of chiral heterocyclic tertiary allylic alcohols possessing a tetrasubstituted carbon stereocenter and an all-carbon tetrasubstituted olefin functionality in good yields with great enantioselectivities up to 99% ee. PMID- 24773000 TI - Tunable fictitious substituent effects on the pi-pi interactions of substituted sandwich benzene dimers. AB - Substituent effects on the pi-pi interactions of aromatic rings are a topic of much recent debate. Real substituents give a complicated combination of inductive, resonant, dispersion, and other effects. To help partition these effects, we present calculations on fictitious "pure" sigma donor/acceptor substituents, hydrogen atoms with nuclear charges other than 1. "Pure" sigma donors with nuclear charge <1 weaken pi-pi stacking in the sandwich benzene dimer. This result is consistent with the electrostatic model of Hunter and Sanders, and different from real substituents. Calculated inductive effects are largely additive and transferable, consistent with a local direct interaction model. A second series of fictitious substituents, neutral hydrogen atoms with an artificially broadened nuclear charge distribution, give similar trends though with reduced additivity. These results provide an alternative perspective on substituent effects in noncovalent interactions. PMID- 24773001 TI - In-depth structural characterization of N-linked glycopeptides using complete derivatization for carboxyl groups followed by positive- and negative-ion tandem mass spectrometry. AB - Tandem mass spectrometry (MS/MS or MS(n)) is a powerful tool for characterizing N linked glycopeptide structures. However, it is still difficult to obtain detailed structural information on the glycan moiety directly from glycopeptide ions. Here, we propose a new method for in-depth analysis of the glycopeptide structure using MS/MS. This method involves complete derivatization of carboxyl groups in glycopeptides. Methylamidation using PyAOP as a condensing reagent has been optimized for derivatizing all carboxyl groups in glycopeptides. By derivatizing carboxyl groups on the peptide moiety (i.e., Asp, Glu, and C-terminus), the glycopeptides efficiently produce informative glycan fragment ions, including the nonreducing end of the glycan moiety under negative-ion collision-induced dissociation (CID) conditions. These glycan fragment ions can define detailed structural features on the glycan moiety (e.g., the specific composition of the two antennae, the location of fucose residues, and the presence/absence of bisecting GlcNAc residues). For sialylated glycopeptides, carboxyl groups on sialic acid residues are simultaneously derivatized using methylamidation, suppressing preferential loss of residues during MS analysis. As a result, both sialylated and nonsialylated glycopeptides can be analyzed in the same manner. Positive-ion CID of methylamine-derivatized glycopeptides mainly provides information on peptide sequence and glycan composition, whereas negative-ion CID provides in-depth structural information on the glycan moiety. The derivatization step can be readily incorporated into conventional pretreatment for glycopeptide MS analysis without loss of sensitivity, making derivatization suitable for practical use. PMID- 24773002 TI - School diversity and racial discrimination among African-American adolescents. AB - The study presented here examined school context as a moderator in the relation between daily perceptions of racial discrimination and depressive symptoms. The sample included 75 Black adolescents who completed daily surveys for 14 days. The results indicated that approximately 97% of adolescents reported experiencing at least one discriminatory experience over the 2-week period. During the daily diary period, the 2-week average was 26 discriminatory experiences with a daily average of 2.5 discriminatory events. The results indicated perceptions of racial discrimination were linked to increased depressive symptoms on the following day. This relation was apparent for Black youth attending predominantly Black and White high schools, but not for Black youth attending schools with no clear racial majority. PMID- 24773003 TI - Ethnic identity, identity coherence, and psychological functioning: testing basic assumptions of the developmental model. AB - The purpose of the present study was to test three fundamental theoretical propositions from Phinney's (1990) developmental model about the relations among ethnic identity, identity coherence, and psychological functioning: (a) ethnic identity is more strongly related to identity coherence for ethnic minorities than for Whites; (b) ethnic identity is more strongly related to psychological functioning for ethnic minorities than for Whites; and (c) identity coherence mediates the association between ethnic identity and psychological functioning for ethnic minorities, but not for Whites. These hypotheses were tested in three independent samples of ethnically diverse youth. In general, we found weak to moderate support for these three hypotheses, suggesting that the theoretically proposed differences in ethnic identity between ethnic minorities and Whites may not be supported by data. Implications for theory and measurement of ethnic identity are discussed. PMID- 24773004 TI - Familism and psychological health: the intervening role of closeness and social support. AB - Familism, a cultural value that emphasizes warm, close, supportive family relationships and that family be prioritized over self, has been associated with psychological health. The goal of this work was to fill a gap in the literature on how familism contributes to psychological health. Drawing from conceptual links between familism and close relationship processes, we hypothesized that familism contributes to better psychological health by facilitating closeness and social support. A university sample of U.S. women and men of Latino (n = 173), European (n = 257), and Asian (n = 642) cultural backgrounds completed measures of familism, closeness to family members, general perceived social support, and psychological health as indexed by perceived stress, general mental health, and depressive symptoms. Structural equation multiple-group modeling analyses found direct effects of familism on closeness to family members and perceived social support and an indirect effect of familism on better psychological health via greater closeness to family members and greater perceived social support. These effects did not differ by cultural background. Consistent with previous research, however, Latinos reported the highest levels of familism of the three cultural groups, and women reported higher familism and support as well as poorer psychological health than men. Discussion is focused on the implications of these findings for understanding the association of familism with psychological health and the relevance of the familism construct for diverse U.S. groups. PMID- 24773005 TI - Through which looking glass? Distinct sources of public regard and self-esteem among first- and second-generation immigrants of color. AB - How we think other people see us has long been believed to influence how we see ourselves, a phenomenon known as reflected appraisal. Among members of ethnic minority groups and immigrant groups, however, inconsistent patterns have been found. This study examined how immigrants' views of their ethnic group and of themselves are tied the appraisals of specific others. We hypothesized that members of the heritage culture and of White Americans are implicated in the reflected appraisal process to differing degrees. Moreover, we hypothesized that immigrants (first-generation) and the children of immigrants (second-generation) are affected differently by the appraisals of White Americans and heritage culture members. Results showed that perceived appraisal by members of the heritage culture was linked to how immigrants felt about their group and to their personal self-esteem. Perceived appraisal of White Americans was not related to how immigrants felt about their group and was only weakly related to personal self-esteem. The results highlight the distinction between public regard from the heritage culture and from White Americans and underscore the importance of the former for immigrants' private regard and self-esteem. PMID- 24773006 TI - The role of collective self-esteem on anxious-depressed symptoms for Asian and Latino children of immigrants. AB - We conducted a 3-wave, longitudinal study to examine the role of ethnic collective self-esteem and United States (U.S.) collective self-esteem on anxious depressed symptoms over time among Asian and Latino immigrant-origin adolescents (n = 171). Growth curve analysis revealed that anxious-depressed symptoms first decreased between 10th and 11th grade and then increased over time for both groups. Additionally higher levels of ethnic collective self-esteem were associated with lower levels of anxious-depressed symptoms only for Asian adolescents. There was a differing pattern for U.S. collective self-esteem such that for Latino adolescents, higher U.S. collective self-esteem was associated with higher anxious-depressed symptoms, whereas for Asian adolescents there was an inverse relationship with anxious-depressed symptoms. The results expand the literature on ethnic and U.S. collective self-esteem and their link to mental health. Implications of the findings for research in general, and for counseling immigrant youth and families in particular, are discussed. PMID- 24773007 TI - Race and bicultural socialization in the Netherlands, Norway, and the United States of America in the adoptions of children from India. AB - A cross-national sample of 622 internationally adopted children from India with White parents in The Netherlands (n = 409), Norway (n = 146), and the United States (n = 67) was used to contrast country-specific bicultural socialization (BCS) practices among families of transracial intercountry adoption. The 3 countries vary in their degrees of minority (US > Netherlands > Norway) and Indian populations (US > Norway > Netherlands). The current study examined parental survey trends among BCS practices, children's negative encounters about adoption, racial and positive discrimination, and parental worry about these issues. Country-specific differences were revealed: The United States and Norway (greatest Indian populations) reported the greatest similarity in BCS practices, classmates being a source of negative reactions/racial discrimination, and parental worry. The American sample encountered greater negative reactions to adoption from others; Dutch children experienced the least negative reactions from others overall, yet as in the United States (samples with the greatest minority heterogeneity) they still noted significant experiences of racial discrimination. Country-specific sociopolitical perceptions about adoption, ethnicity/race, and immigration are considered as factors that may have been used to inform parenting practices that facilitate children's biculturalism into family life (i.e., adoptive family stigma, percentages of Indian/minority populations, immigration policy trends). Concluding, cross-national research such as the current study may help intercountry adoption policymakers and practitioners to better understand and inform BCS practices in adoptive families. PMID- 24773008 TI - Psychological acculturation and juvenile delinquency: comparing Moroccan immigrant families from a general and pretrial detention population. AB - Although several theoretical notions have been proposed predicting a relationship between acculturation orientation and juvenile delinquency, the available empirical research is scarce and limited. To extend former research, in this study, we used latent class analyses to compare bidimensional psychological acculturation orientation of Moroccan immigrant boys in pretrial detention with those of Moroccan boys in the general population. We also examined their parents' acculturation orientation. We found that boys in pretrial detention were clearly overrepresented in the integrated psychological acculturation class and underrepresented in the separated psychological acculturation class when we compared them with the boys in the general population. Highly similar results were found for their parents. In contrast, boys in pretrial detention were as likely to be faced with an intergenerational acculturation gap as boys from the general population. PMID- 24773009 TI - The Cultural Health Attributions Questionnaire (CHAQ): reliability, validity, and refinement. AB - This study describes the reliability and validity of scores on the Cultural Health Attributions Questionnaire (CHAQ), and proposes a refined short form. Murguia, Zea, Reisen, and Peterson (2000) developed the 24-item CHAQ to assess health beliefs among Latinos/Hispanics. The CHAQ incorporates two 12-item subscales: Equity Attributions (EA) and Behavioral-Environmental Attributions (BEA). Although the CHAQ has been published in Spanish and English, psychometric properties have only been evaluated for scores on the Spanish-language version. Participants in the present study were 436 Latinos/Hispanics, half of whom completed the CHAQ in Spanish, and half in English. Multigroup confirmatory factor analysis indicated that the proposed two-factor structure did not fit the data for either language. Subsequent exploratory factor analyses revealed different best-fitting models for the two languages. A common two-factor (EA/BEA) structure was derived from items that loaded univocally in both languages. Additional items were removed to produce a 10-item revised version (CHAQ-R). The two factors were negatively correlated and had good internal consistency reliability. Expected relationships of CHAQ-R scores to acculturation and health locus of control strongly supported convergent validity. The relationship of EA to ethnomedical services usage marginally supported criterion validity. Overall, the results support the reliability and validity of CHAQ-R scores to measure cultural health attributions in Latinos/Hispanics, but further psychometric evaluation is needed. PMID- 24773012 TI - Light-harvesting ability of the fucoxanthin chlorophyll a/c-binding protein associated with photosystem II from the Diatom Chaetoceros gracilis as revealed by picosecond time-resolved fluorescence spectroscopy. AB - The fucoxanthin chlorophyll a/c-binding protein (FCP) is a unique antenna complex possessed by diatoms. Although FCP complexes have been isolated from various diatoms, there is no direct evidence for the existence of FCP associated with photosystem II (FCPII). Here, we report the isolation and spectroscopic characterization of FCPII complex from the diatom Chaetoceros gracilis. The FCPII complex was purified using sucrose centrifugation and anion-exchange chromatography. Clear-native PAGE and SDS-PAGE analyses revealed that the FCPII complex was composed of FCP-A oligomer and FCP-B/C trimer. Time-resolved fluorescence spectra of the FCPII complex were measured at 77 K. The characteristic lifetimes and fluorescence components were determined using global fitting analysis, followed by the construction of fluorescence decay-associated spectra (FDAS). FDAS exhibited fluorescence rises and decays, reflecting excitation energy transfer, with the time constants of 150 ps, 800 ps, and 2.9 ns. The long time constants are most likely attributed to the intercomplex excitation energy transfer between FCP-A oligomer and FCP-B/C trimer in the FCPII complex. The 5.6 ns FDAS likely originates from the final energy traps. In contrast, the FDAS exhibited no quenching component with any time constant. These results indicate that the FCPII complex is efficient in light harvesting and excitation energy transfer. PMID- 24773013 TI - Clearance mechanism assignment and total clearance prediction in human based upon in silico models. AB - We introduce a two-tier model based on an exhaustive data set, where discriminant models based on principal component analysis (PCA) and partial least squares (PLS) are used separately and in conjunction, and we show that PCA is highly discriminant approaching 95% accuracy in the assignment of the primary clearance mechanism. Furthermore, the PLS model achieved a quantitative predictive performance comparable to methods based on scaling of animal data while not requiring the use of either in vivo or in vitro data, thus sparing the use of animal. This is likely the highest performance that can be expected from a computational approach, and further improvements may be difficult to reach. We further offer the medicinal scientist a PCA model to guide in vitro and/or in vivo studies to help limit the use of resources via very rapid computations. PMID- 24773015 TI - Angstrom-precision optical traps and applications. AB - Single-molecule optical-trapping experiments are now resolving the smallest units of motion in biology, including 1-base-pair steps along DNA. This review initially concentrates on the experimental problems with achieving 1-A instrumental stability and the technical advances necessary to overcome these issues. Instrumental advances are complemented by insights in optical-trapping geometry and single-molecule motility assay development to accommodate the elasticity of biological molecules. I then discuss general issues in applying this measurement capability in the context of precision measurements along DNA. Such enhanced optical-trapping assays are revealing the fundamental step sizes of increasingly complex enzymes, as well as informative pauses in enzymatic motion. This information in turn is providing mechanistic insight into kinetic pathways that are difficult to probe by traditional assays. I conclude with a brief discussion of emerging techniques and future directions. PMID- 24773016 TI - Metals in protein-protein interfaces. AB - From the catalytic reactions that sustain the global oxygen, nitrogen, and carbon cycles to the stabilization of DNA processing proteins, transition metal ions and metallocofactors play key roles in biology. Although the exquisite interplay between metal ions and protein scaffolds has been studied extensively, the fact that the biological roles of the metals often stem from their placement in the interfaces between proteins and protein subunits is not always recognized. Interfacial metal ions stabilize permanent or transient protein-protein interactions, enable protein complexes involved in cellular signaling to adopt distinct conformations in response to environmental stimuli, and catalyze challenging chemical reactions that are uniquely performed by multisubunit protein complexes. This review provides a structural survey of transition metal ions and metallocofactors found in protein-protein interfaces, along with a series of selected examples that illustrate their diverse biological utility and significance. PMID- 24773014 TI - Structural and functional insights to ubiquitin-like protein conjugation. AB - Attachment of ubiquitin (Ub) and ubiquitin-like proteins (Ubls) to cellular proteins regulates numerous cellular processes including transcription, the cell cycle, stress responses, DNA repair, apoptosis, immune responses, and autophagy, to name a few. The mechanistically parallel but functionally distinct conjugation pathways typically require the concerted activities of three types of protein: E1 Ubl-activating enzymes, E2 Ubl carrier proteins, and E3 Ubl ligases. E1 enzymes initiate pathway specificity for each cascade by recognizing and activating cognate Ubls, followed by catalyzing Ubl transfer to cognate E2 protein(s). Under certain circumstances, the E2 Ubl complex can direct ligation to the target protein, but most often requires the cooperative activity of E3 ligases. Reviewed here are recent structural and functional studies that improve our mechanistic understanding of E1-, E2-, and E3-mediated Ubl conjugation. PMID- 24773017 TI - Bringing bioelectricity to light. AB - Any bilayer lipid membrane can support a membrane voltage. The combination of optical perturbation and optical readout of membrane voltage opens the door to studies of electrophysiology in a huge variety of systems previously inaccessible to electrode-based measurements. Yet, the application of optogenetic electrophysiology requires careful reconsideration of the fundamentals of bioelectricity. Rules of thumb appropriate for neuroscience and cardiology may not apply in systems with dramatically different sizes, lipid compositions, charge carriers, or protein machinery. Optogenetic tools are not electrodes; thus, optical and electrode-based measurements have different quirks. Here we review the fundamental aspects of bioelectricity with the aim of laying a conceptual framework for all-optical electrophysiology. PMID- 24773018 TI - The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. AB - Mutations in any of at least sixteen FANC genes (FANCA-Q) cause Fanconi anemia, a disorder characterized by sensitivity to DNA interstrand crosslinking agents. The clinical features of cytopenia, developmental defects, and tumor predisposition are similar in each group, suggesting that the gene products participate in a common pathway. The Fanconi anemia DNA repair pathway consists of an anchor complex that recognizes damage caused by interstrand crosslinks, a multisubunit ubiquitin ligase that monoubiquitinates two substrates, and several downstream repair proteins including nucleases and homologous recombination enzymes. We review progress in the use of structural and biochemical approaches to understanding how each FANC protein functions in this pathway. PMID- 24773023 TI - Ventricular septal defect. PMID- 24773024 TI - Conflict of interest and privilege in clinical and medicolegal photography: a short summary. AB - Abstract A clinical photographer's work can have legal consequences. Conflict of interest and privilege are two areas where this can be observed. As healthcare professionals we need to be aware of the impact of the law on our professional practice. PMID- 24773019 TI - Microfluidics expanding the frontiers of microbial ecology. AB - Microfluidics has significantly contributed to the expansion of the frontiers of microbial ecology over the past decade by allowing researchers to observe the behaviors of microbes in highly controlled microenvironments, across scales from a single cell to mixed communities. Spatially and temporally varying distributions of organisms and chemical cues that mimic natural microbial habitats can now be established by exploiting physics at the micrometer scale and by incorporating structures with specific geometries and materials. In this article, we review applications of microfluidics that have resulted in insightful discoveries on fundamental aspects of microbial life, ranging from growth and sensing to cell-cell interactions and population dynamics. We anticipate that this flexible multidisciplinary technology will continue to facilitate discoveries regarding the ecology of microorganisms and help uncover strategies to control microbial processes such as biofilm formation and antibiotic resistance. PMID- 24773020 TI - Eye tracking as a measure of receptive vocabulary in children with autism spectrum disorders. AB - This study examined the utility of eye tracking research technology to measure speech comprehension in 14 young boys with autism spectrum disorders (ASD) and 15 developmentally matched boys with typical development. Using eye tracking research technology, children were tested on individualized sets of known and unknown words, identified based on their performance on the Peabody Picture Vocabulary Test. Children in both groups spent a significantly longer amount of time looking at the target picture when previous testing indicated the word was known (known condition). Children with ASD spent similar amounts of time looking at the target and non-target pictures when previous testing indicated the word was unknown (unknown condition). However, children with typical development looked longer at the target pictures in the unknown condition as well, potentially suggesting emergent vocabulary knowledge. PMID- 24773026 TI - Abatacept (cytotoxic T lymphocyte antigen 4-immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non-responding to anti-tumour necrosis factor-alpha agents. AB - The use of biological agents combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients has strongly improved disease outcome. In this study, the effects of abatacept on the size and function of circulating B and T cells in RA patients not responding to anti-tumour necrosis factor (TNF)-alpha have been analysed, with the aim of identifying immunological parameters helpful to choosing suitable tailored therapies. We analysed the frequency of peripheral B and T cell subsets, B cell function and T regulatory cell (Treg ) inhibitory function in 20 moderate/severe RA patients, according to the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, primary non-responders to one TNF-alpha blocking agent, who received abatacept + MTX. Patients were studied before and 6 months after therapy. We found that abatacept therapy significantly reduced disease activity score on 44 joints (DAS)/erythrocyte sedimentation rate (ESR) values without causing severe side effects. The size of the circulating B and T cell compartments in RA patients was not significantly different from healthy donors, but B cell proliferation and plasma cell differentiation was impaired before therapy and restored by abatacept. While Treg cell frequency was normal, its inhibitory function was absent before therapy and was partially recovered 6 months after abatacept. B and Treg cell function is impaired in RA patients not responding to the first anti TNF-alpha agent. Abatacept therapy was able to rescue immune function and led to an effective and safe clinical outcome, suggesting that RA patients, in whom anti TNF-alpha failed, are immunologically prone to benefit from an agent targeting a different pathway. PMID- 24773027 TI - L-selenomethionine does not protect against testosterone plus 17beta-estradiol induced oxidative stress and preneoplastic lesions in the prostate of NBL rats. AB - Previous animal studies examining dietary selenium effects on prostatic carcinogenesis did not show preventive benefit, including 1 study in a rat model involving testosterone (T) and estradiol (E2)-induced prostatic oxidative stress. Here, we examined modulation of T + E2-induced prostatic oxidative stress, dysplasia, and inflammation by L-selenomethionine at 1.5 or 3.0 mg selenium/kg in NIH-07 diet in Noble (Nbl)/Crl rats treated with T + E2 for 16 wk. Hormone treatment increased immunohistochemical staining for 8-hydroxydeoxyguanosine (8 OHdG) in the prostatic sites of T + E2-induced preneoplasia (P < 0.05), but selenomethionine did not attenuate 8-OHdG staining and dysplasia in the lateral prostate. Glutathione-peroxidase activity (P < 0.05) and mRNA expression were induced by T + E2 (P < 0.0001) but not changed by selenomethionine. Selenomethionine did not cause significant responses in expression and activity of glutathione-peroxidase and MnSOD, except for a reduction of MnSOD protein expression in the lateral prostate (P < 0.01). The absence of reduction of oxidative stress and dysplasia and the minimal effects on antioxidant enzymes caused by selenomethionine are consistent with the null effects observed in selenium supplementation animal studies and clinical trials. Significant (P < 0.01) opposite apoptosis/cell proliferation balance responses to selenomethionine and to T + E2 occurred in the lateral and dorsal prostate, explaining why T + E2 induces lesions selectively in the lateral lobe of NBL rats. PMID- 24773028 TI - Social and behavioral outcomes: pre-injury to six months following childhood traumatic brain injury. AB - This study aimed to extend the limited research investigating social and behavioral outcomes following childhood traumatic brain injury (TBI). The study compared pre-and post-injury measures of these skills and investigated the role of pre-injury child status and pre-injury family functioning in the prediction of outcome at six months post-injury. A secondary aim was to compare rates of impairment at six months post-injury between children post-TBI and a typically developing (TD) control group. This study comprised 140 children, 97 survivors of TBI (67 males) and 43 TD children (24 males), matched for age, sex, and socio economic status. All participants were ascertained between 2007 and 2010, and were between ages 5.5 and 15.0 years. Children with TBI represented consecutive hospital admissions and were recruited at time of injury into a longitudinal study. TD children were recruited from the community, through local schools chosen to provide a range of socio-economic backgrounds. Findings indicated a deterioration of social participation skills post-injury, particularly for those sustaining a more severe injury, and a consistently higher rate of impairment in social and behavioral outcomes in the TBI group. Pre-injury function, injury severity and restrictions to social participation (e.g., reduced sport activities) as recommended by clinicians contributed significantly to outcome. Difficulties are evident in the short-term post-childhood TBI in social and behavioral domains. It is essential to monitor children long-term, particularly as societal expectations and demands increase. PMID- 24773029 TI - Plasma adrenomedullin concentrations in critically ill neonatal foals. AB - BACKGROUND: Bacterial sepsis remains a leading cause of morbidity and mortality in neonatal foals, but accurate diagnostic and prognostic markers are lacking. Adrenomedullin (AM) is a polypeptide with diverse biologic effects on the cardiovascular system that increases in septic humans and laboratory animals. HYPOTHESES: Plasma AM concentration (p[AM]) is increased in septic neonatal foals compared to sick nonseptic and healthy control foals, and p[AM] is predictive of survival in septic neonatal foals. ANIMALS: Ninety critically ill (42 septic, 48 sick nonseptic) and 61 healthy foals <1 week of age. METHODS: A prospective observational clinical study was performed. Venous blood was collected from critically ill foals at admission and from healthy foals at 24 hours of age. Critically ill foals were categorized as septic or sick nonseptic based on blood culture results and sepsis score. Plasma [AM] was measured by using a commercially available ELISA for horses. Data were analyzed by using the Mann Whitney U-test and P < .05 was considered significant. RESULTS: Plasma [AM] was not significantly different between septic and sick nonseptic foals (P = .71), but critically ill foals had significantly increased p[AM] compared to healthy controls (P < .0001). In critically ill foals, p[AM] was not predictive of survival (P = .051). A p[AM] cutoff concentration of 0.041 ng/mL provided a test sensitivity of 91% and specificity of 54% to predict illness. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma [AM] shows promise as a marker of health in neonatal foals, but p[AM] increases nonspecifically during perinatal illnesses and is not necessarily associated with sepsis. PMID- 24773030 TI - The potential impact of a single amino-acid substitution on the efficacy of equine influenza vaccines. AB - REASONS FOR PERFORMING STUDY: The protection induced by an equine influenza (EI) vaccine strain depends on its antigenic relatedness to the challenge virus. Although the World Organisation for Animal Health (OIE) recommend that both Florida sublineage clade 1 (Fc1) and clade 2 (Fc2) viruses should be included in EI vaccines, Japanese EI vaccines have not, thus far, been updated to include a Fc2 virus. OBJECTIVES: To evaluate the efficacy of antibodies raised against Japanese EI vaccine strains in the neutralisation of recent Fc2 viruses. STUDY DESIGN: Antigenic analysis. METHODS: Virus neutralisation tests were performed using antisera from experimentally infected horses and from horses that had received a primary course of the currently available vaccines. RESULTS: Antiserum raised against the Japanese EI vaccine strain, A/equine/La Plata/1993, exhibited poor cross-neutralising activity against the Fc2 viruses isolated recently in Ireland and the UK, which have the substitution of alanine to valine at position 144 in antigenic site A of the haemagglutinin gene. In contrast, the antiserum exhibited good cross-neutralising activity against the Fc2 viruses without the substitution. This finding was supported in experiments with antisera collected from vaccinated horses. CONCLUSIONS: This suggests that the efficacy of the Japanese EI vaccine for some of the recent Fc2 viruses is suboptimal and that vaccines should be updated in accordance with the OIE recommendations. PMID- 24773031 TI - Dyskinesia in Parkinson's disease: mechanisms and current non-pharmacological interventions. AB - Dopamine replacement therapy in Parkinson's disease is associated with several unwanted effects, of which dyskinesia is the most disabling. The development of new therapeutic interventions to reduce the impact of dyskinesia in Parkinson's disease is therefore a priority need. This review summarizes the key molecular mechanisms that underlie dyskinesia. The role of dopamine receptors and their associated signaling mechanisms including dopamine-cAMP-regulated neuronal phosphoprotein, extracellular signal-regulated kinase, mammalian target of rapamycin, mitogen and stress-activated kinase-1 and Histone H3 are summarized, along with an evaluation of the role of cannabinoid and nicotinic acetylcholine receptors. The role of synaptic plasticity and animal behavioral results on dyskinesia are also evaluated. The most recent therapeutic advances to treat Parkinson's disease are discussed, with emphasis on the possibilities and limitations of non-pharmacological interventions such as physical activity, deep brain stimulation, transcranial magnetic field stimulation and cell replacement therapy. The review suggests new prospects for the management of Parkinson's disease-associated motor symptoms, especially the development of dyskinesia. This review aims at summarizing the key molecular mechanisms underlying dyskinesia and the most recent therapeutic advances to treat Parkinson's disease with emphasis on non-pharmacological interventions such as physical activity, deep brain stimulation (DBS), transcranial magnetic field stimulation (TMS) and cell replacement therapy. These new interventions are discussed from both the experimental and clinical point of view, describing their current strength and limitations. PMID- 24773032 TI - Microbiome investigation in the ecological speciation context of lake whitefish (Coregonus clupeaformis) using next-generation sequencing. AB - Few studies have applied NGS methods to investigate the microbiome of vertebrates in their natural environment and in freshwater fishes in particularly. Here, we used pyrosequencing of the 16S gene rRNA to (i) test for differences in kidney bacterial communities (i.e. microbiota) of dwarf and normal whitefish found as sympatric pairs, (ii) test the hypothesis of higher bacterial diversity in normal compared with dwarf whitefish and (iii) test for the occurrence of parallelism with the presence and composition of bacterial communities across species pairs inhabiting different lakes. The kidney microbiota of 253 dwarf and normal whitefish from five lakes was analysed combining a double-nested PCR approach with 454 pyrosequencing. Bacteria were detected in 52.6% of the analysed whitefish. There was no overall significant difference among lakes and forms, although the lake * form interaction was found significant. We identified 579 bacterial genera, which is substantially more than previous descriptions using less sensitive techniques of fish bacterial diversity in kidney, pathogenic or not. Ten of these genera contained eighteen pathogenic species. Differences in bacteria composition between whitefish forms were not parallel among lakes. In accordance with the higher diversity of prey types, normal whitefish kidney tissue consistently had a more diverse bacterial community and this pattern was parallel among lakes. These results add to building evidence from previous studies on this system that the adaptive divergence of dwarf, and normal whitefish has been driven by both parallel and nonparallel ecological conditions across lakes. PMID- 24773033 TI - Activation as an overlooked factor in the BDI-II: a factor model based on core symptoms and qualitative aspects of depression. AB - An adequate assessment of depression has been of concern to many researchers over the last half-century. These efforts have brought forth a manifold of depression rating scales, of which the Beck Depression Inventory (BDI) is 1 of the most commonly used self-assessment scales. Since its revision, the item structure of the BDI-II has been examined in many factor analytic studies, yet it has not been possible to achieve a consensus about the underlying factor structure. Recent findings from a nonmetric multidimensional scaling (NMDS) analysis (Buhler, Keller, & Lage, 2012) of the German norming sample of the BDI-II emphasized a structure with different qualitative aspects of depression, which suggested that the existing factor models do not adequately represent the data. The NMDS results were reviewed, and on the basis of these findings, a different factor model is proposed. In contrast to the common factor models in the literature, the presented model includes an additional factor, which is associated with the activation level of the BDI-II symptoms. The model was evaluated with a 2nd sample of patients diagnosed with a primary affective disorder (N = 569) and obtained good fit indices that even exceeded the fit of the most reliable factor model (Ward, 2006) described in the literature so far. Furthermore, emphasis is placed on the methodological question of how factor models may be derived from the results of NMDS analyses. PMID- 24773034 TI - Developing a fluid intelligence scale through a combination of Rasch modeling and cognitive psychology. AB - Ability testing has been criticized because understanding of the construct being assessed is incomplete and because the testing has not yet been satisfactorily improved in accordance with new knowledge from cognitive psychology. This article contributes to the solution of this problem through the application of item response theory and Susan Embretson's cognitive design system for test development in the development of a fluid intelligence scale. This study is based on findings from cognitive psychology; instead of focusing on the development of a test, it focuses on the definition of a variable for the creation of a criterion-referenced measure for fluid intelligence. A geometric matrix item bank with 26 items was analyzed with data from 2,797 undergraduate students. The main result was a criterion-referenced scale that was based on information from item features that were linked to cognitive components, such as storage capacity, goal management, and abstraction; this information was used to create the descriptions of selected levels of a fluid intelligence scale. The scale proposed that the levels of fluid intelligence range from the ability to solve problems containing a limited number of bits of information with obvious relationships through the ability to solve problems that involve abstract relationships under conditions that are confounded with an information overload and distraction by mixed noise. This scale can be employed in future research to provide interpretations for the measurements of the cognitive processes mastered and the types of difficulty experienced by examinees. PMID- 24773035 TI - A comparison of the predictive properties of nine sex offender risk assessment instruments. AB - Sex offender treatment is most effective when tailored to risk-need-responsivity principles, which dictate that treatment levels should match risk levels as assessed by structured risk assessment instruments. The predictive properties, missing values, and interrater agreement of the scores of 9 structured risk assessment instruments were compared in a national sample of 397 Dutch convicted sex offenders. The instruments included the Rapid Risk Assessment for Sexual Offense Recidivism, Static-99, Static-99R, a slightly modified version of Static 2002 and Static-2002R, Structured Anchored Clinical Judgments Minimum, Risk Matrix 2000, Sexual Violence Risk 20, and a modified version of the Sex Offender Risk Appraisal Guide; sexual and violent (including sexual) recidivism was assessed over 5- and 10-year fixed and variable follow-up periods. In general, the instrument scores showed moderate to large predictive accuracy for the occurrence of reoffending and the number of reoffenses in this sample. Predictive accuracy regarding latency showed more variability across instrument scores. Static-2002R and Static-99R scores showed a slight but consistent advantage in predictive properties over the other instrument scores across outcome measures and follow-up periods in this sample. The results of Sexual Violence Risk 20 and Rapid Risk Assessment for Sexual Offense Recidivism scores were the least positive. A positive association between predictive accuracy and interrater agreement at the item level was found for both sexual recidivism (r = .28, p = .01) and violent (including sexual) recidivism (r = .45, p < .001); no significant association was found between predictive accuracy and missing values at the item level. Results underscore the feasibility and utility of these instruments for informing treatment selection according to the risk-need responsivity principles. PMID- 24773036 TI - A comparison of the criterion validity of popular measures of narcissism and narcissistic personality disorder via the use of expert ratings. AB - The growing interest in the study of narcissism has resulted in the development of a number of assessment instruments that manifest only modest to moderate convergence. The present studies adjudicate among these measures with regard to criterion validity. In the 1st study, we compared multiple narcissism measures to expert consensus ratings of the personality traits associated with narcissistic personality disorder (NPD; Study 1; N = 98 community participants receiving psychological/psychiatric treatment) according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) using 5-factor model traits as well as the traits associated with the pathological trait model according to the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; American Psychiatric Association, 2013). In Study 2 (N = 274 undergraduates), we tested the criterion validity of an even larger set of narcissism instruments by examining their relations with measures of general and pathological personality, as well as psychopathology, and compared the resultant correlations to the correlations expected by experts for measures of grandiose and vulnerable narcissism. Across studies, the grandiose dimensions from the Five-Factor Narcissism Inventory (FFNI; Glover, Miller, Lynam, Crego, & Widiger, 2012) and the Narcissistic Personality Inventory (Raskin & Terry, 1988) provided the strongest match to expert ratings of DSM-IV-TR NPD and grandiose narcissism, whereas the vulnerable dimensions of the FFNI and the Pathological Narcissism Inventory (Pincus et al., 2009), as well as the Hypersensitive Narcissism Scale (Hendin & Cheek, 1997), provided the best match to expert ratings of vulnerable narcissism. These results should help guide researchers toward the selection of narcissism instruments that are most well suited to capturing different aspects of narcissism. PMID- 24773037 TI - Childhood Trauma Questionnaire: factor structure, measurement invariance, and validity across emotional disorders. AB - To study the psychometric properties of the Childhood Trauma Questionnaire-Short Form (CTQ-SF), we determined its dimensional structure, measurement invariance across presence of emotional disorders, the association of the CTQ-SF with an analogous interview-based measure (CTI) across presence of emotional disorders, and the incremental value of combining both instruments in determining associations with severity of psychopathology. The sample included 2,308 adults, ages 18-65, consisting of unaffected controls and chronically affected and intermittently affected persons with an emotional disorder at Time 0 (T0) or 4 years later at T4. Childhood maltreatment was measured at T0 with an interview and at T4 with the CTQ-SF. At each wave, patients were assessed for Diagnostic and Statistical Manual of Mental Disorders (4th ed., or DSM-IV; American Psychiatric Association, 1994)-based emotional disorders (Composite Interview Diagnostic Instrument) and symptom severity (Inventory of Depressive Symptomatology, Beck Anxiety Inventory, Fear Questionnaire). Besides the correlated original 5-factor solution, an indirect higher order and direct bifactorial model also showed a good fit to the data. The 5-factor solution proved to be invariant across disordered-control comparison groups. The CTQ-SF was moderately associated with the CTI, and this association was not attenuated by disorder status. The CTQ-SF was more sensitive in detecting emotional abuse and emotional neglect than the CTI. Combined CTQ-SF/CTI factor scores showed a higher association with severity of psychopathology. We conclude that although the original 5-factor model fits the data well, results of the hierarchical analyses suggest that the total CTQ scale adequately captures a broad dimension of childhood maltreatment. A 2-step measurement approach in the assessment of childhood trauma is recommended in which screening by a self-report questionnaire is followed by a (semi-)structured diagnostic interview. PMID- 24773038 TI - Assessment of oxidative stress in serum by d-ROMs test. AB - Assessment of oxidative stress is an important but technically challenging procedure in medical and biological research. The reactive oxygen metabolites (d ROMs) test is a simple assay marketed for analyzing the total amount of hydroperoxides in serum via the Fenton's reaction. Earlier reports have raised a suspicion that a part of the signal detected in the assay comes from sources other than metabolites generated by oxidative stress. The aim of this study was to identify which serum components interfere with the d-ROMs signal. By application of sodium azide, ethylenediaminetetraacetic acid, sodium dodecylsulphate, varying temperature, and spiking endogenous substances we demonstrate that in the case of mammalian sera the assay determines ceruloplasmin (CP) activity with potential interferences from hydroperoxides, iron level, thiols, and albumin. In sera of avian species hydroperoxides contribute more to the test outcome, but the CP part is insensitive to inhibition by azide. In conclusion, this assay has deficiencies in terms of detecting realistic concentrations of hydroperoxides, is mostly measuring CP and is also interfered with other serum components, making it very difficult to interpret in most biological systems. PMID- 24773039 TI - Examining the factor structure and convergent and discriminant validity of the Levenson self-report psychopathy scale: is the two-factor model the best fitting model? AB - The Levenson, Kiehl, and Fitzpatrick (1995) Self-Report Psychopathy Scale (LSRP) was introduced in the mid-1990s as a brief measure of psychopathy and has since gained considerable popularity. Despite its attractiveness as a brief psychopathy tool, the LSRP has received limited research regarding its factor structure and convergent and discriminant validity. The present study examined the construct validity of the LSRP, testing both its factor structure and the convergent and discriminant validity. Using a community sample of 1,257 undergraduates (869 females; 378 males), we tested whether a 1-, 2-, or 3-factor model best fit the data and examined the links between the resultant factor structures and external correlates. Confirmatory factor analysis (CFA) findings revealed a 3-factor model best matched the data, followed by an adequate-fitting original 2-factor model. Next, comparisons were made regarding the convergent and discriminant validity of the competing 2- and 3-factor models. Findings showed the LSRP traditional primary and secondary factors had meaningful relations with extratest variables such as neuroticism, stress tolerance, and lack of empathy. The 3-factor model showed particular problems with the Callousness scale. These findings underscore the importance of examining not only CFA fit statistics but also convergent and discriminant validity when testing factor structure models. The current findings suggest that the 2-factor model might still be the best way to interpret the LSRP. PMID- 24773040 TI - Exploration of MR-guided head and neck hyperthermia by phantom testing of a modified prototype applicator for use with proton resonance frequency shift thermometry. AB - Magnetic resonance thermometry (MRT) offers non-invasive temperature imaging and can greatly contribute to the effectiveness of head and neck hyperthermia. We therefore wish to redesign the HYPERcollar head and neck hyperthermia applicator for simultaneous radio frequency (RF) heating and magnetic resonance thermometry. In this work we tested the feasibility of this goal through an exploratory experiment, in which we used a minimally modified applicator prototype to heat a neck model phantom and used an MR scanner to measure its temperature distribution. We identified several distorting factors of our current applicator design and experimental methods to be addressed during development of a fully MR compatible applicator. To allow MR imaging of the electromagnetically shielded inside of the applicator, only the lower half of the HYPERcollar prototype was used. Two of its antennas radiated a microwave signal (150 W, 434 MHz) for 11 min into the phantom, creating a high gradient temperature profile (DeltaTmax = 5.35 degrees C). Thermal distributions were measured sequentially, using drift corrected proton resonance frequency shift-based MRT. Measurement accuracy was assessed using optical probe thermometry and found to be about 0.4 degrees C (0.1-0.7 degrees C). Thermal distribution size and shape were verified by thermal simulations and found to have a good correlation (r(2 )= 0.76). PMID- 24773042 TI - Evaluation of reference genes for human chondrocytes cultured in several different thermal environments. AB - PURPOSE: The purpose of this study was to identify reference genes showing stable expression in chondrocytes cultured under several different thermal environments and in different culture systems. MATERIALS AND METHODS: Human articular chondrocytes were cultured by monolayer or pellet culture system at 32 degrees C, 37 degrees C, and 41 degrees C for 3 days. Thereafter, the total RNA was extracted, and quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was performed. The qRT-PCR data was analysed using three different algorithms (geNorm, NormFinder, and BestKeeper) to identify reference genes exhibiting stable expression from among the seven candidate reference genes (B2M, ACTB, GAPDH, HSPCB, RPL13a, YWHAZ, and 18S). RESULTS: The candidate reference genes, except for HSPCB and YWHAZ, showed systematic variations in expression. In the monolayer culture, RPL13a was the most stable gene identified using NormFinder and BestKeeper; on using geNorm, ACTB and GAPDH showed the highest expression stability. In the pellet culture, ACTB was the most stable gene identified using NormFinder and BestKeeper, whereas GAPDH and RPL13a were the most stable reference genes as determined using geNorm. In the combined group, B2M and GAPDH were the most stable genes identified using geNorm, whereas RPL13a and YWHAZ were the most stable as per NormFinder and BestKeeper, respectively. The best combination of two candidate reference genes among all the groups determined using NormFinder was RPL13a and YWHAZ. CONCLUSION: The combination of RPL13a and YWHAZ might be suitable as reference genes for human chondrocytes cultured at 32 degrees C, 37 degrees C, and 41 degrees C in monolayer, pellet, or combined cultures. PMID- 24773041 TI - Magnetic resonance imaging contrast of iron oxide nanoparticles developed for hyperthermia is dominated by iron content. AB - PURPOSE: Magnetic iron oxide nanoparticles (MNPs) are used as contrast agents for magnetic resonance imaging (MRI) and hyperthermia for cancer treatment. The relationship between MRI signal intensity and cellular iron concentration for many new formulations, particularly MNPs having magnetic properties designed for heating in hyperthermia, is lacking. In this study, we examine the correlation between MRI T2 relaxation time and iron content in cancer cells loaded with various MNP formulations. MATERIALS AND METHODS: Human prostate carcinoma DU-145 cells were loaded with starch-coated bionised nanoferrite (BNF), iron oxide (Nanomag(r) D-SPIO), FeridexTM, and dextran-coated Johns Hopkins University (JHU) particles at a target concentration of 50 pg Fe/cell using poly-D-lysine transfection reagent. T2-weighted MRI of serial dilutions of these labelled cells was performed at 9.4 T and iron content quantification was performed using inductively coupled plasma mass spectrometry (ICP-MS). Clonogenic assay was used to characterise cytotoxicity. RESULTS: No cytotoxicity was observed at twice the target intracellular iron concentration (~100 pg Fe/cell). ICP-MS revealed highest iron uptake efficiency with BNF and JHU particles, followed by Feridex and Nanomag-D-SPIO, respectively. Imaging data showed a linear correlation between increased intracellular iron concentration and decreased T2 times, with no apparent correlation among MNP magnetic properties. CONCLUSIONS: This study demonstrates that for the range of nanoparticle concentrations internalised by cancer cells the signal intensity of T2-weighted MRI correlates closely with absolute iron concentration associated with the cells. This correlation may benefit applications for cell-based cancer imaging and therapy including nanoparticle-mediated drug delivery and hyperthermia. PMID- 24773044 TI - Chemical compositions by using LC-MS/MS and GC-MS and biological activities of Sedum sediforme (Jacq.) Pau. AB - In this research, the chemical composition and biological activities of various extracts obtained from whole parts of Sedum sediforme (Jacq.) Pau were compared. The amounts of total phenolic and flavonoid components in crude extracts were determined by expression as pyrocatechol and quercetin equivalents, respectively. All of the extracts (petroleum ether, acetone, methanol, and water) obtained from S. sediforme showed strong antioxidant activity in four tested methods. Particularly, the IC50 values of the methanol extract, which was the richest in terms of total phenolic and flavonoid contents, were found to be lower than those of alpha-tocopherol and BHT in beta-carotene bleaching (9.78 +/- 0.06 MUg/mL), DPPH free radical scavenging (9.07 +/- 0.07 MUg/mL), and ABTS cation radical scavenging (5.87 +/- 0.03 MUg/mL) methods. Furthermore, the methanol extract of S. sediforme showed higher inhibition activity than galanthamine against acetyl- and butyryl-cholinesterase enzymes. Also, acetone and methanol extracts exhibited moderate antimicrobial activity against Candida albicans. The main constituents of fatty acid and essential oil were identified as palmitic acid (C16:0) (28.8%) and alpha-selinene (20.4%), respectively, by GC-MS. In the methanol extract of S. sediforme, quercetin, rutin, naringenin, and protocatechuic, p-coumaric, caffeic, and chlorogenic acids were detected and quantified by LC-MS/MS. Results of the current study showed that the methanol extract of S. sediforme may also be used as a food supplement. PMID- 24773045 TI - Ischemia-induced endothelial cell swelling and mitochondrial dysfunction are attenuated by cinnamtannin D1, green tea extract, and resveratrol in vitro. AB - Polyphenols possess antioxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular unit. Endothelial cell swelling may contribute to a leaky blood-brain barrier which may result in vasogenic edema in the continued presence of the existing cytotoxic edema. We investigated the protective effects of polyphenols on cytotoxic cell swelling in bEND3 endothelial cultures subjected to 5 hours oxygen-glucose deprivation (OGD). A polyphenol trimer from cinnamon (cinnamtannin D1), a polyphenol-rich extract from green tea, and resveratrol prevented the OGD-induced rise in mitochondrial free radicals, cell swelling, and the dissipation of the inner mitochondrial membrane potential. Monocyte chemoattractant protein (also called CCL2), a chemokine, but not tumor necrosis factor-alpha or interleukin-6, augmented the cell swelling. This effect of monochemoattractant protein 1-1 was attenuated by the polyphenols. Cyclosporin A, a blocker of the mitochondrial permeability transition pore, did not attenuate cell swelling but BAPTA-AM, an intracellular calcium chelator did, indicating a role of [Ca(2+)]i but not the mPT in cell swelling. These results indicate that the polyphenols reduce mitochondrial reactive oxygen species and subsequent cell swelling in endothelial cells following ischemic injury and thus may reduce brain edema and associated neural damage in ischemia. One possible mechanism by which the polyphenols may attenuate endothelial cell swelling is through the reduction in [Ca(2+)]i. PMID- 24773046 TI - Statistical length measurement method by direct imaging of carbon nanotubes. AB - The influence of carbon nanotube (CNT) length on their macroscopic properties requires an accurate methodology for CNT length measurement. So far, existing techniques are limited to short (less than a few micrometers) CNTs and sample preparation methods that bias the measured values. Here, we show that the average length of carbon nanotubes (CNTs) can be measured by cryogenic transmission electron microscopy (cryo-TEM) of CNTs in chlorosulfonic acid. The method consists of dissolving at low concentration CNTs in chlorosulfonic acid (a true solvent), imaging the individual CNTs by cryo-TEM, and processing and analyzing the images to determine CNT length. By measuring the total CNT contour length and number of CNT ends in each image, and by applying statistical analysis, we extend the method to cases where each CNT is long enough to span many cryo-TEM images, making the direct length measurement of an entire CNT impractical. Hence, this new technique can be used effectively to estimate samples in a wide range of CNT lengths, although we find that cryo-TEM imaging may bias the measurement towards longer CNTs, which are easier to detect. Our statistical method is also applied to AFM images of CNTs to show that, by using only a few AFM images, it yields estimates that are consistent with literature techniques, based on individually measuring a higher number of CNTs. PMID- 24773047 TI - Quantification of high-resolution 1H-[13C] NMR spectra from rat brain extracts. AB - NMR spectroscopy in combination with (13)C-labeled substrate infusion is a unique technique to obtain information about dynamic metabolic fluxes noninvasively in vivo. In many cases, the in vivo information content obtained during dynamic (13)C studies in rodents can be enhanced by high-resolution (1)H-[(13)C] NMR spectroscopy on brain extracts. Previously, it has been shown that (1)H NMR spectra from rat brain extracts can be accurately quantified with a spectral fitting routine utilizing simulated basis sets using complete prior knowledge of chemical shifts and scalar couplings. The introduction of (13)C label into the various metabolites presents complications that demand modifications of the spectral fitting routine. As different multiplets within a given molecule accumulate various amounts of (13)C label, the fixed amplitude relationship between multiplets typical for (1)H NMR spectra must be abandoned. In addition, (13)C isotope effects lead to spectral multiplet patterns that become dependent on the amount of (13)C label accumulation, thereby preventing the use of a common basis set. Here a modified spectral fitting routine is presented that accommodates variable (13)C label accumulation and (13)C isotope effects. Spectral fitting results are quantitatively compared to manual integration on column-separated samples in which spectral overlap is minimized. PMID- 24773048 TI - CARI ONE induces anagen phase of telogenic hair follicles through regulation of beta-catenin, stimulation of dermal papilla cell proliferation, and melanogenesis. AB - The use of herbal mixtures in the hair growth market has increased dramatically over the last decade. In this study, we investigated the hair growth-promoting activity of CARI ONE, a mixture of medicinal plants and mushrooms, in telogenic 6 week-old C57BL/6N mice. CARI ONE promoted hair growth through stimulation of the telogen to anagen transition. Histomorphometry analysis data indicated that topical application of CARI ONE induced an earlier anagen phase and prolonged the mature anagen phase, and also increased the number and size of hair follicles (HFs) as compared to either the control or 1% minoxidil-treated group. Immunohistochemical analysis revealed an earlier induction of beta-catenin and Trp-1 protein in the HFs of the CARI ONE-treated group compared to that in the control group or 1% minoxidil-treated group. In vitro, CARI ONE promoted the proliferation of dermal papilla cells and resulted in increased melanin content in B16F10 cells in a dose-dependent manner without affecting cell viability. These results suggest that CARI ONE promotes hair growth through induction of the anagen phase in resting HFs. PMID- 24773049 TI - GANRA-5 protects mice from X-ray irradiation-induced dysfunction of the immune system. AB - Ionizing radiation produces reactive oxygen species (ROS), which cause damage to cells. We have synthesized a class of ROS scavengers and found that one of them, named GANRA-5, exhibits high radio-protective effects against both heavy ion irradiation and X-rays, while at the same time displaying low levels of toxicity. Pre-administration with an effective dose of GANRA-5 reduces radiation-induced damage to tissues and increases the survival rate of exposed mice. In this study, we evaluated the changes to the immune system via X-ray irradiation, and investigated how pre-administration of GANRA-5 exhibited preventative characteristics. Compared to the irradiated control groups, GANRA-5 treatment significantly reduced the radiation-induced spleen shrinkage and pathological changes. Moreover, pretreatment with GANRA-5 significantly (p < 0.01) enhanced the cellular immune response, which was characterized by higher peritoneal macrophage as well as splenocyte survival, and a higher ratio of CD4(+)/CD8(+) T lymphocytes. In addition, GANRA-5 treatment before whole body irradiation significantly improved the humoral response (p < 0.01) as indicated by the higher antibody titers of IgG, IgA, and IgM. Furthermore, GANRA-5 treatment significantly (p < 0.01) countered radiation-induced decreases in the titers of serum IL-2 and IL-4 when compared to irradiated but untreated control groups. In summary, these findings indicate that GANRA-5 provides effective protection to the immune system against X-ray-induced immunosuppression. PMID- 24773050 TI - New yellow-emitting Whitlockite-type structure Sr(1.75)Ca(1.25)(PO4)2:Eu(2+) phosphor for near-UV pumped white light-emitting devices. AB - New compound discovery is of interest in the field of inorganic solid-state chemistry. In this work, a whitlockite-type structure Sr1.75Ca1.25(PO4)2 newly found by composition design in the Sr3(PO4)2-Ca3(PO4)2 join was reported. Crystal structure and luminescence properties of Sr1.75Ca1.25(PO4)2:Eu(2+) were investigated, and the yellow-emitting phosphor was further employed in fabricating near-ultraviolet-pumped white light-emitting diodes (w-LEDs). The structure and crystallographic site occupancy of Eu(2+) in the host were identified via X-ray powder diffraction refinement using Rietveld method. The Sr1.75Ca1.25(PO4)2:Eu(2+) phosphors absorb in the UV-vis spectral region of 250 430 nm and exhibit an intense asymmetric broadband emission peaking at 518 nm under lambdaex = 365 nm which is ascribed to the 5d-4f allowed transition of Eu(2+). The luminescence properties and mechanism are also investigated as a function of Eu(2+) concentration. A white LED device which is obtained by combining a 370 nm UV chip with commercial blue phosphor and the present yellow phosphor has been fabricated and exhibit good application properties. PMID- 24773051 TI - Lewis acid/Bronsted acid mediated benz-annulation of thiophenes and electron-rich arenes. AB - A facile preparation of benz-annulated heterocycles were achieved at rt involving a Lewis acid/Bronsted acid mediated annulation of heterocycles using 2,5 dimethoxytetrahydrofuran as a four-carbon synthon. The benz-/naphth-annulation was found to be successful with electron-rich arenes as well. PMID- 24773052 TI - Inhibition of PaCaMKII-E isoform in the dorsal unpaired median neurosecretory cells of cockroach reduces nicotine- and clothianidin-induced currents. AB - Cellular responses to Ca(2+) require intermediary proteins such as calcium/calmodulin-dependent protein kinase II (CaMKII), which transduces the signal into downstream effects. We recently demonstrated that the cockroach genome encodes five different CaMKII isoforms, and only PaCaMKII-E isoform is specifically expressed in the dorsal unpaired median neurosecretory cells. In the present study, using antisense oligonucleotides, we demonstrated that PaCaMKII-E isoform inhibition reduced nicotine-induced currents through alpha-bungarotoxin sensitive and -insensitive nicotinic acetylcholine receptor subtypes. Specifically, PaCaMKII-E isoform is sufficient to repress nicotinic current amplitudes as a result of its depression by antisense oligonucleotides. Similar results were found using the neonicotinoid insecticide clothianidin, which acted as a full agonist of dorsal unpaired median neuron nicotinic acetylcholine receptors. Clothianidin current amplitudes are strongly reduced under bath application of PaCaMKII-E antisense oligonucleotides but no significant results are found with alpha-bungarotoxin co-applied, demonstrating that CaMKII-E isoform affects nicotine currents through alpha-bungarotoxin-sensitive and -insensitive receptor subtypes whereas clothianidin currents are reduced via alpha bungarotoxin-insensitive receptors. In addition, we found that intracellular calcium increase induced by nicotine and clothianidin were reduced by PaCaMKII-E antisense oligonucleotides, demonstrating that intracellular calcium increase induced by nicotine and clothianidin are affected by PaCaMKII-E inhibition. Cellular responses to Ca(2+) require intermediary proteins such as calcium/calmodulin-dependent protein kinase II (CaMKII). We recently demonstrated that the cockroach genome encodes five different CaMKII isoforms and only PaCaMKII-E isoform was specifically expressed in the dorsal unpaired median neurosecretory cells. Here we show that specific inhibition of PaCaMKII-E isoform is associated with a decrease in nicotine- and clothianidin-induced currents. In addition, analysis of calcium changes demonstrates that PaCaMKII-E inhibition induces a decrease in intracellular calcium concentration. PMID- 24773053 TI - The potential influence of stimulus overselectivity in AAC: information from eye tracking and behavioral studies of attention with individuals with intellectual disabilities. AB - This paper examines the phenomenon of stimulus overselectivity, or overselective attention, as it may impact AAC training and use in individuals with intellectual disabilities. Stimulus overselectivity is defined as an atypical limitation in the number of stimuli or stimulus features within an image that are attended to and subsequently learned. Within AAC, the term stimulus could refer to symbols or line drawings on speech-generating devices, drawings or pictures on low technology systems, and/or the elements within visual scene displays. In this context, overselective attention may result in unusual or uneven error patterns such as confusion between two symbols that share a single feature, or difficulties with transitioning between different types of hardware. We review some of the ways that overselective attention has been studied behaviorally. We then examine how eye tracking technology allows a glimpse into some of the behavioral characteristics of overselective attention. We describe an intervention approach, differential observing responses, that may reduce or eliminate overselectivity, and we consider this type of intervention as it relates to issues of relevance for AAC. PMID- 24773054 TI - Design and synthesis of human ABCB1 (P-glycoprotein) inhibitors by peptide coupling of diverse chemical scaffolds on carboxyl and amino termini of (S) valine-derived thiazole amino acid. AB - P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S) valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC50 = 1.0 MUM) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [(125)I] iodoarylazidoprazosin with IC50 = 0.75 MUM and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 MUM). Compound 28 at 3 MUM reduced resistance in cytotoxicity assay to paclitaxel in P gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug binding pocket of human P-gp. PMID- 24773055 TI - Ultrafast dynamics of C30 in solution and within CDs and HSA protein. AB - Steady-state UV-visible absorption and emission together with femto to nanosecond time-resolved emission techniques have been applied to study the dynamics of 3-(2 N-methylbenzimidazolyl)-7-(N,N-diethylamino)coumarin (C30) in neat solvents, as well as in the presence of chemical (beta-CD and DM-beta-CD) and biological (HSA protein) cavities. The formation of inclusion complexes inside the hydrophobic CDs gives 1:1 and 1:2 guest:host complexes, whereas with the HSA protein, the formed 1:1 inclusion complexes are more robust. The picosecond experiments show the importance of the interactions of C30 with the medium, as well as the intramolecular events in the excited-state relaxation as evidenced by the increase in the global emission lifetime from ~0.5 ns in MeOH/H2O mixtures to 2.5 ns in THF, and to 1-3 ns when the dye is trapped within CDs and HSA cavities. Time-resolved anisotropy (r(t)) results indicate the involvement of ultrafast depolarization processes, whereas in the MeOH/H2O mixtures r(0) = 0.27, in DM beta-CD, r(0) = 0.35. The rotational time decays clearly show the robustness of the formed complexes with CDs and HSA protein: ~170 ps in MeOH/H2O solvent mixtures, ~850 ps due to 1:1 and 1:2 beta-CD complexes, and 28 ns for HSA complexes. The femtosecond time-resolved emission experiments reveal the significant changes of the dynamics with the encapsulation of C30 by CDs (from approximately tau1 = 0.3 and tau2 = 2 ps in THF to approximately tau1 = 1.0 and tau2 = 7.5 ps in the MeOH/H2O binary mixture, and to approximately tau1 = 3 and tau2 = 30 ps in the CD complexes). The change is explained in terms of how the water molecules modulate the intramolecular charge transfer (ICT) time (tau1) and how the restriction of the environment modifies the torsional process (tau2). In the case of trapped C30 within the HSA protein the intermolecular interactions with the amino acid residues are revealed, giving rise to a complex photodynamical behavior due to the hydrophobic, H-bonding, electrostatic, and polar nature of the heterogeneous environment inside the protein. The protein confinement does not allow the occurrence of twisting motion in the trapped C30, and we observed a very fast (less than 100 fs) and slower (~13 ps) ICT processes. We believe that the reported findings bring new knowledge for a better understanding of the photobehavior of coumarins in solution and trapped within hydrophobic pockets. The results can be applied to design better coumarin-based fluorescent labels for biological applications. PMID- 24773056 TI - Hydrogen peroxide mediates abscisic acid-induced HSP70 accumulation and heat tolerance in grafted cucumber plants. AB - Root-shoot communications play important roles in plant stress responses. Here, we examined the roles of root-sourced signals in the shoot response to heat in cucumber plants. Cucumber plants grafted onto their own roots and luffa roots were exposed to aerial and root-zone heat to examine their tolerance by assessing the levels of oxidative stress, PSII photoinhibition, accumulation of abscisic acid (ABA), H2 O2 and heat shock protein (HSP) 70 using immunoblotting, chlorophyll fluorescence, immunoassay, CeCl3 staining and Western blotting, respectively. Grafting onto the luffa rootstock enhanced the shoot tolerance to the heat. This enhanced tolerance was associated with increased accumulation of ABA and apoplastic H2 O2 , RBOH transcripts and HSP70 expression and a decrease in oxidative stress in the shoots. The increases in the ABA and H2 O2 concentrations in the shoots were attributed to an increase in ABA transport from roots and an increase in ABA biosynthesis in the shoots when the root-zone and shoots were heat stressed, respectively. Inhibition of H2 O2 accumulation compromised luffa rootstock-induced HSP70 expression and heat tolerance. These results suggest that, under heat stress, ABA triggers the expression of HSP70 in an apoplastic H2 O2 -dependent manner, implicating the role of an ABA-dependent H2 O2 -driven mechanism in a systemic response involving root-shoot communication. PMID- 24773057 TI - Thermodynamic stability versus kinetic stability: is the planar hexacoordinate carbon species D(3h) CN3Mg3+ viable? AB - The experimentally observed planar hypercoordinate carbon species were detected in gas phase experiments and characterized by photoelectron spectroscopy. According to the Boltzmann distribution law, the thermodynamically favorable isomers, especially global minima, were relatively easier to detect than other isomers in such an experimental process. Here, we reported a thermodynamically unfavorable case, i.e., D3h CN3Mg3(+) (1a), which we think is experimentally viable because all isomers that are energetically lower than 1a show bimolecular assembly type structures consisting of an N2 unit and various types of CNMg3(+) units. The natural bond orbital (NBO) analysis suggests that the bonding between N2 and CNMg3(+) is rather weak, and we think it is very hard to retain their basic structures when kinetic factors are considered. Consistently, the four lowest isomers in the second group show dissociation (to free N2 molecule and CNMg3(+) cations) during Born-Oppenheimer molecular dynamic (BOMD) simulations. In contrast, the structure of 1a can be maintained under temperatures up to 2000 K during the BOMD simulation, and ring-opening reaction studies suggest the barrier to be very high, 46.75 kcal/mol. We think the excellent kinetic stability of 1a will compensate for its thermodynamic instability and it will own its existence in the gas phase synthesis. Although many isomers in the second group are energetically more favorable than 1a, they will be dissociated by the kinetic process. In the magnetic field, the positively charged CNMg3(+) units will be separated quickly from N2 molecules in the general gas phase synthesis, and they are therefore undetectable. PMID- 24773058 TI - Type III interferons are expressed by Coxsackievirus-infected human primary hepatocytes and regulate hepatocyte permissiveness to infection. AB - Hepatitis is a common and potentially fatal manifestation of severe Coxsackievirus infections, particularly in newborn children. Little is known of the immune-mediated mechanisms regulating permissiveness to liver infection. It is well established that type I interferons (IFNs) play an important role in the host innate immune response to Coxsackievirus infections. Recent studies have highlighted a role for another IFN family, the type III IFNs (also called IFN lambda), in anti-viral defence. Whether type III IFNs are produced by hepatocytes during a Coxsackievirus infection remains unknown. Moreover, whether or not type III IFNs protects hepatocytes from a Coxsackievirus infection has not been addressed. In this study, we show that primary human hepatocytes respond to a Coxsackievirus B3 (CVB3) infection by up-regulating the expression of type III IFNs. We also demonstrate that type III IFNs induce an anti-viral state in hepatocytes characterized by the up-regulated expression of IFN-stimulated genes, including IFN-stimulated gene (ISG15), 2'-5'-oligoadenylate synthetase 2 (OAS2), protein kinase regulated by dsRNA (PKR) and myxovirus resistance protein 1 (Mx1). Furthermore, our study reveals that type III IFNs attenuate CVB3 replication both in hepatocyte cell lines and primary human hepatocytes. Our studies suggest that human hepatocytes express type III IFNs in response to a Coxsackievirus infection and highlight a novel role for type III IFNs in regulating hepatocyte permissiveness to this clinically relevant type of virus. PMID- 24773059 TI - Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. AB - BACKGROUND: Iatrogenic hypothyroidism is associated with an increased incidence of azotemia after treatment of hyperthyroidism, and decreased survival time in azotemic hyperthyroid cats. HYPOTHESIS: Restoration of euthyroidism will decrease plasma creatinine concentrations. ANIMALS: Nineteen client-owned, methimazole- or carbimazole-treated, hyperthyroid cats with documented iatrogenic hypothyroidism (based on subnormal plasma total thyroxine concentrations [TT4] and increased plasma thyroid-stimulating hormone concentrations). METHODS: Prospective interventional study. Doses of antithyroid medication were reduced until euthyroidism was restored (TT4 10-40 nmol/L). Plasma creatinine concentration and selected other clinicopathologic variables were evaluated before and after restoration of euthyroidism and compared by nonparametric statistics. Data are presented as median [25th, 75th percentile]. RESULTS: Restoration of euthyroidism was associated with a significant decrease in plasma creatinine concentrations (2.61 [1.90, 3.26] mg/dL versus 2.07 [1.42, 2.82] mg/dL; P < .001) and body weight (4.03 [3.59, 4.53] kg versus 3.89 [3.34, 4.18] kg; P = .019), and a significant increase in packed cell volume (30 [28, 39]% versus 34 [29, 39]%; P = .038), heart rate (174 [163, 201] bpm versus 190 [164, 202] bpm; P = .009), and plasma alkaline phosphatase activity (26.6 [17.0, 33.0] IU/L versus 38.0 [23.5, 46.5] IU/L; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Restoration of euthyroidism in medically treated hyperthyroid cats with iatrogenic hypothyroidism causes a reduction in plasma creatinine concentrations, and thus might improve renal function; however, this could be influenced by concurrent changes in body weight. PMID- 24773060 TI - Specific domains of plant defensins differentially disrupt colony initiation, cell fusion and calcium homeostasis in Neurospora crassa. AB - MsDef1 and MtDef4 from Medicago spp. are small cysteine-rich defensins with potent antifungal activity against a broad range of filamentous fungi. Each defensin has a hallmark gamma-core motif (GXCX(3-9) C), which contains major determinants of its antifungal activity. In this study, the antifungal activities of MsDef1, MtDef4, and peptides derived from their gamma-core motifs, were characterized during colony initiation in the fungal model, Neurospora crassa. These defensins and their cognate peptides inhibited conidial germination and accompanying cell fusion with different potencies. The inhibitory effects of MsDef1 were strongly mediated by the plasma membrane localized sphingolipid glucosylceramide. Cell fusion was selectively inhibited by the hexapeptide RGFRRR derived from the gamma-core motif of MtDef4. Fluorescent labelling of this hexapeptide showed that it strongly bound to the germ tube plasma membrane/cell wall. Using N. crassa expressing the Ca(2+) reporter aequorin, MsDef1, MtDef4 and their cognate peptides were each shown to perturb Ca(2+) homeostasis in specific and distinct ways, and the disruptive effects of MsDef1 on Ca(2+) were mediated by glucosylceramide. Together, our results demonstrate that MsDef1 and MtDef4 differ markedly in their antifungal properties and specific domains within their gamma-core motifs play important roles in their different modes of antifungal action. PMID- 24773062 TI - Aerosol delivery of DNA/liposomes to the lung for cystic fibrosis gene therapy. AB - Lung gene therapy is being evaluated for a range of acute and chronic diseases including cystic fibrosis (CF). As these therapies approach clinical realisation it is becoming increasingly clear that the ability to efficiently deliver gene transfer agents (GTAs) to target cell populations within the lung may prove just as critical as the gene therapy formulation itself in terms of generating positive clinical outcomes. Key to the success of any aerosol gene therapy is the interaction between the GTA and nebulisation device. We evaluated the effects of aerosolisation on our preferred formulation, plasmid DNA (pDNA) complexed with the cationic liposome GL67A (pDNA/GL67A) using commercially available nebuliser devices. The relatively high viscosity (6.3 +/- 0.1 cP) and particulate nature of pDNA/GL67A formulations hindered stable aerosol generation in ultrasonic and vibrating mesh nebulisers, but was not problematic in the jet nebulisers tested. Aerosol size characteristics varied significantly between devices but the AeroEclipse II nebuliser operating at 50 psi generated stable pDNA/GL67A aerosols suitable for delivery to the CF lung (MMAD 3.4 +/- 0.1 um). Importantly, biological function of pDNA/GL67A formulations was retained following nebulisation and although aerosol delivery rate was lower than other devices (0.17 +/- 0.01 ml/min) the breath-actuated AeroEclipse II nebuliser generated aerosol only during the inspiratory phase and as such was more efficient than other devices with 83 +/- 3% of generated aerosol available for patient inhalation. Based on these results we have selected the AeroEclipse II nebuliser for the delivery of pDNA/GL67A formulations to the lungs of CF patients as part of Phase IIa/b clinical studies. PMID- 24773061 TI - The influence of sex on renal function decline in people with Type 2 diabetes. AB - AIMS: Several reports have suggested a relationship between male sex and albuminuria in Type 2 diabetes, but impact on renal function decline has not been established. Our aim was to describe the influence of sex on renal function decline in Type 2 diabetes. METHODS: SURDIAGENE, an inception cohort, consisted in 1470 people with Type 2 diabetes. Patients without renal replacement therapy and with >= 3 serum creatinine determinations during follow-up prior to end-stage renal disease were included in the study. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Primary outcome was steep estimated glomerular filtration rate (eGFR) decline, defined as a yearly slope value lower than -3.5 ml min(-1) 1.73 m(-2). Secondary outcomes were estimated glomerular filtration rate trajectories according to sex and occurrence of end-stage renal disease. RESULTS: A total of 22 914 serum creatinine determinations were considered in 1146 participants (60% men), aged 65 +/- 11 years, with a median follow-up duration of 5.7 years (range 0.1-10.2). Median yearly estimated glomerular filtration rate slope was -1.31 ml min(-1) 1.73 m(-2) in women and -1.77 ml min(-1) 1.73 m(-2) in men (P < 0.001). Men were more likely than women to develop end-stage renal disease (22 men vs. 7 women; P(log-rank) = 0.03). Male sex was an independent risk factor of steep estimated glomerular filtration rate decline [adjusted odds ratio = 1.33 (1.02 1.76), P = 0.04] after adjustment for age, time from diagnosis of Type 2 diabetes, glycated haemoglobin, systolic blood pressure and urinary albumin:creatinine ratio. A multivariable linear mixed-effects model showed a significant difference of estimated glomerular filtration rate trajectories between men and women (P < 0.001). CONCLUSION: Male sex is an important independent factor associated with renal function decline in Type 2 diabetes. PMID- 24773063 TI - Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis: have you checked the ovaries? AB - Anti-N-methyl-D-aspartate receptor encephalitis is an autoimmune disorder that can occur as a paraneoplastic phenomenon related to ovarian teratomas. It is a serious but reversible condition with improved outcomes following prompt tumor removal. We report two cases from our recent experience. In the first case a small poorly described lesion, confirmed as a teratoma only at histology, was managed by laparoscopic oopohorectomy. In the second case a large teratoma was managed by laparoscopic cystectomy. Postoperatively both women made a good recovery. Gynecologists may be called upon to perform ovarian surgery outside of normal surgical indications, in young women who will often lack capacity to consent. Fertility-sparing ovarian cystectomy is possible in some cases, but will be challenging for small deeply buried tumors. Blind bilateral oophorectomy has been performed successfully in extreme cases. Information of the benefit of ovarian surgery will be essential to the surgeon during preoperative counseling. PMID- 24773064 TI - Recapitulating cell-cell adhesion using N-cadherin biologically tethered to substrates. AB - Intercellular adhesion modulated by cadherin molecules plays an important role in diverse cellular functions including tissue morphogenesis, regeneration, and pathogenesis. However, it is a challenging task to decipher the effects of cell cell adhesion in vitro because of difficulty in controlling the extent and numbers of cell-cell contacts. In this study, we hypothesize that tethering recombinant extracellular domains of neural cadherin with a C-terminal immunoglobulin Fc domain (N-Cad-Fc) to a substrate with an immobilized anti-Fc antibody (Fc-antibody) and a bifunctional polymer, which is reactive to both protein and substrate, would allow us to recapitulate cell-cell adhesion, independent of the number of cells plated on the substrate. To examine this hypothesis, we first immobilized Fc-antibody to a polyacrylamide hydrogel and a methacrylate-substituted glass using poly(amino-2-hydroxyethyl-co-2 methacryloxyethyl aspartamide)-g-poly(ethylene glycol)-N-hydroxysuccinimide ester (PHMAA-g-PEGNHS) and then incubated the gel in medium containing defined concentrations of the recombinant N-Cad-Fc. The resulting N-Cad-conjugated substrate enabled us to modulate adhesion of bone marrow stromal cells to the gel surface by varying the surface density of N-Cad-Fc. In contrast, direct chemical conjugation of N-Cad-Fc to the gel surface did not support cell adhesion. Additionally, the glass substrate biologically tethered with N-Cad-Fc promoted neuronal adhesion significantly more than substrates coated with poly-l-lysine. We suggest that this novel biological tethering method could be broadly applicable for modifying substrates with a variety of classical cadherins to enable the systematic study of the effects of cadherin-modulated cell-cell adhesion on cellular activities. PMID- 24773065 TI - Analytical validation of a human particle-enhanced nephelometric assay for cystatin C measurement in feline serum and urine. AB - BACKGROUND: In people and dogs, Cystatin C (CysC), a renal glomerular and tubular marker, seems superior to serum creatinine to estimate the glomerular filtration rate (GFR). A particle-enhanced nephelometric immunoassay is available to measure human CysC, but there are no reports in cats. OBJECTIVE: The goal of this study was the validation of the human CysC nephelometric assay with feline serum and urine, and to perform a pilot study comparing serum and urine CysC between healthy cats and cats with chronic kidney disease (CKD). METHODS: Western blot analysis was used to assess cross-reactivity between the polyclonal rabbit anti human CysC antibody and feline CysC. Imprecision and linearity were determined for feline serum and urine CysC. Serum and urine CysC were measured in 10 healthy and 10 CKD cats. RESULTS: Cross-reactivity between the polyclonal rabbit anti human CysC antibody and feline CysC was demonstrated. Intra- and inter-assay coefficients of variation in feline serum and urine were 1.3% and 0.4%, and 12.5%, and 4.1%, respectively. Cats with CKD had a significantly higher serum CysC concentration (1.24 [0.63-2.99] vs 0.79 [0.43-1.05] mg/L; P = .02) and urine CysC/urinary Creatinine (uCr) ratio (565.6 [0-1311] vs < 0.049/uCr mg/mol; P = .005) compared with healthy cats. CONCLUSIONS: The human nephelometric assay showed satisfactory validation results for feline CysC. Cats with CKD had a significantly higher sCysC concentration and uCysC/uCr ratio compared with healthy cats. Additional studies are necessary to evaluate CysC as an early marker of renal damage in cats. PMID- 24773066 TI - Combinatorial antimicrobial effect of curcumin with selected phytochemicals on Staphylococcus epidermidis. AB - Staphylococcus epidermidis is reported to be the main causative agent of nosocomial infections. It has become increasingly difficult to treat this micro organism because of the emergence of new antibiotic-resistant strains and its ability to form biofilm on medical associated devices. Phytochemicals acting in synergy are effective in killing the micro-organisms by lowering the doses, and synergistic compounds evade the development of resistance due to different mechanism of action. This study aims to determine the synergistic antimicrobial potential of curcumin with cinnamaldehyde, eugenol, and ellagic acid against S. epidermidis. Curcumin with ellagic acid as well as eugenol were found to have additive antimicrobial effect, whereas, in combination, curcumin and cinnamaldehyde were found to have synergistic effect against S. epidermidis (fractional inhibitory concentration index (FICI) = 0.5). Synergy between curcumin and cinnamaldehyde was established by time-kill kinetics and was further evaluated for antibiofilm activity. The dose required to inhibit biofilm formation was reduced to half than that needed to inhibit its planktonic culture (minimal inhibitory concentration (MIC) of curcumin = 3.12 MUg/ml; MIC of cinnamaldehyde = 15.62 MUg/ml; FICI = 0.248). Both curcumin and cinnamaldehyde disrupted the bacterial membrane for killing the bacteria as determined by permeability studies on Escherichia coli ML-35p. PMID- 24773067 TI - Biomimetic superoxide dismutase stabilized by photopolymerization for superoxide anions biosensing and cell monitoring. AB - Photopolymerization strategy, as one of the immobilization methods, has attracted considerable interest because of some advantages, such as easy operation, harmlessness to the biomolecules, and long storage stability. (E)-4-(4 Formylstyryl) pyridine (formylstyrylpyridine) was prepared through Heck reaction and used as a photopolymer material to immobilize biomimetic superoxide dismutase under ultraviolet irradiation (UV) irradiation in a short time. The styrylpyridinium moiety of Formylstyrylpyridine was photoreactive and formed a dimer under UV irradiation. Mn2P2O7 multilayer sheet, a novel superoxide dismutase mimic, was synthesized. The formed photopolymer can immobilize Mn2P2O7 firmly under UV irradiation. On the basis of high catalytic activity of Mn2P2O7 biomimetic enzyme and long-term stability of Mn2P2O7-formylstyrylpyridine film, after introducing multiwalled carbon nanotubes (MWCNTs), a novel electrochemical biosensing platform called MWCNTs/Mn2P2O7-formylstyrylpyridine for superoxide anion (O2(*-)) detection was constructed. The biosensor displayed good performance for O2(*-) detection and provided a reliable platform to adhere living cells directly on the modified electrode surface. Therefore, the biosensor was successfully applied to vitro determination of O2(*-) released from living cells, which had a promising prospect for living cells monitoring and diagnosis of reactive oxygen species-related diseases. PMID- 24773068 TI - A cost-analysis model for anticoagulant treatment in the hospital setting. AB - BACKGROUND: Rivaroxaban is the first oral factor Xa inhibitor approved in the US to reduce the risk of stroke and blood clots among people with non-valvular atrial fibrillation, treat deep vein thrombosis (DVT), treat pulmonary embolism (PE), reduce the risk of recurrence of DVT and PE, and prevent DVT and PE after knee or hip replacement surgery. The objective of this study was to evaluate the costs from a hospital perspective of treating patients with rivaroxaban vs other anticoagulant agents across these five populations. METHODS: An economic model was developed using treatment regimens from the ROCKET-AF, EINSTEIN-DVT and PE, and RECORD1-3 randomized clinical trials. The distribution of hospital admissions used in the model across the different populations was derived from the 2010 Healthcare Cost and Utilization Project database. The model compared total costs of anticoagulant treatment, monitoring, inpatient stay, and administration for patients receiving rivaroxaban vs other anticoagulant agents. The length of inpatient stay (LOS) was determined from the literature. RESULTS: Across all populations, rivaroxaban was associated with an overall mean cost savings of $1520 per patient. The largest cost savings associated with rivaroxaban was observed in patients with DVT or PE ($6205 and $2742 per patient, respectively). The main driver of the cost savings resulted from the reduction in LOS associated with rivaroxaban, contributing to ~90% of the total savings. Furthermore, the overall mean anticoagulant treatment cost was lower for rivaroxaban vs the reference groups. LIMITATIONS: The distribution of patients across indications used in the model may not be generalizable to all hospitals, where practice patterns may vary, and average LOS cost may not reflect the actual reimbursements that hospitals received. CONCLUSION: From a hospital perspective, the use of rivaroxaban may be associated with cost savings when compared to other anticoagulant treatments due to lower drug cost and shorter LOS associated with rivaroxaban. PMID- 24773069 TI - Evolution of paternal care in diploid and haplodiploid populations. AB - W. D. Hamilton famously suggested that the inflated relatedness of full sisters under haplodiploidy explains why all workers in the social hymenoptera are female. This suggestion has not stood up to further theoretical scrutiny and is not empirically supported. Rather, it appears that altruistic sib-rearing in the social hymenoptera is performed exclusively by females because this behaviour has its origins in parental care, which was performed exclusively by females in the ancestors of this insect group. However, haplodiploidy might still explain the sex of workers if this mode of inheritance has itself been responsible for the rarity of paternal care in this group. Here, we perform a theoretical kin selection analysis to investigate the evolution of paternal care in diploid and haplodiploid populations. We find that haplodiploidy may either inhibit or promote paternal care depending on model assumptions, but that under the most plausible scenarios it promotes - rather than inhibits - paternal care. Our analysis casts further doubt upon there being a causal link between haplodiploidy and eusociality. PMID- 24773070 TI - Efficient asymmetric syntheses of 1-phenyl-phosphindane, derivatives, and 2- or 3 oxa analogues: mission accomplished. AB - A highly enantioselective synthesis of unsubstituted 1-phenyl-phosphindane and its P-borane and P-oxide derivatives was effectively established via a new fluoride-triggered desilylative carbocyclization strategy. Preparation of the "oxygen atom-doped" 1-phenyl-3-oxa-1-phosphindane-P-borane analogue was otherwise achieved via a tandem P-alpha-iodination-intra-O-alkylation. PMID- 24773071 TI - Tabercarpamines A-J, apoptosis-inducing indole alkaloids from the leaves of Tabernaemontana corymbosa. AB - A total of 10 new indole alkaloids, tabercarpamines A-J (1-10), were isolated from the leaves of Tabernaemontana corymbosa. Tabercarpamines C-F (3-6) are rare C-14/C-15-seco-tabersonine-type monoterpenoid indole alkaloids, and 5 and 6 are the first examples with a lactone linkage between C-14 and C-20. The structures of these alkaloids were elucidated using spectroscopic methods, and the absolute configurations of 1 and 2 were determined using the ECD exciton chirality method. In addition, an MTT assay was used to examine the growth-inhibitory effects of all new isolates and of two known isolates on MCF-7, HepG2, and SMMC-7721 cells; 1 exhibited significant inhibitory effects against these three human cancer cell lines with IC50 values of 8.54, 3.31, and 6.76 MUM, respectively. Additionally, the results from the annexin-V/PI double-staining assay indicated that 1 might inhibit the proliferation of HepG2 cells by inducing apoptosis. PMID- 24773072 TI - Mitochondrial DNA copy number is associated with diagnosis and prognosis of head and neck cancer. AB - CONTEXT: Mitochondrial DNA (mtDNA) copy number correlates with tumor pathology in some cancers. OBJECTIVE: To investigate mtDNA copy number in head and neck cancer (HNC). MATERIALS AND METHODS: mtDNA copy number was determined and compared between HNC patients and malignancy-free controls. RESULTS: The mtDNA copy number was significantly higher in HNC patients, increased with cancer progression and correlated negatively with patient survival. DISCUSSION: mtDNA copy number appears to be associated with HNC stage and survival, but confirmation requires similar studies in larger cohorts. CONCLUSION: Studies to establish the nature of the relationship between mtDNA copy number and HNC are warranted. PMID- 24773073 TI - Role of the p38 pathway in mineral trioxide aggregate-induced cell viability and angiogenesis-related proteins of dental pulp cell in vitro. AB - AIM: To investigate the influence of mineral trioxide aggregate (MTA) on angiogenesis of primary human dental pulp cells (hDPCs) via the MAPK pathway, in particular p38. METHODOLOGY: Human dental pulp cells were cultured with MTA to angiogenesis, after which cell viability, ion concentration, osmolality, NO secretion, the von Willebrand factor (vWF) and angiopoietin-1 (Ang-1) protein expression were examined. PrestoBlue((r)) was used for evaluating the proliferation of hDPCs. An enzyme-linked immunosorbent assay was employed to determine vWF and Ang-1 protein secretion in hDPCs cultured on MTA and the control. Cells cultured on the tissue culture plate without the cement were used as the control. The t-test was used to evaluate the significance of the differences between the mean values. RESULTS: Mineral trioxide aggregate elicited a significant (P < 0.05) increased viability compared with the control (15%, 16% and 13% on days 1, 3 and 5 of cell seeding, respectively). MTA consumed calcium and phosphate ions, and released more Si ions in the medium. MTA significantly (P < 0.05) increased the osmolality of the medium to 313, 328 and 341 mOsm kg(-1) after 1, 3 and 5 days, respectively. P38 was activated through phosphorylation, and the phosphorylation kinase was investigated in the cell system after being cultured with MTA. Expression levels for Ang-1 and vWF in hDPCs on MTA were higher than those of the MTA + p38 inhibitor (SB203580) group (P < 0.05) at all of the time-points. CONCLUSIONS: Mineral trioxide aggregate was able to activate the p38 pathway in hDPCs cultured in vitro. Moreover, Si increased the osmolality required to facilitate the angiogenic differentiation of hDPCs via the p38 signalling pathway. When the p38 pathway was blocked by SB203580, the angiogenic dependent protein secretion decreased. These findings verify that the p38 pathway plays a key role in regulating the angiogenic behaviour of hDPCs cultured on MTA. PMID- 24773074 TI - PAX6 downregulates miR-124 expression to promote cell migration during embryonic stem cell differentiation. AB - PAX6-null mice exhibit defects in multiple organs leading to neonatal lethality, but the mechanism by which this occurs has not yet fully elucidated. In this study, we generated induced pluripotent stem cells (iPSCs) from Pax6-mutant mice and investigated the effect of PAX6 on cell fate during embryoid body (EB) formation. We found that PAX6 promotes cell migration by directly downregulating miR-124, which is important for the fate transition of migratory cells during gastrulation of embryonic stem (ES) cells. Although several downstream targets of miR-124 have been reported, little is known regarding the upstream regulation of miR-124. When we observed EB formation of iPSCs from Pax6-mutant mice, we found that higher levels of miR-124 in Pax6 homozygous EBs (Homo-EBs) inhibited cell migration, whereas inhibition of miR-124 in Homo-EBs rescued the migratory phenotypes associated with PAX6 deficiency. Further, we found that PAX6 binds to the promoter regions of the miR-124-3 gene and directly represses its expression. Therefore, we propose a novel PAX6-miR-124 pathway that controls ES cell migration. Our findings may provide important information for studies on ES cell differentiation and embryonic development. PMID- 24773075 TI - Metabolic engineering of Escherichia coli for production of butyric acid. AB - The butyrate production by engineered Escherichia coli is afflicted by both low titer and low selectivity (defined as the butyrate/acetate (B/A) ratio). To address this issue, a strategy for metabolic engineering of E. coli was implemented including (1) elimination of all major NADH-dependent reactions in the fermentation metabolism, (2) reconstruction of a heterologous pathway leading to butyryl-CoA, (3) recruitment of endogenous atoDA for conversion of butyryl-CoA to butyrate with acetate as a CoA acceptor, and (4) removal of the acetate synthesis pathway. Grown on glucose (20 g/L) plus acetate (8 g/L), the engineered strain consumed almost all glucose and acetate and produced 10 g/L butyrate as a predominant product within 48 h. It leads to high butyrate selectivity with the B/A ratio reaching 143. The result shows that our proposed approach may open a new avenue in biotechnology for production of butyrate in E. coli. PMID- 24773076 TI - Mycobacterium kansasii cutaneous infection in a patient with sarcoidosis treated with anti-TNF agents. AB - We describe a Mycobacterium kansasii cutaneous infection that was diagnosed in a 52-year-old female patient with sarcoidosis receiving anti-TNF agents. The diagnosis was based on the positive culture of the foot ulcerative tissue. The isolation and identification of bacterium was based on phenotypic and molecular methods. Therapy and follow-up of the patient is discussed. PMID- 24773077 TI - Frailty indexes, screening instruments and their application in Belgian primary care. AB - OBJECTIVES: The complex and expensive medical care for a rising number of older patients presents a significant challenge to the health care system. Identifying cost-effective preventive interventions and systematically applying them in the elderly population could help address this challenge. Frailty assessments could prove to be valuable tools by identifying at-risk individuals to which these interventions would be offered. This review seeks to provide the reader with an overview of frailty and explain how frailty assessments could contribute to daily practice. METHODS: PubMed was searched for articles concerning frailty assessment (July 2013). Articles discussing prominent frailty models and articles primarily focused on comparing frailty assessments in the home-dwelling population were used for this article. Domus Medica was searched for guidelines concerning the use of frailty in Belgian primary care. RESULTS: Several notable models of frailty are summarized and discussed to provide the reader with an overview of available frailty assessments. Frailty screening modalities in primary care are discussed, as well as the current recommendations for the use of frailty assessments in Belgian primary care. The advantages of a systematic frailty assessment in primary care and other settings are highlighted. CONCLUSION: This article recommends the assessment of frailty status as a screening tool for the evaluation of the older person in primary care. An overview of available frailty models is offered for this purpose. A consensus should be reached on which model is most appropriate. The screening for frailty promotes early intervention and timely involvement of specialists with the purpose of avoiding unfavourable outcomes, such as death or disability. PMID- 24773079 TI - Free-standing LiNi0.5Mn1.5O4/carbon nanofiber network film as lightweight and high-power cathode for lithium ion batteries. AB - Lightweight and high-power LiNi0.5Mn1.5O4/carbon nanofiber (CNF) network electrodes are developed as a high-voltage cathode for lithium ion batteries. The LiNi0.5Mn1.5O4/CNF network electrodes are free-standing and can be used as a cathode without using any binder, carbon black, or metal current collector, and hence the total weight of the electrode is highly reduced while keeping the same areal loading of active materials. Compared with conventional electrodes, the LiNi0.5Mn1.5O4/CNF network electrodes can yield up to 55% reduction in total weight and 2.2 times enhancement in the weight percentage of active material in the whole electrode. Moreover, the LiNi0.5Mn1.5O4/carbon nanofiber (CNF) network electrodes showed excellent current rate capability in the large-current test up to 20C (1C = 140 mAh/g), when the conventional electrodes showed almost no capacity at the same condition. Further analysis of polarization resistance confirmed the favorable conductivity from the CNF network compared with the conventional electrode structure. By reducing the weight, increasing the working voltage, and improving the large-current rate capability simultaneously, the LiNi0.5Mn1.5O4/CNF electrode structure can highly enhance the energy/power density of lithium ion batteries and thus holds great potential to be used with ultrathin, ultralight electronic devices as well as electric vehicles and hybrid electric vehicles. PMID- 24773078 TI - The general anaesthetic etomidate inhibits the excitability of mouse thalamocortical relay neurons by modulating multiple modes of GABAA receptor mediated inhibition. AB - Modulation of thalamocortical (TC) relay neuron function has been implicated in the sedative and hypnotic effects of general anaesthetics. Inhibition of TC neurons is mediated predominantly by a combination of phasic and tonic inhibition, together with a recently described 'spillover' mode of inhibition, generated by the dynamic recruitment of extrasynaptic gamma-aminobutyric acid (GABA)A receptors (GABAA Rs). Previous studies demonstrated that the intravenous anaesthetic etomidate enhances tonic and phasic inhibition in TC relay neurons, but it is not known how etomidate may influence spillover inhibition. Moreover, it is unclear how etomidate influences the excitability of TC neurons. Thus, to investigate the relative contribution of synaptic (alpha1beta2gamma2) and extrasynaptic (alpha4beta2delta) GABAA Rs to the thalamic effects of etomidate, we performed whole-cell recordings from mouse TC neurons lacking synaptic (alpha1(0/0) ) or extrasynaptic (delta(0/0) ) GABAA Rs. Etomidate (3 MUm) significantly inhibited action-potential discharge in a manner that was dependent on facilitation of both synaptic and extrasynaptic GABAA Rs, although enhanced tonic inhibition was dominant in this respect. Additionally, phasic inhibition evoked by stimulation of the nucleus reticularis exhibited a spillover component mediated by delta-GABAA Rs, which was significantly prolonged in the presence of etomidate. Thus, etomidate greatly enhanced the transient suppression of TC spike trains by evoked inhibitory postsynaptic potentials. Collectively, these results suggest that the deactivation of thalamus observed during etomidate-induced anaesthesia involves potentiation of tonic and phasic inhibition, and implicate amplification of spillover inhibition as a novel mechanism to regulate the gating of sensory information through the thalamus during anaesthetic states. PMID- 24773080 TI - Highly prevalent SERPINB7 founder mutation causes pseudodominant inheritance pattern in Nagashima-type palmoplantar keratosis. AB - BACKGROUND: Nagashima-type palmoplantar keratosis (NPPK) is a distinct autosomal recessive genodermatosis characterized by diffuse transgressive palmoplantar keratoderma (PPK). Very recently, putative loss-of-function mutations in SERPINB7, which encodes a member of the serine protease inhibitor superfamily and is abundantly expressed in the epidermis, have been identified as a cause of NPPK. OBJECTIVES: To confirm further the role of SERPINB7 mutations in the pathogenesis of NPPK. METHODS: We analysed 10 Japanese families with NPPK using Sanger and/or whole-exome sequencing. RESULTS: We identified one novel and three recurrent null mutations in SERPINB7. In all the families, the NPPK trait was inherited in an autosomal recessive manner; in one of the families, there was pseudodominant inheritance, which had not been described in NPPK. CONCLUSIONS: These data clearly provide further evidence that NPPK is caused by loss-of function mutations in SERPINB7. PMID- 24773081 TI - Perinatal outcome in relation to fetal sex in offspring to mothers with pre gestational and gestational diabetes--a population-based study. AB - AIM: The objective of the present study was to investigate if perinatal outcome differs with fetal sex in pregnancies with maternal Type 1 diabetes, Type 2 diabetes or gestational diabetes. METHODS: This was a population-based cohort study, with data from the Medical Birth Registry in Sweden throughout the period 1998-2007. Singleton pregnancies with maternal Type 1 diabetes (n = 4092), Type 2 diabetes (n = 412) and gestational diabetes (n = 8602) were identified based on the International Classification of Diseases, 10th edition code. For comparison, 905 565 pregnancies without diabetes were included. The primary outcome was a composite outcome, consisting of any of the following diagnoses: perinatal mortality rate, major malformation, preterm delivery, acute respiratory disorders and neonatal hypoglycaemia. Logistic regression was used to obtain odds ratios for adverse outcomes in male offspring within the diabetic and reference cohorts, respectively. RESULTS: In pregnancies with diabetes, maternal characteristics did not differ with fetal sex, except for a higher rate of Caesarean delivery in male offspring of women with Type 1 diabetes. Male infants to mothers with Type 1 diabetes and gestational diabetes had significantly increased odds of respiratory disorders [adjusted odds ratio (confidence interval) Type 1 diabetes: 1.50 (1.12 2.02); gestational diabetes: 1.81 (1.27-2.57)]. Male infants to mothers with gestational diabetes also had significantly increased odds of major malformations [adjusted odds ratio: 1.44 (1.07-1.93)]. In offspring of mothers with Type 2 diabetes, odds ratios of most outcomes were higher in male infants; however, not significantly different from female infants. In pregnancies without diabetes, male infants had significantly higher odds of all adverse outcomes, except perinatal mortality rate. CONCLUSION: The risk of adverse perinatal outcome in offspring of mothers with Type 1 diabetes and gestational diabetes did not differ by sex, except for a higher risk in male infants for respiratory disorders. The risk of major malformations was also significantly increased in male offspring to mothers with gestational diabetes. In offspring of mothers with Type 2 diabetes, no significant differences between sexes were found. PMID- 24773083 TI - Phosphine oxide type bipolar host material for high quantum efficiency in thermally activated delayed fluorescent device. AB - Highly efficient thermally activated delayed fluorescence devices were developed using a bipolar host material, 2,7-bis(diphenylphosphoryl)-9-phenyl-9H-carbazole (PPO27), derived from carbazole and diphenylphosphine oxide. The PPO27 host was effective for good charge balance and energy transfer from the PPO27 host to thermally activated delayed fluorescence dopant. The PPO27 device doped with (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile dopant could realize a high quantum efficiency of 24.2%. PMID- 24773082 TI - The impact of demographic, social, and environmental factors on the development of steroid-responsive meningitis-arteritis (SRMA) in the United Kingdom. AB - BACKGROUND: Steroid-responsive meningitis-arteritis (SRMA) is an inflammatory disease of dogs that is suspected to be immune-mediated. The development of other immune-mediated diseases has been linked to vaccinations, time of the year, geographic location, sex, neuter status, and breed. HYPOTHESIS/OBJECTIVES: To identify if the development of SRMA is associated with time of year, vaccination, geographic location, sex, neuter status, and breed. ANIMALS: Sixty SRMA cases and 180 controls, all <=24 months of age and matched for year of presentation, from a referral hospital population in the United Kingdom. METHODS: Retrospective case control study with unconditional logistic regression analysis. RESULTS: Beagles (P = .001), Border Collies (P = .001), Boxers (P = .032), Jack Russell Terriers (P = .001), Weimaraners (P = .048), and Whippets (P < .001) had significantly greater odds of developing SRMA in this population of dogs. Vaccination, time of year, geographic category, sex, and neuter status did not increase the odds of developing SRMA. CONCLUSIONS AND CLINICAL IMPORTANCE: Only breed increased the odds of developing SRMA. It would be prudent to investigate the genetics of the identified breeds to help elucidate the etiopathogenesis of SRMA. PMID- 24773084 TI - Two new cucurbitane triterpenoids from the seeds of Momordica charantia. AB - Two new cucurbitane triterpenoids 1 and 2 were isolated, together with six known compounds, from the seeds of Momordica charantia L. The structures of new compounds were determined to be 3-O-{[beta-d-galactopyranosyl(1 -> 6)]-O-beta-d galactopyranosyl}-23(R), 24(R), 25-trihydroxycucur-bit-5-ene (1), 3-O-[beta-d galactopyranosyl]-25-O-beta-d-galactopyranosyl-7(R), 22(S), 23(R), 24(R), 25 pentahydroxycucurbit-5-ene (2), respectively. Their structures were elucidated by the combination of mass spectrometry, one- and two-dimensional NMR experiments and chemical reactions. PMID- 24773085 TI - Boron nitride nanosheet on gold as an electrocatalyst for oxygen reduction reaction: theoretical suggestion and experimental proof. AB - Boron nitride (BN), which is an insulator with a wide band gap, supported on Au is theoretically suggested and experimentally proved to act as an electrocatalyst for oxygen reduction reaction (ORR). Density-functional theory calculations show that the band gap of a free h-BN monolayer is 4.6 eV but a slight protrusion of the unoccupied BN states toward the Fermi level is observed if BN is supported on Au(111) due to the BN-Au interaction. A theoretically predicted metastable configuration of O2 on h-BN/Au(111), which can serve as precursors for ORR, and free energy diagrams for ORR on h-BN/Au(111) via two- and four-electron pathways show that ORR to H2O2 is possible at this electrode. It is experimentally proved that overpotential for ORR at the gold electrode is significantly reduced by depositing BN nanosheets. No such effect is observed at the glassy carbon electrode, demonstrating the importance of BN-substrate interaction for h-BN to act as the ORR electrocatalyst. A possible role of the edge of the BN islands for ORR is also discussed. PMID- 24773086 TI - Use of portable analytical methods to determine the stoichiometry of reaction for hexahydrotriazine-based hydrogen sulfide scavenger operations. AB - During the reaction between 1,3,5-tris(2-hydroxyethyl)hexahydro-s-triazine and hydrogen sulphide, the principle by-product is the organic sulphide 5-(2 hydroxyethyl)dithiazine. It can be determined by a novel, portable, field-capable ion mobility spectrometry method described herein and enables the "degree spent" to be determined. Dependant upon the level of carbon dioxide in the produced gas, a mixture of ethanolaminium bicarbonate and ethanolamine bisulphide is also produced. Using a field capable spectrophotometric method the level of inorganic sulphide can be determined, thus allowing the ethanolaminium bisulphide concentration to be calculated. Provided the fluid is only partially spent, and there is some unreacted 1,3,5-tris(2-hydroxyethyl)hexahydro-s-triazine remaining; the only source of inorganic sulphide is the amine salt. From a knowledge of the original fluid concentration, the combination of these two methods allows the effective stoichiometry, or observed molar reaction proportions between 1,3,5 tris(2-hydroxyethyl)hexahydro-s-triazine and hydrogen sulphide, to be measured for a specific field location. PMID- 24773087 TI - Plasma biochemistry and urinalysis variables of koalas (Phascolarctos cinereus) with and without oxalate nephrosis. AB - BACKGROUND: Oxalate nephrosis is a highly prevalent disease in the Mount Lofty Ranges koala population in South Australia, but associated clinicopathologic findings remain undescribed. OBJECTIVES: The aims of this study were to determine plasma biochemical and urinalysis variables, particularly for renal function and urinary crystal morphology and composition, in koalas with oxalate nephrosis. METHODS: Blood and urine samples from Mount Lofty Ranges koalas with oxalate nephrosis were compared with those unaffected by renal oxalate crystal deposition from Mount Lofty and Kangaroo Island, South Australia and Moggill, Queensland. Plasma and urine biochemistry variables were analyzed using a Cobas Bio analyzer, and urinary oxalate by high-performance liquid chromatography. Urinary crystal composition was determined by infrared spectroscopy and energy dispersive X-ray analysis. RESULTS: Azotemia (urea > 6.6 mmol/L, creatinine > 150 MUmol/L) was found in 93% of koalas with oxalate nephrosis (n = 15). All azotemic animals had renal insufficiency (urine specific gravity [USG] < 1.035), and in 83%, USG was < 1.030. Koalas with oxalate nephrosis were hyperoxaluric compared with Queensland koalas (P < .01). Urinary crystals from koalas with oxalate nephrosis had atypical morphology and were composed of calcium oxalate. Mount Lofty Ranges koalas unaffected by renal oxalate crystal deposition had renal insufficiency (43%), although only 14% had USG < 1.030 (n = 7). Unaffected Mount Lofty Ranges and Kangaroo Island koalas were hyperoxaluric compared with Queensland koalas (P < .01). CONCLUSIONS: Koalas with oxalate nephrosis from the Mount Lofty Ranges had renal insufficiency, hyperoxaluria, and pathognomonic urinary crystals. The findings of this study will aid veterinary diagnosis of this disease. PMID- 24773088 TI - A classification of congenital uterine anomalies predicting pregnancy outcomes. AB - OBJECTIVE: To evaluate pregnancy outcomes in women with uterine anomalies by applying a method for diagnosing and classifying congenital uterine malformations. DESIGN: Retrospective study. SETTING: Tertiary care center. POPULATION: Ninety-four women with uterine anomalies who delivered after 22 gestational weeks. METHODS: Excluding the 14 women with a history of surgery and seven with one endometrial cavity, 73 women with two endometrial cavities were subdivided into those with two external uterine orifices (2-OS subgroup) and those with one external uterine orifice (1-OS subgroup). MAIN OUTCOME MEASURES: Pregnancy outcomes, such as preterm birth, abnormal fetal presentation, cesarean delivery and placental abruption. RESULTS: The 2-OS subgroup comprised women with a didelphic or complete septate uterus who had a significantly higher rate of cesarean delivery (91% vs. 18%, p < 0.001) than the control group (normal uterine morphology; n = 5763). The 1-OS subgroup comprised women with a bicornuate or incomplete septate uterus who had significantly higher rates of preterm birth (27% vs. 5%, p < 0.001) and placental abruption (14% vs. 0.7%, p < 0.001) than the control group. CONCLUSIONS: Classification of uterine anomalies by the number of uterine endometrial cavities and external uterine orifices is an easy and reliable means of predicting pregnancy outcomes. PMID- 24773089 TI - Highly protein-resistant coatings and suspension cell culture thereon from amphiphilic block copolymers prepared by RAFT polymerization. AB - Novel amphiphilic block copolymers composed of hydrophobic (poly(2-methoxyethyl acrylate): M) and hydrophilic (poly(N,N-dimethylacrylamide): D) segments were synthesized by living radical polymerization: a reversible addition-fragmentation chain-transfer polymerization. Two types of amphiphilic block copolymers, triblock (MDM) and 4-arm block ((MD)4) copolymers with specific compositions (D/M = (750-1500)/250), were prepared by a versatile one-pot synthesis. These copolymers show good adhesion to various types of substrates (e.g., polystyrene, polycarbonate, polypropylene, Ti, and glass), and the surface coating showed high protein repellency and a low contact angle for water, regardless of the substrate. The two opposing characteristics of high protein repellency and good substrate adhesion were achieved by the combined effects of the molecular architecture of the block copolymers, the high molecular weight, and the characteristics of each segment, that is, low protein adsorption capability of both segments and low glass transition temperature of the hydrophobic segment. Further, a polystyrene dish coated with the MDM block copolymer could be sterilized by gamma-ray irradiation and used as a good substrate for a suspension cell culture that exhibits low cell adhesion and good cell growth. PMID- 24773090 TI - C-shaped diastereomers containing cofacial thiophene-substituted quinoxaline rings: synthesis, photophysical properties, and X-ray crystallography. AB - Synthesis and characterization of two diastereomeric C-shaped molecules containing cofacial thiophene-substituted quinoxaline rings are described. A previously known bis-alpha-diketone was condensed with an excess of 4-bromo-1,2 diaminobenzene in the presence of zinc acetate to give a mixture of two C-shaped diastereomers with cofacial bromine-substituted quinoxaline rings. After chromatographic separation, thiophene rings were installed by a microwave assisted Suzuki coupling reaction, resulting in highly emissive diastereomeric compounds that were studied by UV-vis, fluorescence, and NMR spectroscopy, as well as X-ray crystallography. The unique symmetry of each diastereomer was confirmed by NMR spectroscopy. NMR data indicated that the syn isomer has restricted rotation about the bond connecting the thiophene and quinoxaline rings, which was also observed in the solid state. The spectroscopic properties of the C-shaped diastereomers were compared to a model compound containing only a single thiophene-substituted quinoxaline ring. Ground state intramolecular pi-pi interactions in solution were detected by NMR and UV-vis spectroscopy. Red shifted emission bands, band broadening, and large Stokes shifts were observed, which collectively suggest excited state pi-pi interactions that produce excimer like emissions, as well as a remarkable positive emission solvatochromism, indicating charge-transfer character in the excited state. PMID- 24773091 TI - Clients' and therapists' real relationship and session quality in brief therapy: an actor partner interdependence analysis. AB - This study used the Actor Partner Interdependence Model (APIM; Kenny & Cook, 1999) to examine the associations of client- and therapist-rated real relationship (RR) and session quality over time. Eighty-seven clients and their therapists (n = 25) completed RR and session quality measures after every session of brief therapy. Therapists' current session quality ratings were significantly related to all of the following: session number (b = .04), their session quality rating of the previous session (b = .24), their RR in the previous session (b = 1.091), their client's RR in the previous session (b = .17), and interactions between their own and their clients' RR and session number (b = -.16 and beta = .04, respectively). Clients' ratings of current session quality were significantly related to only their own RR in the previous session (b = .47). Implications for future research and practice are discussed. PMID- 24773092 TI - The role of mentalizing and epistemic trust in the therapeutic relationship. AB - Mentalizing--the capacity to understand others' and one's own behavior in terms of mental states-is a defining human social and psychological achievement. It involves a complex and demanding spectrum of capacities that are susceptible to different strengths, weakness, and failings; personality disorders are often associated with severe and consistent mentalizing difficulties (Fonagy & Bateman, 2008). In this article, we will argue for the role of mentalizing in the therapeutic relationship, suggesting that although mentalization-based treatment may be a specific and particular form of practice, the "mentalizing therapist" is a universal constituent of effective psychotherapeutic interventions. PMID- 24773093 TI - Working with the process dimension in relational therapies: guidelines for clinical training. AB - This article offers guidelines for training relationally oriented therapists. We highlight core concepts that are widely used across relationally oriented therapies. We focus on the process dimension and the therapeutic relationship, and illustrate how process comments are the moderator variable that makes each of the core concepts more effective. Guidelines are provided for clinical instructors to help their trainees use these challenging, but potent, interventions that bring intensity to the therapeutic relationship and help provide the corrective emotional experience. PMID- 24773094 TI - Dialectical behavior therapy for adolescent binge eating, purging, suicidal behavior, and non-suicidal self-injury: a pilot study. AB - There are few published randomized controlled trials examining treatment for symptoms of bulimia nervosa (BN) in adolescents. Additionally, many adolescents presenting for treatment for BN symptoms endorse co-occurring mood disturbances, suicidality, and nonsuicidal self-injury (NSSI), and may not meet full Diagnostic and Statistical Manual-IV-Text Revision (DSM-IV-TR) diagnostic criteria for BN. In addition to the limited number of randomized controlled trials, published treatment studies of BN symptoms in adolescence do not specifically address the multiple comorbid symptoms that these adolescents often report. The purpose of this pilot study was to examine the feasibility and effectiveness of an outpatient dialectical behavior therapy (DBT) program for adolescents with symptoms of BN, suicide attempts, and NSSI. Ten eligible participants enrolled in the study; 3 dropped within 4 weeks of initiating treatment. In addition to binge eating and suicidal behavior, participants also endorsed a number of other comorbid mood disorders and substance abuse. Seven participants completed 6 months of treatment and 6-month follow-up assessments. Treatment included access to a crisis management system, individual therapy, skills training, and a therapist consultation team. At posttreatment, participants had significantly reduced self-harm; (Cohen's d = 1.35), frequency of objective binge episodes (Cohen's d = .46), frequency of purging (Cohen's d = .66), and Global Eating Disorder Examination scores (Cohen's d = .64). At follow-up, 6 participants were abstinent of NSSI; 3 participants were abstinent from binge eating. At follow-up, treatment gains were maintained and enhanced. Results indicate that it is feasible to address multiple forms of psychopathology during the treatment of BN symptoms in this age-group. PMID- 24773095 TI - Functional analytic psychotherapy: a behavioral relational approach to treatment. AB - Functional analytic psychotherapy (FAP) is a relational approach to psychotherapy that is behavioral, yet involves an intensive, emotional, and in-depth therapy experience. FAP is approachable by therapists of diverse theoretical backgrounds owing to the minimal use of behavioral jargon, and can be used as an addition or complement to other interventions. The methods described in this article-being aware of clients' clinically relevant behaviors, being courageous in evoking clinically relevant behaviors, reinforcing improvements with therapeutic love, using behavioral interpretations to help clients generalize changes to daily life, and providing intensive and personal experiential training of FAP practitioners-maximize the impact of the therapeutic relationship to promote change and personal growth for both clients and therapists. PMID- 24773096 TI - Transference and insight in psychotherapy with gay and bisexual male clients: the role of sexual orientation identity integration. AB - Clinical writing has suggested that the therapeutic process and relationship in work with lesbian, gay, and bisexual clients may be influenced by the extent to which clients have accepted their sexual orientation and developed a social network supportive of their sexual orientation, a construct we refer to as sexual orientation identity integration. The present cross-sectional study investigated this proposition by examining the identity integration ratings of 90 gay and bisexual male clients in relation to elements of treatment as rated by both the therapist (insight, negative transference, working alliance, session depth, and client improvement) and client (working alliance, session depth, and client improvement). Participants were male-male therapy dyads recruited from lesbian, gay, and bisexual-affirming practices. Client identity integration was negatively associated with transference, and positively associated with ratings of insight, alliance, depth, and improvement. Insight, but not transference, uniquely mediated the positive association between identity integration and most indicators of therapeutic quality. Results from an exploratory model suggested that transference may indirectly influence therapeutic quality by serving as a barrier to insight. PMID- 24773097 TI - Incremental costs associated with myocardial infarction and stroke in patients with type 2 diabetes mellitus: an overview for economic modeling. AB - OBJECTIVE: To identify cost estimates related to myocardial infarction (MI) or stroke in patients with type 2 diabetes mellitus (T2DM) for use in economic models. METHODS: A systematic literature review was conducted. Electronic databases and conference abstracts were screened against inclusion criteria, which included studies performed in patients who had T2DM before experiencing an MI or stroke. Primary cost studies and economic models were included. Costs were converted to 2012 pounds sterling. RESULTS: Fifty-four studies were identified: 13 primary cost studies and 41 economic evaluations using secondary sources for complication costs. Primary studies provided costs from 10 countries. Estimates for a fatal event ranged from L2482-L5222 for MI and from L4900-L6694 for stroke. Costs for the year a non-fatal event occurred ranged from L5071-L29,249 for MI and from L5171-L38,732 for stroke. Annual follow-up costs ranged from L945-L1616 for an MI and from L4704-L12,926 for a stroke. Economic evaluations from 12 countries were identified, and costs of complications showed similar variability to the primary studies. DISCUSSION: The costs identified within primary studies varied between and within countries. Many studies used costs estimated in studies not specific to patients with T2DM. Data gaps included a detailed breakdown of resource use, which affected the ability to compare data across countries. CONCLUSIONS: In the development of economic models for patients with T2DM, the use of accurate estimates of costs associated with MI and stroke is important. When country-specific costs are not available, clear justification for the choice of estimates should be provided. PMID- 24773098 TI - Direct production of enaminones from terminal alkynes via rhodium-catalyzed reaction of formamides with N-sulfonyl-1,2,3-triazoles. AB - A rhodium-catalyzed reaction of formamides with N-sulfonyl-1,2,3-triazoles is developed to formulate a new one-pot procedure for the direct synthesis of alpha amino enaminones from terminal alkynes. PMID- 24773100 TI - Investigation of the effects of a polymerised bovine haemoglobin solution on tension in isolated canine saphenous artery. AB - OBJECTIVES: To investigate the vasoconstriction induced by a polymerised bovine haemoglobin solution, Hb-200, in isolated canine arteries. METHODS: Rings of canine saphenous artery, from euthanatized dogs, were mounted between stainless steel wires in Krebs' solution (95% O2 , 5% CO2 , 37 degrees C) for isometric tension recording. Following incubation with Hb-200, cumulative concentration response curves to phenylephrine (vasoconstrictor) and acetylcholine (vasodilator) were investigated. Responses to acute addition of Hb-200 were also examined in pre-constricted or pre-dilated arteries. Responses were further studied in the presence or absence of the endothelium, inhibitors of endothelium dependent vasodilation (L-NAME, charybdotoxin and apamin), an endothelin antagonist (BQ-788) and the antioxidant superoxide dismutase. RESULTS: Incubation with Hb-200 (0.2 or 2 g/L) significantly enhanced phenylephrine-induced contraction (decreasing half maximal effective concentration, EC50 , P=0.0035) and inhibited acetylcholine-induced relaxation (increasing EC50 , P<0.0001). Acute addition of Hb-200 (0.2 or 2 g/L) significantly increased tension in pre constricted arteries (P=0.0059) and reversed relaxation in pre-dilated arteries (P=0.0005). These acute responses were abolished in endothelium-denuded arteries and arteries incubated with L-NAME. Responses to Hb-200 were unaffected by incubation with charybdotoxin and apamin, BQ-788, or superoxide dismutase. CLINICAL SIGNIFICANCE: Low concentrations of Hb-200 enhance vasoconstriction in isolated canine saphenous artery, primarily by antagonism of nitric oxide. This effect may be detrimental in some dogs (e.g. those at risk of volume overload) but beneficial in others (e.g. those in septic shock). PMID- 24773099 TI - Task-modulated coactivation of vergence neural substrates. AB - While functional magnetic resonance imaging (fMRI) has identified which regions of interests (ROIs) are functionally active during a vergence movement (inward or outward eye rotation), task-modulated coactivation between ROIs is less understood. This study tested the following hypotheses: (1) significant task modulated coactivation would be observed between the frontal eye fields (FEFs), the posterior parietal cortex (PPC), and the cerebellar vermis (CV); (2) significantly more functional activity and task-modulated coactivation would be observed in binocularly normal controls (BNCs) compared with convergence insufficiency (CI) subjects; and (3) after vergence training, the functional activity and task-modulated coactivation would increase in CIs compared with their baseline measurements. A block design of sustained fixation versus vergence eye movements stimulated activity in the FEFs, PPC, and CV. fMRI data from four CI subjects before and after vergence training were compared with seven BNCs. Functional activity was assessed using the blood oxygenation level dependent (BOLD) percent signal change. Task-modulated coactivation was assessed using an ROI-based task-modulated coactivation analysis that revealed significant correlation between the FEF, PPC, and CV ROIs. Prior to vergence training, the CIs had a reduced BOLD percent signal change compared with BNCs for the CV (p<0.05), FEFs, and PPC (p<0.01). The BOLD percent signal change increased within the CV, FEF, and PPC ROIs (p<0.001) as did the task-modulated coactivation between the FEFs and CV as well as the PPC and CV (p<0.05) when comparing the CI pre- and post-training datasets. Results from the Convergence Insufficiency Symptom Survey were correlated to the percent BOLD signal change from the FEFs and CV (p<0.05). PMID- 24773101 TI - Age differences in affective and cardiovascular responses to a negative social interaction: the role of goals, appraisals, and emotion regulation. AB - Older adults often report less affective reactivity to interpersonal tensions than younger individuals, but few studies have directly investigated mechanisms explaining this effect. The current study examined whether older adults' differential endorsement of goals, appraisals, and emotion regulation strategies (i.e., conflict avoidance/de-escalation, self-distraction) during a controlled negative social interaction may explain age differences in affective and cardiovascular responses to the conflict discussion. Participants (N = 159; 80 younger adults, 79 older adults) discussed hypothetical dilemmas with disagreeable confederates. Throughout the laboratory session, participants' subjective emotional experience, blood pressure, and pulse rate were assessed. Older adults generally exhibited less reactivity (negative affect reactivity, diastolic blood pressure reactivity, and pulse rate reactivity) to the task and more pronounced positive and negative affect recovery following the task than did younger adults. Older adults appraised the task as more enjoyable and the confederate as more likeable and more strongly endorsed goals to perform well on the task, which mediated age differences in negative affect reactivity, pulse rate reactivity, and positive affect recovery (i.e., increases in posttask positive affect), respectively. In addition, younger adults showed increased negative affect reactivity with greater use of self-distraction, whereas older adults did not. Together, findings suggest that older adults respond less negatively to unpleasant social interactions than younger adults, and these responses are explained in part by older adults' pursuit of different motivational goals, less threatening appraisals of the social interaction, and more effective use of self-distraction, compared with younger adults. PMID- 24773102 TI - Handling agents and patients: representational cospeech gestures help children comprehend complex syntactic constructions. AB - Gesture is an important precursor of children's early language development, for example, in the transition to multiword speech and as a predictor of later language abilities. However, it is unclear whether gestural input can influence children's comprehension of complex grammatical constructions. In Study 1, 3- (M = 3 years 5 months) and 4-year-old (M = 4 years 6 months) children witnessed 2 participant actions described using the infrequent object-cleft-construction (OCC; It was the dog that the cat chased). Half saw an experimenter accompanying her descriptions with gestures representing the 2 participants and indicating the direction of action; the remaining children did not witness gesture. Children who witnessed gestures showed better comprehension of the OCC than those who did not witness gestures, both in and beyond the immediate physical context, but this benefit was restricted to the oldest 4-year-olds. In Study 2, a further group of older 4-year-old children (M = 4 years 7 months) witnessed the same 2-participant actions described by an experimenter and accompanied by gestures, but the gesture represented only the 2 participants and not the direction of the action. Again, a benefit of gesture was observed on subsequent comprehension of the OCC. We interpret these findings as demonstrating that representational cospeech gestures can help children comprehend complex linguistic structures by highlighting the roles played by the participants in the event. PMID- 24773103 TI - Space or physics? Children use physical reasoning to solve the trap problem from 2.5 years of age. AB - By 3 years of age, children can solve tasks involving physical principles such as locating a ball that rolled down a ramp behind an occluder by the position of a partially visible solid wall (Berthier, DeBlois, Poirer, Novak, & Clifton, 2000; Hood, Carey, & Prasada, 2000). However, the extent to which children use physical information (the properties of the wall) remains unclear because spatial information would suffice (the location of the wall in relation to the ball). We confronted 2- to 6-year-old children with a ball resting on a shelf inside a clear plastic-fronted box. To retrieve the ball, children had to roll it away from a trap or barrier using their fingers. Crucially, a single object acted as a barrier or supporting surface in different conditions, thus requiring a flexible response. Preschoolers solved the task and the critical transfers from 2.5 years of age (Study 1). Interestingly, 2.5-year-olds required to use a tool to displace the ball performed significantly worse than those who could use their fingers (Study 2). In contrast, 2.5- to 4.5-year-olds failed a covered trap box that provided only 2-dimensional predictive cues without any visible physical information, and even 6.5-year-olds performed significantly worse on the covered task compared to the uncovered one (Studies 3 and 4). Our results suggest that children from around 2.5 years of age integrate spatial and physical information when solving problems like the trap box task, rather than simply exploit spatial relationships between features. PMID- 24773104 TI - Contribution of reactive and proactive control to children's working memory performance: Insight from item recall durations in response sequence planning. AB - The present study addressed whether developmental improvement in working memory span task performance relies upon a growing ability to proactively plan response sequences during childhood. Two hundred thirteen children completed a working memory span task in which they used a touchscreen to reproduce orally presented sequences of animal names. Children were assessed longitudinally at 7 time points between 3 and 10 years of age. Twenty-one young adults also completed the same task. Proactive response sequence planning was assessed by comparing recall durations for the 1st item (preparatory interval) and subsequent items. At preschool age, the preparatory interval was generally shorter than subsequent item recall durations, whereas it was systematically longer during elementary school and in adults. Although children mostly approached the task reactively at preschool, they proactively planned response sequences with increasing efficiency from age 7 on, like adults. These findings clarify the nature of the changes in executive control that support working memory performance with age. PMID- 24773105 TI - Conscientiousness and public health: synthesizing current research to promote healthy aging. AB - In this special section, 9 studies and 6 commentaries make a unique contribution to the study of personality. They focus on the five-factor model and, in particular, one of those 5: conscientiousness. This trait has had astonishing success in the actuarial prediction of adaptive outcomes in adulthood and aging, but we have little understanding of the mechanisms that account for this actuarial success. The current studies and comments marshal current knowledge of conscientiousness to advance a mechanistic understanding of these predictions and to exploit that understanding toward interventions to enhance robust adult development and healthy aging. In this introductory article, we underscore the strategy we used to invite presentations and commentary. First, we sought a clearer definition of conscientiousness and a review of its assessment. Second, we sought a review of how the components of this complex trait develop in childhood and are assembled across development. Third, we sought an understanding of how mechanisms linking conscientiousness and health might be transformed across the life span. Fourth, we scrutinized naturally occurring factors that moderate the links between conscientiousness and health for clues to successful interventions. Finally, we sought ways to pull these analyses together to outline the framework for a program of interventions that, collectively, might be applicable at specific points across the life span. Six commentaries place this project in sharp relief. They remind us that the causal status of the associations between conscientiousness and health, reported throughout our 9 studies, are uncertain at best. Second, they remind us that the concept of conscientiousness is still too spare: It fails to embody the social skills required for conscientious behavior, the moral judgment of self or other implicit in its assessment, or the neurobiological mechanisms that might account for differences among individuals. Third, they raise a potent counterfactual: What, in a practical sense, does conceptualization or assessment of conscientiousness contribute-if anything-to the design of interventions to enhance conscientious behavior? PMID- 24773106 TI - Understanding conscientiousness across the life course: an economic perspective. AB - We discuss recent developments in the literature on the role of conscientiousness on healthy aging within an economic framework that helps to systematize and interpret the existing evidence. PMID- 24773107 TI - Conscientiousness in life course context: a commentary. AB - In this commentary, the common themes from the interesting articles in this special section of Developmental Psychology are considered as they illuminate the potential ontogenetic sources of the conscientiousness-well-being-longevity interconnections that have emerged in recent research. In particular, consideration is given to the changing nature of the expression of conscientiousness over the life course and the importance of the causally linked chain of developmental events associated with the sustenance of this trait from early childhood to later life. Methodological as well as conceptual issues are part of the common thematic analysis provided. In addition, several more or less neglected issues are addressed in the commentary. These include an examination of the potential roles of self-presentation social context and social aggregation in the developmentally emergent conscientiousness-well-being relationship. Further, the potential downside of the moral tinge of the conscientiousness construct is considered, as is the cultural variation in the benefits of conscientiousness to well-being. Finally, the applied significance of research on the conscientiousness-well-being link to health promotion over the life course is addressed. The commentary concludes with reflections on the transformation of 1970s trait-like conceptions as unbending tautological predictors of behavior into the situationally and developmentally nuanced conceptions of conscientiousness provided in these collected articles. PMID- 24773108 TI - Understanding the role of conscientiousness in healthy aging: where does the brain come in? AB - In reviewing this impressive series of articles, I was struck by 2 points in particular: (a) the fact that the empirically oriented articles focused on analyses of data from very large samples, with the articles by Friedman, Kern, Hampson, and Duckworth (2014) and Kern, Hampson, Goldbert, and Friedman (2014) highlighting an approach to merging existing data sets through use of "metric bridges" to address key questions not addressable through 1 data set alone, and (b) the fact that the articles as a whole included limited mention of neuroscientific (i.e., brain research) concepts, methods, and findings. One likely reason for the lack of reference to brain-oriented work is the persisting gap between smaller sample size lab-experimental and larger sample size multivariate-correlational approaches to psychological research. As a strategy for addressing this gap and bringing a distinct neuroscientific component to the National Institute on Aging's conscientiousness and health initiative, I suggest that the metric bridging approach highlighted by Friedman and colleagues could be used to connect existing large-scale data sets containing both neurophysiological variables and measures of individual difference constructs to other data sets containing richer arrays of nonphysiological variables-including data from longitudinal or twin studies focusing on personality and health-related outcomes (e.g., Terman Life Cycle study and Hawaii longitudinal studies, as described in the article by Kern et al., 2014). PMID- 24773109 TI - Personality plasticity, healthy aging, and interventions. AB - This commentary on the special section on conscientiousness and healthy aging focuses on several topics brought up in this collection of articles. One is the promise of personality interventions. Despite skepticism on the part of some, such interventions may ultimately prove successful. This is in part because of similarities between personality dimensions and cognitive dimensions and in part due to evidence showing personality is more dynamic and plastic than once believed. The commentary concludes with a discussion of the role of longitudinal investigations to inform interventions. PMID- 24773110 TI - Assessing conscientious personality in primary care: an opportunity for prevention and health promotion. AB - The articles in this special section bolster the already strong evidence base that personality differences in the trait of conscientiousness predict health. What is now needed is a research agenda for translating documented risk associations between low conscientiousness and poor health into policies and interventions that improve health outcomes for individuals and populations. In this commentary, we highlight 1 such avenue: introducing brief personality assessment into primary care practice. We provide examples of how conscientiousness assessment may help health care professionals get to know their patients better and potentially serve as a guide for more personalized care. We also raise key considerations for implementation research aimed at examining the feasibility and utility of integrating conscientiousness assessment into primary care settings. PMID- 24773111 TI - Will interventions targeting conscientiousness improve aging outcomes? AB - The articles appearing in this special section discuss the role that conscientiousness may play in healthy aging. Growing evidence suggests that conscientious individuals live longer and healthier lives. However, the question remains whether this personality trait can be leveraged to improve long-term health outcomes. We argue that even though it may be possible to design therapeutic interventions that increase conscientiousness, there may be more effective and efficient ways to improve population health. We ask for evidence that a focus on conscientiousness improves behavior change efforts that target specific health-related behaviors or large-scale environmental modification. PMID- 24773113 TI - Predictors of self-reported negative mood following a depressive mood induction procedure across previously depressed, currently anxious, and control individuals. AB - OBJECTIVES: This study identified and examined a set of potential predictors of self-reported negative mood following a depressive mood induction procedure (MIP) in a sample of previously depressed, clinically anxious, and control participants. The examined predictor variables were selected on the basis of previous research and theories of depression, and included symptoms of depression and anxiety, negative and positive affect, negative and positive automatic thoughts, dysfunctional beliefs, rumination, self-concept, and occurrence and perceived unpleasantness of recent negative events. METHODS: The sample consisted of 33 previously depressed, 22 currently anxious, and 26 non-clinical control participants, recruited from community sources. Participant group status was confirmed through structured diagnostic interviews. Participants completed the Velten negative self-statement MIP as well as self-report questionnaires of affective, cognitive, and psychosocial variables selected as potential predictors of mood change. RESULTS: Symptoms of anxiety were associated with increased self reported negative mood shift following the MIP in previously depressed participants, but not clinically anxious or control participants. Increased occurrence of recent negative events was a marginally significant predictor of negative mood shift for the previously depressed participants only. None of the other examined variables was significant predictors of MIP response for any of the participant groups. CONCLUSIONS: These results identify factors that may increase susceptibility to negative mood states in previously depressed individuals, with implications for theory and prevention of relapse to depression. The findings also identify a number of affective, cognitive, and psychosocial variables that do not appear to influence mood change following a depressive MIP in previously depressed, currently anxious, and control individuals. Limitations of the study and directions for future research are discussed. PRACTITIONER POINTS: Current anxiety symptomatology was a significant predictor and occurrence of recent negative events was a marginally significant predictor of greater negative mood shift following the depressive mood induction for previously depressed individuals. None of the examined variables predicted change in mood following the depressive mood induction for currently anxious or control individuals. These results suggest that anxiety symptoms and experience with negative events may increase risk for experiencing depressive mood states among individuals with a vulnerability to depression. The generalizability of the present results to individuals with comorbid depression and anxiety is limited. Future research employing appropriate statistical approaches for confirmatory research is needed to test and confirm the present results. PMID- 24773114 TI - Combined use of conventional medicine with traditional Korean medicine to treat children with epilepsy. AB - OBJECTIVE: Few studies have been conducted among pediatric patients to examine clinical outcomes associated with the combined use of Oriental medicine and other therapies to treat epilepsy. The purpose of this study was to examine the clinical and laboratory characteristics of children with epilepsy being treated with traditional Korean medicine (TKM) in addition to their conventional antiepileptic drugs (AEDs), and to survey whether other nonpharmacologic combination treatments were also being used. METHODS: The study included 398 pediatric patients with epilepsy being treated at the Pediatric Neurology Clinic of Pusan National University Children's Hospital. A questionnaire-based survey was carried out to determine the extent to which combination treatments were being used from March 1 to July 31, 2011. RESULTS: Of the 398 epileptic patients, 75 (18.8%) were receiving treatment based on TKM in addition to their AED treatment. The number of AEDs used was significantly greater in this group (mean +/- standard deviation, 2.3 +/- 1.5) than in the group not receiving TKM (2.0 +/- 1.2; p=.028). The number of seizure-free patients in the TKM group (44 patients [59%]) was significantly reduced (p=.037) compared with the group not receiving such treatment (236 patients [73%]). Of the 398 patients, 237 (59.5%) were receiving other combination treatments. Fifty-six of the 75 patients (74.7%) in the TKM group were receiving other combination treatments (p<.001 compared with nonusers), which included language therapy, education therapy (music therapy, art therapy), Chuna therapy, and health food supplements (p=.004, p<.001, p=.011, and p=.004, respectively). The use of other combination treatments, such as rehabilitation therapy, counseling, cognitive behavioral therapy, and neurofeedback therapy, did not differ between the two groups. CONCLUSIONS: The TKM group took more AEDs and had fewer seizure-free patients and more patients receiving other combination treatments, such as language, music, and art therapies. PMID- 24773115 TI - Transportation of sublingual antigens across sublingual ductal epithelial cells to the ductal antigen-presenting cells in mice. AB - BACKGROUND: Sublingual immunotherapy (SLIT) has proven to be safe and efficient for the treatment of type I allergies. However, the mechanisms underlying allergen transportation within the sublingual compartment, the localization of antigens, and the identities of the cells responsible for this immunization remain incompletely understood. OBJECTIVE: In this study, we focused on the sublingual ductal system and analysed the localization and transportation of antigens after their sublingual application. METHODS: In mice given adjuvant-free antigens sublingually, tissues were removed at 0, 0.5, 1, or 2 h after the application and subjected to immunohistochemistry. Cells isolated from the sublingual duct and mucosa were analysed by flow cytometry. RESULTS: Substantial immunoreactivity to ovalbumin (OVA) was evident in sublingual ductal epithelial cells at 30 min and 1 h after sublingual administration of OVA, but it had disappeared at 2 h. The ductal epithelial cells incorporated not only OVA, but also particulate antigens such as latex or silica beads and microbes. MHC class II (MHCII)(+) antigen-presenting cells (APCs) were located around the sublingual ductal system, and MHCII(+) cells were co-localized with, and around, antigen incorporated sublingual duct cells. CD11b(+) CD11c(-) cells were present among CD45(+) MHCII(+) cells at greater frequency in the sublingual duct than in the sublingual mucosa, and they were the main contributors to the incorporation of OVA in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: This study reveals that sublingual antigens can be transported across sublingual ductal epithelial cells to the ductal APCs. If the system is the same in humans as in mice, the ductal APCs may prove to be important target cells for SLIT. PMID- 24773116 TI - New rehabilitation models for neurologic inpatients in Brazil. AB - PURPOSE: To describe the effects of a rehabilitation program in a neurological inpatient unit in terms of independence for activities of daily living and return to work. METHOD: Retrospective study with 148 adults with stroke, traumatic brain injury (TBI), spinal cord injury, and Guillain-Barre syndrome admitted as rehabilitation inpatients within a 1-year period for hospitalization at the Instituto de Reabilitacao Lucy Montoro, Brazil. According to their diagnostic groups, subjects undergone semi-standardized models of intensive multidisciplinary rehabilitation for 4-6 weeks. PRIMARY OUTCOME MEASURES: Functional Independence Measure (FIM), Modified Rankin scale (Rankin), and Glasgow Outcome Scale (GOS Subjects were evaluated at admission, discharge, and 6 months after discharge. RESULTS: Improvement in motor FIMTM, Rankin and GOS was observed in all groups. Cognitive FIM increase was less evident in TBI patients. After 6 months, 37.6% of patients were unemployed, 34% underwent outpatient rehabilitation, and 65.2% maintained gains. CONCLUSIONS: This is the first report on the effects from an inpatients rehabilitation model in Brazil. After a short intensive rehabilitation, there were motor and cognitive gains in all groups. Heterogeneity in functional gains suggests more individualized programs may be indicated. Controlled studies are required with larger samples to compare inpatient and outpatient programs. PMID- 24773117 TI - Self-reported competency--validation of the Norwegian version of the patient competency rating scale for traumatic brain injury. AB - PURPOSE: To evaluate the psychometric properties of the Norwegian version of the Patient Competency Rating Scale (PCRS) in patients with traumatic brain injury (TBI) at 12 months post-injury. METHODS: Demographic and injury-related data were registered upon admission to the hospital in 148 TBI patients with mild, moderate, or severe TBI. At 12 months post-injury, competency in activities and global functioning were measured using the PCRS patient version and the Glasgow Outcome Scale-Extended (GOSE). Descriptive reliability statistics, factor analysis and Rasch modeling were applied to explore the psychometric properties of the PCRS. External validity was evaluated using the GOSE. RESULTS: The PCRS can be divided into three subscales that reflect interpersonal/emotional, cognitive, and activities of daily living competency. The three-factor solution explained 56.6% of the variance in functioning. The internal consistency was very good, with a Cronbach's alpha of 0.95. Item 30, "controlling my laughter", did not load above 0.40 on any factors and did not fit the Rasch model. The external validity of the subscales was acceptable, with correlations between 0.50 and 0.52 with the GOSE. CONCLUSION: The Norwegian version of the PCRS is reliable, has an acceptable construct and external validity, and can be recommended for use during the later phases of TBI. PMID- 24773118 TI - People with lower limb amputation and their sexual functioning and sexual well being. AB - PURPOSE: Following a lower limb amputation, people may experience limitations in performing sexual activities. However, only little research efforts have been devoted to unravel how people experience their sexuality after such an amputation. Therefore, the purpose of the current study is to describe how people with a lower limb amputation experience (changes in) their sexual functioning and sexual well-being. METHODS: A qualitative approach with semi-structured interviews was used. RESULTS: In total 26 interviews with persons with a lower limb amputation were performed. Thematic analysis of the data resulted in eight themes derived from the interviews: importance and description of sexuality; changes in sexual functioning; changes in sexual well-being; practical problems concerning sexuality; self-image; feelings of shame; role of the partner; communication about sexuality with professionals. CONCLUSIONS: Participants in this study indicated some problems concerning sexual functioning and/or sexual well-being. Some of these problems were of practical nature, and participants would have appreciated some information about how to handle this kind of practical sexual problems. However, such information should not be given at the beginning of the rehabilitation process, as at that time sexuality is not a priority for all patients. PMID- 24773119 TI - Effectiveness of an interactive postgraduate educational intervention with patient participation on the adherence to a physiotherapy guideline for hip and knee osteoarthritis: a randomised controlled trial. AB - PURPOSE: To determine the effectiveness of an interactive educational intervention on a physiotherapy guideline for hip and knee osteoarthritis. METHOD: Physiotherapists were randomly allocated to a 3-h interactive educational course with the collaboration of three patient partners or no intervention. Assessments comprised questionnaires on adherence (score range 0-24), knowledge (score range 0-76), and barriers to use the guideline (score range 0-80). Assessments were conducted 1 week before the interactive course (T0) immediately after (T1), and 3 months thereafter (T2). Change scores were compared between the groups by means of Mann-Whitney U tests and linear mixed models. RESULTS: 284 of 4328 eligible PTs (7%) were included. The intervention (n = 133) was significantly more effective than no intervention (n = 151) concerning self reported adherence and knowledge with mean differences in change scores (95% CI) at T1 and T2 being 1.4 (0.7-2.0) and 0.9 (0.2-1.7) for adherence and 6.8 (4.5 9.1) and 3.9 (1.7-6.2) for knowledge, (all p values < 0.005). In both groups the barrier score increased at T1 and decreased at T2, with a significantly larger increase at T1 and decrease at T2 in the intervention group (mean differences 3.1 (1.8-4.4) and 3.3 (0.5-6.1), respectively. CONCLUSIONS: A short interactive educational course with patient participation on a PT guideline on hip and knee osteoarthritis showed a small to moderate positive effect on self-reported guideline adherence and knowledge, whereas for perceived barriers an advantage was only seen on the longer term. PMID- 24773120 TI - Balance outcome measures in cerebellar ataxia: a Delphi survey. AB - PURPOSE: Choosing an appropriate outcome measure for the assessment of balance among people with cerebellar ataxia is currently challenging as no guidelines are available. There is a need for further investigation with clinical experts in order to derive a set of standardized outcome measures with high clinical utility. METHODS: A two-round internet-based Delphi survey was considered. A steering committee was formed to guide the Delphi process. Neurologists and physiotherapists with clinical and research experience in cerebellar ataxia were identified as the expert group. Consensus among the experts for recommendation was set at 75%. RESULTS: Thirty experts representing 10 countries agreed to participate. The response rate for the rounds were 87% and 96%, respectively. Forty-one relevant outcome measures were identified. The Berg Balance Scale (BBS), the Scale for the assessment and rating of ataxia (SARA), the Timed Up and Go test (TUG) were identified as the best outcome measures for use with at least 75% consensus among the experts. CONCLUSION: The recommended outcome measures (SARA, BBS and TUG) are available at no cost, require little equipment and are quick and easy to perform; however, formal psychometric testing of the BBS and TUG in people with cerebellar ataxia is warranted. PMID- 24773121 TI - Evolved variation in cold tolerance among populations of Eldana saccharina (Lepidoptera: Pyralidae) in South Africa. AB - Among-population variation in chill-coma onset temperature (CTmin ) is thought to reflect natural selection for local microclimatic conditions. However, few studies have investigated the evolutionary importance of cold tolerance limits in natural populations. Here, using a common-environment approach, we show pronounced variation in CTmin (+/- 4 degrees C) across the geographic range of a nonoverwintering crop pest, Eldana saccharina. The outcomes of this study provide two notable results in the context of evolved chill-coma variation: (1) CTmin differs significantly between geographic lines and is significantly positively correlated with local climates, and (2) there is a stable genetic architecture underlying CTmin trait variation, likely representing four key genes. Crosses between the most and least cold-tolerant geographic lines confirmed a genetic component to CTmin trait variation. Slower developmental time in the most cold tolerant population suggests that local adaptation involves fitness costs; however, it confers fitness benefits in that environment. A significant reduction in phenotypic plasticity in the laboratory population suggests that plasticity of this trait is costly to maintain but also likely necessary for field survival. These results are significant for understanding field population adaption to novel environments, whereas further work is needed to dissect the underlying mechanism and gene(s) responsible. PMID- 24773123 TI - Efficient coupling of light to graphene plasmons by compressing surface polaritons with tapered bulk materials. AB - Graphene plasmons promise exciting nanophotonic and optoelectronic applications. Owing to their extremely short wavelengths, however, the efficient coupling of photons to propagating graphene plasmons-critical for the development of future devices-can be challenging. Here, we propose and numerically demonstrate coupling between infrared photons and graphene plasmons by the compression of surface polaritons on tapered bulk slabs of both polar and doped semiconductor materials. Propagation of surface phonon polaritons (in SiC) and surface plasmon polaritons (in n-GaAs) along the tapered slabs compresses the polariton wavelengths from several micrometers to around 200 nm, which perfectly matches the wavelengths of graphene plasmons. The proposed coupling device allows for a 25% conversion of the incident energy into graphene plasmons and, therefore, could become an efficient route toward graphene plasmon circuitry. PMID- 24773122 TI - Gene therapy: charting a future course--summary of a National Institutes of Health Workshop, April 12, 2013. AB - Recently, the gene therapy field has begun to experience clinical successes in a number of different diseases using various approaches and vectors. The workshop Gene Therapy: Charting a Future Course, sponsored by the National Institutes of Health (NIH) Office of Biotechnology Activities, brought together early and mid career researchers to discuss the key scientific challenges and opportunities, ethical and communication issues, and NIH and foundation resources available to facilitate further clinical advances. PMID- 24773124 TI - Spectrum of cutaneous manifestations of type 1 diabetes mellitus in 500 South Asian patients. AB - BACKGROUND: Data on cutaneous manifestations of type 1 diabetes mellitus (DM) is scarce. OBJECTIVES: To study the spectrum of dermatoses in patients with type 1 DM and the effects of disease duration and long-term glucose control on these cutaneous manifestations. SUBJECTS AND METHODS: After prior consent, clinical examination and relevant investigations were done in 500 subjects with type 1 DM enrolled between July 2011 and June 2012. Statistical tests were performed using SPSS 16. The presence of various dermatoses was correlated with the duration of diabetes. RESULTS: Of five hundred subjects, 339 (67.8%) had one or more dermatoses. The mean age of the patients was 16.9 +/- 6.9 years (range 1-25 years) and mean total duration of diabetes was 4.43 +/- 4.4 years. Cutaneous adverse effects related to insulin injections (CAII), comprising lipohypertrophy (41%), post-inflammatory hyperpigmentation (3%), lipoatrophy (0.6%) and acanthosis nigricans (0.4%), were the most common findings, followed by limited joint mobility (LJM) (16.8%), xerosis (15.8%) and scleroderma-like skin changes (10%). Patients having long-duration DM (> 4.4 years) were significantly more likely to have lipohypertrophy (P = 0.000), LJM (P = 0.000), scleroderma-like skin changes (P = 0.000), diabetic dermopathy (P = 0.000), acanthosis nigricans (P = 0.005) and skin tags (P = 0.002). Lipohypertrophy, LJM and scleroderma-like skin changes also showed significant correlation with blood glucose level. CONCLUSIONS: Our study suggests that cutaneous changes are common in young Asian patients with type 1 DM. Information, education and counselling of patients and care givers, and awareness among physicians is essential for the prevention and early management of these dermatoses. PMID- 24773125 TI - Ductile all-cellulose nanocomposite films fabricated from core-shell structured cellulose nanofibrils. AB - Cellulosic materials have many desirable properties such as high mechanical strength and low oxygen permeability and will be an important component in a sustainable biomaterial-based society, but unfortunately they often lack the ductility and formability offered by petroleum-based materials. This paper describes the fabrication and characterization of nanocomposite films made of core-shell modified cellulose nanofibrils (CNFs) surrounded by a shell of ductile dialcohol cellulose, created by heterogeneous periodate oxidation followed by borohydride reduction of the native cellulose in the external parts of the individual fibrils. The oxidation with periodate selectively produces dialdehyde cellulose, and the process does not increase the charge density of the material. Yet the modified cellulose fibers could easily be homogenized to CNFs. Prior to film fabrication, the CNF was shown by atomic force microscopy to be 0.5-2 MUm long and 4-10 nm wide. The films were fabricated by filtration, and besides uniaxial tensile testing at different relative humidities, they were characterized by scanning electron microscopy and oxygen permeability. The strength-at-break at 23 degrees C and 50% RH was 175 MPa, and the films could, before rupture, be strained, mainly by plastic deformation, to about 15% and 37% at 50% RH and 90% RH, respectively. This moisture plasticization was further utilized to form a demonstrator consisting of a double-curved structure with a nominal strain of 24% over the curvature. At a relative humidity of 80%, the films still acted as a good oxygen barrier, having an oxygen permeability of 5.5 mL.MUL/(m(2).24 h.kPa). These properties indicate that this new material has a potential for use as a barrier in complex-shaped structures and hence ultimately reduce the need for petroleum-based plastics. PMID- 24773126 TI - New dimeric phthalides from Ligusticum sinense Oliv cv. Chaxiong. AB - A new dimeric phthalide, chaxiongnolide A (1), and a new natural product, chaxiongnolide B (2), together with a known compound Z-ligustilide (3), were isolated from the rhizome of Ligusticum sinense Oliv cv. Chaxiong. Their structures were elucidated by various spectroscopic methods and confirmed by X ray crystallographic analysis. PMID- 24773127 TI - Oxidative stress increases neurogenesis and oligodendrogenesis in adult neural progenitor cells. AB - Hydrogen peroxide (H2O2) is a reactive oxygen species that is involved in immunity and neuroinflammation. Here, we investigated whether and how pathophysiological levels of H2O2 influenced the differentiation of neural progenitor cells (NPCs). H2O2 levels within the range measured at neuroinflammatory events were applied to rat primary NPC cultures during 24 h, and effects were assessed directly after exposure or in NPCs that were differentiated for 7 days after H2O2 removal. Exposed differentiated NPCs showed significantly increased numbers of neurons and oligodendrocytes compared with unexposed controls. To identify the possible origin of this differentiation result, we characterized the undifferentiated culture and found a significant increase in both OLIG2(+) cells and proliferative ASCL1(+) C cells that could contribute to both more neurons and oligodendrocytes. In addition, H2O2-induced neurogenesis was supported by western blot and paralleled by gene expression analyses, which revealed an increased expression of the proneural gene Ngn2 and the neuronally expressed gene beta-III tubulin. To investigate potential mechanisms for the observed effects on NPC differentiation, we performed gene expression profile analyses for oxidative stress and antioxidant-related and chromatin modification genes where the expression of several important genes was affected by the exposure. Increased oligodendrocyte numbers correlated with increased expression of the chromatin modification enzyme Sirt2, suggesting the involvement of Sirt2 in oligodendrocyte differentiation. Our results suggest a modulatory effect on the differentiation potential of NPCs by H2O2. Our findings indicate that H2O2 exposure has significant effects on NPC proliferation, differentiation, and vulnerability. These results have implications for regeneration after any neuroinflammatory event. PMID- 24773128 TI - Characterization of the canine urinary proteome. AB - BACKGROUND: Urine is an attractive biofluid for biomarker discovery as it is easy and minimally invasive to obtain. While numerous studies have focused on the characterization of human urine, much less research has focused on canine urine. OBJECTIVES: The objectives of this study were to characterize the universal canine urinary proteome (both soluble and exosomal), to determine the overlap between the canine proteome and a representative human urinary proteome study, to generate a resource for future canine studies, and to determine the suitability of the dog as a large animal model for human diseases. METHODS: The soluble and exosomal fractions of normal canine urine were characterized using liquid chromatography tandem mass spectrometry (LC-MS/MS). Biological Networks Gene Ontology (BiNGO) software was utilized to assign the canine urinary proteome to respective Gene Ontology categories, such as Cellular Component, Molecular Function, and Biological Process. RESULTS: Over 500 proteins were confidently identified in normal canine urine. Gene Ontology analysis revealed that exosomal proteins were largely derived from an intracellular location, while soluble proteins included both extracellular and membrane proteins. Exosome proteins were assigned to metabolic processes and localization, while soluble proteins were primarily annotated to specific localization processes. Several proteins identified in normal canine urine have previously been identified in human urine where these proteins are related to various extrarenal and renal diseases. CONCLUSIONS: The results of this study illustrate the potential of the dog as an animal model for human disease states and provide the framework for future studies of canine renal diseases. PMID- 24773129 TI - Remineralization of initial enamel carious lesions using fluoridated milk in vitro. AB - OBJECTIVES: Milk is a universal dietary component and it is now recognized as an effective medium for the delivery of fluoride (F). This study sought (i) to evaluate fluoridated milk (2.5 ppm, 5 ppm, 10 ppm) for remineralizing carious lesions and (ii) to determine the optimum frequency for treating carious lesions with fluoridated milk. MATERIALS AND METHODS: Artificial carious lesions, 90-180 MUm deep, were created on extracted third molar teeth that were sectioned to produce specimens of 100-120 MUm thickness. Specimens were randomly divided into 13 groups (n = 20) for treatment with deionized water, plain milk or fluoridated milk (2.5 ppm, 5 ppm, 10 ppm); once daily, twice daily or on alternate days as part of a 20-day pH cycling model. Lesion depth (LD) and mineral content were evaluated before and after pH cycling. Paired t-test, ANOVA and Student-Newman Keuls tests were employed to make comparisons within and between the different groups. RESULTS: Fluoridated milk significantly reduced LD and increased the mineral content of the lesions compared to plain milk and deionized water (p < 0.05). The greatest reduction in LD was with 2.5 ppm F milk used twice daily (p < 0.05). CONCLUSIONS: Milk with 2.5 ppm F used twice daily demonstrated the greatest remineralization of artificial enamel carious lesions in vitro. PMID- 24773130 TI - Effects of different irrigating solutions and disinfection methods on push-out bond strengths of fiber posts. AB - OBJECTIVE: The aim of this study was to evaluate the effects of various irrigating solutions and photoactivated disinfection (PAD) on the push-out bond strengths of fiber posts to root dentin. MATERIALS AND METHODS: Thirty-two human teeth were divided into eight groups, as follows: (1) irrigation with physiologic saline (control), (2) NaOCl irrigation, (3) chlorhexidine (CHX) irrigation, (4) ethanol (EtOH) irrigation, (5) NaOCl followed by 17% EDTA irrigation, (6) NaOCl EDTA supplemented with CHX irrigation, (7) NaOCl-EDTA supplemented with EtOH irrigation and (8) NaOCl-EDTA irrigation supplemented with PAD. After the posts were cemented, the roots were transversally sectioned to obtain four slices (1 mm thick) (n = 16). Push-out tests were conducted by applying a load at 0.5 mm/min, types of fracture failures were recorded and data were analyzed with one-way ANOVA and Tukey post-hoc tests (p = 0.05). RESULTS: Push-out bond strength was significantly affected by the type of irrigating solution and the disinfection protocol (p < 0.05). The bond strength of the EtOH, NaOCl and NaOCl-EDTA-CHX irrigated groups was significantly higher than that of the other groups. The highest bond strength was observed in the EtOH irrigated group and the lowest was the NaOCl-EDTA irrigated group. CONCLUSIONS: Irrigation with NaOCl and EDTA combined caused lower bond strength than observed in the control group. However, supplementing this combination with CHX improved the post-dentin bond strengths; supplementing with PAD did not. PMID- 24773131 TI - Effect of varying core thicknesses and artificial aging on the color difference of different all-ceramic materials. AB - OBJECTIVE: Clinicians should reserve all-ceramics with high translucency for clinical applications in which high-level esthetics are required. Furthermore, it is unclear whether a correlation exists between core thickness and color change. The aim of this study was to examine the effects of different core thicknesses and artificial aging on the color stability of three all-ceramic systems. MATERIALS AND METHODS: Ninety disc-shaped cores with different thicknesses (0.5 mm, 0.8 mm and 1.0 mm) were prepared from three all-ceramic systems, In-Ceram Alumina (IC), IPS e.max Press (EM) and Katana (K). The colors of the samples were measured with a spectrophotometer and the color parameters (L*, a*, b*, DeltaE) were calculated according to the CIE L*a*b* (Commission Internationale de L'Eclairage) color system before and after aging. RESULTS: The effects of aging on color parameters were statistically significant (p < 0.001), regardless of core thickness. For all systems, the CIE a* values increased as the thickness of the core increased. Conversely, such increases in core porcelain thickness were correlated with decreasing CIE L* and b* values. Core thickness had a statistically significant effect on color change among the groups. CONCLUSIONS: Different core thicknesses (from 1.0-0.5 mm) and artificial aging affected color stability of the all-ceramic materials tested. PMID- 24773132 TI - Pharmacokinetics of total thyroxine after repeated oral administration of levothyroxine solution and its clinical efficacy in hypothyroid dogs. AB - BACKGROUND: Oral levothyroxine (l-T4 ) supplementation is commonly used to treat hypothyroid dogs. OBJECTIVES: Investigate the plasma profile and pharmacokinetics of total thyroxine (tT4 ) after PO administration of a l-T4 solution and its clinical efficacy in hypothyroid dogs. ANIMALS: Ten dogs with naturally occurring hypothyroidism. METHODS: After hypothyroidism diagnosis and supplementation with l-T4 solution PO q24h at 20 MUg/kg BW for minimum 4 weeks, the plasma profile and pharmacokinetics of tT4 were determined over 34 hours and the clinical condition of the dogs was evaluated. RESULTS: Before dosing for pharmacokinetic evaluation, mean tT4 concentration was 23 +/- 9 nmol/L. l-T4 was absorbed rapidly (tmax , 5 hours), reaching a mean maximal tT4 concentration of 56 +/- 11 nmol/L. The apparent terminal half-life was 11.8 hours. Clinical signs of hypothyroidism improved or resolved in all dogs after 4 weeks of treatment. The dosage of 20 MUg/kg PO q24h was judged appropriate in 5 dogs, and 4 dogs required slight increases (9-16%). Twice daily treatment, with a 30% increase in dosage, was necessary for 1 dog. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetics of l-T4 in hypothyroid dogs was similar to that reported in healthy euthyroid dogs. Clinical and hormonal responses to l-T4 solution were rapid in all dogs. The starting dosage of 20 MUg/kg PO q24h was suitable for maintenance supplementation in 50% of the dogs, minor dosage modification was required in 4 other dogs, and treatment q12h was required in 1 dog. PMID- 24773133 TI - Training in motivational interviewing in obstetrics: a quantitative analytical tool. AB - OBJECTIVE: To examine whether a 3-day training course in motivational interviewing, which is an approach to helping people to change, could improve the communication skills of obstetric healthcare professionals in their interaction with obese pregnant women. DESIGN: Intervention study. SETTING: The Region of Southern Denmark. METHODS: Eleven obstetric healthcare professionals working with obese pregnant women underwent a 3-day course in motivational interviewing techniques and were assessed before and after training to measure the impact on their overall performance as well as the effect on specific behavioral techniques observed during interviews. FINDINGS: With a few exceptions, the participants changed their behavior appropriate to the motivational interviewing technique. The participants made more interventions towards the principles of motivational interviewing (adherent and nonadherent interventions). Furthermore, the participants asked fewer closed and more open questions before training in motivational interview. In the assessment of proficiency and competency, most of the participants scored higher after the training in motivational interviewing. CONCLUSIONS: Training in motivational interviewing improves healthcare professionals' proficiency and competency when communicating with obese pregnant women, albeit that the effect was not universal. PMID- 24773134 TI - Feasibility of surface-enhanced Raman spectroscopy for rapid detection of aflatoxins in maize. AB - Rapid and sensitive surface-enhanced Raman spectroscopy (SERS) for aflatoxin detection was employed for development of the models to classify and quantify aflatoxin levels in maize at concentrations of 0 to 1,206 MUg/kg. Highly effective SERS substrate (Ag nanosphere) was prepared and mixed with a sample extract for SERS measurement. Strong Raman bands associated with aflatoxins and changes in maize kernels induced by aflatoxin contamination were observed in different SERS spectroscopic regions. The k-nearest neighbors (KNN) classification model yielded high classification accuracy and lower prediction error with no misclassification of contaminated samples as aflatoxin negative. The multiple linear regression (MLR) models showed a higher predictive accuracy with stronger correlation coefficients (r = 0.939-0.967) and a higher sensitivity with lower limits of detection (13-36 MUg/kg) and quantitation (44-121 MUg/kg) over other quantification models. Paired sample t test exhibited no statistically significant difference between the reference values and the predicted values of SERS in most chemometric models. The proposed SERS method would be a more effective and efficient analytical tool with a higher accuracy and lower constraints for aflatoxin analysis in maize compared to other existing spectroscopic methods and conventional Raman spectroscopy. PMID- 24773135 TI - Treatment of periodontitis: key principles include removing subgingival bacterial deposits; providing a local environment and education to support good home care; providing regular professional maintenance. PMID- 24773136 TI - Therapeutic effects of full spectrum light on the development of atopic dermatitis-like lesions in NC/Nga mice. AB - Full spectrum light (FSL) includes UVA, visible light and infrared light. Many studies have investigated the application of FSL in severe cases of atopic dermatitis (AD) in humans; however, FSL has not yet been studied in an animal model. The purpose of this study was to evaluate the therapeutic effects of FSL on AD-like skin lesions using NC/Nga mice, with the aim of mitigating itching and attenuating the expression of adhesion molecules. We examined the effects of FSL on mite allergen-treated NC/Nga mice by assessing skin symptom severity, ear thickness, serum IgE levels, and the cytokine expression. We examined the histology of lesions using hematoxylin-eosin, toluidine blue and immunohistochemical staining. Our findings suggest that FSL phototherapy exerts positive therapeutic effects on Dermatophagoides farinae (Df)-induced AD-like skin lesions in NC/Nga mice by reducing IgE levels, thus promoting recovery of the skin barrier. The mechanisms by which FSL phototherapy exerts its effects may also involve the inhibition of scratching behavior, reduction of IL-6 levels and reductions in adhesion molecule expression. The present study indicates that FSL phototherapy inhibits the development of AD in NC/Nga mice by suppressing cytokine, chemokine and adhesion molecule expression, and thus, could potentially be useful in treating AD. PMID- 24773138 TI - The legacy of Sebastian Kneipp: linking wellness, naturopathic, and allopathic medicine. AB - Sebastian Kneipp (1821-1897) is seen as a vital link between the European nature cure movement of the 19th century and American naturopathy. He promoted a holistic treatment concept founded on five pillars: hydro- and phytotherapy, exercise, balanced nutrition, and regulative therapy. Kneipp attempted to bridge the gap with allopathic medicine, and many modern treatments that are based on his methods indeed blend wellness elements with naturopathic medicine and biomedicine. Because Kneipp's approach to health and healing today are mainly covered in German literature, this paper aims to provide a broader international audience with insights into his life and his treatment methods and to highlight the profound influence Kneipp has had to this day on natural and preventive medicine. The paper emphasizes in particular the continued popularity of Kneipp's holistic approach to health and well-being, which is evident in the many national and international Kneipp Associations, the globally operating Kneipp Werke, postgraduate qualifications in his treatment methods, and the existence of more than 60 accredited Kneipp spas and health resorts in Germany alone. PMID- 24773137 TI - Ethyl glucuronide and ethyl sulfate assays in clinical trials, interpretation, and limitations: results of a dose ranging alcohol challenge study and 2 clinical trials. AB - BACKGROUND: The ethanol metabolites, ethyl glucuronide (EtG) and ethyl sulfate (EtS), are biomarkers of recent alcohol consumption that provide objective measures of abstinence. Our goals are to better understand the impact of cutoff concentration on test interpretation, the need for measuring both metabolites, and how best to integrate test results with self-reports in clinical trials. METHODS: Subjects (n = 18) were administered, 1 week apart, 3 alcohol doses calibrated to achieve blood concentrations of 20, 80, and 120 mg/dl, respectively. Urinary EtG/EtS was measured at timed intervals during a 24-hour hospitalization and twice daily thereafter. In addition, participants from 2 clinical trials provided samples for EtG/EtS and drinking histories. Cutoffs for EtG/EtS of 100/50, 200/100, and 500/250 ng/ml were evaluated. RESULTS: Twelve hours following each challenge, EtG was always positive at the 100 and 200 cutoffs, but at 24 hours sensitivity was poor at all cutoffs following the low dose, and poor after 48 hours regardless of dose or cutoff. Similarly, in the clinical trials EtG sensitivity was good for detecting any drinking during the last 24 hours at the 2 lowest cutoffs, but under 40% during the last 24 to 48 hours. Sensitivity was reduced at the 500 ng/ml cutoff. Discrepancies between EtG and EtS were few. Comparison of self-reports of abstinence and EtG-confirmed abstinence indicated underreporting of drinking. CONCLUSIONS: Any drinking the night before should be detectable the following morning with EtG cutoffs of 100 or 200 ng/ml. Twenty-four hours after drinking, sensitivity is poor for light drinking, but good for heavier consumption. At 48 hours, sensitivity is low following 6 drinks or less. Increasing the cutoff to 500 ng/ml leads to substantially reduced sensitivity. Monitoring both EtG and EtS should usually be unnecessary. We recommend EtG-confirmed self-reports of abstinence for evaluation of outcomes in clinical trials. PMID- 24773139 TI - Customized metabolomics database for the analysis of NMR 1H-1H TOCSY and 13C-1H HSQC-TOCSY spectra of complex mixtures. AB - A customized metabolomics NMR database, termed (1)H((13)C)-TOCCATA, is introduced, which contains complete (1)H and (13)C chemical shift information on individual spin systems and isomeric states of common metabolites. Since this information directly corresponds to cross sections of 2D (1)H-(1)H TOCSY and 2D (13)C-(1)H HSQC-TOCSY spectra, it allows the straightforward and unambiguous identification of metabolites of complex metabolic mixtures at (13)C natural abundance from these types of experiments. The (1)H((13)C)-TOCCATA database, which is complementary to the previously introduced TOCCATA database for the analysis of uniformly (13)C-labeled compounds, currently contains 455 metabolites, and it can be used through a publicly accessible web portal. We demonstrate its performance by applying it to 2D (1)H-(1)H TOCSY and 2D (13)C (1)H HSQC-TOCSY spectra of a cell lysate from E. coli, which yields a substantial improvement over other databases, as well as 1D NMR-based approaches, in the number of compounds that can be correctly identified with high confidence. PMID- 24773140 TI - Residential traffic and incidence of Type 2 diabetes: the German Health Interview and Examination Surveys. AB - AIMS: To investigate whether an indicator of overall traffic intensity is related to the risk of Type 2 diabetes in a nationwide cohort. METHODS: The study population comprised 3604 adults aged 18-79 years and without diabetes from the German National Health Interview and Examination Survey (GNHIES98, 1997-1999) who participated again in a follow-up survey (DEGS1, 2008-2011). The association between the participants' reported traffic intensity at their residential address and Type 2 diabetes incidence was examined using logistic regression models. RESULTS: During a mean of 12.1 years of follow-up, 252 of the participants included in the study developed Type 2 diabetes. Compared with people living in traffic-calmed areas, odds ratios were 1.15 (95% CI 0.80-1.67) for people living on moderately busy side streets, 1.11 (95% CI 0.69-1.80) for people living on considerably busy side streets, 1.41 (95% CI 0.96-2.08) for people living on heavily busy roads, and 1.97 (95% CI 1.07-3.64) for people living on extremely busy roads, after adjusting for age, sex, active and passive smoking, type of heating, education, BMI, waist circumference, sport activity and parental diabetes history. CONCLUSIONS: The twofold higher risk of Type 2 diabetes observed for people exposed to intense traffic in this nationwide cohort extends the limited evidence from previous selected populations. Although the underlying traffic-related components and their biological mechanisms still need to be unravelled, traffic exposure control should be considered in public health strategies to reduce the global burden of diabetes. PMID- 24773141 TI - Bis(imidazolidine)pyridine-NiCl2 Catalyst for nitro-Mannich reaction of isatin derived N-Boc ketimines: asymmetric synthesis of chiral 3-substituted 3-amino-2 oxindoles. AB - An (S,S)-diphenyldiamine-derived bis(imidazolidine)pyridine (PyBidine)-NiCl2 complex catalyzed the nitro-Mannich reaction of isatin-derived N-Boc ketimines to construct a chiral quaternary aminocarbon center at the C3 position of oxindoles in yields of up to 99% with 95% ee. PMID- 24773142 TI - Treatment as prevention: are Argentinean HIV care providers willing to adopt earlier antiretroviral therapy? AB - HIV guidelines increasingly recommend antiretroviral therapy (ART) initiation at a higher CD4 levels. The extent to which these evolving standards are translated into routine clinical care has not been evaluated in Argentina. During October 2012, we conducted an online survey among Argentinean HIV clinicians to assess their attitudes and practices toward ART initiation and its potential use for HIV prevention. Of the 280 physicians included, 61% would prescribe ART at CD4 <= 500 cells/uL for asymptomatic patients. Although, only 11% would recommend ART irrespective of CD4 cell count, 72% would do it for serodiscordant couples, and 75% for sex workers. Most participants agreed that they would consider earlier initiation of ART if transmission risk exists, and that expansion of ART could help decrease HIV incidence. These results suggest that a large proportion of Argentinean HIV care providers are willing to adopt the recently updated Argentinean guidelines recommending earlier ART, especially when high HIV transmission risk exists. PMID- 24773143 TI - Scaling dielectrowetting optical shutters to higher resolution: microfluidic and optical implications. AB - A detailed study is reported on the implications of scaling dielectrowetting optical shutters to higher resolutions. Reducing droplet sizes from millimeters to 100 MUm in diameter increases the relevance of microfluidic physics such as pinning, film breakup, and dewetting speed as well as optical physics such as transmission and diffraction. In addition, in this work we present improved material systems, including optimized dielectric stacks which reduce electrochemical degradation, and blended lower-viscosity fluids which increase dewetting speed. A higher-resolution device of ~250 MUm diameter demonstrates switching speeds of <100 ms and a clear, optically transmissive aperture of >70%. In addition to revealing science not previously discussed, this work has strong applied importance as scaling to higher resolutions is desirable for improving visual appearance in applications ranging from smart windows to electronic signage. PMID- 24773144 TI - Producing a commentary slows concurrent hazard perception responses. AB - Commentary driver training involves teaching drivers how to verbally acknowledge their perceptual and cognitive processes while driving, and has been shown to improve performance in driving-related tasks. However, those studies demonstrating benefits of commentary training have not done so under conditions of live commentary, which is the typical protocol used with advanced drivers. In the current study we present the results of 2 experiments that show that producing a commentary can actually slow responses to hazards on a concurrent hazard perception task. In Experiment 1, participants producing a live commentary showed significantly longer hazard response times than an untrained, silent, control group. In Experiment 2, a shorter, clipped commentary was introduced to attempt to reduce the demands placed upon participants. However, both the clipped and full commentary conditions showed reduced accuracy and longer response times, relative to a silent condition, and no difference was observed between the 2 types of commentary. Analysis of eye movements in both experiments revealed that fixation durations were shorter when a commentary was produced but time to first fixate the hazard was not affected. This suggests that commentaries encourage more active interrogation of the visual scene, but that this can be detrimental to performance in average drivers. PMID- 24773145 TI - T cell-mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells. AB - BACKGROUND: Inhaled peptide challenge has been shown to induce T cell-mediated, isolated late asthmatic reaction (LAR), characterized by recruitment of CD4(+) T cells and increased levels of thymus and activation-regulated chemokine (TARC; CCL17). Epithelial-derived thymic stromal lymphopoietin (TSLP) has been shown to modulate dendritic cell function to promote TH 2 responses via CCL17 production. OBJECTIVES: To elucidate the mechanisms involved in allergen-specific T cell induced LAR and recruitment of CD4(+) T cells by examining the effects of T cell derived factors on the induction of TSLP in primary bronchial epithelial cells (PBEC). METHODS: PBEC grown at air-liquid interface from healthy individuals and patients with asthma were stimulated with double-stranded RNA (dsRNA) or supernatants from activated allergen-specific T cells. TSLP was measured in PBEC culture supernatants. Neutralizing antibodies and signalling inhibitors were used to examine the mechanisms responsible for the induction of epithelial-derived TSLP. The functional activity of PBEC-derived TSLP was measured using a bioassay involving the induction of CCL17 production from monocyte-derived dendritic cells (moDC). RESULTS: Both dsRNA and allergen-specific T cells induced enhanced TSLP secretion from asthmatic PBEC compared to healthy PBEC. Activated PBEC culture supernatant induced TSLP-dependent CCL17 production from moDC in a manner related to clinical asthmatic status. IL-1beta, IL-6, and CXCL8, rather than TH 2 cytokines (IL-4/5/13), appeared to be the principle mediators of allergen specific T cell-dependent induction of epithelial-derived TSLP, which was regulated by the MEK, MAPK, and NFkappaB pathways. CONCLUSION AND CLINICAL RELEVANCE: Our data reveal a novel effect of allergen-specific T cells as a positive regulator of TSLP production by epithelial cells, suggesting T cell airway epithelium interactions that may lead to maintenance and amplification of allergic inflammation. TSLP is currently a candidate for therapeutic intervention in asthma, but the factors that drive TSLP expression (T cell-derived factors) may be equally relevant in the treatment of allergic inflammation. PMID- 24773146 TI - Evaluation of fear of radiation and isolation before and after radioiodine therapy. AB - BACKGROUND: Prior to undergoing radioiodine therapy (RIT), patients regularly have concerns about isolation on the ward (mandatory for RIT for at least 48 hours in Germany due to radiation protection legislation) as well as fear of the presence of radioactive substances. In this study, these fears were investigated before and after RIT. METHODS: A questionnaire was developed for completion both before and after radioiodine therapy. Questions included: (i) "Are you afraid of a therapy with radioactive substances?" (ii) "Do you have reservations about contact with radioactive substances?" and (iii) "Are you anxious about isolation?" Possible answers were made in a qualitative representation using a scale of 1-4 (4=full agreement, 3=mostly agreement, 2=partial agreement, and 1=no agreement). Further questions included, for example, sources of information used prior to therapy. A total of 209 patients treated by single or preplanned multiple RIT were surveyed over a period of 8 months (return 109). Analysis was done in subgroups according to age, education, disease, and number of RITs. RESULTS: Question 1, "Are you afraid of a therapy with radioactive substances?" showed a similar statistically relevant decline in each subgroup (p<0.05), except for patients with multiple RIT (p=0.81). Asked about the handling of radioactive substances and their perception about the safety in this regard, the entire collective showed a highly statistically significant (p<0.01) decrease with little variability between the groups. The question concerning fear of isolation resulted in a significant decrease (p<0.05) in all subgroups, except for patients with multiple RIT (p=0.13). Analysis of sources of information before RIT showed that older patients preferred printed material and rarely used online resources, while younger patients used the internet more frequently, in addition to printed materials. Finally, most patients would undergo radioiodine therapy again (medical indication provided), with 54% fully agreeing and only 4% not agreeing. CONCLUSIONS: The survey demonstrates a reduction in concerns about nuclear radiation, use of unsealed radioactive materials, and isolation on the ward after RIT. Surprisingly, concerns rise again before a subsequent therapy. PMID- 24773148 TI - Primary nodular amyloidosis of the glans penis. PMID- 24773147 TI - Circulating cortisol levels after exogenous cortisol administration are higher in women using hormonal contraceptives: data from two preliminary studies. AB - Exogenous cortisol administration has been used to test the influence of glucocorticoids on a variety of outcomes, including memory and affect. Careful control of factors known to influence cortisol and other endogenous hormone levels is central to the success of this research. While the use of hormonal birth control (HBC) is known to exert many physiological effects, including decreasing the salivary cortisol response to stress, it is unknown how HBC influences circulating cortisol levels after exogenous cortisol administration. To determine those effects, we examined the role of HBC on participants' cortisol levels after receiving synthetic cortisol (hydrocortisone) in two separate studies. In Study 1, 24 healthy women taking HBC and 26 healthy men were administered a 0.1 mg/kg body weight intravenous dose of hydrocortisone, and plasma cortisol levels were measured over 3 h. In Study 2, 61 participants (34 women; 16 were on HBC) received a 15 mg hydrocortisone pill, and salivary cortisol levels were measured over 6 h. Taken together, results from these studies suggest that HBC use is associated with a greater cortisol increase following cortisol administration. These data have important methodological implications: (1) when given a controlled dose of hydrocortisone, cortisol levels may increase more dramatically in women taking HBC versus women not on HBC or men; and (2) in studies manipulating cortisol levels, women on hormonal contraceptives should be investigated as a separate group. PMID- 24773149 TI - Aesthetical Reconstruction of an Anterior Tooth in an Alveolar Cleft Site: A Case Report and 3-Year Follow-up Findings. PMID- 24773150 TI - (+)-Cyclopenol, a new naturally occurring 7-membered 2,5-dioxopiperazine alkaloid from the fungus Penicillium sclerotiorum endogenous with the Chinese mangrove Bruguiera gymnorrhiza. AB - One new naturally occurring 7-membered 2,5-dioxopiperazine alkaloid named (+) cyclopenol (1), along with nine known compounds including viridicatol (2), 3 (dimethylaminomethyl)-1-(1,1-dimethyl-2-propenyl)indole (3), anacine (4), aurantiomide C (5), viridicatin (6), 3-O-methylviridicatin (7), verrucosidin (8), ergosterol (9), and ergosterol peroxide (10), was isolated from the EtOAc extract of fungus Penicillium sclerotiorum, an endophytic fungal strain isolated from Chinese mangrove Bruguiera gymnorrhiza. The chemical structure of the new compound 1 was elucidated on the basis of detailed spectroscopic analysis. The absolute configuration of 1 was determined by single-crystal X-ray analysis with Cu Kalpha radiation (lambda = 1.54178 A). To our knowledge, (+)-cyclopenol (1) represents the first example of 7-membered 2,5-dioxopiperazine isolated from mangrove endophytic fungus. PMID- 24773151 TI - Hybridization occurs between Drosophila simulans and D. sechellia in the Seychelles archipelago. AB - Drosophila simulans and D. sechellia are sister species that serve as a model to study the evolution of reproductive isolation. While D. simulans is a human commensal that has spread all over the world, D. sechellia is restricted to the Seychelles archipelago and is found to breed exclusively on the toxic fruit of Morinda citrifolia. We surveyed the relative frequency of males from these two species in a variety of substrates found on five islands of the Seychelles archipelago. We sampled different fruits and found that putative D. simulans can be found in a variety of substrates, including, surprisingly, M. citrifolia. Putative D. sechellia was found preferentially on M. citrifolia fruits, but a small proportion was found in other substrates. Our survey also shows the existence of putative hybrid males in areas where D. simulans is present in Seychelles. The results from this field survey support the hypothesis of current interbreeding between these species in the central islands of Seychelles and open the possibility for fine measurements of admixture between these two Drosophila species to be made. PMID- 24773152 TI - Epratuzumab for systemic lupus erythematosus. AB - INTRODUCTION: Systemic lupus erythematosus is an autoimmune multiorgan disease in which the lack of an appropriate therapy can lead to rapid organ failure and death. Immunosuppressive therapies such as corticosteroids or cyclophosphamide can slow down the disease progression but sometimes other therapies are needed. Among such therapies, epratuzumab, an antiCD22 antibody, can be potentially efficacious in this disease. AREAS COVERED: Discussion of the results from clinical studies evaluating the efficacy and safety of epratuzumab in patients with moderate or severe systemic lupus erythematosus. EXPERT OPINION: The study demonstrates that epratuzumab can improve the quality of life and can reduce the disease activity burden, but the premature termination of the studies might have limited the generation of further efficacy data. PMID- 24773153 TI - Aeropectin: fully biomass-based mechanically strong and thermal superinsulating aerogel. AB - Monolithic pectin aerogels, aeropectins, were prepared via dissolution-gelation coagulation and subsequent drying with supercritical CO2. Aeropectin had pore sizes that varied from mesopores to small macropores and compression moduli in the range from 4 to 18 MPa. Aeropectins show plastic deformation up to 60% strain before the pore walls collapse. Pectin aerogels have a thermal conductivity below that of air in ambient conditions, making them new thermal superinsulating fully biomass-based materials. The contribution of gas and solid conduction plus radiative heat transfer were determined and discussed. PMID- 24773154 TI - Induced pluripotent stem cell-derived neural stem cells transduced with baculovirus encoding CD40 ligand for immunogene therapy in mouse models of breast cancer. AB - The interaction between CD40 ligand (CD40L) and CD40 can directly inhibit growth of CD40-positive carcinoma cells and may indirectly inhibit tumor growth through coordination of immune responses. Many efforts in CD40L cancer gene therapy have been focused on direct CD40L gene transfer into malignant target cells. This in vivo gene therapy approach relies on high-efficiency gene transfer and could be technically challenging for the treatment of certain cancers, especially multisite metastases. We report herein an alternative means of using the tumor homing property of neural stem cells (NSCs) to deliver CD40L molecules into tumor tissues. NSCs were derived from human induced pluripotent stem cells, transduced in vitro with a baculoviral vector encoding CD40L, and intravenously injected into immunocompetent mice with orthotopic and metastatic breast cancers. Through a bystander mechanism of intercellular transfer of CD40L from the donor NSCs to tumor target cells, the treatment impeded tumor growth, leading to prolonged survival of the tumor-bearing mice. We further showed that compared with the stem cell-based gene therapy that employed a suicide gene, the CD40L immunogene therapy did not cause liver and kidney injury in the treated mice. This new approach may be particularly valuable for metastatic cancer treatments after systemic stem cell administration. PMID- 24773155 TI - Learning curve for fetoscopic laser surgery using cumulative sum analysis. AB - OBJECTIVE: To identify a learning curve and monitor operator performance for fetoscopic laser surgery for twin-to-twin transfusion syndrome using cumulative sum analysis. DESIGN: Retrospective cohort study. SETTING: National tertiary referral center for invasive fetal therapy. POPULATION: A total of 340 consecutive monochorionic pregnancies with twin-to-twin transfusion syndrome treated with fetoscopic laser coagulation between August 2000 and December 2010. METHODS: A learning curve was generated using learning curve cumulative sum analysis and cumulative sum methodology to assess changes in double survival across the case sequence. Laser surgery was initially performed by two operators, joined by a third and fourth operator after 1 and 2 years, respectively. MAIN OUTCOME MEASURES: Individual operator performance, double perinatal survival at 4 weeks. RESULTS: Overall survival of both twins occurred in 59% (201/340), median gestational age at birth was 32.0 weeks. Cumulative sum graphs showed that level of competence for double survival for the operators was reached after 26, 25, 26, and 35 procedures, respectively. Two operators kept their competence level and continued to improve after completing the initial learning process; two others went out of control at one point in time, according to the cumulative sum boundaries. A difference in learning effect was associated with number of procedures performed annually and previous experience with other ultrasound guided invasive procedures. CONCLUSIONS: This study shows that all operators reached a level of competence after at least 25 fetoscopic laser procedures and confirms the value of using the cumulative sum method both for learning curve assessment and for ongoing quality control. PMID- 24773156 TI - Mapping the variation of the carrot metabolome using 1H NMR spectroscopy and consensus PCA. AB - Genetic variation is the most influential factor for carrot (Daucus carota L.) composition. However, difference in metabolite content between carrot varieties has not been described by NMR, although primary metabolites are important for human health and sensory properties. The aim of the present study was to investigate the effect of genotype on carrot metabolite composition using a (1)H NMR-based metabolomics approach. After extraction using aqueous and organic solvents, 25 hydrophilic metabolites, beta-carotene, sterols, triacylglycerols, and phospholipids were detected. Multiblock PCA showed that three principal components could be identified for classification of the five carrot varieties using different spectroscopic regions and the results of the two solvent extraction methods as blocks. The varieties were characterized by differences in carbohydrate, amino acid, nucleotide, fatty acid, sterol, and beta-carotene contents. (1)H NMR spectroscopy coupled with multiblock data analysis was an efficient and useful tool to map the carrot metabolome and identify genetic differences between varieties. PMID- 24773157 TI - Support and continuity during the first 2 weeks postpartum. AB - OBJECTIVES: To investigate mothers' perceived satisfaction with support from antenatal care (AC), postpartum care (PC) and child health care (CHC), respectively, during the first two weeks after childbirth. DESIGN: Cross sectional survey, mixed-method design. ETHICAL ISSUES: The study was approved by the Regional Research and Ethics Committee at the Karolinska Insititutet, Sweden. METHODS: Data were collected using a study-specific questionnaire that focused on mothers' satisfaction with support from AC, PC and CHC during the first 2 weeks after childbirth. All mothers in Stockholm County (n = 546) who gave birth to a live infant during a 1-week period in 2009 were invited to participate. Descriptive and logistic regression analyses and a content analysis were performed. RESULTS: A large discrepancy was found between levels of satisfaction with AC, PC and CHC. Mothers were satisfied with the support from CHC healthcare nurses, but missed follow-up contact from AC and PC midwives. Nearly 40% of all mothers commented on insufficient support including that continuity in the chain of care was lacking and support for mothers' physical and emotional health was insufficient. Delivery at <37 weeks of gestation was associated with reduced satisfaction with both AC and CHC, but not with PC. Mothers who made emergency visits during the first two weeks were more likely to be dissatisfied with support from PC. CONCLUSION: All links in the chain of care are important for the support of mothers during the first 2 weeks after childbirth, but continuity needs to be improved to raise the quality of care for mothers. PMID- 24773158 TI - Photooxidation of tetrahydrobiopterin under UV irradiation: possible pathways and mechanisms. AB - Tetrahydrobiopterin (H4 Bip) is a cofactor for several key enzymes, including NO synthases and aromatic amino acid hydroxylases (AAHs). Normal functioning of the H4 Bip regeneration cycle is extremely important for the work of AAHs. Oxidized pterins may accumulate if the H4 Bip regeneration cycle is disrupted or if H4 Bip autoxidation occurs. These oxidized pterins can photosensitize the production of singlet molecular oxygen (1)O2 and thus cause oxidative stress. In this context, we studied the photooxidation of H4 Bip in phosphate buffer at pH 7.2. We found that UV irradiation of H4 Bip affected its oxidation rate (quantum yield Phi300 = (2.7 +/- 0.4) * 10(-3)). The effect of UV irradiation at lambda = 350 nm on H4 Bip oxidation was stronger, especially in the presence of biopterin (Bip) (Phi350 = (9.7 +/- 1.5) * 10(-3)). We showed that the rate of H4 Bip oxidation linearly depends on Bip concentration. Experiments with KI, a selective quencher of triplet pterins at micromolar concentrations, demonstrated that the oxidation is sensitized by the triplet state biopterin (3) Bip. Apparently, electron transfer sensitization (Type-I mechanism) is dominant. Energy transfer (Type-II mechanism) and singlet oxygen generation play only a secondary role. The mechanisms of H4 Bip photooxidation and their biological meaning are discussed. PMID- 24773161 TI - Periodontal status following treatment of impacted maxillary canines by closed eruption technique: an overview and case report. AB - Delayed tooth eruption is a common problem in many orthodontic patients. This delay may lead to other problems, such as injury to the adjacent tooth, non vitalization, mucogingival and esthetic problems, etc. Multidisciplinary management is essential when the canines of orthodontic patients have failed to erupt on time. This involves combined surgical and orthodontic intervention. This overview and case report presents special considerations required in treating such cases. METHODS: A combined surgical and orthodontic treatment approach is essential in dealing with such cases. The type of surgery depends on correct localization of the canine along with evaluation of certain criteria to determine the correct method for uncovering the tooth. RESULTS: Success of the treatment in such cases should be defined as long-term desirable esthetics and sound periodontal condition. Thorough treatment planning based on specific criteria would ensure this. CONCLUSION: A multidisciplinary approach, atraumatic surgery, and judicious use of orthodontic forces can ensure an excellent result in form, function, and esthetics in cases with delayed canine eruption. PMID- 24773160 TI - Statistical HOmogeneous Cluster SpectroscopY (SHOCSY): an optimized statistical approach for clustering of 1H NMR spectral data to reduce interference and enhance robust biomarkers selection. AB - We propose a novel statistical approach to improve the reliability of (1)H NMR spectral analysis in complex metabolic studies. The Statistical HOmogeneous Cluster SpectroscopY (SHOCSY) algorithm aims to reduce the variation within biological classes by selecting subsets of homogeneous (1)H NMR spectra that contain specific spectroscopic metabolic signatures related to each biological class in a study. In SHOCSY, we used a clustering method to categorize the whole data set into a number of clusters of samples with each cluster showing a similar spectral feature and hence biochemical composition, and we then used an enrichment test to identify the associations between the clusters and the biological classes in the data set. We evaluated the performance of the SHOCSY algorithm using a simulated (1)H NMR data set to emulate renal tubule toxicity and further exemplified this method with a (1)H NMR spectroscopic study of hydrazine-induced liver toxicity study in rats. The SHOCSY algorithm improved the predictive ability of the orthogonal partial least-squares discriminatory analysis (OPLS-DA) model through the use of "truly" representative samples in each biological class (i.e., homogeneous subsets). This method ensures that the analyses are no longer confounded by idiosyncratic responders and thus improves the reliability of biomarker extraction. SHOCSY is a useful tool for removing irrelevant variation that interfere with the interpretation and predictive ability of models and has widespread applicability to other spectroscopic data, as well as other "omics" type of data. PMID- 24773162 TI - Hybridization trends for main group elements and expanding the Bent's rule beyond carbon: more than electronegativity. AB - Trends in hybridization were systematically analyzed through the combination of DFT calculations with NBO analysis for the five elements X (X = B, C, N, O, and F) in 75 HnX-YHm compounds, where Y spans the groups 13-17 of the periods 2-4. This set of substrates probes the flexibility of the hybridization at five atoms X through variations in electronegativity, polarizability, and orbital size of Y. The results illustrate the scope and limitations of the Bent's rule, the classic correlation between electronegativity and hybridization, commonly used in analyzing structural effects in carbon compounds. The rehybridization effects are larger for fluorine- and oxygen-bonds than they are in the similar bonds to carbon. For bonds with the larger elements Y of the lower periods, trends in orbital hybridization depend strongly on both electronegativity and orbital size. For charged species, the effects of substituent orbital size in the more polarizable bonds to heavier elements show a particularly strong response to the charge introduction at the central atom. In the final section, we provide an example of the interplay between hybridization effects with molecular structure and reactivity. In particular, the ability to change hybridization without changes in polarization provides an alternative way to control structure and reactivity, as illustrated by the strong correlation of strain in monosubstituted cyclopropanes with hybridization in the bond to the substituent. PMID- 24773159 TI - Multiple organ dysfunction syndrome in humans and animals. AB - Multiple organ dysfunction syndrome (MODS), defined as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention, is a cause of high morbidity and mortality in humans and animals. Many advances have been made in understanding the pathophysiology and treatment of this syndrome in human medicine, but much still is unknown. This comparative review will provide information regarding the history and pathophysiology of MODS in humans and discuss how MODS affects each major organ system in animals. PMID- 24773164 TI - Preferences for results from genomic microarrays: comparing parents and health care providers. AB - Chromosomal microarray (CMA) testing is now performed frequently in paediatric care. Although CMAs improve diagnostic yields, they increase detection of variants of unknown and uncertain clinical significance (VUS). Understanding parents', paediatricians' and genetic health professionals' (GHPs) views regarding variant disclosure may reduce the potential for communication of unwanted information. A questionnaire was designed to compare disclosure preferences of these three groups in Australia. One hundred and forty-seven parents, 159 paediatricians and 69 GHPs hold similar views with at least 89% of respondents certainly or probably favouring disclosure of all categories of variants. However, some differences were observed between health care providers (HCPs: paediatricians and GHPs) and parents, who were less sure of their disclosure preferences. There was consensus among respondent groups that knowledge of a variant of certain clinical significance would provide more practical and emotional utility compared to VUS. Compared to HCPs, parents placed more emphasis on using knowledge of a VUS when considering future pregnancies (p < 0.001). This study may help HCPs anticipate parents' preferences for genomic testing. As whole exome/genome sequencing is integrated into clinical practice, the potential for differing views of parents and HCPs should be considered when developing guidelines for result disclosure. PMID- 24773165 TI - Multilayered poly(p-phenylenevinylene)/reduced graphene oxide film: an efficient organic current collector in an all-plastic supercapacitor. AB - This article describes the preparation, using layer-by-layer deposition techniques, of an all-solid-state flexible in-plane supercapacitor based on a poly(ethylene terephthalate) (PET) substrate, laminated with two strata of ultrathin multilayer films composed of 30 polyaniline (PANi)/reduced graphene oxide (RGO) bilayers and 30 poly(p-phenylenevinylene) (PPV)/RGO bilayers. The influence of the (PPV/RGO)30 stratum on the electrochemical properties of the (PANi/RGO)30/(PPV/RGO)30 film (denoted P30) (d = 90.1 nm) supported on a PET was evaluated and compared to the corresponding influence of the (PANi/RGO)53 film (denoted P53) (d = 91.5 nm). The volumetric capacitance of P30 at a discharge current of 20 A/cm(3) (957 F/cm(3)) was much higher than that obtained from P53 (733 F/cm(3)), indicating that the (PPV/RGO)30 film performed well as a current collector. Furthermore, an all-solid-state flexible in-plane EC assembled with P30 electrodes in parallel mode (denoted EC30) exhibited an outstanding volumetric capacitance (152 F/cm(3) at 20 A/cm(3)) with a high energy density (9.4 mW h/cm(3)) and power density (6.5 W/cm(3)), compared to EC53 (assembled with P53). The electron-transfer resistance of the P30 electrode corresponded to only 59% of the P53's value (1.53 vs 2.60 kOmega cm(2)). The high capacitance of EC30 was attributed to the low internal resistance of P30, which resulted from the presence of additional in-plane electrical pathways in the electrode. The enhanced transport led to 85% capacitance retention by EC30 (69% for EC53) after a 1000 charge/discharge cycles test. The series resistance variations (DeltaR/R0) of EC30 also indicated good electromechanical durability in the device, with a 5.0% increase in the resistance (contrasted with a 10.8% increase in EC53) over 1000 bending cycles at a minimum radius of 5 mm. The excellent electrochemical properties of EC30 may potentially meet the requirements for miniaturized electrodes in the manufacture of flexible, lightweight, mechanically durable microelectronic applications. PMID- 24773163 TI - Alcohol use and its association with HIV risk behaviors among a cohort of patients attending HIV clinical care in Tanzania, Kenya, and Namibia. AB - This article describes the frequency of alcohol use among HIV-positive patients attending clinical care in sub-Saharan Africa and explores the association between alcohol use, medication adherence, and sexual risk behavior. Data from 3538 patients attending an HIV clinic in Kenya, Tanzania, or Namibia were captured through interview and medical record abstraction. Participants were categorized into three drinking categories: nondrinkers, nonharmful drinkers, and harmful/likely dependent drinkers. A proportional odds model was used to identify correlates associated with categories of alcohol use. Overall, 20% of participants reported alcohol use in the past 6 months; 15% were categorized as nonharmful drinkers and 5% as harmful/likely dependent drinkers. Participants who reported missing a dose of their HIV medications [adjusted odds ratio (AOR): 2.04, 95% confidence interval (CI): 1.67, 2.49]; inconsistent condom use (AOR: 1.49, 95% CI: 1.23, 1.79); exchanging sex for food, money, gifts, or a place to stay (AOR: 1.57, 95% CI: 1.06, 2.32); and having a sexually transmitted infection symptom (AOR: 1.40, 95% CI: 1.10, 1.77) were more likely to be categorized in the higher risk drinking categories. This research highlights the need to integrate alcohol screening and counseling into the adherence and risk reduction counseling offered to HIV-positive patients as part of their routine care. Moreover, given the numerous intersections between alcohol and HIV, policies that focus on reducing alcohol consumption and alcohol-related risk behavior should be integrated into HIV prevention, care, and treatment strategies. PMID- 24773166 TI - Ondansetron reduces naturalistic drinking in nontreatment-seeking alcohol dependent individuals with the LL 5'-HTTLPR genotype: a laboratory study. AB - BACKGROUND: One hypothesis suggests that the differential response to ondansetron and serotonin-specific re-uptake inhibitors (SSRIs) may be due to a functional polymorphism of the 5'-HTTLPR promoter region in SLC6A4, the gene that codes for the serotonin transporter (5-HTT). The LL 5'-HTTLPR genotype is postulated to be specifically sensitive to the effects of ondansetron with SS/SL 5'-HTTLPR genotypes sensitive to SSRIs. This study tests this hypothesis by matching nontreatment-seeking alcohol-dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mismatching them assessing naturalistic and bar-laboratory alcohol drinking. METHODS: Seventy seven AD individuals were randomized to 1 of 2 counterbalanced arms to receive sertraline 200 mg/d or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self-administration experiment (ASAE) and then received placebo for 3 weeks followed by a second ASAE. Individuals then received the alternate drug for 3 weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in standard drinking units) for 7 days prior to each ASAE and milliliters consumed during each ASAE were the primary outcomes. RESULTS: Fifty-five participants completed the study. The genotype * order interaction was significant, F(1, 47) = 8.42, p = 0.006, for DDD. Three analyses of covariance were conducted for DDD during the week before each ASAE. Ondansetron compared to sertraline resulted in a significant reduction in DDD during the week before the first, F(1, 47) = 7.64, p = 0.008, but not the third ASAE. There was no difference in milliliters consumed during each ASAE. CONCLUSIONS: This study modestly supports the hypothesis that ondansetron may reduce DDD in AD individuals with the LL genotype as measured naturalistically. By contrast, there was no support that ondansetron reduces drinking during the ASAEs or that sertraline reduces alcohol use in individuals who have SS/SL genotypes. We provide limited support that ondansetron may reduce drinking in nontreatment-seeking individuals with the LL genotype. PMID- 24773167 TI - HIV-1 genetic variants in the Russian Far East. AB - A molecular analysis of HIV-1 subtypes and recombinants circulating in cities in the Russian Far East was performed. The study included samples from 201 outpatients from Vladivostok, Khabarovsk, and Blagoveshchensk. In most parts of Russia, patients are infected with HIV-1 subtype A, known as the IDU-A variant. Subtype B, including the IDU-B variant, is rare in Russia but widespread in the Ukraine, and the CRF02_AG is prevalent in Central Asian countries and Siberia, Russia. One of the challenges of this study in the Far East was to determine whether the molecular landscape of HIV infection in this region is influenced by the bordering countries, including China and Japan, where a distinct set of HIV subtypes is circulating, such as B', C, and CRF01_AE. The distribution of HIV-1 genetic variants in the cities studied was as follows: subtype A (IDU-A), 55.7%; subtype B, 25.3% (IDU-B variant-24.3%); subtype C, 10.0%; CRF02_AG, 1.5%; and CRF63_02A1, 7.5%. A phylogenetic analysis confirmed the relationship of subtype A viruses with the IDU-A variant predominating in Ukraine, Russia and other former Soviet Union (FSU) countries, of subtype B viruses with IDU-B in the Ukraine and of CRF02_AG variants with variants in Uzbekistan, Russia, and other former USSR countries. Subtype C sequences were not uniform, and most clustered between each other and HIV-1 sequences originating from Africa; there was only one sample possibly related to Chinese variants. Thus, despite close cultural and commercial relationships among Russia, China, and Japan, the distribution of HIV-1 subtypes in the Russian Far East is still primarily influenced by contacts with the countries of the former USSR. PMID- 24773168 TI - Families' concerns after bereavement in hospital: what can we learn? AB - BACKGROUND: Bereavement is a major life event often leading to psychiatric morbidity. Provision of bereavement care is poorly established in general hospital settings. OBJECTIVE: We describe a novel bereavement service in a large secondary care institution and assess its impact. DESIGN AND MEASUREMENTS: In this descriptive study, data from the first year of operation of the service was obtained. The questions from interviews with relatives stemming from the bereavement care service were reviewed and categorized. Potential predictors of requesting a follow-up meeting were analyzed. RESULTS: Of the 1384 bereaved relatives who were written to, 142 requested follow-up and 119 (8.6%) culminated in a bereavement follow-up meeting. The most common questions asked were for further details regarding the diagnosis (29%), why the patient had deteriorated so quickly (28%), what the diagnosis was (24%), and the sequence of events (24%). Relatives of younger patients and those from specialties other than medicine or surgery were more likely to seek bereavement follow-up (p<0.01 in each case). CONCLUSION: A specialized bereavement service is feasible in a large hospital trust and allows follow-up of relatives with ongoing questions and concerns, with the opportunity of reducing severe grief reactions. PMID- 24773169 TI - Identifying risk factors for surgical site complications after laparoscopic ventral hernia repair: evaluation of the Ventral Hernia Working Group grading system. AB - BACKGROUND: In 2010, the Ventral Hernia Working Group (VHWG) published a grading system to assess the risk of surgical site complications in patients undergoing ventral hernia repair. This study evaluated the predictive value of the VHWG classification for the surgical outcomes of laparoscopic ventral hernia repair (LVHR) and identified independent factors associated with surgical site infection (SSI) and surgical site occurrence (SSO). METHODS: A retrospective review was performed of all patients who underwent LVHR over a 10-year period at two institutions. The U.S. Centers for Disease Control and Prevention definition of SSI and the VHWG definition of SSO were used. Univariable analysis was performed using the Student t-test, analysis of variance, chi-square test, or Fisher exact test, as appropriate. Multivariable analysis was used to identify independent factors associated with SSI and SSO. RESULTS: Differences in American Society of Anesthesiologists class, body mass index, diabetes mellitus, chronic obstructive pulmonary disease, tobacco use, hernia type, prior abdominal surgery, prior ventral hernia repair, hernia size, and total infections were identified by grade. There was no difference in SSI or SSO by grade. Multivariable analysis revealed institution and number of prior abdominal operations to be associated with SSI. Institution, prostate disease, and prior ventral hernia repair were associated with SSO. CONCLUSIONS: The VHWG classification was unable to predict SSI and SSO and may not be applicable in LVHR. This study identified independent factors associated with SSI and SSO in LVHR. Although further study is warranted to validate these results, the factors presented may be a useful tool to stratify patient risk of SSI and SSO with LVHR. PMID- 24773170 TI - Surgical Management of Severe Peri-Implantitis in the Esthetic Zone: A Case Report With a 6-Year Follow-Up. PMID- 24773171 TI - A comparative analysis of symptom and medication scoring methods used in clinical trials of sublingual immunotherapy for seasonal allergic rhinitis. AB - Symptom and medication use are the key outcomes for assessing the efficacy of subcutaneous (SCIT) and sublingual allergen immunotherapy (SLIT). Our objective was to explore the similarities and differences between existing scoring mechanisms used in clinical trials of SLIT for seasonal allergens and characterize the impact that such differences may have on efficacy reporting. Randomized, double-blind, placebo-controlled clinical trials investigating the efficacy of SLIT for seasonal allergic rhinitis (2009-2013) were selected for review. Simulated and published data were used to demonstrate differences in scoring methods. Symptom and medication scoring methods across trials, although all designed to achieve the same objective, included important differences. The maximum daily symptom score (DSS) can vary widely depending on the number of symptoms assessed, and terminology of symptoms is not consistent. Similarly, daily medication scoring (DMS) methods differ greatly among studies and are dependent on medications allowed and weighting of scores assigned to each medication. When published DSS and DMS scores were used to calculate simulated daily combined scores (DCSs) based on various published methods, changes from placebo ranged from 19% to 29% when assuming all variables other than the DSS and DMS methods were equal. Variations in trial design, analysis, and seasonal characteristics also have effects on symptom and medication scoring outcomes. We identified multiple differences in trial scoring methods and design that make comparison among trials difficult. Symptom, medication, or combined scores cannot be indirectly compared among trials without taking the methods of scoring and other trial differences into account. PMID- 24773172 TI - Drug reaction with eosinophilia and systemic symptoms, or virus reactivation with eosinophilia and systemic symptoms as a manifestation of immune reconstitution inflammatory syndrome in a patient with HIV? AB - We report a case of drug reaction with eosinophilia and systemic symptoms (DRESS) in a patient with HIV receiving antitoxoplasmic drugs (adiazine and pyrimethamine) and levetiracetam along with highly active antiretroviral therapy (tenofovir-emtricitabine, darunavir and ritonavir). Cytomegalovirus (CMV) infection was reactivated in the 7 weeks before the development of DRESS but was successfully treated with ganciclovir and corticosteroids. DRESS flare was concomitant with another CMV reactivation after the withdrawal of ganciclovir. This case report is an example of DRESS that may be considered real DRESS or virus reactivation with eosinophilia and systemic symptoms (VRESS) as a manifestation of immune reconstitution inflammatory syndrome. The case confirms that herpesvirus reactivation precedes DRESS or VRESS, and suggests the need to monitor herpesvirus infection in patients at risk for the infection or after the initiation of culprit drugs. PMID- 24773173 TI - Can testosterone level be a good predictor of late-onset hypogonadism? AB - Androgens are essential for the development and growth of the genitalia. They regulate the erectile physiology by multiple mechanisms. Several studies have examined associations among sex hormones' serum levels, erectile function and sex drive. We sought to identify a protocol for using testosterone in men with erectile dysfunction and late-onset hypogonadism (LOH). During a 16-month period, men with erectile dysfunction who presented to the andrology clinic were selected. They underwent a complete physical examination and filled out the International Index of Erectile Function-5 questionnaire. Serum luteinising hormone (LH) and testosterone levels were evaluated. Patients received a single intramuscular injection of 250 mg testosterone. Thereafter, serum levels of LH and testosterone were measured 3 weeks later. The mean age was 53 years old. After treating patients with testosterone, 45 (94%) showed improvement in LOH symptoms including libido, loss of energy, irritability and quality of life. The mean International Index of Erectile Function was 9 and 13.1, prior to and after treatment respectively. Mean serum testosterone levels before and after treatment were 4.2 and 4.1 ng ml(-1) respectively (P = 0.849). Mean serum LH revealed a significant decrease after the study (P = 0.004) (6.12 and 5.1 ng ml(-1) , before and after the study respectively). Our findings suggested that testosterone replacement therapy improves libido and LOH symptoms in individuals with almost normal or lower limit normal value of serum testosterone levels. PMID- 24773174 TI - Divorce in the barn owl: securing a compatible or better mate entails the cost of re-pairing with a less ornamented female mate. AB - Two nonmutually exclusive hypotheses can explain why divorce is an adaptive strategy to improve reproductive success. Under the 'better option hypothesis', only one of the two partners initiates divorce to secure a higher-quality partner and increases reproductive success after divorce. Under the 'incompatibility hypothesis', partners are incompatible and hence they may both increase reproductive success after divorce. In a long-term study of the barn owl (Tyto alba), we address the question of whether one or the two partners derive fitness benefits by divorcing. Our results support the hypothesis that divorce is adaptive: after a poor reproductive season, at least one of the two divorcees increase breeding success up to the level of faithful pairs. By breeding more often together, faithful pairs improve coordination and thereby gain in their efficiency to produce successful fledglings. Males would divorce to obtain a compatible mate rather than a mate of higher quality: a heritable melanin-based signal of female quality did not predict divorce (indicating that female absolute quality may not be the cause of divorce), but the new mate of divorced males was less melanic than their previous mate. This suggests that, at least for males, a cost of divorce may be to secure a lower-quality but compatible mate. The better option hypothesis could not be formally rejected, as only one of the two divorcing partners commonly succeeded in obtaining a higher reproductive success after divorce. In conclusion, incompatible partners divorce to restore reproductive success, and by breeding more often together, faithful partners improve coordination. PMID- 24773175 TI - Photoelectron imaging and theoretical study on nascent hydrogen bond network in microsolvated clusters of Au- (CH3OH)n (n = 1-5). AB - We first demonstrate the photoelectron spectroscopic evidence of the transition of two competitive solvation patterns in the Au(-)(CH3OH)n (n = 1-5) clusters. Quantum chemical calculations have been carried out to characterize the geometric structures, energy properties and hydrogen-bonded patterns, and to aid the spectral assignment. It has been found that the nonconventional hydrogen bonds dominate the small clusters (n = 1 and 2), whereas the conventional hydrogen bonds play more and more important role from n = 2 to n = 5. This finding provides concrete hydrogen bond network evolution of Au(-) surrounded by methanol molecules. PMID- 24773177 TI - MoS2 quantum dot-interspersed exfoliated MoS2 nanosheets. AB - We report the synthesis of heterodimensional nanostructures of MoS2 quantum dots interspersed in few-layered sheets of MoS2, using a liquid exfoliation technique in organic solvents. This unique hybrid morphology results from the optimized experimental conditions involving bath sonication followed by ultrasound probe sonication. We show that such heterodimensional hybrid materials could easily be extracted from the solvent as precipitates when post-treated with less polar volatile solvents such as chloroform. Such tailored MoS2 nanostructures, when directly used as electrodes for hydrogen evolution reaction, showed excellent electrocatalytic activity with low overpotential. Hence, we believe this could lead to large-scale synthesis of liquid-exfoliated layered nanostructures for their potential applications. PMID- 24773176 TI - Serum-dependence of affinity-mediated VEGF release from biomimetic microspheres. AB - Vascular endothelial growth factor (VEGF) activity is highly regulated via sequestering within the ECM and cell-demanded proteolysis to release the sequestered VEGF. Numerous studies have demonstrated that VEGF activity mediates cellular events leading to angiogenesis and capillary formation in vivo. This has motivated the study of biomaterials to sustain VEGF release, and in many cases, the materials are inspired by the structure and function of the native ECM. However, there remains a need for materials that can bind to VEGF with high specificity, as the in vivo environment is rich in a variety of growth factors (GFs) and GF-binding moieties. Here we describe a strategy to control VEGF release using hydrogel microspheres with tethered peptides derived from VEGF receptor 2 (VEGFR2). Using biomaterials covalently modified with varying concentrations of two distinct VEGFR2-derived peptides with varying serum stability, we analyzed both biomaterial and environmental variables that influence VEGF release and activity. The presence of tethered VEGF-binding peptides (VBPs) resulted in significantly extended VEGF release relative to control conditions, and the resulting released VEGF significantly increased the expansion of human umbilical vein endothelial cells in culture. VEGF release rates were also strongly influenced by the concentration of serum. The presence of Feline McDonough Sarcoma-like tyrosine kinase 1 (sFlt-1), a serum-borne receptor fragment derived from VEGF receptor 1, increased VEGF release rates, although sFlt-1 was not sufficient to recapitulate the release profile of VEGF in serum. Further, the influence of serum on VEGF release was not due to protease activity or nonspecific VEGF interactions in the presence of serum-borne heparin. VEGF release kinetics correlated well with a generalizable mathematical model describing affinity-mediated release of VEGF from hydrogel microspheres in defined conditions. Modeling results suggest a potential mechanism whereby competition between VEGF and multiple VEGF-binding serum proteins including sFlt 1, soluble kinase insert domain receptor (sKDR), and alpha2-macroglobulin (alpha2 M) likely influenced VEGF release from microspheres. The materials and mathematical model described in this approach may be useful in a range of applications in which sustained, biologically active GF release of a specific GF is desirable. PMID- 24773180 TI - Pain evoked by distension of the uterine cervix in women with dysmenorrhea: evidence for central sensitization. AB - OBJECTIVE: To study sensitization in women with dysmenorrhea using a standardized experimental model. Women with dysmenorrhea experience intense visceral pain during menstruation. The dysmenorrhea pain mechanisms are not known but sensitization may play a role. DESIGN: Prospective experimental study. SAMPLE: Ten women with dysmenorrhea and 10 control women having uterine cervical distensions in the mid-follicular period (days 6-10). SETTING: University clinic. METHOD: Cervical distension was delivered as three phasic stimuli with 1 min between distensions and as a prolonged (1 min) distension. MAIN OUTCOME MEASURE: Sensory intensity rated on a continuous visual analog scale. RESULTS: Distension induced pain was described as dull and aching and referred to the pelvis, lower back and lower abdomen. Larger evoked referred pain areas were present in women with dysmenorrhea compared with control women (p < 0.05). The pain threshold to the first stimulus was significantly higher in patients than controls (p < 0.04), but decreased significantly with repeated distensions (p < 0.01). For the prolonged distension the pain rating increased significantly (p < 0.008) in women with dysmenorrhea, but decreased (p < 0.02) in control women. CONCLUSIONS: Pain sensitization (temporal summation, i.e. increase in pain during prolonged stimulation, and facilitation of referred pain areas as an indicator of central nervous system changes) is present in women with dysmenorrhea. The study provided new information on a poorly understood yet widespread condition and a basis for clinical studies to develop a biomarker tests for objective assessment of dysmenorrhea. PMID- 24773179 TI - The Effect of Chinese rhubarb, Rheum officinale, with and without benazepril on the progression of naturally occurring chronic kidney disease in cats. AB - BACKGROUND: Renal fibrosis is common in progressive kidney disease. Transforming growth factors beta (TGF-beta) are important mediators of all types of fibrosis, including renal fibrosis. Chinese rhubarb has been shown to have antifibrotic properties in part because of inhibition of TGF-beta and has slowed the progression of kidney disease in rodent models. HYPOTHESIS: That administration of a Chinese rhubarb supplement will slow the progression of chronic kidney disease (CKD) in cats and the concurrent administration of Chinese rhubarb and benazepril will be more effective than either alone. ANIMALS: Twenty-nine client owned cats with naturally occurring IRIS Stage 2 or early Stage 3 CKD and without comorbidity such as cancer, urinary tract obstruction, urinary tract infection, poorly controlled hyperthyroidism, or systemic hypertension were enrolled in the study. METHODS: A randomized, positive-controlled, prospective study was performed. Cats received Chinese rhubarb, benazepril, or both in addition to standard treatment for CKD. Repeated measures ANOVA was used to assess changes in serum creatinine concentration, body weight, hematocrit, urine protein: urine creatinine ratio (UPC), and systemic arterial blood pressure over time between and within treatment groups over an average of 22 months. RESULTS: No significant differences were detected in serum creatinine concentration, body weight, hematocrit, UPC, and systemic arterial pressure over time between or within treatment groups. CONCLUSIONS AND CLINICAL IMPORTANCE: This study failed to detect a significant difference in the progression of CKD in cats treated with Chinese rhubarb, benazepril, or both. Further study in specific subsets of cats with CKD is warranted. PMID- 24773181 TI - Sensitive quantitation of polyamines in plant foods by ultrasound-assisted benzoylation and dispersive liquid-liquid microextraction with the aid of experimental designs. AB - A new method involving ultrasound-assisted benzoylation and dispersive liquid liquid microextraction was optimized with the aid of chemometrics for the extraction, cleanup, and determination of polyamines in plant foods. Putrescine, cadaverine, spermidine, and spermine were derivatized with 3,5-dinitrobenzoyl chloride and extracted by dispersive liquid-liquid microextraction using acetonitrile and carbon tetrachloride as dispersive and extraction solvents, respectively. Two-level full factorial design and central composite design were applied to select the most appropriate derivatization and extraction conditions. The developed method was linear in the 0.5-10.0 mg/L range, with a R(2) >= 0.9989. Intra- and interday precisions ranged from 0.8 to 6.9% and from 3.0 to 10.3%, respectively, and the limit of detection ranged between 0.018 and 0.042 MUg/g of fresh weight. This method was applied to the analyses of six different types of plant foods, presenting recoveries between 81.7 and 114.2%. The method is inexpensive, versatile, simple, and sensitive. PMID- 24773178 TI - Adenoviral vector-mediated gene therapy for gliomas: coming of age. AB - INTRODUCTION: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and it carries a dismal prognosis. Adenoviral vector (Ad) mediated gene transfer is being developed as a promising therapeutic strategy for GBM. Preclinical studies have demonstrated safety and efficacy of adenovirus administration into the brain and tumor mass in rodents and into the non-human primates' brain. Importantly, Ads have been safely administered within the tumor resection cavity in humans. AREAS COVERED: This review gives background on GBM and Ads; we describe gene therapy strategies for GBM and discuss the value of combination approaches. Finally, we discuss the results of the human clinical trials for GBM that have used Ads. EXPERT OPINION: The transduction characteristics of Ads, and their safety profile, added to their capacity to achieve high levels of transgene expression have made them powerful vectors for the treatment of GBM. Recent gene therapy successes in the treatment of retinal diseases and systemic brain metabolic diseases encourage the development of gene therapy for malignant glioma. Exciting clinical trials are currently recruiting patients; although, it is the large randomized Phase III controlled clinical trials that will provide the final decision on the success of gene therapy for the treatment of GBM. PMID- 24773182 TI - Prevailing public perceptions of the ethics of gene therapy. AB - Gene therapy research is advancing rapidly, and hopes of treating a large number of brain disorders exist alongside ethical concerns. Most surveys of public attitudes toward these ethical issues are already dated and the content of these surveys has been researcher-driven. To examine current public perceptions, we developed an online instrument that is responsive and relevant to the latest research about ethics, gene therapy, and the brain. The 16-question survey was launched with the platform Amazon Mechanical Turk and was made available to residents of Canada and the United States. The survey was divided into six themes: (1) demographic information, (2) general opinions about gene therapy, (3) medical applications of gene therapy, (4) identity and moral/belief systems, (5) enhancement, and (6) risks. We received and analyzed responses from a total of 467 participants. Our results show that a majority of respondents (>90%) accept gene therapy as a treatment for severe illnesses such as Alzheimer disease, but this receptivity decreases for conditions perceived as less severe such as attention deficit hyperactivity disorder (79%), and for nontherapeutic applications (47%). The greatest area of concern for the application of gene therapy to brain conditions is the fear of not receiving sufficient information before undergoing the treatment. The main ethical concerns with enhancement were the potential for disparities in resource allocation, access to the procedure, and discrimination. When comparing these data with those from the 1990s, our findings suggest that the acceptability of gene therapy is increasing and that this trend is occurring despite lingering concerns over ethical issues. Providing the public and patients with up-to-date information and opportunities to engage in the discourse about areas of research in gene therapy is a priority. PMID- 24773183 TI - New quantitative structure-fragmentation relationship strategy for chemical structure identification using the calculated enthalpy of formation as a descriptor for the fragments produced in electron ionization mass spectrometry: a case study with tetrachlorinated biphenyls. AB - Differential mass spectrometry correlated with quantum chemical calculations (QCC DeltaMS) has been shown to be an efficient tool for the chemical structure identification (CSI) of isomers with similar mass spectra. For this type of analysis, we report here a new strategy based on ordering (ORD), linear correlation (LCOR) algorithms, and their coupling, to filter the most probable structures corresponding to similar mass spectra belonging to a group with dozens of isomers (e.g., tetrachlorinated biphenyls, TeCBs). This strategy quantifies and compares the values of enthalpies of formation (Delta(f)H) obtained by QCC for some isobaric ions from the electron ionization (EI)-MS mass spectra, to the corresponding relative intensities. The result of CSI is provided in the form of lists of decreasing probabilities calculated for all the position-isomeric structures using the specialized software package CSI-Diff-MS Analysis 3.1.1. The simulation of CSI with ORD, LCOR, and their coupling of six TeCBs (IUPAC no. 44, 46, 52, 66, 74, and 77) has allowed us to find the best semiempirical molecular orbital methods for several of their common isobaric fragments. The study of algorithms and strategy for the entire group of TeCBs (42 isomers) was made with one of the optimal variants for the computation of Delta(f)H using semiempirical molecular orbital methods of HyperChem: AM1 for M(+*) and [M - 4Cl](+*) ions and RM1 for [M - Cl](+) and [M - 2Cl](+*). The analytical performance of ORD, LCOR, and their coupling resulted from the CSI simulation of an analyte of known structure, using a decreasing number of isomeric standards, s = 5, 4, 3, and 2. Compared with the results obtained by a classical library search for TeCB isomers, the novel strategies of assigning structures of isomers with very similar mass spectra based on ORD, LCOR, and their coupling were much more efficient, because they provide the correct structure at the top of the probability list. Databases used in these CSI do not contain mass spectra, as in the case of a library search, but a series of Delta(f)H values obtained by QCC. These techniques are capable of relating relative intensities to the chemical structures of analytes via Delta(f)H of ions which turns out to be a good quantitative structure-fragmentation relationship (QSFR) descriptor. PMID- 24773184 TI - Efficient bioactive delivery of aerosolized drugs to human pulmonary epithelial cells cultured in air-liquid interface conditions. AB - In inhalation therapy, drugs are deposited as aerosols onto the air-facing lung epithelium. The currently used in vitro cell assays for drug testing, however, typically dissolve drugs in the medium, completely covering the cells, which represents an unphysiological drug application scenario. Although physiologically realistic in vitro cell culture models of the pulmonary air-blood barrier are available, reliable, easy-to-handle, and efficient technologies for direct aerosol-to-cell delivery are lacking. Here, we introduce the Air-Liquid Interface (ALI) Cell Exposure-Cloud (ALICE-CLOUD) technology, which uses principles of cloud motion for fast and quantitative delivery of aerosolized liquid drugs to pulmonary cells cultured under realistic ALI conditions. Aerosol-to-cell delivery proved to be highly efficient, reproducible, and rapid when using aerosolized fluorescein as surrogate drug. As a proof-of-concept study for the ALICE-CLOUD, we performed functional efficacy studies with the U.S. Food and Drug Administration-approved proteasome inhibitor, Bortezomib, a novel candidate drug for inhalation therapy. Aerosolized Bortezomib had a pronounced anti-inflammatory effect on human epithelial lung cells (A549), as indicated by a significant reduction of (TNFalpha-induced) IL-8 promoter activation. Importantly, cell-based therapeutic efficacy of aerosolized Bortezomib under ALI conditions was similar to that under dissolved and nonaerosolized submerged conditions, but with faster uptake kinetics. Our data indicate that the ALICE-CLOUD is a reliable tool for aerosolized drug screening with cells cultured under ALI conditions, which combines ease of handling with rapid, efficient, and dosimetrically accurate drug to-cell delivery. This may pave the way for screening of inhalable drugs under physiologically more relevant and, hence, potentially more predictive conditions than the currently used submerged cell culture systems. PMID- 24773185 TI - Influence of instruction on velocity and accuracy in soccer kicking of experienced soccer players. AB - The authors' aim was to investigate the speed-accuracy tradeoff in soccer kicking with the dominant and nondominant foot by using different types of instructions prioritizing speed or accuracy in experienced soccer players. Ten male soccer players were randomly given 1 of the 4 instructions that differed in aspects of the kick they should emphasize and what the secondary aim would be (speed or accuracy). It was found that ball velocity was affected by instruction in the expected way: emphasis on accuracy and ball velocity reduced for both kicking feet. In addition kicking accuracy increased when emphasizing this, but only with the dominant foot indicating that Fitts' law only was found in kicks with the dominant foot. PMID- 24773186 TI - Homogeneous and sensitive detection of microRNA with ligase chain reaction and lambda exonuclease-assisted cationic conjugated polymer biosensing. AB - A simple and homogeneous microRNA assay is developed by integration of ligase chain reaction (LCR) and lambda exonuclease-assisted cationic conjugated polymer (CCP) biosensing. LCR is utilized for exponential amplification of microRNA, and lambda exonuclease is introduced to degrade excess fluorescein-labeled probes in LCR for eliminating background signal. After addition of CCP, efficient fluorescence resonance energy transfer from CCP to fluorescein in LCR products occurs. The method is sensitive enough to detect 0.1 fM target microRNA and specific to discriminate one-base difference of microRNAs, which paves a new way for homogeneous microRNA detection and molecular diagnosis. PMID- 24773187 TI - Community-based electronic data collections for HIV prevention research with black/African-American men in the rural, Southern USA. AB - In Florida, the HIV case rate among black men is five times that of white men; tailored HIV prevention interventions are lacking. Historical concerns regarding trust with public health venues and sharing sensitive information make face-to face data collection with some rural, southern black men challenging. We evaluated the feasibility and acceptability of using audio computer-assisted self interviews (ACASIs) by local community-based organization members to collect HIV related information from black men in rural settings. We used logistic regression to estimate associations between using ACASI and participants' sociodemographic characteristics. Of 636 men approached, 586 (92.0%) participated, 479 (81.7%) never completed a computer survey, and 287 (71%) of those reporting a preference preferred ACASI for future data collections. Increased age, past computer use, and sharing a household with someone were significantly associated with ACASI feasibility and acceptability. Using ACASI with black men in rural settings is feasible for HIV intervention research and disparity-reducing goals. PMID- 24773188 TI - Excessively redundant umbilical skin as a potential early clinical feature of Morquio syndrome and FKBP14-related Ehlers-Danlos syndrome. AB - Several umbilical abnormalities have been linked to and utilized to aid in the clinical diagnosis of certain syndromes. For instance, umbilical skin redundancy has long been recognized as a core feature of Rieger syndrome although its association with other disorders is unknown. In this article, we report for the first time the occurrence of this distinct clinical sign in association with two other syndromes: Morquio syndrome and FKBP14-related Ehlers-Danlos syndrome (EDS). Our observation is clinically significant because patients with Morquio syndrome are often diagnosed only after they develop typical skeletal manifestations, which reduces the efficacy of available enzyme replacement therapy, so the umbilical sign we report here can facilitate a much earlier diagnosis. In addition, the extreme rarity of FKBP14-related Ehlers-Danlos syndrome (EDS) can greatly delay the diagnosis of this condition unless it is recognized in the differential diagnosis of redundant umbilical skin as we argue in this report. PMID- 24773189 TI - Plant mineral nutrition for nutrient and food security. PMID- 24773190 TI - Evaluation of advance directives video education for patients. AB - BACKGROUND: Patients and families can make informed decisions at the end-of-life if they have had discussions regarding their wishes, but this is not regularly done due to poor understanding of advance directives (AD). OBJECTIVE: The objective was to evaluate the effectiveness of an AD video to educate patients in both the inpatient and outpatient settings. METHODS: A prospective, nonrandomized, pre/post-survey design study of 45 patients was conducted. Patients in clinics (n=37) and hospital (n=8) were asked to complete surveys measuring baseline understanding, completion, and discussions of AD prior to viewing the video. Patients viewed the video and completed similar surveys for feedback on the effectiveness of the video education. RESULTS: Patients felt the video was informative and helpful and stated more of an urgency to complete AD with increased perceived understanding of the forms. Prior to the educational video, 66.7% of patients stated they had discussed AD with their loved ones, while only 29% stated they had discussed these with their provider. Only 44.4% of participants had completed AD forms, and the majority (70.3%) wanted more information. Participants stated that viewing the video increased their desire to complete AD (78.6%), felt they had enough information to have these discussions and complete the forms (97.6%), and rated the video very highly (mean rank of 8.8 of 10). CONCLUSIONS: AD video education is helpful to patients, improving perceived understanding of AD and increasing patients' intent to discuss and complete AD with family and providers. PMID- 24773192 TI - Good for God? Religious motivation reduces perceived responsibility for and morality of good deeds. AB - Many people view religion as a crucial source of morality. However, 6 experiments (total N = 1,078) revealed that good deeds are perceived as less moral if they are performed for religious reasons. Religiously motivated acts were seen as less moral than the exact same acts performed for other reasons (Experiments 1-2 and 6). Religious motivations also reduced attributions of intention and responsibility (Experiments 3-6), an effect that fully mediated the effect of religious motivations on perceived morality (Experiment 6). The effects were not explained by different perceptions of motivation orientation (i.e., intrinsic vs. extrinsic) across conditions (Experiment 4) and also were evident when religious upbringing led to an intuitive moral response (Experiment 5). Effects generalized across religious and nonreligious participants. When viewing a religiously motivated good deed, people infer that actually helping others is, in part, a side effect of other motivations rather than an end in itself. Thus, religiously motivated actors are seen as less responsible than secular actors for their good deeds, and their helping behavior is viewed as less moral than identical good deeds performed for either unclear or secular motivations. PMID- 24773191 TI - Theoretically motivated interventions for reducing sexual risk taking in adolescence: a randomized controlled experiment applying fuzzy-trace theory. AB - Fuzzy-trace theory is a theory of memory, judgment, and decision making, and their development. We applied advances in this theory to increase the efficacy and durability of a multicomponent intervention to promote risk reduction and avoidance of premature pregnancy and sexually transmitted infections. Seven hundred and thirty-four adolescents from high schools and youth programs in 3 states (Arizona, Texas, and New York) were randomly assigned to 1 of 3 curriculum groups: RTR (Reducing the Risk), RTR+ (a modified version of RTR using fuzzy trace theory), and a control group. We report effects of curriculum on self reported behaviors and behavioral intentions plus psychosocial mediators of those effects: namely, attitudes and norms, motives to have sex or get pregnant, self efficacy and behavioral control, and gist/verbatim constructs. Among 26 outcomes, 19 showed an effect of at least 1 curriculum relative to the control group: RTR+ produced improvements for 17 outcomes and RTR produced improvements for 12 outcomes. For RTR+, 2 differences (for perceived parental norms and global benefit perception) were confined to age, gender, or racial/ethnic subgroups. Effects of RTR+ on sexual initiation emerged 6 months after the intervention, when many adolescents became sexually active. Effects of RTR+ were greater than RTR for 9 outcomes, and remained significantly greater than controls at 1-year follow-up for 12 outcomes. Consistent with fuzzy-trace theory, results suggest that by emphasizing gist representations, which are preserved over long periods and are key memories used in decision making, the enhanced intervention produced larger and more sustained effects on behavioral outcomes and psychosocial mediators of adolescent risk taking. PMID- 24773193 TI - Talk this way: the effect of prosodically conveyed semantic information on memory for novel words. AB - Speakers modulate their prosody to express not only emotional information but also semantic information (e.g., raising pitch for upward motion). Moreover, this information can help listeners infer meaning. Work investigating the communicative role of prosodically conveyed meaning has focused on reference resolution, and potential mnemonic benefits remain unexplored. We investigated the effect of prosody on memory for the meaning of novel words, even when it conveys superfluous information. Participants heard novel words, produced with congruent or incongruent prosody, and viewed image pairs representing the intended meaning and its antonym (e.g., a small and a large dog). Importantly, an arrow indicated the image representing the intended meaning, resolving the ambiguity. Participants then completed 2 memory tests, either immediately after learning or after a 24-hr delay, on which they chose an image (out of a new image pair) and a definition that best represented the word. On the image test, memory was similar on the immediate test, but incongruent prosody led to greater loss over time. On the definition test, memory was better for congruent prosody at both times. Results suggest that listeners extract semantic information from prosody even when it is redundant and that prosody can enhance memory, beyond its role in comprehension. PMID- 24773194 TI - When is irony effortful? AB - Whereas some studies indicate that ironic-as opposed to literal-readings of utterances take longer to process, others indicate that the 2 are processed at comparable speeds. We propose that mindreading processes are at least partly responsible for the mixed results, as we present 3 experiments that include stories having a target utterance with either an Ironic or Literal reading. Experiment 1 replicates earlier findings (Spotorno, Koun, Prado, Van Der Henst, & Noveck, 2012) showing that ironic readings take longer than literal ones when fillers include decoys, stories that call for an ironic remark but present a banal utterance instead and thus diffuse participants' expectations for irony. Starting with Experiment 2, decoys are removed, leading to effects that are arguably revealing of Theory of Mind processes. One is an Early-Late effect, which occurs when ironic utterances are read as readily as literal ones in the 2nd half of an experimental session, creating "mixed" results in the laboratory. In Experiment 3, we further added antecedents before a critical event so that, later, the target utterance would be echoing an explicitly stated thought and would facilitate irony comprehension (Gibbs, 1986; Sperber & Wilson, 1981). Results reveal an Early-Late effect here, too. Further evidence of Theory of Mind activity follows from analyses of participants' Social Skill subscale scores in the Autism-Spectrum Quotient (Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001). Socially inclined participants are more likely than the socially disinclined to use a story's negative event to portend the arrival of an irony; in contrast, socially disinclined participants appear more reactive than the socially inclined to explicit antecedents. PMID- 24773195 TI - Dental ceramics: a current review. AB - Ceramics are used for many dental applications and are characterized in various ways, including by their hardness, brittleness, thermal and electrical insulation, and biocompatibility. The ceramics most commonly used in dentistry are oxides, particularly silicon dioxide (SiO2), or silica; aluminum oxide (Al2O3), or alumina; and zirconium dioxide (ZrO2), or zirconia. This article reviews the microstructure of current dental ceramic materials and how it relates to their mechanical properties, clinical techniques, and optical properties. Typical ceramics currently in use are described, and their clinically relevant properties such as strength, fracture, polishability, and wear are compared. Cementation methods are also discussed. PMID- 24773196 TI - Proper restorative material selection, digital processes allow highly esthetic shade match combined with layered porcelain. AB - Today's digital technologies are affording dentists and laboratory technicians more control over material choices for creating restorations and fabricating dental prostheses. Digital processes can potentially enable technicians to create ideal marginal areas and account for the thickness and support of layering porcelain over substructures in the design process. In this case report of a restoration of a single central incisor, a number of issues are addressed that are central to using the newest digital technology. As demonstrated, shade selection is a crucial early step in any restorative case preparation. PMID- 24773197 TI - Conservative esthetic rehabilitation of a young patient with amelogenesis imperfecta. AB - Conservative management of young adult patients with amelogenesis imperfecta using contemporary materials and techniques is needed in dentistry. These patients have malformed enamel that tends to wear down at a faster rate than normal and is prone to decay. Conventional management of such patients requires devitalization of all involved teeth, followed by post cores and crown lengthening and preparing them to provide sufficient space to receive full coverage restorations. This article outlines a minimally invasive method of managing such cases. By increasing the vertical dimension of occlusion and using very minimal or no preparations and fabrication of lithium-disilicate crowns to adhesively bond to the remaining tooth structure, these teeth can be saved from being devitalized, as demonstrated in a case. This allows the structural integrity of the teeth to be maintained, along with their vitality. PMID- 24773198 TI - Bone vs. bite: correcting a dental cross-bite using a Kois deprogrammer. AB - A patient presented with esthetic concerns that he believed would require lengthy orthodontic treatment, as well as jaw surgery, in order to correct. Functional analysis, however, indicated a cross-bite that was being caused by a functional shift rather than by skeletal asymmetry. Utilizing a simple restorative approach, the case was treated by equilibration of the dentition with the use of a Kois deprogrammer. The treatment plan involved mocking up restorations in composite to establish stable occlusion and quadrant dentistry to replace existing, questionable dental restorations. In the end, significant esthetic improvement was achieved in a highly conservative manner. PMID- 24773199 TI - Guided bone regeneration (GBR) using cortical bone pins in combination with leukocyte- and platelet-rich fibrin (L-PRF). AB - Two of the fundamental requisites for guided bone regeneration (GBR) are space maintenance and primary soft-tissue closure. Allogeneic cortical bone pins measuring 2 mm in diameter in customized lengths can protect surrounding graft materials, support bioresorbable membrane barriers, and resist wound compression from the overlying soft tissues. In addition, a second-generation platelet concentrate, leukocyte- and platelet-rich fibrin (L-PRF), may be incorporated into the augmentation procedure to provide multiple growth factors, accelerate wound healing, and aid in the maintenance of primary closure over the grafted materials. Highlighting two case reports, this article features a GBR technique that uses bone pins in combination with L-PRF membranes to provide both horizontal and vertical ridge augmentation at severely compromised implant sites. PMID- 24773200 TI - Impression-taking: conventional methods remain steadfast as digital technology progresses. PMID- 24773201 TI - Gentamicin/collagen sponge use may reduce the risk of surgical site infections for patients undergoing cardiac operations: a meta-analysis. AB - OBJECTIVE: A meta-analysis of all published randomized controlled trials of the effectiveness of gentamicin/collagen sponges for preventing surgical site infections (SSIs). BACKGROUND: Despite routine use of systemic prophylactic antimicrobial agents, SSIs continue to be associated with substantial morbidity. RESULTS conflict of studies of the efficacy of gentamicin/collagen sponges for preventing SSIs. However, many of these studies have assessed sponge use in only a single specific type of operation. The general effect of sponge use among different types of operations has not been previously assessed. METHODS: The PubMed and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched for articles appearing from 1990 through January 2012 that were related to gentamicin/collagen sponge use and SSIs. Summary estimates were obtained through a random effects model. After reviewing 714 article abstracts and reviewing 22 articles in detail, we pooled the odds ratios (OR) for 13 independent study populations (cardiac, n=4; colorectal, n=4; pilonidal sinus, n=2; hernia, n=2; gastrointestinal, n=1) in which the association between prophylactic use of gentamicin/collagen sponges and SSIs was assessed. RESULTS: Pooling of the results of all studies included in the review in a random effects model showed a significant protective effect of prophylactic use of gentamicin/collagen sponges against SSI (pooled OR: 0.66; 95% confidence interval [CI]: 0.45, 0.97; n=13). However, when the data were stratified by type of operation, a significant protective effect was observed in cardiac procedures (pooled OR: 0.59; 95% CI: 0.37, 0.96; n=4) but not in colorectal procedures (pooled OR: 0.74; 95% CI: 0.29-1.92; n=4). CONCLUSION: Use of gentamicin/collagen sponges was associated with a reduced risk of SSI following cardiac operations but not following colorectal procedures. PMID- 24773202 TI - The gut microbiota and its role in the development of allergic disease: a wider perspective. AB - The gut microbiota are critical in the homoeostasis of multiple interconnected host metabolic and immune networks. If early microbial colonization is delayed, the gut-associated lymphoid tissues (GALT) fail to develop, leading to persistent immune dysregulation in mice. Microbial colonization has also been proposed as a major driver for the normal age-related maturation of both Th1 and T regulatory (Treg) pathways that appear important in suppressing early propensity for Th2 allergic responses. There is emerging evidence that resident symbionts induce tolerogenic gut-associated Treg cells and dendritic cells that ensure the preferential growth of symbionts; keeping pathogenic strains in check and constraining proinflammatory Th1, Th2, and Th17 clones. Some effects of symbionts are mediated by short-chain fatty acids, which play a critical role in mucosal integrity and local and systemic metabolic function and stimulate the regulatory immune responses. The homoeostatic IL-10/TGF-beta dominated tolerogenic response within the GALT also signals the production of secretory IgA, which have a regulating role in mucosal integrity. Contrary to the 'sterile womb' paradigm, recent studies suggest that maternal microbial transfer to the offspring begins during pregnancy, providing a pioneer microbiome. It is likely that appropriate microbial stimulation both pre- and postnatally is required for optimal Th1 and Treg development to avoid the pathophysiological processes leading to allergy. Disturbed gut colonization patterns have been associated with allergic disease, but whether microbial variation is the cause or effect of these diseases is still under investigation. We are far from understanding what constitutes a 'healthy gut microbiome' that promotes tolerance. This remains a major limitation and might explain some of the inconsistency in human intervention studies with prebiotics and probiotics. Multidisciplinary integrative approaches with researchers working in networks, using harmonized outcomes and methodologies, are needed to advance our understanding in this field. PMID- 24773204 TI - Social anxiety and the ironic effects of positive interviewer feedback. AB - BACKGROUND AND OBJECTIVES: Positive interviewer feedback should encourage positive experiences and outcomes for interviewees. Yet, positive feedback is inconsistent with socially anxious interviewees' negative self-views. Socially anxious interviewees might experience increased self-focus while attempting to reconcile the inconsistency between their self-perceptions and that feedback. This could interfere with successful interview performance. DESIGN: This study used a 3 (feedback: positive, negative, no) * 2 (social anxiety: high, low) between-subjects design. METHOD: Undergraduate students (N = 88) completed a measure of dispositional social anxiety. They then engaged in a simulated interview with a White confederate trained to adhere to a standardized script. Interviewees received positive, negative, or no interviewer feedback. Each interview was video recorded to code anxiety displays, impression management tactics, and interview success. RESULTS: Following positive feedback, socially anxious interviewees displayed more anxiety, less assertiveness, and received lower success ratings. Among anxious interviewees, increased self-focus provided an indirect path between positive feedback and lower success. CONCLUSIONS: Consistent with self-verification theory, anxious interviewees had poorer interview performance following positive feedback that contradicted their negative self-views. Thus, socially anxious interviewees might be at a disadvantage when interviewing, especially following positive feedback. Implications for interviewees and interviewers are discussed. PMID- 24773203 TI - Modulation of fatty acid and bile acid metabolism by peroxisome proliferator activated receptor alpha protects against alcoholic liver disease. AB - BACKGROUND: Chronic alcohol intake affects liver function and causes hepatic pathological changes. It has been shown that peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice developed more pronounced hepatic changes than wild-type (WT) mice after chronic exposure to a diet containing 4% alcohol. The remarkable similarity between the histopathology of alcoholic liver disease (ALD) in Ppara-null model and in humans, and the fact that PPARalpha expression and activity in human liver are less than one-tenth of those in WT mouse liver make Ppara-null a good system to investigate ALD. METHODS: In this study, the Ppara-null model was used to elucidate the dynamic regulation of PPARalpha activity during chronic alcohol intake. Hepatic transcriptomic and metabolomic analyses were used to examine alterations of gene expression and metabolites associated with pathological changes. The changes triggered by alcohol consumption on gene expression and metabolites in Ppara-null mice were compared with those in WT mice. RESULTS: The results showed that in the presence of PPARalpha, 3 major metabolic pathways in mitochondria, namely the fatty acid beta oxidation, the tricarboxylic acid cycle, and the electron transfer chain, were induced in response to a 2-month alcohol feeding, while these responses were greatly reduced in the absence of PPARalpha. In line with the transcriptional modulations of these metabolic pathways, a progressive accumulation of triglycerides, a robust increase in hepatic cholic acid and its derivatives, and a strong induction of fibrogenesis genes were observed exclusively in alcohol-fed Ppara-null mice. CONCLUSIONS: These observations indicate that PPARalpha plays a protective role to enhance mitochondrial function in response to chronic alcohol consumption by adaptive transcriptional activation and suggest that activation of this nuclear receptor may be of therapeutic value in the treatment for ALD. PMID- 24773205 TI - Infertility experience and health differentials - a population-based comparative study on infertile and non-infertile women (the HUNT Study). AB - OBJECTIVE: Studies suggest that health complaints, distress and poor life satisfaction are associated with infertility experience. Research on health consequences of infertility experience in women has relied heavily on clinic based samples. This population-based study investigates the association between infertility and health and life satisfaction. DESIGN: Cross-sectional population based health study, conducted between 2006 and 2008. SETTING: All women in a county in Norway were invited. The current material is restricted to women aged 20-49 years. POPULATION: A total of 9200 women participated. METHODS: Health measures were compared between women with infertility experience (infertile women) and women without infertility experience (non-infertile women). Disparities in health and life satisfaction among the infertile women were assessed. MAIN OUTCOME MEASURES: Self-reported health, functional impairment, depression, anxiety, and life satisfaction. RESULTS: Some 15.4% of the women had experienced infertility. Infertile women reported poor self-reported health and functional impairment significantly more often than non-infertile women. Childless infertile women had significantly raised adjusted risks for health complaints and dissatisfaction with life compared with non-infertile women with a child, whereas infertile women with a child did not. Differences in health and life satisfaction emerged among the infertile women, but the differences were not significant. There were no significant differences in depression and anxiety between infertile and non-infertile women, or between the two groups of infertile women (with/without a child). CONCLUSIONS: The study confirms the adverse effect of infertility on health and life-satisfaction. The childless infertile women stand out as being vulnerable to the detrimental consequences of infertility. PMID- 24773206 TI - N-acetylcysteine in trichotillomania: a panacea for compulsive skin disorders? PMID- 24773207 TI - Stability of trans-resveratrol associated with transport proteins. AB - Spectrophotometry and fluorescence combined with docking and molecular dynamics simulations are used to study the effect of the carrier proteins beta lactoglobulin and human serum albumin on the degradative trans-to-cis conversion of resveratrol. The spectroscopic measurements quantify the concentration of resveratrol isoforms after 2 h of irradiation with light at 340 nm, showing that their ratio depends linearly on temperature between 20 and 50 degrees C and obeys an Arrhenius law with activation energies of photoisomerization of 7.8 and 11.2 kcal/mol for beta-lactoglobulin and albumin, respectively, compared to 5.1 kcal/mol in solution. Thus, both proteins protect trans-resveratrol from degradation, with albumin being more effective than beta-lactoglobulin. The computational techniques clarify details of the binding of trans-resveratrol to the proteins and show that the stabilizing effect correlates with an increase of the dihedral order parameter of the ligand. These findings suggest that transport proteins are viable carriers to stabilize and deliver resveratrol in vivo in the biologically effective trans form. PMID- 24773208 TI - Remote programming of MED-EL cochlear implants: users' and professionals' evaluation of the remote programming experience. AB - CONCLUSION: Remote programming is safe and is well received by health-care professionals and cochlear implant (CI) users. It can be adopted into clinic routine as an alternative to face-to-face programming. OBJECTIVES: Telemedicine allows a patient to be treated anywhere in the world. Although it is a growing field, little research has been published on its application to CI programming. We examined hearing professionals' and CI users' subjective reactions to the remote programming experience, including the quality of the programming and the use of the relevant technology. METHODS: Remote CI programming was performed in Italy, Sweden, and Russia. Programming sessions had three participants: a CI user, a local host, and a remote expert. After the session, each CI user, local host, and remote expert each completed a questionnaire on their experience. RESULTS: In all, 33 remote programming sessions were carried out, resulting in 99 completed questionnaires. The overwhelming majority of study participants responded positively to all aspects of remote programming. CI users were satisfied with the results in 96.9% of the programming sessions; 100% of participants would use remote programming again. Although technical problems were encountered, they did not cause the sessions to be considerably longer than face to-face sessions. PMID- 24773209 TI - Synthesis and reactivity of 2-(carboxymethyl)aziridine derivatives. PMID- 24773210 TI - Stomatal malfunctioning under low VPD conditions: induced by alterations in stomatal morphology and leaf anatomy or in the ABA signaling? AB - Exposing plants to low VPD reduces leaf capacity to maintain adequate water status thereafter. To find the impact of VPD on functioning of stomata, stomatal morphology and leaf anatomy, fava bean plants were grown at low (L, 0.23 kPa) or moderate (M, 1.17 kPa) VPDs and some plants that developed their leaves at moderate VPD were then transferred for 4 days to low VPD (M->L). Part of the M->L plants were sprayed with ABA (abscisic acid) during exposure to L. L-plants showed bigger stomata, larger pore area, thinner leaves and less spongy cells compared with M-plants. Stomatal morphology (except aperture) and leaf anatomy of the M->L-plants were almost similar to the M-plants, while their transpiration rate and stomatal conductance were identical to that of L-plants. The stomatal response to ABA was lost in L-plants, but also after 1-day exposure of M-plants to low VPD. The level of foliar ABA sharply decreased within 1-day exposure to L, while the level of ABA-GE (ABA-glucose ester) was not affected. Spraying ABA during the exposure to L prevented loss of stomatal closing response thereafter. The effect of low VPD was largely depending on exposure time: the stomatal responsiveness to ABA was lost after 1-day exposure to low VPD, while the responsiveness to desiccation was gradually lost during 4-day exposure to low VPD. Leaf anatomical and stomatal morphological alterations due to low VPD were not the main cause of loss of stomatal closure response to closing stimuli. PMID- 24773212 TI - Quality of life and outcomes after nonintubated versus intubated video thoracoscopic pleurodesis for malignant pleural effusion: comparison by a case matched study. AB - BACKGROUND: Malignant pleural effusion can be treated successfully by video assisted thoracic surgery (VATS) talc pleurodesis. This procedure can also be performed using local anesthesia on nonintubated patients. OBJECTIVES: To evaluate quality of life and major outcomes after VATS talc pleurodesis performed under local anesthesia in nonintubated patients with malignant pleural effusion. DESIGN: Retrospective, nonrandomized case-matched comparison (nonintubated versus intubated) pairing the patients by computer according to their clinical features. SETTING/SUBJECTS: Since 2002, 231 consecutive patients underwent uniport VATS talc pleurodesis under local anesthesia (nonintubated group). These patients were case matched with 231 homogeneous subjects, selected from a larger group that preferred general anesthesia (intubated group) in the same period. MEASUREMENTS: Quality of life (European Organization for Research and Treatment of Cancer QLQ C30 core questionnaire) and other major outcomes were considered. RESULTS: Pleurodesis was successful in 198 (85.7%) nonintubated and 193 (83.5%) intubated patients, but the former group showed shorter total operating room time (65.8+/ 7.5 versus 84.9+/-13.3 minutes, p<0.0001), duration of postoperative pleural fluid leakage (2.5+/-1.0 versus 4.0+/-1.5 days, p=0.014), postoperative hospital stay (3.1+/-2.5 versus 4.9+/-2.8 days, p=0.011), as well as lower perioperative mortality (0% versus 2.3%, p=0.017), morbidity (5.2% versus 9.0%, p=0.042), and costs (6,090+/-517 versus 9,660+/-713?, p=0.015). Quality of life presented a similar evolution between groups, however, the early postoperative improvement in physical function (p<0.05), global health (p<0.05), and dyspnea (p<0.01) was significantly greater in nonintubated patients. Significant improvements in respiratory exchanges, postoperative acute stress markers, and mental confusion were also documented. Effusion-free (p=0.35) and overall (p=0.52) survival was similar between groups. CONCLUSION: Nonintubated VATS talc pleurodesis can achieve similar results in pleural effusion to the same operation performed under general anesthesia but with earlier improvement of some quality-of-life domains as well as better mortality, morbidity, hospital stay, and costs. PMID- 24773213 TI - Impact of speech-generating devices on the language development of a child with childhood apraxia of speech: a case study. AB - PURPOSE: The purpose of the study was to evaluate the effectiveness of speech generating devices (SGDs) on the communication and language development of a 2 year-old boy with severe childhood apraxia of speech (CAS). METHODS: An A-B design was used over a treatment period of 1 year, followed by three additional follow-up measurements, in order to evaluate the implementation of SGDs in the speech therapy of a 2;7-year-old boy with severe CAS. In total, 53 therapy sessions were videotaped and analyzed to better understand his communicative (operationalized as means of communication) and linguistic (operationalized as intelligibility and consistency of speech-productions, lexical and grammatical development) development. The trend-lines of baseline phase A and intervention phase B were compared and percentage of non-overlapping data points were calculated to verify the value of the intervention. RESULTS: The use of SGDs led to an immediate increase in the communicative development of the child. An increase in all linguistic variables was observed, with a latency effect of eight to nine treatment sessions. CONCLUSIONS: The implementation of SGDs in speech therapy has the potential to be highly effective in regards to both communicative and linguistic competencies in young children with severe CAS. Implications for Rehabilitation Childhood apraxia of speech (CAS) is a neurological speech sound disorder which results in significant deficits in speech production and lead to a higher risk for language, reading and spelling difficulties. Speech-generating devices (SGD), as one method of augmentative and alternative communication (AAC), can effectively enhance the communicative and linguistic development of children with severe CAS. PMID- 24773214 TI - Exploring the use of tablets (iPads) with children and young adults with disabilities in Trinidad. AB - PURPOSE: This study was conducted to review data gathered during a pilot project which trialed the use of a tablet computer, the iPad. METHODS: Students from a segregated special education school and pre-vocational centre, with a wide range of intellectual and physical disabilities, were previously observed participating in 5-10-min introductory learning sessions with the iPad. This study reviewed quantitative and qualitative data collected during these sessions which included data regarding students' level of engagement and overall ability to learn how to operate the iPad and its applications. RESULTS: Results were positive for level of engagement and ease of use with cause and effect applications. For lower functioning students or students not previously exposed to tablet technology, scores were lower but overall remained high based on the 5-point scaling used in this study. CONCLUSION: Regular use of tablet technology in the classroom with applications appropriate to the level of ability of the student has the potential to enhance engagement in learning as well as maximise independence in the classroom. Implications for Rehabilitation The iPad has the capacity to be used with learners of all different ability levels if applications are selected appropriately and learners are given equal opportunity to access this type of technology. Enjoyment when using the iPad was high overall and this type of technology has the potential to promote more engagement in the learning process. Many applications are easy to use and progress students through step by step increasing the potential for independent learning in the classroom. PMID- 24773215 TI - The efficacy of foot orthoses on alteration to center of pressure displacement in subjects with flat and normal feet: a literature review. AB - Abstract Purpose: The aim of this review was to evaluate and compare the effect of foot orthoses on center of pressure (CoP) displacement in healthy patients and those with flat foot. Method: The search strategy was based on the Population Intervention Comparison Outcome (PICO) method. A search was performed in PubMed, Science Direct, Google scholar and ISI web of knowledge databases by using selected keywords. Seventeen articles were selected for final evaluation. The procedure was followed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. Result: The results of the literature review demonstrated that there is lack of evidence to show that FOs improve CoP displacement in subjects with flat foot. Conclusion: There is no consistent evidence to prove the efficacy of FOs on altering CoP displacement in healthy subjects but in those with flat foot, FOs decreased CoP excursion. Implications for Rehabilitation Foot orthoses (FOs) have become an integral part of the treatment of injuries of the foot, ankle, and lower extremity. Assessment of FOs effect on the COP displacement can help to provide a better understanding of the body's compensatory mechanisms and their therapeutic effects. There is no consistent evidence to prove the efficacy of FOs on CoP displacement in healthy subjects but in flat foot subjects foot orthoses decreased CoP excursion has been demonstrated. PMID- 24773216 TI - Synthesis of chrysene derivatives via copper-catalyzed one-pot dimerization of 2 alkynyl-1-acetylbenzenes. AB - An efficient route for highly substituted chrysene derivatives via operationally simple copper-catalyzed one-pot dimerization of 2-alkynyl-1-acetylbenzenes is described. PMID- 24773217 TI - Imaging approach to mechanistic study of nanoparticle interactions with the blood brain barrier. AB - Understanding nanoparticle interactions with the central nervous system, in particular the blood-brain barrier, is key to advances in therapeutics, as well as assessing the safety of nanoparticles. Challenges in achieving insights have been significant, even for relatively simple models. Here we use a combination of live cell imaging and computational analysis to directly study nanoparticle translocation across a human in vitro blood-brain barrier model. This approach allows us to identify and avoid problems in more conventional inferential in vitro measurements by identifying the catalogue of events of barrier internalization and translocation as they occur. Potentially this approach opens up the window of applicability of in vitro models, thereby enabling in depth mechanistic studies in the future. Model nanoparticles are used to illustrate the method. For those, we find that translocation, though rare, appears to take place. On the other hand, barrier uptake is efficient, and since barrier export is small, there is significant accumulation within the barrier. PMID- 24773218 TI - Joint physical custody and adolescents' subjective well-being: a personality * environment interaction. AB - Shared residence after divorce is rising in most Western countries and legally recommended by law in Belgium since 2006. Living with both parents after divorce is assumed to increase children's well-being, through a better parent-child relationship, but may also be stressful, as children live in 2 different family settings. In this study, we investigate whether the association between the residential arrangement of adolescents and 3 measures of subjective well-being (depressive feelings, life satisfaction, and self-esteem) is moderated by the Big Five personality factors. The sample is selected from the national representative Divorce in Flanders study and contains information about 506 children from divorced parents between 14- and 21-years-old. Our findings indicated a consistent pattern of interactions between conscientiousness and joint physical custody for 2 of the 3 subjective well-being indicators. The specific demands of this residential arrangement (making frequent transitions, living at 2 places, adjustment to 2 different lifestyles, etc.) may interfere with the nature of conscientious adolescents: being organized, ordered, and planful. Our results showed support for a Person * Environment interaction, and demonstrate the need for considering the individual characteristics of the child when settling postdivorce residential arrangements. PMID- 24773219 TI - Observed parental responsiveness/warmth and children's coping: cross-sectional and prospective relations in a family depression preventive intervention. AB - The current study examined concurrent and prospective relations between observed parenting behaviors and children's coping strategies in the context of a preventive intervention designed to change both parenting and children's use of secondary control coping. Questionnaires and direct observations were obtained from parents with a history of depression (N = 180) and their children (ages 9-15 years) at baseline, 6-month (after completion of the intervention), and 18-month follow-up assessments. Cross-sectional analyses indicate that baseline observed parental responsiveness/warmth was significantly associated with composite parent/child reports of children's baseline primary control, secondary control, and disengagement coping. Using a mixed effects model, prospective mediational analyses indicate that intervention-driven improvements in observed parental responsiveness/warmth from baseline to 6 months significantly accounted for increases in children's use of secondary control coping strategies from baseline to the 18-month follow-up assessment. No significant mediation effects emerged for primary control coping or disengagement coping. The present findings suggest that it may be possible to improve children's coping strategies not only through targeted interventions, but also indirectly by improving responsive and warm parenting behaviors. Limitations and strengths are noted and implications for future research are outlined. PMID- 24773220 TI - Parenting behaviors and anxious self-talk in youth and parents. AB - The present study examined the association between parental anxious self-talk, parenting behaviors, and youth anxious self-talk. Parents and youth ages 7 to 14 (M = 10.17; N = 208; 53% male) seeking treatment for anxiety were evaluated for anxiety symptoms, youth anxious self-talk, parental anxious self-talk, and youth perceived parenting behavior. Youth and parental anxious self-talk were assessed by both child and parent self-reports; youth-perceived parenting behaviors were assessed by youth-reports. Parenting behaviors included separate ratings of paternal and maternal (a) acceptance, (b) psychological control, and (c) firm/behavioral control. Correlational analyses revealed that maternal anxious self-talk, but not paternal anxious self-talk, was significantly associated with youth's anxious self-talk. Maternal anxious self-talk had an inverse association with youth-perceived maternal acceptance, but was not associated with youth perceived maternal psychological or behavioral control. Higher youth-perceived maternal acceptance was significantly associated with lower youth anxious self talk. Youth-perceived maternal acceptance partially mediated the association between mother's anxious self-talk and youth's anxious self-talk. However, this mediation effect disappeared when taking into account youth depressive symptoms. Results are discussed in relation to clinical implications and future directions in research. PMID- 24773221 TI - Association between mandibular third molar formation and retromolar space. AB - OBJECTIVE: To assess the association between formation stages of the mandibular third molars and the space distal to the permanent molars (retromolar space). MATERIALS AND METHODS: The material included pretreatment lateral cephalographs of 96 orthodontic patients (49 males, 47 females; 8-18 years old). The molar formation stage was assessed through the method of Nolla, which rates the degree of calcification on a scale of 10 stages. The retromolar space was measured from the most concave point of the anterior border of the ramus to the distal surface of the first molar (used because the second molars had not yet erupted in the younger patients). Statistical analyses included t-tests and analyses of variance for group differences and the Pearson product moment to gauge associations among variables. RESULTS: The formation stage advanced with age, but wide standard deviations were noted. Similarly, the retromolar distance increased with age and was greatest between 10 and 12 years. The correlation between retromolar space and developmental stage was high (r = 0.85). On average, an increase of 5 mm of retromolar space corresponds to a 1.8 stage in tooth maturation. CONCLUSIONS: The correlation between third molar mineralization and available retromolar space essentially represents the association between one biologic age (dental formation) and another growth-related event (mandibular skeletal growth). The findings do not necessarily reflect successful emergence or nonimpaction of the molars. Longitudinal data are needed to determine such outcomes. PMID- 24773222 TI - Temporomandibular disorders with skeletal open bite treated with stabilization splint and zygomatic miniplate anchorage: a case report. AB - This case report describes the treatment of a patient with temporomandibular disorder (TMD) and skeletal open bite. First, the patient was treated with a stabilization splint to stabilize the condyles in centric relation and to alleviate TMD signs and symptoms. After making a definitive diagnosis from postsplint records, orthodontic treatment was initiated. Titanium miniplates were placed at bilateral zygomatic buttresses and used as orthodontic anchorage for molar intrusion and distalization. The treatment was completed after 30 months. Satisfactory appearance and function were achieved for this patient. PMID- 24773223 TI - A systematic review on the efficacy and safety of transcatheter device closure of ventricular septal defects (VSD). AB - BACKGROUND: Advances in interventional techniques now allow for transcatheter treatment of some ventricular septal defects (VSD), although there remain concerns about adverse events. We performed a systematic review to look at outcomes and complications associated with transcatheter closure of VSD. METHOD: A PubMed search for series in English on device closure of VSD from 2003 to June 2012 was performed. We excluded small series that were included in multicenter studies and patients who had acquired VSD following myocardial infarction. The random effects model was used to obtain pooled estimates of success and complications. RESULTS: A total of 37 publications comprising 4,406 patients with VSD (perimembranous = 3,758, muscular = 419, intracristal = 47, doubly committed subarterial = 36, multiple = 16, postsurgical = 123, unclassified = 7) were included in this analysis. The age of patients ranged from 3 days to 84 years. The pooled estimate of successful device implantation was 96.6% (95% CI: 95.7 97.5). The most common complication is residual shunt (pooled estimated 25.5%; 95% CI: 18.9-32.1). Others included valvular defects (pooled estimate 4.9%; 95% CI: 3.4-6.4) and arrhythmias (pooled estimate 10.6%; 95% CI: 8.4-12.7). DISCUSSION AND CONCLUSION: Our analysis suggests that transcatheter device closure of VSD is safe and yields good results. The limitations of this study are difficulties in analyzing different devices individually, and segregating the different VSD types. Further stratification by type of VSD, age of patients, and prevention of complications is needed before this can be recommended for routine treatment. PMID- 24773224 TI - Interleukins in gingival crevicular fluid in patients with definitive full coverage restorations. AB - The objective of this study was to determine interleukin (IL)-1alpha and IL-8 levels in the gingival crevicular fluid (GCF) of patients with different levels of crown margin placements. Samples of GCF were obtained from 12 study participants with definitive full-coverage restorations with supragingival or equigingival crown margin placements. The periodontal status of the volunteers ranged from healthy to generalized severe periodontitis. Pocket depth and bleeding on probing were assessed at the clinical examination, and interleukin concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Analysis of variance (ANOVA) was used to statistically compare interleukin concentrations between the control, supragingival, and equigingival GCF samples. Compared to controls (60.4 +/- 8.9 pg/mL), the average IL-1alpha concentration in the GCF samples surrounding the supragingival margins was 53.8 +/- 9.7 pg/mL and was 110.5 +/- 23.3 pg/mL in the equigingival margins. Compared to controls (59.0 +/- 14.1 pg/mL), the average IL-8 concentration in the supragingival margins was 46.9 +/- 9.7 pg/mL and was 131.4 +/- 27.5 pg/mL in the equigingival margins. The trend of higher levels of interleukins in GCF corresponding to equigingival margins was consistent, as was the trend of lower concentrations in supragingival margins compared to the controls; however, statistical significance was not achieved because of the wide biological variation within and between patients. In conclusion, differences in GCF IL-1alpha and IL-8 concentrations were observed when comparing fixed crown restorations with equigingival and supragingival margins. Gingival inflammation may be dependent on the periodontal condition in addition to restoration or margin placement. PMID- 24773226 TI - Effective liquid-phase exfoliation and sodium ion battery application of MoS2 nanosheets. AB - Two-dimensional (2D) molybdenum disulfide (MoS2) has been taken much attention for various applications, such as catalyst, energy storage, and electronics. However, the lack of effective exfoliation methods for obtaining 2D materials in a large quantity has been one of the technical barriers for the real applications. We report a facile liquid-phase exfoliation method to improve the exfoliation efficiency for single-layer MoS2 sheets in 1-methyl-2-pyrrolidinone (NMP) with a sodium hydroxide (NaOH) assistant. The concentration of the exfoliated MoS2 nanosheets was greatly improved compared to that achieved with conventional liquid-phase exfoliation methods using NMP solvent. We demonstrate stable operation of sodium-ion battery by using the exfoliated MoS2 and MoS2-rGO composite as anode materials. PMID- 24773225 TI - Evaluating a unique, specialist psychiatric genetic counseling clinic: uptake and impact. AB - People with psychiatric disorders and their family members have expressed interest in receiving genetic counseling (GC). In February 2012, we opened the first (to our knowledge) specialist psychiatric GC clinic of its kind, for individuals with non-syndromic psychiatric disorders and their families. Prior to GC and at a standard 1-month follow-up session, clinical assessment tools are completed, specifically, the GC outcomes scale (GCOS, which measures empowerment, completed by all clients) and the Illness Management Self Efficacy scale (IMSES, completed by those with mental illness). Consecutive English-speaking clients attending the clinic between 1 February 2012 and 31 January 2013 who were capable of consenting were asked for permission to use their de-identified clinical data for research purposes. Descriptive analyses were conducted to ascertain demographic details of attendees, and paired sample t-tests were conducted to assess changes in GCOS and IMSES scores from pre- to post-GC. Of 143 clients, seven were unable to consent, and 75/136 (55.1%) consented. Most were female (85.3%), self-referred (76%), and had personal experience of mental illness (65.3%). Mean GCOS and IMSES scores increased significantly after GC (p < 0.0001 and p = 0.011, respectively). In a naturalistic setting, GC increases empowerment and self-efficacy in this population. PMID- 24773227 TI - Advantages and risks of nanotechnologies in cancer patients and occupationally exposed workers. AB - INTRODUCTION: In recent years, different nanotechnology platforms for drug delivery in the area of medical biology have gained remarkable attention. AREAS COVERED: Nanoparticles (NPs) used as drug delivery vehicles consist of different materials such as natural or synthetic polymers, lipids or metals. They have an ultra-small size, large surface area-to-mass ratio and high reactivity. Although there are many data on the advantages in terms of both higher efficacy and less adverse effects of nanodrugs, several recent findings have reported unexpected toxicities giving origin to nanotoxicology. EXPERT OPINION: Despite the great promise that NPs show, few studies have examined the human body's reaction due to NP exposure in both patients and workers. To perform this type of evaluation, it is necessary to define an adequate index of exposure, and the measure of this index is representative of what the worker is breathing. The properties of the nanomaterials used for designing NPs, such as in the case of poorly biocompatible materials (carbon nanotubes or heavy metals), and their chemical composition (as in the case of liposomes) largely contribute in determining potential side effects. Awareness of the levels of particles, which can cause health effects, is necessary for the workers and exposed patients. PMID- 24773228 TI - Assay of biothiols by regulating the growth of silver nanoparticles with C-dots as reducing agent. AB - Recently, the development of optical probes for the assay of thiols, e.g., cysteine (Cys), homocysteine (Hcy), and glutathione (GSH), has been an active research area due to their biological significance. We have found that carbon dots (C-dots) exhibit direct reduction of Ag(+) to elemental silver (Ag(0)) and the resulting Ag(0) formed a silver nanoparticle (Ag-NP) spontaneously. The excessive C-dots consume free Ag(+) in the solution by binding Ag(+) with functional groups on the C-dots surface and thus inhibits the growth of Ag-NPs. Biothiols can coordinate with Ag(+) through thiol groups, and afterward, the Ag(+)-biothiol complex gradually releases free Ag(+) to ensure its reduction by C dots and thus facilitates the growth of Ag-NPs on C-dots surface. A colorimetric assay procedure is thus developed for fast detection of biothiols based on Ag-NPs plasmon absorption. The linear calibration range can be regulated by controlling the concentration of Ag(+). Two linear ranges were obtained for the biothiols assay at different levels, which offer ultrahigh sensitivity for the assay of an ultratrace amount of biothiols with detection limits of 1.5, 2.6, and 1.2 nM for Cys, Hcy, and GSH, respectively. The precisions for the assay of Cys, Hcy, and GSH at 20 nM are achieved as 3.1%, 3.1%, and 2.4%. In addition, the sensing system exhibits good selectivity toward biothiols in the presence of other amino acids, the major metal cations, and biomolecules in biological fluids. For the assay of 20 nM Cys, 150-fold of coexisting amino acids, 2500-fold of Ca(2+), Mg(2+), glucose, and ascorbic acid, and 38-fold of HSA are tolerated. In the assay of Cys in human plasma, spiking recoveries of 94% to 108% are obtained at 100 MUM. PMID- 24773229 TI - Defining and managing risk in asthma. AB - Asthma attacks are a major global source of morbidity and cost. The incidence and impact of asthma attacks have not improved despite widespread adoption of effective universal treatment guidelines. Consequently, there is increasing interest in managing asthma based on specific assessments of both current symptoms and future risk. In this review, we consider 'risk' in asthma, and how it might be assessed from the patient's history and objective measurements. We also discuss the potential for encouraging shared decision-making and improving medical consensus through explicit communication of risk and highlight the potential opportunities and challenges in risk assessment to improve asthma management through individualised treatment strategies. PMID- 24773230 TI - Infectious complications in living-donor kidney transplant recipients undergoing multi-modal desensitization. AB - BACKGROUND: Pre-existing humoral barriers challenge the transplantation of living donor kidneys (LDK) into highly sensitized ABO- and human leukocyte antigen (HLA) incompatible recipients. Conditioning these LDK recipients' immune systems is required before they undergo transplantation. We hypothesized that medical desensitization would yield higher post-transplantation rates of infection. METHODS: We conducted a study in which matched controls consisting of non desensitized (NDS) LDK recipients were compared with desensitized (DS) receipients. Pre-transplantation desensitization included treatment with rituximab and mycophenolate mofetil followed by intravenous immunoglobulin (IVIg) and plasmapheresis. All participants in the study underwent induction therapy and maintenance immunosuppression. Primary outcomes included infection (opportunistic, local, systemic) within 12 mo after transplantation. RESULTS: Twenty-five patients underwent desensitization and LDK transplantation. Graft survival in the DS and NDS groups of patients was 96% and 98%, respectively. The mean 3- and 12-mo serum creatinine concentrations in the DS and NDS groups were 1.1+/-0.2 mg/dL and 1.2+/-0.3 mg/dL and 0.95+/-0.4 mg/dL and 0.73+/-0.8 mg/dL (p=0.3 and p=0.01), respectively. Thirty-six percent of the patients in the DS group had one or more infections, vs. 28% of those in the NDS group (p=0.1). No difference was observed in the frequency of opportunistic or systemic infections in the two groups. Local infections were statistically significantly more frequent in the DS group (60% vs. 30%, respectively; p=0.02). CONCLUSION: Pre operative desensitization in highly sensitized LDK recipients is followed by a similar incidence of opportunistic and systemic infections as in NDS patients. Local infections were significantly more frequent in the DS than in the NDS patients in the study. With careful monitoring of infectious complications, pre transplant desensitization permits LDK transplantation into highly sensitized patients. PMID- 24773231 TI - Computerized attention retraining for individuals with elevated health anxiety. AB - BACKGROUND AND OBJECTIVES: Current cognitive-behavioral theorists conceptualize hypochondriasis as excessive health anxiety (HA). Growing evidence suggests that elevated HA is associated with attentional bias (AB) toward potential health threat information. DESIGN: This study aimed to examine the effects of attention retraining among individuals with elevated HA, using the established attention modification programs (AMP) designed to train participants to disengage attention from ideographically chosen health-threat words. METHODS: Thirty-six randomly assigned individuals with elevated HA completed eight twice-weekly sessions of the AMP (n = 18) or the attention control condition (ACC; n = 18). RESULTS: Despite using the well-established AMP protocol widely used within the field of anxiety disorders, we did not find evidence for change in AB following training. Further, AMP did not outperform ACC in reducing HA and other relevant emotional symptoms. However, both AMP and ACC evidenced overall significant symptom reduction in most of the outcome measures, including overall HA, anxiety sensitivity, general depression and anxiety, and somatic complaints. CONCLUSIONS: Further research is needed to better understand the effects and mechanisms of AMP as a possible cognitive intervention for HA. PMID- 24773232 TI - Kinematics and dynamics of burst transitions. AB - Subjects (N = 14) were instructed to walk at comfortable walking speed and to start sprinting on an external (visual) stimulus. This is a burst transition. To accelerate maximally, different strategies can be used. The choice for a strategy was hypothesized to be (a) dependent of the body's dynamical status, which is in its turn dependent on the signal timing within the gait cycle; and (b) influenced by the performance and efficacy of the different strategies. Three-dimensional kinematics and ground reaction forces were used to discriminate between strategies and to calculate work (W(total)). Distance laser data yielded performance measures and the work related to the forward acceleration (W(objective)). Efficacy was calculated as the ratio of W(objective) to W(total). Subjects mainly used 2 strategies among others depending on the timing of the stimulus: (a) subjects placed their body center of mass (BCOM) in front of their center of pressure (COP) by tilting the trunk forward and flexing the knee, resulting in a sudden forward acceleration but a relatively fair efficacy; (b) subjects placed their COP behind their BCOM by placing the foot of the swing leg backward. This led to a high performance with high efficacy and was therefore the most ecologically relevant. PMID- 24773233 TI - Contraception and hormonal management in the perimenopause. AB - This literature review focuses on contraception in perimenopausal women. As women age, their fecundity decreases but does not disappear until menopause. After age 40, 75% of pregnancies are unplanned and may result in profound physical and emotional impact. Clinical evaluation must be relied on to diagnose menopause, since hormonal levels fluctuate widely. Until menopause is confirmed, some potential for pregnancy remains; at age 45, women's sterility rate is 55%. Older gravidas experience higher rates of diabetes, hypertension, and death. Many safe and effective contraceptive options are available to perimenopausal women. In addition to preventing an unplanned and higher-risk pregnancy, perimenopausal contraception may improve abnormal uterine bleeding, hot flashes, and menstrual migraines. Long-acting reversible contraceptives, including the levonorgestrel intrauterine system (LNG-IUS), the etonogestrel subdermal implant (ESI), and the copper intrauterine device (Cu-IUD), provide high efficacy without estrogen. LNG IUS markedly decreases menorrhagia commonly seen in perimenopause. Both ESI and LNG-IUS provide endometrial protection for women using estrogen for vasomotor symptoms. Women without cardiovascular risk factors can safely use combined hormonal contraception. The CDC's Medical Eligibility Criteria for Contraceptive Use informs choices for women with comorbidities. No medical contraindications exist for levonorgestrel emergency-contraceptive pills, though obesity does decrease efficacy. In contrast, the Cu-IUD provides reliable emergency and ongoing contraception regardless of body mass index (BMI). PMID- 24773234 TI - Nonuraemic calciphylaxis and pancreatic cancer: a previously unreported association. PMID- 24773236 TI - Resolving power of dynamic light scattering for protein and polystyrene nanoparticles. AB - Dynamic light scattering (DLS) is a non-invasive, label-free technique for the characterization of particles ranging from nanometer to micrometer size. It is widely used for the analysis of proteins to assess association states and the nature of protein aggregates. Despite its frequent use, little quantitative information on its size resolution capabilities, in particular for protein material, is available. This study explores the resolving power of a standard DLS setup for binary mixtures of latex standard particles and mixtures of protein monomer and protein particles made from cross-linked protein material. At constant instrument settings, the resolving power depends on the size ratio and the mass ratio of the species in a mixture as well as on the total concentration and the scattering characteristics of the material. In this study, we provide a summary at which parameter combinations resolution of two species with varying size is possible. These data guide the quantitative evaluation of DLS results for mixtures. We found that a mixture of an antibody monomer and protein particles of an average hydrodynamic diameter of 50 nm can be resolved at a 1-20-fold excess of monomer (by mass). A mixture of monomer and 70 nm particles can be resolved at a 2-30-fold excess, a mixture of monomer and 190 nm particles at a 200-1700-fold excess of monomer. The findings allow to better judge DLS results for protein samples of unknown composition. PMID- 24773237 TI - Tenth International Conference on Pediatric Mechanical Circulatory Support Systems and Pediatric Cardiopulmonary Perfusion. PMID- 24773238 TI - The world's longest-supported HeartWare ventricular assist device patient: 6 years and counting on minimal anticoagulation. PMID- 24773241 TI - Comparison of extraction protocols to determine differences in wine-extractable tannin and anthocyanin in Vitis vinifera L. cv. Shiraz and Cabernet Sauvignon grapes. AB - Cabernet Sauvignon and Shiraz grapes were sourced from different regions within Australia, and microvinified with a skin contact period of 6 days. Grape samples were extracted using two protocols: a 15% v/v ethanol, 10 g/L tartaric acid extract of gently crushed berries (wine-like, WL) and a 50% v/v ethanol, pH 2 extract of grape berry homogenate. It was found that in WL extracts, grape tannin and anthocyanin concentrations were strongly related to wine tannin, anthocyanin and color density achieved during the skin contact period. No relationship was observed for grape tannin concentration analyzed in homogenate extracts and wine tannin, but a strong, positive relationship was found for anthocyanin concentration. When the data obtained from homogenate extraction was treated separately by grape variety, a stronger relationship between grape and wine tannin concentration was observed. Tannin compositional analysis in wines indicated that higher tannin concentrations were due to the extraction of tannin of higher molecular mass during fermentation, most likely from grape skins. PMID- 24773242 TI - Heterologous expression of the yeast HAL5 gene in tomato enhances salt tolerance by reducing shoot Na+ accumulation in the long term. AB - For salt tolerance to be achieved in the long-term plants must regulate Na(+)/K(+) homeostasis over time. In this study, we show that the salt tolerance induced by overexpression of the yeast HAL5 gene in tomato (Solanum lycopersicum) was related to a lower leaf Na(+) accumulation in the long term, by reducing Na(+) transport from root to shoot over time regardless of the severity of salt stress. Furthermore, maintaining Na(+)/K(+) homeostasis over time was associated with changes in the transcript levels of the Na(+) and K(+) transporters such as SlHKT1;2 and SlHAK5. The expression of SlHKT1;2 was upregulated in response to salinity in roots of transgenic plants but downregulated in the roots of wild type (WT) plants, which seems to be related to the lower Na(+) transport rate from root to shoot in transgenic plants. The expression of the SlHAK5 increased in roots and leaves of both WT and transgenic plants under salinity. However, this increase was much higher in the leaves of transgenic plants than in those of WT plants, which may be associated with the ability of transgenic leaves to maintain Na(+)/K(+) homeostasis over time. Taken together, the results show that the salt tolerance mechanism induced by HAL5 overexpression in tomato is related to the appropriate regulation of ion transport from root to shoot and maintenance of the leaf Na(+)/K(+) homeostasis through modulation of SlHKT1 and SlHAK5 over time. PMID- 24773243 TI - Prophylactic oral nifedipine to reduce preterm delivery: a randomized controlled trial in women at high risk. AB - OBJECTIVE: To establish the efficacy of prophylactic nifedipine vs. placebo in reducing spontaneous preterm delivery in asymptomatic women at high risk for preterm delivery. DESIGN: Prospective multicentric randomized double-blind study. SETTING: Tertiary care centre, University Hospitals of Brescia and Torino, Italy. POPULATION: Eighty-seven singleton pregnancies without uterine contractions and ultrasonographic cervical length of <=25 mm at 24-32 weeks, at risk for preterm delivery, with longitudinal follow up in our Preterm Prevention Clinic. METHODS: Selection was done on the basis of ultrasonographic cervical length; 43 women were randomized to receive placebo and 44 to receive nifedipine. MAIN OUTCOME MEASURES: Primary end point: spontaneous preterm delivery <37 weeks in nifedipine vs. placebo. SECONDARY OUTCOMES: delivery <32 weeks, maternal side effects, neonatal complications, admissions to the Neonatal Intensive Care Unit and randomization/delivery time in nifedipine vs. placebo. RESULTS: There was no trend towards a lower risk of spontaneous preterm delivery, neither at <37 weeks of nifedipine vs. placebo (11.4% vs. 19.0%; p = 0.320), or <32 weeks (2.3% vs. 2.4%; p = 0.973). Nifedipine reduced spontaneous preterm delivery <37 weeks (p = 0.015) in the multiparous women by stratified analysis for parity. SECONDARY OUTCOMES between the groups did not differ except for a higher percentage of maternal side-effects in the nifedipine group (31.8%) vs. placebo (11.9%) (p < 0.05). Subgroup analysis showed a borderline (p = 0.047) lower percentage of spontaneous preterm delivery in women with a ultrasonographic cervical length of <20 mm in the nifedipine group. CONCLUSIONS: Prophylactic nifedipine in asymptomatic women at high risk for preterm delivery had a positive effect on the rate of spontaneous preterm delivery <37 weeks in multiparous women. PMID- 24773244 TI - Variation of Kondo temperature induced by molecule-substrate decoupling in film formation of bis(phthalocyaninato)terbium(III) molecules on Au(111). AB - We demonstrate that the lattice formation of an adsorbed molecule decouples the molecule-substrate interaction to change the Kondo resonance, which occurs due to interactions between conduction electrons and the molecule's unpaired spin. The double-decker bis(phthalocyaninato)terbium(III) complex, which is single-molecule magnet and forms a Kondo resonance on a Au(111) surface through an unpaired pi radical spin, is studied using scanning tunneling microscopy/spectroscopy (STM/STS). In the STS spectra, an unusual sharp, strong peak (peak A) is found only for the molecule in a film. The peak position of peak A (epsilonA) cyclically shifts by several hundred millivolts as the STS tip position shifts along the outer circle of the molecule, reflecting the tilting of the upper phthalocyanine (Pc) ligand from the flat-lying lower Pc ligand. The Kondo resonance, which is detected as a sharp peak at the Fermi level, also shows cyclic variations of the peak width and intensity. As epsilonA approaches EF, the Kondo temperature (TK) increases. We propose a model that peak A originates from the singly occupied molecular orbital state whose energy is shifted by an unscreened final state effect due to a decrease in the molecule-substrate chemisorptive interaction. We further examine this model using density functional theory calculations, confirming a decreased molecule-substrate interaction for molecules in the film compared to that of isolated molecules. Further calculations of a tilted upper Pc ligand configuration show a site-dependent, cyclic variation of the molecule-substrate interaction within a molecule. PMID- 24773245 TI - Altitudinal and seasonal variation in Drosophila species on mount Japfu of Nagaland, a sub-Himalayan hilly state of India. AB - Drosophila (L.) (Diptera: Drosophilidae) has richly contributed to the understanding of patterns of inheritance, variation, speciation, and evolution. Drosophila, with its cosmopolitan nature and complexities in species compositions, is an excellent model for studying the eco-distributional patterns of various species. This study analyzed the altitudinal and seasonal variation in Drosophila species of Mount Japfu in Nagaland, a sub-Himalayan hilly state of northeast India, over the course of one year. A total of 4,680 Drosophila flies belonging to 19 species of 4 subgenera were collected at altitudes of 1500, 1800, 2100, 2400, and 2700 m a.s.l. The subgenus Sophophora Sturtevant was predominant, with 10 species, followed by subgenus Drosophila, with 4 species. Subgenus Dorsilopha and subgenus Scaptodrosophila were represented by 1 species each. The remaining 3 species were not identified. Cluster analysis and constancy methods were used to analyze the species occurrence qualitatively. Altitudinal changes in the population densities and relative abundances of the different species at different seasons were also studied. The diversity of the Drosophila community was assessed by applying Simpson's diversity index. At 1800 m a.s.l., the Simpson's index was low (0.09301), suggesting high Drosophila diversity at this altitude. The density of Drosophila changed significantly during different seasons (F = 26.72; df = 2; p < 0.0001). The results suggest the distributional pattern of a species or related group of species was uneven in space and time. PMID- 24773235 TI - Classification of intrinsically disordered regions and proteins. PMID- 24773247 TI - Nanometer thick elastic graphene engine. AB - Significant progress has been made in the construction and theoretical understanding of molecular motors because of their potential use. Here, we have demonstrated fabrication of a simple but powerful 1 nm thick graphene engine. The engine comprises a high elastic membrane-piston made of graphene and weakly chemisorbed ClF3 molecules as the high power volume changeable actuator, while a 532 nm LASER acts as the ignition plug. Rapid volume expansion of the ClF3 molecules leads to graphene blisters. The size of the blister is controllable by changing the ignition parameters. The estimated internal pressure per expansion cycle of the engine is about ~10(6) Pa. The graphene engine presented here shows exceptional reliability, showing no degradation after 10,000 cycles. PMID- 24773248 TI - "Prospecting" a profitable practice: how precious metals can yield a rewarding return. PMID- 24773246 TI - Genetic profiling by single-nucleotide polymorphism-based array analysis defines three distinct subtypes of orbital meningioma. AB - Orbital meningiomas can be classified as primary optic nerve sheath (ON) meningiomas, primary intraorbital ectopic (Ob) meningiomas and spheno-orbital (Sph-Ob) meningiomas based on anatomic site. Single-nucleotide polymorphism (SNP) based array analysis with the Illumina 300K platform was performed on formalin fixed, paraffin-embedded tissue from 19 orbital meningiomas (5 ON, 4 Ob and 10 Sph-Ob meningiomas). Tumors were World Health Organization (WHO) grade I except for two grade II meningiomas, and one was NF2-associated. We found genomic alterations in 68% (13 of 19) of orbital meningiomas. Sph-Ob tumors frequently exhibited monosomy 22/22q loss (70%; 7/10) and deletion of chromosome 1p, 6q and 19p (50% each; 5/10). Among genetic alterations, loss of chromosome 1p and 6q were more frequent in clinically progressive tumors. Chromosome 22q loss also was detected in the majority of Ob meningiomas (75%; 3/4) but was infrequent in ON meningiomas (20%; 1/5). In general, Ob tumors had fewer chromosome alterations than Sph-Ob and ON tumors. Unlike Sph-Ob meningiomas, most of the Ob and ON meningiomas did not progress even after incomplete excision, although follow-up was limited in some cases. Our study suggests that ON, Ob and Sph-Ob meningiomas are three molecularly distinct entities. Our results also suggest that molecular subclassification may have prognostic implications. PMID- 24773249 TI - Advances in remineralization for early carious lesions: a comprehensive review. AB - A greater understanding of the dental caries process and improved and more diverse methodologies to assess early demineralization and caries has enabled development of a new class of remineralizing therapeutics. Hence, an emerging goal of modern dentistry is to manage non-cavitated carious lesions non invasively through remineralization in an effort to prevent disease progression and improve strength, esthetics, and function of teeth. A critical element fundamental to this current therapeutic philosophy is the need for new and highly efficacious technologies for enamel remineralization. The aim of this article is to provide an overview of new compositions and to review contemporary nonfluoridated systems in terms of their basic composition, mode of delivery, and currently available evidence. PMID- 24773250 TI - Effects of a vibratory device on pain from anesthetic injections. AB - BACKGROUND: A randomized block, split-mouth design was used to determine the effectiveness of a vibratory device with topical anesthetic compared to topical anesthetic only in reducing the pain experienced during an inferior alveolar nerve block. METHODS: Twenty participants each received two inferior alveolar injections with a 5-minute interval between injections, one with topical anesthetic and one with topical anesthetic and a vibratory device. Each injection included a 2-minute application of topical anesthetic gel at the injection site. Local anesthetic was administered bilaterally using a 27-gauge needle with or without the vibratory device. Participants rated the pain they experienced after each injection by using a visual analog scale (VAS). A mean VAS score and standard deviation was determined per group. Data was analyzed with a paired t test (alpha = 0.05). RESULTS: The group receiving the vibratory device with topical anesthetic had a mean VAS score of 21.2 mm +/- 18.6 mm, and the group receiving the topical anesthetic alone had a VAS score of 38.7 mm +/- 23.3 mm. CONCLUSION: The use of the vibratory device and topical anesthetic significantly reduced the pain experienced during the administration of a local anesthetic injection compared with the use of topical anesthetic alone (P = 0.006). PMID- 24773251 TI - The "All-on-4" concept for implant rehabilitation of an edentulous jaw. AB - Complete edentulism is a significant oral health burden associated with a reduction of overall health and quality of life. Osseointegrated implant prostheses offer a number of substantial advantages compared with conventional dentures. Traditional implant therapy, however, requires a period of at least 3 months of osseointegration to load a definitive prosthesis onto an implant. The "All-on-4" treatment concept facilitates immediate function and esthetics, along with various benefits that are associated with efficacious long-term outcomes and patient satisfaction. This article discusses considerations for All-on-4 treatment and presents methodological descriptions for the effective use of this treatment concept. PMID- 24773252 TI - Use of titanium mesh in implant site development for restorative-driven implant placement: case report. Part 1--Restorative protocol for single-tooth esthetic zone sites. AB - Predictably augmenting alveolar bone is a significant challenge in implant site development. A restorative-driven approach to implant placement aids in achieving esthetic harmony in the final restoration. This case report demonstrates techniques for treating patients with significant bony defects using a titanium mesh scaffold along with prosthetic steps in molding and conditioning soft tissues with the provisional restoration and the fabrication of a custom impression coping. This case is part of a larger consecutive case series of 77 titanium mesh units in 62 patients treated in a private periodontal practice setting and restored in private restorative practices, which will be published subsequently. In this titanium mesh case series, 14 other cases (a total of 15) were treated in a similar fashion as described in this case report in the category of "single implant placement in the maxillary anterior region." This case illustrates the primary advantages of the use of titanium mesh in such clinical situations. PMID- 24773253 TI - Bonding protocols for improved long-term clinical success. PMID- 24773254 TI - Effects of high-intensity interval exercise versus continuous moderate-intensity exercise on postprandial glycemic control assessed by continuous glucose monitoring in obese adults. AB - The purpose of this study was to examine the impact of acute high-intensity interval training (HIIT) compared with continuous moderate-intensity (CMI) exercise on postprandial hyperglycemia in overweight or obese adults. Ten inactive, overweight or obese adults (41 +/- 11 yrs, BMI = 36 +/- 7 kg/m(2)) performed an acute bout of HIIT (10 * 1 min at approximately 90% peak heart rate (HRpeak) with 1-min recovery periods) or matched work CMI (30 min at approximately 65% HRpeak) in a randomized, counterbalanced fashion. Exercise was performed 2 h after breakfast, and glucose control was assessed by continuous glucose monitoring under standardized dietary conditions over 24 h. Postprandial glucose (PPG) responses to lunch, dinner, and the following day's breakfast were analyzed and compared with a no-exercise control day. Exercise did not affect the PPG responses to lunch, but performing both HIIT and CMI in the morning significantly reduced the PPG incremental area under the curve (AUC) following dinner when compared with control (HIIT = 110 +/- 35, CMI = 125 +/- 34, control = 162 +/- 46 mmol/L * 2 h, p < 0.05). The PPG AUC (HIIT = 125 +/- 53, CMI = 186 +/- 55, control = 194 +/- 96 mmol/L * 2 h) and the PPG spike (HIIT = Delta2.1 +/- 0.9, CMI = Delta3.0 +/- 0.9, control = Delta3.0 +/- 1.5 mmol/l) following breakfast on the following day were significantly lower following HIIT compared with both CMI and control (p < 0.05). Absolute AUC and absolute glucose spikes were not different between HIIT, CMI, or control for any meal (p > 0.05 for all). We conclude that a single session of HIIT has greater and more lasting effects on reducing incremental PPG when compared with CMI. PMID- 24773255 TI - 'He does not see himself as being different': the perspectives of children and caregivers on relevant areas of functioning in cerebral palsy. AB - AIMS: In the context of the development of the International Classification of Functioning, Disability and Health (ICF) Core Sets for children and adolescents with cerebral palsy (CP), we investigated the strengths and limitations in functioning important to children with CP, through either child self-reports or caregiver proxy reports, using components of the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY). METHOD: We conducted semi-structured interviews with 10 children with CP (children self reporting), 10 caregivers of children self-reporting (10 child-caregiver dyads), and 12 caregivers of children not self-reporting. Mean age 10 y 6 mo, range 4-16 y. A convenience sample was recruited representing Gross Motor Function Classification System (GMFCS) levels I to V. Interviews were audio-taped and the content covered all of the relevant ICF-CY components. The interviews were then transcribed verbatim and coded in N-Vivo 10 using the ICF-CY coding system. RESULTS: We identified 1956 themes that linked to 175 ICF-CY categories. Most of the themes were represented by the ICF-CY components activities and participation and environmental factors. The children interviewed discussed issues related to mobility, self-care, and recreation and leisure, whereas the caregivers focused more on physical limitations and on the environmental factors associated with everyday activities. INTERPRETATION: The children and their caregivers described many of the same areas of functioning but provided unique perspectives. Children talked more frequently about their abilities with CP, whereas the caregivers interviewed talked more about their concern over the limitations and broader issues facing their child. The findings highlight the need to explore the perspectives of both the child and the caregiver when characterizing the functional profile of children with CP. PMID- 24773256 TI - Novel curved balloon catheter for dilating postoperative angled lesions associated with congenital heart disease. AB - OBJECTIVES: This study aimed to analyze the surface stress generated by a novel curved balloon and assess its efficacy for treating angular lesions associated with congenital heart disease. BACKGROUND: Obstructions at the anastomosis of aortopulmonary shunts and cavopulmonary connections may occur postoperatively. Catheter interventions are often performed for such lesions; however, acute angulation may cause balloon slippage or inappropriate stress on the vessel wall. METHODS: We dilated the curved balloon in a curved vessel model and measured the resultant wall stress and its distribution. Clinical evaluations were performed using this balloon in angled lesions. RESULTS: In the curved vessel model, curved balloons generated uniform stress on the lesser and greater curvatures (curved type, lesser/greater = 0.343 MPa/0.327 MPa; P = 0.61), whereas straight balloons caused disproportionate stress (straight type, lesser/greater = 0.358 MPa/0.254 MPa; P = 0.19). However, the difference in average stress was not statistically significant. Furthermore, the stress was uniform along the entire length of the curved balloon, but differed between the mid and end portions of the straight balloon. Curved balloon dilations were performed for 10 lesions in 7 patients. The curved balloon conformed well to the angulated lesion without slipping. The median percent change in the minimal lumen diameter (MLD) was 64% (range, 0 206%). In 5 lesions, MLD increased by >=50%. Oxygen saturation increased by 5% (0 9%). CONCLUSIONS: Although further clinical evaluation is necessary, this novel curved balloon may be a reasonable alternative in angled lesions, providing better conformability and preventing excessive stress to the vessel wall adjacent to the stenosis. PMID- 24773257 TI - Albumin-drug conjugates in the treatment of hepatic disorders. AB - INTRODUCTION: This review deals with the use of serum albumin (SA) as a carrier for the selective delivery of drugs to liver cells. AREAS COVERED: The synthesis and properties of the SA conjugates prepared to enhance the performance of the drugs used in the treatment of viral hepatitis, hepatocellular carcinoma (HCC), liver micrometastases and hepatic fibrosis are reported. EXPERT OPINION: Studies in humans and laboratory animals demonstrated the capacity of SA conjugates to accomplish a liver targeting of the drugs, but at the same time underscored their limits and drawbacks, which can explain why to date these complexes did not reach a practical application. The major drawback is the need of administration by intravenous route, which prevents long-term daily treatments as required by some liver pathologies, such as chronic virus hepatitis and fibrosis. At present, only a conjugate carrying doxorubicin and addressed to the treatment of HCC showed in laboratory animals a solid potentiality to improve the value of the coupled drug. In the future, conjugation to SA could remain a successful strategy to permit the administration of drugs with rapid resolutive effects inside liver cells without causing severe extrahepatic adverse reactions. PMID- 24773258 TI - The ability of an antimicrobial agent to penetrate a biofilm is not correlated with its killing or removal efficiency. AB - The penetration ability of 12 antimicrobial agents, including antibiotics and biocides, was determined against biofilms of B. cereus and P. fluorescens using a colony biofilm assay. The surfactants benzalkonium chloride (BAC) and cetyltrimethyl ammonium bromide (CTAB), and the antibiotics ciprofloxacin and streptomycin were of interest due to their distinct activities. Erythromycin and CTAB were retarded by the presence of biofilms, whereas ciprofloxacin and BAC were not. The removal and killing efficacies of these four agents was additionally evaluated against biofilms formed in microtiter plates. The most efficient biocide was CTAB for both bacterial biofilms. Ciprofloxacin was the best antibiotic although none of the selected antimicrobial agents led to total biofilm removal and/or killing. Comparative analysis of the results obtained with colony biofilms and microtiter plate biofilms show that although extracellular polymeric substances and the biofilm structure are considered a determining factor in biofilm resistance, the ability of an antimicrobial agent to penetrate a biofilm is not correlated with its killing or removal efficiency. Also, the results reinforce the role of an appropriate antimicrobial selection as a key step in the design of disinfection processes for biofilm control. PMID- 24773259 TI - Environmental risk factors related to the incidence of wheeze and asthma in adolescence. AB - BACKGROUND: Asthma is common among adolescents, but there are few population based studies on the risk factors for incident asthma and wheeze at this age group. OBJECTIVE: To study risk factors for incident asthma and wheeze in adolescence. METHOD: Within the Obstructive Lung Disease In Northern Sweden (OLIN) studies, a cohort of 3430 school children (age 7-8 year) was recruited in 1996. In the present study, this cohort was followed from age 12-19 year. At baseline (age 12 year), 3151 participated and skin prick tests (SPT) were performed. The cohort was resurveyed annually, and risk factors for the cumulative incidence of asthma and wheeze from age 12-19 year were analysed using multivariate Cox regression. RESULTS: Female sex (wheeze: HR 1.4 95%CI 1.2-1.6; asthma: HR 1.8 95%CI 1.2-2.5) and a positive SPT to cat, dog or horse at baseline (wheeze: HR 1.6 95%CI 1.2-2.1; asthma: HR 2.3 95%CI 1.4-4.0) were significantly associated with the cumulative incidence of wheeze and asthma. Increasing numbers of siblings were inversely related to the incidence of wheeze (HR 0.9 95%CI 0.8 0.97) and asthma (HR 0.8 95%CI 0.7-0.97). Parental asthma was related to the incidence of asthma (HR 1.8 95%CI 1.2-2.6) while ever smoking (HR 2.0 95%CI 1.6 2.4) and house dampness (HR 1.3 95%CI 1.1-1.6) were risk factors for the incidence of wheeze. Maternal ETS exposure increased the risk of incident asthma in non-sensitized subjects (HR 1.9 95%CI 1.0-3.7). CONCLUSION AND CLINICAL RELEVANCE: Several environmental risk factors related to the incidence of asthma and wheeze in adolescence were identified and may be possible targets for intervention and prevention. PMID- 24773260 TI - Association analysis of three ABCB1 (MDR1) gene variants (C1236T, G2677A/T and C3435T) and their genotype/haplotype combinations with the familial Mediterranean fever. AB - 1. Familial Mediterranean fever (FMF) is considered an autosomal recessive disorder, associated with a single gene named Mediterranean fever (MEFV). The aim of this study was to perform genotyping and haplotyping analysis of the multidrug resistance (ATP-binding cassette, subfamily B, member 1 - ABCB1) gene in FMF patients. 2. Three ABCB1 gene polymorphisms (C1236T, G2677T/A and C3435T) were analyzed in 309 FMF patients and 250 healthy control subjects. All subjects were genotyped by PCR-restriction fragment length polymorphism analysis, and statistical analysis was performed using the Arlequin 3.1.1 and SPSS 16.0 software packages. 3. The CT genotype frequency of the C3435T polymorphism (p = 0.003), the CT-GT-CT (C1236T-G2677T/A-C3435T) triple genotype (p = 0.001) and the C-G (C1236T-G2677T/A) haplotype (p = 0.030) were more common in the FMF patients. The CT-GG-CC triple genotype and T-G-C, C-T-T and T-G-T haplotypes (C1236T G2677T/A-C3435T) were higher in the control subjects (p = 0.011, 0.001, 0.009 and 0.000, respectively). The CT-GG binary genotype and C-T and T-G haplotypes for C1236T-G2677T/A polymorphisms may have a high degree of protective effect against FMF (p = 0.0005, 0.002 and 0.000, respectively). 4. Our study showed that genotypes and haplotypes of ABCB1 gene polymorphisms may affect patients' FMF susceptibility. PMID- 24773261 TI - Structural insight into epothilones antitumor activity based on the conformational preferences and tubulin binding modes of epothilones A and B obtained from molecular dynamics simulations. AB - Molecular dynamics simulations were employed to analyze the conformational preferences and binding modes of epothilones A and B as a source of structural information regarding the antitumor properties of these species. Our results suggest that the conformation of free and tubulin-bound epothilones is strongly influenced by the presence of a methyl group at C12 and that epothilones A and B exploit the binding cavity in a unique and different way. The binding sites of epothilones A and B share a common region of association (Leu215, Leu217, His227, Leu228, Ala231, Phe270, Gly360, and Leu361), but lead to different ligand-residue interactions. Average interaction energies predict a larger stabilization for the epothilone B-tubulin complex, which is mainly driven by the enhancement of the electrostatic component of ligand-residue interactions compared to the epothilone A-tubulin complex. These structural and energetic results can be useful to account for the activity difference between epothilones A and B, and to design more active and potent analogs that resemble the mechanism of action of epothilones against cancer cells. PMID- 24773262 TI - High-resolution electrochemical and topographical imaging using batch-fabricated cantilever probes. AB - New cantilever probes for combined scanning electrochemical microscopy-atomic force microscopy (SECM-AFM) have been batch-fabricated, and their application to high resolution electrochemical-topographical imaging has been demonstrated. The conical probes yield outstanding quality Faradaic current maps alongside subnm level topographical information as exemplified by the electrochemical imaging of exfoliated graphene and graphite samples. Current mapping reveals significant heterogeneities in the electroactivity of these carbon surfaces that do not directly correlate to topographical features, suggesting the presence of adsorbed chemical contaminants or intrinsic impurities. PMID- 24773263 TI - The effects of dexmedetomidine on inflammatory mediators after cardiopulmonary bypass. AB - Cardiac surgery with cardiopulmonary bypass is associated with the development of a systemic inflammatory response that can often lead to dysfunction of major organs. We hypothesised that the highly selective alpha2-adrenergic agonist, dexmedetomidine, attenuates the systemic inflammatory response. Forty-two patients were randomly assigned to receive dexmedetomidine or saline after aortic cross-clamping). The mean (SD) levels of the nuclear protein plasma high-mobility group box 1 increased significantly from 5.1 (2.2) ng ml(-1) during (16.6 (7.3) ng ml(-1) ) and after (14.3 (8.2) ng ml(-1) ) cardiopulmonary bypass in the saline group. In the dexmedetomidine group, the levels increased significantly only during cardiopulmonary bypass (4.0 (1.9) ng ml(-1) baseline vs. 10.8 (2.7) ng ml(-1) ) but not after (7.4 (3.8) ng ml(-1) ). Dexmedetomidine infusion also suppressed the rise in mean (SD) interleukin-6 levels after cardiopulmonary bypass (a rise of 124.5 (72.0) pg ml(-1) vs. 65.3 (30.9) pg ml(-1)). These suppressive effects of dexmedetomidine might be due to the inhibition of nuclear factor kappa B activation and suggest that intra-operative dexmedetomidine may beneficially inhibit inflammatory responses associated with ischaemia-reperfusion injury during cardiopulmonary bypass. PMID- 24773264 TI - FTIR spectroscopy of a light-driven compatible sodium ion-proton pumping rhodopsin at 77 K. AB - Krokinobacter eikastus rhodopsin 2 (KR2) is a light-driven sodium ion pump that was discovered in marine bacteria. Although KR2 is able to pump lithium ions similarly, it is converted into a proton pump in potassium chloride or salts of larger cations. In this paper, we applied light-induced difference Fourier transform infrared (FTIR) spectroscopy to KR2, a compatible sodium ion-proton pump, at 77 K. The first structural study of the functional cycle showed that the structure and structural changes in the primary processes of KR2 are common to all microbial rhodopsins. The red shifted K formation (KR2K) was accompanied by retinal photoisomerization from an all-trans to a 13-cis form, resulting in a distorted retinal chromophore. The observed hydrogen out-of-plane vibrations were H/D exchangeable, indicating that the chromophore distortion by retinal isomerization is located near the Schiff base region in KR2. This tendency was also the case for bacteriorhodopsin and halorhodopsin but not the case for sensory rhodopsin I and II. Therefore, ion pumps such as proton, chloride, and sodium pumps exhibit local structural perturbations of retinal at the Schiff base moiety, while photosensors show more extended structural perturbations of retinal. The retinal Schiff base of KR2 forms a hydrogen bond that is stronger than in BR. KR2 possesses more protein-bound water molecules than other microbial rhodopsins and contains strongly hydrogen-bonded water (O-D stretch at 2333 cm( 1) in D2O). The light-induced difference FTIR spectra at 77 K were identical between the two states functioning as light-driven sodium ion and proton pumps, indicating that the structural changes in the primary processes are identical between different ion pump functions in KR2. In other words, it is unknown which ions are transported by molecules when they absorb photons and photoisomerize. It is likely that the relaxation processes from the K state lead to an alternative function, namely a sodium ion pump or proton pump, depending on the environment. PMID- 24773265 TI - The pharmacology of TRP channels. AB - This themed issue of the British Journal of Pharmacology contains review and research articles on recent advances in transient receptor potential (TRP) channel pharmacology. The review articles, written by a panel of distinguished experts, address the rapid progress in TRP channel research in fields as diverse as oncology, urology, dermatology, migraine, inflammation and pain. These reviews are complemented by original research reports focusing, among others, on the emerging roles of TRPV1 in osteoporosis and cystitis and on evodiamine as a lead structure for the development of potent TRPV1 agonists/desensitizers. Other papers highlight the differences in TRPV3 pharmacology between recombinant and native systems, the mechanisms of TRPM3 activation/inhibition and TRPP2 as a target of naringenin, a dietary flavonoid with anticancer actions. New therapeutic opportunities in pain may arise from the strategy to combine TRP channel and cell membrane impermeant sodium channel blockers to inhibit sensory nerve activity. PMID- 24773266 TI - Evaluation of transverse piezoelectric coefficient of ZnO thin films deposited on different flexible substrates: a comparative study on the vibration sensing performance. AB - We report on the systematic comparative study of highly c-axis oriented and crystalline piezoelectric ZnO thin films deposited on four different flexible substrates for vibration sensing application. The flexible substrates employed for present experimental study were namely a metal alloy (Phynox), metal (aluminum), polyimide (Kapton), and polyester (Mylar). ZnO thin films were deposited by an RF reactive magnetron sputtering technique. ZnO thin films of similar thicknesses of 700 +/- 30 nm were deposited on four different flexible substrates to have proper comparative studies. The crystallinity, surface morphology, chemical composition, and roughness of ZnO thin films were evaluated by respective material characterization techniques. The transverse piezoelectric coefficient (d31) value for assessing the piezoelectric property of ZnO thin films on different flexible substrates was measured by a four-point bending method. ZnO thin films deposited on Phynox alloy substrate showed relatively better material characterization results and a higher piezoelectric d31 coefficient value as compared to ZnO films on metal and polymer substrates. In order to experimentally verify the above observations, vibration sensing studies were performed. As expected, the ZnO thin film deposited on Phynox alloy substrate showed better vibration sensing performance. It has generated the highest peak to peak output voltage amplitude of 256 mV as compared to that of aluminum (224 mV), Kapton (144 mV), and Mylar (46 mV). Therefore, metal alloy flexible substrate proves to be a more suitable, advantageous, and versatile choice for integrating ZnO thin films as compared to metal and polymer flexible substrates for vibration sensing applications. The present experimental study is extremely important and helpful for the selection of a suitable flexible substrate for various applications in the field of sensor and actuator technology. PMID- 24773267 TI - Fracture of the patella after TPLO in dogs. PMID- 24773268 TI - Early communicative gestures and play as predictors of language development in children born with and without family risk for dyslexia. AB - The present study investigated early communicative gestures, play, and language skills in children born with family risk for dyslexia (FR) and a control group of children without this inheritable risk at ages 12, 15, 18, and 24 months. Participants were drawn from the Tromso Longitudinal study of Dyslexia (TLD) which follows children's cognitive and language development from age 12 months through Grade 2 in order to identify early markers of developmental dyslexia. Results showed that symbolic play and parent reported play at age 12 months and communicative gestures at age 15 months explained 61% of the variance in productive language at 24 months in the FR group. These early nonlinguistic measures seem to be potentially interesting markers of later language development in children born at risk for dyslexia. PMID- 24773269 TI - Isolation, purification, and identification of an important pigment, sepiapterin, from integument of the lemon mutant of the silkworm, Bombyx mori. AB - Sepiapterin is the precursor of tetrahydrobiopterin, an important coenzyme of aromatic amino acid hydroxylases, the lack of which leads to a variety of physiological metabolic diseases or neurological syndromes in humans. Sepiapterin is a main pigment component in the integument of the lemon mutant of the silkworm, Bombyx mori (L.) (Lepidoptera: Bombycidae), and is present there in extremely high content, so lemon is a valuable genetic resource to extract sepiapterin. In this study, an effective experimental system was set up for isolation and purification of sepiapterin from lemon silkworms by optimizing homogenization solvent, elution buffer, and separation chromatographic column. The results showed that ethanol was the most suitable solvent to homogenize the integument, with a concentration of 50% and solid:liquid ratio of 1:20 (g/mL). Sepiapterin was purified successively by column chromatography of cellulose Ecteola, sephadex G-25-150, and cellulose phosphate, and was identified by ultraviolet-visible absorption spectrometry. A stable and accurate high performance liquid chromatography method was constructed to identify sepiapterin and conduct qualitative and quantitative analyses. Sepiapterin of high purity was achieved, and the harvest reached about 40 ug/g of integument in the experiments. This work helps to obtaining natural sepiapterin in large amounts in order to use the lemon B. mori mutant to produce BH4 in vitro. PMID- 24773270 TI - Glucosinolates, myrosinase hydrolysis products, and flavonols found in rocket (Eruca sativa and Diplotaxis tenuifolia). AB - Rocket species have been shown to have very high concentrations of glucosinolates and flavonols, which have numerous positive health benefits with regular consumption. This review highlights how breeders and processors of rocket species can utilize genomic and phytochemical research to improve varieties and enhance the nutritive benefits to consumers. Plant breeders are increasingly looking to new technologies such as HPLC, UPLC, LC-MS, and GC-MS to screen populations for their phytochemical content to inform plant selections. This paper collates the research that has been conducted to date in rocket and summarizes all glucosinolate and flavonol compounds identified in the species. The paper emphasizes the importance of the broad screening of populations for phytochemicals and myrosinase degradation products, as well as unique traits that may be found in underutilized gene bank resources. This review also stresses that collaboration with industrial partners is becoming essential for long-term plant breeding goals through research. PMID- 24773271 TI - A tough and high-performance transparent electrode from a scalable and transfer free method. AB - Conductive metal films are patterned into transparent metal nanowire networks by using electrospun fibers as a mask. Both the transmittance and sheet resistance (6 Omega/? at 83% transmittance and 24 Omega/? at 92% transmittance) of the metal nanowire-based electrode out-perform commercial indium doped tin oxide (ITO) electrodes. The metal nanowire-based transparent electrodes were fabricated on both rigid glass and flexible polyethylene terephthalate (PET) substrates. In addition to state of art performance, the transparent electrodes also exhibit outstanding toughness. They can withstand repeated scotch tape peeling and various bending tests. The method for making the metal nanowire is scalable, and a touch screen on flexible substrate is demonstrated. PMID- 24773272 TI - Effects of entecavir on peripheral blood lymphocyte profiles in chronic hepatitis B patients with suboptimal responses to adefovir. AB - The aim of the present study was to assess the long-term impact of entecavir (ETV) on T, B and natural killer (NK) cell immunity in patients with suboptimal responses to adefovir (SRA) chronic hepatitis B (CHB). Thirty SRA CHB patients and 20 age- and gender-matched healthy controls (HC) completed at least 6 months of ETV treatment. Hepatitis B virus (HBV) DNA loads, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and the frequency of different subsets of T, B and NK cells in individual subjects were measured. There were smaller numbers of CD3(-) CD56(+) and CD244(+) NK cells, CD3(+) CD8(+) T cells and cytokine-secreting CD4(+) T cells, but greater numbers of CD3(+) CD4(+) , CD4(+) CD25(+) Foxp3(+) , CD4(+) CD25(+) CD127(low) T cells and CD19(+) CD27(+) B cells, detected in SRA patients. After switching to ETV monotherapy, the levels of HBV DNA and hepatitis B s antigen, as well as hepatitis B e antigen seropositivity, decreased gradually, accompanied by decreases in ALT and AST levels. Furthermore, the number of NK, CD8(+) and cytokine-secreting CD4(+) T cells increased, whereas the number of CD4(+) , CD4(+) CD25(+) Foxp3(+) , CD4(+) CD25(+) CD127(low) T cells and CD19(+) CD27(+) B cells decreased, in SRA CHB patients. The frequency of CD4(+) interferon-gamma-positive T cells was negatively associated with serum HBV DNA levels. Thus, treatment with ETV inhibits HBV replication, modulates T and NK cell immunity and improves liver function in SRA CHB patients. PMID- 24773273 TI - Mental health treatment in the primary care setting: patterns and pathways. AB - The redesign of primary care through the patient-centered medical home offers an opportunity to assess the role of primary care in treating mental health relative to the rest of the health care system. Better understanding the patterns of care between primary care and mental health providers helps guide necessary policy changes. This article reports the findings from 109,593 respondents to the 2002 2009 Medical Expenditure Panel Surveys (MEPS). We examined the extent to which persons with poor mental health visited primary care providers, and distinguished among 4 patterns of care: (a) mental health only, (b) primary care only, (c) dual care (both mental health and primary care) and (d) other provider combinations. Our findings indicate that poor mental health and specific mental health conditions remain prevalent in primary care. An increased focus on patient centered care requires greater integration of primary and mental health care to reduce fragmentation of care and disparities in health outcomes. PMID- 24773274 TI - Developmental trajectories of receptive and expressive communication in children and young adults with cerebral palsy. AB - AIM: The aim of this study was to determine the developmental trajectories of expressive (speech) and receptive (spoken and written language) communication by type of motor disorder and intellectual disability in individuals with cerebral palsy (CP). METHOD: The development of 418 participants (261 males, 157 females; mean age 9y 6mo [SD 6y 2mo], range 1-24y; Gross Motor Function Classification System (GMFCS) level I [n=206], II [n=57], III [n=59], IV [n=54], V [n=42]) was followed for 2 to 4 years in a longitudinal study. Communication performance was measured using the Vineland Adaptive Behavior Scales. The type of motor disorder was differentiated by type of CP as unilateral spastic (USCP, n=161), bilateral spastic (BSCP, n=202), and non-spastic (NSCP, n=55), while intellectual disability was determined by IQ or school type (regular or special). A multilevel analysis was then used to model the developmental trajectories. RESULTS: The most favourable development of expressive communication was seen in USCP (vs BSCP beta [SE]-2.74 [1.06], NSCP beta [SE]-2.67 [1.44]). The difference between the development trajectory levels of children with and without intellectual disability was smaller for children with USCP than for those with BSCP and NSCP. For receptive communication, the most favourable development was found for all children with USCP and for BSCP or NSCP without intellectual disability (vs intellectual disability beta [SE]-4.00 [1.16]). Development of written language was most favourable for children without intellectual disability (vs intellectual disability beta [SE]-23.11 [2.85]). INTERPRETATION: The development of expressive communication was found to be most closely related to type of motor disorder, whereas the development of receptive communication was found to be most closely related to intellectual disability. PMID- 24773275 TI - Does aspirin increase the risk of age-related macular degeneration? AB - This commentary on the review by Christen and Chew discusses the controversy surrounding aspirin use and its association with age-related macular degeneration (AMD). We address the strength of evidence between low-dose aspirin use and AMD and also discuss the risks and benefits of aspirin use in primary versus secondary prevention of cardiovascular diseases in these cases. We also highlight an ongoing randomized controlled trial in this area. PMID- 24773276 TI - 3D imaging provides a high-resolution, volumetric approach for analyzing biofouling. AB - A volumetric approach for determining the fouling burden on surfaces is presented, consisting of a 3D camera imaging system with fine (5 MUm) resolution. Panels immersed in an estuary on the southwest coast of Florida, USA were imaged and the data were used to quantify seasonal changes in the biofouling community. Test panels, which were submerged in seawater for up to one year, were analyzed before and after gentle scrubbing to quantify the biovolume of the total fouling community (ie soft and hard organisms) and the hard fouling community. Total biofouling ranged from 0.01 to 1.16 cm(3) cm(-2) throughout the immersion period; soft fouling constituted 22-87% of the total biovolume. In the future, this approach may be used to inform numerical models of fluid-surface interfaces and to evaluate, with high resolution, the morphology of fouling organisms in response to antifouling technologies. PMID- 24773277 TI - The association of angiographic collaterals with long-term clinical outcomes in patients with chronic stable angina. AB - OBJECTIVES: To determine the impact of coronary collaterals in stable angina. BACKGROUND: Whether spontaneously visible coronary collaterals are associated with long-term clinical outcomes in stable angina remains unclear. METHODS: We prospectively enrolled patients with stable angina referred for coronary angiography and followed them clinically for 1 year. RESULTS: A total of 1,134 consecutive patients were enrolled, and of these, 550 had at least single-vessel coronary artery disease (CAD) and were included. Patients with collaterals had more congestive heart failure (16% vs. 9%, P = 0.023), peripheral vascular disease (22% vs. 15%, P = 0.044), and 2-vessel (36% vs. 26%) and 3-vessel (28% vs. 10%) CAD compared to those without collaterals (P < 0.001). Patients with collaterals were less likely to undergo percutaneous intervention at the time of the index angiogram (32% vs. 61%, P < 0.001). At 1 year, there were no differences in angina (HR 0.74, 95% CI 0.50-1.10; P = 0.141), myocardial infarction (MI) (HR 1.22, 95% CI 0.46-3.21; P = 0.691), revascularization (HR 0.84, 95% CI 0.55-1.30; P = 0.431), death (HR 1.83, 95% CI 0.63-5.31; P = 0.269), or the combined end-point of death, MI, and revascularization (HR 0.87, 95% CI 0.61-1.24; P = 0.426) between patients with and without collaterals. When analyzed according to collateral grade, patients with Rentrop grade 1 had less angina (HR 0.48, 95% CI 0.26-0.89; P = 0.019). CONCLUSIONS: At 1 year, there was no difference in adverse events between patients with or without collaterals. The presence of Rentrop grade 1 collaterals, however, was associated with significantly less angina. PMID- 24773280 TI - Range-adaptive standoff recognition of explosive fingerprints on solid surfaces using a supervised learning method and laser-induced breakdown spectroscopy. AB - The distance between the sensor and the target is a particularly critical factor for an issue as crucial as explosive residues recognition when a laser-assisted spectroscopic technique operates in a standoff configuration. Particularly for laser ablation, variations in operational range influence the induced plasmas as well as the sensitivity of their ensuing optical emissions, thereby confining the attributes used in sorting methods. Though efficient classification models based on optical emissions gathered under specific conditions have been developed, their successful performance on any variable information is limited. Hence, to test new information by a designed model, data must be acquired under operational conditions totally matching those used during modeling. Otherwise, the new expected scenario needs to be previously modeled. To facing both this restriction and this time-consuming mission, a novel strategy is proposed in this work. On the basis of machine learning methods, the strategy stems from a decision boundary function designed for a defined set of experimental conditions. Next, particular semisupervised models to the envisaged conditions are obtained adaptively on the basis of changes in laser fluence and light emission with variation of the sensor-to-target distance. Hence, the strategy requires only a little prior information, therefore ruling out the tedious and time-consuming process of modeling all the expected distant scenes. Residues of ordinary materials (olive oil, fuel oil, motor oils, gasoline, car wax and hand cream) hardly cause confusion in alerting the presence of an explosive (DNT, TNT, RDX, or PETN) when tested within a range from 30 to 50 m with varying laser irradiance between 8.2 and 1.3 GW cm(-2). With error rates of around 5%, the experimental assessments confirm that this semisupervised model suitably addresses the recognition of organic residues on aluminum surfaces under different operational conditions. PMID- 24773279 TI - Comparative study of Hsp27, GSK3beta, Wnt1 and PRDX3 in Hirschsprung's disease. AB - Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system characterized by aganglionosis in distal gut. In this study, we used two dimensional gel electrophoresis (2-DE) technology coupled with matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis to identify differentially expressed proteins in the aganglionic (stenotic) and ganglionic (normal) colon segment tissues from patients with HSCR. We identified 15 proteins with different expression levels between the stenotic and the normal colon segment tissues from patients with HSCR. Nine proteins were upregulated and six proteins downregulated in the stenotic colon segment tissues compared to the normal colon segment tissues. Based on the biological functions, we selected the Hsp27 upregulated proteins and the PRDX3 downregulated proteins to confirm their expression in 20 patients. The protein and mRNA expressions of Hsp27 were statistically higher in the stenotic colon segment tissues than in the normal colon segment tissues, whereas the protein and mRNA expressions of PRDX3 were statistically lower in the stenotic colon segment tissues than in the normal colon segment tissues. These findings of changes in mRNA and protein in tissues from patients with HSCR provide information which may be helpful in understanding the pathomechanism that is implicated in the disease. PMID- 24773281 TI - An evaluation of a new single-use flexible bronchoscope with a large suction channel: reliability of bronchoalveolar lavage in ventilated piglets and initial clinical experience. AB - A single-use flexible bronchoscope with a large suction channel has become available recently and we have evaluated this innovative device. Firstly, bronchoalveolar lavage was performed and quantified in ventilated piglets. Next, the bronchoscope was evaluated in three intensive care units and a satisfaction questionnaire was carried out. Sixteen bronchoalveolar lavages were performed in piglets with a recovery rate of 83 (79-86 [72-89])% of the instilled volume. Quality and performance of all devices tested was identical. The medical satisfaction questionnaire was as follows: 'acceptable' to 'very good' for quality of aspiration, manoeuvrability and quality of vision; 'very good' to 'perfect' for setting up and insertion. This encouraging preliminary evaluation demonstrates the effectiveness of this new single-use device, which may obviate the need for disinfection procedures and, thereby, eradicate a potential vector of patient cross-contamination. PMID- 24773282 TI - Low-threshold stimulated emission using colloidal quantum wells. AB - The use of colloidal semiconductor nanocrystals for optical amplification and lasing has been limited by the need for high input power densities. Here we show that colloidal nanoplatelets produce amplified spontaneous emission with thresholds as low as 6 MUJ/cm(2) and gain as high as 600 cm(-1), both a significant improvement over colloidal nanocrystals; in addition, gain saturation occurs at pump fluences 2 orders of magnitude higher than the threshold. We attribute this exceptional performance to large optical cross-sections, slow Auger recombination rates, and narrow ensemble emission line widths. PMID- 24773283 TI - Inhibitory stroke neighbour priming in character recognition and reading in Chinese. AB - In alphabetic languages, prior exposure to a target word's orthographic neighbour influences word recognition in masked priming experiments and the process of word identification that occurs during normal reading. We investigated whether similar neighbour priming effects are observed in Chinese in 4 masked priming experiments (employing a forward mask and 33-ms, 50-ms, and 67-ms prime durations) and in an experiment that measured eye movements while reading. In these experiments, the stroke neighbour of a Chinese character was defined as any character that differed by the addition, deletion, or substitution of one or two strokes. Prime characters were either stroke neighbours or stroke non-neighbours of the target character, and each prime character had either a higher or a lower frequency of occurrence in the language than its corresponding target character. Frequency effects were observed in all experiments, demonstrating that the manipulation of character frequency was successful. In addition, a robust inhibitory priming effect was observed in response times for target characters in the masked priming experiments and in eye fixation durations for target characters in the reading experiment. This stroke neighbour priming was not modulated by the relative frequency of the prime and target characters. The present findings therefore provide a novel demonstration that inhibitory neighbour priming shown previously for alphabetic languages is also observed for nonalphabetic languages, and that neighbour priming (based on stroke overlap) occurs at the level of the character in Chinese. PMID- 24773284 TI - Associative asymmetry of compound words. AB - Early verbal-memory researchers assumed participants represent memory of a pair of unrelated items with 2 independent, separately modifiable, directional associations. However, memory for pairs of unrelated words (A-B) exhibits associative symmetry: a near-perfect correlation between accuracy on forward (A >?) and backward (?<- B) cued recall. This was viewed as arguing against the independent-associations hypothesis and in favor of the hypothesis that associations are remembered as holistic units. Here we test the Holistic Representation hypothesis further by examining cued recall of compound words. If we suppose preexisting words are more unitized than novel associations, the Holistic Representation hypothesis predicts compound words (e.g., ROSE BUD) will have a higher forward-backward correlation than novel compounds (e.g., BRIEF TAX). We report the opposite finding: Compound words, as well as noncompound words, exhibited less associative symmetry than novel compounds. This challenges the Holistic Representation account of associative symmetry. Moreover, preexperimental associates (positional family size) influenced associative symmetry-but asymmetrically: Increasing family size of the last constituent increasing decoupled forward and backward recall, but family size of the 1st constituent had no such effect. In short, highly practiced, meaningful associations exhibit associative asymmetry, suggesting associative symmetry is not diagnostic of holistic representations but, rather, is a characteristic of ad hoc associations. With additional learning, symmetric associations may be replaced by directional, independently modifiable associations as verbal associations become embedded within a rich knowledge structure. PMID- 24773285 TI - "Heads or tails?"--a reachability bias in binary choice. AB - When asked to mentally simulate coin tosses, people generate sequences that differ systematically from those generated by fair coins. It has been rarely noted that this divergence is apparent already in the very 1st mental toss. Analysis of several existing data sets reveals that about 80% of respondents start their sequence with Heads. We attributed this to the linguistic convention describing coin toss outcomes as "Heads or Tails," not vice versa. However, our subsequent experiments found the "first-toss" bias reversible under minor changes in the experimental setup, such as mentioning Tails before Heads in the instructions. We offer a comprehensive account in terms of a novel response bias, which we call reachability. It is more general than the 1st-toss bias, and it reflects the relative ease of reaching 1 option compared to its alternative in any binary choice context. When faced with a choice between 2 options (e.g., Heads and Tails, when "tossing" mental coins), whichever of the 2 is presented first by the choice architecture (hence, is more reachable) will be favored. This bias has far-reaching implications extending well beyond the context of randomness cognition; in particular, to binary surveys (e.g., accept vs. reject) and tests (e.g., True-False). In binary choice, there is an advantage to what presents first. PMID- 24773286 TI - Forgetting as a consequence and enabler of creative thinking. AB - Four experiments examined the interplay of memory and creative cognition, showing that attempting to think of new uses for an object can cause the forgetting of old uses. Specifically, using an adapted version of the Alternative Uses Task (Guilford, 1957), participants studied several uses for a variety of common household objects before attempting to generate new uses for half of those objects. As revealed by performance on a final cued-recall task, attempting to generate new uses caused participants to forget the studied uses. This thinking induced forgetting effect was observed regardless of whether participants attempted to generate unusual uses or common uses, but failed to emerge when participants used the studied uses as hints to guide their generation of new uses. Additionally, the forgetting effect correlated with individual differences in creativity such that participants who exhibited more forgetting generated more creative uses than participants who exhibited less forgetting. These findings indicate that thinking can cause forgetting and that such forgetting may contribute to the ability to think creatively. PMID- 24773287 TI - Exercise-induced hypoalgesia - interval versus continuous mode. AB - Aerobic exercise at approximately 70% of maximal aerobic capacity moderately reduces pain sensitivity and attenuates pain, even after a single session. If the analgesic effects depend on exercise intensity, then high-intensity interval exercise at 85% of maximal aerobic capacity should further reduce pain. The aim of this study was to explore the exercise-induced analgesic effects of high intensity interval aerobic exercise and to compare them with the analgesic effects of moderate continuous aerobic exercise. Twenty-nine young untrained healthy males were randomly assigned to aerobic-continuous (70% heart rate reserve (HRR)) and interval (4 * 4 min at 85% HRR and 2 min at 60% HRR between cycles) exercise modes, each lasting 30 min. Psychophysical pain tests, pressure and heat pain thresholds (HPT), and tonic heat pain (THP) were conducted before and after exercise sessions. Repeated measures ANOVA was used for data analysis. HPT increased (p = 0.056) and THP decreased (p = 0.013) following exercise unrelated to exercise type. However, the main time effect (pre-/postexercise) was a trend of increased HPT (45.6 +/- 1.9 degrees C to 46.2 +/- 1.8 degrees C; p = 0.082) and a significant reduction in THP (from 50.7 +/- 25 to 45.9 +/- 25.4 numeric pain scale; p = 0.043) following interval exercise. No significant change was found for the pressure pain threshold following either exercise type. In conclusion, interval exercise (85% HRR) has analgesic effects on experimental pain perception. This, in addition to its cardiovascular, muscular, and metabolic advantages may promote its inclusion in pain management programs. PMID- 24773288 TI - The elongation of ovococci. AB - The morphogenesis of ovococci has been reviewed extensively. Recent results have provided new insights concerning the mechanisms of elongation in ovoid bacteria. We present here the proteins involved in the elongation (firmly established and more or less hypothetical) and discuss the relationship between elongation and division of ovococci. PMID- 24773290 TI - Single step integration of ZnO nano- and microneedles in Si trenches by novel flame transport approach: whispering gallery modes and photocatalytic properties. AB - Direct growth of quasi-one-dimensional nano- and microstructures in desired places of complex shaped substrates using simple growth methods is highly demanded aspect for various applications. In this work, we have demonstrated direct integration of ZnO nano- and microneedles into Si trenches by a novel flame transport synthesis approach in a single fabrication step. Growth of partially and fully covered or filled trenches in Si substrate with ZnO nano- and microneedles has been investigated and is discussed here. Detailed microstructural studies revealed the evolution of the ZnO nano- and microneedles as well as their firm adhesion to the wall in the Si trenches. Micro photoluminescence measurements at different locations along the length of needles confirmed the good crystalline quality and also the presence of whispering gallery mode resonances on the top of needles due to their hexagonal shape. Faceted ZnO nano- and microstructures are also very important candidates with regard to photocatalytic activity. First, photocatalytic measurements from the grown ZnO nano- and microneedles have shown strong degradation of methylene blue, which demonstrate that these structures can be of significant interest for photocatalysis and self-cleaning chromatography columns. PMID- 24773289 TI - Early communicative gestures prospectively predict language development and executive function in early childhood. AB - Using an epidemiological sample (N = 1,117) and a prospective longitudinal design, this study tested the direct and indirect effects of preverbal and verbal communication (15 months to 3 years) on executive function (EF) at age 4 years. Results indicated that whereas gestures (15 months), as well as language (2 and 3 years), were correlated with later EF (phis >= .44), the effect was entirely mediated through later language. In contrast, language had significant direct and indirect effects on later EF. Exploratory analyses indicated that the pattern of results was comparable for low- and not-low-income families. The results were consistent with theoretical accounts of language as a precursor of EF ability, and highlighted gesture as an early indicator of EF. PMID- 24773291 TI - Reorganization of personal identity in the context of motivational dynamics and internal dialogical activity. AB - Identity is constantly constructed and reconstructed. It may be assumed that there are six fundamental motivational goals according to which it is organized: self-esteem, self-efficacy, continuity, distinctiveness, belonging, and meaning (Vignoles, 2011). Moreover, identity is shaped by its dialogical nature (Hermans, 2003; van Halen & Janssen, 2004). The longitudinal study was conducted to examine both the motivational and the dialogical basis of identity structure dynamics. The results showed that the more the identity element was connected with a sense of continuity and the more dialogical it was, the greater the perceived centrality of this element was after two months. Furthermore, the more the identity element satisfied the self-esteem and belonging motives, the more positive was the affect ascribed to it. In the behavioral domain of identity, participants more strongly manifested those identity aspects that were earlier rated as more dialogical and satisfying the motive of belonging. The results showed that the motivational underpinnings of identity along with its dialogical nature explain changes in identity structure. PMID- 24773292 TI - Methylated DNA immunoprecipitation and high-throughput sequencing (MeDIP-seq) using low amounts of genomic DNA. AB - DNA modifications, such as methylation and hydroxymethylation, are pivotal players in modulating gene expression, genomic imprinting, X-chromosome inactivation, and silencing repetitive sequences during embryonic development. Aberrant DNA modifications lead to embryonic and postnatal abnormalities and serious human diseases, such as cancer. Comprehensive genome-wide DNA methylation and hydroxymethylation studies provide a way to thoroughly understand normal development and to identify potential epigenetic mutations in human diseases. Here we established a working protocol for methylated DNA immunoprecipitation combined with next-generation sequencing [methylated DNA immunoprecipitation (MeDIP)-seq] for low starting amounts of genomic DNA. By using spike-in control DNA sets with standard cytosine, 5-methylcytosine (5mC), and 5 hydroxymethylcytosine (5hmC), we demonstrate the preferential binding of antibodies to 5mC and 5hmC, respectively. MeDIP-PCRs successfully targeted highly methylated genomic loci with starting genomic DNA as low as 1 ng. The enrichment efficiency declined for constant spiked-in controls but increased for endogenous methylated regions. A MeDIP-seq library was constructed starting with 1 ng of DNA, with the majority of fragments between 250 bp and 600 bp. The MeDIP-seq reads showed higher quality than the Input control. However, after being preprocessed by Cutadapt, MeDIP (97.53%) and Input (94.98%) reads showed comparable alignment rates. SeqMonk visualization tools indicated MeDIP-seq reads were less uniformly distributed across the genome than Input reads. Several commonly known unmethylated and methylated genomic loci showed consistent methylation patterns in the MeDIP-seq data. Thus, we provide proof-of-principle that MeDIP-seq technology is feasible to profile genome-wide DNA methylation in minute DNA samples, such as oocytes, early embryos, and human biopsies. PMID- 24773293 TI - A study of the Phaonia angelicae group (Diptera: Muscidae), with descriptions of six new species from China. AB - The P. angelicae group from China was studied, and six new species are described: P. hanmiensis, n. sp., P. nanlingensis, n. sp., P. reduncicauda, n. sp., P. spargocerca, n. sp., P. subincana, n. sp., and P. varimargina, n. sp. A key to the identification of males of the 40 Chinese species is given. PMID- 24773294 TI - Red wine and oenological extracts display antimicrobial effects in an oral bacteria biofilm model. AB - The antimicrobial effects of red wine and its inherent components on oral microbiota were studied by using a 5-species biofilm model of the supragingival plaque that includes Actinomyces oris, Fusobacterium nucleatum, Streptococcus oralis, Streptococcus mutans and Veillonella dispar. Microbiological analysis (CFU counting and confocal laser scanning microscopy) of the biofilms after the application of red wine, dealcoholized red wine, and red wine extract solutions spiked or not with grape seed and inactive dry yeast extracts showed that the solutions spiked with seed extract were effective against F. nucleatum, S. oralis and A. oris. Also, red wine and dealcoholized wine had an antimicrobial effect against F. nucleatum and S. oralis. Additional experiments showed almost complete and early degradation of flavan-3-ol precursors [(+)-catechin and procyanidin B2] when incubating biofilms with the red wine extract. To our knowledge, this is the first study of antimicrobial properties of wine in an oral biofilm model. PMID- 24773297 TI - Drugs currently in Phase II clinical trials for cocaine addiction. AB - INTRODUCTION: There are no FDA-approved pharmacotherapies for treating cocaine addiction; thus, developing drugs to treat cocaine dependence is an unmet critical need. Fortunately, there are a number of drugs that are currently in Phase II clinical trial/s. This is due in part to the advances from in vivo imaging in humans which provided a roadmap of the neurochemistry of the cocaine dependent brain. Most drugs currently in Phase II clinical trials attempt to modulate the disturbed neurochemistry in cocaine dependents to resemble those of healthy individuals. These predominantly modulate dopamine, serotonin, glutamate, GABA or noradrenaline signalling. AREAS COVERED: This review summarizes the therapeutic potential of each drug as evidenced by clinical and preclinical studies. It also discusses their utility in terms of bioavailability and half life. EXPERT OPINION: Amphetamine salts and topiramate clearly stand out in terms of their potential efficacy in treating cocaine addiction. The efficacy of topiramate was closely associated with regular cognitive-behavioural therapy (CBT), which highlights the importance of a combined effort to promote abstinence and enhance retention via CBT. Cognitive/psychological screening appears necessary for a more symptom-based approach with more reasonable outcomes other than abstinence (e.g., improved quality of life) in treating cocaine addiction. PMID- 24773298 TI - Couple-based interventions for psychopathology: a renewed direction for the field. AB - This article provides a rationale and empirical support for providing couple based interventions when one partner in a relationship is experiencing individual psychopathology. Several investigations indicate that relationship distress and psychopathology are associated and reciprocally influence each other, such that the existence of relationship distress predicts the development of subsequent psychopathology and vice versa. Furthermore, findings indicate that for several disorders, individual psychotherapy is less effective if the client is in a distressed relationship. Finally, even within happy relationships, partners often inadvertently behave in ways that maintain or exacerbate symptoms for the other individual. Thus, within both satisfied and distressed relationships, including the partner in a couple-based intervention provides an opportunity to use the partner and the relationship as a resource rather than a stressor for an individual experiencing some form of psychological distress. The authors propose that a promising approach to including the partner in treatment involves (a) integrating intervention principles from empirically supported interventions for individual therapy for specific disorders with (b) knowledge of how to employ relationships to promote individual and dyadic change. Based on this logic, the article includes several examples to demonstrate how couple-based interventions can be focused on a specific type of psychopathology, including encouraging empirical findings for these interventions. The article concludes with recommendations for how clinicians and researchers can adapt their knowledge of couple therapy to assist couples in which one partner is experiencing notable psychological distress or diagnosable psychopathology. PMID- 24773296 TI - Zebrafish as model organisms for studying drug-induced liver injury. AB - Drug-induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, and new markers and mediators of DILI still need to be identified. This review highlights the strengths and weaknesses of using zebrafish as a high-throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different from that of the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways to those in humans; they possess a wide range of cytochrome P450 enzymes that enable metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de-ethylation. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation. The zebrafish immune system is similar to that of mammals, but the zebrafish inflammatory response to DILI is not yet defined. In order to quantify DILI in zebrafish, a wide variety of methods can be used, including visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring of histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers. PMID- 24773299 TI - Measurement of the circumferential mechanical properties of the umbilical vein: experimental and numerical analyses. AB - Coronary artery disease is responsible for almost 30% of all deaths worldwide. The saphenous vein and umbilical vein (UV) are the most common veins using for treatment as a coronary artery bypass graft (CABG). The mechanical properties of UV belonging to its long-term patency for CABG are very important. However, there is a lack of knowledge on the linear elastic and nonlinear hyperelastic mechanical properties of the UV. In this study, three stress definitions (second Piola-Kichhoff stress, engineering stress and true stress) and four strain definitions (Almansi-Hamel strain, Green-St Venant strain, engineering strain and true strain) are used to determine the elastic modulus, maximum stress and strain of eight human UVs under circumferential loading. The nonlinear mechanical behaviour of the UV is computationally investigated using Mooney-Rivlin hyperelastic model. A numerical finite element analysis is also carried out to simulate the constitutive modelling versus its numerical results. The results show that the Almansi-Hamel strain definition overestimates the elastic modulus while Green-St Venant strain definition underestimates the elastic modulus at different stress definitions. The true stress-true strain definition, which gives more accurate measurements of the tissue's response using the instantaneous values, reveals the Young's modulus and maximum stress of 2.18 and 6.01 MPa, respectively. The Mooney-Rivlin material model is well represented by the nonlinear mechanical behaviour of the UV. The findings of this study could have implications not only for understanding the extension and rupture mechanism of UV but also for interventions and surgeries, including balloon angioplasty, bypass and stenting. PMID- 24773300 TI - Facile fabrication of ultrafine palladium nanoparticles with size- and location control in click-based porous organic polymers. AB - Two click-based porous organic polymers (CPP-1 and CPP-2) are readily synthesized through a click reaction. Using CPP-1 and CPP-2 as supports, palladium nanoparticles (NPs) with uniform and dual distributions were prepared through H2 and NaBH4 reduction routes, respectively. Ultrafine palladium NPs are effectively immobilized in the interior cavities of polymers. The coordination of 1,2,3 triazolyl to palladium and the confinement effect of polymers on palladium NPs are verified by solid-state (13)C NMR and IR spectra, XPS analyses, EDX mapping, and computational calculation. The steric and electronic properties of polymers have a considerable influence on the interaction between polymers and palladium NPs, as well as the catalytic performances of NPs. The ultrafine palladium NPs with uniform distribution exhibit superior stability and recyclability over palladium NPs with dual distributions and palladium on charcoal in the hydrogenation of nitroarenes, and no obvious agglomeration and loss of catalytic activity were observed after recycling several times. The excellent performances mainly result from synergetic effects between palladium NPs and polymers. PMID- 24773301 TI - Platinized aligned carbon nanotube-sheathed carbon fiber microelectrodes for in vivo amperometric monitoring of oxygen. AB - The abnormal level of O2 could disturb various neurochemical processes and even induce neural injury and brain dysfunction. In order to assess critical roles of O2 in the neurochemical processes, it is essential to perform in vivo monitoring of the dynamic changes of O2. In this study, we develop a new electrochemical method for selectively monitoring O2 in vivo, using platinized vertically aligned carbon nanotube (VACNT)-sheathed carbon fibers (Pt/VACNT-CFs) as the electrodes. The VACNT-sheathed CFs (VACNT-CFs) are produced via the pyrolysis of iron phthalocyanine (FePc) on the surface of CFs, followed by electrochemical deposition of platinum nanoparticles to form Pt/VACNT-CFs. The resulting Pt/VACNT CF microelectrodes exhibit fast overall kinetics for the O2 reduction via a four electron reduction process without the formation of toxic H2O2 intermediate. Consequently, effective and selective electrochemical methods are developed for the measurements of O2 in rat brain with the Pt/VACNT-CF microelectrodes, even in the presence of some species at their physiological levels, such as ascorbic acid, dopamine, uric acid, 5-hydroxytryptamine, and of the O2 fluctuation in rat brain in the early stage of global cerebral ischemia/reperfusion, mild hyperoxia, and hypoxia induced by exposing the animal, for a short time, to O2 and N2, respectively, and hindfeet pinch. The use of VACNT-CF as the support for Pt effectively improves the stability of Pt, as compared with the bare CF support, while the FePc pyrolysis ensures the VACNT-CFs to be reproducibly produced. Thus, this study offers a novel and reliable strategy for preparing new microelectrodes for in vivo monitoring of O2 in various physiological processes with a high sensitivity and selectivity. PMID- 24773302 TI - Optical impedance transformer for transparent conducting electrodes. AB - A fundamental limitation of transparent conducting electrode design is thought to be the trade-off between photonic and electronic performances. The photonic transmission property of a transparent conducting electrode, however, is not intrinsic but depends critically on the electromagnetic environment where the electrode is located. We develop the concept of optical impedance transformation, and use this concept to design nanophotonic structures that provide broadband and omnidirectional reduction of optical loss in an ultrathin transparent conducting electrode, without compromising its electrical performance. PMID- 24773303 TI - The endothelial glycocalyx: a review of the vascular barrier. AB - The endothelial glycocalyx is an important part of the vascular barrier. The glycocalyx is intimately linked to the homoeostatic functions of the endothelium. Damage to the glycocalyx precedes vascular pathology. In the first part of this paper, we have reviewed the structure, physiology and pathology of the endothelial glycocalyx, based on a literature search of the past five years. In the second part, we have systematically reviewed interventions to protect or repair the glycocalyx. Glycocalyx damage can be caused by hypervolaemia and hyperglycaemia and can be prevented by maintaining a physiological concentration of plasma protein, particularly albumin. Other interventions have been investigated in animal models: these require clinical research before their introduction into medical practice. PMID- 24773304 TI - Preschoolers trust novel members of accurate speakers' groups and judge them favourably. AB - By age 3, children track a speaker's record of past accuracy and use it as a cue to current reliability. Two experiments (N=95 children) explored whether preschoolers' judgements about, and trust in, the accuracy of a previously reliable informant extend to other members of the informant's group. In Experiment 1, both 3- and 4-year-olds consistently judged an animated character who was associated with a previously accurate speaker more likely to be correct than a character associated with a previously inaccurate speaker, despite possessing no information about these characters' individual records of reliability. They continued to show this preference one week later. Experiment 2 presented 4- and 5-year-olds with a related task using videos of human actors. Both showed preferences for members of previously accurate speakers' groups on a common measure of epistemic trust. This result suggests that by at least age 4, children's trust in speaker testimony spreads to members of a previously accurate speaker's group. PMID- 24773305 TI - Occurrence and genetic characteristics of third-generation cephalosporin resistant Escherichia coli in Swiss retail meat. AB - Prevalence and genetic relatedness were determined for third-generation cephalosporin-resistant Escherichia coli (3GC-R-Ec) detected in Swiss beef, veal, pork, and poultry retail meat. Samples from meat-packing plants (MPPs) processing 70% of the slaughtered animals in Switzerland were purchased at different intervals between April and June 2013 and analyzed. Sixty-nine 3GC-R-Ec isolates were obtained and characterized by microarray, PCR/DNA sequencing, Multi Locus Sequence Typing (MLST), and plasmid replicon typing. Plasmids of selected strains were transformed by electroporation into E. coli TOP10 cells and analyzed by plasmid MLST. The prevalence of 3GC-R-Ec was 73.3% in chicken and 2% in beef meat. No 3GC-R-Ec were found in pork and veal. Overall, the bla(CTX-M-1) (79.4%), bla(CMY-2) (17.6%), bla(CMY-4) (1.5%), and bla(SHV-12) (1.5%) beta-lactamase genes were detected, as well as other genes conferring resistance to chloramphenicol (cmlA1-like), sulfonamides (sul), tetracycline (tet), and trimethoprim (dfrA). The 3GC-R-Ec from chicken meat often harbored virulence genes associated with avian pathogens. Plasmid incompatibility (Inc) groups IncI1, IncFIB, IncFII, and IncB/O were the most frequent. A high rate of clonality (e.g., ST1304, ST38, and ST93) among isolates from the same MPPs suggests that strains persist at the plant and spread to meat at the carcass processing stage. Additionally, the presence of the blaCTX-M-1 gene on an IncI1 plasmid sequence type 3 (IncI1/pST3) in genetically diverse strains indicates interstrain spread of an epidemic plasmid. The bla(CMY-2) and bla(CMY-4) genes were located on IncB/O plasmids. This study represents the first comprehensive assessment of 3GC-R-Ec in meat in Switzerland. It demonstrates the need for monitoring contaminants and for the adaptation of the Hazard Analysis and Critical Control Point concept to avoid the spread of multidrug-resistant bacteria through the food chain. PMID- 24773306 TI - The impact of neighborhood, family, and individual risk factors on toddlers' disruptive behavior. AB - Disadvantaged neighborhoods confer risk for behavior problems in school-aged children but their impact in toddlerhood is unknown. Relations between toddlers' disruptive behavior and neighborhood disadvantage, family disadvantage, violence or conflict exposure, parent depressive symptoms, and parenting behavior were examined using multilevel, multigroup (girl-boy) models. Participants were 1,204 families (mean child age = 24.7 months). Unique associations between disruptive behavior and all risk factors were observed, but the effect of neighborhood disadvantage was negligible when all of the more proximal factors were accounted for. The results suggest both that children in disadvantaged neighborhoods are at greater risk of behavior problems than children in nondisadvantaged neighborhoods and that optimal prevention/intervention work with these children will attend to proximal risk factors. PMID- 24773307 TI - Exercise as medicine: role in the management of primary hypertension. AB - Primary hypertension affects ~1 in 5 Canadians and significantly increases the risk of myocardial infarction, stroke, heart failure, and early mortality. Guidelines for the management of hypertension recommend lifestyle modifications (e.g., increased physical activity, smoking cessation, moderate alcohol consumption, improved dietary choices) as the frontline strategy to prevent and manage high blood pressure (BP). In particular, acute and chronic aerobic exercise has consistently been shown to reduce resting and ambulatory BP, with the largest effects in hypertensive patients. Current guidelines recommend 30-60 min of moderate- to vigorous-intensity aerobic exercise 4-7 days per week, in addition to activities of daily living. The role of resistance training in the management of hypertension is less clear, although available data suggests resistance exercise can be performed safely without risk of increasing BP or adverse events. Presently, resistance exercise (8-10 exercises, 1-2 set(s) of 10 15 repetitions, 2-3 days/week) is advocated only as an adjunct exercise modality. Patients desiring to begin an exercise program should complete the Physical Activity Readiness Questionnaire (PAR-Q or PAR-Q+) or as required, the Electronic Physical Activity Readiness Medical Examination (ePARmed-X) or Physician Clearance Form in consultation with their clinician and (or) trained exercise professional. A greater emphasis on utilizing exercise as medicine will produce positive nonpharmacologic benefits for hypertensive patients and improve overall cardiovascular risk profiles. PMID- 24773309 TI - How do we treat fetal and neonatal alloimmune thrombocytopenia? AB - Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, seen in one in 800 to 1000 neonates. FNAIT is the most common cause of early-onset isolated severe neonatal thrombocytopenia in maternity wards. The complication of this disorder most to be feared is intracranial hemorrhage, leading to death or to neurologic sequels. As there is no systematic screening of at-risk pregnancies, FNAIT is often discovered when signs of bleeding are observed during pregnancy or at delivery. Platelet transfusion is required in case of bleeding or severe thrombocytopenia (<30 * 10(9) /L) during the 48-hour-postdelivery period. Diagnosis of alloimmunization is important for management of the index case and for subsequent pregnancies, due to the increasing severity of this syndrome as it recurs. Noninvasive antenatal therapy is based on maternal perfusion of intravenous immunoglobulins and risk stratification. In our experience, the addition of corticoids during the last trimester significantly improves the efficiency of treatment. Follow-up of antibody concentration during pregnancy may constitute a useful variable for therapy effectiveness. PMID- 24773308 TI - Improvement of cloned embryos development by co-culturing with parthenotes: a possible role of exosomes/microvesicles for embryos paracrine communication. AB - It is well known that embryos cultured in a group can create a microenvironment through secretion of autocrine and paracrine factors that can support and improve the embryos' development when compared to the embryos cultured individually. In this study, we used a co-culture system for paracrine communication between different kinds of embryos. The results showed that co-culture of porcine parthenogenetic (PA) embryos significantly improved the in vitro development of cloned (nuclear transfer, NT) embryos. To reveal the possible mechanism of communication between the two groups, we isolated exosomes/microvesicles (EXs/MVs) from the PA embryos conditioned medium (PA-CM) through differential centrifugation and identified them through transmission electron microscope and immunoflourescence against exosomal/membrane marker CD9. Furthermore, these EXs/MVs were found to contain mRNA of pluripotency genes (Oct4, Sox2, Klf4, c Myc, and Nanog), and the PKH67-labeled EXs/MVs could be internalized by the NT embryos. The current study demonstrates that cloned embryos' developmental competence can be improved through co-culturing with PA embryos and revealed, for the first time, that in vitro-produced embryos can secrete EXs/MVs as a possible communication tool within their microenvironment. Moreover, it provides a new paradigm for embryo-to-embryo communication in vitro. PMID- 24773310 TI - A network analysis of food flows within the United States of America. AB - The world food system is globalized and interconnected, in which trade plays an increasingly important role in facilitating food availability. We present a novel application of network analysis to domestic food flows within the USA, a country with global importance as a major agricultural producer and trade power. We find normal node degree distributions and Weibull node strength and betweenness centrality distributions. An unassortative network structure with high clustering coefficients exists. These network properties indicate that the USA food flow network is highly social and well-mixed. However, a power law relationship between node betweenness centrality and node degree indicates potential network vulnerability to the disturbance of key nodes. We perform an equality analysis which serves as a benchmark for global food trade, where the Gini coefficient = 0.579, Lorenz asymmetry coefficient = 0.966, and Hoover index = 0.442. These findings shed insight into trade network scaling and proxy free trade and equitable network architectures. PMID- 24773311 TI - Organic photovoltaic cells with stable top metal electrodes modified with polyethylenimine. AB - Efficient organic photovoltaic cells (OPV) often contain highly reactive low-work function calcium electron-collecting electrodes. In this work, efficient OPV are demonstrated in which calcium electrodes were avoided by depositing a thin layer of the amine-containing nonconjugated polymer, polyethylenimine (PEIE), between the photoactive organic semiconductor layer and stable metal electrodes such as aluminum, silver, or gold. Devices with structure ITO/poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/poly(3 hexylthiophene):indene-C60-bis-adduct (P3HT:ICBA)/PEIE/Al demonstrated overall photovoltaic device performance comparable to devices containing calcium electron collecting electrodes, ITO/PEDOT:PSS/P3HT:ICBA/Ca/Al, with open-circuit voltage of 775+/-6 mV, short-circuit current density of 9.1+/-0.5 mA cm(-2), fill factor of 0.65+/-0.01, and power conversion efficiency of 4.6+/-0.3%, averaged over 5 devices at 1 sun. PMID- 24773312 TI - Emerging drugs and combination strategies for basal cell carcinoma. AB - INTRODUCTION: Basal cell carcinoma (BCC) is a malignancy that is driven by an activated Hedgehog (Hh) pathway. Smoothened inhibitors are a new promising treatment option for patients with locally advanced or metastatic BCC or basal cell nevus syndrome. But long-term data are still limited, the optimal treatment duration is not yet defined and there are already documented cases with acquired resistance. AREAS COVERED: Treatment modalities with Hh inhibitors, side effects and potential pharmacological combination options are discussed. The current literature, including PubMed, Cochrane database and registered trials on ClinicalTrials.gov, was searched. EXPERT OPINION: BCCs typically regress during therapy with Hh inhibitors. Muscle toxicity, dysgeusia and hair loss can be considered as on target adverse reactions. Muscle toxicity is the dose-limiting toxicity of sonidegib. It was not seen with vismodegib because of its high binding to plasma protein alpha-1-acid glycoprotein. Sonidegib is different and shows a clear dose-toxicity relationship, which allows to address the question of whether there is a dose dependency of regression rate, cure rate and progression free survival. In addition, basic research has offered strategies to enhance efficacy by the combination with other molecules, such as EGFR inhibitors, MEK inhibitors or immunotherapy. PMID- 24773313 TI - Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model. AB - AIMS: Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk. METHODS: Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX. RESULTS: Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model. CONCLUSIONS: A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX). PMID- 24773315 TI - The metathoracic scent gland of the leaf-footed bug, Leptoglossus zonatus. AB - The metathoracic scent gland of 25-day-old adults of both sexes of the leaf footed bug, Leptoglossus zonatus (Dallas) (Heteroptera: Coreidae), are described based on optical microscopy analysis. No sexual dimorphism was observed in the glandular composition of this species. The gland is located in the anteroventral corner of the metathoracic pleura between the middle and posterior coxal pits. The opening to the outside of the gland is very wide and permanently open as it lacks a protective membrane. In the internal part, there is a pair of metathoracic glands that consist of piles of intertwined and occasionally bifurcated cellular tubes or columns. These glands discharge their pheromonal contents into the reservoir through a narrow cuticular tube. The reservoir connects with the vestibule via two opposite and assembled cuticular folds that can separate muscularly in order to allow the flow of liquid away from the insect. The external part consists of an ostiole from which the pheromone is emitted. The ostiole is surrounded by a peritreme, a structure that aids optimum pheromone dispersion. The described gland is of the omphalien type. PMID- 24773314 TI - Molecular phylogeny and ontogeny of a new ciliate genus, Paracladotricha salina n. g., n. sp. (Ciliophora, Hypotrichia). AB - A hypotrichous ciliate, Paracladotricha salina n. g., n. sp., was discovered in hypersaline waters (salinity about 800/00) from Qingdao, China. Its morphology and some major ontogenetic stages were studied and the phylogenetic position was estimated using standard methods. Paracladotricha salina is characterized by a flexible, more or less slender body (size 50-120 * 20-35 MUm), a gonostomatid oral apparatus, one short and two long frontoventral rows, four macronuclear nodules, almost completely reduced dorsal kineties 1-3, and a loss of several parts of the ciliature, namely, the slightly shortened ciliary row of the adoral membranelles, the paroral, and the buccal, the postoral and pretransverse ventral, the transverse, and the caudal cirri. The ontogenesis is rather simple: anlage II of both filial products and anlage III of the opisthe originate de novo, while anlagen IV and V are formed within the parental rows. This combination of features requires the establishment of a new genus, Paracladotricha, which is, according to the morphological data, closely related to Schmidingerothrix and Cladotricha. The small-subunit rRNA gene was sequenced, indicating that P. salina is, as also demonstrated by the oral apparatus, a member of the gonostomatids. We provide a first, vague hypothesis about the phylogenetic relationships of the Gonostomatidae, Cladotrichidae, and Schmidingerotrichidae. However, since molecular data of the type species of these higher taxa are lacking, their validity and relationships remain obscure. PMID- 24773316 TI - No gene in the genome makes sense except in the light of evolution. AB - Evolutionary conservation has been an accurate predictor of functional elements across the first decade of metazoan genomics. More recently, there has been a move to define functional elements instead from biochemical annotations. Evolutionary methods are, however, more comprehensive than biochemical approaches can be and can assess quantitatively, especially for subtle effects, how biologically important--how injurious after mutation--different types of elements are. Evolutionary methods are thus critical for understanding the large fraction (up to 10%) of the human genome that does not encode proteins and yet might convey function. These methods can also capture the ephemeral nature of much noncoding functional sequence, with large numbers of functional elements having been gained and lost rapidly along each mammalian lineage. Here, we review how different strengths of purifying selection have impacted on protein-coding and non-protein-coding loci and on transcription factor binding sites in mammalian and fruit fly genomes. PMID- 24773317 TI - The Ethical, Legal, and Social Implications Program of the National Human Genome Research Institute: reflections on an ongoing experiment. AB - For more than 20 years, the Ethical, Legal, and Social Implications (ELSI) Program of the National Human Genome Research Institute has supported empirical and conceptual research to anticipate and address the ethical, legal, and social implications of genomics. As a component of the agency that funds much of the underlying science, the program has always been an experiment. The ever-expanding number of issues the program addresses and the relatively low level of commitment on the part of other funding agencies to support such research make setting priorities especially challenging. Program-supported studies have had a significant impact on the conduct of genomics research, the implementation of genomic medicine, and broader public policies. The program's influence is likely to grow as ELSI research, genomics research, and policy development activities become increasingly integrated. Achieving the benefits of increased integration while preserving the autonomy, objectivity, and intellectual independence of ELSI investigators presents ongoing challenges and new opportunities. PMID- 24773318 TI - Therapeutics based on stop codon readthrough. AB - Nonsense suppression therapy encompasses approaches aimed at suppressing translation termination at in-frame premature termination codons (PTCs, also known as nonsense mutations) to restore deficient protein function. In this review, we examine the current status of PTC suppression as a therapy for genetic diseases caused by nonsense mutations. We discuss what is currently known about the mechanism of PTC suppression as well as therapeutic approaches under development to suppress PTCs. The approaches considered include readthrough drugs, suppressor tRNAs, PTC pseudouridylation, and inhibition of nonsense mediated mRNA decay. We also discuss the barriers that currently limit the clinical application of nonsense suppression therapy and suggest how some of these difficulties may be overcome. Finally, we consider how PTC suppression may play a role in the clinical treatment of genetic diseases caused by nonsense mutations. PMID- 24773321 TI - Transcription factor WRKY46 regulates osmotic stress responses and stomatal movement independently in Arabidopsis. AB - Drought and salt stress severely inhibit plant growth and development; however, the regulatory mechanisms of plants in response to these stresses are not fully understood. Here we report that the expression of a WRKY transcription factor WRKY46 is rapidly induced by drought, salt and oxidative stresses. T-DNA insertion of WRKY46 leads to more sensitivity to drought and salt stress, whereas overexpression of WRKY46 (OV46) results in hypersensitivity in soil-grown plants, with a higher water loss rate, but with increased tolerance on the sealed agar plates. Stomatal closing in the OV46 line is insensitive to ABA because of a reduced accumulation of reactive oxygen species (ROS) in the guard cells. We further find that WRKY46 is expressed in guard cells, where its expression is not affected by dehydration, and is involved in light-dependent stomatal opening. Microarray analysis reveals that WRKY46 regulates a set of genes involved in cellular osmoprotection and redox homeostasis under dehydration stress, which is confirmed by ROS and malondialdehyde (MDA) levels in stressed seedlings. Moreover, WRKY46 modulates light-dependent starch metabolism in guard cells via regulating QUA-QUINE STARCH (QQS) gene expression. Taken together, we demonstrate that WRKY46 plays dual roles in regulating plant responses to drought and salt stress and light-dependent stomatal opening in guard cells. PMID- 24773319 TI - The genetics of microdeletion and microduplication syndromes: an update. AB - Chromosomal abnormalities, including microdeletions and microduplications, have long been associated with abnormal developmental outcomes. Early discoveries relied on a common clinical presentation and the ability to detect chromosomal abnormalities by standard karyotype analysis or specific assays such as fluorescence in situ hybridization. Over the past decade, the development of novel genomic technologies has allowed more comprehensive, unbiased discovery of microdeletions and microduplications throughout the human genome. The ability to quickly interrogate large cohorts using chromosome microarrays and, more recently, next-generation sequencing has led to the rapid discovery of novel microdeletions and microduplications associated with disease, including very rare but clinically significant rearrangements. In addition, the observation that some microdeletions are associated with risk for several neurodevelopmental disorders contributes to our understanding of shared genetic susceptibility for such disorders. Here, we review current knowledge of microdeletion/duplication syndromes, with a particular focus on recurrent rearrangement syndromes. PMID- 24773322 TI - Prime-boost bacillus Calmette-Guerin vaccination with lentivirus-vectored and DNA based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice. AB - To prevent the global spread of tuberculosis (TB), more effective vaccines and vaccination strategies are urgently needed. As a result of the success of bacillus Calmette-Guerin (BCG) in protecting children against miliary and meningeal TB, the majority of individuals will have been vaccinated with BCG; hence, boosting BCG-primed immunity will probably be a key component of future vaccine strategies. In this study, we compared the ability of DNA-, protein- and lentiviral vector-based vaccines that express the antigens Ag85B and Rv3425 to boost the effects of BCG in the context of immunity and protection against Mycobacterium tuberculosis in C57BL/6 mice. Our results demonstrated that prime boost BCG vaccination with a lentiviral vector expressing the antigens Ag85B and Rv3425 significantly enhanced immune responses, including T helper type 1 and CD8(+) cytotoxic T lymphocyte responses, compared with DNA- and protein-based vaccines. However, lentivirus-vectored and DNA-based vaccines greatly improved the protective efficacy of BCG against M. tuberculosis, as indicated by a lack of weight loss and significantly reduced bacterial loads and histological damage in the lung. Our study suggests that the use of lentiviral or DNA vaccines containing the antigens Ag85B and Rv3425 to boost BCG is a good choice for the rational design of an efficient vaccination strategy against TB. PMID- 24773323 TI - Near infrared laser-induced targeted cancer therapy using thermoresponsive polymer encapsulated gold nanorods. AB - External stimuli, such as ultrasound, magnetic field, and light, can be applied to activate in vivo tumor targeting. Herein, we fabricated polymer encapsulated gold nanorods to couple the photothermal properties of gold nanorods and the thermo- and pH-responsive properties of polymers in a single nanocomposite. The activation mechamism was thus transformed from heat to near-infrared (NIR) laser, which can be more easily controlled. Doxorubicin, a clinical anticancer drug, can be loaded into the nanocomposite through electrostatic interactions with high loading content up to 24%. The nanocomposite's accumulation in tumor post systematic administration can be significantly enhanced by NIR laser irradiation, providing a prerequisite for their therapeutic application which almost completely inhibited tumor growth and lung metastasis. Since laser can be manipulated very precisely and flexibly, the nanocomposite provides an ideally versatile platform to simultaneously deliver heat and anticancer drugs in a laser activation mechanism with facile control of the area, time, and dosage. The NIR laser-induced targeted cancer thermo-chemotherapy without using targeting ligands represents a novel targeted anticancer strategy with facile control and practical efficacy. PMID- 24773324 TI - Extracorporeal membrane oxygenation: experience in acute graft failure after heart transplantation. AB - INTRODUCTION: Acute graft failure is the leading cause of early mortality after heart transplantation (HTx). Extracorporeal membrane oxygenation (ECMO) is an efficient therapeutic option to treat various pathologies, unburden the left and right ventricle, and allow for functional recovery of the transplanted heart. We reviewed our ECMO experience and outcomes in HTx patients. METHODS: Retrospectively, we analyzed all patients who received an orthotopic HTx (n = 298) in our department over a 15-yr period (1997 through 2011) to assess the incidence of post-HTx ECMO implantation, perioperative complications, early and one-yr mortality as well as causes of death. RESULTS: ECMO therapy was utilized to treat graft failure in 28 patients (10.6%) with a mean duration of ECMO support of 4.2 d (six h to 9.4 d). Multivariate analysis revealed as independent predictors for mortality low cardiac output (p = 0.028; odds ratio (OR) = 11.3) and stroke (p = 0.008; OR = 19.7). Cumulative survival rates were 46.4 +/- 9.4% within 30 d and 25.0 +/- 8.2% at one yr. Causes of death were multiorgan failure (n = 9), sepsis (n = 9), lung failure (n = 2), and intracerebral bleeding (n = 2). ECMO was implanted due to primary graft failure (PGF, n = 16), sepsis (n = 4), and right heart failure (n = 6). CONCLUSION: Temporary ECMO support for postoperative output failure is an acceptable option as a last resort for otherwise doomed patients with fatal graft failure after HTx. The small fraction of patients surviving appear to have a decent long-term prognosis. PMID- 24773320 TI - Age-related macular degeneration: genetics and biology coming together. AB - Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40-60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment. PMID- 24773325 TI - Water-gel for gating graphene transistors. AB - Water, the primary electrolyte in biology, attracts significant interest as an electrolyte-type dielectric material for transistors compatible with biological systems. Unfortunately, the fluidic nature and low ionic conductivity of water prevents its practical usage in such applications. Here, we describe the development of a solid state, megahertz-operating, water-based gate dielectric system for operating graphene transistors. The new electrolyte systems were prepared by dissolving metal-substituted DNA polyelectrolytes into water. The addition of these biocompatible polyelectrolytes induced hydrogelation to provide solid-state integrity to the system. They also enhanced the ionic conductivities of the electrolytes, which in turn led to the quick formation of an electric double layer at the graphene/electrolyte interface that is beneficial for modulating currents in graphene transistors at high frequencies. At the optimized conditions, the Na-DNA water-gel-gated flexible transistors and inverters were operated at frequencies above 1 MHz and 100 kHz, respectively. PMID- 24773326 TI - A pilot study to examine the effect of the Tulip oropharyngeal airway on ventilation immediately after mask ventilation following the induction of anaesthesia. AB - The Tulip airway is an adult, disposable, single-sized oropharyngeal airway, that is connectable to an anaesthetic circuit. After a standardised induction of anaesthesia in 75 patients, the ease of insertion, intracuff pressure and intracuff volume were measured, as were the end-tidal carbon dioxide levels, airway pressures and tidal volumes over three breaths. Successful first-time insertion was achieved in 72 patients (96%, CI 88.8-99.2%) and after two attempts in 74 patients (99%, CI 92.8-100%). There was outright failure only in one patient. In 60 patients (80%, CI 72.2-90.4%), the Tulip airway provided a patent airway without additional manoeuvres, but in 14 patients, jaw thrust or head extension was necessary for airway patency. The main need for these adjuncts appeared to be an initial under-inflation of the cuff. These promising results are consistent with recent manikin studies using this device. PMID- 24773327 TI - Documentation of the 5 as for smoking cessation by PCPs across distinct health systems. AB - OBJECTIVES: Physicians can help patients quit smoking using the 5 As of smoking cessation. This study aimed to (1) identify the proportion of known smokers that receive smoking cessation services in the course of routine clinical practice; (2) describe demographic and comorbidity characteristics of patients receiving the 5 As in these systems; and (3) evaluate differences in performance of the 5 As across health systems, gender, and age categories. STUDY DESIGN: Electronic medical records of 200 current smokers from 6 unique health systems (N = 1200) were randomly selected from 2006 to 2010. Primary care encounter progress notes were hand coded for occurrences of the 5 As. METHODS: Bivariate comparisons of delivery of the 3 smoking-cessation services by site, gender, and age category were analyzed using chi2 tests. RESULTS: About 50% of smokers were advised to quit smoking, 39% were assessed for their readiness to quit, and 54% received some type of assistance to help them quit smoking. Only 2% had a documented plan for follow-up regarding their quitting efforts (arrange). Significant differences were found among sites for documentation of receiving the 5 As and between age groups receiving assistance with quitting. There was no statistically significant difference between genders in receipt of the 5 As. CONCLUSIONS: Documentation of adherence to the 5 As varied by site and some demographics. Adjustments to protocols for addressing cessation and readiness to quit may be warranted. Health systems could apply the methodology described in this paper to assess their own performance, and then use that as a basis to guide improvement initiatives. PMID- 24773328 TI - Medical homes and cost and utilization among high-risk patients. AB - OBJECTIVES: Evaluate the effects of the patient-centered medical home (PCMH) model on medical costs and utilization in the nonpediatric population, particularly among high-risk patients. STUDY DESIGN: Longitudinal case-control design, comparing per member per month (PMPM) cost and utilization per 1000 patients for members enrolled in PCMH and non-PCMH practices from 2009 to 2011. METHODS: Commercial health maintenance organization members in nonpediatric practices that adopted the PCMH model in 2009 were matched to patients in nonpediatric practices that did not adopt the model until 2011 or later. Propensity score matching was used to identify a pool of similar controls, and difference-in-differences regression analysis was used to compare PCMH and non PCMH patients relative to baseline. Analysis was conducted using the complete pool of matched patients (N = 6940 cases and 6940 controls), then using the 10% of patients with the highest DxCG risk scores (N = 654 cases and 734 controls). RESULTS: There were no significant cost or utilization differences for the overall population. Total cost decreased significantly more for the PCMH group than for controls in the high-risk group in years 1 and 2 (reductions of $107 and $75 PMPM), driven by lower inpatient costs. The PCMH group experienced a significantly greater reduction in inpatient admissions in all 3 years (61, 48, and 94 hospitalizations per 1000). CONCLUSIONS: PCMH practices had significantly reduced costs and utilization for the highest risk patients, particularly with respect to inpatient care. As high-risk members represent a high-cost group, the most benefit can be gained by targeting these members. PMID- 24773329 TI - Collaborative DTM reduces hospitalization and healthcare costs in patients with diabetes treated with polypharmacy. AB - OBJECTIVES: To evaluate the effects of a collaborative pharmacy benefits manager (PBM)/ health plan-administered drug therapy management (DTM) program on healthcare utilization and costs in patients with diabetes treated with polypharmacy. STUDY DESIGN: Retrospective quasi-experimental design with comparison group. METHODS: This DTM program was a collaborative effort between the PBM, PerformRx, and the care management departments of Keystone First (KF) and AmeriHealth Caritas Pennsylvania (ACP) care management departments, targeting patients with diabetes using >15 medications. Pharmacists reviewed member profiles and made evidencebased prescriber and patient interventions, working directly with prescribers and indirectly with members, via care managers. Care managers provided additional services not otherwise within the scope of DTM. The study group consisted of 954 DTM participants reviewed by a pharmacist between November 1, 2010, and July 31, 2011. The control group consisted of 810 matched DTM participants not reviewed by a pharmacist. RESULTS: Intervention acceptance rates for KF and ACP were 33% and 26%, respectively. The study group demonstrated lower inpatient admissions and emergency department utilization rates, although only the KF study group inpatient admission rate achieved statistical significance (76.4%; P = .0002). The study groups realized statistically significant total cost savings (pharmacy + medical) compared with their corresponding control groups (47.8% KF, P = .0039; 50.7% ACP, P = .0497) despite non-statistically significant increases in pharmacy costs. CONCLUSIONS: A collaborative pharmacist-driven DTM program with a care manager-executed patient outreach component results in reduced hospital utilization and significant healthcare cost savings. PMID- 24773331 TI - Taming wild yeast: potential of conventional and nonconventional yeasts in industrial fermentations. AB - Yeasts are the main driving force behind several industrial food fermentation processes, including the production of beer, wine, sake, bread, and chocolate. Historically, these processes developed from uncontrolled, spontaneous fermentation reactions that rely on a complex mixture of microbes present in the environment. Because such spontaneous processes are generally inconsistent and inefficient and often lead to the formation of off-flavors, most of today's industrial production utilizes defined starter cultures, often consisting of a specific domesticated strain of Saccharomyces cerevisiae, S. bayanus, or S. pastorianus. Although this practice greatly improved process consistency, efficiency, and overall quality, it also limited the sensorial complexity of the end product. In this review, we discuss how Saccharomyces yeasts were domesticated to become the main workhorse of food fermentations, and we investigate the potential and selection of nonconventional yeasts that are often found in spontaneous fermentations, such as Brettanomyces, Hanseniaspora, and Pichia spp. PMID- 24773330 TI - Assessing the chiral switch: approval and use of single-enantiomer drugs, 2001 to 2011. AB - OBJECTIVES: A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid. STUDY DESIGN: Retrospective analysis. METHODS: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period. RESULTS: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs. CONCLUSIONS: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared. PMID- 24773333 TI - Cooperative N-heterocyclic carbene/Bronsted acid catalysis for the tail-to-tail (co)dimerization of methacrylonitrile. AB - The first tail-to-tail dimerization of methacrylonitrile (MAN) has been realized by the cooperative use of N-heterocyclic carbene (NHC) and Bronsted acid catalysts, producing 2,5-dimethylhex-2-enedinitrile with the E/Z ratio of 24:76. Although the NHC alone was not effective for the catalysis, the addition of alcohols resulted in the significant increase of the dimer yield up to 82% in the presence of 5 mol % NHC. Detailed experimental studies including the ESI-MS analysis of the intermediates, stoichiometric (co)dimerizations, and deuterium labeling experiments revealed the mechanistic aspects of the proton transfer, isomerization, umpolung, and rate-limiting steps, allowing us to observe several mechanistic differences between the dimerization of MAN and that of methyl methacrylate. The stoichiometric reactions in the presence and absence of an alcohol suggest that the alcohol additives play a role in promoting the intermolecular proton transfers from the deoxy-Breslow intermediate to the regenerated NHC in the second half of the catalytic cycle. In addition, the codimerizations of MAN with n-butyl methacrylate (n-BuMA) have been studied. While the dimerization of n-BuMA was sluggish in the presence of an alcohol, the catalytic activity for the codimerization was enhanced by the cooperative systems. PMID- 24773332 TI - R848, a Toll-like receptors 7 and 8 agonist, a potential therapy for allergic rhinitis patients. AB - BACKGROUND/PURPOSE(S): There is a growing interest in the targeting of Toll-like receptors (TLRs) for the treatment of allergic diseases. TLRs7/8 ligands are future candidates of therapeutic value in allergic rhinitis (AR). This study focus on TLRs7/8 ligand; resiquimod (R848) as an adjuvant to immunotherapy (IT) in AR patient. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from atopic donors and non atopic donors. PBMCs were cultured in the absence and presence of date palm pollen allergen (Phoenix dactylifera; Pho d) and/or R848. Interleukin-4 (IL-4), IL-10, IL-13 and interferon gamma (IFN-gamma) were measured in the culture supernatants. RESULTS: R848 was able to significantly increase the anti-inflammatory response in atopic donors more than non atopic donors. Nevertheless, the combination of both; R848 and Pho d provides inferior stimulus as compared to R848 alone in both atopic and non atopic donors. CONCLUSION: Invitro treatment of PBMCs with R484 hijacks the pro inflammatory immune process triggered by TLRs7/8 to mediate anti-inflammatory response. This may provide a conception about the activity and efficacy of TLRs7/8 ligands in AR and open the gate for them to be applied in clinically in humans. PMID- 24773334 TI - Effect of bovine colostrum, cheese whey, and spray-dried porcine plasma on the in vitro growth of probiotic bacteria and Escherichia coli. AB - The aim of this study is to evaluate the effects of defatted colostrum (Col), defatted decaseinated colostrum whey, cheese whey, and spray-dried porcine plasma (SDPP) as supplements of a growth medium (de Man - Rogosa - Sharpe (MRS) broth) on the multiplication of lactic acid bacteria, probiotic bacteria, and potentially pathogenic Escherichia coli. Using automated spectrophotometry (in vitro system), we evaluated the effect of the 4 supplements on maximum growth rate (MU(max)), lag time (LagT), and biomass (OD(max)) of 12 lactic acid bacteria and probiotic bacteria and of an E. coli culture. Enrichment of MRS broth with a Col concentration of 10 g/L increased the MU(max) of 5 of the 12 strains by up to 55%. Negative effects of Col or SDPP on growth rates were also observed with 3 probiotic strains; in one instance MU(max) was reduced by 40%. The most effective inhibitor of E. coli growth was SDPP, and this effect was not linked to its lysozyme content. The positive effect of enrichment with the dairy-based ingredient might be linked to enrichment in sugars and increased buffering power of the medium. These in vitro data suggest that both Col and SDPP could be considered as supplements to animal feeds to improve intestinal health because of their potential to promote growth of probiotic bacteria and to inhibit growth of pathogenic bacteria such as E. coli. PMID- 24773335 TI - Conversation and Object Manipulation Influence Children's Learning in a Museum. AB - The effects of parent-child conversation and object manipulation on children's learning, transfer of knowledge, and memory were examined in two museum exhibits and conversations recorded at home. Seventy-eight children (Mage = 4.9) and their parents were randomly assigned to receive conversation cards featuring elaborative questions about exhibit objects, the physical objects themselves, both, or neither, before their exhibit visits. Dyads who received the cards engaged in more elaborative talk and joint nonverbal activities with objects in the first exhibit than those who did not. Dyads who received objects engaged in the most parent-child joint talk. Results also illustrate transfer of information across exhibits and from museum to home. Implications for understanding mechanisms of informal learning and transfer are discussed. PMID- 24773336 TI - Helicobacter pylori gastritis in HIV-infected patients: a review. AB - BACKGROUND: The risk factors for acquiring Helicobacter pylori and Human Immunodeficiency Virus (HIV) infections are different: H. pylori is transmitted by gastro- or fecal-oral routes and is associated with low socioeconomic conditions, while HIV is transmitted through sexual intercourse, infected body fluids, and transplacentally. If the host responses to these infections were independent, the prevalence of H. pylori should be similar in HIV-infected and non-infected patients. Yet, several studies have detected a lower prevalence of H. pylori in patients with HIV infection, whereas other studies found either no differences or greater rates of H. pylori infection in HIV-positive subjects. OBJECTIVE: To review studies that addressed the issue of these two simultaneous infections and attempt to determine whether reliable conclusions can be drawn from this corpus of often contrasting evidence. METHODS: Electronic literature search for relevant publications, followed by manual search of additional citations from extracted articles. RESULTS: The initial search yielded 44 publications; after excluding case reports, reviews, narrowly focused articles, and duplicate reports, there remained 29 articles, which are the corpus of this review. With one exception, all studies reported higher rates of H. pylori infection in HIV-negative subjects. Five studies also examined the CD4 lymphocyte counts and found an inverse correlation between the degree of immunosuppression and the prevalence of active H. pylori infection. CONCLUSIONS: Current evidence suggests that it is likely that H. pylori needs a functional immune system to successfully and persistently colonize the human gastric mucosa. PMID- 24773338 TI - Facile synthesis of highly active PdAu nanowire networks as self-supported electrocatalyst for ethanol electrooxidation. AB - In recent years, direct ethanol fuel cells (DEFCs) are attracting increasing attention owing to their wide applications. However, a significant challenge in the development of DEFC technology is the urgent need for highly active anode catalysts for the ethanol oxidation reaction. In this work, a facile and reproducible method for the high-yield synthesis of PdAu nanowire networks is demonstrated. The whole synthetic process is very simple, just mixing Na2PdCl4, HAuCl4, and KBr in an aqueous solution and using polyvinylpyrrolidone as a protective reagent while sodium borohydride as a reductant. The whole synthetic process can be simply performed at room temperature and completed in 30 min, which can greatly simplify the synthetic process and lower the preparation cost. Electrochemical catalytic measurement results prove that the as-prepared catalysts exhibit dramatically enhanced electrocatalytic activity for ethanol electrooxidation in alkaline solution. The facile synthetic process and excellent catalytic performance of the as-prepared catalysts demonstrate that they can be used as a promising catalyst for DEFCs. PMID- 24773337 TI - A prenatal prediction model for total nucleated cell count increases the efficacy of umbilical cord blood banking. AB - BACKGROUND: The most important factor for the selection of an umbilical cord blood unit (CBU) for hematopoietic stem cell transplantation is the total nucleated cell (TNC) count as a surrogate marker for stem cell content in the CBU. At present, about one in five donors can provide a CBU with a sufficient TNC count for umbilical cord blood (UCB) banking. It is labor-intensive to obtain consent of all eligible donors and optimization of the selection is needed. The purpose of this study was to investigate prenatal clinical predictors for TNC count that would help to identify successful UCB donors already on admission to the delivery unit. STUDY DESIGN AND METHODS: This study was a retrospective analysis of 758 cryopreserved CBUs, collected from 2002 to 2006. Maternal and fetal factors analyzed were maternal age, gravidity, parity, weight, height, diabetes, premature rupture of membranes, gestational age, fetal sex, and birthweight. The impact on a high TNC count (<150 * 10(7) vs. >= 150 * 10(7)) of the CBU was modeled in a multivariate analysis model. RESULTS: Fetal birthweight was the strongest predictor (p < 0.001) of TNC count of at least 150 * 10(7). With a composite score of parity, gestational week, maternal weight and height, fetal sex, and birthweight, a nomogram was developed that increased banking rates from 22.7% to 31.9% while decreasing the number of banked CBUs from 149 to 79. CONCLUSIONS: Our prenatal prediction model increases the efficacy of obtaining informed consent for UCB banking while still allowing relevant numbers of CBUs to be banked. PMID- 24773340 TI - Maternal obesity and IL-6 lead to aberrant developmental gene expression and deregulated neurite growth in the fetal arcuate nucleus. AB - Maternal obesity during pregnancy increases the risk of obesity in the offspring. Several observations have pointed to a causative role for the proinflammatory cytokine IL-6, but whether it is present in the fetal circulation and how it acts on the developing fetus are unclear. We first observed that postnatal day 0 offspring from obese mothers had significantly reduced neuropeptide Y (NPY) innervation of the paraventricular nucleus (PVN) compared with that for offspring of normal-weight controls. Thus, the growth of NPY neurites from the arcuate nucleus (ARC) was impaired in the fetal brain by maternal obesity. The neurite growth regulator, Netrin-1, was expressed in the ARC and PVN and along the pathway between the two at gestational day (GD) 17.5 in normal animals, making it likely to be involved in the development of NPY ARC-PVN projections. In addition, the expression of Dcc and Unc5d, receptors for Netrin-1, were altered in the GD17.5 ARC in obese but not normal weight pregnancies. Thus, this important developmental pathway is perturbed by maternal obesity and may explain the defect in NPY innervation of the PVN that occurs in fetuses developing in obese mothers. To investigate whether IL-6 may play a role in these developmental changes, we found first that IL-6 was significantly elevated in the fetal and maternal circulation in pregnancies of obese mice compared with those of normal-weight mice. In addition, treatment of GD17.5 ARC tissue with IL-6 in vitro significantly reduced ARC neurite outgrowth and altered developmental gene expression similar to maternal obesity in vivo. These findings demonstrate that maternal obesity may alter the way in which fetal ARC NPY neurons respond to key developmental signals that regulate normal prenatal neural connectivity and suggest a causative role for elevated IL-6 in these changes. PMID- 24773339 TI - Sugarcane genome sequencing by methylation filtration provides tools for genomic research in the genus Saccharum. AB - Many economically important crops have large and complex genomes that hamper their sequencing by standard methods such as whole genome shotgun (WGS). Large tracts of methylated repeats occur in plant genomes that are interspersed by hypomethylated gene-rich regions. Gene-enrichment strategies based on methylation profiles offer an alternative to sequencing repetitive genomes. Here, we have applied methyl filtration with McrBC endonuclease digestion to enrich for euchromatic regions in the sugarcane genome. To verify the efficiency of methylation filtration and the assembly quality of sequences submitted to gene enrichment strategy, we have compared assemblies using methyl-filtered (MF) and unfiltered (UF) libraries. The use of methy filtration allowed a better assembly by filtering out 35% of the sugarcane genome and by producing 1.5* more scaffolds and 1.7* more assembled Mb in length compared with unfiltered dataset. The coverage of sorghum coding sequences (CDS) by MF scaffolds was at least 36% higher than by the use of UF scaffolds. Using MF technology, we increased by 134* the coverage of gene regions of the monoploid sugarcane genome. The MF reads assembled into scaffolds that covered all genes of the sugarcane bacterial artificial chromosomes (BACs), 97.2% of sugarcane expressed sequence tags (ESTs), 92.7% of sugarcane RNA-seq reads and 98.4% of sorghum protein sequences. Analysis of MF scaffolds from encoded enzymes of the sucrose/starch pathway discovered 291 single-nucleotide polymorphisms (SNPs) in the wild sugarcane species, S. spontaneum and S. officinarum. A large number of microRNA genes was also identified in the MF scaffolds. The information achieved by the MF dataset provides a valuable tool for genomic research in the genus Saccharum and for improvement of sugarcane as a biofuel crop. PMID- 24773341 TI - A polymorphism in the Crhr1 gene determines stress vulnerability in male mice. AB - Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse CRH receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported genes * environment interactions of early trauma and CRHR1 in humans. We identified 2 main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, because Crhr1 mRNA expression and CRHR1 binding were enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single-nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating gene * stress exposure interactions. Our data support that the described gene * stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1-mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity. PMID- 24773342 TI - Central Sirt1 regulates body weight and energy expenditure along with the POMC derived peptide alpha-MSH and the processing enzyme CPE production in diet induced obese male rats. AB - In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of Sirt1 in the brain, particularly the hypothalamus, in body weight and energy balance regulation is debated. Among the first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague Dawley rats. In that study, central inhibition of Sirt1 decreased body weight and food intake as a result of a Forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin (POMC) and decrease in the orexigenic Agouti-related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which, in turn, increased phosphorylated FoxO1 via improved insulin/pAKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the alpha-MSH maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product alpha-MSH released into the paraventricular nucleus. Increased in alpha-MSH led to augmented TRH levels and circulating T3 levels (thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics. PMID- 24773344 TI - The Niemann-Pick C1 like 1 (NPC1L1) inhibitor ezetimibe improves metabolic disease via decreased liver X receptor (LXR) activity in liver of obese male mice. AB - Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-A(y) mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic beta oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome. PMID- 24773345 TI - Preparation, in vitro screening and molecular modelling of monoquaternary compounds related to the selective acetylcholinesterase inhibitor BW284c51. AB - This paper describes preparation and in vitro evaluation of 19 compounds related to the selective experimental cholinesterase inhibitor BW284c51. The novel compounds were prepared as fragments of parent molecule BW284c51 and evaluated on the model of human recombinant acetylcholinesterase and human plasmatic butyrylcholinesterase. The IC50 values of the prepared compounds were compared to the parent molecule BW284c51. None of the compounds was superior to the parent drug, but two BW284c51 fragments showed promising hAChE inhibition in uM scale and improved selectivity. These two fragments were further subjected to the molecular modelling study and their enzyme interactions were rationalized. The structure-activity relationship of the prepared series was stated. PMID- 24773343 TI - Inducible neuronal inactivation of Sim1 in adult mice causes hyperphagic obesity. AB - Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance. We previously showed that Sim1 heterozygous mice had normal numbers of PVN neurons that were hyporesponsive to melanocortin 4 receptor agonism and showed reduced oxytocin expression. Furthermore, conditional postnatal neuronal inactivation of Sim1 also caused hyperphagic obesity and decreased hypothalamic oxytocin expression. PVN projections to the hindbrain, where oxytocin is thought to act to modulate satiety, were anatomically intact in both Sim1 heterozygous and conditional knockout mice. These experiments provided evidence that Sim1 functions in energy balance apart from its role in hypothalamic development but did not rule out effects of Sim1 deficiency on postnatal hypothalamic maturation. To address this possibility, we used a tamoxifen-inducible, neural-specific Cre transgene to conditionally inactivate Sim1 in adult mice with mature hypothalamic circuitry. Induced Sim1 inactivation caused increased food and water intake and decreased expression of PVN neuropeptides, especially oxytocin and vasopressin, with no change in energy expenditure. Sim1 expression was not required for survival of PVN neurons. The results corroborate previous evidence that Sim1 acts physiologically as well as developmentally to regulate body weight. Inducible knockout mice provide a system for studying Sim1's physiologic function in energy balance and identifying its relevant transcriptional targets in the hypothalamus. PMID- 24773346 TI - Virtual screening for cholesterol absorption inhibitors. AB - BACKGROUND: Cholesterol, derived from two different sources of endogenous synthesis and diet, is essential for the growth and maintenance of mammalian cells. However, elevated level of serum cholesterol is among the associated risk factors for the coronary heart disease. Statins can reduce endogenous sterol synthesis by inhibiting HMG-CoA reductase, whereas cholesterol absorption inhibitors, such as ezetimibe, can block cholesterol uptake from dietary sources by blocking Niemann- Pick C1-like 1 (NPC1L1). OBJECTIVE: The present review focuses on the main research progress of cholesterol absorption inhibitors, the structure of NPC1L1 and discovery of novel chemical entities by virtual screening. CONCLUSION: Studies on the structure-activity relationship reveal that azetidinone is important to maintain activity in azetidinone derivatives and the novel heterocyclic compounds with replacement of beta-lactam scaffold by oxazolidinone also show similar activity as ezetimibe. Moreover, virtual screening is a computer-aided molecular design tool to propose novel cholesterol absorption inhibitors. PMID- 24773347 TI - Synthesis and biological activity of anthrapyrazoles derivatives as potential antitumor agents. AB - We have synthesized a series of anthrapyrazoles derivatives. The biological results indicated that these derivatives exhibited potent in vitro cytotoxicity against different cancer cell lines (human hepatocellular carcinoma HepG2 and BEL 7402, human colonic carcinoma HCT-116 and HT-29) and drug-resistant human hepatoma cell line (SMMC-7721). Among them, the polyamine-based anthrapyrazole derivatives 4c and 4f-g showed superior cytotoxicity than that of Mitoxantrone both on cancer cell lines and the drug-resistant subline. However, the DNA relaxation assay revealed that they had insignificant topoisomerase II inhibition. These results clearly indicate that polyamine side chains will have a profound effect on the cytotoxicity of anthrapyrazoles derivatives. PMID- 24773348 TI - Synthesis and first evaluation of [18F]fluorocyano- and [18F]fluoronitro quinoxalinedione as putative AMPA receptor antagonists. AB - Derivatives of quinoxalinedione (QX) were chosen as chemical lead for the development of new radioligands of the AMPA receptor, since there are several examples of QX-derivatives with high affinity. The radiosyntheses of the new compounds 6-[(18)F]fluoro-7-nitro-QX([(18)F]FNQX) and 7-[(18)F]fluoro-6-cyano-QX ([(18)F]FCQX) with radiochemical yields of 8+/-2 and 3+/- 2%, respectively, as well as the evaluation of their binding properties to the AMPA-receptor were performed. A comparison of the Ki-values of the new QX-derivatives FCQX and FNQX with mono-substituted cyanoand nitro-QX shows negligibly small differences of affinity (within the range of 1.4 to 5 uM), but exhibits a tenfold lower affinity than derivatives with two electron withdrawing groups like the 7-cyano-6-nitro compound CNQX and the 6,7- dinitro compound DNQX. Thus, with respect to the low affinity and a high non-specific binding with in vitro and ex vivo autoradiographic studies, the new compounds do not lend themselves for in vivo imaging. PMID- 24773349 TI - Synthesis, anticonvulsant and antimicrobial activities of some new [1-(2 naphthyl)-2-(pyrazol-1-yl)ethanone]oxime ethers. AB - In this study, 12 new oxime ether derivatives, which were expected to show anticonvulsant and antimicrobial activities, were synthesized. Oxime ether derivatives were synthesized by the reaction of various alkyl halides with 1-(2- naphthyl)-2-(pyrazol-1-yl)ethanone oxime. Anticonvulsant activity of the compounds was determined by maximal electroshock (MES) and subcutaneous metrazol (ScM) seizure tests, while neurological disorders were evaluated using rotorod toxicity test according to the ASP of NIH. Compound 1, 6 and 7 showed anticonvulsant activity at 300 mg/kg dose at 4 h, but compounds 1 and 7 showed toxicity at 300 mg/kg dose at half an hour. Antimicrobial activities of the compounds were also determined using agar microdilution method. Compound 1 and 5 were found to have the highest antifungal activity among the other compounds. PMID- 24773350 TI - Development of thieno[3',2':5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as the estrogen receptor ligands: synthesis, characterization and biological activity. AB - Estrogen receptors (ERs) are members of a superfamily of ligand-modulated nuclear receptors, which have been associated with an increased risk of cardiovascular diseases and breast cancer. Based on molecular docking studies, 1,4 dihydrothieno[3',2':5,6]thiopyrano[4,3-c]pyrazole-3-carboxamide derivatives as estrogen receptor inhibitors with a new scaffold , have been synthesized and tested for the antitumor activity on the ER expressing (ER dependent) human MCF-7 breast cancer cell line. According to the biological activity evaluation, compound 6a demonstrated the most potent antiproliferative activity (relative inhibitory rate: 100%). Several of these compounds exhibited moderate antitumor activity and worthy of further modification to obtain more potent anticancer candidate drugs. PMID- 24773351 TI - Electronic-topological and neural network approaches to the structure- antimycobacterial activity relationships study on hydrazones derivatives. AB - That the implementation of Electronic-Topological Method and a variant of Feed Forward Neural Network (FFNN) called as the Associative Neural Network are applied to the compounds of Hydrazones derivatives have been employed in order to construct model which can be used in the prediction of antituberculosis activity. The supervised learning has been performed using (ASNN) and categorized correctly 84.4% of them, namely, 38 out of 45. Ph1 pharmacophore and Ph2 pharmacophore consisting of 6 and 7 atoms, respectively were found. Anti-pharmacophore features socalled "break of activity" have also been revealed, which means that APh1 is found in 22 inactive molecules. Statistical analyses have been carried out by using the descriptors, such as EHOMO, ELUMO, DeltaE, hardness, softness, chemical potential, electrophilicity index, exact polarizibility, total of electronic and zero point energies, dipole moment as independent variables in order to account for the dependent variable called inhibition efficiency. Observing several complexities, namely, linearity, nonlinearity and multi-co linearity at the same time leads data to be modeled using two different techniques called multiple regression and Artificial Neural Networks (ANNs) after computing correlations among descriptors in order to compute QSAR. Computations resulting in determining some compounds with relatively high values of inhibition are presented. PMID- 24773353 TI - Diels-Alder reaction of tropones with arynes: synthesis of functionalized benzobicyclo[3.2.2]nonatrienones. AB - A new procedure for the mild, practical, and scalable Diels-Alder reaction of tropones with arynes is reported. Differently substituted tropones undergo selective [4 + 2] cycloaddition with arynes generated in situ by the fluoride induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates, allowing the formation of functionalized benzobicyclo[3.2.2]nonatrienone derivatives in moderate to good yields. In addition, the photophysical properties of the cycloadducts are presented. PMID- 24773352 TI - Treatment with qibaomeiran, a kidney-invigorating Chinese herbal formula, antagonizes estrogen decline in ovariectomized rats. AB - Traditional Chinese medicines (TCM) contain multi-interactive compounds that have been used for treatment of peri-menopausal syndrome and have become a new phytoestrogens resource. The QiBaoMeiRan formula (QBMR), including Polygoni multiflori radix, Angelicae sinensis radix, Achyranthis bidentatae radix, semen Cuscutae, fructus Lycii, Poria, and fructus Psoraleae, has been used clinically for treating osteoporosis in post-menopausal women by virtue of its kidney invigorating function. However, no evidence base links QBMR to estrogen replacement therapy. In this study, we undertook a characterization of estrogenic activity of QBMR using ovariectomized (OVX) rats. OVX rats were treated with QBMR at doses of 0.875, 1.75, and 3.5 grams/kg per day for 8 weeks. QBMR treatments demonstrated significant estrogenic activity, as indicated by vaginal cornification, reversal of atrophy of uterus, vagina, and mammary gland, and up regulation of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) expression in the reproductive target tissues, where ERbeta up regulation was stronger than that of ERalpha. Meanwhile, treatment with QBMR significantly increased adrenal weight and serum estradiol levels and tended to decrease serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in a dose-dependent manner. Moreover, QBMR significantly decreased weight gain and rectal temperature increase caused by ovariectomy, and the largest changes in rectal temperature were found at the lowest dose. The data suggest that QBMR's estrogenic responses show tissue variation that reflects different affinities of ERs for QBMR components. This study demonstrates that QBMR activity is mediated through estrogenic components and provides an evidence base for QBMR treatment of post-menopausal symptoms. PMID- 24773354 TI - Outlier removal, sum scores, and the inflation of the Type I error rate in independent samples t tests: the power of alternatives and recommendations. AB - In psychology, outliers are often excluded before running an independent samples t test, and data are often nonnormal because of the use of sum scores based on tests and questionnaires. This article concerns the handling of outliers in the context of independent samples t tests applied to nonnormal sum scores. After reviewing common practice, we present results of simulations of artificial and actual psychological data, which show that the removal of outliers based on commonly used Z value thresholds severely increases the Type I error rate. We found Type I error rates of above 20% after removing outliers with a threshold value of Z = 2 in a short and difficult test. Inflations of Type I error rates are particularly severe when researchers are given the freedom to alter threshold values of Z after having seen the effects thereof on outcomes. We recommend the use of nonparametric Mann-Whitney-Wilcoxon tests or robust Yuen-Welch tests without removing outliers. These alternatives to independent samples t tests are found to have nominal Type I error rates with a minimal loss of power when no outliers are present in the data and to have nominal Type I error rates and good power when outliers are present. PMID- 24773355 TI - Measurement and control of response styles using anchoring vignettes: a model based approach. AB - Response styles are frequently of concern when rating scales are used in psychological survey instruments. While latent trait models provide an attractive way of controlling for response style effects (Morren, Gelissen, & Vermunt, 2011), the analyses are generally limited to accommodating only a small number of response style types. The use of anchoring vignettes provides an opportunity to overcome this limitation. In this article, a new latent trait model is introduced that uses vignette responses to measure and control for any form of response style. An illustration is provided with data from a cross-national study of self reported conscientiousness by Mottus, Allik, Realo, Pullman, et al. (2012). PMID- 24773356 TI - Small sample adjustments for robust variance estimation with meta-regression. AB - Although primary studies often report multiple outcomes, the covariances between these outcomes are rarely reported. This leads to difficulties when combining studies in a meta-analysis. This problem was recently addressed with the introduction of robust variance estimation. This new method enables the estimation of meta-regression models with dependent effect sizes, even when the dependence structure is unknown. Although robust variance estimation has been shown to perform well when the number of studies in the meta-analysis is large, previous simulation studies suggest that the associated tests often have Type I error rates that are much larger than nominal. In this article, I introduce 6 estimators with better small sample properties and study the effectiveness of these estimators via 2 simulation studies. The results of these simulations suggest that the best estimator involves correcting both the residuals and degrees of freedom used in the robust variance estimator. These studies also suggest that the degrees of freedom depend on not only the number of studies but also the type of covariates in the meta-regression. The fact that the degrees of freedom can be small, even when the number of studies is large, suggests that these small-sample corrections should be used more generally. I conclude with an example comparing the results of a meta-regression with robust variance estimation with the results from the corrected estimator. PMID- 24773357 TI - Measurement-comparable effect sizes for single-case studies of free-operant behavior. AB - Single-case research comprises a set of designs and methods for evaluating the effects of interventions, practices, or programs on individual cases, through comparison of outcomes measured at different points in time. Although there has long been interest in meta-analytic techniques for synthesizing single-case research, there has been little scrutiny of whether proposed effect sizes remain on a directly comparable metric when outcomes are measured using different operational procedures. Much of single-case research focuses on behavioral outcomes in free-operant contexts, which may be measured using a variety of different direct observation procedures. This article describes a suite of effect sizes for quantifying changes in free-operant behavior, motivated by an alternating renewal process model that allows measurement comparability to be established in precise terms. These effect size metrics have the advantage of comporting with how direct observation data are actually collected and summarized. Effect size estimators are proposed that are applicable when the behavior being measured remains stable within a given treatment condition. The methods are illustrated by 2 examples, including a re-analysis of a systematic review of the effects of choice-making opportunities on problem behavior. PMID- 24773358 TI - Treatment noncompliance in randomized experiments: statistical approaches and design issues. AB - Treatment noncompliance in randomized experiments threatens the validity of causal inference and the interpretability of treatment effects. This article provides a nontechnical review of 7 approaches: 3 traditional and 4 newer statistical analysis strategies. Traditional approaches include (a) intention-to treat analysis (which estimates the effects of treatment assignment irrespective of treatment received), (b) as-treated analysis (which reassigns participants to groups reflecting the treatment they actually received), and (c) per-protocol analysis (which drops participants who did not comply with their assigned treatment). Newer approaches include (d) the complier average causal effect (which estimates the effect of treatment on the subpopulation of those who would comply with their assigned treatment), (e) dose-response estimation (which uses degree of compliance to stratify participants, producing an estimate of a dose response relationship), (f) propensity score analysis (which uses covariates to estimate the probability that individual participants will comply, enabling estimates of treatment effects at different propensities), and (g) treatment effect bounding (which calculates a range of possible treatment effects applicable to both compliers and noncompliers). The discussion considers the areas of application, the quantity estimated, the underlying assumptions, and the strengths and weaknesses of each approach. PMID- 24773359 TI - An affirmation of the phenomenological psychological descriptive method: a response to Rennie (2012). AB - Rennie (2012) made the claim that, despite their diversity, all qualitative methods are essentially hermeneutical, and he attempted to back up that claim by demonstrating that certain core steps that he called hermeneutical are contained in all of the other methods despite their self-interpretation. In this article, I demonstrate that the method I developed based upon Husserlian phenomenology cannot be so interpreted despite Rennie's effort to do so. I claim that the undertaking of a psychological investigation at large can be considered interpretive but that when the phenomenological method based upon Husserl is employed, it is descriptive. I also object to the attempt to reduce varied theoretical perspectives to the methodical steps of one of the competing theories. Reducing theoretical perspectives to core steps distorts the full value of the theoretical perspective. The last point is demonstrated by showing how the essence of the descriptive phenomenological method is missed if one follows Rennie's core steps. PMID- 24773360 TI - The choice of product indicators in latent variable interaction models: post hoc analyses. AB - The unconstrained product indicator (PI) approach is a simple and popular approach for modeling nonlinear effects among latent variables. This approach leaves the practitioner to choose the PIs to be included in the model, introducing arbitrariness into the modeling. In contrast to previous Monte Carlo studies, we evaluated the PI approach by 3 post hoc analyses applied to a real world case adopted from a research effort in social psychology. The measurement design applied 3 and 4 indicators for the 2 latent 1st-order variables, leaving the researcher with a choice among more than 4,000 possible PI configurations. Sixty so-called matched-pair configurations that have been recommended in previous literature are of special interest. In the 1st post hoc analysis we estimated the interaction effect for all PI configurations, keeping the real world sample fixed. The estimated interaction effect was substantially affected by the choice of PIs, also across matched-pair configurations. Subsequently, a post hoc Monte Carlo study was conducted, with varying sample sizes and data distributions. Convergence, bias, Type I error and power of the interaction test were investigated for each matched-pair configuration and the all-pairs configuration. Variation in estimates across matched-pair configurations for a typical sample was substantial. The choice of specific configuration significantly affected convergence and the interaction test's outcome. The all pairs configuration performed overall better than the matched-pair configurations. A further advantage of the all-pairs over the matched-pairs approach is its unambiguity. The final study evaluates the all-pairs configuration for small sample sizes and compares it to the non-PI approach of latent moderated structural equations. PMID- 24773361 TI - Meta-analysis of the accuracy of tools used for binary classification when the primary studies employ different references. AB - The quality of tools used in binary classification is evaluated by studies that assess the accuracy of the classification. The empirical evidence is summarized in 2 * 2 contingency tables. These provide the joint frequencies between the true status of a sample and the classification made by the test. The accuracy of the test is better estimated in a meta-analysis that synthesizes the results of a set of primary studies. The true status is determined by a reference that ideally is a gold standard, which means that it is error free. However, in psychology, it is rare that all the primary studies have employed the same reference, and often they have used an imperfect reference with suboptimal accuracy instead of an actual gold standard. An imperfect reference biases both the estimates of the accuracy of the test and the empirical prevalence of the target status in the primary studies. We discuss several strategies for meta-analysis when different references are employed. Special attention is paid to the simplest case, where the meta-analyst has 1 group of primary studies using a reference that can be considered a gold standard and a 2nd group of primary studies using an imperfect reference. A procedure is recommended in which the frequencies from the primary studies with the imperfect reference are corrected prior to the meta-analysis itself. Then, a hierarchical meta-analytic model is fitted. An example with actual data from SCOFF (Sick-Control-One-Fat-Food; Hill, Reid, Morgan, & Lacey, 2010; Morgan, Reid, & Lacey, 1999) a simple but efficient test for detecting eating disorders, is described. PMID- 24773362 TI - Lethal and sublethal effects of essential oils from Eucalyptus camaldulensis and Heracleum persicum against the adults of Callosobruchus maculatus. AB - The cowpea weevil, Callosobruchus maculatus F. (Coleoptera: Bruchidae), is an important pest of stored cowpea, Vigna ungiculata (L.) Walpers (Fabales: Fabaceae), with ample distribution in tropical and subtropical regions. Many plant essential oils have a broad-spectrum activity against pest insects, and these oils traditionally have been used in the protection of stored products. In this study, the lethal and sublethal effects of essential oils from Eucalyptus camaldulensis Dehnh. (Myrtales: Myrtaceae) and Heracleum persicum Desf. (Apiales: Apiaceae) were evaluated on the adults of C. maculatus at 26 +/- 1 degrees C, 70 +/- 5% RH, and a photoperiod of 16:8 L:D. The LC50 values of E. camaldulensis and H. persicum were 56.7 and 219.4 uL/L air after 12 hr and 26.1 and 136.4 uL/L air after 24 hr of exposure, respectively. The LT50 values of E. camaldulensis and H.persicum were 6.3 and 10.9 hr, respectively. The results showed that low lethal concentration (LC20) of essential oils negatively affected the longevity, fecundity, and fertility of female adults. The sex ratio of C. maculatus offspring was not significantly affected by essential oils. Therefore, these essential oils can be suggested for controlling C. maculatus in storage systems. The introduction of essential oils into storage systems could potentially decrease seed losses. PMID- 24773363 TI - Ligand control of donor-acceptor excited-state lifetimes. AB - Transient absorption and emission spectroscopic studies on a series of diimineplatinum(II) dichalcogenolenes, LPtL', reveal charge-separated dichalcogenolene -> diimine charge-transfer (LL'CT) excited-state lifetimes that display a remarkable and nonperiodic dependence on the heteroatoms of the dichalcogenolene ligand. Namely, there is no linear relationship between the observed lifetimes and the principle quantum number of the E donors. The results are explained in terms of heteroatom-dependent singlet-triplet (S-T) energy gaps and anisotropic covalency contributions to the M-E (E = O, S, Se) bonding scheme that control rates of intersystem crossing. For the dioxolene complex, 1-O,O', E(T2) > E(S1) and rapid nonradiative decay occurs from S1 to S0. However, E(T2) <= E(S1) for the heavy-atom congeners, and this provides a mechanism for rapid intersystem crossing. Subsequent internal conversion to T1 in 3-S,S produces a long-lived, emissive triplet. The two LPtL' complexes with mixed chalcogen donors and 5-Se,Se show lifetimes intermediate between those of 1-O,O' and 3-S,S. PMID- 24773365 TI - Effect of Tamarindus indica L. leaves' fluid extract on human blood cells. AB - Tamarind leaves are edible; however, their saponin content could be toxic to human blood cells. In this article, the effect of tamarind leaf fluid extract (TFE) on human blood cells was evaluated by using several tests. Results revealed that TFE did not cause significant haemolysis on human red blood cells even at the lowest evaluated concentration (20 mg/mL). Blood protein denaturalisation ratio was consistently lower than in control at TFE concentrations greater than 40 mg/mL. Erythrocyte membrane damage caused by the action of oxidative H2O2 displayed a steady reduction with increasing TFE concentrations. In the reactive oxygen species (ROS) measurement by using flow cytometry assay, leucocyte viability was over 95% at tested concentrations, and a high ROS inhibition was also recorded. Protective behaviour found in TFE should be attributed to its polyphenol content. Thus, tamarind leaves can be regarded as a potential source of interesting phytochemicals. PMID- 24773364 TI - Calcium/calmodulin-dependent protein kinase II regulates cyclooxygenase-2 expression and prostaglandin E2 production by activating cAMP-response element binding protein in rat peritoneal macrophages. AB - Prostaglandin E2 (PGE2 ) is an important inducer of inflammation, which is also closely linked to the progress of tumours. In macrophages, PGE2 production is regulated by arachidonic acid release and cyclooxygenase-2 (COX-2) expression. In the present study, we found that COX-2 expression can be achieved by activating Ca(2+) /Calmodulin (CaM)-dependent protein kinase II (CaMKII) and cAMP-response element-binding protein (CREB) in rat peritoneal macrophages. Our results indicated that lipopolysaccharide and PMA could elicit the transient increase of the concentration of intracellular free calcium ions ([Ca(2+) ]i ), which induced activation of CaMKs with the presence of CaM. The subtype of CaMKs, CaMKII, then triggered the activation of CREB, which elevated COX-2 expression and PGE2 production in a chronological order. These results suggested that Ca(2+) /CaM dependent CaMKII plays an important role in mediating COX-2 expression and PGE2 production by activating CREB in macrophages. The study also provides more useful information to clarify the mechanism of calcium regulation of PGE2 production, which plays an essential role in inflammation and cancers. PMID- 24773366 TI - A review of echocardiography in anaesthetic and peri-operative practice. Part 1: impact and utility. AB - Echocardiography is migrating rapidly across speciality boundaries and clinical demand is expanding. Echocardiography shows promise for evolving applications in the peri-operative assessment and therapeutic management of patients undergoing non-cardiac surgery, whether it be elective or emergency. Although evidence is limited with regard to significant impact on outcomes from anaesthesia and surgery, there is little doubt about the validity and power of two-dimensional real-time viewing of cardiac anatomy and function. Echocardiography can be used to assist in decision-making along the entire peri-operative pathway, and is increasingly delivered by the previously referring physicians. The discussion around more widespread incorporation of cardiac ultrasound into anaesthetic practice must take into account competency, training and governance. Failure to do so adequately may mean that the use of echocardiography is poorly applied and costly. PMID- 24773367 TI - SERS-encoded nanogapped plasmonic nanoparticles: growth of metallic nanoshell by templating redox-active polymer brushes. AB - We report a new strategy to synthesize core-shell metal nanoparticles with an interior, Raman tag-encoded nanogap by taking advantage of nanoparticle-templated self-assembly of amphiphilic block copolymers and localized metal precursor reduction by redox-active polymer brushes. Of particular interest for surface enhanced Raman scattering (SERS) is that the nanogap size can be tailored flexibly, with the sub-2 nm nanogap leading to the highest SERS enhancement. Our results have further demonstrated that surface functionalization of the nanogapped Au nanoparticles with aptamer targeting ligands allows for specific recognition and ultrasensitive detection of cancer cells. The general applicability of this new synthetic strategy, coupled with recent advances in controlled wet-chemical synthesis of functional nanocrystals, opens new avenues to multifunctional core-shell nanoparticles with integrated optical, electronic, and magnetic properties. PMID- 24773368 TI - Silicon nanowire degradation and stabilization during lithium cycling by SEI layer formation. AB - Silicon anodes are of great interest for advanced lithium-ion battery applications due to their order of magnitude higher energy capacity than graphite. Below a critical diameter, silicon nanowires enable the ~300% volume expansion during lithiation without pulverization. However, their high surface-to volume ratio is believed to contribute to fading of their capacity retention during cycling due to solid-electrolyte-interphase (SEI) growth on surfaces. To better understand this issue, previous studies have examined the composition and morphology of the SEI layers. Here we report direct measurements of the reduction in silicon nanowire diameter with number of cycles due to SEI formation. The results reveal significantly greater Si loss near the nanowire base. From the change in silicon volume we can accurately predict the measured specific capacity reduction for silicon nanowire half cells. The enhanced Si loss near the nanowire/metal current collector interface suggests new strategies for stabilizing nanowires for long cycle life performance. PMID- 24773369 TI - Optimal sampling of antipsychotic medicines: a pharmacometric approach for clinical practice. AB - AIM: To determine optimal sampling strategies to allow the calculation of clinical pharmacokinetic parameters for selected antipsychotic medicines using a pharmacometric approach. METHODS: This study utilized previous population pharmacokinetic parameters of the antipsychotic medicines aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone (including 9-OH risperidone) and ziprasidone. d-optimality was utilized to identify time points which accurately predicted the pharmacokinetic parameters (and expected error) of each drug at steady-state. A standard two stage population approach (STS) with MAP-Bayesian estimation was used to compare area under the concentration-time curves (AUC) generated from sparse optimal time points and rich extensive data. Monte Carlo Simulation (MCS) was used to simulate 1000 patients with population variability in pharmacokinetic parameters. Forward stepwise regression analysis was used to determine the most predictive time points of the AUC for each drug at steady-state. RESULTS: Three optimal sampling times were identified for each antipsychotic medicine. For aripiprazole, clozapine, olanzapine, perphenazine, risperidone, 9-OH risperidone, quetiapine and ziprasidone the CV% of the apparent clearance using optimal sampling strategies were 19.5, 8.6, 9.5, 13.5, 12.9, 10.0, 16.0 and 10.7, respectively. Using the MCS and linear regression approach to predict AUC, the recommended sampling windows were 16.5-17.5 h, 10-11 h, 23-24 h, 19-20 h, 16.5-17.5 h, 22.5-23.5 h, 5-6 h and 5.5-6.5 h, respectively. CONCLUSION: This analysis provides important sampling information for future population pharmacokinetic studies and clinical studies investigating the pharmacokinetics of antipsychotic medicines. PMID- 24773370 TI - Acute exercise ameliorates differences in insulin resistance between physically active and sedentary overweight adults. AB - Although regular exercise is associated with reduced cardiometabolic disease risk among overweight adults, it remains unclear whether much of the health benefits of exercise are derived from the most recent session(s) of exercise or if they are the result of adaptations stemming from weeks, months, or even years of training. The purpose of this study was to compare the effects of habitual and acute exercise on key markers of cardiometabolic disease risk in overweight adults. We compared insulin sensitivity index (ISI) using an oral glucose tolerance test, blood pressure (BP), blood lipids, and systemic inflammatory cytokines in 12 overweight to mildly obese adults (BMI: 27-34 kg/m(2)) who exercise regularly (EX; >2.5 h exercise per week) with a well-matched cohort of 12 nonexercisers (Non-EX). Baseline measurements in EX were performed exactly 3 days after exercise, whereas Non-EX remained sedentary. We repeated these measurements the day after a session of exercise in both groups. At baseline, ISI was significantly greater in EX versus Non-EX (3.1 +/- 0.2 vs. 2.3 +/- 0.2; p = 0.02), but BP, blood lipids, and plasma concentration of the systemic inflammatory cytokines we measured were not different between groups. Acute exercise increased ISI the next morning in Non-EX (2.3 +/- 0.2 vs. 2.8 +/- 0.3; p = 0.03) but not EX. As a result, ISI was similar between groups the morning after exercise. In summary, exercising regularly was accompanied by a persistent improvement in insulin sensitivity that lasted at least 3 days after exercise in overweight adults, but just one session of exercise increased insulin sensitivity among sedentary overweight adults to levels equivalent to the regular exercisers. PMID- 24773371 TI - Reinforcement of hiatal defect repair with absorbable mesh fixed with non permanent devices. AB - AIM: To report the results of an open label prospective study on a new technique for laparoscopic hiatal hernia (HH) repair with absorbable mesh fixed with absorbable materials Methods: From January 2011 to May 2013, 43 patients were treated; group A, 20 patients submitted to laparoscopic sleeve gastrectomy (LSG); group B, 13 patients submitted to revisional surgery for the diagnosis of HH and symptomatic GERD post-LSG; and group C, ten patients submitted to 360 degrees fundoplication. All patients underwent cruroplasty reinforced with bio-absorbable mesh fixed with absorbable tacks and/or fibrin glue. Conversion rate, intra operative complications, operative time (tacks vs tacks plus fibrin glue), perioperative complications, perioperative symptoms and radiological control set the criteria for clinical/surgical evaluation. RESULTS: Conversion and mortality rate was 0%. The mean time for mesh fixation with the tacks vs tacks plus fibrin glue was 6.2 +/- 2 vs 7.3 +/- 3 min. The remission of GERD symptoms was observed in 39 patients, and we did not observe any cases of mesh-related complications at a mean follow-up of 17.4 months. Recurrence rate was 2.3% (one asymptomatic patient of group B). CONCLUSIONS: Reinforcement with absorbable mesh-cancel bio mesh is a safe and effective option for laparoscopic HH repair in normal weight and obese patients. PMID- 24773372 TI - Lateral retroperitoneal transpsoas approach to the lumbar spine for the treatment of spondylodiscitis. AB - Spondylodiscitis is an infection of the intervertebral disc and adjacent vertebrae. With the advent of minimally invasive spinal surgery, less invasive approaches have been considered for the treatment of discitis. To date, however, there have been no reported cases of a minimally invasive lateral retroperitoneal transpsoas approach for the treatment of spondylodiscitis. The authors report a case of medically refractory discitis in a patient with multiple comorbidities who underwent a successful limited debridement via a lateral transpsoas corridor. This case describes a minimally invasive approach used to treat a patient with lumbar discitis/osteomyelitis who was otherwise a suboptimal surgical candidate. PMID- 24773373 TI - Validation of a novel basic virtual reality simulator, the LAP-X, for training basic laparoscopic skills. AB - BACKGROUND: Virtual reality surgical simulators are becoming popular as a means of providing trainees with an opportunity to practice laparoscopic skills. The Lap-X (Epona Medical, Rotterdam, the Netherlands) is a novel VR simulator for training basic skills in laparoscopic surgery. The objective of this study was to validate the LAP-X laparoscopic virtual reality simulator by assessing the face and construct validity in order to determine whether the simulator is adequate for basic skills training. MATERIAL AND METHODS: The face and content validity were evaluated using a structured questionnaire. To assess the construct validity, the participants, nine expert surgeons (median age: 40 (32-45)) (>100 laparoscopic procedures) and 11 novices performed three basic laparoscopic tasks using the Lap-X. RESULTS: The participants reported a high level of content validity. No significant differences were found between the expert surgeons and the novices (Ps > 0.246). The performance of the expert surgeons on the three tasks was significantly better than that of the novices in all parameters (Ps < 0.05). CONCLUSIONS: This study demonstrated the face, content and construct validity of the Lap-X. The Lap-X holds real potential as a home and hospital training device. PMID- 24773374 TI - Practical perspectives on the management of overweight and obesity. AB - The prevalence of obesity, defined as a body mass index of 30 or more, has reached epidemic proportions in the United States. Obesity is associated with an increased risk of multiple conditions, including type 2 diabetes mellitus, cardiovascular disease, arthritis, and sleep apnea. To discuss issues related to obesity in the workplace, healthcare, and managed care settings, stakeholders from these areas participated in a roundtable discussion on several topics, including the management of obesity, managed care coverage policies for obesity treatments, and potential strategies for improving patient outcomes. Participants agreed that obesity is a challenging condition to treat. Lifestyle modification, one of the most commonly recommended treatment modalities, is often inadequate on its own, as patients are unable to maintain weight loss over time. Although lifestyle modification remains important, additional tools are needed. In patients who undergo bariatric surgery, lifestyle modification is also necessary for long-term weight maintenance; however, surgery is not appropriate for all patients. Pharmacologic treatment may also be considered, but cost and managed care coverage policies have the potential to limit patient access to this treatment modality. Increased awareness and additional efforts on the part of all stakeholders are needed to improve outcomes for patients affected by obesity. PMID- 24773375 TI - Modulating particle adhesion with micro-patterned surfaces. AB - We report the first experimental study on the modulation of adhesion force distribution by surface micro-patterns and its impact on particle attachment. The effect of substratum topography on particle adhesion was evaluated using well defined microscopic surface patterns consisting of orthogonal arrays of cuboid pillars or pits with different sizes and spacing fabricated by the conventional photolithography and reactive ion etching (RIE). Adhesion of carboxyl modified poly(styrene-co-acrylic-acid) particles of 6 MUm in diameter under favorable deposition conditions was found to be markedly lower on all the micro-patterned surfaces compared with that on the smooth control surface, and particle adhesion depended on the characteristic dimensions of the surface micro-structures relative to the particle size. Particle adhesion was minimal when the pillar cross-sectional dimension was below a critical value close to the diameter of the particle while the spacing between pillars was less important. Meanwhile, particles adhered displayed unique distribution on the micro-patterned surfaces. The majority of particles preferentially adhered on or close to the edge of the pillars (in the valley). Atomic force microscopy measurements using a colloidal probe revealed that the surface features strongly modulated the spatial and probability distribution of adhesion forces on the micro-patterned surfaces. Micro-sized pillars changed the adhesion force probability distribution from monomodal to bimodal, with significantly reduced maximum adhesion force. This was hypothesized to be responsible for the reduced total particle adhesion. PMID- 24773376 TI - Syntheses and N-methyl-D-aspartate receptor antagonist pharmacology of fluorinated arylcycloheptylamines. AB - Selective uncompetitive antagonists of the phencyclidine (PCP) binding site of the N-methyl-D-aspartate receptor (NMDAR) are known to have therapeutic potential as anticonvulsants and neuroprotective agents. Several fluorinated molecules with each containing a cycloheptane ring were designed to probe the PCP pharmacophore and test the influence of fluorine substitution on NMDAR binding and in vivo efficacy. Syntheses and analyses of six novel compounds, 1-(4- fluorophenyl)cycloheptanamine (3), 1-(1-(4-fluorophenyl)cycloheptyl)piperidine (4), 1-(1-(4-fluorophenyl)cycloheptyl) pyrrolidine (5), 1-(3 fluorophenyl)cycloheptanamine (6), 1-(1-(3-fluorophenyl)cycloheptyl)piperidine (7), 1-(1-(3-fluorophenyl) cycloheptyl)pyrrolidine (8) and several related reference arylcyloalkylamines are described. Receptor binding was performed at the PCP site of NMDAR for each compound using [(3)H]-(+)-MK-801 displacement. Unexpectedly, the 3- fluoro- primary amine 6 had the greatest affinity of the series and these binding results support a different structure activity relationship (SAR) profile for arylcycloheptylamines when compared to arylcyclohexylamines like PCP. Five of the novel compounds have affinity (Ki) in the hundred nM (10(-7)) range. In addition, compounds 3, 5, 6, 7 and 8 were evaluated and found to exhibit neuroprotective effects from NMDA induced toxicity in vitro and compounds 6, 7 and 8 exhibited anticonvulsant activities in rats. An ED50 of 13.84 mg/kg was found for compound 6 in rat maximal electroshock (MES) test with a protective index (PI) of 3.66 against ataxia. These results support further investigation of the arylcycloheptylamine class. PMID- 24773377 TI - Atorvastatin increases endothelial progenitor cells in balloon-injured mouse carotid artery. AB - Here we aimed to investigate the effects of atorvastatin on accelerated reendothelialization after carotid balloon injury. A mouse model of carotid arterial injury was established, followed by intragastric administration of atorvastatin at a dose of 0.6 mg.(kg body mass)(-1).d(-1). Pathological sections of carotid artery stained with hematoxylin and eosin were observed under light microscopy. Expression levels of eNOS mRNA and protein were detected with real time quantitative PCR and Western blot analysis, respectively. Proliferation and differentiation of endothelial progenitor cells (EPCs) were observed after treatment, in vitro. Reendothelialization appeared on the neovascular surface, while intimal hyperplasia was inhibited after treatment with atorvastatin. Numbers of CD31-positive cells increased after atorvastatin treatment, as did the number of leucocyte antigen positive cells. The expression of cell markers, such as CD34, eNOS, and VEGF-R, were higher in the atorvastatin-treated group of mononuclear cells. EPC numbers increased with the concentration of atorvastatin. The expression of eNOS mRNA was reduced in the mice with carotid artery injury that were treated with normal saline. The expression levels of eNOS protein were increased in atorvastatin treatment group. In conclusion, atorvastatin stimulates EPCs to differentiate into endothelial cells and promotes the repair of carotid arterial injury. PMID- 24773378 TI - Soaking RNAi in Bombyx mori BmN4-SID1 cells arrests cell cycle progression. AB - RNA interference (RNAi) is an evolutionarily conserved mechanism for sequence specific gene silencing. Previously, the BmN4-SID1 cell expressing Caenorhabditis ele gans SID-1 was established, in which soaking RNAi could induce effective gene silencing. To establish its utility, 6 cell cycle progression related cDNAs, CDK1, MYC, MYB, RNRS, CDT1, and GEMININ, were isolated from the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae), and their expressions were further silenced by soaking RNAi in the BmN4-SID1 cells. The cell cycle progression analysis using flow cytometer demonstrated that the small amount of double stranded RNA was enough to arrest cell cycle progression at the specific cell phases. These data suggest that RNAi in the BmN4-SID1 cells can be used as a powerful tool for loss of-function analysis of B. mori genes. PMID- 24773379 TI - Investigation of the active sites of rhodium sulfide for hydrogen evolution/oxidation using carbon monoxide as a probe. AB - Carbon monoxide (CO) was observed to decrease the activity for hydrogen evolution, hydrogen oxidation, and H2-D2 exchange on rhodium sulfide, platinum, and rhodium metal. The temperature at which the CO was desorbed from the catalyst surface (detected by recovery in the H2-D2 exchange activity of the catalyst) was used as a descriptor for the CO binding energy to the active site. The differences in the CO desorption temperature between the different catalysts showed that the rhodium sulfide active site is not metallic rhodium. Using density functional theory, the binding energy of CO to the Rh sites in rhodium sulfide is found comparable to the binding energy on Pt. Coupled with experiment this supports the proposition that rhodium rather than sulfur atoms in the rhodium sulfide are the active site for the hydrogen reaction. This would indicate the active sites for hydrogen evolution/oxidation as well as oxygen reduction (determined by other groups using X-ray absorption spectroscopy) may be the same. PMID- 24773380 TI - Heteroaromatic pi-stacking energy landscapes. AB - In this study we investigate pi-stacking interactions of a variety of aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. We find that dispersion contributes significantly to the interaction energy and is complemented by a varying degree of electrostatic interactions. We identify geometric preferences and minimum interaction energies for a set of 13 5- and 6-membered aromatic heterocycles frequently encountered in small drug-like molecules. We demonstrate that the electrostatic properties of these systems are a key determinant for their orientational preferences. The results of this study can be applied in lead optimization for the improvement of stacking interactions, as it provides detailed energy landscapes for a wide range of coplanar heteroaromatic geometries. These energy landscapes can serve as a guide for ring replacement in structure-based drug design. PMID- 24773381 TI - Enteric hyperoxaluria secondary to small bowel resection: use of computer simulation to characterize urinary risk factors for stone formation and assess potential treatment protocols. AB - BACKGROUND AND PURPOSE: We used computer modeling to investigate the influence of physicochemical stone risk factors on urinary supersaturation (SS) of calcium oxalate (CaOx) in patients with severe hyperoxaluria, relative hypocalciuria, hypocitraturia, and CaOx nephrolithiasis after extensive small bowel resection, usually performed for Crohn's disease. We also simulated different treatment strategies, including oral calcium supplements and citrate, in such patients. MATERIALS AND METHODS: A baseline urine model was derived by consolidating data acquired by ourselves with those from another patient cohort. Calcium and oxalate excretions in this model were altered to obtain an extreme case. For comparison, additional models were based on published urine data from normal subjects (N) and idiopathic CaOx stone formers (SF). The Joint Expert Speciation System was used to simulate different urine situations based on reported compositional values. RESULTS: [Ca(2+)][Ox(2-)] ionic concentration products and SS(CaOx) are substantially higher in enteric hyperoxaluric patients than in N and SF, despite their relatively lower calcium excretions. Molar Ca:Ox ratios are substantially lower in enteric hyperoxalurics than in N and SF. Oral calcium supplements can reduce SS(CaOx), but monitoring is required to avoid exceeding a safe dosing threshold. A simple calculation can alert the clinician that this threshold is being approached or even exceeded. Increasing urinary pH and citrate decreases SS(CaOx) but not to the same extent as decreasing Ox excretion. CONCLUSIONS: Calcium supplements can help reduce stone risk in patients with severe enteric hyperoxaluria, but initial efforts should be directed toward reducing urinary oxalate by reducing dietary oxalate. Citrate therapy that increases both urine pH and urinary citrate provides an additional therapeutic benefit. PMID- 24773382 TI - An epidemiologic cohort study reviewing the practice of blood product transfusions among a population of pediatric oncology patients. AB - BACKGROUND: Despite the high utilization of blood products by pediatric oncology patients, literature in this population remains scarce. The primary objective of this study was to assess red blood cell (RBC) and platelet (PLT) utilization rates and transfusion thresholds in pediatric oncology patients. The secondary objective was to describe transfusion-related complications including RBC alloantibody development and transfusion reactions. STUDY DESIGN AND METHODS: This epidemiologic cohort study involved pediatric oncology patients at a Canadian academic children's hospital between April 2002 and December 2011. Demographic, clinical, laboratory, and transfusion variables were collected from the Transfusion Registry for Utilization Statistics and Tracking database, a large database that captures more than 50 demographic and clinical variables as well as comprehensive transfusion information and laboratory test results. RESULTS: Of 647 pediatric oncology patients, 430 (66%) received a RBC or PLT transfusion or both during this time period. The median transfusion threshold before a RBC and PLT transfusion was a hemoglobin (Hb) value of 72 g/L (interquartile range [IQR], 68-76 g/L) and a PLT count of 16 * 10(9) /L (IQR, 10 * 10(9) -23 * 10(9) /L), respectively. Ninety-two percent of the issued RBC and PLT products (7507/8154) were cytomegalovirus negative and 90% were irradiated (7299/8154). RBC alloantibody development and transfusion reactions were reported infrequently in 0.5% (2/423) and 4.5% (8/179) of the patients, respectively. CONCLUSION: This study assessed utilization rates, transfusion thresholds, alloantibody development, and transfusion reactions in pediatric oncology patients. The descriptive results from this epidemiologic study provide baseline information to generate hypotheses to be tested in future interventional studies. PMID- 24773383 TI - The effect of chain bending on the photophysical properties of conjugated polymers. AB - The impact of chain bending on the photophysical properties of emissive conjugated polymers (CPs) is studied theoretically using Holstein-style Hamiltonians which treat vibronic coupling involving the ubiquitous vinyl/ring stretching mode nonadiabatically. The photophysical impact of chain bending is already evident at the level of an effective Frenkel Hamiltonian, where the positive exciton band curvature in CPs translates to negative excitonic coupling between monomeric units, as in J-aggregates. It is shown that the absorption and photoluminescence (PL) spectral line shapes respond very differently to chain bending. The misalignment of monomeric transition dipole moments with bending selectively attenuates the 0-0 PL peak intensity while leaving the 0-1 intensity practically unchanged, a property which is ultimately due to the uniquely coherent nature of the 0-0 peak. Hence, the 0-0/0-1 PL ratio, as well as the radiative decay rate, decrease with chain bending, effects that are more pronounced at lower temperatures where exciton coherence extends over a larger portion of the chain. Increasing temperature and/or static disorder reduces the exciton coherence number, Ncoh, thereby reducing the sensitivity to bending. In marked contrast, the absorption vibronic progression is far less sensitive to morphological changes, even at low temperatures, and is mainly responsive to the exciton bandwidth. The above results also hold when using a more accurate 1D semiconductor Hamiltonian which allows for electron-hole separation along the CP chain. The findings may suggest unique ways of controlling the radiative properties of conjugated polymer chains useful in applications such as organic light emitting diodes (OLEDs) and low-temperature sensors. PMID- 24773384 TI - The evolving definition of neuromodulation. PMID- 24773385 TI - Neurotech report. PMID- 24773387 TI - Small molecules that interact with RNA: riboswitch-based gene control and its involvement in metabolic regulation in plants and algae. AB - Riboswitches are RNA elements that bind small molecules and in turn regulate gene expression. This mechanism allows the cell to sense the intracellular concentration of these small molecules. A particular riboswitch typically regulates its adjacent gene by altering the transcription, the translation or the splicing of this gene. Recently, a riboswitch that binds thiamin pyrophosphate (TPP) was characterized and found to regulate thiamin biosynthesis in plants and algae. Furthermore, it appears that this element is an essential regulator of primary metabolism in plants. Manipulation of endogenous riboswitch activity resulted in metabolic phenotypes that underlined the role of these elements and their ligands in preserving metabolic homeostasis. This situation supports the hypothesis that riboswitches could be remnants of the most ancient metabolic regulators. Here, we review the mode of action of the plant and algal TPP riboswitch and its relevance to the metabolic network. We also discuss the potential engineering of riboswitches as metabolite sensors in plants and platforms for gene control. Whether additional such RNA-based mechanisms exist in plants and in algae is still an open question, yet, the importance of these elements to metabolic regulation is beyond doubt. PMID- 24773388 TI - Do children who experience regret make better decisions? A developmental study of the behavioral consequences of regret. AB - Although regret is assumed to facilitate good decision making, there is little research directly addressing this assumption. Four experiments (N = 326) examined the relation between children's ability to experience regret and the quality of their subsequent decision making. In Experiment 1 regret and adaptive decision making showed the same developmental profile, with both first appearing at about 7 years. In Experiments 2a and 2b, children aged 6-7 who experienced regret decided adaptively more often than children who did not experience regret, and this held even when controlling for age and verbal ability. Experiment 3 ruled out a memory-based interpretation of these findings. These findings suggest that the experience of regret facilitates children's ability to learn rapidly from bad outcomes. PMID- 24773390 TI - A tetranitrosyl [4Fe-4S] cluster forms en route to Roussin's black anion: nitric oxide reactivity of [Fe4S4(LS3)L'](2-). AB - Previous studies provide evidence that [4Fe-4S] clusters serve as targets of reactive nitrogen oxide species in biology. The products of this reaction range from dinitrosyliron complexes, [Fe(NO)2L2](-), to Roussin's black anion, [Fe4S3(NO)7](-). To date, the pathways by which these reactions occur have not been fully elucidated. In this study, we prepared the site-differentiated complexes [Fe4S4(LS3)L'](2-) (LS3 = 1,3,5-tris(4,6-dimethyl-3-mercaptophenylthio) 2,4,6-tris(p-tolylthio)benzene; L' = Cl, SEt, SPh, N3, 2-SPyr, Tp, S2CNEt2) to serve as synthetic models for biological [4Fe-4S] clusters and studied their reactivity toward NO(g) and Ph3CSNO. The products were characterized by X-ray crystallography, mass spectrometry, and IR, electron paramagnetic resonance (EPR), and (1)H NMR spectroscopy. In all cases reported here, the reactions proceed via formation of the S = (1)/2 species [Fe4S4(NO)4](-), which ultimately converts to EPR-silent [Fe4S3(NO)7](-). PMID- 24773389 TI - Fc receptor is not required for inducing antibodies but plays a critical role in conferring protection after influenza M2 vaccination. AB - The ectodomain of matrix protein 2 (M2e) of influenza virus is considered a rational target for a universal influenza A vaccine. To better understand M2e immune-mediated protection, Fc receptor common gamma chain deficient (FcRgamma(-/ ) ) and wild-type mice were immunized with a tandem repeat of M2e presented on virus-like particles (M2e5x VLP). Levels of M2e-specific antibodies that were induced in FcRgamma(-/-) mice after immunization with M2e5x VLP were similar to those in wild-type mice. In addition, M2e antibodies induced in FcRgamma(-/-) mice were found to be equally protective as those induced in wild-type mice. However, M2e5x VLP-immunized FcRgamma(-/-) mice were not well protected, as shown by severe weight loss, higher lung viral titres and interleukin-6 inflammatory cytokine production upon influenza virus challenge compared with M2e5x VLP immunized wild-type mice. Importantly, FcRgamma(-/-) mice that were immunized with inactivated influenza virus induced haemagglutination inhibition activity and were well protected without a significant weight loss. Interestingly, interferon-gamma-producing CD4 T and CD8 T cells were found to be prevalent in lungs from M2e5x VLP-immunized FcRgamma(-/-) mice, which appeared to be correlated with a faster recovery after infection. These results indicate that Fc receptors play a primary role in conferring M2e-specific antibody-mediated protection whereas T cells may contribute to the recovery at later stages of infection. PMID- 24773391 TI - Synthesis of enantiopure 10-nornaltrexones in the search for Toll-like receptor 4 antagonists and opioid ligands. AB - 10-Nornaltrexones (3-(cyclopropylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H benzofuro[3,2-e]isoquinolin-7(7aH)-one, 1) have been underexploited in the search for better opioid ligands, and their enantiomers have been unexplored. The synthesis of trans-isoquinolinone 2 (4-aH, 9-O-trans-9-methoxy-3-methyl 2,3,4,4a,5,6-hexahydro-1H-benzofuro[3,2-e]isoquinolin-7(7aH)-one) was achieved through a nonchromatographic optimized synthesis of the intermediate pyridinyl compound 12. Optical resolution was carried out on 2, and each of the enantiomers were used in efficient syntheses of the "unnatural" 4aR,7aS,12bR-(+)-1) and its "natural" enantiomer (-)-1. Addition of a 14-hydroxy (the 4a-hydroxy) group in the enantiomeric isoquinolinones, (+)- and (-)-2), gave (+)- and (-)-10 nornaltrexones. A structurally unique tetracyclic enamine, (12bR)-7,9-dimethoxy-3 methyl-1,2,3,7-tetrahydro-7,12b-methanobenzo[2,3]oxocino[5,4-c]pyridine, was found as a byproduct in the syntheses and offers a different opioid-like skeleton for future study. PMID- 24773392 TI - The role of reactive oxygen species and oxidative stress in carbon monoxide toxicity: an in-depth analysis. AB - The underlying mechanism of the central nervous system (CNS) injury after acute carbon monoxide (CO) poisoning is interlaced with multiple factors including apoptosis, abnormal inflammatory responses, hypoxia, and ischemia/reperfusion like problems. One of the current hypotheses with regard to the molecular mechanism of CO poisoning is the oxidative injury induced by reactive oxygen species, free radicals, and neuronal nitric oxide. Up to now, the relevant mechanism of this injury remains poorly understood. The weakening of antioxidant systems and the increase of lipid peroxidation in the CNS have been implicated, however. Accordingly, in this review, we will highlight the relationship between oxidative stress and CO poisoning from the perspective of forensic toxicology and molecular toxicology. PMID- 24773393 TI - High-intensity interval exercise induces 24-h energy expenditure similar to traditional endurance exercise despite reduced time commitment. AB - Subjects performed high-intensity interval training (HIIT) and continuous moderate-intensity training (END) to evaluate 24-h oxygen consumption. Oxygen consumption during HIIT was lower versus END; however, total oxygen consumption over 24 h was similar. These data demonstrate that HIIT and END induce similar 24 h energy expenditure, which may explain the comparable changes in body composition reported despite lower total training volume and time commitment. PMID- 24773394 TI - Exploring the interactome: microfluidic isolation of proteins and interacting partners for quantitative analysis by electron microscopy. AB - Multimolecular protein complexes are important for many cellular processes. However, the stochastic nature of the cellular interactome makes the experimental detection of complex protein assemblies difficult and quantitative analysis at the single molecule level essential. Here, we present a fast and simple microfluidic method for (i) the quantitative isolation of endogenous levels of untagged protein complexes from minute volumes of cell lysates under close to physiological conditions and (ii) the labeling of specific components constituting these complexes. The method presented uses specific antibodies that are conjugated via a photocleavable linker to magnetic beads that are trapped in microcapillaries to immobilize the target proteins. Proteins are released by photocleavage, eluted, and subsequently analyzed by quantitative transmission electron microscopy at the single molecule level. Additionally, before photocleavage, immunogold can be employed to label proteins that interact with the primary target protein. Thus, the presented method provides a new way to study the interactome and, in combination with single molecule transmission electron microscopy, to structurally characterize the large, dynamic, heterogeneous multimolecular protein complexes formed. PMID- 24773395 TI - A randomised crossover comparison of mouth-to-face-shield ventilation and mouth to-pocket-mask ventilation by surf lifeguards in a manikin. AB - Thirty surf lifeguards (mean (SD) age: 25.1 (4.8) years; 21 male, 9 female) were randomly assigned to perform 2 * 3 min of cardiopulmonary resuscitation on a manikin using mouth-to-face-shield ventilation (AMBU LifeKey) and mouth-to-pocket mask ventilation (Laerdal Pocket Mask). Interruptions in chest compressions, effective ventilation (visible chest rise) ratio, tidal volume and inspiratory time were recorded. Interruptions in chest compressions per cycle were increased with mouth-to-face-shield ventilation (mean (SD) 8.6 (1.7) s) compared with mouth to-pocket-mask ventilation (6.9 (1.2) s, p < 0.0001). The proportion of effective ventilations was less using mouth-to-face-shield ventilation (199/242 (82%)) compared with mouth-to-pocket-mask ventilation (239/240 (100%), p = 0.0002). Tidal volume was lower using mouth-to-face-shield ventilation (mean (SD) 0.36 (0.20) l) compared with mouth-to-pocket-mask ventilation (0.45 (0.20) l, p = 0.006). No differences in inspiratory times were observed between mouth-to-face shield ventilation and mouth-to-pocket-mask ventilation. In conclusion, mouth-to face-shield ventilation increases interruptions in chest compressions, reduces the proportion of effective ventilations and decreases delivered tidal volumes compared with mouth-to-pocket-mask ventilation. PMID- 24773396 TI - Adult-onset Still disease with peculiar persistent plaques and papules. AB - Adult-onset Still disease (AOSD) is a systemic inflammatory disorder characterized clinically by high spiking fever, polyarthralgia/arthritis, a salmon-pink evanescent rash, predominantly neutrophilic leucocytosis, lymphadenopathy, liver dysfunction, and splenomegaly. Recently, a nonclassic, nonevanescent skin rash has been reported. We report a 27-year-old woman with AOSD showing persistent pruritic papular lesions. Histologically, dyskeratotic keratinocytes were seen in the upper epidermis. We describe this case in detail and review the previous literature. Nonclassic pruritic eruptions with characteristic dyskeratotic keratinocytes might provide an important clue for the diagnosis of AOSD. PMID- 24773397 TI - Confinement-driven increase in ionomer thin-film modulus. AB - Ion-conductive polymers, or ionomers, are critical materials for a wide range of electrochemical technologies. For optimizing the complex heterogeneous structures in which they occur, there is a need to elucidate the governing structure property relationships, especially at nanoscale dimensions where interfacial interactions dominate the overall materials response due to confinement effects. It is widely acknowledged that polymer physical behavior can be drastically altered from the bulk when under confinement and the literature is replete with examples thereof. However, there is a deficit in the understanding of ionomers when confined to the nanoscale, although it is apparent from literature that confinement can influence ionomer properties. Herein we show that as one particular ionomer, Nafion, is confined to thin films, there is a drastic increase in the modulus over the bulk value, and we demonstrate that this stiffening can explain previously observed deviations in materials properties such as water transport and uptake upon confinement. Moreover, we provide insight into the underlying confinement-induced stiffening through the application of a simple theoretical framework based on self-consistent micromechanics. This framework can be applied to other polymer systems and assumes that as the polymer is confined the mechanical response becomes dominated by the modulus of individual polymer chains. PMID- 24773398 TI - Improving transitions of care for patients with thromboembolic disease. AB - Patients with or at risk for thromboembolic disease have many transitional interactions within the healthcare system. Transitions of care--when patients move between or within sites of care, or transition from inpatient to outpatient status--create repeated and diverse opportunities for medication errors, rehospitalization, and other adverse events that may increase costs. Although effective antithrombotic therapies are available, these therapies are complex, underprescribed, and frequently suboptimally managed, a situation further exacerbated by poor patient adherence to therapy. Physician and patient education may help address knowledge gaps related to antithrombotic therapy to help ensure that patients receive appropriate therapy and adhere to the therapeutic regimen. Due to the complexities of antithrombotic therapy it is not surprising that when these patients experience transitions of care, the potential for errors and suboptimal outcomes becomes compounded. Efforts are under way to improve the process of transitional care, including the development of protocols for medication reconciliation, improved communication between clinicians at hand-off, the use of electronic medical records, and the introduction of a collaborative approach among different types of healthcare providers, including pharmacists, nurses, and care managers, so that transitional care is provided smoothly and safely. PMID- 24773399 TI - Gender and perceptions of leadership effectiveness: a meta-analysis of contextual moderators. AB - Despite evidence that men are typically perceived as more appropriate and effective than women in leadership positions, a recent debate has emerged in the popular press and academic literature over the potential existence of a female leadership advantage. This meta-analysis addresses this debate by quantitatively summarizing gender differences in perceptions of leadership effectiveness across 99 independent samples from 95 studies. Results show that when all leadership contexts are considered, men and women do not differ in perceived leadership effectiveness. Yet, when other-ratings only are examined, women are rated as significantly more effective than men. In contrast, when self-ratings only are examined, men rate themselves as significantly more effective than women rate themselves. Additionally, this synthesis examines the influence of contextual moderators developed from role congruity theory (Eagly & Karau, 2002). Our findings help to extend role congruity theory by demonstrating how it can be supplemented based on other theories in the literature, as well as how the theory can be applied to both female and male leaders. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24773400 TI - A work-family conflict/subjective well-being process model: a test of competing theories of longitudinal effects. AB - In the present study, we examine competing predictions of stress reaction models and adaptation theories regarding the longitudinal relationship between work family conflict and subjective well-being. Based on data from 432 participants over 3 time points with 2 lags of varying lengths (i.e., 1 month, 6 months), our findings suggest that in the short term, consistent with prior theory and research, work-family conflict is associated with poorer subjective well-being. Counter to traditional work-family predictions but consistent with adaptation theories, after accounting for concurrent levels of work-family conflict as well as past levels of subjective well-being, past exposure to work-family conflict was associated with higher levels of subjective well-being over time. Moreover, evidence was found for reverse causation in that greater subjective well-being at 1 point in time was associated with reduced work-family conflict at a subsequent point in time. Finally, the pattern of results did not vary as a function of using different temporal lags. We discuss the theoretical, research, and practical implications of our findings. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24773401 TI - Self-regulation during job search: the opposing effects of employment self efficacy and job search behavior self-efficacy. AB - Adopting a self-regulatory perspective, the current study examined the within person relationships among job search cognitions, job search behaviors, and job search success (i.e., number of job offers received). Specifically, conceptualizing job search behaviors as guided by a hierarchy of means-end (i.e., job search behavior-employment) goal structure, we differentiated employment self efficacy from job search behavior self-efficacy. Our results showed that higher levels of perceived job search progress could lead to more frequent job search behaviors through enhancing job search behavior self-efficacy. However, higher levels of perceived job search progress could also lead to less frequent job search behaviors through elevating employment self-efficacy. In addition, the relationships between perceived job search progress and efficacy beliefs were moderated by job seekers' level of internal attribution of their progress. Finally, we found that at the within-person level, frequency of job search behaviors was positively related to number of job offers received. These findings were discussed in terms of their theoretical and practical implications. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24773402 TI - Unethical for the sake of the group: risk of social exclusion and pro-group unethical behavior. AB - This research tested the idea that the risk of exclusion from one's group motivates group members to engage in unethical behaviors that secure better outcomes for the group (pro-group unethical behaviors). We theorized that this effect occurs because those at risk of exclusion seek to improve their inclusionary status by engaging in unethical behaviors that benefit the group; we tested this assumption by examining how the effect of exclusion risk on pro-group unethical behavior varies as a function of group members' need for inclusion. A 2 wave field study conducted among a diverse sample of employees working in groups (Study 1) and a constructive replication using a laboratory experiment (Study 2) provided converging evidence for the theory. Study 1 found that perceived risk of exclusion from one's workgroup predicted employees' engagement in pro-group unethical behaviors, but only when employees have a high (not low) need for inclusion. In Study 2, compared to low risk of exclusion from a group, high risk of exclusion led to more pro-group (but not pro-self) unethical behaviors, but only for participants with a high (not low) need for inclusion. We discuss implications for theory and the management of unethical behaviors in organizations. PMID- 24773403 TI - Vocational fit and counterproductive work behaviors: a self-regulation perspective. AB - This article focuses on establishing a link between vocational fit and 1 domain of job performance: counterproductive work behaviors (CWB). The authors offer a model explaining from a self-regulation perspective how the lack of vocational fit generates CWB and test this model in 2 studies and 3 multisource samples. The 1st study offers support for the mediation model linking vocational lack of fit to CWB through frustration. The 2nd study shows across 2 samples, using both self and supervisor ratings of CWB, that vocational fit has incremental validity for the prediction of CWB over established predictors, such as broad and narrow personality traits and affect. PMID- 24773404 TI - Developing leaders' strategic thinking through global work experience: the moderating role of cultural distance. AB - To respond to the challenge of how organizations can develop leaders who can think strategically, we investigate the relation of leaders' global work experiences--that is, those experiences that require the role incumbent to transcend national boundaries--to their competency in strategic thinking. We further examine whether leaders' exposure to a country whose culture is quite distinct from the culture of their own country (i.e., one that is culturally distant) moderates these relationships. Our analyses of 231 upper level leaders reveals that the time they have spent in global work experiences positively relates to their strategic thinking competency, particularly for leaders who have had exposure to a more culturally distant country. We discuss these findings in light of the research on international work experiences and leader development. PMID- 24773405 TI - Pulmonary effects of intravenous atropine induce ventilation perfusion mismatch. AB - Atropine is used for a number of medical conditions, predominantly for its cardiovascular effects. Cholinergic nerves that innervate pulmonary smooth muscle, glands, and vasculature may be affected by anticholinergic medications. We hypothesized that atropine causes alterations in pulmonary gas exchange. We conducted a prospective interventional study with detailed physiologic recordings in anesthetized, spontaneously breathing rats (n = 8). Animals breathing a normoxic gas mixture titrated to a partial arterial pressure of oxygen of 110-120 were exposed to an escalating dose of intravenous atropine (0.001, 0.01, 0.1, 5.0, and 20.0 mg/kg body mass). Arterial blood gas measurements were recorded every 2 min (*5) at baseline, and following each of the 5 doses of atropine. In addition, the animals regional pulmonary blood flow was measured using neutron activated microspheres. Oxygenation decreased immediately following intravenous administration of atropine, despite a small increase in the volume of inspired air with no change in respiratory rate. Arterial blood gas analysis showed an increase in pulmonary dysfunction, characterized by a widening of the alveolar arteriole gradient (p < 0.003 all groups except for the lowest dose of atropine). The microsphere data demonstrates an abrupt and marked heterogeneity of pulmonary blood flow following atropine treatment. In conclusion, atropine was found to decrease pulmonary gas exchange in a dose-dependent fashion in this rat model. PMID- 24773406 TI - Potentiometric-scanning ion conductance microscopy. AB - We detail the operation mechanism and instrumental limitations for potentiometric scanning ion conductance microscopy (P-SICM). P-SICM makes use of a dual-barrel probe, where probe position is controlled by the current measured in one barrel and the potential is measured in a second barrel. Here we determine the interaction of these two barrels and resultant effects in quantitation of signals. Effects due to the size difference in pipet tip opening are examined and compared to model calculations. These results provide a basis for quantitation and image interpretation for P-SICM. PMID- 24773407 TI - Specificity of the receptor for the major sex pheromone component in Heliothis virescens. AB - In a previous study, the Drosophila melanogaster OR67d(GAL4);UAS system was used to functionally characterize the receptor for the major component of the sex pheromone in the tobacco budworm, Heliothis virescens Fabricius (Lepidoptera: Noctuidae), HvOR13. Electrophysiological and behavioral assays showed that transgenic flies expressing HvOR13 responded to (Z)-11-hexadecenal (Z11-16:Ald). However, tests were not performed to determine whether these flies would also respond to secondary components of the H. virescens sex pheromone. Thus, in this study the response spectrum of HvOR13 expressed in this system was examined by performing single cell recordings from odor receptor neuron in trichoid T1 sensilla on antennae of two Or67d(GAL4 [1]); UAS-HvOR13 lines stimulated with Z11 16:Ald and six H. virescens secondary pheromone components. Fly courtship assays were also performed to examine the behavioral response of the Or67d(GAL4[1]); UAS HvOR13 flies to Z11-16:Ald and the secondary component Z9-14:Ald. Our combined electrophysiological and behavioral studies indicated high specificity and sensitivity of HvOR13 to Z11-16:Ald. Interestingly, a mutation leading to truncation in the HvOR13 C-terminal region affected but did not abolish pheromone receptor response to Z11-16:Ald. The findings are assessed in relationship to other HvOR13 heterologous expression studies, and the role of the C-terminal domain in receptor function is discussed. A third line expressing HvOR15 was also tested but did not respond to any of the seven pheromone components. PMID- 24773408 TI - The COMT Val158Met polymorphism regulates the effect of a dopamine antagonist on the feedback-related negativity. AB - Consistent with dopamine accounts of internal and external feedback processing, prior work showed that the dopamine D2 receptor antagonist sulpiride modulates the relationship between the dopaminergic COMT Val158Met polymorphism and the error-related negativity (ERN). Here, we tested in an independent sample whether this Gene * Substance interaction generalizes to the feedback-related negativity (FRN), which presumably shares underlying dopaminergic mechanisms with the ERN. N = 83 female participants genotyped for COMT Val158Met received 200 mg sulpiride versus placebo and performed a virtual ball-catching task. The FRN to positive versus negative feedback was modulated by a significant COMT * Substance interaction. Mirroring prior work on the ERN, the tendency of the FRN to be more pronounced for VAL+ versus MET/MET carriers after placebo was reversed by sulpiride. The findings thus provide new evidence for dopaminergic models of feedback processing. PMID- 24773409 TI - The application of statistical methods to cognate docking: a path forward? AB - Cognate docking has been used as a test for pose prediction quality in docking engines for decades. In this paper, we report a statistically rigorous analysis of cognate docking performance using tools in the OpenEye docking suite. We address a number of critically important aspects of the cognate docking problem that are often handled poorly: data set quality, methods of comparison of the predicted pose to the experimental pose, and data analysis. The focus of the paper lies in the third problem, extracting maximally predictive knowledge from comparison data. To this end, we present a multistage protocol for data analysis that by combining classical null-hypothesis significance testing with effect size estimation provides crucial information about quantitative differences in performance between methods as well as the probability of finding such differences in future experiments. We suggest that developers of software and users of software have different levels of interest in different parts of this protocol, with users being primarily interested in effect size estimation while developers may be most interested in statistical significance. This protocol is completely general and therefore will provide the basis for method comparisons of many different kinds. PMID- 24773411 TI - Lack of efficacy of motor cortex stimulation for the treatment of neuropathic pain in 14 patients. AB - OBJECTIVES: Motor cortex stimulation has been reported as an effective treatment for medically resistant neuropathic pain. The goal of this study is to review the efficacy of this treatment in a series of 14 patients. MATERIALS AND METHODS: The records of a consecutive series of 14 patients undergoing MCS for neuropathic pain at Stanford University Hospital and Clinics between 2002 and 2010 were retrospectively analyzed. The primary outcome measure was a visual analogue scale, which patients completed prior to surgery and following each programming session. The motor cortex was localized using 1) MR image guidance, 2) intraoperative somatosensory evoked potentials and motor response to stimulation, and 3) postoperative imaging. All patients underwent extensive stimulator programming. RESULTS: Five patients exhibited a transient improvement of >50%. Of these, only two patients maintained >50% improvement to their last clinic visit. One of these patients died of unrelated causes, and the other complained of variable response at home. The median time from best to final VAS was 50 days. Average postoperative follow-up was 55.5 weeks. Postoperative imaging demonstrated appropriate lead placement in 12 patients. The other two patients did not undergo postoperative imaging. CONCLUSIONS: In our cohort of 14 patients with neuropathic pain, motor cortex stimulation failed to produce acceptable long term benefit. Possible reasons for this failure are discussed in the context of a small retrospective study. PMID- 24773412 TI - Designed catalysts from Pt nanoparticles supported on macroporous oxides for selective isomerization of n-hexane. AB - Selective isomerization toward branched hydrocarbons is an important catalytic process in oil refining to obtain high-octane gasoline with minimal content of aromatic compounds. Colloidal Pt nanoparticles with controlled sizes of 1.7, 2.7, and 5.5 nm were deposited onto ordered macroporous oxides of SiO2, Al2O3, TiO2, Nb2O5, Ta2O5, and ZrO2 to investigate Pt size- and support-dependent catalytic selectivity in n-hexane isomerization. Among the macroporous oxides, Nb2O5 and Ta2O5 exhibited the highest product selectivity, yielding predominantly branched C6 isomers, including 2- or 3-methylpentane, as desired products of n-hexane isomerization (140 Torr n-hexane and 620 Torr H2 at 360 degrees C). In situ characterizations including X-ray diffraction and ambient-pressure X-ray photoelectron spectroscopy showed that the crystal structures of the oxides in Pt/oxide catalysts were not changed during the reaction and oxidation states of Nb2O5 were maintained under both H2 and O2 conditions. Fourier transform infrared spectra of pyridine adsorbed on the oxides showed that Lewis sites were the dominant acidic site of the oxides. Macroporous Nb2O5 and Ta2O5 were identified to play key roles in the selective isomerization by charge transfer at Pt-oxide interfaces. The selectivity was revealed to be Pt size-dependent, with improved isomer production as Pt sizes increased from 1.7 to 5.5 nm. When 5.5 nm Pt nanoparticles were supported on Nb2O5 or Ta2O5, the selectivity toward branched C6 isomers was further increased, reaching ca. 97% with a minimum content of benzene, due to the combined effects of the Pt size and the strong metal-support interaction. PMID- 24773410 TI - Pharmacotherapy of postpartum depression: an update. AB - INTRODUCTION: Postpartum depression (PPD) is a common and serious illness that affects up to 14% of women in the first month after childbirth. We present an update on the pharmacologic treatment of PPD, although there continues to be a lack of large, randomized controlled trials (RCTs). AREAS COVERED: A review of the literature on the use of antidepressants, hormonal supplements and omega-3 fatty acids for the prevention and the treatment of PPD published since the original review in 2009 and the authors' opinion on the current status of the pharmacological treatment of PPD are covered. An electronic search was performed by using PubMed, Medline and PsychINFO. Inclusion criteria were: i) empirical articles in peer-reviewed English-language journals; ii) well-validated measures of depression; and iii) a uniform scoring system for depression among the sample. EXPERT OPINION: Since the last Expert Opinion review, four antidepressant treatment studies and one prevention study of PPD have been published. Six RCTs evaluating the use of omega-3 fatty acids (four for prevention and two for treatment) have been published. There continues to be lack of data regarding the pharmacotherapy of PPD. However, serotonin reuptake inhibitors should be considered first-line for women with PPD after it has been determined that the proper diagnosis is not bipolar disorder. It is important to individualize treatment for women with PPD and consider the risks and benefits of treatment while breastfeeding. PMID- 24773413 TI - On 'the fear of death' as the primary anxiety: how and why Klein differs from Freud. AB - It is well known that Melanie Klein held the view that 'fear of death' is the primary source of anxiety and that her position is explicitly opposed to that of Sigmund Freud, who maintained that that fear cannot in any way or form be a source of anxiety. In a previous article on Freud's Inhibitions, Symptoms and Anxiety (Blass, 2013), the author argued that, counter to what is commonly portrayed in the literature, Freud's considerations for rejecting the fear of death as a source of anxiety were based on relational and experiential factors that are usually associated with Kleinian psychoanalysis. In light of this affinity of Freud with Klein a question arises as to the actual source of their differences in this context. The present paper offers an answer to this question. The author first presents some of her earlier findings on what led Freud to reject the fear of death as a source of anxiety and then turns to investigate Klein's considerations for accepting it. This takes us beyond her explicit statements on this matter and sheds new light on the relationship of her views regarding death and anxiety and those of Freud. In turn this deepens the understanding of the relationship of Freud and Klein's conceptualizations of the psyche and its internal object relations, pointing to both surprising common ground and foundational differences. PMID- 24773415 TI - Neuroimaging of executive function in survivors of pediatric brain tumors and healthy controls. AB - OBJECTIVE: Research on the long-term sequelae of treatment for pediatric brain tumors has identified significant neurocognitive deficits experienced by many survivors. Despite indications of deficits based on cognitive assessment, the identification of specific neurobiological mechanisms of these deficits using neuroimaging techniques has yet to be considered. METHOD: This study used norm referenced standardized assessment and functional MRI (fMRI) to examine attention and executive functioning deficits of survivors of pediatric brain tumors, as compared with healthy children. RESULTS: Survivors of pediatric brain tumors performed more poorly than healthy children on measures of overall cognitive ability, attention, and executive function during testing, as well as on a working memory task during fMRI. Survivors showed lower blood-oxygen level dependent (BOLD) signal in bilateral frontal regions associated with sustained attention (BA6/8) and greater BOLD signal in left cingulate regions associated with complex problem-solving and performance monitoring (BA32) during working memory task completion. Both group and brain activation accounted for significant variance in neurocognitive functioning. CONCLUSIONS: Survivors of pediatric brain tumor and healthy children differed in brain activation during completion of a working memory task, and brain activation was associated with deficits noted in testing. These findings may improve understanding of mechanisms of cognitive deficits and avenues for intervention for children with brain tumors. PMID- 24773414 TI - Eye movements reveal impaired inhibitory control in adult male fragile X premutation carriers asymptomatic for FXTAS. AB - OBJECTIVE: Fragile X premutation carriers (fXPCs) have an expansion of 55-200 CGG repeats in the FMR1 gene. Male fXPCs are at risk for developing a neurodegenerative motor disorder (FXTAS) often accompanied by inhibitory control impairments, even in fXPCs without motor symptoms. Inhibitory control impairments might precede, and thus indicate elevated risk for motor impairment associated with FXTAS. We tested whether inhibitory impairments are observable in fXPCs by assessing oculomotor performance. METHOD: Participants were males aged 18-48 years asymptomatic for FXTAS. FXPCs (n = 21) and healthy age-matched controls (n = 22) performed four oculomotor tasks. In a Fixation task, participants fixated on a central cross and maintained gaze position when a peripheral stimulus appeared. In a Pursuit task, participants maintained gaze on a square moving at constant velocity. In a Prosaccade task, participants fixated on a central cross, then looked at a peripheral stimulus. An Antisaccade task was identical to the Prosaccade task, except participants looked in the direction opposite the stimulus. Inhibitory cost was the difference in saccade latency between the Antisaccade and Prosaccade tasks. RESULTS: Relative to controls, fXPCs had longer saccade latency in the Antisaccade task. In fXPCs, inhibitory cost was positively associated with vermis area in lobules VI-VII. CONCLUSION: Antisaccades require inhibitory control to inhibit reflexive eye movements. We found that eye movements are sensitive to impaired inhibitory control in fXPCs asymptomatic for FXTAS. Thus, eye movements may be useful in assessing FXTAS risk or disease progression. PMID- 24773416 TI - Impaired facial emotion recognition in patients with ventromedial prefrontal hypoperfusion. AB - Empathy refers to our ability to recognize and share emotions by another human being. Impairment may underlie many of the emotional deficits commonly associated with a range of neuropsychiatric and neurological conditions. The prefrontal cortex (PFC) has long been implicated in these processes, but the specific contribution of subregions of the PFC remain unclear. Studies regarding the role of subregions of the prefrontal cortex such as the ventromedial prefrontal cortex (vmPFC)-in facial emotion recognition have yielded inconsistent results. The present study aimed to investigate the capacity to recognize nonverbal emotional facial expressions in a group of patients with the following: (a) perfusion deficits in the vmPFC (vmPFC group; N = 13), (b) hypoperfusions sparing the vmPFC (nonvmPFC group; N = 12), and in (c) a control group of healthy volunteers (control group; N = 17). Regions of hypoperfusion were identified by means of Single Photon Emission Computed Tomography (SPECT). Participants were asked to recognize facial expressions of the 7 basic emotions (happiness, fear, surprise, anger, disgust, sadness, or neutral). Detection of facial expressions of fear, disgust, and surprise was affected after functional disruption of the vmPFC. The present study confirms the role of the vmPFC in recognizing emotional facial expressions. PMID- 24773417 TI - Within-individual variability in neurocognitive performance: age- and sex-related differences in children and youths from ages 8 to 21. AB - OBJECTIVE: The transition from childhood to adulthood is characterized by improved motor and cognitive performance in many domains. Developmental studies focus on average performance in single domains but ignore consistency of performance across domains. Within-individual variability (WIV) provides an index of that evenness and is a potential marker of development. METHOD: We gave a computerized battery of 14 neurocognitive tests to 9138 youths ages 8-21 from the Philadelphia Neurodevelopmental Cohort. RESULTS: As expected, performance improved with age, with both accuracy and speed peaking in adulthood. WIV, however, showed a U-shaped course: highest in childhood, declining yearly into mid-adolescence, and increasing again into adulthood. Young females outperformed and were less variable than males, but by early adulthood male performance matched that of females despite being more variable. CONCLUSION: We conclude that WIV declines from childhood to adolescence as developmental lags are overcome, and then increases into adulthood reflecting the emergence of cognitive specializations related to skill-honing and brain maturation. PMID- 24773418 TI - Exposure to television food advertising primes food-related cognitions and triggers motivation to eat. AB - OBJECTIVE: This study investigated the effect of exposure to television food advertising on accessibility of food-related cognitions and motivation to eat. DESIGN AND MAIN OUTCOME MEASURES: We initially developed a word stem completion task to measure accessibility of food-related cognitions. In two subsequent experiments, 160 female undergraduate students (Experiment 1) and 124 overweight or obese community-dwelling women (Experiment 2) viewed a series of television commercials advertising either food or non-food products. They then completed the word stem task and also rated their desire to eat. RESULTS: Exposure to televised food advertisements led to the completion of word stems with more food- and eating-related words in both experiments. It also increased self-reported desire to eat, but only for overweight and obese individuals (Experiment 2). In both samples, there was a positive association between accessibility of food-related cognitions and reported desire to eat, following priming with television food advertisements. CONCLUSION: We conclude that an increased activation of food related cognitions may provide a mechanism for the link between food advertising and consumption. This has implications for tackling pathological (over)eating. PMID- 24773419 TI - Total synthesis of hyacinthacines B3, B4, and B5 and purported hyacinthacine B7, 7-epi-hyacinthacine B7, and 7a-epi-hyacinthacine B3 from a common precursor. AB - The total synthesis of hyacinthacines B3, B4, and B5 and purported hyacinthacine B7, 7-epi-hyacinthacine B7, and 7a-epi-hyacinthacine B3 from a common anti-1,2 amino alcohol precursor is described. These syntheses confirmed that the proposed structures and absolute configurations of hyacinthacines B3, B4, and B5 were correct and disclosed that the proposed structure of hyacinthacine B7 was incorrect. Our synthetic and spectroscopic studies suggest that the natural hyacinthacines B5 and B7 are the same compounds; however, without access to authentic samples this cannot be unequivocally proven. PMID- 24773421 TI - Assessing the influence of side-chain and main-chain aromatic benzyltrimethyl ammonium on anion exchange membranes. AB - 3,3'-Di(4"-methyl-phenyl)-4,4'-difluorodiphenyl sulfone (DMPDFPS), a new monomer with two pendent benzyl groups, was easily prepared by Suzuki coupling reaction in high yield. A series of side-chain type ionomers (PAES-Qs) containing pendant side-chain benzyltrimethylammonium groups, which linked to the backbone by alkaline resisting conjugated C-C bonds, were synthesized via polycondensation, bromination, followed by quaternization and alkalization. To assess the influence of side-chain and main-chain aromatic benzyltrimethylammonium on anion exchange membranes (AEMs), the main-chain type ionomers (MPAES-Qs) with the same backbone were synthesized following the similar procedure. GPC and (1)H NMR results indicate that the bromination shows no reaction selectivity of polymer configurations and ionizations of the side-chain type polymers display higher conversions than that of the main-chain type ones do. These two kinds of AEMs were evaluated in terms of ion exchange capacity (IEC), water uptake, swelling ratio, lambda, volumetric ion exchange capacity (IECVwet), hydroxide conductivity, mechanical and thermal properties, and chemical stability, respectively. The side-chain type structure endows AEMs with lower water uptake, swelling ratio and lambda, higher IECVwet, much higher hydroxide conductivity, more robust dimensional stability, mechanical and thermal properties, and higher stability in hot alkaline solution. The side-chain type cationic groups containing molecular configurations have the distinction of being practical AEMs and membrane electrode assemblies of AEMFCs. PMID- 24773420 TI - Therapeutic granulocyte and monocyte apheresis (GMA) for treatment refractory sarcoidosis: a pilot study of clinical effects and possible mechanisms of action. AB - Sarcoidosis is a systemic, inflammatory disorder, which in a proportion of patients runs a chronic progressive course despite immunosuppressive treatment. Therapeutic granulocyte and monocyte apheresis (GMA) has been shown to be an effective treatment option for other systemic inflammatory disorders, but has not yet been investigated in sarcoidosis. The aim of this study was to evaluate the response to GMA in sarcoidosis. Seven patients with sarcoidosis refractory to standard immunosuppressive therapy received 10 GMA sessions. All patients underwent chest X-ray, spirometry, a Chronic Respiratory Disease Questionnaire (CRQ-SAS), blood tests and bronchoscopy with bronchoalveolar lavage (BAL) before treatment and at 2-4 weeks and 3 months (except bronchoscopy) after the last treatment session. Bronchoalveolar lavage fluid (BALF) cell differential counts were recorded and T cells from blood and BALF were analysed for markers of activity, differentiation and T regulatory function. Compared to baseline, five of seven patients reported an improvement in dyspnoea score. In BALF there was an increase in the percentage of macrophages and a decrease in the percentage of lymphocytes and CD4(+) /FoxP3(+) T cells. Furthermore, the decrease in BALF CD4(+) /FoxP3(+) T cells correlated significantly with an improvement in dyspnoea score. In peripheral blood there was a statistically significant increase in the percentage of CD4(+) /CD27(-) T cells and a trend towards an initial increase in the percentage of CD4(+) /FoxP3(+) T cells, followed by a statistically significant decrease. The effects of GMA on regulatory T cells are consistent with those observed in other inflammatory disorders and could potentially translate into a clinical benefit. PMID- 24773422 TI - Individual therapy for couple problems: perspectives and pitfalls. AB - Despite the demonstrated efficacy of conjoint couple therapy, many clients seeking help for couple problems ultimately find themselves in individual therapy for these concerns. Individual therapy for couple problems (ITCP) may evolve from a partner's refusal of conjoint therapy or from the treatment format preferences of either the client or therapist. Having acknowledged the role of partner refusals, we offer some perspectives about the idiosyncratic personal factors and professional background factors that may lead therapists to provide ITCP and discuss the significant pitfalls in its practice. We emphasize five central areas of concern in the ongoing practice of ITCP: structural constraints on change; therapist side-taking and the therapeutic alliance; inaccurate assessments based on individual client reports; therapeutic focus; and ethical issues relevant to both attending and nonattending partners. We conclude by urging that this very important but largely neglected topic be paid greater attention in psychotherapy research, training and continuing education. PMID- 24773423 TI - A Schiff base and its copper(II) complex as a highly selective chemodosimeter for mercury(II) involving preferential hydrolysis of aldimine over an ester group. AB - The syntheses of a new Schiff base, diethyl-5-(2 hydroxybenzylidene)aminoisophthalate (HL), and a copper complex, [Cu(L2)] (1), imparting L(-), have been described. Both the ligand HL and complex 1 have been thoroughly characterized by elemental analyses, electrospray ionization mass spectrometry, FT-IR, NMR ((1)H and (13)C), electronic absorption, and emission spectral studies and their structures determined by X-ray single-crystal analyses. Distinctive chemodosimetric behavior of HL and 1 toward Hg(2+) has been established by UV/vis, emission, and mass spectral studies. Comparative studies further revealed that the chemodosimetric response solely originates from selective hydrolysis of the aldimine moiety over the ester group and 1 exhibited greater selectivity toward Hg(2+) relative to HL while the sensitivity order is reversed. Further, these followed different hydrolytic pathways but ended up with the same product analyzed for diethyl-5-aminoisophthalate (DEA). Hg(2+)-induced displacement of Cu(2+) and subsequent hydrolysis of the -HC?N- moiety in 1 affirmed the identity of the actual species undergoing hydrolysis as HL. The occurrence of Cu(2+) displacement and Hg(2+) detection via hydrolytic transformation has been supported by various physicochemical studies. PMID- 24773424 TI - Power law size-distributed heterogeneity explains colloid retention on soda lime glass in the presence of energy barriers. AB - This article concerns reading the nanoscale heterogeneity thought responsible for colloid retention on surfaces in the presence of energy barriers (unfavorable attachment conditions). We back out this heterogeneity on glass surfaces by comparing mechanistic simulations incorporating discrete heterogeneity with colloid deposition experiments performed across a comprehensive set of experimental conditions. Original data is presented for attachment to soda lime glass for three colloid sizes (0.25, 1.1, and 1.95 MUm microspheres) under a variety of ionic strengths and fluid velocities in an impinging jet system. A comparison of mechanistic particle trajectory simulations incorporating discrete surface heterogeneity represented by nanoscale zones of positive charge (heterodomains) indicates that a power law size distribution of heterodomains ranging in size from 120 to 60 nm in radius was able to explain the observed retention for all conditions examined. In contrast, uniform and random placement of single-sized heterodomains failed to capture experimentally observed colloid retention across the range of conditions examined. PMID- 24773426 TI - Effect of muscle metaboreflex activation on central hemodynamics and cardiac function in humans. AB - We sought to determine how the mode of muscle metaboreflex activation influences the central hemodynamic response and cardiac inotropic and lusotropic function in healthy humans. Ten healthy males performed (i) isometric handgrip (IHG) with and without post-exercise ischemia (PEI) to examine the influence of isolated muscle metaboreflex activation and (ii) rhythmic handgrip (RHG) with and without ischemia to examine the influence of enhanced muscle metaboreflex activation. Heart rate (HR) and blood pressure (BP) were continuously monitored. Stroke volume (SV, Doppler echocardiography) was measured, cardiac output (CO = HR * SV) and total peripheral resistance (TPR = mean BP/CO) calculated, and indices of left ventricular systolic and diastolic function were obtained (tissue Doppler imaging). During isolated muscle metaboreflex activation with PEI following IHG, mean BP (+23 +/- 3 mm Hg) and TPR were elevated from baseline (p < 0.05), whereas HR, SV, and CO were unchanged. Enhanced muscle metaboreceptor activation during ischemic RHG augmented the increase in mean BP, CO, and HR (p < 0.05 ischemic vs. free-flow RHG), whereas SV and TPR were unchanged from baseline. Neither isolated (PEI) nor enhanced muscle metaboreflex activation altered left ventricular systolic function (systolic myocardial velocity), but left atrial systolic function (late diastolic myocardial velocity) was enhanced. These findings indicate that the mode of muscle metaboreceptor activation (during vs. post handgrip) determines whether the resultant pressor response is flow (CO) or vasoconstriction (TPR) mediated, and that although left ventricular systolic function is unchanged, enhanced left atrial systolic function likely aids the preservation of SV during muscle metaboreflex engagement. PMID- 24773427 TI - Clinicopathological features and expression of four keratins (K10, K14, K17 and K19) in six cases of eruptive vellus hair cysts. AB - Six cases of eruptive vellus hair cysts (EVHC) were evaluated for histopathology and the immunohistochemical profile of Ki-67 and four keratins (K10, K14, K17 and K19). The pathological hallmark of EVHC was the existence of vellus hair shafts within the cystic cavity, but atypical pathological changes included two or three cysts and a foreign-body granuloma in three cases. Our results demonstrate that atypical pathological changes are not uncommon in EVHC, and indicate that based on keratin expression, it is likely that EVHC is derived from the infrainfundibulum and sebaceous duct. PMID- 24773428 TI - The circadian timing system in ethanol consumption and dependence. AB - The use of alcohol is an important part of the daily lives of many individuals that may be experienced as a single nightly drink with a meal or a debilitating pattern of intoxication. The circadian timing system imposes a daily temporal order throughout the brain and body. Ethanol, with its complex and broad pharmacology, can thereby alter circadian physiology at multiple levels of organization. Here, we review data from animal models demonstrating that (a) perturbations of the circadian timing system are often, but not necessarily, reflected in altered drinking behaviors or ethanol response; (b) alcohol can act to alter the circadian entrainment and pacemaking functions of the suprachiasmatic nuclei; and (c) the temporal patterning of alcohol exposure and withdrawal in a circadian context can influence processes related to addiction development, particularly increased voluntary alcohol consumption and development of physical dependence as reflected in the physiological withdrawal reaction. New data are presented to show that the withdrawal reaction elicited after long duration alcohol vapor sessions is significantly modulated according to the time of day that it is initiated. Further application of chronobiological principles to alcohol research should enhance mechanistic understanding and suggest potential therapeutic approaches. PMID- 24773430 TI - Regulation of circadian rhythms in mammals by behavioral arousal. AB - Circadian rhythms in most mammals are synchronized to local time by phase and period resetting actions of daily light-dark cycles on a retino-recipient, light entrainable circadian pacemaker, the suprachiasmatic nucleus (SCN). The SCN receives input from other brain regions, some of which mediate the phase and period resetting actions of behavioral arousal on circadian rhythms. We review historical milestones in the discovery of so-called "nonphotic" circadian clock resetting induced by environmentally stimulated arousal, or by feedback from clock-controlled rest-activity cycles. Topics include species generality, interactions between concurrent or successive photic and nonphotic inputs to the circadian clock, neural pathways, neurotransmitters, and clock cell responses that mediate resetting by behavioral arousal. The role of behavioral inputs to the circadian clock in determining the phase of entrainment to local time in natural environments is not well understood. Nonetheless, nonphotic effects are of sufficient magnitude to raise issues for the design of experiments in behavioral neuroscience (any procedure that is sufficiently arousing may alter the timing of circadian clocks that regulate dependent variables of primary interest). Nonphotic inputs to the clock may be exploited in strategies to reset or strengthen circadian rhythms in humans. PMID- 24773429 TI - Basic sleep and circadian science as building blocks for behavioral interventions: a translational approach for mood disorders. AB - Sleep and circadian functioning has been of particular interest to researchers focused on improving treatments for psychiatric illness. The goal of the present paper is to highlight the exciting research that utilizes basic sleep and circadian science as building blocks for intervention in the mood disorders. The reviewed evidence suggests that the sleep and circadian systems are a) disrupted in the mood disorders and linked to symptoms, b) open systems that can be modified, c) the focus of interventions which have been developed to effectively treat sleep disturbance within mood disorders, and d) intimately linked with mood, such that improvements in sleep are associated with improvements in mood. Although significant positive treatment effects are evident, more research is needed to fill the gap in our basic understanding of the relationship between sleep and mood. PMID- 24773431 TI - Fmr1 and Nlgn3 knockout rats: novel tools for investigating autism spectrum disorders. AB - Animal models are critical for gaining insights into autism spectrum disorder (ASD). Despite their apparent advantages to mice for neural studies, rats have not been widely used for disorders of the human CNS, such as ASD, for the lack of convenient genome manipulation tools. Here we describe two of the first transgenic rat models for ASD, developed using zinc-finger nuclease (ZFN) methodologies, and their initial behavioral assessment using a rapid juvenile test battery. A syndromic and nonsyndromic rat model for ASD were created as two separate knockout rat lines with heritable disruptions in the genes encoding Fragile X mental retardation protein (FMRP) and Neuroligin3 (NLGN3). FMRP, a protein with numerous proposed functions including regulation of mRNA and synaptic protein synthesis, and NLGN3, a member of the neuroligin synaptic cell adhesion protein family, have been implicated in human ASD. Juvenile subjects from both knockout rat lines exhibited abnormalities in ASD-relevant phenotypes including juvenile play, perseverative behaviors, and sensorimotor gating. These data provide important first evidence regarding the utility of rats as genetic models for investigating ASD-relevant genes. PMID- 24773432 TI - Vocalization deficits in mice over-expressing alpha-synuclein, a model of pre manifest Parkinson's disease. AB - Communication and swallowing deficits are common in Parkinson's disease (PD). Evidence indicates that voice and speech dysfunction manifest early, prior to motor deficits typically associated with striatal dopamine loss. Unlike deficits in the extremities, cranial sensorimotor deficits are refractory to standard dopamine-related pharmacological and surgical interventions, thus the mechanisms underlying vocal deficits are unclear. Although neurotoxin models have provided some insight, they typically model nigrostriatal dopamine depletion and are therefore limited. Widespread alpha-synuclein (aSyn) pathology is common to familial and sporadic PD, and transgenic mouse models based on aSyn overexpression present a unique opportunity to explore vocalization deficits in relation to extrastriatal, nondopaminergic pathologies. Specifically, mice overexpressing human wild-type aSyn under a broad neuronal promoter (Thy1-aSyn) present early, progressive motor and nonmotor deficits starting at 2-3 months, followed by parkinsonism with dopamine loss at 14 months. We recorded ultrasonic vocalizations from Thy1-aSyn mice and wild-type (WT) controls at 2-3, 6-7, and 9 months. Thy1-aSyn mice demonstrated early, progressive vocalization deficits compared with WT. Duration and intensity of calls were significantly reduced and call profile was altered in the Thy1-aSyn mice, particularly at 2-3 months. Call rate trended toward a more drastic decrease with age in the Thy1-aSyn mice compared with WT. Alpha-synuclein pathology is present in the periaqueductal gray and may underlie the manifestation of vocalization deficits. These results indicate that aSyn overexpression can induce vocalization deficits at an early age in mice and provides a new model for studying the mechanisms underlying cranial sensorimotor deficits and treatment interventions for PD. PMID- 24773434 TI - Structural brain correlates of delay of gratification in the elderly. AB - Delay of gratification (DoG) refers to the ability to postpone immediate rewards in favor of later and better rewards. A successful DoG in children/adolescents is subject to the maturation of the lateral and medial prefrontal cortex, which is more prone to normal age-related atrophy compared with other brain regions. Therefore, we investigated morphological brain correlates of DoG using structural MRI surface-based morphometry as well as determined whether dorsolateral prefrontal cortex (DLPFC) atrophy is related to DoG in the elderly. We used the behavioral Delay of Gratification Test for Adults to measure DoG in 40 healthy older adults aged between 63 and 93 years. When simultaneously controlling for age and intracranial volume, high DoG significantly positively correlated with cortical surface area of the left DLPFC. At a more liberal statistical threshold, we found positive correlations between DoG and cortical thickness of the left and right DLPFC, left and right ventrolateral prefrontal cortex, and left midanterior cingulate cortex. Additionally, cortical surface area in the left DLPFC correlated positively with DoG as well as with the volume of the left caudate nucleus. The results suggest that the DLPFC, medial prefrontal cortex, and the caudate nucleus play a crucial role in DoG in the elderly supporting studies in related constructs such as delay discounting and impulsivity. Further, the study shows that age-related prefrontal atrophy is associated with DoG performance. The findings are in line with concepts of "willpower" that postulate a central role of frontostriatal connectivity in self-regulation and self-control. PMID- 24773433 TI - Enhanced performance of aged rats in contingency degradation and instrumental extinction tasks. AB - Normal aging in rats affects behavioral performance on a variety of associative learning tasks under Pavlovian conditions. There is little information, however, on whether aging also impacts performance of instrumental tasks. Young (9-12 months) and aged (24-27 months) Fisher 344 rats were trained to press distinct levers associated with either maltodextrin or sucrose. The rats in both age groups increased their lever press frequency at a similar rate, suggesting that the initial acquisition of this instrumental task is not affected by aging. Using a contingency degradation procedure, we then addressed whether aged rats could adapt their behavior to changes in action-outcome contingencies. We found that young and aged rats do adapt, but that a different schedule of reinforcement is necessary to optimize performance in each age group. Finally, we also addressed whether aged rats can extinguish a lever press action as well as young rats, using 2 40-min extinction sessions on consecutive days. While extinction profiles were similar in young and aged rats on the first day of training, aged rats were faster to extinguish their lever presses on the second day, in spite of their performance levels being similar at the beginning of the session. Together these data support the finding that acquisition of instrumental lever press behaviors is preserved in aged rats and suggest that they have a different threshold for switching strategies in response to changes in action-outcome associations. This pattern of result implies that age-related changes in the brain are heterogeneous and widespread across structures. PMID- 24773435 TI - Expecting the unexpected: the effects of deviance on novelty processing. AB - Novelty is often prioritized and detected automatically. It attracts attention eliciting the orienting response. However, novelty is not a unitary concept, and the extent to which the orienting response is elicited depends on several factors. In the present study we investigated how stimulus novelty, deviance from the context, and complexity of the stimulus context contribute to the anterior N2 and novelty P3 event-related potential components, using the visual novelty oddball paradigm. In the first experiment the novelty P3 was drastically reduced when the stimulus context was complex compared with simple, and in a second experiment when novels were frequent rather than deviant. No such effect was found for the anterior N2, suggesting it is a function of stimulus characteristics, not deviance. In contrast, the novelty P3 depended on deviance and contextual complexity. PMID- 24773437 TI - Female juvenile play elicits Fos expression in dopaminergic neurons of the VTA. AB - Juveniles of many species engage in rough-and-tumble play behaviors, and these social encounters are important for the expression of typical social behaviors. Play is a highly motivated and rewarding behavior, which suggests that the mesocorticolimbic dopamine system is likely important for reinforcing the behavior. Indeed, systemic dopamine receptor antagonists decrease the expression of play behaviors, but the specific dopaminergic networks important for play are not known. In this study, we examined immediate-early gene expression in specific dopaminergic cell groups after juvenile male and female rats played or did not play. Subjects were housed with a same-sex sibling, and spontaneous play behavior (or lack thereof) was observed for 1 hr. Brains were harvested and immunohistochemistry was used to localize Fos and tyrosine hydroxylase. Cells expressing both proteins were counted in midbrain and forebrain dopaminergic cell groups. Females that played had more double-labeled cells in the ventral tegmental area (VTA) than females that did not play, but there was no effect of play on double-labeled cell counts in any brain region in males. Furthermore, many measures of play in females were positively correlated with the number of double-labeled cells in the VTA, including play duration and pin duration. Our results suggest that play in females likely induces dopamine release from mesocorticolimbic neurons to reinforce play behaviors. Our results also highlight a sex difference in the neural networks mediating play, thus emphasizing the importance of studying the neurobiology of play in both males and females. PMID- 24773436 TI - The impact of anterior thalamic lesions on active and passive spatial learning in stimulus controlled environments: geometric cues and pattern arrangement. AB - The anterior thalamic nuclei are vital for many spatial tasks. To determine more precisely their role, the present study modified the conventional Morris watermaze task. In each of 3 experiments, rats were repeatedly placed on a submerged platform in 1 corner (the 'correct' corner) of either a rectangular pool (Experiment 1) or a square pool with walls of different appearances (Experiments 2 and 3). The rats were then released into the pool for a first test trial in the absence of the platform. In Experiment 1, normal rats distinguished the 2 sets of corners in the rectangular pool by their geometric properties, preferring the correct corner and its diagonally opposite partner. Anterior thalamic lesions severely impaired this discrimination. In Experiments 2 and 3, normal rats typically swam directly to the correct corner of the square pool on the first test trial. Rats with anterior thalamic lesions, however, often failed to initially select the correct corner, taking more time to reach that location. Nevertheless, the lesioned rats still showed a subsequent preference for the correct corner. The same lesioned rats also showed no deficits in Experiments 2 and 3 when subsequently trained to swim to the correct corner over repeated trials. The findings show how the anterior thalamic nuclei contribute to multiple aspects of spatial processing. These thalamic nuclei may be required to distinguish relative dimensions (Experiment 1) as well as translate the appearance of spatial cues when viewed for the first time from different perspectives (Experiments 2, 3). PMID- 24773438 TI - Impaired trace fear conditioning and diminished ERK1/2 phosphorylation in the dorsal hippocampus of adult rats administered alcohol as neonates. AB - Utilizing a rat model of fetal alcohol spectrum disorder (FASD), ethanol was administered over postnatal days (PD) 4 to 9. As adults, control and ethanol rats underwent trace fear conditioning (TFC), in which a tone conditioned stimulus (CS) and footshock unconditioned stimulus (US) were repeatedly paired, though the two stimuli never overlapped in time. Following training in Experiment 1, conditioned fear (freezing) to the tone CS was dose-dependently reduced in ethanol rats relative to controls. Experiment 2 was designed to test whether the TFC deficit varied based on the duration of the trace interval (TI; time from CS offset to US onset). Holding the time separating CS onset from US onset constant at 20 sec, control and ethanol rats were trained with a 5 or 15 sec tone CS, followed 15 or 5 sec later, respectively, by the US. Conditioned fear to the tone CS was significantly reduced in high dose ethanol rats trained with the 15 sec TI only. Acquisition and consolidation of trace fear memories relies on forebrain N methyl-d-aspartate receptor (NMDAR) signaling, including the downstream phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2). Separate rats were trained with the 5 or 15 sec TI and then sacrificed 1 hr later. Significant reductions in pERK1/2-positive neurons were seen in areas CA1 and CA3 of the dorsal hippocampus (DH) following training at both TIs in ethanol rats. The disruption of DH learning-dependent plasticity appears tied to freezing behavior in ethanol rats, but only when the training stimuli are separated by more than 5 sec. PMID- 24773439 TI - Opioid receptors regulate blocking and overexpectation of fear learning in conditioned suppression. AB - Endogenous opioids play an important role in prediction error during fear learning. However, the evidence for this role has been obtained almost exclusively using the species-specific defense response of freezing as the measure of learned fear. It is unknown whether opioid receptors regulate predictive fear learning when other measures of learned fear are used. Here, we used conditioned suppression as the measure of learned fear to assess the role of opioid receptors in fear learning. Experiment 1a studied associative blocking of fear learning. Rats in an experimental group received conditioned stimulus A (CSA) + training in Stage I and conditioned stimulus A and B (CSAB) + training in Stage II, whereas rats in a control group received only CSAB + training in Stage II. The prior fear conditioning of CSA blocked fear learning to conditioned stimulus B (CSB) in the experimental group. In Experiment 1b, naloxone (4 mg/kg) administered before Stage II prevented this blocking, thereby enabling normal fear learning to CSB. Experiment 2a studied overexpectation of fear. Rats received CSA + training and CSB + training in Stage I, and then rats in the experimental group received CSAB + training in Stage II whereas control rats did not. The Stage II compound training of CSAB reduced fear to CSA and CSB on test. In Experiment 2b, naloxone (4 mg/kg) administered before Stage II prevented this overexpectation. These results show that opioid receptors regulate Pavlovian fear learning, augmenting learning in response to positive prediction error and impairing learning in response to negative prediction error, when fear is assessed via conditioned suppression. These effects are identical to those observed when freezing is used as the measure of learned fear. These findings show that the role for opioid receptors in regulating fear learning extends across multiple measures of learned fear. PMID- 24773440 TI - Once is too much: conditioned aversion develops immediately and predicts future cocaine self-administration behavior in rats. AB - Rats emit aversive taste reactivity (TR) behavior (i.e., gapes) following intraoral delivery of a cocaine-paired taste cue and greater conditioned aversive TR at the end of training predicts greater drug-seeking and taking. Here, we examined the development of this conditioned aversive TR behavior on a trial-by trial basis in an effort to determine when the change in behavior occurs and whether early changes in this behavior can be used to predict later drug taking. The results show that conditioned aversive TR to a cocaine-paired cue occurs very early in training (i.e., following as few as 1-2 taste-drug pairings) and, importantly, that it can be used to predict later drug seeking and drug taking in rats. PMID- 24773441 TI - Cue configuration effects in acquisition and extinction of a cocaine-induced place preference. AB - A pervasive finding in animal models of substance abuse is that associations form quickly between contexts and drugs of abuse, such as cocaine. Studies of conditioned place preference (CPP) demonstrate that animals approach cues previously paired with cocaine. This is a commonly used preparation, but the configuration of the CPP apparatus differs across laboratories. Two common apparatus configurations for CPP are one compartment (in which the animal has access to the entire apparatus and spatial cues are irrelevant) or two compartments (in which access is restricted to one half of the apparatus and spatial cues are relevant). We compared the effects of acquisition and extinction of cocaine-induced CPP as a function of configuration. During CPP acquisition, C57BL/6J mice received cocaine paired with one tactile floor (conditioned stimulus; CS+) and saline paired with the other (CS-). CS+ and CS- trials occurred on alternate days in one of three configurations: one-compartment (exposure to the entire apparatus during CS+ or CS-), two-compartment consistent position (exposure to CS+ or CS- in adjacent, spatially distinct compartments), or two-compartment alternating position (exposure to CS+ or CS- in adjacent compartments that alternated spatial locations across days). A stronger preference for the CS+ floor occurred in two- versus one-compartment groups, with the strongest preference observed when cocaine was paired with alternating chamber positions. In contrast, greater loss of preference occurred after extinction in a one-compartment procedure, regardless of one- or two-compartment acquisition history. These findings suggest that a two-compartment configuration facilitated acquisition but attenuated extinction of a cocaine-induced CPP. The use of different CPP configurations may distinguish the underlying substrates and relevant cues for acquisition and extinction processes in cocaine abuse. PMID- 24773442 TI - Finding motifs in birdsong data in the presence of acoustic noise and temporal jitter. AB - Here we present a novel approach to quickly and reliably find long (200 ms - 2 s) stereotyped sequences of sounds ("motifs") in acoustic recordings of birdsong. Robust and time-efficient identification of such sequences is a crucial first step in many studies ranging from development to neuronal basis of motor behavior. Accurately identifying motifs is usually hindered by the presence of animal-intrinsic variability in execution and tempo, and by extrinsic acoustic noise (e.g., movement artifacts, ambient noise). The algorithm we describe in this report has been optimized to work in bird species that sing stereotyped syllable sequences (such as the zebra finch), and requires minimal user involvement (~ 5 min for over 1,000 motifs). Importantly, it is transparent and robust to the choice of parameters. PMID- 24773443 TI - Peanut allergens are rapidly transferred in human breast milk and can prevent sensitization in mice. AB - BACKGROUND: Food allergens have been evidenced in breast milk under physiological conditions, but the kinetic and the role of this passage in food allergies are still unclear. We then aimed to analyze the passage of peanut allergens in human breast milk and their allergenicity/immunomodulatory properties. METHODS: Human breast milk was collected from two non-atopic peanut-tolerant mothers before and at different time points after ingestion of 30 g of commercial roasted peanut. Ara h 6, Ara h 6 immune complexes, and the IgE binding capacity of breast milk samples were measured using specific immunoassays. Their allergenic functionality was then assessed using cell-based assay. Finally, human breast milk obtained before or after peanut ingestion was administered intragastrically to BALB/c mice at different ages, and mice were further experimentally sensitized to peanut using cholera toxin. RESULTS: Ara h 6 is detected as soon as 10 min after peanut ingestion, with peak values observed within the first hour after ingestion. The transfer is long-lasting, small quantities of peanut allergens being detected over a 24-h period. IgG-Ara h 6 and IgA-Ara h 6 immune complexes are evidenced, following a different kinetic of excretion than free allergens. Peanut allergens transferred in milk are IgE reactive and can induce an allergic reaction in vitro. However, administration of human breast milk to young mice, notably before weaning, does not lead to sensitization, but instead to partial oral tolerance. CONCLUSION: The low quantities of immunologically active allergens transferred through breast milk may prevent instead of priming allergic sensitization to peanut. PMID- 24773444 TI - Diagnosis and treatment of bronchiolitis in Finnish and Swedish children's hospitals. AB - AIM: There is no widely accepted consensus on the diagnosis and treatment of bronchiolitis. This study describes current practices in Finnish and Swedish hospitals. METHODS: A questionnaire on the diagnosis and treatment of bronchiolitis in children below 2 years of age was sent to all Finnish and Swedish hospitals providing inpatient care for children. All 22 Finnish hospitals answered, covering 100% of the <12-month-old population and 21 of the 37 Swedish hospitals responded, covering 74%. RESULTS: The mean upper age limit for bronchiolitis was 12.7 months in Finnish hospitals and 12.5 months in Swedish hospitals. In both, laboured breathing, chest retractions and fine crackles were highlighted as the main clinical findings, followed by prolonged expiration. The mean value for the lowest acceptable saturation in room air was 94% in Finnish hospitals and 93% in Swedish hospitals. The most important factors influencing hospitalisation were young age, desaturation and inability to take oral fluids. Finnish doctors preferred intravenous routes, and Swedish doctors preferred nasogastric tubes for supplementary feeding. The first-line drug therapy was inhaled racemic adrenaline in Finland and inhaled levo-adrenaline in Sweden. CONCLUSION: The diagnosis and treatment of bronchiolitis is fairly similar in Finnish and Swedish hospitals. PMID- 24773445 TI - An update on dry eye disease molecular treatment: advances in drug pipelines. AB - INTRODUCTION: Dry eye disease is a common disorder provoking changes in tear film and ocular surface. Untreated dry eye could cause ocular infections, corneal ulcer and blindness. Only a few drugs are authorized so far for the treatment of dry eye disease and the possibilities of evolution in this sector are immense. Consequently, a significant number of new potential solutions are under development or placed in the pharmaceutical pipeline, promising better results and lesser side effects. AREAS COVERED: In this article, the corresponding literature and recent Phase III clinical trial data and the corresponding literature, for dry eye disease treatment are reviewed, revealing the new strategic movements in drug pipelines. EXPERT OPINION: From the clinical trial results, the advancement in tear substitutes and secretagogues in addressing specific deficiencies of tear components even though not resolving the underlying conditions of the disease is evident. The vast majority of new compounds under development are anti-inflammatories, steroids, non-steroids and antibiotics; however, there are also some novel lubricating drops and mucin-tear secretagogues. A future aggressive therapy for dry eye, depending on the severity of the symptoms, would include combinations of soft steroids, anti inflammatories, such as cyclosporine A, with the addition of the new polyvalent mucin and tear secretagogues. PMID- 24773446 TI - Pulse pressure variation to predict fluid responsiveness in spontaneously breathing patients: tidal vs. forced inspiratory breathing. AB - We evaluated whether pulse pressure variation can predict fluid responsiveness in spontaneously breathing patients. Fifty-nine elective thoracic surgical patients were studied before induction of general anaesthesia. After volume expansion with hydroxyethyl starch 6 ml.kg(-1) , patients were defined as responders by a >= 15% increase in the cardiac index. Haemodynamic variables were measured before and after volume expansion and pulse pressure variations were calculated during tidal breathing and during forced inspiratory breathing. Median (IQR [range]) pulse pressure variation during forced inspiratory breathing was significantly higher in responders (n = 29) than in non-responders (n = 30) before volume expansion (18.2 (IQR 14.7-18.2 [9.3-31.3])% vs. 10.1 (IQR 8.3-12.6 [4.8-21.1])%, respectively, p < 0.001). The receiver-operating characteristic curve revealed that pulse pressure variation during forced inspiratory breathing could predict fluid responsiveness (area under the curve 0.910, p < 0.0001). Pulse pressure variation measured during forced inspiratory breathing can be used to guide fluid management in spontaneously breathing patients. PMID- 24773447 TI - Ecologically acceptable usage of derivatives of essential oil of sweet basil, Ocimum basilicum, as antifeedants against larvae of the gypsy moth, Lymantria dispar. AB - Abstract Ethanol solutions of five fractions obtained from essential oil of sweet basil Ocimum basilicum L. (Lamiales: Lamiaceae) (F1-F5) were tested for their antifeedant properties against 2(nd) instar gypsy moth larvae, Lymantria dispar L. (Lepidoptera: Lymantriidae), in laboratory non-choice and feeding-choice experiments. Prior to bioassays, the chemical composition of each fraction was determined by gas chromatography analyses. Significant larval deterrence from feeding was achieved by application of tested solutions to fresh leaves of the host plant. The most effective were were F1 (0.5%), F4 (0.05, 0.1, and 0.5%), and F5 (0.1 and 0.5%), which provided an antifeedant index > 80% after five days. A low rate of larval mortality was observed in no-choice bioassay. In situ screening of chlorophyll fluorescence as an indicator of plant stress level (assessed by the induced fluorometry) confirmed that the tested compounds did not cause alternations in the photosynthetic efficiency of treated leaves. PMID- 24773448 TI - Excited-state dynamics of rhodamine 6G in aqueous solution and at the dodecane/water interface. AB - The excited-state dynamics of rhodamine 6G (R6G) has been investigated in aqueous solution using ultrafast transient absorption spectroscopy and at the dodecane/water interface using the femtosecond time-resolved surface second harmonic generation (SSHG) technique. As the R6G concentration exceeds ca. 1 mM in bulk water, both R6G monomers and aggregates are excited to a different extent when using pump pulses at 500 and 530 nm. The excited-state lifetime of the monomers is shortened compared to dilute solutions because of the occurrence of excitation energy transfer to the aggregates, which themselves decay nonradiatively to the ground state with a ca. 70 ps time constant. At the dodecane/water interface, both monomers and aggregates contribute to the SSHG signal to an extent that depends on the bulk concentration, the pump and probe wavelengths, and the polarization of probe and signal beams. The excited-state lifetime of the monomers at the interface is of the order of a few picoseconds even at bulk concentrations where it is as large as several nanoseconds. This is explained by the relatively high interfacial affinity of R6G that leads to a large interfacial concentration, favoring aggregation and thus rapid excitation energy transfer from monomers to aggregates. PMID- 24773449 TI - Interface control in organic electronics using mixed monolayers of carboranethiol isomers. AB - We employ mixed self-assembled monolayers of carboranethiols to alter the work function of gold and silver systematically. We use isomers of symmetric carboranethiol cage molecules to vary molecular dipole moments and directions, which enable work function tunability over a wide range with minimal alterations in surface energy. Mixed monolayers of carboranethiol isomers provide an ideal platform for the study and fabrication of solution-processed organic field-effect transistors; improved device performance is demonstrated by interface engineering. PMID- 24773450 TI - Building on a solid foundation: SAR and QSAR as a fundamental strategy to reduce animal testing. AB - The development of more efficient, ethical, and effective means of assessing the effects of chemicals on human health and the environment was a lifetime goal of Gilman Veith. His work has provided the foundation for the use of chemical structure for informing toxicological assessment by regulatory agencies the world over. Veith's scientific work influenced the early development of the SAR models in use today at the US Environmental Protection Agency. He was the driving force behind the Organisation for Economic Co-operation and Development QSAR Toolbox. Veith was one of a few early pioneers whose vision led to the linkage of chemical structure and biological activity as a means of predicting adverse apical outcomes (known as a mode of action, or an adverse outcome pathway approach), and he understood at an early stage the power that could be harnessed when combining computational and mechanistic biological approaches as a means of avoiding animal testing. Through the International QSAR Foundation he organized like-minded experts to develop non-animal methods and frameworks for the assessment of chemical hazard and risk for the benefit of public and environmental health. Avoiding animal testing was Gil's passion, and his work helped to initiate the paradigm shift in toxicology that is now rendering this feasible. PMID- 24773451 TI - "Ring opening-ring closure" strategy for the synthesis of aryl-C-glycosides. AB - A new "ring-opening-ring closure" strategy for the synthesis of aryl-C-glycosides was described. This strategy exploited the nickel-catalyzed regioselective beta-O elimination of glycals by reactions with various aryl boronic acids or potassium aryltrifluoroborates to yield the ring-opened products, which underwent the Lewis acid, protonic acid, PhSeCl, or NBS mediated ring closure reactions to afford diverse aryl-C-glycosides. After Lewis acids and protonic acids were screened, it was found that, starting from the ring-opened substrates, the Ph3PHBr or Sc(OTf)3 mediated ring closure reaction provided alpha- or beta-preferred aryl-C Delta(2,3)-glycosides, respectively. Furthermore, beta-D-phenyl-C-glycosides were successfully prepared via the PhSeCl-mediated cyclization reaction, whereas the alpha-D-phenyl-C-glycoside was obtained via the NBS-mediated cyclization reaction. After removal of the 2-substituted functionalities by Bu3SnH/AIBN, the synthesis of 2-deoxy-aryl-C-glycosides was ultimately realized in a stereoselective manner. PMID- 24773452 TI - Equilibrium and dynamic spectroscopic studies of the interaction of monomeric beta-lactoglobulin with lipid vesicles at low pH. AB - beta-Lactoglobulin (betaLG) is a member of the lipocalin protein family that changes structure upon interacting with anionic surfactants and lipid vesicles under higher-pH conditions at which betaLG is dimeric. In this study, a beta sheet to alpha-helix transformation was also observed for monomeric betaLG obtained at pH 2.6 when it was mixed with small unilamellar vesicles (SUVs) of zwitterionic lipids, but being mixed with anionic lipids produced little change. The dynamics and extent of this change were quite dependent on the lipid character, phase, and vesicle size. With 1,2-distearoyl-sn-glycero-3 phosphocholine (DSPC), at ~50 degrees C and pH 2.6, the betaLG converted to a substantially helical form upon addition of ~10 mM lipid in a two-step kinetic process having time constants of ~1 and ~25 h, as monitored by circular dichroism (CD). Fluorescence changes were simpler but implied a rapid initial change in the Trp environments followed by a slower process paralleling the change in secondary structure. Polarization attenuated total reflectance Fourier transform infrared results indicate the formed helices are at least partially inserted into the lipid bilayer and the sheet segments are on the surface. Thermal behavior showed that the secondary structure of the lipid-bound betaLG had two phases, the first being characteristic of the protein-lipid vesicle interaction and the second following the DSPC phase change after which the protein apparently dissociated from the vesicle. Large unilamellar vesicles had a weaker interaction, as judged by CD, which may correlate to the partial exposure of the hydrophobic parts of the SUV bilayer. Other zwitterionic lipids bound betaLG with much slower kinetics and often required sonication to induce interaction, but these also showed dissociation upon lipid phase change. These thermal and kinetic behaviors suggest a mechanism for the interaction of monomeric betaLG with zwitterionic lipids different from that seen previously for the dimeric form. PMID- 24773453 TI - Secondary alkene insertion and precision chain-walking: a new route to semicrystalline "polyethylene" from alpha-olefins by combining two rare catalytic events. AB - While traditional polymerization of linear alpha-olefins (LAOs) typically provides amorphous, low T(g) polymers, chain-straightening polymerization represents a route to semicrystalline materials. A series of alpha-diimine nickel catalysts were tested for the polymerization of various LAOs. Although known systems yielded amorphous or low-melting polymers, the "sandwich" alpha-diimines 3-6 yielded semicrystalline "polyethylene" comprised primarily of unbranched repeat units via a combination of uncommon regioselective 2,1-insertion and precision chain-walking events. PMID- 24773454 TI - Methods for quantifying Staphylococcus aureus in indoor air. AB - Staphylococcus aureus has been detected in indoor air and linked to human infection. Quantifying S. aureus by efficient sampling methods followed by appropriate sample storage treatments is essential to characterize the exposure risk of humans. This laboratory study evaluated the effects of sampler type (all glass impinger (AGI-30), BioSampler, and Andersen one-stage sampler (Andersen 1 STG)), collection fluid (deionized water (DW), phosphate-buffered saline (PBS), and Tween mixture (TM)), and sampling time (3-60 min) on cell recovery. Effects of storage settings on bacterial concentration were also assessed over 48 h. Results showed BioSampler performed better than Andersen 1-STG and AGI-30 (P < 0.05) and TM was superior to PBS and DW (P < 0.05). An increase in sampling time negatively affected the recoveries of cells in PBS of BioSampler and AGI-30 (P < 0.05), whereas cell recoveries in TM were increased at sampling of 6-15 min compared with 3 min. Concentrations of cells collected in PBS were decreased with storage time at 4 and 23 degrees C (P < 0.05), while cells stored in TM showed stable concentrations at 4 degrees C (P > 0.05) and increased cell counts at 23 degrees C (P < 0.05). Overall, sampling by BioSampler with TM followed by sample transportation and storage at 4 degrees C is recommended. PMID- 24773455 TI - Effective and efficient diagnosis of parkinsonism: the role of dopamine transporter SPECT imaging with ioflupane I-123 injection (DaTscanTM). AB - Parkinson's disease (PD), the second-most common neurodegenerative disease, is characterized by motor and nonmotor symptoms. PD is often misdiagnosed; inappropriate treatment due to misdiagnosis has undesired consequences, as does delayed diagnosis. Unfortunately, most people with PD receive a diagnosis only after motor symptoms have emerged, by which time 40% to 60% of dopamine neurons have already been lost. Advances in imaging techniques have provided clinicians with increasingly sophisticated tools. In 2011, the US Food and Drug Administration approved ioflupane I-123 injection (DaTscanTM) for striatal dopamine transporter visualization using single-photon emission computed tomography (SPECT) imaging, which provides an effective tool for assessing striatal dopaminergic deficiency. Among patients with suspected parkinsonian syndromes, of which PD is one, the diagnostic sensitivity and specificity of DaTscan SPECT imaging are high. In clinical studies that were part of the DaTscan new drug application, no serious drug-related adverse events reported by the 1236 participants were attributed to DaTscan. The introduction of DaTscan imaging and its utility necessitate the development of clinical recommendations for appropriate use; thus, a multidisciplinary panel of experts was convened to develop clinical criteria and algorithms to help guide clinicians and managed care organizations in the application of DaTscan SPECT imaging. Based on the consensus of this expert panel, appropriate use of DaTscan SPECT imaging includes cases where: (1) PD diagnosis is uncertain; (2) tremor of uncertain etiology is present; and (3) nonmotor and/ or supportive symptoms and features associated with PD are present but the classical motor syndrome is absent or atypical. PMID- 24773456 TI - Indirect comparison of bazedoxifene vs oral bisphosphonates for the prevention of vertebral fractures in postmenopausal osteoporotic women. AB - OBJECTIVE: Compare the efficacy of bazedoxifene with oral bisphosphonates for reduction of vertebral fracture risk in postmenopausal osteoporotic (PMO) women and in higher-risk patients based on evidence from randomized controlled trials (RCTs). METHODS: Eight RCTs assessing vertebral fracture risk reduction with oral bisphosphonates (n = 7) or bazedoxifene (n = 1) were identified by a systematic literature review. Individual study results were pooled in a network meta analysis (NMA) to indirectly compare treatment effects for overall PMO women and a higher-risk subgroup (FRAX >= 20%). Three sets of NMA analyses were conducted: aggregate data (AD) from the bisphosphonate RCTs and bazedoxifene RCT for the full population or the FRAX >=20% subgroup (NMA AD); bisphosphonate AD and bazedoxifene AD from each FRAX subgroup adjusted for baseline risk (NMA AD meta regression); and bisphosphonate AD and bazedoxifene individual patient data (IPD) adjusted for baseline risk/FRAX (NMA AD/IPD meta-regression). RESULTS: For the overall population, bisphosphonates had lower fracture risks versus bazedoxifene although there is considerable uncertainty in supporting one intervention over another. The relative risk reduction (RRR) for bazedoxifene was -0.23 (95% CrI: 1.11, 0.27) versus ibandronate, -0.17 (-0.76, 0.22) versus alendronate, and -0.06 (-0.62, 0.30) versus risedronate. RESULTS from the meta-regression analyses were similar. For the FRAX >=20% population, estimated fracture rates with bazedoxifene were lower than with bisphosphonates, but again the uncertainty limits strong interpretation. The RRR for bazedoxifene was 0.51 (-0.31, 0.83) versus ibandronate, 0.53 (-0.18, 0.83) versus alendronate, and 0.57 (-0.07, 0.85) versus risedronate. The meta-regression analyses showed comparable findings. CONCLUSION: The analyses only considered vertebral fractures for oral bisphosphonates versus bazedoxifene, and IPD was available only for bazedoxifene. In light of this, bazedoxifene is comparable to bisphosphonates in the overall PMO population and at least as effective as bisphosphonates for preventing vertebral fractures among higher-risk PMO patients. The findings suggest bazedoxifene performs better in higher-risk PMO than in the overall PMO. PMID- 24773458 TI - Advanced micromachining of concave microwells for long term on-chip culture of multicellular tumor spheroids. AB - A novel approach based on advanced micromachining is demonstrated to fabricate concave microwell arrays for the formation of high quality multicellular tumor spheroids. Microfabricated molds were prepared using a state-of-the-art CNC machining center, containing arrays of 3D convex micropillars with size ranging from 150 MUm to 600 MUm. Microscopic imaging of the micropillars machined on the mold showed smooth, curved microfeatures of a dramatic 3D shape. Agarose microwells could be easily replicated from the metallic molds. EMT-6 tumor cells seeded in the primary macrowell sedimented efficiently to the bottom of the concave microwells and formed multicellular spheroids within 48 h. Dense and homogeneous multicellular spheroids were obtained after 10 days of culture, confirming the suitability of the proposed approach. To facilitate long term spheroid culture and reliable on-chip drug assay, polydimethylsiloxane microwells were also replicated from the metallic molds. A solvent swelling method was adapted and optimized to Pluronic F127 towards physically entrapping the block copolymer molecules within the polydimethylsiloxane network and in turn to improve long term cell-binding resistance. Homogeneous multicellular spheroids were efficiently formed in the concave microwells and on-chip drug assays could be reliably carried out using curcumin as a model anti-cancer drug. Advanced micromachining provides an excellent technological solution to the fabrication of high quality concave microwells. PMID- 24773457 TI - Bloodstream infections due to Peptoniphilus spp.: report of 15 cases. AB - Peptoniphilus spp. are Gram-positive anaerobic cocci (GPAC) that were formerly classified in the genus Peptostreptococcus. This study describes 15 cases of Peptoniphilus spp. bloodstream infection (BSI) diagnosed from 2007 to 2011 using 16S rDNA sequencing in patients with pneumonia, pre-term delivery, soft tissue infection or colon or bladder disease. Seven out of 15 (47%) of these cases had polymicrobial BSIs. One of the isolates was closely related to P. duerdenii (EU526290), while the other 14 isolates were most closely related to a Peptoniphilus sp. reference strain (ATCC 29743) and P. hareii (Y07839). Peptoniphilus is a rare but important cause of BSI. PMID- 24773460 TI - Picolinate-containing macrocyclic Mn2+ complexes as potential MRI contrast agents. AB - We report the synthesis of the ligand Hnompa (6-((1,4,7-triazacyclononan-1 yl)methyl)picolinic acid) and a detailed characterization of the Mn(2+) complexes formed by this ligand and the related ligands Hdompa (6-((1,4,7,10 tetraazacyclododecan-1-yl)methyl)picolinic acid) and Htempa (6-((1,4,8,11 tetraazacyclotetradecan-1-yl)methyl)picolinic acid). These ligands form thermodynamically stable complexes in aqueous solution with stability constants of logKMnL = 10.28(1) (nompa), 14.48(1) (dompa), and 12.53(1) (tempa). A detailed study of the dissociation kinetics of these Mn(2+) complexes indicates that the decomplexation reaction at about neutral pH occurs mainly following a spontaneous dissociation mechanism. The X-ray structure of [Mn2(nompa)2(H2O)2](ClO4)2 shows that the Mn(2+) ion is seven-coordinate in the solid state, being directly bound to five donor atoms of the ligand, the oxygen atom of a coordinated water molecule and an oxygen atom of a neighboring nompa(-) ligand acting as a bridging bidentate carboxylate group (MU-eta(1)-carboxylate). Nuclear magnetic relaxation dispersion ((1)H NMRD) profiles and (17)O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn(nompa)](+) indicate that the Mn(2+) ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the (1)H NMRD and (17)O NMR data provides a very high water exchange rate of the inner-sphere water molecule (kex(298) = 2.8 * 10(9) s(-1)) and an unusually high value of the (17)O hyperfine coupling constant of the coordinated water molecule (AO/h = 73.3 +/- 0.6 rad s(-1)). DFT calculations performed on the [Mn(nompa)(H2O)](+).2H2O system (TPSSh model) provide a AO/h value in excellent agreement with the one obtained experimentally. PMID- 24773461 TI - Small-angle neutron scattering study of cyclic poly(ethylene glycol) adsorption on colloidal particles. AB - The adsorptions of cyclic PEG and linear PEG on colloidal silica particles were compared. Their adsorption volume fraction profiles were generated through model fitting of small-angle neutron scattering data from the adsorbed polymer layers. The two important parameters to describe adsorbed polymer layers were discussed in detail. It was found that the adsorption amounts of cyclic PEGs increased with molecular weight but were generally higher than their linear counterparts. However, the root-mean-square layer thickness, delta(rms), of adsorbed cyclic PEGs was found to decrease with molecular weight, opposing adsorbed linear PEGs and the theoretic prediction based on SF model. This disagreement was ascribed to the topological restriction of cyclic polymer at low molecular weight. An illustrated structural evolution with molecular weight for adsorbed polymer at interface was tentatively proposed based on the observations of this study. PMID- 24773462 TI - Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS). AB - Cryopyrin-associated periodic syndrome (CAPS) is characterized by dysregulated inflammation with excessive interleukin (IL)-1beta activation and secretion. Neonatal-onset multi-system inflammatory disease (NOMID) is the most severe form. We explored cytokine responses in 32 CAPS patients before and after IL-1beta blocking therapy. We measured cytokines produced by activated peripheral blood monuclear cells (PBMCs) from treated and untreated CAPS patients after stimulation for 48 h with phytohaemagglutinin (PHA), PHA plus IL-12, lipopolysaccharide (LPS) or LPS plus interferon (IFN)-gamma. We measured IL 1beta, IL-6, IL-10, tumour necrosis factor (TNF), IL-12p70 and IFN-gamma in the supernatants. PBMCs from three untreated CAPS patients were cultured in the presence of the IL-1beta blocker Anakinra. Fifty healthy individuals served as controls. CAPS patients had high spontaneous production of IL-1beta, IL-6, TNF and IFN-gamma by unstimulated cells. However, stimulation indexes (SIs, ratio of stimulated to unstimulated production) of these cytokines to PHA and LPS were low in NOMID patients compared to controls. Unstimulated IL-10 and IL-12p70 production was normal, but up-regulation after PHA and LPS was also low. LPS plus IFN-gamma inadequately up-regulated the production of IL-1beta, IL-6, TNF and IL 10 in CAPS patients. In-vitro but not in-vivo treatment with Anakinra improved SIs by lowering spontaneous cytokine production. However, in-vitro treatment did not improve the low stimulated cytokine levels. Activating mutations in NLRP3 in CAPS are correlated with poor SIs to PHA, LPS and IFN-gamma. The impairment in stimulated cytokine responses in spite of IL-1beta blocking therapy suggests a broader intrinsic defect in CAPS patients, which is not corrected by targeting IL 1beta. PMID- 24773463 TI - A pilot study of an acupuncture protocol to improve visual function in retinitis pigmentosa patients. AB - BACKGROUND: Patients with retinitis pigmentosa are motivated to try complementary or integrative therapies to slow disease progression. Basic science, clinical research and retinitis pigmentosa patients' self-reports support the hypothesis that acupuncture may improve visual function. METHODS: A prospective, case series, pilot study enrolled 12 adult patients with RP treated at an academic medical centre with a standardised protocol that combined electroacupuncture to the forehead and below the eyes and acupuncture to the body, at 10 half-hour sessions over two weeks. Pre- and post-treatment tests included Early Treatment Diabetic Retinopathy Study visual acuity (VA), Pelli-Robson contrast sensitivity (CS), Goldmann visual fields, and dark-adapted full-field stimulus threshold (FST)(n = 9). Scotopic Sensitivity Tester-1 (SST-1) dark-adaptometry was performed on the last two subjects. RESULTS: Six of 12 subjects had measurable, significant visual function improvements after treatment. Three of nine subjects tested with the FST had a significant 10.3 to 17.5 dB (that is, 13- to 53-fold) improvement in both eyes at one week after acupuncture, maintained for at least 10 to 12 months, which was well outside typical test-retest variability (95% CI: 3-3.5 dB) previously found in retinitis pigmentosa. SST-1 dark-adaptation was shortened in both subjects tested on average by 48.5 per cent at one week (range 36 to 62 per cent across 10 to 30 dB), which was outside typical coefficients of variation of less than 30 per cent previously determined in patients with retinitis pigmentosa and normals. Four of the five subjects with psychophysically measured scotopic sensitivity improvements reported subjective improvements in vision at night or in dark environments. One subject had 0.2 logMAR improvement in VA; another had 0.55 logCS improvement. Another subject developed more than 20 per cent improvement in the area of the Goldmann visual fields. The acupuncture protocol was completed and well tolerated by all, without adverse events or visual loss. CONCLUSIONS: Acupuncture entails minimal risk, if administered by a well-trained acupuncturist and may have significant, measurable benefits on residual visual function in patients with retinitis pigmentosa, in particular scotopic sensitivity, which had not previously been studied. These preliminary findings support the need for future controlled studies of potential mechanisms. PMID- 24773464 TI - Advances in the treatment of hepatitis B virus/hepatitis C virus coinfection. AB - INTRODUCTION: Patients with chronic hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection are at a high risk of developing liver cirrhosis and hepatocellular carcinoma, and consequently, warrant effective treatment. AREAS COVERED: Effective treatment should eradicate HCV infection and inhibit HBV replication but without serious adverse reactions. Careful evaluation of disease progression, predominance of one virus over another, comorbidities and concomitant hepatitis delta virus and/or HIV infection are essential for better therapy choices. In the case of HCV predominance, Peg-interferon plus ribavirin with or without a first-generation directly acting antiviral (DAA) should be the first choice, but future treatments will be DAA-based and interferon-free. In the case of HBV predominance, tenofovir or entecavir should be part of treatment. Patients should be closely monitored for early identification and treatment of HCV or HBV reactivation. EXPERT OPINION: High potency and high genetic barrier nucleos(t)ide analogues to inhibit HBV replication have been used for years, with no urgency for new drugs. Several DAAs for interferon-free therapy for HCV eradication will be available in the near future. We hope that the high cost of these drugs will not be a limitation to their use in developing countries. Further investigation of HBV/HCV interaction is needed before and during the administration of new therapies. PMID- 24773465 TI - Temperature-dependent variation in alternative migratory tactics and its implications for fitness and population dynamics in a salmonid fish. AB - Temperature-driven life-history modifications by adaptation occur in ectotherms, and therefore, life-history modifications by adaptation need to be taken into consideration when predicting population responses to the climate change. Partial migration is a common form of life-history diversity in which a population contains both migratory and resident behaviours. Salmonid fish exhibit a wide range of life-history diversity and, in particular, partial migration. We evaluated the effect of temperature-driven life-history modifications on population dynamics in partially migratory masu salmon (Oncorhynchus masou) by field observations and theoretical models. Field observations revealed that spatial patterns of alternative migratory tactics were associated with temperature gradients. The occurrence of resident males increased, whereas the proportion of migrant males and the proportion of delayed migrants including both sexes decreased with increasing temperature and, thereby, with improved early growth conditions. The expected fitness for each migratory tactic was computed in a life-history model with early growth conditions as a function. Individual fitness was maximized by adopting resident tactics under favourable early growth conditions, early migrant tactics under intermediate early growth conditions and delayed migrant tactics under unfavourable early growth conditions. The results suggest that individuals exhibited a status-dependent conditional strategy, that is, the adoption of alternative migratory tactics is influenced by the status of individuals to make the best of a situation. A simulation model suggests that increased residency by males to increased temperature leads to a substantial decrease in the number of migrants. Moreover, the decrease in the number of delayed (older) migrants with increasing temperature magnified fluctuations in abundance. Our findings indicate the importance of temperature-driven life history modifications for predicting dynamics of natural populations under climate warming. PMID- 24773467 TI - Identifying the characteristics of nurse opinion leaders to aid the integration of genetics in nursing practice. AB - AIM: To identify the characteristics of nurses opinion leaders in the context of genetics in health care and consider the findings for the integration of genetics in nursing practice. BACKGROUND: Nurses need a basic understanding of the role genetics plays in their practice and about how best to support patients using genetic knowledge. Opinion leaders have been used previously to incorporate change initiatives and increase educational application. Identifying the characteristics of nurse opinion leaders may aid the engagement and continued integration of genetics into nursing practice. DESIGN: A primarily quantitative approach over two phases, using online surveys conducted during 2011. METHOD: This article focuses on Phase 2 of a wider study. Oncology and primary care nurses were surveyed to identify the characteristics and demographic indicators of nurse opinion leaders. Tests for data normality followed by the suitable test for group comparison was applied with significance level set at <0.05. RESULTS: Nineteen respondents (n = 19/88; 21.6%) were categorized as opinion leaders and two subgroups were identified: Genetic Opinion Leaders and Opinion Leaders with an Interest in Genetics. Seven characteristics were deemed statistically significant (Mann-Whitney, Chi-Square, t-test) in identifying nurse opinion leaders, including being open to experience and having a perceived level of influence over others. CONCLUSION: The identified characteristics could be used to enhance the integration of genetics into nursing practice through the use of opinion leaders. Further thought needs to be given to the refinement of the identified characteristics and to the use of such a unique group of nurses. PMID- 24773468 TI - Western blotting by thin-film direct coating. AB - A novel thin-film direct coating (TDC) technique was developed to markedly reduce the amount of antibody required for Western blotting (WB). Automatic application of the technique for a few seconds easily and homogeneously coats the specific primary antibody on the polyvinylidene fluoride (PVDF) membrane. While conventional WB requires 0.4 MUg of the primary antibody, the proposed technique only uses 4 * 10(-2) MUg, which can be reduced further to 4 * 10(-5) MUg by reducing the coater width. Moreover, the proposed process reduces antibody probing times from 60 to 10 min. The quantification capability of TDC WB showed high linearity within a 4-log2 dynamic range for detecting target antigen glutathione-S-transferase. Furthermore, TDC WB can specifically detect the extrinsic glutathione-S-transferase added in the Escherichia coli or 293T cell lysate with better staining sensitivity than conventional WB. TDC WB can also clearly probe the intrinsic beta-actin, alpha-tubulin, and glyceraldehyde 3 phosphate dehydrogenase, which are usually used as control proteins in biological experiments. This novel technique has been shown to not only have valuable potential for increasing WB efficiency but also for providing significant material savings for future biomedical applications. PMID- 24773466 TI - Refractory asthma: mechanisms, targets, and therapy. AB - Asthma is a common medical condition affecting 300 million people worldwide. Airway inflammation, smooth muscle bronchoconstriction leading to airflow obstruction, and mucous hypersecretion are clinical hallmarks of asthma. The NHLBI Expert Panel Report 3 recommends inhaled corticosteroids (ICS) for patients with moderate to severe persistent asthma. Inhaled corticosteroids (ICS) target gene transcription through their interactions with the glucocorticoid (GC) receptor (GR) at the glucocorticoid response element (GRE). The GC/GR complex enhances anti-inflammatory but inhibits pro-inflammatory mediator production. Classically, asthma has been described as a Th2-associated eosinophil-predominant disease, but recently alternative models have been described including a Th17 mediated neutrophil-predominant phenotype resulting in patients with more severe disease who may be less responsive to steroids. Additional mechanisms of steroid resistance include increased activity of GR phosphorylating kinases which modify the interactions of GR with transcription factors to inhibit the ability of GR to bind with GRE, leading to an increase in pro-inflammatory gene transcription. Oxidative stress also affects the balance between pro-inflammatory and anti inflammatory gene transcription through the modification of transcription factors and cofactors (such as PI3K) leading to the inhibition of histone deacetylase 2. Continued investigations into the mechanisms behind glucocorticoid resistance will lead to novel treatments that improve control of severe refractory asthma. PMID- 24773470 TI - A prospective randomised comparison of two insertion methods for i-gel placement in anaesthetised paralysed patients: standard vs. rotational technique. AB - In this prospective randomised study, we compared two techniques for i-gel(TM) insertion. One hundred and eighty-one anaesthetised, paralysed adult patients were randomly allocated into one of two groups. In the standard group (n = 91), the i-gel was inserted using the standard technique. In the rotation group (n = 90), the i-gel was rotated 90 degrees anticlockwise in the mouth and re-rotated in the hypopharynx to the original alignment. The success rate, insertion time, air leak pressure and complications were assessed. The success rate for insertion at the first attempt was lower for the standard technique, 78 (86%) vs. 87 (97%; p = 0.016). The mean (SD) insertion time was longer (26.9 (14.5) s vs. 22.4 (10.2) s; p = 0.016) and air leak pressure was lower (22.5 (10.4) cm H2O vs. 27.1 (9.4) cm H2O; p = 0.002) in the standard group. The incidence of bloodstaining was higher with the standard technique (8 (9%) vs. 1 (1%); p = 0.034). This study suggests that the rotational technique is superior to the standard technique for i-gel insertion. PMID- 24773471 TI - Species composition and diversity of parasitoids and hyper-parasitoids in different wheat agro-farming systems. AB - Insect communities depend on both their local environment and features of the surrounding habitats. Diverse plant communities may enhance the abundance and species diversity of local natural enemies, which is possible due to a higher abundance and species diversity in complex landscapes. This hypothesis was tested using cereal aphid parasitoids and hyper-parasitoids by comparing 18 spring wheat fields, Triticum aestivum L. (Poales: Poaceae), in structurally-complex landscapes (dominated by semi-natural habitat, > 50%, n = 9) and structurally simple landscapes dominated by arable landscape (dominated by crop land, > 80%, n = 9). The agricultural landscape structure had significant effects on the number of parasitoid and hyper-parasitoid species, as 26 species (17 parasitoids and 9 hyper-parasitoids) were found in the complex landscapes and 21 were found in the simple landscapes (14 parasitoids and 7 hyper-parasitoids). Twenty-one species occurred in both landscape types, including 14 parasitoids and 7 hyper parasitoids species. The species diversity of parasitoids and hyper-parasitoids were significantly different between the complex and simple landscapes. In addition, arable fields in structurally-simple agricultural landscapes with little semi-natural habitats could support a lower diversity of cereal aphid parasitoids and hyper-parasitoids than structurally-complex landscapes. These findings suggest that cereal aphid parasitoids and hyper-parasitoids need to find necessary resources in structurally-complex landscapes, and generalizations are made concerning the relationship between landscape composition and biodiversity in agricultural landscapes. Overall, abundance, species richness, and species diversity increased with increasing plant diversity and landscape complexity in spring wheat fields and increasing amounts of semi-natural habitats in the surrounding landscape. PMID- 24773472 TI - Discriminating toxicant classes by mode of action: 4. Baseline and excess toxicity. AB - Functional similarity of chemicals combines toxicological knowledge (which toxicity pathways can happen in which species under which exposure conditions) with chemical expertise (which parts of the chemical structures and physico chemical properties are involved in which interactions) to discriminate between baseline and excess toxicants. The objective is to identify as many baseline toxicants as possible because their acute fish toxicities can be predicted with sufficient accuracy from their log Kow. Established tools like structural alerts are used to indicate modes of action (MOAs) that are typical causes of excess toxicity. Verhaar classifications are supplemented with additional chemical attributes and physico-chemical property thresholds to cover a larger range of compounds within the baseline toxicity domain. Our approach is precautionary to avoid false negatives with a sensitivity of 96.3%. It classifies 57.1% of the compounds of the EPA Fathead Minnow Acute Toxicity Database (EPAFHM) as baseline toxicants and suggests that more than 50% of acute fish toxicity testing could be replaced by reliable QSAR predictions. Furthermore, functional similarity can support the MOA classification of chemicals in different species. Toxicity profiles with fish, Daphnia and algae reveal specific targets for the compounds and, particularly for chemicals with multiple MOA, identify the most sensitive species. PMID- 24773473 TI - Oxygen vacancies confined in ultrathin indium oxide porous sheets for promoted visible-light water splitting. AB - Finding an ideal model for disclosing the role of oxygen vacancies in photocatalysis remains a huge challenge. Herein, O-vacancies confined in atomically thin sheets is proposed as an excellent platform to study the O vacancy-photocatalysis relationship. As an example, O-vacancy-rich/-poor 5-atom thick In2O3 porous sheets are first synthesized via a mesoscopic-assembly fast heating strategy, taking advantage of an artificial hexagonal mesostructured In oleate complex. Theoretical/experimental results reveal that the O-vacancies endow 5-atom-thick In2O3 sheets with a new donor level and increased states of density, hence narrowing the band gap from the UV to visible regime and improving the carrier separation efficiency. As expected, the O-vacancy-rich ultrathin In2O3 porous sheets-based photoelectrode exhibits a visible-light photocurrent of 1.73 mA/cm(2), over 2.5 and 15 times larger than that of the O-vacancy-poor ultrathin In2O3 porous sheets- and bulk In2O3-based photoelectrodes. PMID- 24773474 TI - Dissecting the effects of concentrated carbohydrate solutions on protein diffusion, hydration, and internal dynamics. AB - We present herein a thorough description of the effects of high glucose concentrations on the diffusion, hydration and internal dynamics of ubiquitin, as predicted from extensive molecular dynamics simulations on several systems described at fully atomistic level. We observe that the protein acts as a seed that speeds up the natural propensity of glucose to cluster at high concentration; the sugar molecules thus aggregate around the protein trapping it inside a dynamic cage. This process extensively dehydrates the protein surface, restricts the motions of the remaining water molecules, and drags the large scale, collective motions of protein atoms slowing down the rate of exploration of the conformational space despite only a slight dampening of fast, local dynamics. We discuss how these effects could be relevant to the function of sugars as preservation agents in biological materials, and how crowding by small sticky molecules could modulate proteins across different reaction coordinates inside the cellular cytosol. PMID- 24773475 TI - Theoretical study on the kinetics of the reaction CH2Br + NO2. AB - The mechanism for the reaction CH2Br + NO2 was investigated by quantum chemical calculation, and the kinetic calculations were carried out by means of multichannel RRKM and variational transition-state theory method. Both singlet and triplet potential energy surfaces (PESs) were considered at the CCSD(T)/6 311++G(d,p)//B3LYP/6-311G(d,p) level. The results show that the singlet PES is preferred, and the initial association is a barrierless process (CH2Br + NO2 -> CH2BrNO2), consistent with previous study, while the reaction occurring on the triplet PES is unfavorable due to the high barriers at the entrance channels. The calculated overall rate constants agree well with the experimental data within the measured temperature range of 221-363 K, fitted to the expression of k(T) = 2.61 * 10(-10)T(-0.76) exp(461/T) cm(3) molecule(-1) s(-1) over the temperature range of 200-2000 K. The product ratios were obtained by using master equation modeling and show that the formation of product CH2O + BrNO (P1) is dominant, in line with the experimental observation. PMID- 24773476 TI - Direct and stereospecific interaction of amphidinol 3 with sterol in lipid bilayers. AB - Amphidinol 3 (AM3), a polyhydroxy-polyene metabolite from the dinoflagellate Amphidinium klebsii, possesses potent antifungal activity. Although AM3 permeabilizes phospholipid membranes only in the presence of sterol, the detailed molecular basis by which AM3 recognizes sterols in membranes remains unknown. Here, we investigated the molecular interaction between sterols and AM3 in membranes from the viewpoint of stereospecific molecular recognition using ergosterol, cholesterol, and epicholesterol, which is the 3-OH epimer of cholesterol. Dye leakage assays, surface plasmon resonance experiments, (2)H and (31)P NMR measurements, and microscopic observations revealed that AM3 directly interacts with membrane sterols through the strict molecular recognition of the stereochemistry of the sterol 3-OH group. The direct interaction enhances the membrane binding efficiency of AM3, which subsequently permeabilizes membranes without altering membrane integrity. PMID- 24773477 TI - Single-molecule positioning in zeromode waveguides by DNA origami nanoadapters. AB - Nanotechnology is challenged by the need to connect top-down produced nanostructures with the bottom-up world of chemistry. A nanobiotechnological prime example is the positioning of single polymerase molecules in small holes in metal films, so-called zeromode waveguides (ZMWs), which is required for single molecule real-time DNA sequencing. In this work, we present nanoadapters made of DNA (DNA origami) that match the size of the holes so that exactly one nanoadapter fits in each hole. By site-selective functionalization of the DNA origami nanoadapters, we placed single dye molecules in the ZMWs, thus optimizing the hole usage and improving the photophysical properties of dyes compared to stochastically immobilized molecules. PMID- 24773478 TI - The cost-effectiveness of CT-guided sacroiliac joint injections: a measure of QALY gained. AB - OBJECTIVE: The purpose of this study is to estimate the total cost and the quality of life years (QALY) gained for computer tomography (CT)-guided sacroiliac joint (SIJ) injections. The cost per QALY gained for the procedure is the primary end-point of this study. METHODS: In our 1-year prospective institutional study, we gathered 30 patients undergoing CT-guided SIJ injections for degenerative changes at the SIJ space. Patient-reported outcomes included both the US population-based EQ-5D (EuroQol) index score and the EQ-visual analog scale (VAS). The EQ-5D is based on mobility, self-care, usual activities, pain/discomfort, and anxiety depression. Utility expenditures were based on hospital charges at our institution. RESULTS: All 30 patients had one pre injection physician visit followed by 43 initial injections (13 bilateral). Each patient underwent one CT scan, and three patients required additional plain films. In the 1 year following the injections, 26 physician visits were documented. Five patients required repeat CT-guided injections. Total 1-year cost for all 30 patients was $34 874.00. Mean decrease in EQ-VAS was 0.60 (P = 0.187). The mean 1-year gain of 0.58 EQ-5D QALY reached statistical significance (P < 0.001). The cost per QALY gained by CT-guided sacroiliac injections was $2004.29. DISCUSSION: In one of the first cost analyses of CT-guided sacroiliac injections, we found that the procedure improves pain and activities of daily living. The cost per QALY gained by CT-guided sacroiliac injections falls well below the threshold cost of 1 QALY, suggesting that the procedure is strongly cost-effective. PMID- 24773479 TI - Stereotactic radiosurgery for primary malignant spinal tumors. AB - OBJECTIVES: We adopted stereotactic radiosurgery (SRS) to treat primary malignant spinal tumors. The objective of this study was to evaluate local control rate and to identify prognostic factors after SRS for primary malignant spinal tumors. METHODS: Medical records and radiological data for 29 patients with primary malignant spinal tumors were retrospectively analyzed. The histological diagnoses were chordoma (11 cases), chondrosarcoma (5 cases), osteosarcoma (3 cases), synovial sarcoma (3 cases), plasmacytoma (2 cases), Ewing sarcoma (2 cases), malignant peripheral nerve sheath tumor (2 cases), and malignant fibrous histiocytoma (1 case). Patient age ranged from 11 to 68 years (median, 46 years). Surgical resection and percutaneous biopsy were chosen as initial treatments in 25 and 4 cases, respectively. Stereotactic radiosurgery was used as primary treatment method in 14 cases and as a salvage treatment for progressed lesions in 15 cases. Distant metastasis was noted in two sarcoma patients. Eleven patients had undergone previous conventional external beam radiation therapy (cEBRT) before SRS. Overall survival, local progression-free survival, and the prognostic factors affecting local recurrence were investigated. RESULTS: Tumor volume ranged from 2.0 to 235 cc (median, 14 cc). Delivered radiation doses were from 12 to 50 Gy with two to six sessions. The mean radiation dose converted into a biological effective dose (BED) was 60 Gy (range, 43-105 Gy). The mean follow-up period was 50 months (range, 8-126 months). The mean overall survival was 84 months for chordoma patients and 104 months for sarcoma patients. No factors that affected overall survival were found. The mean local progression-free survival was 56 months for chordoma patients and 73 months for sarcoma patients. The recurrent mode of presentation was predictive of local progression of spinal sarcomas (P = 0.009). However, in chordoma patients, no factors were found to correlate with local recurrence. CONCLUSION: These preliminary results suggest that SRS could provide good local control when applied as postoperative adjuvant or salvage treatment after cEBRT for primary malignant spinal tumors. PMID- 24773480 TI - Clumsiness in fine motor tasks: evidence from the quantitative drawing evaluation of children with Down Syndrome. AB - INTRODUCTION: Drawing tests are commonly used for the clinical evaluation of cognitive capabilities in children with learning disabilities. We analysed quantitatively the drawings of children with Down Syndrome (DS) and of healthy, mental age-matched controls to characterise the features of fine motor skills in DS during a drawing task, with particular attention to clumsiness, a well-known feature of DS gross movements. METHODS: Twenty-three children with DS and 13 controls hand-copied the figures of a circle, a cross and a square on a sheet. An optoelectronic system allowed the acquisition of the three-dimensional track of the drawing. The participants' posture and upper limb movements were analysed as well. RESULTS: Results showed that the participants with DS tended to draw faster but with less accuracy than controls. DISCUSSION: While clumsiness in gross movements manifests mainly as slow, less efficient movements, it manifests as high velocity and inaccurate movements in fine motor tasks such as drawing. PMID- 24773482 TI - The importance of multidisciplinary skills in research and development. PMID- 24773481 TI - Use of 5% lidocaine medicated plasters for the treatment of pain in routine hospital practice: patient reported pain, functioning and satisfaction. AB - OBJECTIVE: 5% lidocaine medicated plasters are a topical option in the treatment of peripheral neuropathic pain, as monotherapy or as an adjunct to systemic medication. This study sought to determine the impact of lidocaine plaster use on self-reported pain, functioning and patient satisfaction within a large teaching hospital. RESEARCH DESIGN AND METHODS: Patients were selected from the pain and rheumatology outpatient departments in Cardiff, Wales (2008-9). Postal surveys were sent to patients prescribed lidocaine plaster asking whether patients currently used the plaster and, if not, reason for discontinuation. Patients were asked to record pain score before and after therapy initiation, percentage pain relief, duration of effectiveness and impact on functioning. MAIN OUTCOME MEASURES: Pain scores, pain relief and levels of functioning before and after treatment. RESULTS: A total of 850 surveys were dispatched; 408 (48.0%) responses received; 197 (48.3%) patients were current users at survey completion. Median pain score prior to plaster use was 8 (IQR 7-9). One month after initiation, median pain score was 6 (4-8, p < 0.001) overall and 5 (4-7, p < 0.001) for current users. Median pain relief, after initial month of plaster use, was 30% (10-60%) for all patients and 50% (30-70%) for current users, whilst pain relief at time of survey was 30% (0-60%) and 50% (30-70%), respectively. A total of 181 (93.3%) current users claimed the plasters were effective. All three measures of functioning were significantly improved in current users: sleep (63.3% versus 20.1%, p < 0.001), mood (59.2% versus 18.6%, p < 0.001) and activity level (50.0% versus 19.5%, p < 0.001). Median satisfaction was 5 (IQR 1-8) for all patients and 7 (5-9) for current plaster users. CONCLUSIONS: The results of this study need to be considered within the context of a self-reported survey. However, pain, functioning and patient satisfaction were significantly improved in current users of 5% lidocaine medicated plasters. PMID- 24773483 TI - Experimental and theoretical studies in the EU FP7 Marie Curie Initial Training Network Project, Environmental ChemOinformatics (ECO). PMID- 24773484 TI - The QSPR-THESAURUS: the online platform of the CADASTER project. AB - The aim of the CADASTER project (CAse Studies on the Development and Application of in Silico Techniques for Environmental Hazard and Risk Assessment) was to exemplify REACH-related hazard assessments for four classes of chemical compound, namely, polybrominated diphenylethers, per and polyfluorinated compounds, (benzo)triazoles, and musks and fragrances. The QSPR-THESAURUS website (http: / /qspr-thesaurus.eu) was established as the project's online platform to upload, store, apply, and also create, models within the project. We overview the main features of the website, such as model upload, experimental design and hazard assessment to support risk assessment, and integration with other web tools, all of which are essential parts of the QSPR-THESAURUS. PMID- 24773485 TI - Chlorotriazines do not activate the aryl hydrocarbon receptor, the oestrogen receptor or the thyroid receptor in in vitro assays. AB - Atrazine, prometryn, propazine and simazine are chlorotriazines that are commonly employed as herbicides. However, their use is a major cause of concern, due to their reported endocrine disrupting effects in different taxa. Data from studies on the molecular and cellular processes underlying the hormonal action of these substances are contradictory. The ability of these chlorotriazines and the atrazine metabolites, desethyl-s-chlorotriazine and desisopropyl-s chlorotriazine, to trigger responses mediated by the oestrogen receptor (ER), aryl hydrocarbon receptor (AhR) and thyroid receptor (TR), was studied by using in vitro approaches. Transcriptional activation assays were applied to observe the activation of ER and TR. The induction of ethoxyresorufin-O-deethylase (EROD) activity in the RTG-2 cell line served as an indicator of AhR activation. No responses were found in any of the assays, with any of the six chlorotriazines tested. Our observations indicate that the chlorotriazines tested are unlikely to cause their endocrine effects via these receptors. PMID- 24773486 TI - Prediction of acute aquatic toxicity toward Daphnia magna by using the GA-kNN method. AB - In this study, a QSAR model was developed from a data set consisting of 546 organic molecules, to predict acute aquatic toxicity toward Daphnia magna. A modified k-Nearest Neighbour (kNN) strategy was used as the regression method, which provided prediction only for those molecules with an average distance from the k nearest neighbours lower than a selected threshold. The final model showed good performance (R(2) and Q(2) cv equal to 0.78, Q(2) ext equal to 0.72). It comprised eight molecular descriptors that encoded information about lipophilicity, the formation of H-bonds, polar surface area, polarisability, nucleophilicity and electrophilicity. PMID- 24773487 TI - The application of QSAR approaches to nanoparticles. AB - Nanoparticles (NPs) are increasingly used throughout the world for many purposes. The resulting exposure increases the relevance of efforts to assess their effects. The activities of NPs are related to many structural features, including their shape, composition and size. Applying Quantitative Structure-Activity Relationship (QSAR) methods to nanoscale systems becomes challenging, due to the lack of data and insight into the fate and effects of NPs. In this study, the possible use of QSAR methods on NPs is investigated. To this intent, several ways of representing and describing NPs were tested by using different data mining methods. The main conclusion is that QSAR methods are relevant for the study of the activity of NPs, but this should be confirmed by using larger and more diverse sets of data. Moreover, representing the constitution of NPs (in terms of core, coating and surface modification) significantly increases the prediction accuracy of the models. In our case, the most significant features to be represented were found to be the core and surface modification. PMID- 24773488 TI - Estimation of the toxicity of silver nanoparticles by using planarian flatworms. AB - The regeneration of planarian flatworms - specifically, changes to the area of the regeneration bud (blastema) after surgical dissection - was proposed for use as a robust tool for estimating the toxicity of silver nanoparticles. The use of Planaria species, due to their unique regenerative capacity, could result in a reduction in the use of more-traditional laboratory animals for toxicity testing. With our novel approach, silver nanoparticles were found to be moderately toxic to the planarian, Girardia tigrina. PMID- 24773489 TI - Mechanistically-based QSARs to describe metabolic constants in mammals. AB - Biotransformation is one of the processes which influence the bioaccumulation of chemicals. The enzymatic action of metabolism involves two processes, i.e. the binding of the substrate to the enzyme followed by a catalytic reaction, which are described by the Michaelis-Menten constant (Km) and the maximum rate (Vmax). Here, we developed Quantitative Structure-Activity Relationships (QSARs) for Log(1/Km) and LogVmax for substrates of four enzyme classes. We focused on oxidations catalysed by alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), flavin-containing monooxygenase (FMO) and cytochrome P450 (CYP) in mammals. The chemicals investigated were xenobiotics, including alcohols, aldehydes, pesticides and drugs. We applied general linear models for this purpose, employing descriptors related to partitioning, geometric characteristics, and electronic properties of the substrates, which can be interpreted mechanistically. The explained variance of the QSARs varied between 20% and 70%, and it was larger for Log(1/Km) than for LogVmax. The increase of 1/Km with compound logP and size suggests that weak interactions are important, e.g. by substrate binding via desolvation processes. The importance of electronic factors for 1/Km was described in relation to the catalytic mechanism of the enzymes. Vmax was particularly influenced by electronic properties, such as dipole moment and energy of the lowest unoccupied molecular orbital. This can be explained by the nature of the catalysis, characterised by the cleavage and formation of covalent or ionic bonds (strong interactions). The present study may be helpful to understand the underlying principles of the chemical specific activity of four important oxidising enzymes. PMID- 24773490 TI - Ethoxyresorufin-O-deethylase (EROD) activity modulation of 2,3,7,8 tetrachlorodibenzo-p-dioxin and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) in the presence of aqueous suspensions of nano-C60. AB - The increase in commercial production and inevitable release of fullerenes into the environment accelerates concerns about their potential toxicity. Furthermore, the concomitant release of xenobiotics poses a health hazard to humans, and might present potential long-term risks to human health. In the present study, we found that an aqueous suspension of buckminsterfullerene (aqu-nC60) does not result in the induction of ethoxyresorufin-O-deethylase (EROD) activity in H4IIE rat liver cells in vitro. The simultaneous and sequential exposure of aqu-nC60 and the dioxin TCDD induces EROD activity to the same extent as TCDD alone (i.e. in the absence of fullerene), in spite of the high affinity of C60 for TCDD. However, the co-exposure of aqu-nC60 and PCB 126 induces elevated EROD activity, and sequential exposure increases responses 2-fold compared to the control samples. Our in vitro observations suggest a potential source of drug-drug type interaction of fullerene with xenobiotics, particularly after a sequential exposure. PMID- 24773491 TI - Quantitative structure-sorption relationships of pesticides used in the sugarcane industry in the northern coastal area of Paraiba State, Brazil. AB - Sorption coefficients (K(oc)) are useful in the prediction of whether a pesticide will remain dissolved in solution or will become adsorbed onto soil particles after its application. Measuring this process experimentally is difficult, expensive and time-consuming. Hence, much effort has been directed toward estimating K(oc) through statistical modelling. In this study, we investigated the physicochemical properties of pesticides employed by a local sugarcane company, in the northern coastal plain of Paraiba state in Brazil, by using several molecular descriptors, among them, GRid INdependent Descriptors (GRIND). Quantitative assessment of the structure-property relationship (QSPR) model indicated that size, shape, octanol-water coefficient, solubility and the balance between hydrophilic and lipophilic regions, are all relevant to K(oc) values. PMID- 24773492 TI - 9. The toxicity testing problem. PMID- 24773493 TI - Laboratory animal sciences training in gulf co-operation council countries: think globally, act locally. PMID- 24773494 TI - The virtual pharmacology lab - a repository of free educational resources to support animal-free pharmacology teaching. PMID- 24773495 TI - Ethical animal use in education and training: from clinical rotations to ethically sourced cadavers. PMID- 24773497 TI - Syntheses and molecular structures of monomeric and hydrogen-bonded dimeric Dawson-type trialuminum-substituted polyoxotungstates derived under acidic and basic conditions. AB - The syntheses and molecular structures of the two types of alpha-Dawson-type trialuminum-substituted polyoxometalates, [B-alpha-H3P2W15O59{Al(OH2)}3](6-) (1) and [B-alpha-H3P2W15O59{Al(OH)}2{Al(OH2)}]2(16-) (2), are described herein. The potassium and cesium salts of 1, K6[B-alpha-H3P2W15O59{Al(OH2)}3].14H2O (K-1), and Cs6[B-alpha-H3P2W15O59{Al(OH2)}3].13H2O (Cs-1) were formed by a stoichiometric reaction in water of trilacunary alpha-Dawson polyoxotungstate with aluminum nitrate under acidic conditions (pH ~3). The potassium/sodium and tetramethylammonium/sodium salts of 2, K14Na2[B-alpha H3P2W15O59{Al(OH)}2{Al(OH2)}]2.30H2O (KNa-2) and [(CH3)4N]14Na2[B-alpha H3P2W15O59{Al(OH)}2{Al(OH2)}]2.39H2O (TMANa-2) were obtained under basic conditions (pH ~9). These compounds were characterized by X-ray structure analyses, elemental analyses, thermogravimetric/differential thermal analyses, Fourier transform infrared, and solution (31)P, (27)Al, and (183)W NMR spectroscopy. The polyoxoanion 1 is a monomeric, alpha-Dawson-type structure, resulting in an overall C3v symmetry, while the polyoxoanion 2 is a hydrogen bonded dimeric structure, resulting in an overall S3 symmetry in the solid state. The pH dependence of polyoxoanions 1 and 2 in aqueous solution was also investigated by (31)P NMR spectroscopy. PMID- 24773498 TI - Dynamic variables and fluid responsiveness in patients for aortic stenosis surgery. AB - BACKGROUND: Aortic stenosis is the most common valvular disease in developed countries, but it carries an increased mortality during non-cardiac surgery underscoring the importance of adequate hemodynamic management. Further, haemodynamic management of patients immediately after surgery for aortic stenosis can be challenging. Prediction of fluid responsiveness using dynamic variables has not been sufficiently studied in patients for aortic stenosis surgery. METHODS: Observational study evaluating fluid responsiveness on 32 (31 analysed) patients scheduled for aortic valve replacement due to aortic stenosis on mechanical ventilation before and after valve replacement. Increase in stroke volume (oesophagus Doppler) >= 15% to a fluid challenge defined fluid responders. RESULTS: Before surgery (31 fluid loads performed in 31 patients), areas under receiver operating characteristics curves (95% confidence intervals) were stroke volume variation (from arterial pulse contour analysis) 0.77 (0.58-0.90), pulse pressure variation 0.75 (0.54-0.90) and Pleth variability index 0.51 (0.31-0.69). After aortic valve replacement (31 fluid loads performed in 23 patients) the values were stroke volume variation 0.90 (0.74-0.98), pulse pressure variation 0.95 (0.80-1.0) and Pleth variability index 0.72 (0.52-0.87). CONCLUSIONS: The arterial pressure-based variables had moderate predictive values before valve replacement, but it predicted fluid responsiveness well postoperatively. Pleth variability index did not predict fluid responsiveness preoperatively, and it had a moderate predictive value postoperatively. These results indicate that arterial pressure-based dynamic variables have limited potential to guide fluid therapy in patients with aortic stenosis. Their ability to guide fluid therapy after aortic valve replacement seems better. PMID- 24773499 TI - Novel individual metabolic profile characterizes the protein kinase B-alpha (pkbalpha-/-) in vivo model. AB - CONTEXT: Type 2 diabetes and associated co-morbidities run epidemic waves worldwide. Since pathophysiological constellations are individual and display a wide spread of dysmetabolic profiles personalized health care assessments start to emerge. Therefore, we established a specific in silico assessment tool targeting metabolic characterizations individually. MATERIALS AND METHODS: Values obtained from oral glucose and intraperitoneal insulin tolerance tests performed on pkbalpha(-/-) mice (KO) as well as age- and gender-matched controls (WT) were analysed using our established in silico model. RESULTS: Generally, male pkbalpha(-/-) mice (KO) presented significantly increased insulin sensitivity at an age of 6 months compared with age-matched WTs (p = 0.036). Female KO and WT groups displayed improved glucose sensitivities compared with age-matched males (for WT p <= 0.011). DISCUSSION AND CONCLUSION: Specific metabolic characterization should be assessed individually. Therefore, our in silico model enables novel insights inaugurating specific primary preventive strategies targeting individual metabolic profiling precisely. PMID- 24773500 TI - Forest structure drives global diversity of primates. AB - Geographic gradients in the species richness of non-human primates have traditionally been attributed to the variation in forest productivity (related to precipitation levels), although an all-inclusive, global-scale analysis has never been conducted. We perform a more comprehensive test on the role of precipitation and biomass production and propose an alternative hypothesis - the variation in vertical structure of forest habitats as measured by forest canopy height - in determining primate species richness on a global scale. Considering the potential causal relationships among precipitation, productivity and forest structure, we arranged these variables within a path framework to assess their direct and indirect associations with the pattern of primate species richness using structural equation modelling. The analysis also accounted for the influence of spatial autocorrelation in the relationships and assessed possible historical differences among biogeographical regions. The path coefficients indicate that forest canopy height (used as a proxy for vertical forest structure) is a better predictor of primate species richness than either precipitation or productivity on both global and continental scales. The only exception was Asia, where precipitation prevailed, albeit independently from productivity or forest structure. The influence of spatially structured processes varied markedly among biogeographical regions. Our results challenge the traditional rainfall-based viewpoint in favour of forest distribution and structure as primary drivers of primate species richness, which aggregate potential effects from both climatic factors and habitat complexity. These findings may support predictions of the impact of forest removal on primate species richness. PMID- 24773501 TI - Characterization of carbonized polydopamine nanoparticles suggests ordered supramolecular structure of polydopamine. AB - Polydopamine is not only a multifunctional biopolymer with promising optoelectronic properties but it is also a versatile coating platform for different surfaces. The structure and formation of polydopamine is an active area of research. Some studies have supposed that polydopamine is composed of covalently bonded dihydroxyindole, indoledione, and dopamine units, but others proposed that noncovalent self-assembly contributes to polydopamine formation as well. However, it is difficult to directly find the details of supramolecular structure of polydopamine via self-assembly. In this study, we first report the graphite-like nanostructure observed in the carbonized polydopamine nanoparticles in nitrogen (or argon) environment at 800 degrees C. Raman characterization, which presents the typical D band and G band, confirmed the existence of graphite like nanostructures. Our observation provides clear evidence for a layered stacking supramolecular structure of polydopamine. Particularly, the size of graphite-like domains is similar to that of disk-shaped aggregates hypothesized in previous study about the polymerization of 5,6-dihydroxyindole [ Biomacromolecules 2012 , 13 , 2379 ]. Analysis of the hierarchical structure of polydopamine helps us understand its formation. PMID- 24773502 TI - Gender differences in scholastic achievement: a meta-analysis. AB - A female advantage in school marks is a common finding in education research, and it extends to most course subjects (e.g., language, math, science), unlike what is found on achievement tests. However, questions remain concerning the quantification of these gender differences and the identification of relevant moderator variables. The present meta-analysis answered these questions by examining studies that included an evaluation of gender differences in teacher assigned school marks in elementary, junior/middle, or high school or at the university level (both undergraduate and graduate). The final analysis was based on 502 effect sizes drawn from 369 samples. A multilevel approach to meta analysis was used to handle the presence of nonindependent effect sizes in the overall sample. This method was complemented with an examination of results in separate subject matters with a mixed-effects meta-analytic model. A small but significant female advantage (mean d = 0.225, 95% CI [0.201, 0.249]) was demonstrated for the overall sample of effect sizes. Noteworthy findings were that the female advantage was largest for language courses (mean d = 0.374, 95% CI [0.316, 0.432]) and smallest for math courses (mean d = 0.069, 95% CI [0.014, 0.124]). Source of marks, nationality, racial composition of samples, and gender composition of samples were significant moderators of effect sizes. Finally, results showed that the magnitude of the female advantage was not affected by year of publication, thereby contradicting claims of a recent "boy crisis" in school achievement. The present meta-analysis demonstrated the presence of a stable female advantage in school marks while also identifying critical moderators. Implications for future educational and psychological research are discussed. PMID- 24773503 TI - On the proper functions of human mate preference adaptations: comment on Eastwick, Luchies, Finkel, and Hunt (2014). AB - Evolutionary psychologists have hypothesized that humans possess sex differentiated mate preference adaptations. In the context of long-term mating, men are hypothesized to more strongly prefer cues to youth and fecundity, whereas women are hypothesized to more strongly prefer cues to status-related attributes. Eastwick, Luchies, Finkel, and Hunt (2014) recently asserted that if men and women evolved sex-differentiated desires, they should exhibit similarly sex differentiated relational outcomes such as marital satisfaction in response to whether a partner fulfills those desires. This seemingly reasonable extrapolation from sex differences in mate preferences to sex differences in relationship outcomes is, from an evolutionary perspective, problematic and warrants careful conceptual analysis. Evolutionary psychologists have not predicted that selecting a mate with sex-differentiated desirable qualities always translates to more satisfying, trusting, and passionate relational outcomes. Indeed, in some cases obtaining an ideal partner is expected to lead to negative outcomes, such as incurring the costs of heightened courtship effort, mate retention exertion, and the painful experience of jealousy. There are 4 additional concerns with the Eastwick et al. analysis: (a) heterogeneous operationalizations of predictor and criterion variables, (b) inadequate treatment of individual differences in the expression of evolved mate preferences, (c) an overlooking of physical appearance cues central to women's long-term mate preferences, and (d) the impact of nonrandom mateship formation on sex-linked variances in preferred attributes (e.g., low status men and unattractive women may be underrepresented in studies of established couples). As conducted, the Eastwick et al. analyses, while valuable, did not adequately test function-related hypotheses derived from the evolutionary psychology of mate preferences. PMID- 24773504 TI - The many voices of Darwin's descendants: reply to Schmitt (2014). AB - This article elaborates on evolutionary perspectives relevant to the meta analytic portion of our recent review (Eastwick, Luchies, Finkel, & Hunt, 2014). We suggested that if men and women evolved sex-differentiated ideals (i.e., mate preferences), then they should exhibit sex-differentiated desires (e.g., romantic attraction) and/or relational outcomes (e.g., relationship satisfaction) with respect to live opposite-sex targets. Our meta-analysis revealed no support for these sex-differentiated desires and relational outcomes in either established relationship or mate selection contexts. With respect to established relationships, Schmitt (2014) has objected to the idea that relationship quality (one of our primarily romantic evaluation dependent measures) has functional relevance. In doing so, he neglects myriad evolutionary perspectives on the adaptive importance of the pair-bond and the wealth of data suggesting that relationship quality predicts the dissolution of pair-bonds. With respect to mate selection, Schmitt (2014) has continued to suggest that sex-differentiated patterns should emerge in these contexts despite the fact that our meta-analysis included this literature and found no sex differences. Schmitt (2014) also generated several novel sex-differentiated predictions with respect to attractiveness and earning prospects, but neither the existing literature nor reanalyses of our meta-analytic data reveal any support for his "proper" function related hypotheses. In short, there are diverse evolutionary perspectives relevant to mating, including our own synthesis; Schmitt's (2014) conceptual analysis is not the one-and-only evolutionary psychological view, and his alternative explanations for our meta-analytic data remain speculative. PMID- 24773505 TI - The trauma model of dissociation: inconvenient truths and stubborn fictions. Comment on Dalenberg et al. (2012). AB - Dalenberg et al. (2012) argued that convincing evidence (a) supports the longstanding trauma model (TM), which posits that early trauma plays a key role in the genesis of dissociation; and (b) refutes the fantasy model (FM), which posits that fantasy proneness, suggestibility, cognitive failures, and other variables foster dissociation. We review evidence bearing on Dalenberg et al.'s 8 predictions and find them largely wanting in empirical support. We contend that the authors repeat errors committed by many previous proponents of the TM, such as attributing a central etiological role to trauma in the absence of sufficient evidence. Specifically, Dalenberg et al. leap too quickly from correlational data to causal conclusions, do not adequately consider the lack of corroboration of abuse in many studies, and underestimate the relation between dissociation and false memories. Nevertheless, we identify points of agreement between the TM and FM regarding potential moderators and mediators of dissociative symptoms (e.g., family environment, biological vulnerabilities) and the hypothesis that dissociative identity disorder is a disorder of self-understanding. We acknowledge that trauma may play a causal role in dissociation but that this role is less central and specific than Dalenberg et al. contend. Finally, although a key assumption of the TM is dissociative amnesia, the notion that people can encode traumatic experiences without being able to recall them lacks strong empirical support. Accordingly, we conclude that the field should now abandon the simple trauma-dissociation model and embrace multifactorial models that accommodate the diversity of causes of dissociation and dissociative disorders. PMID- 24773506 TI - Reality versus fantasy: reply to Lynn et al. (2014). AB - We respond to Lynn et al.'s (2014) comments on our review (Dalenberg et al., 2012) demonstrating the superiority of the trauma model (TM) over the fantasy model (FM) in explaining the trauma-dissociation relationship. Lynn et al. conceded that our meta-analytic results support the TM hypothesis that trauma exposure is a causal risk factor for the development of dissociation. Although Lynn et al. suggested that our meta-analyses were selective, we respond that each omitted study failed to meet inclusion criteria; our meta-analyses thus reflect a balanced view of the predominant trauma-dissociation findings. In contrast, Lynn et al. were hypercritical of studies that supported the TM while ignoring methodological problems in studies presented as supportive of the FM. We clarify Lynn et al.'s misunderstandings of the TM and demonstrate consistent superiority in prediction of time course of dissociative symptoms, response to psychotherapy of dissociative patients, and pattern of relationships of trauma to dissociation. We defend our decision not to include studies using the Dissociative Experiences Scale-Comparison, a rarely used revision of the Dissociative Experiences Scale that shares less than 10% of the variance with the original scale. We highlight several areas of agreement: (a) Trauma plays a complex role in dissociation, involving indirect and direct paths; (b) dissociation-suggestibility relationships are small; and (c) controls and measurement issues should be addressed in future suggestibility and dissociation research. Considering the lack of evidence that dissociative individuals simply fantasize trauma, future researchers should examine more complex models of trauma and valid measures of dissociation. PMID- 24773507 TI - Recommendations for the management of food allergies in a preschool/childcare setting and prevention of anaphylaxis. AB - Food allergy and anaphylaxis occur most commonly in children under five, the majority of whom attend preschool and early childcare. Children under five differ significantly from school-aged children, as do their care environments, yet specific strategies for managing food allergies in early childcare settings are generally lacking in existing guidelines and legislation. In this review, we outline the scope of the problem, the unique challenges encountered in the preschool environment and existing policy and legislation in Australia, the US, Canada and the UK. We outline the management guidelines and resources available from specialist societies, and the evidence base for specific management strategies including voluntary versus legislative approaches, staff training and education, banning of foods, and availability of multiple and generic adrenaline auto-injectors. We call for greater uniformity and consistency of policy in regards to the recognition and management of infants and children with food allergy in the preschool environment and specific programmes and policies tailored to this environment. PMID- 24773508 TI - Neutrophils from allergic asthmatic patients produce and release metalloproteinase-9 upon direct exposure to allergens. AB - BACKGROUND: Asthma is characterized by airway inflammation and remodelling in which matrix metalloproteinases (MMPs) play an important role. MMP-9 is the major MMP found in the bronchoalveolar lavage fluids and bronchial biopsies from patients with allergic asthma after allergen challenge, where it correlates with the count of neutrophils and macrophages. However, the cellular sources of MMP-9 in this inflammatory condition have not yet been clearly identified. This work was undertaken to analyse whether neutrophils may be a source of MMP-9 in the allergic asthma condition upon allergen challenge. METHODS: Neutrophils from allergic asthmatic patients were in vitro stimulated, and the levels of MMP-9 release were measured in the cell culture supernatants using enzyme-linked immunosorbent assay (ELISA) and zymography. RESULTS: We show that MMP-9 is released by neutrophils, but not by eosinophils from allergic asthmatic patients in response to allergens to which the patients were sensitized. Neutrophils also released MMP-9 in response to anti-IgE Abs, and agonist Abs against FcepsilonRI, FcepsilonRII/CD23 and galectin-3. Inhibitors of transcription and translation, actinomycin D and cycloheximide, partially cancelled this process, suggesting that MMP-9 is also de novo synthesized in response to stimuli. We also show evidence that the MAPKs, p38 and extracellular signal-regulated kinase, as well as the transcription factor NF-kappaB, are involved, as specific chemical inhibitors of these cell-signalling pathways abolished the anti-IgE/allergen dependent MMP-9 release. CONCLUSIONS: These data demonstrate that the exposure of neutrophils to allergens leads to generation of MMP-9, which may then lead to remodelling in asthma. PMID- 24773509 TI - Production, optimization, and partial purification of lipase from Pseudomonas sp. strain BUP6, a novel rumen bacterium characterized from Malabari goat. AB - This study introduces a novel bacterium-Pseudomonas sp. strain BUP6-isolated from the rumen of the Malabari goat with efficiency for producing lipase. It showed significant production of lipase when grown in a newly designed basal medium, supplemented with vegetable oil. Suitability of five vegetable oils such as groundnut oil, coconut oil, olive oil, sunflower oil, and palm oil as inducer for the production of lipase was examined, and groundnut oil supported the highest production of lipase (96.15 U/mL). Various physical parameters required for the maximum production of lipase were statistically optimized. Plackett-Burmann design was employed to study the interactive effects of physical parameters and found that temperature, agitation, and pH effected the production of lipase significantly. The optimum conditions for lipase production (37 degrees C, 200 rpm, and pH 6.9) were detected by Box-Behnken design and response surface methodology, which resulted in the 0.3-fold increase (i.e., 126 U/mL) of the lipase activity over the unoptimized condition. The apparent molecular mass of partially purified lipase was 35 kDa, as judged by SDS-PAGE; the activity of lipase was also confirmed by native PAGE. Thus, this study focuses on the need for the exploitation of rumen microbes for the production of industrially significant and human-friendly biomolecules to meet the future needs. PMID- 24773510 TI - Intimate partner violence and current tobacco smoking in low- to middle-income countries: Individual participant meta-analysis of 231,892 women of reproductive age. AB - Research on the health impact of intimate partner violence (IPV) has primarily focused on gynaecological and sexual health outcomes or psychiatric disorders. Much less is known about the association between IPV and tobacco smoking among women of reproductive age in low- to middle-income countries. This study examines the association between exposure to IPV and current tobacco smoking among women of reproductive age from low- to middle-income countries. We used data from Demographic and Health Surveys from 29 countries (231,892 women, aged 15-49) to examine the association between exposure to IPV and current tobacco smoking. Data were pooled using random-effects meta-analysis. There was a significant association between IPV and current tobacco smoking (pooled adjusted odds ratio [OR] = 1.58; 95% CI: 1.38-1.79) after controlling for age, education, occupation, household wealth, religion and pregnancy status across countries. The association was moderately consistent across the 29 countries (I(2) = 55.3%, p < 0.0001). These findings suggest that exposure to IPV is associated with an increased likelihood of current tobacco smoking among women of reproductive age in low- to middle-income countries. Future research on the association between exposure to IPV and tobacco smoking in prospective cohort studies is warranted. PMID- 24773511 TI - Children prefer to learn from mind-readers. AB - Kim and Harris (, J. Cogn. Dev.) showed that children selectively learned from an informant who produced apparently magical outcomes as compared to another informant who produced only ordinary outcomes in the domain of everyday physics. In the present study, we tested children's ability to differentiate between and selectively learn from informants who displayed either an extraordinary or an ordinary ability in the domain of everyday psychology. Prior studies have shown that children come to appreciate what is ordinarily involved in knowing the private mental states of other people. Drawing on this research, we asked whether 3- to 4- and 5- to 6-year-old children preferentially learned from an informant who knew another person's mind via either an ordinary or an extraordinary form of communication. As compared to younger children, older children were more likely to learn from the extraordinary informant. Moreover, children's ability to differentiate between the two informants was a better predictor of their learning from the extraordinary informant than age. We discuss the findings in the light of prior work on selective learning, children's ideas about prayer and their understanding of impossibility. PMID- 24773512 TI - Behavioural cancer risk factors in women diagnosed with primary breast cancer. AB - AIMS: To investigate behavioural risk factors and self-efficacy among women diagnosed with breast cancer. BACKGROUND: The appearance of new tumours in breast cancer survivors is influenced by risk behaviours. Knowing their prevalence and women's perceived ability to adopt a healthy lifestyle would allow designing educational interventions aimed at modifying these behaviours. DESIGN: An observational cross-sectional study of women diagnosed with breast cancer. METHODS: The study was carried out in Asturias (Spain). A total of 2407 breast cancer patients diagnosed between 1998-2008 were selected and 492 women agreed to participate. Self-reported data on risk factors self-efficacy were gathered through a telephone interview based on the European Code against Cancer conducted between February-June 2010. RESULTS: A total of 16.1% of women in this study were regular smokers, 5% drank alcohol excessively, 49% were overweight, 54% reported a lower level of physical activity than recommended and 7.5% did not use sun protection. The Total Cancer Behavioural Risk indicator was calculated by adding up the results of all modifiable risks contained in the European Code against Cancer, with an average score of 21.6 in a scale from 0-78 points (0 = null cancer risk, 78 = maximum cancer risk). Self-efficacy levels were very high among our participants. CONCLUSION: The results suggest that there is a need to design programmes to promote a healthy lifestyle among women diagnosed with breast cancer. Nurses have an important role to play in planning and implementing these programmes, using the most efficient educational techniques. PMID- 24773513 TI - Disposable copper-based electrochemical sensor for anodic stripping voltammetry. AB - In this work, we report the first copper-based point-of-care sensor for electrochemical measurements demonstrated by zinc determination in blood serum. Heavy metals require careful monitoring, yet current methods are too complex for a point-of-care system. Electrochemistry offers a simple approach to metal detection on the microscale, but traditional carbon, gold (Au), or platinum (Pt) electrodes are difficult or expensive to microfabricate, preventing widespread use. Our sensor features a new low-cost electrode material, copper, which offers simple fabrication and compatibility with microfabrication and PCB processing, while maintaining competitive performance in electrochemical detection. Anodic stripping voltammetry of zinc using our new copper-based sensors exhibited a 140 nM (9.0 ppb) limit of detection (calculated) and sensitivity greater than 1 MUA/MUM in the acetate buffer. The sensor was also able to determine zinc in a bovine serum extract, and the results were verified with independent sensor measurements. These results demonstrate the advantageous qualities of this lab-on a-chip electrochemical sensor for clinical applications, which include a small sample volume (MUL scale), reduced cost, short response time, and high accuracy at low concentrations of analyte. PMID- 24773514 TI - Composition and diversity analysis of the gut bacterial community of the Oriental armyworm, Mythimna separata, determined by culture-independent and culture dependent techniques. AB - The intestinal bacteria community structure and diversity of the Oriental armyworm, Mythimna separata (Walker) (Lepidoptera: Noctuidae), was studied by analysis of a 16S rDNA clone library, denaturing gradient gel electrophoresis,and culture-dependent techniques. The 16S rDNA clone library revealed a bacterial community diversity comprising Cyanobacteria, Firmicutes, Actinobacteria, Gracilicutes and Proteobacteria, among which Escherichia coli (Migula) (Enterobacteriales: Enterobacteriaceae) was the dominant bacteria. The intestinal bacteria isolated by PCR-denaturing gradient gel electrophoresis were classified to Firmicutes, Proteobacteria, and Gracilicutes, and E. coli was again the dominant bacteria. The culture-dependent technique showed that the intestinal bacteria belonged to Firmicutes and Actinobacteria, and Staphylococcus was the dominant bacteria. The intestinal bacteria of M. separata were widely distributed among the groups Cyanobacteria, Firmicutes, Actinobacteria, Gracilicutes, Proteobacteria, and Gracilicutes. 16S rDNA clone library, denaturing gradient gel electrophoresis, and culture-dependent techniques should be integrated to obtain precise results in terms of the microbial community and its diversity. PMID- 24773515 TI - Knowledge of contraceptive methods and services among tertiary students in far North Queensland. AB - Despite the availability of a wide range of contraceptive options in Australia, rates of unintended pregnancy remain high. A survey of tertiary students in Far North Queensland in regard to their knowledge of contraceptive methods and services revealed significant deficiencies, suggesting that existing sex education and contraceptive advice services need improving if unplanned pregnancy rates are to be reduced in this population. PMID- 24773516 TI - Cx37 C1019T polymorphism may contribute to the pathogenesis of coronary heart disease. AB - OBJECTIVE: We conducted a meta-analysis of case-control studies to evaluate whether Cx37 C1019T (rs1764391 C>T) polymorphism may be implicated in the pathogenesis of coronary heart disease (CHD). METHODS: The MEDLINE (1966-2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980-2013), CINAHL (1982 2013), Web of Science (1945-2013), and the Chinese Biomedical Database (CBM) (1982-2013) were searched without language restrictions. Meta-analysis was performed with the use of the STATA statistical software. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated. RESULTS: Nine case control studies with a total of 1426 CHD patients and 929 healthy controls met the inclusion criteria. Our results revealed that Cx37 C1019T polymorphism might be significantly correlated with the risk of CHD (T allele vs. C allele: OR=1.63, 95% CI=1.20-2.21, p=0.002; CT+TT vs. CC: OR=1.86, 95% CI=1.28-2.69, p=0.001; TT vs. CC+CT: OR=1.81, 95% CI=1.24-2.64, p=0.002; TT vs. CC: OR=2.50, 95% CI=1.46 4.27, p=0.001; TT vs. CT: OR=1.53, 95% CI=1.12-2.09, p=0.008; respectively). Further subgroup analysis by country indicated that Cx37 C1019T polymorphism might be closely linked to an increased risk of CHD among Chinese populations, while no positive associations were observed among non-Chinese populations (all p>0.05). CONCLUSION: Our findings provide empirical evidence that Cx37 C1019T polymorphism may contribute to the pathogenesis of CHD, especially among Chinese populations. PMID- 24773517 TI - Preliminary study of gaze toward humans in photographs by individuals with autism, Down syndrome, or other intellectual disabilities: implications for design of visual scene displays. AB - Visual scene displays (VSDs) are a form of augmentative and alternative communication display in which language concepts are embedded into an image of a naturalistic event. VSDs are based on the theory that language learning occurs through interactions with other people, and recommendations for VSD design have emphasized using images of these events that include humans. However, many VSDs also include other items that could potentially be distracting. We examined gaze fixation in 18 school-aged participants with and without severe intellectual/developmental disabilities (i.e., individuals with typical development, autism, Down syndrome and other intellectual disabilities) while they viewed photographs with human figures of various sizes and locations in the image, appearing alongside other interesting, and potentially distracting items. In all groups, the human figures attracted attention rapidly (within 1.5 seconds). The proportions of each participant's own fixation time spent on the human figures were similar across all groups, as were the proportions of total fixations made to the human figures. Although the findings are preliminary, this initial evidence supports the inclusion of humans in VSD images. PMID- 24773518 TI - Oxidative trifluoromethylation and trifluoromethylthiolation reactions using (trifluoromethyl)trimethylsilane as a nucleophilic CF3 source. AB - The trifluoromethyl group is widely prevalent in many pharmaceuticals and agrochemicals because its incorporation into drug candidates could enhance chemical and metabolic stability, improve lipophilicity and bioavailability, and increase the protein bind affinity. Consequently, extensive attention has been devoted toward the development of efficient and versatile methods for introducing the CF3 group into various organic molecules. Direct trifluoromethylation reaction has become one of the most efficient and important approaches for constructing carbon-CF3 bonds. Traditionally, the nucleophilic trifluoromethylation reaction involves an electrophile and the CF3 anion, while the electrophilic trifluoromethylation reaction involves a nucleophile and the CF3 cation. In 2010, we proposed the concept of oxidative trifluoromethylation: the reaction of nucleophilic substrates and nucleophilic trifluoromethylation reagents in the presence of oxidants. In this Account, we describe our recent studies of oxidative trifluoromethylation reactions of various nucleophiles with CF3SiMe3 in the presence of oxidants. We have focused most of our efforts on constructing carbon-CF3 bonds via direct trifluoromethylation of various C-H bonds. We have demonstrated copper-mediated or -catalyzed or metal-free oxidative C-H trifluoromethylation of terminal alkynes, tertiary amines, arenes and heteroarenes, and terminal alkenes. Besides various C-H bonds, aryl boronic acids proved to be viable nucleophilic coupling partners for copper-mediated or catalyzed cross-coupling reactions with CF3SiMe3. To further expand the reaction scope, we also applied H-phosphonates to the oxidative trifluoromethylation system to construct P-CF3 bonds. Most recently, we developed silver-catalyzed hydrotrifluoromethylation of unactivated olefins. These studies explore boronic acids, C-H bonds, and P-H bonds as novel nucleophiles in transition-metal mediated or -catalyzed cross-coupling reactions with CF3SiMe3, opening new viewpoints for future trifluoromethylation reactions. Furthermore, we also achieved the oxidative trifluoromethylthiolation reactions of aryl boronic acids and terminal alkynes to construct carbon-SCF3 bonds by using CF3SiMe3 and elemental sulfur as the nucleophilic trifluoromethylthiolating reagent. These oxidative trifluoromethylation and trifluoromethylthiolation reactions tolerate a wide range of functional groups, affording a diverse array of CF3- and CF3S containing compounds with high efficiencies, and provide elegant and complementary alternatives to classical trifluoromethylation and trifluoromethylthiolation reactions. Because of the importance of the CF3 and SCF3 moieties in pharmaceuticals and agrochemicals, these reactions would have potential applications in the life science fields. PMID- 24773519 TI - Surfactant-triggered disassembly of electrostatic complexes probed at optical and quartz crystal microbalance length scales. AB - A critical advantage of electrostatic assemblies over covalent and crystalline bound materials is that associated structures can be disassembled into their original constituents. Nanoscale devices designed for the controlled release of functional molecules already exploit this property. To bring some insight into the mechanisms of disassembly and release, we study the disruption of molecular electrostatics-based interactions via competitive binding with ionic surfactants. To this aim, free-standing micrometer-size wires were synthesized using oppositely charged poly(diallyldimethylammonium chloride) and poly(acrylic acid) coated iron oxide nanoparticles. The disassembly is induced by the addition of sodium dodecyl sulfates that complex preferentially the positive polymers. The process is investigated at two different length scales: the length scale of the particles (10 nm) through the quartz crystal microbalance technique and that of the wires (>1 MUm) via optical microscopy. Upon surfactant addition, the disassembly is initiated at the surface of the wires by the release of nanoparticles and by the swelling of the structure. In a second step, erosion involving larger pieces takes over and culminates in the complete dissolution of the wires, confirming the hypothesis of a surface-type swelling and erosion process. PMID- 24773521 TI - Fatal injury caused by low-energy trauma - a 10-year rural cohort. AB - BACKGROUND: Death after injury with low energy has gained increasing focus lately, and seems to constitute a significant amount of trauma-related death. The aim of this study was to describe the epidemiology of deaths from low-energy trauma in a rural Norwegian cohort. METHODS: All deaths from external causes in Finnmark County, Norway, from 1995 to 2004 were identified retrospectively through the Norwegian Cause of Death Registry. Deaths caused by hanging, drowning, suffocation, poisoning, and electrocution were excluded. Trauma was categorised as high energy or low energy based on mechanism of injury. All low energy trauma deaths were then reviewed. RESULTS: There were 262 cases of trauma death during the period. Low-energy trauma counted for 43% of the trauma deaths, with an annual crude death rate of 13 per 100,000 inhabitants. Low falls accounted for 99% of the injuries. Fractures were sustained in 89% of cases and head injuries in 11%. Ninety per cent of patients had pre-existing medical conditions, and the median age was 82 years. Death was caused by a medical condition in 85% of cases. Fifty-two per cent of the patients died after discharge from the hospital. CONCLUSION: In this cohort, low-energy trauma was a significant contributor to trauma related death, especially among elderly and patients with pre-existing medical conditions. PMID- 24773520 TI - Hemorrhagic shock shifts the serum cytokine profile from pro- to anti inflammatory after experimental traumatic brain injury in mice. AB - Secondary insults, such as hemorrhagic shock (HS), worsen outcome from traumatic brain injury (TBI). Both TBI and HS modulate levels of inflammatory mediators. We evaluated the addition of HS on the inflammatory response to TBI. Adult male C57BL6J mice were randomized into five groups (n=4 [naive] or 8/group): naive; sham; TBI (through mild-to-moderate controlled cortical impact [CCI] at 5 m/sec, 1-mm depth), HS; and CCI+HS. All non-naive mice underwent identical monitoring and anesthesia. HS and CCI+HS underwent a 35-min period of pressure-controlled hemorrhage (target mean arterial pressure, 25-27 mm Hg) and a 90-min resuscitation with lactated Ringer's injection and autologous blood transfusion. Mice were sacrificed at 2 or 24 h after injury. Levels of 13 cytokines, six chemokines, and three growth factors were measured in serum and in five brain tissue regions. Serum levels of several proinflammatory mediators (eotaxin, interferon-inducible protein 10 [IP-10], keratinocyte chemoattractant [KC], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1alpha [MIP-1alpha], interleukin [IL]-5, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor [G-CSF]) were increased after CCI alone. Serum levels of fewer proinflammatory mediators (IL-5, IL-6, regulated upon activation, normal T-cell expressed, and secreted, and G-CSF) were increased after CCI+HS. Serum level of anti-inflammatory IL-10 was significantly increased after CCI+HS versus CCI alone. Brain tissue levels of eotaxin, IP-10, KC, MCP-1, MIP-1alpha, IL-6, and G-CSF were increased after both CCI and CCI+HS. There were no significant differences between levels after CCI alone and CCI+HS in any mediator. Addition of HS to experimental TBI led to a shift toward an anti inflammatory serum profile--specifically, a marked increase in IL-10 levels. The brain cytokine and chemokine profile after TBI was minimally affected by the addition of HS. PMID- 24773522 TI - Electron-transfer studies of a peroxide dianion. AB - A peroxide dianion (O2(2-)) can be isolated within the cavity of hexacarboxamide cryptand, [(O2)?mBDCA-5t-H6](2-), stabilized by hydrogen bonding but otherwise free of proton or metal-ion association. This feature has allowed the electron transfer (ET) kinetics of isolated peroxide to be examined chemically and electrochemically. The ET of [(O2)?mBDCA-5t-H6](2-) with a series of seven quinones, with reduction potentials spanning 1 V, has been examined by stopped flow spectroscopy. The kinetics of the homogeneous ET reaction has been correlated to heterogeneous ET kinetics as measured electrochemically to provide a unified description of ET between the Butler-Volmer and Marcus models. The chemical and electrochemical oxidation kinetics together indicate that the oxidative ET of O2(2-) occurs by an outer-sphere mechanism that exhibits significant nonadiabatic character, suggesting that the highest occupied molecular orbital of O2(2-) within the cryptand is sterically shielded from the oxidizing species. An understanding of the ET chemistry of a free peroxide dianion will be useful in studies of metal-air batteries and the use of [(O2)?mBDCA-5t-H6](2-) as a chemical reagent. PMID- 24773523 TI - Improving health status and reduction of institutionalization in long-term care- Effects of the Resident Assessment Instrument-Home Care by degree of implementation. AB - A cluster randomized controlled trial showed that the Resident Assessment Instrument (RAI) could not improve or stabilize the health status of people in need of long-term care or reduce the rate of institutionalization in Germany among clients of home care agencies. The aim of this article is to investigate whether the effect of RAI depends on the degree of implementation. A factor analysis was used to distinguish between those agencies that implemented RAI intensively and those that did not. The clients of home care agencies working intensively with RAI were significantly less hospitalized (P = 0.0284) and fared slightly better according to activities of daily living (ADL, instrumental ADL (IADL)), cognitive skills (Mini-Mental Status Test (MMST)) and quality of life (EuroQol (EQ-5D)) compared with the control group. In contrast, those not working intensively with RAI had worse outcomes (IADL, MMST, EQ-5D) than the control group (not significant). It is important to guarantee a successful implementation of RAI. PMID- 24773524 TI - The relationship between the social management of emotional intelligence and academic performance among medical students. AB - Positive social interaction with peers was said to facilitate cognitive and intellectual development leading to good academic performance. There was paucity of published data on the effect of social management (SM) emotional intelligence (EI) on academic performance. We conducted this study to examine their relationship in the undergraduate medical students in a public medical school in Malaysia. This was a cross-sectional study using the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) to measure the SM. The first and final year medical students were invited to participate. Students answered a paper-based demography questionnaire and completed the online MSCEIT in privacy. Independent predictors were identified using multivariate analyses. A total of 163 (84 first year and 79 final year) medical students completed the study (at a response rate of 66.0%). SM score (B = -.10 95% CI -.175 to -.015, p = .021) was significantly related to the continuous assessment (CA) marks (adjusted R(2) = .45, F13,137 = 10.26, p < .0001), and was a predictor of poor result in the overall CA (adjusted OR 1.06 95% CI 1.011-1.105). Negative relationships might exist between emotional social intelligence and academic success in undergraduate medical students. A different collection of social skills and SM EI could be constructive towards academic achievement in medical schools. PMID- 24773526 TI - Gambling expenditure predicts harm: evidence from a venue-level study. AB - BACKGROUND AND AIMS: The Total Consumption Theory of gambling suggests that gambling expenditure is positively associated with gambling-related harm. We test the hypothesis that electronic gaming machine (EGM) expenditure predicts gambling related harm at the level of the EGM venue. DESIGN: Cross-sectional analysis of survey and administrative data. SETTING: General urban adult population of the Northern Territory of Australia. PARTICIPANTS: The sample consisted of 7049 respondents to a mail-survey about venue visitation and gambling behaviour across 62 EGM venues. MEASUREMENTS: Gambling-related harm was defined as the endorsement of two or more items on the Problem Gambling Severity Index. We obtained venue level EGM expenditure data from the local licensing authority for all venues in the study area. We compared the prevalence of gambling-related harm among patrons aggregated at the venue level with the estimated mean EGM expenditure for each adult resident in the venue's service area using a Huff model, correlation analysis and multivariate binomial regression. FINDINGS: Aggregated to the venue level (n = 62), per-capita EGM expenditure was correlated significantly with rates of gambling-related harm (r = 0.27, n = 62, P = 0.03). After adjusting for venue type and number of EGMs, an increase in mean per-capita monthly EGM expenditure from $AU10 to $AU150 was associated with a doubling in the prevalence of gambling-related harm from 9% (95% CI = 6-12%) to 18% (95% CI = 13-23%). CONCLUSIONS: As suggested by the Total Consumption Theory of gambling, aggregate patron electronic gaming machine expenditure predicts the prevalence of gambling related harm at the venue level. PMID- 24773525 TI - Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes. AB - The appearance of circulating islet-specific autoantibodies before disease diagnosis is a hallmark of human type 1 diabetes (T1D), and suggests a role for B cells in the pathogenesis of the disease. Alterations in the peripheral B cell compartment have been reported in T1D patients; however, to date, such studies have produced conflicting results and have been limited by sample size. In this study, we have performed a detailed characterization of the B cell compartment in T1D patients (n = 45) and healthy controls (n = 46), and assessed the secretion of the anti-inflammatory cytokine interleukin (IL)-10 in purified B cells from the same donors. Overall, we found no evidence for a profound alteration of the B cell compartment or in the production of IL-10 in peripheral blood of T1D patients. We also investigated age-related changes in peripheral B cell subsets and confirmed the sharp decrease with age of transitional CD19(+) CD27(-) CD24(hi) CD38(hi) B cells, a subset that has recently been ascribed a putative regulatory function. Genetic analysis of the B cell compartment revealed evidence for association of the IL2-IL21 T1D locus with IL-10 production by both memory B cells (P = 6.4 * 10(-4) ) and islet-specific CD4(+) T cells (P = 2.9 * 10(-3) ). In contrast to previous reports, we found no evidence for an alteration of the B cell compartment in healthy individuals homozygous for the non-synonymous PTPN22 Trp(620) T1D risk allele (rs2476601; Arg(620) Trp). The IL2-IL21 association we have identified, if confirmed, suggests a novel role for B cells in T1D pathogenesis through the production of IL-10, and reinforces the importance of IL 10 production by autoreactive CD4(+) T cells. PMID- 24773527 TI - A simple, rapid one-step ELISA using antibody-antibody complex. AB - The enzyme-linked immunosorbent assay (ELISA) is one of the most frequently employed assays for clinical diagnostic testing and biological research. However, its time-consuming operation is a major drawback. The present work aims to establish a one-step ELISA method through the preparation of a primary antibody (Ab)-secondary Ab complex (Ab-Ab complex) in hopes of realizing more sensitive and faster detection of the trace amount of antigen (Ag). By controlling the mole ratio of the primary Ab to the secondary Ab, one-step ELISA can be successfully achieved. Compared with the traditional ELISA, the one-step ELISA could not only improve the detection sensitivity to 1 ng mL(-1) , but also reduce the operating time by 30%. Moreover, the signal intensity can be controlled by adjusting the ratio of the secondary Ab in the complex or by changing the color development time. This technique is further optimized to detect trace amounts of proteins adsorbed onto poly(N-vinylpyrrolidone) (PVP)-modified silicon surfaces (Si-PVP), and the results are close to the radiolabeling method. It is concluded that the simple one-step ELISA can be used for the rapid detection of trace amount of protein. The method holds promise for the clinical detection of trace Ag in solution and on low-adsorption material surfaces. PMID- 24773528 TI - Role of integrin signalling through integrin-linked kinase in skin physiology and pathology. AB - Cell-matrix adhesions provide structural stability to the tissue and regulate intracellular signalling pathways that are important for cell fate decisions of the different cell populations within the skin. As a consequence of these central functions, genetic or functional impairment of various key protein components of matrix adhesions plays a causative role in the aetiology or pathophysiology in a large variety of skin disorders. Research towards understanding the molecular composition of these adhesions as well as the mechanisms by which they transmit signals is therefore of obvious importance. In this essay, we discuss the roles of integrin-linked kinase, a key component of cell-matrix adhesions, in the (patho)physiology of skin and in particular highlight its role in regulating mechanical tension and matrix remodelling both in the epidermis and in the dermis. PMID- 24773529 TI - Tungsten-catalyzed regioselective and stereospecific ring opening of 2,3-epoxy alcohols and 2,3-epoxy sulfonamides. AB - The first catalytic, highly C3-selective, stereosepecific ring-opening reaction of 2,3-epoxy alcohols and 2,3-epoxy sulfonamides has been accomplished. This process was efficiently promoted by W-salts, and the developed method was applicable to various epoxides with diverse N- and O-nucleophiles affording the products in good to excellent yields (up to 95%) and generally with high regioselectivities (C3:C2 up to >99:1). PMID- 24773531 TI - Solubility of nonelectrolytes: a first-principles computational approach. AB - Using a combination of classical molecular dynamics and symmetry adapted intermolecular perturbation theory, we develop a high-accuracy computational method for examining the solubility energetics of nonelectrolytes. This approach is used to accurately compute the cohesive energy density and Hildebrand solubility parameters of 26 molecular liquids. The energy decomposition of symmetry adapted perturbation theory is then utilized to develop multicomponent Hansen-like solubility parameters. These parameters are shown to reproduce the solvent categorizations (nonpolar, polar aprotic, or polar protic) of all molecular liquids studied while lending quantitative rigor to these qualitative categorizations via the introduction of simple, easily computable parameters. Notably, we find that by monitoring the first-order exchange energy contribution to the total interaction energy, one can rigorously determine the hydrogen bonding character of a molecular liquid. Finally, this method is applied to compute explicitly the Flory interaction parameter and the free energy of mixing for two different small molecule mixtures, reproducing the known miscibilities. This methodology represents an important step toward the prediction of molecular solubility from first principles. PMID- 24773530 TI - Induced pluripotent stem cells have similar immunogenic and more potent immunomodulatory properties compared with bone marrow-derived stromal cells in vitro. AB - AIM: To evaluate the in vitro immunogenic and immunomodulatory properties of induced pluripotent stem cells (iPSCs) compared with bone marrow-derived mesenchymal stromal cells (MSCs). MATERIALS & METHODS: Mouse embryonic fibroblasts (MEFs) were isolated from C3HeB/FeJ and C57BL/6J mice, and reprogrammed to generate iPSCs. Mixed leukocyte reactions were performed using MHC-matched and -mismatched responder leukocytes and stimulator leukocytes, iPSCs or MSCs. To assess immunogenic potential, iPSCs and MSCs were used as stimulator cells for responder leukocytes. To assess immunomodulatory properties, iPSCs and MSCs were cultured in the presence of stimulator and responder leukocytes. MEFs were used as a control. RESULTS: iPSCs had similar immunogenic properties but more potent immunomodulatory effects than MSCs. Co-culture of MHC-mismatched leukocytes with MHC-matched iPSCs resulted in significantly less responder T-cell proliferation than observed for MHC-mismatched leukocytes alone and at more responder leukocyte concentrations than with MSCs. In addition, MHC-mismatched iPSCs significantly reduced responder T-cell proliferation when co-cultured with MHC-mismatched leukocytes, while MHC-mismatched MSCs did not. CONCLUSION: These results provide important information when considering the use of iPSCs in place of MSCs in both regenerative and transplantation medicine. PMID- 24773533 TI - Promotional effects of mesoporous zeolites with Pt nanoparticle catalysts during reforming of methylcyclopentane. AB - Selective C-C and C-H bond activations are an important catalytic process to produce various value-added hydrocarbons via reforming processes. For producing desired product with a high yield, control of reaction pathway through the design of catalyst and fundamental understanding and clarification of reaction mechanism are prerequisite. In this work, we designed heterogeneous catalysts by combining Pt nanoparticles and two different mesoporous zeolites with microporous frameworks of BEA and MFI for the hydrogenative model reforming reaction of hydrocarbon (i.e., methylcyclopentane). Depending on the catalyst combination, the reaction pathways of (i) dehydrogenation, (ii) ring-opening with isomerization, and ring-enlargement with (iii) hydrogenation and (iv) dehydrogenation of C5-cyclic ring to C6-cyclic ring (i.e., cyclohexane and benzene) can be controlled to produce various products with high yields. Furthermore, we revealed a reaction intermediate formed at the interface of Pt and zeolite by real-time surface vibrational sum-frequency generation spectroscopic studies. This study would provide practical and fundamental insights for design of heterogeneous catalyst for controlling reaction pathways. PMID- 24773532 TI - The C-terminal threonine of Abeta43 nucleates toxic aggregation via structural and dynamical changes in monomers and protofibrils. AB - Recent studies suggest that deposition of amyloid beta (Abeta) into oligomeric aggregates and fibrils, hallmarks of Alzheimer's disease, may be initiated by the aggregation of Abeta species other than the well-studied 40- and 42-residue forms, Abeta40 and Abeta42, respectively. Here we report on key structural, dynamic, and aggregation kinetic parameters of Abeta43, extended by a single threonine at the C-terminus relative to Abeta42. Using aggregation time course experiments, electron microscopy, and a combination of nuclear magnetic resonance measurements including backbone relaxation, dark-state exchange saturation transfer, and quantification of chemical shift differences and scalar coupling constants, we demonstrate that the C-terminal threonine in Abeta43 increases the rate and extent of protofibril aggregation and confers slow C-terminal motions in the monomeric and protofibril-bound forms of Abeta43. Relative to the neighboring residues, the hydrophilic Thr43 of Abeta43 favors direct contact with the protofibril surface more so than the C-terminus of Abeta40 or Abeta42. Taken together, these results demonstrate the potential of a small chemical modification to affect the properties of Abeta structure and aggregation, providing a mechanism for the potential role of Abeta43 as a primary nucleator of Abeta aggregates in Alzheimer's disease. PMID- 24773534 TI - Targeting monocyte and macrophage subpopulations for immunotherapy: a patent review (2009 - 2013). AB - INTRODUCTION: Monocytes and macrophages are heterogeneous populations of effector cells in the innate immune system. Once thought to be obligatory precursors for macrophages, monocytes are now known to have several distinct sub-populations and their own independent functions. This separation of the two lineages has opened new therapeutic avenues in inflammation and created new technologies targeting the mononuclear phagocyte system (MPS). AREAS COVERED: A search of Google Patents and PatentScope has revealed numerous patents targeting monocytes and macrophages. This review will focus on seven patents from 2009 to 2013, utilizing autologous monocyte and macrophage adoptive transfer, genetic manipulation of the MPS, therapeutic nanoparticles and liposomes or combinations of these strategies. Patents that target monocyte recruitment are also briefly reviewed. EXPERT OPINION: While monocyte and macrophage targeting has yielded some promising results in animal models, these often fail to translate well to successful clinical trials. The paradigm of how cells in the MPS interact and evolve is constantly being updated, and caution must be exercised in developing immunomodulatory agents until this relationship is better understood. PMID- 24773535 TI - Self-harm in young offenders. AB - The prevalence and correlates of self-harm and suicidal behavior in 515 young offenders (mean age 17.3 years, SD = 1.7) serving community-based orders (CBOs; n = 242) or custodial sentences (n = 273) in Victoria, Australia, are described. Results from structured interviews showed that 83 (16.1%) participants reported self-harming in the previous 6 months, and this was more common among those serving custodial sentences than those serving CBOs (19.4% vs. 12.4%; OR 3.10, 95% CI: 1.74-5.55). Multiple incidents were more common in females and 24% (95% CI: 19-39) of participants who had self-harmed reported having done so with suicidal intent. Self-harm was associated with recent bullying victimization, expulsion from school, past year violent victimization, cannabis dependence, and risk-taking behavior in the preceding year. The epidemiological profile of self harm in this population appears to be distinct from that seen in the general population. Young offenders who self-harm are a vulnerable group with high rates of psychiatric morbidity, substance misuse problems, and social risk factors. They may benefit from targeted psychological interventions designed specifically to address impulsivity, delivered both within-and during the transition from-the youth justice system. PMID- 24773536 TI - Calcium-dependent behavioural responses to acute copper exposure in Oncorhynchus mykiss. AB - Using rainbow trout Oncorhynchus mykiss, the present study demonstrated that: (1) calcium (Ca) increased the range of copper (Cu) concentrations that O. mykiss avoided; (2) Ca conserved the maintenance of pre-exposure swimming activity during inescapable acute (10 min) Cu exposure. Data showed that when presented with a choice of Cu-contaminated water (ranging from 0 to 454 ug Cu l-1 ) and uncontaminated water in a choice tank, O. mykiss acclimated and tested at low Ca concentration (3 mg Ca l-1 avoided the 10 ug Cu l-1 only. By contrast, O. mykiss acclimated and tested at high Ca concentration (158 mg Ca l-1) avoided all the Cu concentrations >=37 ug-1. The Cu avoidance was connected with increased spontaneous swimming speed in the Cu-contaminated water. When subjected to inescapable Cu exposure (35 ug Cu l-1), O. mykiss acclimated and tested at low Ca concentration reduced their spontaneous swimming speed, whereas no response was observed in O. mykiss acclimated and tested at high Ca concentration. Collectively, the data support the conclusion that in O. mykiss the behavioural responses to acute Cu exposure are Ca-dependent. PMID- 24773537 TI - Experimental evidence for parasite-induced over-winter mortality in juvenile Rhodeus amarus. AB - In this study, the effects of the eye fluke Diplostomum pseudospathaceum (Trematoda) infection on over-winter survival of young-of-the-year (YOY) European bitterling Rhodeus amarus (Cyprinidae) were examined between September 2010 and April 2011. The fish were reared in semi-natural conditions to ensure that results were not confounded by other parasite infections. The cumulative mortality of R. amarus from November until April was significantly higher in D. pseudospathaceum-infected fish (57.3%) compared to controls (42.1%). Infection of the parental generation did not have any effect on the mortality of juveniles. The results indicate that D. pseudospathaceum infection increases over-winter mortality of YOY R. amarus. The possible mechanisms causing mortality are discussed. PMID- 24773539 TI - Seasonal and life-phase related differences in growth in Scarus ferrugineus on a southern Red Sea fringing reef. AB - Temporal trends in growth of the rusty parrotfish Scarus ferrugineus were studied on a southern Red Sea fringing reef that experiences seasonal changes in environmental conditions and benthic algal resources. Length increment data from tagging and recapture were compared among periods and sexes and modelled using GROTAG, a von Bertalanffy growth model. The growth pattern of S. ferrugineus was highly seasonal with a maximum occurring between April and June and a minimum between December and March. Body condition followed the seasonal variation in growth, increasing from April to June and decreasing from December to March. The season of maximum growth coincided with high irradiation, temperature increases and peak abundance of the primary food source, the epilithic algal community. There was a decline in growth rate during summer (July to October) associated with a combination of extreme temperatures and lowered food availability. There were strong sexual size dimorphism (SSD) and life-history traits. Terminal-phase (TP) males achieved larger asymptotic lengths than initial-phase individuals (IP) (L(infinity) 34.55 v. 25.12 cm) with growth coefficients (K) of 0.26 and 0.38. The TPs were growing four times as fast as IPs of similar size. Three individuals changed from IP to TP while at liberty and grew eight times faster than IPs of similar size, suggesting that sex change in S. ferrugineus is accompanied by a surge in growth rate. The SSD in S. ferrugineus thus coincided with fast growth that started during sex change and continued into the TP. Faster growth during sex change suggests that the cost associated with sex change is limited. PMID- 24773538 TI - The effects of flow on schooling Devario aequipinnatus: school structure, startle response and information transmission. AB - To assess how flow affects school structure and threat detection, startle response rates of solitary and small groups of giant danio Devario aequipinnatus to visual looming stimuli were compared in flow and no-flow conditions. The instantaneous position and heading of each D. aequipinnatus was extracted from high-speed videos. Behavioural results indicate that (1) school structure is altered in flow such that D. aequipinnatus orient upstream while spanning out in a crosswise direction, (2) the probability of at least one D. aequipinnatus detecting the visual looming stimulus is higher in flow than no flow for both solitary D. aequipinnatus and groups of eight D. aequipinnatus; however, (3) the probability of three or more individuals responding is higher in no flow than in flow. These results indicate a higher probability of stimulus detection in flow but a higher probability of internal transmission of information in no flow. Finally, results were well predicted by a computational model of collective fright response that included the probability of direct detection (based on signal detection theory) and indirect detection (i.e. via interactions between group members) of threatening stimuli. This model provides a new theoretical framework for analysing the collective transfer of information among groups of fishes and other organisms. PMID- 24773540 TI - Time and size at seaward migration influence the sea survival of Salmo salar. AB - Whether time of seaward migration of young Atlantic salmon Salmo salar influences their subsequent survival and growth was investigated in the River Imsa, south western Norway. Salmo salar were tagged when moving downstream through a trap near the outlet between 1976 and 2010 and recaptured on their adult return. Most descended as smolts in April and May, but some descended during the other months of the year. Annual variation in timing of the smolt migration was significantly correlated with variation in water temperature during spring. Mean total body length of the descending S. salar varied with month of seaward migration. The sea survival of S. salar emigrating from the River Imsa between January and May was 2.8 times higher than for those descending between June and December. The sea survival of the various cohorts decreased with increasing river temperature in April to May, prior to the smolt migration, and decreasing day number when the smolts moved to sea. The size of smolts descending the river between April and May did not affect the survival at sea as much as it affected the survival of migrants descending in any other month of the year. The majority of the downstream migrating S. salar were 2 years old, but proportionally, more 1 year olds moved downstream in the autumn than in the rest of the year. Mean duration between downstream migration of the young and the return migration of the grilse was shortest (12.7 months) for those descending in July and August and longest for those descending in October (21 months). Mean monthly specific growth rate was highest for those migrating downstream between May and July and lowest for those emigrating in September. Based on the present results, it was hypothesized that S. salar emigrating between April and August migrated directly out into the ocean, while those that emigrated between October and March stayed in the estuary until the subsequent spring. PMID- 24773541 TI - The behavioural response of adult Petromyzon marinus to damage-released alarm and predator cues. AB - Using semi-natural enclosures, this study investigated (1) whether adult sea lamprey Petromyzon marinus show avoidance of damage-released conspecific cues, damage-released heterospecific cues and predator cues and (2) whether this is a general response to injured heterospecific fishes or a specific response to injured P. marinus. Ten replicate groups of 10 adult P. marinus, separated by sex, were exposed to one of the following nine stimuli: deionized water (control), extracts prepared from adult P. marinus, decayed adult P. marinus (conspecific stimuli), sympatric white sucker Catostomus commersonii, Amazon sailfin catfish Pterygoplichthys pardalis (heterospecific stimuli), 2 phenylethylamine (PEA HCl) solution, northern water snake Nerodia sipedon washing, human saliva (predator cues) and an adult P. marinus extract and human saliva combination (a damage-released conspecific cue and a predator cue). Adult P. marinus showed a significant avoidance response to the adult P. marinus extract as well as to C. commersonii, human saliva, PEA and the adult P. marinus extract and human saliva combination. For mobile P. marinus, the N. sipedon washing induced behaviour consistent with predator inspection. Exposure to the P. pardalis extract did not induce a significant avoidance response during the stimulus release period. Mobile adult female P. marinus showed a stronger avoidance behaviour than mobile adult male P. marinus in response to the adult P. marinus extract and the adult P. marinus extract and human saliva combination. The findings support the continued investigation of natural damage-released alarm cue and predator-based repellents for the behavioural manipulation of P. marinus populations in the Laurentian Great Lakes. PMID- 24773542 TI - Early growth and development of reciprocal hybrids of the starry flounder Platichthys stellatus and stone flounder Kareius bicoloratus. AB - Larval growth and development of hybrid flounder were observed and compared with those of their parent species. The reciprocal hybrids of female starry flounder Platichthys stellatus and male stone flounder Kareius bicoloratus (hybrid Sb) and of female K. bicoloratus and male P. stellatus (hybrid Bs) both survived and grew to juveniles. Development was divided into nine stages (A-I). Many of the hybrids' traits were identical and intermediate to those of their parents. The position of the eye, however, was primarily sinistral in both hybrids (80% in Sb and 76% in Bs), a trait possessed by P. stellatus (80%) in the western Pacific Ocean. The daily growth rates of the larvae were similar. In the parent species, development was more rapid in P. stellatus than in K. bicoloratus whereas rate of development was intermediate in both Sb and Bs hybrids. The size at settlement [standard length (LS ) at stage H (mean +/- s.d.)] was 9.82 +/- 1.47 mm for the hybrid Sb and 9.99 +/- 0.90 mm for the hybrid Bs, while the minimum age at metamorphosis (initial age at stage H) was 29 days after hatching (DAH) in both hybrids. In comparison, LS at settlement in parent species was 6.43 +/- 0.25 mm for P. stellatus and 12.87 +/- 1.29 mm for K. bicoloratus. Minimum age at metamorphosis for the parents was 23 DAH at stage G in P. stellatus and 34 DAH at stage H in K. bicoloratus. Thus, the timing of settlement of hybrids was different from that of their parent species. These traits may occur with high frequency in a natural habitat. PMID- 24773543 TI - A new species of Rhinopetitia Gery 1964 (Ostariophysi: Characiformes: Characidae) from the Rio Teles Pires, Rio Tapajos basin, Brazil. AB - A new species of Rhinopetitia is described from the Rio Teles Pires, a major tributary of the Rio Tapajos. The new taxon is distinguished from its only congener, Rhinopetitia myersi, by having all premaxillary teeth in both rows with seven to nine cusps, maxillary teeth with seven or eight cusps, a distinct dark midlateral stripe on the body and a round humeral blotch (v. outer series of premaxillary teeth with three cusps and inner series of premaxillary teeth with three to five cusps, maxillary teeth with three to five cusps, the absence of a dark midlateral stripe and humeral blotch). Putative characters suggesting a close relationship between Rhinopetitia, Bryconacidnus, Ceratobranchia, Monotocheirodon, Odontostoechus, Othonocheirodus and Rhinobrycon are presented. This putative clade is included in the Stevardiinae, a monophyletic group within the Characidae. PMID- 24773544 TI - Establishment and characterization of a head kidney cell line from large yellow croaker Pseudosciaena crocea. AB - A continuous cell line, LYCK, derived from the head kidney of large yellow croaker Pseudosciaena crocea was established and characterized. The LYCK cell line multiplied well in Leibovitz's-15 (L-15) medium supplemented with 10% foetal bovine serum (FBS) at 28 degrees C. This cell line, with a population doubling time of 29.5 h at passage 35, has been subcultured for >70 passages. Microscopically, LYCK cells were fibroblast-like. Chromosomal analysis revealed that the modal diploid chromosome number of LYCK cells was 48, which was identical to that of the P. crocea kidney. The cellular fluorescence could be observed in LYCK cells at 48 h after being transfected with pEGFP-N1 plasmid DNA, indicating that LYCK cells were competent for target gene expression in vitro. The expression of mRNA transcripts of the antiviral immune-related molecules interferon regulatory factor-3 I(ir3), interferon regulatory factor-7 (irf7), melanoma differentiation-associated protein 5 (mda5) was obviously up-regulated in LYCK cells in response to the stimulation with poly (I:C), whereas the expression of mRNA transcripts of the inflammatory cytokines tumour necrosis factor-alpha2 (tnfTNF-alpha2), interleukin-8 (il8), CC chemokine (lycCC) was up regulated by lipopolysaccharide. These results indicated that the LYCK cell line could serve as a valuable tool for studies on immune-related gene functions in vitro. PMID- 24773545 TI - Tooth microwear formation rate in Gasterosteus aculeatus. AB - Tooth microwear feature densities were significantly increased in a population of laboratory-reared three-spined stickleback Gasterosteus aculeatus in four days, after they were transferred from a limnetic feeding regime to a benthic feeding regime. These results show that even in aquatic vertebrates with non-occluding teeth, changes in feeding can cause changes in tooth microwear in just a few days, as in mammals. PMID- 24773546 TI - Morphological abnormalities in a population of Lampetra planeri, with a short review of petromyzontid teratologies. AB - Reported here are several deviations (n = 15; 1.96%) from typical morphology in a large sample (n = 767) of European brook lamprey Lampetra planeri from a single population in the Loch Lomond catchment; this includes one specimen bearing a true anal fin. A brief review of petromyzontid teratology is provided. PMID- 24773547 TI - Mangrove loss leads to fish hyperutilization of seagrass beds in a UNESCO biosphere reserve. AB - Hurricanes severely damaged a mangrove forest in a UNESCO biosphere reserve in the U.S. Virgin Islands. The system has yet to recover and when alternative habitats have been destroyed, it is shown that juvenile fishes will hyperutilize seagrass beds at densities significantly greater than in areas that maintain functioning mangroves. Despite over a decade of recovery time, the affected mangrove system remains inhospitable to juvenile fishes. PMID- 24773548 TI - To glue or not to glue? Reassembling broken otoliths for population discrimination. AB - Twenty-five Atlantic cod Gadus morhua otoliths were examined using eight shape measurements along with Fourier analysis of their outlines to test whether discrimination using otolith shape is affected by gluing broken otoliths. Small differences in seven of the eight shape measurements were found between unbroken otoliths and the same otoliths after breaking and subsequently gluing together; however, none of the Fourier descriptors differed. Cluster analyses indicated that resultant morphological differences will have no impact when applying discriminant analysis. PMID- 24773549 TI - Discovery of 4-aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 inhibitors. Part I: optimization of in vitro potencies and pharmacokinetic properties. AB - A series of 4-aryl-N-arylcarbonyl-2-aminothiazoles of scaffold 4 was designed and synthesized as Hec1/Nek2 inhibitors. Structural optimization of 4 led to compound 32 bearing C-4' 4-methoxyphenoxy and 4-(o-fluoropyridyl)carbonyl groups that showed low nanomolar in vitro antiproliferative activity (IC50: 16.3-42.7 nM), high intravenous AUC (64.9 MUM.h, 2.0 mg/kg) in SD rats, and significant in vivo antitumor activity (T/C = 32%, 20 mg/kg, IV) in mice bearing human MDA-MB-231 xenografts. Cell responses resulting from Hec1/Nek2 inhibition were observed in cells treated with 32, including a reduced level of Hec1 coimmunoprecipitated with Nek2, degradation of Nek2, mitotic abnormalities, and apoptosis. Compound 32 showed selectivity toward cancer cells over normal phenotype cells and was inactive in a [(3)H]astemizole competitive binding assay for hERG liability screening. Therefore, 32 is as a good lead toward the discovery of a preclinical candidate targeting Hec1/Nek2 interaction. PMID- 24773550 TI - Feasibility study of personalized peptide vaccination for recurrent ovarian cancer patients. AB - CONTEXT: To develop a personalized peptide vaccine (PPV) for recurrent ovarian cancer patients and evaluate its efficacy from the point of view of overall survival (OS), Phase II study of PPV was performed. PATIENTS AND METHODS: Forty two patients, 17 with platinum-sensitive and 25 with platinum-resistant recurrent ovarian cancer, were enrolled in this study and received a maximum of four peptides based on HLA-A types and IgG responses to the peptides in pre vaccination plasma. RESULTS: Expression of 13 of the 15 parental tumor-associated antigens encoding the vaccine peptides, with the two prostate-related antigens being the exceptions, was confirmed in the ovarian cancer tissues. No vaccine related systemic severe adverse events were observed in any patients. Boosting of cytotoxic T lymphocytes or IgG responses specific for the peptides used for vaccination was observed in 18 or 13 of 42 cases at 6th vaccination, and 19 or 29 of 30 cases at 12th vaccination, respectively. The median survival time (MST) values of the platinum-sensitive- and platinum-resistant recurrent cases were 39.3 and 16.2 months, respectively. The MST of PPV monotherapy or PPV in combination with any chemotherapy during the 1st to 12th vaccination of platinum sensitive cases was 39.3 or 32.2 months, and that of platinum-resistant cases was 16.8 or 16.1 months, respectively. Importantly, lymphocyte frequency and epitope spreading were significantly prognostic of OS. DISCUSSION AND CONCLUSION: Because of the safety and possible prolongation of OS, a clinical trial of PPV without chemotherapy during the 1st to 12th vaccination in recurrent ovarian cancer patients is merited. PMID- 24773551 TI - Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats. AB - Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 MUg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood-brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BBB. Rapamycin also inhibited matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4) expression. These data imply that rapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression. The data of this study provide a new possible approach for improving brain edema after cerebral ischemia reperfusion by administration of rapamycin. PMID- 24773552 TI - Prevalence of gestational diabetes mellitus among Indigenous women and comparison with non-Indigenous Australian women: 1990-2009. AB - BACKGROUND: Evidence on long-term trends in gestational diabetes mellitus (GDM) prevalence in Australia is lacking. AIMS: To assess and compare trends in GDM prevalence among Indigenous and non-Indigenous Australian women. MATERIALS AND METHODS: Analysis of crude and age-adjusted GDM prevalence over time by Indigenous status and age, using routinely collected midwives data from Australian states and territories on mothers giving birth from 1990 to 2009. RESULTS: Despite considerable data variation, particularly in 1990-1999, and likely underestimation of GDM prevalence, crude and age-adjusted GDM prevalences were higher in Indigenous than non-Indigenous women at all time-points (4.7% vs 3.1% in 1990-1999; 5.1% vs 4.5% in 2000-2009, P < 0.0001). Data variability precluded quantitative assessment of trends and changes in prevalence ratios before 2000. From 2000 to 2009, GDM prevalence increased significantly among Indigenous women by a mean 2.6% annually (Ptrend <0.0001), and non-Indigenous women by 3.2% annually (Ptrend <0.0001), with no significant trend in the age adjusted Indigenous/non-Indigenous prevalence ratios (PR) (P = 0.34). GDM prevalence increased significantly with age (P < 0.0001), although the increase with age was significantly greater among Indigenous women (PR 5.34 (4.94-5.77), >=35 vs <25 years) compared to non-Indigenous women (PR 3.72 (3.64-3.81), >=35 vs <25 years), Pinteraction <0.0001. CONCLUSIONS: Bearing data quality concerns in mind, GDM prevalence is increasing rapidly among Australian women, more than doubling in non-Indigenous women between 1990 and 2009. Prevalence is consistently higher in Indigenous versus non-Indigenous women, with statistically consistent differences between the groups in recent years. The marked increase in prevalence with age highlights an important period for prevention, particularly for Indigenous women. PMID- 24773558 TI - Nitrogen-containing dimeric nor-multiflorane triterpene from a Turraea sp. AB - The new triterpene turranoic acid (1) and the new N-containing nor-triterpene turraenine (2), along with triptocallic acid B (3) and esculentoic acid (4) were isolated from leaves of a Turraea sp. Compounds 1-3 showed weak to moderate in vitro antiplasmodial activity against the chloroquine-resistant Plasmodium falciparum strain FCM29. Compound 1 also displayed weak cytotoxic activity against the nonsmall lung cancer cell line H522-T1 with an IC50 value of 16.4 MUM. PMID- 24773559 TI - Risk factors for post-traumatic massive cerebral infarction secondary to space occupying epidural hematoma. AB - Post-traumatic massive cerebral infarction (MCI) is a fatal complication of concurrent epidural hematoma (EDH) and brain herniation that commonly requires an aggressive decompressive craniectomy. The risk factors and surgical indications of MCI have not been fully elucidated. In this retrospective study, post traumatic MCI was diagnosed in 32 of 176 patients. The performance of a decompressive craniectomy simultaneously with the initial hematoma-evacuation surgery improved their functional outcomes, compared with delayed surgery (on the 6-month Extended Glasgow Outcome Scale, 5.6+/-1.5 vs. 3.4+/-0.6; p<0.001). Significantly increased risks for MCI were observed in patients with an EDH at a transtemporal location (adjusted odds ratio [OR], 16.48; p=0.003), an EDH larger than 100 mL in volume (OR, 7.04; p=0.001), preoperative shock for longer than 30 min (OR, 13.78; p=0.002), bilateral mydriasis (OR, 7.08; p=0.004), preoperative brain herniation for longer than 90 min (OR, 6.41; p<0.001), and a Glasgow Coma Score of 3-5 points (OR, 2.86; p<0.053). Multi-variate logistic regression analysis revealed no significant association between post-traumatic MCI and age, gender, mid-line shift, Rotterdam computed tomography score, intraoperative hypotension, or serum concentrations of sodium or glucose. Incidence of post traumatic MCI increased from 16.4% in those having any two of the six risk factors to 47.7% in those having any three or more of the six risk factors (p<0.001). Patients with concurrent EDH and brain herniation exhibited an increased risk for post-traumatic MCI with the accumulation of several critical clinical factors. Early decompressive craniectomy based on accurate risk estimation is recommended in efforts to improve patient functional outcomes. PMID- 24773560 TI - Glucose- and pH-responsive charge-reversal surfaces. AB - We have shown a pH- and glucose-responsive charge reversal on silica surface through heterogeneous functionalization utilizing amines and boronic acid moieties. The dual responsiveness of the charge reversal has been unambiguously demonstrated through the desorption of charged chromophores. Interestingly, we observed a concentration-dependent desorption response to glucose at physiologically relevant levels. PMID- 24773561 TI - Comparing cardioprotection by remote ischaemic pre-conditioning in patients with and without diabetes. PMID- 24773563 TI - Prototypical phosphine complexes of antimony(III). AB - Complexes of the generic formula [Cln(PR3)mSb]((3-n)+) (n = 1, 2, 3, or 4 and m = 1 or 2) have been prepared featuring [ClSb](2+), [Cl2Sb](1+), Cl3Sb, or [Cl4Sb](1 ) as acceptors with one or two phosphine ligands {PMe3, PPh3, PCy3 (Cy = C6H11)}. The solid-state structures of the complexes reveal foundational features that define the coordination chemistry of a lone pair bearing stibine acceptor site. The experimental observations are interpreted with dispersion-corrected density functional theory calculations to develop an understanding of the bonding and structural diversity. PMID- 24773562 TI - Cortical atrophy, reduced integrity of white matter and cognitive impairment in subcortical vascular dementia of Binswanger type. AB - AIMS: An association between white matter hyperintensities (WMH) and cognitive dysfunction has long been recognized. However, subjects with identically appearing WMH on magnetic resonance imaging present with a wide variance in cognitive function ranging from normal cognition to dementia. The aim of this study was to compare cortical atrophy and integrity of white matter of patients with subcortical vascular dementia of Binswanger type (SVaD-BT) with those of the normal cognition group with WMH (ncWMH). METHODS: Eleven patients with SVaD-BT and 11 age-, sex-, education- and grade of WMH-matched ncWMH underwent magnetic resonance imaging, including 3-D volumetric images for cortical atrophy and diffusion tensor imaging for integrity of white matter. RESULTS: Compared to ncWMH, SVaD-BT patients showed cortical atrophies in frontal (i.e. frontal pole, precentral gyrus and frontal medial cortex) and occipital areas (i.e. lingual gyrus) followed by atrophies in temporal (i.e. fusiform cortex and middle temporal gyrus) areas. Along with cortical atrophies, reduced integrity with low fractional anisotropy and high mean diffusivity values in genu and splenium of the corpus callosum were detected in SVaD-BT patients. CONCLUSIONS: Our findings suggest that cognitive decline from ncWMH to SVaD-BT may be associated with cortical atrophy and reduced integrity of white matter. PMID- 24773564 TI - Molecular design toward highly efficient photovoltaic polymers based on two dimensional conjugated benzodithiophene. AB - As researchers continue to develop new organic materials for solar cells, benzo[1,2-b:4,5-b']dithiophene (BDT)-based polymers have come to the fore. To improve the photovoltaic properties of BDT-based polymers, researchers have developed and applied various strategies leading to the successful molecular design of highly efficient photovoltaic polymers. Novel polymer materials composed of two-dimensional conjugated BDT (2D-conjugated BDT) have boosted the power conversion efficiency of polymer solar cells (PSCs) to levels that exceed 9%. In this Account, we summarize recent progress related to the design and synthesis of 2D-conjugated BDT-based polymers and discuss their applications in highly efficient photovoltaic devices. We introduce the basic considerations for the construction of 2D-conjugated BDT-based polymers and systematic molecular design guidelines. For example, simply modifying an alkoxyl-substituted BDT to form an alkylthienyl-substituted BDT can improve the polymer hole mobilities substantially with little effect on their molecular energy level. Secondly, the addition of a variety of chemical moieties to the polymer can produce a 2D conjugated BDT unit with more functions. For example, the introduction of a conjugated side chain with electron deficient groups (such as para-alkyl-phenyl, meta-alkoxyl-phenyl, and 2-alkyl-3-fluoro-thienyl) allowed us to modulate the molecular energy levels of 2D-conjugated BDT-based polymers. Through the rational design of BDT analogues such as dithienobenzodithiophene (DTBDT) or the insertion of larger pi bridges, we can tune the backbone conformations of these polymers and modulate their photovoltaic properties. We also discuss the influence of 2D conjugated BDT on polymer morphology and the blends of these polymers with phenyl C61 (or C71)-butyric acid methyl ester (PCBM). Finally, we summarize the various applications of the 2D-conjugated BDT-based polymers in highly efficient PSC devices. Overall, this Account correlates the molecular structures of the 2D conjugated BDT-based polymers with their photovoltaic properties. As a result, this Account can guide the molecular design of organic photovoltaic materials and the development of organic materials for other types of optoelectronic devices. PMID- 24773565 TI - Combination of triple bond and adamantane ring on the vitamin D side chain produced partial agonists for vitamin D receptor. AB - Vitamin D receptor (VDR) ligands are therapeutic agents that are used for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism and have immense potential as therapeutic agents for autoimmune diseases, cancers, and cardiovascular diseases. However, the major side effect of VDR ligands, the development of hypercalcemia, limits their expanded use. To develop tissue selective VDR modulators, we have designed vitamin D analogues with an adamantane ring at the side chain terminal, which would interfere with helix 12, the activation function 2, and modulate the VDR potency. Here we report 25- or 26 adamantyl-23,23,24,24-tetradehydro-19-norvitamin D derivatives (ADTK1-4, 4b,a and 5a,b). These compounds showed high VDR affinities (90% at maximum), partial agonistic activities (EC50 10(-9)-10(-8) M with 40-80% efficacy) in transactivation, and tissue-selective activity in target gene expressions. We investigate the structure-activity relationships of these compounds on the basis of their X-ray crystal structures. PMID- 24773566 TI - ATP4A autoimmunity and Helicobacter pylori infection in children with type 1 diabetes. AB - Persistent presence of ATP4A autoantibodies (ATP4AA) directed towards parietal cells is typical for atrophic body gastritis (ABG), an autoimmune disease associated with type 1 diabetes. We assessed whether Helicobacter pylori (Hp) infection might be associated with positivity for ATP4AA in children with type 1 diabetes. Sera were collected from 70 (38?) type 1 diabetes children [aged 13.2 +/- 4.5 years, age at diagnosis 8.8 +/- 4.3 years, diabetes duration 4.5 +/- 3.8 years, mean HbA1c 7.8 +/- 1.6% (62 +/- 17.5 mmol/mol)] seen at the regional diabetes clinic in Katowice, Poland. Patients were tested concurrently for Hp infection by means of a 13C urea breath test. ATP4AA were measured using a novel radioimmunoprecipitation assay developed at the Barbara Davies Center for Childhood Diabetes, University of Colorado. ATP4AA were present in 21 [30%, 95% confidence interval (CI) = 19-41%] and Hp infection was detected in 23 (33%, 95% CI = 22-44%) children. There was no statistically significant association between ATP4AA presence and Hp status. ATP4AA presence was not associated with current age, age at type 1 diabetes diagnosis, diabetes duration or current HbA1c. ATP4AA were more prevalent in females [42% (26-58%)] than males [16% (3-28%)], P = 0.016. ATP4A are found in nearly one-third of children with type 1 diabetes and more common among females. In this cross-sectional analysis, Hp infection was not associated with autoimmunity against parietal cells. PMID- 24773567 TI - Exhaled breath condensate as a matrix for combustion-based nanoparticle exposure and health effect evaluation. AB - BACKGROUND: Health assessment and medical surveillance of workers exposed to combustion nanoparticles are challenging. The aim was to evaluate the feasibility of using exhaled breath condensate (EBC) from healthy volunteers for (1) assessing the lung deposited dose of combustion nanoparticles and (2) determining the resulting oxidative stress by measuring hydrogen peroxide (H(2)O(2)) and malondialdehyde (MDA). METHODS: Fifteen healthy nonsmoker volunteers were exposed to three different levels of sidestream cigarette smoke under controlled conditions. EBC was repeatedly collected before, during, and 1 and 2 hr after exposure. Exposure variables were measured by direct reading instruments and by active sampling. The different EBC samples were analyzed for particle number concentration (light-scattering-based method) and for selected compounds considered oxidative stress markers. RESULTS: Subjects were exposed to an average airborne concentration up to 4.3*10(5) particles/cm(3) (average geometric size ~60-80 nm). Up to 10*10(8) particles/mL could be measured in the collected EBC with a broad size distribution (50(th) percentile ~160 nm), but these biological concentrations were not related to the exposure level of cigarette smoke particles. Although H(2)O(2) and MDA concentrations in EBC increased during exposure, only H2O2 showed a transient normalization 1 hr after exposure and increased afterward. In contrast, MDA levels stayed elevated during the 2 hr post exposure. CONCLUSIONS: The use of diffusion light scattering for particle counting proved to be sufficiently sensitive to detect objects in EBC, but lacked the specificity for carbonaceous tobacco smoke particles. Our results suggest two phases of oxidation markers in EBC: first, the initial deposition of particles and gases in the lung lining liquid, and later the start of oxidative stress with associated cell membrane damage. Future studies should extend the follow-up time and should remove gases or particles from the air to allow differentiation between the different sources of H(2)O(2) and MDA. PMID- 24773568 TI - Molecular basis underlying Mycobacterium tuberculosis D-cycloserine resistance. Is there a role for ubiquinone and menaquinone metabolic pathways? AB - INTRODUCTION: Tuberculosis remains a formidable threat to global public health. Multidrug-resistant tuberculosis presents increasing burden on the control strategy. D-Cycloserine (DCS) is an effective second-line drug against Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis. Though less potent than isoniazid (INH) and streptomycin, DCS is crucial for antibiotic-resistant tuberculosis. One advantage of DCS is that less drug-resistant M. tuberculosis is reported in comparison with first-line antituberculosis drugs such as INH and rifampin. AREAS COVERED: In this review, we summarise our current knowledge of DCS, and review the drug target and low level resistance of DCS in M. tuberculosis. We summarise the metabolism of D alanine (D-Ala) and peptidoglycan biosynthesis in bacteria. We first compared the amino acid similarity of Mycobacterium alanine racemase and D-Ala:D-alanine ligase and quite unexpectedly found that the two enzymes are highly conserved among Mycobacterium. EXPERT OPINION: We summarise the drug targets of DCS and possible mechanisms underlying its low-level resistance for the first time. One significant finding is that ubiquinone and menaquinone metabolism-related genes are novel genes underlying DCS resistance in Escherichia coli and with homologues in M. tuberculosis. Further understanding of DCS targets and basis for its low level resistance might inspire us to improve the use of DCS or find better drug targets. PMID- 24773569 TI - Concentration-controlled formation of myoglobin/gold nanosphere aggregates. AB - Gold nanoparticles are being increasingly proposed as biotechnological tools for medical diagnosis and therapy purposes. Their safety for human beings and the environment is therefore becoming an emerging issue, which calls for basic research on the interactions between nanostructured gold particles and biological materials, including physicochemical studies of model systems. In this Article, we focus on the "reaction products" of a widely known nanoparticle type, citrate capped 30 nm gold nanospheres, with a model protein, horse myoglobin. Protein adsorption and partial denaturation were accompanied by the formation of nanoparticle aggregates with strongly distinct optical spectroscopy properties and shapes, as observed by transmission electron microscopy. We singled out the concentration of myoglobin as the determinant of these differences, and verified on this basis that surface-enhanced Raman scattering (SERS) spectra can only be obtained by aggregates with strong interparticle optical coupling, which are obtained at low protein concentration. The results can be useful both in improving the spectroscopy of biomolecules and in understanding the formation of the protein corona in biomedical applications. PMID- 24773570 TI - Dietary L-arginine supplement alleviates hepatic heat stress and improves feed conversion ratio of Pekin ducks exposed to high environmental temperature. AB - The current intensive indoor production system of commercial Pekin ducks never allows adequate water for swimming or wetting. Therefore, heat stress is a key factor affecting health and growth of ducks in the hot regions and season. Experiment 1 was conducted to study whether heat stress was deleterious to certain organs of ducks. Forty-one-day-old mixed-sex Pekin ducks were randomly allocated to four electrically heated battery brooders comprised of 10 ducks each. Ducks were suddenly exposed to 37 degrees C ambient temperature for 3 h and then slaughtered, in one brooder at 21 days and in another brooder at 49 days of age. The results showed that body weight and weight of immune organs, particularly liver markedly decreased in acute heat stress ducks compared with the control. Experiment 2 was carried out to investigate the influences of dietary L-arginine (Arg) supplement on weight and compositions of certain lymphoid organs, and growth performance in Pekin ducks, under daily cyclic hot temperature environment. A total of 151-day-old mixed-sex Pekin ducks were randomly divided into one negative control and two treatment groups, fed experimental diets supplemented with 0, 5, and 10 g L-Arginine (L-Arg)/kg to the basal diet respectively. Ducks were exposed to cyclic high temperature simulating natural summer season. The results showed that the addition of L-Arg improves feed conversion ratio (FCR) during a period of 7-week trial, as well as increases hepatic weight relative to body weight at 21 days, while decreases the hepatic water content at 49 days of age. This study indicated that the liver was more sensitive to acute heat stress, and the hepatic relative weight and chemical composition could be regulated by dietary L-Arg supplementation in Pekin ducks being reared at high ambient temperature. These beneficial effects of Arg on liver might be a cause of improved FCR. PMID- 24773571 TI - Patient-prosthesis mismatch in patients undergoing bioprosthetic aortic valve implantation increases risk of reoperation for structural valve deterioration. AB - OBJECTIVES: Patient-prosthesis mismatch has been identified as a risk factor for mortality after aortic valve replacement and for structural valve deterioration (SVD) in patients receiving a bioprosthetic aortic valve. The aim of the present study was to compare the incidence of aortic valve bioprosthesis replacement for SVD in patients with mismatch to a population without mismatch. METHODS: Three hundred eighty-seven adult patients who underwent aortic valve replacement with a bioprosthesis from 1974 to 2009 were retrospectively reviewed. Mismatch was considered to be present if the anticipated indexed effective orifice area was <0.70 cm(2) /m(2) . The median follow-up period was 7.2 years. Follow-up was 97% complete. RESULTS: Patient-prosthesis mismatch was present in 12% of the study population (n = 47). Ten-year freedom from reoperation for aortic bioprosthesis replacement was 74.3 +/- 3.2%. During follow-up, 111 patients underwent reoperation for aortic bioprosthesis replacement. Causes of aortic bioprosthesis replacement were SVD of the bioprosthesis (n = 96), paravalvular leak (n = 10), and acute endocarditis (n = 5). According to unadjusted Kaplan-Meier analysis, patients with mismatch had a higher incidence of aortic bioprosthesis replacement for SVD when compared with patients without mismatch (log rank test: p 0.05). This result was confirmed by multivariable Cox regression analysis, which identified two independent predictors of aortic bioprosthesis replacement for SVD: patients' age (hazard ratio (HR) 0.967) and patient-prosthesis mismatch (HR 2.161). CONCLUSION: Patients suffering from mismatch were twice as likely to undergo reoperation for aortic bioprosthesis replacement for SVD than those without mismatch. PMID- 24773572 TI - Latent growth modeling with domain-specific outcomes comprised of mixed response types in intervention studies. AB - OBJECTIVE: When several continuous outcome measures of interest are collected across time in experimental studies, the use of standard statistical procedures, such as multivariate analysis of variance or growth curve modeling, can be properly used to assess treatment effects. However, when data consist of mixed responses (e.g., continuous and ordered categorical [ordinal] responses), traditional modeling approaches are no longer appropriate. The purpose of this article is to illustrate the use of a more suitable modeling procedure when mixed responses are collected in longitudinal intervention studies. METHOD: Problems with traditional analyses of such data are discussed, as are potential advantages provided by the proposed modeling approach. The application of the multiple domain latent growth modeling approach with mixed responses is illustrated for experimental designs with data from the SeniorWISE study (McDougall et al., 2010). This multisite randomized trial assessed memory functioning of 265 elderly adults across a 26-month period after receiving either a memory or health promotion training program. RESULTS: The latent growth models illustrated allow one to examine treatment effects on the growth of multiple mixed outcomes while incorporating associations among multiple responses, which allows for better missing data treatment, greater power, and more accurate control of Type I error. The interpretation of parameters of interest and treatment effects is discussed using the SeniorWISE data. CONCLUSIONS: Multiple-domain latent growth modeling with mixed responses is a flexible statistical modeling tool that can have substantial benefits for applied researchers. As such, the use of this modeling approach is expected to increase. PMID- 24773573 TI - Randomized controlled trial of two brief alcohol interventions for OEF/OIF veterans. AB - OBJECTIVE: The purpose of this study was to test the efficacy of 2 brief interventions for alcohol misuse in a sample of combat veterans of the wars in Iraq and Afghanistan. METHOD: Participants were 68 combat veterans (91.2% male; 64.7% White, 27.9% Black) with a mean age of 32.31 years (SD = 8.84) who screened positive for hazardous drinking in a Veterans Affairs Medical Center primary care clinic using the Alcohol Use Disorders Identification Test (Babor, Higgins Biddle, Saunders, & Monteiro, 2001). More than half of the sample (57.4%) met criteria for posttraumatic stress disorder (PTSD; based on the Clinician Administered PTSD Scale; Blake et al., 1995). Eligible veterans who elected to participate completed a baseline assessment and were randomized to receive 1 of 2 interventions (personalized feedback delivered with or without a motivational interviewing counseling session). Both interventions included information on hazardous drinking, PTSD symptoms, depression, and coping. Follow-up assessments were conducted at 6 weeks and 6 months post-intervention. RESULTS: Both conditions resulted in statistically significant reductions in quantity and frequency of alcohol use as well as frequency of binge drinking and alcohol related consequences. Within-group effect sizes (ds) were in the small to medium range (.21-.55) for quantity and frequency of alcohol use. There were no statistically significant Condition * Time interactions, suggesting that both interventions were similarly effective. PTSD and non-PTSD veterans responded equally well to both interventions, but veterans with PTSD assigned to feedback plus motivational interviewing reported greater reductions in weekly drinking at the 6-week follow-up. CONCLUSIONS: These findings suggest that brief interventions for alcohol misuse may be effective for reducing drinking, even in an Operation Enduring Freedom/Operation Iraqi Freedom veteran population with a high degree of PTSD. PMID- 24773574 TI - Predictors and moderators of agreement between clinical and research diagnoses for children and adolescents. AB - OBJECTIVE: Diagnoses play an important role in treatment planning and monitoring, but extensive research has shown low agreement between clinician-generated diagnoses and those from structured diagnostic interviews. However, most prior studies of agreement have not used research diagnoses based on gold standard methods, and researchers need to identify characteristics of diagnostically challenging clients. This study examined agreement between youth diagnoses generated through the research-based LEAD (Longitudinal, Expert, and All Data) standard to clinician diagnoses. METHOD: Participants were 391 families seeking outpatient community mental health services for youths ages 6-18 (39.1% female, 88.2% African American). Youths and parents completed research interviews and clinic diagnoses were extracted from clinic records. LEAD diagnoses synthesized results of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime (KSADS-PL) and the youth's developmental, family, and psychiatric history. RESULTS: Agreement between the LEAD and chart diagnoses was low, not exceeding "poor" agreement for most diagnostic categories (kappas = .10-.46, median = .37). Disagreement was largely driven by missed diagnoses, although clinicians also did assign extra diagnoses for some clients. Fewer diagnostic errors occurred when the youth's clinical picture was more clear (e.g., high or low symptom severity, lower comorbidity), when the youth was older, when the family was higher functioning, and when the parent had more depression. However, youth and family characteristics explained very little of the variability in diagnostic errors. CONCLUSIONS: RESULTS support the need to investigate strategies to improve clinician diagnostic accuracy. PMID- 24773575 TI - The impact of alcohol on clinical outcomes in established psychosis: a longitudinal study. AB - BACKGROUND AND AIMS: Alcohol use disorders are common among people with psychosis and are associated with poorer prognoses. In psychosis patients, there are inconsistent findings regarding the link between alcohol disorders and clinical symptomatic outcomes. This study examined the relationships between alcohol consumption and specific clinical outcomes, including affective symptoms, in psychosis. METHODS: Participants were recruited from secondary care services in the United Kingdom. Two hundred and ten participants whose substance use met inclusion for an alcohol disorder were compared with other substance users (n = 117) on baseline demographic, clinical and substance use variables. The alcohol subgroup was assessed at three time-points, with repeated measures of psychopathology and alcohol use over a 2-year period. Generalized estimating equations (GEE) models were used to examine whether change in alcohol use was associated with change in clinical outcomes. We controlled for a wide range of potential confounds, including other substance use. RESULTS: A small but specific effect was evident for change in the quantity of alcohol consumed on change in depression (adjusted coefficient for 10 total units over 90 days: 0.0015, P = 0.047). Alcohol consumption was not associated with subsequent severity of psychotic symptoms (adjusted coefficient for Positive and Negative Syndrome Scale general for 10 average daily units 0.2492, P = 0.420) or severity of anxiety symptoms (adjusted coefficient for 10 average daily units 0.0534, P = 0.473). CONCLUSIONS: For people with psychosis, the most detrimental effect of alcohol consumption appears to be its effect on mood. Some of this effect seems to be reversible, with drinking reduction associated with subsequent mood improvement. PMID- 24773576 TI - Interactive association between biopolymers and biofunctions in carinata seeds as energy feedstock and their coproducts (carinata meal) from biofuel and bio-oil processing before and after biodegradation: current advanced molecular spectroscopic investigations. AB - Recent advances in biofuel and bio-oil processing technology require huge supplies of energy feedstocks for processing. Very recently, new carinata seeds have been developed as energy feedstocks for biofuel and bio-oil production. The processing results in a large amount of coproducts, which are carinata meal. To date, there is no systematic study on interactive association between biopolymers and biofunctions in carinata seed as energy feedstocks for biofuel and bioethanol processing and their processing coproducts (carinata meal). Molecular spectroscopy with synchrotron and globar sources is a rapid and noninvasive analytical technique and is able to investigate molecular structure conformation in relation to biopolymer functions and bioavailability. However, to date, these techniques are seldom used in biofuel and bioethanol processing in other research laboratories. This paper aims to provide research progress and updates with molecular spectroscopy on the energy feedstock (carinata seed) and coproducts (carinata meal) from biofuel and bioethanol processing and show how to use these molecular techniques to study the interactive association between biopolymers and biofunctions in the energy feedstocks and their coproducts (carinata meal) from biofuel and bio-oil processing before and after biodegradation. PMID- 24773577 TI - Antibacterial effect of grapefruit seed extract (GSE) on Makgeolli-brewing microorganisms and its application in the preservation of fresh Makgeolli. AB - To develop a new preservation method, the antimicrobial activity of grapefruit seed extract (GSE) against Makgeolli-brewing microorganisms and food-borne pathogens was assessed, and a general analysis and sensory evaluation of fresh Makgeolli with added GSE was made. The minimum inhibitory concentration (MIC) values of GSE against 10 strains of Makgeolli-brewing microorganism were 0.0122 to 1.5625 MUL/mL. The MIC values against 6 strains of food-borne pathogens were 0.0061 to 0.7813 MUL/mL. On addition of 0.1% (v/v) and 0.2% GSE in bottled fresh Makgeolli, no significant difference in the pH, or the contents of total acids, ethanol, or methanol in the Makgeolli, were observed compared with control Makgeolli (with no GSE), during the preservation period (8 weeks) at 10 degrees C. In the Makgeolli with 0.1% and 0.2% GSE, the total bacterial counts decreased significantly by 4.9% (P < 0.01) and 11.2% (P < 0.001), respectively, versus the control. The decreases in yeast count were significantly lessened by 15.33% and 15.24% (both P < 0.001), respectively, after 8 weeks of storage, compared with the control. In the sensory evaluation of Makgeolli with 0.1% and 0.2% GSE, the refreshment and overall acceptability received significantly better scores than the control (P < 0.01), with no change in sweetness, bitterness, sourness, turbidity, color, or odor. These results suggest that GSE controls the growth of Makgeolli-brewing microorganisms and extends the shelf life (ca. 2 wk), without decreasing overall acceptance. PRACTICAL APPLICATION: A new preservation method for fresh Makgeolli by adding grapefruit seed extract (GSE) was developed. As fresh Makgeolli contains live microorganisms, the preservation period is 1 wk, which is relatively short. GSE controls the growth of Makgeolli-brewing and Makgeolli-spoiling microorganisms. 0.1% to 0.2% GSE is optimum for prolonging the shelf life (2 wk) of bottled fresh Makgeolli, and has no adverse effect on overall acceptability. We demonstrated that GSE is an effective natural additive that prolongs the shelf life of fresh Makgeolli with no significant loss in quality. PMID- 24773578 TI - Chloroquine interferes with dengue-2 virus replication in U937 cells. AB - The objective of this study was to investigate the use of chloroquine (CLQ) as an antiviral agent against dengue. Chloroquine, an amine acidotropic drug known to affect intracellular exocytic pathways by increasing endosomal pH, was used in the in vitro treatment of U937 cells infected with dengue virus type 2 (DENV-2). Viral replication was assessed by quantification of virus produced through detection of copy numbers of DENV-2 RNA, plaque assay and indirect immunofluorescence. qRT-PCR and plaque assays were used to quantify the DENV-2 load in infected U937 cells after CLQ treatment. It was found that a dose of 50 MUg/mL of CLQ was not toxic to the cells and resulted in significantly less virus production in infected U937 cells than occurred in untreated cells. In the present work, CLQ was effective against DENV-2 replication in U937 cells, and also caused a statistically significant reduction in expression of proinflammatory cytokines. The present study indicates that CLQ may be used to reduce viral yield in U937 cells. PMID- 24773579 TI - Dependence of filopodia morphology and the separation efficiency of primary CD4+ T-lymphocytes on nanopillars. AB - Despite significant improvement in separation efficiency using nanostructure based platforms, the mechanism underlying the high efficiency of rare cell capture remains elusive. Here we report on the first mechanistic study by developing highly controlled nanostructures to investigate cell surface nanomorphology to better understand the cellular response of CD4(+) T-lymphocytes in contact with nanostructured surfaces and to elucidate key mechanisms for enhancing separation efficiency. Our results showed that actin-rich filopodia protruded from T-cells in the early stage of cell capture (<20 min), demonstrate the different morphologies in response to various quartz nanopillar (QNP) arrays functionalized with streptavidin and the generation of sufficient adhesion sites for rendering more stable binding through three-dimensional local nanotopographic interactions between filopodia-QNPs and cell-substrate, leading to synergistic effects for enhancing cell-capture efficiency. This responsive mechanism of T cells on nanotopographic templates provides new insights to understand the enhanced cell-capture efficiency and specificity from the primary cell suspension on nanostructured substrates. PMID- 24773580 TI - Isolation and characterization of Bacillus subtilis strain BY-3, a thermophilic and efficient cellulase-producing bacterium on untreated plant biomass. AB - Bioconversion of biomass, particularly crop wastes, into biofuels is being developed as an alternative approach in meeting the high energy demand. In this study, a thermophilic bacterial strain BY-3 that exhibits cellulolytic potential was isolated from faecal samples of Tibetan pigs; this strain was identified as Bacillus subtilis. The strain can produce cellulase when grown on various substrates, including carboxymethyl cellulose, rice straw, corn stover, soluble starch and wheat bran. The maximum cellulase activity of the strain was up to 4.323 +/- 0.065 U ml(-1) when cultivated in the medium containing corn stover (30 g l(-1) ) for 24 h. The results demonstrated that corn stover is the most suitable substrate for cellulase production by the strain BY-3. The crude cellulase of strain BY-3 was most active at pH 5.5 and 60 degrees C, and the enzyme in acetate buffer (50 mmol l(-1) ) demonstrated a good stability at 60 degrees C for at least 1 h. The crude cellulase exhibited a strong antibacterial activity against Staphylococcus aureus. The strain can be used in cost-efficient cellulase production for bioconversion of agricultural residual biomass into biofuels. SIGNIFICANCE AND IMPACT OF THE STUDY: The increased consumption of fossil fuels has caused serious energy crisis and environmental problem. Thus, an alternative energy source is necessary. Bioconversion of biomass, particularly agricultural residuals, into value-added bioproducts, such as biofuels and chemical solvents, has received considerable attention. In this study, the newly isolated thermophilic Bacillus subtilis strain BY-3 produces cellulase efficiently with the use of untreated corn stover as a sole carbon source. This strain possesses the thermostable cellulase that is active with diverse crop wastes with a broad pH range and is a highly promising candidate for agricultural waste management. PMID- 24773581 TI - Role of Nodal-PITX2C signaling pathway in glucose-induced cardiomyocyte hypertrophy. AB - Pathological cardiac hypertrophy is a major cause of morbidity and mortality in cardiovascular disease. Recent studies have shown that cardiomyocytes, in response to high glucose (HG) stimuli, undergo hypertrophic growth. While much work still needs to be done to elucidate this important mechanism of hypertrophy, previous works have showed that some pathways or genes play important roles in hypertrophy. In this study, we showed that sublethal concentrations of glucose (25 mmol/L) could induce cardiomyocyte hypertrophy with an increase in the cellular surface area and the upregulation of the atrial natriuretic peptide (ANP) gene, a hypertrophic marker. High glucose (HG) treatments resulted in the upregulation of the Nodal gene, which is under-expressed in cardiomyocytes. We also determined that the knockdown of the Nodal gene resisted HG-induced cardiomyocyte hypertrophy. The overexpression of Nodal was able to induce hypertrophy in cardiomyocytes, which was associated with the upregulation of the PITX2C gene. We also showed that increases in the PITX2C expression, in response to Nodal, were mediated by the Smad4 signaling pathway. This study is highly relevant to the understanding of the effects of the Nodal-PITX2C pathway on HG induced cardiomyocyte hypertrophy, as well as the related molecular mechanisms. PMID- 24773582 TI - Estimate of fetal weight by ultrasound within two weeks of delivery in the detection of fetal macrosomia. AB - BACKGROUND: Delivery of a macrosomic fetus can be linked with significant maternal and perinatal morbidity. Detection of the macrosomic fetus prior to delivery could have a significant impact on reducing that morbidity. AIMS: The purpose of this study was to determine the likelihood of detection of macrosomia at the time of labour and delivery admission using ultrasound. METHODS: Retrospective review using the electronic medical record and delivery room logs to identify women admitted to labour and delivery with a birthweight of >=4000 g. RESULTS: There were 272 macrosomic neonates delivered between January 2010 and December 2012, of which, 91 (33.46%) were identified as macrosomic by ultrasound. Using Spearman correlation, the association between the estimated fetal weight by ultrasound and birthweight was r = 0.214 (95% CI: 0.098-0.325; P = 0.0004). In bivariate analyses, only White race was significant for macrosomia detection with 59 of 149 (39.6%) identified compared with 32 of 123 (26.02%) (P = 0.020) non White people. In the multivariate model, race remained significant. The odds of being labelled macrosomia for White people was 2.051 (95% CI: 1.188-3.542) compared with non-White people (P = 0.010). CONCLUSIONS: Only 33% of fetuses whose birthweight was >=4000 g were identified by a labour and delivery ultrasound. White race was the only significant factor that increased the odds of having a correct diagnosis of macrosomia by ultrasound. PMID- 24773583 TI - Radical ipso-substitution of a carbon-fluorine bond leading to fluoro-7 azaindolines and fluoro-7-azaindoles. AB - Rare examples of a synthetically useful radical ipso-substitution of a carbon fluorine bond are reported, leading to highly functionalized 5,6-difluoro-7 azaindolines. An unexpected hydrogen atom translocation and fragmentation with loss of molecular nitrogen and formation of a nitrile were observed in the case of an N-benzyl-tetrazole derivative. PMID- 24773584 TI - Studies of cobalt-mediated electrocatalytic CO2 reduction using a redox-active ligand. AB - The cobalt complex [Co(III)N4H(Br)2](+) (N4H = 2,12-dimethyl-3,7,11,17 tetraazabicyclo-[11.3.1]-heptadeca-1(7),2,11,13,15-pentaene) was used for electrocatalytic CO2 reduction in wet MeCN with a glassy carbon working electrode. When water was employed as the proton source (10 M in MeCN), CO was produced (fCO= 45% +/- 6.4) near the Co(I/0) redox couple for [Co(III)N4H(Br)2](+) (E1/2 = -1.88 V FeCp2(+/0)) with simultaneous H2 evolution (fH2= 30% +/- 7.8). Moreover, we successfully demonstrated that the catalytically active species is homogeneous through the use of control experiments and XPS studies of the working glassy-carbon electrodes. As determined by cyclic voltammetry, CO2 catalysis occurred near the formal Co(I/0)redox couple, and attempts were made to isolate the triply reduced compound ("[Co(0)N4H]"). Instead, the doubly reduced ("Co(I)") compounds [CoN4] and [CoN4H(MeCN)](+) were isolated and characterized by X-ray crystallography. Their molecular structures prompted DFT studies to illuminate details regarding their electronic structure. The results indicate that reducing equivalents are stored on the ligand, implicating redox noninnocence in the ligands for H2 evolution and CO2 reduction electrocatalysis. PMID- 24773585 TI - Mechanisms of cellular uptake, intracellular transportation, and degradation of CIGB-300, a Tat-conjugated peptide, in tumor cell lines. AB - CIGB-300 is a cyclic synthetic peptide that induces apoptosis in malignant cells, elicits antitumor activity in cancer animal models, and shows tumor reduction signs when assayed in first-in-human phase I trial in patients with cervical tumors. CIGB-300 impairs phosphorylation by casein kinase 2 through targeting the substrate's phosphoacceptor domain. CIGB-300 was linked to the cell penetrating peptide Tat to facilitate the delivery into cells. Previously, we showed that CIGB-300 had a differential antiproliferative behavior in different tumor cell lines. In this work, we studied differential antiproliferative behavior in terms of cellular uptake, intracellular transportation, and degradation in tumor cell lines with dissimilar sensitivity to CIGB-300. The internalization of CIGB-300 was studied in different malignant cell lines. We found that the cell membrane heparan sulfate proteoglycans act as main receptors for extracellular CIGB-300 uptake. The most sensitive tumor cell lines showed higher intracellular incorporation of CIGB-300 in comparison to less sensitive cell lines. Furthermore, CIGB-300 uptake is time- and concentration-dependent in all studied cell lines. It was shown that CIGB-300 has the ability to penetrate cells mainly by direct membrane translocation. However, a minor proportion of the peptide uses an energy-dependent endocytic pathway mechanism to gain access into cells. CIGB 300 is internalized and transported into cells preferentially by caveolae mediated endocytosis. Lysosomes are involved in CIGB-300 degradation; highly sensitive cell lines showed degradation at earlier times compared to low sensitive cells. Altogether, our data suggests a mechanism of internalization, vesicular transportation, and degradation for CIGB-300 in tumor cells. PMID- 24773586 TI - Antigen-triggered interferon-gamma and interleukin-10 pattern in cured mucosal leishmaniasis patients is shaped during the active phase of disease. AB - An exacerbated type 1 response to leishmanial antigens is the basis of tissue destruction observed in mucosal leishmaniasis (ML). After therapy, a persistent production of high levels of inflammatory cytokines can confer a poor prognosis. Herein we investigated whether the clinical conditions defined during the active phase of ML affect the magnitude of long-term anti-Leishmania immune response. Twenty clinically cured ML cases were studied. Peripheral blood mononuclear cells (PBMC) were cultured with L. braziliensis antigens (Lb-Ag), Toxoplasma gondii antigens (Tg-Ag), concanavalin-A (Con-A) or medium alone, and the lymphocyte proliferative response and cytokine secretion were quantified. Medical records were reviewed for Montenegro skin test (MST) during diagnosis, duration of ML disease or time elapsed after clinical cure. The duration of disease was correlated positively with MST (r = 0.61). Lb-Ag induced interferon (IFN)-gamma was correlated positively with duration of illness (r = 0.69) as well as the frequency of secreting cells [enzyme-linked immunospot (ELISPOT)] assay. No association was observed for Tg-Ag or Con-A. Disease duration was correlated negatively with interleukin (IL)-10 production (r = -0.76). Moreover, a negative correlation between length of time after clinical cure and TNF levels (r = -0.94) or the IFN-gamma : IL-10 ratio (r = -0.89) were also seen. We suggest that the magnitude of the IFN-gamma inflammatory response triggered by ML can be driven by the time of leishmanial antigens exposition during the active phase of the disease. This pattern could persist even long-term after cure. However, despite IFN-gamma levels, the decrease of the TNF and IFN-gamma : IL-10 ratio reflects the control of proinflammatory responses achieved by cure of ML, possibly preventing disease relapses. PMID- 24773587 TI - Traumatic axonal injury: the prognostic value of lesion load in corpus callosum, brain stem, and thalamus in different magnetic resonance imaging sequences. AB - The aim of this study was to explore the prognostic value of visible traumatic axonal injury (TAI) loads in different MRI sequences from the early phase after adjusting for established prognostic factors. Likewise, we sought to explore the prognostic role of early apparent diffusion coefficient (ADC) values in normal appearing corpus callosum. In this prospective study, 128 patients (mean age, 33.9 years; range, 11-69) with moderate (n = 64) and severe traumatic brain injury (TBI) were examined with MRI at a median of 8 days (range, 0-28) postinjury. TAI lesions in fluid-attenuated inversion recovery (FLAIR), diffusion weighted imaging (DWI), and T2*-weighted gradient echo (T2*GRE) sequences were counted and FLAIR lesion volumes estimated. In patients and 47 healthy controls, mean ADC values were computed in 10 regions of interests in the normal-appearing corpus callosum. Outcome measure was the Glasgow Outcome Scale-Extended (GOS-E) at 12 months. In patients with severe TBI, number of DWI lesions and volume of FLAIR lesions in the corpus callosum, brain stem, and thalamus predicted outcome in analyses with adjustment for age, Glasgow Coma Scale score, and pupillary dilation (odds ratio, 1.3-6.9; p = <0.001-0.017). The addition of Rotterdam CT score and DWI lesions in the corpus callosum yielded the highest R2 (0.24), compared to all other MRI variables, including brain stem lesions. For patients with moderate TBI only the number of cortical contusions (p = 0.089) and Rotterdam CT score (p = 0.065) tended to predict outcome. Numbers of T2*GRE lesions did not affect outcome. Mean ADC values in the normal-appearing corpus callosum did not differ from controls. In conclusion, the loads of visible TAI lesions in the corpus callosum, brain stem, and thalamus in DWI and FLAIR were independent prognostic factors in patients with severe TBI. DWI lesions in the corpus callosum were the most important predictive MRI variable. Interestingly, number of cortical contusions in MRI and CT findings seemed more important for patients with moderate TBI. PMID- 24773588 TI - Counseling women with a previous cesarean birth: toward a shared decision-making partnership. AB - Pregnant women who had a previous cesarean birth must choose whether to have a repeat cesarean or to attempt a vaginal birth. Many of these women are candidates for a trial of labor. Current practice guidelines recommend that women should be thoroughly counseled during prenatal care about the benefits and harms of both a trial of labor after cesarean (TOLAC) and an elective repeat cesarean delivery and be offered the opportunity to make an informed decision about mode of birth in collaboration with their provider. The purpose of this article is to improve the process of counseling, decision making, and informed consent by increasing health care providers' knowledge about the essential elements of shared decision making. Factors that affect the decisions to be made and concepts that are critical for effective counseling are explored, including clinical considerations, women's perspectives, decision-making models, health literacy and numeracy, communicating risk, and the use of decision aids. Issues related to birth sites for TOLAC are also discussed, including access, safety, refusal of surgery, and clinical management. PMID- 24773589 TI - The effect of low-molecular-weight poly(ethylene glycol) (PEG) plasticizers on the transport properties of lithium fluorosulfonimide ionic melt electrolytes. AB - The influence of low-molecular-weight poly(ethylene glycol) (PEG, Mw ~ 550 Da) plasticizers on the rheology and ion-transport properties of fluorosulfonimide based polyether ionic melt (IM) electrolytes has been investigated experimentally and via molecular dynamics (MD) simulations. Addition of PEG plasticizer to samples of IM electrolytes caused a decrease in electrolyte viscosity coupled to an increase in ionic conductivity. MD simulations revealed that addition of plasticizer increased self-diffusion coefficients for both cations and anions with the plasticizer being the fastest diffusing species. Application of a VTF model to fit variable-temperature conductivity and fluidity data shows that plasticization decreases the apparent activation energy (Ea) and pre-exponential factor A for ion transport and also for viscous flow. Increased ionic conductivity with plasticization is thought to reflect a combination of factors including lower viscosity and faster polyether chain segmental dynamics in the electrolyte, coupled with a change in the ion transport mechanism to favor ion solvation and transport by polyethers derived from the plasticizer. Current interrupt experiments with Li/electrolyte/Li cells revealed evidence for salt concentration polarization in electrolytes containing large amounts of plasticizer but not in electrolytes without added plasticizer. PMID- 24773591 TI - Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach. AB - Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the alpha,beta-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5 phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 +/- 0.01 MUM in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine binding site in tubulin, as confirmed by a competition assay with N,N' ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 MUM and inhibited the migration and invasion of human breast carcinoma cells at 0.4 MUM. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties. PMID- 24773592 TI - Synthesis, structure, and reactivity of 13- and 14-vertex carboranes. AB - Carboranes are a class of polyhedral boron hydride clusters in which one or more of the BH vertices are replaced by CH units. Their chemistry has been dominated by 12-vertex carboranes for over half a century. In contrast, knowledge regarding supercarboranes (carboranes with more than 12 vertices) had been limited merely to possible cage geometries predicted by theoretical work before 2003. Only in recent years has significant progress been made in synthesizing supercarboranes. Such a breakthrough relied on the use of Carbon-Atoms-Adjacent (CAd) nido carborane dianions or arachno-carborane tetraanions as starting materials. In this Account, we describe our work on constructing and elucidating the chemistry of supercarboranes. Earlier attempted insertions of the formal [BR](2+) unit into Carbon-Atoms-Apart (CAp) 12-vertex nido-[7,9-C2B10H12](2-) did not produce the desired 13-vertex carboranes. Such failure is often attributed to the extraordinary stability of the B12 icosahedron (the "icosahedral barrier"). However, the difference in reducing power between CAp and CAd 12-vertex nido carborane dianions had been overlooked. Our results have shown that CAd nido carborane dianions are weaker reducing agents than the CAp isomers, allowing a capitation to prevail over a redox reactivity. This finding provides an entry point to the synthesis of supercarboranes and a series of 13- and 14-vertex closo carboranes have been prepared and structurally characterized. They share some chemical properties with those of 12-vertex carboranes; on the other hand, they have their own unique characteristics. For example, a 13- vertex closo-carborane can undergo single electron reduction to give a stable carborane radical anion with [2n + 3] framework electrons, which can accept one additional electron to form a 13-vertex CAd nido-carborane dianion. 13-Vertex closo-carborane can also react with various nucleophiles to afford the cage carbon and/or boron extrusion products closo-CB11(-), nido-CB10(-), closo-CB10(-), and closo-C2B10, depending on the nature of the nucleophiles. Studies of supercarboranes remain a relative young research area, particularly in comparison to the rich literature of icosahedral carboranes with 12-vertices. Other supercarboranes are expected to be prepared and structurally characterized as the field progresses, and the results detailed here will further these efforts. PMID- 24773590 TI - An early evaluation of implementation of brief intervention for unhealthy alcohol use in the US Veterans Health Administration. AB - AIMS: The US Veterans Health Administration [Veterans Affairs (VA)] used performance measures and electronic clinical reminders to implement brief intervention for unhealthy alcohol use. We evaluated whether documented brief intervention was associated with subsequent changes in drinking during early implementation. DESIGN: Observational, retrospective cohort study using secondary clinical and administrative data. SETTING: Thirty VA facilities. PARTICIPANTS: Outpatients who screened positive for unhealthy alcohol use [Alcohol Use Disorders Identification Test Consumption (AUDIT-C >= 5)] in the 6 months after the brief intervention performance measure (n = 22 214) and had follow-up screening 9-15 months later (n = 6210; 28%). MEASUREMENTS: Multi-level logistic regression estimated the adjusted prevalence of resolution of unhealthy alcohol use (follow-up AUDIT-C <5 with >=2 point reduction) for patients with and without documented brief intervention (documented advice to reduce or abstain from drinking). FINDINGS: Among 6210 patients with follow-up alcohol screening, 1751 (28%) had brief intervention and 2922 (47%) resolved unhealthy alcohol use at follow-up. Patients with documented brief intervention were older and more likely to have other substance use disorders, mental health conditions, poor health and more severe unhealthy alcohol use than those without (P-values < 0.05). Adjusted prevalences of resolution were 47% [95% confidence interval (CI) = 42-52%] and 48% (95% CI = 42-54%) for patients with and without documented brief intervention, respectively (P = 0.50). CONCLUSIONS: During early implementation of brief intervention in the US Veterans Health Administration, documented brief intervention was not associated with subsequent changes in drinking among outpatients with unhealthy alcohol use and repeat alcohol screening. PMID- 24773593 TI - Accelerating the scoring module of mass spectrometry-based peptide identification using GPUs. AB - BACKGROUND: Tandem mass spectrometry-based database searching is currently the main method for protein identification in shotgun proteomics. The explosive growth of protein and peptide databases, which is a result of genome translations, enzymatic digestions, and post-translational modifications (PTMs), is making computational efficiency in database searching a serious challenge. Profile analysis shows that most search engines spend 50%-90% of their total time on the scoring module, and that the spectrum dot product (SDP) based scoring module is the most widely used. As a general purpose and high performance parallel hardware, graphics processing units (GPUs) are promising platforms for speeding up database searches in the protein identification process. RESULTS: We designed and implemented a parallel SDP-based scoring module on GPUs that exploits the efficient use of GPU registers, constant memory and shared memory. Compared with the CPU-based version, we achieved a 30 to 60 times speedup using a single GPU. We also implemented our algorithm on a GPU cluster and achieved an approximately favorable speedup. CONCLUSIONS: Our GPU-based SDP algorithm can significantly improve the speed of the scoring module in mass spectrometry-based protein identification. The algorithm can be easily implemented in many database search engines such as X!Tandem, SEQUEST, and pFind. A software tool implementing this algorithm is available at http://www.comp.hkbu.edu.hk/~youli/ProteinByGPU.html. PMID- 24773594 TI - Thermooxidative stability of fennel oleoresin microencapsulated in blended biopolymer agents. AB - In this work, the oxidative and thermal stabilities of 4 different encapsulating agents (chitosan [CH], modified starch [MS], gum arabic [GA], and maltodextrin [MD]) used in fennel oleoresin microencapsulation by the freeze-drying technique were evaluated both individually and in blends (binary and ternary ones). The oxidative stability of the encapsulated products was assessed by gas chromatography/mass spectrometry analysis of the secondary oxidation volatiles along with the use of oxidation markers (peroxide value, PV), while a differential scanning calorimetery analysis was conducted. Gum arabic, both plain and its mixtures, exhibited the lowest protection against lipid oxidation, presenting high PVs. However, good microencapsulation efficiency along with the best oxidative stability in terms of PV and thermal stability indicated that the formulations of MS-CH and MS-MD-CH could be suggested as alternative encapsulating agents. PRACTICAL APPLICATION: Herbal oleoresins including fennel can provide various nutritional benefits; however, they are sensitive to oxidation and should be microencapsulated. Therefore, there is a need for encapsulating agents that provide good microencapsulation efficiency and enhance at the same time oxidative and thermal stability. PMID- 24773595 TI - Influence of age of onset on limbic and paralimbic structures in depression. AB - AIM: Major depressive disorder (MDD) onset during childhood/adolescence is associated with a greater illness burden and distinct clinical profile. However, limited research exists on the effect of age of MDD onset on volumetric abnormalities in para/limbic structures during adulthood. METHODS: Subgenual anterior cingulate cortex (sgACC), hippocampus and caudate nucleus volumes were measured by manual tracing in depressed individuals (n = 45) and healthy controls (HC; n = 19). Volumetric comparisons were carried out between HC and MDD patients divided into those with pediatric (<= 18 years; n = 17) and adult onset (>= 19 years; n = 28). RESULTS: The adult MDD-onset group had smaller sgACC volumes than the pediatric-onset and HC groups (age, sex controlled). No differences in caudate and hippocampus volumes existed. sgACC and hippocampal volumes were inversely correlated with depression severity. CONCLUSIONS: Surprisingly, pediatric MDD-onset was not associated with more pronounced sgACC, hippocampus and caudate volume reductions. Nevertheless, age of illness onset appears to be a meaningful dimension of study in efforts to understand the neurobiological heterogeneity of MDD. PMID- 24773596 TI - Equine autologous platelet concentrates: A comparative study between different available systems. AB - REASONS FOR PERFORMING STUDY: Autologous platelet concentrates (APCs) are being used increasingly in horses to enhance regeneration in tissues that have poor natural healing capabilities. Numerous APC systems, which are based on different preparation techniques and were originally developed for human patients, are now routinely used in equine cases. However, preliminary process validation and adequate in vitro biochemical characterisation of most of these systems do not exist for horses. OBJECTIVES: To compare haematological findings and growth factor concentrations of equine APCs obtained with 4 commercially available systems and a noncommercial double-centrifugation technique. STUDY DESIGN: Nonrandomised in vitro experiment. METHODS: Blood samples from 6 horses were processed to produce APCs using one equine-specific filtration-based and 4 different centrifugation-based techniques. Platelet, leucocyte, platelet-derived growth factor-BB and transforming growth factor-beta1 concentrations were measured in all APCs, and their respective enrichment factors were compared. RESULTS: Mean platelet concentration increased in all systems in comparison to baseline; however, the mean enrichment factor, which ranged from 130% to 527% depending on the APC, was statistically significant in only 2 products. One method reduced total leucocyte counts to 9% of the baseline value, while the others had a mean fold increase varying from 116 to 663% of the baseline. Differential leucocyte count also differed between the products. Moreover, the various systems had significantly different mean growth factor enrichments (184 1255% for platelet-derived growth factor-BB and 93-560% for transforming growth factor-beta1 ). CONCLUSIONS: Haematological and biochemical characteristics varied markedly among 5 techniques used in the field to produce APCs in horses. These discrepancies could have an impact on clinical outcomes, and further studies are needed to determine their influence on the quality of tissue regeneration. Clinicians should not rely on the manufacturers' data relating to human patients to select the most appropriate method for horses. PMID- 24773597 TI - Frequency of mealtime insulin bolus predicts glycated hemoglobin in youths with type 1 diabetes. AB - BACKGROUND: Within pediatric diabetes management, two electronic measures of adherence exist: frequency of daily blood glucose monitoring (BGM) and the BOLUS score, a measure of frequency of mealtime insulin bolusing. Past research has demonstrated that the BOLUS score is superior to daily BGM in predicting youths' glycated hemoglobin (HbA1c) in a cross-sectional study. We present data comparing the two adherence measures in predicting HbA1c using a prospective, longitudinal design. SUBJECTS AND METHODS: Blood glucose meter data and insulin pump records were collected from a clinical database of 175 youths with type 1 diabetes (mean age, 11.7 +/- 3.6 years at baseline). Youths' HbA1c levels occurring at the download time and at 3, 6, 9, and 12 months post-downloads were also collected. We calculated youths' mean BGM and BOLUS score using a standardized protocol. RESULTS: Intraclass correlations (ICCs) revealed significant absolute equivalence between youths' predicted HbA1c values using BOLUS and BGM scores and future actual HbA1c values up to 12 months post-download. However, the ICCs of BOLUS scores with future HbA1c values were consistently higher than those of the BGM scores. Also, the predictions of the BOLUS scores were significantly more accurate (P <= 0.002) than those of the BGM scores based on the root mean squared error of predictions. CONCLUSIONS: In a prospective, longitudinal design, youths' BOLUS scores were superior to youths' daily BGM in predicting future values of HbA1c. Calculating a BOLUS score versus BGM can help researchers and clinicians achieve a better prediction of youths' HbA1c. PMID- 24773598 TI - Clinical and radiological heterogeneity in aneurysmal sub-arachnoid haemorrhage according to risk-factor profile. AB - BACKGROUND AND AIM: Risk factors for aneurysmal sub-arachnoid haemorrhage can be divided into environmental and inherited factors; the latter being presumed more important in young patients. We explored in young sub-arachnoid haemorrhage patients whether risk-factor profiles influence clinical and radiological characteristics of aneurysms and sub-arachnoid haemorrhage. METHODS: From the 2139 aneurysmal sub-arachnoid haemorrhage patients who had been entered in our prospectively collected database between January 1997 and August 2012, we retrieved data on young (18-40 years) aneurysmal sub-arachnoid haemorrhage patients and compared those with smoking or hypertension (atherogenic risk factors) with those without. Clinical and radiological characteristics were compared with risk ratios and corresponding 95% confidence intervals. Possible confounding by age and gender was adjusted with multivariable Poisson regression analysis. RESULTS: Patients with atherogenic risk factors (n = 113) were less often female (risk ratio: 0.7; 95% confidence interval: 0.6<->0.9), had less often a small aneurysm (risk ratio: 0.4; 95% confidence interval: 0.2<->0.7), and tended to have less often middle cerebral artery aneurysms (risk ratio: 0.5; 95% confidence interval: 0.3<->1.1) than the 29 patients without these risk factors. After adjustment for gender and age, patients with atherogenic risk factors had more often multiple aneurysms (risk ratio: 7.5; 95% confidence interval: 1.1< >52.9). There were no overt differences in the amount of cisternal and intraventricular blood, the shape of the aneurysm, and configuration of the circle of Willis between the patient groups. After adjustment for gender and age, patients with atherogenic risk factors had more often poor outcome (risk ratio: 3.8; 95% confidence interval: 1.0<->14.5). CONCLUSIONS: Young sub-arachnoid haemorrhage patients without atherogenic risk factors are rare. Clinical and radiological characteristics vary between sub-arachnoid haemorrhage patients with different risk-factor profiles. This clinical heterogeneity should be taken into account in future genetic and other etiological studies. PMID- 24773599 TI - Focused chemical libraries--design and enrichment: an example of protein-protein interaction chemical space. AB - One of the many obstacles in the development of new drugs lies in the limited number of therapeutic targets and in the quality of screening collections of compounds. In this review, we present general strategies for building target focused chemical libraries with a particular emphasis on protein-protein interactions (PPIs). We describe the chemical spaces spanned by nine commercially available PPI-focused libraries and compare them to our 2P2I3D academic library, dedicated to orthosteric PPI modulators. We show that although PPI-focused libraries have been designed using different strategies, they share common subspaces. PPI inhibitors are larger and more hydrophobic than standard drugs; however, an effort has been made to improve the drug-likeness of focused chemical libraries dedicated to this challenging class of targets. PMID- 24773600 TI - Letter to the editor. PMID- 24773601 TI - Letter to the editor. PMID- 24773602 TI - Clinical findings and prevalence of the mutation associated with primary ciliary dyskinesia in Old English Sheepdogs. AB - BACKGROUND: Primary ciliary dyskinesia (PCD) is generally a recessively inherited disorder characterized by dysfunction of motile cilia. A mutation in a new causative gene (CCDC39) has been identified in the Old English Sheepdog (OES). OBJECTIVES: To describe the clinical findings and the molecular changes of affected dogs and estimate the worldwide prevalence of the mutation in a large cohort of OES. ANIMALS: 578 OES, including 28 affected and 550 clinically healthy dogs. METHODS: This retrospective study reviewed the data of OES diagnosed with PCD and OES tested for the mutation. Clinical data including results of physical examination and further investigations were obtained on 11/28 dogs. CCDC39 expression was assessed by qRT-PCR and Western blot analysis in affected dogs and healthy dogs. DNA was extracted on 561/578 dogs and a genetic test by Taqman technology was developed to genotype the CCDC39 mutation in these dogs. RESULTS: Clinical findings were recurrent nasal discharge and cough, pyrexia, leucocytosis, and bronchopneumonia. Ultrastructural defects were characterized by central microtubular abnormalities and decreased number of inner dynein arms (IDAs). Molecular analysis revealed a reduced expression of CCDC39 RNA and an absence of CCDC39 protein in affected dogs compared to healthy dogs. The mutation was more frequent in nonrandomly selected European OES population with a higher proportion of carriers (19%) compared to non-European dogs (7%). CONCLUSION AND CLINICAL IMPORTANCE: CCDC39 mutation is dispersed in a worldwide population and is responsible for PCD in this breed. Genetic testing might enable control of this disease. PMID- 24773603 TI - Environmental exposures and airway inflammation in young thoroughbred horses. AB - BACKGROUND: Inflammatory airway disease (IAD) in horses is a widespread, performance-limiting syndrome believed to develop in response to inhaled irritants in the barn environment. OBJECTIVES: To evaluate changes in bronchoalveolar lavage fluid (BALF) cytology and exposure to particulates, endotoxin, and ammonia during horses' first month in training. ANIMALS: Forty nine client-owned 12- to 36-month-old Thoroughbred horses entering race training. METHODS: In this prospective cohort study, a convenience sample of horses was assigned to be fed hay from a net (n = 16), whereas the remaining horses were fed hay from the ground (n = 33). BALF was collected at enrollment and after 14 and 28 days in training. Respirable particulate, inhalable particulate, respirable endotoxin, and ammonia concentrations were measured at the breathing zone of each horse weekly. RESULTS: Median respirable particulates were significantly higher when horses were fed from hay nets than when fed hay from the ground (hay net 0.28 mg/m(3) , no hay net 0.055 mg/m(3) , P < .001). Likewise, inhalable particulate (hay net 8.3 mg/m(3) , no hay net 3.3 mg/m(3) , P = .0064) and respirable endotoxin (hay net 173.4 EU/m(3) , no hay net 59.2 EU/m(3) , P = .018) exposures were significantly higher when horses were fed from hay nets. Feeding hay from a net resulted in significantly higher BALF eosinophil proportions over time (P < .001). BALF eosinophils were significantly related to respirable particulate exposure (14 days in training rs = 0.37, P = .012, 28 days in training, rs = 0.38, P = .017). CONCLUSIONS AND CLINICAL IMPORTANCE: Pulmonary eosinophilic inflammation develops in response to respirable particulate exposure in young Thoroughbreds, indicating a potential hypersensitivity to inhaled particulate allergens. PMID- 24773605 TI - Exome sequencing helped the fine diagnosis of two siblings afflicted with atypical Timothy syndrome (TS2). AB - BACKGROUND: Long-QT syndrome (LQTS) causes a prolongation of the QT-interval in the ECG leading to life threatening tachyarrhythmia and ventricular fibrillation. One atypical form of LQTS, Timothy syndrome (TS), is associated with syndactyly, immune deficiency, cognitive and neurological abnormalities as well as distinct cranio-facial abnormalities. CASE PRESENTATION: On a family with both children diagnosed with clinical LQTS, we performed whole exome sequencing to comprehensively screen for causative mutations after a targeted candidate gene panel screen for Long-QT syndrome target genes failed to identify any underlying genetic defect. Using exome sequencing, we identified in both affected children, a p.402G > S mutation in exon 8 of the CACNA1C gene, a voltage-dependent Ca2+ channel. The mutation was inherited from their father, a mosaic mutation carrier. Based on this molecular finding and further more careful clinical examination, we refined the diagnosis to be Timothy syndrome (TS2) and thereby were able to present new therapeutic approaches. CONCLUSIONS: Our study highlights the difficulties in accurate diagnosis of patients with rare diseases, especially those with atypical clinical manifestation. Such challenge could be addressed with the help of comprehensive and unbiased mutation screening, such as exome sequencing. PMID- 24773606 TI - Effects of lycopene supplementation in both maternal and offspring diets on growth performance, antioxidant capacity and biochemical parameters in chicks. AB - This study investigated the effects of different supplementation ways of lycopene during pre-hatch (from the diet of hens) and post-hatch (from the diet of progeny) on production performance, antioxidant capacity and biochemical parameters in chicks. In total, 360 hens were fed diets supplemented with 0 (control group) or 40 mg lycopene/kg diet. From 28 to 34 days after the start of supplementation (30 weeks old), 650 qualified eggs were collected to artificial incubation. In this trial, 2 * 2 factorial designs were used. Male chicks hatched from hens fed with 0 or 40 mg lycopene/kg diet were fed a diet containing either 0 or 40 mg lycopene/kg diet. The results showed that, relative to control, in ovo deposited lycopene significantly increased chick birth body weight, improved liver total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) and glutathione to oxidized glutathione ratio (GSH: GSSG), and significantly declined liver malondialdehyde (MDA) level and increased liver lycopene content during 0 14 days after hatching. On days 14 after hatching, dietary lycopene in diet began to take over gradually. Both supplementation ways of lycopene increased immune organ index, serum high-density lipoprotein (HDL) cholesterol, villus length and villus/crypt in duodenum, jejunum and ileum. Data in this study suggested lycopene supplementation could improve antioxidant capacity and immune function, and regulate lipid metabolism in chicks. PMID- 24773607 TI - The function of TLR4 in interferon gamma or interleukin-13 exposed and lipopolysaccharide stimulated gingival epithelial cell cultures. AB - Gingival epithelial cells are part of the first line of host defense against infection. Toll-like receptors (TLRs) serve important immune and nonimmune functions. We investigated how interferon gamma (INF-gamma) and interleukin 13 (IL-13) are involved in the TLR4 ligand-induced regulation of interleukin-8 (IL 8) effects on gingival epithelial cells. We used immunohistochemistry to localize TLR4 in ten healthy and ten periodontitis tissue specimens. Gingival epithelial cells then were primed with Th1 cytokine (INF-gamma) or Th2 cytokine (IL-13) before stimulation with Escherichia coli-derived lipopolysaccharide (LPS) and enzyme-linked immunosorbent assay (ELISA) was performed to detect the level of IL 8 secretion in cell culture supernatants. Although both healthy and periodontitis gingival tissue samples expressed TLR4, the periodontitis samples showed more intense expression on gingival epithelial cells. Gingival epithelial cell cultures were primed with either INF-gamma or IL-13 before stimulation with TLR4 ligand. Supernatants from co-stimulated epithelial cells exhibited IL-8 production in opposite directions, i.e., as one stimulates the release, the other reduces the release. INF-gamma significantly increased TLR4 function, whereas IL 13 significantly decreased TLR4 function, i.e., production of IL-8. Pathogen associated molecular pattern-LPS, shared by many different periodonto-pathogenic bacteria, activates the gingival epithelial cells in a TLR-dependent manner. Diminished or increased TLR function in gingival epithelial cells under the influence of different Th cell types may protect or be harmful due to the altered TLR signaling. PMID- 24773608 TI - Nadir PSA level and time to nadir PSA are prognostic factors in patients with metastatic prostate cancer. AB - BACKGROUND: Primary androgen deprivation therapy (PADT) is the most effective systemic therapy for patients with metastatic prostate cancer. Nevertheless, once PSA progression develops, the prognosis is serious and mortal. We sought to identify factors that predicted the prognosis in a series of patients with metastatic prostate cancer. METHODS: Two-hundred eighty-six metastatic prostate cancer patients who received PADT from 1998 to 2005 in Nara Uro-Oncology Research Group were enrolled. The log-rank test and Cox's proportional hazards model were used to determine the predictive factors for prognosis; rate of castration resistant prostate cancer (CRPC) and overall survival. RESULTS: The median age, follow-up period and PSA level at diagnosis were 73 years, 47 months and 174 ng/mL, respectively. The 5-year overall survival rate was 63.0%. The multivariable analysis showed that Gleason score (Hazard ratio [HR]:1.362; 95% confidence interval [C.I.], 1.023-1.813), nadir PSA (HR:6.332; 95% C.I., 4.006 9.861) and time from PADT to nadir (HR:4.408; 95% C.I., 3.099-6.271) were independent prognostic factors of the incidence of CRPC. The independent parameters in the multivariate analysis that predicted overall survival were nadir PSA (HR:5.221; 95% C.I., 2.757-9.889) and time from PADT to nadir (HR:4.008; 95% C.I., 2.137-7.517). CONCLUSIONS: Nadir PSA and time from PADT to nadir were factors that affect both CRPC and overall survival in a cohort of patients with metastatic prostate cancer. Lower nadir PSA level and longer time from PADT to nadir were good for survival and progression. PMID- 24773609 TI - Calibration-less sizing and quantitation of polymeric nanoparticles and viruses with quartz nanopipets. AB - The feasibility of using quartz nanopipets as simple and cost-effective Coulter counters for calibration-less quantitation and sizing of nanoparticles by resistive pulsing sensing (RPS) was investigated. A refined theory was implemented to calculate the size distribution of nanoparticles based on the amplitude of resistive pulses caused by their translocation through nanopipets of known geometry. The RPS provided diameters of monodisperse latex nanoparticles agreed within the experimental error with those measured by using scanning electron microscopy (SEM), dynamic light scattering (DLS), and nanoparticle tracking analysis (NTA). The nanopipet-based counter, by detecting individual nanoparticles, could resolve with similar resolution as SEM mixtures of monodisperse nanoparticles having partially overlapping size distributions, which could not be discriminated by DLS or NTA. Furthermore, by calculating the hydrodynamic resistance of the nanopipets and consequently the volume flow through the tip enabled for the first time the calibration-less determination of nanoparticle concentrations with nanopipets. The calibration-less methodology is applied to sizing and quantitation of inactivated poliovirus of ~26 nm diameter, which is the smallest size spherical shape virus ever measured by resistive pulse sensing. PMID- 24773610 TI - Near-misses and future disaster preparedness. AB - Disasters garner attention when they occur, and organizations commonly extract valuable lessons from visible failures, adopting new behaviors in response. For example, the United States saw numerous security policy changes following the September 11 terrorist attacks and emergency management and shelter policy changes following Hurricane Katrina. But what about those events that occur that fall short of disaster? Research that examines prior hazard experience shows that this experience can be a mixed blessing. Prior experience can stimulate protective measures, but sometimes prior experience can deceive people into feeling an unwarranted sense of safety. This research focuses on how people interpret near-miss experiences. We demonstrate that when near-misses are interpreted as disasters that did not occur and thus provide the perception that the system is resilient to the hazard, people illegitimately underestimate the danger of subsequent hazardous situations and make riskier decisions. On the other hand, if near-misses can be recognized and interpreted as disasters that almost happened and thus provide the perception that the system is vulnerable to the hazard, this will counter the basic "near-miss" effect and encourage mitigation. In this article, we use these distinctions between resilient and vulnerable near-misses to examine how people come to define an event as either a resilient or vulnerable near-miss, as well as how this interpretation influences their perceptions of risk and their future preparedness behavior. Our contribution is in highlighting the critical role that people's interpretation of the prior experience has on their subsequent behavior and in measuring what shapes this interpretation. PMID- 24773611 TI - The expression of Toll-like receptors 2, 4 and 9 in kidneys of patients with anti neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. AB - Increasing evidence suggested that Toll-like receptors (TLRs) were critically involved in immune responses of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). The current study aimed to investigate the expression of TLR-2, TLR-4 and TLR-9 in kidneys of patients with ANCA-associated vasculitis. Renal biopsy specimens were collected from 24 patients with AAV. The expression of TLR-2, TLR-4 and TLR-9 in kidneys was detected by immunohistochemistry. Double immunofluorescence staining was performed to detect the expression of TLRs on various kinds of cells. In renal specimens, immunohistochemical examination revealed that expression of TLR-2 and TLR-4 could be detected in the glomeruli of AAV patients, while TLR-2 and TLR-4 were scarcely detected in the glomeruli of normal controls. Double immunofluorescence staining of TLR-2, TLR-4 and CD31 indicated that TLR-4 and TLR-2 were expressed on endothelial cells in the glomeruli. In the tubulointerstitial compartment, expression of TLR-2, TLR-4 and TLR-9 could be detected in both AAV patients and normal controls. The mean optical density of TLR-2 and TLR-4 in the tubulointerstitial compartment in AAV patients were significantly higher than that in normal controls. Among AAV patients, correlation analysis showed that the mean optical density of TLR-4 in the glomeruli correlated inversely with the initial serum creatinine, the proportion of total crescents and the proportion of cellular crescents in renal specimens (r = -0.419, P = 0.041; r = -0.506, P = 0.012; r = -0.505, P = 0.012, respectively). The expression of TLR-2 and TLR-4 was dysregulated in kidneys of AAV patients. The expression of TLR-4 in glomeruli was associated with the severity of renal injury. PMID- 24773612 TI - Purification, characterization, cDNA cloning and in vitro expression of a serine proteinase from the intestinal tract of sea cucumber (Stichopus japonicus) with collagen degradation activity. AB - Sea cucumber (Stichopus japonicus) autolysis during transportation and processing is a major problem and the specific proteinases responsible for autolysis have not yet been identified. In the present study, a 34 kDa serine proteinase (SP) was isolated to high purity from sea cucumber intestinal tract by a series of column chromatographies. Peptide mass fingerprinting revealed that six peptide fragments were identical to a proprotein convertase subtilisin/kexin type 9 preproprotein from sea cucumber A. japonicus. The enzyme hydrolyzed gelatin effectively at pH 6.0-9.0 and 35-40 degrees C, and the enzyme activity was strongly inhibited by SP inhibitors. Sea cucumber collagen was hydrolyzed significantly by purified SP at 37 degrees C and more gradually at 4 degrees C, suggesting that SP may be involved in autolysis. In addition, the SP gene that codes for 377 amino acid residues was cloned into an E. coli expression vector and expressed in vitro. A polyclonal antibody against rSP was prepared and found to react specifically against both rSP and endogenous SP, which may prove useful for future studies on the physiological functions of SP. PMID- 24773614 TI - Genetics of upper and lower airway diseases in the horse. AB - Genetic predispositions for guttural pouch tympany, recurrent laryngeal neuropathy and recurrent airway obstruction (RAO) are well documented. There is also evidence that exercise-induced pulmonary haemorrhage and infectious diseases of the respiratory tract in horses have a genetic component. The clinical expression of equine respiratory diseases with a genetic basis results from complex interactions between the environment and the genetic make-up of each individual horse. The genetic effects are likely to be due to variations in several genes, i.e. they are polygenic. It is therefore unlikely that single gene tests will be diagnostically useful in these disorders. Genetic profiling panels, combining several genetic factors with an assessment of environmental risk factors, may have greater value, but much work is still needed to uncover diagnostically useful genetic markers or even causative variants for equine respiratory diseases. Nonetheless, chromosomal regions associated with guttural pouch tympany, recurrent laryngeal neuropathy and RAO have been identified. The association of RAO with other hypersensitivities and with resistance to intestinal parasites requires further study. This review aims to provide an overview of the available data and current thoughts on the genetics of equine airway diseases. PMID- 24773613 TI - Are 1st-trimester beta-human chorionic gonadotrophin and pregnancy-associated plasma protein A levels predictive of intrapartum fetal compromise in a selected normal population? AB - BACKGROUND: The incidence of cerebral palsy in term infants has not changed over the last 30 years. Current intrapartum monitoring techniques are limited by their inherent poor specificity. Changes in fetal haemodynamics in the term fetus, similar to those seen in fetal growth restriction, have been associated with an increased risk of subsequent intrapartum fetal compromise. Alterations in first trimester beta-hCG and PAPP-A levels are predictive of fetal growth restriction. AIMS: In this study, we aimed to establish whether first-trimester beta-hCG and PAPP-A levels were predictive of fetal compromise in labour and whether these first-trimester markers could be correlated with fetal haemodynamics at term in a low-risk population. MATERIALS AND METHODS: Over a two-year period, 427 women with low risk, uncomplicated pregnancies were recruited to this study. All participants underwent a prelabour ultrasound examination during which fetal biometry and haemodynamics were assessed. First-trimester beta-hCG and PAPP-A levels were recorded from the case notes. All cases were followed up within 48 hours of delivery, and first-trimester beta-hCG and PAPP-A levels correlated with intrapartum outcomes and fetal haemodynamics. RESULTS: No significant relationship between first-trimester beta-hCG and PAPP-A levels and subsequent intrapartum fetal compromise was observed. Weak but significant correlations were observed between beta-hCG levels and umbilical venous flow rate, as well as PAPP A levels and uterine artery pulsatility index. CONCLUSIONS: beta-hCG and PAPP-A levels measured during the first trimester are not predictive of subsequent intrapartum fetal compromise within a low-risk population. PMID- 24773615 TI - Tribulus terrestris for treatment of sexual dysfunction in women: randomized double-blind placebo - controlled study. AB - BACKGROUND: Tribulus terrestris as a herbal remedy has shown beneficial aphrodisiac effects in a number of animal and human experiments. This study was designed as a randomized double-blind placebo-controlled trial to assess the safety and efficacy of Tribulus terrestris in women with hypoactive sexual desire disorder during their fertile years. Sixty seven women with hypoactive sexual desire disorder were randomly assigned to Tribulus terrestris extract (7.5 mg/day) or placebo for 4 weeks. Desire, arousal, lubrication, orgasm, satisfaction, and pain were measured at baseline and after 4 weeks after the end of the treatment by using the Female Sexual Function Index (FSFI). Two groups were compared by repeated measurement ANOVA test. RESULTS: Thirty women in placebo group and thirty women in drug group completed the study. At the end of the fourth week, patients in the Tribulus terrestris group had experienced significant improvement in their total FSFI (p < 0.001), desire (p < 0.001), arousal (p = 0.037), lubrication (p < 0.001), satisfaction (p < 0.001) and pain (p = 0.041) domains of FSFI. Frequency of side effects was similar between the two groups. CONCLUSIONS: Tribulus terrestris may safely and effectively improve desire in women with hypoactive sexual desire disorder. Further investigation of Tribulus terrestris in women is warranted. PMID- 24773617 TI - Usefulness of contrast-enhanced ultrasound with Sonazoid for evaluating liver abscess in comparison with conventional B-mode ultrasound. AB - AIM: The purpose of this study was to evaluate the usefulness of contrast enhanced ultrasound (CEUS) with Sonazoid (perfluorobutane) in patients with liver abscess. Sonazoid is a contrast agent with a low mechanical index and is phagocytosed by Kupffer cells. METHODS: Twenty-two patients with liver abscess were evaluated with conventional US, real-time CEUS with Sonazoid, and enhanced computed tomography (CT). After 0.5 mL of Sonazoid was administrated i.v., CEUS images in the vascular and post-vascular phases were observed. RESULTS: Conventional US showed hypoechoic lesions in 13 (59.1%), isoechoic in four (18.2%), hyperechoic in two (9.1%), mixed echoic in two (9.1%) and undetected in one (4.8%) patient. CEUS showed perilesional enhancement in 19 (86.4%) lesions in the vascular phase and well-defined unenhanced areas in 22 (100%) lesions in the post-vascular phase. CEUS revealed that 18 abscesses were cystic type and three were honeycomb type. Twenty-one abscesses (95.5%) had clearer appearances on CEUS than on conventional US in regard to the extent of necrotic or liquefied lesions seen. We could confirm reduction of the lesions after therapy in 13 (92.9%) of 14 patients followed up by CEUS. CONCLUSION: Most of the liver abscesses showed perilesional enhancement in the vascular phase and unenhanced areas in the post vascular phase. The appearance of liver abscesses was clearer on CEUS than on conventional US. CEUS with Sonazoid can be a more effective diagnostic and therapeutic tool for liver abscess. PMID- 24773616 TI - Lead optimization studies of cinnamic amide EP2 antagonists. AB - Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (~10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role. PMID- 24773618 TI - Serious outcomes associated with overdose of medicines containing barbiturates for treatment of insomnia. PMID- 24773619 TI - Quantification of skeletal muscle mitochondrial function by 31P magnetic resonance spectroscopy techniques: a quantitative review. AB - Magnetic resonance spectroscopy (MRS) can give information about cellular metabolism in vivo which is difficult to obtain in other ways. In skeletal muscle, non-invasive (31) P MRS measurements of the post-exercise recovery kinetics of pH, [PCr], [Pi] and [ADP] contain valuable information about muscle mitochondrial function and cellular pH homeostasis in vivo, but quantitative interpretation depends on understanding the underlying physiology. Here, by giving examples of the analysis of (31) P MRS recovery data, by some simple computational simulation, and by extensively comparing data from published studies using both (31) P MRS and invasive direct measurements of muscle O2 consumption in a common analytical framework, we consider what can be learnt quantitatively about mitochondrial metabolism in skeletal muscle using MRS-based methodology. We explore some technical and conceptual limitations of current methods, and point out some aspects of the physiology which are still incompletely understood. PMID- 24773620 TI - U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer's disease due to autosomal dominant genetic mutations and trisomy 21. AB - BACKGROUND: We recently identified U1 small nuclear ribonucleoprotein (snRNP) tangle-like aggregates and RNA splicing abnormalities in sporadic Alzheimer's disease (AD). However little is known about snRNP biology in early onset AD due to autosomal dominant genetic mutations or trisomy 21 in Down syndrome. Therefore we investigated snRNP biochemical and pathologic features in these disorders. FINDINGS: We performed quantitative proteomics and immunohistochemistry in postmortem brain from genetic AD cases. Electron microscopy was used to characterize ultrastructural features of pathologic aggregates. U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations. Aggregates of U1 snRNP immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21. Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF). CONCLUSIONS: These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant beta amyloid processing may influence U1 snRNP aggregate formation. PMID- 24773621 TI - Heat shock protein 70 induction by valproic acid delays photoreceptor cell death by N-methyl-N-nitrosourea in mice. AB - Retinal degenerative diseases (RDs) are a group of inherited diseases characterized by the loss of photoreceptor cells. Selective photoreceptor loss can be induced in mice by an intraperitoneal injection of N-methyl-N-nitrosourea (MNU) and, because of its selectivity, this model is widely used to study the mechanism of RDs. Although it is known that calcium-calpain activation and lipid peroxidation are involved in the initiation of cell death, the precise mechanisms of this process remain unknown. Heat shock protein 70 (HSP70) has been shown to function as a chaperone molecule to protect cells against environmental and physiological stresses. In this study, we investigated the role of HSP70 on photoreceptor cell death in mice. HSP70 induction by valproic acid, a histone deacetylase inhibitor, attenuated the photoreceptor cell death by MNU through inhibition of apoptotic caspase signals. Furthermore, HSP70 itself was rapidly and calpain-dependently cleaved after MNU treatment. Therefore, HSP70 induction by valproic acid was dually effective against MNU-induced photoreceptor cell loss as a result of its anti-apoptotic actions and its ability to prevent HSP70 degradation. These findings might help lead us to a better understanding of the pathogenic mechanism of RDs. Retinal degenerative diseases are characterized by the loss of photoreceptor cells. We proposed the following cascade for N-methyl-N nitrosourea (MNU)-induced photoreceptor cell death: MNU gives rise to cleavage of heat shock protein 70 (HSP70); HSP70 induction by valproic acid (VPA) is dually effective against MNU-induced photoreceptor cell loss because of its anti apoptotic actions and its ability to prevent HSP70 degradation. We hope that the present study heralds a new era in developing therapeutic tools against retinal degenerative diseases. PMID- 24773622 TI - Orally administered misoprostol for induction of labor with prelabor rupture of membranes at term. AB - Prelabor rupture of membranes (PROM) occurs in approximately 8% to 10% of women with term pregnancies. The management of PROM continues to be controversial. Approaches include expectant management and immediate induction of labor. The use of orally administered misoprostol for the management of women with PROM may provide significant advantages when they choose immediate induction of labor. This literature review presents current evidence that supports the use of oral misoprostol for women with PROM, including the benefits of a decreased interval time from PROM to vaginal birth, good safety profile, and reductions in the use of oxytocin augmentation and epidural anesthesia. In addition to clinically proven benefits to women of oral misoprostol for PROM, it also has the potential to reduce chorioamnionitis by reducing the number of sterile vaginal examinations performed thereby reducing the risk of ascending bacteria. Women have also reported acceptability and satisfaction when using oral misoprostol for immediate induction of labor. This review of literature discusses what is known about the use of orally administered misoprostol for the management of term PROM and makes recommendations for clinical use. PMID- 24773623 TI - Application of nuclear medicine to achieve less invasive surgery for malignant solid tumors in children. AB - BACKGROUND: The use of nuclear medicine for the management of malignant tumor, such as radioguided surgery and sentinel lymph node biopsy (SLNB), has been widely accepted in the adult practice. However, there are very few studies to apply those techniques for pediatric diseases. The aim of this study was to investigate the feasibility of application of nuclear medicine in surgery for neuroblastoma (NB) or rhabdomyosarcoma (RMS) in children. METHODS: Radioguided surgery using (123) I-metaiodobenzylguanidine was performed on six children with NB. SLNB using technetium-labeled tin or sulfur colloid was performed on two children with perineal RMS. Histological evaluation of resected specimens was performed to determine the accuracy of intraoperative detection and SLNB. All patients were evaluated for overall survival and complications. RESULTS: Intraoperative tumor localization using hand-held gamma probe was helpful in 85.7% of NB patients. Sensitivity and specificity of this technique were 81.8% and 93.3%, respectively. There were no postoperative complications, and four out of five patients with high-risk NB experienced disease-free survival (median follow up, 57 months). Sentinel lymph nodes were easily detected in patients with perineal RMS, and histological assessment revealed complete consistency with regional lymph node status. CONCLUSIONS: Nuclear medicine may have a potential application in the use of less invasive surgery for advanced NB or perineal RMS, the two most challenging pediatric malignancies. PMID- 24773624 TI - Component contribution of personal protective equipment to the alleviation of physiological strain in firefighters during work and recovery. AB - The purpose of this study was to investigate the components contributions of personal protective equipment on physiological strain in firefighters during exercise and recovery. Eight firefighters participated in trials in which various combinations of personal protective equipment components weighing from 1.3 to 15.1 kg were worn. The results showed that rectal temperature, changes in rectal temperature, mean skin temperature, heart rate, oxygen consumption and blood lactate concentration were smaller in conditions without boots (no-boots) than in other conditions with no helmet, gloves or self-contained breathing apparatus (P < 0.05). Increases in rectal temperature per unit mass of personal protective equipment were approximately twice as small in no-boots condition as the other conditions. These results suggest that the reduction of the boots' mass might be more efficient to alleviate heat strain of firefighters wearing personal protective equipment, rather than the reduction of the mass of self-contained breathing apparatus, helmet or gloves. PRACTITIONER SUMMARY: As firefighters' protective boots induce greater physiological burden when compared with a helmet, gloves or self-contained breathing apparatus, personal protective equipment designers need to consider the improvement of boots in terms of mass reduction, improvement of thermal comfort and ease of doffing during recovery to alleviate physiological strain on firefighters. PMID- 24773625 TI - Physiological changes in response to apnea impact the timing of motor representations: a preliminary study. AB - BACKGROUND: Reduced physiological arousal in response to breath-holding affects internal clock processes, leading swimmers to underestimate the time spent under apnea. We investigated whether reduced physiological arousal during static apnea was likely to affect the temporal organization of motor imagery (MI). METHODS: Fourteen inter-regional to national breath-holding athletes mentally and physically performed two 15 m swimming tasks of identical durations. They performed the two sequences in a counterbalanced order, the first while breathing normally using a scuba, the second under apnea. We assessed MI duration immediately after completion of the corresponding task. Athletes performed MI with and without holding breath. RESULTS: MI durations (26.1 s +/- 8.22) were significantly shorter than actual durations (29.7 s +/- 7.6) without holding breath. Apnea increased MI durations by 10% (+/- 5%). Heart rate decrease in response to breath-holding correlated with MI durations increase (p < .01). Under apnea, participants achieved temporal congruence between MI and PP only when performing MI of the apnea swimming task. Self-report data indicated greater ease when MI was performed in a physiological arousal state congruent with that of the corresponding motor task. CONCLUSIONS: Physiological arousal affected the durations of MI through its effects on internal clock processes and by impacting the congruency in physiological body states between overt and covert motor performance. Present findings have potential implications with regards to the possibility of preventing underestimation of durations spent under a state of reduced physiological arousal. PMID- 24773626 TI - A texture analysis method for MR images of airway dilator muscles: a feasibility study. AB - OBJECTIVES: Airway dilator muscles play an important role in the analysis of breathing-related symptoms, such as obstructive sleep apnoea. Texture analysis (TA) provides a new non-invasive method for analysing airway dilator muscles. In this study, we propose a TA methodology for airway dilator muscles and prove the robustness of this method. METHODS: 15 orthognathic surgery patients underwent 3 T MRI. Computerized TA was performed on 20 regions of interest (ROIs) in the patients' airway dilator muscles. 53 texture parameters were calculated for all ROIs. The robustness of the TA method was analysed by altering the locations, sizes and shapes of the ROIs. RESULTS: Our study shows that there is significant difference in TA results as the size or shape of ROI changes. The change of location of the ROI inside the studied muscle does not affect the TA results. CONCLUSIONS: The TA method is valid for airway dilator muscles. We propose a methodology in which the number of co-occurrence parameters is reduced by using mean values from four different directions (0 degrees , 45 degrees , 90 degrees and 135 degrees ) with pixel spacing of 1 pixel. PMID- 24773627 TI - Munchmeyer's disease-a rare case report and review of literature. AB - Munchmeyer's disease is a rare variety of myositis ossificans. It is a significant clinical entity, diagnosing and understanding its pathophysiology can save a patient from spurious medical workups and anxiety of a suspected neoplasm. The number of authentic cases of this disease in the literature is small. The purpose of this article is to present a case of Munchmeyer's disease and review the literature for the same to date. The rare incidence, obscure aetiology, unknown definitive treatment plan and poor prognosis make this condition an enigma. PMID- 24773628 TI - EgoNet: identification of human disease ego-network modules. AB - BACKGROUND: Mining novel biomarkers from gene expression profiles for accurate disease classification is challenging due to small sample size and high noise in gene expression measurements. Several studies have proposed integrated analyses of microarray data and protein-protein interaction (PPI) networks to find diagnostic subnetwork markers. However, the neighborhood relationship among network member genes has not been fully considered by those methods, leaving many potential gene markers unidentified. The main idea of this study is to take full advantage of the biological observation that genes associated with the same or similar diseases commonly reside in the same neighborhood of molecular networks. RESULTS: We present EgoNet, a novel method based on egocentric network-analysis techniques, to exhaustively search and prioritize disease subnetworks and gene markers from a large-scale biological network. When applied to a triple-negative breast cancer (TNBC) microarray dataset, the top selected modules contain both known gene markers in TNBC and novel candidates, such as RAD51 and DOK1, which play a central role in their respective ego-networks by connecting many differentially expressed genes. CONCLUSIONS: Our results suggest that EgoNet, which is based on the ego network concept, allows the identification of novel biomarkers and provides a deeper understanding of their roles in complex diseases. PMID- 24773629 TI - Central precocious puberty in a 3 year-old girl with Phenylketonuria: a rare association? AB - BACKGROUND: Central precocious puberty (CPP) and phenylketonuria (PKU) are two rare conditions, the latter being the rarer. To date, only one case featuring both these conditions has been reported, and hyperphenylalaninemia was assumed triggering CPP. CASE PRESENTATION: We present a 3.2 years old girl referred with a 12 months history of breast and pubic hair development, and vaginal discharge. Hyperphenylalaninemia had been identified by newborn screening and PKU subsequently confirmed by plasma amino acid and genetic analysis. Early dietary control of plasma phenylalanine had been excellent afterwards, resulting in phenylalanine concentrations consistently within the recommended range. Clinical scenario, hormonal assessment and imaging were in keeping with true idiopathic central precocious puberty. Treatment with long lasting gonadotropin-releasing hormone analogue led to regression of secondary sexual characteristics. CONCLUSION: We describe for the first time CPP in a girl affected with PKU but with persistently well controlled blood phenylalanine concentrations. This finding is in contrast to a previous report which suggested persistently high phenylalaninemia levels as potential trigger for CPP in PKU patients. Our report, together with the lack of evidence in published cohort studies of children with PKU, strongly suggests this rare association is coincidental and independent of the presence of severe hyperphenylalaninemia. PMID- 24773631 TI - Toward an understanding of the influence of cultural background and domain experience on the effects of risk-pricing formats on risk perception. AB - Risk-information framing can be a powerful tool for aiding the communication of risk and improving decision making. However, little work has investigated the extent that these framing effects depend on the characteristics of the perceiver. In our study, we examine whether the effects of different risk-pricing formats on risky choices are the same for all individuals, no matter their domain experience or cultural background, or whether there are interactions between these factors. Survey 1 revealed that three risk-pricing formats of the same choice problem resulted in the same individuals making different risky choices (preference reversal), suggesting that risk perception was distorted by the risk-pricing format manipulation. In Survey 2, the effects of the risk-pricing formats were shown to differ by the participants' cultural background (Asian vs. European) and the extent of their domain experience. The fact that there were no differences between the cultural or domain experience groups in their overall tendency to select riskier (cf. safer) choices indicates that risk behavior differences between groups are often closely linked to perceptual, rather than simply attitudinal, cognitive processes. The results demonstrate the complex, interactive cognitive processes that are used to encode risk information, involving the framing of the information and the cultural background and previous experiences of the individual. We conclude that it is important to consider the characteristics of the individual (e.g., culture, domain experience, etc.) when manipulating risk-information framing with the aim of improving risk communication. PMID- 24773630 TI - Intestinal titres of anti-tissue transglutaminase 2 antibodies correlate positively with mucosal damage degree and inversely with gluten-free diet duration in coeliac disease. AB - It has always been known that anti-tissue transglutaminase 2 (anti-TG2) antibodies are produced in the small intestine. Their serum titres correlate with mucosal damage degree and decrease on a gluten-free diet (GFD). We aimed to correlate intestinal anti-TG2 antibodies levels with degree of mucosal damage and GFD duration. Thirty-four active, 71 potential and 24 CD patients on GFD for at least 2 years were enrolled. Anti-TG2 deposits were detected in intestinal biopsies by double immunofluorescence. Biopsies were cultured for 24 h with medium, and with gliadin peptic tryptic digest (PTG) or A-gliadin peptide 31-43 (P31-43). Anti-TG2 antibodies secreted into supernatants were measured by enzyme linked immunosorbent assay (ELISA). All active CD patients secreted high titres of anti-TG2 antibodies into culture medium that increased with the worsening of mucosal injury (Spearman's r = 0.71; P < 0.0001). Seventy of 71 potential CD patients and 15 of 24 treated CD patients secreted low titres of anti-TG2 antibodies into supernatants, eight of nine negative treated patients being on GFD for more than 10 years. An inverse correlation between antibody titres and duration of GFD was found, (Spearman's r = -0.52; P < 0.01). All active, 53 of 71 potential and six of 24 treated, CD patients showed anti-TG2 mucosal deposits. Five of six positive treated CD patients had been on GFD for fewer than 6 years and were also positive for secreted anti-TG2. In treated patients, PTG/P31-43 was not able to induce secretion of anti-TG2 antibodies into culture medium. Measurement of anti-TG2 antibodies in biopsy supernatants proved to be more sensitive than detection by immunofluorescence to reveal their intestinal production. Intestinal antiTG2 antibodies titres correlated positively with the degree of mucosal damage and inversely with the duration of GFD. PMID- 24773632 TI - Serum levels of desacyl ghrelin in patients with schizophrenia on clozapine monotherapy. AB - AIM: Desacyl ghrelin is a hormone that might be a functional inhibitor of ghrelin, a potent hunger-stimulating peptide. METHODS: We determined fasting serum desacyl ghrelin levels in 24 subjects with schizophrenia on clozapine monotherapy and 24 healthy, age- and sex-matched controls. Biochemical and anthropometric measurements were combined with body composition determined using bioelectric impedance analysis. RESULTS: There were no differences in desacyl ghrelin levels between patients taking clozapine and the control group (272.09 +/ 137.96 vs 259.62 +/- 140.91 pg/mL, z = 0.17, P = 0.87). In the clozapine group, there were no differences between men and women for ghrelin levels (246.66 +/- 123.17 vs 295.39 +/- 151.77 pg/mL, z = -0.98, P = 0.32). In the clozapine group, fasting serum levels of ghrelin negatively correlated with waist-to-hip ratio (WHR) (r = -0.45, P = 0.03) and ionized calcium (r = -0.45, P = 0.03). Levels of ghrelin were lower in patients with WHR above World Health Organization-defined cut-off points (246.84 +/- 114.34 [Q1 = 152.18, Q2 = 220.92, Q3 = 327.85] vs 400.30 +/- 123.36 [Q1 = 283.73, Q2 = 414.03, Q3 = 485.8] pg/mL, z = 2.52, P = 0.01). In the clozapine group, there were no correlation with age, height, weight, body mass index, abdominal circumference, waist circumference, hip circumference, WHR, blood pressure, total cholesterol, high-density lipoproteins, low-density lipoproteins, triglycerides, uric acid, homocysteine, glucose, insulin, clozapine dose, duration of treatment with antipsychotics, duration of treatment with clozapine, total fat, target fat, basal metabolic rate, target weight, lean weight, body water, homoeostasis model assessment of insulin resistance (HOMA) 1-IR, HOMA2-IR and quantitative insulin sensitivity check index. CONCLUSION: Based on our results, we cannot conclude that treatment with clozapine affects levels of desacyl ghrelin. Also, in our study population we did not confirm previously described associations between desacyl ghrelin and various metabolic parameters. PMID- 24773670 TI - New world order(s): healthcare metrics, international borders, and gravitational waves. PMID- 24773671 TI - Minimally invasive cardiac surgery: a safe alternative for aortic valve replacement? PMID- 24773672 TI - High-sensitivity cardiac troponin: from theory to clinical practice. PMID- 24773673 TI - Conduction disorders and transcatheter aortic valve. Clinically relevant or just a mild complication? PMID- 24773674 TI - Minimally invasive aortic valve surgery. A safe and useful technique beyond the cosmetic benefits. AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to compare the in-hospital clinical outcomes of minimally invasive, isolated aortic valve replacement vs median sternotomy. METHODS: Between 2005 and 2012, 615 patients underwent aortic valve replacement at a single institution, 532 by a median sternotomy (E group) and 83 by a J-shaped ministernotomy (M group). RESULTS: No significant differences were found between the E and M groups in terms of age (69.27 [9.31] years vs 69.40 [10.24] years, respectively), logistic EuroSCORE (6.27 [2.91] vs 5.64 [2.17], respectively), size of implanted valve prosthesis (21.94 [2.04] mm vs 21.79 [2.01] mm, respectively), or the incidence of diabetes, hypercholesterolemia, high blood pressure, or chronic obstructive pulmonary disease. Mean cardiopulmonary bypass time was 102.90 (41.68) min for the E group vs 81.37 (25.41) min for the M group (P<.001). Mean cross-clamp time was 77.31 (29.20) min vs 63.45 (17.71) min for the S and M groups, respectively (P<.001). Mortality in the E group was 4.88% (26). There were no deaths in the M group (P<.05). The E group was associated with longer intensive care unit and hospital stays: 4.17 (5.23) days vs 3.22 (2.01) days (P=.045) and 9.58 (7.66) days vs 7.27 (3.83) days (P<.001), respectively. E group patients had more postoperative respiratory complications (42 [8%] vs 1 [1.2%]; P<.05). There were no differences when postoperative hemodynamic, neurologic, and renal complications, systemic infection, and wound infection were analyzed. CONCLUSIONS: In terms of morbidity, mortality, and operative times, outcomes after minimally invasive surgery for aortic valve replacement are at least comparable to those achieved with median sternotomy. The length of the hospital stay was reduced by minimally invasive surgery in our single-institution experience. The retrospective nature of this study warrants further randomized prospective trials to validate our results. PMID- 24773675 TI - Delayed diagnosis of hypertension in diabetic patients monitored in primary care. AB - INTRODUCTION AND OBJECTIVES: Delayed diagnosis of hypertension may result in inadequate blood pressure control and increased cardiovascular risk. The aim of this study was to estimate the delay in hypertension diagnosis in patients with type 2 diabetes and the likelihood of a diagnosis within a suitable period (first 6 months), and to analyze the patient and physician characteristics associated with delayed diagnosis. METHODS: Retrospective dynamic cohort study, with a 7 year follow-up in primary care, of 8074 adult patients with diabetes who met the diagnostic criteria for hypertension. Two thresholds were considered: 140/90mmHg and 130/80mmHg. The time elapsed between meeting these criteria and recording the diagnosis was estimated; the time course of the likelihood of a missed diagnosis and the variables associated with correct diagnosis were assessed by Kaplan-Meier survival analysis and logistic regression analysis, respectively. RESULTS: The mean diagnostic delay was 8.9 (15.4) months in patients with blood pressure>=140/90mmHg compared to 15.2 (19.6) months for those with <140/90mmHg (P<.001). The main variables associated with correct diagnosis were baseline blood pressure>=140/90mmHg (odds ratio=2.77; 95% confidence interval, 2.44-3.15), no history of acute myocardial infarction (odds ratio=2.23; 95% confidence interval, 1.67-2.99), obesity (odds ratio=1.70; 95% confidence interval, 1.44 1.99), absence of depression (odds ratio=1.63; 95% confidence interval, 1.27 2.08), female sex (odds ratio=1.29; 95% confidence interval, 1.14-1.46), older age, and taking more intensive antidiabetic therapy. There was an inverse relationship with the age of physicians and a direct relationship with their professional stability. CONCLUSIONS: The mean diagnostic delay in hypertension among diabetic patients was greater than 6 months and varied according to the diagnostic threshold used. Patients with baseline blood pressure>=140/90mmHg were more likely to receive a timely diagnosis. PMID- 24773676 TI - Correlation between intracoronary ultrasound and fractional flow reserve in long coronary lesions. A three-dimensional intracoronary ultrasound study. AB - INTRODUCTION AND OBJECTIVES: Intracoronary ultrasound estimation of the functional significance of intermediate angiographic lesions has mainly been based on measuring the minimal lumen area. These estimates take no account of lesion length and pay insufficient attention to long coronary lesions. METHODS: We included 61 lesions with visual angiographic stenosis of 40% to 70% that required treatment with a >=20mm stent, studied with ultrasound and fractional flow reserve. Three-dimensional analysis of the ultrasound study was conducted offline and blinded to fractional reserve values. Angiographic and ultrasound parameters were correlated with fractional reserve. RESULTS: From the angiography we obtained data on mean reference diameter (2.87 [0.57] mm), length (29.8 [10.01] mm), and severity of stenosis (50.3% [8.7]%). Mean fractional flow reserve was 0.78 (0.09). We found a weak linear correlation (R) between fractional reserve and the ultrasound parameters that did not include lesion length: fractional reserve-minimal luminal area (R=0.4; P=.003). The correlation was stronger when lesion length was included: fractional reserve-volume of plaque (R=-0.65; P<.0005); fractional reserve-length/mean luminal area (R=0.73; P<.0005). The strongest correlation came from the product of mean stenosis by area multiplied by lesion length (R=-0.78; P<.0005). CONCLUSIONS: In long coronary lesions, the correlation between ultrasound-measured minimal lumen area and functional significance is weak. In these cases, estimates of functional significance should incorporate lesion length or be derived from direct fractional flow reserve measurement. PMID- 24773677 TI - Management of acute heart failure in spanish emergency departments based on age. AB - INTRODUCTION AND OBJECTIVES: To investigate possible age-related differences in the profile, clinical symptoms, management, and short-term outcomes of patients seen for acute heart failure in Spanish emergency departments. METHODS: We performed a multipurpose, multicenter study with prospective follow-up including all patients with acute heart failure attended in 29 Spanish emergency departments. The following variables were collected: demographic, personal history, geriatric syndromes, data of acute episode, discharge destination, in hospital and 30-day mortality and 30-day revisit. The sample was divided into 4 age groups: <65, 65-74, 75-84, and >=85 years. RESULTS: We included 5819 patients: 493 (8.5%) were <65 years old, 971 (16.7%) were 65-74 years old, 2407 (41.4%) were 75-84 years old, and 1948 (33.5%) were >=85 years old; 4424 patients (76.5%) were admitted from the emergency department, 251 of whom (4.5%) died during hospitalization. Statistically significant differences were observed in relation to cardiovascular risk factors, comorbidities, geriatric syndromes, clinical presentation, and diagnostic and therapeutic procedures based on an increase in the age of the groups. A statistically significant linear trend was observed between age group and the probability of hospital admission (P<.001), and hospital (P<.001) and 30-day mortality (P<.001). CONCLUSIONS: The management of acute heart failure in elderly patients requires a multidimensional approach which goes beyond merely cardiological aspects of treatment. PMID- 24773678 TI - Gated-SPECT myocardial perfusion imaging as a complementary technique to magnetic resonance imaging in chronic myocardial infarction patients. AB - INTRODUCTION AND OBJECTIVES: The aim of this study was to compare magnetic resonance and gated-SPECT myocardial perfusion imaging in patients with chronic myocardial infarction. METHODS: Magnetic resonance imaging and gated-SPECT were performed in 104 patients (mean age, 61 [12] years; 87.5% male) with a previous infarction. Left ventricular volumes and ejection fraction and classic late gadolinium enhancement viability criteria (<75% transmurality) were correlated with those of gated-SPECT (uptake >50%) in the 17 segments of the left ventricle. Motion, thickening, and ischemia on SPECT were analyzed in segments showing nonviable tissue or equivocal enhancement features (50%-75% transmurality). RESULTS: A good correlation was observed between the 2 techniques for volumes, ejection fraction (P<.05), and estimated necrotic mass (P<.01). In total, 82 of 264 segments (31%) with >75% enhancement had >50% single SPECT uptake. Of the 106 equivocal segments on magnetic resonance imaging, 68 (64%) had >50% uptake, 41 (38.7%) had normal motion, 46 (43.4%) had normal thickening, and 17 (16%) had ischemic criteria on SPECT. CONCLUSIONS: A third of nonviable segments on magnetic resonance imaging showed >50% uptake on SPECT. Gated-SPECT can be useful in the analysis of motion, thickening, and ischemic criteria in segments with questionable viability on magnetic resonance imaging. PMID- 24773679 TI - Epidemiology of infective endocarditis in Spain in the last 20 years. AB - Infective endocarditis is an uncommon disease, with an estimated incidence of 3.1 to 3.7 episodes per 100 000 inhabitants/year. The incidence is highest in elderly people. The microorganisms most frequently isolated in infective endocarditis are staphylococci and streptococci. In the last few decades, the spectrum of heart diseases predisposing to infective endocarditis has changed, since degenerative heart disease is the most common valve disease, and there are an increasing number of infective endocarditis patients without previously known valve disease. In addition, up to one-third of infective endocarditis patients become infected through contact with the health system. These patients are more frail, which leads to higher in-hospital mortality. As a result of substantial epidemiological changes, few cases of infective endocarditis can be prevented by antibiotic prophylaxis. Despite advances in medical and surgical treatment, in-hospital mortality among infective endocarditis patients is high. Nevertheless, there is room for improvement in reducing the rate of nosocomial bacteremia, the prompt diagnosis of infective endocarditis in at-risk patients, and the early identification of patients with a highest risk of complications, as well as in the creation of multidisciplinary teams for the management of this disease. PMID- 24773680 TI - New treatment for old disease: management of resistant hypertension by percutaneous renal sympathetic denervation. AB - Hypertension is a major contributor to cardiovascular events, such as stroke and myocardial infarction, with accelerated sympathetic nerve activity implicated in its pathogenesis. However, hypertension in many patients is not adequately controlled, despite the availability of numerous medication classes. Novel procedure-as well as device-based strategies, such as percutaneous renal sympathetic nerve denervation therapy-have been developed to improve blood pressure in these refractory patients. Renal sympathetic denervation delivers not only a decrease in blood pressure levels but also renal as well as systemic sympathetic nerve activity. The reduction in blood pressure appears to be sustained over 3 years after the procedure, which implies no counterregulatory mechanism or re-innervation of afferent renal sympathetic nerve so far. Renal sympathetic denervation is expected to be a promising treatment for patients with hypertension, congestive heart failure, chronic kidney disease, and metabolic syndrome implicated in the pathogenesis of potentiated sympathetic nerve activity. This review will focus on the current devices and procedures, their outcomes and prospects in the treatment of hypertension. PMID- 24773681 TI - Dysphagia lusoria caused by Kommerell diverticulum. PMID- 24773682 TI - Endomyocardial fibrosis with massive left ventricular calcification. PMID- 24773683 TI - Hemodynamic changes alert to spontaneous ductus arteriosus spasm. PMID- 24773684 TI - Acute myocardial infarction in patients with a very rare form of anomalous origin of the left main coronary artery. PMID- 24773685 TI - Usefulness of genetic testing for hypertrophic cardiomyopathy in real-world practice. PMID- 24773686 TI - Adequate cholesterol levels in coronary heart disease and diabetic patients. Analysis according to medical specialty and autonomous communities. PMID- 24773687 TI - Percentiles of carotid intima-media thickness in a Spanish population with and without cardiovascular risk factors. PMID- 24773688 TI - Intravascular diagnosis of stent fractures: beyond X-ray imaging. PMID- 24773689 TI - Emotional regulation and heart rate variability in healthy male managers. PMID- 24773690 TI - Brugada phenocopy emerging as a new concept. PMID- 24773691 TI - Brugada phenocopy emerging as a new concept. Response. PMID- 24773692 TI - RASopathies: from Noonan to LEOPARD syndrome. PMID- 24773693 TI - New oral anticoagulants in nonvalvular atrial fibrillation: findings and implications of the ROCKET study. PMID- 24773694 TI - New oral anticoagulants in nonvalvular atrial fibrillation: findings and implications of the ROCKET study. Response. PMID- 24773695 TI - Conservation of major and minor jelly-roll capsid proteins in Polinton (Maverick) transposons suggests that they are bona fide viruses. AB - Polintons (also known as Mavericks) and Tlr elements of Tetrahymena thermophila represent two families of large DNA transposons widespread in eukaryotes. Here, we show that both Polintons and Tlr elements encode two key virion proteins, the major capsid protein with the double jelly-roll fold and the minor capsid protein, known as the penton, with the single jelly-roll topology. This observation along with the previously noted conservation of the genes for viral genome packaging ATPase and adenovirus-like protease strongly suggests that Polintons and Tlr elements combine features of bona fide viruses and transposons. We propose the name 'Polintoviruses' to denote these putative viruses that could have played a central role in the evolution of several groups of DNA viruses of eukaryotes. PMID- 24773696 TI - Associations between quality of life and socioeconomic factors, functional impairments and dissatisfaction with received information and home-care services among survivors living at home two years after stroke onset. AB - BACKGROUND: Quality of life (QoL) assessment is important when monitoring over time the recovery of stroke-survivors living at home. This study explores the associations between QoL and socioeconomic factors, functional impairments and self-reported dissatisfaction with received information and home-care services among survivors two years after stroke onset. This problem remains partially addressed though optimal information and services may improve survivors' QoL. METHODS: Stroke-survivors admitted to all hospitals in Luxembourg 18 months or more previously were identified using the only care-expenditure-reimbursement national system database. The clinical diagnosis was confirmed. Ninety four patients aged 65 years and living at home were interviewed to gather socioeconomic characteristics, functional impairments, dissatisfaction with information and home-care services, and QoL (using the Newcastle Stroke-Specific QoL, newsqol) assessing 11 domains. Data were analyzed using multiple linear regression models. RESULTS: About 50% of survivors had low education and lower income. Functional impairments were common: sensory (45%), motor (35%), memory (32%), language (31%), and vision (20%). Survivors with education (<12th grade) or lower income had low values for most newsqol domains (sex-age-adjusted regression coefficient saRC, i.e. mean difference, between -23 and -8). Patients who were working had better values for pain, mental feelings and sleep domains than did retired people (saRC between -3.9 and 4.2). Various functional impairments were associated with markedly low values of nearly all domains (saRC between -33.5 and -7.5) and motor, language, memory and sensory impairments had the highest impact. The survivors' perceived QoL was markedly low, especially for the domains of interpersonal relationship, sleep, cognition, mental feelings, and pain. Various QoL domains were strongly related to dissatisfaction with information about stroke and its consequences/changes over time, accuracy of information obtained, help received, coordination between services, and the possibility of receiving help when necessary (saRC reaching -30). CONCLUSIONS: Stroke-survivors had major alterations in QoL that reflected depressive symptoms, which should be appropriately treated. These findings may help with the development of public policies aiming at improving QoL among stroke survivors. The newsqol could be used routinely to measure the recovery of survivors over time and their needs in terms of information, help and care services. PMID- 24773697 TI - Fatty acids and cardiac disease: fuel carrying a message. AB - From the viewpoint of the prevention of cardiovascular disease (CVD) burden, there has been a continuous interest in the detrimental effects of the Western type high-fat diet for more than half a century. More recently, this general view has been subject to change as epidemiological studies showed that replacing fat by carbohydrate may even be worse and that various polyunsaturated fatty acids (FA) have beneficial rather than detrimental effects on CVD outcome. At the same time, advances in lipid biology have provided insight into the mechanisms by which the different lipid components of the Western diet affect the cardiovascular system. In fact, this still is a rapidly growing field of research and in recent years novel FA derivatives and FA receptors have been discovered. This includes fish-oil derived FA-derivatives with anti-inflammatory properties, the so-called resolvins, and various G-protein-coupled receptors that recognize FA as ligands. In the present review, we will extensively discuss the role of FA and their metabolites on cardiac disease, with special emphasis on the role of the different saturated and polyunsaturated FA and their respective metabolites in cellular signal transduction and the possible implications for the development of cardiac hypertrophy and cardiac failure. PMID- 24773698 TI - Duration between onset and diagnosis in central nervous system tumors: impact on prognosis and functional outcome. AB - BACKGROUND: The initial presentation of central nervous system (CNS) tumors in children frequently mimics other more common and less serious conditions, resulting in diagnostic difficulty and a prolonged time to diagnosis. Yet whether early diagnosis contributes to better life prognosis and functional outcome has not been elucidated. Only a few such reports have originated from Japan, where neuroimaging techniques are the best in the world. We examined the time to diagnosis, the so-called prediagnostic symptomatic interval (PSI), and its impact on prognosis and functional outcome in children with CNS tumors. METHODS: We reviewed the records of 127 patients aged <15 years with CNS tumors, who were treated at our two institutions between November 1993 and October 2011. RESULTS: The median age at diagnosis was 7.2 years (range, 3 weeks-14.9 years). The male to-female ratio was 63:64. Median PSI was 1.5 months (0-36 months). Overall survival and progression-free survival did not differ significantly between the groups, regardless of whether the PSI was longer than the median PSI. The PSI was significantly longer in patients with long-lasting clinical signs after the initial treatment than in patients with temporary symptoms only at onset. Both univariate and multivariate analysis showed that high histological grading was statistically correlated with short PSI. CONCLUSIONS: A short PSI was significantly associated with high-grade tumors. Earlier diagnosis did not lead to better life prognosis, but possibly to better functional outcome in children with CNS tumors. PMID- 24773704 TI - Methylenetetrahydrofolate reductase C677T gene mutation and hyperhomocysteinemia in Budd-Chiari syndrome and portal vein thrombosis: A systematic review and meta analysis of observational studies. AB - AIM: A systematic review and meta-analysis were conducted to explore the role of the methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation and hyperhomocysteinemia in patients with Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). METHODS: PubMed, EMBASE, Cochrane Library and ScienceDirect databases were searched. Eligible studies should compare the prevalence of the MTHFR C677T mutation or hyperhomocysteinemia or the homocysteine levels between BCS or non-cirrhotic PVT patients and healthy controls or between cirrhotic patients with and without PVT. A pooled odds ratio or weighted mean difference with 95% confidence interval was calculated. RESULTS: Of the 484 articles retrieved, 20 were included. BCS and non-cirrhotic PVT patients had a higher prevalence of homozygous MTHFR mutation than healthy controls. The difference was statistically significant in BCS patients, but not in non-cirrhotic PVT patients. BCS and non-cirrhotic PVT patients had a significantly higher prevalence of hyperhomocysteinemia and homocysteine level than healthy controls. Cirrhotic patients with PVT had a significantly higher prevalence of homozygous MTHFR mutation than those without PVT. However, the association between homocysteine level and PVT in cirrhotic patients was inconsistent among three studies. CONCLUSION: Homozygous MTHFR mutation and hyperhomocysteinemia may be associated with the occurrence of BCS and non-cirrhotic PVT. In addition, homozygous MTHFR mutation may increase the risk of PVT in cirrhotic patients. However, the current evidence failed to support the association of hyperhomocysteinemia with PVT in cirrhotic patients. PMID- 24773703 TI - Proteomics and transcriptomics of the BABA-induced resistance response in potato using a novel functional annotation approach. AB - BACKGROUND: Induced resistance (IR) can be part of a sustainable plant protection strategy against important plant diseases. beta-aminobutyric acid (BABA) can induce resistance in a wide range of plants against several types of pathogens, including potato infected with Phytophthora infestans. However, the molecular mechanisms behind this are unclear and seem to be dependent on the system studied. To elucidate the defence responses activated by BABA in potato, a genome wide transcript microarray analysis in combination with label-free quantitative proteomics analysis of the apoplast secretome were performed two days after treatment of the leaf canopy with BABA at two concentrations, 1 and 10 mM. RESULTS: Over 5000 transcripts were differentially expressed and over 90 secretome proteins changed in abundance indicating a massive activation of defence mechanisms with 10 mM BABA, the concentration effective against late blight disease. To aid analysis, we present a more comprehensive functional annotation of the microarray probes and gene models by retrieving information from orthologous gene families across 26 sequenced plant genomes. The new annotation provided GO terms to 8616 previously un-annotated probes. CONCLUSIONS: BABA at 10 mM affected several processes related to plant hormones and amino acid metabolism. A major accumulation of PR proteins was also evident, and in the mevalonate pathway, genes involved in sterol biosynthesis were down-regulated, whereas several enzymes involved in the sesquiterpene phytoalexin biosynthesis were up-regulated. Interestingly, abscisic acid (ABA) responsive genes were not as clearly regulated by BABA in potato as previously reported in Arabidopsis. Together these findings provide candidates and markers for improved resistance in potato, one of the most important crops in the world. PMID- 24773705 TI - Examining the incremental impact of long-standing health conditions on subjective well-being alongside the EQ-5D. AB - BACKGROUND: Generic preference-based measures such as the EQ-5D and SF-6D have been criticised for being narrowly focused on a sub-set of dimensions of health. Our study aims to explore whether long-standing health conditions have an incremental impact on subjective well-being alongside the EQ-5D. METHODS: Using data from the South Yorkshire Cohort study (N = 13,591) collected between 2010 and 2012 on the EQ-5D, long-standing health conditions (self-reported), and subjective well-being measure--life satisfaction using a response scale from 0 (completely dissatisfied) to 10 (completely satisfied), we employed generalised logit regression models. We assessed the impact of EQ-5D and long-standing health conditions together on life satisfaction by examining the size and significance of their estimated odds ratios. RESULTS: The EQ-5D had a significant association with life satisfaction, in which anxiety/depression and then self-care had the largest weights. Some long-standing health conditions were significant in some models, but most did not have an independent impact on life satisfaction. Overall, none of the health conditions had a consistent impact on life satisfaction alongside the EQ-5D. CONCLUSIONS: Out study suggests that the impact of long-standing health conditions on life satisfaction is adequately captured by the EQ-5D, although the findings are limited by reliance on self-reported conditions and a single item life satisfaction measure. PMID- 24773727 TI - Dose reduction of tocilizumab in rheumatoid arthritis patients with low disease activity. AB - OBJECTIVES: Tocilizumab is effective in the treatment of rheumatoid arthritis (RA). A proportion of patients achieve low disease activity using a lower than registered starting dose. We investigated the feasibility of dose reduction to 4 mg/kg in patients who reached low disease activity at the registered dose of 8 mg/kg. METHODS: In this retrospective study, data were collected of 22 patients successfully treated with tocilizumab 8 mg/kg for about 6 months and tapered to 4 mg/kg because of low disease activity. In case of loss of disease control, the dose could be increased again to 8 mg/kg. The percentage of patients with successful dose reduction and difference in DAS28 was described. RESULTS: Mean DAS28 at time of dose reduction was 2.3 (SD 0.9). After 3 and 6 months follow-up, 77% (95% CI 54-91) and 55% (95% CI 32-76) of patients had successfully reduced the dose without losing disease control, respectively. DAS28 at 3 and 6 months was somewhat higher than baseline, 2.7 (SD 1.2) and 2.5 (SD 1.0) respectively. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose escalation. CONCLUSIONS: Dose reduction of tocilizumab seems feasible in a substantial proportion of patients. Dose escalation after flare was effective in all patients. PMID- 24773728 TI - "It's been quite a challenge": redesigning end-of-life care in acute hospitals. AB - OBJECTIVE: This paper reports the findings of an interview-based study undertaken to investigate the introduction of end-of-life (EoL) care pathways in three acute trusts, as part of a larger project examining service redesign. The aim was to examine the barriers to and facilitators of change. METHOD: Twenty-one in-depth qualitative interviews were conducted with staff working in three National Health Service (NHS) acute hospital trusts. These staff members were involved in end-of life care, and their accounts were analyzed to identify the key issues when introducing service changes in these settings. RESULTS: Thematic analysis revealed five major themes-two of which, leadership and facilitation, and education and training, indicate what needs to be in place if end-of-life care pathways are to be adopted by staff. However, the remaining three themes of difficult conversations, diagnosing dying, and communication across boundaries highlight particular areas of practice and organization that need to be addressed before end-of-life care in hospitals can be improved. SIGNIFICANCE OF RESULTS: Organization of end-of-life care in acute hospitals is challenging, and care pathways provide a degree of guidance as to how services can be delivered. However, even when there is effective leadership at all levels of an organization and an extensive program of education for all staff support the use of care pathways, significant barriers to their introduction remain. These include staff anxieties concerning diagnosing dying and discussing dying and end-of-life care planning with patients and their families. It is hoped these findings can inform the development of the proposed new care plans which are set to replace end of life care pathways in England. PMID- 24773729 TI - Fecundity compensation and fecundity reduction among populations of the three spined stickleback infected by Schistocephalus solidus in Alaska. AB - We surveyed nine populations of the three-spined stickleback infected by the diphyllobothriidean cestode Schistocephalus solidus from south-central Alaska for two apparent forms of tolerance to infection in females capable of producing egg clutches notwithstanding large parasite burdens. Seven populations exhibited fecundity reduction, whereas two populations showed fecundity compensation. Our data suggest that fecundity reduction, a side effect resulting from nutrient theft, occurs in two phases of host response influenced by the parasite : host body mass (BM) ratio. The first is significantly reduced ovum mass without significant reduction in clutch size, and the second one involves significant reductions in both ovum mass and clutch size. Thus, ovum mass of host females who are functionally being starved through nutrient theft seems to be more readily influenced by parasitism and, therefore, decreased before clutch size is reduced. This inference is consistent with expectations based on the biology of and effect of feeding ration on reproduction in stickleback females. Fecundity compensation appears to be uncommon among populations of three-spined stickleback in Alaska and rare among populations throughout the northern hemisphere. Fecundity reduction seems to be common, at least among stickleback populations in Alaska. PMID- 24773754 TI - Factors associated with severe uncontrolled asthma and the perception of control by physicians and patients. AB - INTRODUCTION: Despite current treatments, more than half of patients with asthma are not controlled. The objective was to evaluate the correlation between control perceived by patients and physicians, compared with control evaluated according to criteria of the Spanish Guidelines for Asthma Management (GEMA), and to investigate the factors associated with that control. METHODS: Multicenter, cross sectional, observational study including 343 patients with severe persistent asthma according to GEMA criteria seen in the Department of Pulmonology and Allergology. The correlation between asthma control perceived by the patient, the physician and according to clinical judgment based on the GEMA criteria was calculated, and a multivariate analysis was used to determine variables related to the perception of asthma control. RESULTS: According to GEMA criteria, only 10.2% of patients were well controlled, 27.7% had partial control and 62.1% were poorly controlled. Both the physicians and the patients overestimated control: 75.8% and 59.3% of patients had controlled asthma according to the patient and the physician, respectively, and were not controlled according to GEMA (P<.0001). Patients with uncontrolled asthma according GEMA had higher body mass index (P=.006) and physical inactivity (P=.016). Factors associated with a perceived lack of control by both physicians and patients were: nocturnal awakenings (>= 1 day/week), frequent use of rescue medication (>= 5 days/week) and significant limitation in activities. Discrepant factors between physicians and patients were dyspnea and emergency room visits (patients only), FEV1 <= 80% and a poorer understanding of the disease by the patient (physicians only). CONCLUSIONS: Only 10% of patients with severe asthma evaluated in this study are controlled according to GEMA criteria. Patients and physicians overestimate control and the overestimation by patients is greater. Physical inactivity and obesity are associated with a lack of control according to GEMA. PMID- 24773755 TI - Inhibition of phosphoinositide 3-kinase is associated with reduced angiogenesis and an altered expression of angiogenic markers in endothelioma cells. AB - The phosphoinositide 3-kinase (PI3k) signaling pathway is involved in the regulation of numerous cellular activities. The pathway has also been implicated in the development of various tumors. In the context of vascular tumors, the role of the PI3k signaling still needs to be established. In the present study, the effects of blocking PI3k activation on endothelioma cells derived from mice with vascular tumors were investigated using the crystal violet assay, real-time cell analysis, light microscopy, the aorta ring assay and antibody arrays. The suppression of PI3k led to the inhibition of cell growth, cell migration, as well as angiogenesis. The inhibition of these processes correlated with low Akt activity. Antibody array analysis revealed that there was a suppression of several proangiogenic molecules, including Eotaxin-1 and basic fibroblast growth factor (bFGF) in cultures treated with LY294,002, an inhibitor of PI3k. At the same time, LY294,002 increased the expression of platelet factor 4 (PF4) and the Fas ligand (FasL), molecules which have antiangiogenic properties. The results suggest that PI3k may play a role in the expression of some of the key regulatory molecules involved in angiogenesis, and perhaps in the growth of endotheliomas. As such, it is plausible that the PI3k/Akt pathway may be a target for therapeutic molecules designed for the treatment of endothelial tumors. PMID- 24773756 TI - Characterization of TNF-induced caspase-independent necroptosis. AB - Caspase-independent programmed necrotic cell death (necroptosis) has recently been described. Previously described models of necroptosis required 16h or more of induction, which made the interpretation of findings somewhat difficult. In human monocytic leukemia cell line U937 necroptosis could be induced within 6h by combination of TNF and Z-VAD-fmk. Here we show that the reduction in intracellular ATP levels may not be the sole determinant of necroptosis, and that necroptosis is associated with the loss of mitochondrial membrane potential, but not the activation of Bak/Bax or calcineurin. PMID- 24773757 TI - PECTATE LYASE-LIKE10 is associated with pollen wall development in Brassica campestris. AB - PECTATE LYASE-LIKE10 (PLL10) was previously identified as one of the differentially expressed genes both in microspores during the late pollen developmental stages and in pistils during the fertilization process in Chinese cabbage (Brassica campestris ssp. chinensis). Here, antisense-RNA was used to study the functions of BcPLL10 in Chinese cabbage. Abnormal pollen was identified in the transgenic lines (bcpll10-4, -5, and -6). In fertilization experiments, fewer seeds were harvested when the antisense-RNA lines were used as pollen donor. In vivo and in vitro pollen germination assays less germinated pollen tubes were observed in bcpll10 lines. Scanning electron microscopy observation verified that the tryphine materials were over accumulated around the pollen surface and sticked them together in bcpll10. Moreover, transmission electron microscopy observation revealed that the internal endintine was overdeveloped and predominantly occupied the intine, and disturbed the normal proportional distribution of the two layers in the non-germinal furrow region; and no obvious demarcation existed between them in the germinal furrow region in the bcpll10 pollen. Collectively, this study presented a novel PLL gene that played an important role during the pollen wall development in B. campestris, which may also possess potential importance for male sterility usage in agriculture. PMID- 24773758 TI - Incidence and risk factors of metachronous colorectal neoplasm after curative resection of colorectal cancer in Korean patients. AB - OBJECTIVE: Early detection and endoscopic removal of metachronous neoplasms are important preventive strategies for patients with colorectal cancer (CRC) after curative tumor resection. We aimed to determine the incidence of and the risk factors for metachronous colorectal neoplasms after curative resection for CRC. METHODS: We retrospectively reviewed clinical data of patients who underwent curative resection for CRC at the National Cancer Center, Korea, from July 2004 to July 2007 and were followed up for a mean duration of 40.7 months. The incidence of and the risk factors for developing metachronous neoplasms were analyzed. RESULTS: A total of 1049 patients were included in this study. A follow up colonoscopy showed that 454 (43.3%) patients developed metachronous neoplasms, including 46 (4.4%) with advanced adenoma or cancer. Univariate analyses revealed that age >= 60 years, male gender, diabetes mellitus, hypertension, synchronous adenoma, synchronous multiple adenoma and synchronous advanced adenoma were associated with the development of metachronous neoplasms. Baseline risk factors associated with metachronous advanced neoplasm were age >= 60 years, synchronous multiple adenoma and synchronous advanced adenoma. Multivariate analysis showed that age >= 60 years, synchronous adenoma and diabetes mellitus were risk factors for the development of metachronous neoplasms. The cumulative incidence of metachronous neoplasms was higher in patients with these risk factors than in those without. CONCLUSIONS: Elder age, synchronous adenoma and diabetes mellitus are risk factors for developing metachronous neoplasia. Therefore, careful surveillance colonoscopy are necessary for these patients. PMID- 24773759 TI - Comparative effects of sodium butyrate and flavors on feed intake of lactating sows and growth performance of piglets. AB - We examined the effects of sodium butyrate and flavors on feed intake of lactating sows and growth performance of piglets. A total of 52 primiparous sows (Large White) were randomly divided into four treatments (n = 13) and received 6 g/kg sodium butyrate (SB), fruit-milk (FM) flavor and fruit-milk-anise (FMA) flavor with pair feeding to the mothers receiving the control diet. The feeding trial lasted for 29 days, including 21 days of nursing and 8 days of post-weaning period, respectively. The nursing and weaning piglets received creep diets with the same flavor or SB supplement as their mother. The results showed that FMA flavor increased average daily feed intake (ADFI) of lactating sows (P < 0.01), as well as improved litter weight gain (P = 0.05) and ADFI (P < 0.01) of nursing pigs among treatments. Indeed, greater ADFI and average daily gain of weaning piglets for the initial 8 days after weaning was observed in the FMA group compared with those in the control group (P < 0.01). These findings indicated that adding FMA flavor was superior to SB for increasing feed intake of lactating sows and improving growth performance of piglets. PMID- 24773760 TI - Adapted motivational interviewing to improve the uptake of treatment for glaucoma in Nigeria: study protocol for a randomized controlled trial. AB - BACKGROUND: Glaucoma is a chronic eye disease associated with irreversible visual loss. In Africa, glaucoma patients often present late, with very advanced disease. One-off procedures, such as laser or surgery, are recommended in Africa because of lack of or poor adherence to medical treatment. However, acceptance of surgery is usually extremely low. To prevent blindness, adherence to treatment needs to improve, using acceptable, replicable and cost-effective interventions. After reviewing the literature and interviewing patients in Bauchi (Nigeria) motivational interviewing (MI) was selected as the intervention for this trial, with adaptation for glaucoma (MIG). MI is designed to strengthen personal motivation for, and commitment to a specific goal by eliciting and exploring a person's reasons for change within an atmosphere of acceptance and compassion. The aim of this study is to assess whether MIG increases the uptake of laser or surgery amongst glaucoma patients where this is the recommended treatment. The hypothesis is that MIG increases the uptake of treatment. This will be the first trial of MI in Africa. METHODS: This is a hospital based, single centre, randomized controlled trial of MIG plus an information sheet on glaucoma and its treatment (the latter being "standard care") compared with standard care alone for glaucoma patients where the treatment recommended is surgery or laser.Those eligible for the trial are adults aged 17 years and above who live within 200 km of Bauchi with advanced glaucoma where the examining ophthalmologist recommends surgery or laser. After obtaining written informed consent, participants will be randomly allocated to MIG plus standard care, or standard care alone. Motivational interviewing will be delivered in Hausa or English by one of two MIG trained personnel. One hundred and fifty participants will be recruited to each arm. The primary outcome is the proportion of participants undergoing laser or surgery within two months of the date given to re attend for the procedure. MIG quality will be assessed using the validated MI treatment integrity scale. DISCUSSION: Motivational interviewing may be an important tool to increase the acceptance of treatment for glaucoma. The approach is potentially scalable and may be useful for other chronic conditions in Africa. TRIAL REGISTRATION: ISRCTN79330571 (Controlled-Trials.com). PMID- 24773761 TI - Non-stationary 13C metabolic flux analysis of Chinese hamster ovary cells in batch culture using extracellular labeling highlights metabolic reversibility and compartmentation. AB - BACKGROUND: Mapping the intracellular fluxes for established mammalian cell lines becomes increasingly important for scientific and economic reasons. However, this is being hampered by the high complexity of metabolic networks, particularly concerning compartmentation. RESULTS: Intracellular fluxes of the CHO-K1 cell line central carbon metabolism were successfully determined for a complex network using non-stationary 13C metabolic flux analysis. Mass isotopomers of extracellular metabolites were determined using [U-13C6] glucose as labeled substrate. Metabolic compartmentation and extracellular transport reversibility proved essential to successfully reproduce the dynamics of the labeling patterns. Alanine and pyruvate reversibility changed dynamically even if their net production fluxes remained constant. Cataplerotic fluxes of cytosolic phosphoenolpyruvate carboxykinase and mitochondrial malic enzyme and pyruvate carboxylase were successfully determined. Glycolytic pyruvate channeling to lactate was modeled by including a separate pyruvate pool. In the exponential growth phase, alanine, glycine and glutamate were excreted, and glutamine, aspartate, asparagine and serine were taken up; however, all these amino acids except asparagine were exchanged reversibly with the media. High fluxes were determined in the pentose phosphate pathway and the TCA cycle. The latter was fueled mainly by glucose but also by amino acid catabolism. CONCLUSIONS: The CHO K1 central metabolism in controlled batch culture proves to be robust. It has the main purpose to ensure fast growth on a mixture of substrates and also to mitigate oxidative stress. It achieves this by using compartmentation to control NADPH and NADH availability and by simultaneous synthesis and catabolism of amino acids. PMID- 24773762 TI - Immigrant and non-immigrant women's experiences of maternity care: a systematic and comparative review of studies in five countries. AB - BACKGROUND: Understanding immigrant women's experiences of maternity care is critical if receiving country care systems are to respond appropriately to increasing global migration. This systematic review aimed to compare what we know about immigrant and non-immigrant women's experiences of maternity care. METHODS: Medline, CINAHL, Health Star, Embase and PsychInfo were searched for the period 1989-2012. First, we retrieved population-based studies of women's experiences of maternity care (n = 12). For countries with identified population studies, studies focused specifically on immigrant women's experiences of care were also retrieved (n = 22). For all included studies, we extracted available data on experiences of care and undertook a descriptive comparison. RESULTS: What immigrant and non-immigrant women want from maternity care proved similar: safe, high quality, attentive and individualised care, with adequate information and support. Immigrant women were less positive about their care than non-immigrant women. Communication problems and lack of familiarity with care systems impacted negatively on immigrant women's experiences, as did perceptions of discrimination and care which was not kind or respectful. CONCLUSION: Few differences were found in what immigrant and non-immigrant women want from maternity care. The challenge for health systems is to address the barriers immigrant women face by improving communication, increasing women's understanding of care provision and reducing discrimination. PMID- 24773763 TI - Stem and progenitor cell systems in liver development and regeneration. AB - The liver comprises two stem/progenitor cell systems: fetal and adult liver stem/progenitor cells. Fetal hepatic progenitor cells, derived from foregut endoderm, differentiate into mature hepatocytes and cholangiocytes during liver development. Adult hepatic progenitor cells contribute to regeneration after severe and chronic liver injuries. However, the characteristics of these somatic hepatic stem/progenitor cells remain unknown. Culture systems that can be used to analyze these cells were recently established and hepatic stem/progenitor cell specific surface markers including delta-like 1 homolog (DLK), cluster of differentiation (CD) 13, CD133, and LIV2 were identified. Cells purified using antibodies against these markers proliferate for an extended period and differentiate into mature cells both in vitro and in vivo. Methods to force the differentiation of human embryonic stem and induced pluripotent stem (iPS) cells into hepatic progenitor cells have been recently established. We demonstrated that the CD13(+) CD133(+) fraction of human iPS-derived cells contained numerous hepatic progenitor-like cells. These analyses of hepatic stem/progenitor cells derived from somatic tissues and pluripotent stem cells will contribute to the development of new therapies for severe liver diseases. PMID- 24773764 TI - Effectiveness of a quality management program in dental care practices. AB - BACKGROUND: Structured quality management is an important aspect for improving patient dental care outcomes, but reliable evidence to validate effects is lacking. We aimed to examine the effectiveness of a quality management program in primary dental care settings in Germany. METHODS: This was an exploratory study with a before-after-design. 45 dental care practices that had completed the European Practice Assessment (EPA) accreditation scheme twice (intervention group) were selected for the study. The mean interval between the before and after assessment was 36 months. The comparison group comprised of 56 dental practices that had undergone their first assessment simultaneously with follow-up assessment in the intervention group. Aggregated scores for five EPA domains: 'infrastructure', 'information', 'finance', 'quality and safety' and 'people' were calculated. RESULTS: In the intervention group, small non-significant improvements were found in the EPA domains. At follow-up, the intervention group had higher scores on EPA domains as compared with the comparison group (range of differences was 4.2 to 10.8 across domains). These differences were all significant in regression analyses, which controlled for relevant dental practice characteristics. CONCLUSIONS: Dental care practices that implemented a quality management program had better organizational quality in contrast to a comparison group. This may reflect both improvements in the intervention group and a selection effect of dental practices volunteering for the first round of EPA practice assessment. PMID- 24773765 TI - A customized Web portal for the genome of the ctenophore Mnemiopsis leidyi. AB - BACKGROUND: Mnemiopsis leidyi is a ctenophore native to the coastal waters of the western Atlantic Ocean. A number of studies on Mnemiopsis have led to a better understanding of many key biological processes, and these studies have contributed to the emergence of Mnemiopsis as an important model for evolutionary and developmental studies. Recently, we sequenced, assembled, annotated, and performed a preliminary analysis on the 150-megabase genome of the ctenophore, Mnemiopsis. This sequencing effort has produced the first set of whole-genome sequencing data on any ctenophore species and is amongst the first wave of projects to sequence an animal genome de novo solely using next-generation sequencing technologies. DESCRIPTION: The Mnemiopsis Genome Project Portal (http://research.nhgri.nih.gov/mnemiopsis/) is intended both as a resource for obtaining genomic information on Mnemiopsis through an intuitive and easy-to-use interface and as a model for developing customized Web portals that enable access to genomic data. The scope of data available through this Portal goes well beyond the sequence data available through GenBank, providing key biological information not available elsewhere, such as pathway and protein domain analyses; it also features a customized genome browser for data visualization. CONCLUSIONS: We expect that the availability of these data will allow investigators to advance their own research projects aimed at understanding phylogenetic diversity and the evolution of proteins that play a fundamental role in metazoan development. The overall approach taken in the development of this Web site can serve as a viable model for disseminating data from whole-genome sequencing projects, framed in a way that best-serves the specific needs of the scientific community. PMID- 24773766 TI - Is quality of life post cardiac surgery overestimated? AB - BACKGROUND: Quality of Life (QoL) studies concerns the difference in QoL between the baseline and the post-surgical assessment. Many such studies, however, suffer from incomplete QoL-data with regard to patients with a proven survival--the drop outs. Our hypothesis is that patients with a low preoperative QoL, high operative risk and older age are at higher risk for drop-out, which may result in a biased conclusion. METHODS: This study includes 1675 patients, all of whom were operated between July 1, 2009 and July 1,2012 and have a proven one-year survival, as well as a complete preoperative EuroQoL registration (EQ-5D and EQ-VAS). Based on the calculated 30 and 70 percentiles of age, EuroSCORE risk, and EQ-5D and EQ-VAS values, the group was split into three different subgroups. We studied whether (1) there was a correlation between age, risk, preoperative QoL and postoperative QoL and (2) if the drop-outs were correlated to age, risk and preoperative QoL. RESULTS: There is a statistically significant correlation between postoperative QoL and both age (p = 0.029) and risk (p = 0.002). Both relations have a negative Pearson's r. There is also a statistically significant (p = 0.0001) correlation between pre- and postoperative QoL, now with a positive Pearson's r. The percentage of drop-outs increases in a statistically significant manner with an increased risk (p = 0.001), older age (p = 0.001) and a low preoperative QoL (EQ 5D, p = 0.001 and EQ-VAS, p = 0.003). CONCLUSION: We conclude that QoL post cardiac surgery is overestimated, certainly for older, high risk patients and patients with a low preoperative QoL. PMID- 24773767 TI - Correlation of ultrasound B-lines with high-resolution computed tomography in antisynthetase syndrome. AB - OBJECTIVES: Interstitial lung disease is a common finding in patients with the antisynthetase syndrome. High-resolution computed tomography is the reference test for diagnosis and follow-up of this condition, but it involves considerable radiation exposure. Our aim was to describe chest ultrasound features and its correlation with high-resolution computed tomography findings in a series of patients with the antisynthetase syndrome. METHODS: The study included patients from our antisynthetase syndrome cohort with varying degrees of interstitial lung disease, consulting in our outpatient clinic over a 1-year period. Chest high resolution computed tomography and chest sonography were prospectively performed within a 1-week period. High-resolution computed tomography Warrick score was calculated and chest sonography findings (B-lines) at several sonographic points along the anterior and posterior intercostal spaces were semi-quantitatively analyzed. Rho Spearman statistics were applied for possible correlations. RESULTS: Twenty-one consecutive patients were studied. A median of 59 thoracic points was studied per patient (IQR 6); 44.1% (95% CI 29.9-60.7) of them showed at least one B-line. A correlation coefficient of 0.135 (p=0.5) was found between the percentage of ultrasound points with B-lines and the Warrick's score. Only the number of bronchopulmonary segments showing ground glass findings was associated with the percentage of sonographic points with B-lines (Rho=0.5, p=0.02). CONCLUSIONS: A good correlation between the percentage of sonographic points with B-lines and high-resolution computed tomography ground glass opacities was observed in patients with the antisynthetase syndrome. PMID- 24773768 TI - Spiritual distress of military veterans at the end of life. AB - OBJECTIVE: Although combat experiences can have a profound impact on individuals' spirituality, there is a dearth of research in this area. Our recent study indicates that one unique spiritual need of veterans who are at the end of life is to resolve distress caused by combat-related events that conflict with their personal beliefs. This study sought to gain an understanding of chaplains' perspectives on this type of spiritual need, as well as the spiritual care that chaplains provide to help veterans ease this distress. METHOD: We individually interviewed five chaplains who have provided spiritual care to veterans at the end of life in a Veterans Administration hospital. The interviews were recorded, transcribed, and analyzed based on "grounded theory." RESULTS: Chaplains reported that they frequently encounter veterans at the end of life who are still suffering from thoughts or images of events that occurred during their military career. Although some veterans are hesitant to discuss their experiences, chaplains reported that they have had some success with helping the veterans to open up. Additionally, chaplains reported using both religious (e.g., confessing sins) and nonreligious approaches (e.g., recording military experience) to help veterans to heal. SIGNIFICANCE OF RESULTS: Our pilot study provides some insight into the spiritual distress that many military veterans may be experiencing, as well as methods that a chaplain can employ to help these veterans. Further studies are needed to confirm our findings and to examine the value of integrating the chaplain service into mental health care for veterans. PMID- 24773769 TI - Malignant pleural mesothelioma metastatic to the submandibular salivary gland, simulating glandular hypertrophy, diagnosed by fine-needle aspiration biopsy: a case report and literature review. AB - BACKGROUND: Malignant mesothelioma is a rare neoplasm that generally develops in the pleural or peritoneal cavity. Distant metastases are common; it rarely metastatizes to the head and neck region. CASE PRESENTATION: A 54-year-old white man, a non-smoker, was treated with chemotherapy, surgery and radiation for a malignant pleural mesothelioma. Seven months after the last treatment, he developed a right submandibular enlargement: clinical examination, ultrasound and computerized tomography scans revealed a salivary gland hypertrophy. Anti inflammatory and antibiotic treatment was then started, without improvement. An ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) showed atypical mesothelial cells with nuclear enlargement and increased chromatin representation. Immunocytochemistry showed positivity for calretinin and WT-1.A diagnosis of right submandibular salivary gland involvement from mesothelioma was established, allowing an adequate treatment. CONCLUSION: We report a very rare site of metastasis from malignant pleural mesothelioma. We suggest that US-guided FNAB is a useful, quick, and cheap procedure for a definite diagnosis. PMID- 24773770 TI - Ethics expertise for health technology assessment: a Canadian national survey. AB - OBJECTIVES: The aim of this study was to identify individuals with expertise in ethics analysis in Canada, who might contribute to health technology assessment (HTA); to gauge these individuals' familiarity with, and experience participating in, the production of HTA. METHODS: A contact list was developed using the Canadian Bioethics Society membership list and faculty listings of Canadian universities, bioethics centers, and health agencies. An eighteen-question email survey was distributed to potential respondents to collect data on demographic information, education and work experience in applied ethics, and involvement in HTA. RESULTS: The survey response rate was 52.8 percent (350/663). Respondents worked primarily in academic institutions (50.4 percent) or hospitals (15.4 percent). Many respondents (83.1 percent) had education, formal training, or work related experience in practical ethics related to health care, with many having a doctorate (34.5 percent) or master's degree (19.0 percent). One quarter (24.5 percent; n = 87) of respondents indicated they had been involved in an analysis of ethical issues for HTA. Almost two-thirds (65.4 percent; n = 165) of those who had not previously participated in ethics analysis believed they might usefully contribute to an analysis of ethical issues in HTA. Experts who have conducted ethics analysis in HTA had more than twice the odds of having education and training in ethics and a PhD than those who might contribute to ethics analysis. CONCLUSION: Many people have contributed to ethics analysis in HTA in Canada, and more are willing to do so. Given the absence of a reliable credential for ethics expertise, HTA producers should exercise caution when enlisting ethics experts. PMID- 24773771 TI - Sulfotransferase activity in plucked hair follicles predicts response to topical minoxidil in the treatment of female androgenetic alopecia. AB - Two percent topical minoxidil is the only US Food and Drug Administration approved drug for the treatment of female androgenetic alopecia (AGA). Its success has been limited by the low percentage of responders. Meta-analysis of several studies reporting the number of responders to 2% minoxidil monotherapy indicates moderate hair regrowth in only 13-20% of female patients. Five percent minoxidil solution, when used off-label, may increase the percentage of responders to as much as 40%. As such, a biomarker for predicting treatment response would have significant clinical utility. In a previous study, Goren et al. reported an association between sulfotransferase activity in plucked hair follicles and minoxidil response in a mixed cohort of male and female patients. The aim of this study was to replicate these findings in a well-defined cohort of female patients with AGA treated with 5% minoxidil daily for a period of 6 months. Consistent with the prior study, we found that sulfotransferase activity in plucked hair follicles predicts treatment response with 93% sensitivity and 83% specificity. Our study further supports the importance of minoxidil sulfation in eliciting a therapeutic response and provides further insight into novel targets for increasing minoxidil efficacy. PMID- 24773772 TI - Periodontal conditions, low birth weight and preterm birth among postpartum mothers in two tertiary health facilities in Uganda. AB - BACKGROUND: Literature reports have indicated an increase in research evidence suggesting association between periodontal disease and the risk of pre-term birth (PTB) and low birth weight (LBW). Periodontal diseases in Uganda have been documented as a public health problem, but their association to adverse pregnancy outcomes is unknown. This study was conducted to assess the association between periodontital diseases in postpartum mothers and PTB and LBW of babies in Mulago and Mbarara referral hospitals. METHODS: This was a cross sectional study using medical records, clinical examination and oral interview of mothers at the two tertiary health facilities. Mothers with singleton babies from Mulago (n = 300) and Mbarara Hospital (n = 100) were recruited for the study. The women were clinically examined for periodontal disease by 2 trained and calibrated dentists. Data on PTB and LBW were retrieved from medical records. The data were analyzed to determine the relationship between the four parameters for periodontal disease (bleeding gingiva, periodontal pockets, gingival recession and calculus with plaque deposits) and the adverse pregnancy outcomes. Frequency distribution was used to describe the data. Bivariate and multivariate analyses were used to study the association between the periodontal diseases and adverse pregnancy outcomes. RESULTS: Approximately 26% and 29% of the postpartum mothers examined had bleeding gingiva and periodontal pockets of 4 mm or more deep, respectively. Advanced periodontitis i.e. pocket depth >= 6 mm was recorded in 13 (3.6%) of the mothers. Calculus with plaque deposits were recorded in 86% (n = 343) of the mothers. Gingival recession was recorded in 9.0% of the mothers and significantly and directly related to birth weight (p < 0.05). CONCLUSION: Periodontal conditions of postpartum mothers in this study were found to be better than previously reported amongst the Ugandan population. Bivariate analysis showed a significant association only between gingival recession and low birth weight. However, this finding should be interpreted with caution as it could have occurred by chance. PMID- 24773773 TI - Endoscopic approaches to enteral feeding and nutrition core curriculum. PMID- 24773774 TI - Detection of EGFR mutations in plasma and biopsies from non-small cell lung cancer patients by allele-specific PCR assays. AB - BACKGROUND: Lung cancer patients with mutations in the epidermal growth factor receptor (EGFR) are primary candidates for EGFR-targeted therapy. Reliable analyses of such mutations have previously been possible only in tumour tissue. Here, we demonstrate that mutations can be detected in plasma samples with allele specific PCR assays. METHODS: Pairs of the diagnostic biopsy and plasma obtained just prior to start of erlotinib treatment were collected from 199 patients with adenocarcinoma of non-small-cell lung cancer. DNA from both sample types was isolated and examined for the presence of mutations in exons 18-21 of the EGFR gene, employing the cobas((r)) EGFR Tissue Test and cobas((r)) EGFR Blood Test (in development, Roche Molecular Systems, Inc., CA, USA). RESULTS: Test results were obtained in all 199 (100%) plasma samples and 196/199 (98%) of the biopsies. EGFR-activating mutations were identified in 24/199 (12%) plasma samples and 28/196 (14%) biopsy samples, and 17/196 (9%) matched pairs contained the same mutation. Six EGFR mutations were present only in plasma samples but not in the biopsy samples. The overall concordance of the EGFR gene mutations detected in plasma and biopsy tissue was 179/196 (91%) (kappa value: 0.621). CONCLUSION: Mutational analysis of the EGFR gene in plasma samples is feasible with allele specific PCR assays and represents a non-invasive supplement to biopsy analysis. TRIAL REGISTRATION: M-20080012 from March 10, 2008 and reported to ClinicalTrials.gov: NCT00815971. PMID- 24773781 TI - Integrating bioinformatic resources to predict transcription factors interacting with cis-sequences conserved in co-regulated genes. AB - BACKGROUND: Using motif detection programs it is fairly straightforward to identify conserved cis-sequences in promoters of co-regulated genes. In contrast, the identification of the transcription factors (TFs) interacting with these cis sequences is much more elaborate. To facilitate this, we explore the possibility of using several bioinformatic and experimental approaches for TF identification. This starts with the selection of co-regulated gene sets and leads first to the prediction and then to the experimental validation of TFs interacting with cis sequences conserved in the promoters of these co-regulated genes. RESULTS: Using the PathoPlant database, 32 up-regulated gene groups were identified with microarray data for drought-responsive gene expression from Arabidopsis thaliana. Application of the binding site estimation suite of tools (BEST) discovered 179 conserved sequence motifs within the corresponding promoters. Using the STAMP web server, 49 sequence motifs were classified into 7 motif families for which similarities with known cis-regulatory sequences were identified. All motifs were subjected to a footprintDB analysis to predict interacting DNA binding domains from plant TF families. Predictions were confirmed by using a yeast-one-hybrid approach to select interacting TFs belonging to the predicted TF families. TF-DNA interactions were further experimentally validated in yeast and with a Physcomitrella patens transient expression system, leading to the discovery of several novel TF-DNA interactions. CONCLUSIONS: The present work demonstrates the successful integration of several bioinformatic resources with experimental approaches to predict and validate TFs interacting with conserved sequence motifs in co-regulated genes. PMID- 24773782 TI - Hepatitis E infection in HIV-infected liver and kidney transplant candidates. AB - Hepatitis E virus (HEV) has been reported to cause acute and chronic hepatitis in those with HIV infection and among solid organ transplant recipients in Europe. Limited data indicate that HEV is endemic in the United States, but the prevalence and significance of HEV infection among those with HIV and awaiting solid organ transplantation is unknown. We evaluated anti-HEV IgM and IgG antibodies and HEV RNA in 166 HIV-infected solid organ transplant candidates enrolled in the NIH HIV-Transplant Cohort. Overall prevalence of anti-HEV IgG approached 20% in both liver and renal transplant candidates. Evidence of recent infection was present in approximately 2% of liver transplant candidates and none of the kidney transplant candidates. HEV RNA was not detected in any patient. We conclude that markers of HEV infection are frequent among candidates for transplantation, but active, ongoing viremia is not seen. Evidence of recent infection (acute on chronic) liver disease was present in liver but not kidney recipients. PMID- 24773784 TI - Control of a two-decade endemic situation with carbapenem-resistant Acinetobacter baumannii: electronic dissemination of a bundle of interventions. AB - BACKGROUND: Our institution continued to experience a hyperendemic situation with carbapenem-resistant Acinetobacter baumannii despite a bundle of interventions. We aim to describe the effect of the subsequent implementation of electronic dissemination of the weekly findings of a bundle of interventions. METHODS: This was a quasiexperimental study performed at a 1,500-bed, public, teaching hospital. From January 2011 to March 2012, weekly electronic communications were sent to the hospital leadership and intensive care units (ICUs). These communications aimed to describe, interpret, and package the findings of the previous week's active surveillance cultures, environmental cultures, environmental disinfection, and hand cultures. Additionally, action plans based on these findings were shared with recipients. RESULTS: During 42 months and 1,103,900 patient-days, we detected 438 new acquisitions of carbapenem-resistant A baumannii. Hospital wide, the rate of acquisition decreased from 5.13 +/- 0.39 to 1.93 +/- 0.23 per 10,000 patient-days, during the baseline and postintervention periods, respectively (P < .0001). This effect was also observed in the medical and trauma ICUs, with decreased rates from 67.15 +/- 10.56 to 17.4 +/- 4.6 (P < .0001) and from 55.9 +/- 8.95 to 14.71 +/- 4.45 (P = .0004), respectively. CONCLUSION: Weekly and systematic dissemination of the findings of a bundle of interventions was successful in decreasing the rates of carbapenem resistant A baumannii across a large public hospital. PMID- 24773785 TI - Automated and electronically assisted hand hygiene monitoring systems: a systematic review. AB - BACKGROUND: Hand hygiene is one of the most effective ways to prevent transmission of health care-associated infections. Electronic systems and tools are being developed to enhance hand hygiene compliance monitoring. Our systematic review assesses the existing evidence surrounding the adoption and accuracy of automated systems or electronically enhanced direct observations and also reviews the effectiveness of such systems in health care settings. METHODS: We systematically reviewed PubMed for articles published between January 1, 2000, and March 31, 2013, containing the terms hand AND hygiene or hand AND disinfection or handwashing. Resulting articles were reviewed to determine if an electronic system was used. RESULTS: We identified 42 articles for inclusion. Four types of systems were identified: electronically assisted/enhanced direct observation, video-monitored direct observation systems, electronic dispenser counters, and automated hand hygiene monitoring networks. Fewer than 20% of articles identified included calculations for efficiency or accuracy. CONCLUSIONS: Limited data are currently available to recommend adoption of specific automatic or electronically assisted hand hygiene surveillance systems. Future studies should be undertaken that assess the accuracy, effectiveness, and cost-effectiveness of such systems. Given the restricted clinical and infection prevention budgets of most facilities, cost-effectiveness analysis of specific systems will be required before these systems are widely adopted. PMID- 24773786 TI - Impact of needleless connector change frequency on central line-associated bloodstream infection rate. AB - BACKGROUND: Bloodstream infection is the most common pediatric health care associated infection and is strongly associated with catheter use. These infections greatly increase the cost of hospital stay. METHODS: To assess the association between needleless connector (NC) change frequency and central line associated bloodstream infection (CLABSI) rate, we modeled monthly pediatric stem cell transplant (SCT) CLABSI rate in 3 periods: baseline period during which NC were changed every 96 hours regardless of infusate (period 1); trial period in which NC were changed every 24 hours with blood or lipid infusions (period 2); and a return to NC change every 96 hours regardless of infusate (period 3). Data on potential confounders were collected retrospectively. Autocorrelated segmented regression models were used to compare SCT CLABSI rates in each period, adjusting for potential confounders. CLABSI rates were also assessed for a nonequivalent control group (oncology unit) in which NC were changed every 24 hours with blood or lipid use in periods 2 and 3. RESULTS: SCT CLABSI rates were 0.41, 3.56, and 0.03 per 1,000 central line-days in periods 1, 2, and 3, respectively. In multivariable analysis, the CLABSI rate was significantly higher in period 2 compared with both period 1 (P = .01) and period 3 (P = .003). In contrast, CLABSI rates on the oncology unit were not significantly different among periods. CONCLUSION: In pediatric SCT patients, changing needleless connectors every 24 hours when blood or lipids are infused is associated with increased CLABSI rates. National recommendations regarding NC change frequency should be clarified. PMID- 24773787 TI - Environmental cleaning resources and activities in Canadian acute care hospitals. AB - BACKGROUND: Environmental cleaning interventions have increased cleaning effectiveness and reduced antibiotic-resistant organisms in hospitals. This study examined cleaning in Canadian acute care hospitals with the goal of developing strategies to improve cleaning and reduce antibiotic-resistant organism rates. METHODS: Managers most responsible for environmental services (EVS) completed an extensive online survey that assessed EVS resources and cleaning practices. RESULTS: The response rate was 50.5%; 96 surveys were completed, representing 103 of 204 hospitals. Whereas 86.3% (82/95) of managers responsible for EVS reported their staff was adequately trained and 76.0% (73/96) that supplies and equipment budgets were sufficient, only 46.9% (45/96) reported that EVS had enough personnel to satisfactorily clean their hospital. A substantial minority (36.8%, 35/95) of EVS departments did not audit the cleaning of medical surgical patient rooms on at least a monthly basis. Cleaning audits of medical surgical patient rooms frequently included environmental marking methods in only one third (33.3%, 31/93) of hospitals and frequently included the measurement of residual bioburden in only 13.8% (13/94). CONCLUSION: There was a general need for increased and improved auditing of environmental cleaning in Canadian hospitals, and there were perceived EVS staffing deficits in the majority of hospitals. PMID- 24773788 TI - Surgical wound irrigation: a call for evidence-based standardization of practice. AB - Surgical wound irrigation has long been debated as a potentially critical intraoperative measure taken to prevent the development of surgical site infection (SSI). Unlike many other SSI prevention efforts, there are no official practice guidelines or recommendations from any major medical group for the practice of surgical irrigation. As a result, practitioner implementation of the 3 major irrigation variables (delivery method, volume, and solution additives) can differ significantly. A focus group of key thought leaders in infection prevention and epidemiology convened recently to address the implications of different surgical irrigation practices. They identified an urgent need for well designed clinical trials investigating surgical irrigation practices, improved collaboration between surgical personnel and infection preventionists, and examination of existing evidence to standardize irrigation practices. The group agreed that current published data are sufficient to support the elimination of antibiotic solutions for surgical irrigation; the avoidance of surfactants for surgical irrigation; and the use of sterile normal saline, sterile water, and 1 medical device containing a sterile 0.05% chlorhexidine gluconate solution followed by sterile saline. Given the current lack of sufficient evidence identifying ideal delivery method and volume choices, expert opinion must be relied on to guide best practice. PMID- 24773789 TI - "Take time. Save lives. Clean hands protect." A comparison of two hand hygiene health promotion posters. AB - Two posters were designed to encourage hospital staff hand hygiene. One focused on broad benefits of hand hygiene to patients and staff, and the other highlighted hand hygiene as a long-known measure to infection control. The former was better received in terms of attention, likability, and potential to promote hand hygiene. A third-person effect, the perception of stronger impact of communication messages on others, was observed. Implications on health promotion message design were discussed. PMID- 24773790 TI - Factors related to compliance among critical care nurses with performing oral care protocols for mechanically ventilated patients in the intensive care unit. AB - Oral care is an important component of the ventilator bundle; however, few studies have investigated the factors related to compliance with performing oral care among critical care nurses. In this observational study of 759 oral care opportunities performed by 133 critical care nurses, we found that the overall oral care compliance rate was 83.3%. Multivariate analysis revealed that nurses' age, academic degree, intensive care unit license, and location were independent predictors of performing oral care for patients in the intensive care unit. PMID- 24773791 TI - Outcomes of a ventilator-associated pneumonia bundle on rates of ventilator associated pneumonia and other health care-associated infections in a long-term acute care hospital setting. AB - Long-term trends in ventilator-associated pneumonia (VAP) rates, and other health care-associated infections, were examined prior to, during, and after introduction of a VAP bundle in a long-term acute care hospital setting. VAP incidence rate declined in a step-wise fashion and reached a null value. Incidence rates of bacteremia from any cause declined in a similar fashion. The incidence rates of vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus colonization or infection rates also decreased, but that of Clostridium difficile infection did not. VAP in the long-term acute care hospital setting can be controlled over time with implementation of Centers for Disease Control and Prevention-based VAP bundle. This outcome also may decrease certain other health care-associated infections. PMID- 24773792 TI - Fluoroquinolone- and ceftriaxone-based therapy of community-acquired pneumonia in hospitalized patients: the risk of subsequent isolation of multidrug-resistant organisms. AB - A retrospective cohort study was performed on 175 adult patients treated for community-acquired pneumonia with moxifloxacin or ceftriaxone/azithromycin in a nonintensive care unit. Both cohorts were very similar with regard to a wide range of characteristics including age, severity of disease, comorbidities, length of stay, and mortality. Multidrug-resistant organisms were subsequently isolated from 6 (15%) moxifloxacin-treated patients and 5 (4%) ceftriaxone/azithromycin-treated patients within 90 days after beginning of therapy (P = .026 on logistic regression analysis). PMID- 24773793 TI - Use of the Cystic Fibrosis Foundation's extensive sputum-culturing protocol for patients without cystic fibrosis: implications for infection control and antimicrobial resistance. AB - The US Cystic Fibrosis Foundation has guidelines for culturing respiratory tract specimens from patients with cystic fibrosis. Pulmonary physicians were surveyed regarding their use of these extensive cystic fibrosis culture protocols for patients without cystic fibrosis. The survey results and a discussion of the implications of these practices are reported. PMID- 24773794 TI - Rapid screening for influenza using a multivariable logistic regression model to save labor at a clinic in Iwaki, Fukushima, Japan. AB - To lighten the workload of health care professionals, we conducted a clinical test of a newly developed automated infection screening system using a multivariable logistic regression model. The system was tested with 44 influenza patients and 45 healthy control subjects based on 3 vital signs: facial temperature, heart rate and respiratory rate. The system showed a high accuracy for distinguishing influenza patients from control subjects within 15 seconds. PMID- 24773795 TI - The important role of sink location in handwashing compliance and microbial sink contamination. AB - Handwashing is one of the most important means of reducing the spread of infection. In this study, we investigated how sink location and visibility influences handwashing and microbial contamination detected on clinical sinks in 3 pediatric intensive care units. We conclude that the visibility of sinks directly impacts on handwashing frequency and duration and also impacts on levels of bacterial contamination on and around the sink area. PMID- 24773796 TI - A single genotype of Acinetobacter baumannii expresses multiple antibiotic susceptibility phenotypes. AB - It is common practice to define a bacterium with unequal antibiotic susceptibility phenotypes as a different genotype. Here, we describe the utility of this practice for Acinetobacter baumannii. We determined antibiotic susceptibility for 19 clinical isolates of A baumannii. Repetitive sequence polymerase chain reaction method was used to determine genotypes. Although all isolates were of the same genotype, 79% were predicted to be different based on susceptibility patterns. The antibiotic susceptibility phenotype does not accurately predict the genotype of A baumannii. PMID- 24773797 TI - Care bundle to prevent methicillin-resistant Staphylococcus aureus sternal wound infection after off-pump coronary artery bypass. AB - Methicillin-resistant Staphylococcus aureus (MRSA) sternal wound infection (SWI) after cardiac surgery is endemic in our hospital. An infection control care bundle with preoperative chlorhexidine showering and povidone iodine paint before bathing was introduced in 2006. From 2001 to 2012, 23 (2.3%) of 1,010 patients undergoing off-pump coronary artery bypass had SWIs. SWI significantly decreased after 2006 (1.4% vs 3.4%, respectively; P = .03). Care bundle was more protective against MRSA infection (2.3% vs 0.5%, respectively; P = .021). SWI remained a common complication after off-pump coronary artery bypass. MRSA infection was most common, and the mortality was high. Care bundle can effectively decrease the incidence of SWI, especially infection caused by MRSA. PMID- 24773798 TI - Extended-spectrum beta-lactamase-producing Escherichia coli isolation among older adults: epidemiology and outcomes. AB - Clinical outcomes of older and younger adults with extended-spectrum beta lactamase-producing Escherichia coli isolation were compared. Two hundred thirty two older adults (aged >=65 years), and 145 younger adults with infection were identified between February 2010 and July 2011. After controlling for the propensity score and receipt of effective therapy, older adults were not at increased risk for adverse outcomes. PMID- 24773799 TI - Look-back investigation of a health care worker infected with human immunodeficiency virus. AB - We report the referral of an HIV-infected surgeon and a subsequent first-ever recommended look-back investigation in Hong Kong. Efficient coordination and effective implementation of the look-back investigation yielded a high response rate of 92.3% of priority patients, with none tested HIV positive. Our experience reconfirmed the very small risk of provider-to-patient HIV transmission and the crucial importance of infection control. PMID- 24773800 TI - Modifying the risk: once-a-day bathing "at risk" patients in the intensive care unit with chlorhexidine gluconate. AB - Chlorhexidine gluconate (CHG) decreases hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) that can cause colonization and infection. A standard approach is the bathing of all patients with CHG to prevent MRSA transmission. To decrease CHG utilization, this study assessed selective daily administration of CHG bathing to intensive care unit patients who had an MRSA positive result or a central venous catheter. This risk-based approach was associated with a 72% decrease in hospital-acquired MRSA transmission rate. PMID- 24773801 TI - First report of emergence of OXA-48 carbapenemase-producing Enterobacteriaceae in Singapore: proactive or reactive infection control strategy? PMID- 24773802 TI - Vancomycin-resistant Enterococcus spp isolated from community acquired infections and colonizations in Queretaro City, Mexico. PMID- 24773803 TI - Compliance with central line insertion bundles in an intensive care unit. PMID- 24773804 TI - Reply: Compliance with central line insertion bundles in an intensive care unit. PMID- 24773805 TI - Seasonal influenza vaccination uptake in Quebec, Canada, 2 years after the influenza A(H1N1) pandemic. AB - BACKGROUND: A decrease in seasonal influenza vaccine uptake was observed after the influenza A(H1N1) pandemic in 2009. The goal of our study was to assess seasonal influenza vaccine uptake in 2011-2012, 2 years after the influenza A(H1N1) pandemic mass immunization campaign and to identify the main reasons for having or not having received the vaccine. METHODS: A telephone survey using random-digit dialing methodology was conducted. Case-weights were assigned to adjust for disproportionate sampling and for nonresponse bias. Descriptive statistics were generated for all variables. RESULTS: Seasonal influenza vaccine uptake was 57% among adults aged >=60 years, 35% among adults with chronic medical conditions, and 44% among health care workers. The main reasons given for having been vaccinated were to be protected from influenza and a high perceived susceptibility to influenza, whereas low perceived susceptibility to influenza and low perceived severity of influenza were the main reasons for not having been vaccinated. CONCLUSIONS: An increase in seasonal influenza vaccine uptake was observed 2 years after the influenza A(H1N1) pandemic. However, vaccine coverage is still below the target level of 80%. More efforts are needed to develop effective strategies to increase seasonal influenza vaccine uptake. PMID- 24773806 TI - Fecal carriage of carbapenem-resistant Enterobacteriaceae in a Chinese university hospital. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) is widespread in China. To date, no study available has specifically determined the prevalence and risk factors of inpatients with CRE intestinal colonization in this region. METHODS: Stool samples were screened for the presence of CRE in a Chinese university hospital. A case-control study was performed to identify risk factors associated with CRE fecal colonization. Case patients were those who had CRE colonization. Control subjects had no microbiologic evidence of CRE colonization. Clinical data were obtained from the medical record. RESULTS: The prevalence of CRE was 6.6% (20/303 patients), of which 8 had carbapenemase-producing isolates. KPC-2, IMP-4, and NDM-1 were detected from these isolates. Hospital readmissions (odds ratio [OR], 58.067; 95% confidence interval [95% CI]: 5.517-611.134; P = .001), sickbed changes (OR, 45.904; 95% CI: 8.484-248.376; P < .001), invasive procedures (OR, 8.322; 95% CI: 1.996-34.690; P = .004), and vancomycin (OR, 11.552; 95% CI: 1.155 115.574; P = .037) were independently associated with CRE colonization. CONCLUSION: This study demonstrated that asymptomatic intestinal carriage of CRE was relatively common in one region of China. Our study suggested that the implementation of effective infection control measures is urgently required to control the transmission of CRE in health care facilities in this country. PMID- 24773830 TI - To investigate the prevention of OM-85 on bronchiectasis exacerbations (iPROBE) in Chinese patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Non-cystic fibrosis bronchiectasis is characterized by the irreversible dilatation of the medium-sized bronchi as a result of airway injury from recurrent or chronic inflammation and lower respiratory tract infections. Bronchiectasis airways are commonly colonized with bacterial species. Infections of the airways play important role in bronchiectasis exacerbations. The non specific prevention of recurrent airway infections by immunostimulating agents has gained growing interest. OM-85, consisting of extracts of eight kinds of bacteria important in respiratory infections, could support the respiratory tract resistance to the pathogens. OM-85 has been shown to be a benefit by decreasing the risk of acute exacerbation of chronic obstructive pulmonary disease (COPD) in several perspective clinical trials. Exacerbation of bronchiectasis substantially contributes to a more rapid decline in lung function, reduced quality of life, and healthcare costs. In this context, we plan to conduct a clinical trial to investigate the PReventive effect of OM-85 on Bronchiectasis Exacerbation in Chinese patients (iPROBE). METHODS/DESIGN: This study is designed as a prospective, randomized, double blind, placebo-controlled multicenter trial. A total of 244 patients with bronchiectasis, who have had at least one exacerbation of bronchiectasis in the previous year, will be included. The subjects will randomly receive two courses of 7 mg of OM-85 or a matching placebo. The treatment dose of OM-85 will be one daily capsule taken orally for 10 days each month for 3 consecutive months at the beginning of the study, followed by 3 months of no drug. This schedule will repeat until the patient has been seen for one year. DISCUSSION: We will investigate whether long-term treatment with an oral immunostimulant (OM-85) could decrease exacerbations of bronchiectasis over a one-year period. We will also assess other relevant outcomes, including the rate of event-based exacerbation, lung function parameters, and total scores judged by the St George's respiratory questionnaire, Leicester cough questionnaire, and inflammatory index. We hope that this study will provide new information on the preventive effects of OM-85 on bronchiectasis exacerbations and will address a knowledge gap for this understudied disease. TRIAL REGISTRATION: This study is registered at http://www.clinicaltrials.gov (identifier NCT01968421) on 19 October 2013. PMID- 24773853 TI - Follow-up of serum KL-6 lung fibrosis biomarker levels in 173 patients with systemic sclerosis. AB - OBJECTIVES: A single-centre retrospective longitudinal study to investigate the predictive value of KL-6 serum levels for the outcome of interstitial lung fibrosis in a large systemic sclerosis (SSc) patient cohort. METHODS: ELISA tests for the mucin like glycoprotein KL-6 were performed in sera of 173 SSc patients. The clinical and laboratory data were evaluated by a standardised protocol of chest x-ray, lung function tests, echocardiography and high-resolution computed tomography. 158 patients were 29 +/- 22 months later reinvestigated, 9 patients (2 lcSSc, 7 dcSSc) died from SSc-related causes, and 6 patients were lost to follow-up. RESULTS: Serum titer of KL-6 was negatively correlated with lung function parameters, independent of the time of investigation. There was a significantly higher probability of death among patients with high level of baseline KL-6. There was no statistically significant difference in the deterioration and improvement rates between groups with normal and elevated KL-6 level at study entry, even in patients in early phase of disease (disease duration <3 years). Serum levels of KL-6 significantly decreased in patients receiving cyclophosphamide treatment in spite of the fact that the spirometry results (FVC and DLCO) did not show a significant change. CONCLUSIONS: KL-6 can be used as a lung fibrosis severity marker, but its role as a marker for disease activity is questionable. Furthermore, following cyclophosphamide treatment serum KL-6 levels may decrease independently of the lung function parameters. PMID- 24773854 TI - Porcelain aorta and severe aortic stenosis: is transcatheter aortic valve implantation the new standard? PMID- 24773855 TI - The band arrangement of myocardial fibres determines cardiac morphology and function. PMID- 24773856 TI - Mediterranean diet and cardiovascular prevention. PMID- 24773857 TI - Percutaneous implantation of the CoreValve(r) self-expanding valve prosthesis in patients with severe aortic stenosis and porcelain aorta: medium-term follow-up. AB - INTRODUCTION AND OBJECTIVES: There is little information on the use of transcatheter aortic valve implantation in patients with severe aortic stenosis and porcelain aorta. The primary aim of this study was to analyze death from any cause after CoreValve((r)) implantation in patients with severe aortic stenosis, with and without porcelain aorta. METHODS: In this multicenter, observational prospective study, carried out in 3 hospitals, percutaneous aortic valves were implanted in 449 patients with severely calcified aortic stenosis. Of these, 36 (8%) met the criteria for porcelain aorta. The primary end-point was death from any cause at 2 years. RESULTS: Patients with porcelain aorta more frequently had extracardiac vascular disease (11 [30.6%] vs 49 [11.9%]; P=.002), prior coronary revascularization (15 [41.7%] vs 98 [23.7%]; P=.017), and dyslipidemia (26 [72.2%] vs 186 [45%]; P=.02). In these patients, there was greater use of general anesthesia (15 [41.7%] vs 111 [16.9%]; P=.058) and axillary access (9 [25%] vs 34 [8.2%]; P=.004). The success rate of the procedure (94.4 vs 97.3%; P=.28) and the incidence of complications (7 [19.4%] vs 48 [11.6%]; P=.20) were similar in both groups. There were no statistically significant differences in the primary end point at 24 months of follow-up (8 [22.2%] vs 66 [16%]; P=.33). The only predictive variable for the primary end point was the presence of complications during implantation (hazard ratio=2.6; 95% confidence interval, 1.5-4.5; P=.001). CONCLUSIONS: In patients with aortic stenosis and porcelain aorta unsuitable for surgery, percutaneous implantation of the CoreValve((r)) self-expanding valve prosthesis is safe and feasible. PMID- 24773858 TI - Helical structure of the cardiac ventricular anatomy assessed by diffusion tensor magnetic resonance imaging with multiresolution tractography. AB - INTRODUCTION AND OBJECTIVES: Deeper understanding of the myocardial structure linking the morphology and function of the heart would unravel crucial knowledge for medical and surgical clinical procedures and studies. Several conceptual models of myocardial fiber organization have been proposed but the lack of an automatic and objective methodology prevented an agreement. We sought to deepen this knowledge through advanced computer graphical representations of the myocardial fiber architecture by diffusion tensor magnetic resonance imaging. METHODS: We performed automatic tractography reconstruction of unsegmented diffusion tensor magnetic resonance imaging datasets of canine heart from the public database of the Johns Hopkins University. Full-scale tractographies have been built with 200 seeds and are composed by streamlines computed on the vector field of primary eigenvectors at the diffusion tensor volumes. We also introduced a novel multiscale visualization technique in order to obtain a simplified tractography. This methodology retains the main geometric features of the fiber tracts, making it easier to decipher the main properties of the architectural organization of the heart. RESULTS: Output analysis of our tractographic representations showed exact correlation with low-level details of myocardial architecture, but also with the more abstract conceptualization of a continuous helical ventricular myocardial fiber array. CONCLUSIONS: Objective analysis of myocardial architecture by an automated method, including the entire myocardium and using several 3-dimensional levels of complexity, reveals a continuous helical myocardial fiber arrangement of both right and left ventricles, supporting the anatomical model of the helical ventricular myocardial band described by F. Torrent-Guasp. PMID- 24773859 TI - Assessment of cross-reactive host-pathogen antibodies in patients with different stages of chronic Chagas disease. AB - INTRODUCTION AND OBJECTIVES: Trypanosoma cruzi infection has been shown to induce humoral autoimmune responses against host antigens tissues. Particularly, antibodies cross-reacting with myocardial antigens may play a role in the development of the severe forms of chronic Chagas disease. The aim of this study was to determine the association between clinical stage of the disease and the presence of autoantibodies in patients with chronic Chagasic disease. METHODS: We performed a cross-sectional study in T. cruzi-seropositive patients divided into 3 groups according to the classic classification of chronic Chagas heart of Storino et al. All participants underwent complete clinical examination and their sera were used to measure autoantibody levels. RESULTS: All patients had detectable levels of anti-p2beta and anti-B13 autoantibodies but none had anti-Na K-ATPase antibodies. No association was observed between electrocardiographic conduction disturbances and autoantibody levels. Patients with chronic Chagas disease stage III had the highest levels of anti-B13 antibodies and a high risk of mortality score, showing a clear association between disease stage and this score. CONCLUSIONS: Anti-B13 antibodies were significantly higher in chronic Chagas disease stage III patients, suggesting that these antibodies may be involved in disease progression and that they might be a useful marker of poor prognosis in terms of heart compromise. Our results also reveal an important correlation between the level of anti-B13 autoantibodies and symptomatic heart failure and/or dilated cardiomyopathy. PMID- 24773860 TI - Characteristics of patients with survival longer than 20 years following heart transplantation. AB - INTRODUCTION AND OBJECTIVES: The number of heart-transplant recipients exceeding 20 years of follow-up is steadily increasing. However, little is known about their functional status, comorbidities, and mortality. Identifying the predictors of prolonged survival could guide the selection of candidates for the low number of available donors. METHODS: Functional status, morbidities, and mortality of heart-transplant patients between 1984 and 1992 were analyzed. To identify predictors of 20-year survival, a logistic regression model was constructed using the covariates associated with survival in the univariate analysis. RESULTS: A total of 39 patients who survived 20 years (26% of patients transplanted before 1992) were compared to 90 recipients from the same period who died between 1 and 20 years post-transplantation. Major complications were hypertension, renal dysfunction, infections, and cancer. After a mean follow-up of 30 months, 6 survivors had died, yielding a mortality rate of 6% per year (vs 2.5%-3% in years 1-19). Causes of mortality were infection (50%), malignancy (33%), and allograft vasculopathy (17%). Long-term survivors were younger and leaner, and had nonischemic cardiomyopathy and lower ischemic time. Logistic regression identified recipient age <45 years (odds ratio=3.9; 95% confidence interval, 1.6 9.7; P=.002) and idiopathic cardiomyopathy (odds ratio=3; 95% confidence interval, 1.4-7.8; P=.012) as independent predictors for 20-year survival. CONCLUSIONS: One fourth of all heart-transplant patients in our series survived >20 years with the same graft, and most enjoy independent lives despite significant comorbidities. Recipient age <45 years and idiopathic cardiomyopathy were associated with survival beyond 2 decades. These data may help decide donor allocation. PMID- 24773861 TI - Socioeconomic status and health inequalities for cardiovascular prevention among elderly Spaniards. AB - INTRODUCTION AND OBJECTIVES: Although it is known that social factors may introduce inequalities in cardiovascular health, data on the role of socioeconomic differences in the prescription of preventive treatment are scarce. We aimed to assess the relationship between the socioeconomic status of an elderly population at high cardiovascular risk and inequalities in receiving primary cardiovascular treatment, within the context of a universal health care system. METHODS: Cross-sectional study of 7447 individuals with high cardiovascular risk (57.5% women, mean age 67 years) who participated in the PREDIMED study, a clinical trial of nutritional interventions for cardiovascular prevention. Educational attainment was used as the indicator of socioeconomic status to evaluate differences in pharmacological treatment received for hypertension, diabetes, and dyslipidemia. RESULTS: Participants with the lowest socioeconomic status were more frequently women, older, overweight, sedentary, and less adherent to the Mediterranean dietary pattern. They were, however, less likely to smoke and drink alcohol. This socioeconomic subgroup had a higher proportion of coexisting cardiovascular risk factors. Multivariate analysis of the whole population found no differences between participants with middle and low levels of education in the drug treatment prescribed for 3 major cardiovascular risk factors (odds ratio [95% confidence interval]): hypertension (0.75 [0.56-1.00] vs 0.85 [0.65-1.10]); diabetic participants (0.86 [0.61-1.22] vs 0.90 [0.67-1.22]); and dyslipidemia (0.93 [0.75-1.15] vs 0.99 [0.82-1.19], respectively). CONCLUSIONS: In our analysis, socioeconomic differences did not affect the treatment prescribed for primary cardiovascular prevention in elderly patients in Spain. Free, universal health care based on a primary care model can be effective in reducing health inequalities related to socioeconomic status. PMID- 24773862 TI - Modification of cardiometabolic profile in obese diabetic patients after bariatric surgery: changes in cardiovascular risk. AB - INTRODUCTION AND OBJECTIVES: Bariatric surgery is a valuable tool for metabolic control in obese diabetic patients. The aim of this study was to determine changes in weight and carbohydrate and lipid metabolism in obese diabetic patients during the first 4 years after bariatric surgery. METHODS: A retrospective study was performed in 104 patients (71 women; mean age, 53.0 [0.9] years; mean body mass index, 46.8 [0.7]) with type 2 diabetes mellitus (median duration, 3 years) who underwent laparoscopic proximal gastric bypass. RESULTS: Blood glucose levels and glycated hemoglobin concentrations decreased during the first 1-3 postoperative months. Values stabilized for the rest of the study period, allowing hypoglycemic treatment to be discontinued in 80% of the patients. No significant differences were observed as a function of the body mass index, diabetes mellitus duration, or previous antidiabetic treatment. Weight decreased during the first 15-24 months and slightly increased afterward. Levels of total cholesterol, triglycerides, and low-density lipoprotein significantly decreased, and target values were reached after 12 months in 80% of the patients. No correlation was found between these reductions and weight loss. Similarly, high-density lipoprotein concentrations decreased until 12 months after surgery. Although concentrations showed a subsequent slight increase, target or lower high density lipoprotein values were achieved at 24 months postintervention in 85% of the patients. CONCLUSIONS: Bariatric surgery is effective for the treatment of obese diabetic patients, contributing to their metabolic control and reducing their cardiovascular risk. PMID- 24773863 TI - Giant aneurysm of saphenous vein coronary graft. PMID- 24773864 TI - Comprehensive assessment of myocardial fibroma by cardiovascular magnetic resonance imaging. PMID- 24773865 TI - Unilateral pulmonary artery agenesis, angio-MR findings. PMID- 24773866 TI - Endocardial completion of epicardial linear ablation during hybrid thoracoscopic and catheter ablation of persistent atrial fibrillation. PMID- 24773867 TI - Clinical profile and blood pressure control in patients managed in primary care in Spain: are there any differences between the young and the old? PMID- 24773868 TI - Patient with angina and "congenital bypass". A new case of aortocoronary fistula. PMID- 24773869 TI - Totally subcutaneous ICD implantation as an alternative to the conventional ICD in a patient with a congenital cardiopathy. PMID- 24773870 TI - Comment on the Management of resistant hypertension in a multidisciplinary unit of renal denervation: protocol and results. Response. PMID- 24773871 TI - Comment on the Management of resistant hypertension in a multidisciplinary unit of renal denervation: protocol and results. PMID- 24773872 TI - Relationship between nighttime blood pressure, the renin-angiotensin system, and melatonin. PMID- 24773873 TI - Relationship between nighttime blood pressure, the renin-angiotensin system and melatonin. Response. PMID- 24773912 TI - Dysregulated sleep-wake cycles in young people are associated with emerging stages of major mental disorders. AB - AIM: To determine if disturbed sleep-wake cycle patterns in young people with evolving mental disorder are associated with stages of illness. METHODS: The sleep-wake cycle was monitored using actigraphy across 4 to 22 days. Participants (21 healthy controls and 154 persons seeking help for mental health problems) were aged between 12 and 30 years. Those persons seeking mental health care were categorized as having mild symptoms (stage 1a), an 'attenuated syndrome' (stage 1b) or an 'established mental disorder' (stage 2+). RESULTS: The proportions of individuals with a delayed weekdays sleep schedule increased progressively across illness stages: 9.5% of controls, 11.1% of stage 1a, 25.6% of stage 1b, and 50.0% of stage 2+ (chi(2) (3 d.f.) = 18.4, P < 0.001). A similar pattern was found for weekends (chi(2) (3 d.f.) = 7.6, P = 0.048). Compared with controls, stage 1b participants had later sleep onset on weekends (P = 0.015), and participants at stages 1b and 2+ had later sleep offset on both weekdays and weekends (P < 0.020). Compared with controls, all participants with mental disorders had more wake after sleep onset (P < 0.029) and those at stages 1a and 2+ had lower sleep efficiency (P < 0.040). Older age, medicated status and later weekdays sleep offset were found to be the three strongest correlates of later versus earlier clinical stages. CONCLUSIONS: In relation to clinical staging of common mental disorders in young people, the extent of delayed sleep phase is associated with more severe or persistent phases of illness. PMID- 24773913 TI - Anxiety among adolescent survivors of pediatric cancer: A missing link in the survivorship literature. AB - OBJECTIVE: With growing numbers of pediatric cancer survivors, it is becoming increasingly important to investigate the psychosocial sequelae of surviving cancer diagnosed during childhood or adolescence. It is particularly important to study the psychosocial needs of adolescent survivors of pediatric cancer because adolescence is a critical time during psychosocial development. Although there is existent literature about the general psychosocial adjustment of this population, the literature regarding anxiety is scant. This brief review aimed to assesses currently available literature that addresses anxiety in adolescent cancer survivors. METHOD: Articles assessing psychosocial adjustment in adolescent survivors of pediatric cancer were reviewed for information regarding anxiety symptoms. RESULTS: To the authors' knowledge, there is no literature that focuses specifically on anxiety in this population. However, many articles reported results that indicated the possibility of increased anxiety in this group. SIGNIFICANCE OF RESULTS: It is critical to further investigate anxiety in this group and develop appropriate interventions if necessary. Doing so will aid the process of enhancing psychosocial care for adolescent cancer survivors. PMID- 24773914 TI - Vitamin A and risk of bladder cancer: a meta-analysis of epidemiological studies. AB - BACKGROUND: Epidemiological studies have reported the preventive effect of vitamin A intake on bladder cancer. However, the findings are inconsistent. To address this issue we conducted a meta-analysis to investigate the quantitative effects of vitamin A on bladder cancer. METHODS: We searched MEDLINE and Embase databases and the references of the relevant articles in English to include studies on dietary or blood vitamin A for the risk of bladder cancer. We performed a meta-analysis using both fixed-effects and random-effects models. RESULTS: Twenty-five articles on dietary vitamin A or blood vitamin A were included according to the eligibility criteria. The pooled risk estimates of bladder cancer were 0.82 (95% CI 0.65, 0.95) for total vitamin A intake, 0.88 (95% CI 0.73, 1.02) for retinol intake, and 0.64 (95% CI 0.38, 0.90) for blood retinol levels. We also found inverse associations between subtypes of carotenoids and bladder cancer risk. CONCLUSION: The findings of this meta analysis indicate that high vitamin A intake was associated with a lower risk of bladder cancer. Larger studies with prospective design and rigorous methodology should be considered to validate the current findings. PMID- 24773915 TI - Novel topical cream delivers safe and effective alternative to traditional psoriasis phototherapy. AB - In today's environment of shrinking reimbursement and coverage for many health care procedures, phototherapy for psoriasis has experienced a major decline. Once hailed as the cornerstone of psoriasis therapy, the increasing cost and demanding treatment regimen has resulted in low compliance, limiting access to this safe and effective mode of treatment. We have previously reported on the development and in vitro evaluation of a topical cream that selectively filters solar radiation to deliver narrow-band ultraviolet B. Here, we present the results of a pilot study in psoriasis patients. After an average of 38 sessions, all patients in the treatment arm responded to therapy. In particular, 43% of the treatment group experienced complete clearance and the remainder experienced at a minimum 50% lesion clearance. In contrast, none of the patients in the placebo arm experienced more than 20% lesion clearance. Our preliminary results demonstrate that the novel topical cream could provide a safe, effective, and convenient alternative to artificial light phototherapy. PMID- 24773916 TI - Risks in the implementation and use of smart pumps in a pediatric intensive care unit: application of the failure mode and effects analysis. AB - OBJECTIVES: The aim of this study was to identify risk points in the different stages of the smart infusion pump implementation process to prioritize improvement measures. METHODS: Failure modes and effects analysis (FMEA) in the pediatric intensive care unit (PICU) of a General and Teaching Hospital. A multidisciplinary team was comprised of two intensive care pediatricians, two clinical pharmacists and the PICU nurse manager. FMEA was carried out before implementing CareFusion infusion smart pumps and eighteen months after to identify risk points during three different stages of the implementation process: creating a drug library; using the technology during clinical practice and analyzing the data stored using Guardrails(r) CQI v4.1 Event Reporter software. RESULTS: Several actions for improvement were taken. These included carrying out periodical reviews of the drug library, developing support documents, and including a training profile in the system so that alarms set off by real programming errors could be distinguished from those caused by incorrect use of the system. Eighteen months after the implementation, these measures had helped to reduce the likelihood of each risk point occurring and increase the likelihood of their detection. CONCLUSIONS: Carrying out an FMEA made it possible to detect risk points in the use of smart pumps, take action to improve the tool, and adapt it to the PICU. Providing user training and support tools and continuously monitoring results helped to improve the usefulness of the drug library, increased users' compliance with the drug library, and decreased the number of unnecessary alarms. PMID- 24773917 TI - Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. AB - BACKGROUND: Ganglioside GD2 is expressed on plasma membranes of various types of malignant cells. One of the most promising approaches for cancer immunotherapy is the treatment with monoclonal antibodies recognizing tumor-associated markers such as ganglioside GD2. It is considered that major mechanisms of anticancer activity of anti-GD2 antibodies are complement-dependent cytotoxicity and/or antibody-mediated cellular cytotoxicity. At the same time, several studies suggested that anti-GD2 antibodies are capable of direct induction of cell death of number of tumor cell lines, but it has not been investigated in details. In this study we investigated the functional role of ganglioside GD2 in the induction of cell death of multiple tumor cell lines by using GD2-specific monoclonal antibodies. METHODS: Expression of GD2 on different tumor cell lines was analyzed by flow cytometry using anti-GD2 antibodies. By using HPTLC followed by densitometric analysis we measured the amount of ganglioside GD2 in total ganglioside fractions isolated from tumor cell lines. An MTT assay was performed to assess viability of GD2-positive and -negative tumor cell lines treated with anti-GD2 mAbs. Cross-reactivity of anti-GD2 mAbs with other gangliosides or other surface molecules was investigated by ELISA and flow cytometry. Inhibition of GD2 expression was achieved by using of inhibitor for ganglioside synthesis PDMP and/or siRNA for GM2/GD2 and GD3 synthases. RESULTS: Anti-GD2 mAbs effectively induced non-classical cell death that combined features of both apoptosis and necrosis in GD2-positive tumor cells and did not affect GD2-negative tumors. Anti GD2 mAbs directly induced cell death, which included alteration of mitochondrial membrane potential, induction of apoptotic volume decrease and cell membrane permeability. This cytotoxic effect was mediated exclusively by specific binding of anti-GD2 antibodies with ganglioside GD2 but not with other molecules. Moreover, the level of GD2 expression correlated with susceptibility of tumor cell lines to cytotoxic effect of anti-GD2 antibodies. CONCLUSIONS: Results of this study demonstrate that anti-GD2 antibodies not only passively bind to the surface of tumor cells but also directly induce rapid cell death after the incubation with GD2-positive tumor cells. These results suggest a new role of GD2 as a receptor that actively transduces death signal in malignant cells. PMID- 24773919 TI - Guidance law against maneuvering targets with intercept angle constraint. AB - This study explores the guidance law against maneuvering targets with the intercept angle constraint. The limitation of the traditional guidance law, which simply treats the unknown target acceleration as zero, has been analyzed. To reduce this limitation, a linear extended state observer is constructed to estimate the acceleration of the maneuvering target to enhance the tracking performance of the desired intercept angle. Furthermore, a nonsingular terminal sliding mode control scheme is adopted to design the sliding surface, which is able to avoid the singularity in the terminal phase of guidance. Simulation results have demonstrated that the proposed guidance law outperforms the traditional guidance law in the sense that more accurate intercept angle can be achieved. PMID- 24773920 TI - Pseudomonas aeruginosa clinical and environmental isolates constitute a single population with high phenotypic diversity. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen with a high incidence of hospital infections that represents a threat to immune compromised patients. Genomic studies have shown that, in contrast to other pathogenic bacteria, clinical and environmental isolates do not show particular genomic differences. In addition, genetic variability of all the P. aeruginosa strains whose genomes have been sequenced is extremely low. This low genomic variability might be explained if clinical strains constitute a subpopulation of this bacterial species present in environments that are close to human populations, which preferentially produce virulence associated traits. RESULTS: In this work, we sequenced the genomes and performed phenotypic descriptions for four non-human P. aeruginosa isolates collected from a plant, the ocean, a water-spring, and from dolphin stomach. We show that the four strains are phenotypically diverse and that this is not reflected in genomic variability, since their genomes are almost identical. Furthermore, we performed a detailed comparative genomic analysis of the four strains studied in this work with the thirteen previously reported P. aeruginosa genomes by means of describing their core and pan-genomes. CONCLUSIONS: Contrary to what has been described for other bacteria we have found that the P. aeruginosa core genome is constituted by a high proportion of genes and that its pan-genome is thus relatively small. Considering the high degree of genomic conservation between isolates of P. aeruginosa from diverse environments, including human tissues, some implications for the treatment of infections are discussed. This work also represents a methodological contribution for the genomic study of P. aeruginosa, since we provide a database of the comparison of all the proteins encoded by the seventeen strains analyzed. PMID- 24773940 TI - Psychotic disorder induced by a combination of sorafenib and BAY86-9766. AB - The Ras-Raf-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK cascade is important in the intra-cellular transduction of neurotransmitters, such as dopamine and glutamate. Sorafenib (Nexavar), a multi-kinase inhibitor targeting Raf kinase, vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor, has shown promising results in the treatment of malignancies. BAY86-9766, a novel selective MEK 1/2 inhibitor, is being evaluated in clinical trials as an anticancer drug. We describe herein a hepatocellular carcinoma patient presenting with recurrent psychotic symptoms in the course of the BASIL trial (assessing BAY86-9766 plus sorafenib for the treatment of liver cancer). In this case, VEGFR inhibition caused by sorafenib alone may have contributed to the development of psychosis. A change in ERK activity might also have been involved. However, whether single or combination use of the two drugs is responsible for inducing the psychotic symptoms remains unclear. In summary, the role of the ERK pathway in psychosis is still vague. Further investigation of the ERK activity in patients with psychotic disorders may disclose its role in the pathophysiology of psychosis. PMID- 24773941 TI - The positive influence of methotrexate on the mortality of patients with rheumatoid arthritis is partly independent of its effect on disease activity: results of a re-evaluation 18 years after baseline. AB - OBJECTIVES: Methotrexate (MTX) is the anchor drug in the treatment of patients with rheumatoid arthritis (RA). MTX shows effects on disease activity and mortality. However, it is unclear whether the effect of MTX on mortality depends on its effect on disease activity. METHODS: In a post-hoc analysis we analysed the data of our cohort established in Ratingen, Germany, and included all patients starting treatment with MTX (n=271) between 1980 and 1987. One year after baseline (BL), response to MTX treatment was assessed using a modified ACR 20 response. Follow-up data of 250 patients were available after 10 and 18 years. RESULTS: After 1 year, there were 66% responders and 20% non-responders; only 14% had discontinued MTX treatment due to side effects or lack of efficacy. Most patients continued MTX treatment irrespective of efficacy. Ten years after BL, 61% of the patients were still treated with MTX. After 18 years, the responder group showed a standardised mortality ratio of 1.6 compared to 3.2 for the group of non-responders. However, when adjusting for age, gender, response to MTX treatment one year after BL, number of swollen joints and comorbidities after 10 years an independent association of continued MTX treatment with lower mortality was found for the period 10 to 18 years after BL (hazard ratio (HR): 0.63, 95% confidence interval: 0.43-0.92, p=0.015). CONCLUSIONS: In this cohort, the mortality lowering effect of continued MTX use was partly independent of its effect on disease activity. This finding may affect treatment decisions concerning RA patients with insufficient response to MTX. PMID- 24773988 TI - Strengthening primordial and primary prevention of cardiovascular disease to increase life expectancy. PMID- 24773989 TI - Aortic root imaging in the era of transcatheter aortic valve implantation/transcatheter aortic valve replacement. PMID- 24773990 TI - Comments on the ESC/ESH guidelines for the management of arterial hypertension 2013. A report of the Task Force of the Clinical Practice Guidelines Committee of the Spanish Society of Cardiology. PMID- 24773991 TI - Contributions of cardiovascular mortality to Spanish life expectancy from 1980 to 2009. AB - INTRODUCTION AND OBJECTIVES: This article describes the contribution of the decrease in cardiovascular mortality to the increase in life expectancy at birth in Spain from 1980 to 2009. We explain the demographic factors underlying the decrease in mortality from cardiovascular diseases at older ages and the effect of this decrease on lifespan. METHODS: The contribution of these decreases to Spanish life expectancy at birth was calculated using decomposition methods for life expectancy. We calculated standardized mortality rates by sex and 3 causes of death (cerebrovascular disease, ischemic heart disease, and other heart disease) for 3 age groups: 65 to 79 years, 80 to 89 years, and >= 90 years. RESULTS: From 1980 to 2009, life expectancy at birth in Spain increased by more than 6 years for both sexes. The contribution of the decrease in cardiovascular mortality to the total increase in life expectancy at birth was 63% among women and 53% among men. Among the >= 65-year-old age group, this contribution was 93% among women and 87% among men. CONCLUSIONS: The decrease in cardiovascular mortality, mainly at older ages, has been the main contributor to increased Spanish life expectancy at birth during the last 3 decades. PMID- 24773992 TI - Use of drugs related to the treatment of diabetes mellitus and other cardiovascular risk factors in the Spanish population. The Di@bet.es study. AB - INTRODUCTION AND OBJECTIVES: To assess the patterns of use of 8 therapeutic drug groups for the treatment of diabetes mellitus and other cardiovascular risk factors, and to identify sociodemographic and health determinants of their use in the overall Spanish population. METHODS: A representative sample of the Spanish population within the Di@bet.es study, a cross-sectional population-based survey, was included. STUDY VARIABLES: sociodemographic, clinical, and lifestyle data; physical examination, and an oral glucose tolerance test in patients without known diabetes mellitus. Furthermore, patients were systematically queried about current medication use, and 8 pharmacotherapeutic groups were evaluated: lipid lowering therapy, antihypertensives, oral hypoglycemic agents, insulin, thyroid hormone, uricosurics, psychoactive drugs, and nonsteroidal anti-inflammatory drugs. RESULTS: Sixty-six percent of the Spanish population was taking at least one medication. Therapeutic drug use was associated with age, independently of the higher prevalence of diabetes mellitus, hypertension, or hyperlipidemia in older patients. Sex disparities were found in the use of lipid-lowering agents, allopurinol, levothyroxine, nonsteroidal anti-inflammatory drugs, and psychoactive drugs. Use of psychoactive drugs was related to education level, work status, physical activity, smoking, and alcohol consumption. Almost 30% of patients with diabetes mellitus were taking 6 or more medications daily. Diabetes mellitus was associated with greater use of antihypertensives, lipid-lowering agents, and nonsteroidal anti-inflammatory drugs. CONCLUSIONS: Age and sex are the most important factors determining therapeutic drug use. Lifestyle patterns and sociocultural factors have an impact only on psychoactive drug use. Diabetes mellitus is associated with greater use of antihypertensives, lipid-lowering agents, and nonsteroidal anti-inflammatory drugs. PMID- 24773993 TI - Myocardial ischemia evaluation with dual-source computed tomography: comparison with magnetic resonance imaging. AB - INTRODUCTION AND OBJECTIVES: Computed tomography does not accurately determine which coronary lesions lead to myocardial ischemia and consequently further tests are required to evaluate ischemia induction. The aim of this study was to compare diagnostic accuracy between dual-energy computed tomography and magnetic resonance imaging in the assessment of myocardial perfusion and viability in patients suspected of coronary artery disease. METHODS: A prospective study was performed in 56 consecutive patients (39 men [69.6%]; mean age [standard deviation], 63 [10]; range, 23-81). Computed tomography was performed with the following protocol: 1, adenosine stress perfusion; 2, coronary angiography; and 3, delayed enhancement. Magnetic resonance imaging for the evaluation of stress perfusion and delayed enhancement was performed within 30 days. Two observers in consensus analyzed the perfusion and delayed enhancement images. RESULTS: We studied 952 myocardial segments and 168 vascular territories. In a per-segment analysis, the sensitivity, specificity, and positive and negative predictive values of computed tomography compared with magnetic resonance were 76%, 99%, 89%, and 98% for perfusion defects, and 64%, 99%, 82%, and 99% for delayed enhancement, respectively. In a per-vascular territory analysis, the same measures were 78%, 97%, 86%, and 95% for perfusion defects, and 72%, 99%, 93%, and 97% for delayed enhancement, respectively. The mean radiation dose was 8.2 (2) mSv. CONCLUSIONS: Dual-source computed tomography may allow accurate and concomitant evaluation of perfusion defects and myocardial viability and analysis of coronary anatomy. PMID- 24773994 TI - Radial vs femoral access after percutaneous coronary intervention for ST-segment elevation myocardial infarction. Thirty-day and one-year mortality results. AB - INTRODUCTION AND OBJECTIVES: Little attention has been given to the effect of vascular access site on mortality, while an increasing body of evidence is showing that radial access has much more benefit than femoral access for ST segment elevation myocardial infarction patients. We aimed to assess the influence of vascular access site on mortality at 30 days and at 1 year in ST segment elevation myocardial infarction patients. METHODS: We included all patients with ST-segment elevation myocardial infarction who had undergone primary angioplasty at 2 Galician hospitals between 2008 and 2010. We performed 2 multivariate regression models for each endpoint (30-day and 1-year mortality). The only difference between these models was the inclusion or not of the vascular access site (femoral vs radial). For each of the 4 models we calculated the Hosmer-Lemeshow test and the C-index. We also tested the interaction between hemodynamic instability and vascular access. RESULTS: We included 1461 patients with a mean age of 64. Of these patients, 86% had radial access and 7.4% had hemodynamic instability. All-cause mortality was 6.8% (100/1461) at 30 days and 9.3% (136/1461) at 1 year. Vascular access site follows hemodynamic instability and age in terms of effect on mortality risk, with an odds ratio of 5.20 (95% confidence interval, 2.80-9.66) for 30-day mortality. A similar effect occurs for 1-year mortality. The C-index slightly improves (without achieving statistical significance) with the inclusion of the vascular access site. CONCLUSIONS: Vascular access site should be taken into account when predicting mortality after a primary percutaneous coronary intervention. PMID- 24773996 TI - Spanish Implantable Cardioverter-defibrillator Registry. Ninth official report of the Spanish Society of Cardiology Electrophysiology and Arrhythmias Section (2012). AB - INTRODUCTION AND OBJECTIVES: To summarize the findings of the Spanish Implantable Cardioverter-defibrillator Registry for 2012 compiled by the Electrophysiology and Arrhythmias Section of the Spanish Society of Cardiology. METHODS: Prospective data recorded voluntarily on single-page questionnaires were sent to the Spanish Society of Cardiology by each implantation team. RESULTS: Overall, 4216 device implantations were reported, representing 80.8% of the estimated total number of implantations. The reported implantation rate was 91.2 per million population and the estimated total implantation rate was 113 per million. The proportion of first implantations was 69.4%. We collected data from 161 hospitals (6 fewer than in 2011). The majority of implantable cardioverter defibrillator recipients were men (83.4%). Mean age was 61.8 (13.4) years. Most patients had severe or moderate-to-severe ventricular dysfunction and were in New York Heart Association functional class II. Ischemic heart disease was the most frequent underlying cardiac condition, followed by dilated cardiomyopathy. The number of indications for primary prevention decreased over the previous year and now account for 58.1% of first implantations. Overall, 81% of the implantable cardioverter-defibrillator were implanted by cardiac electrophysiologists. CONCLUSIONS: The 2012 Spanish Implantable Cardioverter-defibrillator Registry includes data on 80.8% of all implantable cardioverter-defibrillators implantations performed in Spain. This is the second consecutive year in which the number of implantations has slightly decreased compared to the previous year. This year, the percentage of implantations for primary prevention indications also decreased. PMID- 24773997 TI - Spanish cardiac catheterization and coronary intervention registry. 22nd official report of the Spanish Society of Cardiology Working Group on Cardiac Catheterization and Interventional Cardiology (1990-2012). AB - INTRODUCTION AND OBJECTIVES: The Working Group on Cardiac Catheterization and Interventional Cardiology presents the yearly report on the data collected for the Spanish registry. METHODS: Institutions provided their data voluntarily (online) and the information was analyzed by the Working Group's Steering Committee. RESULTS: Data were provided by 109 hospitals (71 public and 38 private) that mainly treat adults. There were 136,912 diagnostic procedures, 120, 441 of which were coronary angiograms, slightly fewer than the year before, with a rate of 2979 diagnostic studies per million population. Percutaneous coronary interventions increased slightly to 65,909 procedures, for a rate of 1434 interventions per million population. Of the 99,110 stents implanted, 62% were drug-eluting stents. In all, 17,125 coronary interventions were carried out during the acute phase of myocardial infarction, 10.5% more than in 2011, representing 25.9% of the total number of coronary interventions. The most frequently performed intervention for adult congenital heart disease was atrial septal defect closure (292 procedures). The use of percutaneous mitral valvuloplasty continued to decline (258 procedures) and percutaneous aortic valve implantations increased by only 10% in 2012. CONCLUSIONS: In 2012, the only increase in hemodynamic activity occurred in the field of ST-elevation myocardial infarction, and the increasing trend had slowed for percutaneous aortic valve implantation and other procedures affecting structure. PMID- 24773998 TI - Very late thrombosis in a bifurcation. PMID- 24773999 TI - Atypical bidirectional ventricular tachycardia. PMID- 24774000 TI - Microchannels in recent chronic total occlusions assessed with frequency-domain optical coherence tomography. PMID- 24774001 TI - Chest pain as the predominant symptom in myocarditis in children. PMID- 24774002 TI - Fenestration closure after Fontan surgery. Contributions of percutaneous interventionism. PMID- 24774003 TI - Usefulness of exercise test in cardiac resynchronization therapy follow-up. PMID- 24774004 TI - Analysis of telephone calls to a heart failure unit: reasons for the call and resource use. PMID- 24774005 TI - Usefulness of coronary computed tomography angiography in asymptomatic patients. PMID- 24774007 TI - Predictive value of serum actin-free Gc-globulin for complications and outcome in acute liver failure. AB - This prospective study was designed to evaluate whether early changes in actin free Gc-globulin levels were associated with complications and outcomes and to identify factors associated with persistent low actin-free Gc-globulin levels in acute liver failure (ALF). Thirty-two consecutive ALF patients admitted from October 2011 to December 2012 were followed up until death or complete recovery. All had serum actin-free Gc-globulin estimation at admission and at day three or expiry. Logistic regression analysis was performed to identify independent predictors of mortality. A receiver operating characteristic curve analysis was also performed. Nonsurvivors had significantly lower median actin-free Gc globulin levels than survivors (87.32 vs 180 mg/L; P < 0.001). A receiver operating characteristic curve analysis revealed an area under curve (AUC) of 0.771 and showed that serum actin-free Gc-globulin level of <=124 mg/L would predict mortality with 92% sensitivity and 71.4% specificity. Patients with lower serum actin-free Gc-globulin levels and decreasing trend in serum actin-free Gc globulin levels were found to have more mortality and developed more complications. Logistic regression analysis showed that serum actin-free Gc globulin, total leucocyte count and serum creatinine at admission were independent predictors of mortality. Incorporating these variables, a score predicting mortality risk at admission was derived. The scoring system was compared to MELD score and King's College Criteria as individual predictor of mortality. Serum actin-free Gc-globulin level at presentation is predictive of outcome and can be used for risk stratification. Its persistent low-level predicts mortality and is correlated with various complications. PMID- 24774008 TI - Attitudes of nursing staff towards computerisation: a case of two hospitals in Nairobi, Kenya. AB - BACKGROUND: The health sector is faced with constant changes as new approaches to tackle illnesses are unveiled through research. Information, communication and technology have greatly transformed healthcare practice the world over. Nursing is continually exposed to a variety of changes. Variables including age, educational level, years worked in nursing, computer knowledge and experience have been found to influence the attitudes of nurses towards computerisation. The purpose of the study was to determine the attitudes of nurses towards the use of computers and the factors that influence these attitudes. METHODS: This cross sectional descriptive study was conducted among staff nurses working at one public hospital (Kenyatta National Hospital, (KNH) and one private hospital (Aga Khan University Hospital (AKUH). A convenience sample of 200 nurses filled the questionnaires. Data was collected using the modified Nurses' Attitudes Towards Computerisation (NATC) questionnaire. RESULTS: Nurses had a favorable attitude towards computerisation. Non-users had a significantly higher attitude score compared to the users (p = 0.0274). Statistically significant associations were observed with age (p = 0.039), level of education (p = 0.025), duration of exposure to computers (p = 0.025) and attitudes towards computerisation. CONCLUSION: Generally, nurses have positive attitudes towards computerisation.This information is important for the planning and implementation of computerisation in the hospital as suggested in other studies. PMID- 24774009 TI - Biomechanics of corneal ectasia and biomechanical treatments. AB - Many algorithms exist for the topographic/tomographic detection of corneas at risk for post-refractive surgery ectasia. It is proposed that the reason for the difficulty in finding a universal screening tool based on corneal morphologic features is that curvature, elevation, and pachymetric changes are all secondary signs of keratoconus and post-refractive surgery ectasia and that the primary abnormality is in the biomechanical properties. It is further proposed that the biomechanical modification is focal in nature, rather than a uniform generalized weakening, and that the focal reduction in elastic modulus precipitates a cycle of biomechanical decompensation that is driven by asymmetry in the biomechanical properties. This initiates a repeating cycle of increased strain, stress redistribution, and subsequent focal steepening and thinning. Various interventions are described in terms of how this cycle of biomechanical decompensation is interrupted, such as intrastromal corneal ring segments, which redistribute the corneal stress, and collagen crosslinking, which modifies the basic structural properties. FINANCIAL DISCLOSURES: Proprietary or commercial disclosures are listed after the references. PMID- 24774010 TI - Diagnostic capacity of biomechanical indices from a dynamic bidirectional applanation device in pellucid marginal degeneration. AB - PURPOSE: To evaluate the diagnostic capacity of the keratoconus match index (KMI) and keratoconus match probability (KMP) classification from a dynamic bidirectional applanation device (Ocular Response Analyzer) in eyes with pellucid marginal degeneration (PMD). SETTING: Department of Ophthalmology, University Clinics Saarland, Homburg, Germany. DESIGN: Cross-sectional study. METHODS: Pellucid marginal degeneration eligibility was confirmed by inferior peripheral thinning, corneal protrusion, and irregular astigmatism. The KMI and KMP parameters in PMD eyes (study group) were compared with those in normal eyes (control group). The KMI's overall predictive accuracy was assessed operating characteristic (ROC) curves. The relationship between KMI and corneal hysteresis (CH), the corneal resistance factor (CRF), and a series of Scheimpflug camera indices was evaluated with Spearman analysis (r). RESULTS: The mean KMI in the study group (40 eyes) and control group (40 eyes) was 0.34 +/- 0.43 (SD) and 0.95 +/- 0.30, respectively (P<.001). The KMI correlated significantly with the CH, CRF, and most Scheimpflug camera indices. Regression analysis indicated that the index of height decentration (r = -0.877, P<.001) was the primary determinant of the KMI. Moreover, the KMP index identified 50.0%, 29.16%, and 20.83% of PMD eyes as ectatic, suspect for ectasia, and normal, respectively. The ROC curve analysis of the KMI parameter indicated a predictive accuracy of 94.8% (cutoff point 0.626; sensitivity 85.71%; specificity 90.1%). CONCLUSIONS: The KMI seems to be a promising diagnostic index for PMD. In contrast, the KMP index identified a significant percentage of topographically defined PMD eyes as normal, limiting its diagnostic value in PMD. FINANCIAL DISCLOSURES: No author has a financial or proprietary interest in any material or method mentioned. PMID- 24774011 TI - Modified liver mobilization for the treatment of renal cell carcinoma with thrombosis involving the intrahepatic inferior vena cava. AB - BACKGROUND: We aimed to evaluate the feasibility and clinical significance of using a modified liver-mobilization technique to treat renal cell carcinoma (RCC) combined with intrahepatic inferior vena cava (IVC) thrombosis. METHODS: A total of 11 level III thrombus patients underwent radical nephrectomy with resection of the tumor thrombus from intrahepatic IVC. A father clamp was used in combination with hepatic portal blocking to control the IVC. RESULTS: The intraoperative mortality and postoperative complications were reduced in 11 cases of RCC with intrahepatic IVC thrombosis. The mean blood loss was 800 mL, and mean patient hospital stay was 13 days. Follow-up was conducted for one to four months, with only two cases of recurrence recorded. CONCLUSIONS: The proposed modified liver mobilization technique could safely and effectively treat RCC and reduce intrahepatic IVC thrombosis. PMID- 24774012 TI - Successful treatment of necrobiotic xanthogranuloma with total glucosides of paeony. AB - Necrobiotic xanthogranuloma (NXG) is a rare granulomatous condition that is often associated with a paraproteinemia and in some cases multiple myeloma. We report a case of isolated NXG that responded very well to total glucosides of paeony treatment. Characteristic clinical and histological features of NXG are presented, as well as a discussion regarding management and the use of glucosides of paeony. Treatment with total glucosides of paeony is an effective, safe treatment, which avoids the side effects associated with systemic corticosteroid or cytotoxic agent therapy. PMID- 24774033 TI - Spirituality in the context of life-threatening illness and life-transforming change. AB - OBJECTIVE: Individuals with life-threatening illness often engage in some form of spirituality to meet increased needs for meaning and purpose. This study aimed to identify the role of spirituality in persons who had reported positive, life transforming change in relation to life-threatening cancer or cardiac events, and to connect these roles to palliative and supportive care. METHOD: A purposive sample of 10 cardiac survivors and 9 cancer survivors was recruited. Once the participants had given informed consent and passed screening in relation to life transforming change and distress, they engaged in a semistructured one-hour qualitative interview on the theme of how their life-transforming change occurred in the context of their life-threatening illness. In the present article, our phenomenological analysis focuses on participants' references to purpose and meaning in their lives, with particular attention to the role and context of participants' spirituality. RESULTS: Participants mentioned spirituality, meaning, and purpose in many contexts, including connecting with family and friends, nature, art, music, and sometimes creating a relationship with God. Participants often accessed spirituality by enhancing connections in their own lives: with a higher power, people, their work, or themselves. These enhanced connections gave participants greater meaning and purpose in their lives, and substantially helped participants to adjust to their life-threatening illnesses. SIGNIFICANCE OF RESULTS: Understanding the roles and contexts of spirituality among patients with a life-threatening illness allows us to develop better palliative and supportive care plans. Spiritually oriented supportive care may include support groups, yoga, meditation, nature, music, prayer, or referral to spiritual or religious counselors. A quantitative scale is needed to help healthcare clinicians assess the spiritual and coping needs of individuals with life-threatening illness. PMID- 24774034 TI - Mentoring a health technology assessment initiative in Kazakhstan. AB - OBJECTIVES: The aim of this study was to assist in the development of a health technology assessment (HTA) program for the Ministry of Health (MOH) of the Republic of Kazakhstan METHODS: Mentoring of an initial HTA program in Kazakhstan was provided by the Canadian Society for International Health (CSIH) by means of a partnership with the Kazakhstan MOH. HTA materials, courses, and one-on-one support for the preparation of a series of initial HTA reports by MOH HTA staff were provided by a seven-member CSIH team over a 2.5-year project. RESULTS: Guidance documents on HTA and institutional strengthening were prepared in response to an extensive set of deliverables developed by the MOH and the World Bank. Introductory and train-the-trainer workshops in HTA and economic evaluation were provided for MOH staff members, experts from Kazakhstan research institutes and physicians. Five short HTA reports were successfully developed by staff in the Ministry's HTA Unit with assistance from the CSIH team. Challenges that may be relevant to other emerging HTA programs included lack of familiarity with some essential underlying concepts, organization culture, and limited time for MOH staff to do HTA work. CONCLUSIONS: The project helped to define the need for HTA and mentored MOH staff in taking the first steps to establish a program to support health policy decision making in Kazakhstan. This experience offers practical lessons for other emerging HTA programs, although these should be tailored to the specific context. PMID- 24774035 TI - Folicular reserve changes in torsion-detorsion of the ovary: an experimental study. AB - OBJECTIVE: We assess follicular reserve changes by follicle count in torsion detorsion rat model. STUDY DESIGN: 30 albino rats were randomly divided into 3 groups: sham group (SG), detorsion after 24-hour torsion group (24hTG) and detorsion after 72-hour torsion group (72hTG). Ovaries were torsioned and fixed. They were untwisted 24 and 72 h later. Oophorectomies were performed at 14th day after detorsion. Tissue damage scoring and follicle counts were evaluated microscopically. RESULTS: Tissue damage scores (TDSs) were higher in 72hTG and 24hTG compared to SG. In addition, as we increase torsion duration, TDSs also increased. There was no statistically significant difference in follicle numbers (primordial, primary, secondary and tertiary). CONCLUSION: Duration of torsion and intensity of ovarian damage do not affect follicular reserve in a rat model. Regardless of their macroscopic appearance, ovaries maintain their follicle reserves after torsion. Thus, surgeons should be reassured and encouraged to untwist torsioned ovaries rather than removing them. PMID- 24774036 TI - High levels of endothelial progenitor cells can be associated with thrombosis in patients with Behcet's disease. AB - OBJECTIVES: Behcet's disease (BD) is a systemic disorder characterised by vasculitis. Endothelial progenitor cells are derived from the bone marrow and contribute to new vessel formation. The aim of this study was to investigate the level of endothelial progenitor cells in BD and BD-associated conditions. METHODS: A total of 74 subjects were included in this study, of whom 44 and 30 subjects were patients with BD or healthy subjects, respectively. Endothelial progenitor cells were defined and measured by flow cytometry according to the expression of CD146, CD31 and CD34. We separated BD patients according to the active disease, pathergy test results, thrombosis and gender. MedCalc 12.5 software programme was used for statistical analyses. RESULTS: The level of endothelial progenitor cells was comparable in patients with BD and healthy subjects (p=0.849). It was also comparable in patients with active or inactive BD (p=0.320). The level of endothelial progenitor cells was higher in patients with thrombosis (p=0.04). There was no statistical significant difference between pathergy positive and negative patients (p=0.969). The level of endothelial progenitor cells was not correlated with age, C-reactive protein, erythrocyte sedimentation rate, white blood cells and disease duration (p>0.05). CONCLUSIONS: The level of endothelial progenitor cells was significantly higher in BD patients with thrombosis. On the other hand, they were not associated with disease activity, pathergy test and other conditions. EPCs may be a useful marker for thrombosis in patients with BD. In our opinion, this is the most expected result in this study. PMID- 24774037 TI - Ulnar nerve deep branch compression by a ganglion: a review of nine cases. AB - BACKGROUND AND AIM: Ulnar nerve compression is common at the elbow, but less common at the wrist. The purposes of this study were to report a series of nine patients with pure ulnar nerve deep branch compression by a ganglion and to evaluate the outcome following a surgical treatment. METHODS: A retrospective study was conducted with nine patients from 2000 to 2011. The patients included four male and five female patients. The mean duration of symptoms before surgery was 16 months (range, 5-32 months). Different degrees of muscular atrophy and weakness of the interossei and adductor pollicis muscles were present without sensory loss in the hand. Ganglion excision and decompression of Guyon's canal were performed in all patients. We evaluated postoperative results of this uncommon nerve lesion based on the modified Bishop's scoring system. RESULTS: The ganglion compressing the deep branch originated from the pisohamate joint in eight cases and from the midpalmar space in one case. At the mean follow-up of 23 months (range, 17-31 months), strength improvement of the grip and tip pinch was achieved in all patients. In comparison, grip strength improved from a mean of 63% of the unaffected side preoperatively to 88% of the unaffected side postoperatively. Tip pinch strength improved from a mean of 61% to 87%. According to the modified Bishop's scoring system, six patients (67%) obtained excellent results, two (22%) had good results, and only one (11%) had a fair result. CONCLUSIONS: A ganglion causing ulnar nerve deep branch compression is rare. Early surgical treatment can result in satisfactory functional recovery. PMID- 24774038 TI - Longboard and skateboard injuries. AB - INTRODUCTION: The causes and events related to skateboarding injuries have been widely documented. However, little is known about longboard-related injuries. With five deaths linked to longboarding in the United States and Canada in 2012, some cities are already considering banning the practice. This study compared the types and causes of longboarding-related injuries to those associated with skateboarding. METHODS: We conducted a retrospective cohort study, using an emergency-based surveillance system, on patients under the age of 18 who had been injured while longboarding or skateboarding between 2006 and 2010. RESULTS: A total of 287 longboarding and 4198 skateboarding cases were identified. There were more females in the longboarding group (18.8%) than in the skateboarding one (10.7%, p < 0.002). All the injured longboarders were older than 10 years of age while a fifth of the injured skateboarders were under the age of 11. Longboarders' injuries occurred mainly on streets and roads (75.3% vs. 34.3% in skateboarders, p < 0.000) and rarely in skate parks (1.4% vs. 26.4% in skateboarders, p < 0.000). Longboarders suffered twice as many injuries to their heads and necks (23.3% vs. 13.1%, p < 0.000) and twice as many severe neurological traumas (8.6 vs. 3.7%, p < 0.000) while skateboarders suffered more injuries to their lower extremities (33.7% vs. 24.7%, p < 0.002). CONCLUSION: Longboarding is associated with a different pattern of injuries than skateboarding. Because longboarders suffer more intracranial injuries, the importance of helmet use should be especially strongly reinforced. PMID- 24774061 TI - Mitochondrial target of thiazolidinediones. AB - Insulin-sensitizing thiazolidinediones exert a pleiotropic pharmacology with therapeutic potential in a number of disease states ranging from metabolic syndrome and diabetes to neurodegeneration and cancer. A growing understanding of their mechanism of action, working from the site of their binding in the mitochondrion, provides insight into the mechanism of action of the insulin sensitizers and the reasons for their pleiotropic pharmacology. This review helps to frame the direction of future work that should be helpful in setting a new direction for the discovery and development of new, more useful therapeutic agents for metabolic disease. PMID- 24774062 TI - Delineation of immunodominant and cytadherence segment(s) of Mycoplasma pneumoniae P1 gene. AB - BACKGROUND: Adhesion of Mycoplasma pneumoniae (M. pneumoniae) to host epithelial cells requires several adhesin proteins like P1, P30 and P116. Among these proteins, P1 protein has been inedited as one of the major adhesin and immunogenic protein present on the attachment organelle of M. pneumoniae. In the present study, we scanned the entire sequence of M. pneumoniae P1 protein to identify the immunodominant and cytadherence region(s). M. pneumoniae P1 gene was synthesized in four segments replacing all the UGA codons to UGG codons. Each of the four purified P1 protein fragment was analyzed for its immunogenicity with anti-M. pneumoniae M129 antibodies (Pab M129) and sera of M. pneumoniae infected patients by western blotting and ELISA. Antibodies were produced against all the P1 protein fragments and these antibodies were used for M. pneumoniae adhesion, M. pneumoniae adhesion inhibition and M. pneumoniae surface exposure assays using HEp-2 cells lines. RESULTS: Our results show that the immunodominant regions are distributed throughout the entire length of P1 protein, while only the N- and C- terminal region(s) of P1 protein are surface exposed and block cytadhesion to HEp 2 cells, while antibodies to two middle fragments failed to block cytadhesion. CONCLUSIONS: These results have important implications in designing strategies to block the attachment of M. pneumoniae to epithelial cells, thus preventing the development of atypical pneumonia. PMID- 24774063 TI - Healthy Eating Index 2005 and selected macronutrients are correlated with improved lung function in humans. AB - A number of dietary components have been associated with lung function. However, a comprehensive measure of a healthy diet has not been compared with lung function. Herein, we test the hypothesis that a healthy overall diet, as assessed by the Healthy Eating Index 2005 (HEI-2005), will be associated with increased lung function. This is an investigation using the Atherosclerosis Risk in Communities Research Materials obtained from the National Heart Lung Blood Institute. The study surveyed dietary habits of 15 567 American subjects from 4 communities in 1987 to 1990. Spirometric measures of lung function were also taken at entry to the study and a second time 3 years later. Based on food and nutritional data collected by food frequency questionnaire, an HEI-2005 score was calculated for each subject. This total score, together with its 12 components scores and associated macronutrient, was compared with lung function results by linear regression. Models were controlled for smoking behavior, demographics, and other important covariates. The HEI-2005 total scores were positively associated with forced expiratory volume in 1 second per forced vital capacity (FEV(1)/FVC) at visit 1 (beta = .101 per increase in 1 quintile of HEI-2005) and visit 2 (beta = .140), and FEV(1) as percentage of the predicted FEV(1) at visit 2 (beta = .215) (P < .05). In addition, HEI-2005 component scores that represented high intakes of whole grains (beta = .127 and .096); saturated fats (beta = -.091); and solid fats, alcohol, and added sugar (beta = -.109 and -.131) were significantly associated with FEV(1)/FVC at either visit 1 or visit 2. Intakes of total calories (beta =-.082 at visit 1) and saturated fatty acids (beta = -.085 at visit 2) were negatively associated with FEV(1)/FVC. Dietary polyunsaturated fatty acids (beta = .085 and .116) and long-chain omega-3 fatty acids (beta = .109 and .103), animal protein (beta = .132 and .093), and dietary fiber (beta = .129) were positively associated with lung health. An overall healthy diet is associated with higher lung function. PMID- 24774064 TI - Fruit and vegetable intake, as reflected by serum carotenoid concentrations, predicts reduced probability of polychlorinated biphenyl-associated risk for type 2 diabetes: National Health and Nutrition Examination Survey 2003-2004. AB - Type 2 diabetes has been shown to occur in response to environmental and genetic influences, among them nutrition; food intake patterns; sedentary lifestyle; body mass index; and exposure to persistent organic pollutants, such as polychlorinated biphenyls (PCBs). Nutrition is essential in the prevention and management of type 2 diabetes and has been shown to modulate the toxicity of PCBs. Serum carotenoid concentrations, considered a reliable biomarker of fruit and vegetable intake, are associated with the reduced probability of chronic diseases, such as type 2 diabetes and cardiovascular disease. Our hypothesis is that fruit and vegetable intake, reflected by serum carotenoid concentrations, is associated with the reduced probability of developing type 2 diabetes in US adults with elevated serum concentrations of PCBs 118, 126, and 153. This cross sectional study used the Center for Disease Control and Prevention database, National Health and Nutrition Examination Survey 2003-2004, in logistic regression analyses. Overall prevalence of type 2 diabetes was approximately 11.6% depending on the specific PCB. All 3 PCBs were positively associated with the probability of type 2 diabetes. For participants at higher PCB percentiles (eg, 75th and 90th) for PCB 118 and 126, increasing serum carotenoid concentrations were associated with a smaller probability of type 2 diabetes. Fruit and vegetable intake, as reflected by serum carotenoid concentrations, predicted notably reduced probability of dioxin-like PCB-associated risk for type 2 diabetes. PMID- 24774066 TI - Soy and isoflavone intake associated with reduced risk of ovarian cancer in southern Chinese women. AB - Isoflavones, mainly found in soy, have been shown to inhibit ovarian cancer cell proliferation. We hypothesized that soy consumption and isoflavone intake are related to the risk of ovarian cancer. A case-control study was conducted in southern China to ascertain this hypothesis. Five hundred incident patients with histologically confirmed cancer of the ovary and 500 controls (mean age 59 years) were recruited from four public hospitals in Guangzhou. Information on habitual consumption of soy foods, including soybean, soy milk, fresh tofu, dried tofu, and soybean sprout, was obtained face-to-face from participants through a validated and reliable semi-quantitative food frequency questionnaire. Isoflavone intakes were then estimated using the USDA nutrient database. The ovarian cancer patients reported lower consumption levels of individual and total soy foods (75.3 +/- 53.6 g/day) compared to the controls (110.7 +/- 88.8 g/day). Logistic regression analyses showed that regular intake of soy foods could reduce the ovarian cancer risk, the adjusted odds ratio being 0.29 (95% confidence interval 0.20 to 0.42) for women who consumed at least 120 g/day relative to those less than 61 g/day. Similarly, isoflavone intakes were inversely associated with the ovarian cancer risk, with significant dose-response relationships (P < 0.001). We concluded that consumption of soy foods is associated with a reduced risk of ovarian cancer in southern Chinese women. PMID- 24774065 TI - Depressive symptoms are associated with dietary intake but not physical activity among overweight and obese women from disadvantaged neighborhoods. AB - Evidence suggests that depressive symptoms are associated with poorer dietary intake and inadequate physical activity; however, this association has not been examined in lower-income overweight and obese African American women. The objective of this cross-sectional study was to examine the associations between depressive symptoms and diet and physical activity in 196 women (87% African American; age, 25-51 years). Higher depressive symptoms were hypothesized to predict poorer diet quality, greater emotional eating, lower physical activity levels, and greater sedentary time. Depressive symptoms were measured using the validated short form of the Center for Epidemiological Studies Depression Scale. Dietary intake and quality were assessed using three 24-hour dietary recalls. Emotional eating was evaluated using 4 items from the emotional eating subscale of the Eating Behavior Patterns Questionnaire. Physical activity and sedentary time were objectively measured using the ActiGraph accelerometer. Linear regression models tested the associations between depressive symptoms and each dietary and physical activity outcome variable. Symptoms of depression were positively associated with total daily caloric intake from saturated fat and total sugars, as well as emotional eating scores (P < .05). Although not statistically significant, depressive symptoms were positively associated with sweetened beverage consumption (P = .06) and added sugars (P = .07). Depressive symptoms were not associated with total fat, sodium, fruit and vegetables, fast food consumption, the Alternate Healthy Eating Index score, moderate-to-vigorous physical activity, or sedentary time. Future studies should explore the mechanisms linking the identified associations between depressive symptoms and dietary intake, such as the role of emotional eating. PMID- 24774067 TI - A high isoflavone diet decreases 5' adenosine monophosphate-activated protein kinase activation and does not correct selenium-induced elevations in fasting blood glucose in mice. AB - Selenium (Se) has been implicated as a micronutrient that decreases adenosine monophosphate-activated protein kinase (AMPK) signaling and may increase diabetes risk by reducing insulin sensitivity. Soy isoflavones (IF) are estrogen-like compounds that have been shown to attenuate insulin resistance, hyperglycemia, adiposity, and increased AMPK activation. We hypothesized that a high IF (HIF) diet would prevent the poor metabolic profile associated with high Se intake. The purpose of this study was to examine changes in basal glucose metabolism and AMPK signaling in response to an HIF diet and/or supplemental Se in a mouse model. Male FVB mice were divided into groups receiving either a control diet with minimal IF (low IF) or an HIF diet. Each dietary group was further subdivided into groups receiving either water or Se at a dose of 3 mg Se/kg body weight daily, as Se-methylselenocysteine (SMSC). After 5 months, mice receiving SMSC had elevated fasting glucose (P < .05) and a tendency for glucose intolerance (P = .08). The increase in dietary IF did not result in improved fasting blood glucose. Interestingly, after 6 months, HIF-fed mice had decreased basal AMPK activation in liver and skeletal muscle tissue (P < .05). Basal glucose metabolism was changed by SMSC supplementation as evidenced by increased fasting blood glucose and glucose intolerance. High dietary IF levels did not protect against aberrant blood glucose. In FVB mice, decreased basal AMPK activation is not the mechanism through which Se exerts its effect. These results suggest that more research must be done to elucidate the role of Se and IF in glucose metabolism. PMID- 24774068 TI - Bovine colostrum enhances natural killer cell activity and immune response in a mouse model of influenza infection and mediates intestinal immunity through toll like receptors 2 and 4. AB - Oral administration of bovine colostrum affects intestinal immunity, including an increased percentage of natural killer (NK) cells. However, effects on NK cell cytotoxic activity and resistance to infection as well as a potential mechanism remain unclear. Therefore, we investigated the effects of bovine colostrum (La Belle, Inc, Bellingham, WA) on the NK cytotoxic response to influenza infection and on toll-like receptor (TLR) activity in a primary intestinal epithelial cell culture. We hypothesized that colostrum would increase NK cell activity and that TLR-2 and TLR-4 blocking would reduce interleukin 6 production by epithelial cells in response to contact stimulation with colostrum. Four-month-old female C57BL/6 mice were supplemented with 1 g of colostrum per kilogram of body weight before and after infection with influenza A virus (H1N1). Animals were assessed for weight loss, splenic NK cell activity, and lung virus titers. Colostrum supplemented mice demonstrated less reduction in body weight after influenza infection, indicating a less severe infection, increased NK cell cytotoxicity, and less virus burden in the lungs compared with controls. Colostrum supplementation enhanced NK cell cytotoxicity and improved the immune response to primary influenza virus infection in mice. To investigate a potential mechanism, a primary culture of small intestine epithelial cells was then stimulated with colostrum. Direct activation of epithelial cells resulted in increased interleukin 6 production, which was inhibited with TLR-2 and TLR-4 blocking antibodies. The interaction between colostrum and immunity may be dependent, in part, on the interaction of colostrum components with innate receptors at the intestinal epithelium, including TLR-2 and TLR-4. PMID- 24774069 TI - Circadian rhythms of locomotor activity and hippocampal clock genes expression are dampened in vitamin A-deficient rats. AB - The main external time giver is the day-night cycle; however, signals from feeding and the activity/rest cycles can entrain peripheral clocks, such as the hippocampus, in the absence of light. Knowing that vitamin A and its derivatives, the retinoids, may act as regulators of the endogenous clock activity, we hypothesized that the nutritional deficiency of vitamin A may influence the locomotor activity rhythm as well as the endogenous circadian patterns of clock genes in the rat hippocampus. Locomotor activity was recorded during the last week of the treatment period. Circadian rhythms of clock genes expression were analyzed by reverse transcription-polymerase chain reaction in hippocampus samples that were isolated every 4 hours during a 24-hour period. Reduced glutathione (GSH) levels were also determined by a kinetic assay. Regulatory regions of clock PER2, CRY1, and CRY2 genes were scanned for RXRE, RARE, and RORE sites. As expected, the locomotor activity pattern of rats shifted rightward under constant dark conditions. Clock genes expression and GSH levels displayed robust circadian oscillations in the rat hippocampus. We found RXRE and RORE sites on regulatory regions of clock genes. Vitamin A deficiency dampened rhythms of locomotor activity as well as modified endogenous rhythms of clock genes expression and GSH levels. Thus, vitamin A may have a role in endogenous clock functioning and participate in the circadian regulation of the cellular redox state in the hippocampus, a peripheral clock with relevant function in memory and learning. PMID- 24774070 TI - Pharmacokinetic characterization of mangosteen (Garcinia mangostana) fruit extract standardized to alpha-mangostin in C57BL/6 mice. AB - Previously, we have reported the pharmacokinetic (PK) properties of alpha mangostin in mice. For this study, we evaluated the PK profile of alpha-mangostin using a standardized mangosteen extract in C57BL/6 mice. The primary objective was to determine the PK properties of alpha-mangostin when administered as an extract. This experiment was designed to test our primary hypothesis that alpha mangostin in an extract should achieve a desirable PK profile. This is especially relevant as dietary supplements of mangosteen fruit are regularly standardized to alpha-mangostin. Mice received 100 mg/kg of mangosteen fruit extract orally, equivalent to 36 mg/kg of alpha-mangostin, and plasma samples were analyzed over a 24-hour period. Concentrations of alpha-mangostin were determined by liquid chromatography-tandem mass spectrometry. In addition, we evaluated the stability in the presence of phase I and phase II enzymes in liver and gastrointestinal microsomes. Furthermore, we identified evidence of phase II metabolism of alpha mangostin. Further research will be required to determine if less abundant xanthones present in the mangosteen may modulate the PK parameters of alpha mangostin. PMID- 24774071 TI - Water-insoluble fiber-rich fraction from pineapple peel improves intestinal function in hamsters: evidence from cecal and fecal indicators. AB - Pineapple peel, a byproduct of agricultural processing, contains high levels of water-insoluble fiber-rich fraction (WIFF) (~42%, wt/wt). Our previous work has demonstrated that cellulose, hemicellulose (xylan and xyloglucan), and pectic substances are the major polysaccharides of pineapple-peel WIFF. Based on its chemical composition and unique characteristics, we hypothesized that daily consumption of WIFF would improve intestinal function in hamsters. Male Golden Syrian hamsters were fed a diet supplemented with either 5% cellulose or various amounts of WIFF (2.5%, 5%, or 10%). Activities of fecal bacterial enzymes, short chain fatty acid concentrations, and microbial number in the cecal content, and also biochemical indicators in the cecal and feces of hamsters, were evaluated in all groups. The supplementation of WIFF in a diet at a level of 2.5% significantly (P < .05) decreased the daily fecal ammonia output; shortened the gastrointestinal transit time; reduced the activities of beta-D-glucosidase, beta D-glucuronidase, mucinase, and urease in feces; and also enhanced the total amounts of short-chain fatty acid in the cecal content and the growth of gut microflora such as Lactobacillus spp and Bifidobacterium spp. These results indicate that WIFF could improve cecal ecosystem function of hamsters by reducing the toxic compounds excreted by intestinal microflora. Therefore, pineapple-peel WIFF could be a promising candidate for a functional ingredient beneficial to human intestinal function and health. PMID- 24774072 TI - Fermented soybean product (Cheonggukjang) improved some attributes of protein and growth hormone measurements in Sprague-Dawley rats. AB - We hypothesized that the administration of Cheonggukjang (CKJ) would exert positive effects on factors implicated with growth in Sprague-Dawley (SD) rats. To test this hypothesis, we measured specific aspects of bone and organ growth in male SD rats that were treated for 6 weeks with 3 concentrations of CKJ. Although the CKJ extract contained high concentrations of flavonoids and phenolic compounds, no significant differences in body length, organ weights, or femur weight were detected between the CKJ- and vehicle-treated groups. However, thicknesses of the epiphyseal growth plate in the proximal femoral epiphysis and the compact bone in the linea aspera were broadest in the femur of the 2 CKJ treated groups when compared with the vehicle-treated groups. Furthermore, the levels of growth hormone (GH) and calcium ion were higher in the sera of the high concentration CKJ-treated groups, whereas the expression level of GH receptor was higher in muscle tissue of all CKJ-treated groups and in the liver tissue of the high-concentration CKJ-treated group. In the GH receptor downstream signaling pathway, the phosphorylation levels of Akt and Erk were expressed differently between liver and muscle tissues upon CKJ treatment. However, the phosphorylation level of STAT5 was very similar to the expression level of the GH receptor in all CKJ-treated groups. These results indicate that CKJ extract may increase the thickness of the epiphyseal growth plate and the compact bone of the femur, elevate GH secretion, and stimulate regulation of the GH receptor downstream signaling pathway in the liver and muscle tissues of SD rats. PMID- 24774073 TI - beta-Hydroxy-beta-methylbutyrate facilitates PI3K/Akt-dependent mammalian target of rapamycin and FoxO1/3a phosphorylations and alleviates tumor necrosis factor alpha/interferon gamma-induced MuRF-1 expression in C2C12 cells. AB - beta-Hydroxy-beta-methylbutyrate (HMB) prevents deleterious muscle responses under pathological conditions, including tumor- and chronic steroid therapy related muscle losses. Here, we investigated the hypothesis that HMB may modulate the balance between protein synthesis and degradation in the PI3K/Akt-mediated mammalian target of rapamycin (mTOR) and FoxO1/FoxO3a-dependent mechanisms in differentiated C2C12 muscle cells. We also tested the effect of HMB on the expression of MuRF-1 and atrogin-1 in response to the inflammatory stress. beta Hydroxy-beta-methylbutyrate up-regulated phosphorylation of Akt and mTOR, and these effects were completely abolished in the presence of PI3K inhibitor LY294002. beta-Hydroxy-beta-methylbutyrate also up-regulated FoxO1 and FoxO3a phosphorylation, and these changes were inhibited by LY294002. Although, unexpectedly, HMB failed to reduce the expressions of atrophy-related atrogin-1 messenger RNA and the protein response to the proinflammatory cytokines tumor necrosis factor alpha plus interferon gamma, HMB did attenuate the MuRF-1 expression. Thus, HMB appears to restore the balance between intracellular protein synthesis and proteolysis, likely via activation of the PI3K/Akt dependent mTOR and FoxO1/FoxO3a signaling pathway and the reduction of tumor necrosis factor alpha/interferon gamma-induced MuRF-1 expression, thereby ameliorating aging-related muscle atrophy. PMID- 24774074 TI - Cognitive emotion regulation strategies in outpatients with major depressive disorder. AB - The aim of this study was to examine cognitive emotion regulation strategies in adult outpatients with major depressive disorder (MDD). A clinical sample of 191 MDD outpatients and a non-clinical sample of 267 general adults were recruited. Nine cognitive emotion regulation strategies were assessed in all participants (aged 21-65 years). Results showed that MDD participants had significantly higher scores on the following strategies: self-blame, acceptance, rumination, catastrophizing, and blaming others, but lower scores on positive refocusing, refocus on planning, positive reappraisal, and putting in perspective strategies than general populations. In addition, self-blame, acceptance, and catastrophizing positively correlated and positive reappraisal negatively correlated with depressive symptoms in MDD populations. Further logistic regression analyses indicated that five strategies have significant and independent contributions to the prediction of MDD group membership (a higher reported use of self-blame, catastrophizing, and acceptance, and a lower reported use of positive refocusing, and putting in perspective). The results suggest that cognitive emotion regulation strategies may be a useful target for psychological assessment and treatment in patients with MDD. PMID- 24774075 TI - Anhedonia predicts suicidal ideation in a large psychiatric inpatient sample. AB - This study examined the relationship among symptoms of anhedonia and suicidal ideation at baseline, at termination, and over time in 1529 adult psychiatric inpatients. Anhedonia was associated with suicidality cross-sectionally at baseline and at termination. In addition, change in anhedonia from baseline to termination predicted change in suicidality from baseline to termination, as well as level of suicidality at termination; moreover, anhedonia remained a robust predictor of suicidal ideation independent of cognitive/affective symptoms of depression. Symptom-level analyses also revealed that, even after accounting for the physical aspect of anhedonia (e.g., loss of energy), loss of interest and loss of pleasure were independently associated with higher levels of suicidal ideation at baseline, over time, and at discharge. Loss of interest was most highly predictive of suicidal ideation, providing support for recent differential conceptualizations of anhedonia. Taken together, these findings indicate that the manner in which anhedonia is conceptualized is important in predicting suicidal ideation, and that anhedonia symptoms warrant particular clinical attention in the treatment of suicidal patients. PMID- 24774076 TI - Mental health stigma and primary health care decisions. AB - People with serious mental illness have higher rates of mortality and morbidity due to physical illness. In part, this occurs because primary care and other health providers sometimes make decisions contrary to typical care standards. This might occur because providers endorse mental illness stigma, which seems inversely related to prior personal experience with mental illness and mental health care. In this study, 166 health care providers (42.2% primary care, 57.8% mental health practice) from the Veteran's Affairs (VA) medical system completed measures of stigma characteristics, expected adherence, and subsequent health decisions (referral to a specialist and refill pain prescription) about a male patient with schizophrenia who was seeking help for low back pain due to arthritis. Research participants reported comfort with previous mental health interventions. Path analyses showed participants who endorsed stigmatizing characteristics of the patient were more likely to believe he would not adhere to treatment and hence, less likely to refer to a specialist or refill his prescription. Endorsement of stigmatizing characteristics was inversely related to comfort with one's previous mental health care. Implications of these findings will inform a program meant to enhance VA provider attitudes about people with mental illness, as well as their health decisions. PMID- 24774077 TI - Submandibular gland cystadenocarcinoma with mucinous adenocarcinoma-like areas: a case report. AB - Cystadenocarcinoma is primarily characterized by cystic structures of varying sizes, that are lined by epithelial cells. As a rare neoplasm, only four cases of cystadenocarcinoma of submandibular glands have been previously reported. Herein, we reported a unique case of submandibular gland cystadenocarcinoma in a 44-year old man. By in large, this case had typical morphologic cystadenocarcinoma features. However, mucinous adenocarcinoma-like areas were additionally observed in the tumor tissues. This case was initially misdiagnosed as mucinous adenocarcinoma due to the low incidence of submandibular gland cystadenocarcinoma and the presentation of mucinous adenocarcinoma-like areas in the tumor tissues. Histopathology of additional tumor tissues revealed that mucinous adenocarcinoma like areas accounted for only a small percentage of the tumor tissues, confirming the submandibular gland cystadenocarcinoma diagnosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1387916949121142. PMID- 24774101 TI - Markov modeling and discrete event simulation in health care: a systematic comparison. AB - OBJECTIVES: The aim of this study was to assess if the use of Markov modeling (MM) or discrete event simulation (DES) for cost-effectiveness analysis (CEA) may alter healthcare resource allocation decisions. METHODS: A systematic literature search and review of empirical and non-empirical studies comparing MM and DES techniques used in the CEA of healthcare technologies was conducted. RESULTS: Twenty-two pertinent publications were identified. Two publications compared MM and DES models empirically, one presented a conceptual DES and MM, two described a DES consensus guideline, and seventeen drew comparisons between MM and DES through the authors' experience. The primary advantages described for DES over MM were the ability to model queuing for limited resources, capture individual patient histories, accommodate complexity and uncertainty, represent time flexibly, model competing risks, and accommodate multiple events simultaneously. The disadvantages of DES over MM were the potential for model overspecification, increased data requirements, specialized expensive software, and increased model development, validation, and computational time. CONCLUSIONS: Where individual patient history is an important driver of future events an individual patient simulation technique like DES may be preferred over MM. Where supply shortages, subsequent queuing, and diversion of patients through other pathways in the healthcare system are likely to be drivers of cost-effectiveness, DES modeling methods may provide decision makers with more accurate information on which to base resource allocation decisions. Where these are not major features of the cost-effectiveness question, MM remains an efficient, easily validated, parsimonious, and accurate method of determining the cost-effectiveness of new healthcare interventions. PMID- 24774100 TI - Gastric Helicobacter pylori infection associates with an increased risk of colorectal polyps in African Americans. AB - BACKGROUND: Gastric Helicobacter pylori (H. pylori) infection and colorectal polyps are more prevalent in African Americans than in the general population. We aimed to investigate whether gastric H. pylori infection is associated with colorectal polyps in African Americans. METHODS: Medical records of African Americans, 40 years and older (n = 1256) who underwent bidirectional gastrointestinal endoscopy on the same day were reviewed. H. pylori status was assessed by immunohistochemistry on gastric specimens. Colorectal polyps were confirmed by histological examination of colorectal biopsies. A subset of serum samples from healthy and polyp-bearing patients (n = 163) were analyzed by ELISA for anti-H. pylori and anti-CagA antibodies. The crude and adjusted effect of H. pylori on the risk of colorectal adenoma and polyp were computed by logistic regression models. RESULTS: The prevalence of colorectal polyps and adenomas were 456 (36%) and 300 (24%) respectively. Colorectal polyps were more prevalent in gastric H. pylori infected than non-infected subjects [43% vs. 34%; Odds Ratio (OR) (95% CI): 1.5 (1.2-1.9), P = 0.001]. Patients with H. pylori-associated chronic active gastritis were at high risk to have adenomas [Unadjusted OR (95% CI): 1.3 (1.0-1.8); P = 0.04]. There was no difference in histopathology, size, or location of polyps with respect to H. pylori status. Gastric H. pylori infection, age, male gender and high risk clinical presentations were independent risk factors for colorectal polyps. Serological testing also revealed a higher prevalence of H. pylori and its toxin Cag-A in polyp patients vs. non polyp patients' sera, although in a non-statistically significant manner. CONCLUSIONS: This study showed that current gastric H. pylori infection is associated with an increased risk of colorectal polyps in African Americans. Patients with H. pylori induced gastritis may benefit from early screening colonoscopy as a preventative measure for colorectal cancer. PMID- 24774102 TI - Percutaneous left atrial appendage occlusion. PMID- 24774103 TI - REGICOR: 35 years of excellence in cardiovascular research. PMID- 24774104 TI - Impact of multidetector computed tomography noninvasive coronary angiography on epidemiology: toward direct evidence of cardiovascular risk. PMID- 24774105 TI - The role of carotid ultrasound in assessing carotid atherosclerosis in individuals at low-to-intermediate cardiovascular risk. AB - INTRODUCTION AND OBJECTIVES: Detection of carotid atherosclerosis might help to better identify individuals susceptible to cardiovascular events. We aimed to quantify the number of participants with carotid atherosclerosis and low-to intermediate cardiovascular risk according to the traditional risk factor scoring, and therefore with an elevated risk of cardiovascular events. METHODS: Cross-sectional, observational study performed during a cardiovascular screening program. From a total of 3778 volunteers, low-to-intermediate cardiovascular risk individuals (N=2354) were identified and studied. Physical examination, blood test, and carotid ultrasound followed standard procedures. Common, bulb, and internal carotid arteries were examined and common carotid intima-media thickness was measured. SCORE risk value was calculated for all participants. Univariate and multivariate statistical analysis was performed. RESULTS: Mean age of participants was 58.9 (15) years, 43.8% were men, 23.7% had hypertension, and 20.5% had hypercholesterolemia. The mean SCORE value was 1.47 (1.4). Both carotid intima-media thickness and the prevalence of carotid plaques increased steadily and significantly (P<.005) as advanced decades of life were analyzed. Variables significantly related with the presence of carotid atherosclerosis were age, male sex, and systolic blood pressure. Interestingly, 592 (25.1%) individuals were reclassified to a higher risk due to the presence of carotid atherosclerosis. CONCLUSIONS: There was a clear dissociation between cardiovascular risk scoring and the presence of atherosclerosis, because 1 of 4 study participants at low-to intermediate cardiovascular risk had carotid atherosclerosis. PMID- 24774106 TI - In-hospital mortality due to acute myocardial infarction. relevance of type of hospital and care provided. RECALCAR study. AB - INTRODUCTION AND OBJECTIVES: To investigate the relationship between in-hospital mortality due to acute myocardial infarction and type of hospital, discharge service, and treatment provided. METHODS: Retrospective analysis of 100 993 hospital discharges with a principal diagnosis of myocardial infarction in hospitals of the Spanish National Health Service. In-hospital mortality was adjusted for risk following the models of the Institute for Clinical Evaluative Sciences (Canada) and the Centers for Medicare & Medicaid Services (United States). RESULTS: Hospital characteristics are relevant to explain the variation in the individual probability of dying from myocardial infarction (median odds ratio: 1.3561). The risk-adjusted in-hospital mortality in cluster 3 and especially in cluster 4 hospitals (500 beds to 1000 beds and medium-high complexity) was significantly lower than in hospitals with less than 200 beds. Cluster 5 (more than 1000 beds), which includes a diverse group of hospitals, had a higher mortality rate than clusters 3 and 4. The adjusted mortality in the groups with the best and worst outcomes was 6.74% (cluster 4) and 8.49% (cluster 1), respectively. Mortality was also lower when the cardiology unit was responsible for the discharge or when angioplasty had been performed. CONCLUSIONS: The typology of the hospital, treatment in a cardiology unit, and percutaneous coronary intervention are significantly associated with the survival of a patient hospitalized for myocardial infarction. We recommend that the Spanish National Health Service establish health care networks that favor percutaneous coronary intervention and the participation of cardiology units in the management of patients with acute myocardial infarction. PMID- 24774107 TI - Effectiveness and safety of remote monitoring of patients with an implantable loop recorder. AB - INTRODUCTION AND OBJECTIVES: Implantable loop recorders have proven efficacy in the study of patients with syncope and palpitations. Remote monitoring of patients with pacemakers and implantable cardioverter-defibrillators has been shown to be safe and effective. The purpose of this study was to analyze the safety and effectiveness of remote monitoring in patients with an implantable loop recorder. METHODS: Retrospective observational study in which 109 patients with an implantable loop recorder were analyzed and 2 population groups were compared: 1 receiving conventional follow-up consisting of 3-monthly office visits (41 patients) and 1 with remote monitoring via monthly telephone transmissions and yearly visits (68 patients). The mean follow-up was 64 weeks (range, 0.57-164.57 weeks). The study analyzed diagnosis of a significant event, defined as any event that led to a therapeutic approach and explained the symptoms leading to the implant, as well as the mean time from implant to diagnosis and the specific treatment. RESULTS: A significant event was diagnosed in 82.6% of patients; of these, 54.4% had a normal electrocardiogram; 26.7%, asystole; 15.6%, tachycardia, and 3.3%, bradycardia. The mean time from implant to diagnosis was 260 days (range, 5-947 days) in conventional follow-up, compared with 56 days (range, 0-650 days) in patients with remote monitoring (P<.01), which led to targeted treatment in this group 187 days earlier, on average, with no secondary complications. CONCLUSIONS: Remote monitoring of patients with an implantable loop recorder can significantly shorten the time to diagnosis and targeted treatment, without adversely affecting patient safety. PMID- 24774109 TI - Spanish pacemaker registry. 10th official report of the Spanish Society of Cardiology Working Group on Cardiac Pacing (2012). AB - INTRODUCTION AND OBJECTIVES: Our aim was to analyze the pacemaker implantations and replacements reported to the Spanish Pacemaker Registry in 2012 with special reference to the selection of pacing modes. METHOD: The analysis was based on information provided by the European Pacemaker Patient Identification Card. RESULTS: Data were received from 115 hospitals, with a total of 12 856 cards. An estimated 745.8 pacemaker generators and 53.1 resynchronization devices were implanted per million population. Active fixation leads were implanted in more than 70% of the patients; of these leads, more than 20% were safe for use with magnetic resonance. The most common electrocardiographic indication for pacemaker implantation was atrioventricular block (56%). In all, 28% of the patients with sick sinus syndrome were paced in VVIR mode. CONCLUSIONS: The use of conventional pacemakers remained stable, whereas the implantation of resynchronization devices increased. Active fixation leads are now employed in most patients. The findings of this study confirm the higher incidence of implantation in men and at an earlier age due to the higher rate of conduction disorders. Age is a factor that influences the choice of the appropriate pacing mode. PMID- 24774110 TI - Spanish Heart Transplantation Registry. 24th official report of the Spanish Society of Cardiology Working Group on Heart Failure and Heart Transplantation (1984-2012). AB - INTRODUCTION AND OBJECTIVES: The present article reports the characteristics and results of heart transplantation in Spain since this therapeutic modality was first used in May 1984. METHODS: We summarize the main features of recipients, donors, and surgical procedures, as well as the results of all heart transplantations performed in Spain until December 31, 2012. RESULTS: A total of 247 heart transplantations were performed in 2012. The whole series consisted of 6775 procedures. Recent years have seen a progressive worsening in the clinical characteristics of recipients (34% aged over 60 years, 22% with severe kidney failure, 17% with insulin-dependent diabetes, 29% with previous heart surgery, 16% under mechanical ventilation) and donors (38% aged over 45 years, 26% with recipient: donor weight mismatch>20%), and in surgical conditions (29% of procedures at >4 h ischemia and 36% as emergency transplantations). The probability of survival at 1, 5, 10, and 15 years of follow-up was 78%, 67%, 53%, and 38%, respectively. These results have remained stable since 1995. CONCLUSIONS: In recent years, the number of heart transplantations/year in Spain has remained stable at around 250. Despite the worsening of recipient and donor clinical characteristics and of time-to-surgery, the results in terms of mortality have remained stable and compare favorably with those of other countries. PMID- 24774108 TI - In-hospital and mid-term predictors of mortality after transcatheter aortic valve implantation: data from the TAVI National Registry 2010-2011. AB - INTRODUCTION AND OBJECTIVES: The treatment of severe symptomatic aortic stenosis has been revolutionized by the technique of transcatheter valve replacement. The purpose of this study was to present the outcomes and predictors of mortality in patients enrolled between 2010 and 2011 in the Transcatheter Aortic Valve Replacement National Registry. METHODS: We collected 131 preprocedural, 31 periprocedural, and 76 follow-up variables, and analyzed the immediate implant success rate, the 30-day safety endpoint, and all-cause 30-day and mid-term (mean follow-up, 244 days) mortality. RESULTS: From January 2010 to December 2011, a total of 1416 patients were included: 806 with Edwards valves and 610 with CoreValves. The implant success and 30-day mortality rates were 94% and 8%, respectively, without differences between types of valves and approaches. The 30 day safety endpoint and mid-term mortality rates were 14% and 16%, respectively, which were also similar between groups. The presence of comorbidities (renal failure, peripheral vascular disease, ejection fraction, and atrial fibrillation), the need for conversion to surgery, and at least moderate aortic regurgitation after transcatheter aortic valve implantation were identified as independent predictors of in-hospital and mid-term mortality. CONCLUSIONS: The prognosis of valve implant patients could be improved by including comorbidities in patient selection and by minimizing the degree of residual aortic regurgitation to optimize the results of the procedure. PMID- 24774111 TI - Spanish Catheter Ablation Registry. 12th Official Report of the Spanish Society of Cardiology Working Group on Electrophysiology and Arrhythmias (2012). AB - INTRODUCTION AND OBJECTIVES: This article presents the findings of the 2012 Spanish Catheter Ablation Registry. METHODS: Data were collected in 2 ways: retrospectively using a standardized questionnaire, and prospectively using a central database. Each participating center selected its own preferred method of data collection. RESULTS: Seventy-four Spanish centers voluntarily contributed data to the survey. A total of 11 042 ablation procedures were analyzed, averaging 149 (103) per center. The 3 main conditions treated were atrioventricular nodal reentrant tachycardia (n=2842; 25.7%), cavotricuspid isthmus (n=2485; 23%), and accessory pathways (n=1999; 18%). Atrial fibrillation was the fourth most common substrate treated (n=1852; 17%), representing a slight increase. The number of ventricular arrhythmia ablation procedures was similar to that of 2011, but there was a decrease in procedures for ventricular tachycardia associated with postinfarction scarring. The overall success rate was 94.9%, major complications occurred in 1.9%, and the overall mortality rate was 0.04%. CONCLUSIONS: Data from the 2012 registry show that the number of ablations performed continued to increase. Overall, they also show a high success rate and a low number of complications. Ablation of complex substrates continued to increase, particularly in the case of atrial fibrillation. PMID- 24774112 TI - Giant aneurysm of the right coronary artery: a rare cause of atrial fibrillation. PMID- 24774113 TI - Dehiscence of an aortic valved conduit: a three-dimensional echocardiographic view. PMID- 24774114 TI - Unusual case of huge in-transit thrombus: a challenge for three-dimensional echocardiography. PMID- 24774115 TI - Revista espanola de cardiologia: keeping its finger on the pulse of the digital age. PMID- 24774116 TI - Preoperative levosimendan for right ventricular dysfunction before heart valve replacement surgery. PMID- 24774117 TI - Evaluation of cardiac (123)I-MIBG imaging in patients with severe left ventricular dysfunction and indication for implantable cardioverter defibrillator. PMID- 24774118 TI - Subcutaneous infusion of furosemide administered by elastomeric pumps for decompensated heart failure treatment: initial experience. PMID- 24774119 TI - Impact of assigning heart failure as the underlying cause of death on the calculation of premature mortality due to cardiovascular disease in Spain. PMID- 24774120 TI - Surgical treatment of organic and functional tricuspid valve disease. PMID- 24774121 TI - Sharing research data in cardiology. PMID- 24774122 TI - Detection of synovitis by ultrasonography in clinically inactive juvenile idiopathic arthritis on and off medication. AB - OBJECTIVES: To determine the prevalence of abnormalities detected by ultrasonography (US) in children with juvenile idiopathic arthritis (JIA) showing clinically inactive disease (ID) on medication and off medication. METHODS: INCLUSION CRITERIA: 1) JIA patients, 2) clinician-determined ID, 3) JIA drugs withdrawal or stably dosed modified anti-rheumatic drugs (DMARDs) therapy for at least 6 months prior to inclusion, 4) biologics naive patients. Clinical and US assessments were performed on 44 joints, which were scored for grey-scale (GS) synovitis and Power Doppler (PD) signal. PD signal inside intra-articular synovium or tendon sheath was considered as inflammatory activity. RESULTS: Thirty-four patients were included, of whom 23 patients were labelled as ID on medication and 11 patients without medication. The duration of the current episode of ID at the inclusion time was 9.5 months. Although it was longer for the group off medication there was no significant difference between the two groups (p=0.06). Thirteen patients presented US findings. Number of US-detected synovial abnormalities was higher in patients on medication, but there were no significant differences between both groups in the detection of GS synovitis (p=0.86), GS tenosynovitis (p=0.78) and PD signal (p=0.38). Out of 37 joints presenting US-determined GS-synovitis, 18 joints showed PD signal. CONCLUSIONS: Our study provides evidence of synovitis and tenosynovitis on B-mode US in JIA patients with clinical inactivity. In addition, inflammatory activity upheld by power-Doppler has been shown in a few joints from patients on medication. PMID- 24774123 TI - Learning clinical procedures through Internet visual resources: a qualitative study amongst undergraduate students. AB - OBJECTIVE: Acquiring competency in performing clinical procedures is central to professional education of healthcare providers. Internet visual resources (IVR), defined as visual materials openly accessible on public websites, provides a new channel to learn clinical procedures. This qualitative study aimed to profile the experience and opinions of undergraduate students (in dentistry, medicine and nursing) in learning clinical procedures through IVR. METHODS: From clinical degree programmes (Bachelor of Dental Surgery, Bachelor of Medicine, Bachelor of Surgery, and Bachelor of Nursing) of University of Hong Kong, 31 students were recruited to join six focus group discussions, which were transcribed and subjected to thematic analysis using inductive method, in which themes emerge from data. FINDINGS: Students actively looked for IVRs through various means and used them for pre-clinical preparation, post-clinical revision, learning simple and advanced procedures, exploring alternative and updated techniques, and benchmarking against international peers. IVRs were valued for their visual stimulation, inclusion of a wide variety of real-life cases, convenience in access, user-friendliness and time-saving features. Students tended to share and discuss IVRs with their peers rather than with tutors, even when contents deviated from school teaching or faculty's e-learning materials. When doubts persisted, they chose to follow faculty guidelines for examination purpose. Students were frustrated sometimes by difficulties in judging the scientific quality, lack of immediate interactive discussions and loosely structured presentations in some IVRs. Teachers' attitudes towards IVR appeared to vary greatly. CONCLUSION: Despite the wide spectrum of experience and opinions, IVR was generally viewed by undergraduates from across clinical faculties as enhancing their clinical confidence and self-perceived competency, enriching their learning experience and serving as an important supplement to formal learning in the planned curriculum. PMID- 24774124 TI - Novel roles of hypoxia response system in glucose metabolism and obesity. AB - Oxygen is essential for ATP production in mitochondria through oxidative phosphorylation. Metazoans are equipped with the hypoxia response system that includes hypoxia-inducible factor (HIF), prolyl hydroxylase domain protein (PHD), and von Hippel-Lindau ubiquitin ligase system to combat or adapt hypoxic conditions. PHD is an oxygen-sensing enzyme that is responsible for HIF-alpha hydroxylation and subsequent proteasomal degradation at normoxic conditions. In hypoxic conditions, PHD activity is inhibited and transcriptional activity of HIF is increased, resulting in the induction of a broad range of genes that are involved in glucose metabolism, angiogenesis, and erythropoiesis. A worldwide epidemic of obesity, a critical risk factor for diabetes and cardiovascular diseases, has led to intense studies on adipose tissue biology, which revealed that adipose tissue functions as an endocrine organ that affects the whole body. Recent studies also suggest that inflammation and hypoxia of adipose tissue that occur as adipose tissue mass expands play an important role in the development of insulin resistance, in which PHD/HIF pathway is critically involved. The PHD/HIF pathway may be an attractive and potential target for the treatment of obesity and associated diseases. PMID- 24774195 TI - Pharmacy practice and injection use in community pharmacies in Pokhara city, Western Nepal. AB - BACKGROUND: Community pharmacies in Nepal serve as the first point of contact for the public with the health care system and provide many services, including administering injections. However, there is a general lack of documented information on pharmacy practice and injection use in these pharmacies. This study aims to provide information about pharmacy practice in terms of service and drug information sources, and injection use, including the disposal of used injection equipment. METHODS: A mixed method, cross-sectional study was conducted in 54 community pharmacies in Pokhara city. Data was collected using a pre tested, semi-structured questionnaire, and also by the direct observation of pharmacy premises. Interviews with pharmacy supervisors (proprietors) were also conducted to obtain additional information about certain points. RESULTS: Interviews were carried out with 54 pharmacy supervisors/proprietors (47 males and 7 females) with a mean age and experience of 35.54 and 11.73 years, respectively. Approximately a half of the studied premises were operated by legally recognized pharmaceutical personnel, while the remainder was run by people who did not have the legal authority to operate pharmacies independently. About a quarter of pharmacies were providing services such as the administration of injections, wound dressing, and laboratory and consultation services in addition to medicine dispensing and counseling services. The 'Current Index of Medical Specialties' was the most commonly used source for drug information. Almost two-thirds of patients visiting the pharmacies were dispensed medicines without a prescription. Tetanus Toxoid, Depot-Medroxy Progesterone Acetate, and Diclofenac were the most commonly-used/administered injections. Most of the generated waste (including sharps) was disposed of in a municipal dump without adhering to the proper procedures for the disposal of hazardous waste. CONCLUSIONS: Community pharmacies in Pokhara offer a wide range of services including, but not limited to, drug dispensing, counseling, dressing of wounds, and administering injections. However, the lack of qualified staff and adequate infrastructure may be compromising the quality of the services offered. Therefore, the health authorities should take the necessary measures to upgrade the qualifications of the personnel and to improve the infrastructure for the sake of good pharmacy practice and the safer use of injections. PMID- 24774196 TI - Draining an anal abscess: the skeletal muscle rule. PMID- 24774217 TI - [Not Available]. PMID- 24774171 TI - Bacteriocin-encoding genes and ExPEC virulence determinants are associated in human fecal Escherichia coli strains. AB - BACKGROUND: A set of 1181 E. coli strains of human fecal origin isolated in the South Moravia region of the Czech Republic was collected during the years 2007 2010. Altogether, 17 virulence determinants and 31 bacteriocin-encoding genes were tested in each of them. RESULTS: The occurrence of bacteriocin-encoding genes was found to be positively correlated with the occurrence of E. coli virulence factors. Based on the presence of virulence factors and their combinations, E. coli strains were classified as non-pathogenic E. coli (n = 399), diarrhea-associated E. coli (n = 179) and ExPEC strains (n = 603). Non pathogenic and diarrhea-associated E. coli strains had a low frequency of bacteriocinogeny (32.6% and 36.9%, respectively). ExPEC strains encoding S fimbriae (sfa), P-fimbriae (pap) and having genes for aerobactin biosynthesis (aer, iucC), alpha-hemolysis (alpha-hly) and cytotoxic necrosis factor (cnf1) were often bacteriocinogenic (73.8%), had a high prevalence of bacteriocin multi producers and showed a higher frequency of genes encoding microcins H47, M, V, B17 and colicins E1, Ia and S4. CONCLUSIONS: The occurrence of bacteriocin encoding genes and ExPEC virulence determinants correlate positively in E. coli strains of human fecal origin. Bacteriocin synthesis appears to modulate the ability of E. coli strains to reside in the human intestine and/or the virulence of the corresponding strains. PMID- 24774218 TI - Down regulation of miR-143 is related with tumor size, lymph node metastasis and HPV16 infection in cervical squamous cancer. AB - OBJECTIVE: This study is to investigate the role of miR-143 expression in cervical squamous cell carcinoma (SCC). METHODS: The expression level of miR-143 was examined by quantitative real-time PCR. Human papillomavirus (HPV) genotype was detected by HPV genotype detection kit. The expression level of bcl-2 was detected by immunohistochemistry. RESULTS: The positive rate of HPV was 78% in the patients of cervical SCC. The most prevalent genotype was HPV16, with a positive rate of 42%. The expression level of miR-143 was significantly lower in the cervical SCC tissues than that in the normal cervical tissues (Z=-2.180, P=0.029). Down-regulated miR-143 expression was associated with tumor size, lymph node metastasis and HPV16 infection in cervical cancer patients. No significant associations were found between the expression levels of miR-143 and age, clinical stage, differentiation or lymph vascular space invasion. And, in cervical SCC patients after treatment with Taxol chemotherapy, the expression level of miR-143 was higher and the positive expression of bcl-2 protein was lower. However, the differences in expression changes of miR-143 and bcl-2 were not statistically significant (miR-143, Z=-0.763, P=0.446; bcl-2 protein, chi2=2.277, P=0.131). CONCLUSION: Down-regulated miR-143 is related with tumor size, lymph node metastasis and HPV16 infection in cervical SCC, but miR-143 does not participate in the Taxol sensitivity response. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1401279451112150. PMID- 24774219 TI - Particular distribution of the GJB2/GJB6 gene mutations in Mexican population with hearing impairment. AB - BACKGROUND: Hereditary sensorineural hearing loss (SNHL) is a genetically heterogeneous disorder worldwide. Mutations in the GJB2 gene are a frequent cause of hereditary SNHL. There is a prevalence of certain mutations in various populations which suggests that specific mutations may be influenced by ethnic background. OBJECTIVE: To analyze the prevalence of GJB2, GJB6 mutations in several geographic areas of Mexico in patients with hereditary SNHL. MATERIALS AND METHODS: One hundred and forty Mexican unrelated propositi with prelingual SNHL were included in the study. All patients had three previous generations born in Mexico and belonged to no specific ethnic group. Analyses of the GJB2 and GJB6 genes and mt.1555AG mutation was not detected. CONCLUSION: We found a great variety of mutations depending on the analyzed region in patients with SNHL; 57.86% of patients had affection in one or two alleles in GJB2 or GJB6 genes whereas 42.14% were wild type. In some cases, allele distribution depended on region. Molecular studies of more genes involved in hereditary non-syndromic SNHL are required to completely confirm the molecular basis of hearing loss in Mexican population. PMID- 24774220 TI - Audiological findings, genotype and clinical severity score in Cornelia de Lange syndrome. AB - OBJECTIVE: Cornelia de Lange syndrome (CdLS) is a rare multisystem disorder in which hearing loss (HL) has been reported. However, no data are available concerning the association between audiological findings, clinical severity score and genotype. METHODS: The study involved 44 pediatric patients aged 1-18 years with a confirmed diagnosis of CdLS, all of whom underwent a full otolaryngological and audiological examination. The presence of NIPBL and SMC1 mutations was also evaluated. RESULTS: According to the severity of clinical phenotypes, 12 (27.3%) children were mild, 15 (34.1%) were moderate and 17 (38.6%) were severe. Thirty-eight children (86%) had OME. Eight children had normal hearing, including one (12.5%) with a severe phenotype. Bilateral sensorineural hearing loss (SNHL) was diagnosed in 10 children (22.7%): the degree of HL was severe in 8 (80%), all with a severe phenotype. Conductive hearing loss (CHL) was present in 26 patients (59.1%), of whom 8 (30.8%) had a severe phenotype. A severe phenotype was more prevalent among the patients with moderate to severe HL (10/16, 62.5%) than among those with slight/mild HL or normal hearing (7/28, 25.0% p=0.013). NIPBL mutations were detected in 22 patients (50%): 13 (59.1%) with truncating mutations, four (18.2%) with missense mutations, and five (22.7%) with splicing mutations. The frequency of NIPBL truncating mutations was similar in the children with SNHL and those with CHL, whereas this kind of mutation was not found in children with normal hearing. CONCLUSION: Together with SNHL, CHL is an important cause of HL in children with CdLS, and can be associated with a severe phenotype. Moreover, CHL can be associated with NIPBL mutations, particularly truncating mutations. These results highlight the importance of the early identification of audiological problems in children with CdLS and their precise genetic characterization. PMID- 24774221 TI - Family communication and decision making at the end of life: a literature review. AB - OBJECTIVE: Patients and families coping with a terminal illness are faced with a number of decisions over the course of their disease. The role that family communication plays in the process of decision making is an important one. The objectives for this review are to examine the current state of empirical literature on the relationship between family communication and decision making about end-of-life care, to identify gaps, and to discuss implications for policy, practice, and future research. METHOD: Articles were identified using systematic keyword searches within the following relevant databases: Academic Search Complete, CINAHL Plus, Communications and Mass Media Complete, ERIC, PsychINFO, MEDLINE, SocINDEX, and ProQuest. RESULTS: The three bodies of relevant literature that emerged during this review include: (1) the importance of family communication at the end of life (EoL); (2) family decision making at the EoL; and (3) the interrelationship of communication (both within the family and with healthcare professionals) and decision making at the EoL. While the literature highlights the role of communication between medical professionals and the patient or family members, there is very little focus on the process of how family communication among the family members themselves contributes to decision making at the end of life. SIGNIFICANCE OF RESULTS: Barriers to end-of-life care are important considerations for helping patients to access timely and appropriate services. Understanding the pertinent role of family communication as it relates to the decision for EoL care is the first step in working to provide another avenue for overcoming these barriers. PMID- 24774222 TI - Ischemic memory imaging in nonhuman primates with echocardiographic molecular imaging of selectin expression. AB - BACKGROUND: Selectins are adhesion molecules that are expressed by the vascular endothelium upon activation and may be an imaging target for detecting myocardial ischemia long after resolution. The aim of this study was to test the hypothesis that molecular imaging of selectins with myocardial contrast echocardiographic (MCE) molecular imaging could be used to detect recent brief ischemia in closed chest nonhuman primates. METHODS: Myocardial ischemia was produced in anesthetized adult rhesus macaques (n = 6) by percutaneous balloon catheter occlusion of the left anterior descending or circumflex coronary artery for 5 to 10 min. Three separate macaques served as nonischemic controls. MCE perfusion imaging was performed during coronary occlusion to measure risk area and at 100 to 110 min to exclude infarction. MCE molecular imaging was performed at 30 and 90 min after reperfusion using a lipid microbubble bearing dimeric recombinant human P-selectin glycoprotein ligand-1 (MB-YSPSL). Collection of blood for safety data, electrocardiography, and echocardiography were performed at baseline and before and 10 min after each MB-YSPSL injection. RESULTS: Vital signs, oxygen saturation, electrocardiographic results, ventricular systolic function, pulmonary vascular resistance, and serum safety markers were unchanged by intravenous injection of MB-YSPSL. On echocardiography, left ventricular dysfunction in the risk area had resolved by 30 min, and there was no evidence of infarction on MCE perfusion imaging. On selectin-targeted MCE molecular imaging, signal enhancement was greater (P < .05) in the risk area than remote territory at 30 min (25 +/- 11 vs 11 +/- 4 IU) and 90 min (13 +/- 3 vs 3 +/- 2 IU) after ischemia. There was no enhancement (<1 IU) in control nonischemic subjects. CONCLUSIONS: In primates, MCE molecular imaging of selectins using MB-YSPSL, a recombinant ligand appropriate for humans, is both safe and effective for imaging recent myocardial ischemia. This technique may be useful for detecting recent ischemia in patients with chest pain even in the absence of necrosis. PMID- 24774223 TI - Mechanisms of QT prolongation during hypothermia. PMID- 24774225 TI - Cost-effectiveness and clinical implications of advanced bearings in total knee arthroplasty: a long-term modeling analysis. AB - BACKGROUND: Polyethylene (PE) wear is a major contributor to implant loosening following total knee arthroplasty (TKA). Advanced bearings are therefore required in TKA to reduce or eliminate wear-related loosening. A recently introduced bearing that combines oxidized zirconium with highly cross-linked PE has been shown to drastically reduce wear in in vitro settings, due to its improved tribological characteristics in both tibial and femoral components. However, there are no data on its cost-effectiveness. DATA AND METHODS: A Markov model was developed to assess the cost-effectiveness of this low-wear bearing from a German societal perspective. The model population was derived from a registry of 75,000 patients requiring TKA. The model allocated patients to receive either a low-wear or standard articulation, and followed them until death. Revisions and re revision were included. Input values were derived from registry databases or from published reports in the literature. Threshold analysis and probabilistic sensitivity analysis were conducted to estimate model robustness. RESULTS: The low-wear articulation prevented 24 (2.4 percent) revisions and 8 (0.8 percent) re revisions. The total incremental cost-effectiveness ratio (ICER) of the low-wear articulation was EUR 16,474 per quality-adjusted life-year (QALY). For patients aged less than 55 years, an ICER of EUR 653 per QALY was observed. For patients aged over 75 years, this value was EUR 83,300. Threshold and probabilistic sensitivity analysis indicated that these findings were reasonably robust. CONCLUSION: Low-wear articulations may be considered cost-effective, although the cost effectiveness is age-dependent, with the cost per QALY being significantly lower for younger people than for older people. PMID- 24774224 TI - Down-regulation of sirtuin 3 is associated with poor prognosis in hepatocellular carcinoma after resection. AB - BACKGROUND: Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically. METHODS: The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB). RESULTS: IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis. CONCLUSIONS: Down-regulation of intratumoral and peritumoral Sirt3 were both associated with poor outcome in HCC, moreover, intratumoral Sirt3 was a favorable prognostic predictor in early stage patients. PMID- 24774226 TI - Visual outcomes of phacoemulsification cataract surgery in horses: 1990-2013. AB - OBJECTIVE: To evaluate the long-term visual outcome of phacoemulsification lens extraction surgery in foals and horses and identify any unique postoperative complications that affect the visual outcome. PROCEDURE: This is a retrospective medical records study of phacoemulsification cataract surgery in 95 foals and horses from 1990 to 2013. RESULTS: Cataracts were removed by phacoemulsification from 111 eyes of 95 horses ranging in age from 22 days to 26 years (average 8.0 +/- 5.7 years). Forty-four of the 95 animals were foals (46.3%). Sixteen horses or foals had surgery bilaterally. One hundred and two eyes were blind preoperatively with 97 eyes (95.1%) having evidence of vision immediately postoperatively. Ninety of the 95 horses (94.7%) regained vision in the immediate postoperative period. Five horses did not recover vision postoperatively. Twenty four horses had cataracts associated with equine recurrent uveitis (ERU). Trauma was noted as the cause of cataract in 10 horses, and no specific cause for the cataract identified in 61 horses. The combined visual outcome data from horses with all types of cataracts (n = 95) found 83 (87.3%) horses to be visual <=1 month postoperatively, 47 (49.4%) horses visual for >1-6 months postoperatively, 33 (34.7%) horses visual from >6 to 12 months postoperatively, and 25 horses (26.3%) visual >24 months postoperatively. CONCLUSION: The results of phacoemulsification cataract surgery in horses indicate at least 26.3% of horses are still visual and able to continue their natural activity for 2 years or more postoperatively. PMID- 24774227 TI - A communication training perspective on AND versus DNR directives. AB - BACKGROUND: From a communication perspective, the term "do not resuscitate" (DNR) is challenging to use in end-of-life discussions because it omits the goals of care. An alternative, "Allow Natural Death" (AND), has been proposed as a better way of framing this palliative care discussion. CASE: We present a case where a nurse unsuccessfully discusses end-of-life goals of care using the term DNR. Subsequently, with the aid of a communication trainer, he is coached to successfully use the term "AND" to facilitate this discussion and advance his goal of palliative care communication and planning. DISCUSSION: We contrast the advantages and disadvantages of the term AND from the communication training perspective and suggest that AND-framing language replace DNR as a better way to facilitate meaningful end-of-life communication. One well-designed, randomized, controlled simulation study supports this practice. We also consider the communication implications of "natural" versus "unnatural" death. PMID- 24774228 TI - Comparison of the duration and power spectral changes of monopolar and bipolar M waves caused by alterations in muscle fibre conduction velocity. AB - The muscle compound action potential (M wave) recorded under monopolar configuration reflects both the propagation of the action potentials along the muscle fibres and their extinction at the tendon. M waves recorded under a bipolar configuration contain less cross talk and noise than monopolar M waves, but they do not contain the entire informative content of the propagating potential. The objective of this study was to compare the effect of changes in muscle fibre conduction velocity (MFCV) on monopolar and bipolar M waves and how this effect depends on the distance between the recording electrodes and tendon. The study was based on a simulation approach and on an experimental investigation of the characteristics of surface M waves evoked in the vastus lateralis during 4 s step-wise isometric contractions in knee extension at 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% MVC. The peak-to-peak duration (Durpp) and median frequency (Fmedian) of the M waves were calculated. For monopolar M waves, changes in Durpp and Fmedian produced by MFCV depended on the distance from the electrode to the tendon, whereas, for bipolar M waves, changes in Durpp and Fmedian were largely independent of the electrode-to-tendon distance. When the distance between the detection point and tendon lay between approximately 15 and 40mm, changes in Durpp of bipolar M waves were more pronounced than those of distal monopolar M waves but less marked than those of proximal monopolar M waves, and the opposite occurred for Fmedian. Since, for bipolar M waves, changes in duration and power spectral features produced by alterations in MFCV are not influenced by the electrode-to-tendon distance, the bipolar electrode configuration is a preferable choice over monopolar arrangements to estimate changes in conduction velocity. PMID- 24774256 TI - Abstracts, articles, citations. PMID- 24774257 TI - Platelet function and hyperglycemia in acute coronary syndrome. PMID- 24774258 TI - Comments on the 2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy. PMID- 24774259 TI - Subsequent full publication of abstracts presented in the annual meetings of the Spanish Society of Cardiology. AB - INTRODUCTION AND OBJECTIVES: The Spanish Society of Cardiology holds an annual national meeting with a large number of presentations but the number of full-text publications resulting from these presentations and the journals accepting these manuscripts is unknown. This study aimed to identify the full-text publication rate of accepted abstracts and to analyze the bibliometric features of subsequent publications. METHODS: We randomly selected a sample of 300 oral presentations at the meetings of the Spanish Society of Cardiology in 2002, 2005 and 2008. Subsequent publications were identified through the Science Citation Index Expanded, Scopus, Indice Medico Espanol, and Indice Bibliografico Espanol en Ciencias de la Salud. RESULTS: Of 300 abstracts, 115 resulted in 147 full publications, representing a publication rate of 38.33%. The meeting with the highest publication rate (43%) was held in 2005. The subject category with the highest number of publications was Pediatric Cardiology/Congenital Heart Disease (58.8%). Time to full publication was usually 2 years (30.61%). Articles were published in 57 journals. The journals publishing the highest number of articles were Revista Espanola de Cardiologia (n=55; 37.41%) and the European Heart Journal (n=8; 5.44%). CONCLUSIONS: The high percentage of articles published in the upper half of journals listed in Journal Citation Reports under the category of cardiac and cardiovascular system (83%) can be taken as an objective quality indicator of the results presented at these meetings. However, more than 60% of the abstracts did not result in full publications, thus depriving the scientific community of potentially interesting results. PMID- 24774260 TI - Effect of an optimized treatment with insulin on platelet reactivity after discharge in patients with an acute coronary syndrome and hyperglycemia. AB - INTRODUCTION AND OBJECTIVES: Intensive glucose control with insulin in patients with an acute coronary syndrome reduces platelet reactivity during hospitalization, compared to conventional control. However, the effect of strict, long-term glucose control on platelet reactivity in these patients remains uncertain. METHODS: This is a prospective, randomized trial evaluating the effects of optimized glucose control (target glucose, 80-120mg/dL) with insulin, compared with conventional control (target glucose, <180 mg/dL), on platelet reactivity after hospital discharge in patients with an acute coronary syndrome and hyperglycemia. The primary endpoint was assessment of platelet aggregation after stimulation with adenosine diphosphate 20 MUM at 12-month follow-up. RESULTS: One hundred four patients were randomized to optimized management (n=53) or conventional management (n=51). There were no differences between groups in baseline characteristics or platelet function. After 12 months of follow-up, blood glucose levels were significantly lower in the optimized treatment group (104 vs 119 mg/dL; P<.001). However, platelet aggregation following adenosine diphosphate 20 MUM stimulation showed no differences between the groups (54.2% [14.3%] vs 55.1% [18.3%] respectively; P=.81). There were no significant differences for other platelet function tests. CONCLUSIONS: Long-term optimized glucose control with insulin in patients with an acute coronary syndrome did not result in a reduction in platelet reactivity compared to conventional control. PMID- 24774261 TI - Sex-based differences in clinical features, management, and 28-day and 7-year prognosis of first acute myocardial infarction. RESCATE II study. AB - INTRODUCTION AND OBJECTIVES: To analyze sex-based differences in clinical characteristics, management, and 28-day and 7-year prognosis after a first myocardial infarction. METHODS: Between 2001 and 2003, 2042 first myocardial infarction patients were consecutively registered in 6 Spanish hospitals. Clinical characteristics, management, and 28-day case-fatality were prospectively recorded. Seven-year vital status was also ascertained by data linkage with the National Mortality Index. RESULTS: The registry included 449 women and 1593 men with a first myocardial infarction. Compared with men, women were older, had a higher prevalence of hypertension and diabetes, and were more likely to receive angiotensin-converting enzyme (ACE) inhibitors but were less likely to receive beta-blockers or thrombolysis. No differences were observed in use of invasive procedures. More women had non-ST-segment elevation and unclassified myocardial infarction than men (37.9% vs 31.3% and 9.8% vs 6.1%, respectively; both P<.001). Case-fatality at 28 days was similar in women and men (5.57% vs 4.46%; P=.39). After multivariate adjustment, the odds ratio of 28-day mortality for men was 1.06 (95% confidence interval: 0.49-2.27; P=.883) compared with women. After multivariate adjustment, men had higher 7-year mortality than women, hazard ratio 1.93 (95% confidence interval: 1.46-2.56; P<.001). CONCLUSIONS: There are demographic and clinical differences between men and women with a first myocardial infarction. The short-term prognosis of a first myocardial infarction in this century is similar in both sexes. However, the long-term vital prognosis after a first myocardial infarction is worse in men than in women. These results are observed in both ST-segment elevation myocardial infarction and non-ST segment elevation myocardial infarction events. PMID- 24774262 TI - Use of expert consensus to improve atherogenic dyslipidemia management. AB - INTRODUCTION AND OBJECTIVES: Although atherogenic dyslipidemia is a recognized cardiovascular risk factor, it is often underassessed and thus undertreated and poorly controlled in clinical practice. The objective of this study was to reach a multidisciplinary consensus for the establishment of a set of clinical recommendations on atherogenic dyslipidemia to optimize its prevention, early detection, diagnostic evaluation, therapeutic approach, and follow-up. METHODS: After a review of the scientific evidence, a scientific committee formulated 87 recommendations related to atherogenic dyslipidemia, which were grouped into 5 subject areas: general concepts (10 items), impact and epidemiology (4 items), cardiovascular risk (32 items), detection and diagnosis (19 items), and treatment (22 items). A 2-round modified Delphi method was conducted to compare the opinions of a panel of 65 specialists in cardiology (23%), endocrinology (24.6%), family medicine (27.7%), and internal medicine (24.6%) on these issues. RESULTS: After the first round, the panel reached consensus on 65 of the 87 items discussed, and agreed on 76 items by the end of the second round. Insufficient consensus was reached on 3 items related to the detection and diagnosis of atherogenic dyslipidemia and 3 items related to the therapeutic goals to be achieved in these patients. CONCLUSIONS: The external assessment conducted by experts on atherogenic dyslipidemia showed a high level of professional agreement with the proposed clinical recommendations. These recommendations represent a useful tool for improving the clinical management of patients with atherogenic dyslipidemia. A detailed analysis of the current scientific evidence is required for those statements that eluded consensus. PMID- 24774263 TI - Use of the radial approach in primary angioplasty: results in 1029 consecutive patients and analyses in unfavorable subgroups. AB - INTRODUCTION AND OBJECTIVES: The transradial approach is associated with a reduction in vascular access-related complications after primary percutaneous coronary interventions. The purpose of this study was to examine the feasibility of the routine use of transradial access in primary angioplasty and to evaluate how it affects subgroups with less favorable characteristics. METHODS: We analyzed 1029 consecutive patients with an ST-segment elevation acute coronary syndrome treated with primary angioplasty. RESULTS: Transradial access was the primary approach in 93.1% of the patients. The success rate of primary angioplasty was 95.9%, and 87.6% of the patients were event-free 30 days after the procedure. Crossover was required in 3.0% of the patients with primary transradial access, and this rate remained stable over the years. Predictors of the need for crossover were age older than 75 years (odds ratio=2.50, 95% confidence interval, 1.09-5.71; P=.03) and a history of ischemic heart disease (odds ratio=2.65; 95% confidence interval, 1.12-6.24; P=.02). Primary transfemoral access use was higher in women older than 75 years. Use of the transradial approach in this subgroup did not affect reperfusion time or the success of angioplasty, although there was a greater need for crossover (10.9% vs 2.6%; P=.006). Among patients in cardiogenic shock, the transradial approach was used in 51.5%; reperfusion times and angioplasty success rates were similar to those obtained with transfemoral access, but there was a greater need for crossover. CONCLUSIONS: Transradial access can be used safely and effectively in most primary angioplasty procedures. In older women and in patients in cardiogenic shock, there is a higher crossover requirement, with no detriment to reperfusion time. PMID- 24774264 TI - Prognostic value of NT-proBNP and an adapted monin score in patients with asymptomatic aortic stenosis. AB - INTRODUCTION AND OBJECTIVES: Our objective was to assess the prognostic value of NT-proBNP in patients with asymptomatic moderate/severe aortic stenosis and to validate an adapted Monin score using natriuretic peptide levels in our setting. METHODS: Prospective study of 237 patients with degenerative asymptomatic moderate/severe aortic stenosis. NT-proBNP was determined in all patients, who were then followed up clinically. The adapted Monin score was defined as follows: (peak velocity [m/s]*2)+(logn NT-proBNP*1.5)(+1.5 if woman). A clinical event was defined as surgery, hospital admission due to angina, heart failure or syncope, or death. RESULTS: A total of 51% were women, and the mean age was 74 years. Mean (SD) echocardiographic values were as follows: peak velocity 4.14 (0.87) m/s; mean gradient, 43.2 (16.0) mmHg; aortic valve area, 0.87 (0.72) cm(2), and aortic valve area index, 0.49 (0.14) cm(2)/m(2). The median NT-pro-BNP value was 490.0 [198.0-1312.0] pg/mL. There were 153 events during follow-up (median 18 months). The optimum NT-proBNP cut-point was 515 pg/mL, giving event-free survival rates at 1 and 2 years of 93% and 57%, respectively, in patients with NT-proBNP <515 pg/mL compared with 50% and 31% in those with NT-proBNP >515 pg/mL. Patients were divided into quartiles based on the Monin score. Event-free survival at 1 and 2 years was 87% and 79% in the first quartile, compared with 45% and 28% in the fourth quartile, respectively. CONCLUSIONS: NT-proBNP determination provides prognostic information in patients with asymptomatic moderate/severe aortic stenosis. The adapted Monin score is useful in our setting and allows a more precise prognosis than does the use of NT-proBNP alone. PMID- 24774266 TI - Delayed cardiac tamponade after stent fracture. PMID- 24774265 TI - 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. PMID- 24774267 TI - Symptomatic late-acquired coronary dissection: value of intracoronary images. PMID- 24774268 TI - Left atrial appendage aneurysm and atrial septal defect. PMID- 24774269 TI - Predictors of prolonged hospitalization in cardiology. PMID- 24774270 TI - Initial results from a national follow-up program to monitor radiation doses for patients in interventional cardiology. PMID- 24774271 TI - Do inappropriate implantable cardioverter-defibrillator shocks generate additional costs? PMID- 24774272 TI - Comparative results between metal stent and bioresorbable scaffold at two years postimplantation. PMID- 24774273 TI - Out-of-hospital cardiac arrest. The need for comprehensive information. PMID- 24774274 TI - Out-of-hospital cardiac arrest. The need for comprehensive information. Response. PMID- 24774275 TI - On the characteristics of out-of-hospital sudden cardiac death survivors. PMID- 24774276 TI - On the characteristics of out-of-hospital sudden cardiac death survivors. Response. PMID- 24774277 TI - Left stellate ganglion block in treating electrical storm. Importance of ultrasonography. PMID- 24774300 TI - Organic-inorganic hybrid hierarchical aluminum phenylphosphonate microspheres. AB - Organic-inorganic hybrid phenylphosphonates with hierarchical morphologies have attracted much attention due to their structural versatility for various applications including catalysis, adsorption, and biomedicals, however, so far there have been no reports of the synthesis and application of aluminum phenylphosphonate microspheres. Here, we report a hydrothermal method for the synthesis of the flower-like porous aluminum phenylphosphonate microspheres by using phenylphosphinic acid and aluminum nitrate as the precursors. The nano flakes formed in the initial growing stage are believed to play a key role in the formation of aluminum phenylphosphonate micro-flowers. The self-assembly of the flower-like microspheres has been identified to involve a two-stage growth process: a synergistic Ostwald ripening and oriented nanosheets attachment. The resultant aluminum phenylphosphonate micro-flowers can be easily converted to mesoporous amorphous aluminum phosphates by high temperature treatment without causing any morphology deterioration. The hierarchical aluminum phenylphosphonate microspheres have been applied to enrich peptide. This versatile synthesis method would enable to synthesize other metal phosphonates/phosphates spheres with interesting architecture for the potential application in catalysis, energy storage and nanomedicine. PMID- 24774299 TI - Day and night heat stress trigger different transcriptomic responses in green and ripening grapevine (vitis vinifera) fruit. AB - BACKGROUND: Global climate change will noticeably affect plant vegetative and reproductive development. The recent increase in temperatures has already impacted yields and composition of berries in many grapevine-growing regions. Physiological processes underlying temperature response and tolerance of the grapevine fruit have not been extensively investigated. To date, all studies investigating the molecular regulation of fleshly fruit response to abiotic stress were only conducted during the day, overlooking possible critical night specific variations. The present study explores the night and day transcriptomic response of grapevine fruit to heat stress at several developmental stages. Short heat stresses (2 h) were applied at day and night to vines bearing clusters sequentially ordered according to the developmental stages along their vertical axes. The recently proposed microvine model (DRCF-Dwarf Rapid Cycling and Continuous Flowering) was grown in climatic chambers in order to circumvent common constraints and biases inevitable in field experiments with perennial macrovines. Post-veraison berry heterogeneity within clusters was avoided by constituting homogenous batches following organic acids and sugars measurements of individual berries. A whole genome transcriptomic approach was subsequently conducted using NimbleGen 090818 Vitis 12X (30 K) microarrays. RESULTS: Present work reveals significant differences in heat stress responsive pathways according to day or night treatment, in particular regarding genes associated with acidity and phenylpropanoid metabolism. Precise distinction of ripening stages led to stage-specific detection of malic acid and anthocyanin-related transcripts modulated by heat stress. Important changes in cell wall modification related processes as well as indications for heat-induced delay of ripening and sugar accumulation were observed at veraison, an effect that was reversed at later stages. CONCLUSIONS: This first day - night study on heat stress adaption of the grapevine berry shows that the transcriptome of fleshy fruits is differentially affected by abiotic stress at night. The present results emphasize the necessity of including different developmental stages and especially several daytime points in transcriptomic studies. PMID- 24774301 TI - Good guy or bad guy: the opposing roles of microRNA 125b in cancer. AB - MicroRNAs (miRNAs) are a class of non-coding RNAs that post-transcriptionally silence target mRNAs. Dysregulation of miRNAs is a frequent event in several diseases, including cancer. One miRNA that has gained special interest in the field of cancer research is miRNA-125b (miR-125b). MiR-125b is a ubiquitously expressed miRNA that is aberrantly expressed in a great variety of tumors. In some tumor types, e.g. colon cancer and hematopoietic tumors, miR-125b is upregulated and displays oncogenic potential, as it induces cell growth and proliferation, while blocking the apoptotic machinery. In contrast, in other tumor entities, e.g. mammary tumors and hepatocellular carcinoma, miR-125b is heavily downregulated. This downregulation is accompanied by de-repression of cellular proliferation and anti-apoptotic programs, contributing to malignant transformation. The reasons for these opposing roles are poorly understood. We summarize the current knowledge of miR-125b and its relevant targets in different tumor types and offer several hypotheses for the opposing roles of miR-125b: miR 125b targets multiple mRNAs, which have diverse functions in individual tissues. These target mRNAs are tissue and tumor specifically expressed, suggesting that misregulation by miR-125b depends on the levels of target gene expression. Moreover, we provide several examples that miR-125b upregulation dictates oncogenic characteristics, while downregulation of miR-125b corresponds to the loss of tumor suppressive functions. Thus, in different tumor entities increased or decreased miR-125b expression may contribute to carcinogenesis. PMID- 24774303 TI - Physicians' knowledge and attitudes in the management of wound infection. AB - Despite consensus on the assessment and management of wound infection, there exist deficiencies in its recognition and management. A survey study involving 85 physicians and 3 other clinicians from across Canada was completed to determine current knowledge and attitude towards learning about topics relating to wound infection and its management. The results of the survey describe knowledge gaps and interests to develop expertise in the management of wound infection, suggesting a need for education on this subject. Low levels of current knowledge were reported for all biofilm-related topics. PMID- 24774302 TI - Methylation of leukocyte DNA and ovarian cancer: relationships with disease status and outcome. AB - BACKGROUND: Genome-wide interrogation of DNA methylation (DNAm) in blood-derived leukocytes has become feasible with the advent of CpG genotyping arrays. In epithelial ovarian cancer (EOC), one report found substantial DNAm differences between cases and controls; however, many of these disease-associated CpGs were attributed to differences in white blood cell type distributions. METHODS: We examined blood-based DNAm in 336 EOC cases and 398 controls; we included only high-quality CpG loci that did not show evidence of association with white blood cell type distributions to evaluate association with case status and overall survival. RESULTS: Of 13,816 CpGs, no significant associations were observed with survival, although eight CpGs associated with survival at p < 10-3, including methylation within a CpG island located in the promoter region of GABRE (p = 5.38 x 10-5, HR = 0.95). In contrast, 53 CpG methylation sites were significantly associated with EOC risk (p <5 x10-6). The top association was observed for the methylation probe cg04834572 located approximately 315 kb upstream of DUSP13 (p = 1.6 x10-14). Other disease-associated CpGs included those near or within HHIP (cg14580567; p =5.6x10-11), HDAC3 (cg10414058; p = 6.3x10-12), and SCR (cg05498681; p = 4.8x10-7). CONCLUSIONS: We have identified several CpGs in leukocytes that are differentially methylated by case-control status. Since a retrospective study design was used, we cannot differentiate whether DNAm was etiologic or resulting from EOC; thus, prospective studies of EOC-associated loci are the critical next step. PMID- 24774304 TI - Seroprevalence of Lawsonia intracellularis antibodies in intensive pig farms in China. AB - BACKGROUND: Porcine proliferative enteropathy caused by Lawsonia intracellularis (L. intracellularis) is a major concern to the pig industry worldwide. Although 8.3 billion pigs are produced each year in China, few reports on the prevalence of L.intracellularis infection are available. The aim of the current study was to estimate the seroprevalence of L. intracellularis antibodies in intensive pig farms in China. RESULTS: A total of 1060 serum samples were collected from 14 commercial pig farms located throughout China. Animals from all age groups were sampled including pre-weaning piglets, weaners, fattening pigs, adult sows and boars. Antibodies against L. intracellularis were detected using a specific blocking ELISA. Of the 1060 serum samples, 602 were identified as positive using the ELISA test. The apparent seroprevalence of L. intracellularis seropositivity was 57% (95% CI 50 to 64%). The true prevalence (that is, prevalence corrected for the imperfect sensitivity and specificity of the testing method) was 77% (95% CI 70 to 83%). CONCLUSIONS: The highest true prevalence was observed in sows and boars, suggesting that within a herd these stock classes are a reservoir for infection. The prevalence of L. intracellularis seropositivity in local breed pigs was significantly less than that in imported breeds. A higher seroprevalence was found in pigs in herds in Central and Northern China, which may correspond to the greater use of the intensive production systems in these areas. We conclude that L. intracellularis is widely prevalent in commercial pigs in China. PMID- 24774305 TI - Effect of ambrisentan on digital ulcers in systemic sclerosis: a case report. PMID- 24774327 TI - Engaging Community Health Centers (CHCs) in research partnerships: the role of prior research experience on perceived needs and challenges. AB - Despite community health centers' substantial role in local communities and in the broader safety-net healthcare system, very limited research has been conducted on community health center research experience, infrastructure, or needs from a national perspective. A national survey of 386 community health centers was conducted in 2011 and 2012 to assess research engagement among community health centers and their perceived needs, barriers, challenges, and facilitators with respect to their involvement in public health and health services research. This paper analyzes the differences between health centers that currently conduct or participate in research and health centers that have no prior research experience to determine whether prior research experience is indicative of different perceived challenges and research needs in community health center settings. PMID- 24774328 TI - Governance strategies for conducting text messaging interventions in clinical research. AB - There is increasing interest in medical text messaging interventions being used to achieve positive patient outcomes across a range of clinical research and health practice environments. Short messaging service (SMS) is a low-cost tool that provides an easy communication route to engage potentially broad populations through text messaging, and is part of the growing social trend toward increased adoption of personal communication technologies by patient populations. Testing the effectiveness and impact of various communication strategies requires navigation of a complex web of clinical and research regulations and oversight mechanisms. We describe a case study of the implementation of SMS to provide bidirectional communications between physicians and patients involved in routine care reminders to illustrate the review processes and governance structures needed. By mapping the regulatory and approval processes required to manage and steward a research study across clinical and community boundaries, we provide a guide for other translational health researchers who may utilize similar kinds of personally owned technology interventions as research tools. PMID- 24774352 TI - Older people's attitudes towards resuming driving in the first four months post stroke. AB - AIM: Little is known about how older people recovering from stroke perceive their return to driving, particularly in the early stages of recovery when they may receive driving information. METHODS: Semistructured interviews were conducted with 21 participants (52% female, mean age 74.5 years) within the first 16 weeks post-stroke, while inpatients in either acute or rehabilitation stroke wards. Interview data were analysed using content analysis. RESULTS: Three main themes emerged: 'driving as independence', 'emphasis on physical recovery', and 'limits on driving pre-stroke'. CONCLUSIONS: For the most part, driving was not a key consideration for participants during this phase of their recovery. Physical restrictions and confidence were seen as the main deterrent to driving post stroke; however, this varied according to gender. Driving information is generally not retained in the first four weeks of recovery post-stroke. This has implications for the content and timing of driving information given post-stroke. PMID- 24774351 TI - Behavioral health coaching for rural veterans with diabetes and depression: a patient randomized effectiveness implementation trial. AB - BACKGROUND: Depression and diabetes cause significant burden for patients and the healthcare system and, when co-occurring, result in poorer self-care behaviors and worse glycemic control than for either condition alone. However, the clinical management of these comorbid conditions is complicated by a host of patient, provider, and system-level barriers that are especially problematic for patients in rural locations. Patient-centered medical homes provide an opportunity to integrate mental and physical health care to address the multifaceted needs of complex comorbid conditions. Presently, there is a need to not only develop robust clinical interventions for complex medically ill patients but also to find feasible ways to embed these interventions into the frontlines of existing primary care practices. METHODS/DESIGN: This randomized controlled trial uses a hybrid effectiveness-implementation design to evaluate the Healthy Outcomes through Patient Empowerment (HOPE) intervention, which seeks to simultaneously address diabetes and depression for rural veterans in Southeast Texas. A total of 242 Veterans with uncontrolled diabetes and comorbid symptoms of depression will be recruited and randomized to either the HOPE intervention or to a usual-care arm. Participants will be evaluated on a host of diabetes and depression-related measures at baseline and 6- and 12-month follow-up. The trial has two primary goals: 1) to examine the effectiveness of the intervention on both physical (diabetes) and emotional health (depression) outcomes and 2) to simultaneously pilot test a multifaceted implementation strategy designed to increase fidelity and utilization of the intervention by coaches interfacing within the primary care setting. DISCUSSION: This ongoing blended effectiveness-implementation design holds the potential to advance the science and practice of caring for complex medically ill patients within the constraints of a busy patient-centered medical home. TRIAL REGISTRATION: Behavioral Activation Therapy for Rural Veterans with Diabetes and Depression: NCT01572389. PMID- 24774353 TI - The burden and trends of psychiatric co-morbidities amongst patients with cardiomyopathy. PMID- 24774354 TI - Renal sympathetic denervation with long steerable sheath and mapping system - first-in-man experience in three consecutive patients. PMID- 24774355 TI - Utility of three-dimensional global longitudinal strain of the right ventricle using transthoracic echocardiography for right ventricular systolic function in pulmonary hypertension. PMID- 24774356 TI - Recurrent pulmonary oedema after percutaneous radiofrequency renal denervation. PMID- 24774357 TI - Incidence of arrhythmias during dialysis in intensive-care-unit patients with end stage renal disease. PMID- 24774358 TI - Age- and sex-related differences in coronary plaque high-risk features in patients with acute coronary syndrome assessed by computed tomography angiography. PMID- 24774359 TI - A combination of left ventricular hypertrabeculation/noncompaction and muscular dystrophy in a stroke patient. PMID- 24774360 TI - The source of BNP in rheumatoid arthritis. PMID- 24774361 TI - CREB is activated in smooth muscle cells isolated from atherosclerotic plaques and reduces smooth muscle cell proliferation via p21-dependent mechanism. PMID- 24774362 TI - Reply to the Letter to the editor: "A comment on Thyrotoxic pericarditis". PMID- 24774363 TI - Net clinical benefit outcome should be standardized in trials evaluating antithrombotic drugs: the example of NOACs in atrial fibrillation. PMID- 24774364 TI - Cardioinhibitory vasovagal syncope in a cancer patient. PMID- 24774388 TI - Brugada syndrome and pregnancy: delving into the role of sex hormones in ion channelopathies. PMID- 24774365 TI - The cytosolic thiouridylase CTU2 of Arabidopsis thaliana is essential for posttranscriptional thiolation of tRNAs and influences root development. AB - BACKGROUND: A large number of post-transcriptional modifications of transfer RNAs (tRNAs) have been described in prokaryotes and eukaryotes. They are known to influence their stability, turnover, and chemical/physical properties. A specific subset of tRNAs contains a thiolated uridine residue at the wobble position to improve the codon-anticodon interaction and translational accuracy. The proteins involved in tRNA thiolation are reminiscent of prokaryotic sulfur transfer reactions and of the ubiquitylation process in eukaryotes. In plants, some of the proteins involved in this process have been identified and show a high degree of homology to their non-plant equivalents. For other proteins, the identification of the plant homologs is much less clear, due to the low conservation in protein sequence. RESULTS: This manuscript describes the identification of CTU2, the second CYTOPLASMIC THIOURIDYLASE protein of Arabidopsis thaliana. CTU2 is essential for tRNA thiolation and interacts with ROL5, the previously identified CTU1 homolog of Arabidopsis. CTU2 is ubiquitously expressed, yet its activity seems to be particularly important in root tissue. A ctu2 knock-out mutant shows an alteration in root development. CONCLUSIONS: The analysis of CTU2 adds a new component to the so far characterized protein network involved in tRNA thiolation in Arabidopsis. CTU2 is essential for tRNA thiolation as a ctu2 mutant fails to perform this tRNA modification. The identified Arabidopsis CTU2 is the first CTU2 type protein from plants to be experimentally verified, which is important considering the limited conservation of these proteins between plant and non plant species. Based on the Arabidopsis protein sequence, CTU2-type proteins of other plant species can now be readily identified. PMID- 24774389 TI - Is it possible to train non-cardiologists to perform echocardiography? PMID- 24774390 TI - Triple antithrombotic therapy: risky but sometimes necessary. PMID- 24774391 TI - The clinical significance of pregnancy in Brugada syndrome. AB - INTRODUCTION AND OBJECTIVES: Little is known about the risks and outcomes of pregnancy in women with Brugada syndrome. We therefore evaluated pregnancy outcomes and the influence of pregnancy in patients with Brugada syndrome. METHODS: A retrospective analysis was performed in all pregnant women with Brugada syndrome. We included 104 women with a total of 219 deliveries. RESULTS: There were 15 spontaneous abortions. One infant died suddenly during the night 3 months after birth. Six pregnant women reported they had experienced at least 1 syncope during the pregnancy. Of the 3 women who received an implantable cardioverter-defibrillator before the pregnancy, none received arrhythmia episodes. There were no events during the pregnancy in 4 patients with a previously aborted sudden cardiac death. Of 24 patients with syncope when not pregnant, 18 were asymptomatic and 6 experienced a recurrent syncope during the pregnancy. During the follow-up (mean follow-up 298.9 days; 95% confidence interval, 289.6-308.2), 2 women received appropriate shocks. CONCLUSIONS: In this retrospective, single-center study, serious events were not more frequent during pregnancy and the peripartum period in women with Brugada syndrome. The occurrence of syncope during pregnancy was not associated with a worst outcome in the peri- and postpartum periods or during follow-up. The reported rate of miscarriage and sudden infant death will require further studies to confirm or rule out its association with Brugada syndrome. PMID- 24774392 TI - Mid-term morbidity and mortality of patients after arterial switch operation in infancy for transposition of the great arteries. AB - INTRODUCTION AND OBJECTIVES: The arterial switch operation is currently the preferred surgical approach for complete transposition of the great arteries. We sought to determine the mid-term results of this intervention. METHODS: A single institution retrospective review of clinical records of all consecutive patients who underwent the arterial switch surgery between 1985 and 2010. RESULTS: Overall, the operation was performed on 155 patients (68% boys) at a median age of 13 days: 64% with an intact septum, 46% with a ventricular septal defect, and 4.5% with associated aortic arch anomaly. The usual coronary pattern was found in 63%. Palliative surgery was performed prior to arterial switch in 6.5%. In all, 137 perioperative survivors were followed for a median of 6 years. Late mortality was 2.9%, of which 50% was due to coronary complications. Eighteen percent required surgical and/or percutaneous reintervention: 95.6% for right-sided obstruction and 4.3% for aortic regurgitation. At last follow-up, 92% had functional class I symptoms and 95% were free of arrhythmias. The left ventricular ejection fraction was greater than 55% in 95%, 28% had neoaortic regurgitation (78% mild regurgitation), and 31% had right ventricular outflow tract obstruction with a mean gradient according to echocardiography greater than 25mmHg. CONCLUSIONS: Mid-term survival of patients after arterial switch operation is excellent and their functional status is good. However, a few patients have residual lesions and a need for further intervention during follow up, mostly for right-sided obstructions. Late mortality was uncommon and was related to coronary complications. Neoaortic root dilation and regurgitation are not major issues in early adulthood, but the long-term course of these lesions is still unknown. PMID- 24774393 TI - In-hospital pediatric cardiac arrest in Spain. AB - INTRODUCTION AND OBJECTIVES: The objective was to analyze the characteristics and prognostic factors of in-hospital pediatric cardiac arrest in Spain. METHODS: A prospective observational study was performed to examine in-hospital pediatric cardiac arrest. Two hundred children were studied, aged between 1 month and 18 years, with in-hospital cardiac arrest. Univariate and multivariate logistic regression analyses were performed to assess the influence of each factor on survival to hospital discharge. RESULTS: Return of spontaneous circulation was achieved in 74% of the patients and 41% survived to hospital discharge. The survival rate was significantly higher than that reported in a previous Spanish study 10 years earlier (25.9%). In the univariate analysis, the factors related to mortality were body weight higher than 10 kg; continuous infusion of vasoactive drugs prior to cardiac arrest; sepsis and neurological disorders as causes of cardiac arrest, the need for treatment with adrenaline, bicarbonate, and volume expansion, and prolonged cardiopulmonary resuscitation. In the multivariate analysis, the factors related to mortality were hematologic/oncologic diseases, continuous infusion of vasoactive drugs prior to cardiac arrest, cardiopulmonary resuscitation for more than 20 min, and treatment with bicarbonate and volume expansion. CONCLUSIONS: Survival after in-hospital cardiac arrest in children has significantly improved in recent years. The factors related to in-hospital mortality were hematologic/oncologic diseases, continuous infusion of vasoactive drugs prior to cardiac arrest, the duration of cardiopulmonary resuscitation, and treatment with bicarbonate and volume expansion. PMID- 24774394 TI - Has beta-blocker use increased in patients with heart failure in internal medicine settings? Prognostic implications: RICA registry. AB - INTRODUCTION AND OBJECTIVES: Underuse of beta-blockers has been reported in elderly patients with heart failure. The aim of this study was to evaluate the current prescription of beta-blockers in the internal medicine setting, and its association with morbidity and mortality in heart failure patients. METHODS: The information analyzed was obtained from a prospective cohort of patients hospitalized for heart failure (RICA registry] database, patients included from March 2008 to September 2011) with at least one year of follow-up. We investigated the percentage of patients prescribed beta-blockers at hospital discharge, and at 3 and 12 months, and the relationship of beta-blocker use with mortality and readmissions for heart failure. Patients with significant valve disease were excluded. RESULTS: A total of 515 patients were analyzed (53.5% women), with a mean age of 77.1 (8.7) years. Beta-blockers were prescribed in 62.1% of patients at discharge. A similar percentage was found at 3 months (65.6%) and 12 months (67.9%) after discharge. All-cause mortality and the composite of all-cause mortality and readmission for heart failure were significantly lower in patients treated with beta-blockers (hazard ratio=0.59, 95% confidence interval, 0.41-0.84 vs hazard ratio=0.64, 95% confidence interval, 0.49-0.83). This decrease in mortality was maintained after adjusting by age, sex, ejection fraction, functional class, comorbidities, and concomitant treatment. CONCLUSIONS: The findings of this study indicate that beta-blocker use is increasing in heart failure patients (mainly elderly) treated in the internal medicine setting, and suggest that the use of these drugs is associated with a reduction in clinical events. PMID- 24774395 TI - Update in cardiology: vascular risk and cardiac rehabilitation. AB - Cardiovascular disease develops in a slow and subclinical manner over decades, only to manifest suddenly and unexpectedly. The role of prevention is crucial, both before and after clinical appearance, and there is ample evidence of the effectiveness and usefulness of the early detection of at-risk individuals and lifestyle modifications or pharmacological approaches. However, these approaches require time, perseverance, and continuous development. The present article reviews the developments in 2013 in epidemiological aspects related to prevention, includes relevant contributions in areas such as diet, weight control methods (obesity is now considered a disease), and physical activity recommendations (with warnings about the risk of strenuous exercise), deals with habit-related psychosocial factors such as smoking, provides an update on emerging issues such as genetics, addresses the links between cardiovascular disease and other pathologies such as kidney disease, summarizes the contributions of new, updated guidelines (3 of which have recently been released on topics of considerable clinical importance: hypertension, diabetes mellitus, and chronic kidney disease), analyzes the pharmacological advances (largely mediocre except for promising lipid-related results), and finishes by outlining developments in the oft-neglected field of cardiac rehabilitation. This article provides a briefing on controversial issues, presents interesting and somewhat surprising developments, updates established knowledge with undoubted application in clinical practice, and sheds light on potential future contributions. PMID- 24774396 TI - 2013 update on congenital heart disease, clinical cardiology, heart failure, and heart transplant. AB - This article presents the most relevant developments in 2013 in 3 key areas of cardiology: congenital heart disease, clinical cardiology, and heart failure and transplant. Within the area of congenital heart disease, we reviewed contributions related to sudden death in adult congenital heart disease, the importance of specific echocardiographic parameters in assessing the systemic right ventricle, problems in patients with repaired tetralogy of Fallot and indication for pulmonary valve replacement, and confirmation of the role of specific factors in the selection of candidates for Fontan surgery. The most recent publications in clinical cardiology include a study by a European working group on correct diagnostic work-up in cardiomyopathies, studies on the cost effectiveness of percutaneous aortic valve implantation, a consensus document on the management of type B aortic dissection, and guidelines on aortic valve and ascending aortic disease. The most noteworthy developments in heart failure and transplantation include new American guidelines on heart failure, therapeutic advances in acute heart failure (serelaxin), the management of comorbidities such as iron deficiency, risk assessment using new biomarkers, and advances in ventricular assist devices. PMID- 24774397 TI - Invasive treatment of non-ST-segment elevation acute coronary syndrome: cardiac catheterization/revascularization for all? AB - Patients admitted to hospital with symptoms and signs of non-ST-segment elevation acute coronary syndromes have different risk profiles and are in need of an individualized approach that takes into consideration not only age and sex but also comorbidities such as diabetes, renal failure, hypertension, heart failure, peripheral artery disease, earlier revascularization, etc. According to evidence based medicine and as documented in current guidelines, there is currently evidence for early catheterization and, if feasible, revascularization in high risk patients, especially in men. Nevertheless, because of a lack of definitive evidence, there is uncertainty about treating women in the same way. Because women are usually older and have more comorbidities, they are frailer and revascularization should be indicated with greater caution. There is no evidence that catheterization as such is worse for women than for men; however, for both men and women with low risk, a less invasive approach, such as coronary computed tomography angiography, could be considered as a first diagnostic tool. PMID- 24774398 TI - Perforated aortic valve aneurysm due to infective endocarditis. PMID- 24774399 TI - Live embolism. PMID- 24774400 TI - Pulmonary hypertension in mitral stenosis: an optical coherence tomography study. PMID- 24774401 TI - Fatal bleedings with prasugrel as part of triple antithrombotic therapy. PMID- 24774402 TI - Histologic and angiographic imaging of acute shock dengue myocarditis. PMID- 24774403 TI - Percutaneous closure of iatrogenic aortopulmonary fistula using the Amplatzer Septal Occluder. PMID- 24774404 TI - Complex diagnosis of catecholaminergic polymorphic ventricular tachycardia. PMID- 24774406 TI - Home subcutaneous infusion of furosemide in advanced decompensated heart failure. PMID- 24774407 TI - Home subcutaneous infusion of furosemide in advanced decompensated heart failure. Response. PMID- 24774408 TI - Time since diabetes onset as a determining factor in platelet reactivity. PMID- 24774409 TI - Time since diabetes onset as a determining factor in platelet reactivity. Response. PMID- 24774412 TI - Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients - a retrospective study of clinical and tumor characteristics. AB - BACKGROUND: Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. METHODS: A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-). RESULTS: Patients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively. CONCLUSION: Our data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity. PMID- 24774413 TI - The influence of coping response and health-related quality of life on perceived social support during cancer treatment. AB - OBJECTIVE: In the biopsychosocial approach, perceived social support has served as a protective factor for psychological adjustment to cancer. This study aimed to determine the influence of different coping responses and health-related quality of life (HRQoL) domains on perceived social support during cancer treatment. METHOD: A cross-sectional analysis was carried out in a sample of 757 cancer outpatients. The Medical Outcomes Study Social Support Survey (MOS-SSS) was employed to assess perceived social support. The Mental Adjustment to Cancer (MAC) Scale measured coping response, and HRQoL was tested with the Medical Outcomes Study Short Form-36 (SF-36). Multivariate analyses were carried out to examine the extent to which coping and HRQoL were associated with perceived social support. RESULTS: Coping response explained only 2% of the variance in perceived social support, but Hopelessness had a significant influence on perceived social support (p <= 0.01). HRQoL, physical, and mental domains made a significant contribution toward perceived social support, accounting for around 10% of total variance. More than coping response, HRQoL's physical and mental domains had an important influence on perceived social support during cancer treatment. SIGNIFICANCE OF RESULTS: The findings of the current study report the importance of HRQoL domains in predicting perceived social support during cancer treatment, emphasizing the holistic and multidisciplinary approach to facilitate adjustment to cancer. PMID- 24774414 TI - How adolescent Japanese girls arrive at human papilloma virus vaccination: A semistructured interview study. AB - We examined the human papilloma virus (HPV) vaccination process in adolescent Japanese girls, including protective and obstructive factors to develop and practice enlightenment activities and educational interventions for promoting HPV vaccination to adolescent Japanese girls and their families. We conducted semistructured interviews with 20 adolescent Japanese girls who lived in the wider Tokyo area. To analyze the interview data, we adopted the modified grounded theory approach. We identified three stages in the vaccination process: first encounter with cervical cancer and HPV vaccine, thoughts about vaccination, and adjustment with parents toward vaccination. The girls "knew" their knowledge and information on cervical cancer and the HPV vaccine from experts, parents, and friends, "considered and discussed" HPV vaccination in their own way or with parents, and "arranged" actual vaccination. This process was influenced by the promoting/obstructive factors in each stage. Healthcare providers should understand the experiences and feelings of adolescent girls who were confronted with HPV vaccination in the context of their vaccination process and conduct enlightenment activities to promote vaccination, keeping the promoting and obstructive factors suggested in this study in mind. PMID- 24774415 TI - Engaging responsibly with social media: the BJUI guidelines. PMID- 24774435 TI - Could wild rabbits (Oryctolagus cuniculus) be reservoirs for Leishmania infantum in the focus of Madrid, Spain? AB - Xenodiagnosis has previously proved that hares (Lepus granatensis) from a focus of leishmaniasis in the southwestern Madrid region (Spain) are infective to Phlebotomus perniciosus, the only vector in the area, thus playing a probable role as active reservoirs in a sylvatic transmission cycle linked to the usual domestic one. Although actions have been taken to reduce the population of this lagomorph, a high population of wild rabbits (Oryctolagus cuniculus) is present in the area, which shows detectable anti-Leishmania infantum antibodies and a large number of individuals with DNA of this parasite. With the aim to elucidate the role of this lagomorph in the focus, xenodiagnostic studies carried out with wild rabbits captured in the area demonstrate that they are able to transmit L. infantum to P. perniciosus. Moreover, the study of blood meal preferences of P. perniciosus caught in the focus during and entomological survey shows strong evidence that rabbits are contributing to the maintenance of a high sand fly population in the area. These findings suggest that wild rabbits could play some role in Leishmania transmission. PMID- 24774436 TI - High rates of Leishmania infantum and Trypanosoma nabiasi infection in wild rabbits (Oryctolagus cuniculus) in sympatric and syntrophic conditions in an endemic canine leishmaniasis area: epidemiological consequences. AB - Leishmania infantum infection has been reported in various host species, both domestic and wild, in some cases with high prevalence rates. However, until the recent discovery of infected hares, no studies had provided clear evidence of any significant reservoir other than domestic dogs. Our focus was on another lagomorph, Oryctolagus cuniculus or wild rabbit. This species is native to the Iberian Peninsula and its presence and abundance gave rise to the name of Spain. In an endemic area for canine leishmaniasis in the southeast of Spain, 150 rabbits were captured over a period of three years. Samples of blood, bone marrow, liver, spleen, heart and skin were taken and analysed through parasitological, serological and molecular techniques in order to detect Leishmania and Trypanosoma. 20.7% of the rabbits were infected with L. infantum and 82.4% with Trypanosoma nabiasi, and 14.8% of mixed infections were detected. Both parasites were found in all the animal organs analysed, a factor which, along with the presence of serological cross-reactions, must be taken into account in epidemiological studies on leishmaniasis. O. cuniculus is an abundant and gregarious species, with a long enough average lifespan to ensure L. infantum transmission. The presence of the parasite in the skin and blood of these rabbits with no acute manifestation of disease ensures its contact with the vector, which finds in their warrens a suitable biotope to inhabit. The rabbit therefore seems to meet the most of conditions for being considered a reservoir host of L. infantum. PMID- 24774437 TI - Influence of posturographic platform biofeedback training on the dynamic balance of adult stroke patients. AB - The aim of the experiment was to analyze the influence of posturographic platform biofeedback training on the dynamic balance of patients who experienced ischemic stroke. The study included 21 patients treated at the Rehabilitation Center of the District Hospital in Bialogard, in the Ward of Neurological Rehabilitation with the Stroke Division. The age of the patients (11 in the experimental and 10 in the control group) ranged between 55 and 65 years. The level of dynamic balance was determined with Timed Up and Go Test. The experimental group was subjected to the biofeedback training, practicing maintenance of body balance (forced sway training) on posturographic platform for 15 consecutive days. The perception of dynamic balance in the group subjected to biofeedback training improved to a markedly greater extent (P < .05) as compared with conventionally rehabilitated group. Participation in biofeedback training exerted stronger effect on the dynamic balance of patients who experienced the stroke of the left hemisphere with right-sided hemiparesis than in those with right hemisphere stroke and left-sided hemiparesis. The utilization of feedback mechanisms during training on a posturographic platform can be reflected by enhanced stimulation and further improvement of the control of performed motor tasks. PMID- 24774438 TI - Activation of peroxisome proliferator-activated receptor beta/delta attenuates acute ischemic stroke on middle cerebral ischemia occlusion in rats. AB - BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-beta/delta is a transcription factor that belongs to the nuclear hormone receptor family. There is little information about the effects of the immediate administration of specific ligands of PPAR-beta/delta (GW0742) in animal models of acute ischemic stroke. Using a rat model of middle cerebral ischemia occlusion (MCAO) in vivo, we have investigated the effect of pretreatment with GW0742 before MCAO. METHODS: The neuroprotective effect of GW0742 against acute ischemic stroke was evaluated by the neurologic deficit score (NDS), dry-wet weight, and 2,3,5 triphenyltetrazolium chloride staining. The levels of interleukin (IL)-1beta, nuclear factor (NF)-kappaB, and tumor necrosis factor (TNF)-alpha were detected by an enzyme-linked immunosorbent assay. The expressions of inducible nitric oxide synthase (iNOS), Bax, and Bcl-2 were detected by Western blot. The apoptotic cells were counted by in situ terminal deoxyribonucleotidyl transferase mediated deoxyuridine triphosphate-biotin nick end labeling assay. RESULTS: The pretreatment with GW0742 significantly increased the expression of Bcl-2, and significantly decreased in the volume of infarction, NDS, edema, expressions of IL-1beta, NF-kappaB, TNFalpha, and Bax, contents of iNOS and the apoptotic cells in infarct cerebral hemisphere compared with rats in the vehicle group at 24 hours after MCAO. CONCLUSIONS: The study suggests the neuroprotective effect of the PPAR-beta/delta ligand GW0742 in acute ischemic stroke by a mechanism that may involve its anti-inflammatory and antiapoptotic action. PMID- 24774439 TI - The effects of exercise preconditioning on cerebral blood flow change and endothelin-1 expression after cerebral ischemia in rats. AB - Stroke is an acute cerebrovascular disease with high incidence, morbidity, and mortality. Preischemic treadmill training has been shown to be effective in improving behavioral and neuropathologic indices after cerebral ischemia. However, the exact neuroprotective mechanism of preischemic treadmill training against ischemic injury has not been elucidated clearly. The present study investigated whether preischemic treadmill training could protect the brain from ischemic injury via regulating cerebral blood flow (CBF) and endothelin 1 (ET-1). We analyzed the CBF by laser speckle imaging and ET-1 expression by an enzyme linked immunosorbent assay using an ischemic rat model with preischemic treadmill training. Generally speaking, ET-1 expression decreased and CBF increased significantly in the pretreadmill group. It is worth noting that ET-1 expression is increased at 24 hours of reperfusion in the pretreadmill group compared with the level of the time after middle cerebral artery occlusion. These changes were followed by significant changes in neurologic deficits and cerebral infarct volume. This study indicated that preconditioning exercise protected brain from ischemic injury through the improvement of CBF and regulation of ET-1 expression, which may be a novel component of the neuroprotective mechanism of preischemic treadmill training against brain injury. PMID- 24774440 TI - Stent placement for complex middle cerebral artery aneurysms. AB - BACKGROUND: To evaluate the safety and effectiveness of stent placement for ruptured or unruptured middle cerebral artery (MCA) aneurysms in a larger number. METHODS: Between October 2003 and December 2012, data for 70 patients with 72 complex MCA aneurysms treated with stents at our institution were retrospectively collected and analyzed. RESULTS: Eighty-five stents were successfully deployed in this series. However, failure of followed coiling was encountered in 2 (2.8%) tiny aneurysms of them. Of the 63 aneurysms treated with stent-assisted coiling, complete occlusion was achieved in 22 (34.9%), neck remnant in 15 (23.8%), and residual sac in 26 (36.5%). Of the 9 aneurysms treated with stent alone, the results were contrast stasis in 3 aneurysms and no change in 6. Procedure-related complications occurred in 9 (12.5%) procedures, including 7 of 27 (25.9%) with ruptured aneurysms and 2 of 45 (4.4%) with unruptured aneurysms, which resulted in 1 death and 5 disabilities. Univariate and multivariate analyses show that ruptured aneurysm is an independent factor for the outcome of these patients (odds ratio, 7.35; 95% confidence interval, 1.35-40.0). Angiographic follow-up results (mean, 10.5+/-8.8 months) showed that 72.1% (44 of 61) were completely occluded, 4.9% (3 of 61) recurred, and others were stable or had improved. Intrastent stenosis was observed in 1 (1.6%) patient, which was managed conservatively. During a clinical follow-up period ranging from 7 to 113 months (mean, 33.0+/-22.4 months), 1 disabled patient died from severe pneumonia, whereas the clinical status of the others had improved or was stable. Procedure related morbidity/mortality during the follow-up for the ruptured and unruptured groups were 3.7%/3.7% and 0/0, respectively. CONCLUSIONS: Our study shows that stent placement for the treatment of certain wide-neck MCA aneurysms is feasible, safe, and effective. However, stent placement for acutely ruptured MCA aneurysms harbors a much higher complication rate. PMID- 24774441 TI - Mdivi-1 prevents apoptosis induced by ischemia-reperfusion injury in primary hippocampal cells via inhibition of reactive oxygen species-activated mitochondrial pathway. AB - Apoptosis is one of the major mechanisms of neuronal injury during ischemic reperfusion (I/R). Mitochondrial division inhibitor (mdivi-1) is a selective inhibitor of mitochondrial fission protein Drp1. The previous experiments support that mdivi-1 reduce I/R injury in the heart model of rat, but the neuroprotective effect of the mdivi-1 is not yet clearly defined at the cellular levels in brain. In our present study, we estimated a brain model of I/R injury in vitro by subjecting oxygen and glucose deprivation (OGD) followed by reoxygenation to the cultured rat primary hippocampal cells, which aimed to find the neuroprotective mechanism of mdivi-1. The cell was pretreated with mdivi-1 for 40 minutes and then ischemia for 6 hours followed by reperfusion for 20 hours. The redox state, cell apoptosis, and expression of Drp1, Bcl-2, Bax, and cytochrome C proteins were measured. The data showed that administration of mdivi-1 at the doses of 50 MUM significantly reduced oxidative stress, attenuated cell apoptosis, upregulated Bcl-2 expression, and downregulated Drp1, Bax, and cytochrome C expression. The results suggested that mdivi-1 protected brain from OGD reperfusion injury, which through suppressing the ROS initiated mitochondrial pathway. PMID- 24774442 TI - Lack of influence of dyspareunia on the beneficial effect of intravaginal prasterone (dehydroepiandrosterone, DHEA) on sexual dysfunction in postmenopausal women. AB - INTRODUCTION: We have previously observed that intravaginal prasterone (dehydroepiandrosterone, DHEA) improved all domains of female sexual dysfunction (FSD). AIM: Investigate the influence of moderate/severe pain at sexual activity (dyspareunia) (MSD) at baseline on FSD following prasterone administration. METHODS: The effect of daily administration of prasterone (0, 3.25 mg, 6.5 mg or 13 mg) for 12 weeks on FSD in 215 postmenopausal women with or without MSD at baseline was evaluated in a prospective, randomized, double-blind, and placebo controlled phase III clinical trial. MAIN OUTCOME MEASURES: Differences were examined on desire, arousal and orgasm. RESULTS: Comparable benefits were observed in women not having MSD (n = 56) vs. those having MSD (n = 159). The benefits over placebo in prasterone-treated women for desire, avoiding intimacy and vaginal dryness as well as for the total sexual domain of the MENQOL (Menopause Specific Quality of Life) questionnaire, ranged between 18.0% and 38.2% with P values of <0.05 or <0.01 except in one out of 12 subgroups. For the arousal/sensation, arousal/lubrication and summary score of the ASF (Abbreviated Sexual Function) questionnaire, in the MSD+ group, improvements of 64.2% (P = 0.01), 118% (P = 0.001) and 31.1% (P = 0.03) were observed over placebo, respectively, while similar differences (58.0%, 67.6% and 32.1%) did not reach statistical significance in the MSD- group having up to only 44 prasterone treated women compared with 119 in the MSD+ group. CONCLUSIONS: No MSD at baseline does not apparently affect the effects of intravaginal prasterone on sexual dysfunction. Knowing the absence of significant effects of estrogens on FSD, the present data suggest that vulvovaginal atrophy (VVA) and vulvovaginal sexual dysfunction (VVSD) are two different consequences of sex steroid deficiency at menopause which can respond independently. In addition, the present data seriously question the justification of pain being part of FSD as well as the separation of FSD into separate domains. PMID- 24774443 TI - YB-1 promotes transcription of cyclin D1 in human non-small-cell lung cancers. AB - Cyclin D1, an oncogenic G1 cyclin, and YB-1, a transcription factor involved in cell growth, are both over-expressed in several human cancers. In human lung cancer, the functional association between YB-1 and cyclin D1 has never been elucidated. In this study, we show YB-1 is involved in the transcription of cyclin D1 in human lung cancer. Depletion of endogenous YB-1 by siRNA inhibited progression of G1 phase and down-regulated both the protein and mRNA levels of cyclin D1 in human lung cancer cells. Forced over-expression of YB-1 with a cyclin D1 reporter plasmid increased luciferase activity, and ChIP assay results showed YB-1 bound to the cyclin D1 promoter. Moreover, the amount of YB-1 mRNA positively correlated with cyclin D1 mRNA levels in clinical non-small-cell lung cancer (NSCLC) specimens. Immunohistochemical analysis also indicated YB-1 expression correlated with cyclin D1 expression in NSCLC specimens. In addition, most of the cases expressing both cyclin D1 and CDC6, another molecule controlled by YB-1, had co-existing YB-1 over-expression. Together, our results suggest that aberrant expression of both cyclin D1 and CDC6 by YB-1 over-expression may collaboratively participate in lung carcinogenesis. PMID- 24774444 TI - Transmission parameters estimated for Salmonella typhimurium in swine using susceptible-infectious-resistant models and a Bayesian approach. AB - BACKGROUND: Transmission models can aid understanding of disease dynamics and are useful in testing the efficiency of control measures. The aim of this study was to formulate an appropriate stochastic Susceptible-Infectious-Resistant/Carrier (SIR) model for Salmonella Typhimurium in pigs and thus estimate the transmission parameters between states. RESULTS: The transmission parameters were estimated using data from a longitudinal study of three Danish farrow-to-finish pig herds known to be infected. A Bayesian model framework was proposed, which comprised Binomial components for the transition from susceptible to infectious and from infectious to carrier; and a Poisson component for carrier to infectious. Cohort random effects were incorporated into these models to allow for unobserved cohort specific variables as well as unobserved sources of transmission, thus enabling a more realistic estimation of the transmission parameters. In the case of the transition from susceptible to infectious, the cohort random effects were also time varying. The number of infectious pigs not detected by the parallel testing was treated as unknown, and the probability of non-detection was estimated using information about the sensitivity and specificity of the bacteriological and serological tests. The estimate of the transmission rate from susceptible to infectious was 0.33 [0.06, 1.52], from infectious to carrier was 0.18 [0.14, 0.23] and from carrier to infectious was 0.01 [0.0001, 0.04]. The estimate for the basic reproduction ration (R0) was 1.91 [0.78, 5.24]. The probability of non detection was estimated to be 0.18 [0.12, 0.25]. CONCLUSIONS: The proposed framework for stochastic SIR models was successfully implemented to estimate transmission rate parameters for Salmonella Typhimurium in swine field data. R0 was 1.91, implying that there was dissemination of the infection within pigs of the same cohort. There was significant temporal-cohort variability, especially at the susceptible to infectious stage. The model adequately fitted the data, allowing for both observed and unobserved sources of uncertainty (cohort effects, diagnostic test sensitivity), so leading to more reliable estimates of transmission parameters. PMID- 24774469 TI - Observational studies using propensity score analysis underestimated the effect sizes in critical care medicine. AB - BACKGROUND AND OBJECTIVE: Propensity score (PS) analysis has been increasingly used in critical care medicine; however, its validation has not been systematically investigated. The present study aimed to compare effect sizes in PS-based observational studies vs. randomized controlled trials (RCTs) (or meta analysis of RCTs). METHODS: Critical care observational studies using PS were systematically searched in PubMed from inception to April 2013. Identified PS based studies were matched to one or more RCTs in terms of population, intervention, comparison, and outcome. The effect sizes of experimental treatments were compared for PS-based studies vs. RCTs (or meta-analysis of RCTs) with sign test. Furthermore, ratio of odds ratio (ROR) was calculated from the interaction term of treatment * study type in a logistic regression model. A ROR < 1 indicates greater benefit for experimental treatment in RCTs compared with PS based studies. RORs of each comparison were pooled by using meta-analytic approach with random-effects model. RESULTS: A total of 20 PS-based studies were identified and matched to RCTs. Twelve of the 20 comparisons showed greater beneficial effect for experimental treatment in RCTs than that in PS-based studies (sign test P = 0.503). The difference was statistically significant in four comparisons. ROR can be calculated from 13 comparisons, of which four showed significantly greater beneficial effect for experimental treatment in RCTs. The pooled ROR was 0.71 (95% CI: 0.63, 0.79; P = 0.002), suggesting that RCTs (or meta-analysis of RCTs) were more likely to report beneficial effect for the experimental treatment than PS-based studies. The result remained unchanged in sensitivity analysis and meta-regression. CONCLUSION: In critical care literature, PS-based observational study is likely to report less beneficial effect of experimental treatment compared with RCTs (or meta-analysis of RCTs). PMID- 24774470 TI - Latent class growth analysis successfully identified subgroups of participants during a weight loss intervention trial. AB - INTRODUCTION: Weight loss interventions often present small mean weight changes over time, despite the fact that a substantial proportion of the participants lost more weight. This effect is often leveled out by the substantial proportion of participants who gained weight during the trial. The aim of this study is to identify and describe distinct subgroups of participants with different weight change trajectories during and after a weight loss intervention. METHODS: We used data from a weight loss intervention that was part of a randomized controlled trial on the preventive effect of a tailor-made weight loss intervention and oral glucosamine sulfate on the incidence of knee osteoarthritis in 407 overweight women aged 50 to 60 years. Latent class growth analysis (LCGA) was used to identify subgroups of participants with different weight change trajectories over time. RESULTS: Using LCGA, we identified three subgroups with different trajectories of weight change, one large group (n = 298) with almost no change over time, and two smaller groups (both n = 48), of which one represents participants who steadily gained weight over time, whereas the other represents participants who steadily lost weight over time. Participants that had relatively low body weight around their 40th year of life and that gained weight in the year preceding the study were most likely to belong to the group that lost weight. CONCLUSION: LCGA was a suitable method to identify three distinct groups of participants with different trajectories of weight change. Low body weight at age 40 and weight gain in the year preceding the study were associated with a higher chance of membership of the group that lost weight. It seems weight loss that occurred during this weight loss intervention was mostly recently gained weight. PMID- 24774471 TI - A stepped wedge cluster randomized trial is preferable for assessing complex health interventions. PMID- 24774472 TI - Response to Rezaeian: Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) extension for ecological studies. PMID- 24774474 TI - Most domains of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 are reliable. AB - OBJECTIVES: The study's aim was to assess the internal reliability for the nine domains of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) to evaluate homogeneity across clinical studies and whether sample characteristics predict coefficient heterogeneity. STUDY DESIGN AND SETTING: A systematic literature review was undertaken. Internal reliability was assessed against Cronbach alpha coefficient >0.70. Reliability generalization was undertaken using fixed- and random-effects models. A weighted least squares regression model was applied to determine whether baseline sample characteristics (language, percentage of women, sample size, sample means and standard deviations, and cancer type) predicted variation in alpha coefficients. RESULTS: A total of 33 studies were identified. Eight domains demonstrated good internal reliability (unweighted/weighted by sample variance). One domain, Cognitive Functioning, consistently performed poorly. In terms of moderating variables, none of the sample characteristic variables explained sample variance for the Physical or Role Functioning domains. For the other domains, language, percentage of women, and sample means and variances accounted for some of the heterogeneity observed. CONCLUSION: Most domains on the EORTC QLQ-C30 are reliable and may therefore be used to help inform decision-making processes, such as those involving individual patients. PMID- 24774475 TI - Evidence, values, and decision making. AB - BACKGROUND: The evidence supporting the use of new, or established, interventions may be derived from either (or both) experimental or observational study designs. Although a rigorous examination of the evidence base for clinical and cost effectiveness is essential, it is never sufficient, and those undertaking a health technology assessment (HTA) also have to exercise judgments. METHODS: The basis for this discussion is largely from the author's experience as chairman of the national Institute for Health and Clinical Excellence (NICE). RESULTS: The judgments necessary for HTA to make are twofold. Scientific judgments relate to the interpretation of the science. Social value judgments are concerned with the ethical principles, preferences, culture, and aspirations of society. CONCLUSIONS: How scientific and social value judgments might be most appropriately captured is a challenge for all HTA agencies. Although competent HTA bodies should be able to exercise scientific judgments they have no legitimacy to impose their own social values. These must ultimately be informed by the general public. PMID- 24774473 TI - Validation of international algorithms to identify adults with inflammatory bowel disease in health administrative data from Ontario, Canada. AB - OBJECTIVE: Health administrative databases can be used to track disease incidence, outcomes, and care quality. Case validation is necessary to ensure accurate disease ascertainment using these databases. In this study, we aimed to validate adult-onset inflammatory bowel disease (IBD) identification algorithms. STUDY DESIGN AND SETTING: We used two large cohorts of incident patients from Ontario, Canada to validate algorithms. We linked information extracted from charts to health administrative data and compared the accuracy of various algorithms. In addition, we validated an algorithm to distinguish patients with Crohn's from those with ulcerative colitis and assessed the adequate look-back period to distinguish incident from prevalent cases. RESULTS: Over 5,000 algorithms were tested. The most accurate algorithm to identify patients 18 to 64 years at diagnosis was five physician contacts or hospitalizations within 4 years (sensitivity, 76.8%; specificity, 96.2%; positive predictive value (PPV), 81.4%; negative predictive value (NPV), 95.0%). In patients >=65 years at diagnosis, adding a pharmacy claim for an IBD-related medication improved accuracy. CONCLUSION: Patients with adult-onset incident IBD can be accurately identified from within health administrative data. The validated algorithms will be applied to administrative data to expand the Ontario Crohn's and Colitis Cohort to all patients with IBD in the province of Ontario. PMID- 24774476 TI - Survey to investigate pet ownership and attitudes to pet care in metropolitan Chicago dog and/or cat owners. AB - The aims of this descriptive cross-sectional study were to investigate dog and cat acquisition and attitudes toward pet care among residents of the Chicago area (zip codes 60600-60660); to compare data obtained from owners of shelter-acquired pets with those of residents who acquired their pets from other sources; to compare data from dog owners with cat owners; and to compare pet health practices among the respondents of different zip code income groups. In-person surveys administered at five pet store locations collected data from 529 respondents, representing 582 dogs and 402 cats owned or continuously cared for in the past 3 years. Median household income data for represented zip codes was also obtained. Shelters were the most common source of cats (p<0.01) and were the second most common source of dogs. Cats were more likely to have been acquired as strays, while dogs were more likely to have been acquired from friends/family/neighbors, pet stores, breeders or rescue organizations and to be kept as outdoor-only pets (p<0.01). More cats were kept per household than dogs (dogs mean=1.32/household; cats mean=1.78/household; p<0.01). Pet owners were most commonly 'very likely' (5 on a 1-5/5 Likert scale) to administer all hypothetical treatments discussed, although cat owners were less likely to spend time training their pet (p=0.05). Cat owners were less likely to have taken their pet to a veterinarian for vaccinations or annual physical exams (p<0.01). Shelter-acquired cats were significantly more likely to have been taken by their owners to the veterinarian for annual exams (p=0.05) than cats obtained as strays. Owners of shelter acquired pets were at least as willing as other respondents to administer hypothetical treatments and pay >=$1000 for veterinary treatment. Respondents from site #3 lived in zip codes that had relatively lower median household incomes (p<0.01) and were less likely to spend >=$1000 on their pets than those at the four other sites (p<0.01). Over 90% of pet owners from all acquisition categories expressed very high levels of attachment (>=8-10/10 on a Likert scale), except for owners of cats acquired as strays (84.9%) or from the 'other' category (75.0%). Survey respondents commonly acquired their pets from shelters and those who did were at least as willing to pay for and provide veterinary care as respondents who owned pets acquired from other sources. The data collected provides a snapshot of the attitudes of survey respondents in the Chicago area toward pet acquisition and care. PMID- 24774477 TI - Willingness to pay for contagious bovine pleuropneumonia vaccination in Narok South District of Kenya. AB - Contagious bovine pleuropneumonia (CBPP) is an economically important trans boundary cattle disease which affects food security and livelihoods. A conjoint analysis-contingent valuation was carried out on 190 households in Narok South District of Kenya to measure willingness to pay (WTP) and demand for CBPP vaccine and vaccination as well as factors affecting WTP. The mean WTP was calculated at Kenya Shillings (KSh) 212.48 (USD 3.03) for vaccination using a vaccine with the characteristics that were preferred by the farmers (preferred vaccine and vaccination) and KSh -71.45 (USD -1.02) for the currently used vaccine and vaccination. The proportion of farmers willing to pay an amount greater than zero was 66.7% and 34.4% for the preferred and current vaccine and vaccination respectively. About one third (33.3%) of farmers would need to be compensated an average amount of KSh 1162.62 (USD 13.68) per animal to allow their cattle to be vaccinated against CBPP using the preferred vaccine and vaccination. About two thirds (65.6%) of farmers would need to be compensated an average amount of KSh 853.72 (USD 12.20) per animal to allow their cattle to be vaccinated against CBPP using the current vaccine and vaccination. The total amount of compensation would be KSh 61.39 million (USD 0.88 million) for the preferred vaccine and vaccination and KSh 90.15 million (USD 1.29 million) for the current vaccine and vaccination. Demand curves drawn from individual WTP demonstrated that only 59% and 27% of cattle owners with a WTP greater than zero were willing to pay a benchmark cost of KSh 34.60 for the preferred and current vaccine respectively. WTP was negatively influenced by the attitude about household economic situation (p=0.0078), presence of cross breeds in the herd (p<0.0001) and years since CBPP had been experienced in the herd (p=0.0375). It was positively influenced by education (p=0.0251) and the practice of treating against CBPP (p=0.0432). The benefit cost ratio (BCR) for CBPP vaccination was 2.9-6.1 depending on the vaccination programme. In conclusion, although a proportion of farmers was willing to pay, participation levels may be lower than those required to interrupt transmission of CBPP. Households with characteristics that influence WTP negatively need persuasion to participate in CBPP vaccination. It is economically worthwhile to vaccinate against CBPP. A benefit cost analysis (BCA) using aggregated WTP as benefits can be used as an alternative method to the traditional BCA which uses avoided production losses (new revenue) and costs saved as benefits. PMID- 24774503 TI - The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases. AB - Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthropathies, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis, comprise a group of chronic disorders characterized by an immune-mediated pathogenesis. Although at clinical presentation these diseases appear unrelated, they have been recognized to share similar pathogenic mechanisms. Data from epidemiological and genetic studies further support the concept that IMIDs are interrelated, as they can co-occur in the same patient and share a similar genetic susceptibility. The specific aetiologies of IMIDs remain unknown, but all are known to involve dysregulation of the immune system, including an over-expression of the pro-inflammatory cytokine tumour necrosis factor (TNF). The pivotal role played by TNF in the pathogenesis and pathophysiology of IMIDs has been documented by extensive preclinical and clinical investigations, and confirmed by the efficacy of anti TNF biotechnological drugs, such as etanercept, infliximab and adalimumab, in the therapeutic management of these disorders. In this narrative review, we discuss the available data on the TNF-dependent pathogenesis of IMIDs and associations among the different disorders. Although much remains to be discovered about the pathogenesis and aetiology of IMIDs, their common inflammatory pathological features may explain why they can be successfully targeted by anti-TNF drugs. Among these, adalimumab, a fully human monoclonal antibody, has been approved for treatment of nine distinct IMID indications and it is likely to become a valuable therapeutic tool for this complex cluster of chronic inflammatory disorders. PMID- 24774504 TI - anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab. AB - The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs. PMID- 24774505 TI - Adalimumab in the treatment of immune-mediated diseases. AB - Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behcet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost effectiveness of this versatile TNF inhibitor. PMID- 24774506 TI - Pattern and predictors of maternal care-seeking practices for severe neonatal jaundice in Nigeria: a multi-centre survey. AB - BACKGROUND: Nigeria is frequently associated with disproportionately high rates of severe neonatal jaundice (NNJ) underpinned by widespread Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Timely and appropriate treatment of NNJ is crucial for preventing the associated morbidity and neuro-developmental sequelae. Since mothers are likely to be the first mostly to observe the onset of severe illness in their newborns, we set out to identify the pattern and predictors of maternal care-seeking practices for NNJ in three culturally-distinct settings in Nigeria. METHODS: A multi-centre study was conducted among women attending antenatal clinics in Abuja, Lagos and Port Harcourt from October 2011 to April 2012 using a pretested questionnaire. Predictors of awareness of NNJ, accurate recognition of NNJ, use of potentially harmful therapies and preference for future hospital treatment were determined with multivariate logistic regressions. RESULTS: Of the 488 participants drawn from the three locations, 431 (88.3%) reported awareness of NNJ, predominantly (57.8%) attributable to professional health workers. A total of 309 (63.3%) mothers with prior knowledge of NNJ claimed they could recognise NNJ, but 270 (87.4%) from this group accurately identified the features of NNJ. Multiparous mothers (Adjusted odds ratio, AOR:4.05; 95% CI:1.75-9.36), those with tertiary education (AOR:1.91; CI:1.01 3.61), and those residing in Lagos (AOR:2.96; CI:1.10-7.97) were more likely to have had prior knowledge of NNJ. Similarly, multiparous mothers (AOR:2.38; CI:1.27-4.46) and those with tertiary education (AOR:1.92; CI:1.21-3.05) were more likely to recognise an infant with jaundice accurately. Mothers educated by health workers were 40% less likely to resort to potentially harmful treatment for NNJ (AOR:0.60; CI:0.39-0.92) but more likely to seek hospital treatment in future for an infant suspected with jaundice (AOR:1.88; CI:1.20-2.95). CONCLUSIONS: Women with tertiary education and multiparous mothers who attend routine antenatal clinics are more likely than less educated women, to be associated with appropriate care-seeking practices for infants with NNJ regardless of the socio-cultural setting. Systematic efforts by professional health workers are warranted, as part of routine antenatal care, to engage other groups of mothers especially those likely to indulge in self-use of potentially harmful therapies. PMID- 24774508 TI - Sentinel lymph node mapping for defining site and extent of elective radiotherapy management of regional nodes in Merkel cell carcinoma: a pilot case series. AB - Merkel cell carcinoma is a rare and aggressive skin malignancy. We discuss sentinel lymph node mapping which is a valuable decision aid for radiotherapy management and planning of treatment volumes as illustrated by four cases. PMID- 24774509 TI - Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia. AB - BACKGROUND: Mercaptopurine (6-MP) plays a pivotal role in treatment of childhood acute lymphoblastic leukemia (ALL); however, interindividual variability in toxicity of this drug due to genetic polymorphism in 6-MP metabolizing enzymes has been described. We determined the prevalence of the major genetic polymorphisms in 6-MP metabolizing enzymes in Chilean children with ALL. METHODS: 103 Chilean pediatric patients with a confirmed diagnosis of ALL were enrolled. DNA was isolated from whole blood and genetic polymorphism in thiopurine S methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) coding genes were detected by polymorphism chain reaction-restriction fragment length (PCR-RFLP) assay. RESULTS: The total frequency of variant TPMT alleles was 8%. TPMT*2, TPMT*3A and TPMT*3B alleles were found in 0%, 7%, and 1% of patients, respectively. For ITPA, the frequency of P32T allele was 3%. We did not observe any homozygous variant for TPMT and ITPA alleles. We also analyzed a subgroup of 40 patients who completed the maintenance phase of ALL treatment, and we found that patients carrying a TPMT gene variant allele required a significantly lower median cumulative dosage and median daily dosage of 6-MP than patients carrying wild type alleles. CONCLUSION: TMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL. PMID- 24774511 TI - The effect of nutrition and metabolic status on the development of follicles, oocytes and embryos in ruminants. AB - The impact of nutrition and energy reserves on the fertility of ruminants has been extensively described. However, the metabolic factors and the molecular mechanisms involved in the interactions between nutrition and ovarian function are still poorly understood. These factors could be hormonal (either reproductive and/or metabolic) and/or dietary and metabolic (glucose, amino acids and fatty acids). In this review, we briefly summarize the impact of those nutrients (fatty acids, glucose and amino acids) and metabolic hormones (insulin/IGF-I, growth hormone, T3/4, ghrelin, apelin and the adipokines (leptin, adiponectin and resistin)) implicated in the development of ovarian follicles, oocytes and embryos in ruminants. We then discuss the current hypotheses on the mechanisms of action of these factors on ovarian function. We particularly describe the role of some energy sensors including adenosine monophosphate-activated kinase and peroxisome proliferator-activated receptors in the ovarian cells. PMID- 24774510 TI - Clinicopathological features and prognostic roles of KRAS, BRAF, PIK3CA and NRAS mutations in advanced gastric cancer. AB - BACKGROUND: RAS-RAF-MEK-ERK and PI3K-AKT pathways form a significant cascade for potential molecular target therapy in advanced cancer. The clinical significance of mutations in these genes in advanced gastric cancer (AGC) is uncertain. METHODS: We collected formalin-fixed, paraffin-embedded and fresh frozen tumor samples from AGC patients and analyzed the KRAS, NRAS, BRAF and PIK3CA mutations by direct-sequencing. We retrospectively investigated the clinicopathological features of these mutations in AGC patients, and selected patients with metastatic gastric cancer. RESULTS: Among 167 AGC patients, mutations of KRAS codons 12/13 (N = 8/164, 4.9%), PIK3CA (N = 9/163, 5.5%), and NRAS codon 12/13(N = 3/159, 1.9%) were detected. Comparison of the clinicopathological features of the mutated KRAS, PIK3CA, NRAS genes with an all-wild type of these genes showed that the frequency of the intestinal type was significantly higher in patients whose tumor tissue contained KRAS mutations (P = 0.014). Among 125 patients with metastatic gastric cancer, patients with NRAS codon 12/13 mutations in their tumors had shorter overall survival compared with NRAS wild-type patients (MST: 14.7 vs 8.8 months, P = 0.011). By multivariate analyses, NRAS codon 12/13 mutation was an indicator for poor prognosis in patients with metastatic gastric cancer (adjusted HR 5.607, 95% CI: 1.637-19.203). CONCLUSIONS: Our study indicated that mutations of KRAS, PIK3CA and NRAS were rare in AGC. NRAS mutations were likely to associate with poor prognosis in metastatic state of AGC patients, but further validation of other research is required. PMID- 24774512 TI - Awakening to the other: reflections on developing intercultural competence through an undergraduate study tour. AB - For the past 4 years, undergraduate students from the Faculty of Health, University of Newcastle, Newcastle, Australia, have undertaken a two week cultural study tour in Thailand, being exposed to a broad range of cultural interactions, health settings in rural and remote areas, and health-treatment approaches, including traditional and complementary therapies. Student evaluations and reflections were collected after the 2010 and 2011 study tours. This paper reports on findings following thematic analysis of the data, which identified central themes, including connectivity to others, "awakenings", "embodiment", and looking to the future. Findings included a recognition by students of a growth in awareness and change in perspective, which they felt would impact on their future approach in caring for patients from culturally- and linguistically-diverse backgrounds. We conclude that the study tour provided an effective way of sensitizing students to cultural differences and promoting cross cultural awareness. PMID- 24774513 TI - Differential proteomic analysis of grapevine leaves by iTRAQ reveals responses to heat stress and subsequent recovery. AB - BACKGROUND: High temperature is a major environmental factor limiting grape yield and affecting berry quality. Thermotolerance includes the direct response to heat stress and the ability to recover from heat stress. To better understand the mechanism of the thermotolerance of Vitis, we combined a physiological analysis with iTRAQ-based proteomics of Vitis vinifera cv Cabernet Sauvignon, subjected to 43 degrees C for 6 h, and then followed by recovery at 25/18 degrees C. RESULTS: High temperature increased the concentrations of TBARS and inhibited electronic transport in photosynthesis apparatus, indicating that grape leaves were damaged by heat stress. However, these physiological changes rapidly returned to control levels during the subsequent recovery phase from heat stress. One hundred and seventy-four proteins were differentially expressed under heat stress and/or during the recovery phase, in comparison to unstressed controls, respectively. Stress and recovery conditions shared 42 proteins, while 113 and 103 proteins were respectively identified under heat stress and recovery conditions alone. Based on MapMan ontology, functional categories for these dysregulated proteins included mainly photosynthesis (about 20%), proteins (13%), and stress (8%). The subcellular localization using TargetP showed most proteins were located in the chloroplasts (34%), secretory pathways (8%) and mitochondrion (3%). CONCLUSION: On the basis of these findings, we proposed that some proteins related to electron transport chain of photosynthesis, antioxidant enzymes, HSPs and other stress response proteins, and glycolysis may play key roles in enhancing grapevine adaptation to and recovery capacity from heat stress. These results provide a better understanding of the proteins involved in, and mechanisms of thermotolerance in grapevines. PMID- 24774534 TI - Schizosaccharomyces pombe centromere protein Mis19 links Mis16 and Mis18 to recruit CENP-A through interacting with NMD factors and the SWI/SNF complex. AB - CENP-A is a centromere-specific variant of histone H3 that is required for accurate chromosome segregation. The fission yeast Schizosaccharomyces pombe and mammalian Mis16 and Mis18 form a complex essential for CENP-A recruitment to centromeres. It is unclear, however, how the Mis16-Mis18 complex achieves this function. Here, we identified, by mass spectrometry, novel fission yeast centromere proteins Mis19 and Mis20 that directly interact with Mis16 and Mis18. Like Mis18, Mis19 and Mis20 are localized at the centromeres during interphase, but not in mitosis. Inactivation of Mis19 in a newly isolated temperature sensitive mutant resulted in CENP-A delocalization and massive chromosome missegregation, whereas Mis20 was dispensable for proper chromosome segregation. Mis19 might be a bridge component for Mis16 and Mis18. We isolated extragenic suppressor mutants for temperature-sensitive mis18 and mis19 mutants and used whole-genome sequencing to determine the mutated sites. We identified two groups of loss-of-function suppressor mutations in non-sense-mediated mRNA decay factors (upf2 and ebs1), and in SWI/SNF chromatin-remodeling components (snf5, snf22 and sol1). Our results suggest that the Mis16-Mis18-Mis19-Mis20 CENP-A-recruiting complex, which is functional in the G1-S phase, may be counteracted by the SWI/SNF chromatin-remodeling complex and non-sense-mediated mRNA decay, which may prevent CENP-A deposition at the centromere. PMID- 24774535 TI - Value of databases other than medline for rapid health technology assessments. AB - OBJECTIVES: The objective of this study was to explore the degree to which databases other than MEDLINE contribute studies relevant for inclusion in rapid health technology assessments (HTA). METHODS: We determined the extent to which the clinical, economic, and social studies included in twenty-one full and four rapid HTAs published by three Canadian HTA agencies from 2007 to 2012 were indexed in MEDLINE. Other electronic databases, including EMBASE, were then searched, in sequence, to assess whether or not they indexed studies not found in MEDLINE. Assessment topics ranged from purely clinical (e.g., drug-eluting stents) to those with broader social implications (e.g., spousal violence). RESULTS: MEDLINE contributed the majority of studies in all but two HTA reports, indexing a mean of 89.6 percent of clinical studies across all HTAs, and 88.3 percent of all clinical, economic, and social studies in twenty-four of twenty five HTAs. While EMBASE contributed unique studies to twenty-two of twenty-five HTAs, three rapid HTAs did not include any EMBASE studies. In some instances, PsycINFO and CINAHL contributed as many, if not more, non-MEDLINE studies than EMBASE. CONCLUSIONS: Our findings highlight the importance of assessing the topic specific relative value of including EMBASE, or more specialized databases, in HTA search protocols. Although MEDLINE continues to be a key resource for HTAs, the time and resource limitations inherent in the production of rapid HTAs require that researchers carefully consider the value and limitations of other information sources to identify relevant studies. PMID- 24774536 TI - The effect of Rho kinase inhibition on long-term keratinocyte proliferation is rapid and conditional. AB - INTRODUCTION: We previously demonstrated that the lifespan of primary human keratinocytes could be extended indefinitely by culture in the presence of the Rho kinase (ROCK) inhibitor Y-27632. This technique has proven to be very useful in diverse areas of basic and clinical research. METHODS: In this follow-up study we determine whether the continual presence of Y-27632 is required for sustained proliferation. We also test whether different ROCK inhibitors can be used for this technique and whether it can also promote indefinite proliferation of animal keratinocytes. We measure keratinocyte gene expression, proliferation, behaviour and lifespan in the presence and absence of Y-27632. RESULTS: We demonstrate that the extension of lifespan observed by culture of keratinocytes in the presence of fibroblast feeders and a ROCK inhibitor is reversible and that cells senesce gradually when the inhibitor is removed from the medium. Conversely, keratinocytes that are close to the end of their replicative life span can be revived by ROCK inhibition. We demonstrate that different inhibitors of ROCK can also efficiently extend the lifespan of human keratinocytes and that ROCK inhibition extends the lifespan of animal keratinocytes derived from mouse and bovine epithelia. Gene expression analysis of human epidermal keratinocytes cells grown in the presence of Y-27632 demonstrates that ROCK inhibition primarily inhibits keratinocyte differentiation. Live-imaging of keratinocytes cultured with ROCK inhibitors show that the effect of ROCK inhibition on cellular proliferation is immediate and ROCK inhibited cells proliferate rapidly without differentiation or stratification. CONCLUSIONS: ROCK inhibition rapidly and conditionally induces indefinite proliferation of keratinocytes. This method has far-reaching applications for basic research, as well as for regenerative and personalized medicine. PMID- 24774537 TI - Characteristics of compensated hypogonadism in patients with sexual dysfunction. AB - INTRODUCTION: In the last few years, a view that subclinical endocrine disorders represent milder forms of the clinically overt disease has emerged. Accordingly, it has been proposed that compensated hypogonadism represents a genuine clinical subset of late-onset hypogonadism. AIM: The aim of the present study is to investigate the associations of compensated hypogonadism with particular clinical and psychological characteristics of male subjects complaining of sexual dysfunction. METHODS: After excluding documented genetic causes of hypogonadism, an unselected consecutive series of 4,173 patients consulting our unit for sexual dysfunction was studied. Compensated hypogonadism was identified according to the European Male Ageing study criteria: total testosterone >=10.5 nmol/L and luteinizing hormone >9.4 U/L. MAIN OUTCOME MEASURES: Several hormonal, biochemical, and instrumental (penile Doppler ultrasound) parameters were studied, along with results of the Structured Interview on Erectile Dysfunction (SIEDY) and ANDROTEST. RESULTS: One hundred seventy (4.1%) subjects had compensated hypogonadism, whereas 827 (19.8%) had overt hypogonadism. After adjustment for confounding factors, no specific sexual symptoms were associated with compensated hypogonadism. However, compensated hypogonadism individuals more often reported psychiatric symptoms, as detected by Middlesex Hospital Questionnaire score, when compared with both eugonadal and overt hypogonadal subjects (adjusted odds ratios = 1.018 [1.005;1.031] and 1.014 [1.001;1.028], respectively; both P < 0.005). In addition, subjects with compensated or overt hypogonadism had an increased predicted risk of cardiovascular events (as assessed by Progetto Cuore risk algorithm) when compared with eugonadal individuals. Accordingly, mortality related to major adverse cardiovascular events (MACEs), but not MACE incidence, was significantly higher in subjects with both compensated and overt hypogonadism when compared with eugonadal subjects. CONCLUSIONS: The present data do not support the concept that compensated (subclinical) hypogonadism represents a new clinical entity. The possibility that subclinical hypogonadism could be a normal response of the hypothalamus-pituitary testis axis to somatic illness should be considered. Further studies are urgently needed to clarify this latter point. PMID- 24774538 TI - Targeting the PI3K/AKT/mTOR pathway in estrogen receptor-positive breast cancer. AB - Approximately 70-75% of breast cancers express the estrogen receptor (ER), indicating a level of dependence on estrogen for growth. Endocrine therapy is an important class of target-directed therapy that blocks the growth-promoting effects of estrogen via ER. Although endocrine therapy continues to be the cornerstone of effective treatment of ER-positive (ER+) breast cancer, many patients with advanced ER+ breast cancer encounter de novo or acquired resistance and require more aggressive treatment such as chemotherapy. Novel approaches are needed to augment the benefit of existing endocrine therapies by prolonging time to disease progression, preventing or overcoming resistance, and delaying the use of chemotherapy. The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a key intracellular signaling system that drives cellular growth and survival; hyperactivation of this pathway is implicated in the tumorigenesis of ER+ breast cancer and in resistance to endocrine therapy. Moreover, preclinical and clinical evidence show that PI3K/AKT/mTOR pathway inhibition can augment the benefit of endocrine therapy in ER+ breast cancer, from the first-line setting and beyond. This article will review the fundamental role of the PI3K/AKT/mTOR pathway in driving ER+ breast tumors, and its inherent interdependence with ER signaling. In addition, ongoing strategies to combine PI3K/AKT/mTOR pathway inhibitors with endocrine therapy for improved clinical outcomes, and methods to identify patient populations that would benefit most from inhibition of the PI3K/AKT/mTOR pathway, will be evaluated. PMID- 24774564 TI - Study of the cross-contamination and survival of Salmonella in fresh apples. AB - The present work aimed at studying the cross contamination of apples by Salmonella during the processing of commercial fresh apples and its survival capacity on apple at room temperature. For the first study, the typical process of fresh apples was simulated at laboratory scale in which an apple that was artificially contaminated by Salmonella at different concentration levels (8, 6 and 5 log cfu/apple) was introduced in one batch and processed including a simulated transport/washing step and drying step using sponges to simulate the porous material used in the industry. Results indicated that at 8 log cfu/apple, 50% fresh apples were contaminated after processing, with all analysed environmental samples being positive for the pathogen, consisting of washing water and sponges. However, at lower inoculum levels (5-6 log cfu/apple) no cross contamination was detected in apples, and only environmental samples showed contamination by Salmonella after processing including both water and sponges. Experiments on the survival of Salmonella on apple showed that the pathogen was capable to survive for 12 days, only showing a significant drop at the end of the experiment. Finally, two-class attribute sampling plans were assessed as tool to detect Salmonella in different contamination scenarios in fresh apple. This analysis indicated that with the highest inoculum level, a total of 16 apples would be needed to reach 95% of detecting Salmonella (i.e. lot rejection). In turn, when low levels were assessed (5-6 log cfu/apple), a large number of apples (n=1021) would have to be sampled to obtain the same confidence level (95%). If the environment is sampled (i.e. water and sponges), a lower number of samples would be needed to detect the pathogen. However, the feasibility of environmental sampling has not been assessed from a practical point of view. Overall, the results in this study evidenced that cross contamination by Salmonella might occur during processing of fresh apples and subsequently, the pathogen might survive for a noticeable period of time. PMID- 24774563 TI - Moving forward on facilitation research: response to changing environments and effects on the diversity, functioning and evolution of plant communities. AB - Once seen as anomalous, facilitative interactions among plants and their importance for community structure and functioning are now widely recognized. The growing body of modelling, descriptive and experimental studies on facilitation covers a wide variety of terrestrial and aquatic systems throughout the globe. However, the lack of a general body of theory linking facilitation among different types of organisms and biomes and their responses to environmental changes prevents further advances in our knowledge regarding the evolutionary and ecological implications of facilitation in plant communities. Moreover, insights gathered from alternative lines of inquiry may substantially improve our understanding of facilitation, but these have been largely neglected thus far. Despite over 15 years of research and debate on this topic, there is no consensus on the degree to which plant-plant interactions change predictably along environmental gradients (i.e. the stress-gradient hypothesis), and this hinders our ability to predict how plant-plant interactions may affect the response of plant communities to ongoing global environmental change. The existing controversies regarding the response of plant-plant interactions across environmental gradients can be reconciled when clearly considering and determining the species-specificity of the response, the functional or individual stress type, and the scale of interest (pairwise interactions or community-level response). Here, we introduce a theoretical framework to do this, supported by multiple lines of empirical evidence. We also discuss current gaps in our knowledge regarding how plant-plant interactions change along environmental gradients. These include the existence of thresholds in the amount of species specific stress that a benefactor can alleviate, the linearity or non-linearity of the response of pairwise interactions across distance from the ecological optimum of the beneficiary, and the need to explore further how frequent interactions among multiple species are and how they change across different environments. We review the latest advances in these topics and provide new approaches to fill current gaps in our knowledge. We also apply our theoretical framework to advance our knowledge on the evolutionary aspects of plant facilitation, and the relative importance of facilitation, in comparison with other ecological processes, for maintaining ecosystem structure, functioning and dynamics. We build links between these topics and related fields, such as ecological restoration, woody encroachment, invasion ecology, ecological modelling and biodiversity-ecosystem-functioning relationships. By identifying commonalities and insights from alternative lines of research, we further advance our understanding of facilitation and provide testable hypotheses regarding the role of (positive) biotic interactions in the maintenance of biodiversity and the response of ecological communities to ongoing environmental changes. PMID- 24774582 TI - Ultrasonography of the distal limbs in Nellore and Girolando calves 8 to 12 months of age. AB - BACKGROUND: Ultrasonography can be used anywhere and allows rapid, noninvasive differentiation of soft tissue structures of the musculoskeletal system. The objectives of this study were to describe the ultrasonographic appearance of the structures of the metacarpo-/metatarsophalangeal and the interphalangeal joints, the appearance of the growth plates of the distal metacarpus/metatarsus and of the proximal phalanx and to measure the cross-sectional dimensions of the DDFT and SDFT in Nellore and Girolando calves eight to 12 months of age. RESULTS: In the longitudinal dorsal view the common digital extensor tendon and the digital extensor tendon were depicted as echogenic parallel fiber bundles located directly under the skin. The joint spaces appeared as anechoic interruptions of the hyperechogenic bone surfaces. The normal amount of synovial fluid could not be depicted. The growth plates were seen as anechoic interruptions of the bone surface proximal and distal to the fetlock joint space. In transverse sonograms of the distal palmar/plantar regions, the flexor tendons and branchs of the suspensory ligament were imaged as echogenic structures. The lumen of the digital flexor tendon sheath could not be imaged in these normal cattle. The thin digital distal annular ligament and the reversal of positions of the DDFT and SDFT could be appreciated. No significant differences were found between the cross-sectional measurements of the DDFT and the SDFT from Nellore and Girolando in any age, thoracic/pelvic limbs, right/left sides and lateral/medial digits. CONCLUSIONS: The results of this study establish important ultrasonographic reference data of the normal structures of the distal limbs and the normal dimensions of the flexor tendons in Nellore and Girolando calves for use in clinical practice. PMID- 24774583 TI - A qualitative exploration of discharge destination as an outcome or a driver of acute stroke care. AB - BACKGROUND: Many patients with acute stroke do not receive recommended care in tertiary hospital settings. Allied health professionals have important roles within multidisciplinary stroke teams and influence the quality of care patients receive. Studies examining the role of allied health professionals in acute stroke management are scarce, and very little is known about the clinical decision making of these stroke clinicians. In this study we aimed to describe factors that influence the complex clinical decision making of these professionals as they prioritise acute stroke patients for recommended care. This qualitative study was part of a larger mixed methods study. METHODS: The qualitative methodology applied was a constructivist grounded theory approach.Fifteen allied health professionals working with acute stroke patients at three metropolitan tertiary care hospitals in South Australia were purposively sampled.Semi-structured interviews were conducted face to face using a question guide, and digital recording. Interviews were transcribed and analysed by two researchers using rigorous grounded theory processes. RESULTS: Our analysis highlighted 'predicted discharge destination' as a powerful driver of care decisions and clinical prioritisation for this professional group. We found that complex clinical decision making to predict discharge destination required professionals to concurrently consider patient's pre-stroke status, the nature and severity of their stroke, the course of their recovery and multiple factors from within the healthcare system. The consequences of these decisions had potentially profound consequences for patients and sometimes led to professionals experiencing considerable uncertainty and stress. CONCLUSIONS: Our qualitative enquiry provided new insights into the way allied health professionals make important clinical decisions for patients with acute stroke. This is the first known study to demonstrate that the subjective prediction of discharge destination made early in an acute admission by allied health professionals, has a powerful influence over the care and rehabilitation provided, and the ultimate outcomes for stroke patients. PMID- 24774584 TI - Sjogren's syndrome: another facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). AB - Recently, a new syndrome, namely the "Autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) has been defined. In this syndrome different conditions characterized by common signs and symptoms and induced by the presence of an adjuvant are included. The adjuvant is a substance capable of boosting the immune response and of acting as a trigger in the development of autoimmune diseases. Post-vaccination autoimmune phenomena represent a major issue of ASIA. Indeed, despite vaccines represent a mainstay in the improvement of human health, several of these have been implicated as a potential trigger for autoimmune diseases. Sjogren's Syndrome (SjS) is a systemic chronic autoimmune inflammatory disease characterized by the presence of an inflammatory involvement of exocrine glands accompanied by systemic manifestations. Own to the straight association between infectious agents exposure (mainly viruses) and sicca syndrome development, the possible link between vaccine and SjS is not surprising. Indeed, a few cases of SjS following vaccine delivery have been reported. At the same extent, the induction of SjS following silicone exposure has been described too. Thus, the aim of this review was to focus on SjS and its possible development following vaccine or silicone exposure in order to define another possible facet of the ASIA syndrome. PMID- 24774585 TI - First, let's see where we stand. Then, let's see how far we can or want to go. PMID- 24774586 TI - Improving knowledge of arterial resistant hypertension: what is relevant? PMID- 24774587 TI - Cooperative research in biomedicine. Spain's cardiovascular network, Red de Investigacion Cardiovascular. PMID- 24774589 TI - Resistant hypertension: demography and clinical characteristics in 6,292 patients in a primary health care setting. AB - INTRODUCTION AND OBJECTIVES: The prevalence of resistant hypertension has recently been reported, but there are no studies on its demography. This study aimed to examine the demography and clinical characteristics of resistant hypertension in a large sample of primary care patients. METHODS: A cross sectional study was performed of all computerized medical records of hypertensive patients in Health Area 6 of Madrid (Spain). Of 63 167 hypertensive patients, we selected 48 744 with prescription of antihypertensive medication; of these, we selected those who met the American Heart Association criteria for resistant hypertension. RESULTS: A total of 6292 patients had resistant hypertension, representing 9.9% of all hypertensive patients and 12.9% of those treated. A total of 5.5% were < 50 years (8.5% men and 3.2% women) and 24.7% were > 80 years (15.8% men and 31.4% women) (P < .001). In patients < 50 years, resistant hypertension was associated with male sex (odds ratio female/male = 0.006; 95% confidence interval, 0.000-0.042; P < .001), systolic blood pressure, obesity, stroke, and chronic kidney disease (P < .001). In those > 80 years, resistant hypertension was associated with female sex (odds ratio female/male = 1.27; 95% confidence interval, 1.08-1,10; P = .004), systolic blood pressure, diabetes mellitus, obesity, chronic kidney disease, coronary heart disease, and atrial fibrillation (P < .001). More than 50% of patients > 80 years with resistant hypertension had cardiovascular disease. CONCLUSIONS: One in 4 patients with resistant hypertension is > 80 years. Resistant hypertension is associated with cardiovascular disease, age < 50 years in men and age > 80 years in women. There is a high proportion of cardiovascular disease in elderly patients with resistant hypertension. PMID- 24774590 TI - Rationale and design of PICNIC study: nutritional intervention program in hospitalized patients with heart failure who are malnourished. AB - INTRODUCTION AND OBJECTIVES: Hospitalized patients with heart failure who are malnourished present a worse prognosis than those with an adequate nutritional status. It is unknown whether a nutritional intervention can modify the prognosis of these patients. The aim of this study is to assess the efficacy of a nutritional intervention on morbidity and mortality in hospitalized patients with heart failure who are malnourished. METHODS: PICNIC is a multicentre, randomized, controlled trial in which hospitalized patients with heart failure and malnutrition, as defined by the Mini Nutritional Assessment, are randomly assigned to conventional management of heart failure or conventional management of heart failure and an individualized nutritional intervention consisting of 3 points: optimization of diet, specific recommendations, and prescription, if deemed necessary, of nutritional supplements. A sample size of 182 patients for a maximum follow-up of 12 months has been estimated. The primary endpoint is time to death from any cause or rehospitalization because of heart failure. Analysis is by intention to treat. CONCLUSIONS: PICNIC study will determine the prognostic impact of a nutritional intervention in hospitalized patients with heart failure who are malnourished. PMID- 24774592 TI - Update on arrhythmias and cardiac pacing 2013. AB - This report discusses a selection of the most relevant articles on cardiac arrhythmias and pacing published in 2013. The first section discusses arrhythmias, classified as regular paroxysmal supraventricular tachyarrhythmias, atrial fibrillation, and ventricular arrhythmias, together with their treatment by means of an implantable cardioverter defibrillator. The next section reviews cardiac pacing, subdivided into resynchronization therapy, remote monitoring of implantable devices, and pacemakers. The final section discusses syncope. PMID- 24774593 TI - Update on interventional cardiology 2013. AB - The present article reviews the most important publications and studies in the field of interventional cardiology in 2013. Coronary interventions for ST-segment elevation myocardial infarction are among the most important, with studies that assess different devices and pharmacologic and mechanical strategies in primary angioplasty. Increasingly large groups of patients (with diabetes, of advanced age) and the best coronary revascularization strategy are also the focus of exhaustive research. Percutaneous procedures in the left main coronary artery continue to give rise to a significant number of publications, both because of the results of using different types of stent and because of the intravascular imaging techniques used to guide procedures and the results of their use. New bioabsorbable polymer-coated drug-eluting stents or bioresorbable drug-eluting scaffolds are being compared with second-generation drug-eluting stents to show their efficacy in preventing restenosis and reducing incidence of late thrombosis. Percutaneous treatment of structural heart disease continues to produce many publications, especially regarding percutaneous aortic prostheses, but also on closure of foramen ovale and of left atrial appendage. Finally, renal denervation continues to arouse much interest in the medical literature. PMID- 24774594 TI - Complementary, alternative, and putative nontroponin biomarkers of acute coronary syndrome: new resources for future risk assessment calculators. AB - Biomarkers, other than cardiac troponin, with potential sensitivity and selectivity that provide diagnostic and prognostic insights into the tissue specific injury processes underlying acute coronary syndrome and their possible use in risk stratification algorithms are discussed. Such biomarkers may be useful as complementary or alternative to cardiac troponin (I or T) assays in early diagnosis of acute coronary syndrome, as well as for monitoring acute coronary syndrome progression and prognosis assessment. The information included in this article is based on a critical analysis of selected published biomedical literature accessible through the United States National Library of Medicine's MEDLINE-PubMed and Scopus search engines. The majority of articles cited in this review and perspective, except for a few historical publications as background, were published between January 2000 and December 2013. PMID- 24774591 TI - Efficacy of an integrated hospital-primary care program for heart failure: a population-based analysis of 56,742 patients. AB - INTRODUCTION AND OBJECTIVES: The efficacy of heart failure programs has been demonstrated in clinical trials but their applicability in the real world practice setting is more controversial. This study evaluates the feasibility and efficacy of an integrated hospital-primary care program for the management of patients with heart failure in an integrated health area covering a population of 309,345. METHODS: For the analysis, we included all patients consecutively admitted with heart failure as the principal diagnosis who had been discharged alive from all of the hospitals in Catalonia, Spain, from 2005 to 2011, the period when the program was implemented, and compared mortality and readmissions among patients exposed to the program with the rates in the patients of all the remaining integrated health areas of the Servei Catala de la Salut (Catalan Health Service). RESULTS: We included 56,742 patients in the study. There were 181,204 hospital admissions and 30,712 deaths during the study period. In the adjusted analyses, when compared to the 54,659 patients from the other health areas, the 2083 patients exposed to the program had a lower risk of death (hazard ratio=0.92 [95% confidence interval, 0.86-0.97]; P=.005), a lower risk of clinically-related readmission (hazard ratio=0.71 [95% confidence interval, 0.66 0.76]; P<.001), and a lower risk of readmission for heart failure (hazard ratio=0.86 [95% confidence interval, 0.80-0.94]; P<.001). The positive impact on the morbidity and mortality rates was more marked once the program had become well established. CONCLUSIONS: The implementation of multidisciplinary heart failure management programs that integrate the hospital and the community is feasible and is associated with a significant reduction in patient morbidity and mortality. PMID- 24774595 TI - Antidromic tachycardia secondary to accessory pathway ablation. PMID- 24774596 TI - A serious complication in a patient with a ventricular assist device. PMID- 24774597 TI - Myocardial hypoperfusion in acute aortic dissection. PMID- 24774598 TI - Patent foramen ovale causing severe hypoxemia due to right-to-left shunting in patients without pulmonary hypertension. Clinical suspicion clues for diagnosis and treatment. PMID- 24774599 TI - Differences in the prevalence of complex aortic atheromatosis by type of stroke. PMID- 24774600 TI - Transcatheter aortic valve replacement with a balloon-expandable valve for the treatment of noncalcified bicuspid aortic valve disease. PMID- 24774601 TI - Initiation of an inter-hospital ECMO transfer program for patients suffering from severe acute heart and/or pulmonary failure. PMID- 24774588 TI - Prevalence of atrial fibrillation in Spain. OFRECE study results. AB - INTRODUCTION AND OBJECTIVES: Atrial fibrillation is associated with substantial morbidity and mortality and both its incidence and prevalence are high. Nevertheless, comprehensive data on this condition in Spain are lacking. The aim of this study was to estimate the prevalence of atrial fibrillation in Spain. METHODS: A cross-sectional study was conducted in the general Spanish population older than 40 years. Two-stage random sampling was used, in which first-stage units were primary care physicians randomly selected in every Spanish province and second-stage units were 20 randomly selected persons drawn from each participating physician's assigned population. The reported prevalence was standardized for the age and sex distribution of the Spanish population. The electrocardiogram recordings were read centrally. RESULTS: Overall, 8343 individuals were evaluated. The mean age was 59.2 years (95% confidence interval, 58.6-59.8 years), and 52.4% of the participants were female. The overall age adjusted prevalence of atrial fibrillation was 4.4% (95% confidence interval, 3.8 5.1). Prevalence was similar in both sexes, men 4.4% (3.6-5.2) and women 4.5% (3.6-5.3), rising with increasing age older than 60 years. In patients older than 80 years, the prevalence was 17.7% (14.1-21.3). In 10% of patients an unknown atrial fibrillation was diagnosed. CONCLUSIONS: The prevalence of atrial fibrillation in the general Spanish population older than 40 years is high, at 4.4%. The prevalence is similar in both sexes and rises steeply above 60 years of age. It is estimated that there are over 1 million patients with atrial fibrillation in the Spanish population, of whom over 90,000 are undiagnosed. PMID- 24774603 TI - Emergency physicians also knocking on the door of echocardiography. Response. PMID- 24774604 TI - Emergency physicians also knocking on the door of echocardiography. PMID- 24774605 TI - Usefulness of genetic diagnosis in a woman with hypertrophic cardiomyopathy and the desire for motherhood: information is key. PMID- 24774606 TI - Usefulness of genetic diagnosis in a woman with hypertrophic cardiomyopathy and the desire for motherhood: information is key. Response. PMID- 24774619 TI - Radiographer commenting of trauma radiographs: a survey of the benefits, barriers and enablers to participation in an Australian healthcare setting. AB - INTRODUCTION: Radiographer abnormality detection systems that highlight abnormalities on trauma radiographs ('red dot' system) have been operating for more than 30 years. Recently, a number of pitfalls have been identified. These limitations initiated the evolution of a radiographer commenting system, whereby a radiographer provides a brief description of abnormalities identified in emergency healthcare settings. This study investigated radiographers' participation in abnormality detection systems, their perceptions of benefits, barriers and enablers to radiographer commenting, and perceptions of potential radiographer image interpretation services for emergency settings. METHODS: A cross-sectional survey was implemented. Participants included radiographers from four metropolitan hospitals in Queensland, Australia. Conventional descriptive statistics, histograms and thematic analysis were undertaken. RESULTS: Seventy three surveys were completed and included in the analysis (68% response rate); 30 (41%) of respondents reported participating in abnormality detection in 20% or less of examinations, and 26(36%) reported participating in 80% or more of examinations. Five overarching perceived benefits of radiographer commenting were identified: assisting multidisciplinary teams, patient care, radiographer ability, professional benefits and quality of imaging. Frequently reported perceived barriers included 'difficulty accessing image interpretation education', 'lack of time' and 'low confidence in interpreting radiographs'. Perceived enablers included 'access to image interpretation education' and 'support from radiologist colleagues'. CONCLUSIONS: A range of factors are likely to contribute to the successful implementation of radiographer commenting in addition to abnormality detection in emergency settings. Effective image interpretation education amenable to completion by radiographers would likely prove valuable in preparing radiographers for participation in abnormality detection and commenting systems in emergency settings. PMID- 24774620 TI - Re-rupture rate of primarily repaired distal biceps tendon injuries. AB - BACKGROUND: Distal biceps tendon rupture is a common injury, and primary repair results in excellent return of function and strength. Complications resulting from distal biceps tendon repairs are well reported, but the incidence of re ruptures has never been investigated. METHODS: A search of the Mayo Clinic's Medical/Surgical Index was performed, and all distal biceps tendon repairs from January 1981 through May 2009 were identified. All patients who completed 12 months or more of follow-up were included. All charts were reviewed and patients contacted as necessary to identify a re-rupture. We also investigated the situation causing the re-rupture. RESULTS: We identified a total of 190 distal biceps tendon ruptures that underwent repair and met our inclusion and exclusion criteria. Of the 190 repairs, 172 (90.5%) were performed by the Mayo modification of the Boyd-Anderson 2-incision technique. Bilateral ruptures occurred in 13 patients (7.3%). Six primary ruptures (3.2%) occurred in women, 4 of the 6 being partial ruptures. Partial ruptures were found to be statistically more common than complete ruptures in women (P = .05). We identified 3 re-ruptures (1.5%), all occurring within 3 weeks of the index surgery. CONCLUSION: The re-rupture rate after primary repair of the distal biceps tendon is low at 1.5% and occurs within 3 weeks of index repair. This appears to be due to patient compliance and excessive force placed on repairs. We also found the incidence of women who sustain a distal biceps tendon tear to be 3.2%, with partial tears being statistically more common than complete ruptures. LEVEL OF EVIDENCE: Level IV, case series, treatment study PMID- 24774621 TI - Evidence for minimally invasive therapies in the management of chronic calcific tendinopathy of the rotator cuff: a systematic review and meta-analysis. AB - BACKGROUND: This meta-analysis assessed the short-term to midterm effectiveness of minimally invasive treatments in the management of calcifying tendinopathy of the shoulder cuff, a common source of chronic shoulder pain that leads to pain, a decreased active range of motion, and loss of muscular strength. When conservative therapies fail, minimally invasive treatment options can be considered before resulting to surgery. MATERIALS AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to conduct this review. A systematic literature search was conducted in May 2013 to identify all studies that examined the short-term to midterm effectiveness of minimally invasive treatments for chronic calcifying tendinopathy. The primary end points were identified as function, pain, and total resorption rates. Grades of Recommendation Assessment, Development and Evaluation (GRADE) was used to assess the quality of evidence. RESULTS: Included were 20 studies (1544 participants). Common methodological flaws were related to randomization. In general, there is moderate-quality GRADE evidence that high energy extracorporeal shockwave therapy has a significant effect on pain relief and functional status compared with other interventions. There is variable quality GRADE evidence on the efficiency of other interventions. CONCLUSION: High energy extracorporeal shockwave therapy is the most thoroughly investigated minimally invasive treatment option in the short-term to midterm and has proven to be a safe and effective treatment. Ultrasound-guided needling is safe but has not been proven to be more effective than an ultrasound-guided subacromial corticosteroid injection in recent level I research, and further research will have to prove its effectiveness. PMID- 24774644 TI - Non-professional-help-seeking among young people with depression: a qualitative study. AB - BACKGROUND: Adolescents and young adults often suffer from depression, but tend to avoid seeking professional help. The aim of this study was to explore the reasons for non-professional-help-seeking in a sample of young adults resident in Catalonia with depressive symptoms through a qualitative study. In addition, the subjects were invited to offer their recommendations for making mental health care services more accessible. METHODS: We recruited 105 young persons (17-21 years of age) who had participated in a national survey on adolescents. The sample was divided into thirds, with 37 who had a previous diagnosis of depression, 33 who had self-perceived emotional distress, and 35 controls. The participants were interviewed in depth about their reasons for avoiding professional mental health care services, and the interview results were analyzed using both qualitative and cultural domain techniques and corroborated through comparison with the results of three focus groups. RESULTS: Participants' reasons for avoidance varied both by gender and according to prior experience with health services. Male study participants and female controls mainly understood depressive symptoms as normal and therefore not requiring treatment. Female participants with self-perceived distress were more likely to cite problems of access to treatment and fear of speaking to an unknown person about their problems. Females with a diagnosis expressed lack of trust in the benefits of treatment and fear of the social consequences of help-seeking. In their recommendations for best practices, the study participants suggested educational initiatives, as well as changes in the organization of mental health care services. CONCLUSIONS: A better understanding of the views of young people and a greater effort to involve them as active participants is important for facilitating help-seeking in this age group, and for adapting mental health care services to adolescent users and their social context. PMID- 24774645 TI - Prevalence of hepatitis B and C virus infections among patients with chronic hepatitis at Bereka Medical Center, Southeast Ethiopia: a retrospective study. AB - BACKGROUND: Viral hepatitis exists throughout the world and is a major global public health problem affecting millions of people. Hepatitis B (HBV) and hepatitis C (HCV) virus are the commonest causes of inflammation of the liver leading to chronic liver disease, cirrhosis, hepatocellular carcinoma and even fulminant hepatitis. The objective of this retrospective study was to determine the prevalence of infections with HBV and HCV among patients with chronic hepatitis who visited Bereka Medical Center, southeast Ethiopia. METHODS: Institution based retrospective study design was employed. HBV and HCV test records of all patients with chronic hepatitis who visited Bereka Medical Center from Nov. 2012 to Nov. 2013. A total of 578 (358 for HBV and 220 for HCV) patients with chronic hepatitis screened and the results of all patients were included. All sera were screened using commercially available rapid test kits. Test results were shown in percent and prevalence rates. RESULTS: The overall prevalence of HBV and HCV among chronic hepatitis patients were 22.3% and 3.6% respectively. Prevalence of HBV and HCV among males from the total HBV and HCV screened was 52/358 (14.5%) and 6/220 (2.7%) respectively. 64/80 (80%) of HBV sero-positives were found in between 16 to 45 years of age. Of those 64 HBV sero positive patients, 42/64 (65.6%) were found 16-30 age interval. Furthermore, of those HCV infected, 6/8 (75%) of them fall under 16-30 years of age. 6/8 (75%) of HCV infected patients were males. CONCLUSION: The present study has shown that HBV was highly prevalent among patients who visited the clinic. Males were more susceptible than female patients. 3.6% HCV prevalence was also high. Mass immunization of HBV is recommended to halt HBV infection. PMID- 24774646 TI - Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: a 10-year prospective-longitudinal community study of adolescents and young adults. AB - OBJECTIVE: The concept of fearful spells (FS) denotes distressing spells of anxiety that might or might not qualify for criteria of panic attacks (PA). Few studies examined prospective-longitudinal associations of FS not meeting criteria for PA with the subsequent onset of mental disorders to clarify the role of FS as risk markers of psychopathology. METHOD: A representative community sample of adolescents and young adults (N = 3021, age 14-24 at baseline) was prospectively followed up in up to 3 assessment waves over up to 10 years. FS, PA, anxiety, depressive, and substance use disorders were assessed using the DSM-IV/M-CIDI. Odds Ratios (OR) from logistic regressions were used to examine the predictive value of FS-only (no PA) and PA at baseline for incident disorders at follow-up. RESULTS: In logistic regressions adjusted for sex and age, FS-only predicted the onset of any subsequent disorder, any anxiety disorder, panic disorder, agoraphobia, GAD, social phobia, any depressive disorder, major depression, and dysthymia (ORs 1.54-4.36); PA predicted the onset of any anxiety disorder, panic disorder, GAD, social phobia, any depressive disorder, major depression, dysthymia, any substance use disorder, alcohol abuse/dependence, and nicotine dependence (ORs 2.08-8.75; reference group: No FS-only and no PA). Associations with psychopathology were slightly smaller for FS-only than for PA, however, differences in associations (PA compared to FS-only) only reached significance for any anxiety disorder (OR = 3.26) and alcohol abuse/dependence (OR = 2.26). CONCLUSIONS: Findings suggest that compared to PA, FS-only have similar predictive properties regarding subsequent psychopathology and might be useful for an early identification of high-risk individuals. PMID- 24774647 TI - Relationships of maternal folate and vitamin B12 status during pregnancy with perinatal depression: The GUSTO study. AB - Studies in the general population have proposed links between nutrition and depression, but less is known about the perinatal period. Depletion of nutrient reserves throughout pregnancy and delayed postpartum repletion could increase the risk of perinatal depression. We examined the relationships of plasma folate and vitamin B12 concentrations during pregnancy with perinatal depression. At 26th 28th weeks of gestation, plasma folate and vitamin B12 were measured in women from the GUSTO mother-offspring cohort study in Singapore. Depressive symptoms were measured with the Edinburgh Postnatal Depression Scale (EPDS) during the same period and at 3-month postpartum. EPDS scores of >=15 during pregnancy or >=13 at postpartum were indicative of probable depression. Of 709 women, 7.2% (n = 51) were identified with probable antenatal depression and 10.4% (n = 74) with probable postnatal depression. Plasma folate concentrations were significantly lower in those with probable antenatal depression than those without (mean +/- SD; 27.3 +/- 13.8 vs 40.4 +/- 36.5 nmol/L; p = 0.011). No difference in folate concentrations was observed in those with and without probable postnatal depression. In adjusted regression models, the likelihood of probable antenatal depression decreases by 0.69 for every unit variation (increase) in folate (OR = 0.69 per SD increase in folate; 95% CI: 0.52, 0.94). Plasma vitamin B12 concentrations were not associated with perinatal depression. Lower plasma folate status during pregnancy was associated with antenatal depression, but not with postnatal depression. Replication in other studies is needed to determine the direction of causality between low folate and antenatal depression. CLINICAL TRIAL REGISTRY: NCT01174875. PMID- 24774648 TI - Reduced connexin 43 immunolabeling in the orbitofrontal cortex in alcohol dependence and depression. AB - Reduced density of glial cells and low levels of some astrocyte proteins have been described in the orbitofrontal cortex (OFC) in depression and alcoholism, two disorders often comorbid. These regressive changes may also involve the communication between astrocytes via gap junctions and hemichannels, which play important regulatory roles in neurotransmission. We determined levels and morphological immunostaining parameters of connexin 43 (Cx43), the main protein subunit of astrocyte gap junctions/hemichannels, in the OFC of subjects with depression, alcoholism or comorbid depression/alcoholism as compared to non psychiatric subjects. Postmortem brain samples from 23 subjects with major depressive disorder (MDD), 16 with alcohol dependence, 13 with comorbid MDD and alcohol dependence, and 20 psychiatrically-normal comparison subjects were processed for western blots to determine Cx43 levels. Area fraction of Cx43 immunoreactivity, and density and average size of immunoreactive puncta were measured in histological sections. There was a significant, larger than 60 percent decrease in Cx43 level in the three psychiatric groups as compared to controls. Area fraction of immunoreactivity and immunoreactive punctum size were reduced in all psychiatric groups, but Cx43-immunoreactive puncta density was reduced only in alcohol-dependent subjects. Among psychiatric subjects, no difference in Cx43 levels or immunostaining was found between suicides and non suicides. The present data suggest that dysfunction of the OFC is accompanied by reduction in the levels of gap junction protein Cx43 in depression and alcoholism, and reduction in density of Cx43 immunoreactive puncta only in alcoholism, pointing to altered gap junction or hemichannel-based communication in the pathophysiology of those disorders. PMID- 24774649 TI - Art for twins: Yoruba artists and their statues/twin research studies: twins' education and conceptions; diurnal preference; inherited eye diseases; ultrasound counseling when twins are conjoined/popular twin reports: twin sisters (the film); rare pregnancy; diet test; French twins reared apart and reunited. AB - The Yoruba of Nigeria are well known for their high twinning rate and the statues they create to commemorate deceased twins. An impressive collection of this artwork was displayed at the University of California's Fowler Museum in Los Angeles between October 13, 2013 and March 2, 2014. An overview of this exhibit is provided. Next, twin research on maternal education and conception, diurnal preference, inherited eye diseases, and ultrasound counseling for couples with conjoined twins are briefly summarized. This article concludes with a discussion of media-based items related to twins. The topics include an award-winning twin film, a rare pregnancy, a diet test, and the separation and chance reunion of monozygotic female twins. PMID- 24774670 TI - Double-blind, randomised, placebo-controlled intervention trial to evaluate the effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed coeliac disease. AB - Interactions between the immune system and the intestinal microbiota may play a role in coeliac disease (CD). In the present study, the potential effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed CD were evaluated. A double-blind, randomised, placebo-controlled trial was conducted in thirty-three children who received a capsule containing either B. longum CECT 7347 (109 colony-forming units) or placebo (excipients) daily for 3 months together with a gluten-free diet (GFD). Outcome measures (baseline and post intervention) included immune phenotype of peripheral blood cells, serum cytokine concentration, faecal secretory IgA (sIgA) content, anthropometric parameters and intestinal microbiota composition. Comparisons between the groups revealed greater height percentile increases (P= 0.048) in the B. longum CECT 7347 group than in the placebo group, as well as decreased peripheral CD3+ T lymphocytes (P= 0.004) and slightly reduced TNF-alpha concentration (P= 0.067). Within-group comparisons of baseline and final values did not reveal any differences in T lymphocytes and cytokines in the placebo group, while decreased CD3+ (P =0.013) and human leucocyte antigen (HLA)-DR+ T lymphocytes (P =0.029) and slightly reduced TNF-alpha concentration (P= 0.085) were detected in the B. longum CECT 7347 group. Comparison between the groups showed that the administration of B. longum CECT 7347 reduced the numbers of the Bacteroides fragilis group (P= 0.020) and the content of sIgA in stools (P= 0.011) compared with the administration of placebo. Although this is a first exploratory intervention with limitations, the findings suggest that B. longum CECT 7347 could help improve the health status of CD patients who tend to show alterations in gut microbiota composition and a biased immune response even on a GFD. PMID- 24774694 TI - Campylobacter infections in children exposed to infected backyard poultry in Egypt. AB - Campylobacteriosis is a zoonotic disease which has a worldwide public health impact. The disease is endemic in Egypt; however, the epidemiology in animals and humans has not been fully characterized. The objective of this study was to compare the risk of Campylobacter faecal carriage in children exposed to Campylobacter-infected vs. non-infected backyard poultry and to identify risk factors for a backyard being classified as infected. A total of 103 households which owned backyard poultry were sampled from a rural community in Egypt. Within these households 379 poultry and 106 children were tested for C. jejuni and C. coli; 23.5% and 5.5% of poultry were positive for C. jejuni and C. coli, respectively. In the studied households; 12.3% of children were positive for C. jejuni, and 2.8% were positive for C. coli. Using logistic regression, households with poultry positive for C. jejuni had 3.86 (95% confidence interval 1.0-15.0) times the odds of having children positive for C. jejuni compared to those housed with poultry which all tested negative. Backyard poultry may present a transmission route of C. jejuni to children. Backyards with poor cleaning and disinfection, wet litter and manure disposed of within the backyard had increased odds of being positive for C. jejuni. Enhancing biosecurity and management in poultry backyards may reduce the risk of the disease. PMID- 24774717 TI - Female partner's perception of premature ejaculation and its impact on relationship breakups, relationship quality, and sexual satisfaction. AB - INTRODUCTION: Women's perceptions of the men's ejaculatory behavior, as well as the impact premature ejaculation (PE) has on the couple's functioning, are important factors that need to be considered. AIM: This survey investigated women's perception and importance of ejaculatory function, as well as the specific aspects of PE that cause distress. In addition, the survey further identified the factors with a greater impact on intimacy, relationship, and sexual behavior. METHODS: The 1,463 females belonging to a web panel from three different countries (Mexico, Italy, and South Korea), aged 20-50 years, participated in the survey. A combination of validated and self-constructed questionnaires to assess women's perception of PE, relationship satisfaction and quality, and sexual functioning and satisfaction were used. MAIN OUTCOME MEASURES: Descriptive statistics in form of proportions and percentages, correlation, and regression analyses. RESULTS: A significant correlation between the importance of ejaculatory control and felt distress could be observed (rho = 0.55, P < 0.001). Women reporting less sexual problems considered ejaculatory control more important and reported more PE-related distress (rho = 0.23 and 0.11, respectively; P < 0.001 for both). The male's lack of attention and focus on performance was the most frequently reported reasons for sexual distress (47.6%) followed by "the short time between penetration and ejaculation" (39.9%), and "the lack of ejaculatory control" (24.1%). Almost a quarter of women reported that the man's ejaculatory problem had previously led to relationship breakups (22.8%). Women considering duration to be important were more likely to report breakups. CONCLUSIONS: The study highlights the detrimental effects of PE on relationship and sexual satisfaction in the female partner and how it can lead to the termination of the relationship. Most notably, this is the first study to report that an important source of female distress are not only parameters related to performance such as control or duration but rather inappropriate attention focus and the negligence of other forms of sexual activities. PMID- 24774695 TI - Effects of high temperature on photosynthesis and related gene expression in poplar. AB - BACKGROUND: High temperature, whether transitory or constant, causes physiological, biochemical and molecular changes that adversely affect tree growth and productivity by reducing photosynthesis. To elucidate the photosynthetic adaption response and examine the recovery capacity of trees under heat stress, we measured gas exchange, chlorophyll fluorescence, electron transport, water use efficiency, and reactive oxygen-producing enzyme activities in heat-stressed plants. RESULTS: We found that photosynthesis could completely recover after less than six hours of high temperature treatment, which might be a turning point in the photosynthetic response to heat stress. Genome-wide gene expression analysis at six hours of heat stress identified 29,896 differentially expressed genes (15,670 up-regulated and 14,226 down-regulated), including multiple classes of transcription factors. These interact with each other and regulate the expression of photosynthesis-related genes in response to heat stress, controlling carbon fixation and changes in stomatal conductance. Heat stress of more than twelve hours caused reduced electron transport, damaged photosystems, activated the glycolate pathway and caused H2O2 production; as a result, photosynthetic capacity did not recover completely. CONCLUSIONS: This study provides a systematic physiological and global gene expression profile of the poplar photosynthetic response to heat stress and identifies the main limitations and threshold of photosynthesis under heat stress. It will expand our understanding of plant thermostability and provides a robust dataset for future studies. PMID- 24774718 TI - Late-emerging strains of HIV induce T-cell homeostasis failure by promoting bystander cell death and immune exhaustion in naive CD4 and all CD8 T-cells. AB - The mechanisms involved in the decline of CD4 and CD8 T-cells that lead to HIV induced immune dysregulation are not clearly understood. We hypothesize that late emerging strains of HIV, such as CXCR4-tropic (X4) virions, induce T-cell homeostasis failure by promoting significantly more bystander cell death, and immune exhaustion in naive CD4 and all CD8 T-cells, when compared to strain of HIV, such as CCR5-tropic (R5) virions, found early during the course of infection. In the reported study, inactivated X4 virions induced greater bystander cell death in sort-purified naive CD4 T-cells compared to R5 virions, which was significant (p=0.013), and in memory CD8 T-cells, though the latter was not significant. A clearer understanding of the mechanisms involved in HIV induced depletion of T-cell numbers and function could lead to therapies that prevent T-cell death and restore immune function. These therapies could improve current anti-retroviral and cure-related treatments by boosting the immune system's own ability to combat the virus. PMID- 24774719 TI - Lipid droplets may lay a spacial foundation for vasculogenic mimicry formation in hepatocellular carcinoma. AB - Vasculogenic mimicry is a highly patterned vascular channel distinguished from the endothelium-dependent blood vessel. Vasculogenic mimicry is lined by highly aggressive tumor cells, and is associated with tumor grade, invasion and metastasis, and poor clinical prognosis. Much attention has been focused on the signaling pathways and the tumor microenvironment needed for vasculogenic mimicry formation, however, the studies on the spacial foundation for vasculogenic mimicry formation are limited. There are many lipid droplets in hepatocellular carcinoma due to steatosis, while increased numbers of lipid droplets also have been reported in many other neoplastic processes. The role of lipid droplets in tumor is still unclear. Based on the similar structural and morphological characteristics between vasculogenic mimicry and lipid droplet, we speculate that the lipid droplets may lay a spacial foundation for vasculogenic mimicry formation by a way of "space placeholder" in HCC. Experimental data and limited clinical literatures support the hypothesis to a certain degree. This hypothesis may provide a new idea for the study of vasculogenic mimicry and also provide a new direction for the functional study of lipid droplets in tumor. PMID- 24774720 TI - Rapid detoxification of benzodiazepine or Z-drugs dependence using acetylcholinesterase inhibitors. AB - Dependence on benzodiazepines (BZDs) or Z-drugs (zolpidem, zopicline and zaleplon) is a common clinical phenomenon. Traditional detoxification of BZDs dependence includes tapering used dose gradually and using equivalent doses of long-acting BZDs as substitutes. This kind of regimen tends to take a long time (up to 4weeks) and may require hospitalization. Acetylcholinesterase inhibitors have been shown to reverse BZDs induced sedation. We propose that oral form acetylcholinesterase inhibitors (donepezil, galantamine and rivastigmine) also posses the effect of inhibiting GABA receptors, and act as indirect antagonist, to be applied in the rapid detoxification treatment of BZDs and Z-drug dependence. PMID- 24774721 TI - Randomized phase II trial of hypofractionated proton versus carbon ion radiation therapy in patients with sacrococcygeal chordoma-the ISAC trial protocol. AB - BACKGROUND: Chordomas are relatively rare lesions of the bones. About 30% occur in the sacrococcygeal region. Surgical resection is still the standard treatment. Due to the size, proximity to neurovascular structures and the complex anatomy of the pelvis, a complete resection with adequate safety margin is difficult to perform. A radical resection with safety margins often leads to the loss of bladder and rectal function as well as motoric/sensoric dysfunction. The recurrence rate after surgery alone is comparatively high, such that adjuvant radiation therapy is very important for improving local control rates. Proton therapy is still the international standard in the treatment of chordomas. High LET beams such as carbon ions theoretically offer biologic advantages in slow growing tumors. Data of a Japanese study of patients with unresectable sacral chordoma showed comparable high control rates after hypofractionated carbon ion therapy only. METHODS AND DESIGN: This clinical study is a prospective randomized, monocentric phase II trial. Patients with histologically confirmed sacrococcygeal chordoma will be randomized to either proton or carbon ion radiation therapy stratified regarding the clinical target volume. Target volume delineation will be carried out based on CT and MRI data. In each arm the PTV will receive 64 GyE in 16 fractions. The primary objective of this trial is safety and feasibility of hypofractionated irradiation in patients with sacrococygeal chordoma using protons or carbon ions in raster scan technique for primary or additive treatment after R2 resection. The evaluation is therefore based on the proportion of treatments without Grade 3-5 toxicity (CTCAE, version 4.0) up to 12 months after treatment and/or discontinuation of the treatment for any reason as primary endpoint. Local-progression free survival, overall survival and quality of life will be analyzed as secondary end points. DISCUSSION: The aim of this study is to confirm the toxicity results of the Japanese data in raster scan technique and to compare it with the toxicity analysis of proton therapy given in the same fractionation. Using this data, a further randomized phase III trial is planned, comparing hypofractionated proton and carbon ion irradiation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01811394. PMID- 24774722 TI - Five-year outcome of bone remodelling around implants in the maxillary sinus: assessment of differences between implants placed in autogenous inlay bone blocks and in ungrafted maxilla. AB - The placement of implants in the posterior maxillary area is considered a reliable procedure, offering recognized rehabilitative advantages. The aim of this study was to evaluate the performance of dental implants placed in the sinus floor augmented with a block autograft by comparing the outcomes over 5 years with those of dental implants positioned in non-augmented bone. This retrospective cohort study included 16 patients who had undergone prosthetic rehabilitation supported by dental implants between 2000 and 2006. One implant per patient was included and assigned to one of two predictor groups: grafted versus ungrafted maxillary sinus. Changes in marginal bone level (MBL) and apical bone level (ABL) over time, at 1, 3, and 5 years, were the primary outcome variables. Appropriate pair-wise comparison tests were performed. No significant differences were seen with regard to ABLs and among times between the grafted group (nine implants) and the ungrafted group (seven implants). Significant marginal bone resorption was found over time, primarily at the buccal aspect, in both study groups. The bone surrounding the apex of dental implants appeared stable after sinus augmentation in the grafted area. The behaviour of the two groups with regard to loss of MBLs over time was very similar. PMID- 24774723 TI - Periodontal healing after 'orthodontic extraction' of mandibular third molars: a retrospective cohort study. AB - In this study we investigated periodontal healing of mandibular second molars following 'orthodontic extraction' of adjacent impacted third molars, under the null hypothesis that there would be no difference in probing pocket depths (PPD) and clinical attachment levels (CAL) at the distal aspect of second molars before and after treatment. A retrospective survey was conducted of 64 patients who consecutively underwent 'orthodontic extraction' of mandibular third molars in close anatomical relationship with the mandibular canal from January 1997 to January 2011. Age, smoking habit, and PPD and CAL at the distal aspect of second molars before and after treatment were recorded. A statistically significant difference was found in PPD and CAL before and after treatment for the overall sample and for the sample classified by age (>25 or <=25 years), smoking habit (smoker or non-smoker), and type of third molar impaction (horizontal, mesioangular, or vertical). Median PPD and CAL reductions amounted to 6mm and 5mm, respectively. The null hypothesis was rejected and orthodontic extraction proved to be indicated for those impacted mandibular third molars at high risk of a postoperative periodontal defect at the distal aspect of the adjacent second molar. PMID- 24774724 TI - Management of symptomatic hypertrophic cardiomyopathy: pills, alcohol, or the scalpel? PMID- 24774725 TI - Treatment of recurrent pericarditis. PMID- 24774726 TI - Laws restricting smoking in public places reduce the incidence of acute coronary syndrome in Spain. PMID- 24774727 TI - Effectiveness and safety beyond 10 years of percutaneous transluminal septal ablation in hypertrophic obstructive cardiomyopathy. AB - INTRODUCTION AND OBJECTIVES: Percutaneous transluminal septal ablation is an alternative treatment in patients with hypertrophic obstructive cardiomyopathy. However, due to the relatively new introduction of this technique, there is no information on its very long term results (>10 years). METHODS: The present study included consecutive patients treated in 5 centers between 1998 and 2003. We analyzed clinical, hemodynamic, and echocardiographic data at baseline and follow up. RESULTS: A total of 45 patients were included; there were 31 (69%) women, the mean age was 62.4 (14) years, and 39 patients (86.6%) showed functional class III or IV. Septal thickness was 21.8 (3.5) mm, the peak resting gradient on echocardiography was 77 (39) mmHg, and mitral regurgitation was at least moderate in 22 patients (48.8%). During hospitalization, permanent pacemaker implantation was required in 3 patients and ventricular perforation (by pacing lead) occurred in 1 patient, requiring surgery. After a follow-up of 12.3 years (11.0-13.5 years), 2 patients (4.4%) died from cardiac causes (heart failure and posttransplantation), 3 patients required an implantable cardioverter defibrillator (1 for primary prevention and 2 due to sustained ventricular tachycardia after cardiac surgery), and 2 underwent cardiac surgery (due to endocarditis and mitral regurgitation). In the last clinical review, functional class was I-II in 39 patients (86.6%) (P<.0001), the peak resting gradient was 16 (23) mmHg (P<.0001), and mitral regurgitation was absent or mild in 34 patients (75.5%) (P<.03). CONCLUSIONS: The results of this study suggest that septal ablation is safe and effective in the very long term. The procedure was not associated with a significant incidence of sudden death or symptomatic ventricular arrhythmias. PMID- 24774728 TI - Prognostic impact of chronic total occlusion in a nonculprit artery in patients with acute myocardial infarction undergoing primary angioplasty. AB - INTRODUCTION AND OBJECTIVES: The prognostic value of chronic total occlusion in nonculprit coronary arteries in patients with myocardial infarction undergoing primary angioplasty remains controversial. Several publications have described different methodologies and conflicting findings. In addition, causes of death were not reported. Our aim is to analyze the prognostic impact of chronic total occlusion in nonculprit coronary arteries and the role of left ventricular ejection fraction in this analysis. METHODS: Prospective inclusion of consecutive patients with ST-segment elevation myocardial infarction who underwent primary angioplasty. We recorded baseline characteristics, in-hospital clinical course, and mortality and its causes during follow-up. We assessed the impact of chronic total occlusion on mortality using Cox regression analysis. RESULTS: Chronic total occlusion in nonculprit arteries was present in 125 of 1176 patients (10.6%); in 79 of these 125 patients, chronic total occlusion was present in the proximal segments. The mean follow-up was 339 days; 64 (5.8%) patients died during the first 6 months. Patients with chronic total occlusions had more comorbidities, poorer ventricular function, and higher mortality (hazard ratio=2.79; 95% confidence interval, 1.71-4.56). Chronic total occlusion was also associated with noncardiac death (hazard ratio=3.83; 95% confidence interval, 2.10-7.01). Chronic total occlusion in proximal segments was associated with both cardiac (hazard ratio=3.22; 95% confidence interval, 1.42-7.30) and noncardiac deaths (hazard ratio=3.43; 95% confidence interval, 1.67-7.06). The multivariate analysis performed without including left ventricular ejection fraction showed a significant association between chronic total occlusion and mortality. However, when left ventricular ejection fraction was included in the analysis, this association was nonsignificant (hazard ratio=1.76; 95% confidence interval, 0.85 3.65; P=.166). CONCLUSIONS: Chronic total occlusion in this clinical setting identified patients at higher risk with more comorbidities and higher mortality, but did not behave as an independent predictor of mortality when left ventricular ejection fraction was included in the analysis. PMID- 24774729 TI - Magnitude and management of metabolic syndrome in Spain in 2008-2010: the ENRICA study. AB - INTRODUCTION AND OBJECTIVES: Few studies in Spain have reported the distribution of metabolic syndrome using the harmonized definition and that of premorbid metabolic syndrome, which consists of metabolic syndrome without diabetes mellitus or cardiovascular disease. Moreover, their regional distributions and clinical management are unknown. The present study examined the distributions and clinical management of both syndromes in Spain. METHODS: This cross-sectional study was performed from 2008 to 2010 in 11 149 representative individuals of the Spanish population aged 18 years or older. Data were obtained through standardized physical examination, and analytical measurements were done in a central laboratory. RESULTS: The prevalences (95% confidence interval) of metabolic syndrome and premorbid metabolic syndrome were 22.7% (21.7%-23.7%) and 16.9% (16.0%-17.8%), respectively. The frequency of both syndromes increased with age and was higher in men than in women up to 65 years; above this age, the frequency was higher in women. The communities of the south of Spain and the Balearic and Canary islands had the highest prevalence of both syndromes, in some regions reaching double that of the community with the lowest prevalence. About one third of patients with premorbid metabolic syndrome reported that they had not received health recommendations to improve their lifestyles; of those that did receive advice, adherence was low, particularly for reducing weight (31.9%) and salt intake (38.3%). CONCLUSIONS: The prevalence of metabolic syndrome is high in Spain and considerable geographical differences exist in its distribution. There is substantial room for improvement in the clinical management of premorbid metabolic syndrome. PMID- 24774730 TI - Long-term results of percutaneous balloon valvuloplasty in pulmonary valve stenosis in the pediatric population. AB - INTRODUCTION AND OBJECTIVES: Percutaneous pulmonary valvuloplasty is the preferred interventional procedure for pulmonary valve stenosis. The aim of this study was to evaluate the effectiveness of this technique, assess the factors leading to its success, and determine the long-term results in the pediatric population. METHODS: The study included 53 patients with pulmonary valve stenosis undergoing percutaneous balloon valvuloplasty between December 1985 and December 2000. Right ventricular size and functional echocardiographic parameters, such as pulmonary regurgitation and residual transvalvular gradient, were assessed during long-term follow-up. RESULTS: Peak-to-peak transvalvular gradient decreased from 74 mmHg [interquartile range, 65-100 mmHg] to 20 mmHg [interquartile range, 14-34 mmHg]. The procedure was unsuccessful in 2 patients (3.77%). The immediate success rate was 73.58%. Follow-up ranged from 10 years to 24 years (median, 15 years). During follow-up, all patients developed late pulmonary regurgitation which was assessed as grade II in 58.4% and grade III in 31.2%. There was only 1 case of long-term restenosis (2.1%). Severe right ventricular dilatation was observed in 27.1% of the patients. None of the patients developed significant right ventricular dysfunction. Pulmonary valve replacement was not required in any of the patients. CONCLUSIONS: Percutaneous balloon valvuloplasty is an effective technique in the treatment of pulmonary valve stenosis with good long term results. PMID- 24774731 TI - Influence of a multidisciplinary alert strategy on mortality due to left-sided infective endocarditis. AB - INTRODUCTION AND OBJECTIVES: Mortality from left-sided infective endocarditis remains very high. The aim of this study was to assess the impact of a multidisciplinary alert strategy (AMULTEI), based on clinical, echocardiographic and microbiological findings, implemented in 2008 in a tertiary hospital. METHODS: Cohort study comparing our historical data series (1996-2007) with the number of patients diagnosed with left-sided endocarditis from 2008-2011 (AMULTEI). RESULTS: The AMULTEI cohort included 72 patients who were compared with 155 patients in the historical cohort. AMULTEI patients were significantly older (62.5 vs 57.9 years in the historical cohort; P=.047) and had higher comorbidity (Charlson index, 3.33 vs 2.58 in the historical cohort; P=.023). There was also a trend toward more enterococcal etiology in the AMULTEI group (20.8% vs 11.6% in the historical cohort; P=.067). In the AMULTEI group, early surgery was more frequently performed (48.6% vs 23.2%; P<.001) during hospitalization, the incidence of septic shock was significantly lower (9.7% vs 24.5%; P=.009) and there was a trend toward reductions in neurological complications (19.4% vs 29.0%; P=.25) and severe heart failure (12.5% vs 18.7%; P=.24). In-hospital mortality and mortality during the first month of follow-up were significantly lower in the AMULTEI group (16.7% vs 36.1%; P=.003). CONCLUSIONS: Despite the trend toward older age and more comorbidity measured by the Charlson index, early mortality was significantly lower in patients treated with the AMULTEI strategy. PMID- 24774732 TI - Chronobiology of death in heart failure. AB - INTRODUCTION AND OBJECTIVES: In the general population, heart events occur more often during early morning, on Mondays, and during winter. However, the chronobiology of death in heart failure has not been analyzed. The aim of this study was to determine the circadian, day of the week, and seasonal variability of all-cause mortality in chronic heart failure. METHODS: This was an analysis of all consecutive heart failure patients followed in a heart failure unit from January 2003 to December 2008. The circadian moment of death was analyzed at 6-h intervals and was determined by reviewing medical records and by information provided by the relatives. RESULTS: Of 1196 patients (mean [standard deviation] age, 69 [13] years; 62% male), 418 (34.9%) died during a mean (standard deviation) follow-up of 29 (21) months. Survivors were younger, had higher body mass index, left ventricular ejection fraction, glomerular filtration rate, hemoglobin and sodium levels, and lower Framingham risk scores, amino-terminal pro-B type natriuretic peptide, troponin T, and urate values. They were more frequently treated with angiotensin receptor blockers, beta-blockers, mineralocorticoids receptor antagonists, digoxin, nitrates, hydralazine, statins, loop diuretics, and thiazides. The analysis of the circadian and weekly variability did not reveal significant differences between the four 6-h intervals or the days of the week. Mortality occurred more frequently during the winter (30.6%) compared with the other seasons (P = .024). CONCLUSIONS: All cause mortality does not follow a circadian pattern, but a seasonal rhythm in patients with heart failure. This finding is in contrast to the circadian rhythmicity of cardiovascular events reported in the general population. PMID- 24774733 TI - Protection against myocardial ischemia-reperfusion injury in clinical practice. AB - Even when reperfusion therapy is applied as early as possible, survival and quality of life are compromised in a considerable number of patients with ST segment elevation acute myocardial infarction. Some cell death following transient coronary occlusion occurs during reperfusion, due to poor handling of calcium in the sarcoplasmic reticulum-mitochondria system, calpain activation, oxidative stress, and mitochondrial failure, all promoted by rapid normalization of intracellular pH. Various clinical trials have shown that infarct size can be limited by nonpharmacological strategies--such as ischemic postconditioning and remote ischemic conditioning--or by drugs--such as cyclosporine, insulin, glucagon-like peptide-1 agonists, beta-blockers, or stimulation of cyclic guanosine monophosphate synthesis. However, some clinical studies have yielded negative results, largely due to a lack of consistent preclinical data or a poor design, especially delayed administration. Large-scale clinical trials are therefore necessary, particularly those with primary clinical variables and combined therapies that consider age, sex, and comorbidities, to convert protection against reperfusion injury into a standard treatment for patients with ST-segment elevation acute myocardial infarction. PMID- 24774734 TI - Four MitraClips deployed in a mitral valve. PMID- 24774735 TI - Giant cardiac cyst: rare image of ventricular aneurysm. PMID- 24774736 TI - Mummified heart of an ancient Egyptian. PMID- 24774737 TI - Simultaneous transfemoral aortic valve implantation and endovascular repair of abdominal aortic aneurysm. PMID- 24774738 TI - Usefulness of placing a wire from the contralateral femoral artery to improve the percutaneous treatment of vascular complications in TAVI. PMID- 24774739 TI - Ivabradine might improve exercise capacity in dilated cardiomyopathy in comparison with bisoprolol: assessment with the ergospirometry test. PMID- 24774740 TI - Ventricular septal defect as an unusual complication of percutaneous transcatheter implantation of an aortic valve prosthesis: two-year follow-up. PMID- 24774741 TI - Does CHA2DS2-VASc score select patients who will benefit most from anticoagulation? PMID- 24774742 TI - Does CHA2DS2-VASc score select patients who will benefit most from anticoagulation? Response. PMID- 24774743 TI - Use of antithrombotic therapy in patients with atrial fibrillation in primary care. Importance of INR control. PMID- 24774744 TI - Use of antithrombotic therapy in patients with atrial fibrillation in primary care. Importance of INR control. Response. PMID- 24774745 TI - The impact of temporal lobe epilepsy on musical ability. AB - PURPOSE: Patients with temporal lobe epilepsy (TLE) often show impairment of cognitive processing in different domains. We aimed to evaluate whether also musical ability is impaired in TLE. METHODS: We enrolled patients with lesional TLE and without any other neurological or psychiatric disorder. The side and the etiology of the epilepsy were confirmed by EEG and by MRI. We applied a self developed test of musical ability which evaluates the ability to identify melodies, pitch, rhythm, and emotional content of music. In addition, we compared the results of the patients to the results of age and sex matched healthy control subjects. All patients and subjects were without specific musical training. RESULTS: Patients with left TLE showed a significantly lower score in melody recognition, patients with right TLE showed a significantly lower score in identification of emotion in music. In all other aspects of music ability, no significant difference between left and right TLE could be found. We observed a significantly lower total score in patients with left TLE, but not with right TLE, as compared to healthy subjects. There were no differences with respect to sex. CONCLUSION: Our data confirm that the recognition of melodies shows left hemisphere dominance whereas the identification of emotions in music shows right hemisphere dominance in patients without musical training. Furthermore, our data show that the impairment of cognitive processing in TLE is reflected even in higher cognitive functions such as music processing. However, this impairment was mild. PMID- 24774746 TI - A Bayesian tool for epilepsy diagnosis in the resource-poor world: development and early validation. AB - PURPOSE: The epilepsy treatment gap in resource-poor countries is so large that existing numbers of doctors are unlikely to be able to close it. Other health workers are likely to be needed but they will need help. The diagnosis of an attack as epileptic or not is an essential step in the management of epilepsy. It should be possible to devise a tool to give the probability of episodes being epileptic based on a Bayesian analysis of the results of history taking. METHOD: We asked about the nature of episodes in patients referred to epilepsy camps in Nepal. Answers were then compared to the final clinical diagnosis of epilepsy and the likelihood ratio (LR) of the episode being epileptic obtained for each answer. The most informative LRs, tested sequentially, formed the basis for a tool which was validated in a different Nepalese population. RESULTS: Data was obtained from 67 patients. The pre-test probability of having epilepsy was 0.76. Answers to 11 questions with the most informative LRs were then combined into a tool. This was tested on 14 different patients. Post-test probability scores in those with epilepsy ranged from 0.88 to 1 and for those with non-epilepsy from 0.07 to 0.42. CONCLUSION: It is possible to devise a tool based on simple clinical information using Bayesian principles. Initial validation suggests that this has the potential to enable health workers to diagnose episodes as epileptic or not. This now needs to be tested in different populations. The tool is easily converted to a mobile phone app. PMID- 24774747 TI - Refractory epilepsy and encephalocele: lesionectomy or tailored surgery? PMID- 24774748 TI - CD4+CD25-Foxp3+ T cells: a marker for lupus nephritis? AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogenous autoimmune disease, which can affect different organs. Increased proportions of CD4+CD25 Foxp3+ T cells have been described in SLE patients. The exact role of this cell population in SLE patients still remains unclear. We therefore analyzed this T cell subset in a large cohort of SLE patients with different organ manifestations. METHODS: Phenotypic analyses, proportions and absolute cell numbers of CD4+CD25-Foxp3+ T cells were determined by flow cytometry (FACS) in healthy controls (HC) (n = 36) and SLE patients (n = 61) with different organ manifestations. CD4+CD25-Foxp3+ T cells were correlated with clinical data, the immunosuppressive therapy and different disease activity indices. In patients with active glomerulonephritis, CD4+CD25-Foxp3+ T cells were analyzed in urine sediment samples. Time course analyses of CD4+CD25-Foxp3+ T cells were performed in patients with active disease activity before and after treatment with cyclophosphamide and prednisone. RESULTS: CD4+CD25-Foxp3+ T cells were significantly increased in active SLE patients and the majority expressed Helios. Detailed analysis of this patient cohort revealed increased proportions of CD4+CD25-Foxp3+ T cells in SLE patients with renal involvement. CD4+CD25-Foxp3+ T cells were also detected in urine sediment samples of patients with active glomerulonephritis and correlated with the extent of proteinuria. CONCLUSION: CD4+CD25-Foxp3+ T cells resemble regulatory rather than activated T cells. Comparative analysis of CD4+CD25-Foxp3+ T cells in SLE patients revealed a significant association of this newly described cell population with active nephritis. Therefore CD4+CD25-Foxp3+ T cells might serve as an important tool to recognize and monitor SLE patients with renal involvement. PMID- 24774749 TI - Genetic variations of MMP9 gene and intracerebral hemorrhage susceptibility: a case-control study in Chinese Han population. AB - OBJECTIVE: To investigate the association between genetic variations of matrix metalloproteinase 9 (MMP9) gene and intracerebral hemorrhage (ICH) susceptibility in Chinese Han population. METHODS: The clinical data and peripheral blood samples from the patients with ICH and hypertension, and controlled subjects with hypertension only, were collected. MassARRAY Analyzer was used to genotype the tagger single nucleotide polymorphism (SNP) of MMP9 gene. Haploview4.2 and Unphased3.1.7 were employed to construct haplotypes and to analyze the association between genetic variations (alleles, genotypes and haplotypes) of MMP9 gene and ICH susceptibility. RESULTS: 181 patients with ICH and hypertension, and 197 patients with hypertension only, were recruited between Sep 2009 and Oct 2010. Patients in the ICH group were younger (61.80 +/- 13.27 vs. 72.44 +/- 12.71 years, p<0.05). Other conventional risk factors between the ICH and control groups were similar. There were 6 Tagger SNPs and 4 haplotypes of MMP9 gene in our sample population. Our logistical regression analysis showed that there were no significant associations between genetic variations of the MPP9 gene and ICH susceptibility (all p>0.05). CONCLUSIONS: The genetic variations of MMP9 gene were not significantly associated with ICH susceptibility in the Chinese Han population. PMID- 24774750 TI - Effects of atorvastatin on the inflammation regulation and elimination of subdural hematoma in rats. AB - BACKGROUND AND PURPOSE: It is well known that inflammation influence chronic subdural hematoma (CSDH) formation to a large extent. Atorvastatin has pleiotropic effects on restraining inflammation and promoting angiogenesis besides its cholesterol-lowering function. Hence, atorvastatin may induce anti inflammation effects and facilitate therapeutic effects for subdural hematoma (SDH). METHODS: Adult male Wistar rats were subjected to SDH and successful establishment of SDH was confirmed by magnetic resonance imaging (MRI). The treatment was initiated 6 hours after SDH induction. For the treatment, rats suffering SDH were randomly divided into saline group (the control group, rats were treated by saline, n=29) and atorvastatin group (rats were treated by atorvastatin, 3mg/kg/day, n=30). The volume of lesion before treatment as well as on day 2 and day 7 after initial treatment was measured by MRI, respectively. The behaviors before SDH induction and on the days 1, 3, 5 and 7 after the initial treatment were dynamically evaluated. Gene expression, cytokine secretion and the number of neutrophilic granulocyte and vascular density were measured in both neomembrane and SDH lesion on the day 2 and day 7 after the initial treatment. RESULTS: It was found that the SDH rats treated by atorvastatin had a better behavior recovery compared to the ones treated by saline (p<0.05). By virtue of MRI scanning, it was revealed that SDH volumes were eliminated at a high speed by administration of atorvastatin than that of saline. With the help of the microscopic examination in the neomembrane, it was detected that the density of CD31+ neovasculars in the atorvastatin group was significantly higher than that in the saline group and the number of neutrophilic granulocyte in the atorvastatin group is less than that in the saline group. In comparison with saline treatment, the atorvastatin treatment did not change IL-10 expression and secretion, but it significantly decreased TNF-alpha and IL-6 level as well as VEGF gene expression. CONCLUSIONS: Atorvastatin treatment may eliminate SDH and improve the neural function of the rats through its anti-inflammatory effects. Hence, it indicated that statin induced inflammatory modulation might play a significant role in rats' SDH elimination and the functional recovery. PMID- 24774751 TI - Spontaneous sternocleidomastoid muscle hematoma following thrombolysis for acute ischemic stroke. AB - Spontaneous or traumatic bleeding is a common complication of systemic thrombolysis in patients with acute ischemic stroke. We report the case of an 83 y.o. woman with right facio-brachio-crural hemiparesis, left deviation of the head and aphasia who developed, after thrombolytic therapy, a spontaneous sternocleidomastoid muscle hematoma that regressed few days later. To our knowledge, this is the first case reported in the literature of asymptomatic and spontaneous skeletal muscle hematoma following thrombolysis for the treatment of acute ischemic stroke. The occurrence of lateral cervical tuberculosis lymphadenitis ipsilateral to sternocleidomastoid muscle hematoma may suggest a causal relationship between local chronic inflammation of active mycobacterial infection and thrombolysis-related extravasation. This case should suggest caution in thrombolytic treatment in patients with chronic immune dysregulation and vascular inflammation such as extra-pulmonary tuberculosis. PMID- 24774752 TI - Protocols for metagenomic DNA extraction and Illumina amplicon library preparation for faecal and swab samples. AB - Next-generation sequencing (NGS) technology has extraordinarily enhanced the scope of research in the life sciences. To broaden the application of NGS to systems that were previously difficult to study, we present protocols for processing faecal and swab samples into amplicon libraries amenable to Illumina sequencing. We developed and tested a novel metagenomic DNA extraction approach using solid phase reversible immobilization (SPRI) beads on Western Bluebird (Sialia mexicana) samples stored in RNAlater. Compared with the MO BIO PowerSoil Kit, the current standard for the Human and Earth Microbiome Projects, the SPRI based method produced comparable 16S rRNA gene PCR amplification from faecal extractions but significantly greater DNA quality, quantity and PCR success for both cloacal and oral swab samples. We furthermore modified published protocols for preparing highly multiplexed Illumina libraries with minimal sample loss and without post-adapter ligation amplification. Our library preparation protocol was successfully validated on three sets of heterogeneous amplicons (16S rRNA gene amplicons from SPRI and PowerSoil extractions as well as control arthropod COI gene amplicons) that were sequenced across three independent, 250-bp, paired-end runs on Illumina's MiSeq platform. Sequence analyses revealed largely equivalent results from the SPRI and PowerSoil extractions. Our comprehensive strategies focus on maximizing efficiency and minimizing costs. In addition to increasing the feasibility of using minimally invasive sampling and NGS capabilities in avian research, our methods are notably not avian-specific and thus applicable to many research programmes that involve DNA extraction and amplicon sequencing. PMID- 24774753 TI - Home death is associated with frequency of physician home medical care visits: a questionnaire survey on communications in home medical care settings. AB - AIM: To investigate the factors related to communications in home medical care settings, and the association between such factors and a patient's place of death. METHODS: A questionnaire survey of 295 families of patients who had previously received home medical care was carried out in June and July 2011. The response rate was 83.8% (n = 227). Following the exclusion of families where the patient was still alive, or where the place of death was unknown, 143 questionnaires were available for analysis. Logistic regression was used to identify significant associations between possible factors related to communication and occurrence of home death. RESULTS: Home death was observed in 66.4% (n = 95) of the families analyzed. Home death was significantly associated with the frequency of doctor home-visits per week (OR 2.835, 95% CI 1.436-5.597, P = 0.003). There was no statistically significant association between home death and any of the other variables included: malignant tumors as primary disease, independence in daily activity, duration of home medical care, duration of doctor's visits, experience of doctor-patient communication without family, doctor-family communication without the patient or explanation from the doctor on the phone, existence of home-visit nursing services, existence of family's anxieties and/or questions, age of primary caregiver(s) and sex of primary caregiver(s). CONCLUSION: The frequency of doctor home-visits was the only factor identified that was positively associated with the occurrence of home death in home medical care settings. PMID- 24774754 TI - Radiographic evaluation of the modified Brunelli technique versus a scapholunotriquetral transosseous tenodesis technique for scapholunate dissociation. AB - PURPOSE: To compare reduction of the scapholunate articulation using a transosseous tenodesis through the scaphoid, lunate, and triquetrum (SLT) with the modified Brunelli technique (MBT) in a cadaver model, as measured by scapholunate (SL) angle and diastasis on radiographs. METHODS: Twelve fresh frozen cadaveric wrists were radiographically examined in a neutral posture, ulnar deviation, and clenched fist position. The SL angle and diastasis were recorded in each position with the SL ligament intact, after sectioning the ligament and secondary restraints, and after reconstruction by either the MBT (6 wrists) or SLT technique (6 wrists). Wrists were cycled through their maximum flexion and extension arc 100 times to simulate wrist motion after ligament sectioning and reconstruction. RESULTS: After sectioning and cycling, all wrists demonstrated radiographic evidence of SL diastasis. After ligament reconstruction and cycling, there was no statistically significant difference in diastasis in the MBT reconstructions compared with the SLT reconstructions (3.0 vs 2.4 mm). The SLT group demonstrated better maintenance of the restored SL angle than the MBT reconstructions. CONCLUSIONS: In this cadaveric model, both MBT and SLT reconstructions restored anatomic parameters in the SL joint, with correction of SL diastasis and SL angle. Future studies to assess the clinical outcomes of SLT tenodesis in patients with chronic SL disruptions are important. CLINICAL RELEVANCE: The SLT tenodesis, with a central biologic tether along the SL axis and dorsal reinforcement, may prove clinically useful. PMID- 24774755 TI - Siamese twins with craniofacial duplication and bilateral cleft lip/palate in a ceramic representation of the Chimu culture (Peru): a comparative analysis with a current case. AB - Craniofacial duplication or diprosopus is a very rare malformation that is present in approximately 0.4% of conjoined twins. Here is presented a case of craniofacial duplication in association with bilateral cleft lip/palate in both heads found in a ceramic representation from the early Chimu culture from Peru. A comparative analysis is made with a current case of a 28-week-old fetus with similar characteristics. After reviewing the medical literature on conjoined twins, very few reports of facial cleft in both twins were found, with no reports at all of bilateral cleft lip/palate. This ceramic crock is considered one of the first representations suggestive of craniofacial duplication, and probably the first reporting it in association with facial cleft. PMID- 24774776 TI - Effect of botulinum-A toxin injection into bulbospongiosus muscle on ejaculation latency in male rats. AB - INTRODUCTION: Premature ejaculation (PE) is the most common male sexual dysfunction. A variety of pharmacotherapeutic strategies have been employed to treat men suffering with lifelong PE. However, there are currently no pharmaceuticals approved by the U.S. Food and Drug Administration specifically designed for PE treatment. AIM: Given that the bulbospongiosus muscle is involved in the ejaculatory reflex in both humans and rodents and that local administration of botulinum-A can abolish muscle contractions, the current study examined the effect of injection of botulinum-A toxin into the bulbospongiosus muscle on the ejaculatory latency of male rats. METHODS: After screening for normal sexual activity with sexually receptive female rats, 33 sexually experienced male Long-Evans rats (Harlan Laboratories, Indianapolis, IN, USA) underwent an additional four pretreatment sexual exposures over the course of the following week, during which all components of sexual behavior were video recorded by trained observers. On the day after their fourth experience, rats were anesthetized and received a single injection of either 0.5 unit (n = 11) or 1 unit (n = 11) of botulinum-A toxin or saline vehicle (n = 11). Botulinum-A toxin was dissolved in 0.1 mL of saline vehicle and injected bilaterally into the bulbospongiosus muscle by the percutaneous route. Beginning 2 days after treatment, sexual behaviors were reexamined over the course of the following week on four separate occasions. MAIN OUTCOME MEASURES: The latency to achieve ejaculation, and the frequencies and latencies of mounts and intromissions were video recorded by trained observers in a blinded fashion. RESULTS: Relative to pretreatment measurements, bilateral injection of saline vehicle into the bulbospongiosus muscle did not affect ejaculation latencies. However, rats treated with either 0.5 or 1 unit of botulinum-A toxin exhibited significantly longer latencies to achieve ejaculation relative to pretreatment performance. Of note, botulinum-A toxin did not affect the ability to achieve mounts, intromissions, or ejaculation. CONCLUSIONS: These results demonstrate that botulinum-A toxin injection into the bulbospongiosus muscle is a safe and effective treatment that extends ejaculatory latency in rats without affecting the ability to engage in sexual activity or achieve ejaculation. Further studies are required to evaluate this therapeutic concept in PE patients. PMID- 24774780 TI - The safety and usefulness of neutron brachytherapy and external beam radiation in the treatment of patients with gastroesophageal junction adenocarcinoma with or without chemotherapy. AB - PURPOSE: To assess the safety and usefulness of neutron brachytherapy (NBT) as an adjuvant in the treatment of patients with gastroesophageal junction adenocarcinoma (GEJAC) with external beam radiation (EBRT), with or without chemotherapy. METHODS AND MATERIALS: In total, 197 patients with localized, advanced GEJAC received EBRT and NBT with or without chemotherapy. Radiotherapy consisted of external irradiation to a total dose of 40-54 Gy (median 50 Gy) and brachytherapy to 8-25 Gy (median 20 Gy) in two to five fractions. In total, 88 patients received chemotherapy that consisted of two cycles of a regimen with CDDP and 5FU from days l-4. The cycles were administered on days 1 and 29. MMC was given alone in bolus injection on day 1 each week. The cycles were administered on days 1, 8, 15 and 22. RESULTS: The duration of follow-up ranged from six to 106 months (median 30.4 months). The median survival time for the 197 patients was 13.3 months, and the one, two, three- and five-year rates for overall survival were 57.1%, 35.1%, 23.0% and 9.2%, respectively. For acute toxicity, no incidences of fistula and massive bleeding were observed during this treatment period. In total, 159 (80.7%) patients developed Grade 2 hematologic toxicity and 146 (74.1%) patients developed Grade >= 2 esophagitis. The median times of incidence of fistula and bleeding were 9.5 (3-27.3) months and 12.7 (5 43.4) months, respectively. The incidence of severe, late complications was related to higher NBT dose/f (20-25 Gy/5 F) and higher total dose(>=70 Gy). In total, 75.2% of the patients resumed normal swallowing and 2.0% had some residual dysphagia (non-malignant) requiring intermittent dilatation. CONCLUSION: A combination of EBRT and NBT with the balloon type applicator was feasible and well tolerated. Better local-regional control and overall survival cannot achieved by a higher dose, and in contrast, a higher dose caused more severe esophageal injury. PMID- 24774782 TI - Secondary prevention: the ongoing challenge. PMID- 24774825 TI - Words of wisdom. Re: Improving detection of clinically significant prostate cancer: MRI/TRUS fusion-guided prostate biopsy. PMID- 24774826 TI - Words of wisdom. Re: Early detection of prostate cancer: AUA guideline. PMID- 24774827 TI - Words of wisdom. Re: Use of statins and the risk of death in patients with prostate cancer. PMID- 24774828 TI - Words of wisdom. Re: Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. PMID- 24774829 TI - Words of wisdom. Re: Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. PMID- 24774830 TI - Words of wisdom. Re: Advanced paternal age and mortality of offspring under five years of age: a register-based cohort study. PMID- 24774832 TI - Assessment of therapeutic biomarkers in the treatment of children with postural tachycardia syndrome and vasovagal syncope. AB - BACKGROUND: Postural tachycardia syndrome and vasovagal syncope are common causes of orthostatic intolerance in children. The supplementation with water, or salt, or midodrine, or beta-blocker was applied to children with postural tachycardia syndrome or vasovagal syncope. However, the efficacy of such medication varied and was not satisfied. This review aimed to summarise the current biomarkers in the treatment of the diseases. DATA SOURCES: Studies were collected from online electronic databases, including OVID Medline, PubMed, ISI Web of Science, and associated references. The main areas assessed in the included studies were clinical improvement, the cure rate, and the individualised treatment for postural tachycardia syndrome and vasovagal syncope in children. RESULTS: Haemodynamic change during head-up tilt test, and detection of 24-hour urinary sodium excretion, flow-mediated vasodilation, erythrocytic H2S, and plasma pro adrenomedullin as biological markers were the new ways that were inexpensive, non invasive, and easy to test for finding those who would be suitable for a specific drug and treatment. CONCLUSION: With the help of biomarkers, the therapeutic efficacy was greatly increased for children with postural tachycardia syndrome and vasovagal syncope. PMID- 24774833 TI - Genome-scale metabolic network reconstruction and in silico flux analysis of the thermophilic bacterium Thermus thermophilus HB27. AB - BACKGROUND: Thermus thermophilus, an extremely thermophilic bacterium, has been widely recognized as a model organism for studying how microbes can survive and adapt under high temperature environment. However, the thermotolerant mechanisms and cellular metabolism still remains mostly unravelled. Thus, it is highly required to consider systems biological approaches where T. thermophilus metabolic network model can be employed together with high throughput experimental data for elucidating its physiological characteristics under such harsh conditions. RESULTS: We reconstructed a genome-scale metabolic model of T. thermophilus, iTT548, the first ever large-scale network of a thermophilic bacterium, accounting for 548 unique genes, 796 reactions and 635 unique metabolites. Our initial comparative analysis of the model with Escherichia coli has revealed several distinctive metabolic reactions, mainly in amino acid metabolism and carotenoid biosynthesis, producing relevant compounds to retain the cellular membrane for withstanding high temperature. Constraints-based flux analysis was, then, applied to simulate the metabolic state in glucose minimal and amino acid rich media. Remarkably, resulting growth predictions were highly consistent with the experimental observations. The subsequent comparative flux analysis under different environmental conditions highlighted that the cells consumed branched chain amino acids preferably and utilized them directly in the relevant anabolic pathways for the fatty acid synthesis. Finally, gene essentiality study was also conducted via single gene deletion analysis, to identify the conditional essential genes in glucose minimal and complex media. CONCLUSIONS: The reconstructed genome-scale metabolic model elucidates the phenotypes of T. thermophilus, thus allowing us to gain valuable insights into its cellular metabolism through in silico simulations. The information obtained from such analysis would not only shed light on the understanding of physiology of thermophiles but also helps us to devise metabolic engineering strategies to develop T. thermophilus as a thermostable microbial cell factory. PMID- 24774834 TI - Differential activation of sporamin expression in response to abiotic mechanical wounding and biotic herbivore attack in the sweet potato. AB - BACKGROUND: Plants respond differently to mechanical wounding and herbivore attack, using distinct pathways for defense. The versatile sweet potato sporamin possesses multiple biological functions in response to stress. However, the regulation of sporamin gene expression that is activated upon mechanical damage or herbivore attack has not been well studied. RESULTS: Biochemical analysis revealed that different patterns of Reactive oxygen species (ROS) and antioxidant mechanism exist between mechanical wounding (MW) and herbivore attack (HA) in the sweet potato leaf. Using LC-ESI-MS (Liquid chromatography electrospray ionization mass spectrometry analysis), only the endogenous JA (jasmonic acid) level was found to increase dramatically after MW in a time-dependent manner, whereas both endogenous JA and SA (salicylic acid) increase in parallel after HA. Through yeast one-hybrid screening, two transcription factors IbNAC1 (no apical meristem (NAM), Arabidopsis transcription activation factor (ATAF), and cup-shaped cotyledon (CUC)) and IbWRKY1 were isolated, which interact with the sporamin promoter fragment of SWRE (sporamin wounding-responsive element) regulatory sequences. Exogenous application of MeJA (methyl jasmonate), SA and DIECA (diethyldithiocarbamic acid, JAs biosynthesis inhibitor) on sweet potato leaves was employed, and the results revealed that IbNAC1 mediated the expression of sporamin through a JA-dependent signaling pathway upon MW, whereas both IbNAC1 and IbWRKY1 coordinately regulated sporamin expression through JA- and SA dependent pathways upon HA. Transcriptome analysis identified MYC2/4 and JAZ2/TIFY10A (jasmonate ZIM/tify-domain), the repressor and activator of JA and SA signaling among others, as the genes that play an intermediate role in the JA and SA pathways, and these results were further validated by qRT-PCR (quantitative real-time polymerase chain reaction). CONCLUSION: This work has improved our understanding of the differential regulatory mechanism of sporamin expression. Our study illustrates that sweet potato sporamin expression is differentially induced upon abiotic MW and biotic HA that involves IbNAC1 and IbWRKY1 and is dependent on the JA and SA signaling pathways. Thus, we established a model to address the plant-wounding response upon physical and biotic damage. PMID- 24774835 TI - Effects of dietary microencapsulated sodium butyrate on growth, intestinal mucosal morphology, immune response and adhesive bacteria in juvenile common carp (Cyprinus carpio) pre-fed with or without oxidised oil. AB - The aim of the present study was to investigate the effects of different dietary sustained-release microencapsulated sodium butyrate (MSB) products (0 (non supplement), 1.5 and 3.0 h) for a control or oxidised soyabean oil (SBO) diet on fish production, intestinal mucosal condition, immunity and intestinal bacteria in juvenile common carp (Cyprinus carpio). Dietary MSB increased weight gain and reduced the feed conversion ratio within the control and oxidised SBO groups. Gut mucosa was damaged in the oxidised SBO group fed without MSB, in contrast to a normal appearance found in fish fed the MSB1.5 and MSB3.0 diets in the oxidised SBO group. Microvillus density increased in fish fed the MSB1.5 and MSB3.0 diets in the oxidised SBO group (P< 0.001); however, microvillus density was affected by the different pre-fed diets in the midgut (P< 0.001) and by the different sustained-release times of MSB in the distal gut (DG) (P= 0.003). The interaction between the pre-fed diets and the sustained-release times of dietary MSB was significant for the relative gene expression levels of gut heat shock protein-70 (HSP70), pro-inflammatory cytokines (IL-1beta and TNF-alpha) and anti inflammatory cytokines (transforming growth factor-beta) within each gut segment, except for HSP70 in the DG and IL-1beta in the foregut. Modulation of adherent bacterial communities within each gut segment investigated was not obvious when the common carp were fed the diets with MSB, as similarity coefficients of >0.79 were observed. These results indicated that MSB can be used as a dietary supplement to repair or prevent intestinal damage in carp fed oxidised SBO. PMID- 24774858 TI - Free-living ciliates as potential reservoirs for eukaryotic parasites: occurrence of a trypanosomatid in the macronucleus of Euplotes encysticus. AB - BACKGROUND: Flagellates of the family Trypanosomatidae are obligate endoparasites, which can be found in various hosts. Several genera infect insects and occur as monoxenous parasites especially in representatives of Diptera and Hemiptera. These trypanosomatid flagellates probably share the worldwide distribution of their hosts, which are often infested by large numbers of endoparasites. Traditionally, their taxonomy was based on morphology, host origin, and life cycle. Here we report the characterization of a trypanosomatid infection detected in a protozoan, a ciliate collected from a polluted freshwater pond in a suburb of New Delhi (India). METHODS: Live observations and morphological studies applying light, fluorescence and transmission electron microscopy were conducted. Molecular analyses of host and parasite were performed and used for phylogenetic reconstructions and species (host) or genus level (parasite) identification. RESULTS: Although the morphological characteristics were not revealing, a high similarity of the trypanosomatids 18S rRNA gene sequence to Herpetomonas ztiplika and Herpetomonas trimorpha (Kinetoplastida, Trypanosomatidae), both parasites of biting midges (Culicoides kibunensis and Culicoides truncorum, respectively) allowed the assignment to this genus. The majority of the host population displayed a heavy infection that significantly affected the shape of the host macronucleus, which was the main site of parasite localization. In addition, the growth rate of host cultures, identified as Euplotes encysticus according to cell morphology and 18S rRNA gene sequence, was severely impacted by the infection. CONCLUSIONS: The host-parasite system described here represents a recent example of free-living protists acting as environmental reservoirs for parasitic eukaryotic microorganisms. PMID- 24774859 TI - Transcription factors: specific DNA binding and specific gene regulation. AB - Specific recognition of cis-regulatory regions is essential for correct gene regulation in response to developmental and environmental signals. Such DNA sequences are recognized by transcription factors (TFs) that recruit the transcriptional machinery. Achievement of specific sequence recognition is not a trivial problem; many TFs recognize similar consensus DNA-binding sites and a genome can harbor thousands of consensus or near-consensus sequences, both functional and nonfunctional. Although genomic technologies have provided large scale snapshots of TF binding, a full understanding of the mechanistic and quantitative details of specific recognition in the context of gene regulation is lacking. Here, we explore the various ways in which TFs recognizing similar consensus sites distinguish their own targets from a large number of other sequences to ensure specific cellular responses. PMID- 24774861 TI - Genetic and environmental relationships between change in weight and insulin resistance: the Healthy Twin Study. AB - We aimed to investigate the association between weight change from 20 years of age and insulin resistance (IR), and genetic and environmental relationships between these traits. In 594 Korean twins and family members (209 men, 385 women, 44.0 +/- 10.8 years old), the percentage of weight change was calculated using self-reported body weight at 20 years of age and currently measured bodyweight. IR traits were assessed using fasting plasma glucose and insulin, the homeostasis model assessment of IR index (HOMA-IR), and the quantitative insulin sensitivity check index (QUICKI). Linear mixed analysis was applied after adjusting for household, body mass index (BMI) at the age of 20 years, age, sex, alcohol, smoking, physical activity, and caloric intake. Heritabilities and genetic and environmental correlations were estimated after adjusting for covariates. In 55 monozygotic twin pairs discordant for HOMA-IR level by >0.3, a conditional logistic regression analysis was conducted regarding weight change. Increases in glucose, insulin, and HOMA-IR and a decrease in QUICKI were associated with a higher percentage of weight change (p < .05). Estimated heritabilities for IR traits were 0.401-0.606 (p < .001). In cross-trait relationships, environmental correlations were -0.43-0.42 (p < .05 for all IR), while genetic correlations were -0.27-0.27 (p < .05 for QUICKI, insulin, and HOMA-IR). In 55 pairs of monozygotic twins, the odds ratio (95% confidence interval) for having a higher level of HOMA-IR was 1.10 (1.03-1.17) with 1% increase in weight change since 20 years old, after adjusting for lifestyle-related factors. In conclusion, both genetic and environmental influences played significant roles in the positive association between weight change from 20 years of age and IR. PMID- 24774860 TI - Vitamin D status in chronic dialysis patients with depression: a prospective study. AB - BACKGROUND: Depression is the most widely acknowledged psychological problem among end-stage renal disease (ESRD) patients. Depression may be associated with VD deficiency. The aims of this study are to (a) elucidate the prospective association between HsCRP, VD contents and depressive symptoms in the dialyzed population, and (b) find the effect of calcitriol supplementation on depression in dialyzed patients. METHODS: In this prospective study, 484 dialysis patients (382 hemodialysis [HD] cases and 102 peritoneal dialysis [PD] cases; aged 18-60 years) from two hospitals in southeast China were included. The depression in these patients was evaluated using the Chinese version of Beck's Depression Inventory (BDI). All subjects answered the BDI-I questionnaire for assessment of depression levels in summer. A cut-off value of 16 was set to include dialysis patients with depression. All patients were divided into two groups depending on the absence (Group 1) or presence (Group 2) of depression. The two groups took 0.5 MUg/day 1,25-Dihydroxyvitamin D orally for one year. BDI Scores were recalculated for all patients. Sociodemographic, clinical data, and serum VD contents were also collected. RESULTS: A total of 484 participants (247 men [51.0%] and 237 women [49.0%]) were surveyed. Depressive symptoms were found in 213 (44.0%) patients. The baseline serum VD level (VD2 + VD3) was 17.6 +/- 7.7 nmol/L. Patients with depressive symptoms have significantly higher serum HsCRP level and significantly lower serum VD level compared with the control group. After one-year follow-up, the supplementation of 0.5 MUg/day calcitriol slightly improved the microinflammatory state such as lowering mean serum HsCRP level and improving serum VD level, but not in significantly enhancing the depressive symptoms. CONCLUSIONS: Calcitriol supplementation did not significantly enhance the depressive symptoms in our dialyzed population although patients with low levels of serum VD were more depressed. Therefore, more prospective randomized controlled trials are necessary to reveal the exact cause-and-effect relationship between VD status and depressive symptoms or VD status related to some specific subtypes in dialyzed patients. PMID- 24774863 TI - Interview with Oswalt Kolle (1928-2010): German sex education pioneer. AB - INTRODUCTION: Alfred Kinsey (1894-1956) was the first pioneer of scientific sexology after World War II with his surveys on human sexuality in the male (1948) and the female (1953), which underwent worldwide translations and also had a major impact in Europe. AIM: To clarify the role of the journalist Oswalt Kolle (1928-2010) as the promoter of sex education in Germany and Western Europe in the late 1960s. METHODS: The information is almost exclusively based on a live interview taken with the time witness Oswalt Kolle in February 2010. This scientific technique of oral history is well established in the field of history research today. RESULTS: Kolle has a strong family background in the medical field as his father was a well-known psychiatrist and his grandfather a prominent bacteriologist. Before starting an interest in sex education, Kolle was a successful journalist by interviewing celebrities but turned into one of the most important critics against the restricted views on sex in Germany and Western Europe in the 1960s. His books and films on sexuality were translated into at least 12 languages and were major blockbusters for at least a decade. CONCLUSIONS: Oswalt Kolle had more influence on the public awareness and practice of sexuality in Western Europe and especially Germany than any other single person in his time. PMID- 24774862 TI - Effect of set configuration on hemodynamics and cardiac autonomic modulation after high-intensity squat exercise. AB - The aim of this study was to compare the effect of two different high-intensity resistance exercise (RE) set configurations on the following: systolic blood pressure (SBP), rate pressure product (RPP), heart rate (HR) variability (HRV), and HR complexity (HRC). Ten well-trained males performed three parallel squat sets until failure (traditional training; TT) with the four repetitions maximum load (4RM), and a rest of 3 min between sets. Thereafter, participants performed a cluster training session (CT) of equated load but with resting time distributed between each repetition. Dependent variables were recorded before, during, and after RE. Mean SBP (25.7 versus 10.9% percentage increase; P = 0.016) and RPP (112.5 versus 69.9%; P = 0.01) were significantly higher in TT. The decrease in HRV after exercise and the drop of HRC during exercise were similar in CT and TT. Change of standard deviation of normal RR intervals after TT correlated with change in SBP (r = 0.803; P = 0.009) while the change of Sample Entropy during exercise correlated with the increment of RPP during CT (rho = -0.667; P = 0.05). This study suggests that set configuration influences acute cardiovascular responses during RE. When intensity, volume and work-to-rest ratio are equated, CT is less demanding in terms of SBP and RPP. A greater hemodynamic response during exercise would be associated with a faster parasympathetic recovery. PMID- 24774884 TI - The influence of glaucoma medications on ocular surface disease in primary open angle glaucoma patients with and without conjunctivochalasis. PMID- 24774885 TI - Fall frequency and risk factors in patients with Parkinson's disease in Belgrade, Serbia: a cross-sectional study. AB - AIM: The aim of the present study was to estimate fall frequency as well as demographic and clinical factors related to falling in a cohort of Serbian patients with Parkinson's disease (PD). METHOD: The cross-sectional study comprised 300 consecutive patients recruited at the Neurology Clinic in Belgrade, Serbia, from August 2011 to December 2012. Data were acquired though detailed interviews, while a history of falling referred to the period of 6 months before testing. After a interview related to the circumstances of the last fall sustained by PD patients, the participants were evaluated with the Mini-Mental State Examination, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr scale, the Falls Efficacy Scale and the Self-Assessment Disability Scale, New Freezing of Gait questionnaire for frequency and impact of freezing, and the Hamilton Depression and the Hamilton Anxiety Rating Scale. RESULTS: A total of 60% of individuals reported a fall in the 6-month period before testing. Multivariate regression showed that patients with PD who had a Self-Assessment Disability Scale score of >=56 and Unified Parkinson's Disease Rating Scale total score of >=69 were 2.04 and 3.32 times more likely to fall, respectively (95% CI 1.10-3.79, P = 0.023 for Self-Assessment Disability Scale and 95% CI 1.83-6.00, P = 0.001 for Unified Parkinson's Disease Rating Scale). In contrast, a decrease of risk for falling by 57% was observed among those who practiced regular physical activity before the onset of PD (95% CI 0.23-0.80, P = 0.008). CONCLUSION: There is a strong relationship between falling and self-perceived disability, whereas previous physical exercise had a protective effect. PMID- 24774886 TI - [The construction of gan zhu shuxie (liver controlling conveyance and dispersion), as viewed from the contemporary teaching material of basic theory of Traditional Chinese Medicine]. AB - In current teaching material of basic theory of Traditional Chinese Medicine (TCM), the theory of "liver controlling conveyance and dispersion" covers the functional adjustment of many aspects, including the overall human physiology, digestion, mental activity, blood circulation, water metabolism and reproduction. Through the research of the teaching material of TCM basic theory since the establishment of the People's Republic of China, it can be considered that there are 3 stages for the construction of the theory of "liver controlling conveyance and dispersion". From the 1950s to 1970s, this theory was not mentioned in any teaching materials; from the 1970s to the mid 1980s, different views about this theory can be seen in the teaching materials; after the mid 1980s, this theory in the teaching materials became gradually basically identical. PMID- 24774887 TI - [Feeding venomous insects among the people and the measures to curb and control this addiction by the government in the Song Dynasty]. AB - Feeding venomous insects, a mystic witchcraft of producing poisonous materials to spoil other people has a long history which was still popular in the southern part of the Song Dynasty, aiming at revenge of one's enemy and the occupation of other's property. The Song government took a strict measures to tackle it, including enacting a decree to prohibiting it, encouraging people to report such malpractice, punishing heavily the person committing such criminal behavior and, at the same time, providing recipes and medicines to remedy its ensued disorders. All of these were helpful to the improvement of social morality. PMID- 24774888 TI - [Preliminary research on the medical condition of the "jiu bian" (nine northern border towns) of the early Ming Dynasty]. AB - In the Ming Dynasty, the important affairs of the nine northern border towns were building the city walls, providing armaments and provision and funds for the troops. Thus, the medical resources were relatively insufficient and the management system was not established. The supply of doctors and medicines were always insufficient, with similar conditions appeared in the troops and the royal government. Though the medicines and doctors were sent to the towns in the northern border frequently, yet, it was only a temporary measure. Because of the shortage of medical resources, the northern border towns had to invite doctors from inland, or train local doctor, or choose those who had medical knowledge from the army to take the responsibility of doctors. PMID- 24774889 TI - [A brief analysis on the on-duty systems and dispatching systems in the Imperial Academy of Medicine of the Qing Dynasty]. AB - The "on-duty systems" and "dispatching systems" in the Tai yi yuan (Imperial Academy of Medicine) of the Qing Dynasty served as the "prelude" of the medical officials to carry out their diagnoses and treatments. Mainly serving in the royal court, the "on-duty systems" included 3 sorts, viz., "specially selected on duty", "interior on-duty" and "exterior on-duty". In addition to providing medical services in the royal court, Imperial Academy of Medicine also served other royal members in the Capital, the ministers, the military, the civilians, the metropolitan examinations and the prisons. Thus, the "dispatching systems" was established, also included 3 sorts, viz., "special dispatchments", "dispatchments through reporting to the emperor" and "dispatchments through official communication". PMID- 24774890 TI - [Review of "Appended emergent recipes" recorded in New Chronicle of Wuqiang County of the Qing dynasty]. AB - In the volume 10 of New Chronicle of the Wuqiang County compiled in the 10(th) year of Daoguang reign (1830), there is an attached "Appended emergent recipes" with a large space devoted to TCM first-aid therapies, including 13,000 Chinese characters under 14 topics. Under each topic, the first-aid measures from Xi yuan ji lu (Collected Records of Washing Away Wrong Cases) are first cited, followed by many practical first-aid methods, thus summarizing emergency medicine and experiences since the Song dynasty, embodying the abundant first-aid therapy of northern China, representing the real level of emergent medicine of that period. It is quite seldom to see so rich emergent measures collected in an overall county chronicle and is therefore of significance for the studies on the history of the versions of the book Xi yuan ji lu. PMID- 24774891 TI - [Regional difference of scholars' health-seeking behavior of the Qing dynasty as seen in diary]. AB - It is obvious that from the Xunletang Sanctum Catalogue, Jiachu Diary, Gengfu Diary, Diary of Master Li Wenqing, the difference in the scholars' "health seeking behavior" in different regions in the Qing dynasty due to the difference in medical resources can be figured out. In the cities with developed economy, the medical resources were abundant and readily accessible, patients tended to visit the doctors once they got sick, some even changed their doctors frequently for seeking better therapeutic effects. Accordingly, the doctor-patient relationship was rather simple. In terms of the little town or county, since professional medical workers were much less, and medical resources scarce, patients had to spend more time to search for a doctor, and his/her sickness was thus delayed and lingered for a long time. As a result, such patients had to remedy themselves. Once they chose a doctor, their relation might be maintained for a longer time in a stable and close contact. Restricted by the overall therapeutic level, different scholars in different regions might always pursue help from external mystic energy when they were helpless. PMID- 24774892 TI - [The historical conditions of introduction and diffusion of American ginseng in the Qing Dynasty]. AB - The American ginseng (Panax quinquefolium L.), originally a native product of the United States and Canada, was introduced into China in the Qing Dynasty, and then spread and applied extensively. This was closely related to the contemporary exchange between China and foreign counties, which became the cultural background for the introduction of American ginseng; the development of pharmacology, which contributed to the commercial opportunity for its diffusion; the shortage of resources of ginseng, resulting in the urgent need for its introduction; and the publication of popular books of materia medica, which accelerated the velocity of its diffusion. PMID- 24774893 TI - [Trading of crude drugs between China and Russia as recorded in 3 Chinese versions of Russian works]. AB - Trading of crude drugs between China and Russia appeared before the 19(th) century. By then, exports of Chinese crude drugs to Russia were mainly plants, with Radix et Rhizoma Rhei as the most exported one, followed by both dietary and medicinal aromatic plants, such as fennel, cinnamon bark, pepper, ginger, and Radix Angelica sinensis, and quinine. Imports of Russian drugs were mainly of animal ones, especially those valuable animals like musk sac. In 1854, the importation of a large amount of such sac, numbering as many as 70 000, was very remarkable. Other drugs included stag antler, tender horn of deer, demonstrating typically the regional and productive characteristics of Russia. PMID- 24774894 TI - [A brief history of recognition on urolithiasis before medieval period]. AB - Urinary stone was first found by human as early as 4900 BC when the Egyptian monks applied emesis, catharsis, diuresis, and diaphoresis for its treatment which, as they claimed, can expel the stones out of the body occasionally. In 2700 BC, definite records on urinary stone were seen in Egytian papyrus which attempted to cure this disorder by sucking method. In the 4(th) century BC, the Greek physician Alexandria mentioned that such stones can be expelled after being smashed. By then, the Greeks recognized the existence of renal stone by describing its manifestations. Sushruta, an ancient Indian royal physician mentioned in 6(th) century BC, the picking up of stones by splints through the urethra and the complications of such disorder in his Sushrutasamhita. He also recommended the removal of stones through the perineal part. Unfortunately, many patients died of such operation. Ancient Roman physicians described such operation circumstantially and the herbs for its treatment in the 1(st) century BC. During the 10(th) century, the Arabian physician Abukasis was the first to advocate the method of smashing stones in the urethra with an instrument he devised. In the period before medieval age, the removal of urinary stones through the perineal incision had been the main method which was so limited an approach due to the lack of anatomical knowledge and antiseptic conception. PMID- 24774895 TI - [Textual research on Chen Ye and his Jia cang jing yan fang (Family-preserved Empirical Recipes) of the Song Dynasty]. AB - Chen Ye, an official of the Southern Song Dynasty, also known as Chen Rihua as his styled name, was born in Changle, Fuzhou in the reign of Shaoxing, and died during the reign of Duanping. He had been consecutively in the positions of Jiang shi lang (Court Gentleman for Ceremonial Service), Zhi zhou (Prefect) of Lingding, the Ti xing (Judicial Commissioner) of Guangdong, the Zong ling (Overseer-general) of Sichuan, Shan ding (Reviser), Shu lin and other positions in Tongzhou, Yuanzhou. His works included 1 volume of Gu ling xian sheng nian pu (Mr. Guling's Chronological Biography), 1 volume of Tan xie (On Humor), 1 volume of Shi hua (Poetry), 8 volumes of Jin yuan li shu (Jin Yuan's Smart Technique), 3 volumes of Yi jian zhi lei bian (Classified Compilation of Yijian's Annals), (Zeng guang) Suo sui lu (Augmented Records of Trivial Matters), 5 volumes of Jia cang jing yan fang (Family-preserved Empirical Recipes). He also compiled the 8 volume Yin jiang zhi (Yinjiang's Annals), published the 2-volume Jia cang ji yao fang (Collected Essential Recipes from Family Preservation), and other proses and poetry. Jia cang jing yan fang was a formulary compiled by Chen Ye, which was lost. Altogether 74 of its recipes were cited in Fu ren da quan liang fang (Complete Effective Prescriptions for Women's Diseases), Shou qin yang lao shu (A Book for Pursuing Seniors' Longevity and Healthcare), Pu ji fang (Prescriptions for Universal Relief) and Yong le da dian (Yongle Encyclopedia). PMID- 24774896 TI - [Characteristics of Qin Bowei's teaching material of gynecology]. AB - As the teaching work of gynecology, Qin Bowei's Teaching Material of Gynecology was used in the China Medical College in Shanghai in the Republican period. It is composed of 2 parts, the first part deals with the introduction to the characteristics of female physiology, pathology, principles of treatment based on differential diagnosis and treatment of women's disorders; the 2(nd) part discusses in details the pathogenesis, pathological mechanism, the system of theory-methodology-recipes-medicines. The whole book deals mainly with Traditional Chinese Medicine (TCM) combined with the research results of TCM gynecology by western medical theory of gynecology to make mutual interpretation in a concise structure and clear analysis with uniqueness. It is a rather systematic and essential TCM gynecological teaching material, embodying the author's personal academic idea, with profound influence on the education and compilation of teaching materials of TCM gynecology. PMID- 24774941 TI - Impact of prior statin therapy on the outcome of patients with suspected ventilator-associated pneumonia: an observational study. AB - INTRODUCTION: Ventilator-associated pneumonia (VAP) is the most commonly acquired infection in intensive care units (ICU). Its outcome is related, at least in part, to the host's response. Statins have anti-inflammatory effects and may thus improve the outcome. We aimed to assess the impact of prior statin use in the setting of VAP. METHODS: A six-year cohort study was conducted in a French ICU at a teaching hospital. All of the patients with suspected VAP were included. Baseline characteristics, outcomes, statin exposure, and the description of suspected episodes were collected prospectively. The primary endpoint was 30-day mortality. Patients who were taking statins before admission to the ICU whether or not treatment was continued thereafter ('previous users' group) were compared to those without prior statin therapy ('statin-naive' group). A survival analysis using a Cox model was conducted in the whole cohort and in the subgroup of prior statin users. RESULTS: Among the 349 patients included, 93 (26.6%) had taken statins. At baseline, these patients were at higher risk of complications than statin-naive ones (for example, older, more likely to be men and to have underlying diseases, greater simplified acute physiology score II (SAPS II)). There was, however, no difference regarding severity at the time VAP was suspected (sequential organ failure assessment (SOFA): 9.0 (4.0 to 16.0) versus 8.0 (4.0 to 17.0); P = 0.11). Nonetheless, 30-day mortality in statin users was not different from that in statin-naive patients (35.5% versus 26.2%, respectively; adjusted hazard ratio (HR) = 1.23 (0.79 to 1.90) 95% confidence interval (CI); P = 0.36). In contrast, after limiting analysis to prior statin users and adjusting for potential confounders, those who continued the treatment had better survival than those who did not (HR = 0.47; (0.22 to 0.97) 95% CI; P = 0.04). CONCLUSIONS: Statin continuation in prior users could provide protective effects in patients with suspected VAP. PMID- 24774962 TI - Insulin resistant rats display enhanced rewarding effects of nicotine. AB - BACKGROUND: Tobacco use among persons with Type II diabetes exponentially increases negative health consequences and mortality rates. It is especially troubling that diabetic persons who smoke have a greater difficulty with tobacco cessation as compared to non-diabetic smokers. Diabetes is a metabolic syndrome that consists of insulin resistance due to disruptions in insulin signaling. We have previously shown that insulin depletion enhances the motivational effects of nicotine. METHODS: The present study expands our previous work by examining whether insulin resistance, produced by a high-fat diet (HFD) regimen, enhances the rewarding effects of nicotine, as measured by the conditioned place preference (CPP) paradigm. Rats were placed on either a regular diet (RD) or a HFD for 5 weeks, after which they were assessed for insulin resistance via blood glucose measurements after an insulin challenge. Rats then underwent a nicotine CPP study. RESULTS: The findings revealed that HFD produced insulin resistant and non-insulin resistant animals. Interestingly, the magnitude of nicotine CPP was larger in insulin resistant rats versus RD rats. Nicotine CPP was absent in non insulin resistant animals. A similar increase in body weight was observed in insulin resistant and non-insulin resistant rats as compared to RD rats. These findings suggest that neither the increased body weight nor the HFD per se in the insulin resistant rats contributed to the enhanced nicotine reward. CONCLUSION: These present study suggests that insulin resistant rats undergo unique neurobiological changes related to a disruption in insulin signaling that promotes the rewarding effects of nicotine. PMID- 24774963 TI - Inverted left atrial appendage in an infant during cardiac surgery. AB - Inverted left atrial appendage is an unusual complication associated with congenital cardiac surgery. Inversion of the left atrial appendage may occur during the surgical procedure or afterwards. The left atrial appendage may invert iatrogenically or as a result of the negative pressure during placement or removal of the left atrial vent or during deairing manoeuvres. This event can be life-threatening because of the mass effect of the atrial appendage within the left atrial cavity. PMID- 24774964 TI - Intravenous lipopolysaccharide challenge alters ruminal bacterial microbiota and disrupts ruminal metabolism in dairy cattle. AB - In the present study, three primiparous lactating Holstein cows (260-285 d in lactation) were used in a 3 * 3 Latin square design to assess the effects of three doses (0.0, 0.4 and 0.8 MUg/kg body weight) of lipopolysaccharide (LPS, Escherichia coli 0111:B4) on changes in ruminal microbiota and ruminal fermentation. Ruminal pH was linearly decreased (P< 0.001) by LPS challenge, and the concentrations of acetate, propionate, butyrate, total volatile fatty acids and amino N increased linearly (P< 0.001) according to the LPS dose. LPS infusion linearly decreased (P< 0.001) the organic matter degradability of alfalfa hay and soyabean meal in the rumen, but did not affect (P>0.10) the gene expression of Na+/K+-ATPase and monocarboxylic acid transporter-1, -2 and -4. A plot of principal coordinate analysis based on unweighted UniFrac values and analysis of molecular variance revealed that the structure of ruminal bacterial communities in the control was distinct from that of the ruminal microbiota in the cattle exposed to LPS. At the phylum level, when compared with the control group, LPS infusion in the tested cows linearly increased (P< 0.05) the abundance of Firmicutes, and linearly decreased (P< 0.05) the percentage of Bacteroidetes, Tenericutes, Spirochaetes, Chlorobi and Lentisphaerae. To our knowledge, this is the first study to report that intravenously LPS challenge altered the ruminal bacterial microbiota and fermentation profiles. The present data suggest that systemic LPS could alter ruminal environment and ruminal microbiota composition, leading to a general decrease in fermentative activity. PMID- 24774965 TI - Evaluating contribution of ionic, osmotic and oxidative stress components towards salinity tolerance in barley. AB - BACKGROUND: Salinity tolerance is a physiologically multi-faceted trait attributed to multiple mechanisms. Three barley (Hordeum vulgare) varieties contrasting in their salinity tolerance were used to assess the relative contribution of ionic, osmotic and oxidative stress components towards overall salinity stress tolerance in this species, both at the whole-plant and cellular levels. In addition, transcriptional changes in the gene expression profile were studied for key genes mediating plant ionic and oxidative homeostasis (NHX; RBOH; SOD; AHA and GORK), to compare a contribution of transcriptional and post translational factors towards the specific components of salinity tolerance. RESULTS: Our major findings are two-fold. First, plant tissue tolerance was a dominating component that has determined the overall plant responses to salinity, with root K(+) retention ability and reduced sensitivity to stress-induced hydroxyl radical production being the main contributing tolerance mechanisms. Second, it was not possible to infer which cultivars were salinity tolerant based solely on expression profiling of candidate genes at one specific time point. For the genes studied and the time point selected that transcriptional changes in the expression of these specific genes had a small role for barley's adaptive responses to salinity. CONCLUSIONS: For better tissue tolerance, sodium sequestration, K(+) retention and resistance to oxidative stress all appeared to be crucial. Because these traits are highly interrelated, it is suggested that a major progress in crop breeding for salinity tolerance can be achieved only if these complementary traits are targeted at the same time. This study also highlights the essentiality of post translational modifications in plant adaptive responses to salinity. PMID- 24774966 TI - Sexual assault while too intoxicated to resist: a general population study of Norwegian teenage girls. AB - BACKGROUND: Underage drinking is widespread, but studies on alcohol-related sexual victimization among teenage girls are almost non-existent. Research on individual correlates and risk factors of sexual victimization more generally is also meager. This study focuses on sexual assault while incapacitated due to drunkenness among 15-18 year-old girls and examines how age, drinking behavior, impulsivity and involvement in norm-violating activities are associated with such victimization experiences. METHODS: Data stemmed from a school survey (response rate: 85%) in 16 Norwegian municipalities. Almost all analyses were restricted to girls who had been intoxicated in the past year (n = 2701). In addition to bivariate associations, adjusted odds ratios and relative risks of incapacitated sexual assault (ISA) were estimated. Further, population-attributable fractions were calculated to explore how the prevalence of ISA victimization was likely to be affected if effective preventive measures were targeted solely at high-risk groups. RESULTS: The majority of the girls (71%) had been intoxicated in the past year, of which 7% had experienced ISA victimization in the same period. The proportion of victims decreased by age within the group that had been intoxicated, reflecting that the youngest girls were more likely to get severely drunk. Impulsivity and involvement in norm-violating behaviors were identified as potential risk factors, but the population-attributable fractions indicated that the groups with the highest risk of ISA victimization accounted for only a minority of all the cases of such victimization. CONCLUSION: Sexual assault against teenage girls who are too drunk to resist seems to be prevalent in Norway - notably among the youngest girls who engage in heavy episodic drinking. This study also suggests that one should reconsider the notion that no individual attributes are related to females' sexual assault victimization. It also indicates that a high risk approach to prevention, targeting groups with a high level of impulsivity or behavioral problems, may have limited effect on the prevalence of ISA victimization. Thus, from a public health perspective, it may be advisable to give priority to universal preventive measures to curb young girls' risk of being sexually assaulted in a state of alcohol-induced incapacitation. PMID- 24774967 TI - Triple NF-kB binding sites and LTR sequence similarities in HIV-1C isolates irrespective of helminth co-infection. AB - BACKGROUND: Helminth infections as well as structural alternations in the long terminal repeat (LTR) regions of HIV-1 are known to contribute to elevated HIV RNA level and enhance HIV-1 diseases progression. However, the impact of helminths infections on the occurrences of triple NF-kappaB and genetic variability in LTR region of HIV-1C isolates is not known. We aimed to examine the presence of genetic variability in the LTR region of HIV-1C isolates during chronic HIV-helminth co-infection. METHODS: HIV-1C infected Ethiopians with (n = 22) and without (n = 20) helminth infection were included. The LTR region of HIV was amplified and sequenced. Sequences were aligned with reference set from the Los Alamos HIV database. Phylogenetic analysis and frequency of polymorphic changes was performed by the neighbour-joining method using Geneious Basic software. RESULTS: All LTR sequences from patients with or without of helminth co infection clustered with HIV-1 subtype C with two distinct subclusters (C and C'). The enhancer element was found to have three copies of 10-base pair binding sites for NF-kappaBs which is an evidence for predominance of triple NF-kappaB sites (94%) in HIV-1C isolates irrespective of helminths co-infection and subclusters. Moreover, irrespective of helminth co-infection and C/C' subclusters high sequences similarity in LTR was observed. There was no significant difference in plasma HIV RNA level between HIV-1 C and C' subclusters. CONCLUSIONS: Despite the small sample size, the predominance of triple NF-kappaB binding sites and high sequence similarities in LTR region irrespective of helminths infection suggest the natural occurrence of the three NF-kappaB binding sites in HIV-1C isolates without the influence of secondary infection. Thus, the higher HIV-1C viraemia in helminth co-infected individuals is more likely a result of immune activation rather than LTR sequence variation. Moreover, the lack of significant difference in plasma HIV RNA level between HIV-1 C and C' subcluster may show the lack of functional differences among the two groups. PMID- 24774968 TI - Immune-modulatory effects of dietary Yeast Beta-1,3/1,6-D-glucan. AB - Beta-glucans are a heterogeneous group of natural polysaccharides mostly investigated for their immunological effects. Due to the low systemic availability of oral preparations, it has been thought that only parenterally applied beta-glucans can modulate the immune system. However, several in vivo and in vitro investigations have revealed that orally applied beta-glucans also exert such effects. Various receptor interactions, explaining possible mode of actions, have been detected. The effects mainly depend on the source and structure of the beta-glucans. In the meantime, several human clinical trials with dietary insoluble yeast beta-glucans have been performed. The results confirm the previous findings of in vivo studies. The results of all studies taken together clearly indicate that oral intake of insoluble yeast beta-glucans is safe and has an immune strengthening effect. PMID- 24774988 TI - Systemic nickel allergy after internal fixation of a bunionectomy. AB - Allergic reactions to implanted metals have been estimated to occur in 1% to 5% of orthopedic cases. Stainless steel screws, which contain 14% nickel, are commonly used for internal fixation in an array of podiatric procedures. We present a rare case of a systemic allergic reaction to nickel secondary to stainless steel screw fixation in a bunionectomy procedure. PMID- 24774989 TI - Isolated first metatarsocuneiform joint fusion for correction of metatarsus primus varus deformity and literature review. AB - Correction of a bunion deformity with the use of proximal first ray procedures has historically included additional distal soft tissue and bone work about the first metatarsophalangeal joint. We report the case of a young adult female who underwent isolated first tarsometatarsal fusion for correction of a bunion deformity. Moreover, we describe the published data related to this approach. This technique could have the potential to improve patient outcomes by avoiding postoperative arthrofibrosis of the first metatarsophalangeal joint. PMID- 24774990 TI - Botulinum Toxin Type A Injection Combined With Cast Immobilization for Treating Recurrent Peroneal Spastic Flatfoot Without Bone Coalitions: A Case Report and Review of the Literature. AB - Peroneal spastic flatfoot is an uncommon condition. It often presents as a rigid and usually painful valgus deformity in the hindfoot with peroneal muscles spasms. Although tarsal coalition is an important cause, a few patients have not undergone bone coalitions. We describe a 27-year-old female who experienced recurrent peroneal spastic flatfoot after an injury. She was treated successfully with a combination of botulinum toxin type A and immobilization of the foot in a neutral position with a cast. After 3 years, the condition had not recurred, and she was pain free and walked normally, with no increase in muscle tone. This unique treatment could be of potential use to treat many patients with such conditions. PMID- 24774992 TI - Protection against muscle damage induced by electrical stimulation: efficiency of a preconditioning programme. AB - PURPOSE: The aim of this study was to explore the efficiency of a preconditioning programme composed of neuromuscular electrical stimulation (NMES) in the protection against muscle damage induced by a subsequent bout of NMES. METHODS: Sixteen male volunteers were split up into a control group (CG; n = 8) and a preconditioned group (PCG; n = 8). Both groups attended two NMES bouts (test 1 and test 2) spaced 5 weeks apart. Each one consisted in 100 quadriceps contractions and 100 hamstrings contractions. PCG attended five additional progressive NMES sessions between test 1 and test 2. The outcome measures were the changes in muscle soreness [0-10 pain score on visual analogue pain scale (VAS)], muscle flexibility and serum creatine kinase (CK) activity; they were assessed before (pre-T1) and after (post-T1) test 1 and before (pre-T2) and after (post-T2) test 2. RESULTS: Damage markers increased similarly in both groups after test 1 (at post-T1, VAS scores = 4.18 +/- 2 and 4.43 +/- 1.56 cm in CG and PCG, respectively; CK activity = 2307 +/- 3774 and 1671 +/- 1790 IU l(-1) in CG and PCG, respectively). Compared with test 1, these damage markers were reduced after test 2 in CG (at post-T2, VAS score = 2.68 +/- 1.27 cm and CK activity = 218 +/- 72 IU l(-1) ). Muscle soreness was further reduced after test 2 in PCG (VAS score = 0.37 +/- 0.74 cm). CONCLUSIONS: A protective effect against muscle damage can be obtained after only one NMES bout, and an additional protective effect can be induced by a preconditioning programme. PMID- 24774993 TI - Response of patients with metastatic uveal melanoma to combined treatment with fotemustine and sorafenib. PMID- 24774994 TI - Sleep-related erections throughout the ages. AB - INTRODUCTION: The occurrence of sleep-related erections (SREs) has been known since antiquity. AIM: To highlight historical, theological, and sexual medicine related aspects of SREs throughout the ages. METHODS: Review of old medical books on male sexual functioning and review of scientific medical and theological articles on SREs from about 1900 on. RESULTS: The cyclic character of SREs was first noted by German researchers in the forties of the 20th century. However, already before the beginning of the Christian era, one knew that men had erections and ejaculations during sleep. In the Middle Ages, SREs were generally considered to be rebellious manifestations of the male body, while it seemed to disobey its owner and showed up its perverted and sinful side. From the fifteenth to the end of the 17th century, severe erectile dysfunction (ED) was ground for divorce. The ecclesiastical court records show that if necessary, the members of the jury sat at the defendant's bedside at night to be able to judge any SREs occurring. Since the 17th century, SREs were considered to be part of masturbation, which could cause many ailments and diseases. Psychoanalyst Stekel acknowledged in 1920 that a morning erection, the last SRE, is a naturally occurring phenomenon in healthy men from infancy to old age. Today, some scientists assume that SREs protect the integrity of the penile cavernous bodies. CONCLUSIONS: Throughout the ages, philosophers, theologians, physicians, members of ecclesial law courts, psychoanalysts, psychiatrists, sexologists, physiologists, and urologists have shown interest in SREs. Obviously, the observations and testing of SREs have a long history, from antiquity to modern sleep labs, in men and in women, in newborns and old adults, by penis rings with sharp spikes to fancy strain gauge devices. Despite all these efforts, the mechanisms leading to SREs and its function are however not yet completely understood. PMID- 24774995 TI - Reconstruction of the maxilla by submental flap. AB - BACKGROUND: Palate separates the oral and nasal cavities, hence its reconstruction after pathologic resections or trauma avulsions is important for speech, degulation, mastication and aesthetic facial results. METHODS: In a retrospective study, the cases that were treated by submental flap for palatomaxillary reconstruction during 2007-2012 were selected from the archive files. Size of the skin paddle, type of the flap and the pathology responsible for resection were recorded. RESULTS: In the search of the files, there were 10 patients in which submental flap were used for palatomaxillary reconstruction. The most common complication was fistula at the junction of the palate (20%). All flaps survived and donor site healed without any complication. Treatment for dental rehabilitation was performed in 80% of the patients (60% with conventional removable prostheses, 20% with implant-supported dentures). CONCLUSION: Submental flap in pedicled form (orthograde or retrograde) can be used for reconstruction of the maxilla in Brown class 2a maxillectomy. PMID- 24775061 TI - Red meat consumption is associated with an increased overall cancer risk: a prospective cohort study in Korea. AB - Cancer is a leading cause of death, and the dietary pattern in Korea is changing rapidly from a traditional Korean diet to a Westernised diet. In the present study, we investigated the effects of dietary factors on cancer risk with a prospective cohort study. Among 26,815 individuals who participated in cancer screening examinations from September 2004 to December 2008, 8024 subjects who completed a self-administered questionnaire concerning demographic and lifestyle factors, and a 3 d food record were selected. As of September 2013, 387 cancer cases were identified from the National Cancer Registry System, and the remaining individuals were included in the control group. The hazard ratio (HR) of cancer for the subjects older than or equal to 50 years of age was higher (HR 1.80, 95% CI 1.41, 2.31; P< 0.0001) than that for the other subjects. Red meat consumption, Na intake and obesity (BMI >= 25 kg/m2) were positively associated with overall cancer incidence in men (HR 1.41, 95% CI 1.02, 1.94; P= 0.0382), gastric cancer (HR 2.34, 95% CI 1.06, 5.19; P= 0.0365) and thyroid cancer (HR 1.56, 95% CI 1.05, 2.31; P= 0.0270), respectively. Participants who had at least three dietary risk factors among the high intakes of red meat and Na, low intakes of vegetables and fruits, and obesity suggested by the World Cancer Research Fund/American Institute for Cancer Research at baseline tended to have a higher risk of cancer than the others (HR 1.26, 95% CI 0.99, 1.60; P= 0.0653). In summary, high intakes of red meat and Na were significant risk factors of cancer among Koreans. PMID- 24775062 TI - Portal vein thrombosis after aortic valve replacement surgery in a patient with antithrombin III deficiency--case presentation. AB - We presented an unique case of portal vein thrombosis (PVT) after aortic valve replacement due to antithrombin III (ATIII) deficiency. PVT after aortic valve replacement (AVR) is a serious complication, which has not previously been reported. PMID- 24775063 TI - Increased zooplankton PAH concentrations across hydrographic fronts in the East China Sea. AB - The Changjiang has transported large quantities of polycyclic aromatic hydrocarbons (PAHs) to the East China Sea (ECS), but information of these pollutants in zooplankton is limited. To understand PAHs pollution in zooplankton in the ECS, total concentrations of PAHs in zooplankton from surface waters were measured. Values of PAHs ranged from 2 to 3500 ng m(-3) in the ECS, with highest PAHs levels located at the salinity front between the Changjiang Diluted Water (CDW) and the mid-shelf waters. In contrast, concentrations of zooplankton PAHs in the mid-shelf and outer-shelf waters were significantly lower (2-23 ng m(-3)) than those in the CDW. These results demonstrate that PAHs are conspicuously accumulated in zooplankton at the salinity front between the CDW and the mid shelf waters. These higher levels of PAHs in zooplankton at the salinity front may be further biomagnified in marine organisms of higher trophic levels through their feeding activities. PMID- 24775064 TI - Strategy for mitigation of marine debris: analysis of sources and composition of marine debris in northern Taiwan. AB - Six sites (two sites for each of rocky shores, sandy beaches, and fishing ports) in northern Taiwan were selected to investigate the amount and density of marine debris in each of the four seasons and after spring and neap tides from 2012 to 2013. The results indicate that marine debris was higher on rocky shores than sandy beaches and fishing ports. There is no significant difference between season and tide. The dominant debris was plastic-type, followed by polystyrene. The majority of debris originated from recreational activities, followed from ocean/waterway activities. The results suggest that the following actions are needed: (1) continue and reinforce the plastic-limit policy; (2) increase the cleaning frequency at rocky shores; (3) promote marine environmental education, with a goal of debris-free coasts; (4) recycle fishing gear and to turn that gear into energy; and (5) coordinate between agencies to establish a mechanism to monitor debris. PMID- 24775065 TI - Environmentally relevant exposure of 17alpha-ethinylestradiol impairs spawning and reproductive behavior in the brackish medaka Oryzias melastigma. AB - We assessed the effects of 17alpha-ethinylestradiol (EE2) on spawning and reproductive behavior of the brackish medaka Oryzias melastigma at environmental concentrations. Breeding pairs were exposed to EE2 at either lower concentrations (0, 1, and 10 ng/L) or higher concentrations (0, 50, and 100 ng/L) for 14 days. Swimming performance and reproductive behavior (following, dancing, and copulation) of the males were analyzed at the end of exposure. Additionally, gonad histology was conducted in the males in the higher EE2 experiment. We found that spawning was significantly inhibited in the 50-100 ng/L EE2 groups. Swimming performance was not affected in all groups. Dancing and copulation were significantly suppressed in the 50-100 ng/L groups. No effect was observed in testis histology in the 50-100 ng/L groups. Our data suggests that reproductive behavior of O. melastigma can be utilized as a behavioral endpoint for ecotoxicology studies of endocrine disruptors in estuarine/marine environments. PMID- 24775066 TI - Isolation and characterization of a novel hydrocarbon-degrading bacterium Achromobacter sp. HZ01 from the crude oil-contaminated seawater at the Daya Bay, southern China. AB - Microorganisms play an important role in the biodegradation of petroleum contaminants, which have attracted great concern due to their persistent toxicity and difficult biodegradation. In this paper, a novel hydrocarbon-degrading bacterium HZ01 was isolated from the crude oil-contaminated seawater at the Daya Bay, South China Sea, and identified as Achromobacter sp. Under the conditions of pH 7.0, NaCl 3% (w/v), temperature 28 degrees C and rotary speed 150 rpm, its degradability of the total n-alkanes reached up to 96.6% after 10 days of incubation for the evaporated diesel oil. Furthermore, Achromobacter sp. HZ01 could effectively utilize polycyclic aromatic hydrocarbons (PAHs) as its sole carbon source, and could remove anthracene, phenanthrene and pyrence about 29.8%, 50.6% and 38.4% respectively after 30 days of incubation. Therefore, Achromobacter sp. HZ01 may employed as an excellent degrader to develop one cost effective and eco-friendly method for the bioremediation of marine environments polluted by crude oil. PMID- 24775067 TI - Distributions of polycyclic aromatic hydrocarbons and alkylated polycyclic aromatic hydrocarbons in Osaka Bay, Japan. AB - Contaminations in sediments by polycyclic aromatic hydrocarbons (PAHs) and alkylated PAHs were investigated at 44 sites in Osaka Bay, Japan. Concentrations of total PAHs and alkylated PAHs were in the range 6.40-7800 ng/g dry weights and 13.7-1700 ng/g dry weights, respectively. The PAH concentrations tended to be higher along the shoreline in the vicinities of big ports, industrialized areas, and densely populated regions such as the cities of Osaka and Kobe. The major sources appeared to be pyrogenic or both pyrogenic and petrogenic at most of the sites. PAH concentrations were remarkably high at a site near Kobe, where the concentrations of dibenzo(a,h)anthracene and benzo(g,h,i)perylene exceeded the effects-range-medium concentration and eight PAHs were above the corresponding effects-range-low concentrations. Those PAHs may have been derived from the great fire associated with the large earthquake in 1995. PMID- 24775068 TI - Partitioning behavior of perfluorinated compounds between sediment and biota in the Pearl River Delta of South China. AB - Surface sediment and biota were collected from 12 sampling sites - seven along the Pearl River Delta and five along the Hong Kong coastline. Perfluorinated compound (PFC) concentrations were detected using a high-performance-liquid chromatogram-tandem-mass-spectrometry system. Analytical results indicated that the total PFC concentrations were in the range of 0.15-3.11 ng/g dry weight in sediments, while the total PFC concentrations in oyster and mussel samples were between 0.46-1.96 and 0.66-3.43 ng/g wet weight, respectively. The major types of PFCs detected in the sediment samples were perfluorooctanesulfonic acid (PFOS) and perfluorobutanoic acid (PFBA), with concentrations ranging from low limits of quantification to 0.86+/-0.12 ng/g dry weight and 1.50+/-0.26 ng/g dry weight, respectively. In bivalve samples, PFOS was the dominant contaminant with concentrations ranging from 0.25+/-0.09 to 0.83+/-0.12 ng/g wet weight in oysters and 0.41+/-0.14 to 1.47+/-0.25 ng/g wet weight in mussels. An increase in PFC concentration was found to be correlated with increased human population density in the study areas. PMID- 24775069 TI - PAH concentrations in Coquina (Donax spp.) on a sandy beach shoreline impacted by a marine oil spill. AB - The BP MC252 well failure in the Gulf of Mexico, April 2010 caused concern for crude oil and polycyclic aromatic hydrocarbon (PAHs) exposure along the sandy beaches of the Florida Panhandle. We began collections of Coquina clams (Donax spp.) from the surf zone of Florida Panhandle beaches to monitor PAH contamination to compliment analysis of surf zone sand samples. These clams had higher levels of PAHs relative to ambient sand, and this allowed us to continue to monitor PAH levels after sand concentrations fell below limits of detection. PAH levels in the Coquina tissues were highly variable, perhaps indicative of the heterogeneous distribution of oil and tar on the beaches and exposure to tar particles. Overall, PAH levels decreased continuously in both sand and Coquina tissues, reaching limits of detection within one and two years respectively after oil landed on Florida Panhandle beaches. Our work suggests these surf zone molluscs may be used to monitor pollutant exposure along high energy sandy beach shorelines. PMID- 24775070 TI - Levels of Cd, Cu, Pb and V in marine sediments in the vicinity of the Single Buoy Moorings (SBM3) at Mina Al Fahal in the Sultanate of Oman. AB - Recently in the Sultanate of Oman, there has been a rapid surge of coastal developments. These developments cause metal contamination, which may affect the habitats and communities at and near the coastal region. As a result, a study was conducted to assess the level of metal contamination and its impact on the marine sediments in the vicinity of the Single Buoy Moorings 3 (SBM3) at Mina Al Fahal in the Sultanate of Oman. Marine subtidal sediment samples were collected from six different stations of the SBM3 for the period ranging from June 2009 to April 2010. These samples were then analyzed for their level and distribution of the heavy metals of cadmium (Cd), copper (Cu), lead (Pb) and vanadium (V). Overall, low concentrations of all four heavy metals were measured from the marine sediments, indicating that the marine at SBM3 is of good quality. PMID- 24775071 TI - Selective decontamination of the digestive tract in critically ill patients treated in intensive care units: a mixed-methods feasibility study (the SuDDICU study). AB - BACKGROUND: Hospital-acquired infections (HAIs) are a major cause of morbidity and mortality. Critically ill patients in intensive care units (ICUs) are particularly susceptible to these infections. One intervention that has gained much attention in reducing HAIs is selective decontamination of the digestive tract (SDD). SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of intravenous (i.v.) antibiotics. SDD may reduce infections and improve mortality, but has not been widely adopted in the UK or internationally. Hence, there is a need to identify the reasons for low uptake and whether or not further clinical research is needed before wider implementation would be considered appropriate. OBJECTIVES: The project objectives were to (1) identify and describe the SDD intervention, (2) identify views about the evidence base, (3) identify acceptability of further research and (4) identify feasibility of further randomised controlled trials (RCTs). DESIGN: A four-stage approach involving (1) case studies of two ICUs in which SDD is delivered including observations, interviews and documentary analysis, (2) a three-round Delphi study for in-depth investigation of clinicians' views, including semi-structured interviews and two iterations of questionnaires with structured feedback, (3) a nationwide online survey of consultants in intensive care medicine and clinical microbiology and (4) semistructured interviews with international clinical triallists to identify the feasibility of further research. SETTING: Case studies were set in two UK ICUs. Other stages of this research were conducted by telephone and online with NHS staff working in ICUs. PARTICIPANTS: (1) Staff involved in SDD adoption or delivery in two UK ICUs, (2) ICU experts (intensive care consultants, clinical microbiologists, hospital pharmacists and ICU clinical leads), (3) all intensive care consultants and clinical microbiologists in the UK with responsibility for patients in ICUs were invited and (4) international triallists, selected from their research profiles in intensive care, clinical trials and/or implementation trials. INTERVENTIONS: SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of i.v. antibiotics. MAIN OUTCOME MEASURES: Levels of support for, or opposition to, SDD in UK ICUs; views about the SDD evidence base and about barriers to implementation; and feasibility of further SDD research (e.g. likely participation rates). RESULTS: (1) The two case studies identified complexity in the interplay of clinical and behavioural components of SDD, involving multiple staff. However, from the perspective of individual staff, delivery of SDD was regarded as simple and straightforward. (2) The Delphi study (n = 42) identified (a) specific barriers to SDD implementation, (b) uncertainty about the evidence base and (c) bimodal distributions for key variables, e.g. support for, or opposition to, SDD. (3) The national survey (n = 468) identified uncertainty about the effect of SDD on antimicrobial resistance, infection rates, mortality and cost-effectiveness. Most participants would participate in further SDD research. (4) The triallist interviews (n = 10) focused largely on the substantial challenges of conducting a large, multinational clinical effectiveness trial. CONCLUSIONS: There was considerable uncertainty about possible benefits and harms of SDD. Further large scale clinical effectiveness trials of SDD in ICUs may be required to address these uncertainties, especially relating to antimicrobial resistance. There was a general willingness to participate in a future effectiveness RCT of SDD. However, support was not unanimous. Future research should address the barriers to acceptance and participation in any trial. There was some, but a low level of, interest in adoption of SDD, or studies to encourage implementation of SDD into practice. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 25. See the NIHR Journals Library website for further project information. PMID- 24775072 TI - Triple outlet right ventricle: a previously unknown cardiac malformation. AB - We present the case of an infant with three distinct outflow tracts from the right ventricle. Three outlets from the heart have been previously named the "Tritruncal Heart". We review the two previously reported cases of tritruncal hearts and describe the anatomy, diagnosis, surgical management, and outcome of our case. Embryologic implications are also discussed. PMID- 24775093 TI - Diets enriched in trans-11 vaccenic acid alleviate ectopic lipid accumulation in a rat model of NAFLD and metabolic syndrome. AB - Trans11-18:1 (vaccenic acid, VA) is one of the most predominant naturally occurring trans fats in our food chain and has recently been shown to exert hypolipidemic effects in animal models. In this study, we reveal new mechanism(s) by which VA can alter body fat distribution, energy utilization and dysfunctional lipid metabolism in an animal model of obesity displaying features of the metabolic syndrome (MetS). Obese JCR:LA-cp rats were assigned to a control diet that included dairy-derived fat or the control diet supplemented with 1% VA. VA reduced total body fat (-6%), stimulated adipose tissue redistribution [reduced mesenteric fat (-17%) while increasing inguinal fat mass (29%)] and decreased adipocyte size (-44%) versus control rats. VA supplementation also increased metabolic rate (7%) concomitantly with an increased preference for whole-body glucose utilization for oxidation and increased insulin sensitivity [lower HOMA IR (-59%)]. Further, VA decreased nonalcoholic fatty liver disease activity scores (-34%) and reduced hepatic (-27%) and intestinal (-39%) triglyceride secretion relative to control diet, while exerting differential transcriptional regulation of SREBP1 and FAS amongst other key genes in the liver and the intestine. Adding VA to dairy fat alleviates features of MetS potentially by remodeling adipose tissue and attenuating ectopic lipid accumulation in a rat model of obesity and MetS. Increasing VA content in the diet (naturally or by fortification) may be a useful approach to maximize the health value of dairy derived fats. PMID- 24775094 TI - Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in nonobese diabetic mice. AB - Impairment of gut epithelial barrier function is a key predisposing factor for inflammatory bowel disease, type 1 diabetes (T1D) and related autoimmune diseases. We hypothesized that maternal obesity induces gut inflammation and impairs epithelial barrier function in the offspring of nonobese diabetic (NOD) mice. Four-week-old female NOD/ShiLtJ mice were fed with a control diet (CON; 10% energy from fat) or a high-fat diet (HFD; 60% energy from fat) for 8 weeks to induce obesity and then mated. During pregnancy and lactation, mice were maintained in their respective diets. After weaning, all offspring were fed the CON diet. At 16 weeks of age, female offspring were subjected to in vivo intestinal permeability test, and then ileum was sampled for biochemical analyses. Inflammasome mediators, activated caspase-1 and mature forms of interleukin (IL)-1beta and IL-18 were enhanced in offspring of obese mothers, which was associated with elevated serum tumor necrosis factor alpha level and inflammatory mediators. Consistently, abundance of oxidative stress markers including catalase, peroxiredoxin-4 and superoxide dismutase 1 was heightened in offspring ileum (P<.05). Furthermore, offspring from obese mothers had a higher intestinal permeability. Morphologically, maternal obesity reduced villi/crypt ratio in the ileum of offspring gut. In conclusion, maternal obesity induced inflammation and impaired gut barrier function in offspring of NOD mice. The enhanced gut permeability in HFD offspring might predispose them to the development of T1D and other gut permeability-associated diseases. PMID- 24775095 TI - (18)F-FDG uptake predicts diagnostic yield of transbronchial biopsy in peripheral lung cancer. AB - OBJECTIVES: Recent advances in endobronchial ultrasonography with a guide sheath (EBUS-GS) have enabled better visualization of distal airways, while virtual bronchoscopic navigation (VBN) has been shown useful as a guide to navigate the bronchoscope. However, indications for utilizing VBN and EBUS-GS are not always clear. To clarify indications for a bronchoscopic examination using VBN and EBUS GS, we evaluated factors that predict the diagnostic yield of a transbronchial biopsy (TBB) procedure for peripheral lung cancer (PLC) lesions. METHODS: We retrospectively reviewed the charts of 194 patients with 201 PLC lesions (<=3cm mean diameter), and analyzed the association of diagnostic yield of TBB with [(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) positron emission tomography and chest computed tomography (CT) findings. RESULTS: The diagnostic yield of TBB using VBN and EBUS-GS was 66.7%. High maximum standardized uptake value (SUVmax), positive bronchus sign, and ground-glass opacity component shown on CT were all significant predictors of diagnostic yield, while multivariate analysis showed only high (18)F-FDG uptake (SUVmax >=2.8) and positive bronchus sign as significant predictors. Diagnostic yield was higher for PLC lesions with high (18)F-FDG uptake (SUVmax >=2.8) and positive bronchus sign (84.6%) than for those with SUVmax <2.8 and negative bronchus sign (33.3%). High (18)F-FDG uptake was also correlated with tumor invasiveness. CONCLUSIONS: High (18)F-FDG uptake predicted the diagnostic yield of TBB using VBN and EBUS-GS for PLC lesions. (18)F-FDG uptake and bronchus sign may indicate for the accurate application of bronchoscopy with those modalities for diagnosing PLC. PMID- 24775096 TI - "I don't see an added value for myself": a qualitative study exploring the social cognitive variables associated with influenza vaccination of Belgian, Dutch and German healthcare personnel. AB - BACKGROUND: Health Authorities recommend influenza vaccination of healthcare personnel (HCP) to decrease the transmission of influenza to vulnerable patients. Recent studies have almost exclusively used quantitative questionnaires in order to identify determinants of vaccination behaviour. Interviews enable HCP to express freely why they think they are (not) willing to get vaccinated against influenza. METHODS: By means of semi-structured one-on-one interviews with 123 Belgian, Dutch and German HCP, reasons for and against vaccination, experiences with influenza vaccination, intention to get vaccinated and possible barriers, as well as willingness to advice influenza vaccination to patients were investigated. Data were processed with QSR NVivo 8.0 and analysed using a combination of a deductive and a general inductive approach. RESULTS: Across countries, self-protection, patient protection, and protection of family members were reported as most important reasons to get vaccinated against influenza. Reasons to not get vaccinated against influenza were fear of side effects caused by the vaccine, a low risk-perception, the disbelief in the effectiveness of influenza vaccination, organizational barriers, misconceptions, and undefined negative emotions. CONCLUSIONS: The social cognitive variables underlying the decision of HCP to get vaccinated against influenza (or not) seem to be similar in Belgium, Germany, and the Netherlands, even though some differences surfaced. A quantitative investigation of those social cognitive variables is needed in order to determine the importance of the social cognitive variables in explaining the intention to get vaccinated and the importance of the similarities and differences between countries that have been found in this study. PMID- 24775097 TI - Primary care referrals of patients with potentially serious diseases to the emergency department or a quick diagnosis unit: a cross-sectional retrospective study. AB - BACKGROUND: In Spain, primary healthcare (PHC) referrals for diagnostic procedures are subject to long waiting-times, and physicians and patients often use the emergency department (ED) as a shortcut. We aimed to determine whether patients evaluated at a hospital outpatient quick diagnosis unit (QDU) who were referred to ED from 12 PHC centers could have been directly referred to QDU, thus avoiding ED visits. As a secondary objective, we determined the proportion of QDU patients who might have been evaluated in a less rapid, non-QDU setting. METHODS: We carried out a cross-sectional retrospective cohort study of patients with potentially serious conditions attended by the QDU from December 2007 to December 2012. We established 2 groups of patients: 1) patients referred from PHC to QDU (PHC-QDU group) and 2) patients referred from PHC to ED, then to QDU (PHC-ED-QDU group). Two observers assessed the appropriateness/inappropriateness of each referral using a scoring system. The interobserver agreement was assessed by calculating the kappa index. Multivariate logistic regression analysis was performed to identify the factors associated with the dependent variable 'ED referral'. RESULTS: We evaluated 1186 PHC-QDU and 1004 PHC-ED-QDU patients and estimated that 93.1% of PHC-ED-QDU patients might have been directly referred to QDU. In contrast, 96% of PHC-QDU patients were found to be appropriately referred to QDU first. The agreement for PHC-QDU referrals (PHC-QDU group) was rated as excellent (kappa=0.81), while it was rated as good for PHC-ED referrals (PHC-ED QDU group) (kappa=0.75). The mean waiting-time for the first QDU visit was longer in PHC-QDU (4.8 days) than in PHC-ED-QDU (2.6 days) patients (P=.001). On multivariate analysis, anemia (OR 2.87, 95% CI 1.49-4.55, P<.001), rectorrhagia (OR 2.18, 95% CI 1.10-3.77, P=.01) and febrile syndrome (OR 2.53, 95% CI 1.33 4.12, P=.002) were independent factors associated with ED referral. Nearly one fifth of all QDU patients were found who might have been evaluated in a less rapid, non-QDU setting. CONCLUSIONS: Most PHC-ED-QDU patients might have been directly referred to QDU from PHC, avoiding the inconvenience of the ED visit. A stricter definition of QDU evaluation criteria may be needed to improve and hasten PHC referrals. PMID- 24775098 TI - Lower potassium intake is associated with increased wave reflection in young healthy adults. AB - BACKGROUND: Increased potassium intake has been shown to lower blood pressure (BP) even in the presence of high sodium consumption however the role of dietary potassium on vascular function has received less attention. The aim of this study was to evaluate the relationship between habitual intake of sodium (Na) and potassium (K) and measures of arterial stiffness and wave reflection. METHODS: Thirty-six young healthy adults (21 M, 15 F; 24 +/- 0.6 yrs; systolic BP 117 +/- 2; diastolic BP 63 +/- 1 mmHg) recorded their dietary intake for 3 days and collected their urine for 24 hours on the 3rd day. Carotid-femoral pulse wave velocity (PWV) and the synthesis of a central aortic pressure waveform (by radial artery applanation tonometry and generalized transfer function) were performed. Aortic augmentation index (AI), an index of wave reflection, was calculated from the aortic pressure waveform. RESULTS: Subjects consumed an average of 2244 kcals, 3763 mg Na, and 2876 mg of K. Average urinary K excretion was 67 +/- 5.3 mmol/24 hr, Na excretion was 157 +/- 11 mmol/24 hr and the average Na/K excretion ratio was 2.7 +/- 0.2. An inverse relationship between AI and K excretion was found (r = -0.323; p < 0.05). A positive relationship between AI and the Na/K excretion ratio was seen (r = 0.318; p < 0.05) while no relationship was noted with Na excretion alone (r = 0.071; p > 0.05). Reflection magnitude, the ratio of reflected and forward waves, was significantly associated with the Na/K excretion ratio (r = 0.365; p <0.05) but not Na or K alone. PWV did not correlate with Na or the Na/K excretion ratio (p > 0.05) but showed an inverse relationship with K excretion (r = -0.308; p < 0.05). CONCLUSIONS: These data suggest that lower potassium intakes are associated with greater wave reflection and stiffer arteries in young healthy adults. PMID- 24775099 TI - Effect of the Brugada syndrome mutation A39V on calmodulin regulation of Cav1.2 channels. AB - BACKGROUND: The L-type calcium channel Cav1.2 is important for brain and heart function. The ubiquitous calcium sensing protein calmodulin (CaM) regulates calcium dependent gating of Cav1.2 channels by reducing calcium influx, a process known as calcium-dependent inactivation (CDI). Dissecting the calcium-dependence of CaM in this process has benefited greatly from the use of mutant CaM molecules which are unable to bind calcium to their low affinity (N-lobe) and high affinity (C-lobe) binding sites. Unlike CDI, it is unknown whether CaM can modulate the activation gating of Cav1.2 channels. RESULTS: We examined a Cav1.2 point mutant in the N-terminus region of the channel (A39V) that has been previously linked to Brugada syndrome. Using mutant CaM constructs in which the N- and/or C-lobe calcium binding sites were ablated, we were able to show that this Brugada syndrome mutation disrupts N-lobe CDI of the channel. In the course of these experiments, we discovered that all mutant CaM molecules were able to alter the kinetics of channel activation even in the absence of calcium for WT-Cav1.2, but not A39V-Cav1.2 channels. Moreover, CaM mutants differentially shifted the voltage-dependence of activation for WT and A39V-Cav1.2 channels to hyperpolarized potentials. Our data therefore suggest that structural changes in CaM that arise directly from site directed mutagenesis of calcium binding domains alter activation gating of Cav1.2 channels independently of their effects on calcium binding, and that the N-terminus of the channel contributes to this CaM dependent process. CONCLUSIONS: Our data indicate that caution must be exercised when interpreting the effects of CaM mutants on ion channel gating. PMID- 24775119 TI - Nipple-sparing mastectomy with implant reconstruction: the Westmead experience. AB - BACKGROUND: Nipple-sparing mastectomy (NSM) involves the removal of all breast tissue with preservation of the breast skin envelope and nipple-areola complex (NAC). The objective of this study was to report the outcomes from our initial experience with NSM. METHODS: We retrospectively analysed 87 women who underwent 118 NSMs between October 2008 and May 2012. RESULTS: Indications for NSM were 60 (51%) primary cancer, 15 (13%) residual/recurrent disease, 39 (33%) risk reduction and 4 (3%) benign pathology. Implant loss (n = 10) was associated with subcutaneous placement (P = 0.01), post-operative seroma and infection (P = 0.028, 0.001), skin flap necrosis (P = 0.007) and NAC loss (P = 0.027). Capsular contraction was related to adjuvant radiotherapy (P = 0.044). Local recurrence occurred in four patients, and NAC recurrence with invasive cancer occurred in one patient after a median follow-up of 30 months. CONCLUSION: Our Australian NSM series adds to the published literature supporting the oncological safety of NSM for early-stage breast cancer and risk reduction. PMID- 24775120 TI - The Selfish Goal: autonomously operating motivational structures as the proximate cause of human judgment and behavior. AB - We propose the Selfish Goal model, which holds that a person's behavior is driven by psychological processes called goals that guide his or her behavior, at times in contradictory directions. Goals can operate both consciously and unconsciously, and when activated they can trigger downstream effects on a person's information processing and behavioral possibilities that promote only the attainment of goal end-states (and not necessarily the overall interests of the individual). Hence, goals influence a person as if the goals themselves were selfish and interested only in their own completion. We argue that there is an evolutionary basis to believe that conscious goals evolved from unconscious and selfish forms of pursuit. This theoretical framework predicts the existence of unconscious goal processes capable of guiding behavior in the absence of conscious awareness and control (the automaticity principle), the ability of the most motivating or active goal to constrain a person's information processing and behavior toward successful completion of that goal (the reconfiguration principle), structural similarities between conscious and unconscious goal pursuit (the similarity principle), and goal influences that produce apparent inconsistencies or counterintuitive behaviors in a person's behavior extended over time (the inconsistency principle). Thus, we argue that a person's behaviors are indirectly selected at the goal level but expressed (and comprehended) at the individual level. PMID- 24775121 TI - Selfish goals must compete for the common currency of reward. AB - Selfish Goal Theory is compatible with a behaviorally based theory that recognizes mental processes as behaviors. Both envision choices as made by the competition of purposive processes, which are autonomous in that they are not coordinated by an agentic "self." However, the survival of mental processes - termed "goals" or "interests," respectively - depends on a well-documented active mechanism: reward. PMID- 24775122 TI - Fashioning a selfish self amid selfish goals. AB - The selfish goal, at some point in evolution, gave rise to a selfish self. In humans, this selfish self might exert influence over goals, deciding upon which to execute and which to inhibit. This, in fact, may be one of the chief functions of the self. PMID- 24775123 TI - Selfish goals serve more fundamental social and biological goals. AB - Proximate selfish goals reflect the machinations of more fundamental goals such as self-protection and reproduction. Evolutionary life history theory allows us to make predictions about which goals are prioritized over others, which stimuli release which goals, and how the stages of cognitive processing are selectively influenced to better achieve the aims of those goals. PMID- 24775124 TI - Tag, you're it: affect tagging promotes goal formation and selection. AB - Building upon Huang & Bargh's (H&B's) theory, we propose a complementary view that goal formation and selection are both supported by affect. We suggest that goals may form when affect "tags" discrete behaviors and their outcomes. Further, we propose that goal-associated affect may help guide selection between competing goals, for example, in the case of short-term and long-term goals. PMID- 24775125 TI - Unconsciously competing goals can collaborate or compromise as well as win or lose. AB - This commentary offers a friendly extension of Huang & Bargh's (H&B's) account. Not only do active goals sometimes operate unconsciously to dominate or preempt others, but simultaneously active goals can also collaborate or compromise in shaping behavior. Because neither goal wins complete control of behavior, the result may be that each is only partly satisfied. PMID- 24775126 TI - A deeper integration of Selfish Goal Theory and modern evolutionary psychology. AB - Conceptually integrating Selfish Goal Theory with modern evolutionary psychology amplifies theoretical power. Inconsistency, a key principle of Selfish Goal Theory, illustrates this insight. Conflicting goals of seeking sexual variety and successful mate retention furnish one example. Siblings have evolved goals to cooperate and compete, a second example. Integrating Selfish Goal Theory with evolutionary theory can explain much inconsistent goal-directed behavior. PMID- 24775127 TI - Unconscious habit systems in compulsive and impulsive disorders. AB - It may be useful to consider the application of Huang & Bargh's (H&B's) theory of unconscious motivational processes to psychopathology. In disorders of compulsivity and impulsivity, an unconscious habit system may play a key role in explaining ego-dystonic or self-destructive behaviour. H&B's theory may provide some insights into understanding conditions such as obsessive-compulsive disorder (OCD) and drug addiction; however, additional work is needed to address the neurocircuitry and neurochemistry mediating their abnormal underlying motivational processes. PMID- 24775128 TI - What's in a goal? The role of motivational relevance in cognition and action. AB - We argue that it is possible to go beyond the "selfish goal" metaphor and make an even stronger case for the role of unconscious motivation in cognition and action. Through the relevance of a representation (ROAR) framework, we describe how not only value motivation, which relates to "selfish goals," but also truth motivation and control motivation impact cognition and action. PMID- 24775129 TI - Development links psychological causes to evolutionary explanations. AB - Our conscious abilities are learned in environments that have evolved to support them. This insight provides an alternative way of framing Huang & Bargh's (H&B's) provocative hypothesis. To understand the conflict between unconscious goals and consciousness, we can study the emergence of conscious thought and control in childhood. These developmental processes are also central to the best available current evolutionary theories. PMID- 24775130 TI - The motivational self is more than the sum of its goals. AB - I present evidence in favor of an overarching motivational self: a mental function that regulates expression of multiple goals. Goals often conflict with each other, and the role of a motivational self is to consciously or unconsciously prioritize pursuit of these goals. When observing inconsistency in expression of goals, it is therefore useful to consider whether the motivational self is attempting to balance between conflicting goals or if such inconsistency results from temporary self-control weakness. PMID- 24775131 TI - Mapping the goal space: personality integration and higher-order goals. AB - By situating goals at the heart of human cognitive function, Huang & Bargh (H&B) provide a useful platform for understanding the process of personality integration as the gradual mapping of implicit motives into a coherently organized self-system. This integrative process is a critical feature of human development that must be accounted for by any complete goal theory. PMID- 24775132 TI - Massively representational minds are not always driven by goals, conscious or otherwise. AB - The language of conscious and unconscious goals is rooted in a folk-taxonomy that is likely to inhibit progress in cognitive science. Severing the commitment to this taxonomy would allow Huang & Bargh (H&B) to consider a wider variety of representational forms with motivational force and to entertain the intriguing possibility that variations in the number of active-but-redundant representations account for variance in social behavior. PMID- 24775133 TI - Theoretical integration in motivational science: System justification as one of many "autonomous motivational structures". AB - Recognizing that there is a multiplicity of motives - and that the accessibility and strength of each one varies chronically and temporarily - is essential if motivational scientists are to achieve genuine theoretical and empirical integration. We agree that system justification is a case of nonconscious goal pursuit and discuss implications of the fact that it conflicts with many other psychological goals. PMID- 24775134 TI - On the selection and balancing of multiple selfish goals. AB - The selfish goal metaphor is interesting and intriguing. It accounts for the idiosyncrasies and inconsistencies in peoples' goal pursuits without invoking free will, self-regulatory, or self-control failures. However, people pursue multiple goals, sometimes simultaneously. We argue that the model proposed in the target article may gain significant theoretical and practical value if the principles underlying goal selection and/or balancing on a moment-to-moment basis are clearly specified and integrated with the notion of the selfish goal. PMID- 24775135 TI - The validity of Dawkins's selfish gene theory and the role of the unconscious in decision making. AB - Although the proposed Selfish Goal Theory constitutes a major theoretical tour de force for addressing the issue of inconsistencies in human actions and the role of motivational goals in behavior, as it is based on an unproven biological paradigm (Dawkins's selfish gene theory) and overemphasizes the role of unconscious processes in decision making, it provides a questionable model of the underlying psychological structure of human agency. PMID- 24775136 TI - The effects of being conscious: looking for the right evidence. AB - Huang & Bargh's (H&B's) general picture might underestimate the role played by conscious self and overestimate the behavioral inconsistencies at the personal level. This follows from how they delimit the goals under consideration: Their theses that goals are not consciously selected and that the conscious self is involved just in post hoc rationalization should also be tested against concrete and long-term goals. PMID- 24775137 TI - Genes, hosts, goals: disentangling causal dependencies. AB - The special sense in which the concept of "selfishness" is defined in Dawkins's popularization of basic evolutionary theory is analyzed with regard to its applicability to the relation between goals and those who entertain and pursue them. It is concluded that grounds analogous to those on which independent self interest vis-a-vis their hosts is attributed to genes in Dawkins's sense are lacking in the case of goals in their relation to those who entertain and pursue them. PMID- 24775138 TI - The conscious roots of selfless, unconscious goals. AB - We counter Huang & Bargh's (H&B's) metaphoric description of the unconscious, selfish goal on three points. First, we argue, unconscious goals are rooted in conscious choices related to well-being. Second, unconscious goal pursuit occurs through early-stage orienting mechanisms that promote individuals' well-being. Third, unconscious goals work selflessly, resulting in their own demise. PMID- 24775139 TI - Winner takes it all: addiction as an example for selfish goal dominance. AB - Here we argue that the selfish goal concept may well be suitable to explain inconsistencies not only in micro-behaviors, but also in the gross behavioral repertoire of an individual, which is often associated with psychopathologies, such as addiction. Neurophysiological evidence for pathological conditions like addiction emerged, and this evidence may also serve as an explanatory model for normal behaviors. PMID- 24775140 TI - Unconscious goals: specific or unspecific? The potential harm of the goal/gene analogy. AB - Huang & Bargh's (H&B's) definition of goals is ambiguous between "specific goals" - the end-state of a token action I am about to perform - and "unspecific goals" the end-state of an action-type (without specifying how this would be achieved). The analogy with selfish genes pushes the authors towards the former interpretation, but the latter would provide a more robust theoretical framework. PMID- 24775141 TI - The selfish goal meets the selfish gene. AB - The connection between selfish genes and selfish goals is not merely metaphorical. Many goals that shape contemporary cognition and behavior are psychological products of evolutionarily fundamental motivational systems and thus are phenotypic manifestations of genes. An evolutionary perspective can add depth and nuance to our understanding of "selfish goals" and their implications for human cognition and behavior. PMID- 24775142 TI - Goals reconfigure cognition by modulating predictive processes in the brain. AB - I applaud Huang & Bargh's (H&B's) theory that places goals at the center of cognition, and I discuss two ingredients missing from that theory. First, I argue that the brains of organisms much simpler than those of humans are already configured for goal achievement in situated interactions. Second, I propose a mechanistic view of the "reconfiguration principle" that links the theory with current views in computational neuroscience. PMID- 24775143 TI - Cui bono? Selfish goals need to pay their way. AB - The target article falls short of explaining the phenomena, including motivational conflict, that it sets out to. The two main reasons for this are: (1) It is unclear in what sense goals are "selfish"; (2) We need an account of how selfish goals motivate people. If selfish goals are not in the replication business, then what is in it for them? And if they do not offer people something that they want, how do they ever influence what people do? PMID- 24775144 TI - Automatic goals and conscious regulation in social cognitive affective neuroscience. AB - The Selfish Goal model challenges traditional agentic models that place conscious systems at the helm of motivation. We highlight the need for ongoing supervision and intervention of automatic goals by higher-order conscious systems with examples from social cognitive affective neuroscience. We contend that interplay between automatic and supervisory systems is required for adaptive human behavior. PMID- 24775145 TI - Goals are not selfish. AB - The metaphor of selfish goals is misguided. Organisms can be considered vessels that further the interests of their genes, but not vessels that further the interests of their goals. Although goals can act at cross-purposes to each other and to longevity, such trade-offs are predicted by evolutionary theory. The metaphor of selfish goals provides no purchase on this problem. PMID- 24775146 TI - Should an individual composed of selfish goals be held responsible for her actions? AB - We discuss the implications of the Selfish Goal model for moral responsibility, arguing it suggests a form of skepticism we call the "locus problem." In denying that individuals contain any genuine psychological core of information processing, the Selfish Goal model denies the kind of locus of control intuitively presupposed by ascriptions of responsibility. We briefly consider ways the problem might be overcome. PMID- 24775147 TI - Mirror neurons: from origin to function. AB - This article argues that mirror neurons originate in sensorimotor associative learning and therefore a new approach is needed to investigate their functions. Mirror neurons were discovered about 20 years ago in the monkey brain, and there is now evidence that they are also present in the human brain. The intriguing feature of many mirror neurons is that they fire not only when the animal is performing an action, such as grasping an object using a power grip, but also when the animal passively observes a similar action performed by another agent. It is widely believed that mirror neurons are a genetic adaptation for action understanding; that they were designed by evolution to fulfill a specific socio cognitive function. In contrast, we argue that mirror neurons are forged by domain-general processes of associative learning in the course of individual development, and, although they may have psychological functions, they do not necessarily have a specific evolutionary purpose or adaptive function. The evidence supporting this view shows that (1) mirror neurons do not consistently encode action "goals"; (2) the contingency- and context-sensitive nature of associative learning explains the full range of mirror neuron properties; (3) human infants receive enough sensorimotor experience to support associative learning of mirror neurons ("wealth of the stimulus"); and (4) mirror neurons can be changed in radical ways by sensorimotor training. The associative account implies that reliable information about the function of mirror neurons can be obtained only by research based on developmental history, system-level theory, and careful experimentation. PMID- 24775148 TI - The role of mirror neurons in language acquisition and evolution. AB - I argue that Cook et al.'s attack of the genetic hypothesis of mirror neurons misses its target because the authors miss the point that genetics may specify how neurons may learn, not what they learn. Paying more attention to recent work linking mirror neurons to language acquisition and evolution would strengthen Cook et al.'s arguments against a rigid genetic hypothesis. PMID- 24775149 TI - The insufficiency of associative learning for explaining development: three challenges to the associative account. AB - Three challenges to the sufficiency of the associative account for explaining the development of mirror mechanisms are discussed: Genetic predispositions interact with associative learning, infants show predispositions to imitate human as opposed to nonhuman actions, and early and later learning involve different mechanisms. Legitimate objections to an extreme nativist account are raised, but the proposed solution is equally problematic. PMID- 24775150 TI - Associative learning is necessary but not sufficient for mirror neuron development. AB - Existing computational models of the mirror system demonstrate the additional circuitry needed for mirror neurons to display the range of properties that they exhibit. Such models emphasize the need for existing connectivity to form visuomotor associations, processing to reduce the space of possible inputs, and demonstrate the role neurons with mirror properties might play in monitoring one's own actions. PMID- 24775151 TI - More than associations: an ideomotor perspective on mirror neurons. AB - In this commentary, we propose an extension of the associative approach of mirror neurons, namely, ideomotor theory. Ideomotor theory assumes that actions are controlled by anticipatory representations of their sensory consequences. As we outline below, this extension is necessary to clarify a number of empirical observations that are difficult to explain from a purely associative perspective. PMID- 24775152 TI - Reward in the mirror neuron system, social context, and the implications on psychopathology. AB - Positive and negative reinforcers guide our behaviors as we interact with others in our social environment. Here, we present evidence that highlights a central role for reward in the general functioning of the mirror neuron system (MNS). We also discuss the relevance of reward-related modulation on other previous findings revealing certain properties of the MNS, and on social context and psychopathology. PMID- 24775153 TI - Motor-visual neurons and action recognition in social interactions. AB - Cook et al. suggest that motor-visual neurons originate from associative learning. This suggestion has interesting implications for the processing of socially relevant visual information in social interactions. Here, we discuss two aspects of the associative learning account that seem to have particular relevance for visual recognition of social information in social interactions - namely, context-specific and contingency based learning. PMID- 24775154 TI - A mass assembly of associative mechanisms: a dynamical systems account of natural social interaction. AB - The target article offers a negative, eliminativist thesis, dissolving the specialness of mirroring processes into a solution of associative mechanisms. We support the authors' project enthusiastically. What they are currently missing, we argue, is a positive, generative thesis about associative learning mechanisms and how they might give way to the complex, multimodal coordination that naturally arises in social interaction. PMID- 24775155 TI - Mirror mechanism and dedicated circuits are the scaffold for mirroring processes. AB - In the past decade many studies have demonstrated the existence of a mirror mechanism that matches the sensory representation of a biological stimulus with its somatomotor and visceromotor representation. This mechanism, likely phylogenetically very old, explains several types of mirroring behaviours, at different levels of complexity. The presence in primates of dedicated neuroanatomical pathways for specific sensorimotor integrations processes implies, at least in the primate lineage, a hard-wired mirror mechanism for social cognitive functions. PMID- 24775156 TI - Understanding action with the motor system. AB - We challenge Cook et al.'s claim about the vagueness of the notion of action understanding in relation with mirror neurons. We show the multidimensional nature of action understanding and provide a definition of motor-based action understanding, shedding new light on the various components of action understanding and on their relationship. Finally, we propose an alternative perspective on the origin of mirror neurons, stressing the necessity to abandon the dichotomy between genetic and associative hypotheses. PMID- 24775157 TI - Evolution after mirror neurons: tapping the shared manifold through secondary adaptation. AB - Cook et al. laudably call for careful comparative research into the development of mirror neurons. However, they do so within an impoverished evolutionary framework that does not clearly distinguish ultimate and proximate causes and their reciprocal relations. As a result, they overlook evidence for the reliable develop of mirror neurons in biological and cultural traits evolved to work through them. PMID- 24775158 TI - Mirror representations innate versus determined by experience: a viewpoint from learning theory. AB - From the viewpoint of pattern recognition and computational learning, mirror neurons form an interesting multimodal representation that links action perception and planning. While it seems unlikely that all details of such representations are specified by the genetic code, robust learning of such complex representations likely requires an appropriate interplay between plasticity, generalization, and anatomical constraints of the underlying neural architecture. PMID- 24775159 TI - Higher-level processes in the formation and application of associations during action understanding. AB - The associative account described in the target article provides a viable explanation for the origin of mirror neurons. We argue here that if mirror neurons develop purely by associative learning, then they cannot by themselves explain intentional action understanding. Higher-level processes seem to be involved in the formation of associations as well as in their application during action understanding. PMID- 24775160 TI - Associative and sensorimotor learning for parenting involves mirror neurons under the influence of oxytocin. AB - Mirror neuron-based associative learning may be understood according to associative learning theories, in addition to sensorimotor learning theories. This is important for a comprehensive understanding of the role of mirror neurons and related hormone modulators, such as oxytocin, in complex social interactions such as among parent-infant dyads and in examples of mirror neuron function that involve abnormal motor systems such as depression. PMID- 24775161 TI - The alluring but misleading analogy between mirror neurons and the motor theory of speech. AB - Speech is commonly claimed to relate to mirror neurons because of the alluring surface analogy of mirror neurons to the Motor Theory of speech perception, which posits that perception and production draw upon common motor-articulatory representations. We argue that the analogy fails and highlight examples of systems-level developmental approaches that have been more fruitful in revealing perception-production associations. PMID- 24775162 TI - Hebbian Learning is about contingency, not contiguity, and explains the emergence of predictive mirror neurons. AB - Hebbian Learning should not be reduced to contiguity, as it detects contingency and causality. Hebbian Learning accounts of mirror neurons make predictions that differ from associative learning: Through Hebbian Learning, mirror neurons become dynamic networks that calculate predictions and prediction errors and relate to ideomotor theories. The social force of imitation is important for mirror neuron emergence and suggests canalization. PMID- 24775163 TI - Deciphering mirror neurons: rational decision versus associative learning. AB - The rational-decision approach is superior to the associative-learning approach of Cook et al. at explaining why mirror neurons fire or do not fire - even when the stimulus is the same. The rational-decision approach is superior because it starts with the analysis of the intention of the organism, that is, with the identification of the specific objective or goal that the organism is trying to maximize. PMID- 24775164 TI - Relating the "mirrorness" of mirror neurons to their origins. AB - Ever since their discovery, mirror neurons have generated much interest and debate. A commonly held view of mirror neuron function is that they transform "visual information into knowledge," thus enabling action understanding and non verbal social communication between con-specifics (Rizzolatti & Craighero 2004). This functionality is thought to be so important that it has been argued that mirror neurons must be a result of selective pressure. PMID- 24775165 TI - A developmental perspective on action and social cognition. AB - The target article argues that developmental processes are key to understanding the mirror neuron system, yet neglects several bodies of developmental research that are informative for doing so. Infants' actions and action understanding are structured by goals, and the former lends structure to the latter. Evaluating the origins and functions of mirror neurons depends on integrating investigations of neural, social-cognitive and motor development. PMID- 24775166 TI - The origin and function of mirror neurons: the missing link. AB - We argue, by analogy to the neural organization of the object recognition system, that demonstration of modulation of mirror neurons by associative learning does not imply absence of genetic adaptation. Innate connectivity defines the types of processes mirror neurons can participate in while allowing for extensive local plasticity. However, the proper function of these neurons remains to be worked out. PMID- 24775167 TI - Reconciling genetic evolution and the associative learning account of mirror neurons through data-acquisition mechanisms. AB - An associative learning account of mirror neurons should not preclude genetic evolution of its underlying mechanisms. On the contrary, an associative learning framework for cognitive development should seek heritable variation in the learning rules and in the data-acquisition mechanisms that construct associative networks, demonstrating how small genetic modifications of associative elements can give rise to the evolution of complex cognition. PMID- 24775168 TI - Understanding the role of mirror neurons in action understanding will require more than a domain-general account. AB - Cook et al. propose that mirror neurons emerge developmentally through a domain general associative mechanism. We argue that experience-sensitivity does not rule out an adaptive or genetic argument for mirror neuron function, and that current evidence suggests that mirror neurons are more specialized than the authors' account would predict. We propose that future work integrate behavioral and neurophysiological techniques used with primates to examine the proposed functions of mirror neurons in action understanding. PMID- 24775169 TI - Vocal coordination and vocal imitation: a role for mirror neurons? AB - Some birds and mammals have vocal communication systems in which coordination between individuals is important. Examples would include duetting or antiphonal calling in some birds and mammals, rapid exchanges of the same vocalization, and vocal exchanges between paired individuals and other nearby pairs. Mirror neurons may play a role in such systems but become functional only after experience. PMID- 24775170 TI - Associative learning alone is insufficient for the evolution and maintenance of the human mirror neuron system. AB - Cook et al. argue that mirror neurons originate from associative learning processes, without evolutionary influence from social-cognitive mechanisms. We disagree with this claim and present arguments based upon cross-species comparisons, EEG findings, and developmental neuroscience that the evolution of mirror neurons is most likely driven simultaneously and interactively by evolutionarily adaptive psychological mechanisms and lower-level biological mechanisms that support them. PMID- 24775171 TI - Testing key predictions of the associative account of mirror neurons in humans using multivariate pattern analysis. AB - Cook et al. overstate the evidence supporting their associative account of mirror neurons in humans: most studies do not address a key property, action-specificity that generalizes across the visual and motor domains. Multivariate pattern analysis (MVPA) of neuroimaging data can address this concern, and we illustrate how MVPA can be used to test key predictions of their account. PMID- 24775172 TI - The mirror system in human and nonhuman primates. AB - The description of the mirror neuron system provided by Cook et al. is incomplete for the macaque, and incorrect for humans. This is relevant to exaptation versus associative learning as the underlying mechanism generating mirror neurons, and to the sensorimotor learning as evidence for the authors' viewpoint. The proposed additional testing of the mirror system in rodents is unrealistic. PMID- 24775173 TI - Contagious behavior: an alternative approach to mirror-like phenomena. AB - Contagious behaviors such as yawning and itching/scratching have mirror-like properties and clearly defined stimulus and motor parameters; they are also relatively easy to study and should be part of the debate about mirror neurons and the neurological mechanisms of social behavior. The broadly tuned, multimodal stimuli of contagious behavior challenge present accounts of mirror mechanisms that focus on specific, mirrored acts. PMID- 24775174 TI - Experiential effects on mirror systems and social learning: implications for social intelligence. AB - Investigations of biases and experiential effects on social learning, social information use, and mirror systems can usefully inform one another. Unconstrained learning is predicted to shape mirror systems when the optimal response to an observed act varies, but constraints may emerge when immediate error-free responses are required and evolutionary or developmental history reliably predicts the optimal response. Given the power of associative learning, such constraints may be rare. PMID- 24775175 TI - Confounding the origin and function of mirror neurons. AB - Cook et al. argue that mirror neurons originate in sensorimotor associative learning and that their function is determined by their origin. Both these claims are hard to accept. It is here suggested that a major role in the origin of the mirror mechanism is played by top-down connections rather than by associative learning. PMID- 24775176 TI - The emergence of mirror-like response properties from domain-general principles in vision and audition. AB - Like Cook et al., we suggest that mirror neurons are a fascinating product of cross-modal learning. As predicted by an associative account, responses in motor regions are observed for novel and/or abstract visual stimuli such as point-light and android movements. Domain-specific mirror responses also emerge as a function of audiomotor expertise that is slowly acquired over years of intensive training. PMID- 24775177 TI - Neonatal imitation and an epigenetic account of mirror neuron development. AB - Neonatal imitation should not exclusively be considered at the population-level; instead, we propose that inconsistent findings regarding its occurrence result from important individual differences in imitative responses. We also highlight what we consider to be a false dichotomy of genetic versus learning accounts of the development of mirror neurons, and instead suggest a more parsimonious epigenetic perspective. PMID- 24775178 TI - Conjectures concerning cross-sex hormone treatment of aging transsexual persons. AB - INTRODUCTION: Guidelines for cross-sex hormone treatment of transsexual people are now in place. However, little attention has been paid to the issue of treatment suitability for older people. Does existing treatment need to be adapted as subjects age, and does it make a difference if treatment is only started when the subject is already older? AIM: To assess the necessity of adapting cross-sex hormone administration for elderly transsexual people. MAIN OUTCOME MEASURES: Risks/benefits of continued use of cross-sex hormones with regard to bone health, cardiovascular risks, and malignancies. METHODS: Due to lack of data on the subject population, sex hormone treatment of other conditions in older non-transsexual people has been taken as the best available analogy to determine the extent to which these might be applicable to comparable transsexual persons. Findings in transsexual people receiving cross-sex hormone treatment sometimes modified the above approach of applying guidelines for the elderly to the aging transsexual population. RESULTS: Testosterone administration to female to-male transsexual persons (FtoM) carries little risk with regard to cardiovascular disease and cancer. For those with high hematocrit or cardiac insufficiency the dose can be reduced. Administration of estrogens to male-to female transsexual persons (MtoF), particularly when combined with progestins, does significantly increase the risk of developing cardiovascular disease (almost a twofold incidence compared with the general population). This may require dose adjustment or changing from oral to safer transdermal estrogens. Tumors of the breasts, prostate and pituitary may occur. In FtoM, breast cancer can occur even after breast ablation. Older subjects can commence cross-sex hormone treatment without disproportionate risks. CONCLUSION: Cross-sex hormones may be continued into old age but monitoring for cardiovascular disease and malignancies, both of the old and new sex, is recommended. MtoF will have more health complications in old age than FtoM requiring adaptations of treatment. PMID- 24775184 TI - Noradrenergic terminals regulate L-DOPA-derived dopamine extracellular levels in a region-dependent manner in Parkinsonian rats. AB - AIMS: Serotonin (5-HT) neurons mediate the ectopic release of dopamine (DA) induced by L-DOPA in the Parkinsonian brain. We hypothesized that the participation of noradrenalin transporters (NET) in the clearance of DA may account for the lower effect of L-DOPA in extrastriatal regions compared with the striatum. METHODS: Using a multisite intracerebral microdialysis approach, we tested the influence of the pharmacological blockade of NET and/or the destruction of noradrenalin (NE) fibers on DA and 5-HT release in the striatum, hippocampus (HIPP), substantia nigra pars reticulata (SNr) and prefrontal cortex (PFC) of 6-hydroxydopamine-lesioned rats. RESULTS: L-DOPA (12 mg/kg, i.p.) increased DA extracellular levels to a lesser extent in the SNr, PFC and HIPP compared with the striatum. The NET blockers desipramine (10 mg/kg, i.p.) and reboxetine (3 mg/kg, i.p.) potentiated L-DOPA effect in the PFC, SNr and HIPP but not in the striatum. The NE neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (50 mg/kg, i.p. 1 week before dialysis experiment) potentiated L DOPA effect in the SNr and HIPP. 5-HT extracellular levels were enhanced only when L-DOPA was combined to NET blockers. CONCLUSION: Noradrenalin neurons are indirectly involved in the mechanism of action of L-DOPA in part through the heterologous reuptake of DA in extrastriatal regions. PMID- 24775220 TI - Dietary supplementation with fish oil alters the expression levels of proteins governing mitochondrial dynamics and prevents high-fat diet-induced endothelial dysfunction. AB - Diets supplemented with fish oil (FO), which is rich in n-3 PUFA, have been shown to modify several key risk factors for CVD. The purpose of the present study was to determine the effect of FO supplementation on mitochondrial dynamic protein expression in the endothelium and on endothelial cell function. Male apoE deficient (apoE-/-) mice (8 weeks old, n 12 per group) were fed a high-fat diet containing 45% fat (HFD group) or a HFD with partial replacement of lard with 10% (w/w) FO (FO group) (total EPA and DHA content 64.1 g/kg) for 8 weeks. ApoE-/- mice in the FO group had a greater endothelium-dependent vasorelaxation response to acetylcholine (Ach) than those in the HFD group. The atherosclerotic lesion volume in the aortic sinus of mice in the FO group was 54% lower than that in the HFD group (P< 0.01). In addition, the aortas isolated from mice in the FO group had higher expression levels of Mfn2 and Opa1 but lower expression levels of Fis1 than those from the HFD group. Compared with mice fed the HFD, those fed the FO diet showed significantly lower levels of mitochondrial oxidative stress, cytochrome c release and caspase-3 activity (each P< 0.05). Furthermore, FO-fed mice displayed increased NO release and availability and enhanced endothelial NO synthase activity compared with HFD-fed mice. Taken together, these results reveal a novel mechanism by which FO protects against endothelial cell dysfunction, which may result in improved mitochondrial dynamics. PMID- 24775221 TI - What is an appropriate material to use with a covering technique to prevent the recurrence of spontaneous pneumothorax? AB - BACKGROUND: The purpose of this retrospective study was to identify an appropriate material that can be used as a covering for patients with a spontaneous pneumothorax (SP). A total of 279 patients were studied over a period of eight years. METHODS: The patient characteristics, surgical details and perioperative outcomes were analyzed. We compared the clinicopathological characteristics between recurrent and non-recurrent cases, and examined the associations with the material used for covering the SP, such as polyglycolic acid (PGA) sheets, a fibrinogen-based collagen fleece (TachoComb; TC) or regenerated oxidized cellulose mesh (ROCM). RESULTS: The differences in the gender, smoking habits, lesion site, location, comorbidities, ipsilateral spontaneous pneumothorax (ISP), contralateral spontaneous pneumothorax (CSP) and surgery for ISP did not reach statistical significance between the patients treated with a covering of ROCM and those treated with PGA/TC, although the age of the patients was significantly different in these groups, with the ROCM group having younger patients (p = 0.024). The length of the operation was significantly shorter in the ROCM group (mean: 76.7 minutes) than in the PGA/TC cases (130.4 minutes, p = 0.015). Concerning the intraoperative factors, there were no significant differences with regard to the approach, buttress stapling, covering or surgeon. No postoperative recurrence was observed in this series. There were no significant differences in the perioperative outcomes. However, the drainage period was shorter in subjects who underwent covering with the ROCM (mean: 1.125 days) than with the PGA/TC (2.412 days, p = 0.030). Further, the hospital stay had a tendency to be shorter in subjects who underwent covering with ROCM than with PGA/TC. CONCLUSIONS: ROCM might be superior to PGA/TC as a material for covering SP in terms of the length of the operation and the drainage period. ROCM might decrease the hospital stay and the postoperative recurrence. Prospective studies in a larger cohort of patients will be necessary to define the optimal surgical technique to suppress the recurrence of SP. PMID- 24775222 TI - Update on intravenous recombinant tissue plasminogen activator for acute ischemic stroke. AB - The controversial field of interventional stroke neurology has attracted considerable interest within the stroke community, but no endovascular interventional therapies have proved to be superior to intravenous (IV) recombinant tissue plasminogen activator (rtPA), the standard of care for patients with acute ischemic stroke. In this article, we review the evidence and background of IV thrombolysis for stroke, the clinical application of IV rtPA in practice, and the management of potential complications after thrombolysis. We conducted this review using a search of PubMed for articles published from January 1, 1995, to October 31, 2013, with the following terms: ischemic stroke, tissue plasminogen activator, TPA, alteplase, thrombolysis, and intracranial hemorrhage. Articles were also identified through searches of reference lists and the authors' files. In nearly 2 decades since the publication of the transformative National Institute of Neurological Disorders and Stroke trials, the efficacy and safety of IV rtPA has been consistently verified in international real-world clinical practice. Time from stroke symptom onset to thrombolysis is crucial and probably the most important determinant of success of IV therapy. Thus, optimal care of patients with acute stroke should include community education and standardized protocols to guide immediate patient assessment and triage to medical centers with capability for efficient neurologic assessment, brain imaging, drug administration, and specialized postthrombolysis care. PMID- 24775268 TI - Age-specific prevalence of serrated lesions and their subtypes by screening colonoscopy: a retrospective study. AB - BACKGROUND: Serrated lesions of the colorectum as categorized by pathology include hyperplastic polyps, sessile serrated adenomas without dysplasia, and traditional serrated adenomas with dysplasia. The aim of this study was to investigate the prevalence of various subtypes of serrated lesions by age. METHODS: In this study, 28,544 consecutive asymptomatic patients (aged 22-88 years) were evaluated during health check-ups involving colonoscopies performed by gastroenterologists at a single institution from 2005 to 2012. RESULTS: The adenoma detection rate during colonoscopies for patients aged >=50 years was 31.8% (25.0-35.8%). The serrated lesion detection rate for patients aged >=50 years was 15.3% (10.5-19.6%). Serrated lesions were detected in 15.1% of all patients with subtype prevalences of 14.7% for hyperplastic polyps, 0.5% for sessile serrated adenomas, and 0.1% for traditional serrated adenomas. The prevalence of conventional adenomas increased sharply with age (5.0% in patients aged 20-29 years, 10.9% in those aged 30-39 years, 21.8% in those aged 40-49 years, 29.5% in those aged 50-59 years, 36.9% in those aged 60-69 years, and 40.7% in those aged >=70 years) (trend P = 0.027). In contrast, the prevalence of serrated lesions increased only slightly with age (10.0% in patients aged 20-29 years, 11.8% in those aged 30-39 years, 14.8% in those aged 40-49 years, 15.3% in those aged 50-59 years, 16.8% in those aged 60-69 years, and 16.4% in those aged >=70 years) (trend P = 0.036). CONCLUSIONS: The screening colonoscopy detection rate of serrated lesions, including sessile serrated adenomas and traditional serrated adenomas, appears to be relatively high among young patients aged <50 years. PMID- 24775269 TI - Self-reported depression is increasing among socio-economically disadvantaged adolescents - repeated cross-sectional surveys from Finland from 2000 to 2011. AB - BACKGROUND: Adolescent depression is more common in lower socio-economic groups. Whether this pattern has changed over time, is not known.We examined the prevalence of self-reported depression and its changes in socio-economic groups from 2000 to 2011 among Finnish adolescents. METHODS: Data were based on classroom surveys every second year from 2000-2001 to 2010-2011 using nationwide samples of 14-16-year old Finns (n = 618,084). Data were collected using self administered questionnaires including questions on health, health behaviours, and school experiences. Depression was measured with a Finnish modification of the 13 item Beck Depression Inventory, and divided into no, mild, moderate and severe depression. The association between depression and the social background (parents' education and employment) over time was studied using a multinomial regression analysis. RESULTS: The prevalence of self-reported severe depression slightly increased from 2000-2001 to 2010-2011 in girls. In boys a slight increase was observed when adjusting for background variables. The differences in the prevalence of depression between the social background groups persisted over the entire study period. In both sexes, severe depression nearly doubled among those adolescents whose parents were unemployed and had a low education level; among boys, the prevalence was 6.5% in 2000-2001 and 12.8% in 2010-2011, and among girls 6.4% and 11.4% respectively. CONCLUSION: The largest increases in prevalence of severe depression are seen among socio-economically disadvantaged adolescents. This suggests that inequalities in mental health may become an increasing concern. PMID- 24775270 TI - Expression and regulation of complement receptors by human natural killer cells. AB - Integration of cellular and humoral arms of the innate immune response is fundamental to the development of powerful effector functions in host defence as well as aberrant immune responses. Here, we provide evidence in support of the relationship between complement activation and NK cell functional modulation. We demonstrate that human NK cells and both CD56(bright)CD16(-) and CD56(dim)CD16(+) populations express receptors known to detect the biologically active peptides C3a and C5a (i.e. C3aR, C5aR, C5L2) and the covalently-bound fragments C3b and metabolites iC3b and C3d which serve in immune adhesion (e.g. CR3, CR4). We also show that several pathogen- or tumour/inflammation-related stimuli differentially regulated those complement receptor expression. Furthermore, our results suggest that C3 fragments (C3a, iC3b) have a negative regulatory effect on IFN-gamma production in NK cells. This work provides extensive information of human complement receptors relevant to the integrated actions of complement and NK cells which has been suggested by animal studies. The observations may act as a resource that allows further understanding and exploitation of role of complement in human health and immune mediated diseases. PMID- 24775271 TI - Notch signaling regulates the phosphorylation of Akt and survival of lipopolysaccharide-activated macrophages via regulator of G protein signaling 19 (RGS19). AB - Macrophages play critical roles in innate immune defense by sensing microbes using pattern-recognition receptors. Lipopolysaccharide (LPS) stimulates macrophages via TLR, which leads to activation of downstream signaling cascades. In this study, we investigated the roles of a conserved signaling pathway, Notch signaling, in regulating the downstream signaling cascades of the LPS/TLR4 pathways in macrophages. Using a phospho-proteomic approach and a gamma-secretase inhibitor (GSI) to suppress the processing and activation of Notch signaling, we identified regulator of G protein signaling 19 (RGS19) as a target protein whose phosphorylation was affected by GSI treatment. RGS19 is a guanosine triphosphatase (GTPase)-activating protein that functions to negatively regulate G protein-coupled receptors via Galphai/Galphaq-linked signaling. Stimulation of RAW264.7 cells with LPS increased the level of the phosphorylated form of RGS19, while LPS stimulation in the presence of GSI decreased its level. GSI treatment did not alter the mRNA level of rgs19. Treatment with GSI or silencing of rgs19 in macrophages impaired the phosphorylation of Akt Thr(308) upon LPS stimulation. Furthermore, targeted deletion of a DNA-binding protein and binding partner of the Notch receptor, RBP-Jkappa/CSL, in macrophages resulted in delayed and decreased Akt phosphorylation. Because the PI3K/Akt pathway regulates cell survival in various cell types, the cell cycle and cell death were assayed upon GSI treatment, phosphatidylinositol 3 kinase (PI3K) inhibitor treatment or silencing of rgs19. GSI treatment resulted in decreased cell populations in the G1 and S phases, while it increased the cell population of cell death. Similarly, silencing of rgs19 resulted in a decreased cell population in the G1 phase and an increased cell population in the subG1 phase. Inhibition of Akt phosphorylation by PI3K inhibitor in LPS-stimulated macrophages increased cell population in G1 phase, suggesting a possible cell cycle arrest. Taken together, these results indicate that Notch signaling positively regulates phosphorylation of Akt, possibly via phosphorylation of RGS19, and inhibition of both molecules affects the cell survival and cell cycle of macrophages upon LPS stimulation. PMID- 24775272 TI - Effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein A-V levels in patients with impaired fasting glucose or new onset type 2 diabetes as a function of the APOA5 -1131 T > C polymorphism. AB - BACKGROUND: The purpose of this study was to estimate the effects of a 3-year dietary intervention on age-related changes in triglyceride and apolipoprotein (apo A-V) levels in patients with impaired fasting glucose (IFG) or new-onset type 2 diabetes as a function of the APOA5 -1131 T > C polymorphism. METHODS: We genotyped the APOA5 -1131 T > C polymorphism in 203 Korean individuals with IFG or new-onset type 2 diabetes for the TT (n = 91), TC (n = 98), and CC (n = 14) alleles. Plasma apo A-V and triglyceride levels were evaluated at baseline and after a 3-year dietary intervention. RESULTS: Our results showed that HDL, glucose, insulin, HOMA-IR index, free fatty acids, and apo A-V decreased and brachial-ankle pulse wave velocity (ba-PWV) and malondialdehyde (MDA) increased at the 3-year follow-up visit compared with baseline. Plasma apo A-V levels were reduced in subjects with the C allele (TC or CC) (P = 0.036) and triglyceride levels were reduced in subjects with the TT allele (P = 0.047). Subjects with the C allele showed lower post-treatment apo A-V and higher post-treatment fasting triglyceride levels than subjects with the TT allele. Changes in apo A-V and triglyceride levels were negatively correlated in subjects with the TT allele and positively correlated in subjects with the C allele. CONCLUSIONS: This study showed that the dietary intervention prevented an age-related increase in triglyceride levels in individuals with IFG or new-onset type 2 diabetes who possess the TT allele, but not the CT or CC allele, of the APOA5 -1131 T > C polymorphism. PMID- 24775273 TI - A newly isolated probiotic Enterococcus faecalis strain from vagina microbiota enhances apoptosis of human cancer cells. AB - AIMS: This study aimed to describe probiotic properties and bio-therapeutic effects of newly isolated Enterococcus faecalis from the human vaginal tract. METHODS AND RESULTS: The Enterococcus faecalis strain was originally isolated from the vaginal microbiota of Iranian women and was molecularly identified using 16SrDNA gene sequencing. Some biochemical methodologies were preliminarily used to characterize the probiotic potential of Ent. faecalis, including antibiotic susceptibility, antimicrobial activity, as well as acid and bile resistance. The bio-therapeutic effects of this strain's secreted metabolites on four human cancer cell lines (AGS, HeLa, MCF-7 and HT-29) and one normal cell line (HUVEC) were evaluated by cytotoxicity assay and apoptosis scrutiny. The characterization results demonstrated into the isolated bacteria strain revealed probiotic properties, such as antibiotic susceptibility, antimicrobial activity and resistance under conditions similar to those in the gastrointestinal tract. Results of bio-therapeutic efficacy assessments illustrated acceptable apoptotic effects on four human cancer cell lines and negligible side effects on assayed normal cell line. Our findings revealed that the apoptotic effect of secreted metabolites mainly depended on proteins secreted by Ent. faecalis on different cancer cells. These proteins can induce the apoptosis of cancer cells. CONCLUSION: The metabolites produced by this vaginal Ent. faecalis strain can be used as alternative pharmaceutical compounds with promising therapeutic indices because they are not cytotoxic to normal mammalian cells. Accordingly, the physicochemical, structural and functional properties of the secreted anticancer substances should be further investigated before using them as anticancer therapeutics. SIGNIFICANCE AND IMPACT OF THE STUDY: This study aim to screen total bacterial secreted metabolites as a wealthy source to find the new active compounds to introduce as anticancer therapeutics in the future. PMID- 24775274 TI - The prevalence of attention-deficit/hyperactivity disorder following neonatal aortic arch repair. AB - OBJECTIVE: We sought to determine the prevalence of attention deficit/hyperactivity disorder in a population of children who underwent neonatal heart surgery involving repair of the aortic arch for Norwood Stage I, interrupted aortic arch, and combined repair of aortic coarctation with ventricular septal defect. METHODS: Children between the ages of 5 and 16 were surveyed using the ADHD-IV and the Child Heath Questionnaire-50. Classification as attention-deficit/hyperactivity disorder was defined for this study as either a parent-reported diagnosis of attention-deficit/hyperactivity disorder or ADHD IV inattention score of ?93 percentile. RESULTS: Of the 134 surveys, 57 (43%) were returned completed. A total of 25 (44%) children either had a diagnosis of attention-deficit/hyperactivity disorder and/or ADHD-IV inattention score ?93 percentile. Eleven of the 13 (85%) children with interrupted aortic arch, 3 of the 7 (42.9%) children with combined coarctation/ventricular septal defect repair, and 9 of the 33 (27.3%) children with hypoplastic left-heart syndrome were classified as having attention-deficit/hyperactivity disorder. Only 7 of the 25 (28%) children received medical treatment for this condition. Quality of life indicators in the Child Heath Questionnaire-50 Questionnaire were highly correlated with the ADHD-IV scores. CONCLUSION: The risks for the development of attention-deficit/hyperactivity disorder are multifactorial but are significantly increased in this post-surgical population. This study revealed a low treatment rate for attention-deficit/hyperactivity disorder, and a significant impact on the quality of life in these children. PMID- 24775275 TI - Evaluation of three medetomidine-based protocols for chemical restraint and sedation for non-painful procedures in companion rats (Rattus norvegicus). AB - Three medetomidine-based protocols were evaluated for sedation in companion rats undergoing diagnostic procedures. Group Me received medetomidine at 150 MUg/kg intramuscularly (IM); group Me-Bu received medetomidine 100 MUg/kg IM and butorphanol 2 mg/kg IM, and group Me-Bu-Mi received medetomidine 50 MUg/kg IM, butorphanol 2 mg/kg IM and midazolam 1 mg/kg IM. The righting reflex disappeared more quickly in the Me-Bu-Mi group, but recovery after atipamezole was longer. In group Me, a palpebral reflex was present throughout sedation in more rats than in the other two groups. Pulse and respiratory rates were higher when lower doses of medetomidine were used, although arterial haemoglobin O2 saturation was similar among groups. All protocols tested produced adequate sedation lasting 25 min. PMID- 24775277 TI - Expanding the mind--growing the brain . . . PMID- 24775276 TI - Canine aural cholesteatoma: a histological and immunohistochemical study. AB - Canine aural cholesteatoma is an epidermoid cyst that forms in the middle ear cavity as a rare complication of otitis media but the aetiopathogenesis remains controversial. In the present study, 13 cases of canine aural cholesteatoma were investigated histologically and immunohistochemically and compared with cases of chronic otitis. The immunohistochemical investigation was performed using the following monoclonal antibodies: anti-cytokeratins (CK) 14, 16, 8/18, and 19, and anti-Ki67. The proliferative indexes (PIs) of cholesteatomata and otitis epithelium were calculated as the percentage of Ki67 positive nuclei/total nuclei. Histologically, the cholesteatomata were composed of a hyperplastic, hyperkeratotic epithelium (matrix) resting on a fibrous perimatrix, infiltrated by inflammatory cells and devoid of cutaneous adnexa. Immunohistochemically, the cholesteatoma epithelium was CK14- and CK16-positive, and CK8/18- and CK19 negative. A similar pattern of CK expression was found in otitis externa. In otitis media, ciliated epithelium stained CK8/18- and CK19-positive in all layers, CK14-positive in the basal layers, and CK16-negative. The mean PIs in cholesteatomata and otitides were 18.8 and 17.8, respectively. The immunohistochemical pattern of CK expression in cholesteatomata, when compared with chronic otitis, was suggestive of hyperproliferative epithelium, but its origin could not be demonstrated. Comparable PI values were obtained in cholesteatoma and in chronic otitis, which confirmed that Ki67 is a valuable indicator of a hyperproliferative state, but not a predictor of aggressiveness. PMID- 24775278 TI - Retrospective comparison of open versus laparoscopic ventral and incisional hernia repair. AB - INTRODUCTION: We performed a retrospective study to determine the mid-term recurrence and complication rates of patients following laparoscopic ventral and incisional hernia repair (LVHR) with DualMesh, an expanded polytetrafluoroethylene (ePTFE) mesh. Additionally, a study of the mesh contraction rate was performed postoperatively. METHODS: We compared open mesh repair of ventral and incisional hernias (OR) and LVHR. We also analyzed the shrinkage rate of ePTFE mesh. We included 45 patients (21 OR, 24 LVHR) who underwent mesh repair for primary ventral and incisional hernias between January 2008 and December 2012. Patients' characteristics did not significantly differ between the two groups. RESULTS: Mean operating time was 152.7 min for the OR group and 143.1 min for the LVHR group (P = 0.25). Mean postoperative hospital stay was 13.4 days for the OR group and 6.8 days for the LVHR groups (P = 0.01). The postoperative complication rate was 28.6% for the OR group and 12.5% for the LVHR group (P = 0.03). Among OR patients, causes of morbidity were variable: two recurrent cases, one surgical-site infection, one re-recurrence, one case of enteritis, and one case of heart failure. Among the LVHR patients, there was one surgical-site infection and two cases of seroma. No patients in the LVHR group experienced recurrence, while 14.3% of OR patients had a recurrence. In the LVHR group, the mean ePTFE mesh contraction rate was 10.6%. CONCLUSION: LVHR has advantages compared with OR, and the post-insertion contraction rate of ePTFE mesh was 10.6%. PMID- 24775300 TI - Inhibition of fructan-fermenting equine faecal bacteria and Streptococcus bovis by hops (Humulus lupulus L.) beta-acid. AB - AIMS: The goals of this study were to determine if beta-acid from hops (Humulus lupulus L.) could be used to control fructan fermentation by equine hindgut micro organisms, and to verify the antimicrobial mode of action on Streptococcus bovis, which has been implicated in fructan fermentation, hindgut acidosis and pasture associated laminitis (PAL) in the horse. METHODS AND RESULTS: Suspensions of uncultivated equine faecal micro-organisms produced fermentation acids when inulin (model fructan) was the substrate, but beta-acid (i.e. lupulone) concentrations >=9 ppm inhibited lactate production and mitigated the decrease in pH. Inulin-fermenting Strep. bovis was isolated from the beta-acid-free suspensions after enrichment with inulin. The isolates were sensitive to beta acid, which decreased the viable number of streptococci in faecal suspensions, as well as growth, lactate production and the intracellular potassium of Strep. bovis in pure culture. CONCLUSIONS: These results are consistent with the hypothesis that hops beta-acid prevented the growth of fructan-fermenting equine faecal bacteria, and that the mechanism of action was dissipation of the intracellular potassium of Strep. bovis. SIGNIFICANCE AND IMPACT OF THE STUDY: Bacterial hindgut fermentation of grass fructans has been linked to PAL and other metabolic disorders in horses. Hops beta-acid is a potential phytochemical intervention to decrease the growth of bacteria responsible for PAL. PMID- 24775301 TI - Design and synthesis of molecular probes for the determination of the target of the anthelmintic drug praziquantel. AB - Schistosomiasis is a highly prevalent neglected tropical disease caused by blood dwelling helminths of the genus Schistosoma. Praziquantel (PZQ) is the only drug available widely for the treatment of this disease and is administered in racemic form, even though only the (R)-isomer has significant anthelmintic activity. Progress towards the development of a second generation of anthelmintics is hampered by a lack of understanding of the mechanism of action of PZQ. In this Letter, we report an efficient protocol for the small-scale separation of enantiomers of 2 (hydrolyzed PZQ) using supercritical fluid chromatography (SFC). The enantiopure 2 was then used to develop several molecular probes, which can potentially be used to help identify the protein target of PZQ and study its mode of action. PMID- 24775302 TI - Myrotheciumones: bicyclic cytotoxic lactones isolated from an endophytic fungus of Ajuga decumbens. AB - Two new bicyclic lactones, myrotheciumones A (1) and B (2) which possessed a rare ring-fusion system were isolated from Myrothecium roridum (M. roridum), an endophytic fungus of the medicinal herb plant Ajuga decumbens (A. decumbens) via an in vitro cytotoxicity assay. Structures were deduced from 1D and 2D NMR (Nuclear magnetic resonance) data. Myrotheciumone A's in vitro cytotoxicity and apoptotic activity were evaluated and myrotheciumone A was shown to exert cytotoxicity via inducing apoptosis in cancer cell line. PMID- 24775303 TI - Development of bacterial transglycosylase inhibitors as new antibiotics: moenomycin A treatment for drug-resistant Helicobacter pylori. AB - The problem of multidrug-resistant Helicobacter pylori requires new antibiotics development. We have evaluated a potential antibiotics, moenomycin A, which is classified as a phosphoglycolipid antibiotics that targets transglycosylase and is previously thought to be limited in Gram-positive bacteria. Herein, we report the activity of moenomycin A against multidrug-resistant H. pylori and the isolates from patients with different gastrointestinal diseases. PMID- 24775304 TI - Pim kinase inhibitory and antiproliferative activity of a novel series of meridianin C derivatives. AB - A novel series of meridianin C derivatives substituted at C-5 position were prepared. These derivatives were tested for their kinase inhibitory potencies against all three family members of the pim kinases (Pim-1, Pim-2 and Pim-3). In addition, their antiproliferative activity towards three human leukemia cell lines as MV4-11, Jurkat clone E6-1 and K562 has been evaluated. Structure activity relationships at C-3 and C-5 positions of indole were performed to better understand the mechanism behind the enhanced potency. Compound 7f, the most active compound of the series showed a single-digit nanomolar IC50 with selectivity towards Pim-1 kinase. PMID- 24775305 TI - P3 SAR exploration of biphenyl carbamate based Legumain inhibitors. AB - This Letter describes the further development and SAR exploration of a novel series of Legumain inhibitors. Based upon a previously identified Legumain inhibitor from our group, we explored the SAR of the carbamate phenyl ring system to probe the P3 pocket of the enzyme. This led to the identification of a sub nanomolar inhibitor of Legumain. PMID- 24775306 TI - Antimalarial chemotherapy: artemisinin-derived dimer carbonates and thiocarbonates. AB - Several 2-carbon-linked trioxane dimer secondary alcohol carbonates 14 and thiocarbonates 15, combined with mefloquine and administered in a low single oral dose, prolonged the survival times of malaria-infected mice much more effectively than the popular monomeric antimalarial drug artemether plus mefloquine. Three dimer carbonates 14 and one dimer thiocarbonate 15 partially cured malaria infected mice. PMID- 24775307 TI - Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors. AB - The orally-active CYP17A1 inhibitor abiraterone acetate (AA) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer. Abiraterone potently inhibits both reactions catalyzed by CYP17, the 17alpha-hydroxylase (hydroxylase) reaction as well as the 17,20-lyase (lyase) transformation. CYP17 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids. As a consequence of potent CYP17 hydroxylase inhibition (i.e., lack of lyase selectivity), AA must be co-administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome (MES). Herein, we describe rationally-designed, CYP17 lyase-selective inhibitors that could prove safer and more effective than abiraterone. Using proprietary methodology, the high-affinity pyridine or imidazole metal-binding group found in current clinical CYP17 inhibitors was replaced with novel, less avid, metal-binding groups in concert with potency enhancing molecular scaffold modifications. This process produced a unique series of CYP17 lyase-selective inhibitors that included the oral agent 6 (VT-464), now in Phase 2 prostate cancer clinical trials. The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases. PMID- 24775308 TI - Combination of the ABL kinase inhibitor imatinib with the Janus kinase 2 inhibitor TG101348 for targeting residual BCR-ABL-positive cells. AB - BACKGROUND: The ABL kinase inhibitor imatinib is highly effective in treating most, but not all, patients with chronic myeloid leukemia (CML). This is because residual CML cells are generally present in the bone marrow microenvironment and are refractory to imatinib. Hematopoietic cytokine receptor signaling is mediated by Janus kinases (JAKs) and their downstream transcription factor, signal transducer and activator of transcription (STAT). TG101348 (SAR302503) is an oral inhibitor of JAK2. METHODS: We investigated the efficacy of imatinib and TG101348 using the break point cluster region-c-Abelson (BCR-ABL)-positive cell line and primary CML samples wherein leukemia cells were protected by a feeder cell line (HS-5). RESULTS: Imatinib treatment resulted in partial inhibition of cell growth in HS-5-conditioned medium. Furthermore, combined treatment with imatinib and TG101348 abrogated the protective effects of HS-5-conditioned medium on K562 cells. Phosphorylation of Crk-L, a BCR-ABL substrate, decreased considerably, while apoptosis increased. In addition, the combined treatment of CD34-positive primary samples resulted in considerably increased cytotoxicity, decreased Crk-L phosphorylation, and increased apoptosis. We also investigated TG101348 activity against feeder cells and observed that STAT5 phosphorylation, granulocyte macrophage colony-stimulating factor, and interleukin 6 levels decreased, indicating reduced cytokine production in HS-5 cells treated with TG101348. CONCLUSIONS: These results showed that JAK inhibitors may enhance the cytotoxic effect of imatinib against residual CML cells and that a combined approach may be a powerful strategy against the stroma-associated drug resistance of Philadelphia chromosome-positive cells. PMID- 24775330 TI - Clinical predictors of incident gallstone disease in a Chinese population in Taipei, Taiwan. AB - BACKGROUND: Gallstone disease (GSD) is a common gastrointestinal disorder throughout the world. The authors explored the incidence of GSD in Taiwan and its condition-associated predictive factors. METHODS: The initial study cohort comprised 2386 healthy adult participants, who were voluntarily admitted to a teaching hospital for a physical check-up in 2002 in Taipei, Taiwan. After excluding 126 patients who exhibited prevalent GSD, 2260 non-GSD participants received annual follow-up screenings for GSD until 31 December, 2007. Of those, 1296 (57.3%) patients were re-examined to collect blood samples and conduct ultrasound sonography. RESULTS: Among the 1296 participants who exhibited no GSD at the first screening, 23 patients developed GSD during 3640 person-years of follow-up. The incidence was 0.632% per year (95% CI: 0.292%-2.009%). After conducting a Cox regression, increased age (50-59 years versus < 40 years, RR = 2.16 [95% CI: 1.09-5.97], 60+ years versus < 40 years, RR = 3.81 [95% CI: 2.77 8.63]), high body mass index (>=27 kg/m2 versus < 24 kg/m2, RR = 1.64 [95% CI: 1.07-2.98]), high fasting plasma glucose levels (>=126 mg/dL versus < 110 mg/dL, RR = 1.68, 95% CI: 1.10-3.87), and nonalcoholic fatty liver disease (yes versus no, RR = 1.44, 95% CI: 1.21-1.90) appeared to be significantly related to developing GSD. CONCLUSION: Increased age is a well-established risk factor for developing GSD. The current findings indicated that high body mass index, elevated fasting plasma glucose levels, and nonalcoholic fatty liver disease were also associated with GSD. PMID- 24775353 TI - HLA-DQA1 and HLA-DQB1 genes in Tsachilas Indians from Ecuador: new insights in population analysis by Human Leukocyte Antigens. AB - Human Leucocyte Antigen (HLA) loci are widely known for their role in the generation of immune responses and are often considered to be effective in reconstructing human relationships. This is due to the high degree of polymorphism and the rarity of recombination observed at HLA loci. In this study, we have made an attempt to support the potential of HLA class II loci by analysing DQA1 and DQB1 in 52 Ecuadorians with ties to the Tsachilas community. Little is known about this populations either ethnologically or historically: they are considered retaining much of the ancient Chibchan culture in spite of the lack of significant genetic characterization. A total of 21 alleles were observed, with very low heterozygosity. The obtained data were then assessed for relationship reconstruction. The compiled database of 63 populations was segregated and resolved in clusters corresponding to the ethnogeographic distribution of the populations. This analysis of Central and Southern Amerindians allowed us to support a historical hypothesis related to the origin and migration of Ecuadorian people. Indeed, the relationships with neighbour human groups, especially Cayapas and Colombians, could shed light on the genetic similarity within ancient Chibchan culture that was dispersed by tribes coming up the Barbacoas. This indicates that if an appropriate analysis was to be carried out on a set of populations representative of different geographic locations, and that analysis was properly interpreted, then there would be a high possibility that HLA class II loci could infer accurate assessments, as revealed by uniparental markers. PMID- 24775377 TI - Brain volumes and cognitive function in very-low-birth-weight (VLBW) young adults. AB - BACKGROUND: Preterm born very-low-birth-weight (VLBW: birth weight <=1500 g) survivors have increased risk of perinatal brain injury that may cause deviant brain development and later neuroimpairments, including reduced cognitive functioning. AIMS: In this long-term follow up study of three year-cohorts (birth years 1986-88) of VLBW subjects and term born controls with normal birth weight, the aim was to examine differences in brain volumes at age 20 years. In addition, the relationships between brain volumes and cognitive abilities and perinatal variables were explored. METHODS: Forty-four VLBW subjects and 60 controls were assessed with cognitive testing (Wechsler Adult Intelligence Scale - WAIS-III) and structural MRI at 1.5 T, using the FreeSurfer 5.1 software for volumetric analysis. A subpopulation had MRI performed also at age 15, and for this group changes in brain volumes with age were examined. RESULTS: The VLBW subjects had smaller brain volumes, especially of thalamus, globus pallidus and parts of the corpus callosum, and larger lateral ventricles than controls at age 20. However, no significant group differences in longitudinal change from age 15 to 20 were observed. The most immature and smallest VLBW subjects at birth, and those with the highest perinatal morbidity, showed most pronounced volume deviations. Positive associations between several brain volumes and full IQ, as well as three of four IQ indices in the VLBW group, were observed. CONCLUSION: Reduced volumes of grey and white matter and ventricular dilatation in VLBW young adults may indicate permanent effects on brain development from perinatal brain injury with influence on later cognitive function. PMID- 24775378 TI - Defining the role of left atrial appendage closure in atrial fibrillation. PMID- 24775379 TI - Dynamic evaluation of exercise limitation and functional class in patients with hypertrophic cardiomyopathy. PMID- 24775380 TI - Comments on the ESC guidelines on the management of valvular heart disease (version 2012). A report of the Task Force of the Clinical Practice Guidelines Committee of the Spanish Society of Cardiology. PMID- 24775381 TI - Immediate and one-year results in 35 consecutive patients after closure of left atrial appendage with the Amplatzer cardiac plug. AB - INTRODUCTION AND OBJECTIVES: Left atrial appendage closure can be an attractive option for patients with nonvalvular atrial fibrillation and a contraindication to oral anticoagulants, provided that satisfactory results can be achieved during implantation and follow-up. METHODS: Thirty-five consecutive patients, not eligible for randomized trials with oral anticoagulants, had an Amplatzer occlusion device implanted under general anesthesia. After the first 5 patients, 3-dimensional imaging was incorporated. The results of the implantation and the follow-up were analyzed over a 1-year period. RESULTS: The mean age was 74.65 (7.61) years, with a CHADS2 score of 2.41 (1.53) and a CHA2DS2-VASc score of 3.17 (1.60). Implantation failed in 1 patient and 5 needed a change in the selected plug size. There were no cardiac complications during the implantation or hospital stay. There was 1 vascular complication (arteriovenous fistula). Transesophageal echocardiography monitoring was performed at 24h, 1, 3, 6, and 12 months and we found 5 thrombi which were resolved with heparin. In the follow-up period of 21.14 (10.09) months, 3 patients aged>80 years died, none of them due to heart problems, and one transient ischemic stroke without further consequences. CONCLUSIONS: Left atrial appendage closure by an experienced operator can be a treatment option with few complications and with efficient results at>1 year in reducing thromboembolic and hemorrhagic complications, even in very high-risk groups. PMID- 24775382 TI - Exercise eco-Doppler in hypertrophic cardiomyopathy patients. Determinant factors of exercise intolerance. AB - INTRODUCTION AND OBJECTIVES: At-rest echocardiography is a poor predictor of exercise capacity in patients with hypertrophic cardiomyopathy. We aimed to test the performance of treadmill exercise Doppler echocardiography in the prediction of functional limitations in these patients. METHODS: Eighty-seven consecutive patients with hypertrophic cardiomyopathy underwent treadmill exercise echocardiography with direct measurement of oxygen consumption. Both at rest and at peak exercise, the mitral inflow, mitral regurgitation, left ventricular outflow tract obstruction and mitral annulus velocities were assessed. RESULTS: Forty-three patients developed left ventricular outflow tract obstruction during exercise, which significantly decreased oxygen consumption (21.3 [5.7] mL/kg/min vs 24.6 [6.1] mL/kg/min; P=.012), and had greater left atrial volume (42.1 [14.5] mL/m(2) vs 31.1 [11.6] mL/m(2); P<.001) and a higher degree of mitral regurgitation and E/E' ratio during exercise. Exercise variables improved the predictive value of functional capacity (adjusted R(2) rose from 0.38 to 0.49). Independent predictors of oxygen consumption were age, left atrial volume, E/E' ratio and the presence of left ventricular outflow tract obstruction. In a subset of patients without left ventricular outflow obstruction, only left ventricular and atrial volume indexes were independent predictors of exercise capacity. CONCLUSIONS: In patients with hypertrophic cardiomyopathy, left ventricular outflow tract obstruction and left atrial volume are the main predictors of exercise capacity. Exercise echocardiography is a better predictor of functional performance than at-rest echocardiography, although its predictive power is under 50%. In nonobstructed patients, left atrial and ventricular volumes were the independent factors. PMID- 24775383 TI - Younger women have a higher risk of in-hospital mortality due to acute myocardial infarction in Chile. AB - INTRODUCTION AND OBJECTIVES: Coronary heart disease is the second cause of death in Chilean women, with higher mortality among women, especially at younger ages. The objective was to analyze in-hospital case-fatality by sex and age in patients with acute myocardial infarction in Chile and to evaluate associated factors. METHODS: From the nationwide hospital admissions database and the GEMI registry (a multicenter registry), we selected all cases of acute myocardial infarction (code: I.21) that occurred between 2001 and 2007 in Chile. We estimated odds ratios for in-hospital case-fatality in women by age (crude and adjusted for clinical characteristics and treatment). RESULTS: In total, 49,287 cases of acute myocardial infarction were hospitalized, 31.3% of them women; 9278 patients were incorporated in the GEMI registry (27.1% women). In-hospital case-fatality was higher (P<.001) in women than men (national database, 20.4% vs 11.3%; GEMI, 14.2% vs 7.3%, irrespective of age. In-hospital case-fatality risk was higher in women aged<45 years: national odds ratio=2.3 (95% confidence interval, 1.5-3.3) and GEMI, odds ratio=2.7 (1.1-6.8). The estimated risk was lower in women aged 75 or more years in both databases, 1.3 (1.2-2.4) and 1.5 (1.2-1.9), respectively. Younger women less often received statins, odds ratio=0.7 (0.6-0.8); acetylsalicylic acid, odds ratio=0.4 (0.2-0.6); betablockers, odds ratio=0.8 (0.6 0.9), and thrombolytics, odds ratio=0.6 (0.5-0.8). An interaction was found between Killip class and sex. After adjusting for covariates, women aged<55 years with ST-segment elevation myocardial infarction and Killip class I-II, had the highest risk, odds ratio=4.3 (2.1-8.9). CONCLUSIONS: In the context of a Latin American country, women aged<55 years with ST-segment elevation myocardial infarction and Killip class I-II had a higher risk of death. Known risk factors do not completely explain this excess of risk. PMID- 24775384 TI - Association between adiposity and blood pressure levels between the ages of 6 and 16 years. Analysis in a student population from Madrid, Spain. AB - INTRODUCTION AND OBJECTIVES: The increase in the incidence of hypertension in children can be attributed to the rising prevalence of obesity. The objective is to analyze the impact of overweight and the degree or distribution of adiposity on blood pressure levels in a population of Spanish schoolchildren. METHODS: A cross-sectional study was carried out in 1511 schoolchildren between 6 years and 16 years of age. We measured weight, height, waist circumference, subcutaneous skinfolds, and blood pressure. Nutritional categories were established on the basis of body mass index, waist-to-height ratio, and percent body fat. According to the National High Blood Pressure Education Program Working Group, subjects whose blood pressure was above the 90th percentile of the standard normal distribution were considered to have high blood pressure. RESULTS: In all, 3.17% of the boys and 3.05% of the girls had high blood pressure. According to odds ratio analysis, the risk of high blood pressure increased in individuals with a body mass index indicative of obesity (7.87-fold in boys, 12.32-fold in girls), with a percent body fat>97th percentile (6.98-fold in boys, 18.51-fold in girls), or with a waist-to-height ratio >=0.5 (10.56-fold in boys, 7.82-fold in girls). CONCLUSIONS: Overweight and obesity increase the risk of high blood pressure in children between 6 years and 16 years of age, although the risk level varies depending on the amount and distribution of adipose tissue. Anthropometric indicators of relative adiposity and fat distribution are especially useful in the identification of children and adolescents with high blood pressure. PMID- 24775385 TI - Innovations in heart rhythm disturbances: cardiac electrophysiology, arrhythmias, and cardiac pacing. AB - This article reviews the most relevant articles published in 2012 in the field of arrhythmias, on subjects that include clinical arrhythmology, ablation, cardiac pacing, and the genetics of sudden cardiac death. PMID- 24775386 TI - Update in cardiology: Vascular risk and cardiac rehabilitation. AB - Atherosclerotic cardiovascular disease remains the major cause of premature death in developed and developing countries. Nevertheless, surveys show that most patients still do not achieve the lifestyles, risk factor levels, and therapeutic targets recommended in primary and secondary prevention. The present update reflects the most recent novelties in risk classification and estimation of risk and documents the latest changes in fields such as smoking, diet and nutrition, physical activity, lipids, hypertension, diabetes, and cardiovascular rehabilitation, based on experimental trials and population-based observational studies. PMID- 24775389 TI - Innovation in cardiology: introduction. PMID- 24775390 TI - Imagining the future of diagnostic imaging. AB - Cardiovascular imaging has become essential to achieving a better understanding of cardiovascular diseases. Due to the advent of new technology and the refinement of existing technologies, imaging's role has extended into the biological, functional, and hemodynamic diagnosis of multiple pathophysiologic processes. Current and future trends in cardiovascular imaging will focus on improving early diagnosis of vascular disease, so as to be able to promote cardiovascular health, and on its development as a useful tool in clinical decision-making. Imaging is also increasingly used to quantify the effect of novel therapies. The rapid development of molecular imaging and fusion imaging techniques improves our understanding of cardiovascular processes from the molecular and cellular points of view and makes it possible to design and test new preventive interventions. The proliferation and integration of imaging techniques in different clinical areas and their role in "translational imaging" plays an important part in the implementation of personalized therapeutic and preventive management strategies for patients with cardiovascular disease. PMID- 24775391 TI - Hybrid treatment for acute aortic arch dissection. PMID- 24775392 TI - Dual ventricular response: another road to supraventricular tachycardia in dual atrioventricular nodal physiology. PMID- 24775393 TI - Immature platelet fraction: a new prognostic marker in acute coronary syndrome. PMID- 24775394 TI - Early anticoagulation may improve preprocedural patency of the infarct-related artery in primary percutaneous coronary intervention. PMID- 24775395 TI - Transfemoral Edwards-SAPIEN XT aortic valve implantation without previous valvuloplasty. PMID- 24775396 TI - Is it appropriate to compare the results from two clinical trials with one drug in common? PMID- 24775397 TI - Ischemia: substrate or trigger? PMID- 24775399 TI - Evaluation of comparative treatment effects using indirect comparisons. PMID- 24775400 TI - Evaluation of comparative treatment effects using indirect comparisons. Response. PMID- 24775401 TI - Maternal blood manganese level and birth weight: a MOCEH birth cohort study. AB - BACKGROUND: Manganese (Mn) is an essential trace element for humans and animals, but excess intake of Mn can lead to adverse developmental outcome. Few studies have investigated the effects of deficiency or excess of Mn on the human foetus. In this study, we assessed the quantitative relationship between maternal blood Mn and birth weight of a newborn. METHODS: We performed analysis on 331 full term, live birth singleton mother-infant pairs enrolled from July 2007 to December 2009 in the Mother and Children's Environmental Health (MOCEH) study in Korea. A questionnaire on general characteristics, a review of medical records, and maternal whole blood Mn analysis were performed at full-term pregnancy. We evaluated the relationship between maternal blood level of Mn and the birth outcome using logistic regression and generalised additive model. RESULTS: The mean Mn concentration in whole maternal blood was 22.5 MUg/L. We found a curvilinear relationship between maternal blood Mn and birth weight after adjusting for potential confounders. Birth weight peaked at the maternal blood Mn level of 30 and 35 MUg/L. An increased probability of birth weight below 3000 g was observed at both below 16.9 MUg/L (odds ratio = 2.77, 95% CI: 0.89-8.65) and above 26.9 MUg/L of maternal blood Mn level (odds ratio = 2.66, 95% CI: 0.84 8.08). CONCLUSIONS: Our study found that both extreme level of maternal Mn level was associated with lower birth weight outcome in a nonlinear fashion. PMID- 24775402 TI - Excimer laser in the treatment of mycosis fungoides. AB - BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, which typically presents as a patch or plaque in early-stage disease. Phototherapy including psoralen plus ultraviolet A and ultraviolet B are well established treatment modalities in management of early-stage MF. Only a limited number of reports have evaluated the efficacy of 308-nm excimer laser in therapy of cutaneous T-cell lymphoma. OBJECTIVE: We sought to evaluate the efficacy of 308-nm excimer laser (XTRAC, PhotoMedex, Montgomeryville, PA) in patients with stage IA to IIA MF. METHODS: We reviewed the clinical and laboratory characteristics of 6 consecutive patients given the diagnosis of refractory MF who underwent treatment with excimer laser. RESULTS: We found that the 308-nm excimer laser is a safe and well-tolerated alternative therapy for early-stage MF. In addition, we were able to delineate criteria to help predict treatment response. Our data showed that 4 (66%) patients achieved clinical improvement (3 complete responses, 1 partial response), 1 had stable disease, and 1 had progressive disease. LIMITATIONS: This was a retrospective study consisting of 6 patients. A prospective study with a larger sample size would be desirable for future studies. CONCLUSION: The use of 308-nm excimer laser in the treatment of stage IA to IIA MF showed clinical and pathological benefit for patients with isolated lesions or lesions in areas that may be difficult to treat because of anatomic location. PMID- 24775403 TI - Leishmania tropica in children: a retrospective study. AB - BACKGROUND: Limited data are available regarding topical and systemic therapies for Leishmania tropica in children. OBJECTIVE: We sought to characterize the clinical presentation and evaluate the efficacy and safety of topical and systemic treatments in pediatric patients infected with L tropica. METHODS: A retrospective study was performed on 47 children with L tropica cutaneous leishmaniasis. Treatments included topical or systemic therapy with liposomal amphotericin B or pentavalent antimony. RESULTS: Seventy patients with L tropica cutaneous leishmaniasis were treated at our center between 2008 and 2012, of which 47 (67%) were children. The average age of the pediatric population was 8.8 years, and the face was the most common site of involvement (76%). The average number of lesions was 2.6. 24 children (51%) required systemic therapy. The patients were treated with 3 to 5 mg/kg/d of intravenous liposomal amphotericin B, and a response was observed in 83% of the patients within 3 months. LIMITATIONS: This was a retrospective study. CONCLUSION: The disease burden of L tropica in children is high, and because of facial involvement and a low response to topical therapies, systemic therapy is often required. In our experience, liposomal amphotericin B treatment in children is safe and effective and is required for a considerably shorter duration than treatment with pentavalent antimony. PMID- 24775404 TI - Health promotion interventions for increasing stroke awareness in ethnic minorities: a systematic review of the literature. AB - BACKGROUND: Stroke places a significant burden to all affected individuals, but it is perhaps more significant amongst members of black, minority and ethnic communities, who may experience poorer awareness of stroke symptoms than the general population. Recently, several initiatives tried to improve public awareness that symptoms of stroke need to be treated as a medical emergency. However, ethnic communities present cultural barriers, requiring tailored health promotion interventions, whose effectiveness remains uncertain. Our systematic review aimed to identify relevant published evidence, synthesize the main study components and identify evidence of the effectiveness of the interventions. METHODS: MEDLINE, EMBASE, CINAHL, and PsycInfo were searched for journal articles on health promotion interventions for increasing stroke awareness in ethnic minorities, published in English between 1995 and 2012. Search results were collaboratively assessed by the authors; included studies were analysed to identify their main characteristics, and a thematic analysis of their content was conducted. No meta-analysis was performed, due to the heterogeneity of results. RESULTS: Eighteen studies were included, reporting 15 interventions conducted in the US, for African-Americans or Hispanics; populations sizes differed between interventions. Interventions were mostly carried out in community settings with different educational techniques, focussing on experiential methods. Health professionals usually organized the programs, delivered by nurses, other health professionals or volunteers.The few theory-based interventions focussed on individual-level behavioural change. Practical cultural adaptation strategies were not linked to specific theoretical frameworks. Interventions widely differed as for target populations, settings, delivery methods, contents and professional roles involved. All study designs were quantitative, and the emerging evidence of effectiveness was inconclusive.Such interventions operate in very complex scenarios, and several variables may influence their effectiveness. Therefore, qualitative or mixed-methods study designs may shed light on barriers and facilitators, experiential education strategies and community involvement.Network and community-level theories may help improving design and evaluation of interventions. CONCLUSIONS: Eleven case reports and four RCTs provide evidence about stroke awareness interventions organized in the US. The studies provide only partial and inconclusive evidence about the effectiveness of the interventions. Hence, further research is needed on different countries and ethnic minorities. PMID- 24775405 TI - Clinical and angiographic follow-up of coronary artery fistula interventions in children: techniques and classification revisited. AB - BACKGROUND: Transcatheter closure of coronary artery fistula has emerged as a safe and effective alternative to surgery. However, follow-up angiographic data after closure of the coronary artery fistula is extremely limited. We report our clinical and angiographic follow-up of children who underwent either transcatheter or surgical closure. METHOD: Clinical profile, echocardiography parameters, and closure technique were retrospectively reviewed from the hospital charts. Since 2007, 15 children have been intervened and followed up with electrocardiography, echocardiography, and angiography. RESULTS: A total of 15 children (six girls), with mean age of 6.7+/-5.4 years and weighing 16.3+/-9.8 kg, underwent successful closure (transcatheter=13, surgical=2) without periprocedural complication. Coronary artery fistula arose from the right (n=7) and left coronary artery (n=8) and drained into the right atrium or the right ventricle. Transcatheter closure was carried out using a duct occluder. Of the patients, two underwent surgical closure of the fistula on a beating heart. At 31.8+/-18.7 months follow-up, all the children were asymptomatic and had no evidence of myocardial ischaemia or infarction. However, follow-up angiography revealed thrombotic occlusion of fistula with the patent parent coronary artery in those having branch coronary artery fistula, and five of seven patients with parent coronary artery fistula had near-complete occlusion of fistula extending into the native coronary artery. CONCLUSION: Follow-up angiography revealed a high incidence of parent artery occlusion when the fistula was arising from the native artery and not from one of its branches. Coronary artery fistula intervention of the parent coronary artery fistula always carries the potential risk of ischaemia, unless the distal-most exiting segment is the primary site of occlusion. PMID- 24775406 TI - [Anaesthesia for correction of scoliosis in pediatric patient with Friedreich's ataxia]. AB - Friedreich ataxia (FA) is an inherited autosomal recessive disease characterized by a neurological degenerative process of the cerebellum, spinal cord, and peripheral nerves. FA is associated with ataxia, dysarthria, motor and sensory impairment, scoliosis, cardiomyopathy, and diabetes. There is a significant risk of perioperative major complications during the anesthetic management of these patients. We present the case of a fourteen-year-old patient with FA, who had a posterior spinal fusion and instrumentation underwent to total intravenous anesthesia. PMID- 24775424 TI - Effect of explicit visual feedback distortion on human gait. AB - BACKGROUND: Gait rehabilitation often utilizes correction of stepping movements, and visual feedback is one of the interactive forms that can be used for rehabilitation. We presented a paradigm called visual feedback distortion in which we manipulated the visual representation of step length. Our previous work showed that an implicit distortion of visual feedback of step length entails unintentional modulations in the subjects' gait spatial pattern. Even in the presence of cognitive load through a distraction task, distortion of visual feedback still induced modulation of gait step length. In the current study, subjects were aware of the imposed distortion of visual feedback and they were instructed to maintain their natural gait symmetric pattern during trials. We then studied whether such an explicit "visual feedback distortion" would still influence gait spatial pattern. METHODS: Nine healthy subjects participated in the treadmill walking trial. The step length was defined as the distance between each foot. The on-line visual feedback showing right and left step length information as bar graphs was displayed on a computer screen. When distorting the visual feedback, the height of the bar for only one side was manipulated, so that subjects perceived their step length as being asymmetric. Actual step lengths were measured during trial and analyzed to see the effects of visual feedback distortion. RESULTS: Our results showed that a gradual distortion of visual feedback systematically modulated gait step length away from symmetry even at the expense of an opposing apparent task goal. It was also observed that the amount of induced gait modulation was reduced during the explicit condition compared to the implicit condition where subjects were not aware of distortion. CONCLUSIONS: Our study demonstrated that although the visual feedback display used in this study did not alter visual space or evoke illusions of motion, perturbation of visual information about subjects' movement can cause unintentional motor functions. This suggests that the effect of visual feedback distortion is spontaneous and a gait training involving the visual distortion paradigm may provide an effective way to help subjects correct gait patterns by driving implicit motor functions, thereby bringing benefits to rehabilitation. PMID- 24775425 TI - Olive oil consumption and risk of CHD and/or stroke: a meta-analysis of case control, cohort and intervention studies. AB - Increasing evidence suggests that the Mediterranean diet can reduce the risk of CVD. Olive oil is the hallmark of this dietary pattern. We conducted a meta analysis of case-control, prospective cohort studies and a randomised controlled trial investigating the specific association between olive oil consumption and the risk of CHD (101,460 participants) or stroke (38,673 participants). The results of all observational studies were adjusted for total energy intake. The random-effects model assessing CHD as an outcome showed a relative risk (RR) of 0.73 (95% CI 0.44, 1.21) in case-control studies and 0.96 (95% CI 0.78, 1.18) in cohort studies for a 25 g increase in olive oil consumption. In cohort studies, the random-effects model assessing stroke showed a RR of 0.74 (95% CI 0.60, 0.92). The random-effects model combining all cardiovascular events (CHD and stroke) showed a RR of 0.82 (95% CI 0.70, 0.96). Evidence of heterogeneity was apparent for CHD, but not for stroke. Both the Egger test (P= 0.06) and the funnel plot suggested small-study effects. Available studies support an inverse association of olive oil consumption with stroke (and with stroke and CHD combined), but no significant association with CHD. This finding is in agreement with the recent successful results of the PREDIMED randomised controlled trial. PMID- 24775427 TI - New directions and challenges in histories of health, healing and medicine in South Africa. PMID- 24775428 TI - Reconstructing Harry: a genealogical study of a colonial family 'inside' and 'outside' the Grahamstown Asylum, 1888-1918. AB - Recent scholarship has explored the dynamics between families and colonial lunatic asylums in the late nineteenth century, where families actively participated in the processes of custodial care, committal, treatment and release of their relatives. This paper works in this historical field, but with some methodological and theoretical differences. The Foucauldian study is anchored to a single case and family as an illness narrative that moves cross-referentially between bureaucratic state archival material, psychiatric case records, and intergenerational family-storytelling and family photographs. Following headaches and seizures, Harry Walter Wilbraham was medically boarded from his position as Postmaster in the Cape of Good Hope Colony of South Africa with a 'permanent disease of the brain', and was committed to the Grahamstown Asylum in 1910, where he died the following year, aged 40 years. In contrast to writings about colonial asylums that usually describe several patient cases and thematic patterns in archival material over time and place, this study's genealogical lens examines one white settler male patient's experiences within mental health care in South Africa between 1908 and 1911. The construction of Harry's 'case' interweaves archival sources and reminiscences inside and outside the asylum, and places it within psychiatric discourse of the time, and family dynamics in the years that followed. Thus, this case study maps the constitution of 'patient' and 'family' in colonial life, c.1888-1918, and considers the calamity, uncertainty, stigma and silences of mental illness. PMID- 24775429 TI - 'The hospital was just like a home': self, service and the 'McCord Hospital Family'. AB - For more than a century, McCord Hospital, a partly private and partly state subsidised mission hospital has provided affordable health-care services, as well as work and professional training opportunities for thousands of people in Durban, a city on the east coast of South Africa. This article focuses on one important aspect of the hospital's longevity and particular character, or 'organisational culture': the ethos of a 'McCord Family', integral to which were faith and a commitment to service. While recognising that families - including 'hospital families' like that at McCord - are contentious social constructs, with deeply embedded hierarchies and inequalities based on race, class and gender, we also consider however how the notion of 'a McCord family' was experienced and shared in complex ways. Indeed, during the twentieth century, this ethos was avidly promoted by the hospital's founders and managers and by a wide variety of employees and trainees. It also extended to people at a far geographical remove from Durban. Moreover, this ethos became so powerful that many patients felt that it shaped their convalescence experience positively. This article considers how this 'family ethos' was constructed and what made it so attractive to this hospital's staff, trainees and patients. Furthermore, we consider what 'work' it did for this mission hospital, especially in promoting bonds of multi-racial unity in the contexts of segregation and apartheid society. More broadly, it suggests that critical histories of the ways in which individuals, hospitals, faith and 'families' intersect may be of value for the future of hospitals as well as of interest in their past. PMID- 24775430 TI - 'The trial the world is watching': the 1972 prosecution of Derk Crichton and James Watts, abortion, and the regulation of the medical profession in apartheid South Africa. AB - After its formation in 1910 as a self-governing dominion within the British empire, the Union of South Africa followed a combination of English and Roman Dutch common laws on abortion that decreed the procedure permissible only when necessary to save a woman's life. The government continued doing so after South Africa withdrew from the Commonwealth and became a republic in 1961. In 1972 a sensational trial took place in the South African Supreme Court that for weeks placed clandestine abortion on the front pages of the country's newspapers. Two men, one an eminent doctor and the other a self-taught abortionist, were charged with conspiring to perform illegal abortions on twenty-six white teenagers and young unmarried women. The prosecution of Dr Derk Crichton and James Watts occurred while the National Party government was in the process of drafting abortion legislation and was perceived by legal experts as another test of the judiciary's stance on the common law on abortion. The trial was mainly intended to regulate the medical profession and ensure doctors ceased helping young white women evade their 'duty' to procreate within marriage. Ultimately, the event encapsulated a great deal about elites' attempt to buttress apartheid culture and is significant for, among other reasons, contributing to the production of South Africa's extremely restrictive Abortion and Sterilisation Act (1975). PMID- 24775431 TI - Two tales about illness, ideologies, and intimate identities: sexuality politics and AIDS in South Africa, 1980-95. AB - This article focuses on the micro-narratives of two individuals whose responses to AIDS were mediated by their sexual identity, AIDS activism and the political context of South Africa during a time of transition. Their experiences were also mediated by well-established metanarratives about AIDS and 'homosexuality' created in the USA and the UK which were transplanted and reinforced (with local variations) into South Africa by medico-scientific and political leaders.The nascent process of writing South African AIDS histories provides the opportunity to record responses to AIDS at institutional level, reveal the connections between narratives about AIDS and those responses, and draw on the personal stories of those who were at the nexus of impersonal official responses and the personal politics of AIDS. This article records the experiences of Dennis Sifris, a physician who helped establish one of the first AIDS clinics in South Africa and emptied the dance floors, and Pierre Brouard, a clinical psychologist who was involved in early counselling, support and education initiatives for HIV-positive people, and counselled people about dying, and then about living. Their stories show how, even within government-aligned health care spaces hostile to gay men, they were able to provide support and treatment to people; benefited from international connections with other gay communities; and engaged in socially subversive activities. These oral histories thus provide otherwise hidden insights into the experiences of some gay men at the start of an epidemic that was initially almost exclusively constructed on, and about, gay men's bodies. PMID- 24775432 TI - 'A matter of conscience': the moral authority of the World Medical Association and the readmission of the South Africans, 1976-1994. AB - This article describes the role of transnational anti-apartheid activism in South Africa, Britain and the United States in generating international moral outrage over the readmission of the Medical Association of South Africa (MASA) to the World Medical Association (WMA), which had taken place in 1981 after it had withdrawn from that body in 1976. It discusses an example of a controversy where an international health organisation (IHO) lost moral authority as a result of being accused of white supremacy and a pro-American engagement in Cold War politics. At the time of its readmission to the WMA, the MASA was controversial because of its failure to strike off its membership roll one of the doctors implicated the death in detention of Black Consciousness leader Steve Biko in 1977. It details how these activists viewed the American Medical Association as having campaigned for the MASA's readmission. The WMA's readmission of the MASA cost the former its relationships with the World Health Organisation (WHO) and the British Medical Association - a dispute which continued until South Africa's democratic transition of 1994. With its focus on transnational activism in relation to the WMA and the effects of activists' allegations of racism on its internal politics, this article contributes to the literature on the history of IHOs. Ultimately, this controversy shows the deficiency of international medical professional associations as ethical arbitrators of last resort. PMID- 24775433 TI - New patterns of disclosure: how HIV-positive support group members from KwaZulu Natal speak of their status in oral narratives. AB - This paper examines the representations and emotions associated with disclosure and stigma in Pietermaritzburg, KwaZulu-Natal, seven years after the start of the South African government's ARV roll-out programme on the basis of in-depth oral history interviews of HIV-positive support group members. It argues that the wider availability of ARV treatment, the ensuing reduced fatality rate and the increased number of people, including men, who receive counselling and testing, may mean that HIV/AIDS is less stigmatised and that disclosure has become easier. This does not mean that stigma has disappeared and that the confusion created by competing world-views and belief systems has dissipated. Yet the situation of extreme denial and ideological confusion observed, for example, by Deborah Posel and her colleagues in 2003 and 2004 in the Mpumalanga province seems to have lessened. The interviews hint at the possibility that people living with HIV may have, more than a decade before, a language to express the emotions and feelings associated with HIV/AIDS. They were also found to be more assertive in matters of gender relations. These new attitudes would make disclosure easier and stigma more likely to recede. PMID- 24775438 TI - Lost in translation: A review of Hold Your Breath (produced by Maren Grainger Monsen, MD and Julia Haslett. Icarus Films, 2006. Running time: 58 minutes). PMID- 24775439 TI - The Madness of Bedlam: A Time Team Special, Channel 4 [UK], 1 December 2013, 9 pm GMT. PMID- 24775440 TI - Review of the Kaiser Permanente Medical Care Oral History Project website, http://bancroft.berkeley.edu/ROHO/projects/kaiser/index2.html. PMID- 24775444 TI - Antimicrobial properties and isotope investigations of South African honey. AB - AIMS: The therapeutic potential of honey for the treatment of wound infections is well documented. However, South African (SA) honey has been poorly explored as an antimicrobial agent and given the well-established antimicrobial properties of the indigenous plant species from SA, there is the potential that honey from this geographical region may exhibit noteworthy anti-infective properties. In this study, the antimicrobial properties of 42 SA honey samples were determined. METHODS AND RESULTS: The minimum inhibitory concentration (MIC) agar dilution method was used to determine antimicrobial activity. The MICs of the honeys ranged from 6.25 to 50.00%. Samples 4-(CITYMIX/WC), 12-(BUSHVELD/KZN), 15 (ONION/WC), 16-(FYNBOS/WC), 17-(AKMS/FS), 19-(CITYMIX/FS), 41-(INDIGENOUS/WC) and 52-(SURBURBANGARDEN/WC) displayed broad-spectrum antimicrobial activity. The physicochemical properties including pH, water content and stable isotope analysis (SIA) was analysed. The pH of the honeys ranged between 3.89 and 5.09. The SIA revealed strong overall trends between protein concentration and MIC suggesting close links with antimicrobial activity. CONCLUSION: A number of SA honey samples tested have potential as an effective antimicrobial agent in wound healing. SIGNIFICANCE AND IMPACT OF THE STUDY: The future of South Africa's market for medical grade and therapeutic honeys looks promising as the antimicrobial properties of the honeys have some superior activity. PMID- 24775443 TI - The profile and contribution of rare germline copy number variants to cancer risk in Li-Fraumeni patients negative for TP53 mutations. AB - BACKGROUND: The Li-Fraumeni syndrome (LFS) is an inherited rare cancer predisposition syndrome characterized by a variety of early-onset tumors. Although germline mutations in the tumor suppressor gene TP53 account for over 50% of the families matching LFS criteria, the lack of TP53 mutation in a significant proportion of LFS families, suggests that other types of inherited alterations must contribute to their cancer susceptibility. Recently, increases in copy number variation (CNV) have been reported in LFS individuals, and are also postulated to contribute to LFS phenotypic variability. METHODS: Seventy probands from families fulfilling clinical criteria for either Li-Fraumeni or Li Fraumeni-like (LFS/LFL) syndromes and negative for TP53 mutations were screened for germline CNVs. RESULTS: We found a significantly increased number of rare CNVs, which were smaller in size and presented higher gene density compared to the control group. These data were similar to the findings we reported previously on a cohort of patients with germline TP53 mutations, showing that LFS/LFL patients, regardless of their TP53 status, also share similar CNV profiles. CONCLUSION: These results, in conjunction with our previous analyses, suggest that both TP53-negative and positive LFS/LFL patients present a broad spectrum of germline genetic alterations affecting multiple loci, and that the genetic basis of LFS/LFL predisposition or penetrance in many cases might reside in germline transmission of CNVs. PMID- 24775445 TI - Use of "one-pot, mix-and-read" peptide-MHC class I tetramers and predictive algorithms to improve detection of cytotoxic T lymphocyte responses in cattle. AB - Peptide-major histocompatibility complex (p-MHC) class I tetramer complexes have facilitated the early detection and functional characterisation of epitope specific CD8+ cytotoxic T lymphocytes (CTL). Here, we report on the generation of seven recombinant bovine leukocyte antigens (BoLA) and recombinant bovine beta2 microglobulin from which p-MHC class I tetramers can be derived in ~48 h. We validated a set of p-MHC class I tetramers against a panel of CTL lines specific to seven epitopes on five different antigens of Theileria parva, a protozoan pathogen causing the lethal bovine disease East Coast fever. One of the p-MHC class I tetramers was tested in ex vivo assays and we detected T. parva specific CTL in peripheral blood of cattle at day 15-17 post-immunization with a live parasite vaccine. The algorithm NetMHCpan predicted alternative epitope sequences for some of the T. parva CTL epitopes. Using an ELISA assay to measure peptide BoLA monomer formation and p-MHC class I tetramers of new specificity, we demonstrate that a predicted alternative epitope Tp229-37 rather than the previously reported Tp227-37 epitope is the correct Tp2 epitope presented by BoLA 6*04101. We also verified the prediction by NetMHCpan that the Tp587-95 epitope reported as BoLA-T5 restricted can also be presented by BoLA-1*02301, a molecule similar in sequence to BoLA-T5. In addition, Tp587-95 specific bovine CTL were simultaneously stained by Tp5-BoLA-1*02301 and Tp5-BoLA-T5 tetramers suggesting that one T cell receptor can bind to two different BoLA MHC class I molecules presenting the Tp587-95 epitope and that these BoLA molecules fall into a single functional supertype. PMID- 24775446 TI - A novel KIR3DS1*0130107 allele isolated by sequencing from an Asian donor. AB - This novel KIR3DS1 allele officially named as KIR3DS1*0130107 was isolated from DNA samples from Asia using high-resolution sequenced-based techniques. KIR3DS1*0130107 differs from the first member of the KIR3DS1*013 subgroup (KIR3DS1*0130101) by a single mutation at position 8922A>G (intron 5), just nine nucleotides away from the start of exon 6. PMID- 24775447 TI - Clinical need for evaluation of ischemia. PMID- 24775448 TI - Formulating recommendations with GRADE: a matter of confidence. PMID- 24775449 TI - Mechanoelectric feedback in the ischemic myocardium: an interplay that modulates susceptibility to fibrillation. PMID- 24775450 TI - Distension of the ischemic region predicts increased ventricular fibrillation inducibility following coronary occlusion in swine. AB - INTRODUCTION AND OBJECTIVES: Distension of the ischemic region has been related to an increased incidence of spontaneous ventricular arrhythmias following coronary occlusion. This study analyzed whether regional ischemic distension predicts increased ventricular fibrillation inducibility after coronary occlusion in swine. METHODS: In 18 anesthetized, open-chest pigs, the left anterior descending coronary artery was ligated for 60 min. Myocardial segment length in the ischemic region was monitored by means of ultrasonic crystals. Programmed stimulation was applied at baseline and then continuously between 10 and 60 min after coronary occlusion. RESULTS: Coronary occlusion induced a rapid increase in end-diastolic length in the ischemic region, which reached 109.4% (0.9%) of baseline values 10 min after occlusion (P<.001). On average, 6.6 (0.5) stimulation protocols were completed and 5.4 (0.6) ventricular fibrillation episodes induced between 10 and 60 min of coronary occlusion. Neither baseline serum potassium levels nor the size of the ischemic region were significantly related to ventricular fibrillation inducibility. In contrast, the increase in end-diastolic length 10 min after coronary occlusion was associated directly (r=0.67; P=.002) with the number of induced ventricular fibrillation episodes and inversely (r=-0.55; P=.018) with the number of extrastimuli needed for ventricular fibrillation induction. CONCLUSIONS: Regional ischemic expansion predicts increased ventricular fibrillation inducibility following coronary occlusion. These results highlight the potential influence of mechanical factors, acting not only on the triggers but also on the substrate, in the genesis of malignant ventricular arrhythmias during acute ischemia. PMID- 24775451 TI - Evaluation of the complexity of myocardial activation during ventricular fibrillation. An experimental study. AB - INTRODUCTION AND OBJECTIVES: An experimental model is used to analyze the characteristics of ventricular fibrillation in situations of variable complexity, establishing relationships among the data produced by different methods for analyzing the arrhythmia. METHODS: In 27 isolated rabbit heart preparations studied under the action of drugs (propranolol and KB-R7943) or physical procedures (stretching) that produce different degrees of change in the complexity of myocardial activation during ventricular fibrillation, use was made of spectral, morphological, and mapping techniques to process the recordings obtained with epicardial multielectrodes. RESULTS: The complexity of ventricular fibrillation assessed by mapping techniques was related to the dominant frequency, normalized spectral energy, signal regularity index, and their corresponding coefficients of variation, as well as the area of the regions of interest identified on the basis of these parameters. In the multivariate analysis, we used as independent variables the area of the regions of interest related to the spectral energy and the coefficient of variation of the energy (complexity index=-0.005*area of the spectral energy regions -2.234*coefficient of variation of the energy+1.578; P=.0001; r=0.68). CONCLUSIONS: The spectral and morphological indicators and, independently, those derived from the analysis of normalized energy regions of interest provide a reliable approach to the evaluation of the complexity of ventricular fibrillation as an alternative to complex mapping techniques. PMID- 24775452 TI - Interleukin-6 and high-sensitivity C-reactive protein for the prediction of outcomes in non-ST-segment elevation acute coronary syndromes. AB - INTRODUCTION AND OBJECTIVES: High baseline levels of interleukin-6 and C-reactive protein confer an increased risk of mortality in non-ST-segment elevation acute coronary syndrome. The aim of the study was to determine whether serial measurements of interleukin-6 and high-sensitivity C-reactive protein provide additional information to baseline measurements for risk stratification of non-ST segment elevation acute coronary syndrome. METHODS: Two hundred and sixteen consecutive patients with non-ST-segment elevation acute coronary syndrome were prospectively included. Blood samples were obtained within 24 h of hospital admission and at 30 days of follow-up. The endpoint was a composite of all-cause death, nonfatal myocardial infarction, or acute decompensated heart failure. RESULTS: Both interleukin-6 and high-sensitivity C-reactive protein levels decreased from day 1 to day 30, regardless of adverse events (both P<.001). Interleukin-6 levels at 2 time points (interleukin-6 day 1, per pg/mL; hazard ratio=1.006, 95% confidence interval, 1.002-1.010; P=.002 and interleukin-6 day 30, per pg/mL, hazard ratio=1.047, 95% confidence interval, 1.021-1.075, P<.001) were independent predictors of adverse events, whereas high-sensitivity C reactive protein day 1 and high-sensitivity C-reactive protein day 30 levels were not. Patients with interleukin-6 day 1<=8.24 pg/mL and interleukin-6 day 30<=4.45 pg/mL had the lowest event rates (4.7%), whereas those with both above the median values had the highest event rates (35%). After addition of interleukin-6 day 30 to the multivariate model, C-index increased from 0.71 (95% confidence interval, 0.63-0.78) to 0.80 (95% confidence interval, 0.72-0.86), P=.042, and net reclassification improvement was 0.39 (95% confidence interval, 0.14-0.64; P=.002). CONCLUSIONS: In this population, both interleukin-6 and high-sensitivity C-reactive protein concentrations decreased after the acute phase. Serial samples of interleukin-6 concentrations improved the prognostic risk stratification of these patients. PMID- 24775453 TI - Cardiac manifestations in myotonic dystrophy type 1 patients followed using a standard protocol in a specialized unit. AB - INTRODUCTION AND OBJECTIVES: Myotonic dystrophy type 1 is characterized by muscle damage and systemic manifestations, including cardiac involvement. Our aim was to document the frequency and severity of cardiac involvement (left ventricular dysfunction and arrhythmia or conduction disorders), the need for a pacemaker, implantable cardioverter-defibrillator, or electrophysiological study, and the development of sudden death during follow-up. METHODS: Retrospective observational study of myotonic dystrophy type 1 patients referred to a specialized cardiac unit. Patients received clinical, electrocardiographic (Holter monitoring), and echocardiographic follow-up. RESULTS: We included 81 patients (51.9% men; mean age, 29.9 [14.8] years). The mean follow-up was 5.7 (3.9) years (range: 1-20 years). During this period sinus bradycardia was documented in 48.8%, PR interval>=220 ms in 31.3%, long corrected QT interval in 5%, and QRS interval>=120 ms in 7.5%. A total of 13.8% of patients developed sinus node dysfunction, 10% of patients had supraventricular arrhythmias, 5% had ventricular tachycardia, and 8.8% developed second- or third- degree atrioventricular block. Only 1 patient had severe ventricular dysfunction. During the follow-up, 15 pacemakers and 2 implantable cardioverter-defibrillators were implanted and 5 electrophysiological studies were performed (mainly due to ventricular tachycardia). There was only 1 sudden death. CONCLUSIONS: Arrhythmia or conduction disorders are frequent during the course of myotonic dystrophy type 1 patients. A significant percentage of patients require electrophysiological study and the use of a device (pacemaker or implantable cardioverter defibrillator). In our experience, systolic dysfunction and sudden death are rare. PMID- 24775454 TI - Update on ischemic heart disease and critical care cardiology. AB - This article summarizes the main developments reported during the year 2012 concerning ischemic heart disease, together with the most relevant innovations in the management of acute cardiac patients. PMID- 24775455 TI - Update on cardiac imaging techniques 2012. AB - Cardiac imaging is one of the basic pillars of modern cardiology. The potential list of scenarios where cardiac imaging techniques can provide relevant information is simply endless so it is impossible to include all relevant new features of cardiac imaging published in the literature in 2012 in the limited format of a single article. We summarize the year's most relevant news on cardiac imaging, highlighting the ongoing development of myocardial deformation and 3 dimensional echocardiography techniques and the increasing use of magnetic resonance imaging and computed tomography in daily clinical practice. PMID- 24775456 TI - Update: Innovation in cardiology (II). Telecardiology: past, present and future. AB - Technological advances over the past decades have allowed improved diagnosis and monitoring of patients with acute coronary syndromes as well as patients with advanced heart failure. High-quality digital recordings transmitted wirelessly by cellular telephone networks have augmented the prehospital use of transportable electrocardiogram machines as well as implantable devices for arrhythmia monitoring and therapy. The impact of prehospital electrocardiogram recording and interpretation in patients suspected of acute myocardial infarction should not be underestimated. It enables a more widespread access to rapid reperfusion therapy, thereby reducing treatment delay, morbidity and mortality. Further, continuous electrocardiogram monitoring has improved arrhythmia diagnosis and dynamic ST segment changes have been shown to provide important prognostic information in patients with acute ST-elevation myocardial infarction. Likewise, remote recording or monitoring of arrhythmias and vital signs seem to improve outcome and reduce the necessity of re-admissions or outpatient contacts in patients with heart failure or arrhythmias. In the future telemonitoring and diagnosis is expected to further impact the way we practice cardiology and provide better care for the patient with cardiovascular disease. PMID- 24775457 TI - TAVI through the left subclavian artery with a LIMA graft. PMID- 24775458 TI - A first case of totally percutaneous transaxillary aortic valve implantation. PMID- 24775459 TI - Giant right atrial diverticulum: utility of contrast-enhanced ultrasound. PMID- 24775460 TI - Reversal of hyperoxaluric cardiomyopathy with severe cardiac dysfunction after combined liver and kidney transplantation. PMID- 24775461 TI - Retrospective study of out-of-hospital sudden cardiovascular death in middle-aged adults in Barcelona City. PMID- 24775462 TI - Pseudopheochromocytoma as a cause of resistant and paroxysmal hypertension successfully treated by percutaneous renal denervation. PMID- 24775463 TI - Knowledge of cardiac disease among hospitalized patients. PMID- 24775465 TI - Vascular age derived from SCORE and the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (Version 2012). PMID- 24775466 TI - [The right to die with dignity in an acute-care hospital: a qualitative study]. AB - AIM: To examine the perceptions and beliefs of doctors and nurses, and the barriers and facilitators they must address as regards the right to die with dignity in an acute-care hospital, and to consider the applicability of the provisions of Law 2/2010 of 8 April in this respect. METHOD: A qualitative descriptive study, based on the focus group technique, using discourse analysis of the views of doctors and nurses responsible for the health care of terminal cancer and non-cancer patients in an acute-care hospital. RESULTS: The results obtained show that there are diverse obstacles to assure the rights of terminal patients, and to ensure the proper performance of their duties by healthcare professionals and institutions. The nature and impact of these difficulties depend on the characteristics of the patients and their families, the health workers involved, the organisation of health care, and cultural factors. CONCLUSIONS: The study highlights the need to improve the process of communication with patients and their families, to facilitate shared decision making and to establish measures to clarify issues such as palliative sedation and treatment limitation. It is necessary to improve the applicability of the law on living wills and dignified death in non-cancer specialist areas. Further training is needed regarding ethical, spiritual and anthropological aspects of care in these situations. PMID- 24775559 TI - Burning straw, air pollution, and respiratory infections in China. PMID- 24775515 TI - The Carriage Of Multiresistant Bacteria After Travel (COMBAT) prospective cohort study: methodology and design. AB - BACKGROUND: Antimicrobial resistance (AMR) is one of the major threats to public health around the world. Besides the intense use and misuse of antimicrobial agents as the major force behind the increase in antimicrobial resistance, the exponential increase of international travel may also substantially contribute to the emergence and spread of AMR. However, knowledge on the extent to which international travel contributes to this is still limited. The Carriage Of Multiresistant Bacteria After Travel (COMBAT) study aims to 1. determine the acquisition rate of multiresistant Enterobacteriaceae during foreign travel 2. ascertain the duration of carriage of these micro-organisms 3. determine the transmission rate within households 4. identify risk factors for acquisition, persistence of carriage and transmission of multiresistant Enterobacteriaceae. METHODS/DESIGN: The COMBAT-study is a large-scale multicenter longitudinal cohort study among travellers (n = 2001) and their non-travelling household members (n = 215). Faecal samples are collected before and immediately after travel and 1 month after return from all participants. Follow-up faecal samples are collected 3, 6 and 12 months after return from travellers (and their non-travelling household members) who acquired multiresistant Enterobacteriaceae. Questionnaires are collected from all participants at each time-point. Faecal samples are screened phenotypically for the presence of extended-spectrum beta-lactamase (ESBL) or carbapenemase-producing Enterobacteriaceae. Positive post-travel isolates from travellers with negative pre-travel samples are genotypically analysed for ESBL and carbapenemase genes with microarray and gene sequencing. DISCUSSION: The design and scale of the COMBAT-study will enable us to provide much needed detailed insights into the risks and dynamics of introduction and spread of ESBL- and carbapenemase-producing Enterobacteriaceae by healthy travellers and the potential need and measures to monitor or manage these risks. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov under accession number NCT01676974. PMID- 24775560 TI - Changes in the incidence of health care-associated pathogens at a university hospital from 2005 to 2011. AB - BACKGROUND: Data on health care-associated infections (HAIs) outside of intensive care units (ICU) are scarce. We assessed hospital-wide changes in the incidence of health care-associated pathogens by infection site and by service between 2005 and 2011. METHODS: All data on health care-associated pathogens in 2005-2011 based on comprehensive hospital-wide surveillance were extracted from an electronic database. The incidence of HAI by pathogen was calculated per 1000 patient-days and per 1000 device-days. Regression analyses were conducted to estimate trend changes in the yearly incidence of pathogens for selected HAIs. RESULTS: The majority (8784 of 10,070; 87.2%) of the HAIs recorded over the 7 year period had at least 1 pathogen; a total of 10,585 pathogens were isolated. Overall, across all major service categories (eg, ICU, medicine), significant trends toward decreasing incidence were observed for all pathogens except Clostridium difficile. The decrease in incidence was greatest for central line associated bloodstream infections, less for catheter-associated urinary tract infections, and lowest for ventilator-associated pneumonias. CONCLUSIONS: This study showed significant decreases in incidence of the majority of HAIs caused by various pathogens, but significant increases in patient-days during the study period. Only HAIs due to C difficile showed a significantly increased incidence. PMID- 24775561 TI - Quality improvement intervention reduces episodes of long-term acute care hospital central line-associated infections. AB - BACKGROUND: Reducing central line-associated bloodstream infections (CLABSIs) poses a set of unique challenges in long-term acute care hospitals (LTACHS). Patients are often admitted to LTACHs with central lines in place from the previous hospitalization; thus, LTACHs lack control over insertion techniques and respective central line care and maintenance. This study aimed to demonstrate the impact of a methodical bathing approach with 2% chlorhexidine gluconate (CHG) cloths and a correlation with a reduced prevalence of CLABSIs in our LTACH population. METHODS: This retrospective observational quality initiative conducted in a 105-bed LTACH used plan-do-study-act methodology to assess the effects of a revised bathing approach using 2% CHG. RESULTS: Statistical significance demonstrated a 65% reduction in CLABSI on the pilot unit after the 6 month initial trial. The results of the quality initiative were evaluated through the end of 2012. CONCLUSIONS: The decision was made to implement the revised bathing protocol throughout the entire LTACH hospital stay. PMID- 24775562 TI - Bacterial contamination of medical devices in a Greek emergency department: impact of physicians' cleaning habits. AB - We investigated the bacterial contamination of physicians' stethoscopes, electrocardiography machines, cardiac monitors, and pulse oximeters, as well as physicians' self-reported cleaning habits in the emergency department of a university hospital. Among 100 devices evaluated (stethoscopes included), 99% developed a positive bacterial culture. Coagulase-negative staphylococci predominated (80.3%). Only 13% of physicians reported cleaning their stethoscope after each patient examination; multinomial regression analysis found less contamination on those stethoscopes (P < .001). Studies on the implementation of hygiene measures are needed. PMID- 24775563 TI - Factors predictive of treatment failure in staphylococcal prosthetic vascular graft infections: a prospective observational cohort study: impact of rifampin. AB - BACKGROUND: There exists considerable debate concerning management of prosthetic vascular graft infection (PVGI), especially in terms of antimicrobial treatment. This report studies factors associated with treatment failure in a cohort of patients with staphylococcal PVGI, along with the impact of rifampin (RIF). METHODS: All data on patients with PVGI between 2006 and 2010 were reviewed. Cure was defined as the absence of evidence of infection during the entire post treatment follow-up for a minimum of one year. Failure was defined as any other outcome. RESULTS: 84 patients (72 M/12 F, median age 64.5 +/- 11 y) with diabetes mellitus (n = 25), obesity (n = 48), coronary artery disease (n = 48), renal failure (n = 24) or COPD (n = 22) were treated for PVGI (median follow-up was 470 +/- 469 d). PVGI was primarily intracavitary (n = 47). Staphylococcus aureus (n = 65; including 17 methicillin-resistant S. aureus) and coagulase-negative Staphylocococcus (n = 22) were identified. Surgical treatment was performed in 71 patients. In univariate analysis, significant risk factors associated with failure were renal failure (p = 0.04), aortic aneurysm (p = 0.03), fever (p = 0.009), aneurysm disruption (p = 0.02), septic shock in the peri-operative period (p = 0.005) and antibiotic treatment containing RIF (p = 0.03). In multivariate analysis, 2 variables were independently associated with failure:septic shock [OR 4.98: CI 95% 1.45-16.99; p=0.01] and antibiotic containing rifampin [OR: 0.32: CI95% 0.10-0.96; p=0.04]. CONCLUSION: Results of the present study suggest that fever, septic shock and non-use of antibiotic treatment containing RIF are associated with poor outcome. PMID- 24775565 TI - The era that ends the error: the age of patient safety. PMID- 24775566 TI - Legends in urology. PMID- 24775564 TI - Epidithiodiketopiperazines (ETPs) exhibit in vitro antiangiogenic and in vivo antitumor activity by disrupting the HIF-1alpha/p300 complex in a preclinical model of prostate cancer. AB - The downstream targets of hypoxia inducible factor-1 alpha (HIF-1alpha) play an important role in tumor progression and angiogenesis. Therefore, inhibition of HIF-mediated transcription has potential in the treatment of cancer. One attractive strategy for inhibiting HIF activity is the disruption of the HIF 1alpha/p300 complex, as p300 is a crucial coactivator of hypoxia-inducible transcription. Several members of the epidithiodiketopiperazine (ETP) family of natural products have been shown to disrupt the HIF-1alpha/p300 complex in vitro; namely, gliotoxin, chaetocin, and chetomin. Here, we further characterized the molecular mechanisms underlying the antiangiogenic and antitumor effects of these ETPs using a preclinical model of prostate cancer. In the rat aortic ring angiogenesis assay, gliotoxin, chaetocin, and chetomin significantly inhibited microvessel outgrowth at a GI50 of 151, 8, and 20 nM, respectively. In vitro co immunoprecipitation studies in prostate cancer cell extracts demonstrated that these compounds disrupted the HIF-1alpha/p300 complex. The downstream effects of inhibiting the HIF-1alpha/p300 interaction were evaluated by determining HIF 1alpha target gene expression at the mRNA and protein levels. Dose-dependent decreases in levels of secreted VEGF were detected by ELISA in the culture media of treated cells, and the subsequent downregulation of VEGFA, LDHA, and ENO1 HIF 1alpha target genes were confirmed by semi-quantitative real-time PCR. Finally, treatment with ETPs in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. These results suggest that directly targeting the HIF-1alpha/p300 complex with ETPs may be an effective approach for inhibiting angiogenesis and tumor growth. PMID- 24775567 TI - A review of urinary fistulae in Crohn's disease. AB - INTRODUCTION: Urinary fistulae develop as abnormal connections between the gastrointestinal (GI) and genitourinary (GU) tracts, and occur in multiple disease processes including diverticulitis, malignancy, and Crohn's disease. Crohn's disease is now the most common cause of fistula formation between the ileum and bladder and the third most common cause of fistulae between the colon and the bladder. Few articles provide a comprehensive review of this process. MATERIALS AND METHODS: We performed a PubMed search using such terms as "fistula" and "Crohn's disease" and/or "enterovesical fistula." We reviewed references from selected papers and relevant articles were used for information-gathering and cited accordingly. RESULTS: Fistulae in Crohn's disease generally occur due to preformed abscess formation or bowel perforation from the development of aphthous ulcers. The most common type of urinary fistula is enterovesical, due to the close proximity of the ileum and bladder dome. Computed tomography and cystoscopy are the most common diagnostic tools utilized. Surgical treatment is usually definitive; however medical treatment has been used with some success as well. CONCLUSION: Urinary fistulae represent an uncommon, yet serious problem to patients with Crohn's disease. Patient symptoms and imaging direct the practitioner to proper diagnosis, with direct visualization via cystoscopy confirming the presence of a urinary fistula. Treatment is aimed at relieving symptoms and may be medical or surgical depending on the clinical presentation. PMID- 24775568 TI - Highlights of the 34th Annual Ralph E. Hopkins at Jackson Hole Seminars (JHS) on February 7-12, 2014, Jackson Hole, WY, USA. AB - The prestigious Jackson Hole Seminars (JHS) successfully gathered several world leaders in academic urology and urologists in private practice for a unique scientific experience in Wyoming, USA. Unfortunately, this year Dr. Ralph Hopkins' seat was empty but his spirit continue to be the driving force for the meeting's excellence and friendship. The JHS has pioneered the concept of a Critique Panel comprised of previous speakers that would discuss in depth the presentations of the faculty chosen by the scientific board of the JHS. The 2014 JHS featured Dr. Fernando J. Kim, the President of JHS, Dr. Robert Flanigan, the Program Chair, and the Critique Panel that included: Drs. Peter Albertsen, Arthur Burnett, Michael Coburn, Ann Gormley, and Marshal Stoller. The invited speakers were: Drs. Leonard Gomella (1st prize), Olivier Traxer (2nd prize), Jennifer Anger, Anthony Bella, Jim Hu, and Allen Morey. Some of the in depth discussions and topics are highlighted. PMID- 24775569 TI - Success rates of patients with poor emptying on clean intermittent catheterization. AB - INTRODUCTION: Clean intermittent catheterization (CIC) theoretically reduces incontinence, urinary tract infections (UTIs) and lower urinary tract symptoms (LUTS) in the face of poor emptying. It is unclear whether all patients realize these benefits or if CIC is only helpful for some. MATERIALS AND METHODS: A retrospective review of 321 patients all of whom underwent urodynamic study prior to starting CIC for impaired emptying. Success was considered to be no incontinence, no UTIs, and no LUTS while performing CIC. Patients who did not meet these criteria or who stopped CIC for whatever reason were classified as failures. RESULTS: The mean duration of follow up was 4.3 years (+/- 4.4 years). Overall 51% of the cohort was classified as a success. Among those patients started on CIC to treat incontinence, recurrent UTIs or LUTS the success rate was 43%. We identified the comorbidity of diabetes mellitus, the use of anticholinergic medications, the need for a homecare nurse to perform the CIC, and a post-void residual (PVR) of <300 cc at initial urodynamics to be independently associated with failure on CIC. CONCLUSIONS: CIC resolved incontinence, recurrent UTIs, and LUTS in some but not all patients with impaired emptying. We identified characteristics associated with failure on CIC. Our study has provided some direction as to those individuals most and least likely to benefit from adopting this mode of bladder management for poor emptying. PMID- 24775570 TI - The Lapides legacy: 42 years and cathing. PMID- 24775571 TI - An online UPOINT tool for phenotyping patients with chronic prostatitis. AB - INTRODUCTION: To evaluate the clinical phenotypes of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) using a web based online tool and to compare these clinical features with patients evaluated in a tertiary referral clinic. MATERIALS AND METHODS: Data was collected from 720 men who gave complete online responses on a website which determines the UPOINT clinical phenotype in CP/CPPS and measures symptom severity with the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). This was compared to phenotype and symptom severity of 220 patients evaluated in person at a tertiary referral clinic. RESULTS: The web-based cohort had CPSI scores of 11.1, 4.8, 7.6, and 23.6 for pain, urinary, quality-of-life, and total score, respectively. The percentage of patients positive for each domain was 76%, 74%, 75%, 10%, 46%, and 75% for the urinary, psychosocial, organ specific, infection, neurologic/systemic, and tenderness domains, respectively. There was a positive correlation between CPSI and number of positive UPOINT domains (p = 0.25, p < 0.0001). Comparison between web- and clinic-based groups showed that the clinic group had fewer UPOINT positive domains compared to the web-based group (2.9 versus 3.6, p < 0.0001), but had worse quality-of-life (9.0 versus 7.6, p < 0.0001) and CPSI total scores (25.0 versus 23.6, p = 0.0052). CONCLUSIONS: Men using an online tool to clinically phenotype CP/CPPS show similar correlations between UPOINT domains, symptom severity, age and duration. While symptom severity was worse in patients seen in a tertiary referral clinic, the differences were small. PMID- 24775572 TI - Contemporary management of penile cancer: greater than 15 year MSKCC experience. AB - INTRODUCTION: Penile cancer is a rare malignancy, and few guidelines are available to define treatment paradigms. For greater understanding of the natural history of surgically treated penile cancer, we analyzed the experience at our institution. MATERIALS AND METHODS: Using an institutional database, we identified 127 patients treated for squamous cell carcinoma of the penis from 1995-2011. Cancer-specific survival (CSS) was calculated using the Kaplan-Meier method. Survival data were compared using the log-rank test. The difference in risk of cancer-specific death by lymph node status and histological grade was determined by univariate Cox regression analysis. RESULTS: Five year CSS for pTis, pT1, pT2, and pT3/4 was 100%, 84% (95% CI 58%-95%), 54% (95% CI 33%-71%), and 54% (95% CI 25%-76%), respectively (p <= .005). Three year CSS for patients with N0, N+, and Nx disease was 90% (95% CI 47%-99%), 65% (95% CI 47%-79%), and 86% (95% CI 73%-93%), respectively (p = .03). The receipt of neoadjuvant chemotherapy did not change per 5 year period over the 16 years of our study. Median follow up was 2.8 years. CONCLUSIONS: Penile cancer patients with advanced disease had poor survival. Tumor stage and nodal status were significant predictors of CSS. Penis-sparing approaches may be considered for most patients; however, pathological stage and grade dictate the management and ultimate outcome. Further studies are necessary to clarify the benefits of chemotherapy in this disease. PMID- 24775573 TI - Is retrograde intrarenal surgery for the treatment of renal stones with diameters exceeding 2 cm still a hazard? AB - INTRODUCTION: Major kidney stones have traditionally been treated with percutaneous nephrolithotomy. However, retrograde intrarenal surgery (RIRS), which until a few years ago was considered inappropriate for this purpose, is becoming a viable, attractive alternative. The aim of the current study was to assess the efficacy and safety of RIRS combined with holmium laser lithotripsy for the treatment of stones > 2 cm in diameter in a large series of patients, reporting complications according to the Clavien-Dindo classification. MATERIALS AND METHODS: By retrospective analysis, we identified a total of 162 patients who were affected by stones greater than 2 cm in diameter and who had undergone RIRS. We reviewed demographic and stone characteristics, intraoperative and postoperative outcomes, and complications. RESULTS: The mean stone size was 2.7 cm +/- 0.6 cm. The primary, secondary, and tertiary stone-free rates were 66%, 80.9%, and 87.7%, respectively. The mean number of procedures per patient was 1.48. The complication rates according to the Clavien-Dindo classification were Clavien I in 20.4% of patients, Clavien II in 0%, Clavien III in 4.9%, Clavien IV in 0.6%, and Clavien V in 0%. CONCLUSIONS: As an alternative to standard procedures for the treatment of renal calculi greater than 2 cm in diameter, RIRS is safe and effective, with a low complication rate. PMID- 24775574 TI - A comparative analysis of prostate cancer pre-treatment characteristics stratified by age. AB - INTRODUCTION: To compare the pretreatment characteristics of prostate cancer, prostate-specific antigen (PSA), digital rectal examination (DRE) and Gleason sum score (GSS) by the American Urological Association (AUA) stratified age groups, < 55, 55-69 and >= 70 years old. MATERIALS AND METHODS: A retrospective analysis of 402 sequential prostate cancer patients, who had transrectal ultrasound guided 12 core prostate biopsy for either elevated PSA (over 2.5 ng/mL) or positive DRE or both during a three period, 2010 to 2012. There were 36 patients < 55 years, 226 patients 55 to 69 years and 140 patients >= 70 years (range 44-78 years old). This study was conceptualized after the AUA released prostate cancer screening guidelines in which men >= 70 were deleted from screening. RESULTS: Overall, compared with patients < 70 years old, we found that in patients >= 70 years old: 1) 60.7% had high GSS (7-10) (p = 0.0234); 2) 39.3% had low GSS (6) (p = 0.0234); 3) 31% had PSA level >= 10 ng/mL (p = 0.0010) and 4) 69.1% had high GSS (7-10) in the presence of a positive DRE (p = 0.0278). CONCLUSION: Patients >= 70 years old had a higher incidence of high GSS (7-10) compared to prostate cancer patients < 70 years old. Patients >= 70 years old who also had a positive DRE had the highest incidence of high GSS. PMID- 24775575 TI - Randomized, double-blind, placebo controlled pilot study of intradetrusor injections of onabotulinumtoxinA for the treatment of refractory overactive bladder persisting following surgical management of benign prostatic hyperplasia. AB - INTRODUCTION: We assessed the efficacy of onabotulinumtoxinA (BOTOX, Allergan Inc., Irvine, CA, USA) in patients with refractory overactive bladder (OAB) after treatment for benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: This was a two-center, randomized, double-blinded pilot study conducted in patients with OAB secondary to bladder outlet obstruction (BOO), refractory to anticholinergic medication and persistent for greater than 3 months after surgical intervention to relieve obstruction, with an International Prostate Symptom Score (IPSS) > 12. Patients were randomized in 1:1 fashion to either 200 units of onabotulinumtoxinA versus placebo. Fifteen patients received onabotulinumtoxinA versus 13 who received placebo. Follow up was performed at 1 week and then 1, 3, 6, and 9 months. The primary endpoint was reduction in the frequency of micturition per 24 hours by 3-day voiding diary. Secondary endpoints were maximum flow rate (Qmax), post-void residual (PVR), and IPSS scores. RESULTS: Patients receiving onabotulinumtoxinA demonstrated significantly improved quality of life scores at 180 and 270 days after treatment (p = 0.02 and 0.03, respectively) as well as significantly lower International Consultation on Incontinence Questionnaire (ICIQ) scores (p < 0.05). Baseline urinary frequency was 10.5 versus 11.0 voids/day (p = 0.47). Frequency episodes improved from 11 episodes per day to 8 episodes per day in the treatment arm. The placebo arm did not have a decrease in frequency episodes. This response was durable up to 90 days, although this was not statistically significant. IPSS, PVR, and urgency were unchanged postoperatively in both groups. CONCLUSIONS: OnabotulinumtoxinA was safe in patients with refractory irritative lower urinary tracts symptoms after surgical treatment of BPH. There were improvements in daily frequency, although the results were not statistically significant. Larger trials are needed to help characterize the utility of onabotulinumtoxinA in the treatment of OAB secondary to BPH. PMID- 24775576 TI - Multi-institutional outcomes and cost effectiveness of using alvimopan to lower gastrointestinal morbidity after cystectomy and urinary diversion. AB - INTRODUCTION: Radical cystectomy is associated with significant morbidity and cost, with rates of gastrointestinal complications as high as 30%. Alvimopan is a mu opioid receptor antagonist that has been shown in randomized-control trials to accelerate gastrointestinal recovery in patients undergoing bowel resection with primary anastamosis. We report our experience with gastrointestinal recovery for patients undergoing cystectomy with urinary diversion treated with alvimopan and cost benefit associated. MATERIALS AND METHODS: Between January 2008 and October 2012, 80 patients underwent radical cystectomy with urinary diversion at two institutions. Forty-two patients in our study did not receive alvimopan preoperatively. Thirty-eight patients received perioperative alvimopan and were without postoperative nasogastric decompression. Return of bowel function, initiation of diet, and gastrointestinal complications and estimated cost of hospitalization were evaluated. RESULTS: Times to first flatus (3.1 days versus 4.7 days, p < 0.01, 95% CI 0.96-2.24) and bowel movement (3.9 days versus 4.9 days, p < 0.01, 95% CI 0.45-1.55) were significantly shorter in those patients who received alvimopan. Additionally, the initiation of clear liquid diet (4.1 days versus 5.5 days, p < 0.01, 95% CI 0.70-2.10), regular diet (5.2 days versus 6.3 days, p < 0.01, 95% CI 0.39-1.81) and hospital discharge (6.1 days versus 7.7 days, p = 0.04, 95% CI 0.01-3.21) were accelerated in the alvimopan cohort. There were no incidences of prolonged ileus in patients who received perioperative alvimopan (0% versus 26.2%, p < 0.01). With an approximate average cost of alvimopan administration $825 per hospitalization, the average cost benefit of administration over control was $1515 per hospitalization. The cost benefit was mainly a result of a shorter inpatient hospitalization and lack of gastrointestinal morbidity which accumulated a majority of the difference. CONCLUSION: In our experience, the use of alvimopan perioperatively significantly accelerates the rate of gastrointestinal recovery and hospital discharge, eliminates the need for nasogastric tube decompression, and reduces the incidence of post-operative ileus in patients following radical cystectomy and urinary diversion. PMID- 24775577 TI - The role of preoperative prostatic urethral biopsy in clinical decision-making at the time of radical cystectomy. AB - INTRODUCTION: Involvement of the prostatic urethra by bladder cancer directly impacts prognosis, risk of urethral recurrence, and timing of radical cystectomy (RC); it also affects the type of urinary diversion chosen. Both cold cup biopsies and transurethral (TUR) loop biopsies have been used to evaluate the status of the prostatic urethra. We report our 20 year experience with preoperative and intro-operative prostatic urethral biopsies in order to determine relative efficacy and associated treatment implications. MATERIALS AND METHODS: The Columbia University urologic oncology database was reviewed and yielded 234 men who underwent preoperative endoscopic biopsies of the prostatic urethra before RC between 1990 and 2010. Two techniques were described: 1) cold cup biopsy, and 2) TUR loop biopsy. We evaluated the sensitivity, specificity, and predictive values for these respective techniques relative to the final pathological status of the prostatic urethra (PU) in the RC specimen. RESULTS: Of the 234 urethral biopsies 115 (49.1%) were cold cup and 96 (41.1%) were TUR loop biopsies. In the remaining 9.8% of patients, the technique could not be determined. Eighty-one preoperative biopsies (34.6%) revealed involvement of the urethra. No differences were observed in predictive values, sensitivity, and specificity between the two preoperative techniques. The negative predictive value (NPV) was higher than positive predictive value (PPV) for both preoperative approaches. Thirty-eight patients (16.2%) had a urethral frozen section analysis done intra-operatively. Only 1 patient (3%) had an abnormality on frozen section, being the negative predictive value (NPV) higher than the positive predictive value (PPV) for the test's ability to predict the status of the final urethral margin. Urethrectomy was performed at cystectomy in 52 patients with a positive biopsy; 15 (28.8%) of these patients ultimately had a negative PU on final pathology. Only 2/182 (1%) of the patients with an intact urethra presented with a urethral recurrence with a median follow up of 30.5 months. CONCLUSIONS: Preoperative prostatic urethral biopsy does not adequately predict final prostatic urethral status at radical cystectomy. No differences in predictive capacity could be detected with either cold cup biopsy or TUR biopsy. Intra operative biopsy of the prostatic urethra is predictive of a negative urethral margin. Simultaneous radical urethrectomy should not be performed based up on preoperative prostatic urethral biopsy results alone. PMID- 24775578 TI - Vasectomy as a reversible form of contraception for select patients. AB - INTRODUCTION: To provide an effective form of birth control, men may choose a reversible or permanent form of contraception. Vasectomy is presently offered as a permanent option for male contraception. We have had patients who were interested in vasectomy and reversal as a temporary birth control option. The purpose of this paper is to determine if vasectomy should be offered for selected couples as a temporary form of contraception and under which circumstances. MATERIALS AND METHODS: A literature review was conducted to determine the available reversible contraceptive options, risks, failure rates and contraindications to each, and the risks and success rates of vasectomy and vasectomy reversal. RESULTS: Reversible contraceptives include hormonally based methods for women, non-hormonal anatomic barrier devices and spermatocidal agents. Hormone based therapies may be contraindicated in women with cardiovascular disease, hypertension, and some cancers. Non-hormonal contraceptives are generally less effective and may be unacceptable for some couples due to higher failure rates, difficulty of use and lack of acceptance. Both vasectomy and vasectomy reversal are low risk procedures. Reversal may be performed with a high degree of success, particularly with a short obstructive interval (97% patency if performed < 3 years following vasectomy). CONCLUSION: While vasectomy should be considered a permanent form of sterilization for most couples, there are select couples, unable or unwilling to use other forms of birth control, who would benefit from an informed discussion about using a vasectomy as a reversible form of contraception. PMID- 24775580 TI - Novel management approach to connecting tube erosion of artificial urinary sphincter. AB - Artificial urinary sphincter (AUS) erosion often involve the urethral cuff and is managed by complete or partial device removal. Abdominal wall erosion of AUS tubing has not been previously reported and its management is unknown. We report tube erosion (TE) of AUS successfully managed without device explant. An 81-year old male with AUS for post-prostatectomy incontinence presented with TE at the site of inguinal incision without signs or symptoms of infection. The exposed tube was reduced and wound was closed after copious antibiotic solution irrigation. No complications were noted at 2 month follow up. AUS-TE can be successfully managed conservatively with antiseptic wound site irrigation and reinsertion in absence of infection. PMID- 24775579 TI - Distal hypospadias repair using only glans wing mobilization and approximation. AB - INTRODUCTION: Since its first description in 1994, tubularized incised plate (TIP) technique has become the most commonly performed hypospadias procedure and involves incision of the urethral plate with subsequent tubularization. Glans wings are then developed to cover the neourethra, thereby creating a cosmetically appealing repair. In some distal hypospadias cases, mobilization and approximation of glans wings is sufficient to create a normal appearing urethral meatus. MATERIALS AND METHODS: A retrospective chart review of all pediatric urology patients who underwent hypospadias repair by a single surgeon at the University of Kentucky between July 1, 2010 and April 1, 2013 was performed. Of the 46 patients who underwent one-stage distal hypospadias repair during that time, we performed the technique described above on 13 patients with amenable anatomy. Patients were evaluated for functional and cosmetic outcomes as well as complications at subsequent office visits and via telephone. RESULTS: Patients who underwent distal hypospadias repair with our technique had excellent functional and cosmetic outcomes analogous to those who underwent standard TIP repair. The only major complication in the study group was wound dehiscence in one patient that was required a second surgery. All other patients had excellent cosmetic and functional results without fistula formation, strictures or diverticuli, and with excellent parent satisfaction. CONCLUSIONS: Perceived benefits of this technique include simplicity and rapidity of technique, applicability to glanular, coronal and subcoronal hypospadias, and avoidance of sutures between urethra and glans with potential decrease in meatal stenosis. PMID- 24775581 TI - Radiographical resolution of renal lymphangiomatosis following cardiac transplantation. AB - Renal lymphangiomatosis is a disease characterized by abnormal formation of perirenal lymphatic vessels that fail to communicate with other retroperitoneal lymphatics; as a result, perirenal lymphatics dilate and form cysts. While typically an asymptomatic incidental finding, renal lymphangiomatosis rarely presents as flank or abdominal pain, ascites, impaired renal function, hypertension, hematuria, or proteinuria. Here we present the first known case of renal lymphangiomatosis found to spontaneously resolve following cardiac transplantation. PMID- 24775582 TI - How I do it: prostate cryoablation (PCry). AB - Prostate cryoablation (PCry) is a well-established minimally invasive therapy for the treatment of prostate cancer. Unfortunately, PCry still carries the stigma of a high rate recto-urethral fistula procedure but with the advent of argon/helium gas technology, urethral warmer and high quality transrectal ultrasound imaging, complications decreased and efficacy increased. The Denver Health Medical Center's technique in prostate cryoablation is described as follows. PMID- 24775601 TI - Three-year change in diet quality and associated changes in BMI among schoolchildren living in socio-economically disadvantaged neighbourhoods. AB - Findings from research that has assessed the influence of dietary factors on child obesity have been equivocal. In the present study, we aimed to test the hypothesis that a positive change in diet quality is associated with favourable changes in BMI z-scores (zBMI) in schoolchildren from low socio-economic backgrounds and to examine whether this effect is modified by BMI category at baseline. The present study utilised data from a subsample (n 216) of the Resilience for Eating and Activity Despite Inequality study, a longitudinal cohort study with data collected in 2007-8 (T1) and 2010-11 (T2) in socio economically disadvantaged women and children (5-12 years at T1). Dietary data were collected using a FFQ and diet quality index (DQI) scores derived at both time points. The objective measures of weight, height and physical activity (accelerometers) were included. The other variables were reported in the questionnaires. We examined the association between change in DQI and change in zBMI, using linear regression analyses adjusted for physical activity, screen sedentary behaviour and maternal education level both in the whole sample and in the sample stratified by overweight status at baseline. After accounting for potential covariates, change in diet quality was found to be inversely associated with change in zBMI only in children who were overweight at baseline (P= 0.035), thus supporting the hypothesis that improvement in diet quality is associated with a concurrent improvement in zBMI among already overweight children, but not among those with a normal BMI status. The identification of modifiable behaviours such as diet quality that affect zBMI longitudinally is valuable to inform future weight gain prevention interventions in vulnerable groups. PMID- 24775602 TI - System training and assessment in simultaneous proportional myoelectric prosthesis control. AB - BACKGROUND: Pattern recognition control of prosthetic hands take inputs from one or more myoelectric sensors and controls one or more degrees of freedom. However, most systems created allow only sequential control of one motion class at a time. Additionally, only recently have researchers demonstrated proportional myoelectric control in such systems, an option that is believed to make fine control easier for the user. Recent developments suggest improved reliability if the user follows a so-called prosthesis guided training (PGT) scheme. METHODS: In this study, a system for simultaneous proportional myoelectric control has been developed for a hand prosthesis with two motor functions (hand open/close, and wrist pro-/supination). The prosthesis has been used with a prosthesis socket equivalent designed for normally-limbed subjects. An extended version of PGT was developed for use with proportional control. The control system's performance was tested for two subjects in the Clothespin Relocation Task and the Southampton Hand Assessment Procedure (SHAP). Simultaneous proportional control was compared with three other control strategies implemented on the same prosthesis: mutex proportional control (the same system but with simultaneous control disabled), mutex on-off control, and a more traditional, sequential proportional control system with co-contractions for state switching. RESULTS: The practical tests indicate that the simultaneous proportional control strategy and the two mutex based pattern recognition strategies performed equally well, and superiorly to the more traditional sequential strategy according to the chosen outcome measures. CONCLUSIONS: This is the first simultaneous proportional myoelectric control system demonstrated on a prosthesis affixed to the forearm of a subject. The study illustrates that PGT is a promising system training method for proportional control. Due to the limited number of subjects in this study, no definite conclusions can be drawn. PMID- 24775604 TI - Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial mesenchymal transition. AB - Although protein arginine methyltransferase 5 (PRMT5) has been implicated in various cancers, its expression pattern in lung adenocarcinoma cell lines and tissues has not been elucidated enough. In this study, microarray analysis of 40 non-small-cell lung carcinoma cell lines showed that PRMT5 was a candidate histone methyltransferase gene that correlated with epithelial-mesenchymal transition. Immunocytochemical analysis of these cell lines indicated that the expression of PRMT5 was localized to the cytoplasm of E-cadherin-low and vimentin high cell lines, whereas it was predominant in the nucleus and faint in the cytoplasm of E-cadherin-high and vimentin-low cell lines. Immunohistochemical analysis of lung adenocarcinoma cases (n = 130) revealed that the expression of PRMT5 was high in the cytoplasm of 47 cases (36%) and the nuclei of 34 cases (26%). The marked cytoplasmic expression of PRMT5 was frequently observed in high grade subtypes (1 of 17 low grade, 21 of 81 intermediate grade, and 25 of 32 high grade; P < .0001) such as solid adenocarcinoma with the low expression of thyroid transcription factor 1 (the master regulator of lung) and low expression of cytokeratin 7 and E-cadherin (2 markers for bronchial epithelial differentiation), whereas the high nuclear expression of PRMT5 was frequently noted in adenocarcinoma in situ, a low-grade subtype (6 of 17 low grade, 25 of 81 intermediate grade, and 3 of 32 high grade; P = .0444). The cytoplasmic expression of PRMT5 correlated with a poor prognosis (P = .0089). We herein highlighted the importance of PRMT5 expression, especially its cytoplasmic expression, in the process of epithelial-mesenchymal transition and loss of the bronchial epithelial phenotype of lung adenocarcinoma. PMID- 24775605 TI - Pathologic spectrum of cysts in end-stage kidneys: possible precursors to renal neoplasia. AB - Acquired cystic disease (ACD) is common in patients with end-stage renal disease. Given the significant increased risk of renal cell carcinoma (RCC) in these patients, we characterized the pathologic spectrum of cysts in end-stage kidneys to determine the possible relationship with coincidental neoplasms. Twenty-one native end-stage kidneys contained multiple cysts (0.1-4 cm), which could be categorized into 3 groups based on the cytoplasm of the predominant cell type: clear, eosinophilic, or foamy. Clear cell cysts showed strong staining with carbonic anhydrase IX (CA9) in a cup-shaped manner. Of 7 kidneys with CA9 positive clear cell cysts, 3 had at least 2 foci of RCC (0.5-8 cm), which all demonstrated the morphologic features and immunoprofile of clear cell papillary RCC. Eight kidneys contained foamy cysts, and 4 of these contained ACD-associated RCC, but 1 papillary RCC was also encountered. Six kidneys had eosinophilic cysts, which were negative for CA9, and 3 of these were associated with papillary RCC. Clear cell cysts, although few in number, are common in end-stage nephrectomy specimens. These cysts were present in all kidneys with clear cell papillary RCC and a few kidneys without an obvious mass. In specimens with ACD associated RCC or papillary RCC, cysts lined by epithelial cells with predominantly eosinophilic or foamy cytoplasm were identified. These data support the idea that the cysts in end-stage kidneys could represent the earliest precursor lesion of renal neoplasia. PMID- 24775603 TI - The multiple facets of drug resistance: one history, different approaches. AB - Some cancers like melanoma and pancreatic and ovarian cancers, for example, commonly display resistance to chemotherapy, and this is the major obstacle to a better prognosis of patients. Frequently, literature presents studies in monolayer cell cultures, 3D cell cultures or in vivo studies, but rarely the same work compares results of drug resistance in different models. Several of these works are presented in this review and show that usually cells in 3D culture are more resistant to drugs than monolayer cultured cells due to different mechanisms. Searching for new strategies to sensitize different tumors to chemotherapy, many methods have been studied to understand the mechanisms whereby cancer cells acquire drug resistance. These methods have been strongly advanced along the years and therapies using different drugs have been increasingly proposed to induce cell death in resistant cells of different cancers. Recently, cancer stem cells (CSCs) have been extensively studied because they would be the only cells capable of sustaining tumorigenesis. It is believed that the resistance of CSCs to currently used chemotherapeutics is a major contributing factor in cancer recurrence and later metastasis development. This review aims to appraise the experimental progress in the study of acquired drug resistance of cancer cells in different models as well as to understand the role of CSCs as the major contributing factor in cancer recurrence and metastasis development, describing how CSCs can be identified and isolated. PMID- 24775606 TI - Immunohistochemical screening and fluorescence in situ hybridization confirmation of ALK translocation in lung adenocarcinoma and its clinicopathological significance: a single-center large-scale investigation of Chinese patients. AB - Anaplastic lymphoma kinase (ALK) translocation-positive adenocarcinoma of the lung is a newly recognized molecular subgroup. Limited data on the clinicopathological features of this entity in the Chinese population are available. We performed immunohistochemical staining for the ALK protein and fluorescence in situ hybridization detection of the ALK translocation. We enrolled 793 Chinese patients with lung adenocarcinoma and identified 54 ALK translocation-positive patients (6.8%) in the group. Compared with the entire group of patients, ALK translocation-positive patients were younger (P < .01) and more likely to be nonsmokers (P = .017), but presented with a higher percentage of advanced-stage disease (P = .022) and lymph node metastases (P = .006). ALK translocation-positive patients more commonly exhibited poorly differentiated tumor histology and a predominantly solid tumor growth pattern relative to the ALK translocation-negative patients. Morphologically, ALK translocation was associated with extracellular mucus secretion, a mucinous cribriform structure, and signet ring cell (SRC) components. ALK translocation was present in 42.5% and 34.0% of adenocarcinomas with SRC components or wild-type EGFR, respectively. ALK translocation, occurring at a frequency of 6.8% in Chinese patients, defines a unique molecular subgroup of lung tumors. Fluorescence in situ hybridization should be performed in each case of lung adenocarcinoma with SRC components or wild-type EGFR to identify ALK translocation-positive patients. PMID- 24775607 TI - Absence of association of FCGR2A gene polymorphism rs1801274 with Kawasaki disease in Greek patients. AB - Kawasaki disease is an acute, febrile syndrome in infancy, characterised by vasculitis of medium-sized arteries, and affects predominantly young children. Family-based studies on Kawasaki disease supports the contribution of genetic factors in disorder manifestation. In a recent genome-wide association study, the polymorphism rs1801274 of FCGR2A [Fc fragment of immunoglobulin G, low-affinity IIa, receptor] gene has been implicated in disease pathogenesis. The aim of the present study was to explore the association of this variant, for the first time, in a group of Kawasaki-diseased patients of Greek origin. A total of 47 Kawasaki diseased children and 50 control subjects were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphism assay was performed in rs1801274 genotyping. No association was observed between this polymorphism genotypes' or alleles' distribution between Kawasaki-diseased patients and controls. Furthermore, no association was revealed between this polymorphism and cardiovascular complications in Kawasaki-diseased patients. In the literature, the reported data over this polymorphism association with Kawasaki disease in Caucasian patients are contradictory. In addition, the disease shows low prevalence in the Caucasian populations. Therefore, the independent genetic association studies on rs1801274 with Kawasaki disease in various Caucasian groups increase the amount of genetic data, which could be used in a future meta analysis, increasing the statistical power of the resultant conclusions. PMID- 24775608 TI - Facial neuroma masquerading as acoustic neuroma. AB - Facial nerve neuromas are rare benign tumors that may be initially misdiagnosed as acoustic neuromas when situated near the auditory apparatus. We describe a patient with a large cystic tumor with associated trigeminal, facial, audiovestibular, and brainstem dysfunction, which was suspicious for acoustic neuroma on preoperative neuroimaging. Intraoperative investigation revealed a facial nerve neuroma located in the cerebellopontine angle and internal acoustic canal. Gross total resection of the tumor via retrosigmoid craniotomy was curative. Transection of the facial nerve necessitated facial reanimation 4 months later via hypoglossal-facial cross-anastomosis. Clinicians should recognize the natural history, diagnostic approach, and management of this unusual and mimetic lesion. PMID- 24775610 TI - Reliability of post-chemo radiotherapy F-18-FDG PET/CT for prediction of loco regional failure in human papillomavirus-associated oropharyngeal cancer: misconception and misinterpretation. PMID- 24775609 TI - Visualization of cholesterol deposits in lysosomes of Niemann-Pick type C fibroblasts using recombinant perfringolysin O. AB - BACKGROUND: Niemann-Pick disease type C (NPC) is caused by defects in cholesterol efflux from lysosomes due to mutations of genes coding for NPC1 and NPC2 proteins. As a result, massive accumulation of unesterified cholesterol in late endosomes/lysosomes is observed. At the level of the organism these cholesterol metabolism disorders are manifested by progressive neurodegeneration and hepatosplenomegaly. Until now filipin staining of cholesterol deposits in cells has been widely used for NPC diagnostics. In this report we present an alternative method for cholesterol visualization and estimation using a cholesterol-binding bacterial toxin, perfringolysin O. METHODS: To detect cholesterol deposits, a recombinant probe, perfringolysin O fused with glutathione S-transferase (GST-PFO) was prepared. GST-PFO followed by labeled antibodies or streptavidin was applied for immunofluorescence and immunoelectron microscopy to analyze cholesterol distribution in cells derived from NPC patients. The identity of GST-PFO-positive structures was revealed by a quantitative analysis of their colocalization with several organelle markers. Cellular ELISA using GST-PFO was developed to estimate the level of unesterified cholesterol in NPC cells. RESULTS: GST-PFO recognized cholesterol with high sensitivity and selectivity, as demonstrated by a protein/lipid overlay assay and surface plasmon resonance analysis. When applied to stain NPC cells, GST-PFO decorated abundant deposits of cholesterol in intracellular vesicles that colocalized with filipin-positive structures. These cholesterol deposits were resistant to 0.05%-0.2% Triton X-100 used for cells permeabilization in the staining procedure. GST-PFO-stained organelles were identified as late endosomes/lysosomes based on their colocalization with LAMP-1 and lysobisphosphatidic acid. On the other hand, GST-PFO did not colocalize with markers of the Golgi apparatus, endoplasmic reticulum, peroxisomes or with actin filaments. Only negligible GST-PFO staining was seen in fibroblasts of healthy individuals. When applied to cellular ELISA, GST-PFO followed by anti-GST peroxidase allowed a semiquantitative analysis of cholesterol level in cells of NPC patients. Binding of GST-PFO to NPC cells was nearly abolished after extraction of cholesterol with methyl-beta-cyclodextrin. CONCLUSIONS: Our data indicate that a recombinant protein GST-PFO can be used to detect cholesterol accumulated in NPC cells by immunofluorescence and cellular ELISA. GST-PFO can be a convenient and reliable probe for revealing cholesterol deposits in cells and can be useful in diagnostics of NPC disease. PMID- 24775611 TI - Low gradient severe aortic stenosis with preserved ejection fraction: don't forget the flow! PMID- 24775612 TI - Outcome in aortic stenosis: when the flow makes the difference. PMID- 24775613 TI - Aspirin continues to attract research and debate, 115 years after its synthesis. PMID- 24775614 TI - Severe aortic valve stenosis with low-gradient and preserved ejection fraction: a misclassification issue? AB - INTRODUCTION AND OBJECTIVES: Low-gradient severe aortic stenosis with preserved ejection fraction is a controversial entity. Misclassification of valvulopathy severity could explain the inconsistencies reported in the prognosis of these patients. Planimetry of the aortic area using three-dimensional transesophageal echocardiography could clear up these doubts. The objectives were to assess the agreement between measurements of the valvular aortic area by continuity equation in transthoracic echocardiography and that obtained through planimetry with three dimensional transesophageal echocardiography in low-gradient severe aortic stenosis patients. METHODS: Cross-sectional descriptive study of consecutive patients referred due to severe aortic stenosis. Patients underwent transthoracic echocardiography and three-dimensional transesophageal echocardiography. Paradoxical low-gradient severe aortic stenosis was defined by the presence in the transthoracic echocardiography of aortic valve area<1 cm(2), mean ventricular gradient<40 mmHg, and ejection fraction >= 50%. Concordance between the two techniques was evaluated. RESULTS: Of 212 consecutive severe aortic stenosis patients evaluated, 63 cases (29.7%) fulfilled the paradoxical low-gradient inclusion criteria. We obtained three-dimensional aortic valve planimetry in 61 (96.8%) of those patients. In 52 patients (85.2%), aortic valve area by transesophageal echocardiography was <1 cm(2). The intraclass correlation coefficient between the two methods was 0.505 (95% confidence interval, 0.290 0.671; P<.001). CONCLUSIONS: Paradoxical low-gradient severe aortic stenosis is an actual entity, confirmed in 85% of cases evaluated by three-dimensional transesophageal echocardiography. PMID- 24775615 TI - Systolic volume index by Doppler echocardiography is an useful marker for stratification and prognostic evaluation in patients with severe aortic stenosis and preserved ejection fraction. AB - INTRODUCTION AND OBJECTIVES: The prognosis of patients with severe aortic stenosis, low aortic gradient and preserved ejection fraction is controversial. Our study analyzed the prognosis of these patients and its relation to pressure gradient and aortic valve flow. METHODS: We performed a retrospective cohort study of 363 consecutive patients with severe aortic stenosis and preserved ejection fraction, divided into 4 groups, based on the presence of a systolic volume index greater or lower than 35 mL/m(2) and the presence of a mean aortic gradient greater or lower than 40 mmHg. Group I: normal flow, high gradient (n=169, 47%); group II: normal flow, low gradient (n=98, 27%); group III: low flow, high gradient (n=54, 15%), and group IV: low flow, low gradient (n=42, 12%). The primary endpoint was overall mortality. RESULTS: Independent risk factors for mortality were age (hazard ratio=1.04; 95% confidence interval, 1.01 1.08) and atrial fibrillation (hazard ratio=2.21; 95% confidence interval, 1.24 3.94). Surgical treatment was associated with longer survival in all groups (hazard ratio=0.25; 95% confidence interval: 0.13-0.49). Mortality was higher in patients with low flow than in those with with normal flow (26.6% vs 13.6%; P=.004). The most favorable mean prognosis was found in group II (hazard ratio=0.4; 95% confidence interval, 0.2-0.9). CONCLUSIONS: Patients with severe aortic stenosis, normal ejection fraction and low aortic flow have a worse prognosis. Analysis of aortic flow by Doppler echocardiography is useful in risk stratification and therapeutic decision-making in patients with aortic stenosis. PMID- 24775616 TI - Factors associated with mortality in out-of-hospital cardiac arrests attended in basic life support units in the Basque Country (Spain). AB - INTRODUCTION AND OBJECTIVES: To describe the epidemiological characteristics of cardiac arrests attended in basic life support units in the Basque Country (Spain) and look for factors associated with failure of cardiopulmonary resuscitation. METHODS: We conducted an observational study during 18 months, including all out-of-hospital cardiopulmonary resuscitation provided by basic life support units. The variables defined in the Utstein-style were considered as independent and mortality as the dependent variable. We applied descriptive and analytical statistics and evaluated the magnitude of the association using a logistic regression model, which included variables with P<.05 in the bivariate analysis. RESULTS: Of 1050 cardiac arrests attended, 15.7% of patients were revived in situ. The presumed etiology was cardiac in 55.3% of cases and 71.4% occurred at home. Cardiopulmonary resuscitation was started before the arrival of the ambulance in 22.9% of cases and in 18.2% the rhythm of presentation was shockable. Variables associated with lower mortality were: shockable rhythms (relative risk=0.44; P=.003), patient aged<65 years (relative risk=0.44; P=.002), time to cardiopulmonary resuscitation<8 min (relative risk=0.56; P=.039), and out of-home events (relative risk=0.55; P=.031). CONCLUSIONS: Cardiac arrest survival was low. Cardiopulmonary resuscitation before the arrival of the ambulance was rare. A shockable rhythm, age younger than 65 years, early cardiopulmonary resuscitation efforts, and a location away from home were associated with longer survival. It is necessary to develop strategies designed to reduce ambulance response time and educate the public in basic resuscitation. PMID- 24775617 TI - Low clinical penetrance in causal mutation carriers for cardiac channelopathies. AB - INTRODUCTION AND OBJECTIVES: Cardiac channelopathies are genetic alterations that can cause sudden death. Long QT syndrome and Brugada syndrome are 2 such conditions. Both are diagnosed according to previously published criteria. Our objective was to determine the sensitivity of these criteria in a consecutive series of patients carrying the mutations that cause them. METHODS: We enrolled 15 families and 31 causal mutation carriers with a high pathogenic probability of having long QT syndrome and Brugada syndrome. We conducted clinical and electrocardiographic studies to analyze the extent to which these patients fulfilled the diagnostic criteria. Statistical analysis was with SPSS 17.0. RESULTS: Some 48.3% of the subjects met the criteria indicating a high probability of long QT syndrome or Brugada syndrome. Among those with the mutation for long QT syndrome, only 10 out of 21 had a Schwartz index score >= 4. Both the median Schwartz score and the cQT interval were lower in relatives than in probands. Of those with the mutation for Brugada syndrome, 60% failed to meet current diagnostic criteria, which were more frequently fulfilled in relatives. Pharmacological tests with epinephrine and flecainide helped establish the diagnosis in 2 mutation carriers with negative phenotype. CONCLUSIONS: Current diagnostic criteria for long QT syndrome and Brugada syndrome had low sensitivity in our sample of genetic carriers. Genetic tests supported by pharmacological tests can increase diagnostic sensitivity, especially in asymptomatic relatives. PMID- 24775618 TI - Update on interventional cardiology. AB - This article provides a detailed review of the most important studies on interventional cardiology reported in publications or presentations during the year 2012. With regard to coronary interventions, ST-elevation myocardial infarction is extensively addressed in studies focusing on the relevance of reducing the reperfusion time and the utility of various devices and pharmacological strategies in primary angioplasty. Multiple comparative studies involving different generations of drug-eluting stents are available and indicate a favorable progression in terms of safety and efficacy. The risk of late thrombosis with the new generations of drug-eluting stents seems to be equivalent to that observed with bare-metal stents. The clinical outcomes with these stents in the elderly, in left main coronary artery, or in multivessel disease have also been the subject of important trials. Among the studies on intracoronary diagnostic techniques, those correlating imaging and pressure-based techniques are of special interest. The percutaneous treatment of structural heart disease, particularly transcatheter aortic valve implantation, followed by mitral repair, continues to be the subject of a great number of publications. Finally, renal denervation is currently being widely discussed in the literature. PMID- 24775619 TI - Update on heart failure, heart transplant, congenital heart disease, and clinical cardiology. AB - In the year 2012, 3 scientific sections-heart failure and transplant, congenital heart disease, and clinical cardiology-are presented together in the same article. The most relevant development in the area of heart failure and transplantation is the 2012 publication of the European guidelines for heart failure. These describe new possibilities for some drugs (eplerenone and ivabradine); expand the criteria for resynchronization, ventricular assist, and peritoneal dialysis; and cover possibilities of percutaneous repair of the mitral valve (MitraClip((r))). The survival of children with hypoplastic left heart syndrome in congenital heart diseases has improved significantly. Instructions for percutaneous techniques and devices have been revised and modified for the treatment of atrial septal defects, ostium secundum, and ventricular septal defects. Hybrid procedures for addressing structural congenital heart defects have become more widespread. In the area of clinical cardiology studies have demonstrated that percutaneous prosthesis implantation has lower mortality than surgical implantation. Use of the CHA2DS2-VASc criteria and of new anticoagulants (dabigatran, rivaroxaban and apixaban) is also recommended. In addition, the development of new sequencing techniques has enabled the analysis of multiple genes. PMID- 24775620 TI - Personalized medicine: genetic diagnosis for inherited cardiomyopathies/channelopathies. AB - Major advances in the field of molecular genetics have expanded our ability to identify genetic substrates underlying the pathogenesis of various disorders that follow Mendelian inheritance patterns. Included among these disorders are the potentially lethal and heritable channelopathies and cardiomyopathies for which the underlying genetic basis has been identified and is now better understood. Clinical and genetic heterogeneity are hallmark features of these disorders, with thousands of gene mutations being implicated within these divergent cardiovascular diseases. Genetic testing for several of these heritable channelopathies and cardiomyopathies has matured from discovery to research-based genetic testing to clinically/commercially available diagnostic tests. The purpose of this review is to provide the reader with a basic understanding of human medical genetics and genetic testing in the context of cardiovascular diseases of the heart. We review the state of clinical genetic testing for the more common channelopathies and cardiomyopathies, discuss some of the pertinent issues that arise from genetic testing, and discuss the future of personalized medicine in cardiovascular disease. PMID- 24775621 TI - Baumkuchen-like sinus of valsalva. PMID- 24775622 TI - Hyperkalemia mimicking a pattern of Brugada syndrome. PMID- 24775623 TI - Large infected atrial myxoma with vegetations. PMID- 24775624 TI - With so much attention paid to adenosine diphosphate receptor blockers, is there still a role for aspirin resistance? PMID- 24775625 TI - Infected ascending aorta prostheses. Is prosthesis removal always necessary? How long should antibiotics be given? PMID- 24775626 TI - Simplified approach for ablation of nodal reentrant tachycardia in a patient with tricuspid atresia and extracardiac Fontan palliation. PMID- 24775627 TI - Utility of multidector computed tomography for postprocedure evaluation of endovascular aortic stent-grafts. PMID- 24775628 TI - Role of intravascular ultrasound in stent thrombosis. PMID- 24775629 TI - Use of tolvaptan in patients with hyponatremia due to heart failure: initial experience. PMID- 24775630 TI - Miguel Torner Soler. PMID- 24775631 TI - Importance of definition and technique when using noninvasive coronary angiography to diagnose myocardial bridging. PMID- 24775632 TI - Importance of definition and technique when using noninvasive coronary angiography to diagnose myocardial bridging. Response. PMID- 24775633 TI - Carotid Intima-media thickness and morbidity and mortality in Spain: a definitive prospective study is needed. PMID- 24775634 TI - Predictors of Carotid Intima-media Thickness. PMID- 24775635 TI - Carotid Intima-media thickness in the Spanish population: reference ranges and association with cardiovascular risk factors. Response to related letters. PMID- 24775638 TI - Down-regulation of asparagine synthetase induces cell cycle arrest and inhibits cell proliferation of breast cancer. AB - Asparagine synthetase (ASNS) is deemed to be a promising therapeutic target for the treatment of several cancers, but its functional role in human breast cancer is still unknown. In this study, we employed RNA interference as an efficient tool to silence endogenous ASNS expression in breast cancer cell lines. The relationship between ASNS expression and breast cancer cell growth was investigated, and the therapeutic value of ASNS in breast cancer was further evaluated. Depletion of ASNS remarkably inhibited the proliferation and colony formation capacity of breast cancer cells and arrested cell cycle in the S phase. Our findings suggest that ASNS may contribute to breast cancer tumorigenesis and could be a potential therapeutic target in human breast cancer. PMID- 24775684 TI - Risk factors of coronary heart disease among medical students in King Abdulaziz University, Jeddah, Saudi Arabia. AB - BACKGROUND: Nowadays, Cardiovascular Diseases (CVDs) represents an escalating worldwide public health problem. Providing consistent data on the magnitude and risk factors of CVDs among young population will help in controlling the risks and avoiding their consequences. OBJECTIVE: The objective was to estimate the prevalence of risk factors of Coronary Heart Disease (CHD) among medical students during their clinical clerkship (4th - 6th years). METHODS: A cross-sectional study was done during the educational year 2012-2013 at King Abdulaziz University (KAU), Jeddah. Ethical standards were followed and a multistage stratified random sample method was used for selection of 214 medical students. Data was collected through an interviewing questionnaire, measurements and laboratory investigations. Both descriptive and analytical statistics were done by SPSS version 21. CHD risk percent in thirty years was calculated using Framingham algorithm for each student, then the risk among all students was determined. RESULTS: The commonest risk factors of CHDs were daily intake of high fat diet (73.4%), physical inactivity (57.9%), overweight/or obesity (31.2%) and daily consumption of fast food (13.1%). Hyper-cholesterolemia (17.2%) and hypertension (9.3%) were also prevalent risk factors. Smoking prevalence was low (2.8%). Males had significantly higher mean scores for most of CHD risk factors compared to females (p < 0.05). Systolic Blood pressure was higher among males (119.47 +/- 11.17) compared to females (112.26 +/- 9.06). A highly statistical significant difference was present (Students't test = 4.74, p < 0.001). Framingham Risk Score revealed that CHD risk percent in thirty-years among all students was 10.7%, 2.3% and 0.5% for mild, moderate and severe risk, respectively. CONCLUSION: An alarmingly high prevalence of CHD risk factors was prevailed among medical students, especially among males. However, a low prevalence of smoking may indicate the success of "Smoke-free Campus" program. Screening risk factors of CHD among medical students and implementation of intervention programs are recommended. Programs to raise awareness about CHD risk factors, encourage young adult students to adopt a healthy dietary behavior and promote physical exercise should be initiated. PMID- 24775685 TI - Dose-reduced CT with model-based iterative reconstruction in evaluations of hepatic steatosis: how low can we go? AB - PURPOSE: To determine whether dose-reduced CT with model-based iterative image reconstruction (MBIR) is a useful tool with which to diagnose hepatic steatosis. MATERIALS AND METHODS: This prospective clinical study approved by our Institutional Review Board included 103 (67 men and 36 women; mean age, 64.3 years) patients who provided written informed consent to undergo unenhanced CT. Images of reference-dose CT (RDCT) with filtered back projection (R-FBP) and low- and ultralow-dose CT (dose-length product; 24 and 9% of that of RDCT) with MBIR (L-MBIR and UL-MBIR) were reconstructed. Mean CT numbers of liver (CT[L]) and spleen (CT[S]), and quotient (CT[L/S]) of CT[L] and CT[S] were calculated from selected regions of interest. Bias and limits of agreement (LOA) of CT[L] and CT[L/S] in L-MBIR and UL-MBIR (vs. R-FBP) were assessed using Bland-Altman analyses. Diagnostic methods for hepatic steatosis of CT[L]<48 Hounsfield units (HU) and CT[L/S]<1.1 were applied to L-MBIR and UL-MBIR using R-FBP as the reference standard. RESULTS: Bias was larger for CT[L] in UL-MBIR than in L-MBIR (-3.18HU vs. -1.73HU). The LOA of CT[L/S] was larger for UL-MBIR than for L-MBIR (+/-0.425 vs. +/-0.245) and outliers were identified in CT[L/S] of UL-MBIR. Accuracy (0.92-0.95) and the area under the receiver operating characteristics curve (0.976-0.992) were high for each method, but some were slightly lower in UL MBIR than L-MBIR. CONCLUSION: Dose-reduced CT reconstructed with MBIR is applicable to diagnose hepatic steatosis, however, a low dose of radiation might be preferable. PMID- 24775712 TI - Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. AB - BACKGROUND: Accumulating evidence indicates that the long non-coding RNA HOTAIR plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of HOTAIR in gastric carcinogenesis remains largely unknown. METHODS: HOTAIR expression was measured in 78 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches in vitro and in vivo. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation (RIP). The positive HOTAIR/HER2 interaction was identified and verified by immunohistochemistry assay and bivariate correlation analysis. RESULTS: HOTAIR upregulation was associated with larger tumor size, advanced pathological stage and extensive metastasis, and also correlated with shorter overall survival of gastric cancer patients. Furthermore, HOTAIR overexpression promoted the proliferation, migration and invasion of gastric carcinoma cells, while HOTAIR depletion inhibited both cell invasion and cell viability, and induced growth arrest in vitro and in vivo. In particular, HOTAIR may act as a ceRNA, effectively becoming a sink for miR-331 3p, thereby modulating the derepression of HER2 and imposing an additional level of post-transcriptional regulation. Finally, the positive HOTAIR/HER2 correlation was significantly associated with advanced gastric cancers. CONCLUSIONS: HOTAIR overexpression represents a biomarker of poor prognosis in gastric cancer, and may confer malignant phenotype to tumor cells. The ceRNA regulatory network involving HOTAIR and the positive interaction between HOTAIR and HER2 may contribute to a better understanding of gastric cancer pathogenesis and facilitate the development of lncRNA-directed diagnostics and therapeutics against this disease. PMID- 24775711 TI - Nanomicellar formulation of coenzyme Q10 (Ubisol-Q10) effectively blocks ongoing neurodegeneration in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model: potential use as an adjuvant treatment in Parkinson's disease. AB - Although the support for the use of antioxidants, such as coenzyme Q(10) (CoQ(10)), to treat Parkinson's disease (PD) comes from the extensive scientific evidence, the results of conducted thus far clinical trials are inconclusive. It is assumed that the efficacy of CoQ(10) is hindered by insolubility, poor bioavailability, and lack of brain penetration. We have developed a nanomicellar formulation of CoQ(10) (Ubisol-Q(10)) with improved properties, including the brain penetration, and tested its effectiveness in mouse MPTP (1-methyl-4-phenyl 1, 2, 3, 6-tetrahydropyridine) model with the objectives to assess its potential use as an adjuvant therapy for PD. We used a subchronic MPTP model (5-daily MPTP injections), characterized by 50% loss of dopamine neurons over a period of 28 days. Ubisol-Q(10) was delivered in drinking water. Prophylactic application of Ubisol-Q(10), started 2 weeks before the MPTP exposure, significantly offset the neurotoxicity (approximately 50% neurons died in MPTP group vs. 17% in MPTP+ Ubisol-Q(10) group by day 28). Therapeutic application of Ubisol-Q(10), given after the last MPTP injection, was equally effective. At the time of intervention on day 5 nearly 25% of dopamine neurons were already lost, but the treatment saved the remaining 25% of cells, which otherwise would have died by day 28. This was confirmed by cell counts, analyses of striatal dopamine levels, and improved animals' motor skill on a beam walk test. Similar levels of neuroprotection were obtained with 3 different Ubisol-Q(10) concentrations tested, that is, 30 mg, 6 mg, or 3 mg CoQ(10)/kg body weight/day, showing clearly that high doses of CoQ(10) were not required to deliver these effects. Furthermore, the Ubisol-Q(10) treatments brought about a robust astrocytic activation in the brain parenchyma, indicating that astroglia played an active role in this neuroprotection. Thus, we have shown for the first time that Ubisol-Q(10) was capable of halting the neurodegeneration already in progress; however, to maintain it a continuous supplementation of Ubisol-Q(10) was required. The pathologic processes initiated by MPTP resumed if supplementation was withdrawn. We suggest that in addition to brain delivery of powerful antioxidants, Ubisol-Q(10) might have also supported subcellular oxidoreductase systems allowing them to maintain a favorable cellular redox status, especially in astroglia, facilitating their role in neuroprotection. Based on this data further clinical testing of this formulation in PD patients might be justifiable. PMID- 24775713 TI - The prevalence of opportunistic infections and malignancies in autopsied patients with human immunodeficiency virus infection in Japan. AB - BACKGROUND: Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. METHODS: A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985-2012 were retrospectively reviewed. Clinical data were collected from patient medical records. RESULTS: Mean CD4 counts of patients were 77.0 cells/MUL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/MUL in naive patients (ART ( ) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (-) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (-) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (-) patients (1.5%; P = 0.026). CONCLUSIONS: The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (-) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (-) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART. PMID- 24775714 TI - Influence of feeding graded levels of canned sardines on the inflammatory markers and tissue fatty acid composition of Wistar rats. AB - Canned sardines are a ready-to-use fish product with excellent nutritional properties owing to its high n-3 long-chain PUFA content, mainly EPA (20 : 5n-3) and DHA (22 : 6n-3). The present study aimed to assess the effect of two dosages of canned sardines, recommended for the primary and secondary prevention of human CVD, on the inflammatory marker concentrations and fatty acid composition of erythrocytes and key metabolic tissues (liver, muscle, adipose tissue and brain) in the rat model. Wistar rats were fed a diet containing 11 % (w/w) of canned sardines (low-sardine (LS) diet) and a diet containing 22 % (w/w) of canned sardines (high-sardine (HS) diet) for 10 weeks. Daily food intake, weight gain, and organ and final body weights were not affected by the dietary treatments. The concentrations of total cholesterol, HDL-cholesterol and LDL-cholesterol decreased in both the LS and HS groups, while those of alanine aminotransferase and adiponectin increased. The concentrations of IL-1beta increased only with the highest dosage of sardine. The dose-dependent influence of the graded levels of EPA+DHA was tissue specific. Compared with that of other tissues and erythrocytes, the fatty acid composition of the brain was less affected by the canned sardine-supplemented diets. In contrast, the retroperitoneal adipose tissue was highly responsive. The deposition ratios of EPA and DHA indicated that the LS diet was optimal for DHA deposition across the tissues, except in the retroperitoneal adipose tissue. Taken together, our findings indicate that a LS diet positively affects plasma lipid profiles and inflammatory mediators, whereas a HS diet has contradictory effects on IL-1beta, which, in turn, is not associated with variations in the concentrations of other pro-inflammatory cytokines. This finding requires further investigation and pathophysiological understanding. PMID- 24775715 TI - The impact of not having a ductus arteriosus on clinical outcomes in foetuses diagnosed with tetralogy of Fallot. AB - BACKGROUND: Foetuses with simple tetralogy of Fallot almost universally have a patent ductus arteriosus. Two recently identified cases had an absent patent ductus arteriosus, requiring emergent intervention at birth. The objective of this study was to determine whether foetuses diagnosed with tetralogy of Fallot and no patent ductus arteriosus have poorer outcomes compared with those with tetralogy of Fallot+patent ductus arteriosus. METHODS: All foetal cases of tetralogy of Fallot between January, 2000 and 2012 were retrospectively identified from The Hospital for Sick Children (Toronto, Canada) database. Cases tetralogy of Fallot+no patent ductus arteriosus confirmed on postnatal echo - and controls - tetralogy of Fallot+patent ductus arteriosus, matched for gestational age - were identified from prenatal records, and both clinical and echocardiographic data were reviewed. Optimal outcome was defined as valve sparing repair with no residual lesions. Student's t-tests and Fisher's exact chi2 were used to compare groups. RESULTS: n=115 foetuses were diagnosed with tetralogy of Fallot: 11 (9%) had no patent ductus arteriosus, and were matched to 22 controls - mean gestational age at diagnosis 23.2+/-4.2 weeks, 23.4+/-6.6 weeks, respectively. Cases had a higher proportion of right aortic arches (64% versus 14%, p<0.001). Foetal and postnatal echocardiographic data did not reveal significant differences in branch pulmonary artery sizes, pulmonary valve sizes, or ventricular function. No differences were identified for cyanosis at birth (2/10 versus 7/20, p=0.67), or catheter intervention (5/10 versus 4/22, p=0.12). Optimal outcome rates were similar between cases and controls (4/11 (36%) versus 5/21 (24%), p=0.68). CONCLUSIONS: The patent ductus arteriosus does not appear to have an impact on clinical outcome in foetuses with tetralogy of Fallot. PMID- 24775717 TI - Current management of advanced and castration resistant prostate cancer. AB - INTRODUCTION: Newer approaches to the management of advanced prostate cancer have rapidly evolved. While basic androgen deprivation remains as the first line in newly diagnosed hormone naive metastatic prostate cancer, the agents used and strategies followed have undergone significant changes. Numerous new agents such as sipuleucel-T, abiraterone, enzalutamide, cabazitaxel and radium 223 have all been approved since 2010 to treat metastatic castration resistant prostate cancer (CRPC). New imaging techniques to detect advanced disease such as F-18 PET, 11 C choline PET and other modalities are becoming available. The concepts of "bone health" and the management of side effects related to androgen deprivation therapy are also gaining attention as men are being treated with longer courses of androgen deprivation. Understanding the theory behind these new agents and management approaches while focusing on the practical clinical considerations are essential to improve outcomes in advanced prostate cancer. MATERIALS AND METHODS: A review of the current state of the art in the management of advanced and castration resistant prostate cancer presented in this Canadian Journal of Urology International supplement was performed. Key findings are summarized and presented along with critical updates based on recent publications and meeting presentations. RESULTS: Key concepts identified in the management of advanced prostate cancer included the new understanding of prostate cancer based on translational discoveries, applications of various hormonally based strategies in advanced disease including traditional and recently approved agents. The use of new imaging modalities to identify metastatic disease, immunotherapy approaches and discussions of sequencing and which new agents are likely to be available in the future in the management of CRPC were identified. Bone targeted strategies are also addressed in the setting of androgen deprivation and metastatic disease. CONCLUSIONS: The management of men with advanced prostate cancer has become more multidisciplinary as treatment options have expanded. As the use of these agents and new strategies expand, urologists, medical oncologists and radiation oncologists must all become familiar with this rapidly changing field in order to maximize the outcome of patients with advanced and castration resistant prostate cancer. PMID- 24775718 TI - The changing landscape of advanced and castration resistant prostate cancer: latest science and revised definitions. AB - INTRODUCTION: One fifth of men with newly diagnosed prostate cancer present with locally advanced or metastatic disease. Androgen deprivation therapy (ADT) is the standard systemic therapy in these patients. Despite initial response, essentially all patients will develop castration resistant prostate cancer (CRPC). In this review, we will discuss the revised definitions of CRPC and the latest understanding of the biology of the androgen/androgen receptor axis in the development of advanced prostate cancer. MATERIALS AND METHODS: A systematic literature review was conducted via electronic database articles based on title, abstract, study format, and content. The majority of selected articles were published between 1992 and 2013. Older studies were included selectively if historically relevant. RESULTS: Prostate cancer becomes castration resistant through numerous pathways, including androgen and androgen receptor (AR) dependent mechanisms as well as ligand and AR independent pathways. Therefore the terms androgen-insensitive and hormone-refractory should be avoided and replaced by the term castration resistant. Recent advances in understanding molecular mechanisms of castration resistance have led to development of novel CRPC therapeutics. CONCLUSIONS: CRPC remains an incurable disease. Further understanding of the pathways involved in castration resistance will set the basis for development of therapies to increase survival in these patients. PMID- 24775719 TI - Traditional androgen ablation approaches to advanced prostate cancer: new insights. AB - INTRODUCTION: Androgen deprivation therapy (ADT) is a mature therapy for the treatment of advanced prostate cancer, and yet despite many years of use, there is still much about its use, side effects, efficacy, and outcomes for which the urology community does not have answers. MATERIALS AND METHODS: A literature search was performed to review ADT use in the modern era, specifically examining adjuvant ADT after primary therapy, continuous versus intermittent ADT, disadvantages of luteinizing hormone releasing hormone (LHRH) agonists versus newer LHRH antagonists, and controversies of combined androgen blockade. RESULTS: ADT has little role as primary therapy in North American populations. Evidence for the use of neoadjuvant/adjuvant ADT with radical prostatectomy is less compelling than that for radiation therapy. Data supporting combined androgen blockade over LHRH agonist therapy alone are mixed. Newer LHRH antagonists have a faster onset of reduction in serum testosterone and demonstrate other effects on serum follicle stimulating hormone (FSH) that may impact prostate cancer outcomes. CONCLUSIONS: ADT remains a mainstay of treatment in prostate cancer, and our knowledge of its effectiveness has improved with time. There are still scenarios where not enough information is available and study is ongoing. PMID- 24775716 TI - Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review. AB - OBJECTIVE: It is important for psychiatrists to be aware of certain inborn errors of metabolism (IEMs) as these rare disorders can present as psychosis, and because definitive treatments may be available for treating the underlying metabolic cause. A systematic review was conducted to examine IEMs that often present with schizophrenia-like symptoms. DATA SOURCES: Published literature on MEDLINE was assessed regarding diseases of homocysteine metabolism (DHM; cystathionine beta-synthase deficiency [CbS-D] and homocysteinemia due to methyltetrahydrofolate reductase deficiency [MTHFR-D]), urea cycle disorders (UCD), acute porphyria (POR), Wilson disease (WD), cerebrotendinous-xanthomatosis (CTX) and Niemann-Pick disease type C (NP-C). STUDY SELECTION: Case reports, case series or reviews with original data regarding psychiatric manifestations and cognitive impairment published between January 1967 and June 2012 were included based on a standardized four-step selection process. DATA EXTRACTION: All selected articles were evaluated for descriptions of psychiatric signs (type, severity, natural history and treatment) in addition to key disease features. RESULTS: A total of 611 records were identified. Information from CbS-D (n = 2), MTHFR-D (n = 3), UCD (n = 8), POR (n = 12), WD (n = 11), CTX (n = 14) and NP-C publications (n = 9) were evaluated. Six non-systematic literature review publications were also included. In general, published reports did not provide explicit descriptions of psychiatric symptoms. The literature search findings are presented with a didactic perspective, showing key features for each disease and psychiatric signs that should trigger psychiatrists to suspect that psychotic symptoms may be secondary to an IEM. CONCLUSION: IEMs with a psychiatric presentation and a lack of, or sub-clinical, neurological signs are rare, but should be considered in patients with atypical psychiatric symptoms. PMID- 24775720 TI - Utility of LHRH antagonists for advanced prostate cancer. AB - INTRODUCTION: Androgen deprivation therapy (ADT) is the lynchpin of treatment for advanced prostate cancer. Prescribing physicians and patients have a choice between orchiectomy, luteinizing hormone releasing hormone (LHRH) agonists, combined androgen deprivation (CAD) or LHRH antagonists. MATERIALS AND METHODS: Literature relating to the use of LHRH antagonists in the management of prostate cancer was reviewed. RESULTS: Abarelix was the first-in-class LHRH pure antagonist that was Food and Drug Administration (FDA) approved in 2003. Due to a variety of concerns including hypersensitivity reactions it was withdrawn from the United States (U.S.) market in 2005. The only currently commercially available LHRH antagonist in the U.S. is degarelix available as a once-a-month depot injection. The potential clinical advantage of degarelix compared to the LHRH agonists is the very rapid and sustained testosterone suppression with no identifiable physiological or clinical testosterone surge or flare. The main disadvantage of degarelix compared to the LHRH agonists is the monthly dosing and the inconvenience for some patients and practices. Recent studies tout improved disease control for degarelix compared to monthly leuprolide acetate; however, these results remain controversial. CONCLUSIONS: The rapid T-suppression achieved with degarelix may provide a clinical benefit for various groups of men with advanced or locally advanced disease. PMID- 24775721 TI - Intermittent androgen deprivation therapy for prostate cancer: translating randomized controlled trials into clinical practice. AB - INTRODUCTION: Intermittent androgen deprivation therapy (IADT) for prostate cancer involves cycles of androgen deprivation therapy (ADT) with a period between cycles where testosterone is allowed to rise above castrate levels. A number of recent randomized controlled trials (RCTs) have compared survival and health-related quality-of-life (HRQOL) between IADT and continuous ADT (CADT). This review seeks to critically analyze these published trials for their relevance to clinical practice. MATERIALS AND METHODS: Published trials were retrieved from a systematic search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials databases using relevant keywords. Recent systematic reviews published on this topic were hand-searched for additional applicable references. The evidence was then synthesized for this review. RESULTS: A number of phase III trials have been recently published. IADT was found to be non-inferior in the primary setting for non-metastatic prostate cancer as well as in treatment of biochemical recurrence following radiotherapy. However, these studies overrepresented low risk patients in whom consideration may be given to deferred ADT rather than early treatment with IADT. In the metastatic prostate cancer setting, IADT was not found to be non-inferior to CADT. In most trials, castration related symptoms improved with IADT and overall HRQOL results were mixed. Little data are available on the effect of IADT on long term complications of ADT. CONCLUSIONS: IADT remains a treatment with uncertain outcomes in metastatic prostate cancer and uncertain value over deferring ADT entirely in other prostate cancer clinical states. PMID- 24775722 TI - Secondary hormonal manipulation in castration resistant prostate cancer. AB - INTRODUCTION: Castration resistant prostate cancer (CRPC) is the single common pathway to prostate cancer death. For men with symptomatic metastatic disease, docetaxel chemotherapy remains a standard of care. However, blood prostatic specific antigen (PSA) testing allows the identification of CRPC before clinical metastases or symptoms occur, providing a long diagnostic lead time in many patients. The use of secondary hormonal manipulations (SHMs) in men not candidates for immediate chemotherapy is reviewed. MATERIALS AND METHODS: PubMed was searched for randomized clinical trials, systematic reviews or clinical practice guidelines addressing SHMs in CRPC. RESULTS: A recent systematic review and practice guideline was identified, and used as the evidence base for this review along with reports from randomized trials over the past year. CONCLUSIONS: The goals of therapy with SHMs should be discussed with patients and their preferences considered. In men without clinical evidence of metastases, gonadal androgen suppression should be maintained and generally patients should be observed. There is no clear evidence that SHMs are of benefit in these patients. Abiraterone plus prednisone is of proven benefit in men with CRPC metastases who are without significant symptoms prior to chemotherapy. Based on emerging data, enzalutamide may be of similar benefit. Use of other SHMs should be based on patient preference and consideration of possible adverse effects; with the exception of low dose prednisone, there is little evidence of benefit supporting their use. For patients accepting these uncertainties, a trial of nonsteroidal antiandrogen may be considered as an adjunct to observation, followed by low dose corticosteroid with immediate or delayed addition of abiraterone (in men with metastases) as a reasonable next step. PMID- 24775723 TI - Imaging approaches with advanced prostate cancer: techniques and timing. AB - INTRODUCTION: In conjunction with biomarkers, imaging is an important component of the diagnostic work up and subsequent management of men with prostate cancer. MATERIALS AND METHODS: The relevant literature was retrieved from a search of MEDLINE with appropriate key words. RESULTS: Osseous metastases develop in close to 90% of patients with metastatic prostate cancer, thus making bone scans (single photon, using Tc-99m labeled phosphonates) the mainstay of imaging in advanced prostate cancer. Bone scans are limited by their lack of specificity and an unclear relationship between bone scan changes and disease progression or response to therapy. In addition to Tc-99m bone scans, other technologies that accurately identify of sites of active disease would considerably aid castration resistant prostate cancer (CRPC) management. Accordingly, metabolic imaging, cell surface receptor targeting, and magnetic resonance imaging (MRI) are being studied for their role in evaluating metastatic disease. Due to the increasing availability of advanced imaging modalities, the optimal modality and appropriate clinical time point for its use remains unclear. CONCLUSION: A number of imaging modalities are currently or imminently available for use in advanced prostate cancer. Future research will focus on the appropriate incorporation of these modalities in prostate cancer management. PMID- 24775724 TI - Practical guide to immunotherapy in castration resistant prostate cancer: the use of sipuleucel-T immunotherapy. AB - INTRODUCTION: New treatment options for metastatic castration resistant prostate cancer (mCRPC) have become available over the last few years should primary treatments and androgen deprivation therapies fail. While historically not considered to be amenable to immunotherapy, the treatment of advanced prostate cancer using this approach is an area of intense interest and now clinical application. MATERIALS AND METHODS: Recent literature on castration resistant prostate cancer management with a focus on immunotherapeutic strategies was reviewed. Mechanisms of action involving the immunologic treatment of cancer were identified. Agents in clinical trials with near term application in prostate cancer were also identified. RESULTS: Numerous immunotherapeutic agents for mCRPC are in current clinical trials. The autologous, active cellular immunotherapy, sipuleucel-T, which utilizes a patient's own antigen-presenting cells, is the only Food and Drug Administration (FDA) approved agent. It provides a 4.1 month survival advantage. Other investigational agents in this area include GVAX, a whole cell irradiated vaccine, and a vaccinia-PSA-TRICOM pox virus based approach, all in phase III trials. Immune-checkpoint inhibitors that enhance T cell activity and potentiate antitumor effects are also promising. CONCLUSIONS: A first in class novel treatment modality, sipuleucel-T, is available in the United States for mCRPC. Other immunotherapies are in development and may be available in the near future. Understanding the detailed patient evaluation, initiation and administration of sipuleucel-T as described in this paper, will allow this novel cancer immunotherapy to be better understood and potentially benefit a larger group of appropriately selected patients. PMID- 24775725 TI - Practical guide to the use of abiraterone in castration resistant prostate cancer. AB - INTRODUCTION: While androgen deprivation therapy remains the primary treatment modality for patients with metastatic prostate cancer, treatment is uniformly marked by progression to castration resistant prostate cancer (CRPC). Abiraterone is the first new drug to enter clinical practice in a series of novel agents designed to potently target adrenal and tumor androgen production. MATERIALS AND METHODS: Herein, we review the mechanism of action of abiraterone and the phase III data supporting its approval for patients with metastatic CRPC. We discuss practical treatment considerations, including the incidence and management of side effect and monitoring requirements, and conclude by discussing future directions in the use of abiraterone, including early data supporting an expanded role for abiraterone in castration sensitive disease. RESULTS: Accumulating data emphasize that "androgen independent" or "hormone refractory" tumors remain sensitive to hormonal activation and suggest that despite suppression of circulating testosterone (T), residual tumor androgens play a prominent role in mediating CRPC progression. CONCLUSIONS: Accordingly, therapeutic strategies such abiraterone that more effectively target production of intratumoral androgens are necessary. PMID- 24775726 TI - Practical guide to the use of enzalutamide. AB - INTRODUCTION: We summarize the development, definitive trials, and practical use of enzalutamide for practicing urologists and medical oncologists. The care paradigm for patients with metastatic castration resistant prostate cancer (mCRPC) is a changing landscape, with the ongoing discovery of drivers of cancer progression yielding actionable targets for drug development. Since 2010, sipuleucel-T, cabazitaxel, abiraterone with prednisone, radium 223 and enzalutamide have been Food and Drug Administration approved based upon improvement in overall survival in men with mCRPC. MATERIALS AND METHODS: A MEDLINE search for "enzalutamide or MDV3100" yielded 258 results. Prospective trials were reviewed. Abstracts from ASCO (American Society of Clinical Oncology) meetings and press release information were included where applicable. RESULTS: Enzalutamide, an oral inhibitor of the androgen receptor pathway, was approved in 2012 based upon improvement in overall survival of 4.8 months in men with mCRPC following docetaxel versus placebo. Measures of prostate-specific antigen (PSA) and radiographic response, and clinically significant endpoints such as quality of life improvement and toxicity parameters favored enzalutamide. Toxicity is modest with asthenia and fatigue being most common, with a 1% incidence of seizure reported, though patients can be selected to decrease this risk. CONCLUSION: Enzalutamide is an effective oral therapy for mCRPC, with an overall survival benefit before and following chemotherapy. Toxicity is mild, and seizure risk can be mitigated by careful patient selection. Ongoing studies will help determine the best sequence of novel agents for prostate cancer, along with safe and effective combinations of therapies. Better understanding of tumor characteristics, particularly reliance on the androgen receptor pathway, will lead to personalized approaches to prostate cancer therapy. PMID- 24775727 TI - Practical guide to the use of radium 223 dichloride. AB - INTRODUCTION: Bone seeking radiopharmaceuticals have been used for decades in the palliation of pain from bone metastases emerging from prostate cancer. Recent clinical evidence has demonstrated an improved survival in men with metastatic castration resistant prostate cancer (CRPC) with radium 223. MATERIAL AND METHODS: A review of the literature was performed to identify the role of radiopharmaceuticals in the management of prostate cancer. We focused on prospective trials in order to identify the highest level of evidence describing this therapy. Further, we focused on providing a clinical guide for the use of radium 223. RESULTS: The phase III ALSYMPCA trial which compared radium 223 to placebo in men with symptomatic CRPC demonstrated a statistically significant improvement in median overall survival of 3.6 months and an improvement in time to first skeletal related event. There were higher rates of myelosuppression and diarrhea with radium 223, however, no clinically meaningful differences in the frequency of grade 3 or 4 adverse events were observed between the study groups. CONCLUSION: Radium 223 is a safe and effective therapy in men with symptomatic CRPC providing a survival advantage on par with novel antiandrogens, CYP-17 inhibitors, and chemotherapy. Radium 223 has huge potential in combination strategies as well as for use earlier in the natural history of metastatic prostate cancer. PMID- 24775728 TI - Practical guide to the use of chemotherapy in castration resistant prostate cancer. AB - INTRODUCTION: Chemotherapy, once thought to be toxic and ineffective in men with castration resistant prostate cancer (CRPC), has a significant impact on survival and quality-of-life in these patients. This article summarizes recent studies performed with two Food and Drug Administration (FDA) approved agents which have improved survival in men with CRPC, docetaxel and cabazitaxel. MATERIALS AND METHODS: The literature on cytotoxic chemotherapy for castration resistant prostate cancer was reviewed. The individual efficacy, mechanisms of chemotherapeutic action, and appropriate disease states of administration were identified. Recent clinical trial results of chemotherapy combined with targeted agents was also reviewed. RESULTS: Front line cytotoxic therapy consists of docetaxel combined with prednisone. In two randomized trials, docetaxel based therapy demonstrated a 20%-24% improvement in survival over the palliative standard of care, mitoxantrone combined with prednisone. Eight randomized trials combining docetaxel/prednisone with other antiangiogenic, bone targeted, vaccine or metabolic therapies failed to demonstrate an improvement in survival over docetaxel alone. Cabazitaxel, an analogue of docetaxel which has activity in taxane resistant cell lines, is approved by the FDA, for use in CRPC patients who have previous exposure to docetaxel. CONCLUSIONS: Docetaxel combined with prednisone remains the standard of care as first line cytotoxic therapy for CRPC. Cabazitaxel is an effective second line cytotoxic agent that improves survival; studies are underway comparing cabazitaxel to docetaxel as first line chemotherapy. Given its lack of survival benefit, as well as the emergence of new treatments for prostate cancer, mitoxantrone has a diminished role in the treatment of CRPC. PMID- 24775729 TI - Practical guide to bone health in the spectrum of advanced prostate cancer. AB - INTRODUCTION: In the advanced stage of prostate cancer, bone is consistently the first and, later on, the dominant extra-nodal metastatic site. Bone metastases account for most of prostate cancer's morbidity. MATERIALS AND METHODS: We have performed a literature review using the MEDLINE database for publications on: 1) bone metastases (androgen deprivation therapy); 2) cancer treatment induce bone loss; 3) skeletal related events; 4) denosumab; 5) zoledronic acid. RESULTS: Prostate cancer cells disrupt the normal bone remodeling process, invade the skeletal environment, and ultimately weaken the bone structure. This may result in skeletal complications, also known as skeletal related events (SREs), including pain, fractures, spinal cord compressions requiring surgery, radiotherapy or change in anti-cancer treatments. SREs negatively impact quality of-life and survival and represent a major cost for the healthcare system. The bone metastases conundrum is further aggravated by the fact that androgen deprivation therapy (ADT), the reference systemic treatment of advanced prostate cancer, profoundly affects the skeletal integrity as well. ADT accelerates the physiological bone resorption, leading to osteoporosis and fragility fractures. CONCLUSION: The concept of "bone health" or "skeletal heath" refers to the diagnostic, prevention, and treatment of cancer treatment induced bone loss (CTIBL) and metastasis, and their respective complications, osteoporotic fractures and SREs. PMID- 24775730 TI - How to approach sequencing therapy in patients with metastatic castration resistant prostate cancer. AB - INTRODUCTION: Rapid progress has recently been made in understanding the biology of advanced prostate cancer. This has translated into the development of a number of novel agents to treat metastatic castration resistant prostate cancer (mCRPC). MATERIALS AND METHODS: The relevant literature was retrieved from a search of MEDLINE with appropriate key words. RESULTS: Therapeutic approaches to mCRPC include chemotherapy, hormonal manipulation, immunotherapy and radioisotope therapy. Docetaxel and cabazitaxel are cytotoxic agents which have demonstrated a modest impact on survival. Hormonal manipulation with abiraterone and enzalutamide have also been reported to be beneficial in mCRPC. The radioisotope radium 223 utilizes a novel approach in treating mCRPC and was recently described in a positive phase III trial. Finally, sipuleucel-T is an immunotherapy that has a demonstrated overall survival benefit in mCRPC. CONCLUSIONS: A number of phase III trials have been published that describe agents which are beneficial in treating mCRPC. Future research will focus on sequencing these agents in a clinically rational and economically viable manner. PMID- 24775731 TI - Emerging therapies in castration resistant prostate cancer. AB - INTRODUCTION: Prostate cancer continues to be the second leading cause of cancer related mortality in men within the United States. Despite a consistent decline in prostate cancer mortality over the past two decades, the prognosis for men with metastatic prostate cancer remains poor with no curative therapies. In this article, we review the recently approved and emerging therapeutics for patients with castrate resistant prostate cancer. MATERIALS AND METHODS: An advanced search was conducted on the clinicaltrials.gov database, using search terms "metastatic prostate cancer", and limiting results to phase II-IV clinical trials. Clinically relevant emerging therapeutics were selected and a Medline search for supporting documents was performed. An emphasis was placed on newly approved and promising new therapeutics. RESULTS: A total of four Food and Drug Administration approved medications and eight investigational agents were chosen for review. The background and role of these therapeutics in the treatment of prostate cancer treatment is discussed. CONCLUSIONS: The past few years have yielded a near exponential increase in treatments for metastatic prostate cancer, many of which have a unique mechanism of action. The estimated median survival for patients with metastatic prostate cancer remains dynamic as we begin to integrate these therapeutics into clinical practice and determine the optimal sequence and timing of treatment. PMID- 24775732 TI - Blood pressure variability and morning blood pressure surge in elderly Chinese hypertensive patients. AB - This retrospective study aimed to investigate blood pressure variability (BPV), morning systolic blood pressure surge (MBPS), and the associated factors in 513 elderly (65 years and older) and 188 younger (younger than 65 years) hypertensive Chinese patients who had ambulatory blood pressure monitoring (ABPM) at our hospital from January 1, 2002, to December 31, 2010. The MBPS was lower in the younger patients compared with the elderly patients, and it was highest in the 75 years and older and younger than 80 group (29.0+/-13.4 mm Hg). Compared with other groups, the 80 years and older group had a significant increase in BPV (P<.05). Multiple linear regression analysis showed that body mass index (BMI; P<.01), up to 50 years of smoking (P<=.03), and circadian blood pressure variation (P<.01) were factors associated with MPBS. In summary, systolic BPV and MBPS were increased in elderly Chinese hypertensive patients, and the MBPS was associated with BMI, years of smoking, and circadian blood pressure variation. PMID- 24775733 TI - New astrovirus in human feces from Burkina Faso. AB - BACKGROUND: A significant fraction of cases of diarrhea, a leading cause of childhood mortality worldwide, remain unexplained. OBJECTIVES: To identify viruses in unexplained cases of diarrhea using an unbiased metagenomics approach. STUDY DESIGN: Viral nucleic acids were enriched from the feces from 48 cases of unexplained diarrhea from Burkina Faso, sequenced, and compared against all known viral genomes. RESULTS: The full genome of a highly divergent astrovirus was sequenced in a sample co-infected with parechovirus 1. RT-PCR identified a single astrovirus infection in these 48 patients indicating a low prevalence. Human astrovirus-BF34 was most closely related to mamastrovirus species 8 and 9 also found in human with which it shared 62%, 74%, and 57% amino acid identities over its protease, RNA dependent RNA polymerase and capsid proteins, respectively. CONCLUSIONS: Burkina Faso astrovirus is proposed as prototype for a novel species in the genus Mamastrovirus, here tentatively called Mamastrovirus 20, representing the fifth human astrovirus species. PMID- 24775734 TI - Prion-like aggregation of mutant p53 in cancer. AB - p53 is a master regulatory protein that participates in cellular processes such as apoptosis, DNA repair, and cell cycle control. p53 functions as a homotetrameric tumor suppressor, and is lost in more than 50% of human cancers. Recent studies have suggested that the formation of mutant p53 aggregates is associated with loss-of-function (LoF), dominant-negative (DN), and gain-of function (GoF) effects. We propose that these phenomena can be explained by a prion-like behavior of mutant p53. We discuss the shared properties of cancer and neurodegenerative diseases and how the prion-like properties of p53 aggregates offer potential targets for drug development. PMID- 24775803 TI - Hemolysis, pump thrombus, and neurologic events in continuous-flow left ventricular assist device recipients. AB - BACKGROUND: An ongoing challenge in the management of patients with heart failure who receive left ventricular assist devices (LVADs) is achieving optimal anticoagulation. Adverse prothrombotic events include hemolysis or pump thrombus (H/T) and neurologic events (NEs), and all limit the success of LVAD therapy. Our aim was to study the incidence and clinical outcomes associated with these events in a large single-center cohort. METHODS: We retrospectively reviewed our prospectively collected database of all patients receiving a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD from 2005 to 2012. Demographic, clinical, and outcome data were analyzed using standard statistical methods. All adverse events were recorded. RESULTS: Of 193 patients receiving LVADs, we identified 39 H/T events in 26 (13.4%) patients and 22 NEs in 19 (9.8%) patients. Seventy-four percent of events occurred in the last 3 years of the series, during which time 63% of implants were placed. Of patients with H/T, 8 (31% of those having H/T, 4.1% of total) had more than 1 event and 4 (15.4% of those having H/T, 2.1% of total) underwent pump exchanges. Five (23%) patients had NEs after H/T, and 6 (32%) died as a result of the NE. Of patients with H/T, 27% had preceding episodes of infection, 31% had an international normalized ratio (INR) of less than 1.5, 31% had an INR of 1.5 to 2, 15% had a history of clotting or were hypercoagulable, and 4% had anticoagulation intentionally withheld. Lactate dehydrogenase (LDH), plasma hemoglobin, INR, and platelet determinations were significantly different at the time of H/T compared with baseline values. The survival at 6 months (alive or having undergone transplantation) for those with a prothrombotic event compared with those without was 70% versus 75.2% (p = 0.5). CONCLUSIONS: The incidence of H/T or NEs is significant and results in major morbidity after LVAD placement. Infection and suboptimal anticoagulation are associated with the majority of these events. Identification of patients at higher risk for hemolysis (ie, infection) may allow for modification of anticoagulation regimens to reduce these risks and improve clinical outcomes. PMID- 24775802 TI - Minimally invasive direct coronary artery bypass graft surgery or percutaneous coronary intervention for proximal left anterior descending artery stenosis: a meta-analysis. AB - BACKGROUND: We conducted a metaanalysis comparing early and midterm cardiovascular adverse events associated with minimally invasive direct coronary artery bypass graft surgery (MIDCABG) and percutaneous coronary intervention (PCI), with a focus on drug-eluting stents (DES). METHODS: A systematic literature review (MEDLINE, EMBASE, Scopus, and so forth) yielded 12 studies (7 randomized controlled trials; 5 observational) pooling more than 2,000 patients. A random effect, inverse variance metaanalysis was conducted, and a subgroup analysis of the PCI-DES cohort was performed. Events were compared as risk ratios using a 95% confidence interval (CI). Heterogeneity of results was evaluated by Eggers I(2) test. Results are presented as early (0 to 1 year) and midterm (2 to 5 years). RESULTS: Midterm mortality in the PCI and MIDCABG groups (3.6% and 2.6%, respectively) was comparable (1.24, 95% CI: 0.66 to 2.33; p = 0.5; I(2) = 0%). Risk of early restenosis was lower in the MIDCABG cohort compared with PCI (0.40, 95% CI: 0.16 to 0.99; p = 0.05; I(2) = 57%). Although the early risk of recurrence of angina was comparable, over time it was 61% (43% to 74%) lower for MIDCABG patients (p < 0.001). Midterm results on analysis of the entire cohort demonstrated an increased risk for target vessel reinterventions (3.84, 95% CI: 2.7 to 5.5; p < 0.001) in the PCI cohort. Subgroup analysis revealed that the PCI DES cohort (4 studies; 456 patients) had a higher risk of recurrent angina (risk ratio 3.4, 95% CI: 1.9 to 6.2; p < 0.001; I(2) = 0%) and target vessel reinterventions (risk ratio 4.16, 95% CI: 2.7 to 6.6; p < 0.001; I(2) = 0%) at midterm follow-up (2 to 5 years). CONCLUSIONS: Survival rates are comparable after either MIDCABG or PCI for proximal LAD disease. However, even the use of DES was associated with significantly higher rates of angina recurrence and the need for target vessel reintervention as compared with MIDCABG. PMID- 24775804 TI - Quality indicators for non-small cell lung cancer operations with use of a modified Delphi consensus process. AB - BACKGROUND: The aim of this project was to develop a set of quality indicators to assess surgical decision making in the care of patients with non-small cell lung cancer (NSCLC). METHODS: A multidisciplinary Expert Panel of 16 physicians used a modified Delphi process to identify quality indicators that evaluated the processes of care in patients with NSCLC. A systematic review identified potential indicators, which were rated on actionability, validity, usefulness, discriminability, and feasibility in two rounds of questionnaires. The first questionnaire was completed by the Expert Panel and by the larger thoracic surgical community of practice; the second questionnaire was sent to only the Expert Panel. Expert Panel members attended an in-person meeting to review the results of the two questionnaires and to compile the final list of indicators by consensus. RESULTS: From the literature review, 41 potential indicators were identified. An additional 16 indicators were suggested by the Expert Panel: 13 indicators in the two rounds of questionnaires and three after the discussion at the in-person meeting. One further indicator was identified after the in-person meeting. In the end, 17 indicators were chosen from seven domains: preoperative assessment, staging, surgical procedures, pathology, adjuvant therapy, surgical outcomes, and miscellaneous CONCLUSIONS: By use of a modified Delphi process, 17 indicators to assess the quality of processes of surgical care for patients with NSCLC were developed. PMID- 24775805 TI - Composite outcomes in coronary bypass surgery versus percutaneous intervention. AB - BACKGROUND: Recent observational studies show that patients with multivessel coronary disease have a long-term survival advantage with coronary artery bypass grafting (CABG) compared with percutaneous coronary intervention (PCI). Important nonfatal outcomes may also affect optimal treatment recommendation. METHODS: CABG was compared with percutaneous catheter intervention by using a composite of death, myocardial infarction (MI), or stroke. Medicare patients undergoing revascularization for stable multivessel coronary disease from 2004 through 2008 were identified in national registries. Short-term clinical information from the registries was linked to Medicare data to obtain long-term follow-up out to 4 years from the time of the procedure. Propensity scoring with inverse probability weighting was used to adjust for baseline risk factors. RESULTS: There were 86,244 CABG and 103,549 PCI patients. The mean age was 74 years, with a median 2.67 years of follow-up. At 4 years, the propensity-adjusted adjusted cumulative incidence of MI was 3.2% in CABG compared with 6.6% in PCI (risk ratio, 0.49; 95% confidence interval, 0.45 to 0.53). At 4 years, the cumulative incidence of stroke was 4.5% in CABG compared with 3.1% in PCI patients (risk ratio, 1.43; 95% confidence interval, 1.31 to 1.54). This difference was primarily due to the higher 30-day stroke rate for CABG (1.55% vs 0.37%). For the composite of death, MI, or stroke, the 4-year adjusted cumulative incidence was 21.6% for CABG and 26.7% for PCI (risk ratio, 0.81; 95% confidence interval, 0.78 to 0.83). CONCLUSIONS: The 4-year composite event rate of death, MI, and stroke favored CABG, whereas the risk of stroke alone favored PCI. PMID- 24775806 TI - CHEM-PATH-TRACKER: An automated tool to analyze chemical motifs in molecular structures. AB - In this article, we propose a method for locating functionally relevant chemical motifs in protein structures. The chemical motifs can be a small group of residues or structure protein fragments with highly conserved properties that have important biological functions. However, the detection of chemical motifs is rather difficult because they often consist of a set of amino acid residues separated by long, variable regions, and they only come together to form a functional group when the protein is folded into its three-dimensional structure. Furthermore, the assemblage of these residues is often dependent on non-covalent interactions among the constituent amino acids that are difficult to detect or visualize. To simplify the analysis of these chemical motifs and give access to a generalized use for all users, we developed chem-path-tracker. This software is a VMD plug-in that allows the user to highlight and reveal potential chemical motifs requiring only a few selections. The analysis is based on atoms/residues pair distances applying a modified version of Dijkstra's algorithm, and it makes possible to monitor the distances of a large pathway, even during a molecular dynamics simulation. This tool turned out to be very useful, fast, and user friendly in the performed tests. The chem-path-tracker package is distributed as an independent platform and can be found at http://www.fc.up.pt/PortoBioComp/database/doku.php?id=chem-path-tracker. PMID- 24775807 TI - The effectiveness of shoe insoles for the prevention and treatment of low back pain: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: Low back pain (LBP) is a significant public health problem in Western industrialised countries and has been reported to affect up to 80% of adults at some stage in their lives. It is associated with high health care utilisation costs, disability, work loss and restriction of social activities. An intervention of foot orthoses or insoles has been suggested to reduce the risk of developing LBP and be an effective treatment strategy for people suffering from LBP. However, despite the common usage of orthoses and insoles, there is a lack of clear guidelines for their use in relation to LBP. The aim of this review is to investigate the effectiveness of foot orthoses and insoles in the prevention and treatment of non specific LBP. METHODS: A systematic search of MEDLINE, CINAHL, EMBASE and The Cochrane Library was conducted in May 2013. Two authors independently reviewed and selected relevant randomised controlled trials. Quality was evaluated using the Cochrane Collaboration Risk of Bias Tool and the Downs and Black Checklist. Meta-analysis of study data were conducted where possible. RESULTS: Eleven trials were included: five trials investigated the treatment of LBP (n=293) and six trials examined the prevention of LBP (n=2379) through the use of foot orthoses or insoles. Meta-analysis showed no significant effect in favour of the foot orthoses or insoles for either the treatment trials (standardised mean difference (SMD) -0.74, CI 95%: -1.5 to 0.03) or the prevention trials (relative risk (RR) 0.78, CI 95%: 0.50 to 1.23). CONCLUSIONS: There is insufficient evidence to support the use of insoles or foot orthoses as either a treatment for LBP or in the prevention of LBP. The small number, moderate methodological quality and the high heterogeneity of the available trials reduce the strength of current findings. Future research should concentrate on identification of LBP patients most suited to foot orthoses or insole treatment, as there is some evidence that trials structured along these lines have a greater effect on reducing LBP. PMID- 24775808 TI - Removal of emerging micropollutants from water using cyclodextrin. AB - Small scale laboratory experiment series were performed to study the suitability of a cyclodextrin-based sorbent (beta-cyclodextrin bead polymer, BCDP) for modelling the removal of micropollutants from drinking water and purified waste water using simulated inflow test solutions containing target analytes (ibuprofen, naproxen, ketoprofen, bisphenol-A, diclofenac, beta-estradiol, ethinylestradiol, estriol, cholesterol at 2-6 MUg/L level). This work was focused on the preliminary evaluation of BCDP as a sorbent in two different model systems (filtration and fluidization) applied for risk reduction of emerging micropollutants. For comparison different filter systems combined with various sorbents (commercial filter and activated carbon) were applied and evaluated in the filtration experiment series. The spiked test solution (inflow) and the treated outflows were characterized by an integrated methodology including chemical analytical methods gas chromatography-tandem mass spectrometry (GC MS/MS) and various environmental toxicity tests to determine the efficiency and selectivity of the applied sorbents. Under experimental conditions the cyclodextrin-based filters used for purification of drinking water in most cases were able to absorb more than 90% of the bisphenol-A and of the estrogenic compounds. Both the analytical chemistry and toxicity results showed efficient elimination of these pollutants. Especially the toxicity of the filtrate decreased considerably. Laboratory experiment modelling post-purification of waste water was also performed applying fluidization technology by beta cyclodextrin bead polymer. The BCDP removed efficiently from the spiked test solution most of the micropollutants, especially the bisphenol-A (94%) and the hormones (87-99%) The results confirmed that the BCDP-containing sorbents provide a good solution to water quality problems and they are able to decrease the load and risk posed by micropollutants to the water systems. PMID- 24775809 TI - The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy. AB - It is well known that the activation of Aurora A/B (Aur A/B) or inactivation of BRCA1/2 induces tumor formation. Others and we have reported that the mutual suppression between Aur A/B and BRCA1/2 may manipulate cancer cell growth and tumorigenesis, however, the interactive regulation and mechanism between these molecules are still elusive. In this study, by consecutive silencing of Aur A/B or/and BRCA1/2 with specific shRNAs, we showed that, in BRCA2-deficient pancreatic cancer cell line Capan-1 and in ovarian cancer cell line OVCA433, Aur A/B and BRCA1/2 inversely regulated the expression of each other likely through proteasome-mediated proteolysis but not through gene transcription. Aur A/B and BRCA1/2 conversely regulated cell cycle progression mainly through control of p53 and cyclin A. Moreover, the disruption of Aur A/B blocked abnormal cytokinesis and decreased cell multinuclearity and chromosome tetraploidy, whereas the deprivation of BRCA1/2 promoted the abnormal cytokinesis and enhanced the cell multinuclearity and tetraploidy. Furthermore, we showed by animal assays that the depletion of Aur A/B inhibited tumor growth of both cell lines, while the knockdown of BRCA1/2 promoted the tumor growth. However, the concurrent silencing of Aur A/B and BRCA1/2 diminished the effects of these molecules on the regulation of cell cycle, cytokinesis, and tetraploidy, leading to the burdened tumor sizes similar to those induced by scrambled shRNA-treated control cells. In summary, our study revealed that the negative interplay between Aur A/B and BRCA1/2 inversely controls the cell proliferation, cell cycle progression, cell multinuclearity, and tetraploidization to modulate tumorigenesis. PMID- 24775810 TI - A loop-mediated isothermal amplification assay for the visual detection of duck circovirus. AB - BACKGROUND: Duck circovirus (DuCV) infection in farmed ducks is associated with growth problems or retardation syndromes. Rapid identification of DuCV infected ducks is essential to control DuCV effectively. Therefore, this study aims to develop of an assay for DuCV to be highly specific, sensitive, and simple without any specialized equipment. METHODS: A set of six specific primers was designed to target the sequences of the Rep gene of DuCV, and A loop-mediated isothermal amplification (LAMP) assay were developed and the reaction conditions were optimized for rapid detection of DuCV. RESULTS: The LAMP assay reaction was conducted in a 62 degrees C water bath condition for 50 min. Then the amplification products were visualized directly for color changes. This LAMP assay is highly sensitive and able to detect twenty copies of DuCV DNA. The specificity of this LAMP assay was supported by no cross-reaction with other duck pathogens. CONCLUSION: This LAMP method for DuCV is highly specific and sensitive and can be used as a rapid and direct diagnostic assay for testing clinical samples. PMID- 24775811 TI - Role of testis sparing surgery in the conservative management of small testicular masses: oncological and functional perspectives. AB - INTRODUCTION: Radical orchiectomy (RO) is still considered the standard of care for malignant germ cell tumours, which represent the vast majority of the palpable testicular masses. In those patients diagnosed with small testicular masses (STMs), testis-sparing surgery (TSS) could be an alternative treatment to RO. The aim of this updated review is to evaluate the current indications for TSS, and discuss the oncological and functional results of patients who had undergone organ-sparing surgery for STMs. EVIDENCE ACQUISITION: A non-systematic review of the Literature using the Medline database has been performed, including a free-text protocol using the terms "testis-sparing surgery", "testicular sparing surgery", "partial orchiectomy", "testis tumour", "sex cord tumour", and "testis function". Other significant studies cited in the reference lists of the selected papers were also evaluated. EVIDENCE SYNTHESIS: No randomized controlled trials comparing TSS with radical orchiectomy have been reported yet. In those patients with normal contra-lateral testis, the use of TSS is still controversial. In selected cases of gonadal masses < 2 cm, TSS seems to be a safe and feasible treatment option. Frozen section examination allows us to discriminate between benign and malignant neoplasms during TSS. Intermediate and long-term follow-up results showed no significant risk of local and distant recurrences in the main series reported in the literature. CONCLUSIONS: TSS is an effective treatment for STMs in selected patients, limiting the unnecessary surgical over-treatments, without compromising the oncological and functional outcomes. Further studies are needed in order to confirm the oncological safety. PMID- 24775812 TI - Efficacy and safety of fosfomycin-trometamol in the prophylaxis for transrectal prostate biopsy. Prospective randomized comparison with ciprofloxacin. AB - OBJECTIVE: Prostate biopsy is the standardized diagnostic method for prostate cancer. However, although there is not a standardized protocol, there are recommendations in order to reduce the incidence of complications. The objective of the present work is to assess the efficacy and safety of antibiotic prophylaxis in the prostate biopsy by comparing two antibiotic regimes: two doses of fosfomycin-trometamol 3g (FMT) every 48 hours with 10 doses of oral ciprofloxacin 500 mg every 12 hours during 5 days. MATERIAL AND METHODS: Randomized prospective study was performed with 671 patients who had undergone to walking transrectal ultrasound guided prostate biopsy. Patients of group A (n=312) were treated with ciprofloxacin, and patients of group B (n=359) with FMT. Efficacy and tolerability of two prophylactic regimes were compared. Urine culture was carried out at 2 weeks after biopsy. Initially, patients with asymptomatic bacteriuria were not treated with antibiotics; urine culture was repeated after 1 month, persistent bacteriuria was treated according to antibiogram. RESULTS: No differences between groups were found in age (P=.78), cancer presence (P=.9) or number of biopsy cylinders (P=.93). The mean number of cores obtained was 11.3 +/- 3.25 (range 6-20). Digestive intolerance was observed for 9 patients (2.9%) of group A and 10 patients (2.8%) in group B. One patient (.3%) of group A showed severe allergic reaction. In total, 167 patients (24.6%) had complications: 16 (2.4%) fever, 47 (6.9%) hemospermia, 81 (11.9%) hematuria, 7 (1%) rectal bleeding and 16 (2.4%) urinary retention. No statistically differences between groups were observed (27.6% vs. 22.6%; P=.17). However, hemospermia was more frequent in group A (9.9% vs. 4.5%; P=.006). Bacteriuria after biopsy was detected in 44 patients (6.6%), being more frequent in group B patients (4.2% vs. 8.6%; P=.02) although a higher number of second treatment cycles were not needed (53.9% vs. 29%; P=.17). The likelihood of resistance to ciprofloxacin in patients with bacteriuria in A was greater than that of FMT in B (69.2% vs. 41.9%; P=.0004). CONCLUSIONS: Antibiotic prophylaxis with FMT (2 doses of 3g) in prostate biopsy is an alternative as effective and safe as ciprofloxacin (10 doses of 500 mg), which carries lower rate of resistance. According to our experience, this drug is a safe, well-tolerated, and easily manageable prophylactic option, facilitating patient compliance. More prospective multicenter studies are necessary to confirm these findings. PMID- 24775813 TI - Right and left ventricular diastolic flow field: why are measured intraventricular pressure gradients small? PMID- 24775814 TI - Minimizing risk in the cardiac catheterization laboratory. PMID- 24775815 TI - Therapeutic hypothermia in cardiac arrest. PMID- 24775816 TI - LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. AB - INTRODUCTION AND OBJECTIVES: LEOPARD syndrome is an autosomal dominant condition related to Noonan syndrome, although it occurs less frequently. The aim of this study was to characterize the clinical and molecular features of a large series of LEOPARD syndrome patients. METHODS: We collected clinical data from 19 patients in 10 hospitals. Bidirectional sequencing analysis of PTPN11, RAF1, and BRAF focused on exons carrying recurrent mutations. RESULTS: After facial dysmorphism, structural heart defects (88%) were the most common feature described. Hypertrophic cardiomyopathy (71%) was diagnosed more often than pulmonary valve stenosis (35%). Multiple lentigines or cafe au lait spots were found in 84% of the series, and deafness was diagnosed in 3 patients. Mutations in PTPN11 were identified in 16 (84%) patients (10 patients had the recurrent LEOPARD syndrome mutation, p.Thr468Met) (NP_002825.3T468M). Two other patients had a mutation in RAF, and 1 patient had a mutation in BRAF. When compared with other neurocardiofaciocutaneous syndromes, LEOPARD syndrome patients showed a higher prevalence of hypertrophic cardiomyopathy and cutaneous abnormalities, and a lower prevalence of pulmonary valve stenosis and short stature. CONCLUSIONS: LEOPARD syndrome patients display distinctive features apart from multiple lentigines, such as a higher prevalence of hypertrophic cardiomyopathy and lower prevalence of short stature. Given its clinical implications, active search for hypertrophic cardiomyopathy is warranted in Noonan syndrome spectrum patients, especially in LEOPARD syndrome patients. PMID- 24775817 TI - Percutaneous balloon pericardiotomy as the initial and definitive treatment for malignant pericardial effusion. AB - INTRODUCTION AND OBJECTIVES: Malignant pericardial effusion has a high recurrence rate after pericardiocentesis. We sought to confirm the efficacy of percutaneous balloon pericardiotomy as the initial treatment of choice for these effusions. METHODS: Retrospective analysis of the clinical, echocardiographic, and follow-up characteristics of a consecutive series of percutaneous balloon pericardiotomies carried out in a single center in patients with advanced cancer. RESULTS: Seventeen percutaneous balloon pericardiotomies were performed in 16 patients with a mean age of 66.2 (15.2) years. Fourteen patients had pathologically confirmed metastatic neoplastic disease, 3 had previously required pericardiocentesis, and in the remaining patients percutaneous balloon pericardiotomy was the first treatment for the effusion. All patients had a severe circumferential effusion, and most presented evidence of hemodynamic compromise on echocardiography. In all cases, the procedure was successful, there were no acute complications, and it was well tolerated at the first attempt. There were no infectious complications during follow-up (median, 44 [interquartile range, 36-225] days). One patient developed a large pleural effusion that did not require treatment. Three patients needed a new pericardial procedure: 2 had elective pericardial window surgeries and 1 had a second percutaneous balloon pericardiotomy. CONCLUSIONS: Percutaneous balloon pericardiotomy is a simple, safe technique that can be effective in the prevention of recurrence in many patients with severe malignant pericardial effusion. The characteristics of this procedure make it particularly useful in this group of patients to avoid more aggressive, poorly tolerated approaches. PMID- 24775818 TI - Management of resistant hypertension in a multidisciplinary unit of renal denervation: protocol and results. AB - INTRODUCTION AND OBJECTIVES: Resistant hypertension is a clinical problem because of its difficult management and increased morbidity and mortality. Catheter-based renal denervation has been demonstrated to improve control in these patients. The results of establishing a multidisciplinary unit for the implementation of renal denervation in the management of resistant hypertension are described. METHODS: A team of nephrologists and cardiologists created a protocol for patient selection, intervention, and follow-up. One hundred and ninety-seven patients with poorly controlled essential hypertension, despite taking 3 or more drugs, were included. The ablation technique previously described was supported by a navigator based on rotational angiography. Blood pressure at baseline and after follow-up was compared using the Wilcoxon test for paired samples. RESULTS: One hundred and eight patients (55%) with pseudo-resistant hypertension were excluded. The other 89 were given antialdosteronic drugs, to which 60 patients (30%) responded. The remaining 29 patients (15%) were candidates for denervation. Eleven patients, with blood pressure 164/99 mmHg and taking 4.4 antihypertensive drugs, were ablated. After 72 days of follow-up, systolic and diastolic blood pressure fell by 25 mmHg (P=.02) and 10 mmHg (P=.06), respectively. In 10 patients (91%) at least 1 drug was discontinued. CONCLUSIONS: Renal denervation performed by a multidisciplinary team led to an improvement in blood pressure similar to previous studies, with a greater reduction of antihypertensive drugs. PMID- 24775819 TI - Prevalence of child and youth obesity in Spain in 2012. AB - INTRODUCTION AND OBJECTIVES: Obesity is a major cardiovascular risk factor. In Spain, few studies have physically measured height and weight to estimate the magnitude of the problem. The aim of this study was to determine the prevalence of child and adolescent obesity in Spain in 2012. METHODS: We performed a cross sectional probability sample of 1018 children, representative of the Spanish population aged between 8 and 17 years old, with objectively measured height and weight, along with other sociodemographic variables. We calculated the prevalence of overweight and obesity according to the criteria of the World Health Organization, the International Obesity Task Force, and the enKid study. RESULTS: In the group aged 8 to 17 years old, the prevalence of overweight and obesity was 26% and 12.6%, respectively; 4 in 10 young people were overweight or obese. Excess weight was found in 45% of the group aged 8 to 13 years and in 25.5% of that aged 14 to 17 years. This cardiovascular risk factor was associated with lower social class and lower educational level. CONCLUSIONS: The prevalence of overweight and obesity in children and adolescents in Spain remains high (close to 40%), but has not increased in the last 12 years. PMID- 24775820 TI - Loss of continuous biventricular pacing in cardiac resynchronization therapy patients: incidence, causes, and outcomes. AB - INTRODUCTION AND OBJECTIVES: In recent years, implantation of cardiac resynchronization therapy devices has significantly increased. The benefits of this therapy are directly related to the maintenance of continuous biventricular pacing. This study analyzed the incidence, causes, and outcomes of loss of continuous biventricular pacing, and the approach adopted. METHODS: We analyzed the clinical and follow-up data of a series of consecutive patients from a single center who underwent implantation of a cardiac resynchronization therapy device. RESULTS: The study included 136 patients. During a mean follow-up of 33.4 months, loss of continuous biventricular pacing occurred in 45 patients (33%). The most common causes included atrial tachyarrhythmias (21.3%), lead macrodislodgement (18%), and loss of left ventricular capture (13.1%). In most patients (88.5%), loss of continuous biventricular pacing was transient and correctable, and occurred earlier in the follow-up when the cause was lead macrodislodgement, oversensing, or extracardiac stimulation. There were no significant differences in mortality between patients with and without loss of continuous biventricular pacing (P=.88). CONCLUSIONS: Despite technical advances in cardiac resynchronization therapy, loss of continuous biventricular pacing is common; however, this loss can usually be corrected. In most patients, continuous biventricular pacing can be ensured by close monitoring and follow-up and a proactive approach. PMID- 24775821 TI - Clinical significance of congestive heart failure in prosthetic valve endocarditis. A multicenter study with 257 patients. AB - INTRODUCTION AND OBJECTIVES: There have been no studies conducted in the past that focus on the significance of congestive heart failure in patients with prosthetic valve endocarditis. We studied the incidence of congestive heart failure in patients with prosthetic valve endocarditis and analyzed its profile. In this study, we addressed the prognostic significance of heart failure in patients with prosthetic valve endocarditis and analyzed its outcome based on chosen therapeutic strategies. METHODS: A total of 639 episodes of definite left sided endocarditis were prospectively enrolled. Of them, 257 were prosthetic. Of the 257 episodes, 145 (56%) were diagnosed with heart failure. We compared the profiles of patients with prosthetic valve endocarditis based on the presence of heart failure, and performed a multivariate logistic regression model to establish the prognostic significance of heart failure in patients with prosthetic valve endocarditis and identified the prognostic factors of in hospital mortality in these patients. RESULTS: Persistent infection (odds ratio=3.6; 95% confidence interval, 1.9-6.9) and heart failure (odds ratio=3; 95% confidence interval, 1.5-5.8) are the strongest predictive factors of in-hospital mortality in patients with prosthetic valve endocarditis. The short-term determinants of prognosis in patients with prosthetic valve endocarditis and heart failure are persistent infection (odds ratio=2.8; 95% confidence interval, 1.2-6.5), aortic involvement (odds ratio=2.5; 95% confidence interval, 1.1-5.8), abscess (odds ratio=3.6; 95% confidence interval, 1.4-9.5), diabetes mellitus (odds ratio=2.9; 95% confidence interval, 1.1-7.7), and cardiac surgery (odds ratio=0.2; 95% confidence interval, 0.1-0.5). CONCLUSIONS: The incidence of heart failure in patients with prosthetic valve endocarditis is very high. Heart failure increases the risk of in-hospital mortality by threefold in patients with prosthetic valve endocarditis. Persistent infection, aortic involvement, abscess, and diabetes mellitus are the independent risk factors associated with mortality in patients with prosthetic valve endocarditis and heart failure; however, cardiac surgery is shown to decrease mortality in these patients. PMID- 24775822 TI - Update: Innovation in cardiology (IV). Cardiac tissue engineering and the bioartificial heart. AB - Heart failure is the end-stage of many cardiovascular diseases-such as acute myocardial infarction-and remains one of the most appealing challenges for regenerative medicine because of its high incidence and prevalence. Over the last 20 years, cardiomyoplasty, based on the isolated administration of cells with regenerative capacity, has been the focal point of most studies aimed at regenerating the heart. Although this therapy has proved feasible in the clinical setting, the degree of infarcted myocardium regenerated and of improved cardiac function are at best modest. Hence, tissue engineering has emerged as a novel technology using cells with regenerative capacity, biological and/or synthetic materials, growth, proangiogenic and differentiation factors, and online registry systems, to induce the regeneration of whole organs or locally damaged tissue. The next step, seen recently in pioneering animal studies, is de novo generation of bioartificial hearts by decellularization and preservation of supporting structures for their subsequent repopulation with new contractile, vascular muscle tissue. Ultimately, this new approach would entail transplantation of the "rebuilt" heart, reestablishing cardiac function in the recipient. PMID- 24775823 TI - Vibration and staccato flow pattern in ventricular assist devices. PMID- 24775824 TI - Multidetector computed tomography diagnosis of quadricuspid pulmonary valve. PMID- 24775825 TI - Cardiac involvement in tuberous sclerosis. PMID- 24775826 TI - Neoatherosclerosis as the cause of very late bare-metal stent restenosis: optical coherence tomography evaluation. PMID- 24775827 TI - Myocardial infarction in South Asian immigrants in Catalonia. Results from the ASIAM Study. PMID- 24775828 TI - Constrictive infectious pericarditis caused by Propionibacterium acnes. PMID- 24775829 TI - CoreValve(r) aortic bioprosthesis implantation in a patient with situs inversus totalis with dextrocardia. PMID- 24775830 TI - Valvular heart disease in hyperprolactinemic patients treated with low doses of cabergoline. PMID- 24775831 TI - Diabetes mellitus and risks of dual blockade of the renin-angiotensin-aldosterone system. PMID- 24775832 TI - Prevention of infective endocarditis from the dentist's perspective. PMID- 24775833 TI - Prevention of infective endocarditis from the dentist's perspective. Response. PMID- 24775908 TI - Design and estimation for the national health interview survey, 2006-2015. AB - OBJECTIVES: This report presents an overview, a detailed description of the sample design features, and estimation structures for the 2006-2015 National Health Interview Survey NHIS). It fulfills the same role for the current 2006 2015 NHIS design as NCHS Series 2, No. 130, "Design and Estimation for the National Health Interview Survey, 1995-2004" provided for the previous design, which was extended through 2005. METHODS: The 2006-2015 NHIS sample design uses cost-effective complex sampling techniques including stratification, clustering, and differential sampling rates to achieve several objectives, among them improved reliability of racial, ethnic, and geographical domains. This report describes these methods. RESULTS: This report presents operating characteristics of NHIS 2006-2015. The general sampling structure is presented, along with a discussion of weighting and variance estimation techniques. This report is intended for general users of NHIS data systems. PMID- 24775865 TI - Perturbation of specific pro-mineralizing signalling pathways in human and murine pseudoxanthoma elasticum. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) is characterized by skin (papular lesions), ocular (subretinal neovascularisation) and cardiovascular manifestations (peripheral artery disease), due to mineralization and fragmentation of elastic fibres in the extracellular matrix (ECM). Caused by mutations in the ABCC6 gene, the mechanisms underlying this disease remain unknown. The knowledge on the molecular background of soft tissue mineralization largely comes from insights in vascular calcification, with involvement of the osteoinductive Transforming Growth Factor beta (TGFbeta) family (TGFbeta1-3 and Bone Morphogenetic Proteins [BMP]), together with ectonucleotides (ENPP1), Wnt signalling and a variety of local and systemic calcification inhibitors. In this study, we have investigated the relevance of the signalling pathways described in vascular soft tissue mineralization in the PXE knock-out mouse model and in PXE patients. METHODS: The role of the pro-osteogenic pathways BMP2-SMADs-RUNX2, TGFbeta-SMAD2/3 and Wnt-MSX2, apoptosis and ER stress was evaluated using immunohistochemistry, mRNA expression profiling and immune-co-staining in dermal tissues and fibroblast cultures of PXE patients and the eyes and whiskers of the PXE knock-out mouse. Apoptosis was further evaluated by TUNEL staining and siRNA mediated gene knockdown. ALPL activity in PXE fibroblasts was studied using ALPL stains. RESULTS: We demonstrate the upregulation of the BMP2-SMADs-RUNX2 and TGFbeta-2-SMAD2/3 pathway, co-localizing with the mineralization sites, and the involvement of MSX2-canonical Wnt signalling. Further, we show that apoptosis is also involved in PXE with activation of Caspases and BCL-2. In contrast to vascular calcification, neither the other BMPs and TGFbetas nor endoplasmic reticulum stress pathways seem to be perturbed in PXE. CONCLUSIONS: Our study shows that we cannot simply extrapolate knowledge on cell signalling in vascular soft tissue calcification to a multisystem ectopic mineralisation disease as PXE. Contrary, we demonstrate a specific set of perturbed signalling pathways in PXE patients and the knock-out mouse model. Based on our findings and previously reported data, we propose a preliminary cell model of ECM calcification in PXE. PMID- 24775909 TI - Associations between speech features and phenotypic severity in Treacher Collins syndrome. AB - BACKGROUND: Treacher Collins syndrome (TCS, OMIM 154500) is a rare congenital disorder of craniofacial development. Characteristic hypoplastic malformations of the ears, zygomatic arch, mandible and pharynx have been described in detail. However, reports on the impact of these malformations on speech are few. Exploring speech features and investigating if speech function is related to phenotypic severity are essential for optimizing follow-up and treatment. METHODS: Articulation, nasal resonance, voice and intelligibility were examined in 19 individuals (5-74 years, median 34 years) divided into three groups comprising children 5-10 years (n = 4), adolescents 11-18 years (n = 4) and adults 29 years and older (n = 11). A speech composite score (0-6) was calculated to reflect the variability of speech deviations. TCS severity scores of phenotypic expression and total scores of Nordic Orofacial Test-Screening (NOT-S) measuring orofacial dysfunction were used in analyses of correlation with speech characteristics (speech composite scores). RESULTS: Children and adolescents presented with significantly higher speech composite scores (median 4, range 1-6) than adults (median 1, range 0-5). Nearly all children and adolescents (6/8) displayed speech deviations of articulation, nasal resonance and voice, while only three adults were identified with multiple speech aberrations. The variability of speech dysfunction in TCS was exhibited by individual combinations of speech deviations in 13/19 participants. The speech composite scores correlated with TCS severity scores and NOT-S total scores. Speech composite scores higher than 4 were associated with cleft palate. The percent of intelligible words in connected speech was significantly lower in children and adolescents (median 77%, range 31-99) than in adults (98%, range 93-100). Intelligibility of speech among the children was markedly inconsistent and clearly affecting the understandability. CONCLUSIONS: Multiple speech deviations were identified in children, adolescents and a subgroup of adults with TCS. Only children displayed markedly reduced intelligibility. Speech was significantly correlated with phenotypic severity of TCS and orofacial dysfunction. Follow-up and treatment of speech should still be focused on young patients, but some adults with TCS seem to require continuing speech and language pathology services. PMID- 24775910 TI - The radiologist's workflow environment: evaluation of disruptors and potential implications. AB - Workflow interruptions in the health care delivery environment are a major contributor to medical errors and have been extensively studied within numerous hospital settings, including the nursing environment and the operating room, along with their effects on physician workflow. Less understood, though, is the role of interruptions in other highly specialized clinical domains and subspecialty services, such as diagnostic radiology. The workflow of the on-call radiologist, in particular, is especially susceptible to disruption by telephone calls and other modes of physician-to-physician communication. Herein, the authors describe their initial efforts to quantify the degree of interruption experienced by on-call radiologists and examine its potential implications in patient safety and overall clinical care. PMID- 24775911 TI - Predictive diagnostic value for the clinical features accompanying intellectual disability in children with pathogenic copy number variations: a multivariate analysis. AB - BACKGROUND: Array comparative genomic hybridization (a-CGH) has become the first tier investigation in patients with unexplained developmental delay/intellectual disability (DD/ID). Although the costs are progressively decreasing, a-CGH is still an expensive and labour-intensive technique: for this reason a definition of the categories of patients that can benefit the most of the analysis is needed. Aim of the study was to retrospectively analyze the clinical features of children with DD/ID attending the outpatient clinic of the Mother & Child Department of the University Hospital of Modena subjected to a-CGH, to verify by uni- and multivariate analysis the independent predictors of pathogenic CNVs. METHODS: 116 patients were included in the study. Data relative to the CNVs and to the patients' clinical features were analyzed for genotype/phenotype correlations. RESULTS AND CONCLUSIONS: 27 patients (23.3%) presented pathogenic CNVs (21 deletions, 3 duplications and 3 cases with both duplications and deletions). Univariate analysis showed a significant association of the pathogenic CNVs with the early onset of symptoms (before 1 yr of age) and the presence of malformations and dysmorphisms. Logistic regression analysis showed a significant independent predictive value for diagnosing a pathogenic CNV for malformations (P = 0.002) and dysmorphisms (P = 0.023), suggesting that those features should address a-CGH analysis as a high-priority test for diagnosis. PMID- 24775912 TI - SUMOylation of Grb2 enhances the ERK activity by increasing its binding with Sos1. AB - BACKGROUND: Grb2 (Growth factor receptor-bound protein 2) is a key adaptor protein in maintaining the ERK activity via linking Sos1 (Son of sevenless homolog 1) or other proteins to activated RTKs, such as EGFR. Currently, little knowledge is available concerning the post-translational modification (PTM) of Grb2 except for its phosphorylation. Since emerging evidences have highlighted the importance of SUMOylation (Small ubiquitin-related modifier), a reversible PTM, in modulating protein functions, we wondered if Grb2 could be SUMOylated and thereby influences its functions especially involved in the Ras/MEK/ERK pathway. METHODS: SUMOylation of Grb2 was analyzed with the in vivo SUMOylation assay using the Ni2+-NTA affinity pulldown and the in vitro E.coli-based SUMOylation assay. To test the ERK activity and cell transformation, the murine fibroblast cell line NIH/3T3 and the murine colon cancer cell line CMT-93 were used for the experiments including Grb2 knockdown, ectopic re-expression, cell transformation and migration. Immunoprecipitation (IP) was employed for seeking proteins that interact with SUMO modified Grb2. Xenograft tumor model in mice was conducted to verify that Grb2 SUMOylation regulated tumorigenesis in vivo. RESULTS: Grb2 can be SUMOylated by SUMO1 at lysine 56 (K56), which is located in the linker region between the N-terminal SH3 domain and the SH2 domain. Knockdown of Grb2 reduced the ERK activity and suppressed cell motility and tumorigenesis in vitro and in vivo, which were all rescued by stable ectopic re-expression of wild-type Grb2 but not the mutant Grb2K56R. Furthermore, Grb2 SUMOylation at K56 increased the formation of Grb2-Sos1 complex, which sequentially leads to the activation of Ras/MEK/MAPK pathway. CONCLUSIONS: Our results provide evidences that Grb2 is SUMOylated in vivo and this modification enhances ERK activities via increasing the formation of Grb2-Sos1 complex, and may consequently promote cell motility, transformation and tumorigenesis. PMID- 24775913 TI - Hematuria duration does not predict kidney function at 1 year in ANCA-associated glomerulonephritis. AB - OBJECTIVES: Hematuria is considered a marker of active renal disease in ANCA associated glomerulonephritis (ANCA-GN) with induction immunosuppression often continued until hematuria has resolved. We aim to determine whether longer hematuria duration is associated with lower estimated glomerular filtration rate (eGFR) at 1 year. METHODS: We conducted a retrospective study of 55 patients with biopsy-proven ANCA-GN. Linear regression models were constructed to determine predictors of eGFR at 1 year. The primary exposure was hematuria (>5 rbc/hpf) duration, defined as <90 days vs. >= 90 days following renal biopsy. Covariates included age, gender, ANCA type, baseline eGFR, and baseline proteinuria. RESULTS: Mean age at diagnosis was 58 years (53% male, 80% Caucasian, 38% PR3 ANCA, and 45% MPO-ANCA). At baseline, all patients had hematuria, 95% had proteinuria, and mean serum creatinine was 3.1 [standard deviation (SD) = 2.3]mg/dL. Overall, 93% were treated with steroids in combination with either cyclophosphamide or rituximab. Mean hematuria duration was 92 (SD = 77) days with 34 (62%) patients having hematuria resolution within 90 days. Older age and lower baseline eGFR were associated with lower eGFR at 1 year (p = 0.03 and p < 0.001, respectively). Hematuria resolution (<90 days vs. >= 90 days) was not predictive of eGFR at 1 year (p = 0.93). CONCLUSIONS: In ANCA-GN, hematuria duration does not predict eGFR at 1 year. Our findings provide support that among individuals who are otherwise considered to be in clinical remission, the persistence of hematuria should not delay transition from induction to maintenance immunosuppression. PMID- 24775914 TI - A rational design strategy of the novel topoisomerase II inhibitors for the synthesis of the 4-O-(2-pyrazinecarboxylic)-4'-demethylepipodophyllotoxin with antitumor activity by diminishing the relaxation reaction of topoisomerase II-DNA decatenation. AB - A rational design strategy of the novel podophyllum topoisomerase II (Topo II) inhibitors for the synthesis of the esterification and amidation substituted 4' demethylepipodophyllotoxin (DMEP) derivates was developed in order to discover the potential antitumor prodrug. Firstly, according to the structure-activity relationship, drug combination principle and bioisosterism, the -COO- and the -NH bond substituents at the 4 position of cycloparaffin would be a great modification direction to improve antitumor activity of 4' demethylepipodophyllotoxin (DMEP). Secondly, from the prodrug principle view, the esterification and amidation at the C-4 position of DMEP would be two useful structure modifications for improve solubility. Thirdly, from the activity pocket in Topo II-DNA cleavage complex point of view, a series of heterocyclic with pharmacological activity were chosen as module for improving antitumor activity by binding with Topo II. Finally, nine novel esterification and amidation DMEP derivates were designed and synthesized for the potential Topo II inhibitors with the superior biological activity. All the novel compounds exhibited promising in vitro antitumor activity, especially 4-O-(2-pyrazinecarboxylic)-4' demethylepipodophyllotoxin (compound 1). The antitumor activity of compound 1 against tumor cell line HeLa (i.e., the IC50 value of 0.60 +/- 0.20 MUM), A549 (i.e., the IC50 value of 3.83 +/- 0.08 MUM), HepG2 (i.e., the IC50 value of 1.21 +/- 0.05 MUM), and BGC-823 (i.e., the IC50 value of 4.15 +/- 1.13 MUM) was significantly improved by 66, 16, 12, and 6 times than that of the clinically important podophyllum anticancer drug etoposide (i.e., the IC50 values of 15.32 +/- 0.10, 59.38 +/- 0.77, 67.25 +/- 7.05, and 30.74 +/- 5.13 MUM), respectively. Compound 1 could arrest HeLa cell cycle G2/M and induce apoptosis by strongly diminishing the relaxation reaction of Topo II-DNA decatenation. The correctness of rational drug design was strictly demonstrated by the bioactivity test. PMID- 24775915 TI - Bis(4-hydroxy-2H-chromen-2-one): synthesis and effects on leukemic cell lines proliferation and NF-kappaB regulation. AB - Synthesis of the bis-4-hydroxycoumarin-type compound, 3,3'-[3-(2-hydroxyphenyl)-3 oxopropane-1,1-diyl]bis(4-hydroxy-2H-chromen-2-one), was performed by two alternative pathways, either involving a basic organocatalyzed 1,4-conjugate addition tandem reaction of 4-hydroxycoumarin on chromone-3-carboxylic acid, or a double condensation of 4-hydroxycoumarin on omega-formyl-2'-hydroxyacetophenone. The anti-proliferative effects of the bis-4-hydroxycoumarin-type compound on human K-562 (chronic myeloid leukaemia) and JURKAT (acute T-cell leukaemia) cell lines using trypan blue staining, as well as its involvement in nuclear factor kappa B (NF-kappaB) regulation analyzed by luciferase reporter gene assay, gene expression analysis and western blots were analysed. This compound inhibited TNFalpha-induced NF-kappaB activation in K-562 (IC50 17.5 MUM) and JURKAT (IC50 19.0 MUM) cell lines, after 8h of incubation. Interestingly, it exerted mainly cytostatic effects at low doses on both cell lines tested, whereas it decreased JURKAT cell viability starting at 50 MUM from 24h of treatment. Importantly, it did not affect the viability of peripheral blood mononuclear cells (PBMCs) from healthy donors, even at concentrations above 100 MUM. PMID- 24775916 TI - From norbornane-based nucleotide analogs locked in South conformation to novel inhibitors of feline herpes virus. AB - A synthetic route toward a series of unique cyclic nucleoside phosphonates locked in South conformation is described. The desired conformation is stabilized by a substitution of the sugar moiety by bicyclo[2.2.1]heptane (norbornane) bearing a purine or pyrimidine nucleobase in the bridgehead position. Although the final phosphonate derivatives are devoid of any significant antiviral activity probably due to the unfavorable conformational properties, several intermediates and their analogs exhibit surprising activity against feline herpes virus. Since these compounds do not possess an appropriate hydroxymethyl function allowing phosphorylation and subsequent incorporation into the polynucleotide chain, it seems to be likely that these compounds act by a novel unknown mechanism of action and may represent a new possible alternative for nucleoside and nucleotide therapeutics of this widely spread feline infection. A number of derivatives exerted also a significant antiviral activity against Coxsackievirus B3 and B4. PMID- 24775917 TI - Identification of trisubstituted-pyrazol carboxamide analogs as novel and potent antagonists of farnesoid X receptor. AB - Farnesoid X receptor (FXR, NRIH4) plays a major role in the control of cholesterol metabolism. This suggests that antagonizing the transcriptional activity of FXR is a potential means to treat cholestasis and related metabolic disorders. Here we describe the synthesis, biological evaluation, and structure activity relationship (SAR) studies of trisubstituted-pyrazol carboxamides as novel and potent FXR antagonists. One of these novel FXR antagonists, 4j has an IC50 of 7.5 nM in an FXR binding assay and 468.5 nM in a cell-based FXR antagonistic assay. Compound 4j has no detectable FXR agonistic activity or cytotoxicity. Notably, 4j is the most potent FXR antagonist identified to date; it has a promising in vitro profile and could serve as an excellent chemical tool to elucidate the biological function of FXR. PMID- 24775918 TI - Atrial fibrosis in a chronic murine model of obstructive sleep apnea: mechanisms and prevention by mesenchymal stem cells. AB - BACKGROUND: OSA increases atrial fibrillation (AF) risk and is associated with poor AF treatment outcomes. However, a causal association is not firmly established and the mechanisms involved are poorly understood. The aims of this work were to determine whether chronic obstructive sleep apnea (OSA) induces an atrial pro-arrhythmogenic substrate and to explore whether mesenchymal stem cells (MSC) are able to prevent it in a rat model of OSA. METHODS: A custom-made setup was used to mimic recurrent OSA-like airway obstructions in rats. OSA-rats (n = 16) were subjected to 15-second obstructions, 60 apneas/hour, 6 hours/day during 21 consecutive days. Sham rats (n = 14) were placed in the setup but no obstructions were applied. In a second series of rats, MSC were administered to OSA-rats and saline to Sham-rats. Myocardial collagen deposit was evaluated in Picrosirius-red stained samples. mRNA expression of genes involved in collagen turnover, inflammation and oxidative stress were quantified by real time PCR. MMP 2 protein levels were quantified by Western Blot. RESULTS: A 43% greater interstitial collagen fraction was observed in the atria, but not in the ventricles, of OSA-rats compared to Sham-rats (Sham 8.32 +/- 0.46% vs OSA 11.90 +/- 0.59%, P < 0.01). Angiotensin-I Converting Enzyme (ACE) and Interleukin 6 (IL 6) expression were significantly increased in both atria, while Matrix Metalloproteinase-2 (MMP-2) expression was decreased. MSC administration blunted OSA-induced atrial fibrosis (Sham + Saline 8.39 +/- 0.56% vs OSA + MSC 9.57 +/- 0.31%, P = 0.11), as well as changes in MMP-2 and IL-6 expression. Interleukin 1 beta (IL-1beta) plasma concentration correlated to atrial but not ventricular fibrosis. Notably, a 2.5-fold increase in IL-1beta plasma levels was observed in the OSA group, which was prevented in rats receiving MSC. CONCLUSIONS: OSA induces selective atrial fibrosis in a chronic murine model, which can be mediated in part by the systemic and local inflammation and by decreased collagen degradation. MSCs transplantation prevents atrial fibrosis, suggesting that these stem cells could counterbalance inflammation in OSA. PMID- 24775919 TI - The multiple meanings of global health governance: a call for conceptual clarity. AB - BACKGROUND: The term global health governance (GHG) is now widely used, with over one thousand works published in the scholarly literature, almost all since 2002. Amid this rapid growth there is considerable variation in how the term is defined and applied, generating confusion as to the boundaries of the subject, the perceived problems in practice, and the goals to be achieved through institutional reform. METHODOLOGY: This paper is based on the results of a separate scoping study of peer reviewed GHG research from 1990 onwards which undertook keyword searches of public health and social science databases. Additional works, notably books, book chapters and scholarly articles, not currently indexed, were identified through Web of Science citation searches. After removing duplicates, book reviews, commentaries and editorials, we reviewed the remaining 250 scholarly works in terms of how the concept of GHG is applied. More specifically, we identify what is claimed as constituting GHG, how it is problematised, the institutional features of GHG, and what forms and functions are deemed ideal. RESULTS: After examining the broader notion of global governance and increasingly ubiquitous term "global health", the paper identifies three ontological variations in GHG scholarship - the scope of institutional arrangements, strengths and weaknesses of existing institutions, and the ideal form and function of GHG. This has produced three common, yet distinct, meanings of GHG that have emerged - globalisation and health governance, global governance and health, and governance for global health. CONCLUSIONS: There is a need to clarify ontological and definitional distinctions in GHG scholarship and practice, and be critically reflexive of their normative underpinnings. This will enable greater precision in describing existing institutional arrangements, as well as serve as a prerequisite for a fuller debate about the desired nature of GHG. PMID- 24775920 TI - Continuous theta-burst stimulation over primary somatosensory cortex modulates short-latency afferent inhibition. AB - OBJECTIVE: The present study investigated the effects of continuous theta-burst stimulation (cTBS) over primary somatosensory (SI) and motor (M1) cortices on motor-evoked potentials (MEPs) and short-latency afferent inhibition (SAI). METHODS: MEPs and SAI were recorded from the first dorsal interosseous (FDI) muscle of the right hand following 30Hz cTBS over left-hemisphere SI and M1 delivered to the same participants in separate sessions. Measurements were taken before and up to 60min following cTBS. RESULTS: CTBS over M1 suppressed MEPs and did not alter SAI. In contrast cTBS over SI facilitated MEPs and decreased median and digital nerve evoked SAI. CONCLUSIONS: These findings indicate that SAI amplitude is influenced by cTBS over SI but not M1, suggesting an important role for SI in the modulation of this circuit. These data provide further evidence that cTBS over SI versus M1 has opposite effects on corticospinal excitability. SIGNIFICANCE: To date, plasticity-inducing TMS protocols delivered over M1 have failed to modulate SAI, and the present research continues to support these findings. However, in young adults, cTBS over SI acts to reduce SAI and simultaneously increase corticospinal excitability. Future studies may investigate the potential to modulate SAI via targeting neural activity within SI. PMID- 24775921 TI - Theta burst stimulation to explore the sensory-motor integration of cortical circuits. PMID- 24775922 TI - Informing dose design by modeling transcutaneous spinal direct current stimulation. PMID- 24775944 TI - Advances in the diagnosis of Ascaris suum infections in pigs and their possible applications in humans. AB - Ascariasis is one of the most common parasitic diseases in both humans and pigs. It has been shown to cause growth deficits in both species and to impair cognitive development in children. Notwithstanding its substantial impact on pig economy and public health, diagnosis of ascariasis has mostly relied on the detection of eggs in stool and further development of novel, more sensitive methods has been limited or non-existent. Here, we discuss the currently available techniques for the diagnosis of ascariasis in pigs, their caveats, and the implications of a new serological detection technique for the evaluation of both pig and human ascariasis. PMID- 24775969 TI - Double aortic arch in a newborn with congenital diaphragmatic hernia and tracheoesophageal fistula. AB - Congenital heart disease is associated with congenital diaphragmatic hernia, but diagnosis by echocardiography can be difficult. We present the unusual case of a patient with a double aortic arch and congenital diaphragmatic hernia diagnosed using cardiac magnetic resonance imaging. PMID- 24775970 TI - An outcome prediction model for exsanguinating patients with blunt abdominal trauma after damage control laparotomy: a retrospective study. AB - BACKGROUND: We present a series of patients with blunt abdominal trauma who underwent damage control laparotomy (DCL) and introduce a nomogram that we created to predict survival among these patients. METHODS: This was a retrospective study. From January 2002 to June 2012, 91 patients underwent DCL for hemorrhagic shock. We excluded patients with the following characteristics: a penetrating abdominal injury, age younger than 18 or older than 65 years, a severe or life-threatening brain injury (Abbreviated Injury Scale [AIS] >= 4), emergency department (ED) arrival more than 6 hours after injury, pregnancy, end stage renal disease, or cirrhosis. In addition, we excluded patients who underwent DCL after ICU admission or later in the course of hospitalization. RESULTS: The overall mortality rate was 61.5%: 35 patients survived and 56 died. We identified independent survival predictors, which included a preoperative Glasgow Coma Scale (GCS) score < 8 and a base excess (BE) value < -13.9 mEq/L. We created a nomogram for outcome prediction that included four variables: preoperative GCS, initial BE, preoperative diastolic pressure, and preoperative cardiopulmonary cerebral resuscitation (CPCR). CONCLUSIONS: DCL is a life-saving procedure performed in critical patients, and devastating clinical outcomes can be expected under such dire circumstances as blunt abdominal trauma with exsanguination. The nomogram presented here may provide ED physicians and trauma surgeons with a tool for early stratification and risk evaluation in critical, exsanguinating patients. PMID- 24775990 TI - Ultrasound-assisted lumbar puncture in pediatric emergency medicine. AB - BACKGROUND: Ultrasound-assisted lumbar puncture in the pediatric emergency medicine setting has not been well established, but ultrasound could serve as a valuable tool in this setting. OBJECTIVE: To assess whether ultrasound increases provider confidence in identifying an insertion point for lumbar puncture. METHODS: A feasibility study was conducted using a convenience sample of pediatric emergency patients requiring lumbar puncture. Provider confidence in selecting a needle insertion site for lumbar puncture using ultrasound assistance was compared to provider confidence using traditional landmarks alone. A simple technique using a linear probe is described. RESULTS: Nineteen patients were included in the study, with the primary end point the mean confidence score (based on a five-point Likert scale) in identifying a needle insertion site prior to and after using ultrasound. Using the Wilcoxon signed-rank test, the mean confidence score was 2.89 with the landmark procedure alone, and 4.79 with ultrasound assistance, yielding an average score difference of 1.90 (95% confidence interval 1.23-2.56; Wilcoxon p < 0.001, paired t-test p < 0.001). Thus, compared to the landmark procedure, the use of ultrasound was associated with a significantly higher average confidence score. CONCLUSION: The use of ultrasound in the pediatric emergency setting can be a valuable adjunct with lumbar puncture. PMID- 24776014 TI - Can ACTH therapy improve the long-term outcome of drug-resistant frontal lobe epilepsy? AB - Frontal lobe epilepsy is a common focal epilepsy in children and is often difficult to treat. Adrenocorticotropic hormone (ACTH) or steroids have been used for patients with several forms of medically intractable epilepsy. We evaluated the short, medium, and long-term evolution of patients with frontal lobe epilepsy and secondary bilateral synchrony on the EEG, who received ACTH treatment. Patients were recruited for an add-on trial during clinical practice, and data was retrospectively analysed. The study group comprised 6 patients treated with ACTH. The effects of ACTH were assessed in the short term (at the end of a 6-week period of ACTH treatment), medium term (at 6 months after the end of treatment), and long term (at 12 months after the end of treatment). At short-term follow-up, ACTH treatment was effective for all types of seizures in 5 of 6 patients and ineffective in 1 patient. All patients who were seizure-free at the end of ACTH treatment maintained an excellent outcome, remaining seizure-free at the end of follow-up. Our study demonstrates that ACTH may represent an effective treatment for frontal lobe epilepsy with secondary bilateral synchrony. Further double blind prospective studies are required to confirm our initial findings. PMID- 24775991 TI - Intravenous ghrelin administration increases alcohol craving in alcohol-dependent heavy drinkers: a preliminary investigation. AB - BACKGROUND: There is a need to identify novel pharmacologic targets to treat alcoholism. Animal and human studies suggest a role for ghrelin in the neurobiology of alcohol dependence and craving. Here, we were the first to test the hypothesis that intravenous administration of exogenous ghrelin acutely increases alcohol craving. METHODS: This was a double-blind, placebo-controlled human laboratory proof-of-concept study. Nontreatment-seeking, alcohol-dependent, heavy-drinking individuals were randomized to receive intravenous ghrelin 1 mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol cues. The primary outcome variable was the increase in alcohol craving (also called urge) for alcohol, assessed by the Alcohol Visual Analogue Scale. RESULTS: Out of 103 screenings, 45 individuals received the study drug. Repeated measures of analysis of covariance revealed a group effect across ghrelin doses in increasing alcohol craving (p < .05). A dose-specific examination revealed a significant effect of ghrelin 3 mcg/kg versus placebo in increasing alcohol craving (p < .05) with a large effect size (d = .94). By contrast, no significant ghrelin effect was found in increasing either urge to drink juice or food craving (p = ns). No significant differences in side effects were found (p = ns). CONCLUSIONS: Intravenous administration of exogenous ghrelin increased alcohol craving in alcohol dependent heavy-drinking individuals. Although the small sample requires confirmatory studies, these findings provide preliminary evidence that ghrelin may play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacologic target for treatment. PMID- 24776042 TI - New drug-eluting stents: polymer-free, biodegradable polymers or bioabsorbable scaffolds? PMID- 24776043 TI - The choice of the second graft. PMID- 24776044 TI - Diabetic heart disease and interventional cardiology: how can clinical outcomes be improved? Revascularization guided by hemodynamic parameters (fractional flow reserve). PMID- 24776045 TI - Polymer-free sirolimus-eluting versus polymer-based paclitaxel-eluting stents: an individual patient data analysis of randomized trials. AB - INTRODUCTION AND OBJECTIVES: The angiographic and clinical efficacy of polymer free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents remain a matter of debate. We sought to investigate angiographic and clinical measures of efficacy of polymer-free sirolimus-eluting stents vs polymer-based paclitaxel eluting stents. METHODS: Patient data from the randomized intracoronary stenting and angiographic restenosis-test equivalence between the 2 drug-eluting stents (ISAR-TEST) clinical trial and the LIPSIA Yukon clinical trial (randomized comparison of a polymer-free sirolimus-eluting stent vs a polymer-based paclitaxel-eluting stent in patients with diabetes mellitus) were pooled. The angiographic (primary) endpoint was in-stent late lumen loss at 6 months to 9 months. The clinical (secondary) endpoints were death or myocardial infarction, cardiac death or myocardial infarction, target lesion revascularization, and myocardial infarction. RESULTS: A total of 686 patients (polymer-free sirolimus eluting stents, n=345 vs polymer-based paclitaxel-eluting stents, n=341) and 751 lesions (polymer-free sirolimus-eluting stents, n=383 vs polymer-based paclitaxel eluting stents, n=368) were included in the study. Control angiography (606 lesions, 80.6%) showed comparable in-stent late lumen loss for polymer-free sirolimus-eluting stents vs polymer-based paclitaxel-eluting stents (0.53 [0.59] mm vs 0.46 [0.57] mm; P=.15). Median follow-up was 34.8 months. Polymer-free sirolimus-eluting stents and polymer-based paclitaxel-eluting stents were associated with comparable risk of death or myocardial infarction (relative risk=1.17; 95% confidence interval, 0.49-2.80; P=.71), cardiac death or myocardial infarction (relative risk=1.17; 95% confidence interval, 0.72-1.89; P=.50), target lesion revascularization (relative risk=0.98; 95% confidence interval, 0.65-1.47; P=.93), and myocardial infarction (relative risk=1.79; 95% confidence interval, 0.85-3.76; P=.12). CONCLUSIONS: In this pooled analysis, polymer-free sirolimus-eluting stents were comparable to polymer-based paclitaxel eluting stents with respect to both angiographic and clinical efficacy. PMID- 24776046 TI - Elective implantation of covered stents for coarctation and recoarctation in adolescents and adults. AB - INTRODUCTION AND OBJECTIVES: Stent implantation is an effective therapy for aortic coarctation and recoarctation. However, in adolescents and adults, aortic wall rupture and dissection can occur, as well as aneurysms during follow-up. In order to reduce these complications, we electively implant covered stents. METHODS: Since 2005, we have performed the procedure using femoral access in 17 patients (2 adolescents and 15 adults), 16 electively and 1 as a rescue procedure. We used the Mullins technique in all cases, implanting a NuMED((r)) covered stent. RESULTS: Good stent apposition was achieved in all 17 procedures; 8 patients required a distal flare. Gradient was reduced from 40 (16) mmHg to 2 (2) mmHg (P<.001) and lumen diameter increased from 4 (2) mm to 19 (3) mm (P<.001). Two exceptional cases are discussed: one patient with aortic wall rupture who underwent a rescue procedure using a stent within a covered stent and another patient with total obstruction and intercostal aneurysm in whom the outcome was fatal at 48 h postprocedure (autopsy is shown). Four-year clinical follow-up included Doppler echocardiography; an additional imaging technique was required in 13 patients. All patients recovered well and there were no complications. CONCLUSIONS: Covered stents are effective in treating coarctation and recoarctation in adolescents and adults, are the treatment of choice in patients with complex anatomy, and must be available in the operating room as a rescue device when implanting a conventional stent. PMID- 24776047 TI - Functional improvement in patients with dilated cardiomyopathy after the intracoronary infusion of autologous bone marrow mononuclear cells. AB - INTRODUCTION AND OBJECTIVES: Different studies have shown improvement in patients with idiopathic nonischemic dilated cardiomyopathy treated with cell-therapy. However, factors influencing responsiveness are not well known. This trial investigates functional changes and factors influencing the 6-month gain in ejection fraction in 27 patients with dilated cardiomiopathy treated with intracoronary cell-therapy. METHODS: Patients received intracoronary infusion of autologous bone-marrow mononuclear cells (mean infused, 10.2 [2.9]*10(8)). Flow cytometry and functional analyses of the cells were also performed. RESULTS: The 6-month angiographic gain in ejection fraction ranged from -9% to 34% (mean, 9%). These changes were distinguished into 2 groups: 21 patients (78%) with a significant improvement at the 6-month evaluation (mean gain, 14 [7]%), and 6 patients who had no response (mean gain, -5 [3]%). The responders were younger as compared to the nonresponders (50 [12] years vs 62 [9] years; P<.04). There was an inverse correlation (r=-0.41; P<.003) between the gain in ejection fraction and the high density lipoprotein level, suggesting higher functional gain with low high density lipoprotein levels. The 24 h migratory capability of the infused cells was significantly reduced in the responders' group (5.4 [1.7]*10(8) vs 8.1 [2.3]*10(8); P<.009 for vascular endothelial growth factor and 5.8 [1.7]*10(8) vs 8.4 [2.9]*10(8); P<.002 for stromal cell-derived factor-1). CONCLUSIONS: Younger patients with dilated cardiomiopathy and lower plasma high density lipoprotein levels gain greater benefit from intracoronary cell-therapy. Functional improvement also seems to be enhanced by a lower migratory capacity of the infused cells. PMID- 24776048 TI - Nighttime ambulatory blood pressure is associated with atrial remodelling and neurohormonal activation in patients with idiopathic atrial fibrillation. AB - INTRODUCTION AND OBJECTIVES: Hypertension is a risk factor for atrial fibrillation. Activation of the renin-angiotensin-system seems to be involved in atrial enlargement, with release of atrial and brain natriuretic peptides. The aim of this study was to evaluate the relationship between ambulatory blood pressure and levels of natriuretic peptides, with left atrial size in normotensives with idiopathic atrial fibrillation. METHODS: This was a cross sectional study in patients with idiopathic atrial fibrillation. The following measurements were recorded during the course of the study: office and 24-h ambulatory blood pressure, atrial and brain natriuretic peptides, plasma renin, aldosterone, and angiotensin-converting enzyme. RESULTS: Forty-eight patients (mean age 55 [10] years; 70.6% male) were included in the study. Mean office sitting blood pressure values were 132.49 (14.9)/80.96 (9.2) mmHg. Mean 24-h ambulatory systolic and diastolic blood pressure values were 121.10 (8.3)/72.11 (6.8) mmHg (daytime, 126.8 [9.7]/77.58 [7.9] mmHg; nighttime, 114.56 [11.6]/68.6 [8.8] mmHg). A clear trend towards increased left atrial size with higher ambulatory blood pressure values was noted, which was statistically significant for nighttime values (r=0.34; P=.020 for systolic and r=0.51; p=.0001 for diastolic). A significant correlation between atrial natriuretic peptide and nighttime systolic (r=0.297; P=.047) and diastolic (r=0.312; P=.037) blood pressure was observed. Significant correlations were also observed between left atrial size and atrial natriuretic peptide levels (r=0.577; p<.0001) and brain natriuretic peptide levels (r=0.379; P=.012). CONCLUSIONS: Nighttime blood pressure is associated with left atrial size and the release of natriuretic peptides in normotensive patients with idiopathic atrial fibrillation. PMID- 24776049 TI - Association between blood pressure and mortality in a Spanish cohort of persons aged 65 years or over: a dynamic model. AB - INTRODUCTION AND OBJECTIVES: Few studies have used time-dependent correction to analyze the relationship between blood pressure and all-cause mortality, and to our knowledge none has been performed in older people from the Mediterranean area. This study aimed to estimate the relationship between baseline blood pressure and blood pressure as a time-dependent covariate with the risk of all cause mortality in a population cohort of persons aged 65 or older in Spain. METHODS: Data were taken from the population-based study "Aging in Leganes" with 17 years of follow-up, launched in 1993 in a random sample (n=1560) of persons aged >=65 years. Mortality was assessed in 2010. Cox proportional hazards models were fitted to examine the effects on mortality of blood pressure at baseline and of blood pressure as a time-dependent covariate. RESULTS: The lowest mortality was observed at baseline systolic blood pressure of 136 mmHg and time-dependent covariate value of 147 mmHg. The highest risk of mortality for time-dependent covariates occurred with systolic blood pressure <115 mmHg and >93 mmHg and diastolic blood pressure <80 mmHg. Diastolic blood pressure over 85 mmHg did not increase the risk of death. CONCLUSIONS: Based on the dynamic association between blood pressure and mortality, a U-shaped relationship was found for systolic blood pressure and a negative relationship for diastolic blood pressure and all cause mortality. The lowest mortality corresponded to a systolic blood pressure level slightly over the diagnostic hypertension value and suggests that a value of 140 mmHg is not adequate as a diagnostic and therapeutic threshold in an elderly population. PMID- 24776050 TI - Epidemiology of acute coronary syndromes in Spain: estimation of the number of cases and trends from 2005 to 2049. AB - Acute coronary syndromes are a leading cause of mortality, morbidity, and health care cost in Spain. The aims of this report are to estimate the number of acute coronary syndromes cases in the Spanish population in 2013 and 2021, and the trend from 2005 to 2049. We estimated the number of acute coronary syndromes cases by sex and Spanish autonomous community using data from the most updated population and hospital registries. We present the estimated number of cases with an exact 95% confidence interval, assuming that the number of cases followed a Poisson distribution. There will be 115,752 acute coronary syndromes cases in Spain in 2013 (95% confidence interval, 114,822-116,687). Within 28 days, 39,086 of these patients will die and 85,326 will be hospitalized. Non-ST segment elevation acute coronary syndromes (56%) and acute myocardial infarction (81%) will be the most common admission and discharge diagnoses, respectively. We estimate approximately 109,772 acute coronary syndromes cases in 2021 (95% confidence interval, 108,868-110,635). The trend of acute coronary syndromes cases from 2005 to 2049 will stabilize in the population aged 25 to 74 years, but increase in those older than 74 years. Due to population aging, the number of acute coronary syndrome cases will increase overall until 2049, it may stabilize in the population aged <75 years. The acute coronary syndromes case-fatality has decreased in hospitalized patients but the proportion of sudden deaths remains unchanged. PMID- 24776051 TI - Progress in treatment by percutaneous coronary intervention: the stent of the future. AB - First generation drug-eluting stents have considerably reduced in-stent restenosis and broadened the applications of percutaneous coronary interventions for the treatment of coronary artery disease. The polymer is an integral part of drug-eluting stents in that, it controls the release of an antiproliferative drug. The main safety concern of first generation drug-eluting stents with permanent polymers--stent thrombosis--has been caused by local hypersensitivity, delayed vessel healing, and endothelial dysfunction. This has prompted the development of newer generation drug-eluting stents with biodegradable polymers or even polymer-free drug-eluting stents. Recent clinical trials have shown the safety and efficacy of drug-eluting stents with biodegradable polymer, with proven reductions in very late stent thrombosis as compared to first generation drug-eluting stents. However, the concept of using a permanent metallic prosthesis implies major drawbacks, such as the presence of a foreign material within the native coronary artery that causes vascular inflammation and neoatherosclerosis, and also impedes the restoration of the vasomotor function of the stented segment. Bioresorbable scaffolds have been introduced to overcome these limitations, since they provide temporary scaffolding and then disappear, liberating the treated vessel from its cage. This update article presents the current status of these new technologies and highlights their future perspectives in interventional cardiology. PMID- 24776052 TI - A coarctation on the wrong aortic arch side. PMID- 24776053 TI - Out-of-hospital use of semiautomated external defibrillator electrocardiography. PMID- 24776054 TI - Fatty infiltration around the cardiac nodes. PMID- 24776055 TI - Role of magnetic resonance imaging in the diagnosis of myocarditis in children. PMID- 24776056 TI - Ventricular support with extracorporeal membrane oxygenation: a new rescue alternative for refractory cardiogenic shock. PMID- 24776057 TI - Efficacy of tolvaptan in patients hospitalized for heart failure with refractory hyponatremia. Clinical experience in daily practice. PMID- 24776058 TI - Subclinical coronary atherosclerosis identified by coronary computed tomography angiography in asymptomatic population by coronary artery disease risk level. PMID- 24776059 TI - Results after 6 years of the health care network for coronary reperfusion in patients with acute myocardial infarction in the southern area of Galicia (PROGALIAM-South). PMID- 24776060 TI - Radial and circumferential strain as markers of fibrosis in an experimental model of myocardial infarction. PMID- 24776061 TI - Self-management of vitamin K antagonists is more cost-effective than dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain. PMID- 24776062 TI - Self-management of vitamin K antagonists is more cost-effective than dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain. Response. PMID- 24776063 TI - On the cost-effectiveness of dabigatran. PMID- 24776064 TI - Exercise echocardiography in hypertrophic cardiomyopathy: is upright evaluation needed after all? PMID- 24776065 TI - On the cost-effectiveness of dabigatran. Response. PMID- 24776066 TI - Exercise echocardiography in hypertrophic cardiomyopathy: is upright evaluation needed after all? Response. PMID- 24776067 TI - Differential diagnosis between dual ventricular response and bigeminy arising from the bundle of His. Response. PMID- 24776068 TI - Differential diagnosis between dual ventricular response and bigeminy arising from the bundle of His. PMID- 24776070 TI - 2013 NCHS Urban-Rural Classification Scheme for Counties. AB - OBJECTIVES: This report details development of the 2013 National Center for Health Statistics' (NCHS) Urban-Rural Classification Scheme for Counties (update of the 2006 NCHS scheme) and applies it to health measures to demonstrate urban rural health differences. METHODS: The methodology used to construct the 2013 NCHS scheme was the same as that used for the 2006 NCHS scheme, but 2010 census based data were used rather than 2000 census-based data. All U.S. counties and county-equivalent entities are assigned to one of six levels (four metropolitan and two nonmetropolitan) based on: 1) their February 2013 Office of Management and Budget designation as metropolitan, micropolitan, or noncore; 2) for metropolitan counties, the population size of the metropolitan statistical area (MSA) to which they belong; and 3) for counties in MSAs of 1 million or more, the location of principal city populations within the MSA. The 2013 and 2006 NCHS schemes were applied to data from the National Vital Statistics System (NVSS) and National Health Interview Survey (NHIS) to illustrate differences in selected health measures by urbanization level and to assess the magnitude of differences between estimates from the two schemes. RESULTS AND CONCLUSIONS: County urban rural assignments under the 2013 NCHS scheme are very similar to those under the 2006 NCHS scheme. Application of the updated scheme to NVSS and NHIS data demonstrated the continued usefulness of the six categories for assessing and monitoring health differences among communities across the full urbanization spectrum. Residents of large central and large fringe metro counties differed substantially on many health measures, illustrating the importance of continuing to separate these counties. Residents of large fringe metro counties generally fared better than residents of less urban counties. Estimates obtained from the 2013 and 2006 schemes were similar. PMID- 24776071 TI - Systematic review on reoperative bariatric surgery: American Society for Metabolic and Bariatric Surgery Revision Task Force. AB - BACKGROUND: Reoperative bariatric surgery has become a common practice in many bariatric surgery programs. There is currently little evidence-based guidance regarding specific indications and outcomes for reoperative bariatric surgery. A task force was convened to review the current evidence regarding reoperative bariatric surgery. The aim of the review was to identify procedure-specific indications and outcomes for reoperative procedures. METHODS: Literature search was conducted to identify studies reporting indications for and outcomes after reoperative bariatric surgery. Specifically, operations to treat complications, failed weight loss, and weight regain were evaluated. Abstract and manuscript reviews were completed by the task force members to identify, grade, and categorize relevant studies. RESULTS: A total of 819 articles were identified in the initial search. After review for inclusion criteria and data quality, 175 articles were included in the systematic review and analysis. The majority of published studies are single center retrospective reviews. The evidence supporting reoperative surgery for acute and chronic complications is described. The evidence regarding reoperative surgery for failed weight loss and weight regain generally demonstrates improved weight loss and co-morbidity reduction after reintervention. Procedure-specific outcomes are described. Complication rates are generally reported to be higher after reoperative surgery compared to primary surgery. CONCLUSION: The indications and outcomes for reoperative bariatric surgery are procedure-specific but the current evidence does support additional treatment for persistent obesity, co-morbid disease, and complications. PMID- 24776072 TI - Prophylactic antibiotics in interventional paediatric cardiac catheterisation: old habits die hard? AB - Antibiotic prophylaxis in congenital cardiac disease has long been a topic of debate. Although there is little dispute around antibiotic cover for surgical procedures and catheter interventions where foreign material is being inserted, there are little data specific to non-device-placement procedures such as atrial septostomy or balloon valvotomy. We sought to assess the effect of routine prophylaxis on post-interventional infections via a retrospective pseudo randomised analysis, and an online survey on paediatric interventional cardiologists in the United Kingdom and United States. PMID- 24776089 TI - Patients with cancer in the intensive monitoring unit. New perspectives. AB - In recent years, there has been a significant improvement in the survival of patients with cancer in intensive care units (ICUs). Advances in medical and surgical treatments and better selection of patients has helped improve the life expectancy of this type of patient. An appropriate and early resuscitation in the ICU, without initial limitations on the life support techniques, has been shown to also decrease the mortality of patients with cancer. At present, we should not deny admission to the ICU based only on the underlying neoplastic disease. However, the mortality rate for patients with cancer in the ICU, especially those with hematologic disease, remains high. In some cases, an ICU admission test (ICU test) is required for at least 3 days to identify patients who can benefit from intensive treatment. We would like to propose a decision algorithm for ICU admission that will help in making decisions in an often complex situation. PMID- 24776090 TI - Scrotal extratesticular schwannoma: a case report and review of the literature. AB - BACKGROUND: Schwannomas are tumours arising from Schwann cells, which sheath the peripheral nerves. Here, we report a rare case of left intrascrotal, extratesticular schwannoma. Although rare, scrotal localisation of schwannomas has been reported in male children, adult men, and elderly men. They are usually asymptomatic and are characterised by slow growth. Patients generally present with an intrascrotal mass that is not associated with pain or other clinical signs, and such cases are self-reported by most patients. Imaging modalities (such as ultrasonography, computed tomography, and magnetic resonance imaging) can be used to determine tumour size, exact localisation, and extension. However, the imaging findings of schwannoma are non-specific. Therefore, only complete surgical excision can result in diagnosis, based on histological and immunohistochemical analyses. If the tumour is not entirely removed, recurrences may develop, and, although malignant change is rare, this may occur, especially in patients with a long history of an untreated lesion. Thus, follow up examinations with clinical and imaging studies are recommended for scrotal schwannomas. CASE PRESENTATION: A 52-year-old man presented with a 3-year history of asymptomatic scrotal swelling. Physical examination revealed a palpable, painless, soft mass in the left hemiscrotum. After surgical removal of the mass, its histological features indicated schwannoma. CONCLUSIONS: Schwannoma should be considered in cases of masses that are intrascrotal but extratesticular. Ultrasonography provides the best method of confirming the paratesticular localisation of the tumour, before surgical removal allows histopathological investigation and definitive diagnosis. Surgery is the standard therapeutic approach. To prevent recurrence, particular care should be taken to ensure complete excision. This case report includes a review of the literature on scrotal schwannomas. PMID- 24776091 TI - Development and preclinical evaluation of new (124)I-folate conjugates for PET imaging of folate receptor-positive tumors. AB - In an attempt to develop new folate radiotracers with favorable biochemical properties for detecting folate receptor-positive cancers, we have synthesized [(124)I]-SIB- and [(124)I]-SIP-folate conjugates using a straightforward and two step simple reactions. Radiochemical yields for [(124)I]-SIB- and [(124)I]-SIP folate conjugates were greater than 90 and 60% respectively, with total synthesis time of 30-40min. Radiochemical purities were always greater than 98% without HPLC purification. These synthetic approaches hold considerable promise as rapid and simple method for (124)I-folate conjugate preparation with high radiochemical yield in short synthesis time. In vitro tests on KB cell line showed that the significant amounts of the radioconjugates were associated with cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates and favorable biodistribution profile for [(124)I]-SIP folate conjugate over [(124)I]-SIB-folate conjugate. Biodistribution studies of [(124)I]-SIP-folate conjugate in nude mice bearing human KB cell line xenografts, demonstrated significant tumor uptake. The uptake in the tumors was blocked by excess injection of folic acid, suggesting a receptor-mediated process. These results demonstrate that [(124)I]-SIP-folate conjugate may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis as well as monitoring tumor response to treatment. PMID- 24776092 TI - Synthesis and evaluation of (18)F-labeled bile acid compound: a potential PET imaging agent for FXR-related diseases. AB - The farnesoid-X-receptor (FXR) is a member of the nuclear hormone receptor superfamily. The FXR has critical functions in maintaining bile acid synthesis and homeostasis, liver regeneration and tumorigenesis, intestinal diseases, intestinal tumorigenesis, cholesterol gallstone disease, cholestasis, and atherosclerosis. FXR expression is strongly downregulated in liver fibrosis, hepatocellular adenoma and hepatocellular carcinoma compared to expression levels in adjacent normal tissues. Chenodeoxycholic acid (CDCA) is the most potent physiological ligand for FXR. CDCA was radiolabeled with (18)F based on the efficiency click reaction of 1,3-dipolar cycloaddition of terminal alkynes and organic azides for noninvasively evaluating the relationship between FXR and FXR related disease. The PET tracer [(18)F]8 was produced by 'click' labeling and showed a high non-decay corrected radiochemical yield (end of synthesis (EOS) yield=42+/-3% (n=5) from aqueous [(18)F]fluoride), high radiochemical purity ( >99%), and high specific activity (>320GBq/MUmol). [(18)F]8 had a high metabolic stability in vitro and in vivo. PET imaging studies in nude mice indicated a rapid uptake of the tracer into liver tissue with uniform distribution of radioactivity in the liver. Significant accumulation of radioactivity was found in the liver, gallbladder, and intestine, while no obvious uptake was observed in other organs, such as the bladder, heart, and brain. Thus, this PET tracer represents a novel tool for early detection of abnormalities in the liver and staging of neoplasms. PMID- 24776093 TI - Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter--a potential Auger electron emitting EGFR-targeted radiotherapeutic. AB - INTRODUCTION: Modular nanotransporters (MNTs) are vehicles designed to transport drugs from the cell surface via receptor-mediated endocytosis and endosomal escape to nucleus. Hence their conjugation to Auger electron emitters, can cause severe cell killing, by nuclear localization. Herein we evaluate the use of MNT as a platform for targeted radiotherapy with (67)Ga. METHODS: EGF was the targeting ligand on the MNT, and NOTA was selected for its radiolabeling with (67)Ga. In the radiolabeling study we dealt with the precipitation of MNT (pI 5.7) at the labeling pH (4.5-5.5) of (67)Ga. Cellular and nuclei uptake of (67)Ga NOTA-MNT by the A431 cell line was determined. Its specific cytotoxicity was compared to that of (67)Ga-EDTA, (67)Ga-NOTA-BSA and (67)Ga-NOTA-hEGF, in A431 and U87MGWTT, cell lines, by clonogenic assay. Dosimetry studies were also performed. RESULTS: (67)Ga-NOTA-MNT was produced with 90% yield and specific activity of 25.6mCi/mg. The in vitro kinetics revealed an increased uptake over 24h. 55% of the internalized radioactivity was detected in the nuclei at 1h. The cytotoxicity of (67)Ga-NOTA-MNT on A431 cell line was 17 and 385-fold higher when compared to non-specific (67)Ga-NOTA-BSA and (67)Ga-EDTA. While its cytotoxic potency was 13 and 72-fold higher when compared to (67)Ga-NOTA-hEGF in the A431 and the U87MGWTT cell lines, respectively, validating its nuclear localization. The absorbed dose, for 63% cell killing, was 8Gy, confirming the high specific index of (67)Ga. CONCLUSION: These results demonstrate the feasibility of using MNT as a platform for single cell kill targeted radiotherapy by Auger electron emitters. PMID- 24776094 TI - Can host ecology and kin selection predict parasite virulence? AB - Parasite virulence, or the damage a parasite does to its host, is measured in terms of both host costs (reductions in host growth, reproduction and survival) and parasite benefits (increased transmission and parasite numbers) in the literature. Much work has shown that ecological and genetic factors can be strong selective forces in virulence evolution. This review uses kin selection theory to explore how variations in host ecological parameters impact the genetic relatedness of parasite populations and thus virulence. We provide a broad overview of virulence and population genetics studies and then draw connections to existing knowledge about natural parasite populations. The impact of host movement (transporting parasites) and host resistance (filtering parasites) on the genetic structure and virulence of parasite populations is explored, and empirical studies of these factors using Plasmodium and trematode systems are proposed. PMID- 24776095 TI - LPA rs10455872 polymorphism is associated with coronary lesions in Brazilian patients submitted to coronary angiography. AB - BACKGROUND: Polymorphisms in the LPA gene were associated with coronary artery disease (CAD). However, there are differences in the allelic frequencies, Lp(a) levels, and significant association with CAD according to ethnic groups. In this scenario, the main aim of this study was to assess the influence of the LPA polymorphisms on coronary lesions in Brazilian patients. METHODS: 1,394 consecutive patients submitted to coronary angiography to study suggestive CAD and twenty coronary segments were scored. Genotyping for the LPA rs10455872 and rs3798220 polymorphisms were performed by high resolution melting analysis. RESULTS: The frequencies of the rs10455872 G and rs3798220 C variant alleles were 6.4% and 6.2%, respectively. LPA rs10455872 G variant allele was associated with higher odds ratio of having coronary lesions in an adjusted model (OR = 2.02, 95% CI = 1.10-3.72, p = 0.02). Scores of coronary lesions (extension, severity, and Gensini scores) were significantly different among rs10455872 genotype groups. Coronary lesions was not associated with LPA rs3798220 (OR = 1.09, 95% CI = 0.67 1.76, p = 0.73) and scores of coronary lesions were not different among rs3798220 genotypes. CONCLUSIONS: We confirmed the association of the LPA rs10455872 with CAD in a large sample of Brazilian patients. For the LPA rs3798220, our finding is consistent with studies which showed the lack of this genetic association. PMID- 24776096 TI - A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders. AB - BACKGROUND: Autism Spectrum Disorders (ASD) is a syndrome with a number of etiologies and different mechanisms that lead to abnormal development. The identification of autism biomarkers in patients with different degrees of clinical presentation (i.e., mild, moderate and severe) will give greater insight into the pathogenesis of this disease and will enable effective early diagnostic strategies and treatments for this disorder. METHODS: In this study, the concentration of two toxic heavy metals, lead (Pb) and mercury (Hg), were measured in red blood cells, while glutathione-s-transferase (GST) and vitamin E, as enzymatic and non-enzymatic antioxidants, respectively, were measured in the plasma of subgroups of autistic patients with different Social Responsiveness Scale (SRS) and Childhood Autism Rating Scale (CARS) scores. The results were compared to age- and gender-matched healthy controls. RESULTS: The obtained data showed that the patients with autism spectrum disorder had significantly higher Pb and Hg levels and lower GST activity and vitamin E concentrations compared with the controls. The levels of heavy metals (Hg and Pb), GST and vitamin E were correlated with the severity of the social and cognitive impairment measures (SRS and CARS). Receiver Operating Characteristics (ROC) analysis and predictiveness curves indicated that the four parameters show satisfactory sensitivity, very high specificity and excellent predictiveness. Multiple regression analyses confirmed that higher levels of Hg and Pb, together with lower levels of GST and vitamin E, can be used to predict social and cognitive impairment in patients with autism spectrum disorders. CONCLUSION: This study confirms earlier studies that implicate toxic metal accumulation as a consequence of impaired detoxification in autism and provides insight into the etiological mechanism of autism. PMID- 24776097 TI - Effects of supplementation with different Mg salts in cells: is there a clue? AB - The differing bioavailability of magnesium salts remains an open question, both at the cellular and systemic level. However, this issue is relevant for identifying the most effective magnesium supplement. We compared the effects of three widely used magnesium salts: MgSO4, MgCl2 and Mg pidolate, on the proliferation of four human cell types: promyelocytic leukaemia HL60, osteoblast like Saos-2 and U-2 OS, and endothelial cells from the umbilical vein. The three magnesium salts had no effect on endothelial and leukemic cell growth, but magnesium pidolate impaired cell growth in osteoblast-like cells. In particular, in Saos-2 cells, 1 mM pidolate induced a slight accumulation of cells in the G0/G1 phase of the cell cycle and, in parallel, an early rise in intracellular calcium and a late decrease in intracellular magnesium content. Interestingly, when cultured in 5 mM magnesium pidolate, Saos-2 cells grew as fast as the controls. Moreover, intracellular magnesium and calcium concentrations did not vary. These results suggest a lower bioavailability of magnesium pidolate in osteoblast-like cells. PMID- 24776121 TI - An adolescent athlete with groin pain. PMID- 24776173 TI - Systemic sclerosis sine scleroderma and limited cutaneous systemic sclerosis: similarities and differences. AB - OBJECTIVES: To compare a cohort of patients with systemic sclerosis sine scleroderma (ssSSc) vs. patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: Forty-five patients with ssSSc and 186 patients with lcSSc were investigated. Demographic, clinical and immunologic features and survival were compared. RESULTS: There were no significant differences between ssSSc and lcSSc in gender, age at onset and interval between onset and diagnosis. ssSSc patients fulfilled the ACR criteria for SSc less than lcSSc patients (13%/77%, p<0.0001). There were no significant differences in articular involvement, myopathy, tendon friction rubs and gastrointestinal, pulmonary, cardiac and renal involvements. There was a trend to higher prevalence of pulmonary arterial hypertension (PAH) in ssSSc patients (29%/19%) but not reach significant difference. The prevalence of antinuclear and anticentromere antibodies and slow capilaroscopic pattern was similar. Sicca syndrome (13%/30%; p=0.024), digital ulcers (16%/50%; p<0.0001), calcinosis (11%/26%; p=0.047) and acroosteolysis (0% /10%; p=0.028) were more frequently in lcSSc. Survival at 5, 10, and 15 yr was not different in ssSSc and lcSSc patients (100%/98%, 100%/98%, and 92%/89%, respectively). CONCLUSIONS: ssSSc and lcSSc patients share demographic, clinical and immunologic features. Survival is also similar in both groups. Differences are mainly due to peripheral vascular manifestations. However, despite great similarities, we believe that ssSSc patients should be considered as a different subset in order to avoid misdiagnosis. ssSSc patients should be truly differentiated from early SSc using sensitive and specific studies looking for any asymptomatic organ involvement. PMID- 24776174 TI - The surgical management of Treacher Collins syndrome. AB - Treacher Collins syndrome (TCS), mandibulofacial dysostosis, or Franceschetti Zwahlen-Klein syndrome, is a rare genetic disorder characterised by dysgenesis of the hard and soft tissues of the first and second branchial arches. Early operations focus on maintaining the airway, protecting the eyes, and supporting auditory neurological development. Later operations include staged reconstruction of the mouth, face, and external ear. Bimaxillary surgery can improve the maxillomandibular facial projection, but correction of malar, orbital rim, and temporal defects may be more difficult. We present a clinical review of the syndrome with a chronological approach to the operations. PMID- 24776175 TI - Does health coaching change patients' trust in their primary care provider? AB - OBJECTIVE: To assess the impact of health coaching on patients' in their primary care provider. METHODS: Randomized controlled trial comparing health coaching with usual care. PARTICIPANTS: Low-income English or Spanish speaking patients age 18-75 with poorly controlled type 2 diabetes, hypertension and/or hyperlipidemia. MAIN OUTCOME MEASURE: Patient trust in their primary care provider measured by the 11-item Trust in Physician Scale, converted to a 0-100 scale. ANALYSIS: Linear mixed modeling. RESULTS: A total of 441 patients were randomized to receive 12 months of health coaching (n=224) vs. usual care (n=217). At baseline, the two groups were similar to those in the usual care group with respect to demographic characteristics and levels of trust in their provider. After 12 months, the mean trust level had increased more in patients receiving health coaching (3.9 vs. 1.5, p=0.47), this difference remained significant after adjustment for number of visits to primary care providers (adjusted p=.03). CONCLUSIONS: Health coaching appears to increase patients trust in their primary care providers. PRACTICE IMPLICATIONS: Primary care providers should consider adding health coaches to their team as a way to enhance their relationship with their patients. PMID- 24776198 TI - Multimarker panel for patients with chest pain: case closed? PMID- 24776199 TI - Should heart failure patients move to Catalonia? PMID- 24776200 TI - Atrial fibrillation and obstructive sleep apnea: something more than a coincidence. PMID- 24776201 TI - N-terminal pro-brain natriuretic peptide and high-sensitivity troponin in the evaluation of acute chest pain of uncertain etiology. A PITAGORAS substudy. AB - INTRODUCTION AND OBJECTIVES: High-sensitivity troponin assays have improved the diagnosis of acute coronary syndrome in patients presenting with chest pain and normal troponin levels as measured by conventional assays. Our aim was to investigate whether N-terminal pro-brain natriuretic peptide provides additional information to troponin determination in these patients. METHODS: A total of 398 patients, included in the PITAGORAS study, presenting to the emergency department with chest pain and normal troponin levels as measured by conventional assay in 2 serial samples (on arrival and 6 h to 8h later) were studied. The samples were also analyzed in a central laboratory for high-sensitivity troponin T (both samples) and for N-terminal pro-brain natriuretic peptide (second sample). The endpoints were diagnosis of acute coronary syndrome and the composite endpoint of in-hospital revascularization or a 30-day cardiac event. RESULTS: Acute coronary syndrome was adjudicated to 79 patients (20%) and the composite endpoint to 59 (15%). When the N-terminal pro-brain natriuretic peptide quartile increased, the diagnosis of acute coronary syndrome also increased (12%, 16%, 23% and 29%; P=.01), as did the risk of the composite endpoint (6%, 13%, 16% and 24%; P=.004). N-terminal pro-brain natriuretic peptide elevation (>125ng/L) was associated with both endpoints (relative risk= 2.0; 95% confidence interval, 1.2-3.3; P=.02; relative risk=2.4; 95% confidence interval, 1.4-4.2; P=.004). However, in the multivariable models adjusted by clinical and electrocardiographic data, a predictive value was found for high-sensitivity T troponin but not for N-terminal pro-brain natriuretic peptide. CONCLUSIONS: In low-risk patients with chest pain of uncertain etiology evaluated using high-sensitivity T troponin, N-terminal pro brain natriuretic peptide does not contribute additional predictive value to diagnosis or the prediction of short-term outcomes. PMID- 24776202 TI - Survival in Mediterranean ambulatory patients with chronic heart failure. A population-based study. AB - INTRODUCTION AND OBJECTIVES: Scarce research has been performed in ambulatory patients with chronic heart failure in the Mediterranean area. Our aim was to describe survival trends in our target population and the impact of prognostic factors. METHODS: We carried out a population-based retrospective cohort study in Catalonia (north-east Spain) of 5659 ambulatory patients (60% women; mean age 77 [10] years) with incident chronic heart failure. Eligible patients were selected from the electronic patient records of primary care practices from 2005 and were followed-up until 2007. RESULTS: During the follow-up period deaths occurred in 950 patients (16.8%). Survival after the onset of chronic heart failure at 1, 2, and 3 years was 90%, 80%, 69%, respectively. No significant differences in survival were found between men and women (P=.13). Cox proportional hazard modelling confirmed an increased risk of death with older age (hazard ratio=1.06; 95% confidence interval, 1.06-1.07), diabetes mellitus (hazard ratio=1.53; 95% confidence interval, 1.33-1.76), chronic kidney disease (hazard ratio=1.73; 95% confidence interval, 1.45-2.05), and ischemic heart disease (hazard ratio=1.18; 95% confidence interval, 1.02-1.36). Hypertension (hazard ratio=0.73; 95% confidence interval, 0.64-0.84) had a protective effect. CONCLUSIONS: Service planning and prevention programs should take into consideration the relatively high survival rates found in our area and the effect of prognostic factors that can help to identify high risk patients. PMID- 24776203 TI - Prevalence of undiagnosed atrial fibrillation and of that not being treated with anticoagulant drugs: the AFABE study. AB - INTRODUCTION AND OBJECTIVES: Atrial fibrillation constitutes a serious public health problem because it can lead to complications. Thus, the management of this arrhythmia must include not only its treatment, but antithrombotic therapy as well. The main goal is to determine the proportion of cases of undiagnosed atrial fibrillation and the proportion of patients not being treated with oral anticoagulants. METHODS: A multicenter, population-based, retrospective, cross sectional, observational study. In all, 1043 participants over 60 years of age were randomly selected to undergo an electrocardiogram in a prearranged appointment. Demographic data, CHA2DS2-VASc and HAS-BLED scores, international normalized ratio results, and reasons for not receiving oral anticoagulant therapy were recorded. RESULTS: The overall prevalence of atrial fibrillation was 10.9% (95% confidence interval, 9.1%-12.8%), 20.1% of which had not been diagnosed previously. In the group with known atrial fibrillation, 23.5% of those with CHA2DS2-VASc>=2 were not receiving oral anticoagulant therapy, and 47.9% had a HAS-BLED score>=3. The odds ratio for not being treated with oral anticoagulation was 2.04 (95% confidence interval, 1.11-3.77) for women, 1.10 (95% confidence interval, 1.05-1.15) for more advanced age at diagnosis, and 8.61 (95% confidence interval 2.38-31.0) for a CHA2DS2-VASc score<2. Cognitive impairment (15.2%) was the main reason for not receiving oral anticoagulant therapy. CONCLUSIONS: The prevalence of previously undiagnosed atrial fibrillation in individuals over 60 years of age is 20.1%, and 23.5% of those who have been diagnosed receive no treatment with oral anticoagulants. PMID- 24776204 TI - Palliative arterial switch as first-line treatment before the fontan procedure in patients with single-ventricle physiology and subaortic stenosis. AB - INTRODUCTION AND OBJECTIVES: There are several techniques for the palliative treatment of patients with single-ventricle physiology, ventriculoarterial discordance and subaortic stenosis. The Fontan procedure relies on optimal initial palliation to avoid the development of subaortic stenosis (as well as ventricular hypertrophy and diastolic dysfunction). METHODS: We present seven patients with single-ventricle physiology, transposition of the great arteries and subaortic stenosis, with low systemic output and high pulmonary flow, aged 21 to 383 days (median, 75) and weighing between 3.4 and 9.6kg (median, 4.2). All were treated with a palliative arterial switch, thus "switching" their subaortic stenosis to subpulmonary stenosis. Six patients also underwent aortic arch surgery, 4 an atrial septectomy, and 1 a subaortic membrane resection. RESULTS: One patient died after surgery, another developed recoarctation, which was treated with an angioplasty, 3 patients reached the Glenn stage and 2 the Fontan stage. All had good ventricular function. CONCLUSIONS: A palliative switch is an effective initial treatment for single-ventricle physiology with transposition of the great arteries and subaortic stenosis. This complex initial technique produces good results and allows the patient to progress to the Glenn or Fontan stage. PMID- 24776205 TI - Natural history and clinical outcome of "uncorrected" scimitar syndrome patients: a multicenter study of the italian society of pediatric cardiology. AB - INTRODUCTION AND OBJECTIVES: To analyze the clinical status of patients with "uncorrected" scimitar syndrome in a multicenter Italian study. METHODS: The natural history of scimitar syndrome was analyzed in 44 affected individuals (from 9 Italian centers). RESULTS: The median age at diagnosis was 1.05 years (range, 1 day-41 years). Thirty-three patients (75%) had an isolated form; 11 patients (25%) had associated congenital heart diseases. Twenty-two patients (50%) were symptomatic at diagnosis, including respiratory symptoms (n=20) and congestive heart failure (n=6). Patients with associated congenital heart defects had a higher prevalence of congestive heart failure (4 of 11 [36.4%] vs 2 of 33 [6.1%]; P=.027), pulmonary arterial hypertension (7 of 11 [63.6%] vs 2 of 33 [6.1%]; P=.027) than patients with isolated forms. Ten patients (22.7%) underwent correction of associated cardiac defects, leaving the anomalous pulmonary venous drainage intact. The median length of follow-up after diagnosis was 6.4 years (range, 0.2-27.5 years). Two patients died, both with associated cardiac defects and severe pulmonary arterial hypertension. Of 42 survivors, 39 (92.8%) were asymptomatic at the last follow-up visit; 3 patients still complained respiratory symptoms. There was no difference between isolated and associated forms of the disease. CONCLUSIONS: In most patients, scimitar syndrome presented as an isolated lesion with a benign outcome. Nonetheless, when associated with other cardiac defects and pulmonary arterial hypertension, there was an increased risk of congestive heart failure and mortality. Correction of associated cardiac defects (transforming "associated" into "isolated" forms), together with the therapeutic occlusion of anomalous arterial supply to the lung, led to a benign outcome comparable to that in primarily isolated forms. PMID- 24776206 TI - Epidemiology of atrial fibrillation in Spain in the past 20 years. AB - Atrial fibrillation is the most common sustained arrhythmia. Because of its potentially serious clinical consequences (heart failure, stroke, and cognitive impairment), atrial fibrillation has important socioeconomic and health implications. This article reviews the major studies on the epidemiology of atrial fibrillation in Spain. Recent data suggest that in people older than 40 years, the prevalence of atrial fibrillation may be more than 4%. Given the current Spanish demography, these data would imply that more than 1 million people in Spain have atrial fibrillation. PMID- 24776207 TI - Advances in percutaneous treatment of mitral regurgitation. AB - Percutaneous techniques for the treatment of mitral regurgitation have aroused much interest in recent years. Percutaneous mitral annuloplasty can be performed indirectly by using devices implanted in the coronary sinus or directly by using a retrograde approach. However, as yet, the results of these techniques are scarce and some devices have a high complications rate. The most frequent percutaneous mitral valve repair technique consists of mitral leaflet plication by implanting 1 or more percutaneous clips (MitraClip) in an imitation of the Alfieri surgical technique. Clinical experience with this device is broader than that with any other. The MitraClip device is associated with improved mitral regurgitation in a high percentage of carefully-selected patients. However, the single randomized study performed to date (EVEREST) showed its efficacy to be less than that of surgical repair and we await the results of new randomized studies that should clarify which patient-type can benefit most from this technique. Other left ventricular remodeling devices, tendinous cord implantation, and leaflet ablation are currently undergoing preclinical development or first-in-human experimentation. Finally, the development of biological prostheses for percutaneous mitral valve replacement is at an early stage. Many promising experiments at the preclinical phase and initial experiments in humans will very probably multiply in the near future. However, the true role of this technique in treating mitral valve disease will have to be evaluated in appropriately designed randomized controlled studies. PMID- 24776208 TI - Biventricular implantable cardioverter-defibrillator post-implant radiology: a unique image. PMID- 24776209 TI - Dry pericarditis, diagnosis with cardiac magnetic resonance imaging. PMID- 24776210 TI - Septal myectomy in recurrent subaortic membrane. PMID- 24776211 TI - Stent thrombosis in ostial lesion: diagnosis and treatment guided by optical coherence tomography. PMID- 24776212 TI - Clinical profile and prognosis of patients with low-density lipoprotein cholesterol <70mg/dL and acute coronary syndrome. PMID- 24776213 TI - Results of intra-aortic balloon counterpulsation in patients with st-elevation myocardial infarction with cardiogenic shock undergoing percutaneous coronary intervention: is there a benefit? PMID- 24776214 TI - Disease burden attributable to major risk factors in Western European countries: the challenge of controlling cardiovascular risk factors. PMID- 24776215 TI - Prevention of opioid withdrawal syndrome after pediatric heart transplantation: usefulness of dexmedetomidine. PMID- 24776216 TI - Electrical storm secondary to acute myocardial infarction and heart failure treated with left stellate ganglion block. PMID- 24776217 TI - Development of a conceptually equivalent Chinese-language translation of the US Household Food Security Survey Module for Chinese immigrants to the USA - Corrigendum. PMID- 24776218 TI - Effectiveness of tranexamic acid on intraoperative blood loss in isolated Le Fort I osteotomies--a prospective, triple blinded randomized clinical trial. AB - The aim of this triple blinded randomized clinical trial was to evaluate the efficacy of tranexamic acid when used in conjunction with hypotensive anaesthesia exclusively for Le Fort I osteotomies. 49 patients undergoing Le Fort I osteotomy for correction of dentofacial deformity were divided into two groups; Group 1 received a placebo of saline 5 ml and Group 2 received 10 mg/kg body weight of tranexamic acid. The operating surgeon, anaesthetist and investigator were blinded. The variables of interest recorded in this study included the change in Hb%, PCV, total blood loss, total operating time and quality of the surgical field using Fromme's Ordinal Scale. Statistically significant differences between the two groups were found between the following variables: post-operative Hb%, drop in Hb%, post-operative PCV, drop in PCV, total surgical blood loss, total operating time and quality of surgical field (P < 0.05). Group 2 patients exhibited a smaller drop in Hb% and PCV, with a lower Fromme's Ordinal Scale value and decreased total blood loss and operating time. In conclusion single preoperative administration of tranexamic acid in the dose of 10 mg/kg, when combined with hypotensive anaesthesia is effective in controlling blood loss with regards to single piece Le Fort I surgery. PMID- 24776219 TI - Formalin-fixed paraffin-embedded tissue as a source for quantitation of carcinogen DNA adducts: aristolochic acid as a prototype carcinogen. AB - DNA adducts are a measure of internal exposure to genotoxicants. However, the measurement of DNA adducts in molecular epidemiology studies often is precluded by the lack of fresh tissue. In contrast, formalin-fixed paraffin-embedded (FFPE) tissues frequently are accessible, although technical challenges remain in retrieval of high quality DNA suitable for biomonitoring of adducts. Aristolochic acids (AA) are human carcinogens found in Aristolochia plants, some of which have been used in the preparation of traditional Chinese herbal medicines. We previously established a method to measure DNA adducts of AA in FFPE tissue. In this study, we examine additional features of formalin fixation that could impact the quantity and quality of DNA and report on the recovery of AA-DNA adducts in mice exposed to AA. The yield of DNA isolated from tissues fixed with formalin decreased over 1 week; however, the levels of AA-DNA adducts were similar to those in fresh frozen tissue. Moreover, DNA from FFPE tissue served as a template for PCR amplification, yielding sequence data of comparable quality to DNA obtained from fresh frozen tissue. The estimates of AA-DNA adducts measured in freshly frozen tissue and matching FFPE tissue blocks of human kidney stored for 9 years showed good concordance. Thus, DNA isolated from FFPE tissues may be used to biomonitor DNA adducts and to amplify genes used for mutational analysis, providing clues regarding the origin of human cancers for which an environmental cause is suspected. PMID- 24776221 TI - Distracted driving: What is the state of the science, and what are our knowledge gaps? PMID- 24776220 TI - A critical role of non-classical MHC in tumor immune evasion in the amphibian Xenopus model. AB - Non-classical class Ib (class Ib) genes are found in all jawed vertebrates, including the amphibian Xenopus, which possesses at least 20 distinct Xenopus non classical class Ib genes (XNCs). As an immune evasion strategy, tumors often downregulate surface expression of classical major histocompatibility complex class Ia molecules. In contrast, cancers commonly express class Ib molecules, presenting an alternative for tumor immune recognition. We characterized a novel XNC, XNC10, functionally similar to CD1d from a class Ia-deficient thymic lymphoid tumor (15/0), which grows aggressively in Xenopus LG-15 cloned animals. To investigate the roles of XNC10 in antitumor immunity, we generated stable 15/0 transfectants with silenced XNC10 mRNA and protein expression. Notably, XNC10 silencing resulted in acute tumor rejection by naturally class Ia-deficient syngeneic tadpoles, with greater potency of rejection in tumors with more efficient XNC10 knockdown. In vivo killing assays shows that the rejection of XNC10-deficient tumors is due to a cell-mediated cytotoxic immune response elicited by the tadpole host. Importantly, priming enhances XNC10-deficient tumor rejection. Flow cytometry reveals that XNC10-deficient tumor rejection is associated with an accumulation of XNC10-restricted invariant T cells and conventional CD8 T cells as well as other leukocytes. Similarly, semisolid tumor grafts in tadpoles also exhibit leukocytes infiltration. These findings suggest that XNC10 allows the 15/0-tumor to escape immune recognition and class Ia independent cytotoxicity, thus emphasizing the critical roles of class Ibs in tumor immunity. PMID- 24776222 TI - Towards an understanding of driver inattention: taxonomy and theory. AB - There is little agreement in the scientific literature about what the terms "driver distraction" and "driver inattention" mean, and what the relationship is between them. In 2011, Regan, Hallett and Gordon proposed a taxonomy of driver inattention in which driver distraction is conceptualized as just one of several processes that give rise to driver inattention. Since publication of that paper, two other papers have emerged that bear on the taxonomy. In one, the Regan et al taxonomy was used, for the first time, to classify data from an in-depth crash investigation in Australia. In the other, another taxonomy of driver inattention was proposed and described. In this paper we revisit the original taxonomy proposed by Regan et al. in light of these developments, and make recommendations for how the original taxonomy might be improved to make it more useful as a tool for classifying and coding crash and critical incident data. In addition, we attempt to characterize, theoretically, the processes within each category of the original taxonomy that are assumed to give rise to driver inattention. Recommendations are made for several lines of research: to further validate the original taxonomy; to understand the impact of each category of inattention in the taxonomy on driving performance, crash type and crash risk; and to revise and align with the original taxonomy existing crash and incident investigation protocols, so that they provide more comprehensive, reliable and consistent information regarding the contribution of inattention to crashes of all types. PMID- 24776223 TI - Visual and cognitive distraction metrics in the age of the smart phone: A basic review. AB - Sources of distraction are numerous and varied, and defining and measuring distraction and attention is complicated. The driving task requires constant adjustments and reallocation of attention to cognitive, motor, and visual processes. While it is fairly straightforward to measure distraction in an experimental situation (e.g., simulator, closed course), driver distraction in the real world is highly contextual. While no single metric is capable of capturing the complexities of distraction, several have proved useful in helping researchers gain fuller understanding of it. Few have reached a level of consensus among researchers and user interface designers. ISO and SAE may be considered the 'gold standard' for providing mechanisms through which open scientific consensus-based standards can be achieved.While there are a number of metrics used in predicting distraction, three have been studied closely and are going through the SAE and ISO standards process. They are (1) 'the occlusion method'; (2) the Lane Change Test (LCT); and (3) the Detection Response Task (DRT). The metrics described here apply generally to the experimental context where driving is tightly controlled. Like any method, there are limitations with each-and they don't necessarily agree with one another.Experimental methods and analyses are different than those in naturalistic driving (ND). ND relies more on data mining versus traditional experimental manipulation. ND data are a challenge precisely in that they lack experimental control.In future, driver metrics will go beyond specific measurement of task load, and will include how drivers self regulate when they choose to be distracted. PMID- 24776224 TI - Dynamics of Driver Distraction: The process of engaging and disengaging. AB - Driver distraction research has a long history, spanning nearly 50 years, but intensifying over the last decade. The dominant paradigm guiding this research defines distraction in terms of excessive workload and limited attentional resources. This approach largely ignores how drivers come to engage in these tasks and under what conditions they engage and disengage from driving-the dynamics of distraction. The dynamics of distraction identifies breakdowns of interruption management as an important contributor to distraction, leading to describe distraction in terms of failures of task timing, switching, and prioritization. The dynamics of distraction also identifies disengagement in driving (e.g., mind wandering) as a substantial challenge that secondary tasks might exacerbate or mitigate. Increasing vehicle automation accentuates the need to consider these dynamics of distraction. Automation offers drivers more opportunity to engage in distractions and disengage from driving, and can surprise drivers by unexpectedly requiring drivers to quickly re-engage in driving-placing greater importance of interruption management expertise. This review describes distraction in terms of breakdowns in interruption management and problems of engagement, and summarizes how contingency, conditioning, and consequence traps lead to problems of engaging and disengaging in driving and distractions. PMID- 24776225 TI - Modeling situation awareness and crash risk. AB - In this article we develop a model of the relationship between crash risk and a driver's situation awareness. We consider a driver's situation awareness to reflect the dynamic mental model of the driving environment and to be dependent upon several psychological processes including Scanning the driving environment, Predicting and anticipating hazards, Identifying potential hazards in the driving scene as they occur, Deciding on an action, and Executing an appropriate Response (SPIDER). Together, SPIDER is important for establishing and maintaining good situation awareness of the driving environment and good situation awareness is important for coordinating and scheduling the SPIDER-relevant processes necessary for safe driving. An Order-of-Processing (OP) model makes explicit the SPIDER relevant processes and how they predict the likelihood of a crash when the driver is or is not distracted by a secondary task. For example, the OP model shows how a small decrease in the likelihood of any particular SPIDER activity being completed successfully (because of a concurrent secondary task performance) would lead to a large increase in the relative risk of a crash. PMID- 24776226 TI - An opportunity for convergence? Understanding the prevalence and risk of distracted driving through the use of crash databases, crash investigations, and other approaches. AB - A variety of methodologies for understanding the prevalence of distracted driving, its risk, and other aspects of driver secondary activity, have been used in the last 15 years. Although the current trend is toward naturalistic driving studies, each methodology contributes certain elements to a better understanding that could emerge from a convergence of these efforts. However, if differing methods are to contribute to a common and robust understanding of driver distraction, it is critical to understand the strengths and limitations of each method. This paper reviews several of the non-naturalistic methods. It suggests that "convergence science" - a more concerted and rigorous effort to bring different approaches together into an integrative whole - may offer benefits for identification and definition of issues and countermeasure development to improve driving safety. PMID- 24776227 TI - Estimates of prevalence and risk associated with inattention and distraction based upon in situ naturalistic data. AB - By using in situ naturalistic driving data, estimates of prevalence and risk can be made regarding driver populations' secondary task distractions and crash rates. Through metadata analysis, three populations of drivers (i.e., adult light vehicle, teenaged light vehicle, and adult heavy vehicle) were compared regarding frequency of secondary task behavior and the associated risk for safety-critical incidents. Relative risk estimates provide insight into the risk associated with engaging in a single task. When such risk is considered in combination with frequency of use, it sheds additional light on those secondary tasks that create the greatest overall risk to driving safety. The results show that secondary tasks involving manual typing, texting, dialing, reaching for an object, or reading are dangerous for all three populations. Additionally, novice teen drivers have difficulty in several tasks that the other two populations do not, including eating and external distractions. Truck drivers also perform a number of risky "mobile office" types of tasks, including writing, not seen in the other populations. Implications are described for policy makers and designers of in vehicle and nomadic, portable systems. PMID- 24776228 TI - Special considerations in distracted driving with teens. AB - Novice teen drivers have long been known to have an increased risk of crashing, as well as increased tendencies toward unsafe and risky driving behaviors. Teens are unique as drivers for several reasons, many of which have implications specifically in the area of distracted driving. This paper reviews several of these features, including the widespread prevalence of mobile device use by teens, their lack of driving experience, the influence of peer passengers as a source of distraction, the role of parents in influencing teens' attitudes and behaviors relevant to distracted driving and the impact of laws designed to prevent mobile device use by teen drivers. Recommendations for future research include understanding how engagement in a variety of secondary tasks by teen drivers affects their driving performance or crash risk; understanding the respective roles of parents, peers and technology in influencing teen driver behavior; and evaluating the impact of public policy on mitigating teen crash risk related to driver distraction. PMID- 24776229 TI - U.s. State and federal laws targeting distracted driving. AB - Distracted driving has burgeoned with the proliferation of cell phones, global positioning systems and other in-vehicle and personal electronic devices. Annually more than 3,300 people are killed and an additional 400,000 are injured in the United States in distracted driving crashes. The United States (U.S.) federal and state governments have responded to this public health problem with policies and laws; however, a more comprehensive and more effective approach is still needed. Some restrictions on the use of electronic devices while driving by federal employees and some voluntary guidelines and recommendations have been issued. Public opinion polls show support for addressing the issue of distracted driving with state laws. The majority of states have laws banning text messaging while driving and prohibiting the use of an electronic device by teenage or novice drivers. Some states prohibit all drivers from using a hand-held cellphone. Currently no state has a total ban on the use of personal electronic devices while driving. Successful past traffic safety campaigns changing driver behavior have demonstrated the necessity to adopt a "three Es" approach of Enactment of a law, Education of the public about the law, and rigorous Enforcement of the law. Experience reveals that this approach, along with future federal regulation of in-vehicle electronic devices and the employment of technology to limit the use of electronic devices while driving, is needed to alter personal behavior in order to reduce distractions and keep drivers focused on the driving task. PMID- 24776230 TI - Driver cellphone and texting bans in the United States: evidence of effectiveness. AB - Almost all U.S. states have laws limiting drivers' cellphone use. The evidence suggests that all-driver bans on hand-held phone conversations have resulted in long-term reductions in hand-held phone use, and drivers in ban states reported higher rates of hands-free phone use and lower overall phone use compared with drivers in non-ban states. Bans on all phone use by teenage drivers have not been shown to reduce their phone use. The effects of texting bans on the rates of drivers' texting are unknown. With regard to the effects of bans on crashes, 11 peer-reviewed papers or technical reports of all-driver hand-held phone bans and texting bans were reviewed. Some were single-state studies examining crash measures before and after a state ban; other national or multi-state studies compared crashes in states with and without bans over time. The results varied widely. The lack of appropriate controls and other challenges in conducting strong evaluations limited the findings of some studies. Thus, despite the proliferation of laws limiting drivers' cellphone use, it is unclear whether they are having the desired effects on safety. Priorities for future research are suggested. PMID- 24776231 TI - SMOQ: a tool for predicting the absolute residue-specific quality of a single protein model with support vector machines. AB - BACKGROUND: It is important to predict the quality of a protein structural model before its native structure is known. The method that can predict the absolute local quality of individual residues in a single protein model is rare, yet particularly needed for using, ranking and refining protein models. RESULTS: We developed a machine learning tool (SMOQ) that can predict the distance deviation of each residue in a single protein model. SMOQ uses support vector machines (SVM) with protein sequence and structural features (i.e. basic feature set), including amino acid sequence, secondary structures, solvent accessibilities, and residue-residue contacts to make predictions. We also trained a SVM model with two new additional features (profiles and SOV scores) on 20 CASP8 targets and found that including them can only improve the performance when real deviations between native and model are higher than 5A. The SMOQ tool finally released uses the basic feature set trained on 85 CASP8 targets. Moreover, SMOQ implemented a way to convert predicted local quality scores into a global quality score. SMOQ was tested on the 84 CASP9 single-domain targets. The average difference between the residue-specific distance deviation predicted by our method and the actual distance deviation on the test data is 2.637A. The global quality prediction accuracy of the tool is comparable to other good tools on the same benchmark. CONCLUSION: SMOQ is a useful tool for protein single model quality assessment. Its source code and executable are available at: http://sysbio.rnet.missouri.edu/multicom_toolbox/. PMID- 24776232 TI - Evaluation of portable microscopic devices for the diagnosis of Schistosoma and soil-transmitted helminth infection. AB - The diagnosis of parasitic worm (helminth) infections requires specialized laboratory settings, but most affected individuals reside in locations without access to such facilities. We tested two portable microscopic devices for the diagnosis of helminth infections in a cross-sectional survey in rural Cote d'Ivoire. We examined 164 stool samples under a light microscope and then re examined with a commercial portable light microscope and an experimental mobile phone microscope for the diagnosis of Schistosoma mansoni and soil-transmitted helminths. Additionally, 180 filtered urine samples were examined by standard microscopy and compared with the portable light microscope for detection of Schistosoma haematobium eggs. Conventional microscopy was considered the diagnostic reference standard. For S. mansoni, S. haematobium and Trichuris trichiura, the portable light microscope showed sensitivities of 84.8%, 78.6% and 81.5%, respectively, and specificities of 85.7%, 91.0% and 93.0%, respectively. For S. mansoni and T. trichiura, we found sensitivities for the mobile phone microscope of 68.2% and 30.8%, respectively, and specificities of 64.3% and 71.0%, respectively. We conclude that the portable light microscope has sufficient diagnostic yield for Schistosoma and T. trichiura infections, while the mobile phone microscope has only modest sensitivity in its current experimental set-up. Development of portable diagnostic technologies that can be used at point-of-sample collection will enhance diagnostic coverage in clinical and epidemiological settings. PMID- 24776301 TI - The effect of flexor hallucis longus harvest on hallux function: a retrospective cross-sectional cohort study. AB - BACKGROUND AND AIM: Our aim was to evaluate the long-term morbidity of the hallux function after harvesting a free fibula flap. Special attention was given to the differences between patients who underwent the dissection of an osteo-cutaneous flap (without inclusion of the flexor hallucis longus (FHL) muscle) and patients who were treated with an osteo-myo-cutaneous (with inclusion of the FHL muscle). METHODS: During the period 1995-2009, 167 patients underwent an autologous mandible reconstruction using a free fibula flap. By the time of our investigation, 64 patients were deceased, 29 patients were lost to follow-up, 14 patients did not meet the inclusion criteria and 28 patients were unable or unwilling to come to the hospital. Thus, 32 patients were examined in this study. Combined flexion strength of the hallux flexors and range of motion (ROM) of the metatarsophalangeal (MTP) and interphalangeal (IP) joints were measured. RESULTS: Hallux flexion strength tests showed a significant decrease in strength in the operated leg versus control, 28+/-16.6 versus 37+/-19.2 N/s (p=0.003). The ROM for the MTP was significantly lower for the donor leg than for the control leg: 26+/-12 degrees versus 30+/-10 degrees (p=0.024) for plantar flexion and 30+/ 13 degrees versus 37+/-11 degrees (p<0.001) for dorsal flexion. In addition, the ROM for plantar flexion in the IP joint was significantly lower in the donor group. No significant differences were found when comparing reduction of flexion strength or reduction of ROM in the osteo-cutaneous versus osteo-myo-cutaneous harvest. CONCLUSIONS: The main conclusion to be drawn from our results is that free fibula flap donor site morbidity in terms of hallux function is independent of the inclusion or exclusion of the FHL muscle in the flap. LEVEL OF EVIDENCE III: Retrospective cohort or comparative study; case-control study; or systematic review of these studies. PMID- 24776302 TI - Standard versus over-tensioning in the transfer of extensor indicis proprius to extensor pollicis longus for chronic rupture of the thumb extensor. AB - PURPOSE: The purpose of this study was to evaluate the functional outcomes of the over-tensioning technique compared with those of the standard tensioning technique in the transfer of extensor indicis proprius (EIP) to extensor pollicis longus (EPL) for the chronic rupture of the thumb extensor. METHODS: Data were collected from patients who underwent tendon transfer using EIP between March 2003 and August 2011. 23 were treated with the standard tensioning technique and 25 patients (Group B) with the over-tensioning technique. While standard tension was maintained with the thumb in full extension and the wrist in 30 degrees of flexion, over-tension was maintained with the thumb in full extension and the wrist in the neutral position. All patients were assessed for total range of motion, elevation and flexion deficit, the thumb grip and pinch strength, and the thumb and the index extension strength compared to the unaffected side, EIP-EPL evaluation as suggested by Lemmen et al. and Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH). RESULTS: Group A: total range of motion 115 degrees , elevation deficit 2.0 cm, combined flexion deficit 1.0 cm, thumb extension strength 75%, thumb grip strength 91%, and pinch strength 87%. Functional outcomes were 13 excellent, 6 good, 3 fair, and 1 poor. Median DASH score was 21.3 points. Group B: total range of motion 125 degrees , elevation deficit 1.0 cm, combined flexion deficit 1.5 cm, thumb extension strength 85%, thumb grip strength 88%, and pinch strength 83%. Functional outcomes were 16 excellent, 7 good, 2 fair, and 0 poor. Median DASH score was 19.8 points. There are significant differences in the range of motion, elevation deficit, and extension strength of thumb between the two groups (p=.001, p=.001, and p=.028, respectively). CONCLUSION: While the functional outcomes of both groups were favorably acceptable in a majority of the patients, there were significant differences in aspects of range of motion, elevation deficit, and strength of the thumb between both groups. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 24776300 TI - Nitro drugs for the treatment of trypanosomatid diseases: past, present, and future prospects. AB - There is an urgent need for new, safer, and effective treatments for the diseases caused by the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. In the search for more effective drugs to treat these 'neglected diseases' researchers have chosen to reassess the therapeutic value of nitroaromatic compounds. Previously avoided in drug discovery programs owing to potential toxicity issues, a nitro drug is now being used successfully as part of a combination therapy for human African trypanosomiasis. We describe here the rehabilitation of nitro drugs for the treatment of trypanosomatid diseases and discuss the future prospects for this compound class. PMID- 24776303 TI - New evidence of ethanol's anxiolytic properties in the infant rat. AB - Ethanol induces appetitive, aversive, and anxiolytic effects that are involved in the development of ethanol use and dependence. Because early ethanol exposure produces later increased responsiveness to ethanol, considerable effort has been devoted to analysis of ethanol's appetitive and aversive properties during early ontogeny. Yet, there is a relative scarcity of research related to the anxiolytic effects of ethanol during early infancy, perhaps explained by a lack of age appropriate tests. The main aim of this study was to validate a model for the assessment of ethanol's anxiolytic effects in the infant rat (postnatal days 13 16). The potentially anxiolytic effects of ethanol tested included: i) amelioration of conditioned place aversion, ii) ethanol intake in the presence of an aversive conditioned stimulus, iii) the inhibitory behavioral effect in an anxiogenic environment, and iv) innate aversion to a brightly illuminated area in a modified light/dark paradigm. Ethanol doses employed across experiments were 0.0, 0.5, and 2.0 g/kg. Results indicated that a low ethanol dose (0.5 g/kg) was effective in attenuating expression of a conditioned aversion. Ethanol intake, however, was unaffected by simultaneous exposure to an aversive stimulus. An anxiogenic environment diminished ethanol-induced locomotor stimulation. Finally, animals given 0.5 g/kg ethanol and evaluated in a light/dark box showed increased time spent in the illuminated area and increased latency to escape from the brightly lit compartment than rats treated with a higher dose of ethanol or vehicle. These new results suggest that ethanol doses as low as 0.5 g/kg are effective in ameliorating an aversive and/or anxiogenic state in preweanling rats. These behavioral preparations can be used to assess ethanol's anxiolytic properties during early development. PMID- 24776304 TI - Amount and distribution of neustonic micro-plastic off the western Sardinian coast (Central-Western Mediterranean Sea). AB - A plethora of different sampling methodologies has been used to document the presence of micro-plastic fragments in sea water. European Marine Strategy suggests to improve standard techniques to make future data comparable. We use Manta Trawl sampling technique to quantify abundance and distribution of micro plastic fragments in Sardinian Sea (Western Mediterranean), and their relation with phthalates and organoclorine in the neustonic habitat. Our results highlight a quite high average plastic abundance value (0.15 items/m(3)), comparable to the levels detected in other areas of the Mediterranean. "Site" is the only factor that significantly explains the differences observed in micro-plastic densities. Contaminant levels show high spatial and temporal variation. In every station, HCB is the contaminant with the lowest concentration while PCBs shows the highest levels. This work, in line with Marine Strategy directives, represents a preliminary study for the analysis of plastic impact on marine environment of Sardinia. PMID- 24776326 TI - Risk assessment following ST-segment elevation myocardial infarction. PMID- 24776325 TI - Short-term aerobic exercise and vascular function in CKD stage 3: a randomized controlled trial. AB - BACKGROUND: The present study was designed to determine the effect of short-term moderate-intensity exercise training on arterial stiffness in patients with chronic kidney disease (CKD) stage 3. STUDY DESIGN: Randomized controlled trial with a parallel-group design. SETTING & PARTICIPANTS: Testing and training sessions were performed at Springfield College. 46 (treatment group, n=25; control group, n=21) patients with CKD with diabetes and/or hypertension completed the study. INTERVENTION: The aerobic training program consisted of 16 weeks of supervised exercise training at 50%-60% peak oxygen uptake (Vo2peak) 3 times per week, while the control group remained sedentary. Identical testing procedures were performed following the 16-week intervention. OUTCOMES: The primary outcome was arterial stiffness. Secondary outcomes were aerobic capacity, various blood parameters (endothelin 1, nitrate/nitrite, and high-sensitivity C reactive protein), and health-related quality of life. MEASUREMENTS: Arterial stiffness was assessed with aortic pulse wave velocity (PWV), aerobic capacity by Vo2peak, blood parameters by enzyme-linked immunosorbent assays, and health related quality of life by the 36-Item Short Form Health Survey (SF-36). Participants attended 4 sessions before being randomly assigned to either the treatment or control group. Participants gave consent during the first session, whereas a graded exercise test with measurement of Vo2peak was completed during the second session. During sessions 3 and 4, aortic PWV was measured at rest prior to 40 minutes of either moderate-intensity exercise training or seated rest. A venous blood sample was obtained prior to exercise or rest and participants completed the SF-36 questionnaire. RESULTS: 16 weeks of training led to an 8.2% increase in Vo2peak for the treatment group (P=0.05), but no changes in aortic PWV . LIMITATIONS: Randomization was not concealed and was violated on one occasion; also, use of an indirect measurement of endothelial function and the short duration of the intervention. CONCLUSIONS: Short-term moderate intensity exercise training does not alter arterial stiffness in patients with CKD, but seems to reduce endothelin 1 levels. PMID- 24776327 TI - Cardiac arrest survivors before they reach hospital. Beyond cardiopulmonary resuscitation. PMID- 24776328 TI - Correcting tricuspid regurgitation: an unresolved issue. PMID- 24776329 TI - Long-term prognostic value of a comprehensive assessment of cardiac magnetic resonance indexes after an ST-segment elevation myocardial infarction. AB - INTRODUCTION AND OBJECTIVES: A variety of cardiac magnetic resonance indexes predict mid-term prognosis in ST-segment elevation myocardial infarction patients. The extent of transmural necrosis permits simple and accurate prediction of systolic recovery. However, its long-term prognostic value beyond a comprehensive clinical and cardiac magnetic resonance evaluation is unknown. We hypothesized that a simple semiquantitative assessment of the extent of transmural necrosis is the best resonance index to predict long-term outcome soon after a first ST-segment elevation myocardial infarction. METHODS: One week after a first ST-segment elevation myocardial infarction we carried out a comprehensive quantification of several resonance parameters in 206 consecutive patients. A semiquantitative assessment (altered number of segments in the 17-segment model) of edema, baseline and post-dobutamine wall motion abnormalities, first pass perfusion, microvascular obstruction, and the extent of transmural necrosis was also performed. RESULTS: During follow-up (median 51 months), 29 patients suffered a major adverse cardiac event (8 cardiac deaths, 11 nonfatal myocardial infarctions, and 10 readmissions for heart failure). Major cardiac events were associated with more severely altered quantitative and semiquantitative resonance indexes. After a comprehensive multivariate adjustment, the extent of transmural necrosis was the only resonance index independently related to the major cardiac event rate (hazard ratio=1.34 [1.19-1.51] per each additional segment displaying>50% transmural necrosis, P<.001). CONCLUSIONS: A simple and non-time consuming semiquantitative analysis of the extent of transmural necrosis is the most powerful cardiac magnetic resonance index to predict long-term outcome soon after a first ST-segment elevation myocardial infarction. PMID- 24776330 TI - Clinical characteristics and vital and functional prognosis of out-of-hospital cardiac arrest survivors admitted to five cardiac intensive care units. AB - INTRODUCTION AND OBJECTIVES: Survivors of out-of-hospital cardiac arrest constitute an increasing patient population in cardiac intensive care units. Our aim was to characterize these patients and determine their vital and functional prognosis in accordance with the latest evidence. METHODS: A multicenter, prospective register was constructed with information from patients admitted to 5 cardiac intensive care units from January 2010 through January 2012 with a diagnosis of resuscitated out-of-hospital cardiac arrest. The information included clinical status, cardiac arrest characteristics, in-hospital course, and vital and neurologic status at discharge and at 6 months. RESULTS: A total of 204 patients were included. In 64% of cases, a first shockable rhythm was identified. The time to return of spontaneous circulation was 29 (18) min. An etiologic diagnosis was made in 86% of patients; 44% were discharged with no neurologic sequelae; 40% died in the hospital. At 6 months, 79% of survivors at discharge were still alive and neurologically intact with minimal sequelae. Short resuscitation time, first recorded rhythm, pH on admission >7.1, absence of shock, and use of hypothermia were the independent variables associated with a good neurologic prognosis. CONCLUSIONS: Half the patients who recovered from out of-hospital cardiac arrest had good neurologic prognosis at discharge, and 79% of survivors were alive and neurologically intact after 6 months of follow-up. PMID- 24776331 TI - Short- and long-term outcomes of surgery for severe tricuspid regurgitation. AB - INTRODUCTION AND OBJECTIVES: There is little data available for Spain on the outcomes of surgical treatment for severe tricuspid regurgitation. The aim of this study was to analyze clinical and echocardiographic outcomes in a series of patients who received surgical treatment for severe tricuspid regurgitation and to compare outcomes according to the operative approach to valve repair or replacement. METHODS: Retrospective study in 119 consecutive patients with severe tricuspid regurgitation undergoing valve surgery between April 1996 and February 2010. RESULTS: A total of 61 ringless and 23 ring annuloplasties were performed and 11 bioprostheses and 24 mechanical prostheses were implanted. Perioperative mortality was 18.5% and was associated with age and cardiopulmonary bypass time. During clinical follow-up (median, 41 [interquartile range, 24-89] months), 2 reoperations were required in the ring annuloplasty and mechanical prosthesis groups; prosthetic thrombosis was diagnosed in 4 patients in the latter group. Total mortality after follow-up was 29.9% and was associated with age>70 years and extracorporeal circulation time. The emergence of new severe tricuspid regurgitation was associated with age and ringless annuloplasty (P=.04). CONCLUSIONS: Ringless repair was significantly associated with recurrence of severe tricuspid regurgitation. The use of mechanical prostheses was associated with a high rate of thrombosis. No significant differences in perioperative or total mortality were found between the different methods used for repair or valve replacement. PMID- 24776332 TI - Approach to coronary bifurcation lesions using the everolimus-eluting stent: comparison between a simple strategy and a complex strategy with T-stenting. AB - INTRODUCTION AND OBJECTIVES: Coronary bifurcation lesions can be approached using a simple or a complex strategy. In clinical trials with first-generation drug eluting stents, the complex strategy was not superior to the simple approach. However, to date, the best strategy when using second-generation drug-eluting stents has not been defined. METHODS: We performed a prospective randomized study comparing a simple vs a complex strategy involving T-stenting for the percutaneous revascularization of bifurcation lesions using the everolimus eluting stent. Angiographic and clinical follow-up were performed at 9 months. RESULTS: We included 70 lesions in 69 patients, who were randomized to the simple (34 lesions, 33 patients) or complex strategy (36 lesions and patients). In all, 85.6% of the lesions included were true bifurcations. The crossover rate was 17.1%. The binary restenosis rate was 12.1%, with no differences between the groups. Side branch restenosis tended to be higher with the simple strategy in the intention to treat analysis (10.7% vs 0%) but not in the per protocol analysis (5.9% vs 4.2%). The incidence of major adverse cardiac events (cardiac death, myocardial infarction, and target vessel revascularization) was 9.2%, with no differences between groups. There were no cases of stent thrombosis. CONCLUSIONS: According to the clinical and angiographic findings, the complex strategy was not significantly superior to the simple approach in the revascularization of bifurcation lesions with second-generation everolimus-drug eluting stents. PMID- 24776333 TI - Preservation of the bicuspid aortic valve associated with aneurysms of the aortic root and ascending aorta. AB - INTRODUCTION AND OBJECTIVES: When the bicuspid aortic valve is associated with dilatation of the aorta, surgical repair requires correction of all the components of the aortic root. Here, we review our experience in this type of surgery. METHODS: A descriptive and retrospective observational study was carried out to analyze morbidity and mortality in valve-sparing techniques and evaluate the medium-term durability of the aortic valve. We included all patients with a bicuspid aortic valve and dilatation of the aorta who underwent surgery with a valve-sparing technique in our center between 1999 and 2011. RESULTS: A total of 151 patients underwent surgery. A valve-sparing technique was used in 51 patients. The mean (standard deviation) age of the patients was 51 (12) years and 92% were men. In 69% of the patients, aortic insufficiency was less than grade II and the aortic cusps showed little structural degeneration. Valve reimplantation was performed in 32 patients. There was no hospital mortality. With a median follow-up of 36 months (interquartile range, 18-45 months), none of the patients died or required reoperation, and all patients were free of aortic insufficiency greater than grade II. CONCLUSIONS: Valve-preserving surgery in bicuspid aortic valves associated with dilatation of the aorta shows excellent short- and medium term results in selected valves. The stabilization of all of the components of the aortic root improves the durability of the valve, and the techniques proposed are reproducible and stable in the medium-term. PMID- 24776334 TI - Epidemiology of heart failure in Spain over the last 20 years. AB - Heart failure is a major health care problem in Spain, although its precise impact is unknown due to the lack of data from appropriately designed studies. In contrast with the 2% prevalence of heart failure elsewhere in Europe and in the United States, studies in Spain report figures of 5%, probably because of methodological limitations. Heart failure consumes enormous quantities of health care resources; it is the first cause of hospitalization in persons aged 65 years or older and represents 3% of all hospital admissions and 2.5% of health care costs. There are two patterns of heart failure: one with preserved systolic function, more often associated with high blood pressure, and another with depressed systolic function, more often associated with ischemic heart disease. In 2010, heart failure accounted for 3% of all deaths in men and for 10% of all deaths in women. In recent years, the mortality rate from heart failure has gradually fallen. The rise in hospital admissions for heart failure and the decrease in mortality from this cause could partly be explained by temporary changes in diagnostic coding, but there is evidence that the reduced mortality could also be due to adherence to clinical practice guidelines. PMID- 24776335 TI - Proteomics and metabolomics for mechanistic insights and biomarker discovery in cardiovascular disease. AB - In the last decade, proteomics and metabolomics have contributed substantially to our understanding of cardiovascular diseases. The unbiased assessment of pathophysiological processes without a priori assumptions complements other molecular biology techniques that are currently used in a reductionist approach. In this review, we highlight some of the "omics" methods used to assess protein and metabolite changes in cardiovascular disease. A discrete biological function is very rarely attributed to a single molecule; more often it is the combined input of many proteins. In contrast to the reductionist approach, in which molecules are studied individually, "omics" platforms allow the study of more complex interactions in biological systems. Combining proteomics and metabolomics to quantify changes in metabolites and their corresponding enzymes will advance our understanding of pathophysiological mechanisms and aid the identification of novel biomarkers for cardiovascular disease. PMID- 24776336 TI - Fibrotic periaortitis infiltrating into the aortic and mitral valves. PMID- 24776337 TI - Peri-stent ulcer like appearance late after sirolimus-eluting stent implantation. PMID- 24776338 TI - Cardiac invasion of esophageal tumor. PMID- 24776339 TI - Implantable loop recorder: a new tool in the diagnosis of cryptogenic stroke. PMID- 24776340 TI - Direct transfemoral aortic valve implantation in a patient with a mechanical mitral prosthesis. PMID- 24776341 TI - Dronedarone: an option in the treatment of ventricular arrhythmias. PMID- 24776342 TI - Nonvalvular atrial aneurysmal dilation. PMID- 24776343 TI - Aortitis: an unusual cause of acute chest pain. PMID- 24776344 TI - Baseline right ventricular volumes and function are associated with response to cardiac resynchronization therapy and long-term mortality. PMID- 24776345 TI - The heart of Revista Clinica Espanola, 2012. PMID- 24776373 TI - [Erratum]. PMID- 24776374 TI - Cognitive related electrophysiological changes induced by non-invasive cortical electrical stimulation in crack-cocaine addiction. AB - Prefrontal dysfunction is a hallmark in drug addiction, yet interventions exploring modulation of prefrontal cortex function in drug addiction have not been fully investigated with regard to physiological alterations. We tested the hypothesis that non-invasive prefrontal stimulation would change neural activity in crack-cocaine addiction, investigating the effects of transcranial Direct Current Stimulation (tDCS) of Dorsolateral Prefrontal Cortex (DLPFC) induced cortical excitability modulation on the visual P3 Event Related Potentials (ERP) component under neutral and drug cue exposition in crack-cocaine addicts. Thirteen crack-cocaine users were randomly distributed to receive five applications (once a day, every other day) of bilateral (left cathodal/right anodal) tDCS (20 min, 2 mA, 35 cm2) or sham tDCS over the DLPFC. Brain activity was measured under crack-related or neutral visual-cued ERPs. There were significant differences in P3-related parameters when comparing group of stimulation (active vs. sham tDCS) and number of sessions (single vs. repetitive tDCS). After a single session of tDCS, P3 current intensity in the left DLPFC increased during neutral cues and decreased during crack-related cues. This effect was opposite to what was observed in the sham-tDCS group. In contrast, repetitive tDCS increased current density not only in the DLPFC, but also in a wider array of prefrontal areas, including presumably the frontopolar cortex (FPC) orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC), when subjects were visualizing crack-related cues. Thus, single and repetitive application of tDCS can impact cognitive processing of neutral and especially crack-related visual cues in prefrontal areas, which may be of importance for treatment of crack-cocaine addiction. PMID- 24776375 TI - Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. AB - Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected and current treatment is often suboptimal.To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non cholesterol risk factors and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed.This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources. PMID- 24776376 TI - Relative efficacy of antianginal drugs used as add-on therapy in patients with stable angina: A systematic review and meta-analysis. AB - AIMS: First-line medical management of stable angina generally involves a beta blocker (BB) or calcium channel blocker (CCB), with other classes of medication being added if symptom control is inadequate. Evidence supporting the appropriate choice of a second-line agent is currently unclear. The objective of this systematic review was to quantify the clinical benefit of BB, CCBs, long-acting nitrates (LANs), ranolazine, trimetazidine, ivabradine or nicorandil added to first-line monotherapy for stable coronary artery disease. METHODS: Randomised controlled trials comparing the efficacy of antianginal therapies in patients with stable angina refractory to first-line therapy were identified from a literature search. Exercise tolerance test (ETT) data and clinical outcomes were extracted and combined in a series of meta-analyses. RESULTS: A total of 46 qualifying studies were identified, evaluating 71 treatment comparisons. The combination of ranolazine added to CCB or BB showed positive outcomes across all outcomes assessed. Other combinations of BB, CCB, LAN and trimetazidine showed significant benefits for most but not all outcomes. Ivabradine demonstrated benefits for ETT assessments but these were not matched in clinical domains. No qualifying studies were identified for nicorandil in an add-on role. CONCLUSION: Across a range of commonly assessed exercise and clinical outcomes, the effectiveness of BB+CCB used in combination is broadly confirmed. Ranolazine used with BB or CCB showed benefits across all outcomes assessed, while LAN and trimetazidine used with BB or CCB have shown benefits across some outcomes. Ivabradine added to BB shows inconsistent effects from a single study, whilst there is no relevant evidence for nicorandil. PMID- 24776377 TI - Early life exposure to cigarette smoke and depressive symptoms among women in midlife. AB - INTRODUCTION: Active cigarette smoking has consistently been associated with depression, but little is known about the association between other cigarette smoke exposures, particularly in early life, and depression. We investigated whether exposures to maternal smoking during pregnancy (MSP) and childhood secondhand smoke (SHS) are associated with depressive symptoms in midlife. METHODS: Pregnant mothers were enrolled and were provided data on maternal smoking and other parental characteristics. Female offspring were followed through age 7 years and again in midlife (age range = 38-44 years), when they provided data on smoking history, SHS across the life course, and current depressive symptoms using the Center for Epidemiological Studies Depression Scale (CES-D). RESULTS: Participants exposed to MSP had a higher risk for depression (risk ratio [RR] = 1.83, 95% confidence interval [CI] = 1.08, 3.09) than those without MSP exposure. Relative to those with no MSP and no childhood SHS exposures, participants with MSP and childhood SHS had more than twice the risk of depressive symptoms (RR = 2.40, 95% CI = 1.07, 5.41). Further adjustment for adult factors, particularly current smoking, substantially reduced these associations (e.g., MSP vs. no MSP exposure: RR = 1.36 [95% CI = 0.75, 2.45]). CONCLUSIONS: Early life exposure to cigarette smoke is associated with increased risk for depression in midlife, with the association largely mediated by active smoking. These findings support a role for early life cigarette exposures in shaping smoking and depression risks in later life, and they provide some support for the direction of smoke exposure influence on depression. PMID- 24776378 TI - Hemomucin, an O-glycosylated protein on embryos of the wasp Macrocentrus cingulum that protects it against encapsulation by hemocytes of the host Ostrinia furnacalis. AB - It is unclear how endoparasites passively evade their host's immune reactions in most parasite-host systems. Hemomucin from the parasitoid wasp Macrocentrus cingulum (McHEM) is a 97-kDa transmembrane protein containing 51 potential O glycosylation sites that can be specifically recognized by Arachis hypogaea lectin. Mchem mRNA is highly expressed in M. cingulum eggs, morulae and secondary embryos, and McHEM protein is mainly located on the extraembryonic membrane of embryos. When secondary embryos of M. cingulum were transplanted into naive larvae of their host, Ostrinia furnacalis, the embryos proliferated to generate dozens of embryos. However, more than 90% of these embryos were encapsulated by host hemocytes after blocking with anti-McHEM serum. Similarly, following knockdown of Mchem expression using double-stranded RNA encoding Mchem (dshem), many more embryos were encapsulated by host hemocytes after transplantation compared to controls (p < 0.01). Furthermore, approximately 70% of the embryos were encapsulated by host hemocytes following digestion with O-glycosidase, which specifically digests beta-gal (1->3) linkages between GalNAc and Ser/Thr of proteins. Western blotting results showed that O-glycosidase digested McHEM into a smaller product. These results indicate that McHEM may protect embryos from being encapsulated by their host and that the McHEM sugar chains play an important role. PMID- 24776379 TI - Long-term and short-term responses of the photosynthetic electron transport to fluctuating light. AB - Light energy absorbed by chloroplasts drives photosynthesis. When absorbed light is in excess, the thermal dissipation systems of excess energy are induced and the photosynthetic electron flow is regulated, both contributing to suppression of reactive oxygen species production and photodamages. Various regulation mechanisms of the photosynthetic electron flow and energy dissipation systems have been revealed. However, most of such knowledge has been obtained by the experiments conducted under controlled conditions with constant light, whereas natural light condition is drastically fluctuated. To understand photosynthesis in nature, we need to clarify not only the mechanisms that raise photosynthetic efficiency but those for photoprotection in fluctuating light. Although these mechanisms appear to be well balanced, regulatory mechanisms achieving the balance is little understood. Recently, some pioneering studies have provided new insight into the regulatory mechanisms in fluctuating light. In this review, firstly, the possible mechanisms involved in regulation of the photosynthetic electron flow in fluctuating light are presented. Next, we introduce some recent studies focusing on the photosynthetic electron flow in fluctuating light. Finally, we discuss how plants effectively cope with fluctuating light showing our recent results. PMID- 24776380 TI - A pilot study exploring the mechanisms involved in the longitudinal propagation of acute aortic dissection through computational fluid dynamic analysis. AB - OBJECTIVE: This study sought to elucidate the underlying hemodynamic mechanisms involved in the longitudinal propagation of acute, type-B aortic dissections. METHODS: Three-dimensional patient-specific aortic geometry was reconstructed from computed tomography images of 3 cases, followed by computational fluid dynamic analysis using finite-element analysis modeling. Three models were reconstructed; the normal-aortic model (from a healthy volunteer), the visceral involvement model (from a patient whose visceral arteries were involved) and the progression model (from a patient whose visceral arteries were intact at admission). Wall pressure distribution was analyzed in all three models. RESULTS: In the systolic phase of a cardiac cycle, the wall pressure dropped from the proximal to the distal aorta within the true lumen. This pressure gradient was observed in all three models. A milder pressure gradient was seen in the false lumen in the visceral-involvement model, whereas the pressure in the false lumen remained almost constant in the progression model. The dyssynchrony of the pressure gradients in the true and false lumens caused an imbalance in pressure between the two lumens. CONCLUSION: The interluminal pressure differential may be a contributing factor in the compression of the true lumen and the cleavage force of the aortic wall, leading to the longitudinal propagation of the dissection. PMID- 24776381 TI - Research press releases need better policing. PMID- 24776382 TI - [Statins and gastrointestinal cancers]. AB - The antitumour effect of statins has already been proven in animal experiments and human cancer cell lines in several gastrointestinal cancers. The chemopreventive mechanism is not completely clarified but the enhancement of oxidative stress, increased autophagy, altered expression of pro- and antiproliferative proteins and their influence on intracellular signaling pathways may play a role. Randomized studies, however, failed to confirme the expected results obtained from experimental studies. The goal of this review is to summarize the data available in the literature regarding the chemopreventive effects of statins on several gastrointestinal cancers. Results of clinical trials suggest that 10-20 mg statin daily has no or minimal antitumour effect. Chemopreventive effect of hydrophilic statins could not be detected but it seems to be significant in the case of hydrophobic statins. There are only few data available on the long-term daily use of 30-40 mg statins. Further long-term evaluation of the effect of statins regarding gastrointestinal cancers is needed, and an analysis of compound- and dose-related subgroups would be beneficial. Chemoprevention with statins cannot yet be accepted as standard medical practice. Use of statins as chemopreventive agents cannot be a substitute for regular oncological screening or surveillance. PMID- 24776383 TI - [Psychiatric aspects of child maltreatment]. AB - The paper reviews the epidemiology of child maltreatment, forms of child abuse and possible consequences. British and Hungarian Law, guidelines and the psychiatrist's roles and responsibilities in relation to assessment of problems and treatment are also addressed in the paper. PMID- 24776384 TI - [Postoperative monitoring of children with obstructive sleep apnea syndrome]. AB - INTRODUCTION: Treatment of pediatric obstructive sleep apnea syndrome is surgical. The incidence of postoperative respiratory complications in this population is 5-25%. AIM: The aim of the authors was to present the preoperative evaluation and monitoring procedure elaborated in Heim Pal Children Hospital, Budapest. METHOD: 142 patients were involved in the study. Patient history was obtained and physical examination was performed in all cases. Thereafter, polysomnography was carried out, the severity of the obstructive sleep apnea syndrome was determined, and the patients underwent tonsilloadenotomy. RESULTS: 45 patients with mild, 50 patients with moderate and 47 patients with severe obstructive sleep apnea syndrome were diagnosed. There was no complication in patients with mild disease, while complications were observed in 6 patients in the moderate group and 24 patients in the severe group (desaturation, apnea, stridor, stop breathing) (p<0.000). In patients with severe obstructive sleep apnea syndrome, no significant difference was noted in preoperative apnoea hypapnea index (p = 0.23) and in nadir oxygen saturation values (p = 0.73) between patients with and without complication. CONCLUSIONS: Patients with severe obstructive sleep apnea syndrome should be treated in hospital where pediatric intensive care unit is available. PMID- 24776385 TI - [Liquid-based cervical cytology ThinPrep screening in Hungary]. AB - INTRODUCTION: Liquid-based cervical cytology has been developed as an alternative for conventional Papanicolaou cervical cytology. AIM: The aim of this study was to determine the quality assurance of liquid-based cervical cytology. METHOD: 4573 cervical cytology smears were classified according to the Bethesda (2001) system. Human papilloma virus infection was detected and subtyped from reflex test using real-time polymerase chain reaction. RESULTS: 4573 smears were classified according to the Bethesda (2001) system. Negative diagnosis was made in 2323 cases (50.8%), non neoplastic in 2017 cases (44.1%), and positive for intraepithelial lesions or malignancy in 233 cases (5.1%). Unsatisfactory smear for diagnosis was found in 43 cases (0.9%), low-grade squamous intraepithelial lesion in 87 cases (1.9%), high-grade squamous intraepithelial lesion in 24 cases (0.5%), and carcinoma in 23 cases (0.5%). Fifty-nine of the cases were histologically verified and 4 falsely negative cases were detected. The sensitivity, specificity and the positive predictive value were 93.2%, 100% and 100%, respectively. Compared to an identical time periods of the previous three years, the low- and high-grade squamous intraepithelial lesion increased from 0.82% to 2.51%. Eighty one human papilloma virus tests were performed with a positive predictive value of 99%. CONCLUSIONS: The auditing values of the liquid bases cervical cytology results meet the proposed threshold values. Liquid-bases cervical cytology is an alternative cervical cytology and it seems to be significantly better than conventional Papanicolaou cervical cytology in all parameters. PMID- 24776386 TI - [History of the evolution of obstetric ultrasound imaging]. PMID- 24776388 TI - The involvement of glucocorticoids in psychological stress-induced exacerbations of experimental allergic asthma. AB - BACKGROUND: Psychological stress is associated with the aggravation of asthma symptoms. Glucocorticoids (GC), which are stress hormones released upon exposure to stress, have the potential to shift immune responses towards a predominant Th2 response by priming antigen-presenting cells to produce lower levels of IL-12 as well as reducing the development of regulatory T cells. However, the involvement of GC in psychological stress-induced exacerbations of allergic asthma has not yet been clarified. METHODS: Sensitized mice were exposed to restraint stress followed by forced swimming stress, during which a GC receptor antagonist or a GC synthesis inhibitor was administered, and then antigen was inhaled. Corticosterone levels in the blood were measured in stressed and nonstressed mice. After antigen inhalation, the airway responses to aerosolized methacholine, epithelial mucus secretion and airway inflammation were evaluated, and the IL-13 contents in bronchoalveolar lavage fluid were measured. RESULTS: The exposure to stress significantly increased corticosterone levels. Allergic airway responses and the increase of IL-13 contents evoked by antigen inhalation were significantly higher in stressed mice than in nonstressed mice. The administration of a GC receptor antagonist and a GC synthesis inhibitor during stress exposure significantly reduced the exacerbation of the airway responses and the increase of IL-13 contents in stressed mice challenged with antigen. CONCLUSIONS: These results indicate that the increased release of GC upon exposure to stress has a priming effect on the aggravation of allergic airway responses following the exposure, suggesting a pathophysiological role for the neuroendocrine axis in linking psychological stress to asthma exacerbations. PMID- 24776435 TI - Analysis of bite marks in foodstuffs by computer tomography (cone beam CT)--3D reconstruction. AB - The use of three-dimensional (3D) analysis of forensic evidence is highlighted in comparison with traditional methods. This three-dimensional analysis is based on the registration of the surface from a bitten object. The authors propose to use Cone Beam Computed Tomography (CBCT), which is used in dental practice, in order to study the surface and interior of bitten objects and dental casts of suspects. In this study, CBCT is applied to the analysis of bite marks in foodstuffs, which may be found in a forensic case scenario. 6 different types of foodstuffs were used: chocolate, cheese, apple, chewing gum, pizza and tart (flaky pastry and custard). The food was bitten into and dental casts of the possible suspects were made. The dental casts and bitten objects were registered using an x-ray source and the CBCT equipment iCAT(r) (Pennsylvania, EUA). The software InVivo5(r) (Anatomage Inc, EUA) was used to visualize and analyze the tomographic slices and 3D reconstructions of the objects. For each material an estimate of its density was assessed by two methods: HU values and specific gravity. All the used materials were successfully reconstructed as good quality 3D images. The relative densities of the materials in study were compared. Amongst the foodstuffs, the chocolate had the highest density (median value 100.5 HU and 1,36 g/cm(3)), while the pizza showed to have the lowest (median value -775 HU and 0,39 g/cm(3)), on both scales. Through tomographic slices and three-dimensional reconstructions it was possible to perform the metric analysis of the bite marks in all the foodstuffs, except for the pizza. These measurements could also be obtained from the dental casts. The depth of the bite mark was also successfully determined in all the foodstuffs except for the pizza. Cone Beam Computed Tomography has the potential to become an important tool for forensic sciences, namely for the registration and analysis of bite marks in foodstuffs that may be found in a crime scene. PMID- 24776436 TI - Correlation between lip prints and finger prints in sex determination and pattern predominance in 5000 subjects. AB - Fingerprints are considered to be the most reliable criteria for personal identification. In the past decades, lip-print studies (Cheiloscopy) attracted the attention of many scientists as a new tool for human identification in both civil and criminal issues. The present study was undertaken to observe the correlation between lip prints and finger print pattern in sex determination and to determine the pattern predominance in a sample of 5000 individuals. The study was carried out in 5000 individuals in Department of Oral Medicine and Radiology of Maharishi Markandeshwar College of Dental Sciences and Research, M.M. University, Mullana. Of the participants, 2500 were males and 2500 females. Lip prints and finger prints of the right hand were collected then studied and analyzed statistically. For lip prints TSUCHIHASHIS Y. classification (1970) was followed; HENRYS classification(1897) was followed for finger prints. Whorls were of a high frequency in males, but females presented with a high frequency of loops. Type I, I', II lip print pattern was most predominant in females while Type III and Type IV was most predominant in males. The present study described in detail that for both males and females, the most predominant lip-print patterns showed an association with the respective predominant finger print patterns. The establishment of a database of Cheiloscopy and Dactyloscopyis recommended for all individuals in a certain locality, which could be used as a reference in civil litigations and criminal cases. Such studies may be useful particularly in Forensic science and in justice. PMID- 24776437 TI - Child protection: legal and ethical obligation regarding the report of child abuse in four different countries. AB - Child protection is the duty of every single member of the society. Health professionals who work with children, such as members of dental team, are in the unique position to recognize signs of physical, sexual and emotional abuse as well as (dental) neglect. They should report any suspected case where a child is or may be in need of welfare. The professional responsibility is regulated by legal and ethical obligations. In this preliminary work the authors investigate the legal and ethical Acts, and the similarities vs. differences in obligations regarding reporting child abuse and neglect (CAN) cases in four countries: Croatia, United Kingdom, Italy and Canada. In all four countries all health professionals have a duty to report their suspicion if a child is in a harmful situation. All of them who fail to report, or even neglect or delay to report a suspicion, are liable on conviction to a pecuniary fine which varies from country to country. Depending on the country, if a professional has reasonable grounds to suspect that a child is or may be in need of protection, must report to: CAS (children's aid society), to CSS (center for social services), to police, to a Juvenile Court, or to the ombudsman. In all four countries, dentists are not asked to diagnose 'child maltreatment', but simply report the suspicion with supportive evidence. Ethical obligation comes from medical and dental ethical codes regulated by the Chamber or Council of Dentists. In all four countries legal and ethical obligations in reporting CAN are similar. Differences are related mostly to fines for nonreporting or a delay in reporting. Expanded investigation through other European countries and standard operational procedures is needed, in order to harmonize policies and guidelines for reporting CAN and maximize children protection. PMID- 24776438 TI - A simple safe, reliable and reproducible mechanism for producing experimental bite marks. AB - With improving technology it should be possible to develop an objective, reliable and valid method that can be undertaken by most forensic Odontologists without recourse to expensive or bulky equipment. One of the main factors that affect the physical appearance of bitemark is the amount of force applied during biting. There is little evidence relating the appearance of a bite mark to the amount of force applied and how that force relates to the biters maximal biteforce. This paper describes simple apparatus that can be used to inflict experimental bites on living subjects reproducibly and with minimal risk. The aims of this study are to report on the development of a mechanical apparatus that produces experimental bitemarks on living human subjects with a known force in a safe, reliable and reproducible manner and to relate the force applied during production of the experimental bitemark to the maximum bite force of the biter. Maximum bite force of one of the authors was determined as 324 N. Experimental bitemarks were inflicted on living subjects with known weights. Weights of up to 10 kg were well tolerated by the subjects. The relation between forces used to inflict bites and the maximum bite force of the author is reported, with 10 kg being approximately one third of the maximum bite force. The apparatus was well tolerated and the results were reliable and reproducible. The results from this study could help in determining the severity of bitemarks. This apparatus could help researchers in developing objective based bitemark analysis techniques. PMID- 24776439 TI - Assessment of the uniqueness of human dentition. AB - Comparing ante-mortem and post-mortem dental characteristics has been a reliable, accurate and quick human identification method. This is based on the assumption that each individual's set of teeth is unique; however, there is little evidence to support this assumption. This research aimed to determine the uniqueness of basic dental features in a cohort of multinational dental patients. Dental charts were retrieved from the archives of the College of Dentistry at the University of Sharjah. Dental patterns were coded into letters representing basic dental characteristics, and entered into a computer program that was written specifically for analysing the results of this research. Two thousand dental charts were included in this research; the average age of the sample was 31.9 years (11-87 years). The male:female ratio was 1.4:1 from 55 nationalities. One thousand one hundred and fifty-nine dental charts (57.95%) had absolutely unique dental patterns. The remaining charts (n=841 [42.05%]) were found to have identical patterns with others, the most common of which was 'all virgin' teeth (n=482 [24.1%]). Introducing a single dental modification dropped this percentage to 1.05%. This percentage was further narrowed down to 0.7% when the gender variable was introduced to the comparison. The results of this research support the assumption that dental characteristics show a diversity that is useful for human identification, even when those characteristics are recorded in their simplest forms. PMID- 24776457 TI - Early tranexamic acid use in trauma haemorrhage: why do we give it and which patients benefit most? PMID- 24776458 TI - Widely-used laboratory and clinical Mycobacterium tuberculosis strains: to what extent they are representative of their phylogenetic lineages? PMID- 24776460 TI - Campus Sexual Misconduct: Restorative Justice Approaches to Enhance Compliance With Title IX Guidance. AB - Campus response to sexual violence is increasingly governed by federal law and administrative guidance such as the 1972 Title IX, the 2011 Dear Colleague Letter (DCL), and the 2013 Violence Against Women Act. Educational institutions are directed to expand disciplinary responses and establish coordinated action to eliminate sexual violence and remedy its effects. Compliance fosters a quasi criminal justice approach not suited to all sexual misconduct and inconsistent with developing practice in student conduct management. This article envisions restorative justice (RJ) enhancements to traditional student conduct processes that maintain compliance, expand options, empower victim choice, and increase responsiveness to DCL aims. The article (1) defines sexual violence and sexual harassment within the DCL scope, (2) elaborates the DCL position on permissible alternative resolutions and differentiates mediation from RJ, (3) sequences action steps from case report to finalization, including both restorative and traditional justice pathways; and (4) discusses building support for innovation beginning with existing campus response. PMID- 24776459 TI - Review of survey and experimental research that examines the relationship between alcohol consumption and men's sexual aggression perpetration. AB - This article systematically reviews empirical studies that examine associations between alcohol consumption and men's sexual aggression with the goal of identifying major findings; gaps in current knowledge; and directions for future research, practice, and policy. We identified 25 cross-sectional surveys, 6 prospective studies, and 12 alcohol administration experiments published between 1993 and August 2013 with male college students and young adult (nonincarcerated) samples. Many cross-sectional surveys have demonstrated that distal and proximal measures of men's alcohol consumption are positively associated with sexual assault perpetration, although very few of these studies evaluated how alcohol interacts with other risk and protective factors to exacerbate or inhibit sexual aggression. There are surprisingly few surveys that examine alcohol's effects at the event level and over short-time intervals to identify how changes in alcohol consumption are associated with changes in perpetration status. Alcohol administration studies suggest some important mechanisms that warrant additional investigation. PMID- 24776461 TI - Parasitic castration by Xenos vesparum depends on host gender. AB - Host castration represents a mechanism used by parasites to exploit energy resources from their hosts by interfering with their reproductive development or to extend host lifespan by removing risks associated with reproductive activity. One of the most intriguing groups of parasitic castrators is represented by the insects belonging to the order Strepsiptera. The macroparasite Xenos vesparum can produce dramatic phenotypic alterations in its host, the paper wasp Polistes dominula. Parasitized female wasps have undeveloped ovaries and desert the colony without performing any social task. However, very little attention has been given to the parasitic impact of X. vesparum on the male phenotype. Here, we investigated the effects of this parasite on the sexual behaviour and the morpho physiology of P. dominula males. We found that, differently from female wasps, parasitized males are not heavily affected by Xenos: they maintain their sexual behaviour and ability to discriminate between female castes. Furthermore, the structure of their reproductive apparatus is not compromised by the parasite. We think that our results, demonstrating that the definition of X. vesparum as a parasitoid does not apply to infected males of P. dominula, provide a new perspective to discuss and maybe reconsider the traditional view of strepsipteran parasites. PMID- 24776486 TI - Improving drug accumulation and photothermal efficacy in tumor depending on size of ICG loaded lipid-polymer nanoparticles. AB - A key challenge to strengthen anti-tumor efficacy is to improve drug accumulation in tumors through size control. To explore the biodistribution and tumor accumulation of nanoparticles, we developed indocyanine green (ICG) loaded poly (lactic-co-glycolic acid) (PLGA) -lecithin-polyethylene glycol (PEG) core-shell nanoparticles (INPs) with 39 nm, 68 nm and 116 nm via single-step nanoprecipitation. These INPs exhibited good monodispersity, excellent fluorescence and size stability, and enhanced temperature response after laser irradiation. Through cell uptake and photothermal efficiency in vitro, we demonstrated that 39 nm INPs were more easily be absorbed by pancreatic carcinoma tumor cells (BxPC-3) and showed better photothermal damage than that of 68 nm and 116 nm size of INPs. Simultaneously, the fluorescence of INPs offered a real-time imaging monitor for subcellular locating and in vivo metabolic distribution. Near infrared imaging in vivo and photothermal therapy illustrated that 68 nm INPs showed the strongest efficiency to suppress tumor growth due to abundant accumulation in BxPC-3 xenograft tumor model. The findings revealed that a nontoxic, size-dependent, theranostic INPs model was built for in vivo cancer imaging and photothermal therapy without adverse effect. PMID- 24776487 TI - Targeting and activation of antigen-specific B-cells by calcium phosphate nanoparticles loaded with protein antigen. AB - Cross-linking of the B-cell receptors of an antigen-specific B-cell is the initial signal for B-cell activation, proliferation, and differentiation into antibody secreting plasma cells. Since multivalent particulate structures are efficient activators of antigen-specific B-cells, we developed biodegradable calcium phosphate nanoparticles displaying protein antigens on their surface and explored the efficacy of the B-cell activation after exposure to these nanoparticles. The calcium phosphate nanoparticles were functionalized with the model antigen Hen Egg Lysozyme (HEL) to take advantage of a HEL-specific B-cell receptor transgenic mouse model. The nanoparticles were characterized by scanning electron microscopy and dynamic light scattering. The functionalized calcium phosphate nanoparticles were preferentially bound and internalized by HEL specific B-cells. Co-cultivation of HEL-specific B-cells with the functionalized nanoparticles also increased surface expression of B-cell activation markers. Functionalized nanoparticles were able to effectively cross-link B-cell receptors at the surface of antigen-matched B-cells and were 100-fold more efficient in the activation of B-cells than soluble HEL. Thus, calcium phosphate nanoparticles coated with protein antigens are promising vaccine candidates for induction humoral immunity. PMID- 24776488 TI - Individual differences in risk-related behaviors and voluntary alcohol intake in outbred Wistar rats. AB - Some personality traits and comorbid psychiatric diseases are linked to a propensity for excessive alcohol drinking. The objective of this study was to investigate the association between individual differences in risk-related behaviors, voluntary alcohol intake and preference. Outbred male Wistar rats were tested in a novel open field, followed by assessment of behavioral profiles using the multivariate concentric square field (MCSF) test. Animals were classified into high risk taking and low risk taking on the basis of open-field behavior and into high risk-assessing (HRA) and low risk-assessing (LRA) on the basis of the MCSF profile. Finally, voluntary alcohol intake was investigated using intermittent access to 20% ethanol and water for 5 weeks. Only minor differences in voluntary alcohol intake were found between high risk taking and low risk taking. Differences between HRA and LRA rats were more evident, with higher intake and increased intake over time in HRA relative to LRA rats. Thus, individual differences in risk-assessment behavior showed greater differences in voluntary alcohol intake than risk taking. The findings may relate to human constructs of decision-making and risk taking associated with a predisposition to rewarding and addictive behaviors. Further studies are needed to clarify the relationship between risk-related behaviors, including risk-assessment behavior, and liability for excessive alcohol intake. PMID- 24776490 TI - S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund's adjuvant models in mice. AB - The therapeutic potential of S1RA (E-52862), a selective sigma-1 receptor (sigma1R) antagonist, has been explored in experimental neuropathic pain, but not in inflammatory pain models. The present study investigated the effect of the intraperitoneal administration of S1RA on the hind paw withdrawal response to thermal and mechanical stimulation following an intraplantar injection of carrageenan (CARR) and complete Freund's adjuvant (CFA), which are two well characterized models of acute and chronic inflammatory pain, respectively. S1RA fully reversed both mechanical [dose of drug that produced half of its maximal response (ED50)=35.9 and 42.1 mg/kg for CARR-induced and CFA-induced pain, respectively] and thermal (ED50=27.9 mg/kg, CARR) hypersensitivity, whereas ibuprofen (CARR, mechanical allodynia) and celecoxib (CARR, thermal hyperalgesia; CFA, mechanical allodynia) failed to reach maximum efficacy. Morphine also showed maximum efficacy in all tests. Unlike celecoxib and ibuprofen, which decreased paw volume significantly, CARR-induced paw oedema was not reduced by S1RA and morphine, thus suggesting that the antinociceptive effect of S1RA does not involve a major anti-inflammatory (antioedema) action. S1RA was devoid of efficacy when administered to sigma1R knockout mice, thus suggesting the involvement of sigma1R in the antinociceptive effects exerted by S1RA. We conclude that S1RA represents a promising novel analgesic therapy for inflammatory pain. PMID- 24776489 TI - Glucocorticoid receptor antagonism disrupts the reconsolidation of social reward related memories in rats. AB - Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use. Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated, reconsolidation of memories of physiologically relevant social rewards has received little attention. Social play, the most characteristic social behaviour displayed by young mammals, is highly rewarding, illustrated by the fact that it can induce conditioned place preference (CPP). Here, we investigated the role of signalling mechanisms implicated in memory processes, including reconsolidation, namely glucocorticoid, mineralocorticoid, NMDA glutamatergic and CB1 cannabinoid receptors, in the reconsolidation of social play-induced CPP in rats. Systemic treatment with the glucocorticoid receptor antagonist mifepristone before, but not immediately after, retrieval disrupted the reconsolidation of social play-induced CPP. Mifepristone did not affect social play-induced CPP in the absence of memory retrieval. Treatment with the NMDA receptor antagonist MK-801 modestly affected the reconsolidation of social play-induced CPP. However, the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and CB1 cannabinoid receptor antagonists spironolactone and rimonabant, respectively. We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats. These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories. PMID- 24776491 TI - Developmentally vitamin D-deficient rats show enhanced prepulse inhibition after acute Delta9-tetrahydrocannabinol. AB - Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD-deficient rats show selective cognitive deficits and novelty induced hyperlocomotion and enhanced locomotor responses from acute treatment with psychomimetic drugs, such as amphetamine and MK-801. Here we aimed to examine the effect of a drug from a different class of psychomimetic/psychoactive compounds, Delta9-tetrahydrocannabinol (THC), on tasks of relevance to the cognitive and positive symptoms of schizophrenia. The aim of this study was to investigate whether DVD deficiency modulates the behavioural effects of THC on tests of delay-dependent memory, sensorimotor gating and locomotion. Adult control and DVD-deficient rats were injected with THC (0, 0.3, 0.6, 1.25, 2.5 mg/kg) 15 min before a delay match to sample (DMTS) task using variable delays (0 24 s). A separate group of rats was injected with either 2.5 mg/kg THC or vehicle before tests of either prepulse inhibition (PPI) of the acoustic startle response or in the open field. Control and DVD-deficient rats showed a similar dose dependent impairment in performance on the DMTS. The greatest impairment was observed at 2.5 mg/kg for all delays (0-24 s). DVD-deficient rats showed THC induced enhancement of PPI, which was not observed in control rats. There was no effect of maternal diet on acoustic startle response or locomotor responses in the open field. This study reports the novel findings that DVD-deficient rats were more sensitive to the acute effects of THC on PPI. It appears that prenatal vitamin D deficiency has long-term effects on sensitivity to the behavioural effects of cannabinoids. PMID- 24776492 TI - Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists. AB - To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1 12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics. PMID- 24776515 TI - Group B streptococcal infection in a tertiary hospital in India--1998-2010. AB - This retrospective study was done to determine the incidence of neonatal Group B streptococcal sepsis among newborn between 1998 and 2010. Among 107,692 babies born during this period, the overall incidence of Group B streptococcal sepsis was 0.76/1000 live births with the incidence of early onset sepsis being 0.68 (95% confidence interval: 0.52-0.83)/1000 live births. The overall rate of early onset sepsis decreased to 0.55/1000 live births with introduction of intrapartum antibiotic policy. PMID- 24776516 TI - Risk factors associated with laboratory-confirmed bloodstream infections in a tertiary neonatal intensive care unit. AB - BACKGROUND: Bloodstream infections (BSI) remain a leading cause of morbidity and mortality among infants admitted to neonatal intensive care units (NICUs). At the time of evaluation for suspected BSI, presenting signs may be nonspecific. We sought to determine the clinical signs and risk factors associated with laboratory-confirmed BSI among infants evaluated for late-onset sepsis in a tertiary NICU. METHODS: This prospective cohort study included infants >3 days of age admitted to a level 4 NICU from July 2006 to October 2009 for whom a blood culture was drawn for suspected sepsis. Clinicians documented presenting signs at the time of culture. Laboratory-confirmed BSI was defined as per the National Healthcare Safety Network. Multivariate analyses were performed using a logistic regression random effects model. RESULTS: Six-hundred and eighty eligible episodes of suspected BSI were recorded in 409 infants. Enteral contrast within the preceding 48 hours was the most significant risk factor for laboratory confirmed BSI [Odds Ratio: 9.58 (95% confidence interval: 2.03-45.19)] followed by presence of a central venous catheter. Apnea and hypotension were the most strongly associated presenting signs. CONCLUSION: Among infants evaluated in a tertiary NICU, recent exposure to enteral contrast was associated with increased odds of developing BSI. Apnea and hypotension were the most strongly associated clinical signs of infection. PMID- 24776518 TI - Post-dengue encephalopathy and Parkinsonism. AB - Parkinsonism as a neurologic manifestation of dengue infection is rare with only 1 reported case in an adult patient. We report a case of a 6-year-old child with self-limiting post-dengue encephalopathy and Parkinsonism. This is the first reported pediatric case of post-dengue Parkinsonism and expands the neurologic manifestations associated with dengue infection in children. Clinicians should consider the possibility of post-dengue Parkinsonism in children with a history of pyrexia from endemic areas of dengue. PMID- 24776517 TI - Vancomycin cerebrospinal fluid pharmacokinetics in children with cerebral ventricular shunt infections. AB - This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two of 3 children with a staphylococcal CSF infection had CSF concentrations greater than minimal inhibitory concentration at the end of the dosing interval. PMID- 24776519 TI - Protection against vaccine-preventable diseases in medical students: a follow up. AB - Like other healthcare personnel, medical students with patient contact should be up to date with their immunizations including those specifically targeting occupational risk. Analysis from an ongoing surveillance program for medical students revealed immunization gaps in 102 (77.9%) of 131 students enrolled 2011 2013. Screening medical students' immunization records is worthwhile. PMID- 24776520 TI - Impact of the 13-valent pneumococcal conjugate vaccine on chronic sinusitis associated with Streptococcus pneumoniae in children. AB - BACKGROUND: The widespread use of the 7-valent pneumococcal conjugate vaccine has been associated with epidemiologic changes of mucosal and invasive pneumococcal disease. No study describes the impact of 13-valent pneumococcal conjugate vaccine (PCV13) on chronic sinusitis in children. We describe changes in epidemiology of Streptococcus pneumoniae chronic sinusitis after the introduction of PCV13 at Texas Children's Hospital. METHODS: We identified patients <18 years with positive sinus culture for S. pneumoniae who underwent endoscopic sinus surgery because of chronic sinusitis from August 2008 to December 2013 at Texas Children's Hospital. Isolates were serotyped by the capsular swelling method. Demographic and clinical information was collected retrospectively. The chi test and Fisher's exact test were used to analyze dichotomous variables. RESULTS: We identified 91 cases of chronic sinusitis with positive sinus culture for S. pneumoniae. Sixty-one (67%) isolates were non-PCV13 serotypes. PCV13 cases decreased 31% in the post-PCV13 period (P = 0.003). Serotype 19A decreased 27% in the post-PCV13 period (P = 0.007), but accounted for all the isolates with penicillin minimal inhibitory concentration >= 4 MUg/mL and ceftriaxone minimal inhibitory concentration >= 2 MUg/mL. Serotypes 19A (38%) and 15C (17%) were the most common in the pre- and post-PCV13 periods, respectively. The most common organism co-isolated was Haemophilus influenzae (52%). Isolation of Prevotella spp. increased in the post-PCV13 period (P = 0.02). CONCLUSIONS: S. pneumoniae continues to represent an important pathogen in chronic sinusitis in children <5 years of age. After the introduction of PCV13, S. pneumoniae isolation declined in children with chronic sinusitis at Texas Children's Hospital. We also observed a substantial reduction of PCV13 serotypes, predominantly serotype 19A. PMID- 24776521 TI - Ivabradine: heart rate and left ventricular function. PMID- 24776522 TI - The safety of specific immunotherapy for patients allergic to house-dust mites and pollen in relation to the development of neoplasia and autoimmune disease: a long-term, observational case-control study. AB - BACKGROUND: Specific immunotherapy (SIT) safety has been well documented. However, the prolonged late side effects in patients who terminated SIT several years previously have been reported on in only a limited number of studies. The aim of this study was to perform a 20-year post-SIT observational evaluation for the assessment of any manifestation of serious immunological disease. MATERIALS AND METHODS: In total, 1,144 patients (521 women and 623 men), with a mean age of 22.8 +/- 16.9 years (at the moment of SIT completion) and who had atopic bronchial asthma and/or allergic rhinitis, were observed 20 years after immunotherapy. New neoplastic and autoimmune disease cases were monitored. The SIT group was compared to a control group consisting of 1,154 allergic patients who had never received SIT and had only had symptomatic treatment. RESULTS: There was an inverse association between SIT treatment and the prevalence of new chronic myeloid leukemia and chronic lymphoblastic leukemia cases (OR 0.32, 95% CI 0.18-0.81 and OR 0.58, CI 0.44-0.78, respectively). In other neoplastic diseases, however, prevalences similar to those observed in the control group were confirmed. There were also no significant differences in the autoimmune disease prevalence between the analyzed groups. CONCLUSION: The results of this long-term observational study indicate a lack of a significant prevalence for new instances of neoplastic and autoimmune diseases, which suggests that SIT in the long term is indeed safe. PMID- 24776525 TI - Phase synchronization between collective rhythms of fully locked oscillator groups. AB - A system of coupled oscillators can exhibit a rich variety of dynamical behaviors. When we investigate the dynamical properties of the system, we first analyze individual oscillators and the microscopic interactions between them. However, the structure of a coupled oscillator system is often hierarchical, so that the collective behaviors of the system cannot be fully clarified by simply analyzing each element of the system. For example, we found that two weakly interacting groups of coupled oscillators can exhibit anti-phase collective synchronization between the groups even though all microscopic interactions are in-phase coupling. This counter-intuitive phenomenon can occur even when the number of oscillators belonging to each group is only two, that is, when the total number of oscillators is only four. In this paper, we clarify the mechanism underlying this counter-intuitive phenomenon for two weakly interacting groups of two oscillators with global sinusoidal coupling. PMID- 24776524 TI - Vestibular loss and balance training cause similar changes in human cerebral white matter fractional anisotropy. AB - Patients with bilateral vestibular loss suffer from severe balance deficits during normal everyday movements. Ballet dancers, figure skaters, or slackliners, in contrast, are extraordinarily well trained in maintaining balance for the extreme balance situations that they are exposed to. Both training and disease can lead to changes in the diffusion properties of white matter that are related to skill level or disease progression respectively. In this study, we used diffusion tensor imaging (DTI) to compare white matter diffusivity between these two study groups and their age- and sex-matched controls. We found that vestibular patients and balance-trained subjects show a reduction of fractional anisotropy in similar white matter tracts, due to a relative increase in radial diffusivity (perpendicular to the main diffusion direction). Reduced fractional anisotropy was not only found in sensory and motor areas, but in a widespread network including long-range connections, limbic and association pathways. The reduced fractional anisotropy did not correlate with any cognitive, disease related or skill-related factors. The similarity in FA between the two study groups, together with the absence of a relationship between skill or disease factors and white matter changes, suggests a common mechanism for these white matter differences. We propose that both study groups must exert increased effort to meet their respective usual balance requirements. Since balance training has been shown to effectively reduce the symptoms of vestibular failure, the changes in white matter shown here may represent a neuronal mechanism for rehabilitation. PMID- 24776526 TI - Feasibility and effect of supplementing a modified OTAGO intervention with multisensory balance exercises in older people who fall: a pilot randomized controlled trial. AB - OBJECTIVE: To investigate the feasibility and comparative effect of supplementing a modified OTAGO falls rehabilitation programme with multisensory balance exercises and informed sample size calculation for a definitive trial. DESIGN: Single-blinded randomized controlled trial with pre/postcomparisons using a per protocol analysis. SETTING: Secondary care-based falls clinic, London, UK. SUBJECTS: Community-dwelling older people (n = 21) experiencing >=2 non-syncopal falls during previous 12 months. INTERVENTION: Modified OTAGO exercise classes supplemented with supervised home-based rehabilitation consisting of multisensory balance or stretching exercises. Group classes and home sessions each occurred twice-weekly for eight weeks. MEASUREMENTS: A computerised randomization was used for group allocation. A rater, blinded to intervention, performed the assessment including the Functional Gait Assessment (primary outcome), Physiological Profile Assessment, and questionnaires relating to symptoms, balance confidence, and psychological state (secondary outcomes). RESULTS: Significant within-group improvements were noted for the Functional Gait (p < 0.01, r = -0.63) and Physiological Profile Assessments (p < 0.05, r = -0.63) in the OTAGO+multisensory rehabilitation group only and for balance confidence scores in the OTAGO+stretching group (p < 0.01, r = -0.63). Between-group differences were noted for the Functional Gait (p < 0.01, r = -0.71) and Physiological Profile (p < 0.05, r = -0.54) assessments with the OTAGO+multisensory group showing significantly greater improvement. The drop-out rate was similar for both groups (~30%). No serious adverse events were reported. CONCLUSIONS: Supplementing the OTAGO programme with multisensory balance exercises is feasible in older people who fall and may have a beneficial effect on falls risk as measured using the Functional Gait and Short-form Physiological Profile Assessments. An adequately powered randomized controlled trial would require 36 participants to detect an effect size of 1.35 on the Functional Gait Assessment. PMID- 24776528 TI - A self-powered ultraviolet detector based on a single ZnO microwire/p-Si film with double heterojunctions. AB - Recently, self-powered devices based on a p-n heterojunction have been widely reported, but there are few reports about self-powered UV detectors based on a single ZnO microwire/p-Si film with double heterojunctions. Compared with the common p-n heterojunction type devices, the fabricated devices with double heterojunctions based on a single n-type ZnO microwire and a p-type Si film exhibited excellent electrical performance such as an ideal rectification behaviour and a low turn-on voltage. At zero bias, the fabricated device can deliver a photocurrent of 71 nA, a high photosensitivity of about 3.17 * 10(3) under UV light (0.58 mW cm(-2)) illumination and a fast rising and falling time of both less than 0.3 s. Furthermore, the photocurrent increased with the rising of the optical intensity at low power intensities. The physical mechanism has been explained by energy band diagrams. PMID- 24776527 TI - Performance of eHealth data sources in local influenza surveillance: a 5-year open cohort study. AB - BACKGROUND: There is abundant global interest in using syndromic data from population-wide health information systems--referred to as eHealth resources--to improve infectious disease surveillance. Recently, the necessity for these systems to achieve two potentially conflicting requirements has been emphasized. First, they must be evidence-based; second, they must be adjusted for the diversity of populations, lifestyles, and environments. OBJECTIVE: The primary objective was to examine correlations between data from Google Flu Trends (GFT), computer-supported telenursing centers, health service websites, and influenza case rates during seasonal and pandemic influenza outbreaks. The secondary objective was to investigate associations between eHealth data, media coverage, and the interaction between circulating influenza strain(s) and the age-related population immunity. METHODS: An open cohort design was used for a five-year study in a Swedish county (population 427,000). Syndromic eHealth data were collected from GFT, telenursing call centers, and local health service website visits at page level. Data on mass media coverage of influenza was collected from the major regional newspaper. The performance of eHealth data in surveillance was measured by correlation effect size and time lag to clinically diagnosed influenza cases. RESULTS: Local media coverage data and influenza case rates showed correlations with large effect sizes only for the influenza A (A) pH1N1 outbreak in 2009 (r=.74, 95% CI .42-.90; P<.001) and the severe seasonal A H3N2 outbreak in 2011-2012 (r=.79, 95% CI .42-.93; P=.001), with media coverage preceding case rates with one week. Correlations between GFT and influenza case data showed large effect sizes for all outbreaks, the largest being the seasonal A H3N2 outbreak in 2008-2009 (r=.96, 95% CI .88-.99; P<.001). The preceding time lag decreased from two weeks during the first outbreaks to one week from the 2009 A pH1N1 pandemic. Telenursing data and influenza case data showed correlations with large effect sizes for all outbreaks after the seasonal B and A H1 outbreak in 2007-2008, with a time lag decreasing from two weeks for the seasonal A H3N2 outbreak in 2008-2009 (r=.95, 95% CI .82-.98; P<.001) to none for the A p H1N1 outbreak in 2009 (r=.84, 95% CI .62-.94; P<.001). Large effect sizes were also observed between website visits and influenza case data. CONCLUSIONS: Correlations between the eHealth data and influenza case rates in a Swedish county showed large effect sizes throughout a five-year period, while the time lag between signals in eHealth data and influenza rates changed. Further research is needed on analytic methods for adjusting eHealth surveillance systems to shifts in media coverage and to variations in age-group related immunity between virus strains. The results can be used to inform the development of alert generating eHealth surveillance systems that can be subject for prospective evaluations in routine public health practice. PMID- 24776529 TI - Safety and efficacy of the StarClose vascular closure system following 8-Fr sheath placement for intra-aortic balloon pump: a single-center analysis of 42 consecutive patients. AB - OBJECTIVE: To assess the safety and efficacy of the StarClose device following intra-aortic balloon pump (IABP) counterpulsation using 8-Fr femoral sheaths. SUBJECTS AND METHODS: From June 2008 to August 2012, 42 consecutive patients who received IABP implantation via common femoral artery (CFA) punctures with an 8-Fr sheath (which were then sealed with the StarClose Vascular Closure System at the bedside) were included in this retrospective single-arm study. All the patients underwent duplex control of the puncture site 24 h after deployment of the device, in order to determine the presence or absence of vascular complications including hematoma, pseudoaneurysm, arteriovenous fistula and arterial/venous thrombosis or stenosis. The safety end points were the vascular complications during the hospital stay, and the efficacy end points included device and procedure success. RESULTS: The procedure success rate was 92.9% (39/42) and the device success rate was 88.1% (37/42). Major vascular complications occurred in 3 (7.1%) patients; 1 developed a massive hematoma >10 cm which was managed by blood transfusion and surgical reconstruction, and the other 2 developed pseudoaneurysm which was cured by ultrasound-guided thrombin injection or manual compression. Minor vascular complications occurred in 5 (11.9%) patients, including blood oozing in 2, hematoma <5 cm in 2 and severe pain in the remaining patient. CONCLUSION: CFA closure with the StarClose device was safe, feasible and effective in patients undergoing IABP support using 8-Fr sheath sizes. PMID- 24776530 TI - Proposal of Vespertiliibacter pulmonis gen. nov., sp. nov. and two genomospecies as new members of the family Pasteurellaceae isolated from European bats. AB - Five bacterial strains isolated from bats of the family Vespertilionidae were characterized by phenotypic tests and multilocus sequence analysis (MLSA) using the 16S rRNA gene and four housekeeping genes (rpoA, rpoB, infB, recN). Phylogenetic analyses of individual and combined datasets indicated that the five strains represent a monophyletic cluster within the family Pasteurellaceae. Comparison of 16S rRNA gene sequences demonstrated a high degree of similarity (98.3-99.9%) among the group of bat-derived strains, while searches in nucleotide databases indicated less than 96% sequence similarity to known members of the Pasteurellaceae. The housekeeping genes rpoA, rpoB, infB and recN provided higher resolution compared with the 16S rRNA gene and subdivided the group according to the bat species from which the strains were isolated. Three strains derived from noctule bats shared 98.6-100% sequence similarity in all four genes investigated, whereas, based on rpoB, infB and recN gene sequences, 91.8-96% similarity was observed with and between the remaining two strains isolated from a serotine bat and a pipistrelle bat, respectively. Genome relatedness as deduced from recN gene sequences correlated well with the results of MLSA and indicated that the five strains represent a new genus. Based on these results, it is proposed to classify the five strains derived from bats within Vespertiliibacter pulmonis gen. nov., sp. nov. (the type species), Vespertiliibacter genomospecies 1 and Vespertiliibacter genomospecies 2. The genus can be distinguished phenotypically from recognized genera of the Pasteurellaceae by at least three characteristics. All strains are nutritionally fastidious and require a chemically defined supplement with NAD for growth. The DNA G+C content of strain E127/08(T) is 38.2 mol%. The type strain of Vespertiliibacter pulmonis gen. nov., sp. nov. is E127/08(T) ( = CCUG 64585(T) = DSM 27238(T)). The reference strains of Vespertiliibacter genomospecies 1 and 2 are E145/08 and E157/08, respectively. PMID- 24776531 TI - Ercella succinigenes gen. nov., sp. nov., an anaerobic succinate-producing bacterium. AB - A novel anaerobic succinate-producing bacterium, strain ZWB(T), was isolated from sludge collected from a biogas desulfurization bioreactor (Eerbeek, the Netherlands). Cells were non-spore-forming, motile, slightly curved rods (0.4-0.5 um in diameter and 2-3 um in length), and stained Gram-negative. The temperature range for growth was 25-40 degrees C, with an optimum at 37 degrees C. The pH range for growth was 7.0-9.0, with an optimum at pH 7.5. Strain ZWB(T) was able to ferment glycerol and several carbohydrates mainly to H2, succinate and acetate. Sulfur and fumarate could be used as electron acceptors by strain ZWB(T). The G+C content of the genomic DNA was 37.6 mol%. The most abundant fatty acids were iso-C14 : 0 and iso-C16 : 0 DMA. On the basis of 16S rRNA gene sequence similarity, strain ZWB(T) belongs to the family Ruminococcaceae and it is distantly related to Saccharofermentans acetigenes JCM 14006(T) (92.1%). Based on the physiological features and phylogenetic analysis, strain ZWB(T) represents a novel species of a new genus, for which the name Ercella succinigenes gen. nov., sp. nov. is proposed. The type strain of Ercella succinigenes is ZWB(T) ( = DSM 27333(T) = JCM 19283(T)). PMID- 24776532 TI - Glycomyces fuscus sp. nov. and Glycomyces albus sp. nov., actinomycetes isolated from a hypersaline habitat. AB - Two actinomycete strains, designated TRM 49117(T) and TRM 49136(T), were isolated from a hypersaline habitat in Xinjiang Province, north-west China and were characterized taxonomically by using a polyphasic study. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain TRM 49117(T) had 93.93% similarity with the type strain Glycomyces halotolerans TRM 40137(T) (GenBank accession no. HQ651156) and TRM 49136(T) had 94.32% similarity with G. halotolerans TRM 40137(T). The 16S rRNA gene sequence similarity between the two new isolates was 93%. The isolates contained meso-diaminopimelic acid as the diagnostic diamino acid and anteiso-C15 : 0, iso-C16 : 0 and anteiso-C17 : 0 as major cellular fatty acids. The predominant menaquinones of the isolates were MK 9(H4) and MK-9(H6). The whole-cell sugar patterns of these strains contained xylose and ribose, and strain TRM 49136(T) also contained arabinose. The polar lipid pattern of strain TRM 49117(T) comprised phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol mannosides, phosphatidylcholine, phosphatidylinositol and three additional unknown phospholipids. The polar lipid pattern of strain TRM 49136(T) comprised phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol, glycolipids and two phosphoglycolipids of unknown composition. Genotypic and phenotypic data confirmed that strains TRM 49117(T) and TRM 49136(T) represent two novel species, clearly different from related species of the genus Glycomyces, for which the names Glycomyces fuscus sp. nov. (type strain TRM 49117(T) = CCTCC AA 2013003(T) = NRRL B-59998(T) = KACC 17682(T)) and Glycomyces albus sp. nov. (type strain TRM 49136(T) = CCTCC AA 2013004(T) = NRRL B-24927(T) = KACC 17681(T)) are proposed. PMID- 24776533 TI - Complex regional pain syndrome medicalises limb pain. PMID- 24776535 TI - Printing-based assembly of quadruple-junction four-terminal microscale solar cells and their use in high-efficiency modules. AB - Expenses associated with shipping, installation, land, regulatory compliance and on-going maintenance and operations of utility-scale photovoltaics can be significantly reduced by increasing the power conversion efficiency of solar modules through improved materials, device designs and strategies for light management. Single-junction cells have performance constraints defined by their Shockley-Queisser limits. Multi-junction cells can achieve higher efficiencies, but epitaxial and current matching requirements between the single junctions in the devices hinder progress. Mechanical stacking of independent multi-junction cells circumvents these disadvantages. Here we present a fabrication approach for the realization of mechanically assembled multi-junction cells using materials and techniques compatible with large-scale manufacturing. The strategy involves printing-based stacking of microscale solar cells, sol-gel processes for interlayers with advanced optical, electrical and thermal properties, together with unusual packaging techniques, electrical matching networks, and compact ultrahigh-concentration optics. We demonstrate quadruple-junction, four-terminal solar cells with measured efficiencies of 43.9% at concentrations exceeding 1,000 suns, and modules with efficiencies of 36.5%. PMID- 24776536 TI - Magnetization switching through giant spin-orbit torque in a magnetically doped topological insulator heterostructure. AB - Recent demonstrations of magnetization switching induced by in-plane current in heavy metal/ferromagnetic heterostructures (HMFHs) have drawn great attention to spin torques arising from large spin-orbit coupling (SOC). Given the intrinsic strong SOC, topological insulators (TIs) are expected to be promising candidates for exploring spin-orbit torque (SOT)-related physics. Here we demonstrate experimentally the magnetization switching through giant SOT induced by an in plane current in a chromium-doped TI bilayer heterostructure. The critical current density required for switching is below 8.9 * 10(4) A cm(-2) at 1.9 K. Moreover, the SOT is calibrated by measuring the effective spin-orbit field using second-harmonic methods. The effective field to current ratio and the spin-Hall angle tangent are almost three orders of magnitude larger than those reported for HMFHs. The giant SOT and efficient current-induced magnetization switching exhibited by the bilayer heterostructure may lead to innovative spintronics applications such as ultralow power dissipation memory and logic devices. PMID- 24776537 TI - Electric field control of soliton motion and stacking in trilayer graphene. AB - The crystal structure of a material plays an important role in determining its electronic properties. Changing from one crystal structure to another involves a phase transition that is usually controlled by a state variable such as temperature or pressure. In the case of trilayer graphene, there are two common stacking configurations (Bernal and rhombohedral) that exhibit very different electronic properties. In graphene flakes with both stacking configurations, the region between them consists of a localized strain soliton where the carbon atoms of one graphene layer shift by the carbon-carbon bond distance. Here we show the ability to move this strain soliton with a perpendicular electric field and hence control the stacking configuration of trilayer graphene with only an external voltage. Moreover, we find that the free-energy difference between the two stacking configurations scales quadratically with electric field, and thus rhombohedral stacking is favoured as the electric field increases. This ability to control the stacking order in graphene opens the way to new devices that combine structural and electrical properties. PMID- 24776538 TI - An enantioselective cascade reaction between alpha,beta-unsaturated aldehydes and malonic half-thioesters: a rapid access to chiral delta-lactones. AB - We disclose a novel efficient enantioselective organocatalytic cascade reaction for the preparation of delta-lactones in good to excellent yields (69-93%) and with high to excellent enantioselectivities (88-96% ee). PMID- 24776539 TI - Isolation and characterization of the circulating truncated form of PCSK9. AB - Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a secreted protein which regulates serum LDL cholesterol. It circulates in human and rodent serum in an intact form and a major truncated form. Previous in vitro studies involving the expression of human PCSK9 genetic variants and in vivo studies of furin knockout mice suggest that the truncated form is a furin cleavage product. However, the circulating truncated form of PCSK9 has not been isolated and characterized. Utilizing antibodies which bind to either the catalytic domain or the C-terminal domain of PCSK9, the truncated PCSK9 was isolated from serum. MS was used to determine that this form of PCSK9 is a product of in vivo cleavage at Arg218 resulting in pyroglutamic acid formation of the nascent N terminus corresponding to Gln219 of intact PCSK9. We also determined that the truncated PCSK9 in serum lacked the N-terminal segment which contains amino acids critical for LDL receptor binding. A truncated PCSK9, expressed and purified from HEK293 cells with identical composition as the circulating truncated protein, was not active in inhibition of LDL uptake by HepG2 cells. These studies provide a definitive characterization of the composition and activity of the truncated form of PCSK9 found in human serum. PMID- 24776540 TI - apoE3[K146N/R147W] acts as a dominant negative apoE form that prevents remnant clearance and inhibits the biogenesis of HDL. AB - The K146N/R147W substitutions in apoE3 were described in patients with a dominant form of type III hyperlipoproteinemia. The effects of these mutations on the in vivo functions of apoE were studied by adenovirus-mediated gene transfer in different mouse models. Expression of the apoE3[K146N/R147W] mutant in apoE deficient (apoE(-/-)) or apoA-I-deficient (apoA-I(-/-))*apoE(-/-) mice exacerbated the hypercholesterolemia and increased plasma apoE and triglyceride levels. In apoE(-/-) mice, the apoE3[K146N/R147W] mutant displaced apoA-I from the VLDL/LDL/HDL region and caused the accumulation of discoidal apoE-containing HDL. The WT apoE3 cleared the cholesterol of apoE(-/-) mice without induction of hypertriglyceridemia and promoted formation of spherical HDL. A unique property of the truncated apoE3[K146N/R147W]202 mutant, compared with similarly truncated apoE forms, is that it did not correct the hypercholesterolemia. The contribution of LPL and LCAT in the induction of the dyslipidemia was studied. Treatment of apoE(-/-) mice with apoE3[K146N/R147W] and LPL corrected the hypertriglyceridemia, but did not prevent the formation of discoidal HDL. Treatment with LCAT corrected hypertriglyceridemia and generated spherical HDL. The combined data indicate that the K146N/R147W substitutions convert the full length and the truncated apoE3[K146N/R147W] mutant into a dominant negative ligand that prevents receptor-mediated remnant clearance, exacerbates the dyslipidemia, and inhibits the biogenesis of HDL. PMID- 24776542 TI - Chronic inflammation and progressive calcification as a result of fat necrosis: the worst outcome in fat grafting. AB - BACKGROUND: Autologous fat injection into the breast has been performed widely for breast augmentation and reconstruction because of recent technical and scientific advancements. However, it is important to learn what occurs and how problematic it can be if fat grafting is not conducted appropriately. METHODS: Oil cysts were explanted from three subjects who underwent cosmetic fat grafting to the breast 2, 4, and 6 years previously. The oil cyst samples were examined histopathologically. Computed tomographic, magnetic resonance imaging, and mammographic images obtained sequentially after fat grafting were also analyzed. RESULTS: The cyst wall consisted of innermost and outermost fibrous layers and intermediate tissue that contained the regular adipose portion, a degenerated adipose portion, and a fibrous area. Eggshell-like macrocalcifications were seen in the inner surface. Numerous inflammatory cells, mainly MAC2/CD206 anti inflammatory M2 macrophages, were observed in the degenerated adipose portion. Oil cysts with a longer history showed more calcifications in the innermost layer and a larger fibrous area adjacent to the degenerated fat portion than those with a shorter history. These histopathologic findings and clinical computed tomographic images revealed that oil cysts continued to be inflammatory and calcifications continued to develop over several years. CONCLUSIONS: After fat necrosis, long-term chronic inflammation persists and calcification seems to progress without limits. Oil cysts are the worst outcome of fat grafting and must be avoided by standardizing meticulous injection techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24776543 TI - Three-dimensional nipple-areola tattooing: a new technique with superior results. AB - Traditional coloring techniques for nipple-areola tattooing ignore the artistic principles of light and shadow to create depth on a two-dimensional surface. The method presented in this article is essentially the inverse of traditional technique and results in a more realistic and three-dimensional reconstruction that can appear better than surgical methods. The application of three dimensional techniques or "realism" in tattoo artistry has significant potential to improve the aesthetic outcomes of reconstructive surgery. PMID- 24776541 TI - Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells. AB - Autophagy is a lysosomal bulk degradation pathway for cytoplasmic cargo, such as long-lived proteins, lipids, and organelles. Induced upon nutrient starvation, autophagic degradation is accomplished by the concerted actions of autophagy related (ATG) proteins. Here we demonstrate that two ATGs, human Atg2A and Atg14L, colocalize at cytoplasmic lipid droplets (LDs) and are functionally involved in controlling the number and size of LDs in human tumor cell lines. We show that Atg2A is targeted to cytoplasmic ADRP-positive LDs that migrate bidirectionally along microtubules. The LD localization of Atg2A was found to be independent of the autophagic status. Further, Atg2A colocalized with Atg14L under nutrient-rich conditions when autophagy was not induced. Upon nutrient starvation and dependent on phosphatidylinositol 3-phosphate [PtdIns(3)P] generation, both Atg2A and Atg14L were also specifically targeted to endoplasmic reticulum-associated early autophagosomal membranes, marked by the PtdIns(3)P effectors double-FYVE containing protein 1 (DFCP1) and WD-repeat protein interacting with phosphoinositides 1 (WIPI-1), both of which function at the onset of autophagy. These data provide evidence for additional roles of Atg2A and Atg14L in the formation of early autophagosomal membranes and also in lipid metabolism. PMID- 24776544 TI - Discussion: New anatomical insights on the course and branching patterns of the facial artery: clinical implications of injectable treatments to the nasolabial fold and nasojugal groove. PMID- 24776545 TI - Reconstructive rhinoplasty: operative revision of patients with previous autologous costal cartilage grafts. AB - BACKGROUND: Costal cartilage grafts are used more frequently in secondary rhinoplasty. However, these procedures result in patients that require further revision operations that are not trivial. The purpose of this study was to assess the outcomes of reconstructive rhinoplasty performed on patients with a history of prior secondary or tertiary rhinoplasty using autogenous costal cartilage grafts. METHODS: A retrospective review was conducted of tertiary rhinoplasty procedures. Outcomes of interest included the indications for the revision operation; revision rate following the tertiary costal cartilage revision; whether or not the use of costal cartilage grafts for the reconstructive rhinoplasty was a planned event; and perioperative incidents such as infection, structural collapse, and scarring requiring further surgery. RESULTS: Forty-six patients met inclusionary criteria. The revision rate following tertiary rhinoplasty performed by the primary author was found to be 24 percent (11 of 46). The reasons for these revision operations were nasal airway obstruction (n = 6), aesthetic dissatisfaction (n = 4), and infection (n = 1). Outcomes of the revisions were satisfactory, with no adverse complications requiring further surgery. CONCLUSIONS: Reconstructive rhinoplasty may be required in patients who have undergone previous costal cartilage grafting for secondary rhinoplasty. These revision operations can be performed successfully to help patients achieve both improved function and aesthetic results but have a higher than usual revision rate themselves. The revisions of these operations can be managed with standard revision operations that result in satisfactory outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24776546 TI - Augmentation of intraorbital volume with fat injection. AB - BACKGROUND: Enophthalmos is a challenging surgical problem to correct. Standard techniques to adjust orbital volume require invasive maneuvers such as osteotomies. Fat injection may provide a simple and less-invasive way of augmenting orbital volume to correct enophthalmos. METHODS: The right eye orbital volume of 10 New Zealand White rabbits was augmented with fat. Autologous fat was diced and injected into the retrobulbar space. Computed tomographic scans were evaluated for changes in globe position and retrobulbar volume. Visually evoked potentials were conducted to test the integrity of the optic tract. Rabbits were killed at 12 weeks after surgery. Orbital exenterations were performed to allow for gross and histologic evaluation. RESULTS: Right globe position showed a mean increase in eye proptosis of 3.4 mm at postoperative day 1 and 0.9 mm at 11 weeks postoperatively in comparison with the left globe position. No significant change was noted in the left globe position. Retrobulbar volume demonstrated an initial mean increase of 31 percent and a final mean increase of 9.8 percent at 11 weeks in the right eye compared with the left eye. Visually evoked potentials revealed intact optic pathways in all animals. Gross anatomical evaluation showed deposition of fat grafts. Histologic analysis showed both revascularized and necrotic areas of fat. No retinal or optic nerve damage was identified. CONCLUSIONS: Fat injection can augment orbital volume in an animal model and preserve visual function. Further investigation is necessary to document the clinical safety and value of this technique in humans. PMID- 24776547 TI - A systematic review of distraction osteogenesis in hand surgery: what are the benefits, complication rates, and duration of treatment? AB - BACKGROUND: This work analyzes the utility of distraction osteogenesis as a surgical option for the management of acquired and traumatic hand deformities through a systematic review of the published literature. METHODS: A PubMed search for articles reporting results of distraction osteogenesis in the hand was performed. Data collected included age, sex, cause, bone distracted, latency period, distraction rate, consolidation period, treatment time, length gained, and complications. Proportion data variables were compared using the chi-square test. A meta-analysis was also performed to assess the size effect of variables on complication development. RESULTS: Thirty articles (424 distractions) met inclusion criteria. The average length gained from distraction was 2.2 cm; the average total treatment time was 116 days; the average complication rate was 26.4 percent. Proportion analysis, including all articles, showed that congenital cause had significantly fewer complications compared with traumatic cause (p = 0.0129). A lower complication rate in pediatric patients compared with adults approached but did not reach significance (p = 0.0507). Studies that underwent meta-analysis, including only articles comparing both variables of interest, were homogeneous (I < 25) and without publication bias (Kendall's tau p > 0.05 and symmetric funnel plot). None of the variables analyzed by meta-analysis had a significant odds ratio for complication development (p > 0.05). CONCLUSION: Despite distinct advantages, distraction osteogenesis is associated with a long duration of treatment and high complication rates, particularly in adults and in posttraumatic reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24776548 TI - A novel method of naturally contouring the reconstructed ear: modified antihelix complex affixed to grooved base frame. AB - BACKGROUND: Prior reports of ear reconstruction have cited favorable results. Although greater attention has been devoted to fabricating a more refined cartilaginous framework, many patients still complain that the contours are unnatural. The authors' aim was to offer a new technique that resolves some lingering issues. METHODS: To fabricate the antihelix complex optimally, the authors modified an existing method. Rather than chiseling a sharp, Y-shaped graft of cartilage for structural prominence, the superior crus is broadened, and a gentle slope is sculpted on both aspects. Simultaneously, a groove in the base frame is carved for smooth attachment. The width of the inferior crus is limited to roughly one-third that of the superior crus, and the inferior crus is maintained in high relief. A gentle slope is shaped on the antihelix, and a groove for placement of the antihelix is carved into the base frame. RESULTS: Between 2011 and 2013, a total of 162 patients underwent reconstruction using this modified technique. Three such subjects have been selected to highlight the favorable results achieved. Given modifications confer natural contours to superior and inferior crura, antihelix, and surrounding structures, providing a cohesive framework for the integrity of a reconstructed ear. CONCLUSIONS: The antihelix complex is critical for creating a natural auricle. Harmonious integration of superior and inferior crura and antihelix enhances the overall aesthetics, increasing procedural satisfaction for patient and surgeon alike. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24776549 TI - Discussion: A novel method of naturally contouring the reconstructed ear: modified antihelix complex affixed to grooved base frame. PMID- 24776550 TI - Evidence-based medicine: Blepharoplasty. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Identify the essential preoperative considerations for patients undergoing blepharoplasty. (2) Describe upper and lower eyelid anatomy and the relevance to blepharoplasty techniques. (3) Discuss a standard approach to upper and lower lid blepharoplasty, beginning with preoperative assessment, planning, and marking. 4. Describe the major considerations in periorbital rejuvenation and the critical steps taken during blepharoplasty to create aesthetic improvements. SUMMARY: Blepharoplasty is one of the most common aesthetic procedures performed in the United States. Significant improvements in facial aesthetics can be made with a relatively short operation that can be performed under intravenous sedation or entirely with local anesthesia. Upper blepharoplasty focuses primarily on removal of excess skin and aesthetic placement of the supratarsal crease, along with filling and contouring of a deep upper orbital sulcus with injections when necessary. Lower blepharoplasty addresses the orbitomalar sulcus (lid-cheek junction and tear-trough abnormalities) and pseudoherniation of periorbital fat, and is based on selective removal and repositioning of fat. Upper blepharoplasty generally does not require fat removal. In addition, lower blepharoplasty involves releasing deep structures, whereas upper blepharoplasty is generally more superficial. In general, the upper lid should be approached transcutaneously, whereas lower blepharoplasty can be safely performed through a transconjunctival or a transcutaneous incision. Complications of upper blepharoplasty are uncommon with more current techniques, but lower lid blepharoplasty has potentially disastrous complications. Blepharoplasty can significantly enhance periorbital and midface aesthetics by improving the tired appearance of even young patients, and is an important tool for facial rejuvenation. PMID- 24776551 TI - Evidence-based medicine: Face lift. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Thoroughly recognize the factors that contribute to hematoma after face lift. (2) Describe and apply the current evidence for which technique gives superior results in outcomes after face lift. (3) Use the current evidence to determine whether to incorporate fibrin sealant into the practitioner's intraoperative routine, and its effects on bleeding, fluid accumulation, and bruising. (4) Explain an approach for controlling blood pressure in the perioperative period after face lift. (5) Describe the benefits of controlling nausea and vomiting after face lift. (6) Use appropriate measures to reduce the risk of venous thromboembolism when performing face lift. (7) Assess the role of different forms of local anesthetic in reducing postoperative hematoma. SUMMARY: This article provides a review of the latest evidence regarding the preoperative assessment and perioperative management of patients undergoing face lift. The effects of various pharmacologic interventions and surgical techniques on postoperative complications are also reviewed. In addition, a meta-analysis of recent literature was performed to compare the rates of postoperative hematoma formation following various face lift techniques. PMID- 24776552 TI - Evidence-based medicine: Abdominoplasty. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Develop a surgical plan for improving the contour of the abdominal region by means of abdominoplasty surgery. (2) Describe the current modalities for preventing and managing perioperative pain associated with abdominoplasty surgery. (3) Discuss proper techniques for safely performing simultaneous abdominal wall liposuction and abdominoplasty surgery. (4) Determine the means of decreasing seroma formation and drain duration in abdominoplasty patients. (5) Apply current concepts in preventing and minimizing perioperative complications in abdominoplasty patients. SUMMARY: Abdominoplasty continues to be one of the most popular cosmetic surgeries performed by plastic surgeons throughout the world. Advancements in the area continue to surface which can help improve outcomes. We present an extensive review of the most current literature on this topic. This article offers readers an up-to-date and organized approach to abdominoplasty surgery. PMID- 24776553 TI - Evidence-based medicine: Flexor tendon repair. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Describe and apply the current evidence-based treatment of acute flexor tendon injuries. (2) Compare and contrast the current postoperative therapy regimens following repair of flexor tendons. (3) Apply an evidence-based decision making process for suture techniques of flexor tendon injuries. SUMMARY: Flexor tendon repair remains a challenge for hand surgeons to reliably obtain excellent results. Surgical decisions should rely on the surgeon's experience, outcome studies, and direct evidence. This review is a compilation of the evidence from the literature on optimizing outcomes for flexor tendon repair. PMID- 24776554 TI - Evidence-based medicine: Carpal tunnel syndrome. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Describe and apply the best current high-level evidence in carpal tunnel syndrome. (2) Design a treatment plan to offer tourniquet-free, sedation-free local anesthesia for patients who wish it or who are at high risk with sedation. (3) Describe the evidence and outcomes as they relate to splinting carpal tunnel patients after surgery. SUMMARY: This is the third Maintenance of Certification article on carpal tunnel syndrome. Hentz and Lalonde summarized the best literature in 2008 in the first article. The second article, by Shores and Lee, presented the best evidence regarding assessment, surgical treatment, and outcomes from the literature published between 1999 and 2009. In this article, the author has concentrated on topics not covered in depth in the first two articles and provides an update of the highest level evidence on important topics from 2009 to 2013. Although there is some Level IV and V evidence cited in this article, most is Level I, II, and III. PMID- 24776555 TI - Evidence-based medicine: Dupuytren contracture. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Describe features and clinical importance of Dupuytren diathesis. (2) Explain the difference between the new definition of recurrence used in collagenase studies compared with prior definitions of recurrence. (3) Compare and list the main advantage/main disadvantage of fasciectomy versus minimally invasive treatment (collagenase injection or needle aponeurotomy) of Dupuytren contracture. SUMMARY: The large body of existing literature on Dupuytren disease is spread across many journals in many specialties. It is thus a daunting task for practitioners to follow trends and practice recommendations. It is also a testimony to the lack of an acceptable solution to this common problem. Recent publications provide evidence to highlight controversies and challenge some traditional teachings. Literature from 2010 to 2012 was reviewed with the intent of clarifying some of these issues. PMID- 24776556 TI - Evidence-based medicine: Metacarpal fractures. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Determine the need for operative treatment of metacarpal fractures. (2) Describe the position of immobilization for nonoperative treatment of fifth metacarpal fractures. (3) Assess the differences between intramedullary pinning and transverse pinning of displaced metacarpal fractures. (4) Compare the advantages of plating and pinning for treatment of displaced metacarpal fractures. (5) Recognize appropriate timing and treatment of open metacarpal fractures. SUMMARY: The body of evidence regarding the treatment of metacarpal fractures continues to grow. Conservative management, closed reduction with percutaneous Kirschner wire fixation, intramedullary fixation, and open reduction and internal fixation with plates and/or screws are all accepted treatment modalities. The goal of this review is to highlight the most recent literature and the best evidence available for the management of metacarpal fractures. PMID- 24776557 TI - Evidence-based medicine: Craniosynostosis. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Make the appropriate diagnosis for each of the single-sutural synostoses, based on the physical examination. (2) Explain the functional concerns associated with these synostoses and why surgical correction is indicated. (3) Distinguish between the different types of surgical corrections available, the timing for these various interventions, and in what ways these treatments achieve overall management objectives. (4) Identify the basic goals involved in caring for the syndromic synostoses. SUMMARY: This article provides an overview of the diagnosis and management of infants with craniosynostosis. This review also incorporates some of the treatment philosophies followed at The Craniofacial Center in Dallas, but is not intended to be an exhaustive treatise on the subject. It is designed to serve as a reference point for further in-depth study by review of the reference articles presented. This information base is then used for self assessment and benchmarking in parts of the Maintenance of Certification process of the American Board of Plastic Surgery. PMID- 24776558 TI - Evidence-based medicine: The cleft lip nasal deformity. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Describe the components of unilateral and bilateral secondary cleft lip nasal deformity. (2) Discuss current methods of assessing the deformity and outcomes. (3) Discuss primary treatment options including the use of preoperative orthopedics, nasal molding techniques, and the primary cleft rhinoplasty. (4) Design a treatment plan for cleft patients that will optimize the outcome of nasal appearance and function. (5) Discuss the evidence regarding outcomes of current practices, and describe areas where more research is needed. SUMMARY: This is the third Maintenance of Certification article on the secondary cleft lip nose deformity. In the first article, Guyuron defined the deformities and described techniques for the definitive (adult) rhinoplasty. The second article, by Zbar and Canady, presented evidence regarding the assessment, surgical treatment, and outcomes from the literature published between 1999 and 2009. In this article, the authors summarize important points from the first two articles and then concentrate on the evidence for the following topics: (1) methods currently used in evaluating the severity of the deformities; (2) methods used in evaluating outcomes of different treatments; (3) benefits of rhinoplasty performed at the time of the lip repair and evidence for the effect of rhinoplasties performed after infancy but before maturity; (4) presurgical orthopedics and nasoalveolar molding; (5) common surgical techniques used in primary cleft rhinoplasties; and (6) impact of the nasal deformity on quality of life. Overall, there is little high-level evidence regarding the outcomes of cleft nasal deformity treatment, leaving much room for future study. PMID- 24776559 TI - Duty hours and home call: the experience of plastic surgery residents and fellows. AB - BACKGROUND: Although resident duty hours are strictly regulated by the Accreditation Council for Graduate Medical Education, there are fewer restrictions on at-home call for residents. To date, no studies have examined the experience of home call for plastic surgery trainees or the impact of home call on patient care and education in plastic surgery. METHODS THE AUTHORS DISTRIBUTED: an anonymous electronic survey to plastic surgery trainees at 41 accredited programs. They sought to produce a descriptive assessment of home call and to evaluate the perceived impact of home call on training and patient care. RESULTS: A total of 214 responses were obtained (58.3 percent completion rate). Nearly all trainees reported taking home call (98.6 percent), with 66.7 percent reporting call frequency every third or fourth night. Most respondents (63.3 percent) felt that home call regulations are vague but that Council regulation (44.9 percent) and programmatic oversight (56.5 percent) are adequate. Most (91.2 percent) believe their program could not function without home call and that home call helps to avoid strict duty hour restrictions (71.5 percent). Nearly all respondents (92.3 percent) preferred home call to in-house call. CONCLUSIONS: This is the first study to examine how plastic surgery residents experience and perceive home call within the framework of Accreditation Council for Graduate Medical Education duty hour regulations. Most trainees feel the impact of home call is positive for education (50.2 percent) and quality of life (56.5 percent), with a neutral impact on patient care (66.7 percent). Under the Council's increasing regulations, home call provides a balance of education and patient care appropriate for training in plastic and reconstructive surgery. PMID- 24776560 TI - Fat transfer in 2014: what we do not know. PMID- 24776561 TI - The twenty-first century hospital: checklists, compliance, and disruption. PMID- 24776563 TI - Evaluating long-term outcomes following nipple-sparing mastectomy and reconstruction in the irradiated breast. AB - BACKGROUND: Although it is well established that reconstruction of the irradiated breast is associated with diminished cosmetic results and more frequent complications, little is known about the specific effects of radiation therapy on the reconstructive outcomes after nipple-sparing mastectomy. METHODS: Patients who had nipple-sparing mastectomy and had either previous radiation therapy for breast-conservation therapy or postmastectomy radiation therapy were reviewed. Patient demographics, reconstructive details, and postoperative outcomes were analyzed. Patient photographs were used to evaluate aesthetic parameters. Fisher's exact and t tests were used for comparison of groups, with a value of p < 0.05 considered significant. RESULTS: Eighteen patients were identified as having nipple-sparing mastectomy either after breast-conservation therapy (72.2 percent) or before postmastectomy radiation therapy (27.8 percent), with an average follow-up of 3 years. First-stage complications occurred in six patients (33.3 percent). Nipple position was classified as high-riding in 55.6 percent of patients. Average time to revision was 13.3 months. Most common revisions were for correction of malposition (27.8 percent), capsular contracture (16.7 percent), and high-riding nipple (22.4 percent). Capsular contracture occurred more commonly in patients who needed postmastectomy radiation therapy compared with those who had previously undergone breast-conservation therapy (40 percent versus 7.8 percent). Maintenance of reconstruction occurred in 88.9 percent patients, with eventual implant loss occurring in two patients (11.1 percent). CONCLUSIONS: Nipple-sparing mastectomy and implant reconstruction should be approached cautiously in the setting of radiation therapy. When early complications are present, significant morbidity may occur. Late revision surgery is common in this subset of patients. Implant malposition and a high-riding nipple occur most frequently. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24776564 TI - Risk factors for pannus formation in the post-bariatric surgery population. AB - BACKGROUND: Previous studies describe a relationship between pannus mass and panniculectomy-related complication rates. Patient management may be improved by elucidating the key factors influencing pannus formation. METHODS: A retrospective review was conducted of 135 patients who had undergone laparoscopic Roux-en-Y gastric bypass from 1996 to 2010 and subsequent panniculectomy. Outcome measures included age, sex, body mass index, time of surgery, resected pannus mass, comorbidities, and panniculectomy-related complications. Nonparametric continuous and nominal variables were assessed using Spearman rank-correlation and Mann-Whitney U tests, respectively. RESULTS: One hundred thirty-five patients (123 women and 12 men; mean age, 44.7 years) were included in analysis. All patients had body contouring surgery more than 1 year after bariatric surgery (median time interval, 2.1 years). Median body mass index at the time of bypass, 1 year after bypass, and at the time of body contouring surgery was 48.7, 30.0, and 29.4 kg/m, respectively. Median pannus mass was 2.2 kg. Larger pannus mass was associated with greater age at gastric bypass surgery (p = 0.034), higher pre gastric bypass body mass index (p = 0.031), higher prepanniculectomy body mass index (p < 0.001), and longer time interval between gastric bypass and panniculectomy (p = 0.046). Female patients requiring blood transfusions had a significantly larger pannus mass than those who did not (p = 0.048). CONCLUSION: Performing bariatric surgery on patients at a younger age or having patients reduce body mass index as much as possible before bariatric surgery may be useful for minimizing symptomatic pannus formation and in turn may decrease rates of panniculectomy-related complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 24776565 TI - Mast cells prevent dexamethasone-induced cell death of cultured fibroblasts: relationship to gap junctional intercellular communications. AB - BACKGROUND: Dexamethasone, a common therapy for reducing hypertrophic scar, sometimes fails. However, in cell culture, all dexamethasone-treated fibroblasts die. In co-cultures, gap junction intercellular communications between mast cells and fibroblasts promote profibrotic activities. Does the co-culture of mast cells with fibroblasts prevent dexamethasone-induced fibroblast death? METHODS: Survival of fibroblasts co-cultured with RMC-1 cells, a rat mast cell line, receiving dexamethasone was studied. RMC-1 cells pretreated with a secretagogue that degranulated mast cells and/or with a long-acting gap junction intercellular communications inhibitor were compared to untreated RMC-1 cells co-cultured with fibroblasts and dexamethasone. RESULTS: Fibroblasts alone treated with dexamethasone all died in 3 hours. Fibroblasts co-cultured with intact RMC-1 cells or with degranulated RMC-1 cells in dexamethasone all survived. No fibroblasts survived, co-cultured with RMC-1 cells unable to form gap junction intercellular communications with fibroblasts. CONCLUSIONS: Dexamethasone-treated fibroblasts, forming gap junction intercellular communications with mast cells, may explain why dexamethasone therapy sometimes fails. Gap junction intercellular communications between scar mast cells and fibroblasts or myofibroblasts apparently blocks the death of these cell populations. Preventing gap junction intercellular communications between mast cells and fibroblasts by including anti gap junction intercellular communication agents may enhance the effectiveness of steroid therapy in treating excessive scarring. PMID- 24776566 TI - Augmentation of tendon healing with an injectable tendon hydrogel in a rat Achilles tendon model. AB - BACKGROUND: Many unsolved problems in plastic and hand surgery are related to poor healing of acute and chronic tendon injuries. The authors hypothesized that tendon healing could be augmented by the addition of a tendon-derived, extracellular matrix hydrogel that would guide tissue regeneration. METHODS: Both Achilles tendons of 36 Wistar rats were given full-thickness injuries approximately 5 mm long and 0.5 mm wide from the tendon insertion at the calcaneus to the midsubstance. The hydrogel was injected into the injury site of one leg and compared with control saline in the other. The ultimate failure load, ultimate tensile stress, and stiffness were evaluated at 2, 4, and 8 weeks. Tendon cross-sections underwent histologic analysis (hematoxylin and eosin and picrosirius red) after the animals were killed. Statistical analysis of biomechanical data was performed using a paired t test. RESULTS: There was no significant difference in strength between gel and saline injections in ultimate failure load (p = 0.15), ultimate tensile stress (p = 0.42), or stiffness (p = 0.76) at 2 weeks. However, there was a significant difference in ultimate failure load (74.8 +/- 11.6 N versus 58.4 +/- 14.2 N; p = 0.02) at 4 weeks. The difference in ultimate tensile stress (p = 0.63) and stiffness (p = 0.08) remained insignificant. By 8 weeks, there was no significant difference in strength in ultimate failure load (p = 0.15), ultimate tensile stress (p = 0.39), or stiffness (p = 0.75). CONCLUSIONS: Treatment with the tendon hydrogel significantly increases the ultimate failure load of tendons at the critical 4 week time point, and is a promising method for augmentation of tendon healing. PMID- 24776567 TI - Upper extremity anomalies in Pfeiffer syndrome and mutational correlations. AB - BACKGROUND: Pfeiffer syndrome is characterized by craniosynostosis and a variety of associated upper and lower extremity anomalies. The authors reviewed presentation and treatment of upper extremity anomalies in a series of genotyped patients with Pfeiffer syndrome. METHODS: Medical records of patients with Pfeiffer syndrome seen at the authors' institution over a 16-year period were reviewed. Data on clinical presentation, genetic testing, and treatment were collected. The upper extremity anomalies were documented using plain radiographs and physical examinations by a multidisciplinary craniofacial team. RESULTS: Of 15 patients identified as having FGFR1- or FGFR2-confirmed Pfeiffer syndrome, 12 (80 percent) presented with upper extremity anomalies, most commonly broad thumbs [n = 10 (83 percent)], radial clinodactyly (thumbs) [n = 7 (58 percent)], and symphalangism [n = 7 each (58 percent)]. All patients with upper extremity anomalies had lower extremity anomalies. Six of the 12 patients (50 percent) with upper extremity findings underwent surgical correction. FGFR1 or FGFR2 genotype did not correlate with upper extremity phenotype. CONCLUSIONS: Although broad thumbs are common, patients with Pfeiffer syndrome often present with other upper extremity anomalies that may not require surgical intervention. Genetic and allelic heterogeneity may explain phenotypic variability in these upper extremity anomalies. Characterization of these limb differences should be made by pediatric hand surgeons as part of a craniofacial team. Treatment decisions should be individualized and dictated by the type and severity of clinical presentation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV. PMID- 24776568 TI - Cranial bone grafting for alveolar clefts: a 25-year review of outcomes. AB - BACKGROUND: Cranial bone grafting for an alveolar cleft obtains membranous bone from a low-morbidity donor site. Although iliac crest bone is the favored donor site, there are no objective analyses of three-dimensional radiologic outcomes with cranial bone grafting and no studies evaluating complications and long-term outcomes in a large series of patients undergoing cranial bone grafting. METHODS: A retrospective chart review was conducted on patients who underwent alveolar bone grafting from the cranium over a 25-year period performed by a single surgeon. Data collected included patient characteristics, complications, and clinical outcomes. Radiologic analysis of graft outcomes was determined using Amira volume-rendering software on the most recent 10 consecutive patients. RESULTS: The authors' study cohort included 308 patients, with an average age of 11.5 years. Complications involved harvesting the graft in 3.5 percent, the donor site in 1 percent, and the recipient site in 17.2 percent. Regrafting was required in 7.1 percent, with a clinical success rate of 92.9 percent. The average alveolar defect was 1.19 ml preoperatively and 0.19 ml postoperatively, with 85 percent fill of the cleft defect by radiologic analysis. CONCLUSIONS: Cranial bone grafting for the alveolar cleft is a low-morbidity operation and has success similar to that of iliac crest bone grafting. It should be considered more often as a viable option for the alveolar cleft patient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24776569 TI - Soft-tissue response rate to chin skeletal advancement in patients with lower facial burn scar. AB - BACKGROUND: This study aimed to evaluate the long-term outcomes and the soft tissue response to osseous genioplasty in patients with chin retrusion caused by early life facial burn injury. METHODS: Twenty-two consecutive patients with retrusive chin as a result of severe childhood facial burn were included in this study. Cephalometric analysis and photographs were used to assess the patients for eligibility of a surgical correction. Horizontal hard-tissue advancement and soft-tissue responses were measured as the primary outcomes at the early and late postoperative follow-up visits. RESULTS: A total of 22 patients fulfilled the study requirements. Average preoperative distance between the pogonion, as the most anterior point of the anterior mandibular contour, and a perpendicular line connecting the nasion and the supramental point of the mandible was 0.82 +/- 1.1 mm, which increased significantly to 7.8 +/- 0.8 mm after genioplasty (p < 0.0001). Soft tissue was repositioned on average 6.1 +/- 0.4 mm anteriorly on average, which is in comparison with the amount of chin skeleton advancement, and a response ratio of 0.8:1 was calculated at late follow-up. CONCLUSION: Burn related retrusive chin can appropriately be treated with sliding osseous genioplasty and will require slight overcorrection compared with patients without a history of lower face burn. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24776570 TI - Use of lateral upper arm free flaps for soft-tissue reconstruction of the contracted eye socket. AB - BACKGROUND: Severe orbital soft-tissue loss and contracted eye sockets often present in patients who have had enucleation, exenteration, or other ocular diseases. In this article, the authors report a novel contracted eye socket reconstruction technique using lateral upper arm free flaps and review the surgical outcome in patients with severe orbital soft-tissue loss and contracted eye sockets. METHODS: Twenty-four patients with severe orbital soft-tissue loss and contracted eye sockets were included in this study. A free flap from the lateral upper arm of the patient was inserted into the eye socket, with the artery and vein of the flap pedicle attached to the ipsilateral superficial temporal artery and vein, respectively. Eye socket reconstruction was performed 2 weeks after the first operation. Patients were fitted with a piece of prosthesis 3 months later. Most patients needed a second operation for eyelid and eye socket reconstruction, including lower eyelid laxity and retraction correction, medial and lateral canthoplasty, and upper or lower fornix reconstruction. RESULTS: Postoperative improvement in appearance was evaluated, including texture and color of the flaps, sensation and mobility of the forearm and elbow, and visibility of the surgical scar. All 24 patients were followed up for 6 months to 5 years. Donor sites healed with linear scars, and no sensory or movement loss was found in any of the patients. The reconstructed area appeared good, patients were satisfied with recovering results, and the prosthesis fit well. CONCLUSIONS: The skin from the lateral upper arm has consistent blood vessels and suitable thickness to serve as a source for orbital soft-tissue and contracted eye socket reconstruction, with good cosmetic outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24776571 TI - Perineal perforator-based island flaps: the next frontier in perineal reconstruction. AB - BACKGROUND: Perineal reconstruction is a challenging prospect. Conventional flap reconstruction often involves the sacrifice of a source artery and muscle, resulting in significant donor morbidity. Perforator flaps sought to overcome this but required tedious dissection. In this article, the authors introduce a new concept in perineal reconstruction using perforator-based island flaps. METHODS: The perineal perforator-based island flap is raised based on perforators that most commonly arise from the perineal artery. The flap is designed in the inguinal and gluteal folds in order to achieve aesthetic, tension-free primary closure of the donor site. Eleven patients underwent perineal reconstruction using this approach. Patients ranged in age from 8 to 75 years, with a female-to male ratio of 10:1. RESULTS: All 11 operations were performed by a single surgeon (S.Y.M.H.). There were no cases of flap loss or donor-site complications, as defined by wound infection, dehiscence, or keloid formation. All 11 patients reported excellent satisfaction with regard to donor-site aesthetics. CONCLUSIONS: Perineal perforator-based island flaps represent one of the most successful outcomes of the perforator concept. There is no sacrifice of donor vessels or muscle and minimal donor morbidity. The flap is also easily harvested and allows for challenging free-form flap design because it is based on reliable perforators. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24776572 TI - Abdominal wall and chest wall reconstruction. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: (1) Define the goals of abdominal wall and chest wall reconstruction. (2) Discuss the general principles of and the different surgical techniques for abdominal wall and chest wall reconstruction. (3) List the major advantages and disadvantages of synthetic and bioprosthetic mesh in abdominal and chest wall reconstruction. (4) Define the indications for and major factors to consider in chest wall skeletal stability reconstruction. (5) List the flaps commonly used for chest wall and abdominal wall reconstruction. SUMMARY: Plastic surgeons commonly face reconstructive challenges in repairing the abdominal and chest walls. Reconstructive options in these two areas are rapidly expanding with the availability of new techniques and new products. The purpose of this article is to provide an updated summary of reconstruction of the abdominal and chest walls, focusing on commonly encountered problems. PMID- 24776573 TI - Competency-based medical education for plastic surgery: where do we begin? AB - BACKGROUND: North American surgical education is beginning to shift toward competency-based medical education, in which trainees complete their training only when competence has been demonstrated through objective milestones. Pressure is mounting to embrace competency-based medical education because of the perception that it provides more transparent standards and increased public accountability. In response to calls for reform from leading bodies in medical education, competency-based medical education is rapidly becoming the standard in training of physicians. METHODS: The authors summarize the rationale behind the recent shift toward competency-based medical education and creation of the milestones framework. With respect to procedural skills, initial efforts will require the field of plastic surgery to overcome three challenges: identifying competencies (principles and procedures), modeling teaching strategies, and developing assessment tools. The authors provide proposals for how these challenges may be addressed and the educational rationale behind each proposal. RESULTS: A framework for identification of competencies and a stepwise approach toward creation of a principles oriented competency-based medical education curriculum for plastic surgery are presented. An assessment matrix designed to sample resident exposure to core principles and key procedures is proposed, along with suggestions for generating validity evidence for assessment tools. CONCLUSIONS: The ideal curriculum should provide exposure to core principles of plastic surgery while demonstrating competence through performance of index procedures that are most likely to benefit graduating residents when entering independent practice and span all domains of plastic surgery. The authors advocate that exploring the role and potential benefits of competency-based medical education in plastic surgery residency training is timely. PMID- 24776574 TI - Free tissue transfer in the obese patient: an outcome and cost analysis in 1258 consecutive abdominally based reconstructions. PMID- 24776575 TI - Reply: Free tissue transfer in the obese patient: an outcome and cost analysis in 1258 consecutive abdominally based reconstructions. PMID- 24776576 TI - Breast reconstruction with free tissue transfer from the abdomen in the morbidly obese. PMID- 24776577 TI - Nipple-sparing mastectomy in patients with a history of reduction mammaplasty or mastopexy: how safe is it? PMID- 24776578 TI - Reply: Nipple-sparing mastectomy in patients with a history of reduction mammaplasty or mastopexy: how safe is it? PMID- 24776579 TI - Magnetic resonance imaging and ultrasound evaluation after breast autologous fat grafting combined with platelet-rich plasma. PMID- 24776580 TI - Re: Reply: The poly implant prothese debacle. PMID- 24776581 TI - Facial changes caused by smoking: a comparison between smoking and nonsmoking identical twins. PMID- 24776582 TI - Reply: Facial changes caused by smoking: a comparison between smoking and nonsmoking identical twins. PMID- 24776583 TI - Skin perforator freeways and pathways: understanding the role of true and choke anastomoses between perforator angiosomes and their impact on skin flap planning and outcomes. PMID- 24776584 TI - Reply: Skin perforator freeways and pathways: understanding the role of true and choke anastomoses between perforator angiosomes and their impact on skin flap planning and outcomes. PMID- 24776585 TI - To reduce the secondary revision cleft rhinoplasty rate by special orbicularis reconstruction. PMID- 24776586 TI - Reply: To reduce the secondary revision cleft rhinoplasty rate by special orbicularis reconstruction. PMID- 24776587 TI - Anatomy of the supratrochlear nerve: implications for the surgical treatment of migraine headaches. PMID- 24776588 TI - Analysis of surgical treatments for earlobe keloids: analysis of 174 lesions in 145 patients. PMID- 24776589 TI - Reply: Analysis of surgical treatments for earlobe keloids: analysis of 174 lesions in 145 patients. PMID- 24776590 TI - Autoderm: an alternative bioprosthetic for breast reconstruction. PMID- 24776591 TI - Reply: Autoderm: an alternative bioprosthetic for breast reconstruction. PMID- 24776592 TI - Nanofat grafting: basic research and clinical application. PMID- 24776593 TI - The effects of postmastectomy adjuvant radiotherapy on immediate two-stage prosthetic breast reconstruction: a systematic review. PMID- 24776594 TI - Don't sleep on your DIEP. PMID- 24776595 TI - Implications of oxygenation in fat grafting. PMID- 24776596 TI - The reconstructive pyramid: redefining our yardsticks. PMID- 24776597 TI - Quantitative proteomics analysis reveals similar release profiles following specific PAR-1 or PAR-4 stimulation of platelets. AB - AIMS: Platelets are a natural source of growth factors, cytokines and chemokines, that regulate angiogenesis and inflammation. It has been suggested that differential release of pro- and anti-angiogenic growth factors from platelet alpha-granules by protease-activated receptors (PAR) 1 and 4 may be important for the regulation of angiogenesis. We aimed to compare the releasates of unstimulated platelets with PAR-1- and PAR-4-stimulated platelets. METHODS AND RESULTS: The release of beta-thromboglobulin, platelet factor (PF)-4, thrombospondin, platelet-derived growth factor (PDGF)-A/B, regulated and normal T cell expressed and secreted (RANTES/CCL5), endostatin, CXCL12, and vascular endothelial growth factor (VEGF) was measured with enzyme-linked immunosorbent assay (ELISA). Mass spectrometry (MS)-based quantitative proteomics identified 93 proteins from platelets stimulated with PAR-1 and PAR-4. A strong correlation between the factors released after either stimulus was observed (Spearman's r 0.94, P < 0.001). Analysis with ELISA showed that stimulation with PAR-1 or PAR-4 lead to non-differential release of beta-thromboglobulin, PF-4, thrombospondin, PDGF-A/B, RANTES/CCL5, endostatin, CXCL12, and VEGF. Release of thrombospondin was slightly lower after PAR-1 stimulation (7.2 MUg/mL), compared with PAR-4 induced release (9.8 MUg/mL; P < 0.05). CONCLUSIONS: Both ELISA on established alpha-granule proteins and MS-based quantitative proteomics showed that the most abundant alpha-granule proteins are released in similar quantities from platelets after stimulation with either PAR-1 or PAR-4. Our findings provide evidence against the hypothesis that PAR-1 and PAR-4 stimulation of platelets trigger differential release of alpha-granule, but further studies are needed to draw conclusions for physiological conditions. PMID- 24776598 TI - LOX-1, mtDNA damage, and NLRP3 inflammasome activation in macrophages: implications in atherogenesis. AB - AIMS: Lectin-like ox-LDL scavenger receptor-1 (LOX-1) and mitochondrial DNA (mtDNA) damage play a key role in a variety of cardiovascular diseases, including atherosclerosis, hypertension, and inflammation. We posited that damaged mtDNA could trigger autophagy and NLRP3 inflammasome activation, and LOX-1 may play a critical role in this process. METHODS AND RESULTS: In order to examine this hypothesis, cultured human THP-1 macrophages exposed to lipopolysaccharide (LPS) were applied to study the link between LOX-1, mtDNA damage, autophagy, and NLRP3 inflammasome expression. Our data showed that LPS markedly induced LOX-1 expression, reactive oxygen species (ROS) generation, autophagy, mtDNA damage, and NLRP3 inflammasome. LOX-1 inhibition with a binding antibody or siRNA inhibited ROS generation, autophagy and mtDNA damage, and a decreased expression of NLRP3 inflammasome. To study the LOX-1-NLRP3 inflammasome signalling, we performed studies using ROS inhibitors and an autophagy inducer, and found that both decreased the expression of NLRP3. On the other hand, autophagy inhibitor enhanced the expression of NLRP3 inflammasome. Knockdown of DNase II inhibited autophagy and NLRP3 inflammasome, providing further support for our hypothesis. Finally, we confirmed the relationship between LOX-1, ROS, mtDNA damage, autophagy, and NLRP3 inflammasome activation in primary macrophages. CONCLUSIONS: This study based on THP-1 macrophages and primary macrophages indicates that LOX 1-mediated autophagy and mtDNA damage play an essential role in NLRP3 inflammasome activation in inflammatory disease states. PMID- 24776600 TI - A simple step to reduce radiation exposure in the NICU. PMID- 24776599 TI - The tumour suppressor Ras-association domain family protein 1A (RASSF1A) regulates TNF-alpha signalling in cardiomyocytes. AB - AIMS: Tumour necrosis factor-alpha (TNF-alpha) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express the TNF alpha receptors (TNFRs), the mechanism of TNF-alpha signal transmission is incompletely understood. The aim of this study was to investigate whether the tumour suppressor Ras-association domain family protein 1 isoform A (RASSF1A) modulates TNF-alpha signalling in cardiomyocytes. METHODS AND RESULTS: We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates in this study. Acute stimulation with a low dose of TNF-alpha (10 ug/kg iv) increased cardiac contractility and intracellular calcium transients' amplitude in WT mice. In contrast, RASSF1A(-/-) mice showed a blunted contractile response. Mechanistically, RASSF1A was essential in the formation of the TNFR complex (TNFRC), where it functions as an adaptor molecule to facilitate the recruitment of TNFR type 1-associated death domain protein and TNFR-associated factor 2 to form the TNF-alpha receptor complex. In the absence of RASSF1A, signal transmission from the TNF-alpha receptor complex to the downstream effectors, such as cytoplasmic phospholipase A2 and protein kinase A, was attenuated leading to the reduction in the activation of calcium handling molecules, such as L-type Ca(2+) channel and ryanodine receptors. CONCLUSION: Our data indicate an essential role of RASSF1A in regulating TNF-alpha signalling in cardiomyocytes, with RASSF1A being key in the formation of the TNFRC and in signal transmission to the downstream targets. PMID- 24776601 TI - Universal pulse oximetry screen for critical congenital heart disease in the NICU. PMID- 24776602 TI - A catecholamine-secreting neuroblastoma leading to hydrops fetalis. AB - A case of fetal neuroblastoma of the right adrenal gland, with rapid development of hydrops fetalis due to catecholamine-induced cardiomyopathy, is reported. A fetus with a right suprarenal mass detected during ultrasonography at 32 weeks gestation progressively developed into hydrops fetalis by 35.2 weeks gestation. An emergent cesarean section was performed. At birth, the female neonate was hypertensive, with markedly elevated catecholamine levels; echocardiography showed poor contractility. Morphine, human atrial natriuretic peptide, milrinone, nitroprusside and dobutamine were initiated and her blood pressure was maintained within the normal range and her cardiac contractility improved 2 weeks after birth. Neuroblastoma cells were detected in the placenta, resulting in the right adrenal mass being diagnosed as a neuroblastoma. She was well, and the mass diminished in size within 4 months, without surgery. A fetus with suspected neuroblastoma, indicated by a suprarenal mass, should be managed with appropriate consideration of hydrops. PMID- 24776603 TI - Is Cronobacter sakazakii infection possible in an exclusively breastfed premature neonate in the neonatal intensive care unit? AB - Cronobacter species are Gram-negative rods that may cause life-threatening infections in neonates and infants. They belong to the family of Enterobacteriaceae. The first case was published in 1961 in England and about 150 cases have been reported thus far in the literature. The worst form of infection results in meningitis, leaving survivors with devastating neurological sequelae. We present the case of a premature neonate who was exclusively gavage fed with non-fortified breast milk and developed culture positive sepsis for Cronobacter sakazakii with clinical signs of meningitis at 18 days of life. She had a very traumatic course and survived the illness, but questions remain as to how she obtained this infection and her future neurodevelopmental outcomes. PMID- 24776604 TI - NPHP3 mutations are associated with neonatal onset multiorgan polycystic disease in two siblings. AB - Two siblings with a severe multiorgan polycystic disease presenting in the neonatal period were identified. Their genetic testing identified compound heterozygous NPHP3 gene mutations, parents being heterozygous carriers. The mutations included a splice-site (c.958-2A>G) and a missense mutation (c.2342G>A; p.G781D), both being extremely rare. NPHP3 encodes for nephrocystin 3 present on the cilia-centrosome complex. We hypothesize that these mutations lead to defective cilia-based signaling, required for normal development of the renal, pancreatic, biliary and portal system. This report outlines a rare neonatal ciliopathy presentation of NPHP3 mutations leading to severe multiorgan failure in two siblings. PMID- 24776605 TI - Gnathodiaphyseal dysplasia. PMID- 24776606 TI - Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study. AB - OBJECTIVE: Rate of lactate change is associated with in-hospital mortality in post-cardiac arrest patients. This association has not been validated in a prospective multicenter study. The objective of the current study was to determine the association between percent lactate change and outcomes in post cardiac arrest patients. DESIGN: Four-center prospective observational study conducted from June 2011 to March 2012. SETTING: The National Post-Arrest Research Consortium is a clinical research network conducting research in post cardiac arrest care. The network consists of four urban tertiary care teaching hospitals. PATIENTS: Inclusion criteria consisted of adult out-of-hospital non traumatic cardiac arrest patients who were comatose after return of spontaneous circulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was survival to hospital discharge, and secondary outcome was good neurologic outcome. We compared the absolute lactate levels and the differences in the percent lactate change over 24 hours between survivors and nonsurvivors and between subjects with good and bad neurologic outcomes. One hundred patients were analyzed. The median age was 63 years (interquartile range, 50-75) and 40% were female. Ninety-seven percent received therapeutic hypothermia, and overall survival was 46%. Survivors and patients with good neurologic outcome had lower lactate levels at 0, 12, and 24 hours (p< 0.01). In adjusted models, percent lactate decrease at 12 hours was greater in survivors (odds ratio, 2.2; 95% CI, 1.1-6.2) and in those with good neurologic outcome (odds ratio, 2.2; 95% CI, 1.1 4.4). CONCLUSION: Lower lactate levels at 0, 12, and 24 hours and greater percent decrease in lactate over the first 12 hours post cardiac arrest are associated with survival and good neurologic outcome. PMID- 24776607 TI - Relationship between ICU bed availability, ICU readmission, and cardiac arrest in the general wards. AB - OBJECTIVE: The decision to admit a patient to the ICU is complex, reflecting patient factors and available resources. Previous work has shown that ICU census does not impact mortality of patients admitted to the ICU. However, the effect of ICU bed availability on patients outside the ICU is unknown. We sought to determine the association between ICU bed availability, ICU readmissions, and ward cardiac arrests. DESIGN: In this observational study using data collected between 2009 and 2011, rates of ICU readmission and ward cardiac arrest were determined per 12-hour shift. The relationship between these rates and the number of available ICU beds at the start of each shift (accounting for census and nursing capacity) was investigated. Grouped logistic regression was used to adjust for potential confounders. SETTING: Five specialized adult ICUs comprising 63 adult ICU beds in an academic medical center. PATIENTS: Any patient admitted to a non-ICU inpatient unit was counted in the ward census and considered at risk for ward cardiac arrest. Patients discharged from an ICU were considered at risk for ICU readmission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were available for 2,086 of 2,190 shifts. The odds of ICU readmission increased with each decrease in the overall number of available ICU beds (odds ratio = 1.06; 95% CI, 1.00-1.12; p = 0.03), with a similar but not statistically significant association demonstrated in ward cardiac arrest rate (odds ratio = 1.06; 95% CI, 0.98-1.14; p = 0.16). In subgroup analysis, the odds of ward cardiac arrest increased with each decrease in the number of medical ICU beds available (odds ratio = 1.26; 95% CI, 1.06-1.49; p = 0.01). CONCLUSIONS: Reduced ICU bed availability is associated with increased rates of ICU readmission and ward cardiac arrest. This suggests that systemic factors are associated with patient outcomes, and flexible critical care resources may be needed when demand is high. PMID- 24776608 TI - Prospective study on the clinical course and outcomes in transfusion-related acute lung injury*. AB - OBJECTIVE: Transfusion-related acute lung injury is the leading cause of transfusion-related mortality. A prospective study using electronic surveillance was conducted at two academic medical centers in the United States with the objective to define the clinical course and outcomes in transfusion-related acute lung injury cases. DESIGN: Prospective case study with controls. SETTING: University of California, San Francisco and Mayo Clinic, Rochester. PATIENTS: We prospectively enrolled 89 patients with transfusion-related acute lung injury, 164 transfused controls, and 145 patients with possible transfusion-related acute lung injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with transfusion-related acute lung injury had fever, tachycardia, tachypnea, hypotension, and prolonged hypoxemia compared with controls. Of the patients with transfusion-related acute lung injury, 29 of 37 patients (78%) required initiation of mechanical ventilation and 13 of 53 (25%) required initiation of vasopressors. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury had an increased duration of mechanical ventilation and increased days in the ICU and hospital compared with controls. There were 15 of 89 patients with transfusion-related acute lung injury (17%) who died, whereas 61 of 145 patients with possible transfusion-related acute lung injury (42%) died and 7 of 164 of controls (4%) died. Patients with transfusion related acute lung injury had evidence of more systemic inflammation with increases in circulating neutrophils and a decrease in platelets compared with controls. Patients with transfusion-related acute lung injury and possible transfusion-related acute lung injury also had a statistically significant increase in plasma interleukin-8, interleukin-10, and interleukin-1 receptor antagonist posttransfusion compared with controls. CONCLUSIONS: In conclusion, transfusion-related acute lung injury produced a condition resembling the systemic inflammatory response syndrome and was associated with substantial in hospital morbidity and mortality in patients with transfusion-related acute lung injury compared with transfused controls. Patients with possible transfusion related acute lung injury had even higher in-hospital morbidity and mortality, suggesting that clinical outcomes in this group are mainly influenced by the underlying acute lung injury risk factor(s). PMID- 24776609 TI - Computed tomography-defined abdominal adiposity is associated with acute kidney injury in critically ill trauma patients*. AB - OBJECTIVES: Higher body mass index is associated with increased risk of acute kidney injury after major trauma. Since body mass index is nonspecific, reflecting lean, fluid, and adipose mass, we evaluated the use of CT to determine if abdominal adiposity underlies the body mass index-acute kidney injury association. DESIGN: Prospective cohort study. SETTING: Level I Trauma Center of a university hospital. PATIENTS: Patients older than 13 years with an Injury Severity Score greater than or equal to 16 admitted to the trauma ICU were followed for development of acute kidney injury over 5 days. Those with isolated severe head injury or on chronic dialysis were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical, anthropometric, and demographic variables were collected prospectively. CT images at the level of the L4-5 intervertebral disc space were extracted from the medical record and used by two operators to quantitate visceral adipose tissue and subcutaneous adipose tissue areas. Acute kidney injury was defined by Acute Kidney Injury Network creatinine and dialysis criteria. Of 400 subjects, 327 (81.8%) had CT scans suitable for analysis: 264 of 285 (92.6%) blunt trauma subjects and 63 of 115 (54.8%) penetrating trauma subjects. Visceral adipose tissue and subcutaneous adipose tissue areas were highly correlated between operators (intraclass correlation > 0.99, p < 0.001 for each) and within operator (intraclass correlation > 0.99, p < 0.001 for each). In multivariable analysis, the standardized risk of acute kidney injury was 15.1% (95% CI, 10.6-19.6%), 18.1% (14-22.2%), and 23.1% (18.3-27.9%) at the 25th, 50th, and 75th percentiles of visceral adipose tissue area, respectively (p = 0.001), with similar findings when using subcutaneous adipose tissue area as the adiposity measure. CONCLUSIONS: Quantitation of abdominal adiposity using CT scans obtained for clinical reasons is feasible and highly reliable in critically ill trauma patients. Abdominal adiposity is independently associated with acute kidney injury in this population, confirming that excess adipose tissue contributes to the body mass index-acute kidney injury association. Further studies of the potential mechanisms linking adiposity with acute kidney injury are warranted. PMID- 24776610 TI - Implementation of warnings from Dear Doctor Letters (Rote-Hand-Briefe): an analysis of medication data from a large cohort of elderly patients. AB - BACKGROUND: Dear Doctor Letters (also known as Direct Healthcare Professional Communications) inform physicians about significant newly discovered drug risks and about measures to take to reduce these risks. How far these warnings actually influence prescribing behavior is unclear. METHOD: The Geriatrics in Bavaria Database (GiB-DAT, Geriatrie in Bayern Datenbank) collects data from more than 50 centers offering inpatient geriatric health care. Based on GiB-DAT data, the discharge medication of 76 568 patients (81 +/- 8 years, 67% women) was recorded in a standardized manner and analyzed for the implementation of information contained in two Dear Doctor Letters about the risks of dose-related or drug interaction-related QT interval prolongation caused by citalopram or escitalopram. RESULTS: Patients were discharged with a median of 8 drugs. In the four quarters of 2012 following release of the Dear Doctor Letters, in comparison to the four quarters before their publication, a marked drop from 9.8% to 4.1% was seen in prescriptions for >20 mg/day citalopram--a dosage no longer recommended in elderly patients--and a similar drop from 23.6% to 12.8% in prescriptions for >10 mg/day escitalopram (p<0.0001). Co-prescription of either of these two drugs with other QT interval-prolonging drugs, which was now contraindicated, remained almost unchanged (citalopram: 19.3% [95% confidence interval (CI): 17.9-20.9%] versus 18.4% [95% CI: 17.0-19.8%]; escitalopram: 17.6% [95% CI: 15.8-19.6%] versus 17.1% [95% CI: 14.5-19.9%]). CONCLUSION: Simple information in Dear Doctor Letters, such as a reduction of the maximum daily dose, was better implemented than complicated information regarding contraindicated co-medication. Quality assurance systems such as the GiB-DAT network make it possible to identify problems of this kind. Licensing authorities and pharmaceutical companies should should improve the clinical usability, e.g., by providing official reference lists of drugs with safety warnings. PMID- 24776611 TI - Case management program for patients with chronic heart failure: effectiveness in terms of mortality, hospital admissions and costs. AB - BACKGROUND: At 360 000 cases annually, heart failure is the most common main diagnosis in adults in German hospitals. Treating heart failure is expensive. This study tested whether patients in the case management program (CMP) "CorBene- Better Care for Patients With Heart Failure" have a lower mortality rate and lower hospital admission and readmission rates than patients receiving regular management. METHOD: Routine data from a large German statutory health insurance company were analyzed. After propensity score matching, a total of 1202 patients (intervention group versus control group) were studied in relation to the endpoint "hospital admission and readmission rate" and the variables "annual physician contact rate," "mortality," and "inpatient treatment costs." RESULTS: The intervention group showed a lower rate of hospital admission/readmission (6.2%/18.9% versus 16.6%/36.0%; p<0.0001 / p = 0.041). Mortality rates did not differ significantly (5.0% versus 6.7%; p = 0.217). Analysis of hospital admission data showed no significant differences between the groups in terms of length of hospital stay or costs for heart failure-related treatment per hospital stay. However, the average annual costs for inpatient treatment in the CMP group, at ?222.22 per patient, were 67.5% lower than the equivalent costs in the control group (?683.88) (p<0.0001). CONCLUSION: Fewer patients in the intervention group were admitted and readmitted to hospital, and lower inpatient treatment costs were identified. The physician contact rate was higher than in the control group. PMID- 24776612 TI - Waiting times are too long. PMID- 24776613 TI - Diagnoses as "currency". PMID- 24776614 TI - In reply. PMID- 24776617 TI - Chromosome banding in Amphibia. XXXI. The neotropical anuran families Centrolenidae and Allophrynidae. AB - The mitotic chromosomes of 11 species from the anuran families Centrolenidae and Allophrynidae were analyzed by means of conventional staining, banding techniques, and in situ hybridization. The amount, location, and fluorochrome affinities of constitutive heterochromatin, the number and positions of nucleolus organizer regions, and the patterns of telomeric DNA sequences were determined for most of the species. The karyotypes were found to be highly conserved with a low diploid chromosome number of 2n = 20 and morphologically similar chromosomes. The sister group relationship between the Centrolenidae and Allophrynidae (unranked taxon Allocentroleniae) is clearly corroborated by the cytogenetic data. The existence of heteromorphic XY?/XX? sex chromosomes in an initial stage of morphological differentiation was confirmed in Vitreorana antisthenesi. The genome sizes of 4 centrolenid species were determined using flow cytometry. For completeness and for comparative purposes, all previously published cytogenetic data on centrolenids are included. PMID- 24776615 TI - Biomechanics and the thermotolerance of development. AB - Successful completion of development requires coordination of patterning events with morphogenetic movements. Environmental variability challenges this coordination. For example, developing organisms encounter varying environmental temperatures that can strongly influence developmental rates. We hypothesized that the mechanics of morphogenesis would have to be finely adjusted to allow for normal morphogenesis across a wide range of developmental rates. We formulated our hypothesis as a simple model incorporating time-dependent application of force to a viscoelastic tissue. This model suggested that the capacity to maintain normal morphogenesis across a range of temperatures would depend on how both tissue viscoelasticity and the forces that drive deformation vary with temperature. To test this model we investigated how the mechanical behavior of embryonic tissue (Xenopus laevis) changed with temperature; we used a combination of micropipette aspiration to measure viscoelasticity, electrically induced contractions to measure cellular force generation, and confocal microscopy to measure endogenous contractility. Contrary to expectations, the viscoelasticity of the tissues and peak contractile tension proved invariant with temperature even as rates of force generation and gastrulation movements varied three-fold. Furthermore, the relative rates of different gastrulation movements varied with temperature: the speed of blastopore closure increased more slowly with temperature than the speed of the dorsal-to-ventral progression of involution. The changes in the relative rates of different tissue movements can be explained by the viscoelastic deformation model given observed viscoelastic properties, but only if morphogenetic forces increase slowly rather than all at once. PMID- 24776618 TI - Vitamin D and diabetes mellitus. AB - The vitamin D endocrine system in now recognized as subserving a wide range of fundamental biological functions in cell differentiation, inhibition of cell growth as well as immunomodulation. Both forms of immunity, namely adaptive and innate, are regulated by 1,25(OH)2D3. The immune-modulatory properties of vitamin D suggest that it could play a potential therapeutic role in prevention of type 1 diabetes mellitus (T1DM). It is postulated that large doses of vitamin D supplementation may influence the pattern of immune regulation and subsequent progression to T1DM in a genetically susceptible individual. More studies are required to substantiate the relation between T1DM and vitamin D/vitamin D analogues in the pattern of immune regulations in susceptible individuals. In type 2 diabetes mellitus (T2DM), vitamin D may influence both insulin secretion and sensitivity. An inverse relationship between T2DM and vitamin D is postulated from cross-sectional and prospective studies, though conclusive proof is as yet lacking. Available studies differ in their design and in the recommended daily allowances (RDA) of vitamin D in non-skeletal diseases and beta-cell function. Large, well designed, controlled, randomized interventional studies on the potential role of vitamin D and calcium in prevention and management of T2DM are required to clarify the relationship between vitamin D and glucose homeostasis in T2DM. PMID- 24776619 TI - Biological activity of the e domain of the IGF-1Ec as addressed by synthetic peptides. AB - Insulin-like growth factor-1 (IGF-1) is a multipotent growth factor involved in the growth, development and regulation of homeostasis in a tissue-specific manner. Alternative splicing, multiple transcription initiation sites and different polyadelynation signals give rise to diverse mRNA isoforms, such as IGF 1Ea, IGF-1Eb and IGF-1Ec transcripts. There is increasing interest in the expression of the IGF-1 isoforms and their potential distinct biological role. IGF-1Ec results from alternative splicing of exons 4-5-6 and its expression is upregulated in various conditions and pathologies. Recent studies have shown that IGF-1Ec is preferentially increased after injury in skeletal muscle during post infarctal myocardium remodelling and in cancer tissues and cell lines. A synthetic analogue corresponding to the last 24 aa of the E domain of the IGF-1Ec isoform has been used to elucidate its potential biological role. The aim of the present review is to describe and discuss the putative bioactivity of the E domain of the IGF-1Ec isoform. PMID- 24776620 TI - The endocrinology of baldness. PMID- 24776621 TI - Elevated serum androstenedione is associated with a more severe phenotype in women with polycystic ovary syndrome (PCOS). AB - OBJECTIVE: To evaluate the impact of elevated serum Delta4A levels on the hormonal and metabolic features of the different phenotypes of PCOS. DESIGN: 1276 women with PCOS according to the Rotterdam criteria were included, in whom serum hormonal levels were determined. RESULTS: In PCOS women as a whole, as well as in patients presenting clinical and/or biochemical hyperandrogenemia (phenotypes I and II), Delta4A levels >3.8 ng/ml were positively related to LH, LH/FSH ratio, T, DHEAS, 17 OH progesterone and FAI and negatively related to T/Delta4A ratio. In the milder phenotype III, a positive correlation between Delta4A levels >3.8 ng/ml and T, DHEAS, 17 OH progesterone and FAI and a negative one between increased Delta4A and T/Delta4A ratio were reported. In the whole PCOS group with androstenedione >3.8 ng/ml, an increased ovarian volume was observed, while a greater mean follicular number was found only in phenotypes I and II. CONCLUSIONS: Increased serum Delta4A levels, which are associated with more severe PCOS phenotypes, possibly contribute to the worsening of PCOS features and therefore could be a valuable marker of biochemical hyperandrogenemia. PMID- 24776622 TI - Efficacy and safety of combined parenteral and oral steroid therapy in Graves' orbitopathy. AB - OBJECTIVE: Glucocorticoids (GC) are the treatment of choice for moderate-to severe and active Graves' orbitopathy (GO), but optimal treatment is still . The aim of the present study was to analyze the efficacy and tolerability of combined parenteral GC pulse therapy followed by oral GC in the interpulse period. DESIGN: The study included 50 patients (48 +/- 10 years; 37 female) with untreated, active and moderate-to-severe GO. Patients received 500 mg of methylprednisolone in 500 ml of physiologic saline. Infusion was repeated after 48 h and then followed by tapering doses of oral prednisone and the cycle repeated each month for the next 5 months. The cumulative dose was 10.2g.Ophthalmic assessment was performed before and 6 months after start of treatment. Side effects of GC therapy were evaluated and recorded each month. RESULTS: GC showed the greatest effectiveness on soft tissue changes (incorporated in the CAS). Median CAS values decreased from 4.5 to 2 (p>0.001). Improvement was demonstrated in 37 patients (74%), there was no change in 13 patients (26%) and none of the patients presented with deterioration of inflammatory status. Diplopia improved in 21 patients (42%), was unchanged in 28 patients (56%) and deteriorated in 1 patient (2%). Improvement in visual acuity occurred in 36% of patients. At 6 months, 33/50 patients (66%) demonstrated overall treatment response. Response to GC therapy was influenced by CAS, TSHRAb and smoking behavior. The only independent parameter associated with positive treatment response was CAS >= 4 (p<0.001). Side effects occurred in 35/50 patients (70%) and the vast majority of them were mild to moderate. During the 6-months follow-up period, 2/33 patients (6%) had relapsing GO. CONCLUSION: With appropriate selection of patients and careful monitoring during and after treatment, combined parenteral and oral GC therapy is effective and safe. PMID- 24776623 TI - A complete corticotropin releasing factor system localized in human fetal lung. AB - OBJECTIVE: The Corticotropin Releasing Factor (CRF) system (neuropeptides CRF, Ucn I, II, III and binding sites CRFR1, CRFR2, CRF-BP) is responsible for stress regulation and the homeostasis of an organism. Herein we study the CRF system in human normal and pathological fetal lungs. DESIGN: Lung tissues from 46 archival human fetuses were divided into Group A (normal), Group B (chromosomal abnormalities) and Group C (congenital disorders). Presence of elements of the CRF system was evaluated using immunohistochemistry and was correlated to pathology, lung developmental stage and clinicopathological characteristics. RESULTS: Immunoreactivity for all antigens was found in both epithelial and mesenchymal lung cells of the bronchi and alveoli. Ucn I and CRFR1 were more frequently present in Group A. Ucns were more frequently localized at the pseudoglandular stage. There was a positive correlation between the presence of the CRF neuropeptides and between CRFR1 and CRF. Two fetuses with lung malformations showed low or no detectable presence of the CRF system. CONCLUSIONS: We report the presence of a complete CRF system in human fetal lungs correlating its developmental stage and several pathologies. Our results are in agreement with findings in experimental animal models, implicating the CRF system in fetal lung development, its action being more significant in the early stages. PMID- 24776624 TI - Endothelial progenitor cells as a cardiometabolic risk factor marker in prediabetes. AB - OBJECTIVE: Endothelial progenitor cells (EPCs) have recently been considered as a potential novel marker of vascular integrity, atherosclerosis and cardiovascular risk. This study was performed to investigate the main determinants of EPC levels in individuals with prediabetes. DESIGN: Thirty-nine participants with newly diagnosed prediabetes were enrolled. Flow cytometric analysis was used to quantify EPCs (CD34+CD133+VEGFR-2+). Traditional risk factors, high-sensitivity C reactive protein (hs-CRP), homeostasis model assessment of insulin resistance (HOMA-IR) and anthropometric parameters, including ultrasonographic-determined visceral and subcutaneous fat, were recorded. RESULTS: In univariate analysis, EPC levels significantly correlated with waist circumference (p=0.017), mean arterial pressure (p=0.009), total cholesterol (p=0.003), hs-CRP (p=0.006), HOMA IR (p=0.031) and visceral fat (p=0.040). However, in stepwise multivariate ordinal logistic regression analysis, only visceral fat retained its statistical significance (OR=0.79, 95%Cl:0.64-0.98, p=0.032). CONCLUSIONS: Visceral fat seems to be the main determinant of EPC levels in individuals with prediabetes and to form a plausible link between mild metabolic abnormalities, cardiovascular risk and vascular homeostasis process. PMID- 24776625 TI - Metformin-induced thyrotropin suppression is not associated with cardiac effects. AB - OBJECTIVE: Metformin treatment may induce a decrease/suppression in serum TSH levels, mimicking sub-clinical hyperthyroidism (SHT). The aim of the present study was to retrospectively evaluate changes in several electrocardiographic indices in euthyroid subjects with diabetes who, after starting metformin treatment, developed a low serum TSH as compared to patients with SHT resulting from an underlying thyroid disease or TSH suppressive treatment with L-thyroxine. DESIGN: Heart rate, P wave duration, P wave dispersion, QTmax, QTmin and QT dispersion were assessed in 23 patients with diabetes treated with metformin before and after 6 months of TSH-suppression and in 31 control patients with SHT. RESULTS: No significant changes in electrocardiographic parameters were observed from baseline to the TSH-suppression measurement. A significant difference in P wave duration (102.9 +/- 7.4 vs. 92.1 +/- 5.8 ms, p<0.001), P wave dispersion (13.1 +/- 3.4 vs. 7.1 +/- 3.5 ms, p<0.001), QTmax (399 +/- 18 vs. 388 +/- 16 ms, p=0.024), QTmin (341 +/- 14 vs. 350 +/- 17 ms, p=0.038) and QT dispersion (49.9 +/- 9.6 vs. 30.9 +/- 9.2 ms, p<0.001) were observed between the control group with SHT and the group of diabetic patients with low serum levels of TSH. CONCLUSIONS: Our results show that the TSH-suppressive effect observed in patients taking metformin is not associated with peripheral markers of thyroid hormone excess, at least at the cardiac level. PMID- 24776626 TI - Trends in metabolic syndrome risk factors among adolescents in rural Crete between 1989 and 2011. AB - OBJECTIVE: To investigate all the important factors contributing to the development of metabolic syndrome (MetS) as well as to explore the changes of these factors, over time, by comparing adolescent populations of rural areas of Heraklion, Crete, for the years 2011 and 1989. DESIGN: This study was carried out within two rural areas of the Heraklion region in Crete, Greece. The 1989 study was conducted in the village of Agia Varvara and the respective 2011 study within the municipality of Minoa Pediados. The study population consisted of 150 high school students (97 girls and 69 boys) in 1989 and 66 (30 girls and 36 boys) elementary (6th grade) and high school students in 2011, aged from 12 to 14 years old. Anthropometric, blood pressure and biochemical information was obtained. RESULTS: Of the MetS risk factors studied, only obesity incidence was found higher in 2011 compared to 1989 (obese adolescents 1.3% in 1989 versus 21.2% in 2011, p<0.001). On the other hand, hypertension levels were higher in 1989 compared to 2011 (46.7% versus 6.3%, respectively, p<0.001). In addition, glucose and LDL-C levels were lower in 2011. CONCLUSIONS: The present study supports the fact that there are significant changes in metabolic risk factors through time in adolescent populations of Crete, mainly due to the rise in obesity levels as well as to the decrease in hypertension, total cholesterol and LDL- cholesterol, as observed from the comparison of the years 1989 and 2011. PMID- 24776627 TI - Metabolic profiles of adult Wistar rats in relation to prenatal and postnatal nutritional manipulation: the role of birthweight. AB - OBJECTIVE: This experimental study aimed to prospectively investigate the impact of combinations of prenatal and postnatal food manipulations on the metabolic profile of adult offspring. DESIGN: On day 12 of gestation, 67 timed pregnant rats were randomized into three nutritional groups, control: standard laboratory food; starved: 50% food restricted, FR; fat-fed: fat-rich diet, FF. Seven hundred and seventy-four (774) pups were born on day 21 and culled to 8 (4 males, 4 females) per litter to normalize rearing. Rats born to starved mothers were later subdivided, based on birthweight (BiW), into fetal growth restricted (FGR) and non-FGR. The pups were then weaned to the diet of their fostered mother until one year old. Thus, 12 groups were studied: 1. CONTROL/CONTROL: 14 rats, 2. CONTROL/FR: 12 rats, 3. CONTROL/FF: 15 rats, 4. FGR/CONTROL: 16 rats, 5. FGR/FR: 10 rats, 6. FGR/FF: 15 rats, 7. non- FGR/CONTROL: 10 rats, 8. non- FGR/FR: 17 rats, 9. non- FGR/FF: 10 rats, 10. FF/CONTROL: 15 rats, 11. FF/FR: 14 rats, and 12. FF/FF: 13 rats. During sacrifice, body weight (BW) and liver weight (LW) were measured (expressed in grams) and concentrations of serum glucose, triglycerides, HDL and NEFA were determined. RESULTS: Postnatal food restriction, compared to control diet significantly reduced BW (p=0.004, p=0.036, p<0.001, p=0.008) and LW (p<0.001) in all study groups. Postnatal control diet significantly increased BW in non-FGR compared to FGR rats (p=0.027). No significant differences were detected in biochemical parameters (excluding NEFA) between FGR and non-FGR, regardless of the postnatal diet. CONCLUSIONS: Interaction between prenatal and postnatal nutrition produces distinct metabolic profiles. Apart from BiW, prenatal diet had an important impact on the metabolic profile of the adult offspring, implying that intrauterine events should be considered in the estimation of the metabolic risk of an individual, independently of BiW. PMID- 24776628 TI - Genetic diagnosis of idiopathic hypogonadotrophic hypogonadism: a new point mutation in the KAL2 gene. AB - Kallmann Syndrome (KS) is a genetic disease of embryonic development which is characterized by the association of hypogonadotropic hypogonadism (HH) due to a deficit of the gonadotropin-releasing hormone (GnRH) and a hypo/anosmia (including a hypoplasia of the nasal sulcus and agenesis of the olfactory bulbs). Even though it is a genotypically and phenotypically heterogeneous clinical disease, there are some key genes related to KS (KAL1, FGFR1 (KAL2), GNRHR, KISSR1 (GPR54), GNRH1, NELF and PROK2). The aim of this study was to present a case report of a genetic diagnosis of KS linked to the presence of mutations in the FGFR1 (fibroblast growth factor receptor 1, also known as KAL2) gene. This diagnosis was made in a 44-year old female affected by a hypogonadism for which she had received intermittent treatment until she was 30 years old based on the patient's own decision. The molecular analysis of FGFR1 identified the mutation c. 246_247delAG (p.T82Xfs110) in heterozygosis on exon 3 of the KAL2 gene. This is the first report of this mutation related to idiopathic hypogonadotrophic hypogonadism (IHH). PMID- 24776629 TI - Hypocalcaemia following thyroidectomy unresponsive to oral therapy. AB - Hypocalcaemia due to hypoparathyroidism following thyroidectomy is a relatively common occurrence. Standard treatment is with oral calcium and vitamin D replacement therapy; lack of response to oral therapy is rare. Herein we describe a case of hypoparathyroidism following thyroidectomy unresponsive to oral therapy in a patient with a complex medical history. We consider the potential causes in the context of calcium metabolism including: poor adherence, hungry bone syndrome, malabsorption, vitamin D resistance, bisphosphonate use and functional hypoparathyroidism secondary to magnesium deficiency. Malabsorption due to intestinal hurry was likely to be a contributory factor in this case and very large doses of oral therapy were required to avoid symptomatic hypocalcaemia. PMID- 24776630 TI - Brain and optic chiasmal herniation following cabergoline treatment for a giant prolactinoma: wait or intervene? AB - OBJECTIVE: Dopamine agonists (DA) are the treatment of choice in patients with macroprolactinomas. Brain and optic chiasm herniation are unusual complications following treatment with DA. REPORT: We present a case of a giant prolactinoma complicated by visual deterioration following cabergoline treatment. A 42-year old man was admitted with seizures, right visual loss and visual defect in the upper left temporal quadrant. Magnetic resonance imaging (MRI) identified a giant adenoma, which proved to be a prolactinoma, compressing the optic chiasm and extending into the suprasellar region. Treatment with cabergoline was initiated resulting in improvement in visual fields, tumor shrinkage and prolactin level decrease. Five months later and despite tumor reduction, a deterioration of his visual fields was observed. The second MRI revealed brain and optic chiasmal herniation into the pituitary sella. Cabergoline dose was reduced and surgical resection of the adenoma along with untethering of the optic nerve was performed leading to improvement of the visual defects. CONCLUSIONS: This report describes a rare case of brain and optic chiasmal herniation attributed to DA therapy for a macroprolactinoma. It is important for clinicians to examine visual fields and promptly identify any visual deterioration in patients with macroprolactinomas receiving DA treatment. PMID- 24776631 TI - Apollinaire Bouchardat (1806-1886): founder of modern Diabetology. AB - Apollinaire Bouchardat is regarded as the founder of the field of Diabetology. His contributions to the field include the first known recommendations for specific diets for the management of Diabetes Mellitus and his emphasis on patient education and self-monitoring. He was moreover a great pharmacist as well as a distinguished physician and biochemist. PMID- 24776632 TI - Effects of systematic patient education in skin care and protection in a hand eczema clinic. AB - BACKGROUND: Hand eczema has a high impact on patients' quality of life. The treatment focuses on improving skin barrier function. OBJECTIVES: To evaluate the effects and acceptance of a novel educational program for patients with hand eczema. METHODS: Retrospectively, the records of 36 patients who attended the prevention program and follow-up visits were analyzed. Physician global assessment (PGA) scores, acceptance and behavioral changes were assessed. RESULTS: In 67% of patients, an improvement of the hand eczema could be attributed to the effects of our educational program. The mean PGA score significantly decreased from 3 before education to 2.2 during follow-up. Behavioral changes in both skin care and protection were reported in 81 and 86%, respectively. CONCLUSIONS: Our educational program had a positive effect on clinical outcome as well as adherence to skin care and protection measures. Its integration in a hand eczema clinic was feasible and well accepted by the patients. PMID- 24776633 TI - Interactive assembly algorithms for molecular cloning. AB - Molecular biologists routinely clone genetic constructs from DNA segments and formulate plans to assemble them. However, manual assembly planning is complex, error prone and not scalable. We address this problem with an algorithm-driven DNA assembly planning software tool suite called Raven (http://www.ravencad.org/) that produces optimized assembly plans and allows users to apply experimental outcomes to redesign assembly plans interactively. We used Raven to calculate assembly plans for thousands of variants of five types of genetic constructs, as well as hundreds of constructs of variable size and complexity from the literature. Finally, we experimentally validated a subset of these assembly plans by reconstructing four recombinase-based 'genetic counter' constructs and two 'repressilator' constructs. We demonstrate that Raven's solutions are significantly better than unoptimized solutions at small and large scales and that Raven's assembly instructions are experimentally valid. PMID- 24776634 TI - Chronic, wireless recordings of large-scale brain activity in freely moving rhesus monkeys. AB - Advances in techniques for recording large-scale brain activity contribute to both the elucidation of neurophysiological principles and the development of brain-machine interfaces (BMIs). Here we describe a neurophysiological paradigm for performing tethered and wireless large-scale recordings based on movable volumetric three-dimensional (3D) multielectrode implants. This approach allowed us to isolate up to 1,800 neurons (units) per animal and simultaneously record the extracellular activity of close to 500 cortical neurons, distributed across multiple cortical areas, in freely behaving rhesus monkeys. The method is expandable, in principle, to thousands of simultaneously recorded channels. It also allows increased recording longevity (5 consecutive years) and recording of a broad range of behaviors, such as social interactions, and BMI paradigms in freely moving primates. We propose that wireless large-scale recordings could have a profound impact on basic primate neurophysiology research while providing a framework for the development and testing of clinically relevant neuroprostheses. PMID- 24776635 TI - Olfactory exposure to males, including men, causes stress and related analgesia in rodents. AB - We found that exposure of mice and rats to male but not female experimenters produces pain inhibition. Male-related stimuli induced a robust physiological stress response that results in stress-induced analgesia. This effect could be replicated with T-shirts worn by men, bedding material from gonadally intact and unfamiliar male mammals, and presentation of compounds secreted from the human axilla. Experimenter sex can thus affect apparent baseline responses in behavioral testing. PMID- 24776636 TI - Hepatitis C virus testing perspectives among primary care physicians in four large primary care settings. AB - BACKGROUND: In 1998, the Centers for Disease Control and Prevention (CDC) published Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease, recommending HCV testing for populations most likely to be infected with HCV. However, the implementation of risk-based screening has not been widely adopted in health care settings, and 45% to 85% of infected U.S. adults remain unidentified. OBJECTIVES: To develop a better understanding of why CDC's 1998 recommendations have had limited success in identifying persons with HCV infection and provide information about how CDC's 2012 Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945-1965 may be implemented more effectively. DESIGN: Qualitative data were collected and analyzed from a multidisciplinary team as part of the Birth Cohort Evaluation to Advance Screening and Testing for Hepatitis C project. RESPONDENTS: Nineteen providers were asked open-ended questions to identify current perspectives, practices, facilitators, and barriers to HCV screening and testing. Providers were affiliated with Henry Ford Hospital, Mount Sinai Hospital, the University of Alabama, and the University of Texas Health Science Center. RESULTS: Respondents reported the complexity of the 1998 recommendations, and numerous indicated risk factors were major barriers to effective implementation. Other hindrances to hepatitis C testing included physician discomfort in asking questions about socially undesirable behaviors and physician uncertainty about patient insurance coverage. CONCLUSION: Implementation of the CDC's 2012 recommendations could be more successful than the 1998 recommendations due to their relative simplicity; however, effective strategies need to be used for dissemination and implementation for full success. PMID- 24776638 TI - Hyperreflective foveal lesion observed with optical coherence tomography in cases of epiretinal membranes with a firm foveal attachment. AB - PURPOSE: To report the optical coherence tomography (OCT) findings of the firmly attached foveal area and to investigate the functional results and predictive values in correlation to the degree of firmness of the foveal adherence of the epiretinal membrane (ERM). METHODS: We retrospectively reviewed the medical records regarding 167 eyes of 166 patients who underwent vitrectomy for the removal of the ERM between January 2009 and December 2012. We evaluated the degree of foveal attachment in all the patients based on the surgical video and reviewed the OCT images. The main and secondary outcome measures were OCT findings including the presence and the size of a highly reflective lesion, visual acuity, and the mean duration of the ERM before surgery. RESULTS: An abnormal highly reflective lesion was observed beneath the ERM in the foveal area. We termed this type of finding a "hyperreflective foveal lesion" (HFL). This HFL was present in 22 of 23 eyes (95.7%) with a firm foveal attachment (FFA) and in 2 of 144 eyes (1.4%) without an FFA (P < 0.001). The HFL showed a sensitivity of 96%, specificity of 99%, positive predictive value of 92%, and negative predictive value of 99%, as a predictor of FFA. The mean duration of the ERM before surgery was significantly longer in the group with an FFA than in the group without an FFA (P = 0.029). Regarding the degree of firmness of the adherence in the eyes with an FFA, the group with a greater degree of firmness had a larger HFL as observed with OCT before surgery (P < 0.05). The visual acuity in patients with an FFA was significantly lower than that in patients without an FFA after surgery (P = 0.031). CONCLUSION: Visual acuity after surgery was significantly lower in patients with an FFA. The presence of an HFL in the OCT demonstrated a high predictive value for firmness of the foveal attachment. The size of an HFL in the OCT was associated with the degree of firmness and allowed us to predict inner and outer retinal damages after surgery. PMID- 24776637 TI - Gr-1+CD11b+ cells facilitate Lewis lung cancer recurrence by enhancing neovasculature after local irradiation. AB - Studies have shown that bone marrow-derived cells play an important role in tumor recurrence after chemotherapy and radiotherapy. In this study, we examined the relationship between the accumulation of Gr-1+CD11b+ cells and tumor recurrence after irradiation in tumor-bearing mice. By transplanting bone marrow cells into whole body-irradiated mice depleted of bone marrow, we assessed the role of Gr 1+CD11b+ cells in lung carcinoma models after local irradiation (LI). 20 Gy local irradiation could recruit CD11b+CXCR4+ cells into the irradiated tissues, and the recruited CD11b+CXCR4+ cells could promote tumor recurrence. Further 6 Gy whole body irradiation (WBI6Gy) could decrease tumor recurrence by inhibiting the accumulation of Gr-1+CD11b+ cells and then suppressing tumor vasculogenesis and angiogenesis. Our results suggest that the accumulation of CD11b+Gr-1+ cells promote tumor re-growth after local irradiation by enhancing tumor neovascularization, and low dose of whole body irradiation or irradiation of enlarged spleen may provide a new alternative for anti-angiogenesis therapies. PMID- 24776639 TI - Anatomical and visual outcomes after two-port pars plana vitrectomy reoperation under silicone oil for epimacular membrane or recurrent retinal detachment. AB - PURPOSE: To describe the anatomical and visual outcomes in a series of patients undergoing two-port pars plana vitrectomy reoperation under silicone oil for recurrent retinal detachment (RD) due to proliferative vitreoretinopathy or epimacular membrane (EMM) after RD repair. METHODS: This study is a prospective, consecutive, interventional case series of patients presenting with recurrent RD or EMM under silicone oil. Two-port 25-gauge pars plana vitrectomy reoperation without an infusion port was performed in all cases. RESULTS: Thirty-nine patients were included. Reoperation pathology included recurrent RD with proliferative vitreoretinopathy (n = 33) and EMM alone (n = 6). The mean number of previous retinal surgeries was 2.4 +/- 1.1 (range, 1-5). The mean overall follow-up was 24 +/- 3.7 months. The mean visual acuity change from baseline at final follow-up was an improvement of 0.74 +/- 0.63. Macular reattachment was achieved in 29 of 33 patients with RD, and EMMs were successfully removed in all patients. CONCLUSION: Two-port pars plana vitrectomy reoperation is an efficacious method for repair of consecutive RD due to proliferative vitreoretinopathy or EMM in patients with previous RD repair with silicone oil. Significant visual improvement with a low complication rate may be achieved in patients with advanced proliferative vitreoretinopathy or EMM under silicone oil. PMID- 24776640 TI - Sex, health, and athletes. PMID- 24776641 TI - Controlling the nanoscale rippling of graphene with SiO2 nanoparticles. AB - The electronic properties of graphene can be significantly influenced by mechanical strain. One practical approach to induce strain in graphene is to transfer atomically thin membranes onto pre-patterned substrates with specific corrugations. The possibility of using nanoparticles to impart extrinsic rippling to graphene has not been fully explored yet. Here we study the structure and elastic properties of graphene grown by chemical vapour deposition and transferred onto a continuous layer of SiO2 nanoparticles with diameters of around 25 nm, prepared on a Si substrate by the Langmuir-Blodgett technique. We show that the corrugation of the transferred graphene, and thus the membrane strain, can be modified by annealing at moderate temperatures. The membrane parts bridging the nanoparticles are suspended and can be reversibly lifted by the attractive forces between an atomic force microscope tip and graphene. This allows the dynamic control of the local morphology of graphene nanomembranes. PMID- 24776642 TI - Progression of coronary artery calcification in living kidney donors: a follow-up study. AB - BACKGROUND: Data on the long-term mortality and morbidity of living kidney donors are scarce. In the general population, coronary artery calcification (CAC) and progression of CAC are predictors of future cardiac risk. We conducted a study to determine the progression of CAC in renal transplant donors. METHODS: We used multidetector computed tomography to examine CAC in 75 former renal transplant donors. A baseline and a follow-up scan were performed and changes in CAC scores were evaluated in each subject individually to calculate the incidence of CAC progression. RESULTS: Baseline CAC prevalence was 16% and the mean CAC score was 5.3 +/- 25.8. At the follow-up scan that was performed after an average of 4.8 +/ 0.3 years, CAC prevalence increased to 72% and the mean CAC score to 12.5 +/- 23.4. Progression of the individual CAC score was found between 18.7 and 26.7%, depending on the method used to define progression. In patients with baseline CAC, the mean annualized rate of CAC progression was 2.1. Presence of hypertension, high systolic blood pressure and an increase in BMI were the determinants of CAC progression. CONCLUSIONS: The rate of CAC progression does not seem to be high in carefully selected donors. PMID- 24776644 TI - Superficial scrapings from breast tumors is a source for biobanking and research purposes. AB - Breast cancer is a unique tumor disease in terms of the stringent requirement of predictive biomarker assessments. As recommended by current international guidelines, the established markers consist of estrogen receptor (ER), progesterone receptor, human epidermal growth factor and Ki67, and are primarily analyzed by immunohistochemistry. However, new diagnostic methods based on microarray or next-generation sequencing on DNA and mRNA level are gaining ground. These analyses require fresh-frozen tumor tissue that is generally not available from tumors <10 mm in diameter, comprising almost 25% of all resected breast cancer at our department. We here present a simple and standardized method to generate material from small tumors without risking the histopathological examination. Furthermore, we show that the quality of this material is sufficient for subsequent analysis on mRNA, DNA, and epigenetic level. We were also able to use this method for isolation and expansion of cancer stem cells from the majority of tumors. Consequently, researches can be provided with clinically relevant material for translational studies. In conclusion, this method opens up a new possibility for usage of valuable fresh tumor material for research purposes, biobanking, and next-generation sequencing. PMID- 24776645 TI - A fluorescent light-up probe as an inhibitor of intracellular beta-tryptase. AB - A pyrene-functionalized peptidic inhibitor binds to and inhibits beta-tryptase in a non-competitive and reversible manner even in cells. Upon protein binding a fluorescence increase of the two pyrene fluorophores is observed which allows using as a fluorescent light-up probe for this enzyme. PMID- 24776646 TI - Expanding roles of neutrophils in aging hosts. AB - Neutrophils' role in the clearance of pathogens is well documented, but there is increasing appreciation that neutrophils can participate in the resolution of infection and inflammation. An obvious implication is that alteration of neutrophil functions with old age could significant impact both susceptibility of the host to infection and inflammatory conditions. Advances in recent years suggest additional chinks in the neutrophil antimicrobial arsenals in aged hosts, which render neutrophils less capable of killing pathogens. Moreover there is evidence that changes in neutrophil cross-talk with other immune cells also contribute to poor resolution of inflammation. These advances provide new insight on how these phagocytic cells could contribute to age-related diseases. PMID- 24776647 TI - Comparative chromosome mapping of U2 snRNA and 5S rRNA genes in Gymnotus species (Gymnotiformes, Gymnotidae): evolutionary dynamics and sex chromosome linkage in G . pantanal. AB - A comparative mapping of U2 small nuclear RNA (snRNA) and 5S ribosomal RNA (rRNA) genes was performed in 6 Gymnotus species. All species analyzed presented the U2 snDNA organized in conspicuous blocks and not co-located with rRNA genes. In addition, 5 species showed the U2 snDNA located in a single pair of chromosomes, which seems to be a conserved trait in this genus. Conversely, G. pantanal was the only species displaying several terminal signals in different chromosome pairs, including the X1 sex chromosome but not the Y chromosome. This is the first report of U2 snRNA genes in sex chromosomes of fishes. The absence of sites in the Y chromosome of G. pantanal indicates a possible loss of terminal segments of the chromosomes involved in the Y formation. PMID- 24776648 TI - Flexible metallic nanowires with self-adaptive contacts to semiconducting transition-metal dichalcogenide monolayers. AB - In the pursuit of ultrasmall electronic components, monolayer electronic devices have recently been fabricated using transition-metal dichalcogenides. Monolayers of these materials are semiconducting, but nanowires with stoichiometry MX (M = Mo or W, X = S or Se) have been predicted to be metallic. Such nanowires have been chemically synthesized. However, the controlled connection of individual nanowires to monolayers, an important step in creating a two-dimensional integrated circuit, has so far remained elusive. In this work, by steering a focused electron beam, we directly fabricate MX nanowires that are less than a nanometre in width and Y junctions that connect designated points within a transition-metal dichalcogenide monolayer. In situ electrical measurements demonstrate that these nanowires are metallic, so they may serve as interconnects in future flexible nanocircuits fabricated entirely from the same monolayer. Sequential atom-resolved Z-contrast images reveal that the nanowires rotate and flex continuously under momentum transfer from the electron beam, while maintaining their structural integrity. They therefore exhibit self-adaptive connections to the monolayer from which they are sculpted. We find that the nanowires remain conductive while undergoing severe mechanical deformations, thus showing promise for mechanically robust flexible electronics. Density functional theory calculations further confirm the metallicity of the nanowires and account for their beam-induced mechanical behaviour. These results show that direct patterning of one-dimensional conducting nanowires in two-dimensional semiconducting materials with nanometre precision is possible using electron-beam based techniques. PMID- 24776649 TI - Nanophotonic trapping for precise manipulation of biomolecular arrays. AB - Optical trapping is a powerful manipulation and measurement technique widely used in the biological and materials sciences. Miniaturizing optical trap instruments onto optofluidic platforms holds promise for high-throughput lab-on-a-chip applications. However, a persistent challenge with existing optofluidic devices has been achieving controlled and precise manipulation of trapped particles. Here, we report a new class of on-chip optical trapping devices. Using photonic interference functionalities, an array of stable, three-dimensional on-chip optical traps is formed at the antinodes of a standing-wave evanescent field on a nanophotonic waveguide. By employing the thermo-optic effect via integrated electric microheaters, the traps can be repositioned at high speed (~30 kHz) with nanometre precision. We demonstrate sorting and manipulation of individual DNA molecules. In conjunction with laminar flows and fluorescence, we also show precise control of the chemical environment of a sample with simultaneous monitoring. Such a controllable trapping device has the potential to achieve high throughput precision measurements on chip. PMID- 24776650 TI - Confounding factors in diagnostics of MGMT promoter methylation status in glioblastomas in stereotactic biopsies. AB - BACKGROUND: In nonresectable glioblastoma (GBM), stereotactic biopsies are performed to retrieve tissue for diagnostic purposes. The analysis of O6 methylguanine-DNA methyltransferase (MGMT) promoter methylation adds prognostic and predictive information. OBJECTIVES: The aim of the study was to detect confounding factors that limit the number of conclusive MGMT promoter methylation results. METHODS: We analyzed 71 consecutive GBM patients undergoing stereotactic biopsy on whom MGMT analysis was performed by methylation-specific polymerase chain reaction. Specimens were correlated to imaging by coregistration and prospective documentation of biopsy localization. Our findings were validated in an additional 62 GBM stereotactic biopsies. RESULTS: Our results demonstrate that the best MGMT promoter methylation results were obtained from samples (n = 71) taken in a tangential manner from tumor areas showing contrast enhancement in magnetic resonance imaging. In the additional validation series of 62 stereotactically biopsied GBM, we were able to increase the rate of conclusive MGMT promoter methylation results from 76.1 to 85.48% by strictly planning the route of biopsy in a tangential manner if possible. CONCLUSIONS: These results underline that within the contrast-enhanced tumor part, choosing the trajectory in a tangential manner increases the diagnostic yield for conclusive MGMT promoter methylation analyses in stereotactic biopsies as a basis for patient stratification and individualized therapy. PMID- 24776651 TI - Characterization and function of the first antibiotic isolated from a vent organism: the extremophile metazoan Alvinella pompejana. AB - The emblematic hydrothermal worm Alvinella pompejana is one of the most thermo tolerant animal known on Earth. It relies on a symbiotic association offering a unique opportunity to discover biochemical adaptations that allow animals to thrive in such a hostile habitat. Here, by studying the Pompeii worm, we report on the discovery of the first antibiotic peptide from a deep-sea organism, namely alvinellacin. After purification and peptide sequencing, both the gene and the peptide tertiary structures were elucidated. As epibionts are not cultivated so far and because of lethal decompression effects upon Alvinella sampling, we developed shipboard biological assays to demonstrate that in addition to act in the first line of defense against microbial invasion, alvinellacin shapes and controls the worm's epibiotic microflora. Our results provide insights into the nature of an abyssal antimicrobial peptide (AMP) and into the manner in which an extremophile eukaryote uses it to interact with the particular microbial community of the hydrothermal vent ecosystem. Unlike earlier studies done on hydrothermal vents that all focused on the microbial side of the symbiosis, our work gives a view of this interaction from the host side. PMID- 24776652 TI - Thermal-triggerd proteinquake leads to disassembly of DegP hexamer as an imperative activation step. AB - The Escherichia coli DegP has been reported to function both as molecular chaperone and protease for the quality control of outer membrane protein biogenesis. Activation of the inactive DegP hexamers was believed to occur via their disassembly into trimeric units and subsequent reassembly into larger oligomers (12-mers and 24-mers). Here, we analyzed the thermal stability and the unfolding dynamics of the different secondary structure components of the DegP hexamers using Fourier transform infrared spectroscopy and temperature-jump nanosecond time-resolved IR difference absorbance spectroscopy. We found that the interfacial secondary structure components possess a degreed thermal stability, with the disassembly of the DegP hexamers follows a "proteinquake" manner, such that the fully exposed parts of the interfacial beta-sheets serving as the temperature sensor and epicenter to drive the sequential unfolding/disassembly process that finishes within about 134 ns at room temperature. PMID- 24776653 TI - Prevalence of surgical site infection at the stoma site following four skin closure techniques: a retrospective cohort study. AB - BACKGROUND/AIMS: Surgical site infection (SSI) is a common complication of stoma reversal. Studies have suggested that different skin closures affect SSI rates. Our aim was to determine which skin closure technique following stoma reversal leads to the lowest rate of SSI. METHODS: We conducted a retrospective review of all adult patients undergoing stoma reversal at a single institution (2005-2011) and compared the rate of SSI following four skin closure techniques: primary closure (PC), secondary closure (SC), loose PC (LPC), and circular closure (CC). Univariate analysis included chi(2) or Fisher's exact test and ANOVA or Kruskal Wallis H test for categorical and continuous data, respectively. A multivariate logistic regression model was created to identify predictors of SSI. RESULTS: One hundred and forty-six patients were identified: 40 (27%) PC, 68 (47%) SC, 20 (14%) LPC, and 18 (12%) CC. CC was less likely to have SSI (6%) compared to PC (43%), SC (16%), and LPC (15%; p < 0.01). Increasing body mass index was a predictor of SSI (odds ratio 1.11, 95% confidence interval 1.04-1.12, p < 0.01). CC was associated with the lowest odds of developing SSI [0.07 (0.01-0.63), p = 0.02]. CONCLUSIONS: SSI rate was the lowest for stomas that were closed with CC. PMID- 24776654 TI - Synthesis and sorption properties of hexa-(peri)-hexabenzocoronene-based porous organic polymers. AB - In this communication, we report the synthesis of several novel hexa-(peri) hexabenzocoronene (HBC) containing microporous polymers. These polymers exhibit good adsorption properties for H2, N2 and CO2 gases. Based on fluorescence quenching studies, we have shown that the highly conjugated pi-surfaces may be accessible by guests in solution. PMID- 24776655 TI - Biobehavioral pathways underlying spousal health dynamics: its nature, correlates, and consequences. AB - Marriage is a very special relationship that has a high potential to influence physical and mental health throughout the adult lifespan and into old age. In this viewpoint, we propose a model that outlines plausible biobehavioral pathways that may underlie previously established spousal interrelations in long-term health trajectories and discuss specific resources that may facilitate favorable outcomes for everyone involved. Specifically, we focus on spousal associations in physical activity as an important health behavior and in stress-related processes as a key daily-life mechanism, which both reveal effects that may accumulate over time to impact longer-term health outcomes. We also consider spousal resources such as collaborative problem solving and joint goals as psychological variables that characterize the dynamics within a given marriage. We conclude by discussing areas in theory and research that are ripe for further consideration and lay out target questions for future inquiry. PMID- 24776656 TI - Facile synthesis of V6O13 micro-flowers for Li-ion and Na-ion battery cathodes with good cycling performance. AB - A simple and versatile method for the preparation of V6O13 microflowers is developed via a simple hydrothermal route with the aid of an alkali metal nitrate salt, which has important effects on the formation of V6O13. It is found that V6O13 microflowers display good cycling stability as cathode materials for lithium-ion battery. In addition, they show high capacities for sodium-ion battery. We have V6O13 microflowers discharge capacities up to 225.7 mA h g(-1) for sodium-ion battery. The reason may be the fewer phase transitions occurring upon lithium and sodium insertion for phase-unpure V6O13 microflowers. PMID- 24776657 TI - POSS end-capped diblock copolymers: synthesis, micelle self-assembly and properties. AB - Polyhedral oligomeric silsesquioxane (POSS) end-capped diblock copolymers are synthesized using aminopropylisobutyl POSS (ap-POSS-Br) to initiate atom transfer radical polymerization (ATRP) of methylmethacrylate (MMA) and methacrylisobutyl POSS (MA-POSS). Their chemical structures are confirmed as ap-POSS-PMMA152.0-b P(MA-POSS)4.3, 4.8, 10.0 with 19,840-24,770 g mol(-1) by (1)H NMR and SEC. In tetrahydrofuran (THF) solution, the obtained diblock copolymers could self assemble into 150-300 nm core-shell micelles as ap-POSS/MA-POSS core and PMMA shell, or 164 nm core-shell-crown micelles as P(MA-POSS) core, PMMA shell and ap POSS crown when P(MA-POSS) content is increased. These micelles can produce typical films with lower surface roughness (0.816-1.690 nm), lower water absorption and lower viscoelasticity, but higher hydrophobicity (112-126 degrees water contact angle) and higher thermostability in glass transition temperature Tg>110 degrees C and decompose temperature Td>380 degrees C than pure POSS-PMMA film. In this study, the results strongly support the potential application of the POSS end-capped diblock copolymers as the coatings. PMID- 24776658 TI - Thermo-responsiveness and tunable optical properties of asymmetric polystyrene/PNIPAM-gold composite particles. AB - Environmentally responsive polystyrene/poly (N-isopropylacrylamide)-gold composite particles are successfully synthesized via a Pickering emulsion polymerization method. It is found that the core-shell and asymmetric structured particles are simultaneously formed during the polymerization. Compared with the core-shell structured composite particles, the asymmetric particles have a higher thermo-responsiveness as a result of differences in morphology and formation mechanism. For asymmetric composite particles, an increase in N isopropylacrylamide (NIPAAM) content leads to more significant size variation upon temperature changes. From rheology measurements, the viscosity of asymmetric particles suspension greatly decreases as temperature is increased above the lower critical solution temperature (LCST). The large size decrease in asymmetric composite particles gives rise to a significant scattering intensity increase, as a result of increased refractive index contrast between the PNIPAM content and surrounding water. The resulting size decrease also leads to tunable surface plasmon resonance properties. PMID- 24776659 TI - Kinetics of canine dental calculus crystallization: an in vitro study on the influence of inorganic components of canine saliva. AB - This work identifies carbonated hydroxyapatite (CAP) as the primary component of canine dental calculus, and corrects the long held belief that canine dental calculus is primarily CaCO3 (calcite). CAP is known to be the principal crystalline component of human dental calculus, suggesting that there are previously unknown similarities in the calcification that occurs in these two unique oral environments. In vitro kinetic experiments mimicking the inorganic components of canine saliva have examined the mechanisms of dental calculus formation. The solutions were prepared so as to mimic the inorganic components of canine saliva; phosphate, carbonate, and magnesium ion concentrations were varied individually to investigate the roll of these ions in controlling the nature of the phases that is nucleated. To date, the inorganic components of the canine oral systems have not been investigated at concentrations that mimic those in vivo. The mineral composition of the synthetic calculi grown under these conditions closely resembled samples excised from canines. This finding adds new information about calculus formation in humans and canines, and their sensitivity to chemicals used to treat these conditions. PMID- 24776660 TI - pH-responsive unimolecular micelles self-assembled from amphiphilic hyperbranched block copolymer for efficient intracellular release of poorly water-soluble anticancer drugs. AB - Novel unimolecular micelles from amphiphilic hyperbranched block copolymer H40 poly(epsilon-caprolactone)-b-poly(acrylic acid)-b'-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate (i.e., H40-PCL-b-PAA-b'-MPEG/PEG-FA (HCAE FA)) as new multifunctional nanocarriers to pH-induced accelerated release and tumor-targeted delivery of poorly water-soluble anticancer drugs were developed. The hydrophobic core of the unimolecular micelle was hyperbranched polyester (H40 poly(epsilon-caprolactone) (H40-PCL)). The inner hydrophilic layer was composed of PAA segments, while the outer hydrophilic shell was composed of PEG segments. This copolymer formed unimolecular micelles in the aqueous solution with a mean particle size of 33 nm, as determined by dynamic light scattering (DLS) and transmission electron microscopy (TEM). To study the feasibility of micelles as a potential nanocarrier for targeted drug delivery, we encapsulated a hydrophobic anticancer drug, paclitaxel (PTX), in the hydrophobic core, and the loading content was determined by UV-vis analysis to be 10.35 wt.%. In vitro release studies demonstrated that the drug-loaded delivery system is relatively stable at physiologic conditions but susceptible to acidic environments which would trigger the release of encapsulated drugs. Flow cytometry and fluorescent microscope studies revealed that the cellular binding of the FA-conjugated micelles against HeLa cells was higher than that of the neat micelles (without FA). The in vitro cytotoxicity studies showed that the PTX transported by these micelles was higher than that by the commercial PTX formulation Tarvexol(r). All of these results show that these unique unimolecular micelles may offer a very promising approach for targeted cancer therapy. PMID- 24776661 TI - Studies on the adsorption of chromium(VI) onto 3-Mercaptopropionic acid coated superparamagnetic iron oxide nanoparticles. AB - Chromium (Cr) in the form of Cr(VI) is deemed toxic in water due to its mutagenic and carcinogenic properties. For the successful removal of Cr(VI), we demonstrate a novel adsorbent consisting of superparamagnetic iron oxide nanoparticles (SPION) functionalized with 3-Mercaptopropionic acid (3-MPA). Fourier transform infrared spectroscopy (FT-IR) confirmed the functionalization of nanoparticles and presence of sulfonate groups. Batch adsorption experiments showed that the functionalized adsorbent recovered 45 mg of Cr(VI)/g of 3-MPA coated SPION at initial concentration of 50mg/L aqueous solution at pH 1 with less than 1% of Fe dissolution from SPION. The results from X-ray photoelectron spectroscopy confirmed that Cr(VI) chemisorbed onto the adsorbent. Hence, the XPS spectra did not indicate any reduction of Cr(VI) to Cr(III) upon adsorption. The adsorption data were better fitted for the Freundlich model. Moreover, the Cr(VI) adsorption kinetics on functionalized SPION followed a pseudo-second order rate, revealing chemisorption as the dominant mechanism. The high Cr(VI) removal, rapid adsorption kinetics and stability of adsorbent indicate that 3-MPA coated SPION could be an efficient adsorbent for the removal of Cr(VI). PMID- 24776662 TI - Micellization of sodium laurylethoxysulfate (SLES) and short chain imidazolium ionic liquids in aqueous solution. AB - In the present study the interactions between an anionic surfactant sodium laurylethoxysulfate (SLES) and three short chain imidazolium (1-butyl-3 methylimidazolium) based ionic liquids (bmim-octyl SO4, bmim-methyl SO4 and bmim BF4) in aqueous solution have been investigated. Generally when a surfactant is dissolved in a hydrophilic ionic liquid aqueous solution the critical micelle concentration (cmc) obtained is attributed to the surfactant because the ionic liquid (IL) is considered to be only a cosolvent. However, some short hydrophilic ionic liquids posses surface activity in aqueous solution and behave like a surfactant. In that case mixed aggregates between surfactant and ionic liquid can be formed. The three SLES/IL systems here studied have been treated as typical binary surfactant mixtures in aqueous solution. Surface tension measurements have revealed that mixed aggregates and monolayers of surfactant and ionic liquid instead of single surfactant are responsible for the surface active properties of these aqueous solutions. From the Regular Solution Theory, negative interaction parameters (beta) for mixed aggregates and monolayers have been found for all SLES/IL mole ratios indicating synergism between the anionic surfactant and the ionic liquids. PMID- 24776663 TI - Electrochemical biosensor with ceria-polyaniline core shell nano-interface for the detection of carbonic acid in blood. AB - The normal physiological concentration of carbonic acid in human blood is in the range of 1.08-1.32 mM. However, if the concentration of carbonic acid rises above 3.45 mM, it may lead to respiratory acidosis. In this context, an electrochemical biosensor with CeO2-PANI (polyaniline) core-shell nano-interface was developed for sensing carbonic acid using carbonic anhydrase (CA). CA was immobilized on CeO2-PANI via chitosan on a glassy carbon electrode (GCE/CeO2-PANI/CA/chitosan). The X-ray diffraction (XRD) patterns confirmed the polycrystalline nature of CeO2 and CeO2-PANI nanoparticles. Field emission scanning electron microscopy (FE-SEM) studies showed the aggregation of spherical nanoparticles with size ranging from 37.6 to 47.8 nm and Field emission transmission electron microscopy (FE-TEM) study confirmed the presence of core-shell structure of CeO2-PANI. Immobilization of CA on CeO2-PANI was confirmed by Fourier transform infrared (FT-IR) spectra. Electrochemical studies were carried out with the help of GCE/CeO2-PANI/CA as a working electrode, Ag/AgCl saturated with 0.1 M KCl as a reference electrode and Pt wire as a counter electrode. This biosensor exhibited sensitivity of 696.49 MUA cm(-2) mM(-1) with a linear range of 1.32-2.32 mM. It also showed a fast response time of less than 1s, lowest detection limit of 19.4 MUM, Michaelis Menten constant (KM) of 1.8191 mM and dry stability of 96% up to 18 days. The observed results revealed the potential of the modified working electrode with CeO2-PANI core-shell nano-interface for carbonic acid sensing. The developed biosensor can be applied for the real time clinical diagnosis of diseases such as obstructive pulmonary diseases (COPD). PMID- 24776664 TI - Optimization of isothermal low-energy nanoemulsion formation: hydrocarbon oil, non-ionic surfactant, and water systems. AB - Nanoemulsions can be fabricated using either high-energy or low-energy methods, with the latter being advantageous because of ease of implementation, lower equipment and operation costs, and higher energy efficiency. In this study, isothermal low-energy methods were used to spontaneously produce nanoemulsions using a model system consisting of oil (hexadecane), non-ionic surfactant (Brij 30) and water. Rate and order of addition of surfactant, oil and water into the final mixture were investigated to identify optimal conditions for producing small droplets. The emulsion phase inversion (EPI) and spontaneous emulsion (SE) methods were found to be the most successful, which both require the surfactant to be mixed with the oil phase prior to production. Order of addition and surfactant-to-oil ratio (SOR) influenced the particle size distribution, while addition rate and stirring speed had a minimal effect. Emulsion stability was strongly influenced by storage temperature, with droplet size increasing rapidly at higher temperatures, which was attributed to coalescence near the phase inversion temperature. Nanoemulsions with a mean particle diameter of approximately 60 nm could be produced using both EPI and SE methods at a final composition of 5% hexadecane and 1.9% Brij 30, and were relatively stable to droplet growth at temperatures <25 degrees C. PMID- 24776665 TI - Dispersion of phyllosilicates in aqueous suspensions: role of the nature and amount of surfactant. AB - HYPOTHESES: The present work aims at investigating the effect of pH values and additives on the dispersion of two 1:1 dioctahedral phyllosilicates in the presence of water. Two model clays are used for this purpose, BIP kaolin and NZCC halloysite, presenting the same surface chemistry but different morphologies. The effect of sodium hexametaphosphate, sodium silicate and sodium carbonate is discussed. EXPERIMENTS: Kaolin and halloysite powders were first characterized using X-ray diffraction, thermogravimetric analysis and scanning electron microscopy. Subsequently, suspensions containing 8 mass% of each clay were prepared with or without additives. Experimental measurements regarding the pH values, the zeta potential and the rheological behavior were performed to determine the most suitable additive. FINDINGS: Results show that the conformation of halloysite particles changes regarding pH values of suspensions and is strongly related to the surface charges of these particles. At their natural pH values, halloysite and kaolin suspensions exhibit zeta potentials equal to -50 and -20 mV respectively. This trend indicates that halloysite-based suspensions are well dispersed compared to kaolin-based suspensions. Sodium hexametaphosphate is the most suitable dispersant for both clays. The rheological characterization regarding further applications in casting process indicates a shear-thinning behavior for all studied compositions. PMID- 24776666 TI - Composite nanofibers prepared from metallic iron nanoparticles and polyaniline: high performance for water treatment applications. AB - Presented here is a simple preparation of metallic iron nanoparticles, supported on polyaniline nanofibers at room temperature. The preparation is based on polymerization of interconnected nanofibers by rapid mixing of the aniline monomer with Fe(III) chloride as the oxidant, followed by reductive deposition of Fe(0) nanoparticles, using the polymerization by-products as the Fe precursor. The morphology and other physico-chemical properties of the resulting composite were characterized by scanning and transmission electron microscopy, Brunauer Emmett-Teller method, X-ray diffraction, Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and vibrating-sample magnetometry. The composite fibers were 80-150 nm in diameter and exhibited the expected ferromagnetic behavior. The composite rapidly and efficiently removed As(V), Cr(VI), and also Congo red dye, from aqueous solutions suggesting their usefulness for removal of toxic materials from wastewater. The composite fibers have high capacity for toxin removal: 42.37 mg/g of As(V), 434.78 mg/g of Cr(VI), and 243.9 mg/g of Congo red. The fibers are easily recovered from fluids by exploiting their ferromagnetic properties. PMID- 24776667 TI - Influence of the molecular-scale structures of 1-dodecanethiol and 4 methylbenzenethiol self-assembled monolayers on gold nanoparticles adsorption pattern. AB - In an effort to understand the effects of the molecular structures of self assembled monolayers on the patterns formed by immobilized Au nanoparticles (AuNPs), we characterized and compared the morphologies and properties of AuNPs adsorbed onto self-assembled monolayers formed by 1-dodecanethiol (DDT-SAM) or 4 methylbenzenethiol (MBT-SAM) assembled on Au(111) surfaces. The AuNP adsorption pattern on the MBT-SAM surface was well-dispersed and characterized by a low degree of corrugation. By contrast, an aggregated and highly corrugated AuNP pattern was observed on the surface of the DDT-SAM. This difference was attributed to the retention or removal of citrate anions present on the AuNPs during adsorption onto the SAM surface. Direct interactions between the AuNPs and the highly corrugated hydrophobic surfaces of the DDT-SAMs could strip the citrate layers from the AuNP surfaces, leading to aggregated adsorption. The water molecules appeared to mediate the adsorption of the AuNPs by reducing the hydrophobicity of the MBT-SAM surface and promoting a more dispersed adsorption configuration. PMID- 24776668 TI - New method for the simultaneous determination of diffusion and adsorption of dyes in silica hydrogels. AB - The fine tuning of porosity in sol gel based devices makes possible the design of novel applications in which the transport of molecules through the oxide gel plays a crucial role. In this work we develop a new method for the simultaneous analysis of diffusion and adsorption of small diffusing probes, as anionic and cationic dyes, through silica mesoporous hydrogels synthesized by sol-gel. The novelty of the work resides in the simplicity of acquisition of the experimental data (by means of a desk scanner) and further mathematical modeling, which is in line with high throughput screening procedures, enabling rapid and simultaneous determination of relevant diffusion and adsorption parameters. Net mass transport and adsorption properties of the silica based hydrogels were contrasted to dye adsorption isotherms and textural characterization of the wet gels by SAXS, as well as that of the corresponding aerogels determined by Field Emission Scanning Electron Microscopy (FESEM) and N2 adsorption. Thus, the validation of the results with well-established characterization methods demonstrates that our approach is robust enough to give reliable physicochemical information on these systems. PMID- 24776669 TI - Adsorption and desorption of tyrosine kinase inhibitor erlotinib on gold nanoparticles. AB - We investigated interfacial behaviors of erlotinib (EL) on gold nanoparticles (AuNPs) by means of Raman spectroscopy. The adsorption reactions and structures of EL on AuNP surfaces were examined by UV-Vis absorption spectroscopy and surface-enhanced Raman scattering (SERS). Density functional theory calculations were performed to estimate the energetic stabilities of the drug-AuNP composites. Among the binding units in EL, the acetylenic C=C group was calculated to be the most strongly binding on the AuNP cluster atoms, consistent with the SERS spectra. The concentration-dependent SERS spectra indicated that ~10(-5) M of EL exhibited the highest SERS signals. The attached EL appeared to desorb more efficiently with 2mM glutathione than with cell culture media. The lack of a strong SERS signal of EL in the dark-field microscopy images of AuNP-EL complexes suggested almost complete desorption of EL inside cells. PMID- 24776670 TI - Supramolecular metallogels with complex of phosphonate substituted carbazole derivative and aluminum(III) ion as gelator. AB - Supramolecular metallogels can be gained from the phosphonate substituted 4,4' bis(N-carbazolyl)biphenyl (PCBP) in the presence of aluminum chloride in alcohols, which can donate oxygen to aid proton transfer in the aluminum organophosphorus complexes. Inside the metallogels, three-dimensional fiber networks with nanofibers entangling and intersecting with each other inside are formed. The nanofibers show layered structures with a period thickness of 0.82 nm. As the content of aluminum(III) increases, the size of the fibers becomes smaller and the fibers pack more densely. It makes the transparent gel become turbid but nevertheless improves the stability of the metallogels. NMR, FT-IR and fluorescence spectroscopy show that the coordination interactions between the phosphonate groups of PCBP molecules and aluminum(III) ions as well as the pi-pi interactions among PCBP molecules are involved during the gel formation process. PMID- 24776671 TI - Effect of self-assembly on triiodide diffusion in water based polymer gel electrolytes: an application in dye solar cell. AB - The preparation of ordered polymer gels from the amphiphilic block copolymers, Pluronic(r) F77, P123 and polyethylene glycol in the presence of ionic liquid, iodine and organic additives is presented. At 35%(w/w) concentration these copolymers (F77 and P123) self-assembled into cubic liquid crystalline phase in aqueous solution and characterized by using SAXS and AFM measurements. The effects of micellar aggregation formed by polymers on the ionic transport and triiodide diffusion have been studied by electrochemistry and SANS experiments. The ionic migration or triiodide diffusion through these polymer gels is found to be affected by the PEO/PPO content in the polymer backbone. These gels were successfully employed as an electrolyte in a dye sensitized solar cell. A remarkable solar to electricity conversion efficiency and good stability was obtained using Pluronic(r) F77 based gel, which is attributed to its thermoreversible sol to gel transition. PMID- 24776672 TI - Characterization and cytotoxicity studies on liposome-hydrophobic magnetite hybrid colloids. AB - The aim of this study was to highlight the main features of magnetoliposomes prepared by TLE, using hydrophobic magnetite, and stabilized with oleic acid, instead of using the usual hydrophilic magnetite surrounded by sodium citrate. These biocompatible magnetoliposomes (MLs) were prepared with the purpose of producing a magnetic carrier capable of loading either hydrophilic or lipophilic drugs. The effect of different liposome/magnetite weight ratios on the stability of magnetoliposomes was evaluated by monitoring the mean diameter of the particles, their polydispersity index, and zeta potential over time. The prepared magnetoliposomes showed a high liposome-magnetite association, with magnetoliposomes containing PEG (polyethylene glycol) showing the best magnetite loading values. To verify the position of magnetite nanoparticles in the vesicular structures, the morphological characteristics of the structures were studied using transmission electron microscopy (TEM). TEM studies showed a strong affinity between hydrophobic magnetite nanoparticles, the surrounding oleic acid molecules, and phospholipids. Furthermore, the concentration above which one would expect to find a cytotoxic effect on cells as well as morphological cell nanoparticle interactions was studied in situ by using the trypan blue dye exclusion assay, and the Prussian Blue modified staining method. PMID- 24776673 TI - Analytical model for charge properties of silica particles. AB - An analytical model for surface charge density and zeta potential of silica particles is derived and verified. The model takes into account surface chemistry reactions of the silanol groups and multiple ionic species. The predictions are in good agreement with the experimental data available from the literature. Surface charge density and zeta potential of silica particles strongly depend on both pH and background salt concentration of the aqueous solution. PMID- 24776674 TI - One step solvothermal synthesis of functional hybrid gamma-Fe2O3/carbon hollow spheres with superior capacities for heavy metal removal. AB - One-step hydrothermal method was developed to prepare hybrid gamma-Fe2O3/carbon hollow spheres with a predominant orientation (111) plane of gamma-Fe2O3 and rich oxygen-containing functional groups on carbon. The resulting functional hybrid exhibited extremely high adsorption capacities for toxic Pb(II) and Cr(VI) ions in solutions with easy magnetic separation. The ease of synthesis and low cost, coupled with the efficient and rapid removal of toxic heavy metal ions, make hybrid gamma-Fe2O3/carbon hollow spheres an attractive adsorbent for the purification of waste and contaminated water. PMID- 24776675 TI - Rapid and efficient fabrication of multilevel structured silica micro-/nanofibers by centrifugal jet spinning. AB - A rapid and efficient method consisting of two simple steps, centrifugal jet spinning (CJS) and annealing, is introduced to fabricate multilevel structured silica micro-/nanofibers. Using this technique, which is 500 times faster than electrospinning, silica micro-/nanofibers with a hollow or porous internal structure are formed as a result of non-solvent evaporation induced phase separation in the spinning solution. Silica nanofibers with solid cross sections (364 nm and 781 nm), hollow cross sections (outer and internal diameters of 458 nm and 216 nm respectively), and encapsulated voids (outside diameter of 1.4 MUm where bi-continuous nano-pores 118 nm are observed) are fabricated by tuning the amount of non-solvent in the spinning solutions. This technique can be readily extended to large-scale and efficient fabrication of various ceramic materials with multileveled fibrous structures. PMID- 24776676 TI - Towards completely miscible PMMA nanocomposites reinforced by shear-stiff, nano mica. AB - Optimizing the reinforcement of polymers with nanoplatelets requires optimization of the aspect ratio and the moduli of the filler while providing a complete stress transfer. Employing a novel shear-stiff, nano-mica with large aspect ratio, we focus on maximizing the interfacial interaction between filler and matrix. External surfaces of the nano-mica were selectively modified by a polycationic macro-initiator and two PMMA-polymer brushes of length below and above critical entanglement length, respectively, and the mechanical properties of the three PMMA nanocomposites were measured. The multiple electrostatic anchoring groups of the macro-initiator not only provide reliable adhesion but at the same time allow the variation of the degree of protonation providing a local match between the charge densities of the clay surface and the adsorbed macro initiator. PMMA coating of the nano-mica via surface initiated polymerization yielded long-term stable suspensions in THF that showed birefringence of a nematic phase. Solution blending of the PMMA coated nano-mica allows for dispersing single clay tactoids in the translucent PMMA nanocomposites at 5 wt% clay loading as determined by transmission electron microscopy (TEM). Although significantly improved mechanical properties could be achieved as compared to nanocomposites made with conventional clay fillers, the full potential - as expressed by Halpin-Tsai equations - of the PMMA coated nano-mica can still not be completely utilized. This is attributed to the non-wetting character of the densely packed PMMA brushes attached to planar nanoplatelets. PMID- 24776677 TI - Photo-sensitive ligands on nanoparticles for achieving triggered emulsion inversion. AB - A photocleavable ligand containing an o-nitroveratryl (oNV) linker was synthesized and used to functionalize CdSe quantum dots (QDs) to achieve liquid liquid interface stabilization and the formation of stable water-in-oil (w/o) emulsion droplets. Ligand cleavage upon irradiation of the droplets at 365 nm led to an increase of QD hydrophilicity, and a subsequent emulsion inversion to give oil-in-water (o/w) droplets. The fluorescence of functionalized QDs, initially quenched due to the presence of the oNV group, is turned-on after irradiation and linker cleavage. Photocleavage was monitored by nuclear magnetic resonance (NMR) and Fourier-transform infrared (FT-IR) spectroscopy, and liquid-liquid interface stabilization was evaluated by interfacial tension measurements by pendant drop tensiometry. PMID- 24776678 TI - Adsorption of beta-amyloid oligomers on octadecanethiol monolayers. AB - HYPOTHESIS: beta-Amyloid oligomers of different aggregation and physiological functions exhibit distinct adsorption behavior allowing them to be discriminated in preparations. EXPERIMENTS: Two forms of amyloid oligomers, small 1-4 nm and large 5-10nm were formulated using synthetic 42 amino acids beta-amyloid peptide. Forms differ in their size and physiological function. A systematic study of adsorption of these amyloid species on self-assembled monolayers of octadecanethiol on gold was performed. Structural changes upon adsorption of oligomers were interrogated by the reflection absorption infrared spectroscopy. FINDINGS: The amount of adsorbed peptide material, as detected by surface plasmon resonance spectroscopy, is similar in case of both small and large oligomers. However, adsorption of small oligomers leads to a transformation from beta sheet rich to beta sheet depleted secondary structure. These changes were accompanied by the unique morphology patterns detectable by atomic force microscopy (AFM), while the quartz microbalance with dissipation indicated a formation of a compact adsorbate layer in case of small oligomers. These effects may be integrated and utilized in bioanalytical systems for sensing and detection of Alzheimer's disease related peptide forms in artificial, and possibly, real preparations. PMID- 24776679 TI - Adsorptive removal of oil spill from oil-in-fresh water emulsions by hydrophobic alumina nanoparticles functionalized with petroleum vacuum residue. AB - Oil spills on fresh water can cause serious environmental and economic impacts onshore activities affecting those who exploit freshwater resources and grassland. Alumina nanoparticles functionalized with vacuum residue (VR) were used as a low-cost and high hydrophobic nanosorbents. The nanomaterial resulting showed high adsorption affinity and capacity of oil from oil-in-freshwater emulsion. The effects of the following variables on oil removal were investigated, namely: contact times, solution pH, initial oil concentrations, temperature, VR loadings and salinity. Kinetic studies showed that adsorption was fast and equilibrium was achieved in less than 30 min. The amount adsorbed of oil was higher for neutral system compared to acidic or basic medium. Increasing the VR loading on nanoparticle surface favored the adsorption. Results of this study showed that oil removal for all systems evaluated had better performance at pH value of 7 using nano-alumina functionalized with 4 wt% VR. Adsorption equilibrium and kinetics were evaluated using the Polanyi theory-based Dubinin Ashtakhov (DA) model, and pseudo-first and pseudo-second order-models, respectively. PMID- 24776680 TI - Rattle-type hierarchical particles containing multilevel cores (Ag@AgCl@SiO2 and Au/Ag@AgCl@SiO2) as versatile catalysts. AB - A protocol for the synthesis of rattle-type core@shell particles containing Ag@AgCl or Au/Ag@AgCl core structures was developed, and the use of these particles as catalysts for the decomposition of toxic materials was demonstrated. A monometallic Ag or bimetallic Au/Ag core was incorporated into the interior of SiO2 capsules via controlled heat treatment of metal nanoparticle/SiO2-coated polymer particles, resulting in the formation of rattle-type core@shell structures. By appropriate treatments, it was possible to transform the Ag or Au/Ag core into multilevel cores (Ag@AgCl or Au/Ag@AgCl) within the SiO2 capsules (Ag@AgCl@SiO2 or Au/Ag@AgCl@SiO2). This method for the synthesis of rattle-type core@shell particles is useful for further introducing AgCl fused with plasmonic materials into the capsule structures. The rattle-type core@shell structures were used as photocatalysts for the decomposition of organic pollutants such as methyl orange. Furthermore, these nanocatalysts containing semiconductors such as AgCl were also applied toward the reduction of nitrophenol (NPh) to aminophenol (APh). The Ag@AgCl@SiO2 or Au/Ag@AgCl@SiO2 catalysts showed excellent catalytic properties in the decomposition of toxic substances in terms of their activity and reusability. PMID- 24776681 TI - Understanding the atrial fibrillation substrate: the case for repeat catheter ablation. PMID- 24776682 TI - Poly(3-aminophenylboronic acid)-functionalized carbon nanotubes-based chemiresistive sensors for detection of sugars. AB - The poly(aniline boronic acid) (PABA)-functionalized single-walled carbon nanotube (SWNT) non-enzymatic sensor was developed for the detection of saccharides. The work involved the electrochemical polymerization of 3 aminophenylboronic acid (3-APBA) in the presence of fluoride on the surface of SWNTs and their subsequent evaluation as chemiresistive sensors towards the detection of d-fructose and d-glucose. By varying the sensor's synthesis conditions by charge-controlled electropolymerization, the sensing performance was systematically optimized. Through electrical characterization in terms of change in resistance, cyclic voltammetry confirmed the electrochemical deposition of the PABA coating on the SWNTs. The optimized sensors showed sensing response over a wide dynamic range of concentrations and a limit of detection of 2.92 mM for D-fructose and 3.46 mM for D-glucose. The hybrid sensors could be regenerated on the basis of the reversible nature of the binding between PABA and 1,2- or 1,3 diols at lower values of pH. PMID- 24776684 TI - 'A rare cause of angina': multiple coronary cameral fistulae simulating coronary artery disease in a 71-year-old man. PMID- 24776685 TI - High trait impulsivity predicts food addiction-like behavior in the rat. AB - Impulsivity is a behavioral trait frequently seen not only in drug-addicted individuals but also in individuals who pathologically overeat. However, whether impulsivity predates the development of uncontrollable feeding is unknown. In this study, we hypothesized that a high impulsivity trait precedes and confers vulnerability for food addiction-like behavior. For this purpose, we trained ad libitum-fed male Wistar rats in a differential reinforcement of low rates of responding (DRL) task to select Low- and High-impulsive rats. Then, we allowed Low- and High-impulsive rats to self-administer a highly palatable diet (Palatable group) or a regular chow diet (Chow group) in 1-h daily sessions, under fixed ratio (FR) 1, FR3, FR5, and under a progressive ratio (PR) schedules of reinforcement. In addition, we tested the compulsiveness for food in Low- and High-impulsive rats by measuring the food eaten in the aversive, open compartment of a light/dark conflict test. Finally, we measured the expression of the transcription factor DeltaFosB in the shell and the core of the nucleus accumbens, which is a marker for neuroadaptive changes following addictive drug exposure. The data we obtained demonstrate that impulsivity is a trait that predicts the development of food addiction-like behaviors, including: (i) excessive intake, (ii) heightened motivation for food, and (iii) compulsive-like eating, when rats are given access to highly palatable food. In addition, we show that the food addiction phenotype in high impulsive subjects is characterized by an increased expression of the transcription factor DeltaFosB in the nucleus accumbens shell. These results reveal that impulsivity confers an increased propensity to develop uncontrollable overeating of palatable food. PMID- 24776688 TI - Self-esteem and illness self-concept in emerging adults with Type 1 diabetes: Long-term associations with problem areas in diabetes. AB - This long-term prospective study examined whether illness self-concept (or the degree to which chronic illness becomes integrated in the self) mediated the pathway from self-esteem to problem areas in diabetes in emerging adults with Type 1 diabetes. Having a central illness self-concept (i.e. feeling overwhelmed by diabetes) was found to relate to lower self-esteem, and more treatment, food, emotional, and social support problems. Furthermore, path analyses indicated that self-esteem was negatively related to both levels and relative changes in these problem areas in diabetes over a period of 5 years. Illness self-concept fully mediated these associations. PMID- 24776689 TI - Looking age-appropriate while growing old gracefully: A qualitative study of ageing and body image among older adults. AB - Body dissatisfaction can be significantly detrimental to wellbeing. Little is known about older adults' body image, despite the fact that ageing causes unique bodily changes and that sociocultural pressures to resist these changes abound. We conducted six focus groups with a UK community sample of White British and South Asian older adults aged 65-92 years. Thematic analysis highlighted four themes: appearance indicates capability and identity; physical ability trumps appearance; felt pressures to age 'gracefully' while resisting appearance changes; and gender and cultural differences. These findings suggest that older adults' body image can have important implications for their wellbeing and merits researchers' attention. PMID- 24776686 TI - Selective deletion of GRK2 alters psychostimulant-induced behaviors and dopamine neurotransmission. AB - GRK2 is a G protein-coupled receptor kinase (GRK) that is broadly expressed and is known to regulate diverse types of receptors. GRK2 null animals exhibit embryonic lethality due to a severe developmental heart defect, which has precluded the study of this kinase in the adult brain. To elucidate the specific role of GRK2 in the brain dopamine (DA) system, we used a conditional gene knockout approach to selectively delete GRK2 in DA D1 receptor (D1R)-, DA D2 receptor (D2R)-, adenosine 2A receptor (A2AR)-, or DA transporter (DAT) expressing neurons. Here we show that select GRK2-deficient mice display hyperactivity, hyposensitivity, or hypersensitivity to the psychomotor effects of cocaine, altered striatal signaling, and DA release and uptake. Mice with GRK2 deficiency in D2R-expressing neurons also exhibited increased D2 autoreceptor activity. These findings reveal a cell-type-specific role for GRK2 in the regulation of normal motor behavior, sensitivity to psychostimulants, dopamine neurotransmission, and D2 autoreceptor function. PMID- 24776690 TI - The usefulness of preoperative 18FDG positron-emission tomography and computed tomography for predicting the malignant potential of gastrointestinal stromal tumors. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The tumor size and mitotic count, typical risk category factors, are difficult to determine preoperatively. This study aimed to evaluate the usefulness of preoperative 18F-fluoro-2 deoxyglucose positron-emission tomography/computed tomography (18FDG-PET/CT) for predicting the malignant potential of GISTs by analyzing the correlation between the maximum standardized uptake value (SUVmax) and postoperative factors. METHODS: Thirty consecutive patients underwent surgery after preoperative 18FDG PET/CT and were diagnosed with pathologically confirmed GIST. The tumor size, mitotic count, MIB-1 index and National Institutes of Health (NIH) risk category were compared with SUVmax. RESULTS: Significant correlations between SUVmax and tumor size and NIH risk category were determined. The sensitivity and specificity of SUVmax for predicting the risk of malignancy were 85.7 and 62.5%, respectively. The optimal cut-off value for SUVmax was 3.0 between patients classified into low-risk and high-risk malignancy groups. There was no significant correlation between SUVmax and mitotic count or MIB-1 index. Multivariate analysis indicated that SUVmax was the only predictive risk factor in the high-risk malignancy group. CONCLUSIONS: 18FDG-PET/CT is useful for assessing the malignant potential and bioactivity of GISTs. When SUVmax is >3.0, the tumor must be resected even if it measures <2 cm, because of its high malignant potential. PMID- 24776691 TI - Reuse of internal pulse generator in cases of infection after deep brain stimulation surgery. AB - BACKGROUND: Hardware-related infection after deep brain stimulation (DBS) is one of the most serious complications and may need additional interventions. OBJECTIVES: To reuse the internal pulse generator (IPG) after DBS infection and to reduce the economic costs. METHODS: A database of 102 patients who underwent DBS surgery was used in the study. The incidence, clinical characteristics and management of infections while reusing the IPG after DBS-related infection were analyzed and reported. RESULTS: The overall infection rate was 5.9% (6 of 102 patients). Management consisted of total hardware removal followed by intravenous antibiotics. The IPG was at first kept in a solution, then rinsed with water and dried following sterilization with ethylene oxide gas at 38 degrees C for 18 h. When the treatment of the infection was finished, we reused the IPG and reimplanted the DBS. No hardware-related infection or other complications were observed after reimplantation. CONCLUSIONS: Management of hardware-related infections can be challenging. The medical and economic costs associated with these infections are enormous. The IPG can often be saved in infected patients. Thus, a significant cost burden is eliminated. Properly executed, reuse of IPG should markedly reduce the costs of these devices. PMID- 24776692 TI - Comment on the paper entitled 'Erythropoietin ameliorates oxidative stress and tissue injury following renal ischemia/reperfusion in rat kidney and lung'. PMID- 24776693 TI - Dual-function Pd/NHC catalysis: tandem allylation-isomerization-conjugate addition that allows access to pyrroles, thiophenes and furans. AB - An efficient coupling reaction of allyl acetate with (O-azaaryl)carboxaldehyde by Pd-NHC dual catalysis has been developed. This reaction proceeds via direct coordination between the ortho nitrogen atom in the heterocycle and Pd(0). This dual catalysis is achieved under mild conditions to give 1,4-diones as products with up to 90% yield. PMID- 24776694 TI - Synthesis of isoquinolines via visible light-promoted insertion of vinyl isocyanides with diaryliodonium salts. AB - A synthetic strategy for multi-substituted isoquinoline derivatives has been developed using visible light-promoted vinyl isocyanide insertion with diaryliodonium salts at room temperature. The methodology presented here represents the first example of isoquinoline synthesis via somophilic isocyanide insertion. PMID- 24776695 TI - Comparison of myocardial perfusion during hemodialysis and hemodiafiltration. AB - BACKGROUND: We compared myocardial perfusion in patients first on conventional hemodialysis (HD) and then on hemodiafiltration (HDF). METHODS: Myocardial perfusion scintigraphy was performed in 25 patients pre- and post-HD. Patients were then converted to HDF for 3 months prior to repeating the scintigraphy. (99m)Tc-methoxyisobutylisonitrile was administered intravenously pre-dialysis and then within the last hour of dialysis. Up to 90 min after injection, tomographic images were obtained. Clinical and laboratory data were collected pre- and post dialysis. RESULTS: Five patients did not complete the study. Patients entering the study were on average 41.7 years old and on HD for 4 years (median). The mean standard Kt/V for the two procedures was not statistically different (1.55 for HD and 1.48 for HDF). The mean substitution volume for HDF was 18.48 liters. There were no significant differences in changes in blood pressures between HD and HDF (p = 0.22). There were no significant differences in myocardial perfusion defects in patients on HD compared with those on HDF. During dialysis in both studies, the data showed a general trend to worsening of perfusion defects. CONCLUSIONS: There was no advantage of HDF over HD with no statistical difference in perfusion defects between HD and HDF. There was a trend to worsening of perfusion defects during dialysis in the majority on HD and HDF. Midweek dialysis perfusion scores appeared to be consistently lower than early-week dialysis, but this was not statistically significant. The pathogenesis of the defects may lie at a microcirculatory level. PMID- 24776696 TI - Ultrasensitive dual amplification sandwich immunosensor for breast cancer susceptibility gene based on sheet materials. AB - A new electrochemical dual amplification sandwich immunosensor (DASI) was designed for ultrasensitive and accurate detection of the breast cancer susceptibility gene based on the combination of N-doped graphene, hydroxypropyl chitosan and Co3O4 mesoporous nanosheets. N-doped graphene has better electroconductibility than traditional graphene. It is an ideal electrochemical material with a large specific surface area and low resistance. Hydroxypropyl chitosan replaces the pure chitosan in immobilization of the sensor to achieve the sensitivity increase. Co3O4 mesoporous nanosheets can enhance the effective area of the immunoreaction. This kind of dual amplification sandwich immunosensor was first used for the detection of the breast cancer susceptibility gene. It has a wide linear response range of 0.001-35 ng mL(-1) and a minimum detection limit of 0.33 pg mL(-1). It was demonstrated that the stability, selectivity and reproducibility of the sensor were acceptable. The fabricated immunosensor shows great potential applications in early disease diagnosis. PMID- 24776697 TI - On the validity of the autobiographical emotional memory task for emotion induction. AB - The Autobiographical Emotional Memory Task (AEMT), which involves recalling and writing about intense emotional experiences, is a widely used method to experimentally induce emotions. The validity of this method depends upon the extent to which it can induce specific desired emotions (intended emotions), while not inducing any other (incidental) emotions at different levels across one (or more) conditions. A review of recent studies that used this method indicated that most studies exclusively monitor post-writing ratings of the intended emotions, without assessing the possibility that the method may have differentially induced other incidental emotions as well. We investigated the extent of this issue by collecting both pre- and post-writing ratings of incidental emotions in addition to the intended emotions. Using methods largely adapted from previous studies, participants were assigned to write about a profound experience of anger or fear (Experiment 1) or happiness or sadness (Experiment 2). In line with previous research, results indicated that intended emotions (anger and fear) were successfully induced in the respective conditions in Experiment 1. However, disgust and sadness were also induced while writing about an angry experience compared to a fearful experience. Similarly, although happiness and sadness were induced in the appropriate conditions, Experiment 2 indicated that writing about a sad experience also induced disgust, fear, and anger, compared to writing about a happy experience. Possible resolutions to avoid the limitations of the AEMT to induce specific discrete emotions are discussed. PMID- 24776698 TI - Vitamin D and its effects on glucose homeostasis, cardiovascular function and immune function. AB - In recent years there has been increasing interest in the non-skeletal effects of vitamin D. It has been suggested that vitamin D deficiency may influence the development of diabetes, cardiovascular dysfunction and autoimmune diseases. This review focuses on the current knowledge of the effects of vitamin D and its deficiency on cardiovascular function, glucose homeostasis and immune function, with a particular focus on children. Although, there is good evidence to show that there is an association between vitamin D deficiency and an abnormality of the above systems, there is little evidence to show that vitamin D supplementation leads to an improvement in function, especially in childhood. PMID- 24776699 TI - Three-dimensional spinal morphology can differentiate between progressive and nonprogressive patients with adolescent idiopathic scoliosis at the initial presentation: a prospective study. AB - STUDY DESIGN: This is a prospective case-control study. OBJECTIVE: The objective of this study was to compare 3-dimensional (3D) morphological parameters of the spine at the first visit between a nonprogressive (NP) and a progressive (P) group of immature adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Prediction of curve progression remains challenging in AIS at the first visit. Prediction of progression is based on curve type, curve magnitude, and skeletal or chronological age. METHODS: A prospective cohort of 133 AIS was followed from skeletal immaturity to maturity (mean, 37 mo). The first group was made up of patients with AIS with a minimum 6-degree progression of the major curve between the first and last follow-up (P) (n = 53) and the second group was composed of patients with NP who reached maturity with less than 6-degree progression (n = 81). Computerized measurements were taken on reconstructed 3 dimensional (3D) spine radiographs of the first visit. There were 6 categories of measurements: angle of plane of maximum curvature, Cobb angles (kyphosis, lordosis), 3D wedging (apical vertebra, apical disks), rotation (upper and lower junctional vertebra, apical vertebra, and thoracolumbar junction), torsion, and slenderness (height/width ratio). t tests were also conducted. RESULTS: There was no statistical difference between the 2 groups for age and initial Cobb angle. P presented significant hypokyphosis, and parameters related to rotation presented significant statistical differences between NP and P (plane of maximal curvature, torsion, and apical axial rotation). Depth slenderness also presented statistical differences. CONCLUSION: This study confirms that even at the initial visit, 3D morphological differences exist between P and NP AIS. It supports the use of 3D reconstructions of the spine in the initial evaluation of AIS to help predict outcome. PMID- 24776700 TI - Is it possible to evaluate the parameters of cervical sagittal alignment on cervical computed tomographic scans? AB - STUDY DESIGN: Retrospective study. OBJECTIVE: The purpose of this study was to analyze the relationship of the parameters of cervical sagittal alignment between those obtained from cervical CT and those obtained from radiography, as well as to determine which parameter would help predict physiological lordosis of the cervical spine. SUMMARY OF BACKGROUND DATA: Sagittal balance in the cervical spine is as important as the pelvic incidence and is related to the concept of T1 slope. However, many articles including this article based on unclear cervical x ray radiographs could weakly explain the parameters. To overcome the fundamental limitation of x-ray radiographs, Hallym University Sacred Heart Hospital reported the strong correlation between T1 slope and cervical lordosis on the cervical dimensional CT scans like result by checking by the cervical x-ray radiographs. METHODS: A retrospective analysis of data from 50 asymptomatic adults in whom both cervical CT scans and cervical radiograph were obtained at the same time. The T1 slope, Cobb angle C2-C7, neck tilt, and thoracic inlet angle (TIA) obtained from the CT scans and radiographs were assessed. RESULTS: The T1 slope on x-ray was significantly correlated with the T1 slope on CT. The mean of the T1 slope on x-ray was larger than the mean of the T1 slope on CT (3.3 degrees +/- 6.1 degrees ). More cervical spine lordosis was evident on the cervical radiograph than on the cervical CT scan (5.93 degrees +/- 9.0 degrees ). No significant difference was seen between the TIA on x-ray and the TIA on CT (TIA on x-ray - TIA on CT, -0.1 +/- 7.6, P = 0.959). CONCLUSION: This difference may be due to the differing effect of gravity upon the spine between the upright versus the supine position. Accordingly, TIA and T1 slope may be used as a guide for the assessment of sagittal balance of the cervical spine. PMID- 24776704 TI - A role for pericytes in coronary no-reflow. AB - Despite efforts to restore tissue perfusion after myocardial infarction, coronary no-reflow--a failure to achieve adequate reperfusion of the cardiac microcirculation--is a common complication, which correlates with an increased incidence of death and disability. The treatment of ischaemic stroke is also plagued by no-reflow and, in the brain, a major cause of this phenomenon has been shown to be contractile microvascular pericytes irreversibly constricting capillaries and dying. We propose that cardiac pericytes, which are the second most-common cell type in the heart, impede reperfusion of coronary capillaries in a similar fashion to those in the brain after a stroke. Pericyte constriction might contribute to morbidity in patients by causing microvascular obstruction, even after successful treatment of coronary artery block. The similarity of the no-reflow phenomenon in the brain and in the heart suggests that cardiac pericytes are a novel therapeutic target for coronary no-reflow after myocardial infarction. PMID- 24776705 TI - Venous thromboembolism: High incidence of bleeding with fibrinolysis in intermediate-risk pulmonary embolism. PMID- 24776703 TI - Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. AB - The renin-angiotensin system (RAS) has pivotal roles in the regulation of normal physiology and the pathogenesis of cardiovascular disease. Angiotensin-converting enzyme (ACE) 2, and its product angiotensin 1-7, are thought to have counteracting effects against the adverse actions of other, better known and understood, members of the RAS. The physiological and pathological importance of ACE2 and angiotensin 1-7 in the cardiovascular system are not completely understood, but numerous experimental studies have indicated that these components have protective effects in the heart and blood vessels. Here, we provide an overview on the basic properties of ACE2 and angiotensin 1-7 and a summary of the evidence from experimental and clinical studies of various pathological conditions, such as hypertension, atherosclerosis, myocardial remodelling, heart failure, ischaemic stroke, and diabetes mellitus. ACE2 mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the relevant functions and signalling mechanisms of actions induced by angiotensin 1-7 have not been conclusively determined. The ACE2-angiotensin 1-7 pathway, however, might provide a useful therapeutic target for the treatment of cardiovascular disease, especially in patients with overactive RAS. PMID- 24776706 TI - Clinical classification of plaque morphology in coronary disease. AB - In published post-mortem pathological studies, more than two-thirds of acute coronary events are associated with the rupture of lipid-rich, voluminous, and outwardly remodelled plaques covered by attenuated and inflamed fibrous caps in the proximal part of coronary arteries. Superficial erosion of the plaques is responsible for most of the remaining events; the eroded plaques usually do not demonstrate much lipid burden, do not have thin fibrous caps, are not positively remodelled, and are not critically occlusive. Both noninvasive and invasive imaging studies have been performed to clinically define the plaque characteristics in acute coronary syndromes in an attempt to identify the high risk plaque substrate susceptible to development of an acute coronary event. Optical coherence tomography (OCT)--an intravascular imaging modality with high resolution--can be used to define various stages of plaque morphology, which might allow its use for the identification of high-risk plaques vulnerable to rupture, and their amenability to pre-emptive interventional treatment. OCT might also be employed to characterize plaque pathology at the time of intervention, to provide a priori knowledge of the mechanism of the acute coronary syndrome and, therefore, to enable improved management of the condition. PMID- 24776707 TI - Antibodies to the amino-terminal domain of desmoglein 1 are retained during transition from pemphigus vulgaris to pemphigus foliaceus. AB - BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two blistering skin diseases mediated by antibodies to desmoglein 3 (Dsg3) and/or Dsg1. Phenotypic transition from PV to PF is rarely reported. OBJECTIVES: To determine the immune response to extracellular (EC) domains of Dsgs during this transition. MATERIALS AND METHODS: We report two PV patients who subsequently developed a PF phenotype. To map the conformational epitopes in these cases, we examined the reactivity of the sera of two patients by immunoprecipitation immunoblotting analysis, using five Dsg1/Dsg3 domain-swapped molecules on a backbone of Dsg2. RESULTS: Reactivity exclusively with the EC1 domain of Dsg1 was maintained in both PV and PF stages. No reactivity to Dsg3 in the PF stage was found in patient 1. Various changes in immunoreactivity to Dsg3 were found and the EC1 and EC2 domains of Dsg3 reacted weakly to serum taken at remission and PF stages in patient 2. CONCLUSIONS: Our findings suggest that amino-terminal pathogenic antibodies to the EC domain of Dsg1 were retained, while considerable epitope changes occurred in response to Dsg3 during the shift from PV to PF, with an absolute or significant decrease in pathogenic antibodies to the EC1 domain of Dsg3. PMID- 24776708 TI - The future of population registers: linking routine health datasets to assess a population's current glycaemic status for quality improvement. AB - OBJECTIVES: To determine the diabetes screening levels and known glycaemic status of all individuals by age, gender and ethnicity within a defined geographic location in a timely and consistent way to potentially facilitate systematic disease prevention and management. DESIGN: Retrospective observational study. SETTING: Auckland region of New Zealand. PARTICIPANTS: 1 475 347 people who had utilised publicly funded health service in New Zealand and domicile in the Auckland region of New Zealand in 2010. The health service utilisation population was individually linked to a comprehensive regional laboratory repository dating back to 2004. OUTCOME MEASURES: The two outcomes measures were glycaemia-related blood testing coverage (glycated haemoglobin (HbA1c), fasting and random glucose and glucose tolerance tests), and the proportions and number of people with known dysglycaemia in 2010 using modified American Diabetes Association (ADA) and WHO criteria. RESULTS: Within the health service utilisation population, 792 560 people had had at least one glucose or HbA1c blood test in the previous 5.5 years. Overall, 81% of males (n=198 086) and 87% of females (n=128 982) in the recommended age groups for diabetes screening had a blood test to assess their glycaemic status. The estimated age-standardised prevalence of dysglycaemia was highest in people of Pacific Island ethnicity at 11.4% (95% CI 11.2% to 11.5%) for males and 11.6% (11.4% to 11.8%) for females, followed closely by people of Indian ethnicity at 10.8% (10.6% to 11.1%) and 9.3% (9.1% to 9.6%), respectively. Among the indigenous Maori population, the prevalence was 8.2% (7.9% to 8.4%) and 7% (6.8% to 7.2%), while for 'Others' (mainly Europeans) it was 3% (3% to 3.1%) and 2.2% (2.1% to 2.2%), respectively. CONCLUSIONS: We have demonstrated that the data linkage between a laboratory repository and national administrative datasets has the potential to provide a systematic and consistent individual level clinical information that is relevant to medical auditing for a large geographically defined population. PMID- 24776709 TI - A retrospective cohort study identifying the principal pathological features useful in the diagnosis of inclusion body myositis. AB - OBJECTIVE: The current pathological diagnostic criteria for sporadic inclusion body myositis (IBM) lack sensitivity. Using immunohistochemical techniques abnormal protein aggregates have been identified in IBM, including some associated with neurodegenerative disorders. Our objective was to investigate the diagnostic utility of a number of markers of protein aggregates together with mitochondrial and inflammatory changes in IBM. DESIGN: Retrospective cohort study. The sensitivity of pathological features was evaluated in cases of Griggs definite IBM. The diagnostic potential of the most reliable features was then assessed in clinically typical IBM with rimmed vacuoles (n=15), clinically typical IBM without rimmed vacuoles (n=9) and IBM mimics-protein accumulation myopathies containing rimmed vacuoles (n=7) and steroid-responsive inflammatory myopathies (n=11). SETTING: Specialist muscle services at the John Radcliffe Hospital, Oxford and the National Hospital for Neurology and Neurosurgery, London. RESULTS: Individual pathological features, in isolation, lacked sensitivity and specificity. However, the morphology and distribution of p62 aggregates in IBM were characteristic and in a myopathy with rimmed vacuoles, the combination of characteristic p62 aggregates and increased sarcolemmal and internal major histocompatibility complex class I expression or endomysial T cells were diagnostic for IBM with a sensitivity of 93% and specificity of 100%. In an inflammatory myopathy lacking rimmed vacuoles, the presence of mitochondrial changes was 100% sensitive and 73% specific for IBM; characteristic p62 aggregates were specific (91%), but lacked sensitivity (44%). CONCLUSIONS: We propose an easily applied diagnostic algorithm for the pathological diagnosis of IBM. Additionally our findings support the hypothesis that many of the pathological features considered typical of IBM develop later in the disease, explaining their poor sensitivity at disease presentation and emphasising the need for revised pathological criteria to supplement the clinical criteria in the diagnosis of IBM. PMID- 24776710 TI - Acupuncture for the treatment of chronic obstructive pulmonary disease: a protocol of a systematic review. AB - INTRODUCTION: This review aims to evaluate the efficacy of acupuncture in the treatment of chronic obstructive pulmonary disease (COPD). METHODS AND ANALYSIS: 14 databases will be searched from their inception. These include PubMed, AMED, EMBASE, the Cochrane Library, seven Korean medical databases (Korean Studies Information Service System, DBPIA, Oriental Medicine Advanced Searching Integrated System, Research Information Service System, KoreaMed, The Town Society of Science Technology and the Korean National Assembly Library), three Chinese Databases (China National Knowledge Infrastructure Database (CNKI), the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), and the Wanfang Database). Only randomised clinical trials (RCTs) using acupuncture for COPD will be considered. The selection of the studies, data abstraction and validation will be performed independently by two researchers. Methodological quality will be assessed with the Cochrane risk of bias. DISSEMINATION: The systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print. Updates of the review will be conducted to inform and guide the healthcare practice and policy. TRIAL REGISTRATION NUMBER: PROSPERO 2013: CRD42013004824. PMID- 24776712 TI - Canadian Academy of Sport and Exercise Medicine position statement: Neuromuscular training programs can decrease anterior cruciate ligament injuries in youth soccer players. PMID- 24776711 TI - Development of evidence-based Australian medication-related indicators of potentially preventable hospitalisations: a modified RAND appropriateness method. AB - OBJECTIVE: Indicators of potentially preventable hospitalisations have been adopted internationally as a measure of health system performance; however, few assess appropriate processes of care around medication use, that if followed may prevent hospitalisation. The aim of this study was to develop and validate evidence-based medication-related indicators of potentially preventable hospitalisations. SETTING: Australian primary healthcare. PARTICIPANTS: Medical specialists, general practitioners and pharmacists. A modified RAND appropriateness method was used for the development of medication-related indicators of potentially preventable hospitalisations, which included a literature review, assessment of the strength of the supporting evidence base, an initial face and content validity by an expert panel, followed by an independent assessment of indicators by an expert clinical panel across various disciplines, using an online survey. PRIMARY OUTCOME MEASURE: Analysis of ratings was performed on the four key elements of preventability; the medication-related problem must be recognisable, the adverse outcomes foreseeable and the causes and outcomes identifiable and controllable. RESULTS: A total of 48 potential indicators across all major disease groupings were developed based on level III evidence or greater, that were independently assessed by 78 expert clinicians (22.1% response rate). The expert panel considered 29 of these (60.4%) sufficiently valid. Of these, 21 (72.4%) were based on level I evidence. CONCLUSIONS: This study provides a set of face and content validated indicators of medication-related potentially preventable hospitalisations, linking suboptimal processes of care and medication use with subsequent hospitalisation. Further analysis is required to establish operational validity in a population based sample, using an administrative health database. Implementation of these indicators within routine monitoring of healthcare systems will highlight those conditions where hospitalisations could potentially be avoided through improved medication management. PMID- 24776713 TI - Changing Epidemiology of Methylphenidate Prescriptions in the Community: A Multifactorial Model. AB - OBJECTIVE: To examine dispensing patterns of methylphenidate (MPH) to determine how socioeconomic status (SES), ethnocultural affiliation, and gender affect the medical treatment of ADHD. METHOD: We reviewed MPH prescription records for year 2011 of children aged 6 to 18, from regional pharmacies serving homogeneous neighborhoods. RESULTS: MPH prescriptions showed an increase in prevalence from 4.2% to 7.5% in the years 2007 to 2011, respectively. Jewish children were four times more likely to be prescribed MPH than Arab children, with significant discrepancies along SES and gender lines ( p < .001). Higher SES and male gender were associated with greater use of MPH. General pediatric prescription rates of MPH in all communities increased by 85%, compared with year 2007 statistics ( p < .001). CONCLUSION: Prescription patterns for MPH in children reflect diagnostic patterns of ADHD that appear to be heavily influenced by additive factors of SES, cultural attitudes, and gender. Dispensing data provide valuable information for targeting underserved groups and defining potential areas of abuse. PMID- 24776715 TI - Validation of multiple-breath washout equipment: from bench to clinic and possible pitfalls. PMID- 24776716 TI - Colonic anastomosis with a doxycycline-coated stent: an experimental study in a porcine model. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are supposed to be potential drug targets to prevent leakage after colonic anastomosis. A method of colonic anastomosis by using a stent coated with doxycycline, a MMP inhibitor, was developed and its safety and feasibility, as well as the effect of locally regulating MMPs, were evaluated by comparing with the conventional method or the method with a doxycycline-free stent. METHODS: 48 pigs were assigned randomly to doxycycline-coated stent anastomosis group (DSA), doxycycline-free stent anastomosis group (SA), or conventional anastomosis group (CA). In each group, pigs were subdivided into four subgroups according to postoperative observation time (3, 7, 14, and 30 days). Healing of anastomosis and expressions of MMP-2/9 were evaluated. RESULTS: No anastomotic leakage, stricture or necrosis was observed in the DSA group. No significant difference of bursting pressure was found between the DSA group and SA group. Relative expression of MMP-2 in the DSA group was significantly lower than in the SA group on postoperative days 3 and 7. No significant differences of hydroxyproline content, microvessel density and TGF beta1 level were found in these groups. CONCLUSION: These results suggested this method was feasible and safe for colonic anastomosis with the advantage of locally inhibiting MMPs. PMID- 24776714 TI - ADHD, Conduct Disorder, Substance Use Disorder, and Nonprescription Stimulant Use. AB - OBJECTIVE: To assess whether the relationship of an ADHD diagnosis by adolescence to nonprescription stimulant use in adulthood is direct or indirect, via Conduct Disorder (CD) and/or Substance Use Disorder (SUD). METHOD: Data were obtained from multiple waves of interviews and questionnaires completed by 551 community based participants when they were between the mean ages of 14.1 and 36.6 years. RESULTS: The results of the structural equation model (SEM) supported both a direct association between early ADHD and later nonprescription stimulant use ( B = .18, z = 2.74) and the relationship from ADHD to later nonprescription stimulant use ( B = .01, z = 1.72) via CD and SUD. CONCLUSION: The longitudinal data supporting these paths suggest that efforts to prevent and treat the misuse of nonprescription stimulants may be more effective if attention is paid to those with a history of ADHD, as well as to those who also had CD and SUD. PMID- 24776717 TI - Growth in preterm infants until 36 weeks' postmenstrual age is close to target recommendations. AB - OBJECTIVE: To establish the determinants of weight, length and head circumference changes during their initial hospitalization in very-low-birth-weight preterm infants. SUBJECTS/METHODS: A prospective cohort study was performed. Weight z score and percentage of target dietary intakes (TDIs) were prospectively determined daily during the first 5 weeks of life in a group of preterm infants (n = 111, birth weight <1,500 g, gestational age <34 weeks). Weight, length and head circumference at 36 weeks' postmenstrual age (PMA) were recorded. A mixed effects regression model was used to evaluate changes in weight z-score during the first 5 weeks of life. Simple Pearson correlations and stepwise logistic regression were used to determine the relationship between fetal growth, illness severity, nutritional intake and growth at 36 weeks' PMA. RESULTS: Weight z-score decreased significantly in all infants during the first 5 weeks of life from 0.92 +/- 0.66 at birth to -1.89 +/- 0.65 at 5 weeks. The variation of weight z score during the first 5 weeks of life was influenced by weight z-score at birth, energy and protein intakes and gestational age. Mean energy and protein intakes were 95.5 and 86.4% of TDIs. Weight z-score fell to -2.05 +/- 0.64 at 36 weeks' PMA. Birth weight z-score was significantly correlated with weight z-score at 36 weeks (R2 = 0.71; p < 0.001). Severity of illness influenced the weight z-score at 36 weeks. CONCLUSION: Despite achieving a protein and energy intake close to the described target intake, the rate of growth in our infants was lower than indicated by the intrauterine growth curve. Lower gestational age, lower birth weight and severe illness had a negative effect on growth. PMID- 24776718 TI - Deep-water longline fishing has reduced impact on Vulnerable Marine Ecosystems. AB - Bottom trawl fishing threatens deep-sea ecosystems, modifying the seafloor morphology and its physical properties, with dramatic consequences on benthic communities. Therefore, the future of deep-sea fishing relies on alternative techniques that maintain the health of deep-sea ecosystems and tolerate appropriate human uses of the marine environment. In this study, we demonstrate that deep-sea bottom longline fishing has little impact on vulnerable marine ecosystems, reducing bycatch of cold-water corals and limiting additional damage to benthic communities. We found that slow-growing vulnerable species are still common in areas subject to more than 20 years of longlining activity and estimate that one deep-sea bottom trawl will have a similar impact to 296-1,719 longlines, depending on the morphological complexity of the impacted species. Given the pronounced differences in the magnitude of disturbances coupled with its selectivity and low fuel consumption, we suggest that regulated deep-sea longlining can be an alternative to deep-sea bottom trawling. PMID- 24776719 TI - Climate services to improve public health. AB - A high level expert panel discussed how climate and health services could best collaborate to improve public health. This was on the agenda of the recent Third International Climate Services Conference, held in Montego Bay, Jamaica, 4-6 December 2013. Issues and challenges concerning a demand led approach to serve the health sector needs, were identified and analysed. Important recommendations emerged to ensure that innovative collaboration between climate and health services assist decision-making processes and the management of climate-sensitive health risk. Key recommendations included: a move from risk assessment towards risk management; the engagement of the public health community with both the climate sector and development sectors, whose decisions impact on health, particularly the most vulnerable; to increase operational research on the use of policy-relevant climate information to manage climate- sensitive health risks; and to develop in-country capacities to improve local knowledge (including collection of epidemiological, climate and socio-economic data), along with institutional interaction with policy makers. PMID- 24776720 TI - An interactive wireless communication system for visually impaired people using city bus transport. AB - Visually impaired people have difficulty accessing information about public transportation systems. Several systems have been developed for assisting visually impaired and blind people to use the city bus. Most systems provide only one-way communication and require high-cost and complex equipment. The purpose of this study is to reduce the difficulties faced by visually impaired people when taking city buses, using an interactive wireless communication system. The system comprised a user module and a bus module to establish a direct one-to-one connection. When the user inputs 4-digit numbers, the user module immediately sends out the information. If the bus module receives the matched bus number, it buzzes and the warning LED flashes to notify the bus driver that someone is waiting to board on the bus. User tests were conducted by two visually impaired people in a simulated vehicle and a city bus. The success rate of interactive wireless communication, recognizing the arrival of the bus and boarding the correct bus reached 100% in all of the tests. The interactive wireless communication aid system is a valid and low-cost device for assisting visually impaired people to use city buses. PMID- 24776721 TI - A survey aimed at general citizens of the US and Japan about their attitudes toward electronic medical data handling. AB - OBJECTIVES: To clarify the views of the general population of two countries (US and Japan), concerning the handling of their medical records electronically. METHODS: We contacted people nationwide in the United States at random via Random Digit Dialing (RDD) to obtain 200 eligible responders. The questionnaire was for obtaining the information on their attitudes towards handling of their medical records, disclosure of the name of disease, secondary usage of information, compiling their records into a lifelong medical record, and access to their medical records on the Internet. We had also surveyed people of Shizuoka prefecture in Japan using same questionnaires sent by mail, for which we obtained 457 valid answers. RESULTS: Even in an unidentifiable manner, US people feel profit-oriented usage of medical data without specific consent is not acceptable. There is a significant difference between usage of unidentifiable medical data for profit (about 50% feel negatively) and for official/research purposes (about 30% feel negatively). About 60% of the US responders have a negative view on the proposal that unidentifiable medical information be utilized for profit by private companies to attain healthcare cost savings. As regards compiling a lifelong medical record, positive answers and negative answers are almost equally divided in the US (46% vs. 38%) while more positive attitudes are seen in Japan (74% vs. 12%). However, any incentive measures aimed at changing attitudes to such a compiling including the discount of healthcare costs or insurance fees are unwelcomed by people regardless of their age or health condition in both surveys. Regarding the access to their own medical record via the Internet, 38% of the US responders feel this is unacceptable while 50.5% were willing to accept it. CONCLUSIONS: Participants from the US think that the extent of the sharing their identifiable medical records should be limited to the doctors-in-charge and specified doctors referred to by their own doctors. On the other hand, Japanese people find it acceptable for doctors of the same hospital to share their medical records. Even in unidentifiable manner, people in both countries think the profits resulting from the secondary use of medical records should be returned to the public or patients. With regard to compiling a lifelong medical record, participants from the US provided both positive answers and negative answers, while more positive attitudes were observed in Japan. However, any incentives or measures aimed at changing attitudes towards such a compilation, including provision of a discount on healthcare costs or insurance fees, were not welcomed by participants from US as well as those from Japan, regardless of their age or health condition. PMID- 24776722 TI - Cyanobacterial xenobiotics as evaluated by a Caenorhabditis elegans neurotoxicity screening test. AB - In fresh waters cyanobacterial blooms can produce a variety of toxins, such as microcystin variants (MCs) and anatoxin-a (ANA). ANA is a well-known neurotoxin, whereas MCs are hepatotoxic and, to a lesser degree, also neurotoxic. Neurotoxicity applies especially to invertebrates lacking livers. Current standardized neurotoxicity screening methods use rats or mice. However, in order to minimize vertebrate animal experiments as well as experimental time and effort, many investigators have proposed the nematode Caenorhabditis elegans as an appropriate invertebrate model. Therefore, four known neurotoxic compounds (positive compounds: chlorpyrifos, abamectin, atropine, and acrylamide) were chosen to verify the expected impacts on autonomic (locomotion, feeding, defecation) and sensory (thermal, chemical, and mechanical sensory perception) functions in C. elegans. This study is another step towards successfully establishing C. elegans as an alternative neurotoxicity model. By using this protocol, anatoxin-a adversely affected locomotive behavior and pharyngeal pumping frequency and, most strongly, chemotactic and thermotactic behavior, whereas MC-LR impacted locomotion, pumping, and mechanical behavior, but not chemical sensory behavior. Environmental samples can also be screened in this simple and fast way for neurotoxic characteristics. The filtrate of a Microcystis aeruginosa culture, known for its hepatotoxicity, also displayed mild neurotoxicity (modulated short-term thermotaxis). These results show the suitability of this assay for environmental cyanotoxin-containing samples. PMID- 24776723 TI - Behavioural change, indoor air pollution and child respiratory health in developing countries: a review. AB - Indoor air pollution caused by the indoor burning of solid biomass fuels has been associated with Acute Respiratory Infections such as pneumonia amongst children of less than five years of age. Behavioural change interventions have been identified as a potential strategy to reduce child indoor air pollution exposure, yet very little is known about the impact of behavioural change interventions to reduce indoor air pollution. Even less is known about how behaviour change theory has been incorporated into indoor air pollution behaviour change interventions. A review of published studies spanning 1983-2013 suggests that behavioural change strategies have the potential to reduce indoor air pollution exposure by 20%-98% in laboratory settings and 31%-94% in field settings. However, the evidence is: (1) based on studies that are methodologically weak; and (2) have little or no underlying theory. The paper concludes with a call for more rigorous studies to evaluate the role of behavioural change strategies (with or without improved technologies) to reduce indoor air pollution exposure in developing countries as well as interventions that draw more strongly on existing behavioural change theory and practice. PMID- 24776724 TI - Biofilm formation and antimicrobial susceptibility of Staphylococcus epidermidis strains from a hospital environment. AB - The hospital environment microflora comprise a wide variety of microorganisms which are more or less pathogenic and where staphylococci are one of the most common types. The aim of the presented study was to evaluate the prevalence of the biofilm forming coagulase-negative staphylococci (CoNS) in a hospital environment as a risk factor for nosocomial infections. Among 122 isolated and tested strains of CoNS the most frequent were: S. epidermidis-32 strains, S. haemolyticus-31 strains, S. capitis subsp. capitis- 21 strains, S. hominis-11 strains, S. cohnii subsp. cohnii-nine strains. In case of CoNS, the main molecule responsible for intercellular adhesion is a polysaccharide intercellular adhesin (PIA), encoded on the ica gene operon. The analysis revealed the presence of the icaADBC operon genes in 46.88% of S. epidermidis isolates. IcaA and icaD were present in 34.38% and 28.13% of strains respectively while IcaC gene was present in 37.50% of strains. IcaB gene was found in 21.88% of S. epidermidis strains. In 15 (63%) strains all icaADBC operon genes were observed. The assessment of antibacterial drugs susceptibility demonstrated that analyzed CoNS strains were highly resistant to macrolides and lincosamides and more sensitive to rifampicin and linezolid. Our data indicates that the hospital environment can be colonized by biofilm forming coagulase-negative staphylococci and transmission of these strains can cause an increased risk of serious nosocomial infections. PMID- 24776725 TI - Drinking Water Quality Guidelines across Canadian provinces and territories: jurisdictional variation in the context of decentralized water governance. AB - This article presents the first comprehensive review and analysis of the uptake of the Canadian Drinking Water Quality Guidelines (CDWQG) across Canada's 13 provinces and territories. This review is significant given that Canada's approach to drinking water governance is: (i) highly decentralized and (ii) discretionary. Canada is (along with Australia) only one of two Organization for Economic Cooperation and Development (OECD) member states that does not comply with the World Health Organization's (WHO) recommendation that all countries have national, legally binding drinking water quality standards. Our review identifies key differences in the regulatory approaches to drinking water quality across Canada's 13 jurisdictions. Only 16 of the 94 CDWQG are consistently applied across all 13 jurisdictions; five jurisdictions use voluntary guidelines, whereas eight use mandatory standards. The analysis explores three questions of central importance for water managers and public health officials: (i) should standards be uniform or variable; (ii) should compliance be voluntary or legally binding; and (iii) should regulation and oversight be harmonized or delegated? We conclude with recommendations for further research, with particular reference to the relevance of our findings given the high degree of variability in drinking water management and oversight capacity between urban and rural areas in Canada. PMID- 24776726 TI - Hoechst tagging: a modular strategy to design synthetic fluorescent probes for live-cell nucleus imaging. AB - We report a general strategy to create small-molecule fluorescent probes for the nucleus in living cells. Our strategy is based on the attachment of the DNA binding Hoechst compound to a fluorophore of interest. Using this approach, simple fluorescein, BODIPY, and rhodamine dyes were readily converted to novel turn-on fluorescent nucleus-imaging probes. PMID- 24776728 TI - Target molecule-responsive hydrogels designed via molecular imprinting using bisphenol A as a template. AB - Target molecule-responsive hydrogels with beta-cyclodextrin (beta-CD) were prepared via molecular imprinting using bisphenol A (BPA) as a template. BPA imprinted hydrogels showed greater shrinkage than non-imprinted hydrogels because CD ligands arranged at suitable positions formed CD-BPA-CD complexes that acted as crosslinks. PMID- 24776729 TI - Phytodermatitis in eastern Turkey: a retrospective, observational study. AB - BACKGROUND: Plant life is extremely diverse, with a great deal of geographic and seasonal variation. Consequently, the range of reported adverse reactions is large, and there are important differences worldwide in the incidence and prevalence of these reactions. Systemic ingestion of some plants containing furocoumarins can cause erythema, edema, vesicle and bulla formation and later hyperpigmentation, after exposure to sunlight. They may at times exhibit clinical manifestations that mimic angioedema, and rarely progress to necrosis. This condition is named phyto-phototoxic reaction. OBJECTIVE: Our aim was to identify plant dermatitis such as allergic contact dermatitis, irritant contact dermatitis, and phyto-phototoxic dermatitis in eastern Turkey and to add new data to the literature. METHODS: Thirty patients diagnosed with plant dermatitis were evaluated retrospectively. The demographic and clinical characteristics of the patients (age, gender, the type of dermatitis, and the name of the causative plant) were recorded. CONCLUSIONS: A phyto-phototoxic reaction to Chenopodium album (Chenopodiaceae) developed in 12 cases. Irritant contact dermatitis developed due to Ranunculus kotschyi (Ranunculaceae) in 11 cases. The other plants studied were Malva neglecta Wallr (Malvaceae), Mandragora autumnalis (Solanaceae), Eryngium billardieri (Apiaceae), Ceratocephalus falcatus (Ranunculaceae), Ranunculus damascenus (Ranunculaceae), and Plantago lanceolata (Plantaginaceae). PMID- 24776730 TI - Label-free selective SERS detection of PCB-77 based on DNA aptamer modified SiO2@Au core/shell nanoparticles. AB - A label-free approach to selective detection of 3,3',4,4'-tetrachlorobiphenyl (PCB77) using aptamer modified silica-Au/core-shell nanoparticles (denoted as SiO2@Au core/shell NPs) through surface enhanced Raman scattering (SERS) spectroscopy was proposed. The devised system consisted of SiO2@Au core/shell NPs fixed on the amino-silane functionalized glass slides with the PCB77-binding aptamers attached covalently to the gold surfaces through a thiol linker. The aptamers made of single-stranded DNA (ssDNA) oligomers with one end standing on the Au surface changed the conformation upon conjugation with PCB77, which correspondingly caused the spectral response of the ssDNA oligomers. The intensity ratio I(660 cm(-1))/I(736 cm(-1)) decreased with the amount of PCB77 added, which thus allowed us to measure trace amounts of PCB77 in a selective and quantitative way. This work therefore demonstrates that the design of aptamer modified SiO2@Au core/shell NPs can be utilized for label-free SERS detection of persistent organic pollutants (POPs) in the environment. PMID- 24776731 TI - Thyroid gland. Unlocking the potential of thyroid autoantibodies. PMID- 24776732 TI - Thyroid gland: Do nuclear power plants increase the risk of thyroid cancer? PMID- 24776734 TI - Primary cutaneous follicle center lymphoma, diffuse type, with atypical clinical features. PMID- 24776735 TI - Predictive value of gastrin levels for the diagnosis of gastric enterochromaffin like cell hyperplasia in patients with Hashimoto's thyroiditis. AB - AIM: Gastrin and chromogranin A (CgA) levels have been tested for the diagnosis of enterochromaffin-like cell hyperplasia (ECLH) in patients with type 1 diabetes and autoimmune atrophic gastritis but not for patients with Hashimoto's thyroiditis (HT). The aim of the study was to develop receiver operating characteristic (ROC) curves for gastrin and CgA levels and other clinical and biochemical parameters, as means for pretest probability of gastric ECLH in patients with HT. METHODS: A total of 115 patients with HT were prospectively studied for a median period of 4 (2-7) years. Gastrin, CgA, vitamin B12, anti parietal cell antibodies, free thyroxine, thyrotropin, and neuron-specific enolase levels were measured. Their predictive values were calculated according to the histological findings for ECLH diagnosis from esophagogastroduodenoscopy obtained biopsies. RESULTS: Thirteen patients (11.3%) had ECLH. The areas under the curve for gastrin and CgA level were 0.898 (p < 0.001) and 0.853 (p < 0.001), respectively. The product sensitivity * specificity was 0.803 and 0.653 for gastrin and CgA levels >89.5 and >89.1 ng/ml, respectively. Two and 4 patients with ECLH had normal gastrin and CgA levels, respectively. The most specific combined parameters predicting ECLH were gastrin >89.5 ng/ml with concomitant low B12 levels (96.1% specificity). CONCLUSION: Gastrin levels have high diagnostic accuracy for ECLH identification in patients with HT, and are highly specific when combined with low B12 levels. However, they should be interpreted with caution, as some patients may harbor gastric ECLH even if gastrin levels are not increased, necessitating further follow-up. PMID- 24776733 TI - Hyperinsulinaemic androgen excess in adolescent girls. AB - Hyperinsulinaemic androgen excess is the most common cause of hirsutism, acne and menstrual irregularity in adolescent girls. Here, we propose that the disorder frequently originates from an absolute or relative excess of lipids in adipose tissue, and from associated changes in insulin sensitivity, gonadotropin secretion and ovarian androgen release. Girls from populations with genotypes attuned to nutritionally harsh conditions seem to be particularly vulnerable to the development of hyperinsulinaemic androgen excess in today's obesogenic environment. We propose that hirsutism, hyperandrogenaemia and menstrual irregularity (>=2 years after menarche) is used as a diagnostic triad for the disorder. No pharmacological therapy has been approved for girls with androgen excess; however, lifestyle intervention is essential to reduce adiposity. In girls without obesity who are not sexually active, insulin sensitization has more broadly normalizing effects than estradiol-progestogen combinations. The early recognition of girls at risk of developing hyperinsulinaemic androgen excess might enable prevention in childhood. PMID- 24776736 TI - Fluorescence fluctuations and equivalence classes of Ca2+ imaging experiments. AB - Ca2+ release into the cytosol through inositol 1,4,5-trisphosphate receptors (IP3Rs) plays a relevant role in numerous physiological processes. IP3R-mediated Ca2+ signals involve Ca2+-induced Ca2+-release (CICR) whereby Ca2+ release through one open IP3R induces the opening of other channels. IP3Rs are apparently organized in clusters. The signals can remain localized (i.e., Ca2+ puffs) if CICR is limited to one cluster or become waves that propagate between clusters. Ca2+ puffs are the building blocks of Ca2+ waves. Thus, there is great interest in determining puff properties, especially in view of the current controversy on the spatial distribution of activatable IP3Rs. Ca2+ puffs have been observed in intact cells with optical techniques proving that they are intrinsically Ca2+ dyes, slow exogenous buffers (e.g., EGTA) to disrupt inter-cluster CICR and UV photolyzable caged IP3. Single-wavelength dyes increase their fluorescence upon calcium binding producing images that are strongly dependent on their kinetic, transport and photophysical properties. Determining the artifacts that the imaging setting introduces is particularly relevant when trying to analyze the smallest Ca2+ signals. In this paper we introduce a method to estimate the expected signal-to-noise ratio of Ca2+ imaging experiments that use single wavelength dyes. The method is based on the Number and rightness technique. It involves the performance of a series of experiments and their subsequent analysis in terms of a fluorescence fluctuation model with which the model parameters are quantified. Using the model, the expected signal-to-noise ratio is then computed. Equivalence classes between different experimental conditions that produce images with similar signal-to-noise ratios can then be established. The method may also be used to estimate the smallest signals that can reliably be observed with each setting. PMID- 24776737 TI - Resilience after 3/11: structural brain changes 1 year after the Japanese earthquake. PMID- 24776738 TI - Ethanol-induced epigenetic regulations at the Bdnf gene in C57BL/6J mice. AB - High ethanol intake is well known to induce both anxiolytic and anxiogenic effects, in correlation with chromatin remodeling in the amygdaloid brain region and deficits in cell proliferation and survival in the hippocampus of rodents. Whether only moderate but chronic ethanol intake in C57BL/6J mice could also have an impact on chromatin remodeling and neuroplasticity was addressed here. Chronic ethanol consumption in a free choice paradigm was found to induce marked changes in the expression of genes implicated in neural development and histone post translational modifications in the mouse hippocampus. Transcripts encoding neural bHLH activators and those from Bdnf exons II, III and VI were upregulated, whereas those from Bdnf exon VIII and Hdacs were downregulated by ethanol compared with water consumption. These ethanol-induced changes were associated with enrichment in both acetylated H3 at Bdnf promoter PVI and trimethylated H3 at PII and PIII. Conversely, acetylated H3 at PIII and PVIII and trimethylated H3 at PVIII were decreased in ethanol-exposed mice. In parallel, hippocampal brain derived neurotrophic factor (BDNF) levels and TrkB-mediated neurogenesis in the dentate gyrus were significantly enhanced by ethanol consumption. These results suggest that, in C57BL/6J mice, chronic and moderate ethanol intake produces marked epigenetic changes underlying BDNF overexpression and downstream hippocampal neurogenesis. PMID- 24776739 TI - Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919) specific effects on hippocampal gray matter structure. AB - In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well characterized samples of healthy individuals of West-European ancestry (Munster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G * E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF alpha, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G * E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations. PMID- 24776740 TI - Copy number variation in schizophrenia in Sweden. AB - Schizophrenia (SCZ) is a highly heritable neuropsychiatric disorder of complex genetic etiology. Previous genome-wide surveys have revealed a greater burden of large, rare copy number variations (CNVs) in SCZ cases and identified multiple rare recurrent CNVs that increase risk of SCZ although with incomplete penetrance and pleiotropic effects. Identification of additional recurrent CNVs and biological pathways enriched for SCZ CNVs requires greater sample sizes. We conducted a genome-wide survey for CNVs associated with SCZ using a Swedish national sample (4719 cases and 5917 controls). High-confidence CNV calls were generated using genotyping array intensity data, and their effect on risk of SCZ was measured. Our data confirm increased burden of large, rare CNVs in SCZ cases as well as significant associations for recurrent 16p11.2 duplications, 22q11.2 deletions and 3q29 deletions. We report a novel association for 17q12 duplications (odds ratio=4.16, P=0.018), previously associated with autism and mental retardation but not SCZ. Intriguingly, gene set association analyses implicate biological pathways previously associated with SCZ through common variation and exome sequencing (calcium channel signaling and binding partners of the fragile X mental retardation protein). We found significantly increased burden of the largest CNVs (>500 kb) in genes present in the postsynaptic density, in genomic regions implicated via SCZ genome-wide association studies and in gene products localized to mitochondria and cytoplasm. Our findings suggest that multiple lines of genomic inquiry--genome-wide screens for CNVs, common variation and exonic variation--are converging on similar sets of pathways and/or genes. PMID- 24776742 TI - [Bevacizumab associated with radiotherapy and temozolomide as a first line treatment for high-grade gliomas: one answer but too many questions]. PMID- 24776741 TI - De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. AB - Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 * 10(-)(5), corrected P=2.1 * 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders. PMID- 24776743 TI - A novel, potent dual inhibitor of Arg-gingipains and Lys-gingipain as a promising agent for periodontal disease therapy. AB - The periodontal pathogen Porphyromonas gingivalis produces a unique class of cysteine proteinases termed gingipains that comprises Arg-gingipain (Rgp) and Lys gingipain (Kgp). Growing evidence indicates that these 2 types of gingipains synergistically contribute to the entire virulence of the organism and increase the risk of periodontal disease (PD) by disrupting the host immune system and degrading the host tissue and plasma proteins. Therefore, a dual inhibitor of both gingipains would have attractive clinical potential for PD therapy. In this study, a novel, potent, dual inhibitor of Rgp and Kgp was developed through structure-based drug design, and its biological potency was evaluated in vitro and in vivo. This inhibitor had low nanomolar inhibitory potency (Ki=40 nM for Rgp, Ki=0.27 nM for Kgp) and good selectivity for host proteases and exhibited potent antibacterial activity against P. gingivalis by abrogating its manifold pathophysiological functions. The therapeutic potential of this inhibitor in vivo was also verified by suppressing the vascular permeability that was enhanced in guinea pigs by the organism and the gingival inflammation in beagle dog PD models. These findings suggest that a dual inhibitor of Rgp and Kgp would exhibit noteworthy anti-inflammatory activity in the treatment of PD. PMID- 24776744 TI - Maintaining PGC-1alpha expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function. AB - During pathological hypertrophy, peroxisome proliferator-activated receptor coactivator 1alpha (PGC-1alpha) is repressed in concert with reduced mitochondrial oxidative capacity and fatty acid oxidation (FAO). We therefore sought to determine if maintaining or increasing PGC-1alpha levels in the context of pressure overload hypertrophy (POH) would preserve mitochondrial function and prevent contractile dysfunction. Pathological cardiac hypertrophy was induced using 4 wk of transverse aortic constriction (TAC) in mice overexpressing the human PGC-1alpha genomic locus via a bacterial artificial chromosome (TG) and nontransgenic controls (Cont). PGC-1alpha levels were increased by 40% in TG mice and were sustained following TAC. Although TAC-induced repression of FAO genes and oxidative phosphorylation (oxphos) genes was prevented in TG mice, mitochondrial function and ATP synthesis were equivalently impaired in Cont and TG mice after TAC. Contractile function was also equally impaired in Cont and TG mice following TAC, as demonstrated by decreased +dP/dt and ejection fraction and increased left ventricular developed pressure and end diastolic pressure. Conversely, capillary density was preserved, in concert with increased VEGF expression, while apoptosis and fibrosis were reduced in TG relative to Cont mice after TAC. Hence, sustaining physiological levels of PGC-1alpha expression following POH, while preserving myocardial vascularity, does not prevent mitochondrial and contractile dysfunction. PMID- 24776746 TI - A new protective role for S100A9 in regulation of neutrophil recruitment during invasive pneumococcal pneumonia. AB - The S100A8/A9 heterodimer is abundantly expressed by myeloid cells, especially neutrophils, but its mechanism of action is only partially determined. In this study we investigated S100A8/A9 involvement in the host response to Streptococcus pneumoniae infection making use of S100a9(-/-) mice that lack heterodimer expression in myeloid cells. S100a9(-/-) mice that were infected intranasally with pneumococci rapidly succumbed, with 80% mortality after 48 h, whereas the majority of wild-type mice recovered. Over this time period, S100a9(-/-) mice displayed an average 6-fold reduction in circulating and lung-recruited neutrophils. Taqman analysis of S100a9(-/-) lungs revealed decreased production of a dominant subset of 5 cytokines and chemokines associated with neutrophil recruitment. The greatest differential was with the cytokine granulocyte colony stimulating factor (G-CSF) that causes bone marrow release of neutrophils into the circulation (1900-fold difference at 48 h). Treating S100a9(-/-) mice with G CSF reversed their increased susceptibility to infection by enhancing both circulating neutrophils and neutrophil recruitment into infected lungs, by reducing pneumococcal colony forming units, and by elevation of chemokine CXCL1, cytokine IL-6, and endogenous G-CSF proteins. Thus S100A9, potentially with its partner S100A8, makes a major contribution in the host response to pneumococcal infection by increasing circulating neutrophils principally regulation of G-CSF production. PMID- 24776745 TI - Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice. AB - The ferritin core is composed of fine nanoparticulate Fe(3+) oxohydroxide, and we have developed a synthetic mimetic, nanoparticulate Fe(3+) polyoxohydroxide (nanoFe(3+)). The aim of this study was to determine how dietary iron derived in this fashion is absorbed in the duodenum. Following a 4 wk run-in on an Fe deficient diet, mice with intestinal-specific disruption of the Fpn-1 gene (Fpn KO), or littermate wild-type (WT) controls, were supplemented with Fe(2+) sulfate (FeSO4), nanoFe(3+), or no added Fe for a further 4 wk. A control group was Fe sufficient throughout. Direct intestinal absorption of nanoFe(3+) was investigated using isolated duodenal loops. Our data show that FeSO4 and nanoFe(3+) are equally bioavailable in WT mice, and at wk 8 the mean +/- SEM hemoglobin increase was 18 +/- 7 g/L in the FeSO4 group and 30 +/- 5 g/L in the nanoFe(3+) group. Oral iron failed to be utilized by Fpn-KO mice and was retained in enterocytes, irrespective of the iron source. In summary, although nanoFe(3+) is taken up directly by the duodenum its homeostasis is under the normal regulatory control of dietary iron absorption, namely via ferroportin-dependent efflux from enterocytes, and thus offers potential as a novel oral iron supplement. PMID- 24776747 TI - Systemic effects of ophthalmic cyclopentolate on body weight in neonatal mice. AB - BACKGROUND: Cyclopentolate is standardly used in ophthalmologic examinations of neonates to facilitate screening for retinopathy of prematurity. Reports of systemic effects have raised concerns of an increased risk of feeding intolerance after the examinations. OBJECTIVES: The goal of this study was to evaluate systemic concentrations of cyclopentolate after ophthalmic administration, as well as assess changes in weight as an indirect measure of alteration in feeding. METHODS: Neonatal mice were randomized into three groups to simulate a neonatal model for ophthalmic medication administration. The cyclopentolate group received a one-time administration of tetracaine, cyclopentolate, and phenylephrine ophthalmologic solutions in accordance with the protocol used at the children's hospital. The placebo group received the same ophthalmic drop administration, except for normal saline in place of cyclopentolate, and the control group received no ophthalmic drops and minimal handling. Daily weights and serum samples to measure systemic concentrations of cyclopentolate post-ophthalmic administration were assessed at baseline and for 7 days following drop administration. RESULTS: Analysis of serum levels demonstrated detectability of systemic cyclopentolate after ophthalmic administration as early as 30 min (86 ng/ml), 1 h (60 ng/ml), and 24 h (6.2 ng/ml). There were also differences in weight gained on following ophthalmic administration observed between the cyclopentolate group and placebo group, with the cyclopentolate group weighing significantly less on days 3 and 7 (p = 0.02). CONCLUSIONS: RESULTS indicate cyclopentolate is absorbed systemically and instillation of cyclopentolate decreases weight gain in neonatal mice compared to placebo. These preclinical findings provide rationale for further studies in neonatal patients. PMID- 24776749 TI - Salvage craniotomy for extradural hematoma in the adult patient. PMID- 24776750 TI - High performance C/S composite cathodes with conventional carbonate-based electrolytes in Li-S battery. AB - High stable C/S composites are fabricated by a novel high-temperature sulfur infusion into micro-mesoporous carbon method following with solvent cleaning treatment. The C/S composite cathodes show high Coulombic efficiency, long cycling stability and good rate capability in the electrolyte of 1.0 M LiPF6 + EC/DEC (1:1 v/v), for instance, the reversible capacity of the treated C/S-50 (50% S) cathode retains around 860 mAh/g even after 500 cycles and the Coulombic efficiency is close to 100%, which demonstrates the best electrochemical performance of carbon-sulfur composite cathodes using the carbonate-based electrolyte reported to date. It is believed that the chemical bond of C-S is responsible for the superior electrochemical properties in Li-S battery, that is, the strong interaction between S and carbon matrix significantly improves the conductivity of S, effectively buffers the structural strain/stress caused by the large volume change during lithiation/delithiation, completely eliminates the formation of high-order polysulfide intermediates, and substantially avoids the shuttle reaction and the side reaction between polysulfide anions and carbonate solvent, and thus enables the C/S cathode to use conventional carbonate-based electrolytes and achieve outstanding electrochemical properties in Li-S battery. The results may substantially contribute to the progress of the Li-S battery technology. PMID- 24776752 TI - A heavy metal- and oxidant-free, one-pot synthesis of pyridines and fused pyridines based on a Lewis acid-catalyzed multicomponent reaction. AB - The InCl3-catalyzed sequential multicomponent reaction between 2-furfurylamine, beta-dicarbonyl compounds and alpha,beta-unsaturated aldehydes in ethanol, followed by microwave irradiation in solvent-free conditions, afforded good to excellent yields of highly substituted pyridines, with loss of a 2-furylmethyl side chain. The method was also adapted to the synthesis of quinolones, isoquinolines, phenanthridines and more complex fused pyridine systems. PMID- 24776753 TI - Minimally invasive oesophagectomy: preliminary results after introduction of an intrathoracic anastomosis. AB - BACKGROUND: Intrathoracic anastomosis after oesophagectomy has recently been associated with reduced functional morbidity compared to a cervical anastomosis. METHODS: From January 2011 until August 2012, all operable patients were scheduled to undergo minimally invasive oesophagectomy (MIE) with intrathoracic anastomosis. Patient characteristics, complications, morbidity and mortality were prospectively registered and analysed. RESULTS: Forty-five patients underwent MIE with intrathoracic stapled end-to-side anastomosis. Major changes in operative technique were made 2 times due to non-satisfactory results, dividing the patients into 3 groups. One patient in group 1 died. The anastomotic leakage rate decreased from 44% in group 1 to 0% in groups 2 and 3 (p = 0.007). The pulmonary complication rate decreased from 67% in group 1 to 44% in group 2 (not significant, NS) and 22% in group 3 (p = 0.04). The median hospital stay decreased from 17 days in group 1 to 14 days in group 2 (NS) and 8 days in group 3 (p < 0.001). There were no stenoses, no dilatations and no patients with recurrent laryngeal nerve palsy. CONCLUSIONS: The introduction of the intrathoracic anastomosis led to favourable functional results but was initially associated with considerable morbidity. RESULTS improved after changing operative techniques, but the learning curve may also be responsible. PMID- 24776754 TI - Comparison of body surface area versus weight-based growth hormone dosing for girls with Turner syndrome. AB - BACKGROUND/AIMS: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost effectiveness of GH treatment dosed per m2 BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS). METHODS: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies. RESULTS: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m2 equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m2 BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m2 BSA. CONCLUSION: Dosing GH per m2 BSA is at least as efficacious as dosing per kg BW, and is more cost-effective. PMID- 24776751 TI - The current view for the silencing of the spindle assembly checkpoint. AB - Chromosome bipolar attachment is achieved when sister kinetochores are attached by microtubules emanating from opposite spindle poles, and this process is essential for faithful chromosome segregation during anaphase. A fundamental question in cell biology is how cells ensure that chromosome segregation only occurs after bipolar attachment. It is well documented that unattached kinetochores activate the spindle assembly checkpoint (SAC) to delay chromosome segregation. Therefore, the silencing of the SAC is thought to trigger anaphase onset, but how correct chromosome attachment is coupled with SAC silencing and the subsequent anaphase onset is poorly understood. The establishment of chromosome bipolar attachment not only results in the occupancy of kinetochores by microtubules but also applies tension on sister kinetochores. A long-standing debate is whether the kinetochore attachment (occupancy) or the tension silences the SAC. Recent work in budding yeast reveals the SAC silencing network SSN that prevents SAC silencing prior to tension generation at kinetochores. Therefore, this signaling pathway ensures that SAC silencing and the subsequent anaphase onset occur only after chromosome bipolar attachment applies tension on chromosomes. This review will summarize the recent advances in the understanding of the SAC silencing process. PMID- 24776755 TI - Tests of HPGe- and scintillation-based backpack gamma-radiation survey systems. AB - The performance of three different backpack-mounted gamma-radiation survey systems has been investigated. The systems are based on a LaBr3:Ce detector and a NaI(Tl) detector both with active volume dimensions of 76.2 mm in diameter and 76.2 mm length and a 123% relative efficiency HPGe detector. The detection limits of the systems were tested in a controlled outdoor environment in Sweden, followed by field tests of the HPGe- and LaBr3:Ce-based systems at the site of a radioactive waste repository in Georgia (in the Caucasus region of Eurasia). The results showed that the high efficiency HPGe detector performed significantly better than similar sized LaBr3:Ce and NaI(Tl) detectors, however, the HPGe detector was significantly heavier than the other systems. The use of different analysis methods revealed that creating maps of the survey area was the best method for offline analysis of survey data collected from a large area. Using off site personnel for analysis of the data proved to be beneficial. PMID- 24776756 TI - Cotton fabric-based electrochemical device for lactate measurement in saliva. AB - Lactate measurement is vital in clinical diagnostics especially among trauma and sepsis patients. In recent years, it has been shown that saliva samples are an excellent applicable alternative for non-invasive measurement of lactate. In this study, we describe a method for the determination of lactate concentration in saliva samples by using a simple and low-cost cotton fabric-based electrochemical device (FED). The device was fabricated using template method for patterning the electrodes and wax-patterning technique for creating the sample placement/reaction zone. Lactate oxidase (LOx) enzyme was immobilised at the reaction zone using a simple entrapment method. The LOx enzymatic reaction product, hydrogen peroxide (H2O2) was measured using chronoamperometric measurements at the optimal detection potential (-0.2 V vs. Ag/AgCl), in which the device exhibited a linear working range between 0.1 to 5 mM, sensitivity (slope) of 0.3169 MUA mM(-1) and detection limit of 0.3 mM. The low detection limit and wide linear range were suitable to measure salivary lactate (SL) concentration, thus saliva samples obtained under fasting conditions and after meals were evaluated using the FED. The measured SL varied among subjects and increased after meals randomly. The proposed device provides a suitable analytical alternative for rapid and non-invasive determination of lactate in saliva samples. The device can also be adapted to a variety of other assays that requires simplicity, low-cost, portability and flexibility. PMID- 24776757 TI - Antheraea pernyi silk fibroin-coated PEI/DNA complexes for targeted gene delivery in HEK 293 and HCT 116 cells. AB - Polyethylenimine (PEI) has attracted much attention as a DNA condenser, but its toxicity and non-specific targeting limit its potential. To overcome these limitations, Antheraea pernyi silk fibroin (ASF), a natural protein rich in arginyl-glycyl-aspartic acid (RGD) peptides that contains negative surface charges in a neutral aqueous solution, was used to coat PEI/DNA complexes to form ASF/PEI/DNA ternary complexes. Coating these complexes with ASF caused fewer surface charges and greater size compared with the PEI/DNA complexes alone. In vitro transfection studies revealed that incorporation of ASF led to greater transfection efficiencies in both HEK (human embryonic kidney) 293 and HCT (human colorectal carcinoma) 116 cells, albeit with less electrostatic binding affinity for the cells. Moreover, the transfection efficiency in the HCT 116 cells was higher than that in the HEK 293 cells under the same conditions, which may be due to the target bonding affinity of the RGD peptides in ASF for integrins on the HCT 116 cell surface. This result indicated that the RGD binding affinity in ASF for integrins can enhance the specific targeting affinity to compensate for the reduction in electrostatic binding between ASF-coated PEI carriers and cells. Cell viability measurements showed higher cell viability after transfection of ASF/PEI/DNA ternary complexes than after transfection of PEI/DNA binary complexes alone. Lactate dehydrogenase (LDH) release studies further confirmed the improvement in the targeting effect of ASF/PEI/DNA ternary complexes to cells. These results suggest that ASF-coated PEI is a preferred transfection reagent and useful for improving both the transfection efficiency and cell viability of PEI based nonviral vectors. PMID- 24776758 TI - Synthesis, properties and applications of biodegradable polymers derived from diols and dicarboxylic acids: from polyesters to poly(ester amide)s. AB - Poly(alkylene dicarboxylate)s constitute a family of biodegradable polymers with increasing interest for both commodity and speciality applications. Most of these polymers can be prepared from biobased diols and dicarboxylic acids such as 1,4 butanediol, succinic acid and carbohydrates. This review provides a current status report concerning synthesis, biodegradation and applications of a series of polymers that cover a wide range of properties, namely, materials from elastomeric to rigid characteristics that are suitable for applications such as hydrogels, soft tissue engineering, drug delivery systems and liquid crystals. Finally, the incorporation of aromatic units and alpha-amino acids is considered since stiffness of molecular chains and intermolecular interactions can be drastically changed. In fact, poly(ester amide)s derived from naturally occurring amino acids offer great possibilities as biodegradable materials for biomedical applications which are also extensively discussed. PMID- 24776759 TI - SREBP-1 has a prognostic role and contributes to invasion and metastasis in human hepatocellular carcinoma. AB - Sterol regulatory element-binding protein 1 (SREBP-1) is a well-known nuclear transcription factor involved in lipid synthesis. Recent studies have focused on its functions in tumor cell proliferation and apoptosis, but its role in cell migration and invasion, especially in hepatocellular carcinoma (HCC), is still unclear. In this study, we found that the expression of SREBP-1 in HCC tissues was significantly higher than those in matched tumor-adjacent tissues (p < 0.05). SREBP-1 was expressed at significantly higher levels in patients with large tumor size, high histological grade and advanced tumor-node-metastasis (TNM) stage (p < 0.05). The positive expression of SREBP-1 correlated with a worse 3-year overall and disease-free survival of HCC patients (p < 0.05). Additionally, SREBP-1 was an independent factor for predicting both 3-year overall and disease-free survival of HCC patients (p < 0.05). In vitro studies revealed that downregulation of SREBP-1 inhibited cell proliferation and induced apoptosis in both HepG2 and MHCC97L cells (p < 0.05). Furthermore, wound healing and transwell assays showed that SREBP-1 knockdown prominently inhibited cell migration and invasion in both HepG2 and MHCC97L cells (p < 0.05). These results suggest that SREBP-1 may serve as a prognostic marker in HCC and may promote tumor progression by promoting cell growth and metastasis. PMID- 24776760 TI - Generation of bladder urothelium from human pluripotent stem cells under chemically defined serum- and feeder-free system. AB - Human stem cells are promising sources for bladder regeneration. Among several possible sources, pluripotent stem cells are the most fascinating because they can differentiate into any cell type, and proliferate limitlessly in vitro. Here, we developed a protocol for differentiation of human pluripotent stem cells (hPSCs) into bladder urothelial cells (BUCs) under a chemically defined culture system. We first differentiated hPSCs into definitive endoderm (DE), and further specified DE cells into BUCs by treating retinoic acid under a keratinocyte specific serum free medium. hPSC-derived DE cells showed significantly expressed DE-specific genes, but did not express mesodermal or ectodermal genes. After DE cells were specified into BUCs, they notably expressed urothelium-specific genes such as UPIb, UPII, UPIIIa, P63 and CK7. Immunocytochemistry showed that BUCs expressed UPII, CK8/18 and P63 as well as tight junction molecules, E-CADHERIN and ZO-1. Additionally, hPSCs-derived BUCs exhibited low permeability in a FITC dextran permeability assay, indicating BUCs possessed the functional units of barrier on their surfaces. However, BUCs did not express the marker genes of other endodermal lineage cells (intestine and liver) as well as mesodermal or ectodermal lineage cells. In summary, we sequentially differentiated hPSCs into DE and BUCs in a serum- and feeder-free condition. Our differentiation protocol will be useful for producing cells for bladder regeneration and studying normal and pathological development of the human bladder urothelium in vitro. PMID- 24776761 TI - Nanoinformatics: emerging databases and available tools. AB - Nanotechnology has arisen as a key player in the field of nanomedicine. Although the use of engineered nanoparticles is rapidly increasing, safety assessment is also important for the beneficial use of new nanomaterials. Considering that the experimental assessment of new nanomaterials is costly and laborious, in silico approaches hold promise. Several major challenges in nanotechnology indicate a need for nanoinformatics. New database initiatives such as ISA-TAB-Nano, caNanoLab, and Nanomaterial Registry will help in data sharing and developing data standards, and, as the amount of nanomaterials data grows, will provide a way to develop methods and tools specific to the nanolevel. In this review, we describe emerging databases and tools that should aid in the progress of nanotechnology research. PMID- 24776762 TI - Simultaneous microwave extraction and separation of volatile and non-volatile organic compounds of boldo leaves. From lab to industrial scale. AB - Microwave extraction and separation has been used to increase the concentration of the extract compared to the conventional method with the same solid/liquid ratio, reducing extraction time and separate at the same time Volatile Organic Compounds (VOC) from non-Volatile Organic Compounds (NVOC) of boldo leaves. As preliminary study, a response surface method has been used to optimize the extraction of soluble material and the separation of VOC from the plant in laboratory scale. The results from the statistical analysis revealed that the optimized conditions were: microwave power 200 W, extraction time 56 min and solid liquid ratio of 7.5% of plants in water. Lab scale optimized microwave method is compared to conventional distillation, and requires a power/mass ratio of 0.4 W/g of water engaged. This power/mass ratio is kept in order to upscale from lab to pilot plant. PMID- 24776763 TI - Study on biopharmaceutics classification and oral bioavailability of a novel multikinase inhibitor NCE for cancer therapy. AB - Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P(eff)) of NCE was determined using single pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 MUg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 * 10-4 mg.min-1.cm-2. The P(eff) value of NCE in all intestinal segments was more proximate to the high permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates. PMID- 24776764 TI - The association of IL28B genotype with the histological features of chronic hepatitis C is HCV genotype dependent. AB - The interleukin 28B (IL28B) rs12979860 polymorphism is associated with treatment outcome in hepatitis C virus (HCV) genotype 1 and 4 patients. Its association with the histological features of chronic hepatitis C and disease severity needs further clarifications. To assess the correlation between IL28B genotype, HCV genotype and liver biopsy findings in untreated patients. MATERIALS AND METHODS: Pre-treatment liver biopsies from 335 HCV Caucasian patients (59% males, age 50 years) enrolled in the MIST study were staged for fibrosis and inflammation according to the METAVIR and the Ishak scoring systems; steatosis was dichotomized as <5% or >=5%. IL28B was typed by Taqman Single Nucleotide Polymorphism (SNP) genotyping assay. HCV genotype was 1 in 151 (45%), 2 in 99 (30%), 3 in 50 (15%) and 4 in 35 (10%) patients. IL28B genotype was CC in 117 (34%), CT in 166 (49%) and TT in 52 (15%). At univariate analysis, the IL28B CC genotype was associated with severe portal inflammation in HCV-1 patients (CC vs. CT/TT: 86% vs. 63%, p = 0.005), severe lobular inflammation in HCV-2 patients (CC vs. CT/TT: 44% vs. 23%, p = 0.03), and less fatty infiltration in HCV-1 patients (CC vs. CT/TT: 72% vs. 51%, p = 0.02). Despite the lack of any association between IL28B and fibrosis stage, in HCV-3 patients IL28B CC correlated with METAVIR F3-F4 (CC vs. CT/TT: 74% vs. 26%, p = 0.05). At multivariate analysis, the genotype CC remained associated with severe portal inflammation in HCV-1, only (Odds Ratio (OR): 95% Confidence Interval (CI): 3.24 (1.23-8.51)). IL28B genotype is associated with the histological features of chronic hepatitis C in a HCV genotype dependent manner, with CC genotype being independently associated with severe portal inflammation. PMID- 24776765 TI - Potential activity of fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. seeds as estrogen receptor antagonist based on cytotoxicity and molecular modelling studies. AB - Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 uM. At 11.2 uM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-alpha (hERalpha) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERalpha receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERalpha. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation. PMID- 24776766 TI - Clinical severity of Gitelman syndrome determined by serum magnesium. AB - BACKGROUND/AIMS: Normomagnesemia is considered atypical in Gitelman syndrome (GS). Here, we describe clinical, pathological and genetic characteristics in Chinese GS patients with or without hypomagnesemia in order to determine whether serum magnesium concentration indicates the severity of the disease. METHODS: 7 normomagnesemic and 25 hypomagnesemic GS patients who were confirmed by direct sequencing of SLC12A3 gene were included. Clinical manifestation and laboratory tests were documented. Supine and upright plasma renin activity, angiotensin II and aldosterone were determined by radioimmunoassay. Transient receptor potential channel melastatin subtype 6 (TRPM6) was detected by immunohistochemistry in paraffin-embedded renal biopsy sections of 12 GS patients. 14 patients with glomerular minor lesion served as controls. The distribution of the mutations on the predicted NCC protein was analyzed and compared between two subgroups. RESULTS: Clinical manifestations, electrolyte abnormalities, metabolic alkalosis and renin-angiotensin-aldosterone system activation were found to be milder in normomagnesemic compared with the hypomagnesemic group. Compared with glomerular minor lesion controls, the TRPM6-positive area was significantly decreased in hypomagnesemic patients (4.96 +/- 1.88 vs. 8.63 +/- 2.67%) while it was near normal (7.82 +/- 5.23%) in 2 normomagnesemic GS patients. A higher percentage of intracellular mutations was observed in normomagnesemic patients than hypomagnesemic patients (92.31 vs. 56.52%, p = 0.02). CONCLUSIONS: Normomagnesemia is not rare in GS. Serum magnesium may indicate the severity of GS. PMID- 24776767 TI - The DNA methylome and transcriptome of different brain regions in schizophrenia and bipolar disorder. AB - Extensive changes in DNA methylation have been observed in schizophrenia (SC) and bipolar disorder (BP), and may contribute to the pathogenesis of these disorders. Here, we performed genome-scale DNA methylation profiling using methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) on two brain regions (including frontal cortex and anterior cingulate) in 5 SC, 7 BP and 6 normal subjects. Comparing with normal controls, we identified substantial differentially methylated regions (DMRs) in these two brain regions of SC and BP. To our surprise, different brain regions show completely distinct distributions of DMRs across the genomes. In frontal cortex of both SC and BP subjects, we observed widespread hypomethylation as compared to normal controls, preferentially targeting the terminal ends of the chromosomes. In contrast, in anterior cingulate, both SC and BP subjects displayed extensive gain of methylation. Notably, in these two brain regions of SC and BP, only a few DMRs overlapped with promoters, whereas a greater proportion occurs in introns and intergenic regions. Functional enrichment analysis indicated that important psychiatric disorder-related biological processes such as neuron development, differentiation and projection may be altered by epigenetic changes located in the intronic regions. Transcriptome analysis revealed consistent dysfunctional processes with those determined by DMRs. Furthermore, DMRs in the same brain regions from SC and BP could successfully distinguish BP and/or SC from normal controls while differentially expressed genes could not. Overall, our results support a major role for brain-region-dependent aberrant DNA methylation in the pathogenesis of these two disorders. PMID- 24776771 TI - Cancer genetics: Exosomally derived miR-105 destroys tight junctions. PMID- 24776769 TI - Natural selection and infectious disease in human populations. AB - The ancient biological 'arms race' between microbial pathogens and humans has shaped genetic variation in modern populations, and this has important implications for the growing field of medical genomics. As humans migrated throughout the world, populations encountered distinct pathogens, and natural selection increased the prevalence of alleles that are advantageous in the new ecosystems in both host and pathogens. This ancient history now influences human infectious disease susceptibility and microbiome homeostasis, and contributes to common diseases that show geographical disparities, such as autoimmune and metabolic disorders. Using new high-throughput technologies, analytical methods and expanding public data resources, the investigation of natural selection is leading to new insights into the function and dysfunction of human biology. PMID- 24776772 TI - Evolution: Planting genes. PMID- 24776774 TI - The aromatic character of thienopyrrole-modified 20pi-electron porphyrinoids. AB - Magnetically induced current densities and current pathways have been calculated for six tautomers of substituted and nonsubstituted core-modified porphyrinoids with one of the pyrrole rings replaced by a thienopyrrole moiety. The calculations show that the aromatic properties of the porpyrinoid macrocycle are strongly influenced by the ethyl-formate substituent at the pyrrole ring of the thienopyrrole moiety, whereas the alkyl substituents at the beta positions of the ordinary pyrrole rings have a much smaller effect on the ring-current strength. The ethyl-formate substitution decreases the strength of the paratropic ring current of the macrocycle rendering the energetically lowest tautomer nonaromatic. The substituted tautomers with both porphyrinoid hydrogens inside the macroring are antiaromatic according to the ring current criterion, whereas the three tautomers with one hydrogen at the outer nitrogen of the thienopyrrole moiety are nonaromatic. Current calculations on the nonsubstituted core-modified porphyrinoids show that they are all antiaromatic. The antiaromatic thienopyrrole modified porphyrinoids are dominated by paratropic ring currents inside the macroring and a weaker diatropic current along the periphery of the macroring. The nonaromatic porphyrinoid tautomers sustain significant ring currents around the thienopyrrole moiety, whereas the other pyrrole rings are practically nonaromatic. PMID- 24776773 TI - Antidepressant and neuroprotective effect of the Chinese herb kaixinsan against lentiviral shRNA knockdown brain-derived neurotrophic factor-induced injury in vitro and in vivo. AB - Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. Previous studies have demonstrated that the herbal medicine formula, 'kaixinsan' (KXS), could ameliorate the severity of depression and increase cAMP response element-binding protein expression. There is direct evidence suggesting that the reduction of the BDNF protein in specific brain sites can provoke depressive-like behaviour or affect neurogenesis in vivo. However, the biological mechanisms between the antidepressant and neuroprotective effect of KXS and the alterations in BDNF levels in in vivo and in vitro models remain unclear. Using BDNF knockdown mediated by lentiviral vectors (LV-shBDNF-3) transfected with primary hippocampal neurons and following injection into the dentate gyrus of the hippocampus, it was demonstrated that a reduction in BDNF expression affects cell viability and animal behaviours associated with depression. During treatment with KXS after the lentiviral shRNA silencing of BDNF in cell and animal, cell viability, body weight, the sucrose preference test (SPT), the open field test (OFT) the Morris Water Maze (MWM) task and BDNF expression were measured. KXS attenuated LV-shBDNF 3-induced cell death in primary hippocampal neurons and also improved the sucrose intake in SPT, ambulatory response in OFT and learning ability in MWM against LV shBDNF-3-induced depressive-like syndromes. Moreover, immunoblot analysis confirmed that KXS could reverse LV-shBDNF-induced BDNF reduction either in vitro or in vivo. These findings provide substantial evidence for supporting a neurotrophic hypothesis of depression and specify BDNF targets for potential antidepressant interventions. Moreover, the antagonism between LV-shRNA BDNF knockdown and KXS may depend on multiple compounds with synergistic mechanisms that modulate the different signal transduction networks directly or indirectly, increasing BDNF expression and exerting its neuroprotective and antidepressant like effects. PMID- 24776775 TI - Emergency medicine development in the Nordic countries. PMID- 24776776 TI - Noninvasive ventilation in the emergency department: are protocols the key? PMID- 24776777 TI - Protocols for and training on noninvasive positive pressure ventilation in emergency departments. PMID- 24776770 TI - The rise of regulatory RNA. AB - Discoveries over the past decade portend a paradigm shift in molecular biology. Evidence suggests that RNA is not only functional as a messenger between DNA and protein but also involved in the regulation of genome organization and gene expression, which is increasingly elaborate in complex organisms. Regulatory RNA seems to operate at many levels; in particular, it plays an important part in the epigenetic processes that control differentiation and development. These discoveries suggest a central role for RNA in human evolution and ontogeny. Here, we review the emergence of the previously unsuspected world of regulatory RNA from a historical perspective. PMID- 24776778 TI - Evaluation of screening criteria for palliative care consultation in the MICU: a multihospital analysis. AB - BACKGROUND: There are currently no comprehensive studies in critical care settings that have set out to examine the association of palliative care screening criteria with multiple, adverse patient outcomes. METHODS: A 7-item palliative care screen was developed from consensus reports. Medical intensive care unit (MICU) nurses at four hospitals screened patients upon admission during a 16-week period. Outcomes included percentage of patients screened and their percentage with consultations ordered. Patient screen scores were compared with mortality, hospice discharge and length of stay (LOS). RESULTS: During the period, 1071 patients were admitted to MICUs, of which, 59.3% were screened; 35.3% of patients screened positive. Patients with positive screens (n=225) were more likely to have a consult ordered (33.6% vs 3.4%; p<0.001), and likelihood of consult increased with higher screen scores. Patients with positive screens had significantly longer hospital and MICU LOS (p<0.001), and had increased risk of inpatient mortality (p<0.001) and hospice discharge (p<0.001). Criteria of 'admission from a skilled nursing facility' and 'readmission to the ICU' were significant predictors of LOS; 'cancer,' 'post cardiac arrest,' and 'team perceived need' were predictors of the composite variable of mortality/hospice discharge. 'End-stage dementia' and 'intracranial bleed' were not predictive of adverse outcomes. CONCLUSIONS: Decisions on the appropriateness for palliative care consultation in the MICU can be aided using a trigger screen. We recommend the use of this screen be considered in the MICU with the suggested revisions. Additional studies are needed to determine if the use of the trigger screen is associated with improved clinical outcomes. PMID- 24776779 TI - Palliative medicine specialists' causal explanations for depression in the palliative care setting: a qualitative in-depth interview study. AB - OBJECTIVE: Medical practitioners have different causal explanations for depression, and may have greater difficulty in explaining causality of depression in the palliative care setting. The objective of this study was to investigate and describe the causal explanations of depression in the palliative care setting, from the perspective of palliative medicine specialists. METHODS: Palliative medicine specialists practising in Australia were recruited and purposively sampled. Individual semistructured, in-depth interviews were conducted to explore their explanatory models of depression, including a focus on causal explanations. Nine participants were interviewed to reach data saturation. Interview transcripts were analysed for themes. RESULTS: Six themes for causal explanations of depression were identified: (1) Depression is inexplicable; (2) Biological explanations-primarily neurotransmitter depletion; (3) Psychological explanations-including reaction to circumstances, inability to accept illness and dying, diminished self, and coping mechanisms; (4) Social explanations-including inadequate social support, and contribution from modern medicine and societal norms; (5) Interrelationships between causal factors-mainly multifactoriality; (6) Different explanation for de novo and pre-existing depressions. Participants also articulated a link between causal explanations and clinical interventions. CONCLUSIONS: Palliative medicine specialists hold causal explanations of depression that align with the biopsychosocial and vulnerability-stress models. They use multiple individual explanations with diverse theoretical underpinnings, and largely view depression as multifactorial in causality. Given that causal explanations are linked to clinical interventions, these findings have implications for clinical practice and medical education. PMID- 24776780 TI - Assessment of clients' satisfaction with health service deliveries at jimma university specialized hospital. AB - BACKGROUND: Client satisfaction is considered as one of the desired outcomes of health care and it is directly related with utilization of health services. Nonetheless, there is no adequate information on users' perception about the service provided in the hospital after the implementation of Business process re engineering reform. Hence, the objective of this study was to assess the perceived levels of clients' satisfaction with health services rendered at Jimma University Specialized Hospital. METHODS: A cross sectional study was conducted from March 1-8, 2010 on a sample of 422 service users of the hospital using systematic random sampling technique. Data was collected using structured questionnaire and analyzed by SPSS for windows version 16.0. Statistical tests were employed where necessary at 0.05 level of significance. RESULT: The questionnaire was administered to a total of 422 clients , of which, 51.7 % were male, about 33.4% of the respondents were between the age group 25-34, 41.% of the clients were illiterates, 60% were from the rural areas and 57.8 % received the service free of charge. The findings of the study showed that the overall client satisfaction level with the health services rendered at the hospital was 77%. Satisfaction was reported to be highest (82.7%) with the way the doctors examined them and on the other hand dissatisfaction was reported to be highest (46.9%) by respondents with the time spent to see a doctor. Furthermore, satisfaction with the health care was found to have a significant association with the age of the respondents (p=0.034) and educational level of the respondents (p=0.003). CONCLUSION: This study showed higher clients' satisfaction level in the University Specialized Hospital when compared to previous studies in the same hospital as well as other similar studies in the country. Lack of drugs and supplies, poor information provision, long waiting time, poor cleanliness, lack of privacy and inadequate visiting hours, were found to be the major causes of dissatisfaction. Therefore, the Hospital management should understand these weak service areas and plan for a better service delivery. PMID- 24776781 TI - Current-induced spin polarization on metal surfaces probed by spin-polarized positron beam. AB - Current-induced spin polarization (CISP) on the outermost surfaces of Au, Cu, Pt, Pd, Ta, and W nanoscaled films were studied using a spin-polarized positron beam. The Au and Cu surfaces showed no significant CISP. In contrast, the Pt, Pd, Ta, and W films exhibited large CISP (3~15% per input charge current of 10(5) A/cm(2)) and the CISP of Ta and W were opposite to those of Pt and Pd. The sign of the CISP obeys the same rule in spin Hall effect suggesting that the spin orbit coupling is mainly responsible for the CISP. The magnitude of the CISP is explained by the Rashba-Edelstein mechanism rather than the diffusive spin Hall effect. This settles a controversy, that which of these two mechanisms dominates the large CISP on metal surfaces. PMID- 24776782 TI - Response to comment on: "Pemphigus induced by radiotherapy for breast cancer: an instance of immunocompromised district". PMID- 24776783 TI - Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use. AB - There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3-4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03-0.05 mg/kg/day starting from the age of 8-10 years onward scan be considered. PMID- 24776784 TI - Post-translational cleavage and self-interaction of the phytoplasma effector SAP11. AB - Phytoplasmas are insect-transmitted intracellular plant bacterial pathogens that secrete effector molecules into host cells that interfere with the host's developmental or metabolic processes. Recently, the secreted Aster Yellows phytoplasma strain Witches' Broom protein11 (SAP11) has been shown to act as a virulence factor that alters the development, hormone biosynthesis, phosphate (Pi) homeostasis, and defense responses in the affected plants. We found that SAP11 undergoes proteolytic processing in planta and self-interaction in vitro. These biochemical studies provide foundational insights necessary for the functional characterization of SAP11; however, the biological relevance of post translational cleavage and self-interaction of SAP11 to its role as a virulence factor warrants further investigation. PMID- 24776785 TI - Acquisition of conditioned eyeblink responses is modulated by cerebellar tDCS. AB - BACKGROUND: Classical conditioning of the eyeblink reflex is a simple form of motor learning which depends on the integrity of the cerebellum. Acquisition of conditioned eyeblink responses is markedly reduced in patients with cerebellar disorders. Noninvasive transcranial direct current stimulation (tDCS) has been reported to modify the excitability of the cerebellar cortex. OBJECTIVE: The aim of the study was to assess whether acquisition of conditioned eyeblink responses (CR) is altered by cerebellar tDCS. METHODS: A standard delay conditioning paradigm with a 540 ms tone as conditioned stimulus (CS) coterminating with a 100 ms air puff as unconditioned stimulus (US) was used in a total of 30 healthy subjects (18 female, 12 male, mean age 23.4 +/- 1.9 years). One hundred paired CS US trials and 30 extinction CS alone trials were given. tDCS (2 mA intensity, ramp like onset) was applied over the right cerebellar hemisphere ipsilaterally to the US during the acquisition phase. Subjects were randomly assigned to three groups (n = 10) using anodal, cathodal or sham stimulation. The investigator as well as the participants was blinded to the stimulation modality. RESULTS: CR acquisition was significantly enhanced by anodal tDCS (mean total CR incidence 73.4 +/- 25.2%) and significantly reduced by cathodal stimulation (12.6 +/- 17.2%) compared to sham stimulation (43.8 +/- 24.1%). During anodal tDCS CR onset occurred significantly earlier, that is mean onset of responses was shifted closer to CS onset. CONCLUSION: Acquisition and timing of conditioned eyeblink responses is modified by cerebellar tDCS in a polarity dependent manner. PMID- 24776786 TI - Clinician accessible tools for GUI computational models of transcranial electrical stimulation: BONSAI and SPHERES. AB - Computational models of brain current flow during transcranial electrical stimulation (tES), including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), are increasingly used to understand and optimize clinical trials. We propose that broad dissemination requires a simple graphical user interface (GUI) software that allows users to explore and design montages in real-time, based on their own clinical/experimental experience and objectives. We introduce two complimentary open-source platforms for this purpose: BONSAI and SPHERES. BONSAI is a web (cloud) based application (available at neuralengr.com/bonsai) that can be accessed through any flash-supported browser interface. SPHERES (available at neuralengr.com/spheres) is a stand-alone GUI application that allow consideration of arbitrary montages on a concentric sphere model by leveraging an analytical solution. These open-source tES modeling platforms are designed go be upgraded and enhanced. Trade-offs between open-access approaches that balance ease of access, speed, and flexibility are discussed. PMID- 24776788 TI - Synthesis and evaluation of turn-on fluorescent probes for imaging steroid sulfatase activities in cells. AB - We have synthesized and evaluated two self-immobilizing, turn-on fluorescent probes carrying a coumarin molecular framework for imaging intracellular human steroid sulfatase (STS) activity. The 8-fluoromethyl coumarin derivative, which gives stronger fluorescence response in the incubation study with STS preparations, was successfully applied to visualize STS activity in cells. PMID- 24776787 TI - The quest for Luschka's duct: an eponym leading a life of its own? AB - BACKGROUND: The German anatomist Hubert von Luschka gave name to several structures in the human body. One of great discussion is the duct of Luschka, part of the biliary system. There are different descriptions of the duct of Luschka. This might lead to confusion in the debate and as to what therapy should best be provided in case of an injured duct of Luschka. METHODS: We reviewed the literature on descriptions of Luschka's duct and studied the original German descriptions by Hubert von Luschka. RESULTS: While reading the original work by von Luschka on the hepatobiliary system, we were not able to find a description of either one of the two structures that are nowadays referred to as 'the duct of Luschka'. CONCLUSIONS: von Luschka maybe never described the so-called duct of Luschka. He did, however, describe the peribiliary glands in the intra- and extrahepatic bile ducts and gallbladder wall. These might have been misinterpreted as a duct running along the gallbladder fossa. The lack of a clear definition is the reason for the development of rather confusing and sometimes misleading eponyms as the duct of Luschka. The eponym 'duct of Luschka' should, therefore, better not be used. PMID- 24776789 TI - Hemodialysis patient outcomes: provider characteristics. AB - BACKGROUND/AIMS: Physician characteristics are associated with differential performance on quality measures and patient outcomes in several medical fields. We aimed to determine whether characteristics of physicians who provide care to dialysis patients were associated with patient outcomes. METHODS: This cohort study used United States Renal Data System data for patients who initiated in center hemodialysis between October 1, 2003, and September 30, 2006 (n = 91,276). Patient characteristics were defined and physicians identified from Part B Medicare claims for outpatient dialysis services submitted during months 4-6 of hemodialysis. Physician characteristics were obtained from the American Medical Association Physician Master File. Associations of physician characteristics with 1-year patient mortality and first hospitalization were determined using Cox proportional hazards analysis; associations with quality of care (defined by influenza vaccination and waitlisting for kidney transplant) were determined using logistic regression. RESULTS: Physician characteristics were not associated with patient mortality. After adjustment for patient and other provider characteristics, patients whose physicians had practiced longer or were in administrative, research, or teaching practices were more likely to be hospitalized; patients whose providers practiced in smaller metropolitan statistical areas (MSAs) were less likely. More years since training was associated with greater chance of waitlisting, and practicing in smaller MSAs with less chance. Graduation from a foreign medical school, practicing in smaller MSAs, and travelling farther from office to dialysis unit were associated with greater odds of influenza vaccination. CONCLUSIONS: Several characteristics of physicians seeing incident outpatient hemodialysis patients were associated with hospitalization and quality of care, but none with mortality. PMID- 24776790 TI - Prenatal exposure to DDE and PCB 153 and respiratory health in early childhood: a meta-analysis. AB - BACKGROUND: Persistent organic pollutants may affect the immune and respiratory systems, but available evidence is based on small study populations. We studied the association between prenatal exposure to dichlorodiphenyldichloroethylene (DDE) and polychlorinated biphenyl 153 (PCB 153) and children's respiratory health in European birth cohorts. METHODS: We included 4608 mothers and children enrolled in 10 birth cohort studies from 7 European countries. Outcomes were parent-reported bronchitis and wheeze in the first 4 years of life. For each cohort, we performed Poisson regression analyses, modeling occurrences of the outcomes on the estimates of cord-serum concentrations of PCB 153 and DDE as continuous variables (per doubling exposure) and as cohort-specific tertiles. Summary estimates were obtained through random-effects meta-analyses. RESULTS: The risk of bronchitis or wheeze (combined variable) assessed before 18 months of age increased with increasing DDE exposure (relative risk [RR] per doubling exposure = 1.03 [95% confidence interval = 1.00-1.07]). When these outcomes were analyzed separately, associations appeared stronger for bronchitis. We also found an association between increasing PCB 153 exposure and bronchitis in this period (RR per doubling exposure = 1.06 [1.01-1.12]) but not between PCB 153 and wheeze. No associations were found between either DDE or PCB 153 and ever-wheeze assessed after 18 months. Inclusion of both compounds in the models attenuated risk estimates for PCB 153 tertiles of exposure, whereas DDE associations were more robust. CONCLUSION: This large meta-analysis suggests that prenatal DDE exposure may be associated with respiratory health symptoms in young children (below 18 months), whereas prenatal PCB 153 levels were not associated with such symptoms. PMID- 24776791 TI - Expressed Sense of Self by People With Alzheimer's Disease in a Support Group Interpreted in Terms of Agency and Communion. AB - The self is constructed in cooperation with other people and social context influences how people perceive and express it. People with Alzheimer's disease (AD) often receive insufficient support in constructing their preferred selves, but little is known about how they express themselves together with other people with AD. In accordance with Harre's social constructionist theory of self, this study aimed to describe how five people with mild and moderate AD express their Self 2 (i.e., their personal attributes and life histories) in a support group with a facilitator experienced in communicating with people with AD. The participants' expressions of their Self 2 were analyzed with qualitative abductive content analysis and interpreted in terms of agency and communion and a lack of agency and communion. The findings highlight the importance of supporting a sense of agency and communion when assisting people with AD in constructing their self. PMID- 24776792 TI - Quality of Life and Psychological Distress Among Older Adults: The Role of Living Arrangements. AB - This study asks (a) What are the relationships between types of living arrangements and psychological well-being for older adults? and (b) How do these relationships differ by gender? Data come from the 2010 wave of the National Health Interview Survey and include non-institutionalized adults aged 65 and older (N = 4,862). Dependent variables include self-rated quality of life and psychological distress. The study finds that older adults living alone or with others fare worse than those living with a spouse only. Yet, the outcomes of different types of living arrangements for older adults vary by gender. Women living with others are at greater risk of worse quality of life and serious psychological distress than men. Programs and policies must be responsive to the diverse needs of this population, rather than attempting a "one-size-fits-all" approach to housing and community-based services designed to promote older adults' psychological well-being and independence. PMID- 24776793 TI - Contribution of nucleus accumbens core (AcbC) to behavior control during a learned resting period: introduction of a novel task and lesion experiments. AB - In recent years, the study of resting state neural activity has received much attention. To better understand the roles of different brain regions in the regulation of behavioral activity in an arousing or a resting period, we developed a novel behavioral paradigm (8-arm food-foraging task; 8-arm FFT) using the radial 8-arm maze and examined how AcbC lesions affect behavioral execution and learning. Repetitive training on the 8-arm FFT facilitated motivation of normal rats to run quickly to the arm tips and to the center platform before the last-reward collection. Importantly, just after this point and before confirmation of no reward at the next arm traverse, locomotor activity decreased. This indicates that well-trained rats can predict the absence of the reward at the end of food seeking and then start another behavior, namely planned resting. Lesions of the AcbC after training selectively impaired this reduction of locomotor activity after the last-reward collection without changing activity levels before the last-reward collection. Analysis of arm-selection patterns in the lesioned animals suggests little influence of the lesion in the ability to predict the reward absence. AcbC lesions did not change exploratory locomotor activity in an open-field test in which there were no rewards. This suggests that the AcbC controls the activity level of planned resting behavior shaped by the 8 arm FFT. Rats receiving training after AcbC lesioning showed a reduction in motivation for reward seeking. Thus, the AcbC also plays important roles not only in controlling the activity level after the last-reward collection but also in motivational learning for setting the activity level of reward-seeking behavior. PMID- 24776794 TI - Signal amplification and transduction in phytochrome photosensors. AB - Sensory proteins must relay structural signals from the sensory site over large distances to regulatory output domains. Phytochromes are a major family of red light-sensing kinases that control diverse cellular functions in plants, bacteria and fungi. Bacterial phytochromes consist of a photosensory core and a carboxy terminal regulatory domain. Structures of photosensory cores are reported in the resting state and conformational responses to light activation have been proposed in the vicinity of the chromophore. However, the structure of the signalling state and the mechanism of downstream signal relay through the photosensory core remain elusive. Here we report crystal and solution structures of the resting and activated states of the photosensory core of the bacteriophytochrome from Deinococcus radiodurans. The structures show an open and closed form of the dimeric protein for the activated and resting states, respectively. This nanometre-scale rearrangement is controlled by refolding of an evolutionarily conserved 'tongue', which is in contact with the chromophore. The findings reveal an unusual mechanism in which atomic-scale conformational changes around the chromophore are first amplified into an angstrom-scale distance change in the tongue, and further grow into a nanometre-scale conformational signal. The structural mechanism is a blueprint for understanding how phytochromes connect to the cellular signalling network. PMID- 24776795 TI - Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. AB - Astrocytes, the most abundant cells in the central nervous system, promote synapse formation and help to refine neural connectivity. Although they are allocated to spatially distinct regional domains during development, it is unknown whether region-restricted astrocytes are functionally heterogeneous. Here we show that postnatal spinal cord astrocytes express several region-specific genes, and that ventral astrocyte-encoded semaphorin 3a (Sema3a) is required for proper motor neuron and sensory neuron circuit organization. Loss of astrocyte encoded Sema3a leads to dysregulated alpha-motor neuron axon initial segment orientation, markedly abnormal synaptic inputs, and selective death of alpha- but not of adjacent gamma-motor neurons. In addition, a subset of TrkA(+) sensory afferents projects to ectopic ventral positions. These findings demonstrate that stable maintenance of a positional cue by developing astrocytes influences multiple aspects of sensorimotor circuit formation. More generally, they suggest that regional astrocyte heterogeneity may help to coordinate postnatal neural circuit refinement. PMID- 24776796 TI - Structural biology: Action at a distance in a light receptor. PMID- 24776797 TI - Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. AB - Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure by providing human cardiomyocytes to support heart regeneration. Studies of human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) in small animal models have shown favourable effects of this treatment. However, it remains unknown whether clinical-scale hESC-CM transplantation is feasible, safe or can provide sufficient myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (more than one billion cells per batch) and cryopreserved with good viability. Using a non-human primate model of myocardial ischaemia followed by reperfusion, we show that cryopreservation and intra myocardial delivery of one billion hESC-CMs generates extensive remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a 3-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small-animal models, non-fatal ventricular arrhythmias were observed in hESC-CM-engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome. PMID- 24776798 TI - Niche filling slows the diversification of Himalayan songbirds. AB - Speciation generally involves a three-step process--range expansion, range fragmentation and the development of reproductive isolation between spatially separated populations. Speciation relies on cycling through these three steps and each may limit the rate at which new species form. We estimate phylogenetic relationships among all Himalayan songbirds to ask whether the development of reproductive isolation and ecological competition, both factors that limit range expansions, set an ultimate limit on speciation. Based on a phylogeny for all 358 species distributed along the eastern elevational gradient, here we show that body size and shape differences evolved early in the radiation, with the elevational band occupied by a species evolving later. These results are consistent with competition for niche space limiting species accumulation. Even the elevation dimension seems to be approaching ecological saturation, because the closest relatives both inside the assemblage and elsewhere in the Himalayas are on average separated by more than five million years, which is longer than it generally takes for reproductive isolation to be completed; also, elevational distributions are well explained by resource availability, notably the abundance of arthropods, and not by differences in diversification rates in different elevational zones. Our results imply that speciation rate is ultimately set by niche filling (that is, ecological competition for resources), rather than by the rate of acquisition of reproductive isolation. PMID- 24776799 TI - Trace-gas metabolic versatility of the facultative methanotroph Methylocella silvestris. AB - The climate-active gas methane is generated both by biological processes and by thermogenic decomposition of fossil organic material, which forms methane and short-chain alkanes, principally ethane, propane and butane. In addition to natural sources, environments are exposed to anthropogenic inputs of all these gases from oil and gas extraction and distribution. The gases provide carbon and/or energy for a diverse range of microorganisms that can metabolize them in both anoxic and oxic zones. Aerobic methanotrophs, which can assimilate methane, have been considered to be entirely distinct from utilizers of short-chain alkanes, and studies of environments exposed to mixtures of methane and multi carbon alkanes have assumed that disparate groups of microorganisms are responsible for the metabolism of these gases. Here we describe the mechanism by which a single bacterial strain, Methylocella silvestris, can use methane or propane as a carbon and energy source, documenting a methanotroph that can utilize a short-chain alkane as an alternative to methane. Furthermore, during growth on a mixture of these gases, efficient consumption of both gases occurred at the same time. Two soluble di-iron centre monooxygenase (SDIMO) gene clusters were identified and were found to be differentially expressed during bacterial growth on these gases, although both were required for efficient propane utilization. This report of a methanotroph expressing an additional SDIMO that seems to be uniquely involved in short-chain alkane metabolism suggests that such metabolic flexibility may be important in many environments where methane and short-chain alkanes co-occur. PMID- 24776800 TI - Circular polarization in the optical afterglow of GRB 121024A. AB - Gamma-ray bursts (GRBs) are most probably powered by collimated relativistic outflows (jets) from accreting black holes at cosmological distances. Bright afterglows are produced when the outflow collides with the ambient medium. Afterglow polarization directly probes the magnetic properties of the jet when measured minutes after the burst, and it probes the geometric properties of the jet and the ambient medium when measured hours to days after the burst. High values of optical polarization detected minutes after the burst of GRB 120308A indicate the presence of large-scale ordered magnetic fields originating from the central engine (the power source of the GRB). Theoretical models predict low degrees of linear polarization and no circular polarization at late times, when the energy in the original ejecta is quickly transferred to the ambient medium and propagates farther into the medium as a blast wave. Here we report the detection of circularly polarized light in the afterglow of GRB 121024A, measured 0.15 days after the burst. We show that the circular polarization is intrinsic to the afterglow and unlikely to be produced by dust scattering or plasma propagation effects. A possible explanation is to invoke anisotropic (rather than the commonly assumed isotropic) electron pitch-angle distributions, and we suggest that new models are required to produce the complex microphysics of realistic shocks in relativistic jets. PMID- 24776802 TI - Biodiversity: Supply and demand. PMID- 24776801 TI - BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks. AB - Replication fork stalling can promote genomic instability, predisposing to cancer and other diseases. Stalled replication forks may be processed by sister chromatid recombination (SCR), generating error-free or error-prone homologous recombination (HR) outcomes. In mammalian cells, a long-standing hypothesis proposes that the major hereditary breast/ovarian cancer predisposition gene products, BRCA1 and BRCA2, control HR/SCR at stalled replication forks. Although BRCA1 and BRCA2 affect replication fork processing, direct evidence that BRCA gene products regulate homologous recombination at stalled chromosomal replication forks is lacking, due to a dearth of tools for studying this process. Here we report that the Escherichia coli Tus/Ter complex can be engineered to induce site-specific replication fork stalling and chromosomal HR/SCR in mouse cells. Tus/Ter-induced homologous recombination entails processing of bidirectionally arrested forks. We find that the Brca1 carboxy (C)-terminal tandem BRCT repeat and regions of Brca1 encoded by exon 11-two Brca1 elements implicated in tumour suppression-control Tus/Ter-induced homologous recombination. Inactivation of either Brca1 or Brca2 increases the absolute frequency of 'long-tract' gene conversions at Tus/Ter-stalled forks, an outcome not observed in response to a site-specific endonuclease-mediated chromosomal double-strand break. Therefore, homologous recombination at stalled forks is regulated differently from homologous recombination at double-strand breaks arising independently of a replication fork. We propose that aberrant long-tract homologous recombination at stalled replication forks contributes to genomic instability and breast/ovarian cancer predisposition in BRCA mutant cells. PMID- 24776803 TI - The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. AB - The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis. Despite the importance of maintaining cell integrity throughout life, how the HSC pool achieves this and how individual HSCs respond to stress remain poorly understood. Many sources of stress cause misfolded protein accumulation in the endoplasmic reticulum (ER), and subsequent activation of the unfolded protein response (UPR) enables the cell to either resolve stress or initiate apoptosis. Here we show that human HSCs are predisposed to apoptosis through strong activation of the PERK branch of the UPR after ER stress, whereas closely related progenitors exhibit an adaptive response leading to their survival. Enhanced ER protein folding by overexpression of the co-chaperone ERDJ4 (also called DNAJB9) increases HSC repopulation capacity in xenograft assays, linking the UPR to HSC function. Because the UPR is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signalling is coordinated within tissue hierarchies and integrated with stemness. Broadly, these findings reveal that the HSC pool maintains clonal integrity by clearance of individual HSCs after stress to prevent propagation of damaged stem cells. PMID- 24776805 TI - Gold nanoparticles supported on titanium dioxide: an efficient catalyst for highly selective synthesis of benzoxazoles and benzimidazoles. AB - A highly efficient and selective reaction for the synthesis of 2-substituted benzoxazoles and benzimidazoles catalyzed by Au/TiO2 has been developed via two hydrogen-transfer processes. This reaction has a good tolerance to air and water, a wide substrate scope, and represents a new avenue for practical C-N and C-O bond formation. More importantly, no additional additives, oxidants and reductants are required for the reaction and the catalyst can be recovered and reused readily. PMID- 24776804 TI - Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells. AB - The transfer of somatic cell nuclei into oocytes can give rise to pluripotent stem cells that are consistently equivalent to embryonic stem cells, holding promise for autologous cell replacement therapy. Although methods to induce pluripotent stem cells from somatic cells by transcription factors are widely used in basic research, numerous differences between induced pluripotent stem cells and embryonic stem cells have been reported, potentially affecting their clinical use. Because of the therapeutic potential of diploid embryonic stem-cell lines derived from adult cells of diseased human subjects, we have systematically investigated the parameters affecting efficiency of blastocyst development and stem-cell derivation. Here we show that improvements to the oocyte activation protocol, including the use of both kinase and translation inhibitors, and cell culture in the presence of histone deacetylase inhibitors, promote development to the blastocyst stage. Developmental efficiency varied between oocyte donors, and was inversely related to the number of days of hormonal stimulation required for oocyte maturation, whereas the daily dose of gonadotropin or the total number of metaphase II oocytes retrieved did not affect developmental outcome. Because the use of concentrated Sendai virus for cell fusion induced an increase in intracellular calcium concentration, causing premature oocyte activation, we used diluted Sendai virus in calcium-free medium. Using this modified nuclear transfer protocol, we derived diploid pluripotent stem-cell lines from somatic cells of a newborn and, for the first time, an adult, a female with type 1 diabetes. PMID- 24776806 TI - Oesophagus: tissue-engineered oesophagus successfully transplanted in rats. PMID- 24776807 TI - Viral hepatitis: new hepatitis C therapies-a medical pick and mix. PMID- 24776808 TI - Hepatitis: HBV infection alters bile acid metabolism gene profile. PMID- 24776809 TI - Predictors of safe delivery service utilization in arsi zone, South-East ethiopia. AB - BACKGROUND: Evidence show that lack of access to and use of, essential obstetric care services to be a crucial factor that contributes to the high maternal morbidity and mortality. Skilled attendance during labor, delivery and early post partum period could reduce deaths due to obstructed labor, hemorrhage, sepsis and eclampsia. There is limited information on the mothers' use of skilled delivery services in the study area. This study assessed the predictors of safe delivery service utilization in Arsi Zone, Southeast Ethiopia. METHODS: A cross- sectional community based study using quantitative and qualitative methods was conducted from February 15(th) to March 15(th) 2006. A total of 1089 women who had at least one birth one year prior to the study were involved in the study from nine rural and four urban kebeles in three Woredas (Districts) selected using a systematic sampling method from all households in the study area. A pre-tested structured interviewer administered questionnaire was used to collect data. Information on the utilization of safe delivery service and socio-demographic, individual and institutional factors and past obstetric history were collected. Focus Group Discussion guide was used for qualitative data collection. The data were edited, cleaned, and entered into a computer and analyzed using SPSS for windows version 12.0. RESULT: One thousand seventy four women who had at least one birth were interviewed making a response rate 98.6%. Two hundred seventy one (75.0%) of urban and 373(52.0%) rural women received antenatal care from skilled health professional at least once during their last pregnancy. Thirty-one (4.3%) of rural and 145 (40.4%) of urban women delivered in health institution. In multivariate analysis showed that residential area OR= 8.5, 95%CI; (5.1,13.9), parity OR=0.18, 95%CI; (0.08, 0.42), and ANC service use OR= 4.5, 95%CI; (2.2,8.9), and maternal education OR=4.6, 95%CI; (1.7,12.8), were most significant predictors of safe delivery service use by mothers (P< 0.01). CONCLUSION: Birth attended by skilled personnel was low in the study area. Maternal education, her birth experience and her use of prenatal services are important predictors. Promoting information, education and communication on safe delivery service utilization, expansion of health service and empowerment of women are needed. PMID- 24776810 TI - Radioembolization with yttrium-90 microspheres work up: Practical approach and literature review. AB - Radioembolization (RE) is a selective internal radiotherapy technique in which yttrium-90 blended microspheres are infused through the hepatic arteries. It is based on the fact that primary and secondary hepatic tumors are vascularized mostly by arterial blood flow whereas healthy hepatocytes obtain their blood supply mostly from the portal network. This enables high radiation doses to be delivered, sparing the surrounding non-malignant liver parenchyma. Most of the complications are caused by unexpected particles passing into the gastrointestinal tract through branches originating from the main hepatic arterial supply. Knowledge of this hepatic arterial network and of its variations and the technical considerations this raises are required in preparation for treatment. This work describes the specific anatomical features and techniques for this anatomy through recent literature illustrated by cases from our own experience. PMID- 24776811 TI - Percutaneous hepatic ablation: what needs to be known in 2014. AB - Percutaneous treatments for liver tumors were initially reserved for patients deemed to be inoperable and whose tumors were small in both size and number. As a result of the widening range of both techniques and technologies these treatments have gradually become incorporated into increasingly complex treatment strategies for increasingly broad patient groups. The place reserved for these techniques, which are still dominated by monopolar radiofrequency ablation, which is now facing strong competition from second-generation microwaves, is governed by each center's knowledge and skills in the techniques. This review describes the possible indications for percutaneous ablation depending on clinical findings and the technical and technological choices made. PMID- 24776812 TI - Synthesis and isomerization of some novel pyrazolopyrimidine and pyrazolotriazolopyrimidine derivatives. AB - 4-Imino-1-p-tolyl-1,4-dihydropyrazolo[3,4-d]pyrimidin-5-ylamine (2) and (1-p tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-hydrazine (3) were prepared starting from ethyl 4-cyano-1-p-tolyl-1H-pyrazol-5-ylimidoformate (1). The structure of compound 3 was confirmed through preparation of the pyrazole derivatives 4 and 5. Also, the synthesis and structural characterization of pyrazolo[4,3 e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 7 and 9 and their isomerization to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 6 and 8, respectively, under different suitable reaction conditions were reported. Moreover, the syntheses of 2-substituted-pyrazolo[4,3-e][1,2,4]triazolo[1,5 c]pyrimidine derivatives 10 and 11 was described. PMID- 24776813 TI - Two trypanocidal dipeptides from the roots of Zapoteca portoricensis (Fabaceae). AB - Zapoteca portoricensis (Jacq) HM Hernandez is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate) and anabellamide, were isolated from the methanol root extract of Zapoteca portoricensis and their chemical structures deduced by one dimensional and two dimensional NMR and mass spectrometry. These compounds were isolated for the first time from this plant, and no report has been found on their previous isolation from the genus Zapoteca. Evaluation of their trypanocidal activity showed that compound 1 exhibited potent activity against Trypanosoma brucei rhodesiense with an IC50 value of 3.63 MUM and selectivity index of 25.3. PMID- 24776814 TI - Physical and mental health and social functioning in older alcohol-dependent inpatients: the role of age of onset. AB - AIMS: Age of onset is an important criterion to distinguish subgroups of alcohol dependent patients. This study investigated physical and mental health and social functioning of older inpatients with early (age <25), late (25-44), and very late (>=45) onset of alcohol dependence. METHODS: In a specialized detoxification ward for older patients in The Hague, the Netherlands, 157 older alcohol-dependent inpatients (38% women, mean age 62.7 +/- 6.5) were interviewed with the European version of the Addiction Severity Index. RESULTS: As a group, older alcohol dependent patients had substantial physical, mental and social problems, which were largely independent of the age of onset of alcohol dependence. Patients with early-onset alcohol dependence had more chronic medical problems and more suicidal thoughts than patients with late-onset alcohol dependence. The very-late onset group did not significantly differ from the other two groups in any of the variables under study. CONCLUSIONS: Despite previous studies showing more favourable outcomes for the (very) late-onset compared to the early-onset alcohol dependent group, their comorbid (mental) health and social problems are in many respects similar, and require careful assessment and treatment. This may be crucial for successful treatment and improving quality of life in these patients. PMID- 24776815 TI - A carbon nanotube-based Raman-imaging immunoassay for evaluating tumor targeting ligands. AB - Herein, we describe a versatile immunoassay that uses biotinylated single-walled carbon nanotubes (SWNTs) as a Raman label, avidin-biotin chemistry to link targeting ligands to the label, and confocal Raman microscopy to image whole cells. Using a breast tumor cell model, we demonstrate the usefulness of the method to assess membrane receptor/ligand systems by evaluating a monoclonal antibody, Her-66, known to target the Her2 receptors that are overexpressed on these cells. We present two-dimensional Raman images of the cellular distribution of the SWNT labels corresponding to the distribution of the Her2 receptors in different focal planes through the cell with validation of the method using immunofluorescence microscopy, demonstrating that the Her-66-SWNT complexes were targeted to Her2 cell receptors. PMID- 24776816 TI - DRD3 gene rs6280 polymorphism may be associated with alcohol dependence overall and with Lesch type I alcohol dependence in Koreans. AB - BACKGROUND: Several polymorphisms of the dopamine D3 receptor (DRD3) gene are reported to be involved in the susceptibility to alcoholism. Although the DRD3 rs6280 (Ser9Gly) polymorphism plays an important role in various psychiatric disorders, findings regarding the association between this single-nucleotide polymorphism (SNP) and alcohol dependence (AD) have been inconsistent. Therefore, the present study investigated the association between the DRD3 gene rs6280 polymorphism with AD and Lesch type I AD in Korean subjects. METHODS: The DRD3 rs6280 SNP was genotyped in a case-control sample comprising 245 AD patients and 130 healthy controls (HCs). Alcohol Use Disorders Identification Test (AUDIT) scores were also compared relative to genotype in all of the participants. RESULTS: This SNP was significantly associated with both AD overall (chi(2) = 10.09 and p = 0.001, and chi(2) = 10.60 and p = 0.005, for the recessive and additive models, respectively) and with Lesch type I AD (chi(2) = 11.70 and p = 0.001, and chi(2) = 11.70 and p = 0.003, for the recessive and additive models, respectively). The allele frequency differed significantly (chi(2) = 8.45, p = 0.004) between Lesch type I AD and HC subjects. The AUDIT total (F = 6.56, p = 0.011), hazardous alcohol use (F = 7.12, p = 0.008), dependence symptoms (F = 5.10, p = 0.025), and harmful alcohol use (F = 4.83, p = 0.029) scores were significantly higher in those who did not possess the S allele (genotype GG) than in those who did (genotypes SS +/- SG). CONCLUSIONS: The findings of this study suggest that the DRD3 rs6280 polymorphism is associated with the development of both AD overall and Lesch type I AD in Koreans. PMID- 24776819 TI - Pemphigus induced by radiotherapy for breast cancer: an instance of immunocompromised district. PMID- 24776817 TI - The effects of cigarette smoke extract on ovulation, oocyte morphology and ovarian gene expression in mice. AB - Cigarette smoking can harm fertility, but the existing research has targeted primarily on ovarian follicles, embryos or sex hormone. In this study, we tested cigarette smoke extract on ovulation, oocyte morphology and ovarian gene expression associated with inhibition of oxidative stress using C57BL/6 mice. Mice in the experimental group were administered a cigarette smoke extract (CSE) solution (2 mg/ml) orally daily, while the blank control group was given dimethylsulfoxide (DMSO). A positive control group (menadione) was used that received an intraperitoneal injection of 15 mg/kg menadione in oil solution daily. We found that the CSE group manifested a reduced diameter of zona pellucida-free oocyte (ZP-free OD) and a morphologically misshapen first polar body (PB). Our results suggest that CSE exposure is associated with a shrink size and poor quality of oocytes. Quitting smoking is a wise choice to ensure good fertility. PMID- 24776820 TI - Phase stability of Li-Mn-O oxides as cathode materials for Li-ion batteries: insights from ab initio calculations. AB - In this work, we present a density-functional theory (DFT) investigation of the phase stability, electrochemical stability and phase transformation mechanisms of the layered and over-lithiated Mn oxides. This study includes the thermodynamic stability of Li and oxygen vacancies, to examine the electrochemical activation mechanisms of these cathode materials. The DFT calculations provide phase diagrams of the Li-Mn-O system in both physical and chemical potential spaces, including the crystals containing vacancies as independent phases. The results show the ranges of electrochemical activity for both layered LiMnO2 and over lithiated Li2MnO3. By using a thermodynamic model analysis, we found that the required temperature for oxygen evolution and Li vacancy formation is too high to be compatible with any practical synthesis temperature. Using solid-state transition calculations, we have identified the key steps in the phase transition mechanism of the layered LiMnO2 into the spinel phase. The calculated effects of pH on the Li-Mn-O phase stability elucidated the mechanism of Mn(2+) formation from the spinel phase under acidic conditions. PMID- 24776821 TI - Determination of Toll-like receptor-induced cytokine profiles in the blood and cerebrospinal fluid of Chikungunya patients. AB - BACKGROUND: Chikungunya infection caused by Chikungunya virus (CHIKV) is an inflammatory disease affecting the joints and may also lead to neurological complications. We investigated a panel of human Toll-like receptor (TLR)-induced cytokines in Chikungunya patients with and without neurological complications. METHODS: In a case-control study, a panel of 12 cytokines and chemokines, TNF alpha, IFN-alpha, IL-1beta, IL-6, IL-12, IL-17A, IL-8, monocyte chemotactic protein (MCP)-1, RANTES, interferon (IFN)-gamma-induced protein (IP)-10, monokine induced by IFN-gamma (MIG) and thymus and activation-regulated chemokine (TARC), was analysed using a conventional ELISA protocol in the serum samples of Chikungunya patients without neurological complications and in the cerebrospinal fluid (CSF) and paired serum samples of Chikungunya patients with neurological complications. RESULTS: The levels of 3 cytokines, IL-1beta, IL-17A and IL-8, and 4 chemokines, MCP-1, RANTES, IP-10 and TARC, were raised in serum samples of Chikungunya patients without neurological complications, whereas, 4 cytokines, TNF-alpha, IFN-alpha, IL-6 and IL-8, and 4 chemokines, MCP-1, RANTES, MIG and TARC, were elevated in CSF samples of Chikungunya patients with neurological complications. Moreover, the levels of IL-6 and IL-8 cytokines were significantly elevated in the CSF compared to paired serum samples in Chikungunya patients with neurological complications. CONCLUSIONS: In CHIKV infection, multiple cytokines are elevated in serum and CSF. The elevation in IL-6 and IL-8 cytokines in CSF correlates with neurological involvement. PMID- 24776825 TI - Self-decoration of Pt metal particles on TiO(2) nanotubes used for highly efficient photocatalytic H(2) production. AB - Pt decorated TiO2 has, over the past decades, been a key material for photocatalytic hydrogen production. The present work shows that growing anodic self-organized TiO2 nanotubes from Ti-Pt alloy with a low Pt content of 0.2 at% leads to oxide nanotube layers that are self-decorated with Pt nanoparticles of 4 5 nm in diameter. The average particle spacing is in the range of ~50 nm and is partially adjustable by the anodization conditions. This intrinsic decoration of TiO2 nanotubes with Pt leads to a highly active photocatalyst for the production of H2 under UV or visible light conditions. PMID- 24776823 TI - The use of laser microdissection in the identification of suitable reference genes for normalization of quantitative real-time PCR in human FFPE epithelial ovarian tissue samples. AB - Quantitative real-time PCR (qPCR) is a powerful and reproducible method of gene expression analysis in which expression levels are quantified by normalization against reference genes. Therefore, to investigate the potential biomarkers and therapeutic targets for epithelial ovarian cancer by qPCR, it is critical to identify stable reference genes. In this study, twelve housekeeping genes (ACTB, GAPDH, 18S rRNA, GUSB, PPIA, PBGD, PUM1, TBP, HRPT1, RPLP0, RPL13A, and B2M) were analyzed in 50 ovarian samples from normal, benign, borderline, and malignant tissues. For reliable results, laser microdissection (LMD), an effective technique used to prepare homogeneous starting material, was utilized to precisely excise target tissues or cells. One-way analysis of variance (ANOVA) and nonparametric (Kruskal-Wallis) tests were used to compare the expression differences. NormFinder and geNorm software were employed to further validate the suitability and stability of the candidate genes. Results showed that epithelial cells occupied a small percentage of the normal ovary indeed. The expression of ACTB, PPIA, RPL13A, RPLP0, and TBP were stable independent of the disease progression. In addition, NormFinder and geNorm identified the most stable combination (ACTB, PPIA, RPLP0, and TBP) and the relatively unstable reference gene GAPDH from the twelve commonly used housekeeping genes. Our results highlight the use of homogeneous ovarian tissues and multiple-reference normalization strategy, e.g. the combination of ACTB, PPIA, RPLP0, and TBP, for qPCR in epithelial ovarian tissues, whereas GAPDH, the most commonly used reference gene, is not recommended, especially as a single reference gene. PMID- 24776826 TI - Health workforce deployment, attrition and density in East wollega zone, Western ethiopia. AB - BACKGROUND: In East Wollega Zone, despite the success in creating considerable number of health facilities, short-age of health personnel, geographical imbalance and increasing attrition is found to be a persistent barrier to the effectiveness of the health system. However, available data is not rich enough to provide reliable information as to what extent these problems exist in the Zone. Hence, this study was conducted to assess health workforce density, deployment and attrition in East Wollega Zone. METHODS: A six years retrospective record review from 2000-2005 was conducted between February 1, and March 30, 2006 in eleven randomly selected districts of East Wollega Zone. Data obtained from records and interviews made with selected resource persons were organized by triangulating quantitatively and qualitatively. Quantitative data was analyzed using SPSS 12.01 for windows and thematic frame work analysis was used for qualitative data. RESULTS: Health workforce deployment rate for the years 2000 2005 ranged from 8.2% to 15.4 %. In contrast, attrition rate for the same period ranged from 2.9 % to 8.5 %. Attrition rate for the time after decentralization (2003-2005) was nearly two times greater than before decentralization (OR, 2.04, CI, 1.51, 2.85, P=0.00). Moreover, attrition rate was nearly three times greater for a high level professional when compared to the lower level (OR, 3.15, CI , 2.63, 4.37, P=0.00). Attrition rate for males was two times higher as compared to females (OR, 2.07, CI, 1.67, 3.74, P=0.00). About (26.3%) of all health workers and (36.7%) of nurses and midwives were deployed to the capital town of the zone. Factors identified as most likely cause for the lower deployment and higher attritions were budget related constraints, lack of continuing education opportunity and poor career development. CONCLUSIONS: The number of health personnel in East Wollega was low both by international standards and relative to the national density. Moreover, attrition was higher for the time after decentralization process. Hence, measures that seek to increase the size of the health workforce through increased recruitment, higher retention of existing staff and better geographical balance have to be urgently explored. PMID- 24776827 TI - The manager's behavior:contradictions and perceptions. PMID- 24776828 TI - Foundation of evidence-based decision making for health care managers, part 1: systematic review. AB - Evidence-based decision making has become a benchmark of best practice. Sources of evidence are systematic reviews and meta-analyses. To support their decision making, health care managers and supervisors need to be able to critically read and interpret systematic reviews and meta-analyses. They also need to be able to determine the applicability of the evidence to their problems and settings. This 2-part series of articles aims to equip health care managers and supervisors with these skills. This article, part 1, explains the types of systematic reviews, defines key terms, and outlines the process of systematic reviews and meta analyses. Part 2 focuses on the additional procedures associated with meta analyses, describes the potential shortcomings of both systematic reviews and meta-analyses, and finally, provides a way to appraise the applicability of their results. PMID- 24776829 TI - Accountable care organizations: financial advantages of larger hospital organizations. AB - Accountable care organizations (ACOs) are groups of providers who agree to accept the responsibility for elevating the health status of a defined group of patients, with the goal of enabling people to take charge of their health and enroll in shared decision making with providers. The large initial investment required (estimated at $1.8 million) to develop an ACO implies that the participation of large health care organizations, especially hospitals and health systems, is required for success. Findings of this study suggest that ACOs based in a larger hospital organization are more likely to meet Centers for Medicare and Medicaid Services criteria for formation because of financial and structural assets of those entities. PMID- 24776830 TI - Measuring efficiency among US federal hospitals. AB - This study evaluates the efficiency of federal hospitals, specifically those hospitals administered by the US Department of Veterans Affairs and the US Department of Defense. Hospital executives, health care policymakers, taxpayers, and federal hospital beneficiaries benefit from studies that improve hospital efficiency. This study uses data envelopment analysis to evaluate a panel of 165 federal hospitals in 2007 and 157 of the same hospitals again in 2011. Results indicate that overall efficiency in federal hospitals improved from 81% in 2007 to 86% in 2011. The number of federal hospitals operating on the efficiency frontier decreased slightly from 25 in 2007 to 21 in 2011. The higher efficiency score clearly documents that federal hospitals are becoming more efficient in the management of resources. From a policy perspective, this study highlights the economic importance of encouraging increased efficiency throughout the health care industry. This research examines benchmarking strategies to improve the efficiency of hospital services to federal beneficiaries. Through the use of strategies such as integrated information systems, consolidation of services, transaction-cost economics, and focusing on preventative health care, these organizations have been able to provide quality service while maintaining fiscal responsibility. In addition, the research documented the characteristics of those federal hospitals that were found to be on the Efficiency Frontier. These hospitals serve as benchmarks for less efficient federal hospitals as they develop strategies for improvement. PMID- 24776831 TI - Reduction of intensive care unit length of stay: the case of early mobilization. AB - Bed rest or immobilization is frequently part of treatment for patients in the intensive care unit (ICU) with critical illness. The average ICU length of stay (LOS) is 3.3 days, and for every day spent in an ICU bed, the average patient spends an additional 1.5 days in a non-ICU bed. The purpose of this research study was to analyze the effects of early mobilization for patients in the ICU to determine if it has an impact on the LOS, cost of care, and medical complications. The methodology for this study was a literature review. Five electronic databases were used, with a total of 26 articles referenced for this research. Early mobilization suggested a decrease in delirium by 2 days, reduced risk of readmission or death, and reduced ventilator-assisted pneumonia, central line, and catheter infections. Length of stay in the ICU was reduced with statistical significance in several studies examining early mobilization. Limited research on cost of ICU LOS indicated potential savings with early mobilization. When implementing early mobilization in the ICU, total costs were decreased and medical complications were reduced. Early mobilization should become a standard of care for critically ill but stable patients in the ICU. PMID- 24776832 TI - Dress codes and appearance policies: challenges under federal legislation, part 3: Title VII, the Americans with Disabilities Act, and the National Labor Relations Act. AB - As more and more individuals express themselves with tattoos and body piercings and push the envelope on what is deemed appropriate in the workplace, employers have an increased need for creation and enforcement of reasonable dress codes and appearance policies. As with any employment policy or practice, an appearance policy must be implemented and enforced without regard to an individual's race, color, sex, national origin, religion, disability, age, or any other protected status. A policy governing dress and appearance based on the business needs of an employer that is applied fairly and consistently and does not have a disproportionate effect on any protected class will generally be upheld if challenged in court. By examining some of the more common legal challenges to dress codes and how courts have resolved the disputes, health care managers can avoid many potential problems. This article, the third part of a 3-part examination of dress codes and appearance policies, focuses on the issues of race and national origin under the Civil Rights Act, disability under the Americans With Disabilities Act, and employees' rights to engage in concerted activities under the National Labor Relations Act. Pertinent court cases that provide guidance for employers are addressed. PMID- 24776833 TI - Implementation of the physician assistant in Dutch health care organizations: primary motives and outcomes. AB - Physician assistants (PAs) are trained to perform medical procedures that were traditionally performed by medical physicians. Physician assistants seem to be deployed not only to increase efficiency but also to ensure the quality of care. What is not known is the primary motive for employing PAs within Dutch health care and whether the employment of the PAs fulfills the perceived need for them. Supervising medical specialists who used PAs in their practices were interviewed about their primary motives and outcomes. The interviews were semistructured. Two scientists coded the findings with respect to motives and outcomes. In total, 55 specialists were interviewed about their motives for employing a PA, and 15 were interviewed about the outcomes of employing a PA. With respect to the primary motives for employing a PA, the most frequent motive was to increase continuity and quality of care, followed by relieving the specialist's workload, increasing efficiency of care, and substituting for medical residents. The outcomes were found to be consistent with the motives. In conclusion, the primary motive for employing a PA in Dutch health care is to increase continuity and quality of care. PMID- 24776835 TI - Building an ethical organizational culture. AB - The success of a health care institution-as defined by delivering high-quality, high-value care, positive patient outcomes, and financial solvency-is inextricably tied to the culture within that organization. The ability to achieve and sustain alignment between its mission, values, and everyday practices defines a positive organizational culture. An institution that has a diminished organizational culture, reflected in the failure to consistently align management and clinical decisions and practices with its mission and values, will struggle. The presence of misalignment or of ethics gaps affects the quality of care being delivered, the morale of the staff, and the organization's image in the community. Transforming an organizational culture will provide a foundation for success and a framework for daily ethics-grounded operations in any organization. However, building an ethics-grounded organization is a challenging process requiring strong organization leadership and planning. Using a case study, the authors provide a multiyear, continuous step-by-step strategy consisting of identifying ethics culture gaps, establishing an ethics taskforce, clarifying and prioritizing the problems, developing strategy for change, implementing the strategy, and evaluating outcomes. This process will assist organizations in aligning its actions with its mission and values, to find success on all fronts. PMID- 24776836 TI - Fostering acceptance of computerized physician order entry: insights from an implementation study. AB - Computerized physician order entry (CPOE) allows physicians to enter orders in a computer rather than handwriting them. Computerized physician order entry is touted as a major improvement in patient safety, and although the literature suggests that such systems have the potential to improve patient outcomes, studies also suggest that CPOE may have significant drawbacks that accompany those benefits. Physicians have often been resistant to accept its implementation. This study investigates the implementation of CPOE at a 217-bed rural hospital in the southeastern United States. Drawing on a mixed-method approach, we identify correlates of change acceptance and propose a set of recommendations for health care managers to foster acceptance of CPOE. Findings from physician surveys (n = 19) indicate that older physicians are less accepting of CPOE, but high-quality change communication may overcome resistance even among older physicians. With insights derived from the organizational change literature, findings bring to the fore a set of practices that managers can use to foster acceptance of CPOE. The thrust of these practices is that managers should make physicians active participants in fine-tuning CPOE within the unique needs and constraints of the local hospital setting. PMID- 24776838 TI - Towards covalent organic frameworks with predesignable and aligned open docking sites. AB - A strategy for the synthesis of covalent organic frameworks with open docking sites is developed. The docking sites are ordered on the channel walls and structurally predesignable for meeting various types of noncovalent interactions, thus opening a way towards designing supramolecular materials based on crystalline porous organic frameworks. PMID- 24776837 TI - Impact of a pedometer program on nurses working in a health-promoting hospital. AB - The aim of this research was to describe the impact of a pedometer-based activity program on a subset of nurses in a university-affiliated, multisite health care center in Canada. This study used a longitudinal design with preintervention postintervention (8 weeks) and follow-up (6 months). At baseline, 60 nurses participated; 51 (85%) remained for the postprogram assessment and 33 (55%) also completed the follow-up questionnaire. Data were collected through self administered questionnaires (weight, height, fatigue, insomnia, stress and step data) and blood tests (total cholesterol and low-density lipoprotein and high density lipoprotein cholesterol). At postprogram, participants reported 12 thinsp;912 steps on average per day. At follow-up, 79% of participants indicated that they maintained their physical activity after the pedometer program. A significant decrease in insomnia was evident in postprogram scores compared with baseline scores, and this decrease was maintained at follow-up. A significant decrease in minutes spent sitting per week was also observed from baseline to postprogram and also maintained at follow-up. Participants' stress and low density lipoprotein cholesterol levels decreased from baseline to postprogram (marginally significant). Finally, their weight decreased from baseline to follow up (marginally significant). The pedometer program generated some positive outcomes for nurses after 6 months. PMID- 24776839 TI - Electron transport in MoWSeS monolayers in the presence of an external electric field. AB - The influence of an external electric field on single-layer transition-metal dichalcogenides TX2 with T = Mo, W and X = S, Se (MoWSeS) has been investigated by means of density-functional theory within two-dimensional periodic boundary conditions under consideration of relativistic effects including the spin-orbit interactions. Our results show that the external field modifies the band structure of the monolayers, in particular, the conduction band. This modification has, however, very little influence on the band gap and effective masses of holes and electrons at the K point, and also the spin-orbit splitting of these monolayers is almost unaffected. Our results indicate a remarkable stability of the electronic properties of TX2 monolayers with respect to gate voltages. A reduction of the electronic band gap is observed starting only from field strengths of 2.0 V A(-1) (3.5 V A(-1)) for selenides (sulphides), and the transition to a metallic phase would occur at fields of 4.5 V A(-1) (6.5 V A( 1)). PMID- 24776840 TI - Oxalate quantification in hemodialysate to assess dialysis adequacy for primary hyperoxaluria. AB - BACKGROUND: Patients with primary hyperoxaluria (PH) overproduce oxalate which is eliminated via the kidneys. If end-stage kidney disease develops they are at high risk for systemic oxalosis, unless adequate oxalate is removed during hemodialysis (HD) to equal or exceed ongoing oxalate production. The purpose of this study was to validate a method to measure oxalate removal in this unique group of dialysis patients. METHODS: Fourteen stable patients with a confirmed diagnosis of PH on HD were included in the study. Oxalate was measured serially in hemodialysate and plasma samples in order to calculate rates of oxalate removal. HD regimens were adjusted according to a given patient's historical oxalate production, amount of oxalate removal at dialysis, residual renal clearance of oxalate, and plasma oxalate levels. RESULTS: After a typical session of HD, plasma oxalate was reduced by 78.4 +/- 7.7%. Eight patients performed HD 6 times/week, 2 patients 5 times/week, and 3 patients 3 times/week. Combined oxalate removal by HD and the kidneys was sufficient to match or exceed endogenous oxalate production. After a median period of 9 months, pre-dialysis plasma oxalate was significantly lower than initially (75.1 +/- 33.4 vs. 54.8 +/- 46.6 mmol/l, p = 0.02). CONCLUSION: This methodology can be used to individualize the dialysis prescription of PH patients to prevent oxalosis during the time they are maintained on HD and to reduce risk of oxalate injury to a transplanted kidney. PMID- 24776841 TI - Low serum allopregnanolone is associated with symptoms of depression in late pregnancy. AB - BACKGROUND: Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) is a neurosteroid which has an inhibitory function through interaction with the GABAA receptor. This progesterone metabolite has strong sedative and anxiolytic properties, and low endogenous levels have been associated with depressed mood. This study aimed to investigate whether the very high serum allopregnanolone levels in late pregnancy covary with concurrent self-rated symptoms of depression and anxiety. METHODS: Ninety-six women in pregnancy weeks 37-40 rated symptoms of depression and anxiety with the Montgomery-Asberg Depression Rating Scale (MADRS S) and Spielberger State-Trait Anxiety Inventory. Their serum allopregnanolone was analyzed by Celite chromatography and radioimmunoassay. RESULTS: Ten women had elevated depression scores (MADRS-S >= 13), and this group had significantly lower allopregnanolone levels compared to women with MADRS-S scores in the normal range (39.0 +/- 17.9 vs. 54.6 +/- 18.7 nmol/l, p = 0.014). A significant negative correlation was found between self-rated depression scores and allopregnanolone concentrations (Pearson's correlation coefficient = -0.220, p = 0.031). The linear association between self-rated depression scores and allopregnanolone serum concentrations remained significant when adjusted for gestational length, progesterone levels, and parity. Self-rated anxiety, however, was not associated with allopregnanolone serum concentrations during pregnancy. CONCLUSION: High allopregnanolone serum concentrations may protect against depressed mood during pregnancy. PMID- 24776842 TI - Dissection of estrogen receptor alpha signaling pathways in osteoblasts using RNA sequencing. AB - The effects of 17-beta-estradiol in osteoblasts are primarily mediated by the nuclear transcription factors, estrogen receptor (ER)alpha and ERbeta. ERs function through three general modes of action: DNA-binding dependent through estrogen response elements (EREs; designated nuclear ERE signaling); nuclear signaling via protein-protein interactions to other transcription factors (nuclear non-ERE signaling); and extra-nuclear signaling (membrane-bound functions of ERs). Identification of the specific transcriptional signatures regulated by each of these modes of action should contribute to an enhanced understanding of estrogen signaling in osteoblasts. To achieve this goal, we utilized specific mutations of ERalpha that eliminate the ability of the receptor to signal through a specific mode of action. The non-classical ERalpha knock-in (NERKI) mutation is incapable of signaling through direct DNA binding to EREs and the nuclear only ERalpha (NOER) mutation eliminates all membrane-localized signaling. Comparison of the gene expression patterns elicited by these mutations with the wild-type ERalpha (WT) pattern provides mode-specific data concerning transcriptional regulation by ERalpha. We expressed these constructs in the ER negative osteoblastic cell line hFOB (-/+ estrogen) and performed global RNA sequencing. Using a series of pair-wise comparisons, we generated three lists of genes that were regulated either by the nuclear ERE-dependent, nuclear ERE independent, or extra-nuclear actions of ERalpha. Pathway and gene ontology analyses revealed that genes regulated through the nuclear ERE and nuclear non ERE pathways were largely involved in transcriptional regulation, whereas genes regulated through extra-nuclear mechanisms are involved in cytoplasmic signaling transduction pathways. We also intersected our data with genes linked to bone density and fractures from a recent genome-wide association study and found 25 of 72 genes (35%) regulated by estrogen. These data provide a comprehensive list of genes and pathways targeted by these specific modes of ERalpha action and suggest that "mode-specific" ligands could be developed to modulate specific ERalpha functionality in bone. PMID- 24776843 TI - Jasmonoyl-l-isoleucine hydrolase 1 (JIH1) contributes to a termination of jasmonate signaling in N. attenuata. AB - The jasmonate signaling pathway is essential for plant development, reproduction, and defense against herbivores and pathogens. When attacked by herbivores, plants elicit defense responses through the rapid accumulation of jasmonates. Although the transduction of the jasmonate burst into downstream responses has been largely resolved in the past decade, how the jasmonate burst is switched off remained unknown. Recently, two mechanisms that involve cytochrome p450-mediated hydroxylation/carboxylation and NaJIH1-mediated hydrolysis of JA-Ile were identified as major termination mechanisms of JA signaling. Due to a lack of hydrolysis, N. attenuata plants silenced in the expression of the JIH1 gene accumulated significantly more JA-Ile than did wild type plants and became more resistant to herbivore attack. Although less likely, additional functions of JIH1, such as contributing to the pool of free Ile and thereby increasing JA-Ile accumulation, remained untested. Here we show that increased isoleucine availability does not explain the observed phenotype in JIH1-deficient N. attenuata plants. PMID- 24776844 TI - Associations between functional polymorphisms in the NFkappaB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease. AB - Antitumor necrosis factor-alpha (TNF-alpha) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NFkappaB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-alpha signaling (TNFA (TNF-alpha) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFkappaB (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P ? 0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFkappaB through the Toll-like receptor (TLR) pathways, genes regulating TNF-alpha signaling and cytokines regulated by NFkappaB are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1beta, IL-6 and IFN-gamma may be potential targets for treating patients with IBD who do not respond to anti TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting. PMID- 24776846 TI - Critical care. A silver lining in the quest for improved survival in sepsis. AB - Two recent trials have highlighted that our strategies to restore tissue perfusion early and decrease mortality in patients with sepsis are varied and evidence for an effective therapy to reduce the incidence of kidney injury is lacking. However, newly reported data suggest an overall improved standard of care for patients. PMID- 24776845 TI - Immune system modulation of kidney regeneration--mechanisms and implications. AB - The immune system is an important guardian of tissue homeostasis. In response to injury, resident and infiltrating immune cells orchestrate all phases of danger control, resolution of inflammation and tissue regeneration or scar formation. As mammalian postnatal kidneys are not capable of de novo nephrogenesis, recovery is limited to the regeneration or repair of existing nephrons. The regenerative capacity of the nephron varies between compartments; the epithelial cells of the tubule regenerate more efficiently than the structurally highly organized podocytes. Cells of the surrounding environment modulate nephron regeneration by secreting paracrine mediators. This Review discusses immune mediators and pathways that regulate the intrinsic regenerative capacity of the nephron. Eliminating injurious triggers, modulating renal inflammation and specifically enhancing the regenerative capacity of nephrons might be a promising strategy to improve long-term outcomes in patients with acute kidney injury and/or chronic kidney disease. PMID- 24776847 TI - Corticotropin-releasing hormone receptors mediate apoptosis via cytosolic calcium dependent phospholipase A2 and migration in prostate cancer cell RM-1. AB - Peripheral corticotropin-releasing hormone receptors (CRHRs) are G protein coupled receptors that play different roles depending on tissue types. Previously, we discovered the mechanism of CRHR-mediated apoptosis of mouse prostate cancer cell line (RM-1) to be a change of Bcl-2:Bax ratio, and CRH was found to inhibit transforming growth factor beta migration of breast cancer cells via CRHRs. In the present study, we investigated cytosolic calcium-dependent phospholipase A2 (cPLA2) bridging CRHR activations and Bcl-2:Bax ratio and the effect of CRHR activation on cell migration. Silencing of cPLA2 attenuated a CRHR1 agonist, CRH-induced apoptosis, and the decrease of the Bcl-2:Bax ratio, whereas silencing of cPLA2 aggravated CRHR2 agonist, Urocortin 2 (Ucn2)-inhibited apoptosis, and the increase of the Bcl-2:Bax ratio. CRH in a time- and concentration-dependent manner increased cPLA2 expression mainly through interleukin 1beta (IL1beta) upregulation. Ucn2 decreased cPLA2 expression through neither tumor necrosis factor alpha nor IL1beta. CRH-suppressed decay of cPLA2 mRNA and Ucn2 merely suppressed its production. Overexpression of CRHR1 or CRHR2 in HEK293 cells correspondingly upregulated or downregulated cPLA2 expression after CRH or Ucn2 stimulation respectively. In addition, both CRH and Ucn2 induced migration of RM-1 cells. Our observation not only established a relationship between CRHRs and cell migration but also for the first time, to our knowledge, demonstrated that cPLA2 participates in CRHR1-induced apoptosis and CRHR2-inhibited apoptosis. PMID- 24776848 TI - Evolutionary conservation and modulation of a juvenile growth-regulating genetic program. AB - Body size varies enormously among mammalian species. In small mammals, body growth is typically suppressed rapidly, within weeks, whereas in large mammals, growth is suppressed slowly, over years, allowing for a greater adult size. We recently reported evidence that body growth suppression in rodents is caused in part by a juvenile genetic program that occurs in multiple tissues simultaneously and involves the downregulation of a large set of growth-promoting genes. We hypothesized that this genetic program is conserved in large mammals but that its time course is evolutionarily modulated such that it plays out more slowly, allowing for more prolonged growth. Consistent with this hypothesis, using expression microarray analysis, we identified a set of genes that are downregulated with age in both juvenile sheep kidney and lung. This overlapping gene set was enriched for genes involved in cell proliferation and growth and showed striking similarity to a set of genes downregulated with age in multiple organs of the juvenile mouse and rat, indicating that the multiorgan juvenile genetic program previously described in rodents has been conserved in the 80 million years since sheep and rodents diverged in evolution. Using microarray and real-time PCR, we found that the pace of this program was most rapid in mice, more gradual in rats, and most gradual in sheep. These findings support the hypothesis that a growth-regulating genetic program is conserved among mammalian species but that its pace is modulated to allow more prolonged growth and therefore greater adult body size in larger mammals. PMID- 24776849 TI - Influence of parental alcohol-related attitudes, behavior and parenting styles on alcohol use in late and very late adolescence. AB - Parents influence adolescent drinking behavior, but to what extent does this association diminish with age, however? The cross-sectional data was drawn from the Scania drug use survey 2007, consisting of 4,828 secondary education students in the 9th and 11th grade. The age- and gender-adjusted findings indicate that having parents who are consenting to alcohol use (OR 1.4), having been provided with alcohol by one's parents (OR 1.8), having parents with an authoritarian (OR 1.5) or neglectful (OR 2.1) parenting style, and having parents who both have a university degree (OR 1.3) were factors significantly associated with monthly heavy episodic drinking. These findings lead to the conclusion that parenting styles as well as parental attitudes and behaviors are important throughout the high school years. Thus, prevention targeting parents should emphasize both these domains. PMID- 24776850 TI - Comparative structural modeling of six old yellow enzymes (OYEs) from the necrotrophic fungus Ascochyta rabiei: insight into novel OYE classes with differences in cofactor binding, organization of active site residues and stereopreferences. AB - Old Yellow Enzyme (OYE1) was the first flavin-dependent enzyme identified and characterized in detail by the entire range of physical techniques. Irrespective of this scrutiny, true physiological role of the enzyme remains a mystery. In a recent study, we systematically identified OYE proteins from various fungi and classified them into three classes viz. Class I, II and III. However, there is no information about the structural organization of Class III OYEs, eukaryotic Class II OYEs and Class I OYEs of filamentous fungi. Ascochyta rabiei, a filamentous phytopathogen which causes Ascochyta blight (AB) in chickpea possesses six OYEs (ArOYE1-6) belonging to the three OYE classes. Here we carried out comparative homology modeling of six ArOYEs representing all the three classes to get an in depth idea of structural and functional aspects of fungal OYEs. The predicted 3D structures of A. rabiei OYEs were refined and evaluated using various validation tools for their structural integrity. Analysis of FMN binding environment of Class III OYE revealed novel residues involved in interaction. The ligand para hydroxybenzaldehyde (PHB) was docked into the active site of the enzymes and interacting residues were analyzed. We observed a unique active site organization of Class III OYE in comparison to Class I and II OYEs. Subsequently, analysis of stereopreference through structural features of ArOYEs was carried out, suggesting differences in R/S selectivity of these proteins. Therefore, our comparative modeling study provides insights into the FMN binding, active site organization and stereopreference of different classes of ArOYEs and indicates towards functional differences of these enzymes. This study provides the basis for future investigations towards the biochemical and functional characterization of these enigmatic enzymes. PMID- 24776852 TI - Disparities among 2009 pandemic influenza A (H1N1) hospital admissions: a mixed methods analysis--Illinois, April-December 2009. AB - During late April 2009, the first cases of 2009 pandemic influenza A (H1N1) (pH1N1) in Illinois were reported. On-going, sustained local transmission resulted in an estimated 500,000 infected persons. We conducted a mixed method analysis using both quantitative (surveillance) and qualitative (interview) data; surveillance data was used to analyze demographic distribution of hospitalized cases and follow-up interview data was used to assess health seeking behavior. Invitations to participate in a telephone interview were sent to 120 randomly selected Illinois residents that were hospitalized during April-December 2009. During April-December 2009, 2,824 pH1N1 hospitalizations occurred in Illinois hospitals; median age (interquartile range) at admission was 24 (range: 6-49) years. Hospitalization rates/100,000 persons for blacks and Hispanics, regardless of age or sex were 2-3 times greater than for whites (blacks, 36/100,000 (95% Confidence Interval ([95% CI], 33-39)); Hispanics, 35/100,000 [95%CI,32-37] (; whites, 13/100,000[95%CI, 12-14); p<0.001). Mortality rates were higher for blacks (0.9/100,000; p<0.09) and Hispanics (1/100,000; p<0.04) when compared with the mortality rates for whites (0.6/100,000). Of 33 interview respondents, 31 (94%) stated that they had heard of pH1N1 before being hospitalized, and 24 (73%) did not believed they were at risk for pH1N1. On average, respondents reported experiencing symptoms for 2 days (range: 1-7) before seeking medical care. When asked how to prevent pH1N1 infection in the future, the most common responses were getting vaccinated and practicing hand hygiene. Blacks and Hispanics in Illinois experienced disproportionate pH1N1 hospitalization and mortality rates. Public health education and outreach efforts in preparation for future influenza pandemics should include prevention messaging focused on perception of risk, and ensure community wide access to prevention messages and practices. PMID- 24776853 TI - Attitudes, motivators, and barriers to a career in surgery: a national study of U.K. undergraduate medical students. AB - INTRODUCTION: Numerous factors influence the career choices of undergraduate medical students, although little work has focused specifically on the surgical specialties. We aimed to investigate medical students' early experiences of surgery along with the motivators and barriers to selecting a surgical career. METHODS: All final-year medical students were invited to participate in an online survey. A range of quantitative data (expressed as a proportion of total respondents) and qualitative data (grouped and thematically analyzed) were collected to evaluate students' attitudes to careers in surgery and potential influences on these. RESULTS: A total of 482 students from 20 medical schools throughout England and Wales completed the survey. Overall, 91% of respondents had work experience before medical school, in which the greatest satisfaction was reported in the 21% who undertook placements in surgery. In addition, 58% expressed a desire to spend time working abroad and 59% to undertake a period of research; the primary motivator for both was career/professional development. Surgery was the most popular career choice amongst respondents. The 2 most important factors in decisions pertaining to their career were reported as interest in the specialty and work-life balance. Students draw career advice from numerous sources, most commonly mentors (49%) and student surgical societies (46%). Only 1% wanted more website information, with personal contact being paramount. DISCUSSION: It is vital for the continuing strength of the profession and the quality of surgery for the public that we continue to attract the best undergraduates into careers in surgery. Surgeons of all grades must be aware that how they are perceived by students affects future career choices. Early experiences of surgery are fundamental in assisting medical students to make informed career choices. PMID- 24776851 TI - RACK-1 regulates let-7 microRNA expression and terminal cell differentiation in Caenorhabditis elegans. AB - The let-7 microRNA (miRNA) regulates cell cycle exit and terminal differentiation in the C. elegans heterochronic gene pathway. Low expression of let-7 results in retarded vulva and hypodermal cell development in C. elegans and has been associated with several human cancers. Previously, the versatile scaffold protein receptor for activated C kinase 1 (RACK1) was proposed to facilitate recruitment of the miRNA-induced silencing complex (miRISC) to the polysome and to be required for miRNA function in C. elegans and humans. Here, we show that depletion of C. elegans RACK-1 by RNAi increases let-7 miRNA levels and suppresses the retarded terminal differentiation of lateral hypodermal seam cells in mutants carrying the hypomorphic let-7(n2853) allele or lacking the let-7 family miRNA genes mir-48 and mir-241. Depletion of RACK-1 also increases the levels of precursor let-7 miRNA. When Dicer is knocked down and pre-miRNA processing is inhibited, depletion of RACK-1 still leads to increased levels of pre-let-7, suggesting that RACK-1 affects a biogenesis mechanism upstream of Dicer. No changes in the activity of the let-7 promoter or the levels of primary let-7 miRNA are associated with depletion of RACK-1, suggesting that RACK-1 affects let-7 miRNA biogenesis at the post-transcriptional level. Interestingly, rack-1 knockdown also increases the levels of a few other precursor miRNAs. Our results reveal that RACK-1 controls the biogenesis of a subset of miRNAs, including let-7, and in this way plays a role in the heterochronic gene pathway during C. elegans development. PMID- 24776854 TI - A longitudinal study of the American Board of Surgery examination index: can residents pass both the qualifying examination and certifying examination the first time? AB - BACKGROUND: There have been significant recent decreasing pass rate trends on the American Board of Surgery (ABS) Certifying Examination (CE) in the absence of clear trends on the Qualifying Examination (QE). The ABS examination index (ABS EI) represents the ratio of candidates per program that passed both the QE and CE on the first attempt. The aim of this study is to longitudinally evaluate the ABS EIs for residency programs. The hypothesis is that the ABS-EIs have also decreased over time. METHODS: In this retrospective study from 2002 to 2012, the ABS-EIs were obtained from the ABS for each of the general surgery residency programs. Nonparametric statistics were performed between early (2002-2007) and late (2007-2012) time periods for differences in ABS-EI and examination performance, using an alpha = 0.05. RESULTS: There were 235 included residency programs in this study. The first-attempt pass rate on the QE was 3961 of 4647 (85.2%) for the early period and 4204 of 4888 (86.1%) for the late period (p = 0.29). The first-attempt pass rate on the CE was 3555 of 4097 (86.8%) for the early period and 3450 of 4243 (81.3%) for the late period (p < 0.001). The median ABS-EI per program was 0.77 (interquartile range: 0.63-0.86) (range: 0.30-1.00) in the early period and 0.70 (interquartile range: 0.61-0.83) (range: 0.19-1.00) in the late period. Matched Wilcoxon signed rank tests showed that program ABS-EI and CE performance decreased (both p < 0.001), whereas QE performance remained the same (p = 0.48) over time. CONCLUSIONS: Fewer residents per program pass both the QE and CE on the first attempt, as shown by the decreasing ABS-EI over time. The ABS-EI trends may serve as a needs assessment for individual residency program education curricula and are important to residency programs and incoming general surgery applicants. PMID- 24776855 TI - International surgical residency electives: a collaborative effort from trainees to surgeons working in low- and middle-income countries. AB - In today's ever-globalizing climate, the academic sector bears a certain responsibility to incorporate global health opportunities into residency training programs. The worldwide unmet surgical need has been growing; it has been estimated by the World Health Organization that by 2030, surgical diseases will contribute significantly to the burden of global health. International electives (IE) offered during training may partially address this growing need. In addition, it can help trainees develop a heightened awareness of the social determinants of health in resource-limited areas, as well as gain insight into different cultures, health beliefs, and pathologic conditions. General surgery residency programs that offer IE may also stand to benefit by attracting a broader applicant pool, as well as by having the ability to train residents to rely less upon expensive tests and equipment, while further developing residents' physical examination and communications skills. The challenges that IE pose for trainees include the required adaptation to an environment devoid of an advanced and modern medical system, and a difficulty in learning a new language, culture, and local customs. However, IE may also be hazardous for home institutions as they may drain local resources and take limited educational experiences away from local providers. Despite the active promotion of international volunteerism by the American Board of Surgery, few surgery residency programs offer IE as part of the curriculum, with cost and supervision being the major obstacles to overcome. Consequently, it may be difficult to generate American surgical leaders in international health. In this article, we outline the steps needed to bring IE to an institution and how general surgery residency programs can help bridge the gap between surgeons in high-income countries and the growing surgical needs of the international community. PMID- 24776856 TI - Rovsing sign revisited-effects of an erroneous translation on medical teaching and research. AB - OBJECTIVE: To investigate whether Rovsing sign in the diagnosis of appendicitis is described and applied inaccurately in the current literature, scientific papers, and books; quantify the problem; and investigate the cause of this error. BACKGROUND: The method of eliciting Rovsing sign is not described uniformly throughout the literature. METHODS: PubMed, MEDLINE, and Embase searches were conducted, and 1178 individual studies were searched for the use of Rovsing sign. A total of 57 studies were included in this study; of these, 14 described the way that the sign was executed. Additionally, 3 current English (text)books on surgery, 3 German (text)books on surgery, and 3 German books on anatomy were analyzed. The descriptions in studies and books were compared with the original publication by Niels Thorkild Rovsing in 1907. RESULTS: No included study that described the method of eliciting Rovsing sign provided a correct description. None of the 3 English (text)books on surgery described the sign accurately, but all 6 German (text)books provided a correct description. CONCLUSION: Rovsing sign is used erroneously in clinical practice and medical research and is most likely already taught incorrectly to most medical students. All statistical data available on this sign must be questioned and reinvestigated in future well designed studies to assess the actual value of Rovsing sign in the diagnosis of appendicitis. PMID- 24776857 TI - Use of 3-dimensional printing technology and silicone modeling in surgical simulation: development and face validation in pediatric laparoscopic pyeloplasty. AB - OBJECTIVES: Pediatric laparoscopy poses unique training challenges owing to smaller workspaces, finer sutures used, and potentially more delicate tissues that require increased surgical dexterity when compared with adult analogs. We describe the development and face validation of a pediatric pyeloplasty simulator using a low-cost laparoscopic dry-laboratory model developed with 3-dimensional (3D) printing and silicone modeling. DESIGN AND SETTING: The organs (the kidney, renal pelvis, and ureter) were created in a 3-step process where molds were created with 3D modeling software, printed with a Spectrum Z510 3D printer, and cast with Dragon Skin 30 silicone rubber. The model was secured in a laparoscopy box trainer. A pilot study was conducted at a Canadian Urological Association meeting. A total of 24 pediatric urology fellows and 3 experienced faculty members then assessed our skills module during a minimally invasive surgery training course. Participants had 60 minutes to perform a right-side pyeloplasty using laparoscopic tools and 5-0 VICRYL suture. Face validity was demonstrated on a 5-point Likert scale. PARTICIPANTS AND RESULTS: The dry-laboratory model consists of a kidney, a replaceable dilated renal pelvis and ureter with an obstructed ureteropelvic junction, and an overlying peritoneum with an inscribed fundamentals of laparoscopic surgery pattern-cutting exercise. During initial validation at the Canadian Urological Association, participants rated (out of 5) 4.75 +/- 0.29 for overall impression, 4.50 +/- 0.41 for realism, and 4.38 +/- 0.48 for handling. During the minimally invasive surgery course, 22 of 24 fellows and all the faculty members completed the scoring. Usability was rated 4 or 5 by 14 participants (overall, 3.6 +/- 1.22 by novices and 3.7 +/- 0.58 by experts), indicating that they would use the model in their own training and teaching. Esthetically, the model was rated 3.5 +/- 0.74 (novices) and 3.3 +/- 0.58 (experts). CONCLUSIONS: We developed a pediatric pyeloplasty simulator by applying a low-cost reusable model for laparoscopic training and skills acquisition. The model's usability, realism, and feel are good, it can be imaged under common modalities, and it shows promise as an educational tool. PMID- 24776858 TI - Surgery residency curriculum examination scores predict future American Board of Surgery in-training examination performance. AB - IMPORTANCE: A protected block curriculum (PBC) with postcurriculum examinations for all surgical residents has been provided to assure coverage of core curricular topics. Biannual assessment of resident competency will soon be required by the Next Accreditation System. OBJECTIVE: To identify opportunities for early medical knowledge assessment and interventions, we examined whether performance in postcurriculum multiple-choice examinations (PCEs) is predictive of performance in the American Board of Surgery In-Training Examination (ABSITE) and clinical service competency assessments. DESIGN: Retrospective single institutional education research study. SETTING: Academic general surgery residency program. PARTICIPANTS: A total of 49 surgical residents. INTERVENTION: Data for PGY1 and PGY2 residents participating in the 2008 to 2012 PBC are included. Each resident completed 6 PCEs during each year. MAIN OUTCOME MEASURES: The results of 6 examinations were correlated to percentage-correct ABSITE scores and clinical assessments based on the 6 Accreditation Council for Graduate Medical Education core competencies. Individual ABSITE performance was compared between PGY1 and PGY2. Statistical analysis included multivariate linear regression and bivariate Pearson correlations. RESULTS: A total of 49 residents completed the PGY1 PBC and 36 completed the PGY2 curriculum. Linear regression analysis of percentage-correct ABSITE and PCE scores demonstrated a statistically significant correlation between the PGY1 PCE 1 score and the subsequent PGY1 ABSITE score (p = 0.037, beta = 0.299). Similarly, the PGY2 PCE 1 score predicted performance in the PGY2 ABSITE (p = 0.015, beta = 0.383). The ABSITE scores correlated between PGY1 and PGY2 with statistical significance, r = 0.675, p = 0.001. Performance on the 6 Accreditation Council for Graduate Medical Education core competencies correlated between PGY1 and PGY2, r = 0.729, p = 0.001, but did not correlate with PCE scores during either years. CONCLUSIONS AND RELEVANCE: Within a mature PBC, early performance in a PGY1 and PGY2 PCE is predictive of performance in the respective ABSITE. This information can be used for formative assessment and early remediation of residents who are predicted to be at risk for poor performance in the ABSITE. PMID- 24776859 TI - Improvement in American Board of Surgery in-training examination performance with a multidisciplinary surgeon-directed integrated learning platform. AB - BACKGROUND: The American Board of Surgery In-Training Examination (ABSITE) is a predictor of resident performance on the general surgery-qualifying examination and plays a role in obtaining competitive fellowships. A learning management system (LMS) permits the delivery of a structured curriculum that appeals to the modern resident owing to the ease of accessibility and all-in-one organization. This study hypothesizes that trainees using a structured surgeon-directed LMS will achieve improved ABSITE scores compared with those using an unstructured approach to the examination. STUDY DESIGN: A multidisciplinary print and digital review course with practice questions, review textbooks, weekly reading assignments, and slide and audio reviews integrated within an online LMS was made available to postgraduate year (PGY)-3 and PGY-4 residents in 2008 and 2009. Surveys were emailed requesting ABSITE scores to compare outcomes in those trainees that used the course with those who used an unstructured approach. Statistical analysis was conducted via descriptive statistics and Pearson chi square with p < 0.05 deemed statistically significant. RESULTS: Surveys were mailed to 508 trainees. There was an 80% (408) response rate. Residents who used structured approaches in both the years achieved the highest scores, followed by those who adopted a structured approach in PGY-4. The residents using an unstructured approach in both the years showed no significant improvement. CONCLUSION: Residents who used a structured LMS performed significantly better than their counterparts who used an unstructured approach. A properly constructed online education curriculum has the potential to improve ABSITE scores. PMID- 24776860 TI - Invited commentary for "Perceptions of SVS members and surgery department chairs of the integrated 0 + 5 vascular surgery training paradigm". PMID- 24776861 TI - Usefulness of bowel sound auscultation: a prospective evaluation. AB - INTRODUCTION: Although the auscultation of bowel sounds is considered an essential component of an adequate physical examination, its clinical value remains largely unstudied and subjective. OBJECTIVE: The aim of this study was to determine whether an accurate diagnosis of normal controls, mechanical small bowel obstruction (SBO), or postoperative ileus (POI) is possible based on bowel sound characteristics. METHODS: Prospectively collected recordings of bowel sounds from patients with normal gastrointestinal motility, SBO diagnosed by computed tomography and confirmed at surgery, and POI diagnosed by clinical symptoms and a computed tomography without a transition point. Study clinicians were instructed to categorize the patient recording as normal, obstructed, ileus, or not sure. Using an electronic stethoscope, bowel sounds of healthy volunteers (n = 177), patients with SBO (n = 19), and patients with POI (n = 15) were recorded. A total of 10 recordings randomly selected from each category were replayed through speakers, with 15 of the recordings duplicated to surgical and internal medicine clinicians (n = 41) blinded to the clinical scenario. The sensitivity, positive predictive value, and intra-rater variability were determined based on the clinician's ability to properly categorize the bowel sound recording when blinded to additional clinical information. Secondary outcomes were the clinician's perceived level of expertise in interpreting bowel sounds. RESULTS: The overall sensitivity for normal, SBO, and POI recordings was 32%, 22%, and 22%, respectively. The positive predictive value of normal, SBO, and POI recordings was 23%, 28%, and 44%, respectively. Intra-rater reliability of duplicated recordings was 59%, 52%, and 53% for normal, SBO, and POI, respectively. No statistically significant differences were found between the surgical and internal medicine clinicians for sensitivity, positive predictive value, or intra-rater variability. Overall, 44% of clinicians reported that they rarely listened to bowel sounds, whereas 17% reported that they always listened. CONCLUSIONS: Auscultation of bowel sounds is not a useful clinical practice when differentiating patients with normal versus pathologic bowel sounds. The listener frequently arrives at an incorrect diagnosis. If routine abdominal auscultation is to be continued, our findings emphasize the need for improvements in training and education as well as advancements in the understanding of the objective acoustical properties of bowel sounds. PMID- 24776862 TI - Animal laboratories are not needed to train medical students. PMID- 24776863 TI - Gender differences in successful National Institutes of Health funding in ophthalmology. AB - OBJECTIVE: To determine whether gender differences in individual National Institutes of Health (NIH) awards and in funding totals exist in ophthalmology, and to further characterize whether factors such as experience, academic rank, and terminal degree play a role. DESIGN: A retrospective review of awards granted to primary investigators (PIs) in ophthalmology departments from 2011 through the present was conducted. PIs were classified by gender, degree, experience, and academic position. The NIH funding database was used to gather award data. SETTING: Academic medical center. RESULTS: Men had higher mean NIH awards ($418,605) than their female colleagues ($353,170; p = 0.005) and had higher total funding per PI (p = 0.004). Men had statistically higher awards at the level of assistant professor than their female counterparts (p < 0.05). A gender difference was statistically significant and most marked among researchers holding an MD (or equivalent) degree. When controlled for publication experience, men had higher NIH awards throughout their careers, although this difference only reached statistical significance on comparison of faculty with 10 or fewer years of experience. CONCLUSIONS: Male PIs receiving grants since 2011 had higher awards than their female colleagues did, most markedly among PIs in the earlier portions of their career. Differences in gender representation among senior faculty and in positions of leadership in academic ophthalmology may be partially a result of disparities in research output, as scholarly productivity is an important component of the academic advancement process in ophthalmology. PMID- 24776864 TI - Assessing competency in practice-based learning: a foundation for milestones in learning portfolio entries. AB - BACKGROUND: Graduate medical education is undergoing a dramatic shift toward competency-based assessment of learners. Competency assessment requires clear definitions of competency and validated assessment methods. The purpose of this study is to identify criteria used by surgical educators to judge competence in Practice-Based Learning and Improvement (PBL&I) as demonstrated in learning portfolios. METHODS: A total of 6 surgical learning and instructional portfolio entries served as documents to be assessed by 3 senior surgical educators. These faculty members were asked to rate and then identify criteria used to assess PBL&I competency. Individual interviews and group discussions were conducted, recorded, and transcribed to serve as the study dataset. Analysis was performed using qualitative methodology to identify themes for the purpose of defining competence in PBL&I. The assessment themes derived are presented with narrative examples to describe the progression of competency. RESULTS: The collaborative coding process resulted in identification of 7 themes associated with competency in PBL&I related to surgical learning and instructional portfolio entries: (1) self-awareness regarding effect of actions; (2) identification and thorough description of learning goals; (3) cases used as catalyst for reflection; (4) reconceptualization with appropriate use and critique of cited literature; (5) communication skills/completeness of entry template; (6) description of future behavioral change; and (7) engagement in process--identifies as personally relevant. CONCLUSIONS: The identified themes are consistent with and complement other criteria emerging from reflective practice literature and experiential learning theory. This study provides a foundation for further development of a tool for assessing learner portfolios consistent with the Accreditation Council for Graduate Medical Education's Next Accreditation System requirements. PMID- 24776865 TI - A novel approach to teaching surgical skills to medical students using an ex vivo animal training model. AB - OBJECTIVES: Traditional surgical teaching is influenced by restrictive factors, such as financial pressures and ethical constraints. The teaching of surgical skills during a medical school education seems not to be robust enough at present, possibly resulting in stressful circumstance for surgical novices. However, the authors are convinced that practical training is fundamental for preparing medical students optimally for challenges in the operating theater and have, therefore, examined a novel method of teaching basic surgical skills to medical students. METHODS: A total of 20 medical students received surgical skill training, which included theoretical lessons, working with ex vivo pig training models, and active participation in the operating theater. All the trainees took written tests and were rated in an Objective Structured Clinical Examination. Before and after training, the students completed a self-assessment form involving the choice of the correct surgical indication and the performance of surgical procedures. RESULTS: The students' performance in the written examination and in the Objective Structured Clinical Examination increased significantly after training (p <= 0.001). Furthermore, the evaluation of the self-assessment form revealed significant improvements in all categories (p <= 0.001). CONCLUSIONS: Our surgical training method appears to improve the surgical abilities of medical students and to increase their self-confidence with respect to surgical procedures. Therefore, the authors recommend the integration of this method into the medical school curriculum to prepare medical students well for surgical challenges. PMID- 24776867 TI - Effect of the full implementation of the European Working Time Directive on operative training in adult cardiac surgery. AB - OBJECTIVES: Surgical specialties rely on practice and apprenticeship to acquire technical skills. In 2009, the final reduction in working hours to 48 per week, in accordance with the European Working Time Directive (EWTD), has also led to an expansion in the number of trainees. We examined the effect of these changes on operative training in a single high-volume [>1500 procedures/year] adult cardiac surgical center. METHODS: Setting: A single high-volume [>1500 procedures/year] adult cardiac surgical center. Design: Consecutive data were prospectively collected into a database and retrospectively analyzed. Procedures and Main Outcome Measures: Between January 2006 and August 2010, 6688 consecutive adult cardiac surgical procedures were analyzed. The proportion of cases offered for surgical training were compared for 2 non-overlapping consecutive time periods: 4504 procedures were performed before the final implementation of the EWTD (Phase 1: January 2006-December 2008) and 2184 procedures after the final implementation of the EWTD (Phase 2: January 2009-August 2010). Other predictors of training considered in the analysis were grade of trainee, logistic European system for cardiac operative risk evaluation (EuroSCORE), type of surgical procedure, weekend or late procedure, and consultant. Logistic regression analysis was used to determine the predictors of training cases (procedure performed by trainee) and to evaluate the effect of the EWTD on operative surgical training after correcting for confounding factors. RESULTS: Proportion of training cases rose from 34.6% (1558/4504) during Phase 1 to 43.6% (953/2184) in Phase 2 (p < 0.0001), despite higher mean logistic EuroSCORE [4.29 (6.8) during Phase 1 vs 4.95 (7.2) during Phase 2, p < 0.0001] and higher proportion of cases performed out of hours [153 (3.4) during Phase 1 vs 116 (5.3) during Phase 2, p < 0.0001]. During Phase 1, senior trainees (last 2 years of training) performed 803 (17.8%) procedures, whereas other trainees (first 4 years of training) performed 755(16.8%) cases. During Phase 2, senior trainees performed 763 (34.9%) procedures, whereas other trainees performed 190 (8.7%) cases (p < 0.0001). Independent positive predictors of training cases emerging from the multivariable logistic regression model included consultant in charge, final EWTD, and senior trainees. Independent negative predictors of training cases included logistic EuroSCORE, out-of-hours' procedures, and surgery other than coronary artery bypass grafts. CONCLUSION: Implementation of the final phase of EWTD has not decreased training in a high-volume center. The positive adjustment of trainers' attitudes and efforts to match trainees' needs allow maintenance of adequate training, despite reduction in working hours and increasing patients' risk profile. PMID- 24776866 TI - Face, content, and construct validation of the Bristol TURP trainer. AB - INTRODUCTION: Validation studies are an important part of simulator evaluation and are considered necessary to establish the effectiveness of simulation-based training. The widely used Bristol transurethral resection of prostate (TURP) simulator has not been formally validated. OBJECTIVES: Evaluation of the face, content, and construct validities of the Bristol TURP simulator as an endourology training tool. DESIGN: Using established validation methodology, face, content, and construct validities were evaluated. Face and content validities were assessed using a structured quantitative survey. Construct validity was assessed by comparing the performance of experts and novices using a validated performance scale and resection efficiency. PARTICIPANTS AND SETTING: Overall, 8 novice urologists and 8 expert urologists participated in the study. The study was conducted in a dedicated surgical simulation training facility. RESULTS: All 16 participants felt the model was a good training tool and should be used as an essential part of urology training (face validity). Content validity evaluation showed that most aspects of the simulator were adequately realistic (mean Likert scores 3.38-3.57/5); however, the model does not simulate bleeding. Experts significantly outperformed novices (p < 0.001) across all measures of performance, therefore establishing construct validity. CONCLUSIONS: The Bristol TURP simulator shows face, content, and construct validities, although some aspects of the simulator were not very realistic (e.g., bleeding). This study provides evidence for the continuing use of this simulator in endourology training. PMID- 24776868 TI - Research productivity and gender disparities: a look at academic plastic surgery. AB - OBJECTIVES: The h-index has utility in examining the contributions of faculty members by quantifying both the amount and the quality of research output and as such is a metric in approximating academic productivity. The objectives of this study were (1) to evaluate the relationship between h-index and academic rank in plastic surgery and (2) to describe the current gender representation in academic plastic surgery to assess whether there are any gender disparities in academic productivity. DESIGN: The h-index was used to evaluate the research contributions of plastic surgeons from academic departments in the United States. RESULTS: There were 426 (84%) men and 79 (16%) women in our sample. Those in higher academic ranks had higher h-index scores (p < 0.0005). There was a significant difference in overall mean h-index by gender, where the mean scores were 9.0 and 6.0 for men and women, respectively (p = 0.0005). When analyzed by academic rank, there was a significant difference in academic productivity between men and women in assistant and associate professor positions (6.4 vs 5.1, respectively; p = 0.04). CONCLUSIONS: The h-index is able to objectively and reliably quantify academic productivity in plastic surgery. We found that h-indices increased with higher academic rank, and men had overall higher scores than their female colleagues. Adoption of this metric as an adjunct to other objective and subjective measures by promotions committees may provide a more reliable measure of research relevance and academic productivity in academic plastic surgery. PMID- 24776869 TI - A tool for training in decision making for emergency general surgery--explicit training is possible through facilitation. AB - BACKGROUND: Emergency general surgery is increasingly recognized as an area for improvement within the National Health Service in the United Kingdom. Our aim was to test the feasibility of a tool we developed in assessing and facilitating surgical decision making by trainees in the emergency setting. METHODS: A decision-making tool based on common decisions in surgery was designed and incorporated prospectively into patient clerking. The 10 decisions available to surgeons were divided into 3 major headings: discharge decisions, observation decisions, and operative decisions. "Ideal decisions" were derived from the final diagnosis on discharge by 2 independent clinicians and compared with initial decisions made by surgeons. We analyzed the data with a view to validate the tool using 2 methods. Firstly, we looked at the percentage of correct decisions made by different grades of surgeon, and secondly, we analyzed the trends in deviations from ideal decisions. RESULTS: The decision-making tool was completed for 136 emergent surgical admissions over 2 months. Interns made less "ideal" decisions compared with residents (45% vs 56%, respectively; p = 0.10, Fisher exact test) and attending surgeons (45% vs 70%, respectively; p = 0.0001). Interns made more "admit and observe or investigate" decisions compared with residents (63% vs 55%, respectively; p = 0.27) and attending surgeons (63% vs 51%, respectively; p = 0.01), who were more likely to decide to operate on or discharge patients. A repeat study over the subsequent 2-month period has shown comparable findings in proportion of ideal decisions for each grade of surgeon. CONCLUSIONS: There are significant differences in the proportion of "ideal decisions" and types of decisions between interns and attending surgeons suggesting a learning curve and potential for using this tool in decision-making training. The tool inherently facilitates discussion over decisions made by making these explicit. Repeating the study revealed an internal consistency. PMID- 24776871 TI - Assessment of procedural skills using virtual simulation remains a challenge. AB - OBJECTIVE: The LAP Mentor is a procedural simulator that provides a stepwise training for laparoscopic cholecystectomy. This study addresses its "construct" validity that is present when a simulator is able to discriminate between persons with known differences in performance level on the laparoscopic cholecystectomy in real life. DESIGN: Three groups with different skill levels performed 2 trials of 4 distinct parts of the cholecystectomy procedure (cholecystectomy exercises) and 1 full procedure on the LAP Mentor. Assessment parameters concerning the quantity and the quality of performance were compared between groups using the Kruskal-Wallis and Mann-Whitney U tests. SETTING: The entire research was performed in the Center for Surgical Technologies, Leuven, Belgium. PARTICIPANTS: For study purposes, 5 expert abdominal laparoscopists (>100 laparoscopic cholecystectomies performed), 11 surgical residents (10-30 cholecystectomies performed), and 10 novices (minimal laparoscopic experience) were recruited. RESULTS: With regard to the quantity of performance (time needed and number of movements), the experts showed significantly better results compared with the novices in the cholecystectomy exercises. Only in the full procedure, the results of all the parameters (except speed) were significantly different between the 3 groups, with the best results observed for the experts and worst for the novices. With respect to quality of performance, only the parameter "accuracy rate of dissection" in exercise 3 showed significantly better performance by the experts. CONCLUSIONS: Only the full procedure of the LAP Mentor procedural simulator has enough discriminative power to claim construct validity. However, the lack of quality control, which is indispensible in the evaluation of procedural skills, makes it currently unsuited for the assessment of procedural laparoscopic skills. The role of the simulator in a training context remains to be elucidated. PMID- 24776870 TI - Results of a near-peer musculoskeletal medicine curriculum for senior medical students interested in orthopedic surgery. AB - INTRODUCTION: It has been previously demonstrated that medical students do not achieve an adequate musculoskeletal knowledge base on graduation from American medical schools. Several curriculums have been developed to address this measured deficit. Students entering orthopedic surgery residencies have a better musculoskeletal knowledge foundation than their peers but still fail to achieve an acceptable level of proficiency on graduation from medical school. METHODS: Fourth-year medical students participating in senior elective rotations in orthopedic surgery over a 2-year period were given a series of lectures developed and presented by post graduate year 3 orthopedic surgery residents. Students completed a validated musculoskeletal competency examination and a survey following the conclusion of their experience, evaluating the effect of this curriculum. RESULTS: A total of 71 students over 2 years participated in the near peer curriculum, with all students completing the validated test. The mean score for the students was 83.6%. Of the 71 students, 60 (84.5%) scored more than the previously published passing rate of 73.1%. There was no correlation identified with the mean test scores and the number of previous orthopedic surgery rotations. From the survey, 96% of the students rated the near-peer curriculum as appropriate for their level, whereas 75% noted that their own medical school's musculoskeletal curriculum was too advanced for their level of training. CONCLUSION: A series of lectures was developed by midlevel orthopedic residents for students interested in pursuing a career in orthopedic surgery. After participation in the curriculum, students scored 30-percentage points higher than a previously published test. This study demonstrates that a resident-initiated, near-peer curriculum increases the fundamental knowledge level of students entering orthopedic surgery. An added benefit appeared to be the skills obtained by the residents who created and delivered the lecture series. PMID- 24776872 TI - Standardizing the culture of trauma rotation handoffs. AB - OBJECTIVE: One of the General Surgery milestones focuses on effective handoffs between residents as they change shifts. Although the content of handoffs is crucial, we recognized that the culture of handoffs was equally important. After the reorganization of the trauma service at our institution, there were difficulties in maintaining the standardized handoff culture. We analyzed the culture of handoffs on the trauma service to create an environment more conducive to effective handoffs. DESIGN: All trauma activations from 2012 to 2013 were evaluated from our institution's trauma data registry. Data on timing of activations and disposition of the patient were analyzed to understand service work flow. A survey was developed and administered to the residents to assess the culture of trauma handoffs. SETTING: This work occurred at an academic, state designated level 1 trauma center. PARTICIPANTS: All current residents in the general surgery residency who rotated on the trauma service in the last 5 years. RESULTS: There were 1654 admissions to the trauma service from June 2012 to July 2013. The single busiest hour for trauma admissions (7% of admissions) was the same time the residents were designated to handoff. Interruptions occurred often; 83% of residents indicated that a handoff interruption occurred daily, and 73% indicated a new activation interrupted handoffs weekly. A large majority, 61%, felt patient care was frequently compromised by an ineffective handoff. Similarly, as a direct result of inadequate handoffs, 50% felt uncomfortable answering nurses' pages at night. CONCLUSIONS: The unique situation of the trauma service impaired the handoff culture for residents. Assessment of our trauma activation flow indicates the timing of handoffs was adversely affecting our resident's ability to handoff effectively, requiring interventions to improve the efficacy and safety of handoffs. PMID- 24776873 TI - Integrated military and civilian surgical residency: a review of one program, its development, and future trends. PMID- 24776874 TI - Patient safety in the era of the 80-hour workweek. AB - OBJECTIVE: In 2003, duty-hour regulations (DHR) were initially implemented for residents in the United States to improve patient safety and protect resident's well-being. The effect of DHR on patient safety remains unclear. The study objective was to evaluate the effect of DHR on patient safety. DESIGN: Using an interrupted time series analysis, we analyzed selected patient safety indicators (PSIs) for 376 million discharges in teaching (T) vs nonteaching (NT) hospitals before and after implementation of DHR in 2003 that restricted resident work hours to 80 hours per week. The PSIs evaluated were postoperative pulmonary embolus or deep venous thrombosis (PEDVT), iatrogenic pneumothorax (PTx), accidental puncture or laceration, postoperative wound dehiscence (WD), postoperative hemorrhage or hematoma, and postoperative physiologic or metabolic derangement. Propensity scores were used to adjust for differences in patient comorbidities between T and NT hospitals and between discharge quarters. The primary outcomes were differences in the PSI rates before and after DHR implementation. The PSI differences between T and NT institutions were the secondary outcome. SETTING: T and NT hospitals in the United States. PARTICIPANTS: Participants were 376 million patient discharges from 1998 to 2007 in the Nationwide Inpatient Sample. RESULTS: Declining rates of PTx in both T and NT hospitals preintervention slowed only in T hospitals postintervention (p = 0.04). Increasing PEDVT rates in both T and NT hospitals increased further only in NT hospitals (p = 0.01). There were no differences in the PSI rates over time for hemorrhage or hematoma, physiologic or metabolic derangement, accidental puncture or laceration, or WD. T hospitals had higher rates than NT hospitals both preintervention and postintervention for all the PSIs except WD. CONCLUSIONS: Trends in rates for 2 of the 6 PSIs changed significantly after DHR implementation, with PTx rates worsening in T hospitals and PEDVT rates worsening in NT hospitals. Lack of consistent patterns of change suggests no measurable effect of the policy change on these PSIs. PMID- 24776875 TI - Recruitment of Young Medical Apprentices (RYOMA) project: a comprehensive surgical education program at a local academic institute in Japan. AB - OBJECTIVES: The number of young surgeons in Japan has significantly decreased in recent years, which may lead to future problems in the medical field. Therefore, comprehensive training programs for young surgeons are needed. DESIGN: Retrospective study SETTING: We developed a specific education program called the "Recruitment of Young Medical Apprentices" (RYOMA) project. PARTICIPANTS: We performed this project between January 2008 and August 2013 on fourth- to sixth year medical students and internship doctors. The RYOMA project included step-by step surgical education programs on open and scopic procedures as dry, wet, and animal laboratory training. Our goal was to increase the number of young and specialist surgeons. RESULTS: Based on an interview questionnaire answered by 90 medical students, most young students were interested in surgical training and several chose to become surgeons in the future. The most positive opinions regarding the field of surgery were the impressive results achieved with surgery, whereas negative opinions included the difficulty of the surgical skill, physical concerns related to difficult work environments, and the severity of surgical procedures. The present program has begun to resolve negative opinions through adequate training or simulations. Of the 19 medical students and internship doctors who attended the RYOMA project in 2008, 17 trainees (90%) were satisfied with this special surgical program and 16 (88%) showed interest in becoming surgeons. The number of participants considering the field of surgery increased between 2008 and 2013. Of 23 participants, 19 (83%) had a positive opinion of the program after the training. CONCLUSIONS: Gaining experience in surgical training from an early stage in medical school and step-by-step authorized education by teaching staff are important for recruiting students and increasing the number of young surgeons. PMID- 24776876 TI - Surgical journal club as a community of practice: a case study. AB - BACKGROUND: Journal club has become a signature pedagogy in postgraduate medical education. In this article, social learning theory, through the lens of "communities of practice" (CoP), is applied to elucidate the process of learning in journal club. MATERIALS AND METHODS: The study is a case study of a surgical journal club. Video recordings of 2 journal club sessions were followed by semistructured audio-recorded interviews with a sample of journal club participants. Thematic content analysis was performed, mapping data to themes arising based on the key tenets of CoP. RESULTS: Features of the 4 tenets of CoP learning (community, meaning, identity, and practice) were identified in both the video recordings of journal club and the participant interviews. A shared enterprise and common sense of purpose (community) was seen throughout the video recordings, but feelings of belonging to the community were much stronger for senior members (consultants/attending staff and senior trainees) compared with junior members (junior trainees and students). Experiences and perspectives were more commonly exchanged between senior trainees and consultants, with junior trainees not partaking in discussions, an example of newcomers beginning at the periphery. The main impediment to learning was found with low senior member attendance at journal club, thus limiting access to narratives of senior experience of practice and feedback. CONCLUSIONS: In attempting to improve journal club design for learning, ensuring the participation of senior community members and thus access to narratives of experience along with active engagement of junior members to allow them develop their own meaning should be incorporated into the journal club design. PMID- 24776877 TI - Implementation and evaluation of a novel operating room curriculum for the obstetrics and gynecology clerkship. AB - OBJECTIVE: Primary objective is to estimate the effect of an operating room (OR) curriculum on obstetrics and gynecology (Ob/Gyn) students' clinical knowledge related to the OR. Secondary objective is to estimate the effect of the curriculum on student confidence and satisfaction related to the OR experience. STUDY DESIGN: Prospective cohort study of 6 Ob/Gyn clerkship groups from September 2011 to June 2012. Three control groups received usual teaching and 3 intervention groups received the OR curriculum plus usual teaching. The primary outcome was the measurement of student knowledge using preclerkship and postclerkship questionnaires. Student confidence and satisfaction related to the OR experience were also measured using questionnaires. Standard clerkship evaluations were reviewed to rate the quality of faculty teaching. Between-group scores were compared using Student t test. A total of 26 students per group were needed to detect a 20% difference in between-group change in clinical knowledge (alpha = 0.05, 80% power). SETTING: Women and Infants' Hospital, Providence, Rhode Island, a tertiary care teaching hospital for the Warren Alpert Medical School of Brown University. PARTICIPANTS: Ob/Gyn clerkship students. RESULTS: Overall, 70 students were enrolled-68 completed evaluation measures immediately after clerkship and 27 at 6 months after clerkship. More intervention subjects were fourth-year students (p = 0.03) and had completed surgery clerkships (p = 0.003). At baseline, groups demonstrated similar clinical knowledge and confidence (p > 0.05). Although there was no difference between groups in knowledge scores immediately after clerkship, at 6 months, the intervention group had greater retention in clinical knowledge scores (1.2 +/- 2.6 vs 3.5 +/- 1.8; p = 0.02). At clerkship completion, intervention group was more satisfied with student-faculty interaction (mean sum score = 14.7 +/- 3.5 vs 16.9 +/- 3.0; p = 0.01). On review of standard clerkship evaluations, intervention subjects gave significantly higher scores for quality of faculty teaching (3.82 +/- 1.18 vs 4.39 +/- 0.67; p = 0.01). CONCLUSIONS: Our OR curriculum improved knowledge retention, increased student satisfaction with student-faculty interactions in the OR, and improved faculty teaching evaluation. PMID- 24776878 TI - Homage: education and life lessons as taught by Dr James D. Hardy. AB - Dr James D. Hardy served as Chairman of the Department of Surgery at the University of Mississippi Medical Center Jackson, Mississippi, from 1955 to 1987. During his tenure, he had an unprecedented effect on the education of medical students, residents, and professionals in his field. Not only did he speak and write voluminously about medical education and the roles both teacher and student play in this interaction but also emphasized the importance of the family unit to the academic physician. This article serves to highlight Dr Hardy's thoughts about discipline, research, and personal experience as they pertain to medical education, as well as to impart some of his wisdom about life, family, and personal well-being. PMID- 24776879 TI - Performance variables and professional experience in simulated laparoscopy: a two group learning curve study. AB - OBJECTIVE: Virtual reality simulators are increasingly used in laparoscopy training. Such simulators allow objective assessment of performance. However, both low-level variables and overall scores generated by the simulator can be hard to interpret. We present a method to generate intermediate performance variables and show how the resulting variables can be used to investigate the development of laparoscopic skills. DESIGN: A beginner group (n = 16) and a group with intermediate laparoscopic experience (n = 9) participated in a 5-session, basic skills training course hosted by the Department of Technical Medicine at the University of Twente. Multiple simulator-generated variables were aggregated into 4 performance variables: duration, left-hand motion, right-hand motion, and damage. Differences in performance were analyzed in relation to proficiency values. RESULTS: Damage performance differentiated the most between groups and proficiency values; motion performance variables differentiated the least. The more experienced group outperformed the beginner group at damage by the end of the course. CONCLUSIONS: Differentiating between duration, left-hand motion, right-hand motion, and damage is a useful way to investigate laparoscopic performance development. Different performance variables follow different trajectories toward expertise. Valid and reliable clinical damage parameters are needed to investigate the relation of real-world damage to simulator damage. PMID- 24776880 TI - Characterizing information decay in patient handoffs. AB - OBJECTIVE: The purpose of this study was to analyze the decay of information with multiple sequential patient handoff reports given by third-year medical students who have not had standardized patient handoff training. METHODS: We examine the information decay of quantitative parameters included in 2 different simulated patient history and physical handoffs conducted among third-year medical students. Both student self-surveys and third party observer surveys tracked accuracy of information. A total of 93 students were surveyed for the first patient scenario and 103 students were surveyed for second patient scenario. Survey data were aggregated into 2 separate spreadsheets, one for each patient scenario tested. A total of 16 data points pertaining to the checklist were analyzed for common trends in handoff accuracy and information decay. RESULTS: Quantitative analysis of information passed between handoffs showed that between the 2 case scenarios, there was a consistent loss of information between one presenter to the next. Overall, 33% of information was lost between the first and third handoffs. Within the progression of individual handoffs, a narrative decay was demonstrated. There was a regression in handoff accuracy, trending down to an average of only 45% of information being passed on successfully by the time each presenter reached the last piece of information in their patient presentation. When examining the survey data points that had greater than an 80% success rate of being included in the handoffs, there appeared to be no correlation between their inherent qualities. CONCLUSIONS: This study showed there is a significant decrease in accuracy of information during sequential patient handoff exercises. The information decay may be a result of time, memory, or relevance of the information to the student. Future studies incorporating teaching effective handoffs early in the clinical curriculum would be an area of future research. PMID- 24776881 TI - Perception of undergraduate pediatric surgery clerkship in a developing country. PMID- 24776882 TI - Perception of undergraduate pediatric surgery clerkship in a developing country. AB - OBJECTIVE: Medical students' perception of their clerkship may influence their choice of ultimate career. In most medical schools, pediatric surgery clerkship (PSC) is not compulsory. This study evaluates the perception of PSC by students and determines the importance of this on the choice of pediatric surgery as a career. METHODS: We surveyed 2009 and 2010 graduating medical classes of University of Nigeria, Nsukka, using self-administered questionnaires. The clerkship evaluation was assessed using a 3-point scale (1 = poor and 3 = excellent). Students who had PSC were analyzed to compare their rating of pediatric surgery vis-a-vis other clinical clerkships and determine the effect of the clerkship on their ultimate choice of a career. RESULTS: Overall response rate was 70.3% (275/391), and 119 (43.3%) had PSC. For overall quality, PSC rated (2.16) compared with general surgery (2.04), internal medicine (2.11), obstetrics and gynecology (2.13), and pediatrics (2.37). Aspects of PSC that rated poorly include opportunity to participate in direct patient care, feedback on performance during clerkship, ability to manage problem in a general medical setting, and experience in learning history-taking skills and interpretation of laboratory data. Among the students who had PSC, 14 (11.8%) selected pediatric surgery as a specialty choice compared with 13 (8.3%) who did not have PSC (p = 0.457). Of those that had PSC, pediatric surgery was selected as a career by 2 of 19 (10.5%), 6 of 63 (9.5%), and 6 of 37 (16.2%) who rated PSC as poor, just right, and excellent, respectively. The decision to select pediatric surgery was influenced mostly by clerkship experience in 37% (10/27) and personal satisfaction in 40.7% (11/27). Improvement in the quality of PSC may involve more participation of the students in direct patient care (n = 54; 45.4%) and enhancement in student-faculty interaction (n = 31; 26.1%). CONCLUSION: PSC may have a good rating in our setting. Nonetheless, improving the quality and experience of the clerkship through a well-thought-out curriculum modification may enhance interest in pediatric surgery as a career choice. PMID- 24776883 TI - Troublesome knowledge in pediatric surgical trainees: a qualitative study. AB - BACKGROUND: Meyer and Land (2003) describe threshold concepts as being "akin to a portal, opening up a new and previously inaccessible way of thinking about something." As a consequence, threshold concepts have a transformational potential and may lead to an associated change in identity. The successful completion of pediatric surgical training in the United Kingdom is a lengthy and complex professional journey in which trainees emerge as consultants with a professional identity. We sought to explore how "threshold concepts" applied to pediatric surgical training with a view to identifying elements that were "troublesome." METHODS: Semistructured interviews were conducted. Transcripts were generated from audio recordings and thematically analyzed by the authors. Constant comparison was used to refine themes. Participants were purposively recruited across all years of training. A total of 8 pediatric surgical trainees participated in the study. Approval from obtained from the Human Research Ethics committee. RESULTS: Although there is overlap between themes, analysis revealed "troublesome" areas of training related to knowledge (breadth and rarity of some conditions), clinical judgment (shifting expectation of independence), technical skills (accessing opportunities), transitions between roles (increasing responsibility and remoteness of support), relationships with trainers, and the effect of negative experiences. CONCLUSIONS: Viewing trainees' experiences of surgical training through the lens of "threshold concepts" provides insight to the importance of viewing the curriculum in a holistic way. Negative experiences in training were an important catalyst for development, inducing a fundamental change in perception, which might be characterized as a rupture of a "meaning frame." Trainees in pediatric surgery can be viewed as moving to a mature specialist identity via a transitional state-liminality, from entry into specialist training. PMID- 24776884 TI - Proliferation, dispersal and patterned aggregation of iridophores in the skin prefigure striped colouration of zebrafish. AB - Colour patterns are a striking feature of animals; they evolve rapidly and play an important role in natural as well as sexual selection. It has been proposed that colour pattern formation in adult vertebrates depends on Turing-type interactions between pigment cells; however, little is known about the actual developmental mechanisms underlying the complex and prolonged ontogeny of this important adult feature. Zebrafish (Danio rerio) owe their name to a repetitive pattern of dark stripes and light interstripes parallel to the anteroposterior body axis that develop during juvenile stages. By inducible Cre/loxP-mediated recombination in neural-crest-derived progenitors, we created labelled clones of skin pigment cells that were imaged over several weeks in juvenile and adult fish. Metamorphic iridophores arise from postembryonic stem cells located at the dorsal root ganglia of the peripheral nervous system. They emerge in the skin at the horizontal myoseptum to form the first interstripe and proliferate while spreading bidirectionally along the dorsoventral axis. Patterned aggregation of iridophores during their dispersal generates a series of interstripes that define the stripe regions. Melanophore progenitors appear in situ in the presumptive stripe region where they melanize and expand in size to form compact stripes. Thus, although depending on mutual interactions between different pigment cells, stripes and interstripes are formed by a completely different cellular route. PMID- 24776887 TI - QTL conferring fusarium crown rot resistance in the elite bread wheat variety EGA Wylie. AB - Fusarium crown rot (FCR) is one of the most damaging cereal diseases in semi-arid regions worldwide. The genetics of FCR resistance in the bread wheat (Triticum eastivum L.) variety EGA Wylie, the most resistant commercial variety available, was studied by QTL mapping. Three populations of recombinant inbred lines were developed with this elite variety as the resistant parent. Four QTL conferring FCR resistance were detected and resistance alleles of all of them were derived from the resistant parent EGA Wylie. One of these loci was located on the short arm of chromosome 5D (designated as Qcrs.cpi-5D). This QTL explains up to 31.1% of the phenotypic variance with an LOD value of 9.6. The second locus was located on the long arm of chromosome 2D (designated as Qcrs.cpi-2D) and explained up to 20.2% of the phenotypic variance with an LOD value of 4.5. Significant effects of both Qcrs.cpi-5D and Qcrs.cpi-2D were detected in each of the three populations assessed. Another two QTL (designated as Qcrs.cpi-4B.1 and Qcrs.cpi-4B.2, respectively) were located on the short arm of chromosome 4B. These two QTL explained up to 16.9% and 18.8% of phenotypic variance, respectively. However, significant effects of Qcrs.cpi-4B.1 and Qcrs.cpi-4B.2 were not detected when the effects of plant height was accounted for by covariance analysis. The elite characteristics of this commercial variety should facilitate the incorporation of the resistance loci it contains into breeding programs. PMID- 24776885 TI - Cyclin B2 and p53 control proper timing of centrosome separation. AB - Cyclins B1 and B2 are frequently elevated in human cancers and are associated with tumour aggressiveness and poor clinical outcome; however, whether and how B type cyclins drive tumorigenesis is unknown. Here we show that cyclin B1 and B2 transgenic mice are highly prone to tumours, including tumour types where B-type cyclins serve as prognosticators. Cyclins B1 and B2 both induce aneuploidy when overexpressed but through distinct mechanisms, with cyclin B1 inhibiting separase activation, leading to anaphase bridges, and cyclin B2 triggering aurora-A mediated Plk1 hyperactivation, resulting in accelerated centrosome separation and lagging chromosomes. Complementary experiments revealed that cyclin B2 and p53 act antagonistically to control aurora-A-mediated centrosome splitting and accurate chromosome segregation in normal cells. These data demonstrate a causative link between B-type cyclin overexpression and tumour pathophysiology, and uncover previously unknown functions of cyclin B2 and p53 in centrosome separation that may be perturbed in many human cancers. PMID- 24776888 TI - Detection rate of anterior prostate cancer in 226 patients submitted to initial and repeat transperineal biopsy. AB - OBJECTIVE: To evaluate the detection rate of anterior zone (AZ) prostate cancer (PCa) in patients submitted to initial and repeat transperineal prostate biopsy. METHODS: From January 2013 to August 2013, 226 patients (median age 64 years) with negative digital rectal examination underwent initial (144 cases) and repeat (82 cases) transperineal prostate biopsy for PSA >10 ng/ml, PSA 4.1-10.0 or 2.6 4.0 ng/ml with free/total PSA <=25% and <=20%, respectively. A median of 22 versus 32 cores were performed, including 4 cores of the AZ versus 6 cores (4 anterior plus 2 cores of the transition zone, TZ) at initial versus repeat biopsy, respectively. The detection rate of PCa of the peripheral zone (PZ), AZ and TZ was prospectively evaluated. RESULTS: The median PSA was 7.6 ng/ml; overall, a stage cT1c PCa was found in 104/226 (46%) patients, in 70 (48.6%) and 34 (41.5%) of the men who underwent initial and repeat biopsy, respectively. An AZ PCa was found in 11.5 vs. 8.8% (p = 0.32) of the patients submitted to initial versus repeat biopsy, respectively. AZ cancers demonstrated a number of positive cores (p = 0.03), greatest percentage of cancer (p = 0.001) and total percentage of cancer (p = 0.001) significantly lower in comparison with PZ PCa; moreover, 56.2 vs. 36.5% of AZ versus PZ PCa were characterized by a microfocus of cancer (p = 0.001), respectively. CONCLUSIONS: AZ biopsies increase the detection rate of PCa (about 10% of cases) at initial and repeat biopsy, allowing reduction of the biopsy false-negative rate. PMID- 24776889 TI - Enhanced Antimicrobial Activity of AamAP1-Lysine, a Novel Synthetic Peptide Analog Derived from the Scorpion Venom Peptide AamAP1. AB - There is great interest in the development of antimicrobial peptides as a potentially novel class of antimicrobial agents. Several structural determinants are responsible for the antimicrobial and cytolytic activity of antimicrobial peptides. In our study, a new synthetic peptide analog, AamAP1-Lysine from the naturally occurring scorpion venom antimicrobial peptide AamAP1, was designed by modifying the parent peptide in order to increase the positive charge and optimize other physico-chemical parameters involved in antimicrobial activity. AamAP1-Lysine displayed potent antibacterial activity against Gram-positive and Gram-negative bacteria. The minimum inhibitory concentration was in the range of 5 to 15 uM with a 10 fold increase in potency over the parent peptide. The hemolytic and antiproliferative activity of AamAP1-Lysine against eukaryotic mammalian cells was minimal at the concentration range needed to inhibit bacterial growth. The antibacterial mechanism analysis indicated that AamAP1 Lysine is probably inducing bacterial cell death through membrane damage and permeabilization determined by the release of beta-galactosidase enzyme from peptide treated E. coli cells. DNA binding studies revealed that AamAP1-Lysine caused complete retardation of DNA migration and could display intracellular activities in addition to the membrane permeabilization mode of action reported earlier. In conclusion, AamAP1-Lysine could prove to be a potential candidate for antimicrobial drug development in future studies. PMID- 24776892 TI - ConRad--Global Conference on Radiation Topics--Preparedness, Response, Protection and Research--Munich, 13-16 May 2013. PMID- 24776893 TI - The accident at the Fukushima Daiichi Nuclear Power Plant in 2011. AB - A huge earthquake struck the northeast coast of the main island of Japan on 11 March 2011, triggering a tsunami with more than 10-m-high waves hitting the area. The earthquake was followed by numerous sustained aftershocks. The earthquake and aftershocks left almost 16,000 people dead and more than 2,800 missing (as of 11 March 2014). The earthquake affected the Fukushima Daiichi Nuclear Power Plant (NPP) of Tokyo Electric Power Company (TEPCO), causing serious damage to the NPP and resulting in large amounts of radioactive materials being released into not only controlled areas but also the environment. Damage was caused to the cooling systems of the NPP, although they automatically shut down after the earthquake. The trouble with the cooling systems led to hydrogen explosions and core meltdown. The major nuclides released on land were 131I, 134Cs, and 137Cs. The release of these radioactive materials resulted in contamination of first responders and workers and also a high ambient dose of radiation around the NPP. The local hospital system, including that for radiation emergency medicine, was dysfunctional. Hospitals that had been designated as radiation emergency facilities were not able to function because the earthquake and tsunami had caused damage to their facilities; some of these were located within a 20-km radius of the NPP and in the evacuation areas. Local fire department personnel were also ordered to evacuate. Fukushima prefecture changed the screening level required for decontamination from 13,000 to 100,000 cpm, with decontamination by wiping being performed for over 13,000 cpm. However, as hospitals and fire departments had to abide by lower levels than that of the prefecture for receiving or transporting contaminated patients, these personnel could not accept or transport contaminated people from the NPPs. In addition, hospitals not designated as radiation emergency facilities would not receive patients from the NPPs because of concerns about the health effects of radiation. From this disaster, it was learned that basic knowledge of radiation and its effects is extremely important for health care providers. PMID- 24776894 TI - Combined drug and surgery treatment of plutonium-contaminated wounds: indications obtained using a rodent model. AB - There is an important requirement following accidental actinide contamination of wounds to limit the dissemination and retention of such alpha-emitting radionuclides. To reduce wound and systemic contamination, treatment approaches include chelation therapy with or without wound excision. However, it has been hypothesized that wound excision could lead to increased contaminant release and systemic organ retention. This study in the rat addresses this question. Anesthetized rats were contaminated with plutonium nitrate following wounding by deep incision of hind leg muscle. Excision of tissue at the contaminated site was performed 7 d later with or without Diethylene Triamine Pentaacetic Acid (DTPA) treatment (30 MUmol kg-1 i.v.). Pu urinary excretion was then measured for a further 3 d, and animals were euthanized at 14 d after contamination. Tissue samples were evaluated for Pu activity and histology. At 7 d after contamination, around 50% of the initial activity remained at the wound site. An average of 16% of this activity was then removed by surgery. Surgery alone resulted in increased urinary excretion, suggesting release from the wound site, but no subsequent increases in organ retention (bone, liver) were observed at 14 d. Indeed, organ Pu activity was slightly reduced. The combination of surgery and DTPA or DTPA treatment alone was much more effective than excision alone as shown by the markedly increased urinary Pu excretion and decreased tissue levels. This is the first report in an experimental rodent model of resection of Pu-contaminated wound. Urinary excretion data provide evidence for the release of activity as a result of surgery, but this does not appear to lead to further Pu organ retention. However, a combination of prior DTPA treatment with wound excision is particularly effective. PMID- 24776895 TI - The medical decision model and decision maker tools for management of radiological and nuclear incidents. AB - Effective decision making during a rapidly evolving emergency such as a radiological or nuclear incident requires timely interim decisions and communications from onsite decision makers while further data processing, consultation, and review are ongoing by reachback experts. The authors have recently proposed a medical decision model for use during a radiological or nuclear disaster, which is similar in concept to that used in medical care, especially when delay in action can have disastrous effects. For decision makers to function most effectively during a complex response, they require access to onsite subject matter experts who can provide information, recommendations, and participate in public communication efforts. However, in the time before this expertise is available or during the planning phase, just-in-time tools are essential that provide critical overview of the subject matter written specifically for the decision makers. Recognizing the complexity of the science, risk assessment, and multitude of potential response assets that will be required after a nuclear incident, the Office of the Assistant Secretary for Preparedness and Response, in collaboration with other government and non-government experts, has prepared a practical guide for decision makers. This paper illustrates how the medical decision model process could facilitate onsite decision making that includes using the deliberative reachback process from science and policy experts and describes the tools now available to facilitate timely and effective incident management. PMID- 24776896 TI - Cardiac fibrillation risk of Taser weapons. AB - The debate on potential health hazards associated with delivering electric discharges to incapacitated subjects, in particular on whether electric discharge weapons are lethal, less lethal or non-lethal, is still controversial. The cardiac fibrillation risks of Taser weapons X26 and X3 have been investigated by measuring the delivered high-tension pulses in dependence on load impedance. Excitation thresholds and sinus-to-Taser conversion factors have been determined by numerical modeling of endocardial, myocardial, and epicardial cells. Detailed quantitative assessment of cardiac electric exposure has been performed by numerical simulation at the normal-weighted anatomical model NORMAN. The impact of anatomical variation has been quantified at an overweight model (Visible Man), both with a spatial resolution of 2 * 2 * 2 mm voxels. Spacing and location of dart electrodes were systematically varied and the worst-case position determined. Based on volume-weighted cardiac exposure assessment, the fibrillation probability of the worst-case hit was determined to 30% (Taser X26) and 9% (Taser X3). The overall risk assessment of Taser application accounting for realistic spatial hit distributions was derived from training sessions of police officers under realistic scenarios and by accounting for the influence of body (over-)weight as well as gender. The analysis of the results showed that the overall fibrillation risk of Taser use is not negligible. It is higher at Taser X26 than at Taser X3 and amounts to about 1% for Europeans with an about 20% higher risk for Asians. Results demonstrate that enhancement as well as further reduction of fibrillation risk depends on responsible use or abuse of Taser weapons. PMID- 24776897 TI - Radiation exposure case management after incorporation of radionuclides. AB - The release of radioactive material due to accidents or terroristic actions can result in radioactive contamination of the environment and may lead to intake and incorporation of radionuclides with the consequence of prolonged radiation exposure. In this case, a decision about countermeasures must be carried out as soon as possible to reduce the resulting radiation dose. In order to be prepared for such a scenario, an Assessment and Documentation System has been developed to support the rapid assessment of internal exposures and to assist in decision making. Radionuclide distributions, excretion rates, and resulting exposures have been calculated on the basis of a reference scenario. The documentation of the results in the form of tables and graphs allows the easy and quick interpretation of measurements in terms of exposure and intake. The system in its present status gives information about possibilities of countermeasures; it is the intention of the next steps of development to give advice on the basis of estimated avertable doses. PMID- 24776898 TI - Gene expression analysis in Mayak workers with prolonged occupational radiation exposure. AB - The authors evaluated gene expression in the peripheral blood in relation to occupational exposure in Mayak workers to find out about the existence of a permanent post exposure signature. Workers were exposed to combined incorporated 239Pu and external gamma rays (n = 82) or to external gamma rays only (n = 18), and 50 unexposed individuals served as controls. Peripheral blood was taken from workers older than 70 y. RNA was isolated, converted into cDNA, and stored at -20 degrees C. A two-stage study design was performed focusing on examinations on the transcriptional (mRNA) and post-transcriptional level (microRNA). In the first stage, 40 samples were identified for screening purposes and selection of candidate genes. For examinations on the transcriptional level, whole genome microarrays and qRT-PCR were employed on the post-transcriptional level (667 microRNAs). Candidate genes were assessed by (1) introducing a twofold difference in gene expression over the reference group and (2) showing a significant p-value using the Kruskal-Wallis test. From 42,545 transcripts of the whole genome microarray, 376 candidate genes (80 up-regulated and 296 down-regulated relative to the reference group) were selected. Expression of almost all of these genes (70-98%) appeared significantly associated with internal 239Pu and to a lesser extent were associated with external gamma-ray exposure (2-30%). Associations in the same direction were found for 45 microRNAs. Although both exposures led to modulations of different gene sets in different directions, the authors could detect no differences in gene set enrichment analysis. PMID- 24776899 TI - Threshold limits for biological indication of prolonged radiation exposure using mFISH. AB - Chromosome aberration (translocation) yield was investigated by mFISH in peripheral blood lymphocytes of Mayak Production Association (PA) workers with prolonged occupational exposure to ionizing radiation (IR). A dose threshold for cytogenetic indication of a prolonged occupational radiation exposure was estimated for Mayak PA workers using functions of dose distributions. Two limits were estimated for the indication of IR exposure to workers with a prolonged external gamma-ray exposure: These are a background translocation yield of N0 = 0.812 +/- 0.149% and a dose threshold of indication D0 estimated to be approximately 1 Gy. PMID- 24776900 TI - Mitigating radiation-induced toxicity: an overview of new approaches developed at the French Military Biomedical Research Institute. AB - Acute radiation syndrome represents the clinical response of radiation-sensitive key tissues (i.e., hematopoietic, gastrointestinal and neurovascular) following exposure to high doses of ionizing radiation. In this context, the hematopoietic syndrome remains the first therapeutic challenge. Today, identifying new drugs and developing new strategies to cope with acute radiation syndrome remain a priority, especially to prevent/cure the radiation-induced multiple organ dysfunction syndrome then failure. Cytokine, non-cytokine drugs, and cell/gene therapy represent a pattern of sophisticated approaches developed by this group and others to achieve this goal. PMID- 24776901 TI - Preclinical development of a bridging therapy for radiation casualties: appropriate for high risk personnel. AB - The authors demonstrate the efficacy of a bridging therapy in a preclinical animal model that allows the lymphohematopoietic system of severely immunocompromised individuals exposed to acute, high-dose ionizing irradiation to recover and to survive. CD2F1 mice were irradiated acutely with high doses causing severe, potentially fatal hematopoietic or gastrointestinal injuries and then transfused intravenously with progenitor-enriched, whole blood, or peripheral blood mononuclear cells from mice injected with tocopherol succinate- and AMD3100- (a chemokine receptor anatogonist used to improve the yield of mobilized progenitors). Survival of these mice over a 30-d period was used as the primary measured endpoint of therapeutic effectiveness. The authors demonstrate that tocopherol succinate and AMD3100 mobilize progenitors into peripheral circulation and that the infusion of mobilized progenitor enriched blood or mononuclear cells acts as a bridging therapy for lymphohematopoietic system recovery in mice exposed to whole-body ionizing irradiation. The results demonstrate that infusion of whole blood or blood mononuclear cells from tocopherol succinate (TS)- and AMD3100-injected mice improved the survival of mice receiving high radiation doses significantly. The efficacy of TS-injected donor mice blood or mononuclear cells was comparable to that of blood or cells obtained from mice injected with granulocyte colony-stimulating factor. Donor origin-mobilized progenitors were found to localize in various tissues. The authors suggest that tocopherol succinate is an optimal agent for mobilizing progenitors with significant therapeutic potential. The extent of progenitor mobilization that tocopherol succinate elicits in experimental mice is comparable quantitatively to clinically used drugs such as granulocyte-colony stimulating factor and AMD3100. Therefore, it is proposed that tocopherol succinate be considered for further translational development and ultimately for use in humans. PMID- 24776902 TI - Overview of use of G-CSF and GM-CSF in the treatment of acute radiation injury. AB - Depression of hematopoietic elements due to significant levels of whole-body or partial-body irradiation due to radiation-induced suppression of mitosis in the stem and progenitor cells can result in life-threatening injury. Successful administration of intensive care of patients experiencing acute radiation sickness (ARS; also called acute radiation syndrome) is dependent upon the ability to stimulate the recovery of surviving hematopoietic stem cells (HSC), assuming the non-hematopoietic injuries are also survivable with treatment. To date, there have been a number of studies involving radiation accidents where patients were treated with cytokines. Although the data overall seem to indicate that the period of neutropenia is shortened and survival prolonged, so far there is no statistically significant proof that cytokine administration actually decreases mortality in radiation-injured humans. Some studies have shown no improved survival when used in a mouse model; however, studies in canines and primates have shown improved survival. CSF therapy is considered a valuable adjunct to treatment with antibiotics and strict hygiene controls in certain irradiated patients. It appears that these drugs do shorten the periods of neutropenia in irradiated patients and must be considered part of the therapeutic armamentarium in the treatment of ARS in a mass casualty situation. Based on review of the human experience with G-CSF and GM-CSF, as well as some animal studies, current consensus opinions support the prompt administration of these materials to patients suffering significant bone marrow depression from exposure to ionizing radiation. PMID- 24776903 TI - A basic fibroblast growth factor analog for protection and mitigation against acute radiation syndromes. AB - The effects of fibroblast growth factors and their potential as broad-spectrum agents to treat and mitigate radiation injury have been studied extensively over the past two decades. This report shows that a peptide mimetic of basic fibroblast growth factor (FGF-P) protects and mitigates against acute radiation syndromes. FGF-P attenuates both sepsis and bleeding in a radiation-induced bone marrow syndrome model and reduces the severity of gastrointestinal and cutaneous syndromes; it should also mitigate combined injuries. FGF-2 and FGF-P induce little or no deleterious inflammation or vascular leakage, which distinguishes them from most other growth factors, angiogenic factors, and cytokines. Although recombinant FGFs have proven safe in several ongoing clinical trials, they are expensive to synthesize, can only be produced in limited quantity, and have limited shelf life. FGF-P mimics the advantageous features of FGF-2 without these disadvantages. This paper shows that FGF-P not only has the potential to be a potent yet safe broad-spectrum medical countermeasure that mitigates acute radiotoxicity but also holds promise for thermal burns, ischemic wound healing, tissue engineering, and stem-cell regeneration. PMID- 24776904 TI - Transient gene therapy to treat cutaneous radiation syndrome: development in a minipig model. AB - Cutaneous radiation syndrome is the delayed consequence of localized skin exposure to high doses of ionizing radiation. Adipocyte derived stem cells injection may improve tissue regeneration through secreted factors. Thus mesenchymal stem cells secretome optimization, using transient transfection, may represent a new strategy to treat this syndrome. Sonic hedgehog, a secreted protein involved in cell proliferation and angiogenesis, has been chosen as a first candidate. Here preliminary results are reported of the therapeutic potential of transient gene therapy to cure cutaneous radiation syndrome in a minipig model. Adipocyte derived stem cells were transiently transfected by electroporation with a plasmid coding for Sonic Hedgehog. Gottingen minipigs were locally irradiated using a (60)Co gamma source at the dose of 50 Gy and received Phosphate Buffer Salin (controls: n = 8), stem cells (50 * 106 each time, n = 5) or transfected stem cells (25+/-7 * 106 each time, n = 1). All controls exhibited a homogeneous clinical evolution of cutaneous radiation syndrome with final necrosis (day 91). In stem cell injected minipigs, an ultimate wound healing was observed in four out of five grafted animals (day 130 +/- 28, complete in two of them) (historical results). The Sonic hedgehog animal, albeit injected with a lower number of transfected stem cells, presented a very similar evolution of skin healing without necrosis or uncontrolble pain. Globally this preliminary report suggests that local injection of Sonic Hedgehog transfected adipocyte derived stem cells may improve wound healing. Thus work is ongoing to evaluate this therapeutic strategy on a larger number of animals. PMID- 24776905 TI - Ciprofloxacin increases survival after ionizing irradiation combined injury: gamma-H2AX formation, cytokine/chemokine, and red blood cells. AB - Exposure to ionizing radiation alone (radiation injury, RI) or combined with traumatic tissue injury (radiation combined injury, CI) is a crucial life threatening factor in nuclear and radiological accidents. It is well documented that RI and CI occur at the molecular, cellular, tissue, and system levels. However, their mechanisms remain largely unclear. It has been observed in dogs, pigs, rats, guinea pigs, and mice that radiation exposure combined with burns, wounds, or bacterial infection results in greater mortality than radiation exposure alone. In this laboratory, the authors found that B6D2F1/J female mice exposed to 9.75 Gy 60Co-gamma photon radiation followed by 15% total body surface area wounds experienced 50% higher mortality (over a 30-d observation period) compared to irradiation alone. CI enhanced DNA damages, amplified iNOS activation, induced massive release of pro-inflammatory cytokines, overexpressed MMPs and TLRs, and aggravated sepsis that led to cell death. In the present study, B6D2F1/J mice that received CI were treated with ciprofloxacin (CIP, 90 mg/kg p.o., q.d. within 2 h after CI through day 21). At day 1, CIP treatment reduced CI-induced gamma-H2AX formation significantly. At day 10, CIP treatment not only reduced cytokine/chemokine concentrations significantly, including IL-6 and KC (i.e., IL-8 in humans), but also enhanced IL-3 production compared to vehicle-treated controls. CIP also elevated red blood cell counts, hemoglobin levels, and hematocrits. At day 30, CIP treatment increased 45% survival after CI (i.e., 2.3-fold increase over vehicle treatment). The results suggest that CIP may prove to be an effective therapeutic drug for CI. PMID- 24776906 TI - Significance of bioindicators to predict survival in irradiated minipigs. AB - The minipig is emerging as a potential alternative non-rodent animal model. Several biological markers (e.g., blood counts, laboratory parameters, and clinical signs) have been proposed for rapid triage of radiation victims. Here, the authors focus on the significance of bio-indicators for prediction of survivors after irradiation and compare it with human data; the relationship between these biomarkers and radiation dose is not part of this study. Male Gottingen minipigs (age 4-5 mo, weight 9-10 kg) were irradiated (or sham irradiated) bilaterally with gamma-photons (60Co, 0.5-0.6 Gy min-1) in the dose range of 1.6-12 Gy. Peripheral blood cell counts, laboratory parameters, and clinical symptoms were collected up to 10 d after irradiation and analyzed using logistic regression analysis and calculating ROC curves. In moribund pigs, parameters such as decreased lymphocyte/granulocyte counts, increased C-reactive protein, alkaline phosphatase values, as well as increased citrulline values and body temperature, significantly (p < 0.002 up to p < 0.0001) discriminated non survivors from survivors with high precision (ROC > 0.8). However, most predictive within the first 3 d after exposure was a combination of decreased lymphocyte counts and increased body temperature observed as early as 3 h after radiation exposure (ROC: 0.93-0.96, p < 0.0001). Sham-irradiated animals (corresponding to "worried wells") could be easily discriminated from dying pigs, thus pointing to the diagnostic significance of this analysis. These data corroborate with earlier findings performed on human radiation victims suffering from severe hematological syndrome and provide further evidence for the suitability of the minipig model as a potential alternative non-rodent animal model. PMID- 24776907 TI - An amino acid mixture mitigates radiation-induced gastrointestinal toxicity. AB - Electrolyte and nutrient absorption occur in villous epithelial cells. Radiation often results in reduced electrolyte and nutrient absorption, which leads to gastrointestinal toxicity. Therefore, the authors studied: (1) radiation-induced changes in glucose and amino acid absorption across ileal tissues and (2) the effect of amino acid mixtures on absorptive capacity. NIH Swiss mice were irradiated (0, 1, 3, 5, or 7 Gy) using a 137Cs source at 0.9 Gy min-1. Transepithelial short circuit current (I(sc)), dilution potential, and isotope flux determinations were made in Ussing chamber studies and correlated to plasma endotoxin and IL-1beta levels. Amino acids that increased electrolyte absorption and improved mucosal barrier functions were used to create a mitigating amino acid mixture (MAAM). The MAAM was given to mice via gastric gavage; thereafter, body weight and survival were recorded. A significant decrease in basal and glucose-stimulated sodium absorption occurred after 0, 1, 3, 5, and 7 Gy irradiation. Ussing chamber studies showed that paracellular permeability increased following irradiation and that the addition of glucose resulted in a further increase in permeability. Following irradiation, certain amino acids manifested decreased absorption, whereas others were associated with increased absorption. Lysine, aspartic acid, glycine, isoleucine, threonine, tyrosine, valine, tryptophan, and serine decreased plasma endotoxins were selected for the MAAM. Mice treated with the MAAM showed increased electrolyte absorption and decreased paracellular permeability, IL-1beta levels, and plasma endotoxin levels. Mice treated with MAAM also had increased weight gain and better survival following irradiation. The MAAM has immediate potential for use in mitigating radiation-induced acute gastrointestinal syndrome. PMID- 24776908 TI - Cytokinesis-block micronucleus assay by manual and automated scoring: calibration curves and dose prediction. AB - The cytokinesis-block micronucleus assay in peripheral blood lymphocytes is one of the best standardized and validated techniques for individual radiation dose assessment. This method has been proposed as an alternative to the dicentric chromosome assay, which is considered the "gold standard" in biological dosimetry because it requires less time and cytogenetic expertise. Nevertheless, for application as a biodosimetry tool in large-scale nuclear or radiological accidents, the manually performed cytokinesis-block micronucleus assay needs further strategies (e.g., the automation of micronucleus scoring) to speed up the analysis. An essential prerequisite for radiation dose assessment is to establish a dose-effect curve. In this study, blood samples of one healthy subject were irradiated with seven increasing doses of x-ray (240 kVp, 1 Gy min-1) ranging from 0.25-4.0 Gy to generate calibration curves based on manual as well as on automated scoring mode. The quality of the calibration curves was evaluated by determination of the dose prediction accuracy after the analysis of 10 blood samples from the same donor exposed to unknown radiation doses. The micronucleus frequencies in binucleated cells were scored manually as well as automatically and were used to assess the absorbed radiation doses with reference to the respective calibration curve. The accuracy of the dose assessment based on manual and automatic scoring mode was compared. PMID- 24776909 TI - Useful radiation dose biomarkers for early identification of partial-body exposures. AB - Although less urgent than the physical injuries caused by an unexpected nuclear and radiological (NR) event, radiation damages can be treated more effectively if the intensity and extent of the exposure are evaluated rapidly. In this work, the authors followed within the first 7 d after exposure a few early biomarkers that could be easily deployable (simple and fast sampling and analysis) to determine their potential in distinguishing a total body irradiation (TBI) from a dose equivalent partial exposure. A plausible accident scenario was created for this study by exposing unilaterally nonhuman primates of body mass comparable to humans to 5 Gy, to either the whole body or to part of it. Using logistic regression analysis, it was shown that both a combination of three parameters together [absolute neutrophil count; monocyte count on the first day; and C reactive protein (CRP) 5 d after exposure] or CRP 7 d after irradiation completely separated the partial exposures from the TBIs. A quasi-complete separation using receiver-operator characteristic (ROC) was observed for neutrophil count to lymphocyte count ratio during the first day after exposure. PMID- 24776910 TI - Comparison of the needs for biodosimetry for large-scale radiation events for military versus civilian populations. AB - The aim of this paper is to compare and contrast the needs for biodosimetry for initial triage for military forces and civilian populations when there are radiation exposures that involve potentially a large number of persons. Several differences in the likely scenarios for exposure of military forces include a greater likelihood of having higher rates of significant exposures, inhomogeneous exposures, significant doses from neutrons, and combined injury. Measurements will be able to begin sooner than for exposures in civilian settings because medical facilities usually are an integral part of the way military forces are deployed. It also will be very feasible to have personnel that will be trained and equipped specifically for rapid deployment to assess dose. As a consequence, the most appropriate biodosimetry techniques will include features that are not present or are less important for civilian settings; i.e., the need for changes that become measureable very soon after the radiation is received, the ability to complete measurements in very close proximity to the subjects (so samples do not need to be transported out and results returned), increased capability of resolving homogeneity of the exposure, ability to be carried out in an injured person, capability of determining whether neutrons have made a significant contribution to dose, and the ability to rely on more sophisticated equipment and trained personnel to carry out the measurements at the point of care. PMID- 24776911 TI - Validation of semi-automatic scoring of dicentric chromosomes after simulation of three different irradiation scenarios. AB - Large scale radiological emergencies require high throughput techniques of biological dosimetry for population triage in order to identify individuals indicated for medical treatment. The dicentric assay is the "gold standard" technique for the performance of biological dosimetry, but it is very time consuming and needs well trained scorers. To increase the throughput of blood samples, semi-automation of dicentric scoring was investigated in the framework of the MULTIBIODOSE EU FP7 project, and dose effect curves were established in six biodosimetry laboratories. To validate these dose effect curves, blood samples from 33 healthy donors (>10 donors/scenario) were irradiated in vitro with 60Co gamma rays simulating three different exposure scenarios: acute whole body, partial body, and protracted exposure, with three different doses for each scenario. All the blood samples were irradiated at Ghent University, Belgium, and then shipped blind coded to the participating laboratories. The blood samples were set up by each lab using their own standard protocols, and metaphase slides were prepared to validate the calibration curves established by semi-automatic dicentric scoring. In order to achieve this, 300 metaphases per sample were captured, and the doses were estimated using the newly formed dose effect curves. After acute uniform exposure, all laboratories were able to distinguish between 0 Gy, 0.5 Gy, 2.0, and 4.0 Gy (p < 0.001), and, in most cases, the dose estimates were within a range of +/- 0.5 Gy of the given dose. After protracted exposure, all laboratories were able to distinguish between 1.0 Gy, 2.0 Gy, and 4.0 Gy (p < 0.001), and here also a large number of the dose estimates were within +/- 0.5 Gy of the irradiation dose. After simulated partial body exposure, all laboratories were able to distinguish between 2.0 Gy, 4.0 Gy, and 6.0 Gy (p < 0.001). Overdispersion of the dicentric distribution enabled the detection of the partial body samples; however, this result was clearly dose-dependent. For partial body exposures, only a few dose estimates were in the range of +/- 0.5 Gy of the given dose, but an improvement could be achieved with higher cell numbers. The new method of semi-automation of the dicentric assay was introduced successfully in a network of six laboratories. It is therefore concluded that this method can be used as a high-throughput screening tool in a large-scale radiation accident. PMID- 24776912 TI - Early-response biomarkers for assessment of radiation exposure in a mouse total body irradiation model. AB - Nuclear accidents or terrorist attacks could expose large numbers of people to ionizing radiation. Early biomarkers of radiation injury will be critical for triage, treatment, and follow-up of such individuals. The authors evaluated the utility of multiple blood biomarkers for early-response assessment of radiation exposure using a murine (CD2F1, males) total-body irradiation (TBI) model exposed to 60Co gamma rays (0.6 Gy min-1) over a broad dose range (0-14 Gy) and timepoints (4 h-5 d). Results demonstrate: 1) dose-dependent changes in hematopoietic cytokines: Flt-3 ligand (Flt3L), interleukin 6 (IL-6), granulocyte colony stimulating factor (G-CSF), thrombopoietin (TPO), erythropoietin (EPO), and acute phase protein serum amyloid A (SAA); 2) dose-dependent changes in blood cell counts: lymphocytes, neutrophils, platelets, and ratio of neutrophils to lymphocytes; 3) protein results coupled with peripheral blood cell counts established very successful separation of groups irradiated to different doses; and 4) enhanced separation of dose was observed as the number of biomarkers increased. Results show that the dynamic changes in the levels of SAA, IL-6, G CSF, and Flt3L reflect the time course and severity of acute radiation syndrome (ARS) and may function as prognostic indicators of ARS outcome. These results also demonstrate proof-in-concept that plasma proteins show promise as a complimentary approach to conventional biodosimetry for early assessment of radiation exposures and, coupled with peripheral blood cell counts, provide early diagnostic information to manage radiation casualty incidents effectively, closing a gap in capabilities to rapidly and effectively assess radiation exposure early, especially needed in case of a mass-casualty radiological incident. PMID- 24776913 TI - Dose estimation using dicentric chromosome assay and cytokinesis block micronucleus assay: comparison between manual and automated scoring in triage mode. AB - In cases of an accidental overexposure to ionizing radiation, it is essential to estimate the individual absorbed dose of a potentially radiation-exposed person. For this purpose, biological dosimetry can be performed to confirm, complement or even replace physical dosimetry when this proves to be unavailable. The most validated biodosimetry techniques for dose estimation are the dicentric chromosome assay, the "gold standard" for individual dose assessment, and cytokinesis-block micronucleus assay. However, both assays are time consuming and require skilled scorers. In case of large-scale accidents, different strategies have been developed to increase the throughput of cytogenetic service laboratories. These are the decrease of cell numbers to be scored for triage dosimetry; the automation of procedures including the scoring of, for example, aberrant chromosomes and micronuclei; and the establishment of laboratory networks in order to enable mutual assistance if necessary. In this study, the authors compared the accuracy of triage mode biodosimetry by dicentric chromosome analysis and the cytokinesis block micronucleus assay performing both the manual and the automated scoring mode. For dose estimation using dicentric chromosome assay of 10 blind samples irradiated up to 6.4 Gy of x-rays, a number of metaphase spreads were analyzed ranging from 20 up to 50 cells for the manual and from 20 up to 500 cells for the automatic scoring mode. For dose estimation based on the cytokinesis block micronucleus assay, the micronucleus frequency in both 100 and 200 binucleated cells was determined by manual and automatic scoring. The results of both assays and scoring modes were compared and analyzed considering the sensitivity, specificity, and accuracy of dose estimation with regard to the discrimination power of clinically relevant binary categories of exposure doses. PMID- 24776914 TI - EPR retrospective dosimetry with fingernails: report on first application cases. AB - For localized irradiation to hands, in case of sources accidentally handled, it is very difficult to estimate the dose distribution by calculation. Doses may reach several tens of grays, and the dose distribution is usually very heterogeneous. Until recently, doses in such situations could be estimated only by analysis of bone biopsies using Electron Paramagnetic Resonance (EPR) spectroscopy. This technique was used previously on surgical wastes or after amputation of a finger. In this case, the dose information was available in one or a few locations on the hand only, due to the limited number of biopsy fragments usually collected. The idea to measure free radicals (FRs) induced by radiation in nails to estimate a dose is not new, but up to now, no application cases were reported. As a matter of fact, the EPR analysis of nails is complex due to the presence of intrinsic signals and parasitic signals induced by the mechanical stress (when nails are collected), which overlaps the radio-induced components. In addition, the radio-induced FRs identified up to now are unstable and very sensitive to humidity. In these conditions, it was difficult to foresee any application for dosimetry with fingernails. Recently, stable radio-induced FRs in nails has been identified and an associated protocol for dose assessment developed. This protocol has been applied by the Institut de Radioprotection et de Surete Nucleaire on fingernail samples from victims of three different radiological accidents that occurred between 2008 and 2012 in different places. PMID- 24776915 TI - Comparing risk estimates following diagnostic CT radiation exposures employing different methodological approaches. AB - The current study has two aims: the first is to quantify the difference between radiation risks estimated with the use of organ or effective doses, particularly when planning pediatric and adult computed tomography (CT) examinations. The second aim is to determine the method of calculating organ doses and cancer risk using dose-length product (DLP) for typical routine CT examinations. In both cases, the radiation-induced cancer risks from medical CT examinations were evaluated as a function of gender and age. Lifetime attributable risk values from CT scanning were estimated with the use of ICRP (Publication 103) risk models and Russian national medical statistics data. For populations under the age of 50 y, the risk estimates based on organ doses usually are 30% higher than estimates based on effective doses. In older populations, the difference can be up to a factor of 2.5. The typical distributions of organ doses were defined for Chest Routine, Abdominal Routine, and Head Routine examinations. The distributions of organ doses were dependent on the anatomical region of scanning. The most exposed organs/tissues were thyroid, breast, esophagus, and lungs in cases of Chest Routine examination; liver, stomach, colon, ovaries, and bladder in cases of Abdominal Routine examination; and brain for Head Routine examinations. The conversion factors for calculation of typical organ doses or tissues at risk using DLP were determined. Lifetime attributable risk of cancer estimated with organ doses calculated from DLP was compared with the risk estimated on the basis of organ doses measured with the use of silicon photodiode dosimeters. The estimated difference in LAR is less than 29%. PMID- 24776919 TI - Molecular self-assembly at nanometer scale modulated surfaces: trimesic acid on Ag(111), Cu(111) and Ag/Cu(111). AB - The balance between molecule-molecule and molecule-surface interactions is a determining factor in the creation of well-ordered organic networks formed by self-assembly on crystalline metal surfaces. We have used a scanning tunneling microscope under ultrahigh vacuum conditions to study the molecular self-assembly of trimesic acid on a surface that is modulated on a comparable nanometer scale as the size of the molecules. This is made of one layer of silver grown on a Cu(111) surface where it forms a periodic reconstruction. It is shown that the self-assembly of trimesic acid at room temperature, where intermolecular interactions are taking place via hydrogen bonds, is strongly disturbed due to the modulated substrate and the spatially varying potential imposed on the molecules. Annealing to 350 K partly deprotonates the molecules and changes the intermolecular interactions to stronger ionic hydrogen bonds. This reduces the influence of the modulated substrate and allows the molecules to self-assemble into long-range ordered networks on the surface. Comparisons are made to self assembly on the flat surfaces of Ag(111) and Cu(111), where we always find well ordered molecular networks. PMID- 24776918 TI - Characterization of H7 influenza A virus in wild and domestic birds in Korea. AB - During surveillance programs in Korea between January 2006 and March 2011, 31 H7 avian influenza viruses were isolated from wild birds and domestic ducks and genetically characterized using large-scale sequence data. All Korean H7 viruses belonged to the Eurasian lineage, which showed substantial genetic diversity, in particular in the wild birds. The Korean H7 viruses from poultry were closely related to those of wild birds. Interestingly, two viruses originating in domestic ducks in our study had the same gene constellations in all segment genes as viruses originating in wild birds. The Korean H7 isolates contained avian-type receptors (Q226 and G228), no NA stalk deletion (positions 69-73), no C-terminal deletion (positions 218-230) in NS1, and no substitutions in PB2-627, PB1-368, and M2-31, compared with H7N9 viruses. In pathogenicity experiments, none of the Korean H7 isolates tested induced clinical signs in domestic ducks or mice. Furthermore, while they replicated poorly, with low titers (100.7-1.3 EID50/50 ul) in domestic ducks, all five viruses replicated well (up to 7-10 dpi, 100.7 4.3EID50/50 ul) in the lungs of mice, without prior adaptation. Our results suggest that domestic Korean viruses were transferred directly from wild birds through at least two independent introductions. Our data did not indicate that wild birds carried poultry viruses between Korea and China, but rather, that wild type H7 viruses were introduced several times into different poultry populations in eastern Asia. PMID- 24776920 TI - Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation. AB - We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia-induced status epilepticus. A novel de novo SCN1A mutation was identified by whole-exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A-associated epileptic encephalopathy. [Published with video sequences]. PMID- 24776921 TI - Association study of GABRG2 polymorphisms with suicidal behaviour in schizophrenia patients with alcohol use disorder. AB - BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder where the role of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, has been implicated in its aetiopathophysiology. Several genes coding for GABAA subunits, including the GABRG2 gene that encodes the gamma2 subunit, are clustered at 5q31 q35, a chromosomal region that is associated with schizophrenia in genome scan studies. We recently reported GABRG2 to be associated with schizophrenia in our case-control and family samples. METHODS: We tested eight single-nucleotide polymorphisms spanning the GABRG2 gene for an association with suicidal behaviour in our schizophrenia sample of European ancestry (n = 197), taking into account history of alcohol abuse or dependence. RESULTS: We found the haplotypes of the rs183294 and rs209356 markers to be significantly associated with history of suicide attempt (p < 0.01) as well as suicide specifier scores (p < 0.05). The association appeared to be originating in patients with a history of alcohol dependence or abuse. CONCLUSIONS: Taken together, the results of the present study suggest that GABRG2 may be involved in suicidal behaviour in schizophrenia patients with alcohol dependence or abuse, but replications are required. These results may help in the discovery of novel treatments for alcoholism and/or prevention of suicide. PMID- 24776922 TI - Co-circulation and genomic recombination of coxsackievirus A16 and enterovirus 71 during a large outbreak of hand, foot, and mouth disease in Central China. AB - A total of 1844 patients with hand, foot, and mouth disease (HFMD), most of them were children of age 1-3-year-old, in Central China were hospitalized from 2011 to 2012. Among them, 422 were infected with coxsackievirus A16 (CVA16), 334 were infected with enterovirus 71 (EV71), 38 were co-infected with EV71 and CVA16, and 35 were infected with other enteroviruses. Molecular epidemiology analysis revealed that EV71 and CVA16 were detected year-round, but EV71 circulated mainly in July and CVA16 circulated predominantly in November, and incidence of HFMD was reduced in January and February and increased in March. Clinical data showed that hyperglycemia and neurologic complications were significantly higher in EV71 infected patients, while upper respiratory tract infection and C-reactive protein were significantly higher in CVA16-associated patients. 124 EV71 and 80 CVA16 strains were isolated, among them 56 and 68 EV71 strains were C4a and C4b, while 25 and 55 CVA16 strains were B1a and B1b, respectively. Similarity plots and bootscan analyses based on entire genomic sequences revealed that the three C4a sub-genotype EV71 strains were recombinant with C4b sub-genotype EV71 in 2B-2C region, and the three CVA16 strains were recombinant with EV71 in 2A-2B region. Thus, CVA16 and EV71 were the major causative agents in a large HFMD outbreak in Central China. HFMD incidence was high for children among household contact and was detected year-round, but outbreak was seasonal dependent. CVA16 B1b and EV71 C4b reemerged and caused a large epidemic in China after a quiet period of many years. Moreover, EV71 and CVA16 were co-circulated during the outbreak, which may have contributed to the genomic recombination between the pathogens. It should gain more attention as there may be an upward trend in co-circulation of the two pathogens globally and the new role recombination plays in the emergence of new enterovirus variants. PMID- 24776925 TI - Whole-exome sequencing for the identification of susceptibility genes of Kashin Beck disease. AB - OBJECTIVE: To identify and investigate the susceptibility genes of Kashin-Beck disease (KBD) in Chinese population. METHODS: Whole-exome capturing and sequencing technology was used for the detection of genetic variations in 19 individuals from six families with high incidence of KBD. A total of 44 polymorphisms from 41 genes were genotyped from a total of 144 cases and 144 controls by using MassARRAY under the standard protocol from Sequenom. Association was applied on the data by using PLINK1.07. RESULTS: In the sequencing stage, each sample showed approximately 70-fold coverage, thus covering more than 99% of the target regions. Among the single nucleotide polymorphisms (SNPs) used in the transmission disequilibrium test, 108 had a p value of <0.01, whereas 1056 had a p-value of <0.05. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicates that these SNPs focus on three major pathways: regulation of actin cytoskeleton, focal adhesion, and metabolic pathways. In the validation stage, single locus effects revealed that two of these polymorphisms (rs7745040 and rs9275295) in the human leukocyte antigen (HLA)-DRB1 gene and one polymorphism (rs9473132) in CD2-associated protein (CD2AP) gene have a significant statistical association with KBD. CONCLUSIONS: HLA-DRB1 and CD2AP gene were identified to be among the susceptibility genes of KBD, thus supporting the role of the autoimmune response in KBD and the possibility of shared etiology between osteoarthritis, rheumatoid arthritis, and KBD. PMID- 24776926 TI - Prevalence of intracranial atherosclerosis among patients with coronary artery disease: a 1-year hospital-based study. AB - BACKGROUND: There are limited data on the prevalence of intracranial atherosclerotic disease (ICAD) in patients with coronary artery disease (CAD) worldwide and especially among Egyptians. The purpose of the present study was to determine the prevalence and correlates of ICAD in patients with CAD. METHODS: From January 1, 2012 to January 1, 2013, we recruited 118 consecutive patients who had ischemic heart disease. All patients were assessed for vascular risk factors and the existence of stroke or transient ischemic attack (TIA) and were evaluated by extracranial and transcranial color-coded sonography. All patients underwent coronary angiography. Clinical, echocardiographic and angiographic variables were tested by univariate and multivariate analysis. RESULTS: Out of 118 consecutive patients with CAD, intracranial disease was detected in 14 patients (11.9%). Eight patients (6.8%) had stenosis >50%, while 6 patients (5.1%) had stenosis <50%. The univariate analysis showed that the strongest variables associated with ICAD were the presence of recent or old stroke or TIA, followed by moderate or severe extracranial stenosis, and multivessel or left main CAD. CONCLUSION: We observed low prevalence (6.8%) of high-grade ICAD among Egyptian patients with CAD. Multivessel or left main CAD and moderate-to-severe extracranial carotid stenosis were the strongest predictors for the existence of ICAD among CAD patients. PMID- 24776927 TI - Dose of hemodialysis and survival: a marginal structural model analysis. AB - BACKGROUND: Observational studies have consistently demonstrated the survival benefits of a greater dialysis dose in maintenance hemodialysis (MHD) patients, whereas randomized controlled trials have shown conflicting results. The possible causal impact of dialysis dose on mortality needs to be investigated using rich cohort data analyzed with novel statistical methods such as marginal structural models (MSMs) that account for time-varying confounding and exposure. METHODS: We quantified the effect of delivered dose of hemodialysis (HD) [single-pool Kt/V (spKt/V)] on mortality risk in a contemporary cohort of 68,110 patients undergoing HD 3 times weekly (7/2001- 9/2005). We compared conventional Cox proportional hazard and MSM survival analyses, accounting for time-varying confounding by applying longitudinally modeled inverse-probability-of-dialysis dose weights to each observation. RESULTS: In conventional Cox models, baseline spKt/V showed a weak negative association with mortality, while higher time averaged spKt/V was strongly associated with lower mortality risk. In MSM analyses, compared to a spKt/V range of 1.2 - <1.4, a spKt/V range of <1.2 was associated with a higher risk of mortality [HR (95% CI) 1.67 (1.54 - 1.80)], whereas mortality risks were significantly lower with higher spKt/V [HRs (95% CI): 0.74 (0.70-0.78), 0.63 (0.59-0.66), 0.56 (0.52-0.60), and 0.56 (0.52-0.61) for spKt/V ranges of 1.4 - <1.6, 1.6-<1.8, 1.8 - <2.0, and >=2.0, respectively]. Thus, MSM analyses showed that the greatest survival advantage of a higher dialysis dose was observed for a spKt/V range of 1.8-<2.0, and the dialysis dose mortality relationship was robust in almost all subgroups of patients. CONCLUSIONS: Higher HD doses were robustly associated with greater survival in MSM analyses that more fully and appropriately accounted for time-varying confounding. PMID- 24776923 TI - Ischaemic stroke in young adults: risk factors and long-term consequences. AB - Contrary to trends in most other diseases, the average age of ischaemic stroke onset is decreasing, owing to a rise in the incidence of stroke among 'young' individuals (under 50 years of age). This Review provides a critical overview of the risk factors and aetiology of young ischaemic stroke and addresses its long term prognosis, including cardiovascular risk, functional outcome and psychosocial consequences. We highlight the diminishing role of 'rare' risk factors in the pathophysiology of young stroke in light of the rising prevalence of 'traditional' vascular risk factors in younger age groups. Long-term prognosis is of particular interest to young patients, because of their long life expectancy and major responsibilities during a demanding phase of life. The prognosis of young stroke is not as favourable as previously thought, with respect either to mortality or cardiovascular disease or to psychosocial consequences. Therefore, secondary stroke prevention is probably a life-long endeavour in most young stroke survivors. Due to under-representation of young patients in past trials, new randomized trials focusing on this age group are needed to confirm the benefits of long-term secondary preventive medication. The high prevalence of poor functional outcome and psychosocial problems warrants further study to optimize treatment and rehabilitation for these young patients. PMID- 24776928 TI - The voltage-gated sodium channel TPC1 confers endolysosomal excitability. AB - The physiological function and molecular regulation of plasma membrane potential have been extensively studied, but how intracellular organelles sense and control membrane potential is not well understood. Using whole-organelle patch clamp recording, we show that endosomes and lysosomes are electrically excitable organelles. In a subpopulation of endolysosomes, a brief electrical stimulus elicits a prolonged membrane potential depolarization spike. The organelles have a previously uncharacterized, depolarization-activated, noninactivating Na(+) channel (lysoNaV). The channel is formed by a two-repeat six-transmembrane spanning (2*6TM) protein, TPC1, which represents the evolutionary transition between 6TM and 4*6TM voltage-gated channels. Luminal alkalization also opens lysoNaV by markedly shifting the channel's voltage dependence of activation toward hyperpolarization. Thus, TPC1 is a member of a new family of voltage-gated Na(+) channels that senses pH changes and confers electrical excitability to organelles. PMID- 24776931 TI - Exploring few-layer graphene and graphene oxide as fillers to enhance the oxygen atom corrosion resistance of composites. AB - Few-layer graphene (FLG) and graphene oxide (GO) were explored to enhance the oxygen-atom corrosion resistance of composites. FLG flakes of two different average lateral sizes (large: ~1.3 MUm(2) and small: ~0.23 MUm(2)) were prepared by a centrifugation-based size selection route. After exposure to oxygen atoms, although all fillers could enhance the oxygen-atom corrosion resistance of the composites, we found a much greater enhancement using large FLG, i.e. adding 1 wt% large FLG can achieve a 42% decrease in the composites' mass loss. Bonding and barrier effects of the flaked fillers are responsible for the enhanced resistance. These preliminary yet intriguing results pave a novel way for resisting oxygen-atom corrosion. PMID- 24776929 TI - Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness. AB - cAMP mediates autonomic regulation of heart rate by means of hyperpolarization activated cyclic nucleotide-gated (HCN) channels, which underlie the pacemaker current If. cAMP binding to the C-terminal cyclic nucleotide binding domain enhances HCN open probability through a conformational change that reaches the pore via the C-linker. Using structural and functional analysis, we identified a binding pocket in the C-linker of HCN4. Cyclic dinucleotides, an emerging class of second messengers in mammals, bind the C-linker pocket (CLP) and antagonize cAMP regulation of the channel. Accordingly, cyclic dinucleotides prevent cAMP regulation of If in sinoatrial node myocytes, reducing heart rate by 30%. Occupancy of the CLP hence constitutes an efficient mechanism to hinder beta adrenergic stimulation on If. Our results highlight the regulative role of the C linker and identify a potential drug target in HCN4. Furthermore, these data extend the signaling scope of cyclic dinucleotides in mammals beyond their first reported role in innate immune system. PMID- 24776930 TI - Plant perception of beta-aminobutyric acid is mediated by an aspartyl-tRNA synthetase. AB - Specific chemicals can prime the plant immune system for augmented defense. beta aminobutyric acid (BABA) is a priming agent that provides broad-spectrum disease protection. However, BABA also suppresses plant growth when applied in high doses, which has hampered its application as a crop defense activator. Here we describe a mutant of Arabidopsis thaliana that is impaired in BABA-induced disease immunity (ibi1) but is hypersensitive to BABA-induced growth repression. IBI1 encodes an aspartyl-tRNA synthetase. Enantiomer-specific binding of the R enantiomer of BABA to IBI1 primed the protein for noncanonical defense signaling in the cytoplasm after pathogen attack. This priming was associated with aspartic acid accumulation and tRNA-induced phosphorylation of translation initiation factor eIF2alpha. However, mutation of eIF2alpha-phosphorylating GCN2 kinase did not affect BABA-induced immunity but relieved BABA-induced growth repression. Hence, BABA-activated IBI1 controls plant immunity and growth via separate pathways. Our results open new opportunities to separate broad-spectrum disease resistance from the associated costs on plant growth. PMID- 24776932 TI - Impact of serum high mobility group box 1 and soluble receptor for advanced glycation end-products on subclinical atherosclerosis in patients with granulomatosis with polyangiitis. AB - The objective of this study was to evaluate whether levels of high mobility group box 1 (HMGB1) in granulomatosis with polyangiitis (GPA) patients are associated with carotid atherosclerosis, related to levels of soluble receptor for advanced glycation end-products (sRAGE) and influenced by immunosuppressive or lipid lowering therapy. Twenty-three GPA patients and 20 controls were evaluated for HMGB1- and sRAGE levels and for carotid atherosclerosis using ultrasound to determine intima-media thickness (IMT). In vitro the effect of atorvastatin on the production of HMGB1 by lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVEC) was assessed. Serum HMGB1 and sRAGE levels did not differ between patients and controls. A negative correlation was found between sRAGE and maximum IMT but HMGB1 and carotid IMT were not related. HMGB1 levels were reduced in GPA patients on statins and prednisolone. In vitro, atorvastatin reduced HMGB1 levels in supernatants of activated HUVEC. In conclusion, carotid IMT is inversely correlated with sRAGE levels but not with HMGB1 levels. Statins and prednisolone are associated with reduced serum HMGB1 levels and atorvastatin decreases HMGB1 release by activated HUVEC in vitro, indicating an additional anti-inflammatory effect of statins. PMID- 24776934 TI - Sensor applications of soft magnetic materials based on magneto-impedance, magneto-elastic resonance and magneto-electricity. AB - The outstanding properties of selected soft magnetic materials make them successful candidates for building high performance sensors. In this paper we present our recent work regarding different sensing technologies based on the coupling of the magnetic properties of soft magnetic materials with their electric or elastic properties. In first place we report the influence on the magneto-impedance response of the thickness of Permalloy films in multilayer sandwiched structures. An impedance change of 270% was found in the best conditions upon the application of magnetic field, with a low field sensitivity of 140%/Oe. Second, the magneto-elastic resonance of amorphous ribbons is used to demonstrate the possibility of sensitively measuring the viscosity of fluids, aimed to develop an on-line and real-time sensor capable of assessing the state of degradation of lubricant oils in machinery. A novel analysis method is shown to sensitively reveal the changes of the damping parameter of the magnetoelastic oscillations at the resonance as a function of the oil viscosity. Finally, the properties and performance of magneto-electric laminated composites of amorphous magnetic ribbons and piezoelectric polymer films are investigated, demonstrating magnetic field detection capabilities below 2.7 nT. PMID- 24776933 TI - A DNA microarray-based assay to detect dual infection with two dengue virus serotypes. AB - Here; we have described and tested a microarray based-method for the screening of dengue virus (DENV) serotypes. This DNA microarray assay is specific and sensitive and can detect dual infections with two dengue virus serotypes and single-serotype infections. Other methodologies may underestimate samples containing more than one serotype. This technology can be used to discriminate between the four DENV serotypes. Single-stranded DNA targets were covalently attached to glass slides and hybridised with specific labelled probes. DENV isolates and dengue samples were used to evaluate microarray performance. Our results demonstrate that the probes hybridized specifically to DENV serotypes; with no detection of unspecific signals. This finding provides evidence that specific probes can effectively identify single and double infections in DENV samples. PMID- 24776935 TI - A comparative study of information-based source number estimation methods and experimental validations on mechanical systems. AB - This paper investigates one eigenvalue decomposition-based source number estimation method, and three information-based source number estimation methods, namely the Akaike Information Criterion (AIC), Minimum Description Length (MDL) and Bayesian Information Criterion (BIC), and improves BIC as Improved BIC (IBIC) to make it more efficient and easier for calculation. The performances of the abovementioned source number estimation methods are studied comparatively with numerical case studies, which contain a linear superposition case and a both linear superposition and nonlinear modulation mixing case. A test bed with three sound sources is constructed to test the performances of these methods on mechanical systems, and source separation is carried out to validate the effectiveness of the experimental studies. This work can benefit model order selection, complexity analysis of a system, and applications of source separation to mechanical systems for condition monitoring and fault diagnosis purposes. PMID- 24776936 TI - The first electrochemical MIP sensor for tamoxifen. AB - We present an electrochemical MIP sensor for tamoxifen (TAM)-a nonsteroidal anti estrogen-which is based on the electropolymerisation of an O-phenylenediamine resorcinol mixture directly on the electrode surface in the presence of the template molecule. Up to now only "bulk" MIPs for TAM have been described in literature, which are applied for separation in chromatography columns. Electro polymerisation of the monomers in the presence of TAM generated a film which completely suppressed the reduction of ferricyanide. Removal of the template gave a markedly increased ferricyanide signal, which was again suppressed after rebinding as expected for filling of the cavities by target binding. The decrease of the ferricyanide peak of the MIP electrode depended linearly on the TAM concentration between 1 and 100 nM. The TAM-imprinted electrode showed a 2.3 times higher recognition of the template molecule itself as compared to its metabolite 4-hydroxytamoxifen and no cross-reactivity with the anticancer drug doxorubucin was found. Measurements at +1.1 V caused a fouling of the electrode surface, whilst pretreatment of TAM with peroxide in presence of HRP generated an oxidation product which was reducible at 0 mV, thus circumventing the polymer formation and electrochemical interferences. PMID- 24776937 TI - An uncertainty-based distributed fault detection mechanism for wireless sensor networks. AB - Exchanging too many messages for fault detection will cause not only a degradation of the network quality of service, but also represents a huge burden on the limited energy of sensors. Therefore, we propose an uncertainty-based distributed fault detection through aided judgment of neighbors for wireless sensor networks. The algorithm considers the serious influence of sensing measurement loss and therefore uses Markov decision processes for filling in missing data. Most important of all, fault misjudgments caused by uncertainty conditions are the main drawbacks of traditional distributed fault detection mechanisms. We draw on the experience of evidence fusion rules based on information entropy theory and the degree of disagreement function to increase the accuracy of fault detection. Simulation results demonstrate our algorithm can effectively reduce communication energy overhead due to message exchanges and provide a higher detection accuracy ratio. PMID- 24776938 TI - An adaptive scheme for robot localization and mapping with dynamically configurable inter-beacon range measurements. AB - This work is motivated by robot-sensor network cooperation techniques where sensor nodes (beacons) are used as landmarks for range-only (RO) simultaneous localization and mapping (SLAM). This paper presents a RO-SLAM scheme that actuates over the measurement gathering process using mechanisms that dynamically modify the rate and variety of measurements that are integrated in the SLAM filter. It includes a measurement gathering module that can be configured to collect direct robot-beacon and inter-beacon measurements with different inter beacon depth levels and at different rates. It also includes a supervision module that monitors the SLAM performance and dynamically selects the measurement gathering configuration balancing SLAM accuracy and resource consumption. The proposed scheme has been applied to an extended Kalman filter SLAM with auxiliary particle filters for beacon initialization (PF-EKF SLAM) and validated with experiments performed in the CONET Integrated Testbed. It achieved lower map and robot errors (34% and 14%, respectively) than traditional methods with a lower computational burden (16%) and similar beacon energy consumption. PMID- 24776939 TI - A case of ovarian paragonimiasis mimicking ovarian carcinoma. AB - BACKGROUND: The purpose of this report is to describe ovarian paragonimiasis, a rare form of lung fluke infestation, mimicking ovarian cancer. CASE: A 47-year old Thai woman presented with a pelvic mass. Imaging suggested ovarian cancer with pulmonary and hepatic metastases. She was scheduled for complete surgical staging. However, a frozen section revealed Paragonimus eggs in the enlarged ovarian mass. A total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed instead of complete staging. All other lesions were also proven later to be Paragonimus infestation. Postoperative treatment with antiparasitic drugs resulted in dramatic improvement, with nearly complete resolution of all lesions at 4 months of follow-up. CONCLUSION: This is an unusual case of ovarian paragonimiasis mimicking ovarian cancer, which is instructive and informative for differential diagnoses of pelvic masses. PMID- 24776940 TI - Effectiveness of disinfection therapies and promotion of osteoblast growth on osseotite and nanotite implant surfaces. AB - OBJECTIVES: To evaluate the effectiveness of 4 procedures to disinfect implant surfaces intentionally inoculated with bacteria and afterward to evaluate osteoblast viability to the disinfected implant surfaces. MATERIALS AND METHODS: Eighty-eight commercially pure Osseotite and Nanotite titanium implant discs were inoculated with Porphyromonas gingivalis. The implant surfaces were disinfected with EDTA, tetracycline, citric acid, or neodymium-doped yttrium aluminum garnet (Nd:YAG) laser. The implant discs were then placed in cultures of osteoblast cells. RESULTS: Osseotite implant discs were easier to disinfect compared with the Nanotite implant discs. Citric acid and tetracycline were the most effective solutions for the disinfection of P. gingivalis from the Osseotite implant discs. CONCLUSION: The Nanotite implant discs were the most difficult to disinfect, likely because of their chemical and physical properties. Citric acid and tetracycline were most effective for disinfecting the Osseotite implant discs, and further clinical research is needed to verify these effects in vivo. The Nd:YAG laser was the weakest disinfection method, and it is not recommended for disinfecting implant surfaces until its effectiveness is improved. PMID- 24776941 TI - Effect of metformin on periimplant wound healing in a rat model of type 2 diabetes. AB - PURPOSE: To investigate the effects of hyperglycemia and metformin (a popular biguanide antidiabetic) on periimplant healing. METHODS: Thirty-six male rats were assigned to 3 groups: (1) nondiabetic Wistar-Kyoto rats (controls), (2) Goto Kakizaki (GK) spontaneously diabetic rats (GK group), and (3) GK rats were fed metformin (100 mg/kg body weight per day) in their water for 4 weeks (GK + Met group). The right maxillary first molars were extracted and sites were allowed 1 month to heal. Titanium implants (1 * 3 mm) were placed in healed extraction sites. Six rats from each group were analyzed at weeks 1 and 4 by micro computed tomography for bone/implant contact ratio, percent bone volume, trabecular number, and bone mineral density. Blood was also analyzed for glucose, HbA1c, and pyridinoline (PYD). RESULTS: At week 1, glucose levels in the GK-Met rats were high, and all bone parameters were similar to GK rats (lower bone parameters and higher PYD than controls). At week 4, glucose levels in the GK-Met rats and all parameters were similar to controls. CONCLUSIONS: Hyperglycemic GK type 2 diabetic rats showed improved blood glucose and wound healing around oral implants after metformin administration. PMID- 24776942 TI - Comparative analysis of 2 resonance frequency measurement devices: Osstell Mentor and Osstell ISQ. AB - OBJECTIVE: Comparing reliability of Osstell Mentor and Osstell ISQ in implant stability measurement, and assessing whether their measurements are comparable. MATERIALS AND METHOD: Implant stability was measured with both devices on 58 implants in 15 patients. Six measurements were completed with each device with 2 different transducers (3 measurements with each transducer), that is, 12 measurements for each implant. RESULTS: Mean implant stability quotient (ISQ) value with Osstell ISQ was 72.59, 72.47, and 73.17 in the first measurements, respectively. With Osstell Mentor, the results were 72.43, 72.60, and 73.26, respectively; mean ranges were 3.37, 3.60, and 3.75, respectively. However, mean value with Osstell ISQ and Osstell Mentor was 72.87 and 72.04, respectively. The intraclass correlation coefficient was 0.98. This means an almost perfect degree of concordance between both devices. CONCLUSIONS: Resonance frequency analysis systems in Osstell Mentor and Osstell ISQ show almost perfect reproducibility and repeatability. PMID- 24776943 TI - Ectodermal dysplasia: an 11-year follow-up of siblings with 2 implant treatment approaches. AB - PURPOSE: To describe 2 different treatment approaches for a 20-year-old Caucasian man and his 22-year-old sister who were affected by ectodermal dysplasia (ED) and compromised maxillary bone. MATERIALS AND METHODS: The sister had a history of an iliac crest transplant with 6 implants placed in the maxillary and mandibular arches, 6 years before complications. It was necessary to debride the right sinus, remove the failing infected bone graft and 2 implants. Her brother presented with missing teeth, few remaining deciduous teeth, and wearing all acrylic resin temporary partials in both the maxillary and mandibular arches. RESULTS: Zygomatic and pterygomaxillary implants were used to rehabilitate the brother with a screw-retained fixed prostheses. His sister had 6 new maxillary implants. Both siblings' mandibular arches were restored with screw-retained implant-supported prostheses. CONCLUSION: Although these siblings affected with ED had different treatment approaches, they both eventually obtained successful outcomes. The brother's treatment was expedited. Both siblings have been followed for a period of 11 years, and all postoperative evaluations have been uneventful. PMID- 24776944 TI - Investigation of the risk factors associated with the survival rate of dental implants. AB - PURPOSE: The propose of this article was to evaluate the risk factors associated with the survival rate of the dental implants. MATERIAL AND METHODS: This retrospective study evaluated the survival rate of 940 implants placed at the Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Istanbul University, from January 2003 to January 2011. The potential risk factors associated with the survival rate of the implants were investigated. RESULTS: Fifteen (1.5%) of the 940 implants failed during the follow-up period. Smoking did not affect the survival rate of the implants (log-rank, 1.5; P = 0.219). The survival rate of the implants placed in the maxilla was lower than that of the implants placed in the mandible (log-rank, 4.81; P = 0.028). The 5-year survival rate of the dental implants was 98.5%. CONCLUSIONS: There are still conflicting results about the risk factors associated with the survival rate of the implants. According to the results of this study, it is concluded that only the location of the implants is associated with the survival rates of the implants. All implant systems showed high survival rates. PMID- 24776945 TI - Synthesis of copolymerized porous organic frameworks with high gas storage capabilities at both high and low pressures. AB - A series of copolymerized porous organic frameworks (C-POFs) were synthesized with monomers of tetrakis(4-bromophenyl)methane and tris(4-bromophenyl)amine in different ratios by a Yamamoto-type Ullmann cross-coupling reaction. These C-POFs exhibit high physicochemical stability, large surface areas and excellent H2, CH4 and CO2 adsorption properties both at low and high pressures. PMID- 24776946 TI - Natural and engineered biosynthesis of fluorinated natural products. AB - Both natural products and synthetic organofluorines play important roles in the discovery and design of pharmaceuticals. The combination of these two classes of molecules has the potential to be useful in the ongoing search for new bioactive compounds but our ability to produce site-selectively fluorinated natural products remains limited by challenges in compatibility between their high structural complexity and current methods for fluorination. Living systems provide an alternative route to chemical fluorination and could enable the production of organofluorine natural products through synthetic biology approaches. While the identification of biogenic organofluorines has been limited, the study of the native organisms and enzymes that utilize these compounds can help to guide efforts to engineer the incorporation of this unusual element into complex pharmacologically active natural products. This review covers recent advances in understanding both natural and engineered production of organofluorine natural products. PMID- 24776952 TI - POSS dendrimers constructed from a 1 -> 7 branching monomer. AB - Here, we demonstrate the first known approach to create G1 and G2 POSS dendrimers with 9 and 65 POSS units, and 56 and 392 terminal vinyl groups from a 1 -> 7 branching monomer in only one and three steps. PMID- 24776951 TI - Effect of submarine groundwater discharge on bacterial indicators and swimmer health at Avalon Beach, CA, USA. AB - Use of fecal indicator bacteria (FIB) for monitoring beach water quality is based on their co-occurrence with human pathogens, a relationship that can be dramatically altered by fate and transport processes after leaving the human intestine. We conducted a prospective cohort study at Avalon Beach, California (USA), where the indicator relationship is potentially affected by the discharge of sewage-contaminated groundwater and by solar radiation levels at this shallow, relatively quiescent beach. The goals of this study were to determine: 1) if swimmers exposed to marine water were at higher risk of illness than non swimmers; 2) if FIB measured in marine water were associated with swimmer illness, and; 3) if the associations between FIB and swimmer health were modified by either submarine groundwater discharge or solar radiation levels. There were 7317 individuals recruited during the summers of 2007-08, 6165 (84%) of whom completed follow-up within two weeks of the beach visit. A total of 703 water quality samples were collected across multiple sites and time periods during recruitment days and analyzed for FIB using both culture-based and molecular methods. Adjusted odds ratios (AOR) indicated that swimmers who swallowed water were more likely to experience Gastrointestinal Illness (GI Illness) within three days of their beach visit than non-swimmers, and that this risk was significantly elevated when either submarine groundwater discharge was high (AOR [95% CI]:2.18 [1.22-3.89]) or solar radiation was low (2.45 [1.25-4.79]). The risk of GI Illness was not significantly elevated for swimmers who swallowed water when groundwater discharge was low or solar radiation was high. Associations between GI Illness incidence and FIB levels (Enterococcus EPA Method 1600) among swimmers who swallowed water were not significant when we did not account for groundwater discharge, but were strongly associated when groundwater discharge was high (1.85 [1.06, 3.23]) compared to when it was low (0.77 [0.42, 1.42]; test of interaction: P = 0.03). These results demonstrate the need to account for local environmental conditions when monitoring for, and making decisions about, public health at recreational beaches. The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. PMID- 24776953 TI - Early add-on treatment vs alternative monotherapy in patients with partial epilepsy. AB - AIM: The aim of this study was to evaluate the impact of two different therapeutic strategies in patients with partial seizures who were intractable to the first prescribed antiepileptic drug (AED); alternative monotherapy vs early add-on treatment. METHODS: We conducted an open, cluster-randomised, prospective, controlled trial in patients with persistent partial seizures, despite treatment with one AED, who were never administered any other AEDs. Neurologists were randomised to two strategies: in group A, an alternative monotherapy with a second AED was employed; in group B, add-on treatment with a second AED was employed. The primary outcome was the percentage of seizure-free patients during a two-month period after six months of treatment. The secondary outcomes were: (i) the percentage of patients achieving a 50% reduction in the number of seizures at six months; (ii) the quality of life based on the Quality Of Life In Epilepsy scale; and (iii) tolerability. RESULTS: A total of 143 neurologists were included and randomised, and 264 patients were evaluated. At six months, the primary outcome was 51% in group A and 45% in group B (p=0.34). The percentage of patients achieving a 50% reduction in the number of seizures at six months was 76% in group A and 84% in group B (p=0.53). The quality of life and the tolerability did not significantly differ between the two groups. CONCLUSIONS: Alternative monotherapy or early treatment initiation with another AED drug resulted in similar efficacy, and the side effects associated with monotherapy and combined therapies were similar, which suggests that individual susceptibility is more important than the number and burden of AEDs used. PMID- 24776954 TI - STM sustains stem cell function in the Arabidopsis shoot apical meristem and controls KNOX gene expression independently of the transcriptional repressor AS1. AB - The Arabidopsis KNOX gene SHOOT MERISTEMLESS (STM) is required for both the development and the sustained function of the shoot apical meristem (SAM) and can induce de novo meristem formation when expressed ectopically. STM acts through induction of cytokinin (CK) synthesis to inhibit cellular differentiation and additionally functions to organize undifferentiated cells into a self-sustaining meristem. STM has been shown to positively regulate the related KNOX genes KNAT1/BP and KNAT2, and it has been proposed that this is mediated through repression of the ARP-type transcriptional repressor ASYMMETRIC LEAVES1 (AS1). Here we investigate the role of STM in SAM organization, stem cell maintenance and the regulation of KNOX gene expression. We show that culture of stm mutant explants in high CK conditions does not restore proper sustained shoot growth, supporting the idea of STM having CK-independent roles in meristem function. Furthermore, we show that STM is required for continued stem cell function in the SAM by sustaining expression of the stem cell-promoting factor WUS and preventing cells of the meristem organizing center from adopting lateral organ-specific fates. We also demonstrate that transcriptional activation of class-1 KNOX genes by STM is independent of AS1, since AS1 transcript levels are not reduced in response to STM and STM is able to transactivate expression of both KNAT1/BP and KNAT2 in the as1 mutant background. PMID- 24776955 TI - Clinical presentation, pathological features and natural course of metastatic uveal melanoma, an orphan and commonly fatal disease. AB - BACKGROUND: Uveal melanoma (UM) is a rare disease characterized by an unpredictable course and a variable outcome. We assessed the natural course of patients with metastatic uveal melanoma (MUM). METHODS: Data from 76 patients with MUM who were treated in Leuven between 1957 and 2008 were examined retrospectively. Statistical analysis involved the nonparametric, Kaplan-Meier and log rank tests. RESULTS: The median age at diagnosis of UM was 58 years (range 30-94). Synchronous metastases were found in 9% of the cases; all other patients had metachronous disease after a median interval of 40 months (range 7 420). Statistical analysis failed to identify factors related to the time until metastatic spread with the exception of a significant negative correlation with age at UM diagnosis (Spearman: rho = -0.4, p < 0.001). The most frequent metastatic site was the liver (in 96% of the patients). The median time from diagnosis of UM until death was 47 months (range 2-236) and only 5 months in patients with metastatic disease (range 1-128). CONCLUSIONS: MUM is an orphan disease. Advances in MUM can only be achieved by the networking of sites interested in this rare tumor type, with systematic collection of data and tumor tissue for improving our understanding of the molecular biology of this disease. PMID- 24776956 TI - Induced gamma oscillations differentiate familiar and novel voices in children with MECP2 duplication and Rett syndromes. AB - Normal levels of the methyl CpG-binding protein 2 (MeCP2) are critical to neurologic functioning, and slight alterations result in intellectual disability and autistic features. It was hypothesized that children with MECP2 duplication (overexpression of MeCP2) and Rett syndrome (underexpression of MeCP2) would exhibit distinct electroencephalographic (EEG) indices of auditory stimulus discrimination. In this study, gamma-band oscillatory responses to familiar and novel voices were examined and related to social functioning in 17 children (3-11 years old) with MECP2 duplication (n = 12) and Rett syndrome (n = 5). Relative to the stranger's voice, gamma activity in response to the mother's voice was increased in MECP2 duplication but decreased in Rett syndrome. In MECP2 duplication, greater mother versus stranger differences in gamma activity were associated with higher social functioning. For the first time, brain responses in a passive voice discrimination paradigm show that overexpression and underexpression of MeCP2 have differential effects on cortical information processing. PMID- 24776958 TI - The Loneliness of the Aging in Two Contemporary Novels. AB - PURPOSE OF THE STUDY: In The Loneliness of the Dying (1985), sociologist Norbert Elias claims that "aging" and "old age" have become frightening, almost taboo terms in Western society because death is increasingly made invisible in advanced societies. Years ago, death was a part of life and the dead were granted the honor of passing away in their homes, surrounded by their communities; in present day society, most have never seen a corpse and are ignorant of anything related to death. DESIGN AND METHODS: According to Elias, the consequences of this distancing from death have been a distancing from the aging process as a whole. This paper aims to analyze to what extent Norbert Elias's theories about death and the aging process are reflected in contemporary British fiction, using two novels as case studies. RESULTS: Ending Up (1974) and These Foolish Things (2004) depict older British characters who decide to share their last years when they realize that they are increasingly forgotten and invisible both within their communities and their families. IMPLICATIONS: In each of their particular styles, bleak and ironic in the case of Kingsley Amis's Ending Up, and refreshingly humorous and moving in the case of Deborah Moggach's These Foolish Things, both authors reflect on possible outcomes for an increasingly aging population. PMID- 24776957 TI - Cerebral candidiasis in a 4-year-old boy after intestinal surgery. AB - Cerebral candidiasis is a devastating disease which contributes to a high mortality. Most of the cerebral candidiasis are never microbiologically or radiologically confirmed. In this case, a 4-year-old boy who developed cerebral candidiasis was successfully rescued and presented. The diagnosis of cerebral candidiasis was established based on both microbiologic and radiologic examinations. The pathogen was revealed to be Candida albicans by cerebrospinal fluid and central venous catheter cultures, and the cerebral involvement was recorded by series head magnetic resonance imaging (MRI) with an appearance of special encephalitis demonstrated. The imaging studies played a critical role throughout the diagnosis and treatment. Familiarity with the imaging findings in the appropriate clinical setting may result in a heightened level of awareness of this infection and, consequently, in earlier diagnosis and treatment. PMID- 24776959 TI - Finite-key analysis for measurement-device-independent quantum key distribution. AB - Quantum key distribution promises unconditionally secure communications. However, as practical devices tend to deviate from their specifications, the security of some practical systems is no longer valid. In particular, an adversary can exploit imperfect detectors to learn a large part of the secret key, even though the security proof claims otherwise. Recently, a practical approach--measurement device-independent quantum key distribution--has been proposed to solve this problem. However, so far its security has only been fully proven under the assumption that the legitimate users of the system have unlimited resources. Here we fill this gap and provide a rigorous security proof against general attacks in the finite-key regime. This is obtained by applying large deviation theory, specifically the Chernoff bound, to perform parameter estimation. For the first time we demonstrate the feasibility of long-distance implementations of measurement-device-independent quantum key distribution within a reasonable time frame of signal transmission. PMID- 24776960 TI - Insight into the structure and the mechanism of the slow proton transfer in the GFP double mutant T203V/S205A. AB - Mutations near the fluorescing chromophore of the green fluorescent protein (GFP) have direct effects on the absorption and emission spectra. Some mutants have significant band shifts and most of the mutants exhibit a loss of fluorescence intensity. In this study we continue our investigation of the factors controlling the excited state proton transfer (PT) process of GFP, in particular to study the effects of modifications to the key side chain Ser205 in wt-GFP, proposed to participate in the proton wire. To this aim we combined mutagenesis, X-ray crystallography, steady-state spectroscopy, time-resolved emission spectroscopy and all-atom explicit molecular dynamics (MD) simulations to study the double mutant T203V/S205A. Our results show that while in the previously described GFP double mutant T203V/S205V the PT process does not occur, in the T203V/S205A mutant the PT process does occur, but with a 350 times slower rate than in wild type GFP (wt-GFP). Furthermore, the kinetic isotope effect in the GFP double mutant T203V/S205A is twice smaller than in the wt-GFP and in the GFP single mutant S205V, which forms a novel PT pathway. On the other hand, the crystal structure of GFP T203V/S205A does not reveal a viable proton transfer pathway. To explain PT in GFP T203V/S205A, we argue on the basis of the MD simulations for an alternative, novel proton-wire pathway which involves the phenol group of the chromophore and water molecules infrequently entering from the bulk. This alternative pathway may explain the dramatically slow PT in the GFP double mutant T203V/S205A compared to wt-GFP. PMID- 24776962 TI - The comparison of thyroxine versus thyroxine plus oral iodine in the treatment of congenital hypothyroidism due to iodine deficiency. AB - AIM: Iodine deficiency is one of the most important causes of congenital hypothyroidism. In addition to thyroid hormone replacement, iodine supplementation is also given to newborns with congenital hypothyroidism due to iodine deficiency. We aimed to determine whether it is beneficial to administer iodine supplementation in addition to the L-thyroxine (L-T4) treatment of newborns with congenital hypothyroidism due to iodine deficiency. MATERIALS AND METHODS: Of 51 newborns, 26 who were diagnosed with congenital hypothyroidism due to iodine deficiency were treated with L-T4. The remaining 25 cases were given L T4 plus 100 MUg/day of oral iodine. Free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), thyroglobulin (TG), thyroid volume, urine iodine and breast milk iodine levels were measured in the first and third months of treatment, and the data were compared between the two groups. RESULTS: First- and third-month values of fT3, fT4, TSH, TG and thyroid volume for both groups were statistically similar. There was no significant difference between the two groups in respect to falling levels of fT3 and TSH, the rate of increase of fT4 levels or the shrinkage rate of thyroid volume. CONCLUSION: In this study, the addition of oral iodine to L-T4 treatment provided no benefit compared to treatment with L-T4 alone. PMID- 24776963 TI - Age and growth of the round stingray Urotrygon rogersi, a particularly fast growing and short-lived elasmobranch. AB - We examined the age and growth of Urotrygon rogersi on the Colombian coast of the Eastern Tropical Pacific Ocean by directly estimating age using vertebral centra. We verified annual deposition of growth increments with marginal increment analysis. Eight growth curves were fitted to four data sets defined on the basis of the reproductive cycle (unadjusted or adjusted for age at first band) and size variables (disc width or total length). Model performance was evaluated using Akaike's Information Criterion (AIC), AIC weights and multi-model inference criteria. A two-phase growth function with adjusted age provided the best description of growth for females (based on five parameters, DWinfinity = 20.1 cm, k = 0.22 yr-1) and males (based on four and five parameters, DW(infinity) = 15.5 cm, k = 0.65 yr-1). Median maturity of female and male U. rogersi is reached very fast (mean +/- SE = 1.0 +/- 0.1 year). This is the first age and growth study for a species of the genus Urotrygon and results indicate that U. rogersi attains a smaller maximum size and has a shorter lifespan and lower median age at maturity than species of closely related genera. These life history traits are in contrast with those typically reported for other elasmobranchs. PMID- 24776961 TI - Non-invasive detection of early retinal neuronal degeneration by ultrahigh resolution optical coherence tomography. AB - Optical coherence tomography (OCT) has revolutionises the diagnosis of retinal disease based on the detection of microscopic rather than subcellular changes in retinal anatomy. However, currently the technique is limited to the detection of microscopic rather than subcellular changes in retinal anatomy. However, coherence based imaging is extremely sensitive to both changes in optical contrast and cellular events at the micrometer scale, and can generate subtle changes in the spectral content of the OCT image. Here we test the hypothesis that OCT image speckle (image texture) contains information regarding otherwise unresolvable features such as organelle changes arising in the early stages of neuronal degeneration. Using ultrahigh resolution (UHR) OCT imaging at 800 nm (spectral width 140 nm) we developed a robust method of OCT image analyses, based on spatial wavelet and texture-based parameterisation of the image speckle pattern. For the first time we show that this approach allows the non-invasive detection and quantification of early apoptotic changes in neurons within 30 min of neuronal trauma sufficient to result in apoptosis. We show a positive correlation between immunofluorescent labelling of mitochondria (a potential source of changes in cellular optical contrast) with changes in the texture of the OCT images of cultured neurons. Moreover, similar changes in optical contrast were also seen in the retinal ganglion cell- inner plexiform layer in retinal explants following optic nerve transection. The optical clarity of the explants was maintained throughout in the absence of histologically detectable change. Our data suggest that UHR OCT can be used for the non-invasive quantitative assessment of neuronal health, with a particular application to the assessment of early retinal disease. PMID- 24776964 TI - The association between blood-cerebrospinal fluid barrier dysfunction and the therapeutic effect in tuberculous meningitis patients. AB - OBJECTIVE: To explore the correlation of blood-cerebrospinal fluid (CSF) barrier (BCB) dysfunction with the therapeutic effect of antitubercular agents and their resistance, hoping to provide theoretical evidence for improvement of the therapeutic effect. METHODS: Albumin in CSF and serum was assayed by IMMAGE. The CSF/serum albumin ratio (QALB) was used to evaluate the permeability of the BCB. Real-time fluorescence quantitative PCR was used to detect the amount of Mycobacterium tuberculosis DNA, and an MTBDRplus reagent kit was used to determine the type of drug resistance of the M. tuberculosis. RESULTS: The correlation analysis showed that significant correlation existed between the grade of severity of tuberculous meningitis and the QALB, and the grade of severity and the total leukocyte count in the CSF, for which the correlation coefficients were 0.366 (p < 0.05) and 0.365 (p < 0.05), respectively. The QALB in the group of patients who recovered was significantly higher than that in those patients who experienced disease progression (p = 0.019). CONCLUSIONS: Our study showed that the permeability of the BCB correlated with the cure rate in tuberculous meningitis. Specifically, in the treatment of tuberculous meningitis, it is of key importance to utilize the benefit of the permeability of the BCB to achieve a better outcome. PMID- 24776965 TI - (13)C enrichment of the CO2 in breast milk and in the breath is rapidly modified by changes in the (13)C content of the diet. AB - BACKGROUND: C4 plants (e.g. corn and sugar cane) have greater (13)C enrichment than C3 plants (e.g. wheat and sugar beet). OBJECTIVE: To assess whether (13)C enrichment of CO2 in the breath and breast milk of women on diets based on C3 and C4 foods changes from one diet to the other. MATERIALS AND METHODS: Six breast feeding women were studied at 5-6 months postpartum. They ate a controlled C4 diet on days 1 and 2 followed by a C3 diet on days 3 and 4. Diet duplicates, breast milk on days 2 and 4 and hourly breath samples were collected over 4 days. (13)C enrichment was measured by isotope-ratio mass spectrometry. Values of delta(13)C were calculated from the international PDBV standard (delta(13)CPDBV). Differences between means were compared by paired t test or t test for repeated measurements. RESULTS: delta(13)CPDBV values were significantly higher in the C4 diet than in the C3 diet composites (p < 0.01). In breath CO2, the delta(13)CPDBV value was greater on days 1 and 2 (range -15.4 to -13.2, respectively) and declined on days 3 and 4 (range -20.0 to -21.8, respectively, p < 0.01). The lipid and milk serum fractions of breast milk had significantly higher delta(13)CPDBV on the C3 diet than on the C4 diet (p < 0.01). CONCLUSIONS: Subjects eating a C4 diet have a higher delta(13)CPDBV value in the breath and breast milk fractions, which diminish rapidly on a C3 diet. Further studies focusing on individual nutrients are warranted. PMID- 24776966 TI - Nanochemistry-derived Bi2WO6 nanostructures: towards production of sustainable chemicals and fuels induced by visible light. AB - Low cost and easily made bismuth tungstate (Bi2WO6) could be one of the key technologies to make chemicals and fuels from biomass, atmospheric carbon dioxide and water at low cost using solar radiation as an energy source. Its narrow band gap (2.8 eV) enables ideal visible light (lambda > 400 nm) absorption. Yet, it is the material's shape, namely the superstructure morphology wisely created via a nanochemistry approach, which leads to better electron-hole separation and much higher photoactivity. Recent results coupled to the versatile photochemistry of this readily available semiconductor suggest that the practical application of nanochemistry-derived Bi2WO6 nanostructures for the synthesis of value-added fine chemicals and fuel production is possible. We describe progress in this important field of chemical research from a nanochemistry viewpoint, and identify opportunities for further progress. PMID- 24776967 TI - Continuous spikes and waves during slow sleep in a child with karyotype 47, XYY. AB - The XYY syndrome is a sex chromosome aneuploidy occurring in one of 1,000 live male births. Only few data exist regarding the correlation between this syndrome and epilepsy. An EEG pattern suggestive of benign focal epilepsy with centro temporal spikes has recently been described in four XYY patients. We report the first patient with XYY trisomy, rolandic spikes, and atypical evolution with continuous spikes and waves during slow sleep (CSWSS). The present report suggests that the association between an EEG pattern similar to that of BECTS and 47, XYY karyotype may not be coincidental. Moreover, we show that an atypical evolution with CSWSS may occur in this chromosomal disorder. PMID- 24776970 TI - Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. AB - Sodium channel Nav1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Nav1.7 and Nav1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Nav1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Nav1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Nav1.9 as a cause of painful peripheral neuropathy. PMID- 24776969 TI - Critical brain regions for tool-related and imitative actions: a componential analysis. AB - Numerous functional neuroimaging studies suggest that widespread bilateral parietal, temporal, and frontal regions are involved in tool-related and pantomimed gesture performance, but the role of these regions in specific aspects of gestural tasks remains unclear. In the largest prospective study of apraxia related lesions to date, we performed voxel-based lesion-symptom mapping with data from 71 left hemisphere stroke participants to assess the critical neural substrates of three types of actions: gestures produced in response to viewed tools, imitation of tool-specific gestures demonstrated by the examiner, and imitation of meaningless gestures. Thus, two of the three gesture types were tool related, and two of the three were imitative, enabling pairwise comparisons designed to highlight commonalities and differences. Gestures were scored separately for postural (hand/arm positioning) and kinematic (amplitude/timing) accuracy. Lesioned voxels in the left posterior temporal gyrus were significantly associated with lower scores on the posture component for both of the tool related gesture tasks. Poor performance on the kinematic component of all three gesture tasks was significantly associated with lesions in left inferior parietal and frontal regions. These data enable us to propose a componential neuroanatomic model of action that delineates the specific components required for different gestural action tasks. Thus, visual posture information and kinematic capacities are differentially critical to the three types of actions studied here: the kinematic aspect is particularly critical for imitation of meaningless movement, capacity for tool-action posture representations are particularly necessary for pantomimed gestures to the sight of tools, and both capacities inform imitation of tool-related movements. These distinctions enable us to advance traditional accounts of apraxia. PMID- 24776971 TI - Voltage-gated sodium channel mutations and painful neuropathy: Na(v)1.9 joins the family. PMID- 24776972 TI - Social attention and the ventromedial prefrontal cortex. PMID- 24776973 TI - Mapping and modeling three dimensional lead contamination in the wetland sediments of a former trap-shooting range. AB - Legacy lead (Pb) contamination from sport shooting activities is a well-known hazard. Assessing the risk this contamination presents to the environment and public health requires a detailed understanding of its spatial distribution, yet our knowledge in this area is limited, especially for wetland shooting ranges. In this study, we analyzed 1351 sediment samples from 456 surficial (0-5 cm) locations and 38 sediment cores (0.3 to 0.9 m) to quantify the three dimensional spatial distribution of Pb contamination in an urban wetland at the site of a former trap shooting range located in southwestern Wisconsin, USA. Non destructive X-ray images of the sediment cores were used to quantify Pb shot abundance and burial depth. Surficial and core sediment samples were processed and analyzed for total Pb content via X-ray fluorescence (XRF) analysis. X-ray and XRF results were interpolated to create a three-dimensional model of Pb shot density and sediment concentration across the study area. Over 31,000 m(3) of sediment surpassed the US Environmental Protection Agency's contamination threshold of 400mg/kg Pb, with a maximum calibrated value of 26,700 mg/kg Pb occurring near the center of the expected shot fallout zone. Shot densities of >50,000 pellets/m(2) were found in the shot fallout zone, primarily 10-30 cm below the sediment surface. X-ray image analysis and XRF analysis of sediment cores provide an accurate and inexpensive technique for rapidly mapping Pb contamination associated with gun clubs and hunting; these findings will benefit environmental contamination studies and remediation efforts at active and abandoned shooting ranges worldwide. PMID- 24776974 TI - Prostate cancer: alcohol, cancer and 5alpha-reductase inhibitors-is there a link? AB - Two major trials have been performed to determine the effect of 5alpha-reductase inhibitors on subsequent diagnoses of prostate cancer. Both trials showed that high alcohol intake significantly increased prostate cancer risk among men allocated to the treatment arms. The recommendation that patients eliminate alcohol when taking 5alpha-reductase inhibitors seems appropriate. PMID- 24776975 TI - Prostate cancer: tools to predict insignificant prostate cancer are inaccurate in unscreened men. PMID- 24776976 TI - Prostate cancer: enzalutamide impresses in European studies. PMID- 24776977 TI - Charge carrier mobility in organic molecular materials probed by electromagnetic waves. AB - Charge carrier mobility is an essential parameter providing control over the performance of semiconductor devices fabricated using a variety of organic molecular materials. Recent design strategies toward molecular materials have been directed at the substitution of amorphous silicon-based semiconductors; accordingly, numerous measurement techniques have been designed and developed to probe the electronic conducting nature of organic materials bearing extremely wide structural variations in comparison with inorganic and/or metal-oxide semiconductor materials. The present perspective highlights the evaluation methodologies of charge carrier mobility in organic materials, as well as the merits and demerits of techniques examining the feasibility of organic molecules, crystals, and supramolecular assemblies in semiconductor applications. Beyond the simple substitution of amorphous silicon, we have attempted to address in this perspective the systematic use of measurement techniques for future development of organic molecular semiconductors. PMID- 24776978 TI - Evictionism and libertarianism. AB - There is a new sheriff in town on the abortion question. It is called evictionism. It diverges, philosophically, from both the pro-life and the pro choice positions. It assumes that the birth of a human being starts with the fertilized egg but claims that the unwanted baby is a trespasser that may be evicted in the gentlest manner possible. PMID- 24776979 TI - On art and science: an epistemic framework for integrating social science and clinical medicine. AB - Calls for incorporating social science into patient care typically have accounted for neither the logistic constraints of medical training nor the methodological fallacies of utilizing aggregate "social facts" in clinical practice. By elucidating the different epistemic approaches of artistic and scientific practices, this paper illustrates an integrative artistic pedagogy that allows clinical practitioners to generate social scientific insights from actual patient encounters. Although there is no shortage of calls to bring social science into medicine, the more fundamental processes of thinking by which art and science proceed have not been addressed to this end. As such, the art of medical practice is conceptualized as an innate gift, and thus little is done to cultivate it. Yet doing so is more important than ever because uncertainty in diagnosing and treating chronic illnesses, the most significant contemporary mortality risks, suggests a re-expanding role for clinical judgment. PMID- 24776980 TI - Public moralities and markets in organs. AB - Schweda and Schicktanz argue that the debate over the ethics of using financial incentives to procure human transplant organs rests on socioempirical premises that need to be critically assessed. They contend that once this is achieved a completely new perspective on the debate should be adopted, with organ donation being viewed primarily as a reciprocal social interaction between donor and recipient. This paper challenges this conclusion, arguing that rather than supporting a new perspective on the debate over the commercial procurement of organs, the observations of Schweda and Schicktanz support the view that human organs should be commercialized. PMID- 24776981 TI - Cochrane column. PMID- 24776982 TI - Mutation rate plasticity in rifampicin resistance depends on Escherichia coli cell-cell interactions. AB - Variation of mutation rate at a particular site in a particular genotype, in other words mutation rate plasticity (MRP), can be caused by stress or ageing. However, mutation rate control by other factors is less well characterized. Here we show that in wild-type Escherichia coli (K-12 and B strains), the mutation rate to rifampicin resistance is plastic and inversely related to population density: lowering density can increase mutation rates at least threefold. This MRP is genetically switchable, dependent on the quorum-sensing gene luxS- specifically its role in the activated methyl cycle--and is socially mediated via cell-cell interactions. Although we identify an inverse association of mutation rate with fitness under some circumstances, we find no functional link with stress-induced mutagenesis. Our experimental manipulation of mutation rates via the social environment raises the possibility that such manipulation occurs in nature and could be exploited medically. PMID- 24776983 TI - Staphylococcal enterotoxins in the etiopathogenesis of mucosal autoimmunity within the gastrointestinal tract. AB - The staphylococcal enterotoxins (SEs) are the products of Staphylococcus aureus and are recognized as the causative agents of classical food poisoning in humans following the consumption of contaminated food. While illness evoked by ingestion of the SE or its producer organism in tainted food are often self-limited, our current understanding regarding the evolution of S. aureus provokes the utmost concern. The organism and its associated toxins, has been implicated in a wide variety of disease states including infections of the skin, heart, sinuses, inflammatory gastrointestinal disease, toxic shock, and Sudden Infant Death Syndrome. The intricate relationship between the various subsets of immunocompetent T cells and accessory cells and the ingested material found within the gastrointestinal tract present daunting challenges to the maintenance of immunologic homeostasis. Dysregulation of the intricate balances within this environment has the potential for extreme consequences within the host, some of which are long-lived. The focus of this review is to evaluate the relevance of staphylococcal enterotoxin in the context of mucosal immunity, and the underlying mechanisms that contribute to the pathogenesis of gastrointestinal autoimmune disease. PMID- 24776984 TI - Human leukemia inhibitory factor produced by the ExpressTec method from rice (Oryza sativa L.) is active in human neural stem cells and mouse induced pluripotent stem cells. AB - Stem cell-based therapy has the potential to treat an array of human diseases. However, to study the therapeutic potential and safety of these cells, a scalable cell culture medium is needed that is free of human or bovine-derived serum proteins. Thus, cost-effective recombinant serum proteins and cytokines are needed to produce such mediums. One such cytokine, leukemia inhibitory factor (LIF), has been shown to be a critical paracrine factor that maintains stem cell pluripotency in murine embryonic stem cells and human naive stem cells while simultaneously inhibiting differentiation. We recently produced recombinant human LIF (rhLIF) in a rice-based protein expression system known as ExpressTec. (12) We described expression of rice-derived rhLIF and demonstrated its biological equivalency to E. coli-derived rhLIF in traditional and embryonic mouse stem cell systems. Here we describe the expression yield of rice-derived rhLIF and the scale up production capacity. We provide further evidence of the efficacy of rice derived rhLIF in additional stem cell systems including human neural stem cells and mouse induced pluripotent stem (iPS) cells. The expression level, biological activity, and potential for production at commercial scale of rice-derived rhLIF provides a proof-of-principal for ExpressTec-derived proteins to produce regulatory-friendly, high performance, and dependable stem cell media. PMID- 24776985 TI - Defective Wound-healing in Aging Gingival Tissue. AB - Aging may negatively affect gingival wound-healing. However, little is known about the mechanisms underlying this phenomenon. The present study examined the cellular responses associated with gingival wound-healing in aging. Primary cultures of human gingival fibroblasts were obtained from healthy young and aged donors for the analysis of cell proliferation, cell invasion, myofibroblastic differentiation, and collagen gel remodeling. Serum from young and old rats was used to stimulate cell migration. Gingival repair was evaluated in Sprague-Dawley rats of different ages. Data were analyzed by the Mann-Whitney and Kruskal-Wallis tests, with a p value of .05. Fibroblasts from aged donors showed a significant decrease in cell proliferation, migration, Rac activation, and collagen remodeling when compared with young fibroblasts. Serum from young rats induced higher cell migration when compared with serum from old rats. After TGF-beta1 stimulation, both young and old fibroblasts demonstrated increased levels of alpha-SMA. However, alpha-SMA was incorporated into actin stress fibers in young but not in old fibroblasts. After 7 days of repair, a significant delay in gingival wound-healing was observed in old rats. The present study suggests that cell migration, myofibroblastic differentiation, collagen gel remodeling, and proliferation are decreased in aged fibroblasts. In addition, altered cell migration in wound-healing may be attributable not only to cellular defects but also to changes in serum factors associated with the senescence process. PMID- 24776986 TI - Effect of needle insertion speed on tissue injury, stress, and backflow distribution for convection-enhanced delivery in the rat brain. AB - Flow back along a needle track (backflow) can be a problem during direct infusion, e.g. convection-enhanced delivery (CED), of drugs into soft tissues such as brain. In this study, the effect of needle insertion speed on local tissue injury and backflow was evaluated in vivo in the rat brain. Needles were introduced at three insertion speeds (0.2, 2, and 10 mm/s) followed by CED of Evans blue albumin (EBA) tracer. Holes left in tissue slices were used to reconstruct penetration damage. These measurements were also input into a hyperelastic model to estimate radial stress at the needle-tissue interface (pre stress) before infusion. Fast insertion speeds were found to produce more tissue bleeding and disruption; average hole area at 10 mm/s was 1.87-fold the area at 0.2 mm/s. Hole measurements also differed at two fixation time points after needle retraction, 10 and 25 min, indicating that pre-stresses are influenced by time-dependent tissue swelling. Calculated pre-stresses were compressive (0 to 485 Pa) and varied along the length of the needle with smaller average values within white matter (116 Pa) than gray matter (301 Pa) regions. Average pre stress at 0.2 mm/s (351.7 Pa) was calculated to be 1.46-fold the value at 10 mm/s. For CED backflow experiments (0.5, 1, and 2 uL/min), measured EBA backflow increased as much as 2.46-fold between 10 and 0.2 mm/s insertion speeds. Thus, insertion rate-dependent damage and changes in pre-stress were found to directly contribute to the extent of backflow, with slower insertion resulting in less damage and improved targeting. PMID- 24776988 TI - Evolutionary and developmental trends in vertebrate neural systems: selected papers of the 7th European Conference on Comparative Neurobiology, Budapest, Hungary, April 25-27, 2013. Preface. PMID- 24776987 TI - The insertion Green Monster (iGM) method for expression of multiple exogenous genes in yeast. AB - Being a simple eukaryotic organism, Saccharomyces cerevisiae provides numerous advantages for expression and functional characterization of proteins from higher eukaryotes, including humans. However, studies of complex exogenous pathways using yeast as a host have been hampered by the lack of tools to engineer strains expressing a large number of genetic components. In addition to inserting multiple genes, it is often desirable to knock out or replace multiple endogenous genes that might interfere with the processes studied. Here, we describe the "insertion Green Monster" (iGM) set of expression vectors that enable precise insertion of many heterologous genes into the yeast genome in a rapid and reproducible manner and permit simultaneous replacement of selected yeast genes. As a proof of principle, we have used the iGM method to replace components of the yeast pathway for methionine sulfoxide reduction with genes encoding the human selenoprotein biosynthesis machinery and generated a single yeast strain carrying 11 exogenous components of the selenoprotein biosynthetic pathway in precisely engineered loci. PMID- 24776989 TI - Revival of calcium-binding proteins for neuromorphology: secretagogin typifies distinct cell populations in the avian brain. AB - In the vertebrate nervous system, the Ca(2+)-binding proteins parvalbumin, calbindin and calretinin have been extensively used to elaborate the molecular diversity of neuronal subtypes. Secretagogin is a phylogenetically conserved Ca(2+)-binding protein, which marks neuronal populations largely distinct from other Ca(2+)-binding proteins in mammals. Whether secretagogin is expressed in nonmammalian vertebrates, particularly in birds, and, if so, with a brain cytoarchitectonic design different from that of mammals is unknown. Here, we show that secretagogin is already present in the hatchlings' brain with continued presence into adulthood. Secretagogin-immunoreactive neurons primarily accumulate in the olfactory bulb, septum, subpallial amygdala, hippocampus, hypothalamus, habenular nuclei and deep layers of the optic tectum of adult domestic chicks (Gallus domesticus). In the olfactory bulb, secretagogin labels periglomerular neurons as well as a cell continuum ascending dorsomedially, reaching the ventricular wall. Between the hippocampus and septal nuclei, the interconnecting thin septal tissue harbors secretagogin-immunoreactive neurons that contact the ventricular wall with their ramifying dendritic processes. Secretagogin is also present in the neuroendocrine hypothalamus, with particularly rich neuronal clusters seen in its suprachiasmatic and infundibular nuclei. Secretagogin expression identified a hitherto undescribed cell contingent along intratelencephalic cell-free laminae separating brain regions or marking the palliosubpallial boundary, as well as a dense neuronal population in the area corticoidea lateralis. In both the telencephalon and midbrain, secretagogin complemented the distribution of the canonical 'neuronal' Ca(2+)-binding proteins. Our findings identify novel neuronal subtypes, connectivity patterns in brain areas functionally relevant to olfaction, orientation, behavior as well as endocrine functions, which will help refine existing concepts on the neuronal diversity and organizational principles of the avian brain. PMID- 24776990 TI - Identification of striatal and pallidal regions in the subpallium of anamniotes. AB - The telencephalic basal ganglia (BG) of amniotes consist of two subdivisions, striatum and pallidum, which share many features, including development, cell types, neurotransmitter organization and hodology. In particular, these two subdivisions during development are defined on the basis of discrete gene expression patterns (genoarchitecture or genoarchitectonics). The characterization of the BG in the subpallium of representatives of the different classes of anamniote vertebrates was first approached in studies dealing with their localization, hodology and main neurochemical characteristics. Thus, it was proposed that an impressive degree of conservation exists across species. New insights can be gained by the comparative analysis of the expression of conserved transcription factors that distinctly define the striatal and pallidal components of the BG in all vertebrates. In addition, the expression of other genes that characterize neighboring regions of the BG is also useful to define the boundaries of each subdivision. Following this approach, we have analyzed the BG in the brain of juvenile representatives of amphibians, lungfishes, holosteans, Polypteriformes and Chondrichthyes. In addition, we briefly review previous data in teleosts and agnathans. The markers used include islet 1 and Dlx as striatal markers, whereas Nkx2.1 is essential for the identification of the pallidum. In turn, Pax6 and in particular Tbr1 are expressed in the pallium. These markers have been systematically analyzed in combination with neuronal markers of specific subpallial territories and cell populations, such as tyrosine hydroxylase, gamma-aminobutyric acid, nitric oxide synthase, substance P and enkephalin. The results highlight that many genes share common distribution patterns and are arranged in conserved combinations whose identification has served to define homologies between components of the BG in distant species. PMID- 24776991 TI - Brainstem circuits underlying the prey-catching behavior of the frog. AB - Prey-catching behavior (PCB) of the frog consists of a sequence of movements as a stimulus-response chain of the behavioral pattern in which each action presents a signal for the subsequent event. The transformation of visual information into appropriate spatiotemporal patterns of motor activity is carried out by the motor pattern generators located in the brainstem reticular formation. The motor pattern generators provide input to the motoneurons either directly or via the last-order premotor interneurons (LOPI). Although the feeding program is predetermined in this way, various sensory mechanisms control the motor activity. By using neuronal labeling methods, we have studied the morphological details of sensorimotor integration related to the hypoglossal motoneurons to provide further insight into the neuronal circuits underlying the PCB in ranid frogs. Our major findings are as follows. (1) Dendrodendritic and dendrosomatic contacts established by the crossing dendrites of hypoglossal (XII) motoneurons may serve as a morphological option for co-activation, synchronization and proper timing of the bilateral activity of tongue muscles. The crossing dendrites may also provide a feedforward amplification of various signals to the XII motoneurons. The overlapping dendritic territories of the motoneurons innervating protractor and retractor muscles may facilitate the coordinated activities of the agonistic and antagonistic muscles. (2) The musculotopic organization of the XII motoneurons is reflected in the distribution of LOPI for the protractor and retractor muscles of the tongue. (3) Direct sensory inputs from the trigeminal, vestibular, glossopharyngeal-vagal, hypoglossal and spinal afferent fibers to the XII motoneurons may modulate the basic motor pattern and contribute to the plasticity of neuronal circuits. (4) The electrical couplings observed in the vestibulocerebellar neuronal circuits may synchronize and amplify the afferent signals. The combination of chemical and electrical impulse transmission provides a mechanism by which motoneurons can be activated sequentially. PMID- 24776992 TI - Evolutionary and developmental contributions for understanding the organization of the basal ganglia. AB - Herein we take advantage of the evolutionary developmental biology approach in order to improve our understanding of both the functional organization and the evolution of the basal ganglia, with a particular focus on the globus pallidus. Therefore, we review data on the expression of developmental regulatory genes (that play key roles in patterning, regional specification and/or morphogenesis), gene function and fate mapping available in different vertebrate species, which are useful to (a) understand the embryonic origin and basic features of each neuron subtype of the basal ganglia (including neurotransmitter/neuropeptide expression and connectivity patterns); (b) identify the same (homologous) subpopulations in different species and the degree of variation or conservation throughout phylogeny, and (c) identify possible mechanisms that may explain the evolution of the basal ganglia. These data show that the globus pallidus of rodents contains two major subpopulations of GABAergic projection neurons: (1) neurons containing parvalbumin and neurotensin-related hexapetide (LANT6), with descending projections to the subthalamus and substantia nigra, which originate from progenitors expressing Nkx2.1, primarily located in the pallidal embryonic domain (medial ganglionic eminence), and (2) neurons containing preproenkephalin (and possibly calbindin), with ascending projections to the striatum, which appear to originate from progenitors expressing Islet1 in the striatal embryonic domain (lateral ganglionic eminence). Based on data on Nkx2.1, Islet1, LANT6 and proenkephalin, it appears that both cell types are also present in the globus pallidus/dorsal pallidum of chicken, frog and lungfish. In chicken, the globus pallidus also contains neurons expressing substance P (SP), perhaps originating in the striatal embryonic domain. In ray-finned and cartilaginous fishes, the pallidum contains at least the Nkx2.1 lineage cell population (likely representing the neurons containing LANT6). Based on the presence of neurons containing enkephalin or SP, it is possible that the pallidum of these animals also includes the Islet1 lineage cell subpopulation, and both neuron subtypes were likely present in the pallidum of the first jawed vertebrates. In contrast, lampreys (jawless fishes) appear to lack the pallidal embryonic domain and the Nkx2.1 lineage cell population that mainly characterize the pallidum in jawed vertebrates. In the absence of data in other jawless fishes, the ancestral condition in vertebrates remains to be elucidated. Perhaps, a major event in telencephalic evolution was the novel expression of Nkx2.1 in the subpallium, which has been related to Hedgehog expression and changes in the regulatory region of Nkx2.1. PMID- 24776994 TI - Immunoreactivity distribution of vasotocin and vasoactive intestinal peptide in brain nuclei of two songbird species with different breeding systems. AB - Vasopressin influences social behaviour in mammals, in particular social recognition and bonding. However, much less is known about its avian analogue, vasotocin, although vasotocin appears to modulate singing behaviour and agonistic interactions together with vasoactive intestinal peptide (VIP) in some songbirds. The objectives of our study were to compare the expression of vasotocin and VIP in brain nuclei hypothetised to be part of the social behavioural network, i.e. septal areas, bed nucleus of the stria terminalis and medial preoptic nucleus (POM), in two songbird species in the wild: the blue tit (Cyanistes caeruleus) and European penduline tit (Remiz pendulinus). These two closely related passerine birds differ in their pair bonding and mating systems: blue tits are socially monogamous with extensive pair bond lasting for several months, whereas in the European penduline tit, pair bond is short and it dissolves during or after laying of the eggs. The two species did not differ in the distribution of vasotocin in the observed brain regions; however, VIP was more abundant in all three regions of penduline tits than in blue tits. We found a sex difference in favour of males in the distribution of vasotocin- and VIP-immunoreactive neurones, fibres and terminals in all three regions in penduline tits. In blue tits, such gender differences were only observed in the POM. The limited differences between the two species suggest that the levels of vasotocin and VIP in the socially relevant brain regions are likely influenced by many other social or environmental factors than just by differences in the duration of pair bonding. PMID- 24776993 TI - Evolution and development of the mammalian cerebral cortex. AB - Comparative developmental studies of the mammalian brain can identify key changes that can generate the diverse structures and functions of the brain. We have studied how the neocortex of early mammals became organized into functionally distinct areas, and how the current level of cortical cellular and laminar specialization arose from the simpler premammalian cortex. We demonstrate the neocortical organization in early mammals, which helps to elucidate how the large, complex human brain evolved from a long line of ancestors. The radial and tangential enlargement of the cortex was driven by changes in the patterns of cortical neurogenesis, including alterations in the proportions of distinct progenitor types. Some cortical cell populations travel to the cortex through tangential migration whereas others migrate radially. A number of recent studies have begun to characterize the chick, mouse and human and nonhuman primate cortical transcriptome to help us understand how gene expression relates to the development and anatomical and functional organization of the adult neocortex. Although all mammalian forms share the basic layout of cortical areas, the areal proportions and distributions are driven by distinct evolutionary pressures acting on sensory and motor experiences during the individual ontogenies. PMID- 24776995 TI - Evolution and development of hair cell polarity and efferent function in the inner ear. AB - The function of the inner ear critically depends on mechanoelectrically transducing hair cells and their afferent and efferent innervation. The first part of this review presents data on the evolution and development of polarized vertebrate hair cells that generate a sensitive axis for mechanical stimulation, an essential part of the function of hair cells. Beyond the cellular level, a coordinated alignment of polarized hair cells across a sensory epithelium, a phenomenon called planar cell polarity (PCP), is essential for the organ's function. The coordinated alignment of hair cells leads to hair cell orientation patterns that are characteristic of the different sensory epithelia of the vertebrate inner ear. Here, we review the developmental mechanisms that potentially generate molecular and morphological asymmetries necessary for the control of PCP. In the second part, this review concentrates on the evolution, development and function of the enigmatic efferent neurons terminating on hair cells. We present evidence suggestive of efferents being derived from motoneurons and synapsing predominantly onto a unique but ancient cholinergic receptor. A review of functional data shows that the plesiomorphic role of the efferent system likely was to globally shut down and protect the peripheral sensors, be they vestibular, lateral line or auditory hair cells, from desensitization and damage during situations of self-induced sensory overload. The addition of a dedicated auditory papilla in land vertebrates appears to have favored the separation of vestibular and auditory efferents and specializations for more sophisticated and more diverse functions. PMID- 24776996 TI - Connecting ears to eye muscles: evolution of a 'simple' reflex arc. AB - Developmental and evolutionary data from vertebrates are beginning to elucidate the origin of the sensorimotor pathway that links gravity and motion detection to image-stabilizing eye movements--the vestibulo-ocular reflex (VOR). Conserved transcription factors coordinate the development of the vertebrate ear into three functional sensory compartments (graviception/translational linear acceleration, angular acceleration and sound perception). These sensory components connect to specific populations of vestibular and auditory projection neurons in the dorsal hindbrain through undetermined molecular mechanisms. In contrast, a molecular basis for the patterning of the vestibular projection neurons is beginning to emerge. These are organized through the actions of rostrocaudally and dorsoventrally restricted transcription factors into a 'hodological mosaic' within which coherent and largely segregated subgroups are specified to project to different targets in the spinal cord and brain stem. A specific set of these regionally diverse vestibular projection neurons functions as the central element that transforms vestibular sensory signals generated by active and passive head and body movements into motor output through the extraocular muscles. The large dynamic range of motion-related sensory signals requires an organization of VOR pathways as parallel, frequency-tuned, hierarchical connections from the sensory periphery to the motor output. We suggest that eyes, ears and functional connections subserving the VOR are vertebrate novelties that evolved into a functionally coherent motor control system in an almost stereotypic organization across vertebrate taxa. PMID- 24776997 TI - Functional real-time optoacoustic imaging of middle cerebral artery occlusion in mice. AB - BACKGROUND AND PURPOSE: Longitudinal functional imaging studies of stroke are key in identifying the disease progression and possible therapeutic interventions. Here we investigate the applicability of real-time functional optoacoustic imaging for monitoring of stroke progression in the whole brain of living animals. MATERIALS AND METHODS: The middle cerebral artery occlusion (MCAO) was used to model stroke in mice, which were imaged preoperatively and the occlusion was kept in place for 60 minutes, after which optoacoustic scans were taken at several time points. RESULTS: Post ischemia an asymmetry of deoxygenated hemoglobin in the brain was observed as a region of hypoxia in the hemisphere affected by the ischemic event. Furthermore, we were able to visualize the penumbra in-vivo as a localized hemodynamically-compromised area adjacent to the region of stroke-induced perfusion deficit. CONCLUSION: The intrinsic sensitivity of the new imaging approach to functional blood parameters, in combination with real time operation and high spatial resolution in deep living tissues, may see it become a valuable and unique tool in the development and monitoring of treatments aimed at suspending the spread of an infarct area. PMID- 24776998 TI - Accurate detection of Parkinson's disease in tremor syndromes using olfactory testing. AB - BACKGROUND/AIMS: The diagnostic value of olfactory testing for the discrimination of tremor-dominant Parkinson's disease (PD) from other tremor disorders remains enigmatic. We evaluated whether olfactory testing can accurately detect PD in tremor patients. METHODS: A retrospective analysis of 299 consecutive subjects referred for the differential diagnosis of a tremor disorder was done. Olfactory testing was performed using 'Sniffin' Sticks', resulting in a composite TDI score of odor threshold (T), discrimination (D), and identification (I). Receiver operating curve (ROC) plots were used to calculate sensitivity/specificity for the detection of PD. RESULTS: Of all subjects, 167 (55.9%) had PD and 85 (28.4%) had essential tremor (ET). The mean TDI score in PD was significantly reduced compared to those in ET and other tremor disorders with no differences between ET and other tremor disorders. ROC analysis revealed strong correlations of TDI scores with PD [area under the curve: 0.85 (95% CI: 0.80-0.89); p < 0.001]. The highest Youden index was observed for a TDI score <25 (Youden index: 0.58). Using this cutoff score and that generated from normative data of healthy controls, the TDI score provided high sensitivity (negative predictive value) and specificity (positive predictive value) of approximately 80% for detecting PD. CONCLUSION: Olfactory testing is a useful, easily applied and inexpensive diagnostic test which is helpful to detect PD among tremor patients. PMID- 24776999 TI - Central serous chorioretinopathy. AB - The pathogenesis of central serous chorioretinopathy (CSC) is still not fully understood. The involvement of corticosteroids is undisputed, although their exact role has not been clarified; other parts of the underlying mechanism of CSC have been mainly elucidated by imaging techniques such as fluorescein and indocyanine green angiography. Even though most cases of CSC are self-limiting, severe as well as recurrent courses exist, and for these patients only a limited number of treatment options are available: laser photocoagulation, with a risk of scotoma and choroidal neovascularization, and photodynamic therapy. In this review article, we give an overview of its epidemiology, the current understanding of its pathogenesis as well as systemic and ocular risk factors. We illuminate modern diagnostic tools as well as current treatment options in the context of CSC, particularly in the light of a better understanding of corticosteroids and their receptors involved in its pathogenesis. PMID- 24777001 TI - High-throughput computational screening of metal-organic frameworks. AB - There is an almost unlimited number of metal-organic frameworks (MOFs). This creates exciting opportunities but also poses a problem: how do we quickly find the best MOFs for a given application? Molecular simulations have advanced sufficiently that many MOF properties - especially structural and gas adsorption properties - can be predicted computationally, and molecular modeling techniques are now used increasingly to guide the synthesis of new MOFs. With increasing computational power and improved simulation algorithms, it has become possible to conduct high-throughput computational screening to identify promising MOF structures and uncover structure-property relations. We review these efforts and discuss future directions in this new field. PMID- 24777000 TI - Procoagulant, tissue factor-bearing microparticles in bronchoalveolar lavage of interstitial lung disease patients: an observational study. AB - Coagulation factor Xa appears involved in the pathogenesis of pulmonary fibrosis. Through its interaction with protease activated receptor-1, this protease signals myofibroblast differentiation in lung fibroblasts. Although fibrogenic stimuli induce factor X synthesis by alveolar cells, the mechanisms of local posttranslational factor X activation are not fully understood. Cell-derived microparticles are submicron vesicles involved in different physiological processes, including blood coagulation; they potentially activate factor X due to the exposure on their outer membrane of both phosphatidylserine and tissue factor. We postulated a role for procoagulant microparticles in the pathogenesis of interstitial lung diseases. Nineteen patients with interstitial lung diseases and 11 controls were studied. All subjects underwent bronchoalveolar lavage; interstitial lung disease patients also underwent pulmonary function tests and high resolution CT scan. Microparticles were enumerated in the bronchoalveolar lavage fluid with a solid-phase assay based on thrombin generation. Microparticles were also tested for tissue factor activity. In vitro shedding of microparticles upon incubation with H2O2 was assessed in the human alveolar cell line, A549 and in normal bronchial epithelial cells. Tissue factor synthesis was quantitated by real-time PCR. Total microparticle number and microparticle associated tissue factor activity were increased in interstitial lung disease patients compared to controls (84+/-8 vs. 39+/-3 nM phosphatidylserine; 293+/-37 vs. 105+/-21 arbitrary units of tissue factor activity; mean+/-SEM; p<.05 for both comparisons). Microparticle-bound tissue factor activity was inversely correlated with lung function as assessed by both diffusion capacity and forced vital capacity (r2 = .27 and .31, respectively; p<.05 for both correlations). Exposure of lung epithelial cells to H2O2 caused an increase in microparticle bound tissue factor without affecting tissue factor mRNA. Procoagulant microparticles are increased in interstitial lung diseases and correlate with functional impairment. These structures might contribute to the activation of factor X and to the factor Xa-mediated fibrotic response in lung injury. PMID- 24777002 TI - Correction of facial and mandibular asymmetry using a computer aided design/computer aided manufacturing prefabricated titanium implant. AB - Patients with significant craniofacial asymmetry may have functional problems associated with their occlusion and aesthetic concerns related to the imbalance in soft and hard tissue profiles. This report details a case of facial asymmetry secondary to left mandible angle deficiency due to undergoing previous radiotherapy. We describe the correction of the bony deformity using computer aided design/computer aided manufacturing custom-made titanium onlay using novel direct metal laser sintering. The direct metal laser sintering onlay proved a very accurate operative fit and showed a good aesthetic correction of the bony defect with no reported complications postoperatively. It is a useful low morbidity technique, and there is no resorption or associated donor-site complications. PMID- 24777003 TI - Assessment of migrated foreign bodies in the maxillae by x-ray fluorescence spectrometry. AB - Two cases of foreign bodies that were incidentally observed on orthopantomographs are reported in this study. The foreign bodies were analyzed using an x-ray fluorescence spectrometer to identify what the migrated foreign bodies were and what migration pathways they had taken. The removed metallic foreign bodies from the maxillae of 2 patients, who were referred to the Department of Dentistry and Oral Surgery of the University of Fukui Hospital, were analyzed using an x-ray fluorescence spectrometer in the Department of Dental and Biomedical Materials Science, Nagasaki University. The major component of foreign body in patient 1 was silver, and that in case 2 was iron. On the basis of the imaging results and the patients' clinical history, the foreign bodies were considered to be caused by iatrogenic migration. Understanding the existence of foreign bodies and their migration pathway into the jaw bone can thus make clinicians more aware of such migrations and can thereby contribute to reducing iatrogenic accidents. PMID- 24777004 TI - Heminasal agenesis: a reconstructive challenge. AB - Heminasal agenesis is a rare congenital malformation often associated with deformities of the eyes and lacrimal system, midface, and proboscis lateralis. Reconstruction is especially challenging because of missing lining, cartilage, and skin. We present a case of heminasal agenesis in a 5-year-old girl with concomitant hypertelorism, coloboma of the eyelids, and maxillary hypoplasia. The patient underwent facial bipartition for hypertelorism correction and cantilever bone graft. A forehead flap was designed using an anaplastic model from the patient's twin sister. Cartilage harvested from the conchal bowl and rib provided alar and dorsal support. Reconstructive goals, timing, and options are discussed. PMID- 24777005 TI - Le Fort II midfacial distraction combined with orthognathic surgery in the treatment of nasomaxillary hypoplasia. AB - Patients with nasomaxillary hypoplasia have severe facial concavity and compromised skeletal class III malocclusion. Its treatment is still a challenge to surgeons. Our aim was to evaluate the combination of midfacial distraction and orthognathic surgery in the treatment of nasomaxillary hypoplasia. Four patients with nasomaxillary hypoplasia were enrolled in this study. After Le Fort II osteotomy, the rotational distraction of nasomaxillary complex was performed to rehabilitate facial convexity. Then bilateral sagittal split ramus osteotomy with or without Le Fort I osteotomy was used to correct malocclusion. All patients healed uneventfully, and the maxillae moved forward conspicuously. No obvious pain and severe discomfort were complained during distraction. A significant advancement and downward movement of the maxilla were shown by cephalometric analysis. The combination of midfacial distraction and orthognathic surgery provides us an ideal alternative in the treatment of nasomaxillary hypoplasia. PMID- 24777006 TI - The use of microcannula for facial wasting rehabilitation with polyacrylamide gel injection: is it better than needle? PMID- 24777007 TI - The primary closure approach of dog bite injuries of the nose. AB - The nose holds an outstanding position on the face, acquiring great importance within the context of facial aesthetics. Because of the functional, psychological, and social aspects of trauma in a society increasingly demanding about aesthetics, treatment institution must reduce, as accurate as possible, the sequelae that hinder social integration. This clinical report relates an immediate nasal reconstruction of a complex animal bite wound. A 7-year-old patient was victim of a dog bite with avulsion of the left nasal ala and part of the ipsilateral nasal tip. The treatment was immediate nasal reconstruction with auricular composite graft. After 1 year of follow-up, the shape of nasal ala was stable, and the color was consistent with the surrounding tissue. The 2 nasal sides exhibited satisfactory symmetry when evaluated. It can be concluded that the composite graft derived from the auricular helix is a safe option for reconstruction of nasal ala defects with compromised margins in pediatric patients when conditions of reimplantation do not exist. PMID- 24777008 TI - Extensive keratinized tissue augmentation during implant rehabilitation after Le Fort I osteotomy: using a new porcine collagen membrane (Mucoderm). AB - The aim of this study was to test a new collagen matrix (Mucoderm) positioned during oral implant abutment connection. A patient previously treated with Le Fort I for bone augmentation and 8 implants showing minimal amount of keratinized tissue was selected for an extensive keratinized tissue augmentation and deepening of the oral vestibule by apically positioning a split palatal flap and palatal grafting with Mucoderm. Clinical data at 9 and 14 days and 1 and 2 months showed resorption of the collagen graft, augmentation of the keratinized tissue around the implants, and deepening of the vestibule, with minimal morbidity and reduced surgical treatment time. However, some vestibular keratinized tissue contraction was evident. The new collagen matrix may be a promising material as a substitute for an autologous gingival/connective tissue graft. Despite the preliminary results of this innovative article, before drawing any general conclusion, the benefit of the procedure should be further evaluated by prospective clinical trials. PMID- 24777009 TI - Management of orbital infections related to sinusitis. PMID- 24777010 TI - A simple approach to reduction and stabilization of segmental fractures of the alveolar housing in complex facial trauma. PMID- 24777011 TI - Primary intraosseous squamous cell carcinoma of the mandible. Is adjuvant therapy still necessary to improve a 5-year survival rate? PMID- 24777012 TI - Head and neck rhabdomyosarcoma in adults. AB - AIM: The purpose of this study was to explore the treatment and prognosis of head and neck rhabdomyosarcoma (RMS) in adults. METHODS: Fifty-nine patients with head and neck RMS in adults (AHNRMS) treated in one institution were selected. Multivariate analysis was used to evaluate the various variables related to overall survival (OS). RESULTS: The estimated 5-year OS was 36%. The rate of cervical lymph node (CLN) involvement was 28%. Patients with embryonic RMS who underwent chemotherapy enjoyed a favorable outcome according to the multivariate analysis (P = 0.047). Local recurrence (n = 30) and distant metastasis (n = 17) were the main causes of treatment failure. The rate of local recurrence or distant metastasis in the patients who underwent chemotherapy also decreased. Positive surgical margin (32%) was frequently seen in the AHNRMS. Primary site (P = 0.01), tumor size (P < 0.0001), CLN (P = 0.003), and margin status (P = 0.0002) were significant prognostic factors related to OS. CONCLUSIONS: Head and neck RMS in adults is a rare malignancy with a poor outcome, which is more likely to have CLN involvement compared with other soft tissue sarcomas of the head and neck. Standard treatment for AHNRMS should comprise surgery and chemotherapy. PMID- 24777013 TI - A technical note about flap fixation technique to prevent salivary fistulas in reconstructive oral cavity surgery. AB - Salivary fistulas are frequent complications in oral oncological reconstructive surgery by means of pedicled or free flaps. The most common risk factors are malnutrition, advanced disease, and healing alterations due to radiation therapy or infections. However, they can be observed also in healthy patients where the flap suture breakdown is the only cause. During the reconstructive phase, flaps are anchored to the remnant tongue, hyoid bone, and residual gingival mucosa; the last structure often does not offer suitable margins for a strong suture. The aim of this study was to propose a transmandibular fixation of the flap that allows, in a safe, efficient, and unexpensive way, the creation of a saliva-proof neofloor of the mouth, independently from the quality and thickness of residual gingival mucosa. PMID- 24777014 TI - A clinicoradiographic and pathological study of pericoronal follicles associated to mandibular third molars. AB - BACKGROUND: Third molar surgery is considered the most frequently performed procedure in oral surgery. Although there are some indications for the removal of this tooth, such as the possibility of cystic degeneration or a tumor of the adjacent pericoronal follicle, there is no consensus in the literature about their prophylactic removal. OBJECTIVES: The aims of this study were to investigate the pathological alterations related to mandibular third molar dental follicles and to perform a narrative literature review. METHODS: A prospective clinical, radiographic, and histopathologic study was conducted with pericoronal follicles of third molars. After histopathologic evaluation and establishment of diagnosis, 2 groups were defined: G1 (pericoronal tissues with pathological alterations based on histopathologic analysis) and G2 (pericoronal tissues without pathological alterations based on histopathologic analysis). In addition, a systematic review of the literature was performed. RESULTS: One hundred thirteen specimens were analyzed. G1 was the most prevalent (P = 0.0004). Lesions were found in patients between 20 and 25 years of age (P < 0.004). The most prevalent histological diagnosis was the paradental cyst (47.7%; P < 0.0001). The narrative literature review showed that the majority of cases were mainly dentigerous cysts (P < 0.05). CONCLUSIONS: The mandibular third molars in young adults showed a direct relationship with age and a statistical propensity for the development of these cystic alterations, notably paradental cysts. PMID- 24777015 TI - Ultrasonic versus drills implant site preparation: a histologic analysis in bovine ribs. AB - PURPOSE: Ultrasonic surgery is a recently developed system for cutting bone with microvibrations. The aim of the current study was a histologic comparison between conventional drills versus ultrasonic surgery devices in implant bed preparation. METHODS: Ten bovine ribs were used, and a total of 100 perforations were randomly performed: half (n = 50) (group A) of the perforations were done through conventional drills using a single cylindrical bur (Bone System, Milan, Italy), 13 mm in height and 2 mm in width at a speed of 400 rpm, and the other half (n = 50) (group B) using an ultrasonic device (Surgysonic; Esacrom, Imola Italy), mounted with a diamond-coated cylindrical tip. After implant sites' preparation, the ribs were immediately stored in 10% buffered formalin and processed to obtain thin ground sections. RESULTS: At higher magnification, microcracks at the interface were detected. In group A, they were numerous and showed a thickness and depth ranging from 20 to 120 MUm and from 500 to 1000 MUm, respectively. In group B, very few or no microcracks were present. Statistically significant differences were found in the microcracks density in the cortical bone but not in the cancellous bone. CONCLUSIONS: The findings from this study suggest that ultrasonic implant site preparation showed a higher performance in terms of accuracy and uniformity of the osteotomy cut, compared with conventional rotary instruments. Further studies should be conducted to understand whether a smooth, congruent implant bed able to retain fine bone structures may affect the early phases of bone healing and therefore improve osseointegration. PMID- 24777016 TI - Freeman-Sheldon syndrome and respiratory obstruction: a novel use of distraction osteogenesis. AB - Freeman-Sheldon syndrome, or distal arthrogryposis type IIA (DA 2A), is a rare and severe multiple congenital contracture syndrome that is associated with upper airway obstruction. This obstruction has been clinically significant enough to warrant tracheostomy and has been associated with mortality. We describe a patient who presented to us as a neonate and the novel management of her respiratory obstruction in the setting of DA 2A. Bilateral mandibular osteotomies were performed and bilateral internal mandibular distracters were placed. She was distracted a total of 3 cm over 15 days without event and successfully extubated on the postoperative day 16. Preoperative polysomnogram demonstrated an obstructive apnea hypopnea index of 43.7, but a repeat polysomnogram demonstrated an apnea hypopnea index of 8.1. In this study, we report the first use of distraction osteogenesis in the setting of severe obstructive sleep apnea syndrome secondary to DA 2A. PMID- 24777017 TI - Maxillary distraction osteogenesis in cleft lip and palate cases with midface hypoplasia using rigid external distractor: an alternative technique. AB - BACKGROUND: Patients with operated cleft lip and palate present with a problem of midface hypoplasia, and such patients have been traditionally treated with orthognathic surgery. Such a procedure has its own limitations of relapse and hence a newer modality of distraction osteogenesis with histiogenesis can be chosen to overcome such limitations for midfacial advancement. The purpose of this study is to evaluate an alternative technique and its postoperative stability in maxillary distraction osteogenesis in patients of cleft lip and cleft palate using a rigid external device (RED). METHOD: Nine patients with midface bone stock deficiency were selected for maxillary advancement. At the first surgery under general anesthesia, after Le Fort I osteotomy, RED system was used with the alternative technique. After distraction, evaluation was done for ease of the procedure, stability, and complications. Lateral cephalograms were evaluated at 3 stages: T1, pre-distraction; T2, post-distraction; and T3, 1 year post-distraction. RESULTS: A mean 13.4-mm midface advancement was shown with bone formation at the pterygomaxillary region without losing the vector and having a standby mode in case the wire broke during distraction The results were stable even at 1 year of follow-up. CONCLUSION: Maxillary position improved in relation to the cranial base. This study showed that the RED was versatile in midface advancement. PMID- 24777018 TI - Minor salivary gland neoplasms. AB - OBJECTIVE: This study aimed to investigate the clinical presentation, histopathologic and epidemiological aspects, as well as the treatment modalities and outcomes of patients with minor salivary gland tumors (MSGTs). SUBJECTS AND METHODS: A series of 23 patients with MSGTs were reviewed retrospectively. RESULTS: This study included 11 (48%) benign and 12 (52%) malignant tumors of minor salivary glands. Minor salivary gland tumors were more common in men (70%) than in women (30%). The mean age was 31.3 years for benign tumors and 46.3 years for malignant tumors. Pleomorphic adenoma was the most common benign tumor, followed by myoepithelioma. Mucoepidermoid carcinoma and adenoid cystic carcinoma were the most common malignant tumors. The most common symptom was a painless mass of the palate. Surgical treatment was performed in all patients. Adjuvant radiotherapy was used in 3 malignant tumors. Twenty-three patients were followed up for a median of 5 years. Two patients with malignant tumors underwent a second surgery for postoperative local recurrence. They were successfully treated with the second surgery. CONCLUSIONS: Minor salivary gland tumors are relatively uncommon neoplasms of the head and neck region. There is limited literature on MSGTs. This study provides a versatile approach for MSGTs from demographic data and clinical presentations to treatment modalities and treatment outcomes. PMID- 24777019 TI - Dynamic reconstruction of the philtrum using coronal muscle splitting technique in microform cleft lip. AB - PURPOSE: The philtral column and dimple are especially important in patients with cleft lip. Recently, we have found that, at maximal puckering, the appearance of the philtrum worsens although the philtral column is well formed at rest. In this study, we explore the effectiveness of the coronal muscle splitting technique in a microform cleft lip through comparative analysis of the postoperative results between the control group (patients without coronal muscle splitting) and the study group (patients with coronal muscle splitting). METHODS: Philtral reconstruction was performed in 24 patients with microform cleft lip between March 2006 and March 2010. The philtrum was reconstructed in 12 patients using the coronal muscle splitting technique and in the other 12 patients without this technique. The convexity of the philtral column and the dimpling of the philtrum were evaluated at rest and at maximal puckering through digital photographs and videos taken preoperatively and postoperatively. In addition, we compared the postoperative results between the 2 groups using the paired t-test. RESULTS: Postoperative evaluation was done at 6 to 48 months (mean, 25 mo). There was no statistically significant difference in the shape of the philtral column and the philtral dimple between the 2 groups preoperatively (P > 0.05). Reconstruction of the philtral column in the study group rendered better results than in the control group at both rest and maximal puckering (P < 0.001 and P < 0.001). Reconstruction of the philtral dimple in the study group rendered better results than in the control group at both rest and maximal puckering (P = 0.018 and 0.035). CONCLUSIONS: The coronal muscle splitting technique offers more esthetic and functional results in the formation of the philtral column and dimple both at rest and at maximal puckering than in the control group in cases of philtral reconstruction of the microform cleft lip. PMID- 24777020 TI - Mature form of ameloblastic fibrodentinoma: a case report. AB - Ameloblastic fibrodentinoma (AFD) is classified as a rarely seen benign mixed odontogenic tumor. Ameloblastic fibrodentinoma is common in children and young adults with painless swelling and mostly seen at the mandibular posterior region and usually associated with unerupted tooth. In this clinical report, an 11-year old-boy referred to Ankara University, Faculty of Dentistry, with the complaint of pain and swelling at the mandibular posterior region, diagnosed as AFD, is presented. Extraoral examination showed swelling at the affected side. In intraoral examination, a rough painful swelling was invincible with a delayed eruption of deciduous second molar tooth. Panoramic radiography revealed well defined radiolucency with large radiopacity above the crown of unerupted permanent second molar in the left mandible. The provisional diagnosis was complex odontoma. Biopsy resulted as AFD. The treatment achieved with total excision of the tumor and the second premolar tooth. Resorbable fixation plates were used for strengthening the excised region of the mandible. No recurrence or clinical complaints were noted during 1-year follow-up. PMID- 24777021 TI - New surgical technique and distraction osteogenesis for ankylosed dental movement. AB - Dental ankylosis often presents a significant vertical alveolar defect that is an esthetic problem for prosthetic rehabilitation. Moreover, surgical-orthodontic treatment by corticotomies and distraction devices provides special attention to avoid the loss of blood supply to the segment; furthermore, gingival recessions may appear because the gingival tissues cannot proliferate as fast as the immediate repositioning of the tooth. This case report presents a surgical technique for buccal, palatal, and vertical movements, and examines the effects of a tooth/arch-borne tooth distractor appliance, for the alignment of ankylosed teeth. The slow movements of tooth and bone block and fine cut simplifies orthodontic treatment in patients and makes it possible to achieve complex movements in a relatively short period. The reported dislocation procedure allows a use of buccal-lingual vertical osteotomy with horizontal osteotomy to correct tooth positions via bony block movement maintaining gingival tissues in position. The used sonic saw have proven to be a valuable alternative to manual or rotating tools, oscillating saws, or piezoelectric units because it is faster and easier for surgical approach. PMID- 24777022 TI - Cartilage-sparing techniques versus percutaneous adjustable closed otoplasty for prominent ear deformity. AB - OBJECTIVE: The goal of this study is to follow longitudinally the prominent ears treated by either cartilage-sparing techniques (CSTs) or percutaneous adjustable closed otoplasty (PACO) and compare them as to efficacy, reoccurrence, complications, and patient contentedness. METHODS: The CSTs were applied to the first group, that is, 17 patients (32 ears) with stiff auricular cartilage; whereas PACO was applied to the second group, 15 patients (28 ears) with soft auricular cartilage. Auriculocephalic distances were recorded at 4 levels preoperatively, at the completion of the surgery, and again postoperatively at the 1st, 3rd, 6th, and 12th months. Patients' satisfaction was assessed using different scales. RESULTS: Between the 2 groups, no significant difference was observed in age and satisfaction scales. Mean operating time using PACO was much shorter than using CST. Excluding hematoma, no statistically significant difference in complication rates was observed between the groups. Auriculocephalic distances in both groups were found to have increased comparably up to the 12th month. CONCLUSIONS: A comparison of CST and PACO showed that they have comparable rates of efficacy, outcome, reoccurrence, and patient contentedness. For prominent ear deformities with soft cartilage, PACO should be preferred because of its advantages of shorter time in surgery, lack of need for lengthy postoperative compressive bandage, comparable efficacy, and letting patients to look at the results right after the operation. PMID- 24777024 TI - Transition from hopeless dentition to full-arch fixed-implant-supported rehabilitation by a staged extraction approach: rationale and technique. AB - Transition from a hopeless dentition to a fixed-implant-supported full-arch reconstruction can be difficult for patients if wearing a transitional removable denture is involved. In addition, an increased risk for trauma to bone augmentation areas and to the implant-bone interface exists when using a removable transitional complete denture during the implant healing period; such risk can compromise implant success or increase crestal bone loss around implants before the final restoration. This article describes a treatment approach that allows replacement of the hopeless dentition with an osseointegrated fixed prosthesis, without rendering the patient totally edentulous before the delivery of the final implant-supported prosthesis. A staged approach using a few hopeless teeth to support a provisional fixed restoration during the healing process can help avoid discomfort and improve implants' outcome. A treatment plan for a maxillary arch reconstruction is used to illustrate the staged approach protocol. This protocol addresses patients' psychologic need to remain dentate during partial or full-mouth rehabilitation, while providing good esthetics and function during restoration of a dental arch. PMID- 24777023 TI - Latissimus dorsi-rib pedicle flap for mandibular reconstruction as a salvage procedure for failed free fibula flap. AB - BACKGROUND: Mandibular reconstruction is usually performed by using free vascular flaps. However, there are instances in which it must be carried out with pedicle flaps. Insofar, the main option recommended is the pectoralis major (PM) + rib pedicle flap. METHODS: A 45-year-old patient affected by a primitive mandibular tumor presented after an unsuccessful reconstruction with free fibula flaps. He refused a PM + rib pedicle reconstruction, while he accepted to undergo a latissimus dorsi (LD) + rib flap reconstruction. RESULTS: The postoperative course was uneventful. Also, the range of movements of the upper limb involved in the operation showed no significant changes after surgery. CONCLUSIONS: The LD + rib flap proved to be a useful alternative procedure for mandibular reconstruction after cancer ablation in patients who are not candidates for vascularized bone-containing free flaps and refuse the PM + rib flap reconstruction. PMID- 24777025 TI - What is the best strategy for Asians with involutional entropion? AB - BACKGROUND: Even though many different procedures have been proposed to involutional entropion, there is no established criterion standard in terms of the choice of the operative method. Considering the anatomical difference of the lower eyelid structure between Asians and whites, we evaluated the effectiveness of our surgical approach to involutional entropion exclusively for Japanese patients. METHODS: Twenty-one patients complained of discomfort around the eye, and they also suffered from foreign body sensation, ocular pain, epiphora, and photophobia. All the patients with the involutional entropion were surgically treated with combined procedures (the lower eyelid retractors advancement, the modified Hotz method, and the modified Wheeler method). RESULTS: Twenty-three lower eyelids of 21 patients with involutional entropion underwent surgery. There were 10 men and 11 women with a mean age of 78 years (range, 69-94 years). All patients we operated on were completely satisfied with any residual ocular symptoms. There was no case of recurrence following the primary procedure during 16 months of the mean follow-up period. CONCLUSION: Based on the anatomical difference in various ethnic groups, we propose the best strategy for Asian patients with the involutional entropion. PMID- 24777026 TI - Anterior Stafne bone defect mimicking an odontogenic cyst. PMID- 24777027 TI - Photoelastic stress analysis surrounding different implant designs under simulated static loading. AB - OBJECTIVE: The proposal of this study was to use a photoelasticity method to analyze the stress dissipation in the bone surrounding an implant under simulated loading. MATERIALS AND METHODS: Four implant systems with different internal connection designs were studied: conical connection (group 1), triangular connection (group 2), Morse taper (group 3), and internal hexagon (group 4). After the models' inclusion in a photoelastic resin, they were subjected to static loads of 100, 150, and 200 N. The lengths of fringes that were generated were measured at the bone crest parallel to the neck of the implant and along the implant body, as well as the dissipation of force across the entire area of extension. RESULTS: Lower stress was observed at the crestal bone in groups 1 and 3 with no significant increase (P < 0.05) in different levels of load, whereas the stress levels in groups 2 and 4 were observed to be higher with loads of all intensities with significant differences from the other groups (P < 0.05). CONCLUSIONS: The type of connection and the implant neck design influenced the dissipation of force. The conical-type connection exhibited better load dissipation in the neck area, regardless of the load applied on the implant. PMID- 24777028 TI - Cephalometric evaluation of ocular protrusion at stages of growth. AB - The sagittal relationships between the orbital globe and the ocular orbit have great importance in aesthetic and functional evaluations. These relationships are useful in diagnosis and treatment of some malformations in which the orbital volume is reduced such as craniostenosis. The aim of the present study was the cephalometric evaluation of the ocular protrusion at different growth stages. Ninety-two patients with negative history of craniosynostosis, severe myopia, and skeletal class I were selected for the present study. Lateral teleradiography x ray was performed for all the patients, and 5 groups were carried out based on the dentition phase. Cephalometric analyses were performed on the lateral teleradiography x-ray. Mean values of ocular protrusion (B-Or post) for females and males were found and digitized for the 5 groups tested. All other sagittal and vertical measurements were successfully computed by the trained operator. B Or post showed values between -14.93 mm and -16.90 mm among the groups. The cephalometric analysis proposed in the present study allowed to successfully evaluate sagittal and vertical relationship of the orbital globe and the orbital cavity in growing patients. Moreover, the B-Or post maintained its value during growth in the present study. PMID- 24777030 TI - The ligation of aspirin to cisplatin demonstrates significant synergistic effects on tumor cells. AB - Asplatin, a fusion of aspirin and cisplatin, exhibits significant cytotoxicity in tumor cells and almost fully overcomes the drug resistance of cisplatin resistant cells. Asplatin is highly accumulated in cancer cells and is activated upon the reduction by ascorbic acid. PMID- 24777029 TI - Pointing treatments are task relevant: a visuomotor priming study. AB - The present study focused on priming effects on pointing with everyday objects. In a set of four experiments, a visuomotor priming paradigm was used to investigate the nature of visuomotor processing (automatic versus task relevant). By manipulating congruency of orientation and location we found that location congruency facilitates the initiation time of pointing whereas orientation congruency does not. We provide evidence to show that motor planning is influenced by the goal of the action, and that how visual information is processed and held in memory depends on the task relevance. These data are consistent with the proposed interaction between visuomotor and higher processes during the planning and execution of actions such as pointing. PMID- 24777031 TI - The Maintenance Immunosuppression Scheme Influences Early C4d Urinary Excretion in Kidney Graft Recipients but Does Not Affect the Long-term Graft Survival. AB - C4d urinary excretion varies according to the risk of graft rejection or progression of chronic allograft nephropathy. The most common maintenance immunosuppression (IS) schemes include cyclosporine (CSA) or tacrolimus (TAC) with azathiopryne (AZA) or mycophenolate mophetil (MMF). The chosen IS may influence kidney transplant outcomes and possibly modify urinary C4d. The aim of the study was to determine whether early C4d urinary excretion varies in patients after kidney allograft transplantation (KTx) regarding administered IS and if these factors may help to predict long-term KTx outcomes. The study involved 185 patients who underwent KTx. The urinary specimens were assessed by enzyme-linked immunosorbent assay test for C4d excretion. To increase the objectivity, C4d excretion was divided by urinary creatinine excretion (ng/mgCr). The study population was grouped according to the IS scheme, that is, CSA + AZA, CSA + MMF, and TAC + MMF. At baseline, the greatest C4d urinary excretion was noticed in patients treated with CSA + AZA, 199.5 +/- 175.9 ng/mL (5.3 +/- 7.1 ng/mgCr) and the lowest in those in whom tacrolimus and mycophenolate mophetil was administered, 166.6 +/- 186.3 ng/mL (3.9 +/- 6.2 ng/mgCr). In the CSA + MMF group, C4d excretion was 195.6 +/- 200.3 ng/mL (5.0 +/- 6.6 ng/mgCr). Statistically significant differences were seen only between the CSA + AZA and TAC + MMF groups, analysis of variance P < 0.05 (P < 0.01 for C4d/urinary creatinine ratio). No statistically significant differences were found in graft survival rates between different immunosuppressive regimens. Although early C4d measurements vary in patients after kidney allograft transplantation regarding administered IS, this IS dependant variation does not seem to affect the long term graft survival. PMID- 24777032 TI - Wegener's granulomatosis with an atypical presentation as acute tonsillitis. AB - Wegener's granulomatosis (WG) is a rare necrotizing granulomatous vasculitis of unknown etiology commonly involving vessels, the upper and lower respiratory system and the kidneys. There are various symptoms and signs of WG due to a wide spectrum of involvement sites. The initial presentation of the disease as intraoral lesions is rare. In this paper, a case of WG that presented with a necrotic lesion confined to the right tonsil before other symptoms and signs occurred is described. The diagnosis was established based on the clinical presentation and the histopathological findings of the characteristic inflammatory pattern. PMID- 24777033 TI - Panayiotopoulos syndrome and symptomatic occipital lobe epilepsy of childhood: a clinical and EEG study. AB - AIM: Panayiotopoulos syndrome (PS) is an age-related seizure susceptibility syndrome that affects the central autonomic system. Although the majority of the few ictal recordings obtained so far suggest an occipital origin, semiological and interictal EEG data appear to favour more extensive involvement. In this study, the characteristics (including those based on semiology and EEG) of children with Panayiotopoulos syndrome (n=24) and those with lesion-related, symptomatic occipital lobe epilepsy (SOLE) (n=23) were compared. METHODS: Detailed semiological information and EEG parameters including the localisation, distribution, density (n/sec), reactivity, and morphological characteristics of spike-wave foci and their relationship with different states of vigilance were compared between the two groups. RESULTS: The age at seizure onset was significantly younger in patients with symptomatic occipital lobe epilepsy than in those with PS (mean age at onset: 3.4 versus 5.6 years, respectively; p=0.044). Autonomic seizures (p=0.001) and ictal syncope (p=0.055) were more frequent in PS than in symptomatic occipital lobe epilepsy (87.5% and 37.5% versus 43.5% and 13%, respectively). The interictal spike-wave activity increased significantly during non-rapid eye movement (non-REM) sleep in both groups. The spike waves in non-REM seen in PS tended to spread mainly to central and centro temporal regions. CONCLUSIONS: The results indicate that although common features do exist, Panayiotopoulos syndrome differs from symptomatic occipital lobe epilepsy and has a unique low epileptogenic threshold related to particular brain circuits. PMID- 24777034 TI - Evaluation of the broad-range PCR-electrospray ionization mass spectrometry (PCR/ESI-MS) system and virus microarrays for virus detection. AB - Advanced nucleic acid-based technologies are powerful research tools for novel virus discovery but need to be standardized for broader applications such as virus detection in biological products and clinical samples. We have used well characterized retrovirus stocks to evaluate the limit of detection (LOD) for broad-range PCR with electrospray ionization mass spectrometry (PCR/ESI-MS or PLEX-ID), RT-PCR assays, and virus microarrays. The results indicated that in the absence of background cellular nucleic acids, PLEX-ID and RT-PCR had a similar LOD for xenotropic murine retrovirus-related virus (XMRV; 3.12 particles per uL) whereas sensitivity of virus detection was 10-fold greater using virus microarrays. When virus was spiked into a background of cellular nucleic acids, the LOD using PLEX-ID remained the same, whereas virus detection by RT-PCR was 10 fold less sensitive, and no virus could be detected by microarrays. Expected endogenous retrovirus (ERV) sequences were detected in cell lines tested and known species-specific viral sequences were detected in bovine serum and porcine trypsin. A follow-up strategy was developed using PCR amplification, nucleotide sequencing, and bioinformatics to demonstrate that an RD114-like retrovirus sequence that was detected by PLEX-ID in canine cell lines (Madin-Darby canine kidney (MDCK) and Cf2Th canine thymus) was due to defective, endogenous gammaretrovirus-related sequences. PMID- 24777036 TI - Cobalt porphyrin electrode films for electrocatalytic water oxidation. AB - Catalysts play very important roles in artificial photosynthesis for solar energy conversion. In this present study, two water-insoluble cobalt porphyrin complexes, cobalt(II) meso-tetraphenylporphyrin (CoP-1) and cobalt(II) 5,10,15,20 tetrakis-(4-bromophenyl)porphyrin (CoP-2), were synthesized and coated as thin films on the FTO working electrode. The films showed good activities for electrocatalytic water oxidation in aqueous solutions at pH 9.2. The Faradaic efficiencies of both films approached to ~100%, measured using a fluorescence based oxygen sensor. The turnover frequencies were close to 0.50 s(-1) and 0.40 s(-1) for CoP-1 and CoP-2, respectively, under an applied anodic potential of 1.3 V (vs. Ag/AgCl) at pH 9.2. Importantly, no cobalt oxide particles were observed on the working electrode after catalysis. The stability of the catalyst films was further evaluated by UV-vis spectroscopy, inhibition measurements, mass spectrometry, scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). The pH dependence of water oxidation on CoP-1 and CoP-2 suggested a proton-coupled electron transfer (PCET) mechanism. The catalyst films could be recycled and showed almost unchanged catalytic activities when they were reused in new electrocatalytic studies of water oxidation. PMID- 24777037 TI - Effects of the volume of processed plasma on the outcome, arterial pressure and blood procalcitonin levels in patients with severe sepsis and septic shock treated with coupled plasma filtration and adsorption. AB - AIMS: To understand how coupled plasma filtration and adsorption (CPFA) could influence the time course of the advanced stages of sepsis, mean arterial pressure (MAP) and norepinephrine dosage. METHODS: Patients with severe sepsis and septic shock with >=2 organ failures not responding to volume resuscitation and vasopressor infusion were treated with CPFA within 8 h of admission to the intensive care unit. RESULTS: Thirty-nine patients were treated (median age: 63 years, median SAPS II score: 45) and 28 survived advanced sepsis. In the latter, the median MAP increased and the norepinephrine dosage decreased significantly after CPFA, whereas in the nonsurvivors these values did not change significantly. The volume of treated plasma was significantly higher in survivors than nonsurvivors. CONCLUSION: These results suggest a possible existence of a dose-response effect for CPFA. Future studies are therefore recommended to evaluate the efficacy of this treatment and to determine its best timing and intensity. PMID- 24777035 TI - Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden. AB - Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages. As well as detecting the known bladder cancer driver mutations, we report the identification of recurrent protein-inactivating mutations in CDKN1A and FAT1. The former are not mutually exclusive with TP53 mutations or MDM2 amplification, showing that CDKN1A dysfunction is not simply an alternative mechanism for p53 pathway inactivation. We find strong positive associations between higher tumour stage/grade and greater clonal diversity, the number of somatic mutations and the burden of copy number changes. In principle, the identification of sub-clones with greater diversity and/or mutation burden within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression. PMID- 24777038 TI - Continuous ECG monitoring for tracking down atrial fibrillation after stroke: Holter or automated analysis strategy? AB - BACKGROUND: Tracking down atrial fibrillation (AF) in the stroke unit is a relevant challenge for the prevention of recurrent AF-related stroke. The optimal terms of use of continuous ECG monitoring (CEM) are unknown. We compared 24-hour routine Holter ECG with two different CEM analysis strategies for AF detection. METHODS: We prospectively enrolled consecutive ischemic stroke patients. All AF naive patients received CEM during hospitalization. Two methods for reading CEM data were compared: manual analysis using the Holter function (hCEM) and semiautomated analysis using software (aCEM). The McNemar test was used to compare AF detection rates. RESULTS: Of the 362 patients included, 58 (16.0%) were non-AF-naive patients and 304 were AF-naive patients. AF-Naive patients underwent CEM with a median duration of 5.3 days (3.4-9.7). We detected 22 new AF cases (7.2%) with first-24-hour hCEM, 31 (10.2%) with aCEM, and 42 (13.8%) with hCEM. hCEM and aCEM both significantly increased the AF detection rate compared to first-24-hour hCEM. hCEM detected more new AF cases than aCEM (+3.6%, p = 0.003). CONCLUSIONS: In stroke patients, early and prolonged aCEM and hCEM both increase the AF detection rate compared to first-24-hour hCEM. hCEM gives the best AF detection rate. We suggest that in aCEM, detection based only on the ventricular rhythm analysis explains its lower specificity and sensitivity. PMID- 24777039 TI - A multicenter case-control study on screening of single nucleotide polymorphisms in estrogen-metabolizing enzymes and susceptibility to uterine leiomyoma in han chinese. AB - Uterine leiomyoma (UL) is an estrogen-responsive benign tumor in the female reproductive system and the main risk of hysterectomy for women. However, gene polymorphism of estrogen-metabolizing enzymes may lead to the different susceptibility to UL. We detected 10 single mucleotide polymorphisms in three key estrogen metabolite enzymes (COMT, CYP1A1, CYP1B1) in a Chinese Han population consisting of 800 patients and 800 healthy women from five different medical centers. The genetic polymorphism of rs3087869 (IVS1+2329C>T) (OR 3.200, 95% CI 1.614-6.345) and rs4680 (Val158Met) (OR 5.675, 95% CI 2.696-11.942) loci on COMT, rs1048943 (Ile462Val) (OR 4.629, 95% CI 2.216-9.672) and rs4646422 (Gly45Asp) (OR 3.240, 95% CI 1.624-6.461) loci on CYP1A1 and rs1065827 (Ala119Ser) (OR 5.635, 95% CI 2.990-10.619) locus on CYP1B1 were the risk factors to UL development and rs1056836 (Leu432Val) (OR 0.188, 95% CI 0.061-0.575) locus on CYB1B1 may be the protective factor to UL. The results provide a theoretical basis for genetic screening and early intervention to UL-susceptible populations. PMID- 24777040 TI - Surfactant-free synthesis of GeO(2) nanocrystals with controlled morphologies. AB - Germanium dioxide has many applications in the optoelectronics sector and is the subject of substantial research interest. In this contribution we report the preparation of germanium dioxide nanoparticles (NPs) of varied sizes and morphologies using a facile sol-gel methodology that requires no addition of templating agents (e.g., surfactants). Morphological control is achieved by tailoring the reaction mixture water/ethanol ratio, ammonium hydroxide concentration, time, and temperature. PMID- 24777041 TI - Double ABCX model of stress and adaptation in the context of families that care for children with a tracheostomy at home: application of a theory. AB - Theories provide a roadmap for scientific inquiry, help organize knowledge, and establish the foundation for knowledge development. The Double ABCX Model of Family Stress and Adaptation is a middle-range theory developed in social science and widely used by researchers of various disciplines. This model encompasses the major variables of interest in this study, including stress, coping, duration of tracheostomy, and quality-of-life, and forms an excellent framework for this specific research study. The purpose of this article was to discuss relationships between various individual and environmental factors that can impact health and well-being in families. In addition, this article illustrates how the application of the model helps nurses and healthcare providers understand the significance of the family context on positive well-being and promote optimal caring practices to achieve a balance in the midst of illness and suffering. PMID- 24777043 TI - Femtosecond laser-assisted keratopigmentation for the management of visual disabilities due to peripheral iridectomies. AB - PURPOSE: To report the technique and result of keratopigmentation using a femtosecond laser for the treatment of functional visual disabilities caused by peripheral iridectomies. DESIGN: Case report. METHODS: Two eyes of 2 patients underwent femtosecond laser-assisted keratopigmentation (FLAK) for moderate to severe visual dysfunction secondary to peripheral iridectomies. The main outcomes measures of the study were changes in visual-related symptoms, cosmesis, and intraoperative surgical complications. RESULTS: Following FLAK, the visual related symptoms (ghosting, glare, and monocular diplopia) improved in both cases with significant improvement to total elimination of symptoms. No patient lost any lines of visual acuity, and no significant complications were observed during the follow-up period. The cosmetic appearance was reported as very good. CONCLUSIONS: FLAK is minimally invasive and results in a significant decrease in the subjective glare and photophobia and even in resolution of monocular diplopia. The cosmetic outcome was also favorable. This technique allows surgeons to correct visual disabilities associated with iris defects with a high success rate while avoiding more aggressive intraocular surgery. PMID- 24777042 TI - Adenosine A(2A) receptor up-regulates retinal wave frequency via starburst amacrine cells in the developing rat retina. AB - BACKGROUND: Developing retinas display retinal waves, the patterned spontaneous activity essential for circuit refinement. During the first postnatal week in rodents, retinal waves are mediated by synaptic transmission between starburst amacrine cells (SACs) and retinal ganglion cells (RGCs). The neuromodulator adenosine is essential for the generation of retinal waves. However, the cellular basis underlying adenosine's regulation of retinal waves remains elusive. Here, we investigated whether and how the adenosine A(2A) receptor (A(2A)R) regulates retinal waves and whether A(2A)R regulation of retinal waves acts via presynaptic SACs. METHODOLOGY/PRINCIPAL FINDINGS: We showed that A(2A)R was expressed in the inner plexiform layer and ganglion cell layer of the developing rat retina. Knockdown of A(2A)R decreased the frequency of spontaneous Ca2+ transients, suggesting that endogenous A(2A)R may up-regulate wave frequency. To investigate whether A(2A)R acts via presynaptic SACs, we targeted gene expression to SACs by the metabotropic glutamate receptor type II promoter. Ca2+ transient frequency was increased by expressing wild-type A(2A)R (A2AR-WT) in SACs, suggesting that A(2A)R may up-regulate retinal waves via presynaptic SACs. Subsequent patch-clamp recordings on RGCs revealed that presynaptic A(2A)R-WT increased the frequency of wave-associated postsynaptic currents (PSCs) or depolarizations compared to the control, without changing the RGC's excitability, membrane potentials, or PSC charge. These findings suggest that presynaptic A(2A)R may not affect the membrane properties of postsynaptic RGCs. In contrast, by expressing the C terminal truncated A(2A)R mutant (A(2A)R-DeltaC) in SACs, the wave frequency was reduced compared to the A(2A)R-WT, but was similar to the control, suggesting that the full-length A(2A)R in SACs is required for A(2A)R up-regulation of retinal waves. CONCLUSIONS/SIGNIFICANCE: A(2A)R up-regulates the frequency of retinal waves via presynaptic SACs, requiring its full-length protein structure. Thus, by coupling with the downstream intracellular signaling, A(2A)R may have a great capacity to modulate patterned spontaneous activity during neural circuit refinement. PMID- 24777044 TI - Four Measures of Intraocular Pressure Fluctuation: Which Correlates Most Optimally With Actual Office-hour Readings? AB - PURPOSE: To compare the power of the 4 intraocular pressure (IOP) measures, that is, peak, mean, range, and SD, over a 24-hour period in predicting IOP variations in order to determine which measure of IOP fluctuation correlates best with actual office-hour readings in glaucoma patients and healthy subjects. METHODS: For this prospective study, 25 subjects with untreated primary open-angle glaucoma and 33 healthy individuals were hospitalized for 24 hours. Measurements of the subjects' IOP for both eyes were recorded with a Goldmann applanation tonometer every 3 hours in the sitting position during the daytime (9 AM to 9 PM) and with a TonoPen in both the sitting and supine positions for 24 hours. Only 1 eye was selected randomly per subject for the final analysis. The strength of association between the estimated values and the actual 24-hour IOP data in habitual body positions was analyzed using the coefficient of determination (R). The differences were calculated. The percentage of subjects with estimated IOP values falling within the cutoff values from the 24-hour data were assessed. RESULTS: The peak IOP was captured outside office hours in 57% of the young subjects, 75% in the elderly control group, and 52% of the glaucoma patients. The estimation of the strength of association for the mean IOP and peak IOP showed strong to moderate correlations (R range from 0.29 to 0.95) compared with the estimation of range and SD of IOP fluctuation, which demonstrated weak to moderate relationships (R range from 0.001 to 0.69). The percentage of significant cases mostly corresponded with the correlation. CONCLUSIONS: With the combination of sitting and supine position readings during office hours, the study provides promising results in estimating the mean and peak IOP in glaucoma patients and healthy subjects; however, it showed little advantage in range and SD of IOP fluctuation. PMID- 24777045 TI - Ahmed Glaucoma Valve Implantation for Uveitic Glaucoma Secondary to Behcet Disease. AB - PURPOSE: To evaluate outcomes of patients with uveitic glaucoma secondary to Behcet disease (BD) who underwent Ahmed glaucoma valve (AGV) implantation. PATIENTS AND METHODS: A retrospective chart review of 14 eyes of 10 patients with uveitic glaucoma associated with BD who underwent AGV implantation at a tertiary referral center. Treatment success was defined as intraocular pressure (IOP) between 6 and 21 mm Hg with or without antiglaucoma medication, without further additional glaucoma surgery or loss of light perception. The main outcome measures were IOP, best-corrected visual acuity measured with Snellen charts, and number of glaucoma medications. RESULTS: Mean duration of postoperative follow-up was 18.2+/-6.6 months (range, 6 to 31 mo). Of the 14 eyes, 10 (71.4%) were pseudophakic and 5 (35.7%) had primary AGV implantation without a history of previous glaucoma surgery. At the most recent follow-up visit, 13 of the 14 eyes had an IOP between 6 and 21 mm Hg. Mean IOP was significantly reduced during follow-up, as compared with preoperative values (P<=0.005). The cumulative probability of surgical success rate was 90.9% at 18 months based on Kaplan-Meier survival analysis. The mean number of antiglaucoma medications required to achieve the desired IOP decreased from 3.4+/-0.5 preoperatively to 1.0+/-1.1 postoperatively (P<=0.05). Visual acuity loss of >2 lines occurred in 4 eyes (28.5%) due to optic atrophy associated with retinal vasculitis. Temporary hypotony developed during follow-up in 4 eyes (28.5%) at first postoperative week. CONCLUSIONS: For the management of uveitic glaucoma associated with BD, AGV implantation is a successful method for glaucoma control but requires additional surgical interventions for high early hypotony rates. PMID- 24777046 TI - Combining Frequency Doubling Technology Perimetry and Scanning Laser Polarimetry for Glaucoma Detection. AB - PURPOSE: To determine the ability of frequency doubling technology (FDT) and scanning laser polarimetry with variable corneal compensation (GDx-VCC) to detect glaucoma when used individually and in combination. METHODS: One hundred ten normal and 114 glaucomatous subjects were tested with FDT C-20-5 screening protocol and the GDx-VCC. The discriminating ability was tested for each device individually and for both devices combined using GDx-NFI, GDx-TSNIT, number of missed points of FDT, and normal or abnormal FDT. Measures of discrimination included sensitivity, specificity, area under the curve (AUC), Akaike's information criterion (AIC), and prediction confidence interval lengths. RESULTS: For detecting glaucoma regardless of severity, the multivariable model resulting from the combination of GDx-TSNIT, number of abnormal points on FDT (NAP-FDT), and the interaction GDx-TSNIT*NAP-FDT (AIC: 88.28, AUC: 0.959, sensitivity: 94.6%, specificity: 89.5%) outperformed the best single-variable model provided by GDx-NFI (AIC: 120.88, AUC: 0.914, sensitivity: 87.8%, specificity: 84.2%). The multivariable model combining GDx-TSNIT, NAP-FDT, and interaction GDx-TSNIT*NAP FDT consistently provided better discriminating abilities for detecting early, moderate, and severe glaucoma than the best single-variable models. CONCLUSIONS: The multivariable model including GDx-TSNIT, NAP-FDT, and the interaction GDx TSNIT*NAP-FDT provides the best glaucoma prediction compared with all other multivariable and univariable models. Combining the FDT C-20-5 screening protocol and GDx-VCC improves glaucoma detection compared with using GDx or FDT alone. PMID- 24777047 TI - Does the ISNT Rule Apply to the Retinal Nerve Fiber Layer? AB - PURPOSE: To determine whether the ISNT rule (Inferior>Superior>Nasal>Temporal) or the "IST" rule (Inferior>Superior>Temporal) can be applied to the peripapillary retinal nerve fiber layer (RNFL) thickness as measured using Heidelberg Retinal Tomography (HRT) and Optical Coherence Tomography (OCT). MATERIALS AND METHODS: This was a cross-sectional study of 189 normal and 42 glaucomatous eyes. RNFL thicknesses measured in different quadrants using HRT and OCT were compared to determine the percentage of eyes obeying the ISNT and IST rule. RESULTS: The HRT measured mean RNFL thickness in normal eyes showed that 25.9% obeyed the ISNT rule and 70.4% conformed to the "IST" rule. The "IST" rule was able to identify normal eyes better (P=0.040), but had a poor sensitivity (45%) and specificity (70%) to diagnose glaucoma. The OCT-measured average RNFL thickness showed that 47.1% of normal eyes obeyed the ISNT rule and 58.7% conformed to the "IST" rule. Exclusion of the nasal sector also increased the number of glaucomatous eyes conforming to the IST rule (31% obeyed the ISNT rule and 50% obeyed the IST rule). Sensitivities and specificities of the ISNT and the IST rules for OCT quantified RNFL ranged from 42% to 77%. CONCLUSIONS: A larger number of normal eyes obeyed the IST rule compared with the ISNT rule for the RNFL thickness measured by HRT and OCT. Exclusion of the nasal sector from the analysis (IST rule) marginally improved the specificity in diagnosing glaucoma at the cost of the sensitivity, making neither of these parameters (ISNT and IST) likely to be useful clinically. PMID- 24777048 TI - Is Episcleritis Associated to Glaucoma? AB - OBJECTIVE: The aim of this study was to show possible connection between episcleritis and open-angle glaucoma. DESIGN: This was a retrospective study. MATERIALS AND METHODS: Data on 21 patients who suffered from episcleritis and had no previous attack of episcleritis or glaucoma were collected for a period of 8 years (from 2004 to 2011). RESULTS: Six of the 21 patients of the study group (28.6%) were diagnosed as suffering from glaucoma. Four patients had a diffuse conjunctival congestion, 1 had sectoral congestion, and for 1 patient there was no record of conjunctival congestion. Two of the 6 patients with episcleritis and glaucoma experienced recurrent episcleritis events during the follow-up period. CONCLUSIONS: This study suggests an association between episcleritis and open angle glaucoma. PMID- 24777049 TI - Tuning of gate adsorption: modification of a flexible metal-organic framework by secondary organic ligands. AB - For realizing selective adsorption of targeted molecules, a flexible metal organic framework (MOF) was modified with monodentate secondary ligands. Although the modified MOF retains CO2 adsorptivities with a vertical adsorption uptake, the material also shows gate adsorptivities of a specific gas molecule that the pristine MOF does not adsorb. PMID- 24777051 TI - Cooperative ion-exchange and self-redox process to load catalytic metal nanoparticles into a MOF with Johnson-type cages. AB - Through a cooperative ion-exchange and self-redox process, a new MOF material with nanosized Johnson-type cages has successfully produced Pd- or Ag-NPs in its pores without any external reducing agents, leading to the formation of M-NP embedded catalysts for the hydrogenation of styrene. PMID- 24777050 TI - Secretoglobin 1A1 and 1A1A differentially regulate neutrophil reactive oxygen species production, phagocytosis and extracellular trap formation. AB - Secretoglobin family 1A member 1 (SCGB 1A1) is a small protein mainly secreted by mucosal epithelial cells of the lungs and uterus. SCGB 1A1, also known as club (Clara) cell secretory protein, represents a major constituent of airway surface fluid. The protein has anti-inflammatory properties, and its concentration is reduced in equine recurrent airway obstruction (RAO) and human asthma. RAO is characterized by reversible airway obstruction, bronchoconstriction and neutrophilic inflammation. Direct effects of SCGB 1A1 on neutrophil functions are unknown. We have recently identified that the SCGB1A1 gene is triplicated in equids and gives rise to two distinct proteins. In this study we produced the endogenously expressed forms of SCGBs (SCGB 1A1 and 1A1A) as recombinant proteins, and analyzed their effects on reactive oxygen species production, phagocytosis, chemotaxis and neutrophil extracellular trap (NET) formation ex vivo. We further evaluated whether NETs are present in vivo in control and inflamed lungs. Our data show that SCGB 1A1A but not SCGB 1A1 increase neutrophil oxidative burst and phagocytosis; and that both proteins markedly reduce neutrophil chemotaxis. SCGB 1A1A reduced chemotaxis significantly more than SCGB 1A1. NET formation was significantly reduced in a time- and concentration dependent manner by SCGB 1A1 and 1A1A. SCGB mRNA in bronchial biopsies, and protein concentration in bronchoalveolar lavage fluid, was lower in horses with RAO. NETs were present in bronchoalveolar lavage fluid from horses with exacerbated RAO, but not in fluid from horses with RAO in remission or in challenged healthy horses. These findings indicate that SCGB 1A1 and 1A1A have overlapping and diverging functions. Considering disparities in the relative abundance of SCGB 1A1 and 1A1A in airway secretions of animals with RAO suggests that these functional differences may contribute to the pathogenesis of RAO and other neutrophilic inflammatory lung diseases. PMID- 24777052 TI - Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis. AB - BACKGROUND: Aberrations in the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/AKT pathway are common in solid tumors. Numerous drugs have been developed to target different components of this pathway. However the prognostic value of these aberrations is unclear. METHODS: PubMed was searched for studies evaluating the association between activation of the PI3K/mTOR/AKT pathway (defined as PI3K mutation [PIK3CA], lack of phosphatase and tensin homolog [PTEN] expression by immunohistochemistry or western-blot or increased expression/activation of downstream components of the pathway by immunohistochemistry) with overall survival (OS) in solid tumors. Published data were extracted and computed into odds ratios (OR) for death at 5 years. Data were pooled using the Mantel-Haenszel random-effect model. RESULTS: Analysis included 17 studies. Activation of the PI3K/mTOR/AKT pathway was associated with significantly worse 5-year survival (OR:2.12, 95% confidence intervals 1.42-3.16, p<0.001). Loss of PTEN expression and increased expression/activation of downstream components were associated with worse survival. No association between PIK3CA mutations and survival was observed. Differences between methods for assessing activation of the PI3K/mTOR/AKT pathway were statistically significant (p = 0.04). There was no difference in the effect of up-regulation of the pathway on survival between different cancer sites (p = 0.13). CONCLUSION: Activation of the PI3K/AKT/mTOR pathway, especially if measured by loss of PTEN expression or increased expression/activation of downstream components is associated with poor survival. PIK3CA mutational status is not associated with adverse outcome, challenging its value as a biomarker of patient outcome or as a stratification factor for patients treated with agents acting on the PI3K/AKT/mTOR pathway. PMID- 24777053 TI - Clinical outcomes and complications associated with TORS for OSAHS: a benchmark for evaluating an emerging surgical technology in a targeted application for benign disease. AB - BACKGROUND: The aim of this study was to create benchmarks for evaluating clinical outcomes and complications of transoral robotic surgeries (TORS) in a multicenter setting. METHODS: 243 TORS for obstructive sleep apnea/hypopnea syndrome (OSAHS) operations, carried out between 2008 and 2012, were analyzed at 7 different centers. The average hospitalization was 3.5 days. The mean patient age was 50 +/- 12 years, the average BMI at the time of the procedure was 28.53 +/- 3.87 and the majority of the patients were men (81%). RESULTS: The mean preoperative and postoperative apnea/hypopnea index was 43.0 +/- 22.6 and 17.9 +/ 18.4, respectively (p < 0.001). The mean preoperative and postoperative Epworth Sleepiness Scale score was 12.34 +/- 5.19 and 5.7 +/- 3.49, respectively (p < 0.001). The mean pre- and postoperative lowest O2 saturation was 79.5 +/- 8.77 and 83.9 +/- 6.38%, respectively (p < 0.001). CONCLUSIONS: Patients undergoing TORS as part of a multilevel approach for the treatment of OSAHS have a reasonable expectation of success with minimal long-term morbidity. PMID- 24777054 TI - Sensitivity and specificity of the World Health Organization dengue classification schemes for severe dengue assessment in children in Rio de Janeiro. AB - BACKGROUND: The clinical definition of severe dengue fever remains a challenge for researchers in hyperendemic areas like Brazil. The ability of the traditional (1997) as well as the revised (2009) World Health Organization (WHO) dengue case classification schemes to detect severe dengue cases was evaluated in 267 children admitted to hospital with laboratory-confirmed dengue. PRINCIPAL FINDINGS: Using the traditional scheme, 28.5% of patients could not be assigned to any category, while the revised scheme categorized all patients. Intensive therapeutic interventions were used as the reference standard to evaluate the ability of both the traditional and revised schemes to detect severe dengue cases. Analyses of the classified cases (n = 183) demonstrated that the revised scheme had better sensitivity (86.8%, P<0.001), while the traditional scheme had better specificity (93.4%, P<0.001) for the detection of severe forms of dengue. CONCLUSIONS/SIGNIFICANCE: This improved sensitivity of the revised scheme allows for better case capture and increased ICU admission, which may aid pediatricians in avoiding deaths due to severe dengue among children, but, in turn, it may also result in the misclassification of the patients' condition as severe, reflected in the observed lower positive predictive value (61.6%, P<0.001) when compared with the traditional scheme (82.6%, P<0.001). The inclusion of unusual dengue manifestations in the revised scheme has not shifted the emphasis from the most important aspects of dengue disease and the major factors contributing to fatality in this study: shock with consequent organ dysfunction. PMID- 24777055 TI - Controlling the crystalline three-dimensional order in bulk materials by single wall carbon nanotubes. AB - The construction of ordered single-wall carbon nanotube soft-materials at the nanoscale is currently an important challenge in science. Here we use single-wall carbon nanotubes as a tool to gain control over the crystalline ordering of three dimensional bulk materials composed of suitably functionalized molecular building blocks. We prepare p-type nanofibres from tripeptide and pentapeptide-containing small molecules, which are covalently connected to both carboxylic and electron donating 9,10-di(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene termini. Adding small amounts of single-wall carbon nanotubes to the so-prepared p-nanofibres together with the externally controlled self assembly by charge screening by means of Ca(2+) results in new and stable single-wall carbon nanotube-based supramolecular gels featuring remarkably long-range internal order. PMID- 24777057 TI - Assessment of fluid and nutritional status using multifrequency bioelectrical impedance analysis in peritoneal dialysis patients. AB - BACKGROUND/AIMS: The purpose of this study was to evaluate the clinical usefulness and relevance of bioelectrical impedance analysis (BIA) for assessing the fluid and nutritional status in peritoneal dialysis (PD) patients. METHODS: Statistical analyses between various measures of fluid and nutritional status were performed in 106 cases of 64 patients. RESULTS: Extracellular fluid/total body water (ECF/TBW) was correlated with systolic blood pressure, extremity edema, and antihypertensive medications (p = 0.042, p < 0.001, and p = 0.029, respectively). Body cell mass (BCM)/height(2) was correlated with SGA rating and PCR (p < 0.001 and p = 0.002, respectively). ECF/TBW and BCM/height(2) significantly predicted extremity edema (p < 0.001) and SGA rating (p = 0.001), respectively. ROC analysis yielded an ECF/TBW cut-off of 0.36 and a BCM/height(2) cut-off of 11.23. When the BCM/height(2) cut-off of 11.23 was applied to subclinical patients (SGA score >=6), a significant difference in SGA rating was detected in subgroups (p = 0.010). CONCLUSION: BIA yields useful and relevant information about hydration and nutritional status in PD patients. PMID- 24777056 TI - Pathophysiological decrease in the regional cerebral blood flow in Hashimoto's encephalopathy: a multiple-case SPECT study. AB - BACKGROUND: The aim of this study was to evaluate the changes in regional cerebral blood flow (rCBF) in multiple cases of Hashimoto's encephalopathy (HE). METHODS: Seven untreated patients with HE and 10 age-matched healthy controls underwent brain single photon emission computed tomography (SPECT) with N isopropyl-p-[(123)I]iodoamphetamine. All patients had anti-NH2-terminal of alpha enolase autoantibodies (Abs), which served as a useful diagnostic marker for HE, in addition to anti-thyroid Abs in their sera and responded to corticosteroid therapy. The obtained SPECT images were compared between the patients and the controls using 3D-SSP analysis. RESULTS: The rCBF of all patients with HE was significantly decreased in the bilateral anterior cingulate areas and left prefrontal cortex compared with the controls (p < 0.05). Focusing on the HE patients with acute neuropsychiatric symptoms (n = 5) such as consciousness disturbance and/or psychosis, the decreased rCBF in these areas was more significant, and the rCBF in the right frontal cortex was also decreased. CONCLUSION: Statistical analysis of these multiple-case SPECT images revealed the regions of decreased CBF associated with clinical symptoms, especially acute neuropsychiatric symptoms, in HE patients. This study shed light on the pathophysiological decrease in rCBF observed in HE. PMID- 24777058 TI - Completeness of reporting of race and ethnicity data in the nationally notifiable diseases surveillance system, United States, 2006-2010. AB - CONTEXT: During 1994-1997, approximately 70% and 60% of the cases of conditions reported to the National Notifiable Diseases Surveillance System included persons of known race and ethnicity, respectively. A major goal of the Healthy People 2020 initiative is to eliminate health disparities. OBJECTIVE: To describe trends in the completeness of race and ethnicity in case reports of the National Notifiable Diseases Surveillance System during 2006-2010. METHODS: The National Notifiable Diseases Surveillance System is a public health surveillance system that aggregates case reports of infectious diseases and conditions that are designated nationally notifiable and are collected by US states and territories. The Centers for Disease Control and Prevention (Atlanta, Georgia) maintains this surveillance system in collaboration with the Council of State and Territorial Epidemiologists. We used Cochran-Armitage Trend Test (SAS, version 9.2) to test the hypothesis that the percentage of case reports with the completeness of race and ethnicity data increased or decreased linearly during 2006-2010. MAIN OUTCOME MEASURE: Completeness of race and ethnicity variables. RESULTS: The 32 conditions reviewed included 1 030 804 case records. Seventy percent of records included a known value for race, and 49% of records included ethnicity during 2006-2010. During 2006-2010, race was known in 70% or more of records in 24 of 32 conditions and in 23 of 51 jurisdictions. During 2006-2010, the systemwide reporting of race remained at the same level of completeness (70%) but the reporting of ethnicity increased slightly from 48% in 2006 to 53% in 2010. In comparison with race, the proportions of records coded to ethnicity were less among all conditions. CONCLUSIONS: Significant change has occurred in the completeness of reporting of ethnicity but not race during 2006-2010. However, the reporting of ethnicity still lags substantially behind the reporting of race. Jurisdictions that identify conditions with lower rates of completeness of race and ethnicity can assess the net benefits of efforts to improve the completeness of race and ethnicity data. PMID- 24777059 TI - How T cells taste gluten in celiac disease. PMID- 24777060 TI - T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. AB - Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95% of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-alpha2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity. PMID- 24777061 TI - Role of polymerase beta in complementing aprataxin deficiency during abasic-site base excision repair. AB - DNA polymerase beta (pol beta) lyase removal of 5'-deoxyribose phosphate (5'-dRP) from base excision repair (BER) intermediates is critical in mammalian BER involving the abasic site. We found that pol beta also removes 5'-adenylated dRP from BER intermediates after abortive ligation. The crystal structure of a human pol beta-DNA complex showed the 5'-AMP-dRP group positioned in the lyase active site. Pol beta expression rescued methyl methanesulfonate sensitivity in aprataxin (hnt3)- and FEN1 (rad27)-deficient yeast. PMID- 24777062 TI - Off-loading of cyclic hydrostatic pressure promotes production of extracellular matrix by chondrocytes. AB - The addition of cyclic hydrostatic pressure (cHP) to cell culture medium has been used to promote extracellular matrix (ECM) production by articular chondrocytes. Though a combination of cHP followed by atmospheric pressure (AP) has been examined previously, the rationale of such a combination was unclear. We compared the effects of loading once versus twice (combinations of cHP followed by AP) regarding both gene expression and biochemical and histological phenotypes of chondrocytes. Isolated bovine articular chondrocytes were embedded in a collagen gel and incubated for 14 days under conditions combining cHP and AP. The gene expression of aggrecan core protein and collagen type II were upregulated in response to cHP, and those levels were maintained for at least 4 days after cHP treatment. Accumulation of cartilage-specific sulfated glycosaminoglycans following cHP for 7 days and subsequent AP for 7 days was significantly greater than that of the AP control (p < 0.05). Therefore, incubation at AP after loading with cHP was found to beneficially affect ECM accumulation. Manipulating algorithms of cHP combined with AP will be useful in producing autologous chondrocyte-based cell constructs for implantation. PMID- 24777063 TI - Peri-ictal headache due to epileptiform activity in a disconnected hemisphere. AB - A 4-year-old girl with intractable epilepsy due to left-side hemispheric cortical dysplasia underwent a hemispherotomy. She was seizure-free after the surgery. EEG showed persistent abundant epileptiform activity over the left (disconnected) hemisphere, including ictal patterns that neither generalised nor had clinical correlates. Antiepileptic medication was completely withdrawn four years following the surgery. One week after the withdrawal, she developed episodes of intense left-sided hemicranias (ipsilateral to the surgery) with vomiting and photophobia that did not resemble her habitual seizures and were unresponsive to non-steroidal anti-inflammatory drugs. Video-EEG showed association of the headache attacks with ictal patterns over the disconnected hemisphere. Brain MRI revealed increased signal changes in the left hemisphere. Attacks responded promptly to i.v. midazolam and carbamazepine at a low dose. Mechanisms underlying peri-ictal headache originating in the disconnected hemisphere are discussed. [Published with video sequences]. PMID- 24777064 TI - Effect of ordering of PtCu3 nanoparticle structure on the activity and stability for the oxygen reduction reaction. AB - In this study the performance enhancement effect of structural ordering for the oxygen reduction reaction (ORR) is systematically studied. Two samples of PtCu3 nanoparticles embedded on a graphitic carbon support are carefully prepared with identical initial composition, particle dispersion and size distribution, yet with different degrees of structural ordering. Thus we can eliminate all coinciding effects and unambiguously relate the improved activity of the ORR and more importantly the enhanced stability to the ordered nanostructure. Interestingly, the electrochemically induced morphological changes are common to both ordered and disordered samples. The observed effect could have a groundbreaking impact on the future directions in the rational design of active and stable platinum alloyed ORR catalysts. PMID- 24777065 TI - Simultaneous encapsulation of an infinite T4(0)A(0)6(0) water tape and discrete water hexamers in a hydrogen-bonded Ag(I) supramolecular framework. AB - Self-assembly of Ag2O, 1,4-bis(pyrid-4-yl)benzene (dpb) and 1,3 benzenedicarboxylic acid (H2bdc) resulted in a one-dimensional mixed-ligand Ag(I) coordination polymer [Ag2(dpb)2(bdc).9H2O]n (1), in which infinite 1D T4(0)A(0)6(0) water tapes and discrete water hexamers were simultaneously encapsulated. Chair-like water hexamers and D2h water tetramers with two dangling water molecules were alternately hydrogen-bonded into the unprecedented 1D T4(0)A(0)6(0) water tape. Additionally, results on the thermal stability, UV-Vis absorption and photoluminescence spectra of 1 were discussed. PMID- 24777066 TI - Ordered alignment of a one-dimensional pi-conjugated nickel bis(dithiolene) complex polymer produced via interfacial reactions. AB - A liquid-liquid interfacial synthesis using 1,2,4,5-benzenetetrathiol and nickel(II) ions produced a thin black film of a pi-conjugated polymer featuring the nickel bis(dithiolene) motif. Its ordered structure was not originally identified due to its amorphicity; however, it was observed to align regularly on a highly oriented pyrolytic graphite substrate using scanning tunnelling microscopy. PMID- 24777067 TI - Stereopsidales--a new order of mushroom-forming fungi. AB - One new order, one new family, and one new combination are presented, as the result of molecular phylogenetic analyses. The new order Stereopsidales and the new family Stereopsidaceae are described incorporating Stereopsis radicans and S. globosa, formerly Clavulicium globosum. We show that not only do these species represent an old overlooked lineage, but both species harbor cryptic diversity. In addition, a third species, C. macounii, appears as a plausible sister to the new lineage, but there is conflict in the data. All specimens of S. radicans and S. globosa analysed here are from the South and Central Americas; several records of S. radicans have been made also from tropical Asia. We expect the true diversity in this group to be a lot higher than presented in this paper. Stereopsis radicans was formerly included in Polyporales, but a placement within that order is rejected by our data through SH tests. The dataset consisted of four nuclear markers: rpb2, tef1, LSU and SSU, each of which was analysed separately using maximum likelihood and Bayesian inference. Recombination detection tests indicate no plausible recombinations. The potential of S. radicans, S. globosa and C. macounii being amphitallic is briefly discussed. PMID- 24777068 TI - Analogues of etomidate: modifications around etomidate's chiral carbon and the impact on in vitro and in vivo pharmacology. AB - BACKGROUND: R-etomidate possesses unique desirable properties but potently suppresses adrenocortical function. Consequently, efforts are being made to define structure-activity relationships with the goal of designing analogues with reduced adrenocortical toxicity. The authors explored the pharmacological impact of modifying etomidate's chiral center using R-etomidate, S-etomidate, and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). METHODS: The gamma-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed alpha1(L264T)beta3gamma2L and alpha1(L264T)beta1gamma2L gamma-aminobutyric acid type A receptors (for each drug, n = 6 oocytes per subtype). In rats, hypnotic potencies and durations of action were measured using a righting reflex assay (n = 26 to 30 doses per drug), and adrenocortical potencies were quantified by using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). RESULTS: All four drugs activated both gamma-aminobutyric acid type A receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1 to 2 orders of magnitude. R-etomidate had the highest gamma-aminobutyric acid type A receptor modulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate, and cyclopropyl etomidate were 27.4-, 18.9-, and 23.5-fold more potent activators of receptors containing beta3 subunits than beta1 subunits; however, dihydrogen etomidate's subunit selectivity was only 2.48-fold and similar to that of propofol (2.08-fold). S-etomidate was 1/23rd as potent an adrenocortical inhibitor as R-etomidate. CONCLUSION: The linkage between the structure of etomidate's chiral center and its pharmacology suggests that altering etomidate's chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities. PMID- 24777069 TI - Family Caregiver Role and Burden Related to Gender and Family Relationships. AB - This study described and contrasted family caregivers and explored the effect of gender and family relationship on the caregiver's role perception, workload, burden, and family help. Home care agencies and community organizations assisted with the recruitment of 533 multicultural, predominantly Latino caregivers who were interviewed at home. The Caregiver Identity Theory guided the study. Survey instruments were standardized tools or were constructed and pretested for this study. Descriptive statistics and t-test analyses assisted in describing the sample, and multivariate analyses were used to contrast the caregiver groups. Findings suggested a gendered approach to self-appraisal and coping. Men in this predominantly Latino and Caribbean sample felt less burden and depression than women who believed caregiving is a female duty. Family nurses should pay attention to the most vulnerable groups-older spouses resistant to using family and community resources and hard-working female adult children-and assess each family situation individually. PMID- 24777070 TI - Understanding Parental Experiences Through Their Narratives of Restitution, Chaos, and Quest: Improving Care for Families Experiencing Childhood Cancer. AB - The purpose of this secondary analysis was to develop an enhanced understanding of the experiences of parents who have children in treatment for cancer. Data collected from 16 parents (12 mothers and 4 fathers) were analyzed using Frank's dialogical narrative analysis. Findings demonstrated that parents' experiences were represented in chaos, restitution, and quest narratives. Each of these narratives was only one instance of a very complex and changing parental experience that cannot be understood in isolation from the others. The holistic understanding provided by these findings contributes to a more comprehensive understanding of parental experiences of their child's illness and highlights the need for health professionals to invite conversations about parents' illness experience and attend to the specific narrative type parents are presenting to support them adequately. Additional research is required to develop supportive approaches for each narrative which takes into account the complexities of parents' experiences. PMID- 24777071 TI - Proteomic analysis of putative heme-binding proteins in Streptococcus pyogenes. AB - Streptococcus pyogenes is an important human bacterium with high pathogenicity. Heme is a major source of iron that plays a critical role in bacterial survival and virulence. In this study, heme-affinity chromatography, two-dimensional electrophoresis and mass spectrometry were combined to identify putative heme binding proteins and heme-regulatory proteins. In total, 68 heme-regulatory proteins and 284 putative heme-binding proteins were identified, among which 37 proteins showed expression alterations in response to heme deficiency. Bioinformatics analysis revealed that several key metabolic pathways had changed in the absence of heme, among which glycolysis was a major pathway impaired under heme-deficient conditions. New potential heme-binding proteins were successfully identified in this study providing novel clues for the study of the heme transport mechanism. Heme-binding proteins may play fundamental roles in many important biological pathways and thus contribute to bacterial pathogenicity. PMID- 24777072 TI - Effect of KTP laser cochleostomy on morphology in the guinea pig inner ear. AB - BACKGROUND: The main advantage of using the KTP (potassium-titanyl-phosphate) laser for stapedotomy instead of the conventional micropick instrument is the smaller risk for mechanical damage. However, the KTP laser could theoretically inflict damage to inner ear structures. We hypothesize that KTP laser light [wavelength (lambda) = 532 nm] is hardly absorbed in perilymph but well absorbed in solid structures. The aim of this pilot study was to assess if damage occurred after KTP laser cochleostomy in an animal model and, if so, to what extent and at which settings. MATERIALS AND METHODS: In six guinea pigs, a KTP laser cochleostomy at the basal turn was created. Laser settings of 1, 3 and 5 W and 100 ms pulse time (n = 2 each) were used. Histological preparations were studied for damage to neuroendothelial cells and intrascalar blood. RESULTS: No damage to inner ear neuroendothelial cells was observed, even at the highest power. Blood clots in the scala tympani from vessels in the cochlear wall were seen. The effects were minimal in the lowest, currently clinically used settings. CONCLUSION: KTP laser cochleostomy gives no damage to inner ear neuroendothelial cells but may cause intrascalar hemorrhages. PMID- 24777073 TI - Rh(III)-catalyzed synthesis of 1-aminoindole derivatives from 2-acetyl-1 arylhydrazines and diazo compounds in water. AB - A novel and direct approach to synthesize 1-aminoindole derivatives by Rh(iii) catalyzed cyclization of 2-acetyl-1-arylhydrazines with diazo compounds via aryl C-H activation has been developed. This intermolecular annulation involving tandem C-H activation, cyclization and condensation steps proceeds efficiently in water, obviates the need of external oxidants, and displays a broad substituent scope. PMID- 24777074 TI - Clinical outcomes after arteriovenous fistula creation in chronic kidney disease. AB - BACKGROUND: Optimal timing of arteriovenous fistula (AVF) surgery in chronic kidney disease (CKD) is uncertain. METHODS: A single-centre retrospective study of pre-dialysis CKD patients having first AVF surgery. RESULTS: The median estimated glomerular filtration rate (eGFR) at the time of AVF surgery in 100 patients was 15 ml/min/1.73 m(2), with patients classified as having an early AVF if eGFR was >15 ml/min/1.73 m(2) (n = 46) or a late AVF if eGFR was <=15 ml/min/1.73 m(2) (n = 54). In the eGFR <=15 group, 81% of patients started haemodialysis (HD), compared with 63% of the eGFR >15 patients (p = 0.04). The median time to starting HD was 30.3 months in the eGFR >15 group compared to 10.7 months for the eGFR <=15 group (log rank p = 0.018). There were no differences in the requirements for a dialysis catheter (eGFR >15 24% vs. eGFR <=15 11%, p = 0.20) or additional access procedures between the two groups. CONCLUSIONS: AVF surgery with an eGFR >15 ml/min/1.73 m(2) was associated with a higher risk of AVF non-use and a more prolonged time to the need for HD. PMID- 24777075 TI - Acute compressive myelopathy due to vertebral haemangioma. AB - A 47-year-old woman with a history of anaemia presented to the emergency room with an acute onset of leg weakness. Physical examination of the bilateral lower extremities was significant for 0/5 muscle strength in all muscle groups with decreased pinprick and temperature sensation. A sensory level at the umbilicus was appreciated. Fine touch and proprioception were preserved. Bowel and bladder function were intact. CT revealed several thoracic, vertebral haemangiomatas. An MRI was suggestive of an epidural clot at the T8-T10-weighted posterior epidural space. At the level of the lesion, the cerebrospinal fluid space was completely effaced, and the flattened spinal cord exhibited signs of oedema and compressive myelopathy. The patient immediately underwent surgical decompression of the spinal cord. An epidural clot and vessel conglomeration were identified. A postoperative spinal angiogram confirmed the diagnosis of vertebral haemangioma. At 1-month follow-up, the patient regained strength and sensation. PMID- 24777076 TI - A curious case of spontaneous duodenal haematoma presenting a diagnostic challenge. AB - Duodenal haematomas are uncommon. They are usually diagnosed on CT of the abdomen. The established treatment strategies are conservative management, surgical evacuation and percutaneous drainage. We present a case of spontaneous duodenal haematoma in a patient with no risk factors posing as a diagnostic challenge due to atypical CT findings. This case also illustrates the utility of ultrasound-guided needle aspiration as a practical treatment option for such haematomas. PMID- 24777077 TI - Herpes zoster encephalopathy or acyclovir neurotoxicity: a management dilemma. AB - This is a case report of a 69-year-old morbidly obese woman who presented with mental status changes after she was treated with acyclovir for shingles. The predominant symptoms were word-finding difficulties and visual hallucinations. Complicating her presentation was acyclovir-induced acute renal injury causing her creatinine level to rise up to 7.4 mg/dL. Acyclovir was discontinued on the suspicion of acyclovir neurotoxicity. Even though PCR for varicella zoster virus in the cerebrospinal fluid was positive, acyclovir was not restarted and the patient continued to improve and returned to her baseline. PMID- 24777078 TI - Common femoral vein canal lipoma causing chronic unilateral lower limb swelling. AB - A 64-year-old woman presented to vascular clinic with a 2-year history of right ankle swelling, associated with pain on walking. Initial venous duplex imaging showed no obvious cause. Further imaging showed a lipoma compressing the common femoral vein. We consider the relative merits of the imaging modalities of the groin and the literature available on lipomas causing compression. PMID- 24777079 TI - CSF pseudocyst: an unusual cause of back pain. PMID- 24777080 TI - Amyand's hernia with a periappendicular abscess. AB - We present a rare case of a perforated vermiform appendix presenting as a strangulated inguinal hernia. An 89-year-old man presented to the surgical assessment unit with a 1-week history of progressively worsening abdominal pain, fever and a tender mass in the right iliac fossa. A diagnosis of strangulated inguinal hernia was made. Intraoperatively, a perforated appendix and a pus filled sac were found. An appendicectomy and a Bassini repair of the hernia were performed with a satisfactory postoperative outcome. In the majority of cases Amyand's hernia is an intraoperative finding and its management depends on the extent of appediceal disease. In cases of perforated appendix with periappendiceal abscess within the hernial sac, an appedicectomy with Bassini's repair is recommended. PMID- 24777081 TI - An inability to learn to read caused by shaken baby syndrome. AB - We report a 12-year-old boy who suffered from shaken baby syndrome at the age of 4 months and has been unable to learn to read even high-frequency, three-letter words, despite slow but accurate letter naming. He had a right homonymous hemianopia and evidence of impaired higher visual function, but not at a severe enough level to account for his inability to read. Speech production and reception of language were impaired for his age but at least of an order of magnitude better than his reading performance. MRI scanning revealed focal damage to the dorsal and ventral reading pathways. This case challenges the Kennard principle, a widely accepted assumption which claims that the earlier a brain injury occurs, the better the recovery. It also adds to the growing literature suggesting that early damage to multiple parts of the language learning network can result in relatively selective impairments later in life. PMID- 24777082 TI - Adult intussusception presenting as rectal prolapse. AB - We present a case of an elderly man with what appeared to be an episode of rectal prolapse following straining while defaecating. Laparotomy revealed the prolapse to be an intussusception of large bowel with a villous adenoma as its lead point. Reduction resection was performed with primary anastomosis, and the patient recovered well from the surgery. Rectal prolapse has often been viewed as a benign condition in the elderly, but more thought needs to be put into the diagnosis in patients with risks of malignancy. Prolapse of an intussuscepted bowel segment in adults is an exceedingly rare presentation, often signifying a risk of malignancy. Appropriate investigations and surgical techniques need to be employed in effectively resolving symptoms while minimising the chances of tumour seeding. PMID- 24777083 TI - Motor neurone disease presenting as polycythaemia. AB - Motor neurone disease (MND) is a chronic, progressive and currently incurable neurodegenerative disorder. This case report discusses an instance of MND presenting initially as polycythaemia, caused via insidious respiratory failure through ventilatory insufficiency. This case aims to improve clinicians' awareness of this atypical presentation and highlights the need for a high index of suspicion of respiratory failure in any patient with polycythaemia. Finally it demonstrates an improvement in quality of life associated with the use of non invasive ventilation (NIV) in a patient with MND. PMID- 24777084 TI - Flucytosine-induced colitis. AB - A 52-year-old man with a history of HIV (CD4 count 155, and viral load 154 K), who is on antiretroviral treatment presented in the emergency room with acute onset of headache. The patient had lumbar puncture and found to have elevated intracranial pressure and cryptococcal antigen was positive. The patient was started on flucytosine. After 10 days of treatment, the patient developed watery diarrhoea. An extensive infectious workup was carried out, which did not reveal any infectious aetiology. A colonoscopy was carried out which revealed acute colitis in the colon and the pathology confirmed the colonoscopic findings with severe colitis in the colon. At this time, the patient's diarrhoea was attributed to flucytosine and it was stopped. The patient's diarrhoea improved after 5 days of stopping flucytosine. PMID- 24777085 TI - Acquired gynatresia. AB - Vaginal stenosis (gynatresia) is commonly congenital, occurring as a part of Mayer-Kustner-Hauser syndrome. Those occurring postabortal or postpartum are rarely seen nowadays. Here, we report two cases, one in which there was complete stenosis postpartum following a retained gauze and another case, with chemical vaginal burns following attempted abortion by a local untrained midwife. PMID- 24777086 TI - Three cases of Spontaneous Vertebral Artery Dissection (SVAD), resulting in two cases of Wallenberg syndrome and one case of Foville syndrome in young, healthy men. AB - First patient, presented with sudden onset of headache, left hypoacusia and right hemiparesis, posteriorly developing gaze-evoked nystagmus and worsening right sided weakness. Diagnosis of vertebral artery dissection and Foville Syndrome were made through clinical assessment and CT-carotid angiogram-MR angiography. Second patient, presented with four episodes of pain over left side of the nose and left eye pain over 1 month; admitted for acute facial pain without limb weakness. During admission, tingling over V1/V2 facial territory, vertigo, hypotension, uvula deviation and right lower limb numbness. CT-carotid angiogram confirmed vertebral artery with dissection. MRI revealed left lateral medullary infarct. Third patient, presented with sudden onset of left facial numbness and right upper limb weakness; 1 day after, right arm and leg hypoesthesia with hoarseness. MRA revealed dissection of left distal vertebral artery and MRI showed infarction in lower medulla oblongata. PMID- 24777087 TI - Massive pneumoperitoneum following colonoscopic sigmoid perforation. PMID- 24777088 TI - Successful treatment of bleeding large duodenal gastrointestinal stromal tumour in a patient under dual antiplatelet therapy after recent drug-eluting coronary stent implantation. AB - We report a case of a 69-year-old man who started dual antiplatelet therapy (APT) with aspirin and clopidogrel after recent implantation of drug-eluting coronary stent and developed massive bleeding due to large duodenal gastrointestinal stromal tumour (GIST). Following endoscopic haemostasis and discontinuation of dual APT, neoadjuvant chemotherapy with imatinib was started under continuation of 'single' APT with aspirin. A good chemotherapeutic response was achieved without recurrence of bleeding, and subsequent less invasive surgical resection of the tumour was performed, while preoperative single APT was continued for prevention of stent thrombosis. The patient recovered well without any thromboembolic or bleeding events. Neoadjuvant imatinib therapy and subsequent less invasive surgery under continuation of APT is one of the preferred approaches for patients with duodenal GIST with severe thromboembolic comorbidities, as in the current case. PMID- 24777089 TI - Escherichia coli positive infratentorial subdural empyema secondary to mastoiditis and underlying cholesteatoma. AB - Infratentorial subdural empyema is a neurosurgical emergency that is associated with an alarmingly high morbidity and mortality if appropriate management is delayed. It is an important differential to consider when confronted with a patient with a reduced Glasgow Coma Scale, focal neurology and symptoms of raised intracranial pressure in the presence of a head and neck infection. It is also important that the primary team managing these patients is aware of the many pathogens that may be involved, including Escherichia coli. Early recognition, prompt diagnosis, timely involvement of the appropriate multidisciplinary teams, including neurosurgery, otorhinolaryngology, radiology and microbiology should be sought, and urgent intervention are imperative in avoiding a fatal outcome. This article presents a case of E coli-positive infratentorial subdural empyema secondary to mastoiditis due to underlying cholesteatoma, and a review of the pertinent literature. PMID- 24777090 TI - Characterization of a respiratory syncytial virus L protein inhibitor. AB - The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function. PMID- 24777091 TI - Ceftobiprole activity against over 60,000 clinical bacterial pathogens isolated in Europe, Turkey, and Israel from 2005 to 2010. AB - Ceftobiprole medocaril is a newly approved drug in Europe for the treatment of hospital-acquired pneumonia (HAP) (excluding patients with ventilator-associated pneumonia but including ventilated HAP patients) and community-acquired pneumonia in adults. The aim of this study was to evaluate the in vitro antimicrobial activity of ceftobiprole against prevalent Gram-positive and -negative pathogens isolated in Europe, Turkey, and Israel during 2005 through 2010. A total of 60,084 consecutive, nonduplicate isolates from a wide variety of infections were collected from 33 medical centers. Species identification was confirmed, and all isolates were susceptibility tested using reference broth microdilution methods. Ceftobiprole had high activity against methicillin-susceptible Staphylococcus aureus (MSSA) (100.0% susceptible), methicillin-susceptible coagulase-negative staphylococci (CoNS), beta-hemolytic streptococci, and Streptococcus pneumoniae (99.3% susceptible), with MIC90 values of 0.25, 0.12, <= 0.06, and 0.5 MUg/ml, respectively. Ceftobiprole was active against methicillin-resistant S. aureus (MRSA) (98.3% susceptible) and methicillin-resistant CoNS, having a MIC90 of 2 MUg/ml. Ceftobiprole was active against Enterococcus faecalis (MIC50/90, 0.5/4 MUg/ml) but not against most Enterococcus faecium isolates. Ceftobiprole was very potent against the majority of Enterobacteriaceae (87.3% susceptible), with >80% inhibited at <= 0.12 MUg/ml. The potency of ceftobiprole against Pseudomonas aeruginosa (MIC50/90, 2/>8 MUg/ml; 64.6% at MIC values of <= 4 MUg/ml) was similar to that of ceftazidime (MIC50/90, 2/>16 MUg/ml; 75.4% susceptible), but limited activity was observed against Acinetobacter spp. and Stenotrophomonas maltophilia. High activity was also observed against all Haemophilus influenzae (MIC90, <= 0.06 MUg/ml) and Moraxella catarrhalis (MIC50/90, <= 0.06/0.25 MUg/ml) isolates. Ceftobiprole demonstrated a wide spectrum of antimicrobial activity against this very large longitudinal sample of contemporary pathogens. PMID- 24777092 TI - In silico detection and typing of plasmids using PlasmidFinder and plasmid multilocus sequence typing. AB - In the work presented here, we designed and developed two easy-to-use Web tools for in silico detection and characterization of whole-genome sequence (WGS) and whole-plasmid sequence data from members of the family Enterobacteriaceae. These tools will facilitate bacterial typing based on draft genomes of multidrug resistant Enterobacteriaceae species by the rapid detection of known plasmid types. Replicon sequences from 559 fully sequenced plasmids associated with the family Enterobacteriaceae in the NCBI nucleotide database were collected to build a consensus database for integration into a Web tool called PlasmidFinder that can be used for replicon sequence analysis of raw, contig group, or completely assembled and closed plasmid sequencing data. The PlasmidFinder database currently consists of 116 replicon sequences that match with at least at 80% nucleotide identity all replicon sequences identified in the 559 fully sequenced plasmids. For plasmid multilocus sequence typing (pMLST) analysis, a database that is updated weekly was generated from www.pubmlst.org and integrated into a Web tool called pMLST. Both databases were evaluated using draft genomes from a collection of Salmonella enterica serovar Typhimurium isolates. PlasmidFinder identified a total of 103 replicons and between zero and five different plasmid replicons within each of 49 S. Typhimurium draft genomes tested. The pMLST Web tool was able to subtype genomic sequencing data of plasmids, revealing both known plasmid sequence types (STs) and new alleles and ST variants. In conclusion, testing of the two Web tools using both fully assembled plasmid sequences and WGS-generated draft genomes showed them to be able to detect a broad variety of plasmids that are often associated with antimicrobial resistance in clinically relevant bacterial pathogens. PMID- 24777093 TI - Validation of antibiotic susceptibility testing guidelines in a routine clinical microbiology laboratory exemplifies general key challenges in setting clinical breakpoints. AB - This study critically evaluated the new European Committee for Antimicrobial Susceptibility Testing (EUCAST) antibiotic susceptibility testing guidelines on the basis of a large set of disk diffusion diameters determined for clinical isolates. We report several paradigmatic problems that illustrate key issues in the selection of clinical susceptibility breakpoints, which are of general importance not only for EUCAST but for all guidelines systems, i.e., (i) the need for species-specific determinations of clinical breakpoints/epidemiological cutoffs (ECOFFs), (ii) problems arising from pooling data from various sources, and (iii) the importance of the antibiotic disk content for separating non-wild type and wild-type populations. PMID- 24777094 TI - Phasevarions mediate epigenetic regulation of antimicrobial susceptibility in Neisseria meningitidis. AB - Phase variation is a common feature of host-adapted bacterial pathogens such as Neisseria meningitidis. Recently, we reported that this rapid on/off switching of gene expression occurs in DNA methyltransferases, altering expression in multiple genes via changes in global methylation. In the current study, we compared MIC values of strains with ModA11, ModA12, and ModD1 phasevarions, revealing MIC differences due to ModA11 and ModA12 switching, with a ModA11_OFF strain showing 4-fold reduced susceptibilities to ceftazidime and ciprofloxacin. PMID- 24777095 TI - High incidence and endemic spread of NDM-1-positive Enterobacteriaceae in Henan Province, China. AB - The emergence and spread of New Delhi metallo-beta-lactamase 1 (NDM-1)-producing carbapenem-resistant Enterobacteriaceae (CRE) present an urgent threat to human health. In China, the bla(NDM-1 gene has been reported mostly in Acinetobacter spp. but is rarely found in Enterobacteriaceae. Here, we report a high incidence and endemic spread of NDM-1-producing CRE in Henan Province in China. Sixteen (33.3%) of the 48 CRE isolates obtained from patients during June 2011 to July 2012 were positive for bla(NDM-1), and the gene was found to be carried on plasmids of various sizes (~ 55 to ~ 360 kb). These plasmids were readily transferrable to recipient Escherichia coli by conjugation, conferred resistance to multiple antibiotics, and belonged to multiple replicon types. The bla(NDM-1) positive CRE isolates were genetically diverse, and six new multilocus sequence typing (MLST) sequence types were linked to the carriage of NDM-1. Five of the isolates were classified as extensively drug-resistant (XDR) isolates, four of which also carried the fosA3 gene conferring resistance to fosfomycin, an alternative drug for treating infections by CRE. In each bla(NDM-1)-positive CRE isolate, the bla(NDM-1) gene was downstream of an intact ISAba125 element and upstream of the bleMBL gene. Furthermore, gene environment analysis suggested the possible transmission of bla(NDM-1)-containing sequences from Acinetobacter spp. to Klebsiella pneumoniae and Klebsiella oxytoca. These findings reveal the emergence and active transmission of NDM-1-positive CRE in China and underscore the need for heightened measures to control their further spread. PMID- 24777096 TI - Inhibitor-resistant TEM- and OXA-1-producing Escherichia coli isolates resistant to amoxicillin-clavulanate are more clonal and possess lower virulence gene content than susceptible clinical isolates. AB - In a previous prospective multicenter study in Spain, we found that OXA-1 and inhibitor-resistant TEM (IRT) beta-lactamases constitute the most common plasmid borne mechanisms of genuine amoxicillin-clavulanate (AMC) resistance in Escherichia coli. In the present study, we investigated the population structure and virulence traits of clinical AMC-resistant E. coli strains expressing OXA-1 or IRT and compared these traits to those in a control group of clinical AMC susceptible E. coli isolates. All OXA-1-producing (n = 67) and IRT-producing (n = 45) isolates were matched by geographical and temporal origin to the AMC susceptible control set (n = 56). We performed multilocus sequence typing and phylogenetic group characterization for each isolate and then studied the isolates for the presence of 49 virulence factors (VFs) by PCR and sequencing. The most prevalent clone detected was distinct for each group: group C isolates of sequence type (ST) 88 (C/ST88) were the most common in OXA-1 producers, B2/ST131 isolates were the most common in IRT producers, and B2/ST73 isolates were the most common in AMC-susceptible isolates. The median numbers of isolates per ST were 3.72 in OXA-1 producers, 2.04 in IRT producers, and 1.69 in AMC susceptible isolates; the proportions of STs represented by one unique isolate in each group were 19.4%, 31.1%, and 48.2%, respectively. The sum of all VFs detected, calculated as a virulence score, was significantly higher in AMC susceptible isolates than OXA-1 and IRT producers (means, 12.5 versus 8.3 and 8.2, respectively). Our findings suggest that IRT- and OXA-1-producing E. coli isolates resistant to AMC have a different and less diverse population structure than AMC-susceptible clinical E. coli isolates. The AMC-susceptible population also contains more VFs than AMC-resistant isolates. PMID- 24777097 TI - The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells. AB - Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium Coxiella burnetii in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-C. burnetii activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process. PMID- 24777098 TI - Emergence of high-level azithromycin resistance in Campylobacter jejuni isolates from pediatric diarrhea patients in Kolkata, India. PMID- 24777099 TI - Benefits of a pharmacology antimalarial reference standard and proficiency testing program provided by the Worldwide Antimalarial Resistance Network (WWARN). AB - Comprehensive assessment of antimalarial drug resistance should include measurements of antimalarial blood or plasma concentrations in clinical trials and in individual assessments of treatment failure so that true resistance can be differentiated from inadequate drug exposure. Pharmacometric modeling is necessary to assess pharmacokinetic-pharmacodynamic relationships in different populations to optimize dosing. To accomplish both effectively and to allow comparison of data from different laboratories, it is essential that drug concentration measurement is accurate. Proficiency testing (PT) of laboratory procedures is necessary for verification of assay results. Within the Worldwide Antimalarial Resistance Network (WWARN), the goal of the quality assurance/quality control (QA/QC) program is to facilitate and sustain high quality antimalarial assays. The QA/QC program consists of an international PT program for pharmacology laboratories and a reference material (RM) program for the provision of antimalarial drug standards, metabolites, and internal standards for laboratory use. The RM program currently distributes accurately weighed quantities of antimalarial drug standards, metabolites, and internal standards to 44 pharmacology, in vitro, and drug quality testing laboratories. The pharmacology PT program has sent samples to eight laboratories in four rounds of testing. WWARN technical experts have provided advice for correcting identified problems to improve performance of subsequent analysis and ultimately improved the quality of data. Many participants have demonstrated substantial improvements over subsequent rounds of PT. The WWARN QA/QC program has improved the quality and value of antimalarial drug measurement in laboratories globally. It is a model that has potential to be applied to strengthening laboratories more widely and improving the therapeutics of other infectious diseases. PMID- 24777100 TI - The T2 Mycobacterium tuberculosis genotype, predominant in Kampala, Uganda, shows negative correlation with antituberculosis drug resistance. AB - Surveillance of the circulating Mycobacterium tuberculosis complex (MTC) strains in a given locality is important for understanding tuberculosis (TB) epidemiology. We performed molecular epidemiological studies on sputum smear positive isolates that were collected for anti-TB drug resistance surveillance to establish the variability of MTC lineages with anti-TB drug resistance and HIV infection. Spoligotyping was performed to determine MTC phylogenetic lineages. We compared patients' MTC lineages with drug susceptibility testing (DST) patterns and HIV serostatus. Out of the 533 isolates, 497 (93.2%) had complete DST, PCR, and spoligotyping results while 484 (90.1%) participants had results for HIV testing. Overall, the frequency of any resistance was 75/497 (15.1%), highest among the LAM (34.4%; 95% confidence interval [CI], 18.5 to 53.2) and lowest among the T2 (11.5%; 95% CI, 7.6 to 16.3) family members. By multivariate analysis, LAM (adjusted odds ratio [OR(adj)], 5.0; 95% CI, 2.0 to 11.9; P < 0.001) and CAS (OR(adj), 2.9; 95% CI, 1.4.0 to 6.3; P = 0.006) families were more likely to show any resistance than was T2. All other MTC lineages combined were more likely to be resistant to any of the anti-TB drugs than were the T2 strains (OR(adj), 1.7; 95% CI, 1.0 to 2.9; P = 0.040). There were no significant associations between multidrug resistance and MTC lineages, but numbers of multidrug-resistant TB strains were small. No association was established between MTC lineages and HIV status. In conclusion, the T2 MTC lineage negatively correlates with anti-TB drug resistance, which might partly explain the reported low levels of anti-TB drug resistance in Kampala, Uganda. Patients' HIV status plays no role with respect to the MTC lineage distribution. PMID- 24777101 TI - Metabolic compensation of fitness costs associated with overexpression of the multidrug efflux pump MexEF-OprN in Pseudomonas aeruginosa. AB - The acquisition of antibiotic resistance has been associated with a possible nonspecific, metabolic burden that is reflected in decreased fitness among resistant bacteria. We have recently demonstrated that overexpression of the MexEF-OprN multidrug efflux pump does not produce a metabolic burden when measured by classical competitions tests but rather leads to a number of changes in the organism's physiology. One of these changes is the untimely activation of the nitrate respiratory chain under aerobic conditions. MexEF-OprN is a proton/substrate antiporter. Overexpression of this element should result in a constant influx of protons, which may lead to cytoplasmic acidification. Acidification was not observed in aerobiosis, a situation in which the MexEF overproducing mutant increases oxygen consumption. This enhanced oxygen uptake serves to eliminate intracellular proton accumulation, preventing the cytoplasmic acidification that was observed exclusively under anaerobic conditions, a situation in which the fitness of the MexEF-OprN-overproducing mutant decreases. Finally, we determined that the early activation of the nitrate respiratory chain under aerobic conditions plays a role in preventing a deleterious effect associated with the overexpression of MexEF-OprN. Our results show that metabolic rewiring may assist in overcoming the potential fitness cost associated with the acquisition of antibiotic resistance. Furthermore, the capability to metabolically compensate for this effect is habitat dependent, as demonstrated by our results under anaerobic conditions. The development of drugs that prevent metabolic compensation of fitness costs may help to reduce the persistence and dissemination of antibiotic resistance. PMID- 24777102 TI - Crystal structure of Mox-1, a unique plasmid-mediated class C beta-lactamase with hydrolytic activity towards moxalactam. AB - Mox-1 is a unique plasmid-mediated class C beta-lactamase that hydrolyzes penicillins, cephalothin, and the expanded-spectrum cephalosporins cefepime and moxalactam. In order to understand the unique substrate profile of this enzyme, we determined the X-ray crystallographic structure of Mox-1 beta-lactamase at a 1.5-A resolution. The overall structure of Mox-1 beta-lactamase resembles that of other AmpC enzymes, with some notable exceptions. First, comparison with other enzymes whose structures have been solved reveals significant differences in the composition of amino acids that make up the hydrogen-bonding network and the position of structural elements in the substrate-binding cavity. Second, the main chain electron density is not observed in two regions, one containing amino acid residues 214 to 216 positioned in the Omega loop and the other in the N terminus of the B3 beta-strand corresponding to amino acid residues 303 to 306. The last two observations suggest that there is significant structural flexibility of these regions, a property which may impact the recognition and binding of substrates in Mox-1. These important differences allow us to propose that the binding of moxalactam in Mox-1 is facilitated by the avoidance of steric clashes, indicating that a substrate-induced conformational change underlies the basis of the hydrolytic profile of Mox-1 beta-lactamase. PMID- 24777103 TI - In vitro activity of AZD5847 against geographically diverse clinical isolates of Mycobacterium tuberculosis. AB - The MIC of the novel antituberculosis (anti-TB) drug AZD5847 was determined against 146 clinical isolates from diverse geographical regions, including eastern Europe, North America, Africa, and Asia, using the automated Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 system. These isolates originated from specimen sources such as sputum, bronchial alveolar lavage fluid, pleural fluid, abscess material, lung biopsies, and feces. The overall MIC90 was 1.0 mg/liter (range, 0.125 to 4 mg/liter). The MICs of AZD5847 for isolates of Mycobacterium tuberculosis were similar among drug-sensitive strains, multidrug resistant (MDR) strains, and extensively drug resistant (XDR) strains. The good in vitro activity of AZD5847 against M. tuberculosis and the lack of cross resistance make this agent a promising anti-TB drug candidate. PMID- 24777104 TI - Pharmacological study of cefoxitin as an alternative antibiotic therapy to carbapenems in treatment of urinary tract infections due to extended-spectrum beta-lactamase-producing Escherichia coli. AB - Cefoxitin could be an alternative to carbapenems in extended-spectrum-beta lactamase-producing Escherichia coli (ESBL-EC) infections. However, pharmacological and clinical data regarding cefoxitin are limited. Using a recent pharmacological model and the MICs of ESBL-EC collected from pyelonephritis, we determined the probabilities to reach four pharmacological targets: free cefoxitin concentrations above the MIC during 50% and 100% of the administration interval (T>MIC = 50% and T>MIC = 100%, respectively) and free cefoxitin concentrations above 4* MIC during 50% and 100% of the administration interval (T>4MIC = 50% and T>4MIC = 100%, respectively). Cefoxitin could be used to treat ESBL-EC pyelonephritis, but administration modalities should be optimized according to MICs in order to reach pharmacological targets. PMID- 24777105 TI - A low-affinity penicillin-binding protein 2x variant is required for heteroresistance in Streptococcus pneumoniae. AB - Heteroresistance to penicillin in Streptococcus pneumoniae is the ability of subpopulations to grow at a higher antibiotic concentration than expected from the MIC. This may render conventional resistance testing unreliable and lead to therapeutic failure. We investigated the role of the primary beta-lactam resistance determinants, penicillin-binding protein 2b (PBP2b) and PBP2x, and the secondary resistance determinant PBP1a in heteroresistance to penicillin. Transformants containing PBP genes from the heteroresistant strain Spain(23F) 2349 in the nonheteroresistant strain R6 background were tested for heteroresistance by population analysis profiling (PAP). We found that pbp2x, but not pbp2b or pbp1a alone, conferred heteroresistance to R6. However, a change of pbp2x expression was not observed, and therefore, expression does not correlate with an increased proportion of resistant subpopulations. In addition, the influence of the CiaRH system, mediating PBP-independent beta-lactam resistance, was assessed by PAP on ciaR disruption mutants but revealed no heteroresistant phenotype. We also showed that the highly resistant subpopulations (HOM*) of transformants containing low-affinity pbp2x undergo an increase in resistance upon selection on penicillin plates that partially reverts after passaging on selection-free medium. Shotgun proteomic analysis showed an upregulation of phosphate ABC transporter subunit proteins encoded by pstS, phoU, pstB, and pstC in these highly resistant subpopulations. In conclusion, the presence of low affinity pbp2x enables certain pneumococcal colonies to survive in the presence of beta-lactams. Upregulation of phosphate ABC transporter genes may represent a reversible adaptation to antibiotic stress. PMID- 24777106 TI - Enhanced antiretroviral therapy in rhesus macaques improves RT-SHIV viral decay kinetics. AB - Using an established nonhuman primate model, rhesus macaques were infected intravenously with a chimeric simian immunodeficiency virus (SIV) consisting of SIVmac239 with the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase from clone HXBc2 (RT-SHIV). The impacts of two enhanced (four- and five-drug) highly active antiretroviral therapies (HAART) on early viral decay and rebound were determined. The four-drug combination consisted of an integrase inhibitor, L-870-812 (L-812), together with a three-drug regimen comprising emtricitabine [(-)-FTC], tenofovir (TFV), and efavirenz (EFV). The five-drug combination consisted of one analog for each of the four DNA precursors {using TFV, (-)-FTC, (-)-beta-D-(2R,4R)-1,3-dioxolane-2,6-diaminopurine (amdoxovir [DAPD]), and zidovudine (AZT)}, together with EFV. A cohort treated with a three drug combination of (-)-FTC, TFV, and EFV served as treated controls. Daily administration of a three-, four-, or five-drug combination of antiretroviral agents was initiated at week 6 or 8 after inoculation and continued up to week 50, followed by a rebound period. Plasma samples were collected routinely, and drug levels were monitored using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Viral loads were monitored with a standard TaqMan quantitative reverse transcriptase PCR (qRT-PCR) assay. Comprehensive analyses of replication dynamics were performed. RT-SHIV infection in rhesus macaques produced typical viral infection kinetics, with untreated controls establishing persistent viral loads of >10(4) copies of RNA/ml. RT-SHIV loads at the start of treatment (V0) were similar in all treated cohorts (P > 0.5). All antiretroviral drug levels were measureable in plasma. The four-drug and five-drug combination regimens (enhanced HAART) improved suppression of the viral load (within 1 week; P < 0.01) and had overall greater potency (P < 0.02) than the three-drug regimen (HAART). Moreover, rebound viremia occurred rapidly following cessation of any treatment. The enhanced HAART (four- or five-drug combination) showed significant improvement in viral suppression compared to the three-drug combination, but no combination was sufficient to eliminate viral reservoirs. PMID- 24777108 TI - Results of construction of protective loop ileostomies and reversal surgery for colorectal surgery. AB - BACKGROUND: Protective loop ileostomies in colorectal surgery are constructed to reduce morbidity and reinterventions related to the primary operation. However, ileostomies are associated with stoma-related morbidity and postoperative complications following reversal surgery. Dutch national data show increased use of loop ileostomies in colorectal surgery for cancer justifying an adequate assessment of its morbidity. This study was undertaken to investigate morbidity associated with protective loop ileostomies in colorectal surgery. METHODS: Retrospectively, 118 consecutive patients undergoing left-sided colonic or rectal resection with protective loop ileostomy were included. Primary outcome was 30 day mortality. Secondary endpoints included total complication rate (including stoma-related morbidity), total reintervention risk, anastomotic leakage risk and total length of stay. RESULTS: No mortality was observed. Overall major complication, reintervention and anastomotic leakage risk for colorectal surgery were 20, 20 and 3.9%, respectively. Combined length of stay for stoma-related morbidity and reversal surgery was 12.7 days. The risk for stoma-related morbidity was 35%, and the risk for nonelective reversal was 12%. Closure rate (mean follow-up of 15 months) was 87% with a mean interval of 125 days. Reversal surgery was not correlated with mortality but with major complications (11%) and reintervention risk, anastomotic leakage risk (3.8%) and a mean length of stay of 9 days. CONCLUSION: Construction of loop ileostomies in left-sided colonic or rectal resection is associated with a low risk for anastomotic leakage at the expense of substantial stoma-related morbidity and morbidity related to reversal surgery. More accurate identification of colorectal cancer patients benefitting from protective loop ileostomy seems to be warranted. PMID- 24777107 TI - Organizer-derived Bmp2 is required for the formation of a correct Bmp activity gradient during embryonic development. AB - Bone morphogenetic proteins (Bmps) control dorsoventral patterning of vertebrate embryos through the establishment of a ventrodorsal gradient of the activated downstream cytoplasmic effectors Smad1/5/8. Some Bmp ligands are expressed in the ventral and lateral regions and in the organizer during gastrulation of the embryo, but it remains unclear how organizer-derived Bmps contribute to total Bmp ligand levels and to the establishment of the correct phospho-Smad1/5/8 gradient along the ventrodorsal axis. Here we demonstrate that interference with organizer specific Bmp2b signalling in zebrafish embryos alters the phospho-Smad1/5/8 gradient throughout the ventrodorsal axis, elevates the levels of the Bmp antagonist Chordin and dorsalizes the embryos. Moreover, we show that organizer derived Bmp2b represses chordin transcription in the organizer and contributes to the control of the Chordin gradient. Combining these experimental results with simulations of Bmp's reaction-diffusion dynamics, our data indicate that organizer-produced Bmp2b is required for the establishment and maintenance of a Bmp activity gradient and for appropriate embryonic dorsoventral patterning during gastrulation. PMID- 24777109 TI - "TRIMing" the patient population to increase the benefit of mTOR inhibition. PMID- 24777110 TI - Tracking and evaluating molecular tumor markers with cancer registry data: HER2 and breast cancer. PMID- 24777111 TI - US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. AB - BACKGROUND: In 2010, Surveillance, Epidemiology, and End Results (SEER) registries began collecting human epidermal growth factor 2 (HER2) receptor status for breast cancer cases. METHODS: Breast cancer subtypes defined by joint hormone receptor (HR; estrogen receptor [ER] and progesterone receptor [PR]) and HER2 status were assessed across the 28% of the US population that is covered by SEER registries. Age-specific incidence rates by subtype were calculated for non Hispanic (NH) white, NH black, NH Asian Pacific Islander (API), and Hispanic women. Joint HR/HER2 status distributions by age, race/ethnicity, county-level poverty, registry, stage, Bloom-Richardson grade, tumor size, and nodal status were evaluated using multivariable adjusted polytomous logistic regression. All statistical tests were two-sided. RESULTS: Among case patients with known HR/HER2 status, 36810 (72.7%) were found to be HR(+)/HER2(-), 6193 (12.2%) were triple negative (HR(-)/HER2(-)), 5240 (10.3%) were HR(+)/HER2(+), and 2328 (4.6%) were HR(-)/HER2(+); 6912 (12%) had unknown HR/HER2 status. NH white women had the highest incidence rate of the HR(+)/HER2(-) subtype, and NH black women had the highest rate of the triple-negative subtype. Compared with women with the HR(+)/HER2(-) subtype, triple-negative patients were more likely to be NH black and Hispanic; HR(+)/HER2(+) patients were more likely to be NH API; and HR( )/HER2(+) patients were more likely to be NH black, NH API, and Hispanic. Patients with triple-negative, HR(+)/HER2(+), and HR(-)/HER2(+) breast cancer were 10% to 30% less likely to be diagnosed at older ages compared with HR(+)/HER2(-) patients and 6.4-fold to 20.0-fold more likely to present with high grade disease. CONCLUSIONS: In the future, SEER data can be used to monitor clinical outcomes in women diagnosed with different molecular subtypes of breast cancer for a large portion (approximately 28%) of the US population. PMID- 24777113 TI - Suppression (but not reappraisal) impairs subsequent error detection: an ERP study of emotion regulation's resource-depleting effect. AB - Past event-related potentials (ERPs) research shows that, after exerting effortful emotion inhibition, the neural correlates of performance monitoring (e.g. error-related negativity) were weakened. An undetermined issue is whether all forms of emotion regulation uniformly impair later performance monitoring. The present study compared the cognitive consequences of two emotion regulation strategies, namely suppression and reappraisal. Participants were instructed to suppress their emotions while watching a sad movie, or to adopt a neutral and objective attitude toward the movie, or to just watch the movie carefully. Then after a mood scale, all participants completed an ostensibly unrelated Stroop task, during which ERPs (i.e. error-related negativity (ERN), post-error positivity (Pe) and N450) were obtained. Reappraisal group successfully decreased their sad emotion, relative to the other two groups. Compared with participants in the control group and the reappraisal group, those who suppressed their emotions during the sad movie showed reduced ERN after error commission. Participants in the suppression group also made more errors in incongruent Stroop trials than the other two groups. There were no significant main effects or interactions of group for reaction time, Pe and N450. Results suggest that reappraisal is both more effective and less resource-depleting than suppression. PMID- 24777112 TI - Amplification of TRIM44: pairing a prognostic target with potential therapeutic strategy. AB - BACKGROUND: Many prognostic biomarkers have been proposed recently. However, there is a lack of therapeutic strategies exploiting novel prognostic biomarkers. We aimed to propose therapeutic options in patients with overexpression of TRIM44, a recently identified prognostic gene. METHODS: Genomic and transcriptomic data of epithelial cancers (n = 1932), breast cancers (BCs; n = 1980) and esophago-gastric cancers (EGCs; n = 163) were used to identify genomic aberrations driving TRIM44 overexpression. The driver gene status of TRIM44 was determined using a small interfering RNA (siRNA) screen of the 11p13 amplicon. Integrative analysis was applied across multiple datasets to identify pathway activation and potential therapeutic strategies. Validation of the in silico findings were performed using in vitro assays, xenografts, and patient samples (n = 160). RESULTS: TRIM44 overexpression results from genomic amplification in 16.1% of epithelial cancers, including 8.1% of EGCs and 6.1% of BCs. This was confirmed using fluorescent in situ hybridization. The siRNA screen confirmed TRIM44 to be a driver of the amplicon. In silico analysis revealed an association between TRIM44 and mTOR signalling, supported by a decrease in mTOR signalling after siRNA knockdown of TRIM44 in cell lines and colocalization of TRIM44 and p mTOR in patient samples. In vitro inhibition studies using an mTOR inhibitor (everolimus) decreased cell viability in two TRIM44-amplified cells lines by 88% and 70% compared with 35% in the control cell line. These findings were recapitulated in xenograft models. CONCLUSIONS: Genomic amplification drives TRIM44 overexpression in EGCs and BCs. Targeting the mTOR pathway provides a potential therapeutic option for TRIM44-amplified tumors. PMID- 24777114 TI - Metabolic responses of running shod and barefoot in mid-forefoot runners. AB - BACKGROUND: The purposes of this study were to compare the oxygen cost, metabolic parameters and temporalspatial variables between barefoot and shod running in trained mid-forefoot runners. METHODS: Experienced runners (N.=21; 30+/-10.9 years; 16 men) performed two separate 20 minute treadmill running bouts at ~77% of estimated maximal heart rate. Rate of oxygen consumption (VO2), energy cost, fuel use and heart rate (HR) were collected continuously using a portable gas analyzer. Three-dimensional motion capture was used to measure temporalspatial parameters. RESULTS: Participants ran at a mean self-selected speed of 3.1+/-0.3 m/s for both conditions, at intensities corresponding to mean HR values of 146 bpm (shod) and 144 bpm (barefoot). Steady State VO2 was not different between the shod and barefoot conditions (39.4+/- 4.7 mL/kg*min vs. 40+/-5.2 mL/kg*min, respectively). The total energy expended in the shod and barefoot conditions was 974+/-134 kJ and 979+/-142 kJ. The average non-protein respiratory exchange ratios, proportions and amount of fat and carbohydrate used were not different between conditions. Cadence was 2.5% higher and center of gravity vertical displacement was 0.5 cm less for the barefoot condition (P<0.05). CONCLUSION: In trained mid-forefoot runners experienced with barefoot running, there are not significant metabolic differences between shod and barefoot running conditions. Barefoot running increases cadence and decreases foot contact time and vertical displacement. Experienced participants were likely able to titrate kinematics to standardize energy output and fuel use for a given running distance and speed irrespective of shoe wear. PMID- 24777115 TI - Playing a part in research? University students' attitudes to direct-to-consumer genomics. AB - AIMS: This study examined the attitudes of 1,146 Swiss University students to direct-to-consumer (DTC) genomic testing and to genomic research participation. METHODS: Data were collected through a self-completion online questionnaire by students from 2 higher education institutions in Zurich, Switzerland. The survey aimed to capture motivation for undergoing or refraining from genomic testing, reactions to mock genetic risk results, and views about contributing data to scientific research. Descriptive and inferential statistics were used for the analysis. RESULTS: A total of 1.5% of the students had undergone testing. Most respondents were studying natural sciences and were interested in undergoing DTC genomic testing. The main motive was to contribute their data to scientific research, followed closely by their interest to find out disease risks and personal traits. Overall, 41% of the respondents were not interested in DTC tests. The primary reasons were concerns about receiving potentially worrying results. There was a significant correlation between studying natural sciences, as opposed to the humanities, and interest in undergoing testing. Male respondents were more interested in testing compared to females. There was a strong interest in genetic research participation and notably limited privacy concerns. CONCLUSION: Although 59% of the respondents were interested in DTC genomic testing, they were not likely to be affected by them or act upon them. This raises questions about concerns relating to potential risks of DTC genomics users and users' understanding of genetic information including their awareness of privacy risks. Furthermore, the strong interest in genetic research participation signals an underexplored personal utility of genomic testing which needs to be both better understood and better harnessed. PMID- 24777116 TI - Beyond yolk-shell nanostructure: a single Au nanoparticle encapsulated in the porous shell of polymer hollow spheres with remarkably improved catalytic efficiency and recyclability. AB - Novel Au-polymer hollow hybrids having a single Au nanoparticle encapsulated in each porous polymer shell with superior catalytic efficiency and recyclability have been demonstrated. PMID- 24777117 TI - Seizure control in Unverricht-Lundborg disease: a single-centre study. AB - New antiepileptic drug (AED) options for generalised seizure types have been adopted for use as treatment for Unverricht-Lundborg disease. Whether this has led to improved seizure control or functional outcome in ULD patients remains obscure. We retrospectively identified all patients seen at Helsinki University Hospital due to Unverricht-Lundborg disease during 2003-2008 in order to determine which AED treatments had been retained for long-term use. The majority of the patients had severe functional disabilities. In the year preceding the last hospital visit, all patients (n=20) were receiving polytherapy and 14 patients had been free of tonic-clonic seizures. During follow-up, improvement in myoclonia had been recorded for the majority of patients with either add-on piracetam, topiramate, or levetiracetam, but valproate was still in use by all patients. Treatment with lamotrigine had been started and retained less often relative to other AEDs. Add-on AED treatment was often associated with significant adverse effects. Unverricht-Lundborg disease patients may benefit from add-on treatment with levetiracetam or topiramate for seizure control. Treatment of eventual comorbidities with other than AEDs is also discussed. PMID- 24777118 TI - Three-component vesicle aggregation driven by adhesion interactions between Au nanoparticles and polydopamine-coated nanotubes. AB - Large-scale and robust vesicle aggregates were obtained through molecular recognition among cell-sized polymer vesicles, carbon nanotubes and AuNPs, driven by adhesion interactions between Au and polydopamine. Vesicle fusion was effectively avoided in this three-component vesicle aggregation process. PMID- 24777119 TI - Self-assembled alkanethiol monolayers on gold surfaces: resolving the complex structure at the interface by STM. AB - The surface properties of metals and metal oxides can be modified by adding a single layer of organic molecules. A most popular route for depositing such a molecular layer is via the formation of self-assembled monolayers (SAMs). The molecules that form SAMs have a functionality which binds to the surface and the adsorption is self-regulated to terminate at exactly one single molecular layer. The very first example, which has become the most widely studied system, of SAMs on metal surfaces consists of chemisorbed alkylthiolate on gold. Despite the simplicity in the preparation of alkanethiol SAMs and the seemingly straightforward structure of such SAMs, the detailed bonding between the sulfur head group and gold is still subject to debate. Experimental and theoretical effort in the last six years has led to a much improved understanding of this classical system of SAMs. In this review, we will highlight the most recent progress in the study of the interfacial structure of alkanethiol SAMs on gold. We focus on the important phenomenon of phase transition that occurs from n propanethiol to n-butanethiol, and propose a unified structural model to explain how the (3 * 4) phase for short chain alkanethiol monolayers (methyl-, ethyl- and propylthiolate monolayers) changes into the (3 * 2?3)-rect./c(4 * 2) phase for long chain molecular monolayers. PMID- 24777120 TI - The usefulness of EPR spectroscopy in the study of compounds with metal-metal multiple bonds. AB - This Perspective reviews some of the contributions that EPR spectroscopy has made for the understanding of the bonding and electronic structure of molecular species with metal-to-metal multiple bonds. The goal is to show how useful this technique can be in (a) elucidating whether unpaired electrons reside in metal based or ligand-based molecular orbitals, (b) providing information on the metal center's total electronic spin, an aspect that offers support to its oxidation state, (c) informing about the distribution of the unpaired electrons between the metals and the organic ligand, (d) detecting molecular dynamics and phase transitions to complement X-ray studies and (e) using high-frequency, high-field EPR for studying compounds that might be EPR-silent when only commonly available spectrometers are used. A brief comparison with NMR is provided in the ESI where it is noted that for typical laboratory magnetic fields, the energy gap between resonant states in EPR is in the microwave region of the electromagnetic spectrum (GHz) while for NMR it is in the radiofrequency range (MHz). Our aim is to encourage the inorganic chemistry community and more broadly other chemists and physicists to collaborate while characterizing new paramagnetic inorganic complexes. Enough basic background is provided as ESI to allow senior-level undergraduate and graduate students to understand the simplicity as well as the power of EPR spectroscopy with a view to encourage them to use this technique in their own research activities. Finally, it should be noted that this report commemorates the fiftieth anniversary of the description in Science of the first species with a quadruple bond. PMID- 24777123 TI - A novel family of structurally stable double stranded DNA catenanes. AB - Here we describe the design, assembly and characterisation of different structurally stable and highly polyvalent DNA catenanes. We synthesized a series of different catenated DNA nanostructures, among them symmetric ones containing two 126 or 168 base-pair rings, non-symmetric ones with a 126 and a 168 base-pair ring, and a [3]catenane containing three 126 base-pair rings. Reversible and quantitative on/off switching of the mobility of the rings was demonstrated as a proof-of-concept for the employment of these catenanes as dynamic DNA nanostructures. PMID- 24777122 TI - RUNX family members are covalently modified and regulated by PIAS1-mediated sumoylation. AB - Transcription factors of the RUNX family (RUNXs), which play pivotal roles in normal development and neoplasia, are regulated by various post-translational modifications. To understand the molecular mechanisms underlying the regulation of RUNXs, we performed a large-scale functional genetic screen of a fly mutant library. The screen identified dPias (the fly ortholog of mammalian PIASs), an E3 ligase for the SUMO (small ubiquitin-like modifier) modification, as a novel genetic modifier of lz (the fly ortholog of mammalian RUNX3). Molecular biological analysis revealed that lz/RUNXs are sumoylated by dPias/PIAS1 at an evolutionarily conserved lysine residue (K372 of lz, K144 of RUNX1, K181 of RUNX2 and K148 of RUNX3). PIAS1-mediated sumoylation inhibited RUNX3 transactivation activity, and this modification was promoted by the AKT1 kinase. Importantly, PIAS1 failed to sumoylate some RUNX1 mutants associated with breast cancer. In nude mice, tumorigenicity was promoted by RUNX3 bearing a mutation in the sumoylation site, but suppressed by wild-type RUNX3. Our results suggest that RUNXs are sumoylated by PIAS1, and that this modification could play a critical role in the regulation of the tumor-suppressive activity of these proteins. PMID- 24777124 TI - Palladium-catalyzed three-component reaction of N-tosylhydrazone, norbornene and aryl halide. AB - A palladium-catalyzed three-component reaction of N-tosylhydrazone, norbornene and aryl halide has been demonstrated. In this reaction, an intermolecular Heck type reaction occurs, which is followed by the alkyl palladium carbene migratory insertion process. This transformation provides an efficient and convenient methodology for the double functionalization of norbornene with good to excellent yields. PMID- 24777121 TI - Novel symbiotic protoplasts formed by endophytic fungi explain their hidden existence, lifestyle switching, and diversity within the plant kingdom. AB - Diverse fungi live all or part of their life cycle inside plants as asymptomatic endophytes. While endophytic fungi are increasingly recognized as significant components of plant fitness, it is unclear how they interact with plant cells; why they occur throughout the fungal kingdom; and why they are associated with most fungal lifestyles. Here we evaluate the diversity of endophytic fungi that are able to form novel protoplasts called mycosomes. We found that mycosomes cultured from plants and phylogenetically diverse endophytic fungi have common morphological characteristics, express similar developmental patterns, and can revert back to the free-living walled state. Observed with electron microscopy, mycosome ontogeny within Aureobasidium pullulans may involve two organelles: double membrane-bounded promycosome organelles (PMOs) that form mycosomes, and multivesicular bodies that may form plastid-infecting vesicles. Cultured mycosomes also contain a double membrane-bounded organelle, which may be homologous to the A. pullulans PMO. The mycosome PMO is often expressed as a vacuole-like organelle, which alternatively may contain a lipoid body or a starch grain. Mycosome reversion to walled cells occurs within the PMO, and by budding from lipid or starch-containing mycosomes. Mycosomes discovered in chicken egg yolk provided a plant-independent source for analysis: they formed typical protoplast stages, contained fungal ITS sequences and reverted to walled cells, suggesting mycosome symbiosis with animals as well as plants. Our results suggest that diverse endophytic fungi express a novel protoplast phase that can explain their hidden existence, lifestyle switching, and diversity within the plant kingdom. Importantly, our findings outline "what, where, when and how", opening the way for cell and organelle-specific tests using in situ DNA hybridization and fluorescent labels. We discuss developmental, ecological and evolutionary contexts that provide a robust framework for continued tests of the mycosome phase hypothesis. PMID- 24777125 TI - Introduction. PMID- 24777126 TI - Anatomy of the hippocampal formation. AB - The hippocampus is one of several brain regions that together comprise the hippocampal formation. The hippocampal formation is a prominent C-shaped structure bulging in the floor of the temporal horn of the lateral ventricle. The hippocampus proper consists of three major subfields (CA1-CA3). The other regions that together comprise the hippocampal formation consist of the dentate gyrus, the subicular complex, and the entorhinal cortex. Based on its extrinsic connectivity, the hippocampal formation receives a vast amount of highly processed multimodal sensory information that is funneled into the hippocampal formation mainly by the entorhinal cortex. The entorhinal cortex is connected to associational neocortical areas in a reciprocal manner. Extensive hippocampal integration of sensory information is established by a largely unidirectional chain of intrinsic hippocampal projections. Our current knowledge on hippocampal connectivity and function is largely based on studies of rodents and monkeys. It still remains to be determined to which extent such neuroanatomical data of experimental animals is applicable to the human hippocampal formation. PMID- 24777127 TI - Structure and vascularization of the human hippocampus. AB - The hippocampus is a temporal brain structure belonging to the limbic lobe and is fundamentally involved in memory processing, learning, and emotions. It consists of two allocortex laminae: the gyrus dentatus and the cornu ammonis, one rolled up inside the other, creating a bulge in the temporal horn of the lateral ventricle. Arterial vascularization of the hippocampus is dependent on the collateral branches of the posterior cerebral artery and the anterior choroidal artery, forming the network of superficial hippocampal arteries that in turn lead to deep intrahippocampal arteries. Venous vascularization is provided by the intrahippocampal veins, which drain into the superficial hippocampal veins. Knowledge of anatomical organization and vascularization of the hippocampus is essential to understanding its dysfunctions and its appearance on MRI. PMID- 24777128 TI - Coordinated network activity in the hippocampus. AB - The hippocampus expresses a variety of highly organized network states which bind its individual neurons into collective modes of activity. These patterns go along with characteristic oscillations of extracellular potential known as theta, gamma, and ripple oscillations. Such network oscillations share some important features throughout the entire central nervous system of higher animals: they are restricted to a defined behavioral state, they are mostly generated by subthreshold synaptic activity, and they entrain active neurons to fire action potentials at strictly defined phases of the oscillation cycle, thereby providing a unifying 'zeitgeber' for coordinated multineuronal activity. Recent work from the hippocampus of rodents and humans has revealed how the resulting spatiotemporal patterns support the formation of neuronal assemblies which, in our present understanding, form the neuronal correlate of spatial, declarative, or episodic memories. In this review, we introduce the major types of spatiotemporal activity patterns in the hippocampus, describe the underlying neuronal mechanisms, and illustrate the concept of memory formation within oscillating networks. Research on hippocampus-dependent memory has become a key model system at the interface between cellular and cognitive neurosciences. The next step will be to translate our increasing insight into the mechanisms and systemic functions of neuronal networks into urgently needed new therapeutic strategies. PMID- 24777129 TI - What animals can teach clinicians about the hippocampus. AB - Abnormalities in hippocampal structure and function have been reported in a number of human neuropathological and neurodevelopmental disorders, including Alzheimer's disease, autism spectrum disorders, Down syndrome, epilepsy, and schizophrenia. Given the complexity of these disorders, animal studies are invaluable and remain to date irreplaceable, providing fundamental knowledge regarding the basic mechanisms underlying normal and pathological human brain structure and function. However, there is a prominent ill-conceived view in current research that scientists should be restricted to using animal models of human diseases that can lead to results applicable to humans within a few years. Although there is no doubt that translational studies of this kind are important and necessary, limiting animal studies to applicable questions is counterproductive and will ultimately lead to a lack of knowledge and an inability to address human health problems. Here, we discuss findings regarding the normal postnatal development of the monkey hippocampal formation, which provide an essential framework to consider the etiologies of different neuropathological disorders affecting human hippocampal structure and function. We focus on studies of gene expression in distinct hippocampal regions that shed light on some basic mechanisms that might contribute to the etiology of schizophrenia. We argue that researchers, as well as clinicians, should not consider the use of animals in research only as 'animal models' of human diseases, as they will continue to need and benefit from a better understanding of the normal structure and functions of the hippocampus in 'model animals'. PMID- 24777130 TI - Memory function and the hippocampus. AB - There has been a long tradition in memory research of adopting the view of a vital role of the medial temporal lobe and especially the hippocampus in declarative memory. Despite the broad support for this notion, there is an ongoing debate about what computations are performed by the different substructures. The present chapter summarizes several accounts of hippocampal functions in terms of the cognitive processes subserved by these structures, the information processed, and the underlying neural operations. Firstly, the value of the distinction between recollection and familiarity for the understanding of the role the hippocampus plays in memory is discussed. Then multiple lines of evidence for the role of the hippocampus in memory are considered. Cumulating evidence suggests that the hippocampus fosters the binding of disparate cortical representations of items and their spatiotemporal context into a coherent representation by means of a sparse conjunctive neural coding. This association of item and context will then lead to the phenomenological experience of recollection. In contrast, surrounding cortical areas have broader neural coding that provide a scalar signal of the similarity between two inputs (e.g. between the encoding and the retrieval). By this they form the basis of a feeling of familiarity, but also might encode the commonalities between these different inputs. However, a more complete picture of the importance of the hippocampus for declarative memories can only be drawn when the interactions of the medial temporal lobe with other brain areas are also taken into account. PMID- 24777131 TI - Neuropsychological measures of hippocampal function. AB - The role of the medial temporal lobe, specifically the hippocampus, in learning and memory has been consistently demonstrated over the past years and has led to the identification of the hippocampus as a target imaging marker for several neurological and psychiatric disorders. Hippocampal dysfunctions and smaller hippocampal volumes have been reported as characteristic for these disorders, and hippocampal asymmetry has been shown to be associated with memory deficits in older adults. These findings underline the importance of screenings for memory functions using neuropsychological cognitive test batteries within the clinical context. To the best of our knowledge, there has been no comprehensive review that has presented neuropsychological tests related to the hippocampus in detail. However, we did not aim to provide a complete overview of neuropsychological tests related to hippocampal function, which would fail in the light of the widespread area. This chapter focuses on neuropsychological tests that assess cognitive functions that depend on the hippocampus in a state-of-the-art fashion and additionally provide the link to several disorders for which hippocampal abnormalities are a common characteristic. PMID- 24777132 TI - Conventional and diffusion-weighted MRI of the hippocampus. AB - The human hippocampus is a highly complex structure located on the medial surface of the cerebral hemispheres as a part of the intralimbic gyrus. For clinical purposes, in addition to routine transverse MRI slices, acquisitions parallel and perpendicular to the long axis of the hippocampus need to be performed to fully appreciate its curved anatomy. Clinicians should be acquainted with the normal appearance of the hippocampus regarding size, shape, symmetry, and signal as well as with the width and form of the cerebrospinal fluid spaces surrounding the hippocampus to be able to recognize abnormalities. The human hippocampus can be affected in a variety of very different acute or chronic neurological diseases, such as stroke and certain forms of encephalitis or epilepsy and dementia. Many of these pathologies are associated with distinct lesion patterns on conventional MRI. In hippocampal sclerosis, the typical imaging features - T2 hyperintensity, atrophy on T1-weighted images, and disturbed internal structures of the hippocampus - can be reliably diagnosed by visual analysis. Several visual rating scales exist for the evaluation of medial temporal lobe atrophy for the assessment of patients with cognitive disturbances; however, quantitative MRI based volumetric analysis is increasingly being applied in research as well as clinical studies. In acute neurological disorders, diffusion-weighted imaging has the ability to demonstrate even minute and transient hyperintense hippocampal lesions. On the basis of distinct lesions patterns, diffusion-weighted MRI can provide additional diagnostic information that may facilitate and support a final diagnosis, especially in those cases in which clinical symptoms are inconclusive. PMID- 24777133 TI - Functional MRI studies of the hippocampus. AB - Developments in tasks and imaging techniques applied over the last decades have yielded substantial support for the hypothesized role of the hippocampus in mnemonic processes. Human imaging research has now moved on to disentangle the contributions of the different hippocampal subregions and adjacent cortices, so as to bridge the gap between rodent and human data. Besides the importance of such studies for basic research, the investigation of hippocampal (dys)function has clinical relevance for diseases ranging from neurological disorders such as Alzheimer's disease or epilepsy to mental disorders such as schizophrenia or anxiety disorders. So far, most of the present review articles and books about the hippocampus and its functions focus on traditional declarative memory paradigms and 'encoding versus retrieval'. In this chapter we concentrate on a less travelled, but not less important, route concerning the role of the hippocampus in a well-established associative learning (encoding) paradigm: pavlovian fear conditioning. Fear conditioning is hypothesized to model aversive associative learning on a nonpathological level and is further assumed to recruit the same networks that are relevant for anxiety disorders, with the hippocampus being specific for contextual fear conditioning. We highlight the findings in humans by addressing its role in mediating spatial and temporal aspects of a context, involving different kinds of a fear-conditioning procedure (delay vs. trace conditioning), and its role in extinction, both from a theoretical and clinical perspective. PMID- 24777134 TI - The hippocampus in neurodegenerative disease. AB - AD is the commonest neurodegenerative disorder resulting ultimately in dementia, a stage during which there is a loss of previously acquired intellectual skill and independent occupational and social function. Neurodegenerative changes within the hippocampus and an extended neuronal network involving the medial temporal and medial parietal lobe result in the archetypal memory impairment seen in Alzheimer's disease (AD). As attention focuses increasingly on early diagnosis and treatment of dementia, this understanding of the hippocampal involvement in AD has helped to develop diagnostic tools for use in early disease. However, hippocampal damage is also a common feature among non-AD neurodegenerative dementias. Neuroimaging techniques, in conjunction with behavioral and pathological techniques, can be used to determine the involvement of the hippocampus in AD and other neurodegenerative diseases. PMID- 24777135 TI - Stress, memory, and the hippocampus. AB - Stress hormones, i.e. cortisol in human and cortisone in rodents, influence a wide range of cognitive functions, including hippocampus-based declarative memory performance. Cortisol enhances memory consolidation, but impairs memory retrieval. In this context glucocorticoid receptor sensitivity and hippocampal integrity play an important role. This review integrates findings on the relationships between the hypothalamus-pituitary-adrenal (HPA) axis, one of the main coordinators of the stress response, hippocampus, and memory. Findings obtained in healthy participants will be compared with selected mental disorders, including major depressive disorder (MDD), posttraumatic stress disorder (PTSD), and borderline personality disorder (BPD). These disorders are characterized by alterations of the HPA axis and hippocampal dysfunctions. Interestingly, the acute effects of stress hormones on memory in psychiatric patients are different from those found in healthy humans. While cortisol administration has failed to affect memory retrieval in patients with MDD, patients with PTSD and BPD have been found to show enhanced rather than impaired memory retrieval after hydrocortisone. This indicates an altered sensitivity to stress hormones in these mental disorders. PMID- 24777136 TI - Epilepsy and the hippocampus. AB - The association between epilepsy and the hippocampus is well known and important. Mesial temporal epilepsy with hippocampal sclerosis is a syndromic diagnostic entity and indeed a quite common one. There are different theories on the pathophysiological pathways, as the hippocampus is often involved in seizures, even if they are not generated there. Whether hippocampal sclerosis is a cause or the effect of seizures is a subject of ongoing debate, but the predominant opinion is that seizures probably do not cause relevant hippocampal volume loss in the mature brain. A diagnosis of epilepsy with hippocampal sclerosis is made based on typical semiological signs and symptoms, interictal and ictal EEG findings, cerebral imaging, and neuropsychological testing. Antiepileptic medication is indicated as a first-line treatment. Should the epilepsy prove to be medically intractable, which is commonly the case in these patients, an early evaluation regarding epilepsy surgery must be performed. Different epilepsy surgery techniques are available, from minimal ones like the selective amygdalohippocampectomy to more extensive ones like additional temporal lobe resection. Postoperative results concerning seizures and neuropsychological outcomes are very encouraging and depend on various predictive factors. Alternative procedures like stereotactic radiofrequency amygdalohippocampectomy and hippocampal stimulation are currently being assessed, partly with very promising results. PMID- 24777137 TI - Transient global amnesia. AB - Transient global amnesia (TGA) is a sudden and severe anterograde memory disturbance accompanied by various degrees of retrograde amnesia and sometimes executive dysfunction. TGA affects elderly individuals and men and women equally. During the episode, patients cannot recall novel episodic information and therefore repeatedly ask the same questions. They are not fully oriented to space and time. Diagnostic criteria first established in 1985, and elaborated in 1990, demand that there is no clouding of consciousness, other impairments of cognition, or a history of epilepsy or head trauma. An episode of TGA resolves within 24 h leaving a memory gap for the length of the attack. While in rare cases TGA might happen repeatedly, it mostly occurs as a single attack. TGA is considered a benign disorder as memory deficits resolve completely and do not lead to long-term sequelae. In up to 90% of reported TGA cases, a precipitating event - mainly described as physical or emotional stress - is present. The cause of TGA has been a matter of long-standing debate among researchers. In search of an answer, several possible causes (ischemia, migraine, epileptic seizures, or, more recently, a disturbance of venous hemodynamics) have been hypothesized. However, to date there is no scientific proof of any of these mechanisms. By using diffusion-weighted MRI 24-48 h after a TGA episode, small dot-like lesions have been detected in the hippocampus. This has led to the implication that the selective vulnerability of CA1 neurons to metabolic stress might play a role in the pathophysiology of TGA. PMID- 24777138 TI - Hippocampal stroke. AB - The first to link disturbance of memory and lesions of the medial temporal lobe was the Russian neurologist von Bechterew, who in 1989 presented the brain of a 60-year-old man who had suffered from severe amnesia. Autopsy showed bilateral damage of the medial temporal lobe. Several following postmortem case studies confirmed the association between permanent amnesia and bitemporal stroke. Reports of transient memory deficits in unilateral stroke in combination with other neurological and neuropsychological deficits followed. With the advent of brain imaging, persistent or transient amnesia as the sole or primary manifestation of acute - mostly left-sided - hippocampal stroke was described. With the use of modern MRI techniques the identification of typical ischemic stroke lesion patterns affecting the hippocampus has become possible. Although overt cognitive deficits in unilateral hippocampal stroke seem to be rare, a careful neuropsychological examination might be necessary to detect resulting neuropsychological deficits including disturbances of verbal and nonverbal episodic long-term memory and spatial orientation. PMID- 24777139 TI - Preface. Hippocampus from a neurologist's point of view. PMID- 24777140 TI - Faster growth of the major prokaryotic versus eukaryotic CO2 fixers in the oligotrophic ocean. AB - Because maintenance of non-scalable cellular components--membranes and chromosomes--requires an increasing fraction of energy as cell size decreases, miniaturization comes at a considerable energetic cost for a phytoplanktonic cell. Consequently, if eukaryotes can use their superior energetic resources to acquire nutrients with more or even similar efficiency compared with prokaryotes, larger unicellular eukaryotes should be able to achieve higher growth rates than smaller cyanobacteria. Here, to test this hypothesis, we directly compare the intrinsic growth rates of phototrophic prokaryotes and eukaryotes from the equatorial to temperate South Atlantic using an original flow cytometric (14)CO2 tracer approach. At the ocean basin scale, cyanobacteria double their biomass twice as frequently as the picoeukaryotes indicating that the prokaryotes are faster growing CO2 fixers, better adapted to phototrophic living in the oligotrophic open ocean-the most extensive biome on Earth. PMID- 24777141 TI - MTERF1 regulates the oxidative phosphorylation activity and cell proliferation in HeLa cells. AB - The mitochondrial transcription termination factor (MTERF) family is a group of highly conserved DNA-binding proteins composed of four key members, MTERF1-4. To date, several studies have investigated the binding sites of MTERF1 on mitochondrial genome and the regulation of mitochondrial gene transcription, but the more intricate connection between mitochondrial genes transcription regulation, mitochondrial oxidative phosphorylation (OXPHOS), and cell proliferation is still poorly understood. In this study, we constructed over expression and knockdown vectors of MTERF1 that were transfected into HeLa cells to investigate the functions of MTERF1. Results showed that although MTERF1 is a positive regulatory factor of mitochondrial genes transcription, it had no significant effect on the replication of mitochondrial DNA. Over-expression of MTERF1 increased mitochondrial oxidative phosphorylation activity and promoted ATP synthesis, cyclin D1 expression, and cell proliferation, while its knockdown inhibited ATP synthesis, decreased cyclin D1 expression, and slowed the cell growth. These results suggested that MTERF1 may promote cell proliferation by regulating oxidative phosphorylation activity in HeLa cells. Ultimately, these findings create a foundation for further and more conclusive studies on the physiological functions of MTERF family by providing novel insights into the potential mechanisms underlying cell proliferation regulation. PMID- 24777142 TI - Parental predictors of children's animal abuse: findings from a national and intergenerational sample. AB - This study examines the intra- and intergenerational links between intimate partner violence (IPV) and animal abuse by analyzing a national, longitudinal, and multigenerational sample of 1,614 individuals collected by the National Youth Survey Family Study from 1990 to 2004. Using multilevel random-intercept regression modeling, parents' own history of animal abuse is predictive of their later involvement in IPV perpetration and victimization, net of important controls. In turn, parents' IPV violent perpetration (but not violent victimization) is predictive of their children's history of animal abuse-measured 14 years later. Intergenerational continuity of animal abuse, however, is not significant. Implications of these findings are discussed, as are the study's limitations, and future research directions. PMID- 24777143 TI - Lithium reduces the effects of rotenone-induced complex I dysfunction on DNA methylation and hydroxymethylation in rat cortical primary neurons. AB - RATIONALE: Mitochondrial complex I dysfunction and alterations in DNA methylation levels are consistently reported in bipolar disorder (BD) and are regulated by lithium. One of the mechanisms by which lithium may exert its effects in BD is by improving mitochondrial complex I function. Therefore, we examined whether complex I dysfunction induces methylation and hydroxymethylation of DNA and whether lithium alters these effects in rat primary cortical neurons. METHODS: Rotenone was used to induce mitochondrial complex I dysfunction. Cell viability was measured by MTT assay, and ATP levels were assessed by Cell-Titer-Glo. Complex I activity was measured using an ELISA-based assay. Apoptosis, DNA methylation, and hydroxymethylation levels were measured by immunocytochemistry. RESULTS: Rotenone decreased complex I activity and ATP production, but increased cell death and apoptosis. Rotenone treatment increased levels of 5-methylcytosine (5mc) and hydroxymethylcytosine (5hmc), suggesting a possible association between complex I dysfunction and DNA alterations. Lithium prevented rotenone-induced changes in mitochondrial complex I function, cell death and changes to DNA methylation and hydroxymethylation. CONCLUSIONS: These findings suggest that decreased mitochondrial complex I activity may increase DNA methylation and hydroxymethylation in rat primary cortical neurons and that lithium may prevent these effects. PMID- 24777144 TI - Preventing catheter-related bacteremia with taurolidine-citrate catheter locks: a systematic review and meta-analysis. AB - BACKGROUND: Preliminary evidence from some studies suggests that taurolidine citrate locks decrease catheter-related bacteremia (CRB), which is a major cause of morbidity and mortality in patients using intravascular catheters. No previous study has sought to summarize existing evidence on the use of taurolidine-citrate locks. A systematic review and meta-analysis were undertaken to determine whether taurolidine-citrate was more effective than heparin in the prevention of CRB. METHODS: The major English (PubMed, EBSCO, Web of Science and OVID) and Chinese (CBM, CNKI, VIP and Wanfang Data) healthcare databases were searched for randomized controlled trials comparing the efficacy and safety of taurolidine citrate lock solution (TCLS) and heparin lock solution in the prevention of CRB. RESULTS: Three studies involving 236 patients with a total of 34,984 catheter days were included. The use of TCLS significantly decreased the risk of CRB (relative risk = 0.47, 95% CI: 0.25-0.89) and Gram-negative bacterial infection. There was no significant difference in Gram-positive infections and exit-site infections. CONCLUSIONS: Catheter locking with TCLS reduced the risk of CRB and Gram-negative bacterial infection. Adverse events include thrombotic events. PMID- 24777145 TI - Thyroglossal duct cyst cancer most likely arises from a thyroid gland remnant. AB - Thyroglossal duct cancer is a rare entity, occurring in 1.5 % of all thyroglossal duct cysts (TDC). A definitive consensus about its neoplastic origin has not been established as two contrasting theories exist, one proposing an origin in extra thyroid remnants and the other a metastatic localization of a primary thyroid cancer. We compare morphological and molecular characteristics of both thyroglossal and thyroid carcinomas in a case series from our institute. We evaluated histology of 80 TDC. In 12 cases, prior cytological evaluation had been performed by liquid-based cytology (LBC). The BRAF gene was examined for mutations, and the histology of both thyroglossal duct and synchronous thyroid carcinoma was reevaluated. In 9 out of 80 (11 %) TDC cases, a papillary thyroid cancer (PTC) was diagnosed. In five out of nine (56 %) thyroglossal carcinomas, a synchronous thyroid cancer was diagnosed: 3 PTC and 2 follicular variant PTC (FVPC). In five thyroglossal carcinomas, mutated BRAF (V600E) was found, three in PTC and in thyroglossal as well as in the synchronous tumor in the thyroid. All the patients are in a disease-free status and still alive. Our results suggest that the majority of thyroglossal carcinomas most likely develop as a primary malignancy from a thyroid remnant. Neither the presence of V600E BRAF mutations nor that of a well-differentiated thyroid carcinoma changed the outcome or disease-free survival. We suggest that a diagnosis of thyroglossal carcinoma should be followed by a detailed evaluation of the thyroid gland. In the absence of clinical and radiological thyroid alterations, follow-up as for thyroid cancer is the correct management. PMID- 24777147 TI - Hemangiopericytoma of the parapharyngeal space: a diagnostic challenge. AB - Parapharyngeal space tumors are known for having a difficult approach, misleading diagnosis and for representing a treatment challenge. Hemangiopericytomas account for less than 1% of all vascular neoplasms and 3% of all soft tissue sarcomas. Only 14 cases have been reported in the worldwide literature in this location. We present a case of a 44-year-old male who was referred for evaluation. A CT scan and MRI showed a large parapharyngeal mass of a possible salivary gland origin. The patient underwent a lateral cervicotomy associated with a transparotid transmandibular approach, obtaining a vimentin-positive immunostaining tumor defining the diagnosis. The accurate management and prognosis of this type of neoplasm are provided by the definite diagnosis obtained by a correct histopathologic assessment. A high clinical suspicion is essential. PMID- 24777148 TI - Chronic periodic lateralised epileptic discharges and anti-N-methyl-D-aspartate receptor antibodies. AB - Periodic lateralised epileptiform discharges (PLEDs) are uncommon transient electroencephalographic findings accompanied by acute brain lesions. A small proportion of PLEDs persist for more than three months and are called "chronic" PLEDs, the pathophysiology of which is still debated. Herein, we report a man with right hemispheric PLEDs which lasted for more than 14 months and mild left hemispatial neglect after he experienced status epilepticus. Although MRI was normal, positron emission tomography revealed right temporo-parieto-occipital hypometabolism, which coincided with the source area of PLEDs estimated by magnetoencephalography. In addition, levels of anti-N-methyl-D-aspartate (NMDA) receptor antibodies and granzyme B were found to be high in the cerebrospinal fluid. Following two courses of steroid pulse therapy, the patient's left spatial neglect improved and the PLEDs were partially resolved. These findings suggest that the chronic PLEDs present in this case were an interictal phenomenon and that their pathophysiology involved autoimmune processes. PMID- 24777149 TI - Potential celiac children: 9-year follow-up on a gluten-containing diet. AB - OBJECTIVES: Potential celiac disease (CD) is defined by the presence of serum anti-tissue-transglutaminase (anti-TG2) antibodies and normal duodenal mucosa. The major clinical problem is the management of asymptomatic patients and how to predict the development of villous atrophy. This prospective longitudinal cohort study describes the natural history of potential CD up to 9 years and explores risk factors associated with the development of mucosal damage. METHODS: Two hundred and ten potential CD children were eligible for the study; 175/210 asymptomatic children were left on a gluten-containing diet. Antibodies and clinical symptoms were checked every 6 months, and a small bowel biopsy was taken every 2 years to evaluate histological, immunohistochemical, and anti-TG2 deposits. Patients were genotyped for HLA and a set of non-HLA CD-associated genes. RESULTS: Forty-three percent of patients showed persistently elevated anti TG2 level, 20% became negative during follow-up, and 37% showed a fluctuant anti TG2 course with transiently negative values. At 3 years of follow-up, 86% of cases remained potential; 73 and 67% still had normal duodenal architecture at 6 and 9 years, respectively. Male sex, slight mucosal inflammation at time 0, and a peculiar genetic profile delineate a cohort of individuals who were prone to develop mucosal damage during time. CONCLUSIONS: A sizeable proportion of asymptomatic potential celiac patients showed fluctuation or negativization of antibody production, and many of these, with persistently positive anti-TG2, did not develop mucosal damage after 9 years of follow-up. Celiac population is a multivariate aggregate of individuals with different genetic and phenotypic profiles. Caution is required before prescribing a gluten-free diet for life to asymptomatic individuals with potential CD. PMID- 24777150 TI - Effects of intravenous and oral esomeprazole in the prevention of recurrent bleeding from peptic ulcers after endoscopic therapy. AB - OBJECTIVES: The use of intravenous proton-pump inhibitors (PPIs) has shown to reduce recurrent bleeding and improve patient outcome after endoscopic hemostasis on patients with peptic ulcer. However, the efficacy of oral PPI is uncertain. Studies from Asia indicated that even oral PPI can achieve the same therapeutic effect. This study is designed to compare the efficacy of high-dose intravenous PPI to oral PPI in preventing recurrent bleeding after endoscopic hemostasis. METHODS: This is a single-center, randomized-controlled, double-blind, and double dummy study. Patients had Forrest IA/IB or IIA/IIB peptic ulcer bleeding and received endoscopic hemostasis before recruitment into the study. They were randomized to receive either (i) esomeprazole IV bolus at a dose of 80 mg plus infusion at 8 mg/h for 72 h and oral placebo every 12 h (IVP group), or (ii) IV placebo bolus plus infusion for 72 h and high-dose oral esomeprazole at a dose of 40 mg every 12 h (ORP group). Patients were followed up for 30 days after index bleeding. The primary end point was defined as the 30-day recurrent bleeding after successful endoscopic hemostasis. RESULTS: A total of 118 patients were randomized to the IVP group and 126 to the ORP group in this study. In all, 39.8% in the IVP and 42.9% in the ORP group used non-steroidal anti-inflammatory drug and/or aspirin before bleeding. In the IVP group (vs. ORP), Forrest IA represented 1.7% (5.6%), IB 41.5% (38.1%), IIA 52.5% (50.8%), and IIB 4.2% (5.6%). Recurrent bleeding in 30 days was reported in 7.7% of patients in the IVP group and 6.4% of patients in the ORP group, and the difference of recurrent bleeding was -1.3% (95% CI: -7.7%, 5.1%). There was no difference in blood transfusion, repeated endoscopic therapy, and hospital stay between the two groups. CONCLUSIONS: High-dose oral esomeprazole at 40 mg BID may be considered as a useful alternative to IV bolus plus infusion of esomeprazole in the management of ulcer bleeding in patients who are not candidates for high-dose IV infusion. However, as this study was stopped prematurely and was not designed as an equivalency trial, a much larger study would be necessary to document whether there is equivalency or non-inferiority of the two treatments in a heterogeneous patient population. PMID- 24777151 TI - Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. AB - OBJECTIVES: There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use. METHODS: MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case-control, and cross sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/- NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment. RESULTS: Fifteen case-control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case-control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42). CONCLUSIONS: SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has previously been estimated. This risk is significantly elevated when SSRI medications are used in combination with NSAIDs, and physicians prescribing these medications together should exercise caution and discuss this risk with patients. PMID- 24777152 TI - Persistence of cognitive impairment after resolution of overt hepatic encephalopathy. AB - OBJECTIVES: Hepatic encephalopathy (HE) represents a spectrum of neurocognitive impairment seen in cirrhotic patients and is considered to be fully reversible with treatment; however, recent evidence suggests otherwise. This longitudinal study was carried out to evaluate the persistence of cognitive impairment in cirrhotics with prior overt HE (OHE) episode despite treatment. METHODS: Of the 213 patients screened, 107 patients who met the eligibility criteria were enrolled and 102 patients completed the study (52 patients without prior OHE episode and 50 patients with prior OHE). All patients underwent psychometric hepatic encephalopathy score (PHES) evaluation at three separate visits (day 1, day 3, and between 30 and 60 days). A one-point improvement in PHES between the first and second evaluation was considered as a measure of learning. RESULTS: Patients with a previous OHE episode showed learning impairment in PHES on repetition on day 3 (P=0.084), whereas patients without a previous OHE episode demonstrated learning effect (P<0.0001) irrespective of whether they had minimal HE (MHE) or not. Univariate analysis demonstrated that Child-Turcotte-Pugh score, lactulose and/or rifaximin therapy, the presence of MHE, and a previous OHE episode were associated with learning impairment. Multivariate analysis demonstrated that only the presence of a previous episode of OHE (adjusted odds ratio 38.398; 95% confidence interval 9.192-160.4; P<0.0001) significantly affected learning. CONCLUSIONS: This study conclusively demonstrated learning impairment in cirrhotic patients with a previous episode of OHE despite normal mental status. Improvement in PHES on repetition may be a measure of learning. PMID- 24777153 TI - Detailed analysis of pro-apoptotic signaling and metabolic adaptation triggered by a N-heterocyclic carbene-gold(I) complex. AB - Due to their broad spectrum of biological activity and antiproliferative effect on different human cancer cell lines, gold compounds have been in the focus of drug research for many years. Gold(I)-N-heterocyclic carbene complexes are of particular interest, because of their stability, ease of derivatization and clear cytotoxicity in cancer cells. To obtain a more detailed view of the molecular mechanisms underlying their cellular activity, we used a novel gold(I)-N heterocyclic carbene complex, [triphenylphosphane-(1,3-diethyl-5-methoxy benzylimidazol-2-ylidene)]gold(I) iodide and investigated changes in cellular signaling pathways using quantitative signal transduction protein microarray analysis. We also analyzed changes in cell metabolism in a time-dependent manner by on-line metabolic measurements and used isolated mitochondria to elucidate the direct effects on this cell organelle. We found strong cytotoxic effects in cancer cells, accompanied by an immediate and irreversible loss of mitochondrial respiration as well as by a crucial imbalance of the intracellular redox state, resulting in apoptotic cell death. ELISA microarray analysis of signal transduction pathways revealed a time-dependent up-regulation of pro-apoptotic signaling proteins, e.g. p38 and JNK, whereas pro-survival signals that are directly linked to the thioredoxin system were down-regulated, which pinpoints to thioredoxin reductase as a central target of the compound. Further results suggest that DNA is an indirect target of the compound. Based on our findings, we outline a signaling model for the molecular mechanism underlying the antiproliferative activity of the gold(I)-N-heterocyclic carbene complex investigated, which provides a good general model for the known pattern of cell death induced by this class of substances. PMID- 24777154 TI - Size-selected gold clusters on porous titania as the most "gold-efficient" heterogeneous catalysts. AB - Research on homogeneous and heterogeneous catalysis is indeed convergent and finds subnanometric particles to be at the heart of catalytically active species. Here, monodisperse gold clusters are deposited from the gas phase onto porous titania generating well-defined model systems and the resulting composite materials exhibit a sharp size-dependency on the number of gold atoms per cluster and exceptionally high-turnovers toward the bromination of 1,4-dimethoxybenzene are observed. This indicates that the deliberate generation of active centres is of utmost importance for the creation of the most "gold-efficient" catalysts. PMID- 24777155 TI - Human gingiva-derived mesenchymal stromal cells contribute to periodontal regeneration in beagle dogs. AB - Gingiva-derived mesenchymal stromal cells (GMSCs) have been considered as a promising alternative strategy for periodontal regeneration based on their potential for multilineage differentiation in vitro and the ability to form new bone in vivo. In order to investigate the capacity of GMSCs for periodontal regeneration and the fate of GMSCs during periodontal tissue repair, enhanced green fluorescent protein-labeled GMSCs were transplanted into class III furcation defects created in beagle dogs. The results showed that the transplanted GMSCs significantly enhanced the regeneration of the damaged periodontal tissue, including the alveolar bone, cementum and functional periodontal ligament (PDL). Moreover, GMSCs were able to differentiate into osteoblasts, cementoblasts and PDL fibroblasts in vivo. These findings indicate that GMSCs represent a novel cell source for periodontal tissue reconstruction. PMID- 24777156 TI - On the relationship between the indirectly measured attitude towards beer and beer consumption: the role of attitude accessibility. AB - Although some studies have demonstrated that the indirectly measured attitude towards alcohol is related to alcohol use, this relationship has not always been confirmed. In the current study, we attempted to shed light on this issue by investigating whether the predictive validity of an indirect attitude measure is dependent upon attitude accessibility. In a sample of 88 students, the picture picture naming task, an adaptation of the affective priming paradigm, was used to measure the automatically activated attitude towards beer. Attitude accessibility was measured using a speeded evaluative categorization task. Behavioral measures were the amount of beer poured and drunk during a bogus taste test and the choice between a bottle of beer or water at the end of the experiment. In line with our hypothesis, the indirectly measured attitude towards beer predicted behavior during the taste test only when it was highly accessible. In contrast, this attitude was related to choice behavior irrespective of attitude accessibility. This study confirms that indirect attitude measures can be valuable predictors of alcohol-related behavior, but that it is sometimes necessary to take attitude accessibility into account. PMID- 24777158 TI - Dehydration affects spinal cord cross-sectional area measurement on MRI in healthy subjects. AB - STUDY DESIGN: This was a prospective cohort observational study. OBJECTIVE: To determine the effect of dehydration and rehydration on spinal cord cross sectional area (CSA) measurement on magnetic resonance imaging (MRI). SETTING: MRI Research Centre, University of British Columbia, Canada. METHODS: Ten healthy subjects (aged 21-32 years) were scanned on a 3T MRI scanner at four time points: (1) baseline, (2) rescan after 1 h, (3) the next day after fasting for a minimum of 14 h and (4) after rehydration with 1.5 l of water over the course of 1 h. Two independent, established semi-automatic CSA measurement techniques (one based on two-dimensional (2D) edge detection, the other on three-dimensional (3D) surface fitting) were applied to a 3D T1-weighted scan of each subject at each time point, with the operator blinded to scan order. The percentage change in CSA from baseline to each subsequent time point was calculated. One-tailed paired t-tests were used to assess the significance of the changes from baseline. RESULTS: A decrease in CSA following dehydration was detected by both measurement methods, with a mean change of -0.654% (s.d.=0.778, P<0.05) and -0.650% (s.d.=1.071, P<0.05) for the first and second methods, respectively. CONCLUSION: Dehydration can confound CSA measurements on MRI. The magnitude of the effect is significant relative to short-term pathological changes that have been observed in diseases such as multiple sclerosis. PMID- 24777157 TI - Reducing process barriers in acute hospital for spinal cord damage patients needing spinal rehabilitation unit admission. AB - STUDY DESIGN: Prospective open cohort case series. OBJECTIVES: To identify opportunities for improvement by recording duration of key processes from acute hospital admission until spinal rehabilitation unit (SRU) admission. SETTING: SRU, Victoria, Australia. METHODS: Consecutive referrals of patients with recent spinal cord damage had prospective documentation of the key clinical and demographic characteristics and duration (days) of the following sequential discrete processes: acute hospital admission until referral to SRU, referral until SRU assessment, SRU assessment until ready for transfer to SRU and ready for transfer until SRU admission. RESULTS: A total of 347 patients were referred with median age (interquartile range (IQR)) of 65 (52-76) years. Most patients were male (n=203, 58.5%), had paraplegia (n=267, 77%) and an aetiology due to spinal cord myelopathy (n=280, 80.7%). There was a median of 12 days (IQR 6-20) from acute hospital admission until referral, a median of 1 day (IQR 0-2) from referral till assessment, a median of 0 (IQR 0-3.5) days from assessment till deemed ready and a median of 7 (IQR 2-20) days from deemed ready until transfer to SRU. Overall, patients spent 34.2% (4951/14 478 days) of their acute hospital length of stay waiting for a SRU bed. CONCLUSIONS: There are opportunities to improve the efficiency of the acute hospital journey for patients referred to a SRU. The biggest opportunities exist for reducing the time from acute hospital admission till referral to SRU and the time from deemed ready for transfer to SRU till admission. PMID- 24777159 TI - The effects of steroids on the incidence of gastrointestinal haemorrhage after spinal cord injury: a case-controlled study. PMID- 24777160 TI - Risk factors predicting upper urinary tract deterioration in patients with spinal cord injury: a prospective study. AB - STUDY DESIGN: A prospective study. OBJECTIVES: To investigate the risk factors predicting upper urinary tract (UUT) deterioration in patients with spinal cord injury (SCI). SETTING: Beijing, China. METHODS: We reviewed the medical records and UUT imaging studies of 112 patients, with a mean follow-up of 2 years. Variables evaluated for possible influence on UUTs included patient age, gender and educational background; injury level and completeness; bladder management method; and the presence of adverse outcomes such as recurrent urinary tract infections and bladder stones. Video urodynamic data were also reviewed. Total renal function was assessed by serum creatinine. UUT abnormalities were assessed by renal ultrasound or magnetic resonance imaging. RESULTS: Lumbosacral spinal cord lesions likely contribute to UUT deterioration. UUT abnormalities were present in 23 patients (65.7%) in a spontaneous voiding group, 10 patients (20%) in a clean intermittent catheterization group, 15 patients (78.9%) in an indwelling urethral catheterization group and 7 patients (87.5%) in a suprapubic Foley catheterization group (P<0.001). When dividing bladder management method into two groups, catheter-free (spontaneous and intermittent voiding) and indwelling catheter (urethral and suprapubic catheterization), there was UUT dysfunction in 33 patients (38.3%) and 22 patients (81.5%), respectively (P<0.001). CONCLUSIONS: Lumbosacral SCI and chronic indwelling urethral and suprapubic catheterization were predictors of UUT deterioration. PMID- 24777161 TI - Gunshot injuries in the spine. AB - STUDY DESIGN: Review article. OBJECTIVES: To review the literature regarding treatment approaches in cases of gunshot wounds (GSWs) affecting the spine. SETTING: Brazil. METHODS: Narrative review of medical literature. RESULTS: GSWs are an increasing cause of morbidity and mortality. Most patients with spinal GSW have complete neurological deficit. The injury is more common in young men and is frequently immobilizing. The initial approach should follow advanced trauma life support, and broad-spectrum antibiotic therapy should be initiated immediately, especially in patients with perforation of the gastrointestinal tract. The indications for surgery in spinal GSW are deterioration of the neurologic condition in a patient with incomplete neurological deficit, the presence of liquor fistula, spinal instability, intoxication by the metal from the bullet or risk of bullet migration. CONCLUSION: Surgical treatment is associated with a higher complication rate than conservative treatment. Therefore, the surgeon must know the treatment limitations and recognize patients who would truly benefit from surgery. PMID- 24777162 TI - Adaptation and validation of the Spanish version of the Spinal Cord Lesion related Coping Strategies Questionnaire (SCL CSQ-S). AB - STUDY DESIGN: Cross-sectional validation study. OBJECTIVES: To adapt the Spinal Cord Lesion-related Coping Strategies Questionnaire into the Spanish language (SCL CSQ-S) and to examine the relationship between coping strategies, global quality of life and psychological adaptation. SETTING: Data were collected through individuals with spinal cord injury (SCI) now living in the community who completed their routine follow-up assessment at the Institute Guttmann in Barcelona, Spain. METHODS: Forward and backward translation into Spanish of the English version of the questionnaire. Questionnaires of global Quality of Life, Community Integration, Coping, Depression, Anxiety and Functional Independence were administered to 349 adults with paraplegia and 162 adults with tetraplegia. Statistical analysis included confirmatory factor analysis and regression analysis. RESULTS: The factorial structure of the questionnaire was partly verified. The original correlated, three-factor model sufficiently fit the data obtained in this study: chi(2)(48)=109.46; P<0.001; Comparative Fit Index=0.96; Tucker-Lewis Index=0.96; Root Mean Square Error of Approximation=0.050 (0.038 0.062); Akaike information criterion=13.46. Items were found to be good indicators of their respective latent factors, showing adequate factorial charge ranges (between 0.41 and 0.75). The reliability coefficient (Cronbach's alpha) for the Acceptance subscale was 0.74, for Social reliance 0.76 and for Fighting spirit 0.69. Coping strategies as measured by SCL-CSQ-S contributed to the prediction of outcomes related to adaptation to disability. CONCLUSION: The results of the study show some evidence for the robustness of the structure of SCL CSQ-S and show that the Spanish version of the questionnaire largely replicate previous results. Coping strategies, especially Acceptance, are related to adaptation to injury. PMID- 24777163 TI - Central motor and sensory conduction in patients with hepatic myelopathy. AB - STUDY DESIGN: Experimental neurophysiological study. OBJECTIVES: The hepatic myelopathy (HM) is characterized by progressive weakness and spasticity of the lower extremities, while there are only a few reports of sensory impairment. However, sensory function has been poorly explored in HM. We believe that an electrophysiological assessment of dorsal columns by somatosensory evoked potentials (SEPs) and of cortico-spinal lateral tracts by motor evoked potentials (MEPs) should be of considerable value in the functional evaluation of the spinal cord involvement in patients with HM. SETTING: Salzburg (Austria) and Merano (Italy). METHODS: Eight patients diagnosed with HM were studied with MEPs and SEPs. Neurological examination revealed different degrees of cortico-spinal tract involvement in all patients and sensory abnormalities in three patients. RESULTS: Central motor conduction to lower limb muscles was abnormal in all patients, while central sensory conduction was abnormal in seven out of the eight patients. Both central motor and sensory conduction to upper limbs are normal in all patients. CONCLUSION: The main finding is that electrophysiological evidence of central sensory involvement is present in a very high percentage of patients with HM, and that the threshold for electrophysiological abnormalities is below that for clinical manifestations. Therefore, central sensory and motor conduction studies are sensitive methods for detecting, localizing and monitoring spinal cord damage in HM. PMID- 24777164 TI - Autonomic dysreflexia during bowel evacuation procedures and bladder filling in subjects with spinal cord injury. AB - STUDY DESIGN: Randomized, controlled clinical trial. OBJECTIVES: Bladder and bowel management may cause serious autonomic dysreflexia (AD) in subjects with high spinal cord injury (SCI). We aimed at investigating autonomic responses to digital rectal evacuation (DE), transanal irrigation (TAI) with 500 ml and filling cystometry (FC) in SCI. SETTING: Aarhus University Hospital, Denmark. METHODS: Eight subjects with SCI (AIS A) at or above T6 (high SCI) and a previous history of AD were compared with three subjects with SCI (AIS A) between T10 and L2 (low SCI). In randomized order, DE, TAI and FC were performed. AD was defined as an acute rise in systolic blood pressure (sBP) of ?30 mm Hg above baseline. Blood levels of norepinephrine and epinephrine were determined before and shortly after the procedures. RESULTS: During all three procedures, AD occurred in all patients with high SCI but not in those with low SCI. In high SCI subjects, DE increased median sBP from 127 (range: 86-154) to 188 (range: 140-206) mm Hg (P<0.02), TAI from 126 (range: 91-146) to 163 (range: 130-188) mm Hg (P<0.02) and FC from 125 (range: 106-149) to 200 (range: 179-220) mm Hg (P<0.01). The sBP increase was lower during TAI than during DE (P<0.05) or FC (P<0.02). In high SCI subjects, the blood levels of norepinephrine, but not those of epinephrine, increased significantly during all three stimuli (all P<0.05). CONCLUSION: Bowel and bladder management caused AD in high SCI. The response is less severe during TAI than during FC or DE. PMID- 24777165 TI - Mountain time trial in handcycling: exercise intensity and predictors of race time in people with spinal cord injury. AB - STUDY DESIGN: Cross-sectional analyses. OBJECTIVES: To analyze exercise intensity during a mountain time trial in handcycling and to determine predictors of race time. SETTING: Eight Dutch rehabilitation centers and Austrian mountain. METHODS: Forty participants with spinal cord injury (SCI; high lesion level (>T6): N=11; low lesion level (?T6): N=29) handcycled a 20.2-km mountain time trial. Heart rate (HR) was monitored in 17 (high: N=5, low: N=12) participants during the race to determine exercise intensity, expressed relative to the heart rate reserve (%HRR). Two weeks before the race all participants completed laboratory tests to measure anthropometrics and peak values for power output (POpeak), oxygen uptake (VO2peak) and HR. RESULTS: Mean race time was 4 h and 1 min (s.d.: 1 h and 24 min), with no difference in race time between lesion groups. Mean exercise intensity during the race was 70+/-7%HRR. Exercise was mainly (73% of the race time) at a vigorous intensity (60-89%HRR), with 29% of the total time in the 80 89%HRR zone. No clear differences were found in exercise intensities between lesion groups. The strongest predictors for better race times were higher mean %HRR during race (R(2)=57%), lower waist circumference (R(2)=39%), higher POpeak (R(2)=39%) and VO2peak (R(2)=32%). CONCLUSION: A 20-km mountain time trial in a handcycle is intensive. Faster race times were achieved by those with a lower waist circumference, greater fitness level and ability to perform at higher average exercise intensities during the race. Level of SCI was not significantly associated with race time. PMID- 24777166 TI - Prediction of neurological recovery in spontaneous spinal epidural hematoma using apparent diffusion coefficient values. AB - OBJECTIVE: Magnetic resonance imaging (MRI) is useful in diagnosing spontaneous spinal epidural hematoma (SSEH). The purpose of the present study is to determine whether apparent diffusion coefficient (ADC) values could determine severity of spinal cord damage and predict functional recovery in SSEH. METHODS: The study involved four consecutive patients with SSEH (two men and two women: aged 21-76 years). Using axial slices, ADC values were determined in four separate regions of the spinal cord. These areas were classified into the following three groups based on findings in T2-weighted images: normal T2 intensity; persistent T2 abnormality; and temporary T2 abnormality. ADC values among different groups were compared. The relationship between preoperative ADC values and neurological grades were also evaluated. RESULTS: ADC values in normal T2 areas were 0.89 +/- 0.10 * 10(-3) mm(2) s(-1), whereas those for the persistent T2 abnormality group were significantly lower (0.63 +/- 0.14 * 10(-3)). In a patient who was Frankel A on admission and in the follow-up, the ADC value was as low as 0.41 * 10(-3). Functional recovery was also limited in the spinal cord segments with lower ADC values. In the temporary T2 abnormality group, ADC values were significantly higher (1.05 +/- 0.10 * 10(-3)). CONCLUSIONS: In SSEH, if MRI demonstrated T2 hyperintensity with lower ADC values, patients may suffer from irreversible spinal cord damages. ADC values of the spinal cord can be added as a new factor that reliably indicated the severity of spinal cord damage and predicted functional recovery. PMID- 24777167 TI - Fracture toughness of graphene. AB - Perfect graphene is believed to be the strongest material. However, the useful strength of large-area graphene with engineering relevance is usually determined by its fracture toughness, rather than the intrinsic strength that governs a uniform breaking of atomic bonds in perfect graphene. To date, the fracture toughness of graphene has not been measured. Here we report an in situ tensile testing of suspended graphene using a nanomechanical device in a scanning electron microscope. During tensile loading, the pre-cracked graphene sample fractures in a brittle manner with sharp edges, at a breaking stress substantially lower than the intrinsic strength of graphene. Our combined experiment and modelling verify the applicability of the classic Griffith theory of brittle fracture to graphene. The fracture toughness of graphene is measured as the critical stress intensity factor of and the equivalent critical strain energy release rate of 15.9 J m(-2). Our work quantifies the essential fracture properties of graphene and provides mechanistic insights into the mechanical failure of graphene. PMID- 24777168 TI - Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms. AB - OBJECTIVE: To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVM), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040). METHODS: We used data from 338 BAVM cases participating in the University of California, San Francisco (UCSF)-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R(2)>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: 74 BAVM with aneurysm versus 504 controls and 131 BAVM without aneurysm versus 504 controls. RESULTS: We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI 0.99 to 1.53, p=0.064) and rs1333040-T (OR=1.27, 95% CI 1.01 to 1.58, p=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI 1.03 to 2.22, p=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI 0.72 to 1.34, p=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r(2)>0.8) with rs10757278. CONCLUSIONS: Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM-associated aneurysms share similar vascular pathology mechanisms with other aneurysm types. PMID- 24777169 TI - Accelerometer-based quantitative analysis of axial nocturnal movements differentiates patients with Parkinson's disease, but not high-risk individuals, from controls. AB - INTRODUCTION: There is a need for prodromal markers to diagnose Parkinson's disease (PD) as early as possible. Knowing that most patients with overt PD have abnormal nocturnal movement patterns, we hypothesised that such changes might occur already in non-PD individuals with a potentially high risk for future development of the disease. METHODS: Eleven patients with early PD (Hoehn & Yahr stage <=2.5), 13 healthy controls and 33 subjects with a high risk of developing PD (HR-PD) were investigated. HR-PD was defined by the occurrence of hyperechogenicity of the substantia nigra in combination with prodromal markers (eg, slight motor signs, olfactory dysfunction). A triaxial accelerometer was used to quantify nocturnal movements during two nights per study participant. Outcome measurements included mean acceleration, and qualitative axial movement parameters, such as duration and speed. RESULTS: Mean acceleration of nocturnal movements was lower in patients with PD compared to controls. Frequency and speed of axial movements did not differ between patients with PD and controls, but mean size and duration were lower in PD. The HR-PD group did not significantly differ from the control group in any of the parameters analysed. CONCLUSIONS: Compared with controls, patients with PD had an overall decreased mean acceleration, as well as smaller and shorter nocturnal axial movements. These changes did not occur in our potential HR-PD individuals, suggesting that relevant axial movement alterations during sleep have either not developed or cannot be detected by the means applied in this at-risk cohort. PMID- 24777170 TI - Rh(III)-catalyzed regioselective hydroarylation of alkynes via directed C-H functionalization of pyridines. AB - Rh(III)-catalyzed C-3 selective alkenylation of pyridine derivatives via hydroarylation of alkynes has been developed. The reaction shows high regioselectivity, high yield and good functional group tolerance, providing a convenient strategy for the synthesis of trisubstituted (pyridin-3-yl)alkenes. PMID- 24777171 TI - Synthesis of mesoporous Beta and Sn-Beta zeolites and their catalytic performances. AB - Mesoporous Beta zeolite has been successfully prepared through hydrothermal synthesis in the presence of cationic ammonium-modified chitosan as the meso template. Through a subsequent solid-gas reaction between highly dealuminated mesoporous Beta zeolite and SnCl4 steam at an elevated temperature, mesoporous Sn Beta has been facilely obtained. It was revealed that the addition of cationic chitosan induced the nanocrystal aggregation to particle sizes of ~300 nm, giving rise to the intercrystalline/interparticle mesoporosity. In the Sn-implanting procedure, Sn species were demonstrated to be doped into the framework of the resulting mesoporous Beta zeolite in a tetrahedral environment without structural collapse. Due to the micro/mesoporous structures, both mesoporous Beta and Sn Beta exhibited superior performances in alpha-pinene isomerization, Baeyer Villiger oxidation of 2-adamantanone by hydrogen peroxide and the isomerization of glucose in water, respectively. PMID- 24777172 TI - Lymphocyte-based model systems for allergy research: a historic overview. AB - During the last decades, a multitude of studies applying distinct in vitro and in vivo model systems have contributed greatly to our better understanding of the initiation and regulation of inflammatory processes leading to allergic diseases. Over the years, it has become evident that among lymphocytes, not only IgE producing B cells and allergy-orchestrating CD4(+) helper cells but also cytotoxic CD8(+) T cells, gammadelta-T cells and innate lymphoid cells, as well as regulatory lymphocytes, might critically shape the immune response towards usually innocuous allergens. In this review, we provide a historic overview of pioneering work leading to the establishment of important lymphocyte-based model systems for allergy research. Moreover, we contrast the original findings with our currently more refined knowledge to appreciate the actual validity of the respective models and to reassess the conclusions obtained from them. Conflicting studies and interpretations are identified and discussed. The tables are intended to provide an easy overview of the field not only for scientists newly entering the field but also for the broader readership interested in updating their knowledge. Along those lines, herein we discuss in vitro and in vivo approaches to the investigation of lymphocyte effector cell activation, polarization and regulation, and describe depletion and adoptive transfer models along with gene knockout and transgenic (tg) methodologies. In addition, novel attempts to establish humanized T cell antigen receptor tg mouse models for allergy research are described and discussed. PMID- 24777173 TI - Impact of identifying factors which trigger bothersome tinnitus on the treatment outcome in tinnitus retraining therapy. AB - The aim of this work was to ascertain any differences in the effectiveness of rehabilitation therapy in relation to the presence or absence of a known negative reinforcement responsible for the tinnitus-related pathology. Between 1 January 2001 and 31 December 2008, we recruited 294 subjects suffering from incapacitating tinnitus and/or hyperacusis. The patients underwent tinnitus retraining therapy (TRT) according to the methods described by Jastreboff and Hazell [Tinnitus Retraining Therapy: Implementing the Neurophysiological Model. Cambridge, Cambridge University Press, 2004, pp 121-133]. We clinically assessed the presence or absence of known phenomena of associative learning, regarding the presence of adverse events temporally correlated with tinnitus and the treatment outcome. The separate analysis of the 2 subgroups shows a statistically significant difference in the improvement rate between the group with a known triggering factor and the group without a triggering factor, with a preponderance of the former with a 91% improvement rate versus approximately 56% for the latter. In our study, the inability to identify factors triggering bothersome tinnitus negatively affected the treatment outcome in TRT. PMID- 24777174 TI - Accuracy of the spot sign on computed tomography angiography as a predictor of haematoma enlargement after acute spontaneous intracerebral haemorrhage: a systematic review. AB - BACKGROUND: A common early complication of intracerebral haemorrhage (ICH) is haematoma enlargement (HE), a strong independent predictor of a poor outcome. Therapeutic options to limit haematoma progression are currently scarce. Haemostatic therapy may be effective in patients with ICH, but it carries the risk of thromboembolic events in unselected patients. Accurate patient selection would, therefore, be of key importance for delivering potentially successful therapeutic strategies. Currently, there is no gold standard to accurately predict HE. The presence of contrast extravasation within the haematoma on computed tomography angiography (CTA), the 'spot sign', has been reported in several studies and seems a particularly promising marker but lacks a standardised evaluation so far. SUMMARY: We conducted a systematic review of published data to address the research question: In adults with acute spontaneous ICH, how accurately does the spot sign predict HE on follow-up imaging and thus poor functional outcome or mortality? We searched PubMed and Embase databases (from 1980 to May 2012), using a highly sensitive search strategy and including all studies involving adult patients with spontaneous ICH evaluated with CTA and follow-up CT scans, reporting any measure of clinical outcome, and reporting or allowing calculation of accuracy measures of the spot sign in predicting HE and clinical outcome. Baseline characteristics, accuracy measures and effect measures, as well as bias assessment, were reported according to PRISMA recommendations. The quality of the studies was appraised using an adapted version of the REMARK reporting recommendations. From 259 potentially relevant studies, we finally selected 6 studies (1 of them was a multicentre cohort study) covering a total of 709 patients. Studies varied substantially in terms of size, methodological quality, definitions of terms, outcomes selected and results. In particular, definition of the spot sign was not consistent in all studies. Furthermore, the only outcome measure consistently available was HE, while definitions and analyses of clinical outcomes seemed not adequate. Lastly, the choice of candidate variables for univariate and multivariate analyses did not include all determinants of HE and poor functional outcome. High heterogeneity was demonstrated (I(2): 94% for HE) with substantial potential of bias. KEY MESSAGES: Studies of the spot sign are diverse and therefore complex to interpret. Our research question could not be answered due to heterogeneity and potential of bias in the selected studies. Further appropriately powered studies using standardised definitions and taking all predictors of HE and poor clinical outcome into account are required for a proper clinical implementation. PMID- 24777180 TI - The Drosophila deubiquitinating enzyme dUSP36 acts in the hemocytes for tolerance to Listeria monocytogenes infections. AB - Listeria monocytogenes is a facultative intracellular pathogen which can infect Drosophila melanogaster. Upon infection, Drosophila mounts an immune response including antimicrobial peptide production and autophagy activation. A set of previously published results prompted us to study the role of the deubiquitinating enzyme dUSP36 in response to L. monocytogenes infections. We show in this report that flies with dUsp36-specific inactivation in hemocytes are susceptible to L. monocytogenes infections (as are flies with autophagy-deficient hemocytes) but are still able to control bacterial growth. Interestingly, flies with dUsp36-depleted hemocytes are not sensitized to infection by other pathogens. We conclude that dUsp36 plays a major role in hemocytes for tolerance to L. monocytogenes. PMID- 24777181 TI - Four-component strategy for selective synthesis of azepino[5,4,3-cd]indoles and pyrazolo[3,4-b]pyridines. AB - A novel four-component strategy for the selective synthesis of fused azepino[5,4,3-cd]indoles and pyrazolo [3,4-b]pyridines has been established. The bond-forming efficiency, accessibility of starting materials and substrate scope provide invaluable access to tetra-, and bis-heterocyclic scaffolds. PMID- 24777182 TI - Human AdV-specific T cells: persisting in vitro functionality despite lethal irradiation. AB - Viral infections caused by human adenovirus (HAdV) or CMV remain life-threatening complications in immunocompromised patients undergoing allogeneic hematopoietic stem cell transplantation. Adoptive immunotherapy with virus-specific T cells showed impressive clinical results without or with only mild GvHD. However, because of high costs and high regulatory barriers, these protocols are accessible to only a few centers. The infusion of unmanipulated donor lymphocytes (DLIs) that contain virus-specific T cells is not feasible because of the risk of GvHD. Reports about three patients treated with irradiated granulocytes or DLIs that potentially comprised virus-specific T cells discussed an active role of virus-specific lymphocytes despite irradiation, but real evidence could not be provided. Therefore, we tested the effect of irradiation on HAdV-specific T cells, which had been expanded in vitro, by stimulating PBMCs with HAdV-peptide pools and IL-15 for 12 days. Cells were then irradiated with 30 Gy, as performed for normal granulocyte concentrates. Cell viability and polyfunctional activity were determined by flow cytometry. Even 48 h after irradiation, 15.6% of expanded HAdV-specific T cells were apparently viable and cytolytically active. Although the in vivo antiviral activity was not tested, these data support earlier assumptions about the potential role of irradiated cells in patients. PMID- 24777183 TI - Challenges and opportunities for HSCT outcome registries: perspective from international HSCT registries experts. AB - Patient registries, frequently referred to as outcome registries, are 'organized systems' that use observational study methods to collect uniform data. Registries are used to evaluate specified outcomes for a population defined by a particular disease, condition or exposure that serves one or more predetermined scientific, clinical or policy purposes. Outcome registries were established very early in the development of hematopoietic SCT (HSCT). Currently, myriads of national and international HSCT registries collect information about HSCT activities and outcomes. These registries have contributed significantly to determining trends, patterns, treatment practices and outcomes. There are many different HSCT registries, each with different aims and goals; some are led by professional organizations, others by government authorities, health care providers or third parties. Some registries simply assess activity and others study outcomes. These registries are complementary and are gradually developing interoperability with each other to expand future collaborative research activities. A key development in the last few years was the incorporation of recommendations into the World Health Organization guiding principles on cell, tissue and organ transplantation. The data collection and analysis should be an integral part of therapy and an obligation rather than a choice for transplant programs. This article examines challenges in ensuring data quality and functions of outcome registries, using HSCT registries as an example. It applies to all HSCT-related data, but is predominantly focused on HSCT registries of professional organizations. PMID- 24777184 TI - Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. AB - We hypothesized that clinical risk factors could be identified within 2 weeks of onset of severe (stage 3 or 4) acute gut GVHD for identifying a patient population with a very poor outcome. Among 1462 patients who had allogeneic hematopoietic cell transplantation (HCT) between January 2000 and December 2005, 116 (7.9%) developed stage 3-4 gut GVHD. The median time for onset of stage 3-4 gut GVHD was 35 (4-135) days after allogeneic HCT. Eighty-five of the 116 patients (73%) had corticosteroid resistance before or within 2 weeks after the onset of stage 3-4 gut GVHD. Significant risk factors for mortality included corticosteroid resistance (hazards ratio (HR)=2.93; P=0.0005), age >18 years (HR=4.95; P=0.0004), increased serum bilirubin (HR 2.53; P=0.0001) and overt gastrointestinal bleeding (HR 2.88; P=0.0004). Among patients with stage 3-4 gut GVHD, the subgroup with 0, 1 or 2 risk factors had a favorable prognosis, whereas the subgroup with 3 or 4 risk factors had a dismal prognosis. This information should be considered in designing future studies of severe gut GVHD and in counseling patients about prognosis. PMID- 24777185 TI - Activated MHC-mismatched T helper-1 lymphocyte infusion enhances GvL with limited GvHD. AB - DLI is traditionally used to provide graft-versus-leukemia (GvL) effects when given to patients relapsing post-hematopoietic cell transplantation (HCT). However, it is often associated with significant GvHD and has only modest efficacy against acute leukemias. Therefore, novel cellular therapies are needed to improve the outcome of high-risk or relapsed leukemia patients following HCT. Activated T helper-1 (aTh-1) lymphocytes are CD4(+)CD25(+)CD40L(+)CD62L(lo) effector memory cells that produce large amounts of IFN-gamma and TNF-alpha. We demonstrate that post-transplant adoptive aTh-1 cell therapy enhances GvL with limited GvHD in an MHC-mismatched murine BMT model. aTh-1 infusions result in superior leukemia-free survival when compared with unstimulated splenocytes (SC), purified CD4(+) T-cells and T-cell-enriched SC. aTh-1 cells display cytotoxicity against A20 leukemia cells in vitro and persist in vivo for at least 2 months following adoptive transfer. Furthermore, in contrast to unstimulated SC, aTh-1 cell infusion is associated with only transient, mild suppression of donor derived hematopoiesis. aTh-1 cell therapy is safe, effective and warrants further investigation as an alternative to DLI. PMID- 24777186 TI - Peanut allergy transferred by BMT. PMID- 24777187 TI - The commitment and evaluation of the quality management plan by professionals from accredited stem cell transplant centers in Spain. PMID- 24777188 TI - Negative selection by apoptosis enriches progenitors in naive and expanded human umbilical cord blood grafts. AB - The influence of TNF-alpha and Fas-ligand (FasL) on viability and function was evaluated in fresh- and expanded-umbilical cord blood (UCB) cells. CD34(+) progenitors and T cells display outstanding survival, whereas ~30% and >50% B lymphocytes and myeloid cells undergo spontaneous apoptosis within 24 and 48 h, respectively. Although the impact of exposure to toxic doses of FasL and TNF alpha was undetectable in measurements of apoptosis; removal of dead cells after 2 days of incubation with the ligands revealed a twofold increase in frequency of colony-forming cells (CFU). The sensitivity of progenitors to apoptosis was also unaffected by Fas cross-linking following TNF-induced upregulation of the receptor, increasing CFU frequency without impairing SCID repopulating cell (SRC) activity. Most significant enrichment in CD34(+) progenitors and corresponding increase in CFU frequency were observed when FasL was applied during the final week of ex vivo expansion under the influence of nicotinamide, without impairing SRC activity. These data emphasize differential sensitivities of UCB progenitors and lineage-positive cells to apoptotic signaling mediated by the Fas and TNF receptors, which might be useful in improving the efficiency of ex vivo expansion and improving UCB cell engraftment. PMID- 24777189 TI - Neuropathic dermatomes and cutaneous ulceration in patients with chronic GVHD. PMID- 24777190 TI - Isolated orbital relapse of multiple myeloma in a patient with severe chronic GVHD after allogeneic hematopoietic SCT. PMID- 24777192 TI - Feasibility of marrow harvesting from pediatric sibling donors without hematopoietic growth factors and allotransfusion. AB - We retrospectively studied 108 marrow harvests from 105 pediatric sibling donors. The median age of donors was 8 years (range: 1-15) and the median body weight was 27 kg (range: 10-100). The volumes of aspirated marrow were 5.0-23.8 mL/kg donor body weight, and harvested bone marrow volume exceeded 15 mL/kg in 42% of the donors. A total of 100 autologous blood donations were performed, and eight donors had red cells salvaged from their harvests reinfused. The median Hb levels before and after harvests were 12.3 g/dL (range: 10.0-14.7) and 11.0 g/dL (range: 8.9-13.8), respectively. None of the donors received allogeneic blood transfusions or hematopoietic growth factors such as EPO and G-CSF before or after collection. Transplanted dose was 1.4-10.8 * 10(8) cells/kg recipient body weight without differences due to donor age. Higher concentrations of nucleated and CD34(+) cells were obtained from younger donors. All donors tolerated the procedures well, with no serious complications. Thus, children may safely donate marrow for allogeneic transplantation, and the yields of nucleated cells for engraftment are substantial. PMID- 24777191 TI - EBMT risk score can predict the outcome of leukaemia after unmanipulated haploidentical blood and marrow transplantation. AB - Systematic, standardised pretransplant risk assessment is an important tool for predicting patient outcomes following allogeneic haematopoietic SCT (HSCT). To assess the European Group for Blood and Marrow Transplantation (EBMT) risk score capacities for predicting patient outcomes following unmanipulated haploidentical blood and marrow transplantation (HBMT), we analysed 502 leukaemia patients who received transplants at our centre between 2008 and 2010. The cohort OS and leukaemia-free survival (LFS) were 72.1% and 68.1%, whereas the cumulative non relapse mortality (NRM) and relapse incidences were 16.5% and 16.1%. According to univariate analysis, the values for OS, LFS and NRM were worse for an EBMT risk score of 6 (40.0, 40.0, 50.0%) than a score of 1 (83.1, 78.3, 8.4%). Hazard ratios steadily increased for each additional score point. Likewise, a higher EBMT risk score was associated with an increased relapse incidence. Importantly, the EBMT risk score prognostic value regarding OS, LFS, NRM and relapse was maintained in the multivariate analysis. Moreover, we also made a haploidentical EBMT (haplo-EBMT) risk score, which used number of HLA disparity instead of donor type, and the haplo-EBMT risk scores can also be used to predict patient outcomes following unmanipulated HBMT. PMID- 24777193 TI - Complement component C3 mediates Th1/Th17 polarization in human T-cell activation and cutaneous GVHD. AB - The complement system has been shown to regulate T-cell activation and alloimmune responses in GVHD. Mice deficient in the central component of complement system C3 have significantly lower GVHD-related mortality/morbidity, and C3 modulates Th1/Th17 polarization in mouse GVHD. To investigate whether anticomplement therapy has any impact on human T-cell activation, a drug candidate Compstatin was used to inhibit C3 activation in this study. We found the frequency of IFN gamma (Th1)-, IL-4 (Th2)-, IL-17 (Th17)-, IL-2- and TNF-alpha-producing cells were significantly reduced among activated CD4(+) cells in the presence of Compstatin. Compstatin treatment decreased the proliferation of both CD4(+) and CD8(+) T cells upon TCR stimulation. However, Compstatin does not affect the production of IL-2 and TNF-alpha in activated CD8(+) T cells, and the differentiation of CD8(+) T cells into distinct memory and effector subsets remained intact. Furthermore, we examined complement deposition in skin and lip biopsy samples of patients diagnosed with cutaneous GVHD. C3 deposition was detected in the squamous epithelium and dermis, blood vessels and damaged sweat glands, and was associated with gland damage and regeneration. We conclude that C3 mediates Th1/Th17 polarization in human T-cell activation and skin GVHD in patients. PMID- 24777194 TI - Estimation of size of cord blood inventory based on high-resolution typing of HLAs. AB - Methods for estimating the cord blood (CB) inventory size required vary according to the ethnic diversity of the HLA, degree of HLA matching and HLA-typing resolution. We estimated the CB inventory size required using 7190 stored CB units (CBU) and 2450 patients who were awaiting or underwent allogeneic hematopoietic stem cell transplantation. With high-resolution typing of HLA-A, B and DRB1, 94.6% of Korean patients could find CBUs in 100 000 CBUs with a 5/6 match, and 95.7% could find CBUs in 5000 CBUs with a 4/6 match. With low resolution typing of HLA-A and B and high-resolution typing of leukocyte antigen DRB1, 95% of patients could find CBUs in 50 000 CBUs with a 5/6 match, and 96.7% could find CBUs in 3000 CBUs with a 4/6 match. With additional high-resolution typing for HLA-A and B, which could improve transplantation outcome, the size of the CB inventory would need to increase twofold for Koreans. PMID- 24777196 TI - Structural development of gold and silver nanoparticles within hexagonally ordered spherical micellar diblock copolymer thin films. AB - The spatial arrangement of metal nanoparticle (NP) arrays in block copolymers has many potential applications in OFET-type memory devices. In this study, we adopted a trapping approach in which we used a monolayer thin film of polystyrene block-poly(4-vinylpyridine) (PS56k-b-P4VP8k)-a highly asymmetric diblock copolymer having a spherical micelle morphology-to incorporate various amounts of one-phase-synthesized dodecanethiol-passivated silver (DT-Ag) NPs and a fixed amount of ligand-exchanged pyridine-coated gold (Py-Au) NPs into the polystyrene (PS) and poly(4-vinylpyridine) (P4VP) blocks, respectively. We characterized the packing of these metal NPs in the two blocks of the nanostructured diblock copolymer using reciprocal-space synchrotron grazing incidence small-angle X-ray scattering (GISAXS) as well as atomic force microscopy (AFM) and transmission electron microscopy (TEM) in the real space. The packing of the Ag NPs in the PS block was dependent on their content, which we tuned by varying the concentrations in the composite solution at a constant rate of spin-coating. The two-dimensional hierarchical arrangement of Ag and Au NPs within the BCP thin films was enhanced after addition of the Py-Au NPs into the P4VP block and after spin-coating a thinner film from a low concentration solution (0.1 wt%), due to the DT-Ag NPs accumulating around the Py-Au/P4VP cores; this two-dimensional hierarchical arrangement decreased at a critical DT-Ag NP weight ratio (c) of 0.8 when incorporating the Py-Au NPs into the P4VP domains through spin-coating at higher solution concentration (0.5 wt%), where the DT-Ag NPs realigned by rotating 20 degrees along the z axis in the real space, due to oversaturation of the DT-Ag NPs within the PS domains. PMID- 24777195 TI - Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: a multicentre analysis from the Asia Lymphoma Study Group. AB - Eighteen patients (men=14; women=4) with natural killer (NK)/T-cell lymphomas (CR1, N=9; CR2, N=7; PR, N=1; progressive disease, N=1) undergoing allogeneic haematopoietic SCT (HSCT) (myeloablative, N=14; reduced intensity, N=4) were analyzed. With a median follow-up of 20.5 months, the 5-year OS was 57% and 5 year EFS was 51%. The use of the SMILE regimen pre-HSCT was the most important positive prognostic indicator, resulting in significantly superior OS and EFS (P<0.01). Acute GVHD had a significant negative impact on OS (P=0.03). CR1 and CR2 patients had similar survivals, but all patients who were not transplanted in remission died. Chronic GVHD, International Prognostic Index, disease stage, primary sites of involvement, conditioning regimen and source of HSC did not affect survival. Although allogeneic HSCT leads to reasonable survival for NK/T cell lymphoma patients, results need to be compared with those in patients receiving L-asparaginase-containing regimens. Novel prognostic models incorporating biomarkers, such as circulating EBV DNA, are needed to identify high-risk patients who may benefit from allogeneic HSCT. PMID- 24777197 TI - Enhanced adsorption of acidic gases (CO2, NO2 and SO2) on light metal decorated graphene oxide. AB - The adsorption of several acidic gases (CO2, NO2 and SO2) on light metal (Li, Al) decorated graphene oxide (GO) is theoretically studied, based on the first principles calculations. Configuration relaxation, binding energy and charge transfer are carried out to discuss the acidic gas adsorption ability of light metal decorated GO. It is found out that Li, Al could be anchored stably by hydroxyl and epoxy groups on GO, and then a strong adsorption of CO2, NO2 and SO2 will occur above these light metals. In contrast to Ti, Li decorated GO exhibits a comparable adsorption ability of acidic gases, but a much smaller interaction with O2 about 2.85-3.98 eV lower in binding energy; and Al decorated GO displays much higher binding energy of all acidic gases with an enhancement of about 0.59 2.29 eV. The results of enhanced acidic gas adsorption ability and a reduced interference by O2 imply that Li, Al decorated GO may be useful and promising for collection and filtration of exhaust gases. PMID- 24777198 TI - High-temperature electromagnons in the magnetically induced multiferroic cupric oxide driven by intersublattice exchange. AB - Magnetically induced ferroelectric multiferroics present an exciting new paradigm in the design of multifunctional materials, by intimately coupling magnetic and polar order. Magnetoelectricity creates a novel quasiparticle excitation--the electromagnon--at terahertz frequencies, with spectral signatures that unveil important spin interactions. To date, electromagnons have been discovered at low temperature (<70 K) and predominantly in rare-earth compounds such as RMnO3. Here we demonstrate using terahertz time-domain spectroscopy that intersublattice exchange in the improper multiferroic cupric oxide (CuO) creates electromagnons at substantially elevated temperatures (213-230 K). Dynamic magnetoelectric coupling can therefore be achieved in materials, such as CuO, that exhibit minimal static cross-coupling. The electromagnon strength and energy track the static polarization, highlighting the importance of the underlying cycloidal spin structure. Polarized neutron scattering and terahertz spectroscopy identify a magnon in the antiferromagnetic ground state, with a temperature dependence that suggests a significant role for biquadratic exchange. PMID- 24777199 TI - Picosecond dynamics of hydrogen bond rearrangements during phase separation of a triethylamine and water mixture. AB - The earliest stages of phase separation in a liquid triethylamine (TEA)-water mixture were observed using a picosecond IR laser pulse to produce a temperature jump and ultrafast Raman spectroscopy. Raman spectral changes in the water OH stretching region showed that the temperature rise induced by IR pulses equilibrated within a few tens of picoseconds. Amplitude changes in the TEA CH stretching region of difference Raman spectra consisted of an initial faster and a subsequent slower process. The faster process within 100 ps is attributed to hydrogen bond weakening caused by the temperature rise. The slower process attributed to phase separation was observed for several nanoseconds, showing the number of hydrogen bond between TEA and water gradually decreased with time. The kinetics of hydrogen bond scission during phase separation indicated a linear growth of the phase-separated component, as observed previously on the nanosecond time scale, rather than the more usual exponential growth. A peak blueshift was observed in the difference Raman spectra during phase separation. This shift implies that hydrogen bond scission of TEA-water aggregates involving very few water molecules took place in the initial stage of phase separation (up to 2 ns), and then was followed by the breaking of TEA-water pairs surrounded by water molecules. This effect may be a result from spatial inhomogeneities associated with the phase separation process: aggregates or clusters existing naturally in solution even below the lower critical soluble temperature. PMID- 24777201 TI - Validity of consumer-based physical activity monitors. AB - BACKGROUND: Many consumer-based monitors are marketed to provide personal information on the levels of physical activity and daily energy expenditure (EE), but little or no information is available to substantiate their validity. PURPOSE: This study aimed to examine the validity of EE estimates from a variety of consumer-based, physical activity monitors under free-living conditions. METHODS: Sixty (26.4 +/- 5.7 yr) healthy males (n = 30) and females (n = 30) wore eight different types of activity monitors simultaneously while completing a 69 min protocol. The monitors included the BodyMedia FIT armband worn on the left arm, the DirectLife monitor around the neck, the Fitbit One, the Fitbit Zip, and the ActiGraph worn on the belt, as well as the Jawbone Up and Basis B1 Band monitor on the wrist. The validity of the EE estimates from each monitor was evaluated relative to criterion values concurrently obtained from a portable metabolic system (i.e., Oxycon Mobile). Differences from criterion measures were expressed as a mean absolute percent error and were evaluated using 95% equivalence testing. RESULTS: For overall group comparisons, the mean absolute percent error values (computed as the average absolute value of the group-level errors) were 9.3%, 10.1%, 10.4%, 12.2%, 12.6%, 12.8%, 13.0%, and 23.5% for the BodyMedia FIT, Fitbit Zip, Fitbit One, Jawbone Up, ActiGraph, DirectLife, NikeFuel Band, and Basis B1 Band, respectively. The results from the equivalence testing showed that the estimates from the BodyMedia FIT, Fitbit Zip, and NikeFuel Band (90% confidence interval = 341.1-359.4) were each within the 10% equivalence zone around the indirect calorimetry estimate. CONCLUSIONS: The indicators of the agreement clearly favored the BodyMedia FIT armband, but promising preliminary findings were also observed with the Fitbit Zip. PMID- 24777200 TI - MicroRNA-410 reduces the expression of vascular endothelial growth factor and inhibits oxygen-induced retinal neovascularization. AB - Retinal neovascularization (RNV) is an eye disease that can cause retinal detachment and even lead to blindness. RNV mainly occurs in the elderly population. The pathogenesis of RNV has been previously reported to be highly related to the expression of vascular endothelial growth factor A (VEGFA), basic fibroblast growth factor (bFGF) and other angiogenic factors. It has also been reported that VEGFA and other factors associated with RNV could be regulated by certain microRNAs (miRNA), a group of small non-coding RNAs which are able to regulate the expression of many genes in vivo. Here, we demonstrate that the miRNA miR-410 is highly expressed in mice within two weeks after birth. miR-410 could suppress VEGFA expression through interaction with the 3'UTR of the VEGFA messenger RNA. Overexpressing a miR-410 mimic effectively suppresses VEGFA expression in various cell lines. Further experiments on oxygen-induced retinopathy (OIR) in mice revealed that eye drops containing large amounts of miR 410 efficiently downregulate VEGFA expression, prevent retinal angiogenesis and effectively treat RNV. These results not only show the underlying mechanism of how miR-410 targets VEGFA but also provide a potential treatment strategy for RNV that might be used in the near future. PMID- 24777202 TI - Genome-wide association and linkage analyses localize a progressive retinal atrophy locus in Persian cats. AB - Hereditary eye diseases of animals serve as excellent models of human ocular disorders and assist in the development of gene and drug therapies for inherited forms of blindness. Several primary hereditary eye conditions affecting various ocular tissues and having different rates of progression have been documented in domestic cats. Gene therapy for canine retinopathies has been successful, thus the cat could be a gene therapy candidate for other forms of retinal degenerations. The current study investigates a hereditary, autosomal recessive, retinal degeneration specific to Persian cats. A multi-generational pedigree segregating for this progressive retinal atrophy was genotyped using a 63 K SNP array and analyzed via genome-wide linkage and association methods. A multi-point parametric linkage analysis localized the blindness phenotype to a ~1.75 Mb region with significant LOD scores (Z ~ 14, theta = 0.00) on cat chromosome E1. Genome-wide TDT, sib-TDT, and case-control analyses also consistently supported significant association within the same region on chromosome E1, which is homologous to human chromosome 17. Using haplotype analysis, a ~1.3 Mb region was identified as highly associated for progressive retinal atrophy in Persian cats. Several candidate genes within the region are reasonable candidates as a potential causative gene and should be considered for molecular analyses. PMID- 24777204 TI - Effectiveness of therapeutic selective neck dissection in laryngeal cancer. AB - BACKGROUND: The aim of this study was to evaluate the effectiveness of selective neck dissection (SND) in patients with laryngeal cancer and clinically positive cervical nodes. SUBJECTS AND METHODS: A retrospective review of the clinical records of 58 consecutive untreated patients affected by laryngeal carcinoma and submitted to surgical treatment was performed. RESULTS: Twenty-six (44.8%) patients received monolateral neck dissection and 32 (55.2%) bilateral neck dissection. A total of 90 hemineck dissections were performed. Histopathological examination revealed that 25 of the 58 patients had negative nodes (pN0) and 33 had positive nodes (pN+). Extracapsular spread was found in 12 of the 33 pN+ patients. Twenty-eight of the 58 (48.2%) patients were submitted to adjuvant radiotherapy. Six of the 58 patients submitted to neck dissection had neck recurrence (rate of 10.3%). The only independent prognostic factor for neck recurrence was extracapsular spread. For the 58 patients, the 5-year overall survival was 50% and the disease-specific survival 68.9%. The 5-year disease specific survival was 76% for pN0 patients and 63.6% for pN+ patients. CONCLUSIONS: SND can represent a therapeutic procedure because it has shown oncological results comparable to those of comprehensive neck dissection, especially when SND is combined with adjuvant radiotherapy. PMID- 24777203 TI - Regulation of glycogen breakdown and its consequences for skeletal muscle function after training. AB - Repeated bouts of physical exercise, i.e., training, induce mitochondrial biogenesis and result in improved physical performance and attenuation of glycogen breakdown during submaximal exercise. It has been suggested that as a consequence of the increased mitochondrial volume, a smaller degree of metabolic stress (e.g., smaller increases in ADP and Pi) is required to maintain mitochondrial respiration in the trained state during exercise at the same absolute intensity. The lower degree of Pi accumulation is believed to account for the diminished glycogen breakdown, since Pi is a substrate for glycogen phosphorylase, the rate-limiting enzyme for glycogenolysis. However, in this review, we present an alternative explanation for the diminished glycogen breakdown. Thus, the lower degree of metabolic stress after training is also associated with smaller increases in AMP (free concentration during contraction at specific intracellular sites) and this results in less activation of phosphorylase b (the non-phosphorylated form of phosphorylase), resulting in diminished glycogen breakdown. Concomitantly, the smaller accumulation of Pi, which interferes with cross-bridge function and intracellular Ca(2+) handling, contributes to the increased fatigue resistance. The delay in glycogen depletion also contributes to enhanced performance during prolonged exercise by functioning as an energy reserve. PMID- 24777205 TI - Diagnosis of snake envenomation using a simple phospholipase A2 assay. AB - Diagnosis of snake envenomation is challenging but critical for deciding on antivenom use. Phospholipase A2 enzymes occur commonly in snake venoms and we hypothesized that phospholipase activity detected in human blood post-bite may be indicative of envenomation. Using a simple assay, potentially a bedside test, we detected high phospholipase activity in sera of patients with viper and elapid envenomation compared to minimal activity in non-envenomed patients. PMID- 24777207 TI - Pediatric care recommendations for freestanding urgent care facilities. AB - Treatment of children at freestanding urgent care facilities has become common in pediatric health care. Well-managed freestanding urgent care facilities can improve the health of the children in their communities, integrate into the medical community, and provide a safe, effective adjunct to, but not a replacement for, the medical home or emergency department. Recommendations are provided for optimizing freestanding urgent care facilities' quality, communication, and collaboration in caring for children. PMID- 24777208 TI - The need to promote all pediatric stem cell donors' understanding and interests. PMID- 24777206 TI - Unmet needs of siblings of pediatric stem cell transplant recipients. AB - BACKGROUND AND OBJECTIVES: In 2010, the Bioethics Committee of the American Academy of Pediatrics issued recommendations that pediatric hematopoietic stem cell donors should have an independent advocate. Formulating appropriate guidelines is hindered by the lack of prospective empirical evidence from families about the experience of siblings during typing and donation. Our aim was to provide these data. METHODS: Families with a child scheduled to undergo hematopoietic stem cell transplant were recruited. All family members, including children aged 9 to 22 years, were eligible. Qualitative interviews were conducted within 3 time periods: pretransplant, 6 to 8, and 9 to 11 months posttransplant. Quantitative scales assessing decision satisfaction and regret were administered at time 2. RESULTS: Thirty-three families were interviewed. Of the 119 family members, 76% perceived there was no choice in the decision to HLA-type siblings; 77% perceived no choice in sibling donation; 86% had no concerns about typing other than needle sticks; and 64% had no concerns about donation. Common concerns raised were dislike of needle sticks (19%), stress before typing results (14%), and fear of donation (15%). Posttransplantation, 33% of donors wished they had been given more information; 56% of donors stated they benefited from donation. Only 1 donor expressed regret posttransplant. CONCLUSIONS: Most family members did not view sibling typing and donation as a choice, were positive about the experience, and did not express regrets. We recommend education for all siblings before typing, comprehensive education for the donor by a health care provider pretransplant, and systematic donor follow-up after transplantation. PMID- 24777209 TI - Patient- and family-centered care coordination: a framework for integrating care for children and youth across multiple systems. AB - Understanding a care coordination framework, its functions, and its effects on children and families is critical for patients and families themselves, as well as for pediatricians, pediatric medical subspecialists/surgical specialists, and anyone providing services to children and families. Care coordination is an essential element of a transformed American health care delivery system that emphasizes optimal quality and cost outcomes, addresses family-centered care, and calls for partnership across various settings and communities. High-quality, cost effective health care requires that the delivery system include elements for the provision of services supporting the coordination of care across settings and professionals. This requirement of supporting coordination of care is generally true for health systems providing care for all children and youth but especially for those with special health care needs. At the foundation of an efficient and effective system of care delivery is the patient-/family-centered medical home. From its inception, the medical home has had care coordination as a core element. In general, optimal outcomes for children and youth, especially those with special health care needs, require interfacing among multiple care systems and individuals, including the following: medical, social, and behavioral professionals; the educational system; payers; medical equipment providers; home care agencies; advocacy groups; needed supportive therapies/services; and families. Coordination of care across settings permits an integration of services that is centered on the comprehensive needs of the patient and family, leading to decreased health care costs, reduction in fragmented care, and improvement in the patient/family experience of care. PMID- 24777210 TI - High-deductible health plans. AB - High-deductible health plans (HDHPs) are insurance policies with higher deductibles than conventional plans. The Medicare Prescription Drug Improvement and Modernization Act of 2003 linked many HDHPs with tax-advantaged spending accounts. The 2010 Patient Protection and Affordable Care Act continues to provide for HDHPs in its lower-level plans on the health insurance marketplace and provides for them in employer-offered plans. HDHPs decrease the premium cost of insurance policies for purchasers and shift the risk of further payments to the individual subscriber. HDHPs reduce utilization and total medical costs, at least in the short term. Because HDHPs require out-of-pocket payment in the initial stages of care, primary care and other outpatient services as well as elective procedures are the services most affected, whereas higher-cost services in the health care system, incurred after the deductible is met, are unaffected. HDHPs promote adverse selection because healthier and wealthier patients tend to opt out of conventional plans in favor of HDHPs. Because the ill pay more than the healthy under HDHPs, families with children with special health care needs bear an increased cost burden in this model. HDHPs discourage use of nonpreventive primary care and thus are at odds with most recommendations for improving the organization of health care, which focus on strengthening primary care.This policy statement provides background information on HDHPs, discusses the implications for families and pediatric care providers, and suggests courses of action. PMID- 24777211 TI - Promoting education, mentorship, and support for pediatric research. AB - Pediatricians play a key role in advancing child health research to best attain and improve the physical, mental, and social health and well-being of all infants, children, adolescents, and young adults. Child health presents unique issues that require investigators who specialize in pediatric research. In addition, the scope of the pediatric research enterprise is transdisciplinary and includes the full spectrum of basic science, translational, community-based, health services, and child health policy research. Although most pediatricians do not directly engage in research, knowledge of research methodologies and approaches promotes critical evaluation of scientific literature, the practice of evidence-based medicine, and advocacy for evidence-based child health policy. This statement includes specific recommendations to promote further research education and support at all levels of pediatric training, from premedical to continuing medical education, as well as recommendations to increase support and mentorship for research activities. Pediatric research is crucial to the American Academy of Pediatrics' goal of improving the health of all children. The American Academy of Pediatrics continues to promote and encourage efforts to facilitate the creation of new knowledge and ways to reduce barriers experienced by trainees, practitioners, and academic faculty pursuing research. PMID- 24777212 TI - Child life services. AB - Child life programs are an important component of pediatric hospital-based care to address the psychosocial concerns that accompany hospitalization and other health care experiences. Child life specialists focus on the optimal development and well-being of infants, children, adolescents, and young adults while promoting coping skills and minimizing the adverse effects of hospitalization, health care, and/or other potentially stressful experiences. Using therapeutic play, expressive modalities, and psychological preparation as primary tools, in collaboration with the entire health care team and family, child life interventions facilitate coping and adjustment at times and under circumstances that might otherwise prove overwhelming for the child. Play and developmentally appropriate communication are used to: (1) promote optimal development; (2) educate children and families about health conditions; (3) prepare children and families for medical events or procedures; (4) plan and rehearse useful coping and pain management strategies; (5) help children work through feelings about past or impending experiences; and (6) establish therapeutic relationships with patients, siblings, and parents to support family involvement in each child's care. PMID- 24777213 TI - Prenatal exposure to methyldopa leading to hypertensive crisis and cardiac failure in a neonate. AB - A 2-week-old infant with normal intracardiac anatomy presented to the emergency department in a hypertensive crisis with acute cardiac failure. Despite extensive evaluation, no underlying disease was found. The patient's hypertension and cardiac dysfunction resolved after 1 week of supportive care in the PICU, and she was discharged within 2 weeks of presentation. The patient's history revealed transplacental exposure to the alpha-adrenergic agonist methyldopa for 10 weeks before delivery. Her age at presentation and the self-limited nature of cardiac sequelae with complete resolution of cardiac dysfunction suggest withdrawal effects from this exposure. Whereas the rebound hypertensive effects of alpha adrenergic agonists are well established in the adult population, this report shows an unusual adverse outcome of in utero exposure to methyldopa. PMID- 24777214 TI - Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. AB - BACKGROUND: In pediatric settings, parents often raise concerns about possible gastrointestinal (GI) symptoms in autism spectrum disorder (ASD), yet the specificity of these concerns are not well studied. OBJECTIVE: To conduct a meta analysis of research investigating GI symptoms among children with ASD. METHODS: We searched Medline, PsycINFO, and PubMed databases (1980-2012) in peer-reviewed journals. Analysis involved studies with a comparison group presenting quantitative data on GI symptoms using combinations of terms for ASD and GI indicators. The systematic search yielded 15 studies. We calculated effect sizes and 95% confidence intervals (CIs) using a random-effects model. RESULTS: Children with ASD experience significantly more general GI symptoms than comparison groups, with a standardized mean difference of 0.82 (0.24) and a corresponding odds ratio (OR) of 4.42 (95% CI, 1.90-10.28). Analysis also indicated higher rates of diarrhea (OR, 3.63; 95% CI, 1.82-7.23), constipation (OR, 3.86; 95% CI, 2.23-6.71), and abdominal pain (OR, 2.45; 95% CI, 1.19-5.07). CONCLUSIONS: Results indicate greater prevalence of GI symptoms among children with ASD compared with control children. Identified studies involved high methodological variability and lack of comprehensive data prohibited analysis of GI pathophysiologies (eg, gastroesophageal reflux) typically associated with organic etiologies, limiting conclusions about the underpinnings of the observed association. Future research must address critical questions about the causes and long-term impact of GI symptoms in ASD. Such analyses will require more systematic research and clinical activities, including improved diagnostic screening, standardized assessment, and exploration of potential moderators (eg, dietary restrictions). PMID- 24777215 TI - Who should get the last PICU bed? AB - Administrators sometimes face ethical dilemmas about the allocation of institutional resources. One such situation is when elective surgery cases require reserved ICU beds and the ICU is full. Such situations arise frequently in children's hospitals today. They are sometimes complicated by questions about whether every patient in the ICU belongs there. We present such a situation and responses from Mark Del Becarro, Vice President for Medical Affairs at Seattle Children's Hospital; Aaron Wightman, a nephrology fellow and bioethicist at Seattle Children's Hospital; and Emily Largent, a doctoral student in the joint JD/PhD Program in Health Policy at Harvard University. PMID- 24777216 TI - United States birth weight reference corrected for implausible gestational age estimates. AB - OBJECTIVES: To provide an updated US birth weight for gestational age reference corrected for likely errors in last menstrual period (LMP)-based gestational age dating, as well as means and SDs, to enable calculation of continuous and categorical measures of birth weight for gestational age. METHODS: From the 2009 2010 US live birth files, we abstracted singleton births between 22 and 44 weeks of gestation with at least 1 nonmissing estimate of gestational age (ie, LMP or obstetric/clinical) and birth weight. Using an algorithm based on birth weight and the concordance between these gestational age estimates, implausible LMP based gestational age estimates were either excluded or corrected by using the obstetric/clinical estimate. Gestational age- and sex-specific birth weight means, SDs, and smoothed percentiles (3rd, 5th, 10th, 90th, 95th, 97th) were calculated, and the 10th and 90th percentiles were compared with published population-based references. RESULTS: A total of 7 818 201 (99% of eligible) births were included. The LMP-based estimate of gestational age comprised 85% of the dataset, and the obstetric/clinical estimate comprised the remaining 15%. Cut points derived from the current reference identified ~10% of births as <=10th and >=90th percentiles at all gestational weeks, whereas cut points derived from previous US-based references captured variable proportions of infants at these thresholds within the preterm and postterm gestational age ranges. CONCLUSIONS: This updated US-based birth weight for gestational age reference corrects for likely errors in gestational age dating and allows for the calculation of categorical and continuous measures of birth size. PMID- 24777217 TI - Use of antihistamines after serious allergic reaction to methimazole in pediatric Graves' disease. AB - Antithyroid drugs are usually considered first-line therapy for management of pediatric Graves' disease because they avoid permanent hypothyroidism, provide a chance for remission, and are less invasive than the alternatives of thyroidectomy or radioactive iodine. Methimazole (MMI) is the only antithyroid drug recommended in pediatrics due to the risk of propylthiouracil-induced liver toxicity. Allergic reactions with MMI occur in up to 10% of patients and, when mild, can be managed with concurrent antihistamine therapy. Guidelines recommend discontinuation of MMI with serious allergic reactions. We present the case of an adolescent girl with Graves' disease and a serious allergic reaction after starting MMI whose family refused radioactive iodine and was reluctant to proceed to surgery. Antihistamine therapy was successfully used to allow continued treatment with MMI. This case demonstrates extension of management guidelines for minor cutaneous allergic reactions to MMI, through the use of antihistamines for a serious allergic reaction, allowing us to continue MMI and provide treatment consistent with the family's preferences and values. PMID- 24777218 TI - Anterior cruciate ligament injuries: diagnosis, treatment, and prevention. AB - The number of anterior cruciate ligament (ACL) injuries reported in athletes younger than 18 years has increased over the past 2 decades. Reasons for the increasing ACL injury rate include the growing number of children and adolescents participating in organized sports, intensive sports training at an earlier age, and greater rate of diagnosis because of increased awareness and greater use of advanced medical imaging. ACL injury rates are low in young children and increase sharply during puberty, especially for girls, who have higher rates of noncontact ACL injuries than boys do in similar sports. Intrinsic risk factors for ACL injury include higher BMI, subtalar joint overpronation, generalized ligamentous laxity, and decreased neuromuscular control of knee motion. ACL injuries often require surgery and/or many months of rehabilitation and substantial time lost from school and sports participation. Unfortunately, regardless of treatment, athletes with ACL injuries are up to 10 times more likely to develop degenerative arthritis of the knee. Safe and effective surgical techniques for children and adolescents continue to evolve. Neuromuscular training can reduce risk of ACL injury in adolescent girls. This report outlines the current state of knowledge on epidemiology, diagnosis, treatment, and prevention of ACL injuries in children and adolescents. PMID- 24777219 TI - Xenon ventilation during therapeutic hypothermia in neonatal encephalopathy: a feasibility study. AB - BACKGROUND AND OBJECTIVES: Therapeutic hypothermia has become standard of care in newborns with moderate and severe neonatal encephalopathy; however, additional interventions are needed. In experimental models, breathing xenon gas during cooling offers long-term additive neuroprotection. This is the first xenon feasibility study in cooled infants. Xenon is expensive, requiring a closed circuit delivery system. METHODS: Cooled newborns with neonatal encephalopathy were eligible for this single-arm, dose-escalation study if clinically stable, under 18 hours of age and requiring less than 35% oxygen. Xenon duration increased stepwise from 3 to 18 hours in 14 subjects; 1 received 25% xenon and 13 received 50%. Respiratory, cardiovascular, neurologic (ie, amplitude-integrated EEG, seizures), and inflammatory (C-reactive protein) effects were examined. The effects of starting or stopping xenon rapidly or slowly were studied. Three matched control subjects per xenon treated subject were selected from our cooling database. Follow-up was at 18 months using mental developmental and physical developmental indexes of the Bayley Scales of Infant Development II. RESULTS: No adverse respiratory or cardiovascular effects, including post-extubation stridor, were seen. Xenon increased sedation and suppressed seizures and background electroencephalographic activity. Seizures sometimes occurred during rapid weaning of xenon but not during slow weaning. C-reactive protein levels were similar between groups. Hourly xenon consumption was 0.52 L. Three died, and 7 of 11 survivors had mental and physical developmental index scores >=70 at follow up. CONCLUSIONS: Breathing 50% xenon for up to 18 hours with 72 hours of cooling was feasible, with no adverse effects seen with 18 months' follow-up. PMID- 24777220 TI - Brief approaches to developmental-behavioral promotion in primary care: updates on methods and technology. AB - Well-child visits are a critical opportunity to promote learning and development, encourage positive parenting practices, help children acquire behavioral self control, enhance the development and well-being of children and their families, identify problems not amenable to brief in-office counseling, and refer for services when needed. This article outlines the communication skills, instructional methods, and resource options that enable clinicians to best assist families. Also covered is how to monitor progress and outcomes. A total of 239 articles and 52 Web sites on parent/patient education were reviewed for this study. Providers require a veritable armamentarium of instructional methods. Skills in nonverbal and verbal communication are needed to elicit the parent/patient agenda, winnow topics to a manageable subset, and create the "teachable moment." Verbal suggestions, with or without standardized spoken instructions, are useful for conveying simple messages. However, for complex issues, such as discipline, it is necessary to use a combination of verbal advice, written information, and "teach-back," aided by role-playing/modeling or multimedia approaches. Selecting the approaches most likely to be effective depends on the topic and family characteristics (eg, parental literacy and language skills, family psychosocial risk and resilience factors, children's developmental-behavioral status). When providers collaborate well (with parents, patients, and other service providers) and select appropriate educational methods, families are better able to act on advice, leading to improvements in children's well-being, health, and developmental-behavioral outcomes. Provided are descriptions of methods, links to parenting resources such as cell phone applications, Web sites (in multiple languages), interactive technology, and parent training courses. PMID- 24777221 TI - Pediatric anthrax clinical management: executive summary. PMID- 24777223 TI - Public perceptions of pharmacogenetics. AB - BACKGROUND AND OBJECTIVES: Pharmacogenetics (PGx) promises to optimize patient response to therapy. However, the public's acceptance of PGx is not well known, notably when this applies to children. Our objective was to explore perceptions of PGx testing among individuals, who differ from each other by either parental status or educational exposure to PGx, and to explore parents' views between PGx testing for oneself and PGx testing for their children. METHODS: An exploratory survey was conducted among parents and other adults. Surveys P and C were completed by parents, survey NP by middle-aged nonparents, and survey MS by medical students. RESULTS: Proper explanation before PGx testing appeared to be the most important issue to the respondents (eg, P = 1.55 * 10(-38) for survey NP). Respondents who were more knowledgeable about PGx were also more comfortable with PGx testing (eg, P = 2.53 * 10(-7) in case of mild disease). When PGx testing was for one's child, parents valued their own understanding more than their child's assent (P = 1.57 * 10(-17)). CONCLUSIONS: The acceptability of PGx testing, either for oneself or for one's child, seemed to depend on baseline PGx knowledge, but not on parenthood. PMID- 24777222 TI - Cervical spine injury patterns in children. AB - BACKGROUND AND OBJECTIVE: Pediatric cervical spine injuries (CSIs) are rare and differ from adult CSIs. Our objective was to describe CSIs in a large, representative cohort of children. METHODS: We conducted a 5-year retrospective review of children <16 years old with CSIs at 17 Pediatric Emergency Care Applied Research Network hospitals. Investigators reviewed imaging reports and consultations to assign CSI type. We described cohort characteristics using means and frequencies and used Fisher's exact test to compare differences between 3 age groups: <2 years, 2 to 7 years, and 8 to 15 years. We used logistic regression to explore the relationship between injury level and age and mechanism of injury and between neurologic outcome and cord involvement, injury level, age, and comorbid injuries. RESULTS: A total of 540 children with CSIs were included in the study. CSI level was associated with both age and mechanism of injury. For children <2 and 2 to 7 years old, motor vehicle crash (MVC) was the most common injury mechanism (56%, 37%). Children in these age groups more commonly injured the axial (occiput-C2) region (74%, 78%). In children 8 to 15 years old, sports accounted for as many injuries as MVCs (23%, 23%), and 53% of injuries were subaxial (C3-7). CSIs often necessitated surgical intervention (axial, 39%; subaxial, 30%) and often resulted in neurologic deficits (21%) and death (7%). Neurologic outcome was associated with cord involvement, injury level, age, and comorbid injuries. CONCLUSIONS: We demonstrated a high degree of variability of CSI patterns, treatments and outcomes in children. The rarity, variation, and morbidity of pediatric CSIs make prompt recognition and treatment critical. PMID- 24777229 TI - Reducing unplanned extubations in the NICU. AB - BACKGROUND AND OBJECTIVES: Unplanned extubation can be a significant event that places the patient at risk for adverse events. Our goal was to reduce unplanned extubations to <1 unplanned extubation per 100 patient-intubated days. METHODS: All unplanned extubations in the NICU beginning in October 2009 were audited. Data collected included time of day, patient weight, and patient care activity at the time of the event. Bundles of potentially better practices were implemented in sequential Plan-Do-Study-Act cycles. Rates of unplanned extubation (number per patient-intubated day) for each month were analyzed by using control charts, and causes of unplanned extubation were analyzed by using Pareto charts. RESULTS: We found a significant decrease in the unplanned extubation rate after implementation of the first bundle of potentially better practices in May 2010 (2.38 to 0.41 per 100 patient-intubated days). Several more Plan-Do-Study-Act cycles were conducted to sustain this improvement. A persistent reduction in the unplanned extubation rate (0.58 per 100 patient-intubated days) began in February 2013. Causes included dislodgement during care and procedures and variation in the fixation of the endotracheal tube. The majority of events occurred in very low birth weight infants during the daytime shift. CONCLUSIONS: Unplanned extubations in the NICU can be reduced by education of staff and by implementing standard practices of care. Sustainability of any practice change to improve quality is critically dependent on culture change within the NICU. We suggest that the benchmark for unplanned extubation should be a rate <1 per 100 patient intubated days. PMID- 24777224 TI - Neonatal outcomes of prenatally diagnosed congenital pulmonary malformations. AB - BACKGROUND AND OBJECTIVE: Congenital pulmonary malformations (CPM) are mostly recognized on prenatal ultrasound scans. In a minority of cases, they may impair breathing at birth. The factors predictive of neonatal respiratory distress are not well defined, but an understanding of these factors is essential for decisions concerning the need for the delivery to take place in a tertiary care center. The aim of this study was to identify potential predictors of respiratory distress in neonates with CPM. METHODS: We selected cases of prenatal diagnosis of hyperechoic and/or cystic lung lesions from RespiRare, the French prospective multicenter registry for liveborn children with rare respiratory diseases (2008 2013). Prenatal parameters were correlated with neonatal respiratory outcome. RESULTS: Data were analyzed for 89 children, 22 (25%) of whom had abnormal breathing at birth. Severe respiratory distress, requiring oxygen supplementation or ventilatory support, was observed in 12 neonates (13%). Respiratory distress at birth was significantly associated with the following prenatal parameters: mediastinal shift (P = .0003), polyhydramnios (P = .05), ascites (P = .0005), maximum prenatal malformation area (P = .001), and maximum congenital pulmonary malformation volume ratio (CVR) (P = .001). Severe respiratory distress, requiring oxygen at birth, was best predicted by polyhydramnios, ascites, or a CVR >0.84. CONCLUSIONS: CVR >0.84, polyhydramnios, and ascites increased the risk of respiratory complications at birth in fetuses with CPM, and especially of severe respiratory distress, requiring oxygen supplementation or more intensive intervention. In such situations, the delivery should take place in a tertiary care center. PMID- 24777230 TI - Addendum--adolescent pregnancy: current trends and issues. PMID- 24777226 TI - Pediatric anthrax clinical management. AB - Anthrax is a zoonotic disease caused by Bacillus anthracis, which has multiple routes of infection in humans, manifesting in different initial presentations of disease. Because B anthracis has the potential to be used as a biological weapon and can rapidly progress to systemic anthrax with high mortality in those who are exposed and untreated, clinical guidance that can be quickly implemented must be in place before any intentional release of the agent. This document provides clinical guidance for the prophylaxis and treatment of neonates, infants, children, adolescents, and young adults up to the age of 21 (referred to as "children") in the event of a deliberate B anthracis release and offers guidance in areas where the unique characteristics of children dictate a different clinical recommendation from adults. PMID- 24777231 TI - Revisiting the quality chasm. PMID- 24777233 TI - Characterization of T cell epitopes in bovine alpha-lactalbumin. AB - BACKGROUND: Recent studies have indicated that peptides containing T cell epitopes may be used for immunotherapy. While for several cow's milk allergens the T cell epitopes have been described, the T cell epitopes in the major allergen alpha-lactalbumin (alpha-LAC) are unknown. Therefore, the aim of this study was to determine the T cell epitopes in alpha-LAC. METHODS: Nineteen synthetic peptides spanning alpha-LAC were obtained. Cow's milk-specific T cell lines (TCLs) of 46 subjects were generated and tested for their specificity for alpha-LAC. The lines responding to alpha-LAC were subsequently tested to determine their activation in response to the peptides. RESULTS: More than half of the TCLs generated did not respond to alpha-LAC or lost their responsiveness during subsequent experiments, which indicates that alpha-LAC has low immunogenicity. Only 8 TCLs recognized 1 or more peptides. The recognition of the peptides was diverse and no major epitopes could be defined. CONCLUSION: The immunogenicity of alpha-LAC is very low compared to other major allergens in cow's milk. Moreover, there seems to be no dominant epitope present in the protein. Therefore, it seems unlikely that peptides of this protein can be used for immunotherapy. PMID- 24777234 TI - Predominance of covalency in water-vapor-responsive MMX-type chain complexes revealed by (129)I Mossbauer spectroscopy. AB - (129)I Mossbauer spectroscopy was applied to water-vapor-responsive MMX-type quasi-one-dimensional iodide-bridged Pt complexes (MMX chains) in order to investigate their electronic state quantitatively. Two sets of octuplets observed in K2(H3NC3H6NH3)[Pt2(pop)4I].4H2O (2.4H2O) and one octuplet observed in K2(cis H3NCH2CH=CHCH2NH3)[Pt2(pop)4I].4H2O (1.4H2O) and dehydrated complexes (1 and 2) indicate a unique alternating charge-polarization + charge-density-wave (ACP + CDW) electronic state and a charge-density-wave (CDW) electronic state, respectively. These spectra correspond to their crystal structure and the change of electronic states upon dehydration. Since these complexes consist of an alternating array of positively charged and negatively charged layers, the charge on the iodide ion (rhoIS) was discussed on the basis of the isomer shift (IS). The rhoIS of the water-vapor-responsive MMX chains was mainly -0.13 to -0.21, which are the smallest of all MMX chains reported so far. Hence, it indicates that the negative charge on the iodide ion is strongly donated to the Pt ion in these complexes. This covalent interaction predominates in the ACP + CDW state as well as in the CDW state. Therefore, the ACP + CDW state is in fact the CDW state with the ACP-type lattice distortion. Because the rhoIS became smaller with the decreasing Pt-I-Pt distance, it can be concluded that the covalent interaction plays an important role in determining the electronic states of the MMX chains with pop (= P2H2O5(2-)) ligands. PMID- 24777232 TI - Dipstick screening for urinary tract infection in febrile infants. AB - OBJECTIVE: This study compares the performance of urine dipstick alone with urine microscopy and with both tests combined as a screen for urinary tract infection (UTI) in febrile infants aged 1 to 90 days. METHODS: We queried the Intermountain Healthcare data warehouse to identify febrile infants with urine dipstick, microscopy, and culture performed between 2004 and 2011. UTI was defined as >50 000 colony-forming units per milliliter of a urinary pathogen. We compared the performance of urine dipstick with unstained microscopy or both tests combined ("combined urinalysis") to identify UTI in infants aged 1 to 90 days. RESULTS: Of 13 030 febrile infants identified, 6394 (49%) had all tests performed and were included in the analysis. Of these, 770 (12%) had UTI. Urine culture results were positive within 24 hours in 83% of UTIs. The negative predictive value (NPV) was >98% for all tests. The combined urinalysis NPV was 99.2% (95% confidence interval: 99.1%-99.3%) and was significantly greater than the dipstick NPV of 98.7% (98.6%-98.8%). The dipstick positive predictive value was significantly greater than combined urinalysis (66.8% [66.2%-67.4%] vs 51.2% [50.6%-51.8%]). These data suggest 8 febrile infants would be predicted to have a false-positive combined urinalysis for every 1 infant with UTI initially missed by dipstick screening. CONCLUSIONS: Urine dipstick testing compares favorably with both microscopy and combined urinalysis in febrile infants aged 1 to 90 days. The urine dipstick test may be an adequate stand-alone screen for UTI in febrile infants while awaiting urine culture results. PMID- 24777238 TI - Subwavelength imaging in the visible range using a metal coated carbon nanotube forest. AB - We demonstrate subwavelength imaging in the visible range by using a metal coated carbon nanotube forest. Under 532 nm illumination, a 160 nm separated double slit is resolved. This corresponds to the resolution of 0.3 wavelength. By controlling the growing conditions and with the help of the microtoming technique, we made a dense carbon nanotube forest layer of 400 nm thickness. The metal coated carbon nanotube forest, acting as a wire medium nanolens, delivers imaging information including details in the evanescent fields near the objects. PMID- 24777237 TI - Translational research of herniated discs: current status of diagnosis and treatment. AB - Lumbar herniated discs commonly occur in patients 20-40 years of age, and result in acute symptoms of shooting and intractable pain in the low back and/or lower extremities. However, the prognosis of these patients is considered to be very good. Moreover, 70% of these patients have been reported to be free from sciatica at approximately 6 months after the first onset. Magnetic resonance imaging (MRI) studies have described the spontaneous resorption process of herniated discs, which is a major cause of the reduction of symptoms in patients. New advancements in MRI have recently been developed that have facilitated the examination of nerve tract fibers and identification of symptomatic nerve tissue. Furthermore, the mechanism underlying the resorption process of a herniated disc has been determined. Inflammatory cytokines such as TNF (tumor necrosis factor)-alpha, angiogenic factors such as vascular endothelial growth factor, and enzymes such as matrix metalloproteinases are intricately related to each other. In our previous studies, matrix metalloproteinase-7 (MMP-7) has been shown to play a crucial role in the initiation of herniated disc resorption. Therefore, we developed recombinant human MMP-7 for intradiscal therapy through an industry university joint research program. We have already performed in vitro and in vivo experiments to confirm its efficacy; this therapy avoids the side effects associated with surgery, such as nerve tissue damage. Moreover, the phase 1/2 studies of recombinant human (rh) MMP-7 are currently ongoing in the United States, and careful monitoring is required for these clinical trials. In conclusion, patients with lumbar herniated discs may benefit from the development of a less invasive treatment for disc herniation, which can be applied even immediately after the onset of disease symptoms. PMID- 24777239 TI - Pd and Au@Pd nanodendrites: a one-pot synthesis and their superior catalytic properties. AB - We developed a facile one-pot synthetic strategy to prepare highly branched metal nanocrystals including monometallic Pd and bimetallic Au@Pd nanodendrites, and demonstrated their superior catalytic properties. PMID- 24777240 TI - Toward a view-oriented approach for aligning RDF-based biomedical repositories. AB - INTRODUCTION: This article is part of the Focus Theme of METHODS of Information in Medicine on "Managing Interoperability and Complexity in Health Systems". BACKGROUND: The need for complementary access to multiple RDF databases has fostered new lines of research, but also entailed new challenges due to data representation disparities. While several approaches for RDF-based database integration have been proposed, those focused on schema alignment have become the most widely adopted. All state-of-the-art solutions for aligning RDF-based sources resort to a simple technique inherited from legacy relational database integration methods. This technique - known as element-to-element (e2e) mappings is based on establishing 1:1 mappings between single primitive elements - e.g. concepts, attributes, relationships, etc. - belonging to the source and target schemas. However, due to the intrinsic nature of RDF - a representation language based on defining tuples < subject, predicate, object > -, one may find RDF elements whose semantics vary dramatically when combined into a view involving other RDF elements - i.e. they depend on their context. The latter cannot be adequately represented in the target schema by resorting to the traditional e2e approach. These approaches fail to properly address this issue without explicitly modifying the target ontology, thus lacking the required expressiveness for properly reflecting the intended semantics in the alignment information. OBJECTIVES: To enhance existing RDF schema alignment techniques by providing a mechanism to properly represent elements with context-dependent semantics, thus enabling users to perform more expressive alignments, including scenarios that cannot be adequately addressed by the existing approaches. METHODS: Instead of establishing 1:1 correspondences between single primitive elements of the schemas, we propose adopting a view-based approach. The latter is targeted at establishing mapping relationships between RDF subgraphs - that can be regarded as the equivalent of views in traditional databases -, rather than between single schema elements. This approach enables users to represent scenarios defined by context-dependent RDF elements that cannot be properly represented when adopting the currently existing approaches. RESULTS: We developed a software tool implementing our view-based strategy. Our tool is currently being used in the context of the European Commission funded p-medicine project, targeted at creating a technological framework to integrate clinical and genomic data to facilitate the development of personalized drugs and therapies for cancer, based on the genetic profile of the patient. We used our tool to integrate different RDF-based databases - including different repositories of clinical trials and DICOM images - using the Health Data Ontology Trunk (HDOT) ontology as the target schema. CONCLUSIONS: The importance of database integration methods and tools in the context of biomedical research has been widely recognized. Modern research in this area - e.g. identification of disease biomarkers, or design of personalized therapies - heavily relies on the availability of a technical framework to enable researchers to uniformly access disparate repositories. We present a method and a tool that implement a novel alignment method specifically designed to support and enhance the integration of RDF-based data sources at schema (metadata) level. This approach provides an increased level of expressiveness compared to other existing solutions, and allows solving heterogeneity scenarios that cannot be properly represented using other state-of-the-art techniques. PMID- 24777241 TI - Fat-removal orbital decompression for disfiguring proptosis associated with Graves' ophthalmopathy: safety, efficacy and predictability of outcomes. AB - The objective of this study was to analyse clinical outcomes of patient who underwent fat-removal orbital decompression (FROD) for disfiguring proptosis associated with Graves' ophthalmopathy. This is a retrospective review of 21 eyes of 11 patients who have received transforniceal FROD for disfiguring Graves' exophthalmos at the Hong Kong Eye Hospital from January 2009 to March 2012. The amount of orbital fat removed and proptosis reduction in terms of Hertel value and complications were evaluated. The mean volume of orbital fat removed was 4.0 +/- 1.1 ml (range 1.6-5.5 ml), and the mean change of Hertel value was 4.2 +/- 1.3 (range 1-6, p < 0.000). None has visual loss or new-onset diplopia at primary gaze after FROD. No complications such as retrobulbar haemorrhage, meningitis, sinusitis, tissue necrosis, infraorbital paraesthesia or unsightly scar were observed. FROD could achieve reasonable proptosis reduction. It had a good safety profile, and results were predictable. PMID- 24777242 TI - An exciting collaboration between AACR and CRI. PMID- 24777243 TI - A message from the founding editor-in-chief. PMID- 24777244 TI - Logic of the immune system. AB - Our immune system evolves under continuous selection to protect us against pathogens, a trait that can be used to deploy the immune system or its component parts for diagnostic and therapeutic purposes in cancer. What follows is a thumbnail sketch of the logic that underlies immune recognition, so that those not directly active in the field of immunology may grasp both possibilities and pitfalls when considering applying the tools and concepts of immunology to cancer and cancer therapy. PMID- 24777246 TI - 2013 AACR-Cancer Research Institute Lloyd J. Old Award in Cancer Immunology. PMID- 24777245 TI - Getting personal with neoantigen-based therapeutic cancer vaccines. AB - Despite years of preclinical efforts and hundreds of clinical studies, therapeutic cancer vaccines with the routine ability to limit or eliminate tumor growth in humans have been elusive. With advances in genome sequencing, it is now possible to identify a new class of tumor-specific antigens derived from mutated proteins that are present only in the tumor. These "neoantigens" should provide highly specific targets for antitumor immunity. Although many challenges remain in producing and testing neoantigen-based vaccines customized for each patient, a neoantigen vaccine offers a promising new approach to induce highly focused antitumor T cells aimed at eradicating cancer cells. PMID- 24777247 TI - T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. AB - T cells can be redirected to overcome tolerance to cancer by engineering with integrating vectors to express a chimeric antigen receptor (CAR). In preclinical models, we have previously shown that transfection of T cells with mRNA coding for a CAR is an alternative strategy that has antitumor efficacy and the potential to evaluate the on-target off-tumor toxicity of new CAR targets safely due to transient mRNA CAR expression. Here, we report the safety observed in four patients treated with autologous T cells that had been electroporated with mRNA coding for a CAR derived from a murine antibody to human mesothelin. Because of the transient nature of CAR expression on the T cells, subjects in the clinical study were given repeated infusions of the CAR-T cells to assess their safety. One subject developed anaphylaxis and cardiac arrest within minutes of completing the third infusion. Although human anti-mouse immunoglobulin (Ig)G antibodies have been known to develop with CAR-transduced T cells, they have been thought to have no adverse clinical consequences. This is the first description of clinical anaphylaxis resulting from CAR-modified T cells, most likely through IgE antibodies specific to the CAR. These results indicate that the potential immunogenicity of CARs derived from murine antibodies may be a safety issue for mRNA CARs, especially when administered using an intermittent dosing schedule. PMID- 24777248 TI - Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. AB - Antitumor activity of CTLA-4 antibody blockade is thought to be mediated by interfering with the negative regulation of T-effector cell (Teff) function resulting from CTLA-4 engagement by B7-ligands. In addition, a role for CTLA-4 on regulatory T cells (Treg), wherein CTLA-4 loss or inhibition results in reduced Treg function, may also contribute to antitumor responses by anti-CTLA-4 treatment. We have examined the role of the immunoglobulin constant region on the antitumor activity of anti-CTLA-4 to analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies. Anti-CTLA-4 antibody containing the murine immunoglobulin G (IgG)2a constant region exhibits enhanced antitumor activity in subcutaneous established MC38 and CT26 colon adenocarcinoma tumor models compared with anti-CTLA-4 containing the IgG2b constant region. Interestingly, anti-CTLA-4 antibodies containing mouse IgG1 or a mutated mouse IgG1-D265A, which eliminates binding to all Fcgamma receptors (FcgammaR), do not show antitumor activity in these models. Assessment of Teff and Treg populations at the tumor and in the periphery showed that anti-CTLA-4-IgG2a mediated a rapid and dramatic reduction of Tregs at the tumor site, whereas treatment with each of the isotypes expanded Tregs in the periphery. Expansion of CD8(+) Teffs is observed with both the IgG2a and IgG2b anti-CTLA-4 isotypes, resulting in a superior Teff to Treg ratio for the IgG2a isotype. These data suggest that anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral Tregs along with concomitant activation of Teffs. PMID- 24777249 TI - Myeloid-derived suppressor cells attenuate TH1 development through IL-6 production to promote tumor progression. AB - Collaborative action between tumor cells and host-derived suppressor cells leads to peripheral tolerance of T cells to tumor antigens. Here, we showed that in tumor-bearing mice, generation of tumor antigen-specific effector T-helper cells (TH1) was significantly attenuated, and impaired TH1 differentiation was restored by the temporal blockade of interleukin (IL)-6 activity at the T-cell priming phase. Furthermore, we found that Gr-1(+) myeloid-derived suppressor cells (MDSC) served as a source of IL-6 in tumor-bearing mice. Adoptive transfer of effector CD4(+) T cells revealed that MDSC-sensitized effector CD4(+) T cells were less potent in mounting antitumor immune responses, although effector T cells generated together with Gr-1(+) cells from tumor-free mice eradicated established tumors. CD8(+) T cells, IFN-gamma, and MHC-class II expression in host mice were indispensable for the antitumor activity initiated by effector CD4(+) T cells. Despite comparable suppressive activity of IL-6(+/+) and IL-6(-/-) MDSC on primary T-cell activation, transfer of IL-6(+/+) MDSC, but not IL-6(-/-) MDSC, dampened the efficient induction of effector TH1 cells and counteracted CD4(+) T cell-mediated antitumor immunity including cognate help for CD8(+) T cells in vivo. These findings suggest that, apart from the inhibitory effects on primary T cell activation, MDSC promote tumor progression by attenuating functional differentiation of tumor-specific CD4(+) T cells into effector TH1 cells through IL-6 production to promote tumor progression. This novel mode of MDSC-induced tolerance of effector CD4(+) T cells should be considered as the basis for the rational design of effective T cell-mediated antitumor therapies. PMID- 24777250 TI - Mycophenolate-associated bronchiectasis. PMID- 24777251 TI - 'Lnc'-ing enhancers to MYC regulation. AB - Long noncoding RNAs (lncRNAs) are emerging as important functional components in the establishment of long-range chromosomal interactions. In a recent paper published in Cell Research, Xiang et al. provide mechanistic insight into this phenomenon by characterizing the role of CCAT1-L, a colorectal cancer-specific lncRNA, in intra-chromosome looping between the MYC gene promoter and distal upstream enhancer elements that regulate MYC transcription. PMID- 24777253 TI - Efficacy and safety of dutasteride for the treatment of symptomatic benign prostatic hyperplasia (BPH): a systematic review and meta-analysis. PMID- 24777252 TI - CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation. AB - Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage proliferation is promoted by macrophage colony-stimulating factor (M-CSF)-induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2-interacting protein-1 (CKIP-1) as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP-1 was phosphorylated at Serine 342 by constitutively active GSK3beta, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degradation of CKIP-1. Upon M-CSF stimulation, Akt is activated by CSF-1R-PI3K and then inactivates GSK3beta, leading to the stabilization of CKIP-1 and beta-catenin proteins. beta-catenin promotes the expression of proliferation genes including cyclin D and c-Myc. CKIP-1 interacts with TRAF6, a ubiquitin ligase required for K63-linked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6-mediated Akt activation. By this means, CKIP-1 inhibits macrophage proliferation specifically at the late stage after M-CSF stimulation. Furthermore, CKIP-1 deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1(-/-) mice spontaneously develop a macrophage-dominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation. PMID- 24777254 TI - Comparative pilot study of implantation techniques for pudendal neuromodulation: technical and clinical outcome in first 20 patients with chronic pelvic pain. AB - PURPOSE: Neurostimulation of the pudendal nerve (PN) is considered for patients who have failed sacral neuromodulation. Previous techniques for PN localization are described to be uncomplicated and promise to achieve accuracy in electrode placement. However, in clinical use, they appear challenging. We developed a puncture technique using fixed anatomical landmarks for a fast and reproducible localization of the PN. METHODS: Full-body cadavers and dissected anatomical preparations were studied for the course of the PN. Fluoroscopically controlled fixed anatomical landmarks locating the pudendal trunk were defined. Lead placement following established techniques was performed, and the topographic relationship to the PN was documented by dissection. In a pilot series of 20 patients with chronic pelvic pain, pudendal neuromodulation (PNM) was performed uni- and bilateral using the different approaches. Technical and clinical outcomes of the various techniques were compared. RESULTS: Fixed anatomical landmarks such as ischial spine, ischial tuberosity, acetabulum and anal rim resulted in a right-angled triangle with a new start and target point for puncture. Initials of the landmarks add up to the teaching acronym STAR. STAR technique including a puncture angle of 60 degrees and a gluteal lead exit places 3-4 electrode poles at the nerve. In clinical trial, mean operation time for bilateral PNM in STAR was 85 min with mean puncture attempts of 3.5 to reach the nerve. Pain decreased statistically significant only in bilateral PNM. CONCLUSIONS: The STAR approach appears to achieve technical standardisation and optimized reproducibility in pudendal lead placement resulting into an increased feasibility of PNM. PMID- 24777255 TI - Cocaine constriction of rat basilar artery in situ: roles of nitric oxide and endothelin-1. AB - This study investigated whether cocaine constriction of rat basilar artery in situ is mediated by nitric oxide (NO) inhibition and/or endothelin (ET)-1 release. Cocaine (3-100 umol/l) concentration-dependently constricted the basilar artery to a maximum of 18%. Nomega-nitro-L-arginine (100 umol/l) was without effect on constriction to 3 and 10 umol/l cocaine. PD145065 (1 and 10 umol/l), an ETA/B receptor antagonist, variably and at most partially inhibited the 100 umol/l cocaine constriction. Capsaicin denervation of sensory nerves innervating the basilar, which contain ET-1 and NO synthase, also failed to influence cocaine constriction. These findings suggest that cocaine constriction of cerebral vessels (1) varies with respect to the involvement of ET-1 release and (2) unlike findings in the peripheral vasculature, the constriction is not mediated by inhibition of NO. PMID- 24777256 TI - Beyond deficits: intimate partner violence, maternal parenting, and child behavior over time. AB - Exposure to intimate partner violence (IPV) has negative consequences for children's well-being and behavior. Much of the research on parenting in the context of IPV has focused on whether and how IPV victimization may negatively shape maternal parenting, and how parenting may in turn negatively influence child behavior, resulting in a deficit model of mothering in the context of IPV. However, extant research has yet to untangle the interrelationships among the constructs and test whether the negative effects of IPV on child behavior are indeed attributable to IPV affecting mothers' parenting. The current study employed path analysis to examine the relationships among IPV, mothers' parenting practices, and their children's externalizing behaviors over three waves of data collection among a sample of 160 women with physically abusive partners. Findings indicate that women who reported higher levels of IPV also reported higher levels of behavior problems in their children at the next time point. When parenting practices were examined individually as mediators of the relationship between IPV and child behavior over time, one type of parenting was significant, such that higher IPV led to higher authoritative parenting and lower child behavior problems [corrected]. On the other hand, there was no evidence that higher levels of IPV contributed to more child behavior problems due to maternal parenting. Instead, IPV had a significant cumulative indirect effect on child behavior via the stability of both IPV and behavior over time. Implications for promoting women's and children's well-being in the context of IPV are discussed. PMID- 24777257 TI - Blepharophimosis syndrome with absent tear production. AB - The purpose of this report was to present a case of congenital alacrima in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). A 9 month-old boy presented with characteristic clinical findings of BPES confirmed by genetic testing. On further history taking and evaluation, the patient was noted to have no tear production, despite clinically present palpebral lobes of the lacrimal glands. BPES is an autosomal dominant condition characterized by narrowed horizontal palpebral fissures, severe bilateral symmetric ptosis, epicanthus inversus, and telecanthus. To the authors' knowledge, this represents the second reported case of congenital alacrima in this syndrome. The first case described in the literature was in a 9-month-old girl who had congenital absence of the lacrimal glands. BPES may present with alacrima requiring vigilant lifelong lubrication and careful consideration in decisions for eyelid surgery including ptosis repair. PMID- 24777258 TI - Eyelid desmoplastic trichilemmoma: 2 case reports and review. AB - Desmoplastic trichilemmomas (DTs) are a rare variant of trichilemmomas first described in 1985. Since then, 11 cases involving the eyelid have been reported. Two cases of this study raise this total to 13. DTs are often clinically confused with basal cell carcinoma and must be proven by biopsy to obtain the correct diagnosis. These lesions are more commonly present in patients older than 50 years. Despite the fact that they are benign, they are often associated with basal cell carcinomas and as such should be managed carefully, requiring excisional biopsy with frozen borders or Mohs controlled margins. PMID- 24777259 TI - Safety of onabotulinum toxin a injection to the central upper eyelid and eyebrow regions. AB - PURPOSE: To evaluate the safety of onabotulinum toxin A injected into the central upper eyelid and eyebrow regions. METHODS: The authors retrospectively reviewed the charts of all patients undergoing onabotulinum toxin A injection to the central upper eyelid and eyebrow between February, 2012, and November, 2012. Age, gender, indication, injection sites, number of central units, total number of units, and occurrence of adverse events were all recorded. RESULTS: A total of 300 procedures on 88 patients were performed, in whom the central upper eyelid and/or central eyebrow was injected with onabotulinum toxin A. There were 68 female and 20 male patients. Average age was 68.7+/-13.3 years (range, 42-92 years). Indications for central eyelid/eyebrow treatment included blepharospasm (34 patients, 176 procedures), hemifacial spasm (21 patients, 40 procedures), facial nerve disorders (2 patients, 9 procedures), and facial rhytides/eyebrow ptosis (31 patients, 75 procedures). The amount of neurotoxin injected into the central eyelid and eyebrow ranged from 2 to 12.5 units per encounter. Complications included diplopia (4% of total encounters), lagophthalmos (1% of total encounters), blepharoptosis (1% of total encounters), and blurry vision (1% of total encounters). Minor local effects, including bruising, bleeding, pain, and mild swelling, were recorded in 3.3% of total encounters. CONCLUSIONS: Placement of onabotulinum toxin A into the central upper eyelid and eyebrow is associated with a low rate of blepharoptosis. Central eyelid and eyebrow neurotoxin injection can be safely added to the regimen when treatment calls for chemodenervation of the central orbicularis oculi. PMID- 24777260 TI - Stereotactic microdebrider in deep lateral orbital decompression for patients with thyroid eye disease. AB - PURPOSE: Stereotactic navigation systems have been used in neurosurgery and otolaryngology with great success. The current investigation illustrates the novel use of a microdebrider with built-in stereotactic guidance in a series of thyroid orbitopathy patients who underwent deep lateral orbital wall decompression surgery. METHODS: A noncomparative, interventional, retrospective case series of patients who underwent deep lateral deep orbital wall decompression from 2006 to 2013 was conducted in accordance with Institutional Review Board policy and the Declaration of Helsinki. Patient demographics, indications for surgery, pre-, intra-, and postoperative findings along with complications were recorded. RESULTS: One hundred eight deep lateral orbital decompression surgeries were performed in 69 patients using the Straightshot M4 Microdebrider with built-in stereotactic guidance (Medtronics). Seventy-eight cases were in women and 30 cases were in men. The average age was 50.4 years (SD = 11.9 years). Indications for surgery included proptosis, exposure keratopathy, or compressive optic neuropathy. No patient experienced intraoperative complications. Specifically, cerebrospinal fluid leak, visual loss, infection, or unanticipated inflammation were not encountered. The average postoperative follow up time was 5.35 months. Mean reduction in proptosis was 3.72 mm (SD = 2.1). Visual acuity improved in 32.4% (35/108) of cases. CONCLUSIONS: This surgical instrument combines a single handpiece locator, microdebrider, irrigator, retractor, and suction device into one. It enhances anatomical localization during orbital decompression and, with an integrated tissue guard, may decrease the risk of injury to orbital soft tissues. Stereotactic navigation enhances the surgeon's ability to determine the maximal limits of decompression in real time by confirming depth of bone removal and may potentially increase surgeons' confidence in orbital decompression surgery. PMID- 24777261 TI - UV-independent p53 mutations in sebaceous carcinoma of the eyelid. AB - PURPOSE: Sebaceous carcinoma of the eyelid is a potentially fatal malignancy that has been associated with p53 gene mutations. The purpose of this study is to determine the frequency of p53 mutations in sebaceous carcinoma of the eyelid and to determine whether there is any relationship between the presence of p53 mutations and tumor invasiveness. METHODS: Retrospective case series. Fourteen samples of sebaceous carcinoma that had been resected from Caucasian patients between 1994 and 2010 were analyzed for p53 gene mutations with PCR and Sequencher software. Patient charts were reviewed to draw clinicopathologic correlations in relation with the presence of p53 gene mutations. RESULTS: Seven of 14 (50%) sebaceous carcinoma samples were found to have p53 gene mutations. None of the samples had tandem mutations, which are caused by UV exposure. No statistically significant trend was found between the presence of p53 mutations and metastasis, recurrence, tumor size, TNM stage, and pagetoid spread. There was a similar frequency of p53 gene mutations found in stage T1, T2, and T3 tumors. CONCLUSIONS: p53 Mutations are found in a high percentage of sebaceous carcinomas in the Caucasian population. The absence of tandem mutations is consistent with the belief that sebaceous carcinoma develops as a UV-independent process. There does not appear to be a significant correlation between the presence of p53 mutations and tumor size, recurrence, metastasis, pagetoid spread, or location. The similar frequency of p53 mutations in both low- and high-stage tumors implies that p53 gene mutations may be involved in early stages of carcinogenesis of sebaceous carcinoma. PMID- 24777262 TI - MRI findings of myocutaneous and fasciocutaneous flaps used for reconstruction of orbital exenteration defects. AB - PURPOSE: To facilitate detection of tumor recurrence, the authors reviewed the MRI characteristics of myocutaneous and fasciocutaneous free flaps following orbital exenteration for treatment of orbital or maxillofacial tumors. METHODS: The authors retrospectively reviewed the MRI characteristics, including T1 and T2 signal intensity, and enhancement pattern of 28 such flaps. RESULTS: The study included 17 myocutaneous flaps and 11 fasciocutaneous flaps placed in 28 patients. For 23 flaps, additional imaging was performed after baseline imaging (range, 2-65 months after surgery). On precontrast T1 imaging, 15 of 17 myocutaneous flaps demonstrated a striated appearance similar to that of native muscle. Twenty-six of the 28 flaps in the series were T2 hyperintense. On baseline imaging, 26 flaps showed linear (n = 5), patchy (n = 10), or homogeneous (n = 11) enhancement. No flaps demonstrated mass-like enhancement. Five fasciocutaneous and 5 myocutaneous flaps showed decreased enhancement on follow up imaging, while 4 myocutaneous flaps showed increased enhancement. Fourteen patients received postoperative radiation, 4 of which demonstrated increased enhancement, which subsequently decreased in 3 flaps. Fourteen of 23 followed flaps became smaller over time. CONCLUSIONS: On MRI, both myocutaneous and fasciocutaneous flaps placed after orbital exenteration generally demonstrate persistent non-mass-like enhancement and T2 hyperintensity, and both types of flaps may become smaller over time. Head and neck radiologists, ophthalmologic and plastic surgeons, and oncologists should be aware of the range of imaging features of these flaps to avoid misinterpreting the postoperative appearance as tumor recurrence. PMID- 24777263 TI - Favre-Racouchot Disease of the Periocular Region. AB - This study details the case of periocular Favre-Racouchot disease an often underdiagnosed entity with a complex differential diagnosis. This is an unusual condition that can potentially affect the periocular region; however, there is little information regarding Favre-Racouchot disease reported in the peer reviewed ophthalmology literature. Increased awareness of Favre-Racouchot disease among ophthalmologists, oculofacial surgeons, and other specialists can lead to proper diagnosis impacting treatment options and patient outcome. PMID- 24777264 TI - Graded mullerectomy for correction of graves upper eyelid retraction: effect on eyelid movements. AB - PURPOSE: To measure the effect of mullerectomy from posterior approach on the amplitudes of spontaneous blinking and downward eyelid saccades. METHODS: Spontaneous blinks and downward upper eyelid saccadic movements of 16 patients (23 eyelids) with Graves orbitopathy were measured before and after mullerectomy from posterior approach. A new video system was used to continuously register the blinking activity while subjects viewed a commercial movie for 5 minutes. Downward eyelid saccades (30 degrees of downgaze) were also measured with the video system. RESULTS: Mullerectomy had no effect on the amplitude of the blink. However, as the eyelid margins were significantly lowered by the surgery, the amplitude of the blink movements relative to the pupil center increased substantially. The number of movements occluding the pupil center increased from 0% to 13%. Due to the increased efficiency of blinking, the blink rate decreased. Surgery induced a mean increase of 1.1 mm of downward saccades. CONCLUSIONS: The effects of mullerectomy on the blinks are indirect and related to correction of eyelid retraction. The relative amplitude of blink movements increases and blink rate decreases. Mullerectomy does affect the downward eyelid saccades increasing the ability of the upper eyelid to relax on downgaze. PMID- 24777265 TI - Foam sclerotherapy for periorbital dermoid cysts. AB - PURPOSE: To report nonsurgical treatment of periorbital dermoid cysts with foam sclerotherapy using sodium tetradecyl sulfate (STS). METHODS: Single-center, retrospective, interventional case series. Clinical records of all patients diagnosed to have congenital orbital dermoid cyst and treated with STS foam sclerotherapy between 2012 and 2013 were reviewed. The ectodermal contents of the dermoid cyst were aspirated through a stab incision with 18G needle, followed by saline lavage. Intraluminal foam sclerotherapy was then performed using STS (30 mg/ml) in a proportion of 10% of the total aspirate volume. Retrospective data analysis included demographic profile, clinicoradiologic findings, and treatment outcomes of foam sclerotherapy. RESULTS: Four patients were treated in the given period. Average age at presentation was 20.2 years. All cysts were reported to be congenital in nature, and the location was medial angular in 2 cases, lateral angular in 1 case, and lateral orbitotemporal in 1 case. The average aspirate of the pultaceous cyst content was 3.75 ml (range, 2-5 ml). Of the 4 patients, 2 dermoid cysts resolved completely within 8 weeks. Two cysts showed partial response and required a second foam sclerotherapy to achieve complete resolution. At an average follow up of 13.25 months (range, 11-16 months), complete cyst resolution was noted. No sclerotherapy-related complications were observed. CONCLUSIONS: Foam sclerotherapy is successful in obliterating periorbital dermoid cysts and provides a minimally invasive nonsurgical approach to achieve an aesthetic result. PMID- 24777266 TI - LESCs: Lateralizing Eyelid Sleep Compression Study. AB - PURPOSE: To study the hypothesis that in normal patients, changes in eyelid elasticity may occur asymmetrically and in relation to the side on which the individual sleeps. DESIGN: Prospective, consecutive, single-center study within a large, tertiary-referral ophthalmology department within a university hospital. METHODS: This prospective study was carried out consecutively on 262 normal patients. The 3 inclusion criteria were 1) age>=55 years, 2) absence of facial nerve palsy, and 3) absence of eyelid trauma or surgery. Immediately before the ocular plastic surgeon assessed the patient, each patient was questioned in a separate consulting room by the attending orthoptist as to his or her customary side of sleeping. After detailed explanation, the "history-masked" ocular plastic surgeon then assessed the patient's upper eyelid laxity, the main outcome measurement. This was performed by asking the seated patient to look down and then gently grasping the upper eyelids close to the eyelid margin, just medial to the lateral commissure. The ocular plastic surgeon, with thumbs pronated, simultaneously distracted both upper eyelids superiorly, laterally, and anteriorly. The measured separation of the upper eyelid from the globe conjunctiva was obtained using calipers. Eyelid laxity grading was designated as grade 1: 0 to 1.9 mm; grade 2: 2.0 to 3.9 mm; grade 3: 4 to 9 mm; and grade 4: floppy. RESULTS: Two hundred sixty-two patients (58% females) who consecutively satisfied the selection criteria were evaluated, of which 70.22% (183/262) patients had significantly greater laxity of the upper eyelid that corresponded to the side on which they customarily slept. An unpaired t test used to compare the eyelid laxity between the sleeping side and nonsleeping side was statistically significant (p<0.001). CONCLUSION: Normal patients demonstrate a correlation between the side on which they historically or customarily sleep and the laxity of their ipsilateral upper eyelid. PMID- 24777268 TI - On-Q pump for pain control after orbital implant surgery. AB - PURPOSE: To introduce an elastomeric continuous infusion pump for pain control after outpatient orbital implant surgery. METHODS: Retrospective, noncomparative consecutive case series of all patients undergoing enucleation, evisceration, or secondary orbital implantation using the On-Q pain system between August 2004 and January 2006. Postoperative pain score, need for narcotics, and adverse events were recorded. The On-Q catheter is inserted intraoperatively through the lateral lower eyelid into the muscle cone under direct visualization, prior to the orbital implant placement. The On-Q system continually infuses anesthesia (bupivacaine) to the retrobulbar site for 5 days. RESULTS: Among 20 patients, mean postoperative period pain score, with On-Q in place, was 1.3 (scale of 0 to 10). Nine patients (45%) did not need any adjunctive oral narcotics. Two patients experienced postoperative nausea. One catheter connector leaked, thereby decreasing delivery of retrobulbar anesthetic resulting a pain level of 6, the highest level in the study. There were no postoperative infections. No systemic toxic effects from bupivacaine were observed clinically. CONCLUSION: The On-Q pain pump is widely available, low cost, and requires minimal patient manipulation for the use in orbital implant surgery. The device was safe and appeared to minimize postoperative pain in the authors' case series. PMID- 24777267 TI - Renal Carcinoid Tumor Metastatic to the Uvea, Medial Rectus Muscle, and the Contralateral Lacrimal Gland. AB - Renal carcinoid tumor is an exceedingly rare malignancy. A 57-year-old man with a renal carcinoid tumor discovered after metastasizing to intraocular and bilateral orbital structures is described. The patient presented with a blind painful OS and a right superotemporal subconjunctival mass. Imaging studies revealed a large left intraocular tumor, a mass in the left medial rectus muscle, and right lacrimal gland enlargement. The OS was enucleated, and incisional biopsies were performed from the other 2 lesions. Histopathological studies demonstrated metastatic neuroendocrine tumor with chromogranin and synaptophysin positivity. Systemic work up revealed a right renal mass and multiple hepatic metastatic lesions. Radical nephrectomy was performed, and octreotide, capecitabine, and temozolomide were administered. Removal of the primary tumor and the eye that had no prospect for useful vision and further treatment with octreotide, capecitabine, and temozolomide provided a disease progression-free period of 24 months and allowed the patient to function normally. PMID- 24777269 TI - Under-through levator complex plication for correction of mild to moderate congenital ptosis. AB - PURPOSE: Congenital ptosis is most commonly of mild to moderate severity, with good to fair levator function. The appropriate procedures for this condition are levator resection or levator aponeurosis approaches. Among the latter, the levator plication method has received little attention because of a relatively high rate of ptosis recurrence secondary to weak adhesion. In this study, the authors described and retrospectively analyzed the results of an alternative plication technique, the "under-through levator complex plication" method. This method differs from conventional levator plication primarily by the posterior part of the levator complex being advanced to the tarsal plate to produce strong adhesion. METHODS: Five hundred and ten eyelids of 255 consecutive patients who underwent the under-through levator complex plication for congenital bilateral symmetrical ptosis were included in this study. Final outcomes were assessed at more than 5 months after surgery. RESULTS: The mean preoperative and postoperative marginal reflex distance 1 (MRD1) were 1.73 and 3.71 mm, respectively, and the mean amount of levator plication for every 1-mm increase in MRD1 was 3.31 mm. After the levator complex was plicated by the amount planned preoperatively, 65.1% of eyelids were at the target height. After subsequent intraoperative adjustments of the amount of plication, the overall surgery success rate was 94.5%. Recurrent ptosis due to relapse was not observed. CONCLUSIONS: The newly described surgical technique has overcome the limitations of conventional levator plication, by increasing the success rate and markedly reducing the relapse rate, while preserving the advantages of the conventional technique. PMID- 24777270 TI - Reliability of air bubble test in assessment of anatomical and functional success after external dacryocystorhinostomy. AB - PURPOSE: To assess the sensitivity and specificity of air bubble test (ABT) for anatomical and functional success after external dacryocystorhinostomy (Ext-DCR). METHODS: In a retrospective interventional case series, patients with nasolacrimal duct obstruction who had undergone Ext-DCR procedure were included. Functional success was defined as no symptom or mild excess tear in the cold weather and anatomical success as free irrigation at last follow-up time (at least 6 months). Air bubble test was performed by putting antibiotic drops into the eye and asking the patient to exhale while keeping the nose and mouth closed. Formation of bubbles inside the eye (hissing noise) was considered as positive test. Specificity, sensitivity, and positive and negative predictive values were then calculated for both anatomical and functional success. RESULTS: There were 85 procedures in 77 patients. Anatomical and overall functional success was 98.8% (84/85) and 95.3% (81/85), respectively. Air bubble test showed a sensitivity of 82.1% and specificity of 100% for the anatomical success after Ext-DCR. Sensitivity and specificity were 83.9% and 75% for the functional success. CONCLUSION: Positive ABT indicated no anatomical failure after Ext-DCR in this series. PMID- 24777271 TI - Canalicular laceration repair: an analysis of variables affecting success. AB - PURPOSE: To evaluate the outcomes of all canalicular lacerations at a high-volume urban tertiary eye care center and calculate the impact of variables of repair on success. METHODS: A retrospective review over a 10-year span of all primary canalicular laceration repairs was performed. Variables included patient demographics, repair setting, surgeon level of training, mechanism of injury, associated injuries, type of stent used, and success of repair. RESULTS: One hundred thirty-seven patients met the inclusion criteria and were used for analysis. The mechanism of injury was primarily due to altercations (31.4%), followed by accidents (21.9%). Most repairs were performed in the operating room (72.3%) with an overall success rate of 85.9% compared with 36.8% in the minor procedure room. The success rate varied significantly by level of training, with a fellowship-trained oculoplastic surgery attending physician attaining the highest success rate of 84.0%. The success by primary surgeon training level was statistically significant (p<0.0001). The efficacy of a monocanalicular stent was also studied and was not significantly different from bicanalicular stenting when other variables were accounted for (p=0.1186). CONCLUSION: The overall success of canalicular laceration repair is good. However, the setting of repair and level of training greatly affect the success of repair. In a tertiary care setting, an attending surgeon with subspecialty training in oculoplastic surgery should participate in the canalicular laceration repair to maximize the success rate. Performing the repair in the operating room rather than a minor procedure room setting may further improve the patient outcomes. PMID- 24777272 TI - Minimum incision no skin suture external dacryocystorhinostomy. AB - PURPOSE: To report the technique and results of 5-mm incision no skin suture external dacryocystorhinostomy procedure (Ext-DCR). METHODS: In a retrospective interventional case series, 77 patients (85 procedures) with nasolacrimal duct obstruction (NLDO) were included. The size of skin incision was 5 mm. Silicone tube was inserted in all and planned to be removed 6 weeks after the operation. Functional success was defined as no symptom or just excess tear in the cold weather and anatomical success as free irrigation at last follow-up time (at least 6 months) when patients' satisfaction (visual analogue score) on the site of incision was also recorded. RESULTS: There were 85 procedures in 77 patients (52 women; 67.5%) with primary acquired (82) or traumatic (3) NLDO and with a mean age of 52.9 years and follow up of 12.9 months. Associated common canalicular stenosis (membrane) was found in 15 (17.6%), canalicular stenosis in 2 (2.4%), and both in 2 (2.4%) cases. Anatomical and overall functional success was 98.8% (84/85) and 95.3% (81/85), respectively. Subjects with canalicular stenosis had a lower anatomical (75%) and functional (50%) success rates, which were statistically significant (p=0.00). Wound elongation (up to 8 mm) was observed in 3 cases, which did not require skin suturing. Mean patient satisfaction score for the appearance of incision was 99.2. CONCLUSION: Minimum incision (5 mm) no skin suture Ext-DCR offers high patient satisfaction and success rates. PMID- 24777273 TI - The effectiveness of postoperative early ostium cleaning in transcanalicular diode laser-assisted dacryocystorhinostomy. AB - PURPOSE: To search the effectiveness of postoperative first week ostium cleaning in transcanalicular diode laser-assisted dacryocystorhinostomy (TDL-DCR). MATERIALS AND METHODS: A total of 123 eyes of 123 patients with acquired dacryostenosis who had surgery were retrospectively evaluated. Diode laser was used in all patients. All patients were operated under local anesthesia by a single surgeon. Intranasal endoscopic cleaning of the ostium by surgical suction under local anesthesia was performed as an extra job in the postoperative first week visit. RESULTS: Mean age of the patients was 55 (range, 41-78 years) years. Mean follow up was 13.4 months. Successful outcomes were achieved in 117 of 123 (95.1%) patients. Reoperation was performed in 6 patients with restenosis and were free of symptoms in 1-year follow up. CONCLUSION: Postoperative first week cleaning of the nasal ostium by surgical suction with the aiding of nasal endoscopy is a very effective method increasing the success rate of TDL-DCR. PMID- 24777274 TI - Transconjunctival epiblepharon repair. AB - PURPOSE: To document the use of a transconjunctival approach to lower eyelid epiblepharon repair. MATERIALS AND METHODS: Retrospective chart review of all patients who underwent transconjunctival lower eyelid epiblepharon repair. RESULTS: Nine patients underwent repair via this approach. All patients experienced the resolution of their keratitis and cilia-cornea touch by a 3-month postoperative interval, and no patient developed a postoperative complication. Furthermore, no patient developed cutaneous scarring. CONCLUSIONS: Conventional approaches to lower eyelid epiblepharon repair have necessitated the creation of a skin and muscle flap, thus risking the development of scarring and a cosmetically unacceptable eyelid crease. This report documents the use of a transconjunctival approach for the management of this condition that avoids external incisions and provides excellent outcomes without scarring of the anterior lamella of the eyelid. PMID- 24777275 TI - Cerebrospinal fluid transferrin levels are reduced in patients with early multiple sclerosis. AB - BACKGROUND: Previous magnetic resonance imaging (MRI) studies have demonstrated increased iron deposition in the basal ganglia of multiple sclerosis (MS) patients. However, it is not clear whether these alterations are associated with changes of iron metabolism in body fluids. OBJECTIVES: The purpose of this study was to investigate if iron metabolism markers in cerebrospinal fluid (CSF) and serum of clinically isolated syndrome (CIS) and MS patients differ from controls and how they relate to clinical and imaging parameters. METHODS: We analysed serum ferritin, transferrin and soluble transferrin-receptor and CSF ferritin and transferrin by nephelometry in non-anaemic CIS (n=60) or early MS (n=14) patients and 68 controls. In CIS/MS we additionally assessed the T2 lesion load. RESULTS: CSF transferrin was significantly decreased in CIS/MS compared to controls (p<0.001), while no significant differences were seen in serum. Higher CSF transferrin levels correlated with lower physical disability scores (r= -0.3, p<0.05). CSF transferrin levels did not correlate with other clinical data and the T2 lesion load. CONCLUSION: Our biochemical study provides evidence that altered iron homeostasis within the brain occurs in the very early phases of the disease, and suggests that the transporter protein transferrin may play a role in the increased iron deposition known to occur in the brain of MS patients. PMID- 24777277 TI - Cognitive impairment in patients with multiple sclerosis predicts worse caregiver's health-related quality of life. AB - BACKGROUND: Little information exists about how cognitive impairment in multiple sclerosis (MS) patients impacts on their caregivers' health-related quality of life (HRQoL). BACKGROUND: The objective of this paper is to examine the extent to which cognitive impairment in MS patients contributes to caregivers' HRQoL. METHODS: A total of 63 MS patients, 63 caregivers and 59 matched controls were recruited. Patients and controls underwent a neuropsychological assessment, including tests of working memory, speed of information processing, executive function, and verbal fluency. HRQoL of the caregivers was assessed by CAREQOL-MS. In logistic regression models, we adjusted for the effects of confounding variables. In these models, the dependent variable was the CAREQOL-MS (higher median of CAREQOL-MS (worse HRQoL) vs. lower median of CAREQOL-MS (better HRQoL) (reference)), and the independent variable was the impairment on each neuropsychological test vs. its integrity (reference). RESULTS: Cognitive impairment in MS patients was significantly associated with worse caregiver HRQoL (adjusted odds ratio (OR) = 3.10, 95% confidence interval (CI) = 1.07-11.55, p = 0.04). In secondary analyses in which each neuropsychological test was entered in the analyses separately, only Symbol Digit Modalities Test (a measurement of information processing speed) impairment (OR = 4.22, 95%, CI = 1.16-14.53, p = 0.03) was significantly associated with worse caregiver HRQoL. CONCLUSIONS: MS patients' caregivers' HRQoL is significantly influenced by information processing speed impairment of MS patients. PMID- 24777279 TI - A new interpretation of SAXS peaks in sulfonated poly(ether ether ketone) (sPEEK) membranes for fuel cells. AB - The structure of a commercial sulfonated poly(ether ether ketone) (sPEEK) membrane was analyzed by Small-Angle X-Ray Scattering (SAXS) for different water uptakes obtained after immersion in liquid water at various temperatures. For low membrane swelling, the SAXS profile displays only a wide-angle peak in the 0.2 0.3 A(-1) region. As the membrane swells, two supplementary correlation peaks arise and shift towards small angles, which are the signature of a structural evolution of the membrane, whereas the wide angle peak remains stable. The SAXS spectra of sPEEK membranes can thus display three correlation peaks simultaneously. Therefore we propose a new interpretation of these SAXS spectra which conclude that the two small angle peaks are attributed to the so-called matrix and ionomer peaks and the wide-angle peak is ascribed to the mean separation distance between sulfonic acid groups grafted onto the polymer backbone. This peak attribution implies that the sPEEK nano-phase separation is triggered by an immersion in hot water (ionomer peak apparition). Our new peak attribution was confirmed by studying the impact of temperature, electron density contrast and ionic exchange capacity. PMID- 24777276 TI - Risk of relapse phenotype recurrence in multiple sclerosis. AB - OBJECTIVES: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype. METHODS: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis. RESULTS: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8-5, p = 10(-14)). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease. CONCLUSION: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance. PMID- 24777278 TI - Multiple sclerosis registries in Europe - results of a systematic survey. AB - BACKGROUND: Identification of MS registries and databases that are currently in use in Europe as well as a detailed knowledge of their content and structure is important in order to facilitate comprehensive analysis and comparison of data. METHODS: National MS registries or databases were identified by literature search, from the results of the MS Barometer 2011 and by asking 33 national MS societies. A standardized questionnaire was developed and sent to the registries' leaders, followed by telephone interviews with them. RESULTS: Twenty registries were identified, with 13 completing the questionnaire and seven being interviewed by telephone. These registries differed widely for objectives, structure, collected data, and for patients and centres included. Despite this heterogeneity, common objectives of the registries were epidemiology (n=10), long term therapy outcome (n=8), healthcare research (n=9) and support/basis for clinical trials (n=8). While physician-based outcome measures (EDSS) are used in all registries, data from patients' perspectives were only collected in six registries. CONCLUSIONS: The detailed information on a large number of national MS registries in Europe is a prerequisite to facilitating harmonized integration of existing data from MS registries and databases, as well as comprehensive analyses and comparison across European populations. PMID- 24777280 TI - Management of very high risk pregnancy with secondary anti-phospholipid syndrome and triple positivity to the anti-phospholipid antibodies. AB - There is a significantly increased risk of pregnancy complications in women with anti-phospholipid syndrome (APS). The risk is further heightened in those with previous arterial or venous thromboembolism and so-called 'triple positivity' for anti-phospholipid antibodies (i.e., when lupus anticoagulant, and anti cardiolipin (aCL) and anti-beta2 glycoprotein-I (anti-beta2Gp-I) antibodies are all detected). Management of these cases is extremely difficult and little is available in the medical literature to guide therapy. This report describes the use of regular plasma exchanges (PEx) to bring about a successful pregnancy outcome in a woman with secondary APS and previous recurrent miscarriages. The patient was also anticoagulated with enoxaparin and administered aspirin, prednisolone, azathioprine and hydroxychloroquine. Through regular PEx and immunomodulation therapy, levels of aCL and anti-beta2Gp-I antibodies were monitored and documented to fall as pregnancy progressed. Although the outcome in this case was successful, further experience is required before this regimen can be accepted as the standard of care for these patients at very high risk of pregnancy loss. PMID- 24777281 TI - Two-dimensional g-C(3)N(4): an ideal platform for examining facet selectivity of metal co-catalysts in photocatalysis. AB - Two-dimensional g-C3N4 nanosheets with few-layer thickness, ensuring equivalent charge migrations to various Pd facets, provide an ideal model system for reliably examining the facet selectivity of Pd co-catalysts. It reveals that reduction of CO2 can occur better on Pd{111} facets while H2O prefers to generate H2 on Pd{100}. PMID- 24777282 TI - Antiferromagnetic metal and Mott transition on Shastry-Sutherland lattice. AB - The Shastry-Sutherland lattice, one of the simplest systems with geometrical frustration, which has an exact eigenstate by putting singlets on diagonal bonds, can be realized in a group of layered compounds and raises both theoretical and experimental interest. Most of the previous studies on the Shastry-Sutherland lattice are focusing on the Heisenberg model. Here we opt for the Hubbard model to calculate phase diagrams over a wide range of interaction parameters, and show the competing effects of interaction, frustration and temperature. At low temperature, frustration is shown to favor a paramagnetic metallic ground state, while interaction drives the system to an antiferromagnetic insulator phase. Between these two phases, there are an antiferromagnetic metal phase and a paramagnetic insulator phase (which should consist of a small plaquette phase and a dimer phase) resulting from the competition of the frustration and the interaction. Our results may shed light on more exhaustive studies about quantum phase transitions in geometrically frustrated systems. PMID- 24777284 TI - Bis(phosphinoselenoic amides) as versatile chelating ligands for alkaline earth metal (Mg, Ca, Sr and Ba) complexes: syntheses, structure and epsilon caprolactone polymerisation. AB - We report here a series of heavier alkaline earth metal complexes with N,N' (ethane-1,2-diyl)bis(P,P-diphenylphosphinoselenoic amide) using two synthetic routes. In the first route, the heavier alkaline earth metal bis(trimethylsilyl)amides [M{N(SiMe3)2}2(THF)n] (M = Ca, Sr, Ba), when treated with phosphinoselenoic amine [Ph2P(Se)NHCH2CH2NHPPh2(Se)] (1), afforded the corresponding alkaline earth metal complexes of the composition [(THF)3M{Ph2P(Se)NCH2CH2NPPh2(Se)}] [M = Ca (2), Sr (3), Ba (4)]. The metal complexes 2-4 were also obtained from a one-pot reaction, where potassium phosphinoselenoic amide was generated in situ by the reaction of compound 1 and [KN(SiMe3)2], followed by the addition of the respective metal diiodides in THF at room temperature. The magnesium complex [(THF)3Mg{Ph2P(Se)NCH2CH2NPPh2(Se)}] (5) was also prepared. The solid-state structures of alkaline earth metal complexes 2-5 were established by single crystal X-ray diffraction analysis. In the solid state, all the metal complexes are monomeric but in complexes 2-4, ligand 1 is chelated in a tetra-dentate fashion to each metal ion but in complex 5, ligand 1 behaves as a bidentate ligand. Complexes 2-4 were tested as catalysts for the ring-opening polymerisation of epsilon-caprolactone and a high level of activity for the barium complex 4 was observed, with narrow polydispersity. We also report the synthesis and structure of the bis(amidophosphino borane) ligand [Ph2P(BH3)NHCH2CH2NHPPh2(BH3)] (6) and the corresponding barium complex [(THF)2Ba{Ph2P(BH3)NCH2CH2NPPh2(BH3)}]2 (7). PMID- 24777283 TI - Postnatal development of the molecular complex underlying astrocyte polarization. AB - Astrocytes are highly polarised cells with processes that ensheath microvessels, cover the brain surface, and abut synapses. The endfoot membrane domains facing microvessels and pia are enriched with aquaporin-4 water channels (AQP4) and other members of the dystrophin associated protein complex (DAPC). Several lines of evidence show that loss of astrocyte polarization, defined by the loss of proteins that are normally enriched in astrocyte endfeet, is a common denominator of several neurological diseases such as mesial temporal lobe epilepsy, Alzheimer's disease, and stroke. Little is known about the mechanisms responsible for inducing astrocyte polarization in vivo. Here we introduce the term endfoot basal lamina junctional complex (EBJC) to denote the proteins that consolidate and characterize the gliovascular interface. The present study was initiated in order to resolve the developmental profile of the EBJC in mouse brain. We show that the EBJC is established after the first week postnatally. Through a combination of methodological approaches, including light microscopic and high resolution immunogold cytochemistry, quantitative RT-PCR, and Western blotting, we demonstrate that the different members of this complex exhibit distinct ontogenic profiles-with the extracellular matrix (ECM) proteins laminin and agrin appearing earlier than the other members of the complex. Specifically, while laminin and agrin expression peak at P7, quantitative immunoblot analyses indicate that AQP4, alpha-syntrophin, and the inwardly rectifying K(+) channel Kir4.1 expression increases towards adulthood. Our findings are consistent with ECM having an instructive role in establishing astrocyte polarization in postnatal development and emphasize the need to explore the involvement of ECM in neurological disease. PMID- 24777285 TI - The hybrid concept for realization of an ultra-thin plasmonic metamaterial antireflection coating and plasmonic rainbow. AB - We report on the design, simulation, fabrication, and characterization of a novel two layer anti-reflective coating (ARC) based on a plasmonic metamaterial and a dielectric. Promoted by the strong material dispersion of the plasmonic metamaterial, our novel concept (called hybrid ARC) combines two possible arrangements for layers in an anti-reflection coating into a single structure; albeit at two different wavelengths. This, however, causes a broadband reduction of reflection that is less sensitive against oblique incidence when compared to traditional antireflective coatings. Furthermore, we show that the current metamaterial on a metal reflector can be used for the visualization of different coloration such as plasmonic rainbow despite its sub-wavelength thickness. PMID- 24777286 TI - A preliminary study of gender differences in autobiographical memory in children with an autism spectrum disorder. AB - Autobiographical memory was assessed in 24 children (12 male, 12 female, aged between 8 and 16 years) with autism spectrum disorder (ASD) and a comparison group of 24 typically developing (TD) children matched for age, IQ, gender and receptive language. Results suggested that a deficit in specific memory retrieval in the ASD group was more characteristic of male participants. Females in both the TD and ASD groups generated more detailed and emotional memories than males. They also demonstrated superior verbal fluency scores; verbal fluency and autobiographical memory cueing task performance were significantly positively correlated in females. Results are discussed in light of recent research suggesting gender differences in the phenotype of ASD. PMID- 24777287 TI - Training facial expression production in children on the autism spectrum. AB - Children with autism spectrum disorder (ASD) show deficits in their ability to produce facial expressions. In this study, a group of children with ASD and IQ matched, typically developing (TD) children were trained to produce "happy" and "angry" expressions with the FaceMaze computer game. FaceMaze uses an automated computer recognition system that analyzes the child's facial expression in real time. Before and after playing the Angry and Happy versions of FaceMaze, children posed "happy" and "angry" expressions. Naive raters judged the post-FaceMaze "happy" and "angry" expressions of the ASD group as higher in quality than their pre-FaceMaze productions. Moreover, the post-game expressions of the ASD group were rated as equal in quality as the expressions of the TD group. PMID- 24777289 TI - Diversification of 99Mo/(99m)Tc Supply. PMID- 24777288 TI - Variability of Proliferation and Diffusion in Different Lung Cancer Models as Measured by 3'-Deoxy-3'-18F-Fluorothymidine PET and Diffusion-Weighted MR Imaging. AB - Molecular imaging allows the noninvasive assessment of cancer progression and response to therapy. The aim of this study was to investigate molecular and cellular determinants of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET and diffusion-weighted (DW) MR imaging in lung carcinoma xenografts. METHODS: Four lung cancer cell lines (A549, HTB56, EBC1, and H1975) were subcutaneously implanted in nude mice, and growth was followed by caliper measurements. Glucose uptake and tumor proliferation were determined by (18)F-FDG and (18)F-FLT PET, respectively. T2-weighted MR imaging was performed, and the apparent diffusion coefficient (ADC) was determined by DW MR imaging as an indicator of cell death. Imaging findings were correlated to histology with markers for tumor proliferation (Ki67, 5-bromo-2'-deoxyuridine [BrdU]) and cell death (caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling). The expression of human equilibrative nucleoside transporter 1 (hENT1), thymidine kinase 1 (TK1), thymidylate synthase, and thymidine phosphorylase (TP) were analyzed by Western blot and immunohistochemistry. Thymidine levels were determined by liquid chromatography-mass spectrometry. RESULTS: Xenografts varied with respect to in vivo growth rates. MR imaging and PET revealed intratumoral heterogeneities, which were confirmed by histology. (18)F-FLT uptake differed significantly between tumor lines, with A549 and H1975 demonstrating the highest radiotracer accumulation (A549, 8.5 +/- 3.2; HTB56, 4.4 +/- 0.7; EBC1, 4.4 +/- 1.2; and H1975, 12.1 +/- 3.5 maximal percentage injected dose per milliliter). In contrast, differences in (18)F-FDG uptake were only marginal. No clear relationship between (18)F-FLT accumulation and immunohistochemical markers for tumor proliferation (Ki67, BrdU) as well as hENT1, TK1, or TS expression was detected. However, TP was highly expressed in A549 and H1975 xenografts, which was accompanied by low tumor thymidine concentrations, suggesting that tumor thymidine levels influence (18)F-FLT uptake in the tumor models investigated. MR imaging revealed higher ADC values within proliferative regions of H1975 and A549 tumors than in HTB56 and EBC1. These ADC values were negatively correlated with cell density but not directly related to cell death. CONCLUSION: A direct relationship of (18)F-FLT with proliferation or ADC with cell death might be complicated by the interplay of multiple processes at the cellular and physiologic levels in untreated tumors. This issue must be considered when using these imaging modalities in preclinical or clinical settings. PMID- 24777290 TI - Follow-up or Surveillance (18)F-FDG PET/CT and Survival Outcome in Lung Cancer Patients. AB - The value of performing follow-up PET/CT imaging more than 6 mo after the conclusion of therapy-either as a routine practice or because of clinically suspected recurrence-is not well established. The purpose of this study was to evaluate the added value of follow-up PET/CT to the clinical assessment and survival outcome of lung cancer patients. METHODS: This was a retrospective study of 261 biopsy-proven lung cancer patients at a single tertiary center. In total, 488 follow-up PET/CT scans done 6 or more months after the completion of initial treatment were included in this study. Median follow-up from the completion of primary treatment was 29.3 mo (range, 6.1-295.1 mo). Overall survival (OS) benefit was measured using Kaplan-Meier plots with a Mantel-Cox log-rank test. A multivariate Cox regression model was provided with clinical covariates. RESULTS: Of the 488 PET/CT scans, 281 were positive and 207 negative for recurrence. Overall median survival from the time of the PET/CT study was 48.5 mo. The median survival of PET-positive and PET-negative groups was 32.9 and 81.6 mo, respectively (P < 0.0001). A subgroup analysis demonstrated a similar difference in OS for 212 scans completed between 6 and 24 mo after treatment (P = 0.0004) and 276 scans completed after 24 mo (P = 0.0006). In the context of clinical assessment, PET/CT identified recurrence in 43.7% (107/245) of scans without prior clinical suspicion and ruled out recurrence in 15.2% (37/243) of scans with prior clinical suspicion. There was a significant difference in OS when grouped by clinical suspicion (P = 0.0112) or routine follow-up (P < 0.0001). In a multivariate Cox regression model, factors associated with OS were age (P < 0.0001) and PET/CT result (P = 0.0003). An age-stratified subgroup analysis demonstrated a significant difference in OS by PET scan result among patients younger than 60 y and between 60 and 70 y but not in those older than 70 y (P < 0.0001, P = 0.0004, and P = 0.8193, respectively). CONCLUSION: (18)F-FDG PET/CT performed for follow-up more than 6 mo after the completion of primary treatment adds value to clinical judgment and is a prognostic marker of OS in lung cancer patients, regardless of the timing of the follow-up scan, and especially in patients younger than 70 y. PMID- 24777291 TI - Late Imaging with [1-(11)C]Acetate Improves Detection of Tumor Fatty Acid Synthesis with PET. AB - Tumors are often characterized by high levels of de novo fatty acid synthesis. The kinetics of acetate incorporation into tricarboxylic acid cycle intermediates and into lipids suggest that detection of tumors with [1-(11)C]acetate PET could be improved by imaging at later time points. METHODS: The uptake and metabolism of [1-(11)C], [1-(13)C], and [1-(14)C]acetate were measured in mouse prostate and lung cancer models to investigate the time course of (11)C label incorporation into tumor metabolites. RESULTS: Radioactivity in the lipid fraction, as compared with the aqueous fraction, in extracts of C4-2B human prostate xenografts peaked at 90 min after [1-(14)C]acetate injection, which coincided with peak (13)C label incorporation into the fatty acids palmitate and stearate. Contrast between the tumor and tissues, such as blood and muscle, increased in PET images acquired over a period of 120 min after [1-(11)C]acetate injection, and Patlak plots were linear from 17.5 min after injection. Similar results were obtained in a genetically engineered K-ras(G12D); p53(null) lung cancer model, in which the mean tumor-to-lung ratio at 90 min after [1-(14)C]acetate injection was 4.4-fold higher than at 15 min. CONCLUSION: These findings suggest that when imaging de novo fatty acid synthesis with [1-(11)C]acetate it is preferable to measure uptake at later time points, when the effects of perfusion and (11)C incorporation into tricarboxylic acid cycle intermediates and bicarbonate are declining. The data presented here suggest that future clinical PET scans of tumors should be acquired later than 30 min, when tracer accumulation due to de novo fatty acid synthesis prevails. PMID- 24777292 TI - Expert statement: pneumothorax associated with endoscopic valve therapy for emphysema--potential mechanisms, treatment algorithm, and case examples. AB - The use of endoscopically placed unidirectional valves for the treatment of emphysema is increasing. With better patient selection, there is also an increased likelihood of complications associated with the procedure, such as postprocedural pneumothorax. There is, however, little evidence of pneumothorax management in patients with severe COPD and emphysema. This report describes an expert recommendation that has been developed to outline pneumothorax management after valve placement to inform physicians and patients of the risk-benefit profile and to assist them in decision making. Skilled and aggressive pneumothorax management is necessary in this patient population, and by following these recommendations traumatic scenarios, prolonged drainage, extended hospitalizations, and/or surgery might be avoided in many cases. PMID- 24777293 TI - miR-145 inhibits migration and invasion of glioma stem cells by targeting ABCG2. AB - Despite advances in clinical therapies and technologies, the prognosis for patients with malignant glioma is poor. Our previous research demonstrated that glioma stem cells (GSCs) were crucial for glioma malignancy and accelerated tumor migration and invasion. The migration and invasion of malignant glioma cells into the surrounding normal brain tissues cause the poor outcome. miR-145, a miRNA found to be expressed in neurons, was recently found to have reduced expression in glioblastoma multiforme tumors. And miR-145 loss in glioma cells led to increased cell proliferation and invasion. However, its function on the migration and invasion of GSCs was still unknown. In this study, we aimed to identify the effects and mechanisms of miR-145 on the migration and invasion of GSCs. Our investigations revealed that miR-145 was low expressed in malignant glioma tissues and their corresponding GSCs. Knockdown of miR-145 in vitro could enhance the migration and invasion of GSCs, while up-regulation of miR-145 had the opposite effects. Further investigation of the potential mechanism demonstrated that the function of miR-145 in regulating the migration and invasion of GSCs is mediated by its targeting of ABCG2 mRNA. ABCG2 is an ATP-binding cassette transporter protein, which was identified to be overexpressed in GSCs and higher grade glioma tissues. We found that miR-145 was negative correlated with ABCG2 levels in GSCs, and reduction in ABCG2 expression decreased the cell migration and invasion of GSCs. Further, a luciferase reporter proved that ABCG2 was a direct target of miR-145 in GSCs. Thus, these findings underscore the potential of miR-145 to regulate the migration and invasion of GSCs through targeting ABCG2. PMID- 24777295 TI - Pediatric giant pituitary adenomas: are they different from adults? A clinical analysis of a series of 12 patients. AB - OBJECTIVES: To evaluate clinical presentation and microsurgical outcome of giant pituitary adenomas (GPAs) in pediatric age. METHODS: All patients <18 years, who were operated on at our center for GPA (tumor >40 mm in maximum diameter) were included in study. Clinical features, hormonal profile, radiology, surgical approach, results and complications were analysed. RESULTS: A total of 12 children with GPA were managed microsurgically. Visual deterioration (73 %) was most common presentation. Functioning adenomas were found in 83 % patients, with prolactinomas being most common. Twelve patients underwent a total of 16 microsurgical procedures, with a single surgery done in eight (75 %) patients. Out of the 12 primary surgeries, eight (67 %) were performed trans-sphenoidally. A near-total excision (>90 % tumor removal) could be achieved in six (50 %) patients. Visual improvement was observed in 44 % patients. However, there was no improvement in those where the eye was negative to perception of light prior to surgery. At the last follow-up, all the patients with functioning adenomas were in hormonal remission, and there was no residual/recurrent tumor in patients with non-functional adenomas. 25 % experienced single or multiple perioperative or postoperative complications. There was one perioperative death (8 %). CONCLUSIONS: GPAs are very rare in the pediatric population, with majority being functional and more aggressive in nature as compared to in adults. However, most of them can be approached trans-sphenoidally. The combination of surgery and radiotherapy, as well as medical therapy with bromocriptine, achieves good tumor control, despite a high rate of residual tumor and tumor recurrence. PMID- 24777296 TI - Comparison of posterior fossa decompression with or without duraplasty in children with Type I Chiari malformation. AB - PURPOSE: Chiari malformation type I (CM1) is a common and often debilitating neurosurgical disease. Whether to treat CM1 patients with a traditional posterior fossa decompression with duraplasty (PFDD) or a less invasive extradural decompression (PFDO) is controversial. The purpose of this study was to compare clinical outcome and syrinx resolution between the two procedures. METHODS: We retrospectively reviewed the records of 36 patients treated with PFDD and 29 patients with PFDO between 2003 and 2011. We compared baseline demographic, clinical, and radiographic characteristics. The primary clinical outcome was the Chicago Chiari Outcome Scale (CCOS). The primary radiographic outcome was qualitative syrinx improvement or resolution. RESULTS: At baseline, age and sex distributions, radiographic characteristics, and presenting symptoms were similar in patients undergoing PFDD and PFDO. Patients undergoing PFDO had shorter surgical time (1.5 vs. 2.8 h; p < 0.001) and length of hospital stay (2.1 days compared to 3.3 days; p < 0.001). Cerebrospinal fluid-related complications were more common in patients receiving PFDD (7/36) than PFDO (0/29) (p = 0.014). Clinical improvement, defined by the mean CCOS score, was comparable in patients receiving PFDO (14.7) and PFDD (14.6) (p = 0.70). Among patients with postoperative syrinx imaging, 10/13 in the PFDD group improved or resolved, compared to 8/8 in the PFDO group (p = 0.26). CONCLUSIONS: Extradural decompression for CM1 produces comparable rates of clinical and radiographic improvement as the more invasive decompression with duraplasty. Given the increased morbidity and resource utilization associated with PFDD, PFDO should be considered an attractive first-line option for most CM1 patients. PMID- 24777294 TI - Epigenetic regulation of memory by acetylation and methylation of chromatin: implications in neurological disorders, aging, and addiction. AB - Synaptic plasticity is one of the most fundamental properties of neurons that underlie the formation of the memory in brain. In recent years, epigenetic modification of both DNA and histones such as DNA methylation and histone acetylation and methylation emerges as a potential regulatory mechanism that governs the transcription of several genes responsible for memory formation and behavior. Furthermore, the recent identification of nitrosylation of proteins has shown to either activate or repress gene transcription by modulating histone methylation or acetylation status in mature neuron. Recent studies suggest that the use of major substrates of abuse, e.g., cocaine, induces alterations in molecular and cellular mechanisms of epigenetics that underlie long-term memories in the striatum and prefrontal cortex. Moreover, downregulation of genes due to alterations in epigenetics leads to cognitive deficiencies associated with neurological disorders such as Alzheimer's disease, Huntington's disease, psychiatric disorder such as Rett's syndrome and aging. In this review, I will discuss the evidence for several epigenetic mechanisms in the coordination of complex memory formation and storage. In addition, I will address the current literature highlighting the role of acetylation and methylation of chromatin in memory impairment associated with several neurological disorders, aging, and addiction. PMID- 24777297 TI - Bacillus pakistanensis sp. nov., a halotolerant bacterium isolated from salt mines of the Karak Area in Pakistan. AB - A rod shaped, non-motile, endospore forming, Gram-stain positive and moderately halotolerant strain, designated as NCCP-168(T), was isolated from salt mines sampled in the Karak district of Khyber Pakhtunkhwa Province in Pakistan. To delineate its taxonomic position, the strain was subjected to polyphasic characterization. Cells of strain NCCP-168(T) can grow at 10-40 (?)C (optimum at 30-35 (?)C), in a pH range of 5.0-9.0 (optimum at pH 8.0) and in 0-17 % (w/v) NaCl on agar medium. The phylogenetic analysis based on the 16S rRNA gene sequence showed that strain NCCP-168(T) belongs to the genus Bacillus with the highest similarity to Bacillus seohaeanensis BH724(T) (97.1 %), and less than 97 % similarity with other closely related taxa (95.6 % with B. subtilis subsp. subtilis NCIB3610(T)). DNA-DNA relatedness between strain NCCP-168(T) and the type strains of closely related species was lower than 30 %. Chemotaxonomic data (major menaquinone, MK-7; cell wall peptidoglycan type, A1gamma [meso diaminopimelic acid]; major fatty acids, iso-C15:0 29.9 %, anteiso-C15:0 29.3 %, iso-C16:0 11.4 %, iso-C14:0 8.9 % and anteiso-C17:0 7.0 %; major polar lipids, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine) support the affiliation of strain NCCP-168(T) with genus Bacillus. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain NCCP-168(T) can be distinguished from the closely related taxa and thus represents a novel species in the genus Bacillus, for which the name Bacillus pakistanensis sp. nov. is proposed, with the type strain NCCP-168(T) (= KCTC 13786(T) = DSM 24834(T) = JCM 18975(T)). PMID- 24777298 TI - Facile oxidation of NHC-Au(I) to NHC-Au(III) complexes by CsBr3. AB - CsBr3 was investigated as a new and convenient oxidant for NHC-Au(I) complexes (NHC = imidazo[1,5-a]pyridin-3-ylidene) for the preparation of the respective Au(III) complexes. The Au(I) complexes were synthesized by the silver salt method using [(NHC)2Ag]PF6 and (tht)AuBr. Unexpectedly, the reactions yielded both neutral (NHC)AuBr and ionic [(NHC)2Au]PF6, depending on the N-substituent of the NHC ligand. Oxidation with CsBr3 gave the complexes (NHC)AuBr3 and [(NHC)2AuBr2]PF6 in high yields and purity, which proves the suitability of this reagent. The complexes were further characterised by X-ray diffraction and electronic absorption and emission spectroscopy. The Au(I) complexes exhibit a dual emission attributable to intraligand fluorescence and phosphorescence at both room temperature and 77 K. Upon irradiation with polychromatic light (lambda > 305 nm), the Au(III) complexes are cleanly photo-reduced to the Au(I) congener. PMID- 24777299 TI - Citrate anticoagulation during continuous renal replacement therapy in pediatric critical care. AB - OBJECTIVE: To provide the pediatric intensivist an in-depth understanding of citrate as regional anticoagulant during continuous renal replacement therapy. DATA SOURCES AND DATA SELECTION: We searched the PubMed.gov database using the initial key words: citrate anticoagulation [title] AND continuous; citrate [title] AND pediatric AND continuous; prospective pediatric renal replacement AND citrate; and regional citrate anticoagulation. Additional searchers were performed using EMBASE, CINAHL, and SCOPUS with similar keywords and limits. Further articles were gathered from bibliographic references of relevant studies and reviews. Only articles published in English were reviewed. DATA EXTRACTION AND DATA SYNTHESIS: In the pediatric population, there are no prospective interventional or randomized studies comparing regional versus systemic anticoagulation. However, there are 11 (retrospective and prospective observational studies) in the pediatric population using citrate anticoagulation. These studies have shown that regional citrate anticoagulation in the pediatric population can be effective, provide equivalent circuit survival, and decrease bleeding compared with heparin anticoagulation. In the adult population, there are six prospective randomized controlled trials comparing the efficacy of regional citrate anticoagulation versus heparin. Two systematic reviews with meta analysis of these six trials have been performed. The adult data on the use of regional citrate anticoagulation during continuous renal replacement therapy show a decreased risk of bleeding and at the least equivalent circuit survival as compared to heparin. Current pediatric and adult studies support regional citrate anticoagulation as an effective alternative to systemic heparin anticoagulation in most patient populations. CONCLUSIONS: Continuous renal replacement therapy is the most common modality of renal replacement in the critical care setting. Regional anticoagulation is an ideal option in a critically ill child after recent surgery or with coagulopathy. Therefore, regional citrate anticoagulation in the pediatric critical care population requiring renal replacement therapy is commonly employed. Complications of citrate anticoagulation can be avoided with a greater understanding of the properties and clearance of citrate. Continued reporting of observational data and the development of prospective multicenter trials using citrate anticoagulation are needed to ensure safe and standardized care in the pediatric population. PMID- 24777300 TI - Vasoactive-inotropic score is associated with outcome after infant cardiac surgery: an analysis from the Pediatric Cardiac Critical Care Consortium and Virtual PICU System Registries. AB - OBJECTIVE: To empirically derive the optimal measure of pharmacologic cardiovascular support in infants undergoing cardiac surgery with bypass and to assess the association between this score and clinical outcomes in a multi institutional cohort. DESIGN: Prospective, multi-institutional cohort study. SETTING: Cardiac ICUs at four academic children's hospitals participating in the Pediatric Cardiac Critical Care Consortium during the study period. PATIENTS: Children younger than 1 year at the time of surgery treated postoperatively in the cardiac ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred ninety-one infants undergoing surgery with bypass were enrolled consecutively from November 2011 to April 2012. Hourly doses of all vasoactive agents were recorded for the first 48 hours after cardiac ICU admission. Multiple derivations of an inotropic score were tested, and maximum vasoactive-inotropic score in the first 24 hours was further analyzed for association with clinical outcomes. The primary composite "poor outcome" variable included at least one of mortality, mechanical circulatory support, cardiac arrest, renal replacement therapy, or neurologic injury. High vasoactive-inotropic score was empirically defined as more than or equal to 20. Multivariable logistic regression was performed controlling for center and patient characteristics. Patients with high vasoactive-inotropic score had significantly greater odds of a poor outcome (odds ratio, 6.5; 95% CI, 2.9-14.6), mortality (odds ratio, 13.2; 95% CI, 3.7-47.6), and prolonged time to first extubation and cardiac ICU length of stay compared with patients with low vasoactive-inotropic score. Stratified analyses by age (neonate vs infant) and surgical complexity (low vs high) showed similar associations with increased morbidity and mortality for patients with high vasoactive-inotropic score. CONCLUSIONS: Maximum vasoactive-inotropic score calculated in the first 24 hours after cardiac ICU admission was strongly and significantly associated with morbidity and mortality in this multi-institutional cohort of infants undergoing cardiac surgery. Maximum vasoactive-inotropic score more than or equal to 20 predicts an increased likelihood of a poor composite clinical outcome. The findings were consistent in stratified analyses by age and surgical complexity. PMID- 24777301 TI - Timing, duration, and severity of hyponatremia following pediatric brain tumor surgery*. AB - OBJECTIVE: To describe the time course, variability, and magnitude of serum sodium changes among children undergoing intracranial tumor surgery. DESIGN: Retrospective cohort study. SETTING: Tertiary children's hospital in Salt Lake City, UT. PATIENTS: Children 0-19 years undergoing first neurosurgical procedure for an intracranial tumor, treated during January 2001 and February 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three hundred nineteen patients were placed in three exclusive groups based on the lowest serum sodium measurement during admission: 1) severe hyponatremia: serum sodium less than or equal to 130 mEq/L; 2) mild hyponatremia: 131-135 mEq/L; and 3) normal sodium: more than 135 mEq/L. Timing and severity of sodium perturbations were assessed within each group. Hundred thirty-seven patients (43%) had mild hyponatremia, 39 (12%) had severe hyponatremia, and 143 (45%) had normal sodium. After surgery, sodium decreased in all groups with lower averaged concentrations during postoperative days 0-1 and 5-6, although patients with severe hyponatremia had the greatest decline. Nearly 80% of hyponatremic patients had mild hyponatremia prior to development of severe hyponatremia; median time between mild hyponatremia and severe hyponatremia was 1.6 days (interquartile range, 0.4-5.6). Seventy-five percent of patients manifest mild hyponatremia within two postoperative days; however, severe hyponatremia developed later with 75% of patients manifesting severe hyponatremia within six postoperative days. Nine patients had initial severe hyponatremia between days 6 and 20 after surgery. Patients with severe hyponatremia had greater sodium variability with significantly lower nadirs, greater maximum values, and larger decreases within 24-hour periods compared with other sodium groups. Seventy-five percent of children with severe hyponatremia spent more than 4 days with abnormally low sodium values. Among hyponatremic patients, obstructive hydrocephalus and age less than 3.5 years were significant independent risk factors for severe hyponatremia. CONCLUSION: Hyponatremia developed in just over half of children. Young children with hydrocephalus have increased risk of severe hyponatremia. Those with severe hyponatremia need frequent and prolonged monitoring because of risk for repeat sodium changes. Further study is needed to evaluate ideal monitoring and treatment of severe hyponatremia after intracranial tumor surgery. PMID- 24777304 TI - Rate constants for collisional quenching of NO (A(2)Sigma(+), v = 0) by He, Ne, Ar, Kr, and Xe, and infrared emission accompanying rare gas and impurity quenching. AB - The quenching rates of NO (A(2)Sigma(+), v = 0) with He, Ne, Ar, Kr and Xe have been studied at room temperature by measurements of the time dependence of the fluorescence decay following laser excitation. The rates are slow, with upper limits of rate constants determined as between 1.2 and 2.0 * 10(-14) cm(3) molecule(-1) s(-1), considerably lower than those reported before in the literature. Such slow rates can be markedly influenced by impurities such as O2 and H2O which have quenching rate constants close to gas kinetic values. Time resolved Fourier transform infrared emission has been used to observe the products of the quenching processes with the rare gases and with impurities. For He, Ne Ar and Kr there is no difference within experimental error of the populations in NO (X(2)Pi v >= 2) produced with and without rare gas present, but the low quantum yields of such quenching (of the order of 5% for an atmosphere of rare gas) preclude quantitative information on the quantum states being obtained. For quenching by Xe the collisional formation of electronically excited Xe atoms dominates the emission at early times. Vibrationally excited NO (X(2)Pi, v) and products of reactive quenching are observed in the presence of O2 and H2O. PMID- 24777302 TI - Biomarkers S100B and neuron-specific enolase predict outcome in hypothermia treated encephalopathic newborns*. AB - OBJECTIVES: To evaluate if serum S100B protein and neuron-specific enolase measured during therapeutic hypothermia are predictive of neurodevelopmental outcome at 15 months in children with neonatal encephalopathy. DESIGN: Prospective longitudinal cohort study. SETTING: A level IV neonatal ICU in a freestanding children's hospital. PATIENTS: Term newborns with moderate to severe neonatal encephalopathy referred for therapeutic hypothermia during the study period. INTERVENTIONS: Serum neuron-specific enolase and S100B were measured at 0, 12, 24, and 72 hours of hypothermia. MEASUREMENTS AND MAIN RESULTS: Of the 83 infants enrolled, 15 (18%) died in the newborn period. Survivors were evaluated by the Bayley Scales of Infant Development-II at 15 months. Outcomes were assessed in 49 of 68 survivors (72%) at a mean age of 15.2 +/- 2.7 months. Neurodevelopmental outcome was classified by Bayley Scales of Infant Development II Mental Developmental Index and Psychomotor Developmental Index scores, reflecting cognitive and motor outcomes, respectively. Four-level outcome classifications were defined a priori: normal = Mental Developmental Index/Psychomotor Developmental Index within 1 SD (> 85), mild = Mental Developmental Index/Psychomotor Developmental Index less than 1 SD (70-85), moderate/severe = Mental Developmental Index/Psychomotor Developmental Index less than 2 SD (< 70), or died. Elevated serum S100B and neuron-specific enolase levels measured during hypothermia were associated with increasing outcome severity after controlling for baseline and socioeconomic characteristics in ordinal regression models. Adjusted odds ratios for cognitive outcome were 2.5 (95% CI, 1.3-4.8) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase, and for motor outcome, 2.6 (95% CI, 1.2-5.6) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase. CONCLUSIONS: Serum S100B and neuron specific enolase levels in babies with neonatal encephalopathy are associated with neurodevelopmental outcome at 15 months. These putative biomarkers of brain injury may help direct care during therapeutic hypothermia. PMID- 24777303 TI - Acute rehabilitation practices in critically ill children: a multicenter study. AB - OBJECTIVE: To evaluate acute rehabilitation practices in pediatric critical care units across Canada. DESIGN: Retrospective cohort study. SETTING: Six Canadian, tertiary care pediatric critical care units. PATIENTS/SUBJECTS: Six hundred children aged under 17 years admitted to pediatric critical care unit during a winter and summer month of 2011 with a greater than 24-hour length of stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome of interest was the nature and timing of pediatric critical care unit rehabilitation practices.Rehabilitation was classified according to mobility and nonmobility interventions. Predictors of mobilization and the time to mobilization were evaluated through regression and time-dependent survival analyses, respectively. The most common form of rehabilitation provided in pediatric critical care unit was physical therapy (45.5% patients) followed by occupational therapy (4.5%) and speech and language therapy (1.5%). Interventions were primarily nonmobility in nature (69.7% of sessions), most frequently in the form of chest physiotherapy (42.7% of sessions). The median time to mobilization was 2 days (interquartile range, 1-6) as compared with 1 day for nonmobility interventions (interquartile range, 1-3). Only 57 patients (9.5%) received early mobilization. Regression analyses revealed that increasing age, admission during winter, neuromuscular blockade, and sedative infusions were associated with an increased likelihood of receiving mobility therapy. Increasing age was a predictor of early mobilization, while neuromuscular blockade was associated with delayed mobilization. No significant differences in adverse events were found between nonmobility and mobility interventions. CONCLUSIONS: Only half of the children receive rehabilitation while in the pediatric critical care unit, and when it occurs, therapy is primarily focused on respiratory function. Mobilization appears to be reserved for at-risk children who were muscle relaxed and sedated; however, its implementation in these patients is delayed. Future pediatric-specific research is essential to identify patients at risk and to understand treatment priorities and rehabilitation strategies to improve functional recovery in critically ill children. PMID- 24777305 TI - Neuroimaging diagnosis of pineal region tumors-quest for pathognomonic finding of germinoma. AB - INTRODUCTION: Our study aimed to elucidate the imaging features for the differentiation of pineal germinoma and other pineal region tumors. METHODS: Image data sets of computed tomographic (CT) scan and magnetic resonance imaging (MRI) data of 93 pineal region tumors including 33 germinomas, 30 nongerminomatous germ cell tumors (NGGCTs), 20 pineal parenchymal tumors (PPTs), and 10 miscellaneous tumors of pineal region were reviewed. Imaging features on CT and MRI were qualitatively assessed by three readers. To know the reasons for morphological differences between germinomas and NGGCTs, histological investigation was done. RESULTS: Localized calcification was seen in more than 70 % of germ cells tumors (GCTs: germinomas and NGGCTs) while it was scattered in more than half of PPTs. Cystic components in tumors were most frequent in NGGCTs (62 %). Multiplicity of lesion was restricted to GCTs: 39.4 % in germinoma and 10.0 % in NGGCTs. Thick peritumoral edema was more frequent in germinoma than in NGGCT: 40.6 vs. 14.8 % (p=0.0433, Fisher's test). Bithalamic extension of tumor was seen in 78.8 % of germinomas. It was significantly rare in other groups of tumors (p<0.0001, Fisher's test). The relative collagen amount per unit area was significantly lower in germinoma than in NGGCTs. CONCLUSION: By paying attention to characteristic features as bithalamic extension, thick peritumoral edema, calcification pattern, multiplicity, and their combination, the preoperative differential diagnosis of pineal germinoma will become more accurate. PMID- 24777306 TI - The extent of the perihemorrhagic perfusion zone correlates with hematoma volume in patients with lobar intracerebral hemorrhage. AB - INTRODUCTION: Existing data on perfusion imaging assumes the perihemorrhagic zone (PHZ) in patients with intracerebral hemorrhage (ICH) to be size steady. This study investigates the size of the perihemorrhagic zone (PHZ) in patients with lobar ICH in relation to hematoma volume during the course of treatment using perfusion CT (PCT). METHODS: The present analysis is based on a previously reported cohort of 20 patients undergoing surgical evacuation for lobar SICH, with pre- and early postoperative PCT scanning. Time to peak of the residue function (T max) was measured based on the 360 degrees cortical banding method and singular value decomposition. The size of PHZ was determined before and after treatment and correlated with hematoma volume. RESULTS: Preoperative mean hematoma volume constituted 63.0 ml (interquartile ranges (IQR) 39.7-99.4 ml), which correlated significantly (r=0.563, p=0.010) with mean PHZ size (5.67 cm, IQR 5.44-8.17 cm). Following a surgical hematoma evacuation, mean hematoma volume was reduced to 2.5 ml IQR 0.0-9.5 ml, which also resulted in a significant reduction of PHZ size to 0.45 cm(IQR 0.0-1.36 cm; p<0.001). There was no association between postoperative hematoma volume and size of the PHZ. CONCLUSION: Our findings illustrate that the extent of the PHZ cannot be generally assumed to be constant in size and that this differs significantly following hematoma reduction in patients with space occupying lobar SICH. PMID- 24777307 TI - Suppressive action of acetate on interleukin-8 production via tubulin-alpha acetylation. AB - Acetate is the major short-chain fatty acid produced by commensal bacteria in the gut and is known as a nutrient source for epithelial cells of the mucosa. Acetate also suppresses interleukin (IL)-2 production in T cells by inhibiting nuclear factor of activated T cells (NFAT) nuclear translocation via tubulin-alpha acetylation. Using acetylation of tubulin-alpha as a biomarker, we have examined the influence of acetate in the large intestine. Because of high concentrations of acetate in fecal material, tubulin-alpha acetylation is dominant in the proximal large intestine relative to other sections of the large intestine and is induced in epithelial cells of the colonic mucosa. Flagellin stimulation induces IL-8 production in epithelial cells and acetate suppresses this IL-8 production via tubulin-alpha acetylation. Flagellin stimulation activates nuclear factor kappaB, CREB and AP-1, but not NFAT. Of these transcription factors, acetate specifically inhibits AP-1 activation. Acetate impairs flagellin-induced activation of the Rap1-MEK-ERK-Elk-1 pathway with acetylation of tubulin-alpha that is bound to Rap1, resulting in reduced expression of c-Fos, a subunit of AP 1. These findings reveal a novel action of acetate via tubulin-alpha acetylation in epithelial cells of the colonic mucosa. PMID- 24777308 TI - NKT cell depletion in humans during early HIV infection. AB - Natural killer T (NKT) cells bridge across innate and adaptive immune responses and have an important role in chronic viral infections such as human immunodeficiency virus (HIV). NKT cells are depleted during chronic HIV infection, but the timing, drivers and implications of this NKT cell depletion are poorly understood. We studied human peripheral blood NKT cell levels, phenotype and function in 31 HIV-infected subjects not on antiretroviral treatment from a mean of 4 months to 2 years after HIV infection. We found that peripheral CD4(+) NKT cells were substantially depleted and dysfunctional by 4 months after HIV infection. The depletion of CD4(+) NKT cells was more marked than the depletion of total CD4(+) T cells. Further, the early depletion of NKT cells correlated with CD4(+) T-cell decline, but not HIV viral levels. Levels of activated CD4(+) T cells correlated with the loss of NKT cells. Our studies suggest that the early loss of NKT cells is associated with subsequent immune destruction during HIV infection. PMID- 24777309 TI - CD154+ CD4+ T-cell dependence for effective memory influenza virus-specific CD8+ T-cell responses. AB - CD40-CD154 (CD40 ligand) interactions are essential for the efficient priming of CD8(+) cytotoxic T lymphocyte (CTL) responses. This is typically via CD4(+)CD154(+) T-cell-dependent 'licensing' of CD40(+) dendritic cells (DCs); however, DCs infected with influenza A virus (IAV) upregulate CD154 expression, thus enabling efficient CTL priming in the absence of CD4(+) T activation. Therefore, it is unclear whether CD4 T cells and DCs have redundant or unique roles in the priming of primary and secondary CTL responses after infection. Here we determine the precise cellular interactions involved in CD40-CD154 regulation of both primary and secondary IAV-specific CTL responses. Infection of both CD40 KO and CD154 KO mice resulted in diminished quantitative and qualitative CTL responses after both primary and secondary infection. Adoptive transfer of CD154(+), but not CD154 KO, CD4 T cells into CD154 KO mice restored both primary and secondary IAV-specific CD8 T-cell responses. These data show that, although CD154 expression on CD4 T cells and other cell types (that is, DCs) may be redundant for the priming of primary CTL responses, CD154 expression by CD4 T cells is required for the priming memory CD8 T cells that are capable of fully responding to secondary infection. PMID- 24777310 TI - The influence of hypoxia on the differentiation capacities and immunosuppressive properties of clonal mouse mesenchymal stromal cell lines. AB - Multipotent mesenchymal stromal cells are multipotent cells capable of differentiating into different mesodermal cell types. Enigmatically, mesenchymal stromal cells present in the bone marrow support early lymphopoiesis yet can inhibit mature lymphocyte growth. Critical features of the bone marrow microenvironment, such as the level of oxygen, play an important role in mesenchymal stromal cell biology. Herein, we show that a panel of continuously growing mouse mesenchymal stromal cell lines, namely OP9, MS5, PA6, ST2 and B16 14, exhibit mesenchymal stromal cell characteristic phenotypes and respond physiologically to oxygen deprivation. Culturing freshly isolated bone marrow derived mesenchymal stromal cells or cell lines at 5% O2 resulted in a dramatic increase in expression of hypoxia-inducible factor family members and of key genes involved in their differentiation. Phenotypically, their osteogenic and adipogenic differentiation capacity was generally improved in hypoxia, whereas their inhibitory effects on in vitro T-cell proliferation were preserved. Taken together, we conclude that these continuously growing mouse cell lines behave as canonical mesenchymal stromal cells and respond physiologically to hypoxia, thereby providing a potent tool for the study of different aspects of mesenchymal stromal cell biology. PMID- 24777311 TI - Invariant chain-MHC class II complexes: always odd and never invariant. PMID- 24777312 TI - C5a2 can modulate ERK1/2 signaling in macrophages via heteromer formation with C5a1 and beta-arrestin recruitment. AB - The complement system is a major component of our innate immune system, in which the complement proteins C5a and C5a-des Arg bind to two G-protein-coupled receptors: namely, the C5a receptor (C5a1) and C5a receptor like-2 receptor (C5a2, formerly called C5L2). Recently, it has been demonstrated that C5a, but not C5a-des Arg, upregulates heteromer formation between C5a1 and C5a2, leading to an increase in IL-10 release from human monocyte-derived macrophages (HMDMs). A bioluminescence resonance energy transfer (BRET) assay was used to assess the recruitment of beta-arrestins by C5a and C5a-des Arg at the C5a1 and C5a2 receptors. C5a demonstrated elevated beta-arrestin 2 recruitment levels in comparison with C5a-des Arg, whereas no significant difference was observed at C5a2. A constitutive complex that formed between beta-arrestin 2 and C5a2 accounted for half of the BRET signal observed. Interestingly, both C5a and C5a des Arg exhibited higher potency for beta-arrestin 2 recruitment via C5a2, indicating preference for C5a2 over C5a1. When C5a was tested in a functional ERK1/2 assay in HMDMs, inhibition of ERK1/2 was observed only at concentrations at or above the EC50 for heteromer formation. This suggested that increased recruitment of the beta-arrestin-C5a2 complex at these C5a concentrations might have an inhibitory role on C5a1 signaling through ERK1/2. An improved understanding of C5a2 modulation of signaling in acute inflammation could be of benefit in the development of ligands for conditions such as sepsis. PMID- 24777313 TI - Targeting regulatory T cells in tumor immunotherapy. PMID- 24777314 TI - Functional cytotoxic T lymphocytes against IGRP206-214 predict diabetes in the non-obese diabetic mouse. AB - CD8(+) T cells are prominent in autoimmune diabetes of both humans and non-obese diabetic (NOD) mice. For example, CD8(+) T cells against islet-specific glucose 6 phosphatase catalytic subunit-related protein (IGRP) can be detected readily in older NOD mice. It has been suggested that the enumeration of islet-specific CD8(+) T cells in the peripheral blood may be a predictive biomarker for autoimmune type 1 diabetes (T1D). Here, we determined the natural history of the functional endogenous IGRP(206-214)-specific cytotoxic T lymphocytes (CTLs) in NOD mice with regard to age (3- to 15-week-old pre-diabetic mice and diabetic mice) and sex. We demonstrated that in vivo IGRP(206-214)-specific CTLs significantly increased after 12 weeks of age and in vivo cytotoxicity in female NOD mice was significantly higher than in male NOD mice. To determine the in vivo IGRP(206-214)-specific CTL frequency without killing the mice, we performed splenectomies on a cohort of mice after injecting IGRP(206-214)-coated targets and then followed their diabetes progression. We found that CTL frequency correlated with future of disease onset. Thus, our data support that IGRP(206 214)-specific CTLs may be a potent biomarker for T1D. PMID- 24777315 TI - First-principles vdW-DF study on the enhanced hydrogen storage capacity of Pt adsorbed graphene. AB - Ab initio vdW calculations with the DFT level of theory were used to investigate hydrogen (H2) adsorption on Pt-adsorbed graphene (Pt-graphene). We have explored the most energetically favorable sites for single Pt atom adsorption on the graphene surface. The interaction of H2 with the energetically favorable Pt graphene system was then investigated. We found that H2 physisorbs on pristine graphene with a binding energy of -0.05 eV, while the binding energy is enhanced to -1.98 eV when H2 binds Pt-adsorbed graphene. We also found that up to four H2 molecules can be adsorbed on the Pt-graphene system with a -0.74 eV/H2 binding energy. The effect of graphene layer stretching on the Pt-graphene capacity/ability for hydrogen adsorption was evaluated. Our results show that the number of H2 molecules adsorbed on the Pt-graphene surface rises to six molecules with a binding energy of approximately -0.29 eV/H2. Our first-principles results reveal that the Young's modulus was slightly decreased for Pt adsorption on the graphene layer. The first-principles calculated Young's modulus for the H2 adsorbed Pt-graphene system demonstrates that hydrogen adsorption can dramatically increase the Young's modulus of such systems. As a result, hydrogen adsorption on the Pt-graphene system might enhance the substrate strength. PMID- 24777316 TI - Modeling the mechanism of action of lycopene as a hydroxyl radical scavenger. AB - The anti-oxidant action of lycopene as a hydroxyl radical scavenger through hydrogen abstraction and addition reaction mechanisms has been investigated. Geometries of seven different conformations of lycopene were optimized employing density functional theory in gas phase which was followed by treatment of their solvation in aqueous media. Thus the all-trans conformation of lycopene was found to be most stable in both gas phase and aqueous media. Four overlapping fragments of all-trans lycopene were considered for calculations of Gibbs barrier energies and rate constants. It is found that several hydrogen atoms can be abstracted from lycopene by a hydroxyl radical barrierlessly. Further, it is shown that addition of an OH radical can also take place to each of the various carbon atoms of lycopene with fairly low barrier energies. Thus lycopene is shown to be an effective anti-oxidant. PMID- 24777317 TI - Theoretical investigations on the enhancing effect of the cation-pi interaction on the halogen bond in the M???HCCX???NH3 (M = Li+, Na+, Cu+, Ag+, Au+; X = Cl, Br) complexes. AB - The M???HCCX???NH3 (M = Li+, Na+, Cu+, Ag+, Au+; X = Cl, Br) complexes were designed to study the influence of cation-pi interaction on the X???N halogen bonds under M05-2X/aug-cc-pVDZ(PP) level. In comparison with the HCCX???NH3 complexes, the bond distances of the halogen bonds have decreased, and the interaction energies become more negative. The results show that the X???N halogen bonds have been strengthened by the cation-pi interactions. For different cations, the enhancing effect is more intensive in the order of Au+ > Cu+ > Ag+ > Li+ > Na+, which indicates that transition metal cations can enhance the halogen bond in a stronger manner. Molecular electrostatic potential and second-order perturbation stabilization energy were calculated to deepen the discussion. In addition, atoms in molecules analysis was performed and the electron density shift was studied. PMID- 24777318 TI - Geometries, stabilities and electronic properties of beryllium-silicon Be2Si(n) clusters. AB - The equilibrium geometries, growth patterns, stabilities, and electronic properties of bimetallic Be2Si(n) (n = 1-11) clusters are systematically investigated at the B3LYP/6-311G(d) level of theory. Harmonic vibrational analysis has been performed to assure that the optimized geometries are stable. The optimized results suggest that the three-dimensional structures are observed for the most stable isomers of Be2Si(n) clusters when n > 2. The calculated vertical ionization potential for the lowest-energy isomers are comparable to the experimental values of Si(n+2). According to the averaged binding energy, fragmentation energy, second-order energy difference and HOMO-LUMO gaps calculations, we identify that the Be2Si2 and Be2Si5 clusters are more stable, and Be atoms doping enhance the chemical reactivity of the Si n host. The natural population and natural electron configuration analyses indicate that the Be atoms possess positive charge at n = 1-5 but negative charge at n = 6-11. The chemical hardness of Be2Si(n) clusters show three local maxima at n = 2, 5, and 9, whereas three local minima are found for the corresponding chemical potential, meaning these clusters are more stable than their neighboring cluster sizes. PMID- 24777319 TI - Estimates of pesticide concentrations and fluxes in two rivers of an extensive French multi-agricultural watershed: application of the passive sampling strategy. AB - In this study, the passive sampling strategy was evaluated for its ability to improve water quality monitoring in terms of concentrations and frequencies of quantification of pesticides, with a focus on flux calculation. Polar Organic Chemical Integrative Samplers (POCIS) were successively exposed and renewed at three sampling sites of an extensive French multi-agricultural watershed from January to September 2012. Grab water samples were recovered every 14 days during the same period and an automated sampler collected composite water samples from April to July 2012. Thirty-nine compounds (pesticides and metabolites) were analysed. DEA, diuron and atrazine (banned in France for many years) likely arrived via groundwater whereas dimethanamid, imidacloprid and acetochlor (all still in use) were probably transported via leaching. The comparison of the three sampling strategies showed that the POCIS offers lower detection limits, resulting in the quantification of trace levels of compounds (acetochlor, diuron and desethylatrazine (DEA)) that could not be measured in grab and composite water samples. As a consequence, the frequencies of occurrence were dramatically enhanced with the POCIS compared to spot sample data. Moreover, the integration of flood events led to a better temporal representation of the fluxes when calculated with the POCIS compared to the bimonthly grab sampling strategy. We conclude that the POCIS could be an advantageous alternative to spot sampling, offering better performance in terms of quantification limits and more representative data. PMID- 24777320 TI - Recent updates on electrochemical degradation of bio-refractory organic pollutants using BDD anode: a mini review. AB - Boron-doped diamond (BDD) is playing an important role in environmental electrochemistry and has been successfully applied to the degradation of various bio-refractory organic pollutants. However, the review concerning recent progress in this research area is still very limited. This mini-review updated recent advances on the removal of three kinds of bio-refractory wastewaters including pharmaceuticals, pesticides, and dyes using BDD electrode. It summarized the important parameters in three electrochemical oxidation processes, i.e., anodic oxidation (AO), electro-Fenton (EF), and photoelectro-Fenton (PEF) and compared their different degradation mechanisms and behaviors. As an attractive improvement of PEF, solar photoelectro-Fenton using sunlight as UV/vis source presented cost-effectiveness, in which the energy consumption for enrofloxacin removal was 0.246 kWh/(g TOC), which was much lower than that of 0.743 and 0.467 kWh/(g TOC) by AO and EF under similar conditions. Finally the existing problems and future prospects in research were suggested. PMID- 24777321 TI - Coagulant recovery from water treatment plant sludge and reuse in post-treatment of UASB reactor effluent treating municipal wastewater. AB - In the present study, feasibility of recovering the coagulant from water treatment plant sludge with sulphuric acid and reusing it in post-treatment of upflow anaerobic sludge blanket (UASB) reactor effluent treating municipal wastewater were studied. The optimum conditions for coagulant recovery from water treatment plant sludge were investigated using response surface methodology (RSM). Sludge obtained from plants that use polyaluminium chloride (PACl) and alum coagulant was utilised for the study. Effect of three variables, pH, solid content and mixing time was studied using a Box-Behnken statistical experimental design. RSM model was developed based on the experimental aluminium recovery, and the response plots were developed. Results of the study showed significant effects of all the three variables and their interactions in the recovery process. The optimum aluminium recovery of 73.26 and 62.73 % from PACl sludge and alum sludge, respectively, was obtained at pH of 2.0, solid content of 0.5 % and mixing time of 30 min. The recovered coagulant solution had elevated concentrations of certain metals and chemical oxygen demand (COD) which raised concern about its reuse potential in water treatment. Hence, the coagulant recovered from PACl sludge was reused as coagulant for post-treatment of UASB reactor effluent treating municipal wastewater. The recovered coagulant gave 71 % COD, 80 % turbidity, 89 % phosphate, 77 % suspended solids and 99.5 % total coliform removal at 25 mg Al/L. Fresh PACl also gave similar performance but at higher dose of 40 mg Al/L. The results suggest that coagulant can be recovered from water treatment plant sludge and can be used to treat UASB reactor effluent treating municipal wastewater which can reduce the consumption of fresh coagulant in wastewater treatment. PMID- 24777322 TI - Examination of oxygen release from plants in constructed wetlands in different stages of wetland plant life cycle. AB - The quantification of oxygen release by plants in different stages of wetland plant life cycle was made in this study. Results obtained from 1 year measurement in subsurface wetland microcosms demonstrated that oxygen release from Phragmites australis varied from 108.89 to 404.44 mg O2/m(2)/d during the different periods from budding to dormancy. Plant species, substrate types, and culture solutions had a significant effect on the capacity of oxygen release of wetland plants. Oxygen supply by wetland plants was estimated to potentially support a removal of 300.37 mg COD/m(2)/d or 55.87 mg NH4-N/m(2)/d. According to oxygen balance analysis, oxygen release by plants could provide 0.43-1.12% of biochemical oxygen demand in typical subsurface-flow constructed wetlands (CWs). This demonstrates that oxygen release of plants may be a potential source for pollutants removal especially in low-loaded CWs. The results make it possible to quantify the role of plants in wastewater purification. PMID- 24777323 TI - Silica removal in industrial effluents with high silica content and low hardness. AB - High silica content of de-inked paper mill effluents is limiting their regeneration and reuse after membrane treatments such as reverse osmosis (RO). Silica removal during softening processes is a common treatment; however, the effluent from the paper mill studied has a low hardness content, which makes the addition of magnesium compounds necessary to increase silica removal. Two soluble magnesium compounds (MgCl2?6H2O and MgSO4?7H2O) were tested at five dosages (250 1,500 mg/L) and different initial pH values. High removal rates (80-90%) were obtained with both products at the highest pH tested (11.5). With these removal efficiencies, it is possible to work at high RO recoveries (75-85%) without silica scaling. Although pH regulation significantly increased the conductivity of the waters (at pH 11.5 from 2.1 to 3.7-4.0 mS/cm), this could be partially solved by using Ca(OH)2 instead of NaOH as pH regulator (final conductivity around 3.0 mS/cm). Maximum chemical oxygen demand (COD) removal obtained with caustic soda was lower than with lime (15 vs. 30%). Additionally, the combined use of a polyaluminum coagulant during the softening process was studied; the coagulant, however, did not significantly improve silica removal, obtaining a maximum increase of only 10%. PMID- 24777324 TI - Australian native plant species Carpobrotus rossii (Haw.) Schwantes shows the potential of cadmium phytoremediation. AB - Many polluted sites are typically characterized by contamination with multiple heavy metals, drought, salinity, and nutrient deficiencies. Here, an Australian native succulent halophytic plant species, Carpobrotus rossii (Haw.) Schwantes (Aizoaceae) was investigated to assess its tolerance and phytoextraction potential of Cd, Zn, and the combination of Cd and Zn, when plants were grown in soils spiked with various concentrations of Cd (20-320 mg kg(-1) Cd), Zn (150 2,400 mg kg(-1) Zn) or Cd + Zn (20 + 150, 40 + 300, 80 + 600 mg kg(-1)). The concentration of Cd in plant parts followed the order of roots > stems > leaves, resulting in Cd translocation factor (TF, concentration ratio of shoots to roots) less than one. In contrast, the concentration of Zn was in order of leaves > stems > roots, with a Zn TF greater than one. However, the amount of Cd and Zn were distributed more in leaves than in stems or roots, which was attributed to higher biomass of leaves than stems or roots. The critical value that causes 10% shoot biomass reduction was 115 MUg g(-1) for Cd and 1,300 MUg g(-1) for Zn. The shoot Cd uptake per plant increased with increasing Cd addition while shoot Zn uptake peaked at 600 mg kg(-1) Zn addition. The combined addition of Cd and Zn reduced biomass production more than Cd or Zn alone and significantly increased Cd concentration, but did not affect Zn concentration in plant parts. The results suggest that C. rossii is able to hyperaccumulate Cd and can be a promising candidate for phytoextraction of Cd from polluted soils. PMID- 24777326 TI - Combining chemical and biological endpoints, a major challenge for twenty-first century's environmental specimen banks. AB - Environmental specimen banks (ESBs) are not a new phenomenon, but in the last decades, the steep rate in the establishment of new ESBs is a sign to address new research approaches for scientists. In this way, environmental biobanking is becoming a well-organized and effective vehicle to collect samples of high quality making them available for future researchers. The endpoints promoted in the ESBs are mainly based on chemical approaches, but the necessity to add biological endpoint is fundamental (e.g., assessment of the environmental health status). Moreover, advances and development of high sensitive, high-throughput techniques along with ecotoxicological approaches based on biomarkers are stimulating a new demand for stored specimens and associated data. Like in chemically targeted environmental specimen banking, the banked samples for the assessment of biological effects also require guidance informed by knowledge of their practices and challenges, along with policies for the correct advancement of research goals and appropriate and effective biobank governance. PMID- 24777325 TI - Chronic dietary exposure of zebrafish to PAH mixtures results in carcinogenic but not genotoxic effects. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants that can be present at high levels as mixtures in polluted aquatic environments. Many PAHs are potent mutagens and several are well-known carcinogens. Despite numerous studies on individual compounds, little is known about the toxicity of PAHs mixtures that are encountered in environmental situations. In the present work, zebrafish were continuously fed from 5 days post-fertilisation to 14 months post fertilisation (mpf) with a diet spiked with fractions of either pyrolytic (PY), petrogenic light oil (LO), or petrogenic heavy oil (HO) origin at three concentrations. A decrease in survival was identified after 3 mpf in fish fed with the highest concentration of HO or LO, but not for PY. All PAH fractions caused preneoplastic and neoplastic disorders in long-term-exposed animals. Target tissues were almost exclusively of epithelial origin, with the bile duct epithelium being the most susceptible to chronic exposure to all PAH fractions, and with germ cells being the second most responsive cells. Significantly higher incidences of neoplasms were observed with increasing PAH concentration and exposure duration. The most severe carcinogenic effects were induced by dietary exposure to HO compared to exposure to LO or PY (45, 30 and 7 %, respectively, after 9 to 10 months of exposure to an intermediate concentration of PAHs). In contrast, earliest carcinogenic effects were detected as soon as 3 mpf after exposure to LO, including the lowest concentration, or to PY. PAH bioactivation and genotoxicity in blood was assessed by ethoxyresorufin-O-deethylase activity quantification and comet and micronuclei assays, respectively, but none of these were positive. Chronic dietary exposure of zebrafish to PAH mixtures results in carcinogenotoxic events that impair survival and physiology of exposed fish. PMID- 24777327 TI - Historical development and future perspectives of Environmental Specimen Bank in China: a mini review. AB - Environmental problems as well as their related ecosystem stress and human health risk in China have raised wide concerns along with the rapid economic development in recent years. Numerous studies with a sharp increase in publication number have addressed the ubiquitous of anthropogenic chemicals in various environmental compartments and human tissues. However, very few data were available to clarify the temporal trend and to give the retrospective analysis of chemical pollution in China. Environmental Specimen Bank (ESB) is a system for the systematic collection and long-term storage of specimens, which has been established since the 1970s in developed counties and recognized as a fundamental complement for environmental monitoring and scientific research. Currently, the value of ESB is becoming more broadly recognized globally, and China is still at the early stage. This article described the history and status and put forwarded the future key points of Chinese ESB development for illustrating the intensive environmental changes in China and the world. PMID- 24777328 TI - Occurrences and inventories of heavy metals and brominated flame retardants in wastes from printed circuit board production. AB - Pollutants including heavy metals and brominated flame retardant were detected in 10 types of production wastes from a typical printed circuit board manufacturing plant, and their inventories were estimated. Rinsing water from etching process had the highest concentrations of copper (665.51 mg/L), lead (1.02 mg/L), nickel (3.60 mg/L), chromium (0.97 mg/L), and tin (1.79 mg/L). Powdered solid waste (SW) from the cut lamination process contained the highest tetrabromobisphenol-A (TBBPA) levels (49.86 mg/kg). Polybrominated diphenyl ethers (PBDEs) were absent in this plant, in agreement with the international regulations of PBDE phase out. The pollutant inventories in the wastes exhibited in the order of copper > > zinc > tin ~ nickel > lead > chromium > > TBBPA. The potential environmental impact of pollutants in SW during production and disposal were further investigated. A high partitioning of pollutant concentration between the total suspended particle and SW (-0.10 < log K TS < 2.12) was observed for most pollutants, indicating the emission pathway from SW to the airborne atmosphere in the workshop. Although SW met the toxicity characteristic leaching procedure, drilling powder with the smallest particle diameter still showed high leachabilities of lead and tin which may lead to a negative environmental impact during disposal. PMID- 24777329 TI - Response of bacterial pdo1, nah, and C12O genes to aged soil PAH pollution in a coke factory area. AB - Soil pollution caused by polycyclic aromatic hydrocarbons (PAHs) is threatening human health and environmental safety. Investigating the relative prevalence of different PAH-degrading genes in PAH-polluted soils and searching for potential bioindicators reflecting the impact of PAH pollution on microbial communities are useful for microbial monitoring, risk evaluation, and potential bioremediation of soils polluted by PAHs. In this study, three functional genes, pdo1, nah, and C12O, which might be involved in the degradation of PAHs from a coke factory, were investigated by real-time quantitative PCR (qPCR) and clone library approaches. The results showed that the pdo1 and C12O genes were more abundant than the nah gene in the soils. There was a significantly positive relationship between the nah or pdo1 gene abundances and PAH content, while there was no correlation between C12O gene abundance and PAH content. Analyses of clone libraries showed that all the pdo1 sequences were grouped into Mycobacterium, while all the nah sequences were classified into three groups: Pseudomonas, Comamonas, and Polaromonas. These results indicated that the abundances of nah and pdo1 genes were positively influenced by levels of PAHs in soil and could be potential microbial indicators reflecting the impact of soil PAH pollution and that Mycobacteria were one of the most prevalent PAHs degraders in these PAH polluted soils. Principal component analysis (PCA) and correlation analyses between microbial parameters and environmental factors revealed that total carbon (TC), total nitrogen (TN), and dissolved organic carbon (DOC) had positive effects on the abundances of all PAH-degrading genes. It suggests that increasing TC, TN, and DOC inputs could be a useful way to remediate PAH-polluted soils. PMID- 24777330 TI - Characterization of the extracellular biodemulsifiers secreted by Bacillus cereus LH-6 and the enhancement of demulsifying efficiency by optimizing the cultivation conditions. AB - A highly efficient demulsifying strain, LH-6, was isolated from petroleum contaminated soil and identified as Bacillus cereus by 16S rDNA gene analysis. It achieved 95.61 and 95.40 % demulsifying ratios within 12 h for water-in-oil (W/O) and oil-in-water (O/W) model emulsions, respectively. Fourier transform infrared spectroscopy (FT-IR) and thin-layer chromatography (TLC) detections indicated that the LH-6's extracellular biodemulsifiers were different types of lipopeptides for the W/O and O/W emulsions. Optimization of the culture medium composition was conducted to improve the biosynthesis and demulsifying efficiency of the biodemulsifier. The optimal carbon source was liquid paraffin, while waste frying oil could also be an alternative carbon source. The optimal nitrogen sources were ammonium sulfate and yeast extract. To further enhance the biodemulsifier efficiency, the optimal cultivation conditions were determined using response surface methodology (RSM) based on central composite rotation design (CCRD). Using the optimized cultivation conditions, the demulsifying ratios increased to 98.23 and 97.65 % for the W/O and O/W model emulsions, respectively. PMID- 24777331 TI - Measurements of the streaming potential of clay soils from tropical and subtropical regions using self-made apparatus. AB - The streaming potential has been wildly used in charged parallel plates, capillaries, and porous media. However, there have been few studies involving the zeta potential of clay soils based on streaming potential measurements. A laboratory apparatus was developed in this study to measure the streaming potential (DeltaE) of bulk clay soils' coupling coefficient (C) and cell resistance (R) of saturated granular soil samples. Excellent linearity of DeltaE versus liquid pressure (DeltaP) ensured the validity of measurements. The obtained parameters of C and R can be used to calculate the zeta potential of bulk soils. The results indicated that the zeta potentials measured by streaming potential method were significantly correlated with the zeta potentials of soil colloids determined by electrophoresis (r (2) = 0.960**). Therefore, the streaming potential method can be used to study the zeta potentials of bulk clay soils. The absolute values of the zeta potentials of four soils followed the order: Ultisol from Jiangxi > Ultisol from Anhui > Oxisol from Guangdong > Oxisol from Hainan, and this was consistent with the cation exchange capacities of these soils. The type and concentration of electrolytes affected soil zeta potentials. The zeta potential became less negative with increased electrolyte concentration. The zeta potentials were more negative in monovalent than in divalent cationic electrolyte solutions because more divalent cations were distributed in the shear plane of the diffuse layer as counter-cations on the soil surfaces than monovalent cations at the same electrolyte concentration. PMID- 24777332 TI - Transparent conductors composed of nanomaterials. AB - This is a review on recent developments in the field of transparent conductive coatings (TCCs) for ITO replacement. The review describes the basic properties of conductive nanomaterials suitable for fabrication of such TCCs (metallic nanoparticles and nanowires, carbon nanotubes and graphene sheets), various methods of patterning the metal nanoparticles with formation of conductive transparent metallic grids, honeycomb structures and 2D arrays of interconnected rings as well as fabrication of TCCs based on graphene and carbon nanotubes. Applications of TCCs in electronic and optoelectronic devices, such as solar cells, electroluminescent and electrochromic devices, touch screens and displays, and transparent EMI shielders, are discussed. PMID- 24777333 TI - Antitumor activity of a polysaccharide from longan seed on lung cancer cell line A549 in vitro and in vivo. AB - In this study, a water-soluble longan seed polysaccharide (WLSP), with a molecular weight of 57 kDa, was isolated from longan seed. Gas chromatography (GC) analysis showed that WLSP was composed mainly of rhamnose (Rha), mannose (Man), arabinose (Ara), galactose (Gal), and glucose (Glc), with molar ratios of 2.4:1.5:2.3:5.6:6.5. The result in 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay showed that WLSP showed a dose-dependent antiproliferative effect on the proliferation of A549 human lung cancer cells, which is consistent with the amount of lactate dehydrogenase (LDH) release from A549 cells. Prompted by this antiproliferative effect, we further examined its antiproliferative mechanism and in vivo anticancer effect. Our results showed that WLSP had the ability to cause cell cycle arrest in G1 phase, activation of caspases 3 and 9, and cleavage of poly[ADP (ribose)] polymerase (PARP) in A549 cells. The result of this in vivo study showed that WLSP could suppress the growth of xenograft A549 tumors and induce apoptosis. Taken together, these results indicate that WLSP exert an anticancer effect in vitro and in vivo and may be useful for the prevention of lung tumorigenesis. PMID- 24777334 TI - Combination of radiofrequency ablation with transarterial chemoembolization for hepatocellular carcinoma: an up-to-date meta-analysis. AB - The aim of this meta-analysis was to compare the effectiveness of combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) with that of RFA alone in patients with hepatocellular carcinoma (HCC). Randomized controlled trials comparing RFA plus TACE with RFA alone for HCC were included into this meta-analysis, and the search strategy followed the requirement of the Cochrane Library Handbook. Overall survival rate and recurrence-free survival rate were analyzed and compared by using Review Manager (version 5). We identified 7 randomized controlled trials comprising 571 patients who were treated by RFA plus TACE versus RFA alone for HCC. Meta-analyses showed that the combination of RFA and TACE was associated with a significantly higher overall survival rates (OR1 year = 2.39, 95 % CI, 1.35-4.21, P = 0.003; OR3 years = 1.85, 95 %CI 1.26-2.71, P = 0.002), and recurrence-free survival rate (OR1 year = 2.00, 95 % CI 1.26-3.18, P = 0.003; OR3 years = 2.13, 95 %CI 1.41-3.20, P < 0.001). Additionally, the quality of the evidence was high for the 1- and 3-year survival rate; no evidence of publication bias was observed. The combination of RFA with TACE can improve the overall survival rate and the recurrence-free survival rate for patients with HCC. PMID- 24777335 TI - Heterogeneity in the expression of receptors in the human breast cancer metastasized to the brain. AB - Assessment of the human epidermal growth factor receptor-2 (Her2/ErbB2) and estrogen receptor (ER) and progesterone receptor (PR) expression in breast cancer has been an accepted standard to predict clinical outcome. Expression of these receptors in primary breast cancer has also been an important predictor of visceral organ metastasis. Many studies of breast cancer have reported risk factors for brain metastasis that include Her2/ErbB2 positivity, ER negativity, and negativity for all the above three receptors. However, it is not clear whether expression of these receptors would persist subsequent to brain metastasis. To address this possibility, we analyzed different breast cancer brain metastases (BCBM) for the expression of Her2/ErbB2, ER, and PR by immunohistochemistry procedure. The results showed that BCBM are heterogeneous in the receptor expression: Five BCBMs were Her2/ErbB2-positive and one negative; four BCBMs were ER-positive, and two were negative; five BCBMs were PR-positive and one negative. However, expression of these receptors in their combination is also heterogeneous: Four BCBMs were positive for all of the Her2/ErbB2, ER, and PR; one BCBM was positive for Her2/ErbB2 and PR but negative for ER; one BCBM was positive for PR but negative for Her2/ErbB2/ER. Similar heterogeneity in the expression of these receptors was also observed in primary tumors. Importantly, BCBM tumors that were assigned as ER- and PR-positive contained tumor cells that lacked expression of these receptors in other regions of the biopsies. Taken together, our findings indicate that the BCBM exhibit heterogeneity in the expression amounts of Her2/ErbB2, ER, and PR, which could be a result of the influence of tumor microenvironment in the brain or different tumor cells populating the metastatic region. PMID- 24777336 TI - Generation of a monoclonal antibody specific to a new candidate tumor suppressor, cell adhesion molecule 2. AB - Cell adhesion molecule 2 (CADM2) is an immunoglobulin (Ig)-like cell adhesion molecule, which belongs to the CADMs family. The four members of CADMs family including three Ig-like domains and a short cytoplasmic tail share high degree of identity with each other, making it difficult to specifically identify each members using western blotting or immunohistochemistry. And most of anti-CADM2 antibodies available commercially or used in published papers are rabbit polyclonal antibodies, exhibiting nonspecific recognition in studies. In this study, we developed a monoclonal antibody (mAb) specific to an epitope on the extracellular domain of CADM2 using conventional hybridoma technology. Western blot assays indicated that the established mAb, named as 2B11, was specific for CADM2 recognition without interference of other members of CADMs family. Furthermore, 2B11 was competent to detect CADM2 expression specifically on the surface membranes of several types of tumor tissues, avoiding the false results with the polyclonal antibodies due to nonspecific staining. In conclusion, the mAb 2B11 could be suitable for specific detection of CADM2 expression in tumor cells or tissues. PMID- 24777337 TI - Expression of basic fibroblast growth factor, CD31, and alpha-smooth muscle actin and esophageal cancer recurrence after definitive chemoradiation. AB - There is cumulative evidence that stromal reaction in cancer has an important diagnostic and prognostic significance. The aims of this study were to analyze the expression of basic fibroblast growth factor (FGF-2), CD31, and alpha-smooth muscle actin (SMA) in esophageal cancer patients and to establish their significance as indicators of disease recurrence after definitive chemoradiation (CRT). Protein expressions of FGF-2, CD31, and SMA were evaluated by immunohistochemistry and Western blot analysis in 70 patients, 20 with esophageal squamous cell carcinoma (ESCC) and 50 with locally recurrent ESCC after definitive CRT. Twenty matched normal esophageal squamous epithelium were also studied as controls. Esophageal cancer tissues showed positive expression of FGF 2, CD31, and SMA; in contrast, FGF-2 expression was not detected and only little staining for CD31 and SMA was noted in normal epithelium. Protein levels of FGF 2, CD31, and SMA were significantly elevated in recurrent ESCC. Among the patients with locally recurrent disease, expression of FGF-2 and SMA was notably high in whom the tumor recurred locally within 24 months after definitive CRT. The 2- and 5-year local recurrence-free survival rate was 15.4 % and 0 in patients with high FGF-2 expression, compared with 45.8 and 33.3 % in those who expressed low FGF-2, respectively (P = 0.005). Of patients who expressed high SMA, the 2- and 5-year local recurrence-free survival rate was 21.7 and 8.7 %, respectively, compared to those with low SMA expression which was 37.0 and 22.2 %, respectively (P = 0.016). Overexpression of FGF-2 and SMA is associated with local recurrence and reduced recurrence-free survival after definitive CRT for ESCC. The data also suggest that targeting stromal cells may be an attractive approach for esophageal cancer therapy strategies. PMID- 24777338 TI - Transcriptome profiling of the cancer and normal tissues from gastric cancer patients by deep sequencing. AB - Gastric cancer is the second highest cause of global cancer mortality. Genome wide screening of transcriptome dysregulation between cancer and normal tissues would provide insights into the molecular basis of gastric cancer initiation and progression. Recently, next-generation sequencing technique has started to revolutionize biomedical studies. RNA-seq method has become a superior approach in cancer studies, which enables accurate measurement of gene expression levels. In this work, we used RNA-seq data from tumor and matched normal samples to investigate their transcriptional changes. We totally identified 114 significantly differentially expressed genes, and these genes are highly enriched in some gene ontology (GO) categories, such as "digestive system process," "regulation of body fluid levels," "secretion," "digestion," etc. This study provided the preliminary survey of the transcriptome of Chinese gastric cancer patients, which provides better insights into the complexity of regulatory changes during tumorgenesis. PMID- 24777339 TI - MLP Tools: a PyMOL plugin for using the molecular lipophilicity potential in computer-aided drug design. AB - The molecular lipophilicity potential (MLP) is a well-established method to calculate and visualize lipophilicity on molecules. We are here introducing a new computational tool named MLP Tools, written in the programming language Python, and conceived as a free plugin for the popular open source molecular viewer PyMOL. The plugin is divided into several sub-programs which allow the visualization of the MLP on molecular surfaces, as well as in three-dimensional space in order to analyze lipophilic properties of binding pockets. The sub program Log MLP also implements the virtual log P which allows the prediction of the octanol/water partition coefficients on multiple three-dimensional conformations of the same molecule. An implementation on the recently introduced MLP GOLD procedure, improving the GOLD docking performance in hydrophobic pockets, is also part of the plugin. In this article, all functions of the MLP Tools will be described through a few chosen examples. PMID- 24777340 TI - Diethylaminoethyl (DEAE) binding fraction from Taenia solium metacestode improves the neurocysticercosis serodiagnosis. AB - Neurocysticercosis (NC) is one of the most important diseases caused by parasites affecting the central nervous system. We fractionated by ion-exchange chromatography using diethylaminoethyl (DEAE)-sepharose resin the total saline extract (S) from Taenia solium metacestodes and evaluated obtained fractions (DEAE S1 and DEAE S2) by enzyme-linked immunosorbent assay (ELISA, n = 123) and immunoblotting (IB, n = 22) to detect human NC in serum. Diagnostic parameters were established by ROC and TG ROC curves for ELISA tests. IB was qualitatively analyzed. S and DEAE S1 presented sensitivity of 87. 5% and DEAE S2 90%. The best specificity was observed for DEAE S2 (90.4%). In IB, using DEAE S2 samples from NC patients presented bands of 20-25, 43-45, 55-50, 60-66, 82, 89, and 140 kDa. The great diagnostic parameters reached by DEAE S2 suggest the potential applicability of this fraction in NC immunodiagnosis. PMID- 24777341 TI - Sensilla on the antenna of blow fly, Triceratopyga calliphoroides Rohdendorf (Diptera: Calliphoridae). AB - Blow fly, Triceratopyga calliphoroides Rohdendorf, is a common and synanthropic species of medical and forensic significance in eastern Asia. Field monitoring studies have indicated that olfaction system plays an important role in guiding the behavior of insect species. To further our understanding of fly olfaction, scanning electron microscopy (SEM) and laser scanning confocal microscopy (LSCM) are applied to examine the sensillar morphology of adults, with an emphasis on sensory pit and sacculus. Both microtrichiae and several mechanoreceptors are detected on antennal scape and pedicel. Except for these two structures, pedicellar buttons are also found in antennal pedicellar depression after the separation of antennal pedicel and funiculus. Eight types of antennal sensilla are observed on external surface of antennal funiculus (one type of trichoid sensilla, three types of basiconic sensilla, three types of coeloconic sensilla, and one type of clavate-like sensilla), while two types (one type of basiconic sensilla and one type of coeloconic-like sensilla) are detected at the inner surface of sensory pits or sacculus. As the first to investigate cuticular invaginations of blow flies via paraffin section, the internal structure of abundant sensory pits and an excessively complex sacculus on antennal funiculus are revealed. After comparison to other species previously studied, this phenomenon is proved to be the most unique feature of T. calliphoroides, armed with a discussion on its morphology, function, and possible evolutionary implications. PMID- 24777342 TI - Comparison of the sensitivity of coprological methods in detecting Anoplocephala perfoliata invasions. AB - The autopsy of 487 slaughter horses revealed the presence of Anoplocephala perfoliata in 36 animals. The invasions varied in the intensity (3 to 2,069 tapeworms) and in the level of tapeworms' proglottid maturity. Twenty nine horses were found to contain tapeworms with gravid proglottid. Fecal samples collected from the rectum were tested using following techniques: flotation with solution saturated NaCl, decantation, McMaster's, and modified sedimentation-flotation methods (50 g feces samples, flotation solution-saturated NaCl and sucrose, specific gravity 1.25 g/ml). The number of A. perfoliata positive fecal samples was significantly higher using the sedimentation-flotation methods 21 (58.33%) than flotation 6 (16.66%), decantation 3 (8.33%), and McMaster's 1 (2.77%) techniques. The sensitivities of the coprological methods during the patent period were 20.69, 10.34, 3.45, and 72.41% for the flotation, decantation, McMaster's, and sedimentation-flotation method, respectively. Sedimentation flotation techniques proved to be more sensitive than other one. The lowest intensity of invasion possible to detect using this method was nine tapeworms with gravid proglottid. PMID- 24777343 TI - In vitro development of Eucoleus bohmi eggs in different environmental conditions. AB - The development of Eucoleus bohmi eggs was evaluated in vitro in order to acquire information on the life cycle of this neglected respiratory nematode affecting canids. Fecal cultures were prepared using fecal samples from a positive dog and maintained at different conditions of temperature (20 +/- 1 and 5 +/- 1 degrees C) and relative humidity (RH) (85 +/- 5 and 45 +/- 5%). Egg development was microscopically examined at days +7, +15, and +30. In addition, in order to assess the vitality of eggs maintained at 5 +/- 1 degrees C for 30 days, these latter cultures were moved, placed at 20 +/- 1 degrees C and 85 +/- 5% RH, and observed for further 30 and 40 days. The results showed that at 20 +/- 1 degrees C and 85 +/- 5% RH, the totality of eggs completed development in 30 days, while about 26 and 70% of eggs were already fully developed after 7 and 15 days, respectively. No egg development occurred after 30 days at 5 +/- 1 degrees C, while 100% of eggs placed at 5 +/- 1 degrees C for 30 days and then moved at 20 +/- 1 degrees C and 85 +/- 5% RH for further 40 days were found fully developed. PMID- 24777344 TI - Eco-friendly graphene synthesis on Cu foil electroplated by reusing Cu etchants. AB - Graphene film grown by chemical vapor deposition using Cu substrate is promising for industrial applications. After etching the Cu substrate, which is essential step in graphene transfer process, the etchant solution must be chemically treated to prevent water pollution. Here we investigated that a method of reusing Cu etchant used to synthesize graphene, the synthesis of graphene on the resulting reused Cu films (R-G), and the application of R-G to organic light emitting diodes (OLEDs) and organic photovoltaic cells (OPVs). The turn-on voltage of OLEDs based on the R-G electrode was 4.2 V, and the efficiencies of OPVs based on the R-G electrode were 5.9-5.95%, that are similar to or better than those of the indium-tin-oxide-based devices. These results suggest that the reusing of Cu foil by the electroplating method could reduce the cost of graphene synthesis, thus opening a wide range of applications in graphene electronics. PMID- 24777345 TI - Expression of Sucrose Transporter cDNAs Specifically in Companion Cells Enhances Phloem Loading and Long-Distance Transport of Sucrose but Leads to an Inhibition of Growth and the Perception of a Phosphate Limitation. AB - Sucrose (Suc) is the predominant form of carbon transported through the phloem from source to sink organs and is also a prominent sugar for short-distance transport. In all streptophytes analyzed, Suc transporter genes (SUTs or SUCs) form small families, with different subgroups evolving distinct functions. To gain insight into their capacity for moving Suc in planta, representative members of each clade were first expressed specifically in companion cells of Arabidopsis (Arabidopsis thaliana) and tested for their ability to rescue the phloem-loading defect caused by the Suc transporter mutation, Atsuc2-4. Sequence similarity was a poor indicator of ability: Several genes with high homology to AtSUC2, some of which have phloem-loading functions in other eudicot species, did not rescue the Atsuc2-4 mutation, whereas a more distantly related gene, ZmSUT1 from the monocot Zea mays, did restore phloem loading. Transporter complementary DNAs were also expressed in the companion cells of wild-type Arabidopsis, with the aim of increasing productivity by enhancing Suc transport to growing sink organs and reducing Suc-mediated feedback inhibition on photosynthesis. Although enhanced Suc loading and long-distance transport was achieved, growth was diminished. This growth inhibition was accompanied by increased expression of phosphate (P) starvation-induced genes and was reversed by providing a higher supply of external P. These experiments suggest that efforts to increase productivity by enhancing sugar transport may disrupt the carbon-to-P homeostasis. A model for how the plant perceives and responds to changes in the carbon-to-P balance is presented. PMID- 24777346 TI - Genome-Wide Analysis of Heat-Sensitive Alternative Splicing in Physcomitrella patens. AB - Plant growth and development are constantly influenced by temperature fluctuations. To respond to temperature changes, different levels of gene regulation are modulated in the cell. Alternative splicing (AS) is a widespread mechanism increasing transcriptome complexity and proteome diversity. Although genome-wide studies have revealed complex AS patterns in plants, whether AS impacts the stress defense of plants is not known. We used heat shock (HS) treatments at nondamaging temperature and messenger RNA sequencing to obtain HS transcriptomes in the moss Physcomitrella patens. Data analysis identified a significant number of novel AS events in the moss protonema. Nearly 50% of genes are alternatively spliced. Intron retention (IR) is markedly repressed under elevated temperature but alternative donor/acceptor site and exon skipping are mainly induced, indicating differential regulation of AS in response to heat stress. Transcripts undergoing heat-sensitive IR are mostly involved in specific functions, which suggests that plants regulate AS with transcript specificity under elevated temperature. An exonic GAG-repeat motif in these IR regions may function as a regulatory cis-element in heat-mediated AS regulation. A conserved AS pattern for HS transcription factors in P. patens and Arabidopsis (Arabidopsis thaliana) reveals that heat regulation for AS evolved early during land colonization of green plants. Our results support that AS of specific genes, including key HS regulators, is fine-tuned under elevated temperature to modulate gene regulation and reorganize metabolic processes. PMID- 24777347 TI - Cavitation Resistance in Seedless Vascular Plants: The Structure and Function of Interconduit Pit Membranes. AB - Plant water transport occurs through interconnected xylem conduits that are separated by partially digested regions in the cell wall known as pit membranes. These structures have a dual function. Their porous construction facilitates water movement between conduits while limiting the spread of air that may enter the conduits and render them dysfunctional during a drought. Pit membranes have been well studied in woody plants, but very little is known about their function in more ancient lineages such as seedless vascular plants. Here, we examine the relationships between conduit air seeding, pit hydraulic resistance, and pit anatomy in 10 species of ferns (pteridophytes) and two lycophytes. Air seeding pressures ranged from 0.8 +/- 0.15 MPa (mean +/- sd) in the hydric fern Athyrium filix-femina to 4.9 +/- 0.94 MPa in Psilotum nudum, an epiphytic species. Notably, a positive correlation was found between conduit pit area and vulnerability to air seeding, suggesting that the rare-pit hypothesis explains air seeding in early-diverging lineages much as it does in many angiosperms. Pit area resistance was variable but averaged 54.6 MPa s m-1 across all surveyed pteridophytes. End walls contributed 52% to the overall transport resistance, similar to the 56% in angiosperm vessels and 64% in conifer tracheids. Taken together, our data imply that, irrespective of phylogenetic placement, selection acted on transport efficiency in seedless vascular plants and woody plants in equal measure by compensating for shorter conduits in tracheid-bearing plants with more permeable pit membranes. PMID- 24777348 TI - The European Court legitimates access of Italian couples to assisted reproductive techniques and to pre-implantation genetic diagnosis. AB - On 28 August 2012, the European Court of Human Rights (ECHR) issued a judgment regarding the requirements for the legitimate access of couples to assisted reproductive techniques (ART) and to pre-implantation genetic diagnosis (PGD). This judgment concerns the case of an Italian couple who found out after their first child was born with cystic fibrosis that they were healthy carriers of the disease. When the woman became pregnant again in 2010 and underwent fetal screening, it was found that the unborn child also had cystic fibrosis, whereupon she had the pregnancy terminated on medical grounds. In order to have the embryo genetically screened prior to implantation under the procedure of PGD, the couple sought to use in vitro fertilisation to have another child. Since article 1 of the Italian law strictly limits access to ART to sterile/infertile couples or those in which the man has a sexually transmissible disease, the couple appealed to the European court, raising the question of the violation of articles 8 and 14 of the European Convention on Human Rights. The applicants lodged a complaint that they were not allowed legitimate access to ART and to PGD to select an embryo not affected by the disease. The European Court affirmed that the prohibition imposed by Italian law violated article 8 of the European Convention on Human Rights. Focusing on important regulatory and legal differences among EU Nations in providing ART treatments and PGD, we derived some important similarities and differences. PMID- 24777349 TI - Region-specific differences in the human myenteric plexus: an immunohistochemical study using donated elderly cadavers. AB - PURPOSE AND METHODS: To identify site-dependent and individual differences in neuronal nitric oxide synthase (nNOS)-positive nerves of the myenteric plexus, we examined full-thickness walls of the stomach, pylorus, duodenum, ileum, colon, and rectum in 7 male and 8 female cadavers (mean ages, 80 and 87 years, respectively). RESULTS: The areas occupied by nNOS-positive nerve fibers in the myenteric plexus were fragmentary and overlapped with areas occupied by vasoactive intestinal polypeptide-positive fibers. The nNOS-positive fiber containing areas per 1-mm length of intermuscular space tended to be larger at more anal sites, with positive areas four times greater in the rectum than in the stomach. Interindividual differences in rectal areas were extremely large, ranging from 0.017 mm(2) in one 80-year-old man to 0.067 mm(2) in another 80-year old man. Similarly, the numbers of nNOS-positive ganglion cell bodies per 1-mm length in the rectum ranged from 4 to 28. These areas and numbers were weakly correlated (r = 0.62; p = 0.02). Interindividual differences in the rectum appeared not to depend on either age or gender. CONCLUSIONS: Anatomic studies using donated cadavers carried the advantage of obtaining any parts of intestine within an individual, in contrast to surgically removed specimens. We speculated excess control of evacuation with laxatives as one of causes of atrophy of the rectal myenteric plexus. PMID- 24777350 TI - Rectal leiomyosarcoma in association with ulcerative colitis: a rare condition with an unusual presentation. PMID- 24777351 TI - Sacral neuromodulation for anorectal dysfunction secondary to congenital imperforate anus: report of two cases. PMID- 24777352 TI - Colonic invasion induced by malignant peritoneal mesothelioma. PMID- 24777353 TI - Sorption behavior of heavy metals on poorly crystalline manganese oxides: roles of water conditions and light. AB - The objective of this study was to determine the effects of solution properties and light on the metal uptake and release in a nanosized, poorly crystalline manganese oxide (delta-MnO2) system. The results from synthetic water matrices revealed that the aggregation state was strongly affected by ionic strength, Ca(2+), and humic acid, and the particle aggregation subsequently changed the ability of delta-MnO2 to adsorb and sequester heavy metal ions (Cu(ii)). The extent of Cu(ii) uptake onto delta-MnO2 exhibited a negative correlation with the attachment efficiency value, which suggested that a lower sorption capacity could be achieved under aggregation-inducing conditions. Upon exposure to light, the adsorbed Cu(ii) was released from the delta-MnO2 surface via photoinduced dissolution of MnO2. The concentration of Cu(ii) desorbed was substantially higher when the humic acid was present together with Ca(2+). The present investigation enables us to better understand the adsorption-desorption processes of heavy metals occurring at the MnO2-solution interface in response to common environmental stimuli. PMID- 24777354 TI - Survival in patients with hepatocellular carcinoma treated with 90Y-microsphere radioembolization. Prediction by 18F-FDG PET. AB - AIM: This retrospective study aims to evaluate the predictive value of FDG PET/CT in patients with unresectable hepatocellular carcinoma (HCC) undergoing radioembolization with yttrium-90 labeled microspheres (RE). PATIENTS, METHODS: The study cohort comprised 33 patients who were treated with RE at our institution and underwent FDG PET/CT at baseline and four weeks after radioembolization. According to the baseline FDG metabolic status of the HCC lesions, patients were divided into two groups: FDG-negative (n = 12) and FDG positive (n = 21) HCC. FDG-positive patients were further divided into early metabolic responders and non-responders according to the relative change in SUVmax of the treated lesions. Survival analyses were performed with the Kaplan Meier method (log-rank test, p < 0.05). Multivariate analysis was performed to assess the influence of prognostic factors on overall survival (OS). RESULTS: FDG negative patients had a significantly longer OS (13 months, 95%CI 7-19) than FDG positive patients (9 months, 95%CI 7-11; p = 0.010). Among FDG-positive patients, metabolic responders survived significantly longer than metabolic non-responders (10 months, 95%CI 8-12 vs. 5 months, 95%CI 4-6; p = 0.003). From the other baseline factors (including performance status, hepatic tumour burden, presence of extra-hepatic disease, administered activity) only the BCLC stage had a significant impact on OS (p = 0.028). CONCLUSION: Pre- and post-therapeutic FDG PET independently predicts overall survival in patients with HCC undergoing radioembolization. Interestingly, early metabolic response seems to be assessable as early as four weeks post-treatment. PMID- 24777355 TI - Can peptide receptor radionuclide therapy be safely applied in florid bone metastases? A pilot analysis of late stage osseous involvement. AB - AIM: Highly advanced metastatic bone disease with extensive osseous infiltration of neuroendocrine tumours (NET) may preclude patients from treatment with peptide receptor radionuclide therapy (PRRT) in concern about haematotoxicity. This study aims to assess the safety and efficacy of PRRT with 177Lu-octreotate in a patient cohort with this condition. PATIENTS, METHODS: 41 PRRT courses were performed in 11 patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) and florid bone metastases (severely advanced widespread metastatic bone disease). A mean activity of 6.95 GBq 177Lu-octreotate was administered per treatment cycle, aimed at four courses with standard intervals of 3 months. Haematological parameters were determined prior to each treatment course, in 2-4 weeks intervals between the courses, 8-12 weeks after the last course of PRRT and in 3 monthly intervals thereafter. Toxicity was recorded using Common Terminology Criteria for Adverse Events v3.0. Restaging was performed 3 months after termination of PRRT with CT/MRI and functional imaging (modified MDA criteria). RESULTS: Significant (grade III-IV), reversible haematotoxicity occurred in 4 (35%) patients and after 10 (24%) administrations. It either resolved spontaneously (1 patient) or was controlled by supportive measures (3 patients), such as blood transfusions (3 patients) or deferral of the subsequent therapy cycle (1 patient). Patients returned to baseline blood values within up to 23 months after termination of PRRT. The observed treatment response of bone metastases consisted of a partial response in 2, a minor response in 1, stable disease in 7, and progressive disease in 1 patient. Of the 4 patients with metastatic bone pain, 1 experienced complete and 3 partial resolution of symptoms within 3-10 weeks after commencement of PRRT. CONCLUSION: These preliminary data indicate that PRRT with 177Lu-octreotate can be safely applied even in florid bone metastases with extensive, severely advanced osseous replacement. The higher myelosuppression rate was not associated with serious complications and should not preclude patients from being treated and potentially experiencing remarkable treatment efficacy despite the very advanced stage. PMID- 24777356 TI - Multiple cardiac masses and distant metastatic foci in a patient with high grade pleomorphic sarcoma of the heart revealed by follow-up FDG PET/CT. PMID- 24777357 TI - Ex situ identification of the Cu+ long-range diffusion path of a Cu-based anode for lithium ion batteries. AB - An ex situ observation was made by XRD patterns, SEM and TEM images, as well as cyclic voltammogram curves of CuO/Cu integrated anodes for lithium ion batteries. For the first time, the existence of a Cu(+) ion long-range transfer path was identified at the potential widow of 1.30-1.60 V during both charging and discharging processes. Both SEM and TEM images show that these nanowires networks hanging CuO nanoparticles provide a Cu(+) diffusion path within our designed CuO/Cu integrated anode. This work provides new insights into the conversion reaction of inorganic anode materials, and can favor the development of high performance conversion anodes for lithium-ion batteries. PMID- 24777358 TI - The complete mitochondrial genome of the brown leg mite, Aleuroglyphus ovatus (Acari: Sarcoptiformes): evaluation of largest non-coding region and unique tRNAs. AB - The circular mitochondrial genome (mitogenome) of Aleuroglyphus ovatus was sequenced. It was 14,328 bp long, and consisted of 37 coding genes including 13 protein-coding genes, two ribosomal RNA genes, and 22 transfer RNA genes. This is the first description of the complete mitogenome of a species in the Acaridae (Acari: Sarcoptiformes). The mtDNA gene order for A. ovatus is identical to those of Dermatophagoides farinae and D. pteronyssinus, but distinctly different from the mtDNA of other Acari. Most inferred tRNA genes of A. ovatus are extremely truncated (48-62 bp), lack stem-loops on either the T- or D-arm (except the trnK), and are unable to fold into the canonical tRNA cloverleaf structure. The largest non-coding region (378 bp) contained several conserved sequences involved in the regulation of mitogenome replication, including one core sequence (ACAT) associated with termination of the J-strand replication and several hypothetical stem-loop structures. The microsatellite-like (AT)n sequence in the largest non coding region was observed in two other Astigmata species, but it has not been found in other Acari. PMID- 24777359 TI - Effect of hexythiazox and spiromesifen resistance on the life cycle of the predatory mite Neoseiulus californicus (Acari: Phytoseiidae). AB - Neoseiulus californicus (McGregor) (Acari: Phytoseiidae) is one of the most important and effective predators of Tetranychus spp. (Acari: Tetranychidae). This study analyzed the effects of hexythiazox and spiromesifen resistance on biological characteristics of N. californicus. Pre-oviposition, oviposition, post oviposition times, adult lifespan, total number of eggs laid per female, net reproductive rate (R0), intrinsic rate of increase (rm), doubling time (DT), mean generation time (T) and finite rate of increase (lambda) were compared among three populations: 63.9-fold hexythiazox resistant (HEX14), 53.6-fold spiromesifen resistant (SPR13) and a susceptible base population. Pre-oviposition and oviposition times, mean number of eggs/female, adult lifespan, R0 and rm values were all significantly higher for the two resistant populations than for the susceptible population. Life tables of HEX14, SPR13 and the susceptible population showed that R0 was 35.0, 26.5 and 19.4 (females/female generation), rm was 0.35, 0.32 and 0.30 (females/female/day), DT was 1.92, 2.07 and 2.27 days, T was 9.8, 9.8 and 9.7 days, and lambda was 1.43, 1.39 and 1.35 (individuals/female/day), respectively. PMID- 24777361 TI - Methane oxidation over A-site ordered and disordered Sr(0.8)Gd(0.2)CoO(3-delta) perovskites. AB - A tetragonal phase Sr0.8Gd0.2CoO3-delta with ordered Gd(3+)/Sr(2+) ions and oxygen vacancy sites is found to be about five times less active in the reaction of methane combustion than a quenched cubic perovskite phase with randomly distributed (disordered) Gd(3+)/Sr(2+) ions over the A-sites of the crystal lattice. PMID- 24777362 TI - Editor's note. PMID- 24777360 TI - Unpinning of rotating spiral waves in cardiac tissues by circularly polarized electric fields. AB - Spiral waves anchored to obstacles in cardiac tissues may cause lethal arrhythmia. To unpin these anchored spirals, comparing to high-voltage side effect traditional therapies, wave emission from heterogeneities (WEH) induced by the uniform electric field (UEF) has provided a low-voltage alternative. Here we provide a new approach using WEH induced by the circularly polarized electric field (CPEF), which has higher success rate and larger application scope than UEF, even with a lower voltage. And we also study the distribution of the membrane potential near an obstacle induced by CPEF to analyze its mechanism of unpinning. We hope this promising approach may provide a better alternative to terminate arrhythmia. PMID- 24777363 TI - Introduction: "the sexual aberrations"--where do we stand today? PMID- 24777364 TI - Be careful what you wish for! The surrender of gender. AB - Close examination of Freud's Three Essays on the Theory of Sexuality (1905a) reveals an ambiguity in Freud's language as he simultaneously tries to escape 19th-century psychiatric paradigms concerning sexuality and perversion while also retaining a normative approach to adult sexuality that created new categories of pathology. The result is an ambivalent legacy that has both hampered and helped contemporary clinicians as they deal with a diverse array of presentations of gender and sexual orientation in today's world. PMID- 24777365 TI - The widening scope of indications for perversion. AB - Much has changed in clinical practice and theory that bears on the diagnosis and treatment of perversion since Freud's Three Essays on the Theory of Sexuality (1905). Definitions of perversion have been freed from assumptions of a heterosexual normality and from moralistic interpretations. The authors endorse the current emphasis on aggression and early narcissistic problems and include the notion of splitting and sexualized scenarios in their definition of perversion. They present several vignettes of male and female patients to demonstrate the debts owed to Freud's theories and the way in which their thinking differs. They emphasize the understanding of the transference countertransference picture and the patient's management and control of excitement. PMID- 24777367 TI - The three essays and the meaning of the infantile sexual in psychoanalysis. AB - Freud's Three Essays on Sexual Theory (1905a) are still today highly significant because of their novel way of considering the human sexual dimension. The author intends to show that a close reading of the Essays, combined with the reintroduction of the seduction theory by Jean Laplanche, provides a specific and foundational sexual theory for psychoanalysis. PMID- 24777366 TI - Sexual aberration or instinctual vicissitude? Revisiting freud's "the sexual aberrations". AB - The author reconsiders Freud's "The Sexual Aberrations," the first of his Three Essays on the Theory of Sexuality (1905), in light of contemporary psychoanalytic theory. Are the concepts of sexual aberration and norm still viable? The author argues that they are necessary but insufficient elements in current theory. He then presents a competing model in which sexuality can be reduced to a more elemental level of disturbance and wish, where it is an expression of a nonsexual wish--for example, to possess or control the object to eliminate separateness. The author presents clinical material to demonstrate this alternative model. PMID- 24777368 TI - The fate of aggression in maso-masochistic relationships. AB - This paper examines an underexplored dimension of interpersonal relating: the relationship formed between two individuals who relate to each other in masochistic ways. The common assumption is that a sadist forms an alliance with a masochist, and that a balance is struck between an individual who is "one up" and another who is "one down." However, relationships are frequently established between two people who both experience themselves as chronically "one down," each playing victim to the other's aggression. This paper explores disavowed aggression in this type of couple, the implications of this disavowal for treatment, and the sadomasochistic reverberations within the therapist. PMID- 24777369 TI - Spontaneous remissions: Norman Reider's forgotten paper, part I. AB - Almost sixty years ago, Norman Reider published a paper about spontaneous "remissions" he had observed. He discussed the manner in which psychoanalytic theory provided a way to partially explain these otherwise mysterious remissions or improvements in symptoms, some without benefit of either psychoanalysis or psychotherapy. Especially important were his comments about the negligible role of interpretation or insight in these examples. His conjectures reflected controversies that were current at the time and that remain unsettled. Of special interest is his introduction of some highly original ways to think of applying psychoanalytic ideas to supportive psychotherapy. But few analysts today have heard of this paper. A reconsideration of his paper allows us to be vividly reminded about our enduring and profound confusion about exactly what constitutes a "cure" at all. Spontaneous shifts in the severity of symptoms may be viewed as experiments of nature that we have neglected to investigate as valuable restraints on our immodest therapeutic claims. PMID- 24777370 TI - Spontaneous "cures": Norman Reider's forgotten paper, part II. AB - Part I of this paper combined an introduction to Norman Reider's original 1955 paper with a republication of the paper itself. Part II is a discussion of the complexities of a comparison of past and present psychoanalytic literature. The concept of enactment is proposed as one of many possible alternative views in considering Reider's notion of spontaneous "cures." A careful consideration of these spontaneous cures within the ordinary ups and downs of any psychoanalytic treatment sheds important light on our continuing confusion about how we define the term cure, and therefore about the nature of change during psychoanalytic treatment. This alternative perspective is only one of many plausible ones for present-day readers. The purpose of this republication is not to propose an explanation for "what really happened" with Reider and his patients; rather, it is to reconsider the fallacy of evaluating his paper outside its historical context and thereby failing to appreciate his courage in presenting what at the time were radical views. Questions about the complexity and confusion regarding cure and change require reexamination of the neglect of epistemology on the part of psychoanalysis in prolonging the confusion about distinguishing psychotherapy and psychoanalysis. PMID- 24777371 TI - Different architectures of creativity: Louis and Nathaniel Kahn. AB - The author analyzes Nathaniel Kahn's documentary film My Architect: A Son's Journey, a tribute to the writer-director's father Louis, the famous architect, who died suddenly when Nathaniel was eleven years old. The film's poetic, evocative images form a testimony to the silent working through that Nathaniel did in searching for his lost father and to the complex intertwining of mourning and creativity. Creativity is seen as both the cause and the effect of working through, as it gives life to a new meaning and allows replacement of the lost object by an object found again. Bereavement, symbolization, and the birth of representation appear to be connected with one another, both when the most elementary representations are involved and when the more complex and artistic ones are. Where and when it is possible to recover a representation that can survive the absence of the lost object, there is a potentially creative psychic space that can be made fertile again. PMID- 24777379 TI - Introduction to the thematic issue "From brain function to therapy". PMID- 24777380 TI - The role of the N-methyl-D-aspartate receptor in the proliferation of adult hippocampal neural stem and precursor cells. AB - New neurons are continuously generated from resident pools of neural stem and precursor cells (NSPCs) in the adult brain. There are multiple pathways through which adult neurogenesis is regulated, and here we review the role of the N methyl-D-aspartate receptor (NMDAR) in regulating the proliferation of NSPCs in the adult hippocampus. Hippocampal-dependent learning tasks, enriched environments, running, and activity-dependent synaptic plasticity, all potently up-regulate hippocampal NSPC proliferation. We first consider the requirement of the NMDAR in activity-dependent synaptic plasticity, and the role the induction of synaptic plasticity has in regulating NSPCs and newborn neurons. We address how specific NMDAR agonists and antagonists modulate proliferation, both in vivo and in vitro, and then review the evidence supporting the hypothesis that NMDARs are present on NSPCs. We believe it is important to understand the mechanisms underlying the activation of adult neurogenesis, given the potential that endogenous stem cell populations have for repopulating the hippocampus with functional new neurons. In conditions such as age-related memory decline, neurodegeneration and psychiatric disease, mature neurons are lost or become defective; as such, stimulating adult neurogenesis may provide a therapeutic strategy to overcome these conditions. PMID- 24777381 TI - What did the bronze eye-like prism tell us? PMID- 24777382 TI - Transcriptome profile of human neuroblastoma cells in the hypomagnetic field. AB - Research has shown that the hypomagnetic field (HMF) can affect embryo development, cell proliferation, learning and memory, and in vitro tubulin assembly. In the present study, we aimed to elucidate the molecular mechanism by which the HMF exerts its effect, by comparing the transcriptome profiles of human neuroblastoma cells exposed to either the HMF or the geomagnetic field. A total of 2464 differentially expressed genes (DEGs) were identified, 216 of which were up-regulated and 2248 of which were down-regulated after exposure to the HMF. These DEGs were found to be significantly clustered into several key processes, namely macromolecule localization, protein transport, RNA processing, and brain function. Seventeen DEGs were verified by real-time quantitative PCR, and the expression levels of nine of these DEGs were measured every 6 h. Most notably, MAPK1 and CRY2, showed significant up- and down-regulation, respectively, during the first 6 h of HMF exposure, which suggests involvement of the MAPK pathway and cryptochrome in the early bio-HMF response. Our results provide insights into the molecular mechanisms underlying the observed biological effects of the HMF. PMID- 24777383 TI - From brain function to therapy. PMID- 24777384 TI - Deep brain stimulation for disorders of memory and cognition. AB - The next several decades will see an exponential rise in the number of patients with disorders of memory and cognition, and of Alzheimer's disease in particular. Impending demographic shifts, an absence of effective treatments, and the significant burden these conditions place on patients, caregivers, and society, mean there is an urgent need to develop novel therapies. Deep brain stimulation (DBS) is a neurosurgical procedure that is a standard-of-care for many patients with treatment-refractory Parkinson's disease, dystonia, and essential tremor. DBS has proven to be an effective means of modulating activity in disrupted motor circuitry, and has shown promise as a modulator of other dysfunctional circuits, including for mood and anxiety disorders. The deficits in Alzheimer's disease and other disorders of memory and cognition are also beginning to be thought of as arising from dysfunction in neural circuits. Such dysfunction may be amenable to modulation using focal brain stimulation. A global experience is now emerging for the use of DBS for these conditions, targeting key nodes in the memory circuit, including the fornix and nucleus basalis of Meynert. Such work holds promise as a novel therapeutic approach for one of medicine's most urgent priorities. PMID- 24777385 TI - Transcriptional regulation of the rat sperm-associated antigen 11e (Spag 11e) gene during endotoxin challenge. AB - The lipopolysaccharide (LPS) inducible expression of antimicrobial proteins of the Sperm-Associated Antigen 11 (Spag11) family is dependent on nuclear factor kappaB (NF-kappaB) activation and epigenetic factors. However, the regulatory mechanisms that govern their gene expression during endotoxin challenge are unknown. In this study, we demonstrate that the Spag11e gene upstream sequence contains binding sites for androgen receptor (AR), NF-kappaB, nuclear factor-1, E twenty-six and activator protein 2. The role of these transcription factors in inducing Spag11e gene during LPS challenge was analysed by measuring luciferase activity in HEK cells transiently transfected with deletion constructs that lacked one or more of the binding sites. Deletion of AR-binding site resulted in loss of luciferase activity and no further decrease was observed when progressive deletions of the other transcription factor binding sites were made. Mutations in AR or NF-kappaB binding site resulted in loss of luciferase activity. Electrophoretic gel-mobility shift assays indicated that AR and NF-kappaB proteins bind to the synthesised radio-labelled oligomers used as probes and the mobility shifted when respective antibodies were added. Results of this study indicate the direct involvement of AR and NF-kappaB in LPS-induced Spag11e expression, thereby expanding our understanding of antimicrobial gene expression during endotoxin challenge. PMID- 24777387 TI - Validating DICOM transcoding with an open multi-format resource. PMID- 24777386 TI - Group-wise FMRI activation detection on DICCCOL landmarks. AB - Group-wise activation detection in task-based fMRI has been widely used because of its robustness to noises and its capacity to deal with variability of individual brains. However, current group-wise fMRI activation detection methods typically rely on the co-registration of individual brains' fMRI images, which has difficulty in dealing with the remarkable anatomic variation of different brains. As a consequence, the resulted misalignments could significantly degrade the required inter-subject correspondences, thus substantially reducing the sensitivity and specificity of group-wise fMRI activation detection. To deal with these challenges, this paper presents a novel approach to detecting group-wise fMRI activation on our recently developed and validated Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOL). The basic idea here is that the first-level general linear model (GLM) analysis is first performed on the fMRI signal of each corresponding DICCCOL landmark in individual brain's own space, and then the estimated effect sizes of the same landmark from a group of subjects are statistically assessed with the mixed-effect model at the group level. Finally, the consistently activated DICCCOL landmarks are determined and declared in a group-wise fashion in response to external block-based stimuli. Our experimental results have demonstrated that the proposed approach can detect meaningful activations. PMID- 24777388 TI - Management of a complicated buried bumper syndrome with a technique involving dye test, cannulation, and extraction. PMID- 24777389 TI - Healing patterns of clavicular birth injuries as a guide to fracture dating in cases of possible infant abuse. AB - BACKGROUND: Dating fractures is critical in cases of suspected infant abuse. There are little scientific data to guide radiologists, and dating is generally based on personal experience and conventional wisdom. OBJECTIVE: Since birth related clavicular fractures are not immobilized and their age is known, we propose that an assessment of these injuries may serve as a guide for dating inflicted fractures in young infants, acknowledging that patterns observed in the clavicle may not be entirely generalizable to other bones injured in the setting of abuse. MATERIALS AND METHODS: One hundred thirty-one radiographs of presumed birth-related clavicular fractures in infants between 0 and 3 months of age were reviewed by two pediatric radiologists with 30 and 15 years' experience. Readers were asked to evaluate images based on several parameters of fracture healing, with a focus on subperiosteal new bone formation (SPNBF) and callus formation. SPNBF and callus were each evaluated with regard to presence, thickness and character. Responses were correlated with known fracture ages. RESULTS: SPNBF was rarely seen in fractures less than 7 days old and was most often present by 10 days. Callus formation was rarely seen in fractures less than 9 days old and was most often present by 15 days. SPNBF thickness increased with fracture age and the character of SPNBF evolved from single-layered to solid/multilayered. Callus thickness decreased with fracture age and callus matrix evolved from soft to intermediate to hard in character. CONCLUSION: There is an evolution in clavicular fracture healing in young infants that follows a predictable pattern. These findings afford the prospect that predictable patterns of infant clavicular fracture healing can provide an evidence base that may be applicable in cases of suspected infant abuse. PMID- 24777390 TI - Significant enhancement of optical absorption through nano-structuring of copper based oxide semiconductors: possible future materials for solar energy applications. AB - The optical absorption coefficient is a crucial parameter in determining solar cell efficiency under operational conditions. It is well known that inorganic nanocrystals are a benchmark model for solar cell nanotechnology, given that the tunability of optical properties and stabilization of specific phases are uniquely possible at the nanoscale. A hydrothermal method was employed to fabricate nanostructured copper oxides where the shape, size and phase were tailored by altering the growth parameters, namely the base media used, the reaction temperature, and the reaction time. The nano crystalline structures, phases, morphology, molecular vibrational modes, and optical properties were investigated using X-ray diffraction (XRD), scanning electron microscopy (SEM), Raman spectroscopy, photoluminescence (PL), and UV-vis spectroscopy. A significantly large optical absorption coefficient, of the order of twice that of Si in the visible range, was observed in a particular phase mixture of nanostructured copper oxides. An optical absorption coefficient of 7.05 10(+5) cm(-1) at 525 nm was observed in a particular nanostructured phase mixture of copper oxides which is appreciably larger than commercially pure CuO (1.19 10(+5) cm(-1)) and Si (1.72 10(+5) cm(-1)). A possible mechanism of formation of phase mixtures and morphology of copper oxides has also been discussed, which opens up a roadmap in synthesis of similar morphology nanostructures for efficient solar cells. PMID- 24777391 TI - Mechanically tough, elastic and stable rope-like double nanohelices. AB - Double helix nanostructures have been the object of intense theoretical and experimental investigations in recent years due to their various types of available materials and unique morphology. Among these structures, rope-like double nanohelices of two strands in contact along a line can be obtained using any one-dimensional nanostructure. In this work, we establish a novel theory for quantitatively exploring the statics and dynamics of rope-like double nanohelices by employing the concept of the extensible Cosserat curve. The rope-like double nanohelices are tough, relatively elastic, and mechanically stable, which agrees well with the experiments. The characteristics of the interaction between the two strands, the tensile modulus and the torque are precisely described and explained across the entire stretching region. The proposed model offers in depth quantitative insight into the mechanics of double helix nanostructures, and supplies a reliable reference for further experimental research. PMID- 24777392 TI - Post cardiac injury syndrome after initially uncomplicated CRT-D implantation: a case report and a systematic review. AB - BACKGROUND: Post cardiac injury syndrome (PCIS) is an inflammatory process that occurs in the setting of injury to the pericardium, epicardium or myocardium. It may follow cardiac surgery, myocardial infarction, trauma, intracardiac ablation, percutaneous coronary intervention or implantation of a pacemaker or cardioverter defibrillator. METHODS: In this paper, we report the first case of PCIS after implantation of a "Cardiac Resynchronization Therapy Defibrillator" (CRT-D) device and review systematically the available literature. To obtain information on PCIS after implantation of heart rhythm devices (HRD), we performed a systematic review of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). The collected data included age, gender, initial diagnosis, procedure type, time to PCIS, symptoms, clinical manifestations, therapy and outcome. Included were reports in English, French and Spanish. RESULTS: In our systematic review, we found PCIS after HRD implantation in 17 additional cases. The age ranged from 23 to 84 years. Symptoms developed within 1 day-4 months after implantation. The use of active-fixation atrial leads was reported in nine cases. Fever, dyspnoea, chest pain, tachypnoea, tachycardia, palpitation, malaise, ankle edema, dry cough, night sweats, nausea and vomiting were reported as associated symptoms. CONCLUSION: PCIS should be considered as a rare, but serious complication of HRD implantation, may cause recurrent hospitalization and can be life threatening. The incidence and possible causes of PCIS after HRD, such as active fixation leads and specific lead positions as well as its treatment deserve further investigation in prospective studies. PMID- 24777393 TI - Condom refusal and young Black men: the influence of pleasure, sexual partners, and friends. AB - The study investigated pleasure-related, partner-related, and social normative correlates of recent condom refusal in young Black men (YBM). A cross-sectional study of YBM (N = 561) attending clinics treating sexually transmitted diseases in three cities was conducted. Mean age was 19.6 years (SD = 1.87). Nearly one of every two young men (46.8 %) indicated recent refusal to use a condom after a request from their partner. Significant findings included the following: partner related beliefs "I feel closer to my partner without a condom" (OR = 2.52, 95 % confidence interval (CI) = 1.65-3.83) and "condoms make sex hurt for the female partner" (OR = 1.69, 95 % CI = 1.14-2.52), a scale measure of pleasure-related beliefs (OR = 2.58, 95 % CI = 1.73-3.84), and a scale measure of negative social beliefs associated with condom usage (OR = 1.05, 95 % CI = 1.00-1.10). Interventions addressing pleasure-related, partner-related, and social normative beliefs as barriers to condom use are warranted for YBM. PMID- 24777394 TI - Weak ventral striatal responses to monetary outcomes predict an unwillingness to resist cigarette smoking. AB - As a group, cigarette smokers exhibit blunted subjective, behavioral, and neurobiological responses to nondrug incentives and rewards, relative to nonsmokers. Findings from recent studies suggest, however, that there are large individual differences in the devaluation of nondrug rewards among smokers. Moreover, this variability appears to have significant clinical implications, since reduced sensitivity to nondrug rewards is associated with poorer smoking cessation outcomes. Currently, little is known about the neurobiological mechanisms that underlie these individual differences in the responsiveness to nondrug rewards. Here, we tested the hypothesis that individual variability in reward devaluation among smokers is linked to the functioning of the striatum. Specifically, functional magnetic resonance imaging was used to examine variability in the neural response to monetary outcomes in nicotine-deprived smokers anticipating an opportunity to smoke-circumstances found to heighten the devaluation of nondrug rewards by smokers in prior work. We also investigated whether individual differences in reward-related brain activity in those expecting to have access to cigarettes were associated with the degree to which the same individuals subsequently were willing to resist smoking in order to earn additional money. Our key finding was that deprived smokers who exhibited the weakest response to rewards (i.e., monetary gains) in the ventral striatum were least willing to refrain from smoking for monetary reinforcement. These results provide evidence that outcome-related signals in the ventral striatum serve as a marker for clinically meaningful individual differences in reward-motivated behavior among nicotine-deprived smokers. PMID- 24777395 TI - Biases of attention in chronic smokers: men and women are not alike. AB - The activation of motivational systems by stimuli in the environment that are associated with rewarding experiences is able to trigger plastic changes in the brain, thereby altering the attentional priority of those stimuli. As a result, attentional deployment is often abnormal in addiction, with drug-related stimuli attracting attention automatically and gaining control over behavior. For example, smokers show attentional biases toward smoke-related cues, but the mechanisms underlying these effects and the nature of their link to addiction are still debated. Here, we investigated the influence of gender and individual factors on the temporal dynamics of attentional deployment toward smoke-related stimuli in young smokers. Crucially, we found a striking gender difference, with only males exhibiting a typical attentional bias for smoke-related items, and the bias revealed strong time dependency. Additionally, for both males and females, various personality traits and smoking habits predicted the direction and strength of the measured bias. Overall, these results unveil a crucial influence of several predictors-notably, gender-on the biases of attention toward smoke related items in chronic smokers. PMID- 24777396 TI - Towards energy neutral wastewater treatment: methodology and state of the art. AB - Conventional biological wastewater treatment processes are energy-intensive endeavors that yield little or no recovered resources and often require significant external chemical inputs. However, with embedded energy in both organic carbon and nutrients (N, P), wastewater has the potential for substantial energy recovery from a low-value (or no-value) feedstock. A paradigm shift is thus now underway that is transforming our understanding of necessary energy inputs, and potential energy or resource outputs, from wastewater treatment, and energy neutral or even energy positive treatment is increasingly emphasized in practice. As two energy sources in domestic wastewater, we argue that the most suitable way to maximize energy recovery from wastewater treatment is to separate carbon and nutrient (particularly N) removal processes. Innovative anaerobic treatment technologies and bioelectrochemical processes are now being developed as high efficiency methods for energy recovery from waste COD. Recently, energy savings or even generation from N removal has become a hotspot of research and development activity, and nitritation-anammox, the newly developed CANDO process, and microalgae cultivation are considered promising techniques. In this paper, we critically review these five emerging low energy or energy positive bioprocesses for sustainable wastewater treatment, with a particular focus on energy optimization in management of nitrogenous oxygen demand. Taken together, these technologies are now charting a path towards to a new paradigm of resource and energy recovery from wastewater. PMID- 24777397 TI - Terrorism in Pakistan: a behavioral sciences perspective. AB - This article reviews the behavioral science perspectives of terrorism in Pakistan. It can be argued that Pakistan has gained worldwide attention for "terrorism" and its role in the "war against terrorism". The region is well placed geopolitically for economic successes but has been plagued by terrorism in various shapes and forms. A behavioral sciences perspective of terrorism is an attempt to explain it in this part of the world as a complex interplay of historical, geopolitical, anthropological and psychosocial factors and forces. Drawing from theories by Western scholars to explain the behavioral and cognitive underpinnings of a terrorist mind, the authors highlight the peculiarities of similar operatives at individual and group levels. Thorny issues related to the ethical and human right dimensions of the topic are visited from the unique perspective of a society challenged by schisms and divergence of opinions at individual, family, and community levels. The authors have attempted to minimize the political descriptions, although this cannot be avoided entirely, because of the nature of terrorism. PMID- 24777398 TI - Lymphocyte-derived microparticles induce apoptosis of airway epithelial cells through activation of p38 MAPK and production of arachidonic acid. AB - The airway epithelium is critical for the normal integrity and function of the respiratory system. Excessive epithelial cell apoptosis contributes to cell damage and airway inflammation. We previously demonstrated that lymphocyte derived microparticles (LMPs) induce apoptosis of human bronchial epithelial cells. However, the underlying mechanisms contributing to LMPs-evoked epithelial cell death are largely unknown. Here we used bronchial and lung tissue cultures to confirm the pro-apoptotic effects of LMPs. In cell culture experiments, we found that LMPs induced human airway epithelial cell apoptosis with associated increases in caspase-3 activity. In addition, LMPs treatment triggered oxidative stress in epithelial cells by enhancing production of malondialdehyde, superoxide, and reactive oxygen species (ROS), and by inhibiting production of the antioxidant glutathione. Moreover, decreasing cellular ROS with the antioxidant N-acetylcysteine rescued epithelial cell viability. Together, these results demonstrate an important role for oxidative stress in LMPs-induced cell death. In epithelial cells, LMPs treatment induced phosphorylation of p38 MAPK and arachidonic acid accumulation. Moreover, arachidonic acid was significantly cytotoxic towards LMPs-treated epithelial cells, whereas inhibition of p38 MAPK was protective against these cytotoxic effects. Similarly, inhibition of arachidonic acid production led to decreased caspase-3 activity, thus rescuing airway epithelial cells from LMPs-induced cell death. In conclusion, our results show that LMPs induce airway epithelial cell apoptosis by activating p38 MAPK signaling and stimulating production of arachidonic acid, with consequent increases in oxidative stress and caspase-3 activity. As such, LMPs may be regarded as deleterious markers of epithelial cell damage in respiratory diseases. PMID- 24777399 TI - [Amyloid beta protein suppresses hippocampal theta rhythm and induces behavioral disinhibition and spatial memory deficit in rats]. AB - Hippocampal neuronal network oscillation is closely related to the memory, anxiety and behavioral inhibition of mammalian. The cognitive decline and behavioral disinhibition in the patients with Alzheimer's disease (AD) may be relevant to amyloid beta protein (Abeta)-induced impairment in hippocampal neuronal cooperative activity. However, it is not well known whether intrahippocampal injection of Abeta could induce behavioral disinhibition and neuronal network disorder, as well as cognition decline in animals. In the present study, we observed the effects of intracerebral injection of Abeta(1-42) on the spatial memory and behavioral inhibition of rats by using Morris water maze and elevated plus-maze tests. Further, we analyzed hippocampal theta rhythm by recording hippocampal local field potential. The results showed that: (1) bilateral hippocampal injection of Abeta(1-42) reduced the anxious behavior of rats, with a significant behavioral disinhibition in the elevated plus-maze test, representing as an increase in the mean entering times and mean residence time in the open arm; (2) Abeta(1-42) injection resulted in a significant impairment of spatial memory in rats, with significantly increased mean escape latencies in hidden platform test; (3) Abeta(1-42) disrupted the induction of theta rhythm induced by tail pinch, with a significant reduction in the peak power, not the peak power frequency of the theta rhythm. These experimental results indicate that intrahippocampal injection of Abeta(1-42) can induce behavioral disinhibition and theta rhythm suppression, as well as spatial memory impairment in rats, which suggests that the cognition deficits and behavior impairments in AD are probably associated with the Abeta-induced disruption of hippocampal theta rhythm and consequent down-regulation of synaptic plasticity. PMID- 24777400 TI - [Localization and expression pattern of MDM2 in axon initial segments of neuron in rodent brain]. AB - To investigate the murine double minute 2 (MDM2) localization and expression pattern in brain, immunohistochemistry, immunofluorescent staining and immunoblotting methods were used to analyze it in brains of Kunming mice during postnatal development, in brains of adult SD rats and in primarily cultured neurons. The distribution of MDM2 and markers of axon initial segment (AIS) was analyzed by double immunolabeling. In addition, Nutlin-3, a MDM2 antagonist, was injected into hippocampus to analyze the effect on the distribution of MDM2 and AIS protein Nav1.6 in AIS. The results showed that the dynamic expression patterns of MDM2 protein in cerebral cortex and hippocampus of Kunming mice after birth were different. However, it was similar that MDM2 was gradually enriched to AIS during postnatal development, especially after postnatal day 7. The MDM2 in AIS was also observed in different brain regions of adult SD rat brain and in primarily cultured neurons, where MDM2 was colocalized with AIS markers such as AnkG and Nav1.6. In addition, hippocampal injection of Nutlin-3 could induce the loss of the characteristic distribution of MDM2 in AIS. Moreover, Nutlin-3 not only caused a decrease of Nav1.6 distributing in AIS, but also disrupted the polarized distribution of MAP2 in neurons. These results indicate that MDM2 can be enriched at the AIS of adult rodent brain, which might play a role in regulation of the maintenance of AIS function and neuronal polarity. PMID- 24777401 TI - [Inhibitory effects of epileptic spikes on theta rhythm in rat pilocarpine model of temporal lobe epilepsy]. AB - Epilepsy clinically has an inhibitory impact on cognitive function, but whether it is associated with epileptogenesis is unclear. Since the epileptic spike characterizes temporal lobe epilepsy (TLE), the present study was aimed to analyze the transient effects of sporadic spikes (SSs) on theta rhythm during epileptogenesis. The local field potentials (LFPs) were recorded in CA1 area in four rats with the pilocarpine injections during exploration, and theta phase stability and power were globally estimated around SSs, also during prolonged period without SS (both as experiments) as well as pre-injections (control). Finally, the LFPs were simulated by changing the average excitatory and inhibitory synaptic gain values (including slow and fast inhibition loops) with the help of simplified dynamical model of CA1 networks, and then theta phase stability was evaluated in several cases. It was found that the SSs could have negative impacts on theta rhythm both transiently and persistently, which may be dependent on the temporal courses leading to epilepsy, being acuter in early stage than later stage, but even in latent stage, theta power was strong. The simulations partly demonstrated that the synaptic imbalance concomitant with the occurrence of SSs might be related to the dynamics of theta phase stability. The results indicate that the SSs might have persistent negative impacts on the cognition rhythm, and the effects might alter during epileptogenesis, leading to the cognitive dysfunction. PMID- 24777402 TI - [Receptor kinetics analyses of long-term potentiation of synaptic transmission in spinal cord motoneurons in vitro]. AB - The aim of the present study is to observe the receptor kinetics property of long term potentiation (LTP) of excitatory postsynaptic potential (EPSP) in spinal cord motoneurons (MNs) by descending activation. The intracellular recording techniques were conducted in spinal cord MNs of neonatal rats aged 8-14 days. The changes of EPSP induced by ipsilateral ventrolateral funiculus (iVLF) stimulation (iVLF-EPSPs) were observed, and receptor kinetics of iVLF-EPSPs were analyzed. The results showed that, the amplitude, area under curve and maximum left slope of EPSP were positively correlated with stimulus intensity (P < 0.05 or P < 0.01), while the apparent receptor kinetic parameters apparent dissociation rate constant (K(2)), apparent equilibrium dissociation constant (K(T)) of EPSP were negatively correlated with stimulus intensity (P < 0.01 or P < 0.05). The iVLF EPSPs were persistently increased after tetanic stimulation (100 Hz, 50 pulses/train, duration 0.4-1.0 ms, 6 trains, main interval 10 s, 10-100 V) in 5 of 11 tested MNs. The amplitude of iVLF-EPSPs was potentiated to more than 120% of baseline and lasted at least 30 min, which could be referred to as iVLF-LTP. Meanwhile, the area under curve and maximum left slope of EPSPs were also increased to more than 120% of baseline. During iVLF-LTP, apparent receptor kinetics analyses of iVLF-EPSPs indicated that K(2) and KT were decreased significantly to less than 80% of the baseline within 10 min and gradually and partially recovered in 3 MNs. These results of receptor kinetics analyses of iVLF EPSPs suggest a possible enhancement in affinity of postsynaptic receptors in the early stage of iVLF-LTP in some MNs. PMID- 24777403 TI - The plateau zokors' learning and memory ability is related to the high expression levels of foxP2 in the brain. AB - Plateau zokor (Myospalax baileyi) is a subterranean mammal. Plateau zokor has high learning and memory ability, and can determine the location of blocking obstacles in their tunnels. Forkhead box p2 (FOXP2) is a transcription factor implicated in the neural control of orofacial coordination and sensory-motor integration, particularly with respect to learning, memory and vocalization. To explore the association of foxP2 with the high learning and memory ability of plateau zokor, the cDNA of foxP2 of plateau zokor was sequenced; by using plateau pika as control, the expression levels of foxP2 mRNA and FOXP2 protein in brain of plateau zokor were determined by real-time PCR and Western blot, respectively; and the location of FOXP2 protein in the brain of plateau zokor was determined by immunohistochemistry. The result showed that the cDNA sequence of plateau zokor foxP2 was similar to that of other mammals and the amino acid sequences showed a relatively high degree of conservation, with the exception of two particular amino acid substitutions [a Gln (Q)-to-His (H) change at position 231 and a Ser (S)-to-Ile (I) change at position 235]. Higher expression levels of foxP2 mRNA (3 fold higher) and FOXP2 protein (>2-fold higher) were detected in plateau zokor brain relative to plateau pika brain. In plateau zokor brain, FOXP2 protein was highly expressed in the cerebral cortex, thalamus and the striatum (a basal ganglia brain region). The results suggest that the high learning and memory ability of plateau zokor is related to the high expression levels of foxP2 in the brain. PMID- 24777404 TI - [Epigallocatechin gallate attenuates the expression of regulated upon activation normal T cell expressed and secreted induced by lipopolysaccharide in human retinal endothelial cells]. AB - The present study was undertaken to determine the effect of epigallocatechin gallate (EGCG) on lipopolysaccharide (LPS)-induced production of inflammatory chemokine regulated upon activation normal T cell expressed and secreted (RANTES) in human retinal endothelial cells (HRECs) and to explore the underlying regulatory mechanism. HRECs were stimulated with LPS in the presence or absence of EGCG at various concentrations (100, 50, 25, 12.5, 6.25 MUmol/L). The optimum concentration of drug was determined by a real-time cell-electronic sensing (RT CES) system, and MTS chromatometry was used to detect the toxicity of LPS and EGCG on HRECs. RANTES production in the culture supernatant was measured by ELISA. The expression levels of Akt and phosphorylated Akt were examined by Western blot assay. The result showed that LPS markedly stimulated RANTES secretion from HRECs. EGCG treatment significantly suppressed LPS-induced RANTES secretion in a dose-dependent manner. Furthermore, EGCG exhibited a dose dependent inhibitory effect on LPS-induced phosphorylation of Akt. Taken together, our data suggest that EGCG suppresses LPS-induced RANTES secretion, possibly via inhibiting Akt phosphorylation in HRECs. PMID- 24777405 TI - [Precursor brain-derived neurotrophic factor reduces survival and axonal sprouting of rat spiral ganglion neurons in vitro]. AB - The aim of the present study was to investigate the effect of precursor brain derived neurotrophic factor (proBDNF) on survival and neurite outgrowth of cultured rat spiral ganglion neurons (SGNs). Spiral ganglions (SG) were collected from postnatal day 5 Sprague Dawley (SD) rats, then enzymatically digested and suspended. Dissociated SGNs were plated on poly-D-lysine/laminin coated eight well chamber plates and maintained at 37 degrees C for 4 h to promote the attachment of the neurons. Cultured SGNs were randomly divided into five groups: control group, BDNF group (BDNF 10 ng/mL), C10 group (proBDNF 10 ng/mL), C50 group (proBDNF 50 ng/mL), and C100 group (proBDNF 100 ng/mL). All groups were incubated in a serum-free medium. 48 h after incubation, SGNs were fixed and stained for betaIII tubulin. Immunostaining of the cultured SGNs showed that, compared with the control group, the cellular survival of C50 group and C100 group were significantly reduced (P < 0.001). Furthermore, surviving numbers of the three proBDNF-treated groups were all lower than the BDNF group. In order to assess the effect of proBDNF on cell morphology, SGNs were divided into two categories: SGNs with or without neurites. The results demonstrated that proBDNF significantly increased the proportions of SGNs without neurites in C10, C50 and C100 groups compared with that in control group (P < 0.001). In addition, c-Jun N terminal kinase (JNK) inhibitor, SP600125 (20 MUmol/L) significantly increased the surviving number of SGNs in C50 group. These results suggest that proBDNF reduces the survival rate of cultured SGNs and inhibits the sprouting of neurites. Furthermore, the inhibition of JNK signaling attenuates the effect of proBDNF on SGNs survival. PMID- 24777406 TI - Amyloid-beta transporter expression at the choroid plexus in normal aging: the possibility of reduced resistance to oxidative stress insults. AB - Accumulation of amyloid-beta peptides (Abeta) results in amyloid burden in normal aging brain. Clearance of this peptide from the brain occurs via active transport at the interfaces separating the central nervous system (CNS) from the peripheral circulation. The present study was to investigate the change of Abeta transporters expression at the choroid plexus (CP) in normal aging. Morphological modifications of CP were observed by transmission electron microscope. Real-time RT-PCR was used to measure mRNA expressions of Abeta(42) and its transporters, which include low density lipoprotein receptor-related protein-1 and 2 (LRP-1 and -2), P-glycoprotein (P-gp) and the receptor for advanced glycation end-products (RAGE), at the CP epithelium in rats at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months. At the same time, the mRNA expressions of oxidative stress related proteins were also measured. The results showed that a striking deterioration of the CP epithelial cells and increased Abeta(42) mRNA expression were observed in aged rats, and there was a decrease in the transcription of the Abeta efflux transporters, LRP-1 and P-gp, no change in RAGE mRNA expression and an increase in LRP-2, the CP epithelium Abeta influx transporter. Heme oxygenase 1 (HO-1) and caspase-3 expressions at the CP epithelium increased with age at the mRNA level. These results suggest the efficacy of the CP in clearing of Abeta deceases in normal aging, which results in the increase of brain Abeta accumulation. And excess Abeta interferes with oxidative phosphorylation, leads to oxidative stress and morphological structural changes. This in turn induces further pathological cascades of toxicity, inflammation and neurodegeneration process. PMID- 24777407 TI - Sphingosine-1-phosphate receptors respond differently to early myocardial ischemia and ischemia-reperfusion in vivo. AB - Sphingosine-1-phosphate (S1P) has been demonstrated to be a mediator and marker of heart diseases. We hypothesized that the expression of S1P receptors is involved in the S1P-mediated cardioprotection in vivo and may serve as a biomarker of ischemic heart disease. In vivo models of myocardial ischemia (MI) and ischemia-reperfusion (IR) were established by ligation of the left anterior descending artery (LAD) of rat heart, the mRNA expressions of S1PR1-3 were detected using real time PCR at different time intervals after ischemia (LAD for 15 min, 30 min, and 1 h) and IR. The results showed that mRNA expression of S1PR3, but not S1PR1 and S1PR2, increased greatly after IR. No statistical difference was found in any of the three S1P receptors after MI within 1 h. Regarding the studies of lipid concentration changes in myocardiopathy, we conclude that S1P receptors are not early response biomarkers for MI. There are different mechanisms when S1P plays a protection role in heart during MI and IR. The cooperation of lipid content and S1P receptor expression appears to form a regulation network during MI and IR. PMID- 24777408 TI - Presence of autoantibodies against beta1-adrenoceptor aggravates the kidney injury in rats. AB - Since the autoantibodies against the second extracellular loop of beta(1) adrenoceptor (beta(1)-AABs) have been found in the sera of patients with idiopathic dilated cardiomyopathy (IDCM), the involvement of autoimmune mechanisms in the pathogenesis of many cardiovascular diseases has extensively been investigated. Our previous study found that urinary occult blood and protein excretion were frequently found in the rats with positive beta(1)-AABs, but the mechanisms are unclear. Therefore, we infused the beta(1)-AABs into the vein periodically in an attempt to investigate whether beta(1)-AABs could induce morphological and functional changes in the kidneys of adult and aged rats and explore the possible mechanisms. The synthetic peptide according to the sequences of the second extracellular loop of beta(1)-adrenoceptor (beta(1)-AR-ECII) was used to immunize the adult rats to acquire enough beta(1)-AABs for use. Neonatal rat ventricular myocytes (NRVMs) culture was used to observe the biological effects of beta(1)-AABs on the beating rate. The purified beta(1)-AABs were transfused into the vein of rats. The sera level of blood urea nitrogen (BUN), creatinine (CR), uric acid (UA), urinary specific gravity, protein excretion, occult blood and urinary glucose were detected at the different time points by biochemistry and urine analyzers. HE and Masson's trichrome staining were used to detect the changes in kidney structure of passively immunized rats. Enhanced green fluorescent protein (EGFP) and beta(1)-AR-EGFP plasmids were transfected into the human embryonic kidney 293 (HEK293) cells in order to observe the changes in cell injury with the treatment of beta(1)-AABs. It was found that the sera level of BUN, CR and UA increased gradually and the ratio of BUN to CR decreased progressively with the administration of beta(1)-AABs. The increasing of proteinuria, urinary occult blood and urinary glucose was detected by urine analyzer in beta(1)-AABs group. By HE and Masson's coloration, lots of mononuclear cell infiltration and collagen fibers deposition could be observed at the 24th week of immunization. After the treatment of beta(1)-AABs, the caspase-3 activity increased significantly in the HEK293 cells transfected with beta(1)-AR EGFP plasmids, while no significant changes were observed for lactate dehydrogenase (LDH) activity. The results indicate that long-term presence of beta(1)-AABs can induce the morphological and functional damage of the kidneys in adult and aged rats. PMID- 24777409 TI - [Protective effects of hyperbaric oxygen treatment on kidney cells of type 2 diabetic rats]. AB - The major objective was to explore the effect of early hyperbaric oxygen (HBO) therapy on the tissue structure, apoptosis, and metalloproteinases of kidney cells in Goto-Kakizaki (GK) rats with type 2 diabetes mellitus. GK rats (n = 24) were divided randomly and evenly into model, metformin hydrochloride (MH), and hyperbaric oxygen (HBO) groups, while healthy Wistar rats (n = 8) were used as normal control group. The healthy rats in the normal control group and the GK rats in the model group were both intragastrically administered with purified water (5 mL/kg) once per day. Meanwhile, the rats in the MH group received intragastric administration of MH (250 mg/kg) once daily, while the rats in the HBO group inhaled pure oxygen under a constant pressure (0.15 MPa) for 30 min. After 3 weeks of treatment, the body weight of each rat was measured, and the blood samples were collected from tails. Subsequently, the kidneys of all rats were excised for weighing mass and further examination. For each renal sample, the sections were firstly embedded with paraffin and sliced to prepare histopathologic sections stained using HE, PAS and Masson, respectively, for subsequent observation with optical microscopy. Later, the apoptosis of kidney cells was examined using the TUNEL method by computing the apoptotic index. Furthermore, the histopathologic sections were also examined using the immunohistochemistry approach with Caspase-3, MMP-2, and TIMP-2 antibodies, respectively. At the same time, the plasma concentration of TGF-beta1 of the rats in each group was detected using ELISA method. These resultant data showed that the pathological changes of the HBO group were less than those of the model group with respect to increased glomerular volume density of mesangial cells, broadening mesangial matrix and thickening basement membrane as well as swelling renal tubular epithelial cells. The index of cell apoptosis and Caspase-3 expression in the HBO group showed no significant differences (P > 0.05) compared with those in the normal control and MH groups respectively, but demonstrated significant decrease compared with that in the model group (P < 0.01). Meanwhile, the MMP-2 and TIMP-2 expressions of the HBO group were stronger than those in the model and MH groups, but weaker than those in the normal control group (P < 0.05). Although the plasma concentration of TGF-beta1 in HBO, MH and model groups was greater than that in the normal control group, no significant statistical difference was distinguished among these four groups (P > 0.05). These results indicate that the HBO treatment can inhibit the apoptosis and Caspase-3 expression of renal cells of GK rats, adjust the activity of MMP-2 and its inhibitors, and reduce the accumulation of extracellular matrix. This implies that the HBO treatment might protect renal tissues, thus delaying occurrence and retaining development of diabetic nephropathy. PMID- 24777410 TI - [Inhibitory effect of 18beta-glycyrrhetinic acid on KCl- and PE-induced constriction of rat renal interlobar artery in vitro]. AB - The aim of the present study is to investigate the effect of 18beta glycyrrhetinic acid (18beta-GA) on KCl- and PE-induced constriction of rat renal interlobar artery (RIA). Pressure myograph system was used to observe the constriction induced by KCl and PE (endothelial independent vasoconstrictor) in acutely separated RIA of Wistar rats with or without 18beta-GA pretreatment. Whole-cell patch clamp recordings were used to observe the effect of 18beta-GA on membrane input capacitance (C(input)), membrane input conductance (G(input)) or membrane input resistance (R(input)) of smooth muscle cells embedded in arteriole segment. The results showed that both KCl (30-100 mmol/L) and PE (0.1-30 MUmol/L) induced contraction of RIA in a concentration-dependent way. After pretreatment with 18beta-GA (100 MUmol/L), KCl- or PE-induced constriction of RIA was significantly decreased. After application of 18beta-GA (100 MUmol/L), the C(input), G(input) and R(input) of the in situ smooth muscle cells were very close to those of dispersed single smooth muscle cells. These results suggest 18beta-GA inhibits the contraction induced by KCl and PE, and the underlying mechanism may involve the inhibitory effect of 18beta-GA on gap junction. PMID- 24777411 TI - [Calcium-activated chloride channels are involved in two-phase hypoxic pulmonary vasoconstriction in rat pulmonary arteries]. AB - The aim of the present study was to investigate the roles of calcium-activated chloride channels (Cl(Ca)) in the two-phase hypoxic pulmonary vasoconstriction (HPV). The second pulmonary artery branches were dissected from male Sprague Dawley rats, and the changes in vascular tone were measured by using routine blood vascular perfusion in vitro. The result showed that, under normoxic conditions, Cl(Ca) inhibitors (NFA and IAA-94) significantly relaxed second pulmonary artery contracted by norepinephrine (P < 0.01), but merely had effects on KCl-induced second pulmonary artery contractions. A biphasic contraction response was induced in second pulmonary artery ring pre-contracted with norepinephrine exposed to hypoxic conditions for at least one hour, but no biphasic contraction was observed in pulmonary rings pre-contracted with KCl. NFA and IAA-94 significantly attenuated phase II sustained hypoxic contraction (P < 0.01), and also attenuated phase I vasodilation, but had little effect on phase I contraction. These results suggest that Cl(Ca) is an important component forming phase II contraction in secondary pulmonary artery, but not involved in phase I contraction. PMID- 24777412 TI - [An efficient way in mouse brain dissection]. AB - Laboratory mice are common experimental animals in biological, medical, pharmacological and psychological researches primarily because they are easy to maintain and reproduce quickly. The protection of the welfare of experimental animals is gaining greater attention during the application of a large number of mice. It's therefore essential to consider how to reduce the unnecessary use of animals and fully exploit each experimental animal. We report, in this article, an efficient way to dissect various brain regions from a mouse for protein immunoblot and/or neuronal culture, providing technical reference information for minimizing the number of animals used in projects, and refining methods and procedures to quick brain dissection. PMID- 24777413 TI - [Application of high-content screening and flow cytometry analysis techniques to evaluation of myocardial fibroblasts proliferation]. AB - The proliferation of cardiac fibroblasts (CFs) is a key pathological process in the cardiac remodeling. To establish an objective, quantitative method for the analysis of cell proliferation and cell cycle, we applied the high-content screening (HCS) and flow cytometry (FCM) techniques. CFs, isolated by enzyme digestion from newborn C57BL/6J mice, were serum starved for 12 h and then given 10% fetal bovine serum (FBS) for 24 h. Followed by BrdU and DAPI (or 7-AAD) staining, CFs proliferation and cell cycle were analyzed by HCS and FCM, respectively. Discoidin domain receptor 2 (DDR2) staining indicated that the purity of isolated CFs was over 95%. (1) HCS analysis showed that the ratio of BrdU-positive cells was significantly increased in 10% FBS treated group compared with that in serum-free control group [(12.96 +/- 0.67)% vs (2.77 +/- 0.33)%; P < 0.05]. Cell cycle analysis showed that CFs in G0/G1 phase were diploid, and CFs in S phase were companied with proliferation, DNA replication and enlarged nuclei; CFs in G2 phase were tetraploid, and CFs in M phase produced two identical cells (2N). (2) FCM analysis showed that the ratio of BrdU-positive cells was increased in 10% FBS treated group compared with that in the control group [(11.10 +/- 0.42)% vs (2.22 +/- 0.31)%; P < 0.05]; DNA content histogram of cell cycle analysis indicated that the platform of S phase elevated in 10% FBS group compared with control group. (3) There were no differences between the two methods in the results of proliferation and cell cycle analysis. In conclusion, HCS and FCM methods are reliable, stable and consistent in assessment of the proliferation and cell cycle in CFs. PMID- 24777414 TI - [Progress on PI3K/Akt signaling pathway regulating self-renewal and pluripotency of embryonic stem cells]. AB - The phosphatidylinositol 3-kinase (PI3K) and its downstream target protein kinase B (Akt/PKB) can be activated by a variety of extracellular and intracellular signals. They are important signaling molecules and key survival factors involved in cell proliferation, differentiation, apoptosis and other cellular processes. Recently, many reports demonstrate that type I PI3K/Akt signaling pathway plays an important role in maintenance of self-renewal and pluripotency of embryonic stem (ES) cells. Further studies with regard to the self-renewal and pluripotency of ES cells and underlying molecular mechanisms are crucial to its application in cell replacement therapy, regenerative medicine and tissue engineering. The present review focuses on the recent progress on the mediation of PI3K/Akt signaling pathway on the maintenance of self-renewal and pluripotency of ES cells. PMID- 24777415 TI - [Progress on relationship between exercise improving insulin resistance and AMP activated protein kinase]. AB - The AMP-activated protein kinase (AMPK) widely exists in skeletal muscle, liver, pancreas, adipose tissue and central nervous system. As a "cellular energy regulator", activation of AMPK can improve insulin resistance in various mechanisms. To overall understand the importance of AMPK in exercise, the article summarized the research progress on AMPK exercise activation in skeletal muscle, liver and adipose tissue as well as exercise improving cardiovascular insulin resistance by AMPK, and looked forward to the study future of AMPK exercise activation. PMID- 24777416 TI - [Progress in the physiological and pathophysiological functions of sodium calcium exchangers]. AB - Sodium calcium exchanger (NCX), which is widely expressed in the plasma membrane, mitochondrial membrane and secretory vesicles in diverse kinds of cells, belongs to a type of cation translocators. NCX works in two modes, the forward mode and reverse mode, to regulate the intracellular Ca(2+) concentration bi directionally. In the forward mode, NCX carries Ca(2+) out of the cell against its electrochemical gradients coupled to the influx of Na(+) down its electrochemical gradients; alternatively, Ca(2+) enters through the reverse mode of NCX, and Na(+) is carried out of the cell. Exactly through the two-way modes, NCX can regulate intracellular Ca(2+) concentration fleetly and accurately, and plays a critical role in a series of physiological processes including intracellular signal transduction, growth and development of cells, excitation and its coupled functions of excitable cells. NCX are acknowledged to be involved in myofiber contraction, neurotransmission, migration and differentiation of neurogliocyte, activation of immune cells, secretion of cytokines and hormones etc. Moreover, abnormal activation of the reverse mode of NCX plays a vital role in many pathological processes including cell apoptosis, ischemia-reperfusion injury, insulin secretion, tumor etc. Here we reviewed the research status about the NCX's participation in some physiological and pathophysiological processes, so as to provide comprehensive understanding about its functions. PMID- 24777417 TI - [Progress in the role of farnesoid X receptor in metabolic regulation and tumor cell proliferation]. AB - Farnesoid X receptor (FXR) is a ligand-activated transcriptional factor belonged to the superfamily of nuclear receptors. In the past decades, FXR has been found with important roles in the regulation of metabolic homeostasis of bile acids, cholesterol, lipids and carbohydrates. Recent studies further demonstrate the potential protective effect of FXR against metabolic diseases, such as hyperglycemia and hyperlipidemia, as well as inflammatory bowel diseases (IBD). In addition, FXR plays an essential role in liver regeneration, tumor cell proliferation and apoptosis. However, the role of FXR in the development of tumor is still obscure and even with discrepancy. This article reviews the function of FXR in metabolic regulation and recent progress in basic, clinical and pharmacological researches related to tumor cell proliferation involving FXR. PMID- 24777418 TI - Spatiotemporally and mechanically controlled triggering of mast cells using atomic force microscopy. AB - Mast cells are thought to be sensitive to mechanical forces, for example, coughing in asthma or pressure in "physical urticarias." Conversion of mechanical forces to biochemical signals could potentially augment antigenic signaling. Studying the combined effects of mechanical and antigenic cues on mast cells and other hematopoietic cells has proven difficult. Here, we present an approach using a modified atomic force microscope cantilever to deliver antigenic signals to mast cells while simultaneously applying mechanical forces. We developed a strategy to concurrently record degranulation events by fluorescence microscopy during antigenic triggering. Finally, we also measured the mechanical forces generated by mast cells while antigen receptors are ligated. We showed that mast cells respond to antigen delivered by the atomic force microscopy cantilever with prompt degranulation and the generation of strong pushing and pulling forces. We did not discern any relationship between applied mechanical forces and the kinetics of degranulation. These experiments present a new method for dissecting the interactions of mechanical and biochemical cues in the signaling responses of immune cells. PMID- 24777419 TI - Partitioning neuronal variability. AB - Responses of sensory neurons differ across repeated measurements. This variability is usually treated as stochasticity arising within neurons or neural circuits. However, some portion of the variability arises from fluctuations in excitability due to factors that are not purely sensory, such as arousal, attention and adaptation. To isolate these fluctuations, we developed a model in which spikes are generated by a Poisson process whose rate is the product of a drive that is sensory in origin and a gain summarizing stimulus-independent modulatory influences on excitability. This model provides an accurate account of response distributions of visual neurons in macaque lateral geniculate nucleus and cortical areas V1, V2 and MT, revealing that variability originates in large part from excitability fluctuations that are correlated over time and between neurons, and that increase in strength along the visual pathway. The model provides a parsimonious explanation for observed systematic dependencies of response variability and covariability on firing rate. PMID- 24777423 TI - Grafted bone marrow stromal cells: a contributor to glial repair after spinal cord injury. AB - In the CNS, astrocytes, oligodendrocytes and microglias are involved in not only development but also pathology such as spinal cord injury (SCI). Glial cells play dual roles (negative vs. positive effects) in these processes. After SCI, detrimental effects usually dominate and significantly retard functional recovery, and curbing these effects is critical for promoting neurological improvement. Bone marrow stromal cells (BMSCs) represent a new therapeutic approach for SCI by enabling improved sensory and motor functions in animal models. Although transdifferentiation to spinal neurons was poor, because of their pleiotropic nature, the protective effects of BMSCs are broad and are primarily mediated through modulation of transdifferentiation into host spinal glial components. Transplantation of BMSCs can positively alter the spinal microenvironment and enhance recovery. The objective of this review is to discuss these and other related mechanisms. Since BMSCs transplantation has been applied in other clinical fields, we hope to provide useful clues for the clinical application of BMSCs to treat the SCI in the near future. PMID- 24777424 TI - Familial visceral myopathy diagnosed by exome sequencing of a patient with chronic intestinal pseudo-obstruction. AB - A 55-year-old woman with a history of bowel dysmotility presented with abdominal distension and peritonitis. Family history included premature deaths with intestinal symptomatology, suggesting autosomal dominant inheritance. Computed tomography showed a distended small bowel. Symptoms were alleviated by enterocutaneous stomas. Initial ileal biopsy suggested neuropathy; however, exome sequencing revealed an Arg148Ser mutation in the enteric smooth muscle actin gamma 2 (ACTG2) gene. Histological reassessment showed abnormal muscularis propria and smooth muscle actin, with the same findings in sibling, confirming familial visceral myopathy. Thus, noninvasive genomic analysis can provide early and specific diagnosis of familial visceral myopathy, which may help to avoid inappropriate surgery. PMID- 24777420 TI - Cellular origins of auditory event-related potential deficits in Rett syndrome. AB - Dysfunction in sensory information processing is a hallmark of many neurological disorders, including autism spectrum disorders, schizophrenia and Rett syndrome (RTT). Using mouse models of RTT, a monogenic disorder caused by mutations in MECP2, we found that the large-scale loss of MeCP2 from forebrain GABAergic interneurons led to deficits in auditory event-related potentials and seizure manifestation, whereas the restoration of MeCP2 in specific classes of interneurons ameliorated these deficits. PMID- 24777425 TI - Endoscopic treatment of delayed colon perforation: the enteroscopy overtube approach. AB - BACKGROUND AND STUDY AIMS: Delayed perforation is a rare complication of therapeutic colonoscopy, and it is severe and sometimes lethal. This paper reports on a new minimally invasive method for the treatment of delayed colonic perforation. PATIENTS AND METHODS: Three patients with delayed colonic perforation underwent the therapy, which involved three steps: (1) closure with endoclips and loop, (2) overtube placement, and (3) antibiotic wash through a nasobiliary tube. RESULTS: The procedure was successful in all three patients and no recurrence was observed during 5 - 41 months of follow-up. CONCLUSIONS: Although this study involved only a small number of patients and no control arm, the method involving an overtube appears to be a feasible and effective endoscopic treatment for delayed colonic perforation. PMID- 24777426 TI - Endoscopic submucosal dissection for gastric tumors in various types of remnant stomach. AB - BACKGROUND AND STUDY AIMS: The aim of this study was to examine the clinical outcomes of endoscopic submucosal dissection (ESD) for gastric tumors in various types of remnant stomach. PATIENTS AND METHODS: Between January 2002 and March 2013, ESD was performed for 750 gastric tumors. Of these lesions, 49 were in a remnant stomach, and were included in the study. RESULTS: The en bloc resection rate was 100 %. The curative resection rate was 82 %. The rate of perforation was high in patients with gastric conduits (28.6 %). Perforation was significantly more common in patients with lesions located on the suture line (4.9 % vs. 50.0 %; P = 0.0043). CONCLUSION: ESD for gastric tumors in the remnant stomach can be considered feasible and safe in clinical practice. However, the procedure is technically more difficult in patients with a gastric conduit, due to the increased risk of perforation at the suture line. PMID- 24777427 TI - Second-generation colon capsule endoscopy vs. colonoscopy in pediatric ulcerative colitis: a pilot study. AB - BACKGROUND AND STUDY AIMS: Second-generation colon capsule endoscopy (CCE-2) may overcome the invasiveness of colonoscopy in the evaluation of mucosal inflammation, especially in pediatric ulcerative colitis. The aim of this pilot study was to determine the diagnostic accuracy of CCE-2 in evaluating disease activity, using colonoscopy as a gold standard. Disease extent, tolerability, interobserver agreement, and safety were also evaluated. METHODS: A total of 30 consecutive pediatric patients with ulcerative colitis were prospectively enrolled (mean age 14.1 +/- 3.2 years). Patients underwent CCE-2 followed by colonoscopy in the late afternoon or the following day. The blinded procedures were performed, and the diagnostic accuracy of CCE-2 to assess disease activity was determined using a modified Matts score, which classified patients as either normal (Matts score <= 6) or with active inflammation (Matts score > 6). Interobserver agreement was assessed using the kappa statistic. RESULTS: One patient was excluded from the analysis because they were unable to swallow the capsule, leaving 29 patients available for analysis. The sensitivity of CCE-2 for disease activity was 96 % (95 % confidence interval [CI] 79 - 99) and specificity was 100 % (95 %CI 61 - 100). The positive and negative predictive values of CCE-2 were 100 % (95 %CI 85 - 100) and 85 % (95 %CI 49 - 97), respectively. No serious adverse events were reported. CCE-2 had a higher overall tolerability than colonoscopy (P < 0.05). Interobserver agreement was excellent in all cases (kappa > 0.86). CONCLUSIONS: Using a modified Matts score, CCE-2 was accurate in evaluating significant mucosal inflammation in children with ulcerative colitis. TRIAL REGISTRATION: ClinicalTrials.gov -- NCT01740349. PMID- 24777428 TI - Assessing the impact of short-term surgical education on practice: a retrospective study of the introduction of mesh for inguinal hernia repair in sub Saharan Africa. AB - PURPOSE: Inguinal hernia repair is the most common general surgery operation performed globally. However, the adoption of tension-free hernia repair with mesh has been limited in low-income settings, largely due to a lack of technical training and resources. The present study evaluates the impact of a 2-day training course instructing use of polypropylene mesh for inguinal hernia repair on the practice patterns of sub-Saharan African physicians. METHODS: A surgical training course on tension-free mesh repair of hernias was provided to 16 physicians working in rural Ghanaian and Liberian hospitals. Three physicians were requested to prospectively record all their inguinal hernia surgeries, performed with or without mesh, during the 14-month period following the training. Demographic variables, diagnoses, and complications were collected by an independent data collector for mesh and non-mesh procedures. RESULTS: Surgery with mesh increased significantly following intervention, from near negligible levels prior to the training to 8.1 % of all inguinal hernia repairs afterwards. Mesh repair accounted for 90.8 % of recurrent hernia repairs and 2.9 % of primary hernia repairs after training. Overall complication rates between mesh and non mesh procedures were not significantly different (p = 0.20). CONCLUSIONS: Three physicians who participated in an intensive education course were routinely using mesh for inguinal hernia repair 14 months after the training. This represents a significant change in practice pattern. Complication rates between patients who underwent inguinal hernia repairs with and without mesh were comparable. The present study provides evidence that short-term surgical training initiatives can have a substantial impact on local healthcare practice in resource-limited settings. PMID- 24777429 TI - Modified laparoscopic intraperitoneal onlay mesh in complicated inguinal hernia surgery. AB - PURPOSE: To analyse the recurrence rate and postoperative complications in inguinal hernia patients where the laparoscopic intraperitoneal onlay mesh technique (IPOM) was used due to preperitoneal fibrosis. METHODS: Patients who had undergone inguinal herniotomy with the IPOM technique at Horsens Regional Hospital during the calender years of 2004 through 2010 filled out a questionnaire specific for recurrence and postoperative complications and had a clinical examination. Furthermore the medical records and national databases were analysed for reoperations for recurrent hernias. RESULTS: 37 patients (38 hernias) were operated. Two patients had a recurrent hernia (5 %), four patients (11 %) reported chronic pain and six patients (16 %) reported various bowel symptoms after the operation. CONCLUSIONS: The optimal treatment of these relatively rare and complicated patients is still an issue of debate, but in the light of the present study it seems that the IPOM technique is equal to or has a better profile compared to Lichtenstein in terms of re-recurrence and chronic pain. We believe that the IPOM technique has a place in the treatment of these patients. PMID- 24777433 TI - The J-pouch for patients with Crohn's disease and indeterminate colitis: (when) is it an option? PMID- 24777430 TI - Strangulated ileostomy evisceration following lateralizing mesh repair of parastomal hernia. AB - Parastomal hernia formation and ostomy prolapse are relatively common complications of intestinal ostomy construction. Underlay mesh placement with lateralization of the stoma limb appears to be the method of repair with the lowest recurrence rate. Prophylaxis of new stomas with mesh is advocated by many authors. We report the case of an 81-year-old man with chronic steroid-dependent COPD who presented to the emergency department with strangulated small bowel evisceration 9 days following completion abdominal colectomy, and creation of an end ileostomy reinforced with intraperitoneal mesh. This rare complication was related to this patient's risk factors for poor healing including poor nutrition, age, chronic COPD and coughing and steroid dependence with immunosuppression. PMID- 24777434 TI - A novel technique for wound protector deployment and efficient specimen extraction following laparoscopic sleeve gastrectomy. AB - Challenges of specimen extraction during laparoscopic sleeve gastrectomy and other resectional laparoscopic procedures can often be proven to be time consuming and frustrating, and the risk of wound infection and port site tumor implantation increases. In this paper, we discuss our experience with an efficient approach to specimen extraction utilizing a novel technique for deployment of a very small self-expanding wound protector through a 12- or 15-mm port. We also report our observations with regard to the learning curve of this technique and the influence of BMI to retractor insertion times and specimen extraction times during laparoscopic sleeve gastrectomy. PMID- 24777436 TI - Primary and secondary organics in the tropical Amazonian rainforest aerosols: chiral analysis of 2-methyltetraols. AB - This work presents the application of a new method to facilitate the distinction between biologically produced (primary) and atmospherically produced (secondary) organic compounds in ambient aerosols based on their chirality. The compounds chosen for this analysis were the stereomers of 2-methyltetraols, (2R,3S)- and (2S,3R)-methylerythritol, (l- and d-form, respectively), and (2S,3S)- and (2R,3R) methylthreitol (l- and d-form), shown previously to display some enantiomeric excesses in atmospheric aerosols, thus to have at least a partial biological origin. In this work PM10 aerosol fractions were collected in a remote tropical rainforest environment near Manaus, Brazil, between June 2008 and June 2009 and analysed. Both 2-methylerythritol and 2-methylthreitol displayed a net excess of one enantiomer (either the l- or the d-form) in 60 to 72% of these samples. These net enantiomeric excesses corresponded to compounds entirely biological but accounted for only about 5% of the total 2-methyltetrol mass in all the samples. Further analysis showed that, in addition, a large mass of the racemic fractions (equal mixtures of d- and l-forms) was also biological. Estimating the contribution of secondary reactions from the isomeric ratios measured in the samples (=ratios 2-methylthreitol over 2-methylerythritol), the mass fraction of secondary methyltetrols in these samples was estimated to a maximum of 31% and their primary fraction to a minimum of 69%. Such large primary fractions could have been expected in PM10 aerosols, largely influenced by biological emissions, and would now need to be investigated in finer aerosols. This work demonstrates the effectiveness of chiral and isomeric analyses as the first direct tool to assess the primary and secondary fractions of organic aerosols. PMID- 24777435 TI - Evolution of standardized clinical pathways: refining multidisciplinary care and process to improve outcomes of the surgical treatment of esophageal cancer. AB - BACKGROUND: The aim of this study is to determine the effect of the implementation and evolution of a multidisciplinary esophagectomy care pathway on postoperative outcomes over a 20-year experience. STUDY DESIGN: All patients undergoing esophagectomy for cancer between 1991 and 2012 were included. Patients were divided into four groups (Gp1 1991-1996, Gp2 1997-2002, Gp3 2003-2007, and Gp4 2008-2012). RESULTS: Five hundred and ninety-five patients were included (Gp1 92, Gp2 159, Gp3 161, and Gp4 183). Age remained consistent over time; however, a progressive significant increase was observed in BMI and Charlson comorbidity index. Increases were also noted in patients with clinical stage III cancers, in the use of neoadjuvant chemoradiotherapy, in salvage esophagectomy and in the utilization of pretreatment jejunostomy. We observed a significant reduction in estimated blood loss (EBL) and operative room IV fluid administration (ORFA) during the study period. Median ICU stay and length of hospital stay (LOS) (10 (5 50) to 8 (5-115) days) decreased over time. In-hospital mortality (0.3 %) and postoperative complications remained consistent over time. cumulative sum (CUSUM) analysis showed that EBL, ORFA, and LOS all declined during the study period, reaching mean values at case 120, 310, and 175, respectively. CONCLUSIONS: The results of this study show that process improvement within the pathway is likely more significant than the level of comorbidities, application of neoadjuvant chemoradiation, or technical approach in patients undergoing esophagectomy. PMID- 24777437 TI - Novel multi-layered 1-D nanostructure exhibiting the theoretical capacity of silicon for a super-enhanced lithium-ion battery. AB - Silicon/carbon (Si/C) nanocomposites have recently received much attention as Li ion battery negative electrodes due to their mutual synergetic effects in capacity and mechanical integrity. The contribution of Si to the total capacity of the Si/C nanocomposites determines their structural efficiency. Herein, we report on a multi-layered, one-dimensional nanostructure that exhibits the theoretical specific capacity of Si in the nanocomposite. Concentrically tri layered, compartmentalized, C-core/Si-medium/C-shell nanofibers were fabricated by triple coaxial electrospinning. The pulverization of Si was accommodated inside the C-shell, whereas the conductive pathway of the Li-ions and electrons was provided by the C-core, which was proven by ex situ Raman spectroscopy. The compartmentalized Si in between the C-core and C-shell led to excellent specific capacity at a high current rate (>820 mA h g(-1) at 12000 mA g(-1)) and the realization of the theoretical specific capacity of the Li15Si4 phase of Si nanoparticles (3627 mA h g(-1)). The electrochemical characterization and inductively coupled plasma-atomic emission spectrometry provided direct evidence of full participation of Si in the electrochemical reactions. PMID- 24777439 TI - Attachment, Sexual Assertiveness, and Sexual Outcomes in Women with Provoked Vestibulodynia and Their Partners: A Mediation Model. AB - Provoked vestibulodynia (PVD) is a prevalent women's sexual pain disorder, which is associated with sexual function difficulties. Attachment theory has been used to understand adult sexual outcomes, providing a useful framework for examining sexual adaptation in couples confronted with PVD. Research to date indicates that anxious and avoidant attachment dimensions correlate with worse sexual outcomes in community and clinical samples. The present study examined the association between attachment, pain, sexual function, and sexual satisfaction in a sample of 101 couples in which the women presented with PVD. The actor-partner interdependence model was used in order to investigate both actor and partner effects. This study also examined the role of sexual assertiveness as a mediator of these associations via structural equation modeling. Women completed measures of pain intensity and both members of the couple completed measures of romantic attachment, sexual assertiveness, sexual function, and satisfaction. Results indicated that attachment dimensions did not predict pain intensity. Both anxious and avoidant attachment were associated with lower sexual satisfaction. Only attachment avoidance predicted lower sexual function in women. Partner effects indicated that higher sexual assertiveness in women predicted higher sexual satisfaction in men. Finally, women's sexual assertiveness was found to be a significant mediator of the relationship between their attachment dimensions, sexual function, and satisfaction. Findings highlight the importance of examining how anxious and avoidant attachment may lead to difficulties in sexual assertiveness and to less satisfying sexual interactions in couples where women suffer from PVD. PMID- 24777440 TI - Patterns of client behavior with their most recent male escort: an application of latent class analysis. AB - Research examining interactions between male escorts and clients has relied heavily on data from escorts, men working on the street, and behavioral data aggregated over time. In the current study, 495 clients of male escorts answered questions about sexual behavior with their last hire. Latent class analysis identified four client sets based on these variables. The largest (n = 200, 40.4 %, labeled Typical Escort Encounter) included men endorsing behavior prior research found typical of paid encounters (e.g., oral sex and kissing). The second largest class (n = 157, 31.7 %, Typical Escort Encounter + Erotic Touching) included men reporting similar behaviors, but with greater variety along a spectrum of touching (e.g., mutual masturbation and body worship). Those classed BD/SM and Kink (n = 76, 15.4 %) reported activity along the kink spectrum (BD/SM and role play). Finally, men classed Erotic Massage Encounters (n = 58, 11.7 %) primarily engaged in erotic touch. Clients reporting condomless anal sex were in the minority (12.2 % overall). Escorts who engage in anal sex with clients might be appropriate to train in HIV prevention and other harm reduction practices-adopting the perspective of "sex workers as sex educators." PMID- 24777441 TI - Post sex affectionate exchanges promote sexual and relationship satisfaction. AB - The current research examined the role of post sex affection in promoting sexual and relationship satisfaction in ongoing romantic partnerships. Since romantic partners view the period after engaging in sex as an important time for bonding and intimacy, we sought to determine if and how the duration and quality of post sex affection might promote satisfaction in romantic relationships. In two studies, we tested the link between post sex affectionate behavior (e.g., cuddling, caressing, shared intimacy) and sexual and relationship satisfaction. In Study 1, a cross-sectional survey of individuals in romantic relationships (N = 335), duration of post sex affection was associated with higher sexual satisfaction and, in turn, higher relationship satisfaction. In Study 2, a daily experience study of 101 established couples (N = 202) with a 3-month follow-up, day-to-day changes in post sex affection duration and quality were associated with both partners' sexual and relationship satisfaction, and engaging in longer and more satisfying post sex affection over the course of the study was associated with higher relationship and sexual satisfaction 3 months later. In general, the pattern of results was consistent for men and women, but the association between the duration of post sex affection and relationship satisfaction was stronger for women than for men (Study 1) and women, but not men, felt more sexually satisfied when their partner reported higher quality post sex affection (Study 2). The findings suggest that the period after sex is a critical time for promoting satisfaction in intimate bonds. PMID- 24777442 TI - The perception of a familiar face is no more than the sum of its parts. AB - Why do faces become easier to recognize with repeated exposure? Previous research has suggested that familiarity may induce a qualitative shift in visual processing from an independent analysis of individual facial features to analysis that includes information about the relationships among features (Farah, Wilson, Drain, & Tanaka Psychological Review, 105, 482-498, 1998; Maurer, Grand, & Mondloch Trends in Cognitive Science, 6, 255-260, 2002). We tested this idea by using a "summation-at-threshold" technique (Gold, Mundy, & Tjan Psychological Science, 23, 427-434, 2012; Nandy & Tjan Journal of Vision, 8, 3.1-20, 2008), in which an observer's ability to recognize each individual facial feature shown independently is used to predict their ability to recognize all of the features shown in combination. We find that, although people are better overall at recognizing familiar as opposed to unfamiliar faces, their ability to integrate information across features is similar for unfamiliar and highly familiar faces and is well predicted by their ability to recognize each of the facial features shown in isolation. These results are consistent with the idea that familiarity has a quantitative effect on the efficiency with which information is extracted from individual features, rather than a qualitative effect on the process by which features are combined. PMID- 24777443 TI - How to measure ecosystem stability? An evaluation of the reliability of stability metrics based on remote sensing time series across the major global ecosystems. AB - Increasing frequency of extreme climate events is likely to impose increased stress on ecosystems and to jeopardize the services that ecosystems provide. Therefore, it is of major importance to assess the effects of extreme climate events on the temporal stability (i.e., the resistance, the resilience, and the variance) of ecosystem properties. Most time series of ecosystem properties are, however, affected by varying data characteristics, uncertainties, and noise, which complicate the comparison of ecosystem stability metrics (ESMs) between locations. Therefore, there is a strong need for a more comprehensive understanding regarding the reliability of stability metrics and how they can be used to compare ecosystem stability globally. The objective of this study was to evaluate the performance of temporal ESMs based on time series of the Moderate Resolution Imaging Spectroradiometer derived Normalized Difference Vegetation Index of 15 global land-cover types. We provide a framework (i) to assess the reliability of ESMs in function of data characteristics, uncertainties and noise and (ii) to integrate reliability estimates in future global ecosystem stability studies against climate disturbances. The performance of our framework was tested through (i) a global ecosystem comparison and (ii) an comparison of ecosystem stability in response to the 2003 drought. The results show the influence of data quality on the accuracy of ecosystem stability. White noise, biased noise, and trends have a stronger effect on the accuracy of stability metrics than the length of the time series, temporal resolution, or amount of missing values. Moreover, we demonstrate the importance of integrating reliability estimates to interpret stability metrics within confidence limits. Based on these confidence limits, other studies dealing with specific ecosystem types or locations can be put into context, and a more reliable assessment of ecosystem stability against environmental disturbances can be obtained. PMID- 24777444 TI - Interventions to improve safe and effective medicines use by consumers: an overview of systematic reviews. AB - BACKGROUND: Many systematic reviews exist on interventions to improve safe and effective medicines use by consumers, but research is distributed across diseases, populations and settings. The scope and focus of such reviews also vary widely, creating challenges for decision-makers seeking to inform decisions by using the evidence on consumers' medicines use.This is an update of a 2011 overview of systematic reviews, which synthesises the evidence, irrespective of disease, medicine type, population or setting, on the effectiveness of interventions to improve consumers' medicines use. OBJECTIVES: To assess the effects of interventions which target healthcare consumers to promote safe and effective medicines use, by synthesising review-level evidence. METHODS: SEARCH METHODS: We included systematic reviews published on the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects. We identified relevant reviews by handsearching databases from their start dates to March 2012. SELECTION CRITERIA: We screened and ranked reviews based on relevance to consumers' medicines use, using criteria developed for this overview. DATA COLLECTION AND ANALYSIS: We used standardised forms to extract data, and assessed reviews for methodological quality using the AMSTAR tool. We used standardised language to summarise results within and across reviews; and gave bottom-line statements about intervention effectiveness. Two review authors screened and selected reviews, and extracted and analysed data. We used a taxonomy of interventions to categorise reviews and guide syntheses. MAIN RESULTS: We included 75 systematic reviews of varied methodological quality. Reviews assessed interventions with diverse aims including support for behaviour change, risk minimisation and skills acquisition. No reviews aimed to promote systems-level consumer participation in medicines-related activities. Medicines adherence was the most frequently-reported outcome, but others such as knowledge, clinical and service-use outcomes were also reported. Adverse events were less commonly identified, while those associated with the interventions themselves, or costs, were rarely reported.Looking across reviews, for most outcomes, medicines self monitoring and self-management programmes appear generally effective to improve medicines use, adherence, adverse events and clinical outcomes; and to reduce mortality in people self-managing antithrombotic therapy. However, some participants were unable to complete these interventions, suggesting they may not be suitable for everyone.Other promising interventions to improve adherence and other key medicines-use outcomes, which require further investigation to be more certain of their effects, include:. simplified dosing regimens: with positive effects on adherence;. interventions involving pharmacists in medicines management, such as medicines reviews (with positive effects on adherence and use, medicines problems and clinical outcomes) and pharmaceutical care services (consultation between pharmacist and patient to resolve medicines problems, develop a care plan and provide follow-up; with positive effects on adherence and knowledge).Several other strategies showed some positive effects, particularly relating to adherence, and other outcomes, but their effects were less consistent overall and so need further study. These included:. delayed antibiotic prescriptions: effective to decrease antibiotic use but with mixed effects on clinical outcomes, adverse effects and satisfaction;. practical strategies like reminders, cues and/or organisers, reminder packaging and material incentives: with positive, although somewhat mixed effects on adherence;. education delivered with self-management skills training, counselling, support, training or enhanced follow-up; information and counselling delivered together; or education/information as part of pharmacist-delivered packages of care: with positive effects on adherence, medicines use, clinical outcomes and knowledge, but with mixed effects in some studies;. financial incentives: with positive, but mixed, effects on adherence.Several strategies also showed promise in promoting immunisation uptake, but require further study to be more certain of their effects. These included organisational interventions; reminders and recall; financial incentives; home visits; free vaccination; lay health worker interventions; and facilitators working with physicians to promote immunisation uptake. Education and/or information strategies also showed some positive but even less consistent effects on immunisation uptake, and need further assessment of effectiveness and investigation of heterogeneity.There are many different potential pathways through which consumers' use of medicines could be targeted to improve outcomes, and simple interventions may be as effective as complex strategies. However, no single intervention assessed was effective to improve all medicines-use outcomes across all diseases, medicines, populations or settings.Even where interventions showed promise, the assembled evidence often only provided part of the picture: for example, simplified dosing regimens seem effective for improving adherence, but there is not yet sufficient information to identify an optimal regimen.In some instances interventions appear ineffective: for example, the evidence suggests that directly observed therapy may be generally ineffective for improving treatment completion, adherence or clinical outcomes.In other cases, interventions may have variable effects across outcomes. As an example, strategies providing information or education as single interventions appear ineffective to improve medicines adherence or clinical outcomes, but may be effective to improve knowledge; an important outcome for promoting consumers' informed medicines choices.Despite a doubling in the number of reviews included in this updated overview, uncertainty still exists about the effectiveness of many interventions, and the evidence on what works remains sparse for several populations, including children and young people, carers, and people with multimorbidity. AUTHORS' CONCLUSIONS: This overview presents evidence from 75 reviews that have synthesised trials and other studies evaluating the effects of interventions to improve consumers' medicines use.Systematically assembling the evidence across reviews allows identification of effective or promising interventions to improve consumers' medicines use, as well as those for which the evidence indicates ineffectiveness or uncertainty.Decision makers faced with implementing interventions to improve consumers' medicines use can use this overview to inform decisions about which interventions may be most promising to improve particular outcomes. The intervention taxonomy may also assist people to consider the strategies available in relation to specific purposes, for example, gaining skills or being involved in decision making. Researchers and funders can use this overview to identify where more research is needed and assess its priority. The limitations of the available literature due to the lack of evidence for important outcomes and important populations, such as people with multimorbidity, should also be considered in practice and policy decisions. PMID- 24777445 TI - Membranous lipodystrophy: skeletal findings on CT and MRI. AB - Membranous lipodystrophy, also known as Nasu-Hakola disease, is a rare hereditary condition with manifestations in the nervous and skeletal systems. The radiographic appearance of skeletal lesions has been well described in the literature. However, CT and MRI findings of lesions in the bone have not been documented to date. This report describes the radiographic, CT, MRI, and histopathologic skeletal findings in a case of membranous lipodystrophy. With corroborative pathologic findings, a diagnosis of membranous lipodystrophy on imaging allows for appropriate clinical management of disease manifestations. PMID- 24777446 TI - Glypican-3-expressing gastric metastasis of hepatocellular carcinoma via curative subtotal gastrectomy: a case report. PMID- 24777447 TI - In vitro digestion of citric acid esters of mono- and diglycerides (CITREM) and CITREM-containing infant formula/emulsions. AB - CITREM is an emulsifier used in the food industry and contains citric acid esters of mono- and diglycerides (GCFE). It is generally recognized as safe but no publication on its digestibility under gastrointestinal conditions and impact on fat digestion was available. It was shown here that fatty acids are released from CITREM by gastric lipase, pancreatic lipase, pancreatic-lipase-related protein 2 and carboxyl ester hydrolase. A two-step in vitro digestion model mimicking lipolysis in the stomach and upper small intestine of term and preterm infants was then used to evaluate the digestibility of CITREM alone, CITREM-containing infant formula and fat emulsions, and isolated GCFE fractions. Overall, it was shown that fat digestion is not significantly changed by the presence of CITREM, and fatty acids contained in CITREM compounds are released to a large extent by lipases. Nevertheless, undigestible water-soluble compounds containing glycerol and citric acid units were identified, indicating that the ester bond between citric acid and glycerol is not fully hydrolyzed throughout the proposed digestion. PMID- 24777448 TI - Radiofrequency treatment enhances the catalytic function of an immobilized nanobiohybrid catalyst. AB - Biocatalysis, the use of enzymes in chemical transformation, has undergone intensive development for a wide range of applications. As such, maximizing the functionality of enzymes for biocatalysis is a major priority to enable industrial use. To date, many innovative technologies have been developed to address the future demand of enzymes for these purposes, but maximizing the catalytic activity of enzymes remains a challenge. In this study, we demonstrated that the functionality of a nanobiocatalyst could be enhanced by combining immobilization and radiofrequency (RF) treatment. Aminopeptidase PepA encapsulating 2 nm platinum nanoparticles (PepA-PtNPs) with the catalytic activities of hydrolysis and hydrogenation were employed as multifunctional nanobiocatalysts. Immobilizing the nanobiocatalysts in a hydrogel using metal chelation significantly enhanced their functionalities, including catalytic power, thermal-stability, pH tolerance, organic solvent tolerance, and reusability. Most importantly, RF treatment of the hydrogel-immobilized PepA PtNPs increased their catalytic power by 2.5 fold greater than the immobilized PepA. Our findings indicate that the catalytic activities and functionalities of PepA-PtNPs are greatly enhanced by the combination of hydrogel-immobilization and RF treatment. Based on our findings, we propose that RF treatment of nanobiohybrid catalysts immobilized on the bulk hydrogel represents a new strategy for achieving efficient biocatalysis. PMID- 24777449 TI - Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. AB - Incidence and mortality for sex-unspecific cancers are higher among men, a fact that is largely unexplained. Furthermore, age-related loss of chromosome Y (LOY) is frequent in normal hematopoietic cells, but the phenotypic consequences of LOY have been elusive. From analysis of 1,153 elderly men, we report that LOY in peripheral blood was associated with risks of all-cause mortality (hazards ratio (HR) = 1.91, 95% confidence interval (CI) = 1.17-3.13; 637 events) and non hematological cancer mortality (HR = 3.62, 95% CI = 1.56-8.41; 132 events). LOY affected at least 8.2% of the subjects in this cohort, and median survival times among men with LOY were 5.5 years shorter. Association of LOY with risk of all cause mortality was validated in an independent cohort (HR = 3.66) in which 20.5% of subjects showed LOY. These results illustrate the impact of post-zygotic mosaicism on disease risk, could explain why males are more frequently affected by cancer and suggest that chromosome Y is important in processes beyond sex determination. LOY in blood could become a predictive biomarker of male carcinogenesis. PMID- 24777450 TI - RAF1 mutations in childhood-onset dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a substantial percentage of DCMs remains unknown, and no gene-specific therapy is available. On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ancestry, we discovered rare, functional RAF1 mutations in 3 of the cohorts (South Indian, North Indian and Japanese). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in these three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but in AKT that was hyperactivated in a BRAF dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders. PMID- 24777451 TI - Heterotrimeric G proteins regulate nitrogen-use efficiency in rice. AB - The drive toward more sustainable agriculture has raised the profile of crop plant nutrient-use efficiency. Here we show that a major rice nitrogen-use efficiency quantitative trait locus (qNGR9) is synonymous with the previously identified gene DEP1 (DENSE AND ERECT PANICLES 1). The different DEP1 alleles confer different nitrogen responses, and genetic diversity analysis suggests that DEP1 has been subjected to artificial selection during Oryza sativa spp. japonica rice domestication. The plants carrying the dominant dep1-1 allele exhibit nitrogen-insensitive vegetative growth coupled with increased nitrogen uptake and assimilation, resulting in improved harvest index and grain yield at moderate levels of nitrogen fertilization. The DEP1 protein interacts in vivo with both the Galpha (RGA1) and Gbeta (RGB1) subunits, and reduced RGA1 or enhanced RGB1 activity inhibits nitrogen responses. We conclude that the plant G protein complex regulates nitrogen signaling and modulation of heterotrimeric G protein activity provides a strategy for environmentally sustainable increases in rice grain yield. PMID- 24777454 TI - [Open Access vs. HaMiPla]. PMID- 24777452 TI - Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance. AB - The importance of microRNAs and long noncoding RNAs in the regulation of pluripotency has been documented; however, the noncoding components of stem cell gene networks remain largely unknown. Here we investigate the role of noncoding RNAs in the pluripotent state, with particular emphasis on nuclear and retrotransposon-derived transcripts. We have performed deep profiling of the nuclear and cytoplasmic transcriptomes of human and mouse stem cells, identifying a class of previously undetected stem cell-specific transcripts. We show that long terminal repeat (LTR)-derived transcripts contribute extensively to the complexity of the stem cell nuclear transcriptome. Some LTR-derived transcripts are associated with enhancer regions and are likely to be involved in the maintenance of pluripotency. PMID- 24777455 TI - [Raoul Tubiana]. PMID- 24777453 TI - Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits. AB - Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 * 10(-13)). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 * 10(-22)) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 * 10(-7)) and WBC count (P = 3.1 * 10(-5)). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits. PMID- 24777456 TI - Contralateral c7 transfer for treatment of brachial plexus root avulsion. AB - Since the first report of the clinical application of contralateral C7 transfer, this procedure has become widely accepted and is used in the treatment of brachial plexus root avulsion injuries. The technique of this procedure has been markedly improved during the past years. The prespinal route may lead to a shorter nerve graft or even to direct coaptation. The results differ a lot from the different studies. There are many factors affecting the results of contralateral C7 transfer, such as age, time for regeneration and techniques of contralateral C7 transfer. Although dividing C7 will not cause a permanent loss in sensory and motor function of the healthy limb, it is worth pointing out that the C7 transection level should not be too distal, otherwise the fibers from the upper and lower trunk could be injured and permanent motor and sensory deficits may occur. Also, the surgeons should balance the risks and benefits for the patient before making the decision to operate in this manner. PMID- 24777457 TI - Cost analysis of brachial plexus injuries: variability of compensation by insurance companies before and after surgery. AB - Traumatic paralysis of the brachial plexus is an extremely disabling pathology. The type of trauma most frequently suffered by this group of patients is due to motorcycle injuries. It therefore affects a population of young patients. In the majority of cases, these patients receive compensation for permanent damage from insurance companies. Surgery of the brachial plexus enables various forms of functional recovery, depending on the number of roots of the brachial plexus involved in the injury. The aim of this study is to compare the functional deficit and the extent of the related compensation before and after surgical intervention, and to evaluate the saving in economic terms (understood as the cost of compensation paid by insurance companies) obtainable through surgical intervention. The authors analysed the functional recovery obtained through surgery in 134 patients divided into 4 groups on the basis of the number of injured roots. The levels of compensation payable to the patient before surgical intervention, and 3 years after, were then compared. The results showed that the saving obtainable through surgical treatment of brachial plexus injuries may exceed 65% of the economic value of the compensation that would have been attributable to the same patients if they had not undergone surgical treatment. PMID- 24777458 TI - [Therapeutic options for reconstruction of the dorsal trunk wall]. AB - Posterior trunk defects represent a major reconstructive problem, which require the entire armamentarium of the reconstructive surgeon. Given the special anatomy of the back, flap selection includes transposition flaps, perforator flaps, muscle flaps, turn-over flaps and free flaps, eventually with interposition of vein grafts. The majority of the defects can be closed with pedicled muscle or musculocutaneous flaps. In our patient collective, sufficient closure could be obtained with all procedures, except the latissimus dorsi turn-over flap. Based on our clinical experience, we propose an algorithm for closure of posterior trunk defects related to the anatomical region. PMID- 24777459 TI - [3D-imaging and analysis for plastic surgery by smartphone and tablet: an alternative to professional systems?]. AB - BACKGROUND: A new approach of using photographs from smartphones for three dimensional (3D) imaging was introduced besides the standard high quality 3D camera systems. In this work, we investigated different capture preferences and compared the accuracy of this 3D reconstruction method with manual tape measurement and an established commercial 3D camera system. METHODS: The facial region of one plastic mannequin head was labelled with 21 landmarks. A 3D reference model was captured with the Vectra 3D Imaging System(r). In addition, 3D imaging was executed with the Autodesk 123d Catch(r) application using 16, 12, 9, 6 and 3 pictures from Apple(r) iPhone 4 s(r) and iPad(r) 3rd generation. The accuracy of 3D reconstruction was measured in 2 steps. First, 42 distance measurements from manual tape measurement and the 2 digital systems were compared. Second, the surface-to-surface deviation of different aesthetic units from the Vectra(r) reference model to Catch(r) generated models was analysed. For each 3D system the capturing and processing time was measured. RESULTS: The measurement showed no significant (p>0.05) difference between manual tape measurement and both digital distances from the Catch(r) application and Vectra(r). Surface-to-surface deviation to the Vectra(r) reference model showed sufficient results for the 3D reconstruction of Catch(r) with 16, 12 and 9 picture sets. Use of 6 and 3 pictures resulted in large deviations. Lateral aesthetic units showed higher deviations than central units. Catch(r) needed 5 times longer to capture and compute 3D models (average 10 min vs. 2 min). CONCLUSION: The Autodesk 123d Catch(r) computed models suggests good accuracy of the 3D reconstruction for a standard mannequin model, in comparison to manual tape measurement and the surface-to-surface analysis with a 3D reference model. However, the prolonged capture time with multiple pictures is prone to errors. Further studies are needed to investigate its application and quality in capturing volunteer models. Soon mobile applications may offer an alternative for plastic surgeons to today's cost intensive, stationary 3D camera systems. PMID- 24777460 TI - Does open guide suture technique improve the patency rate in submillimeter rat artery anastomosis? AB - OBJECTIVE: The anastomosis of sub-millimeter vessels is fraught with significant technical challenges even for the experienced microsurgeon. The supermicrosurgery era is increasing the demand for repair of very small vessels. Our study aims to ascertain whether the open guide suture technique provides a superior patency rate compared with conventional technique when anastomosing rat artery less than a millimeter. METHODS: Anastomosis of transected rat femoral, superficial femoral and central tail arteries were done in 24 in bred albino rats. The external diameters ranged from 0.4 mm to 0.8 mm. The repair was assigned into the Open guide suture technique group or the conventional group (n=12 in each group). The duration of repair, grade of leakage, patency of the repair at 30 min were noted and compared between the groups. RESULTS: The patency rate was 92.7% in each group. There was no statistically significant difference between the 2 groups with respect to anastomotic times, grade of leakage external diameter and type of vessel repaired (p-values >0.05). CONCLUSION: It appears open guide suture technique simplifies repair but may not offer a better patency rate in rat arterial anastomosis under 1 mm when compared to the conventional technique. PMID- 24777461 TI - [Autologous fat injection for treatment of carpometacarpal joint osteoarthritis of the thumb - a promising alternative]. AB - Classical surgical options for osteoarthritis of the thumb carpometacarpal joint irreversibly des-troy the normal anatomy of the wrist. Although overall satisfaction rates with these procedures are high, time to achieve normal hand function and ability to work may take 12-16 weeks. Therefore a non-ablative less invasive surgical option would be interesting. We injected adipose tissue into the thumb carpometacarpal joint in a pilot study. Average preoperative pain according to a VAS was 7.4 in action and 3.8 during rest. It was reduced considerably to 2.2 in action and 0 during rest after 1 month and to 2.4 and 0.8, respectively, 3 months after surgery. The reduction of pain in action was statistically significant 1 month after injection (p=0.042). Average grip strength was 78% and pinch grip strength was 74% in comparison to the healthy side preop-eratively, 89% and 80% one month postoperatively and 93% and 89%, respectively, 3 months postoperatively. An average DASH score of 58 preoperative was reduced to 36 after 1 month and 33 after 3 months. The amelioration of hand function was statistically significant (p=0.042 and p=0.043). There were no side effects and all patients were satisfied. These preliminary results are promising. Adipose tissue injection seems to be an alternative to consider, especially as it does not exclude classical surgical options in cases of failure. PMID- 24777462 TI - [Desmoid tumour around the DIEP anastomosis - a rare complication after breast reconstruction]. AB - Abdominal desmoid tumors are so called non-metastatic tumors. They occur by proliferation of fibroblasts of muscle, fascia or aponeuroses. After breast reconstruction with a DIEP flap (Deep Inferior epigastric Artery Perforator Flap), a progressive growth of a desmoid tumor was seen around the DIEP anastomosis. A total excision was not possible without compromising the vascular pedicle. With taking into account a recurrence rate up to 65% another operation is probably necessary. In this case the main vessels of the graft have to be cut out and a necrosis of the flap can or may appear. PMID- 24777463 TI - Salvage surgery of the limb with severe pseudoamniotic band syndrome: case report and literature review. AB - Pseudoamniotic band syndrome is a rare iatrogenic complication of twin-to-twin transfusion syndrome treated with foetoscopic procedures. We report a severe pseudoamniotic band syndrome in the recipient monochorionic diamniotic twin pregnancy with twin-to-twin transfusion syndrome following a selective foeticide procedure. A male newborn with a severe circumferential amniotic band in the left leg was treated by single-stage excision of the ring and arterio-venous decompression. No complications were encountered. A microsurgical approach to improve the circulation together with ring excision may be useful in some cases. PMID- 24777465 TI - [FESSH Travel Award: hand trauma centres in Europe]. PMID- 24777464 TI - [Advertising rights for doctors - the legal borders]. AB - BACKGROUND: The increasing liberalisation of the advertising rights for physicians. OBJECTIVES: Which new advertising forms present themselves for doctors and where are the limits of the advertising right. METHODS: Evaluation of case law and consulting practice. RESULTS: Only advertisement which is contrarious to professional standards is inadmissible. As long as the preferred advertising is in the range of the Musterberufsordnung, Berufsordnungen der Lander, HWG and UWG it is permitted. CONCLUSION: The advertisement for physicians will find out new ways and possibilities in the future. The individual chambers and courts, how-ever, have not yet developed uniform line, so that in case of doubt professional help is advised. PMID- 24777466 TI - [Report of the DGH Retreat in Dusseldorf]. PMID- 24777467 TI - [Young forum of the German Society for Handsurgery (DGH)]. PMID- 24777468 TI - Presence of power Doppler synovitis in rheumatoid arthritis patients with synthetic and/or biological disease-modifying anti-rheumatic drug-induced clinical remission: experience from a Chinese cohort. AB - The aim of this study was to evaluate the ultrasonographic synovitis in rheumatoid arthritis (RA) patients who reached clinical remission. Two hundred and two RA patients were enrolled into this study. One hundred and eleven RA patients achieved clinical remission with the treatment of synthetic and/or biologic disease-modifying anti-rheumatic drugs (DMARDs). Subclinical synovitis was assessed by power Doppler ultrasonography (PDUS). PD synovitis was semi quantitatively recorded. Twenty-two joint regions were imaged: bilateral wrists, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints. PD remission was defined as a total PD score of 0. The subclinical synovitis in the RA patients who achieved clinical remission was evaluated. The correlations between PD total scores and clinical/laboratory parameters were analyzed. Among the 111 RA patients who achieved clinical remission, 110 (99.1 %), 67 (60.4 %), 55 (49.5 %), 50 (45.0 %), and 54 (48.6 %) patients, respectively, satisfied DAS28 (CRP), DAS28 (ESR), CDAI, SDAI, and 2010 ACR/EULAR remission criteria. However, only 54 (48.6 %) patients achieved PD remission. Subclinical synovitis was detectable in 57 (51.8 %), 30 (44.8 %), 22 (40.0 %), 19 (38.0 %), and 18 (33.3 %) patients accordingly. On the contrary, 11 (26.8 %) out of 41 patients who fulfilled all five clinical remission criteria had evidence of subclinical synovitis. In those 91 patients who did not achieved clinical remission, total PD score was correlated with swollen joint counts (SJC), tender joint counts (TJC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complex disease activity indexes (P < 0.01), but not the titers of rheumatoid factor and anti-cyclic citrullinated peptide. Among those 57 patients with subclinical synovitis after reaching clinical remission, no correlation was found between PD total score and SJC, TJC, ESR, CRP, and complex disease activity indexes. Presence of subclinical synovitis is common in patients achieving clinical remission. The stricter clinical remission criteria may reflect less PD synovitis. In patients with active RA, PD total score of synovitis was positively correlated with disease activity. PMID- 24777469 TI - The association between the polymorphism rs2231142 in the ABCG2 gene and gout risk: a meta-analysis. AB - Gout is a common metabolic disorder with high heritability. We tried to explore the association between rs2231142 and gout. We searched "rs2231142 or Q141K and gout" in four databases and scholar searching website until 1 June, 2013 and included data from 52,010 participants in meta-analysis and subgroup analysis. The T allele of rs2231142 was associated with increased gout susceptibility (odds ratio [OR] [95 % confidence interval (95 % CI)] = 1.73 [1.55-1.91], P < 0.001). It increased gout risk in Caucasians with OR (95 % CI) = 1.68 (1.50-1.87), P < 0.001; Asians with OR (95 % CI) = 1.93 (1.54-2.31), P < 0.001; Africans with OR (95 % CI) = 1.76 (1.15-2.36), P < 0.001; and New Zealand Pacific Islanders with OR (95 % CI) = 2.94 (1.72-4.15), P < 0.001, but not in New Zealand Maoris, with OR (95 % CI) = 1.12 (0.57-1.67), P = 0.061. No publish or other biases were observed. The T allele of rs2231142 was associated with increased risk of gout. PMID- 24777470 TI - Prevalence of osteoporosis in men aged 65-75 in a primary care setting. A practice audit after application of the Canadian 2010 guidelines for osteoporosis screening. AB - Current Canadian osteoporosis guidelines recommend routine bone density screening of men at age 65. The purpose of this study is to determine the prevalence of osteoporosis in men aged 65-75 in after application of screening guidelines. All males aged 65-75 years who attended a large primary care clinic were advised of the 2010 Canadian osteoporosis guidelines and advised to obtain a bone density scan at or after their 65th birthday. Those who did not have a bone density scan since their 65th birthday were advised to obtain a scan, unless there was obvious reason not to do so (i.e. known osteoporosis). A record of the results for each patient were kept and tallied to determine the prevalence of osteoporosis. Osteoporosis was defined as a T-score of <= -2.5 in either the hip or lumbar spine. Of 574 male subjects in this clinic, between the ages of 65-75, 557 had a bone density scan, either already having done so at the time of being informed of the guidelines or obtaining a scan in the subsequent year after being informed of the guidelines. The prevalence of osteoporosis was 1.6% (9/557, 95% confidence interval 0.8-3.1%) in this sample. The average age of subjects with osteoporosis was 70.5 +/- 1.4 years (range 68-75). None of the subjects under 68 years of age were found to have osteoporosis. The prevalence of osteoporosis in unselected male cohorts aged 65 may be too low to justify the routine bone density screening recommended in the 2010 Canadian osteoporosis guidelines. PMID- 24777471 TI - Chronic gonococcal arthritis with C5 deficiency presenting with brief flare-ups: case study and literature review. AB - Gonococcal arthritis is typically acute and appears within 3 weeks after initial infection. Chronic gonococcal arthritis is now exceptionally rare, since the advent of the antibiotic era. Numerous host factors are involved in gonococcal dissemination, such as complement deficiency, HIV and gonococcus strain characteristics. Gonococcal arthritis shares the same risk factors. In this instance, our patient was a 16-year-old girl suffering from persistent polyarthralgia with joint swelling presenting with brief flare-ups for a period of 1 year. She disclosed a single episode of unprotected sexual intercourse 1 year ago, i.e. just before developing her first rheumatological symptoms. Therefore, we performed a joint aspiration (arthrocentesis), and synovial fluid was inoculated directly into aerobic and anaerobic blood culture bottles, which tested positive for Neisseria gonorrhoeae within 24 h. Clinical presentation was consistent with previous reports of chronic gonococcal arthritis. Further investigation revealed a C5 complement deficiency, which might explain the chronic Neisseria process. A favourable outcome was reached after a ten-day course of IV ceftriaxone, with no apparent sequelae found during follow-up 6 weeks later. This case demonstrates an unusual gonococcal arthritis with brief flare-ups for the course of a year, followed by a subacute form. N. meningitidis infections, similar to N. gonorrhoeae, are typically acute and may sometimes be involved in chronic processes. However, this characteristic appears to be rare in the case of N. gonorrhoeae. Risk factors for this chronic process will be discussed with a review of the literature. PMID- 24777472 TI - Commitment devices: using initiatives to change behavior. PMID- 24777473 TI - ACO payment models and the path to accountability. PMID- 24777474 TI - Daily physical activity and physical function in adult maintenance hemodialysis patients. AB - BACKGROUND: Maintenance hemodialysis (MHD) patients reportedly display reduced daily physical activity (DPA) and physical performance. Low daily physical activity and decreased physical performance are each associated with worse outcomes in chronic kidney disease patients. Although daily physical activity and physical performance might be expected to be related, few studies have examined such relationships in MHD patients, and methods for examining daily physical activity often utilized questionnaires rather than activity monitors. We hypothesized that daily physical activity and physical performance are reduced and correlated with each other even in relatively healthier MHD patients. METHODS: Daily physical activity, 6-min walk distance (6-MWT), sit-to-stand, and stair-climbing tests were measured in 72 MHD patients (32 % diabetics) with limited comorbidities and 39 normal adults of similar age and gender mix. Daily physical activity was examined by a physical activity monitor. The human activity profile was also employed. RESULTS: Daily physical activity with the activity monitor, time-averaged over 7 days, and all three physical performance tests were impaired in MHD patients, to about 60-70 % of normal values (p < 0.0001 for each measurement). Human activity profile scores were also impaired (p < 0.0001). MHD patients spent more time sleeping or in marked physical inactivity (p < 0.0001) and less time in >= moderate activity (p < 0.0001). These findings persisted when comparisons to normals were restricted to men or women separately. After adjustment, daily physical activity correlated with 6-MWT but not the two other physical performance tests. Human activity profile scores correlated more closely with all three performance tests than did DPA. CONCLUSIONS: Even in relatively healthy MHD patients, daily physical activity and physical performance are substantially impaired and correlated. Whether training that increases daily physical activity or physical performance will improve clinical outcome in MHD patients needs to be examined. PMID- 24777475 TI - Does the gender of the bully/victim dyad and the type of bullying influence children's responses to a bullying incident? AB - Children's responses to bullying are context related; they will vary depending on the specific bullying episode. The aim of the present study was to explore whether children's responses to bullying vary depending on the gender of the bully and victim and the type of bullying portrayed. In total, 437 children aged 9-11 years from four primary schools in the UK took part in the study. Each child read a story about one child bullying another. There were 12 different versions of the story, varying the type of bullying (verbal, physical, or relational/indirect) and the gender of the bully and victim (i.e., male bully female victim, female bully-male victim, male bully-male victim, female bully female victim). Each child was randomly allocated to one of the 12 stories. After reading the story the children then responded to a series of questions to assess their perceptions of the victim and bully and situation. Overall females liked the bully more than males; females also reported liking the female victim more than the male victim and females were more likely than males to intervene with a female victim. The bullying was viewed as more serious, more sympathy was shown to the victim, and there was a greater likelihood of intervention when the incident involved a female bully. There was less liking for the bully if the situation involved a female victim of physical bullying. The findings are explained in terms of social identity theory and social norms about typical male and female behavior. PMID- 24777476 TI - iASPP is a novel autophagy inhibitor in keratinocytes. AB - The protein iASPP (encoded by PPP1R13L) is an evolutionarily conserved p53 inhibitor, the expression of which is often upregulated in human cancers. We have recently shown that iASPP is a crucial regulator of epidermal homeostasis. Here, we report that iASPP also acts as autophagy inhibitor in keratinocytes. Our data show that depletion of iASPP protects keratinocytes from apoptosis by modulating the expression of Noxa (also known as PMAIP1). In our model, iASPP expression can affect the fission-fusion cycle, mass and shape of mitochondria. iASPP-silenced keratinocytes display disorganization of cytosolic compartments and increased metabolic stress caused by deregulation of mTORC1 signaling. Moreover, increased levels of lipidated LC3 protein confirmed the activation of autophagy in iASPP depleted cells. We have identified a novel mechanism modulating autophagy in keratinocytes that relies upon iASPP expression specifically reducing the interaction of Atg5-Atg12 with Atg16L1, an interaction that is essential for autophagosome formation or maturation. Using organotypic culture, we further explored the link between autophagy and differentiation, and we showed that impairing autophagy affects epidermal terminal differentiation. Our data provide an alternative mechanism to explain how epithelial integrity is maintained against environmental stressors and might also improve the understanding of the etiology of skin diseases that are characterized by defects in differentiation and DNA damage responses. PMID- 24777477 TI - CLIP-170 recruits PLK1 to kinetochores during early mitosis for chromosome alignment. AB - The cytoplasmic linker protein (CLIP)-170, an outer kinetochore protein, has a role in kinetochore-microtubule attachment and chromosome alignment during mitosis. However, the mechanism by which CLIP-170 is involved in chromosome alignment is not known. Here, we show that CLIP-170 colocalizes with Polo-like kinase 1 (PLK1) at kinetochores during early mitosis. Depletion of CLIP-170 results in a significant reduction in PLK1 recruitment to kinetochores and causes kinetochore-fiber (K-fiber) instability and defects in chromosome alignment at the metaphase plate. These phenotypes are dependent on the phosphorylation of CLIP-170 at a CDK1-dependent site, T287, as ectopic expression of wild-type CLIP 170, but not the expression of a non-phosphorylatable mutant, CLIP-170-T287A, restores PLK1 localization at kinetochores and rescues K-fiber stability and chromosome alignment in CLIP-170-depleted cells. These data suggest that CLIP-170 acts as a novel recruiter and spatial regulator of PLK1 at kinetochores during early mitosis, promoting K-fiber stability and chromosome alignment for error free chromosome segregation. PMID- 24777479 TI - Arl13b and the non-muscle myosin heavy chain IIA are required for circular dorsal ruffle formation and cell migration. AB - The Arf-like protein Arl13b has been implicated in ciliogenesis and Sonic hedgehog signaling. Furthermore, we have previously shown that it regulates endocytic recycling traffic and interacts with actin. Herein, we report that the non-muscle myosin heavy chain IIA, also known as Myh9, is an Arl13b effector. Moreover, we found that both proteins localized to circular dorsal ruffles (CDRs) induced by platelet-derived growth factor stimulation and are required for their formation. CDRs are ring-shaped actin-dependent structures formed on the dorsal cell surface and are involved in diverse processes, such as macropinocytosis, integrin recycling, internalization of receptor tyrosine kinases and cell migration. We found that Arl13b or Myh9 silencing impaired cell migration, suggesting that Arl13b is required for this function through the interaction with Myh9. Moreover, Arl13b silencing impaired neural crest cell migration in zebrafish embryos. Furthermore, we showed that Arl13b is required for the formation of CDRs in migrating cells. Thus, our results indicate a new role for Arl13b in actin cytoskeleton remodeling through the interaction with Myh9, by driving the formation of CDRs necessary for cell migration. PMID- 24777478 TI - Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. AB - Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, and their morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy is still poorly understood. Here, we show that treatment of cultured neonatal rat cardiomyocytes with the hypertrophic agonist norepinephrine promotes mitochondrial fission (characterized by a decrease in mitochondrial mean volume and an increase in the relative number of mitochondria per cell) and a decrease in mitochondrial function. We demonstrate that norepinephrine acts through alpha1 adrenergic receptors to increase cytoplasmic Ca(2+), activating calcineurin and promoting migration of the fission protein Drp1 (encoded by Dnml1) to mitochondria. Dominant-negative Drp1 (K38A) not only prevented mitochondrial fission, it also blocked hypertrophic growth of cardiomyocytes in response to norepinephrine. Remarkably, an antisense adenovirus against the fusion protein Mfn2 (AsMfn2) was sufficient to increase mitochondrial fission and stimulate a hypertrophic response without agonist treatment. Collectively, these results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodeling. PMID- 24777480 TI - Interferon regulatory factor 6 regulates keratinocyte migration. AB - Interferon regulatory factor 6 (Irf6) regulates keratinocyte proliferation and differentiation. In this study, we tested the hypothesis that Irf6 regulates cellular migration and adhesion. Irf6-deficient embryos at 10.5 days post conception failed to close their wound compared with wild-type embryos. In vitro, Irf6-deficient murine embryonic keratinocytes were delayed in closing a scratch wound. Live imaging of the scratch showed deficient directional migration and reduced speed in cells lacking Irf6. To understand the underlying molecular mechanisms, cell-cell and cell-matrix adhesions were investigated. We show that wild-type and Irf6-deficient keratinocytes adhere similarly to all matrices after 60 min. However, Irf6-deficient keratinocytes were consistently larger and more spread, a phenotype that persisted during the scratch-healing process. Interestingly, Irf6-deficient keratinocytes exhibited an increased network of stress fibers and active RhoA compared with that observed in wild-type keratinocytes. Blocking ROCK, a downstream effector of RhoA, rescued the delay in closing scratch wounds. The expression of Arhgap29, a Rho GTPase-activating protein, was reduced in Irf6-deficient keratinocytes. Taken together, these data suggest that Irf6 functions through the RhoA pathway to regulate cellular migration. PMID- 24777481 TI - Expression of endoglin isoforms in the myeloid lineage and their role during aging and macrophage polarization. AB - Endoglin plays a crucial role in pathophysiological processes such as hereditary hemorrhagic telangiectasia (HHT), preeclampsia and cancer. Endoglin expression is upregulated during the monocyte-to-macrophage transition, but little is known about its regulation and function in these immune cells. Two different alternatively spliced isoforms of endoglin have been reported, L-endoglin and S endoglin. Although L-endoglin is the predominant variant, here, we found that there was an increased expression of the S-endoglin isoform during senescence of the myeloid lineage in human and murine models. We performed a stable isotope labelling of amino acids in cell culture (SILAC) analysis of both L-endoglin and S-endoglin transfectants in the human promonocytic cell line U937. Analysis of differentially expressed protein clusters allowed the identification of cellular activities affected during aging. S-endoglin expression led to decreased cellular proliferation and a decreased survival response to granulocyte-macrophage colony stimulating factor (GM-CSF)-induced apoptosis, as well as increased oxidative stress. Gene expression and functional studies suggested that there was a non redundant role for each endoglin isoform in monocyte biology. In addition, we found that S-endoglin impairs the monocytic differentiation into the pro inflammatory M1 phenotype and contributes to the compromised status of macrophage functions during aging. PMID- 24777483 TI - FGFR1 N546K mutation in a case of papillary glioneuronal tumor (PGNT). PMID- 24777482 TI - Human pontine glioma cells can induce murine tumors. AB - Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question. PMID- 24777484 TI - Different geographical distributions of two chemotypes of Barbarea vulgaris that differ in resistance to insects and a pathogen. AB - The interactions of plants with herbivores and pathogens have been suggested to drive the evolution of resistances in plants and in some cases new lineages and taxa. However, such divergence may require reproductive isolation, e.g., in allopatry. In the crucifer Barbarea vulgaris, some plants are resistant to the flea beetle Phyllotreta nemorum, due to production of specific saponins, whereas others are susceptible. Resistant and susceptible plants additionally differ in resistance to the pathogen Albugo candida, content of glucosinolates, and leaf pubescence, and they are genetically strongly divergent and partially reproductively incompatible. This suggests that at some point they were separated for a considerable length of time. Previously, the insect susceptible P-type had been described only from Denmark, Sweden, and Estonia, whereas the resistant G type is widely distributed in Western Europe. Here, we tested whether the two plant types have divergent geographical distributions and maintain their distinct trait associations throughout their range. The insect-susceptible type was found in Russia, the Baltics, and parts of Fennoscandia, but not in Central Europe. In contrast, the insect resistant type was found from Finland and westwards. Their different trait associations were consistent within the two ranges. We therefore suggest that the two plant types diverged in allopatry at some time in the past, and evolved different resistances in response to local antagonists. The two plant types probably maintain their distinctness due to a hybridization barrier. Thus, the present distributions of the two types may be shaped by both historical processes and current differential biotic selection. PMID- 24777485 TI - When vegetation change alters ecosystem water availability. AB - The combined effects of vegetation and climate change on biosphere-atmosphere water vapor (H2 O) and carbon dioxide (CO2 ) exchanges are expected to vary depending, in part, on how biotic activity is controlled by and alters water availability. This is particularly important when a change in ecosystem composition alters the fractional covers of bare soil, grass, and woody plants so as to influence the accessibility of shallower vs. deeper soil water pools. To study this, we compared 5 years of eddy covariance measurements of H2 O and CO2 fluxes over a riparian grassland, shrubland, and woodland. In comparison with the surrounding upland region, groundwater access at the riparian sites increased net carbon uptake (NEP) and evapotranspiration (ET), which were sustained over more of the year. Among the sites, the grassland used less of the stable groundwater resource, and increasing woody plant density decoupled NEP and ET from incident precipitation (P), resulting in greater exchange rates that were less variable year to year. Despite similar gross patterns, how groundwater accessibility affected NEP was more complex than ET. The grassland had higher respiration (Reco ) costs. Thus, while it had similar ET and gross carbon uptake (GEP) to the shrubland, grassland NEP was substantially less. Also, grassland carbon fluxes were more variable due to occasional flooding at the site, which both stimulated and inhibited NEP depending upon phenology. Woodland NEP was large, but surprisingly similar to the less mature, sparse shrubland, even while having much greater GEP. Woodland Reco was greater than the shrubland and responded strongly and positively to P, which resulted in a surprising negative NEP response to P. This is likely due to the large accumulation of carbon aboveground and in the surface soil. These long-term observations support the strong role that water accessibility can play when determining the consequences of ecosystem vegetation change. PMID- 24777486 TI - In vivo loss of cement-bone interlock reduces fixation strength in total knee arthroplasties. AB - Prevention of aseptic loosening of total knee arthroplasties (TKAs) remains a clinical challenge. Understanding how changes in morphology at the implant-bone interface with in vivo service affect implant stability and strength could lead to new approaches to mitigate loosening. Enbloc TKA retrievals and freshly cemented TKA tibial components were used to determine if the mechanical strength of the interface depended on the amount of cement-bone interlock and the morphology of the supporting bone under the cement layer. Implants were sectioned into small specimens of the cement-interface-bone from under the tibial tray. Micro-CT scans were used to document interlock morphology and architecture of the supporting trabecular bone. Axial compression tests were used to assess mechanical behavior. Postmortem retrievals had lower contact fraction (42 +/- 55%) compared to freshly-cemented constructs (121 +/- 61%) (p = 0.0008). Supporting bone architecture parameters were not different for the two groups. Increased interface contact fraction and supporting bone volume fraction (BV/TV) were positive predictors of interface strength (r(2) = 0.72, p = 0.0001). For the same supporting bone BV/TV, postmortem specimens had weaker interfaces; they were also more compliant. Cemented TKAs with in vivo service experience a loss of fixation strength and increased micro-motion due to the loss of cement-bone interlock. PMID- 24777487 TI - Atypical gastric bleeding in a 55-year-old man, beyond the scope of treatment? PMID- 24777488 TI - Does a prior diagnosis of Barrett's oesophagus influence risk of dying from oesophageal adenocarcinoma? PMID- 24777489 TI - Speakers' acceptance of real-time speech exchange indicates that we use auditory feedback to specify the meaning of what we say. AB - Speech is usually assumed to start with a clearly defined preverbal message, which provides a benchmark for self-monitoring and a robust sense of agency for one's utterances. However, an alternative hypothesis states that speakers often have no detailed preview of what they are about to say, and that they instead use auditory feedback to infer the meaning of their words. In the experiment reported here, participants performed a Stroop color-naming task while we covertly manipulated their auditory feedback in real time so that they said one thing but heard themselves saying something else. Under ideal timing conditions, two thirds of these semantic exchanges went undetected by the participants, and in 85% of all nondetected exchanges, the inserted words were experienced as self-produced. These findings indicate that the sense of agency for speech has a strong inferential component, and that auditory feedback of one's own voice acts as a pathway for semantic monitoring, potentially overriding other feedback loops. PMID- 24777490 TI - Combined use of 18F-FDG PET/CT and MRI for response monitoring of breast cancer during neoadjuvant chemotherapy. AB - PURPOSE: To explore the potential complementary value of PET/CT and dynamic contrast-enhanced MRI in predicting pathological response to neoadjuvant chemotherapy (NAC) of breast cancer and the dependency on breast cancer subtype. METHODS: We performed (18)F-FDG PET/CT and MRI examinations before and during NAC. The imaging features evaluated on both examinations included baseline and changes in (18)F-FDG maximum standardized uptake value (SUVmax) on PET/CT, and tumour morphology and contrast uptake kinetics on MRI. The outcome measure was a (near) pathological complete response ((near-)pCR) after surgery. Receiver operating characteristic curves with area under the curve (AUC) were used to evaluate the relationships between patient, tumour and imaging characteristics and tumour responses. RESULTS: Of 93 patients, 43 achieved a (near-)pCR. The responses varied among the different breast cancer subtypes. On univariate analysis the following variables were significantly associated with (near-)pCR: age (p = 0.033), breast cancer subtype (p < 0.001), relative change in SUVmax on PET/CT (p < 0.001) and relative change in largest tumour diameter on MRI (p < 0.001). The AUC for the relative reduction in SUVmax on PET/CT was 0.78 (95% CI 0.68-0.88), and for the relative reduction in tumour diameter at late enhancement on MRI was 0.79 (95% CI 0.70-0.89). The AUC increased to 0.90 (95% CI 0.83-0.96) in the final multivariate model with PET/CT, MRI and breast cancer subtype combined (p = 0.012). CONCLUSION: PET/CT and MRI showed comparable value for monitoring response during NAC. Combined use of PET/CT and MRI had complementary potential. Research with more patients is required to further elucidate the dependency on breast cancer subtype. PMID- 24777491 TI - Preoperative PET/CT standardized FDG uptake values of pelvic lymph nodes as a significant prognostic factor in patients with endometrial cancer. AB - PURPOSE: Using integrated PET/CT, we evaluated the prognostic relevance of preoperative pelvic lymph node (LN) (18)F-FDG uptake in endometrioid endometrial cancer. METHODS: We retrospectively reviewed patients with pathologically proven endometrial cancer who underwent preoperative (18)F-FDG PET/CT scans to evaluate the prognostic significance of PET/CT parameters and other clinicopathological variables. We used Cox proportional hazards regression to examine the relationship between recurrence and the maximum standardized uptake value (SUVmax) in pelvic LNs (SUVLN) on FDG PET/CT. RESULTS: Clinical data, treatment modalities and results were reviewed in 70 eligible patients. The median postsurgical follow-up was 29 months (range 6 to 95 months). Receiver-operating characteristic analysis identified the significant SUVLN cut-off value as 15. The SUVLN correlated with FIGO stage (P < 0.001), LN metastasis (P < 0.001), lymphovascular space invasion (P < 0.001), SUVtumour (P = 0.001), metastatic LN size (P = 0.004), primary tumour size (P = 0.012), tumour grade (P = 0.015) and depth of tumour invasion (P = 0.035). Regression analysis showed a statistically significant association between recurrence and SUVLN (P = 0.002). Recurrence differed significantly (P < 0.001) between patients with SUVLN >15 and those with SUVLN <=15. CONCLUSION: Preoperative pelvic LN FDG uptake exhibited a strong significant association with recurrence of endometrioid endometrial cancer. PMID- 24777492 TI - Detoxification treatments for opiate dependent adolescents. AB - BACKGROUND: The scientific literature examining effective treatments for opioid dependent adults clearly indicates that pharmacotherapy is a necessary and acceptable component of effective treatments for opioid dependence. Nevertheless, no studies have been published that systematically assess the effectiveness of the pharmacological detoxification among adolescents. OBJECTIVES: To assess the effectiveness of any detoxification treatment alone or in combination with psychosocial intervention compared with no intervention, other pharmacological intervention or psychosocial interventions on completion of treatment, reducing the use of substances and improving health and social status. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (2014, Issue 1), PubMed (January 1966 to January 2014), EMBASE (January 1980 to January 2014), CINHAL (January 1982 to January 2014), Web of Science (1991-January 2014) and reference lists of articles. SELECTION CRITERIA: Randomised controlled clinical trials comparing any pharmacological interventions alone or associated with psychosocial intervention aimed at detoxification with no intervention, placebo, other pharmacological intervention or psychosocial intervention in adolescents (13 to 18 years). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by The Cochrane Collaboration MAIN RESULTS: Two trials involving 190 participants were included. One trial compared buprenorphine with clonidine for detoxification. No difference was found for drop out: risk ratio (RR) 0.45 (95% confidence interval (CI): 0.20 to 1.04) and acceptability of treatment: withdrawal score mean difference (MD): 3.97 (95% CI -1.38 to 9.32). More participants in the buprenorphine group initiated naltrexone treatment: RR 11.00 (95% CI 1.58 to 76.55), quality of evidence moderate.The other trial compared maintenance treatment versus detoxification treatment: buprenorphine naloxone maintenance versus buprenorphine detoxification. For drop out the results were in favour of maintenance treatment: RR 2.67 (95% CI 1.85, 3.86), as well as for results at follow-up RR 1.36 [95% CI 1.05to 1.76); no differences for use of opiate, quality of evidence low. AUTHORS' CONCLUSIONS: It is difficult to draw conclusions on the basis of two trials with few participants. Furthermore, the two studies included did not consider the efficacy of methadone that is still the most frequent drug utilised for the treatment of opioid withdrawal. One possible reason for the lack of evidence could be the difficulty in conducting trials with young people due to practical and ethical reasons. PMID- 24777493 TI - Extensive female-mediated gene flow and low phylogeography among seventeen goat breeds in southwest China. AB - Indigenous Chinese goat mtDNA is highly diverse but lacks geographic specificity; however, whether gene flow or gene exchange contributed to this remains unknown. We reanalyzed a consensus fragment of 481 bp in the D-loop region from 339 individuals. The network and neighbor-joining tree revealed three divergent maternal haplogroups (A, B1, and B2) in 17 local breeds. Although high polymorphism resulting in 198 different haplotypes was observed (h = 0.984 +/- 0.002; pi = 0.0336 +/- 0.0008), neither the distribution of haplotypes nor PCA analysis revealed any obvious geographic structure in the local breeds. Extensive gene flow was widely detected among breeds from southwest China. High levels of gene exchange were detected between Qianbei Brown goats and the other breeds, indicating either more contribution or introgression to their gene pools. This study will be helpful in understanding the phylogeography and gene flow among the goat breeds of southwest China. PMID- 24777494 TI - Paeoniflorin protects cells from GalN/TNF-alpha-induced apoptosis via ER stress and mitochondria-dependent pathways in human L02 hepatocytes. AB - Paeoniflorin (PF) is one of the main effective components extracted from the root of Paeonia lactiflora, which has been used clinically to treat hepatitis in traditional Chinese medicine, but the details of the underlying mechanism remain unknown. The present study was designed to investigate the mechanism of protective effect of PF on d-galactosamine (GalN) and tumor necrosis factor-alpha (TNF-alpha)-induced cell apoptosis using human L02 hepatocytes. Our results confirmed that PF could attenuate GalN/TNF-alpha-induced apoptotic cell death in a dose-dependent manner. The disruption of mitochondrial membrane potential and the disturbance of intracellular Ca(2+) concentration were also recovered by PF. Western blot analysis revealed that GalN/TNF-alpha induced the activation of a number of signature endoplasmic reticulum (ER) stress and mitochondrial markers, while PF pre-treatment had a marked dose-dependent suppression on them. Additionally, the anti-apoptotic effect of PF was further evidenced by the inhibition of caspase-3/9 activities in L02 cells. These findings suggest that PF can effectively inhibit hepatocyte apoptosis and the underlying mechanism is related to the regulating mediators in ER stress and mitochondria-dependent pathways. PMID- 24777495 TI - Over-expression of methionine sulfoxide reductase A in the endoplasmic reticulum increases resistance to oxidative and ER stresses. AB - MsrA and MsrB catalyze the reduction of methionine-S-sulfoxide and methionine-R sulfoxide, respectively, to methionine in different cellular compartments of mammalian cells. One of the three MsrBs, MsrB3, is an endoplasmic reticulum (ER) type enzyme critical for stress resistance including oxidative and ER stresses. However, there is no evidence for the presence of an ER-type MsrA or the ER localization of MsrA. In this work, we developed an ER-targeted recombinant MsrA construct and investigated the potential effects of methionine-S-sulfoxide reduction in the ER on stress resistance. The ER-targeted MsrA construct contained the N-terminal ER-targeting signal peptide of human MsrB3A (MSPRRSLPRPLSLCLSLCLCLCLAAALGSAQ) and the C-terminal ER-retention signal sequence (KAEL). The over-expression of ER-targeted MsrA significantly increased cellular resistance to H2O2-induced oxidative stress. The ER-targeted MsrA over-expression also significantly enhanced resistance to dithiothreitol-induced ER stress; however, it had no positive effects on the resistance to ER stresses induced by tunicamycin and thapsigargin. Collectively, our data suggest that methionine-S sulfoxide reduction in the ER compartment plays a protective role against oxidative and ER stresses. PMID- 24777496 TI - Decreased serum brain-derived neurotrophic factor in Chinese patients with Type 2 diabetes mellitus. PMID- 24777497 TI - Preparation of recombinant human canstatin using transgenic Dunaliella salina. PMID- 24777498 TI - Innate immune cells in inflammation and cancer. AB - The innate immune system has evolved in multicellular organisms to detect and respond to situations that compromise tissue homeostasis. It comprises a set of tissue-resident and circulating leukocytes primarily designed to sense pathogens and tissue damage through hardwired receptors and eliminate noxious sources by mediating inflammatory processes. While indispensable to immunity, the inflammatory mediators produced in situ by activated innate cells during injury or infection are also associated with increased cancer risk and tumorigenesis. Here, we outline basic principles of innate immune cell functions in inflammation and discuss how these functions converge upon cancer development. PMID- 24777499 TI - Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. AB - Despite the limited success of immunotherapies in solid malignancy, two human cancers, melanoma and renal cancer, have, for many years, responded to systemic administration of immune-targeted biologics and showed signals of response to certain therapeutic vaccines. These findings underpinned a long-held perception that melanoma and renal cancer were uniquely "immunogenic" but that virtually all other human cancers were not and thus would not respond to immune modulation. That notion has now been shattered by the significant and durable responses in non-small cell lung cancer induced by therapeutic treatment with antibodies blocking the PD-1 checkpoint. The immunotherapy success in lung cancer thus provides a gateway to development of treatments for multiple cancer types that were previously believed not accessible to immune-based therapies. PMID- 24777500 TI - Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. AB - Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records of patients treated with ipilimumab and radiotherapy for melanoma at our institution between 2005 and 2011. The review included details of treatment, response, adverse events (AE), and overall survival (OS). Twenty-nine patients underwent 33 courses of non-brain radiotherapy between their first and last dose of ipilimumab. Immune-related AEs (ir-AEs) were observed in 43% of patients receiving ipilimumab at 10 mg/kg and in 22% of patients receiving 3 mg/kg; the frequency of ir-AEs was not significantly different compared with previous studies of ipilimumab alone. Radiotherapy-related AEs were significantly more common in patients receiving higher doses of radiation. Palliation of symptoms was reported by 77% of patients after radiotherapy. Median OS was 9 and 39 months in patients receiving radiotherapy during induction and maintenance with ipilimumab, respectively. In this retrospective study, concurrent ipilimumab and radiotherapy was neither associated with higher than expected rates of AEs nor did it abrogate palliative effects of radiotherapy or survival benefits of ipilimumab. Further studies to prospectively explore the efficacy of this therapeutic combination are warranted. PMID- 24777502 TI - For a rise of comparative cognitive science. PMID- 24777503 TI - Dynamic object perception by pigeons: discrimination of action in video presentations. AB - Two experiments examined the discrimination by pigeons of relative motion using computer-generated video stimuli. Using a go/no-go procedure, pigeons were tested with video stimuli in which the camera's perspective went either "around" or "through" an approaching object in a semi-realistic context. Experiment 1 found that pigeons could learn this discrimination and transfer it to videos composed from novel objects. Experiment 2 found that the order of the video's frames was critical to the discrimination of the videos. We hypothesize that the pigeons perceived a three-dimensional representation of the objects and the camera's relative motion and used this as the primary basis for discrimination. It is proposed that the pigeons might be able to form generalized natural categories for the different kinds of motions portrayed in the videos. PMID- 24777501 TI - Radretumab radioimmunotherapy in patients with brain metastasis: a 124I-L19SIP dosimetric PET study. AB - Radioimmunotherapy (RIT) with (131)I-labeled L19SIP (radretumab; a small immunoprotein format antibody directed against the ED-B domain of fibronectin; ~ 80 kDa molecular weight) has been investigated in several clinical trials. Here, we describe the use of immuno-PET imaging with iodine-124 ((124)I)-labeled L19SIP to predict doses delivered to tumor lesions and healthy organs by a subsequent radretumab RIT in patients with brain metastases from solid cancer. Bone marrow doses were evaluated both during the diagnostic phase and posttherapy, measuring activities in blood (germanium detector) and whole body (lanthanum bromide detector). Expected doses for radretumab administration (4,107 MBq/m(2)) were calculated from data obtained after administration of an average of 167 MBq (124)I-L19SIP to 6 patients. To assess lesion average doses, the positron emission tomography (PET) scanner was calibrated for the use of (124)I with an International Electrotechnical Commission (IEC) Body Phantom and recovery coefficients were calculated. The average dose to bone red marrow was 0.21 Gy/GBq, with high correlation between provisional and actual posttherapy doses. Although the fraction of injected activity in normal organs was similar in different patients, the antibody uptake in the neoplastic lesions varied by as much as a factor of 60. Immuno-PET with (124)I-labeled L19SIP offers significant advantages over conventional (131)I imaging, in particular accuracy of dosimetric results. Furthermore, the study indicates that antibody uptake can be highly variable even in different lesions of the same patient and that immuno-PET procedures may guide product development with armed antibodies. PMID- 24777504 TI - Van Gogh, Chagall and pigeons: picture discrimination in pigeons and humans. AB - The author has previously reported that pigeons can discriminate paintings by different artists. Here, I replicated the previous findings, carried out additional tests and compared discrimination by pigeons with that of humans. In Experiment 1, pigeons were trained to discriminate between paintings by Van Gogh and Chagall. After training, the subjects were tested with different paintings by the same artists. The subjects showed generalization to these paintings. The subjects maintained their discriminative ability for black-and-white paintings and partially occluded paintings. When they were tested with mosaic paintings, the number of correct responses decreased, depending on the level of processing needed. In Experiment 2, human subjects were tested with the same paintings. The subjects showed generalization and decrement of correct responses depending on the degree of mosaic processing. These observations suggest that the visual cognitive function of pigeons is comparable to that of humans. The convergence of higher visual cognition between the two species may stem from similar selection pressures on avian ancestors and our ancestors through their evolution. PMID- 24777505 TI - Do pigeons (Columba livia) perceive object unity? AB - Human infants perceive two rods moving in concert behind an occluder as one unitary rod. In four experiments we tested whether pigeons also perceive unity of objects. Pigeons were trained on a matching-to-sample task to discriminate between one unitary rod moving at a constant speed and two aligned rods moving together at the same speed. The latter stimulus was identical to the former except for a gap in the center. In experiment 1, we tested pigeons in probe trials in which a rectangle occluded the center of the sample rods, to see which comparison stimulus, the unitary rod or the aligned two rods, the subjects would match to the sample. Two of the three subjects pecked at the two rods significantly more often than at the unitary rod. In experiment 2, we trained the same pigeons to match the sample rods moving "in front of" the occluder. Pigeons persisted in matching two separate rods to the unitary rod moving in front of the occluder. In experiments 3 and 4, we used a parallelogram and an undulating shape as the occluder to alter the shape and the size of the portions above and below the occluder by the motion of the sample rods. Both subjects chose the two rods significantly more often than chance in experiment 3 and one of them did so in experiment 4. The results suggest that pigeons do not complete occluded portions even though the two elements move in concert. These negative results suggest that some alternative way of identifying objects may have evolved in pigeons. PMID- 24777506 TI - Effects of number of items on the baboon's discrimination of same from different visual displays. AB - Three experiments explored the baboon's discrimination of visual displays that comprised 2 to 24 black-and-white computer icons; the displayed icons were either the same as (same) or different from one another (different). The baboons' discrimination of same from different displays was a positive function of the number of icons. When the number of icons was decreased to 2 or 4, the baboons responded indiscriminately to the same and different displays, exhibiting strong position preferences. These results are both similar to and different from those of pigeons that were trained and tested under comparable conditions. PMID- 24777507 TI - Effects of element separation on perceptual grouping by humans (Homo sapiens) and chimpanzees (Pan troglodytes): perception of Kanizsa illusory figures. AB - The processing of Kanizsa-square illusory figures was studied in two experiments with four humans and two chimpanzees. Subjects of the two species were initially trained to select a Kanizsa-square illusory figure presented in a computerized two-alternative forced choice task. After training, adding narrow closing segments to the pacman inducers that composed the Kanisza illusory figures lowered performance in both chimpanzees and humans, suggesting that the discrimination could be controlled by the perception of illusory forms. A second experiment assessed transfer of performance with five sets of figures in which the size of the inducers and their separation were manipulated. Only for chimpanzees was performance directly controlled by separation, suggesting that chimpanzees are more sensitive than humans to the separation between visual elements. PMID- 24777508 TI - Acquisition of navigation by chimpanzees (Pan troglodytes) in an automated fingermaze task. AB - These experiments investigated how chimpanzees learn to navigate visual fingermazes presented on a touch monitor. The aim was to determine whether training the subjects to solve several different mazes would establish a generalized map-reading skill such that they would solve new mazes correctly on the first presentation. In experiment 1, two captive adult female chimpanzees were trained to move a visual object (a ball) with a finger over the monitor surface toward a target through a grid of obstacles that formed a maze. The task was fully automated with storage of movement paths on individual trials. Training progressed from very simple mazes with one obstacle to complex mazes with several obstacles. The subjects learned to move the ball to the target in a curved path so as to avoid obstacles and blind alleys. After training on several mazes, both subjects developed a high level of efficiency in moving the ball to the target in a path that closely approached the ideal shortest path. New mazes were then presented to determine whether the subjects had acquired a more generalized maze solving performance. The subjects solved 65-100% of the new mazes the first time they were presented by moving the ball around obstacles to the target without making detours into blind alleys. In experiment 2, one of the chimpanzees was trained using mazes with two routes to the target. One of the routes was blocked at one of many possible locations. After training to avoid the blind alley in different mazes, new mazes were presented that also had one route blocked. The subject correctly solved 90.7% of the novel mazes. When the mazes had one short and one long open route to the target the subject preferred the shorter route. When the short route was blocked, the subject solved only 53.3% of the mazes because of the preference for the shorter route even when blocked. The overall results suggest that with the training methods used the subjects learned to solve specific mazes with a trial-and-error method. Although both subjects were able to solve many of the novel mazes they did not fully develop a more general "map reading" skill. PMID- 24777509 TI - Use of numerical symbols by the chimpanzee (Pan troglodytes): Cardinals, ordinals, and the introduction of zero. AB - An adult female chimpanzee with previous training in the use of Arabic numerals 1 9 was introduced to the meaning of "zero" in the context of three different numerical tasks. The first two were cardinal tasks where the subject was required either to select numerals corresponding to the number of items presented on a computer screen (productive use of numerals) or to match sets of the appropriate size to numerals presented as samples (receptive use). The third task addressed the ordinal meaning of the same symbols where the subject was required to respond to numerals sequentially, arranging them into an ascending series. The subject mastered the recognition of the meaning of zero in all three tasks. However, details of her usage of the symbol revealed that transfer of the meaning between different kinds of tasks was incomplete, suggesting that the level of abstraction characteristic of human numerical ability was not attained in the chimpanzee. Over the course of acquisition leading to the high levels of accuracy eventually observed, the newly introduced zero appeared to shift along the length of a continuous numerical scale toward the lower end, while confusions with 1 remained the most frequently encountered mistakes. Such patterns of error thus suggest that Ai's understanding of the meaning of zero in relation to the rest of the number symbols was not consistent with an "absence of items versus presence of items" scheme. PMID- 24777510 TI - Discrimination and categorization of photographs of natural objects by chimpanzees (Pan troglodytes). AB - Two experiments assessed the ability of four adult female chimpanzees to categorize natural objects. Chimpanzees were initially trained to match different color photographs of familiar objects from four possible categories. In training, all the comparison stimuli were from the same category in one condition, and from different categories in another condition. For all subjects, training performance was consistently better for the "different category" than for the "same category" trials. Probe trials were shown after training. In probe trials, the sample and positive comparison stimuli were different items from the same category, and the foils were selected from among the three other test categories. Individual performance was above chance in probe trials, suggesting that categorization by chimpanzees may transcend perceptual resemblance. These results were later replicated with novel stimulus items from the same four categories (experiment 2). Altogether, this research demonstrates that chimpanzees grouped perceptually different exemplars within the same category, and further suggests that these animals formed conceptual representations of the categories. PMID- 24777511 TI - The use of tokens as rewards and tools by chimpanzees (Pan troglodytes). AB - This paper explores the effectiveness of token rewards in maintaining chimpanzees (Pan troglodytes) in working at intellectually costly tasks, and studies the "saving" behavior of the subjects, investigating the factors that can condition it. Two experiments were run. Tokens were introduced as rewards in a matching-to sample task and used as exchange tools for food by three adult female chimpanzees. Subjects' performances were maintained at constant high levels of accuracy, suggesting that the tokens were almost equivalent to direct food rewards. The results also showed the emergence of saving behavior. The subjects spontaneously saved the tokens during the matching-to-sample task before exchanging them for food. The chimpanzees also learned a new symbolic discrimination task, with tokens as the reward. During this learning process a rarely reported phenomenon emerged: one of the subjects showed symmetry, a form of stimulus equivalence. PMID- 24777512 TI - Cognitive and physiological markers of emotional awareness in chimpanzees (Pan troglodytes). AB - The ability to understand emotion in others is one of the most important factors involved in regulating social interactions in primates. Such emotional awareness functions to coordinate activity among group members, enable the formation of long-lasting individual relationships, and facilitate the pursuit of shared interests. Despite these important evolutionary implications, comparative studies of emotional processing in humans and great apes are practically nonexistent, constituting a major gap in our understanding of the extent to which emotional awareness has played an important role in shaping human behavior and societies. This paper presents the results of two experiments that examine chimpanzees' responses to emotional stimuli. First, changes in peripheral skin temperature were measured while subjects viewed three categories of emotionally negative video scenes; conspecifics being injected with needles (INJ), darts and needles alone (DART), and conspecific directing agonism towards the veterinarians (CHASE). Second, chimpanzees were required to use facial expressions to categorize emotional video scenes, i.e., favorite food and objects and veterinarian procedures, according to their positive and negative valence. With no prior training, subjects spontaneously matched the emotional videos to conspecific facial expressions according to their shared emotional meaning, indicating that chimpanzee facial expressions are processed emotionally, as are human expressions. Decreases in peripheral skin temperature, indicative of negative sympathetic arousal, were significantly lower when subjects viewed the INJ and DART videos, compared to the CHASE videos, indicating greater negative arousal when viewing conspecifics being injected with needles, and needles themselves, than when viewing conspecifics engaged in general agonism. PMID- 24777513 TI - Acquisition of auditory-visual intermodal matching-to-sample by a chimpanzee (Pan troglodytes): comparison with visual-visual intramodal matching. AB - A chimpanzee acquired an auditory-visual intermodal matching-to-sample (AVMTS) task, in which, following the presentation of a sample sound, the subject had to select from two alternatives a photograph that corresponded to the sample. The acquired AVMTS performance might shed light on chimpanzee intermodal cognition, which is one of the least understood aspects in chimpanzee cognition. The first aim of this paper was to describe the training process of the task. The second aim was to describe through a series of experiments the features of the chimpanzee AVMTS performance in comparison with results obtained in a visual intramodal matching task, in which a visual stimulus alone served as the sample. The results show that the acquisition of AVMTS was facilitated by the alternation of auditory presentation and audio-visual presentation (i.e., the sample sound together with a visual presentation of the object producing the particular sample sound). Once AVMTS performance was established for the limited number of stimulus sets, the subject showed rapid transfer of the performance to novel sets. However, the subject showed a steep decay of matching performance as a function of the delay interval between the sample and the choice alternative presentations when the sound alone, but not the visual stimulus alone, served as the sample. This might suggest a cognitive limitation for the chimpanzee in auditory-related tasks. PMID- 24777514 TI - Left-side dominance for song discrimination in Bengalese finches (Lonchura striata var. domestica). AB - Male Bengalese finches are left-side dominant for the motor control of song in the sensorimotor nucleus (the high vocal center, or HVc) of the telencephalon. We examined whether perceptual discrimination of songs might also be lateralized in this species. Twelve male Bengalese finches were trained by operant conditioning to discriminate between a Bengalese finch song and a zebra finch song. Before training, the left HVc was lesioned in four birds and the right HVc was lesioned in four other birds. The remaining four birds were used as controls without surgery. Birds with a left HVc lesion required significantly more time to learn to discriminate between the two songs than did birds with a right HVc lesion or intact control birds. These results suggest that the left HVc is not only dominant for the motor control of song, but also for the perceptual discrimination of song. PMID- 24777515 TI - Social processes in communication and cognition in callitrichid monkeys: a review. AB - Studies of vocal development in nonhuman primates have found little evidence for plasticity in vocal production, somewhat more for usage of calls, with the greatest plasticity arising in response to calls of others. Generally, similar results were obtained with callitrichid monkeys, the marmosets and tamarins, but with several interesting exceptions. Infant pygmy marmosets show babbling behavior with improvement in adult call structure related to the amount and diversity of babbling. Adult marmosets alter call structure in response to changes in social partners, and wild marmosets have vocal dialects and modify call structure according to how far they are from other group members, suggesting the potential to modify call structure in different social and environmental contexts, though direct learning of novel vocalizations has not been observed. Infant cotton-top tamarins do not produce adult-like calls in appropriate contexts, at least in the first few months of life, but through food sharing from adults infants learn about appropriate foods and the appropriate contexts for food vocalizations. Tamarins modify call structure and usage with changes in social status. Tamarins, unlike other monkeys tested, can learn to avoid noxious foods through observation of other group members, and can learn about novel food locations. Recent studies provide evidence of contextual imitation in marmosets. The plasticity in vocal communication and evidence of social learning in marmosets and tamarins relative to other monkeys may be related to the cooperative breeding system of marmosets and tamarins. With a high degree of behavioral coordination among group members, there is a priority on monitoring signals and behavior of others and adjusting one's own signals and behavior. This creates the context for vocal plasticity and social learning. PMID- 24777516 TI - Reconciliation and variation in post-conflict stress in Japanese macaques (Macaca fuscata fuscata): testing the integrated hypothesis. AB - Reconciliation in primates, a post-conflict affiliative interaction between former opponents, appears to have two functions: (1) to repair relationship damaged by aggression such that animals who share more valuable relationships are more likely to reconcile, and (2) to reduce the post-conflict uncertainty and stress of former combatants. The 'integrated hypothesis' of reconciliation links these functions by arguing that the disturbance of a valuable relationship by aggression should result in particularly high levels of stress, which in turn should facilitate efforts to reconcile and thus gain relief from post-conflict stress. A key prediction of the integrated hypothesis is that victims of aggression suffer more stress following conflicts with individuals with whom they share a valuable relationship. In this article, we test the integrated hypothesis by observing the post-conflict behaviour of victims among a free-ranging provisioned troop of Japanese macaques (Macaca fuscata fuscata) living in Shiga Heights, Nagano, Japan. In this troop, monkeys reconciled roughly one in seven conflicts. The only factor that we could significantly relate to the occurrence of reconciliation was kinship; kin reconciled more frequently than non-kin did. Receiving aggression increased and reconciliation reduced the probability of being re-attacked after aggressive interactions, supporting the hypothesis that reconciliation repairs relationships. Victims' self-directed behaviour (SDB) - a behavioural index of stress comprising increases in scratching, self-grooming, and body-shaking - was elevated following aggression but decreased rapidly following reconciliation, supporting the idea that reconciliation functions to reduce post-conflict stress. Post-conflict SDB varied as follows: (1) victims showed a higher level of stress following aggression with kin than with non-kin, and (2) juvenile victims were less distressed than adults. The level of post conflict SDB performed by juveniles following conflicts with kin was indistinguishable from that performed by adults but was greatly reduced following attacks from non-kin. These results indicate that post-conflict SDB keenly reflects the value of relationships between opponents, and that the post-conflict behaviour of free-ranging Japanese macaques fits the predictions of the integrated hypothesis. PMID- 24777517 TI - Can competitive paradigms increase the validity of experiments on primate social cognition? AB - Experiments vary in their ability to distinguish between competing hypotheses. In tests on primate cognition the majority of this variation is due to an experimenter's ability to test primates in valid settings while providing the adequate amount of experimental control. While experimenters studying primate cognition can use methods of control perfected in captivity, it is still very unclear how to design and then objectively evaluate the external validity of new experimental paradigms. I recommend that more effort be allocated to specify how to create relevant test settings for primates. Primate social life is highly competitive. This means that all aspects of primates themselves, including their cognitive abilities, have likely been shaped by the need to out-compete conspecifics. Based on this hypothesis, sophisticated cognitive abilities of primates might best be demonstrated in competitive contexts. Thus, it is suggested that one possible measure of validity is whether investigators integrate a competitive component into their experimental designs. To evaluate this methodological prediction I review the literature on chimpanzee perspective taking as a case study including several recent studies that include a competitive component in their experimental designs. PMID- 24777518 TI - Attention to repeated events in human infants (Homo sapiens): effects of joint visual attention versus stimulus change. AB - The goal of this study was to examine the effect of joint visual attention on infants' behavior during subsequent events. Thirty-seven mother-infant (aged from 9 to 13 months) pairs were twice shown a pair of line drawing stimuli on a computer screen. For the control group, the mother never paid attention to the stimuli. For experimental group 1, the mother pointed to one stimulus in the first presentation but did not point to it in the second presentation. The infants gazed longer at the stimulus pointed to by their mothers in the first presentation. In the second presentation, during which mothers did not attend to the stimuli, infants gazed longer at the stimulus which had been pointed to by the mothers in the first presentation. In experimental group 2, one of two stimuli blinked during the first presentation but not the second presentation. Infants gazed for longer at the blinking stimulus in the first presentation, but there was no difference in looking time toward the two stimuli in the second presentation. These results suggest that joint visual attention affects infants' looking behavior during subsequent events, and that simple stimulus change does not. PMID- 24777519 TI - Tactics to obtain a hidden food item in chimpanzee pairs (Pan troglodytes). AB - Five dyads of chimpanzees were tested in a competitive situation, as a pilot study to examine chimpanzees' understanding of conspecifics' knowledge. A human experimenter baited one of five containers in an outdoor enclosure. Chimpanzee A (witness) could see where the food was hidden, while chimpanzee B (witness-of witness) could not see the baited place but could observe the chimpanzee A watching the food being hidden. Then the two were released into the enclosure. This procedure was repeated for a certain number of days along with a control condition in which neither could see the baited location. The witness-of-witness developed tactics to forestall the witness in two pairs. The witness misled the witness-of-witness by taking a route to an empty container in several cases. These episodes might represent examples of deception. Tactics and counter-tactics thus developed through the interaction between the witness and the witness-of witness, illustrating the high social intelligence of chimpanzees. An examination of the changes in tactics suggests a possibility that the witness-of-witness understands the witness's knowledge of the location of hidden food. PMID- 24777520 TI - Social facilitation of eating novel food in tufted capuchin monkeys (Cebus apella): input provided by group members and responses affected in the observer. AB - Learning about food palatability from watching what conspecifics eat might be one of the advantages of group living. A previous study investigated whether group members' presence or eating activity account for social facilitation of eating of foods never previously tasted. Capuchins encountered novel colored foods when (1) alone (Alone condition) or (2) with group members visible in the nearby cage (Group-present condition) or (3) with group members present and eating a familiar food that had not been colored (Group+food condition). Social facilitation of eating occurred when group members were eating, despite the difference in color between the familiar food eaten by them and the novel food presented to the experimental subject. To clarify what subjects learnt from group members when social facilitation occurred, we further analyze here the data from the previous study. The number of visual exposures to the colored novel food (as a group member) correlated with increased consumption of that novel food when encountered later (as experimental subject). In contrast, the number of times that an individual fed on the familiar food (as a group member) did not decrease its consumption of novel food (as experimental subject). Therefore, capuchins (1) habituated to the colors of the novel foods, and (2) did not take into account that seeing group members eating a food does not provide information about the palatability of a differently colored food. Since social facilitation of eating occurs when foods do not match in color, at least in capuchins, social facilitation of eating should not be considered as a way of learning about a safe diet, but rather as a way of overcoming neophobia. PMID- 24777521 TI - Testing for social learning in the "artificial fruit" processing of wildborn orangutans (Pongo pygmaeus), Tanjung Puting, Indonesia. AB - Social learning about actions, objects and sequencing was investigated in a group of 14 wildborn orangutans (four adult females and ten 3- to 5-year-old juveniles). Human models showed alternative methods and sequences for dismantling an artificial fruit to groups of participants matched by gender and age. Each participant received three to six 2-min trials in which they were given access to the artificial fruit for manipulation. Independent coders, who were unaware of which method each participant had seen, gave confidence ratings and collected action frequencies from watching video recordings of the experimental trials. No significant differences were found between groups in terms of the coders' confidence ratings, the action frequencies or the sequence of manipulations. These negative results may at least partly reflect the immaturity of a large proportion of the participants. A positive correlation was found between age and the degree of matching to the method shown. Although none of the juveniles succeeded in opening the "fruit", two out of the four adults did so and they also seemed to match more closely the sequence of elements touched over successive trials. The results are compared with similar data previously collected from human children, chimpanzees, gorillas, capuchin monkeys and common marmosets. PMID- 24777522 TI - Do apes and monkeys rely upon conceptual reversibility? : A review of studies using seriated nesting cups in children and nonhuman primates. AB - The ability to seriate nesting cups as a sensorimotor task has posed interesting questions for cognitive scientists. Greenfield et al. [(1972) Cognit Psychol 3:291-310] found parallels between children's combinatorial activity with nesting cups and patterns of phonological and grammatical constructions. The parallels suggested the possibility of a neurally based developmental homology between language and instrumental action [Greenfield (1991) Behav Brain Sci 14:531-595]. Children who predominantly used subassembly, a hierarchical method of combining cups, succeeded at seriating nesting cups more often than those who did not. Greenfield and others [e.g., Piaget and Inhelder (1969) The psychology of the child. Basic Books, New York; DeLoache et al. (1985) Child Dev 56:928-939] argued that success in seriation reflects the child's growing recognition of a reversible relationship: a particular element in a series is conceived of as being smaller than the previous element and larger than the subsequent element. But is a concept of reversibility or a hierarchical form of object manipulation necessary to seriate cups? In this article, we review studies with very young children and nonhuman primates to determine how individuals that do not evidence conceptual reversibility manage the seriation task. We argue that the development of skill in seriation is experientially, rather than conceptually, driven and that it may be unnecessary to link seriation with cognitive conceptions of reversibility or linguistic capacities. Rather, in ordering a set of objects by size, perceptual-motor learning may enable contemplative refinement. PMID- 24777523 TI - Leaf-folding behavior for drinking water by wild chimpanzees (Pan troglodytes verus) at Bossou, Guinea. AB - The use of leaves for drinking water by wild chimpanzees (Pan troglodytes verus) at Bossou, Guinea, was observed intensively. The natural hollow of a tree, used by chimpanzees, was filled up with fresh water every morning. Seventy episodes of leaf-using behavior by 14 chimpanzees were directly observed and video-recorded. The chimpanzees at Bossou most frequently (70.3%) used a particular kind of leaf, Hybophrynium braunianum as tool material. The chimpanzees folded one or more leaves in the mouth. This technique, "leaf folding", was observed more frequently (57.9 %) than "leaf sponge" or "leaf spoon". Chimpanzees began to perform this behavior at about 2.5 years old. Infant chimpanzees showed more frequent observations of others (especially their mothers) using leaves before trying to drink water with leaves. Both observation and trial and error might be necessary for the acquisition of this tool-use behavior. PMID- 24777524 TI - Development of combinatory manipulation in chimpanzee infants (Pan troglodytes). AB - I made systematic observations of three infant chimpanzees aged 2-4 years, who participated in a series of diagnostic tests of combinatory manipulation. The tasks were stacking blocks, seriating nesting cups, and inserting an object into the corresponding hole in a plate or a box. These tasks were originally devised for developmental diagnosis of human infants. The chimpanzee infants displayed combinatory manipulation comparable to that of 1-year-old human infants. Common motor characteristics were observed across the tasks, namely "repetition" of actions, "adjustment" of actions, "reversal" of actions, and "shifts" of attention. Humans and chimpanzees share these actions when manipulating multiple objects to complete a task. Repetition, adjustment, and reversal of actions and shifts of attention underlie higher levels of cognition common to both species. PMID- 24777525 TI - Manual dexterity in the gorilla: bimanual and digit role differentiation in a natural task. AB - The manipulative actions of mountain gorillas Gorilla g. beringei were examined in the context of foraging on hard-to-process plant foods in the field, in particular those used in tackling thistle Carduus nyassanus. A repertoire of 72 functionally distinct manipulative actions was recorded. Many of these actions were used in several variants of grip, finger(s) and movement path, both by different individuals and by the same individual at different times. The repertoire appears somewhat greater than that observed in comparable studies of monkeys, but a far more striking difference is found in the use of differentiated actions in concert. Mountain gorillas routinely and frequently deal with problems that involve: (1) bimanual role differentiation, with the two hands taking different roles but synchronized in time and space, and (2) digit role differentiation, with independent control of parts of the same hand used for separate purposes at the same time. The independent control that allows these abilities, so crucial to human manual constructional ability, is apparently general in African great apes. Role differentiation, between and within the hand, is evidently a primitive characteristic in the human arsenal of skills. PMID- 24777526 TI - Weekly teriparatide administration for the treatment of delayed union: a report of two cases. AB - Two cases of delayed union that were effectively treated with weekly TPTD administration are described. The effect of this therapy was observed within 4 weeks. INTRODUCTION: In the first case, a 72-year-old woman underwent osteotomy for the treatment of hallux valgus. Bone union was still not observed 4 months after surgery. Therefore, weekly teriparatide (56.5 mg) injections were administered, resulting in the initiation of bone union within 4 weeks and complete bone union 4 months after the first teriparatide injection. In the second case, a 72-year-old woman underwent open reduction and internal fixation of an olecranon fracture. Bone union was delayed 4 months after surgery; therefore, weekly teriparatide (56.5 mg) injections were started. RESULTS: The initiation of bone union was slightly evident within 4 weeks, and complete healing was achieved 4 months after the first teriparatide injection. In both cases, no serious teriparatide-related adverse effects were observed. CONCLUSION: Weekly teriparatide administration was effective for bone healing and useful for delayed union; moreover, the effect of this therapy showed within 4 weeks. PMID- 24777527 TI - Microfluidic investigation of the deposition of asphaltenes in porous media. AB - The deposition of asphaltenes in porous media, an important problem in science and macromolecular engineering, was for the first time investigated in a transparent packed-bed microreactor (MUPBR) with online analytics to generate high-throughput information. Residence time distributions of the MUPBR before and after loading with ~29 MUm quartz particles were measured using inline UV-Vis spectroscopy. Stable packings of quartz particles with porosity of ~40% and permeability of ~500 mD were obtained. The presence of the packing materials reduced dispersion under the same velocity via estimation of dispersion coefficients and the Bodenstein number. Reynolds number was observed to influence the asphaltene deposition mechanism. For larger Reynolds numbers, mechanical entrapment likely resulted in significant pressure drops for less pore volumes injected and less mass of asphaltenes being retained under the same maximum dimensionless pressure drop. The innovation of packed-bed microfluidics for investigations on asphaltene deposition mechanisms could contribute to society by bridging macromolecular science with microsystems. PMID- 24777528 TI - Molecular characterization of circulating pandemic strains of influenza A virus during 2012 to 2013 in Lucknow (India). AB - The pandemic H1N1 strain of Influenza A virus [A(H1N1)pdm09] is now well adapted in human populations. However, it is still causing sporadic outbreaks worldwide with different severity. The present study was planned to understand the genetic diversity (based on the HA1 gene) of influenza A(H1N1)pdm09 strains circulating during the post pandemic period. The HA1 gene was selected because the HA1 protein is immunogenic, functions as a receptor binding site and indirectly affects transmission and pathogenicity of virus. A total of 2,818 cases were enrolled. Nasal/throat swabs from all cases were tested by one-step real time PCR for detection of influenza virus types and subtypes according to the CDC protocol. Of these, 134 cases were A(H1N1)pdm09 positive, 34 of which were screened for HA1 gene (position 434-905) sequencing (Big-Dye terminator using 3130 ABI, Genetic analyzer). Molecular and phylogenetic analysis was performed using PhyML approach (v. 3.0). All A(H1N1)pdm09 positive and negative cases were clinically characterized. Phylogentically, all Lucknow strains (n = 33) except one fall with the clade seven reference strain. One strain showed 99.9% similarities with clade one reference strain A/California/07/2009. In mutational analysis, 33 strains had the S220T mutation, which is at an antigenic site and characteristic of clade seven along with few minor mutations; K180I/T/Q, V190I, S200P, S202T, A203T, A214T, S220T, V251I, and A273T. These results suggest that clade seven was the most widely circulating clade in Lucknow and A(H1N1)pdm09 cases showed mild clinical symptoms as compared to A(H3N2) or influenza B cases. PMID- 24777529 TI - Assessment technique for acne treatments based on statistical parameters of skin thermal images. AB - Acne vulgaris as an inflammatory disease, with an excessive production of subdermal fat, modifies the dynamics of the bloodstream, and consequently temperature, on the affected skin zone. A high percentage of this heat interchange is manifested as electromagnetic radiation with far-infrared wavelengths, which can be captured through a thermal imaging camera. A technique based on thermal image analysis for efficiency assessment in acne vulgaris is described. The procedure is based on computing statistical parameters of thermal images captured from the affected skin zone being attended by an acne treatment. The proposed technique was used to determine the skin thermal behavior according to acne severity levels in different acne treatment stages. Infrared images of acne skin zones on eight patients, diagnosed with acne vulgaris and attended by one specific acne treatment, were weekly registered during 11 weeks. The infrared images were captured until no more improvement in affected zones was detected. The obtained results suggest a direct relationship between the used statistical parameters, particularly first- and second-order statistics, and the acne vulgaris severity level on the affected zones. PMID- 24777530 TI - Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1beta production. AB - Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1beta (IL-1beta) as an antiviral host response, and deregulation of the pathways involved can promote inflammatory disease. Here we report a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune system adaptor CARD9. Transfection of dendritic cells with dsDNA or infection of dendritic cells with a DNA virus induced the formation of dsDNA-Rad50-CARD9 signaling complexes for activation of the transcription factor NF-kappaB and the generation of pro-IL-1beta. Primary cells conditionally deficient in Rad50 or lacking CARD9 consequently exhibited defective DNA-induced production of IL 1beta, and Card9(-/-) mice had impaired inflammatory responses after infection with a DNA virus in vivo. Our results define a cytosolic DNA-recognition pathway for inflammation and a physical and functional connection between a conserved DNA damage sensor and the innate immune response to pathogens. PMID- 24777531 TI - USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. AB - Deubiquitinases (DUBs) are a new class of drug targets, although the physiological function of only few DUBs has been characterized. Here we identified the DUB USP15 as a crucial negative regulator of T cell activation. USP15 stabilized the E3 ubiquitin ligase MDM2, which in turn negatively regulated T cell activation by targeting the degradation of the transcription factor NFATc2. USP15 deficiency promoted T cell activation in vitro and enhanced T cell responses to bacterial infection and tumor challenge in vivo. USP15 also stabilized MDM2 in cancer cells and regulated p53 function and cancer-cell survival. Our results suggest that inhibition of USP15 may both induce tumor cell apoptosis and boost antitumor T cell responses. PMID- 24777532 TI - The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. AB - Intestinal regulatory T cells (Treg cells) are necessary for the suppression of excessive immune responses to commensal bacteria. However, the molecular machinery that controls the homeostasis of intestinal Treg cells has remained largely unknown. Here we report that colonization of germ-free mice with gut microbiota upregulated expression of the DNA-methylation adaptor Uhrf1 in Treg cells. Mice with T cell-specific deficiency in Uhrf1 (Uhrf1(fl/fl)Cd4-Cre mice) showed defective proliferation and functional maturation of colonic Treg cells. Uhrf1 deficiency resulted in derepression of the gene (Cdkn1a) that encodes the cyclin-dependent kinase inhibitor p21 due to hypomethylation of its promoter region, which resulted in cell-cycle arrest of Treg cells. As a consequence, Uhrf1(fl/fl)Cd4-Cre mice spontaneously developed severe colitis. Thus, Uhrf1 dependent epigenetic silencing of Cdkn1a was required for the maintenance of gut immunological homeostasis. This mechanism enforces symbiotic host-microbe interactions without an inflammatory response. PMID- 24777534 TI - Washing red cells after leucodepletion does not decrease human leukocyte antigen sensitization risk in patients with chronic kidney disease. AB - BACKGROUND: Standard leucodepleted blood transfusions can induce the production of human leukocyte antigen (HLA)-specific antibodies, which are associated with longer transplant waiting times and poorer graft outcomes. We hypothesized that additional washing of leucodepleted red cells might reduce antigenic stimulus by removal of residual leukocytes and soluble HLA. METHODS: A retrospective review of HLA antibodies in children with chronic kidney disease stage 4-5 who had >= two HLA antibody screens between 2000 and 2009, pre- and post-transfusion, and were HLA antibody-negative at first testing. Patients were divided according to whether they received standard leucodepleted blood or "washed cells". To assess the efficacy of washing methods, total leukocytes were enumerated pre- and post- manual and automated washing of standard leucodepleted red cells that had been supplemented with whole blood to achieve measurable leukocyte levels pre-washing. RESULTS: A total of 106 children were included: 23 received no blood transfusions (group 1), six had washed cells only (group 2), 59 had standard transfusions only (group 3), and 18 had both standard and washed cells (group 4). Sensitization rates were 26, 17, 44, and 44 % in groups 1-4 (p = 0.32). Patients in groups 3 and 4 had more transfusions with red cells, platelets, and plasma products. There was no difference in HLA sensitization risk with washed or standard red cells on analysis of co-variance controlling for platelets and plasma transfusions. The red cell washing study showed no significant reduction in leukocytes using manual methods. Although there was a statistically significant reduction (33 %) from baseline pre-washing using the automated method, from 6.54 +/- 0.84 * 10(6) to 4.36 +/- 0.67 * 10(6) leukocytes per unit, the majority of leukocytes still remained. CONCLUSIONS: There was no evidence that using washed leucodepleted red cells reduced patient HLA sensitization rates. Washing leucodepleted red cells is unlikely to reduce the risk of HLA sensitization due to the limited effect on residual leukocytes. PMID- 24777535 TI - Slit2-Robo signaling in inflammation and kidney injury. AB - Acute kidney injury is an increasingly common global health problem and is associated with severe morbidity and mortality. In addition to facing high mortality rates, the survivors of acute kidney injury are at increased risk of developing chronic kidney disease and end-stage renal disease. Renal ischemia reperfusion injury (IRI) is the most common cause of acute kidney injury, and results from impaired delivery of oxygen and nutrients to the kidney. Massive leukocyte influx into the post-ischemic kidney is one of the hallmarks of IRI. The recruited leukocytes exacerbate tissue damage and, if uncontrolled, initiate the progressive changes that lead to renal fibrosis and chronic kidney disease. Early on, recruitment and activation of platelets promotes microthrombosis in the injured kidney, further exacerbating kidney damage. The diversity, complexity, and multiplicity of pathways involved in leukocyte recruitment and platelet activation make it extremely challenging to control these processes, and past efforts have met with limited success in human trials. A generalized strategy to inhibit infiltration of inflammatory leukocytes and platelets, thereby reducing inflammation and injury, may prove to be more beneficial. In this review, we summarize recent findings demonstrating that the neuronal guidance cues, Slit and Roundabout (Robo), prevent the migration of multiple leukocyte subsets towards diverse inflammatory chemoattractants, and have potent anti-platelet functions in vitro and in vivo. These properties uniquely position Slit2 as a novel therapeutic that could be used to prevent acute kidney injury associated with IRI. PMID- 24777536 TI - A synthesis of methane emissions from 71 northern, temperate, and subtropical wetlands. AB - Wetlands are the largest natural source of atmospheric methane. Here, we assess controls on methane flux using a database of approximately 19 000 instantaneous measurements from 71 wetland sites located across subtropical, temperate, and northern high latitude regions. Our analyses confirm general controls on wetland methane emissions from soil temperature, water table, and vegetation, but also show that these relationships are modified depending on wetland type (bog, fen, or swamp), region (subarctic to temperate), and disturbance. Fen methane flux was more sensitive to vegetation and less sensitive to temperature than bog or swamp fluxes. The optimal water table for methane flux was consistently below the peat surface in bogs, close to the peat surface in poor fens, and above the peat surface in rich fens. However, the largest flux in bogs occurred when dry 30-day averaged antecedent conditions were followed by wet conditions, while in fens and swamps, the largest flux occurred when both 30-day averaged antecedent and current conditions were wet. Drained wetlands exhibited distinct characteristics, e.g. the absence of large flux following wet and warm conditions, suggesting that the same functional relationships between methane flux and environmental conditions cannot be used across pristine and disturbed wetlands. Together, our results suggest that water table and temperature are dominant controls on methane flux in pristine bogs and swamps, while other processes, such as vascular transport in pristine fens, have the potential to partially override the effect of these controls in other wetland types. Because wetland types vary in methane emissions and have distinct controls, these ecosystems need to be considered separately to yield reliable estimates of global wetland methane release. PMID- 24777537 TI - Lipoic acid biosynthesis defects. AB - Lipoate is a covalently bound cofactor essential for five redox reactions in humans: in four 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). Two enzymes are from the energy metabolism, alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase; and three are from the amino acid metabolism, branched chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase, and the GCS. All these enzymes consist of multiple subunits and share a similar architecture. Lipoate synthesis in mitochondria involves mitochondrial fatty acid synthesis up to octanoyl-acyl-carrier protein; and three lipoate-specific steps, including octanoic acid transfer to glycine cleavage H protein by lipoyl(octanoyl) transferase 2 (putative) (LIPT2), lipoate synthesis by lipoic acid synthetase (LIAS), and lipoate transfer by lipoyltransferase 1 (LIPT1), which is necessary to lipoylate the E2 subunits of the 2-oxoacid dehydrogenases. The reduced form dihydrolipoate is reactivated by dihydrolipoyl dehydrogenase (DLD). Mutations in LIAS have been identified that result in a variant form of nonketotic hyperglycinemia with early-onset convulsions combined with a defect in mitochondrial energy metabolism with encephalopathy and cardiomyopathy. LIPT1 deficiency spares the GCS, and resulted in a combined 2-oxoacid dehydrogenase deficiency and early death in one patient and in a less severely affected individual with a Leigh-like phenotype. As LIAS is an iron-sulphur-cluster dependent enzyme, a number of recently identified defects in mitochondrial iron sulphur cluster synthesis, including NFU1, BOLA3, IBA57, GLRX5 presented with deficiency of LIAS and a LIAS-like phenotype. As in DLD deficiency, a broader clinical spectrum can be anticipated for lipoate synthesis defects depending on which of the affected enzymes is most rate limiting. PMID- 24777538 TI - Comparing approaches to expose type C fractures of the distal humerus for ORIF in elderly patients: six years clinical experience with both the triceps-sparing approach and olecranon osteotomy. AB - BACKGROUND: Although open reduction and internal fixation (ORIF) is a standard fracture treatment method, the optimal way to expose a fracture prior to ORIF is debated. We compared the effects of two exposure methods, the triceps-sparing approach and olecranon osteotomy, on the functional outcomes of ORIF-treated type C distal humerus fractures in elderly people. METHODS: From January 2006 to January 2011, 75 elderly patients with type C distal humerus fractures were treated with ORIF, and we retrospectively reviewed their medical records, radiographs, and follow-up charts to identify any complications. Patients' Mayo Elbow Performance Score (MEPS) and range of motion were determined at their final clinic visit. RESULTS: Sixty-seven patients (89 %) attended the final visit. Of these patients, 36 received olecranon osteotomy and 31 received the triceps sparing approach. For patients with type C1 and C2 fractures, we observed reductions in procedure times, blood loss, complication rates, and MEPS outcomes (all P < 0.01) with the triceps-sparing approach compared with olecranon osteotomy. Except for MEPS outcomes, all of these approach-related improvements were also statistically significantly for type C3 fractures (all P < 0.01). Overall, we did not observe any cases of fracture nonunion, implantation breakage or loosening, or elbow stiffening in our series. CONCLUSIONS: In our study, we found better functional outcomes for type C1 and C2 distal humerus fractures that were exposed using the triceps-sparing approach rather than olecranon osteotomy. Even for the most complex type of fracture, C3 fractures, similar recoveries in elbow function were achieved using either approach. LEVEL OF EVIDENCE: Level III. PMID- 24777539 TI - Feasibility of arthroscopic 3-dimensional, purely autologous chondrocyte transplantation for chondral defects of the hip: a case series. AB - INTRODUCTION: The purpose of this retrospective study was to describe technical aspects of arthroscopic, purely autologous chondrocyte transplantation of the hip and to report short-term data of the postoperative outcome in a consecutive series of patients. MATERIALS AND METHODS: We retrospectively analyzed six patients with a full-thickness chondral defect of the hip joint. The defect was treated with an arthroscopically applicable 3-dimensional purely autologous chondrocyte transplant product (chondrosphere((r)); co.don((r)) AG, Berlin, Germany) in a two-step surgical procedure. Patient-administered scores were assessed at baseline (day before transplantation) and at 6 weeks, 3, 6 and 12 months. RESULTS: Six out of six initially included patients (five males, one female) with a median age of 32.5 years and an average defect size of 3.5 cm(2) were available for follow-up after a mean of 11.2 months. Five acetabular and one femoral defect were treated. An overall statistically significant improvement was observed for all assessment scores (NHS, mHHS and SF 36). CONCLUSION: In this study, we displayed the feasibility and technical aspects of arthroscopic matrix associated, purely autologous chondrocyte transplantation as a treatment option for full-thickness cartilage defects of the hip. The patient-administered assessment scores demonstrated an increase in activity level and quality of life after a 1-year follow-up. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 24777541 TI - The value of oblique pinhole images in pre-operative localisation with (99m)Tc MIBI for primary hyperparathyroidism. AB - Technetium-99m labelled 2-methoxyisobutylisonitrile (MIBI) has been extensively utilised for pre-operative localisation of parathyroid adenomas. Imaging techniques have varied widely, with many centres not performing routine oblique images; thus this study aimed to examine the value of routine oblique pinhole imaging. Ninety-two patients underwent pre-operative (99m)Tc-MIBI imaging including early and delayed anterior oblique pinhole images in addition to standard anterior pinhole images and a thyroid study prior to surgery for primary hyperparathyroidism. These studies were reviewed blindly comparing anterior and oblique images and anterior images only in relation to surgical findings. Of the 92 patients, 83 were found to have 86 parathyroid adenomas or parathyroid adenoma/hyperplasia at surgery. When compared to anterior images only, oblique views improved overall sensitivity from 76% to 88% (P<0.05), correctly localised 11 more adenomas than anterior images alone (13%) and improved the confidence of interpretation in 17 patients (20%). In conclusion, routine oblique pinhole views result in greater sensitivity and reporter confidence in pre-operative parathyroid localisation with (99m)Tc-MIBI. PMID- 24777540 TI - Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. AB - BACKGROUND: A promising approach to the treatment of chronic ischaemic heart disease (IHD) and heart failure is the use of stem cells. The last decade has seen a plethora of randomised controlled trials (RCTs) developed worldwide which have generated conflicting results. OBJECTIVES: The critical evaluation of clinical evidence on the safety and efficacy of autologous adult bone marrow derived stem cells (BMSC) as a treatment for chronic ischaemic heart disease (IHD) and heart failure. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 3), MEDLINE (from 1950), EMBASE (from 1974), CINAHL (from 1982) and the Transfusion Evidence Library (from 1980), together with ongoing trial databases, for relevant trials up to 31st March 2013. SELECTION CRITERIA: Eligible studies included RCTs comparing autologous adult stem/progenitor cells with no autologous stem/progenitor cells in participants with chronic IHD and heart failure. Co interventions such as primary angioplasty, surgery or administration of stem cell mobilising agents, were included where administered to treatment and control arms equally. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all references for eligibility, assessed trial quality and extracted data. We undertook a quantitative evaluation of data using fixed-effect meta-analyses. We evaluated heterogeneity using the I2 statistic; we explored considerable heterogeneity (I2 > 75%) using a random-effects model and subgroup analyses. MAIN RESULTS: We include 23 RCTs involving 1255 participants in this review. Risk of bias was generally low, with the majority of studies reporting appropriate methods of randomisation and blinding, Autologous bone marrow stem cell treatment reduced the incidence of mortality (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.14 to 0.53, P = 0.0001, 8 studies, 494 participants, low quality evidence) and rehospitalisation due to heart failure (RR 0.26, 95% CI 0.07 to 0.94, P = 0.04, 2 studies, 198 participants, low quality evidence) in the long term (>=12 months). The treatment had no clear effect on mortality (RR 0.68, 95% CI 0.32 to 1.41, P = 0.30, 21 studies, 1138 participants, low quality evidence) or rehospitalisation due to heart failure (RR 0.36, 95% CI 0.12 to 1.06, P = 0.06, 4 studies, 236 participants, low quality evidence) in the short term (< 12 months), which is compatible with benefit, no difference or harm. The treatment was also associated with a reduction in left ventricular end systolic volume (LVESV) (mean difference (MD) -14.64 ml, 95% CI -20.88 ml to -8.39 ml, P < 0.00001, 3 studies, 153 participants, moderate quality evidence) and stroke volume index (MD 6.52, 95% CI 1.51 to 11.54, P = 0.01, 2 studies, 62 participants, moderate quality evidence), and an improvement in left ventricular ejection fraction (LVEF) (MD 2.62%, 95% CI 0.50% to 4.73%, P = 0.02, 6 studies, 254 participants, moderate quality evidence), all at long-term follow-up. Overall, we observed a reduction in functional class (New York Heart Association (NYHA) class) in favour of BMSC treatment during short-term follow-up (MD -0.63, 95% CI -1.08 to -0.19, P = 0.005, 11 studies, 486 participants, moderate quality evidence) and long-term follow-up (MD -0.91, 95% CI -1.38 to -0.44, P = 0.0002, 4 studies, 196 participants, moderate quality evidence), as well as a difference in Canadian Cardiovascular Society score in favour of BMSC (MD -0.81, 95% CI -1.55 to -0.07, P = 0.03, 8 studies, 379 participants, moderate quality evidence). Of 19 trials in which adverse events were reported, adverse events relating to the BMSC treatment or procedure occurred in only four individuals. No long-term adverse events were reported. Subgroup analyses conducted for outcomes such as LVEF and NYHA class revealed that (i) route of administration, (ii) baseline LVEF, (iii) cell type, and (iv) clinical condition are important factors that may influence treatment effect. AUTHORS' CONCLUSIONS: This systematic review and meta-analysis found moderate quality evidence that BMSC treatment improves LVEF. Unlike in trials where BMSC were administered following acute myocardial infarction (AMI), we found some evidence for a potential beneficial clinical effect in terms of mortality and performance status in the long term (after at least one year) in people who suffer from chronic IHD and heart failure, although the quality of evidence was low. PMID- 24777542 TI - In vivo evaluation of (111)In-DTPA-N-TIMP-2 in Kaposi sarcoma associated with HIV infection. AB - Matrix metalloproteinases are the major agents responsible for the degradation of extracellular matrix and are produced at high levels by transformed and tumour cells, where they participate in the metastatic process by allowing local invasion. They are also more active at sites of new normal growth and angiogenesis. In the early stages of Kaposi sarcoma (KS), in vitro studies have demonstrated that vascular invasion can be inhibited by inhibitors of matrix metalloproteinases. Imaging of visceral and cutaneous KS presents a problem and therefore the potential use of a labelled inhibitor of metalloproteinases, N-TIMP 2, with indium-111 was thought to present a possible imaging tool. The biokinetics, dosimetry and potential for imaging with (111)In-DTPA-N-TIMP-2 were assessed in five patients with HIV infection and KS. Between 103.1 and 108.0 MBq of this agent was injected into each patient, and the dynamic uptake over the kidneys was assessed, whole body scans were performed and blood samples were obtained. The clearance from the blood was rapid, with a first component half time of 16.6+/-3.4 min and a second component half-time of 9.68+/-2.68 h. Two out of five patients experienced minor shivering but one of these patients was generally unwell before the study. The last three patients had no such problems. The tracer distributed predominantly to the kidneys and did not localise in other tissues. No KS lesions were clearly identified. (111)In-DTPA-N-TIMP-2 can be successfully prepared and administered to patients safely, with a biodistribution and dosimetry which would allow its use as an imaging tracer. It is unlikely to be of use for imaging KS, but may have a role in other tumours that produce matrix metalloproteinases. PMID- 24777543 TI - The clinical value of (18)F-FDG detection with a dual-head coincidence camera: a review. AB - Positron emission tomography (PET) has evolved into a technique that can accurately determine the distribution of positron-emitting radionuclides. The addition of a coincidence detection mode to a standard dual-head detector system has resulted in the option of single-photon and annihilation coincidence detection. This new device for imaging fluorine-18 2-fluoro-2-deoxy-D-glucose ((18)F-FDG) accumulation in neoplasms became commercially available in 1994. Besides conventional low-energy imaging in the collimated single-photon mode, it offers a relatively inexpensive opportunity to perform uncollimated PET by switching to the coincidence acquisition mode. This review summarises the clinical value of (18)F-FDG detection with a dual-head coincidence camera in oncology. The results are compared with the overall results obtained using dedicated PET scanners. With respect to head and neck tumours, (18)F-FDG coincidence mode gamma camera imaging (CGI) yields results that are in agreement with those obtained with dedicated PET scanners. With regard to other malignancies, such as lung cancer, lymphoma and brain tumours, data in the literature are too scarce to draw any definite conclusions. In general, the results of (18)F-FDG CGI in tumours >15 mm seem to be comparable to those obtained with dedicated PET scanners, whereas in tumours <15 mm, the relative sensitivity of (18)F-FDG CGI is approximately 80%. Using attenuation correction, the diagnostic yield of (18)F-FDG CGI may increase. However, further clinical investigation is required to definitely establish its value in staging primary disease, therapy monitoring and assessment of tumour recurrence in clinical oncology. PMID- 24777544 TI - Reply. PMID- 24777545 TI - Trans-anethole protects cortical neuronal cells against oxygen-glucose deprivation/reoxygenation. AB - Trans-anethole has been studied on pharmacological properties such as anti inflammation, anti-oxidative stress, antifungal and anticancer. However, to date, the anti-ischemic effects of trans-anethole have not been assessed. Therefore, we investigated the neuroprotection of trans-anethole against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced cortical neuronal cell injury, an in vitro model of ischemia. The abilities of trans-anethole to block excitotoxicity, oxidative stress and mitochondrial dysfunction were evaluated in OGD/R-induced neurons. Trans-anethole significantly ameliorated OGD/R-induced neuronal cell injury by attenuating the intracellular calcium overload via the activation of NMDA receptors. Trans-anethole also inhibited OGD/R-induced reactive oxygen species overproduction, which may be derived from the scavenging activity in peroxyl radicals, assessed in an oxygen radical absorbance capacity assay. Furthermore, trans-anethole was shown to attenuate the depolarization of mitochondrial transmembrane. These results indicated that the neuroprotective effect of trans-anethole on OGD/R-induced neuronal injury might be due to its ability to inhibit excitotoxicity, oxidative stress and mitochondrial dysfunction. Considering these multiple pathways causing ischemic neuronal damage, the multi-functional effect of trans-anethole suggested that it may be effective in treating ischemic stroke. PMID- 24777546 TI - Diabetes and the brain: issues and unmet needs. AB - Diabetes mellitus (DM) is associated with an increased risk of mild cognitive impairment, dementia and stroke. The association between DM and dementia appears to be stronger for vascular cognitive impairment than for Alzheimer's disease, suggesting cerebrovascular disease may be an important factor in cognitive impairment in DM. Although the exact mechanisms by which DM affects the brain remain unclear, changes to brain vasculature, disturbances of cerebral insulin signaling, insulin resistance, glucose toxicity, oxidative stress, accumulation of advanced glycation end products, hypoglycemic episodes, and alterations in amyloid metabolism may all be involved. Cognitive impairment and dementia associated with DM may also be mediated via vascular risk factors, in particular brain ischemia, the occurrence of which can have an additive or synergistic effect with concomitant neurodegenerative processes. To date, no drug has been approved for the treatment of vascular dementia and there are no specific pharmacological treatments for preventing or reducing cognitive decline in patients with DM. Most focus has been on tighter management of vascular risk factors, although evidence of reduced cognitive decline through reducing blood pressure, lipid-lowering or tighter glycemic control is inconclusive. Tailored, multimodal therapies may be required to reduce the risk of cognitive dysfunction and decline in patients with DM. The use of pleiotropic drugs with multimodal mechanisms of action (e.g., cerebrolysin, Actovegin) may have a role in the treatment of cognitive dysfunction and their use may warrant further investigation in diabetic populations. PMID- 24777547 TI - Vitamin A and amygdala: functional and morphological consequences. AB - Intake of vitamin A is essential for correct embryonic development of the central nervous system (CNS). Its increased intake during gravidity can cause various malformations and dysfunctions of the CNS. In our work, we intended to investigate the effect of vitamin A on emotional behavior and morphology of nitrergic neurons in basolateral nucleus of the rat amygdala. For this purpose, we have administered retinoic acid (RA), a metabolite of vitamin A, to females on 14-16 days of pregnancy at a dose 1 mg RA/kg body weight. Adult progeny of these mothers were tested in elevated plus maze test, the most widely used test for measuring anxiety-like behavior. After the test, brains of the rats were processed for reduced nicotinamide adenine dinucleotide phosphate diaphorase histochemistry, which is commonly used to mark cells containing nitric oxide synthase. Our results have shown that RA applied during the sensitive phase of intrauterine development influences emotional behavior of adult rats. Animals exposed to RA had increased levels of fear and anxiety, which has been manifested by reducing the time spent in the open arms of plus maze test. Interestingly, detected behavioral changes do not correlate with the result of our morphological study. The number and morphology of nitrergic neurons in amygdala were very similar in experimental and control rats. Our results demonstrate that prenatal exposure to RA has no effect on morphological structure of amygdala, but influences its function. PMID- 24777548 TI - Cerebellar degeneration-related autoantigen 1 (CDR1) gene expression in Alzheimer's disease. PMID- 24777549 TI - Accuracy of fine needle aspiration and core lung biopsies to predict histology in patients with non-small cell lung cancer. AB - Management of advanced non-small cell lung cancer patients is dependent on the histologic diagnosis for both testing and treatment. This study was designed to determine the ability of fine needle aspiration and core biopsies to correctly determine histologic diagnosis in non-small cell lung cancer. Our institutional cardiothoracic surgery database was reviewed for cases of non-small cell lung cancer treated with lobectomy after a preoperative biopsy by CT guidance or bronchoscopy over a 10-year period from 2002 to 2011. The histologic diagnosis of the final lobectomy specimen was compared to the histologic diagnosis from the preoperative biopsy, and the concordance rate was calculated. 119 biopsy specimens from 117 patients were reviewed. Eighty of the 119 biopsies had the same histologic diagnosis as the lobectomy specimen, yielding an overall concordance rate of 67.2 %. Patients with poorly differentiated tumors were at the highest risk of an incorrect histologic diagnosis on preoperative biopsy. Reliance on fine needle aspiration and core biopsies to determine histologic diagnosis in non-small cell lung cancer may put some patients at risk for suboptimal treatment. PMID- 24777550 TI - The utilization and choices of aneuploidy screening in a midwestern population. AB - The types, interpretation, and use of first- and second-trimester aneuploidy screening are often unclear for many women. This impairs appropriate decision making and understanding of the implications of prenatal genetic testing options. The purpose of this study was to examine the utilization of Stepwise Sequential screening in our Midwestern population, demographic factors associated with choice of screening and method of risk reporting and it's potential impact on women's choices. First trimester screening was performed for 2,634 women during the study period. Results were not reported or "framed" as "positive" or "negative". Rather, the specific age-risk and screen-risk for T21 were relayed, along with options for follow-up Stepwise Sequential screening and invasive testing. Nearly 80 % of women declined Stepwise Sequential screening. Minorities and women of lower education were least likely to pursue further screening. Less than 4 % of the study population elected invasive testing. First trimester screening was associated with a 53 % reduction in amniocenteses and 20 % fewer CVS's compared to pre-first trimester screening availability. Reporting age-and screen-risks for T21, rather than classifying results as "positive" or "negative" based on a pre-determined threshold, was associated with a low uptake of further testing. PMID- 24777551 TI - Maternal uniparental isodisomy causing autosomal recessive GM1 gangliosidosis: a clinical report. AB - Uniparental disomy is a genetic cause of disease that may result in the inheritance of an autosomal recessive condition. A child with developmental delay and hypotonia was seen and found to have severely abnormal myelination. Lysosomal enzyme testing identified an isolated deficiency of beta-galactosidase. Subsequently, homozygous missense mutations in the galactosidase, beta 1 (GLB1) gene on chromosome 3 were found. Parental testing confirmed inheritance of two copies of the same mutated maternal GLB1 gene, and no paternal copy. SNP analysis was also done to confirm paternity. The patient was ultimately diagnosed with autosomal recessive GM1 gangliosidosis caused by maternal uniparental isodisomy. We provide a review of this patient and others in which uniparental disomy (UPD) of a non-imprinted chromosome unexpectedly caused an autosomal recessive condition. This is the first case of GM1 gangliosidosis reported in the literature to have been caused by UPD. It is important for genetic counselors and other health care providers to be aware of the possibility of autosomal recessive disease caused by UPD. UPD as a cause of autosomal recessive disease drastically changes the recurrence risk for families, and discussions surrounding UPD can be complex. Working with families to understand UPD when it occurs requires a secure and trusting counselor-family relationship. PMID- 24777552 TI - Disclosure of genetic research results to members of a founder population. AB - There is currently extensive discussion and debate in the literature on how, when, and to whom genetic research results should be returned (see Genetics in Medicine, April 2012 issue). Here, we describe our experience in disclosing genetic information on Mendelian disorders discovered during the course of our research in the Hutterites. We first assessed attitudes toward the disclosure of carrier results, which revealed that many individuals wanted carrier information and that many intended to use the information in family planning. Based on this information, we developed a pilot study to test and disclose cystic fibrosis (CF) carrier status. Next, a larger scale project was developed in order to disclose genetic research results for 14 diseases to those interested in receiving the information. We developed brochures, offered a live interactive educational program, conducted a consent process, and disclosed results in letters mailed to the consented individuals. Overall, ~80% of individuals who participated in the educational program signed consent forms for the release of their results for 14 diseases. We describe our experience with returning individual genetic research results to participants in a population-based research study. PMID- 24777554 TI - Mitochondrial DNA mutations and cognition: a case-series report. AB - Mutations in the mitochondrial genome can impair normal metabolic function in the central nervous system (CNS) where cellular energy demand is high. Primary mitochondrial DNA (mtDNA) mutations have been linked to several mitochondrial disorders that have comorbid psychiatric, neurologic, and cognitive sequelae. Here, we present a series of cases with primary mtDNA mutations who were genotyped and evaluated across a common neuropsychological battery. Nineteen patients with mtDNA mutations were genotyped and clinically and cognitively evaluated. Pronounced deficits in nonverbal/visuoperceptual reasoning, verbal recall, semantic word generativity, and processing speed were evident and consistent with a "mitochondrial dementia" that has been posited. However, variation in cognitive performance was noteworthy, suggesting that the phenotypic landscape of cognition linked to primary mtDNA mutations is heterogeneous. Our patients with mtDNA mutations evidenced cognitive deficits quite similar to those commonly seen in Alzheimer's disease and could have clinical relevance to the evaluation of dementia. PMID- 24777553 TI - Amino acid polymorphism in the reverse transcriptase region of hepatitis B virus and the relationship with nucleos(t)ide analogues treatment for preventing mother to-infant transmission. AB - A high maternal serum hepatitis B virus (HBV) DNA level is associated with vaccine failure. The administration of nucleos(t)ide analogues (NAs) in pregnancy for decreasing serum HBV is regarded as an effective and safe method to reduce HBV perinatal transmission. However, the effect of NAs treatment is closely related to amino acid polymorphisms in the HBV reverse transcriptase (RT) region. The full-length RT coding region of 334 HBV isolates from untreated Chinese women of childbearing age with persistent HBV infection were sequenced and amino acid polymorphic analysis was performed to evaluate its impact on NAs treatment for decreasing HBV perinatal transmission. Of the 334 isolates, 36 (10.8%) harbored NAs resistance (NAr) mutations which were mainly putative drug mutations related to lamivudine. The primary drug mutation rtA181T/V was detected in three HBeAg negative women with an HBV DNA level of <4 log IU/ml. These NAr mutations were rarely detected in women with an HBV DNA level of >=7 log IU/ml (P = 0.014) or in women younger than 35 years (P = 0.001). The NAr mutation rate among young women (<35 years) who had a high HBV DNA level (>=7 log IU/ml) was significantly lower than in women who had lower HBV DNA levels (<7 log IU/ml) or who were older (>=35 years; P = 0.017). These results suggest that younger women with a high HBV DNA level harbor fewer NAr mutations and that this population may respond to NAs treatment for the prevention of mother-to-infant transmission. PMID- 24777555 TI - [Fat prolapse following trauma to the bulb and orbit?]. PMID- 24777556 TI - [Results of dacryocystorhinostomy according to Toti from 2000 to 2012]. AB - BACKGROUND: The aim of this study was to describe the efficiency, long-term success, patient satisfaction and recurrence rate after dacryocystorhinostomy according to Toti in a retrospective analysis. MATERIAL AND METHODS: At the Eye Clinic of the Paracelsus Medical University Salzburg 188 eyes of 176 patients with stenosis/obstruction of lacrimal duct were surgically treated between January 2000 and December 2012. Of these patients 173 eyes had no surgery before DCR according to Toti and 15 eyes had already been operated with diverse dacryocystorhinostomies. All patients underwent dacryocystorhinostomy according to Toti. Pre- and postoperative clinical finings were analysed retrospectively. Postoperative long-term results regarding patient satisfaction, absence of inflammation, epiphora and annoyance through local scar building had been evaluated with a questionnaire in a cross-sectional analysis. RESULTS: The primary success rate of DCR according to Toti was 91,9 % and the secondary success rate 98,3 % in patients without surgery preoperatively. Classifying by localisation of stenosis, better results could be reached in patients with postsaccal stenosis/obstructions (94,3 %) than in those with presaccal obstructions (77,8 %) or with mixed pre- and postsaccal stenosis/obstructions (86,7 %). Also in the patient group with previous surgery primary and secondary success rates of 93,3 % could be achieved after DCR according to Toti. CONCLUSIONS: This study confirms that DCR according to Toti is a highly successful technique minimising epiphora and discomfort. The best success rate was found in patients with postsaccal stenosis/obstructions. The local scar was not found to be disturbing. PMID- 24777557 TI - One medicine--one health--one biology and many proteins: proteomics on the verge of the One Health approach. AB - Starting from Hippocrates, at the Age of Pericles, the One Health initiative takes inspiration from the Greek father of medicine and is based on his approach which recognizes that human health, animal health and environmental health are part of a whole body. Chiron, the wisest of all centaurs, is the classical mythological representation of an integrated view between man and the environment. Thus, he is the tangible example of the Hippocratic dyad where healthcare is achieved by the integration of man with nature. As a mythological Chiron in modern systems medicine, the integrated body of evidence in proteomics investigations is providing key molecular and analytical knowledge to achieve an evidence based approach. Hereafter we introduce some examples published in this themed proteomics issue. PMID- 24777558 TI - Using next-generation sequencing to detect mutations endowing resistance to pesticides: application to acetolactate-synthase (ALS)-based resistance in barnyard grass, a polyploid grass weed. AB - BACKGROUND: Next-generation sequencing (NGS) technologies offer tremendous possibilities for accurate detection of mutations endowing pesticide resistance, yet their use for this purpose has not emerged in crop protection. This study aims at promoting NGS use for pesticide resistance diagnosis. It describes a simple procedure accessible to virtually any scientist and implementing freely accessible programs for the analysis of NGS data. RESULTS: Three PCR amplicons encompassing seven codons of the acetolactate-synthase gene crucial for herbicide resistance were sequenced using non-quantified pools of crude DNA extracts from 40 plants in each of 28 field populations of barnyard grass, a polyploid weed. A total of 63,959 quality NGS sequence runs were obtained using the 454 technology. Three herbicide-resistance-endowing mutations (Pro-197-Ser, Pro-197-Leu and/or Trp-574-Leu) were identified in seven populations. The NGS results were confirmed by individual plant Sanger sequencing. CONCLUSION: This work demonstrated the feasibility of NGS-based detection of pesticide resistance, and the advantages of NGS compared with other molecular biology techniques for analysing large numbers of individuals. NGS-based resistance diagnosis has the potential to play a substantial role in monitoring resistance, maintaining pesticide efficacy and optimising pesticide applications. PMID- 24777559 TI - Image reconstruction in k-space from MR data encoded with ambiguous gradient fields. AB - PURPOSE: In this work, the limits of image reconstruction in k-space are explored when non-bijective gradient fields are used for spatial encoding. THEORY: The image space analogy between parallel imaging and imaging with non-bijective encoding fields is partially broken in k-space. As a consequence, it is hypothesized and proven that ambiguities can only be resolved partially in k space, and not completely as is the case in image space. METHODS: Image-space and k-space based reconstruction algorithms for multi-channel radiofrequency data acquisitions are programmed and tested using numerical simulations as well as in vivo measurement data. RESULTS: The hypothesis is verified based on an analysis of reconstructed images. It is found that non-bijective gradient fields have the effect that densely sampled autocalibration data, used for k-space reconstruction, provide less information than a separate scan of the receiver coil sensitivity maps, used for image space reconstruction. Consequently, in k space only the undersampling artifact can be unfolded, whereas in image space, it is also possible to resolve aliasing that is caused by the non-bijectivity of the gradient fields. CONCLUSION: For standard imaging, reconstruction in image space and in k-space is nearly equivalent, whereas there is a fundamental difference with practical consequences for the selection of image reconstruction algorithms when non-bijective encoding fields are involved. PMID- 24777560 TI - Does anatomy explain the origin of a leak after sleeve gastrectomy? AB - BACKGROUND: Sleeve gastrectomy is a bariatric surgical procedure that may result in particular morbidity or mortality due to gastric fistula in the proximal part of the gastric tube. Two theories are currently proposed to explain this specific leak location. The vascular theory attributes the leaks to reduced perfusion in the gastric tube, and the mechanical theory suggests the etiology as gastric tube hyper-pressure due to pyloric conservation. The aim of this study was to map the arterial gastric vascular supply on fresh cadavers after performing sleeve gastrectomy to evaluate the effect of vascular changes on gastric leakage. METHODS: We performed sleeve gastrectomies on 11 cadaveric trunks with a detailed anatomical study of the gastric vascular supply after latex injection in the three branches arising from the celiac trunk. RESULTS: In 55 % of cases, the sleeve procedure changed the gastric vascular supply. In 9.1 %, it divided the three left gastric artery branches arising from the lesser curvature. Few changes were noted in the antrum or pylorus. CONCLUSIONS: This anatomical study demonstrates that the vascular supply of the proximal part of the gastric tube can be damaged by a sleeve procedure, which can sever one or more of the branches arising from the left gastric artery. Such weakness could be exacerbated by disparities in vascular supply. The uninterrupted vascular supply of the antrum and pylorus may explain the preferential localization of the fistula to the proximal part of the gastric tube. PMID- 24777561 TI - Complete small-bowel obstruction from a migrated intra-gastric balloon: emergency laparoscopy for retrieval via enterotomy and intra-corporeal repair. AB - A 49-year-old female (weight 81 kg, height 161 cm, BMI 31.2) presented at the emergency department complaining of 2-day history of worsening cramp-like abdominal pain and vomiting. She had not passed stools or flatus in the last 36 h and reported to have had an intra-gastric balloon (BioEnterics Intra-gastric Balloon, Allergan. Inc, Irvine, Calif) inserted 9 months earlier to treat grade I obesity. The balloon was introduced during an upper endoscopy at another institution in Latin America, and she denied having any follow-up since moving to Europe. While in the E.R., an abdominal x-ray and abdominal triple contrast CT scan (with oral water-soluble contrast) showed a complete small-bowel obstruction caused by the distal migration of a foreign body. This was consistent with the intra-gastric balloon impacted in the distal jejunum. Free fluid was also evident. Emergency surgery was mandatory, and a laparoscopic approach was chosen. After identification of the cecum and ileocecal valve, the small intestine was carefully inspected starting from the distal ileum by "run-the-bowel", proximally. An evident transition point between collapsed and distended bowel loops was identified, and a clear bulging of the bowel wall caused by the deflated and impacted balloon was observed at the site. A transverse enterotomy 3.5 cm in length was performed with laparoscopic scissors, distally to the obstruction site. The balloon was gently pulled out, taking care not to tear or damage the bowel and once removed was placed within an endobag. Laparoscopic enterorrhaphy was performed with double-layer intra-corporeal suture. The postoperative course was uneventful. PMID- 24777562 TI - Inter- and intra-subject variability of neuromagnetic resting state networks. AB - Functional connectivity studies conducted at the group level using magnetoencephalography (MEG) suggest that resting state networks (RSNs) emerge from the large-scale envelope correlation structure within spontaneous oscillatory brain activity. However, little is known about the consistency of MEG RSNs at the individual level. This paper investigates the inter- and intra subject variability of three MEG RSNs (sensorimotor, auditory and visual) using seed-based source space envelope correlation analysis applied to 5 min of resting state MEG data acquired from a 306-channel whole-scalp neuromagnetometer (Elekta Oy, Helsinki, Finland) and source projected with minimum norm estimation. The main finding is that these three MEG RSNs exhibit substantial variability at the single-subject level across and within individuals, which depends on the RSN type, but can be reduced after averaging over subjects or sessions. Over- and under-estimations of true RSNs variability are respectively obtained using template seeds, which are potentially mislocated due to inter-subject variations, and a seed optimization method minimizing variability. In particular, bounds on the minimal number of subjects or sessions required to obtain highly consistent between- or within-subject averages of MEG RSNs are derived. Furthermore, MEG RSN topography positively correlates with their mean connectivity at the inter subject level. These results indicate that MEG RSNs associated with primary cortices can be robustly extracted from seed-based envelope correlation and adequate averaging. MEG thus appears to be a valid technique to compare RSNs across subjects or conditions, at least when using the current methods. PMID- 24777563 TI - Training satisfaction and work environment in Otorhinolaryngology, Head and Neck surgery: a comparison between France and Germany. AB - With the coalescing of Europe, increased mobility of professionals emerges. Initiatives to harmonize medical education were launched. In Otolaryngology, Head and Neck surgery (ORL) an European board examination was created to ensure standards. Quality of training, satisfaction and quality of life of residents and recent ORL specialists were compared to assess different aspects of work and hierarchical relationships in France (FRA) and Germany (GER) by means of an anonymous questionnaire. 120 FRA and 125 GER questionnaires were included. 78 % of respondents were residents. 86 % would choose the same training again. In both countries, a majority felt well considered with responsibilities adapted to their level of training and with supportive supervisors. Germans reported average daily work hours of 9.6 versus 11 in FRA with compensated overtime (76 %) and a possibility of part-time work (62 %), both nearly inexistent in FRA. In GER, the day-off after duty was more often respected. French attributed their seniors better pedagogic skills, taking time for explanations and providing better teaching. Offering a good training was a more important objective in French training centers (77 vs. 51 %). In both countries, surgical training relied on coaching. Research activities were comparable. The overall satisfaction with ORL training was high. Differences concerned structure of training, guidance by senior doctors and the working conditions. The study results provide guidance before choosing a program and may help to improve current training by identifying positive aspects that, if combined could lead to a convergence of programs. However, present high standards of education must be maintained. PMID- 24777564 TI - Management of embedded metallic stents used in the treatment of grades III and IV subglottic, and upper tracheal stenosis in adults. AB - The aim of this study was to evaluate the post-operative complications of using balloon-expandable metallic stents in treatment of benign, major subglottic and tracheal stenosis in adult patients whom conventional therapy has failed and to demonstrate how to deal with these complications in the long run. A retrospective review of five cases; adlut patiets with benign, major subglottic and upper tracheal stenosis whom were treated with balloon expandable metallic stents at King Abdulaziz University Hospital, in the years between 2008 and 2013. Granulation tissue formed in five of the four cases and restenosis occurred. Other complications encountered were stent infection and dislodgment. The complications were managed by removing the stents surgically via a laryngofissure incision and required the placement of a Montgomery T-tube. Managing the restenosis due to granulation tissue formation around the metallic stents is best achieved by removing the embedded metallic stents surgically via open technique and then by placement of a Montgomery T-tube as a bridging option to successful decannulation. Open surgical procedures remain the mainstay treatment for advanced airway stenosis. PMID- 24777565 TI - The utility of neck/thyromental ratio in defining low-risk patients with obstructive sleep apnea in sleep clinics. AB - We aimed to evaluate the importance of neck/thyromental distance in the diagnosis of moderate to severe obstructive sleep apnea (OSA) in sleep clinics. 185 patients (122 males, 63 females) referred to our sleep clinic with OSA symptoms were enrolled to the study. The patients had level-1 polysomnography (PSG). The neck circumference (N), thyromental distance (T), and STOP test were recorded in all patients. Using an obstructive AHI > 15 event/h on PSG as the cut-off, the best N/T ratio to find patients with OSA was calculated with the receiver operator curve analyses. The best cut-off for N/T was chosen as 4.6. We used Modified STOP test: STO-NT test in which P (for hypertension item) was replaced with N/T ratio. N/T ratio >4.6 was scored as "positive". Two positives out of four questions in STO-NT were scored as high risk for OSA. The OSA prevalence was 60 % for AHI > 15. The mean ratio of N/T was significantly different between groups with AHI > 15 and AHI <= 15. N and N/T ratio were moderately correlated with AHI. Sensitivity, specificity, negative predictive value, positive predictive value, and negative likelihood ratio of STOP test for AHI > 15 were 88.5, 28.4, 61.8, 65.4 % and 0.40, whereas 97.3, 23, 85, 65.9 % and 0.12 for STO NT test, respectively. STO-NT test seems better than STOP test in determining patients who do not likely to have moderate to severe OSA in sleep clinics so can be preferred to decide on therapies other than CPAP in a short time. PMID- 24777566 TI - Day-case septoplasty: a default pathway or is case selection the key? AB - Septoplasty has been identified as suitable for day surgery, but is not commonly performed as such. Guidelines for day surgery stipulate that the unexpected re admission rate should be 2-3 %; however previous studies have not attained this target. The purpose of this study was to ascertain the surgical and patient factors associated with re-admission following day-case septoplasty. A retrospective case-notes analysis of day-case septoplasties between 1 January 2010 and 31 December 2012 was undertaken. Data on patient demographics, surgeon grade and operative technique were examined using a univariate analysis model. A total of 256 septoplasties were performed. 23 patients were admitted, overwhelmingly due to bleeding in the immediate post-operative period, giving an overall admission rate of 9.0 % within the first 24 h. Factors associated with re admission included the use of intranasal splints (relative risk (RR) 5.34, p < 0.001), the performance of additional operative procedures (RR 4.96, p < 0.001) and surgery on patients with co-morbidities (RR 3.37, p = 0.002). There was no correlation between unexpected admission and patient gender, age, surgeon grade, performance of revision surgery and operative factors including nasal preparation with cocaine, local anaesthetic infiltration, type of incision, number of mucoperichondrial flaps raised, extensive bony dissection, performance of a turbinate procedure, quilting, closure of incision and post-operative packing. Day-case septoplasty in patients with co-morbidities and where additional surgical procedures are performed may be associated with unexpected overnight admission. Thus, safe and efficient day-case septoplasty may not be suitable as a universal default pathway but one where case selection is key. PMID- 24777567 TI - Microsystem-assisted synthesis of carbon dots with fluorescent and colorimetric properties for pH detection. AB - The present paper describes the use of a microfluidic system to synthesize carbon dots (Cdots) and their use as optical pH sensors. The synthesis is based on the thermal decomposition of ascorbic acid in dimethyl sulfoxide. The proposed microsystem is composed of a fluidic and a thermal platform, which enable proper control of synthesis variables. Uniform and monodispersed 3.3 nm-sized Cdots have been synthesized, the optical characterization of which showed their down/upconversion luminescence and colorimetric properties. The obtained Cdots have been used for pH detection with down and upconverison fluorescent properties as excitation sources. The naked eye or a photographic digital camera has also been implemented as detection systems with the hue parameter showing a linear pH range from 3.5 to 10.2. On the other hand, experiments on the cytotoxicity and permeability of the Cdots on human embryonic kidney cells revealed their adsorption on cells without causing any impact on the cellular morphology. PMID- 24777568 TI - Irreversible denaturation of proteins through aluminum-induced formation of backbone ring structures. AB - A combination of ab initio calculations, circular dichroism, nuclear magnetic resonance, and X-ray photoelectron spectroscopy has shown that aluminum ions can induce the formation of backbone ring structures in a wide range of peptides, including neurodegenerative disease related motifs. These ring structures greatly destabilize the protein and result in irreversible denaturation. This behavior benefits from the ability of aluminum ions to form chemical bonds simultaneously with the amide nitrogen and carbonyl oxygen atoms on the peptide backbone. PMID- 24777569 TI - A cleavable silica-binding affinity tag for rapid and inexpensive protein purification. AB - We describe a new affinity purification tag called Car9 that confers proteins to which it is fused micromolar affinity for unmodified silica. When appended to the C-terminus of GFPmut2 through a flexible linker, Car9 promotes efficient adsorption to silica gel and the fusion protein can be released from the particles by incubation with L-lysine. Using a silica gel column and the lysine elution approach in fast protein liquid chromatography (FPLC) mode, Car9-tagged versions of GFPmut2, mCherry and maltose binding protein (MBP) can be recovered from clarified lysates with a purity of 80-90%. Capitalizing on silica's ability to handle large pressure drops, we further show that it is possible to go from cell lysates to purified protein in less than 15 min using a fully disposable device. Finally, we demonstrate that the linker-Car9 region is susceptible to proteolysis by E. coli OmpT and take advantage of this observation to excise the C-terminal extension of GFPmut2-Car9 by incubating purified fusion protein with cells that overproduce the outer membrane protease OmpT. The set of strategies described herein, should reduce the cost of affinity purification by at least 10 fold, cut down purification times to minutes, and allow for the production of proteins with native (or nearly native) termini from their C-terminally-tagged versions. PMID- 24777570 TI - Tumor necrosis factor (TNF) inhibitors revolutionalized therapy for both psoriasis and psoriatic arthritis. Foreword. PMID- 24777571 TI - Treatment of psoriasis: focus on clinic-based management with infliximab. AB - Psoriasis is a disabling chronic inflammatory condition of the skin and joints that typically requires long-term treatment. Recommended treatments for psoriasis include a wide range of topical and systemic options, from topical agents and targeted phototherapy for mild psoriasis to traditional systemic agents such as methotrexate, cyclosporine and acitretin for more serious disease. The introduction of targeted biological agents such as T-cell-modulating agents, tumor necrosis factor alpha (TNFalpha) antagonists and interleukin (IL)-12 and IL 23 inhibitors has provided new choices for the management of psoriasis and psoriatic arthritis that may offer better long-term efficacy and tolerability than traditional approaches. Most biological agents are administered by subcutaneous injection. Infliximab, a TNFalpha antagonist, is the only biological agent approved for psoriasis that is administered by intravenous infusion, in the setting of hospital-based or specialized infusion center-based clinics. Infliximab allows weight-based dosing and may offer more rapid disease control than other biological agents, with significant improvements seen as early as 1 week after treatment initiation. This article gives an overview of psoriasis management, focusing on clinic-based infusion therapy with infliximab. PMID- 24777572 TI - Infliximab treatment of psoriasis in supervised infusion centers: case management experience. AB - Psoriasis is a systemic chronic inflammatory disease that affects 1-3% of the world's population. Knowledge of the pathogenesis of psoriasis, particularly in the understanding of the role of T cells and tumor necrosis factor alpha (TNFalpha), and advances in immunology have led to the development of biological agents, which, due to their great effectiveness, speed of response and good tolerability, have revolutionized patient management. One of these is infliximab, a human chimeric immunoglobulin G1 monoclonal antibody composed of human antibody constant regions and murine variable regions that was developed specifically to target TNFalpha. The six cases presented in this series highlight the feasibility, efficacy and safety of infliximab for psoriasis when administered in a variety of patients in several infusion centers across Spain. All six patients showed improvement in their psoriasis after the initiation of infliximab and no significant tolerability issues or injection site reactions were reported, despite the presence of several comorbid conditions or patient characteristics that traditionally reduce the efficacy of psoriasis treatments. This suggests that while the management of psoriasis patients with comorbid conditions and various unfavorable prognostic characteristics requires a multidisciplinary approach to ensure the patient obtains the best therapeutic response, infliximab is an effective and well tolerated treatment in these patients. PMID- 24777573 TI - The black and white truth about domestic violence. AB - The radiological findings of child abuse have been a focus of radiological education. Intimate partner violence (IPV) is a significant health burden; however, this is not frequently illustrated in the radiology literature. Health care providers play a crucial role in screening, treating, and preventing future acts of domestic violence. Radiologists in particular are in a unique position in cases of domestic violence, unbiased by interaction with the victim and potentially the abuser. Head and neck injuries are the most common; however, any part of the body is at risk for injury in cases of domestic violence. Fostering awareness of domestic violence and familiarizing radiologists with the most common imaging findings of IPV can help these specialists make the proper diagnosis and improve patient care. PMID- 24777574 TI - Review of outside studies by radiology residents: national survey of chief residents. AB - The purpose of this study was to establish practice patterns of radiology residents in regards to interpretation and reporting of outside studies for transferred patients. We performed a national survey of radiology residency chief residents, administered by email through the Association of Program Directors in Radiology (APDR). There were 81 chief resident respondents, representing 42.8 % of 187 total Accreditation Council for Graduate Medical Education (ACGME) approved radiology residency training programs in the USA. In 97.5 % of programs, residents perform interpretations of outside studies. Up to 76.7 % of respondents state that when outside studies are reviewed by residents, an original report is available in less than one quarter of cases. While 55.1 % of respondents state that there is a mechanism for recording their findings and impressions for outside studies, only 32.1 % are aware of a policy requiring documentation. Of the respondents, 42.3 % report they have no means for documenting their findings and impressions on outside studies. Further, 65.4 % state that there is no policy requiring an attending to review and document agreement with their interpretation of outside studies. There is wide institutional variation in both policy and practice regarding reinterpretation of outside studies for patients transferred to academic hospitals. While the majority of radiology residents are providing the service of reinterpreting outside studies, only a minority of residency programs have a policy requiring (1) documentation of their impressions or (2) attending oversight and documentation of discrepant opinions. PMID- 24777575 TI - A moving paradox: a binational view of obesity and residential mobility. AB - This paper takes a unique approach to the study of immigrant and native health differentials by addressing the role of internal as well as international mobility and considering the binational context in which such moves occur. The analyses take advantage of a unique dataset of urban residents in Mexico and the United States to compare Mexican origin immigrants and US-born Spanish-speaking residents in one urban setting in the United States and residents in a similar urban setting in Mexico. The binational approach allows for the test of standard indicators used to proxy acculturation (duration of residence in the United States, household language use) and measures of residential mobility among Mexican-Americans, Mexican immigrants and residents in Mexico. The results confirm a lower prevalence of obesity among Mexicans in Mexico and recent immigrants to the United States when compared to longer residents in the United States. However, for Mexican urban residents, more residential moves are associated with less obesity, while more residential mobility is associated with higher obesity in the urban sample in the United States. PMID- 24777576 TI - Alpha-synuclein oligomerization in manganese-induced nerve cell injury in brain slices: a role of NO-mediated S-nitrosylation of protein disulfide isomerase. AB - Over-exposure to manganese (Mn) has been known to induce endoplasmic reticulum (ER) stress involving protein misfolding. The proper maturation and folding of native proteins rely on the activity of protein disulfide isomerase (PDI). However, the exact mechanism of Mn-induced alpha-synuclein oligomerization is unclear. To explore whether alpha-synuclein oligomerization was associated with S nitrosylation of PDI, we made the rat brain slice model of manganism and pretreated slices with L-Canavanine, a selective iNOS inhibitor. After slices were treated with Mn (0, 25, 100, and 400 MUM) for 24 h, there were dose dependent increases in apoptotic percentage of cells, lactate dehydrogenase (LDH) releases, production of NO, inducible nitric oxide synthase (iNOS) activity, the mRNA and protein expressions of iNOS, and PDI. Moreover, S-nitrosylated PDI and alpha-synuclein oligomerization also increased. However, there was a significant increase in the PDI activity of 25-MUM Mn-treated slices. Then, PDI activity and the affinity between PDI and alpha-synuclein decreased significantly in response to Mn (100 and 400 MUM), which was associated with S-nitrosylation of PDI. The results indicated that S-nitrosylated PDI could affect its activity. We use the L Canavanine pretreatment brain slices to inhibit S-nitrosylation of PDI. The results showed that L-Canavanine pretreatment could reduce Mn-induced nerve cell injury and alpha-synuclein oligomerization. Additionally, there was a significant recovery in PDI activity in L-Canavanine-pretreated slices. The findings revealed that Mn induced nitrosative stress via the activation of iNOS and subsequent S nitrosylation of PDI in cultured slices. Moreover, S-nitrosylation of PDI is an important signaling event in the Mn-induced alpha-synuclein oligomerization in brain slices. PMID- 24777578 TI - [Unusual differential diagnosis of a nasopharyngeal mass]. PMID- 24777577 TI - The regulatory mechanism of neurogenesis by IGF-1 in adult mice. AB - Growth factors like insulin-like growth factor 1 (IGF-1) is reported to mediate neurogenesis in the subgranular zone (SGZ) and the subventricular zone (SVZ) of the adult mammalian brain, but its regulatory mechanism remains unclear. We generated transgenic mice overexpressing IGF-1 specifically in neural stem cells (NSCs) and assessed the effect of IGF-1 on neurogenesis in adult mice NSCs. Overexpression of IGF-1 could stimulate the expression of phospho-Akt and phospho ERK1/2 while inducing proliferation and differentiation of NSCs in the SGZ and SVZ. The MEK/ERK inhibitor U0126 could inhibit ERK1/2 phosphorylation, further inhibiting the proliferation of NSCs in the SGZ and SVZ but had no effect on the phosphorylation of Akt. By contrast, The PI3K/Akt inhibitor LY294002 inhibited phosphorylation of Akt and differentiation of NSCs in the SGZ and SVZ, resulting in no change in the proliferation of NSCs and ERK1/2 phosphorylation. These results demonstrate that IGF-1 upregulates the proliferation of NSCs by triggering MEK/ERK pathway signaling in the adult mice SGZ and SVZ. Meanwhile, IGF-1 also induces differentiation of NSCs via the PI3K/Akt pathway in adult mice. However, we found no evidence of crosstalk between the PI3K/Akt and MEK/ERK pathways in adult mice NSCs. Our work provides new experimental evidence of the involvement of the PI3K/Akt and MEK/ERK pathways in the proliferation and differentiation of the NSCs of adult mice. PMID- 24777579 TI - [Liposomal local therapy of sinunasal symptoms in ANCA associated vasculitis]. AB - BACKGROUND: GPA, eGPA and MPA constitute the group of AAV. ENT manifestations are part of the typical clinical picture of these diseases. Usually, patients are treated with systemic immunomodulatory drugs, mostly based on organ affection. In clinical routine, an insufficient decrease of sinunasal manifestations during a solely systemic therapeutic concept can repeatedly be -observed. MATERIAL AND METHODS: Between February 2009 and November 2012, 20 patients with AAV were diagnosed in or referred to our department for further treatment. Clinical symptoms and manifestations were measured by the use of international accepted activity scores. The effect of a local therapy with liposomes for a period of 2 months on sinunasal symptoms was prospectively evaluated by using visual analogue scales and standardized questionnaires. RESULTS: Within the described collective 100% of patients did show ENT-symptoms at the time of initial diagnosis. Every patient did receive immunomodulatory therapy, but in 61.1% of cases there was just slight or no improvement on sinunasal symptoms. After a 2-month period of liposomal local therapy, a significant reduction of sinunasal complaints could be observed, both evaluated via visual analogue scales (p<0.001 to p=0.014, depending on the evaluated symptom) and standardized questionnaires (p<0.001). CONCLUSIONS: The local application of liposomes in addition to a systemic therapy is effective in alleviating sinunasal manifestations in patients with AAV. PMID- 24777580 TI - Prevalence of HBV, HDV, HCV, and HIV infection during pregnancy in northern Benin. AB - Pregnant women are not screened for HBsAg and anti-HCV antibodies in many African countries. As there are few data concerning the prevalence of HBV, HDV, and HCV serological markers in Benin, the aim of this study was to evaluate their 2011 prevalence in pregnant women undergoing HIV screening in a rural area of north Benin, and compare the data with those reported for the same area in 1986. The sera of 283 women were examined for HBsAg, anti-HBs, anti-HBc, anti-HCV, and anti HIV 1/2 antibodies. In the case of HBsAg positivity, a search was made for the HBeAg, anti-HDV, and HBV genotypes; in the case of anti-HCV positivity, a search was made for the HCV genotypes. HBsAg, anti-HBs, anti-HBc, anti-HCV, and anti-HIV 1/2 were positive in respectively 44 (15.5%), 82 (29.0%), 234 (82.7%), 21 (7.4%), and nine samples (3.2%). Of the HBsAg-positive samples, five (11.4%) were positive for HBeAg, five (11.4%) for anti-HDV, and 19 for HBV genotype E. Of the anti-HCV-positive samples, five were positive for genotype 2a/2c and one for genotype 1a. The prevalence of anti-HBc alone (HBsAg and anti-HBs negative) was very high (41.3%). In comparison with the 1986 data, the prevalence of HBsAg and anti-HBc remained unchanged, that of HBeAg and anti-HDV had decreased, and that of anti-HIV 1/2 had increased. As these data confirm that HBV and HCV are highly endemic in the study area, it may be appropriate to introduce HBsAg and anti-HCV screening for pregnant women. J. Med. Virol. 86:1281-1287, 2014. (c) 2014 Wiley Periodicals, Inc. PMID- 24777582 TI - Design, synthesis and structure-activity relationship of novel oxime ether strobilurin derivatives containing substituted benzofurans. AB - BACKGROUND: Strobilurins are one of the most important classes of agricultural fungicides. To discover new strobilurin analogues with broad spectrum and high activity, a series of novel oxime ether strobilurin derivatives containing substituted benzofurans in the side chain were synthesised and bioassayed. RESULTS: The synthesised compounds were characterised by (1) H NMR, (13) C NMR, MS and HRMS. Bioassays demonstrated that most target compounds possessed good or excellent fungicidal activities, especially against Erysiphe graminis and Pyricularia oryzae. Furthermore, methyl 3-methoxypropenoate oxime ethers exhibited remarkably higher activities against E. graminis, Colletotrichum lagenarium and Puccinia sorghi Schw. Notably, (E,E)-methyl 3-methoxy-2-{2-[({[5 fluoro-1-(benzofuran-2-yl)ethylidene]amino}oxy)methyl]phenyl}propenoate (BSF2) and (E,E)-methyl 3-methoxy-2-{2-[({[5-chloro-1-(benzofuran-2 yl)ethylidene]amino}oxy)methyl]phenyl}propenoate (BSF3) were identified as the most promising candidates for further study. CONCLUSION: The present work demonstrates that oxime ether strobilurin derivatives containing benzofurans can be used as possible lead compounds for developing novel fungicides. PMID- 24777581 TI - Lipidomic analyses of female mice lacking hepatic lipase and endothelial lipase indicate selective modulation of plasma lipid species. AB - Hepatic lipase (HL) and endothelial lipase (EL) share overlapping and complementary roles in lipoprotein metabolism. The deletion of HL and EL alleles in mice raises plasma total cholesterol and phospholipid concentrations. However, the influence of HL and EL in vivo on individual molecular species from each class of lipid is not known. We hypothesized that the loss of HL, EL, or both in vivo may affect select molecular species from each class of lipids. To test this hypothesis, we performed lipidomic analyses on plasma and livers from fasted female wild-type, HL-knockout, EL-knockout, and HL/EL-double knockout mice. Overall, the loss of HL, EL, or both resulted in minimal changes to hepatic lipids; however, select species of CE were surprisingly reduced in the livers of mice only lacking EL. The loss of HL, EL, or both reduced the plasma concentrations for select molecular species of triacylglycerol, diacylglycerol, and free fatty acid. On the other hand, the loss of HL, EL, or both raised the plasma concentrations for select molecular species of phosphatidylcholine, cholesteryl ester, diacylglycerol, sphingomyelin, ceramide, plasmanylcholine, and plasmenylcholine. The increased plasma concentration of select ether phospholipids was evident in the absence of EL, thus suggesting that EL might exhibit a phospholipase A2 activity. Using recombinant EL, we showed that it could hydrolyse the artificial phospholipase A2 substrate 4-nitro-3 (octanoyloxy)benzoic acid. In summary, our study shows for the first time the influence of HL and EL on individual molecular species of several classes of lipids in vivo using lipidomic methods. PMID- 24777583 TI - Diagnostic nanoparticle targeting of the EGF-receptor in complex biological conditions using single-domain antibodies. AB - For effective localization of functionalized nanoparticles at diseased tissues such as solid tumours or metastases through biorecognition, appropriate targeting vectors directed against selected tumour biomarkers are a key prerequisite. The diversity of such vector molecules ranges from proteins, including antibodies and fragments thereof, through aptamers and glycans to short peptides and small molecules. Here, we analyse the specific nanoparticle targeting capabilities of two previously suggested peptides (D4 and GE11) and a small camelid single-domain antibody (sdAb), representing potential recognition agents for the epidermal growth factor receptor (EGFR). We investigate specificity by way of receptor RNA silencing techniques and look at increasing complexity in vitro by introducing increasing concentrations of human or bovine serum. Peptides D4 and GE11 proved problematic to employ and conjugation resulted in non-receptor specific uptake into cells. Our results show that sdAb-functionalized particles can effectively target the EGFR, even in more complex bovine and human serum conditions where targeting specificity is largely conserved for increasing serum concentration. In human serum however, an inhibition of overall nanoparticle uptake is observed with increasing protein concentration. For highly affine targeting ligands such as sdAbs, targeting a receptor such as EGFR with low serum competitor abundance, receptor recognition function can still be partially realised in complex conditions. Here, we stress the value of evaluating the targeting efficiency of nanoparticle constructs in realistic biological milieu, prior to more extensive in vivo studies. PMID- 24777584 TI - Commissioning and first clinical application of mARC treatment. AB - BACKGROUND: The modulated arc (mARC) technique has recently been introduced for Siemens ARTISTE linear accelerators. We present the first experiences with the commissioning of the system and first patient treatments. PATIENTS AND METHODS: Treatment planning and delivery are presented for the Prowess Panther treatment planning system or, alternatively, an in-house code. Dosimetric verification is performed both by point dose measurements and in 3D dose distribution. RESULTS: Depending on the target volume, one or two arcs can be used to create highly conformal plans. Dosimetric verification of the converted mARC plans with step and-shoot plans shows deviations below 1 % in absolute point dose; in the 3D dose distribution, over 95 % of the points pass the 3D gamma criteria (3 % deviation in local dose and 3 mm distance to agreement for doses > 20 % of the maximum). Patient specific verification of the mARC dose distribution with the calculations has a similar pass rate. Treatment times range between 2 and 5 min for a single arc. CONCLUSIONS: To our knowledge, this is the first report of clinical application of the mARC technique. The mARC offers the possibility to save significant amounts of time, with single-arc treatments of only a few minutes achieving comparable dose distribution to IMRT plans taking up to twice as long. PMID- 24777585 TI - [In memory of Professor Dr. Gyorgy Nemeth (1935-2014)]. PMID- 24777586 TI - Free-breathing steady-state free precession cine cardiac magnetic resonance with respiratory navigator gating. AB - PURPOSE: To develop and validate a respiratory motion compensation method for free-breathing cardiac cine imaging. METHODS: A free-breathing navigator-gated cine steady-state free precession acquisition (Cine-Nav) was developed which preserves the equilibrium state of the net magnetization vector, maintains the high spatial and temporal resolutions of standard breath-hold (BH) acquisition, and images entire cardiac cycle. Cine image data is accepted only from cardiac cycles occurring entirely during end-expiration. Prospective validation was performed in 10 patients by obtaining in each three complete ventricular image stacks with different respiratory motion compensation approaches: (1) BH, (2) free-breathing with 3 signal averages (3AVG), and (3) free-breathing with Cine Nav. RESULTS: The subjective image quality score (1 = worst, 4 = best) for Cine Nav (3.8 +/- 0.4) was significantly better than for 3AVG (2.2 +/- 0.5, P = 0.002), and similar to BH (4.0 +/- 0.0, P = 0.13). The blood-to-myocardium contrast ratio for Cine-Nav (6.3 +/- 1.5) was similar to BH (5.9 +/- 1.6, P = 0.52) and to 3AVG (5.6 +/- 2.5, P = 0.43). There were no significant differences between Cine-Nav and BH for the ventricular volumes and mass. In contrast, there were significant differences between 3AVG and BH in all of these measurements but right ventricular mass. CONCLUSION: Free-breathing cine imaging with Cine-Nav yielded comparable image quality and ventricular measurements to BH, and was superior to 3AVG. PMID- 24777588 TI - On the security of two remote user authentication schemes for telecare medical information systems. AB - The telecare medical information systems (TMISs) support convenient and rapid health-care services. A secure and efficient authentication scheme for TMIS provides safeguarding patients' electronic patient records (EPRs) and helps health care workers and medical personnel to rapidly making correct clinical decisions. Recently, Kumari et al. proposed a password based user authentication scheme using smart cards for TMIS, and claimed that the proposed scheme could resist various malicious attacks. However, we point out that their scheme is still vulnerable to lost smart card and cannot provide forward secrecy. Subsequently, Das and Goswami proposed a secure and efficient uniqueness-and anonymity-preserving remote user authentication scheme for connected health care. They simulated their scheme for the formal security verification using the widely accepted automated validation of Internet security protocols and applications (AVISPA) tool to ensure that their scheme is secure against passive and active attacks. However, we show that their scheme is still vulnerable to smart card loss attacks and cannot provide forward secrecy property. The proposed cryptanalysis discourages any use of the two schemes under investigation in practice and reveals some subtleties and challenges in designing this type of schemes. PMID- 24777587 TI - Diagnostic value of strain echocardiography, galectin-3, and tenascin-C levels for the identification of patients with pulmonary and cardiac sarcoidosis. AB - BACKGROUND: Cardiac involvement in sarcoidosis has been associated with poor prognosis. We evaluated myocardial contractility quantitatively in a cohort of pulmonary sarcoidosis (PS) patients with and without cardiac involvement. We also studied markers of fibrosis (tenascin-C [Tn-C] and galectin-3 [Gl-3]) as diagnostic tools for PS and cardiac sarcoidosis (CS). METHODS: Forty ambulatory patients with PS of grades 1-2 and 26 healthy subjects were prospectively enrolled. All patients with PS underwent cardiac magnetic resonance (CMR) to explore the presence of CS. The study population was divided into three groups: controls (n = 26), non-CS patients (n = 34), and CS patients (n = 6). Speckle tracking strain echocardiography (STE) was performed on all patients, and Gl-3 and Tn-C values were measured in all patients and controls. RESULTS: PS patients had higher levels of Gl-3 and Tn-C than did controls, and the STE parameters of PS patients, including global longitudinal strain (GLS) and global circumferential strain (GCS), were lower than those of controls (p < 0.001 for all comparisons). GLS values were lower in CS patients than in the other groups (p = 0.05). CONCLUSIONS: PS patients demonstrate reduced cardiac contractility, independent of CMR-proven structural cardiac lesions, while patients with structural lesions have a more pronounced drop in strain parameters. Tn-C and Gl 3 are promising markers for the diagnosis of PS, but they are not specific for cardiac involvement. PMID- 24777589 TI - Invited commentary: Videothoracoscopy-assisted surgical lung biopsy for interstitial lung diseases. PMID- 24777590 TI - Perioperative management of patients on new oral anticoagulants. AB - BACKGROUND: New oral anticoagulants (NOACs) offer an alternative to warfarin for preventing stroke in patients with atrial fibrillation. NOACs are expected to replace warfarin and other vitamin K antagonists for most of their indications in the future. Knowledge of the use of NOACs in the perioperative period is important for optimal care. METHODS: Studies that reported on the use of NOACs were identified, focusing on evidence-based guidance relating to the perioperative period. PubMed was searched for relevant articles published between January 2000 and January 2014. RESULTS: The anticipated expanded clinical use of NOACs such as rivaroxaban (XareltoTM), apixaban (EliquisTM) and dabigatran (PradaxaTM) has the potential to simplify perioperative anticoagulant management because of fewer drug-drug interactions, rapid onset of action, predictable pharmacokinetics and relatively short half-lives. However, coagulation status cannot be monitored by international normalized ratio and no antidotes are currently available. In elective surgery, it is important to discontinue the use of NOACs, with special consideration of renal function as route of elimination. Guidelines for the management of bleeding complications in patients on NOACs are provided, and may be considered for trauma and emergency surgery. Haemodialysis could be considered for bleeding with use of dabigatran. Better options for reversal of the effects of NOACs when bleeding occurs may follow with novel drugs. CONCLUSION: Management of NOACs in elective and emergency conditions requires knowledge of time of last intake of drug, current renal function and the planned procedure in order to assess the overall risk of bleeding. Currently no antidote exists to reverse the effects of these drugs. PMID- 24777591 TI - The effect of therapeutic and supratherapeutic oral doses of nomegestrol acetate (NOMAC)/17beta-estradiol (E2) on QTcF intervals in healthy women: results from a randomized, double-blind, placebo- and positive-controlled trial. AB - BACKGROUND AND OBJECTIVE: Nomegestrol acetate (NOMAC)/17beta-estradiol (E2) is a monophasic oral contraceptive that contains a progesterone-derived progestogen (NOMAC), and E2, a bio-identical estrogen. The primary objective of this thorough QT/QTc study was to investigate whether once-daily administration of therapeutic (2.5/1.5 mg) and supratherapeutic (12.5/7.5 mg) doses of NOMAC/E2 were associated with prolongation of the mean Fridericia-corrected QT (QTcF) interval in electrocardiograms at steady-state concentrations of NOMAC/E2 versus placebo. The co-primary objective was to establish assay sensitivity after a single dose of moxifloxacin (positive control). METHODS: This was a randomized, double-blind, parallel-group trial comparing 2.5/1.5 mg of NOMAC/E2 (therapeutic dose), 12.5/7.5 mg of NOMAC/E2 (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Double-blind study medication was administered from day -1 to 14. Healthy women aged 18-50 years were randomized. RESULTS: The largest time-matched mean QTcF difference compared with placebo for the therapeutic dose of NOMAC/E2 was 1.6 ms, with an upper limit (UL) of a one-sided 95% confidence interval (CI) of 5.2 ms, and 3.1 ms with an UL 95% CI of 7.0 ms for the supratherapeutic dose. The UL for the time-matched QTcF differences compared with placebo were below the 10 ms threshold defined in the ICH E14 guideline for all time points, both for the therapeutic and the supratherapeutic dose. For moxifloxacin, assay sensitivity was demonstrated. CONCLUSIONS: This thorough QT/QTc study showed that therapeutic and supratherapeutic doses of NOMAC/E2 were not associated with clinically relevant QTc interval prolongation in healthy women after a 2-week period of dosing. PMID- 24777592 TI - Advantages of percutaneous abdominal biopsy under PET-CT/ultrasound fusion imaging guidance: a pictorial essay. AB - Positron emission tomography (PET) is a functional imaging technique that can investigate the metabolic characteristics of tissues. Currently, PET images are acquired and co-registered with a computed tomography (CT) scan (PET-CT), which is employed for correction of attenuation and anatomical localization. In spite of the high negative predictive value of PET, false-positive results may occur; indeed, Fluorine 18 ((18)F)-fluorodeoxyglucose ((18)F-FDG) uptake is not specific to cancer. As (18)F-FDG uptake may also be seen in non-malignant infectious or inflammatory processes, FDG-avid lesions may necessitate biopsy to confirm or rule out malignancy. However, some PET-positive lesions may have little or no correlative ultrasound (US) and/or CT findings (i.e., low conspicuity on morphological imaging). Since it is not possible to perform biopsy under PET guidance alone, owing to intrinsic technical limitations, PET information has to be integrated into a CT- or US-guided biopsy procedure (multimodal US/PET-CT fusion imaging). The purpose of this pictorial essay is to describe the technique of multimodal imaging fusion between real-time US and PET/CT, and to provide an overview of the clinical settings in which this multimodal integration may be useful in guiding biopsy procedures in PET-positive abdominal lesions. PMID- 24777593 TI - Assessment of liver volume with computed tomography and comparison of findings with ultrasonography. AB - BACKGROUND AND PURPOSE: In this study, we aimed to investigate the impact of non alcoholic hepatic steatosis on the liver volume. As investigating hepatic steatosis, we utilized computed tomography (CT) to determine the degree of steatosis and we utilized hepatobiliary ultrasonography (USG) for densitometry and correlation. MATERIALS AND METHODS: As hepatosteatosis group, 35 patients over 18 years of age and whose abdominal CT scans were requested by several clinics and performed routinely were included in this study, and as control group, 40 healthy subjects without hepatosteatosis (clinically and radiologically) and correlated with hepatosteatosis group in terms of age and gender were included in this study. CT densitometry and liver attenuation index (LAI) of all individuals who participated in our study were calculated, and contrast images of patients were transferred to CT-Volume Software (Siemens Syngo Multimodality Workplace; Version VE52A). In this study, interactive and automated volume measurement techniques were used together. The volumes were measured separately in patient and control group. RESULTS: In this study for each stage in USG, there was found a direct correlation in terms of LAI and volume, and this correlation was statistically significant (p < 0.01). Furthermore, statistical significance between size and USG stage draws attention (p < 0.05). A significance relationship between USG stage and age could not be determined. CONCLUSION: As a result, we have reached the conclusion that CT densitometry can be used as an assistive technique along with USG to determine the degree of steatosis in the non-alcoholic fatty liver disease, and there is a positive linear correlation between the liver size and volume, and liver volume increases in the non-alcoholic fatty liver disease. PMID- 24777594 TI - Subcutaneous trastuzumab: drug development and current position. AB - HER2-positive breast cancer, accounting for 15 % of the total breast cancer patient population, carries in itself a bad prognosis, which has now become much better after the advent of anti-HER2 drugs. HER2-targeted therapy has significantly improved disease free- and overall survival in HER2-positive breast cancer, and has rendered better disease control both in the early and advanced disease setting. Trastuzumab treatment duration is often prolonged and poses significant time and resource challenges both on the treatment institutions and on the patient. The recent development of a subcutaneous formulation has meant a significant advance in this respect. We review the drug development of the compound and the current evidence on its use. PMID- 24777595 TI - Folate intake and the risk of breast cancer: a systematic review and meta analysis. AB - There is conflicting epidemiological evidence on the role of folate and breast cancer risk. We conducted a systematic review and quantitative meta-analysis of folate intake and folate blood levels and the risk of breast cancer. Four electronic databases (Medline, PubMed, Embase, and Current Contents Connect) were searched to April 11, 2014, with no language restrictions for observational studies that measured folate intake or blood levels and the risk of breast cancer. The meta-analysis of dietary folate intake comprising 36 studies with 34,602 cases, and a total sample size of 608,265 showed a decreased risk of breast cancer, with an odds ratio (OR) of 0.84 [95 % confidence interval (CI) 0.77-0.91]. When stratified by menopausal status and by study design, none of the meta-analyses of prospective studies showed any statistically significant decrease in the risk of breast cancer. The meta-analysis of total folate showed no statistically significant association with breast cancer OR of 0.98 (95 % CI 0.91-1.07). There was no significant association between either dietary or total folate intake and breast cancer when stratified by hormonal receptor status. The meta-analysis of blood folate levels found no significant association with the risk of breast cancer, with an OR of 0.86 (95 % CI 0.60-1.25). Breast cancer does not appear to be associated with folate intake, and this did not vary by menopausal status or hormonal receptor status. Folate blood levels also do not appear to be associated with breast cancer risk. PMID- 24777596 TI - Mycorrhizal compatibility and symbiotic reproduction of Gavilea australis, an endangered terrestrial orchid from south Patagonia. AB - Gavilea australis is a terrestrial orchid endemic from insular south Argentina and Chile. Meeting aspects of mycorrhizal fungi identity and compatibility in this orchid species is essential for propagation and conservation purposes. These knowledge represent also a first approach to elucidate the mycorrhizal specificity of this species. In order to evaluate both the mycorrhizal compatibility and the symbiotic seed germination of G. australis, we isolated and identified its root endophytic fungal strains as well as those from two sympatric species: Gavilea lutea and Codonorchis lessonii. In addition, we tested two other strains isolated from allopatric terrestrial orchid species from central Argentina. All fungal strains formed coilings and pelotons inside protocorms and promoted, at varying degrees, seed germination, and protocorm development until seedlings had two to three leaves. These results suggest a low mycorrhizal specificity of G. australis and contribute to a better knowledge of the biology of this orchid as well as of other sympatric Patagonian orchid species, all of them currently under serious risk of extinction. PMID- 24777597 TI - Maternal, fetal, and neonatal parameters for prognosis and counseling of HCMV congenital infection. AB - To investigate retrospectively the prognostic significance of maternal, fetal, and neonatal parameters and clinical outcome in 150 HCMV congenital infections during the period 1995-2009. HCMV fetal infection was investigated in amniotic fluid and fetal blood samples. HCMV congenital infection was confirmed in newborn urine and blood samples. Symptomatic infection was defined in HCMV-infected fetuses and in infected newborns on the basis of physical and instrumental findings. Follow-up at 3, 6, 12 months, and then annually up to school age, included clinical evaluation, funduscopic, audiologic, neurologic, and cognitive assessment. Overall, 122/150 (81.3%) newborns were asymptomatic and 28/150 (18.7%) were symptomatic at birth. The best prognostic maternal parameter of symptomatic infection at birth was gestational age at infection (P = 0.037). The best fetal virological markers were HCMV DNA levels in amniotic fluid (P < 0.001), antigenaemia levels (P = 0.007), HCMV DNA levels in blood (P = 0.004), and HCMV-specific IgM index values (P = 0.002). The only significant neonatal parameter was HCMV DNA level in blood [P = 0.006; OR, 3.62 (95% CI, 1.46-8.97)]. Symptoms at birth correlated significantly with long-term sequelae (P = 0.021). A trend towards a risk of sequelae in early (n = 15/58 examined) versus late (n = 6/57 examined) maternal infection was documented. The risk of symptomatic congenital infection at birth increased linearly with the number of significant maternal, fetal, and neonatal parameters. PMID- 24777598 TI - Total extraperitoneal endoscopic hernioplasty (TEP). AB - One can no longer think about modern hernia surgery without mentioning endoscopic techniques. But due to their high technical demands the learning curve is comparatively long. And by technical mistakes and their consequences (pain, recurrence, complications) the benefits of the endoscopic techniques can easily be turned to drawbacks. The following text explains the steps of the total extraperitoneal endoscopic hernioplasty (TEP) technique in detail pointing out alternatives and risks. From preparation, indication and positioning, from trocar placement to extraperitoneal dissection and mesh placement, the principles of TEP are elucidated in respect of local anatomy and possible complications. The text as well as the accompanying video in the Mediathek are based on the authors' 20 years of experience in the TEP technique. Both of them may help in safe TEP application to minimise the complication rate as well as recurrences. Then patients can benefit from the advantages of this technique. PMID- 24777599 TI - [Liver - main topic in abdominal surgery: from the less touched almost avoided to a persuaded organ from a surgical perspective (reflections to issue 2/2014 - editorial)]. PMID- 24777600 TI - [Gender-specific influencing factors on incidence, risk factors and outcome of carcinoma of the liver, gallbladder, extrahepatic bile duct and pancreas]. AB - BACKGROUND: This overview comments on gender-specific differences in incidence, risk factors and prognosis in patients with carcinoma of the liver, gallbladder, extrahepatic bile duct and pancreas. METHOD: For the literature review, the MEDLINE database (PubMed) was searched under the key words "liver cancer", "gallbladder cancer", "extrahepatic bile duct carcinoma", "pancreatic cancer" AND "gender". RESULTS: There were significant gender differences in the epidemiology of the analysed carcinomas. The incidence of hepatocellular carcinoma (HCC) is much higher in men than in women, one of 86 men, but only 1 out of 200 women develop a malignant primary liver tumour in Germany in the course of their life. The lifetime risk for carcinomas of the gallbladder and extrahepatic bile ducts in Germany amounts to about 0.6 % for women and 0.5 % for men, specifically gallbladder carcinomas are observed more frequently in women than in men. For pancreatic cancer, no clear gender preference exists in Germany, although the mortality risk for men is higher than that for women (age-adjusted standardised death rate in men 12.8/100, 000 persons, in women 9.5). Remarkable is furthermore the shift of the tumour incidence in the last decades. Liver cancer has increased among men in Germany by about 50 % in the last 30 years, the incidence of gallbladder carcinoma has inversely dropped. The prognosis of these cancers across all tumour stages is uniformly bad in an unselected patient population. This is probably the main reason why only little - if any - gender differences in survival are described. CONCLUSION: In addition to avoiding the known risk factors such as hepatitis B and C virus infection, alcohol abuse, and smoking, the avoidance of overweight and obesity plays an increasingly important role in the prevention of these cancers. PMID- 24777601 TI - [Bariatric and metabolic surgery in Germany 2012 - results of the quality assurance study on surgery for obesity (data of the German Bariatric Surgery Registry)]. PMID- 24777602 TI - The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling. AB - MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology. PMID- 24777603 TI - Endogenous siderophore 2,5-dihydroxybenzoic acid deficiency promotes anemia and splenic iron overload in mice. AB - Eukaryotes produce a siderophore-like molecule via a remarkably conserved biosynthetic pathway. 3-OH butyrate dehydrogenase (BDH2), a member of the short chain dehydrogenase (SDR) family of reductases, catalyzes a rate-limiting step in the biogenesis of the mammalian siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA). Depletion of the mammalian siderophore by inhibiting expression of bdh2 results in abnormal accumulation of intracellular iron and mitochondrial iron deficiency in cultured mammalian cells, as well as in yeast cells and zebrafish embryos We disrupted murine bdh2 by homologous recombination to analyze the effect of bdh2 deletion on erythropoiesis and iron metabolism. bdh2 null mice developed microcytic anemia and tissue iron overload, especially in the spleen. Exogenous supplementation with 2,5-DHBA alleviates splenic iron overload in bdh2 null mice. Additionally, bdh2 null mice exhibit reduced serum iron. Although BDH2 has been proposed to oxidize ketone bodies, we found that BDH2 deficiency did not alter ketone body metabolism in vivo. In sum, our findings demonstrate a key role for BDH2 in erythropoiesis. PMID- 24777604 TI - Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells. AB - While glucocorticoids (GCs) are used clinically to treat many conditions, their neonatal and prenatal usage is increasingly controversial due to reports of delayed adverse outcomes, especially their effects on brain development. Such alterations may reflect the impact of GCs on neural progenitor/stem cell (NPSC) function. We previously demonstrated that the lipid raft protein caveolin-1 (Cav 1) was required for rapid GC signaling in embryonic mouse NPSCs operating through plasma membrane-bound glucocorticoid receptors (GRs). We show here that genomic GR signaling in NPSCs requires Cav-1. Loss of Cav-1 impacts the transcriptional response of many GR target genes (e.g., the serum- and glucocorticoid-regulated kinase 1 gene) that are likely to mediate the antiproliferative effects of GCs. Microarray analysis of wild-type C57 or Cav-1-deficient NPSCs identified approximately 100 genes that are differentially regulated by GC treatment. These changes in hormone responsiveness in Cav-1 knockout NPSCs are associated with the loss of GC-regulated phosphorylation of GR at serine 211 but not at serine 226. Chromatin recruitment of total GR to regulatory regions of target genes such as Fkbp-5, RhoJ, and Sgk-1, as well as p211-GR recruitment to Sgk-1, are compromised in Cav-1 knockout NPSCs. Cav-1 is therefore a multifunctional regulator of GR in NPSCs influencing both rapid and genomic action of the receptor to impact cell proliferation. PMID- 24777605 TI - Interference with ubiquitination in CFTR modifies stability of core glycosylated and cell surface pools. AB - It is recognized that both wild-type and mutant CFTR proteins undergo ubiquitination at multiple lysines in the proteins and in one or more subcellular locations. We hypothesized that ubiquitin is added to specific sites in wild-type CFTR to stabilize it and at other sites to signal for proteolysis. Mass spectrometric analysis of wild-type CFTR identified ubiquitinated lysines 68, 710, 716, 1041, and 1080. We demonstrate that the ubiquitinated K710, K716, and K1041 residues stabilize wild-type CFTR, protecting it from proteolysis. The polyubiquitin linkage is predominantly K63. N-tail mutants, K14R and K68R, lead to increased mature band CCFTR, which can be augmented by proteasomal (but not lysosomal) inhibition, allowing trafficking to the surface. The amount of CFTR in the K1041R mutant was drastically reduced and consisted of bands A/B, suggesting that the site in transmembrane 10 (TM10) was critical to further processing beyond the proteasome. The K1218R mutant increases total and cell surface CFTR, which is further accumulated by proteasomal and lysosomal inhibition. Thus, ubiquitination at residue 1218 may destabilize wild-type CFTR in both the endoplasmic reticulum (ER) and recycling pools. Small molecules targeting the region of residue 1218 to block ubiquitination or to preserving structure at residues 710 to 716 might be protein sparing for some forms of cystic fibrosis. PMID- 24777607 TI - Dithiolodithiole as a building block for conjugated materials. AB - The development of new conjugated organic materials for dyes, sensors, imaging, and flexible light emitting diodes, field-effect transistors, and photovoltaics has largely relied upon assembling pi-conjugated molecules and polymers from a limited number of building blocks. The use of the dithiolodithiole heterocycle as a conjugated building block for organic materials is described. The resulting materials exhibit complimentary properties to widely used thiophene analogues, such as stronger donor characteristics, high crystallinity, and a decreased HOMO LUMO gap. The dithiolodithiole (C4S4) motif is readily synthetically accessible using catalytic processes, and both the molecular and bulk properties of materials based on this building block can be tuned by judicious choice of substituents. PMID- 24777606 TI - Impact of adjuvant chemotherapy on long-term employment of survivors of early stage breast cancer. AB - BACKGROUND: Many women with early-stage breast cancer are working at the time of diagnosis and survive without disease recurrence. The short-term impact of chemotherapy receipt on employment has been demonstrated, but the long-term impact merits further research. METHODS: The authors conducted a longitudinal multicenter cohort study of women diagnosed with nonmetastatic breast cancer between 2005 and 2007, as reported to the population-based Los Angeles and Detroit Surveillance, Epidemiology, and End Results program registries. Of 3133 individuals who were sent surveys, 2290 (73%) completed a baseline survey soon after diagnosis and of these, 1536 (67%) completed a 4-year follow-up questionnaire. RESULTS: Of the 1026 patients aged < 65 years at the time of diagnosis whose breast cancer did not recur and who responded to both surveys, 746 (76%) worked for pay before diagnosis. Of these, 236 (30%) were no longer working at the time of the follow-up survey. Women who received chemotherapy as part of their initial treatment were less likely to be working at the time of the follow-up survey (38% vs 27%; P = .003). Chemotherapy receipt at the time of diagnosis (odds ratio, 1.4; P = .04) was found to be independently associated with unemployment during survivorship in a multivariable model. Many women who were not employed during the survivorship period wanted to work: 50% reported that it was important for them to work and 31% were actively seeking work. CONCLUSIONS: Unemployment among survivors of breast cancer 4 years after diagnosis is often undesired and appears to be related to the receipt of chemotherapy during initial treatment. These findings should be considered when patients decide whether to receive adjuvant chemotherapy, particularly when the expected benefit is low. PMID- 24777608 TI - Genome-wide analysis of AP2/ERF family genes from Lotus corniculatus shows LcERF054 enhances salt tolerance. AB - Lotus corniculatus is used in agriculture as a main forage plant. Members of the Apetala2/ethylene response factor (AP2/ERF) family play important roles in regulating gene expression in response to many forms of stress, including drought and salt. Here, starting from database of the L. corniculatus var. japonicus genome, we identified 127 AP2/ERF genes by insilico cloning method. The phylogeny, gene structures, and putative conserved motifs in L. corniculatus var. japonicus ERF proteins were analyzed. Based on the number of AP2/ERF domains and the function of the genes, 127 AP2/ERF genes from L. corniculatus var. japonicus were classified into five subfamilies named the AP2, dehydration-responsive element binding factor (DREB), ERF, RAV, and a soloist. Outside the AP2/ERF domain, many L. corniculatus var. japonicus-specific conserved motifs were detected. Expression profile analysis of AP2/ERF genes by quantitative real-time PCR revealed that 19 LcERF genes, including LcERF054 (KJ004728), were significantly induced by salt stress. The results showed that the LcERF054 gene encodes a nuclear transcription activator. Overexpression of LcERF054 in Arabidopsis enhanced the tolerances to salt stress, showed higher germination ratio of seeds, and had elevated levels of relative moisture contents, soluble sugars, proline, and lower levels of malondialdehyde under stress conditions compared to wild-type plants. The expression of hyperosmotic salinity response genes COR15A, LEA4-5, P5CS1, and RD29A was found to be elevated in the LcERF054 overexpressing Arabidopsis plants compared to wild type. These results revealed that the LcERF genes play important roles in L. corniculatus cv Leo under salt stress and that LcERFs are attractive engineering targets in applied efforts to improve abiotic stress tolerances in L. corniculatus cv Leo or other crops. PMID- 24777610 TI - Combined hepatocellular-cholangiocarcinoma: a population-level analysis of an uncommon primary liver tumor. AB - Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver cancer. Our aims were to analyze the demographic, clinical, and pathological characteristics of cHCC-CC at a population level and to investigate the effects of these features as well as different management strategies on the prognosis. The Surveillance, Epidemiology, and End Results (SEER) database was analyzed for 1988-2009. Data analyses were performed with chi-square tests, analyses of variance, Kaplan-Meier curves, and Cox proportional hazards regression. Four hundred sixty-five patients with cHCC-CC, 52,825 patients with hepatocellular carcinoma (HCC), and 7181 patients with cholangiocarcinoma (CC) were identified. cHCC-CC was more common in patients who were white, male, and older than 65 years. Treatment was more frequently nonsurgical/interventional. Patients with cHCC-CC, HCC, and CC had 5-year overall survival (OS) and disease-specific survival rates of 10.5%, 11.7%, and 5.7% (P < 0.001) and 17.8%, 21.0%, and 11.9% (P < 0.001), respectively. For cHCC-CC patients, an increasing invasiveness of the therapeutic approach was significantly associated with prolonged survival (P < 0.001). In a multivariate model, black race, a distant SEER stage, and a tumor size of 5.0 to 10.0 cm were independently associated with lower survival for cHCC CC patients; a year of diagnosis after 1995 and surgical treatment with minor hepatectomy, major hepatectomy (MJH), or liver transplantation (LT) were independently associated with better survival for cHCC-CC patients. Patients diagnosed with cHCC-CC, HCC, and CC and treated with LT had 5-year OS rates of 41.1%, 67.0%, and 29.0%, respectively (P < 0.001). In conclusion, cHCC-CC patients appear to have intermediate demographic, clinical, and survival characteristics in comparison with HCC and CC patients. cHCC-CC patients undergoing LT showed inferior survival in comparison with HCC patients, and the role and indications for LT in cHCC-CC have yet to be defined. At this time, MJH may be considered the best therapeutic approach for such patients. PMID- 24777609 TI - The transcriptional network of WRKY53 in cereals links oxidative responses to biotic and abiotic stress inputs. AB - The transcription factor WRKY53 is expressed during biotic and abiotic stress responses in cereals, but little is currently known about its regulation, structure and downstream targets. We sequenced the wheat ortholog TaWRKY53 and its promoter region, which revealed extensive similarity in gene architecture and cis-acting regulatory elements to the rice ortholog OsWRKY53, including the presence of stress-responsive abscisic acid-responsive elements (ABRE) motifs and GCC-boxes. Four proteins interacted with the WRKY53 promoter in yeast one-hybrid assays, suggesting that this gene can receive inputs from diverse stress-related pathways such as calcium signalling and senescence, and environmental cues such as drought and ultraviolet radiation. The Ser/Thr receptor kinase ORK10/LRK10 and the apoplastic peroxidase POC1 are two downstream targets for regulation by the WRKY53 transcription factor, predicted based on the presence of W-box motifs in their promoters and coregulation with WRKY53, and verified by electrophoretic mobility shift assay (EMSA). Both ORK10/LRK10 and POC1 are upregulated during cereal responses to pathogens and aphids and important components of the oxidative burst during the hypersensitive response. Taken with our yeast two hybrid assay which identified a strong protein-protein interaction between microsomal glutathione S-transferase 3 and WRKY53, this implies that the WRKY53 transcriptional network regulates oxidative responses to a wide array of stresses. PMID- 24777611 TI - Diagnosis and treatment of Marfan syndrome: an update. PMID- 24777612 TI - Pilot study of a novel combination of two therapeutic vaccines in advanced non small-cell lung cancer patients. AB - Cancer vaccines contain tumor antigens in a pro-inflammatory context with the purpose to generate potent antitumor immune responses. However, tumor cells develop different immunosuppressive mechanisms that limit the effectiveness of an anticancer immune response. Therefore, therapeutic vaccine treatment alone is usually not sufficient to generate tumor regression or survival improvement, especially in the advanced disease scenario in which most clinical studies have been conducted. Combining cancer vaccines with different anticancer therapies such as chemotherapy, radiotherapy and other immunotherapeutic agents has had different levels of success. However, the combination of cancer vaccines with different mechanisms of action has not been explored in clinical trials. To address this issue, the current review summarizes the main clinical and immunological results obtained with two different therapeutic vaccines used in advanced non-small-cell lung cancer patients, inducing an immune response against epidermal growth factor (CIMAvax-EGF) and NGcGM3 ganglioside (racotumomab). We also discuss preliminary findings obtained in a trial of combination of these two vaccines and future challenges with these therapies. PMID- 24777613 TI - Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter analysis. AB - OBJECTIVE: Dendritic cell (DC)-based cancer vaccines may have a significant benefit to patients with advanced pancreatic cancer. However, variations among clinical studies make it difficult to compare clinical outcomes. Here, we identified factors that determined the clinical benefits by analyzing data obtained at seven Japanese institutions that employed the same DC preparation and treatment regimens. METHODS: Of 354 patients who met the inclusion criteria, 255 patients who received standard chemotherapy combined with peptide-pulsed DC vaccines were analyzed. RESULTS: The mean survival time from diagnosis was 16.5 months (95 % CI 14.4-18.5) and that from the first vaccination was 9.9 months (95 % CI 8.0-12.9). Known prognostic baseline factors related to advanced pancreatic cancer, namely ECOG-PS, peritoneal metastasis, liver metastasis, and the prognostic nutrition index, were also representative. Importantly, we found that erythema reaction after vaccination was an independent and treatment-related prognostic factor for better survival and that OK-432 might be a good adjuvant enhancing the antitumor immunity during DC vaccination. CONCLUSIONS: This is the first report of a multicenter clinical study suggesting the feasibility and possible clinical benefit of an add-on DC vaccine in patients with advanced pancreatic cancer who are undergoing chemotherapy. These findings need to be addressed in well-controlled prospective randomized trials. PMID- 24777614 TI - Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice. AB - Tumor progression in the colon moves from aberrant crypt foci to adenomatous polyps to invasive carcinomas. The composition of the tumor-infiltrating leukocyte population affects the ability of the immune system to fight the tumor. T cell infiltration into colorectal adenocarcinomas, particularly T helper 1 (Th1) type T cells as well as increased regulatory T cell (Treg) frequencies, is correlated with improved prognosis. However, whether Th1 cells and Tregs are already present at the adenoma stage is not known. In this study, the APC(Min/+) mouse model of intestinal adenomatous polyposis was used to investigate tumor associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas. Compared to unaffected tissue, adenomas accumulated CD4(+)FoxP3(+) putative Treg in parallel with lower frequencies of conventional T cells and B cells. The accumulation of Treg was also observed in human adenomatous polyps. Despite high Treg numbers, the function of conventional T cells present in the APC(Min/+) adenomas was not different from those in the unaffected tissue. Adenomas displayed an altered chemokine balance, with higher CCL17 and lower CXCL11 and CCL25 expression than in the unaffected tissue. In parallel, CXCR3(+) Tregs were largely absent from adenomas. The data indicate that already in early stages of tumor development, the balance of lymphocyte recruiting chemokines is altered possibly contributing to the observed shift toward higher frequencies of Treg. PMID- 24777616 TI - Damage Control Resuscitation In Trauma. AB - INTRODUCTION: Most preventable trauma deaths are due to uncontrolled hemorrhage. METHODS: In this article, we briefly describe the pathophysiology of the classical triad of death in trauma, namely, acidosis, hypothermia, and coagulopathy, and then suggest damage control resuscitation strategies to prevent and/or mitigate the effects of each in the bleeding patient. RESULTS: Damage control resuscitation strategies include body rewarming, restrictive fluid administration, permissive hypotension, balanced blood product administration, and the implementation of massive transfusion protocols. CONCLUSION: Resuscitating and correcting the coagulopathy of the exsanguinating trauma patient is essential to improve chances of survival. PMID- 24777617 TI - Perioperative acupuncture: why are we not using it? PMID- 24777618 TI - Feasibility of electric property tomography of pelvic tumors at 3T. AB - PURPOSE: Investigation of the validity of the "transceive phase assumption" for Electric Property Tomography of pelvic tumors at 3T. The acquired electric conductivities of pelvic tumors are beneficial for improved specific absorption rate determination in hyperthermia treatment planning. METHODS: Electromagnetic simulations and magnetic resonance imaging measurements of a pelvic-sized phantom and the human pelvis of a volunteer and a cervix cancer patient. RESULTS: The reconstructed conductivity values of the phantom tumor model are in good quantitative agreement (mean deviation: 1-10%) with the probe measurements. Furthermore, the average reconstructed conductivity of a pelvic tumor model was in close agreement with the input conductivity (0.86 S/m vs. 0.90 S/m). The reconstructed tumor conductivity of the presented patient (cervical carcinoma, Stage: IVA) was 1.16 +/- 0.40 S/m. CONCLUSION: This study demonstrates the feasibility of electric property tomography to measure quantitatively the conductivity of centrally located tumors in a pelvic-sized phantom and human pelvis with a standard magnetic resonance (MR) system and MR sequences. A good quantitative agreement was found between the reconstructed sigma-values and probe measurements for a wide range of sigma-values and for off-axis located spherical compartment. As most pelvic tumors are located in the central region of the pelvis, these results can be exploited in hyperthermia treatment planning systems. PMID- 24777619 TI - [Antibiotic Consumption and the Development of Antibiotic Resistance in Surgical Units]. AB - BACKGROUND: Antibiotic resistence is increasing worldwide. AIM: A longitudinal analysis of the influence of the density of antibiotic use on the development of resistance in surgical units was undertaken. MATERIAL AND METHODS: Over five years the incidence of pathogens and the resistance rates of isolates from patients of normal surgical units and those of a surgical ICU at a university hospital were examined. The resistence rates were correlated with the density of antibiotic use - calculated from the antibiotic consumption (in DDD) and the number of patient-days. RESULTS: At both units, Enterobacteriaceae and Enterococci were mostly cultured. Among the Enterobacteriaceae, E. coli, Klebsiella spp., Proteus mirabilis and Enterobacter predominated. In the group of Enterococci, E. faecalis predominated at wards whereas at ICU E. faecium was the most frequent. Anaerobes ranked third at normal wards and Candida spp. at ICU. From 2007 to 2011, there was an increasing resistance against ciprofloxacin in P. mirabilis (r = 0.87; p = 0.054) and against imipenem (r = 0.86; p = 0.06) and piperacillin (r = 0.81; p = 0.09) in P. aeruginosa at normal wards. At ICU, the resistance rates of imipenem in P. aeruginosa rose (r = 0.88; p = 0.049). Resistance against ciprofloxacin in E. coli increased (r = 0.65; p = 0.23). Due to the increasing use of ciprofloxacin and meropenem at normal wards, the density of antibiotic usage rose 1.4 %/year (r = 0.94; p = 0.02). Despite the increase of meropenem use at ICU (r = 0.9; p = 0.035), the total antibiotic uptake rate remained almost constant. The antibiotic usage density was 3-fold higher at ICU than at normal wards. At normal wards, the ciprofloxacin usage correlated with the rate of resistance against ciprofloxacin in P. mirabilis P. m. At ICU, an association was detected between the uptake rate of ceftazidime and the rate of resistance against cefotaxime in the CES group. In P. aeruginosa, the use of piperacillin and the rate of resistance against piperacillin correlated. CONCLUSION: The high uptake rates of fluoroquinolones and carbapenems were accompanied by increases in resistances. The resistance rates are influenced by hygiene management and microbiological diagnostics. The extensive use of carbapenems should be reassessed on both units to counter further development of antibiotic resistance. PMID- 24777620 TI - Risk factors for 'small for gestational age babies'. AB - OBJECTIVE: To identify the risk factors for small for gestational age (SGA) babies. METHODS: The present study was a nested case control study which was carried out by two Medical Officers of Health areas (The field level administrative unit responsible for provision of preventive and promotive health services) in Colombo district. SGA babies were identified using 'weight for gestational age' curves developed for Sri Lankan babies. Newborns of 1,200 pregnant women, who were identified within the first 8 wk of amenorrhea and who delivered in selected hospitals were included in the study. Sample size was calculated as n=167 cases and 4 n=668 controls, with four controls for each case. A case was defined as a newborn whose birth weight was less than the 10th percentile of the weight for gestational age, the control being a newborn whose birth weight was between the 10th and the 90th percentile of the weight for gestational age. RESULTS: Multivariate analysis identified 7 significant risk factors as, number of live born children=0, inadequate weight gain during pregnancy according to initial BMI, maximum and minimum physical work, mother's pre-pregnant weight less than 38 kg, high level of stress at second trimester, presence of pregnancy induced hypertension (PIH) and inadequate support from husband. CONCLUSION: The risk factors indicate the directions for planning intervention programs. PMID- 24777621 TI - A double blind randomized trial showing probiotics to be ineffective in acute diarrhea in Indonesian children. AB - OBJECTIVE: To investigate the efficacy of probiotics added to oral rehydration solution and zinc in the treatment of acute infectious diarrhea in Indonesian children. METHODS: A prospective randomized double blind placebo-controlled trial was performed to test the efficacy of a probiotic food supplement in 112 children in the Kenari subdistrict, central Jakarta, aged 6-36 mo with acute infectious diarrhea and moderate dehydration. The supplemented group was given standard therapy (oral rehydration solution and zinc) and the probiotic strains Lactobacillus (L.) rhamnosus R0011 1.9 * 10(9) colony forming units (cfu) and L. acidophilus R0052 0.1 * 10(9) cfu/d for 7 d, while the control group was given standard therapy and placebo. RESULTS: Median duration of diarrhea was 68.5 h (range 13-165) in the supplemented and 61.5 h (range 21-166) in the control group (P = 0.596). Median daily frequency of defecation until diarrhea stopped was 5.0 in the supplemented vs. 5.5 in the control group (P = 0.795). CONCLUSIONS: This probiotic food supplement tested did not reduce the duration of acute infectious diarrhea as compared to oral rehydration and zinc. PMID- 24777622 TI - Response of Indian growth hormone deficient children to growth hormone therapy: association with pituitary size. AB - OBJECTIVE: To ascertain the impact of pituitary size as judged by Magnetic Resonance Imaging (MRI), on response to Growth Hormone (GH) therapy in GH deficient children. METHODS: Thirty nine children (9.1 +/- 2.7 y, 22 boys) with non-acquired GH deficiency (21 Isolated GH deficiency and 18 Combined pituitary hormone deficiency) were consecutively recruited and followed up for one year. Clinical, radiological (bone age and MRI) and biochemical parameters were studied. RESULTS: Children with hypoplastic pituitary (pituitary height < 3 mm) had more severe height deficit (height for age Z-score -6.0 vs. -5.0) and retardation of skeletal maturation (bone age chronological age ratio of 0.59 vs. 0.48) at baseline as compared to children with normal pituitary heights (p < 0.05 for both). After one year of GH therapy, height for age Z scores and percentage change in height for age Z scores were significantly higher in children with hypoplastic pituitaries (13.8 +/- 3.6 and 28.7 % vs. 11.2 +/- 4.1 and 21.4 %). Significant co-relation was observed between pituitary height and height for age Z-scores at baseline (r = 0.39, p < 0.05). The predicted adult height using Tanner Whitehouse-2 equations improved from 140.8 to 152.3 cm in children with hypoplastic pituitary when compared to an increase from 145.8 to 153.5 cm observed in children with normal pituitary height (p < 0.05). CONCLUSIONS: Indian growth hormone deficient children with hypoplastic pituitary respond better to therapy with GH in short term. PMID- 24777623 TI - Traumatic abdominal wall hernia. PMID- 24777624 TI - Graves' orbitopathy precipitated by iatrogenic hypothyroidism secondary to carbimazole for Graves' disease. PMID- 24777625 TI - A baby girl with distended abdomen and unusual course of umbilical catheter. PMID- 24777626 TI - Hepatitis C virus genotypes circulating in patients with chronic hepatitis C in Thailand and their responses to combined PEG-IFN and RBV therapy. AB - Different genotypes of hepatitis C virus (HCV) are circulating in different areas of the world. In Thailand, distribution of HCV genotypes has been investigated mostly in the central area while the information in other regions is limited. This study aimed to determine the HCV genotypes circulating in chronic hepatitis C patients in Chiang Mai, Thailand and to investigate the response of different HCV genotypes to pegylated interferon (PEG-IFN) and ribavirin (RBV) treatment. Patients infected chronically with HCV were treated with PEG-IFN/RBV based on the standard regimens for each HCV genotype and followed up the patients until the end of treatment and 6 months afterward. Out of 158 patients, three major HCV genotypes and eight subtypes were identified. Genotype 3 was the most predominant at 54.5%, followed by genotypes 1 (31%) and 6 (14.5%). Among subtypes, 3a was the most prevalent subtype (45%), followed by 1b (18.4%), 1a and 6f (each at 12.6%), 3b (9.5%), and 6a, 6i, 6n (each at 0.63%). Patients with genotype 3 showed higher rate of responding to the treatment at 80.2% compared to genotypes 1 (73.5%) and 6f (65%). Additionally, patients with genotype 6f showed higher rate of relapsing (25%) compared to genotypes 1 and 3 (14.3% and 16.3%, respectively). In conclusion, this study reported multiple HCV genotypes circulated in Thai patients and the response of different HCV genotypes to PEG-IFN/RBV treatment. PMID- 24777627 TI - A new cold-adapted, organic solvent stable lipase from mesophilic Staphylococcus epidermidis AT2. AB - The gene encoding a cold-adapted, organic solvent stable lipase from a local soil isolate, mesophilic Staphylococcus epidermidis AT2 was expressed in a prokaryotic system. A two-step purification of AT2 lipase was achieved using butyl sepharose and DEAE sepharose column chromatography. The final recovery and purification fold were 47.09 % and 3.45, respectively. The molecular mass of the purified lipase was estimated to be 43 kDa. AT2 lipase was found to be optimally active at pH 8 and stable at pH 6-9. Interestingly, this enzyme demonstrated remarkable stability at cold temperature (<30 degrees C) and exhibited optimal activity at a temperature of 25 degrees C. A significant enhancement of the lipolytic activity was observed in the presence of Ca(2+), Tween 60 and Tween 80. Phenylmethylsulfonylfluoride, a well known serine inhibitor did not cause complete inhibition of the enzymatic activity. AT2 lipase exhibited excellent preferences towards long chain triglycerides and natural oils. The lipolytic activity was stimulated by dimethylsulfoxide and diethyl ether, while more than 50 % of its activity was retained in methanol, ethanol, acetone, toluene, and n hexane. Taken together, AT2 lipase revealed highly attractive biochemical properties especially because of its stability at low temperature and in organic solvents. PMID- 24777628 TI - CT-derived atrial and ventricular septal signs for risk stratification of patients with acute pulmonary embolism: clinical associations of CT-derived signs for prediction of short-term mortality. AB - A left-bulging atrial septum (AS) is an abnormal sign indicating hemodynamic overloading of the right heart. We tried to evaluate whether computed tomography (CT)-derived AS bulging and ventricular septum (VS) bowing signs would be used to identify patients with acute pulmonary embolism (PE) and significant hemodynamic derangements. In the prospective registry, 208 consecutive patients with a first episode of acute PE diagnosed by chest CT were grouped by clinical hemodynamic assessment: massive or submassive PE (Group 1), and small PE (Group 2). The curvatures of the AS and VS, and the diameters of right ventricle (RV) and left ventricle were measured on chest CT. Group 1 showed higher degrees of echocardiographic RV dysfunction, and abnormal CT-derived VS and AS curvatures versus Group 2. An abnormal VS bowing sign was observed in 32 (32.7%) and 6 (5.5%) patients in Groups 1 and 2, respectively (P < 0.001). An abnormal AS bulging sign was observed in 59 (60.2%) and 32 (29.1%) patients in Groups 1 and 2, respectively (P < 0.001). An algorithm was designed to predict clinically significant hemodynamic abnormality based on these signs. The patients deemed "higher risk" exhibited higher 90-day all-cause mortality than patients in the lower-risk group (P = 0.029). Conventional chest CT-derived hemodynamic findings, including abnormal AS and VS signs, can be used to identify high-risk patients with acute PE and to predict early mortality. PMID- 24777630 TI - A molecular approach to self-supported cobalt-substituted ZnO materials as remarkably stable electrocatalysts for water oxidation. AB - In regard to earth-abundant cobalt water oxidation catalysts, very recent findings show the reorganization of the materials to amorphous active phases under catalytic conditions. To further understand this concept, a unique cobalt substituted crystalline zinc oxide (Co:ZnO) precatalyst has been synthesized by low-temperature solvolysis of molecular heterobimetallic Co(4-x)Zn(x) O4 (x = 1 3) precursors in benzylamine. Its electrophoretic deposition onto fluorinated tin oxide electrodes leads after oxidative conditioning to an amorphous self supported water-oxidation electrocatalyst, which was observed by HR-TEM on FIB lamellas of the EPD layers. The Co-rich hydroxide-oxidic electrocatalyst performs at very low overpotentials (512 mV at pH 7; 330 mV at pH 12), while chronoamperometry shows a stable catalytic current over several hours. PMID- 24777629 TI - Realizing the promise of reverse phase protein arrays for clinical, translational, and basic research: a workshop report: the RPPA (Reverse Phase Protein Array) society. AB - Reverse phase protein array (RPPA) technology introduced a miniaturized "antigen down" or "dot-blot" immunoassay suitable for quantifying the relative, semi quantitative or quantitative (if a well-accepted reference standard exists) abundance of total protein levels and post-translational modifications across a variety of biological samples including cultured cells, tissues, and body fluids. The recent evolution of RPPA combined with more sophisticated sample handling, optical detection, quality control, and better quality affinity reagents provides exquisite sensitivity and high sample throughput at a reasonable cost per sample. This facilitates large-scale multiplex analysis of multiple post-translational markers across samples from in vitro, preclinical, or clinical samples. The technical power of RPPA is stimulating the application and widespread adoption of RPPA methods within academic, clinical, and industrial research laboratories. Advances in RPPA technology now offer scientists the opportunity to quantify protein analytes with high precision, sensitivity, throughput, and robustness. As a result, adopters of RPPA technology have recognized critical success factors for useful and maximum exploitation of RPPA technologies, including the following: preservation and optimization of pre-analytical sample quality, application of validated high-affinity and specific antibody (or other protein affinity) detection reagents, dedicated informatics solutions to ensure accurate and robust quantification of protein analytes, and quality-assured procedures and data analysis workflows compatible with application within regulated clinical environments. In 2011, 2012, and 2013, the first three Global RPPA workshops were held in the United States, Europe, and Japan, respectively. These workshops provided an opportunity for RPPA laboratories, vendors, and users to share and discuss results, the latest technology platforms, best practices, and future challenges and opportunities. The outcomes of the workshops included a number of key opportunities to advance the RPPA field and provide added benefit to existing and future participants in the RPPA research community. The purpose of this report is to share and disseminate, as a community, current knowledge and future directions of the RPPA technology. PMID- 24777632 TI - Barking up the wrong tree: MicroRNAs in bile as markers for biliary complications. PMID- 24777631 TI - Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins. AB - Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-rifampicin, rifabutin, and rifapentine with antiretroviral drugs are reviewed and discussed. A rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co infected patients whenever efavirenz cannot be used and rifabutin is not available. Despite significant pharmacokinetic interactions between antiretrovirals and antitubercular drugs, adequate clinical response of both infections can be achieved with an acceptable safety profile when the pharmacological characteristics of drugs are known, and appropriate combination regimens, dosing, and timing of initiation are used. However, more clinical research is needed for newer drugs, such as rifapentine and the recently introduced integrase inhibitor antiretrovirals, and for specific population groups, such as children, pregnant women, and patients affected by multidrug resistant TB. PMID- 24777634 TI - Multifunctional Fe3O4@TiO2@Au magnetic microspheres as recyclable substrates for surface-enhanced Raman scattering. AB - Herein, we demonstrate the design and fabrication of multifunctional triplex Fe3O4@TiO2@Au core-shell magnetic microspheres (MSs), which show excellent surface enhanced Raman scattering (SERS) activity with high reproducibility and stability. In addition, due to their excellent catalytic properties, the as prepared Fe3O4@TiO2@Au magnetic MSs can clean themselves by photocatalytic degradation of target molecules adsorbed onto the substrate under irradiation with visible light, and can be re-used for several cycles with convenient magnetic separability. The influence of the size and distribution of Au nanoparticles (NPs) on the Fe3O4@TiO2 beads is investigated. The optimized samples employing Au NPs of 15 nm size and an areal density of about 2120 Au NPs on every MS show the best SERS activity and recyclable performance. The experimental results show that these magnetic MSs indicate a new route in eliminating the 'single-use' problem of traditional SERS substrates and exhibit their applicability as analytical tools for the detection of different molecular species. PMID- 24777633 TI - Beyond statins: new lipid lowering strategies to reduce cardiovascular risk. AB - Statins are the first-line therapy in LDL-Cholesterol (LDL-C) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease. Yet, a significant proportion of patients remain at high risk. Recently, a number of new therapies have been developed to further lower LDL-C. These agents may provide clinical benefit on top of statin therapy in patients with high residual risk, severe hypercholesterolemia or as an alternative for patients who are intolerant to statins. We review four novel approaches based on the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein-B100 (apoB), Cholesteryl ester transport protein (CETP) and microsomal triglyceride transfer protein (MTP). ApoB and MTP inhibitors (Mipomersen and Lomitapide) are indicated only for homozygous familial hypercholesterolemia patients. The results of ongoing trials with CETP and PCSK9 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease. PMID- 24777635 TI - Getting over the patriarchal barriers: women's management of men's smoking in Chinese families. AB - Chinese family is a patriarchal power system. How the system influences young mothers' agency in managing family men's smoking is unknown. Applying a gender lens, this ethnographic study explored how mothers of young children in Chinese extended families reacted to men's smoking. The study sample included 29 participants from 22 families. Semi-structured interviews and field observations were transcribed and analysis was conducted using open coding and constant comparison. The findings indicate that young mothers' interventions to reduce family men's home smoking were mediated by gendered relationships between the mothers and the smokers. The mothers could directly confront their husbands' smoking, although they were more conservative about their men's smoking in the presence of other family smokers. They experienced difficulty in directly confronting senior family men's smoking but found ways to skirt patriarchal constraints, either by persuading seniors to stop smoking in subtle ways, or more importantly, by using other non-smoking family members as 'mediators' to influence senior men's smoking. While future smoking cessation interventions should support mothers in protecting their children from tobacco smoke, the interventions should also include other family members who are in a better power position, particularly the grandparents of the children, to reduce home smoking. PMID- 24777636 TI - Statin-induced impairment of monocyte migration is gender-related. AB - Statins, widely used for treatment of hypercholesterolemia, have been demonstrated to exert pleiotropic beneficial effects independently of their cholesterol-lowering action, such as anti-inflammatory activity. A gender disparity has been observed in their cholesterol lowering activity as well as in response to these "off label" effects. Monocytes play a central role in atherosclerotic disease and, more in general, in inflammatory responses, through their chemotactic function and cytokine production. On these bases, in the present work, we examined the effect of statins on homeostasis and migration properties of freshly isolated monocytes from male and female healthy donors. Two prototypic natural and synthetic statins with different polarity, that is, type 1 and type 2 statins, have been considered: simvastatin and atorvastatin. Freshly isolated monocytes from peripheral blood of male and female healthy donors were treated with these drugs in the absence or presence of lipopolysaccharide (LPS) stimulation. Results obtained indicated that the polar statin efficiently inhibited chemotaxis of monocytes more than the apolar statin and that this effect was more significantly induced in cells from females than in cells from males. Dissecting the mechanisms involved, we found that these results could mainly be due to differential effects on: (i) the release of key cytokines, for example, MCP-1 and TNF-alpha; (ii) the maintenance of the redox homeostasis; (iii) a target activity on microfilament network integrity and function. All in all these results could suggest a reappraisal of "off-label" effects of statins taking into account either their chemical structure, that is, molecular polarity, or the gender issue. PMID- 24777641 TI - Real-time homonuclear broadband and band-selective decoupled pure-shift ROESY. AB - Unambiguous spectral assignments in (1)H solution-state NMR are central, for accurate structural elucidation of complex molecules, which is often hampered by signal overlap, primarily because of scalar coupling multiplets, even at typical high magnetic fields. The recent advances in homodecoupling methods have shown powerful means of achieving high resolution pure-shift (1)H spectra in 1D and also in 2D J-correlated experiments, by effectively collapsing the multiplet structures. The present work extends these decoupling strategies to through-space correlation experiments as well and describes two new pure-shift ROESY pulse schemes with homodecoupling during acquisition, viz., homodecoupled broadband (HOBB)-ROESY and homodecoupled band-selective (HOBS)-ROESY. Furthermore, the ROESY blocks suppress the undesired interferences of TOCSY cross peaks and other offsets. Despite the reduced signal sensitivity and prolonged experimental times, the HOBB-ROESY is particularly useful for molecules that exhibit an extensive scalar coupling network spread over the entire (1)H chemical shift range, such as natural/synthetic organic molecules. On the other hand, the HOBS-ROESY is useful for molecules that exhibit well-separated chemical shift regions such as peptides (NH, Halpha and side-chain protons). The HOBS-ROESY sensitivities are comparable with the conventional ROESY, thereby saves the experimental time significantly. The power of these pure-shift ROESY sequences is demonstrated for two different organic molecules, wherein complex conventional ROE cross peaks are greatly simplified with high resolution and sensitivity. The enhanced resolution allows deriving possibly more numbers of ROEs with better accuracy, thereby facilitating superior means of structural characterization of medium-size molecules. PMID- 24777642 TI - The influence of age on the histological grading of meningiomas. AB - This study was undertaken to assess the relationship between the age of patients at the time of their surgery and histological grading of meningiomas. A retrospective review was conducted for 1,083 consecutive patients with meningiomas who had surgical removal between January 1991 and December 2006. Histological grading for each tumor was done utilizing the WHO classification for meningiomas. The incidence of WHO grade II or III tumors between the elderly and the non-elderly groups was compared. The mean age at diagnosis for the WHO grade I, II, and III tumors was 55.1 (+/-14.79), 59.0 (+/-15.54), and 64.3 years (+/ 13.28) (p value = 0.007), respectively. We found that 11.9 % of meningiomas diagnosed after the age of 60 years was WHO grade II or III, while this value was only 6.9 % for patients 60 years or younger (p = 0.0006). Our study showed that the combined incidence of WHO grade II and III meningiomas increases as age advances. We believe that this constitutes an important piece of information requiring neurosurgeons to carefully and continuously observe the elderly patients harboring meningiomas. PMID- 24777637 TI - Ubiquitous points of control over regulatory T cells. AB - Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins involved in processes including DNA repair, cell cycle progression, protein quality control, and signal transduction. It has long been appreciated that ubiquitin-mediated events are important for certain signaling pathways leading to leukocyte activation and the stimulation of effector function. Now it is clear that the activities of molecules and pathways central to immune regulation are also modified and controlled by ubiquitin tagging. Among the mechanisms of immune control, regulatory T cells (or Tregs) are themselves particularly sensitive to such regulation. E3 ligases and deubiquitinases both influence Tregs through their effects on the signaling pathways pertinent to these cells or through the direct, posttranslational regulation of Foxp3. In this review, we will summarize and discuss several examples of ubiquitin-mediated control over multiple aspects of Treg biology including the generation, function and phenotypic fidelity of these cells. Fully explored and exploited, these potential opportunities for Treg modulation may lead to novel immunotherapies for both positive and negative fine tuning of immune restraint. PMID- 24777643 TI - Normal perfusion pressure breakthrough phenomenon: experimental models. AB - One of the most life-threatening complications after the obliteration of intracranial arteriovenous malformations is the development of oedema and/or multifocal haemorrhage. Two main theories have been postulated so far in order to explain this situation. On one hand, "normal perfusion pressure breakthrough phenomenon" is based on the loss of cerebral vessel autoregulation due to the chronic vasodilation of perinidal microcirculation. On the other hand, the "occlusive hyperaemia" deals with thrombotic and venous obstruction phenomena that may also generate such manifestations. The aim of this study is to resume the main concepts of the "normal perfusion pressure breakthrough phenomenon" theory as well as the related animal models described up to date, their advantages and disadvantages, and the main conclusions obtained as a result of the experimental research. PMID- 24777645 TI - Eating patterns in youth with restricting and binge eating/purging type anorexia nervosa. AB - OBJECTIVE: To describe eating patterns in youth with restricting and binge/purge type anorexia nervosa (AN) and to examine whether eating patterns are associated with binge eating or purging behaviors. METHOD: Participants included 160 children and adolescents (M = 15.14 +/- 2.17 years) evaluated at The University of Chicago Eating Disorders Program who met criteria for DSM-5 restrictive type AN (AN-R; 75%; n = 120) or binge eating/purging type AN (AN-BE/P; 25%; n = 40). All participants completed the eating disorder examination on initial evaluation. RESULTS: Youth with AN-R and AN-BE/P differed in their eating patterns, such that youth with AN-R consumed meals and snacks more regularly relative to youth with AN-BE/P. Among youth with AN-BE/P, skipping dinner was associated with a greater number of binge eating episodes (r = -.379, p < .05), while skipping breakfast was associated with a greater number of purging episodes (r = -.309, p < .05). DISCUSSION: Youth with AN-R generally follow a regular meal schedule, but are likely consuming insufficient amounts of food across meals and snacks. In contrast, youth with AN-BE/P tend to have more irregular eating patterns, which may play a role in binge eating and purging behaviors. Adults monitoring of meals may be beneficial for youth with AN, and particularly those with AN-BE/P who engage in irregular eating patterns. PMID- 24777644 TI - Drug and gene delivery to the back of the eye: from bench to bedside. PMID- 24777646 TI - Formation of high-valent iron-oxo species in superoxide reductase: characterization by resonance Raman spectroscopy. AB - Superoxide reductase (SOR), a non-heme mononuclear iron protein that is involved in superoxide detoxification in microorganisms, can be used as an unprecedented model to study the mechanisms of O2 activation and of the formation of high valent iron-oxo species in metalloenzymes. By using resonance Raman spectroscopy, it was shown that the mutation of two residues in the second coordination sphere of the SOR iron active site, K48 and I118, led to the formation of a high-valent iron-oxo species when the mutant proteins were reacted with H2O2. These data demonstrate that these residues in the second coordination sphere tightly control the evolution and the cleavage of the O-O bond of the ferric iron hydroperoxide intermediate that is formed in the SOR active site. PMID- 24777647 TI - Comparative effectiveness of liver transplant strategies for end-stage liver disease patients on renal replacement therapy. AB - There are complex risk-benefit tradeoffs with different transplantation strategies for end-stage liver disease patients on renal support. Using a Markov discrete-time state transition model, we compared survival for this group with 3 strategies: simultaneous liver-kidney (SLK) transplantation, liver transplantation alone (LTA) followed by immediate kidney transplantation if renal function did not recover, and LTA followed by placement on the kidney transplant wait list. Patients were followed for 30 years from the age of 50 years. The probabilities of events were synthesized from population data and clinical trials according to Model for End-Stage Liver Disease (MELD) scores (21-30 and >30) to estimate input parameters. Sensitivity analyses tested the impact of uncertainty on survival. Overall, the highest survival rates were seen with SLK transplantation for both MELD score groups (82.8% for MELD scores of 21-30 and 82.5% for MELD scores > 30 at 1 year), albeit at the cost of using kidneys that might not be needed. Liver transplantation followed by kidney transplantation led to higher survival rates (77.3% and 76.4%, respectively, at 1 year) than placement on the kidney transplant wait list (75.1% and 74.3%, respectively, at 1 year). When uncertainty was considered, the results indicated that the waiting time and renal recovery affected conclusions about survival after SLK transplantation and liver transplantation, respectively. The subgroups with the longest durations of pretransplant renal replacement therapy and highest MELD scores had the largest absolute increases in survival with SLK transplantation versus sequential transplantation. In conclusion, the findings demonstrate the inherent tension in choices about the use of available kidneys and suggest that performing liver transplantation and using renal transplantation only for those who fail to recover their native renal function could free up available donor kidneys. These results could inform discussions about transplantation policy. PMID- 24777648 TI - Invited commentary: Positive youth development and human complexity. AB - The process of positive development for adolescents includes struggling to address a wide variety of complex, often unstated bio-psycho-social-cultural challenges. These include formulating workable values, learning self-regulation, preparation for adult work roles-and innumerable other un-tidy puzzles. Variable based research can only scratch the surface of how youth go about these processes; nonetheless, systematic longitudinal research like this can provide valuable information about developmental pathways and directions of change. Highlights from these papers include the finding that older youth report more goals aimed at meaningful connection with others and contributing to society; yet also that moral character did not differ by age. The papers suggest that relationships adults, hope, school engagement, participation in out-of-school programs, and intentional self-regulation can serve as mediators of positive development. Yet, a striking finding was that comparatively few youth in the study manifest a pattern of change marked by the coupling of increases in positive youth development and decreases in risk/problem behavior. We believe there is much beneath the surface to be uncovered. PMID- 24777649 TI - Mexican-American adolescents' gender role attitude development: the role of adolescents' gender and nativity and parents' gender role attitudes. AB - Gender development has long term implications for education and career endeavors and family formation behaviors, but we know very little about the role of sociocultural factors in developmental and individual differences. In this study, we investigated one domain of gender development, gender role attitudes, in Mexican-American adolescents (N = 246; 51 % female), using four phases of longitudinal data across 8 years. Data were collected when adolescents averaged 12.51 years (SD = 0.58), 14.64 years (SD = 0.59), 17.72 years (SD = 0.57), and 19.60 years of age (SD = 0.66). Mothers' and fathers' gender role attitudes also were assessed in Phases 1, 3, and 4. Findings revealed that gender attitude development varied as a function of the interaction between adolescents' nativity and gender. Among Mexico-born adolescents, females exhibited significant declines in traditional attitudes from early to late adolescence, but males' attitudes were stable over time. U.S.-born females and males, in contrast, did not differ in their gender attitude trajectories. Examining the links between mothers', fathers', and adolescents' gender role attitudes revealed within-person associations between mothers' and adolescents' gender role attitudes: on occasions when mothers reported more traditional attitudes relative to their own cross-time average, adolescents also reported more traditional attitudes than usual. In addition, fathers' more traditional gender role attitudes were associated with daughters', but not sons', more traditional gender role attitudes at the between-person level. The discussion focuses on the interpretation of Mexican-American adolescents' gender role attitude development from a cultural ecological perspective. PMID- 24777650 TI - Effects of continuous passage on immunomodulatory properties of human adipose derived stem cells. AB - Human adipose-derived stem cells (hADSCs) have the ability to influence immune response, and hence are key cell sources for tissue repair and regeneration. In this study we explored the effect of continuous passage on the immunomodulatory properties of hADSCs to provide some advises for large-scale production of hADSCs for clinical applications. We found that after continuous passage, the specific surface markers expression levels as well as the adipogenic and osteogenic differentiation capacities of hADSCs had no obvious changes. However, the secretion levels of IL-10 and HGF reduced dramatically along with passage numbers. Furthermore, the INF-gamma level was found higher in which medium peripheral blood mononuclear cells were co-cultured with hADSCs with higher passage numbers. Also, the in vivo experiments showed that the peritonitis model mice, which were injected with higher passage numbers of hADSCs, tended to have higher levels of inflammation. All these together indicated that continuous passage has only minor effect on the cell phenotypes but will impair the immunomodulatory properties of hADSCs. This suggests that hADSCs could be prepared by continuous passage, but only those cells of lower passage numbers would be ideal therapeutic tools. PMID- 24777651 TI - Analytical functions for beta and gamma absorbed fractions of iodine-131 in spherical and ellipsoidal volumes. AB - BACKGROUND: The beta and gamma absorbed fractions in organs and tissues are the important key factors of radionuclide internal dosimetry based on Medical Internal Radiation Dose (MIRD) approach. OBJECTIVES: The aim of this study is to find suitable analytical functions for beta and gamma absorbed fractions in spherical and ellipsoidal volumes with a uniform distribution of iodine-131 radionuclide. METHODS: MCNPX code has been used to calculate the energy absorption from beta and gamma rays of iodine-131 uniformly distributed inside different ellipsoids and spheres, and then the absorbed fractions have been evaluated. RESULTS: We have found the fit parameters of a suitable analytical function for the beta absorbed fraction, depending on a generalized radius for ellipsoid based on the radius of sphere, and a linear fit function for the gamma absorbed fraction. CONCLUSION: The analytical functions that we obtained from fitting process in Monte Carlo data can be used for obtaining the absorbed fractions of iodine-131 beta and gamma rays for any volume of the thyroid lobe. Moreover, our results for the spheres are in good agreement with the results of MIRD and other scientific literatures. PMID- 24777652 TI - Counterpoint: Establishing consensus in the diagnosis of GDM following the HAPO study. AB - The International Association of Diabetes in Pregnancy Study Groups (IADPSG) recommended a new protocol of 1-step testing with a 75 g oral glucose tolerance test for gestational diabetes in 2010. Since that time, these recommendations have been carefully scrutinized and accepted by a variety of organizations, but challenged or rejected by others. In the current review, we present more details regarding the background to the development of the IADPSG recommendations and seek to place them in context with the available epidemiologic and randomized controlled trial data. In this "counterpoint," we also provide specific rebuttal for errors of fact and disputed contentions provided by Long and Cundy in their 2013 article in Current Diabetes Reports. PMID- 24777653 TI - Digital drug safety surveillance: monitoring pharmaceutical products in twitter. AB - BACKGROUND: Traditional adverse event (AE) reporting systems have been slow in adapting to online AE reporting from patients, relying instead on gatekeepers, such as clinicians and drug safety groups, to verify each potential event. In the meantime, increasing numbers of patients have turned to social media to share their experiences with drugs, medical devices, and vaccines. OBJECTIVE: The aim of the study was to evaluate the level of concordance between Twitter posts mentioning AE-like reactions and spontaneous reports received by a regulatory agency. METHODS: We collected public English-language Twitter posts mentioning 23 medical products from 1 November 2012 through 31 May 2013. Data were filtered using a semi-automated process to identify posts with resemblance to AEs (Proto AEs). A dictionary was developed to translate Internet vernacular to a standardized regulatory ontology for analysis (MedDRA((r))). Aggregated frequency of identified product-event pairs was then compared with data from the public FDA Adverse Event Reporting System (FAERS) by System Organ Class (SOC). RESULTS: Of the 6.9 million Twitter posts collected, 4,401 Proto-AEs were identified out of 60,000 examined. Automated, dictionary-based symptom classification had 86 % recall and 72 % precision [corrected]. Similar overall distribution profiles were observed, with Spearman rank correlation rho of 0.75 (p < 0.0001) between Proto AEs reported in Twitter and FAERS by SOC. CONCLUSION: Patients reporting AEs on Twitter showed a range of sophistication when describing their experience. Despite the public availability of these data, their appropriate role in pharmacovigilance has not been established. Additional work is needed to improve data acquisition and automation. PMID- 24777654 TI - Cardiovascular effects of drugs used to treat Alzheimer's disease. AB - Drugs that are used to treat Alzheimer's disease include the acetyl cholinesterase inhibitors (ACHIs) donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine. Adverse cardiovascular events with these drugs are very uncommon. However, there is evidence that ACHI therapy is associated with a small but significant increase in the risk of syncope and bradycardia. There are also a few reports that these drugs may occasionally be associated with QT prolongation and torsades de pointes ventricular tachycardia. Adverse cardiovascular effects of ACHIs including syncope and bradycardia are less common than their adverse gastrointestinal effects, but they remain important considerations in susceptible individuals. In contrast, animal studies and some observational studies suggest that ACHIs may reduce myocardial infarction and cardiovascular mortality and have favourable effects on hemodynamics and survival in heart failure. Further research is required to confirm these potential beneficial effects. Little is known about the cardiovascular effects of memantine but there have been reports of bradycardia and reduced cardiovascular survival associated with its use. PMID- 24777655 TI - Solution-processed copper-nickel nanowire anodes for organic solar cells. AB - This work describes a process to make anodes for organic solar cells from copper nickel nanowires with solution-phase processing. Copper nanowire films were coated from solution onto glass and made conductive by dipping them in acetic acid. Acetic acid removes the passivating oxide from the surface of copper nanowires, thereby reducing the contact resistance between nanowires to nearly the same extent as hydrogen annealing. Films of copper nanowires were made as oxidation resistant as silver nanowires under dry and humid conditions by dipping them in an electroless nickel plating solution. Organic solar cells utilizing these completely solution-processed copper-nickel nanowire films exhibited efficiencies of 4.9%. PMID- 24777656 TI - [Mild neurocognitive disorder - a disease? For]. PMID- 24777657 TI - The impact of health insurance on health outcomes and spending of the elderly: evidence from China's New Cooperative Medical Scheme. AB - This paper investigates the effects of China's New Cooperative Medical Scheme (NCMS) on health outcomes and healthcare expenditure of the elderly in rural China, using panel data from the 2005 and 2008 waves of the Chinese Longitudinal Healthy Longevity Survey. We employ a strategy that combines propensity score matching with a difference-in-differences approach to address selection bias. Results show that the NCMS has significantly improved the elderly enrollees' activities of daily living and cognitive function but has not led to better self assessed general health status. We find no significant effect of NCMS on mortality for the previously uninsured elderly in NCMS counties, although there is moderate evidence that it is associated with reduced mortality for the elderly enrollees. We also find that the elderly participants are more likely to get adequate medical services when sick, which provides a good explanation for the beneficial health effects of NCMS. However, there is no evidence that the NCMS has reduced their out-of-pocket spending. Furthermore, we also find that low income seniors benefit more from NCMS participation in terms of health outcomes and perceived access to health care, suggesting that the NCMS helps reduce health inequalities among the rural elderly. PMID- 24777658 TI - Identification and quantification of 35 psychotropic drugs and metabolites in hair by LC-MS/MS: application in forensic toxicology. AB - Despite a non-invasive sampling, hair samples are generally collected in limited amounts for an obvious esthetic reason. In order to reduce the required quantity of samples, a multianalytes method allowing simultaneous identification and quantification of 35 psychoactive drugs was developed. After incubation of 50 mg of hair in a phosphate buffer pH 5 for one night at room temperature, the substances of interest were extracted by a simple liquid-liquid extraction step, with a dichloromethane/ether mixture (70:30, v/v). After evaporation under a gentle stream of nitrogen and reconstitution in formate buffer (2 mM, pH 3)/acetonitrile (90:10, v/v), twenty microliter were injected into the LC-MS/MS system for a chromatographic run of 29 min using an Atlantis T3 column (150 * 2.1 mm, 3 MUm) (Waters Corp, Milford, USA) and a gradient mixture of 2 mM, pH 3.0 ammonium formate, and 2 mM, pH 3.0 ammonium formate/acetonitrile. The data acquisition was performed in scheduled MRM mode. Intra- and inter-day precisions, estimated using the coefficient of variation and relative bias, were lower than 20 % for all concentration levels, except for two compounds. The limits of detection and quantification ranged from 0.5 to 10 pg/mg. After complete validation, this method has been successfully used in several forensic cases, three of which are reported. PMID- 24777659 TI - One donor, two types of preservation: first description of a donation after circulatory death donor with normothermic abdominal perfusion and simultaneous cold perfusion of lungs. PMID- 24777660 TI - Laparoscopic versus open incisional and ventral hernia repair: a systematic review and meta-analysis. AB - BACKGROUND: Laparoscopic incisional and ventral hernia repair (LIVHR) is an alternative approach to conventional open incisional and ventral hernia repair (OIVHR). A consensus on outcomes of LIVHR when compared with OIVHR has not been reached. METHODS: As the basis for the present study, we performed a systematic review and meta-analysis of all randomized controlled trials comparing LIVHR and OIVHR. RESULTS: Eleven studies involving 1,003 patients were enrolled. The incidences of wound infection were significantly lower in the laparoscopic group than that in the open group (laparoscopic group 2.8 %, open group 16.2 %; RR = 0.19, 95 % CI 0.11-0.32; P < 0.00001). The rates of wound drainage were significantly lower in the laparoscopic group than that in the open group (laparoscopic group 2.6 %, open group 67.0 %; RR = 0.06, 95 % CI 0.03-0.09; P < 0.00001). However, the rates of bowel injury were significantly higher in the laparoscopic group than in the open group (laparoscopic group 4.3 %, open group 0.81 %; RR = 3.68, 95 % CI 1.56-8.67; P = 0.003). There were no significant differences between the two groups in the incidences of hernia recurrence, postoperative seroma, hematoma, bowel obstruction, bleeding, and reoperation. Descriptive analyses showed a shorter length of hospital stay in the laparoscopic group. CONCLUSIONS: Laparoscopic incisional and ventral hernia repair is a feasible and effective alternative to the open technique. It is associated with lower incidences of wound infection and shorter length of hospital stay. However, caution is required because it is associated with an increased risk of bowel injury compared with the open technique. Given the relatively short follow-up duration of trials included in the systematic review, trials with long-term follow-up are needed to compare the durability of laparoscopic and open repair. PMID- 24777661 TI - A comparison of complications in 400 patients after native nail versus silicone nail splints for fingernail splinting after injuries. AB - BACKGROUND: The fingertip is the most commonly injured part of the hand and is an important aesthetic part of the hand. METHODS: In this retrospective study we analyzed data from 700 patients operated on between 1997 and 2008 for complications after nail splinting with native nail or silicone nail. Inclusion criteria were patients living in Bern/Berner Land, complete documentation, same surgical team, standard antibiotics, acute trauma, no nail bed transplantation, and no systemic diseases. Groups were analyzed for differences in age, gender, cause and extension of trauma, bony injury and extent, infection, infectious agent, and nail deformities. Statistical analysis was done using the chi (2) test, Fisher's exact test, and Pearson correlation coefficients. RESULTS: A total of 401 patients, with a median age of 39.5 years, were included. There were more men with injured nails. Two hundred forty native nails and 161 silicone splints were used. There were 344 compression injuries, 44 amputations, and 13 avulsion injuries. Forty-three patients had an infection, with gram-positive bacteria (Staphylococcus aureus) causing most infections. A total of 157 nail dystrophies were observed, split nails most often. The native nail splint group showed significantly (p < 0.015) fewer nail deformities than the silicone nail splint group; otherwise, there were no statistical differences. However, there were twice as many infections in the silicone nail group. CONCLUSION: It seems to be advantageous to use the native nail for splinting after trauma, when possible. In case of a destroyed and unusable nail plate, a nail substitute has to be used. PMID- 24777662 TI - Identification of potential drug targets in Salmonella enterica sv. Typhimurium using metabolic modelling and experimental validation. AB - Salmonella enterica sv. Typhimurium is an established model organism for Gram negative, intracellular pathogens. Owing to the rapid spread of resistance to antibiotics among this group of pathogens, new approaches to identify suitable target proteins are required. Based on the genome sequence of S. Typhimurium and associated databases, a genome-scale metabolic model was constructed. Output was based on an experimental determination of the biomass of Salmonella when growing in glucose minimal medium. Linear programming was used to simulate variations in the energy demand while growing in glucose minimal medium. By grouping reactions with similar flux responses, a subnetwork of 34 reactions responding to this variation was identified (the catabolic core). This network was used to identify sets of one and two reactions that when removed from the genome-scale model interfered with energy and biomass generation. Eleven such sets were found to be essential for the production of biomass precursors. Experimental investigation of seven of these showed that knockouts of the associated genes resulted in attenuated growth for four pairs of reactions, whilst three single reactions were shown to be essential for growth. PMID- 24777664 TI - Assessment of mutagenic, genotoxic, and cytotoxic potential of water samples of Harike wetland: a Ramsar site in India using different ex vivo biological systems. AB - Harike is a wetland of international importance under the Ramsar Convention. The present study entails the investigation of mutagenic, genotoxic and cytotoxic effect of surface water samples collected from five different areas of the Harike wetland by using the histidine reversion point mutation assay in Salmonella typhimurium (TA98 and TA100) strain with or without S9, bioluminescence mutagenicity assay using Vibrio harveyi (A16) strain, plasmid-nicking assay using pBR322 and 3(4,5-dimethyl-thiazol-2-yl)2,5-diphenyl-tetrazolium bromide assay as well as confocal imaging studies using Chinese hamster ovarian cell line, respectively. It was observed that although, the water sample of all the areas of wetland demonstrated mutagenic, genotoxic as well as cytotoxic activity, the effect was quite significant with the water samples from River Satluj and Khatan area (i.e. reservoir mainly contains Satluj water). The metal analysis of water samples was also conducted with atomic absorption spectrophotometer. The mutagenicity, genotoxicity and cytotoxicity of water samples emerged to be correlated with metal concentration. The source of toxic components seems to be associated with various industrial effluents and agricultural run-off. The results of the present study carry great importance in documenting the water quality monitoring data of the wetland. PMID- 24777663 TI - The paracrine feedback loop between vitamin D3 (1,25(OH)2D3) and PTHrP in prehypertrophic chondrocytes. AB - The endocrine feedback loop between vitamin D3(1,25(OH)2D3) and parathyroid hormone (PTH) plays a central role in skeletal development. PTH-related protein (PTHrP) shares homology and its receptor (PTHR1) with PTH. The aim of this study was to investigate whether there is a functional paracrine feedback loop between 1,25(OH)2D3 and PTHrP in the growth plate, in parallel with the endocrine feedback loop between 1,25(OH)2D3 and PTH. This was investigated in ATDC5 cells treated with 10(-8) M 1,25(OH)2D3 or PTHrP, Col2-pd2EGFP transgenic mice, and primary Col2-pd2EGFP growth plate chondrocytes isolated by FACS, using RT-qPCR, Western blot, PTHrP ELISA, chromatin immunoprecipitation (ChIP) assay, silencing of the 1,25(OH)2D3 receptor (VDR), immunofluorescent staining, immunohistochemistry, and histomorphometric analysis of the growth plate. The ChIP assay confirmed functional binding of the VDR to the PTHrP promoter, but not to the PTHR1 promoter. Treatment with 1,25(OH)2D3 decreased PTHrP protein production, an effect which was prevented by silencing of the VDR. Treatment with PTHrP significantly induced VDR production, but did not affect 1alpha- and 24 hydroxylase expression. Hypertrophic differentiation was inhibited by PTHrP and 1,25(OH)2D3 treatment. Taken together, these findings indicate that there is a functional paracrine feedback loop between 1,25(OH)2D3 and PTHrP in the growth plate. 1,25(OH)2D3 decreases PTHrP production, while PTHrP increases chondrocyte sensitivity to 1,25(OH)2D3 by increasing VDR production. In light of the role of 1,25(OH)2D3 and PTHrP in modulating chondrocyte differentiation, 1,25(OH)2D3 in addition to PTHrP could potentially be used to prevent undesirable hypertrophic chondrocyte differentiation during cartilage repair or regeneration. PMID- 24777666 TI - Quantitative muscle ultrasound and quadriceps strength in patients with post polio syndrome. AB - INTRODUCTION: We investigated whether muscle ultrasound can distinguish muscles affected by post-polio syndrome (PPS) from healthy muscles and whether severity of ultrasound abnormalities is associated with muscle strength. METHODS: Echo intensity, muscle thickness, and isometric strength of the quadriceps muscles were measured in 48 patients with PPS and 12 healthy controls. RESULTS: Patients with PPS had significantly higher echo intensity and lower muscle thickness than healthy controls. In patients, both echo intensity and muscle thickness were associated independently with muscle strength. A combined measure of echo intensity and muscle thickness was more strongly related to muscle strength than either parameter alone. CONCLUSIONS: Quantitative ultrasound distinguishes healthy muscles from those affected by PPS, and measures of muscle quality and quantity are associated with muscle strength. Hence, ultrasound could be a useful tool for assessing disease severity and monitoring changes resulting from disease progression or clinical intervention in patients with PPS. PMID- 24777665 TI - Effects of trilostane and fipronil on the reproductive axis in an early life stage of the Japanese medaka (Oryzias latipes). AB - Given the critical role of the hypothalamic-pituitary-gonadal (HPG) axis, it is conceivable that perturbations at any point along this axis can potentially affect reproduction in fish and other vertebrates. We investigated the effects of a 3beta-hydroxysteroid dehydrogenase (3beta-HSD) inhibitor, trilostane (TRI), and a gamma-aminobutyric acid (GABA)-receptor antagonist, fipronil (FIP), on the HPG axis using an early life stage of the Japanese medaka. The newly hatched larvae were exposed to TRI (100, 300 and 1000 MUg/L) and FIP (3, 10 and 30 MUg/L), respectively, until 28 days post-hatching. Exposure to TRI decreased the body length in males, whereas FIP inhibited growth in both sexes. The induction of steroidogenesis-regulating genes (including 3beta-hsd) in males exposed to TRI, accompanied by increased vtg and er transcription, indicating a compensatory response to the presumed 3beta-HSD inhibition. These compensatory responses were not observed in TRI-treated females. Regarding FIP exposure, the GABA blocker resulted in the down-regulation of fshr and lhr. A compensatory up-regulation of steroidogenesis-regulating genes partially explained the elevated transcripts of vtg genes in both males and females after FIP exposure. These results suggest that both the inhibition of 3beta-HSD and the antagonism of GABA receptors are relevant modes of endocrine disruption that could impact the normal regulation of the HPG axis. PMID- 24777667 TI - Mucinous tumors of the ovary: current thoughts on diagnosis and management. AB - Mucinous tumors of the ovary represent a spectrum of neoplastic disorders, including benign mucinous cystadenoma, pseudomyxoma peritonei, mucinous tumors of low malignant potential (borderline), and invasive mucinous ovarian carcinoma. These tumors are related closely to each other and are distinct from other histologic subtypes of epithelial ovarian neoplasms from a clinical, histologic, and molecular standpoint. A continuum appears to be present from benign to borderline to malignant, which is different from other types of epithelial ovarian cancer. Mutational profiles are also distinct, as KRAS mutations are common, but p53 and BRCA mutations are infrequent. These characteristics lead to specific biologic behavior and guide both clinical management and research efforts in patients with mucinous ovarian tumors. PMID- 24777668 TI - An understanding of intervertebral disc development, maturation and cell phenotype provides clues to direct cell-based tissue regeneration therapies for disc degeneration. AB - Cell-based regenerative medicine therapies have been proposed for repairing the degenerated intervertebral disc (a major cause of back pain). However, for this approach to be successful, it is essential to characterise the phenotype of its native cells to guarantee that implanted cells differentiate and maintain the correct phenotype to ensure appropriate cell and tissue function. While recent studies have increased our knowledge of the human nucleus pulposus (NP) cell phenotype, their ontogeny is still unclear. The expression of notochordal markers by a subpopulation of adult NP cells suggests that, contrary to previous reports, notochord-derived cells are retained in the adult NP, possibly coexisting with a second population of cells originating from the annulus fibrosus or endplate. It is not known, however, how these two cell populations interact and their specific role(s) in disc homeostasis and disease. In particular, notochordal cells are proposed to display both anabolic and protective roles; therefore, they may be the ideal cells to repair the degenerate disc. Thus, understanding the ontogeny of the adult NP cells is paramount, as it will inform the medical and scientific communities as to the ideal phenotype to implant into the degenerate disc and the specific pathways involved in stem cell differentiation towards such a phenotype. PMID- 24777669 TI - Are current scoliosis school screening recommendations evidence-based and up to date? A best evidence synthesis umbrella review. AB - PURPOSE: Recommendations addressing school screening for adolescents with idiopathic scoliosis are contradictory. Consequently a critical evaluation of the methodological quality of available systematic reviews, including those upon which these recommendations are based, was conducted. METHODS: Articles meeting the minimal criteria to be considered a systematic review were included for a best evidence synthesis, umbrella review of secondary studies. The primary outcome measure was "any recommendation addressing the continuation, or not, of school screening programs". Multiple general bibliographic databases, guideline registries, as well as websites of institutions were searched. The AMSTAR tool was used to critically appraise the methodology of included reviews. Venn diagrams were created to examine potential overlaps across included papers within different reviews. RESULTS: Six reviews undertaken between 2002 and 2011, scored as moderate to low quality, were included. The 2012 US Preventive Services Task Force recommendation against screening was found to be based on an outdated (2004) low-quality review, whilst two higher quality and more recent (2009 and 2010) reviews support the continuation of school screening programs. CONCLUSIONS: As the existing recommendations supporting screening are based on moderate quality evidence whilst the recommendations against screening are based on low quality evidence, the latter recommendations appear to be both unconvincing and methodologically invalid. PMID- 24777670 TI - Early neurological recovery course after surgical treatment of cervical spondylotic myelopathy: a prospective study with 2-year follow-up using three different functional assessment tests. AB - PURPOSE: Though surgical decompression is today a common option for treatment of cervical spondylotic myelopathy (CSM), little is known about the exact postoperative early neurological recovery course. The purpose of this study was to analyze the functional recovery, its dynamics, its intensity and its pattern, in the early postoperative period after surgical decompression for CSM. METHODS: A prospective non-controlled observational study was performed from March 2006 to July 2008, and included consecutive patients with CSM who underwent surgical decompression. Functional assessments were done before the operation, at 1 month, 6, 12, 18 and 24 months after surgery using three tests: the Japanese Orthopaedic Association (JOA) test, the nine-hole peg test (9HPT) and the Crockard walking test. RESULTS: Sixty-seven patients were included (mean age of 61 years). The global JOA score improved after surgery, reaching statistical significance at 1 month (from 11.5 +/- 2.6 to 13.6 +/- 2.0 points, p = 0.0078), then settling to a plateau till the end of follow-up at 24 months (12.7 +/- 2.6 points). The 9HPT and the Crockard test did not show any significant improvement after surgery. CONCLUSIONS: Neurological recovery after surgical decompression has been proved to be very fast during the first month, but stabilizes afterwards. The JOA score is the best assessment to reveal neurological improvement in the early recovery course. PMID- 24777672 TI - A novel approach to estimate trabecular bone anisotropy from stress tensors. AB - Continuum finite element (FE) models of bones and bone-implant configurations are usually based on clinical CT scans. In virtually all of these models, material properties assigned to the bone elements are chosen as isotropic. It has been shown, however, that cancellous bone can be highly anisotropic and that its elastic behavior is best described as orthotropic. Material models have been proposed to derive the orthotropic elastic constants from measurements of density and a fabric tensor. The use of such relationships in FE models derived from CT scans, however, is hampered by the fact that the measurement of such a fabric tensor is not possible from clinical CT images since the resolution of such images is not good enough to resolve the trabecular micro-architecture. In this study, we explore an alternative approach that is based on the paradigm that bone adapts its micro-architecture to the loading conditions, hence that fabric and stress tensors should be aligned and correlated. With this approach, the eigenvectors and eigenvalues of the element continuum-level stress tensor are used as an estimate of the element fabric tensor, from which the orthotropic material properties then are derived. Using an iterative procedure, element orthotropic material properties and fabric tensors are updated until a converged situation is reached. The goals of this study were to investigate the feasibility and accuracy of such an iterative approach to derive orthotropic material properties for a human proximal femur and to investigate whether models derived in this way can provide more accurate results than isotropic models. Results were compared to those obtained from models of the same femurs for which the fabric was measured from micro-CT scans. It was found that the iterative approach could well estimate the orientation of the fabric principal directions. When comparing the stress/damage values in the models with material properties based on estimated and measured fabric tensors, the differences were not significant, suggesting that the material properties based on the estimated fabric tensor well reflected those based on the measured fabric tensor. Errors were less than those obtained when using isotropic models. It is concluded that this novel approach can provide a reasonable estimate of anisotropic material properties of cancellous bone. We expect that this approach can lead to more accurate results in particular for models used to study implants, which are usually anchored in highly anisotropic cancellous bone regions. PMID- 24777671 TI - Dynamic motion characteristics of the lower lumbar spine: implication to lumbar pathology and surgical treatment. AB - PURPOSE: Many studies have reported on the segmental motion range of the lumbar spine using various in vitro and in vivo experimental designs. However, the in vivo weightbearing dynamic motion characteristics of the L4-5 and L5-S1 motion segments are still not clearly described in literature. This study investigated in vivo motion of the lumbar spine during a weight-lifting activity. METHODS: Ten asymptomatic subjects (M/F: 5/5; age: 40-60 years) were recruited. The lumbar segment of each subject was MRI-scanned to construct 3D models of the L2-S1 vertebrae. The lumbar spine was then imaged using a dual fluoroscopic imaging system as the subject performed a weight-lifting activity from a lumbar flexion position (45 degrees ) to maximal extension position. The 3D vertebral models and the fluoroscopic images were used to reproduce the in vivo vertebral positions along the motion path. The relative translations and rotations of each motion segment were analyzed. RESULTS: All vertebral motion segments, L2-3, L3-4, L4-5 and L5-S1, rotated similarly during the lifting motion. L4-5 showed the largest anterior-posterior (AP) translation with 2.9 +/- 1.5 mm and was significantly larger than L5-S1 (p < 0.05). L5-S1 showed the largest proximal-distal (PD) translation with 2.8 +/- 0.9 mm and was significantly larger than all other motion segments (p < 0.05). CONCLUSIONS: The lower lumbar motion segments L4-5 and L5-S1 showed larger AP and PD translations, respectively, than the higher vertebral motion segments during the weight-lifting motion. The data provide insight into the physiological motion characteristics of the lumbar spine and potential mechanical mechanisms of lumbar disease development. PMID- 24777673 TI - Pulmonic regurgitation and management challenges in the adult with tetralogy of fallot. AB - OPINION STATEMENT: Patients with tetralogy of Fallot (TOF) are living longer than ever because of advances in surgery in childhood since the 1950s. However, surgery in childhood is not a cure and remains only a palliative procedure because almost all patients will require further intervention throughout life. The most common intervention required in adulthood is pulmonary valve replacement (PVR) because of residual pulmonary regurgitation leading to right ventricular dilation and eventual dysfunction. The most appropriate timing for PVR remains difficult to determine and is based on many factors. Our practice is to weigh not only objective factors such as right ventricular size and function but also careful objective assessment of the patient's current quality of life and functional status. PMID- 24777674 TI - Maternal WIC participation improves breastfeeding rates: a statewide analysis of WIC participants. AB - This study examined the association between length of exposure to Women, Infants, and Children (WIC) services and breastfeeding initiation/duration. All women with singleton live births, first certified into MA WIC prenatally or postpartum (2001 2009), with complete breastfeeding and covariate data (maternal race, age, education, smoking status, BMI, HH income and size, birth weight, whether full or preterm, and sex) were included (n = 122,506). Regressions models were used to examine timing of WIC entry (i.e., trimester of prenatal or postpartum) with: (1) breastfeeding initiation, (2) mean duration (3) and 3, 6 and 12 month durations. Among prenatal entrants, first (vs. third) trimester entry was associated with a higher likelihood of initiation for both primiparous, and multiparous mothers (10 and 32 % respectively; p < .01). Prenatal entrants breastfed 1.7 (primiparous), and 3.4 (multiparous) weeks longer than postpartum entrants (p < .0001). Among multiparous women, first trimester entry was associated a greater likelihood of breastfeeding for three (15 % greater), six (25 % greater) and twelve (33 % greater) months compared to third trimester entrants (p < .0001). Greater exposure to WIC services improves breastfeeding rates among a low income diverse population of women. PMID- 24777675 TI - Corticosteroid use and risk of orofacial clefts. AB - BACKGROUND: Maternal use of corticosteroids during early pregnancy has been inconsistently associated with orofacial clefts in the offspring. A previous report from the National Birth Defect Prevention Study (NBDPS), using data from 1997 to 2002, found an association with cleft lip and palate (odds ratio, 1.7; 95% confidence interval [CI], 1.1-2.6), but not cleft palate only (odds ratio, 0.5, 95%CI, 0.2-1.3). From 2003 to 2009, the study population more than doubled in size, and our objective was to assess this association in the more recent data. METHODS: The NBDPS is an ongoing multi-state population-based case-control study of birth defects, with ascertainment of cases and controls born since 1997. We assessed the association of corticosteroids and orofacial clefts using data from 2372 cleft cases and 5922 controls born from 2003 to 2009. Maternal corticosteroid exposure was based on telephone interviews. RESULTS: The overall association of corticosteroids and cleft lip and palate in the new data was 1.0 (95% CI, 0.7-1.4). There was little evidence of associations between specific corticosteroid components or timing and clefts. CONCLUSION: In contrast to the 1997 to 2002 data from the NBDPS, the 2003 to 2009 data show no association between maternal corticosteroid use and cleft lip and palate in the offspring. PMID- 24777676 TI - Dendritic cells: master regulators of the immune response. AB - Dendritic cells (DC) are responsible for initiating all antigen-specific immune responses. As such, they are the master regulators of the immune response and serve this function by linking the microbial sensing features of the innate immune system to the exquisite specificity of the adaptive response. They are exceptionally efficient at antigen presentation and also adept at generating just the right type of T cells in response to a given pathogen. Importantly, DCs also help guide the immune system to respond to foreign antigens while avoiding the generation of autoimmune responses to self. DCs are thus paradoxically important in cancer, generating both immunity and tolerance. Given their central role in controlling the immune response in patients with cancer, DCs are emerging as a critical cell type that must be considered as we come to understand basic cancer immunobiology. They should also be considered as potential targets or at least as key players in any effort intended to generate therapeutic vaccines. PMID- 24777677 TI - Microbes and inflammation in colorectal cancer. AB - Over the past decade, there has been a renaissance in research on physiologic interactions between humans and their resident microbiota, the vast numbers of bacteria, fungi, and viruses that live within and on the body. The burgeoning interest in what constitutes the human microbiome has also focused on the contribution of microbes to carcinogenesis. Given the microbiomes of malignancies arising at mucosal sites, the microbiota may prove as influential as stromal cells and immune cells in the tumor microenvironment. Herein, we focus on the interconnections of microbes and inflammation in colorectal carcinogenesis. PMID- 24777678 TI - Ipilimumab treatment results in an early decrease in the frequency of circulating granulocytic myeloid-derived suppressor cells as well as their Arginase1 production. AB - Blocking the immune checkpoint molecule CTL antigen-4 (CTLA-4) with ipilimumab has proven to induce long-lasting clinical responses in patients with metastatic melanoma. To study the early response that takes place after CTLA-4 blockade, peripheral blood immune monitoring was conducted in five patients undergoing ipilimumab treatment at baseline, three and nine weeks after administration of the first dose. Along with T-cell population analysis, this work was primarily focused on an in-depth study of the myeloid-derived suppressor cell (MDSC) populations. Ipilimumab treatment resulted in lower frequencies of regulatory T cells along with reduced expression levels of PD-1 at the nine-week time point. Three weeks after the initial ipilimumab dose, the frequency of granulocytic MDSCs was significantly reduced and was followed by a reduction in the frequency of arginase1-producing CD3(-) cells, indicating an indirect in trans effect that should be taken into account for future evaluations of ipilimumab mechanisms of action. PMID- 24777679 TI - Chemoimmunotherapy using pegylated liposomal Doxorubicin and interleukin-18 in recurrent ovarian cancer: a phase I dose-escalation study. AB - Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m(2)) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 MUg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 MUg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 MUg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 MUg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial. PMID- 24777681 TI - Alternative variants of human HYDIN are novel cancer-associated antigens recognized by adaptive immunity. AB - A mutation in the hydin gene has been recently described as one possible mechanism leading to lethal congenital hydrocephalus in mice, and a similar defect is proposed to be involved in an autosomal recessive form of hydrocephalus in human. Here, we report for the first time on the cancer association and immunogenicity of two HYDIN variants in humans. One is a previously described sequence derived from the chromosome 1 gene copy, that is, KIAA1864. The second is encoded by a novel alternative transcript originating from the chromosome 16, which we identified by immunoscreening of a testis-derived cDNA expression library with sera of patients with colorectal cancer, and called MO-TES391. Both variants are targeted by immunoglobulin G antibodies in a significant subset of cancer patients but only rarely in healthy donors. Moreover, we identify HLA A*0201-restricted sequences derived from MO-TES391 and KIAA1864, which are specifically recognized by human cytotoxic CD8(+) T cells. Taken together, these results suggest frequent and coordinated adaptive immune responses against HYDIN variants in patients with cancer and propose HYDIN as a novel cancer-associated antigen. PMID- 24777680 TI - Highly optimized DNA vaccine targeting human telomerase reverse transcriptase stimulates potent antitumor immunity. AB - High levels of human telomerase reverse transcriptase (hTERT) are detected in more than 85% of human cancers. Immunologic analysis supports that hTERT is a widely applicable target recognized by T cells and can be potentially studied as a broad cancer immunotherapeutic, or a unique line of defense against tumor recurrence. There remains an urgent need to develop more potent hTERT vaccines. Here, a synthetic highly optimized full-length hTERT DNA vaccine (phTERT) was designed and the induced immunity was examined in mice and non-human primates (NHP). When delivered by electroporation, phTERT elicited strong, broad hTERT specific CD8 T-cell responses including induction of T cells expressing CD107a, IFN-gamma, and TNF-alpha in mice. The ability of phTERT to overcome tolerance was evaluated in an NHP model, whose TERT is 96% homologous to that of hTERT. Immunized monkeys exhibited robust [average 1,834 spot forming unit (SFU)/10(6) peripheral blood mononuclear cells (PBMC)], diverse (multiple immunodominant epitopes) IFN-gamma responses and antigen-specific perforin release (average 332 SFU/10(6) PBMCs), suggesting that phTERT breaks tolerance and induces potent cytotoxic responses in this human-relevant model. Moreover, in an HPV16 associated tumor model, vaccination of phTERT slows tumor growth and improves survival rate in both prophylactic and therapeutic studies. Finally, in vivo cytotoxicity assay confirmed that phTERT-induced CD8 T cells exhibited specific cytotoxic T lymphocyte (CTL) activity, capable of eliminating hTERT-pulsed target cells. These findings support that this synthetic electroporation-delivered DNA phTERT may have a role as a broad therapeutic cancer vaccine candidate. PMID- 24777682 TI - Anatomy of the zona orbicularis of the hip: a magnetic resonance study. AB - PURPOSE: This study aimed at describing the anatomy of the zona orbicularis (ZO), based on magnetic resonance arthrography (MRA) and magnetic resonance imaging (MRI) scans and to assess the presence of synovial folds in relation to the ZO. METHODS: A retrospective review was performed using consecutive hip and pelvic MRA and MRI examinations from our institution. We identified 25 normal scans of each variety. Patients were scanned in a neutral hip position and 3D FIESTA sequence images were included in a number of cases. Using electronic callipers, measurements were obtained of the ZO thickness and of the location of the ZO with respect of the femoral head and neck. RESULTS: On MRA, the ZO appeared as a horseshoe in 18/25 patients, being absent anteriorly. On MRI the ZO was less consistent and absent in 12/25 posteriorly, in 8/25 inferiorly and in 2/25 anteriorly. Where present, the ZO usually coincided with the boundary of femoral head sphericity and the narrowest point of the isthmus of the femoral neck. The medial synovial fold was identified in all MRA studies (25/25). CONCLUSIONS: The ZO of the hip is most consistently identified when the joint is distended and in approximately 75% of cases appears as a horseshoe-shaped structure. Superiorly, the ZO is aligned perpendicular to the long axis of the femoral neck. The ZO twists from postero-lateral to antero-medial as it moves inferiorly. Our findings are consistent with the hypothesis that the ZO functions as a ring that resists femoral head distraction and contributes to dynamic circulation of synovial fluid. PMID- 24777683 TI - Hollow nickel nanocorn arrays as three-dimensional and conductive support for metal oxides to boost supercapacitive performance. AB - A novel three-dimensional (3D) metal/metal oxide core/branch array electrode has been fabricated as a supercapacitor electrode. Hollow Ni nanocorn arrays are constructed on Ni foams and act as a highly conductive and stable support to Co3O4 nanoflakes. Enhanced pseudocapacitive performance compared to bare Co3O4 nanosheets is demonstrated with high rate capability and excellent cycling stability. PMID- 24777684 TI - Control of the conductance of engineered protein nanopores through concerted loop motions. AB - Protein nanopores have attracted much interest for nucleic acid sequencing, chemical sensing, and protein folding at the single molecule level. The outer membrane protein OmpG from E. coli stands out because it forms a nanopore from a single polypeptide chain. This property allows the separate engineering of each of the seven extracellular loops that control access to the pore. The longest of these loops, loop 6, has been recognized as the main gating loop that closes the pore at low pH values and opens it at high pH values. A method was devised to pin each of the loops to the embedding membrane and measure the single-pore conductances of the resulting constructs. The electrophysiological and complementary NMR measurements show that the pinning of individual loops alters the structure and dynamics of neighboring and distant loops in a correlated fashion. Pinning loop 6 generates a constitutively open pore and patterns of concerted loop motions control access to the OmpG nanopore. PMID- 24777685 TI - Maternal employment during pregnancy and birth outcomes: evidence from Danish siblings. AB - I use Danish survey and administrative data to examine the impact of maternal employment during pregnancy on birth outcomes. As healthier mothers are more likely to work and health shocks to mothers may impact employment and birth outcomes, I combine two strategies: First, I control extensively for time-varying factors that may correlate with employment and birth outcomes, such as pre pregnancy family income and maternal occupation, pregnancy-related health shocks, maternal sick listing, and health behaviors (smoking and alcohol consumption). Second, to account for remaining time-invariant heterogeneity between mothers, I compare outcomes of mothers' consecutive children. Mothers who work during the first pregnancy trimester have a lower risk of preterm birth. I find no effect on the probability of having a baby of small size for gestational age. To rule out that health selection of mothers between pregnancies drives the results, I focus on mothers whose change in employment status is likely not to be driven by underlying health (mothers who are students in one of their pregnancies and mothers with closely spaced births). Given generous welfare benefits and strict workplace regulations in Denmark, my findings support a residual explanation, namely, that exclusion from employment may stress mothers in countries with high female employment rates. PMID- 24777686 TI - A nation-wide study of the family aggregation and risk factors in anorexia nervosa over three generations. AB - OBJECTIVE: This nation-wide register-based study investigated how often anorexia nervosa (AN) and co-morbid disorders occur in affected families compared with control families. Furthermore, the study addressed the impact of sex, year of birth, and degree of urbanization in terms of risk factors. METHOD: A total of N = 2,370 child and adolescent psychiatric subjects born between 1951 and 1996 and registered in the Danish Psychiatric Central Research Register (DPCRR) had any mental disorder before the age of 18 and developed AN at some point during their life-time. In addition, N = 7,035 controls without any psychiatric diagnosis before age 18 and matched for age, sex, and residential region were included. Psychiatric diagnoses were also obtained on the first-degree relatives as a part of the Danish Three Generation Study (3GS). A family load component was obtained by using various mixed regression models. RESULTS: AN occurred significantly more often in case than in control families. AN Risk factors included having a sibling with AN, affective disorders in family members, and co-morbid affective, anxiety, obsessive-compulsive, personality, or substance use disorders. Furthermore, female sex, and ascending year of birth were significantly associated with having AN. Urbanization was not related to the family load of AN and case-relatives did not develop AN earlier than control relatives. DISCUSSION: These findings based on a very large and representative dataset provide evidence for the family aggregation and further risk factors in AN. PMID- 24777687 TI - An efficient fractal method for detection and diagnosis of breast masses in mammograms. AB - In this paper, we present an efficient fractal method for detection and diagnosis of mass lesion in mammogram which is one of the abnormalities in mammographic images. We used 110 images that were carefully selected by a radiologist, and their abnormalities were also confirmed by biopsy. These images included circumscribed benign, ill-defined, and spiculated malignant masses. Firstly, we discriminated lesions automatically using new fractal dimensions. The results which were examined by different types of breast density showed that the proposed method was able to yield quite satisfactory detection results. Secondly, noting that contours of masses playing the most important role in diagnosis of different mass types, we defined new fractal features based on information extraction from the contours. This information is able to identify the roughness in mass contours and determines the extent of spiculation or smoothness of the masses. In this manner, in classification of the spiculated malignant masses from the circumscribed benign tumors, we achieved highly satisfactory results, i.e., 0.98 measured in terms of area under ROC curve (AUC). In this paper, it is also shown that the roughness in contours is a suitable characteristic feature for diagnosis of ill-defined malignant tumors with AUC equal to 0.94 in their classification. The extracted information was also found to be useful in the classification of early malignancies whereas in the classification of spiculated and ill-defined malignant masses in their early stage from those of benign tumors, we achieved high accuracy of 0.99 and 0.90 for AUC, respectively. PMID- 24777690 TI - Multifunctional poly(Vinyl Amine)s bearing Azetidinium groups: one pot preparation in water and antimicrobial properties. AB - A simple, robust one pot procedure for the preparation of waterborne multifunctional poly(vinyl amine)s (PVAms) is presented. By post-polymerization modification of PVAm with a bifunctional coupler and functional couplers cationic, reactive azetidinium groups, and alkyl chains are introduced in the side chains of PVAms. The structure-activity relations (effect of hydrophobic and cationic modifications) of these antimicrobial polymers are studied; the minimum inhibitory concentration (MIC) against both (Gram positive and Gram negative bacteria) of the library of multifunctional poly(vinyl amine)s are determined to identify the candidates with the highest efficacy. Furthermore, the hemolytic activity-the effective concentration at which 50 and 10% of red blood cells are killed (HC50 and HC10 )-of selected polymers is determined. The ability of the polymers prepared to differentiate between microorganisms (Gram positive and Gram negative bacteria) and mammalian cells (red blood cells) is understood by comparing MIC and HC values. Finally, as an example, the best polymer is used to prepare an antimicrobial surface. PMID- 24777691 TI - Safety and efficacy of colesevelam HCl in the treatment of elderly patients. AB - BACKGROUND AND OBJECTIVES: Colesevelam significantly lowers cholesterol in patients with hypercholesterolemia, and both cholesterol and hemoglobin A1C (A1C) in patients with type 2 diabetes mellitus (T2DM). The purpose of this post hoc analysis was to evaluate the efficacy and safety/tolerability of colesevelam in older (>=65 years) and younger (<65 years) adults. METHODS: We conducted post hoc analyses of pooled clinical trial data from seven phase II and III randomized, double-blind, placebo-controlled, primary hyperlipidemia and T2DM clinical trials. The hyperlipidemia safety/tolerability analysis included seven studies (>=65 years, n = 154; <65 years, n = 381); the efficacy analysis utilized one study with sufficient patients in both age groups for meaningful comparison. The T2DM analyses included four studies (safety/tolerability: >=65 years, n = 249; <65 years, n = 880) or three studies (efficacy). In the hyperlipidemia studies, patients received colesevelam 1.5-4.5 g/day or placebo, alone or with a statin, for 4 weeks to 6 months. In the T2DM studies, colesevelam 3.75 g/day or placebo was added to existing antidiabetes therapies for 16 or 26 weeks. Low-density lipoprotein cholesterol (LDL-C), A1C, and adverse events were assessed. RESULTS: In the hyperlipidemia analysis, colesevelam versus placebo produced similar mean reductions from baseline in LDL-C in older (-16.6 vs. +0.5 %) and younger (-13.7 vs. +0.4 %) patients. In the T2DM analysis, older and younger patients had similar reductions from baseline in A1C (treatment difference -0.59 and -0.54 %, respectively; both p < 0.001) and LDL-C (-14.7 and -15.5 %, respectively; both p < 0.001) with colesevelam. In both analyses, adverse event incidence was generally similar between subgroups. In the T2DM analysis, hypoglycemia was slightly more frequent with colesevelam versus placebo in older patients (5.8 vs. 2.3 %); no reports of hypoglycemia were considered serious adverse events. CONCLUSIONS: In primary hyperlipidemia and in T2DM, colesevelam appeared to be generally as safe, well tolerated, and efficacious in patients aged >=65 years as in those aged <65 years. PMID- 24777692 TI - The incidence of clinically isolated syndrome in a multi-ethnic cohort. AB - The purpose of this study was to determine the incidence of clinically isolated syndrome (CIS), a potential precursor of multiple sclerosis (MS), and whether it varies by race/ethnicity in a multi-ethnic, population-based cohort. We conducted a retrospective cohort study of over 9 million person-years of observation from the multi-ethnic, community-dwelling members of Kaiser Permanente Southern California Health Plan from January 1, 2008 to December 31, 2010. Incidence of CIS and risk ratios comparing incidence rates between racial/ethnic groups were calculated using Poisson regression. We identified 468 newly diagnosed CIS cases that did not meet McDonald criteria for MS. The average age at diagnosis was 39.0 years (range 2.7-85.8) and 68.8% were women. The female preponderance was more pronounced among black (75.7%) and Hispanics (70.5%) than in white and Asian individuals with CIS (66.5 and 54.5%, respectively; P = 0.14). The most common presenting symptom in Hispanics was optic neuritis (P = 0.008), and in blacks, transverse myelitis (P = 0.07). Incidence of CIS was lower in Hispanics (3.8, 95% CI 3.2-4.4, P < 0.0001) and Asians (2.4, 95% CI 1.5-3.6, P < 0.0001) and similar in blacks (6.8, 95% CI 5.3-8.5, P = 0.30) compared with whites (5.9, 95% CI 5.1 6.7). The incidence of CIS varies by race/ethnicity and sex in a similar pattern to MS. In addition, the clinical presentation of CIS varies by race/ethnicity. These findings strengthen the probability that the old belief that blacks have a decreased risk of MS is no longer true. These findings highlight that studies that include minorities are likely to lead to important insights into the etiology and prognosis of CIS and MS. PMID- 24777693 TI - Morphological features of MS lesions on FLAIR* at 7 T and their relation to patient characteristics. AB - Recently, a new MRI technique was developed at 3 Tesla (T), called fluid attenuated inversion recovery* (FLAIR*). In this study, we implemented FLAIR* in an existing MS cohort at 7 T, to investigate whether we could corroborate results of previous 7 T studies that introduced specific MS lesion characteristics. Furthermore, we aimed to investigate the meaning of these lesion characteristics by relating them to clinical characteristics of the MS patient. Three-dimensional FLAIR and T2*-weighted images of 33 MS patients and 7 healthy controls were fused into FLAIR* images. Lesion type, signal intensity and morphology were analysed on FLAIR*, side-by-side with the original FLAIR and T2*, and correlated with clinical characteristics using Spearman's rho. Three morphological features of MS lesions were visualised: (1) central vessel (CV) within lesions, present in 78 % of total MS lesions; (2) hypointense rims around MS lesions, present in eight patients; (3) FLAIR* lesions that were hypointense at T2*, present in 13 patients. The presence of hypointense (rims around) lesions was not related to clinical characteristics. The simultaneous presence of rimlike lesions and hypointense lesions within MS patients was significantly correlated (rho = 0.52, P < 0.01). We conclude that the implementation of the new MRI technique FLAIR* at ultra-high-field 7 T combines and corroborates the results of preceding 7 T research, by showing three morphological features of MS lesions. In addition, our study shows that these phenomena do not show a relation to patient's clinical characteristics and cannot be allocated to certain MS disease subtypes. PMID- 24777698 TI - Negative effect of clenbuterol on physical capacities and neuromuscular control of muscle atrophy in adult rats. AB - INTRODUCTION: Clenbuterol has been used to alleviate chronic obstructive pulmonary disease and elicit an anabolic response in muscles. The aim of this study was to determine the influence of muscle mass variation on physical capacities in rats. METHODS: The left hindlimbs of Wistar rats were immobilized for 20 days in plantarflexion with a splint and then remobilized for 16 days. The effect of a non-myotoxic dose of clenbuterol during the immobilization period was evaluated. Physical capacities were coordination, free locomotion, grip strength, and bilateral deficit. RESULTS: Immobilization induced a loss of muscle mass, coordination, and strength without any effect on free locomotion. The positive anabolic effect of clenbuterol did not prevent a loss of physical capacities resulting from immobilization. CONCLUSIONS: Muscle mass correlated strongly with coordination and isometric strength in untreated rats. Anabolic effect, fiber phenotype modification, and perturbation in neuromuscular communication with clenbuterol improved muscle mass, but it altered physical capacities. PMID- 24777700 TI - T cells generated in the absence of a thoracic thymus fail to establish homeostasis. AB - Cervical thymus mimics the thoracic thymus in supporting T-cell development and exists in a subset of mice and humans. Importantly, it remains unknown whether the cervical thymus can generate T cells that are self-tolerant in the complete absence of signals from the thoracic thymus. Using a fetal liver reconstitution model in thoracic thymectomized RAG(-/-) mice, we found that T cells could be generated without contribution from the thoracic thymus. However, these mice had decreased T cells, increased proportions of effector memory T cells and Treg phenotype cells, increased serum IgG1/2b, and increased frequency of T cells expressing IFN-gamma, IL-17 or IL-10. Half of the mice that received a thoracic thymectomy and fetal liver cells, unlike sham surgery controls, developed substantial morbidity with age. Disease was associated with lymphopenia-driven activation rather than inherent defects in the cervical thymus, as both thoracic and cervical thymocytes could generate disease in lymphopenic recipients. Administration of the homeostatic cytokine IL-7 caused a rapid, transient increase in T-cell numbers and reduced the time to disease onset. Together the data suggests that the cervical thymus can function in the complete absence of the thoracic thymus; however, the T cells generated do not establish homeostasis. PMID- 24777701 TI - Discrimination of adenine nucleotides and pyrophosphate in water by a zinc complex of an anthracene-based cyclophane. AB - Combining metal-anion coordination and pi-pi stacking interactions, a zinc complex of a novel anthracene-based cyclophane was designed to recognise adenine nucleoside polyphosphates. This complex was found to show selective fluorescence enhancement for ATP, ADP, AMP and PPi in neutral aqueous solution. Among them, ADP induced the largest fluorescence change to the complex, while ATP showed the strongest binding affinity to the complex. This property was used to sense ATP in the presence of excess amounts of other phosphates such as ADP, AMP, PPi and Pi. PMID- 24777702 TI - Application of a vibrating device for the prevention of flexion contracture after total knee arthroplasty. AB - Our research team developed a new, heel support-based static and vibrating complementary treatment method for the prevention of flexion contractures often arising after total knee arthroplasty. We examined the efficiency of the method performing a randomized clinical trial with 144 patients undergoing total knee replacement. Seventy-nine patients were treated for 1 week with a generally used continuous passive motion (CPM) device complemented with our new method, which was based on the application of a static and an alternating heel support. The 65 patients in the control group were treated with only a CPM device as in usual clinical practice. The femoro-tibial angle was measured immediately following surgery, and after 1 week of treatment. At the end of the 1 week treatment, the target extension angle (0 degrees +/- 5 degrees ) was achieved by significantly more patients with the new combined method. This way the elevated heel rest and the vibrating device proved to be a good adjunct treatment along with the CPM used in routine clinical practice in the first place for the prevention of flexion contractures. PMID- 24777703 TI - Acid-catalyzed oxidative radical addition of ketones to olefins. AB - Based on a mechanistic study, we have discovered a Bronsted acid catalyzed formation of ketone radicals. This is believed to proceed via thermally labile alkenyl peroxides formed in situ from ketones and hydroperoxides. The discovery could be utilized to develop a multicomponent radical addition of unactivated ketones and tert-butyl hydroperoxide to olefins. The resulting gamma peroxyketones are synthetically useful intermediates that can be further transformed into 1,4-diketones, homoaldol products, and alkyl ketones. A one-pot reaction yielding a pharmaceutically active pyrrole is also described. PMID- 24777704 TI - Characterization of adipocyte stress response pathways during hibernation in thirteen-lined ground squirrels. AB - To avoid the harsh conditions of winter climates, hibernating mammals undergo a systematic depression of physiological function by reducing their metabolic rate. During this process, hibernators are exposed to significant stresses (e.g., low body temperature, ischemia-reperfusion) that must be dealt with appropriately to avoid irreversible tissue damage. Consequently, we investigated the contribution of stress-responsive antioxidant enzymes, heat shock proteins, signal transduction pathways (e.g., mitogen-activated protein kinases, MAPK), and transcription factors for their role in conferring tolerance to stress in the hibernating thirteen-lined ground squirrel (Ictidomys tridecemlineatus). Using a combination of multiplex protein panels and traditional immunoblotting procedures, we have focused on these stress factors in brown adipose tissue (BAT) and white adipose tissue (WAT) over cycles of torpor-arousal since they provide the means for heat production as a result of non-shivering thermogenesis and the mobilization of critical energy reserves, respectively. We show the differential and tissue-specific regulation of stress factors including a unified upregulation of the antioxidant enzyme Thioredoxin 1 in both tissues, an upregulation of superoxide dismutase (SOD1 and SOD2) in WAT, and an increase in heat shock proteins during the transitory periods of the torpor-arousal cycle (HSP90alpha in BAT and HSP60 in WAT). Additionally, an upregulation of the active form of ERK1/2 and p38 in BAT and select transcription factors (e.g., CREB-1 and ELK-1) in both tissues were identified. These data provide us with greater insight into the molecular mechanisms responsible for this animal's natural stress tolerance and outline molecular signatures which define stress resistance. PMID- 24777706 TI - Mutations in ALDH1A3 represent a frequent cause of microphthalmia/anophthalmia in consanguineous families. AB - Anophthalmia or microphthalmia (A/M), characterized by absent or small eye, can be unilateral or bilateral and represent developmental anomalies due to the mutations in several genes. Recently, mutations in aldehyde dehydrogenase family 1, member A3 (ALDH1A3) also known as retinaldehyde dehydrogenase 3, have been reported to cause A/M. Here, we screened a cohort of 75 patients with A/M and showed that mutations in ALDH1A3 occurred in six families. Based on this series, we estimate that mutations in ALDH1A3 represent a major cause of A/M in consanguineous families, and may be responsible for approximately 10% of the cases. Screening of this gene should be performed in a first line of investigation, together with SOX2. PMID- 24777707 TI - An interdisciplinary approach for renal transplant recipients with severe pneumonia: a single ICU experience. PMID- 24777705 TI - Management of sepsis in neutropenic patients: 2014 updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO). AB - Sepsis is a major cause of mortality during the neutropenic phase after intensive cytotoxic therapies for malignancies. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. Clinical guidelines on sepsis treatment have been published by others. However, optimal management may differ between neutropenic and non-neutropenic patients. Our aim is to give evidence-based recommendations for haematologist, oncologists and intensive care physicians on how to manage adult patients with neutropenia and sepsis. PMID- 24777708 TI - The cost-utility of aflibercept for the treatment of age-related macular degeneration compared to bevacizumab and ranibizumab and the influence of model parameters. AB - BACKGROUND: Age-related macular degeneration (AMD) is a blinding disease placing considerable burden on society due to blindness-associated costs. Intravitreal anti-vascular endothelial growth factors (anti-VEGFs) are effective in reducing the incidence of blindness, but at potentially high costs, depending on the cost of the drug used. Aflibercept has been introduced as an anti-VEGF equally effective to ranibizumab, but less costly. For this new drug, new cost effectiveness analyses are needed, and AMD models used today give biased results. We investigated the cost-effectiveness of aflibercept compared to bevacizumab, ranibizumab, and no treatment and studied the influence of commonly used model parameters. METHODS: A patient-level, visual acuity-based, 2-eye model was developed. Data on effectiveness were derived from randomized controlled trials evaluating the outcomes of aflibercept, bevacizumab, and ranibizumab. Utility and resource utilization were assessed in interviews with AMD patients. Costs were based on standard health care cost prices. Time horizons were two and five years. A societal perspective was employed. RESULTS: Over five years, costs associated with aflibercept treatment were 36,030, with 2.15 QALYs. Costs associated with the bevacizumab regimens, ABC study as-needed (PRN); CATT study PRN; and CATT study 1*/month, were 19,367; 26,746; and 30,520, with 2.16; 2.17; and 2.15 QALYs, respectively. Costs associated with ranibizumab PRN and 1*/month were 45,491 and 74,837 with 2.16 and 2.15 QALYs, respectively. 'No treatment' was associated with 9530 and 1.96 QALYs. The incremental cost-effectiveness ratios versus 'no treatment' were: aflibercept 140,274; bevacizumab-51,062 (ABC PRN), 83,256 (CATT PRN) and 110,361 (1*/month); ranibizumab-181,667 (PRN) and 349,773 (1*/month). Results were highly dependent on whether only one or both eyes were included, length of time horizon, and whether the costs of blindness and low vision were included in the analysis. CONCLUSIONS: Aflibercept is a cost effective treatment for AMD over ranibizumab. However, aflibercept is not a cost effective treatment when compared to bevacizumab. Application of inappropriate model assumptions leads to a biased cost-saving estimate of the cost effectiveness of aflibercept. Therefore, cost-effectiveness analyses should be conducted with appropriate models. PMID- 24777709 TI - The prevalence of amblyogenic factors in children with persistent congenital nasolacrimal duct obstruction. AB - BACKGROUND: To evaluate the prevalence of amblyopia risk factors in children that underwent probing for persistent congenital nasolacrimal duct obstruction (CNLDO). METHODS: The medical records of children with CNLDO (after 1 year of age) that underwent probing were reviewed. Amblyopia risk factors, based on the American Association for Pediatric Ophthalmology and Strabismus referral criteria in 2013, were sought in the patients' records before probing. The proportion of the patients with anisometropia >1.5 diopters (D) was separately calculated. In unilateral cases of CNLDO, sphere, astigmatism, and spherical equivalent of the eyes with CNLDO were compared with contralateral eyes in order to assess the effect of CNLDO on refractive error. In the follow-up examinations, the success of the probing or the need for additional procedures (Crawford intubation, Monoka intubation, or dacryocystorhinostomy) was evaluated. The prevalence of anisometropia between 'successful probing' and 'failed probing' groups was compared. RESULTS: A total of 433 cases were included in the study. 41 cases (9.46 %) had amblyopia risk factors. Twenty-four cases (5.5 %) had anisometropia >1.5 D (spherical or cylindrical). In unilateral cases of CNLDO, the sphere and spherical equivalent of the eyes with CNLDO were significantly greater than those of the contralateral eyes (p < 0.001 for both). Thirty-nine patients (9 %) required other interventions due to failure of probing (failed probing group). There were significantly more anisometropia prevalence in this group, compared with the successful probing group, at the initial examination (p = 0.03). CONCLUSIONS: The findings of greater prevalence of anisometropia >1.5 D (compared with the prevalence in the general population) and significantly greater sphere and spherical equivalents in the eye with CNLDO (compared with contralateral eye) in unilateral cases with CNLDO, suggested some relationships between anisometropia and long-term untreated CNLDO. The finding of more anisometropia in failed probing cases may support the theory of structural abnormality as an explanation for the possible relationship between congenital nasolacrimal duct obstruction and anisometropia. PMID- 24777710 TI - Expression, characterization, and improvement of a newly cloned halohydrin dehalogenase from Agrobacterium tumefaciens and its application in production of epichlorohydrin. AB - A gene encoding halohydrin dehalogenase (HHDH) from Agrobacterium tumefaciens CCTCC M 87071 was cloned and expressed in Escherichia coli. To increase activity and stability of HHDH, 14 amino acid residues around the active site and substrate-binding pocket based on the structural analysis and molecular docking were selected as targets for site-directed mutagenesis. The studies showed that the mutant HHDH (Mut-HHDH) enzyme had a more accessible substrate-binding pocket than the wild-type HHDH (Wt-HHDH). Molecular docking revealed that the distance between the substrate and active site was closer in mutant which improved the catalytic activity. The expressed Wt-HHDH and Mut-HHDH were purified and characterized using 1,3-dichloro-2-propanol (1,3-DCP) as substrates. The specific activity of the mutant was enhanced 26-fold and the value of k cat was 18.4-fold as compared to the Wt-HHDH, respectively. The Mut-HHDH showed threefold extension of half-life at 45 degrees C than that of Wt-HHDH. Therefore it is possible to add 1,3-DCP concentration up to 100 mM and epichlorohydrin (ECH) was produced at a relatively high conversion and yield (59.6 %) using Mut-HHDH as catalyst. This Mut-HHDH could be a potential candidate for the upscale production of ECH. PMID- 24777711 TI - A design-by-treatment interaction model for network meta-analysis with random inconsistency effects. AB - Network meta-analysis is becoming more popular as a way to analyse multiple treatments simultaneously and, in the right circumstances, rank treatments. A difficulty in practice is the possibility of 'inconsistency' or 'incoherence', where direct evidence and indirect evidence are not in agreement. Here, we develop a random-effects implementation of the recently proposed design-by treatment interaction model, using these random effects to model inconsistency and estimate the parameters of primary interest. Our proposal is a generalisation of the model proposed by Lumley and allows trials with three or more arms to be included in the analysis. Our methods also facilitate the ranking of treatments under inconsistency. We derive R and I(2) statistics to quantify the impact of the between-study heterogeneity and the inconsistency. We apply our model to two examples. PMID- 24777712 TI - A pilot program in telepsychiatry for residents: initial outcomes and program development. PMID- 24777713 TI - Assessing medical students' communication skills by the use of standardized patients: emphasizing standardized patients' quality assurance. AB - OBJECTIVE: The objective structured examination is one of the most valid, reliable, and effective tools for assessing clinical and communication skills, often by use of standard patients (SPs). SPs can also be assessors of those skills. One of the crucial areas when utilizing SP-based assessment is the quality and consistency assurance of their portrayal of the case and their ability to fill in checklists in an adequate way. The aim of this study was to assess the validity and reliability of SPs' ability to assess students' communication skill via a Calgary-Cambridge checklist. METHOD: This cross sectional and correlational study was conducted at the Tehran University of Medical Science. We first analyzed validity; the criterion validity of the SPs' filling in the checklists was assessed through determining the correlation between the SPs' completed checklists and the checklists filled in by three physician raters individually and then reproducibility: it was assessed by a test retest approach inter-rater reliability. RESULT: The mean correlation for assessing the validity of SPs' completed checklists by individual SPs was 0.81. The inter-rater reliability was calculated by kappa coefficient, and the total correlation among the three raters was 0.85. The reliability of the test-retest approach showed no significant differences between the test and re-test results. CONCLUSION: The increased number of medical students and different faculties' responsibilities such as doing educational, research, and health services duties assessing medical student communication skills is a complex issue. The results of our study showed that trained SPs can be used as a valid tool to assess medical students' communication skills, which is also more cost effective and reduces work load of medical faculties. PMID- 24777714 TI - Reactive oxygen species-dependent nitric oxide production in reciprocal interactions of glioma and microglial cells. AB - Conditioned mediums (CMs) from glioma cells U87, GBM-8401, and C6 significantly induced iNOS protein and NO production by microglial cells BV-2 but without altering the cell viability or cell-cycle progression of BV2 microglia. Significant increases in intracellular peroxide by U87-CM and C6-CM were detected by a DCHF-DA assay, and vitamin (Vit) C and N-acetyl cysteine (NAC)-reduced intracellular peroxide levels elicited by CMs lead to inhibition of iNOS/NO production The extracellular signal-regulated kinase (ERK) inhibitor, U0126, and c-Jun N-terminal kinase (JNK) inhibitor, SP600125, suppressed U87-CM- and C6-CM induced iNOS/NO production by respectively blocking phosphorylated ERK (pERK) and JNK (pJNK) protein expressions stimulated by U87-CM and C6-CM. Increased migration of U87 and C6 glioma cells by a co-culture with BV-2 microglial cells or adding the nitric oxide (NO) donor, sodium nitroprusside (SNP) was observed, and that was blocked by adding an NO synthase (NOS) inhibitor, N-nitro L-arginine methyl ester (NAME). Contributions of ROS, pERK, and pJNK to the migration of glioma cells was further demonstrated in a transwell coculture system of U87 and C6 gliomas with BV-2 microglial cells. Furthermore, expressions of tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 messenger (m)RNA in U87 and C6 cells were detected by an RT-PCR, and TNF-alpha and MCP-1 induced iNOS protein expression in time- and concentration-dependent manners. Neutralization of TNF-alpha or MCP-1 in U87-CM and C6-CM using a TNF-alpha or MCP 1 antibody inhibited iNOS protein expression, and increased intracellular peroxide by TNF-alpha or MCP-1 was identified in BV-2 cells. The reciprocal activation of glioma cells and microglia via ROS-dependent iNOS/NO elevation at least partially mediated by TNF-alpha and MCP-1 is elucidated. PMID- 24777715 TI - Gold nanoparticles electroporation enhanced polyplex delivery to mammalian cells. AB - Nonviral methods have been explored as the replacement of viral systems for their low toxicity and immunogenicity. However, they have yet to reach levels competitive to their viral counterparts. In this paper, we combined physical and chemical methods to improve the performance of polyplex delivery of DNA and small interfering RNA. Specifically, gold nanoparticles (AuNPs) were used to carry polyplex (a chemical approach) while electroporation (a physical approach) was applied for fast and direct cytosolic delivery. In this hybrid approach, cationic polymer molecules condense and/or protect genetic probes as usual while AuNPs help fix polycations to reduce their cytotoxicity and promote the transfection efficiency of electroporation. AuNPs of various sizes were first coated with polyethylenimine, which were further conjugated with DNA plasmids or small interfering RNA molecules to form AuNPs-polyplex. The hybrid nanoparticles were then mixed with cells and introduced into cell cytosol by electroporation. The delivery efficiency was evaluated with both model anchor cells (i.e., NIH/3T3) and suspension cells (i.e., K562), together with their impact on cell viability. We found that AuNP-polyplex showed 1.5~2 folds improvement on the transfection efficiency with no significant increase of toxicity when compared to free plasmid delivery by electroporation alone. Such a combination of physical and chemical delivery concept may stimulate further exploration in the delivery of various therapeutic materials for both in vitro and in vivo applications. PMID- 24777716 TI - Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is rare in children, but represents a similarly serious and chronic condition as in adults. Children with PNH frequently experience complications of chronic hemolysis, recurrent thrombosis, marrow failure, serious infections, abdominal pain, chronic fatigue, and decreased quality of life with reduced survival. The terminal complement inhibitor eculizumab is proven to be effective and safe in adults and approved by the FDA for treatment of PNH. PROCEDURE: This 12-week, open-label, multi-center phase I/II study evaluated pharmacokinetics, pharmacodynamics, efficacy, and safety in seven children with PNH 11-17 years of age. Eculizumab was intravenously administered at 600 mg weekly for 4 weeks, 900 mg in week 5, and 900 mg every 2 weeks thereafter (http://clinicaltrials.gov NCT00867932). RESULTS: Eculizumab therapy resulted in complete and sustained inhibition of hemolysis in all participants with a reduction of lactate dehydrogenase to normal levels. All hematological parameters stabilized. No definitive, study drug-related adverse events were observed. Only one severe SAE of hospitalization due to aplastic anemia occurred, which was not study drug-related. CONCLUSION: Eculizumab appears to be a safe and effective therapy for children with PNH. PMID- 24777717 TI - Aggregation-induced emission enhancement upon Al3+ complexation with a tetrasulfonated calix[4]bisazacrown fluorescent molecular sensor. AB - Aggregation-induced emission and aggregation-induced emission enhancement have attracted much attention due to their great potential in real-world applications. Up to now most of the reports are based on the restriction of free rotation of the luminogens in the aggregates. In the present work, we found that the dansyl fluorophore with typical intramolecular charge transfer characteristic also exhibited aggregation-induced emission enhancement, which was based on the change of micro-environmental polarity of the fluorophore. In the light of the phenomenon, a new water-soluble ligand bearing a tetrasulfonated calix[4]arene was constructed for ratiometric detection of Al(3+) based on an aggregation induced emission enhancement mechanism. It displayed a distinct selectivity to Al(3+) among the tested cations in lutidine buffer solution (pH 6-7) with a detection limit of 1.8 MUM. A reversible response was also demonstrated by the addition of EDTA or F(-). PMID- 24777718 TI - Epidemiology of ductal carcinoma in situ in Western Australia: implications for surgical margins and management. AB - BACKGROUND: In 2010, the Australian Institute of Health and Welfare published a report examining the characteristics of Australian women diagnosed with ductal carcinoma in situ (DCIS). This study identified the characteristics of women who were diagnosed with DCIS in Western Australia (WA) 1996-2005, and built on a national study by determining the rate of second operation and breast cancer events (BCE) in WA. METHODS: A retrospective analysis of data from the WA Cancer Registry and the Hospital Morbidity Database was undertaken. The main outcome measures were histological characteristics, second operation rate, breast cancer events. RESULTS: A total of 1356 cases of DCIS were diagnosed in WA between 1996 and 2005, with a minimum 5-year follow-up. The age-standardised incidence rate in 2005 was 15.4 per 100,000 women. 72 % of patients received breast-conserving therapy for primary treatment, 18 % of patients requiring a second operation to obtain adequate margins and 35 % of patients received postoperative radiotherapy. 17.3 % of cases had a subsequent BCE, with the 5- and 10-year probabilities being 4.36 and 8.27 %, respectively. A BCE was significantly associated with age (p < 0.001), no second operation (p < 0.001) and no radiotherapy (p = 0.049 recurrence, p = 0.043 invasion). CONCLUSION: This study supports the need to ensure adequate margins during primary surgery for DCIS is obtained to reduce the need for a second operation or the risk of a subsequent BCE. The consideration of mastectomy versus radiotherapy should be made in conjunction with the identified risk factors, specifically age and whether a second operation was performed. PMID- 24777719 TI - To be held and to hold one's own: narratives of embodied transformation in the treatment of long lasting musculoskeletal problems. AB - This study elaborates on narrative resources emerging in the treatment of longlasting musculoskeletal and psychosomatic disorders in Norwegian psychomotor physiotherapy (NPMP). Patients' experiences produced in focus group interviews were analyzed from a narrative perspective, combining common themes across groups with in depth analysis of selected particular stories. NPMP theory expanded by Logstrup's and Ricoeur's philosophy, and Mattingly's and Frank's narrative approach provided the theoretical perspective. Patients had discovered meaning imbued in muscular tension. Control shifted from inhibiting discipline and cognitive strategies, towards more contingence with gravity and sensation, and increased freedom to be what and who they were. Trust, time, open speech, and being respectfully listened to were described as therapeutic pre-conditions. The body was experienced as the source of their voice as their own. As tension patterns transformed, novel experience in sensation appeared to feed narrative imagination, reshaping past plots, embodied identity and future prospects. NPMP was disclosed as a treatment integrating detection, battle and repair as narrative subplots, but the core narrative was the journey of transformation. Novel embodied narrative resources nourished the quest for a life and identity in tune with the body as one's own. PMID- 24777720 TI - Paley's multiplier method does not accurately predict adult height in children with bone sarcoma. AB - BACKGROUND: The majority of patients with osteosarcoma and Ewing's sarcoma are diagnosed before skeletal maturity. Paley's multiplier is used for height prediction in healthy children, and has been suggested as a method to make growth predictions for children with osteosarcoma and Ewing's sarcoma when considering limb salvage options. To our knowledge, no evaluation of this method in this particular patient group has been performed, but a temporary growth deficit has been observed in children undergoing chemotherapy. QUESTIONS/PURPOSES: We asked whether (1) Paley's formula reliably predicts growth in children who received polychemotherapy; (2) chemotherapy impairs growth velocity; and (3) final adult height is impaired in these patients. METHODS: Retrospectively, data for 94 patients with osteosarcoma and Ewing's sarcoma were retrieved from databases of two sarcoma centers. Onset before 14 years of age in girls and 16 years in boys and a minimum followup until 18 years were required (mean, 67 months; range, 31 124 months) criteria. Exclusion criteria were the intake of growth hormones or no chemotherapy. Thirty-three patients (35%) fulfilled all inclusion criteria. Predicted adult heights were compared with actual adult height. The development of a growth deficit was evaluated for 23 children (without chemotherapy for recurrence) using age- and gender-specific standard deviation scores for height (WHO Z-scores). RESULTS: Height prediction using Paley's method showed a high percentage of false predictions (outside +/- 1 SD, 70%; outside +/- 2 SD, 61%). On average, the mean total height of the patients was overestimated (2.3 cm). The median absolute error of prediction was 5.0 cm (range, -17 to 8). Patients with osteosarcoma and Ewing's sarcoma showed a significant growth impairment during polychemotherapy. A catchup phase in growth before skeletal maturity was observed in patients with osteosarcoma but not with Ewing's sarcoma. CONCLUSIONS: Owing to its lack of reliability in this patient group, methods other than Paley's should be evaluated to predict adult height. Although limited by a small number of patients, our study results indicate a decreased adult height in patients with bone sarcoma after chemotherapy. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Instructions for Authors for complete description of levels of evidence. PMID- 24777721 TI - Modifier 22 for acetabular fractures in morbidly obese patients: does it affect reimbursement? AB - BACKGROUND: Modifier 22 in the American Medical Association's Current Procedural Terminology (CPT(r)) book is a billing code for professional fees used to reflect an increased amount of skill, time, and work required to complete a procedure. There is little disagreement that using this code in the setting of surgery for acetabulum fractures in the obese patient is appropriate; however, to our knowledge, the degree to which payers value this additional level of complexity has not been determined. QUESTIONS/PURPOSES: We asked whether (1) the use of Modifier 22 increased reimbursements in morbidly obese patients and (2) there was any difference between private insurance and governmental payer sources in treatment of Modifier 22. METHODS: Over a 4-year period, we requested immediate adjudication with payers when using Modifier 22 for morbidly obese patients with acetabular fractures. We provided payers with evidence of the increased time and effort required in treating this population. Reimbursements were calculated for morbidly obese and nonmorbidly obese patients. Of the 346 patients we reviewed, 57 had additional CPT(r) codes or modifiers appended to their charges and were excluded, leaving 289 patients. Thirty (10%) were morbidly obese and were billed with Modifier 22. Fifty-three (18%) were insured by our largest private insurer and 69 (24%) by governmental programs (Medicare/Medicaid). Eight privately insured patients (15%) and seven governmentally insured patients (10%) were morbidly obese and were billed with Modifier 22. For our primary question, we compared reimbursement rates between patients with and without Modifier 22 for obesity within the 289 patients. We then performed the same comparison for the 53 privately insured patients and the 69 governmentally insured patients. RESULTS: Overall, there was no change in mean reimbursement when using Modifier 22 in morbidly obese patients, compared to nonmorbidly obese patients (USD 2126 versus USD 2149, p < 0.94). There was also no difference in mean reimbursements with Modifier 22 in either the privately insured patients (USD 3445 versus USD 2929, p = 0.16) or the governmentally insured patients (USD 1367 versus USD 1224, p=0.83). CONCLUSIONS: Despite educating payers on the increased complexity and time needed to deal with morbidly obese patients with acetabular fractures, we have not seen an increased reimbursement in this challenging patient population. This could be a disincentive for many centers to treat these challenging injuries. Further efforts are needed to convince government payer sources to increase compensation in these situations. LEVEL OF EVIDENCE: Level IV, economic and decision analyses. See Instructions for Authors for a complete description of levels of evidence. PMID- 24777722 TI - Ilizarov fixator combined with an intramedullary nail for tibial nonunions with bone loss: is it effective? AB - BACKGROUND: Treatment of tibial nonunion with bone loss is extremely difficult. A variety of techniques have been described, but each has shortcomings, in particular prolonged external fixation time as well as serious complications such as nonunion and infection. Accordingly, we developed a technique that seeks to reduce these complications by using a circular external fixator in addition to an intramedullary nail to achieve union, limb lengthening, and stability of the regenerated segment. DESCRIPTION OF TECHNIQUE: First, the pseudoarthrosis area is resected, and acute compression is continued until bone contact at the docking site was achieved. Then primary grafting is applied to the docking site using a graft harvested from the patient's iliac bone, and the predrilled nail holes localized on the middle segment of the tibia are locked with a free-hand technique. Finally, lengthening is performed to overcome the leg-length discrepancy with an external fixator. METHODS: Between 2008 and 2011, this technique was used to treat five patients with tibial nonunion with bone loss. All patients were available for a minimum of a 14-month followup (mean, 30 months; range, 14-58 months). General indications for the procedure were age older than 16 years, tibial nonunion with bone loss, and the absence of any psychiatric disorder. We evaluated external fixation time, external fixation index (defined as the duration of external fixation in months divided by the total amount of bone transported and/or the amount of lengthening in centimeters), and time to union on plain radiographs, clinical results using the Paley bone and functional assessment scores, and postoperative complications from chart review. RESULTS: The external fixation time was 4 months (range, 3-5 months), and the average external fixation index was 0.4 months/cm. The mean time to bone union was 4.6 months (range, 3.5-5.5 months). All angles were determined to be in the normal range. No patients developed refracture or malalignment either on the docking site or the osteotomy site. Paley bone evaluation results were excellent in all five patients, and Paley functional results were excellent in four and good in one. We observed 10 pin-site infections as minor complications, and one patient was left with a residual equinus deformity of 5 degrees as a major complication according to the Paley classification. CONCLUSIONS: Our technique combining acute shortening and distraction osteogenesis had promising results for the treatment of tibial nonunion with bone loss in a small group of patients. However, future studies directly comparing available approaches to this difficult problem are required. Because this problem is uncommon, these studies will almost certainly require the cooperation of multiple large participating centers. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24777723 TI - Editor's Spotlight/Take 5: Is changing hospitals for revision total joint arthroplasty associated with more complications? PMID- 24777724 TI - CORR Insights(r): Sonication of antibiotic spacers predicts failure during two stage revision for prosthetic knee and hip infections. PMID- 24777725 TI - Does increased topside conformity in modular total knee arthroplasty lead to increased backside wear? AB - BACKGROUND: Modular metal-backed tibia components allow surgeons intraoperative flexibility. Although it is known that modular tibia components introduce the possibility for backside wear resulting from relative motion between the polyethylene insert and the tibial baseplate, it is not known to what degree variability in the conformity of the tibial polyethylene liner itself might contribute to backside wear. QUESTIONS/PURPOSES: The purpose of this study was to determine whether a flat, cruciate-retaining tibial polyethylene bearing generates less backside wear than a more conforming (curved) tibial polyethylene bearing in an analysis of specimens explanted during revision surgery. METHODS: The study included 70 total knee inserts explanted at revision surgery, all implanted and explanted by the same surgeon. Two different cruciate-retaining insert options in an otherwise similar knee system were used: one with a curved on-flat (17) articular geometry and one with a highly conforming curved-on-curved design (53); both groups were sequential cohorts. The composite backside wear depth for the insert as well as the volume of backside wear was measured and compared between groups. RESULTS: The median linear backside-normalized wear for the posterior lipped inserts was 0.0063 mm/year (range, 0-0.085 mm/year), which was lower than for the curved inserts at 0.05 mm/year (range, 0.00003-0.14 mm/year) (p<0.001). The median calculated volumetric backside-normalized wear for the posterior lipped inserts was 14.2 mm3/year (range, 0-282.8 mm3/year) compared with 117 mm3/year (range, 2.1-312 mm3/year) for the curved inserts (p<0.001). CONCLUSIONS: In this retrieval study, more conforming tibial inserts demonstrated more backside-normalized wear than the flatter designs. This suggests that in this modular total knee arthroplasty design, higher articular conformity to address the issues of high bearing contact stress comes at a price: increased torque transmitted to the backside insert-to-tray interface. We suggest further work be undertaken to examine newer insert designs to evaluate if our conclusions hold true with the newer generation locking mechanism, tibial tray finish and polyethylene designs, as more highly conforming tibial inserts are introduced into the market. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24777726 TI - What is the use of imaging before referral to an orthopaedic oncologist? A prospective, multicenter investigation. AB - BACKGROUND: Patients often receive advanced imaging before referral to an orthopaedic oncologist. The few studies that have evaluated the value of these tests have been single-center studies, and there were large discrepancies in the estimated frequencies of unnecessary use of diagnostic tests. QUESTIONS/PURPOSES: (1) Is there regional variation in the use of advanced imaging before referral to an orthopaedic oncologist? (2) Are these prereferral studies helpful to the treating orthopaedic oncologist in making a diagnosis or treatment plan? (3) Are orthopaedic surgeons less likely to order unhelpful studies than other specialties? (4) Are there any tumor or patient characteristics that are associated with the ordering of an unhelpful study? METHODS: We performed an eight-center prospective analysis of patients referred for evaluation by a fellowship-trained orthopaedic oncologist. We recorded patient factors, referral details, advanced imaging performed, and presumptive diagnosis. The treating orthopaedic oncologist determined whether each study was helpful in the diagnosis or treatment of the patient based on objective and subjective criteria used in prior investigations. We analyzed the data using bivariate methods and logistic regression to determine regional variation and risk factors predictive of unhelpful advanced imaging. Of the 371 participants available for analysis, 301 (81%) were referred with an MRI, CT scan, bone scan, ultrasound, or positron emission tomography scan. RESULTS: There were no regional differences in the use of advanced imaging (range of patients presenting with advanced imaging 66%-88% across centers, p = 0.164). One hundred thirteen patients (30%) had at least one unhelpful study; non-MRI advanced imaging was more likely to be unhelpful than MRIs (88 of 129 [68%] non-MRI imaging versus 46 of 263 [17%] MRIs [p < 0.001]). Orthopaedic surgeons were no less likely than nonorthopaedic surgeons to order unhelpful studies before referral to an orthopaedic oncologist (56 of 179 [31%] of patients referred by orthopaedic surgeons versus 35 of 119 [29%] referred by primary care providers and 22 of 73 [30%] referred by nonorthopaedic specialists, p = 0.940). After controlling for potential confounding variables, benign bone lesions had an increased odds of referral with an unhelpful study (59 of 145 [41%] of benign bone tumors versus 54 of 226 [24%] of soft tissue tumors and malignant bone tumors; odds ratio, 2.80; 95% confidence interval, 1.68-4.69, p < 0.001). CONCLUSIONS: We found no evidence that the proportion of patients referred with advanced imaging varied dramatically by region. Studies other than MRI were likely to be considered unhelpful and should not be routinely ordered by referring physicians. Diligent education of orthopaedic surgeons and primary care physicians in the judicious use of advanced imaging in benign bone tumors may help mitigate unnecessary imaging. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24777727 TI - The KSS 2011 reflects symptoms, physical activities, and radiographic grades in a Japanese population. AB - BACKGROUND: Cultural and ethnic differences are present both in subjective and objective measures of patient health, but scoring systems do not always reflect these differences, and so validation of outcomes tools in different cultural settings is important. Recently, a revised version of The Knee Society Score(r) (KSS 2011) was developed, but to our knowledge, the degree that this tool evaluates clinical symptoms, physical activities, and radiographic grades in the general Japanese population is not known. QUESTIONS/PURPOSES: We therefore asked: (1) how KSS 2011 reflects knee conditions and function in the general Japanese population, in particular evaluating changes with increasing patient age; (2) can objective measures of physical function be correlated with KSS 2011; and (3) does radiographic osteoarthritis (OA) grade correlate with KSS 2011? METHODS: Two hundred twenty-six people in the general Japanese population, aged 35 to 92 years, with and without knee arthritis, voluntarily participated in this cross sectional study. Residents who had no serious disease or symptoms based on a self assessment were recruited. This study consisted of a questionnaire including self administered KSS 2011, physical examination, and weightbearing radiographs of the knee. Leg muscle strength, Timed Up and Go test, and body mass index (BMI) were examined in all the participants. Radiographs were graded according to the Kellgren and Lawrence scale (KL grade). RESULTS: Multivariable linear regression analysis showed that KSS 2011 correlated with age (coefficient: -0.30+/-0.12, p=0.011), BMI (coefficient: -1.47+/-0.42, p<0.001), leg muscle strength (coefficient: 0.41+/-0.13, p=0.002), and Timed Up and Go Test (coefficient: 1.96+/-0.92, p=0.034), but not sex, as independent variables by a stepwise method. KSS 2011 was also correlated with radiographic OA evaluated by KL grade (coefficient: -12.2+/-2.9, p<0.001). CONCLUSIONS: KSS 2011 reflects symptoms, physical activities, and radiographic OA grades of the knee in an age-dependent manner in the general Japanese population. LEVEL OF EVIDENCE: Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 24777728 TI - Carpal tunnel syndrome impairs thumb opposition and circumduction motion. AB - BACKGROUND: Carpal tunnel syndrome is associated with sensory and motor impairments resulting from the compressed and malfunctioning median nerve. The thumb is critical to hand function, yet the pathokinematics of the thumb associated with carpal tunnel syndrome are not well understood. QUESTIONS/PURPOSES: The purpose of this study was to evaluate thumb motion abnormalities associated with carpal tunnel syndrome. We hypothesized that the ranges of translational and angular motion of the thumb would be reduced as a result of carpal tunnel syndrome. METHODS: Eleven patients with carpal tunnel syndrome and 11 healthy control subjects voluntarily participated in this study. Translational and angular kinematics of the thumb were obtained using marker based video motion analysis during thumb opposition and circumduction movements. RESULTS: Motion deficits were observed for patients with carpal tunnel syndrome even though maximum pinch strength was similar. The path length, normalized by palm width of the thumb tip for the patients with carpal tunnel syndrome was less than for control participants (opposition: 2.2 palm width [95% CI, 1.8-2.6 palm width] versus 3.1 palm width [95% CI, 2.8-3.4 palm width], p < 0.001; circumduction: 2.2 palm width [95% CI, 1.9-2.5 palm width] versus 2.9 palm width [95% CI, 2.7-3.2 palm width], p < 0.001). Specifically, patients with carpal tunnel syndrome had a deficit of 0.3 palm width (95% CI, 0.04-0.52 palm width; p = 0.022) in the maximum position of their thumb tip ulnarly across the palm during opposition relative to control participants. The angular ROM also was reduced for the patients with carpal tunnel syndrome compared with the control participants in extension/flexion for the metacarpophalangeal (opposition: 34 degrees versus 58 degrees , p = .004; circumduction: 33 degrees versus 58 degrees , p < 0.001) and interphalangeal (opposition: 37 degrees versus 62 degrees , p = .028; circumduction: 41 degrees versus 63 degrees , p = .025) joints. CONCLUSIONS: Carpal tunnel syndrome disrupts kinematics of the thumb during opposition and circumduction despite normal pinch strength. CLINICAL RELEVANCE: Improving understanding of thumb pathokinematics associated with carpal tunnel syndrome may help clarify hand function impairment associated with the syndrome given the critical role of the thumb in dexterous manipulation. PMID- 24777729 TI - Epidemiology of multiligament knee reconstruction. AB - BACKGROUND: The multiple-ligament-injured knee represents a special challenge, being an uncommon injury that is both severe and complicated to treat. Many studies have evaluated patients treated for this injury, but most are limited in their scope. The evaluation of this injury and its treatment using an administrative database might provide a different perspective. QUESTIONS/PURPOSES: Using a large administrative database, we determined (1) the number of multiligament knee reconstructions in New York State, (2) the rate of 90-day hospital readmission, and (3) the frequency of subsequent knee surgery. We examined the rates of these outcomes as a function of diagnosis, admission type, discharge status, comorbidity burden, and patient demographic factors. METHODS: We used the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS), a database with information on patient characteristics, diagnoses, and treatments, to identify patients who underwent a multiligament procedure in a nonfederal facility from 1997 to 2005 using ICD-9-CM and Current Procedural Terminology codes. SPARCS collects data from all nonfederal acute care facilities, with an estimated reporting completeness of almost 99% for the years in this study. We evaluated data on patient age, sex, admission type, discharge status, and comorbidity burden (using Elixhauser comorbidities) and developed a multivariable logistic regression model to assess the influence of confounding variables. RESULTS: We identified 1032 patients in this database who underwent multiligament knee reconstruction in New York State from 1997 to 2005. The frequency of readmission within 90 days was 4.8% (n = 49). Readmission was more likely for patients who underwent inpatient multiligament reconstruction (odds ratio [OR] = 2.3; 95% CI: 1.2-4.4; p = 0.014), had a diagnosis of dislocation (OR = 2.2; 95% CI: 1.2-3.9; p = 0.011), or had various Elixhauser comorbidities, including chronic lung disease (OR = 6.4; 95% CI: 1.5 27.2; p = 0.013), fluid and electrolyte disorders (OR = 19.7; 95% CI: 2.5-155.7; p = 0.005), and anemia deficiency (OR = 5.6; 95% CI: 1.05-29.4; p = 0.044). Two hundred eighty-seven patients (28%) underwent subsequent knee surgery between their index procedure and 2006. Subsequent surgery was more likely for patients who underwent inpatient multiligament reconstruction (OR = 1.4; 95% CI: 1.1-1.9; p = 0.011) or were readmitted within 90 days of the index surgery (OR = 4.2; 95% CI: 2.3-7.6; p < 0.001). CONCLUSIONS: Our findings have the potential to aid clinicians in identifying their patients with multiligament reconstruction at highest risk for 90-day readmission and subsequent knee surgery. Future research, particularly large prospective studies evaluating surgical approaches and timing, will be critical in advancing the treatment of multiligament knee injuries. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24777730 TI - What are the functional outcomes of endoprosthestic reconstructions after tumor resection? AB - BACKGROUND: The majority of published functional outcome data for tumor megaprostheses comes in the form of subjective functional outcome scores. Sparse objective data exist demonstrating functional results, activity levels, and efficiency of gait after endoprosthetic reconstruction in patients treated for orthopaedic tumors. Patients embarking on massive surgical operations, often in the setting of debilitating medical therapies, face mortality and a myriad of unknowns. Objective functional outcomes provide patients with reasonable expectations and a means to envision life after treatment. Objective outcomes also provide a means for surgeons to compare techniques, rehabilitation protocols, and implants. QUESTIONS/PURPOSES: We asked the following questions: (1) What is the efficiency of gait (ie, oxygen consumption) at final recovery from endoprosthetic reconstruction for oncologic resections? (2) What is the knee strength after lower extremity endoprosthetic reconstruction as compared with the contralateral limb? (3) How active are patients with tumor megaprostheses at home and in the community? METHODS: Sixty-nine patients with endoprosthetic reconstructions for primary lower extremity bone sarcoma met inclusion criteria and were invited by mailing to undergo oxygen cost study and strength testing. Twenty-four patients (seven proximal femoral replacements, nine distal femoral replacements, and eight proximal tibia replacements) underwent evaluation in the gait laboratory at a mean of 13.2 years after their reconstruction. All patients were then asked to wear step activity monitors at home and in the community for 7 consecutive days. RESULTS: Median O2 consumption (in mL/kg/m) among the endoprothesis groups was not different from the control patients with the numbers available (proximal femoral replacement 0.17, distal femoral replacement 0.16, proximal tibia replacement 0.18, control 0.15, p = 0.21). With the numbers available, there was no difference in walking speed as compared with the control group (proximal femoral replacement 1.20 m/s, distal femoral replacement 1.27 m/s, proximal tibia replacement 1.12 m/s, control 1.27 m/s, p = 0.08). Patients with proximal tibia replacements had reduced knee extension and flexion strength compared with patients in other reconstruction groups (84% reduction in extension versus those with proximal femoral replacements, 35%, and distal femoral replacement, 53%, p = 0.001, and 43% reduction in flexion versus proximal femoral replacement, 11%, distal femoral replacement, 2%, p = 0.006). With the numbers available, mean strides per day were not different among the reconstruction groups (proximal femoral replacement = 4709 strides/day [3094-6696], distal femoral replacement = 2854 [2461-6015], and proximal tibia replacement = 4411 [3093-6215], p = 0.53). CONCLUSIONS: Although knee strength was reduced in patients with proximal tibia replacements compared with femoral reconstructions, all groups had an efficient gait and were active at home and in the community at a mean of 13.2 years after surgery. Despite the magnitude of these surgeries, these patients are similarly active as patients after standard total hip arthroplasty. These findings provide objective data from which patients undergoing tumor megaprosthesis reconstructions of the lower extremity can reasonably base expectations of efficient gait and active lifestyles outside of the hospital setting. These data may provide hope and long-term goals for patients facing the uncertainty of chemotherapy and surgical treatment. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24777731 TI - Opioid use after fracture surgery correlates with pain intensity and satisfaction with pain relief. AB - BACKGROUND: In 2012, Medicare began to tie reimbursements to inpatient complications, unplanned readmissions, and patient satisfaction, including satisfaction with pain management. QUESTIONS/PURPOSES: We aimed to identify factors that correlate with (1) pain intensity during a 24-hour period after surgery; (2) less than complete satisfaction with pain control; (3) less than complete satisfaction with staff attention to pain relief while in the hospital; and we also wished (4) to compare inpatient and discharge satisfaction scores. METHODS: Ninety-seven inpatients completed measures of pain intensity (numeric rating scale), satisfaction with pain relief, self-efficacy when in pain, and symptoms of depression days after operative fracture repair. The amount of opioid used in oral morphine equivalents taken during the prior 24 hours was calculated. Through initial bivariate and then multivariate analysis, we identified factors that were associated with pain intensity, less than complete satisfaction with pain control, and less than complete satisfaction with staff attention to pain relief. RESULTS: Patients who took more opioids reported greater pain intensity (r = 0.38). No factors representative of greater nociception (fracture type, number of fractures, days from injury to surgery, days from surgery to enrollment, or type of surgery) correlated with greater pain intensity. The best multivariable model for greater pain intensity included: depression or anxiety disorder (p = 0.019), smoking (0.047), and greater opioid intake (p = 0.001). Multivariable analysis for less than ideal satisfaction with pain control included the Pain Self-Efficacy Questionnaire (PSEQ) (odds ratio [OR], 0.95; 95% CI, 0.92-0.99) alone; for less than ideal satisfaction with staff attention to pain control, the PSEQ (OR, 0.96; 95% CI, 0.92-0.99) and opioid medication use before admission (OR, 3.6; 95% CI, 1.1-12) were included. CONCLUSIONS: After operative fracture treatment, patients who take more opioids report greater pain intensity and less satisfaction with pain relief. Greater self-efficacy was the best determinant of satisfaction with pain relief. Evidence-based interventions to increase self-efficacy merit additional study for the management of postoperative pain during recovery from a fracture. LEVEL OF EVIDENCE: Level II, prognostic study. See the Instructions for Authors for a complete description of levels of evidence. PMID- 24777732 TI - Control of the electronic ground state on an electron-transfer copper site by second-sphere perturbations. AB - The Cu(A) center is a dinuclear copper site that serves as an optimized hub for long-range electron transfer in heme-copper terminal oxidases. Its electronic structure can be described in terms of a sigma(u)* ground-state wavefunction with an alternative, less populated ground state of pi(u) symmetry, which is thermally accessible. It is now shown that second-sphere mutations in the Cu(A) containing subunit of Thermus thermophilus ba3 oxidase perturb the electronic structure, which leads to a substantial increase in the population of the pi(u) state, as shown by different spectroscopic methods. This perturbation does not affect the redox potential of the metal site, and despite an increase in the reorganization energy, it is not detrimental to the electron-transfer kinetics. The mutations were achieved by replacing the loops that are involved in protein-protein interactions with cytochrome c, suggesting that transient protein binding could also elicit ground-state switching in the oxidase, which enables alternative electron-transfer pathways. PMID- 24777733 TI - B-cell-intrinsic STAT6 signaling controls germinal center formation. AB - Infection with helminths and exposure to antigens induce a strong type 2 immune response resulting in the secretion of the cytokines IL-4 and IL-13 by CD4(+) T cells and several innate cell types. IL-4 and IL-13 promote class switch recombination to IgG1 and IgE while their role for germinal center (GC) formation is poorly understood. We found a dramatic reduction in the numbers of GC B cells when investigating different type 2 immune responses in IL-4/IL-13-deficient mice. IL-4/IL-13 from T cells located outside B-cell follicles was sufficient for GC formation. We further revealed that IL-4/IL-13 acts directly on B cells for the formation of a robust GC response. The frequency of apoptotic GC B cells was not altered in the absence of IL-4/IL-13 and proliferation was even enhanced. However, deficiency of signal transducer and activator of transcription 6 signaling in B cells resulted in failure to downregulate the chemotactic receptor Gpr183 (Ebi2) and downregulation of this receptor has been shown to be essential for proper GC B-cell differentiation. Thus, T-cell-derived extrafollicular IL 4/IL-13 and signal transducer and activator of transcription 6-regulated genes in B cells play a critical role for orchestration of the GC response in type 2 immunity. PMID- 24777734 TI - Rapidly rising incidence of childhood type 1 diabetes in Chinese population: epidemiology in Shanghai during 1997-2011. AB - The aim of this study was to investigate incidence trend of childhood type 1 diabetes in Shanghai, a megalopolis in east China. We established a population based retrospective registry for the disease in the city's registered population during 1997-2011 and collected 622 incident type 1 diabetes in children aged 0-14 years. Standardized incidence rates and 95 % CI were estimated by applying the capture-recapture method and assuming Poisson distribution. Incidence trend was analyzed using the Poisson regression model. The mean annual incidence of childhood type 1 diabetes was 3.1 per 100,000 person-years. We did not observe significant difference in incidence between boys and girls. The incidence is unstable and had a mean annual increase 14.2 % per year during the studied period. A faster annual increase was observed in boys, warmer seasons, and in the outer regions of the city. If present trends continue, the number of new type 1 diabetes cases will double from 2016 to 2020, and prevalent cases will sextuple by 2025. Our results showed the incidence of childhood type 1 diabetes was rising rapidly in Shanghai. More studies are needed to analyze incidence changes in other regions of China for appropriate allocation of healthcare resources. PMID- 24777735 TI - Relation between vibrotactile perception thresholds and reductions in finger blood flow induced by vibration of the hand at frequencies in the range 8-250 Hz. AB - PURPOSE: This study investigated how the vasoconstriction induced by vibration depends on the frequency of vibration when the vibration magnitude is defined by individual thresholds for perceiving vibration [i.e. sensation levels (SL)]. METHODS: Fourteen healthy subjects attended the laboratory on seven occasions: for six vibration frequencies (8, 16, 31.5, 63, 125, or 250 Hz) and a static control condition. Finger blood flow (FBF) was measured in the middle fingers of both hands at 30-second intervals during five successive periods: (i) no force or vibration, (ii) 2-N force, no vibration, (iii) 2-N force, vibration, (iv) 2-N force, no vibration, (v) no force or vibration. During period (iii), vibration was applied to the right thenar eminence via a 6-mm diameter probe during ten successive 3-min periods as the vibration magnitude increased in ten steps (-10 to +40 dB SL). RESULTS: With vibration at 63, 125, and 250 Hz, there was vasoconstriction on both hands when the vibration magnitude reached 10 dB SL. With vibration at 8, 16, and 31.5 Hz, there was no significant vasoconstriction until the vibration reached 25 dB SL. At all frequencies, there was greater vasoconstriction with greater magnitudes of vibration. CONCLUSIONS: It is concluded that at the higher frequencies (63, 125, and 250 Hz), the Pacinian channel mediates vibrotactile sensations near threshold and vasoconstriction occurs when vibration is perceptible. At lower frequencies (8, 16, and 31.5 Hz), the Pacinian channel does not mediate sensations near threshold and vasoconstriction commences at greater magnitudes when the Pacinian channel is activated. PMID- 24777736 TI - Locomotor and diaphragm muscle fatigue in endurance athletes performing time trials of different durations. AB - PURPOSE: Fatigue in leg muscles might differ between running and cycling due to inherent differences in muscle activation patterns. Moreover, postural demand placed upon the diaphragm during running could augment the development of diaphragm fatigue. METHODS: We investigated quadriceps and diaphragm fatigue in 11 runners and 11 cyclists (age: 29 +/- 5 years; [Formula: see text]O2,peak: 66.9 +/- 5.5 ml min(-1) kg(-1)) by assessing quadriceps twitch force (Q tw) and transdiaphragmatic twitch pressure (P di,tw) before and after 15- and 30-min time trials (15TT, 30TT). Inspiratory muscle fatigue was also obtained after volitional normocapnic hyperpnoea (NH) where postural demand is negligible. We hypothesized that running and cycling would induce different patterns of fatigue and that runners would develop less respiratory muscle fatigue when performing NH. RESULTS: The reduction in Q tw was greater in cyclists (32 +/- 6 %) compared to runners (13 +/- 8 %, p < 0.01), but not different for 15TTs (23 +/- 13 %) and 30TTs (21 +/- 11 %, p = 0.34). Overall P di,tw was more reduced after 15TTs (24 +/- 8 %) than after 30TTs (20 +/- 9 %, p = 0.04) while being similar for runners and cyclists (p = 0.78). Meanwhile, breathing duration in NH and the magnitude of inspiratory muscle fatigue were also not different (both p > 0.05). CONCLUSION: Different levels of leg muscle fatigue in runners and cyclists could in part be related to the specific muscle activation patterns including concentric contractions in both modalities but eccentric contractions in runners only. Diaphragm fatigue likely resulted from the large ventilatory load which is characteristic for both exercise modalities and which was higher in 15TTs than in 30TTs (+27 %, p < 0.01) while postural demand appears to be of less importance. PMID- 24777737 TI - Ramp-incremented and RPE-clamped test protocols elicit similar VO2max values in trained cyclists. AB - PURPOSE: The present study compared the efficacy of ramp incremented and ratings of perceived exertion (RPE)-clamped test protocols for eliciting maximal oxygen uptake (VO2max). METHODS: Sixteen trained cyclists (age 34 +/- 7 years) performed a ramp-incremented protocol and an RPE-clamped protocol 1 week apart in a randomized, counterbalanced order. The RPE-clamped protocol consisted of five, 2 min stages where subjects self-selected work rate and pedal cadence to maintain the prescribed RPE. After completing both test protocols subjects were asked which they preferred. RESULTS: The mean +/- SD test time of 568 +/- 72 s in the ramp protocol was not significantly different to the 600 +/- 0 s in the RPE clamped protocol (mean difference = 32 s; p = 0.09), or was the VO2max of 3.86 +/ 0.73 L min(-1) in the ramp protocol significantly different to the 3.87 +/- 0.72 L min(-1) in the RPE-clamped protocol (mean difference = 0.002 L min(-1); p = 0.97). Furthermore, no significant differences were observed for peak power output (p = 0.21), maximal minute ventilation (p = 0.97), maximal respiratory exchange ratio (p = 0.09), maximal heart rate (p = 0.51), and post-test blood lactate concentration (p = 0.58). The VO2max attained in the preferred protocol was significantly higher than the non-preferred protocol (mean difference = 0.14 L min(-1); p = 0.03). CONCLUSION: The RPE-clamped test protocol was as effective as the ramp-incremented protocol for eliciting VO2max and could be considered as a valid alternative protocol, particularly where a fixed test duration is desirable. PMID- 24777738 TI - Motor point map of upper body muscles. AB - PURPOSE: The purpose of the present study was to systematically investigate the upper body motor point (MP) positions of selected muscles and to create an atlas of the identified MPs. METHODS: MPs were searched bilaterally in 15 male and 15 female subjects by scanning the skin with a special pen electrode at low stimulation frequency (3 Hz) and current amplitude (<10 mA). The following muscles were investigated: biceps brachii, triceps brachii, deltoideus, trapezius, latissimus dorsi, erector spinae (lumbar part), pectoralis minor and major, and rectus abdominis. RESULTS: A total of 1,563 MPs were identified. The MPs could be clustered into 31 distinct positions on each side of the body. However, the number of MPs per muscle varied between subjects: 2 MPs were found for the biceps brachii, 2-3 for the triceps brachii, 4-5 for the deltoideus, 2-3 for the pectoralis major, 1 MP for the pectoralis minor, 4-5 for the trapezius, 3 4 for the latissimus dorsi, 4-5 for the rectus abdominis, and 2-3 for the erector spinae in its lumbar part. Referring to the applied grid, upper limb and lower back muscles presented a low inter-individual variation, whereas MPs of the deltoideus, the pectoralis major, and the rectus abdominis were characterized by a poor homogeneity. All MPs were found to be highly symmetrical between both sides of the body (r = 0.96; p < 0.001). CONCLUSION: The presented data and the corresponding map will help physiotherapists, and conditioning specialists improve their neuromuscular electrical stimulation therapy or training, respectively. PMID- 24777740 TI - Regeneration of the periodontium for preservation of the damaged tooth. AB - The population of the world grows every year, and life expectancy tends to increase. Thus, long-term preservation of teeth in aged individuals is an urgent issue. The main causes of tooth loss are well known to be periodontitis, caries, fractures, and orthodontic conditions. Although implant placement is a widely accepted treatment for tooth loss, most patients desire to preserve their own teeth. Many clinicians and researchers are therefore challenged to treat and preserve teeth that are irreversibly affected by deep caries, periodontitis, fractures, and trauma. Tissue engineering techniques are beneficial in addressing this issue; stem cells, signal molecules, and scaffolds are the main elements of such techniques. In this review, we describe these three elements with respect to their validation for regeneration of the periodontium and focus particularly on the potency of diverse scaffolds. In addition, we provide a short overview of the ongoing studies of 4-methacryloxyethyl trimellitate anhydride/methyl methacrylate tri-n-butyl-borane resin including calcium chloride or hydroxyapatite for periodontium regeneration. PMID- 24777739 TI - A novel ZRS mutation leads to preaxial polydactyly type 2 in a heterozygous form and Werner mesomelic syndrome in a homozygous form. AB - Point mutations in the zone of polarizing activity regulatory sequence (ZRS) are known to cause human limb malformations. Although most mutations cause preaxial polydactyly (PPD), triphalangeal thumb (TPT) or both, a mutation in position 404 of the ZRS causes more severe Werner mesomelic syndrome (WMS) for which malformations include the distal arm or leg bones in addition to the hands and/or feet. Of more than 15 reported families with ZRS mutations, only one homozygous individual has been reported, with no change in phenotype compared with heterozygotes. Here, we describe a novel point mutation in the ZRS, 402C>T (AC007097.4:g.105548C>T), that is transmitted through two Mexican families with one homozygous individual. The homozygous phenotype for this mutation, WMS, is more severe than the numerous heterozygous individuals genotyped from both families who have TPT and PPD. A mouse transgenic enhancer assay shows that this mutation causes an expansion of the enhancer's expression domain in the developing mouse limb, confirming its pathogenicity. Combined, our results identify a novel ZRS mutation in the Mexican population, 402C>T, and suggest that a dosage effect exists for this ZRS mutation. PMID- 24777741 TI - High fluoride and low calcium levels in drinking water is associated with low bone mass, reduced bone quality and fragility fractures in sheep. AB - Chronic environmental fluoride exposure under calcium stress causes fragility fractures due to osteoporosis and bone quality deterioration, at least in sheep. Proof of skeletal fluorosis, presenting without increased bone density, calls for a review of fracture incidence in areas with fluoridated groundwater, including an analysis of patients with low bone mass. INTRODUCTION: Understanding the skeletal effects of environmental fluoride exposure especially under calcium stress remains an unmet need of critical importance. Therefore, we studied the skeletal phenotype of sheep chronically exposed to highly fluoridated water in the Kalahari Desert, where livestock is known to present with fragility fractures. METHODS: Dorper ewes from two flocks in Namibia were studied. Chemical analyses of water, blood and urine were executed for both cohorts. Skeletal phenotyping comprised micro-computer tomography (MUCT), histological, histomorphometric, biomechanical, quantitative backscattered electron imaging (qBEI) and energy-dispersive X-ray (EDX) analysis. Analysis was performed in direct comparison with undecalcified human iliac crest bone biopsies of patients with fluoride-induced osteopathy. RESULTS: The fluoride content of water, blood and urine was significantly elevated in the Kalahari group compared to the control. Surprisingly, a significant decrease in both cortical and trabecular bones was found in sheep chronically exposed to fluoride. Furthermore, osteoid parameters and the degree and heterogeneity of mineralization were increased. The latter findings are reminiscent of those found in osteoporotic patients with treatment-induced fluorosis. Mechanical testing revealed a significant decrease in the bending strength, concurrent with the clinical observation of fragility fractures in sheep within an area of environmental fluoride exposure. CONCLUSIONS: Our data suggest that fluoride exposure with concomitant calcium deficit (i) may aggravate bone loss via reductions in mineralized trabecular and cortical bone mass and (ii) can cause fragility fractures and (iii) that the prevalence of skeletal fluorosis especially due to groundwater exposure should be reviewed in many areas of the world as low bone mass alone does not exclude fluorosis. PMID- 24777742 TI - Testicular tissue cryopreservation in prepubertal male children: an analysis of parental decision-making. AB - BACKGROUND: Infertility is an unfortunate treatment-related consequence for some pediatric malignancies as well as some non-malignant conditions treated with stem cell transplant. Unlike pubertal males, prepubertal males cannot produce semen for cryopreservation. This manuscript reports on the acceptability and safety of a multi-institutional protocol for offering testicular tissue cryopreservation to families of prepubertal male children at highest risk for infertility. Data on decision influences, decision-making control, and emotional state when considering this option are described. PROCEDURE: Prepubertal males facing gonadotoxic therapy were offered testicular cryopreservation. Post-biopsy, patients were followed for acute side effects. In addition, parents and patients were asked to complete questionnaires, whether or not they chose to cryopreserve tissue. RESULTS: Seventy-four prepubertal male children were approached. Fifty seven families (77%) consented to the testicular biopsy; 48 of 57 underwent the procedure. There was one post-operative side effect. Parents who agreed to testicular cryopreservation and those that did not felt in control of this decision. Parents who consented to the biopsy and refusers were not deterred by the experimental nature of the protocol. An important decision-making influence was the risk of the biopsy. CONCLUSION: Biopsy and cryopreservation of testicular tissue from prepubertal male children was performed successfully and safely at three institutions. Parents faced with this option at diagnosis can make an informed decision and weigh carefully the risks and benefits. Although asked to make a decision soon after they were given a difficult diagnosis, parents uniformly felt in control of this decision. PMID- 24777743 TI - Modeling biophysical and biological properties from the characteristics of the molecular electron density, electron localization and delocalization matrices, and the electrostatic potential. AB - The electron density and the electrostatic potential are fundamentally related to the molecular hamiltonian, and hence are the ultimate source of all properties in the ground- and excited-states. The advantages of using molecular descriptors derived from these fundamental scalar fields, both accessible from theory and from experiment, in the formulation of quantitative structure-to-activity and structure-to-property relationships, collectively abbreviated as QSAR, are discussed. A few such descriptors encode for a wide variety of properties including, for example, electronic transition energies, pK(a)'s, rates of ester hydrolysis, NMR chemical shifts, DNA dimers binding energies, pi-stacking energies, toxicological indices, cytotoxicities, hepatotoxicities, carcinogenicities, partial molar volumes, partition coefficients (log P), hydrogen bond donor capacities, enzyme-substrate complementarities, bioisosterism, and regularities in the genetic code. Electronic fingerprinting from the topological analysis of the electron density is shown to be comparable and possibly superior to Hammett constants and can be used in conjunction with traditional bulk and liposolubility descriptors to accurately predict biological activities. A new class of descriptors obtained from the quantum theory of atoms in molecules' (QTAIM) localization and delocalization indices and bond properties, cast in matrix format, is shown to quantify transferability and molecular similarity meaningfully. Properties such as "interacting quantum atoms (IQA)" energies which are expressible into an interaction matrix of two body terms (and diagonal one body "self" terms, as IQA energies) can be used in the same manner. The proposed QSAR-type studies based on similarity distances derived from such matrix representatives of molecular structure necessitate extensive investigation before their utility is unequivocally established. PMID- 24777744 TI - Agonistic autoantibodies directed against G-protein-coupled receptors and their relationship to cardiovascular diseases. AB - Agonistic autoantibodies (AABs) against G-protein-coupled receptor (GPCR) are present mainly in diseases of the cardiovascular system or in diseases associated with cardiovascular disturbances. The increasing knowledge about the role of autoantibodies against G-protein-coupled receptor (GPCR-AABs) as pathogenic drivers, the resulting development of strategies aimed at their removal or neutralization, and the evidenced patient benefit associated with such therapies have created the need for a summary of GPCR-AAB-associated diseases. Here, we summarize the present knowledge about GPCR-AABs in cardiovascular diseases. The identity of the GPCR-AABs and their prevalence in each of several specific cardiovascular diseases are documented. The structure of GPCR is also briefly discussed. Using this information, differences between classic agonists and GPCR AABs in their GPCR binding and activation are presented and the resulting pathogenic consequences are discussed. Furthermore, treatment strategies that are currently under study, most of which are aimed at the removal and in vivo neutralization of GPCR-AABs, are indicated and their patient benefits discussed. In this context, immunoadsorption using peptides/proteins or aptamers as binders are introduced. The use of peptides or aptamers for in vivo neutralization of GPCR-AABs is also described. Particular attention is given to the GPCR-AABs directed against the adrenergic beta1-, beta2-, and alpha1-receptor as well as the muscarinic receptor M2, angiotensin II-angiotensin receptor type I, endothelin1 receptor type A, angiotensin (1-7) Mas-receptor, and 5 hydroxytryptamine receptor 4. Among the diseases associated with GPCR-AABs, special focus is given to idiopathic dilated cardiomyopathy, Chagas' cardiomyopathy, malignant and pulmonary hypertension, and kidney diseases. Relationships of GPCR-AABs are indicated to glaucoma, peripartum cardiomyopathy, myocarditis, pericarditis, preeclampsia, Alzheimer's disease, Sjorgren's syndrome, and metabolic syndrome after cancer chemotherapy. PMID- 24777745 TI - Targeting B cells and autoantibodies in the therapy of autoimmune diseases. AB - B cells and B cell-derived autoantibodies play a central role in the pathogenesis of many autoimmune diseases. Thus, depletion of B cells via monoclonal antibodies such as Rituximab is an obvious therapeutic intervention and has been used successfully in many instances. More recently, novel therapeutic options targeting either the autoantibody itself or resetting the threshold for B cell activation have become available and show promising immunomodulatory and anti inflammatory effects in a variety of animal models. The aim of this review is to summarize these results and to provide an insight into the underlying molecular and cellular pathways of these novel therapeutic interventions targeting autoantibodies and B cells and to discuss their value for human therapy. PMID- 24777747 TI - Introduction: B cell-mediated autoimmune diseases. PMID- 24777746 TI - B cell-mediated pathogenesis of ANCA-mediated vasculitis. AB - B cells and their progeny that produce and release anti-neutrophil cytoplasmic autoantibodies (ANCA) are the primary cause for an aggressive form of necrotizing small vessel vasculitis. Cytoplasmic ANCA antigens are released at the surface and in the microenvironment of cytokine-primed neutrophils. Binding of ANCA to ANCA antigens activates neutrophils by both Fc receptor engagement and direct Fab'2 binding to antigen on the cell surface. ANCA-activated neutrophils release factors that induce alternative complement pathway activation, which establishes a potent inflammatory amplification loop that causes severe necrotizing vascular inflammation. The origin of the ANCA autoimmune response is unknown but appears to involve genetically determined HLA specificities that allow the autoimmune response to develop. One putative immunogenic mechanism begins with an immune response to a peptide that is complementary to the autoantigen and evolves through an anti-idiotypic network to produce autoantibodies to the autoantigen. Another putative immunogenic mechanism begins with an immune response to a microbe-derived molecular mimic of the autoantigen resulting in antibodies that cross-react with the autoantigen. Release of neutrophil extracellular traps, apoptosis, and increased granule protein expression of ANCA antigens may facilitate the initiation of an ANCA autoimmune response, augment established pathogenic ANCA production, or both. The ANCA B cell autoimmune response is facilitated by quantitatively and qualitatively impaired T cell and B cell suppression and by release from activated neutrophils of B cell-activating factors that enhance B cell proliferation and retard B cell apoptosis. PMID- 24777748 TI - Nonclinical safety biomarkers of drug-induced vascular injury: current status and blueprint for the future. AB - Better biomarkers are needed to identify, characterize, and/or monitor drug induced vascular injury (DIVI) in nonclinical species and patients. The Predictive Safety Testing Consortium (PSTC), a precompetitive collaboration of pharmaceutical companies and the U.S. Food and Drug Administration (FDA), formed the Vascular Injury Working Group (VIWG) to develop and qualify translatable biomarkers of DIVI. The VIWG focused its research on acute DIVI because early detection for clinical and nonclinical safety monitoring is desirable. The VIWG developed a strategy based on the premise that biomarkers of DIVI in rat would be translatable to humans due to the morphologic similarity of vascular injury between species regardless of mechanism. The histomorphologic lexicon for DIVI in rat defines degenerative and adaptive findings of the vascular endothelium and smooth muscles, and characterizes inflammatory components. We describe the mechanisms of these changes and their associations with candidate biomarkers for which advanced analytical method validation was completed. Further development is recommended for circulating microRNAs, endothelial microparticles, and imaging techniques. Recommendations for sample collection and processing, analytical methods, and confirmation of target localization using immunohistochemistry and in situ hybridization are described. The methods described are anticipated to aid in the identification and qualification of translational biomarkers for DIVI. PMID- 24777749 TI - Circulating miR-9* and miR-384-5p as potential indicators for trimethyltin induced neurotoxicity. AB - Circulating microRNAs (miRNAs) show promise as biomarkers due to their tissue specific expression and high stability. This study was conducted to investigate whether nervous system-enriched miR-9* and hippocampus-enriched miR-384-5p could be indicators of neurotoxicity in serum. Rats were given a single administration of trimethyltin (TMT) chloride at 6, 9, or 12 mg/kg by gavage, and brain and serum were collected 1, 4, and 7 days after administration. MiR-9* and miR-384-5p levels in serum and hippocampus were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR), and their neurotoxicity detection sensitivities were compared with nervous symptoms, auditory response, and histopathology. TMT caused tremor, hypersensitivity, and decreased auditory response at 12 mg/kg on day 1 and at 9 mg/kg on day 4. Histopathologically, neural cell death and glial reaction were observed in brain (mainly hippocampus) at 12 mg/kg on day 1, 4, and 7 and at 6 and 9 mg/kg on day 4 and 7. MiR-9* and miR-384-5p levels were elevated in serum at 9 and 12 mg/kg on days 4 and 7 (at 9 mg/kg on day 7, miR-9* only) but were not changed in hippocampus. These miRNAs were considered to be elevated with the evolution of neural cell death and were thus considered possible novel indicators of neurotoxicity. PMID- 24777750 TI - Oxidative damage repair by glutamine in fish enterocytes. AB - Fish intestine is very sensitive to oxidative damage. Repair of damaged enterocytes may be involved to restore normal function of fish intestine. However, studies of fish enterocyte repair are scarce. The present study aimed to investigate the potential repair role of glutamine after a H2O2 challenge. In this study, fish enterocytes were post-treated with graded levels of glutamine (0, 4, 8, 12 and 20 mM of glutamine) after expose to 100 MUM H2O2. The basal control cells were kept in the glutamine-free minimum essential medium only. Results showed that the H2O2-induced decreases in 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide optical density, alkaline phosphatase and Na(+), K(+)-ATPase activities were completely restored by subsequent glutamine treatments. In addition, cellular injury (lactate dehydrogenase), lipid peroxidation (malondialdehyde) and protein oxidation (protein carbonyls) caused by H2O2 were reversed by subsequent glutamine treatments. Furthermore, the H2O2 induced decreases in glutathione contents, glutathione reductase, superoxide dismutase and glutathione peroxidase activities were completely restored by subsequent glutamine treatments. In summary, the present study indicated that glutamine improved the repair activity in fish enterocytes after challenge with H2O2. PMID- 24777751 TI - New trends of an old disease: the acute post infectious glomerulonephritis at the beginning of the new millenium. AB - The association between acute renal disease and infection has been known since the mid '800s: acute post-infectious glomerulonephritis (PIGN) is a reactive immunological process against the kidney secondary to an infection, classically caused by a Streptococcus. The typical clinical presentation of PIGN is an acute nephritic syndrome with macro- or microscopic hematuria, proteinuria, hypertension, edema and renal function impairment of variable degree. The histology is characterized by an intracapillary glomerular proliferation, but may rarely be associated with an extracapillary proliferation. The classical childhood form is still present nowadays, even with severe cases, in developing countries, while in the last decades it almost disappeared in industrialized countries, where post-infectious GN are often found in elderly patients with multiple comorbidities. These clinical variants are usually related to other infective agents, like Staphylococcus aureus, both methicillin resistant (MRSA) and susceptible, and may be characterized by an IgA-dominant deposition. Kidney biopsy is rarely needed, especially in the child, while in the adult or old patient a biopsy is warranted if there is an atypical presentation or evolution, like rapidly progressive renal failure, absent or delayed function recovery, persisting low C3, nephrotic range proteinuria and persisting high proteinuria. Current therapy strategies rely on culture-guided systemic antibiotics, especially in the old patient, in which MRSA are relatively frequent, support therapy and only in very selected cases on steroids. These latter cases include the rare PIGN with crescents and those with a severe interstitial inflammation. PMID- 24777752 TI - Automated Aufbau of antibody structures from given sequences using Macromoltek's SmrtMolAntibody. AB - This study was a part of the second antibody modeling assessment. The assessment is a blind study of the performance of multiple software programs used for antibody homology modeling. In the study, research groups were given sequences for 11 antibodies and asked to predict their corresponding structures. The results were measured using root-mean-square deviation (rmsd) between the submitted models and X-ray crystal structures. In 10 of 11 cases, the results using SmrtMolAntibody show good agreement between the submitted models and X-ray crystal structures. In the first stage, the average rmsd was 1.4 A. Average rmsd values for the framework was 1.2 A and for the H3 loop was 3.0 A. In stage two, there was a slight improvement with an rmsd for the H3 loop of 2.9 A. PMID- 24777753 TI - Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. AB - Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently completed enrollment. PMID- 24777754 TI - Expression variability and function of the RET gene in adult peripheral blood mononuclear cells. AB - RET is a gene playing a key role during embryogenesis and in particular during the enteric nervous system development. High levels of RET gene expression are maintained in different human tissues also in adulthood, although their physiological role remains unclear. In particular, collected evidences of a RET contribution in the development and maintenance of the immune system prompted us to investigate its levels of surface expression on peripheral blood mononuclear cells (PBMCs) from adult healthy donors. Despite variability among samples, RET expression was conserved at similar levels in the different immune cell subsets, with higher correlations in similar lymphocyte populations (i.e. CD4(+) and CD8(+) T cells). Conversely, no correlation was found between the amount of RET receptor, the expression of its putative ligands and co-receptors and the genotypes at the RET locus. Moreover, we investigated the RET-associated inflammatory pathways in PBMCs from healthy donors both in resting conditions and upon glial cell derived neurotrophic factor (GDNF) and GPI-linked co-receptors alpha 1 (GFRalpha1) mediated RET activation. RET mRNA levels positively correlated with the transcript amount of interleukin-8 (IL-8), a cytokine produced by monocytes and macrophages, though we could not demonstrate its direct effect on RET expression by in vitro experiments on THP1 human monocytic cells. These results imply that RET expression might be influenced by either cis- and/or trans-factors, which together would account for its high variability within the general population, and suggest a putative functional role of the RET gene in modulating immune cell responses during inflammation and carcinogenesis. PMID- 24777755 TI - The base discriminating potential of pyrrolidinyl PNA demonstrated by magnetic Fe(x)O(y) particles. AB - Pyrrolidinyl PNA was immobilized on Fe(x)O(y) magnetic particles and was able to capture and thereby discriminate single base alterations in DNA counterstrands better than DNA. The selectivities of matched vs. mismatched oligonucleotides measured by the absorption differences were up to 10-12 which are remarkable values for linear probes. PMID- 24777757 TI - Enantioselective total synthesis of (-)-lansai B and (+)-nocardioazines A and B. AB - The concise total syntheses of the bis(pyrroloindolines) (-)-lansai B and (+) nocardioazines A and B are reported. The key pyrroloindoline building blocks are rapidly prepared by enantioselective formal [3+2] cycloaddition reactions. The macrocycle of (+)-nocardioazine A is constructed by an unusual intramolecular diketopiperazine formation. PMID- 24777756 TI - Diagnostic discrepancies in malignant astrocytoma due to limited small pathological tumor sample can be overcome by IDH1 testing. AB - The accurate grading of malignant astrocytomas has significant prognostic and therapeutic implications. Traditional histopathological grading can be challenging due to regional tumor heterogeneity, especially in scenarios where small amounts of tissue are available for pathologic review. Here, we hypothesized that a critical tumor resection volume is needed for correct grading of astrocytomas by histopathology. For insufficient tissue sampling, IDH1 molecular testing can act as a complementary marker to improve diagnostic accuracy. Volumetric analyses were obtained using preoperative and postoperative MRI images. Histological specimens were gathered from 403 patients with malignant astrocytoma who underwent craniotomy. IDH1 status was assessed by immunohistochemistry and sequencing. Patients with >20 cubic centimeters (cc) of the total tumor volume resected on MRI have higher rate of GBM diagnosis compared to <20 cc [odds ratio (OR) 2.57, 95% confidence interval (CI) 1.6-4.06, P < 0.0001]. The rate of IDH1 status remained constant regardless of the tumor volume resected (OR 0.81, 95% CI 0.48-1.36, P < 0.43). The rate of GBM diagnosis is twofold greater for individual surgical specimen >10 cc than those of lower volume (OR 2.48, 95% CI 1.88-3.28, P < 0.0001). Overall survival for AA patients with >20 cc tumor resection on MRI is significantly better than those with <20 cc tumor resected (P < 0.05). No volume-dependent differences were observed in patients with GBM (P < 0.4), IDH1 wild type (P < 0.1) or IDH1 mutation (P < 0.88). IDH1 status should be considered when total resection volume is <20 cc based on MRI analysis and for surgical specimen <10 cc to complement histopathologic diagnosis of malignant astrocytomas. In these specimens, under diagnosis of GBM may occur when analysis is restricted to histopathology alone. PMID- 24777758 TI - Isolation and identification of antioxidative peptides from frog (Hylarana guentheri) protein hydrolysate by consecutive chromatography and electrospray ionization mass spectrometry. AB - Frog (Hylarana guentheri) proteins were hydrolyzed by papain and Flavourzyme to obtain antioxidative peptides. The antioxidant activities of the frog protein hydrolysates (FPHs) were measured, including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity (IC50=9.94+/-0.13 mg/mL), reducing power (0.39+/-0.01 at 5.0 mg/mL), and oxygen radical absorbance capacity (ORAC) value (789.15+/ 75.10 MUmol Trolox equivalents/g). The hydrolysates were purified by ultrafiltration, ion exchange chromatography, gel filtration chromatography, and reverse-phase high-performance liquid chromatography (RP-HPLC). Through analysis of ESI-MS/MS, two dipeptides were identified as Leu/Ile-Lys (259.1607 Da) and Phe Lys (293.1446 Da), respectively. PMID- 24777759 TI - Exogenous spermidine alleviates UV-induced growth inhibition of Synechocystis sp. PCC 6803 via reduction of hydrogen peroxide and malonaldehyde levels. AB - Effects of exogenously added spermidine (Spd) to UV-treated Synechocystis sp. PCC 6803 cultures on their growth, intracellular pigments, hydrogen peroxide (H2O2), malonaldehyde (MDA) contents, and antioxidant enzymes were investigated. Growth inhibition of cells subjected to 1-h UV-A, UV-B, and UV-C irradiation was abolished in culture added with 0.5 mM Spd. Both chlorophyll a and carotenoid contents were decreased under UV radiations in cells grown in BG11 medium. However, the contents of these two pigments were slightly increased under UV radiations in Spd-supplemented cells with the consequence of enhanced oxygen evolution. Intracellular levels of H2O2 and MDA generated during 1-h UV irradiation were decreased when the culture medium contained 0.5 mM Spd. The antioxidative enzymes, catalase, and superoxide dismutase had a little or no response towards Spd supplementation under UV irradiation except for some increase in superoxide dismutase activity under UV-C. Total intracellular polyamines were decreased during Spd supplementation under UV stress; however, the cells showed a drastic increase in the amount of Put under this condition. Altogether, exogenous Spd is likely a potential compound that enables Synechocystis cells to cope with UV stress. PMID- 24777760 TI - An O-acetylserine (thiol) lyase from Leucaena leucocephala is a cysteine synthase but not a mimosine synthase. AB - In plants, the final step of cysteine formation is catalyzed by O-acetylserine (thiol) lyase (OAS-TL). The purpose of this study was to isolate and characterize an OAS-TL from the tree legume Leucaena leucocephala (leucaena). Leucaena contains a toxic, nonprotein amino acid, mimosine, which is also formed by an OAS TL, and characterization of this enzyme is essential for developing a mimosine free leucaena for its use as a protein-rich fodder. The cDNA for a cytosolic leucaena OAS-TL isoform was obtained through interspecies suppression subtractive hybridization. A 40-kDa recombinant protein was purified from Escherichia coli and used in enzyme activity assays where it was found to synthesize only cysteine. The enzyme followed Michaelis-Menten kinetics, and the Km was calculated to be 1,850+/-414 MUM sulfide and the Vmax was 200.6+/-19.92 MUM cysteine min(-1). The N-terminal affinity His-tag was cleaved from the recombinant OAS-TL to eliminate its possible interference in binding with the substrate, 3-hydroxy-4-pyridone, for mimosine formation. The His-tag-cleaved OAS TL was again observed to catalyze the formation of cysteine but not mimosine. Thus, the cytosolic OAS-TL from leucaena used in this study is specific for only cysteine synthesis and is different from previously reported OAS-TLs that also function as beta-substituted alanine synthases. PMID- 24777761 TI - Kinetics of porphyrin fluorescence accumulation in pediatric brain tumor cells incubated in 5-aminolevulinic acid. AB - BACKGROUND: Fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) enables more complete resections of tumors in adults. 5-ALA elicits accumulation of fluorescent porphyrins in various cancerous tissues, which can be visualized using a modified neurosurgical microscope with blue light. Although this technique is well established in adults, it has not been investigated systematically in pediatric brain tumors. Specifically, it is unknown how quickly, how long, and to what extent various pediatric tumors accumulate fluorescence. The purpose of this study was to determine utility and time course of 5-ALA-induced fluorescence in typical pediatric brain tumors in vitro. METHODS: Cell cultures of medulloblastoma [DAOY and UW228], cPNET [PFSK] atypical teratoid rhabdoid tumor [BT16] and ependymoma [RES196] were incubated with 5-ALA for either 60 minutes or continuously. Porphyrin fluorescence intensities were determined using a fluorescence-activated cell sorter (FACS) after 1, 3, 6, 9, 12 and 24 hours. C6 and U87 cells served as controls. RESULTS: All pediatric brain tumor cell lines displayed fluorescence compared to their respective controls without 5-ALA (p < 0.05). Sixty minutes of incubation resulted in peaks between 3 and 6 hours, whereas continuous incubation resulted in peaks at 12 hours or beyond. 60 minute incubation peak levels were between 52 and 91 % of maxima achieved with continuous incubation. Accumulation and clearance varied between cell types. CONCLUSIONS: We demonstrate that 5-ALA exposure of cell lines derived from typical pediatric central nervous system (CNS) tumors induces accumulation of fluorescent porphyrins. Differences in uptake and clearance indicate that different application modes may be necessary for fluorescence-guided resection, depending on tumor type. PMID- 24777762 TI - Outcome of superior mesenteric-portal vein resection during pancreatectomy for borderline ductal adenocarcinoma: results of a prospective comparative study. AB - BACKGROUND: Approximately 20 % of patients affected by pancreatic ductal adenocarcinoma are amenable to surgical resection. Several tumours are reported as "borderline resectable" because of their proximity to the major vessels. In the effort to achieve a radical tumour removal, vein resection has been proposed, but its oncological benefits remain debated. METHODS: Our aim is to investigate morbidity, mortality and survival after pancreatectomy with vein resection. RESULTS: Forty patients underwent pancreatectomy and vein resection (group A), and 20 patients (group B) underwent bilio-enteric and/or gastro-entero bypass. In group A, cancer vein invasion was microscopically proven in 14 cases (35 %). Vein infiltration, tumour differentiation and node-positive disease were not adverse prognostic variables. No difference in survival was seen over a 1-year follow-up. After this period, group A showed significant survival benefits with a longer stabilisation of the disease (p = 0.005). Tumour-free resection margins and adjuvant chemoradiotherapy were the most important prognostic factors (p < 0.05). CONCLUSIONS: Suspicion of vein infiltration should not be a contraindication to resection. Pancreatectomy can be safely performed with an acceptable morbidity and better survival trend. PMID- 24777763 TI - NK cells are primed by ANRS MVA(HIV)-infected DCs, via a mechanism involving NKG2D and membrane-bound IL-15, to control HIV-1 infection in CD4+ T cells. AB - Natural killer (NK) cells are the major antiviral effector cell population of the innate immune system. It has been demonstrated that NK-cell activity can be modulated by the interaction with dendritic cells (DCs). The HIV-1 vaccine candidate Modified Vaccinia Ankara encoding an HIV polypeptide (MVA(HIV)), developed by the French National Agency for Research on AIDS (ANRS), has the ability to prime NK cells to control HIV-1 infection in DCs. However, whether or not MVA(HIV)-primed NK cells are able to better control HIV-1 infection in CD4(+) T cells, and the mechanism underlying the specific priming, remain undetermined. In this study, we show that MVA(HIV)-primed NK cells display a greater capacity to control HIV-1 infection in autologous CD4(+) T cells. We also highlight the importance of NKG2D engagement on NK cells and DC-produced IL-15 to achieve the anti-HIV-1 specific priming, as blockade of either NKG2D or IL-15 during MVA(HIV) priming lead to a subsequent decreased control of HIV-1 infection in autologous CD4(+) T cells. Furthermore, we show that the decreased control of HIV-1 infection in CD4(+) T cells might be due, at least in part, to the decreased expression of membrane-bound IL-15 (mbIL-15) on DCs when NKG2D is blocked during MVA(HIV)-priming of NK cells. PMID- 24777764 TI - An image processing pipeline to detect and segment nuclei in muscle fiber microscopic images. AB - Muscle fiber images play an important role in the medical diagnosis and treatment of many muscular diseases. The number of nuclei in skeletal muscle fiber images is a key bio-marker of the diagnosis of muscular dystrophy. In nuclei segmentation one primary challenge is to correctly separate the clustered nuclei. In this article, we developed an image processing pipeline to automatically detect, segment, and analyze nuclei in microscopic image of muscle fibers. The pipeline consists of image pre-processing, identification of isolated nuclei, identification and segmentation of clustered nuclei, and quantitative analysis. Nuclei are initially extracted from background by using local Otsu's threshold. Based on analysis of morphological features of the isolated nuclei, including their areas, compactness, and major axis lengths, a Bayesian network is trained and applied to identify isolated nuclei from clustered nuclei and artifacts in all the images. Then a two-step refined watershed algorithm is applied to segment clustered nuclei. After segmentation, the nuclei can be quantified for statistical analysis. Comparing the segmented results with those of manual analysis and an existing technique, we find that our proposed image processing pipeline achieves good performance with high accuracy and precision. The presented image processing pipeline can therefore help biologists increase their throughput and objectivity in analyzing large numbers of nuclei in muscle fiber images. PMID- 24777765 TI - [Migraine with prolonged eyelid edema: a series of 10 cases]. AB - INTRODUCTION: Migraine may present with cranial autonomic symptoms typical of trigeminal-autonomic cephalalgias, thus posing diagnostic difficulties. AIM. To report a series of patients with prominent eyelid oedema associated with migraine. PATIENTS AND METHODS: Ten patients attending the headache offices in three hospitals (nine women, one man; age: 26-53 years-old) with recurrent eyelid oedema as a migraine accompaniment. RESULTS: According to the diagnostic criteria of the International Classification of Headache Disorders (ICHD-III, beta version), eight patients had migraine without aura, one had migraine with aura, and one had chronic migraine. Eyelid oedema appeared during the most severe headache attacks, and had longer duration than the pain. Pharmacological or systemic causes of the oedema were ruled out in all cases. Other associated autonomic symptoms were conjunctival injection (n = 3), lacrimation (n = 2) and rhinorrhoea (n = 1). Both the pain and the oedema improved with symptomatic and preventive therapies for migraine. CONCLUSIONS: Eyelid oedema may occasionally be a migraine accompaniment. It appears in some patients during their most severe migraine attacks, and may improve with the acute and preventive treatment for migraine. PMID- 24777766 TI - [Alternate form of the test de aprendizaje verbal Espana-Complutense (TAVEC)]. AB - INTRODUCTION: Parallel forms of neuropsychological tests are scarce. Practice effects associated to repeated testing with the same test confound the interpretation of observed changes in serial assessments. Practice effects are especially likely with memory testing. AIM: To develop an alternate form to the test de aprendizaje verbal Espana-Complutense (TAVEC), one of the most common memory tests used for Spanish speaking population. SUBJECTS AND METHODS: Participants in the normative study were 110 undergraduates. Participants in the study of the alternate vs original forms were 70 neurologically normal volunteers ranged in age from 18 to 89 years. Forms were administered in counterbalanced order, with a test-retest interval of 15-20 days. RESULTS: Multivariate analyses showed that none of the effects for form, order of administration or session achieved significance. Interactions also failed to reach significance. Aforementioned results were observed in the total sample and the different age groups: young adults (18-29 years), middle-age (30-59 years) and older (60-89 years). Correlational analyses supported the validity and internal consistence of the alternate form. CONCLUSIONS: Results indicate the equivalence between the original TAVEC and the form elaborated in this study. This alternate form may be used in serial assessment of learning and memory deterioration. PMID- 24777767 TI - [Brainstem dysgenesis: functional prognosis and rehabilitative treatment. A series of nine cases]. AB - INTRODUCTION: Brainstem dysgenesis is a heterogeneous clinical entity, with low incidence and high clinical variability, which affects structures in the brainstem. Diagnosis is based on the combination of symptoms, neuroimaging and neurophysiological studies. AIM: To determine the common clinical features, functional prognosis and rehabilitative treatment needs in a group of children with brainstem dysgenesis. PATIENTS AND METHODS: Observation-based retrospective study of nine patients diagnosed with brainstem dysgenesis monitored in an outpatients department. RESULTS: The mean age of the patients was 5.5 years. Five presented alterations in the neuroimaging scan and, in the five with a neurophysiological study, the results showed it to be altered. Six presented muscular hypotonia, eight had amimia/hypomimia, six had central hypoacusis and five had gastrostomy. A third of them presented an episode of cardiorespiratory arrest. Delayed psychomotor skills were detected in all cases. Currently five of them are capable of walking autonomously indoors and four of them outdoors. A high percentage of them (77.7%) understand simple orders and are capable of communicating (66.6%). CONCLUSIONS: Alterations affecting the cranial nerves and muscle tone together with dysphagia are the most common manifestations in our population. The risk of bronchial aspiration and cardiorespiratory arrest is a threat to the lives of these patients. All the children present psychomotor retardation and half of them manage to accomplish autonomous walking. Given the diversity of the disability displayed by these patients, we believe a personalised, integral rehabilitative treatment is needed to obtain an optimal level of functioning. Further studies with wider samples are required to be able to obtain homogeneous groups and to establish the functional prognosis and needs in terms of rehabilitative treatment. PMID- 24777768 TI - [Neural correlates of perceptual decisions: the role of the ventral premotor cortex]. AB - Although the premotor cortex was initially viewed as the substrate of pure motor functions, it was soon realized that this cortical region is also involved in higher order cognitive processes. By using behavioral tasks together with electrophysiological recordings it has been possible to advance in our understanding on the functional role of this area. Given its pattern of connections, the premotor ventral cortex is well suited to participate in perceptual decisions, in which sensory information is combined with knowledge on previous outcomes and expectancies to reach a behavioral choice. The neuronal correlates of the decision process have been described in several cortical areas of primates. In this work we describe our experimental results showing that different stages or elements of perceptual decisions are encoded in the firing rate of premotor ventral cortex neurons. This provides compelling evidence suggesting that this area is involved in the use of sensory evidence -maintained in working memory or retrieved from long-term memory- to reach a decision. Furthermore, after the behavioral response the same neurons convey all the information needed to evaluate the outcome of the choice. This suggests that the premotor ventral cortex could participate in shaping future behavior as a result of this evaluation. PMID- 24777769 TI - [Functional connectivity and complex networks in focal epilepsy. Pathophysiology and therapeutic implications]. AB - INTRODUCTION: The traditional surgical approach to treat drug-resistant focal epileptic patients is in the resection or disconnection of the epileptic focus. However, a significant minority of patients continue to experience seizures after surgery, which shows the incomplete level of knowledge that currently we have of this pathology. AIM: This paper introduces some concepts of functional connectivity and complex networks methodology with its application to the study of neurophysiological recordings from patients suffering from drug-resistant focal epilepsy. DEVELOPMENT: In order to fully understand the new developments in the area of complex networks and its applications to the study of epilepsy, we will here review fundamental concepts in complex networks methodology, synchronization and functional connectivity. Some of the most recent published works dealing with focal epilepsy viewed under this new perspective will be revised and commented. CONCLUSIONS: We think that a wider perspective in the study of epilepsy, such as the one reviewed in this work, will allow epileptologists to consider surgical alternatives in the usual treatment of focal epilepsy at those currently performed in most medical centers around the world. Combining the traditional knowledge with new insights provided by network theory will certainly fill many of the gaps we have today in the fragmented understanding of epilepsy. PMID- 24777770 TI - [Chronic calcified subdural haematoma: armoured brain]. PMID- 24777772 TI - [Fluctuating ptosis as the presenting symptom of spontaneous liquoral hypotension syndrome]. PMID- 24777773 TI - [Occipital neuralgia secondary to vasculitis of the occipital artery. Diagnosis using colour duplex]. PMID- 24777774 TI - Expression of octopaminergic receptor genes in 4 nonneural tissues in female Nicrophorus vespilloides beetles. AB - Octopamine regulates the function of many tissues and physiological processes in invertebrates. The expression of octopamine receptor genes has been examined in multiple tissue types in several different insect orders. However, little work has addressed this issue in Coleoptera. Most studies characterize individual genes in different tissue types, but here we describe the expression of 6 octopamine receptor genes in thoracic musculature, oviducts, Malpighian tubules, and fat body of female Nicrophorus vespilloides beetles to characterize both different genes and different tissues within a single study. We then compare the gene expression profiles found in this beetle to other insects to examine the extent to which expression profiles are conserved across insects. We also examine the relative involvement of octopamine verses octopamine/tyramine receptors based on receptor gene expression in each tissue to help elucidate if tyramine plays a role in the regulation of these tissues. We find a high degree of overlap in the expression profile of the 6 genes examined in the thoracic musculature, a moderate amount for the oviducts, and divergent profiles for Malpighian tubules and fat body. Based on expression difference in receptor subtypes, our results also support the suggestion that tyramine is a biogenic amine with physiological actions separate from octopamine. PMID- 24777775 TI - Systematic implicit solvent coarse graining of dimyristoylphosphatidylcholine lipids. AB - We have used systematic structure-based coarse graining to derive effective site site potentials for a 10-site coarse-grained dimyristoylphosphatidylcholine (DMPC) lipid model and investigated their state point dependence. The potentials provide for the coarse-grained model the same site-site radial distribution functions, bond and angle distributions as those computed in atomistic simulations carried out at four different lipid-water molar ratios. It was shown that there is a non-negligible dependence of the effective potentials on the concentration at which they were generated, which is also manifested in the properties of the lipid bilayers simulated using these potentials. Thus, effective potentials computed at low lipid concentration favor to more condensed and ordered structure of the bilayer with lower average area per lipid, while potentials obtained at higher lipid concentrations provide more fluid-like structure. The best agreement with the reference data and experiment was achieved using the set of potentials derived from atomistic simulations at 1:30 lipid:water molar ratio providing fully saturated hydration of DMPC lipids. Despite theoretical limitations of pairwise coarse-grained potentials expressed in their state point dependence, all the resulting potentials provide a stable bilayer structure with correct partitioning of different lipid groups across the bilayer as well as acceptable values of the average lipid area, compressibility and orientational ordering. In addition to bilayer simulations, the model has proven its robustness in modeling of self-aggregation of lipids from randomly dispersed solution to ordered bilayer structures, bicelles, and vesicles. PMID- 24777776 TI - Influence of p-cresol on the proteome of the autotrophic nitrifying bacterium Nitrosomonas eutropha C91. AB - In this study, the effect of the organic micropollutant and known inhibitor of nitrification, p-cresol, was investigated on the metabolism of the ammonia oxidizing bacteria (AOB) Nitrosomonas eutropha C91 using MS-based quantitative proteomics. Several studies have demonstrated that AOB are capable of biotransforming a wide variety of aromatic compounds making them suitable candidates for bioremediation, yet the underlying molecular mechanisms are poorly described. The effect of two different concentrations of the aromatic micropollutant p-cresol (1 and 10 mg L(-1)) on the metabolism of N. eutropha C91, relative to a p-cresol absent control, was investigated. Though the rate of nitrification in N. eutropha C91 appeared essentially unaffected at both concentrations of p-cresol relative to the control, the expressional pattern of the proteins of N. eutropha C91 changed significantly. The presence of p-cresol resulted in the repressed expression of several key proteins related to N metabolism, seemingly impairing energy production in N. eutropha C91, contradicting the observed unaltered rates of nitrification. However, the expression of proteins of the TCA cycle and proteins related to xenobiotic degradation, including a p-cresol dehydrogenase, was found to be stimulated by the presence of p-cresol. This indicates that N. eutropha C91 is capable of degrading p-cresol and that it assimilates degradation intermediates into the TCA cycle. The results reveal a pathway for p-cresol degradation and subsequent entry point in the TCA cycle in N. eutropha C91. The obtained data indicate that mixotrophy, rather than cometabolism, is the major mechanism behind p-cresol degradation in N. eutropha C91. PMID- 24777777 TI - Terminal RFLP analysis to determine the oral microbiota with hyposalivation. AB - Previous studies of oral microbiota by culture-dependent or targeted DNA approaches demonstrated that hyposalivation, a reduction in salivary secretions, might increase the amount of certain oral pathogens. However, the relationship between hyposalivation and the balance of oral microbiota, especially uncultivable bacteria, remains still unclear. The aim of this study was to elucidate the relationship between hyposalivation and oral microbiota by analyzing terminal restriction fragment length polymorphism (T-RFLP) of 16S rDNA. The 61 subjects were divided into two groups, hyposalivation group and normo salivation group. The microbiota of tongue-coating samples was analyzed by T RFLP. The amount of saliva, the number of Candida albicans, and also the dental status including plaque index, gingival index, bleeding on probing, probing pocket depth and decayed, missing, and filled teeth (DMFT) were assessed. Regarding the dental status, none of the evaluated factors were significantly different between the groups except the number of DMFT. According to the T-RFLP profiles, the patterns of microbiota in the tongue coating were classified into two groups, Clusters I and II. Cluster I is made up 76% of subjects with hyposalivation, while Cluster II is made up 61% of subjects with normo-salivation (p<0.001). Compared with the microbiota found in Cluster II, that in Cluster I had higher proportions of T-RFs corresponding to genera Veillonella, Dialister, Prevotella, Fusobacterium, and Streptococcus. T-RFLP analysis showed a significant role of salivary volume in determining the composition of the microbial community, regardless of the cultivability of the bacteria. PMID- 24777778 TI - Associations between functional TNFR2 196 M/R polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. AB - Several studies have examined the effects of tumor necrosis factor receptor (TNFR) 1 +38 A/G and TNFR2 196 M/R polymorphisms on susceptibility to RA and have reported conflicting results. The purpose of this study was to examine whether the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms are associated with RA susceptibility. We performed a literature search using the Medical Literature Analysis and Retrieval System Online and Embase citation indices, and conducted a meta-analysis to examine the association between the TNFR1 +38 A/G and TNFR2 196 M/R polymorphisms and RA. Our meta-analysis included a total of 13 studies from 11 articles, consisting of 11 studies of the TNFR2 polymorphism (2,092 cases and 1,483 controls), and two studies of the TNFR1 polymorphism (672 cases and 288 controls). The meta-analysis revealed a significant association between the TNFR2 196 RR genotype and RA risk (OR 1.737, 95 % CI 1.275-2.367, P = 4.6 * 10(-5)). Stratification by ethnicity indicated an association between the TNFR2 196 RR genotype and RA in Europeans (OR 2.054, 95 % CI 1.305-3.232, P = 0.002), but not in East Asians (OR 1.596, 95 % CI 0.642-3.971, P = 0.314). Analysis using a homozygote contrast model showed the same pattern for the TNFR2 196 RR genotype in a European and East Asian population. However, no association was found between the TNFR1 +36 A/G polymorphism and RA in a European population. Our meta analysis demonstrated that the functional TNFR2 196 M/R polymorphism is associated with susceptibility to RA in the European population. PMID- 24777779 TI - Predictive role of neutrophil to lymphocyte ratio in Henoch-Schonlein purpura related gastrointestinal bleeding. AB - We read with interest the recent article 'The relationship of neutrophil-to lymphocyte ratio with gastrointestinal bleeding in Henoch-Schonlein purpura' by Makay et al. (Rheumatol Int. doi: 10.1007/s00296-014-2986-2 , 2014). In their study, researchers aimed to evaluate the relationship between blood neutrophil to lymphocyte ratio (NLR) and gastrointestinal bleeding in children with Henoch Schonlein purpura (HSP). In discussion part, the authors concluded that blood NLR may be considered as a useful marker for predicting gastrointestinal bleeding in HSP. We would like to thank Makay et al. for their valuable contribution. PMID- 24777780 TI - The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. AB - The molecular genetic basis that leads to Lewy Body (LB) pathology in 15-20% of Alzheimer disease cases (LBV/AD) was largely unknown. Alpha-synuclein (SNCA) and Leucine-rich repeat kinase2 (LRRK2) have been implicated in the pathogenesis of Parkinson's disease (PD), the prototype of LB spectrum disorders. We tested the association of SNCA variants with LB pathology in AD. We then stratified the SNCA association analyses by LRRK2 genotype. We also investigated the expression regulation of SNCA and LRRK2 in relation to LB pathology. We evaluated the differences in SNCA-mRNA and LRRK2-mRNA levels as a function of LB pathology in the temporal cortex (TC) from autopsy-confirmed LBV/AD cases and AD controls. We further investigated the cis-effect of the LB pathology-associated genetic variants within the SNCA and LRRK2 loci on the mRNA expression of these genes. SNCA SNPs rs3857059 and rs2583988 showed significant associations with increased risk for LB pathology. When the analyses were stratified by LRRK2-rs1491923 genotype, the associations became stronger for both SNPs and an association was also observed with rs2619363. Expression analysis demonstrated that SNCA- and LRRK2-mRNA levels were significantly higher in TC from LBV/AD brains compared with AD controls. Furthermore, SNCA-mRNA expression level in the TC was associated with rs3857059; homozygotes for the minor allele showed significant higher expression. LRRK2-transcript levels were increased in carriers of rs1491923 minor allele. Our findings demonstrated that SNCA contributes to LB pathology in AD patients, possibly via interaction with LRRK2, and suggested that expression regulation of these genes may be the molecular basis underlying the observed LB associations. PMID- 24777782 TI - Guidelines for pancreaticobiliary cytology from the Papanicolaou Society of Cytopathology: A review. AB - The newest installment on state-of-the-art standards of practice in cytopathology from the Papanicolaou Society of Cytopathology (PSC) focuses on the pancreaticobiliary system. Similar to the National Cancer Institute recommendations for aspiration cytology of the thyroid, the PSC guidelines for pancreaticobiliary cytology addresses indications, techniques, terminology and nomenclature, ancillary studies, and postprocedure management. Each committee was composed of a multidisciplinary group of experts in diagnosing, managing, and treating patients with pancreaticobiliary disease. Draft documents were posted on an interactive Web-based forum hosted by the PSC Web site (www.papsociety.org) and the topics of terminology, ancillary testing, and management were presented at national and international meetings over an 18-month period for discussion and feedback from practicing pathologists around the world. This review provides a synopsis of these guidelines. PMID- 24777781 TI - Connective tissue alterations in Fkbp10-/- mice. AB - Osteogenesis imperfecta (OI) is an inherited brittle bone disorder characterized by bone fragility and low bone mass. Loss of function mutations in FK506-binding protein 10 (FKBP10), encoding the FKBP65 protein, result in recessive OI and Bruck syndrome, of which the latter is additionally characterized by joint contractures. FKBP65 is thought to act as a collagen chaperone, but it is unknown how loss of FKBP65 affects collagen synthesis and extracellular matrix formation. We evaluated the developmental and postnatal expression of Fkbp10 and analyzed the consequences of its generalized loss of function. Fkbp10 is expressed at low levels in E13.5 mouse embryos, particularly in skeletal tissues, and steadily increases through E17.5 with expression in not only skeletal tissues, but also in visceral tissues. Postnatally, expression is limited to developing bone and ligaments. In contrast to humans, with complete loss of function mutations, Fkbp10(-/-) mice do not survive birth, and embryos present with growth delay and tissue fragility. Type I calvarial collagen isolated from these mice showed reduced stable crosslink formation at telopeptide lysines. Furthermore, Fkbp10(-/ ) mouse embryonic fibroblasts show retention of procollagen in the cell layer and associated dilated endoplasmic reticulum. These data suggest a requirement for FKBP65 function during embryonic connective tissue development in mice, but the restricted expression postnatally in bone, ligaments and tendons correlates with the bone fragility and contracture phenotype in humans. PMID- 24777783 TI - An alpha-glucan isolated from root of Isatis Indigotica, its structure and adjuvant activity. AB - The root of Isatis indigotica is a traditional Chinese herbal medicine. An alpha glucan (IIP-A-1) was firstly isolated from the roots. In this study we elucidated the chemical structure of IIP-A-1 and determined its adjuvant activity by co immunizing mice with H1N1 influenza virus split and recombinant hepatitis B surface antigen (HBsAg), respectively. The polysaccharide was pretreated with periodate oxidation, Smith degradation and methylation in order to analyze its structure using GC, HPGPC, FT-IR, NMR and GC-MS. The adjuvant effect was evaluated by determining the antibody titers of serum against H1N1 influenza and HBsAg using ELISA. The proliferation and TNF-alpha secretion of macrophages administrated with different dose of IIP-A-1 were measured in vitro. The results of this study revealed that IIP-A-1 was an alpha-glucan with the molecular weight of 3,600 Da. The backbone was alpha-(1 -> 4)-D-glucan with (1 -> 6) branch chain. The alpha-glucan could significantly enhance the immune response of mice immunized with H1N1 influenza or HBsAg in vivo and exert good dose-dependent effects on the proliferation and the TNF-alpha secretion of macrophages in vitro. These results supported that IIP-A-1 was expected to be an efficacious adjuvant candidate for prophylactic and therapeutic vaccines. PMID- 24777784 TI - Dismal outcome of T-cell lymphoma patients failing first-line treatment: results of a population-based study from the Modena Cancer Registry. AB - We conducted a population-based study to establish the outcome of T-cell lymphoma (TCL) patients failing systemic first-line therapy. All TCL patients failing first-line systemic therapy in the province of Modena were identified from Modena Cancer Registry between 1997 and 2010. A total of 53 patients were analysed. Regarding the type of failure, 18 patients relapsed, and 35 progressed during first treatment. Among relapsed patients, the median time from date of response to relapse after first treatment was 6.2 months (range 1.87-102). A total of 18 patients (34%) died before receiving salvage treatment, 21 received platinum or gemcitabine-containing regimens (7 addressed to autologous stem cell transplant (ASCT)), 12 other CT regimens; 2 received radiotherapy (RT). The median survival after relapse (SAR) was 2.5 months. After a median follow-up for living patients after failure of 35 months (range 8-111 months), 44 patients died, and the cause of death was found to be lymphoma progression in all (98%) but one of them. The median SAR was 2.5 months. The 3-year SAR was 19%. Univariate and multivariate Cox regression analyses for SAR were performed. In multivariate analysis, performance status and type of failure were associated with a higher risk of death after relapse. The outcome of TCL patients failing first-line therapy is poor. Only a few cases that could receive ASCT had promising chances of long remission. There is urgent need for novel agents for patients requiring second line treatment. PMID- 24777785 TI - Homozygous hemoglobin S with concomitant hemoglobin G-Philadelphia: a diagnostic challenge. PMID- 24777786 TI - Plant isoprenoids: a general overview. PMID- 24777787 TI - Measuring the activity of 1-deoxy-D-xylulose 5-phosphate synthase, the first enzyme in the MEP pathway, in plant extracts. AB - The first enzyme in the methylerythritol phosphate (MEP) pathway is 1-deoxy-D xylulose 5-phosphate (DXP) synthase (DXS). As such this enzyme is considered to be important in the control of plastidial isoprenoid production. Measuring the activity of DXS in plant extracts is therefore crucial to understanding the regulation of the MEP pathway. Due to the relatively low amounts of DXS, the activity of this enzyme can only be measured using highly sensitive analytical equipment. Here, a method is described to determine the DXS enzyme activity in a crude plant extract, by measuring DXP production directly using high performance liquid chromatography linked to a tandem triple quadrupole mass spectrometry detector (LC-MS/MS). PMID- 24777788 TI - Determination of 3-hydroxy-3-methylglutaryl CoA reductase activity in plants. AB - The enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase catalyzes the NADPH mediated reductive deacylation of HMG-CoA to mevalonic acid, which is the first committed step of the mevalonate pathway for isoprenoid biosynthesis. In agreement with its key regulatory role in the pathway, plant HMG-CoA reductase is modulated by many diverse external stimuli and endogenous factors and can be detected to variable levels in every plant tissue. A fine determination of HMG CoA reductase activity levels is required to understand its contribution to plant development and adaptation to changing environmental conditions. Here, we report a procedure to reliably determine HMG-CoA reductase activity in plants. The method includes the sample collection and homogenization strategies as well as the specific activity determination based on a classical radiochemical assay. PMID- 24777789 TI - Farnesyl diphosphate synthase assay. AB - Farnesyl diphosphate synthase (FPS) catalyzes the sequential head-to-tail condensation of isopentenyl diphosphate (IPP, C5) with dimethylallyl diphosphate (DMAPP, C5) and geranyl diphosphate (GPP, C10) to produce farnesyl diphosphate (FPP, C15). This short-chain prenyl diphosphate constitutes a key branch-point of the isoprenoid biosynthetic pathway from which a variety of bioactive isoprenoids that are vital for normal plant growth and survival are produced. Here we describe a protocol to obtain highly purified preparations of recombinant FPS and a radiochemical assay method for measuring FPS activity in purified enzyme preparations and plant tissue extracts. PMID- 24777790 TI - Metabolite profiling of plastidial deoxyxylulose-5-phosphate pathway intermediates by liquid chromatography and mass spectrometry. AB - Metabolite profiling is a powerful tool that enhances our understanding of complex regulatory processes and extends to the comparative analysis of plant gene function. However, at present, there are relatively few examples of metabolite profiling being used to characterize the regulatory aspects of the plastidial deoxyxylulose-5-phosphate (DXP) pathway in plants. Since the DXP pathway is one of two pathways in plants that are essential for isoprenoid biosynthesis, it is imperative that robust analytical methods be employed for the characterization of this metabolic pathway. Recently, liquid chromatography-mass spectrometry (LC-MS), in conjunction with traditional molecular biology approaches, established that the DXP pathway metabolite, methylerythritol cyclodiphosphate (MEcPP), previously known solely as an intermediate in the isoprenoid biosynthetic pathway, is a stress sensor that communicates environmental perturbations sensed by plastids to the nucleus, a process referred to as retrograde signaling. In this chapter, we describe two LC-MS methods from this study that can be broadly used to characterize DXP pathway intermediates. PMID- 24777791 TI - Analysis of carotenoids and tocopherols in plant matrices and assessment of their in vitro antioxidant capacity. AB - Carotenoids and tocopherols are lipid secondary metabolites that play essential roles in plants. They are also relevant compounds from a nutritional standpoint and attract much attention due to their proposed antioxidant properties. In this chapter, methodologies for the extraction and HPLC analysis of these compounds are described as well as a widely used protocol to assess their antioxidant capacity. PMID- 24777792 TI - Simultaneous analyses of oxidized and reduced forms of photosynthetic quinones by high-performance liquid chromatography. AB - Plastoquinones and phylloquinones are the major plant quinones localized in chloroplasts, and they act as photosynthetic electron redox mediators in thylakoid membranes. These quinones are analyzed by two processes: extraction with organic solvents and quinone assay by high-performance liquid chromatography (HPLC) analysis. Solvent choice is very important from the viewpoint of stability of the redox state in the extraction processes and during storage of plant quinones. We introduce procedures and solvents to avoid changes in the redox state of quinones, in addition to achieving high extraction efficiency. Traditional methods have problems of low sensitivity and require preparation steps to remove interfering substances, such as plant pigments. HPLC systems have been developed utilizing the fluorescent properties of quinols (reduced forms) to measure quinones. Plastoquinones were detected by reversed-phase HPLC with dual detectors (ultra-violet and fluorescence detection). However, the peak of phylloquinone and plastoquinone isomers with shorter side chains often overlaps with a large peak of fast-eluting pigments. To address these issues, HPLC with fluorescence detection after post-column reduction to convert quinones to fluorescent quinol was applied for measurement of fast-eluting quinones (low hydrophobicity quinones and quinols) such as phylloquinone. Using post-column reduction methods with sodium borohydride or platinum black, not only the reduced forms (fluorescent) but also the oxidized forms (non-fluorescent) could be clearly measured by HPLC with a fluorescence detector. PMID- 24777793 TI - Determination of sterol lipids in plant tissues by gas chromatography and Q-TOF mass spectrometry. AB - Sterols are an abundant lipid class in the extraplastidic membranes of plant cells. In addition to free sterols, plants contain different conjugated sterols, i.e. sterol esters, sterol glucosides, and acylated sterol glucosides. Sterol lipids can be measured by gas chromatography after separation via thin-layer chromatography. Here, we describe a comprehensive technique based on the quantification of all four sterol classes by direct infusion quadrupole time-of flight (Q-TOF) mass spectrometry. PMID- 24777794 TI - Analysis of plant polyisoprenoids. AB - Polyisoprenoid alcohols are representatives of high-molecular terpenoids. Their hydrocarbon chains are built of 5 to more than 100 isoprene units giving rise to polymer molecules that differ in chain-length and/or geometrical configuration. Plants have been shown to accumulate diverse polyisoprenoid mixtures with tissue specific composition. In this chapter, methods of analysis of polyisoprenoid alcohols in plant material are described, including isolation and purification of polyisoprenoids from plant tissue, fast semiquantitative analysis of the polyisoprenoid profile by thin-layer chromatography (straight phase adsorption and reversed phase partition techniques), and quantification of polyisoprenoids with the aid of high performance liquid chromatography. This approach results in full characterization of complex polyisoprenoid mixtures accumulated in various plant tissues and other matrixes. PMID- 24777795 TI - Analysis of diterpenes and triterpenes from plant foliage and roots. AB - Terpene specialized metabolites exhibit multiple functions in plant-environment interactions and plant development. Molecular biologists investigating the biochemistry and molecular function of terpenes need to apply robust but yet sensitive analytical methods optimized and adapted to the structural diversity and often varying concentrations of terpene compounds in plant tissues. Here we present hands-on protocols for sample preparation and GC-MS or LC-MS/MS analysis of selected diterpene and triterpene hydrocarbons or oxygenated derivatives from roots and shoots of Arabidopsis and rice. PMID- 24777796 TI - Gas chromatography-mass spectrometry method for determination of biogenic volatile organic compounds emitted by plants. AB - Gas chromatography-mass spectrometry (GC-MS) is one of the most widely used methods for analyzing the emissions of biogenic volatile organic compounds (VOCs) from plants. Preconcentration of VOCs on the cartridges filled with different adsorbents is a well-accepted method for sampling of headspace. Here, we describe a gas-chromatographic method for determination of different isoprenoids (isoprene, monoterpenes, homoterpenes, and sesquiterpenes). The technique is based on adsorption of compounds of interest on multibed adsorbent cartridges followed by thermodesorption, and detection and analysis by GC-MS. PMID- 24777797 TI - Analysis of steroidal alkaloids and saponins in Solanaceae plant extracts using UPLC-qTOF mass spectrometry. AB - Plants of the Solanaceae family are renowned for the production of cholesterol derived steroidal glycosides, including the nitrogen containing glycoalkaloids and steroidal saponins. In this chapter we describe the use of UPLC (Ultra Performance Liquid Chromatography) coupled with qTOF (Quadrupole Time-of-Flight) mass spectrometry for profiling of these two large classes of semipolar metabolites. The presented method includes an optimized sample preparation protocol, a procedure for high resolution chromatographic separation and metabolite detection using the TOF mass spectrometer which provides high resolution and mass accuracy. A detailed description for non-targeted data analysis and a strategy for putative identification of steroidal glycosides from complex extracts based on interpretation of mass fragmentation patterns is also provided. The described methodology allows profiling and putative identification of multiple steroidal glycoside compounds from the assortment of Solanaceae species producing these molecules. PMID- 24777798 TI - Isoprenoid and metabolite profiling of plant trichomes. AB - Plant glandular trichomes are specialized secretory structures located on the surface of the aerial parts of plants with large biosynthetic capacity, often with terpenoids as output molecules. The collection of plant trichomes requires a method to separate trichomes from leaf epidermal tissues. For metabolite profiling, trichome tissue needs to be rapidly quenched in order to maintain the indigenous state of intracellular intermediates. Appropriate extraction and chromatographic separation methods must be available, which address the wide ranging polarity of metabolites. In this chapter, a protocol for trichome harvest using a frozen paint brush is presented. A work flow for broad-range metabolite profiling using LC-MS(2) analysis is described, which is applicable to assess very hydrophilic isoprenoid precursors as well as more hydrophobic metabolites from trichomes and other plant tissues. PMID- 24777799 TI - Sample preparation for single cell transcriptomics: essential oil glands in Citrus fruit peel as an example. AB - Many plant natural products are synthesized in specialized cells and tissues. To learn more about metabolism in these cells, they have to be studied in isolation. Here, we describe a protocol for the isolation of epithelial cells that surround secretory cavities in Citrus fruit peel. Cells isolated using laser microdissection are suitable for RNA isolation and downstream transcriptome analyses. PMID- 24777800 TI - Prenylquinone profiling in whole leaves and chloroplast subfractions. AB - Prenylquinones are indispensable molecules in plants and animals. In plants, phylloquinone (vitamin K) and plastoquinone are electron carriers during photosynthesis in chloroplasts, whereas tocopherol (vitamin E) functions as a lipid antioxidant. The biosynthetic pathways of the prenylquinones have been largely characterized but the mechanisms regulating their production and distribution in various subcompartments of the chloroplast are only starting to emerge. Research on chloroplast lipid droplets (plastoglobules) has unraveled a complex network of intersecting prenylquinone metabolic pathways that are providing unprecedented insight into the regulatory processes. In this chapter, we describe how to isolate chloroplast membrane fractions, in particular the plastoglobule lipid droplets, and how to profile the prenylquinones that are contained in these fractions. PMID- 24777801 TI - Confocal laser scanning microscopy detection of chlorophylls and carotenoids in chloroplasts and chromoplasts of tomato fruit. AB - Plant cells are unique among eukaryotic cells because of the presence of plastids, including chloroplasts and chromoplasts. Chloroplasts are found in green tissues and harbor the photosynthetic machinery (including chlorophyll molecules), while chromoplasts are present in non-photosynthetic tissues and accumulate large amounts of carotenoids. During tomato fruit development, chloroplasts are converted into chromoplasts that accumulate high levels of lycopene, a linear carotenoid responsible for the characteristic red color of ripe fruit. Here, we describe a simple and fast method to detect both types of fully differentiated plastids (chloroplasts and chromoplasts), as well as intermediate stages, in fresh tomato fruits. The method is based on the differential autofluorescence of chlorophylls and carotenoids (lycopene) detected by Confocal Laser Scanning Microscopy. PMID- 24777802 TI - Heterologous expression of triterpene biosynthetic genes in yeast and subsequent metabolite identification through GC-MS. AB - Heterologous expression of plant metabolic enzymes in microorganisms is extensively used for identifying genes involved in their pathways and producing useful compounds. Here, we describe a plasmid-based yeast expression system that easily allows the expression of different triterpene biosynthetic genes in wild type yeast, providing a useful platform for identifying their functions and facilitating combinatorial biosynthesis of triterpenoids. PMID- 24777803 TI - High-throughput testing of terpenoid biosynthesis candidate genes using transient expression in Nicotiana benthamiana. AB - To respond to the rapidly growing number of genes putatively involved in terpenoid metabolism, a robust high-throughput platform for functional testing is needed. An in planta expression system offers several advantages such as the capacity to produce correctly folded and active enzymes localized to the native compartments, unlike microbial or prokaryotic expression systems. Two inherent drawbacks of plant-based expression systems, time-consuming generation of transgenic plant lines and challenging gene-stacking, can be circumvented by transient expression in Nicotiana benthamiana. In this chapter we describe an expression platform for rapid testing of candidate terpenoid biosynthetic genes based on Agrobacterium mediated gene expression in N. benthamiana leaves. Simultaneous expression of multiple genes is facilitated by co-infiltration of leaves with several engineered Agrobacterium strains, possibly making this the fastest and most convenient system for the assembly of plant terpenoid biosynthetic routes. Tools for cloning of expression plasmids, N. benthamiana culturing, Agrobacterium preparation, leaf infiltration, metabolite extraction, and automated GC-MS data mining are provided. With all steps optimized for high throughput, this in planta expression platform is particularly suited for testing large panels of candidate genes in all possible permutations. PMID- 24777804 TI - Heterologous stable expression of terpenoid biosynthetic genes using the moss Physcomitrella patens. AB - Heterologous and stable expression of genes encoding terpenoid biosynthetic enzymes in planta is an important tool for functional characterization and is an attractive alternative to expression in microbial hosts for biotechnological production. Despite improvements to the procedure, such as streamlining of large scale Agrobacterium infiltration and upregulation of the upstream pathways, transient in planta heterologous expression quickly reaches limitations when used for production of terpenoids. Stable integration of transgenes into the nuclear genome of the moss Physcomitrella patens has already been widely recognized as a viable alternative for industrial-scale production of biopharmaceuticals. For expression of terpenoid biosynthetic genes, and reconstruction of heterologous pathways, Physcomitrella has unique attributes that makes it a very promising biotechnological host. These features include a high native tolerance to terpenoids, a simple endogenous terpenoid profile, convenient genome editing using homologous recombination, and cultivation techniques that allow up-scaling from single cells in microtiter plates to industrial photo-bioreactors. Beyond its use for functional characterization of terpenoid biosynthetic genes, engineered Physcomitrella can be a green biotechnological platform for production of terpenoids. Here, we describe two complementary and simple procedures for stable nuclear transformation of Physcomitrella with terpenoid biosynthetic genes, selection and cultivation of transgenic lines, and metabolite analysis of terpenoids produced in transgenic moss lines. We also provide tools for metabolic engineering through genome editing using homologous recombination. PMID- 24777805 TI - Quantification of plant resistance to isoprenoid biosynthesis inhibitors. AB - Plants use two pathways for the production of the same universal isoprenoid precursors: the mevalonic acid (MVA) pathway and the methylerythritol 4-phosphate (MEP) pathway. Inhibitors of the MVA pathway prevent the activity of the shoot apical meristem and the development of true leaves in seedlings, whereas those inhibiting the MEP pathway show an additional bleaching phenotype. Here, we describe two methods to quantify plant resistance to inhibitors of the MVA pathway or the MEP pathway based on seedling establishment and photosynthetic pigment measurements. Although the methods are presented for Arabidopsis, they are valid for other plant species. These methods can be used as inexpensive and high-throughput alternatives to in vitro assays to estimate the activity of the corresponding target enzymes and to screen for mutants with altered levels or activities of these enzymes. PMID- 24777806 TI - A flexible protocol for targeted gene co-expression network analysis. AB - The inference of gene co-expression networks is a valuable resource for novel hypotheses in experimental research. Routine high-throughput microarray transcript profiling experiments and the rapid development of next-generation sequencing (NGS) technologies generate a large amount of publicly available data, enabling in silico reconstruction of regulatory networks. Analysis of the transcriptome under various experimental conditions proved that genes with an overall similar expression pattern often have similar functions. Consistently, genes involved in the same metabolic pathway are found in co-expressed modules. In this chapter, we describe a detailed workflow for analyzing gene co-expression networks using large-scale gene expression data and explain critical steps from design and data analysis to prediction of functionally related modules. This protocol is platform independent and can be used for data generated by ATH1 arrays, tiling arrays, or RNA sequencing for any organism. The most important feature of this workflow is that it can infer statistically significant gene co expression networks for any number of genes and transcriptome data sets and it does not involve any particular hardware requirements. PMID- 24777807 TI - Curcumin prevents cerebral ischemia reperfusion injury via increase of mitochondrial biogenesis. AB - Curcumin is known to have neuroprotective properties in cerebral ischemia reperfusion (I/R) injury. However, the underlying molecular mechanisms remain largely unknown. Recently, emerging evidences suggested that increased mitochondrial biogenesis enabled preventing I/R injury. Here, we sought to determinate whether curcumin alleviates I/R damage through regulation of mitochondrial biogenesis. Sprague-Dawley rats were subjected to a 2-h period of right middle cerebral artery occlusion followed by 24 h of reperfusion. Prior to onset of occlusion, rats had been pretreated with either low (50 mg/kg, intraperitoneal injection) or high (100 mg/kg, intraperitoneal injection) dose of curcumin for 5 days. Consequently, we found that curcumin pretreatment enabled improving neurological deficit, diminishing infarct volume and increasing the number of NeuN-labeled neurons in the I/R rats. Accordingly, the index of mitochondrial biogenesis including nuclear respiratory factor-1, mitochondrial transcription factor A and mitochondrial number significantly down-regulated in I/R rats were reversed by curcumin pretreatment in a dose-dependent manner, and the mitochondrial uncoupling protein 2 presented the similar change. Taken together, our findings provided novel evidence that curcumin may exert neuroprotective effects by increasing mitochondrial biogenesis. PMID- 24777808 TI - Effects of icotinib on advanced non-small cell lung cancer with different EGFR phenotypes. AB - Icotinib is the first oral epidermal growth factor receptor (EGFR) tyrosine kinase receptor inhibitor, which has been proven to exert significant inhibitory effects on non-small cell lung cancer in vitro. Clinical evidence has showed that the efficacy of Icotinib on retreating advanced non-small cell lung cancer is comparable to Gefitinib. However, different phenotypes of EGFR can affect the therapeutic outcomes of EGFR tyrosine kinase receptor inhibitor. Therefore, our study focused on efficacy and safety of Icotinib in patients with advanced non small cell lung cancer of different EGPR phenotypes. Clinical data of patients with advanced non-small cell lung cancer who received Icotinib treatment from August, 2011 to May, 2013 were retrospectively analyzed. Kaplan-Meier analysis was used for survival analysis and comparison. 18 wild-type EGFR and 51 mutant type were found in a total of 69 patients. Objective response rate of patients with mutant type EGFR was 54.9 % and disease control rate was 86.3 %. Objective response rate of wild-type patients was 11.1 % (P = 0.0013 vs mutant type), disease control rate was 50.0 % (P = 0.0017). Median progression-free survival (PFS) of mutant type and wild-type patients were 9.7 and 2.6 months, respectively (P < 0.001). Median PFS of exon 19 mutated mutant patients was 11.3 months, mean PFS of exon 21 L858R mutated mutant patients was 8.7 months (P = 0.3145). Median overall survival (OS) of EGFR mutated patients had not reached. OS time of 13 wild-type patients was 12.9 months (P < 0.001). The common adverse reactions of Icotinib included rash, diarrhea, itching skin with occurrence rates of 24.6 % (17/69), 13.0 % (9/69), and 11.6 % (8/69), respectively. Most adverse reactions were grade I-II. Icotinib has great efficacy in EGFR mutated patients, making it an optimal regimen to treat EGFR mutated patients. Furthermore, most of adverse reactions associated with Icotinib treatment were tolerable. PMID- 24777809 TI - SNPs in microRNA-binding sites in the ITGB1 and ITGB3 3'-UTR increase colorectal cancer risk. AB - The purpose of the study was to investigate the potential associations between single-nucleotide polymorphisms (SNPs) in microRNA (miRNA)-binding sites in the integrin beta-1 (ITGB1) gene and integrin beta-3 (ITGB3) gene 3'-untranslated regions, and colorectal cancer (CRC) susceptibility in a Chinese population. A hospital-based case-control study was performed in 200 patients with CRC and 200 matched healthy donors. Two SNPs in miRNA binding of ITGB1 and ITGB3 genes (rs17468 and rs2317676) were genotyped by polymerase chain reaction-restrict fragment length polymorphism assay. The association between genotypes and CRC risk was evaluated by computing the odds ratio (OR) and 95 % confidence interval (CI) from multivariate unconditional logistic regression analyses. The frequency of the T genotype in ITGB1 rs17468 and G genotype in ITGB3 rs2317676 occurred more frequently in CRC patients than in controls (P < 0.05). We found that CT and TT genotypes of rs17468 were associated with a significantly increased risk of CRC (OR = 1.67, 95 % CI = 1.090-2.559 for CT + TT vs. CC), also the AG and GG genotype in ITGB3 rs2317676 (OR = 1.65, 95 % CI = 1.114-2.458 for AG + GG vs. AA). In conclusion, our results showed that both the ITGB1 rs17468 SNP and ITGB3 rs2317676 SNP were associated with an increased risk of CRC, which suggests that these 2 SNPs might contribute to CRC risk in a Chinese population. PMID- 24777810 TI - Correlations between CT perfusion parameters and vascular endothelial growth factor expression and microvessel density in implanted VX2 lung tumors. AB - To evaluate the correlation between CT perfusion parameters and tumor angiogenesis, expression of VEGF is implanted in VX2 lung tumor. VX2 tumor cells were injected in 15 healthy New Zealand rabbits. After 20 days, tumors with diameter over 7 mm were scanned with 16 row spiral CT. Using Software Perfusion 3, blood flow (BF), blood volume (BV), permeability surface area product (PS), and the maximum attenuation value (MAV) were obtained. After CT examination, rabbit was sacrificed, and slices from tumor tissue were prepared and checked with immunohistochemical staining with anti-CD34 and anti-VEGF monoclonal antibodies. Correlation of CT perfusion parameters with MVD and VEGF expression was determined by using Pearson correlation analysis. Blood supply of tumor and regions around tumor was higher than that of normal lung tissue. PS value increased sharply in tumor tissue. PS value in regions around tumor was also higher than that of normal lung tissue but lower than that of tumor tissue. Significant positive correlation was observed between CT perfusion parameters (BF, BV, PS, and MAV) and expression of VEGF and MVD in tumor tissue. CT perfusion parameters provide reliable information of the microcirculation in tumor tissue; therefore, it can be used as indexes to characterize angiogenesis of tumor. PMID- 24777811 TI - Effects of ezetimibe on endothelial progenitor cells and microparticles in high risk patients. AB - Imbalance on endothelial turnover can predict cardiovascular outcomes. We aimed at evaluating the effects of lipid-modifying therapies on circulating endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and platelet microparticles (PMPs) in high cardiovascular risk subjects with elevated C reactive protein (CRP). Sixty-three individuals with coronary heart disease (CHD) or CHD risk equivalent on stable statin therapy, with LDL-cholesterol <100 mg/dL and CRP >= 2.0 mg/L were selected. After a 4-week run-in period with atorvastatin 10 mg, those with persistent CRP >= 2.0 mg/L were randomized to another 4-week treatment period with atorvastatin 40 mg, ezetimibe 10 mg or atorvastatin 40 mg/ezetimibe 10 mg. EPC (CD34(+)/CD133(+)/KDR(+)), EMP (CD51(+)), and PMP (CD42(+)/CD31(+)) were quantified by flow cytometry. Atorvastatin 40 mg and atorvastatin 40 mg/ezetimibe 10 mg reduced LDL-cholesterol (P < 0.001, paired T test, vs. baseline). Combined therapy, but not ezetimibe reduced CRP. CD34(+)/KDR(+) EPC were reduced after ezetimibe alone (P = 0.011 vs. baseline, Wilcoxon test) or combined with atorvastatin (P = 0.016 vs. baseline, Wilcoxon test). In addition, ezetimibe increased CD51(+) EMP (P = 0.017 vs. baseline, Wilcoxon test). No correlations between these markers and LDL-cholesterol or CRP were observed. These results contribute to understand the link between inflammation and vascular homeostasis and highlight the broader benefit of statins decreasing inflammation and preventing microparticles release, an effect not observed with ezetimibe alone. PMID- 24777812 TI - Computational identification of pathogenic associated nsSNPs and its structural impact in UROD gene: a molecular dynamics approach. AB - Uroporphyrinogen decarboxylase is a cytosolic enzyme involved in the biosynthetic pathway of heme production. Decreased activity of this enzyme results in porphyria cutanea tarda and hepato erythropoietic porphyria. Nonsynonymous single nucleotide polymorphisms (nsSNPs) alter protein sequence and can cause disease. Identifying the deleterious nsSNPs that contribute to disease is an important task. We used five different in silico tools namely SIFT, PANTHER, PolyPhen2, SNPs&GO, and I-mutant3 to identify deleterious nsSNPs in UROD gene. Further, we used molecular dynamic (MD) approach to evaluate the impact of deleterious mutations on UROD protein structure. By comparing the results of all the five prediction results, we screened 35 (51.47 %) nsSNPs as highly deleterious. MD analysis results show that all the three L161Q, L282R, and I334T deleterious variants were affecting the UROD protein structural stability and flexibility. Our findings provide strong evidence on the effect of deleterious nsSNPs in UROD gene. A detailed MD study provides a new insight in the conformational changes occurred in the mutant structures of UROD protein. PMID- 24777813 TI - Prognostic implications of SLIT and ROBO1 expression in gallbladder cancer. AB - SLIT, a secretory glycoprotein, and its receptor roundabout (ROBO) are expressed in several types of cancer and have been implicated in tumor angiogenesis. The purpose of this study was to determine the prognostic implications of SLIT and ROBO1 expression and their association with clinicopathologic characteristics in gallbladder cancer. A retrospective analysis of 109 consecutive patients who underwent primary gallbladder cancer resection was conducted. Univariate and multivariate models were used to analyze the effect of clinicopathologic factors on survival. Expression of SLIT and ROBO1 was evaluated by immunohistochemistry, and their association with clinicopathologic characteristics was analyzed using mean testing. Multivariate linear regression analysis was also applied to investigate the independent predictors of ROBO1 expression. Seventy-five patients were included in the post-resection survival analysis, with 1-year and 3-year overall survival rates of 60 and 40 %, respectively. Univariate analysis revealed that pN classification, pT classification, pM classification, liver involvement, perineural invasion, TNM staging, Nevin staging, and microscopic resection margins affect prognosis. Multivariate analysis confirmed that pN classification, liver involvement, and perineural invasion are independent prognostic factors. In the mean tests of 109 cases, the mean difference of SLIT immunoreactivity was significant according to the presence of gallstones (P = 0.003) and liver involvement (P = 0.005), while the mean difference of ROBO1 immunoreactivity was significant according to liver involvement (P < 0.001), TNM staging (P < 0.001), and Nevin staging (P < 0.001). Multivariate analysis of ROBO1 immunoreactivity showed that SLIT immunoreactivity and TNM stage (adjusted R (2) = 0.203) or SLIT immunoreactivity and Nevin stage (adjusted R (2) = 0.195) were independent predictors of ROBO1 expression. pN classification, liver involvement, perineural invasion, and pathologic stage are significant prognostic factors for gallbladder cancer survival. SLIT expression is associated with cholelithiasis and liver involvement, and ROBO1 expression is associated with liver involvement and pathologic stage. In addition, SLIT expression and pathologic stage predict ROBO1 expression independently. PMID- 24777814 TI - Expression of the HPV18E2 gene in cervical cancer and premalignant lesions and its clinical significance. AB - This study aims to observe the expression of the HPV18E2 gene in cervical cancer and premalignant lesions and to investigate its clinical significance. The expression of the HPV18E2 gene in the cervical tissues obtained from 38 women with cervical lesions was detected using the RT-PCR method. The pathological changes were graded based on cervical intraepithelial neoplasia (CIN) criteria. The HPV18E2 gene was expressed mainly in cervical premalignant lesions, 60 % in Grade I CIN, 33.3 % in Grade II CIN, and 28.6 % in Grade III CIN. No expression was detected in cervical cancer and chronic cervical inflammation. This study suggests that peptides vaccine targeting the HPV18E2 protein may disrupt and prohibit the progress of diseases induced by HPV 18 infection (i.e., CIN and cervical cancer). PMID- 24777815 TI - Regulation of Gbetagammai-dependent PLC-beta3 activity in smooth muscle: inhibitory phosphorylation of PLC-beta3 by PKA and PKG and stimulatory phosphorylation of Galphai-GTPase-activating protein RGS2 by PKG. AB - In gastrointestinal smooth muscle, agonists that bind to Gi-coupled receptors activate preferentially PLC-beta3 via Gbetagamma to stimulate phosphoinositide (PI) hydrolysis and generate inositol 1,4,5-trisphosphate (IP3) leading to IP3 dependent Ca(2+) release and muscle contraction. In the present study, we identified the mechanism of inhibition of PLC-beta3-dependent PI hydrolysis by cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG). Cyclopentyl adenosine (CPA), an adenosine A1 receptor agonist, caused an increase in PI hydrolysis in a concentration-dependent fashion; stimulation was blocked by expression of the carboxyl-terminal sequence of GRK2(495-689), a Gbetagamma scavenging peptide, or Galphai minigene but not Galphaq minigene. Isoproterenol and S-nitrosoglutathione (GSNO) induced phosphorylation of PLC-beta3 and inhibited CPA-induced PI hydrolysis, Ca(2+) release, and muscle contraction. The effect of isoproterenol on all three responses was inhibited by PKA inhibitor, myristoylated PKI, or AKAP inhibitor, Ht-31, whereas the effect of GSNO was selectively inhibited by PKG inhibitor, Rp-cGMPS. GSNO, but not isoproterenol, also phosphorylated Galphai-GTPase-activating protein, RGS2, and enhanced association of Galphai3-GTP and RGS2. The effect of GSNO on PI hydrolysis was partly reversed in cells (i) expressing constitutively active GTPase-resistant Galphai mutant (Q204L), (ii) phosphorylation-site-deficient RGS2 mutant (S46A/S64A), or (iii) siRNA for RGS2. We conclude that PKA and PKG inhibit Gbetagammai-dependent PLC-beta3 activity by direct phosphorylation of PLC-beta3. PKG, but not PKA, also inhibits PI hydrolysis indirectly by a mechanism involving phosphorylation of RGS2 and its association with Galphai-GTP. This allows RGS2 to accelerate Galphai-GTPase activity, enhance Galphabetagammai trimer formation, and inhibit Gbetagammai-dependent PLC-beta3 activity. PMID- 24777816 TI - [A case report of the difficulty treating an endstage oncologic ENT patient with parenteral nutrition]. AB - The occurrence of cachexia at the end of life of patients suffering from cancer is a common seen problem. Within the last years new definitions, diagnostic criteria and classification systems of cachexia have been developed to improve the clinical practice. Still therapeutic interventions are limited; the role of parenteral nutrition (PN) remains controversial. PN cannot be generally recommended in patients with incurable malignancies, not even in ill-nourished patients with inadequate oral or enteral nutrition due to a changed metabolism. Treating a cachectic endstage patient suffering from head-neck-cancer we were faced with different problems. PMID- 24777817 TI - Sub-toxic nicotine concentrations affect extracellular matrix and growth factor signaling gene expressions in human osteoblasts. AB - Exposure to nicotine and other compounds contained in cigarette smoking affects human health. This study examined the effects of exposure to a single or multiple sub-toxic nicotine concentrations on human osteoblasts. Cell growth and expression of genes involved in bone differentiation, extracellular matrix (ECM) metabolism, and growth factor signaling pathways were investigated in nicotine treated cells compared to untreated cells. Depending on osteoblast concentration and maturation stages, nicotine differently regulated cell growth. Real-time PCR showed regulated expressions of genes expressed by nicotine-treated osteoblasts compared to untreated cells. Among ECM genes, type I collagen was down-regulated and osteonectin was up-regulated in nicotine-treated osteoblasts; similarly, fibroblast growth factor-1 (FGF1) and fibroblast growth factor-2 (FGF2), two members of FGF signaling system, were discordantly modulated; genes involved in osteoblast maturation and differentiation such as alkaline phosphatase (ALP), runt-related transcription factor-2 (RUNX2), and bone sialoprotein (BSP) were over-expressed after drug treatment. Our results show a positive association between nicotine exposure and osteoblast phenotype and illustrate for the first time a mechanism whereby acute or chronic exposure to sub-toxic nicotine concentrations may affect bone formation through the impairment of growth factor signaling system and ECM metabolism. PMID- 24777818 TI - Enzyme-mediated site-specific bioconjugation of metal complexes to proteins: sortase-mediated coupling of copper-64 to a single-chain antibody. AB - The enzyme-mediated site-specific bioconjugation of a radioactive metal complex to a single-chain antibody using the transpeptidase sortase A is reported. Cage amine sarcophagine ligands that were designed to function as substrates for the sortase A mediated bioconjugation to antibodies were synthesized and enzymatically conjugated to a single-chain variable fragment. The antibody fragment scFv(anti-LIBS) targets ligand-induced binding sites (LIBS) on the glycoprotein receptor GPIIb/IIIa, which is present on activated platelets. The immunoconjugates were radiolabeled with the positron-emitting isotope (64)Cu. The new radiolabeled conjugates were shown to bind selectively to activated platelets. The diagnostic potential of the most promising conjugate was demonstrated in an in vivo model of carotid artery thrombosis using positron emission tomography. This approach gives homogeneous products through site specific enzyme-mediated conjugation and should be broadly applicable to other metal complexes and proteins. PMID- 24777819 TI - Assessment of gastroenteric viruses from wastewater directly discharged into Uruguay River, Uruguay. AB - The aim of this study was to assess the viral contamination of group A rotavirus (RVA), norovirus (NoV), and human astrovirus (HAstV) in sewage directly discharged into Uruguay River and to characterize RVA genotypes circulating in Uruguay. For this purpose, sewage samples (n = 96) were collected biweekly from March 2011 to February 2012 in four Uruguayan cities: Bella Union, Salto, Paysandu, and Fray Bentos. Each sample was concentrated by ultracentrifugation method. Qualitative and quantitative RT-PCR for RVA, NoV, and HAstV were performed. A wide dissemination of gastroenteric viruses was observed in the sewage samples analyzed with 80% of positivity, being NoV (51%) the most frequently detected followed by RVA with a frequency of 49% and HAstV with 45%. Genotypes of RVA were typed using multiplex semi-nested RT-PCR as follows: P[8] (n = 15), P[4] (n = 8), P[10] (n = 1), P[11] (n = 1), G2 (n = 29), and G3 (n = 2). The viral load ranged from 10(3) to 10(7) genomic copies/liter, and they were detected roughly with the same frequency in all participant cities. A peak of RVA and HAstV detection was observed in colder months (June to September), whereas no seasonality was observed for NoV. This study demonstrates for the first time, the high degree of gastroenteric viral contamination in the country; highlighting the importance of developing these analyses as a tool to determine the viral contamination in this hydrographic boundary region used by the local populations for recreation and consumption, establishing an elevated risk of gastroenteric diseases for human health. PMID- 24777820 TI - New force field parameters for metalloproteins I: Divalent copper ion centers including three histidine residues and an oxygen-ligated amino acid residue. AB - Transition metal ion complexation with proteins is ubiquitous across such diverse fields as neurodegenerative and cardiovascular diseases and cancer. In this study, the structures of divalent copper ion centers including three histidine and one oxygen-ligated amino acid residues and the relative binding affinities of the oxygen-ligated amino acid residues with these metal ion centers, which are debated in the literature, are presented. Furthermore, new force field parameters, which are currently lacking for the full-length metal-ligand moieties, are developed for metalloproteins that have these centers. These new force field parameters enable investigations of metalloproteins possessing these binding sites using molecular simulations. In addition, the impact of using the atom equivalence and inequivalence atomic partial charge calculation procedures on the simulated structures of these metallopeptides, including hydration properties, is described. PMID- 24777821 TI - OsMPK3 is a TEY-type rice MAPK in Group C and phosphorylates OsbHLH65, a transcription factor binding to the E-box element. AB - KEY MESSAGE: OsMPK3 is a TEY-type rice MAPK belonging to Group C and directly phosphorylates OsbHLH65 in the nucleus. OsMPK3 and OsbHLH65 are induced by biotic stress and defense-related hormones. Mitogen-activated protein kinases (MAPKs) are involved in the majority of signaling pathways that regulate plant development and stress tolerance via the phosphorylation of target molecules. Plant MAPKs are classified into two subtypes, TEY and TDY, according to the TxY (x = E or D) motif in their activation loop, and the TDY motif is unique to plant MAPKs. In rice, 17 MAPKs have been classified into six groups. To date, the functions of many TDY-type rice MAPKs have been characterized, but little is known of the TEY-type MAPKs in Group C and their possible target substrates. In the study reported here, we determined that a TEY-type rice MAPK belonging to subgroup C, named OsMPK3, phosphorylates its substrate OsbHLH65 in the nucleus. Our electrophoresis mobility shift assay results revealed that OsbHLH65 specifically binds to the E-box cis-element, but not to the G-box. Both OsMPK3 and OsbHLH65 were induced by treatments with rice blast (Magnaporthe grisea), brown planthopper (Nilaparvata lugens), and defense-related hormones, such as methyl jasmonic acid and salicylic acid. Our results suggest the possibility that OsMPK3 contributes to the defense signal transduction by phosphorylating the basic helix-loop-helix transcription factor. PMID- 24777822 TI - Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics. AB - The discovery and characterization of breast cancer resistance protein (BCRP) as an efflux transporter conferring multidrug resistance has set off a remarkable trajectory in the understanding of its role in physiology and disease. While the relevance in drug resistance and general pharmacokinetic properties quickly became apparent, the lack of a characteristic phenotype in genetically impaired animals and humans cast doubt on the physiological importance of this ATP-binding cassette family member, similarly to fellow multidrug transporters, despite well known endogenous substrates. Later, high-performance genetic analyses and fine resolution tissue expression data forayed into unexpected territories concerning BCRP relevance, and ultimately, the rise of quantitative proteomics allows putting observed interactions into absolute frameworks for modeling and insight into interindividual and species differences. This overview summarizes existing knowledge on the BCRP transporter on molecular, tissue and system level, both in physiology and disease, and describes a selection of experimental procedures that are the most widely applied for the identification and characterization of substrate and inhibitor-type interactions. PMID- 24777823 TI - Progesterone, as well as 17beta-estradiol, is important for regulating AHR battery homoeostasis in the rat uterus. AB - Several studies indicate that the aryl hydrocarbon receptor (AHR), which plays an important role in mediating the toxicity of many industrial chemicals, plays an important role in the physiology of female reproductive tract organs. This makes it likely that the AHR and additional components of the AHR signalling pathway are under the control of female sex steroids. In a previous study, we could already demonstrate the regulation of many members of the AHR battery by 17beta estradiol (E2) in the uterus of rats. In this study, we addressed the potential role of progesterone (P4) in this context. In a comparative approach using ovariectomized rats which were treated for 3 days with either vehicle control, E2, progesterone (P4) or the combination of both hormones in addition to sham operated animals, we could demonstrate that in addition to E2, P4 is also an important factor in regulating AHR signalling in the rat uterus. P4 has effects similar to E2 on uterine Ahr, Arnt and Arnt2 mRNA levels, resulting in a downregulation of these genes, while the E2-mediated downregulation of key AHR response genes Cyp1a1, Gsta2 and Ugt1 is completely antagonized by P4. As with E2, P4 leads to an increase in uterine AHR levels, especially in the endometrial epithelium despite the decrease in corresponding mRNA levels. This indicates a complex gene-specific regulatory network involving E2, P4 and possibly AHR itself to maintain all components of the AHR signalling cascade at the required levels during all stages of the oestrous cycle and pregnancy. PMID- 24777824 TI - Persistence of human parvovirus B19 in tissues from adult individuals: a comparison with serostatus and its clinical utility. AB - Human parvovirus B19 (PVB19) is linked to variety of diseases, including erythema infectiosum, transient aplastic crisis, fetal hydrops, cardiomyopathy and, recently, hepatitis and arthritis. Persistence of PVB19 in asymptomatic individuals has been reported in skin, synovium, myocardium and bone marrow. A higher level of PVB19 DNA has been observed in various tissues from cases of disease than in controls. Simultaneously, equal detection of PVB19 DNA has been shown in both cases and controls. Thus, it has become fundamental to study PVB19 DNA persistence in tissues that are unaffected by disease. This will help to better understand PVB19 DNA persistence in symptomatic and asymptomatic individuals and its possible pathogenic role in various diseases. A total of 70 adult autopsies were included and divided into seropositive (SP) and seronegative (SN) groups based on PVB19 IgG. Nested PCR for PVB19 DNA was carried out in myocardium, liver, kidney, and bone marrow. Of the 70 patients, 60% belonged to the SP group and 40% to the SN group. Seropositivity ranged from 50% in the 12 to 20 year old group to 66.7% in the 61 to 80 year old group. The viral genome was detected in 34.3% of myocardium, 20% of bone marrow, 10% of kidney and 8.6% of liver samples. There was no significant difference in the persistence rates between the SP and SN groups. The persistence of PVB19 DNA in various tissues ranged from 8.3% to 36% in the SP group and 10% to 30% in the SN group. The persistence of PVB19 DNA in all the tissues was low, and PVB19 serostatus had no influence on the persistence of PVB19 DNA. PMID- 24777825 TI - Sweet pepper confirmed as a reservoir host for tomato yellow leaf curl virus by both agro-inoculation and whitefly-mediated inoculation. AB - Tomato yellow leaf curl virus (TYLCV), a member of the genus Begomovirus, has a single-stranded DNA genome. TYLCV can induce severe disease symptoms on tomato plants, but other hosts plants such as cucurbits and peppers are asymptomatic. A full-length DNA clone of a Korean TYLCV isolate was constructed by rolling-circle amplification from TYLCV-infected tomatoes in Korea. To assess relative susceptibility of sweet pepper varieties to TYLCV, 19 cultivars were inoculated with cloned TYLCV by agro-inoculation. All TYLCV-infected sweet peppers were asymptomatic, even though Southern hybridization and polymerase chain reaction analysis showed TYLCV genomic DNA accumulation in roots, stems, and newly produced shoots. Southern hybridization indicated that TYLCV replicated and moved systemically from agro-inoculated apical shoot tips to roots or newly produced shoots of sweet peppers. Whitefly-mediated inoculation experiments showed that TYLCV can be transmitted to tomatoes from TYLCV-infected sweet peppers. Taken together, these results indicate that sweet pepper can be a reservoir for TYLCV in nature. PMID- 24777826 TI - Complete sequencing and phylogenetic analysis of porcine kobuvirus in domestic pigs in Northwest China. AB - Porcine kobuvirus, a member of the genus Kobuvirus that is associated with diarrhea, has been reported in many countries. We determined the complete genome sequence and investigated the genetic evolution of the kobuvirus strain swKoV CH441, which was detected in the highland of Gansu province in Northwest China. The viral genome is 8149 nucleotides (nt) long, including a 29-nt poly(A) tail of the 3' end, and is 90 nt shorter in the 2B coding region than those of other kobuvirus strains whose sequences are available in the GenBank database. Phylogenetic analysis showed that swKoV CH441 was most closely related to porcine kobuvirus CH/HNXX-4 but more distantly related to other strains, including the strains GS-1/2012/CH and GS-2/2012/CH, which were detected in Gansu province, indicating that porcine kobuvirus may have geographic and host differences in evolution. PMID- 24777827 TI - Diagnostic potential of recombinant nonstructural protein 3B to detect antibodies induced by foot-and-mouth disease virus infection in bovines. AB - Detection of antibodies to nonstructural proteins (NSP) of foot-and-mouth disease virus is the preferred diagnostic method to differentiate infected from vaccinated animals. In India, an endemic region practising preventive biannual vaccination, 3AB3 indirect ELISA (r3AB3 I-ELISA) has been employed as the primary screening test for serosurveillance. However, because of the variability observed in the immune response to the NSPs, the likelihood of detecting or confirming an infected animal is increased if an antibody profile against multiple NSPs is considered for diagnosis. In this study, all three copies of NSP 3B were expressed in a prokaryotic system to develop an indirect ELISA (r3B I-ELISA). At the decided cutoff of 40 percent positivity, the diagnostic sensitivity and specificity of the r3B I-ELISA were estimated to be 92.1% (95% CI: 89.0-94.5) and 98.1% (95% CI: 96.9-98.8), respectively, as compared to 97.04% and 95.04% for r3AB3 I-ELISA. Although r3B I-ELISA displayed lower sensitivity compared to the screening assay, which could possibly be attributed to additional relevant B-cell epitopes in the carboxy-terminal half of the 3A protein, the former achieved considerably higher specificity on repeatedly vaccinated animals. NSP antibodies could be detected from 10 to as late as 998 days postinfection in experimental calves. Substantial agreement in the test results (90.6%) was found between the two ELISAs. The r3B I-ELISA, when used in conjunction with the r3AB3 I-ELISA as an integrated system, can potentially augment the efficiency and confidence of detection of infected herds against the backdrop of intensive vaccination. PMID- 24777828 TI - Complete genome sequence of a novel phage, vB_MoxS-ISF9, infecting methylotrophic Microbacterium: first report of a virulent Microbacterium phage. AB - Here, we report the first genome sequence of a new virulent phage of Microbacterium oxydans, termed vB_MoxS-ISF9, which was isolated from sewage. Transmission electron microscopy showed that the isolated phage, which has a hexagonal head of about 80 nm in diameter and a long non-contractile tail of about 240 nm, belongs to the family Siphoviridae. The vB_MoxS-ISF9 DNA was completely sequenced and found to be 59,254 bp in length, with a G+C content of 62.76% and 120 putative open reading frames (ORFs). The predicted protein products of the ORFs were identified, and their sequences were analyzed. In a comparison with all available phage genomes, vB_MoxS-ISF9 did not show any significant similarity to other previously reported bacteriophages. To the beast of our knowledge, this is the first report of the isolation and complete genomic sequencing of a virulent phage against a member of the genus Microbacterium. PMID- 24777829 TI - Kaposi's sarcoma-associated herpesvirus infection of human bone-marrow-derived mesenchymal stem cells and their angiogenic potential. AB - Kaposi's sarcoma (KS) is a vascular tumor, and KS spindle cells express endothelial-cell-specific markers. Generally, it is believed that KS originates from endothelial cells. However, as various mesodermal-derived tissue markers are also expressed in KS spindle cells, the exact origin of KS still needs to be elucidated. Here, Kaposi's sarcoma-associated herpesvirus (KSHV) was used to infect human mesenchymal stem cells derived from bone marrow (hMSC-bm), and we investigated the angiogenic properties of these cells, which are one of the most important pathologic features of KS. KSHV-infected hMSC-bm showed latent infection and increased tube formation activity in vitro. In addition, the expression of endothelial-cell-specific markers and a growth factor that affects the angiogenesis of endothelial cells was induced in KSHV-infected cells. This study suggests that human mesenchymal stem cells might have important roles in KS pathogenesis. PMID- 24777830 TI - Respiratory and sympathetic chemoreflex regulation by Kolliker-Fuse neurons in rats. AB - Chemoreceptor activation increases phrenic nerve activity (PNA) and sympathetic nerve activity (SNA). The dorsolateral pontine neurons, including the parabrachial nucleus and the Kolliker-Fuse (KF) region project to several brainstem areas involved in autonomic and respiratory regulation. Here the objective was to further test the hypothesis that the KF region could contribute to central and peripheral sympathetic chemoreflex activation. In urethane anesthetized sino-aortic denervated or intact and vagotomized male Wistar rats (N = 7-8/group), hypercapnia (end-expiratory CO2 from 5 to 10 %) or KCN increased mean arterial pressure (MAP), splanchnic SNA, and PNA frequency and amplitude. Bilateral injection of muscimol (GABA-A agonist; 2 mM-50 nl) into the KF region increased resting PNA amplitude and reduced resting PNA frequency, without significant changes in resting MAP and SNA. Bilateral blockade of the KF region reduced the rise in MAP, sSNA, and PNA frequency and amplitude produced by hypercapnia or hypoxia. Our data suggest that the KF neurons could integrate and modulate breathing and sympathetic outflow during chemoreceptor activation. PMID- 24777832 TI - Ensemble of trees approaches to risk adjustment for evaluating a hospital's performance. AB - A commonly used method for evaluating a hospital's performance on an outcome is to compare the hospital's observed outcome rate to the hospital's expected outcome rate given its patient (case) mix and service. The process of calculating the hospital's expected outcome rate given its patient mix and service is called risk adjustment (Iezzoni 1997). Risk adjustment is critical for accurately evaluating and comparing hospitals' performances since we would not want to unfairly penalize a hospital just because it treats sicker patients. The key to risk adjustment is accurately estimating the probability of an Outcome given patient characteristics. For cases with binary outcomes, the method that is commonly used in risk adjustment is logistic regression. In this paper, we consider ensemble of trees methods as alternatives for risk adjustment, including random forests and Bayesian additive regression trees (BART). Both random forests and BART are modern machine learning methods that have been shown recently to have excellent performance for prediction of outcomes in many settings. We apply these methods to carry out risk adjustment for the performance of neonatal intensive care units (NICU). We show that these ensemble of trees methods outperform logistic regression in predicting mortality among babies treated in NICU, and provide a superior method of risk adjustment compared to logistic regression. PMID- 24777831 TI - PIAS1 and STAT-3 impair the tumoricidal potential of IFN-gamma-stimulated mouse dendritic cells generated with IL-15. AB - Primarily defined by their antigen-presenting property, dendritic cells (DCs) are being implemented as cancer vaccines in immunotherapeutic interventions. DCs can also function as direct tumor cell killers. How DC cytotoxic activity can be efficiently harnessed and the mechanisms controlling this nonconventional property are not fully understood. We report here that the tumoricidal potential of mouse DCs generated from myeloid precursors with GM-CSF and IL-15 (IL-15 DCs) can be triggered with the Toll-like receptor (TLR) 4 ligand lipopolysaccharide to a similar extent compared with that of their counterparts, conventionally generated with IL-4 (IL-4 DCs). The mechanism of tumor cell killing depends on the induction of iNOS expression by DCs. In contrast, interferon (IFN)-gamma induces the cytotoxic activity of IL-4 but not IL-15 DCs. Although the IFN-gamma STAT-1 signaling pathway is overall functional in IL-15 DCs, IFN-gamma fails to induce iNOS expression in these cells. iNOS expression is negatively controlled in IFN-gamma-stimulated IL-15 DCs by the cooperation between the E3 SUMO ligase PIAS1 and STAT-3, and can be partially restored with PIAS1 siRNA and STAT-3 inhibitors. PMID- 24777833 TI - A machine learning approach to create blocking criteria for record linkage. AB - Record linkage, a part of data cleaning, is recognized as one of most expensive steps in data warehousing. Most record linkage (RL) systems employ a strategy of using blocking filters to reduce the number of pairs to be matched. A blocking filter consists of a number of blocking criteria. Until recently, blocking criteria are selected manually by domain experts. This paper proposes a new method to automatically learn efficient blocking criteria for record linkage. Our method addresses the lack of sufficient labeled data for training. Unlike previous works, we do not consider a blocking filter in isolation but in the context of an accompanying matcher which is employed after the blocking filter. We show that given such a matcher, the labels (assigned to record pairs) that are relevant for learning are the labels assigned by the matcher (link/nonlink), not the labels assigned objectively (match/unmatch). This conclusion allows us to generate an unlimited amount of labeled data for training. We formulate the problem of learning a blocking filter as a Disjunctive Normal Form (DNF) learning problem and use the Probably Approximately Correct (PAC) learning theory to guide the development of algorithm to search for blocking filters. We test the algorithm on a real patient master file of 2.18 million records. The experimental results show that compared with filters obtained by educated guess, the optimal learned filters have comparable recall but reduce throughput (runtime) by an order-of-magnitude factor. PMID- 24777834 TI - Testing the extreme male brain theory of autism spectrum disorder in a familial design. AB - Autism Spectrum Disorder (ASD) may be an extreme manifestation of some male typical traits in both neuroanatomy and cognition. Using the ratio of the second to fourth digit (2D:4D) and digit length as biomarkers of (pre- and postnatal) testosterone levels, examined was whether hypermasculinized digit ratios and/or lengths were familial traits in ASD and investigated their relation to sexually dimorphic cognitive abilities. 2D:4D ratios and digit lengths of 216 children with ASD, 202 unaffected siblings, and 360 parents were compared with those of 174 control children and their 146 parents. Generalized Estimation Equations, Generalized Linear Models, and Linear Mixed Models were used to investigate parent-offspring relationships and group differences. In ASD probands and their relatives alike, digit length relative to overall height was significantly increased in comparison to controls. No significant group differences were found between affected and unaffected subjects, or between males and females. Additionally, 2D:4D ratios increased with age. No (consistent) associations were found between 2D:4D ratio or digit lengths and systemizing and empathizing skills. The findings emphasize the role of familially based elevated pre- and postnatal testosterone levels in the liability for ASD, but challenge the use of 2D:4D ratio as a proxy of prenatal testosterone exposure solely. Given that many genes influence digit length, the exact mechanisms underlying a familial predisposition toward increased digit length in ASD are as yet unknown and needs to be explored in future studies. PMID- 24777835 TI - Safety profile of long-term intraventricular access devices in pediatric patients receiving radioimmunotherapy for central nervous system malignancies. AB - BACKGROUND: The use of Ommaya catheters or ventriculoperitoneal shunts with programmable valves (pVP-shunts) for intraventricular drug administration is increasingly more common. PROCEDURE: We reviewed the safety and complication rate associated with ventricular access devices in patients receiving compartmental intraventricular radioimmunotherapy (cRIT). RESULTS: One hundred fifty one patients with recurrent primary or metastatic central nervous system (CNS) tumors (1-34 years) had a ventricular access device (143 Ommaya reservoirs, 8 VP shunts with programmable valves) placed for drug administration and cerebrospinal fluid acquisition. Patients received 2-5 serial injections (124) I- or (131) I- labeled monoclonal antibody 3F8 or 8H9. For each injection, catheters remained accessed for pharmacokinetic studies up to 48 hours or were individually accessed 3 6*/injection. Thereafter catheters were accessed for periodic routine cytology. Six patients (4%) had complications including three with catheter migration in the newly-placed setting requiring surgical revision. Two patients had pericatheter cyst formation (with cyst formation before radioimmunotherapy administration in one patient) resulting in elective removal and endoscopic cystoventriculostomy in both patients. There were no catheter-related infections, hemorrhages, seizures, focal deficits, or valve malfunctioning. Four patients later required Ommaya conversion to VP shunts because of hydrocephalus secondary to disease progression. CONCLUSIONS: We report a long-term safety profile of ventricular access devices in patients receiving cRIT. Minimal acute complications are observed despite the frequency of cerebrospinal fluid acquisition; long-term complications are rare. Programmable VP shunts appear to be a safe and effective alternative to Ommaya catheters. PMID- 24777837 TI - Significant role of female sex hormones in cardiac myofilament activation in angiotensin II-mediated hypertensive rats. AB - Ovariectomy leads to suppression of cardiac myofilament activation in healthy rats implicating the physiological essence of female sex hormones on myocardial contraction. However, the possible function of these hormones during pathologically induced myofilament adaptation is not known. In this study, sham operated and ovariectomized female rats were chronically exposed to angiotensin II (AII), which has been shown to cause myocardial adaptation. In the shams, AII induced cardiac adaptation by increasing myofilament Ca(2+) sensitivity. Interestingly, this hypersensitivity was further enhanced in AII-infused ovariectomized rats. Ovariectomy increased the phosphorylation levels of cardiac tropomyosin, which may underlie the mechanism of hypersensitivity. On the other hand, AII infusion did not alter maximal tension that was suppressed after ovariectomy. This finding coincided with a comparable increase in beta-isoform of myosin heavy chains in both ovariectomized groups. Together, it is conceivable that female sex hormones serve as predominant factors that regulate cardiac myofilament activation. Furthermore, they may prevent stress-induced myofilament maladaptation. PMID- 24777839 TI - Monitoring surface processes during heterogeneous asymmetric hydrogenation of ketones on a chirally modified platinum catalyst by operando spectroscopy. AB - Surface processes occurring at the catalytic chiral surface of a cinchona modified Pt catalyst during the asymmetric hydrogenation of activated ketones have been monitored for the first time using operando ATR-IR spectroscopy. Fundamental information about this catalytic system could be gained, including the chiral modification process of the catalyst, the surface interaction of reactant ketone with preadsorbed chiral modifier, the role of hydrogen as well as the influence of the product enantiomers in the catalytic cycle. The formation of a diastereomeric transient surface complex between ketone and chiral modifier was found to be related to the ketone consumption. Among the studied activated ketones, a correlation between stereoselection and the strength of the intermolecular hydrogen bond was identified. Dissociated hydrogen from the catalytic surface is found to play a crucial role in the formation of the diastereomeric surface complex. PMID- 24777838 TI - Patient involvement in medication safety in hospital: an exploratory study. AB - BACKGROUND: Medication errors are common in hospital inpatients. While many interventions have been proposed to address these problems, few have been shown to have significant benefits. A complementary approach is to facilitate greater involvement of patients with their inpatient medication. However, there is relatively little research in this area and it is not known which interventions lead to improved healthcare outcomes. Work is therefore needed to investigate the roles that healthcare professionals and patients believe are appropriate for hospital inpatients to take relating to safety. OBJECTIVE: To explore the extent to which hospital inpatients reported that they engaged with medication safety related behaviours, the extent to which they would like to, and the extent to which healthcare professionals reported that they would support such engagement. SETTING: An NHS hospital Trust in West London. METHODS: 100 Patients and healthcare professionals were recruited on ten wards within the Trust and invited to complete quantitative questionnaires. Data were analysed descriptively and exploratory comparisons made between different groups of respondents. MAIN OUTCOME MEASURES: inpatient medication safety involvement scale and control preference scale for patient involvement in decision making. RESULTS: 100 patients (98 % response rate) and 104 healthcare professionals (59 % response rate) were recruited. The majority of patients and healthcare professionals were supportive of hospital inpatients being involved with their medication. However there was a significant gap between desire for patient involvement and what patients reported having experienced. Female patients and those under 65 wanted a significantly higher level of involvement than males and over 65s. Few associations were found between healthcare professionals' reported support for involvement and their profession or gender. However, pharmacists and nurses were significantly more likely to report supporting patients asking questions about their medicines and self administering their own medicines than doctors. CONCLUSION: Healthcare professionals and patients desire a higher level of patient involvement with their medication while in hospital than patients currently report. Interventions need to be developed to bridge the gap between desired and actual patient involvement. PMID- 24777840 TI - Estimation of the melatonin suppression index through clear and yellow-tinted intraocular lenses. AB - PURPOSE: To estimate the melatonin suppression index (MSI), which may reflect the nonvisual photoreception function, through commercially available foldable, clear and yellow-tinted intraocular lenses (IOLs). METHODS: The MSIs for 13 IOL models (6 clear IOLs, 7 yellow-tinted IOLs) with three lens powers were calculated based on previously reported data about the melatonin suppression spectrum, spectral intensity of a 20-W white fluorescent lamp and spectral transmission of IOLs in wavelengths from 300 to 800 nm. The models tested were the SA60AT and SN60AT (Alcon Japan); the VA-60BBR, YA-60BBR, and NM-1 (Hoya); the AU6K and AN6K (Kowa); the N4-18B and N4-18YG (Nidek); the X-60 and NX-60 (Santen); and the KS-3Ai and KS-AiN (Staar Japan). RESULTS: The MSIs of the clear IOLs ranged from 1.12 to 1.18 mW cm(-2) sr(-1) and those of the yellow-tinted IOLs from 0.74 to 1.01 mW cm(-2) sr(-1). All yellow-tinted IOLs had significantly lower MSIs (P < 0.0001 0.0021) than the clear IOLs; the %MSI cutoff values for yellow-tinted IOLs compared to the clear IOLs were 11.4-36.2 %. The MSIs of the six clear IOLs did not differ based on lens powers (P = 0.2159-0.6144). Except for one IOL model, all yellow-tinted IOLs had a lower MSI with higher lens powers compared to those with lower lens powers (P < 0.0001-0.0055). Compared to phakic eyes (MSI, 1.03 mW cm(-2) sr(-1)), the MSIs of the clear IOLs were higher (%MSI cutoff, -14.6 to 8.4 %), whereas those of the yellow-tinted IOLs were lower (2.6-28.1 %). Compared to aphakic eyes (MSI, 1.21 mW cm(-2) sr(-1)), the MSIs of the clear (2.1-7.4 %) and yellow-tinted (16.7-38.6 %) IOLs were lower. CONCLUSIONS: Yellow-tinted IOLs absorb more circadian rhythm-associated light than clear IOLs. The difference in the lens power is significantly related to the MSI value in some yellow-tinted IOLs. To correlate the current data with the clinical relevance of these findings, the percent loss of the MSI leading to a circadian rhythm disorder needs to be clarified. PMID- 24777841 TI - Vision-related quality of life and visual function following intravitreal bevacizumab injection for persistent diabetic macular edema after vitrectomy. AB - PURPOSE: To investigate the vision-related quality of life (VR-QOL) and visual function in patients undergoing intravitreal injection of bevacizumab (IVB) for persistent diabetic macular edema (DME) after vitrectomy. METHODS: This institutional study enrolled 20 consecutive patients (20 eyes) who had received 1.25 mg IVB for persistent macular edema after vitrectomy for DME at least 3 months previously. Visual function and VR-QOL were measured before, and 1 and 3 months after IVB. Measurements included the logarithm of the minimum angle of resolution (logMAR), best corrected visual acuity (BCVA), letter contrast sensitivity, severity of metamorphopsia using M-CHARTS, central retinal thickness using optical coherence tomography, and VR-QOL with the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). RESULTS: One month after IVB, statistically significant improvements were observed in central retinal thickness, letter contrast sensitivity, and the VFQ-25 "mental health" subscale score (P < 0.05, Dunnett test). LogMAR BCVA, metamorphopsia, and the VFQ-25 composite score did not improve significantly. Three months after IVB, there were no significant improvements in any parameters examined. CONCLUSIONS: Intravitreal bevacizumab injection for persistent DME after vitrectomy temporarily improved central retinal thickness, contrast sensitivity, and the psychometric aspect of the VR-QOL, but these effects did not last for over 3 months. PMID- 24777842 TI - Genetics of immune-mediated adverse drug reactions: a comprehensive and clinical review. AB - Adverse drug reactions (ADRs) are common and are a major problem in drug therapy. Patients experience unnecessary morbidity and mortality whilst many effective drugs are withdrawn because of ADRs in a minority of patients. Recent studies have demonstrated significant associations between human leukocyte antigens (HLA) and predisposition to ADRs such as drug-induced skin injury (DISI) and drug induced liver injury (DILI). HLA-B*58:01 has been significantly associated with allopurinol-induced hypersensitivity. Associations between HLA and carbamazepine hypersensitivity reactions demonstrate both ethnicity and phenotype specificity; with HLA-B*15:02 associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in South East Asian patients only whilst HLA-A*31:01 is associated with all phenotypes of hypersensitivity in multiple ethnicities. Studies of ximelagatran, an oral direct thrombin inhibitor withdrawn because of hepatotoxicity, found associations between HLA-DRB1*07:01 and HLA-DQA1*02:01 and ximelagatran DILI. Interestingly, HLA-B*57:01 is associated with both abacavir DISI and flucloxacillin DILI but the reasons for the different phenotype of ADR remains unknown. Pharmacogenetic screening for HLA-B*57:01 prior to abacavir therapy has significantly reduced the incidence of abacavir hypersensitivity syndrome in clinical practice. No other HLA associations have been translated into clinical practice because of multiple reasons including failure to replicate, inadequate sample sizes, and our lack of understanding of pathophysiology of ADRs. Here, we review genetic associations that have been reported with ADRs and discuss the challenges that scientists, clinicians, pharmaceutical industry and regulatory agencies face when attempting to translate these associations into clinically valid and cost-effective tests to reduce the burden of ADRs in future. PMID- 24777843 TI - Vanadium as a chemoprotectant: effect of vanadium(III)-L-cysteine complex against cyclophosphamide-induced hepatotoxicity and genotoxicity in Swiss albino mice. AB - Vanadium is an essential micronutrient for living systems and has antioxidant and genoprotective property. In the present study, the protective role of an organovanadium compound vanadium(III)-L-cysteine (VC-III) was evaluated against hepatotoxicity and genotoxicity induced by cyclophosphamide (CP) (25 mg/kg b.w., i.p.) in Swiss albino mice. Treatment with VC-III (1 mg/kg b.w., p.o.) mitigated CP-induced hepatic injury as indicated by reduction in activities of alanine transaminase, aspartate transaminase, alkaline phosphatase by 1.57-, 1.58- and 1.32-fold in concomitant treatment schedule and by 1.83-, 1.77- and 1.45-fold in pretreatment schedule, respectively, and confirmed by histopathological evidences. Parallel to these changes, VC-III ameliorated CP-induced oxidative stress in liver by 1.46-, 1.26-, 1.32- and 1.42-fold in concomitant treatment group and by 1.95-, 1.40-, 1.46- and 1.73-fold in pretreatment group at the level of H2O2, superoxide, nitric oxide and lipid peroxidation, respectively. VC-III also enhanced activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and glutathione (reduced) level in mice liver by 1.46-, 1.37-, 1.29-, 1.44- and 1.45-fold in concomitant treatment schedule and by 1.64-, 1.65-, 1.42-, 1.49- and 1.57-fold in pretreatment schedule, respectively. In addition, the organovanadium compound could efficiently attenuate CP-induced chromosomal aberrations, DNA fragmentation and apoptosis in bone marrow cells and DNA damage in lymphocytes by 1.49-, 1.43-, 1.48- and 1.59-fold in concomitant treatment group and by 1.76-, 1.92-, 1.99- and 2.15-fold in pretreatment group, respectively. Thus, the present study showed that VC-III could exert protection against CP-induced hepatotoxicity and genotoxicity. PMID- 24777844 TI - Prenatal bilateral adrenal calcifications, hypogonadism, and nephrotic syndrome: beyond Wolman disease. PMID- 24777845 TI - Vascular distribution of nanomaterials. AB - Once considered primarily occupational, novel nanotechnology innovations, and applications have led to widespread domestic use and intentional biomedical exposures. With these exciting advances, the breadth and depth of toxicological considerations must also be expanded. The vascular system interacts with every tissue in the body, striving to maintain homeostasis. Engineered nanomaterials (ENM) have been reported to distribute in many different tissues and organs. However, these observations have tended to use approaches requiring tissue homogenization and/or gross organ analyses. These techniques, while effective in establishing presence, preclude an exact determination of where ENM are deposited within a tissue. If nanotechnology is to achieve its full potential, it is necessary to identify this exact distribution and deposition of ENM throughout the cardiovascular system, with respect to vascular hemodynamics and in vivo ENM modifications taken into account. Distinct levels of the vasculature will first be described as individual compartments. Then the vasculature will be considered as a whole. These unique compartments and biophysical conditions will be discussed in terms of their propensity to favor ENM deposition. Understanding levels of the vasculature will also be discussed. Ultimately, future studies must verify the mechanisms speculated on and presented herein. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website. PMID- 24777848 TI - Regression of endothelial dysfunction in patients with endometriosis after surgical treatment: a 2-year follow-up study. AB - STUDY QUESTION: How does endothelial function change in women with endometriosis after surgical treatment? SUMMARY ANSWER: Surgical treatment of endometriosis leads to endothelial function improvement, resulting in reduction of cardiovascular risk. WHAT IS KNOWN ALREADY: Some recent studies have demonstrated that in young women with endometriosis, even if structural alterations are absent, endothelial dysfunction, expressed as flow-mediated dilation (FMD) impairment, can nevertheless occur. However, there are no data about changes of endothelial function in women with endometriosis after surgical treatment of endometriosis. STUDY DESIGN, SIZE, DURATION: This is a follow-up study carried out in 68 women enrolled in a previous study. Endothelial function was evaluated 2 years after surgical procedure and compared with baseline values. PARTICIPANTS/MATERIALS, SETTING, METHODS: Twenty-two patients who had undergone surgical treatment of endometriosis (named as patients with STE) and 10 control subjects without endometriosis, from the original study sample participated in this follow-up study. Assessment of endothelial function by FMD evaluation and measurements of serum markers of endothelial activation and inflammation were done in all these subjects. MAIN RESULTS AND THE ROLE OF CHANCE: After a 2-year follow-up period, FMD increased significantly with respect to baseline values among patients with STE [average pre- to post-difference: 5.07%, 95% confidence intervals (CI) 3.50, 6.63%; P < 0.001] but not among controls (average pre- to post-difference: 1.56%, 95% CI -0.55, 3.67%; P = 0.13). Follow-up FMD values were not significantly different between patients with STE and controls (average difference 1.50%, 95% CI -1.24, 4.23%; P = 0.27). Follow-up markers of inflammation and endothelial cells activation were similar among patients with STE and controls. LIMITATIONS, REASONS FOR CAUTION: Although this study represents the first in the literature assessing endothelial function after surgical treatment of endometriosis, further longitudinal studies are desirable to define better the real risk that women with a history of endometriosis will develop cardiovascular events. WIDER IMPLICATIONS OF THE FINDINGS: Endothelial dysfunction may be a better predictor of future cardiovascular events than traditional risk factors and the improvement in endothelial function we observed in patients after STE may have significant implications for their future cardiovascular risk. STUDY FUNDING/COMPETING INTEREST(S): No external funding has been either sought or obtained for this study. There are no conflicts of interest to declare. PMID- 24777847 TI - Increased androgen receptor gene copy number is associated with TMPRSS2-ERG rearrangement in prostatic small cell carcinoma. AB - Small cell carcinoma of the prostate (PSCC) is a highly aggressive malignancy that often develops in patients previously treated with hormonal therapy for metastatic prostatic acinar adenocarcinoma. The TMPRSS2-ERG gene rearrangement is highly specific for prostate cancer and shared by PSCC; however, the role of androgen receptor (AR) gene alterations and interaction with TMPRSS2-ERG rearrangement are incompletely understood in PSCC. Sixty-one cases of PSCC were examined for AR gene copy number and TMPRSS2-ERG rearrangement by fluorescence in situ hybridization (FISH) and AR protein expression by immunohistochemistry. Of 61 cases of PSCC, 51% (31/61) demonstrated increased AR gene copy number (FISH+), 54% (33/61) were positive for TMPRSS2-ERG gene fusion, and 38% (23/61) showed AR protein expression. Of the 31 AR FISH+ cases, 23 also showed TMPRSS2-ERG gene fusion, and 16 expressed AR protein. Of the 33 cases with TMPRSS2-ERG fusion, 28 were AR FISH+ or expressed AR protein. Statistically significant correlations were observed between AR gene copy number or AR protein expression and TMPRSS2 ERG gene fusion (P = 0.001 and P = 0.03, respectively). In summary, high AR gene copy number emerges during the development of PSCC, often in association with TMPRSS2-ERG rearrangement. This potential mechanism warrants further study. Improvement will come from understanding the biology of the disease and integrating new therapies into the treatment of this rare and aggressive tumor. PMID- 24777849 TI - Learning curve for the detection of pouch of Douglas obliteration and deep infiltrating endometriosis of the rectum. AB - STUDY QUESTION: How long does it take to be proficient in diagnosing pouch of Douglas (POD) obliteration and deep infiltrating endometriosis (DIE) of the rectum with transvaginal sonography (TVS)? SUMMARY ANSWER: Sonographers familiar with the general use of TVS are expected to be proficient in the diagnosis of endometriosis nodules of the rectum and the detection of POD obliteration using the 'sliding sign' after ~40 examinations, performed in a referral clinic for pelvic pain. WHAT IS ALREADY KNOWN: With rectal DIE, the reasons for the obvious diagnostic problems are complex. Menstrual pain or cramps are still considered to be 'normal' and do not provide a reason for patients and even health-care providers to seek expert help. Furthermore, the performance of TVS for diagnosing pelvic endometriosis has been shown to be accurate only in experienced hands. STUDY DESIGN, SIZE AND DURATION: This prospective study included 121 selected patients with suspected endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Symptomatic patients, referred to a pelvic pain clinic, were examined by an expert sonographer (E.S.) and consecutively by two trainees (T1/2). MAIN RESULTS AND THE ROLE OF CHANCE: The learning curve using the cumulative sum shows that the trainees, listed as T1/T2, reached the predefined level of proficiency in detecting bowel nodules after examining 42 and 37 patients, for T1 and T2, respectively. The prevalence rate of bowel nodules demonstrated by the ES was 21%. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) as well as the accuracy for TVS of T1 and T2 in comparison with the results of ES were 72 and 89, 96 and 95, 87 and 80, 90 and 98, and 89 and 94%, respectively. The prevalence rate of POD obliteration, as demonstrated by a negative sliding sign, was 27%. The trainees reached the predefined level of proficiency after examining 42 and 33 patients, for T1 and T2, respectively. The sensitivity, specificity, PPV, NPV as well as the accuracy of TVS for T1 and T2 in comparison with the results of the ES were 83 and 89, 95 and 95, 91 and 80, 90 and 98, and 91 and 94%, respectively. LIMITATIONS, REASONS FOR CAUTION: We performed this analysis in a tertiary referral centre with a high number of advanced cases of DIE, not reflecting a standard population. WIDER IMPLICATION OF THE FINDINGS: Integrated in TVS training courses, typical sonographic video clips for DIE of the rectum, including the use of disease-specific signs, could help to improve diagnostic accuracy in DIE and shorten diagnostic delays. STUDY FUNDING/COMPETING INTERESTS: No funding was received for this study. None of the authors has any competing interests. PMID- 24777850 TI - Preconception predictors of gestational diabetes: a multicentre prospective cohort study on the predominant complication of pregnancy in polycystic ovary syndrome. AB - STUDY QUESTION: Can we develop an adequate preconception prediction model to identify those women with polycystic ovary syndrome (PCOS) who have an increased risk of developing gestational diabetes mellitus (GDM) during subsequent pregnancy? STUDY ANSWER: The risk of developing GDM in women with PCOS can be adequately predicted prior to conception by a prediction model. WHAT IS KNOWN ALREADY: Women with PCOS are at increased risk of pregnancy complications, especially GDM. GDM has serious short-term and long-term effects on mother and baby. STUDY DESIGN, SIZE, DURATION: This study is a part of a multicentre prospective cohort study, which was conducted between April 2008 and April 2012. A total of 326 women with PCOS were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and a wish to conceive were included prior to conception and followed until 6 weeks after delivery. Maternal, neonatal and birth complications were reported. A multivariate model was developed to predict the most common pregnancy complication, GDM, by using univariate and multivariate logistic regression of preconception patient characteristics. The area under the curve (AUC) of the receiver-operating characteristic was used to test the performance of the model. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 189 women (58%) achieved an ongoing pregnancy (8% multiples) and delivered a live born neonate. One or two maternal complications occurred in 62 (33%) pregnant women, mainly GDM (n = 41; 22%) and pregnancy-induced hypertension (n = 14; 7%). In children, one or two complications were observed in 49 (26%) of 206 children born, e.g. premature delivery (n = 23; 12%) and small for gestational age (n = 15; 8%). The preconception prediction model for GDM performed well (AUC 0.87, 95% CI 0.81-0.93). First-degree relatives with type 2 diabetes mellitus, serum levels of fasting glucose, fasting insulin, androstenedione and sex hormone-binding globulin before conception were identified as predictors. LIMITATIONS, REASONS FOR CAUTIONS: The prediction model has not yet been externally validated in another group of patients. Also, there were missing data for some of the determinants, which were accounted for by multiple imputation. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS who achieve a pregnancy have an increased risk of GDM. The prediction model can be used to identify women particularly at risk for GDM who should be monitored closely to enable preventative measures that may reduce the risk of developing GDM and its adverse consequences. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used for the study. M.A.W., S.M.V.V., A.J.G., A.F. and M.P.H.K. have nothing to disclose. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, European Society of Human Reproduction and Embryology and MSD. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, Merck-Serono, MSD, Organon, Schering Plough, Sharp & Dome and Serono. M.J.C. has received grant support from the following companies (in alphabetic order): Illumina and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Ferring, Ova-Science, PregLem SA, Roche and Watson Laboratories. TRIAL REGISTRATION NUMBER: NCT00821379 [Clinicaltrials.gov]. PMID- 24777851 TI - Macrophages: gatekeepers of tissue integrity. AB - Macrophages form a heterogeneous group of hematopoietic cells that reside in tissues, where they are required to maintain organ integrity. Tissue macrophages contribute to tissue formation, metabolism, homeostasis, and repair. They have a unique ability to sense and respond to tissue damage. They serve as the first line of defense during infection and help promote immune tolerance in the steady state. Although most tissue macrophages share a high phagocytic and degradative potential, they are heterogeneous in origin, as well as in homeostatic function and response to insults. Here, we will discuss recent developments in our understanding of the origin of tissue macrophages and their functional specialization in tissues. PMID- 24777852 TI - Increased frequency of ICOS+ CD4 T cells as a pharmacodynamic biomarker for anti CTLA-4 therapy. AB - Pharmacodynamic biomarkers can play an important role in understanding whether a therapeutic agent has "hit its target" to impact biologic function. A pharmacodynamic biomarker for anti-CTLA-4 therapy remains to be elucidated. We previously reported that anti-CTLA-4 therapy increases the frequency of CD4 T cells expressing the inducible costimulator (ICOS) molecule. To determine whether the frequency of ICOS(+) CD4 T cells could be used as a pharmacodynamic biomarker for anti-CTLA-4 therapy, we carried out flow cytometric studies and statistical analyses on data from 56 individuals, which included 10 healthy donors, 36 patients who received anti-CTLA-4 monoclonal antibody (mAb), and 10 patients who received treatment with a different immunomodulatory agent (gp100 DNA vaccine). After treatment with anti-CTLA-4 mAb (ipilimumab; Bristol-Myers Squibb), we detected a statistically significant increase in the frequency of ICOS(+) CD4 T cells. After two doses of anti-CTLA-4 therapy, the assay was found to have an estimated specificity of 96% [95% confidence interval (CI), 88-100] and sensitivity of 71% (95% CI, 54-85), with positive expression defined as a frequency that is more than the upper bound of 95% CI among baseline samples from all subjects. Our data suggest that an increased frequency of ICOS(+) CD4 T cells measured by flow cytometry can be used as a reproducible pharmacodynamic biomarker to indicate biologic activity in the setting of anti-CTLA-4 therapy, which should enable appropriate immune monitoring to determine whether patients receiving anti-CTLA-4 monotherapy or combination treatment strategies are having an adequate biologic response. PMID- 24777853 TI - Phosphatidylserine-targeting antibody induces M1 macrophage polarization and promotes myeloid-derived suppressor cell differentiation. AB - Multiple tumor-derived factors are responsible for the accumulation and expansion of immune-suppressing myeloid-derived suppressor cells (MDSC) and M2-like tumor associated macrophages (TAM) in tumors. Here, we show that treatment of tumor bearing mice with docetaxel in combination with the phosphatidylserine-targeting antibody 2aG4 potently suppressed the growth and progression of prostate tumors, depleted M2-like TAMs, and MDSCs, and increased the presence of M1-like TAMs and mature dendritic cells in the tumors. In addition, the antibody markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. In vitro studies confirmed that 2aG4 repolarized TAMs from an M2- to an M1-like phenotype and drove the differentiation of MDSCs into M1-like TAMs and functional dendritic cells. These data suggest that phosphatidylserine is responsible for the expansion of MDSCs and M2-like TAMs in tumors, and that bavituximab, a phosphatidylserine-targeting antibody currently in clinical trials for cancer, could reverse this process and reactivate antitumor immunity. PMID- 24777855 TI - The immunophenotypes of blast cells in B-cell precursor acute lymphoblastic leukemia: How different are they from their normal counterparts? PMID- 24777854 TI - Causes of aging are likely to be many: robin holliday and changing molecular approaches to cell aging, 1963-1988. AB - Causal complexities involved in biological phenomena often generate ambiguous experimental results that may create epistemic niches for new approaches and interpretations. The exploration for new approaches may foment momentum of larger epistemological shifts, and thereby introduce the possibilities of adopting new technologies. This paper describes British molecular biologist Robin Holliday's cell aging research from 1963 to the 1980s that transformed from simple hypothesis testing to working on various alternative and integrative approaches designed to deal with complex data. In the 1960s, hoping to use biochemical investigations of cells to settle a debate about whether DNA mutations or protein errors caused aging, Holliday carried out a series of experiments with fruit flies, fungi, and human fibroblast cells. The results seemed to demonstrate that cytoplasmic protein errors caused cell aging. However, other scientists obtained contradictory results and raised issues about potential flaws in Holliday's experiments. In the 1970s, working as the director of the Genetics Division of the National Institute for Medical Research in Mill Hill, United Kingdom, Holliday relied on available talents of his associates, including computational expertise, to explore alternative hypotheses and approaches. By the early 1980s, they had worked out an epigenetic explanation and had established integrative, evolutionary models of cell aging that incorporated both DNA mutations and protein errors as critical factors. By delineating Holliday's research path from simply testing hypotheses to integrating multiple factors involved in aging, this paper offers an account of the difficulties in targeting molecular cause in cell aging around the 1970s, whose failures nevertheless opened up an epistemic niche for integration. PMID- 24777856 TI - DNGR-1 is dispensable for CD8+ T-cell priming during respiratory syncytial virus infection. AB - During respiratory syncytial virus (RSV) infection CD8(+) T cells both assist in viral clearance and contribute to immunopathology. CD8(+) T cells recognize viral peptides presented by dendritic cells (DCs), which can directly present viral antigens when infected or, alternatively, "cross-present" antigens after endocytosis of dead or dying infected cells. Mouse CD8alpha(+) and CD103(+) DCs excel at cross-presentation, in part because they express the receptor DNGR-1 that detects dead cells by binding to exposed F-actin and routes internalized cell debris into the cross-presentation pathway. As RSV causes death in infected epithelial cells, we tested whether cross-presentation via DNGR-1 is necessary for CD8(+) T-cell responses to the virus. DNGR-1-deficient or wild-type mice were intranasally inoculated with RSV and the magnitude of RSV-specific CD8(+) T-cell induction was measured. We found that during live RSV infection, cross presentation via DNGR-1 did not have a major role in the generation of RSV specific CD8(+) T-cell responses. However, after intranasal immunization with dead cells infected with RSV, a dependence on DNGR-1 for RSV-specific CD8(+) T cell responses was observed, confirming the ascribed role of the receptor. Thus, direct presentation by DCs may be the major pathway initiating CD8(+) T-cell responses to RSV, while DNGR-1-dependent cross-presentation has no detectable role. PMID- 24777857 TI - The target for statins, HMG-CoA reductase, is expressed in ductal carcinoma-in situ and may predict patient response to radiotherapy. AB - BACKGROUND: Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benefit from radiotherapy is warranted. Statins have been suggested to exert radio-sensitizing effects. The target for cholesterol lowering statins is HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. The aim of this study was to examine HMGCR expression in DCIS and study its treatment predictive value. METHODS: A population-based cohort including 458 women diagnosed with primary DCIS between 1986 and 2004 were followed until November 2011 to study long-term survival. Tumor tissue microarrays were constructed, and immunohistochemical analyses were performed to detect cytoplasmic protein expression of HMGCR. The association between DCIS HMGCR expression and invasive breast cancer recurrence-free survival (RFSinv) and overall survival (OS) was analyzed by Kaplan-Meier curves, log rank test, and Cox proportional hazard analysis. RESULTS: HMGCR was strongly expressed in 24 % of the assessed DCIS samples, moderately expressed in 46 %, and weakly expressed in 23 %; no expression was detected in 7 % of the samples. During the follow-up time (median 13.8 years), 61 patients were diagnosed with an invasive breast cancer recurrence, and 80 patients died. A crude analysis showed no survival benefit from radiotherapy. However, patients with strong HMGCR expression showed an improved RFSinv (log rank, p = 0.03) and OS (log rank, p = 0.04) after radiotherapy. No statistically significant interaction was observed for HMGCR and radiotherapy (RFSinv p = 0.69 and OS p = 0.29). CONCLUSIONS: This study demonstrates HMGCR expression in DCIS and suggests HMGCR as a predictive marker of response to postoperative radiotherapy in DCIS, although the test for interaction was nonsignificant. Future DCIS studies addressing the potential of statin treatment targeting HMGCR are warranted. PMID- 24777858 TI - The extent of extracapsular extension may influence the need for axillary lymph node dissection in patients with T1-T2 breast cancer. AB - BACKGROUND: Whether extracapsular extension (ECE) of tumor in the sentinel lymph node (SLN) is an indication for axillary lymph node dissection (ALND) in patients managed by American College of Surgeons Oncology Group Z0011 criteria is controversial. Here we examine the correlation between ECE in the SLN and disease burden in the axilla. METHODS: Patients meeting Z0011 clinicopathologic criteria (pT1-2, cN0 with <3 positive SLNs) were selected from a prospectively maintained database (2006-2013). Chart review documented the presence and extent of ECE. Neoadjuvant chemotherapy patients were excluded. Comparisons were made by presence and extent (<=2 vs. >2 mm) of ECE. RESULTS: Of 11,730 patients, 778 were pT1-2, cN0 with <3 positive SLNs without ECE, and 331 (2.8 %) had ECE. Of these, 180 had <=2 mm and 151 had >2 mm of ECE. Patients with ECE were older (57 vs. 54 years; p = 0.001) and had larger (2.0 vs. 1.7 cm; p < 0.0001), multifocal (p = 0.006), hormone receptor-positive tumors (p = 0.0164) with lymphovascular invasion (p < 0.0001). Presence and extent of ECE were associated with greater axillary disease burden; 20 and 3 % of patients with and without ECE, respectively, had >=4 additional positive nodes at completion ALND (p < 0.0001), and 33 % of patients with >2 mm ECE had >=4 additional positive nodes at completion ALND, compared with 9 % in the <2 mm group (p < 0.0001). On multivariate analysis, >2 mm of ECE was the strongest predictor of >=4 positive nodes at completion ALND (odds ratio 14.2). CONCLUSIONS: Presence and extent of ECE were significantly correlated with nodal tumor burden at completion ALND, thus suggesting that >2 mm of ECE may be an indication for ALND or radiotherapy when applying Z0011 criteria to patients with metastases in <3 SLNs. ECE reporting should be standardized to facilitate future studies. PMID- 24777859 TI - iOD907, the first genome-scale metabolic model for the milk yeast Kluyveromyces lactis. AB - We describe here the first genome-scale metabolic model of Kluyveromyces lactis, iOD907. It is partially compartmentalized (four compartments), composed of 1867 reactions and 1476 metabolites. The iOD907 model performed well when comparing the positive growth of K. lactis to Biolog experiments and to an online catalogue of strains that provides information on carbon sources in which K. lactis is able to grow. Chemostat experiments were used to adjust non-growth-associated energy requirements, and the model proved accurate when predicting the biomass, oxygen and carbon dioxide yields. When compared to published experiments, in silico knockouts accurately predicted in vivo phenotypes. The iOD907 genome-scale metabolic model complies with the MIRIAM (minimum information required for the annotation of biochemical models) standards for the annotation of enzymes, transporters, metabolites and reactions. Moreover, it contains direct links to Kyoto encyclopedia of genes and genomes (KEGG; for enzymes, metabolites and reactions) and to the Transporters Classification Database (TCDB) for transporters, allowing easy comparisons to other models. Furthermore, this model is provided in the well-established systems biology markup language (SBML) format, which means that it can be used in most metabolic engineering platforms, such as OptFlux or Cobra. The model is able to predict the behavior of K. lactis under different environmental conditions and genetic perturbations. Furthermore, by performing simulations and optimizations, it can be important in the design of minimal media and will allow insights on the milk yeast's metabolism, as well as identifying metabolic engineering targets for improving the production of products of interest. PMID- 24777860 TI - Dementia and sensitivity to anesthetics. PMID- 24777867 TI - Measurement of stable changes of self-management skills after rehabilitation: a latent state-trait analysis of the Health Education Impact Questionnaire (heiQTM). AB - PURPOSE: To assess stable effects of self-management programs, measurement instruments should primarily capture the attributes of interest, for example, the self-management skills of the measured persons. However, measurements of psychological constructs are always influenced by both aspects of the situation (states) and aspects of the person (traits). This study tests whether the Health Education Impact Questionnaire (heiQTM), an instrument assessing a wide range of proximal outcomes of self-management programs, is primarily influenced by person factors instead of situational factors. Furthermore, measurement invariance over time, changes in traits and predictors of change for each heiQTM scale were examined. METHODS: Subjects were N = 580 patients with rheumatism, asthma, orthopedic conditions or inflammatory bowel disease, who filled out the heiQTM at the beginning, the end of and 3 months after a disease-specific inpatient rehabilitation program in Germany. Structural equation modeling techniques were used to estimate latent trait-change models and test for measurement invariance in each heiQTM scale. Coefficients of consistency, occasion specificity and reliability were computed. RESULTS: All scales showed scalar invariance over time. Reliability coefficients were high (0.80-0.94), and consistency coefficients (0.49-0.79) were always substantially higher than occasion specificity coefficients (0.14-0.38), indicating that the heiQTM scales primarily capture person factors. Trait-changes with small to medium effect sizes were shown in five scales and were affected by sex, age and diagnostic group. CONCLUSION: The heiQTM can be used to assess stable effects in important outcomes of self-management programs over time, e.g., changes in self-management skills or emotional well-being. PMID- 24777868 TI - Social constraints and quality of life among Chinese-speaking breast cancer survivors: a mediation model. AB - PURPOSE: Literature has revealed detrimental effects of unsupportive interpersonal interactions on adjustment to cancer. However, no studies have examined this effect and the underlying psychological pathways among Chinese speaking breast cancer survivors. The study investigated the relationship between social constraints and adjustment to cancer and the underlying psychological pathways among Chinese-speaking breast cancer survivors. METHODS: Chinese speaking breast cancer survivors (N = 120) completed a questionnaire package assessing social constraints, intrusive thoughts, affect, and quality of life. RESULTS: Results revealed a negative relationship between social constraints and quality of life. Such a relationship between social constraints and quality of life was mediated by negative affect and intrusive thoughts, while the association of intrusive thoughts and quality of life were completely mediated by positive and negative affect. CONCLUSION: Findings highlight the negative association between unsupportive interpersonal interactions and adjustment through cognitive and affective pathways among Chinese-speaking breast cancer survivors. PMID- 24777876 TI - Rapid automatic segmentation of the human cerebellum and its lobules (RASCAL)- implementation and application of the patch-based label-fusion technique with a template library to segment the human cerebellum. AB - Reliable and fast segmentation of the human cerebellum with its complex architecture of lobes and lobules has been a challenge for the past decades. Emerging knowledge of the functional integration of the cerebellum in various sensori-motor and cognitive-behavioral circuits demands new automatic segmentation techniques, with accuracies similar to manual segmentations, but applicable to large subject numbers in a reasonable time frame. This article presents the development and application of a novel pipeline for rapid automatic segmentation of the human cerebellum and its lobules (RASCAL) combining patch based label-fusion and a template library of manually labeled cerebella of 16 healthy controls from the International Consortium for Brain Mapping (ICBM) database. Leave-one-out experiments revealed a good agreement between manual and automatic segmentations (Dice kappa = 0.82). Intraclass correlation coefficients (ICC) were calculated to test reliability of segmented volumes and were highest (ICC > 0.9) for global measures (total and hemispherical grey and white matter) followed by larger lobules of the posterior lobe (ICC > 0.8). Further we applied the pipeline to all 152 young healthy controls of the ICBM database to look for hemispheric and gender differences. The results demonstrated larger native space volumes in men then women (mean (+/- SD) total cerebellar volume in women = 217 cm(3) (+/- 26), men = 259 cm(3) (+/- 29); P < 0.001). Significant gender-by hemisphere interaction was only found in stereotaxic space volumes for white matter core (men > women) and anterior lobe volume (women > men). This new method shows great potential for the precise and efficient analysis of the cerebellum in large patient cohorts. PMID- 24777877 TI - Drug safety testing paradigm, current progress and future challenges: an overview. AB - Early assessment of the toxicity potential of new molecules in pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into development phase. Due to the high attrition rate in the pharma industry in last few years, it has become imperative for the nonclinical toxicologist to focus on novel approaches which could be helpful for early screening of drug candidates. The need is that the toxicologists should change their classical approach to a more investigative approach. This review discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them earlier than ever before. This includes progress in the field of in vitro models, surrogate models, molecular toxicology, 'omics' technologies, translational safety biomarkers, stem-cell based assays and preclinical imaging. The traditional boundaries between teams focusing on efficacy/ safety and preclinical/ clinical aspects in the pharma industry are disappearing, and translational research-centric organizations with a focused vision of bringing drugs forward safely and rapidly are emerging. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers. PMID- 24777878 TI - Mode of action human relevance (species concordance) framework: Evolution of the Bradford Hill considerations and comparative analysis of weight of evidence. AB - The mode of action human relevance (MOA/HR) framework increases transparency in systematically considering data on MOA for end (adverse) effects and their relevance to humans. This framework continues to evolve as experience increases in its application. Though the MOA/HR framework is not designed to address the question of "how much information is enough" to support a hypothesized MOA in animals or its relevance to humans, its organizing construct has potential value in considering relative weight of evidence (WOE) among different cases and hypothesized MOA(s). This context is explored based on MOA analyses in published assessments to illustrate the relative extent of supporting data and their implications for dose-response analysis and involved comparisons for chemical assessments on trichloropropane, and carbon tetrachloride with several hypothesized MOA(s) for cancer. The WOE for each hypothesized MOA was summarized in narrative tables based on comparison and contrast of the extent and nature of the supporting database versus potentially inconsistent or missing information. The comparison was based on evolved Bradford Hill considerations rank ordered to reflect their relative contribution to WOE determinations of MOA taking into account increasing experience in their application internationally. This clarification of considerations for WOE determinations as a basis for comparative analysis is anticipated to contribute to increasing consistency in the application of MOA/HR analysis and potentially, transparency in separating science judgment from public policy considerations in regulatory risk assessment. PMID- 24777879 TI - Photo quiz. A man with newly diagnosed HIV/AIDS with unusual severe opportunistic infection and no AIDS-defining disease. PMID- 24777883 TI - Complete response after autologous stem cell transplant in multiple myeloma. AB - We evaluated long-term outcome of patients achieving complete response (CR) after autologous stem cell transplantation (ASCT) for multiple myeloma. Between April 1990 and June 2012 191 patients underwent ASCT. The median age was 53 years (range, 26-68 years), 135 were men. Pretransplant, patients received induction therapy with VAD (vincristine, doxorubicin, dexamethasone; n = 77), novel agents (n = 92), or alkylating agent-based, n = 22); 43% received more than one line of induction regimen. Response to transplant was defined as per EBMT criteria. The median follow-up for the entire group was 85 months (range, 6-232.5 months). Following transplant 109 (57.1%) patients achieved CR. Median progression-free survival (PFS) for patients with CR was higher compared to those with VGPR and PR, (107 vs. 18 vs. 18 months, P < 0.001). Number of lines of therapy pretransplant (one or two vs. more than two lines of therapy (P < 0.001), and absolute lymphocyte count of <= 3000/cmm were predictors of superior PFS. Median overall survival (OS) for patients with CR was higher, (204 months), compared to those with VGPR (71.5 months, P < 0.001) and PR (51.5 months, P < 0.001), respectively. On Cox regression analysis, patients who received one line of induction therapy pretransplant (hazard ratio, HR 2.154, P < 0.001) and those with absolute lymphocyte count of <= 3000/mm(3) (HR 0.132, P < 0.001) had superior PFS. For overall survival, induction treatment up to one line (HR 2.403, P < 0.004) and Hb > 7.1 G/dL at diagnosis (HR 4.756, P < 0.01) were associated with superior outcome. On landmark analysis at 12 months, PFS and OS continued to remain superior for patients attaining CR. Achievement of CR post transplant is associated with longer OS and PFS. Among complete responders, those who receive one line of induction therapy pretransplant have superior outcome. PMID- 24777884 TI - High serum trypsin levels and the -409 T/T genotype of PRSS1 gene are susceptible to neonatal sepsis. AB - Neonatal sepsis remains an important and common cause of morbidity and mortality among newborn infants, especially in developing countries. The aim of the present study was to determine whether serum trypsin levels and genotypes of cationic trypsinogen (PRSS1) gene could be served as markers for predicting neonatal sepsis. The serum trypsin levels and genotypes of PRSS1 were examined in both 50 infants with infection during neonatal period and 56 healthy neonates as controls. The infected infants were further subdivided into infants with sepsis group (n=18) and infected infants without sepsis (n=32). The genotype of PRSS1 was analyzed by direct sequencing, and the serum trypsin level was measured by immunoassay. It showed that the median value of serum trypsin was significantly higher in infected infants (31.90 ng/mL) than in controls (12.85 ng/mL; P=0.030). More importantly, sepsis subgroup (50.95 ng/mL) had significantly higher median serum trypsin than infected infants without sepsis subgroup (19.10 ng/mL) and controls (12.85 ng/mL) (P=0.015 and P=0.002, respectively). Additionally, the median serum trypsin levels were found significantly higher in infants who had T/T (37.90 ng/mL) genotype of PRSS1 compared with those who had C/T genotype (12.80 ng/mL; P=0.005). This study suggested that serum trypsin and rs10273639 C/T of PRSS1 were revealed to be novel markers for predicting neonatal sepsis. PMID- 24777885 TI - Contractions reverse stress softening in rat esophagus. AB - Strain/stress induced tissue softening is usually referred to irreversible softening. The aim of this study was to investigate whether stress softening in rat esophagus is reversible after potassium chloride (KCl) induced contraction. Three series of inflation-deflation loadings were carried out on esophageal specimens obtained from 20 Wistar rats. All specimens were subjected to the first two series in Ca(2+)-free Krebs solution(Krebs(-)) and then incubated in Ca(2+) containing Krebs solution (Krebs(+)) for 1 h. Ten specimens were distended to pressure 1.0 kPa and activated with KCl for 3 min. The other ten specimens, however, were distended to 1.0 kPa without KCl activation. Subsequently, after incubation in Krebs(-) for 1 h, all 20 specimens were subjected to the third series testing. The stored energy in the esophageal tissues (hysteresis loop area) and the esophageal wall stiffness were compared between two groups within the three series loadings. Results indicated that incubation in Krebs(+) cannot recover the stress softening induced energy and stiffness loss, but in contrast, these loss were recovered markedly (p < 0.05) after KCl activation. In conclusion, stress softening in rat esophagus is reversible after the activation of KCl-induced contractions. This mechanism could be related to regeneration of tissue properties in rat esophagus. PMID- 24777886 TI - Computational study of the dynamics of a bileaflet mechanical heart valve in the mitral position. AB - A computational study of the flow-structure interaction of a bileaflet mechanical heart valve in the mitral position is presented. Flow in a simple model of the left ventricle is simulated using an immersed boundary method, and the dynamics of the valve leaflets are solved in a fully-coupled manner with the flow. Simulations are conducted for two distinct valve orientations and multiple valve hinge locations, and the performance of the valve is compared in terms of metrics associated with leaflet motion, mitral regurgitation, and mechanical energy losses through the valve. Results indicate that a bileaflet mechanical heart valve with a more centrally located hinge, and implanted in the anatomical orientation provides the best overall performance. The fluid and leaflet dynamics, as well as the clinical implications underlying these findings are discussed. PMID- 24777887 TI - Supramolecular assembly of metal-ligand chromophores for sensing and phosphorescent OLED applications. AB - The exploration of phosphorescent materials based on transition metal-ligand chromophoric complexes represents an important area of research in molecular materials. The knowledge and fundamental understanding of their photophysical properties offer a possible fine-tuning of their electronic absorption and luminescence properties. The strong propensity of d(8) transition metal compounds to form non-covalent metal...metal interactions facilitates supramolecular assembly and the formation of supramolecular nanostructures with interesting photophysical properties. The introduction of supramolecular assembly with hierarchical complexity involving non-covalent interactions could lead to research dimensions of unlimited possibilities and opportunities. This article briefly summarizes the latest progress on the use of d(8) metal-ligand chromophores as chemosensors, as exemplified by alkynylplatinum(II) complexes with emphasis on supramolecular assembly involving non-covalent interactions, and the recent advances in the utilization of d(8) metal-ligand phosphors, as exemplified by alkynylgold(III) system, for the exploration and development of phosphorescent OLEDs. PMID- 24777891 TI - Highly active metastable ruthenium nanoparticles for hydrogen production through the catalytic hydrolysis of ammonia borane. AB - Late transition metal nanoparticles (NPs) with a favorably high surface area to volume ratio have garnered much interest for catalytic applications. Yet, these NPs are prone to aggregation in solution, which has been mitigated through attachment of surface ligands, additives or supports; unfortunately, protective ligands can severely reduce the effective surface area on the NPs available for catalyzing chemical transformations. The preparation of 'metastable' NPs can readily address these challenges. We report herein the first synthesis of monodisperse metastable ruthenium nanoparticles (RuNPs), having sub 5 nm size and an fcc structure, in aqueous media at room temperature, which can be stored for a period of at least 8 months. The RuNPs can subsequently be used for the catalytic, quantitative hydrolysis of ammonia-borane (AB) yielding hydrogen gas with 21.8 turnovers per min at 25 degrees C. The high surface area available for hydrolysis of AB on the metastable RuNPs translated to an Ea of 27.5 kJ mol(-1) , which is notably lower than previously reported values for RuNP based catalysts. PMID- 24777892 TI - Editorial: scientific excellence on the island of Formosa. PMID- 24777895 TI - Unique features and risk factors of Helicobacter pylori infection at the main children's intermediate school in Rabigh, Saudi Arabia. AB - BACKGROUND: This study was conducted to determine characters and risk factors of Helicobacter pylori infection and its relationship with recurrent abdominal pain and other gastrointestinal symptoms at the main children's intermediate school in Rabigh, Saudi Arabia. METHODS: A cross-sectional study was conducted at a boys' intermediate school. A questionnaire for the gastrointestinal (GI) symptoms and relevant personal and socioeconomic risk factors related to H. pylori infection was distributed followed by H. pylori IgG antibody assay and 14C urea breath test to detect active infection. RESULTS: H. pylori was diagnosed by positive urea breath test in 51.5 % of students. H. pylori infection was symptomatic with at least one upper GI symptom in 89.7 % of infected students which was higher than symptomatic cases reported in any other study. H. pylori-infected students had significantly more association with the presence of any upper GI symptom (p < 0.001), recurrent abdominal pain (p < 0.001), anorexia (p < 0.001), nausea (p < 0.026), family history of peptic disease (p < 0.001), drinking desalinated municipal water (p < 0.001), lower income (p = 0.02), and eating outside home (p = 0.003) than uninfected students. Logistic regression analysis showed that the most significant predictors of H. pylori infection were presence of any upper GI symptom (OR 5.3, 95 % CI 2.32-15.71), family history of peptic disease (OR 2.2, 95 % CI 1.11-3.9), and drinking desalinated municipal water (OR 2.1, 95 % CI 1.09 3.2). CONCLUSIONS: This study presented unique features and risk factors of H. pylori infection in 12-15-year-old Saudi boys in Rabigh, and mainly supported the role of H. pylori in causing recurrent abdominal pain. PMID- 24777896 TI - Effect of tumor cells and tumor microenvironment on NK-cell function. AB - The ability of tumors to manage an immune-mediated attack has been recently included in the "next generation" of cancer hallmarks. In solid tumors, the microenvironment that is generated during the first steps of tumor development has a pivotal role in immune regulation. An intricate net of cross-interactions occurring between tumor components, stromal cells, and resident or recruited immune cells skews the possible acute inflammatory response toward an aberrant ineffective chronic inflammatory status that favors the evasion from the host's defenses. Natural killer (NK) cells have powerful cytotoxic activity, but their activity may be eluded by the tumor microenvironment. Immunosubversion, immunoediting or immunoselection of poorly immunogenic tumor cells and interference with tumor infiltration play a major role in evading NK-cell responses to tumors. Tumor cells, tumor-associated fibroblasts and tumor-induced aberrant immune cells (i.e. tolerogenic or suppressive macrophages, dendritic cells (DCs) and T cells) can interfere with NK-cell activation pathways or the complex receptor array that regulate NK-cell activation and antitumor activity. Thus, the definition of tumor microenvironment-related immunosuppressive factors, along with the identification of new classes of tissue-residing NK-like innate lymphoid cells, represent key issues to design effective NK-cell-based therapies of solid tumors. PMID- 24777897 TI - IMP-45-producing multidrug-resistant Pseudomonas aeruginosa of canine origin. PMID- 24777898 TI - Pitfalls in evidence assessment: the case of chlorhexidine and alcohol in skin antisepsis. AB - Chlorhexidine has attracted increasing attention for its role in skin antisepsis in recent years. It was tested in several prominent clinical trials and subsequently recommended in important guidelines for blood culture collection, vascular catheter insertion and surgical skin preparation. We noticed and subsequently reported a widespread misinterpretation of evidence surrounding chlorhexidine and its role in skin antisepsis. Multiple clinical trial reports and systematic reviews that had assessed the clinical efficacy of chlorhexidine/alcohol combinations for skin antisepsis had attributed efficacy solely to the chlorhexidine component. This misinterpretation was carried over into the tertiary literature, including evidence-based guidelines. Here we discuss some of the scientific, ethical, patient safety and infection control implications of this misinterpretation, as well as broader implications for evidence-based medicine. PMID- 24777899 TI - Predicting the parasite killing effect of artemisinin combination therapy in a murine malaria model. AB - OBJECTIVES: To develop a mechanism-based model that describes the time course of the malaria parasite in infected mice receiving a combination therapy regimen of dihydroartemisinin and piperaquine. METHODS: Total parasite density-time data from Swiss mice inoculated with Plasmodium berghei were used for the development of population models in S-ADAPT. The mice were administered a single intraperitoneal dose of 30 mg/kg dihydroartemisinin, 10 mg/kg piperaquine phosphate or a combination of both antimalarials at 64 h post-inoculation. In a separate study, mice received multiple dihydroartemisinin doses (5 * 10 mg/kg or 30 mg/kg dihydroartemisinin followed by two 10 mg/kg doses). Parasite recrudescence after treatment was defined using a model that incorporated each erythrocytic stage of the P. berghei life cycle. RESULTS: The disposition of dihydroartemisinin and piperaquine was described by a one-compartment and two compartment model, respectively. The estimated clearance was 1.95 L/h for dihydroartemisinin and 0.109 L/h for piperaquine. A turnover model described the parasite killing curve after single-agent dosing, with an estimated mean IC50 of 0.747 MUg/L for dihydroartemisinin and 16.8 MUg/L for piperaquine. In addition, the rate of parasite killing by dihydroartemisinin was almost 50-fold faster than for piperaquine. Parameters from the monotherapy models adequately described the parasite density-time curve following dihydroartemisinin/piperaquine combination therapy or multiple-dose regimens of dihydroartemisinin. CONCLUSIONS: This study has developed mechanistic models that describe the parasite-time curve after single, multiple or combination dosing of antimalarials to mice. These structural models have potential application for pre-clinical investigations to design and refine artemisinin-based combination therapy dosage regimens. PMID- 24777900 TI - Evaluation of the novel combination of daptomycin plus ceftriaxone against vancomycin-resistant enterococci in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation model. AB - OBJECTIVES: Daptomycin has demonstrated synergy with beta-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to daptomycin. We investigated daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model. METHODS: Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess beta-lactam-induced changes in cell surface charge. RESULTS: For 8019 and 6981, daptomycin 6 mg/kg with ceftriaxone and daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than daptomycin 6 mg/kg alone from 48 to 96 h (P <= 0.005). The addition of ceftriaxone significantly enhanced activity of daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding. CONCLUSIONS: The combination of daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of daptomycin and innate immunity killing of VRE by ceftriaxone and other beta-lactams. PMID- 24777901 TI - Impact of implementation of a novel antimicrobial stewardship tool on antibiotic use in nursing homes: a prospective cluster randomized control pilot study. AB - OBJECTIVES: To evaluate the impact of 'Resident Antimicrobial Management Plan' (RAMP), a novel antimicrobial stewardship tool on systemic antibiotic use for treatment of infection in nursing homes (NHs). METHODS: A pilot cluster randomized control study was conducted in 30 NHs in London. Pre-intervention, we collected point prevalence data on antimicrobial use on three occasions and total antimicrobial consumption for a 12 week period. Post-intervention data were collected in the same manner and included assessment of compliance with RAMP in the intervention group (IG). RESULTS: The number of residents included was 1628 pre-intervention [825 IG/803 control group (CG)] and 1610 post-intervention (838 IG/772 CG). The corresponding pre- and post-intervention point prevalence of systemic antibiotic prescribing for treatment of infection was 6.46% and 6.52% in the IG [estimated prevalence ratio: 1.01 (95% CI: 0.81-1.25), P = 0.94] compared with 5.27% and 5.83%, respectively, in the CG [estimated prevalence ratio: 1.11 (95% CI: 0.87-1.41), P = 0.4]. Total antibiotic consumption was 69.78 defined daily doses/1000 residents/day (DRD) pre-intervention and 66.53 DRD post intervention in the IG compared with 49.68 and 51.92 DRD, respectively, in the CG. There was a significant decrease of 4.9% (3.25 DRD) in the IG (95% CI: 1.0% 8.6%) (P = 0.02) compared with a significant increase of 5.1% (2.24 DRD) in the CG (95% CI: 0.2%-10.2%) (P = 0.04). Main indications for antibiotics were lower respiratory tract infections (34.1%), urinary tract infections (28.5%) and skin/soft tissue infections (25.1%). CONCLUSIONS: This pilot study demonstrated that use of RAMP was associated with a statistically significant decrease in total antibiotic consumption and has the potential to be an important antimicrobial stewardship tool for NHs. PMID- 24777902 TI - Geographical clustering of mecC-positive Staphylococcus aureus from bovine mastitis in France. PMID- 24777903 TI - CTX-M-137, a hybrid of CTX-M-14-like and CTX-M-15-like beta-lactamases identified in an Escherichia coli clinical isolate. AB - OBJECTIVES: To characterize a novel CTX-M chimera, CTX-M-137, from Escherichia coli clinical isolates in China. METHODS: Isolates were collected from five hospitals between 22 February 2009 and 20 December 2011. Resistance genes were investigated by PCR. blaCTX-M-137 was cloned and purified for kinetic measurements. Conjugation experiments, S1-PFGE and Southern blotting were performed to study the plasmid harbouring blaCTX-M-137. The genetic environment of blaCTX-M-137 was determined by genomic cloning and sequencing. RESULTS: A total of 247 cephalosporin-resistant E. coli were identified. blaCTX-M group genes were the most prevalent extended-spectrum beta-lactamase (ESBL) genes, with 71 isolates harbouring blaCTX-M-1 group genes and 137 isolates harbouring blaCTX M-9 group genes. A novel chimera of CTX-M-14-like and CTX-M-15-like ESBLs, designated CTX-M-137, was identified from a 60-year-old man with a urinary tract infection. The N-terminus of CTX-M-137 matched CTX-M-14 and the C-terminus matched CTX-M-15. CTX-M-137 conferred resistance to ceftazidime, cefotaxime and aztreonam. Purified CTX-M-137 showed good hydrolytic activity against ceftazidime and cefotaxime, and was inhibited by clavulanic acid. The blaCTX-M-137 was carried on an ~83 kb IncI1 plasmid. blaCTX-M-137 was carried on a complete transposition unit ISEcp1-blaCTX-M-137-Deltaorf477 inserted into yagA, which is part of the IncI1 plasmid backbone. CONCLUSIONS: We identified a novel CTX-M chimera, CTX-M-137, with a CTX-M-14-like N-terminus and a CTX-M-15-like C terminus. Our findings suggest an ongoing diversification of CTX-M-type ESBLs through recombination events. PMID- 24777904 TI - Characterization of the embB gene in Mycobacterium tuberculosis isolates from Barcelona and rapid detection of main mutations related to ethambutol resistance using a low-density DNA array-authors' response. PMID- 24777905 TI - Comment on: S-nitrosoglutathione (GSNO) is cytotoxic to intracellular amastigotes and promotes healing of topically treated Leishmania major or Leishmania braziliensis skin lesions. PMID- 24777906 TI - Analysis of Staphylococcus aureus clinical isolates with reduced susceptibility to ceftaroline: an epidemiological and structural perspective. AB - OBJECTIVES: Ceftaroline, approved in Europe in 2012, has activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC90 values of 1-2 mg/L depending on geographical location. During a global 2010 surveillance programme, conducted prior to the European launch, 4 S. aureus isolates, out of 8037 tested, possessing ceftaroline MIC values of >2 mg/L were identified. The objective of this study was to characterize these four isolates to elucidate the mechanism of ceftaroline resistance. METHODS: MIC determinations were performed using broth microdilution and whole genome sequencing was performed to enable sequence-based analyses. RESULTS: The only changes in proteins known to be required for full expression of methicillin resistance that correlated with the ceftaroline MIC were in penicillin-binding protein 2a (PBP2a). Isolates with a ceftaroline MIC of 2 mg/L had a Glu239Lys mutation in the non-penicillin-binding domain whereas the four isolates with ceftaroline MIC values of 8 mg/L carried an additional Glu447Lys mutation in the penicillin-binding domain. The impact of these mutations was analysed using the known X-ray structure of S. aureus PBP2a and a model for ceftaroline resistance proposed. Analysis of the core genomes showed that the isolates with reduced susceptibility to ceftaroline were epidemiologically related. CONCLUSIONS: Mutations in PBP2a can affect the activity of ceftaroline against MRSA. Although a rare event, based on surveillance studies, it appears a first-step change in the non-penicillin binding domain together with a second-step in the penicillin-binding domain may result in elevation of the ceftaroline MIC to >2 mg/L. PMID- 24777907 TI - Treatment failure with 2 g of azithromycin (extended-release formulation) in gonorrhoea in Japan caused by the international multidrug-resistant ST1407 strain of Neisseria gonorrhoeae. AB - OBJECTIVES: Antimicrobial resistance in Neisseria gonorrhoeae is a major public health concern globally. We report the first verified treatment failure of gonorrhoea with 2 g of azithromycin (extended-release formulation) in Japan and characteristics of the corresponding N. gonorrhoeae isolates. METHODS: Pre- and post-treatment isolates (n = 4) were investigated by Etest for antimicrobial susceptibility. The isolates were examined for molecular epidemiology by multilocus sequence typing (MLST), N. gonorrhoeae multi-antigen sequence typing (NG-MAST) and multiple-locus variable-number tandem repeat analysis (MLVA), and for the presence of azithromycin resistance determinants (23S rRNA gene mutations, erm genes and mtrR mutations). RESULTS: All isolates were resistant to azithromycin (MIC 4 mg/L) and ciprofloxacin, but remained susceptible to cefixime, ceftriaxone and spectinomycin. All isolates were assigned to MLST ST1901 and NG-MAST ST1407 and three of four isolates possessed MLVA profile 8-3 21-16-1. All isolates contained the previously described C2599T mutation (N. gonorrhoeae numbering) in all four 23S rRNA alleles and the previously described single-nucleotide (A) deletion in the mtrR promoter region. CONCLUSIONS: This verified treatment failure occurred in a patient infected with an MLST ST1901/NG MAST ST1407 strain of N. gonorrhoeae. While this international strain commonly shows resistance or decreased susceptibility to multiple antimicrobials, including extended-spectrum cephalosporins, the strain reported here remained fully susceptible to the latter antimicrobials. Hence, two subtypes of azithromycin-resistant gonococcal MLST ST1901/NG-MAST ST1407 appear to have evolved and to be circulating in Japan. Azithromycin should not be recommended as a single antimicrobial for first-line empirical treatment of gonorrhoea. PMID- 24777908 TI - A zanamivir dimer with prophylactic and enhanced therapeutic activity against influenza viruses. AB - OBJECTIVES: Emerging drug resistance to antiviral therapies is an increasing challenge for the treatment of influenza virus infections. One new antiviral compound, BTA938, a dimeric derivative of the viral neuraminidase inhibitor zanamivir, contains a 14-carbon linker bridging two zanamivir moieties. In these studies, we evaluated antiviral efficacy in cell cultures infected with influenza virus and in mouse models of lethal influenza using H1N1pdm09, H3N2 and oseltamivir-resistant (H275Y) viruses. METHODS: In vitro activity was evaluated against 22 strains of influenza virus. Additionally, in vivo studies compared the efficacy of BTA938 or zanamivir after intranasal treatment. We also tested the hypothesis of a dual mode of action for BTA938 using scanning electron microscopy (SEM). RESULTS: BTA938 inhibited the viruses at nanomolar concentrations in vitro with a median 50% effective concentration value of 0.5 nM. In mouse models, the dimer provided ~10-fold greater protection than zanamivir. The data also showed that a single low dose (3 mg/kg) protected 100% of mice from an otherwise lethal oseltamivir-resistant (H275Y) influenza virus infection. Remarkably, a single prophylactic treatment (10 mg/kg) administered 7 days before the challenge protected 70% of mice and when administered 1 or 3 days before the challenge it protected 90% of mice. Additionally, SEM provides evidence that the increased antiviral potency may be mediated by an enhanced aggregation of virus on the cell surface. CONCLUSIONS: In vitro and in vivo experiments showed the high antiviral activity of BTA938 for the treatment of influenza virus infections. Moreover, we demonstrated that a single dose of BTA938 is sufficient for prophylactic and therapeutic protection in mouse models. PMID- 24777911 TI - Homogeneous oxidation of water by iron complexes with macrocyclic ligands. AB - The activity of eleven separated iron complexes and nine in situ-generated iron complexes towards catalytic water oxidation have been examined in aqueous solutions with Ce(NH4)2(NO3)6 as the oxidant. Two iron complexes bearing tridentate and tetradentate macrocyclic ligands were found to be novel water oxidation catalysts. The one with tetradentate ligand exhibited a promising activity with a turnover number of 65 for oxygen evolution. PMID- 24777909 TI - GLP-1R activation for the treatment of stroke: updating and future perspectives. AB - Stroke is the leading cause of adult disability in Westernized societies with increased incidence along ageing and it represents a major health and economical threat. Inactive lifestyle, smoking, hypertension, atherosclerosis, obesity and diabetes all dramatically increase the risk of stroke. While preventive strategies based on lifestyle changes and risk factor management can delay or decrease the likelihood of having a stroke, post stroke pharmacological strategies aimed at minimizing stroke-induced brain damage are highly needed. Unfortunately, several candidate drugs that have shown significant preclinical neuroprotective efficacy, have failed in clinical trials and no treatment for stroke based on neuroprotection is available today. Glucagon-like peptide 1 (GLP 1) is a peptide originating in the enteroendocrine L-cells of the intestine and secreted upon nutrient ingestion. The activation of the GLP-1R by GLP-1 enhances glucose-dependent insulin secretion, suppresses glucagon secretion and exerts multifarious extrapancreatic effects. Stable GLP-1 analogues and inhibitors of the proteolytic enzyme dipeptidyl peptidase 4 (DPP-4) (which counteract endogenous GLP-1 degradation) have been developed clinically for the treatment of type 2 diabetes. Besides their antidiabetic properties, experimental evidence has shown neurotrophic and neuroprotective effects of GLP-1R agonists and DPP-4 inhibitors in animal models of neurological disorders. Herein, we review recent experimental data on the neuroprotective effects mediated by GLP-1R activation in stroke. Due to the good safety profile of the drugs targeting the GLP-1R, we also discuss the high potential of GLP-1R stimulation in view of developing a safe clinical treatment against stroke based on neuroprotection in both diabetic and non-diabetic patients. PMID- 24777910 TI - Charge density influences C1 domain ligand affinity and membrane interactions. AB - The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between the ligand, C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site, per se, to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we showed that increasing charge along the rim of the binding cleft of the protein kinase C delta C1 b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands and thus contributes an element to the structure-activity relations for C1 domain ligands. Coexpressing pairs of C1-containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain. PMID- 24777912 TI - Mechanically gated electrical switches by creasing of patterned metal/elastomer bilayer films. PMID- 24777913 TI - Basophil activation through ASGM1 stimulation triggers PAF release and anaphylaxis-like shock in mice. AB - Basophils have been shown to contribute to anaphylaxis through either an IgE FcepsilonRI-dependent pathway or an IgG-FcgammaR pathway. However, it remains largely unclear whether basophils can be activated to promote anaphylaxis via a non-FcR pathway as well. The glycolipid receptor ASGM1 (Asialoganglioside gangliotetraosylceramide), which has an exposed GalNAcbeta1-4Gal moiety and serves as a receptor for pathogen associated molecular patterns such as flagellin, was recently found to be expressed on basophils. Here, we demonstrate that stimulation of basophils with anti-ASGM1 antibodies promotes platelet activating factor (PAF) secretion in vitro and in vivo. Moreover, we found that ASGM1 stimulation triggers basophil- and PAF-dependent anaphylactic shock in pertussis toxin (PTX)-pretreated mice. Thus, ASGM1 has a crucial role in basophil activation and basophil-mediated anaphylaxis-like shock in mice, especially when the vascular permeability is increased by PTX treatment. Our findings describe a novel anaphylaxis-associated pathway that is antigen-, antibody-, and FcR independent. PMID- 24777914 TI - Diesel exhaust particulates affect cell signaling, mucin profiles, and apoptosis in trachea explants of Balb/C mice. AB - Particulate matter from diesel exhaust (DEP) has toxic properties and can activate intracellular signaling pathways and induce metabolic changes. This study was conducted to evaluate the activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) and to analyze the mucin profile (acid (AB(+) ), neutral (PAS(+) ), or mixed (AB/PAS(+) ) mucus) and vacuolization (V) of tracheal explants after treatment with 50 or 100 MUg/mL DEP for 30 or 60 min. Western blot analyses showed small increases in ERK1/2 and JNK phosphorylation after 30 min of 100 MUg/mL DEP treatment compared with the control. An increase in JNK phosphorylation was observed after 60 min of treatment with 50 MUg/mL DEP compared with the control. We did not observe any change in the level of ERK1/2 phosphorylation after treatment with 50 MUg/mL DEP. Other groups of tracheas were subjected to histological sectioning and stained with periodic acid-Schiff (PAS) reagent and Alcian Blue (AB). The stained tissue sections were then subjected to morphometric analysis. The results obtained were compared using ANOVA. Treatment with 50 MUg/mL DEP for 30 min or 60 min showed a significant increase (p < 0.001) in the amount of acid mucus, a reduction in neutral mucus, a significant reduction in mixed mucus, and greater vacuolization. Our results suggest that compounds found in DEPs are able to activate acid mucus production and enhance vacuolization and cell signaling pathways, which can lead to airway diseases. PMID- 24777916 TI - [Guidelines: general principles and clinical application in nephrology]. AB - Clinical practice guidelines (GL) are multiplying and spreading throughout the scientific world. Nephrology is no exception and GL are more often recalled in the daily activity. Therefore, it can be useful to propose an excursus on the issue, to report the most important principles on the base of GL and moreover, to remember that GL are the synthesis between the scientific evidences published in literature and the critical analysis performed by an international committee of experts. Not all GL have the same clinical value. As a matter of fact, GL have a different strength of recommendation and grading according to the clinical evidences published. The number and methodological accuracy of the available studies on a specific subject are crucial to define the quality, the grading and the strength of GL. GL must also be shared with a wide number of specialists and other interested people such as patient organizations as well as health political institutions. Although the knowledge of GL is widespread, their practical use is still limited. The spreading of the knowledge regarding how GL are arranged, their appropriate reading about procedures and/or treatments to be done or not, it will convert GL into a reliable tool for daily clinical practice. Therefore it is not a confused and incomprehensible set of rules imposed by some scientific organizations. PMID- 24777917 TI - [Chronic uremia and palliative care]. AB - Nowadays the choice to start with a renal replacement therapy (or its withdrawal once begun) is a critical issue leading to review the paradigm of constantly treating terminal uremia by means of dialysis technologies, without caring for effective prognosis nor for patients preferences, in a more affordable physician patient relationship. Furthermore dialysis patients mean age is increasing and such population bears the burden of comorbidities that seriously affect survival and quality of life. In any case, dialysis withdrawing does not mean neglecting the patient: the start, or continuation of a very low protein diet program may represent a reasonable alternative, not only for uremic symptoms control but also providing a slowing of disease progression (at least postponing further the start of renal replacement therapy). Basically, in our opinion, the decision to start dialysis in an eligible patient, mainly in the elderly or frails, it should be driven by an adequate balance among all the factors. These factors play a role not only concerning survival, but also in life quality issues and patients preferences. Thus, we argue that ethical issues must be taken into account as well as compelling clinical factors which usually nephrologists refer to. To pursue this goal, it could be useful to set up specific educational pathways addressed to physicians, nurses and technicians of renal units. It also could be instrumental in developing new strategies to manage end stage renal failure, considering not only hospital facilities,but also nursing and patients homes. Incoming guidelines could help nephrologists in improving their behaviors to face these new issues. PMID- 24777915 TI - Brain tissue properties differentiate between motor and limbic basal ganglia circuits. AB - Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcome. PMID- 24777918 TI - [Nutritional support in acute kidney injury]. AB - Optimal nutritional requirements and nutrient intake composition for patients with acute kidney injury is still a partially unresolved issue. Targeting nutritional support to the actual protein and energy needs improves the clinical outcome of critically ill patients. So far, very few data are currently available on this topic in acute kidney injury. In this specific clinical condition, the risk for under- and overfeeding may be increased by factors interfering on nutrient need estimation, such as rapidly changing body weight due to fluid balance variations, nutrient losses and hidden calorie sources from renal replacement therapy. Moreover, since acute kidney injury is now considered a kidney-centered inflammatory syndrome, the renoprotective role of specific pharmaconutrients with anti-inflammatory properties remains to be fully defined. This review is aimed at discussing recently published results concerning quantitative and qualitative aspects of the nutritional approach to acute kidney injury in critically ill patients. PMID- 24777919 TI - [Intensive weight-loss in dialysis: a personalized approach]. AB - Obesity is increasingly encountered in dialysis patients, who have difficulty to lose weight. Several Transplant Centres require BMI <30-35 Kg/m2 at waiting-list. Thus, losing weight becomes a must for young obese patients, however the best policy to obtain it (if any) is not defined. The aim of the present case report is to suggest that tailored dialysis and intensive diets could be a successful combination, that should be tested on a larger scale. A 56-year-old obese male patient (BMI 37.7 kg/m2) on daily home hemodialysis since 10 months (ESRD due to focal segmental glomerulosclerosis) started a coach-assisted qualitative ad libitum diet. The diet, alternating 8 weeks of rapid weight loss and maintenance phases, was based on a combinations of different foods, chosen on the account of glycaemic index and biochemical properties. It was salt free and olive oil was permitted in liberal quantities. Dialysis duration was increased to allow weight loss, and dialysate Na was incremented to permit a strict low sodium diet. Over a period of 21 months, the patient attained a -18.5 Kg weight loss (50% overweight loss; BMI -6.3 Kg/m2), reaching the goal to be included in a kidney transplant waiting list. Main metabolic data remained stable (pre diet and end of the diet period: albumin 3.5-3.8 g/dL; HCO3 26.1-24.8 mmol/L discontinuing citrate) or improved (haemoglobin 11.4-12.1 g/dL, halving EPO dose; calcium 2.3-2.5 mmol/L; phosphate 1.5-1.5 mmol/L; PTHi 1718-251 pg/mL, reducing chelation). CONCLUSION: Daily dialysis may allow enrolling obese hemodialysis patients in intensive weight loss programs, under strict clinical control. PMID- 24777920 TI - [Healthcare marketing elements]. AB - Marketing puts its foundation on a few key concepts: need-demand, product service, satisfaction, exchange, market, or business structure manufacturing / supply. The combination of these elements allows you to build an effective marketing strategy. Crucial in this respect is to remember the Porter matrix, which shows that for a correct analysis of the relevant market is necessary to refer to the "five forces at play", ie: customers, competitors, new entrants and substitutes threat. Another key lever for proper marketing oriented approach is the continuous and constant monitoring of the application, anticipating their dissatisfactions. PMID- 24777921 TI - [The future of the European nephrology belongs to the young: the Young Nephrologists' Platform]. AB - Young people are the future of research, especially in nephrology. The prevalence of young nephrologists within the main scientific European societies varies from the 12% to 34% and the 20% of the ERA-EDTA members are less than 40 years old in 2013. Recently, the ERA-EDTA has launched a new platform, the Young Nephrologists Platform (YNP), which the aim is to become the first modern network of young nephrologists from Europe and beyond. YNP aims at promoting the aggregation of young people through modern communication channels such as social networks, blogs and through the construction of a database collecting information on attitudes and personal experiences of each young nephrologist. A mentorship program, focused and young-oriented clinical courses on hot topics and the direct involvement of young nephrologists in working groups and scientific studies are some of the other interesting initiatives driven by YNP. The future of nephrology belongs to the young and YNP could represent a good springboard for the professional growth of young nephrologists. PMID- 24777922 TI - [Uremic encephalopathy in regular dialysis treatment: uremic stroke?]. AB - This case report a 59 years-old male in regular dialysis treatment with neurologic emergency characterized by neurologic signs as deep sopor the cause of which was uremic encephalopathy. At presentation, laboratory investigations revealed creatinine 12,75 mg/dl, BUN 174 mg/% and hyperkalemia 7,5 mq/L. The most common abnormal test results were EEG and ECG. CT brain showed no evidence of hemorrhagic areas or hematoma subdural. The patient was treated with hemodialysis and after the first hour of hemodialysis, laboratory control revealed hypokaliemia with metabolic acidosis due to arteiovenous fistula recirculation. After placement of jugular venous hemodialysis catheter and intensive treatment, the patient showed gradual improvement of uremic stroke due to arteriovenous fistula recirculation for high grade venous stenoses. Arteriovenous fistula dysfunction remains a major contributor to the morbidity and mortality of hemodialysis patients. The failure of a newly created AVF to mature and to develop stenosis in an estabilished AVF are two common clinical predicaments. The goal is to identify a dysfunctional AVF early enough to intervene in a timely manner, either to assist the maturation process or to prevent thrombosis. Most clinical features of neurologic complications in uremics are nonspecific and do not reliable, but it is important to identify specific causes such as vascular access recirculation for adequate treatment and regression of uremic stroke. PMID- 24777923 TI - [The contribution of dialysis and laboratoristic methods for the control of phosphates]. AB - Prevention and correction of hyperphosphatemia is the first main goal of CKD-MBD management. Therefore, special attention is required to prevent a positive phosphate balance. In addition to a careful use of phosphate binders and dietary, phosphate control is needed to optimize the control of phosphate balance. In well nourished patients is necessary to provide an optimal dialysis removal schedule. A solution could be the increase of the number of dialysis sessions per week and to carry out longer dialysis session strategies. Nevertheless, many patients have a high phosphate (P) intake linked to the high dietary protein requirement of dialysis patients, hence the use of intestinal P binders is mandatory to reduce P net intestinal absorption. Unfortunately the phosphate molecule must be considered as a medium molecular toxin. Nowadays it remains difficult to remove with modern dialysis strategies and ones clearance is still dependent on dialysis time. The best solutions are: hemodiafiltration with high-volume reinfusion, daily dialysis, long dialysis and modern peritoneal dialysis. Today, this scheduled strategies are difficult because of logistic and cost problems. However the milestone will be an adequate nutrition surveillance, especially with nursing collaboration toward dialysis treatments. This strategy should start in outpatient pre-dialysis ambulatory. PMID- 24777924 TI - [A brief update on FGF23 for the clinical nephrologist]. AB - Fibroblast growth factor-23 (FGF23) is a hormone that controls homeostasis of calcium and phosphate metabolism in health and disease. Unlike most other hormones, FGF23 rises exponentially with declining kidney function, reaching extreme elevations in many end-stage renal disease patients. Clinical and experimental data further suggest that FGF23 is a very early biomarker of kidney injury, and its predictive value of adverse clinical outcomes has been confirmed across the entire spectrum of chronic kidney disease, including pre-dialysis and dialysis populations as well as renal transplant recipients. The questions if, how and when FGF23 will impact future clinical practice in nephrology remain open. Several putative trajectories have been outlined, including the use of FGF23 as a biomarker for selection of treatment, enrichment strategies in clinical trials, but also direct blockade of FGF23 signaling as a treatment target on its own. In this condensed review, we provide an update on FGF23 and briefly discuss its current and potential future role in chronic kidney disease. PMID- 24777925 TI - [Nephrological paradox]. AB - Patients that are followed by nephrologists from the beginning of the illness, they show a deceleration in the progression of the Chronic Kidney Disease towards dialysis and a better quality of life (less osteodystrophy, anaemia and fluids overload, better pressure management). However, in 2013 it still exists a great lack of knowledge about the professional figure of nephrologist. Residents of Nephrological School of Catania decided to conduct a survey to evaluate common knowledge of renal diseases and their treatments. The survey was conducted in two cities of Sicily. The results show that people are generally uninformed and disoriented about renal illness and their risks. PMID- 24777926 TI - [The effects of continuous renal replacement therapy (CRRT) and intermittent haemodialysis (IHD) in the treatment of dabigatran overdose. Case report]. AB - A 85-year-old man, with CKD (e-GFR 35 mL/min), had been given Dabigatran (a direct thrombin inhibitor) at 110 mg daily dose because of atrial fibrillation. Due to intercurrent diarrhea and dehydration, renal function worsened (e-GFR 11 mL/min) and Dabigatran excretion decreased, thereby inducing drug overload. In this case, Dabigatran must be removed by dialysis, but the most appropriate schedule is still undefined. The effects of both continuous haemodiafiltration (CVVHDF) and intermittent haemodialysis (IHD) on plasma Dabigatran (Echarin Chromogenic Assay) were reported. Dialysis clearance of Dabigatran was reported as ratio to urea clearance (Dab/Urea(Cl)). Coagulation was assessed by both DOA aPTTratio and Thrombin Time-ratio (TTratio). Dabigatran was elevated at 597 ng/mL predialysis (bleeding threshold being 30 ng/mL), and decreased to 96 ng/mL (-84%) after 20 hours of CVVHDF (Urea(Cl) = 67 mL/min). Dab/Urea(Cl) was 0.49. Three hours after dialysis, Dabigatran rebounded to 208 ng/mL. On IHD (Urea(Cl)=238 mL/min), predialysis Dabigatran was 52 ng/mL and decreased to 8 ng/mL (-85%) after 3.5 hours of treatment. Dab/Urea(Cl) was 0.47. Fourteen hours later, Dabigatran rebounded at 19 ng/mL. There was a positive correlation between Dabigatran and TTratio (r = 0.92; p<0.0001), whereas DOA-aPTT did not increase above 2.5 times the reference values, even in face of the highest values of Dabigatran. Therefore, TTratio is more reliable than DOA-aPTT in detecting Dabigatran overdose. Post-dialysis rebound of Dabigatran occurred also with CVVHDF, thereby suggesting that accurate monitoring of both Dabigatran levels and bleeding risk are mandatory, also after long-lasting dialysis sessions. PMID- 24777927 TI - [Foam in urine: from Hippocrates to the Medical School of Salerno]. AB - The formation of persistent little bubbles in urine, similar to those of beer, was noticed since ancient times by the first scholars of uroscopy. The diagnostic interest, rare and uncertain in Hippocrates, has increased over time. The Hippocratic school limited itself to observe the sign without interpreting the pathophysiology and they did not compare it with other clinical signs. Hippocratic texts only expressed an opinion on the severity and prognosis of the pathology which had produced it. Galen does not differ much from the Hippocratic school, however he tries to interpret the cause of the formation of bubbles in urine. Certainly, because of being unfamiliar to the laws of fluids and to the surperficial tension of liquids, he believes that the air contained in the bubbles of the foam in the urine comes from inside the organism. However, he realizes that the foam in urine is formed only when the urine is denser (more viscous).The Byzantine uroscopy, with Theophilus Protospatharius and Stephen of Athens considers the presence of foam quite important. In fact, they state that the bubbles appear in the urine when there is a severe failure of the organism. It is a sign of the attempt of the body to eliminate the bad humours produced in the different zones where digestion takes place. Several authors from the School of Salerno express different opinions on the production of foam in urine. Cofone affirms it derives from the putrefied blood in dense urine and he also uses this sign for diagnostic and prognostic results. Mattheus Archiepiscopus confirms Galens belief that the foam derives from wind bubbles produced in the stomach. The "De Urinis" of Maestro Mauro is strongly influenced by the writings of Constantine the African, who reports the experience of Isaac. The "humani corporis regiones" and the "regiones urine" are described and therefore Mauro tries to localize in which region of the body the bad humours were produced. In particular, the chapter on "De ycteritia" is an exact description of the foam in urine generated by the elimination of bad humours produced in excess by the liver (bile salts). PMID- 24777928 TI - [Technological challenges and strategies for developing low-protein/protein-free cereal foods for the dietotherapic treatment]. AB - Western countries are finding health care costs to be a continuously increasing financial burden in excess of previous budgetary allocations. Medical nutrition therapies (MNT) have proven to be an efficient cost minimising tool whilst concurrently improving the patient's quality of life. These MNTs are defined as specially processed or formulated foods that are used for the dietary management of patients. Among the medical foods, low-protein/protein-free (LP/PF) foods have been shown to improve the physical manifestation of metabolic disorders in patients with amino acid or protein-related diseases, such as Phenylketonuria, Tyrosinaemia type I, as well as chronic kidney, and coeliac. Most of the cereal based LP/PF foods currently marketed are a blend of refined or chemically-based food ingredients with unpalatable frequently artificial flavours, having excessive sweetness to mask the chemical taste of ingredients (drug-like approach). However, the adoption of an alternative to convention, such as a food like approach to developing medical foods, it is a surprisingly complex process. This is specifically true when the technological aspects of LP/PF foods and, in particular, protein-free cereal foods are considered. The primary processing issues arise while trying to replace gluten in baked cereal products. This represents a significant technological challenge, since gluten is an essential structural network-building protein necessary for baked goods. In this article, the suitable food technology challenges and strategies for developing LP/PF cereal foods able to overcome the significant limitations of a food-like approach will be addressed. PMID- 24777929 TI - [Italian adaptation of the European Renal Best Practice (ERBP) guideline on kidney donor and recipient evaluation and perioperative care]. AB - Recently, the ERBP (European Renal Best Practice) guideline on kidney donor and recipient evaluation and perioperative care has been published and disseminated to the international nephrology community. This guideline aims at providing evidence-based recommendations on the evaluation of the kidney transplant candidate. They evaluate the immunologic workup of kidney donors and recipients, they recommend the evaluation, selection and preparation of deceased and living kidney donors and the perioperative care of the kidney transplant recipient. We report here the Italian adaptation of these guidelines, with a focus on the main statements elaborated for each single clinical question. PMID- 24777930 TI - Winners of the 2013 American College of Rheumatology Annual Image Competition. PMID- 24777933 TI - Identification and characterization of the chemical constituents of Simiao Wan by ultra high performance liquid chromatography with mass spectrometry coupled to an automated multiple data processing method. AB - The chemical constituents of Simiao Wan (SW), a traditional Chinese medicine preparation, are difficult to determine and remain unclear. To more efficiently detect ions, a multiple data processing approach has been used in the characterization of the compounds. In this study, a rapid and sensitive method based on ultra high performance liquid chromatography with mass spectrometry and the multiple data processing approach was established to characterize the chemical constituents of SW. Ultra high performance liquid chromatography with mass spectrometry coupled with the multiple data processing approach could efficiently remove nonrelated ion signals from accurate mass data. We report the application of the multiple data processing approach for comprehensive detection and rapid identification of chemical constituents of SW. Of note, the total analysis time for separation was less than 20 min without losing any resolution. In the variable, importance in projection plot of orthogonal projection to latent structure-discriminant analysis, a total of 72 ions of interest (37 ions in positive mode, 38 ions in negative mode and three ions in both mode) were extracted or tentatively characterized based on their retention times, exact mass measurement for each molecular ion and subsequent fragment ions. In summary, the methodology proposed in this study could be valuable for the structural characterization and identification of the multiple constituents in the traditional Chinese medicine formula SW. PMID- 24777934 TI - Primary pulmonary classical Hodgkin lymphoma: a case report. AB - Primary pulmonary Hodgkin lymphoma (PPHL) is a rare entity. Most reported cases occurred before the availability of PET scan for accurate staging of the disease. We report a case of PPHL for which PET/CT scan was used and surgery was performed to confirm the diagnosis. A review of cases of PPHL since 1990 suggests that adjuvant chemotherapy and/or radiation therapy after surgical resection of the lung lesions achieve better disease control than surgical resection alone. PMID- 24777936 TI - Mechanochemical synthesis of maghemite/silica nanocomposites: advanced materials for aqueous room-temperature catalysis. AB - A simple, environmentally friendly, and highly reproducible protocol has been developed for the mechanochemical preparation of advanced nanocatalytic materials in a one-pot process. The materials proved to have unprecedented activities in aqueous Suzuki couplings at room temperature, paving the way for a new generation of highly active and stable advanced nanocatalysts. PMID- 24777935 TI - Multi-parametric MRI characterization of inflammation in murine skeletal muscle. AB - Myopathies often display a common set of complex pathologies that include muscle weakness, inflammation, compromised membrane integrity, fat deposition, and fibrosis. Multi-parametric, quantitative, non-invasive imaging approaches may be able to resolve these individual pathological components. The goal of this study was to use multi-parametric MRI to investigate inflammation as an isolated pathological feature. Proton relaxation, diffusion tensor imaging (DTI), quantitative magnetization transfer (qMT-MRI), and dynamic contrast enhanced (DCE MRI) parameters were calculated from data acquired in a single imaging session conducted 6-8 hours following the injection of lambda-carrageenan, a local inflammatory agent. T2 increased in the inflamed muscle and transitioned to bi exponential behavior. In diffusion measurements, all three eigenvalues and the apparent diffusion coefficient increased, but lambda3 had the largest relative change. Analysis of the qMT data revealed that the T1 of the free pool and the observed T1 both increased in the inflamed tissue, while the ratio of exchanging spins in the solid pool to those in the free water pool (the pool size ratio) significantly decreased. DCE-MRI data also supported observations of an increase in extracellular volume. These findings enriched the understanding of the relation between multiple quantitative MRI parameters and an isolated inflammatory pathology, and may potentially be employed for other single or complex myopathy models. PMID- 24777937 TI - In vivo molecular imaging of thrombosis and thrombolysis using a fibrin-binding positron emission tomographic probe. AB - BACKGROUND: Fibrin is a major component of arterial and venous thrombi and represents an ideal candidate for molecular imaging of thrombosis. Here, we describe imaging properties and target uptake of a new fibrin-specific positron emission tomographic probe for thrombus detection and therapy monitoring in 2 rat thrombosis models. METHODS AND RESULTS: The fibrin-binding probe FBP7 was synthesized by conjugation of a known short cyclic peptide to a cross-bridged chelator (CB-TE2A), followed by labeling with copper-64. Adult male Wistar rats (n=26) underwent either carotid crush injury (mural thrombosis model) or embolic stroke (occlusive thrombosis model) followed by recombinant tissue-type plasminogen activator treatment (10 mg/kg, IV). FBP7 detected thrombus location in both animal models with a high positron emission tomographic target-to background ratio that increased over time (>5-fold at 30-90 minutes, >15-fold at 240-285 minutes). In the carotid crush injury animals, biodistribution analysis confirmed high probe uptake in the thrombotic artery (~0.5%ID/g; >5-fold greater than blood and other tissues of the head and thorax). Similar results were obtained from ex vivo autoradiography of the ipsilateral versus contralateral carotid arteries. In embolic stroke animals, positron emission tomographic computed tomographic imaging localized the clot in the internal carotid/middle cerebral artery segment of all rats. Time-dependent reduction of activity at the level of the thrombus was detected in recombinant tissue-type plasminogen activator-treated rats but not in vehicle-injected animals. Brain autoradiography confirmed clot dissolution in recombinant tissue-type plasminogen activator treated animals, but enduring high thrombus activity in control rats. CONCLUSIONS: We demonstrated that FBP7 is suitable for molecular imaging of thrombosis and thrombolysis in vivo and represents a promising candidate for bench-to-bedside translation. PMID- 24777938 TI - Natural history of paradoxical low-gradient severe aortic stenosis. AB - BACKGROUND: Up to 30% of patients with severe aortic stenosis (SAS; indexed aortic valve area <0.6 cm(2)/m(2)) present with low transvalvular gradient despite a normal left ventricular ejection fraction. Presently, there is intense controversy as to the prognostic implications of such findings. Accordingly, the aim of the present work was to compare the natural history of patients with paradoxical low-gradient (PLG) or high-gradient (HG) SAS. METHODS AND RESULTS: We prospectively studied 349 patients with SAS and preserved left ventricular ejection fraction. Patients were categorized into HG-SAS (n=144) and PLG-SAS (n=205) according to mean transvalvular gradient (mean gradient >40 or <=40 mm Hg). Primary end points were all-cause mortality and echocardiographic disease progression. To evaluate natural history, patients undergoing aortic valve replacement were censored at the time of surgery (n=92). During a median follow up of 28 months, 148 patients died. Kaplan-Meier survival curves showed better survival in PLG-SAS than in HG-SAS, both in the overall population (48% versus 31%; P<0.01) and in the asymptomatic subgroup (59% versus 35%; P<0.02). In asymptomatic patients, Cox analysis identified age, diabetes mellitus, left atrial volume, and mean gradient as independent predictors of death. Finally, at last echocardiographic follow-up, PLG-SAS demonstrated significant increases in mean gradient (from 29+/-6 to 38+/-11 mm Hg; P<0.001). CONCLUSIONS: Our study indicates that PLG-SAS is a less malignant form of AS compared with HG-SAS, because their spontaneous outcome is better. We further demonstrated that patients with PLG-SAS are en route toward the more severe HG-SAS form, because the majority of them evolve into HG-SAS over time. PMID- 24777939 TI - Outcomes after coronary artery calcium and other cardiovascular biomarker testing among asymptomatic medicare beneficiaries. AB - BACKGROUND: Biomarkers improve cardiovascular disease (CVD) risk prediction, but their comparative effectiveness in clinical practice is not known. We sought to compare the use, spending, and clinical outcomes in asymptomatic Medicare beneficiaries evaluated for CVD with coronary artery calcium (CAC) or other cardiovascular risk markers. METHODS AND RESULTS: We used a 20% sample of 2005 to 2011 Medicare claims to identify fee-for-service beneficiaries aged >=65.5 years with no CVD claims in the previous 6 months. We matched patients with CAC with patients who received high-sensitivity C-reactive protein (hs-CRP; n=8358) or lipid screening (n=6250) using propensity-score methods. CAC was associated with increased noninvasive cardiac testing within 180 days (hazard ratio, 2.22, 95% confidence interval, 1.68-2.93, P<0.001, versus hs-CRP; hazard ratio, 4.30, 95% confidence interval, 3.04-6.06, P<0.001, versus lipid screening) and increased coronary angiography and revascularization. During 3-year follow-up, CAC was associated with higher CVD-related spending ($6525 versus $4432 for hs-CRP, P<0.001; and $6500 versus $3073 for lipid screening, P<0.001) and fewer CVD related events when compared with hs-CRP (hazard ratio, 0.74, 95% confidence interval, 0.58-0.94, P=0.017) but not compared with lipid screening (hazard ratio, 0.84, 95% confidence interval, 0.64-1.11, P=0.23). CONCLUSIONS: CAC testing among asymptomatic Medicare beneficiaries was associated with increased use of cardiac tests and procedures, higher spending, and slightly improved clinical outcomes when compared with hs-CRP testing. PMID- 24777940 TI - Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells. AB - In the bone marrow (BM), memory plasma cells (PCs) survive for long time periods in dedicated microenvironmental survival niches, resting in terms of proliferation. Several cell types, such as eosinophils and reticular stromal cells, have been reported to contribute to the survival niche of memory PCs. However, until now it has not been demonstrated whether the niche is formed by a fixed cellular microenvironment. By intravital microscopy, we provide for the first time evidence that the direct contacts formed between PCs and reticular stromal cells are stable in vivo, and thus the PCs are sessile in their niches. The majority (~ 80%) of PCs directly contact reticular stromal cells in a non random fashion. The mesenchymal reticular stromal cells in contact with memory PCs are not proliferating. On the other hand, we show here that eosinophils in the vicinity of long-lived PCs are vigorously proliferating cells and represent a dynamic component of the survival niche. In contrast, if eosinophils are depleted by irradiation, newly generated eosinophils localize in the vicinity of radiation resistant PCs and the stromal cells. These results suggest that memory PC niches may provide attraction for eosinophils to maintain stability with fluctuating yet essential accessory cells. PMID- 24777941 TI - Mutations in RARS cause hypomyelination. AB - Hypomyelinating disorders of the central nervous system are still a diagnostic challenge, as many patients remain without genetic diagnosis. Using magnetic resonance imaging (MRI) pattern recognition and whole exome sequencing, we could ascertain compound heterozygous mutations in RARS in 4 patients with hypomyelination. Clinical features included severe spasticity and nystagmus. RARS encodes the cytoplasmic arginyl-tRNA synthetase, an enzyme essential for RNA translation. This protein is among the subunits of the multisynthetase complex, which emerges as a key player in myelination. PMID- 24777942 TI - Synthesis and surface engineering of magnetic nanoparticles for environmental cleanup and pesticide residue analysis: a review. AB - In recent years, water pollution and pesticide accumulation in the food chain have become a serious environmental and health hazard problem. Direct determination of these contaminants is a difficult task due to their low concentration level and the matrix interferences. Therefore, an efficient separation and preconcentration procedure is often required prior to the analysis. With the advancement in nanotechnology, various types of magnetic core shell nanoparticles have successfully been synthesized and received considerable attention as sorbents for decontamination of diverse matrices. Magnetic core shell nanoparticles with surface modifications have the advantages of large surface-area-to-volume ratio, high number of surface active sites, no secondary pollutant, and high magnetic properties. Due to their physicochemical properties, surface-modified magnetic core-shell nanoparticles exhibit high adsorption efficiency, high rate of removal of contaminants, and easy as well as rapid separation of adsorbent from solution via external magnetic field. Such facile separation is essential to improve the operation efficiency. In addition, reuse of nanoparticles would substantially reduce the treatment cost. In this review article, we have attempted to summarize recent studies that address the preconcentration methods of pesticide residue analysis and removal of toxic contaminants from aquatic systems using magnetic core-shell nanoparticles as adsorbents. PMID- 24777943 TI - Respiratory muscle function in infants with spinal muscular atrophy type I. AB - OBJECTIVE: To determine the feasibility and safety of respiratory muscle function testing in weak infants with a progressive neuromuscular disorder. RATIONALE: Respiratory insufficiency is the major cause of morbidity and mortality in infants with spinal muscular atrophy type I (SMA-I). HYPOTHESIS: Tests of respiratory muscle strength, endurance, and breathing patterns can be performed safely in SMA-I infants. Useful data can be collected which parallels the clinical course of pulmonary function in SMA-I. STUDY DESIGN AND SUBJECT SELECTION: An exploratory study of respiratory muscle function testing and breathing patterns in seven infants with SMA-I seen in our neuromuscular clinic. Measurements were made at initial study visit and, where possible, longitudinally over time. METHODOLOGY: We measured maximal inspiratory (MIP) and transdiaphragmatic pressures, mean transdiaphragmatic pressure, airway occlusion pressure at 100 msec of inspiration, inspiratory and total respiratory cycle time, and aspects of relative thoracoabdominal motion using respiratory inductive plethysmography (RIP). The tension time index of the diaphragm and of the respiratory muscles, phase angle (Phi), phase relation during the total breath, and labored breathing index were calculated. RESULTS: Age at baseline study was 54-237 (median 131) days. Reliable data were obtained safely for MIP, phase angle, labored breathing index, and the invasive and non-invasive tension time indices, even in very weak infants. Data obtained corresponded to the clinical estimate of severity and predicted the need for respiratory support. CONCLUSIONS: The testing employed was both safe and feasible. Measurements of MIP and RIP are easily performed tests that are well tolerated and provide clinically useful information for infants with SMA-I. PMID- 24777944 TI - Rapid chemical characterisation of stilbenes in the root bark of Norway spruce by off-line HPLC/DAD-NMR. AB - INTRODUCTION: Stilbenes are plant secondary metabolites that have shown promising and varied biological activities. Stilbenes are presently actively studied for the exploitation of this primary raw material resource, involving the concept of biorefining. Methods for the rapid discovery of new and known stilbene structures from various plant sources are thus keenly sought. OBJECTIVE: To establish a simple and rapid technique of off-line HPLC with a diode-array detector (DAD) and NMR for the unambiguous structural elucidation of stilbene structures in the root bark of Norway spruce [Picea abies (L.) Karst.]. MATERIAL AND METHODS: The stilbene containing fraction was extracted from the plant bark with an ethanol:water mixture (95:5, v/v) preceded by defatting of hydrophobic compounds with n-hexane using the accelerated solvent extraction technique. A portion of the ethanol-water soluble extract was hydrolysed with beta-glucosidase to prepare stilbene aglycones. The extracts were further purified and enriched using a polymeric adsorbent. Stilbene-enriched extracts were directly characterised by off-line HPLC/DAD-NMR in conjunction with HPLC/DAD and HPLC/DAD with electrospray ionisation MS(n). RESULTS: Trans-isorhapontin and trans-astringin were identified as the major, and trans-piceid as a minor, stilbene glucosides of the bark of roots of Picea abies. Not only stilbene glucosides but also the corresponding stilbene aglycones, such as trans-resveratrol, trans-piceatannol and trans isorhapontigenin, were rapidly identified from the hydrolysed extract. The acquired heteronuclear single-quantum coherence and heteronuclear multiple bond correlation spectra were used to assign the complete carbon NMR chemical shifts of trans-isorhapontin and trans-astringin without the need of acquiring a (13)C NMR spectrum. CONCLUSION: The off-line HPLC/DAD-NMR method is expedient for the unambiguous identication of structurally similar stilbenes in plant extracts. PMID- 24777945 TI - Modulated ionomer distribution in the catalyst layer of polymer electrolyte membrane fuel cells for high temperature operation. AB - Ionomer distribution is an important design parameter for high performance polymer electrolyte membrane fuel cells (PEMFCs); however, the nano-scale modulation of the ionomer morphology has not been intensively explored. Here, we propose a new route to modulate the ionomer distribution that features the introduction of poly(ethylene glycol) (PEG) to the cathode catalyst layer and the leaching the PEG phase from the catalyst layer using a water effluent during operation. The key concept in the approach is the expansion of the ionomer thin film through the PEG addition. We demonstrate that the modulated ionomer distribution increases the electrochemical active area and proton transport property, without loss in oxygen transport, at a fixed ionomer content. At a high temperature of 120 degrees C, the power performance at 0.6 V is increased by 1.73-fold with the modulated ionomer distribution as a result of 1.25-fold increase in the electrochemical active area and two-fold increase in the proton transport rate in the catalyst layer. PMID- 24777946 TI - Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway. AB - Interleukin-33 (IL-33), an IL-1 family cytokine and nuclear alarmin, is constitutively expressed in epithelial barrier tissues and human blood vessels. However, little is known about the induced expression of IL-33 in monocytes and macrophages, which are major cytokine-producing cells of the innate immune system. Here, we report the induction of IL33 expression in both human monocytes and mouse macrophages from C57BL/6 mice by the acute-phase protein serum amyloid A (SAA). SAA-induced transcriptional activation of the Il33 gene, resulting in nuclear accumulation of the IL-33 protein. TLR2, one of the SAA receptors, was primarily responsible for the induction of IL-33. Progressive deletion of the human IL-33 promoter led to the identification of two potential binding sites for interferon regulatory factor 7 (IRF7), one of which (-277/-257) was found to be important for SAA-stimulated IL-33 promoter activity. IRF7 was recruited to the IL-33 promoter upon SAA stimulation, and silencing IRF7 expression in THP-1 cells abrogated SAA-induced Il33 expression. SAA also promoted an interaction between TNF receptor-associated factor 6 and IRF7. Taken together, these results identify IRF7 as a critical transcription factor for SAA-induced Il33 expression in monocytes and macrophages. PMID- 24777947 TI - Probabilistic classification learning with corrective feedback is associated with in vivo striatal dopamine release in the ventral striatum, while learning without feedback is not. AB - The basal ganglia (BG) mediate certain types of procedural learning, such as probabilistic classification learning on the 'weather prediction task' (WPT). Patients with Parkinson's disease (PD), who have BG dysfunction, are impaired at WPT-learning, but it remains unclear what component of the WPT is important for learning to occur. We tested the hypothesis that learning through processing of corrective feedback is the essential component and is associated with release of striatal dopamine. We employed two WPT paradigms, either involving learning via processing of corrective feedback (FB) or in a paired associate manner (PA). To test the prediction that learning on the FB but not PA paradigm would be associated with dopamine release in the striatum, we used serial (11) C raclopride (RAC) positron emission tomography (PET), to investigate striatal dopamine release during FB and PA WPT-learning in healthy individuals. Two groups, FB, (n = 7) and PA (n = 8), underwent RAC PET twice, once while performing the WPT and once during a control task. Based on a region-of-interest approach, striatal RAC-binding potentials reduced by 13-17% in the right ventral striatum when performing the FB compared to control task, indicating release of synaptic dopamine. In contrast, right ventral striatal RAC binding non significantly increased by 9% during the PA task. While differences between the FB and PA versions of the WPT in effort and decision-making is also relevant, we conclude striatal dopamine is released during FB-based WPT-learning, implicating the striatum and its dopamine connections in mediating learning with FB. PMID- 24777948 TI - Assessing health in agriculture--towards a common research framework for soils, plants, animals, humans and ecosystems. AB - In agriculture and food systems, health-related research includes a vast diversity of topics. Nutritional, toxicological, pharmacological, epidemiological, behavioural, sociological, economic and political methods are used to study health in the five domains of soils, plants, livestock, humans and ecosystems. An idea developed in the early founding days of organic agriculture stated that the health of all domains is one and indivisible. Here we show that recent research reveals the existence and complex nature of such health links among domains. However, studies of health aspects in agriculture are often separated by disciplinary boundaries. This restrains the understanding of health in agricultural systems. Therefore we explore the opportunities and limitations of bringing perspectives together from the different domains. We review current approaches to define and assess health in agricultural contexts, comparing the state of the art of commonly used approaches and bringing together the presently disconnected debates in soil science, plant science, veterinary science and human medicine. Based on a qualitative literature analysis, we suggest that many health criteria fall into two paradigms: (1) the Growth Paradigm, where terms are primarily oriented towards continued growth; (2) the Boundary Paradigm, where terms focus on maintaining or coming back to a status quo, recognising system boundaries. Scientific health assessments in agricultural and food systems need to be explicit in terms of their position on the continuum between Growth Paradigm and Boundary Paradigm. Finally, we identify areas and concepts for a future direction of health assessment and research in agricultural and food systems. PMID- 24777949 TI - Differential loss of KIR4.1 immunoreactivity in multiple sclerosis lesions. AB - OBJECTIVE: Serum antibodies against the glial potassium channel KIR4.1 are found in a subpopulation of multiple sclerosis (MS) patients. Little is known about the expression of KIR4.1 in human normal brain tissue and in MS lesions. METHODS: We analyzed the expression pattern of KIR4.1 in normal brain tissue and MS lesions of the subcortical white matter by immunohistochemistry. Markers of related glial proteins, myelin, and inflammatory cells were analyzed in parallel. RESULTS: KIR4.1 is expressed in oligodendrocytes and astrocytes in the adult human brain. In oligodendrocytes, KIR4.1 appears as a homotetramer channel, in astrocytes as homo- and heterotetramer channels together with KIR5.1. In acute MS lesions, KIR4.1 immunoreactivity (IR) was differentially lost on periplaque oligodendrocytes and perivascular astrocytes. In part of acute lesions, complement activation, apoptotic KIR4.1(+) glial cells, and phagocytes containing KIR4.1(+) fragments accompanied loss of glial KIR4.1 IR. Periplaque reactive astrocytes showed enhanced IR for both KIR4.1 and KIR5.1. In chronic active MS lesions, apart from a general loss of oligodendrocytes in the demyelinated area, we observed a decrease of astroglial KIR4.1 but not glial fibrillary acidic protein IR. In chronic inactive and remyelinating MS lesions, KIR4.1 IR was restored on astrocytes and found in a subset of presumably new myelinating oligodendrocytes. INTERPRETATION: The expression profile of KIR4.1 in glial cells and stage-dependent alterations of KIR4.1 IR in MS lesions are compatible with an immune response against KIR4.1 at least in a subset of MS patients. PMID- 24777950 TI - Long-term outcome of parapneumonic effusions in children: Lung function and exercise tolerance. AB - OBJECTIVES: a: To evaluate the long-term outcome of parapneumonic effusions (PPE) in children regarding lung function and exercise tolerance, (b) to investigate the role of bronchial asthma in the outcome of PPE. METHODS: The design of the study included 51 children with PPE, at least 2 years after the initial infection. They were divided in two groups. Group A (38 children) consisted of children with PPE but without asthma prior initial infection. Group B (13 children) included children with PPE and asthma prior infection. Thirty-six children were taken as healthy controls (group C). All children performed spirometry and a maximal incremental cardiopulmonary exercise test on cycle ergometer. RESULTS: Children of both groups (A and B) showed statistically significant lower values in FVC%, FEV1%, and FEV1 /FVC compared to controls (group C). Children of group B had also significant lower FEF(25-75%) values compared to controls. Children of group B had significant lower FEV1 /FVC values compared to group A. All children of the three groups showed no differences in maximal exercise capacity (VO2max). Children of group A had higher respiratory equivalent to oxygen (VE/VO2) during exercise compared to healthy subjects. CONCLUSIONS: There are small effects on lung function and exercise capacity in the long-term, among children with PPE, but of no clinical importance. Pre existing bronchial asthma doesn't influence the outcome significantly. PMID- 24777951 TI - Determination of L-hydroxyproline using hydrophilic interaction chromatography coupled to tandem mass spectrometry with lyophilized concentrated extraction in milk and dairy products. AB - In this study, a screening and confirmation method for the determination of l hydroxyproline (Hyp) as a target compound in milk and dairy products using high performance liquid chromatography with tandem mass spectrometry was developed. The samples were lyophilized after acidic hydrolysis, followed by cleanup with graphitized carbon black to remove pigments. Hyp was separated by a hydrophilic interaction chromatographic column and analyzed by high-performance liquid chromatography with tandem mass spectrometry working with multiple reaction monitoring mode using an electrospray ionization interface in a positive-ion mode. Average recoveries in spiked milk and dairy products ranged from 68.0 to 101.1% with relative standard deviations between 2.0 and 11.7% (n = 7). A reagent matched standard calibration curve was used for quantification of Hyp, with linear correlation coefficient (R(2)) > 0.99 in the concentration range of 0.1 100 MUg/mL. The LOQs were from 0.25 to 5 mg/kg, which were usually sufficient to verify the Hyp in samples. The confirmation concentration of Hyp ranged from 10 to 50 mg/kg. PMID- 24777952 TI - Is measurement of cervical length an accurate predictive tool in women with a history of preterm delivery who present with threatened preterm labor? AB - OBJECTIVE: To determine whether sonographically measured cervical length is an effective predictive tool in women with threatened preterm labor and a history of past spontaneous preterm delivery. METHODS: This was a retrospective cohort study of all women with singleton pregnancies who presented with preterm labor at less than 34 + 0 weeks' gestation and underwent sonographic measurement of cervical length in a tertiary medical center between 2007 and 2012. The accuracy of cervical length in predicting preterm delivery was compared between women with and those without a history of spontaneous preterm delivery. Women with risk factors for preterm delivery other than a history of preterm delivery were excluded from both groups. RESULTS: Overall, 1023 women who presented with preterm labor met the study criteria, of whom 136 (13.3%) had a history of preterm delivery (past-PTD group) and 887 (86.7%) had no risk factors for preterm delivery (low-risk group). The rate of preterm delivery was significantly higher for women with a history of preterm delivery (36.8% vs 22.5%; P < 0.001). Cervical length was significantly correlated with the examination-to-delivery interval in low-risk women (r = 0.32, P < 0.001) but not in women who had had a previous preterm delivery (r = 0.07, P = 0.4). On multivariable analysis, cervical length was independently associated with the risk of preterm delivery for women in the low-risk group but not for women with a history of previous preterm delivery. For women with previous preterm delivery who presented with threatened preterm labor, cervical length failed to distinguish between those who did and those who did not deliver prematurely (area under the receiver-operating characteristics curve range, 0.475-0.506). When using standardized thresholds, the sensitivity and specificity of cervical length for the prediction of preterm delivery were significantly lower in women with previous preterm delivery than in women with no risk factors for preterm delivery. CONCLUSION: Cervical length appears to be of limited value in the prediction of preterm delivery among women with threatened preterm labor who are at high risk for preterm delivery owing to a history of spontaneous preterm delivery in a previous pregnancy. PMID- 24777953 TI - Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. AB - Hyperinsulinemia is believed to play a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and associated cardiovascular risk. However, the relative contribution of insulin clearance to hyperinsulinemia and its relationship to liver histology have not been carefully evaluated before. To examine this, we enrolled 190 patients (32 without nonalcoholic fatty liver disease [NAFLD], 36 with simple steatosis [SS], and 122 with biopsy-proven NASH). Insulin secretion and hepatic insulin clearance were estimated by means of an oral glucose tolerance test, whereas peripheral insulin sensitivity and whole body insulin clearance were measured during a euglycemic insulin clamp. A liver biopsy was performed to assess histology (grade/stage). Patients with NASH had similar hepatic insulin sensitivity, compared to patients with SS, but more severe adipose tissue insulin resistance and worse hyperinsulinemia. Patients with SS and NASH had a similar ~30% reduction (P<0.01) in hepatic insulin clearance, when compared to patients without NAFLD. Reduced hepatic insulin clearance was not associated with severity of inflammation, ballooning, and fibrosis. In contrast, worse histological inflammation and ballooning (but not steatosis or fibrosis) were associated with a progressive reduction in whole-body insulin clearance (P<0.001 for trend). There was no significant difference in insulin secretion between patients with SS versus NASH. CONCLUSION: Decreased hepatic insulin clearance develops with a mild increase in liver fat (LFAT) accumulation. It appears to be largely driven by hepatic steatosis, whereas steatohepatitis is more closely associated with reduced whole-body insulin clearance. Hyperinsulinemia in NAFLD correlated strongly with impaired insulin clearance, but not with insulin secretion. Strategies that reduce LFAT and improve insulin clearance hold the potential to revert the unfavorable effects of hyperinsulinemia in these patients. PMID- 24777954 TI - Thermoset coatings from epoxidized sucrose soyate and blocked, bio-based dicarboxylic acids. AB - A new 100% bio-based thermosetting coating system was developed from epoxidized sucrose soyate crosslinked with blocked bio-based dicarboxylic acids. A solvent free, green method was used to block the carboxylic acid groups and render the acids miscible with the epoxy resin. The thermal reversibility of this blocking allowed for the formulation of epoxy-acid thermoset coatings that are 100% bio based. This was possible due to the volatility of the vinyl ethers under curing conditions. These systems have good adhesion to metal substrates and perform well under chemical and physical stress. Additionally, the hardness of the coating system is dependent on the chain length of the diacid used, making it tunable. PMID- 24777955 TI - Susceptibility of nine organophosphorus pesticides in skimmed milk towards inoculated lactic acid bacteria and yogurt starters. AB - BACKGROUND: Previous research has shown that fresh milk might be polluted by some organophosphorus pesticides (OPPs). In this study the dissipation of nine OPPs, namely chlorpyrifos, chlorpyrifos-methyl, diazinon, dichlorvos, fenthion, malathion, phorate, pirimiphos-methyl and trichlorphon, in skimmed milk was investigated to clarify their susceptibility towards lactic acid bacteria (LAB) and yogurt starters. RESULTS: Skimmed milk was spiked with nine OPPs, inoculated with five strains of LAB and two commercial yogurt starters at 42 degrees C for 24 and 5 h respectively and subjected to quantitative OPP analysis by gas chromatography. Degradation kinetic constants of these OPPs were calculated based on a first-order reaction model. OPP dissipation in the milk was enhanced by the inoculated strains and starters, resulting in OPP concentrations decreasing by 7.0-64.6 and 7.4-19.2% respectively. Totally, the nine OPPs were more susceptible to Lactobacillus bulgaricus, as it enhanced their degradation rate constants by 18.3-133.3%. Higher phosphatase production of the assayed stains was observed to bring about greater OPP degradation in the milk. CONCLUSION: Both LAB and yogurt starters could enhance OPP dissipation in skimmed milk, with the nine OPPs studied having different susceptibilities towards them. Phosphatase was a key factor governing OPP dissipation. The LAB of higher phosphatase production have more potential to decrease OPPs in fermented foods. PMID- 24777956 TI - Ultrasound-assisted extraction and preliminary purification of proanthocyanidins and chlorogenic acid from almond (Prunus dulcis) skin. AB - An aqueous solution of polyethylene glycol (PEG) as a green solvent was employed for the first time to develop the ultrasound-assisted extraction of proanthocyanidins (PA) and chlorogenic acid (CA) from almond skin. The optimized extraction parameters were determined based on response surface methodology, and corresponded to an ultrasound power of 120 W, a liquid-to-solid ratio of 20:1 (mL/g), and a PEG concentration of 50% (v/v). Under these optimized conditions, the extraction yields of PAs and CA from almond skin were 32.68 +/- 0.22 and 16.01 +/- 0.19 mg/g, respectively. Compared with organic solvent extraction, PEG solution extraction produced higher yields. Different macroporous resins were compared for their performance in purifying PAs and CA from almond skin extract. Static adsorption/desorption experimental results demonstrated that AB-8 resin exhibits excellent purification performance at pH 4. Under the optimized dynamic adsorption/desorption conditions on the AB-8 column, the total recovery of purification for PAs and CA was 80.67%. The total content of PAs and CA in the preliminarily purified extract was 89.17% (with respective contents of 60.90 and 28.27%). PMID- 24777957 TI - Pulmonary exacerbations and parent-reported outcomes in children <6 years with cystic fibrosis. AB - Pulmonary exacerbations (PEs) are used as clinical endpoints in infants and preschool children with cystic fibrosis (CF); however, their characteristics and impact in this age range are poorly understood. We used data from the Infant Study of Inhaled Saline, a multicenter trial of inhaled hypertonic versus isotonic saline, to describe PEs in children with CF <6 years and evaluate associations between PEs and parent-reported outcomes assessed by a weekly parent questionnaire (10 items) and three scales of the Cystic Fibrosis Questionnaire Revised (CFQ-R), and other participant characteristics. There were 659 PEs among 253 of the 321 ISIS participants (mean age 2.3 years) during 287 participant years follow-up. Of the 659 PEs, 636 (97%) were treated with oral and 45 (7%) with IV antibiotics (not mutually exclusive). Among 222 participants with PEs who had completed parent questionnaires during a PE and at baseline, 9 of the 10 symptoms were each present in a statistically significantly higher proportion of participants during a PE than at baseline. Lower (worse) baseline Respiratory Symptom and Physical Functioning CFQ-R scores were significantly associated with higher PE rate: rate ratio 1.08 (95%CI: 1.02, 1.14) and 1.21 (1.07, 1.36) per 10 point lower score in respective scale. A higher PE rate was also significantly associated with worse CFQ-R Respiratory Symptom and Physical Functioning scores at the end of the study, adjusted for baseline scores. Though most PEs did not require IV antibiotics, PEs appeared to have a negative impact on parent-reported health outcomes in infants and preschoolers with CF. Pediatr Pulmonol. 2015; 50:236-243. (c) 2014 Wiley Periodicals, Inc. PMID- 24777958 TI - LXR-dependent and -independent effects of oxysterols on immunity and tumor growth. AB - Oxysterols are involved in maintaining cellular cholesterol levels. Recently, oxysterols have been demonstrated to modulate the function of immune cells and tumor growth. These effects can be dependent on the activation of the oxysterol binding liver X receptors (LXRs) or, as recently demonstrated for T and B cells, DCs and neutrophils, can be independent of LXR activation. LXR-dependent oxysterol effects can be ascribed to the activation of LXRalpha, LXRbeta or LXRalphabeta isoforms, which induces transcriptional activation or trans repression of target genes. The prevalent activation of one isoform seems to be cell-, tissue-, or context-specific, as shown in some pathologic processes, i.e., infectious diseases, atherosclerosis, and autoimmunity. Oxysterol-LXR signaling has recently been shown to inhibit antitumor immune responses, as well as to modulate tumor cell growth. Here, we review the mechanisms that link oxysterols to tumor growth, and discuss possible networks at the basis of LXR-dependent and independent oxysterol effects on immune cells and tumor development. PMID- 24777959 TI - Topical high-concentration menthol: reproducibility of a human surrogate pain model. AB - BACKGROUND: Human experimental pain models play an important role in studying neuropathic pain mechanisms. The objective of the present study was to test the reproducibility of the topical menthol model over a 1-week period. METHOD: We performed an open, two-period study in 10 healthy volunteers with 40 menthol applications. The side of menthol application was randomly assigned. Two trial periods were separated by 1 week. Before and after applying menthol, selected quantitative sensory testing (QST) was performed. The area of mechanical pin prick hyperalgesia was quantified. Spontaneous pain was recorded. RESULTS: Application of menthol induced a statistically significant decrease in the cold pain threshold (CPT) (p < 0.001) and mechanical pain threshold and an increase in the mechanical pain sensitivity (MPS) (p < 0.001), indicating cold and mechanical (pin-prick) hyperalgesia. Test-retest reliability was best for CPT (r = 0.959) and MPS (r = 0.930). Intraclass correlation values showed excellent reliability for cold pain and MPS (ICC = 0.96, 0.89). The QST values post-menthol showed high inter-period correlation factors and no significant inter-period differences (paired t-test, t = 1.767-1.361; p = 0.111-0.988). The area size of mechanical hyperalgesia was not reliably reproducible. CONCLUSION: For an observation period of 1 week, the signs of cold and mechanical hyperalgesia were reproducible with a highly significant correlation of about r = 0.8 and good agreement except for the area size of mechanical pin-prick hyperalgesia. These results demonstrate that the topical menthol pain model is suitable for pharmacological interventions repeated within an observation period of 1 week. PMID- 24777961 TI - Severe fetal brain shrinkage following heavy maternal alcohol consumption. PMID- 24777960 TI - Linking MRI postprocessing with magnetic source imaging in MRI-negative epilepsy. AB - OBJECTIVE: MRI-negative (MRI-) pharmacoresistant focal epilepsy (PFE) patients are most challenging for epilepsy surgical management. This study utilizes a voxel-based MRI postprocessing technique, implemented using a morphometric analysis program (MAP), aiming to facilitate detection of subtle focal cortical dysplasia (FCD) in MRI- patients. Furthermore, the study examines the concordance between MAP-identified regions and localization from magnetic source imaging (MSI). METHODS: Included in this retrospective study were 25 MRI- surgical patients. MAP was performed on T1-weighted MRI, with comparison to a normal database. The pertinence of MAP+ areas was confirmed by MSI, surgical outcome and pathology. Analyses of MAP and MSI were performed blindly from patients' clinical information and independently from each other. RESULTS: The detection rate of subtle changes by MAP was 48% (12/25). Once MAP+ areas were resected, patients were more likely to be seizure-free (p=0.02). There were no false positives in the 25 age-matched normal controls. Seven patients had a concordant MSI correlate. Patients in whom a concordant area was identified by both MAP and MSI had a significantly higher chance of achieving a seizure-free outcome following complete resection of this area (p=0.008). In the 9 resected MAP+ areas, pathology revealed FCD type IA in 7 and type IIB in 2. INTERPRETATION: MAP shows promise in identifying subtle FCD abnormalities and increasing the diagnostic yield of conventional MRI visual analysis in presurgical evaluation of PFE. Concordant MRI postprocessing and MSI analyses may lead to the noninvasive identification of a structurally and electrically abnormal subtle lesion that can be surgically targeted. PMID- 24777962 TI - Lack of adaptation to a new host in a generalist herbivore: implications for host plant resistance to twospotted spider mites in cotton. AB - BACKGROUND: The twospotted spider mite (Tetranychus urticae Koch) is an important pest of cotton. This pest has a broad host range, but when changing between hosts an initial decline in fitness often occurs. This is usually followed by an increase in fitness after rapid adaptation to the new host, usually within five generations. RESULTS: The generality of this adaptive response was tested by assessing elements of fitness when mites were reared on a host to which they were adapted (Gossypium hirsutum L. cv. Sicot 71) or on a new host, Gossypium arboreum L. (accession BM13H). In a first experiment, mites reared on the new host for ten generations showed declining immature survival compared with those reared on the adapted host. In a second experiment, the intrinsic capacity for increase of mites cultured on the new host for six generations was significantly lower than that of mites cultured on the adapted host for six generations and then transferred to the new host. Hence, exposure to the new host for six or ten generations resulted in declining fitness. CONCLUSION: This 'negative adaptation' indicates robust antibiosis traits in G. arboreum accession BM13H, which therefore have value in developing mite-resistant G. hirsutum cultivars. PMID- 24777963 TI - Mast cells: potential positive and negative roles in tumor biology. AB - Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. PMID- 24777964 TI - Harnessing the potential of radiation-induced immune modulation for cancer therapy. AB - The conventional use of radiotherapy is for local tumor control. Radiotherapy of the primary tumor can prevent the development of distant metastases, but this modality is generally not effective for treating preexisting systemic disease. However, radiation-induced tumor destruction may be considered a novel strategy for in situ cancer vaccination, in which tumor antigens released from dying tumor cells may be presented in an immunostimulatory context. Moreover, radiation has been demonstrated to induce immunogenic modulation in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell mediated killing. Finally, radiotherapy typically has a favorable toxicity profile and is associated with the absence of systemic immunosuppression. Together, these properties suggest that radiotherapy may serve as an important component of combinatorial immunotherapies aimed at augmenting systemic antitumor immunity. Here, we provide an overview of the radiation-induced modulations of the immune system that may be harnessed for cancer therapy. PMID- 24777965 TI - The 2013 Novartis Prize for Clinical Immunology. PMID- 24777966 TI - Spontaneous peripheral T-cell responses toward the tumor-associated antigen cyclin D1 in patients with clear cell renal cell carcinoma. AB - Renal cell carcinoma (RCC) is a heterogeneous group of kidney cancers with clear cell RCC (ccRCC) as the major subgroup. To expand the number of clinically relevant tumor-associated antigens (TAA) that can be targeted by immunotherapy, we analyzed samples from 23 patients with primary ccRCC for the expression and immunogenicity of various TAAs. We found high-frequency expression of MAGE-A9 and NY-ESO-1 in 36% and 55% of samples, respectively, and overexpression of PRAME, RAGE-1, CA-IX, Cyclin D1, ADFP, C-MET, and RGS-5 in many of the tumor samples. We analyzed the blood of patients with HLA-A2(+) ccRCC for the presence of CD8(+) T cells specific for TAA-derived HLA-A2-restricted peptides and found spontaneous responses to cyclin D1 in 5 of 6 patients with Cyclin D1-positive tumors. Cyclin D1-specific CD8(+) T cells secreted TNF-alpha, IFN-gamma, and interleukin-2 (IL 2), and degranulated, indicating the presence of polyfunctional tumor-specific CD8(+) T cells in the blood of these patients with ccRCC. The high frequency (43%) of Cyclin D1 overexpression and the presence of functional cyclin D1 specific T cells in 83% of these patients with ccRCC suggest that cyclin D1 may be a target for immunotherapeutic strategies. PMID- 24777967 TI - NY-ESO-1 expression in meningioma suggests a rationale for new immunotherapeutic approaches. AB - Meningiomas are the most common primary intracranial tumors. Surgical resection remains the treatment of choice for these tumors. However, a significant number of tumors are not surgically accessible, recur, or become malignant, necessitating the repetition of surgery and sometimes radiation. Chemotherapy is rarely used and is generally not recognized as an effective treatment. Cancer/testis (CT) genes represent a unique class of genes, which are expressed by germ cells, normally silenced in somatic cells, but activated in various cancers. CT proteins can elicit spontaneous immune responses in patients with cancer and this feature makes them attractive targets for immunotherapy-based approaches. We analyzed mRNA expression of 37 testis-restricted CT genes in a discovery set of 18 meningiomas by reverse transcription PCR. The overall frequency of expression of CT genes ranged from 5.6% to 27.8%. The most frequently expressed was NY-ESO-1, in 5 patients (27.8%). We subsequently analyzed NY-ESO-1 protein expression in a larger set of meningiomas by immunohistochemistry and found expression in 108 of 110 cases. In some cases, NY ESO-1 expression was diffused and homogenous, but in most instances it was heterogeneous. Importantly, NY-ESO-1 expression was positively correlated with higher grade and patients presenting with higher levels of NY-ESO-1 staining had significantly worse disease-free and overall survival. We have also shown that NY ESO-1 expression may lead to humoral immune response in patients with meningioma. Considering the limited treatment options for patients with meningioma, the potential of NY-ESO-1-based immunotherapy should be explored. PMID- 24777968 TI - CD4+ T effectors specific for the tumor antigen NY-ESO-1 are highly enriched at ovarian cancer sites and coexist with, but are distinct from, tumor-associated Treg. AB - Whereas tumor infiltration by T effectors is generally associated with a more favorable prognosis, the accumulation of CD4(+) regulatory T cells (Treg) within tumors is instead often associated with poor disease outcome. Because approaches to improve antitumor immunity aim, on one hand, at expanding tumor antigen specific T cells and, on the other, at eliminating or inactivating Treg, an outstanding question is whether, and to what extent, tumor antigen-specific CD4(+) T effectors present at tumor sites overlap with tumor-associated Treg. Here, we used MHC class II/peptide tetramers incorporating an immunodominant peptide from the human tumor-specific antigen NY-ESO-1 to assess antigen-specific CD4(+) T cells among conventional CD4(+) T effectors and Treg at sites of ovarian cancer. We found that, in patients who spontaneously respond to the antigen, the frequency of NY-ESO-1 tetramer(+) cells detected ex vivo was highly enriched in tumors as compared with the periphery. At tumor sites, NY-ESO-1 tetramer(+) cells were detected concomitantly with high proportions of Treg but were distinct from the latter and displayed characteristics of TH1 effectors. Thus, even in the presence of high proportions of Treg, tumor antigen-specific CD4(+) T cells can accumulate in ovarian tumors and maintain an effector phenotype. PMID- 24777969 TI - Combining oncolytic HSV-1 with immunogenic cell death-inducing drug mitoxantrone breaks cancer immune tolerance and improves therapeutic efficacy. AB - Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 MUmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8(+) T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death-inducing chemotherapeutics enhance the immunogenicity of the tumor-associated antigens, breaking immunologic tolerance established toward these antigens. PMID- 24777970 TI - Effect of Montanide and poly-ICLC adjuvant on human self/tumor antigen-specific CD4+ T cells in phase I overlapping long peptide vaccine trial. AB - Vaccination of patients with ovarian cancer with overlapping long peptides (OLP) from cancer-testis antigen NY-ESO-1 and poly-ICLC in Montanide-ISA-51 (Montanide) was found to consistently induce integrated immune responses (antibody, CD4(+), and CD8(+) T cells). Using detailed methods, we investigated the respective effects of poly-ICLC and Montanide adjuvant on pre- and postvaccine NY-ESO-1 specific CD4(+) T cells, because of their central function for induction and maintenance of both antibody and CD8(+) T cells. Polyclonal NY-ESO-1-specific CD4(+) T-cell lines were generated from 12 patients using CD154-based selection of precursors before and after vaccination with (i) OLP alone, (ii) OLP in Montanide, or (iii) OLP and poly-ICLC in Montanide. Kinetics, quantification, fine specificity, avidity, and cytokine-producing pattern were analyzed in depth and compared between vaccine cohorts. Vaccination with OLP alone did not elicit CD4(+) T-cell responses; it suppressed high-avidity CD4(+) T-cell precursors that recognized naturally processed NY-ESO-1 protein before vaccination. Emulsification of OLP in Montanide was required for the expansion of high-avidity NY-ESO-1-specific CD4(+) T-cell precursors. Poly-ICLC significantly enhanced CD4(+) Th1 responses while suppressing the induction of interleukin (IL)-4 producing Th2 and IL-9-producing Th9 cells. In summary, Montanide and poly-ICLC had distinct and cooperative effects for the induction of NY-ESO-1-specific Th1 cells and integrated immune responses by OLP vaccination. These results support the use of admixing poly-ICLC in Montanide adjuvant to rapidly induce antitumor type I immune responses by OLP from self/tumor antigens in human cancer vaccines. PMID- 24777971 TI - Over-pressurized bioreactors: application to microbial cell cultures. AB - In industrial biotechnology, microbial cultures are exposed to different local pressures inside bioreactors. Depending on the microbial species and strains, the increased pressure may have detrimental or beneficial effects on cellular growth and product formation. In this review, the effects of increased air pressure on various microbial cultures growing in bioreactors under moderate total pressure conditions (maximum, 15 bar) will be discussed. Recent data illustrating the diversity of increased air pressure effects at different levels in microbial cells cultivation will be presented, with particular attention to the effects of oxygen and carbon dioxide partial pressures on cellular growth and product formation, and the concomitant effect of oxygen pressure on antioxidant cellular defense mechanisms. PMID- 24777972 TI - pH shift protein recovery with organic acids on texture and color of cooked gels. AB - BACKGROUND: Isoelectric solubilization and precipitation (ISP) processing uses pH shifts to separate protein from fish frames, which may increase commercial interest for silver carp. Texture and color properties of gels made from silver carp protein recovered at different pH strategies and organic acid types were compared. ISP was applied to headed gutted silver carp using 10 mol L(-1) sodium hydroxide (NaOH) and either glacial acetic acid (AA) or a (1:1) formic and lactic acid combination (F&L). Protein gels were made with recovered protein and standard functional additives. RESULTS: Texture profile analysis and the Kramer shear test showed that protein gels made from protein solubilized at basic pH values were firmer, harder, more cohesive, gummier and chewier (P < 0.05) than proteins solubilized under acidic conditions. Acidic solubilization led to whiter (P < 0.05) gels, and using F&L during ISP yielded whiter gels under all treatments (P < 0.05). CONCLUSION: Gels made from ISP-recovered silver carp protein using organic acids show potential for use as a functional ingredient in restructured foods. PMID- 24777973 TI - A randomized controlled trial of an Internet-based cognitive-behavioural intervention for non-specific chronic pain: an effectiveness and cost effectiveness study. AB - BACKGROUND: Cognitive-behavioural treatment can nowadays be delivered through the Internet. This form of treatment can have various advantages with regard to availability and accessibility. Previous studies showed that Internet-based treatment for chronic pain is effective compared to waiting-list control groups. METHODS: We conducted a randomized controlled trial comparing an Internet-based cognitive-behavioural intervention with e-mail therapist contact to a face-to face cognitive-behavioural group intervention. Of the 72 participants who were randomly assigned to an Internet or a group course, 50 participants completed the intervention. Participants were assessed at baseline (T0), immediately after the 7-week course (T1) and at the booster session 2 months later (T2). Pain-related catastrophizing was the primary outcome measure. Pain intensity, fatigue, pain related interference, locus of control, pain coping, global health-related quality of life and medical expenses were secondary outcome variables. RESULTS: Significant improvement was found on catastrophizing, pain coping, locus of control and aspects of global health-related quality of life in both the Internet and the group courses directly after the course and at the booster session. Pain intensity was improved in both courses at the booster session. At T2, improvement in catastrophizing, pain intensity, pain coping and some quality of life dimensions was significantly greater in completers of the Internet course than in the group course. Furthermore, the Internet course was cost-effective compared to the group course. CONCLUSIONS: We conclude that the Internet-based cognitive behavioural intervention was at least as effective as the face-to-face group intervention and, on some outcome measures appeared to be even more effective. PMID- 24777974 TI - Folding of Aquaporin 1: multiple evidence that helix 3 can shift out of the membrane core. AB - The folding of most integral membrane proteins follows a two-step process: initially, individual transmembrane helices are inserted into the membrane by the Sec translocon. Thereafter, these helices fold to shape the final conformation of the protein. However, for some proteins, including Aquaporin 1 (AQP1), the folding appears to follow a more complicated path. AQP1 has been reported to first insert as a four-helical intermediate, where helix 2 and 4 are not inserted into the membrane. In a second step, this intermediate is folded into a six helical topology. During this process, the orientation of the third helix is inverted. Here, we propose a mechanism for how this reorientation could be initiated: first, helix 3 slides out from the membrane core resulting in that the preceding loop enters the membrane. The final conformation could then be formed as helix 2, 3, and 4 are inserted into the membrane and the reentrant regions come together. We find support for the first step in this process by showing that the loop preceding helix 3 can insert into the membrane. Further, hydrophobicity curves, experimentally measured insertion efficiencies and MD-simulations suggest that the barrier between these two hydrophobic regions is relatively low, supporting the idea that helix 3 can slide out of the membrane core, initiating the rearrangement process. PMID- 24777975 TI - Caspase recruitment domain 6 protects against cardiac hypertrophy in response to pressure overload. AB - Caspase recruitment domain 6 (CARD6), a crucial member of the CARD family, was initially shown to be involved in the immune system and oncogenesis. However, the role of CARD6 in chronic pressure overload-induced cardiac hypertrophy remains unexplored. To evaluate the impact of CARD6 on pathological cardiac hypertrophy, cardiac-specific CARD6 knockout mice and transgenic mice with cardiac-specific CARD6 overexpression were generated and subjected to aortic banding for 4 weeks. Our results demonstrated that CARD6-deficient mice aggravated aortic banding triggered cardiac hypertrophy, ventricular dilation, fibrosis, and dysfunction, as measured by echocardiography, immunostaining, and molecular/biochemical analyses. Conversely, CARD6-overexpressing mice exhibited an attenuated hypertrophic response to chronic pressure overload. Similarly, using cultured neonatal rat cardiomyocytes, we found that adenovirus vector-driven overexpression of CARD6 dramatically limited angiotensin II-induced myocyte hypertrophy, whereas knockdown of CARD6 by AdshCARD6 (adenoviral short hairpin CARD6) exhibited the opposite phenotypes. Furthermore, analysis of the signaling events in vitro and in vivo revealed that CARD6-mediated protection against cardiac hypertrophy was attributed to the interruption of mitogen-activated protein kinase kinase (MEK) kinase-1-dependent MEK-extracellular signal-regulated protein kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase 1/2 (JNK1/2) activation. Altogether, these data indicated that CARD6 serves as a novel cardioprotective factor via negative regulation of MEK kinase-1-dependent MEK-ERK1/2 and JNK1/2 signaling. Thus, our study suggests that CARD6 may be a novel target for the treatment of pathological cardiac hypertrophy and failure. PMID- 24777976 TI - Hypertension and dementia. PMID- 24777978 TI - Importance of estrogen metabolites. PMID- 24777977 TI - Activity of protein kinase C-alpha within the subfornical organ is necessary for fluid intake in response to brain angiotensin. AB - Angiotensin-II production in the subfornical organ acting through angiotensin-II type-1 receptors is necessary for polydipsia, resulting from elevated renin angiotensin system activity. Protein kinase C and mitogen-activated protein kinase pathways have been shown to mediate effects of angiotensin-II in the brain. We investigated mechanisms that mediate brain angiotensin-II-induced polydipsia. We used double-transgenic sRA mice, consisting of human renin controlled by the neuron-specific synapsin promoter crossed with human angiotensinogen controlled by its endogenous promoter, which results in brain specific overexpression of angiotensin-II, particularly in the subfornical organ. We also used the deoxycorticosterone acetate-salt model of hypertension, which exhibits polydipsia. Inhibition of protein kinase C, but not extracellular signal regulated kinases, protein kinase A, or vasopressin V1A and V2 receptors, corrected the elevated water intake of sRA mice. Using an isoform selective inhibitor and an adenovirus expressing dominant negative protein kinase C-alpha revealed that protein kinase C-alpha in the subfornical organ was necessary to mediate elevated fluid and sodium intake in sRA mice. Inhibition of protein kinase C activity also attenuated polydipsia in the deoxycorticosterone acetate salt model. We provide evidence that inducing protein kinase C activity centrally is sufficient to induce water intake in water-replete wild-type mice, and that cell surface localization of protein kinase C-alpha can be induced in cultured cells from the subfornical organ. These experimental findings demonstrate a role for central protein kinase C activity in fluid balance, and further mechanistically demonstrate the importance of protein kinase C-alpha signaling in the subfornical organ in fluid intake stimulated by angiotensin-II in the brain. PMID- 24777979 TI - Identification of bona fide alternative renin transcripts expressed along cortical tubules and potential roles in promoting insulin resistance in vivo without significant plasma renin activity elevation. AB - Renin belongs to a family of aspartyl proteases and is the rate-limiting enzyme in the synthesis of the potent vasoactive peptide angiotensin II. Processing of renal renin has been extensively investigated in juxtaglomerular granular cells, in which prorenin and active renin are present in secretory condensed granules. Previous studies demonstrated alternative renin transcription in rat adrenal glands. Different studies reported novel intracellular forms of renin deduced from novel 5' variants derived from renin mRNA in both mice and humans. Comprehensive detailed studies in genetically engineered mice showed that both a secreted and an intracellular form of renin plays divergent mechanism regulating fluid intake and metabolism by the brain renin-angiotensin system; however, the presence, regulation, and functions of these renin isoforms in kidney and adrenal gland are not fully understood in mice. To investigate the characteristics of renin isoforms in mice, we performed a systematic inventory of renin transcripts of mice with and without a duplication of the renin gene alternatively from previous studies. We discovered a novel isoform of renin of the Ren2 gene, which conserved functionally important residues of the prosegment and incomplete isoforms of the Ren1C/D gene lacking a pre-pro segment. In situ hybridization assays revealed alternative renin isoforms expressed along cortical tubules. Newly generated transgenic mice with systemic overexpression of alternative renin transcript showed enhanced local angiotensin II generation without elevation of plasma renin activity and systemic insulin resistance in vivo, providing new pathophysiological insights into insulin resistance exaggerated by bona fide renin isoform. PMID- 24777980 TI - Adverse childhood experiences are associated with detrimental hemodynamics and elevated circulating endothelin-1 in adolescents and young adults. AB - Growing evidence suggests that adverse childhood experiences (ACEs) increase the risks for coronary heart disease and hypertension in mid and late adulthood. We previously reported that early life stress induces a hyperreactive endothelin dependent cardiovascular phenotype in a rat model. In the present study, we evaluated whether exposure to ACEs is associated with greater peripheral resistance, arterial stiffness, blood pressure, or elevated circulating endothelin-1 levels in humans. In 221 healthy adolescents and young adults (mean age, 21 years; range, 13-29 years), we found a graded association of ACE exposure with plasma endothelin-1 levels, of which on average 18% and 24% were higher in participants with 1 ACE and >=2 ACEs, respectively, compared with those with no ACEs (P=0.001). Participants with moderate/severe exposure to ACEs (>=2 ACEs) had significantly higher total peripheral resistance index (+12%), diastolic blood pressure (+5%), and pulse wave velocity (+9%) compared with those who were not exposed. These associations were independent of age, race, sex, body mass index, and childhood socioeconomic status. Our results indicate that early life stress promotes cardiovascular disease risk, specifically detrimental vascular and cardiac function, detectable in young adulthood. PMID- 24777981 TI - Flaxseed consumption reduces blood pressure in patients with hypertension by altering circulating oxylipins via an alpha-linolenic acid-induced inhibition of soluble epoxide hydrolase. AB - In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic ( 10 mm Hg) and diastolic (-7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid alpha-linolenic acid. Plasma alpha-linolenic acid increased with ingestion of flaxseed and was inversely associated with blood pressure. However, the antihypertensive mechanism was unclear. Oxylipins derived from polyunsaturated fatty acids regulate vascular tone. Therefore, the objective was to examine whether flaxseed consumption altered plasma oxylipins in a manner that influenced blood pressure. Plasma of FlaxPAD (Flaxseed for Peripheral Arterial Disease) participants underwent solid phase extraction and high-performance liquid chromatography-mass spectrometry/mass spectrometry analysis. The flaxseed group exhibited significant decreases in 8 plasma oxylipins versus control. Six of these (5,6-, 8,9-, 11,12-, 14,15-dihydroxyeicosatrienoic acid and 9,10- and 12,13 dihydroxyoctadecenoic acid) were products of soluble epoxide hydrolase, a pharmacological target for antihypertensive treatment. Patients exhibiting a decrease in total plasma soluble epoxide hydrolase-derived oxylipins, exhibited a significant decrease in systolic blood pressure (mean [95% confidence interval], 7.97 [-14.4 to -1.50] mm Hg) versus those who exhibited increased plasma soluble epoxide hydrolase-derived oxylipins (+3.17 [-4.78 to 11.13] mm Hg). These data suggest that a flaxseed bioactive may have decreased blood pressure via soluble epoxide hydrolase inhibition. Using a soluble epoxide hydrolase inhibitor screening assay, increasing concentrations of alpha-linolenic acid decreased soluble epoxide hydrolase activity (P=0.0048; rho=-0.94). In conclusion, alpha linolenic acid in flaxseed may have inhibited soluble epoxide hydrolase, which altered oxylipin concentrations that contributed to the antihypertensive effects in patients with peripheral arterial disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781950. PMID- 24777982 TI - Estrogen metabolism by cytochrome P450 1B1 modulates the hypertensive effect of angiotensin II in female mice. AB - To determine the role of cytochrome P450 (CYP) 1B1 in the sex difference in response to angiotensin II (Ang II)-induced hypertension, female Cyp1b1(+/+) and Cyp1b1(-/-) mice were infused with Ang II (700 ng/kg per minute) or vehicle with or without ovariectomy. In addition, mice were treated with the CYP1B1 inhibitor, 2,3',4,5'-tetramethoxystilbene (TMS; 300 MUg/kg IP, every third day), and 17-beta estradiol metabolites, 2-hydroxyestradiol (2-OHE), 4-OHE, or 2-methoxyestradiol (1.5 mg/kg per day IP, for 2 weeks) and systolic blood pressure (SBP) measured. Ang II increased SBP more in Cyp1b1(-/-) than in Cyp1b1(+/+) mice (119+/-3-171+/ 11 versus 120+/-4-149+/-4 mm Hg; P<0.05). Ang II caused cardiovascular remodeling and endothelial dysfunction and increased vascular reactivity and oxidative stress in Cyp1b1(-/-) but not in Cyp1b1(+/+)mice. The Ang II-induced increase in SBP was enhanced by ovariectomy and TMS in Cyp1b1(+/+) but not in Cyp1b1(-/-) mice. 2-OHE did not alter Ang II-induced increase in SBP in Cyp1b1(+/+) mice but minimized it in Cyp1b1(-/-) mice, whereas 4-OHE enhanced Ang II-induced increase in SBP in Cyp1b1(+/+) mice but did not alter the increased SBP in Cyp1b1(-/-) mice. 2-OHE-derived catechol-O-methyltransferase metabolite, 2-methoxyestradiol, inhibited Ang II-induced increase in SBP in Cyp1b1(-/-) mice. Ang II increased plasma levels of 2-methoxyestradiol in Cyp1b1(+/+) but not in Cyp1b1(-/-) mice and increased activity of cardiac extracellular signal-regulated kinase 1/2, p38 mitogen-activated kinase, c-Src, and Akt in Cyp1b1(-/-) but not in Cyp1b1(+/+) mice. These data suggest that CYP1B1 protects against Ang II-induced hypertension and associated cardiovascular changes in female mice, most likely mediated by 2 methoxyestradiol-inhibiting oxidative stress and the activity of these signaling molecules. PMID- 24777983 TI - Urinary angiotensinogen excretion is associated with blood pressure independent of the circulating renin-angiotensin system in a group of african ancestry. AB - Although the circulating renin-angiotensin system (RAS) is suppressed in salt sensitive populations, the role of the intrarenal RAS in blood pressure (BP) control in these groups independent of the circulating RAS is uncertain. We evaluated the relationship between 24-hour urinary angiotensinogen excretion and either office (mean of 5 measurements; n=425) or 24-hour ambulatory (n=340) BP independent of the circulating RAS in a community-based sample of African descent that had never received antihypertensive drug therapy. Circulating RAS activity was determined from plasma renin and angiotensinogen and serum aldosterone concentrations. Urinary angiotensinogen to creatinine ratio (angiotensinogen/creat) was correlated with plasma angiotensinogen concentrations (P<0.0005) but not with indexes of salt intake. However, urinary angiotensinogen/creat was independently associated with office systolic BP (partial r=0.16; P<0.001), whereas plasma angiotensinogen (partial r=0.07; P=0.14) was not independently associated with office systolic BP. Urinary angiotensinogen/creat was also associated with 24-hour systolic BP (partial r=0.11; P<0.05). The relationships between urinary angiotensinogen/creat and BP survived further adjustments for plasma angiotensinogen and serum aldosterone concentrations, plasma renin concentrations, estimated glomerular filtration rate, urinary Na(+)/K(+), or 24-hour urinary Na(+) excretion rates (P<0.005 for all). Participants with the highest compared with the lowest quartile of urinary angiotensinogen/creat showed an 8.2-mm Hg higher office (P<0.005) and 4.6-mm Hg higher 24-hour (P=0.01) systolic BP. In conclusion, independent of the systemic RAS, including plasma angiotensinogen concentrations, urinary angiotensinogen excretion is associated with BP in a salt-sensitive, low-renin group of African descent. These data lend further support for a role of the RAS in BP control in salt-sensitive groups of African ancestry. PMID- 24777984 TI - Cell-autonomous role of endothelial GTP cyclohydrolase 1 and tetrahydrobiopterin in blood pressure regulation. AB - Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase (eNOS) function and NO generation. Augmentation of BH4 levels can prevent eNOS uncoupling and can improve endothelial dysfunction in vascular disease states. However, the physiological requirement for de novo endothelial cell BH4 biosynthesis in eNOS function remains unclear. We generated a novel mouse model with endothelial cell-specific deletion of GCH1, encoding GTP cyclohydrolase 1, an essential enzyme for BH4 biosynthesis, to test the cell autonomous requirement for endothelial BH4 biosynthesis in vivo. Mice with a floxed GCH1 allele (GCH1(fl/fl)) were crossed with Tie2cre mice to delete GCH1 in endothelial cells. GCH1(fl/fl)Tie2cre mice demonstrated virtually absent endothelial NO bioactivity and significantly greater O2 (*-) production. GCH1(fl/fl)Tie2cre aortas and mesenteric arteries had enhanced vasoconstriction to phenylephrine and impaired endothelium-dependent vasodilatations to acetylcholine and SLIGRL. Endothelium-dependent vasodilatations in GCH1(fl/fl)Tie2cre aortas were, in part, mediated by eNOS-derived hydrogen peroxide (H2O2), which mediated vasodilatation through soluble guanylate cyclase. Ex vivo supplementation of aortic rings with the BH4 analogue sepiapterin restored normal endothelial function and abolished eNOS-derived H2O2 production in GCH1(fl/fl)Tie2cre aortas. GCH1(fl/fl)Tie2cre mice had higher systemic blood pressure than wild-type littermates, which was normalized by NOS inhibitor, NG nitro-L-arginine methyl ester. Taken together, these studies reveal an endothelial cell-autonomous requirement for GCH1 and BH4 in regulation of vascular tone and blood pressure and identify endothelial cell BH4 as a pivotal regulator of NO versus H2O2 as alternative eNOS-derived endothelial-derived relaxing factors. PMID- 24777985 TI - Gender-dependent association of body mass index and waist circumference with disability in the Chinese oldest old. AB - OBJECTIVES: To explore associations of BMI and waist circumference (WC) with disability among the Chinese oldest old. METHODS: The 5,495 oldest old in the sixth wave of Chinese Longitudinal Healthy Longevity Study conducted in 2011 were included in this study. Disability was assessed by activities of daily living (ADL); height and weight for BMI and WC were measured; information including socio-demographics, lifestyles, and health status was collected. RESULTS: Generalized additive models analysis showed that the association of BMI/WC with ADL disability was nonlinear. Among the males, logistic regression results supported a "J" shape association between ADL disability with BMI/WC-the highest tertile group in BMI or WC was significantly associated with an increased risk of ADL disability: odds ratio 1.78 (95% confidence interval (CI): 1.26-2.52) for BMI and 2.01 (95% CI: 1.44-2.82) for WC. Among females, an inverse "J" shape association was found, only the lowest tertile group before the cutoff point had an increased risk of ADL disability: odds ratio 1.42 (95%CI: 1.02-1.97) for BMI and 1.47 (95% CI:1.06-2.04) for WC. CONCLUSIONS: Associations of BMI and WC with ADL disability are significant even in the oldest old, but differ between the genders. PMID- 24777986 TI - Effect of ambient light on monoclonal antibody product quality during small-scale mammalian cell culture process in clear glass bioreactors. AB - During a small-scale cell culture process producing a monoclonal antibody, a larger than expected difference was observed in the charge variants profile of the harvested cell culture fluid (HCCF) between the 2 L and larger scales (e.g., 400 L and 12 kL). Small-scale studies performed at the 2 L scale consistently showed an increase in acidic species when compared with the material made at larger scale. Since the 2 L bioreactors were made of clear transparent glass while the larger scale reactors are made of stainless steel, the effect of ambient laboratory light on cell culture process in 2 L bioreactors as well as handling the HCCF was carefully evaluated. Photoreactions in the 2 L glass bioreactors including light mediated increase in acidic variants in HCCF and formulation buffers were identified and carefully analyzed. While the acidic variants comprised of a mixture of sialylated, reduced disulfide, crosslinked (nonreducible), glycated, and deamidated forms, an increase in the nonreducible forms, deamidation and Met oxidation was predominantly observed under light stress. The monoclonal antibody produced in glass bioreactors that were protected from light behaved similar to the one produced in the larger scale. Our data clearly indicate that care should be taken when glass bioreactors are used in cell culture studies during monoclonal antibody production. PMID- 24777987 TI - Connecting growth and defense: the emerging roles of brassinosteroids and gibberellins in plant innate immunity. AB - Brassinosteroids (BRs) and gibberellins (GAs) are two groups of phytohormones that regulate many common developmental processes throughout the plant life cycle. Fueled by large-scale 'omics' technologies and the burgeoning field of plant computational biology, the past few years have witnessed paradigm-shifting advances in our understanding of how BRs and GA are perceived and their signals transduced. Accumulating evidence also implicates BR and GA in the coordination and integration of plant immune responses. Similarly to other growth regulators, BR and GA play ambiguous roles in molding pathological outcomes, the effects of which may depend not only on the pathogen's lifestyle and infection strategy, but also on specialized features of each interaction. Analysis of the underpinning molecular mechanisms points to a crucial role of GA-inhibiting DELLA proteins and the BR-regulated transcription factor BZR1. Acting at the interface of developmental and defense signaling, these proteins likely serve as central hubs for pathway crosstalk and signal integration, allowing appropriate modulation of plant growth and defense in response to various stimuli. In this review, we outline the latest discoveries dealing with BR and GA modulation of plant innate immunity and highlight interactions between BR and GA signaling, plant defense, and microbial virulence. PMID- 24777988 TI - Negative feedback regulation of auxin signaling by ATHB8/ACL5-BUD2 transcription module. AB - The role of auxin as main regulator of vascular differentiation is well established, and a direct correlation between the rate of xylem differentiation and the amount of auxin reaching the (pro)cambial cells has been proposed. It has been suggested that thermospermine produced by ACAULIS5 (ACL5) and bushy and dwarf2 (BUD2) is one of the factors downstream to auxin contributing to the regulation of this process in Arabidopsis. Here, we provide an in-depth characterization of the mechanism through which ACL5 modulates xylem differentiation. We show that an increased level of ACL5 slows down xylem differentiation by negatively affecting the expression of homeodomain-leucine zipper (HD-ZIP) III and key auxin signaling genes. This mechanism involves the positive regulation of thermospermine biosynthesis by the HD-ZIP III protein Arabidopsis thaliana homeobox8 tightly controlling the expression of ACL5 and BUD2. In addition, we show that the HD-ZIP III protein REVOLUTA contributes to the increased leaf vascularization and long hypocotyl phenotype of acl5 likely by a direct regulation of auxin signaling genes such as like auxin resistant2 (LAX2) and LAX3. We propose that proper formation and differentiation of xylem depend on a balance between positive and negative feedback loops operating through HD-ZIP III genes. PMID- 24777990 TI - Internalized and newly synthesized Arabidopsis PIN-FORMED2 pass through brefeldin A compartments: a new insight into intracellular dynamics of the protein by using the photoconvertible fluorescence protein Dendra2 as a tag. PMID- 24777991 TI - Modulation of mAb quality attributes using microliter scale fed-batch cultures. AB - A high-throughput DoE approach performed in a 96-deepwell plate system was used to explore the impact of media and feed components on main quality attributes of a monoclonal antibody. Six CHO-S derived clonal cell lines expressing the same monoclonal antibody were tested in two different cell culture media with six components added at three different levels. The resulting 384 culture conditions including controls were simultaneously tested in fed-batch conditions, and process performance such as viable cell density, viability, and product titer were monitored. At the end of the culture, supernatants from each condition were purified and the product was analyzed for N-glycan profiles, charge variant distribution, aggregates, and low molecular weight forms. The screening described here provided highly valuable insights into the factors and combination of factors that can be used to modulate the quality attributes of a molecule. The approach also revealed specific intrinsic differences of the selected clonal cell lines - some cell lines were very responsive in terms of changes in performance or quality attributes, whereas others were less affected by the factors tested in this study. Moreover, it indicated to what extent the attributes can be impacted within the selected experimental design space. The outcome correlated well with confirmations performed in larger cell culture volumes such as small-scale bioreactors. Being fast and resource effective, this integrated high-throughput approach can provide information which is particularly useful during early stage cell culture development. PMID- 24777989 TI - Growth-defense tradeoffs in plants: a balancing act to optimize fitness. AB - Growth-defense tradeoffs are thought to occur in plants due to resource restrictions, which demand prioritization towards either growth or defense, depending on external and internal factors. These tradeoffs have profound implications in agriculture and natural ecosystems, as both processes are vital for plant survival, reproduction, and, ultimately, plant fitness. While many of the molecular mechanisms underlying growth and defense tradeoffs remain to be elucidated, hormone crosstalk has emerged as a major player in regulating tradeoffs needed to achieve a balance. In this review, we cover recent advances in understanding growth-defense tradeoffs in plants as well as what is known regarding the underlying molecular mechanisms. Specifically, we address evidence supporting the growth-defense tradeoff concept, as well as known interactions between defense signaling and growth signaling. Understanding the molecular basis of these tradeoffs in plants should provide a foundation for the development of breeding strategies that optimize the growth-defense balance to maximize crop yield to meet rising global food and biofuel demands. PMID- 24777992 TI - Early weight regain after gastric bypass does not affect insulin sensitivity but is associated with elevated ghrelin. AB - OBJECTIVES: We sought to determine: (1) if early weight regain between 1 and 2 years after Roux-en-Y gastric bypass (RYGB) is associated with worsened hepatic and peripheral insulin sensitivity, and (2) if preoperative levels of ghrelin and leptin are associated with early weight regain after RYGB. METHODS: Hepatic and peripheral insulin sensitivity and ghrelin and leptin plasma levels were assessed longitudinally in 45 subjects before RYGB and at 1 month, 6 months, 1 year, and 2 years postoperatively. Weight regain was defined as >=5% increase in body weight between 1 and 2 years after RYGB. RESULTS: Weight regain occurred in 33% of subjects, with an average increase in body weight of 10 +/- 5% (8.5 +/- 3.3 kg). Weight regain was not associated with worsening of peripheral or hepatic insulin sensitivity. Subjects with weight regain after RYGB had higher preoperative and postoperative levels of ghrelin compared to those who maintained or lost weight during this time. Conversely, the trajectories of leptin levels corresponded with the trajectories of fat mass in both groups. CONCLUSIONS: Early weight regain after RYGB is not associated with a reversal of improvements in insulin sensitivity. Higher preoperative ghrelin levels might identify patients that are more susceptible to weight regain after RYGB. PMID- 24777993 TI - Prescription of potentially inappropriate medications to elderly hemodialysis patients: prevalence and predictors. AB - BACKGROUND: In elderly hemodialysis (HD) patients, the risk of medication-related problems is particularly high. Thus, certain medications should generally not be prescribed to those patients. The Beers criteria for potentially inappropriate medications (PIMs) have been publicized. Still, with regard to elderly HD patients, the prevalence and risk factors for prescription of PIMs are unknown. METHODS: This was a cross-sectional study of data from the Japan Dialysis Outcomes and Practice Patterns Study (2002-08). Patients were included if they were 65 years old or older and were currently receiving HD treatment at a hospital or clinic. We counted the number of patients who were prescribed at least one PIM, as defined by the modified Beers criteria. We used multiple logistic regression analysis to determine which patient characteristics and facility characteristics were associated with prescription of PIMs. RESULTS: Data from 1367 elderly patients were analyzed. More than half of the patients (57%) had been prescribed a PIM. The three most frequently prescribed PIMs were H2 blockers (33%), antiplatelet agents (19%) and alpha-blockers (13%). PIM prescriptions were less likely at facilities that conducted multidisciplinary rounds {adjusted odds ratio (AOR): 0.67 [95% confidence interval (CI): 0.48 0.93]} and at teaching hospitals [AOR: 0.59 (95% CI, 0.39-0.90)]. PIM prescriptions are more likely if more than one physician has clearance to alter the HD regimen [AOR: 1.65 (95% CI, 1.12-2.44)]. CONCLUSIONS: PIMs were prescribed to many elderly HD patients in Japan. Nephrologists should become more aware of PIMs. Multidisciplinary rounds could benefit patients by reducing the prescription of PIMs. PMID- 24777994 TI - The Journal of the American Osteopathic Association: the next generation. PMID- 24777995 TI - Wikipedia: proceed with caution. PMID- 24777996 TI - Osteopathic graduate medical education: new research standards needed. PMID- 24777997 TI - An unexpectedly progressed lumbar herniated disk. PMID- 24777999 TI - Somatic dysfunction and use of osteopathic manual treatment techniques during ambulatory medical care visits: a CONCORD-PBRN study. AB - CONTEXT: Osteopathic manual treatment (OMT) of somatic dysfunction is a unique approach to medical care that may be studied within a practice-based research network. OBJECTIVE: To measure patient characteristics and osteopathic physician practice patterns within the Consortium for Collaborative Osteopathic Research Development-Practice-Based Research Network (CONCORD-PBRN). DESIGN: Cross sectional card study. SETTING: Eleven member clinics within the CONCORD-PBRN coordinated by The Osteopathic Research Center. PATIENTS: A total of 668 patients seen between January and March 2013. MAIN STUDY MEASURES: Patient age and sex; primary diagnoses; somatic dysfunction as manifested by tenderness, asymmetry, restricted motion, or tissue texture changes; and use of 14 OMT techniques. Results were stratified by anatomical region and adjusted for clustering within member clinics. Clustering was measured by the intracluster correlation coefficient. RESULTS: Patient ages ranged from 7 days to 87 years (adjusted mean age, 49.2 years; 95% confidence interval [CI], 43.3-55.1 years). There were 450 females (67.4%) and 508 patient visits (76.0%) involved a primary diagnosis of disease of the musculoskeletal system and connective tissue. Structural examination was performed during 657 patient visits (98.4%), and 649 visits (97.2%) involved OMT. Restricted motion and tenderness were the most and least common palpatory findings, respectively. Cranial (1070 [14.5%]), myofascial release (1009 [13.7%]), muscle energy (1001 [13.6%]), and counterstrain (980 [13.3%]) techniques were most commonly used, accounting for more than one-half of the OMT provided. Pediatric patients were more likely than adults to receive OMT within the head (adjusted odds ratio [OR], 9.53; 95% CI, 1.28-71.14). Geriatric patients were more likely than adults to receive a structural examination (adjusted OR, 1.83; 95% CI, 1.09-3.07) and OMT (adjusted OR, 1.62; 1.02-2.59) within the lower extremity. Females were more likely than males to receive a structural examination (adjusted OR, 2.44; 95% CI, 1.44-4.16) and OMT (adjusted OR, 2.11; 95% CI, 1.26-3.52) within the sacrum and OMT within the pelvis (adjusted OR, 1.79; 95% CI, 1.12-2.88). Intracluster correlation coefficients for the 4 most commonly used OMT techniques ranged from 0.34 to 0.72. CONCLUSION: This study provides proof of concept of the feasibility of studying osteopathic medical practice on a national level by developing and growing the CONCORD-PBRN. PMID- 24778000 TI - Association of low back pain, somatic dysfunction, and lumbar bone mineral density: reproducibility of findings. AB - CONTEXT: Somatic dysfunction as diagnosed by palpation should be associated with an objective measure. Bone mineral density (BMD) has been shown to be elevated in lumbar vertebrae with somatic dysfunction and in the lumbar region of individuals with chronic low back pain (LBP). OBJECTIVE: To investigate the association of lumbar somatic dysfunction and BMD T-score variability in participants with chronic LBP and without LBP (non-LBP) and to determine the reproducibility of previously published results. METHODS: Two examiners, blinded to symptom history, evaluated participants for tissue texture abnormalities, rotational asymmetry, anterior motion restriction, and tenderness at vertebral levels L1 to L4. Participants also underwent dual-energy x-ray absorptiometry of vertebral levels L1 to L4 for the assessment of BMD T scores. Generalized linear models were used to compare the chronic LBP and non-LBP groups on the presence and severity of somatic dysfunction and to test whether group and the presence and severity of somatic dysfunction were related to BMD T scores. RESULTS: Forty-three chronic LBP (54%) and 36 non-LBP participants (46%) completed the study. Although the presence of somatic dysfunction in the 2 groups was not significantly different, the presence of tenderness was significantly more common in the chronic LBP group (P<.001), as was the severity for tissue texture abnormalities (P=.03), motion restriction (P=.04), and tenderness (P<.001). Of the 316 vertebrae assessed, 31 (10%, all in the chronic LBP group) had moderate/severe tenderness. The vertebral somatic dysfunction burden score, the total somatic dysfunction burden score, the vertebral somatic dysfunction severity score, and the total somatic dysfunction severity score were higher in the chronic LBP group (all P<.001). The vertebral BMD T score was significantly higher for vertebrae demonstrating moderate/severe rotational asymmetry compared with those demonstrating mild or no rotational asymmetry (P=.01) and for vertebrae demonstrating moderate/severe tenderness compared with those demonstrating no tenderness (P=.04). CONCLUSION: Study results suggest that somatic dysfunction was more significant in chronic LBP participants. Although the correlation between the presence of somatic dysfunction and segmental BMD T scores was not reproduced, BMD T scores were higher for vertebrae demonstrating moderate/severe rotational asymmetry and tenderness. PMID- 24778001 TI - Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions. AB - CONTEXT: Since its launch in 2001, Wikipedia has become the most popular general reference site on the Internet and a popular source of health care information. To evaluate the accuracy of this resource, the authors compared Wikipedia articles on the most costly medical conditions with standard, evidence-based, peer-reviewed sources. METHODS: The top 10 most costly conditions in terms of public and private expenditure in the United States were identified, and a Wikipedia article corresponding to each topic was chosen. In a blinded process, 2 randomly assigned investigators independently reviewed each article and identified all assertions (ie, implication or statement of fact) made in it. The reviewer then conducted a literature search to determine whether each assertion was supported by evidence. The assertions found by each reviewer were compared and analyzed to determine whether assertions made by Wikipedia for these conditions were supported by peer-reviewed sources. RESULTS: For commonly identified assertions, there was statistically significant discordance between 9 of the 10 selected Wikipedia articles (coronary artery disease, lung cancer, major depressive disorder, osteoarthritis, chronic obstructive pulmonary disease, hypertension, diabetes mellitus, back pain, and hyperlipidemia) and their corresponding peer-reviewed sources (P<.05) and for all assertions made by Wikipedia for these medical conditions (P<.05 for all 9). CONCLUSION: Most Wikipedia articles representing the 10 most costly medical conditions in the United States contain many errors when checked against standard peer-reviewed sources. Caution should be used when using Wikipedia to answer questions regarding patient care. PMID- 24778002 TI - Effect of osteopathic manipulative therapy in the attentive performance of children with attention-deficit/hyperactivity disorder. AB - CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder most commonly affecting children and teenagers. It is characterized by the coexistence of attention problems and impulsivity and hyperactivity. Although several studies have been conducted on the efficacy of conventional and alternative therapies in children with ADHD, few studies have specifically investigated the efficacy of osteopathic manipulative therapy (OMTh). OBJECTIVE: To evaluate the efficacy of OMTh in the treatment of children with ADHD. METHODS: Children aged 5 to 15 years with a primary diagnosis of ADHD who were admitted to a single neuropsychiatry unit from November 2008 to September 2009 were randomly assigned to an intervention group (OMTh + conventional care) or a control group (conventional care only). Biancardi-Stroppa Modified Bell Cancellation Test accuracy and rapidity scores were recorded for both groups at baseline and after 10 weeks. Statistical analyses included univariate tests and multivariate linear regressions. RESULTS: A total of 28 participants were included in the study: 14 in the OMTh group and 14 in the control group. Univariate statistical analysis showed no statistically significant differences between the intervention and control groups in terms of characteristics measured at baseline, except for psychosocial intervention (P=.05). Multivariate linear regression showed that OMTh was positively associated with changes in the Biancardi-Stroppa Test accuracy (beta=7.948 points; P=.04) and rapidity (beta=9.089 points; P=.03) scores. CONCLUSION: Participants who received OMTh had greater improvement in Biancardi-Stroppa Test scores than participants who received conventional care only, suggesting that OMTh can potentially increase performances of selective and sustained attention in children with ADHD. To confirm these findings, studies of larger and more diverse populations are warranted. PMID- 24778003 TI - Management of ionizing radiation injuries and illnesses, part 2: nontherapeutic radiologic/nuclear incidents. AB - In the second of 5 articles on the management of injuries and illnesses caused by ionizing radiation, the authors discuss nontherapeutic radiologic/nuclear incidents: use of a radiologic exposure device, use of a radiologic dispersal device, nuclear power plant safety failure, and detonation of an improvised nuclear device. The present article focuses on how such incidents--whether involving deliberate or accidental methods of radiation exposure--produce casualties and how physicians need to understand the pathologic process of injuries caused by these incidents. To identify the diagnoses associated with nontherapeutic exposure in time to improve morbidity and mortality, physicians must maintain a high index of suspicion when faced with a specific constellation of symptoms. In some scenarios, the sheer number of uninjured, unaffected persons who might present to health care institutions or professionals may be overwhelming. Public health and safety issues may seriously disrupt the ability to respond to and recover from a radiologic and nuclear incident, especially a nuclear detonation. PMID- 24778004 TI - The 'little m.d.' or the 'big D.O.': the path to the California merger. AB - In the years following the American Osteopathic Association's sanctioning of the broad teaching of chemical and biological agents, osteopathic physicians moved closer to allopathic physicians with respect to diagnosis and treatment. In the 1930s, osteopathic colleges began to adopt standards and improve their basic science and clinical training, which allowed them to produce graduates who did substantially better in passing external examinations to become licensed as physicians and surgeons. Nevertheless, many state legislatures refused to grant DOs unlimited licenses and osteopathic physicians were unable to obtain medical commissions during the Second World War. In California, despite significant accomplishments on the social and legislative fronts, a growing number of osteopathic physicians believed that their DO degree and independent status as a separate medical profession was an impediment to achieving equality with their allopathic counterparts, and they worked toward a merger or amalgamation with their long-time opponents. PMID- 24778005 TI - Sever disease (calcaneal apophysitis). PMID- 24778006 TI - To an intern: what if you were the patient? PMID- 24778007 TI - Molecular biomarkers and classification models in the evaluation of the prognosis of colorectal cancer. AB - Colorectal cancer (CRC) is the second leading cause of cancer-related death. Despite the progress that has been made towards the identification of the molecular mechanisms involved in CRC, currently there are many unclear points. The current opinion is that microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and chromosomal instability (CIN) seem to play a significant role. MSI is related to point mutations in defect mismatch repair system of DNA. There are two well-established MSI phenotypes: MSI-high (MSI-H) and MSI-low (MSI-L or MSS). CIN refers to a different cellular event which originates from the presence of an abnormal chromosome complement or number. CIMP is the third most commonly involved event, and is defined by widespread methylation of CpG islands of suppressor promoters, with two phenotypes: CIMP high and CIMP-low which interact with MSI or CIN status V-raf murine sarcoma viral oncogene homolog B (BRAF) is a serine-threonine protein kinase that acts as a downstream effector of the Kirsten rat sarcoma viral oncogene homolog (KRAS) pathway. Various studies have revealed that BRAF V600E mutations appear to be a valid indicator of poor prognosis. KRAS is a proto- oncogene which encodes a GTP ase involved in cellular response to extracellular stimuli. Its prognostic value is still controversial. However, wild-type KRAS is associated with better response to Endothelial Growth Factor Receptor inhibitors combined with standard chemotherapy. Loss of Heterozygosity, especially involving 18q, is a well-known potential mechanism for tumorigenesis that has been studied in CRC. Vascular endothelial growth factor is a pro-angiogenic factor linked with the aggressiveness of CRC. Emerging data show that cycloxygenase 2 overexpression is significantly associated with worse outcomes in CRC. Recent studies highlight mi croRNAs as promising prognostic biomarkers. More specifically, the down regulation of miR-451, miR-625, miR-29c, miR-126, miR-129 and miR133 is purported to be a poor prognostic factor, while miR-224 was overexpressed in CRC. PMID- 24778008 TI - Advanced epithelial ovarian cancer: from standard chemotherapy to promising molecular pathway targets--where are we now? AB - Ovarian cancer is the most frequent cause of death from gynaecological malignancy in the Western countries, and differences in outcome among different histological subtypes are being increasingly recognized. It is generally considered as chemosensitive, but resistant clones evolve in the majority of cases, at varying rates. In this brief review, we describe advances in conventional chemotherapy, particularly the use of weekly paclitaxel. We then focus on new promising agents that target certain pathways which drive the genesis and evolution of ovarian cancer; these include poly(ADP-ribose) polymerase (PARP) inhibitors targeting tumor cells deficient in homologous recombination. We also discuss other targets including the folate receptor. Ovarian cancer has also proved to be one of the most sensitive types of cancer to an anti-angiogenic approach and we summarize recent experience using a range of agents. PMID- 24778009 TI - Gastrectomy for stage IV gastric cancer. a systematic review and meta-analysis. AB - AIM: Gastrectomy as a primary treatment for patients with metastatic gastric cancer (M1) is highly controversial. Herein, a review of the literature was undertaken with the aim of assessing evidence regarding associated morbidity and mortality, overall survival, palliation and quality of life. MATERIALS AND METHODS: A systematic review of the literature from 1980 to 2013 was undertaken to identify relevant studies. Outcome data were pooled, and combined overall effect sizes were calculated using fixed or random effects models. The search identified 19 non-randomized studies reporting on 2,911 patients. RESULTS: Overall postoperative mortality and morbidity were 14% and 27% and were higher in Western than in Asian patients. In studies published during the past decade postoperative mortality was less than 5%. The weighted 1- and 2-year overall survival rates were 38% and 17%, and were twice as high in Asian versus Western patients. In the meta-analysis, the 1-year overall survival was significantly higher in patients undergoing gastrectomy versus conservative (odds ratio (OR)=4.9, 95% confidence interval (CI)=3.2 to 7.5, p<0.0001) or gastrectomy versus non-resectional treatment (OR=2.6, 95% CI=1.7 to 4.3, p<0.0001). Studies reporting on quality of life and palliation indicate a possible benefit of such palliative gastrectomy. CONCLUSION: A possible benefit of gastrectomy compared to non-resectional treatment for stage IV gastric cancer in terms of survival and palliation was evident but has to be cautiously interpreted due to potential sources of bias of retrospective non-randomized studies. Several questions regarding the optimal management of these patients remain unanswered and require a properly-designed randomized trial. PMID- 24778010 TI - Colorectal cancer: seed and soil hypothesis revisited. AB - The local growth and metastatic potential of colorectal cancer is the outcome of a dynamic balance between cancer cells and the immune system, at both a local and systemic level, summarized as the "seed and soil" hypothesis. Until recently, the staging and treatment approaches for colorectal cancer appeared to be orientated predominantly to the 'seed' component, virtually neglecting, in daily clinical practice, the impact of the 'soil' in the natural course of the disease. We are currently witnessing an increasing amount of evidence, spanning from clinical to laboratory research, which highlight that cancer growth and metastasis is the result of the dynamic balance between the disease itself and the impaired function of the immune system. Herein, we attempt to elucidate the vicious circle between impaired immune response and colorectal cancer progression, highlighting the urgent need for a qualitive turn in confronting cancer, which is based on two pillars with regulation of both the seed and the soil. PMID- 24778012 TI - MicroRNA signatures in subtypes of follicular lymphoma. AB - BACKGROUND: MicroRNAs are regulators of gene expression implicated in vital cellular processes including differentiation, cell growth and apoptosis. Distinct microRNA signatures have been identified for many malignancies including follicular lymphoma (FL). However, no microRNA expression profile characteristic of FL subtypes, e.g. FL with B-cell lymphoma-6 (BCL6) locus rearrangement (FL(BCL2+/BCL6+), FL(BCL2-/BCL6+)) or FL with diffuse growth pattern have been reported. MATERIALS AND METHODS: MicroRNA signatures from 44 cases of FL were generated employing a quantitative real-time polymerase chain reaction approach. 15 cases of diffuse FL and 15 cases of FL(BCL2+/BCL6+)/FL(BCL2-/BCL6+) were compared against 14 cases of typical FL(BCL2+/BCL6-). RESULTS: Numerous microRNAs were found to be differentially expressed between FL(BCL2+/BCL6+) and FL(BCL2 /BCL6+), as well as diffuse FL, when compared to typical cases of FL. Up regulation of several oncogenic microRNAs as well as down-regulation of tumor suppressor microRNAs was identified. Cluster analysis, however, revealed no microRNA signatures distinct from the reference group for either subtype. CONCLUSION: These results indicate an involvement of microRNAs in the pathogenesis of FL and its subtypes. Marked de-regulation of oncogenic RNAs and tumor suppressors appears to correspond with a more aggressive phenotype frequently observed in FL(BCL2+/BCL6+), FL(BCL2-/BCL6+) and diffuse FL. PMID- 24778011 TI - Bone morphogenetic protein-focused strategies to induce cytotoxicity in lung cancer cells. AB - BACKGROUND: High bone morphogenetic protein (BMP)-2 expression in lung carcinoma correlates with poor patient prognosis. The present study explored strategies to repress BMP signaling. MATERIALS AND METHODS: The cytotoxicity of BMP2-knockdown, dorsomorphin derivatives, and microRNAs was tested in transformed and non transformed lung cells. Microarray analyses of 1,145 microRNAs in A549 lung adenocarcinoma cells and two other transformed lung cell types relative to BEAS 2B bronchial epithelial cells were performed. RESULTS: Reduced BMP2 synthesis inhibited A549 cell growth. The dorsomorphin derivative LDN-193189, but not DMH1 or DMH4, was strongly cytotoxic towards A549 cells, but not towards BEAS-2B cells. Microarray analysis revealed that 106 miRNAs were down-regulated and 69 miRNAs were up-regulated in the three transformed lines. Three down-regulated miRNAs, hsa-mir-34b, hsa-mir-34c-3p, and hsa-miR-486-3p, repressed a BMP2 reporter gene and were cytotoxic in A549 cells, but not towards BEAS-2B cells. CONCLUSION: The observed cytotoxicity suggests that reducing BMP signaling is a useful line of attack for therapy of lung cancer. PMID- 24778013 TI - Neamine inhibits oral cancer progression by suppressing angiogenin-mediated angiogenesis and cancer cell proliferation. AB - BACKGROUND: Angiogenin undergoes nuclear translocation and stimulates ribosomal RNA transcription in both endothelial and cancer cells. Consequently, angiogenin has a dual effect on cancer progression by inducing both angiogenesis and cancer cell proliferation. The aim of this study was to assess whether neamine, a blocker of nuclear translocation of angiogenin, possesses antitumor activity toward oral cancer. MATERIALS AND METHODS: The antitumor effect of neamine on oral cancer cells was examined both in vitro and in vivo. RESULTS: Neamine inhibited the proliferation of HSC-2, but not that of SAS oral cancer cells in vitro. Treatment with neamine effectively inhibited growth of HSC-2 and SAS cell xenografts in athymic mice. Neamine treatment resulted in a significant decrease in tumor angiogenesis, accompanied by a decrease in angiogenin- and proliferating cell nuclear antigen-positive cancer cells, especially of HSC-2 tumors. CONCLUSION: Neamine effectively inhibits oral cancer progression through inhibition of tumor angiogenesis. Neamine also directly inhibits proliferation of certain types of oral cancer cells. Therefore, neamine has potential as a lead compound for oral cancer therapy. PMID- 24778014 TI - Fluorescent resonance energy transfer imaging of VEGFR dimerization. AB - Activation of vascular endothelial growth factor receptor 1 (VEGFR1/FLT1) and 2 (VEGFR2/KDR) involves receptor dimerization. Formation of VEGFR dimer has so far not been visualized in single intact cells. In the present study we describe different optical assays which can be used to observe dimerization of VEGFR1 and VEGFR2. Bimolecular fluorescence complementation (BIFC) assays confirmed homo,- and heterodimerization of transfected receptors. Fluorescence resonance energy transfer (FRET) techniques in living and fixed CHO-K1 cells allowed observation of VEGFR1 homodimer,- and VEGFR1 and VEGFR2 heterodimer formation after ligand stimulation. After inhibition of ligand binding by the VEGFA JH121 antibody VEGFR1 homodimerization was completely abolished. Under the same conditions, cells transfected by VEGFR1 and VEGFR2 maintained relevant receptor heterodimerization. These techniques to monitor VEGFR1 and VEGFR2 homo- and heterodimerization in living and fixed cells may help in the search for new angiogenesis-directed inhibitors of VEGFR dimerization. PMID- 24778015 TI - Reproducibility of histogram and texture parameters derived from intravoxel incoherent motion diffusion-weighted MRI of FN13762 rat breast Carcinomas. AB - AIM: To determine the reproducibility of histogram and texture parameters derived from intravoxel incoherent motion (IVIM) diffusion-weighted magnetic resonance imaging (MRI) of FN13762 rat breast carcinomas. MATERIALS AND METHODS: IVIM diffusion-weighted MRI was performed twice, nine days after tumor implantation in 11 rats. At each session, histogram and texture parameters of entire tumors were extracted from apparent diffusion coefficient (ADC), true-diffusion coefficient (Dt), pseudo-diffusion coefficient (Dp), and perfusion fraction (Pf) maps. Intraobserver and interscan measurement reproducibilities were evaluated using intraclass correlation coefficients (ICC). RESULTS: Mean, entropy, 5th, 10th, 25th percentiles from ADC and Dt maps revealed good intra-observer and interscan agreements [lower limits of 95% confidence interval (CI) for ICC>=0.75]. However, all parameters from Dp and Pf maps gave relatively poor intra-observer and interscan agreements (lower limits of 95% CI for ICC<0.75). CONCLUSION: Histogram and texture parameters derived from ADC and Dt maps were more reproducible than those from Dp and Pf maps. PMID- 24778016 TI - Serum detection of thymidine kinase 1 as a means of early detection of lung cancer. AB - BACKGROUND: Thymidine kinase 1 (TK1) is a biomarker elevated in several malignancies, including lung cancer. Up-regulation of TK1 is an early event in carcinogenesis and therefore a target for early cancer detection. We have developed a novel Enzyme Linked Immunosorbent Assay (ELISA) to detect TK1 in serum. MATERIALS AND METHODS: Forty patients with pulmonary nodules and 18 healthy individuals had their serum collected prior to surgery. All samples were analyzed using a radioassay and ELISA. RESULTS: TK1 was significantly elevated in all lung cancer samples. Patients with stage I (n=16) and stage II (n=17) disease had significantly higher TK1 levels than controls. The area under the curve was 0.792, using 4.9 nM TK1 as cut-off, for early-stage lung cancer. The sensitivity and specificity were 75.0 and 83.3, respectively. TK1 concentration was a more sensitive and accurate indicator of lung cancer than TK1 activity. CONCLUSION: TK1 is significantly elevated in serum from patients with stage I and stage II lung cancer as measured using the established ELISA. This novel TK1 ELISA is both sensitive and specific for the detection of early-stage and advanced lung cancer, and therefore may be an important tool in the management of this disease. PMID- 24778018 TI - Overexpression of NOTCH-regulated ankyrin repeat protein is associated with breast cancer cell proliferation. AB - BACKGROUND/AIM: NOTCH-regulated ankyrin repeat protein (NRARP) has been implicated in crosstalk between NOTCH and wingless-type mouse mammary tumor virus integration site (WNT) signals during development. Our study aimed to clarify its role in breast cancer cells. MATERIALS AND METHODS: Public microarray data were used to analyze gene expression in human and rat breast cancer. A short interfering RNA was introduced into MCF7 and T47D human breast cancer cells for NRARP silencing. Gene expression was analyzed by quantitative polymerase chain reaction. RESULTS: The NRARP transcript was commonly overexpressed in various rat mammary cancer models. In addition, a subset of human breast cancer also expressed high levels of NRARP transcript, which correlated positively with up regulation of cell proliferation-related genes. Silencing of NRARP suppressed the growth of MCF7 and T47D cells and lowered the expression of cell cycle-related genes in MCF7 cells. CONCLUSION: NRARP may stimulate cell proliferation in human breast cancer. PMID- 24778017 TI - Novel vitamin D analogs as potential therapeutics: metabolism, toxicity profiling, and antiproliferative activity. AB - AIM: To discover novel [20(OH)D3] analogs as antiproliferative therapeutics. MATERIALS AND METHODS: We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism. RESULTS: 20S- and 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 MUg/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes. CONCLUSION: Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents. PMID- 24778019 TI - Gene expression profiling of epithelial-mesenchymal transition in primary breast cancer cell culture. AB - BACKGROUND/AIM: Epithelial-mesenchymal transition (EMT) is a process co-opted by cancer cells to invade and form metastases. In the present study we analyzed gene expression profiles of primary breast cancer cells in culture in order to highlight genes related to EMT. MATERIALS AND METHODS: Microarray expression analysis of primary cells isolated from a specimen of a patient with an infiltrating ductal carcinoma of the breast was performed. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) analyses validated microarray gene expression trends. RESULTS: Thirty-six candidate genes were selected and used to generate a molecular network displaying the tight relationship among them. The most significant Gene Ontology biological processes characterizing this network were involved in cell migration and motility. CONCLUSION: Our data revealed the involvement of new genes which displayed tight relationships among them, suggesting a molecular network in which they could contribute to control of EMT in breast cancer. This study may offer a basis for understanding complex mechanisms which regulate breast cancer progression and for designing individualized anticancer therapies. PMID- 24778020 TI - Down-regulation of WAVE2, WASP family verprolin-homologous protein 2, in gastric cancer indicates lymph node metastasis and cell migration. AB - BACKGROUND: WAVE2 plays a crucial role in actin polymerisation and cell migration. We aimed to investigate the expression and cellular functions of WAVE2 in human gastric cancer (GC). MATERIALS AND METHODS: The level of WAVE2 was determined using quantitative PCR (Q-PCR) in a cohort of human gastric tissues. Expression of WAVE2, ARP2, NWASP, ROCK1 and ROCK2 was examined using RT-PCR in paired tissues. WAVE2 and ARP2 protein co-expression was examined. Anti-WAVE2 transgene ribozymes were constructed and transiently transfected into human GC cells. RESULTS: Down-regulation of WAVE2 expression in GC was significantly correlated with lymph node metastasis. WAVE2 was positively correlated with E cadherin and negatively with TWIST. Immunohistochemically, WAVE2 and ARP2 were not co-expressed in serial mirror sections. In vitro, WAVE2 knockdown was shown to increase cell motility, whilst ROCK inhibitor treatment reduced this effect in HGC27 cells. CONCLUSION: WAVE2 is down-regulated in GC and loses its metastatic role in GC. Knockdown of WAVE2 could increase metastatic potential by promoting the growth, invasiveness, motility, adhesiveness and suppressing EMT (epithelial mesenchymal transition) of GC cells. PMID- 24778021 TI - The real deal: using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells. AB - BACKGROUND/AIM: Sonodynamic therapy (SDT) is a form of ultrasound therapy in which chemotherapeutic agents known as sonosensitizers are administered to increase the efficacy of ultrasound's preferential damage to neoplastic cells. Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. Cytochalasin B is a cytokinesis inhibitor that preferentially enlarges and multinucleates malignant cells, making them much more sensitive to ultrasonic irradiation. MATERIALS AND METHODS: The present study investigated the extent of preferential damage inflicted by cytochalasin B on U937 leukemia/human blood cell populations. Cell mixtures were treated with cytochalasin B and then sonicated under a relatively low intensity (3W/cm(2)). RESULTS: Cytochalasin B preferentially damages U937 cells both before and after sonication. This agent also reduces rapid proliferation as the clonogenicity of U937 cells was considerably reduced following treatment. CONCLUSION: Cytochalasin B may have profound therapeutic applications when combined with SDT. PMID- 24778022 TI - Establishment of a novel cell line from intraductal papillary neoplasm of the bile duct. AB - BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a novel and increasingly-occurring disease. Its characteristics remain uncertain because of the lack of an in vitro culture system. We established and characterized a novel cell line from a human IPNB. MATERIALS AND METHODS: We obtained tumor tissue from a surgical specimen from a patient with IPNB. Cells were primary co-cultured with mouse stromal cells in serum-free medium. Tumor characteristics were compared among the primary IPNB, established cell line, and xenograft. RESULTS: We successfully established an IPNB cell line. We temporary termed this cell line Kobe Bile Duct Cancer (KBDC)-11. Xenograft formed a tumor which had ductal structures and mucus production as the primary tumor did. Overexpression of p53, MUC staining pattern, and CD133 expression were common among the primary IPNB, KBDC-11, and the xenograft. CONCLUSION: This novel cell line established from IPNB exhibited the same features as IPNB and might contribute to studies of IPNB and its process of malignant transformation. PMID- 24778023 TI - Differential expression of galectin-1 and galectin-3 in canine non-malignant and malignant mammary tissues and in progression to metastases in mammary tumors. AB - BACKGROUND: Galectin-1 and galectin-3 are carbohydrate-binding proteins that have been implicated in the pathobiology of several types of cancer. The aim of the present study was to investigate the expression pattern of both these galectins in canine non-neoplastic mammary tissues and mammary tumors (CMT). MATERIALS AND METHODS: Protein and mRNA expression of galectin-1 and -3 were assessed in 12 benign and 41 malignant CMT. RESULTS: Galectin-1 was overexpressed in the majority of malignant CMT cases in tumor cells and stroma. Its expression in malignant tumor cells was associated with smaller-sized tumours. Distant metastases presented a strong intensity of galectin-1 and reduced galectin-3 expression, while the opposite was observed in circulating tumor cells. Interestingly intravascular tumor cells presented galectin-3 up-regulation at the mRNA level. Double-labelling further made it clear that galectin-3 and galectin-1 expression did not overlap in normal-adjacent mammary and CMT cells. CONCLUSION: Taken together, our data suggest that malignant CMT cell sub-populations have alternating expression of galectin-1 or -3. This might confer survival advantage to tumour cells in different phases of tumour progression. PMID- 24778024 TI - Formyl Peptide receptor 1 expression is associated with tumor progression and survival in gastric cancer. AB - BACKGROUND: Formyl peptide receptor 1 (FPR1) as a regulator of innate inflammatory response has been implicated in tumor progression of gliomas. The purpose of the present study was to evaluate the prognostic significance and the ligand-receptor interaction of FPR1 in gastric cancer (GC). PATIENTS AND METHODS: FPR1 was immunohistochemically-analyzed in tissue sections originating from 116 GC patients. Reverse transcription-polymerase chain reaction (RT-PCR) was used for the assessment of interaction between FPR1 and the FPR1 ligand annexin A1 (AnxA1) in GC cells. RESULTS: High FPR1 expression was significantly associated with stage IV disease, submucosal invasion, serosal invasion, and clinical outcome of GC. Multivariate analysis showed that high FPR1 expression was an independent risk factor of poor overall survival in GC patients. FPR1 expression increased significantly when AnxA1 overexpression was present in GC cells. A positive feedback regulation of FPR1 was involved in the AnxA1-FPR1 signal transduction. CONCLUSION: FPR1 expression may be used as a novel indicator to predict outcome in GC patients after gastrectomy. PMID- 24778025 TI - Ouabain enhances lung cancer cell detachment. AB - A human steroid hormone, ouabain, has been shown to play a role in several types of cancer cell behavior; however, its effects on cancer metastasis are largely unknown. Herein, we demonstrate that sub-toxic concentrations of ouabain facilitate cancer cell detachment from the extracellular matrix in human lung cancer cells. Ouabain at concentrations of 0-10 pM significantly enhanced cell detachment in dose- and time- dependent manners, while having minimal effect on cell viability. The detachment-inducing effect of ouabain was found to be mediated through focal-adhesion kinase and ATP-dependent tyrosine kinase pathways. Alpha-5 and beta-1 integrins were found to be down-regulated in response to ouabain treatment. Since detachment of cancer cells is a prerequisite process for metastasis to begin, these insights benefit our understanding over the molecular basis of cancer biology. PMID- 24778026 TI - Novel insights into the expression of CGB1 & 2 genes by epithelial cancer cell lines secreting ectopic free hCGbeta. AB - BACKGROUND: Ectopic secretion of human chorionic gonadotrophin free beta (hCGbeta) by epithelial cancer is associated with aggressive tumors which more readily metastasize, possibly by acting as an autocrine anti-apoptotic agent. hCGbeta is encoded by six homologous CGB genes, with poorly-understood variable transcriptionally active expression profiles; CGB1 and CGB2 have always been considered pseudogenes. However, transcripts from CGB1 and -2 can be detected in placental, testicular and pituitary tissues. The expression and function of these genes in cancer is less well-known. MATERIALS AND METHODS: Expression profiles of CGB genes in epithelial cancer cells by quantitative polymerase chain reaction (qPCR) were explored, along with the consequence of specific siRNA silencing of CGB1 and 2. Immunohistochemical and immunoassay techniques were used to detect the translation and secretion of hCGbeta in these cells. RESULTS: CGB1 and -2 gene transcripts were only detected in cells which secreted hCGbeta. siRNA mediated silencing of CGB1 and -2 transcripts significantly reduced secreted protein in concordance with a reduction in cell survival to a greater degree than that of other CGB genes. CONCLUSION: CGB genes 1 and 2, previously considered as pseudogenes, are notably expressed by epithelial cancer cell lines. The transcription of these genes, but not other CGB genes, correlates with a functionally expressed protein and propensity for cancer growth. PMID- 24778027 TI - Global microRNA profiling of pancreatic neuroendocrine neoplasias. AB - BACKGROUND: Pancreatic neuroendocrine neoplasms (pNEN) are rare tumors with a poor prognosis. Although increasing data have accumulated on the molecular pathology of pNEN, very scarce data exist on microRNAs in pNEN and no data are published on microRNAs as potential biomarkers of pNEN in serum. This study aimed to identify microRNA signatures of pNEN in tissue and serum. MATERIALS AND METHODS: We included tissue samples from 37 patients with pNEN, 9 patients with non-neoplastic pancreatic pathology, seven samples of micro-dissected pancreatic islets and serum samples of 27 patients with pNEN, as well as of 15 healthy volunteers. MicroRNA expression profiles were established using real-time quantitative Polymerase Chain reaction (PCR) for 754 microRNAs. RESULTS: MicroRNA signatures differed between pNEN, pancreatic islets and total pancreas, with virtually no overlap between the groups of de-regulated microRNAs. Expression of miR-642 correlated with Ki67 (MiB1) score and miR-210 correlated with metastatic disease. When comparing microRNA levels in serum from patients with pNEN and healthy volunteers, 13 microRNAs were more abundant in the serum of patients. MiR 193b was also up-regulated in pNEN tissue when compared to pancreatic islets and remained significantly increased in serum even when corrected for multiple testing. CONCLUSION: Evaluation of microRNAs appears to be promising in the assessment of pNEN. In particular, miR-193b, which is also increased in serum, may be a potential new biomarker of pNEN. PMID- 24778028 TI - MALDI imaging on tissue microarrays identifies molecular features associated with renal cell cancer phenotype. AB - AIM: To identify molecular features associated with clinico-pathological parameters in renal cell cancer. MATERIALS AND METHODS: Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging was employed for a kidney cancer tissue microarray containing tissue samples from 789 patients for which clinical follow-up data were available. RESULTS: A comparison of mass spectrometric signals with clinico-pathological features revealed significant differences between papillary and clear cell renal cell cancer. Within the subgroup of clear cell RCC, statistical associations with tumor stage (seven signals, p<0.01 each), Fuhrman grade (seven signals, p<0.0001 each), and presence of lymph node metastases (10 signals, p<0.01 each) were found. In addition, the presence of one signal was significantly linked to shortened patient survival (p=0.0198). CONCLUSION: Our data pinpoint towards various molecules with potential relevance in renal cell cancer. They also demonstrate that the combination of the MALDI mass spectrometry imaging and large-scale tissue microarray platforms represents a powerful approach to identify clinically relevant molecular cancer features. PMID- 24778029 TI - Association of caveolin-1 genotypes with gastric cancer in Taiwan. AB - Gastric cancer is one of the leading causes of tumor-related death worldwide, for which the prevalence and mortality rates are very high in developed countries. Caveolin-1 (Cav-1) is the main protein in the caveolin family and plays a role in tumorigenesis signaling. The contribution of CAV1 genetic variants to gastric cancer is still largely unknown. In the present study, we aimed to investigate the role of CAV1 genotypes in gastric cancer risk. We recruited 358 gastric patients and 358 cancer-free controls for CAV1 genotyping analysis. Six single nucleotide polymorphisms (SNPs) of CAV1, C521A (rs1997623), G14713A (rs3807987), G21985A (12672038), T28608A (rs3757733), T29107A (rs7804372), and G32124A (rs3807992), were genotyped by the polymerase chain reaction-restriction fragment length polymorphism method. There was a significant difference between the gastric cancer and control groups in the genotypic frequency distribution of the CAV1 G14713A genotypes (p=1.24*10(-5)), with those carrying the A allele having a higher risk for gastric cancer compared to those with the GG genotype (p=0.0001). Our findings suggested that CAV1 genotype may determine the individual susceptibility to gastric cancer, and that the CAV1 G14713A genotype may serve as a novel biomarker for early detection and prediction of gastric cancer. PMID- 24778030 TI - Targeting aurora kinase A inhibits hypoxia-mediated neuroblastoma cell tumorigenesis. AB - BACKGROUND/AIM: It is unknown whether hypoxia regulates aurora kinase A (AURKA), a serine/threonine kinase, in neuroblastoma to stimulate cell growth or migration. We sought to determine whether AURKA mediates hypoxia-induced regulation of neuroblastoma tumorigenicity. MATERIALS AND METHODS: Human neuroblastoma BE(2)-C cells were treated with CoCl2, a chemical hypoxia mimetic, and MLN8237, a pharmalogical inhibitor of AURKA, to assess cell viability, colony formation and transwell migration. Focal adhesion kinase (FAK) expression was analyzed after silencing of AURKA under normoxic vs. hypoxic conditions. RESULTS: Hypoxia up-regulated expression of AURKA mRNA and protein. CoCl2 stimulated cell proliferation and migration, while inhibiting colony formation. MLN8237 reduced colony formation and cell migration. Silencing of AURKA reduced expression of FAK and pFAK under normoxia and hypoxia. CONCLUSION: Hypoxia positively regulates AURKA expression. Hypoxia-induced stimulation of colony formation and migration is, in part, mediated by AURKA. These findings establish that AURKA is a critical regulator of hypoxia-mediated tumor progression in neuroblastoma. PMID- 24778031 TI - Natural immunomodulators and their stimulation of immune reaction: true or false? AB - Natural immunomodulators are getting more and more popular. The popularity, however, often brings over-optimistic claims and mediocre effects. The purpose of the present study was to directly compare eleven most commonly used immunomodulators. Through testing both cellular and humoral branches of immune reactions, we found that most of the immunomodulators tested have limited, if any, effects, with glucan being consistently the most active molecule strongly stimulating every reaction evaluated. These data were also confirmed using a Lewis lung cancer model, where only glucan and resveratrol lowered the number of metastases. PMID- 24778032 TI - Contribution of plasma proteins, albumin and alpha 1-acid glycoprotein, to pharmacokinetics of a multi-targeted receptor tyrosine kinase inhibitor, sunitinib, in analbuminemic rats. AB - The present study investigated the role of the major plasma proteins, albumin and alpha1-acid glycoprotein (AAG), in the pharmacokinetics of sunitinib using Sprague-Dawley (SD) rats and analbuminemic rats with considerably low concentration of albumin established from SD rats. When sunitinib (3 mg/kg) was administered intravenously, the plasma concentrations of sunitinib at the early distribution phase were significantly lower in analbuminemic rats than those in SD rats. The corresponding pharmacokinetic parameters of systemic clearance and volume of distribution at steady-state of sunitinib were significantly larger in analbuminemic rats (2.17 l/h/kg and 3.94 l/kg, respectively) than those in SD rats (1.26 l/h/kg and 2.37 l/kg, respectively). In in vitro protein-binding experiments using an equilibrium dialysis method, the binding profiles of sunitinib in SD and analbuminemic rats were linear, and the unbound fraction in analbuminemic rats (0.110) was significantly larger than that of SD rats (0.062). However, no significant differences in the unbound plasma concentration-time curves and pharmacokinetic parameters of sunitinib were observed between SD and analbuminemic rats. Protein-binding profiles of sunitinib to human serum albumin and AAG showed concentration independency and the binding potency was 65.3% and 33.7%, respectively. These results suggest that AAG has a low affinity for sunitinib and that the contribution of AAG to plasma protein-binding of sunitinib is relatively low compared to albumin. The present study suggests that the increased systemic clearance of sunitinib in analbuminemic rats might be due to an increase in the volume of distribution at steady-state, which could be due to the significant increase in the unbound fraction of sunitinib due to the low concentration of albumin. PMID- 24778033 TI - Immunohistochemical expression of STAM2 in gastrointestinal stromal tumors. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract, believed to originate from the interstitial cells of Cajal or their stem cell-like precursors. Recent studies incidentally found the expression in interstitial cells of Cajal of the signal transducing adaptor molecule-2 (STAM2), which is an endosomal protein acting as a regulator of receptor signaling and trafficking. Here, we investigated the immunohistochemical expression of STAM2 in GIST. MATERIALS AND METHODS: To evaluate the level of STAM2 expression, the percentage of cells staining positively for STAM2 and their staining intensity were graded on a scale of 0-3 and then multiplied to give the staining index as: 0=none; 1-3=low; 4-6=moderate and 9=high. RESULTS: In 51 analyzed GIST samples, expression of STAM2 was observed in 45 cases (88.2%). Based on antibody screening, we observed a positive correlation between the expression of GIST marker stem cell growth factor receptor, also known as tyrosine-protein kinase KIT or CD117, and STAM2 expression (r=0.387, p<0.003). To identify possible STAM2 function in GIST, we performed correlation analysis between STAM2 expression and tumor size, primary tumor site, tumor type, mitotic count, Ki-67 proliferative index, risk stratification and development of recurrent/metastatic disease. Among these parameters, only correlation between the percentage of STAM2-positive cells and mitotic count was statistically significant (r=-0.362, p<0.01). CONCLUSION: Further studies are required to unravel the role of STAM2 in the oncogenic cell phenotype of GIST. PMID- 24778034 TI - miR-592 and miR-552 can distinguish between primary lung adenocarcinoma and colorectal cancer metastases in the lung. AB - BACKGROUND/AIM: Distinguishing between primary and metastatic adenocarcinomas in the lung may sometimes be difficult by conventional histopathological methods. In addition, novel biomarkers are needed for the more accurate subtyping of primary lung carcinomas. MATERIALS AND METHODS: MicroRNA microarrays were performed on 26 primary lung adenocarcinomas, 3 squamous cell carcinomas, 6 small cell lung cancers (SCLCs), and 2 colorectal cancer metastases in the lung. RESULTS: Forty four microRNAs differentially expressed between three histological subtypes at p<10(-6) predicted histology with 100% accuracy in 100 randomly drawn datasets. Prominent among differentially expressed genes were miR-375, miR-217 and miR 216a, which were found overexpressed in SCLC compared to lung adenocarcinomas. Lung adenocarcinomas overexpressed miR-29b-1, miR-375, miR-2110, miR-29c-star, 199b-5p, and 146b-3p and underexpressed miR-617, miR-205-star, and miR-1246 compared to squamous cell carcinomas. In primary vs. metastatic lung adenocarcinomas, miR-552 and miR-592 were differentially expressed at p<10(-6); the level of expression of miR-552 in colorectal cancer metastases was 39-times higher and that of miR-592 was six-times higher. Furthermore, microRNA profiles of primary colorectal cancer in our database indicated that these two microRNAs were overexpressed in primary colorectal cancer relative to primary lung adenocarcinomas. CONCLUSION: MicroRNA profiles predict the histology of primary lung carcinomas, and differentiate between primary lung adenocarcinomas and colorectal cancer metastases. PMID- 24778035 TI - Relation of INHBA gene expression to outcomes in gastric cancer after curative surgery. AB - Inhibin-betaA (INHBA), a ligand belonging to the transforming growth factor-beta superfamily, is associated with cell proliferation in cancer. We studied the relations of INHBA gene expression to clinicopathological factors and outcomes in 168 patients with gastric cancer who underwent curative surgery. Relative INHBA gene expression was measured in surgical specimens of cancer tissue and adjacent normal mucosa by quantitative real-time, reverse-transcription polymerase chain reaction. INHBA expression levels were significantly higher in cancer tissue than in adjacent normal mucosa and were related to TNM stage and venous invasion. High INHBA gene expression was associated with significantly poorer 5-year overall survival than was low expression. On multivariate analysis, INHBA gene expression was an independent prognostic factor. Overexpression of the INHBA gene is considered a useful independent predictor of outcomes in patients with gastric cancer after curative surgery. PMID- 24778036 TI - Genetics of lymphocytes influences the emergence of second cancer in chronic lymphocytic leukemia. AB - BACKGROUND: Patients affected by chronic lymphocytic leukemia (CLL) have an increased risk of developing a second cancer. There is not a definitive explanation for this phenomenon, although some hypotheses have been postulated. The aim of the present work was to assess the presence of second cancer in untreated patients with CLL who were cytogenetically characterized, and secondly to investigate if there is a correlation between the genetics of CLL and the emergence of second cancer. PATIENTS AND METHODS: We performed conventional cytogenetics and Fluorescent in situ hybridization analyses in a series of 106 patients. RESULTS: We observed that nearly 8% of cases developed second cancer, mostly epithelial tumors. The majority of them presented two common features, del(13)(q14.3) and the presence of at least two genetic alterations. CONCLUSION: We suggest that the genetic background of CLL, particularly the presence of several genetic alterations, influences the emergence of second cancer in patients affected by CLL. PMID- 24778037 TI - Expression of Pdcd4 tumor suppressor in human melanoma cells. AB - BACKGROUND: Programmed cell death 4 (Pdcd4) is a tumor suppressor frequently lost in tumors of various origins thus contributing to tumor progression. Expression of Pdcd4 in melanoma, however, has not been extensively studied to date. MATERIALS AND METHODS: Pdcd4 protein levels were assessed in 23 human melanoma cell lines and in normal melanocytes by western blot analysis. Also, effects of LY294002, rapamycin and PD098059 on Pdcd4 protein levels were analyzed. RESULTS: Pdcd4 is suppressed in ~25% of human cell lines established from advanced melanoma lesions. Pdcd4 protein levels in melanoma cells were up-regulated by treatment with inhibitors of Akt signaling, one of the key pathways leading to Pdcd4 suppression, and to a lesser extent by inhibiting MEK/ERK pathway. CONCLUSION: Pdcd4 loss is not a common event in melanoma progression yet suppression of Pdcd4 defines a subset of melanoma cells and can be used for molecular typing of melanoma. Our results help determine the significance of Pdcd4 loss in melanoma as well as its up-regulation by Akt pathway inhibitors, which are promising tools in melanoma treatment. PMID- 24778038 TI - Levonorgestrel-impregnated Intrauterine device reduces occurrence of hyperplastic polyps: a population-based follow-up cohort study. AB - BACKGROUND: The main objective was to investigate if occurrence of hyperplastic polyps was reduced by use of the levonorgestrel-impregnated intrauterine system (LNG-IUS, Mirena(r); Bayer) and if the LNG-IUS was more effective compared to oral medroxyprogesterone acetate (MPA) or observation-only. PATIENTS AND METHODS: Patients (N=59) with hyperplastic polyps were given LNG-IUS, 10 mg oral MPA taken 10 days per cycle, or had observation-only for six months. Diagnosis of histological specimens was performed by light microscopy according to the WHO classification and D-score prior to and after six months therapy. RESULTS: No polyps were found in women treated with LNG-IUS (18/18). Five women treated with cyclic MPA (5/20, 25%) and two (2/21, 9%) with observation had normal endometrium without polyps after six months. CONCLUSION: No former study has shown that LNG IUS is effective at reducing the occurrence of hyperplastic endometrial polyps. The effect is superior to that of oral progestin and observation-only. PMID- 24778039 TI - Impact of Epoetin-beta on anemia and health-related quality of life in cancer patients: a prospective observational study using the generic 15D instrument. AB - AIM: Cancer-related anemia has a negative impact on the health-related quality of life (HRQoL). Our aim was to evaluate prospectively the effect of treatment of anemia with an erythropoietin on the hemoglobin level and HRQoL in cancer patients with anemia. PATIENTS AND METHODS: Consecutive patients (N=114) treated for the first time with epoetin (epoetin beta 30000 IU/wk, NeoRecormon(r)) for anemia during cancer treatment were eligible for study inclusion. Baseline characteristics were collected from patients' records. HRQoL was measured by the generic 15D instrument and fatigue by visual analogue scale (VAS) at baseline and four months from the start of the treatment with epoetin. The majority (87%) of patients had solid tumors; 69% with a metastatic disease and 89% disease with comorbidities. RESULTS: The mean hemoglobin concentration (SD) in blood increased from 96.6 (8.9) g/L to 112.9 (21.2) g/L, by 16.5 (20.6) g/L (p<0.0001). The mean 15D score rose from 0.72 to 0.77. The change was statistically significant (p=0.0047) and clinically important. The mean fatigue VAS score decreased by 16.0 points, or from 55.4 to 38.4 (+24.4) (p<0.0001). CONCLUSION: Correction of anemia increased the health-related quality of life in anemic cancer patients, as measured with the generic 15D instrument and the fatigue VAS. PMID- 24778040 TI - High levels of Wilms' tumor 1 (WT1) expression were associated with aggressive clinical features in ovarian cancer. AB - AIM: The aim of the present study was to evaluate the correlation between WT1 expression levels and clinical features, to investigate the prognostic value of WT1 expression and to use lentiviral constructs to examine whether overexpression of WT1 affects cell proliferation and invasion in ovarian cancer patients. MATERIALS AND METHODS: Real-time quantitative PCR (qPCR) methods were employed to analyze WT1 expression levels in clinical samples from 63 patients with ovarian cancer. The correlation between the copy number of WT1 mRNA and clinical variables was analyzed. RESULTS: The median copy number of WT1 mRNA was 53.94 (range=2.135-32,257) in all subjects and WT1 expression levels were found significantly increased in patients with a higher stage cancer (p<0.05), lymphnode (p<0.001) and omentum metastasis (p<0.001), as well as ascites production (p<0.05), compared to patients lacking these clinical variables. No significant difference in WT1 expression levels were observed between patients with and without recurrence. The median disease-free survival time in patients with low WT1 expression levels was significantly longer (p=0.038) than that in patients with high WT1 expression. However, overall survival curves showed no statistically significant (p=0.457) differences between patients with high- and low-WT1 expression levels. An in vitro study revealed that WT1 over-expression enhanced cell proliferation and invasion in ovarian cancer cells transduced with lentiviral constructs. CONCLUSION: Using qPCR, we found that high levels of WT1 expression correlated with aggressive clinical features in ovarian cancer. High WT1 expression may impact on median disease-free survival in ovarian cancer. PMID- 24778041 TI - Modern GERD treatment: feasibility of minimally invasive esophageal sphincter augmentation. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is a common chronic disease requiring adequate treatment since it represents one major cause of development of Barrett's esophagus and eventually carcinoma. Novel laparoscopic magnetic sphincter augmentation for GERD was evaluated prospectively. PATIENTS AND METHODS: A total of 23 patients with GERD underwent minimally invasive implantation of LINXTM Reflux Management System. Primary outcome measures were overall feasibility, short-term procedure safety and efficacy. Secondary GERD related quality of life was assessed. RESULTS: All implantations were performed without serious adverse events. A significant decrease in all major GERD complaints were found: heartburn: 96%-22% (p<0.001); bloating: 70%-30% (p=0.006); respiratory complaints: 57%-17% (p=0.039); sleep disturbance: 65%-4% (p<0.001). A four-week follow-up reduction of >=50% of proton pump inhibitor (PPI) dose was achieved in over 80% of patients. Self-limiting difficulty in swallowing was found in 70% within four weeks. One patient required for endoscopic dilation. GERD-related quality of life improved significantly. CONCLUSION: LINXTM implantation is a standardized, technically simple, safe and well-tolerated expeditious procedure. PMID- 24778042 TI - Outcomes of patients with metastatic cervical cancer in a phase I clinical trials program. AB - BACKGROUND: We evaluated clinical outcomes of patients with metastatic cervical cancer referred to a Phase I Clinical Trials Program. PATIENTS AND METHODS: We reviewed the electronic medical records of 54 consecutive phase I patients with metastatic cervical cancer over 6.5 years and analyzed the correlation between clinical outcome and potential predictors. RESULTS: All patients had received at least one systemic therapy for metastatic disease before referral. Only two patients declined phase I trial therapy. The median progression-free (PFS) and overall (OS) survivals were 3.6 and 10.6 months, respectively. Patients harboring phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations or phosphatase and tensin homolog loss, and those with more than two sites of metastasis who received more than one prior systemic chemotherapy before the referral had median PFS of 6.7 and 1.8 months, and median OS of 12.6 and 2.9 months, respectively. CONCLUSION: Patients with more than two metastatic sites who had received more than one prior system therapy had dismal outcomes. An aberrant PI3K pathway was frequently identified and associated with favorable outcome, providing a promising target. PMID- 24778043 TI - Novel serum nucleosomics biomarkers for the detection of colorectal cancer. AB - BACKGROUND: To improve prognosis of patients with colorectal cancer, powerful blood-based biomarkers enabling for early detection are needed. As genome-wide DNA hypomethylation is associated with carcinogenesis, and cell-free DNA, thought to be of tumor origin, is found in the circulation of patients with cancer, we investigated the relevance of 5-methylcytosine-modified DNA present in cell-free circulating nucleosomes as a serum biomarker using a convenient enzyme-linked immunosorbent assay (ELISA) technique. MATERIALS AND METHODS: Serum samples from 90 individuals [24 with colorectal cancer (CRC), 10 with benign colorectal diseases (BCD) and 56 healthy controls (HC)] were tested for the differential diagnostic performance of a novel ELISA for nucleosome-bound methylated DNA. Methodical features, including intra- and interassay imprecision, were tested using serum pools. To minimize interassay variability, values were transformed to adjusted optical densities and robust statistics were applied for clinical evaluation. Findings were later re-evaluated on a set of 113 patients (49 CRC, 26 BCD and 38 HC). RESULTS: Intra- and interassay reproducibility were 3.4% and 15.3%, respectively. Levels of circulating methylated DNA were significantly decreased in CRC and BCD when compared to HC (p<0.05), although there was no difference between BCD and CRC. For discrimination of CRC from HC, the area under the curve in receiver operating characteristic curve was 0.78 and sensitivities were 33% at 95% specificity and 75% at 70% specificity, respectively. The findings were generally confirmed when validated in the second set of patients. CONCLUSION: Reduced methylation of DNA on circulating nucleosomes detected by ELISA can potentially serve as a diagnostic tool in patients with CRC. PMID- 24778044 TI - Preoperative assessment of peritoneal carcinomatosis in patients undergoing hyperthermic intraperitoneal chemotherapy following cytoreductive surgery. AB - The present study evaluates the accuracy of computed tomographic (CT) scan and positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET)/CT for the quantification of peritoneal carcinomatosis (PC) in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Data were retrospectively collected for 58 patients, who were considered for CRS and HIPEC. The predictability, sensitivity, specificity and accuracy values of FDG-PET/CT and CT were tested. Preoperative CT and FDG-PET/CT failed to detect PC in 9% and 17% of cases, respectively, with a sensitivity of 91% and 82%, a specificity of 33% and 67%, an area under the curve (AUC) of 62% and 74% and a negative likelihood ratio of 0.27 (CI.95 0.07-1.09) and 0.27 (CI.95 0.11 0.62), respectively (p=0.469). Both techniques showed a high prevalence of PC extent underestimation (CT 47% and FDG-PET/CT 43% of cases). Small bowel involvement and optimal CRS had a prevalence of 60% and 76%, respectively, and both the CT and FDG-PET/CT imaging techniques were inaccurate at predicting them (AUC 53% and 52% for small bowel involvement, and 63% and 58% for optimal CRS, respectively). In conclusion both CT and FDG-PET/CT had low preoperative staging reliability for PC, and this can strongly influence the ability to implement the correct treatment strategy for patients with PC. PMID- 24778045 TI - HLA-A*02 in relation to outcome in human papillomavirus positive tonsillar and base of tongue cancer. AB - BACKGROUND/AIM: Patients with human papillomavirus (HPV)-positive tonsillar and base of tongue cancer have a better outcome than those with corresponding HPV negative tumors (80% vs. 40% 5-year disease free survival with conventional radiotherapy). They should not all need chemoradiotherapy, but before tapering treatment, more markers are needed to predict treatment response. In the present study, human leukocyte antigen (HLA) - HLA-A*02 was analyzed with HPV as a prognostic factor for tonsillar and base of tongue cancer. PATIENTS AND METHODS: Pre-treatment biopsies, previously tested for HPV DNA, from 425 patients diagnosed with tonsillar and base of tongue cancer between 2000-2009 at the Karolinska University Hospital were examined for HLA-A*02. RESULTS: HLA-A*02 was present in 144/305 (47.2%) of the HPV-positive and 63/120 (52.8%) of the HPV negative tumours. Among 383 patients treated with curative intent, absence of HLA A*02 was correlated with increased disease-free survival in the HPV-positive (p=0.016), but not in the HPV-negative group. CONCLUSION: Absence of HLA-A*02 correlated with better disease-free survival for patients with HPV-positive tonsillar and base of tongue cancer. PMID- 24778046 TI - A phase II trial of two durations of Bevacizumab added to neoadjuvant gemcitabine for borderline and locally advanced pancreatic cancer. AB - BACKGROUND: We report the results of a phase II trial of adding the anti-ascular endothelial growth factor (VEGF) bevacizumab to gemcitabine neoadjuvant chemotherapy for patients with borderline and unresectable non-metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were assigned to one of the two treatment arms. Both groups received 1,000 mg/m(2) gemcitabine on days 1, 8, and 15 of a 4-week cycle for a total of four cycles. Group 1 received 5 mg/kg bevacizumab for six weeks (three doses), every second week, starting at week 6 of gemcitabine therapy. Group 2 received 5 mg/kg bevacizumab for 12 weeks (six doses), every second week, starting at week 1 of gemcitabine therapy. The objective of the present study was to assess the rate of complete radical resection and overall survival. RESULTS: A total of 30 patients were enrolled: 19 patients had unresectable and 11 patients had borderline-resectable pancreatic cancer. Eleven patients (37%) underwent resection. The median overall survival of patients who underwent tumor resection was 13 months (95% confidence interval=11 15 months). CONCLUSION: In general, adding bevacizumab to neoadjuvant gemcitabine does not improve outcomes for patients with locally advanced pancreatic cancer. However, in individual cases, surgery is consequently possible and prolonged survival may be observed. PMID- 24778047 TI - Evidence that Mifepristone, a progesterone receptor antagonist, can cross the blood brain barrier and provide palliative benefits for glioblastoma multiforme grade IV. AB - BACKGROUND: Mifepristone, a progesterone receptor antagonist, has been found to provide palliative benefits for various types of spontaneous murine cancer in randomized controlled trials and in anecdotal reports from a variety of advanced metastatic human cancer not known to be associated with progesterone receptors. The theory of its mechanism is that it prevents the secretion of a progesterone induced immunomodulatory protein in the tumor microenvironment, or in the tumor cell itself, called the progesterone-induced blocking factor, which inhibits natural killer cells from attacking the cancer cell. Many anticancer chemotherapeutic agents fail to cross the blood-brain barrier and thus prove ineffective for brain cancer. The objective of the present study was to determine if mifepristone could provide palliative benefits to a patient with end-stage stage IV glioblastoma multiforme. CASE REPORT: A 43-year-old male with end-stage stage IV glioblastoma multiforme was exclusively treated with mifepristone 200 mg orally daily. RESULTS: The patient showed definite palliative effects for several weeks and his life was significantly extended beyond pre-treatment predictors. CONCLUSION: It appears that mifepristone does cross the blood-brain barrier and could be considered for palliative therapy of other patients with chemotherapy resistant brain cancer. PMID- 24778048 TI - The clinical impact of the lymph node ratio as a prognostic factor after resection of pancreatic cancer. AB - BACKGROUND: The prognostic value of lymph node (LN) status in patients who underwent resection for pancreatic cancer (PC) was examined in the present study. PATIENTS AND METHODS: Fifty-six patients who underwent macroscopic curative resection for PC were analyzed. Twelve factors, including the number of LN metastases, LN ratio, and N category according to the Japanese Pancreatic Society classification, were analyzed using univariate and multivariate analysis. RESULTS: The optimal cut-off value was 0.2 for the LN ratio. Positive surgical margins (p=0.022) and LN ratio >=0.2 (p=0.017) were identified as independent prognostic factors. Among the 33 patients with regional LN metastasis, patients with LN ratio >=0.2 had significantly worse prognosis than those with LN ratio <0.2 (median survival time 14 vs. 26 months, p=0.048), however, the differences in survival between those with N1 and those with N2 by Japanese Pancreatic Society classification were not statistically significant (p=0.85). CONCLUSION: The LN ratio might be more useful than other parameters as a predictor for survival after resection of PC. PMID- 24778049 TI - Sequential Tyrosine Kinase Inhibitors (TKIs) in metastatic renal cell carcinoma: results from a large cohort of patients. AB - BACKGROUND: Only scanty data are available to evaluate the impact of sequential TKIs on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). This retrospective study investigated the efficacy of the sequence sorafenib-sunitinib (SO-SU) and vice versa (SU-SO) in a real-life scenario. PATIENTS AND METHODS: Median progression free-survival (PFS) and OS were evaluated. The correlation between PFS and OS was also assessed. RESULTS: In total, 104 patients received SO-SU and 21 (16.8%) SO-SU. No differences in PFS or OS were observed (PFS for SO-SU=26.1 months, and for SU-SO=20.0 months; OS=35.3 and 27.0 months, respectively). For both sequences, only a weakly-positive correlation between PFS and OS was observed. CONCLUSION: Our data support the use of the sequence of the two TKIs in a real-life setting. No strong evidence of a correlation between PFS and OS was observed. PMID- 24778050 TI - The impact of combined thoracoscopic and laparoscopic surgery on pulmonary complications after radical esophagectomy in patients with resectable esophageal cancer. AB - BACKGROUND: Pulmonary complications (PCs) after esophagectomy for patients with esophageal cancer have been correlated with prolonged hospital stays and in hospital mortality. Previous studies have shown that minimally-invasive esophagectomy (MIE) is associated with a lower rate of PCs compared to conventional open surgery. Although PCs were reportedly associated with many factors, including surgical approaches, patients' demographics, and perioperative variables, the predictive factors for PCs including MIE, have not been fully evaluated. PATIENTS AND METHODS: A total of 209 patients with resectable esophageal cancer who underwent three types of esophagectomy were included in the present study; (i) 93 cases who underwent the combined thoracoscopic MIE and laparoscopic MIE; (ii) 42 cases who underwent the combined open thoracotomy and laparoscopic MIE; (iii) 74 cases who underwent the combined open thoracotomy and open laparotomy, which were defined as the total MIE group, hybrid MIE group, and total open group, respectively. We compared clinical outcomes of the three groups and identified postoperative predictive factors of PCs using multivariate analysis. RESULTS: The incidence of PCs was significantly reduced (p=0.015) in the total-MIE group (8/93: 8.5%) compared with the total-open group (16/74: 21.6%), but it was not significantly reduced in the hybrid MIE group (5/42: 11.9%) compared with the total open group (p=0.19). The multivariate analysis showed that the presence of cardiac comorbidity [odds ratio (OR)=5.90; p=0.013], lung comorbidity (OR=3.95; p=0.031), and anastomotic leakage (OR=6.00; p<0.01) were independent risk factors for PCs after esophagectomy. In contrast, total MIE reduced the risk of PCs (OR=0.328; p=0.036). CONCLUSION: The combination of thoracoscopic and laparoscopic MIE presents as an excellent surgical procedure for the reduction of PCs after esophagectomy. PMID- 24778051 TI - Survival of patients undergoing cytoreductive surgery for metastatic renal cell carcinoma in the targeted-therapy era. AB - BACKGROUND/AIM: In the cytokine era, cytoreductive nephrectomy (CN) improves survival for patients with metastatic renal cell carcinoma (mRCC). We analyzed the effect of CN on the survival of patients diagnosed with mRCC in the era of tyrosine kinase inhibitors (2005-present). PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify adult patients diagnosed with mRCC between 2005 and 2009. The primary outcome was overall survival, analyzed with multivariable Cox models. RESULTS: Out of 7,143 incident mRCC cases reported to SEER between 2005-2009, 2,629 (37%) underwent CN. Patients undergoing CN were younger, and more likely to be white, male, and married. Patients with stage T3 tumors were most likely to undergo CN (64%). Patients that underwent CN had improved one-year survival (61% vs. 22%). On multivariable analysis, CN was associated with improved overall survival(hazard ratio[HR]=0.40 95% confidence interval [CI]=0.37-0.43). CONCLUSION: In the targeted-therapy era, patients with mRCC undergoing CN have improved survival after adjusting for tumor stage and demographic characteristics. PMID- 24778052 TI - Mifepristone causing complete remission of rapidly advancing leukemia with measurement of progesterone-induced blocking factor. AB - BACKGROUND: Mifepristone has been demonstrated to cause palliation from murine and human cancer, even in cancers not known to be positive for expression of progesterone receptors. The aim of the present study was to determine if rapidly advancing chronic lymphocytic leukemia responds to mifepristone therapy, and if so, is this effect related to increased expression of the progesterone-induced blocking factor? CASE REPORT: An 81-year-old woman with chronic lymphocytic leukemia whose condition progressed to the acute rapidly progressing stage agreed to be exclusively treated orally with 200 mg mifepristone daily. RESULTS: The patient showed a dramatic improvement after a short exposure time to mifepristone. Complete remission has persisted so far for 12 months on exclusive mifepristone therapy. Her PIBF levels were normal before mifepristone therapy and did not change after treatment. CONCLUSION: Mifepristone can provide marked improvement of human leukemia even in the absence of increased serum PIBF levels. PMID- 24778053 TI - Successful management of metachronous liver metastasis after pancreaticoduodectomy for pancreatic ductal carcinoma using hepatectomy and chemotherapy: a case report. AB - A 63-year-old woman was admitted to our Hospital for treatment of pancreatic head ductal carcinoma, and underwent pancreaticoduodedectomy (PD) in October 2007. At one month after surgery, she received systemic adjuvant chemotherapy using S-1 for three months. Because the serum carbohydrate antigen 19-9 (CA19-9) value was elevated at 23 months after surgery, the patient underwent systemic chemotherapy using gemcitabine. The serum CA19-9 decreased, but abdominal Computed Tomography (CT) revealed a hepatic metastasis in the ventrolateral segment of left hepatic lobe at 28 months after surgery. The chemotherapy was changed to oral S-1. At 35 months after surgery, abdominal CT revealed reduction of liver metastasis and that the serum CA19-9 was normalized, but chemotherapy had to be withdrawn because of severe myelosuppression. Because of her good general condition, the patient underwent partial hepatectomy for the liver metastasis. Histopathological examination demonstrated a complete response. Thirty six months after hepatectomy and 6 years after PD, the patient remains well without recurrence. We herein report a case of successful treatment for metachronous liver metastasis from pancreatic ductal carcinoma after PD by chemotherapy and hepatectomy and review the current literature. PMID- 24778054 TI - The efficacy of liver resection for multinodular hepatocellular carcinoma. AB - BACKGROUND AND AIM: The aim of the present study was to evaluate the efficacy of liver resection for multinodular hepatocellular carcinoma (MNHCC). PATIENTS AND METHODS: A total of 399 patients who underwent R0 resection for HCC from 1992 to 2011 were subjected to analysis. Out of these 399 patients, 107 patients had multinodular HCC, while 292 had a single tumor. RESULTS: The 3- and 5-year overall survival rates of patients with MNHCC were 62.0% and 38.1% respectively. By a multivariate analysis of the survival of the 107 patients after liver resection for MNHCC, it was shown that the presence of four or more tumors and a lower serum albumin level were unfavorable prognostic factors for long-term survival. With respect to the patients with four or more HCCs, portal vein invasion was an independent unfavorable prognostic factor for long-term survival. However, in patients with four or more HCCs without portal vein invasion, overall survival rates of those with preoperative serum albumin level >4.0 mg/dl and a platelet count >10(5)/mm(3) were significantly higher than those of patients with albumin <4.0mg/dl or platelet count <10(5)/mm(3) (p=0.049). CONCLUSION: Liver resection can provide a survival benefit, even for patients with multiple HCCs. Even if patients have four or more tumors without portal vein invasion and with well-preserved liver function, resection for HCC may be the treatment of choice. PMID- 24778055 TI - Clinicopathological and prognostic significance of FOXM1 expression in esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis because invasion and metastasis are prevalent. To improve diagnosis, it is important to identify and characterize tumor-specific molecular markers in ESCC. FOXM1 is overexpressed and correlates with pathogenesis in a variety of human malignancies. We aimed to investigate the clinical significance of FOXM1 overexpression in ESCC. PATIENTS AND METHODS: FOXM1 expression was assessed in ESCC specimens from 174 curatively-resected cases. The relationships between FOXM1 expression, clinicopathological parameters, and prognoses were examined. RESULTS: Immunohistochemical analysis showed that 94 (54.0%) tumors were positive for FOXM1 expression. FOXM1 positivity did not correlate with any clinicopathological parameter. However, FOXM1-positive cases had poorer prognoses than FOXM1-negative ones (p=0.0037, log-rank test). In multivariate analysis, the following were independent prognostic factors: pT, pN, neoadjuvant chemotherapy, and FOXM1 expression (hazard ratio=1.69, 95% confidence interval=1.06-2.75, p=0.027). CONCLUSION: FOXM1 may be a novel prognostic factor in patients with ESCC who undergo curative resection. PMID- 24778056 TI - The value of elective parotidectomy in advanced squamous cell carcinoma of the skin of the head. AB - BACKGROUND: Parotid metastases from cutaneous squamous cell carcinoma (CSCC) are associated with poor prognosis. However, the incidence of occult parotid lymph node metastases in high-risk CSCC is unclear. Therefore, the role of elective parotidectomy is still controversial. The purpose of the present study was to analyze the value of elective parotidectomy in patients with high-risk CSCC. PATIENTS AND METHODS: The clinical data including histological and radiological results, as well as surgery-related complications, of 13 patients with high-risk CSCC who underwent elective parotidectomy were retrospectively analyzed. RESULTS: Occult parotid lymph node metastases were detected by histological examination in only 1 out of 13 patients after elective parotidectomy. Surgery-related complications and morbidity were not observed. CONCLUSION: In the absence of clinical disease in the parotid gland, the risk of occult metastases is not high enough to warrant for elective parotidectomy in patients with CSCC. PMID- 24778057 TI - Fabry disease simulating Crohn's ileitis. AB - Fabry disease is an inherited (X-linked) lysosomal storage disorder caused by deficiency of alpha-galactosidase A, leading to accumulation of globotriaosylceramide in various tissues. A 57-year-old male with a family history and laboratory findings of Fabry disease, was consulted for severe abdominal pain, undulating pyrexia, weight loss and diarrhea. The tentative clinical diagnosis of Crohn's ileitis was supported at computed tomographic examination, at laparotomy and at inspection of the resected ileal segment. Histology revealed chronic and acute inflammation, thick-walled occluded vessels, fibrosis and characteristic bi-refringent lamellar deposits of globotriaosylceramide and calcifications. Multi-nucleated giant cells contained phagocytized bi-refringent material. Transmission electron microscopy showed cells with irregular cytoplasmic bodies displaying distinctive zebra-like lamellar structures. It is submitted that the gastrointestinal phenotype of Fabry disease may concur with symptoms resembling abdominal Crohn's disease. PMID- 24778059 TI - Neuroendocrine pancreatic carcinoma after initial diagnosis of acute postpartal coeliac disease in a 37-year old woman - fatal coincidence or result of a neglected disease? AB - An acute presentation after pregnancy of coeliac disease (CD) in the puerperium is a rare condition which has been described mostly in primigravidae in patients highly suspicious of latent CD. We report the case of a 37-year-old woman who was referred to our Hospital because of refractory watery diarrhea and malnutrition syndrome. Endoscopy of the upper gastrointestinal tract revealed the classic visual features of CD and in addition, some duodenal ulcers negative for Helicobacter pylori, which seems to be another clinical feature in patients with CD. The diagnosis of acute onset of fulminant postpartal CD (Marsh score stage 3c) was confirmed histologically. Remarkably, simultaneous well-differentiated neuroendocrine non-functioning pancreatic neuroendocrine carcinoma (PNET) was diagnosed on radiological abdominal imaging which was performed since serum gastrin was remarkably high, treated by distal pancreatectomy and splenectomy. This report is, to our knowledge, the first description of the two entities, CD and PNET occurring together. Since results of antral histological studies showed diffuse hyperplasia of G-cells, probably in response to hypergastrinaemia, enterochromaffin cell carcinogenesis might have served as a possible link between both diseases. PMID- 24778058 TI - Laparoscopic radical prostatectomy: 10 years of experience at a single institution. AB - BACKGROUND/AIM: The Urological Clinic of the S. Orsola-Malpighi University Hospital, Bologna has been carrying out laparoscopic radical prostatectomy since 2002. In this study, we report the results after 10 years of LRP, analyzing in particular the oncological and functional aspects. PATIENTS AND METHODS: Between March 2002 and August 2011, 400 patients underwent laparoscopic radical prostatectomy. Cancer control, recovery of continence and potency were evaluated at 1, 3, 6 and 12 months. All data were retrospectively collected on the basis of thorough clinical and pathological examination. RESULTS: Follow-up ranged from 10 to 122 months. Pathological examination revealed pT2 and pT3 cancers in 63.5% and 36.5% of patients, respectively. The incidence of positive surgical margins and biochemical relapse rate was 33.8% and 12.0%, respectively. CONCLUSION: 10 Years after the first laparoscopic radical prostatectomy was performed at our Center, we can state that it is a reliable alternative to traditional surgery, with satisfactory oncological and functional results. PMID- 24778060 TI - A new score predicting survival prognosis after whole-brain radiotherapy alone for brain metastases in elderly patients. AB - BACKGROUND/AIM: Elderly patients represent an important subgroup of patients with brain metastases. A survival score has been developed specifically for these patients. PATIENTS AND METHODS: A total of 544 elderly patients (aged >=65 years) receiving whole-brain radiotherapy alone were divided into a test (n=272) and a validation group (n=272). In the multivariate analysis of the test group, survival was significantly associated with gender, performance status, and number of organs involved by extracranial metastases. These factors were included in the score. Total scores representing the sum of the three factor scores were 3-13 points. Four prognostic groups were formed. RESULTS: The 6-month survival rates were 2% for those with 3-6 points, 17% for those with 7-9 points, 56% for those with 10-12 points and 90% for those with 13 points in the test group (p<0.001), and 4%, 21%, 50% and 86%, respectively, in the validation group (p<0.001). CONCLUSION: This score is reproducible and helps estimate the survival prognosis of elderly patients with brain metastasis. PMID- 24778061 TI - Prognostic value of a cell-cycle progression score in men with prostate cancer managed with active surveillance after MRI-guided prostate biopsy--a pilot study. AB - BACKGROUND/AIM: Initial inaccurate staging is a common problem associated with active surveillance (AS) for patients detected by transrectal ultrasound-guided prostate biopsy (TRUS-GB). Subsequently, repeated biopsies are necessary to monitor such patients. Thus, in addition to the already established clinicopathological criteria, there is a considerable demand for new, objective decision criteria to more accurately select AS candidates. Recently, a novel RNA expression signature derived from 31 cell-cycle progression (CCP) genes has been shown to be a strong predictor of outcome in patients after radical prostatectomy or radiotherapy. This is a qualitative pilot study to evaluate the prognostic value of the CCP-score (CCP-S) for the first time in men managed with AS after MRI-guided prostate biopsy (MRI-GB). PATIENTS AND METHODS: Nine patients previously diagnosed with prostate cancer during an ongoing, prospective trial assessing MRI-GB with additional TRUS-GB and were subsequently managed with AS. CCP-S were retrospectively derived from biopsy specimens. The CCP-S is defined as the expression level of 31 CCP genes, normalized to 15 housekeeping genes, and is clinically validated in a range between -1.3 and 4.7. To assess the estimated 10 year mortality risk (without curative treatment), the CCP-S from each patient was combined with the individual CAPRA (Cancer of the Prostate Risk Assessment) score (CAPRA-S). RESULTS: Median patient age was 72 (range=58-77) years. Mean pre biopsy PSA level was 6.33+/-1.94 (range 4.23-9.97) ng/ml. Eight cases had Gleason score 6 (3+3) and one cancer had Gleason score 7 (3+4). Median CCP-S was -0.9 (range=-1.5 to 0.0). Combining CCP-S with CAPRA-S [CAPRA-S: 1 (n=4), 2 (n=4), 3 (n=1)] the estimated 10-year mortality risk was not calculable for three patients because their CCP-S [CCP-S -1.4 (n=2) and -1.5 (n=1)] was outside the validated range. For the other 6 patients the estimated 10-year mortality ranged from 1.0 3.0%. CONCLUSION: The CCP-S confirms accurate staging of AS patients detected by MRI-based biopsy strategies and may significantly reduce inaccurate staging of AS patients and subsequent unnecessary re-biopsies. The CCP score may help to more accurately select for active surveillance candidates. PMID- 24778062 TI - Influence of thyroid transcription factor-1 on fluorodeoxyglucose uptake and prognosis of non-small cell lung cancer. AB - AIM: To assess the correlation between thyroid transcription factor-1 (TTF1) protein expression in primary tumors from patients with non-small cell lung cancer (NSCLC) and fluorodeoxyglucose (FDG) uptake, and to determine its effect on survival outcomes. PATIENTS AND METHODS: We categorized 112 patients with NSCLC according to TTF1 expression (TTF1(+): n=59, TTF1(-): n=53), and retrospectively determined whether positron-emission topography measurements, including standardized uptake values [mean (SUVm) and maximum (SUVmax)], metabolic tumor volume (MTV), total lesion glycolysis (TLG), and other clinical factors could predict progression-free (PFS) or overall (OS) survival of these patients. RESULTS: The SUVm, SUVmax, MTV, and TLG values were lower in the TTF1(+) group; their survival outcomes were also better. The SUVm, SUVmax, and TLG values were good prognostic indicators for OS and PFS in this group. CONCLUSION: Primary NSCLC tumors expressing TTF1 had lower FDG uptake than those that did not and this was a good prognostic indicator. PMID- 24778063 TI - Prevention of osteonecrosis of the jaw in patients with bone metastases treated with bisphosphonates. AB - Bisphosphonates (BPs) are potent inhibitors of osteoclast-mediated bone resorption and are widely used in the treatment of bone metastases. Osteonecrosis of the jaw (ONJ) is the worst side-effect related to BP use. At our Center, we have implemented internal guidelines regarding the management of patients with bone metastases from solid tumors. Our analysis includes 200 patients affected by solid tumors with bone metastases who received zoledronic acid. They underwent a baseline mouth assessment to evaluate their dental conditions and to perform dental care; a dental follow-up was performed every six months. All patients received calcium and vitamin D daily. Dental examination and application of preventive measures led to a total reduction in ONJ in our patients treated with zoledronic acid. The keystone in management of ONJ is prevention, and the risk of developing ONJ during treatment with zoledronic acid is reduced by implementing preventive measures. PMID- 24778064 TI - Impact of combination chemotherapy with itraconazole on survival of patients with refractory ovarian cancer. AB - BACKGROUND: After progression during chemotherapy, persistent ovarian cancer rarely responds to cytotoxic agents. We evaluated the use of adjunctive itraconazole for treating refractory ovarian cancer. PATIENTS AND METHODS: Medical records of patients with ovarian cancer were retrospectively reviewed to select those with a history of platinum and taxane administration, clinical progression within six months of the last platinum administration, continuation of chemotherapy after the first progression during chemotherapy. RESULTS: Among 55 patients, itraconazole in combination with chemotherapy was administered to 19 patients. The median progression-free survival (PFS) was 103 days and 53 days for chemotherapy with and without itraconazole, respectively (p=0.014). The corresponding median overall survival was 642 days and 139 days, respectively (p=0.006). The hazard ratio for PFS was 0.24 (p=0.002) and for overall survival was 0.27 (p=0.006) for therapy with itraconazole. CONCLUSION: Adjunctive itraconazole is promising for patients with refractory ovarian cancer. PMID- 24778065 TI - Second malignancies in philadelphia-negative myeloproliferative neoplasms-single center experience. AB - AIM: The aim of this work was to retrospectively analyze patients with Philadelphia-negative myeloproliferative neoplasms through evaluation of frequency and characteristics of second malignancies (other than acute leukaemia and myelodysplastic syndrome). PATIENTS AND METHODS: Records of 172 patients were reviewed; an analysis was performed on data from 66 patients treated with hydroxyurea, 105 patients treated with other cytoreductive therapy, and 25 patients without treatment. RESULTS: A higher occurrence of second malignancies was found in the group treated with hydroxyurea (7.6%; other cytoreduction: 1.2%; without therapy: 0). After a median follow-up of 89 months in the hydroxyurea group, 13 patients developed second cancer during hydroxyurea therapy, located on the skin (68.75%) and other sites (31.25%). CONCLUSION: The incidence of second malignancies during hydroxyurea therapy in our cohort patient was significantly higher than the incidence of malignancies in the Czech population of corresponding age. PMID- 24778066 TI - Advantages of laparoscopy versus laparotomy in extremely obese women (BMI>35) with early-stage endometrial cancer: a multicenter study. AB - BACKGROUND: The aim of the present study was to demonstrate the advantages of laparoscopy versus laparotomy for treatment of extremely obese women with early stage endometrial cancer. MATERIALS AND METHODS: Seventy-five extremely obese patients with Body Mass Index >35 kg/m(2) and clinical stage I endometrial cancer underwent hysterectomy and bilateral salpingo-oophorectomy, and in all cases we performed systematic pelvic lymphadenectomy by laparoscopy (mean BMI of 38+/-7.3 kg/m(2)) or laparotomy (mean BMI of 39+/-8.1 kg/m(2)). RESULTS: In two (4.4%) patients of the laparoscopy group we observed a port site haematoma that was resolved without a second surgery. In three patients of the laparotomy-group, we observed dehiscence of the abdominal suture with surgical site infection that was re-sutured. CONCLUSION: Laparoscopy can be considered a safe and effective therapeutic procedure for managing early-stage endometrial cancer in extremely obese women with a lower complication rate, lower surgical site infection and postoperative hospitalization. PMID- 24778067 TI - Number of extraspinal organs with metastases: a prognostic factor of survival in patients with metastatic spinal cord compression (MSCC) from non-small cell lung cancer (NSCLC). AB - BACKGROUND/AIM: In patients irradiated for MSCC from NSCLC, the number of extraspinal organs involved by metastases was investigated for associations with survival. PATIENTS AND METHODS: The data of 131 patients irradiated with 10*3 Gy in two weeks for MSCC were evaluated. The number of involved extraspinal organs plus eight other factors were retrospectively analyzed. RESULTS: The 6-month survival rates were 72%, 57%, 20%, and 11% for the involvement of 0, 1, 2, and >=3 extraspinal organs, respectively (p<0.001). On multivariate analysis, the number of involved extraspinal organs remained significant (risk ratio 1.60; 95% CI 1.28-2.00; p<0.001). Gender (p=0.028), ECOG performance score (p=0.001), histology (p=0.014), ambulatory status (p=0.002), and time to developing motor deficits (p=0.041) were also independent prognostic factors for survival. CONCLUSION: The number of extraspinal organs with metastases is an independent prognostic factor for the survival of NSCLC patients presenting with MSCC and should be considered in future studies. PMID- 24778068 TI - Early manifestation of communicating hydrocephalus after fractionated stereotactic radiotherapy for aggressive giant atypical prolactinoma. AB - Aggressive giant invasive pituitary adenomas refractory to standard surgical or medical treatment remain a genuine challenge. In addition, communicating hydrocephalus (CH) attributed to malabsorption of cerebrospinal fluid (CSF) developing after radiotherapy for pituitary adenomas has not been previously reported. Herein, we describe the case of a 48-year-old male presenting with a giant atypical prolactinoma refractory to previous therapies, including pharmacotherapy and repetitive surgery. He underwent image-guided fractionated stereotactic radiotherapy in 28 fractions, resulting in early manifestation of CH associated with undisputed, both radiological and hormonal response. He recovered well after a shunt placement, with otherwise favorable consequences such as sustained tumor regression, decreasing prolactin level, and retained visual function for a 22-month follow-up. Fractionated stereotactic radiotherapy would provide a viable treatment alternative for these refractory cases, while caution should be exercised regarding the possibility of iatrogenic CH. PMID- 24778069 TI - Early metabolic response on 18F-fluorodeoxyglucose-positron-emission tomography/computed tomography after concurrent chemoradiotherapy for advanced stage III non-small cell lung cancer is correlated with local tumor control and survival. AB - AIM: We evaluated the relationship of early metabolic responses on (18)F fluorodeoxyglucose-positron-emission tomography/computed tomography (PET/CT) performed within one month after concurrent chemoradiotherapy (CCRT) with local tumor control and survival in patients with advanced stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred and nineteen patients with unresectable stage III NSCLC who completed definitive CCRT were included. PET/CT was performed 2-4 weeks after completion of radiotherapy. RESULTS: The maximum standardized uptake value (SUVmax) reduction ratio of the primary lesion (primary SRR, 80%, p<0.001), gross tumor volume (150 cm(3), p=0.036), and pre-radiotherapy ratio of SUVmax of the metastatic lymph node to that of the primary lesion (60%, p=0.05) were significantly associated with OS in multivariate analysis. The primary SRR was the only statistically significant parameter for local control. CONCLUSION: Early metabolic response of the primary lesion after CCRT correlated with local control and overall survival in patients with unresectable stage III NSCLC. PMID- 24778070 TI - Developing a decision-making model based on an interdisciplinary oncological care group for the management of colorectal cancer. AB - AIM: To report our experience on implementation and preliminary results of a decision-making model based on the recommendations of an Interdisciplinary Oncological Care Group developed for the management of colorectal cancer. PATIENTS AND METHODS: The multidisciplinary team identified a reference guideline using appraisal of guidelines for research and evaluation (AGREE) tool based on a sequential assessment of the guideline quality. Thereafter, internal guidelines with diagnostic and therapeutic management for early, locally advanced and metastatic colonic and rectal cancer were drafted; organizational aspects, responsibility matrices, protocol actions for each area of specialty involved and indicators for performing audits were also defined. RESULTS: The National Institute for Health and Care Excellence (NICE) UK guideline was the reference for drafting the internal guideline document; from February to November 2013, 125 patients with colorectal cancer were discussed by and taken under the care of the Interdisciplinary Oncological Care Group. The first audit performed in December 2013 revealed optimal adherence to the internal guideline, mainly in terms of uniformity and accuracy of perioperative staging, coordination and timing of multi-modal therapies. To date, all patients under observation are within the diagnostic and therapeutic course, no patient came out from the multidisciplinary "path" and only in 14% of cases have the first recommendations proposed been changed. The selected indicators appear effective and reliable, while at the moment, it is not yet possible to assess the impact of the multidisciplinary team on clinical outcome. CONCLUSION: Although having a short observation period, our model seems capable of determining optimal uniformity of diagnostic and therapeutic management, to a high degree of patient satisfaction. A longer observation period is necessary in order to confirm these observations and for assessing the impact on clinical outcome. PMID- 24778071 TI - Periapical cemento-osseous dysplasia: clinicopathological features. AB - Periapical cemento-osseous dysplasia (PCOD) is a rare benign lesion, often asymptomatic, in which fibrous tissue replaces the normal bone tissue, with metaplasic bone and neo-formed cement. We present a rare case of mandibular PCOD in a woman of 55 years, who presented with moderate swelling and mobility of teeth 32-33-34. Endoral radiography showed that these teeth had been devitalized; they had deep periodontal pockets and marked radicular radiotransparency; the root apices exhibited mixed radiotransparency and radio-opacity. Clinical and radiographical findings led to a diagnosis of periapical rarefying osteitis, and the three teeth were thus extracted. Due to the persistence of swelling and slight pain post-extraction, a cone-beam computed tomographic scan was taken; this showed a mixed radiotransparent and radio-opaque lesion in the area of the extracted teeth. A bone biopsy of the affected area was taken for histopathological evaluation; a diagnosis of PCOD was rendered. This case demonstrates the importance of a full investigation when a patient presents after tooth extraction with non-healing socket, pain, and swelling. A multidisciplinary approach is required to manage these rare cases. PMID- 24778072 TI - A novel minimally invasive technique of high-dose rate image-based intracavitary brachytherapy for endometrial cancer using a single fine and soft, flexible applicator. AB - AIM: We report on a minimally invasive computed tomography (CT)/magnetic resonance imaging (MRI)-based image-guided intracavitary brachytherapy (ICBT) for an elder patient with endometrial cancer, who was unfit for anesthesia, using a fine and soft flexible applicator. PATIENTS AND METHODS: The patient was an 82 year-old female. She was identified as having T1bN0M0 (stage IB) tumor, and histological findings revealed grade 2 adenocarcinoma. She was contraindicated for surgery because of advanced age and severe pulmonary emphysema; therefore, she was managed with CT/MRI-based ICBT alone. The total treatment dose was 26 Gy (6.5 Gy per fraction). The dose-volume histogram of the gross tumor volume, the clinical target volume, and organs at risk were calculated. RESULTS: The patient safely completed the ICBT course without pre-medication. Tumor growth was controlled, with complete disappearance after 32 months. No acute or late adverse effects were observed. MRI-guided ICBT can visualize the gross tumor volume in the uterine body, which cannot be detected by CT. CONCLUSION: We successfully and safely performed minimally invasive CT/MRI-based ICBT without pre-medication in a patient with endometrial cancer with high surgical risks, using a fine and soft, flexible applicator. PMID- 24778073 TI - Osteosarcoma of the patella mimicking giant cell tumor: imaging features with histopathological correlation. AB - Patellar tumors represent an uncommon etiology of anterior knee pain and their diagnosis is often delayed. We present an unusual case of conventional osteosarcoma arising in the patella of a 47-year-old man. The patient presented with a 1-year history of increasing anterior knee pain and swelling. Plain radiographs revealed a multi-locular lytic lesion in the inferolateral side of the patella. Computed tomography scans demonstrated an intraosseous lytic lesion with cortical thinning/breakthrough anteriorly. On magnetic resonance imaging, the lesion exhibited low signal intensity on T1-weighted images and heterogeneous high signal intensity on T2-weighted images. Fluid-fluid levels were also observed on T2-weighted images. Contrast-enhanced fat-suppressed T1-weighted images demonstrated strong enhancement of the lesion. These imaging features were suggestive of a benign condition; however, the diagnosis of osteosarcoma was confirmed by histopathology. After neoadjuvant chemotherapy, a wide resection with a free anterolateral thigh flap was performed. The patient subsequently underwent adjuvant chemotherapy and had no evidence of local recurrence or distant metastasis six months after surgery. Our case highlights the difficulty in the diagnosis of patellar osteosarcoma and the importance of performing a biopsy before definitive treatment. PMID- 24778074 TI - Gastrointestinal stromal tumor of colon: a case report and review of literature. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract. GISTs originate from cells of Cajal and related stem cells. Surgery and imatinib therapy are the main lines of treatment. CASE REPORT: We report on a case with GIST in the colon treated with surgical resection followed by adjuvant imatinib therapy. This treatment showed no side-effects, and subsequent colonoscopy was unremarkable. CONCLUSION: The diagnosis was delayed for 12 months after initial presentation of vague abdominal pain, thus highlighting the need to improve clinical suspicion in order to detect GISTs in earlier stages when resection may be curative. Colonic GIST, in particular, may mimic presentation similar to ovarian cyst, as seen in the present case. This case report corroborates that patients with high-grade GISTs can be effectively treated with imatinib therapy. However, duration of treatment may vary depending on the grade of the tumor and side-effects. PMID- 24778075 TI - Preoperative 18F-FDG PET-CT maximum standardized uptake value predicts recurrence of biliary tract cancer. AB - (18)F-Fluorodeoxyglucose positron-emission with computed tomography ((18)F-FDG PET-CT) is an imaging technique based on the increased uptake of glucose characteristically seen in malignant lesions. The preoperative maximum standardized uptake value (SUVmax) of PET-CT has been identified as a powerful significant prognostic factor for predicting recurrence in malignant tumors. Therefore, the aim of this study was to determine whether (18)F-FDG PET-CT has a prognostic significance in patients with biliary tract cancer after surgical resection. From April 2006 to February 2013, 64 patients who underwent curative resection for biliary tract cancer were reviewed retrospectively. Clinical diagnoses of patients were: intrahepatic cholangio-carcinoma (n=6), hilar cholangiocarcinoma (n=6), extrahepatic cholangiocarcinoma (n=22), gall bladder cancer (n=14) and ampullar cancer (n=16). The mean preoperative SUVmax value was 5.1+/-4.7. The mean follow-up duration was 27 months. Recurrence-free survival at 1, 2 and 5 years were 75.9%, 63.3% and 47.1%. In the univariate analysis, N stage, poor tumor differentiation, the presence of lymphatic invasion and high SUVmax (>5.0) were significant risk factors for recurrence. The multivariate analysis showed a high preoperative SUVmax (>5.0) to be an independent risk factor for tumor recurrence (p=0.008). In conclusion, preoperative SUVmax of the primary tumor was significantly associated with recurrence in patients with biliary tract cancer. PMID- 24778076 TI - Re-irradiation of spinal cord compression due to metastasis in elderly patients. AB - BACKGROUND/AIM: The present study investigated efficacy and toxicity of re irradiation for an in-field recurrence of spinal cord compression due to metastasis (SCCM) in elderly patients. PATIENTS AND METHODS: Data of 60 patients aged >=65 years who were irradiated for an in-field recurrence of SCCM were retrospectively analyzed. The fractionation regimen of re-irradiation and eight additional potential prognostic factors were evaluated for motor function. RESULTS: Median time to in-field recurrence was 6 (2-45) months. After re irradiation, 25 patients (42%) showed improvement of motor function, 28 (47%) no change, and 7 (12%) deterioration. No second in-field recurrences were observed. Post-treatment motor function was not associated with the fractionation regimen. Radiation myelopathy was not observed. The cumulative biologically-effective dose for myelopathy was 80-137 Gy2. CONCLUSION: Re-irradiation for in-field recurrences of SCCM in elderly patients appears safe and effective. Myelopathy appears unlikely, if the cumulative biologically effective dose is 137 Gy2 or less. The fractionation regimen had no significant impact on motor function. PMID- 24778077 TI - A success story: how a single targeted-therapy molecule impacted on treatment and outcome of diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is a rather aggressive disease and the natural course of this lymphoma is very dismal. However, first the introduction of anthracycline-containing chemotherapy regimens and then the addition of rituximab were important steps forward. Since no complete real-life analyses have yet been published, we analyzed all patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in the whole region of Tyrol and compared the results to a historical CHOP(-like)-treated cohort. Two hundred and nineteen consecutive patients underwent R-CHOP and 72% achieved a complete remission (CR); 20% suffered a relapse and 31% died. 5-Year progression-free survival (PFS) and overall survival (OS) were 56% and 69%, respectively. We identified several parameters influencing PFS and OS significantly in univariate analysis, but only stage III/IV and hemoglobin <13 g/dl were independent prognosticators for PFS and age >60 years for OS. In comparison to the CHOP(-like)-treated group, the CR rate was similar, while the percentage of relapse was nearly twice in the historical cohort, namely 44%. This translated into a dramatically improved PFS and OS for the R-CHOP group. In conclusion, in a real-life setting R-CHOP results in high percentages of response and long-term remission. Moreover we showed that in the rituximab era, factors other than the single parameters of the international prognostic index significantly influence PFS and OS. Finally, we confirm the independent impact of rituximab on the outcome of an unselected population with DLBCL. PMID- 24778078 TI - Detection and cultivation of circulating tumor cells in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive disease with very poor prognosis which tends to affect older patients. Progress in the management of this group of patients has been limited by the rarity of the disease and hence, difficulty in conducting randomized trials. The vast majority of cancer deaths occur due to metastasis of the primary tumor to distant sites via circulating tumor cells (CTCs) in the circulation. CTCs are extremely rare and limits in technology used to capture these cells hamper our complete understanding over the metastatic process. In the present study we present a new method for detection and cultivation of CTCs isolated from peripheral blood of MPM patients. PATIENTS AND METHODS: Patients with diagnosed MPM were enrolled into this study. RESULTS: A size-based separation method for viable CTC enrichment from unclothed peripheral blood has been introduced; MetaCell. The size-based enrichment process was based on filtration of peripheral blood (PB) through porous polycarbonate membrane. The separated CTCs are cultured on the membrane in vitro under standard cancer cell culture conditions and observed by an inverted microscope. CONCLUSION: The reported methodology allows for quick and easy enrichment of CTCs and their cultivation. The cultivated cells can be used for next specification of gene expression and histological/biological specificity of concrete mesothelioma. PMID- 24778079 TI - Lack of association between KRAS mutations and 18F-FDG PET/CT in Caucasian metastatic colorectal cancer patients. AB - BACKGROUND: Although Kirsten rat sarcoma (KRAS) gene mutational testing is essential for the optimal design of therapeutic strategies for colorectal cancer, it is not always feasible or reliable. In this retrospective study, we examined whether (18)F-Fluorodeoxyglucose positron-emission tomography/computed tomography ((18)F-FDG PET/CT) scans can serve as a surrogate examination for KRAS mutational testing. PATIENTS AND METHODS: KRAS codon 12 and 13 mutational status was tested in 44 colorectal primary tumors and was compared with the (18)F-FDG PET/CT maximum standardized uptake value (SUVmax) values of the respective metastatic lesions. Glucose transporter-1 (GLUT1) mRNA levels were also measured in colorectal primary tumors. RESULTS: No statistically significant correlation between (18)F-FDG PET/CT SUVmax values and KRAS mutation status was found (parametric t-test: p=0.4753; non-parametric Kruskal-Wallis test: p=0.51). This result cannot be attributed to the effect of differing GLUT1 mRNA levels, as shown by multivariate analysis. CONCLUSION: Our study failed to promote (18)F-FDG PET/CT uptake as a surrogate examination for KRAS mutation testing. PMID- 24778080 TI - Contemporary review of large adrenal tumors in a tertiary referral center. AB - BACKGROUND: Large adrenal tumors (LATs, >=6 cm) are uncommon and associated with malignancy in 25% of cases. Their surgical management remains debatable. The aim of the present report was to evaluate the current incidence, nature and management of LAT. PATIENTS AND METHODS: We carried out a retrospective review of LATs managed in a tertiary referral center (2002-2011). RESULTS: Eighty-one patients were included (out of a total of 750 with adrenal tumors, 11%). Nine patients had no surgical intervention (11%). Fifty-two LATs were malignant (64%): adrenocortical carcinoma (44%), metastasis (27%) and pheochromocytoma (21%). Patients with malignant tumors exhibited a poorer 5-year overall survival than those with benign tumors (53.4% versus 96.3%, p=0.001). Disease-related mortality was approximately 60%, 29% and 0% for those with metastasis, adrenal carcinoma and malignant pheochromocytoma, respectively. The recurrence rate was the same for the three malignant sub-groups (30%). CONCLUSION: LATs are rare and more frequently malignant than previously reported. Some are benign and do not require for surgical intervention. Surgical indication and approach should be tailored for each patient. PMID- 24778081 TI - Status of Anaplastic Lymphoma Kinase (ALK) in malignant mesothelioma. AB - BACKGROUND: Malignant mesothelioma (MM) is a particularly aggressive type of primary tumor, associated with exposure to asbestos, and characterized by high mortality. To date, there is no curative therapy for MM. The receptor anaplastic lymphoma kinase (ALK) was found to be mutated in many cases of cancer and used as a target in biological therapies. We investigated whether this pharmacological treatment could also be applicable to MM. MATERIALS AND METHODS: The state of ALK was analyzed by immunohistochemistry and fluorescent in situ hybridization in 63 MM tissue specimens. RESULTS: None of the 63 MM samples showed overexpression or translocation of ALK. CONCLUSION: Our preliminary data exclude the utility of analysis of the ALK gene in MM and suggest that ALK inhibitor therapy is not applicable to MM. PMID- 24778084 TI - Prenatal development of the digestive system in the horse. AB - Since the horse has a highly precocial reproductive strategy, most organs are functionally well developed at birth and thus, embryonic and fetal life is interesting. Data on the development of important organs are very limited. Here, we detailed macroscopically and histologically the equine digestive system, focusing on the first third of gestation. At 21 days, the oral cavity was an empty space, and the liver contained proliferating endodermal cells. At 25 days, a fusiform stomach and the pancreatic bud were present. At 28 days, a small tongue and the esophagus occurred. At 30 days, primary and secondary palates were developed, the liver contained cords of hepatocytes, and the pancreas was triangular. At 40 days, crypts had formed in the intestinal loops, cell differentiation was observed in the hepatic parenchyma, and the pancreas was elongated. Pancreatic acini and islets were observed in fetuses of 50 days and intestines were highly convoluted. Three segments of the pharynx were distinguishable at 75 days. At 105 days, the intestinal villi were wide with round tips; especially, the liver, stomach, and oral cavity showed key steps of anatomical and cellular differentiation in early fetuses, whereas other areas, such as pancreas or pharynx were still immature in the investigated phase. Pluripotency analysis using Oct4 showed initial intense staining in all of the digestive system tissues and a later decreased becoming restricted to specific cell layers. In conclusion, our data may contribute to perform a chronological reference of developmental events for approaches predicting pregnancy disorders in horses. PMID- 24778085 TI - Guidance for performing multivariate data analysis of bioprocessing data: pitfalls and recommendations. AB - Biotech unit operations are often characterized by a large number of inputs (operational parameters) and outputs (performance parameters) along with complex correlations among them. A typical biotech process starts with the vial of the cell bank, ends with the final product, and has anywhere from 15 to 30 such unit operations in series. Besides the above-mentioned operational parameters, raw material attributes can also impact process performance and product quality as well as interact among each other. Multivariate data analysis (MVDA) offers an effective approach to gather process understanding from such complex datasets. Review of literature suggests that the use of MVDA is rapidly increasing, fuelled by the gradual acceptance of quality by design (QbD) and process analytical technology (PAT) among the regulators and the biotech industry. Implementation of QbD and PAT requires enhanced process and product understanding. In this article, we first discuss the most critical issues that a practitioner needs to be aware of while performing MVDA of bioprocessing data. Next, we present a step by step procedure for performing such analysis. Industrial case studies are used to elucidate the various underlying concepts. With the increasing usage of MVDA, we hope that this article would be a useful resource for present and future practitioners of MVDA. PMID- 24778086 TI - Hospitalization burden and survival among older glioblastoma patients. AB - BACKGROUND: Half of all glioblastoma patients are at least 65 years old. The frequency and duration of hospitalization from disease- and treatment-related morbidity in this population are unknown. METHODS: We performed a retrospective cohort study among patients aged 65 years and older with glioblastoma diagnosed between 1999 and 2007 using SEER-Medicare linked data. Diagnoses and procedures were identified using administrative claims data. Logistic regression was performed to identify predictors of high hospitalization burden. RESULTS: Among the 5029 patients in the cohort, 52% were ages 65-74, and 52% were male. Twenty six percent of patients underwent extensive resection, 72% received radiotherapy, and 18% received temozolomide. Median survival was 4.9 months. Among all patients, 21% were hospitalized at least 30 cumulative days between diagnosis and death, and 22% of all patients spent at least one-fourth of their remaining lives as inpatients. Higher comorbidity score (adjusted hazard ratio [AHR], 1.72; 95% CI, 1.42-2.07) and black race (AHR, 1.56; 95% CI, 1.11-2.18) were associated with an increased risk of being hospitalized for at least 25% of remaining life, whereas radiation (AHR, 0.49; 95% CI, 0.42-0.58), temozolomide (AHR, 0.31; 95% CI, 0.23-0.42), and extensive surgery (AHR, 0.83; 95% CI, 0.69-0.99) were associated with a decreased risk. CONCLUSIONS: These data highlight the burden of hospitalization faced by a large proportion of older glioblastoma patients. In the setting of short survival, strategies to reduce the amount of time these patients spend hospitalized are urgently needed, to help maintain quality of life at the end of life. PMID- 24778087 TI - Ontogeny of the larynx and flight ability in Jamaican fruit bats (Phyllostomidae) with considerations for the evolution of echolocation. AB - Echolocating bats have adaptations of the larynx such as hypertrophied intrinsic musculature and calcified or ossified cartilages to support sonar emission. We examined growth and development of the larynx relative to developing flight ability in Jamaican fruit bats to assess how changes in sonar production are coordinated with the onset of flight during ontogeny as a window for understanding the evolutionary relationships between these systems. In addition, we compare the extent of laryngeal calcification in an echolocating shrew species (Sorex vagrans) and the house mouse (Mus musculus), to assess what laryngeal chiropteran adaptations are associated with flight versus echolocation. Individuals were categorized into one of five developmental flight stages (flop, flutter, flap, flight, and adult) determined by drop-tests. Larynges were cleared and stained with alcian blue and alizarin red, or sectioned and stained with hematoxylin and eosin. Our results showed calcification of the cricoid cartilage in bats, represented during the flap stage and this increased significantly in individuals at the flight stage. Thyroid and arytenoid cartilages showed no evidence of calcification and neither cricoid nor thyroid showed significant increases in rate of growth relative to the larynx as a whole. The physiological cross-sectional area of the cricothyroid muscles increased significantly at the flap stage. Shrew larynges showed signs of calcification along the margins of the cricoid and thyroid cartilages, while the mouse larynx did not. These data suggest the larynx of echolocating bats becomes stronger and sturdier in tandem with flight development, indicating possible developmental integration between flight and echolocation. PMID- 24778089 TI - Amatoxins (alpha- and beta-Amanitin) and phallotoxin (Phalloidin) analyses in urines using high-resolution accurate mass LC-MS technology. AB - Mycotoxin intoxications can result from the consumption of amatoxins like alpha- and beta-amanitin or of phallotoxin, present in several toxic mushrooms like Amanita phalloides. To identify and quantify amatoxins and phallotoidin in biological matrixes, we developed a method using liquid chromatography coupled with an ultra-high-resolution and accurate mass instrument (liquid chromatography high-resolution-mass spectrometry, LC-HR-MS), Q ExactiveTM (Thermo Fisher). The method includes a simple solid-phase extraction of urine samples spiked with flurazepam as internal standard (IS), using Bond Elut Agilent Certify cartridges (C18, 200 mg, 3 mL). LC separation was performed on a C18 Accucore column (100 * 2.1 mm, 2.6 um) using a gradient of 10 mM ammonium acetate buffer containing 0.1% (v/v) formic acid and of acetonitrile with 0.1% (v/v) formic acid. Separation of analytes was obtained in 7 min, with respective retention times for alpha amanitin, beta-amanitin, phalloidin and IS of 1.9, 1.7, 3.5 and 3.8 min, respectively. Quantitation on the LC-HR-MS system was performed by extracting the exact mass value of each protonated species using a 5-p.p.m. mass window, which was 919.3614, 920.3455, 789.3257 and 388.1586 for alpha-amanitin, beta-amanitin, phalloidin and IS, respectively. Calibration curves were obtained by spiking drug free urine at 1-100 ng/mL. Mean correlation coefficients, r(2), were above 0.99 for each amatoxins and phalloidin. According to currently accepted validation procedures, the method was tested for selectivity, calibration, accuracy, matrix effect, precision and recovery. Authentic urine samples from 43 patients suffering from a suspected intoxication with mushrooms were analyzed by LC-HR-MS, and the results were compared with ELISA competitive immunoassay. The LC-HR-MS presented large benefits over immunoassay of being specific, faster and more sensitive, making it suitable for daily emergency toxicological analysis. PMID- 24778090 TI - Pharmacokinetics of iso-alpha-acids in volunteers following the consumption of beer. AB - Hop-derived iso-alpha-acid (IAA) ingredient congeners are specific to beer. Concentrations of IAAs were determined in blood of five volunteers over 6 h following the consumption of small volumes of beer containing relatively high (Pale Ale beer) or low (wheat beer) concentrations of IAAs. IAAs were quickly absorbed with peak trans-IAA concentrations at 0.5 h followed by a drop of generally 10-fold at 2 h and low or not detectable trans-IAA levels at 6 h. However, the qualitative monitoring showed that the cis-IAAs were detected at all time-points. Preliminary pharmacokinetics of these compounds in humans shows relatively small interindividual differences and an estimated short half-life of ~30 min. Comparison of 0.5 and 2 h blood specimens demonstrated that the trans isomers were eliminated faster than the cis counterparts. Preliminary urine analysis showed only unmodified 'co' analytes detectable throughout the 6 h. In authentic forensic casework where typically large amounts of conventionally hopped beer are consumed, this approach may provide a novel method to target ingredient congeners consistent with beer ingestion. PMID- 24778093 TI - Aberrant tissue positioning of metallophilic macrophages in the thymus of XCL1 deficient mice. AB - Metallophilic macrophages hold a strategic position within the thymic tissue and play a considerable function in thymic physiology. The development and positioning of these cells within thymic tissue are regulated by complex molecular mechanisms involving different cytokine/chemokine axes. Herein, we studied the role of XCL1 signaling in these processes. We show that in the XCL1 deficient thymus numerous metallophilic macrophages are aberrantly positioned in the thymic cortex, instead of their normal location in the cortico-medullary zone. Still, these cells retain their normal appearance: very large size with prominent, ramifying cytoplasmic prolongations. This shows that XCL1 signaling is not involved in morphological development, but rather in correct positioning of metallophilic macrophages within the thymic tissue. In contrast to thymic metallophilic macrophages, the positioning of splenic marginal metallophilic macrophages is not affected by XCL1-deficiency. PMID- 24778094 TI - University of Zagreb Medical School Repository: promoting institutional visibility. PMID- 24778088 TI - C. elegans as a model for membrane traffic. AB - The counterbalancing action of the endocytosis and secretory pathways maintains a dynamic equilibrium that regulates the composition of the plasma membrane, allowing it to maintain homeostasis and to change rapidly in response to alterations in the extracellular environment and/or intracellular metabolism. These pathways are intimately integrated with intercellular signaling systems and play critical roles in all cells. Studies in Caenorhabditis elegans have revealed diverse roles of membrane trafficking in physiology and development and have also provided molecular insight into the fundamental mechanisms that direct cargo sorting, vesicle budding, and membrane fisson and fusion. In this review, we summarize progress in understanding membrane trafficking mechanisms derived from work in C. elegans, focusing mainly on work done in non-neuronal cell-types, especially the germline, early embryo, coelomocytes, and intestine. PMID- 24778095 TI - The resonance phenomenon in population persistence: can the same theory guide both national security policies and personalized medicine? AB - The theory of resonance in population persistence proposes that the survival of a population that is exposed to externally inflicted loss processes (disturbances) during part of its life cycle is dependent on the relation between the average period of the disturbances and the average generation time of the population. This suggests that the size of a population can be controlled by manipulating the period between external disturbances. This theory, first formalized in a study of intertidal Red Sea mollusks exposed to periodic storms, has been found to apply to such seemingly disparate phenomena as the spread of a pathogen among susceptible individuals and the response of malignant cancer cells to chemotherapy. The current article provides a brief review of the evolution of the resonance theory into a tool that can be applied to designing vaccination policies - specifically, in preparedness for bio-terrorism attacks - and in personalized medicine. A personalized protocol based on the resonance theory was applied to a cancer patient, stabilizing his tumor progression, relieving his hematopoietic toxicity, and extending his survival. PMID- 24778097 TI - Improved visibility of character conflicts in quasi-median networks with the EMPOP NETWORK software. AB - AIM: To provide a valuable tool for graphical representation of mitochondrial DNA (mtDNA) data that enables visual emphasis on complex substructures within the network to highlight possible ambiguities and errors. METHOD: We applied the new NETWORK graphical user interface, available via EMPOP (European DNA Profiling Group Mitochondrial DNA Population Database; www.empop.org) by means of two mtDNA data sets that were submitted for quality control. RESULTS: The quasi-median network torsi of the two data sets resulted in complex reticulations, suggesting ambiguous data. To check the corresponding raw data, accountable nodes and connecting branches of the network could be identified by highlighting induced subgraphs with concurrent dimming of their complements. This is achieved by accentuating the relevant substructures in the network: mouse clicking on a node displays a list of all mtDNA haplotypes included in that node; the selection of a branch specifies the mutation(s) connecting two nodes. It is indicated to evaluate these mutations by means of the raw data. CONCLUSION: Inspection of the raw data confirmed the presence of phantom mutations due to suboptimal electrophoresis conditions and data misinterpretation. The network software proved to be a powerful tool to highlight problematic data and guide quality control of mtDNA data tables. PMID- 24778098 TI - Endocardial focal activation originating from Purkinje fibers plays a role in the maintenance of long duration ventricular fibrillation. AB - AIM: To determine the role of repetitive endocardial focal activations and Purkinje fibers in the maintenance of long duration ventricular fibrillation (LDVF, VF>1 minute) in canine hearts in vivo. METHODS: The study was conducted in electrophysiological laboratory of Shanghai Ruijin hospital from July 2010 to August 2012. A 64-electrode basket was introduced through a carotid artery into the left ventricle (LV) of 11 beagle dogs for global endocardial electrical mapping. In the Lugol's solution group (n=5), the subendocardium was ablated by washing with Lugol's solution. In the control group, (n=6) saline was used for ablation. Before and after saline or Lugol ablation, we determined QRS duration and QT/QTc interval in sinus rhythm (SR). We also measured the activation rates in the first 2 seconds of each minute during 7 minutes of VF for each group. If VF terminated spontaneously in less than 7 minutes, the VF segments used in activation rate analysis were reduced accordingly. RESULTS: At the beginning of VF there was no difference between the groups in the activation rate. However, after 1 minute of LDVF the Lugol's solution group had significantly slower activation rate than the control group. In the control group, all episodes of LDVF (6/6) were successfully sustained for 7 minutes, while in the Lugol's solution group 4/5 episodes of LDVF spontaneously terminated before 7 minutes (4.8+/-1.4 minutes) (P=0.015). In the control group, at 5.1+/-1.3 minutes of LDVF, a successive, highly organized focal LV endocardial activation pattern was observed. During this period, activations partly arose in PF and spread to the working ventricular myocardium. Mapping analysis showed that these events were consistent with repetitive endocardial focal activations. No evidence of similar focal activations was observed in the Lugol's solution group. CONCLUSIONS: Repetitive endocardial focal activations in the LV endocardium may be associated with activation of subendocardial PFs. This mechanism may play an important role in the maintenance of LDVF. PMID- 24778096 TI - Markers for sepsis diagnosis in the forensic setting: state of the art. AB - Reliable diagnoses of sepsis remain challenging in forensic pathology routine despite improved methods of sample collection and extensive biochemical and immunohistochemical investigations. Macroscopic findings may be elusive and have an infectious or non-infectious origin. Blood culture results can be difficult to interpret due to postmortem contamination or bacterial translocation. Lastly, peripheral and cardiac blood may be unavailable during autopsy. Procalcitonin, C reactive protein, and interleukin-6 can be measured in biological fluids collected during autopsy and may be used as in clinical practice for diagnostic purposes. However, concentrations of these parameters may be increased due to etiologies other than bacterial infections, indicating that a combination of biomarkers could more effectively discriminate non-infectious from infectious inflammations. In this article, we propose a review of the literature pertaining to the diagnostic performance of classical and novel biomarkers of inflammation and bacterial infection in the forensic setting. PMID- 24778099 TI - Enhanced activation of matrix metalloproteinase-9 correlates with the degree of papillary thyroid carcinoma infiltration. AB - AIM: To determine whether matrix metalloproteinase-9 (MMP-9) may be a useful adjunctive tool for predicting unfavorable biological behavior of papillary thyroid carcinoma (PTC) by evaluating the expression profile and proteolytic activity of MMP-9 in PTC by different techniques and correlating the findings with clinicopathological prognostic factors. METHODS: Immunohistochemical localization of MMP-9 was analyzed with antibodies specific for either total or active MMP-9. Activation ratios of MMP-9 were calculated by quantifying gel zymography bands. Enzymatic activity of MMP-9 was localized by in situ zymography after inhibiting MMP-2 activity. RESULTS: Immunostaining of total and active MMP 9 was observed in tumor tissue and occasionally in non-neoplastic epithelium. Only active MMP-9 was significantly associated with extrathyroid invasion, lymph node metastasis, and the degree of tumor infiltration (P<0.001, P=0.004, and P<0.001, respectively). Gelatin zymography revealed a correlation between the MMP 9 activation ratio and nodal involvement, extrathyroid invasion, and the degree of tumor infiltration. In situ zymography showed that gelatinases exerted their activity in tumor parenchymal and stromal cells. Moreover, after application of MMP-2 inhibitor, the remaining gelatinase activity, corresponding to MMP-9, was highest in cancers with the most advanced degree of tumor infiltration. CONCLUSIONS: This is the first report suggesting that the evaluation of active MMP-9 by immunohistochemistry and determination of its activation ratio by gelatin zymography may be a useful adjunct to the known clinicopathological factors in predicting tumor behavior. Most important, in situ zimography with an MMP-2 inhibitor for the first time demonstrated a strong impact of MMP-9 activity on the degree of tumor infiltration during PTC progression. PMID- 24778100 TI - Possible transfusion-related acute lung injury (TRALI) in cardiac surgery patients. AB - AIM: To determine the incidence of possible transfusion-related acute lung injury (TRALI) and related risk factors in cardiac surgery patients. METHODS: A single center prospective cohort study was conducted from January 2009 to March 2010 at the Zagreb University Hospital Center, Croatia. Patient-, transfusion-, and surgery-related data were collected. The study included 262 patients who were observed for respiratory worsening including measurements of arterial oxygen saturation (SaO2), fraction of inspired oxygen (FiO2), and partial pressure of arterial oxygen (PaO2). Possible TRALI was defined according to the Toronto Consensus Conference definition broadened for 24-hour post-transfusion. This cohort was divided in two groups. TRALI group included 32 participants with diagnosis of TRALI and the control group included 220 patients with or without respiratory worsening, but with no signs of ALI. RESULTS: Possible TRALI was observed in 32 (12.2%) patients. Compared with the control group, possible TRALI patients had higher American Association of Anesthesiology scores, higher rate of respiratory comorbidity (43.8% vs 15.5%), and required more red blood cells (median 4, range [2.5-6] vs 2 [1-3]), plasma (5 [0-6] vs 0 [0-2]), and platelet units (0 [0-8] vs 0 [0-0]) (P<0.001 all). Risk factors for possible TRALI were total number of transfused blood units (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.10-1.37) and duration of cardiopulmonary bypass (OR 1.08; 95% CI 1.05-1.11). Post-transfusion PaO2/FiO2 ratio was significantly decreased in possible TRALI patients and significantly increased in transfused controls without acute lung injury. CONCLUSION: We observed a higher rate of possible TRALI cases than in other studies on cardiac surgery patients. Serial monitoring of PaO2/FiO2 ratio and detection of its post-transfusion worsening aids in identification of possible TRALI cases. PMID- 24778101 TI - Albendazolesulphoxide concentrations in plasma and hydatid cyst and prediction of parasitological and clinical outcomes in patients with liver hydatidosis caused by Echinococcus granulosus. AB - AIM: To investigate the relationship between plasma and cyst concentrations of albendazolesulphoxide (ASO) and their effects on parasitological findings and disease recurrence in patients with liver hydatidosis. METHODS: The study was conducted at the University Hospital for Infectious Diseases Dr. Fran Mihaljevic, Zagreb, Croatia, between August 2006 and January 2011. Consecutive patients (N=48, age 6-77 years) were treated with albendazole (3*5 mg/kg/d) over 28 days before surgical cyst removal (n=34) or percutaneous evacuation (PAIR) (n=14). Plasma ASO was determined on days 10 and 28 of treatment and cyst concentrations at surgery/PAIR. RESULTS: Disease recurred in 3 surgically treated patients. Variability of ASO concentrations was substantial. Plasma concentrations on day 10 were higher than on day 28 (geometric means ratio [GMR] 2.00; 95%CI 1.38-2.91, P<0.001) and higher than cyst concentrations at the time of treatment (GMR=1.58, 1.01-2.34, P=0.045). Higher cyst (but not plasma) concentrations were independently associated with lower odds of protoscolex motility (OR=0.23, 0.01 0.70, P<0.001) and higher odds of protoscolex destruction (OR=1.17, 1.04-1.46, P<0.001). With adjustment for age and protoscolex motility, higher day 10 plasma concentrations (but not cyst concentrations) were associated with lower odds of disease recurrence (OR=0.49, 0.09-0.97, P=0.035). Plasma concentrations did not predict cyst concentrations. CONCLUSION: Viability of protoscolices progressively decreased with increasing ASO concentrations in the cyst. Data strongly suggested that higher plasma concentrations reduced the risk of disease recurrence. PMID- 24778102 TI - Alcohol abuse as the strongest risk factor for violent offending in patients with paranoid schizophrenia. AB - AIM: To determine predictive risk factors for violent offending in patients with paranoid schizophrenia in Croatia. METHOD: The cross-sectional study including male in-patients with paranoid schizophrenia with (N=104) and without (N=102) history of physical violence and violent offending was conducted simultaneously in several hospitals in Croatia during one-year period (2010-2011). Data on their sociodemographic characteristics, duration of untreated illness phase (DUP), alcohol abuse, suicidal behavior, personality features, and insight into illness were collected and compared between groups. Binary logistic regression model was used to determine the predictors of violent offending. RESULTS: Predictors of violent offending were older age, DUP before first contact with psychiatric services, and alcohol abuse. Regression model showed that the strongest positive predictive factor was harmful alcohol use, as determined by AUDIT test (odds ratio 37.01; 95% confidence interval 5.20-263.24). Psychopathy, emotional stability, and conscientiousness were significant positive predictive factors, while extroversion, pleasantness, and intellect were significant negative predictive factors for violent offending. CONCLUSION: This study found an association between alcohol abuse and the risk for violent offending in paranoid schizophrenia. We hope that this finding will help improve public and mental health prevention strategies in this vulnerable patient group. PMID- 24778103 TI - Future directions of forensic DNA databases. PMID- 24778104 TI - The value of bio-objects and policy discourses in Europe. PMID- 24778105 TI - The first Russian seminar on science communication. PMID- 24778106 TI - Understanding attention deficit disorder: a neuroscience prospective. PMID- 24778107 TI - A review of evidence for the link between sleep duration and hypertension. AB - There are lines of evidence from experimental sleep deprivation studies, population-based epidemiological studies, and an interventional study that point to the potential efficacy of adequate quality sleep to prevent and treat hypertension. Experimental sleep restriction has been shown to raise blood pressure and heart rate. Insufficient sleep on a chronic basis can raise average 24-hour blood pressure and lead to structural adaptations that entrain the cardiovascular system to operate at an elevated blood pressure equilibrium and increase the risk for hypertension. Disruptions in the timing and duration of sleep could also disrupt circadian rhythmicity and autonomic balance, which can increase the prevalence of the nondipping pattern, disturb diurnal rhythm of cardiac output, and increase blood pressure variability. Short sleep duration has been found to be associated with higher blood pressure and hypertension in both cross-sectional and longitudinal epidemiological studies. The association appears stronger in middle-aged adults and in women. Experimental sleep extension has been shown to significantly reduce blood pressure in individuals with prehypertension or stage 1 hypertension. The observed association between sleep duration and hypertension raises the hypothesis that interventions to extend sleep and improve sleep quality could serve as effective primary, secondary, and tertiary preventive measures for hypertension. PMID- 24778108 TI - Power analysis and sample size estimation for sequence-based association studies. AB - MOTIVATION: Statistical methods have been developed to test for complex trait rare variant (RV) associations, in which variants are aggregated across a region, which is typically a gene. Power analysis and sample size estimation for sequence based RV association studies are challenging because of the necessity to realistically model the underlying allelic architecture of complex diseases within a suitable analytical framework to assess the performance of a variety of RV association methods in an unbiased manner. SUMMARY: We developed SEQPower, a software package to perform statistical power analysis for sequence-based association data under a variety of genetic variant and disease phenotype models. It aids epidemiologists in determining the best study design, sample size and statistical tests for sequence-based association studies. It also provides biostatisticians with a platform to fairly compare RV association methods and to validate and assess novel association tests. AVAILABILITY AND IMPLEMENTATION: The SEQPower program, source code, multi-platform executables, documentation, list of association tests, examples and tutorials are available at http://bioinformatics.org/spower. PMID- 24778109 TI - Regulatory interactions maintaining self-renewal of human embryonic stem cells as revealed through a systems analysis of PI3K/AKT pathway. AB - MOTIVATION: Maintenance of the self-renewal state in human embryonic stem cells (hESCs) is the foremost critical step for regenerative therapy applications. The insulin-mediated PI3K/AKT pathway is well appreciated as being the central pathway supporting hESC self-renewal; however, the regulatory interactions in the pathway that maintain cell state are not yet known. Identification of these regulatory pathway components will be critical for designing targeted interventions to facilitate a completely defined platform for hESC propagation and differentiation. Here, we have developed a systems analysis approach to identify regulatory components that control PI3K/AKT pathway in self-renewing hESCs. RESULTS: A detailed mathematical model was adopted to explain the complex regulatory interactions in the PI3K/AKT pathway. We evaluated globally sensitive processes of the pathway in a computationally efficient manner by replacing the detailed model by a surrogate meta-model. Our mathematical analysis, supported by experimental validation, reveals that negative regulators of the molecules IRS1 and PIP3 primarily govern the steady state of the pathway in hESCs. Among the regulators, negative feedback via IRS1 reduces the sensitivity of various reactions associated with direct trunk of the pathway and also constraints the propagation of parameter uncertainty to the levels of post receptor signaling molecules. Furthermore, our results suggest that inhibition of negative feedback can significantly increase p-AKT levels and thereby, better support hESC self renewal. Our integrated mathematical modeling and experimental workflow demonstrates the significant advantage of computationally efficient meta-model approaches to detect sensitive targets from signaling pathways. AVAILABILITY AND IMPLEMENTATION: FORTRAN codes for the PI3K/AKT pathway and the RS-HDMR implementation are available from the authors upon request. PMID- 24778110 TI - Origins of a 350-kilobase genomic duplication in Mycobacterium tuberculosis and its impact on virulence. AB - In the present study, we have investigated the evolution and impact on virulence of a 350-kb genomic duplication present in the most recently evolved members of the Mycobacterium tuberculosis East Asian lineage. In a mouse model of infection, comparing HN878 subclones HN878-27 (no duplication) and HN878-45 (with the 350-kb duplication) revealed that the latter is impaired for in vivo growth during the initial 3 weeks of infection. Furthermore, the median survival time of mice infected with isolate HN878-45 is significantly longer (77 days) than that of mice infected with HN878-27. Whole-genome sequencing of both isolates failed to reveal any mutational events other than the duplication that could account for such a substantial difference in virulence. Although we and others had previously speculated that the 350-kb duplication arose in response to some form of host applied selective pressure (P. Domenech, G. S. Kolly, L. Leon-Solis, A. Fallow, M. B. Reed, J. Bacteriol. 192: 4562-4570, 2010, and B. Weiner, J. Gomez, T. C. Victor, R. M. Warren, A. Sloutsky, B. B. Plikaytis, J. E. Posey, P. D. van Helden, N. C. Gey van Pittius, M. Koehrsen, P. Sisk, C. Stolte, J. White, S. Gagneux, B. Birren, D. Hung, M. Murray, J. Galagan, PLoS One 7: e26038, 2012), here we show that this large chromosomal amplification event is very rapidly selected within standard in vitro broth cultures in a range of isolates. Indeed, subclones harboring the duplication were detectable after just five rounds of in vitro passage. In contrast, the duplication appears to be highly unstable in vivo and is negatively selected during the later stages of infection in mice. We believe that the rapid in vitro evolution of M. tuberculosis is an underappreciated aspect of its biology that is often ignored, despite the fact that it has the potential to confound the data and conclusions arising from comparative studies of isolates at both the genotypic and phenotypic levels. PMID- 24778111 TI - Characterization of immunological cross-reactivity between enterotoxigenic Escherichia coli heat-stable toxin and human guanylin and uroguanylin. AB - Enterotoxigenic Escherichia coli (ETEC) expressing the heat-stable toxin (ST) (human-type [STh] and porcine-type [STp] variants) is among the five most important enteric pathogens in young children living in low- and middle-income countries. ST mediates diarrheal disease through activation of the guanylate cyclase C (GC-C) receptor and is an attractive vaccine target with the potential to confer protection against a wide range of ETEC strains. However, immunological cross-reactivity to the endogenous GC-C ligands guanylin and uroguanylin is a major concern because of the similarities to ST in amino acid sequence, structure, and function. We have investigated the presence of similar epitopes on STh, STp, guanylin, and uroguanylin by analyzing these peptides in eight distinct competitive enzyme-linked immunosorbent assays (ELISAs). A fraction (27%) of a polyclonal anti-STh antibody and an anti-STh monoclonal antibody (MAb) cross reacted with uroguanylin, the latter with a 73-fold-lower affinity. In contrast, none of the antibodies raised against STp, one polyclonal antibody and three MAbs, cross-reacted with the endogenous peptides. Antibodies raised against guanylin and uroguanylin showed partial cross-reactivity with the ST peptides. Our results demonstrate, for the first time, that immunological cross-reactions between ST and the endogenous peptides can occur. However, the partial nature and low affinity of the observed cross-reactions suggest that the risk of adverse effects from a future ST vaccine may be low. Furthermore, our results suggest that this risk may be reduced or eliminated by basing an ST immunogen on STp or a selectively mutated variant of STh. PMID- 24778112 TI - Structural conservation, variability, and immunogenicity of the T6 backbone pilin of serotype M6 Streptococcus pyogenes. AB - Group A streptococcus (GAS; Streptococcus pyogenes) is a Gram-positive human pathogen that causes a broad range of diseases ranging from acute pharyngitis to the poststreptococcal sequelae of acute rheumatic fever. GAS pili are highly diverse, long protein polymers that extend from the cell surface. They have multiple roles in infection and are promising candidates for vaccine development. This study describes the structure of the T6 backbone pilin (BP; Lancefield T antigen) from the important M6 serotype. The structure reveals a modular arrangement of three tandem immunoglobulin-like domains, two with internal isopeptide bonds. The T6 pilin lysine, essential for polymerization, is located in a novel VAKS motif that is structurally homologous to the canonical YPKN pilin lysine in other three- and four-domain Gram-positive pilins. The T6 structure also highlights a conserved pilin core whose surface is decorated with highly variable loops and extensions. Comparison to other Gram-positive BPs shows that many of the largest variable extensions are found in conserved locations. Studies with sera from patients diagnosed with GAS-associated acute rheumatic fever showed that each of the three T6 domains, and the largest of the variable extensions (V8), are targeted by IgG during infection in vivo. Although the GAS BP show large variations in size and sequence, the modular nature of the pilus proteins revealed by the T6 structure may aid the future design of a pilus-based vaccine. PMID- 24778113 TI - Epithelial microvilli establish an electrostatic barrier to microbial adhesion. AB - Microvilli are membrane extensions on the apical surface of polarized epithelia, such as intestinal enterocytes and tubule and duct epithelia. One notable exception in mucosal epithelia is M cells, which are specialized for capturing luminal microbial particles; M cells display a unique apical membrane lacking microvilli. Based on studies of M cell uptake under different ionic conditions, we hypothesized that microvilli may augment the mucosal barrier by providing an increased surface charge density from the increased membrane surface and associated glycoproteins. Thus, electrostatic charges may repel microbes from epithelial cells bearing microvilli, while M cells are more susceptible to microbial adhesion. To test the role of microvilli in bacterial adhesion and uptake, we developed polarized intestinal epithelial cells with reduced microvilli ("microvillus-minus," or MVM) but retaining normal tight junctions. When tested for interactions with microbial particles in suspension, MVM cells showed greatly enhanced adhesion and uptake of particles compared to microvillus positive cells. This preference showed a linear relationship to bacterial surface charge, suggesting that microvilli resist binding of microbes by using electrostatic repulsion. Moreover, this predicts that pathogen modification of electrostatic forces may contribute directly to virulence. Accordingly, the effacement effector protein Tir from enterohemorrhagic Escherichia coli O157:H7 expressed in epithelial cells induced a loss of microvilli with consequent enhanced microbial binding. These results provide a new context for microvillus function in the host-pathogen relationship, based on electrostatic interactions. PMID- 24778114 TI - The Salmonella effector SteA contributes to the control of membrane dynamics of Salmonella-containing vacuoles. AB - Salmonella enterica serovar Typhimurium is a bacterial pathogen causing gastroenteritis in humans and a typhoid-like systemic disease in mice. S. Typhimurium virulence is related to its capacity to multiply intracellularly within a membrane-bound compartment, the Salmonella-containing vacuole (SCV), and depends on type III secretion systems that deliver bacterial effector proteins into host cells. Here, we analyzed the cellular function of the Salmonella effector SteA. We show that, compared to cells infected by wild-type S. Typhimurium, cells infected by DeltasteA mutant bacteria displayed fewer Salmonella-induced filaments (SIFs), an increased clustering of SCVs, and morphologically abnormal vacuoles containing more than one bacterium. The increased clustering of SCVs and the appearance of vacuoles containing more than one bacterium were suppressed by inhibition of the activity of the microtubule motor dynein or kinesin-1. Clustering and positioning of SCVs are controlled by the effectors SseF and SseG, possibly by helping to maintain a balanced activity of microtubule motors on the bacterial vacuoles. Deletion of steA in S. Typhimurium DeltasseF or DeltasseG mutants revealed that SteA contributes to the characteristic scattered distribution of DeltasseF or DeltasseG mutant SCVs in infected cells. Overall, this shows that SteA participates in the control of SCV membrane dynamics. Moreover, it indicates that SteA is functionally linked to SseF and SseG and suggests that it might contribute directly or indirectly to the regulation of microtubule motors on the bacterial vacuoles. PMID- 24778115 TI - FTT0831c/FTL_0325 contributes to Francisella tularensis cell division, maintenance of cell shape, and structural integrity. AB - The Francisella FTT0831c/FTL_0325 gene encodes amino acid motifs to suggest it is a lipoprotein and that it may interact with the bacterial cell wall as a member of the OmpA-like protein family. Previous studies have suggested that FTT0831c is surface exposed and required for virulence of Francisella tularensis by subverting the host innate immune response (M. Mahawar et al., J. Biol. Chem. 287:25216-25229, 2012). We also found that FTT0831c is required for murine pathogenesis and intramacrophage growth of Schu S4, but we propose a different model to account for the proinflammatory nature of the resultant mutants. First, inactivation of FTL_0325 from live vaccine strain (LVS) or FTT0831c from Schu S4 resulted in temperature-dependent defects in cell viability and morphology. Loss of FTT0831c was also associated with an unusual defect in lipopolysaccharide O antigen synthesis, but loss of FTL_0325 was not. Full restoration of these properties was observed in complemented strains expressing FTT0831c in trans, but not in strains lacking the OmpA motif, suggesting that cell wall contact is required. Finally, growth of the LVS FTL_0325 mutant in Mueller-Hinton broth at 37 degrees C resulted in the appearance of membrane blebs at the poles and midpoint, prior to the formation of enlarged round cells that showed evidence of compromised cellular membranes. Taken together, these data are more consistent with the known structural role of OmpA-like proteins in linking the OM to the cell wall and, as such, maintenance of structural integrity preventing altered surface exposure or release of Toll-like receptor 2 agonists during rapid growth of Francisella in vitro and in vivo. PMID- 24778116 TI - SpyAD, a moonlighting protein of group A Streptococcus contributing to bacterial division and host cell adhesion. AB - Group A streptococcus (GAS) is a human pathogen causing a wide repertoire of mild and severe diseases for which no vaccine is yet available. We recently reported the identification of three protein antigens that in combination conferred wide protection against GAS infection in mice. Here we focused our attention on the characterization of one of these three antigens, Spy0269, a highly conserved, surface-exposed, and immunogenic protein of unknown function. Deletion of the spy0269 gene in a GAS M1 isolate resulted in very long bacterial chains, which is indicative of an impaired capacity of the knockout mutant to properly divide. Confocal microscopy and immunoprecipitation experiments demonstrated that the protein was mainly localized at the cell septum and could interact in vitro with the cell division protein FtsZ, leading us to hypothesize that Spy0269 is a member of the GAS divisome machinery. Predicted structural domains and sequence homologies with known streptococcal adhesins suggested that this antigen could also play a role in mediating GAS interaction with host cells. This hypothesis was confirmed by showing that recombinant Spy0269 could bind to mammalian epithelial cells in vitro and that Lactococcus lactis expressing Spy0269 on its cell surface could adhere to mammalian cells in vitro and to mice nasal mucosa in vivo. On the basis of these data, we believe that Spy0269 is involved both in bacterial cell division and in adhesion to host cells and we propose to rename this multifunctional moonlighting protein as SpyAD (Streptococcus pyogenes Adhesion and Division protein). PMID- 24778117 TI - Synergistic effects of Clostridium perfringens enterotoxin and beta toxin in rabbit small intestinal loops. AB - The ability of Clostridium perfringens type C to cause human enteritis necroticans (EN) is attributed to beta toxin (CPB). However, many EN strains also express C. perfringens enterotoxin (CPE), suggesting that CPE could be another contributor to EN. Supporting this possibility, lysate supernatants from modified Duncan-Strong sporulation (MDS) medium cultures of three CPE-positive type C EN strains caused enteropathogenic effects in rabbit small intestinal loops, which is significant since CPE is produced only during sporulation and since C. perfringens can sporulate in the intestines. Consequently, CPE and CPB contributions to the enteropathogenic effects of MDS lysate supernatants of CPE positive type C EN strain CN3758 were evaluated using isogenic cpb and cpe null mutants. While supernatants of wild-type CN3758 MDS lysates induced significant hemorrhagic lesions and luminal fluid accumulation, MDS lysate supernatants of the cpb and cpe mutants caused neither significant damage nor fluid accumulation. This attenuation was attributable to inactivating these toxin genes since complementing the cpe mutant or reversing the cpb mutation restored the enteropathogenic effects of MDS lysate supernatants. Confirming that both CPB and CPE are needed for the enteropathogenic effects of CN3758 MDS lysate supernatants, purified CPB and CPE at the same concentrations found in CN3758 MDS lysates also acted together synergistically in rabbit small intestinal loops; however, only higher doses of either purified toxin independently caused enteropathogenic effects. These findings provide the first evidence for potential synergistic toxin interactions during C. perfringens intestinal infections and support a possible role for CPE, as well as CPB, in some EN cases. PMID- 24778118 TI - Staphylococcal enterotoxin B-induced microRNA-155 targets SOCS1 to promote acute inflammatory lung injury. AB - Staphylococcal enterotoxin B (SEB) causes food poisoning in humans. It is considered a biological weapon, and inhalation can trigger lung injury and sometimes respiratory failure. Being a superantigen, SEB initiates an exaggerated inflammatory response. While the role of microRNAs (miRNAs) in immune cell activation is getting increasing recognition, their role in the regulation of inflammatory disease induced by SEB has not been studied. In this investigation, we demonstrate that exposure to SEB by inhalation results in acute inflammatory lung injury accompanied by an altered miRNA expression profile in lung infiltrating cells. Among the miRNAs that were significantly elevated, miR-155 was the most overexpressed. Interestingly, miR-155(-/-) mice were protected from SEB-mediated inflammation and lung injury. Further studies revealed a functional link between SEB-induced miR-155 and proinflammatory cytokine gamma interferon (IFN-gamma). Through the use of bioinformatics tools, suppressor of cytokine signaling 1 (SOCS1), a negative regulator of IFN-gamma, was identified as a potential target of miR-155. While miR-155(-/-) mice displayed increased expression of Socs1, the overexpression of miR-155 led to its suppression, thereby enhancing IFN-gamma levels. Additionally, the inhibition of miR-155 resulted in restored Socs1expression. Together, our data demonstrate an important role for miR-155 in promoting SEB-mediated inflammation in the lungs through Socs1 suppression and suggest that miR-155 may be an important target in preventing SEB-mediated inflammation and tissue injury. PMID- 24778119 TI - Chemokines and antimicrobial peptides have a cag-dependent early response to Helicobacter pylori infection in primary human gastric epithelial cells. AB - Helicobacter pylori infection systematically causes chronic gastric inflammation that can persist asymptomatically or evolve toward more severe gastroduodenal pathologies, such as ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. The cag pathogenicity island (cag PAI) of H. pylori allows translocation of the virulence protein CagA and fragments of peptidoglycan into host cells, thereby inducing production of chemokines, cytokines, and antimicrobial peptides. In order to characterize the inflammatory response to H. pylori, a new experimental protocol for isolating and culturing primary human gastric epithelial cells was established using pieces of stomach from patients who had undergone sleeve gastrectomy. Isolated cells expressed markers indicating that they were mucin-secreting epithelial cells. Challenge of primary epithelial cells with H. pylori B128 underscored early dose-dependent induction of expression of mRNAs of the inflammatory mediators CXCL1 to -3, CXCL5, CXCL8, CCL20, BD2, and tumor necrosis factor alpha (TNF-alpha). In AGS cells, significant expression of only CXCL5 and CXCL8 was observed following infection, suggesting that these cells were less reactive than primary epithelial cells. Infection of both cellular models with H. pylori B128DeltacagM, a cag PAI mutant, resulted in weak inflammatory-mediator mRNA induction. At 24 h after infection of primary epithelial cells with H. pylori, inflammatory-mediator production was largely due to cag PAI substrate-independent virulence factors. Thus, H. pylori cag PAI substrate appears to be involved in eliciting an epithelial response during the early phases of infection. Afterwards, other virulence factors of the bacterium take over in development of the inflammatory response. Using a relevant cellular model, this study provides new information on the modulation of inflammation during H. pylori infection. PMID- 24778122 TI - Coronary aneurysm with stent dislocation leading to the diagnosis of Marfan syndrome. PMID- 24778120 TI - Heart failure in patients with human immunodeficiency virus infection: epidemiology, pathophysiology, treatment, and future research. PMID- 24778123 TI - Cardiac magnetic resonance imaging in giant cell myocarditis: intriguing associations with clinical and pathological features. PMID- 24778124 TI - Embolic protection devices. PMID- 24778125 TI - Cardiology patient page. A patient's guide to recovery after deep vein thrombosis or pulmonary embolism. PMID- 24778126 TI - Letter from Egom regarding article, "High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy". PMID- 24778127 TI - Response to letter regarding article, "High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy". PMID- 24778128 TI - The melanoma research alliance: the power of patient advocacy to accelerate research and novel therapies. AB - Patient advocacy organizations play a major role in accelerating research and are particularly important in a disease like melanoma, for which there is an urgent need for new tools and treatments. Melanoma is a growing public health burden. In the United States alone, the incidence of melanoma has tripled over the past 30 years, and one American dies every hour from the disease. To accelerate the field, the Melanoma Research Alliance (MRA) was founded in 2007 and is now the largest private funder of melanoma research, having invested more than $48 million in innovative and translational research projects worldwide to date. This investment is bearing fruit in the recent transformation of the melanoma clinical landscape, which has brought new hope to patients and their families. Yet, even with new drugs on the market, much more needs to be done until melanoma is effectively addressed. MRA is part of a growing group of nonprofit disease research foundations collectively called "venture philanthropies" that are playing a powerful role in transforming the outlook for their disease by overcoming barriers that bog down progress, targeting key areas, and enhancing collaboration. MRA is leading an innovative agenda to accelerate efforts on behalf of patients. Our goal, while significant, is straightforward: to end suffering and death due to melanoma. PMID- 24778129 TI - The 2013 William B. Coley Award for Distinguished Research In Basic and Tumor Immunology. PMID- 24778130 TI - Inverse association between programmed death ligand 1 and genes in the VEGF pathway in primary clear cell renal cell carcinoma. AB - Increased angiogenesis and tumor-induced immune evasion are two mechanisms by which clear cell renal cell carcinoma (ccRCC) proliferate and metastasize; however, the relationship between these pathways in human ccRCC is poorly understood. We conducted a nested case-control study using 98 archived tumor samples from patients diagnosed with primary ccRCC between 1990 and 2006, half of which were identified by immunohistochemistry (IHC) as either programmed death ligand 1 (PDL-1)-positive or PDL-1-negative. RNAs were extracted from the formalin-fixed paraffin-embedded tumor slides and the expression of the VEGFA, VEGFR1, VEGFR2, and PDL-1 genes was quantified. We assessed the presence of tumor infiltrating lymphocytes (TIL) by IHC for CD3, and then analyzed the relationship among VEGFA, VEGFR1, VEGFR2, CD3, and PDL-1. When analyzed as a continuous variable, PDL-1 protein expression by IHC inversely correlates with the expression of the three VEGF-related genes: VEGFA (r = -0.23; P = 0.01), VEGFR1 (r = -0.34; P < 0.001), and VEGFR2 (r = -0.23; P = 0.01). When dichotomized, the PDL-1-positive cohort trended toward a lower expression of VEGFA (fold change = 0.72; P = 0.056) and VEGFR1 (fold change = 0.69; P = 0.057). In addition, there was a significant and positive relationship between the presence of TIL as assessed by IHC for CD3 and PDL-1 by IHC (r = 0.25; P = 0.015), and there was a trend toward an inverse relationship between TIL and VEGFA gene expression (r = 0.18; P = 0.089). In conclusion, this is the first demonstration of an inverse association between the angiogenesis and PDL-1 pathways in tumor samples from primary ccRCC, and this relationship may be related to the immunosuppressive effects of VEGF signaling. PMID- 24778131 TI - mTOR inhibition improves antitumor effects of vaccination with antigen-encoding RNA. AB - Vaccination with in vitro transcribed RNA encoding tumor antigens is an emerging approach in cancer immunotherapy. Attempting to further improve RNA vaccine efficacy, we have explored combining RNA with immunomodulators such as rapamycin. Rapamycin, the inhibitor of mTOR, was used originally for immunosuppression. Recent reports in mouse systems, however, suggest that mTOR inhibition may enhance the formation and differentiation of the memory CD8(+) T-cell pool. Because memory T-cell formation is critical to the outcome of vaccination approaches, we studied the impact of rapamycin on the in vivo primed RNA vaccine induced immune response using the chicken ovalbumin-expressing B16 melanoma model in C57BL/6 mice. Our data show that treatment with rapamycin at the effector-to memory transition phase skews the vaccine-induced immune response toward the formation of a quantitatively and qualitatively superior memory pool and results in a better recall response. Tumor-infiltrating immune cells from these mice display a favorable ratio of effector versus suppressor cell populations. Survival of mice treated with the combined regimen of RNA vaccination with rapamycin is significantly longer (91.5 days) than that in the control groups receiving only one of these compounds (32 and 46 days, respectively). Our findings indicate that rapamycin enhances therapeutic efficacy of antigen specific CD8(+) T cells induced by RNA vaccination, and we propose further clinical exploration of rapamycin as a component of immunotherapeutic regimens. PMID- 24778132 TI - CD8+ T-cell responses rapidly select for antigen-negative tumor cells in the prostate. AB - Stimulation of patients' immune systems for the treatment of solid tumors is an emerging therapeutic paradigm. The use of enriched autologous T cells for adoptive cell therapy or vaccination with antigen-loaded dendritic cells have shown clinical efficacy in melanoma and prostate cancer, respectively. However, the long-term effects of immune responses on selection and outgrowth of antigen negative tumor cells in specific tumor types must be determined to understand and achieve long-term therapeutic effects. In this study, we have investigated the expression of a tumor-specific antigen in situ after treatment with tumor specific CD8(+) T cells in an autochthonous mouse model of prostate cancer. After T-cell treatment, aggregates of dead antigen-positive tumor cells were concentrated in the lumen of the prostate gland and were eventually eliminated from the prostate tissue. Despite the elimination of antigen-positive tumor cells, prostate tumor continued to grow in T-cell-treated mice. Interestingly, the remaining tumor cells were antigen negative and downregulated MHC class I expression. These results show that CD8(+) T cells are effective in eliminating antigen-bearing prostate tumor cells but they also can select for the outgrowth of antigen-negative tumor cells. These findings provide insights into the requirements for an effective cancer immunotherapy within the prostate that not only induces potent immune responses but also avoids selection and outgrowth of antigen-negative tumor cells. PMID- 24778133 TI - Plasmacytoid dendritic cells support melanoma progression by promoting Th2 and regulatory immunity through OX40L and ICOSL. AB - Even though melanoma is considered to be one of the most immunogenic solid tumors, handling its development remains a challenge. The basis for such escape from antitumor immune control has not yet been documented. Plasmacytoid dendritic cells (pDC) are emerging as crucial but still enigmatic cells in cancer. In melanoma, the function of tumor-infiltrating pDCs remains poorly explored. We investigated the pathophysiologic role of pDCs in melanoma, both ex vivo from a large cohort of melanoma patients and in vivo in melanoma-bearing humanized mice. pDCs were found in high proportions in cutaneous melanoma and tumor-draining lymph nodes, yet associated with poor clinical outcome. We showed that pDCs migrating to the tumor microenvironment displayed particular features, subsequently promoting proinflammatory Th2 and regulatory immune profiles through OX40L and ICOSL expression. Elevated frequencies of interleukin (IL)-5-, IL-13- and IL-10-producing T cells in patients with melanoma correlated with high proportions of OX40L- and ICOSL-expressing pDCs. Strikingly TARC/CCL17, MDC/CCL22, and MMP-2 found in the melanoma microenvironment were associated with pDC accumulation, OX40L and ICOSL modulation, and/or early relapse. Thus, melanoma actively exploits pDC plasticity to promote its progression. By identifying novel insights into the mechanism of hijacking of immunity by melanoma, our study exposes potential for new therapeutic opportunities. PMID- 24778137 TI - Onyx embolization of dural arteriovenous fistulas of the cavernous sinus through the superior pharyngeal branch of the ascending pharyngeal artery. AB - We report three cases of dural arteriovenous fistula (DAVF) of the cavernous sinus treated by Onyx injection through the superior pharyngeal branch of the ascending pharyngeal artery. The treatment of choice of DAVFs of the cavernous sinus is endovascular, and it is preferentially done via transvenous occlusion of the cavernous sinus. The cavernous sinus can be reached through either the inferior petrosal sinus or the superior ophthalmic vein. When these venous routes are occluded, the first attempt is to pass through the occluded inferior petrosal sinus, but sometimes this attempt can fail. In some cases there are small transosseous feeders to the fistula arising from the superior pharyngeal branch of the ascending pharyngeal artery. When all of the more conventional approaches are unattainable, this route can be attempted. In our experience, it allowed safe and rapid occlusion of the fistula. PMID- 24778138 TI - Balloon remodeling of complex anterior communicating artery aneurysms: technical considerations and complications. AB - INTRODUCTION: Reports of the limitations and feasibility of balloon remodeling for treatment of complex anterior communicating artery (ACoA) aneurysms are scarce. METHODS: Ninety-nine patients were treated with balloon-assisted coil embolization for ACoA aneurysms between August 2004 and October 2012. Records were reviewed for aneurysm characteristics, balloon trajectory (vessel and side), bilateral access, treatment-related complications, and aneurysm recurrence determined by magnetic resonance angiography (MRA). Morphological outcomes following treatment were categorized into Raymond class I, II, or III. RESULTS: Fifty-three aneurysms (53.5%) were unruptured and 46 (46.4%) were ruptured. Aneurysmal occlusion (Raymond I or II) was achieved in 89 patients (89.9%); three (3.0%) were incompletely embolized and treatment was aborted in six (6.1%). Balloon trajectories were from the A1 to either the ipsilateral or contralateral A2. In 17 cases (17.2%), bilateral A1 access was used to achieve balloon protection of the contralateral A2. In four cases (4.0%), balloon remodeling was aborted due to technical difficulty. There were 15 (15.2%) treatment-related complications; five (5.1%) were intraoperative ruptures, one of which resulted in a neurological deficit and another in death. All other complications were clinically silent, producing a permanent complication rate of 2.0%. Mean radiographic follow-up was 2.5 years, and six patients (6.1%) were retreated for recurrence or known remnant. CONCLUSIONS: Balloon remodeling should be considered for broad-based complex ACoA aneurysms. This technique provides a high rate of aneurysm occlusion with an acceptable complication profile, and avoids the need for dual antiplatelet therapy. The balloon trajectory will depend on aneurysm morphology and bilateral access may be useful in selected cases. PMID- 24778134 TI - Novel mechanism of tumor suppression by polarity gene discs large 1 (DLG1) revealed in a murine model of pediatric B-ALL. AB - Drosophila melanogaster discs large (dlg) is an essential tumor suppressor gene (TSG) controlling epithelial cell growth and polarity of the fly imaginal discs in pupal development. A mammalian ortholog, Dlg1, is involved in embryonic urogenital morphogenesis, postsynaptic densities in neurons, and immune synapses in lymphocytes. However, a potential role for Dlg1 as a mammalian TSG is unknown. Here, we present evidence that loss of Dlg1 confers strong predisposition to the development of malignancies in a murine model of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Using mice with conditionally deleted Dlg1 alleles, we identify a novel "pre-leukemic" stage of developmentally arrested early B-lineage cells marked by preeminent c-Myc expression. Mechanistically, we show that in B-lineage progenitors Dlg1 interacts with and stabilizes the PTEN protein, regulating its half-life and steady-state abundance. The loss of Dlg1 does not affect the level of PTEN mRNAs but results in a dramatic decrease in PTEN protein, leading to excessive phosphoinositide 3-kinase signaling and proliferation. Our data suggest a novel model of tumor suppression by a PDZ domain-containing polarity gene in hematopoietic cancers. PMID- 24778139 TI - Mycotic aneurysm detection rates with cerebral angiography in patients with infective endocarditis. AB - BACKGROUND: Cerebral angiography remains the gold standard for the detection of mycotic aneurysms, and it has been estimated that ruptured mycotic aneurysms result in 5% of the neurological complications of patients with infective endocarditis (IE). OBJECTIVE: To determine the diagnostic yield of cerebral angiography in the above patient population and to assess patient factors that might suggest greater or lesser utility. METHODS: We retrospectively reviewed 168 patients who underwent cerebral angiography with a diagnosis of IE or infected left ventricular assist device at the Cleveland Clinic between January 2003 and March 2010 in accordance with institutional review board guidelines. Chart and imaging review was performed. RESULTS: 15/168 patients (8.9%) had mycotic aneurysms; 93.3% (14/15) of the patients with mycotic aneurysms presented with CNS hemorrhage and 66.7% (10/15) had acute ischemic findings. Of the 15 patients with mycotic aneurysms on angiography, seven underwent CT angiography and six underwent MR angiography, which showed mycotic aneurysms in three (42.9%) and two cases (one of which was questionable; 33.3%), respectively. CONCLUSIONS: Patients with IE or similar sources of central bacterial emboli are prone to neurovascular complications. Approximately 9% of patients with IE at our institution who undergo cerebral angiography have mycotic aneurysms. Presentation with hemorrhage appears to be more predictive of aneurysm, as approximately 22% of patients with IE and hemorrhage were found to have an aneurysm compared with only 1% when hemorrhage was absent. Thus, patients with IE presenting with intracranial hemorrhage should undergo vascular imaging, preferably with cerebral angiography. PMID- 24778140 TI - Delayed stenosis following stentriever use in acute stroke intervention. AB - We report two cases of delayed post-embolectomy stenosis--that is, a new stenosis in the vascular bed of a previous endovascular embolectomy. The first case was discovered incidentally in a patient returning after embolectomy for evaluation of cerebral aneurysms. The second case was discovered on an MR angiogram obtained to screen for stenosis. This was prompted by our experience with the first case. To our knowledge, this phenomenon has not been reported previously. PMID- 24778141 TI - Endovascular coil retrieval using a TrevoProVue stentriever. AB - A 65-year-old man with a left cavernous internal carotid artery cerebral aneurysm experienced a premature detachment of the first framing coil (10 mm * 40 cm Penumbra Complex Standard) during a coil embolization procedure. The coil herniated into the anterior cerebral artery and pericallosal artery. Multiple attempts to retrieve the coil using both a 2 and 4 mm Microsnare (Amplatz GooseNeck) failed. A Trevo ProVue retrievable stent was then used to retrieve the coil without any adverse events. This case report highlights a novel use of a stent for the removal of a foreign body from the cerebrovascular system. PMID- 24778142 TI - Early detection of fragile X syndrome: applications of a novel approach for improved quantitative methylation analysis in venous blood and newborn blood spots. AB - BACKGROUND: Standard fragile X syndrome (FXS) diagnostic tests that target methylation of the fragile X mental retardation 1 (FMR1) CpG island 5' of the CGG expansion can be used to predict severity of the disease in males from birth, but not in females. METHODS: We describe methylation specific-quantitative melt analysis (MS-QMA) that targets 10 CpG sites, with 9 within FMR1 intron 1, to screen for FXS from birth in both sexes. The novel method combines the qualitative strengths of high-resolution melt and the high-throughput, quantitative real-time PCR standard curve to provide accurate quantification of DNA methylation in a single assay. Its performance was assessed in 312 control (CGG <40), 143 premutation (PM) (CGG 56-170), 197 full mutation (FM) (CGG 200 2000), and 33 CGG size and methylation mosaic samples. RESULTS: In male and female newborn blood spots, MS-QMA differentiated FM from control alleles, with sensitivity, specificity, and positive and negative predictive values between 92% and 100%. In venous blood of FM females between 6 and 35 years of age, MS-QMA correlated most strongly with verbal IQ impairment (P = 0.002). In the larger cohort of males and females, MS-QMA correlated with reference methods Southern blot and MALDI-TOF mass spectrometry (P < 0.05), but was not significantly correlated with age. Unmethylated alleles in high-functioning FM and PM males determined by both reference methods were also unmethylated by MS-QMA. CONCLUSIONS: MS-QMA has an immediate application in FXS diagnostics, with a potential use of its quantitative methylation output for prognosis in both sexes. PMID- 24778143 TI - Optimal management of acute type A aortic dissection with mesenteric malperfusion. AB - Acute type A aortic dissection (TAAD) remains a morbid condition; although overall outcomes have improved, patients presenting with preoperative malperfusion syndromes continue to have excessive mortality following conventional open surgical repair. Mesenteric malperfusion is generally associated with the worst prognosis and postoperative mortality in this group. With advances in the endovascular treatment of aortic pathology, options now exist to percutaneously manage mesenteric malperfusion prior to central aortic repair. This strategy may be associated with improved outcomes. To review this, a best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'In patients with acute type A aortic dissections with mesenteric malperfusion, does management of the malperfusion prior to central aortic repair reduce perioperative mortality'. Overall, more than 309 papers were found as a result of the reported search, of which 11 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that, in patients with acute TAAD complicated by mesenteric malperfusion, initial management with percutaneous interventional procedures to reverse the malperfusion followed by delayed central aortic repair is a reasonable strategy; this is because of the extremely poor prognosis associated with immediate central aortic repair in this group. PMID- 24778144 TI - Rarefaction of the aorta under Dacron wrap: a rare complication. AB - Treatment for ascending aortic dilatation varies from a wait-and-watch approach to aortic replacement. The use of an external prosthesis to gird and support the proximal aorta is safe and durable for selected aortic aneurysms. We report a rare complication in a 62-year-old man with bicuspid aortic valve and coronary artery disease who had undergone coronary artery bypass surgery and ascending aortic wrapping 10 years previously. During subsequent aortic valve surgery, he was incidentally found to have erosion of Dacron wrap through the aortic wall. PMID- 24778151 TI - Human innate lymphoid cells. AB - Innate lymphoid cells (ILCs) are lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity and tissue remodeling. ILCs are categorized into 3 groups based on their distinct patterns of cytokine production and the requirement of particular transcription factors for their development and function. Group 1 ILCs (ILC1s) produce interferon gamma and depend on Tbet, group 2 ILCs (ILC2s) produce type 2 cytokines like interleukin-5 (IL-5) and IL-13 and require GATA3, and group 3 ILCs (ILC3s) include lymphoid tissue inducer cells, produce IL-17 and/or IL-22, and are dependent on RORgammat. Whereas ILCs play essential roles in the innate immune system, uncontrolled activation and proliferation of ILCs can contribute to inflammatory autoimmune diseases. In this review, we provide an overview of the characteristics of ILCs in the context of health and disease. We will focus on human ILCs but refer to mouse studies if needed to clarify aspects of ILC biology. PMID- 24778152 TI - Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells. AB - In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined. PMID- 24778154 TI - Neutrophil homeostasis and its regulation by danger signaling. AB - Hematopoiesis in general is demand driven and adaptive, but in contrast to erythropoiesis or thrombocytopoiesis, our knowledge on how neutrophil production is adapted to individual needs remains incomplete. Recently, neutrophil homeostasis has been shown to depend on danger receptors, macrophages, and even circadian rhythms. Puzzle pieces for a broader view of neutrophil homeostasis accumulate, and we will herein try to put seemingly contradictory evidence in a perspective of neutrophil homeostasis and emergency granulopoiesis determined by innate immunologic signaling. PMID- 24778153 TI - Somatic mutation as a mechanism of Wnt/beta-catenin pathway activation in CLL. AB - One major goal of cancer genome sequencing is to identify key genes and pathways that drive tumor pathogenesis. Although many studies have identified candidate driver genes based on recurrence of mutations in individual genes, subsets of genes with nonrecurrent mutations may also be defined as putative drivers if they affect a single biological pathway. In this fashion, we previously identified Wnt signaling as significantly mutated through large-scale massively parallel DNA sequencing of chronic lymphocytic leukemia (CLL). Here, we use a novel method of biomolecule delivery, vertical silicon nanowires, to efficiently introduce small interfering RNAs into CLL cells, and interrogate the effects of 8 of 15 mutated Wnt pathway members identified across 91 CLLs. In HEK293T cells, mutations in 2 genes did not generate functional changes, 3 led to dysregulated pathway activation, and 3 led to further activation or loss of repression of pathway activation. Silencing 4 of 8 mutated genes in CLL samples harboring the mutated alleles resulted in reduced viability compared with leukemia samples with wild type alleles. We demonstrate that somatic mutations in CLL can generate dependence on this pathway for survival. These findings support the notion that nonrecurrent mutations at different nodes of the Wnt pathway can contribute to leukemogenesis. PMID- 24778155 TI - Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. AB - Chronic myeloid leukemia (CML) is a stem cell (SC) neoplasm characterized by the BCR/ABL1 oncogene. Although mechanisms of BCR/ABL1-induced transformation are well-defined, little is known about effector-molecules contributing to malignant expansion and the extramedullary spread of leukemic SC (LSC) in CML. We have identified the cytokine-targeting surface enzyme dipeptidylpeptidase-IV (DPPIV/CD26) as a novel, specific and pathogenetically relevant biomarker of CD34(+)/CD38(?) CML LSC. In functional assays, CD26 was identified as target enzyme disrupting the SDF-1-CXCR4-axis by cleaving SDF-1, a chemotaxin recruiting CXCR4(+) SC. CD26 was not detected on normal SC or LSC in other hematopoietic malignancies. Correspondingly, CD26(+) LSC decreased to low or undetectable levels during successful treatment with imatinib. CD26(+) CML LSC engrafted NOD SCID-IL-2Rgamma(-/-) (NSG) mice with BCR/ABL1(+) cells, whereas CD26(?) SC from the same patients produced multilineage BCR/ABL1(-) engraftment. Finally, targeting of CD26 by gliptins suppressed the expansion of BCR/ABL1(+) cells. Together, CD26 is a new biomarker and target of CML LSC. CD26 expression may explain the abnormal extramedullary spread of CML LSC, and inhibition of CD26 may revert abnormal LSC function and support curative treatment approaches in this malignancy. PMID- 24778157 TI - Doctors need not give blood transfusion to mentally ill Jehovah's Witness, judge rules. PMID- 24778158 TI - Cutting Europe's meat and dairy consumption would benefit health and environment, says report. PMID- 24778156 TI - OKT3 prevents xenogeneic GVHD and allows reliable xenograft initiation from unfractionated human hematopoietic tissues. AB - Immunodeficient mice are now readily engrafted with human hematopoietic cells. However, these mice are susceptible to graft-versus-host disease (GVHD) induced by the engraftment and rapid expansion of coinjected human T cells. Therefore, highly purified sample populations must be used, adding significant time, expense, and effort. Here, we have explored in vivo and in vitro methods utilizing anti-T-cell antibodies to circumvent this problem. Intraperitoneal injection of the antibody within 48 hours prevented GVHD. Alternatively, short term in vitro incubation of cells with antibody immediately before transplant was equally effective. Although in vitro antithymocyte globulin treatment resulted in a dramatic loss of SCID-repopulating cells (SRCs), treatment with OKT3 or UCHT1 abrogated GVHD risk and preserved engraftment potential. Leukemia samples that presented with substantial human T-cell contamination were effectively rescued from GVHD. In addition, OKT3 treatment of unfractionated cord blood resulted in robust engraftment of primary and secondary mice that was indistinguishable from grafts obtained using purified CD34(+) cells. Limiting dilution analysis of unfractionated blood demonstrated a SRC frequency of 1 in 300 to 500 CD34(+) cells, similar to that of purified hematopoietic stem and progenitor cells. This protocol streamlines xenograft studies while significantly reducing the cost and time of the procedure. PMID- 24778159 TI - Eosinophils and cancer. AB - Eosinophils have long been known to infiltrate tumors, and in most cases, this is associated with an improved prognosis. However, the reasons behind this infiltration and the mechanism of action of the eosinophil have remained elusive. In this article, we explore the biology of eosinophils and examine their function in homeostasis and disease states, specifically focusing on what is currently known about the association of the eosinophil with cancer. PMID- 24778160 TI - Pathogen-driven cancers and emerging immune therapeutic strategies. AB - Infectious agents play an etiologic role in approximately 20% of cancer cases worldwide. Eleven pathogens (seven viruses, three parasites, and one bacterium) are known to contribute to oncogenesis either directly via the expression of their protein products or indirectly via chronic inflammation. Although prevention of infection and antimicrobial treatments have helped in reducing infection rates and the incidence of associated malignancies, therapies for these cancers remain limited. The importance of immune control over malignant progression is highlighted by the fact that many cancers, particularly those induced by pathogens, occur more frequently among immunosuppressed patients as compared with healthy individuals. Therefore, therapeutic strategies that can elicit a robust immune response and restore tumor detection may be a beneficial approach for treating these cancers. In addition, the study of immune escape mechanisms used by pathogens and their associated cancers may provide insight into the mechanisms of malignant transformation and improved therapies for cancer more generally. PMID- 24778161 TI - Anti-PD1 following ipilimumab for mucosal melanoma: durable tumor response associated with severe hypothyroidism and rhabdomyolysis. AB - Treatment with fully human monoclonal antibodies against programmed death 1 (PD1) receptor has shown great promise for a number of advanced malignancies. Although inflammatory adverse events have been well described with anti-CTL antigen 4 (CTLA4) therapy, experience with the range of adverse effects of anti-PD1 remains comparatively limited. Here, we report on a patient with advanced mucosal melanoma who received four doses of MK-3475, a fully human monoclonal antibody against PD1, and experienced a durable near-complete response but developed severe hypothyroidism, rhabdomyolysis, and acute kidney injury. To our knowledge, this is the first case reported of a patient with advanced mucosal melanoma who responded to anti-PD1 therapy. With the promising antitumor effects of anti-PD1 in a wide array of tumors, we expect an increasing number of patients to be exposed to anti-PD1 therapies. Recognition of infrequent presentations of adverse events such as elevated creatine kinase levels and thyroid disorders in patients who receive anti-PD1 therapy is important. PMID- 24778162 TI - Myeloid-derived suppressor cells in the development of lung cancer. AB - Myeloid-derived suppressor cells (MDSC) are widely implicated in immune suppression associated with tumor progression and chronic inflammation. However, very little is known about their possible role in tumor development. Here, we evaluated the role of MDSC in two experimental models of lung cancer: inflammation-associated lung cancer caused by chemical carcinogen urethane in combination with exposure to cigarette smoke; and a transgenic CC10Tg model not associated with inflammation. Exposure of mice to cigarette smoke alone resulted in significant accumulation in various organs of cells with typical MDSC phenotype (Gr-1(+)CD11b(+)). However, these cells lacked immunosuppressive activity and could not be defined as MDSC. When cigarette smoke was combined with a single dose of urethane, it led to the development of tumor lesions in lungs within 4 months. By that time, Gr-1(+)CD11b(+) cells accumulated in the spleen and lung and had potent immunosuppressive activity, and thus could be defined as MDSC. In the CC10Tg model, accumulation of immunosuppressive MDSC was observed only at 4 months of age, after the appearance of tumor lesions in the lungs. Accumulation of MDSC in both models was abrogated in S100A9 knockout mice. This resulted in a dramatic improvement in survival of mice in both models. Thus, cigarette smoke results in the expansion of immature myeloid cells lacking suppressive activity. Accumulation of bona fide MDSC in both models was observed only after the development of tumor lesions. However, MDSC played a major role in tumor progression and survival, which suggests that their targeting may provide clinical benefits in lung cancer. PMID- 24778163 TI - Locally delivered CD40 agonist antibody accumulates in secondary lymphoid organs and eradicates experimental disseminated bladder cancer. AB - Immunotherapy with intratumoral injection of adenoviral vectors expressing CD40L has yielded positive results in experimental and clinical bladder cancer. We therefore hypothesized that anti-CD40 antibody would be effective in this setting. Agonistic CD40 antibodies were developed as vaccine adjuvants but have later been used as treatment of advanced solid tumors and hematologic cancers. Systemic anti-CD40 therapy has been associated with immune-related adverse events, such as cytokine release syndrome and liver toxicity, and local delivery is an attractive approach that could reduce toxicity. Herein, we compared local and systemic anti-CD40 antibody delivery to evaluate efficacy, toxicity, and biodistribution in the experimental MB49 bladder cancer model. Antitumor effects were confirmed in the B16 model. In terms of antitumor efficacy, local anti-CD40 antibody stimulation was superior to systemic therapy at an equivalent dose and CD8 T cells were crucial for tumor growth inhibition. Both administration routes were dependent on host CD40 expression for therapeutic efficacy. In vivo biodistribution studies revealed CD40-specific antibody accumulation in the tumor draining lymph nodes and the spleen, most likely reflecting organs with frequent target antigen-expressing immune cells. Systemic administration led to higher antibody concentrations in the liver and blood compared with local delivery, and was associated with elevated levels of serum haptoglobin. Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates antitumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic. PMID- 24778164 TI - Enhanced permeability responses to inflammation in streptozotocin-induced diabetic rat venules: Rho-mediated alterations of actin cytoskeleton and VE cadherin. AB - Diabetes is a progressive disease that often leads to microvascular complications. This study investigates the impact of diabetes on microvessel permeability under basal and inflammatory conditions. Streptozotocin-induced diabetic rats were used to mimic type 1 diabetes. Parallel experiments were conducted in intact mesenteric venules in normal rats and diabetic rats experiencing hyperglycemia for 2-3 wk. Microvessel permeability was determined by measuring hydraulic conductivity (Lp). The correlated changes in endothelial intracellular Ca(2+) concentration ([Ca(2+)]i), adherens junctions, and cytoskeleton F-actin were examined with fluorescence imaging. Diabetic vessels showed moderately increased basal Lp, but upon platelet-activating factor (PAF) exposure, these vessels showed an ~10-fold higher Lp increase than the normal vessels. Concomitantly, we observed higher increases in endothelial [Ca(2+)]i, enhanced stress fiber formation, vascular endothelial-cadherin separation, and larger gap formation between endothelial cells than those occurring in normal vessels. PAF receptor staining showed no significant difference between normal and diabetic vessels. The application of Rho kinase inhibitor Y27632 did not affect PAF-induced increases in endothelial [Ca(2+)]i but significantly reduced PAF-induced Lp increases by 90% in diabetic vessels. The application of both Y27632 and nitric oxide (NO) synthase inhibitor attenuated PAF-induced Lp increases more than using one inhibitor alone. Our studies indicate that diabetic conditions prime endothelial cells into a phenotype with increased susceptibility to inflammation without altering receptor expression and that the increased Rho activation and NO production play important roles in exaggerated permeability increases when diabetic vessels were exposed to inflammatory mediators, which may account for the exacerbated vascular dysfunction when diabetic patients are exposed to additional inflammation. PMID- 24778165 TI - The vascular renin-angiotensin system contributes to blunted vasodilation induced by transient high pressure in human adipose microvessels. AB - Increased intraluminal pressure can reduce endothelial function in resistance arterioles; however, the mechanism of this impairment is unknown. The purpose of this study was to determine the effect of local renin-angiotensin system inhibition on the pressure-induced blunting of endothelium-dependent vasodilation in human adipose arterioles. Arterioles (100-200 MUm) were dissected from fresh adipose surgical specimens, cannulated onto glass micropipettes, pressurized to an intraluminal pressure of 60 mmHg, and constricted with endothelin-1. Vasodilation to ACh was assessed at 60 mmHg and again after a 30-min exposure to an intraluminal pressure of 150 mmHg. The vasodilator response to ACh was significantly reduced in vessels exposed to 150 mmHg. Exposure of the vessels to the superoxide scavenger polyethylene glycol-SOD (100 U/ml), the ANG II type 1 receptor antagonist losartan (10(-6) mol/l), or the angiotensin-converting enzyme inhibitor captopril (10(-5) mol/l) prevented the pressure-induced reduction in ACh-dependent vasodilation observed in untreated vessels. High intraluminal pressure had no effect on papaverine-induced vasodilation or ANG II sensitivity. Increased intraluminal pressure increased dihydroethidium fluorescence in cannulated vessels, which could be prevented by polyethylene glycol-SOD or losartan treatment and endothelial denudation. These data indicate that high intraluminal pressure can increase vascular superoxide and reduce nitric oxide mediated vasodilation via activation of the vascular renin-angiotensin system. This study provides evidence showing that the local renin-angiotensin system in the human microvasculature may be pressure sensitive and contribute to endothelial dysfunction after acute bouts of hypertension. PMID- 24778167 TI - The contribution of K(+) channels to human thoracic duct contractility. AB - In smooth muscle cells, K(+) permeability is high, and this highly influences the resting membrane potential. Lymph propulsion is dependent on phasic contractions generated by smooth muscle cells of lymphatic vessels, and it is likely that K(+) channels play a critical role in regulating contractility in this tissue. The aim of this study was to investigate the contribution of distinct K(+) channels to human lymphatic vessel contractility. Thoracic ducts were harvested from 43 patients and mounted in a wire myograph for isometric force measurements or membrane potential recordings with an intracellular microelectrode. Using K(+) channel blockers and activators, we demonstrate a functional contribution to human lymphatic vessel contractility from all the major classes of K(+) channels [ATP-sensitive K(+) (KATP), Ca(2+)-activated K(+), inward rectifier K(+), and voltage-dependent K(+) channels], and this was confirmed at the mRNA level. Contraction amplitude, frequency, and baseline tension were altered depending on which channel was blocked or activated. Microelectrode impalements of lymphatic vessels determined an average resting membrane potential of -43.1 +/- 3.7 mV. We observed that membrane potential changes of <5 mV could have large functional effects with contraction frequencies increasing threefold. In general, KATP channels appeared to be constitutively open since incubation with glibenclamide increased contraction frequency in spontaneously active vessels and depolarized and initiated contractions in previously quiescent vessels. The largest change in membrane voltage was observed with the KATP opener pinacidil, which caused 24 +/- 3 mV hyperpolarization. We conclude that K(+) channels are important modulators of human lymphatic contractility. PMID- 24778166 TI - Physiological and structural differences in spatially distinct subpopulations of cardiac mitochondria: influence of cardiac pathologies. AB - Cardiac tissue contains discrete pools of mitochondria that are characterized by their subcellular spatial arrangement. Subsarcolemmal mitochondria (SSM) exist below the cell membrane, interfibrillar mitochondria (IFM) reside in rows between the myofibrils, and perinuclear mitochondria are situated at the nuclear poles. Microstructural imaging of heart tissue coupled with the development of differential isolation techniques designed to sequentially separate spatially distinct mitochondrial subpopulations have revealed differences in morphological features including shape, absolute size, and internal cristae arrangement. These findings have been complemented by functional studies indicating differences in biochemical parameters and, potentially, functional roles for the ATP generated, based upon subcellular location. Consequently, mitochondrial subpopulations appear to be influenced differently during cardiac pathologies including ischemia/reperfusion, heart failure, aging, exercise, and diabetes mellitus. These influences may be the result of specific structural and functional disparities between mitochondrial subpopulations such that the stress elicited by a given cardiac insult differentially impacts subcellular locales and the mitochondria contained within. The goal of this review is to highlight some of the inherent structural and functional differences that exist between spatially distinct cardiac mitochondrial subpopulations as well as provide an overview of the differential impact of various cardiac pathologies on spatially distinct mitochondrial subpopulations. As an outcome, we will instill a basis for incorporating subcellular spatial location when evaluating the impact of cardiac pathologies on the mitochondrion. Incorporation of subcellular spatial location may offer the greatest potential for delineating the influence of cardiac pathology on this critical organelle. PMID- 24778169 TI - High-throughput measurement of gap junctional intercellular communication. AB - Gap junctional intercellular communication (GJIC) is a critical part of cellular activities and is necessary for electrical propagation among contacting cells. Disorders of gap junctions are a major cause for cardiac arrhythmias. Dye transfer through microinjection is a conventional technique for measuring GJIC. To overcome the limitations of manual microinjection and perform high-throughput GJIC measurement, here we present a new robotic microinjection system that is capable of injecting a large number of cells at a high speed. The highly automated system enables large-scale cell injection (thousands of cells vs. a few cells) without major operator training. GJIC of three cell lines of differing gap junction density, i.e., HeLa, HEK293, and HL-1, was evaluated. The effect of a GJIC inhibitor (18-alpha-glycyrrhetinic acid) was also quantified in the three cell lines. System operation speed, success rate, and cell viability rate were quantitatively evaluated based on robotic microinjection of over 4,000 cells. Injection speed was 22.7 cells per min, with 95% success for cell injection and >90% survival. Dye transfer cell counts and dye transfer distance correlated with the expected connexin expression of each cell type, and inhibition of dye transfer correlated with the concentration of GJIC inhibitor. Additionally, real time monitoring of dye transfer enables the calculation of coefficients of molecular diffusion through gap junctions. This robotic microinjection dye transfer technique permits rapid assessment of gap junction function in confluent cell cultures. PMID- 24778168 TI - Prevention of export of anoxia/reoxygenation injury from ischemic to nonischemic cardiomyocytes via inhibition of endocytosis. AB - Myocardial infarct size is determined by the death of nonischemic border zone cardiomyocytes caused by export of injury signals from the infarct zone. The countermeasures to limit infarct size, therefore, should be aimed at nonselective blockade of most, if not all, injury signals from entering nonischemic cells. To test whether inhibition of endocytosis might limit infarct size, HL-1 cardiomyocytes were subjected to anoxia (6 h) and reoxygenation (1 h). Anoxic and reoxygenated cells showed a multifold increase in mitochondrial ROS production accompanied with upregulation of scavenger receptors lectin-like oxidized low density lipoprotein receptor-1 and CD36 and stimulation of stress signals, including NADPH oxidase subunit p22(phox), SOD2, and beclin-1. Incubation of healthy cardiomyocytes in media from anoxic and reoxygenated cells (conditioned media) resulted in qualitatively similar responses, including increase in the generation of mitochondrial ROS, p22(phox), SOD2, and beclin-1. Anoxia and reoxygenation caused collapse of clathrin-mediated endocytosis and stimulation of macropinocytosis, whereas in cultures exposed to conditioned media, the activity of endocytosis was uniformly higher. Conditioned media also significantly aggravated cytotoxic effects of TNF-alpha and angiotensin II, and suppression of endocytosis reversed these trends, resulting in an overall increase of metabolic activity. Moreover, inhibition of endocytosis prevented binding of oxidized cellular fragments with greater efficiency than targeted neutralization of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1. Many of the observations in HL-1 cardiomyocytes were confirmed in primary cardiomyocyte cultures. Our data suggest that endocytosis is upregulated in border zone cardiomyocytes, and inhibition of endocytosis may be an effective approach to prevent export of injury signals from the infarct zone. PMID- 24778170 TI - Sensor spacing affects the tissue impedance spectra of rabbit ventricular epicardium. AB - This study was designed to test the hypothesis that a complex composite impedance spectra develops when stimulation and recording of cardiac muscle with sufficiently fine spatial resolution in a four-electrode configuration is used. With traditional (millimeter scale) separations, the ratio between the recorded interstitial central potential difference and total supplied interstitial current is constant at all frequencies. This occurs because the fraction of supplied current that redistributes to the intracellular compartment depends on effective membrane resistance between electrodes, which is low, to a much greater extent than effective membrane capacitance. The spectra should therefore change with finer separations at which effective membrane resistance increases, as supplied current will remain primarily interstitial at lower frequencies and redistribute between compartments at higher frequencies. To test this hypothesis, we built arrays with sensors separated (d) by 804 MUm, 452 MUm, and 252 MUm; positioned those arrays across myocyte axes on rabbit ventricular epicardium; and resolved spectra in terms of resistivity (rhot) and reactivity (chit) over the 10 Hz to 4,000 Hz range. With all separations, we measured comparable spectra with predictions from passive membrane simulations that used a three-dimensional structural framework in which intracellular, interstitial, and membrane properties were prescribed based on the limited data available from the literature. At the finest separation, we found mean rhot at 100 Hz and 4,000 Hz that lowered from 395 Omega-cm to 236 Omega-cm, respectively, with maximal mean chit of 160 Omega-cm. This experimental confirmation of spectra development in whole heart experiments is important because such development is central to achieve measurements of intracellular and interstitial passive electrical properties in cardiac electrophysiological experiments using only interstitial access. PMID- 24778171 TI - Manipulation of central blood volume and implications for respiratory control function. AB - The respiratory operating point (ventilatory or arterial PCO2 response) is determined by the intersection point between the controller and plant subsystem elements within the respiratory control system. However, to what extent changes in central blood volume (CBV) influence these two elements and the corresponding implications for the respiratory operating point remain unclear. To examine this, 17 apparently healthy male participants were exposed to water immersion (WI) or lower body negative pressure (LBNP) challenges to manipulate CBV and determine the corresponding changes. The respiratory controller was characterized by determining the linear relationship between end-tidal PCO2 (PetCO2 ) and minute ventilation (Ve) [Ve = S * (PetCO2 - B)], whereas the plant was determined by the hyperbolic relationship between Ve and PetCO2 (PetCO2 = A/Ve + C). Changes in Ve at the operating point were not observed under either WI or LBNP conditions despite altered PetCO2 (P < 0.01), indicating a moving respiratory operating point. An increase (WI) and a decrease (LBNP) in CBV were shown to reset the controller element (PetCO2 intercept B) rightward and leftward, respectively (P < 0.05), without any change in S, whereas the plant curve remained unaltered at the operating point. Collectively, these findings indicate that modification of the controller element rather than the plant element is the major factor that contributes toward an alteration of the respiratory operating point during CBV shifts. PMID- 24778172 TI - Age-related impairment of conducted dilation in human coronary arterioles. AB - Conducted vasodilation is essential to coordinate vascular resistance along distances to ensure adequate tissue perfusion. We hypothesized that conducted vasodilation of coronary resistance arteries declines with age. Coronary arterioles were dissected from right atrial appendage of patients (n = 27) undergoing cardiac surgery. Arterioles (~100 MUm) were cannulated and pressurized (80 mmHg), and developed spontaneous myogenic tone. Conducted vasodilation was initiated by locally administering the endothelium-dependent agonist bradykinin (BK; 100 MUM) ejected from a glass micropipette (~3 MUm tip opening, positioned in close proximity to the vessel wall). Diameter changes were measured at local and upstream sites (500 and 1,000 MUm from the stimulus) with videomicroscopy. Local administration of BK elicited vasodilation, the magnitude of which increased with the duration of stimulus (69 +/- 6, 81 +/- 6, 90 +/- 2%, after 1, 3, and 5 * 100 ms, respectively). BK-induced dilation remained substantial at upstream sites (500 MUm: 53 +/- 7%; 1,000 MUm: 46 +/- 9%). The gap junction uncoupler carbenoxolone or 18-alpha-glycyrrhetinic acid did not affect local responses, but diminished conducted vasodilation. Inhibitors of small/intermediate conductance calcium-activated potassium channels (SKCa/IKCa), apamin and TRAM34, reduced dilations both at local and remote sites. We found that conducted dilation, but not the local response, was significantly reduced in older (>=64 yr) patients. The nitric oxide (NO) synthesis inhibitor N(omega) nitro-l-arginine methyl ester did not affect local responses, but markedly reduced conducted dilation in younger (<64 yr) individuals. Collectively, we show that human coronary arterioles exhibit SKCa/IKCa-mediated hyperpolarization spread through gap junctions, which contributes to conducted vasodilation initiated by focal application of BK. We demonstrate that conducted dilation declines with age, likely due to reduced NO availability, which plays a permissive role in propagating longitudinal vasomotor signaling. PMID- 24778173 TI - An electrocardiographic sign of ischemic preconditioning. AB - Ischemic preconditioning is a form of intrinsic cardioprotection where an episode of sublethal ischemia protects against subsequent episodes of ischemia. Identifying a clinical biomarker of preconditioning could have important clinical implications, and prior work has focused on the electrocardiographic ST segment. However, the electrophysiology biomarker of preconditioning is increased action potential duration (APD) shortening with subsequent ischemic episodes, and APD shortening should primarily alter the T wave, not the ST segment. We translated findings from simulations to canine to patient models of preconditioning to test the hypothesis that the combination of increased [delta (Delta)] T wave amplitude with decreased ST segment elevation characterizes preconditioning. In simulations, decreased APD caused increased T wave amplitude with minimal ST segment elevation. In contrast, decreased action potential amplitude increased ST segment elevation significantly. In a canine model of preconditioning (9 mongrel dogs undergoing 4 ischemia-reperfusion episodes), ST segment amplitude increased more than T wave amplitude during the first ischemic episode [DeltaT/DeltaST slope = 0.81, 95% confidence interval (CI) 0.46-1.15]; however, during subsequent ischemic episodes the T wave increased significantly more than the ST segment (DeltaT/DeltaST slope = 2.43, CI 2.07-2.80) (P < 0.001 for interaction of occlusions 2 vs. 1). A similar result was observed in patients (9 patients undergoing 2 consecutive prolonged occlusions during elective percutaneous coronary intervention), with an increase in slope of DeltaT/DeltaST of 0.13 (CI 0.15 to 0.42) in the first occlusion to 1.02 (CI 0.31-1.73) in the second occlusion (P = 0.02). This integrated analysis of the T wave and ST segment goes beyond the standard approach to only analyze ST elevation, and detects cellular electrophysiology changes of preconditioning. PMID- 24778174 TI - Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart. AB - The mitochondrion has been implicated in the development of diabetic cardiomyopathy. Examination of cardiac mitochondria is complicated by the existence of spatially distinct subpopulations including subsarcolemmal (SSM) and interfibrillar (IFM). Dysfunction to cardiac SSM has been reported in murine models of type 2 diabetes mellitus; however, subpopulation-based mitochondrial analyses have not been explored in type 2 diabetic human heart. The goal of this study was to determine the impact of type 2 diabetes mellitus on cardiac mitochondrial function in the human patient. Mitochondrial subpopulations from atrial appendages of patients with and without type 2 diabetes were examined. Complex I- and fatty acid-mediated mitochondrial respiration rates were decreased in diabetic SSM compared with nondiabetic (P <= 0.05 for both), with no change in IFM. Electron transport chain (ETC) complexes I and IV activities were decreased in diabetic SSM compared with nondiabetic (P <= 0.05 for both), with a concomitant decline in their levels (P <= 0.05 for both). Regression analyses comparing comorbidities determined that diabetes mellitus was the primary factor accounting for mitochondrial dysfunction. Linear spline models examining correlative risk for mitochondrial dysfunction indicated that patients with diabetes display the same degree of state 3 and electron transport chain complex I dysfunction in SSM regardless of the extent of glycated hemoglobin (HbA1c) and hyperglycemia. Overall, the results suggest that independent of other pathologies, mitochondrial dysfunction is present in cardiac SSM of patients with type 2 diabetes and the degree of dysfunction is consistent regardless of the extent of elevated HbA1c or blood glucose levels. PMID- 24778175 TI - Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. AB - OBJECTIVE: To investigate whether discrepancies in trials of use of bone marrow stem cells in patients with heart disease account for the variation in reported effect size in improvement of left ventricular function. DESIGN: Identification and counting of factual discrepancies in trial reports, and sample size weighted regression against therapeutic effect size. Meta-analysis of trials that provided sufficient information. DATA SOURCES: PubMed and Embase from inception to April 2013. ELIGIBILITY FOR SELECTING STUDIES: Randomised controlled trials evaluating the effect of autologous bone marrow stem cells for heart disease on mean left ventricular ejection fraction. RESULTS: There were over 600 discrepancies in 133 reports from 49 trials. There was a significant association between the number of discrepancies and the reported increment in EF with bone marrow stem cell therapy (Spearman's r=0.4, P=0.005). Trials with no discrepancies were a small minority (five trials) and showed a mean EF effect size of -0.4%. The 24 trials with 1-10 discrepancies showed a mean effect size of 2.1%. The 12 with 11-20 discrepancies showed a mean effect of size 3.0%. The three with 21-30 discrepancies showed a mean effect size of 5.7%. The high discrepancy group, comprising five trials with over 30 discrepancies each, showed a mean effect size of 7.7%. CONCLUSIONS: Avoiding discrepancies is difficult but is important because discrepancy count is related to effect size. The mechanism is unknown but should be explored in the design of future trials because in the five trials without discrepancies the effect of bone marrow stem cell therapy on ejection fraction is zero. PMID- 24778176 TI - Increased expression of colonic Wnt9A through Sp1-mediated transcriptional effects involving arylsulfatase B, chondroitin 4-sulfate, and galectin-3. AB - In cultured human colonic epithelial cells and mouse colonic tissue, exposure to the common food additive carrageenan leads to inflammation, activation of Wnt signaling, increased Wnt9A expression, and decline in the activity of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase). In this study, the novel transcriptional mechanism by which carrageenan and decline in ARSB increase Wnt9A expression in NCM460 and HT-29 human colonic epithelial cells and in mouse colon is presented. Increased expression of Wnt9A has been associated with multiple malignancies, including colon carcinoma, and with ectodermal and mesoendodermal morphogenesis. When ARSB activity was reduced by siRNA or by exposure to carrageenan (1 MUg/ml for 24 h), degradation of chondroitin 4-sulfate (C4S) was inhibited, leading to accumulation of more highly sulfated C4S, which binds less galectin-3, a beta-galactoside-binding protein. Nuclear galectin-3 increased and mediated increased binding of Sp1 to the Sp1 consensus sequence in the Wnt9A promoter, shown by oligonucleotide-binding assay and by chromatin immunoprecipitation assay. When galectin-3 was silenced, the increases in Sp1 binding to the Wnt9A promoter and in Wnt9A expression, which followed carrageenan or ARSB silencing, were inhibited. Mithramycin A, a specific inhibitor of Sp1 oligonucleotide binding, and Sp1 siRNA blocked the carrageenan- and ARSB siRNA induced increases in Wnt9A expression. These studies reveal how carrageenan exposure can lead to transcriptional events in colonic epithelial cells through decline in arylsulfatase B activity, with subsequent impact on C4S, galectin-3, Sp1, and Wnt9A and can exert significant effects on Wnt-initiated signaling and related vital cell processes. PMID- 24778177 TI - Structural determinants of phosphatidylinositol 4,5-bisphosphate (PIP2) regulation of BK channel activity through the RCK1 Ca2+ coordination site. AB - Big or high conductance potassium (BK) channels are activated by voltage and intracellular calcium (Ca(2+)). Phosphatidylinositol 4,5-bisphosphate (PIP2), a ubiquitous modulator of ion channel activity, has been reported to enhance Ca(2+) driven gating of BK channels, but a molecular understanding of this interplay or even of the PIP2 regulation of this channel's activity remains elusive. Here, we identify structural determinants in the KDRDD loop (which follows the alphaA helix in the RCK1 domain) to be responsible for the coupling between Ca(2+) and PIP2 in regulating BK channel activity. In the absence of Ca(2+), RCK1 structural elements limit channel activation through a decrease in the channel's PIP2 apparent affinity. This inhibitory influence of BK channel activation can be relieved by mutation of residues that (a) connect either the RCK1 Ca(2+) coordination site (Asp(367) or its flanking basic residues in the KDRDD loop) to the PIP2-interacting residues (Lys(392) and Arg(393)) found in the alphaB helix or (b) are involved in hydrophobic interactions between the alphaA and alphaB helix of the RCK1 domain. In the presence of Ca(2+), the RCK1-inhibitory influence of channel-PIP2 interactions and channel activity is relieved by Ca(2+) engaging Asp(367). Our results demonstrate that, along with Ca(2+) and voltage, PIP2 is a third factor critical to the integral control of BK channel activity. PMID- 24778178 TI - Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation. AB - N(6)-Methyladenosine (m(6)A) is the most prevalent internal RNA modification in eukaryotes. ALKBH5 belongs to the AlkB family of dioxygenases and has been shown to specifically demethylate m(6)A in single-stranded RNA. Here we report crystal structures of ALKBH5 in the presence of either its cofactors or the ALKBH5 inhibitor citrate. Catalytic assays demonstrate that the ALKBH5 catalytic domain can demethylate both single-stranded RNA and single-stranded DNA. We identify the TCA cycle intermediate citrate as a modest inhibitor of ALKHB5 (IC50, ~488 MUm). The structural analysis reveals that a loop region of ALKBH5 is immobilized by a disulfide bond that apparently excludes the binding of dsDNA to ALKBH5. We identify the m(6)A binding pocket of ALKBH5 and the key residues involved in m(6)A recognition using mutagenesis and ITC binding experiments. PMID- 24778179 TI - HERC2 targets the iron regulator FBXL5 for degradation and modulates iron metabolism. AB - FBXL5 (F-box and leucine-rich repeat protein 5) is the F-box protein subunit of, and therefore responsible for substrate recognition by, the SCF(FBXL5) ubiquitin ligase complex, which targets iron regulatory protein 2 (IRP2) for proteasomal degradation. IRP2 plays a central role in the maintenance of cellular iron homeostasis in mammals through posttranscriptional regulation of proteins that contribute to control of the intracellular iron concentration. The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo, given that mice lacking FBXL5 die during early embryogenesis as a result of unrestrained IRP2 activity and oxidative stress attributable to excessive iron accumulation. Despite its pivotal role in the control of iron homeostasis, however, little is known of the upstream regulation of FBXL5 activity. We now show that FBXL5 undergoes constitutive ubiquitin-dependent degradation at the steady state. With the use of a proteomics approach to the discovery of proteins that regulate the stability of FBXL5, we identified the large HECT-type ubiquitin ligase HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2) as an FBXL5-associated protein. Inhibition of the HERC2-FBXL5 interaction or depletion of endogenous HERC2 by RNA interference resulted in the stabilization of FBXL5 and a consequent increase in its abundance. Such accumulation of FBXL5 in turn led to a decrease in the intracellular content of ferrous iron. Our results thus suggest that HERC2 regulates the basal turnover of FBXL5, and that this ubiquitin-dependent degradation pathway contributes to the control of mammalian iron metabolism. PMID- 24778180 TI - Haptoglobin genotype-dependent differences in macrophage lysosomal oxidative injury. AB - The major function of the Haptoglobin (Hp) protein is to control trafficking of extracorpuscular hemoglobin (Hb) thru the macrophage CD163 receptor with degradation of the Hb in the lysosome. There is a common copy number polymorphism in the Hp gene (Hp 2 allele) that has been associated with a severalfold increased incidence of atherothrombosis in multiple longitudinal studies. Increased plaque oxidation and apoptotic markers have been observed in Hp 2-2 atherosclerotic plaques, but the mechanism responsible for this finding has not been determined. We proposed that the increased oxidative injury in Hp 2-2 plaques is due to an impaired processing of Hp 2-2-Hb complexes within macrophage lysosomes, thereby resulting in redox active iron accumulation, lysosomal membrane oxidative injury, and macrophage apoptosis. We sought to test this hypothesis in vitro using purified Hp-Hb complex and cells genetically manipulated to express CD163. CD163-mediated endocytosis and lysosomal degradation of Hp-Hb were decreased for Hp 2-2-Hb complexes. Confocal microscopy using lysotropic pH indicator dyes demonstrated that uptake of Hp 2-2-Hb complexes disrupted the lysosomal pH gradient. Cellular fractionation studies of lysosomes isolated from macrophages incubated with Hp 2-2-Hb complexes demonstrated increased lysosomal membrane oxidation and a loss of lysosomal membrane integrity leading to lysosomal enzyme leakage into the cytoplasm. Additionally, markers of apoptosis, DNA fragmentation, and active caspase 3 were increased in macrophages that had endocytosed Hp 2-2-Hb complexes. These data provide novel mechanistic insights into how the Hp genotype regulates lysosomal oxidative stress within macrophages after receptor-mediated endocytosis of Hb. PMID- 24778181 TI - Cyclin-dependent kinase 8 module expression profiling reveals requirement of mediator subunits 12 and 13 for transcription of Serpent-dependent innate immunity genes in Drosophila. AB - The Cdk8 (cyclin-dependent kinase 8) module of Mediator integrates regulatory cues from transcription factors to RNA polymerase II. It consists of four subunits where Med12 and Med13 link Cdk8 and cyclin C (CycC) to core Mediator. Here we have investigated the contributions of the Cdk8 module subunits to transcriptional regulation using RNA interference in Drosophila cells. Genome wide expression profiling demonstrated separation of Cdk8-CycC and Med12-Med13 profiles. However, transcriptional regulation by Cdk8-CycC was dependent on Med12 Med13. This observation also revealed that Cdk8-CycC and Med12-Med13 often have opposite transcriptional effects. Interestingly, Med12 and Med13 profiles overlapped significantly with that of the GATA factor Serpent. Accordingly, mutational analyses indicated that GATA sites are required for Med12-Med13 regulation of Serpent-dependent genes. Med12 and Med13 were also found to be required for Serpent-activated innate immunity genes in defense to bacterial infection. The results reveal a novel role for the Cdk8 module in Serpent dependent transcription and innate immunity. PMID- 24778182 TI - alpha-SNAP interferes with the zippering of the SNARE protein membrane fusion machinery. AB - Neuronal exocytosis is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Before fusion, SNARE proteins form complexes bridging the membrane followed by assembly toward the C-terminal membrane anchors, thus initiating membrane fusion. After fusion, the SNARE complex is disassembled by the AAA-ATPase N-ethylmaleimide-sensitive factor that requires the cofactor alpha-SNAP to first bind to the assembled SNARE complex. Using chromaffin granules and liposomes we now show that alpha-SNAP on its own interferes with the zippering of membrane-anchored SNARE complexes midway through the zippering reaction, arresting SNAREs in a partially assembled trans-complex and preventing fusion. Intriguingly, the interference does not result in an inhibitory effect on synaptic vesicles, suggesting that membrane properties also influence the final outcome of alpha-SNAP interference with SNARE zippering. We suggest that binding of alpha-SNAP to the SNARE complex affects the ability of the SNARE complex to harness energy or transmit force to the membrane. PMID- 24778183 TI - Gossypol increases expression of the pro-apoptotic BH3-only protein NOXA through a novel mechanism involving phospholipase A2, cytoplasmic calcium, and endoplasmic reticulum stress. AB - Gossypol is a putative BH3 mimetic proposed to inhibit BCL2 and BCLXL based on cell-free assays. We demonstrated previously that gossypol failed to directly inhibit BCL2 in cells or induce apoptosis in chronic lymphocytic leukemia (CLL) cells or platelets, which require BCL2 or BCLXL, respectively, for survival. Here, we demonstrate that gossypol rapidly increased activity of phospholipase A2 (PLA2), which led to an increase in cytoplasmic calcium, endoplasmic reticulum (ER) stress, and up-regulation of the BH3-only protein NOXA. Pretreatment with the PLA2 inhibitor, aristolochic acid, abrogated the increase in calcium, ER stress, and NOXA. Calcium chelation also abrogated the gossypol-induced increase in calcium, ER stress, and NOXA, but not the increase in PLA2 activity, indicating that PLA2 is upstream of these events. In addition, incubating cells with the two products of PLA2 (lysophosphatidic acid and arachidonic acid) mimicked treatment with gossypol. NOXA is a pro-apoptotic protein that functions by binding the BCL2 family proteins MCL1 and BFL1. The BCL2 inhibitor ABT-199 is currently in clinical trials for CLL. Resistance to ABT-199 can occur from up regulation of other BCL2 family proteins, and this resistance can be mimicked by culturing CLL cells on CD154(+) stroma cells. We report here that AT-101, a derivative of gossypol in clinical trials, overcomes stroma-mediated resistance to ABT-199 in primary CLL cells, suggesting that a combination of these drugs may be efficacious in the clinic. PMID- 24778184 TI - Growth differentiation factor 9 (GDF9) forms an incoherent feed-forward loop modulating follicle-stimulating hormone beta-subunit (FSHbeta) gene expression. AB - Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses from the hypothalamus and regulates follicle-stimulating hormone beta-subunit (FSHbeta) gene expression in pituitary gonadotropes in a frequency-sensitive manner. The mechanisms underlying its preferential and paradoxical induction of FSHbeta by low frequency GnRH pulses are incompletely understood. Here, we identify growth differentiation factor 9 (GDF9) as a GnRH-suppressed autocrine inducer of FSHbeta gene expression. GDF9 gene transcription and expression were preferentially decreased by high frequency GnRH pulses. GnRH regulation of GDF9 was concentration-dependent and involved ERK and PKA. GDF9 knockdown or immunoneutralization reduced FSHbeta mRNA expression. Conversely, exogenous GDF9 induced FSHbeta expression in immortalized gonadotropes and in mouse primary pituitary cells. GDF9 exposure increased FSH secretion in rat primary pituitary cells. GDF9 induced Smad2/3 phosphorylation, which was impeded by ALK5 knockdown and by activin receptor-like kinase (ALK) receptor inhibitor SB-505124, which also suppressed FSHbeta expression. Smad2/3 knockdown indicated that FSHbeta induction by GDF9 involved Smad2 and Smad3. FSHbeta mRNA induction by GDF9 and GnRH was synergistic. We hypothesized that GDF9 contributes to a regulatory loop that tunes the GnRH frequency-response characteristics of the FSHbeta gene. To test this, we determined the effects of GDF9 knockdown on FSHbeta induction at different GnRH pulse frequencies using a parallel perifusion system. Reduction of GDF9 shifted the characteristic pattern of GnRH pulse frequency sensitivity. These results identify GDF9 as contributing to an incoherent feed-forward loop, comprising both intracellular and secreted components, that regulates FSHbeta expression in response to activation of cell surface GnRH receptors. PMID- 24778185 TI - Tyrosine phosphorylation of Dbl regulates GTPase signaling. AB - Rho GTPases are molecular "switches" that cycle between "on" (GTP-bound) and "off" (GDP-bound) states and regulate numerous cellular activities such as gene expression, protein synthesis, cytoskeletal rearrangements, and metabolic responses. Dysregulation of GTPases is a key feature of many diseases, especially cancers. Guanine nucleotide exchange factors (GEFs) of the Dbl family are activated by mitogenic cell surface receptors and activate the Rho family GTPases Cdc42, Rac1, and RhoA. The molecular mechanisms that regulate GEFs from the Dbl family are poorly understood. Our studies reveal that Dbl is phosphorylated on tyrosine residues upon stimulation by growth factors and that this event is critical for the regulated activation of the GEF. These findings uncover a novel layer of complexity in the physiological regulation of this protein. PMID- 24778186 TI - Identification of yeast and human 5-aminoimidazole-4-carboxamide-1-beta-d ribofuranoside (AICAr) transporters. AB - 5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAr) is the precursor of the active monophosphate form (AICAR), a small molecule with potent anti proliferative and low energy mimetic properties. The molecular bases for AICAR toxicity at the cellular level are poorly understood. Here, we report the isolation and characterization of several yeast AICAr-hypersensitive mutants. Identification of the cognate genes allowed us to establish that thiamine transporters Thi7 and Thi72 can efficiently take up AICAr under conditions where they are overexpressed. We establish that, under standard growth conditions, Nrt1, the nicotinamide riboside carrier, is the major AICAr transporter in yeast. A study of AICAR accumulation in human cells revealed substantial disparities among cell lines and confirmed that AICAr enters cells via purine nucleoside transporters. Together, our results point to significant differences between yeast and human cells for both AICAr uptake and AICAR accumulation. PMID- 24778187 TI - Insulin-regulated Glut4 translocation: membrane protein trafficking with six distinctive steps. AB - The trafficking kinetics of Glut4, the transferrin (Tf) receptor, and LRP1 were quantified in adipocytes and undifferentiated fibroblasts. Six steps were identified that determine steady state cell surface Glut4: (i) endocytosis, (ii) degradation, (iii) sorting, (iv) sequestration, (v) release, and (vi) tethering/docking/fusion. Endocytosis of Glut4 is 3 times slower than the Tf receptor in fibroblasts (ken = 0.2 min(-1) versus 0.6 min(-1)). Differentiation decreases Glut4 ken 40% (ken = 0.12 min(-1)). Differentiation also decreases Glut4 degradation, increasing total and cell surface Glut4 3-fold. In fibroblasts, Glut4 is recycled from endosomes through a slow constitutive pathway (kex = 0.025-0.038 min(-1)), not through the fast Tf receptor pathway (kex = 0.2 min(-1)). The kex measured in adipocytes after insulin stimulation is similar (kex = 0.027 min(-1)). Differentiation decreases the rate constant for sorting into the Glut4 recycling pathway (ksort) 3-fold. In adipocytes, Glut4 is also sorted from endosomes into a second exocytic pathway through Glut4 storage vesicles (GSVs). Surprisingly, transfer from endosomes into GSVs is highly regulated; insulin increases the rate constant for sequestration (kseq) 8-fold. Release from sequestration in GSVs is rate-limiting for Glut4 exocytosis in basal adipocytes. AS160 regulates this step. Tethering/docking/fusion of GSVs to the plasma membrane is regulated through an AS160-independent process. Insulin increases the rate of release and fusion of GSVs (kfuseG) 40-fold. LRP1 cycles with the Tf receptor and Glut4 in fibroblasts but predominantly with Glut4 after differentiation. Surprisingly, AS160 knockdown accelerated LRP1 exocytosis in basal and insulin-stimulated adipocytes. These data indicate that AS160 may regulate trafficking into as well as release from GSVs. PMID- 24778188 TI - Control of adipose tissue expandability in response to high fat diet by the insulin-like growth factor-binding protein-4. AB - Adipose tissue expansion requires growth and proliferation of adipocytes and the concomitant expansion of their stromovascular network. We have used an ex vivo angiogenesis assay to study the mechanisms involved in adipose tissue expansion. In this assay, adipose tissue fragments placed under pro-angiogenic conditions form sprouts composed of endothelial, perivascular, and other proliferative cells. We find that sprouting was directly stimulated by insulin and was enhanced by prior treatment of mice with the insulin sensitizer rosiglitazone. Moreover, basal and insulin-stimulated sprouting increased progressively over 30 weeks of high fat diet feeding, correlating with tissue expansion during this period. cDNA microarrays analyzed to identify genes correlating with insulin-stimulated sprouting surprisingly revealed only four positively correlating (Fads3, Tmsb10, Depdc6, and Rasl12) and four negatively correlating (Asph, IGFbp4, Ppm1b, and Adcyap1r1) genes. Among the proteins encoded by these genes, IGFbp4, which suppresses IGF-1 signaling, has been previously implicated in angiogenesis, suggesting a role for IGF-1 in adipose tissue expandability. Indeed, IGF-1 potently stimulated sprouting, and the presence of activated IGF-1 receptors in the vasculature was revealed by immunostaining. Recombinant IGFbp4 blocked the effects of insulin and IGF-1 on mouse adipose tissue sprouting and also suppressed sprouting from human subcutaneous adipose tissue. These results reveal an important role of IGF-1/IGFbp4 signaling in post-developmental adipose tissue expansion. PMID- 24778189 TI - Assembly of the respiratory mucin MUC5B: a new model for a gel-forming mucin. AB - Mucins are essential components in mucus gels that form protective barriers at all epithelial surfaces, but much remains unknown about their assembly, intragranular organization, and post-secretion unfurling to form mucus. MUC5B is a major polymeric mucin expressed by respiratory epithelia, and we investigated the molecular mechanisms involved during its assembly. Studies of intact polymeric MUC5B revealed a single high affinity calcium-binding site, distinct from multiple low affinity sites on each MUC5B monomer. Self-diffusion studies with intact MUC5B showed that calcium binding at the protein site catalyzed reversible cross-links between MUC5B chains to form networks. The site of cross linking was identified in the MUC5B D3-domain as it was specifically blocked by D3 peptide antibodies. Biophysical analysis and single particle EM of recombinant MUC5B N terminus (D1D2D'D3; NT5B) and subdomains (D1, D1-D2, D2-D'-D3, and D3) generated structural models of monomers and disulfide-linked dimers and suggested that MUC5B multimerizes by disulfide linkage between D3-domains to form linear polymer chains. Moreover, these analyses revealed reversible homotypic interactions of NT5B at low pH and in high calcium, between disulfide-linked NT5B dimers, but not monomers. These results enable a model of MUC5B to be derived, which predicts mechanisms of mucin intracellular assembly and storage, which may be common to the other major gel-forming polymeric mucins. PMID- 24778191 TI - Clinical examination is essential to reduce overdiagnosis and overtreatment. PMID- 24778190 TI - The alpha-helical region in p24gamma2 subunit of p24 protein cargo receptor is pivotal for the recognition and transport of glycosylphosphatidylinositol anchored proteins. AB - Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are group of proteins that depend on p24 cargo receptors for their transport from the endoplasmic reticulum to the Golgi apparatus. The GPI anchor is expected to act as a sorting and transport signal, but so far little is known about the recognition mechanism. In the present study we investigate the GPI-AP transport in cell knockdown of p24gamma, the most diverse p24 subfamily. Knockdown of p24gamma2 but not of other p24gamma family members impaired the transport of a reporter GPI-AP. Restoration of the knockdown-induced phenotype using chimeric constructs between p24gamma2 and the related p24gamma1 further implied a role of the alpha-helical region of p24gamma2 but not its GOLD domain in the specific binding of GPI-APs. We conclude that motifs in the membrane-adjacent alpha-helical region of p24gamma2 are involved in recognition of GPI-APs and are consequently responsible for the incorporation of these proteins into coat protein complex II-coated transport vesicles. PMID- 24778192 TI - Histoplasma capsulatum: more widespread than previously thought. PMID- 24778193 TI - Association between moderate-to-severe diarrhea in young children in the global enteric multicenter study (GEMS) and types of handwashing materials used by caretakers in Mirzapur, Bangladesh. AB - Handwashing practices among caretakers of case and control children < 5 years of age enrolled in the Global Enteric Multicenter Study in Mirzapur, Bangladesh were characterized and analyzed for association with moderate-to-severe diarrhea. Soap or detergent ownership was common, yet 48% of case and 47.7% of control caretakers also kept ashes for handwashing, including 36.8% of the wealthiest households. Soap, detergent, and ash were used for multiple hygiene purposes and were kept together at handwashing areas. Caretakers preferred soap for handwashing, but frequently relied on ash, or a detergent/ash mixture, as a low cost alternative. Moderate-to-severe diarrhea was equally likely for children of caretakers who kept soap versus those who kept ash (matched OR = 0.91; 0.62 1.32). Contact with ash and water reduced concentrations of bacterial enteropathogens, without mechanical scrubbing. Thus, washing hands with ash is a prevalent behavior in Mirzapur and may help diminish transmission of diarrheal pathogens to children. PMID- 24778194 TI - Rickettsia felis in Ctenocephalides felis felis from five geographic regions of Brazil. AB - This study evaluated rickettsial infection in 701 Ctenocephalides felis felis fleas that were collected from dogs and cats in 31 municipalities, encompassing all regions and major biomes of Brazil. A total of 268 (38.2%) fleas from 30 municipalities were polymerase chain reaction (PCR) positive for the rickettsial gltA gene. The PCR products from 44 fleas, consisting of at least 1 PCR-positive flea from each of 30 municipalities, generated DNA sequences identical to Rickettsia felis. Rickettsial prevalence was highly variable among 30 municipalities, with values ranging from 2.9% to 100%. Significantly higher infection rates by R. felis were associated with the Pampa biome (southern Brazil), and the temperate climate that prevails in southern Brazil. In contrast, lowest R. felis-infection rates were significantly associated with the Caatinga biome, and its semiarid climate. Further studies should evaluate the effect of temperature and moisture on the R. felis infection in Ctenocephalides fleas world widely. PMID- 24778195 TI - A highly conserved region between amino acids 221 and 266 of dengue virus non structural protein 1 is a major epitope region in infected patients. AB - The immune response to dengue virus (DENV) infection generates high levels of antibodies (Abs) against the DENV non-structural protein 1 (NS1), particularly in cases of secondary infection. Therefore, anti-NS1 Abs may play a role in severe dengue infections, possibly by interacting (directly or indirectly) with host factors or regulating virus production. If it does play a role, NS1 may contain epitopes that mimic those epitopes of host molecules. Previous attempts to map immunogenic regions within DENV-NS1 were undertaken using mouse monoclonal Abs (MAbs). The aim of this study was to characterize the epitope regions of nine anti-NS1 human monoclonal Abs (HuMAbs) derived from six patients secondarily infected with DENV-2. These anti-NS1 HuMAbs were cross-reactive with DENV-1, -2, and -3 but not DENV-4. All HuMAbs bound a common epitope region located between amino acids 221 and 266 of NS1. This study is the first report to map a DENV-NS1 epitope region using anti-DENV MAbs derived from patients. PMID- 24778196 TI - Effect of aerial insecticide spraying on West Nile virus disease--north-central Texas, 2012. AB - During 2012, four north-central Texas counties experienced high West Nile virus (WNV) disease incidence. Aerial insecticide spraying was conducted in two counties. To evaluate the effect of spraying on WNV disease, we calculated incidence rate ratios (IRRs) in treated and untreated areas by comparing incidence before and after spraying; for unsprayed areas, before and after periods were defined by using dates from a corresponding sprayed area. In treated areas, WNV neuroinvasive disease incidence before and after spraying was 7.31/100,000 persons and 0.28/100,000 persons, respectively; the IRR was 26.42 (95% confidence interval [CI]: 12.42-56.20). In untreated areas, the before and after incidence was 4.80/100,000 persons and 0.45/100,000 persons, respectively; the IRR was 10.57 (95% CI: 6.11-18.28). The ratio of IRRs was 2.50 (95% CI: 0.98 6.35). Disease incidence decreased in both areas, but the relative change was greater in aerial-sprayed areas. PMID- 24778197 TI - Performance of the CareStart glucose-6-phosphate dehydrogenase (G6PD) rapid diagnostic test in Gressier, Haiti. AB - Administering primaquine (PQ) to treat malaria patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency can pose a serious risk of drug-induced hemolysis (DIH). New easy to use point-of-care rapid diagnostic tests are being developed as an alternative to labor-intensive spectrophotometric methods, but they require field testing before they can be used at scale. This study screened 456 participants in Gressier, Haiti using the Access Bio CareStart qualitative G6PD rapid detection test compared with the laboratory-based Trinity Biotech quantitative spectrophotometric assay. Findings suggest that the CareStart test was 90% sensitive for detecting individuals with severe deficiency and 84.8% sensitive for detecting individuals with moderate and severe deficiency compared with the Trinity Biotech assay. A high negative predictive value of 98.2% indicates excellent performance in determining those patients able to take PQ safely. The CareStart G6PD test holds much value for screening malaria patients to determine eligibility for PQ therapy. PMID- 24778198 TI - Incidence of and risk factors for hospital-acquired diarrhea in three tertiary care public hospitals in Bangladesh. AB - During April 2007-April 2010, surveillance physicians in adult and pediatric medicine wards of three tertiary public hospitals in Bangladesh identified patients who developed hospital-acquired diarrhea. We calculated incidence of hospital-acquired diarrhea. To identify risk factors, we compared these patients to randomly selected patients from the same wards who were admitted > 72 hours without having diarrhea. The incidence of hospital-acquired diarrhea was 4.8 cases per 1,000 patient-days. Children < 1 year of age were more likely to develop hospital-acquired diarrhea than older children. The risk of developing hospital-acquired diarrhea increased for each additional day of hospitalization beyond 72 hours, whereas exposure to antibiotics within 72 hours of admission decreased the risk. There were three deaths among case-patients; all were infants. Patients, particularly young children, are at risk for hospital-acquired diarrhea and associated deaths in Bangladeshi hospitals. Further research to identify the responsible organisms and transmission routes could inform prevention strategies. PMID- 24778200 TI - US vaccine program will prevent 732 000 deaths, CDC says. PMID- 24778199 TI - Whole genome analysis of sierra nevada virus, a novel mononegavirus in the family nyamiviridae. AB - A novel mononegavirus was isolated in 1975 from ticks (Ornithodoros coriaceus) collected during investigation of an outbreak of epizootic bovine abortion (EBA) in northern California. It was originally designated "bovine abortion-tick virus" (BA-T virus). The EBA is now known to be associated with a deltaproteobacterium infection, and not a virus. The BA-T virus had remained uncharacterized until now. We have determined by electron microscopy, serology, and genome sequencing that the BA-T virus is a fourth member of the newly proposed family Nyamiviridae, and we have renamed it Sierra Nevada virus (SNVV). Although antigenically distinct, phylogenetically SNVV is basal to Nyamanini virus (NYMV) and Midway virus (MIDWV), two other tick-borne agents. Although NYMV was found to infect land birds, and MIDWV seabirds, it is presently unknown whether SNVV naturally infects birds or mammals. PMID- 24778201 TI - CLARA: an integrated clinical research administration system. AB - Administration of human subject research is complex, involving not only the institutional review board but also many other regulatory and compliance entities within a research enterprise. Its efficiency has a direct and substantial impact on the conduct and management of clinical research. In this paper, we report on the Clinical Research Administration (CLARA) platform developed at the University of Arkansas for Medical Sciences. CLARA is a comprehensive web-based system that can streamline research administrative tasks such as submissions, reviews, and approval processes for both investigators and different review committees on a single integrated platform. CLARA not only helps investigators to meet regulatory requirements but also provides tools for managing other clinical research activities including budgeting, contracting, and participant schedule planning. PMID- 24778202 TI - The Greater Plains Collaborative: a PCORnet Clinical Research Data Network. AB - The Greater Plains Collaborative (GPC) is composed of 10 leading medical centers repurposing the research programs and informatics infrastructures developed through Clinical and Translational Science Award initiatives. Partners are the University of Kansas Medical Center, Children's Mercy Hospital, University of Iowa Healthcare, the University of Wisconsin-Madison, the Medical College of Wisconsin and Marshfield Clinic, the University of Minnesota Academic Health Center, the University of Nebraska Medical Center, the University of Texas Health Sciences Center at San Antonio, and the University of Texas Southwestern Medical Center. The GPC network brings together a diverse population of 10 million people across 1300 miles covering seven states with a combined area of 679 159 square miles. Using input from community members, breast cancer was selected as a focus for cohort building activities. In addition to a high-prevalence disorder, we also selected a rare disease, amyotrophic lateral sclerosis. PMID- 24778203 TI - Genetic structure within the Mesoamerican gene pool of wild Phaseolus lunatus (Fabaceae) from Mexico as revealed by microsatellite markers: Implications for conservation and the domestication of the species. AB - * PREMISE OF THE STUDY: Understanding genetic structure in wild relatives of a crop is important for crop improvement and conservation. Recently, two gene pools (MI and MII) were reported in wild Lima bean (Phaseolus lunatus) from Mexico, a domestication center of Mesoamerican landraces. However, the evidence was based on limited genomic sampling. Here we sought to confirm the existence of these two gene pools by increased genome and population sampling.* METHODS: We characterized 67 wild populations of P. lunatus from Mexico with 10 microsatellite loci and studied the genetic structure by means of AMOVA, cluster analyses, assignment tests, and a georeferenced map.* KEY RESULTS: AMOVA indicated that most of the variation is found among populations (77%) rather than within populations (23%). Assignment tests were key to confirm not only the presence of the two gene pools (MI and MII) in Mexico, but also to propose the possible existence of two subgroups within MI (MIa and MIb). While MI and MII are mainly divergent geographically, MIa and MIb overlap in their distribution. Admixed individuals, which may represent cases of gene flow among gene pools, were detected.* CONCLUSIONS: Our results show that the genetic structure of wild Lima bean in Mexico is more complex than previously thought and propose the presence of three gene pools (MIa, MIb, and MII), each one possessing relatively high levels of genetic diversity. We still need additional evidence, however, to confirm without doubt the split of the gene pool MI into subgroups MIa and MIb. PMID- 24778204 TI - Doctor is not to blame for baby left brain damaged 32 years ago, court finds. PMID- 24778205 TI - Diarrhoea caused by rotavirus in a regional Peruvian hospital: determination of circulating genotypes. AB - BACKGROUND: Gastroenteritis caused by rotavirus is responsible for approximately 810 deaths per year in children under 5 years of age in Peru and emerging rotavirus genotypes have led to concerns regarding cross-protection by the vaccines available. Moreover, there are no reports on the molecular epidemiology of rotavirus diarrhoea in Peru. METHODS: A total of 131 stool samples were obtained from children under 5 years hospitalised from January 2010 to December 2012 in the Hospital Regional de Cajamarca (Peru). ELISA and RT-PCR techniques were performed for rotavirus detection. G and P typing of rotavirus-positive samples were performed by semi-nested multiplex RT-PCR, and sequencing was performed to confirm the PCR results. RESULTS: Of the 117 samples available, 22 (18.8%) tested positive for rotavirus by ELISA and 42 (35.9%) tested positive by RT-PCR. Among the G genotypes identified, G9 (35.7%; 15/42) and G12 (33.3%; 14/42) were the most prevalent, with the most common combination being G12/P[6] (23.8%; 10/42). CONCLUSIONS: A high prevalence of the G12/P[6] genotype was detected. It is known that this genotype is not covered by the current vaccines available. More in-depth studies are needed to determine the current rotavirus genotypes presents in Peru. PMID- 24778206 TI - Measles surveillance in Nigeria: enough information for policy making? AB - Data collected through routine surveillance of measles cases will ideally be used to make policy decisions for vaccination programs. Nigeria has recently implemented a passive surveillance system for measles. Results indicate increasing measles cases in Southwest Nigeria but this may or may not indicate a true increase in measles cases. Only very basic assessments of the logistics of the system have been conducted. Further investigations of the quality of the data and performance of reporting sites must be made to determine the reliability of information being generated by the surveillance system before conclusions can be drawn. PMID- 24778209 TI - Rate of false conviction of criminal defendants who are sentenced to death. AB - The rate of erroneous conviction of innocent criminal defendants is often described as not merely unknown but unknowable. There is no systematic method to determine the accuracy of a criminal conviction; if there were, these errors would not occur in the first place. As a result, very few false convictions are ever discovered, and those that are discovered are not representative of the group as a whole. In the United States, however, a high proportion of false convictions that do come to light and produce exonerations are concentrated among the tiny minority of cases in which defendants are sentenced to death. This makes it possible to use data on death row exonerations to estimate the overall rate of false conviction among death sentences. The high rate of exoneration among death sentenced defendants appears to be driven by the threat of execution, but most death-sentenced defendants are removed from death row and resentenced to life imprisonment, after which the likelihood of exoneration drops sharply. We use survival analysis to model this effect, and estimate that if all death-sentenced defendants remained under sentence of death indefinitely, at least 4.1% would be exonerated. We conclude that this is a conservative estimate of the proportion of false conviction among death sentences in the United States. PMID- 24778208 TI - Control of type III secretion activity and substrate specificity by the cytoplasmic regulator PcrG. AB - Pathogenic Gram-negative bacteria use syringe-like type III secretion systems (T3SS) to inject effector proteins directly into targeted host cells. Effector secretion is triggered by host cell contact, and before contact is prevented by a set of conserved regulators. How these regulators interface with the T3SS apparatus to control secretion is unclear. We present evidence that the proton motive force (pmf) drives T3SS secretion in Pseudomonas aeruginosa, and that the cytoplasmic regulator PcrG interacts with distinct components of the T3SS apparatus to control two important aspects of effector secretion: (i) It coassembles with a second regulator (Pcr1) on the inner membrane T3SS component PcrD to prevent effectors from accessing the T3SS, and (ii) In conjunction with PscO, it controls protein secretion activity by modulating the ability of T3SS to convert pmf. PMID- 24778210 TI - Histone demethylase KDM5B is a key regulator of genome stability. AB - Maintenance of genomic stability is essential for normal organismal development and is vital to prevent diseases such as cancer. As genetic information is packaged into chromatin, it has become increasingly clear that the chromatin environment plays an important role in DNA damage response. However, how DNA repair is controlled by epigenetic mechanisms is not fully understood. Here we report the identification and characterization of lysine-specific histone demethylase 5B (KDM5B), a member of the JmjC domain-containing histone demethylases, as an important player in multiple aspects of DNA double-strand break (DSB) response in human cells. We found that KDM5B becomes enriched in DNA damage sites after ironizing radiation and endonuclease treatment in a poly(ADP ribose) polymerase 1- and histone variant macroH2A1.1-dependent manner. We showed that KDM5B is required for efficient DSB repair and for the recruitment of Ku70 and BRCA1, the essential component of nonhomologous end-joining and homologous recombination, respectively. Significantly, KDM5B deficiency disengages the DNA repair process, promotes spontaneous DNA damage, activates p53 signaling, and sensitizes cells to genotoxic insults. Our results suggest that KDM5B is a bona fide DNA damage response protein and indicate that KDM5B is an important genome caretaker and a critical regulator of genome stability, adding to the understanding of the roles of epigenetics in the maintenance of genetic fidelity. PMID- 24778212 TI - Architectures of planetary systems and implications for their formation. AB - Doppler planet searches revealed that many giant planets orbit close to their host star or in highly eccentric orbits. These and subsequent observations inspired new theories of planet formation that invoke gravitation interactions in multiple planet systems to explain the excitation of orbital eccentricities and even short-period giant planets. Recently, NASA's Kepler mission has identified over 300 systems with multiple transiting planet candidates, including many potentially rocky planets. Most of these systems include multiple planets with closely spaced orbits and sizes between that of Earth and Neptune. These systems represent yet another new and unexpected class of planetary systems and provide an opportunity to test the theories developed to explain the properties of giant exoplanets. Presently, we have limited knowledge about such planetary systems, mostly about their sizes and orbital periods. With the advent of long-term, nearly continuous monitoring by Kepler, the method of transit timing variations (TTVs) has blossomed as a new technique for characterizing the gravitational effects of mutual planetary perturbations for hundreds of planets. TTVs can provide precise, but complex, constraints on planetary masses, densities, and orbits, even for planetary systems with faint host stars. In the coming years, astronomers will translate TTV observations into increasingly powerful constraints on the formation and orbital evolution of planetary systems with low mass planets. Between TTVs, improved Doppler surveys, high-contrast imaging campaigns, and microlensing surveys, astronomers can look forward to a much better understanding of planet formation in the coming decade. PMID- 24778211 TI - Inhaled oxytocin increases positive social behaviors in newborn macaques. AB - Early caregiver-infant interactions are critical for infants' socioemotional and cognitive development. Several hormones and neuromodulators, including oxytocin, affect these interactions. Exogenous oxytocin promotes social behaviors in several species, including human and nonhuman primates. Although exogenous oxytocin increases social function in adults--including expression recognition and affiliation--it is unknown whether oxytocin can increase social interactions in infants. We hypothesized that nebulized oxytocin would increase affiliative social behaviors and such effects would be modulated by infants' social skills, measured earlier in development. We also hypothesized that oxytocin's effects on social behaviors may be due to its anxiolytic effects. We tested these hypotheses in a blind study by nebulizing 7- to 14-d-old macaques (n = 28) with oxytocin or saline. Following oxytocin administration, infants' facial gesturing at a human caregiver increased, and infants' salivary oxytocin was positively correlated with the time spent in close proximity to a caregiver. Infants' imitative skill (measured earlier in development: 1-7 d of age) predicted oxytocin-associated increases in affiliative behaviors--lip smacking, visual attention to a caregiver, and time in close proximity to a caregiver--suggesting that infants with higher propensities for positive social interactions are more sensitive to exogenous oxytocin. Oxytocin also decreased salivary cortisol, but not stress related behaviors (e.g., scratching), suggesting the possibility of some anxiolytic effects. To our knowledge, this study provides the first evidence that oxytocin increases positive social behaviors in newborns. This information is of critical importance for potential interventions aimed at ameliorating inadequate social behaviors in infants with higher likelihood of developing neurodevelopmental disorder. PMID- 24778213 TI - GFRalpha1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. AB - The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto oncogene (RET) receptors. GDNF family receptor (GFR)alpha1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRalpha1 released by nerves enhances PNI, even in the absence of cancer cell GFRalpha1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRalpha1 in a dose dependent fashion. Dorsal root ganglia (DRG) release soluble GFRalpha1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRalpha1(+/-) mice compared with GFRalpha1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRalpha1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRalpha1 expression, suggesting an alternate source of GFRalpha1 in PNI. These findings collectively demonstrate that GFRalpha1 released by nerves enhances PNI through GDNF-RET signaling and that GFRalpha1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior. PMID- 24778214 TI - Structure of the branched intermediate in protein splicing. AB - Inteins are autoprocessing domains that cut themselves out of host proteins in a traceless manner. This process, known as protein splicing, involves multiple chemical steps that must be coordinated to ensure fidelity in the process. The committed step in splicing involves attack of a conserved Asn side-chain amide on the adjacent backbone amide, leading to an intein-succinimide product and scission of that peptide bond. This cleavage reaction is stimulated by formation of a branched intermediate in the splicing process. The mechanism by which the Asn side-chain becomes activated as a nucleophile is not understood. Here we solve the crystal structure of an intein trapped in the branched intermediate step in protein splicing. Guided by this structure, we use protein-engineering approaches to show that intein-succinimide formation is critically dependent on a backbone-to-side-chain hydrogen-bond. We propose that this interaction serves to both position the side-chain amide for attack and to activate its nitrogen as a nucleophile. Collectively, these data provide an unprecedented view of an intein poised to carry out the rate-limiting step in protein splicing, shedding light on how a nominally nonnucleophilic group, a primary amide, can become activated in a protein active site. PMID- 24778215 TI - Declines in large wildlife increase landscape-level prevalence of rodent-borne disease in Africa. AB - Populations of large wildlife are declining on local and global scales. The impacts of this pulse of size-selective defaunation include cascading changes to smaller animals, particularly rodents, and alteration of many ecosystem processes and services, potentially involving changes to prevalence and transmission of zoonotic disease. Understanding linkages between biodiversity loss and zoonotic disease is important for both public health and nature conservation programs, and has been a source of much recent scientific debate. In the case of rodent-borne zoonoses, there is strong conceptual support, but limited empirical evidence, for the hypothesis that defaunation, the loss of large wildlife, increases zoonotic disease risk by directly or indirectly releasing controls on rodent density. We tested this hypothesis by experimentally excluding large wildlife from a savanna ecosystem in East Africa, and examining changes in prevalence and abundance of Bartonella spp. infection in rodents and their flea vectors. We found no effect of wildlife removal on per capita prevalence of Bartonella infection in either rodents or fleas. However, because rodent and, consequently, flea abundance doubled following experimental defaunation, the density of infected hosts and infected fleas was roughly twofold higher in sites where large wildlife was absent. Thus, defaunation represents an elevated risk in Bartonella transmission to humans (bartonellosis). Our results (i) provide experimental evidence of large wildlife defaunation increasing landscape-level disease prevalence, (ii) highlight the importance of susceptible host regulation pathways and host/vector density responses in biodiversity-disease relationships, and (iii) suggest that rodent-borne disease responses to large wildlife loss may represent an important context where this relationship is largely negative. PMID- 24778217 TI - Profile of Norbert Perrimon. PMID- 24778216 TI - Enhancer RNAs participate in androgen receptor-driven looping that selectively enhances gene activation. AB - The androgen receptor (AR) is a key factor that regulates the behavior and fate of prostate cancer cells. The AR-regulated network is activated when AR binds enhancer elements and modulates specific enhancer-promoter looping. Kallikrein related peptidase 3 (KLK3), which codes for prostate-specific antigen (PSA), is a well-known AR-regulated gene and its upstream enhancers produce bidirectional enhancer RNAs (eRNAs), termed KLK3e. Here, we demonstrate that KLK3e facilitates the spatial interaction of the KLK3 enhancer and the KLK2 promoter and enhances long-distance KLK2 transcriptional activation. KLK3e carries the core enhancer element derived from the androgen response element III (ARE III), which is required for the interaction of AR and Mediator 1 (Med1). Furthermore, we show that KLK3e processes RNA-dependent enhancer activity depending on the integrity of core enhancer elements. The transcription of KLK3e was detectable and its expression is significantly correlated with KLK3 (R(2) = 0.6213, P < 5 * 10(-11)) and KLK2 (R(2) = 0.5893, P < 5 * 10(-10)) in human prostate tissues. Interestingly, RNAi silencing of KLK3e resulted in a modest negative effect on prostate cancer cell proliferation. Accordingly, we report that an androgen induced eRNA scaffolds the AR-associated protein complex that modulates chromosomal architecture and selectively enhances AR-dependent gene expression. PMID- 24778218 TI - Intake and transformation to a glycoside of (Z)-3-hexenol from infested neighbors reveals a mode of plant odor reception and defense. AB - Plants receive volatile compounds emitted by neighboring plants that are infested by herbivores, and consequently the receiver plants begin to defend against forthcoming herbivory. However, to date, how plants receive volatiles and, consequently, how they fortify their defenses, is largely unknown. In this study, we found that undamaged tomato plants exposed to volatiles emitted by conspecifics infested with common cutworms (exposed plants) became more defensive against the larvae than those exposed to volatiles from uninfested conspecifics (control plants) in a constant airflow system under laboratory conditions. Comprehensive metabolite analyses showed that only the amount of (Z)-3 hexenylvicianoside (HexVic) was higher in exposed than control plants. This compound negatively affected the performance of common cutworms when added to an artificial diet. The aglycon of HexVic, (Z)-3-hexenol, was obtained from neighboring infested plants via the air. The amount of jasmonates (JAs) was not higher in exposed plants, and HexVic biosynthesis was independent of JA signaling. The use of (Z)-3-hexenol from neighboring damaged conspecifics for HexVic biosynthesis in exposed plants was also observed in an experimental field, indicating that (Z)-3-hexenol intake occurred even under fluctuating environmental conditions. Specific use of airborne (Z)-3-hexenol to form HexVic in undamaged tomato plants reveals a previously unidentified mechanism of plant defense. PMID- 24778220 TI - Controllability in protein interaction networks. AB - Recently, the focus of network research shifted to network controllability, prompting us to determine proteins that are important for the control of the underlying interaction webs. In particular, we determined minimum dominating sets of proteins (MDSets) in human and yeast protein interaction networks. Such groups of proteins were defined as optimized subsets where each non-MDSet protein can be reached by an interaction from an MDSet protein. Notably, we found that MDSet proteins were enriched with essential, cancer-related, and virus-targeted genes. Their central position allowed MDSet proteins to connect protein complexes and to have a higher impact on network resilience than hub proteins. As for their involvement in regulatory functions, MDSet proteins were enriched with transcription factors and protein kinases and were significantly involved in bottleneck interactions, regulatory links, phosphorylation events, and genetic interactions. PMID- 24778219 TI - Drosha as an interferon-independent antiviral factor. AB - Utilization of antiviral small interfering RNAs is thought to be largely restricted to plants, nematodes, and arthropods. In an effort to determine whether a physiological interplay exists between the host small RNA machinery and the cellular response to virus infection in mammals, we evaluated antiviral activity in the presence and absence of Dicer or Drosha, the RNase III nucleases responsible for generating small RNAs. Although loss of Dicer did not compromise the cellular response to virus infection, Drosha deletion resulted in a significant increase in virus levels. Here, we demonstrate that diverse RNA viruses trigger exportin 1 (XPO1/CRM1)-dependent Drosha translocation into the cytoplasm in a manner independent of de novo protein synthesis or the canonical type I IFN system. Additionally, increased virus infection in the absence of Drosha was not due to a loss of viral small RNAs but, instead, correlated with cleavage of viral genomic RNA and modulation of the host transcriptome. Taken together, we propose that Drosha represents a unique and conserved arm of the cellular defenses used to combat virus infection. PMID- 24778221 TI - Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. AB - The newly emerging Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes a Severe Acute Respiratory Syndrome-like disease with ~43% mortality. Given the recent detection of virus in dromedary camels, zoonotic transfer of MERS-CoV to humans is suspected. In addition, little is known about the role of human neutralizing Ab (nAb) pressure as a driving force in MERS-CoV adaptive evolution. Here, we used a well-characterized nonimmune human Ab-phage library and a panning strategy with proteoliposomes and cells to identify seven human nAbs against the receptor-binding domain (RBD) of the MERS-CoV Spike protein. These nAbs bind to three different epitopes in the RBD and human dipeptidyl peptidase 4 (hDPP4) interface with subnanomolar/nanomolar binding affinities and block the binding of MERS-CoV Spike protein with its hDPP4 receptor. Escape mutant assays identified five amino acid residues that are critical for neutralization escape. Despite the close proximity of the three epitopes on the RBD interface, escape from one epitope did not have a major impact on neutralization with Abs directed to a different epitope. Importantly, the majority of escape mutations had negative impacts on hDPP4 receptor binding and viral fitness. To our knowledge, these results provide the first report on human nAbs against MERS-CoV that may contribute to MERS-CoV clearance and evolution. Moreover, in the absence of a licensed vaccine or antiviral for MERS, this panel of nAbs offers the possibility of developing human mAb-based immunotherapy, especially for health-care workers. PMID- 24778222 TI - PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. AB - Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the "senescence-messaging secretome" (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho-deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and emphysema. Because plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor (SERPIN), is elevated in kl/kl mice and is a critical determinant of replicative senescence in vitro, we hypothesized that a reduction in extracellular proteolytic activity contributes to the accelerated aging-like phenotype of kl/kl mice. Here we show that PAI-1 deficiency retards the development of senescence and protects organ structure and function while prolonging the lifespan of kl/kl mice. These findings indicate that a SERPIN-regulated cell-nonautonomous proteolytic cascade is a critical determinant of senescence in vivo. PMID- 24778223 TI - Bacterial scaffold directs pole-specific centromere segregation. AB - Bacteria use partitioning systems based on the ParA ATPase to actively mobilize and spatially organize molecular cargoes throughout the cytoplasm. The bacterium Caulobacter crescentus uses a ParA-based partitioning system to segregate newly replicated chromosomal centromeres to opposite cell poles. Here we demonstrate that the Caulobacter PopZ scaffold creates an organizing center at the cell pole that actively regulates polar centromere transport by the ParA partition system. As segregation proceeds, the ParB-bound centromere complex is moved by progressively disassembling ParA from a nucleoid-bound structure. Using superresolution microscopy, we show that released ParA is recruited directly to binding sites within a 3D ultrastructure composed of PopZ at the cell pole, whereas the ParB-centromere complex remains at the periphery of the PopZ structure. PopZ recruitment of ParA stimulates ParA to assemble on the nucleoid near the PopZ-proximal cell pole. We identify mutations in PopZ that allow scaffold assembly but specifically abrogate interactions with ParA and demonstrate that PopZ/ParA interactions are required for proper chromosome segregation in vivo. We propose that during segregation PopZ sequesters free ParA and induces target-proximal regeneration of ParA DNA binding activity to enforce processive and pole-directed centromere segregation, preventing segregation reversals. PopZ therefore functions as a polar hub complex at the cell pole to directly regulate the directionality and destination of transfer of the mitotic segregation machine. PMID- 24778224 TI - Some inconvenient truths about biosignatures involving two chemical species on Earth-like exoplanets. AB - The detection of strong thermochemical disequilibrium in the atmosphere of an extrasolar planet is thought to be a potential biosignature. In this article we present a previously unidentified kind of false positive that can mimic a disequilibrium or any other biosignature that involves two chemical species. We consider a scenario where the exoplanet hosts a moon that has its own atmosphere and neither of the atmospheres is in chemical disequilibrium. Our results show that the integrated spectrum of the planet and the moon closely resembles that of a single object in strong chemical disequilibrium. We derive a firm limit on the maximum spectral resolution that can be obtained for both directly imaged and transiting planets. The spectral resolution of even idealized space-based spectrographs that might be achievable in the next several decades is in general insufficient to break the degeneracy. Both chemical species can only be definitively confirmed in the same object if absorption features of both chemicals can be unambiguously identified and their combined depth exceeds 100%. PMID- 24778226 TI - QnAs with Simon A. Levin. Interviewed by Paul Gabrielsen. PMID- 24778225 TI - Lack of testicular seipin causes teratozoospermia syndrome in men. AB - Obesity impairs male fertility, providing evidence for a link between adipose tissue and reproductive function; however, potential consequences of adipose tissue paucity on fertility remain unknown. Lack of s.c. fat is a hallmark of Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), which is caused by mutations in BSCL2-encoding seipin. Mice with a targeted deletion of murine seipin model BSCL2 with severe lipodystrophy, insulin resistance, and fatty liver but also exhibit male sterility. Here, we report teratozoospermia syndrome in a lipodystrophic patient with compound BSCL2 mutations, with sperm defects resembling the defects of infertile seipin null mutant mice. Analysis of conditional mouse mutants revealed that adipocyte-specific loss of seipin causes progressive lipodystrophy without affecting fertility, whereas loss of seipin in germ cells results in complete male infertility and teratozoospermia. Spermatids of the human patient and mice devoid of seipin in germ cells are morphologically abnormal with large ectopic lipid droplets and aggregate in dysfunctional clusters. Elevated levels of phosphatidic acid accompanied with an altered ratio of polyunsaturated to monounsaturated and saturated fatty acids in mutant mouse testes indicate impaired phospholipid homeostasis during spermiogenesis. We conclude that testicular but not adipose tissue-derived seipin is essential for male fertility by modulating testicular phospholipid homeostasis. PMID- 24778227 TI - Juvenile hormone regulates body size and perturbs insulin signaling in Drosophila. AB - The role of juvenile hormone (JH) in regulating the timing and nature of insect molts is well-established. Increasing evidence suggests that JH is also involved in regulating final insect size. Here we elucidate the developmental mechanism through which JH regulates body size in developing Drosophila larvae by genetically ablating the JH-producing organ, the corpora allata (CA). We found that larvae that lack CA pupariated at smaller sizes than control larvae due to a reduced larval growth rate. Neither the timing of the metamorphic molt nor the duration of larval growth was affected by the loss of JH. Further, we show that the effects of JH on growth rate are dependent on the forkhead box O transcription factor (FOXO), which is negatively regulated by the insulin signaling pathway. Larvae that lacked the CA had elevated levels of FOXO activity, whereas a loss-of-function mutation of FOXO rescued the effects of CA ablation on final body size. Finally, the effect of JH on growth appears to be mediated, at least in part, via ecdysone synthesis in the prothoracic gland. These results indicate a role of JH in regulating growth rate via the ecdysone- and insulin-signaling pathways. PMID- 24778228 TI - Heterodimeric coiled-coil interactions of human GABAB receptor. AB - Metabotropic GABAB receptor is a G protein-coupled receptor that mediates inhibitory neurotransmission in the CNS. It functions as an obligatory heterodimer of GABAB receptor 1 (GBR1) and GABAB receptor 2 (GBR2) subunits. The association between GBR1 and GBR2 masks an endoplasmic reticulum (ER) retention signal in the cytoplasmic region of GBR1 and facilitates cell surface expression of both subunits. Here, we present, to our knowledge, the first crystal structure of an intracellular coiled-coil heterodimer of human GABAB receptor. We found that polar interactions buried within the hydrophobic core determine the specificity of heterodimer pairing. Disruption of the hydrophobic coiled-coil interface with single mutations in either subunit impairs surface expression of GBR1, confirming that the coiled-coil interaction is required to inactivate the adjacent ER retention signal of GBR1. The coiled-coil assembly buries an internalization motif of GBR1 at the heterodimer interface. The ER retention signal of GBR1 is not part of the core coiled-coil structure, suggesting that it is sterically shielded by GBR2 upon heterodimer formation. PMID- 24778229 TI - A rifamycin inactivating phosphotransferase family shared by environmental and pathogenic bacteria. AB - Many environmental bacteria are multidrug-resistant and represent a reservoir of ancient antibiotic resistance determinants, which have been linked to genes found in pathogens. Exploring the environmental antibiotic resistome, therefore, reveals the diversity and evolution of antibiotic resistance and also provides insight into the vulnerability of clinically used antibiotics. In this study, we describe the identification of a highly conserved regulatory motif, the rifampin (RIF) -associated element (RAE), which is found upstream of genes encoding RIF inactivating enzymes from a diverse collection of actinomycetes. Using gene expression assays, we confirmed that the RAE is involved in RIF-responsive regulation. By using the RAE as a probe for new RIF-associated genes in several actinomycete genomes, we identified a heretofore unknown RIF resistance gene, RIF phosphotransferase (rph). The RPH enzyme is a RIF-inactivating phosphotransferase and represents a new protein family in antibiotic resistance. RPH orthologs are widespread and found in RIF-sensitive bacteria, including Bacillus cereus and the pathogen Listeria monocytogenes. Heterologous expression and in vitro enzyme assays with purified RPHs from diverse bacterial genera show that these enzymes are capable of conferring high-level resistance to a variety of clinically used rifamycin antibiotics. This work identifies a new antibiotic resistance protein family and reinforces the fact that the study of resistance in environmental organisms can serve to identify resistance elements with relevance to pathogens. PMID- 24778230 TI - Field experiments of success-breeds-success dynamics. AB - Seemingly similar individuals often experience drastically different success trajectories, with some repeatedly failing and others consistently succeeding. One explanation is preexisting variability along unobserved fitness dimensions that is revealed gradually through differential achievement. Alternatively, positive feedback operating on arbitrary initial advantages may increasingly set apart winners from losers, producing runaway inequality. To identify social feedback in human reward systems, we conducted randomized experiments by intervening in live social environments across the domains of funding, status, endorsement, and reputation. In each system we consistently found that early success bestowed upon arbitrarily selected recipients produced significant improvements in subsequent rates of success compared with the control group of nonrecipients. However, success exhibited decreasing marginal returns, with larger initial advantages failing to produce much further differentiation. These findings suggest a lesser degree of vulnerability of reward systems to incidental or fabricated advantages and a more modest role for cumulative advantage in the explanation of social inequality than previously thought. PMID- 24778231 TI - Third-party punishment increases cooperation in children through (misaligned) expectations and conditional cooperation. AB - The human ability to establish cooperation, even in large groups of genetically unrelated strangers, depends upon the enforcement of cooperation norms. Third party punishment is one important factor to explain high levels of cooperation among humans, although it is still somewhat disputed whether other animal species also use this mechanism for promoting cooperation. We study the effectiveness of third-party punishment to increase children's cooperative behavior in a large scale cooperation game. Based on an experiment with 1,120 children, aged 7 to 11 y, we find that the threat of third-party punishment more than doubles cooperation rates, despite the fact that children are rarely willing to execute costly punishment. We can show that the higher cooperation levels with third party punishment are driven by two components. First, cooperation is a rational (expected payoff-maximizing) response to incorrect beliefs about the punishment behavior of third parties. Second, cooperation is a conditionally cooperative reaction to correct beliefs that third party punishment will increase a partner's level of cooperation. PMID- 24778232 TI - Cell cycle-specific cleavage of Scc2 regulates its cohesin deposition activity. AB - Sister chromatid cohesion (SCC), efficient DNA repair, and the regulation of some metazoan genes require the association of cohesins with chromosomes. Cohesins are deposited by a conserved heterodimeric loading complex composed of the Scc2 and Scc4 proteins in Saccharomyces cerevisiae, but how the Scc2/Scc4 deposition complex regulates the spatiotemporal association of cohesin with chromosomes is not understood. We examined Scc2 chromatin association during the cell division cycle and found that the affinity of Scc2 for chromatin increases biphasically during the cell cycle, increasing first transiently in late G1 phase and then again later in G2/M. Inactivation of Scc2 following DNA replication reduces cellular viability, suggesting that this post S-phase increase in Scc2 chromatin binding affinity is biologically relevant. Interestingly, high and low Scc2 chromatin binding levels correlate strongly with the presence of full-length or amino-terminally cleaved forms of Scc2, respectively, and the appearance of the cleaved Scc2 species is promoted in vitro either by treatment with specific cell cycle-staged cellular extracts or by dephosphorylation. Importantly, Scc2 cleavage eliminates Scc2-Scc4 physical interactions, and an scc2 truncation mutant that mimics in vivo Scc2 cleavage is defective for cohesin deposition. These observations suggest a previously unidentified mechanism for the spatiotemporal regulation of cohesin association with chromosomes through cell cycle regulation of Scc2 cohesin deposition activity by Scc2 dephosphorylation and cleavage. PMID- 24778233 TI - Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164. AB - Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from alpha2-plasmin inhibitor (alpha2-PI1 8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An alpha2-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-alpha2-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin alpha2-PI1-8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations >=25 MUg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 MUg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-alpha2-PI1-8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis. PMID- 24778234 TI - CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIB binding to the cell surface. AB - CCR5 and CXCR4, the respective cell surface coreceptors of R5 and X4 HIV-1 strains, both form heterodimers with CD4, the principal HIV-1 receptor. Using several resonance energy transfer techniques, we determined that CD4, CXCR4, and CCR5 formed heterotrimers, and that CCR5 coexpression altered the conformation of both CXCR4/CXCR4 homodimers and CD4/CXCR4 heterodimers. As a result, binding of the HIV-1 envelope protein gp120IIIB to the CD4/CXCR4/CCR5 heterooligomer was negligible, and the gp120-induced cytoskeletal rearrangements necessary for HIV-1 entry were prevented. CCR5 reduced HIV-1 envelope-induced CD4/CXCR4-mediated cell cell fusion. In nucleofected Jurkat CD4 cells and primary human CD4(+) T cells, CCR5 expression led to a reduction in X4 HIV-1 infectivity. These findings can help to understand why X4 HIV-1 strains infection affect T-cell types differently during AIDS development and indicate that receptor oligomerization might be a target for previously unidentified therapeutic approaches for AIDS intervention. PMID- 24778235 TI - Rescue of embryonic stem cells from cellular transformation by proteomic stabilization of mutant p53 and conversion into WT conformation. AB - p53 is a well-known tumor suppressor that is mutated in over 50% of human cancers. These mutations were shown to exhibit gain of oncogenic function compared with the deletion of the gene. Additionally, p53 has fundamental roles in differentiation and development; nevertheless, mutant p53 mice are viable and develop malignant tumors only on adulthood. We set out to reveal the mechanisms by which embryos are protected from mutant p53-induced transformation using ES cells (ESCs) that express a conformational mutant of p53. We found that, despite harboring mutant p53, the ESCs remain pluripotent and benign and have relatively normal karyotype compared with ESCs knocked out for p53. Additionally, using high content RNA sequencing, we show that p53 is transcriptionally active in response to DNA damage in mutant ESCs and elevates p53 target genes, such as p21 and btg2. We also show that the conformation of mutant p53 protein in ESCs is stabilized to a WT conformation. Through MS-based interactome analyses, we identified a network of proteins, including the CCT complex, USP7, Aurora kinase, Nedd4, and Trim24, that bind mutant p53 and may shift its conformation to a WT form. We propose this conformational shift as a novel mechanism of maintenance of genomic integrity, despite p53 mutation. Harnessing the ability of these protein interactors to transform the oncogenic mutant p53 to the tumor suppressor WT form can be the basis for future development of p53-targeted cancer therapy. PMID- 24778236 TI - UNC93B1 is essential for the plasma membrane localization and signaling of Toll like receptor 5. AB - The proper trafficking and localization of Toll-like receptors (TLRs) are important for specific ligand recognition and efficient signal transduction. The TLRs sensing bacterial membrane components are expressed on the cell surface and recruit signaling adaptors to the plasma membrane upon stimulation. On the contrary, the nucleotide-sensing TLRs are mostly found inside cells and signal from the endolysosomes in an acidic pH-dependent manner. Trafficking of the nucleotide-sensing TLRs from the endoplasmic reticulum to the endolysosomes strictly depends on UNC93B1, and their signaling is completely abolished in the 3d mutant mice bearing the H412R mutation of UNC93B1. In contrast, UNC93B1 was considered to have no role for the cell surface-localized TLRs and signaling via TLR1, TLR2, TLR4, and TLR6 is normal in the 3d mice. Unexpectedly, we discovered that TLR5, a cell surface receptor for bacterial protein flagellin, also requires UNC93B1 for plasma membrane localization and signaling. TLR5 physically interacts with UNC93B1, and the cells from the 3d or UNC93B1-deficient mice not only lack TLR5 at the plasma membrane but also fail to secret cytokines and to up-regulate costimulatory molecules upon flagellin stimulation, demonstrating the essential role of UNC93B1 in TLR5 signaling. Our study reveals that the role of UNC93B1 is not limited to the TLRs signaling from the endolysosomes and compels the further probing of the mechanisms underlying the UNC93B1-assisted differential targeting of TLRs. PMID- 24778237 TI - Income inequality in today's China. AB - Using multiple data sources, we establish that China's income inequality since 2005 has reached very high levels, with the Gini coefficient in the range of 0.53 0.55. Analyzing comparable survey data collected in 2010 in China and the United States, we examine social determinants that help explain China's high income inequality. Our results indicate that a substantial part of China's high income inequality is due to regional disparities and the rural-urban gap. The contributions of these two structural forces are particularly strong in China, but they play a negligible role in generating the overall income inequality in the United States, where individual-level and family-level income determinants, such as family structure and race/ethnicity, play a much larger role. PMID- 24778238 TI - Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus. AB - The source, timing, and geographical origin of the 1918-1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1 lineages using a host-specific molecular clock approach that is demonstrably more accurate than previous methods. Our results suggest that the 1918 pandemic virus originated shortly before 1918 when a human H1 virus, which we infer emerged before ~1907, acquired avian N1 neuraminidase and internal protein genes. We find that the resulting pandemic virus jumped directly to swine but was likely displaced in humans by ~1922 by a reassortant with an antigenically distinct H1 HA. Hence, although the swine lineage was a direct descendent of the pandemic virus, the post-1918 seasonal H1N1 lineage evidently was not, at least for HA. These findings help resolve several seemingly disparate observations from 20th century influenza epidemiology, seroarcheology, and immunology. The phylogenetic results, combined with these other lines of evidence, suggest that the high mortality in 1918 among adults aged ~20 to ~40 y may have been due primarily to their childhood exposure to a doubly heterosubtypic putative H3N8 virus, which we estimate circulated from ~1889-1900. All other age groups (except immunologically naive infants) were likely partially protected by childhood exposure to N1 and/or H1-related antigens. Similar processes may underlie age-specific mortality differences between seasonal H1N1 vs. H3N2 and human H5N1 vs. H7N9 infections. PMID- 24778239 TI - Undocumented water column sink for cadmium in open ocean oxygen-deficient zones. AB - Cadmium (Cd) is a micronutrient and a tracer of biological productivity and circulation in the ocean. The correlation between dissolved Cd and the major algal nutrients in seawater has led to the use of Cd preserved in microfossils to constrain past ocean nutrient distributions. However, linking Cd to marine biological processes requires constraints on marine sources and sinks of Cd. Here, we show a decoupling between Cd and major nutrients within oxygen-deficient zones (ODZs) in both the Northeast Pacific and North Atlantic Oceans, which we attribute to Cd sulfide (CdS) precipitation in euxinic microenvironments around sinking biological particles. We find that dissolved Cd correlates well with dissolved phosphate in oxygenated waters, but is depleted compared with phosphate in ODZs. Additionally, suspended particles from the North Atlantic show high Cd content and light Cd stable isotope ratios within the ODZ, indicative of CdS precipitation. Globally, we calculate that CdS precipitation in ODZs is an important, and to our knowledge a previously undocumented marine sink of Cd. Our results suggest that water column oxygen depletion has a substantial impact on Cd biogeochemical cycling, impacting the global relationship between Cd and major nutrients and suggesting that Cd may be a previously unidentified tracer for water column oxygen deficiency on geological timescales. Similar depletions of copper and zinc in the Northeast Pacific indicate that sulfide precipitation in ODZs may also have an influence on the global distribution of other trace metals. PMID- 24778240 TI - Syntrophic exchange in synthetic microbial communities. AB - Metabolic crossfeeding is an important process that can broadly shape microbial communities. However, little is known about specific crossfeeding principles that drive the formation and maintenance of individuals within a mixed population. Here, we devised a series of synthetic syntrophic communities to probe the complex interactions underlying metabolic exchange of amino acids. We experimentally analyzed multimember, multidimensional communities of Escherichia coli of increasing sophistication to assess the outcomes of synergistic crossfeeding. We find that biosynthetically costly amino acids including methionine, lysine, isoleucine, arginine, and aromatics, tend to promote stronger cooperative interactions than amino acids that are cheaper to produce. Furthermore, cells that share common intermediates along branching pathways yielded more synergistic growth, but exhibited many instances of both positive and negative epistasis when these interactions scaled to higher dimensions. In more complex communities, we find certain members exhibiting keystone species like behavior that drastically impact the community dynamics. Based on comparative genomic analysis of >6,000 sequenced bacteria from diverse environments, we present evidence suggesting that amino acid biosynthesis has been broadly optimized to reduce individual metabolic burden in favor of enhanced crossfeeding to support synergistic growth across the biosphere. These results improve our basic understanding of microbial syntrophy while also highlighting the utility and limitations of current modeling approaches to describe the dynamic complexities underlying microbial ecosystems. This work sets the foundation for future endeavors to resolve key questions in microbial ecology and evolution, and presents a platform to develop better and more robust engineered synthetic communities for industrial biotechnology. PMID- 24778241 TI - Endophilin A1 induces different membrane shapes using a conformational switch that is regulated by phosphorylation. AB - Membrane remodeling is controlled by proteins that can promote the formation of highly curved spherical or cylindrical membranes. How a protein induces these different types of membrane curvature and how cells regulate this process is still unclear. Endophilin A1 is a protein involved in generating endocytotic necks and vesicles during synaptic endocytosis and can transform large vesicles into lipid tubes or small and highly curved vesicles in vitro. By using EM and electron paramagnetic resonance of endophilin A1, we find that tubes are formed by a close interaction with endophilin A1's BIN/amphiphysin/Rvs (BAR) domain and deep insertion of its amphipathic helices. In contrast, vesicles are predominantly stabilized by the shallow insertion of the amphipathic helical wedges with the BAR domain removed from the membrane. By showing that the mechanism of membrane curvature induction is different for vesiculation and tubulation, these data also explain why previous studies arrived at different conclusions with respect to the importance of scaffolding and wedging in the membrane curvature generation of BAR proteins. The Parkinson disease-associated kinase LRRK2 phosphorylates S75 of endophilin A1, a position located in the acyl chain region on tubes and the aqueous environment on vesicles. We find that the phosphomimetic mutation S75D favors vesicle formation by inhibiting this conformational switch, acting to regulate endophilin A1-mediated curvature. As endophilin A1 is part of a protein superfamily, we expect these mechanisms and their regulation by posttranslational modifications to be a general means for controlling different types of membrane curvature in a wide range of processes in vivo. PMID- 24778242 TI - A forager-herder trade-off, from broad-spectrum hunting to sheep management at Asikli Hoyuk, Turkey. AB - Asikli Hoyuk is the earliest known preceramic Neolithic mound site in Central Anatolia. The oldest Levels, 4 and 5, spanning 8,200 to approximately 9,000 cal B.C., associate with round-house architecture and arguably represent the birth of the Pre-Pottery Neolithic in the region. Results from upper Level 4, reported here, indicate a broad meat diet that consisted of diverse wild ungulate and small animal species. The meat diet shifted gradually over just a few centuries to an exceptional emphasis on caprines (mainly sheep). Age-sex distributions of the caprines in upper Level 4 indicate selective manipulation by humans by or before 8,200 cal B.C. Primary dung accumulations between the structures demonstrate that ruminants were held captive inside the settlement at this time. Taken together, the zooarchaeological and geoarchaeological evidence demonstrate an emergent process of caprine management that was highly experimental in nature and oriented to quick returns. Stabling was one of the early mechanisms of caprine population isolation, a precondition to domestication. PMID- 24778243 TI - Cattle ranching intensification in Brazil can reduce global greenhouse gas emissions by sparing land from deforestation. AB - This study examines whether policies to encourage cattle ranching intensification in Brazil can abate global greenhouse gas (GHG) emissions by sparing land from deforestation. We use an economic model of global land use to investigate, from 2010 to 2030, the global agricultural outcomes, land use changes, and GHG abatement resulting from two potential Brazilian policies: a tax on cattle from conventional pasture and a subsidy for cattle from semi-intensive pasture. We find that under either policy, Brazil could achieve considerable sparing of forests and abatement of GHGs, in line with its national policy targets. The land spared, particularly under the tax, is far less than proportional to the productivity increased. However, the tax, despite prompting less adoption of semi intensive ranching, delivers slightly more forest sparing and GHG abatement than the subsidy. This difference is explained by increased deforestation associated with increased beef consumption under the subsidy and reduced deforestation associated with reduced beef consumption under the tax. Complementary policies to directly limit deforestation could help limit these effects. GHG abatement from either the tax or subsidy appears inexpensive but, over time, the tax would become cheaper than the subsidy. A revenue-neutral combination of the policies could be an element of a sustainable development strategy for Brazil and other emerging economies seeking to balance agricultural development and forest protection. PMID- 24778244 TI - Projected changes in African easterly wave intensity and track in response to greenhouse forcing. AB - Synoptic-scale African easterly waves (AEWs) impact weather throughout the greater Atlantic basin. Over the African continent, AEWs are instrumental in initiating and organizing precipitation in the drought-vulnerable Sahel region. AEWs also serve as the precursors to the most intense Atlantic hurricanes, and contribute to the global transport of Saharan dust. Given the relevance of AEWs for the climate of the greater Atlantic basin, we investigate the response of AEWs to increasing greenhouse gas concentrations. Using an ensemble of general circulation models, we find a robust increase in the strength of the winds associated with AEWs along the Intertropical Front in West Africa by the late 21st century of the representative concentration pathway 8.5. AEW energy increases directly due to an increase in baroclinicity associated with an enhanced meridional temperature gradient between the Sahara and Guinea Coast. Further, the pattern of low-level warming supports AEW development by enhancing monsoon flow, resulting in greater convergence and uplift along the Intertropical Front. These changes in energetics result in robust increases in the occurrence of conditions that currently produce AEWs. Given relationships observed in the current climate, such changes in the location of AEW tracks and the magnitude of AEW winds carry implications for the relationship between AEWs and precipitation in the Sahel, the mobilization of Saharan dust, and the likelihood of cyclogenesis in the Atlantic. Our results therefore suggest that changes in AEW characteristics could play a critical role in shaping the response of Atlantic basin climate to future increases in greenhouse gas concentrations. PMID- 24778245 TI - Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia. AB - The brain's default mode network (DMN) is highly heritable and is compromised in a variety of psychiatric disorders. However, genetic control over the DMN in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is largely unknown. Study subjects (n = 1,305) underwent a resting-state functional MRI scan and were analyzed by a two-stage approach. The initial analysis used independent component analysis (ICA) in 324 healthy controls, 296 SZ probands, 300 PBP probands, 179 unaffected first-degree relatives of SZ probands (SZREL), and 206 unaffected first-degree relatives of PBP probands to identify DMNs and to test their biomarker and/or endophenotype status. A subset of controls and probands (n = 549) then was subjected to a parallel ICA (para-ICA) to identify imaging-genetic relationships. ICA identified three DMNs. Hypo-connectivity was observed in both patient groups in all DMNs. Similar patterns observed in SZREL were restricted to only one network. DMN connectivity also correlated with several symptom measures. Para-ICA identified five sub-DMNs that were significantly associated with five different genetic networks. Several top-ranking SNPs across these networks belonged to previously identified, well-known psychosis/mood disorder genes. Global enrichment analyses revealed processes including NMDA-related long-term potentiation, PKA, immune response signaling, axon guidance, and synaptogenesis that significantly influenced DMN modulation in psychoses. In summary, we observed both unique and shared impairments in functional connectivity across the SZ and PBP cohorts; these impairments were selectively familial only for SZREL. Genes regulating specific neurodevelopment/transmission processes primarily mediated DMN disconnectivity. The study thus identifies biological pathways related to a widely researched quantitative trait that might suggest novel, targeted drug treatments for these diseases. PMID- 24778246 TI - A 9,000-year-old caribou hunting structure beneath Lake Huron. AB - Some of the most pivotal questions in human history necessitate the investigation of archaeological sites that are now under water. Nine thousand years ago, the Alpena-Amberley Ridge (AAR) beneath modern Lake Huron was a dry land corridor that connected northeast Michigan to southern Ontario. The newly discovered Drop 45 Drive Lane is the most complex hunting structure found to date beneath the Great Lakes. The site and its associated artifacts provide unprecedented insight into the social and seasonal organization of prehistoric caribou hunting. When combined with environmental and simulation studies, it is suggested that distinctly different seasonal strategies were used by early hunters on the AAR, with autumn hunting being carried out by small groups, and spring hunts being conducted by larger groups of cooperating hunters. PMID- 24778248 TI - Changing the academic culture: valuing patents and commercialization toward tenure and career advancement. AB - There is national and international recognition of the importance of innovation, technology transfer, and entrepreneurship for sustained economic revival. With the decline of industrial research laboratories in the United States, research universities are being asked to play a central role in our knowledge-centered economy by the technology transfer of their discoveries, innovations, and inventions. In response to this challenge, innovation ecologies at and around universities are starting to change. However, the change has been slow and limited. The authors believe this can be attributed partially to a lack of change in incentives for the central stakeholder, the faculty member. The authors have taken the position that universities should expand their criteria to treat patents, licensing, and commercialization activity by faculty as an important consideration for merit, tenure, and career advancement, along with publishing, teaching, and service. This position is placed in a historical context with a look at the history of tenure in the United States, patents, and licensing at universities, the current status of university tenure and career advancement processes, and models for the future. PMID- 24778247 TI - Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation. AB - The efforts to grow mechanically functional cartilage from human mesenchymal stem cells have not been successful. We report that clinically sized pieces of human cartilage with physiologic stratification and biomechanics can be grown in vitro by recapitulating some aspects of the developmental process of mesenchymal condensation. By exposure to transforming growth factor-beta, mesenchymal stem cells were induced to condense into cellular bodies, undergo chondrogenic differentiation, and form cartilagenous tissue, in a process designed to mimic mesenchymal condensation leading into chondrogenesis. We discovered that the condensed mesenchymal cell bodies (CMBs) formed in vitro set an outer boundary after 5 d of culture, as indicated by the expression of mesenchymal condensation genes and deposition of tenascin. Before setting of boundaries, the CMBs could be fused into homogenous cellular aggregates giving rise to well-differentiated and mechanically functional cartilage. We used the mesenchymal condensation and fusion of CMBs to grow centimeter-sized, anatomically shaped pieces of human articular cartilage over 5 wk of culture. For the first time to our knowledge biomechanical properties of cartilage derived from human mesenchymal cells were comparable to native cartilage, with the Young's modulus of >800 kPa and equilibrium friction coeffcient of <0.3. We also demonstrate that CMBs have capability to form mechanically strong cartilage-cartilage interface in an in vitro cartilage defect model. The CMBs, which acted as "lego-like" blocks of neocartilage, were capable of assembling into human cartilage with physiologic like structure and mechanical properties. PMID- 24778249 TI - Transcription factor E93 specifies adult metamorphosis in hemimetabolous and holometabolous insects. AB - All immature animals undergo remarkable morphological and physiological changes to become mature adults. In winged insects, metamorphic changes either are limited to a few tissues (hemimetaboly) or involve a complete reorganization of most tissues and organs (holometaboly). Despite the differences, the genetic switch between immature and adult forms in both types of insects relies on the disappearance of the antimetamorphic juvenile hormone (JH) and the transcription factors Kruppel-homolog 1 (Kr-h1) and Broad-Complex (BR-C) during the last juvenile instar. Here, we show that the transcription factor E93 is the key determinant that promotes adult metamorphosis in both hemimetabolous and holometabolous insects, thus acting as the universal adult specifier. In the hemimetabolous insect Blattella germanica, BgE93 is highly expressed in metamorphic tissues, and RNA interference (RNAi)-mediated knockdown of BgE93 in the nymphal stage prevented the nymphal-adult transition, inducing endless reiteration of nymphal development, even in the absence of JH. We also find that BgE93 down-regulated BgKr-h1 and BgBR-C expression during the last nymphal instar of B. germanica, a key step necessary for proper adult differentiation. This essential role of E93 is conserved in holometabolous insects as TcE93 RNAi in Tribolium castaneum prevented pupal-adult transition and produced a supernumerary second pupa. In this beetle, TcE93 also represses expression of TcKr-h1 and TcBR C during the pupal stage. Similar results were obtained in the more derived holometabolous insect Drosophila melanogaster, suggesting that winged insects use the same regulatory mechanism to promote adult metamorphosis. This study provides an important insight into the understanding of the molecular basis of adult metamorphosis. PMID- 24778250 TI - Thioredoxin-related protein of 14 kDa is an efficient L-cystine reductase and S denitrosylase. AB - Thioredoxin-related protein of 14 kDa (TRP14, also called TXNDC17 for thioredoxin domain containing 17, or TXNL5 for thioredoxin-like 5) is an evolutionarily well conserved member of the thioredoxin (Trx)-fold protein family that lacks activity with classical Trx1 substrates. However, we discovered here that human TRP14 has a high enzymatic activity in reduction of l-cystine, where the catalytic efficiency (2,217 min(-1)?uM(-1)) coupled to Trx reductase 1 (TrxR1) using NADPH was fivefold higher compared with Trx1 (418 min(-1)?uM(-1)). Moreover, the l cystine reduction with TRP14 was in contrast to that of Trx1 fully maintained in the presence of a protein disulfide substrate of Trx1 such as insulin, suggesting that TRP14 is a more dedicated l-cystine reductase compared with Trx1. We also found that TRP14 is an efficient S-denitrosylase with similar efficiency as Trx1 in catalyzing TrxR1-dependent denitrosylation of S-nitrosylated glutathione or of HEK293 cell-derived S-nitrosoproteins. Consequently, nitrosylated and thereby inactivated caspase 3 or cathepsin B could be reactivated through either Trx1- or TRP14-catalyzed denitrosylation reactions. TRP14 was also, in contrast to Trx1, completely resistant to inactivation by high concentrations of hydrogen peroxide. The oxidoreductase activities of TRP14 thereby complement those of Trx1 and must therefore be considered for the full understanding of enzymatic control of cellular thiols and nitrosothiols. PMID- 24778251 TI - Noise differentially impacts phoneme representations in the auditory and speech motor systems. AB - Although it is well accepted that the speech motor system (SMS) is activated during speech perception, the functional role of this activation remains unclear. Here we test the hypothesis that the redundant motor activation contributes to categorical speech perception under adverse listening conditions. In this functional magnetic resonance imaging study, participants identified one of four phoneme tokens (/ba/, /ma/, /da/, or /ta/) under one of six signal-to-noise ratio (SNR) levels (-12, -9, -6, -2, 8 dB, and no noise). Univariate and multivariate pattern analyses were used to determine the role of the SMS during perception of noise-impoverished phonemes. Results revealed a negative correlation between neural activity and perceptual accuracy in the left ventral premotor cortex and Broca's area. More importantly, multivoxel patterns of activity in the left ventral premotor cortex and Broca's area exhibited effective phoneme categorization when SNR >= -6 dB. This is in sharp contrast with phoneme discriminability in bilateral auditory cortices and sensorimotor interface areas (e.g., left posterior superior temporal gyrus), which was reliable only when the noise was extremely weak (SNR > 8 dB). Our findings provide strong neuroimaging evidence for a greater robustness of the SMS than auditory regions for categorical speech perception in noise. Under adverse listening conditions, better discriminative activity in the SMS may compensate for loss of specificity in the auditory system via sensorimotor integration. PMID- 24778252 TI - TRIM65 regulates microRNA activity by ubiquitination of TNRC6. AB - MicroRNAs (miRNAs) are small evolutionarily conserved regulatory RNAs that modulate mRNA stability and translation in a wide range of cell types. MiRNAs are involved in a broad array of biological processes, including cellular proliferation, differentiation, and apoptosis. To identify previously unidentified regulators of miRNA, we initiated a systematic discovery-type proteomic analysis of the miRNA pathway interactome in human cells. Six of 66 genes identified in our proteomic screen were capable of regulating lethal-7a (let-7a) miRNA reporter activity. Tripartite motif 65 (TRIM65) was identified as a repressor of miRNA activity. Detailed analysis indicates that TRIM65 interacts and colocalizes with trinucleotide repeat containing six (TNRC6) proteins in processing body-like structures. Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6. PMID- 24778253 TI - Extracortical origin of some murine subplate cell populations. AB - The subplate layer, the deepest cortical layer in mammals, has important roles in cerebral cortical development. The subplate contains heterogeneous cell populations that are morphologically diverse, with several projection targets. It is currently assumed that these cells are generated in the germinative zone of the earliest cortical neuroepithelium. Here we identify a pallial but extracortical area located in the rostromedial telencephalic wall (RMTW) that gives rise to several cell populations. Postmitotic neurons migrate tangentially from the RMTW toward the cerebral cortex. Most RMTW-derived cells are incorporated into the subplate layer throughout its rostrocaudal extension, with others contributing to the GABAergic interneuron pool of cortical layers V and VI. PMID- 24778254 TI - Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques. AB - The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress. This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases. PMID- 24778255 TI - Collagen-binding protein, Aegyptin, regulates probing time and blood feeding success in the dengue vector mosquito, Aedes aegypti. AB - Mosquito salivary glands have important roles in blood feeding and pathogen transmission. However, the biological relevance of many salivary components has yet to be determined. Aegyptin, a secreted salivary protein from Aedes aegypti, binds collagen and inhibits platelet aggregation and adhesion. We used a transgenic approach to study the relevance of Aegyptin in mosquito blood feeding. Aedes aegypti manipulated genetically to express gene-specific inverted-repeat RNA sequences exhibited significant reductions in Aegyptin mRNA accumulation (85 87%) and protein levels (>80-fold) in female mosquito salivary glands. Transgenic mosquitoes had longer probing times (78-300 s, P < 0.0001) when feeding on mice compared with controls (15-56 s), feeding success was reduced, and those feeding took smaller blood meals. However, no differences in feeding success or blood meal size were found in membrane feeding experiments using defibrinated human blood. Salivary gland extracts from transgenic mosquitoes failed to inhibit collagen-induced platelet aggregation in vitro. Reductions of Aegyptin did not affect salivary ADP-induced platelet aggregation inhibition or disturb anticlotting activities. Our results demonstrate the relevance of Aegyptin for A. aegypti blood feeding, providing further support for the hypothesis that platelet aggregation inhibition is a vital salivary function in blood feeding arthropods. It has been suggested that the multiple mosquito salivary components mediating platelet aggregation (i.e., Aegyptin, apyrase, D7) represent functional redundancy. Our findings do not support this hypothesis; instead, they indicate that multiple salivary components work synergistically and are necessary to achieve maximum blood feeding efficiency. PMID- 24778256 TI - Crumbs promotes expanded recognition and degradation by the SCF(Slimb/beta-TrCP) ubiquitin ligase. AB - In epithelial tissues, growth control depends on the maintenance of proper architecture through apicobasal polarity and cell-cell contacts. The Hippo signaling pathway has been proposed to sense tissue architecture and cell density via an intimate coupling with the polarity and cell contact machineries. The apical polarity protein Crumbs (Crb) controls the activity of Yorkie (Yki)/Yes activated protein, the progrowth target of the Hippo pathway core kinase cassette, both in flies and mammals. The apically localized Four-point-one, Ezrin, Radixin, Moesin domain protein Expanded (Ex) regulates Yki by promoting activation of the kinase cascade and by directly tethering Yki to the plasma membrane. Crb interacts with Ex and promotes its apical localization, thereby linking cell polarity with Hippo signaling. We show that, as well as repressing Yki by recruiting Ex to the apical membrane, Crb promotes phosphorylation dependent ubiquitin-mediated degradation of Ex. We identify Skp/Cullin/F box(Slimb/beta-transducin repeats-containing protein) (SCF(Slimb/beta-TrCP)) as the E3 ubiquitin ligase complex responsible for Ex degradation. Thus, Crb is part of a homeostatic mechanism that promotes Ex inhibition of Yki, but also limits Ex activity by inducing its degradation, allowing precise tuning of Yki function. PMID- 24778257 TI - Arabidopsis ABCG14 is essential for the root-to-shoot translocation of cytokinin. AB - Cytokinins are phytohormones that induce cytokinesis and are essential for diverse developmental and physiological processes in plants. Cytokinins of the trans-zeatin type are mainly synthesized in root vasculature and transported to the shoot, where they regulate shoot growth. However, the mechanism of long distance transport of cytokinin was hitherto unknown. Here, we report that the Arabidopsis ATP-binding cassette (ABC) transporter subfamily G14 (AtABCG14) is mainly expressed in roots and plays a major role in delivering cytokinins to the shoot. Loss of AtABCG14 expression resulted in severe shoot growth retardation, which was rescued by exogenous trans-zeatin application. Cytokinin content was decreased in the shoots of atabcg14 plants and increased in the roots, with consistent changes in the expression of cytokinin-responsive genes. Grafting of atabcg14 scions onto wild-type rootstocks restored shoot growth, whereas wild type scions grafted onto atabcg14 rootstocks exhibited shoot growth retardation similar to that of atabcg14. Cytokinin concentrations in the xylem are reduced by ~90% in the atabcg14 mutant. These results indicate that AtABCG14 is crucial for the translocation of cytokinin to the shoot. Our results provide molecular evidence for the long-distance transport of cytokinin and show that this transport is necessary for normal shoot development. PMID- 24778258 TI - Evolutionary history of redox metal-binding domains across the tree of life. AB - Oxidoreductases mediate electron transfer (i.e., redox) reactions across the tree of life and ultimately facilitate the biologically driven fluxes of hydrogen, carbon, nitrogen, oxygen, and sulfur on Earth. The core enzymes responsible for these reactions are ancient, often small in size, and highly diverse in amino acid sequence, and many require specific transition metals in their active sites. Here we reconstruct the evolution of metal-binding domains in extant oxidoreductases using a flexible network approach and permissive profile alignments based on available microbial genome data. Our results suggest there were at least 10 independent origins of redox domain families. However, we also identified multiple ancient connections between Fe2S2- (adrenodoxin-like) and heme- (cytochrome c) binding domains. Our results suggest that these two iron containing redox families had a single common ancestor that underwent duplication and divergence. The iron-containing protein family constitutes ~50% of all metal containing oxidoreductases and potentially catalyzed redox reactions in the Archean oceans. Heme-binding domains seem to be derived via modular evolutionary processes that ultimately form the backbone of redox reactions in both anaerobic and aerobic respiration and photosynthesis. The empirically discovered network allows us to peer into the ancient history of microbial metabolism on our planet. PMID- 24778259 TI - Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. AB - Neurosteroids are synthesized within the brain and act as endogenous anxiolytic, anticonvulsant, hypnotic, and sedative agents, actions that are principally mediated via their ability to potentiate phasic and tonic inhibitory neurotransmission mediated by gamma-aminobutyric acid type A receptors (GABAARs). Although neurosteroids are accepted allosteric modulators of GABAARs, here we reveal they exert sustained effects on GABAergic inhibition by selectively enhancing the trafficking of GABAARs that mediate tonic inhibition. We demonstrate that neurosteroids potentiate the protein kinase C-dependent phosphorylation of S443 within alpha4 subunits, a component of GABAAR subtypes that mediate tonic inhibition in many brain regions. This process enhances insertion of alpha4 subunit-containing GABAAR subtypes into the membrane, resulting in a selective and sustained elevation in the efficacy of tonic inhibition. Therefore, the ability of neurosteroids to modulate the phosphorylation and membrane insertion of alpha4 subunit-containing GABAARs may underlie the profound effects these endogenous signaling molecules have on neuronal excitability and behavior. PMID- 24778260 TI - Unusually long-lived pause required for regulation of a Rho-dependent transcription terminator. AB - Up to half of all transcription termination events in bacteria rely on the RNA dependent helicase Rho. However, the nucleic acid sequences that promote Rho dependent termination remain poorly characterized. Defining the molecular determinants that confer Rho-dependent termination is especially important for understanding how such terminators can be regulated in response to specific signals. Here, we identify an extraordinarily long-lived pause at the site where Rho terminates transcription in the 5'-leader region of the Mg(2+) transporter gene mgtA in Salmonella enterica. We dissect the sequence elements required for prolonged pausing in the mgtA leader and establish that the remarkable longevity of this pause is required for a riboswitch to stimulate Rho-dependent termination in the mgtA leader region in response to Mg(2+) availability. Unlike Rho dependent terminators described previously, where termination occurs at multiple pause sites, there is a single site of transcription termination directed by Rho in the mgtA leader. Our data suggest that Rho-dependent termination events that are subject to regulation may require elements distinct from those operating at constitutive Rho-dependent terminators. PMID- 24778261 TI - Gait synchronization in Caenorhabditis elegans. AB - Collective motion is observed in swarms of swimmers of various sizes, ranging from self-propelled nanoparticles to fish. The mechanisms that govern interactions among individuals are debated, and vary from one species to another. Although the interactions among relatively large animals, such as fish, are controlled by their nervous systems, the interactions among microorganisms, which lack nervous systems, are controlled through physical and chemical pathways. Little is known, however, regarding the mechanism of collective movements in microscopic organisms with nervous systems. To attempt to remedy this, we studied collective swimming behavior in the nematode Caenorhabditis elegans, a microorganism with a compact nervous system. We evaluated the contributions of hydrodynamic forces, contact forces, and mechanosensory input to the interactions among individuals. We devised an experiment to examine pair interactions as a function of the distance between the animals and observed that gait synchronization occurred only when the animals were in close proximity, independent of genes required for mechanosensation. Our measurements and simulations indicate that steric hindrance is the dominant factor responsible for motion synchronization in C. elegans, and that hydrodynamic interactions and genotype do not play a significant role. We infer that a similar mechanism may apply to other microscopic swimming organisms and self-propelled particles. PMID- 24778263 TI - Capping protein regulatory cycle driven by CARMIL and V-1 may promote actin network assembly at protruding edges. AB - Although capping protein (CP) terminates actin filament elongation, it promotes Arp2/3-dependent actin network assembly and accelerates actin-based motility both in vitro and in vivo. In vitro, capping protein Arp2/3 myosin I linker (CARMIL) antagonizes CP by reducing its affinity for the barbed end and by uncapping CP capped filaments, whereas the protein V-1/myotrophin sequesters CP in an inactive complex. Previous work showed that CARMIL can readily retrieve CP from the CP:V-1 complex, thereby converting inactive CP into a version with moderate affinity for the barbed end. Here we further clarify the mechanism of this exchange reaction, and we demonstrate that the CP:CARMIL complex created by complex exchange slows the rate of barbed-end elongation by rapidly associating with, and dissociating from, the barbed end. Importantly, the cellular concentrations of V-1 and CP determined here argue that most CP is sequestered by V-1 at steady state in vivo. Finally, we show that CARMIL is recruited to the plasma membrane and only at cell edges undergoing active protrusion. Assuming that CARMIL is active only at this location, our data argue that a large pool of freely diffusing, inactive CP (CP:V 1) feeds, via CARMIL-driven complex exchange, the formation of weak-capping complexes (CP:CARMIL) at the plasma membrane of protruding edges. In vivo, therefore, CARMIL should promote Arp2/3-dependent actin network assembly at the leading edge by promoting barbed-end capping there. PMID- 24778262 TI - Cav3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage. AB - Intracellular Ca(2+) transient is crucial in initiating the differentiation of mesenchymal cells into chondrocytes, but whether voltage-gated Ca(2+) channels are involved remains uncertain. Here, we show that the T-type voltage-gated Ca(2+) channel Cav3.2 is essential for tracheal chondrogenesis. Mice lacking this channel (Cav3.2(-/-)) show congenital tracheal stenosis because of incomplete formation of cartilaginous tracheal support. Conversely, Cav3.2 overexpression in ATDC5 cells enhances chondrogenesis, which could be blunted by both blocking T type Ca(2+) channels and inhibiting calcineurin and suggests that Cav3.2 is responsible for Ca(2+) influx during chondrogenesis. Finally, the expression of sex determination region of Y chromosome (SRY)-related high-mobility group-Box gene 9 (Sox9), one of the earliest markers of committed chondrogenic cells, is reduced in Cav3.2(-/-) tracheas. Mechanistically, Ca(2+) influx via Cav3.2 activates the calcineurin/nuclear factor of the activated T-cell (NFAT) signaling pathway, and a previously unidentified NFAT binding site is identified within the mouse Sox9 promoter using a luciferase reporter assay and gel shift and ChIP studies. Our findings define a previously unidentified mechanism that Ca(2+) influx via the Cav3.2 T-type Ca(2+) channel regulates Sox9 expression through the calcineurin/NFAT signaling pathway during tracheal chondrogenesis. PMID- 24778264 TI - Electrostatics, hydration, and proton transfer dynamics in the membrane domain of respiratory complex I. AB - Complex I serves as the primary electron entry point into the mitochondrial and bacterial respiratory chains. It catalyzes the reduction of quinones by electron transfer from NADH, and couples this exergonic reaction to the translocation of protons against an electrochemical proton gradient. The membrane domain of the enzyme extends ~180 A from the site of quinone reduction to the most distant proton pathway. To elucidate possible mechanisms of the long-range proton-coupled electron transfer process, we perform large-scale atomistic molecular dynamics simulations of the membrane domain of complex I from Escherichia coli. We observe spontaneous hydration of a putative proton entry channel at the NuoN/K interface, which is sensitive to the protonation state of buried glutamic acid residues. In hybrid quantum mechanics/classical mechanics simulations, we find that the observed water wires support rapid proton transfer from the protein surface to the center of the membrane domain. To explore the functional relevance of the pseudosymmetric inverted-repeat structures of the antiporter-like subunits NuoL/M/N, we constructed a symmetry-related structure of a possible alternate access state. In molecular dynamics simulations, we find the resulting structural changes to be metastable and reversible at the protein backbone level. However, the increased hydration induced by the conformational change persists, with water molecules establishing enhanced lateral connectivity and pathways for proton transfer between conserved ionizable residues along the center of the membrane domain. Overall, the observed water-gated transitions establish conduits for the unidirectional proton translocation processes, and provide a possible coupling mechanism for the energy transduction in complex I. PMID- 24778265 TI - Bone Plug Versus Suture-Only Fixation of Meniscal Grafts: Effect on Joint Contact Mechanics During Simulated Gait. AB - BACKGROUND: Meniscus allograft transplantation (MAT) is primarily undertaken to relieve the symptoms associated with meniscal deficiencies. However, its ability to restore normal knee joint contact mechanics under physiological loads is still unclear. PURPOSE: To quantify the dynamic contact mechanics associated with 2 commonly used fixation techniques in MAT of the medial compartment: transosseous suture fixation via bone plugs and suture-only fixation at the horns. STUDY DESIGN: Controlled laboratory study. METHODS: Physiological loads to mimic gait were applied across 7 human cadaveric knees on a simulator. A sensor placed on the medial tibial plateau recorded dynamic contact stresses under the following conditions: (1) intact meniscus, (2) MAT using transosseous suture fixation via bone plugs at the anterior and posterior horns, (3) MAT using suture-only fixation, and (4) total medial meniscectomy. A "remove-replace" procedure was performed to place the same autograft for both MAT conditions to minimize the variability in graft size, geometry, and material property and to isolate the effects of the fixation technique. Contact stress, contact area, and weighted center of contact stress (WCoCS) were quantified on the medial plateau throughout the stance phase. RESULTS: Knee joint contact mechanics were sensitive to the meniscal condition primarily during the first half of the gait cycle. After meniscectomy, the mean peak contact stress increased from 4.2 +/- 1.2 MPa to 6.2 +/- 1.0 MPa (P = .04), and the mean contact area decreased from 546 +/- 132 mm2 to 192 +/- 122 mm2 (P = .01) compared with the intact meniscus during early stance (14% of the gait cycle). After MAT, the mean contact stress significantly decreased with bone plug fixation (5.0 +/- 0.7 MPa) but not with suture-only fixation (5.9 +/- 0.7 MPa). Both fixation techniques partially restored the contact area, but bone plug fixation restored it closer to the intact condition. The location of WCoCS in the central cartilage region (not covered by the meniscus) shifted peripherally throughout the stance phase. Bone plug fixation exhibited correction to this peripheral offset, but suture-only fixation did not. CONCLUSION: Under dynamic loading, transosseous fixation at the meniscal horns provides superior load distribution at the involved knee compartment after meniscal transplantation compared with suture-only fixation. Particular attention should be directed to the ability of medial MAT to function during the early stance phase. CLINICAL RELEVANCE: Transosseous fixation via bone plugs provides superior load distribution of a transplanted meniscal allograft compared with suture fixation alone at time zero. PMID- 24778266 TI - Surgical Predictors of Early Revision Surgery After Anterior Cruciate Ligament Reconstruction: Results From the Swedish National Knee Ligament Register on 13,102 Patients. AB - BACKGROUND: An important objective of anterior cruciate ligament (ACL) registries is to detect and report early graft failure and revision surgery after ACL reconstruction. PURPOSE: To investigate surgical variables and identify predictors of revision surgery after ACL reconstruction. STUDY DESIGN: Prospective cohort study; Level of evidence, 2. METHODS: This prospective cohort study was based on data from the Swedish National Knee Ligament Register during the years 2005 through 2011. Eight surgical variables were investigated: graft selection, graft width, single-bundle or double-bundle techniques, femoral graft fixation, tibial graft fixation, injury-to-surgery interval, injuries to menisci, and injuries to cartilage. The primary endpoint was the 2-year incidence of revision surgery. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated and adjusted for confounders by use of multivariate statistics. RESULTS: A total of 13,102 patients were included (5541 women [42%] and 7561 men [58%]; P < .001). Hamstring tendon autografts accounted for 90% (11,764 patients) of all reconstructions, of which 96% were performed with a single-bundle technique (11,339 patients). Patellar tendon autografts accounted for the remaining 10% (1338 patients). At index reconstruction, observed injuries to menisci and cartilage were common (40% and 28%, respectively). The overall 2-year incidence of revision surgery was 1.60% (women, 1.57%; men, 1.63%; P = .854). Patients with metal interference screw fixation of a semitendinosus tendon autograft on the tibia had a significantly reduced risk of early revision surgery (RR = 0.32; 95% CI, 0.12-0.90; P = .031). CONCLUSION: Metal interference screw fixation of a semitendinosus tendon autograft on the tibia was an independent predictor of significantly lower 2-year incidence of revision surgery. Graft selection, graft width, a single-bundle or a double-bundle technique, femoral graft fixation, the injury-to-surgery interval, and meniscus injury were not predictors of early revision surgery. PMID- 24778267 TI - Treatment of Large Knee Osteochondral Lesions With a Biomimetic Scaffold: Results of a Multicenter Study of 49 Patients at 2-Year Follow-up. AB - BACKGROUND: Osteochondral knee lesions represent a challenging condition encountered by orthopaedic surgeons. A variety of methods have been developed to repair articular cartilage defects. However, these techniques are limited by donor site morbidity or by the requirement for a staged procedure. PURPOSE: To assess the effectiveness of a biomimetic osteochondral scaffold for the treatment of large osteochondral knee lesions. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From 2009 to 2011, a total of 49 patients affected by isolated large osteochondral knee lesions (mean [+/- SD] size, 4.35 +/- 1.26 cm2) were treated with the biomimetic scaffold. Patients were evaluated using the International Knee Documentation Committee (IKDC), Tegner, and visual analog scale (VAS) pain scores, as well as magnetic resonance imaging (MRI) up to 3-year follow-up. The MOCART (magnetic resonance observation of cartilage repair tissue) score was performed to analyze different variables. Biopsies were carried out in 5 patients. Four of the 5 second-look arthroscopies and biopsies were performed on patients with failed results because of ethical issues. RESULTS: The mean IKDC subjective score increased significantly from 45.45 +/- 19.29 preoperatively to 70.86 +/- 18.08 at 1-year follow-up and to 75.42 +/- 19.31 at 2-year follow-up (P < .001). The IKDC objective score changed from 50% normal and nearly normal knees before treatment to 89.79% at the 2-year follow-up. There was a statistically significant improvement (P < .005) in VAS score from the preoperative level (6.69 +/- 1.88) to the 2-year follow-up (1.96 +/- 2.47). Tegner scores increased (P < .001) from the preoperative value (2.20 +/- 0.67) to the 2-year follow-up (4.9 +/ 1.73) without achieving preinjury level. A correlation was found between the IKDC subjective score and age (P < .001, r = -0.497, rho = -0.502). Patients affected by osteochondritis dissecans (OCD) achieved a statistically significantly better outcome (P < .05). A subgroup of 19 competitive athletes showed a statistically significantly improvement (P < .001) in the subjective IKDC (86.5 +/- 13.2) compared with the nonathletic subpopulation (69.03 +/- 19.41) at the 2-year follow-up. The MRI findings of 30 patients were available at 2-year follow-up: 70% showed complete filling of the lesion, 63.3% had an intact articular surface, and 86% had mild or no effusion. In all cases, in dual T2 weighted fast spin echo sequence, the repair tissue showed a hyperintensive signal with respect to the surrounding subchondral bone; however, no edema was observed. CONCLUSION: The study findings indicate that the biomimetic scaffold that was investigated is an off-the-shelf, cell-free, and cost-effective implant that can regenerate either cartilage or subchondral bone. The scaffold allows a 1 step surgical procedure that can be used for osteochondral lesions, OCD, and in some cases osteonecrosis. PMID- 24778268 TI - Improvements on Cardiovascular Diseases Risk Factors in Obese Adolescents: A Randomized Exercise Intervention Study. AB - BACKGROUND: It is unclear how different exercise intensities affect cardiovascular disease (CVD) risk factors in obese adolescents. The aim of this study was to compare the effects of high-intensity (HIT) vs. low-intensity (LIT) aerobic training on CVD risk factors in obese adolescents. METHODS: Forty-three obese adolescents (age: 15.7 +/- 1.3 years, BMI: 34.3 +/- 4.1 kg/m(2)) participated this study either HIT (corresponding to ventilatory threshold I; N = 20) or LIT (20% below ventilatory threshold I; N = 23) for 12 weeks. All sessions were isocaloric (350 kcal). All participants received the same nutritional, psychological, and clinical counseling. Subjects were assessed in fatness, fitness, lipid profile, and glucose at baseline and after 12 weeks. The CVD risk factors assessed were waist circumference (WC), total cholesterol (TC), high density lipoprotein (HDL), glucose, and fitness, which were single and clustered analyzed (z scores sum). RESULTS: Body mass, Body Mass Index, fatness, and WC were improved (P < .001) in both groups. The sum of z scores (WC + TC + glucose fitness-HDL) improved in both HIT (12 weeks = -2.16 SD; Cohen's d = .45) and LIT (12 weeks = -2.13 SD; Cohen's d = .60) without groups differences. Changes in fitness were associated with changes in WC (r = -.48; P = .003). CONCLUSION: HIT does not promote any additional improvements in CVD risk factors than LIT in obese adolescents. PMID- 24778269 TI - UK Research Paper of the Year: evidence that matters. PMID- 24778273 TI - CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. AB - Research over the past decade has revealed the increasingly complex biologic features of the CD4(+) T-cell lineage. This T-cell subset, which was originally defined on the basis of helper activity in antibody responses, expresses receptors that recognize peptides that have been processed and presented by specialized antigen-presenting cells. At the core of the adaptive immune response, CD4 T cells display a large degree of plasticity and the ability to differentiate into multiple sublineages in response to developmental and environmental cues. These differentiated sublineages can orchestrate a broad range of effector activities during the initiation, expansion, and memory phase of an immune response. The contribution of CD4 cells to host defense against pathogenic invasion and regulation of autoimmunity is now well established. Emerging evidence suggests that CD4 cells also actively participate in shaping antitumor immunity. Here, we outline the biologic properties of CD4 T-cell subsets with an emphasis on their contribution to the antitumor response. PMID- 24778270 TI - The clinical approach to small fibre neuropathy and painful channelopathy. AB - Small fibre neuropathy (SFN) is characterised by structural injury selectively affecting small diameter sensory and/or autonomic axons. The clinical presentation is dominated by pain. SFN complicates a number of common diseases such as diabetes mellitus and is likely to be increasingly encountered. The diagnosis of SFN is demanding as clinical features can be vague and nerve conduction studies normal. New diagnostic techniques, in particular measurement of intraepidermal nerve fibre density, have significantly improved the diagnostic efficiency of SFN. Management is focused on the treatment of the underlying cause and analgesia, as there is no neuroprotective therapy. A recent and significant advance is the finding that a proportion of cases labelled as idiopathic SFN are in fact associated with gain of function mutations of the voltage-gated sodium channels Nav1.7 and Nav1.8 (encoded by the genes SCN9A and SCN10A, respectively). There is a further group of heritable painful conditions in which gain of function mutations in ion channels alter excitability of sensory neurones but do not cause frank axon degeneration; these include mutations in Nav1.7 (causing erythromelalgia and paroxysmal extreme pain disorder) and TRPA1 (resulting in familial episodic pain disorder). These conditions are exceptionally rare but have provided great insight into the nociceptive system as well as yielding potential analgesic drug targets. In patients with no pre-existing risk factor, the investigation of an underlying cause of SFN should be systematic and appropriate for the patient population. In this review, we focus on how to incorporate recent developments in the diagnosis and pathophysiology of SFN into clinical practice. PMID- 24778274 TI - The Cancer Research Institute 2013 Annual Symposium: Dynamics of host-tumor interaction. AB - The 21st annual Cancer Research Institute (CRI) cancer immunotherapy symposium, entitled "Dynamics of Host-Tumor Interaction," was held in New York City from September 30 through October 2, 2013. The symposium comprised 27 presentations, organized into five sessions and exploring such topics as the role of chronic inflammation in creating a protumorigenic microenvironment, the interactions between the cancer stroma and immune cells in trafficking and cancer metastasis, the role of the host microbiota in immune responses to cancer, and the interactions between cancer cells and immunoregulatory elements, including regulatory T cells and T-cell checkpoint proteins. The conference began with a keynote address by Michael Karin, recipient of the 2013 Coley Award, who discussed the role of inflammation as a Janus-faced process in the body's fight against cancer-both tumor destroying and tumor promoting. The conference concluded with a session on therapeutics and translational research aimed at improving existing cancer immunotherapies. PMID- 24778275 TI - Tumoral immune suppression by macrophages expressing fibroblast activation protein-alpha and heme oxygenase-1. AB - The depletion of tumor stromal cells that are marked by their expression of the membrane protein fibroblast activation protein-alpha (FAP) overcomes immune suppression and allows an anticancer cell immune response to control tumor growth. In subcutaneous tumors established with immunogenic Lewis lung carcinoma cells expressing ovalbumin (LL2/OVA), the FAP(+) population is comprised of CD45(+) and CD45(-) cells. In the present study, we further characterize the tumoral FAP(+)/CD45(+) population as a minor subpopulation of F4/80(hi)/CCR2(+)/CD206(+) M2 macrophages. Using bone marrow chimeric mice in which the primate diphtheria toxin receptor is restricted either to the FAP(+)/CD45(+) or to the FAP(+)/CD45(-) subset, we demonstrate by conditionally depleting each subset that both independently contribute to the immune suppressive tumor microenvironment. A basis for the function of the FAP(+)/CD45(+) subset is shown to be the immune inhibitory enzyme, heme oxygenase 1 (HO-1). The FAP(+)/CD45(+) cells are the major tumoral source of HO-1, and an inhibitor of HO-1, Sn mesoporphyrin, causes the same extent of immune-dependent arrest of LL2/OVA tumor growth as does the depletion of these cells. Because this observation of immune suppression by HO-1 expressed by the FAP(+)/CD45(+) stromal cell is replicated in a transplanted model of pancreatic ductal adenocarcinoma, we conclude that pharmacologically targeting this enzyme may improve cancer immunotherapy. PMID- 24778276 TI - Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab. AB - Ipilimumab, an antibody that blocks CTL antigen 4 (CTLA-4), improves overall survival (OS) for patients with metastatic melanoma. Given its role in angiogenesis and immune evasion, serum VEGF levels were evaluated for association with clinical benefit in ipilimumab-treated patients. Sera were collected from 176 patients treated at 3 (n = 98) or 10 mg/kg (n = 68). The VEGF levels before treatment and at induction completion (week 12) were analyzed using the Meso Scale Discovery kit. The association of the levels of VEGF with clinical responses and OS were assessed using the Fisher exact and Kaplan-Meier log-rank tests. VEGF as a continuous variable was associated with OS (P = 0.002). Using 43 pg/mL as the cutoff pretreatment VEGF value defined by maximally selected log rank statistics, pretreatment VEGF values correlated with clinical benefit at week 24 (P = 0.019; 159 patients evaluable). Pretreatment VEGF >= 43 pg/mL was associated with decreased OS (median OS 6.6 vs. 12.9 months, P = 0.006; 7.4 vs. 14.3 months, P = 0.037 for 3 mg/kg; and 6.2 vs. 10.9 months, P = 0.048 for 10 mg/kg). There was no correlation between VEGF changes and clinical outcome. Serum VEGF may be a predictive biomarker for ipilimumab treatment and is worthy of prospective investigation with various forms of immunologic checkpoint blockade. PMID- 24778277 TI - Immune impact induced by PROSTVAC (PSA-TRICOM), a therapeutic vaccine for prostate cancer. AB - PSA-TRICOM (PROSTVAC) is a novel vector-based vaccine designed to generate a robust immune response against prostate-specific antigen (PSA)-expressing tumor cells. The purpose of this report is to present an overview of both published studies and new data in the evaluation of immune responses to the PSA-TRICOM vaccine platform, currently in phase III testing. Of 104 patients tested for T cell responses, 57% (59/104) demonstrated a >= 2-fold increase in PSA-specific T cells 4 weeks after vaccine (median 5-fold increase) compared with pre-vaccine, and 68% (19/28) of patients tested mounted post-vaccine immune responses to tumor associated antigens not present in the vaccine (antigen spreading). The PSA specific immune responses observed 28 days after vaccine (i.e., likely memory cells) are quantitatively similar to the levels of circulating T cells specific for influenza seen in the same patients. Measurements of systemic immune response to PSA may underestimate the true therapeutic immune response (as this does not account for cells that have trafficked to the tumor) and does not include antigen spreading. Furthermore, although the entire PSA gene is the vaccine, only one epitope of PSA is evaluated in the T-cell responses. Because this therapeutic vaccine is directed at generating a cellular/Th1 immune response (T-cell costimulatory molecules and use of a viral vector), it is not surprising that less than 0.6% of patients (2/349) tested have evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. An ongoing phase III study will evaluate the systemic immune responses and correlation with clinical outcomes. PMID- 24778278 TI - Combined targeting of costimulatory (OX40) and coinhibitory (CTLA-4) pathways elicits potent effector T cells capable of driving robust antitumor immunity. AB - Ligation of the TNF receptor family costimulatory molecule OX40 (CD134) with an agonist anti-OX40 monoclonal antibody (mAb) enhances antitumor immunity by augmenting T-cell differentiation as well as turning off the suppressive activity of the FoxP3(+)CD4(+) regulatory T cells (Treg). In addition, antibody-mediated blockade of the checkpoint inhibitor CTLA-4 releases the "brakes" on T cells to augment tumor immunotherapy. However, monotherapy with these agents has limited therapeutic benefit particularly against poorly immunogenic murine tumors. Therefore, we examined whether the administration of agonist anti-OX40 therapy in the presence of CTLA-4 blockade would enhance tumor immunotherapy. Combined anti OX40/anti-CTLA-4 immunotherapy significantly enhanced tumor regression and the survival of tumor-bearing hosts in a CD4 and CD8 T cell-dependent manner. Mechanistic studies revealed that the combination immunotherapy directed the expansion of effector T-bet(high)/Eomes(high) granzyme B(+) CD8 T cells. Dual immunotherapy also induced distinct populations of Th1 [interleukin (IL)-2, IFN gamma], and, surprisingly, Th2 (IL-4, IL-5, and IL-13) CD4 T cells exhibiting increased T-bet and Gata-3 expression. Furthermore, IL-4 blockade inhibited the Th2 response, while maintaining the Th1 CD4 and effector CD8 T cells that enhanced tumor-free survival. These data demonstrate that refining the global T cell response during combination immunotherapy can further enhance the therapeutic efficacy of these agents. PMID- 24778279 TI - Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. AB - The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8alpha hinge and transmembrane regions, and the human CD3zeta and 4 1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-gamma and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8(+) T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted. PMID- 24778281 TI - Microvesicle cargo of tumor-associated MUC1 to dendritic cells allows cross presentation and specific carbohydrate processing. AB - Tumor-associated glycoproteins are a group of antigens with high immunogenic interest: The glycoforms generated by the aberrant glycosylation are tumor specific and the novel glycoepitopes exposed can be targets of tumor-specific immune responses. The MUC1 antigen is one of the most relevant tumor-associated glycoproteins. In cancer, MUC1 loses polarity and becomes overexpressed and hypoglycosylated. Changes in glycan moieties contribute to MUC1 immunogenicity and can modify the interactions of tumor cells with antigen-presenting cells such as dendritic cells that would affect the overall antitumor immune response. Here, we show that the form of the MUC1 antigen, i.e., soluble or as microvesicle cargo, influences MUC1 processing in dendritic cells. In fact, MUC1 carried by microvesicles translocates from the endolysosomal/HLA-II to the HLA-I compartment and is presented by dendritic cells to MUC1-specific CD8(+) T cells stimulating IFN-gamma responses, whereas the soluble MUC1 is retained in the endolysosomal/HLA-II compartment independently by the glycan moieties and by the modality of internalization (receptor-mediated or non-receptor mediated). MUC1 translocation to the HLA-I compartment is accompanied by deglycosylation that generates novel MUC1 glycoepitopes. Microvesicle-mediated transfer of tumor associated glycoproteins to dendritic cells may be a relevant biologic mechanism in vivo contributing to define the type of immunogenicity elicited. Furthermore, these results have important implications for the design of glycoprotein-based immunogens for cancer immunotherapy. PMID- 24778280 TI - CD4 T cells require ICOS-mediated PI3K signaling to increase T-Bet expression in the setting of anti-CTLA-4 therapy. AB - The transcription factor T-bet controls the Th1 genetic program in T cells for effective antitumor responses. Anti-CTLA-4 immunotherapy elicits dramatic antitumor responses in mice and in human patients; however, factors that regulate T-bet expression during an antitumor response mediated by anti-CTLA-4 remain to be elucidated. We were the first to report that treatment with anti-CTLA-4 led to an increase in the frequency of T cells expressing inducible costimulator (ICOS). In both treated patients and mice, our data revealed that CD4(+)ICOS(hi) T cells can act as effector T cells, which produce the Th1 cytokine IFN-gamma. We also showed in a small retrospective analysis that an increased frequency of CD4(+)ICOS(hi) T cells correlated with better clinical outcome and the absence of ICOS or its ligand (ICOSL) in mouse models led to impaired tumor rejection. Here, we show that CD4(+)ICOS(hi) T cells from anti-CTLA-4-treated patients had an increase in signaling via the phospoinositide-3-kinase (PI3K) pathway and an increase in expression of T-bet. An ICOS-specific siRNA transfected into human T cells led to diminished PI3K signaling and T-bet expression. Therefore, we hypothesized that ICOS, and specifically ICOS-mediated PI3K signaling, was required for T-bet expression. We conducted studies in ICOS-deficient and ICOS-YF mice, which have a single amino acid change that abrogates PI3K signaling by ICOS. We found that ICOS-mediated PI3K signaling is required for T-bet expression during an antitumor response elicited by anti-CTLA-4 therapy. Our data provide new insight into the regulation of T-bet expression and suggest that ICOS can be targeted to improve Th1 antitumor responses. PMID- 24778282 TI - WHO voices concern over rising numbers of MERS-CoV cases. PMID- 24778283 TI - Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To determine the efficacy of medical marijuana in several neurologic conditions. METHODS: We performed a systematic review of medical marijuana (1948 November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders. We graded the studies according to the American Academy of Neurology classification scheme for therapeutic articles. RESULTS: Thirty-four studies met inclusion criteria; 8 were rated as Class I. CONCLUSIONS: The following were studied in patients with MS: (1) Spasticity: oral cannabis extract (OCE) is effective, and nabiximols and tetrahydrocannabinol (THC) are probably effective, for reducing patient-centered measures; it is possible both OCE and THC are effective for reducing both patient-centered and objective measures at 1 year. (2) Central pain or painful spasms (including spasticity related pain, excluding neuropathic pain): OCE is effective; THC and nabiximols are probably effective. (3) Urinary dysfunction: nabiximols is probably effective for reducing bladder voids/day; THC and OCE are probably ineffective for reducing bladder complaints. (4) Tremor: THC and OCE are probably ineffective; nabiximols is possibly ineffective. (5) Other neurologic conditions: OCE is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease. Oral cannabinoids are of unknown efficacy in non-chorea-related symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy. The risks and benefits of medical marijuana should be weighed carefully. Risk of serious adverse psychopathologic effects was nearly 1%. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications. PMID- 24778284 TI - Ophthalmic nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy. PMID- 24778285 TI - How experienced community neurologists make diagnoses during clinical encounters. PMID- 24778286 TI - Gait speed in Parkinson disease correlates with cholinergic degeneration. PMID- 24778289 TI - Mystery Case: pendular see-saw nystagmus as a delayed complication of traumatic brain injury. PMID- 24778290 TI - Pearls & Oy-sters: rapidly progressive dementia: prions or immunomediated? PMID- 24778291 TI - Teaching NeuroImages: sonographic "retrobulbar spot sign" in differentiating etiologies of sudden visual loss. PMID- 24778292 TI - The RESTORE trial: what did we learn about multiple sclerosis? PMID- 24778293 TI - Use of e-cigarettes in UK has tripled in two years, finds survey. PMID- 24778296 TI - US drug firm Pfizer seeks to buy UK company AstraZeneca. PMID- 24778295 TI - Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. AB - BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature. METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out. RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 +/- 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia. CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered. PMID- 24778297 TI - Jeremy Hunt interferes too much in day to day running of NHS, stakeholders say. PMID- 24778298 TI - Labour Party calls for action as a fifth of hospitals fail inspections. PMID- 24778299 TI - A neonatal agranulocytosis. PMID- 24778300 TI - Commentary. PMID- 24778301 TI - Commentary. PMID- 24778302 TI - Herpesviruses encode their own microRNAs. PMID- 24778303 TI - Which protein bands are significant? PMID- 24778304 TI - Where has all the beta1-transferrin gone? PMID- 24778305 TI - Personalized therapeutics and companion diagnostics: a new paradigm in testing and treatment. PMID- 24778306 TI - Interpretation of Alvin Coburn's The Bridge, Venice in pen and ink. PMID- 24778307 TI - Physicians, scientists, and the wider culture: Sir William Osler. PMID- 24778308 TI - Health ombudsman should be given more powers, MPs say. PMID- 24778309 TI - Alex Mogilner: math illuminates biology. PMID- 24778310 TI - Contractile forces regulate cell division in three-dimensional environments. AB - Physical forces direct the orientation of the cell division axis for cells cultured on rigid, two-dimensional (2D) substrates. The extent to which physical forces regulate cell division in three-dimensional (3D) environments is not known. Here, we combine live-cell imaging with digital volume correlation to map 3D matrix displacements and identify sites at which cells apply contractile force to the matrix as they divide. Dividing cells embedded in fibrous matrices remained anchored to the matrix by long, thin protrusions. During cell rounding, the cells released adhesive contacts near the cell body while applying tensile forces at the tips of the protrusions to direct the orientation of the cell division axis. After cytokinesis, the daughter cells respread into matrix voids and invaded the matrix while maintaining traction forces at the tips of persistent and newly formed protrusions. Mechanical interactions between cells and the extracellular matrix constitute an important mechanism for regulation of cell division in 3D environments. PMID- 24778311 TI - PKA-dependent dynein switching from lysosomes to adenovirus: a novel form of host virus competition. AB - Cytoplasmic dynein is responsible for transport of several viruses to the nucleus. Adenovirus recruits dynein directly. Transport depends on virus-induced activation of protein kinase A (PKA) and other cellular protein kinases, whose roles in infection are poorly understood. We find that PKA phosphorylates cytoplasmic dynein at a novel site in light intermediate chain 1 (LIC1) that is essential for dynein binding to the hexon capsid subunit and for virus motility. Surprisingly, the same LIC1 modification induces a slow, but specific, dispersal of lysosomes (lyso)/late endosomes (LEs) that is mediated by inhibition of a newly identified LIC1 interaction with the RILP (Rab7-interacting lysosomal protein). These results identify an organelle-specific dynein regulatory modification that adenovirus uses for its own transport. PKA-mediated LIC1 phosphorylation causes only partial lyso/LE dispersal, suggesting a role for additional, parallel mechanisms for dynein recruitment to lyso/LEs. This arrangement provides a novel means to fine tune transport of these organelles in response to infection as well as to developmental and physiological cues. PMID- 24778312 TI - A novel Netrin-1-sensitive mechanism promotes local SNARE-mediated exocytosis during axon branching. AB - Developmental axon branching dramatically increases synaptic capacity and neuronal surface area. Netrin-1 promotes branching and synaptogenesis, but the mechanism by which Netrin-1 stimulates plasma membrane expansion is unknown. We demonstrate that SNARE-mediated exocytosis is a prerequisite for axon branching and identify the E3 ubiquitin ligase TRIM9 as a critical catalytic link between Netrin-1 and exocytic SNARE machinery in murine cortical neurons. TRIM9 ligase activity promotes SNARE-mediated vesicle fusion and axon branching in a Netrin dependent manner. We identified a direct interaction between TRIM9 and the Netrin 1 receptor DCC as well as a Netrin-1-sensitive interaction between TRIM9 and the SNARE component SNAP25. The interaction with SNAP25 negatively regulates SNARE mediated exocytosis and axon branching in the absence of Netrin-1. Deletion of TRIM9 elevated exocytosis in vitro and increased axon branching in vitro and in vivo. Our data provide a novel model for the spatial regulation of axon branching by Netrin-1, in which localized plasma membrane expansion occurs via TRIM9 dependent regulation of SNARE-mediated vesicle fusion. PMID- 24778314 TI - The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. AB - The fibroblastic element of the tumor microenvironment has been of great interest to cancer biologists but less so to cancer immunologists. Yet, the sharing of a common mesenchymal cell type in the stroma of tumors and at sites of chronic inflammatory lesions, some of which have an autoimmune basis, has been a strong hint that this cellular component of the tumor microenvironment may have an immunologic function. Recent studies have confirmed this possibility. These fibroblast-like cells, which are termed carcinoma-associated fibroblasts (CAF), can be identified by their expression of the membrane protein, fibroblast activation protein-alpha (FAP). The conditional depletion of the FAP(+) CAF permits immune control not only of an artificial, transplanted tumor, but also of an autochthonous model of pancreatic ductal adenocarcinoma (PDA) that replicates the molecular, histologic, clinical, and immunologic characteristics of the human disease. Immune suppression by the FAP(+) CAF is mediated by CXCL12, the chemokine that binds to cancer cells and excludes T cells by a mechanism that depends on signaling by the CXCL12 receptor CXCR4. Inhibition of CXCR4 leads to the elimination of cancer cells by enabling the rapid, intratumoral accumulation of preexisting, PDA-specific CD8(+) T cells, and reveals the antitumor efficacy of the T-cell checkpoint antagonist anti-PD-L1. Recent studies have also shown that the FAP(+) CAF is related to FAP-expressing stromal cells of normal tissues, demonstrating that cancers recruit a member of an essential stromal cell lineage that is involved not only in wound repair but also in normal tissue homeostasis. These findings extend the concept introduced by cancer biologists that the fibroblastic component of tumors has a critical role in the adaptation of the cancer to the host. PMID- 24778313 TI - Talin-bound NPLY motif recruits integrin-signaling adapters to regulate cell spreading and mechanosensing. AB - Integrin-dependent cell adhesion and spreading are critical for morphogenesis, tissue regeneration, and immune defense but also tumor growth. However, the mechanisms that induce integrin-mediated cell spreading and provide mechanosensing on different extracellular matrix conditions are not fully understood. By expressing beta3-GFP-integrins with enhanced talin-binding affinity, we experimentally uncoupled integrin activation, clustering, and substrate binding from its function in cell spreading. Mutational analysis revealed Tyr747, located in the first cytoplasmic NPLY(747) motif, to induce spreading and paxillin adapter recruitment to substrate- and talin-bound integrins. In addition, integrin-mediated spreading, but not focal adhesion localization, was affected by mutating adjacent sequence motifs known to be involved in kindlin binding. On soft, spreading-repellent fibronectin substrates, high-affinity talin-binding integrins formed adhesions, but normal spreading was only possible with integrins competent to recruit the signaling adapter protein paxillin. This proposes that integrin-dependent cell-matrix adhesion and cell spreading are independently controlled, offering new therapeutic strategies to modify cell behavior in normal and pathological conditions. PMID- 24778315 TI - IL-10: master switch from tumor-promoting inflammation to antitumor immunity. AB - Human cancer is characterized by deficits in antigen-specific immunity and intratumoral CD8(+) T cells. On the other hand, inflammatory macrophages and mediators of chronic inflammation are highly prevalent in patients with late stage cancer. Intratumoral T-cell deficiency and chronic inflammation have been linked independently to a poor prognosis in patients with cancer, and therapeutic approaches to overcome either pathology separately are in clinical testing. The anti-inflammatory cytokine interleukin (IL)-10 suppresses macrophage and proinflammatory Th17 T-cell responses by inhibiting the inflammatory cytokines IL 6 and IL-12/23. Corroborating the anti-inflammatory action of IL-10, deficiency in IL-10 leads to a stimulation of inflammatory responses and inflammatory bowel disease. The anti-inflammatory role of IL-10 fostered the assumption that IL-10 undermines the immune response to cancer. However, mice and humans deficient in IL-10 signaling develop tumors spontaneously and at high rates. Overexpression of IL-10 in models of human cancer or treatment with a pegylated IL-10 (PEG-IL-10) led to tumor rejection and long-lasting tumor immunity. IL-10 stimulates cytotoxicity of CD8(+) T cells and the expression of IFN-gamma in CD8(+) T cells. IL-10-induced tumor rejections are dependent on the expression of IFN-gamma and granzymes in tumor-resident CD8(+) T cells and the upregulation of MHC molecules. These findings reconcile earlier clinical data, which showed that recombinant IL 10 increased IFN-gamma and granzymes in the blood of treated individuals. PEG-IL 10 is therefore a unique therapeutic agent, which simultaneously stimulates antitumor immunity and inhibits tumor-associated inflammation. PMID- 24778316 TI - Transient complement inhibition promotes a tumor-specific immune response through the implication of natural killer cells. AB - Although the role of the complement system in cancer development has been studied, its involvement in the development of an antitumoral immune response remains poorly understood. Using cobra venom factor (CVF) to inhibit the complement cascade via C3 molecule exhaustion in immunocompetent mice bearing B16gp33 melanoma tumors, we show that transient inhibition of the complement system allowed for the development of a more robust gp33-specific antitumoral CD8(+) T-cell response. This immune response proved to be natural killer (NK) dependent, suggesting an interaction of complement proteins with this cellular subset leading to T lymphocyte activation and enhanced cytotoxic T-cell activity against tumor cells. This study demonstrates for the first time the implication of the complement system in the development of NK-mediated cytotoxic T-cell dependent antitumoral immune responses. The complement pathway could therefore be a potent therapeutic target to improve NK-dependent antitumoral immune responses in patients with cancer. PMID- 24778317 TI - Disruption of CD8+ Treg activity results in expansion of T follicular helper cells and enhanced antitumor immunity. AB - Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs CD8 Treg suppressive activity. Here, we report that the growth of B16 melanoma is substantially delayed in these Qa-1-mutant mice after therapeutic immunization with B16 melanoma cells engineered to express granulocyte macrophage colony-stimulating factor compared with Qa-1 B6-WT controls. Reduced tumor growth is associated with enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor infiltrating T cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8(+) T effectors compared with CD8 Tregs. These data suggest that the CD8(+) T effector-Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Tregs represents a potentially effective strategy to enhance antitumor immunity. PMID- 24778318 TI - Establishment of tumor-associated immunity requires interaction of heat shock proteins with CD91. AB - Host antitumor adaptive immune responses are generated as a result of the body's immunosurveillance mechanisms. How the antitumor immune response is initially primed remains unclear, given that soluble tumor antigens generally are quantitatively insufficient for cross-priming and tumors generally lack the classical pathogen-associated molecular patterns to activate costimulation and initiate cross-priming. We explored the interaction of the tumor-derived heat shock proteins (HSP) with their common receptor (CD91) on antigen-presenting cells (APC) as a mechanism for host-priming of T-cell-mediated antitumor immunity. Using targeted genetic disruption of the interaction between HSPs and CD91, we demonstrated that specific ablation of CD91 in APCs prevented the establishment of antitumor immunity. The antitumor immunity was also inhibited when the transfer of tumor-derived HSPs to APCs was prevented using an endogenous inhibitor of CD91. Inhibition was manifested in a reduction of cross-presentation of tumor-derived antigenic peptides in the lymph nodes, providing a molecular basis for the observed immunity associated with tumor development. Our findings demonstrate that early in tumor development, the HSP-CD91 pathway is critical for the establishment of antitumor immunity. PMID- 24778319 TI - Ex vivo assays of dendritic cell activation and cytokine profiles as predictors of in vivo effects in an anti-human CD40 monoclonal antibody ChiLob 7/4 phase I trial. AB - Immunostimulatory antibodies entering the clinic create challenge in terms of not only pharmacodynamics for monitoring anticipated mechanisms but also predetermining cytotoxicity. We show the use of ex vivo whole-blood samples to predict the activation requirements, cytokine signature, and adverse events of an anti-human-CD40 chimeric IgG1 antibody, ChiLob 7/4. Assessments were initially undertaken on human myeloid (mDC1) and plasmacytoid (pDC) dendritic cells, in which an absolute need for cross-linking was shown through the upregulation of activation markers CD83 and CCR7. Subsequent cytokine secretion evaluations of ex vivo whole blood showed the cross-linked antibody-induced increases in MIP1beta, interleukin (IL)-8, IL-12, TNFalpha, and IL-6. This cytokine signature compared favorably with the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS), in which levels of TNFalpha and IL-6 were significantly higher, suggesting a less intense proinflammatory response and possible modified cytokine release syndrome when used in human trials. Following first-in-human use of this agent within a dose escalation study, in vivo evaluations of dendritic cell activation and secreted cytokines closely matched the predetermined immunomonitoring endpoints. Patients showed a comparable pattern of MIP1beta, IL-8, and IL-12 secretion, but no TNFalpha and IL-6 were identified. Mild symptoms relating to a cytokine release syndrome were seen at an equivalent dosage to that observed for dendritic cell activation and cytokine release. In summary, ChiLob 7/4 induces a distinctive pattern of dendritic cell activation and cytokine secretion in ex vivo assays that can be predictive of in vivo responses. Such preclinical approaches to monoclonal antibody evaluation may inform both the starting dosages and the anticipated cytokine release events that could occur, providing a valuable adjunct for future first-in-human assessments of immunostimulatory antibodies. PMID- 24778320 TI - Untreated stage IV melanoma patients exhibit abnormal monocyte phenotypes and decreased functional capacity. AB - Monocytes may contribute to tumor progression in part by mediating tumor-induced immunosuppression. Alterations to the monocyte populations and functions in untreated patients with late-stage melanoma are not fully understood. To characterize these alterations, we compared the frequency, phenotype, and functional capacity of peripheral blood monocytes and other myeloid cells in untreated, newly diagnosed stage IV melanoma patients (n = 18) with those in healthy volunteers. Stage IV untreated melanoma patients exhibited a sizeable decrease in the percentage of monocytes (P < 0.0001) that included a drop in the percentage of the CD14(+)CD16(-) classical monocyte pool (P = 0.006). Although there was not a significant difference in the CD14(+)HLA-DR(low/-) monocyte population between the patients with melanoma and the healthy volunteers, the HLA DR levels were considerably lower in the patients' CD14(+)CD16(+) intermediate (P < 0.0001) and CD14(low)CD16(+) nonclassical monocyte populations (P = 0.001). Decreased surface expression of CD86 (P = 0.0006) and TNFRII (P = 0.0001) and increased expression of tissue factor and PD-L1 (P = 0.003) were identified on monocytes from patients with melanoma. Furthermore, these monocytes had decreased ability to upregulate CD80 expression and cytokine production following stimulation with agonist of Toll-like receptor 3 (TLR3). Peripheral blood dendritic cell subsets were decreased in untreated stage IV melanoma patients. Our study demonstrates that untreated late-stage melanoma patients exhibit monocytopenia in addition to phenotypic and functional deficiencies that may negatively affect their immune function. These findings open new avenues into examining the role of monocyte populations in melanoma development. PMID- 24778321 TI - Gene-modified human alpha/beta-T cells expressing a chimeric CD16-CD3zeta receptor as adoptively transferable effector cells for anticancer monoclonal antibody therapy. AB - The central tumoricidal activity of anticancer monoclonal antibodies (mAb) is exerted by FcgammaR IIIa (CD16)-expressing effector cells in vivo via antibody dependent cell-mediated cytotoxicity (ADCC), as observed for natural killer (NK) cells. In practice, chemotherapy-induced leukopenia and exhaustion of NK cells resulting from ADCC often hamper the clinical efficacy of cancer treatment. To circumvent this drawback, we examined in vivo the feasibility of T cells, gene modified to express a newly generated affinity-matured (158V/V) chimeric CD16 CD3zeta receptor (cCD16zeta-T cells), as a transferable alternative effector for cancer mAb therapy. cCD16zeta-T cells were readily expandable in ex vivo culture using anti-CD2/CD3/CD28 beads and recombinant human interleukin-2 (rhIL-2), and they successfully displayed ADCC-mediated tumoricidal activity in vitro. During ADCC, ligation of opsonized cancer cells to the introduced cCD16zeta-T cells stimulated the effector cells to produce proinflammatory cytokines and release toxic granules through the activation of the Nuclear factor of activated T cells (NFAT) pathway after phosphorylation of the CD3zeta chain. In parallel, these stimulated cCD16zeta-T cells transiently proliferated and differentiated into effector memory T cells. In contrast, NK cells activated by rhIL-2 displayed similar ADCC activity, but failed to proliferate. Human cCD16zeta-T cells infused concomitantly with anti-CD20 mAb synergistically inhibited the growth of disseminated Raji cells, a CD20(+) lymphoma cell line, in immunodeficient mice, whereas similarly infused rhIL-2-treated NK cells survived for a shorter time and displayed less effective tumor suppression. Our findings strongly suggest the clinical feasibility of cCD16zeta-T cells as adoptively transferable ADCC effector cells that could potentially enhance the clinical responses mediated by currently available anticancer mAbs. PMID- 24778322 TI - Influenza virus infection elicits protective antibodies and T cells specific for host cell antigens also expressed as tumor-associated antigens: a new view of cancer immunosurveillance. AB - Most tumor-associated antigens (TAA) are self-molecules that are abnormally expressed in cancer cells and become targets of antitumor immune responses. Antibodies and T cells specific for some TAAs have been found in healthy individuals and are associated with lowered lifetime risk for developing cancer. Lower risk for cancer has also been associated with a history of febrile viral diseases. We hypothesized that virus infections could lead to transient expression of abnormal forms of self-molecules, some of which are TAAs; facilitated by the adjuvant effects of infection and inflammation, these molecules could elicit specific antibodies, T cells, and lasting immune memory simultaneously with immunity against viral antigens. Such infection-induced immune memory for TAA would be expected to provide life-long immune surveillance of cancer. Using influenza virus infection in mice as a model system, we tested this hypothesis and demonstrated that influenza-experienced mice control 3LL mouse lung tumor challenge better than infection-naive control mice. Using 2D difference gel electrophoresis and mass spectrometry, we identified numerous molecules, some of which are known TAAs, on the 3LL tumor cells recognized by antibodies elicited by two successive influenza infections. We studied in detail immune responses against glyceraldehyde-3-phosphate dehydrogenase (GAPDH), histone H4, HSP90, malate dehydrogenase 2, and annexin A2, all of which were overexpressed in influenza-infected lungs and in tumor cells. Finally, we show that immune responses generated through vaccination against peptides derived from these antigens correlated with improved tumor control. PMID- 24778323 TI - Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. AB - Correcting T-cell immunosuppression may unleash powerful antitumor responses; however, knowledge about the mechanisms and modifiers that may be targeted to improve therapy remains incomplete. Here, we report that polyamine elevation in cancer, a common metabolic aberration in aggressive lesions, contributes significantly to tumor immunosuppression and that a polyamine depletion strategy can exert antitumor effects that may also promote immunity. A polyamine-blocking therapy (PBT) that combines the well-characterized ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO) with AMXT 1501, a novel inhibitor of the polyamine transport system, blocked tumor growth in immunocompetent mice but not in athymic nude mice lacking T cells. PBT had little effect on the proliferation of epithelial tumor cells, but it increased the number of apoptotic cells. Analysis of CD45(+) tumor immune infiltrates revealed that PBT decreased levels of Gr-1(+)CD11b(+) myeloid suppressor cells and increased CD3(+) T cells. Strikingly, in a model of neoadjuvant therapy, mice administered with PBT one week before surgical resection of engrafted mammary tumors exhibited resistance to subsequent tumor rechallenge. Collectively, our results indicate that therapies targeting polyamine metabolism do not act exclusively as antiproliferative agents, but also act strongly to prevent immune escape by the tumor. PBT may offer a general approach to heighten immune responses in cancer. PMID- 24778324 TI - Patients need support to self manage their long term conditions. PMID- 24778326 TI - Evaluation of Columbia, USMARC-Composite, Suffolk, and Texel rams as terminal sires in an extensive rangeland production system: VIII. Quality measures of lamb longissimus dorsi. AB - Quality measures of lamb longissimus dorsi were evaluated in 514 crossbred wether lambs to assess sire breed differences. Wethers were produced over 3 yr from single-sire matings of 22 Columbia, 22 U.S. Meat Animal Research Center (USMARC) Composite (Composite), 21 Suffolk, and 17 Texel rams to adult Rambouillet ewes. Lambs were reared to weaning in an extensive western rangeland production system and finished in a feedlot on a high-energy finishing diet. One of three harvest groups were randomly assigned to each lamb, and lambs were transported to The Ohio State University abattoir when the mean BW of wethers remaining in the feedlot reached 54.4, 61.2, or 68.0 kg. After harvest, subjective lean quality scores were assigned and LM pH (immediately after and 24 h after harvest), color (quantified as Minolta L*, a*, and b*), intramuscular fat (IMF), cooking loss percentage, and Warner-Bratzler shear force (WBSF) were determined. Statistical models included fixed effects of sire breed, year of birth, and harvest group and random effects of sire (nested within sire breed and year) and maternal grandsire. Year and harvest group were significant (P < 0.04) for all traits, except harvest group was not for WBSF and lean quality (P > 0.28). At comparable numbers of days on feed, Texel-sired wethers had the greatest (more desirable; P < 0.01) subjective lean quality scores while Composite- and Suffolk-sired lambs were intermediate and Columbia-sired lambs had the lowest (less desirable). Minolta L* values were greater (P < 0.02) for Texel- than Columbia-sired lambs, although this difference is not visually discernible by humans. No significant (P > 0.05) sire breed effects were detected for LM pH at or 24 h after harvest, Minolta a* and b*, IMF, percentage of cooking loss, and WBSF at comparable numbers of days on feed. At comparable chilled carcass weight, significant (P < 0.01) sire breed effects were detected for subjective lean quality score. Texel sired lambs had greater scores than Columbia- and Suffolk-sired lambs, but Composite-sired lambs did not differ from lambs sired by the other sire breeds. Sire breed effects were not detected (P > 0.15) for LM pH at or 24 h after harvest, Minolta L*, a*, and b*, cooking loss percentage, IMF, and WBSF at comparable chilled carcass weight. Therefore, results of the present study indicated that the 4 sire breeds produced crossbred lamb carcasses that had similar and desirable LM quality measurements, meeting consumer expectations. PMID- 24778325 TI - Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through activation of the Wnt/beta-catenin signaling pathway. AB - Although alcohol effects within the liver have been extensively studied, the complex mechanisms by which alcohol causes liver cancer are not well understood. It has been suggested that ethanol (EtOH) metabolism promotes tumor growth by increasing hepatocyte proliferation. In this study, we developed a mouse model of tumor promotion by chronic EtOH consumption in which EtOH feeding began 46 days after injection of the chemical carcinogen diethylnitrosamine (DEN) and continued for 16 weeks. With a final EtOH concentration of 28% of total calories, we observed a significant increase in the total number of preneoplastic foci and liver tumors per mouse in the EtOH+DEN group compared with corresponding pair-fed (PF)+DEN and chow+DEN control groups. We also observed a 4-fold increase in hepatocyte proliferation (P < 0.05) and increased cytoplasmic staining of active beta-catenin in nontumor liver sections from EtOH+DEN mice compared with PF+DEN controls. In a rat model of alcohol-induced liver disease, we found increased hepatocyte proliferation (P < 0.05); depletion of retinol and retinoic acid stores (P < 0.05); increased expression of cytosolic and nuclear expression of beta-catenin (P < 0.05) and phosphorylated-glycogen synthase kinase 3beta (p GSK3beta), P < 0.05; significant upregulation in Wnt7a mRNA expression; and increased expression of several beta-catenin targets, including, glutamine synthetase (GS), cyclin D1, Wnt1 inducible signaling pathways protein (WISP1), and matrix metalloproteinase-7(MMP7), P < 0.05. These data suggest that chronic EtOH consumption activates the Wnt/beta-catenin signaling pathways to increase hepatocyte proliferation, thus promoting tumorigenesis following an initiating insult to the liver. PMID- 24778327 TI - Reduced supplementation frequency increased insulin-like growth factor 1 in beef steers fed medium quality hay and supplemented with a soybean hull and corn gluten feed blend. AB - Reducing supplementation frequency in calf growing programs can reduce labor and equipment operation costs. However, little is understood about the metabolic response of ruminants to large fluctuations in nutrient intake. Eighteen Angus or Angus * Simmental cross steers (287 +/- 20 kg and 310 +/- 3.6 d of age) were individually fed 1 of 3 dietary treatments using Calan gates. Dietary treatments consisted of ad libitum hay and no supplement (NS), ad libitum hay and 1% BW (as fed basis) of supplement daily (DS), or ad libitum hay and 2% BW (as-fed basis) of supplement every other day (SA). The supplement was 90% DM and contained (as fed basis) 47% corn gluten feed, 47% soybean hulls, 2% feed grade limestone, and 4% molasses. Hay intake and ADG was measured over a 52-d period. Steers were then moved to individual tie stalls. Steers were fed at 0800 h and blood samples were collected every hour from 0600 to 1400 h and at 1800, 2200, and 0200 h over a 2-d period. Gains were increased (P < 0.01) by supplementation but did not differ (P = 0.68) due to supplementation frequency. Average daily gain was 0.45, 0.90, and 0.87 kg .hd(-1).d(-1) (SEM +/- 0.05) for steers NS, DS, and SA, respectively. Across the 2-d supplementation cycle area under the concentration time curve (AUC) for plasma glucose was increased (P < 0.01) by supplementation but did not differ (P = 0.41) due to supplementation frequency. The AUC for plasma insulin was increased by supplementation (P < 0.01) but did not differ (P = 0.67) due to supplementation frequency. Plasma IGF-1 was increased (P = 0.01) by supplementation and was greater (P = 0.04) for steers supplemented SA than DS. Gains of steers supplemented with a soybean hull and corn gluten feed blend on alternate days did not differ from those supplemented daily suggesting the steers were able to efficiently utilize large boluses of nutrients fed every other day. The effect of less frequent supplementation on IGF-1 deserves further examination as this hormone has been shown to increase protein synthesis. PMID- 24778328 TI - Sow postural changes, responsiveness to piglet screams, and their impact on piglet mortality in pens and crates. AB - Free farrowing pens (pens) improve the welfare of sows but may increase sow activity and negatively influence piglet production. The aim of this study was to assess the effect of pens and crates on sow postural changes, piglet trapping, sow responses to piglet screams, piglet mortality, and piglet BW gain. It was predicted that provision of greater space (in pens) would increase not only the frequency of sow postural changes and the probability of trappisng but also sow responses to the screams of piglets; thus, the outcome would be no differences in fatal piglet crushing or overall mortality between the housing systems. Sows were randomly moved to either a farrowing pen (n = 20) or farrowing crate (n = 18). Sow behavior was recorded and analyzed for 72 h from the birth of the first piglet (BFP). Sow postural changes included rolling from a ventral to lateral position and vice versa and going from standing to sitting, standing to lying, and sitting to lying. Occurrences of piglet trapping and sow responsiveness to real crushing situations were analyzed. Sow responsiveness was assessed in response to audio playbacks (PB) of piglet screams on d 3 postpartum (48 to 72 h after BFP; PB crush calls) and real piglet crushing during the first 72 h after BFP (real crush calls). Piglet BW gain was estimated 24 h after BFP, piglet BW was recorded at weaning, and piglet crushing and piglet mortality were recorded during the 72 h after BFP. Data were analyzed using PROC MIXED and PROC GENMOD of SAS. Sows in pens showed more postural changes (P = 0.04) and tended to have greater incidences of piglet trapping (P = 0.07) than those in crates. Sow response to PB crush calls was greater in pens (P = 0.04) but did not differ for real crush calls between pens and crates (P = 0.62). There was no effect on the probability of piglet crushing (P = 0.38) and mortality (P = 0.41) during the 72 h after BFP nor in piglet mortality at weaning (P = 0.81) between pens and crates. Piglet BW gain at 24 h after BFP (P = 0.01) and piglet BW at weaning (P = 0.02) were greater in pens. Sows in pens showed more postural changes and tended to trap more piglets; however, the response to real crush calls did not differ between the two housing systems. Despite this, there was no increase in piglet crushing or mortality in pens, which might be influenced by the better piglet body condition observed in pens, which in turn could influence their ability to avoid crushing by the sow. PMID- 24778329 TI - Evaluation of Saccharomyces cerevisiae fermentation product as an alternative to monensin on growth performance, cost of gain, and carcass characteristics of heavy-weight yearling beef steers. AB - Two hundred fifty-two cross-bred yearling steers (406 +/- 24 kg BW) were used in a completely randomized block design with a 2 * 2 factorial arrangement of treatments (7 pens/treatment) to evaluate the effects of dietary Saccharomyces cerevisiae fermentation product (SFP) and monensin (MON) on growth performance and carcass characteristics. Dietary treatments arranged as a 2 * 2 factorial were 1) with or without SFP and 2) with or without MON. Finishing diets contained 19.7% of DM as dried distiller's grains with solubles. Both SFP and MON were added in the total mixed ration in place of an equal amount of cornmeal (DM basis; target intake = 2.8 g of SFP and 33 mg of MON/kg of dietary DM). Each treatment group was offered ad libitum access to a transition ration from d 1 to 8 and then to the finishing ration from d 9 to 125. Body weights were collected on d 0, 28, 56, 84, 110, and 125. Initial and final BW was an average of 2-d weights (d -1 and 0 and d 124 and 125, respectively). Steers were shipped for harvest on d 125. Overall ADG was decreased (P = 0.03) in steers supplemented with SFP, but final BW was similar among treatments. Feeding SFP was associated with lighter (P < 0.01) HCW and a greater (P = 0.01) number of carcasses grading USDA Choice. Twelfth rib fat thickness was not affected by SFP (P = 0.82) or MON (P = 0.35), but numerical decreases in 12th rib fat thickness among cattle receiving SFP or MON alone contributed to a tendency (P = 0.07) for greater 12 rib fat thickness when SFP and MON were provided. There was no effect of treatment on cost of gain (P >= 0.21). The effects of SFP in the current study may have been limited in heavy yearling steers due to consumption of a finishing diet containing 19.7% dried distiller's grains with solubles. PMID- 24778330 TI - Genetic and phenotypic parameters for carcass and meat quality traits in commercial crossbred pigs. AB - Pork quality and carcass characteristics are now being integrated into swine breeding objectives because of their economic value. Understanding the genetic basis for these traits is necessary for this to be accomplished. The objective of this study was to estimate phenotypic and genetic parameters for carcass and meat quality traits in 2 Canadian swine populations. Data from a genomic selection study aimed at improving meat quality with a mating system involving hybrid Landrace * Large White and Duroc pigs were used to estimate heritabilities and phenotypic and genetic correlations among them. Data on 2,100 commercial crossbred pigs for meat quality and carcass traits were recorded with pedigrees compromising 9,439 animals over 15 generations. Significant fixed effects (company, sex, and slaughter batch), covariates (cold carcass weight and slaughter age), and random additive and common litter effects were fitted in the models. A series of pairwise bivariate analyses were implemented in ASReml to estimate phenotypic and genetic parameters. Heritability estimates (+/-SE) for carcass traits were moderate to high and ranged from 0.22 +/- 0.08 for longissimus dorsi muscle area to 0.63 +/- 0.04 for trimmed ham weight, except for firmness, which was low. Heritability estimates (+/-SE) for meat quality traits varied from 0.10 +/- 0.04 to 0.39 +/- 0.06 for the Minolta b* of ham quadriceps femoris muscle and shear force, respectively. Generally, most of the genetic correlations were significant (P < 0.05) and ranged from low (0.18 +/- 0.07) to high (-0.97 +/- 0.35). There were high negative genetic correlations between drip loss with pH and shear force and a positive correlation with cooking loss. Genetic correlations between carcass weight (both hot and cold) with carcass marbling were highly positive. It was concluded that selection for increasing primal and subprimal cut weights with better pork quality may be possible. Furthermore, the use of pH is confirmed as an indicator for pork water-holding capacity and cooking loss. The heritabilities of carcass and pork quality traits indicated that they can be improved using traditional breeding methods and genomic selection, respectively. The estimated genetic parameters for carcass and meat quality traits can be incorporated into the breeding programs that emphasize product quality in these Canadian swine populations. PMID- 24778331 TI - The behavior of sheep and goats co-grazing on pasture with different types of vegetation in the karst region. AB - The Slovenian karst region and similar types of land are difficult to cultivate and often exposed to the process of being abandoned and overgrown with shrubs, trees, and brushwood. Co-grazing in a mixed group may be a way to optimize the management of sheep and goat flocks in such areas. To obtain more knowledge of the natural behavior of small ruminants, the experiment was designed on pasture in the mountain karst region. The experimental area was divided in 6 paddocks, of which 3 paddocks were covered with grass, herbs, and legumes (i.e., grassy paddock [GP]). In the other 3 paddocks the area was additionally overgrown with hazel, beech trees, and bushes (i.e., woody paddock [WP]). In a mixed flock of 40 Slovenian local sheep breed (Istrian Pramenka) and 10 crossbreed goats (Saanen * Alpine goat), 10 animals per species were focally observed during daylight (0500 2100 h). The natural behavior was scored on 12 d, 2 consecutive days in each of the paddocks. Animals were rotated between 6 paddocks according to the balanced schedule. They stayed at each paddock for 5 or 6 d. Observations started on the third day after moving the animals into a specific paddock, following 2 d of adaptation. The results indicated that botanically diverse paddock together with climate conditions affected the behavior. Goats were grazing more (P < 0.001) whereas sheep less in the WP (P = 0.05). In sheep, drinking and salt consumption were higher (both P < 0.001) in the WP, suggesting that salt triggered additional water consumption. The WP enabled conditions where more comfort behavior, that is, autogrooming (both species P < 0.001) and object grooming (both species P < 0.001), was performed. On the second day of observation, animals grazed more compared to the first day (both species P < 0.001), most likely due to lower forage availability. Goats drank (P < 0.001) and consumed more salt on the second day (P < 0.001). With higher temperature sheep and goats grazed less (P < 0.05 and P < 0.001, respectively) and goats drank more (P < 0.05). Sheep showed more while goats less autogrooming when temperature was lower (both P < 0.001). More autogrooming was shown on the second day of observation but only in goats (P < 0.001). The performed behavior of co-grazing sheep and goats suggests different foraging strategies and adaptation between the species, which may be taken into account for management decisions under specific environmental conditions in the mountain karst region. PMID- 24778332 TI - A marker-derived gene network reveals the regulatory role of PPARGC1A, HNF4G, and FOXP3 in intramuscular fat deposition of beef cattle. AB - High intramuscular fat (IMF) awards price premiums to beef producers and is associated with meat quality and flavor. Studying gene interactions and pathways that affect IMF might unveil causative physiological mechanisms and inform genomic selection, leading to increased accuracy of predictions of breeding value. To study gene interactions and pathways, a gene network was derived from genetic markers associated with direct measures of IMF, other fat phenotypes, feedlot performance, and a number of meat quality traits relating to body conformation, development, and metabolism that might be plausibly expected to interact with IMF biology. Marker associations were inferred from genomewide association studies (GWAS) based on high density genotypes and 29 traits measured on 10,181 beef cattle animals from 3 breed types. For the network inference, SNP pairs were assessed according to the strength of the correlation between their additive association effects across the 29 traits. The co-association inferred network was formed by 2,434 genes connected by 28,283 edges. Topological network parameters suggested a highly cohesive network, in which the genes are strongly functionally interconnected. Pathway and network analyses pointed towards a trio of transcription factors (TF) as key regulators of carcass IMF: PPARGC1A, HNF4G, and FOXP3. Importantly, none of these genes would have been deemed as significantly associated with IMF from the GWAS. Instead, a total of 313 network genes show significant co-association with the 3 TF. These genes belong to a wide variety of biological functions, canonical pathways, and genetic networks linked to IMF-related phenotypes. In summary, our GWAS and network predictions are supported by the current literature and suggest a cooperative role for the 3 TF and other interacting genes including CAPN6, STC2, MAP2K4, EYA1, COPS5, XKR4, NR2E1, TOX, ATF1, ASPH, TGS1, and TTPA as modulators of carcass and meat quality traits in beef cattle. PMID- 24778333 TI - Effects of service sire on prenatal mortality and prolificacy in ewes. AB - Ability to select service sires that minimize partial or complete losses of pregnancy could have major economic impacts in sheep production systems. This study tested the null hypothesis that survival of potential progeny did not vary with breed type of service sire or among individual rams. Data included 980 ewes on 10 farms; each ewe was pregnant to 1 of 67 rams of 12 breeds. Number of conceptuses was estimated once during pregnancy by ultrasonography, either transrectal (embryos) or transabdominal (fetuses), and was compared with number of lambs born to estimate losses. Data were examined first for number of lambs born and second for documented losses. Individual service sires affected number born (P < 0.001), which varied from 0.70 to 2.45 lambs per pregnant ewe. The main effects of breed type on lambs born were not significant, but breed types of both service sires (P < 0.0002) and ewes (P < 0.001) interacted with diagnosed number of conceptuses. Lambs born varied with ewe age (P < 0.0001) and among farms (P < 0.0001), and statistically, farms interacted with number of diagnosed conceptuses (P < 0.0001); season had no effect. In documented losses, there were both main effects of individual service sire and a service sire * number of diagnosed embryos interaction (P < 0.005). Thus, ewes bred to some rams were more apt to lose single pregnancies, whereas ewes bred to other rams were more apt to lose 1 or more embryos or fetuses from multiple pregnancies. Breed type of service sire affected (P < 0.05) prenatal death. Complete losses of single conceptuses tended to be greater in ewes bred to black-faced or hair-type rams (service sire breed type * number of diagnosed conceptuses; P < 0.09). Breed type of ewes also varied in incidence of complete losses (P < 0.05); hair-type ewes (46%) lost more (P < 0.02) documented conceptuses from examination to birth than black-faced (27%), white-faced (20%), or dairy-type (25%) ewes. Greater losses of singles than of multiples occurred in black-faced (37% vs. 18%) and hair-type (64% vs. 27%) ewes than in other breeds (ewe breed type * number of conceptuses; P < 0.03) per ewe. Surprisingly, purebred conceptuses were lost less often (24%) than crossbreds (36.4%; P < 0.002). Selection of rams based on records of prenatal losses in ewes they serviced may be a method to decrease embryonic and fetal wastage. However, further study to determine repeatability of differences among service sires from year to year will be required. PMID- 24778335 TI - Evaluation of mechanical and thermal nociception as objective tools to measure painful and nonpainful lameness phases in multiparous sows. AB - The objective of this study was to quantify pain sensitivity differences using mechanical nociception threshold (MNT) and thermal nociception threshold (TNT) tests when sows were in painful and nonpainful transient lameness phases. A total of 24 mixed parity crossbred sows (220.15 +/- 21.23 kg) were utilized for the MNT test, and a total of 12 sows (211.41 +/- 20.21 kg) were utilized for the TNT test. On induction day (D0), all sows were anesthetized and injected with Amphotericin B (10mg/mL) in the distal interphalangeal joint space in both claws of one randomly selected hind limb to induce transient lameness. Three days were compared: (1) D-1 (sound phase, defined as 1 d before induction), (2) D+1 (most lame phase, defined as 1 d after induction), and (3) D+6 (resolution phase, defined as 6 d after induction). After completion of the first round, sows were given a 7-d rest period and then the procedures were repeated with lameness induced in the contralateral hind limb. During the MNT test, pressure was applied perpendicularly to 3 landmarks in a randomized sequence for each sow: 1) middle of cannon on the hind limb (cannon), 2) 1 cm above the coronary band on the medial hind claw (medial claw), and 3) 1 cm above the coronary band on the lateral hind claw (lateral claw). During the TNT test, a radiant heat stimulus was directed 1 cm above the coronary band. The data were analyzed using the MIXED procedure in SAS with sow as the experimental unit. Differences were analyzed between sound and lame limbs on each day. For the MNT test, pressure tolerated by the lame limb decreased for every landmark (P < 0.05) when comparing D-1 and D+1. The sound limb tolerated more pressure on D+1 and D+6 than on baseline D-1 (P < 0.05). Thermal stimulation tolerated by the sound limb did not change over the 3 d (P > 0.05). However, the sows tolerated less heat stimulation on their lame limb on D+1 compared to D-1 levels (P < 0.05). Both MNT and TNT tests indicated greater pain sensitivity thresholds when sows were acutely lame. PMID- 24778336 TI - Trend analysis of plasma insulin level around parturition in relation to parity in Saanen goats. AB - The present study investigated the effect of parity on plasma insulin level around parturition in Saanen goats. On d -14, -7, 0, 3, 7, 10, and 14 from parturition, plasma glucose, NEFA, free AA, cortisol, and insulin concentrations were analyzed in 10 primiparous and 10 multiparous goats. At parturition, BW of primiparous goats was about 75% of that of multiparous ones (P < 0.001) and then their milk production was lower than that of multiparous ones (P < 0.001). At parturition, glucose increased (P < 0.01) in both primiparous and multiparous goats and then decreased (P < 0.01) on d 3 of lactation, remaining higher (P < 0.01) in primiparous than multiparous goats until the end of the study period. In both groups, free AA decreased (P < 0.01) at parturition, returning to prepartum levels (P < 0.01) on d 3 of lactation without difference between groups. Only in multiparous goats, plasma NEFA increased at parturition (P < 0.01), returning to prepartum levels on d 14 (P < 0.01). Changes in glucose and AA could have been caused by cortisol, which increased (P < 0.01) at parturition in both primiparous and multiparous goats, returning to prepartum levels (P < 0.01) on d 7 of lactation, without difference between the parity groups. In multiparous goats, insulin decreased soon after parturition (P < 0.05), remaining at low levels until the end of the study period, whereas in primiparous goats, insulin did not vary until d 14 of lactation, when it decreased (P < 0.05) also in this group. Therefore, between d 3 and 14 of lactation, insulin was higher in primiparous than multiparous goats (P < 0.05). Only in primiparous goats, at kidding, insulin was negatively correlated to BW (P < 0.01), and after parturition it was negatively correlated with milk yield (P < 0.05) and plasma NEFA (P < 0.05). We hypothesize that higher insulin levels in primiparous Saanen goats, which are still immature at their first breeding season, acted to limit both the mobilization of bodily reserves and the capture of nutrients by the lactating mammary gland, thus providing nutrients for their own physical and physiological development. PMID- 24778337 TI - Methicillin-resistant Staphylococcus aureus in cattle food chains - prevalence, diversity, and antimicrobial resistance in Germany. AB - Livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) have been found in various farm animal species throughout the world. It was the objective of this study to estimate the prevalence of MRSA in different cattle food chains (milk, beef, and veal) in Germany, to analyze the MRSA diversity along each food chain and to compare the characteristics of the different subtypes. Samples were collected between 2009 and 2012 from dairy herds (bulk tank milk), veal herds (dust from the stables), veal calves, and beef cattle at slaughter (nasal swabs) and carcasses of veal calves (surface cuts) and beef as well as veal at retail. Sampling was proportionally distributed over the country according to the cattle population (on-farm sampling), slaughterhouse capacity (abattoir samples), and the human population (meat at retail). Methicillin-resistant S. aureus were isolated using harmonized methods from all sample types and populations investigated. The highest proportion of positive samples was found in nasal swabs from veal calves at slaughter in 2012 (144/320; 45.0%) and the lowest rate in bulk tank milk in 2009 (14/388; 4.1%). Most isolates, irrespective of the origin, were from spa types t011 and t034. Both have been assigned to the clonal complex (CC) 398. Few isolates (15/632; 2.4%) were from spa types not associated with the CC398. Spa-type patterns were similar along individual food chains but differed between food chains. Antimicrobial resistance patterns differed between isolates from the different food chains and spa types. Isolates from the veal chain displayed the highest resistance rates. We conclude that there is substantial diversity in the MRSA prevalence across different cattle production sectors. PMID- 24778338 TI - Effects of calf weaning age and subsequent management system on growth and reproductive performance of beef heifers. AB - Brahman * British crossbred heifers (n = 40 and 38 heifers in yr 1 and 2, respectively) were used to evaluate the effects of calf weaning age and subsequent management system on growth and reproductive performance. On d 0, heifers were ranked by BW (89 +/- 16 kg) and age (72 +/- 13 d) and randomly assigned to a conventional management group that was normally weaned on d 180 (NW; n = 10 heifers annually) or early weaned (EW) on d 0 and 1) limit fed a high concentrate diet at 3.5% of BW (as fed) in drylot until d 180 (EW180; n = 10 heifers annually), 2) limit fed a high-concentrate diet at 3.5% of BW (as fed) in drylot until d 90, then grazed on Bahiagrass pastures until d 180 (EW90; n = 10 heifers annually), or 3) grazed on annual ryegrass pastures until d 60 (yr 1; n = 10 heifers) or 90 (yr 2; n = 8 heifers), then on Bahiagrass pastures until d 180 (EWRG). On d 180, all heifers were grouped by treatment and rotated on Bahiagrass pastures until d 390. Grazing heifers were supplemented at 1.0% BW until d 180 and at 1.5% BW from d 180 to 390. From d 0 to 90, EW180 and EW90 heifers were heavier (P <= 0.02) than NW and EWRG heifers, whereas NW heifers tended (P = 0.09) to be heavier on d 90 than EWRG heifers. In yr 1 and 2, EW180 heifers were heaviest (P < 0.0001) on d 180. In yr 1, EWRG heifers were lightest (P < 0.0001), whereas EW90 and NW heifers had similar BW (P = 0.58). Conversely, EW90, EWRG, and NW heifers achieved similar BW on d 180 of yr 2 (P >= 0.18). Positive correlations were detected (P <= 0.05) between liver IGF-1 mRNA abundance on d 90 and ADG from d 0 to 90 and between liver IGF-1 mRNA abundance on d 180 and ADG from d 90 to 180. The EW180 heifers were youngest (P <= 0.01) at puberty. From d 260 to 340, the percentage of pubertal heifers was greater (P <= 0.03) for EW90 vs. NW heifers but did not differ (P >= 0.15) between EWRG and NW heifers. The ADG from d 0 to 90 and the plasma IGF-1 on d 90 and 180 explained approximately 34% of the variability in age at puberty. In summary, the EW90 and EW180 heifer management systems evaluated in this study altered the BW at the time of NW and were good alternatives for anticipating puberty achievement compared to NW heifers. PMID- 24778339 TI - Effect of development system on growth and reproductive performance of beef heifers. AB - Reproductive performance was evaluated in beef heifers born over a 2-yr period to determine the effects of target breeding weight (TBW) and development system (SYS) on growth and subsequent reproductive efficiency. Spring-born Angus heifers (253 +/- 0.7 kg) were randomly allocated over 2 consecutive yr (yr 1, n = 80; yr 2, n = 96) to be developed to either 55% (350 kg) of mature BW (moderate gain, MG) or 62% (395 kg) of mature BW (high gain, HG). Each MG and HG group was further assigned to 1 of 2 replicated systems: (1) bale graze bromegrass-alfalfa round bales in field paddocks (BG) or (2) fed bromegrass-alfalfa round bales in drylot pens (DL). Heifers were fed a diet of bromegrass-alfalfa hay (56.9% TDN; 9.8% CP) and barley grain supplement (85.1% TDN; 12.3% CP). After the 202-d development period, heifers were exposed to bulls for a 63-d breeding season. Target BW * SYS interactions were not detected for any measured parameters. During the winter development period, MG heifers had lower (P = 0.01) ADG than HG heifers and MG heifers had lighter (P = 0.01) BW at breeding. The proportion of heifers attaining puberty by 14.5 mo of age was less (P = 0.05) in MG (20 +/- 4%) than HG heifers (52 +/- 3%). From the end of the 202-d development period to pregnancy diagnosis, ADG was greater (P = 0.04) in MG heifers than HG heifers (0.83 vs. 0.71 kg/d). First-calf pregnancy rates were 86 and 88% for MG and HG heifers, respectively (P = 0.41). Second- and third-calf pregnancy rates of cows, developed in either a MG or HG system as heifers, were not different (P = 0.74; 94.7 vs. 95.9% and 93.8 vs. 93.9%, respectively). Economic analysis revealed a $58 reduced development cost for heifers developed to 55% compared with 62% of mature BW without a loss in reproductive performance. PMID- 24778340 TI - Digesta sampling sites and marker methods for estimation of ruminal outflow in bulls fed different proportions of corn silage or sugarcane. AB - The objective of this experiment was to assess ruminal outflow and apparent total tract digestibility using digesta samples from 3 sites (reticulum, omasum, and abomasum) and 3 marker methods (single marker: indigestible NDF [iNDF; sample without separation]; double marker: iNDF + Co-EDTA [filtered sample]; and triple marker: iNDF + ytterbium [Yb] acetate + Co-EDTA [filtered and centrifuged]) in bulls fed corn silage and sugarcane-based diets. Eight crossbred (Holstein * Zebu) bulls (353 +/- 37 kg of BW; 24 +/- 1 mo of age) with ruminal and abomasal cannulas were randomly distributed into two 4 * 4 Latin squares that were balanced for residual effects. The following experimental diets were used: 1) 60% corn silage + 40% concentrate, 2) 40% corn silage + 60% concentrate, 3) 60% fresh sugarcane + 40% concentrate, and 4) 40% fresh sugarcane + 60% concentrate. Reticular, omasal, and abomasal digesta samples were collected at 9-h intervals over 3 d. At the end of the experiment, a composite sample was prepared for each bull, and these samples were subsequently assigned to the 3 marker methods. The concentrations of CP, NDF, and iNDF of reticular digesta differed (P < 0.01) from those of the omasum and abomasum. Use of omasal and abomasal samples led to similar estimates of ruminal outflow and ruminal digestibility for DM (P = 0.65), OM (P = 0.68), CP (P = 0.85), and NDF (P = 0.57). In contrast, the ruminal outflow of digesta based on reticular sampling appeared to be underestimated. We recommend sampling from the omasum because sampling from this region is less invasive than sampling from the abomasum. Although we did not observe differences in ruminal NDF digestibility among the different marker methods, we did observe that ruminal digestibility of CP was greater for the single marker method than for the double and triple marker methods; we therefore recommend the use of the double or triple marker method. PMID- 24778341 TI - Management of women at high risk of breast cancer. PMID- 24778342 TI - Environmental radioactivity in southern Serbia at locations where depleted uranium was used. AB - In the 1999 bombing of the Federal Republic of Yugoslavia, NATO forces used ammunition containing depleted uranium. The cleaning of depleted uranium that followed was performed in southern Serbia by the Vinca Institute of Nuclear Sciences between 2002 and 2007 at the locations of Pljackovica, Borovac, Bratoselce, and Reljan. This paper presents detailed results of radioactivity monitoring four years after cleaning (2011), which included the determination of gamma emitters in soil, water, and plant samples, as well as gross alpha and beta activities in water samples. The gamma spectrometry results showed the presence of natural radionuclides 226Ra, 232Th, 40K, 235U, 238U, and the produced radionuclide 137Cs (from the Chernobyl accident). In order to evaluate the radiological hazard from soil, the radium equivalent activity, the gamma dose rate, the external hazard index, and the annual effective dose were calculated. Considering that a significant number of people inhabit the studied locations, the periodical monitoring of radionuclide content is vital. PMID- 24778343 TI - Occurrence of black Aspergilli in indoor environments of six countries. AB - Black Aspergilli (Aspergillus section Nigri) are widely distributed in various habitats. They act as food spoilage organisms, human pathogens, and mycotoxin producers and are frequently encountered in indoor environments. Black Aspergilli, specifically A. niger, A. welwitschiae, and A. carbonarius, produce different ochratoxins and fumonisins. Ochratoxins are known to induce renal disorders following inhalation, which necessitates the determination of potential mycotoxin-producing species in our environment. This paper aimed to compare the diversity and species distribution of black Aspergilli in the indoor environments of six different countries using morphological and molecular methods. A total of 178 black Aspergillus isolates were identified from six countries. In contrast with results from previous studies, A. niger was not the only black Aspergillus detected in indoor air. Species distribution differed among countries, although the distribution in European countries (Croatia, Hungary, the Netherlands, and Turkey) with a temperate climate was considerably similar. The highest species diversity was observed in indoor samples from Thailand, while the lowest was found in Algeria. Potentially ochratoxin- and fumonisin-producing fungi were detected in the indoor air of all six countries. Further studies need to clarify the effect of these fungi and their mycotoxins on human and animal health. PMID- 24778344 TI - Are nurse presenteeism and patient safety culture associated: a cross-sectional study. AB - Working as a nurse involves great dedication and sacrifice: working night shifts, working overtime, and coming to work sick. The last is also known as presenteeism. Research has shown that poor nurse performance can affect both caregiver's and patient's safety. The aim of this cross-sectional study was to investigate whether nurse presenteeism affected patient safety culture and to look deeper into the characteristics of nurse presenteeism and patient safety culture in Croatia. The study was conducted in one general hospital in Croatia over April and May 2012 and specifically targeted medical nurses as one of the largest groups of healthcare professionals. They were asked to fill two questionnaires: the six-item Stanford Presenteeism Scale (SPS-6) and the Hospital Survey on Patient Safety Culture (HSOPSC). We found no association between presenteeism and patient safety culture. Overall positive perception of safety was our sample's strength, but other dimensions were positively rated by less than 65 % of participants. The lowest positive response concerned "nonpunitive response to error", which is consistent with previous studies. Presenteeist nurses did not differ in their characteristics from nurses without presenteeism (gender, age, years of experience, working hours, contact with patients and patient safety grades). Our future research will have to include a broader healthcare population for us to be able to identify weak spots and suggest improvements toward high-quality and cost-effective health care. PMID- 24778345 TI - Clinical differences between early- and late-onset severe preeclampsia and analysis of predictors for perinatal outcome. AB - AIMS: To analyze the clinical differences between early- and late-onset cases of severe preeclampsia and to evaluate parameters that could help to predict perinatal outcome. METHODS: Over a period of 6 years, all cases of severe preeclampsia (n=68) at our institution were included in a retrospective cohort analysis. Differences between early (<34 weeks, n=44) and late (>=34 weeks, n=24) onset of the disease were evaluated. Risk factors for low 5-min Apgar score (<=7), small-for-gestational-age (SGA) infants and neonatal acidosis (umbilical arterial pH <7.20) were identified and considered in a multiple logistic regression model. RESULTS: Early- and late-onset severe preeclampsia differed from each other remarkably. Perinatal outcome was unfavorable in early-onset disease and seemed to be mainly a result of premature delivery and development of fetal growth restriction. Abnormal uterine Doppler velocimetry increased the risk of low 5-min Apgar values [odds ratio (OR) 8.0, P=0.012] and preterm birth <34+0 weeks (OR 17.9, P<0.001). An increased resistance of the umbilical artery was associated with a higher risk for SGA birth weight (OR 4.9, P=0.010). CONCLUSION: Preeclampsia is a heterogeneous syndrome even if only severe cases were analyzed. Abnormal Doppler flow characteristics facilitated the identification of patients who were at increased risk for worse perinatal outcome. PMID- 24778346 TI - Emerging evidence of insulin-like growth factor 2 as a memory enhancer: a unique animal model of cognitive dysfunction with impaired adult neurogenesis. AB - In the current aging society, cognitive dysfunction is one of the most serious issues that should be urgently resolved. It also affects a wide range of age groups harboring neurological and psychiatric disorders, such as Alzheimer's disease and schizophrenia. Although the molecular mechanism of memory impairment still remains to be determined, neuronal loss and dysfunction has been revealed to mainly attribute to its pathology. The discovery of neural stem cells in the adult brain that are proliferating and able to generate functional neurons has given rise to the idea that neuronal loss could be rescued by manipulating endogenous neural progenitor and stem cells. To this end, we must characterize them in detail and their developmental programming must be better understood. A growing body of evidence has indicated that insulin-like peptides are involved in learning and memory and maintenance of neural progenitor and stem cells, and clinical trials of insulin as a memory enhancer have begun. In contrast to the expectation of insulin and IGF1, the roles of IGF2 in cognitive ability have been poorly understood. However, recent evidence demonstrated in rodents suggests that IGF2 may play a pivotal role in adult neurogenesis and cognitive function. Here, we would like to review the rapidly growing world of IGF2 in cognitive neuroscience and introduce the evidence that its deficit is indeed involved in the impairment of the hippocampal neurogenesis and cognitive dysfunction in the model mouse of 22q11.2 deletion syndrome, which deletes Dgcr8, a critical gene for microRNA processing. PMID- 24778347 TI - Serum and follicular fluid fetuin-A in women undergoing in vitro fertilization. AB - BACKGROUNDS: This case-control study was designed to assess the possible role of fetuin-A, a multifunctional protein, in reproductive processes of women undergoing in vitro fertilization (IVF). METHODS: Paired serum and follicular fluid (FF) samples were obtained from 35 unselected patients who received IVF treatment. Their main clinical chartacteristics: age 35.2+/-5.4 years, BMI 22.9+/ 2.8, duration of infertility 3.2+/-2.0 years, gonadotropin administered 1199.4+/ 202.3 IU, and estradiol level on day 6 of stimulation 1827+/-1342 pmol/L. In total 25 healthy women of similar age admitted for minor elective surgery served as controls for serum analysis. Fetuin-A and high-sensitivity C-reactive protein (hsCRP) were measured in serum and FF by using commercially available ELISA kits and turbidimetric immunoassay, respectively. RESULTS: Serum fetuin-A levels of patients participating IVF are markedly elevated when compared to those of healthy women (1.30+/-0.58 g/L vs. 0.55+/-0.09 g/L, p<0.000). Fetuin-A in FF proved to be comparable to its serum levels (1.17+/-0.45 g/L) and no relationship could be detected between the respective individual values. Moreover, markers of reproductive potential (number of oocytes and embryos) appeared to be independent of serum and FF fetuin-A. hsCRP in serum and FF was not related to fetuin-A and did not influence the number of oocytes and embryos. CONCLUSIONS: Fetuin-A concentration is high in FF of patients undergoing IVF, however, it can not be used as an estimate of fertilization success. PMID- 24778348 TI - Breast tissue segmentation from x-ray radiographs. AB - In this paper, we propose a robust and accurate method that segments mammograms to three distinct regions: breast tissue, pectoral muscle and background. Our approach is built around a neural, two-layer committee machine. On the first layer, individual experts, each formed by a feature vector and a classifier, vote the local class label of the mammogram. The votes are given as an input, together with a prior map, to the second layer of the committee machine, which combines the inputs by a gating network. As the first layer features, we use effective, well-known local features based on image intensity, intensity histograms, local binary patterns, and histograms of oriented gradient. As with the first-layer classifiers and the gating network, we use support vector machines. Our experiments on a database of 495 mammograms, divided into independent training, validations and test subsets, show that our method is able to segment the breast tissue without failure, and it challenges the manual expert segmentation in the level of accuracy. PMID- 24778349 TI - Measurements of the neutron dose equivalent for various radiation qualities, treatment machines and delivery techniques in radiation therapy. AB - In radiation therapy, high energy photon and proton beams cause the production of secondary neutrons. This leads to an unwanted dose contribution, which can be considerable for tissues outside of the target volume regarding the long term health of cancer patients. Due to the high biological effectiveness of neutrons in regards to cancer induction, small neutron doses can be important. This study quantified the neutron doses for different radiation therapy modalities. Most of the reports in the literature used neutron dose measurements free in air or on the surface of phantoms to estimate the amount of neutron dose to the patient. In this study, dose measurements were performed in terms of neutron dose equivalent inside an anthropomorphic phantom. The neutron dose equivalent was determined using track etch detectors as a function of the distance to the isocenter, as well as for radiation sensitive organs. The dose distributions were compared with respect to treatment techniques (3D-conformal, volumetric modulated arc therapy and intensity-modulated radiation therapy for photons; spot scanning and passive scattering for protons), therapy machines (Varian, Elekta and Siemens linear accelerators) and radiation quality (photons and protons). The neutron dose equivalent varied between 0.002 and 3 mSv per treatment gray over all measurements. Only small differences were found when comparing treatment techniques, but substantial differences were observed between the linear accelerator models. The neutron dose equivalent for proton therapy was higher than for photons in general and in particular for double-scattered protons. The overall neutron dose equivalent measured in this study was an order of magnitude lower than the stray dose of a treatment using 6 MV photons, suggesting that the contribution of the secondary neutron dose equivalent to the integral dose of a radiotherapy patient is small. PMID- 24778350 TI - A novel description of FDG excretion in the renal system: application to metformin-treated models. AB - This paper introduces a novel compartmental model describing the excretion of 18F fluoro-deoxyglucose (FDG) in the renal system and a numerical method based on the maximum likelihood for its reduction. This approach accounts for variations in FDG concentration due to water re-absorption in renal tubules and the increase of the bladder's volume during the FDG excretion process. From the computational viewpoint, the reconstruction of the tracer kinetic parameters is obtained by solving the maximum likelihood problem iteratively, using a non-stationary, steepest descent approach that explicitly accounts for the Poisson nature of nuclear medicine data. The reliability of the method is validated against two sets of synthetic data realized according to realistic conditions. Finally we applied this model to describe FDG excretion in the case of animal models treated with metformin. In particular we show that our approach allows the quantitative estimation of the reduction of FDG de-phosphorylation induced by metformin. PMID- 24778351 TI - Spectral K-edge subtraction imaging. AB - We describe a spectral x-ray transmission method to provide images of independent material components of an object using a synchrotron x-ray source. The imaging system and process is similar to K-edge subtraction (KES) imaging where two imaging energies are prepared above and below the K-absorption edge of a contrast element and a quantifiable image of the contrast element and a water equivalent image are obtained. The spectral method, termed 'spectral-KES' employs a continuous spectrum encompassing an absorption edge of an element within the object. The spectrum is prepared by a bent Laue monochromator with good focal and energy dispersive properties. The monochromator focuses the spectral beam at the object location, which then diverges onto an area detector such that one dimension in the detector is an energy axis. A least-squares method is used to interpret the transmitted spectral data with fits to either measured and/or calculated absorption of the contrast and matrix material-water. The spectral-KES system is very simple to implement and is comprised of a bent Laue monochromator, a stage for sample manipulation for projection and computed tomography imaging, and a pixelated area detector. The imaging system and examples of its applications to biological imaging are presented. The system is particularly well suited for a synchrotron bend magnet beamline with white beam access. PMID- 24778352 TI - MRI characterization of cobalt dichloride-N-acetyl cysteine (C4) contrast agent marker for prostate brachytherapy. AB - Brachytherapy, a radiotherapy technique for treating prostate cancer, involves the implantation of numerous radioactive seeds into the prostate. While the implanted seeds can be easily identified on a computed tomography image, distinguishing the prostate and surrounding soft tissues is not as straightforward. Magnetic resonance imaging (MRI) offers superior anatomical delineation, but the seeds appear as dark voids and are difficult to identify, thus creating a conundrum. Cobalt dichloride-N-acetyl-cysteine (C4) has previously been shown to be promising as an encapsulated contrast agent marker. We performed spin-lattice relaxation time (T1) and spin-spin relaxation time (T2) measurements of C4 solutions with varying cobalt dichloride concentrations to determine the corresponding relaxivities, r1 and r2. These relaxation parameters were investigated at different field strengths, temperatures and orientations. T1 measurements obtained at 1.5 and 3.0 T, as well as at room and body temperature, showed that r1 is field-independent and temperature-independent. Conversely, the T2 values at 3.0 T were shorter than at 1.5 T, while the T2 values at body temperature were slightly higher than at room temperature. By examining the relaxivities with the C4 vials aligned in three different planes, we found no orientation-dependence. With these relaxation characteristics, we aim to develop pulse sequences that will enhance the C4 signal against prostatic stroma. Ultimately, the use of C4 as a positive contrast agent marker will encourage the use of MRI to obtain an accurate representation of the radiation dose delivered to the prostate and surrounding normal anatomical structures. PMID- 24778355 TI - Taiwan food scandals prompt new, stricter laws. PMID- 24778353 TI - Randomized trials with missing outcome data: how to analyze and what to report. PMID- 24778356 TI - Improving the prevention of pressure ulcers as a way to reduce health care expenditures. PMID- 24778357 TI - Star researchers join Canadian Medical Hall of Fame. PMID- 24778359 TI - Uganda's anti-gay law worries doctors and researchers. PMID- 24778360 TI - India moves to boost its Parsi population. PMID- 24778361 TI - Bupropion abuse and overdose. PMID- 24778358 TI - Use of labour induction and risk of cesarean delivery: a systematic review and meta-analysis. AB - BACKGROUND: Induction of labour is common, and cesarean delivery is regarded as its major complication. We conducted a systematic review and meta-analysis to investigate whether the risk of cesarean delivery is higher or lower following labour induction compared with expectant management. METHODS: We searched 6 electronic databases for relevant articles published through April 2012 to identify randomized controlled trials (RCTs) in which labour induction was compared with placebo or expectant management among women with a viable singleton pregnancy. We assessed risk of bias and obtained data on rates of cesarean delivery. We used regression analysis techniques to explore the effect of patient characteristics, induction methods and study quality on risk of cesarean delivery. RESULTS: We identified 157 eligible RCTs (n = 31,085). Overall, the risk of cesarean delivery was 12% lower with labour induction than with expectant management (pooled relative risk [RR] 0.88, 95% confidence interval [CI] 0.84 0.93; I(2) = 0%). The effect was significant in term and post-term gestations but not in preterm gestations. Meta-regression analysis showed that initial cervical score, indication for induction and method of induction did not alter the main result. There was a reduced risk of fetal death (RR 0.50, 95% CI 0.25-0.99; I(2) = 0%) and admission to a neonatal intensive care unit (RR 0.86, 95% CI 0.79 0.94), and no impact on maternal death (RR 1.00, 95% CI 0.10-9.57; I(2) = 0%) with labour induction. INTERPRETATION: The risk of cesarean delivery was lower among women whose labour was induced than among those managed expectantly in term and post-term gestations. There were benefits for the fetus and no increased risk of maternal death. PMID- 24778363 TI - Brain shaving: adaptive detection for brain PET data. AB - The intricacy of brain biology is such that the variation of imaging end-points in health and disease exhibits an unpredictable range of spatial distributions from the extremely localized to the very diffuse. This represents a challenge for the two standard approaches to analysis, the mass univariate and the multivariate that exhibit either strong specificity but not as good sensitivity (the former) or poor specificity and comparatively better sensitivity (the latter). In this work, we develop an analytical methodology for positron emission tomography that operates an extraction ('shaving') of coherent patterns of signal variation while maintaining control of the type I error. The methodology operates two rotations on the image data, one local using the wavelet transform and one global using the singular value decomposition. The control of specificity is obtained by using the gap statistic that selects, within each eigenvector, a subset of significantly coherent elements. Face-validity of the algorithm is demonstrated using a paradigmatic data-set with two radiotracers, [(11)C]-raclopride and [(11)C]-(R) PK11195, measured on the same Huntington's disease patients, a disorder with a genetic based diagnosis. The algorithm is able to detect the two well-known separate but connected processes of dopamine neuronal loss (localized in the basal ganglia) and neuroinflammation (diffusive around the whole brain). These processes are at the two extremes of the distributional envelope, one being very sparse and the latter being perfectly Gaussian and they are not adequately detected by the univariate and the multivariate approaches. PMID- 24778364 TI - Response-driven imaging biomarkers for predicting radiation necrosis of the brain. AB - Radiation necrosis is an uncommon but severe adverse effect of brain radiation therapy (RT). Current predictive models based on radiation dose have limited accuracy. We aimed to identify early individual response biomarkers based upon diffusion tensor (DT) imaging and incorporated them into a response model for prediction of radiation necrosis. Twenty-nine patients with glioblastoma received six weeks of intensity modulated RT and concurrent temozolomide. Patients underwent DT-MRI scans before treatment, at three weeks during RT, and one, three, and six months after RT. Cases with radiation necrosis were classified based on generalized equivalent uniform dose (gEUD) of whole brain and DT index early changes in the corpus callosum and its substructures. Significant covariates were used to develop normal tissue complication probability models using binary logistic regression. Seven patients developed radiation necrosis. Percentage changes of radial diffusivity (RD) in the splenium at three weeks during RT and at six months after RT differed significantly between the patients with and without necrosis (p = 0.05 and p = 0.01). Percentage change of RD at three weeks during RT in the 30 Gy dose-volume of the splenium and brain gEUD combined yielded the best-fit logistic regression model. Our findings indicate that early individual response during the course of RT, assessed by radial diffusivity, has the potential to aid the prediction of delayed radiation necrosis, which could provide guidance in dose-escalation trials. PMID- 24778365 TI - Sparsity-regularized image reconstruction of decomposed K-edge data in spectral CT. AB - The development of spectral computed tomography (CT) using binned photon-counting detectors has garnered great interest in recent years and has enabled selective imaging of K-edge materials. A practical challenge in CT image reconstruction of K-edge materials is the mitigation of image artifacts that arise from reduced view and/or noisy decomposed sinogram data. In this note, we describe and investigate sparsity-regularized penalized weighted least squares-based image reconstruction algorithms for reconstructing K-edge images from few-view decomposed K-edge sinogram data. To exploit the inherent sparseness of typical K edge images, we investigate use of a total variation (TV) penalty and a weighted sum of a TV penalty and an l1-norm with a wavelet sparsifying transform. Computer simulation and experimental phantom studies are conducted to quantitatively demonstrate the effectiveness of the proposed reconstruction algorithms. PMID- 24778366 TI - The contribution of human OCT1, OCT3, and CYP3A4 to nitidine chloride-induced hepatocellular toxicity. AB - Nitidine chloride (NC), a quaternary ammonium alkaloid, has numerous pharmacological effects, such as anticancer activity. However, it was found that NC also has hepatocellular toxicity. Because organic cation transporters 1 and 3 (OCT1 and OCT3) might mediate the influx of NC into hepatocytes, multidrug and toxin extrusion 1 (MATE1) probably mediates the efflux of NC from hepatocytes, while cytochrome P450 (P450) enzymes might contribute to NC metabolism, the present study was to evaluate the contribution of OCT1, OCT3, MATE1, and P450 enzymes to NC-induced hepatocellular toxicity. Our results showed that the uptake of NC in Madin-Darby canine kidney (MDCK) cells expressing human (h) OCT1 and OCT3 (MDCK-hOCT1 and MDCK-hOCT3) was significantly higher than that in mock cells; the hOCT1- and hOCT3-mediated uptake followed typical Michaelis-Menten kinetics. Meanwhile, NC was also a substrate of hMATE1, although its transport capacity was much lower than that of OCT1 NC-induced cytotoxicity in MDCK-hOCT1 or MDCK-hOCT3 cells was obviously higher than that in mock cells. Quinidine and (+)-tetrahydropalmatine [(+)-THP], OCT1 and OCT3 inhibitors, significantly reduced the uptake of NC in MDCK-hOCT1 cells, MDCK-hOCT3 cells, and rat primary hepatocytes, but only (+)-THP markedly attenuated the NC-induced toxicity. In addition, P450 enzymes, such as CYP3A4, mediated the metabolism of NC, and NC induced toxicity in MDCK-hOCT1/hCYP3A4 cells was lower than that in MDCK-hOCT1 cells. Our results indicated that NC is a substrate of hOCT1, hOCT3, and CYP3A4; that OCT1 and OCT3 mediate the uptake of NC in hepatocytes and subsequently cause hepatotoxicity; and that NC-induced toxicity could be attenuated by CYP3A4 mediated metabolism. PMID- 24778367 TI - Identification of a functional homolog of the mammalian CYP3A4 in locusts. AB - Insects have been proposed as a new tool in early drug development. It was recently demonstrated that locusts have an efflux transporter localized in the blood-brain barrier (BBB) that is functionally similar to the mammalian P glycoprotein efflux transporter. Two insect BBB models have been put forward, an ex vivo model and an in vivo model. To use the in vivo model it is necessary to fully characterize the locust as an entire organism with regards to metabolic pathways and excretion rate. In the present study, we have characterized the locust metabolism of terfenadine, a compound that in humans is specific to the cytochrome P450 enzyme 3A4. Using high-resolution mass spectrometry coupled to ultra-high-performance liquid chromatography, we have detected metabolites identical to human metabolites of terfenadine. The formation of human metabolites in locusts was inhibited by ketoconazole, a mammalian CYP3A4 inhibitor, suggesting that the enzyme responsible for the human metabolite formation in locusts is functionally similar to human CYP3A4. Besides the human metabolites of terfenadine, additional metabolites were formed in locusts. These were tentatively identified as phosphate and glucose conjugates. In conclusion, not only may locusts be a model useful for determining BBB permeation, but possibly insects could be used in metabolism investigation. However, extensive characterization of the insect model is necessary to determine its applicability. PMID- 24778368 TI - The effects of titanium mesh on passive-scattering proton dose. AB - High-density metallic implants can introduce considerable uncertainties in proton therapy treatment planning. These uncertainties eventually translate into proton range errors, which may cause significant underdosing to the target volume or overdosing to normal tissue beyond the target. This study investigated the dosimetric impact of a 0.6 mm titanium (Ti) mesh implant in passive-scattering proton beam therapy through the study of the depth dose and output in water, and the dose profiles in solid water at various depths. The measurements were performed for a beam with a range of 8.5 cm and a modulation of 7.5 cm. The titanium mesh was placed at a depth of 1 cm below the surface of the phantom for all measurements. A range reduction of 0.5 +/- 0.1 mm was observed for a beam perpendicular to the mesh, with no further reductions when the incident angle increased to 60 degrees . We conclude that the dosimetric effect of a 0.6 mm titanium mesh implant is small for a passive scattering proton beam. With proper correction applied to metal artifacts, consistent results were observed in the phantom study in the treatment planning system. PMID- 24778369 TI - Mirror neuron research: the past and the future. PMID- 24778370 TI - Human primary motor cortex is both activated and stabilized during observation of other person's phasic motor actions. AB - When your favourite athlete flops over the high-jump bar, you may twist your body in front of the TV screen. Such automatic motor facilitation, 'mirroring' or even overt imitation is not always appropriate. Here, we show, by monitoring motor cortex brain rhythms with magnetoencephalography (MEG) in healthy adults, that viewing intermittent hand actions of another person, in addition to activation, phasically stabilizes the viewer's primary motor cortex, with the maximum of half a second after the onset of the seen movement. Such a stabilization was evident as enhanced cortex-muscle coherence at 16-20 Hz, despite signs of almost simultaneous suppression of rolandic rhythms of approximately 7 and 15 Hz as a sign of activation of the sensorimotor cortex. These findings suggest that inhibition suppresses motor output during viewing another person's actions, thereby withholding unintentional imitation. PMID- 24778371 TI - Corticospinal mirror neurons. AB - Here, we report the properties of neurons with mirror-like characteristics that were identified as pyramidal tract neurons (PTNs) and recorded in the ventral premotor cortex (area F5) and primary motor cortex (M1) of three macaque monkeys. We analysed the neurons' discharge while the monkeys performed active grasp of either food or an object, and also while they observed an experimenter carrying out a similar range of grasps. A considerable proportion of tested PTNs showed clear mirror-like properties (52% F5 and 58% M1). Some PTNs exhibited 'classical' mirror neuron properties, increasing activity for both execution and observation, while others decreased their discharge during observation ('suppression mirror neurons'). These experiments not only demonstrate the existence of PTNs as mirror neurons in M1, but also reveal some interesting differences between M1 and F5 mirror PTNs. Although observation-related changes in the discharge of PTNs must reach the spinal cord and will include some direct projections to motoneurons supplying grasping muscles, there was no EMG activity in these muscles during action observation. We suggest that the mirror neuron system is involved in the withholding of unwanted movement during action observation. Mirror neurons are differentially recruited in the behaviour that switches rapidly between making your own movements and observing those of others. PMID- 24778372 TI - Hebbian learning and predictive mirror neurons for actions, sensations and emotions. AB - Spike-timing-dependent plasticity is considered the neurophysiological basis of Hebbian learning and has been shown to be sensitive to both contingency and contiguity between pre- and postsynaptic activity. Here, we will examine how applying this Hebbian learning rule to a system of interconnected neurons in the presence of direct or indirect re-afference (e.g. seeing/hearing one's own actions) predicts the emergence of mirror neurons with predictive properties. In this framework, we analyse how mirror neurons become a dynamic system that performs active inferences about the actions of others and allows joint actions despite sensorimotor delays. We explore how this system performs a projection of the self onto others, with egocentric biases to contribute to mind-reading. Finally, we argue that Hebbian learning predicts mirror-like neurons for sensations and emotions and review evidence for the presence of such vicarious activations outside the motor system. PMID- 24778373 TI - Neural systems for preparatory control of imitation. AB - Humans have an automatic tendency to imitate others. Previous studies on how we control these tendencies have focused on reactive mechanisms, where inhibition of imitation is implemented after seeing an action. This work suggests that reactive control of imitation draws on at least partially specialized mechanisms. Here, we examine preparatory imitation control, where advance information allows control processes to be employed before an action is observed. Drawing on dual route models from the spatial compatibility literature, we compare control processes using biological and non-biological stimuli to determine whether preparatory imitation control recruits specialized neural systems that are similar to those observed in reactive imitation control. Results indicate that preparatory control involves anterior prefrontal, dorsolateral prefrontal, posterior parietal and early visual cortices regardless of whether automatic responses are evoked by biological (imitative) or non-biological stimuli. These results indicate both that preparatory control of imitation uses general mechanisms, and that preparatory control of imitation draws on different neural systems from reactive imitation control. Based on the regions involved, we hypothesize that preparatory control is implemented through top-down attentional biasing of visual processing. PMID- 24778374 TI - Bodily selves in relation: embodied simulation as second-person perspective on intersubjectivity. AB - This article addresses basic aspects of social cognition focusing on the pivotal role played by the lived body in the constitution of our experience of others. It is suggested that before studying intersubjectivity we should better qualify the notion of the self. A minimal notion of the self, the bodily self, defined in terms of its motor potentialities, is proposed. The discovery of mirror mechanisms for action, emotions and sensations led to the proposal of an embodied approach to intersubjectivity-embodied simulation (ES) theory. ES and the related notion of neural reuse provide a new empirically based perspective on intersubjectivity, viewed first and foremost as intercorporeality. ES challenges the notion that folk psychology is the sole account of interpersonal understanding. ES is discussed within a second-person perspective on mindreading. PMID- 24778376 TI - Tinbergen on mirror neurons. AB - Fifty years ago, Niko Tinbergen defined the scope of behavioural biology with his four problems: causation, ontogeny, survival value and evolution. About 20 years ago, there was another highly significant development in behavioural biology-the discovery of mirror neurons (MNs). Here, I use Tinbergen's original four problems (rather than the list that appears in textbooks) to highlight the differences between two prominent accounts of MNs, the genetic and associative accounts; to suggest that the latter provides the defeasible 'best explanation' for current data on the causation and ontogeny of MNs; and to argue that functional analysis, of the kind that Tinbergen identified somewhat misleadingly with studies of 'survival value', should be a high priority for future research. In this kind of functional analysis, system-level theories would assign MNs a small, but potentially important, role in the achievement of action understanding-or another social cognitive function-by a production line of interacting component processes. These theories would be tested by experimental intervention in human and non-human animal samples with carefully documented and controlled developmental histories. PMID- 24778375 TI - Auditory-vocal mirroring in songbirds. AB - Mirror neurons are theorized to serve as a neural substrate for spoken language in humans, but the existence and functions of auditory-vocal mirror neurons in the human brain remain largely matters of speculation. Songbirds resemble humans in their capacity for vocal learning and depend on their learned songs to facilitate courtship and individual recognition. Recent neurophysiological studies have detected putative auditory-vocal mirror neurons in a sensorimotor region of the songbird's brain that plays an important role in expressive and receptive aspects of vocal communication. This review discusses the auditory and motor-related properties of these cells, considers their potential role on song learning and communication in relation to classical studies of birdsong, and points to the circuit and developmental mechanisms that may give rise to auditory vocal mirroring in the songbird's brain. PMID- 24778377 TI - Mirroring and the development of action understanding. AB - The discovery of mirror neurons in the monkey motor cortex has inspired wide ranging hypotheses about the potential relationship between action control and social cognition. In this paper, we consider the hypothesis that this relationship supports the early development of a critical aspect of social understanding, the ability to analyse others' actions in terms of goals. Recent investigations of infant action understanding have revealed rich connections between motor development and the analysis of goals in others' actions. In particular, infants' own goal-directed actions influence their analysis of others' goals. This evidence indicates that the cognitive systems that drive infants' own actions contribute to their analysis of goals in others' actions. These effects occur at a relatively abstract level of analysis both in terms of the structure infants perceive in others' actions and relevant structure in infants' own actions. Although the neural bases of these effects in infants are not yet well understood, current evidence indicates that connections between action production and action perception in infancy involve the interrelated neural systems at work in generating planned, intelligent action. PMID- 24778378 TI - Neurofeedback training produces normalization in behavioural and electrophysiological measures of high-functioning autism. AB - Autism spectrum disorder (ASD) is a neurodevelopmental condition exhibiting impairments in behaviour, social and communication skills. These deficits may arise from aberrant functional connections that impact synchronization and effective neural communication. Neurofeedback training (NFT), based on operant conditioning of the electroencephalogram (EEG), has shown promise in addressing abnormalities in functional and structural connectivity. We tested the efficacy of NFT in reducing symptoms in children with ASD by targeting training to the mirror neuron system (MNS) via modulation of EEG mu rhythms. The human MNS has provided a neurobiological substrate for understanding concepts in social cognition relevant to behavioural and cognitive deficits observed in ASD. Furthermore, mu rhythms resemble MNS phenomenology supporting the argument that they are linked to perception and action. Thirty hours of NFT on ASD and typically developing (TD) children were assessed. Both groups completed an eyes open/-closed EEG session as well as a mu suppression index assessment before and after training. Parents filled out pre- and post-behavioural questionnaires. The results showed improvements in ASD subjects but not in TDs. This suggests that induction of neuroplastic changes via NFT can normalize dysfunctional mirroring networks in children with autism, but the benefits are different for TD brains. PMID- 24778379 TI - Autism and the mirror neuron system: insights from learning and teaching. AB - Individuals with autism have difficulties in social learning domains which typically involve mirror neuron system (MNS) activation. However, the precise role of the MNS in the development of autism and its relevance to treatment remain unclear. In this paper, we argue that three distinct aspects of social learning are critical for advancing knowledge in this area: (i) the mechanisms that allow for the implicit mapping of and learning from others' behaviour, (ii) the motivation to attend to and model conspecifics and (iii) the flexible and selective use of social learning. These factors are key targets of the Early Start Denver Model, an autism treatment approach which emphasizes social imitation, dyadic engagement, verbal and non-verbal communication and affect sharing. Analysis of the developmental processes and treatment-related changes in these different aspects of social learning in autism can shed light on the nature of the neuropsychological mechanisms underlying social learning and positive treatment outcomes in autism. This knowledge in turn may assist in developing more successful pedagogic approaches to autism spectrum disorder. Thus, intervention research can inform the debate on relations among neuropsychology of social learning, the role of the MNS, and educational practice in autism. PMID- 24778380 TI - Action observation treatment: a novel tool in neurorehabilitation. AB - This review focuses on a novel rehabilitation approach known as action observation treatment (AOT). It is now a well-accepted notion in neurophysiology that the observation of actions performed by others activates in the perceiver the same neural structures responsible for the actual execution of those same actions. Areas endowed with this action observation-action execution matching mechanism are defined as the mirror neuron system. AOT exploits this neurophysiological mechanism for the recovery of motor impairment. During one typical session, patients observe a daily action and afterwards execute it in context. So far, this approach has been successfully applied in the rehabilitation of upper limb motor functions in chronic stroke patients, in motor recovery of Parkinson's disease patients, including those presenting with freezing of gait, and in children with cerebral palsy. Interestingly, this approach also improved lower limb motor functions in post-surgical orthopaedic patients. AOT is well grounded in basic neuroscience, thus representing a valid model of translational medicine in the field of neurorehabilitation. Moreover, the results concerning its effectiveness have been collected in randomized controlled studies, thus being an example of evidence-based clinical practice. PMID- 24778381 TI - The mirror neuron system as revealed through neonatal imitation: presence from birth, predictive power and evidence of plasticity. AB - There is strong evidence that neonates imitate previously unseen behaviours. These behaviours are predominantly used in social interactions, demonstrating neonates' ability and motivation to engage with others. Research on neonatal imitation can provide a wealth of information about the early mirror neuron system (MNS), namely its functional characteristics, its plasticity from birth and its relation to skills later in development. Although numerous studies document the existence of neonatal imitation in the laboratory, little is known about its natural occurrence during parent-infant interactions and its plasticity as a consequence of experience. We review these critical aspects of imitation, which we argue are necessary for understanding the early action-perception system. We address common criticisms and misunderstandings about neonatal imitation and discuss methodological differences among studies. Recent work reveals that individual differences in neonatal imitation positively correlate with later social, cognitive and motor development. We propose that such variation in neonatal imitation could reflect important individual differences of the MNS. Although postnatal experience is not necessary for imitation, we present evidence that neonatal imitation is influenced by experience in the first week of life. PMID- 24778382 TI - Dyadic brain modelling, mirror systems and the ontogenetic ritualization of ape gesture. AB - The paper introduces dyadic brain modelling, offering both a framework for modelling the brains of interacting agents and a general framework for simulating and visualizing the interactions generated when the brains (and the two bodies) are each coded up in computational detail. It models selected neural mechanisms in ape brains supportive of social interactions, including putative mirror neuron systems inspired by macaque neurophysiology but augmented by increased access to proprioceptive state. Simulation results for a reduced version of the model show ritualized gesture emerging from interactions between a simulated child and mother ape. PMID- 24778383 TI - Frequency and topography in monkey electroencephalogram during action observation: possible neural correlates of the mirror neuron system. AB - The observation of actions executed by others results in desynchronization of electroencephalogram (EEG) in the alpha and beta frequency bands recorded from the central regions in humans. On the other hand, mirror neurons, which are thought to be responsible for this effect, have been studied only in macaque monkeys, using single-cell recordings. Here, as a first step in a research programme aimed at understanding the parallels between human and monkey mirror neuron systems (MNS), we recorded EEG from the scalp of two monkeys during action observation. The monkeys were trained to fixate on the face of a human agent and subsequently to fixate on a target upon which the agent performed a grasping action. We found that action observation produced desynchronization in the 19-25 Hz band that was strongest over anterior and central electrodes. These results are in line with human data showing that specific frequency bands within the power spectrum of the ongoing EEG may be modulated by observation of actions and therefore might be a specific marker of MNS activity. PMID- 24778384 TI - Listening to speech recruits specific tongue motor synergies as revealed by transcranial magnetic stimulation and tissue-Doppler ultrasound imaging. AB - The activation of listener's motor system during speech processing was first demonstrated by the enhancement of electromyographic tongue potentials as evoked by single-pulse transcranial magnetic stimulation (TMS) over tongue motor cortex. This technique is, however, technically challenging and enables only a rather coarse measurement of this motor mirroring. Here, we applied TMS to listeners' tongue motor area in association with ultrasound tissue Doppler imaging to describe fine-grained tongue kinematic synergies evoked by passive listening to speech. Subjects listened to syllables requiring different patterns of dorso ventral and antero-posterior movements (/ki/, /ko/, /ti/, /to/). Results show that passive listening to speech sounds evokes a pattern of motor synergies mirroring those occurring during speech production. Moreover, mirror motor synergies were more evident in those subjects showing good performances in discriminating speech in noise demonstrating a role of the speech-related mirror system in feed-forward processing the speaker's ongoing motor plan. PMID- 24778385 TI - The mirror mechanism: recent findings and perspectives. AB - Mirror neurons are a specific type of visuomotor neuron that discharge both when a monkey executes a motor act and when it observes a similar motor act performed by another individual. In this article, we review first the basic properties of these neurons. We then describe visual features recently investigated which indicate that, besides encoding the goal of motor acts, mirror neurons are modulated by location in space of the observed motor acts, by the perspective from which the others' motor acts are seen, and by the value associated with the object on which others' motor acts are performed. In the last part of this article, we discuss the role of the mirror mechanism in planning actions and in understanding the intention underlying the others' motor acts. We also review some human studies suggesting that motor intention in humans may rely, as in the monkey, on the mirror mechanism. PMID- 24778386 TI - What are you doing? How active and observational experience shape infants' action understanding. AB - From early in life, infants watch other people's actions. How do young infants come to make sense of actions they observe? Here, we review empirical findings on the development of action understanding in infancy. Based on this review, we argue that active action experience is crucial for infants' developing action understanding. When infants execute actions, they form associations between motor acts and the sensory consequences of these acts. When infants subsequently observe these actions in others, they can use their motor system to predict the outcome of the ongoing actions. Also, infants come to an understanding of others' actions through the repeated observation of actions and the effects associated with them. In their daily lives, infants have plenty of opportunities to form associations between observed events and learn about statistical regularities of others' behaviours. We argue that based on these two forms of experience-active action experience and observational experience-infants gradually develop more complex action understanding capabilities. PMID- 24778388 TI - ICRP draft publication on 'radiological protection against radon exposure'. AB - To control the main part of radon exposure, the Main Commission of the International Commission on Radiological Protection (ICRP) recommends an integrated approach focused as far as possible on the management of the building or location in which radon exposure occurs whatever the purpose of the building and the types of its occupants. This approach is based on the optimisation principle and a graded approach according to the degree of responsibilities at stake, notably in workplace, as well as the level of ambition of the national authorities. The report which is being developed by the Committee 4 is considering the recently consolidated ICRP general recommendations, the new scientific knowledge about the radon risk and the experience gained by many organisations and countries in the control of radon exposure. PMID- 24778387 TI - Neural mirroring mechanisms and imitation in human infants. AB - Studying human infants will increase our understanding of the nature, origins and function of neural mirroring mechanisms. Human infants are prolific imitators. Infant imitation indicates observation-execution linkages in the brain prior to language and protracted learning. Investigations of neural aspects of these linkages in human infants have focused on the sensorimotor mu rhythm in the electroencephalogram, which occurs in the alpha frequency range over central electrode sites. Recent results show that the infant mu rhythm is desynchronized during action execution as well as action observation. Current work is elucidating properties of the infant mu rhythm and how it may relate to prelinguistic action processing and social understanding. Here, we consider this neuroscience research in relation to developmental psychological theory, particularly the 'Like-Me' framework, which holds that one of the chief cognitive tasks of the human infant is to map the similarity between self and other. We elucidate the value of integrating neuroscience findings with behavioural studies of infant imitation, and the reciprocal benefit of examining mirroring mechanisms from an ontogenetic perspective. PMID- 24778389 TI - Reply to R. Bhargava et al and K. Lambein et al. PMID- 24778390 TI - Vemurafenib-Induced Disseminated Intravascular Coagulation in Metastatic Melanoma. PMID- 24778391 TI - Clarithromycin Leading to Complete Remission in the First-Line Treatment of Ocular Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma. PMID- 24778392 TI - Nodular Regenerative Hyperplasia After Treatment With Trastuzumab Emtansine. PMID- 24778393 TI - Modafinil for the treatment of fatigue in lung cancer: results of a placebo controlled, double-blind, randomized trial. AB - PURPOSE: Fatigue is a distressing symptom occurring in more than 60% of patients with cancer. The CNS stimulants modafinil and methylphenidate are recommended for the treatment of cancer-related fatigue, despite a limited evidence base. We aimed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Adults with advanced NSCLC and performance status of 0 to 2, who were not treated with chemotherapy or radiotherapy within the last 4 weeks, were randomly assigned to daily modafinil (100 mg on days 1 to 14; 200 mg on days 15 to 28) or matched placebo. The primary outcome was change in Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue score from baseline to 28 days, adjusted for baseline fatigue and performance status. Secondary outcomes included safety and patient-reported measures of depression, daytime sleepiness, and quality of life. RESULTS: A total of 208 patients were randomly assigned, and 160 patients (modafinil, n = 75; placebo, n = 85) completed questionnaires at both baseline and day 28 and were included in the modified intention-to-treat analysis. FACIT-Fatigue scores improved from baseline to day 28 (mean score change: modafinil, 5.29; 95% CI, 2.57 to 8.02; placebo, 5.09; 95% CI, 2.54 to 7.65), but there was no difference between treatments (0.20; 95% CI, -3.56 to 3.97). There was also no difference between treatments for the secondary outcomes; 47% of the modafinil group and 23% of the placebo group stated that the intervention was not helpful. CONCLUSION: Modafinil had no effect on cancer related fatigue and should not be prescribed outside a clinical trial setting. Its use was associated with a clinically significant placebo effect. PMID- 24778395 TI - Muscular Relapse in a Patient With Multiple Myeloma. PMID- 24778394 TI - Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. AB - PURPOSE: Patients with Cowden syndrome (CS) with underlying germline PTEN mutations are at increased risk of breast, thyroid, endometrial, and renal cancers. To our knowledge, risk of subsequent cancers in these patients has not been previously explored or quantified. PATIENTS AND METHODS: We conducted a 7 year multicenter prospective study (2005 to 2012) of patients with CS or CS-like disease, all of whom underwent comprehensive PTEN mutational analysis. Second malignant neoplasms (SMNs) were ascertained by medical records and confirmed by pathology reports. Standardized incidence ratios (SIRs) for all SMNs combined and for breast, thyroid, endometrial, and renal cancers were calculated. RESULTS: Of the 2,912 adult patients included in our analysis, 2,024 had an invasive cancer history. Germline pathogenic PTEN mutations (PTEN mutation positive) were identified in 114 patients (5.6%). Of these 114 patients, 46 (40%) had an SMN. Median age of SMN diagnosis was 50 years (range, 21 to 71 years). Median interval between primary cancer and SMN was 5 years (range, <1 to 35 years). Of the 51 PTEN mutation-positive patients who presented with primary breast cancer, 11 (22%) had a subsequent new primary breast cancer and 10-year second breast cancer cumulative risk of 29% (95% CI, 15.3 to 43.7). Risk of SMNs compared with that of the general population was significantly elevated for all cancers (SIR, 7.74; 95% CI, 5.84 to 10.07), specifically for breast (SIR, 8.92; 95% CI, 5.85 to 13.07), thyroid (SIR, 5.83; 95% CI, 3.01 to 10.18), and endometrial SMNs (SIR, 14.08.07; 95% CI, 7.10 to 27.21). CONCLUSION: Patients with CS with germline PTEN mutations are at higher risk for SMNs compared with the general population. Prophylactic mastectomy should be considered on an individual basis given the significant risk of subsequent breast cancer. PMID- 24778396 TI - Is there any benefit from hypofractionation in external-beam irradiation for prostate cancer? PMID- 24778397 TI - Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. AB - PURPOSE: To better understand oral human papillomavirus (HPV) infection and cancer risk among long-term sexual partners of patients with HPV-positive oropharyngeal cancer (HPV-OPC). PATIENTS AND METHODS: An oral rinse sample, risk factor survey, cancer history, and oral examination (partners only) were collected from patients with HPV-OPC and their partners. Oral rinse samples were evaluated for 36 types of HPV DNA using PGMY 09/11 primers and line-blot hybridization and HPV16 copy number using quantitative polymerase chain reaction. Oral HPV prevalence was compared with infection among those age 45 to 65 years using National Health and Nutrition Examination Survey (NHANES) 2009-2010. RESULTS: A total of 164 patients with HPV-OPC and 93 of their partners were enrolled. Patients were primarily men (90%), were never-smokers (51%), and had performed oral sex (97%), with a median age of 56 years; they had a high prevalence of oncogenic oral HPV DNA (61%) and oral HPV16 DNA (54%) at enrollment. Female partners had comparable oncogenic oral HPV prevalence compared with members of the general population of the same age (1.2% v 1.3%). Among the six male partners, no oncogenic oral HPV infections were detected. No precancers or cancers were identified during partner oral cancer screening examinations. However, a history of cervical disease was reported by nine partners (10.3%) and two female patients (11.8%), and three patients (2.0%) reported a previous partner who developed invasive cervical cancer. CONCLUSION: Oral HPV16 DNA is commonly detected among patients with HPV-OPC at diagnosis, but not among their partners. Partners of patients with HPV-OPC do not seem to have elevated oral HPV infection compared with the general population. PMID- 24778398 TI - Trifecta of science: originality, controversy, confirmation. PMID- 24778399 TI - 2013 update of the American Society of Clinical Oncology/College of American Pathologists guideline for human epidermal growth factor receptor 2 testing: impact on immunohistochemistry-negative breast cancers. PMID- 24778400 TI - Hypofractionated radiation therapy for prostate cancer: more food for thought from recent trial. PMID- 24778401 TI - Myasthenia Gravis Induced by Ipilimumab in Patients With Metastatic Melanoma. PMID- 24778402 TI - Reply to M.J. Brenner et al and I.R. Vogelius et al. PMID- 24778404 TI - Interpretation of human epidermal growth factor receptor 2 (HER2) in situ hybridization assays using 2013 update of American Society of Clinical Oncology/College of American Pathologists HER2 Guidelines. PMID- 24778403 TI - Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. AB - Discovery of Bruton's tyrosine kinase (BTK) mutations as the cause for X-linked agammaglobulinemia was a milestone in understanding the genetic basis of primary immunodeficiencies. Since then, studies have highlighted the critical role of this enzyme in B-cell development and function, and particularly in B-cell receptor signaling. Because its deletion affects mostly B cells, BTK has become an attractive therapeutic target in autoimmune disorders and B-cell malignancies. Ibrutinib (PCI-32765) is the most advanced BTK inhibitor in clinical testing, with ongoing phase III clinical trials in patients with chronic lymphocytic leukemia and mantle-cell lymphoma. In this article, we discuss key discoveries related to BTK and clinically relevant aspects of BTK inhibitors, and we provide an outlook into clinical development and open questions regarding BTK inhibitor therapy. PMID- 24778406 TI - Too heavy, too late: investigating perinatal health outcomes in immigrants residing in Spain. A cross-sectional study (2009-2011). AB - BACKGROUND: Studies have shown that immigrants residing in Spain have lower risks of delivering low birthweight (LBW) and preterm babies despite their socioeconomic disadvantages (the healthy migrant paradox). However, less is known about other important perinatal outcomes derived from birth weight and gestational age such as macrosomia and post-term birth. This paper aims to compare the main indicators related to birth weight and gestational age (LBW, macrosomia, preterm and post-term) for immigrants and Spaniards. METHODS: Cross sectional study based on the Spanish vital statistics for years 2009-2011. Multinomial regression models were performed to obtain crude and adjusted ORs and their 95% CIs. RESULTS: After adjusting for known confounders, compared with Spaniards, most immigrant groups show lower or not significantly different risks of delivering LBW (OR between 0.65 and 0.87) or, more exceptionally, preterm babies (between 0.75 and 0.93). However, most of them also show higher risks of delivering macrosomic (OR between 1.21 and 2.58) and post-term babies (OR between 1.11 and 1.50). Mothers from sub-Saharan Africa show a higher risk in all perinatal outcomes studied. CONCLUSIONS: The immigrant health paradox should be carefully assessed in comprehensive terms. Together with a predominantly lower risk of LBW, most immigrants have a higher risk of macrosomia, post-term and preterm births. These results have policy-making implications since studying the right tail of the birth weight and gestational age distributions implies considering a different set of risk factors. PMID- 24778412 TI - Transparent reporting of missing outcome data in clinical trials: applying the general principles of CONSORT 2010. PMID- 24778413 TI - Topical antibiotic therapy is superior to systemic antibiotics for acute tympanostomy tube otorrhoea, but may not be necessary for all children. PMID- 24778411 TI - Schizophrenia--time to commit to policy change. AB - Care and outcomes for people with schizophrenia have improved in recent years, but further progress is needed to help more individuals achieve an independent and fulfilled life. This report sets out the current need, informs policy makers and all relevant stakeholders who influence care quality, and supports their commitment to creating a better future. The authors recommend the following policy actions, based on research evidence, stakeholder consultation, and examples of best practice worldwide. (1) Provide an evidence-based, integrated care package for people with schizophrenia that addresses their mental and physical health needs. (2) Provide support for people with schizophrenia to enter and to remain in their community, and develop mechanisms to help guide them through the complex benefit and employment systems. (3) Provide concrete support, information, and educational programs to families and carers on how to enhance care for an individual living with schizophrenia in a manner that entails minimal disruption to their lives. (4) All stakeholders, including organizations that support people living with schizophrenia, should be consulted to regularly revise, update, and improve policy on the management of schizophrenia. (5) Provide support, which is proportionate to the impact of the disease, for research and development of new treatments. (6) Establish adequately funded, ongoing, and regular awareness-raising campaigns that form an integral part of routine plans of action. Implementation of the above recommendations will require engagement by every stakeholder, but with commitment from all, change can be achieved. PMID- 24778414 TI - Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. AB - The recently identified Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe and fatal acute respiratory illness in humans. However, no prophylactic and therapeutic agents specifically against MERS-CoV are currently available. Entry of MERS-CoV into target cells depends on binding of the receptor binding domain (RBD) of the viral envelope spike glycoprotein to the cellular receptor dipeptidyl peptidase 4 (DPP4). We report the isolation and characterization of two potent human RBD-specific neutralizing monoclonal antibodies (MERS-4 and MERS-27) derived from single-chain variable region fragments of a nonimmune human antibody library. MERS-4 and MERS-27 inhibited infection of both pseudotyped and live MERS-CoV with IC50 (half-maximal inhibitory concentration) at nanomolar concentrations. MERS-4 also showed inhibitory activity against syncytia formation mediated by interaction between MERS-CoV spike glycoprotein and DPP4. Combination of MERS-4 and MERS-27 demonstrated a synergistic effect in neutralization against pseudotyped MERS-CoV. Biochemical analysis indicated that MERS-4 and MERS-27 blocked RBD interaction with DPP4 on the cell surface. MERS-4, in particular, bound soluble RBD with an about 45-fold higher affinity than DPP4. Mutagenesis analysis suggested that MERS 4 and MERS-27 recognized distinct regions in RBD. These results suggest that MERS 4 and MERS-27 are RBD-specific potent inhibitors and could serve as promising candidates for prophylactic and therapeutic interventions against MERS-CoV infection. PMID- 24778416 TI - Lipid metabolism signatures in NASH-associated HCC.--letter. PMID- 24778415 TI - Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity. AB - Immunization against self-tumor antigens can induce T-regulatory cells, which inhibit proliferation of type I CD4(+) T-helper (TH1) and CD8(+) cytotoxic T cells. Type I T cells are required for potent antitumor immunity. We questioned whether immunosuppressive epitopes could be identified and deleted from a cancer vaccine targeting insulin-like growth factor-binding protein (IGFBP-2) and enhance vaccine efficacy. Screening breast cancer patient lymphocytes with IFN gamma and interleukin (IL)-10 ELISPOT, we found epitopes in the N-terminus of IGFBP-2 that elicited predominantly TH1 whereas the C-terminus stimulated TH2 and mixed TH1/TH2 responses. Epitope-specific TH2 demonstrated a higher functional avidity for antigen than epitopes, which induced IFN-gamma (P = 0.014). We immunized TgMMTV-neu mice with DNA constructs encoding IGFBP-2 N-and C-termini. T cell lines expanded from the C-terminus vaccinated animals secreted significantly more type II cytokines than those vaccinated with the N-terminus and could not control tumor growth when infused into tumor-bearing animals. In contrast, N terminus epitope-specific T cells secreted TH1 cytokines and significantly inhibited tumor growth, as compared with naive T cells, when adoptively transferred (P = 0.005). To determine whether removal of TH2-inducing epitopes had any effect on the vaccinated antitumor response, we immunized mice with the N terminus, C-terminus, and a mix of equivalent concentrations of both vaccines. The N-terminus vaccine significantly inhibited tumor growth (P < 0.001) as compared with the C-terminus vaccine, which had no antitumor effect. Mixing the C terminus with the N-terminus vaccine abrogated the antitumor response of the N terminus vaccine alone. The clinical efficacy of cancer vaccines targeting self tumor antigens may be greatly improved by identification and removal of immunosuppressive epitopes. PMID- 24778417 TI - Chemotherapeutic targeting of cancer-induced immunosuppressive cells. AB - The expansion of immunosuppressive cells represents a cardinal strategy deployed by tumors to escape from detection and elimination by the immune system. Regulatory T lymphocytes (Treg) and myeloid-derived suppressor cells (MDSC), major components of these inhibitory cellular networks, have drawn intense scrutiny in recent years. In patients with cancer and in animal tumor models, these suppressor cells accumulate in the tumor microenvironment, secondary lymphoid tissues, and in the blood. Equipped with the ability to suppress innate and adaptive anticancer immunity, these cells also foster disease development by promoting tumor neoangiogenesis and by enhancing cancer metastasis. They therefore represent major impediments for anticancer therapies, particularly for immune-based interventions. Recent work has provided evidence that beyond their direct cytotoxic or cytostatic effects on cancer cells, several conventional chemotherapeutic drugs and agents used in targeted therapies can promote the elimination or inactivation of suppressive Tregs or MDSCs, resulting in enhanced antitumor immunity. We analyze findings pertinent to this concept, discuss the possible molecular bases underlying the selective targeting of these immunosuppressive cells by antineoplastic agents, and consider current challenges and future prospects related to the integration of these molecules into more efficient anticancer chemoimmunotherapeutic strategies. PMID- 24778418 TI - Releasing pressure in tumors: what do we know so far and where do we go from here? A review. AB - Tumor interstitial pressure is a fundamental feature of cancer biology. Elevation in tumor pressure affects the efficacy of cancer treatment. It causes heterogenous intratumoral distribution of drugs and macromolecules. It also causes the development of hypoxia within tumor bulk, leading to reduced efficacy of therapeutic drugs and radiotherapy. Tumor pressure has been associated with increased metastatic potential and poor prognosis in some tumors. The formation of increased pressure in solid tumors is multifactorial. Factors known to affect tumor pressure include hyperpermeable tortuous tumor vasculatures, the lack of functional intratumoral lymphatic vessels, abnormal tumor microenvironment, and the solid stress exerted by proliferating tumor cells. Reducing this pressure is known to enhance the uptake and homogenous distribution of many therapies. Pharmacologic and biologic agents have been shown to reduce tumor pressure. These include antiangiogenic therapy, vasodilatory agents, antilymphogenic therapy, and proteolytic enzymes. Physical manipulation has been shown to cause reduction in tumor pressure. These include irradiation, hyperbaric oxygen therapy, hyper- or hypothermic therapy, and photodynamic therapy. This review explores the methods to reduce tumor pressure that may open up new avenues in cancer treatment. PMID- 24778419 TI - PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. AB - Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs. We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia inducible factor-1alpha (HIF-1alpha) but not HIF-2alpha. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF 1alpha to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs. Simultaneous blockade of PD-L1 along with inhibition of HIF-1alpha may thus represent a novel approach for cancer immunotherapy. PMID- 24778420 TI - The specificity of DNA recognition by the RAGE receptor. AB - A recent paper by Sirois et al. in The Journal of Experimental Medicine reports that the receptor for advanced glycation end-products (RAGE) promotes uptake of DNA into endosomes and lowers the immune recognition threshold for the activation of Toll-like receptor 9. Two crystal structures suggested that the DNA phosphate deoxyribose backbone is recognized by RAGE through well-defined interactions. However, the electron densities for the DNA molecules are weak enough that the presented modeling of DNA is questionable, and models only containing RAGE account for the observed diffraction data just as well as the RAGE-DNA complexes presented by the authors. PMID- 24778422 TI - Polytrauma to right diaphragm, descending thoracic aorta, and innominate artery. AB - Traumatic diaphragmatic rupture with concomitant great vessel injuries is a catastrophic and life-threatening injury group that requires immediate identification and management. It can be both diagnostically and therapeutically very challenging. We report a case of combined traumatic diaphragmatic, aortic and innominate artery injuries, which was managed successfully. To have a fruitful outcome, management of this injury complex should preferably be staged depending on the hemodynamic stability of the patient. In a patient with traumatic diaphragmatic injuries, one should also have a high index of suspicion of associated great vessel injuries. PMID- 24778423 TI - Which calculation method of glomerular filtration rate is suitable in patients with normal or mildly impaired renal function? PMID- 24778424 TI - Health benefits of the Mediterranean Diet: an update of research over the last 5 years. AB - The Mediterranean Diet (MedDiet) has been reported to be protective against the occurrence of several diseases. Increasing evidence suggests that the MedDiet could counter diseases associated with chronic inflammation, including metabolic syndrome, atherosclerosis, cancer, diabetes, obesity, pulmonary diseases, and cognition disorders. Adoption of a MedDiet was associated with beneficial effects on the secretion of anti-inflammatory cytokines, antioxidant cellular and circulating biomarkers as well as with regulation of gene polymorphisms involved in the atherosclerotic process. The MedDiet has been considered for the prevention of cardiovascular and other chronic degenerative diseases focusing on the impact of a holistic dietary approach rather than on single nutrients. Epidemiological dietary scores measuring adherence to a MedDiet have been developed. This narrative review considers the results of up-to-date clinical studies (with a focus on the last 5 years) that evaluated the effectiveness of the MedDiet in reducing the prevalence of chronic and degenerative diseases. PMID- 24778426 TI - Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without Mannitol. AB - BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of mannitol as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single agent cisplatin with and without mannitol. METHODS: This single-center retrospective analysis was a quasi experiment created by the national mannitol shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive mannitol were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m2 dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of mannitol are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m2 cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of mannitol. PMID- 24778425 TI - Clot strength is negatively associated with ambulatory function in patients with peripheral artery disease and intermittent claudication. AB - Peripheral artery disease (PAD) is associated with exercise impairment and greater thrombotic risk. We investigated whether clot formation and platelet aggregation assessed by thromboelastography and light-transmission aggregometry correlate with the severity of symptomatic PAD assessed by ambulatory function measures. We studied 40 symptomatic patients with PAD in whom severity of disease was assessed using ankle-brachial index, peak walking time (PWT), claudication onset time, peak oxygen uptake, daily ambulatory activity, and walking impairment questionnaire (WIQ) scores. Clot strength correlated negatively with peak oxygen uptake, PWT, WIQ distance, and stair-climbing scores. Time to clot formation did not correlate with exercise parameters. Platelet aggregation was negatively correlated with WIQ distance score and was positively correlated with PWT and peak oxygen uptake. In conclusion, clot strength and platelet aggregation correlated with objective and self-perceived ambulatory measures. Patients with PAD having more severe walking impairment may be likely to form stronger clots. PMID- 24778427 TI - Of volume regulation, arterial constriction, and apoptotic breakdown. PMID- 24778428 TI - The cytoplasmic cage domain of the mechanosensitive channel MscS is a sensor of macromolecular crowding. AB - Cells actively regulate the macromolecular excluded volume of the cytoplasm to maintain the reciprocal fraction of free aqueous solution that is optimal for intracellular processes. However, the mechanisms whereby cells sense this critical parameter remain unclear. The mechanosensitive channel of small conductance (MscS channel), which is the major regulator of turgor in bacteria, mediates efflux of small osmolytes in response to increased membrane tension. At moderate sustained tensions produced by a decrease in external osmolarity, MscS undergoes slow adaptive inactivation; however, it inactivates abruptly in the presence of cytoplasmic crowding agents. To understand the mechanism underlying this rapid inactivation, we combined extrapolated and equilibrium molecular dynamics simulations with electrophysiological analyses of MscS mutants to explore possible transitions of MscS and generated models of the resting and inactivated states. Our models suggest that the coupling of the gate formed by TM3 helices to the peripheral TM1-TM2 pairs depends on the axial position of the core TM3 barrel relative to the TM1-TM2 shaft and the state of the associated hollow cytoplasmic domain ("cage"). They also indicate that the tension-driven inactivation transition separates the gate from the peripheral helices and promotes kinks in TM3s at G113 and that this conformation is stabilized by association of the TM3b segment with the beta domain of the cage. We found that mutations destabilizing the TM3b-beta interactions preclude inactivation and make the channel insensitive to crowding agents and voltage; mutations that strengthen this association result in a stable closed state and silent inactivation. Steered simulations showed that pressure exerted on the cage bottom in the inactivated state reduces the volume of the cage in the cytoplasm and at the same time increases the footprint of the transmembrane domain in the membrane, implying coupled sensitivity to both membrane tension and crowding pressure. The cage, therefore, provides feedback on the increasing crowding that disengages the gate and prevents excessive draining and condensation of the cytoplasm. We discuss the structural mechanics of cells surrounded by an elastic cell wall where this MscS specific feedback mechanism may be necessary. PMID- 24778429 TI - Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle. AB - Transient receptor potential vanilloid 4 (TRPV4) channels are Ca(2+)-permeable, nonselective cation channels expressed in multiple tissues, including smooth muscle. Although TRPV4 channels play a key role in regulating vascular tone, the mechanisms controlling Ca(2+) influx through these channels in arterial myocytes are poorly understood. Here, we tested the hypothesis that in arterial myocytes the anchoring protein AKAP150 and protein kinase C (PKC) play a critical role in the regulation of TRPV4 channels during angiotensin II (AngII) signaling. Super resolution imaging revealed that TRPV4 channels are gathered into puncta of variable sizes along the sarcolemma of arterial myocytes. Recordings of Ca(2+) entry via single TRPV4 channels ("TRPV4 sparklets") suggested that basal TRPV4 sparklet activity was low. However, Ca(2+) entry during elementary TRPV4 sparklets was ~ 100-fold greater than that during L-type CaV1.2 channel sparklets. Application of the TRPV4 channel agonist GSK1016790A or the vasoconstrictor AngII increased the activity of TRPV4 sparklets in specific regions of the cells. PKC and AKAP150 were required for AngII-induced increases in TRPV4 sparklet activity. AKAP150 and TRPV4 channel interactions were dynamic; activation of AngII signaling increased the proximity of AKAP150 and TRPV4 puncta in arterial myocytes. Furthermore, local stimulation of diacylglycerol and PKC signaling by laser activation of a light-sensitive Gq-coupled receptor (opto alpha1AR) resulted in TRPV4-mediated Ca(2+) influx. We propose that AKAP150, PKC, and TRPV4 channels form dynamic subcellular signaling domains that control Ca(2+) influx into arterial myocytes. PMID- 24778430 TI - Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells. AB - The sinoatrial node, whose cells (sinoatrial node cells [SANCs]) generate rhythmic action potentials, is the primary pacemaker of the heart. During diastole, calcium released from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) interacts with membrane currents to control the rate of the heartbeat. This "calcium clock" takes the form of stochastic, partially periodic, localized calcium release (LCR) events that propagate, wave-like, for limited distances. The detailed mechanisms controlling the calcium clock are not understood. We constructed a computational model of SANCs, including three dimensional diffusion and buffering of calcium in the cytosol and SR; explicit, stochastic gating of individual RyRs and L-type calcium channels; and a full complement of voltage- and calcium-dependent membrane currents. We did not include an anatomical submembrane space or inactivation of RyRs, the two heuristic components that have been used in prior models but are not observed experimentally. When RyRs were distributed in discrete clusters separated by >1 um, only isolated sparks were produced in this model and LCR events did not form. However, immunofluorescent staining of SANCs for RyR revealed the presence of bridging RyR groups between large clusters, forming an irregular network. Incorporation of this architecture into the model led to the generation of propagating LCR events. Partial periodicity emerged from the interaction of LCR events, as observed experimentally. This calcium clock becomes entrained with membrane currents to accelerate the beating rate, which therefore was controlled by the activity of the SERCA pump, RyR sensitivity, and L-type current amplitude, all of which are targets of beta-adrenergic-mediated phosphorylation. Unexpectedly, simulations revealed the existence of a pathological mode at high RyR sensitivity to calcium, in which the calcium clock loses synchronization with the membrane, resulting in a paradoxical decrease in beating rate in response to beta-adrenergic stimulation. The model indicates that the hierarchical clustering of surface RyRs in SANCs may be a crucial adaptive mechanism. Pathological desynchronization of the clocks may explain sinus node dysfunction in heart failure and RyR mutations. PMID- 24778432 TI - Reduced Tic Symptomatology in Tourette Syndrome After an Acute Bout of Exercise: An Observational Study. AB - In light of descriptive accounts of attenuating effects of physical activity on tics, we used an experimental design to assess the impact of an acute bout of aerobic exercise on tic expression in young people (N = 18) with Tourette Syndrome (TS). We compared video-based tic frequency estimates obtained during an exercise session with tic rates obtained during pre-exercise (baseline) and post exercise interview-based sessions. Results showed significantly reduced tic rates during the exercise session compared with baseline, suggesting that acute exercise has an attenuating effect on tics. Tic rates also remained reduced relative to baseline during the post-exercise session, likely reflecting a sustained effect of exercise on tic reduction. Parallel to the observed tic attenuation, exercise also had a beneficial impact on self-reported anxiety and mood levels. The present findings provide novel empirical evidence for the beneficial effect of exercise on TS symptomatology bearing important research and clinical implications. PMID- 24778431 TI - Asymmetric functional contributions of acidic and aromatic side chains in sodium channel voltage-sensor domains. AB - Voltage-gated sodium (NaV) channels mediate electrical excitability in animals. Despite strong sequence conservation among the voltage-sensor domains (VSDs) of closely related voltage-gated potassium (KV) and NaV channels, the functional contributions of individual side chains in Nav VSDs remain largely enigmatic. To this end, natural and unnatural side chain substitutions were made in the S2 hydrophobic core (HC), the extracellular negative charge cluster (ENC), and the intracellular negative charge cluster (INC) of the four VSDs of the skeletal muscle sodium channel isoform (NaV1.4). The results show that the highly conserved aromatic side chain constituting the S2 HC makes distinct functional contributions in each of the four NaV domains. No obvious cation-pi interaction exists with nearby S4 charges in any domain, and natural and unnatural mutations at these aromatic sites produce functional phenotypes that are different from those observed previously in Kv VSDs. In contrast, and similar to results obtained with Kv channels, individually neutralizing acidic side chains with synthetic derivatives and with natural amino acid substitutions in the INC had little or no effect on the voltage dependence of activation in any of the four domains. Interestingly, countercharge was found to play an important functional role in the ENC of DI and DII, but not DIII and DIV. These results suggest that electrostatic interactions with S4 gating charges are unlikely in the INC and only relevant in the ENC of DI and DII. Collectively, our data highlight domain specific functional contributions of highly conserved side chains in NaV VSDs. PMID- 24778434 TI - The Effectiveness of the Snug Vest on Stereotypic Behaviors in Children Diagnosed With an Autism Spectrum Disorder. AB - Various reviews of the effects of sensory integration therapy (SIT) have concluded that such interventions fail to reduce stereotypy. However, a new, and as yet untested, SIT iteration, an inflatable wearable vest known as the Snug Vest purports to decrease such repetitive behavior. In the current study, three children who emitted different forms of stereotypy participated in an alternating treatments design in which each participant wore a fully inflated vest and either a fully deflated vest or no vest. The results of the study show that the Snug Vest failed to reduce any participants' stereotypy. We highlight our findings in the context of professional practice and discuss several potential limitations. PMID- 24778433 TI - Variables Associated With Tic Exacerbation in Children With Chronic Tic Disorders. AB - Research has shown that motor and vocal tics fluctuate in frequency, intensity, and form in response to environmental and contextual cues. Behavioral models have proposed that some of the variation in tics may reflect context-dependent interactive learning processes such that once tics are performed, they are influenced by environmental contingencies. The current study describes the results of a function-based assessment of tics (FBAT) from a recently completed study comparing Comprehensive Behavioral Intervention for Tics (CBIT) with supportive psychotherapy. The current study describes the frequency with which antecedent and consequence variables were reported to exacerbate tics and the relationships between these functional variables and sample baseline characteristics, comorbidities, and measures of tic severity. Results showed that tic-exacerbating antecedents and consequences were nearly ubiquitous in a sample of children with chronic tic disorder. In addition, functional variables were related to baseline measures of comorbid internalizing symptoms and specific measures of tic severity. PMID- 24778435 TI - Polymorphic Microsatellite Loci for Endemic Mussismilia Corals (Anthozoa: Scleractinia) of the Southwest Atlantic Ocean. AB - In the Southwest Atlantic, coral reefs are unique due to their growth form, low species richness, and a high level of endemic coral species, which include the most important reef builders. Although these reefs are the only true biogenic reefs in the South Atlantic Ocean, population genetic studies are still lacking. The purpose of this study was to develop a suite of microsatellite loci to help gain insights into the population diversity and connectivity of the endemic scleractinian coral with the largest distributional range along the Southwest Atlantic coast, Mussismilia hispida Fourteen microsatellite loci were characterized, and their degree of polymorphism was analyzed in 33 individuals. The number of alleles varied between 4 and 17 per loci, and H o varied between 0.156 and 0.928, with 2 loci showing significant heterozygote deficiency. Cross amplification tests on the other 2 species of the genus (Mussismilia braziliensis and Mussismilia harttii) demonstrated that these markers are suitable for studies of population diversity and structure of all 3 species of Mussismilia Because they are the most important reef builders in the Southwest Atlantic, the developed microsatellite loci may be important tools for connectivity and conservation studies of these endemic corals. PMID- 24778437 TI - Nulla dies sine linea. PMID- 24778436 TI - A pilot randomised controlled trial to evaluate the feasibility and acceptability of the Baby Triple P Positive Parenting Programme in mothers with postnatal depression. AB - Few interventions for Postnatal Depression (PND) have focused on parenting difficulties; the aim of this research was to investigate the feasibility and evaluate a parenting intervention (Baby Triple P) in women with PND. This was a pilot randomised controlled trial (RCT) to evaluate and determine the feasibility of the newly developed Baby Triple P compared with treatment as usual (TAU) in women with PND. In all, 27 female participants aged from 18 to 45 years (mean age = 28.4 years, standard deviation (SD) = 6.1), with a primary diagnosis of major depression and an infant under 12 months (mean age = 6.2 months, SD = 3.2 months), were recruited from primary care trusts in Greater Manchester, United Kingdom. Participants were randomly allocated to receive either eight Baby Triple P sessions in addition to TAU or TAU only. Outcomes were assessed at post treatment (Time 2) and 3 months post-treatment (Time 3). Self-report outcomes were as follows: Beck Depression Inventory, Oxford Happiness Inventory, What Being the Parent of a New Baby is Like, Postpartum Bonding Questionnaire and the Brief Parenting Beliefs Scale-baby version. An assessor-rated observational measure of mother-infant interaction, the CARE Index and measure of intervention acceptability were also completed. Significant improvements from Time 1 to Time 2 and Time 1 to Time 3 were observed across both groups. Although women allocated to Baby Triple P showed more favourable improvements, the between-group differences were not significant. However, the intervention was highly acceptable to women with PND. A large-scale RCT is indicated. PMID- 24778438 TI - Diagnostic test for dementias. PMID- 24778439 TI - How to interpret meta-analysis models: fixed effect and random effects meta analyses. AB - This section of the journal is aimed at providing the essential information readers should know about the topics that are addressed in the 'Statistics in practice' paper published in the same issue of the journal. This stand-alone section has to be seen as an articulated summary of the main notions clinicians have to know about some basic concepts in statistics, which may be useful for their evidence-based practice. After going through these notes, readers are encouraged to read the 'Statistics in practice' articles. Of course, we welcome any feedback from you (via email or Twitter) about this! The EBMH Editors Relative treatment effects studied in trials are typically measured using an effect size. The observed effect sizes are synthesised to obtain a summary treatment effect via meta-analysis. PMID- 24778440 TI - CD4+ T cells from human neonates and infants are poised spontaneously to run a nonclassical IL-4 program. AB - Senescence or biological aging impacts a vast variety of molecular and cellular processes. To date, it is unknown whether CD4(+) Th cells display an age dependent bias for development into specific subpopulations. In this study, we show the appearance of a distinct CD4(+) T cell subset expressing IL-4 at an early stage of development in infant adenoids and cord blood that is lost during aging. We identified by flow cytometric, fluorescent microscopic, immunoblot, and mass spectrometric analysis a population of CD4(+) T cells that expressed an unglycosylated isoform of IL-4. This T cell subpopulation was found in neonatal but not in adult CD4(+) T cells. Furthermore, we show that the mRNA of the Th2 master transcription factor GATA3 is preferentially expressed in neonatal CD4(+) T cells. The Th2 phenotype of the IL-4(+)CD4(+) T cells could be reinforced in the presence of TGF-beta. Although the IL-4(+)CD4(+) T cells most likely originate from CD31(+)CD4(+) T recent thymic emigrants, CD31 was downregulated prior to secretion of IL-4. Notably, the secretion of IL-4 requires a so far unidentified trigger in neonatal T cells. This emphasizes that cytokine expression and secretion are differentially regulated processes. Our data support the hypothesis of an endogenously poised cytokine profile in neonates and suggest a link between cytokine production and the developmental stage of an organism. The determination of the IL-4 isoform-expressing cells in humans might allow the identification of Th2 precursor cells, which could provide novel intervention strategies directed against Th2-driven immunopathologies such as allergies. PMID- 24778442 TI - Recombinant human hyaluronidase PH20 does not stimulate an acute inflammatory response and inhibits lipopolysaccharide-induced neutrophil recruitment in the air pouch model of inflammation. AB - Hyaluronidase (Hyal) and low m.w. hyaluronan (LMW HA) fragments have been widely reported to stimulate the innate immune response. However, most hyaluronidases used were purified from animal tissues (e.g., bovine testis Hyal [BTH]), and contain endotoxin and other unrelated proteins. We tested a highly purified recombinant human Hyal (rHuPH20) and endotoxin-free HA fragments from M(r) 5,000 to 1,500,000 in the rodent air pouch model of inflammation to determine their potential for stimulation of the innate immune response. Exogenous LMW HA fragments (average M(r) 200,000) failed to induce either cytokine/chemokine production or neutrophil infiltration into the air pouch. Challenging the air pouch with LPS or BTH stimulated production of cytokines and chemokines but rHuPH20 did not, suggesting that neither PH20 nor generation of LMW HA fragments in situ stimulates cytokine and chemokine production. LPS and BTH also induced neutrophil infiltration into the air pouch, which was not observed with rHuPH20 treatment. Endotoxin-depleted BTH had much reduced proinflammatory activity, suggesting that the difference in inflammatory responses between rHuPH20 and BTH is likely due to endotoxin contaminants in BTH. When rHuPH20 was dosed with LPS, the induction of cytokines and chemokines was the same as LPS alone, but neutrophil infiltration was inhibited, likely by interrupting HA-CD44 interaction. Our results indicate that neither rHuPH20 nor its directly generated HA catabolites have inflammatory properties in the air pouch model, and rHuPH20 can instead inhibit some aspects of inflammation, such as neutrophil infiltration into the air pouch. PMID- 24778441 TI - Longitudinal requirement for CD4+ T cell help for adenovirus vector-elicited CD8+ T cell responses. AB - Despite the widespread use of replication-incompetent recombinant adenovirus (Ad) vectors as candidate vaccine platforms, the mechanism by which these vectors elicit CD8(+) T cell responses remains poorly understood. Our data demonstrate that induction and maintenance of CD8(+) T cell responses by Ad vector immunization is longitudinally dependent on CD4(+) T cell help for a prolonged period. Depletion of CD4(+) T cells in wild type mice within the first 8 d following Ad immunization resulted in dramatically reduced induction of Ag specific CD8(+) T cells, decreased T-bet and eomesodermin expression, impaired KLRG1(+) effector differentiation, and atypical expression of the memory markers CD127, CD27, and CD62L. Moreover, these CD8(+) T cells failed to protect against a lethal recombinant Listeria monocytogenes challenge. Depletion of CD4(+) T cells between weeks 1 and 4 following immunization resulted in increased contraction of memory CD8(+) T cells. These data demonstrate a prolonged temporal requirement for CD4(+) T cell help for vaccine-elicited CD8(+) T cell responses in mice. These findings have important implications in the design of vaccines aimed at eliciting CD8(+) T cell responses and may provide insight into the impaired immunogenicity of vaccines in the context of AIDS and other CD4(+) T cell immune deficiencies. PMID- 24778443 TI - IFN-gamma-producing CD4+ T cells promote generation of protective germinal center derived IgM+ B cell memory against Salmonella Typhi. AB - Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C- and F-based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4(+) T cell-dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-gamma-secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-gamma and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM(+) B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN gammaR signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs. PMID- 24778444 TI - NADPH oxidase modifies patterns of MHC class II-restricted epitopic repertoires through redox control of antigen processing. AB - The chemistries within phagosomes of APCs mediate microbial destruction as well as generate peptides for presentation on MHC class II. The antimicrobial effector NADPH oxidase (NOX2), which generates superoxide within maturing phagosomes, has also been shown to regulate activities of cysteine cathepsins through modulation of the lumenal redox potential. Using real-time analyses of lumenal microenvironmental parameters, in conjunction with hydrolysis pattern assessment of phagocytosed proteins, we demonstrated that NOX2 activity not only affects levels of phagosomal proteolysis as previously shown, but also the pattern of proteolytic digestion. Additionally, it was found that NOX2 deficiency adversely affected the ability of bone marrow-derived macrophages, but not dendritic cells, to process and present the I-A(b)-immunodominant peptide of the autoantigen myelin oligodendrocyte glycoprotein (MOG). Computational and experimental analyses indicated that the I-A(b) binding region of the immunodominant peptide of MOG is susceptible to cleavage by the NOX2-controlled cysteine cathepsins L and S in a redox-dependent manner. Consistent with these findings, I-A(b) mice that were deficient in the p47(phox) or gp91(phox) subunits of NOX2 were partially protected from MOG-induced experimental autoimmune encephalomyelitis and displayed compromised reactivation of MOG-specific CD4(+) T cells in the CNS, despite eliciting a normal primary CD4(+) T cell response to the inoculated MOG Ag. Taken together, this study demonstrates that the redox microenvironment within the phagosomes of APCs is a determinant in MHC class II repertoire production in a cell-specific and Ag-specific manner, which can ultimately impact susceptibility to CD4(+) T cell-driven autoimmune disease processes. PMID- 24778446 TI - Recognition of distinct cross-reactive virus-specific CD8+ T cells reveals a unique TCR signature in a clinical setting. AB - Human CMV still remains problematic in immunocompromised patients, particularly after solid organ transplantation. CMV primary disease and reactivation greatly increase the risks associated with incidences of chronic allograft rejection and decreased survival in transplant recipients. But whether this is due to direct viral effects, indirect viral effects including cross-reactive antiviral T cell immunopathology, or a combination of both remains undetermined. In this article, we report the novel TCR signature of cross-reactive HLA-A*02:01 (A2) CMV (NLVPMVATV [NLV])-specific CD8(+) T cells recognizing a specific array of HLA-B27 alleles using technical advancements that combine both IFN-gamma secretion and multiplex nested RT-PCR for determining paired CDR3alpha/beta sequences from a single cell. This study represents the first evidence, to our knowledge, of the same A2-restricted cross-reactive NLV-specific TCR-alpha/beta signature (TRAV3TRAJ31_TRBV12-4TRBJ1-1) in two genetically distinct individuals. Longitudinal posttransplant monitoring of a lung transplant recipient (A2, CMV seropositive) who received a HLA-B27 bilateral lung allograft showed a dynamic expansion of the cross-reactive NLV-specific TCR repertoire before CMV reactivation. After resolution of the active viral infection, the frequency of cross-reactive NLV-specific CD8(+) T cells reduced to previremia levels, thereby demonstrating immune modulation of the T cell repertoire due to antigenic pressure. The dynamic changes in TCR repertoire, at a time when CMV reactivation was subclinical, illustrates that prospective monitoring in susceptible patients can reveal nuances in immune profiles that may be clinically relevant. PMID- 24778445 TI - Maternal KIR in combination with paternal HLA-C2 regulate human birth weight. AB - Human birth weight is subject to stabilizing selection; babies born too small or too large are less likely to survive. Particular combinations of maternal/fetal immune system genes are associated with pregnancies where the babies are <= 5th birth weight centile, specifically an inhibitory maternal KIR AA genotype with a paternally derived fetal HLA-C2 ligand. We have now analyzed maternal KIR and fetal HLA-C combinations at the opposite end of the birth weight spectrum. Mother/baby pairs (n = 1316) were genotyped for maternal KIR as well as fetal and maternal HLA-C. Presence of a maternal-activating KIR2DS1 gene was associated with increased birth weight in linear or logistic regression analyses of all pregnancies >5th centile (p = 0.005, n = 1316). Effect of KIR2DS1 was most significant in pregnancies where its ligand, HLA-C2, was paternally but not maternally inherited by a fetus (p = 0.005, odds ratio = 2.65). Thus, maternal KIR are more frequently inhibitory with small babies but activating with big babies. At both extremes of birth weight, the KIR associations occur when their HLA-C2 ligand is paternally inherited by a fetus. We conclude that the two polymorphic immune gene systems, KIR and HLA-C, contribute to successful reproduction by maintaining birth weight between two extremes with a clear role for paternal HLA. PMID- 24778447 TI - Cross-desensitization of CCR1, but not CCR2, following activation of the formyl peptide receptor FPR1. AB - The cross-regulation of G protein-coupled receptors (GPCRs) plays an important role in the immune response. Studies from several laboratories have suggested that a hierarchy of sensitivities to cross-desensitization exists for the chemoattractant GPCRs. We carried out experiments to study the capacity of the formyl peptide receptor-1 (FPR1) to desensitize chemokine receptors CCR1 and CCR2. Our results show that activation of FPR1 resulted in the desensitization and partial internalization of CCR1, but not CCR2, in both primary human monocytes and HEK293 cells coexpressing CCR1, CCR2, and FPR1 (HR1R2F cells). The desensitization of CCR1 by FPR1 stimulation was not due to the simple depletion of the Ca(2+) stores, but was dependent on activation of protein kinase C. Furthermore, we found that the cross-desensitization of CCR1 by FPR1 was associated with CCR1 phosphorylation and moderate reduction of CCR1 cell-surface expression. In contrast, CCR2 was not phosphorylated or internalized after FPR1 activation. Additional studies showed that optimal cross talk between FPR1 and CCR1 was dependent on the functional activity of protein kinase Cbeta. These results provide a mechanistic basis for the capacity of certain GPCR ligands to exert rapid and selective cross-inactivation of other chemoattractant receptors, and suggest that FPR1 is able to exert "traffic control" in the migration of inflammatory cells by rapidly inhibiting the cell responses to potentially "low priority" chemoattractants such as CCR1 agonists without inhibiting the response to "higher priority" CCR2 chemoattractants. PMID- 24778448 TI - Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production. AB - Naive CD4(+) T cells require signals from the TCR and CD28 to produce IL-2, expand, and differentiate. However, these same signals are not sufficient to induce autocrine IL-2 production by naive CD8(+) T cells, which require cytokines provided by other cell types to drive their differentiation. The basis for failed autocrine IL-2 production by activated CD8(+) cells is unclear. We find that Ikaros, a transcriptional repressor that silences IL-2 in anergic CD4(+) T cells, also restricts autocrine IL-2 production by CD8(+) T cells. We find that CD8(+) T cell activation in vitro in the absence of exogenous cytokines and CD4 help leads to marked induction of Ikaros, a known repressor of the Il2 gene. Naive murine CD8 T cells haplo-insufficient for Ikzf1 failed to upregulate Ikaros, produced autocrine IL-2, and differentiated in an IL-2-dependent manner into IFN-gamma producing CTLs in response to TCR/CD28 stimulation alone. Furthermore, Ikzf1 haplo-insufficient CD8(+) T cells were more effective at controlling Listeria infection and B16 melanoma growth in vivo, and they could provide help to neighboring, non-IL-2-producing cells to differentiate into IFN-gamma-producing effectors. Therefore, by repressing autocrine IL-2 production, Ikaros ensures that naive CD8(+) T cells remain dependent on licensing by APCs and CD4(+) T cells, and it may therefore act as a cell-intrinsic safeguard against inappropriate CTL differentiation and immunopathology. PMID- 24778449 TI - Endoplasmic reticulum targeting alters regulation of expression and antigen presentation of proinsulin. AB - Peptide ligands presented by MHC class I (MHC-I) molecules are produced by degradation of cytosolic and nuclear, but also endoplasmic reticulum (ER) resident, proteins by the proteasome. However, Ag processing of ER proteins remains little characterized. Studying processing and presentation of proinsulin, which plays a pivotal role in autoimmune diabetes, we found that targeting to the ER has profound effects not only on how proinsulin is degraded, but also on regulation of its cellular levels. While proteasome inhibition inhibited degradation and presentation of cytosolic proinsulin, as expected, it reduced the abundance of ER-targeted proinsulin. This targeting and protein modifications modifying protein half-life also had profound effects on MHC-I presentation and proteolytic processing of proinsulin. Thus, presentation of stable luminal forms was inefficient but enhanced by proteasome inhibition, whereas that of unstable luminal forms and of a cytosolic form were more efficient and compromised by proteasome inhibitors. Distinct stability of peptide MHC complexes produced from cytosolic and luminal proinsulin suggests that different proteolytic activities process the two Ag forms. Thus, both structural features and subcellular targeting of Ags can have strong effects on the processing pathways engaged by MHC-I-restricted Ags, and on the efficiency and regulation of their presentation. PMID- 24778451 TI - Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury. AB - High levels of inspired oxygen, hyperoxia, are frequently used in patients with acute respiratory failure. Hyperoxia can exacerbate acute respiratory failure, which has high mortality and no specific therapies. We identified novel roles for PTEN-induced putative kinase 1 (PINK1), a mitochondrial protein, and the cytosolic innate immune protein NLRP3 in the lung and endothelium. We generated double knockouts (PINK1(-/-)/NLRP3(-/-)), as well as cell-targeted PINK1 silencing and lung-targeted overexpression constructs, to specifically show that PINK1 mediates cytoprotection in wild-type and NLRP3(-/-) mice. The ability to resist hyperoxia is proportional to PINK1 expression. PINK1(-/-) mice were the most susceptible; wild-type mice, which induced PINK1 after hyperoxia, had intermediate susceptibility; and NLRP3(-/-) mice, which had high basal and hyperoxia-induced PINK1, were the least susceptible. Genetic deletion of PINK1 or PINK1 silencing in the lung endothelium increased susceptibility to hyperoxia via alterations in autophagy/mitophagy, proteasome activation, apoptosis, and oxidant generation. PMID- 24778450 TI - Increased immunoaccessibility of MOMP epitopes in a vaccine formulated with amphipols may account for the very robust protection elicited against a vaginal challenge with Chlamydia muridarum. AB - There is a need to implement a vaccine to protect against Chlamydia trachomatis infections. To test a new vaccine, mice were immunized with the Chlamydia muridarum native major outer membrane protein (nMOMP) solubilized with either amphipol A8-35 or the detergent Z3-14. OVA was used as a negative control, and mice were inoculated intranasally with C. muridarum as positive controls. Animals vaccinated with nMOMP mounted strong Chlamydia-specific humoral and cell-mediated immune responses. Mice vaccinated with nMOMP/A8-35 had a higher ratio of Abs to denatured elementary bodies (EB) over live EB, recognized more synthetic MOMP peptides and had higher neutralizing titers than sera from mice immunized with nMOMP/Z3-14. T cell lymphoproliferative responses and levels of IFN-gamma were also higher in mice vaccinated with nMOMP/A8-35 than with nMOMP/Z3-14. Following immunization, animals were challenged intravaginally with C. muridarum. On the basis of the number of mice with positive vaginal cultures, length of vaginal shedding, total number of positive vaginal cultures, and number of Chlamydia inclusion forming units recovered, nMOMP/A8-35 elicited a more robust protection than nMOMP/Z3-14. By depleting T cells with Abs, we determined that CD4(+) and not CD8(+) T cells mediated the protection elicited by nMOMP/A8-35. Mice were subsequently mated, and based on the number of pregnant mice and number of embryos, animals that were vaccinated with nMOMP/A8-35 or nMOMP/Z3-14 had fertility rates equivalent to the positive control group immunized with live EB and the fertility controls. In conclusion, increased accessibility of epitopes in the nMOMP/A8-35 preparation may account for the very robust protection against infection and disease elicited by this vaccine. PMID- 24778452 TI - Human cardiac extracellular matrix supports myocardial lineage commitment of pluripotent stem cells. AB - OBJECTIVES: Cross-talk between organ-specific extracellular matrix (ECM) and stem cells is often assumed but has not been directly demonstrated. We developed a protocol for the preparation of human cardiac ECM (cECM) and studied whether cECM has effects on pluripotent stem cell differentiation that may be useful for future cardiac regeneration strategies in patients with end-stage heart failure. METHODS: Of note, 0.3 mm-thick cECM slices were prepared from samples of myocardium from patients with end-stage non-ischaemic dilated cardiomyopathy, using a three-step protocol involving hypotonic lysis buffer, sodium dodecyl sulphate (SDS) and foetal bovine serum (FBS). Murine embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and mesenchymal stromal cells (MSCs) were seeded and grown in standard culture, on cECM or on non-specific ECM preparations (Matrigel(r) or Geltrex(r)). Cell attachment, apoptosis induction (Caspase 3/7 activity) and metabolic activity (3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium conversion) were followed. Transcriptional activation of genes involved in pluripotency; early and late myocardial development; and endothelial, ectodermal or endodermal commitment were monitored by quantitative real-time polymerase chain reaction (rtPCR). Protein expression of selected markers was confirmed by immunohistology. RESULTS: cECM supported the proliferation of ESCs and iPSCs, and Caspase 3/7 activity was significantly lower compared with standard culture. Cardiac lineage commitment was favoured when ESCs or iPSCs were grown on cECM, as evidenced by the significantly increased mRNA expression of cardiac alpha myosin heavy polypeptide 6 (Myh6), cardiac troponin T2 (Tnnt2) and NK2 homeobox 5 (Nkx2.5) as well as positive immunohistology for cardiac troponin T and heavy-chain cardiac myosin protein. In contrast, Matrigel or Geltrex did not induce cardiac-specific markers. MSCs showed no evidence of cardiomyocyte differentiation. CONCLUSIONS: Human cardiac ECM seems to direct differentiation of pluripotent stem cells towards a cardiomyocyte phenotype. This phenomenon supports the use of cardiac ECM preparations for guided stem cell differentiation and myocardial repair, and may ultimately increase the therapeutic efficacy of cell therapy in heart failure patients. PMID- 24778455 TI - Standing up for science: The antivivisection movement and how to stand up to it. PMID- 24778453 TI - Mechanisms of epigenetic memory and addiction. AB - Epigenetic regulation of cellular identity and function is at least partly achieved through changes in covalent modifications on DNA and histones. Much progress has been made in recent years to understand how these covalent modifications affect cell identity and function. Despite the advances, whether and how epigenetic factors contribute to memory formation is still poorly understood. In this review, we discuss recent progress in elucidating epigenetic mechanisms of learning and memory, primarily at the DNA level, and look ahead to discuss their potential implications in reward memory and development of drug addiction. PMID- 24778454 TI - Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression. AB - Development of novel therapies is critical for T-cell acute leukaemia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleukin 18 (IL-18) as transcriptionally up-regulated in MEKi treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL 18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xenografted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development. PMID- 24778456 TI - S-sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair. AB - The repair of DNA damage is fundamental to normal cell development and replication. Hydrogen sulfide (H2S) is a novel gasotransmitter that has been reported to protect cellular aging. Here, we show that H2S attenuates DNA damage in human endothelial cells and fibroblasts by S-sulfhydrating MEK1 at cysteine 341, which leads to PARP-1 activation. H2S-induced MEK1 S-sulfhydration facilitates the translocation of phosphorylated ERK1/2 into nucleus, where it activates PARP-1 through direct interaction. Mutation of MEK1 cysteine 341 inhibits ERK phosphorylation and PARP-1 activation. In the presence of H2S, activated PARP-1 recruits XRCC1 and DNA ligase III to DNA breaks to mediate DNA damage repair, and cells are protected from senescence. PMID- 24778457 TI - Roosting behaviour and habitat selection of Pteropus giganteus reveals potential links to Nipah virus epidemiology. AB - 1. Flying foxes Pteropus spp. play a key role in forest regeneration as seed dispersers and are also the reservoir of many viruses, including Nipah virus in Bangladesh. Little is known about their habitat requirements, particularly in South Asia. Identifying Pteropus habitat preferences could assist in understanding the risk of zoonotic disease transmission broadly, and in Bangladesh, could help explain the spatial distribution of human Nipah virus cases. 2. We analysed characteristics of Pteropus giganteus roosts and constructed an ecological niche model to identify suitable habitat in Bangladesh. We also assessed the distribution of suitable habitat in relation to the location of human Nipah virus cases. 3. Compared to non-roost trees, P. giganteus roost trees are taller with larger diameters, and are more frequently canopy trees. Colony size was larger in densely forested regions and smaller in flood-affected areas. Roosts were located in areas with lower annual precipitation and higher human population density than non-roost sites. 4. We predicted that 2-17% of Bangladesh's land area is suitable roosting habitat. Nipah virus outbreak villages were 2.6 times more likely to be located in areas predicted as highly suitable habitat for P. giganteus compared to non-outbreak villages. 5. Synthesis and applications. Habitat suitability modelling may help identify previously undocumented Nipah outbreak locations and improve our understanding of Nipah virus ecology by highlighting regions where there is suitable bat habitat but no reported human Nipah virus. Conservation and public health education is a key component of P. giganteus management in Bangladesh due to the general misunderstanding and fear of bats that are a reservoir of Nipah virus. Affiliation between Old World fruit bats (Pteropodidae) and people is common throughout their range, and in order to conserve these keystone bat species and prevent emergence of zoonotic viruses, it is imperative that we continue to improve our understanding of Pteropus resource requirements and routes of virus transmission from bats to people. Results presented here can be utilized to develop land management strategies and conservation policies that simultaneously protect fruit bats and public health. PMID- 24778458 TI - Membership of Defined Responses in Stimulus Classes. AB - Sidman (2000) has suggested that in addition to conditional and discriminative stimuli, class-consistent defined responses can also become part of an equivalence class. In the current study, this assertion was tested using a mixed schedule procedure that allowed defined response patterns to be "presented" as samples in the absence of different occasioning stimuli. Four typically developing adults were first trained to make distinct response topographies to two visual color stimuli, and then were taught to match those color stimuli to two different form-sample stimuli in a matching task. Three separate tests were given in order to determine whether training had established two classes each comprised of a response, a color, and a form: a form-response test in which the forms were presented to test if the participants would make differential responses to them; and two response-matching tests to test if the participants would match visual stimulus comparisons to response-pattern samples. Three of the four participants showed class-consistent responding in the tests, although some participants needed additional training prior to passing the tests. In general, the data indicated that the different response patterns had entered into a class with the visual stimuli. These results add to a growing literature on the role of class-consistent responding in stimulus class formation, and provide support for the notion that differential responses themselves can become a part of an equivalence class. PMID- 24778459 TI - The Relationship Between Expressive Vocabulary Knowledge and Reading Skills for Adult Struggling Readers. AB - This study examined expressive vocabulary and its relationship to reading skills for 232 native English-speaking adults who read between the third- and fifth grade levels. The Boston Naming Test (BNT; Kaplan, Goodglass, & Weintraub, 2001) was used to measure expressive vocabulary. Participants scored lower than the normative sample of adults on all aspects of the test; they had fewer spontaneously correct answers, and were not helped by stimulus or phonemic cues. Hierarchical regression analyses revealed that expressive vocabulary accounted for significant variance in both reading comprehension and exception word reading, but not for general word reading or nonword reading. PMID- 24778460 TI - X ray storage performance of KCl:Eu2+ with high cumulated dose. AB - The effects of high cumulative radiation dose on the luminescence properties of KCl:Eu2+ are investigated. Pellet samples of KCl:Eu2+ were given doses of up to 200 kGy at the Louisiana State University Synchrotron facility. After synchrotron irradiation, samples were optically bleached and given a clinical dose of 2 Gy from a 6 MV medical linear accelerator. Optical properties were evaluated using photostimulated luminescence (PSL), photoluminescence (PL), and temperature dependent PSL measurements. For a cumulated dose of up to 5-10 kGy, the PSL emission intensity increased by 15% compared to the PSL signal with no radiation history. For doses higher than 10 kGy, the PSL emission intensity retained at least 70% of the original intensity. Spatial correlation of the charge storage centers increased for doses up to 5 kGy and then decreased for higher cumulative doses. Emission band at 975 nm was attributed to transitions of Eu1+. PL spectra showed an intense peak centered at 420 nm for all cumulative doses. The results of this work show that KCl:Eu2+ storage phosphors are excellent reusable materials for radiation therapy dosimetry. PMID- 24778461 TI - Temperature dependence of the photostimulated luminescence in KCl:Eu2+ AB - The goal of this work is to understand the physical mechanism behind the signal stabilization process in KCl:Eu2+, a storage phosphor material that has generated renewed interest due to its potential in radiation therapy dosimetry application. The temperature dependency of the photostimulated luminescence (PSL) spectra and intensity vs. time post x ray irradiation was measured. Commercial BaFBr:Eu2+ materials were included in this study for comparison. Unlike BaFBr:Eu2+, broadening of the F(Cl-) stimulation band and red-shift of the peak were observed for KCl:Eu2+ with increasing temperature. For irradiations at temperatures lower than 200 K, PSL intensity of KCl:Eu2+ showed recuperation behavior in the first 2 hrs post-irradiation and stayed almost constant with time thereafter. Moreover, spatially-correlated storage centers increased from 24% for irradiation at 50 K to 31% at 195 K and almost 100% at room temperature. The data suggest that certain types of charge storage-centers were mobile and contribute to the fast fading in PSL. PMID- 24778462 TI - Subsemble: an ensemble method for combining subset-specific algorithm fits. AB - Ensemble methods using the same underlying algorithm trained on different subsets of observations have recently received increased attention as practical prediction tools for massive datasets. We propose Subsemble: a general subset ensemble prediction method, which can be used for small, moderate, or large datasets. Subsemble partitions the full dataset into subsets of observations, fits a specified underlying algorithm on each subset, and uses a clever form of V fold cross-validation to output a prediction function that combines the subset specific fits. We give an oracle result that provides a theoretical performance guarantee for Subsemble. Through simulations, we demonstrate that Subsemble can be a beneficial tool for small to moderate sized datasets, and often has better prediction performance than the underlying algorithm fit just once on the full dataset. We also describe how to include Subsemble as a candidate in a SuperLearner library, providing a practical way to evaluate the performance of Subsemlbe relative to the underlying algorithm fit just once on the full dataset. PMID- 24778463 TI - Potential uses, limitations, and basic procedures of micronuclei and nuclear abnormalities in buccal cells. AB - The use of biomarkers as tools to evaluate genotoxicity is increasing recently. Methods that have been used previously to evaluate genomic instability are frequently expensive, complicated, and invasive. The micronuclei (MN) and nuclear abnormalities (NA) technique in buccal cells offers a great opportunity to evaluate in a clear and precise way the appearance of genetic damage whether it is present as a consequence of occupational or environmental risk. This technique is reliable, fast, relatively simple, cheap, and minimally invasive and causes no pain. So, it is well accepted by patients; it can also be used to assess the genotoxic effect derived from drug use or as a result of having a chronic disease. Furthermore the beneficial effects derived from changes in life style or taking additional supplements can also be evaluated. In the present paper, we aim to focus on the explanation of MN test and its usefulness as a biomarker; we further give details about procedures to perform and interpret the results of the test and review some factors that could have an influence on the results of the technique. PMID- 24778464 TI - Christianity and Eugenics: The Place of Religion in the British Eugenics Education Society and the American Eugenics Society, c.1907-1940. AB - Historians have regularly acknowledged the significance of religious faith to the eugenics movement in Britain and the USA. However, much of this scholarship suggests a polarised relationship of either conflict or consensus. Where Christian believers participated in the eugenics movement this has been represented as an abandonment of 'orthodox' theology, and the impression has been created that eugenics was a secularising force. In contrast, this article explores the impact of religious values on two eugenics organisations: the British Eugenics Education Society, and the American Eugenics Society. It is demonstrated that concerns over religion resulted in both these organisations modifying and tempering the public work that they undertook. This act of concealing and minimising the visibly controversial aspects of eugenics is offered as an addition to the debate over 'mainline' versus 'reform' eugenics. PMID- 24778465 TI - Sexual activity and body image: examining gender variability and the influence of psychological distress in cancer patients. AB - Psychosocial factors impacting on the overall quality of life for cancer patients may differ between men and women. This study examined the influence that psychological distress, clinical, and social variables have on sexual activity and body image in adult oncology patients. Symptom data was collected from the Memorial Symptom Assessment Scale (MSAS). Analysis indicated women and patients with reported functional limitations were more likely to be less satisfied with how they looked. The final model showed that younger adults, Caucasians, those who were married and patients with some functional limitations were more likely to have problems with sexual interest/activity. Gender was not a significant predictor of having problems with sexual interest/activity. These results can be used by clinicians to identify patients who may be at an increased risk for negative body image and problems in sexual functioning. Further research regarding gender differences in cancer-related psychological symptoms is needed to assist healthcare professionals in providing comprehensive care while alleviating unresolved and interrelated health and psychosocial symptoms. PMID- 24778466 TI - In vitro endothelial cell proliferation assay reveals distinct levels of proangiogenic cytokines characterizing sera of healthy subjects and of patients with heart failure. AB - Although myocardial angiogenesis is thought to play an important role in heart failure (HF), the involvement of circulating proinflammatory and proangiogenic cytokines in the pathogenesis and/or prognosis of HF has not been deeply investigated. By using a highly standardized proliferation assay with human endothelial cells, we first demonstrated that sera from older (mean age 52 +/- 7.6 years; n = 46) healthy donors promoted endothelial cell proliferation to a significantly higher extent compared to sera obtained from younger healthy donors (mean age 29 +/- 8.6 years; n = 20). The promotion of endothelial cell proliferation was accompanied by high serum levels of several proangiogenic cytokines. When we assessed endothelial cell proliferation in response to HF patients' sera, we observed that a subset of sera (n = 11) promoted cell proliferation to a significantly lesser extent compared to the majority of sera (n = 18). Also, in this case, the difference between the patient groups in the ability to induce endothelial cell proliferation correlated to significant (P < 0.05) differences in serum proangiogenic cytokine levels. Unexpectedly, HF patients associated to the highest endothelial proliferation index showed the worst prognosis as evaluated in terms of subsequent cardiovascular events in the follow-up, suggesting that high levels of circulating proangiogenic cytokines might be related to a worse prognosis. PMID- 24778469 TI - Fish smoking and COPD: A fishy affair. PMID- 24778467 TI - Reduction of the number of major representative allergens: from clinical testing to 3-dimensional structures. AB - Vast amounts of allergen sequence data have been accumulated, thus complicating the identification of specific allergenic proteins when performing diagnostic allergy tests and immunotherapy. This study aims to rank the importance/potency of the allergens so as to logically reduce the number of allergens and/or allergenic sources. Meta-analysis of 62 allergenic sources used for intradermal testing on 3,335 allergic patients demonstrated that in southern China, mite, sesame, spiny amaranth, Pseudomonas aeruginosa, and house dust account for 88.0% to 100% of the observed positive reactions to the 62 types of allergenic sources tested. The Kolmogorov-Smironov Test results of the website-obtained allergen data and allergen family featured peptides suggested that allergen research in laboratories worldwide has been conducted in parallel on many of the same species. The major allergens were reduced to 21 representative allergens, which were further divided into seven structural classes, each of which contains similar structural components. This study therefore has condensed numerous allergenic sources and major allergens into fewer major representative ones, thus allowing for the use of a smaller number of allergens when conducting comprehensive allergen testing and immunotherapy treatments. PMID- 24778468 TI - Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis. AB - Although biologic therapies have changed the course of rheumatoid arthritis (RA), today's major challenge remains to identify biomarkers to target treatments to selected patient groups. Circulating micro(mi)RNAs represent a novel class of molecular biomarkers whose expression is altered in RA. Our study aimed at quantifying miR-125b in blood and serum samples from RA patients, comparing healthy controls and patients with other forms of rheumatic diseases and arthritis, and evaluating its predictive value as biomarker for response to rituximab. Detectable levels of miR-125b were measured in total blood and serum samples and were significantly elevated in RA patients compared to osteoarthritic and healthy donors. The increase was however also found in patients with other forms of chronic inflammatory arthritis. Importantly, high serum levels of miR 125b at disease flare were associated with good clinical response to treatment with rituximab three months later (P = 0.002). This predictive value was not limited to RA as it was also found in patients with B lymphomas. Our results identify circulating miR-125b as a novel miRNA over expressed in RA and suggest that serum level of miR-125b is potential predictive biomarker of response to rituximab treatment. PMID- 24778470 TI - Unusual sojourn of not-so-unusual pathogens. PMID- 24778471 TI - The relationship between lung function and indoor air pollution among rural women in the Niger Delta region of Nigeria. AB - BACKGROUND: Burning of biomass is widely used by the rural poor for energy generation. Long term exposure to biomass smoke is believed to affect lung function and cause respiratory symptoms. MATERIALS AND METHODS: Women with long term occupational exposure to burning firewood were recruited from a rural fishing community in Nigeria. A questionnaire was used to obtain information on symptoms of chronic bronchitis and spirometery was performed to measure lung function. Data obtained from the subjects was compared with that from healthy controls. RESULTS: Six hundred and eighty six women were recruited for this study made up of 342 subjects and 346 controls. Sixty eight (19.9%) of the subjects had chronic bronchitis compared with eight (2.3%) of the controls (chi(2) = 54.0, P < 0.001). The subjects had lower values for the lung function as well as the percentage predicted values (P < 0.05). Fish smoking and chronic bronchitis were significantly associated with predicted lung volumes. CONCLUSION: Chronic exposure to biomass smoke is associated with chronic bronchitis and reduced lung functions in women engaged in fish smoking. PMID- 24778472 TI - Comparison between childhood and adult tuberculosis in a rural tuberculosis unit of West Bengal: A retrospective study. AB - BACKGROUND AND OBJECTIVES: Tuberculosis (TB) is an important cause of childhood morbidity and mortality with different clinical presentations and outcomes as compared to TB in adults. The present study was designed to compare these differences and to determine if childhood TB was an important predictor of adverse outcome following treatment under the Revised National Tuberculosis Control Program (RNTCP). MATERIALS AND METHODS: Retrospective record based study of cases registered between January 2008 and December 2011, at the Amdanga TB Unit (TU), West Bengal. RESULTS: Of the total 1,508 cases notified, 3.4% were childhood TB. Differences with adult TB were noted in the number of cases categorized as cat II and III in children (P = 0.012 and 0.000, respectively). New smear positive pulmonary TB was significantly lower (21.6%, P = 0.000), while new extra-pulmonary TB (39.2%, P = 0.000) was significantly higher in children. Smear negative cases comprised 7.8 and 11.4% of the childhood and adult cases of TB, respectively. Retreatment cases were significantly higher in adults (P = 0.012). Among the registered new smear positive cases, the differences in favourable and adverse outcomes did not have a significant statistical difference (P = .100). Childhood TB was not a significant risk factor for adverse outcome following treatment (adjusted odds ratio [AOR] = 0.80, 95% confidence interval [CI] = 0.28-2.32). CONCLUSIONS: The registration of childhood TB under the RNTCP in the TU was low. There were differences in the clinical presentation and treatment outcomes of TB among children and adults. Childhood TB was not a significant predictor of adverse treatment following treatment. PMID- 24778473 TI - Impact of obesity on bronchial asthma in Indian population. AB - BACKGROUND AND OBJECTIVE: Obesity and asthma are common inflammatory conditions, having presence of both local and systemic inflammation and this relationship is not well understood. This study was undertaken to compare pulmonary function parameters, inflammatory marker like C-reactive protein (hs-CRP), exhaled nitric oxide (FENO) and atopic profile between non-obese and obese bronchial asthma patients in Indian population. The study aims to elucidate the association between the systemic and local inflammatory response relating to obesity in asthmatics. MATERIALS AND METHODS: Sixty bronchial asthma patients were recruited for the study, and were divided equally into obese (BMI>30 kg/m(2)) and non-obese (BMI<25 kg/m(2)) groups. These were assessed for pulmonary function parameters, blood hs-CRP levels, exhaled breath analysis of nitric oxide and skin prick testing for atopic profile. The study was approved by institutional ethical committee. RESULTS: The mean body mass index (BMI) for the non-obese and obese group was 21.64 kg/m(2) and 34.1 kg/m(2) respectively (P = 0.001). The functional residual capacity (FRC% predicted) (100.9 +/- 4.21 vs 80.40 +/- 4.03; P = 0.009) and expiratory reserve volume (ERV% predicted) (95.13 +/- 6.71 vs. 67.03 +/- 4.54; P = 0.001) both were significantly lower in the obese group. The non-obese and obese group had hs-CRP levels of 3.01 mg/L and 4.07 mg/L, respectively; the difference being statistically insignificant (P = 0.15). Similarly, FENO levels of non-obese and obese group were 63.20 ppb and 63.75 ppb, respectively; difference was not statistically significant (P = 0.95). Atopic profile of both the groups did not differ significantly. CONCLUSION: Obesity does not appear to increase the local and systemic inflammatory responses in bronchial asthma patients in Indian population. PMID- 24778474 TI - Weaning of mechanically ventilated chronic obstructive pulmonary disease patients by using non-invasive positive pressure ventilation: A prospective study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients frequently pose difficulty in weaning from invasive mechanical ventilation (MV). Prolonged invasive ventilation brings along various complications. Non-invasive positive pressure ventilation (NIPPV) is proposed to be a useful weaning modality in such cases. OBJECTIVE: To evaluate the usefulness of NIPPV in weaning COPD patients from invasive MV, and compare it with weaning by conventional pressure support ventilation (PSV). MATERIALS AND METHODS: For this prospective randomized controlled study, we included 50 COPD patients with type II respiratory failure requiring initial invasive MV. Upon satisfying weaning criteria and failing a t piece weaning trial, they were randomized into two groups: Group I (25 patients) weaned by NIPPV, and group II (25 patients) weaned by conventional PSV. The groups were similar in terms of disease severity, demographic, clinical and biochemical parameters. They were compared in terms of duration of MV, weaning duration, length of intensive care unit (ICU) stay, occurrence of nosocomial pneumonia and outcome. RESULTS: Statistically significant difference was found between the two groups in terms of duration of MV, weaning duration, length of ICU stay, occurrence of nosocomial pneumonia and outcome. CONCLUSION: NIPPV appears to be a promising weaning modality for mechanically ventilated COPD patients and should be tried in resource-limited settings especially in developing countries. PMID- 24778475 TI - Awareness in patients with COPD about the disease and pulmonary rehabilitation: A survey. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. It overloads the healthcare system and increase healthcare expenditure. As a patient's awareness enables him/her to acquire better self-management skills, it helps to reduce the severity and frequency of exacerbations, prevents hospitalizations, and improves health related quality of life. The current study aims to assess the awareness amongst COPD patients about the disease itself and pulmonary rehabilitation. MATERIALS AND METHODS: A cross-sectional survey was carried out in order to evaluate awareness through "a COPD awareness questionnaire". This was developed and validated for its content. A total of 21 questions were included in this questionnaire. These questions were divided into two domains that included pulmonary disease (1-12) and pulmonary rehabilitation (13-21). RESULTS: Three hundred patients were recruited of which 282 were included in the study. The subject group consisted of 177 males and 105 females. The mean age of the subjects was 63.54 +/- 10.656. Awareness in the "disease domain" was 47.84% and "pulmonary rehabilitation domain" was 25.14%. Awareness about the causes of COPD was 34.8%, of common symptoms was 83.0%, and of activities of daily living that could increase breathlessness was found to be 73.8%. The need to consult a physiotherapist was reported by only 26.2%. 81.2% of the subjects believed that breathing exercise could cause breathlessness; whereas, only 19.5% were aware of secretion removal techniques. CONCLUSION: The findings of the study suggest an imminent need to educate the public about the disease and the scope of pulmonary rehabilitation and its role in the management of COPD. The education of patients in this regard needs to be incorporated into standard health care practice in order to improve their self-management skills and their quality of life. PMID- 24778476 TI - Pulmonary sarcoidosis: An important differential diagnosis in transbronchial lung biopsies. AB - BACKGROUND: Sarcoidosis is a systemic granulomatous disease of unknown etiology. Lungs and lymphatics are the principal sites affected by this disease. The disorder is often not suspected by physicians. MATERIALS AND METHODS: This was a retrospective study done on 140 transbronchial lung biopsies received for histopathological examination in the Department of Pathology for 1 year in a multispeciality tertiary care hospital, in Delhi. RESULTS: Out of 140 transbronchial lung biopsies studied, 13 cases of sarcoidosis were diagnosed histopathologically. In these patients a clinical, pathological, and radiological corelation was done. And a final diagnosis of sarcoidosis was given after excluding other granulomatous lesions. CONCLUSION: Transbronchial lung biopsies have become an important tool in the diagnosis of sarcoidosis in present time. Hence sarcoidosis should be considered as a differential diagnosis when dealing with granulomatous lesions in lung biopsies. PMID- 24778477 TI - Diagnostic utility of adenosine deaminase in exudative pleural effusions. AB - OBJECTIVE: To determine the diagnostic utility of adenosine deaminase (ADA) in exudative pleural effusions of different etiologies. SETTING AND DESIGN: It was an observational study conducted at a tertiary care teaching institute. MATERIALS AND METHODS: Of a total of 171 pleural fluid samples, 122 were found to be exudates and were included in the study. Pleural fluid ADA was done for all included patients. Pleural fluid ADA >=40 U/l was taken as diagnostic cut off for TB effusion. STATISTICAL ANALYSIS: Sensitivity, specificity positive and negative predictive value of pleural fluid ADA for diagnosing TB was calculated by using clinical calculator - 1, Richard Lowry 2001-2013. RESULTS: There were 171 patients with pleural effusion, out of which 122 (71.8%) were found to be exudative and were studied further. There were 49 (40.1%), 36 (29.5%) and 33 (27%) cases of TB, malignancy and para pneumonic effusion respectively, whereas 4 (3.3%) cases remained undiagnosed. Median ADA values for TB, malignancy and para pneumonic effusion were 55.8 U/l (range 9.7-756 U/l), 18 U/l (6.5-81 U/l) and 25 U/l (3.4-172 U/l) respectively. Pleural fluid ADA >40U/l yielded 85.7% sensitivity, 80.8% specificity, 75% positive predictive value and 89.5% negative predictive value. CONCLUSION: Pleural fluid ADA remains useful in diagnosing tuberculosis pleural effusion. The median ADA for TB effusion in present cohort was 51.8 IU/ml. Pleural fluid ADA of 40 U/L yielded 89.5% negative predictive value and 75% positive predictive value. Pleural fluid ADA is cost effective and good screening test for diagnosis of TB. PMID- 24778478 TI - Medical marijuana: A panacea or scourge. AB - Marijuana (Cannabis sativa) has been used for recreational and medical purposes since ages. Marijuana smoking is an evil, which is on the rise with about 180.6 million active users worldwide. The recent legalization of marijuana in Uruguay has generated global interest. The purpose of this short review is to describe the various preparations, uses and adverse effects of medical marijuana. It also deals with the adverse effects of marijuana smoking when used for recreational purposes. ased on the current literature, medical use of marijuana is justified in certain conditions as an alternative therapy. PMID- 24778479 TI - Bilateral diaphragmatic paralysis in an HIV patient: Second reported case and literature review. AB - Human immunodeficiency virus (HIV) disease is widespread all over the world, and the neurological and respiratory complications have been described previously. Peripheral neuropathy is one of the commonest neurological complications of the HIV infection. In this report we describe a HIV positive male smoker who was admitted to the hospital because of community acquired pneumonia. Bilateral diaphragmatic paralysis was diagnosed for which no other cause was found and was attributed to the HIV infection. Isolated phrenic neuropathy and diaphragmatic paralysis in an HIV positive patient is extremely rare and only a single such association has been described previously. PMID- 24778480 TI - Pulmonary cryptococcosis with cryptococcal meningitis in an immunocompetent host. AB - Cryptococcosis is a systemic fungal infection associated with significant morbidity and mortality. It predominantly affects people with immunosuppresion and human immunodeficiency virus infection. Extrapulmonary dissemination is rare in immunocompetent hosts. We present here a case of disseminated cryptococcosis in an immunocompetent patient who presented with an unusually large pulmonary mass and meningitis and successfully managed with medical therapy. PMID- 24778481 TI - Pleural Aspergillosis in an otherwise healthy individual. AB - Pleural Aspergillosis is a rare entity, with most of the cases occurring on a background of lung disease or surgery. We report a case of a 16-year-old boy who developed pleural Aspergillosis in the absence of any obvious pre-disposing factors. Patient presented with fever, dry cough and left sided chest discomfort of 6 weeks duration. A chest radiograph revealed features of the left pyopneumothorax. Despite being started on presumptive antituberculous treatment and intercostal drainage his symptoms failed to resolve. The sputum and pus were then subjected to fungal smears and culture, which indicated growth of Aspergillus fumigatus. We report this case in view of the extreme rarity of pleural Aspergillosis occurring in a young healthy individual with no evidence of prior lung pathology. Furthermore, the source of infection was traced back to a very unusual possible focus - a decayed tooth infected with A. fumigatus, thus making the case even more interesting. PMID- 24778482 TI - Delayed esophageal perforation from stereotactic body radiation therapy for locally recurrent central nonsmall cell lung cancer. AB - Stereotactic body radiation therapy (SBRT) is a novel form of external beam radiation therapy. It is used to treat early and locally recurrent nonsmall cell lung cancer (NSLC) in medically inoperable patients. It uses high dose, hypofractionated radiotherapy, with targeting of the tumor by precise spatial localization, thus minimizing injury to surrounding tissues. It can be safely used to ablate NSLC in both central and peripheral locations. We present two cases of delayed esophageal perforation after SBRT for locally recurrent central NSLC. The perforations occurred several months after the therapy. They were treated with covered esophageal stents, with mortality, due to the perforation in one of the patients. SBRT should be judiciously used to ablate centrally located NSLC and patients who develop episodes of esophagitis during or after SBRT, need to be closely followed with endoscopy to look for esophageal ulcerations. These ulcers should be closely followed for healing as these may degenerate into full thickness perforations several months after SBRT. PMID- 24778483 TI - A case of masquerading bronchopneumonia. AB - S. stercoralis infection is very common in South East Asian countries including India. Chronic infection is very common with symptoms of diarrhea, abdominal pain, nausea, vomiting, anemia, and cough. Hyperinfection and dissemination usually occur in immunocompromised patients with symptoms mimicking asthma, COPD, or aseptic meningitis. Very few cases of hyperinfection and dissemination have been documented in immunocompetent patients. We report this case for its rarity and future references. PMID- 24778484 TI - Imaging findings of pulmonary carcinosarcoma: A case report. AB - Pulmonary carcinosarcoma is a rare lung tumor, which contains both malignant carcinomatous and heterotopic sarcomatous components. There are only few case reports on the imaging diagnosis of this rare tumor. Herein, we present the radiological findings of this rare tumor, which was suspected on computed tomography (CT) scan due to atypical CT findings of malignant lung mass (not usually seen in bronchogenic carcinoma) and was finally confirmed histologically. PMID- 24778485 TI - Hemoptysis secondary to actinomycosis: A rare presentation. AB - We present a 70-year-old female patient who had the history of hypertension and presented with massive haemoptysis. She had been complaining of cough with expectoration and mild streaking of blood in sputum for about 3 days with only crepts in right infrascapular and infra-axillary regions as positive clinical findings. Bronchoscopy revealed a cauliflower-like lesion in the upper- right lobe bronchus; bronchial aspirate showed occasional colonies of gram positive filamentous bacteria surrounded by neutrophils. The Trucut biopsy showed sheets of neutrophils with colonies of filamentous bacteria consistent with actinomycotic infection. She was started on intravenous benzyl penicillin 20 million units 6 hourly. She recovered with no further bouts of hemoptysis and was discharged on amoxicillin + clavulanic acid in a stable condition and she remained under similar condition for more than a year on follow up. Actinomycosis is a rare disease caused by a harmless commensal species, Actinomyces. Diagnosis of actinomycosis is a challenging situation, and more so, very few cases causing hemoptysis have come to light so far. PMID- 24778486 TI - Bronchoscopic resection of endobronchial inflammatory myofibroblastic tumor: A case report and systematic review of the literature. AB - Inflammatory myofibroblastic tumour (IMT) is a rare tumour affecting the tracheo bronchial tree in the adult population. The clinical presentation of this tumour is diverse and diagnosis can be definitively clinched by histopathological examination. Treatment of this tumour usually requires surgical resection with bronchoscopic resection being described in few cases. We describe a 32 year old male presenting with hemoptysis who was diagnosed to have IMT. Resection of the tumour was done with the help of rigid bronchoscopy. Post-resection, hemoptysis stopped and no recurrence of tumour was noted on subsequent follow-up. We also present a systematic review of literature of all the cases of tracheo-bronchial IMT treated with bronchoscopic resection and conclude it to be a useful alternative to surgery in such cases. PMID- 24778487 TI - A rare case of underlying pulmonary sequestration in a patient with recently diagnosed medium and large vessel vasculitis. AB - Vasculitis of medium- and large-sized arteries is an inflammatory and stenotic disease characterized by a strong predilection for the aortic arch and its branches. It presents with symptoms and signs as per the vessels and organs involved. Pulmonary sequestration is a rare abnormality characterized by a mass of nonfunctioning lung tissue that receives its vascular supply from a systemic artery and is separated from the normal tracheobronchial tree. The following is a rare case report showing the presence of pulmonary sequestration in a patient with recently diagnosed hypertension and intestinal angina due to medium and large vessel vasculitis. PMID- 24778488 TI - Air-fluid level in the right lung. PMID- 24778489 TI - Congenital anomaly of the lung. PMID- 24778490 TI - Hodgkin's lymphoma presenting as chylothorax. PMID- 24778491 TI - Hemangioma in the posterior mediastinum. PMID- 24778492 TI - An unusual cause of lung mass in a young female. PMID- 24778493 TI - An unusual case of hemoptysis. PMID- 24778494 TI - Fluid collection from intercostal drainage catheter-simplified. PMID- 24778495 TI - Diffuse alveolar hemorrhage in a patient of rheumatoid arthritis. PMID- 24778496 TI - Yet another pulmonary manifestation of tuberous sclerosis. PMID- 24778497 TI - Recurrent subcutaneous emphysema in a treated pulmonary tuberculosis patient: Is there any association? PMID- 24778498 TI - Nodular histiocytic hyperplasia of pericardium: An uncommon lesion posing diagnostic challenge. PMID- 24778499 TI - A comment on effect of cigarette smoking on nasal mucociliary clearance: A comparative analysis using saccharin test. PMID- 24778500 TI - Authors' reply. PMID- 24778501 TI - How to be a prudent dentist in the 21(st) century. PMID- 24778503 TI - A study on pulp stones in a group of the population in Andhra Pradesh, India: An institutional study. AB - AIM: The aim of this study was to determine the occurrence of pulp stones in a group of the population of Andhra Pradesh. This study also aims to determine the association of pulp stones in different sexes, tooth type, dental arches and sides and with systemic diseases. MATERIALS AND METHODS: A total of 4449 teeth of 2000 patients were examined, comprising of patients with C.V.S. disorders; Type II diabetes mellitus and gastritis were examined. Patients were selected from the radiology department who came for diagnostic radiograph of posterior teeth. The presence or absences of pulp stones were recorded. STATISTICAL ANALYSIS USED: Statistical analysis of the data was done using the statistical package for the social sciences (SPSS 15.0-SPSS Inc., 233 South Waker Drive, 11(th) floor, Chicago, IL 60606-6412.) using Chi-square analysis. Differences were considered as significant when P <= 0.05. RESULTS: Pulp stones were found in 799 (17.9%) of 4449 teeth detected. Significantly, higher numbers of pulp stones were recorded in patients with systemic diseases. The occurrences of pulp stones were significantly higher in maxillary first and second molars. No significant difference was found between sexes and sides. CONCLUSIONS: Positive correlation was found between systemic disorder and occurrence of pulp stones. PMID- 24778504 TI - Fracture resistance of endodontically treated maxillary central incisors with varying ferrule heights and configurations: In vitro study. AB - OBJECTIVE: The objective of this study is to determine the best ferrule configuration of endodontically treated teeth. MATERIALS AND METHODS: A total of 40 freshly extracted maxillary central incisors were collected. Teeth were allocated into following four groups of each having 10 teeth. Group 1 teeth restored with crowns (CRN), Group 2 endodontically treated teeth restored with crowns (RCT and CRN), Group 3 endodontically treated teeth restored with cast dowel cores and crowns incorporating uniform 2 mm ferrule (2 FRL), Group 4 endodontically treated teeth restored with cast dowel cores and crowns incorporating uniform 1 mm ferrule (1 FRL). Crown preparation was performed with varying ferrule heights, crowns were cemented with resin modified glass ionomer cement and were kept in 100% humidity for 3 days, all specimens were loaded to failure in a universal testing machine at 0.5 mm/min. Results were obtained in the form of kilo Newton and Newton. RESULT: The statistical analysis applied was an analysis of variance to detect the presence of group differences. Pair wise comparisons between the groups were analyzed with the Tukey Kramer significant difference test for multiple comparisons. CONCLUSION: Ferrule had a significant role in the fracture resistance of custom cast post core restored teeth. Endodontically treated maxillary central incisors with a uniform 2 mm ferrule were more fracture resistant than those with a uniform 1 mm ferrule. PMID- 24778502 TI - Vertical root fractures and their management. AB - Vertical root fractures associated with endodontically treated teeth and less commonly in vital teeth represent one of the most difficult clinical problems to diagnose and treat. In as much as there are no specific symptoms, diagnosis can be difficult. Clinical detection of this condition by endodontists is becoming more frequent, where as it is rather underestimated by the general practitioners. Since, vertical root fractures almost exclusively involve endodontically treated teeth; it often becomes difficult to differentiate a tooth with this condition from an endodontically failed one or one with concomitant periodontal involvement. Also, a tooth diagnosed for vertical root fracture is usually extracted, though attempts to reunite fractured root have been done in various studies with varying success rates. Early detection of a fractured root and extraction of the tooth maintain the integrity of alveolar bone for placement of an implant. Cone beam computed tomography has been shown to be very accurate in this regard. This article focuses on the diagnostic and treatment strategies, and discusses about predisposing factors which can be useful in the prevention of vertical root fractures. PMID- 24778505 TI - Evaluation of the presence of Enterococcus Faecalis in root cementum: A confocal laser scanning microscope analysis. AB - AIM: The aim of this study is to address the cause of persistent infection of root cementum by Enterococcus faecalis. MATERIALS AND METHODS: A sample of 60 human single-rooted teeth were divided into three groups. Group I (control group) had no access opening and one-third of the apical root cementum was sealed using varnish. Group II had no preparation of teeth samples. In group III, apical root cementum was exposed to organic acid and roughened using diamond point to mimic apical resorption. After access opening in groups II and III, all teeth samples were sterilized using gamma irradiation (25 kGy). E. faecalis broth was placed in the root canal and apical one-third of the tooth was immersed in the broth for 8 weeks with alternate day refreshment followed by biomechanical preparation, obturation and coronal seal. Apical one-third of all teeth samples were again immersed in the broth for 8 weeks with alternate day refreshment to mimic secondary infection. The samples were observed under a confocal microscope after splitting the teeth into two halves. RESULTS: E. faecalis penetrated 160 MUm deep into the root cementum in group III samples and only showed adhesion in group II samples. CONCLUSION: Penetration and survival of E. faecalis deep inside the cementum in extreme conditions could be the reason for persistent infection. PMID- 24778506 TI - Cut off values of laser fluorescence for different storage methods at different time intervals in comparison to frozen condition: A 1 year in vitro study. AB - AIMS: The aim of the following study is to evaluate the change in laser fluorescence (LF) values for extracted teeth stored in different solutions over 1 year period, to give cut-off values for different storage media at different time intervals to get them at par with the in vivo conditions and to see which medium gives best results with the least change in LF values and while enhancing the validity of DIAGNOdent in research. MATERIALS AND METHODS: Ninety extracted teeth selected, from a pool of frozen teeth, were divided into nine groups of 10 each. Specimens in Groups 1-8 were stored in 1% chloramine, 10% formalin, 10% buffered formalin, 0.02% thymol, 0.12% chlorhexidine, 3% sodium hypochlorite, a commercially available saliva substitute-Wet Mouth (ICPA Pharmaceuticals) and normal saline respectively at 4 degrees C. The last group was stored under frozen condition at -20 degrees C without contact with any storage solution. DIAGNOdent was used to measure the change the LF values at day 30, 45, 60, 160 and 365. STATISTICAL ANALYSIS USED: The mean change in LF values in different storage mediums at different time intervals were compared using two-way ANOVA. RESULTS: At the end of 1 year, significant decrease in fluorescence (P < 0.05) was observed in Groups 1-8. Maximum drop in LF values occurred between day 1 and 30. Group 9 (frozen specimens) did not significantly change their fluorescence response. CONCLUSIONS: An inevitable change in LF takes place due to various storage media commonly used in dental research at different time intervals. The values obtained from our study can remove the bias caused by the storage media and the values of LF thus obtained can hence be conveniently extrapolated to the in vivo condition. PMID- 24778507 TI - Comparative evaluation of apically extruded debris during root canal preparation using ProTaperTM, HyflexTM and WaveoneTM rotary systems. AB - BACKGROUND AND AIMS: Extrusion of any debris during endodontic treatment may potentially cause post-operative complications such as flare-ups. The purpose of this in vitro study was to assess the amount of apically extruded debris during the root canal preparation using rotary and reciprocating nickel-titanium instrumentation systems. MATERIALS AND METHODS: In this study, 60 human mandibular first premolars were randomly assigned to 3 groups (n = 20 teeth/group). The root canals were instrumented according to the manufacturers' instructions using the Reciprocating single-file system WaveOneTM (Dentsply Maillefer, Ballaigues, Switzerland) and full-sequence rotary Hyflex CMTM (Coltene Whaledent, Allstetten, Switzerland) and ProTaperTM (Dentsply Maillefer, Ballaigues, Switzerland) instruments. The canals were then irrigated using bidistilled water. The debris that was extruded apically was collected in preweighed eppendorf tubes and assessed with an electronic balance and compared. STATISTICAL ANALYSIS USED: The debris extrusion was compared and statistically analyzed using analysis of variance and the post hoc Student-Newman-Keuls test. RESULTS: The WaveOneTM and ProTaperTM rotary instruments produced significantly more debris compared with Hyflex CMTM rotary instruments (P < 0.05). CONCLUSIONS: Under the conditions of this study, all systems that were used resulted in extrusion of apical debris. Full-sequence rotary instrumentation was associated with less debris extrusion compared with the use of reciprocating single-file systems. PMID- 24778508 TI - Comparative anti-microbial efficacy of Azadirachta indica irrigant with standard endodontic irrigants: A preliminary study. AB - OBJECTIVE: The anti-microbial efficacy of 2.5% sodium hypochlorite (SHC) and 0.2% chlorhexidine gluconate were compared with an experimental irrigant formulated from the Neem tree, Azadirachta indica A. Juss. MATERIALS AND METHODS: A sample of 36 single rooted anterior teeth with periapical radiolucency and absence of response to vitality tests that required root canal treatment were selected for this study. The test irrigants and their combinations were assigned to five different groups and saline served as the control. Access cavities were prepared using an aseptic technique and samples collected for both anaerobic culture and Gram stained smears, followed by irrigation and sample collection again. The number of organisms were expressed in colony forming units/ml after 72 h of incubation; the smears were analyzed for their microbial loads and tissue clearance and assessed as per defined criteria. RESULTS: Our results found the maximum reduction in microbial loads, when analyzed by culture method, with a combination of SHC and the experimental neem irrigant. Maximum tissue clearance on the Gram Stained smears was also found with the same combination. CONCLUSION: Neem irrigant has anti-microbial efficacy and can be considered for endodontic use. PMID- 24778509 TI - Comparative evaluation of the canal curvature modifications after instrumentation with One Shape rotary and Wave One reciprocating files. AB - AIMS: This study compared the canal curvature modifications after instrumentation with One Shape (Micro Mega) rotary file and Wave One primary reciprocating file (Dentsply Maillefer, Ballaigues, Switzerland). MATERIALS AND METHODS: Thirty International Organization for Standardization 15, 0.02 taper, Endo Training Blocks (Dentsply Maillefer) were used. In all specimens working length (WL) was established at the reference point 0. Glide path was achieved with Path-File 1, 2 and 3 (Dentsply Maillefer) at the WL. Group 1 were shaped with One Shape file and group 2 with Wave One files. Pre and post-digital images were superimposed, processed with Corel draw Graphic Suite X5 (Corel Corporation, Ottawa, Canada), Adobe Photoshop CS3 (Adobe Systems Inc., San Jose, CA) and Solid works student Edition software (Dassault Systems Solid Works Corp, S.A., Velizy, France). RESULTS: Mean was more for Wave One compared with One Shape. One-way ANOVA and t test showed a significant difference between One Shape and Wave One at 5% level of significance (P < 0.05). CONCLUSIONS: Canals prepared with Wave One file preserved canal shape, respected the anatomical shape of J-shaped canal and produced a continuously tapered funnel. PMID- 24778510 TI - Computed tomography evaluation of residual root thickness after pre-flaring using gates Glidden drills: The sequence effect. AB - AIM: The aim of the present study is to evaluate the residual root thickness in mesiolingual (ML) canals of mandibular molars after pre-flaring using different sequences of Gates-Glidden (GG) drills. MATERIALS AND METHODS: Computed tomography (CT) scans of the ML canals of 60 mandibular first molars were provided from areas within 1, 2, 3 and 4 mm of the furcation area and minimum initial root thickness (MIRT) of concave areas was measured at each level. The samples were divided into two groups (G1 and G2) which were prepared by the step back and crown-down techniques, respectively. In both groups, anti-curvature filing was used. On secondary CT images of the samples in the same position, the minimum residual root thickness (MRRT) and the amount of removed dentin were analyzed by t-test and ANOVA. RESULTS: There was no significant difference for MIRT between the two groups. The MRRT was greater in the G2 group in all the sections, with no significant difference between them. The average of MRRT was not <0.5 mm in any of the groups or sections. CONCLUSION: Based on the results of this study when the appropriate root thickness is present initially, GG drills used in any sequence may be suitable, safe and cost effective for pre-flaring of mesial canals of mandibular first molars with preserving the root thickness of furcation areas. PMID- 24778511 TI - Evaluation of penetration depth of a commercially available resin infiltrate into artificially created enamel lesions: An in vitro study. AB - BACKGROUND: Early enamel lesions have a potential to re-mineralize and prevent caries progress. AIM: The aim of the following study is to determine the depth of penetration of low viscosity resin into artificially created enamel lesions. MATERIALS AND METHODS: A sample of 20 sound premolars, indicated for orthodontic extraction, formed the study group. The teeth were coated with a nail varnish, leaving a window of 4 mm * 4 mm, on buccal surfaces of sound, intact enamel. Each tooth was subsequently immersed in demineralizing solution for 4 days to produce artificial enamel lesions. The demineralized area was then infiltrated with low viscosity resin (Icon Infiltrant, DMG, Hamburg, Germany) as per the manufacturer's instructions. All the restored teeth were then immersed in methylene blue dye for 24 h at 37 degrees C. Teeth were then sectioned longitudinally through the lesion into two halves. The sections were observed under stereomicroscope at *80 magnification and depth of penetration of the material was measured quantitatively using Motic software. RESULTS: The maximum depth of penetration of the resin material was 6.06 +/- 3.31 MUm. CONCLUSIONS: Resin infiltration technique appears to be effective in sealing enamel lesions and has great potential for arresting white spot lesions. PMID- 24778512 TI - Bond strength between composite resin and resin modified glass ionomer using different adhesive systems and curing techniques. AB - AIM: To evaluate bond strength between RMGI and composite using different adhesive systems and curing techniques. MATERIALS AND METHODS: Sixty prepared samples of RMGI were randomly divided into six groups according to adhesive systems (total-etch, two-step self-etch and all-in-one) and curing techniques (co curing and pre-curing). In co-curing technique, the adhesive systems were applied on uncured RMGI samples and co-cured together. In the pre-curing technique, before application of adhesive systems, the RMGI samples were cured. Composite layers were applied and shear bond strength was measured. Two samples of each group were evaluated by SEM. Failure mode was determined by streomicroscope. RESULTS: Both curing methods and adhesive systems had significant effect on bond strength (P-value < 0.05). There was an interaction between two factors (P-value <0.05). Both self-etch adhesives had significantly higher shear bond strength than the total-etch adhesive (P-value <0.05). The co-curing technique improved the bond strength in self-etch adhesives, but decreased the bond strength in total-etch adhesive (P-value<0.05). CONCLUSION: The application of self-etch adhesive systems and co-curing technique can improve the bond strength between the RMGI and composite. PMID- 24778513 TI - Effect of QMix, peracetic acid and ethylenediaminetetraacetic acid on calcium loss and microhardness of root dentine. AB - OBJECTIVES: The objective of this in vitro study was to assess the effect of different chelating agents on the calcium loss and its subsequent effect on the microhardness of the root dentin. MATERIALS AND METHODS: Ten single rooted lower premolars were selected. The teeth were decoronated and thick transverse sections of 2 mm were obtained from the coronal third of the root. Each section was then divided into four quarters, each part constituting a sample specimen from the same tooth for each group. The treatment groups were: Group 1 (Control): 5% Sodium hypochlorite (NaOCl) for 5 min + distilled water for 5 min; Group 2: 5% NaOCl for 5 min + 17% ethylenediaminetetraacetic acid (EDTA) for 5 min; Group 3: 5% NaOCl for 5 min + 2.25% Peracetic acid (PAA) for 5 min and Group 4: 5% NaOCl for 5 min + QMix for 5 min respectively. The calcium loss of the samples was evaluated using the Atomic Absorption Spectrophotometer followed by determination of their microhardness using Vickers Hardness Tester. Data was analyzed using one way ANOVA, Post hoc Tukey test and Pearson correlation. RESULTS: The maximum calcium loss and minimum microhardness was observed in Group 3 followed by Group 2, Group 4 and Group 1. There was a statistically significant difference between all the groups except between Groups 2 and 4. CONCLUSIONS: Irrigation with NaOCl + 2.25% PAA caused the maximum calcium loss from root dentin and reduced microhardness. A negative correlation existed between the calcium loss and reduction in the microhardness of root dentin. PMID- 24778514 TI - A comparative evaluation of different irrigation activation systems on smear layer removal from root canal: An in-vitro scanning electron microscope study. AB - AIM: The aim of the following study is to compare the evaluation of different irrigation activation system-F-File, CanalBrush (CB) and EndoActivator (EA) in removing smear layer from root canal. MATERIALS AND METHODS: Root canals of eighty single rooted decoronated premolar teeth were instrumented using crown down technique and then equally divided into four groups on basis of irrigation activation methods used: Without irrigation - control group, irrigation with F File, CB, EA into Group I, II, III respectively. Samples were then longitudinally sectioned and examined under scanning electron microscope by three qualified observers using score from 1 to 4. Data was analyzed using Statistical Package for Social Sciences (SPSS), version 15.0 (SPSS Inc., Chicago IL) at significance level of P <= 0.05. RESULTS: Minimum mean score was observed in Group II at coronal, apical locations. Group III had minimum score at middle third. Groups difference in score were found to be significant statistically for all three locations as well as for overall assessment (P < 0.001). CONCLUSION: CB remove smear layer more efficiently from the root canal than F-File and EA in coronal and apical region. PMID- 24778515 TI - Comparative evaluation of immunohistochemistry, histopathology and conventional radiography in differentiating periapical lesions. AB - BACKGROUND AND AIM: Periapical lesions often present differently on the radiograph resulting in a dilemma in the mind of the dentist to arrive at a final diagnosis. Although, histopathologic diagnosis has been used for confirmation of the true nature of periapical lesion, the concept of transformation of periapical granulomas containing epithelium without cystification into cyst remains controversial. The aim of this in vivo study was to evaluate the efficacy of conventional radiography and histopathology in differentiating periapical lesions in adjunct with immunohistochemical analysis. AIM: Periapical lesions often present differently on the radiograph resulting in a dilemma in the mind of the dentist to arrive at a final diagnosis. Although, histopathologic diagnosis has been used for confirmation of the true nature of periapical lesion, the concept of transformation of periapical granulomas containing epithelium without cystification into cyst remains controversial. The aim of this in vivo study was to evaluate the efficacy of conventional radiography and histopathology in differentiating periapical lesions in adjunct with immunohistochemical analysis. MATERIALS AND METHOD: Thirty patients having large periapical radiolucency that do not heal successfully with routine endodontic therapy in relation to either maxillary or mandibular anterior teeth were selected for the study. Intraoral periapical radiographs were obtained and provisional diagnosis of the apical areas were made. Endodontic surgery was performed to enable histopathogical investigation. The histopathological interpretation was done to arrive at a final diagnosis and selected questionable granulomas were subjected for cytokeratin (CK 14) stain. RESULTS: The histopathological profile of lesions consisted of 66.66% periapical granulomas, 10% cysts, 6.67% abscess and 16.67% granulomas with cystic potential. The radiographic and histopathologic correlation was found in only 30% of these cases. Strong CK-14 expression was observed in all five cases of periapical granuloma with cystic potential. CONCLUSION: The radiographic diagnosis of periapical lesions remains inconclusive. Although histopathologic examination of periapical lesions gives true nature, the precise nature of subsets of periapical granulomas may be achieved with adjunct use of immunohistochemical markers. PMID- 24778516 TI - Comparison of acceptance, preference and efficacy between pressure anesthesia and classical needle infiltration anesthesia for dental restorative procedures in adult patients. AB - INTRODUCTION: Intraoral local anesthesia is essential for delivering dental care. Needless devices have been developed to provide anesthesia without injections. Little controlled research is available on its use in dental restorative procedures in adult patients. The aims of this study were to compare adult patients acceptability and preference for needleless jet injection with classical local infiltration as well as to evaluate the efficacy of the needleless anesthesia. MATERIALS AND METHODS: Twenty non fearful adults with no previous experience of dental anesthesia were studied using split-mouth design. The first procedure was performed with classical needle infiltration anesthesia. The same amount of anesthetic solution was administered using MADA jet needleless device in a second session one week later, during which a second dental restorative procedure was performed. Patients acceptance was assessed using Universal pain assessment tool while effectiveness was recorded using soft tissue anesthesia and pulpal anesthesia. Patients reported their preference for the anesthetic method at the third visit. The data was evaluated using chi square test and student's t test. RESULTS: Pressure anesthesia was more accepted and preferred by 70% of the patients than traditional needle anesthesia (20%). Both needle and pressure anesthesia was equally effective for carrying out the dental procedures. CONCLUSION: Patients experienced significantly less pain and fear (p<0.01) during anesthetic procedure with pressure anesthesia. However, for more invasive procedures needle anesthesia will be more effective. PMID- 24778517 TI - Influence of filler existence on microleakage of a self-etch adhesive system. AB - AIM: This study evaluated the effect of filler existence in self-etch adhesive resin on the marginal leakage of a class V restoration. MATERIALS AND METHODS: Class V cavities were prepared and restored with a resin composite on the buccal surfaces of 48 premolars lined with unfilled or filled adhesives (n = 24). After thermo cycling, teeth in each group were divided to two subgroups (n = 12), specimens of the first subgroup were incubated for 24 h in distilled water at 37 degrees C, and for the second group three months in the same condition. Specimens were placed in 50% silver nitrate for 24 h at 37 degrees C, and then were cut buccolingually 1 mm thick. Dye penetration was measured using a stereomicroscope and scaled from 0 to 5 in a blind method. SEM images were made to evaluate the dentin-adhesive interfaces. Collected data were analyzed using the nonparametric Kruskal-Wallis and Mann-Whitney U-tests at a significant level of P<0.05. RESULTS: There was no significant difference between microleakage of filled and unfilled adhesive at 24 h and 3 months (P<0.05). There was a significant difference in cervical microleakage between 24 h and 3 months, which was independ on filler load of the adhesive (P<0.001). In contrast, there was no significant difference in occlusal microleakage between 24 h and 3 months and the cervical microleakage was significantly higher than occlusal microleakage after 3 months. SEM images reveald that unfilled adhesive infiltrate slightly better than filled adhesive. CONCLUSION: The application of filler particles in a self etch adhesive system had no influence on marginal leakage at both the enamel and dentin margins. While the unfilled adhesive infiltrate better than the filled adhesive, its long term performance is not promising. PMID- 24778518 TI - Epiphany sealer penetration into dentinal tubules: Confocal laser scanning microscopic study. AB - AIMS: The aim of the following study was to evaluate the percentage and average depth of epiphany sealer penetration into dentinal tubules among the coronal, middle and apical thirds of the root using the confocal laser scanning microscopy (CLSM). MATERIALS AND METHODS: A total of 10 maxillary central incisors were prepared and obturated with Resilon-Epiphany system. Sealer was mixed with fluorescent rhodamine B isothiyocyanate dye for visibility under confocal microscope. Teeth were cross-sectioned into coronal, middle and apical sections-2 mm thick. Sections were observed under CLSM. Images were analyzed for percentage and average depth of sealer penetration into dentinal tubules using the lasso tool in Adobe Photoshop CS3 (Adobe systems incorporated, San jose, CA) and laser scanning microscopy (LSM 5) image analyzer. STATISTICAL ANALYSIS USED: One-way analysis of variance with Student Neuman Keuls post hoc tests, Kruskal-Wallis test and Wilcoxon signed-rank post hoc tests. RESULTS: The results showed that a higher percentage of sealer penetration in coronal section-89.23%, followed by middle section-84.19% and the apical section-64.9%. Average depth of sealer penetration for coronal section was 526.02 MUm, middle-385.26 MUm and apical 193.49 MUm. CONCLUSIONS: Study concluded that there was higher epiphany sealer penetration seen in coronal followed by middle and least at apical third of the roots. PMID- 24778519 TI - The effect of ferrule presence and type of dowel on fracture resistance of endodontically treated teeth restored with metal-ceramic crowns. AB - AIM: The purpose of the present study was to comparatively evaluate the effect of presence of a 2 mm ferrule and different type of dowels on fracture resistance of mandibular premolars. MATERIALS AND METHODS: Fifty uniradicular mandibular premolars were divided into five groups (n = 10). Ten teeth received no treatment (group I). Samples in group II & III were decoronated 2 mm above cemento-enamel junction and received custom cast dowel-core and fiber dowel-composite core respectively, with 2 mm ferrule. Samples in group IV & V were decoronated at CEJ and were restored using cast dowels and fiber dowel-composite cores, without any ferrule. The restored teeth received metal ceramic crowns and were mechanically loaded. The specimens were subjected to a static load, until fracture, to determine the fracture resistance and fracture mode. RESULTS: The samples with 2 mm ferrule had a higher fracture resistance than non ferrule groups. Within non ferrule groups, there were no significant differences in the fracture resistance. Specimen restored with cast dowel had more incidence of non-repairable fracture. CONCLUSIONS: Presence of ferrule increased the fracture resistance of endodontically treated teeth. In case of absence of ferrule, fiber dowels had similar fracture resistance as that of cast dowels and showed increased incidence of repairable fracture. PMID- 24778520 TI - Endodontic management of a patient with Bernard-Soulier syndrome. AB - Bernard-Soulier syndrome is a rare inherited disorder with giant platelets, thrombocytopenia and a prolonged bleeding time. These abnormalities are caused by genetic defects of the glycoprotein Ib/IX/V complex that constitutes the von Willebrand factor receptor on the platelet surface. We are documenting a 30-year old female patient reported with a chief complaint of swelling in relation to right maxillary canine for 5 days. The primary treatment remains platelet transfusion. Root canal treatment was performed following platelet rich plasma transfusion. As the tooth was necrotic and had a periapical pathology post operative bleeding was absent. The root canal treatment was uneventful and the patient was asymptomatic. Optimum oral hygiene practices were emphasized to avoid dental diseases. PMID- 24778521 TI - Endodontic management of a two rooted, three canaled mandibular canine with a fractured instrument. AB - It is important to assess the root canal morphology and its variations before initiating the endodontic procedure. This is because the inability to clean the complete root canal system forms the seat for the persistent infection which ultimately leads to endodontic treatment failure. This case reports the use of dental operating microscope for the successful endodontic management of a two rooted and three canaled mandibular canine with the fractured instrument in the middle canal of a 38-year-old healthy Asian woman. This case report highlights the need to use the dental operating microscope and ultrasonics in locating the elusive canal orifices. It is important to note the internal and external root canal morphological variations before starting the endodontic treatment without any pre-operative assumptions about the usual anatomy of the toot. PMID- 24778522 TI - Masterclass on Apical Periodontitis by Dr. PNR Nair. PMID- 24778523 TI - Search for research. PMID- 24778524 TI - Silver lining and sage advise. PMID- 24778525 TI - Trichoscopy in alopecias: diagnosis simplified. AB - Trichoscopy is the term coined for dermoscopic imaging of the scalp and hair. This novel diagnostic technique, both simple and non-invasive, can be used as a handy bed side tool for diagnosing common hair and scalp disorders. Trichoscopic observations can be broadly grouped as hair signs, vascular patterns, pigment patterns and interfollicular patterns. In this article, we have briefly described the trichoscopic findings in the common categories of cicatricial and non cicatricial alopecias such as androgenetic alopecia, alopecia areata, telogen effluvium, tinea capitis, trichotillomania, lichen planopilaris, discoid lupus erythematosus and hair shaft disorders. Besides diagnosing alopecia, it has the potential for obviating unnecessary biopsies and when a biopsy is still needed it is helpful in choosing an ideal biopsy site. Moreover, trichoscopy is a valuable tool for evaluating the treatment response photographically at each follow-up. The last statement here is deleted as asked. PMID- 24778526 TI - Evaluation of utility of phenol in alopecia areata. AB - BACKGROUND: Alopecia areata (AA) is a common hair disorder of unknown etiology and prognosis with no definitive cure. AIMS AND OBJECTIVE: (i) To study the efficacy and immunomodulatory action of 88% phenol on hair growth on test area in AA. (ii) To study various epidemiological factors in relation to AA. MATERIALS AND METHODS: A total of 50 subjects presenting with nonscarring patchy hair loss on scalp were enrolled in this prospective open label study to receive 88% phenol at 3 weekly intervals in a tertiary care hospital. Efficacy was assessed using scoring system for density, pigmentation, and texture of growing hair. RESULTS: Texture and pigmentation of hair growth was significantly improved at 9 week, while density of hair growth showed steady improvement, which was significant from 9 week onwards. About 78% of patients showed good to excellent response while none of them showed poor response. CONCLUSION: 88% phenol was found to be efficacious with all patients showing hair regrowth. 88% phenol can be considered as a treatment of choice for stable AA due to its ease of application, easy availability, and low cost. PMID- 24778527 TI - Hair loss in children: common and uncommon causes; clinical and epidemiological study in jordan. AB - BACKGROUND: Alopecia is a common complaint in dermatology clinics, and can be caused by a number of conditions, and has patterns that are different from that seen in adults. AIM OF STUDY: No previous studies investigating the clinical types of hair loss in Jordan and its epidemiology. The ultimate aim was to provide a guide for the evaluation of hair loss commonly occurring in childhood in our environment. PATIENTS AND METHODS: A total of 2800 children were seen at the dermatology clinics (Karak teaching hospital and Mutah university medical center) during January 2009 to October 2013 complaining of various clinical dermatological symptoms. RESULTS: Of these patients, 210 children were complaining of hair loss and scalp disorders (7.5% of pediatric dermatology cases seen in Jordan). The most common presentation was asymptomatic patchy hair loss (40%). Other symptoms were scaly scalp (22.9%), diffuse hair loss (21.4%), change in hair texture and color (8.1%), pruritus (5.7%), and pain in the scalp (1%). Tinea capitis was the commonest causes of hair loss (40.0%) followed by alopecia areata (26.2%) and telogen effluvium (17.6%). Other common causes of hair loss were observed in this study, these include chronic diffuse form of hair loss, trichotillomania, and traction alopecia. CONCLUSIONS: As has been observed in this study, hair problem may be due to important nutritional deficiency such as iron and zinc elements, and this is very important problem to think of especially in developing countries. Therefore, hair examination by a pediatrician or dermatologist is an important part of the physical examination. PMID- 24778528 TI - Cyto-histopathological and Clinical Correlation of Pilomatricomas: A 4 Year Study. AB - AIM: The aim of the following study is to characterize the cytological features of pilomatricomas (PMXs) on fine-needle aspiration (FNA) and correlate with the histopathological features. MATERIALS AND METHODS: FNA, histopathological and clinical diagnosis of 12 cases of PMXs were analyzed. Clinical, aspiration findings and histopathological features were correlated with histopathological diagnosis which was taken as the gold standard. A written consent was taken from patients or parents as appropriate. Morphological features of both aspiration as well as histopathological features were graded. The study was duly approved by the Hospital Scientific Review Committee. RESULTS: Out of the 7600 cases studied retrospectively over a period of 4 years, only 12 cases were diagnosed as PMXs. These tumors were mainly located in the head and neck region and mostly affected young females (median age 9.5 years). The mean size of these lesions was 0.9 cm. Out of the 12 histopathologically proven cases of PMX, the correct clinical diagnosis was given in only one case while cytopathological diagnosis was achieved in four cases. CONCLUSION: PMX is a rare tumor, which is mostly found in the pediatric age group. The clinical features should be keenly observed. Keeping in mind the diagnostic pitfalls a cytopathologist may encounter, histopathology should be regarded as the gold standard for diagnosis. PMID- 24778529 TI - Renbok phenomenon in an alopecia areata patient with psoriasis. AB - The Renbok phenomenon designates the withdrawal of a lesion when a different one appears. We describe a 23-year-old patient with psoriasis, who experienced regression of a psoriatic plaque on the scalp concurrently with the appearance of a patch of alopecia areata (AA). In 3 months, plaques of psoriasis appeared inside the patch of hair loss, accompanied by terminal hair growth in the plaques. Such rapid interchange between these two autoimmune disorders have not been described previously, and might reflect a quick substitution between two different T-cell populations, namely Th-17 and Th-1. Better understanding of the trigger for such an exchange can help in elucidating the pathogenesis for AA. PMID- 24778530 TI - Extensive tonsure pattern trichotillomania-trichoscopy and histopathology aid to the diagnosis. AB - Trichotillomania manifests as a compulsive desire to pull out own hair. The clinical presentation of trichotillomania is usually characteristic, with varying length hair distributed within areas of alopecia on otherwise normal scalp. In severe forms, tonsure pattern of baldness results, involving the entire scalp sparing the hair at the margins. Extensive tonsure pattern trichotillomania is rare and difficult to differentiate from other nonscarring alopecias on clinical grounds alone. Trichoscopy and histopathology of scalp play a corroborative role in definitive diagnosis. We hereby report two cases of extensive tonsure pattern trichotillomania, with special reference to their trichoscopic and histopathological features. PMID- 24778531 TI - Graham little piccardi lasseur syndrome: a rare case report with concomitant hypertrophic lichen planus. AB - Graham Little Piccardi Lasseur Syndrome (GLPLS) is a rare variant of lichen planopilaris comprising of a triad of multifocal and patchy cicatricial alopecia of scalp, non-cicatricial alopecia of axillae and pubic region and keratotic follicular papules over a body. Its exact etiology is not known until date, but primarily involves an immune mediated inflammatory reaction against the bulge region of hair follicles resulting in cicatricial alopecia. We report an extensive and diffuse presentation of this rare syndrome in a middle-aged female with hypertrophic lichen planus (LP) present on malar region of face, etiologically relating GLPLS to LP. PMID- 24778532 TI - Square alopecia: a new type of transient alopecia of the scalp following fluoroscopically endovascular embolization. AB - Endovascular interventional procedures are the first choice of treatment for many vascular intracranial lesions, especially those with complex anatomy. These procedures may cause numerous skin lesions depending on the dose of radiation to which patients have been exposed. In this report, we presented a case of a 38 year-old man who developed a square plaque of alopecia in the occipital area after two selective embolization of a left posterior parasagittal arteriovenous malformation. The alopecia was transient and the hair grew up 2 months later after the last procedure. This case illustrates one of the effects of radiation on the scalp and expands our knowledge about the clinical manifestation of this transient disease. PMID- 24778533 TI - Lichen planopilaris versus discoid lupus erythematosus: a trichoscopic perspective. AB - Trichoscopy enables visualization of subsurface structures and color patterns of scalp and hair. Recently, its applications expanded to diagnose inflammatory conditions such as lichen planopilaris (LPP), scalp psoriasis, and discoid lupus erythematosus (DLE). Clinically, both LPP and DLE appear similar as cicatricial alopecia on the scalp making the diagnosis difficult. Here, we report the utility of trichoscopy in the clinical diagnosis of LPP and DLE. Clinically, suspected lesions of DLE and LPP on the scalp of each patient were observed under trichoscopy. Histopathology of lesions confirmed the clinical diagnosis. Authors observed characteristic trichoscopic features in LPP as well as in DLE proving the clinical diagnosis. Hence, trichoscopy can be used to diagnose LPP and DLE clinically avoiding skin biopsy. PMID- 24778534 TI - Sweat gland adenocarcinoma of scalp. AB - Sweat gland adenocarcinoma is a rare tumor particularly over scalp. They have potential to be benign as well as distant metastasis. Usually presents with papules or nodules. Ulcerative morphology is uncommon. Wide surigical excision with regional lymph not dissection is the treatment of choice. A 42-year-old female with sweat gland adenocarcinoma of scalp is reported with cervical lymph node involvement. PMID- 24778535 TI - Circle hairs: clinical, trichoscopic and histopathologic findings. AB - Circle hairs (CH) represent a body hair growth disorder characterized by asymptomatic presence of hairs with typical circular or spiraliform arrangement, not associated with follicular or inflammatory abnormalities. Although this condition is rarely reported, it is probably underestimated, as a medical consultation for CH only is rare in practice. Trichoscopic and histopathological findings of CH have never been reported and this article will present and discuss six cases along with literature review. PMID- 24778536 TI - Kerion due to microsporum gypseum in a 1-month-old infant. AB - Microsporum gypseum is a rare cause of kerion in infancy. Light microscopy, fluorescent microscopy and fungal culture of the infected hair aids in early and correct diagnosis. Griseofulvin is the drug of choice for ectothrix fungi. We report a case of neonatal kerion caused by M. gypseum occurring at the age of 1 month, successfully treated with griseofulvin. PMID- 24778537 TI - Frontal fibrosing alopecia and lupus overlap in a man: guilt by association? AB - Frontal fibrosing alopecia (FFA) is a scarring alopecia, now an accepted subset variant of lichen planopilaris (LPP). Its occurrence in males is rare, with only nine cases reported to date. We describe a case of FFA in a male in association with lupus erythematosus. Multiple biopsies from the scalp, eyebrow and arm showed features consistent with LPP, in keeping with the clinical presentation of FFA. Direct immunofluorescence studies showed a positive lupus band test. Further serological investigation confirmed the presence of antinuclear, anticardiolipin and lupus anticoagulant antibodies. Whilst the findings of lupus erythematosus may be coincidental or a forme fruste of the disease occurring in association with FFA, it is feasible that lupus and LPP may occur as an overlap syndrome. This case underscores the importance of multiple biopsies and the role of direct immunofluorescence in disclosing more than one pathology in the follow-up of patients with scarring alopecia. PMID- 24778538 TI - Nodules on the hair: a rare case of mixed piedra. AB - Piedra is a superficial fungal infection of the hair shaft characterized by nodules along the hair shaft. Black piedra affects the scalp hair more frequently than white piedra. Occurrence of both types of piedra simultaneously in a patient is extremely rare. We describe here a rare case of mixed piedra of scalp hair. PMID- 24778539 TI - Monilethrix. PMID- 24778540 TI - Netherton syndrome with pili torti. PMID- 24778541 TI - Alopecia areata and down syndrome: a true association or a coincidence. PMID- 24778542 TI - Managing a case of trichotillomania with trichobezoar. PMID- 24778543 TI - Functional Analysis Outcomes and Comparison of Direct Observations and Informant Rating Scales in the Assessment of Severe Behavior Problems of Infants and Toddlers At-Risk for Developmental Delays. AB - Severe problem behaviors, like aggression, self-injury, and repetitive behaviors, in people with intellectual and developmental disabilities often appear during early development and may persist without early intervention. The frequencies of self-injurious behavior, aggression, tantrums, property destruction and stereotyped behavior among 17 infants and toddlers at risk for developmental delays and severe behavior problems were assessed using two methods: 1) direct observation of responses during 10 s partial interval recording during analogue functional analysis and 2) the Behavior Problem Inventory-01 (BPI-01; Rojahn et al, 2001), an informant rating scale. Analogue functional analysis results suggested that the most common function for problem behavior was automatic reinforcement, followed by negative reinforcement in the form of escape from demands. Agreement across the two types of measurement systems as to occurrence of the behaviors reported on the BPI-01 and direct observations during analogue functional analyses was greater than 75% across aggression, self-injury, and stereotyped behavior. Agreement at a more molecular level of the ranking of the most commonly occurring specific behaviors was considerably lower. Results are discussed in terms of future research on identifying conditions that set the occasion for high levels of agreement between indirect and direct measurement systems for severe behavior problems. PMID- 24778544 TI - A Behaviorally-Anchored Rating System to Monitor Treatment Integrity for Community Clinicians Using the Adolescent Community Reinforcement Approach. AB - This study evaluated a process for training raters to reliably rate clinicians delivering the Adolescent Community Reinforcement Approach (A-CRA) in a national dissemination project. The unique A-CRA coding system uses specific behavioral anchors throughout its 73 procedure components. Five randomly-selected raters each rated "passing" and "not passing" examples of the 19 A-CRA procedures. Ninety-four percent of the final ICCs were at least 'good' (>=.60) and 66.7% were 'excellent' (>=.75), and 95% of the ratings exceeded the 60% or better agreement threshold between raters and the gold standard. Raters can be trained to provide reliable A-CRA feedback for large-scale dissemination projects. PMID- 24778545 TI - Measuring Dimensions of Coalition Functioning for Effective and Participatory Community Practice. AB - Social Work has a long history of community practice, but community practice models have been understudied. An important first step in conducting such studies is the establishment of psychometrically sound measures relevant for evaluations of community practice. In this paper, data are used from a community-randomized trial of Communities That Care (CTC), a coalition-based model of community practice shown to be effective at transforming communities and changing rates of youth problem behavior. Coalition functioning is reported by coalition members in 12 communities across intervention implementation phases. A four-dimensional model of coalition functioning (goal-directedness, efficiency, opportunities for participation, and cohesion) was confirmed using factor analysis and the dimensions were found to be invariant across time. One test of validity of these dimensions is conducted by correlating coalition members' ratings of coalition functioning with those of external observers. PMID- 24778546 TI - The marginal valuation of fertility. AB - Substantial theoretical and empirical evidence demonstrates that fertility entails economic, physiological, and demographic trade-offs. The existence of trade-offs suggests that fitness should be maximized by an intermediate level of fertility, but this hypothesis has not had much support in the human life-history literature. We suggest that the difficulty of finding intermediate optima may be a function of the way fitness is calculated. Evolutionary analyses of human behavior typically use lifetime reproductive success as their fitness criterion. This fitness measure implicitly assumes that women are indifferent to the timing of reproduction and that they are risk-neutral in their reproductive decision making. In this paper, we offer an alternative, easily-calculated fitness measure that accounts for differences in reproductive timing and yields clear preferences in the face of risky reproductive decision-making. Using historical demographic data from a genealogically-detailed dataset from 19th century Utah, we show that this measure is highly concave with respect to reproductive effort. This result has three major implications: (1) if births are properly timed, a lower-fertility reproductive strategy can have the same fitness as a high-fertility strategy, (2) intermediate optima are far more likely using fitness measures that are strongly concave with respect to effort, (3) we expect mothers to have strong investment preferences with respect to the risk inherent in reproduction. PMID- 24778547 TI - The physiological responses of chronic heart failure patients to maximal strength test and a balke incremental test. AB - It has been demonstrated that resistance exercises may improve chronic heart failure (CHF) patients' functional ability and quality of life, however, physicians do not recommend this form of exercise because of a concern for reported increases in afterload and blood pressure (BP) during the exercise. This study compared the heart rate (HR), BP and rate pressure product (RPP) of CHF patients for a Balke incremental test and a maximal strength test (MS). Fifteen men diagnosed with CHF participated in the study. All subjects performed both a Balke incremental test and MS test for eight different resistance exercises. The subjects' HR and BP were monitored during the incremental test and immediately after each resistance exercise. HR, systolic BP and RPP were significantly lower during the MS test than during both the peak Balke incremental test and during exercise at 80% of peak VO2 (p < 0.05). No significant RPP differences were found between upper and lower body resistance exercises (p > 0.05). The physiological responses in this study were less severe during a MS test than those reported during an incremental Balke treadmill test. Also the finding suggests that MS tests may be an acceptable method to assess the maximal strength of patients with moderate heart failure. Key PointsThe physiological responses of CHF patients to maximal strength test were less severe than those reported during a walking incremental test.There were similar hemodynamic responses during upper and lower resistance exercises.Maximal strength test appears to be an acceptable method to assess the maximal strength of patients with moderate CHF. PMID- 24778548 TI - An evaluation of the rearfoot posture in individuals with patellofemoral pain syndrome. AB - Structural abnormalities of the foot may cause abnormal subtalar joint compensatory motion in order to attain normal function of the lower extremity during gait although studies have not been conclusive. Current conflict in the literature may be related to the differing measures focused on the varying protocols and also the absence of a control group in some studies. This study investigated the rearfoot posture including Subtalar Joint Neutral Position (STJN) and Relaxed Calcaneal Standing (RCS) measurements in patellofemoral pain syndrome (PFPS) and healthy subjects. The angle of STJN during non-weight bearing position and the two dimensional (2D) rearfoot RCS posture was measured using a goniometer in 14 healthy females and 13 females with PFPS. The RCS posture was also measured three dimensionally (3D) by attaching external markers to a tibia shell and the calcaneus and videoing with a four-camera three-dimensional motion analysis system. A one way ANOVA was used to assess the differences between the groups. The 2D and 3D RCS were significantly different between the groups (p <= 0.001) with mean -0.23 degrees +/- 1.35 degrees , 2.52 degrees +/- 3.11 degrees for the control group and 2.35 degrees +/- 1.4 degrees , 7.02 degrees +/- 3.33 degrees for the clinical group respectively. STJN showed a slight rearfoot varus (although significant p = 0.04) in PFPS (-2.20 degrees +/- 1.51 degrees ) compared to the control group (-1.00 degrees +/- 1.36 degrees ). Negative values indicated inversion and positive values indicated eversion. The 2D and 3D RCS showed a significantly more everted posture of the rearfoot for the PFPS group. Subtalar joint varus may contribute to the increased eversion during relaxed standing in the PFPS group. Rearfoot measurements may be an important addition to other clinical measurements taken to explore the underlying aetiology of subjects with PFPS. Key PointsRearfoot posture of PFPS subjects showed a small varus position of Subtalar Joint Neutral and a rearfoot valgus in relaxed standing posture.Relaxed Calcaneal Standing and Subtalar Joint Neutral Position measurements may be an important addition to other clinical measurements taken to explore the underlying aetiology of subjects with PFPS. PMID- 24778549 TI - Muscular oxidative capacity in ovariectomized rats discussion on the endurance performance of female athletes with sports-related-amenorrhea. AB - The purpose of this study was to evaluate the effects of ovariectomy on intramuscular energy metabolism in adult rats. Based on the results, we discussed the skeletal muscle metabolism in female athlete with sports related amenorrhea. Twenty-five adult (20-week-old) Sprague-Dawley female rats were used. Fifteen rats underwent ovariectomy (OVX group), and the other ten rats were sham-operated (Sham group). One and four weeks after surgery, muscular oxidative capacity was measured using (31)P-MR spectra of the gastrocnemius-plantaris-soleus (GPS) muscles group at rest and during electric stimulation. Wet weight and maximum tension of the whole GPS muscles group were also measured. From the MRS measurements, the muscle oxidative capacity in the OVX group was significantly lower than that in the Sham group (p < 0.05) at both one and four weeks after surgery. The muscle's wet weight one week after surgery in the OVX group was the same as the Sham group, while four weeks after surgery it was significantly greater than that in the Sham group (p < 0.05). There were no significant differences in maximum tension among the groups. In conclusion, in adult rats the oxidative capacity decreased due to ovariectomy despite the increase in muscle weight. It is suggested that the muscular endurance capacity in female adult athletes with sports related amenorrhea may deteriorate. Key PointsIn vivo measurement of muscular energy metabolism.Effects of ovariectomy on muscle function and volume.Muscle function of sports-related amenorrhea. PMID- 24778550 TI - Perceived exertion as an exercise intensity indicator in chronic heart failure patients on Beta-blockers. AB - The Rating of Perceived Exertion (RPE) has been used as a supplementary tool for prescription of exercise training intensity for healthy and special populations. Despite the wide use of the RPE scale, there is an inconsistency regarding the accuracy of that scale for chronic heart failure (CHF) patients treated with beta blockers. The study examined the correlation between RPE and heart rate (HR), percentage of maximal HR (%MHR), ventilation (VE) and oxygen consumption (VO2) during graded treadmill testing and examined the RPE scale as a guideline for training intensity for CHF patients treated with beta-blockers. Fourteen men age 57.7 +/- 10.2 yrs diagnosed with CHF and treated with beta-blockers participated in the study. During a Balke treadmill test the subjects RPE, HR, VE and VO2 ml.kg(-1).min(-1) were monitored. Low to moderate significant correlations were found between RPE and HR, %MHR, VE and VO2 ml.kg(-1).min(-1) (r = 0.44, 0.43, 0.55 and 0.69 respectively, all p < 0.001). Some subjects exhibited clinical symptoms (e.g. fall of systolic blood pressure, ST depression/elevation) despite relatively low RPE. The RPE may be used to indicate the level of exercise intensity; however it may not represent the HR responses in CHF patients on beta blocker medication. Therefore, it is recommended to monitor the HR in combination with RPE when prescribing exercise intensity for CHF patients on beta blocker medication. Key PointsRPE correlated with HR, VE and VO2 in CHF patients on beta blockers.There was a large RPE inter-individual variability during graded treadmill tests.RPE can be used as an exercise intensity indicator for patients on beta-blockers, however, it must be taken with caution. PMID- 24778551 TI - Training alterations in elite cyclists may cause transient changes in glomerular filtration rate. AB - Training alterations in elite cyclists may cause transient changes in glomerular filtration rate. To these authors' knowledge, no biochemical investigation of chronic renal function in athletes during a training cycle exists. The purpose of the present archival study was to evaluate the effects of training on homeostatic renal function, evaluated predicted glomerular filtration rate (GFR). Eight male competitive college cyclists (mean +/- SD: age: 22.2 +/- 3.8 yrs, height: 1.80 +/ 0.06 m, mass: 76.6 +/- 7.9 kg, and body fat was 7 +/- 2%) volunteered to undergo 12 weeks of training, and were required to undergo blood sampling at timed intervals to calculate GFR. Homeostatic GFR was altered significantly during various points in the investigation. Volume and average cycling speed were found to have moderate correlations to alterations in GFR. In addition to these findings, 7 of the 8 subjects had GFR's below normal physiological ranges during some point in the experiment. The duration, intensity, and volume of cycling appear to have an influence on renal function. This influence is pronounced during periods when the athletes are unaccustomed to the training load. Key PointsChronic cycling training is associated with alterations of glomerular filtration rate.Intensity of cycling exercise is associated with a reduction or resting glomerular filtration rate.Serum creatinine and serum urea nitrogen are not associated with changes in glomerular filtration rate in chronically exercising cyclists. PMID- 24778552 TI - Evaluating the influence of massage on leg strength, swelling, and pain following a half-marathon. AB - Massage therapy is commonly used following endurance running races with the expectation that it will enhance post-run recovery of muscle function and reduce soreness. A limited number of studies have reported little or no influence of massage therapy on post-exercise muscle recovery. However, no studies have been conducted in a field setting to assess the potential for massage to influence muscle recovery following an actual endurance running race. To evaluate the potential for repeated massage therapy interventions to influence recovery of quadriceps and hamstring muscle soreness, recovery of quadriceps and hamstring muscle strength and reduction of upper leg muscle swelling over a two week recovery period following an actual road running race. Twelve adult recreational runners (8 male, 4 female) completed a half marathon (21.1 km) road race. On days 1,4, 8, and 11 post-race, subjects received 30 minutes of standardized massage therapy performed by a registered massage therapist on a randomly assigned massage treatment leg, while the other (control) leg received no massage treatment. Two days prior to the race (baseline) and preceding the treatments on post-race days 1, 4, 8, and 11 the following measures were conducted on each of the massage and control legs: strength of quadriceps and hamstring muscles, leg swelling, and soreness perception. At day 1, post-race quadriceps peak torque was significantly reduced (p < 0.05), and soreness and leg circumference significantly elevated (p < 0.05) relative to pre-race values with no difference between legs. This suggested that exercise-induced muscle disruption did occur. Comparing the rate of return to baseline measures between the massaged and control legs, revealed no significant differences (p > 0.05). All measures had returned to baseline at day 11. Massage did not affect the recovery of muscles in terms of physiological measures of strength, swelling, or soreness. However, questionnaires revealed that 7 of the 12 participants perceived that the massaged leg felt better upon recovery. Key PointsMassage does not appear to affect physiological indices of muscle recovery post exercise.Massage does appear to positively influence perceptions of recovery.More research needs to be completed on the purported benefits of massage. PMID- 24778553 TI - Variation in football players' sprint test performance across different ages and levels of competition. AB - The purpose of this study was to compare sprint test performance performed by football players of different ages and levels of competition. One hundred and forty six Portuguese players from different teams completed the test (seven maximal sprints interspersed with 25 s active recovery). A 6 (level of competition: 1(st) national division, 2(nd) national division, 1(st) regional division, sub 16, sub 14, sub 12) 7 (sprint trial: sprint 1, sprint 2, sprint 3, sprint 4, sprint 5, sprint 6, sprint 7) repeated measures ANOVA was carried out on subjects sprint times. The main effect of level of competition was statistically significant, F(5, 140) = 106.28, p < 0.001. Subjects from 1(st) national division were significantly faster than subjects from 2(nd) national division; subjects from 1(st) regional division obtained similar performances when compared to sub 16 and sub 14 level; subjects from sub 12 level were the slowest. The main effect of sprint trial was also statistically significant, F (6, 840) = 7.37, p < 0.001. Mean sprint times from the first trial were significantly slower than mean sprint times from the second, third and fourth trial. Results from the fifth, sixth and seventh trials were slower, denoting a decrement in performance. The two main effects were qualified by a significant level of competition x sprint trial interaction, F (30, 840) = 9.47 p < 0.001, identifying markedly different performance profiles. Coaches should be aware that normative data regarding this test can play a very important role if used frequently and consistently during the whole season. Key PointsGroups of different ages (Sub 16, Sub 14 and Sub 12) and groups of different training quality (1(st) and 2(nd) national divisions and 1(st) regional division) were clearly discriminated by sprint test performances.Professional players exhibited higher performances in sprint test.Fatigue effects were the strongest between 5th to the 7th sprint. PMID- 24778554 TI - Exercise-Induced Hypervolemia may not be Consequential to Dehydration During Exercise. AB - The purpose of this investigation was to determine whether the increase in plasma volume (PV) frequently observed 24 hours after exercise is proportional to the magnitude of dehydration occurring during exercise. Seven males (age 21.6 +/- 4.4 y, body mass 71.5 +/- 8.5 kg; VO2peak 43 +/- 7 mL.kg.minute(-1), peak 60-second cycling power output 282 +/- 16 W) completed three cycling sessions at 50% of peak power output in an ambient environment of 35oC, 50% relative humidity; with the exercise lasting either 30, 60 or 90 minutes (in random order) to elicit varying levels of dehydration (assessed by body mass changes). The percent change in PV was calculated 24 hours after each exercise session. All exercise sessions were separated by 7-days. Participants' body mass (means +/- SD) decreased by 1.03 +/- 0.22% in the 30-minute exercise protocol; 1.43 +/- 0.26% in the 60 minute protocol; and 1.59 +/- 0.37% in the 90-minute protocol. Significant PV expansions were not evident 24 hours after any protocol (0.76 +/- 4.58% in the 30 minute protocol; 1.40 +/- 4.58% in the 60-minute protocol, and 2.92 +/- 3.2% in the 90-minute protocol). Regression analysis revealed a poor correlation between percent dehydration and percent change in plasma volume (r = 0.24). Our study revealed that the magnitude of dehydration elicited during this study was insufficient to stimulate a significant expansion in PV. Key PointsIt may be advantageous to prolong or accentuate the hypotension following exercise by postural manipulation or delaying hydration to evoke a significant and observable increase in PV.A greater understanding of the stimulus of exercise-induced hypervolemia is required by exercise physiologists if they are to prescribe appropriate strategies to evoke hypervolemia. PMID- 24778556 TI - Young investigator special issue. PMID- 24778555 TI - Understanding the role of behavior and cognitions in a group exercise setting. AB - The first purpose of the present study examined whether individuals with different exercise behaviors (classified by attendance) experienced different or similar cognitive patterns. It was hypothesized that different behavior would lead to different cognitive appraisals. It was predicted that there would be a difference between the three behavioral frequency groups with regard to self efficacy measures and goal measures. The second purpose of the study was to describe, evaluate and observe whether social factors were associated with participating in exercise in groups. It was hypothesized that those who engage in exercise classes would elicit a social focus. Participants for the study included 39 females who registered in-group fitness classes at a mid-sized university. Attendance over the 10-week course was assessed and participants completed a self report questionnaire during week seven. The attendance data were used to create 3 exercise frequency groups (regular attenders, sporadic attenders, and dropouts) based on ACSM's exercise guidelines. Analysis of Variance (ANOVA), means and frequencies were used to describe the data. There were no significant differences on measures of self-efficacy, goal measures, enjoyment, and external motivation among the three groups (all p's > 0.05). An analysis of the whole group (N=39) discovered a low social focus and high ratings of self-efficacy. Continued research is necessary to investigate the benefit of social support in a group exercise setting, as well as to better understand how self-regulation through self-efficacy and goal factors influences and is influenced by actual behavior. Key PointsExercise behavior did not seem to differentiate individuals in terms of cognitive factors.Results show low social focus and high self-efficacy in group exercise classes.Continued research is needed to better understand how self regulation through self-efficacy and goal factors influence and is influenced by exercise behavior. PMID- 24778557 TI - Stem cells news update: a personal perspective. AB - This article is a follow-up to a previous Commentary published in 2011. It updates some of the events mentioned in that Commentary and continues with more interesting and exciting news on stem cell research and the emerging field of Regenerative Medicine. Some of the news includes: 1) the 2012 Nobel Prize for Medicine awarded to John B. Gurdon and Shinya Yamanaka; 2) the cloning of human embryonic stem cells; 3) the continued search for truly pluripotent adult stem cells via in vitro and in vivo protocols; 4) the breakthrough in organ replacements; 5) the global stem cell race; 6) the global stem cell cryo preservation business; 7) the worldwide stem cell donor registries, and 8) the issue of government regulation on stem cell therapy. PMID- 24778558 TI - RTN4 and FBXL17 Genes are Associated with Coronary Heart Disease in Genome-Wide Association Analysis of Lithuanian Families. AB - Coronary heart disease (CHD) is a complex and heterogeneous cardiovascular disease. There are many genome-wide association studies (GWAS) performed worldwide to extract the causative genetic factors. Moreover, each population may have some exceptional genetic characteristic. Thus, the background of our study is from the previous Lithuanian studies (the LiVicordia Project), which demonstrated the differences of the atherosclerosis process between Lithuanian and Swedish male individuals. In this study we performed GWAS of 32 families of Lithuanian origin in search of significant candidate genetic markers [single nucleotide polymorphisms (SNPs)] of CHD in this population. After careful clinical and biochemical phenotype evaluation, the ~770K SNPs genotyping (Illumina HumanOmniExpress-12 v1.0 array) and familial GWAS analyses were performed. Twelve SNPs were found to be significantly associated with the CHD phenotype (p value <0.0001; the power >0.65). The odds ratio (OR) values were calculated. Two SNPs (rs17046570 in the RTN4 gene and rs11743737 in the FBXL17 gene) stood out and may prove to be important genetic factors for CHD risk. Our results correspond with the findings in other studies, and these two SNPs may be the susceptibility loci for CHD. PMID- 24778559 TI - The incidence and type of chromosomal translocations from prenatal diagnosis of 3800 patients in the republic of macedonia. AB - Robertsonian and reciprocal chromosomal translocations are the most frequent type of structural chromosomal aberrations in the human population. We report the frequency and type of detected translocations in 10 years of prenatal diagnosis of 3800 prenatal samples. The materials came from amniocentesis and chorionic villus samples (CVS). We detected seven Robertsonian translocations (0.18%), eight autosomal reciprocal translocations (0.21%) and one sex chromosome translocation (0.03%). The overall frequency of all translocations was 0.42%. Balanced state translocations were 0.29% and the frequency of translocations in an unbalanced state was 0.13%. There was one balanced de novo X-autosome translocation [46,X,t(X;10)(p11.23;q22.3)] and one balanced double translocation [46,XX,t(1;21);t(7;16)(1p21; 21q11) (7q31;16q23)] inherited from the mother. Most of the detected translocations were the result of unknown familial translocations, but some of them had been previously detected in one of the parents. In order to detect the recurrence risk for future pregnancies, we proposed genetic counseling in each of the cases and we established whether the parents were heterozygous for the same translocation. Histopatological findings for some unbalanced translocations correlated with phenotypes of detected unbalanced karyotypes. PMID- 24778560 TI - Molecular Cytogenetic Study of the NF2 Gene Deletion in Meningioma in Sudanese Patients. AB - Meningioma is the second most common adult central nervous system tumor. Mutations and/or deletions within the tumor suppressor gene neurofibromatosis type 2 (NF2) are associated with meningioma development and progression. We studied 29 meningioma samples by cytogenetic analysis and interphase fluorescence in situ hybridization (I-FISH) using a locus-specific probe for the NF2 gene region. We detected loss of the NF2 gene in all samples except for one. In 10 of the 29 samples, karyotypic analyses confirmed the I-FISH results and revealed additional numerical and/or structural rearrangements in nine of them. Our study confirmed: i) the limited role of banding cytogenetics in assessing chromosomal rearrangements in meningioma, as this tumor is hard to be grown in cell culture; ii) we could show that two-color I-FISH is well-suited for NF2-deletion screening. Our results were in accordance with those of comparable studies, even though the frequency of 97.0% of meningiomas with NF2 deletions is exceptionally high in the studied Sudanese patients. PMID- 24778561 TI - Determination of fetal rhesus d status by maternal plasma DNA analysis. AB - In this study, we assessed the feasibility of fetal RhD genotyping by analysis of cell-free fetal DNA(cffDNA) extracted from plasma samples of Rhesus (Rh) D negative pregnant women by using real-time polymerase chain reaction (PCR). Fetal genotyping was performed on 30 RhD-negative women between 9 and 39 weeks of gestation who were referred to us for invasive testing [amniocentesis/chorionic villi sampling (CVS)]. The fetal RHD genotype was determined based on real-time PCR method. Exons 7 and 10 of the RHD and SRY genes were targeted. Among the pregnant women, 12 were carrying male and 17 were carrying female fetuses. Out of 29 pregnant women, 21 had RhD-positive and nine had RhD-negative fetuses. One sample (case 12, whose blood group was found to be AB Rh [+]) was excluded due to controversial results from repeated serological analyses. All prenatal results were in concordance with postnatal RhD status and fetal sex without false- positive or -negative results. Performing real-time PCR on cffDNA showed accurate, efficient and reliable results, allowing rapid and high throughput non invasive determination of fetal sex and RhD status in clinical samples. PMID- 24778562 TI - Twenty-Four Genes are Upregulated in Patients with Hypospadias. AB - Hypospadias is a congenital hypoplasia of the penis, with displacement of the urethral opening along the ventral surface, and has been reported to be one of the most common congenital anomalies, occurring in approximately 1:250 to 1:300 live births. As hypospadias is reported to be an easily diagnosed malformation at the crossroads of genetics and environment, it is important to study the genetic component in order to elucidate its etiology. In this study, the gene expression profiles both in human hypospadias tissues and normal penile tissues were studied by Human Gene Expression Array. Twenty-four genes were found to be upregulated. Among these, ATF3 and CYR61 have been reported previously. Other genes that have not been previously reported were also found to be upregulated: BTG2, CD69, CD9, DUSP1, EGR1, EIF4A1, FOS, FOSB, HBEGF, HNRNPUL1, IER2, JUN, JUNB, KLF2, NR4A1, NR4A2, PTGS2, RGS1, RTN4, SLC25A25, SOCS3 and ZFP36 (p <0.05). Further studies including genome-wide association studies (GWAS) with expression studies in a large patient group will help us for identifiying the candidate gene(s) in the etiology of hypospadias. PMID- 24778563 TI - Role of the CYP1A2 Gene Polymorphism on Early Ageing from Occupational Exposure. AB - The ageing process is influenced by many internal and external factors. The toxic substances in the environment can cause genomic damages to cells, which increase the risk of early ageing. Furthermore, the cytochrome P450 1A2 (CYP1A2) gene polymorphism is a susceptibility factor and may enhance the risk of DNA damage in cells. The current study was carried out to show whether occupational exposure could cause genotoxicity in cells carrying the CYP1A2 gene polymorphism, thus enhancing the likelihood of early ageing. This study was conducted on mechanical workshop workers and a control group by collecting buccal cells from their mouths. Restriction fragment length polymorphism-polymerase chain reaction (RFLP PCR) was used to identify the CYP1A2 gene polymorphism in the cells. In addition, three extra methods including micronuclei (MN) test, comet assay and real-time PCR (RT-PCR) were applied to determine the effects of gene polymorphisms on DNA damage and ageing from occupational exposure. The results showed that DNA damage in the cells carrying the mutated genotype was higher than the wild genotype. In addition, the difference in MN frequency (p = 0.001) and relative telomere length (p = 0.002) between workers and controls was significant (p <0.05) in the mutated genotype. The findings indicated a possible protective effect of gene polymorphism against early ageing, which was characterized by lack of a significant influence of CYP1A2 gene polymorphism on genetic material in the subjects (p >0.05). It was concluded that the CYP1A2 gene could be a contributing factor to prevent early ageing from occupational exposure. PMID- 24778564 TI - Ethnic variation in interleukin-6 -174 (g/c) polymorphism in the malaysian population. AB - Interleukin-6 (IL-6) is one of the cytokines that has been well studied and implicated in many diseases including cancers. The frequency of the IL-6 -174 (G/C) polymorphism had been proven to differ in various populations. Malaysia is a country with three major ethnic populations, Malays, Chinese and Indians. In this study, we proposed to determine the G or C allele frequency of the IL-6 -174 polymorphism in these three populations. A total of 348 blood samples were available for analysis. The median age for the subjects was 31 years. There were a total of 245 males and 103 females. A total of 86 Malays (25.0%), 122 Chinese (33.0%) and 140 Indians (40.0%) were genotyped. The result showed a significant difference in the G or C allele frequency of the -174 polymorphism. The total frequencies for the G and C alleles were 91.0 and 9.0%, respectively. In the Malays, the allele frequency of the C allele was 4.0% compared with 19.0% in the Indians. The C allele was not detected in the Chinese population. This finding is the first reported on the Malaysian population and may be important in determining risk of diseases associated with the IL-6 polymorphism in these three populations. PMID- 24778565 TI - Lack of Association of Tumor Necrosis Factor-alpha G-308A and Transforming Growth Factor-beta1 C-509T Polymorphisms in Patients with Deep Neck Space Infections. AB - Deep neck space infections are defined as infections that spread along the fascial planes and spaces of the head and neck. Even in the era of antibiotics, these infections can and have been potentially life-threatening conditions. The role of single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) genes in deep neck infections has not been studied. Thus, the aim of this study was to investigate the distribution of the TNF-alpha G-308A and TGF-beta1 C-509T polymorphisms in patients suffering from infections of deep neck spaces and to determine the correlation of these polymorphisms with the values of inflammation markers [C reactive protein (CRP) and white blood cell (WBC) count]. A total of 41 patients with infections of deep neck spaces and 44 healthy controls were screened for TNF alpha G-308A and TGF-beta1 C-509T polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The distribution of the TNF-alpha G-308A genotype in patients did not reveal statistically significant correlation compared to con-trols (p = 0.483, chi(2) = 0.491) as well as the distribution of the TGF-beta1 C-509T genotypes (p = 0.644, chi(2) = 0.725). The distribution of TNF-alpha -308 and TGF-beta1 -509 alleles was not significantly different in patients compared to controls. Moreover, CRP levels and WBC counts were not associated with TNF-alpha G-308A and TGF-beta1 C 509T promoter polymorphisms in patients with deep neck infections. In conclusion, our study suggests that the TNF-alpha G-308A and TGF-beta1 C-509T polymorphisms are not associated with infections of deep neck spaces. PMID- 24778566 TI - Dicentric Chromosome 14;18 Plus Two Additional CNVs in a Girl with Microform Holoprosencephaly and Turner Stigmata. AB - We report a 20-year-old female with features evocative of Turner syndrome (short stature, broad trunk, mild webbed neck), dysmorphic face, minor features of holo prosencephaly (HPE), small hands and feet, excessive hair growth on anterior trunk and intellectual disability. Cytogenetic analysis identified a pseudodicentric 14;18 chromosome. Genome wide single nucleotide polymorphism (SNP) array showed a terminal deletion of approximately 10.24 Mb, from 18p11.32 to 18p11.22, flanked by a duplication of approximately 1.15 Mb, from 18p11.22 to 18p11.21. In addition, the SNP array revealed a duplication of 516 kb in 16p11.2. We correlated the patient's clinical findings with the features mentioned in the literature for these copy number variations. This case study shows the importance of microarray analysis in the detection of cryptic chromosomal rearrangements in patients with intellectual disability and multiple congenital anomalies. PMID- 24778567 TI - Molecular Cytogenetic Characterization of an inv(Y)(p11.2q11.221~q11.222) in a Syrian Family. AB - Constitutional chromosomal abnormalities are an important cause of miscarriage, infertility, congenital anomalies and mental retardation in humans. Pericentric inversions of the human Y-chromosome [inv(Y)] are rather common and show an estimated incidence of 0.6-1:1,000 in males in the general population. Most of the reported cases with inv(Y) are familial. For carriers of pericentric inversions the risk of mental retardation or multiple abortions is not apparently increased and there is no relation with abnormal phenotypic features. Polymerase chain reaction (PCR) analysis to detect microdeletions along the Y-chromosome as well as cytogenetic and fluorescence in situ hybridization (FISH) analysis were done to delineate the characteristics of an inv(Y) in a Syrian family. Thus, we present a detailed molecular-cytogenetic characterization of a father and his two sons having an inv(Y)(p11. 2q11.221~q11.222) with varying mental retardation features but otherwise normal phenotype. PMID- 24778568 TI - A case of treacher collins syndrome. AB - Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development with an incidence of 1/50,000 live births. Mutations of the TCOF1 gene have been found to be responsible for most cases of this mandibulofacial disorder. Here we report TCS in an individual who has a heterozygous c.1021_1022delAG deletion in exon 7 of the TCOF1 gene (NG_011341.1). This is the second Turkish patient with a severe TCS phenotype resulting from a de novo c.1021_1022delAG mutation. PMID- 24778569 TI - Hair depigmentation and dermatitis - an unexpected presentation of cystic fibrosis. AB - Hair depigmentation is very rare presentation of cystic fibrosis (CF). We present 3.5-month-old female patient who had dermatitis and depigmentation of hair and eye lashes, malnutrition, edema and anemia as presenting symptoms of CF. After pancreatic enzyme and vitamin supplementation therapy, skin changes gradually disappeared, and her hair regained its normal brown colour. PMID- 24778570 TI - Double Aneuploidy 48,XXY,+21 Associated with a Congenital Heart Defect in a Neonate. AB - A neonate with a double aneuploidy associated with congenital heart defect (CHD) suffered from cyanosis after birth. He had typical features of Down syndrome (DS) including hypertelorism, slightly lowset ears with protruding pinna. Doppler echocardiography indicated complex congenital heart disease with an ostium secundum atrial septal defect, enlarged right ventricle, and mild tricuspid valve regurgitation. Further chromosomal analysis showed a karyotype of 48,XXY,+21: a double aneuploidy of DS and Klinefelter syndrome (KS). Until now, only seven cases of double aneuploidy associated with CHD defect have been reported. PMID- 24778571 TI - Inheritance of a Chromosome 3 and 21 Translocation in the Fetuses, with One also Having Trisomy 21, in Three Pregnancies in One Family. AB - The majority of chromosome rearrangements are balanced reciprocal and Robertsonian translocations. It is now known that such abnormalities cause no phenotypic effect on the carrier but lead to increased risk of producing unbalanced gametes. Here, we report the inheritance of a translocation between chromosomes 3 and 21 in a family with one of two fetuses with Down Syndrome carrying the same translocation and the other also carrying the same translocation without the additional chromosome 21. Chromosomal analysis from fetal amniotic fluid and peripheral blood lymphocytes from the family were performed at the Cukurova University Hospital at Adana, Turkey. We assessed a family in which the translocation between chromosomes 3 and 21 segregates: one of the three progenies carried the 47,XX,+21,t(3;21)(q21;q22) karyotype and presented with Down Syndrome; another of the three progenies carried the 46,XX,t(3;21) (q21;q22) karyotype and the third had the 46,XY karyotype. Their mother is phenotypically normal. Apparently this rearrangement occurred due to an unbalanced chromosome segregation of the mother [t(3;21)(q21;q22)mat]. This family will enable us to explain the behavior of segregation patterns and the mechanism for each type of translocation from carrier to carrier and their effects on reproduction and numerical aberrations. These findings can be used in clinical genetics and may be used as an effective tool for reproductive guidance and genetic counseling. PMID- 24778574 TI - Assessing Stability and Change in a Second-Order Confirmatory Factor Model of Meaning in Life. AB - Research indicates that meaning in life is an important correlate of health and well-being. However, relatively little is known about the way a sense of meaning may change over time. The purpose of this study is to explore two ways of assessing change in meaning within a second-order confirmatory factor analysis framework. First, tests are conducted to see if the first and second-order factor loadings and measurement error terms are invariant over time. Second, a largely overlooked technique is used to assess change and stability in meaning at the second-order level. Findings from a nationwide survey reveal that the first and second-order factor loadings are invariant of time. Moreover, the second-order measurement error terms, but not the first-order measurement error terms, are invariant, as well. The results further reveal that standard ways of assessing stability mask significant change in meaning that is due largely to regression to the mean. PMID- 24778572 TI - Sarcoma immunotherapy: past approaches and future directions. AB - Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25-50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease. PMID- 24778573 TI - Antimicrobial peptides and induced membrane curvature: geometry, coordination chemistry, and molecular engineering. AB - Short cationic, amphipathic antimicrobial peptides are multi-functional molecules that have roles in host defense as direct microbicides and modulators of the immune response. While a general mechanism of microbicidal activity involves the selective disruption and permeabilization of cell membranes, the relationships between peptide sequence and membrane activity are still under investigation. Here, we review the diverse functions that AMPs collectively have in host defense, and show that these functions can be multiplexed with a membrane mechanism of activity derived from the generation of negative Gaussian membrane curvature. As AMPs preferentially generate this curvature in model bacterial cell membranes, the selective generation of negative Gaussian curvature provides AMPs with a broad mechanism to target microbial membranes. The amino acid constraints placed on AMPs by the geometric requirement to induce negative Gaussian curvature are consistent with known AMP sequences. This 'saddle-splay curvature selection rule' is not strongly restrictive so AMPs have significant compositional freedom to multiplex membrane activity with other useful functions. The observation that certain proteins involved in cellular processes which require negative Gaussian curvature contain domains with similar motifs as AMPs, suggests this rule may be applicable to other curvature-generating proteins. Since our saddle-splay curvature design rule is based upon both a mechanism of activity and the existing motifs of natural AMPs, we believe it will assist the development of synthetic antimicrobials. PMID- 24778575 TI - tBu3P-Coordinated 2-Phenylaniline-Based Palladacycle Complex As Precatalyst for Pd-Catalyzed Coupling Reactions of Aryl Halides with Polyfluoroarenes via C-H Activation Strategy. AB - tBu3P-Coordinated 2-phenylaniline-based palladacycle complex was demonstrated to be an efficient precatalyst for Pd-catalyzed coupling reactions of aryl halides with polyfluoroarenes via C-H activation strategy. The readily accessibility and easy handling nature of tBu3P- coordinated 2-aminobiphenyl-based palladacycle complex and the high yields of the reaction makes tBu3P-coordinated 2 aminobiphenyl-based palladacycle complex an attractive precatalyst for the cross coupling reaction of aryl halides with polyfluoroarenes. PMID- 24778576 TI - Migraine and obesity: moving beyond BMI. PMID- 24778577 TI - The Social Context of Infant Intention Understanding. AB - Traditional looking-time paradigms are often used to assess infants' attention to socio-cognitive phenomena, but the link between these laboratory scenarios and real-world interactions is unclear. The current study investigated hypothesized relations between traditional social-cognitive looking-time paradigms and their real-world counterparts in caregiver-infant social interaction. Seventy-five 10- to 12-month-old infants participated in a structured play session with their caregiver, as well as a traditional looking-time paradigm targeting intentional action. Infants' ability to quickly parse intentional displays correlated with several key qualities of their everyday interactions. In particular, caregiver and infant interaction quality, maternal supportiveness, caregiver and infant joint engagement skill, and social attentiveness in infants correlated with faster habituation to looking-time displays. These results support a linkage between social-cognitive looking-time laboratory paradigms and more naturalistic partner interaction, at this key age. The data both provide external validation for the large body of social-cognitive findings emerging from laboratory looking time paradigms, and contribute to a growing literature tracking the developmental trajectory of infants' understanding of people over the first two years. PMID- 24778578 TI - Use of the mechanical leech for successful zone I replantation. AB - Replantation of zone I finger injuries remains a challenge, particularly if the fingertip was previously scarred or atrophied, which makes it difficult to secure a suitable vein at the amputation site. In cases of artery-only anastomosis, we propose using a mechanical leech technique to maintain sufficient venous outflow until the internal circulation regenerates. We applied this procedure to eight patients who had zone 1 amputations without veins that were suitable for anastomosis. Emergent surgery was performed and an artery-only anastomosis was created. As there were no veins available, we cut a branch of the central artery and anastomosed it with a 24-gauge angioneedle, which served as a conduit for venous drainage. The overall survival rate for zone I replantation using mechanical leech was 87.5% and the average time to maintain the mechanical leech was 5 days. The mechanical leech technique may serve as an alternative option for the management of venous congestion when no viable veins are available. PMID- 24778579 TI - SAMuS: service-oriented architecture for multisensor surveillance in smart homes. AB - The design of a service-oriented architecture for multisensor surveillance in smart homes is presented as an integrated solution enabling automatic deployment, dynamic selection, and composition of sensors. Sensors are implemented as Web connected devices, with a uniform Web API. RESTdesc is used to describe the sensors and a novel solution is presented to automatically compose Web APIs that can be applied with existing Semantic Web reasoners. We evaluated the solution by building a smart Kinect sensor that is able to dynamically switch between IR and RGB and optimizing person detection by incorporating feedback from pressure sensors, as such demonstrating the collaboration among sensors to enhance detection of complex events. The performance results show that the platform scales for many Web APIs as composition time remains limited to a few hundred milliseconds in almost all cases. PMID- 24778580 TI - A generalized quantum-inspired decision making model for intelligent agent. AB - A novel decision making for intelligent agent using quantum-inspired approach is proposed. A formal, generalized solution to the problem is given. Mathematically, the proposed model is capable of modeling higher dimensional decision problems than previous researches. Four experiments are conducted, and both empirical experiments results and proposed model's experiment results are given for each experiment. Experiments showed that the results of proposed model agree with empirical results perfectly. The proposed model provides a new direction for researcher to resolve cognitive basis in designing intelligent agent. PMID- 24778582 TI - Reflection reduction on DDR3 high-speed bus by improved PSO. AB - The signal integrity of the circuit, as one of the important design issues in high-speed digital system, is usually seriously affected by the signal reflection due to impedance mismatch in the DDR3 bus. In this paper, a novel optimization method is proposed to optimize impedance mismatch and reduce the signal reflection. Specifically, by applying the via parasitic, an equivalent model of DDR3 high-speed signal transmission, which bases on the match between the on-die termination (ODT) value of DDR3 and the characteristic impedance of the transmission line, is established. Additionally, an improved particle swarm optimization algorithm with adaptive perturbation is presented to solve the impedance mismatch problem (IPSO-IMp) based on the above model. The algorithm dynamically judges particles' state and introduces perturbation strategy for local aggregation, from which the local optimum is avoided and the ability of optimization-searching is activated. IPSO-IMp achieves higher accuracy than the standard algorithm, and the speed increases nearly 33% as well. Finally, the simulation results verify that the solution obviously decreases the signal reflection, with the signal transmission quality increasing by 1.3 dB compared with the existing method. PMID- 24778581 TI - Can Na18F PET/CT be used to study bone remodeling in the tibia when patients are being treated with a Taylor Spatial Frame? AB - Monitoring and quantifying bone remodeling are of interest, for example, in correction osteotomies, delayed fracture healing pseudarthrosis, bone lengthening, and other instances. Seven patients who had operations to attach an Ilizarov-derived Taylor Spatial Frame to the tibia gave informed consent. Each patient was examined by Na(18)F PET/CT twice, at approximately six weeks and three months after the operation. A validated software tool was used for the following processing steps. The first and second CT volumes were aligned in 3D and the respective PET volumes were aligned accordingly. In the first PET volume spherical volumes of interest (VOIs) were delineated for the crural fracture and normal bone and transferred to the second PET volume for SUVmax evaluation. This method potentially provides clinical insight into questions such as, when has the bone remodeling progressed well enough to safely remove the TSF? and when is intervention required, in a timelier manner than current methods? For example, in two patients who completed treatment, the SUVmax between the first and second PET/CT examination decreased by 42% and 13%, respectively. Further studies in a larger patient population are needed to verify these preliminary results by correlating regional Na(18)F PET measurements to clinical and radiological findings. PMID- 24778583 TI - Tracking control of a leg rehabilitation machine driven by pneumatic artificial muscles using composite fuzzy theory. AB - It is difficult to achieve excellent tracking performance for a two-joint leg rehabilitation machine driven by pneumatic artificial muscles (PAMs) because the system has a coupling effect, highly nonlinear and time-varying behavior associated with gas compression, and the nonlinear elasticity of bladder containers. This paper therefore proposes a T-S fuzzy theory with supervisory control in order to overcome the above problems. The T-S fuzzy theory decomposes the model of a nonlinear system into a set of linear subsystems. In this manner, the controller in the T-S fuzzy model is able to use simple linear control techniques to provide a systematic framework for the design of a state feedback controller. Then the LMI Toolbox of MATLAB can be employed to solve linear matrix inequalities (LMIs) in order to determine controller gains based on the Lyapunov direct method. Moreover, the supervisory control can overcome the coupling effect for a leg rehabilitation machine. Experimental results show that the proposed controller can achieve excellent tracking performance, and guarantee robustness to system parameter uncertainties. PMID- 24778584 TI - Minimum risk facility location-allocation problem with type-2 fuzzy variables. AB - Facility location decision is basically viewed as a long-term strategy, so the inherited uncertainty of main parameters ought to be taken into account in order to make models applicable. In this paper, we examine the impact of uncertain transportation costs and customers' demands on the choice of optimal location decisions and allocation plans. This leads to the formulation of the facility location-allocation (FLA) problem as a fuzzy minimum risk programming, in which the uncertain parameters are assumed to be characterized by type-2 fuzzy variables with known type-2 possibility distributions. Since the inherent complexity of type-2 fuzzy FLA may be troublesome, existing methods are no longer effective in handling the proposed problems directly. We first derive the critical value formula for possibility value-at-risk reduced fuzzy variable of type-2 triangular fuzzy variable. On the basis of formula obtained, we can convert original fuzzy FLA model into its equivalent parametric mixed integer programming form, which can be solved by conventional numerical algorithms or general-purpose software. Taking use of structural characteristics of the equivalent optimization, we design a parameter decomposition method. Finally, a numerical example is presented to highlight the significance of the fuzzy FLA model. The computational results show the credibility and superiority of the proposed parametric optimization method. PMID- 24778585 TI - Analyses of crime patterns in NIBRS data based on a novel graph theory clustering method: Virginia as a case study. AB - This paper suggests a novel clustering method for analyzing the National Incident Based Reporting System (NIBRS) data, which include the determination of correlation of different crime types, the development of a likelihood index for crimes to occur in a jurisdiction, and the clustering of jurisdictions based on crime type. The method was tested by using the 2005 assault data from 121 jurisdictions in Virginia as a test case. The analyses of these data show that some different crime types are correlated and some different crime parameters are correlated with different crime types. The analyses also show that certain jurisdictions within Virginia share certain crime patterns. This information assists with constructing a pattern for a specific crime type and can be used to determine whether a jurisdiction may be more likely to see this type of crime occur in their area. PMID- 24778586 TI - Evaluation on genotoxicity and teratogenicity of aqueous extract from Cyclocarya paliurus leaves. AB - Tremendous attentions have been attracted to the foods labeled with natural, green, organic, and nuisanceless conception of healthy diet. Therefore, it is of great significance to establish relative defining guidance for safe assessment of botanicals. Cyclocarya paliurus (Batal.) Iljinsk (family Cyclocaryaceae), called sweet tea tree, is a well-known edible and medicinal plant, which has been widely used in China as drug formulation for the treatment of hypertension and diabetes. Despite its benefits, no reports have been described on the safe assessment of C. paliurus leaves aqueous extract. In this study, we have conducted the genotoxicity assay (including Ames test, bone marrow polychromatic erythrocyte micronucleus test, and sperm abnormality test in mice) and traditional teratogenicity assay in rats (maternal toxicity, embryo toxicity, and teratogenicity test) to assess the genetic and teratogenic safety of aqueous extracts from C. paliurus leaves. Results of each assay show that the highest dose of C. paliurus leaves aqueous extract is considered relatively nonmutagenic and nonteratogenic, revealing that C. paliurus leaves possess safety and quality as a functional additional ingredient in food. PMID- 24778587 TI - Simple-random-sampling-based multiclass text classification algorithm. AB - Multiclass text classification (MTC) is a challenging issue and the corresponding MTC algorithms can be used in many applications. The space-time overhead of the algorithms must be concerned about the era of big data. Through the investigation of the token frequency distribution in a Chinese web document collection, this paper reexamines the power law and proposes a simple-random-sampling-based MTC (SRSMTC) algorithm. Supported by a token level memory to store labeled documents, the SRSMTC algorithm uses a text retrieval approach to solve text classification problems. The experimental results on the TanCorp data set show that SRSMTC algorithm can achieve the state-of-the-art performance at greatly reduced space time requirements. PMID- 24778588 TI - Fast readout architectures for large arrays of digital pixels: examples and applications. AB - Modern pixel detectors, particularly those designed and constructed for applications and experiments for high-energy physics, are commonly built implementing general readout architectures, not specifically optimized in terms of speed. High-energy physics experiments use bidimensional matrices of sensitive elements located on a silicon die. Sensors are read out via other integrated circuits bump bonded over the sensor dies. The speed of the readout electronics can significantly increase the overall performance of the system, and so here novel forms of readout architectures are studied and described. These circuits have been investigated in terms of speed and are particularly suited for large monolithic, low-pitch pixel detectors. The idea is to have a small simple structure that may be expanded to fit large matrices without affecting the layout complexity of the chip, while maintaining a reasonably high readout speed. The solutions might be applied to devices for applications not only in physics but also to general-purpose pixel detectors whenever online fast data sparsification is required. The paper presents also simulations on the efficiencies of the systems as proof of concept for the proposed ideas. PMID- 24778590 TI - On Hardy-Pachpatte-Copson's inequalities. AB - We establish new inequalities similar to Hardy-Pachpatte-Copson's type inequalities. These results in special cases yield some of the recent results. PMID- 24778589 TI - Overexpression of the synthetic chimeric native-T-phylloplanin-GFP genes optimized for monocot and dicot plants renders enhanced resistance to blue mold disease in tobacco (N. tabacum L.). AB - To enhance the natural plant resistance and to evaluate the antimicrobial properties of phylloplanin against blue mold, we have expressed a synthetic chimeric native-phylloplanin-GFP protein fusion in transgenic Nicotiana tabacum cv. KY14, a cultivar that is highly susceptible to infection by Peronospora tabacina. The coding sequence of the tobacco phylloplanin gene along with its native signal peptide was fused with GFP at the carboxy terminus. The synthetic chimeric gene (native-phylloplanin-GFP) was placed between the modified Mirabilis mosaic virus full-length transcript promoter with duplicated enhancer domains and the terminator sequence from the rbcSE9 gene. The chimeric gene, expressed in transgenic tobacco, was stably inherited in successive plant generations as shown by molecular characterization, GFP quantification, and confocal fluorescent microscopy. Transgenic plants were morphologically similar to wild-type plants and showed no deleterious effects due to transgene expression. Blue mold sensitivity assays of tobacco lines were performed by applying P. tabacina sporangia to the upper leaf surface. Transgenic lines expressing the fused synthetic native-phyllopanin-GFP gene in the leaf apoplast showed resistance to infection. Our results demonstrate that in vivo expression of a synthetic fused native-phylloplanin-GFP gene in plants can potentially achieve natural protection against microbial plant pathogens, including P. tabacina in tobacco. PMID- 24778591 TI - Seismic stability of subsea tunnels subjected to seepage. AB - Strength reduction method and ADINA software are adopted to study the stability of submarine tunnel structures subjected to seepage and earthquake under different seawater depths and overlying rock strata thicknesses. First, the excess pore water pressure in the rock mass is eliminated through consolidation calculation. Second, dynamic time-history analysis is performed by inputting the seismic wave to obtain the maximum horizontal displacement at the model top. Finally, static analysis is conducted by inputting the gravity and the lateral border node horizontal displacement when the horizontal displacement is the largest on the top border. The safety factor of a subsea tunnel structure subjected to seepage and earthquake is obtained by continuously reducing the shear strength parameters until the calculation is not convergent. The results show that the plastic zone initially appears at a small scope on the arch feet close to the lining structure and at both sides of the vault. Moreover, the safety factor decreases with increasing seawater depth and overlying rock strata thickness. With increasing seawater depth and overlying rock strata thickness, maximum main stress, effective stress, and maximum displacement increase, whereas displacement amplitude slightly decreases. PMID- 24778592 TI - Thermophysical and mechanical properties of granite and its effects on borehole stability in high temperature and three-dimensional stress. AB - When exploiting the deep resources, the surrounding rock readily undergoes the hole shrinkage, borehole collapse, and loss of circulation under high temperature and high pressure. A series of experiments were conducted to discuss the compressional wave velocity, triaxial strength, and permeability of granite cored from 3500 meters borehole under high temperature and three-dimensional stress. In light of the coupling of temperature, fluid, and stress, we get the thermo-fluid solid model and governing equation. ANSYS-APDL was also used to stimulate the temperature influence on elastic modulus, Poisson ratio, uniaxial compressive strength, and permeability. In light of the results, we establish a temperature fluid-stress model to illustrate the granite's stability. The compressional wave velocity and elastic modulus, decrease as the temperature rises, while poisson ratio and permeability of granite increase. The threshold pressure and temperature are 15 MPa and 200 degrees C, respectively. The temperature affects the fracture pressure more than the collapse pressure, but both parameters rise with the increase of temperature. The coupling of thermo-fluid-solid, greatly impacting the borehole stability, proves to be a good method to analyze similar problems of other formations. PMID- 24778593 TI - Usalpharma: a cloud-based architecture to support quality assurance training processes in health area using virtual worlds. AB - This paper discusses how cloud-based architectures can extend and enhance the functionality of the training environments based on virtual worlds and how, from this cloud perspective, we can provide support to analysis of training processes in the area of health, specifically in the field of training processes in quality assurance for pharmaceutical laboratories, presenting a tool for data retrieval and analysis that allows facing the knowledge discovery in the happenings inside the virtual worlds. PMID- 24778594 TI - A domain decomposition method for time fractional reaction-diffusion equation. AB - The computational complexity of one-dimensional time fractional reaction diffusion equation is O(N2M) compared with O(NM) for classical integer reaction diffusion equation. Parallel computing is used to overcome this challenge. Domain decomposition method (DDM) embodies large potential for parallelization of the numerical solution for fractional equations and serves as a basis for distributed, parallel computations. A domain decomposition algorithm for time fractional reaction-diffusion equation with implicit finite difference method is proposed. The domain decomposition algorithm keeps the same parallelism but needs much fewer iterations, compared with Jacobi iteration in each time step. Numerical experiments are used to verify the efficiency of the obtained algorithm. PMID- 24778595 TI - Ear recognition based on Gabor features and KFDA. AB - We propose an ear recognition system based on 2D ear images which includes three stages: ear enrollment, feature extraction, and ear recognition. Ear enrollment includes ear detection and ear normalization. The ear detection approach based on improved Adaboost algorithm detects the ear part under complex background using two steps: offline cascaded classifier training and online ear detection. Then Active Shape Model is applied to segment the ear part and normalize all the ear images to the same size. For its eminent characteristics in spatial local feature extraction and orientation selection, Gabor filter based ear feature extraction is presented in this paper. Kernel Fisher Discriminant Analysis (KFDA) is then applied for dimension reduction of the high-dimensional Gabor features. Finally distance based classifier is applied for ear recognition. Experimental results of ear recognition on two datasets (USTB and UND datasets) and the performance of the ear authentication system show the feasibility and effectiveness of the proposed approach. PMID- 24778596 TI - Impulse noise: can hitting a softball harm your hearing? AB - The purpose of this study is to identify whether or not different materials of softball bats (wooden, aluminum, and composite) are a potential risk harm to hearing when batting players strike a 12'' core .40 softball during slow, underhand pitch typical of recreational games. Peak sound pressure level measurements and spectral analyses were conducted for three controlled softball pitches to a batting participant using each of the different bat materials in an unused outdoor playing field with regulation distances between the pitcher's mound and batter's box. The results revealed that highest recorded peak sound pressure level was recorded from the aluminum (124.6 dBC) bat followed by the composite (121.2 dBC) and wooden (120.0 dBC) bats. Spectral analysis revealed composite and wooden bats with similar broadly distributed amplitude-frequency response. The aluminum bat also produced a broadly distributed amplitude frequency response, but there were also two very distinct peaks at around 1700 Hz and 2260 Hz above the noise floor that produced its ringing (or ping) sound after being struck. Impulse (transient) sounds less than 140 dBC may permit multiple exposures, and softball bats used in a recreational slow pitch may pose little to no risk to hearing. PMID- 24778597 TI - Assessing the impact of policy changes in the Icelandic cod fishery using a hybrid simulation model. AB - Most of the Icelandic cod is caught in bottom trawlers or longliners. These two fishing methods are fundamentally different and have different economic, environmental, and even social effects. In this paper we present a hybrid simulation framework to assess the impact of changing the ratio between cod quota allocated to vessels with longlines and vessels with bottom trawls. It makes use of conventional bioeconomic models and discrete event modelling and provides a framework for simulating life cycle assessment (LCA) for a cod fishery. The model consists of two submodels, a system dynamics model describing the biological aspect of the fishery and a discrete event model for fishing activities. The model was run multiple times for different quota allocation scenarios and results are presented where different scenarios are presented in the three dimensions of sustainability: environmental, social, and economic. The optimal allocation strategy depends on weighing the three different factors. The results were encouraging first-steps towards a useful modelling method but the study would benefit greatly from better data on fishing activities. PMID- 24778598 TI - Postoperative pharyngolaryngeal adverse events with laryngeal mask airway (LMA Supreme) in laparoscopic surgical procedures with cuff pressure limiting 25 cmH2O: prospective, blind, and randomised study. AB - To reduce the incidence of postoperative pharyngolaryngeal adverse events, laryngeal mask airway (LMA) manufacturers recommend maximum cuff pressures not exceeding 60 cmH2O. We performed a prospective randomised study, comparing efficacy and adverse events among patients undergoing laparoscopic surgical procedures who were allocated randomly into low (limiting 25 cmH2O, L group) and high (at 60 cmH2O, H group) LMA cuff pressure groups with LMA Supreme. Postoperative pharyngolaryngeal adverse events were evaluated at discharge from postanaesthetic care unit (PACU) (postoperative day 1, POD 1) and 24 hours after discharge from PACU (postoperative day 2, POD 2). All patients were well tolerated with LMA without ventilation failure. Before pneumoperitoneum, cuff volume and pressure and oropharyngeal leak pressure (OLP) showed significant differences. Postoperative sore throat at POD 2 (3 versus 12 patients) and postoperative dysphagia at POD 1 and POD 2 (0 versus 4 patients at POD 1; 0 versus 4 patients at POD 2) were significantly lower in L group, compared with H group. In conclusion, LMA with cuff pressure limiting 25 cmH2O allowed both efficacy of airway management and lower incidence of postoperative adverse events in laparoscopic surgical procedures. This clinical trial is registered with KCT0000334. PMID- 24778600 TI - Towards application of one-class classification methods to medical data. AB - In the problem of one-class classification (OCC) one of the classes, the target class, has to be distinguished from all other possible objects, considered as nontargets. In many biomedical problems this situation arises, for example, in diagnosis, image based tumor recognition or analysis of electrocardiogram data. In this paper an approach to OCC based on a typicality test is experimentally compared with reference state-of-the-art OCC techniques--Gaussian, mixture of Gaussians, naive Parzen, Parzen, and support vector data description-using biomedical data sets. We evaluate the ability of the procedures using twelve experimental data sets with not necessarily continuous data. As there are few benchmark data sets for one-class classification, all data sets considered in the evaluation have multiple classes. Each class in turn is considered as the target class and the units in the other classes are considered as new units to be classified. The results of the comparison show the good performance of the typicality approach, which is available for high dimensional data; it is worth mentioning that it can be used for any kind of data (continuous, discrete, or nominal), whereas state-of-the-art approaches application is not straightforward when nominal variables are present. PMID- 24778601 TI - Numerical study of entropy generation due to coupled laminar and turbulent mixed convection and thermal radiation in an enclosure filled with a semitransparent medium. AB - The effect of radiation on laminar and turbulent mixed convection heat transfer of a semitransparent medium in a square enclosure was studied numerically using the Finite Volume Method. A structured mesh and the SIMPLE algorithm were utilized to model the governing equations. Turbulence and radiation were modeled with the RNG k-epsilon model and Discrete Ordinates (DO) model, respectively. For Richardson numbers ranging from 0.1 to 10, simulations were performed for Rayleigh numbers in laminar flow (104) and turbulent flow (108). The model predictions were validated against previous numerical studies and good agreement was observed. The simulated results indicate that for laminar and turbulent motion states, computing the radiation heat transfer significantly enhanced the Nusselt number (Nu) as well as the heat transfer coefficient. Higher Richardson numbers did not noticeably affect the average Nusselt number and corresponding heat transfer rate. Besides, as expected, the heat transfer rate for the turbulent flow regime surpassed that in the laminar regime. The simulations additionally demonstrated that for a constant Richardson number, computing the radiation heat transfer majorly affected the heat transfer structure in the enclosure; however, its impact on the fluid flow structure was negligible. PMID- 24778602 TI - A splay tree-based approach for efficient resource location in P2P networks. AB - Resource location in structured P2P system has a critical influence on the system performance. Existing analytical studies of Chord protocol have shown some potential improvements in performance. In this paper a splay tree-based new Chord structure called SChord is proposed to improve the efficiency of locating resources. We consider a novel implementation of the Chord finger table (routing table) based on the splay tree. This approach extends the Chord finger table with additional routing entries. Adaptive routing algorithm is proposed for implementation, and it can be shown that hop count is significantly minimized without introducing any other protocol overheads. We analyze the hop count of the adaptive routing algorithm, as compared to Chord variants, and demonstrate sharp upper and lower bounds for both worst-case and average case settings. In addition, we theoretically analyze the hop reducing in SChord and derive the fact that SChord can significantly reduce the routing hops as compared to Chord. Several simulations are presented to evaluate the performance of the algorithm and support our analytical findings. The simulation results show the efficiency of SChord. PMID- 24778599 TI - Biological functionalities of transglutaminase 2 and the possibility of its compensation by other members of the transglutaminase family. AB - Transglutaminase 2 (TG2) is the most widely distributed and most abundantly expressed member of the transglutaminase family of enzymes, a group of intracellular and extracellular proteins that catalyze the Ca2+-dependent posttranslational modification of proteins. It is a unique member of the transglutaminase family owing to its specialized biochemical, structural and functional elements, ubiquitous tissue distribution and subcellular localization, and substrate specificity. The broad substrate specificity of TG2 and its flexible interaction with numerous other gene products may account for its multiple biological functions. In addition to the classic Ca2+-dependent transamidation of proteins, which is a hallmark of transglutaminase enzymes, additional Ca2+-independent enzymatic and nonenzymatic activities of TG2 have been identified. Many such activities have been directly or indirectly implicated in diverse cellular physiological events, including cell growth and differentiation, cell adhesion and morphology, extracellular matrix stabilization, wound healing, cellular development, receptor-mediated endocytosis, apoptosis, and disease pathology. Given the wide range of activities of the transglutaminase gene family it has been suggested that, in the absence of active versions of TG2, its function could be compensated for by other members of the transglutaminase family. It is in the light of this assertion that we review, herein, TG2 activities and the possibilities and premises for compensation for its absence. PMID- 24778603 TI - Endogenous plasticity in neuro-rehabilitation following partial spinal cord lesions. AB - Currently, much interest in neuro-rehabilitation is focused on mechanisms related to axonal outgrowth and formation of new circuits although still little is known about the functionality in motor behavior. This is a highly exciting avenue of research and most important to consider when dealing with large lesions. Here, we address endogenous mechanisms with the potential of modifying the function of already existing spinal circuits via associative plasticity. We forward a hypothesis based on experimental findings suggesting that potentiation of synaptic transmission in un-injured pathways can be monitored and adjusted by a Cerebellar loop involving the Reticulospinal, Rubrospinal and Corticospinal tracts and spinal interneurons with projection to motoneurons. This mechanism could be of relevance when lesions are less extensive and the integrity of the neural circuits remains in part. Endogenous plasticity in the spinal cord could be of clinical importance if stimulated in an adequate manner, e.g., by using optimal training protocols. PMID- 24778604 TI - Do audio-visual motion cues promote segregation of auditory streams? AB - An audio-visual experiment using moving sound sources was designed to investigate whether the analysis of auditory scenes is modulated by synchronous presentation of visual information. Listeners were presented with an alternating sequence of two pure tones delivered by two separate sound sources. In different conditions, the two sound sources were either stationary or moving on random trajectories around the listener. Both the sounds and the movement trajectories were derived from recordings in which two humans were moving with loudspeakers attached to their heads. Visualized movement trajectories modeled by a computer animation were presented together with the sounds. In the main experiment, behavioral reports on sound organization were collected from young healthy volunteers. The proportion and stability of the different sound organizations were compared between the conditions in which the visualized trajectories matched the movement of the sound sources and when the two were independent of each other. The results corroborate earlier findings that separation of sound sources in space promotes segregation. However, no additional effect of auditory movement per se on the perceptual organization of sounds was obtained. Surprisingly, the presentation of movement-congruent visual cues did not strengthen the effects of spatial separation on segregating auditory streams. Our findings are consistent with the view that bistability in the auditory modality can occur independently from other modalities. PMID- 24778605 TI - Effects of estrogen on higher-order cognitive functions in unstressed human females may depend on individual variation in dopamine baseline levels. PMID- 24778606 TI - RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations. AB - RNA interference (RNAi) knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementary (sc) AAV2/8 vector to develop an RNAi-based therapy in two dominant retinal degeneration mouse models. The allele-specific model expresses transgenic bovine GCAP1(Y99C) establishing a rapid RP-like phenotype, whereas the nonallele-specific model expresses mouse GCAP1(L151F) producing a slowly progressing cone-rod dystrophy (CORD). The late onset GCAP1(L151F)-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse guanylate cyclase-activating protein 1 (GCAP1) showed strong expression at 1 week post-injection. In both allele-specific [GCAP1(Y99C)-RP] and nonallele-specific [GCAP1(L151F)-CORD] models of dominant retinal dystrophy, RNAi-mediated gene silencing enhanced photoreceptor survival, delayed onset of degeneration and improved visual function. Such results provide a "proof of concept" toward effective RNAi-based gene therapy mediated by scAAV2/8 for dominant retinal disease based on GCAP1 mutation. Further, nonallele-specific RNAi knockdown of GCAP1 may prove generally applicable toward the rescue of any human GCAP1-based dominant cone-rod dystrophy. PMID- 24778607 TI - A common developmental plan for neocortical gene-expressing neurons in the pallium of the domestic chicken Gallus gallus domesticus and the Chinese softshell turtle Pelodiscus sinensis. AB - The six-layered neocortex is a unique characteristic of mammals and likely provides the neural basis of their sophisticated cognitive abilities. Although all mammalian species share the layered structure of the neocortex, the sauropsids exhibit an entirely different cytoarchitecture of the corresponding pallial region. Our previous gene expression study revealed that the chicken pallium possesses neural subtypes that express orthologs of layer-specific genes of the mammalian neocortex. To understand the evolutionary steps leading toward animal group-specific neuronal arrangements in the pallium in the course of amniote diversification, we examined expression patterns of the same orthologs and a few additional genes in the pallial development of the Chinese softshell turtle Pelodiscus sinensis, and compared these patterns to those of the chicken. Our analyses highlighted similarities in neuronal arrangements between the two species; the mammalian layer 5 marker orthologs are expressed in the medial domain and the layer 2/3 marker orthologs are expressed in the lateral domain in the pallia of both species. We hypothesize that the mediolateral arrangement of the neocortical layer-specific gene-expressing neurons originated in their common ancestor and is conserved among all sauropsid groups, whereas the neuronal arrangement within the pallium could have highly diversified independently in the mammalian lineage. PMID- 24778608 TI - Resting state functional connectivity in early blind humans. AB - Task-based neuroimaging studies in early blind humans (EB) have demonstrated heightened visual cortex responses to non-visual paradigms. Several prior functional connectivity studies in EB have shown altered connections consistent with these task-based results. But these studies generally did not consider behavioral adaptations to lifelong blindness typically observed in EB. Enhanced cognitive abilities shown in EB include greater serial recall and attention to memory. Here, we address the question of the extent to which brain intrinsic activity in EB reflects such adaptations. We performed a resting-state functional magnetic resonance imaging study contrasting 14 EB with 14 age/gender matched normally sighted controls (NS). A principal finding was markedly greater functional connectivity in EB between visual cortex and regions typically associated with memory and cognitive control of attention. In contrast, correlations between visual cortex and non-deprived sensory cortices were significantly lower in EB. Thus, the available data, including that obtained in prior task-based and resting state fMRI studies, as well as the present results, indicate that visual cortex in EB becomes more heavily incorporated into functional systems instantiating episodic recall and attention to non-visual events. Moreover, EB appear to show a reduction in interactions between visual and non-deprived sensory cortices, possibly reflecting suppression of inter sensory distracting activity. PMID- 24778609 TI - Consequences at adulthood of transient inactivation of the parahippocampal and prefrontal regions during early development: new insights from a disconnection animal model for schizophrenia. AB - The psychic disintegration characteristic of schizophrenia is thought to result from a defective connectivity, of neurodevelopmental origin, between several integrative brain regions. The parahippocampal region and the prefrontal cortex are described as the main regions affected in schizophrenia. Interestingly, latent inhibition (LI) has been found to be reduced in patients with schizophrenia, and the existence of a dopaminergic dysfunction is also generally well accepted in this disorder. In the present review, we have integrated behavioral and neurochemical data obtained in a LI protocol involving adult rats subjected to neonatal functional inactivation of the entorhinal cortex, the ventral subiculum or the prefrontal cortex. The data discussed suggest a subtle and transient functional blockade during early development of the aforementioned brain regions is sufficient to induce schizophrenia-related behavioral and dopaminergic abnormalities in adulthood. In summary, these results support the view that our conceptual and methodological approach, based on functional disconnections, is valid for modeling some aspects of the pathophysiology of schizophrenia from a neurodevelopmental perspective. PMID- 24778610 TI - Learning to smell danger: acquired associative representation of threat in the olfactory cortex. AB - Neuroscience research over the past few decades has reached a strong consensus that the amygdala plays a key role in emotion processing. However, many questions remain unanswered, especially concerning emotion perception. Based on mnemonic theories of olfactory perception and in light of the highly associative nature of olfactory cortical processing, here I propose a sensory cortical model of olfactory threat perception (i.e., sensory-cortex-based threat perception): the olfactory cortex stores threat codes as acquired associative representations (AARs) formed via aversive life experiences, thereby enabling encoding of threat cues during sensory processing. Rodent and human research in olfactory aversive conditioning was reviewed, indicating learning-induced plasticity in the amygdala and the olfactory piriform cortex. In addition, as aversive learning becomes consolidated in the amygdala, the associative olfactory (piriform) cortex may undergo (long-term) plastic changes, resulting in modified neural response patterns that underpin threat AARs. This proposal thus brings forward a sensory cortical pathway to threat processing (in addition to amygdala-based processes), potentially accounting for an alternative mechanism underlying the pathophysiology of anxiety and depression. PMID- 24778612 TI - Network analysis of perception-action coupling in infants. AB - The functional networks that support action observation are of great interest in understanding the development of social cognition and motor learning. How infants learn to represent and understand the world around them remains one of the most intriguing questions in developmental cognitive neuroscience. Recently, mathematical measures derived from graph theory have been used to study connectivity networks in the developing brain. Thus far, this type of analysis in infancy has only been applied to the resting state. In this study, we recorded electroencephalography (EEG) from infants (ages 4-11 months of age) and adults while they observed three types of actions: (a) reaching for an object; (b) walking; and (c) object motion. Graph theory based analysis was applied to these data to evaluate changes in brain networks. Global metrics that provide measures of the structural properties of the network (characteristic path, density, global efficiency, and modularity) were calculated for each group and for each condition. We found statistically significant differences in measures for the observation of walking condition only. Specifically, in comparison to adults, infants showed increased density and global efficiency in combination with decreased modularity during observation of an action that is not within their motor repertoire (i.e., independent walking), suggesting a less structured organization. There were no group differences in global metric measures for observation of object motion or for observation of actions that are within the repertoire of infants (i.e., reaching). These preliminary results suggest that infants and adults may share a basic functional network for action observation that is sculpted by experience. Motor experience may lead to a shift towards a more efficient functional network. PMID- 24778611 TI - Unique features of the human brainstem and cerebellum. AB - The cerebral cortex is greatly expanded in the human brain. There is a parallel expansion of the cerebellum, which is interconnected with the cerebral cortex. We have asked if there are accompanying changes in the organization of pre cerebellar brainstem structures. We have examined the cytoarchitectonic and neurochemical organization of the human medulla and pons. We studied human cases from the Witelson Normal Brain Collection, analyzing Nissl sections and sections processed for immunohistochemistry for multiple markers including the calcium binding proteins calbindin, calretinin, and parvalbumin, non-phosphorylated neurofilament protein, and the synthetic enzyme for nitric oxide, nitric oxide synthase. We have also compared the neurochemical organization of the human brainstem to that of several other species including the chimpanzee, macaque and squirrel monkey, cat, and rodent, again using Nissl staining and immunohistochemistry. We found that there are major differences in the human brainstem, ranging from relatively subtle differences in the neurochemical organization of structures found in each of the species studied to the emergence of altogether new structures in the human brainstem. Two aspects of human cortical organization, individual differences and left-right asymmetry, are also seen in the brainstem (principal nucleus of the inferior olive) and the cerebellum (the dentate nucleus). We suggest that uniquely human motor and cognitive abilities derive from changes at all levels of the central nervous system, including the cerebellum and brainstem, and not just the cerebral cortex. PMID- 24778613 TI - An ITK implementation of a physics-based non-rigid registration method for brain deformation in image-guided neurosurgery. AB - As part of the ITK v4 project efforts, we have developed ITK filters for physics based non-rigid registration (PBNRR), which satisfies the following requirements: account for tissue properties in the registration, improve accuracy compared to rigid registration, and reduce execution time using GPU and multi-core accelerators. The implementation has three main components: (1) Feature Point Selection, (2) Block Matching (mapped to both multi-core and GPU processors), and (3) a Robust Finite Element Solver. The use of multi-core and GPU accelerators in ITK v4 provides substantial performance improvements. For example, for the non rigid registration of brain MRIs, the performance of the block matching filter on average is about 10 times faster when 12 hyperthreaded multi-cores are used and about 83 times faster when the NVIDIA Tesla GPU is used in Dell Workstation. PMID- 24778614 TI - Sharing privacy-sensitive access to neuroimaging and genetics data: a review and preliminary validation. AB - The growth of data sharing initiatives for neuroimaging and genomics represents an exciting opportunity to confront the "small N" problem that plagues contemporary neuroimaging studies while further understanding the role genetic markers play in the function of the brain. When it is possible, open data sharing provides the most benefits. However, some data cannot be shared at all due to privacy concerns and/or risk of re-identification. Sharing other data sets is hampered by the proliferation of complex data use agreements (DUAs) which preclude truly automated data mining. These DUAs arise because of concerns about the privacy and confidentiality for subjects; though many do permit direct access to data, they often require a cumbersome approval process that can take months. An alternative approach is to only share data derivatives such as statistical summaries-the challenges here are to reformulate computational methods to quantify the privacy risks associated with sharing the results of those computations. For example, a derived map of gray matter is often as identifiable as a fingerprint. Thus alternative approaches to accessing data are needed. This paper reviews the relevant literature on differential privacy, a framework for measuring and tracking privacy loss in these settings, and demonstrates the feasibility of using this framework to calculate statistics on data distributed at many sites while still providing privacy. PMID- 24778615 TI - Ageing differentially affects neural processing of different conflict types-an fMRI study. AB - Interference control and conflict resolution is affected by ageing. There is increasing evidence that ageing does not compromise interference control in general but rather shows distinctive effects on different components of interference control. Different conflict types, [e.g., stimulus-stimulus (S-S) or stimulus-response (S-R) conflicts] trigger different cognitive processes and thus activate different neural networks. In the present functional magnetic resonance imaging (fMRI) study, we used a combined Flanker and Stimulus Response Conflict (SRC) task to investigate the effect of ageing on S-S and S-R conflicts. Behavioral data analysis revealed larger SRC effects in elderly. fMRI Results show that both age groups recruited similar regions [caudate nucleus, cingulate gyrus and middle occipital gyrus (MOG)] during Flanker conflict processing. Furthermore, elderly show an additional activation pattern in parietal and frontal areas. In contrast, no common activation of both age groups was found in response to the SRC. These data suggest that ageing has distinctive effects on S S and S-R conflicts. PMID- 24778616 TI - The molecular basis of memory. Part 3: tagging with "emotive" neurotransmitters. AB - Many neurons of all animals that exhibit memory (snails, worms, flies, vertebrae) present arborized shapes with many varicosities and boutons. These neurons, release neurotransmitters and contain ionotropic receptors that produce and sense electrical signals (ephaptic transmission). The extended shapes maximize neural contact with the surrounding neutrix [defined as: neural extracellular matrix (nECM) + diffusible (neurometals and neurotransmitters)] as well as with other neurons. We propose a tripartite mechanism of animal memory based on the dynamic interactions of splayed neurons with the "neutrix." Their interactions form cognitive units of information (cuinfo), metal-centered complexes within the nECM around the neuron. Emotive content is provided by NTs, which embody molecular links between physiologic (body) responses and psychic feelings. We propose that neurotransmitters form mixed complexes with cuinfo used for tagging emotive memory. Thus, NTs provide encoding option not available to a Turing, binary based, device. The neurons employ combinatorially diverse options, with >10 NMs and >90 NTs for encoding ("flavoring") cuinfo with emotive tags. The neural network efficiently encodes, decodes and consolidates related (entangled) sets of cuinfo into a coherent pattern, the basis for emotionally imbued memory, critical for determining a behavioral choice aimed at survival. The tripartite mechanism with tagging of NTs permits of a causal connection between physiology and psychology. PMID- 24778617 TI - Cardiorespiratory fitness mediates the effects of aging on cerebral blood flow. AB - The brain's vasculature is likely to be subjected to the same age-related physiological and anatomical changes affecting the rest of the cardiovascular system. Since aerobic fitness is known to alleviate both cognitive and volumetric losses in the brain, it is important to investigate some of the possible mechanisms underlying these beneficial changes. Here we investigated the role that estimated cardiorespiratory fitness (eCRF) plays in determining the relationship between aging and cerebral blood flow (CBF) in a group of older adults (ages 55-85). Using arterial spin labeling to quantify CBF, we found that blood flow in the gray matter was positively correlated with eCRF and negatively correlated with age. Subsequent analyses revealed that eCRF fully mediated the effects of age on CBF in the gray matter, but not in the white matter. Additionally, regional measures of CBF were related to regional measures of brain volume. These findings provide evidence that age-related effects on cerebrovascular health and perfusion in older adults are largely influenced by their eCRF levels. PMID- 24778618 TI - Age-related changes of protein SUMOylation balance in the AbetaPP Tg2576 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a complex disorder that affects the central nervous system causing a severe neurodegeneration. This pathology affects an increasing number of people worldwide due to the overall aging of the human population. In recent years SUMO protein modification has emerged as a possible cellular mechanism involved in AD. Some of the proteins engaged in the physiopathological process of AD, like BACE1, GSK3-beta tau, AbetaPP, and JNK, are in fact subject to protein SUMO modifications or interactions. Here, we have investigated the SUMO/deSUMOylation balance and SUMO-related proteins during the onset and progression of the pathology in the Tg2576 mouse model of AD. We examined four age-stages (1.5, 3, 6, 17 months old) and observed shows an increase in SUMO-1 protein conjugation at 3 and 6 months in transgenic mice with respect to WT in both cortex and hippocampus. Interestingly this is paralleled by increased expression levels of Ubc9 and SENP1 in both brain regions. At 6 months of age also the SUMO-1 mRNA resulted augmented. SUMO-2-ylation was surprisingly decreased in old transgenic mice and was unaltered in the other time windows. The fact that alterations in SUMO/deSUMOylation equilibrium occur from the early phases of AD suggests that global posttranslational modifications may play an important role in the mechanisms underlying disease pathogenesis, thus providing potential targets for pharmacological interventions. PMID- 24778619 TI - Arterial pressure and cerebral blood flow variability: friend or foe? A review. AB - Variability in arterial pressure and cerebral blood flow has traditionally been interpreted as a marker of cardiovascular decompensation, and has been associated with negative clinical outcomes across varying time scales, from impending orthostatic syncope to an increased risk of stroke. Emerging evidence, however, suggests that increased hemodynamic variability may, in fact, be protective in the face of acute challenges to perfusion, including significant central hypovolemia and hypotension (including hemorrhage), and during cardiac bypass surgery. This review presents the dichotomous views on the role of hemodynamic variability on clinical outcome, including the physiological mechanisms underlying these patterns, and the potential impact of increased and decreased variability on cerebral perfusion and oxygenation. We suggest that reconciliation of these two apparently discrepant views may lie in the time scale of hemodynamic variability; short time scale variability appears to be cerebroprotective, while mid to longer term fluctuations are associated with primary and secondary end organ dysfunction. PMID- 24778620 TI - Epigenetic features in the oyster Crassostrea gigas suggestive of functionally relevant promoter DNA methylation in invertebrates. AB - DNA methylation is evolutionarily conserved. Vertebrates exhibit high, widespread DNA methylation whereas invertebrate genomes are less methylated, predominantly within gene bodies. DNA methylation in invertebrates is associated with transcription level, alternative splicing, and genome evolution, but functional outcomes of DNA methylation remain poorly described in lophotrochozoans. Recent genome-wide approaches improve understanding in distant taxa such as molluscs, where the phylogenetic position, and life traits of Crassostrea gigas make this bivalve an ideal model to study the physiological and evolutionary implications of DNA methylation. We review the literature about DNA methylation in invertebrates and focus on DNA methylation features in the oyster. Indeed, though our MeDIP-seq results confirm predominant intragenic methylation, the profiles depend on the oyster's developmental and reproductive stage. We discuss the perspective that oyster DNA methylation could be biased toward the 5'-end of some genes, depending on physiological status, suggesting important functional outcomes of putative promoter methylation from cell differentiation during early development to sustained adaptation of the species to the environment. PMID- 24778621 TI - Drug Injection to Sites other than Arm: A Study of Iranian Heroin Injectors. AB - For almost all injecting drug users (IDUs), the first site of injection is the arm. Years after injection, IDUs may shift to using other sites for intravenous (IV) access. Although injection to sites other than the arm is associated with higher risks, literature is limited regarding this behavior. We aimed to determine the prevalence and associated factors of using IV access points other than the arm among a national sample of IDUs in Iran. Data came from the National Drug Dependence Survey, 2007, which had enrolled 863 IDUs with at least one daily injection. Data on socio-demographics, pattern of drug use, and injection-related behaviors were entered into a logistic regression to determine predictors of injection to sites other than the arm. From all participants, 54.8% reported current injection sites in areas other than the arm. The other injection sites were the femoral venous sinus (17.0%), followed by the groin (14.5%) and neck (11.5%). Logistic regression revealed that living alone [odds ratio (OR) = 1.789, 95% confidence interval (CI) = 1.218-2.629], being Sunni (OR = 3.475, 95% CI = 1.775-6.801), having higher family income (OR = 1.002, 95% CI = 1.001-1.003), higher age at first drug use (OR = 1.039, 95% CI = 1.009-1.069), longer injection duration (OR = 1.071, 95% CI = 1.041-1.102), and more injection frequency (OR = 1.255, 95% CI = 1.072-1.471) were associated with higher likelihood of using injection sites other than the arm. Using sites other than the arm for IV injection is linked to socio-demographics, drug use data, and injection-related characteristics that can be used by policy makers. This information can be used for harm reduction planning. PMID- 24778622 TI - Are certain foods addictive? PMID- 24778623 TI - Distractibility during retrieval of long-term memory: domain-general interference, neural networks and increased susceptibility in normal aging. AB - The mere presence of irrelevant external stimuli results in interference with the fidelity of details retrieved from long-term memory (LTM). Recent studies suggest that distractibility during LTM retrieval occurs when the focus of resource limited, top-down mechanisms that guide the selection of relevant mnemonic details is disrupted by representations of external distractors. We review findings from four studies that reveal distractibility during episodic retrieval. The approach cued participants to recall previously studied visual details when their eyes were closed, or were open and irrelevant visual information was present. The results showed a negative impact of the distractors on the fidelity of details retrieved from LTM. An fMRI experiment using the same paradigm replicated the behavioral results and found that diminished episodic memory was associated with the disruption of functional connectivity in whole-brain networks. Specifically, network connectivity supported recollection of details based on visual imagery when eyes were closed, but connectivity declined in the presence of visual distractors. Another experiment using auditory distractors found equivalent effects for auditory and visual distraction during cued recall, suggesting that the negative impact of distractibility is a domain-general phenomenon in LTM. Comparisons between older and younger adults revealed an aging related increase in the negative impact of distractibility on retrieval of LTM. Finally, a new study that compared categorization abilities between younger and older adults suggests a cause underlying age-related decline of visual details in LTM. The sum of our findings suggests that cognitive control resources, although limited, have the capability to resolve interference from distractors during tasks of moderate effort, but these resources are overwhelmed when additional processes associated with episodic retrieval, or categorization of complex prototypes, are required. PMID- 24778624 TI - Getting the right grasp on executive function. AB - Executive Function (EF) refers to important socio-emotional and cognitive skills that are known to be highly correlated with both academic and life success. EF is a blanket term that is considered to include self-regulation, working memory, and planning. Recent studies have shown a relationship between EF and motor control. The emergence of motor control coincides with that of EF, hence understanding the relationship between these two domains could have significant implications for early detection and remediation of later EF deficits. The purpose of the current study was to investigate this relationship in young children. This study incorporated the Behavioral Rating Inventory of Executive Function (BRIEF) and two motor assessments with a focus on precision grasping to test this hypothesis. The BRIEF is comprised of two indices of EF: (1) the Behavioral Regulation Index (BRI) containing three subscales: Inhibit, Shift, and Emotional Control; (2) the Metacognition Index (MI) containing five subscales: Initiate, Working Memory, Plan/Organize, Organization of Materials, and Monitor. A global executive composite (GEC) is derived from the two indices. In this study, right-handed children aged 5-6 and 9-10 were asked to: grasp-to-construct (Lego(r) models); and grasp-to-place (wooden blocks), while their parents completed the BRIEF questionnaire. Analysis of results indicated significant correlations between the strength of right hand preference for grasping and numerous elements of the BRIEF including the BRI, MI, and GEC. Specifically, the more the right hand was used for grasping the better the EF ratings. In addition, patterns of space-use correlated with the GEC in several subscales of the BRIEF. Finally and remarkably, the results also showed a reciprocal relationship between hand and space use for grasping and EF. These findings are discussed with respect to: (1) the developmental overlap of motor and executive functions; (2) detection of EF deficits through tasks that measure lateralization of hand and space use; and (3) the possibility of using motor interventions to remediate EF deficits. PMID- 24778625 TI - Ischemic posterior circulation stroke: a review of anatomy, clinical presentations, diagnosis, and current management. AB - Posterior circulation strokes represent approximately 20% of all ischemic strokes (1, 2). In contrast to the anterior circulation, several differences in presenting symptoms, clinical evaluation, diagnostic testing, and management strategy exist presenting a challenge to the treating physician. This review will discuss the anatomical, etiological, and clinical classification of PC strokes, identify diagnostic pitfalls, and overview current therapeutic regimens. PMID- 24778627 TI - The role and influence of gut microbiota in pathogenesis and management of obesity and metabolic syndrome. AB - The obesity epidemic has drastically impacted the state of health care in the United States. Aside from poor diet hygiene and genetics, there are many other factors thought to play a role in the emergence of obesity and the metabolic syndrome. There has been a paradigm shift toward further investigating the gut microbiota and its implications in the pathogenesis of a variety of disease states, including inflammatory bowel disease, Clostridium difficile, and most recently obesity and the metabolic syndrome. This article is intended to evaluate the role of gut microbiota in the pathogenesis of obesity and metabolic syndrome and its influence in future management. PMID- 24778626 TI - Control of IGFBP-2 Expression by Steroids and Peptide Hormones in Vertebrates. AB - IGFBP-2 (1) has been described as a brain tumor oncogene (2) and is widely expressed in cancers from different origins (3-8). IGFBP-2 alone cannot cause malignant transformation, yet progression of brain tumors to higher grade (9) and also has been provided as a protective element in earlier stages of multistage colon carcinogenesis (10). Therefore, it is crucial to understand the factors that determine expression patterns of IGFBP-2 under normal and malignant conditions. The present review provides a comprehensive update of known factors that have an impact on expression of IGFBP-2. PMID- 24778628 TI - Phototrophic biofilm assembly in microbial-mat-derived unicyanobacterial consortia: model systems for the study of autotroph-heterotroph interactions. AB - Microbial autotroph-heterotroph interactions influence biogeochemical cycles on a global scale, but the diversity and complexity of natural systems and their intractability to in situ manipulation make it challenging to elucidate the principles governing these interactions. The study of assembling phototrophic biofilm communities provides a robust means to identify such interactions and evaluate their contributions to the recruitment and maintenance of phylogenetic and functional diversity over time. To examine primary succession in phototrophic communities, we isolated two unicyanobacterial consortia from the microbial mat in Hot Lake, Washington, characterizing the membership and metabolic function of each consortium. We then analyzed the spatial structures and quantified the community compositions of their assembling biofilms. The consortia retained the same suite of heterotrophic species, identified as abundant members of the mat and assigned to Alphaproteobacteria, Gammaproteobacteria, and Bacteroidetes. Autotroph growth rates dominated early in assembly, yielding to increasing heterotroph growth rates late in succession. The two consortia exhibited similar assembly patterns, with increasing relative abundances of members from Bacteroidetes and Alphaproteobacteria concurrent with decreasing relative abundances of those from Gammaproteobacteria. Despite these similarities at higher taxonomic levels, the relative abundances of individual heterotrophic species were substantially different in the developing consortial biofilms. This suggests that, although similar niches are created by the cyanobacterial metabolisms, the resulting webs of autotroph-heterotroph and heterotroph heterotroph interactions are specific to each primary producer. The relative simplicity and tractability of the Hot Lake unicyanobacterial consortia make them useful model systems for deciphering interspecies interactions and assembly principles relevant to natural microbial communities. PMID- 24778629 TI - Mining a database of single amplified genomes from Red Sea brine pool extremophiles-improving reliability of gene function prediction using a profile and pattern matching algorithm (PPMA). AB - Reliable functional annotation of genomic data is the key-step in the discovery of novel enzymes. Intrinsic sequencing data quality problems of single amplified genomes (SAGs) and poor homology of novel extremophile's genomes pose significant challenges for the attribution of functions to the coding sequences identified. The anoxic deep-sea brine pools of the Red Sea are a promising source of novel enzymes with unique evolutionary adaptation. Sequencing data from Red Sea brine pool cultures and SAGs are annotated and stored in the Integrated Data Warehouse of Microbial Genomes (INDIGO) data warehouse. Low sequence homology of annotated genes (no similarity for 35% of these genes) may translate into false positives when searching for specific functions. The Profile and Pattern Matching (PPM) strategy described here was developed to eliminate false positive annotations of enzyme function before progressing to labor-intensive hyper-saline gene expression and characterization. It utilizes InterPro-derived Gene Ontology (GO) terms (which represent enzyme function profiles) and annotated relevant PROSITE IDs (which are linked to an amino acid consensus pattern). The PPM algorithm was tested on 15 protein families, which were selected based on scientific and commercial potential. An initial list of 2577 enzyme commission (E.C.) numbers was translated into 171 GO-terms and 49 consensus patterns. A subset of INDIGO sequences consisting of 58 SAGs from six different taxons of bacteria and archaea were selected from six different brine pool environments. Those SAGs code for 74,516 genes, which were independently scanned for the GO-terms (profile filter) and PROSITE IDs (pattern filter). Following stringent reliability filtering, the non-redundant hits (106 profile hits and 147 pattern hits) are classified as reliable, if at least two relevant descriptors (GO-terms and/or consensus patterns) are present. Scripts for annotation, as well as for the PPM algorithm, are available through the INDIGO website. PMID- 24778630 TI - The giant ciliate Zoothamnium niveum and its thiotrophic epibiont Candidatus Thiobios zoothamnicoli: a model system to study interspecies cooperation. AB - Symbioses between chemoautotrophic sulfur-oxidizing (thiotrophic) bacteria and protists or animals are among the most diverse and prevalent in the ocean. They are extremely difficult to maintain in aquaria and no thiotrophic symbiosis involving an animal host has ever been successfully cultivated. In contrast, we have cultivated the giant ciliate Zoothamnium niveum and its obligate ectosymbiont Candidatus Thiobios zoothamnicoli in small flow-through aquaria. This review provides an overview of the host and the symbiont and their phylogenetic relationships. We summarize our knowledge on the ecology, geographic distribution and life cycle of the host, on the vertical transmission of the symbiont, and on the cultivation of this symbiosis. We then discuss the benefits and costs involved in this cooperation compared with other thiotrophic symbioses and outline our view on the evolution and persistence of this byproduct mutualism. PMID- 24778631 TI - Immune modulation of the brain-gut-microbe axis. PMID- 24778632 TI - Significance of interleukin-33 and its related cytokines in patients with breast cancers. AB - Interleukin-33 (IL-33) is a recently identified cytokine, an important member of the interleukin-1 family. IL-33 binds to its receptor ST2 to induce type 2 cytokines and exert both pro-inflammatory and protective functions in host defense and disease. Murine breast carcinoma models suggest disruption of ST2 signaling may enhance the anti-tumor immune response, suggesting IL-33 impedes anti-tumor immunity. However, the role of IL-33 in patients with breast cancers (BC) is not elucidated. We detected the expression of IL-33 in tumor tissue, and IL-33 and its related cytokines in serum from BC patients. Using Luminex and immunohistochemistry methods, we found that serum levels of IL-33 were nearly twofold higher in patients with BC, compared to patients with benign breast diseases. In cancer tissues, expression of IL-33 was higher than matched normal breast tissues from the same patients, and was also associated with a well differentiated phenotype, HER2 overexpression, more lymph nodes involvement, and a family history of malignant carcinoma. These results suggest that IL-33 may play an important role in the progress of BC and may be a useful biomarker for predicting the progress and metastasis of BC. PMID- 24778634 TI - Recombinant BCG: Innovations on an Old Vaccine. Scope of BCG Strains and Strategies to Improve Long-Lasting Memory. AB - Bacille Calmette-Guerin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB). Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort toward the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG) published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words TB, rBCG vaccine, and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of Mycobacterium tuberculosis (Mtb) immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and overexpression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T-cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGDeltaureC:hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long lasting memory. PMID- 24778633 TI - Neuro-endocrine networks controlling immune system in health and disease. AB - The nervous and immune systems have long been considered as compartments that perform separate and different functions. However, recent clinical, epidemiological, and experimental data have suggested that the pathogenesis of several immune-mediated disorders, such as multiple sclerosis (MS), might involve factors, hormones, and neural mediators that link the immune and nervous system. These molecules are members of the same superfamily, which allow the mutual and bi-directional neural-immune interaction. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones that control food intake and metabolism, has suggested that nutritional/metabolic status, acting at central level, can control immune self-tolerance, since it promotes experimental autoimmune encephalomyelitis, an animal model of MS. Here, we summarize the most recent advances and the key players linking the central nervous system, immune tolerance, and the metabolic status. Understanding this coordinated interaction may pave the way for novel therapeutic approaches to increase host defense and suppress immune-mediated disorders. PMID- 24778635 TI - Biological Impact of the TSHbeta Splice Variant in Health and Disease. AB - Thyroid stimulating hormone (TSH), a glycoprotein hormone composed of alpha and beta chains, is produced by thyrotrope cells of the anterior pituitary. Within the conventional endocrine loop, pituitary-derived TSH binds to receptors in the thyroid, resulting in the release of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). T4 and T3 in turn regulate nearly every aspect of mammalian physiology, including basal metabolism, growth and development, and mood and cognition. Although TSHbeta has been known for years to be produced by cells of the immune system, the significance of that has remained largely unclear. Recently, a splice variant of TSHbeta (TSHbetav), which consists of a truncated but biologically functional portion of the native form of TSHbeta, was shown to be produced by bone marrow cells and peripheral blood leukocytes, particularly cells of the myeloid/monocyte lineage. In contrast, full-length native TSHbeta is minimally produced by cells of the immune system. The present article will describe the discovery of the TSHbetav and will discuss its potential role in immunity and autoimmunity, inflammation, and bone remodeling. PMID- 24778636 TI - Gut microbiota and the paradox of cancer immunotherapy. AB - It is recently shown that beneficial environmental microbes stimulate integrated immune and neuroendocrine factors throughout the body, consequently modulating regulatory T-lymphocyte phenotypes, maintaining systemic immune balance, and determining the fate of preneoplastic lesions toward regression while sustaining whole body good health. Stimulated by a gut microbiota-centric systemic homeostasis hypothesis, we set out to explore the influence of the gut microbiome to explain the paradoxical roles of regulatory T-lymphocytes in cancer development and growth. This paradigm shift places cancer prevention and treatment into a new broader context of holobiont engineering to cultivate a tumor-suppressive macroenvironment. PMID- 24778637 TI - Senescence and programmed cell death in plants: polyamine action mediated by transglutaminase. AB - Research on polyamines (PAs) in plants laps a long way of about 50 years and many roles have been discovered for these aliphatic cations. PAs regulate cell division, differentiation, organogenesis, reproduction, dormancy-break and senescence, homeostatic adjustments in response to external stimuli and stresses. Nevertheless, the molecular mechanisms of their multiple activities are still matter of research. PAs are present in free and bound forms and interact with several important cell molecules; some of these interactions may occur by covalent linkages catalyzed by transglutaminase (TGase), giving rise to "cationization" or cross-links among specific proteins. Senescence and programmed cell death (PCD) can be delayed by PAs; in order to re-interpret some of these effects and to obtain new insights into their molecular mechanisms, their conjugation has been revised here. The TGase-mediated interactions between proteins and PAs are the main target of this review. After an introduction on the characteristics of this enzyme, on its catalysis and role in PCD in animals, the plant senescence and PCD models in which TGase has been studied, are presented: the corolla of naturally senescing or excised flowers, the leaves senescing, either excised or not, the pollen during self-incompatible pollination, the hypersensitive response and the tuber storage parenchyma during dormancy release. In all the models examined, TGase appears to be involved by a similar molecular mechanism as described during apoptosis in animal cells, even though several substrates are different. Its effect is probably related to the type of PCD, but mostly to the substrate to be modified in order to achieve the specific PCD program. As a cross-linker of PAs and proteins, TGase is an important factor involved in multiple, sometimes controversial, roles of PAs during senescence and PCD. PMID- 24778638 TI - Novel functional roles for PERIANTHIA and SEUSS during floral organ identity specification, floral meristem termination, and gynoecial development. AB - The gynoecium is the female reproductive structure of angiosperm flowers. In Arabidopsis thaliana the gynoecium is composed of two carpels that are fused into a tube-like structure. As the gynoecial primordium arises from the floral meristem, a specialized meristematic structure, the carpel margin meristem (CMM), develops from portions of the medial gynoecial domain. The CMM is critical for reproductive competence because it gives rise to the ovules, the precursors of the seeds. Here we report a functional role for the transcription factor PERIANTHIA (PAN) in the development of the gynoecial medial domain and the formation of ovule primordia. This function of PAN is revealed in pan aintegumenta (ant) as well as seuss (seu) pan double mutants that form reduced numbers of ovules. Previously, PAN was identified as a regulator of perianth organ number and as a direct activator of AGAMOUS (AG) expression in floral whorl four. However, the seu pan double mutants display enhanced ectopic AG expression in developing sepals and the partial transformation of sepals to petals indicating a novel role for PAN in the repression of AG in floral whorl one. These results indicate that PAN functions as an activator or repressor of AG expression in a whorl-specific fashion. The seu pan double mutants also display enhanced floral indeterminacy, resulting in the formation of "fifth whorl" structures and disruption of WUSCHEL (WUS) expression patterns revealing a novel role for SEU in floral meristem termination. PMID- 24778640 TI - Inflammation blood and tissue factors of plaque growth in an experimental model evidenced by a systems approach. AB - PURPOSE: The multifactorial pathogenesis of coronary atherosclerotic lesion formation has been investigated in a swine model of high cholesterol diet induced atherogenesis and data processed by a systems approach. METHODS: Farm pigs were fed on standard or high cholesterol diet of 8 and 16 weeks duration. Plasma assessment of total cholesterol, HDL, LDL, and ELISA of some cytokines and ICAM-1 were performed on baseline and end-diet samples. Segments of the right coronary artery were incubated for 24 h in serum-free medium to collect secreted proteins and their expression analyzed by mass spectrometry. Data of plasma and tissue factors were processed by a statistical systems inference approach: both histologic parameters of coronary intimal thickness (IT) and of lesion area (LA) were chosen as dependent variables (coronary atherosclerotic burden). RESULTS: Relations among plasma adhesion molecules, cytokines, lipoproteins, tissue proteins and histology indexes were integrated in a model regression scheme. Bayesian model averaging (BMA) variable selection was chosen as a method to identify relevant factors associated to atherosclerotic burden: TNFalpha was identified as an associated plasma marker, oxLDL and HDL as relevant lipoproteins; macrophage function related antioxidant Catalase enzyme, lysosome associated Cathepsin D, S100-A10, and Transforming growth factor-beta-induced protein ig-h3 were identified and selected as associated to atherogenesis outcome. CONCLUSIONS: The results of this systems approach are consistent with the hypothesis that, in high cholesterol diet-induced experimental atherogenesis, the interaction between plasma cytokines, lipoproteins and artery-specific proteins, influences lesion initiation and growth. In particular, some macrophage function related proteins are found significantly and positively associated to atherosclerotic burden, suggesting a novel molecular framework into the atherogenesis-inflammatory disorder. PMID- 24778639 TI - tmRNA-mediated trans-translation as the major ribosome rescue system in a bacterial cell. AB - Transfer messenger RNA (tmRNA; also known as 10Sa RNA or SsrA RNA) is a small RNA molecule that is conserved among bacteria. It has structural and functional similarities to tRNA: it has an upper half of the tRNA-like structure, its 5' end is processed by RNase P, it has typical tRNA-specific base modifications, it is aminoacylated with alanine, it binds to EF-Tu after aminoacylation and it enters the ribosome with EF-Tu and GTP. However, tmRNA lacks an anticodon, and instead it has a coding sequence for a short peptide called tag-peptide. An elaborate interplay of actions of tmRNA as both tRNA and mRNA with the help of a tmRNA binding protein, SmpB, facilitates trans-translation, which produces a single polypeptide from two mRNA molecules. Initially alanyl-tmRNA in complex with EF-Tu and SmpB enters the vacant A-site of the stalled ribosome like aminoacyl-tRNA but without a codon-anticodon interaction, and subsequently truncated mRNA is replaced with the tag-encoding region of tmRNA. During these processes, not only tmRNA but also SmpB structurally and functionally mimics both tRNA and mRNA. Thus trans-translation rescues the stalled ribosome, thereby allowing recycling of the ribosome. Since the tag-peptide serves as a target of AAA(+) proteases, the trans translation products are preferentially degraded so that they do not accumulate in the cell. Although alternative rescue systems have recently been revealed, trans-translation is the only system that universally exists in bacteria. Furthermore, it is unique in that it employs a small RNA and that it prevents accumulation of non-functional proteins from truncated mRNA in the cell. It might play the major role in rescuing the stalled translation in the bacterial cell. PMID- 24778641 TI - Homogenous chaotic network serving as a rate/population code to temporal code converter. AB - At present, it is obvious that different sections of nervous system utilize different methods for information coding. Primary afferent signals in most cases are represented in form of spike trains using a combination of rate coding and population coding while there are clear evidences that temporal coding is used in various regions of cortex. In the present paper, it is shown that conversion between these two coding schemes can be performed under certain conditions by a homogenous chaotic neural network. Interestingly, this effect can be achieved without network training and synaptic plasticity. PMID- 24778642 TI - The Prevalence, Risk Factors, and Clinical Correlates of Erosive Esophagitis and Barrett's Esophagus in Iranian Patients with Reflux Symptoms. AB - Background. Erosive esophagitis (EE) and Barrett's esophagus (BE) are the two important complications of gastroesophageal reflux disease. We aimed to investigate the prevalence of and the risk factors for EE and BE in an Iranian group of patients with reflux symptoms. We also examined the relationship between reflux symptoms and endoscopic findings. Methods. A total of 736 patients with gastroesophageal reflux disease (GERD) symptoms were enrolled and all underwent upper gastrointestinal endoscopy. Diagnosis of Barrett's esophagus was confirmed by pathologic examination and Helicobacter pylori (H. pylori) infection was demonstrated by rapid urease test. Results. Two hundred eighty-three and 34 patients were found to have EE and BE, respectively. Multivariate analysis showed that hiatal hernia (P < 0.001) and H. pylori infection (P < 0.002) were the two significantly related risk factors for esophagitis. Only age was related to BE, with BE patients being more likely to be older (P < 0.001) than others. Conclusions. Prevalence of EE and BE in Iranian reflux patients is similar to that seen in western countries. H. pylori infection and the presence of hiatal hernia may be strong risk factors for esophagitis as does older age for Barrett's esophagus. Finally, reflux symptoms have no significant relationship with endoscopic findings. PMID- 24778643 TI - Incidence and paris classification of pediatric inflammatory bowel disease. AB - New epidemiological data suggest that the incidence of inflammatory bowel disease (IBD) is increasing. As a result the burden of disease accounts for more strains to the health care system. The clinical variability queries whether disease characteristics are related to clinical outcome. Our aim was to delineate the latest results of incidence trends in pediatric IBD and to compare the first experiences with Paris Classification. Incidence of pediatric IBD has been increasing in Western Europe and in Eastern Europe. To better characterize IBD, Paris Classification was introduced and validated recently. Ileocolonic involvement is the most characteristic disease location in Crohn's disease (CD) based on applying Paris Classification. The rate of perianal disease and complicated behaviour in CD was similar. It is of interest that CD patients with colonic involvement were less likely to have stricturing disease compared with patients with ileal involvement. In addition, pancolitis dominated in ulcerative colitis (UC). However, most countries lack prospective, nationwide epidemiological studies to estimate incidence trends. This review emphasizes the importance of nationwide registries that enroll all pediatric IBD cases serving reliable data for "everyday practice." These first reports have shown that Paris Classification is a useful tool to determine the pediatric IBD phenotype. PMID- 24778644 TI - Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity. AB - Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) where the communication ability of nerve cells in the brain and spinal cord with each other gets impaired. Some current findings suggest the role of glutamate excitotoxicity in the development and progression of MS. An excess release of glutamate leads to the activation of ionotropic and metabotropic receptors, thus resulting in accumulation of toxic cytoplasmic Ca(2+) and cell death. However, it has been observed that gamma-aminobutyric acid A (GABAA) receptors located in the nerve terminals activate presynaptic Ca(2+)/calmodulin-dependent signaling to inhibit depolarization-evoked Ca(2+) influx and glutamate release from isolated nerve terminals, which suggest a potential implication of GABAA receptor in management of MS. With this proof of concept, we tried to explore the potential of selective GABAA receptor agonists or positive allosteric modulators (diazepam and phenobarbitone sodium) and GABAA level enhancer (sodium valproate) for management of MS by screening them for their activity in experimental autoimmune encephalomyelitis (EAE) model in rats and cuprizone-induced demyelination model in mice. In this study, sodium valproate was found to show the best activity in the animal models whereas phenobarbitone sodium showed moderate activity. However, diazepam was found to be ineffective. PMID- 24778645 TI - Is telephysiotherapy an option for improved quality of life in patients with osteoarthritis of the knee? AB - This study investigated effect of a 6-week telephysiotherapy programme on quality of life (QoL) of patients with knee osteoarthritis (OA). Fifty patients with knee OA were randomly and equally assigned into two treatment groups: clinic group (CG) and telephysiotherapy group (TG). The CG received physiotherapist administered osteoarthritis-specific exercises in the clinic thrice weekly for 6 weeks while the TG received structured telephone monitoring with self administered osteoarthritis-specific exercises for the same duration at home. Participants' QoL was assessed using WHOQoL-Bref at baseline, second, fourth, and sixth week of intervention. Data were analyzed using ANOVA and independent Student's t-test. Within-group comparison showed significant improvements in physical health domain (P = 0.00* for TG and CG) and psychological domain (P = 0.02* for TG; P = 0.00* for CG) of WHOQoL following six-week intervention. However, there were no significant differences (P > 0.05) in TG and CG's social relationship and environment domains. Between-group comparison showed no significant differences (P > 0.05) between CG and TG's physical health, psychological, and social relationships domains of WHOQoL following 6-week intervention. However, there was significant difference in the environment domain (P < 0.05). Telephysiotherapy using telephone medium improved QoL in patients with knee OA comparable to clinic based treatment. PMID- 24778646 TI - A Comparative Systematic Review of the Optimal CD4 Cell Count Threshold for HIV Treatment Initiation. AB - HIV infection is no longer characterized by high morbidity, rapid progression to AIDS, and death as when the infection was first identified. While anti-retroviral drugs have improved the outcome of AIDS patients, clinical research on the appropriate time to initiate therapy continues to evolve. Optimal therapy initiation would maximize the benefits of these drugs, while minimizing side effects and drug resistance. Recent 2013 WHO guidelines changed HIV therapy initiation from 350 cells/ MU L to 500 cells/ MU L. This systematic review provides an evidence-based comparison of starting treatment at >500 cells/ MU L with starting treatment at the range between 350 cells/ MU L and 500 cells/ MU L. An 11% increase in risk was detected from initiation therapy at the 350-500 cells/ MU L range (0.37 [0.26, 0.53]), when compared with starting treatment before 500 cells/ MU L (0.33 [0.22, 0.48]). Most individual study comparisons showed a benefit for starting treatment at 500 cells/ MU L in comparison with starting at the 350-500 cells/ MU L range with risks ranging from 19% to 300%, though a number of comparisons were not statistically significant. Overall, the study provides evidence based support for initiating anti retroviral therapy at cell counts >500 cells/ MU L wherever possible to prevent AIDS mortality and morbidity. PMID- 24778647 TI - Secondary structure preferences of mn (2+) binding sites in bacterial proteins. AB - 3D structures of proteins with coordinated Mn(2+) ions from bacteria with low, average, and high genomic GC-content have been analyzed (149 PDB files were used). Major Mn(2+) binders are aspartic acid (6.82% of Asp residues), histidine (14.76% of His residues), and glutamic acid (3.51% of Glu residues). We found out that the motif of secondary structure "beta strand-major binder-random coil" is overrepresented around all the three major Mn(2+) binders. That motif may be followed by either alpha helix or beta strand. Beta strands near Mn(2+) binding residues should be stable because they are enriched by such beta formers as valine and isoleucine, as well as by specific combinations of hydrophobic and hydrophilic amino acid residues characteristic to beta sheet. In the group of proteins from GC-rich bacteria glutamic acid residues situated in alpha helices frequently coordinate Mn(2+) ions, probably, because of the decrease of Lys usage under the influence of mutational GC-pressure. On the other hand, the percentage of Mn(2+) sites with at least one amino acid in the "beta strand-major binder random coil" motif of secondary structure (77.88%) does not depend on genomic GC content. PMID- 24778648 TI - Effect of bile Acid on fetal lung in rat model of intrahepatic cholestasis of pregnancy. AB - Objective. To determine the correlation between maternal bile acid (BA) level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods. Forty pregnant rats were treated with (A) 5.5 mg/kg BA, (B) 1.4 mg/kg BA, and (C) 1 ml physiological saline. Levels of total bile acid (TBA), ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results. Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions. The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats. PMID- 24778649 TI - High Risk First Degree Relatives of Type 1 Diabetics: An Association with Increases in CXCR3(+) T Memory Cells Reflecting an Enhanced Activity of Th1 Autoimmune Response. AB - We analyzed the level of (a) CXCR3(+) (Th1) and CCR4(+) (Th2) T memory cells (b) interferon- gamma inducible chemokine (IP-10)(Th1) and thymus and activation regulated chemokine (TARC)(Th2), in 51 first degree relatives (FDRs) of type 1 diabetics (T1D) (17 high risk FDRs (GADA(+), IA-2(+)) and 34 low risk FDRs (GADA( ), IA-2(-))), 24 recent-onset T1D (R-T1D), and 18 healthy subjects. T memory subsets were analyzed by using four-color immunofluorescence staining and flowcytometry. IP-10 and TARC were determined by ELISA. High risk FDRs showed higher levels of CXCR3(+) and lower level of CCR4(+) T memory cells compared to low risk FDRs (64.98 +/- 5.19 versus 42.13 +/- 11.11; 29.46 +/- 2.83 versus 41.90 +/- 8.58%, resp., P < 0.001). Simultaneously, both IP-10 and TARC levels were increased in high risk versus low risk FDRs (160.12 +/- 73.40 versus 105.39 +/- 71.30; 438.83 +/- 120.62 versus 312.04 +/- 151.14 pg/mL, P < 0.05). Binary logistic regression analysis identified the level of CXCR3(+) T memory cells as predictors for high risk FDRs, together with high levels of IP-10. The results imply that, in FDRs, the risk for T1D might be strongly influenced by enhanced activity of Th1 and diminished activity of Th2 autoimmune response. PMID- 24778650 TI - Prevalence of nonclassic congenital adrenal hyperplasia in Turkish children presenting with premature pubarche, hirsutism, or oligomenorrhoea. AB - Background. Nonclassic congenital adrenal hyperplasia (NCAH), caused by mutations in the gene encoding 21-hydroxylase, is a common autosomal recessive disorder. In the present work, our aim was to determine the prevalence of NCAH presenting as premature pubarche (PP), hirsutism, or polycystic ovarian syndrome (PCOS) and to evaluate the molecular spectrum of CYP21A2 mutations in NCAH patients. Methods. A total of 126 patients (122 females, 4 males) with PP, hirsutism, or PCOS were included in the present study. All patients underwent an ACTH stimulation test. NCAH was considered to be present when the stimulated 17-hydroxyprogesterone plasma level was >10 ng/mL. Results. Seventy-one of the 126 patients (56%) presented with PP, 29 (23%) with PCOS, and 26 (21%) with hirsutism. Six patients (4,7%) were diagnosed with NCAH based on mutational analysis. Four different mutations (Q318X, P30L, V281L, and P453S) were found in six NCAH patients. One patient with NCAH was a compound heterozygote for this mutation, and five were heterozygous. Conclusion. NCAH should be considered as a differential diagnosis in patients presenting with PP, hirsutism, and PCOS, especially in countries in which consanguineous marriages are prevalent. PMID- 24778651 TI - Screening of viral pathogens from pediatric ileal tissue samples after vaccination. AB - In 2010, researchers reported that the two US-licensed rotavirus vaccines contained DNA or DNA fragments from porcine circovirus (PCV). Although PCV, a common virus among pigs, is not thought to cause illness in humans, these findings raised several safety concerns. In this study, we sought to determine whether viruses, including PCV, could be detected in ileal tissue samples of children vaccinated with one of the two rotavirus vaccines. A broad spectrum, novel DNA detection technology, the Lawrence Livermore Microbial Detection Array (LLMDA), was utilized, and confirmation of viral pathogens using the polymerase chain reaction (PCR) was conducted. The LLMDA technology was recently used to identify PCV from one rotavirus vaccine. Ileal tissue samples were analyzed from 21 subjects, aged 15-62 months. PCV was not detected in any ileal tissue samples by the LLMDA or PCR. LLMDA identified a human rotavirus A from one of the vaccinated subjects, which is likely due to a recent infection from a wild type rotavirus. LLMDA also identified human parechovirus, a common gastroenteritis viral infection, from two subjects. Additionally, LLMDA detected common gastrointestinal bacterial organisms from the Enterobacteriaceae, Bacteroidaceae, and Streptococcaceae families from several subjects. This study provides a survey of viral and bacterial pathogens from pediatric ileal samples, and may shed light on future studies to identify pathogen associations with pediatric vaccinations. PMID- 24778652 TI - Outcome of endodontic treatments made by postgraduate students in the dental clinic of bretonneau hospital. AB - Objective. The objective of this retrospective study is double: (1) to assess the 1-4 years of outcome of endodontic treatment performed by postgraduate students in endodontics in the Dental Clinic of Bretonneau Hospital and (2) to examine outcome predictors. Method. 363 teeth in 296 patients were treated between 2007 and 2011. 183 patients (224 teeth) were lost during the followup. 113 patients were included in the study (recall: 38%), corresponding to 139 teeth of which 8 were extracted. 131 remaining teeth (36%) were examined clinically and radiographically. Apical periodontitis (AP) was absent (PAI = 1) or present (PAI >= 2). Outcome was classified as "healed," "healing," or "diseased". Results. The success rate was 92%. No failure was observed among the 23 initial endodontic treatments. Among the 108 retreated teeth, 80% were "healed" and 11% were "healing." An association was found between success rate and preoperative signs or symptoms (absent 95% versus present 83%), preoperative root filling density (inadequate 93% versus adequate 57%), but not between preoperative AP status and success. Conclusion. Outcomes in this retrospective study were similar to those previously reported. However, a larger sample size is needed to assess outcome predictors more precisely. PMID- 24778654 TI - Female genital mutilation and obstetric outcomes: flawed systematic review and meta-analysis does not accurately reflect the available evidence. PMID- 24778653 TI - The epigenetic landscape of acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Certain cytogenetic and molecular genetic mutations are recognized to have an impact on prognosis, leading to their inclusion in some prognostic stratification systems. Recently, the advent of high-throughput whole genome or exome sequencing has led to the identification of several novel recurrent mutations in AML, a number of which have been found to involve genes concerned with epigenetic regulation. These genes include in particular DNMT3A, TET2, and IDH1/2, involved with regulation of DNA methylation, and EZH2 and ASXL-1, which are implicated in regulation of histones. However, the precise mechanisms linking these genes to AML pathogenesis have yet to be fully elucidated as has their respective prognostic relevance. As massively parallel DNA sequencing becomes increasingly accessible for patients, there is a need for clarification of the clinical implications of these mutations. This review examines the literature surrounding the biology of these epigenetic modifying genes with regard to leukemogenesis and their clinical and prognostic relevance in AML when mutated. PMID- 24778655 TI - Matching biological mesh and negative pressure wound therapy in reconstructing an open abdomen defect. AB - Reconstruction of open abdominal defects is a clinical problem which general and plastic surgeons have to address in cooperation. We report the case of a 66-year old man who presented an abdominal dehiscence after multiple laparotomies for a sigmoid-rectal adenocarcinoma that infiltrated into the abdominal wall, subsequently complicated by peritonitis and enteric fistula. A cutaneous dehiscence and an incontinent abdominal wall resulted after the last surgery. The abdominal wall was reconstructed using a biological porcine cross-linked mesh Permacol (Covidien Inc., Norwalk, CT). Negative Pressure Wound Therapy (NPWT), instead, was used on the mesh in order to reduce wound dimensions, promote granulation tissue formation, and obtain secondary closure of cutaneous dehiscence which was finally achieved with a split-thickness skin graft. Biological mesh behaved like a scaffold for the granulation tissue that was stimulated by the negative pressure. The biological mesh was rapidly integrated in the abdominal wall restoring abdominal wall continence, while the small dehiscence, still present in the central area, was subsequently covered with a split-thickness skin graft. The combination of these different procedures led us to solve this complicated case obtaining complete wound closure after less than 2 months. PMID- 24778656 TI - Levamisole-contaminated cocaine: an emergent cause of vasculitis and skin necrosis. AB - The prevalence of cocaine adulterated with levamisole-induced vasculitis is increasing and physicians should be aware of this unique entity. There have been many reports of cutaneous vasculitis syndrome caused by cocaine which is contaminated with levamisole. Levamisole was used as an antihelminth drug and later was rescinded from use in humans due to adverse effects. Through this paper, we will report a 39-year-old crack cocaine user who presented with purpuric rash and skin necrosis of his ear lobes. Levamisole-induced vasculitis syndrome was suspected. A urine toxicology screen was positive for cocaine, opiates, and marijuana. Blood work revealed positive titres of ANA and p-ANCA, as well as anti-cardiolipin antibody. Biopsy taken from the left ear showed focal acute inflammation, chronic inflammation with thrombus formation, and extravasated blood cells. Treatment was primarily supportive with wound care. PMID- 24778657 TI - Recurrent retrorectal teratoma. AB - Retrorectal tumors are a rare group of neoplasms that occur most commonly in the neonatal and infant population. They vary in presentation, but teratomas are the most common and often present as a protruding mass from the sacrococcygeal region. Immediate surgical resection is indicated when found and coccygectomy is performed to prevent recurrence. When teratomas recur, the patients most often have vague symptoms and the tumors usually have malignant transformation. Here, we present the case of a young woman who underwent surgical resection of a sacrococcygeal teratoma at 3 days of age where the coccyx was not removed. She presented at 31 years of age with lower extremity paresthesias and radiography revealed a cystic mass extending from the sacrum. After resection, pathology revealed a recurrent teratoma with nests of adenocarcinoma. PMID- 24778658 TI - "Dancing eye syndrome" secondary to opsoclonus-myoclonus syndrome in small-cell lung cancer. AB - Among paraneoplastic neurologic disorders (PND), opsoclonus-myoclonus syndrome, so-called "dancing eye syndrome," is a rare disorder combining multivectorial eye movements, involuntary multifocal myoclonus, and cerebellar ataxia. Although several paraneoplastic antibodies against postsynaptic or cell-surface antigens have been reported, usually most patients are serum antibody negative. We report a 65-year-old patient with opsoclonus-myoclonus syndrome revealing a small-cell lung carcinoma. If serologic antineuronal anti-body screening was negative, autoantibodies against glutamic acid decarboxylase (anti-GAD) were positive. Despite the specific anticancer treatment and high dose corticosteroids, the patient developed a severe and progressive encephalopathy and died 10 days later. PMID- 24778659 TI - Publish or perish: Where are we heading? PMID- 24778660 TI - Structural Model of psychological risk and protective factors affecting on quality of life in patients with coronary heart disease: A psychocardiology model. AB - BACKGROUND: Conducted researches show that psychological factors may have a very important role in the etiology, continuity and consequences of coronary heart diseases. This study has drawn the psychological risk and protective factors and their effects in patients with coronary heart diseases (CHD) in a structural model. It aims to determine the structural relations between psychological risk and protective factors with quality of life in patients with coronary heart disease. MATERIALS AND METHODS: The present cross-sectional and correlational studies were conducted using structural equation modeling. The study sample included 398 patients of coronary heart disease in the university referral Hospital, as well as other city health care centers in Isfahan city. They were selected based on random sampling method. Then, in case, they were executed the following questionnaires: Coping with stressful situations (CISS- 21), life orientation (LOT-10), general self-efficacy (GSE-10), depression, anxiety and stress (DASS-21), perceived stress (PSS-14), multidimensional social support (MSPSS-12), alexithymia (TAS-20), spiritual intelligence (SQ-23) and quality of life (WHOQOL-26). RESULTS: The results showed that protective and risk factors could affect the quality of life in patients with CHD with factor loadings of 0.35 and -0.60, respectively. Moreover, based on the values of the framework of the model such as relative chi-square (CMIN/DF = 3.25), the Comparative Fit Index (CFI = 0.93), the Parsimony Comparative Fit Index (PCFI = 0.68), the Root Mean Square Error of Approximation (RMSEA = 0.07) and details of the model (significance of the relationships) it has been confirmed that the psychocardiological structural model of the study is the good fitting model. CONCLUSION: This study was among the first to research the different psychological risk and protective factors of coronary heart diseases in the form of a structural model. The results of this study have emphasized the necessity of noticing the psychological factors in primary prevention by preventive programs and in secondary prevention by rehabilitation centers to improve the quality of life of the people with heart diseases. PMID- 24778661 TI - The effects of atorvastatin on mustard-gas-exposed patients with chronic obstructive pulmonary disease: A randomized controlled trial. AB - BACKGROUND: Statins have anti-inflammatory effects in patients with chronic obstructive pulmonary disease (COPD). This study designed to evaluate the effects of atorvastatin on serum highly sensitive C-reactive protein (hs-CRP) and pulmonary function in sulfur mustard exposed patients with COPD. MATERIALS AND METHODS: Fifty patients with chronic obstructive pulmonary disease due to sulfur mustard and high serum hs-CRP entered in this study. Participants were randomized to receive 40 mg atorvastatin or placebo in a double-blind clinical trial. Forty five patients completed the study (n = 23 atorvastatin and n = 22 placebo). Pulse oximetry (SpO2), pulmonary function test (PFT), and 6 min walk distance test (6MWD) was measured. COPD assessment test (CAT) and St. George's respiratory questionnaire (SGRQ) were also completed by patients at the beginning of trial and after 9 weeks of prescription of 40 mg/day atorvastatin or placebo. At fourth week, SpO2, PFT, and 6MWD were again measured. After 9 weeks serum hs-CRP was re measured. RESULTS: There was no significant difference between atorvastatin and the placebo group in SpO2, FEV1, and 6MWD after fourth week (P = 0.79, P = 0.12, P = 0.12, respectively). The difference between baseline and ninth week was calculated for two groups of trial and control in term of serum hs-CRP, SpO2, FEV1, and 6MWD. Significant improvement was not observed between two groups in above mentioned variables (P = 0.35, P = 0.28, P = 0.94, P = 0.43, respectively). However, the quality of life was improved by administration of atorvastatin using the CAT score (P < 0.001) and SGRQ total score (P = 0.004). CONCLUSION: Atorvastatin does not alter serum hs-CRP and lung functions but may improve quality of life in SM-injured patients with COPD. PMID- 24778662 TI - The effects of intradermal botulinum toxin type a injections on pain symptoms of patients with diabetic neuropathy. AB - BACKGROUND: Considering the dramatic increasing rate of diabetes and consequently its related complications, most importantly diabetic peripheral neuropathy (DPN), challenges regarding proper treatment of DPN and its effect on the quality-of life and care of diabetic patients, the aim of this current study is to evaluate the effect of intradermal botulinum toxin type A (BTX-A) injections on pain symptoms of patients with diabetic neuropathic pain. MATERIALS AND METHODS: In this randomized double-blind placebo-controlled clinical trial study, diabetic patients aged <70 years with neuropathic pain in both feet were enrolled. Diabetic neuropathy (DN) in selected patients was diagnosed using DN4 questionnaire and nerve conduction velocity examinations. They randomized in two intervention (BTX-A injection/100 unit, N = 20) and placebo groups (normal saline injection, N = 20). The outcome of injection on diabetic neuropathic pain was assessed using neuropathy pain scale (NPS) and visual analog scale (VAS) score and compared in two studied groups. RESULTS: There was no significant difference in DN4, NPS and VAS scales of studied population after intervention in the placebo group. Intradermal injection of BTX-A reduced NPS scores for all items except cold sensation (P = 0.05). It reduced DN4 scores for electric shocks, burning, pins and needles and brushing (P < 0.05). According to VAS scale 30% and 0% of patients in intervention and placebo groups have no pain after intervention (P = 0.01). CONCLUSION: Intradermal injection of BTX-A is a well-tolerated agent that has a significant effect on DPN pain. PMID- 24778663 TI - Adipose-derived stem cells from the breast. AB - BACKGROUND: The adipose tissue is deemed as an ideal source of adipose-derived stem cells (ADSCs). Previous studies have reported that ADSCs can be isolated from several organs and locations; however, slight attention has been paid to the breast. We would like to report our experiences in isolating breast ADSCs (bADSCs). MATERIALS AND METHODS: Adipose tissues were harvested from the breasts of seven hypertrophic breast patients. Collagenase I was used to isolate the primary ADSCs. Surface markers were analyzed by flow cytometry. Cellular morphologies were observed. Proliferations of different passages were compared. Viabilities after the cryopreservation were evaluated. Adipogenic and osteogenic differentiation was induced. RESULTS: Primary cultured cells showed morphologies similar to fibroblasts, and expressed surface markers including CD13, CD44, CD90, and CD105. There was no statistical difference of proliferation between different passages (P > 0.05) and between with and without cryopreservation (P > 0.05). Additionally, isolated cells were differentiated into adipocytes and osteoblasts. CONCLUSION: bADSCs may represent an alternative candidate for tissue engineering. Further studies are needed to obtain more comprehensive understanding on bADSCs. PMID- 24778664 TI - Clinical outcome of en-block resection and reconstruction with nonvascularized fibular autograft for the treatment of giant cell tumor of distal radius. AB - BACKGROUND: Although giant cell tumor (GCT) is considered to be a primary benign bone tumor, its aggressive behavior makes its diagnosis and treatment, difficult and challenging. This is especially true in distal radius where GCT appears to be more aggressive and difficult to control locally. We report our clinical outcome of en-block resection and reconstruction with non-vascularized fibular autograft in 15 patients with distal radius GCT. MATERIALS AND METHODS: We retrospectively reviewed 15 patients with GCT (Grade 2 and 3) of distal radius who were treated with en-block resection and non-vascularized fibular autograft. Five of 15 were recurrent GCT treated initially with extended curettage; local adjuvant therapy and filling the cavity with cement or bone graft. We followed the patients for mean 7.2 years post operation (range: 4-11 years). Patients were evaluated post operation with clinical examination, plain radiography of distal radius and chest X-ray and/or computed tomography scan. Furthermore pain, function, range of motion and grip strength of the affected limb were evaluated and mMayo wrist score was assessed. RESULTS: A total of 11 patients were women and 4 were men. Mean age of patients was 29 years (range: 19-48). We had no lung metastasis and bony recurrence occurred in one patient (6.6%). Nearly 53.3% of patients had excellent or good functional wrist score, 80% of the patients were free of pain or had only occasional pain and 80% of patients returned to work. Mean range of motion of the wrist was 77 degrees of flexion-extension and mean grip strength was 70% of the normal hand. CONCLUSION: En-block resection of distal radius GCT and reconstruction with non-vascularized fibular autograft is an effective technique for treatment in local control of the tumor and preserving function of the limb. PMID- 24778665 TI - Analgesic effects of adding lidocaine to morphine pumps after orthopedic surgeries. AB - BACKGROUND: Opiate is used in patient-controlled intravenous analgesia pumps (PCIA) for controlling pain in post-surgical patients. Other drugs are remarkably added to opioid pumps to enhance quality, lengthen analgesia, and reduce side effects. Lidocaine, a local anesthetic which inhibits sodium channels, has anesthetic and analgesic effects when injected locally or intravenously. The objective of this study is to evaluate the analgesic effects of adding lidocaine 1% to different doses of morphine via IV pump to patient-controlled analgesia (PCA) after orthopedic surgeries. MATERIALS AND METHODS: In a randomized clinical trial, 60 patients who had undergone orthopedic surgery of lower extremities were divided into three equal groups to control postoperative pain. Intravenous pump with 5 ml/h flow rate was used as the analgesic method. The solution consisted of lidocaine 1% plus 20 mg morphine for the first group, lidocaine 1% plus 10 mg morphine for the second group, and only 20 mg morphine for the third group (control group). Patients were checked every 12 h, and Visual Analog Scale (VAS), extra opioid doses, nausea/vomiting, and sedation scale were examined. RESULTS: Pain score was lower in the first group compared to the other two groups. Mean VAS was 2.15 +/- 0.2, 2.75 +/- 0.2, and 2 +/- 0.25 on the first day and 1.88 +/- 0.1, 2.74 +/- 0.3, and 2.40 +/- 0.3 on the second day, respectively, in the three groups and the difference was statistically significant (P < 0.01 and <0.05, respectively). Also, 10% of patients in the first group needed extra opioid doses, while this figure was 30% in the second group and 25% in the third group (P < 0.01). Nausea/vomiting and sedation scores were not statistically different among the three groups. CONCLUSION: Compared to lidocaine 1% plus 10 mg morphine or 20 mg morphine alone in PCIA, adding lidocaine 1% to 20 mg morphine decreases the pain score and opioid dose after orthopedic surgeries without having side effects. PMID- 24778666 TI - Prediction equations for pulmonary function values in healthy children in Mashhad city, North East Iran. AB - BACKGROUND: Pulmonary function tests (PFTs) are used in assessing physiological to clinical status of the respiratory system, which is expressed as a percentage of predicted values. Predicted PFTs values are varies in different ethnics. Predicted PFTs values were studied in a sample of Iranian children. MATERIALS AND METHODS: Prediction equations for PFTs were derived from urban children in the city of Mashhad (northeast Iran). Regression analysis using height and age as independent variables was applied to provide predicted values for both sexes. PFT values were measured in 414 healthy children (192 boy and 222 female, aged 4-10 years). Forced vital capacity (FVC), forced expiratory volume in one second (FEV1), maximal mid-expiratory flow (MMEF), peak expiratory flow (PEF), MEF at 75%, 50% and 25% of the FVC (MEF75, MEF50 and MEF25 respectively) were measured. RESULTS: There were positive correlations between each pulmonary function variable with height and age. The largest positive correlations were found for FVC (r = 0.712, P < 0.0001) and FEV1 (r = 0.642, P < 0.0001) in boys and girls respectively with height and for PEF (0.698, P < 0.0001) and MEF (r = 0.624, P < 0.0001) with age. Comparison of PFTs derived from the equations of the present study showed significant differences with those of several previous studies (P < 0.001 for most cases). CONCLUSION: A set of PFT reference values and prediction equations for both sexes has been derived using relatively large, healthy, Iranian children for the first time, which the generated results were differ from several prediction equations. PMID- 24778667 TI - Utilization of coronary computed tomography angiography for rapid risk stratification in emergency chest pain units. AB - BACKGROUND: Coronary computed tomography angiography (CCTA) is a well-known method for evaluating anatomic coronary stenosis, but the reliability of CCTA to predict cardiovascular events is an issue of controversy. MATERIALS AND METHODS: In this prospective observational study, 58 patients with acute chest pain and low-to-moderate risk were selected and CCTA was performed on them. During follow up, the occurrence of major adverse cardiac events (MACE), defined as, cardiac death, myocardial infarction or coronary revascularization, were evaluated. Sensitivity, specificity, and positive and negative predictive values of CCTA for the occurrence of MACE, at the six-month follow up, were also evaluated. RESULTS: A total of nine (15.5 %) were positive in terms of the MACE criteria and they all had positive CCTA results. It seemed that there was 100% sensitivity for CCTA in predicting the occurrence of MACE. Forty-nine patients had no MACE, among whom 48 patients had negative CCTA. The specificity of CCTA in predicting the occurrence of MACE was 98%. All patients with positive CCTA showed significant stenosis in angiography. CONCLUSION: It appears that CCTA allows us to predict the prognosis of patients with acute chest pain and low-to moderate-risk in terms of MACE occurrence. PMID- 24778668 TI - Validity and reliability of the Persian version of mobile phone addiction scale. AB - BACKGROUND: With regard to large number of mobile users especially among college students in Iran, addiction to mobile phone is attracting increasing concern. There is an urgent need for reliable and valid instrument to measure this phenomenon. This study examines validity and reliability of the Persian version of mobile phone addiction scale (MPAIS) in college students. MATERIALS AND METHODS: this methodological study was down in Isfahan University of Medical Sciences. One thousand one hundred and eighty students were selected by convenience sampling. The English version of the MPAI questionnaire was translated into Persian with the approach of Jones et al. (Challenges in language, culture, and modality: Translating English measures into American Sign Language. Nurs Res 2006; 55: 75-81). Its reliability was tested by Cronbach's alpha and its dimensionality validity was evaluated using Pearson correlation coefficients with other measures of mobile phone use and IAT. Construct validity was evaluated using Exploratory subscale analysis. RESULTS: Cronbach's alpha of 0.86 was obtained for total PMPAS, for subscale1 (eight items) was 0.84, for subscale 2 (five items) was 0.81 and for subscale 3 (two items) was 0.77. There were significantly positive correlations between the score of PMPAS and IAT (r = 0.453, P < 0.001) and other measures of mobile phone use. Principal component subscale analysis yielded a three-subscale structure including: inability to control craving; feeling anxious and lost; mood improvement accounted for 60.57% of total variance. The results of discriminate validity showed that all the item's correlations with related subscale were greater than 0.5 and correlations with unrelated subscale were less than 0.5. CONCLUSION: Considering lack of a valid and reliable questionnaire for measuring addiction to the mobile phone, PMPAS could be a suitable instrument for measuring mobile phone addiction in future research. PMID- 24778669 TI - Parenting stress among mothers of children with different physical, mental, and psychological problems. AB - BACKGROUND: Parents of children with developmental problems are always bearing a load of stress. The aim of this study is to compare the stress in mothers of children with different disabilities to each other, considering their demographic background. MATERIALS AND METHODS: This was a cross-sectional study conducted in Isfahan, Iran during 2012 on 285 mothers of 6-12 years old children with chronic physical disease, psychological disorder, and sensory-motor and mental problems. Abedin's parenting stress questionnaire was used and obtained data were analyzed using multivariate analysis of variance or covariance as appropriate. RESULTS: Mothers of children with sensory-motor mental and chronic physical problems experience more stress than mothers of children with psychological disorders (P < 0.05). The stress score of mothers of children with psychological disorders was lower than the other two groups. Also there was a significant difference between the score of mothers of children with chronic physical problems and mothers of children with psychological disorders regarding parent-child dysfunctional interaction (P < 0.01). A significant difference was observed in terms of stress among mothers of children with sensory-motor mental problems with different number of children (P < 0.05); also mothers of children with chronic physical problems in different levels of education have experienced different levels of parenting stress (P < 0.05). CONCLUSION: Due to high level of parenting stress among our studied samples, special education and early intervention are needed for parents in our study population in order to deepening their diagnostic knowledge and professional consultation on stress management. PMID- 24778670 TI - Snakebite management in Iran: Devising a protocol. AB - BACKGROUND: Snakebite in Iran has been a health concern. However, management of snakebite is not standardized and varies from center to center. This study is aimed at devising an evidence-based comprehensive protocol for snakebite management in Iran, to reduce unnecessary variations in practice. MATERIALS AND METHODS: A narrative search in electronic databases was performed. Fifty peer reviewed articles, guidelines, and textbooks were reviewed and practical details were extracted. Our currently used protocol in the Mashhad Toxicology Center was supplemented with this information. Consequently an improved wide-range protocol was developed. The protocol was then discussed and amended within a focus group comprised of medical toxicologists and internal medicine specialists. The amended version was finally discussed with expert physicians specialized in different areas of medicine, to be optimized by supplementing other specific considerations. RESULTS: During a one-year process, the protocol was finalized. The final version of the protocol, which was designed in six steps, comprised of three components: A schematic algorithm, a severity grading scale, and instructions for supportive and adjunctive treatments. The algorithm pertains to both Viperidae and Elapidae snakebite envenomations and consists of a planned course of action and dosing of antivenom, based on the severity of the envenomation. CONCLUSION: Snakebite envenomation is a clinical toxicologic emergency, which needs to be treated in a timely and organized manner. Hence, a multi-aspect protocol was designed to improve the clinical outcomes, reduce unnecessary administration of antivenom, and help physicians make more proper clinical judgments. PMID- 24778672 TI - Assessment of endothelium: Dependent vasodilation with a non-invasive method in patients with preeclampsia compared to normotensive pregnant women. AB - BACKGROUND: To assess the endothelial function via noninvasive method, in pregnant women with preeclampsia compared to to normotensive pregnant women. MATERIALS AND METHODS: Brachial artery diameter was measured via ultrasound, in 28 women with preeclampcia in case group and normotensive pregnant women in control group, at rest, after inflation of sphygmomanometer cuff up to 250-300 mmHg, immediately after deflation of the cuff, 60-90 minutes later and 5 min after administration of sublingual trinitroglycerin (TNG). Results of these measurements as well as demographic characteristics of participants in both groups were recorded in special forms. Data were analyzed via Statistical Package for Social Sciences (SPSS) version 16, using t-test and repeated measures analysis of variance (ANOVA). P-value < 0.05 was considered statistically significant. The results were presented as mean +/- standard deviation (SD). RESULTS: The mean of brachial artery diameter at rest in the case and control groups was 4.49 +/- 0.39 and 4.08 +/- 0.38 mm, respectively (P = 0.1). Also the results showed that the brachial artery diameter, immediately after deflation of the cuff, was 4.84 +/- 0.4 and 4.37 +/- 0.30 mm in the case and control groups (P < 0.001), respectively. The mean brachial artery diameter, 60-90 s after deflation of the cuff, was 4.82 +/- 0.41 and 4.42 +/- 0.38 mm in the case and control groups (P < 0.00), respectively. The brachial artery diameter, 5 min after sublingual NO administration, was 4.95 +/- 0.6 and 4.40 +/- 0.45 mm in case and control groups (P < 0.001), respectively. Applying of repeated measures ANOVA showed that the mean difference between case and control groups was statistically significant (P < 0.001). CONCLUSION: Current study concluded that there is no difference in endothelium-dependent vasodilation between women with preeclampsia and pregnant women with normal blood pressure. PMID- 24778671 TI - Review on iron and its importance for human health. AB - It is well-known that deficiency or over exposure to various elements has noticeable effects on human health. The effect of an element is determined by several characteristics, including absorption, metabolism, and degree of interaction with physiological processes. Iron is an essential element for almost all living organisms as it participates in a wide variety of metabolic processes, including oxygen transport, deoxyribonucleic acid (DNA) synthesis, and electron transport. However, as iron can form free radicals, its concentration in body tissues must be tightly regulated because in excessive amounts, it can lead to tissue damage. Disorders of iron metabolism are among the most common diseases of humans and encompass a broad spectrum of diseases with diverse clinical manifestations, ranging from anemia to iron overload, and possibly to neurodegenerative diseases. In this review, we discuss the latest progress in studies of iron metabolism and bioavailability, and our current understanding of human iron requirement and consequences and causes of iron deficiency. Finally, we discuss strategies for prevention of iron deficiency. PMID- 24778673 TI - Unusual case of adult hemophagocytic syndrome. AB - Hemophagocytic syndrome (HPS) is an uncommon manifestation in systemic lupus erythematosus (SLE). Clinical features of HPS include fever, pancytopenia, abnormal liver enzyme, hepatosplenomegaly, lymphadenopathy, and coagulation disorder. HPS comprises primary and reactive forms. Herein, we describe a case of untreated SLE with HPS as one of the first manifestations of systemic Lupus. PMID- 24778674 TI - Bone marrow abnormalities in HIV infected children, report of three cases and review of the literature. AB - Bone marrow abnormalities in HIV infected adults include hypocellularity, myelodysplasia and poor marrow recovery. Data in children is limited. We report a series of three HIV infected with varied bone marrow abnormalities. First child was a 7-year-old boy with pulmonary tuberculosis, anemia, thrombocytopenia and bone marrow examination showed hypoplastic marrow. He succumbed to his disease within seven days of hospitalization. Second child was a three and a half year old girl who had severe anemia and her bone marrow examination showed dyserythropoiesis. Third child was a 7-year-old boy who had splenic abscesses and pancytopenia and bone marrow examination showed myelofibrosis with increased plasma cells. He also succumbed due to a fatal pulmonary bleed. Thus, advanced HIV disease in children can lead to bone marrow suppression in form of hypoplasia or myelofibrosis which can be fatal. PMID- 24778675 TI - Female genital tract tuberculosis presenting as ovarian cancer. AB - BACKGROUND: Tuberculosis (TB) is still a major worldwide concern. There is no pathognomonic clinical feature or imaging findings for definite diagnosis of extra pulmonary TB. Therefore, TB involvement of Gastrointestinal or Genitourinary tract can be easily confused with peritoneal carcinomatosis and advanced ovarian carcinoma. Our aim is to emphasize the importance of considering the disease based upon the epidemiologic clues of the patients, while interpreting the positive results for a suspicious ovarian malignancy. CASES: This paper illustrates 8 cases of ovarian or peritoneal tuberculosis, whose initial diagnoses were malignant processes of the GU tract. CONCLUSION: Tuberculosis (TB) should be always being considered in the differential diagnosis of advanced ovarian cancer, especially in the regions that are endemic for the disease. PMID- 24778676 TI - Human herpes virus 8-unrelated primary effusion lymphoma-like lymphoma in a patient with hepatitis B virus-related liver cirrhosis: A case report. AB - This study describes a rare case of Human Immunodeficiency Virus and Human Herpes Virus 8 (HHV-8) negative primary effusion lymphoma (PEL)-like lymphoma in a patient with hepatitis B virus-related liver cirrhosis, diagnosed in a 66-year old male who rapidly progressed to a sense of abdominal fullness. Cytological analysis of the pleural effusion demonstrated large atypical lymphoid cells with rounded nuclei, prominent nucleoli, and abundant cytoplasm. Immunocytochemistry of the pleural effusion detected atypical CD20(+) lymphoid cells. The patient was hospitalized, and died following sepsis and multi-organ failure. Our case highlights that HHV-8-unrelated PEL-like lymphoma patients have different pathogenetic mechanisms of causality at the biological level, immunophenotype, clinical behavior, and prognosis. PMID- 24778677 TI - Amyand's hernia in a neonate: A case report. AB - Acute appendicitis secondary to hernia incarceration presenting as scrotal swelling is exceptionally rare in neonates. We report a neonate who presented with tender swelling in the right scrotum. Ultrasonography detected features of a rare Amyand's hernia. Surgical exploration and histopathological examination confirmed the diagnosis. PMID- 24778678 TI - Oxidative stress and hyperglycemia in aluminum phosphide poisoning. PMID- 24778679 TI - Portal vein and superior mesenteric vein thrombosis after cesarean hysterectomy. PMID- 24778680 TI - Comparison of bupivacaine and lidocaine use for postoperative pain control in endodontics. AB - INTRODUCTION: Many patients suffer from mild, moderate or severe pain during or after root canal therapy. Theoretically, post-operative pain control can be achieved by using long-acting local anesthetics. The aim of this study was to evaluate the efficacy of a long acting anesthesia, bupivacaine, on preventing post-operative pain associated with endodontic treatment, and to compare it with lidocaine. MATERIALS AND METHODS: This study was a double blind and randomized clinical trial on 30 patients' anterior maxillary teeth. The patients were divided into two groups of fifteen. One group was administered lidocanine (2% with 1:100000 epinephrine) local anesthesia and the other group was given bupivacaine (0.5% without epinephrine). The pain in patients were compared using the visual analogue scale (VAS) at definite times i.e. before treatment, during treatment and 2,4,6,8,10,12,24,36 and 48 hours after operation. Data were analyzed using One-way ANOVA tests. RESULTS: Bupivacaine significantly decreased postoperative pain compared to lidocaine. Postoperative pain was directly related to preoperative pain. Women reported more pain, though significant difference in postoperative pain report was not found between different ages. CONCLUSION: In conclusion, a single dose of bupivacaine 0.5% used in infiltration anesthesia could be more effective in reduction or prevention of post-operative endodontic pain compared with lidocaine. PMID- 24778681 TI - Mandibular first and second molars with three mesial canals: a case series. AB - Adequate cleaning, shaping and filling of the root canal system are mandatory for successful root canal treatment. Thorough knowledge of root canal morphology and unusual anatomy of the tooth is critical for the practitioner. The occurrence and location of the third mesial canal (Middle Mesial Canal) in mandibular first and second molars in relation to other two mesial canals that were treated in private practice were studied. In 27 clinical cases, the presence of a middle mesial canal was demonstrated. The third canal was located in the middle of the distance between the mesiobuccal and mesiolingual canals. This canal configuration was found in six second lower molars and twenty one first molars. Middle mesial canal in all of our cases joined to mesiobuccal or mesiolingual canals. None of the teeth consisted of three independent canals with three apical foramina. In conclusion, every attempt should be made to find and treat all root canals of a tooth. PMID- 24778682 TI - In vitro comparison of apical leakage in root canals obturated with 0.04 and 0.02 tapered gutta-percha. AB - INTRODUCTION: Gutta-percha is the most commonly used material for root canal obturation; it has been recently manufactured with different tapers. The aim of this in vitro study was to compare microleakage of canals obturated with standard gutta-percha (0.02 taper) or the new 0.04 taper gutta-percha master cone using the cold lateral condensation technique. MATERIALS AND METHODS: Forty-four extracted single rooted teeth were selected. The crowns were removed and all the canals were prepared using RaCe rotary files. The teeth were then divided into experimental (n=2) and control (n=2) groups. In the first study group, the teeth were obturated with 0.02 taper gutta-percha master cone and lateral condensation. In the second study group, the canals were obturated by 0.04 tapered master cones and the same obturation method. The degree of leakage was measured using fluid filtration method. Data were analyzed statistically by student t-test. RESULTS: There was no significant difference between the mean microleakage of two experimental groups (P=0.558). CONCLUSION: Lateral condensation technique using 0.04 tapered master cones can provide an effective apical seal similar to 0.02 gutta-percha cones. PMID- 24778683 TI - A comparative study on the shaping ability of k3, profile and protaper instruments in simulated curved root canals. AB - INTRODUCTION: The objective of this study was to compare the shaping ability of three rotary filing systems; constant taper K3 instruments, constant taper ProFile instruments and progressive taper ProTaper rotary instruments in clear resin blocks with simulated curved root canals. MATERIALS AND METHODS: Forty five resin blocks were divided into three groups. Group A preparation was conducted with K3, Group B with ProFile and Group C with ProTaper instruments. Pre and post instrumentation images were superimposed and assessment of the canal shape was completed with a computer image analysis program at 14 levels of the root canal system. RESULTS: Group A inner and outer curvature pre and post instrumentation values were significantly different (P<0.05) at levels 3; at level 13 only the outer curvature and levels 6, 7, 8 the inner curvature had significantly different values between pre and post instrumentation. Group C had significant P values (P<0.05) at levels 2, 3, 4, 12, 13 in the outer curvature and at levels 6, 7, 8 of the inner curvature. CONCLUSION: Overall, all three rotary instruments maintained root canal curvatures well. ProTaper instruments significantly removed more resin material from outer canal curvature in the apical third when compared to the other two groups. PMID- 24778684 TI - Relation between pulpal neuropeptides and dental caries. AB - INTRODUCTION: Dental pulp has neural fibers that produce neuropeptides like Substance P (SP) and calcitonin gene-related peptide (CGRP). The inflammation of dental pulp can lead to an increase amount of SP and CGRP release, especially in symptomatic irreversible pulpitis. Therefore, it can be assumed that neuropeptides have some role in the progression of inflammation of the dental pulp. The aim of this study was to determine the relation between the presence and concentration of neuropeptides in dental pulps of carious teeth caries. MATERIALS AND METHODS: For this purpose, pulpal tissues were collected from 40 teeth (20 carious and 20 intact). Pulpal samples were cultured for 72 hours. ELISA reader was used for the detection of SP and CGRP in supernatant fluids. Statistical analysis was made by Mann-Whitney U and Chi square tests. RESULTS: SP and CGRP were present in 65% and 20% of inflamed pulpal samples, respectively and 40% and 5% of normal pulpal samples, respectively. Level of SP was significantly higher in inflamed pulp samples compared to intact pulps; however, there was no statistical difference when the other groups and neuropeptides were compared. The mean concentration of SP in normal pulps was 3.4 times greater than that of CGRP; interestingly in inflamed pulps the concentration of SP was 22.3 times greater than CGRP. CONCLUSION: We can conclude that in inflamed dental pulps, the concentration of SP is higher than CGRP. It can be hypothesized that CGRP has less effect on the inflammatory changes of dental pulps. PMID- 24778685 TI - Comparative study on the microleakage of three root canal sealers. AB - INTRODUCTION: The aim of this study was to examine and compare the apical sealing ability of AH26, AH Plus and AH Plus Jet using the fluid filtration model. MATERIALS AND METHODS: In this experimental study, 70 single-rooted teeth were dissected from the cement-enamel junction. Canals were prepared with ProTaper rotary system and hand K-files and irrigated with 5.25% NaOCl and 17% EDTA. Ten teeth were assigned to the control group and divided into 5 positive and 5 negative controls. Remaining specimens were divided into 3 groups of 20 samples each and filled with gutta percha by lateral condensation technique. Each sample group was filled with either AH26, AH Plus or AH Plus Jet. Microleakage was assessed on the 2(nd) and 30(th) day by the amount of air bubble movement within the capillary glass tube connected to the root. One-way ANOVA test was used for analysis. RESULTS: AH Plus Jet had the least microleakage value and AH Plus presented the highest rate; however, the differences were not statistically significant. CONCLUSION: Under the conditions of this study, all three studied sealers provided satisfactory seal within the two time intervals. AH Plus Jet demonstrated slightly lower microleakage values; therefore, its application can be recommended in endodontic therapy. PMID- 24778686 TI - The Effect of Blood on Apical Microleakage of Epiphany and AH26: An In Vitro Study. AB - INTRODUCTION: Blood contamination of the canal during preparation can be a major problem in endodontics; this may result in apical microleakage. The aim of this in vitro study was to evaluate the effect of blood on apical microleakage of a resin-based root canal sealer (AH26) and a polymer-based root canal sealer (Epiphany). MATERIALS AND METHODS: In this experimental study, 50 decoronated central incisors and canine teeth were prepared by RaCe rotary system and randomly divided into 4 groups (n=10). Groups A1 and A2 were obturated by Epiphany/Resilon and AH26/Gutta-percha, respectively. The obturations were performed with a single cone technique after drying root canals. In B1 and B2 groups, the test groups, 0.02cc citrated human blood was injected into dried root canals and they were obturated in the same manner. Ten specimens were served as positive and negative controls (n=5).The apical leakage was measured by means of a computerized fluid filtration method after 1 day and 3 weeks. The data was analyzed by One-Sample Kolmogorov-Smirnov, Independent Sample t-test and univariate analysis. Statistical significances were preset at alpha=0.05. RESULTS: There was no significant difference in apical microleakage of the two sealers after 1 day and 3 weeks in dry and blood environment (P>0.05). Sealer and environment had no interaction (P>0.05). CONCLUSION: Blood contamination has no significant effect on the apical microleakage of Epiphny and AH26. PMID- 24778687 TI - An ex-vivo study on the shaping parameters of two nickel-titanium rotary systems compared with hand instruments. AB - INTRODUCTION: Rotary nickel-titanium (NiTi) instruments are thought to allow shaping of narrow, curved root canals more efficiently and more effectively than stainless steel hand instruments. However, the continued search for even more effective and safer instruments has resulted in new rotary systems being introduced on a regular basis. The aim of this study was to compare shaping parameters of RaCe and Mtwo NiTi rotary files with stainless steel K-Flexofile hand instrument. MATERIALS AND METHODS: A total of 60 mandibular first molars with 20-40 degree of curvature in mesial root were divided in to three groups and each was prepared with one kind of instrument (RaCe, Mtwo, stainless steel K Flexofile). Using pre and post-radiographs, canal curvature was measured, with the Schneider technique. Preparation time was recorded. For evaluating canal centering and transportation, the tooth was sectioned 3, 6 and 9 mm from the apex. Pre and post- preparation photographs were taken from mesiolingual canal. Data was statistically analyzed using One-way ANOVA and Chi-Square tests. RESULTS: RaCe and Mtwo maintained canal curvature better than K-Flexofile (P<0.001). Mtwo prepared the canal in a shorter time (P<0.001). CONCLUSION: Significant statistical difference was not found in the three canal sections between the various systems. RaCe resulted in significantly fewer canal aberrations and better centering ability. PMID- 24778688 TI - Hydroxyl ion diffusion through intact and resorbed roots at various time intervals. AB - INTRODUCTION: The purpose of this study was to investigate root surface pH changes over a period of 4 weeks following treatment with calcium-hydroxide dressing of intact and resorbed roots. MATERIALS & METHODS: The canals of 30 single-rooted teeth were instrumented with ProTaper rotary files and randomly divided into 2 experimental groups of 14 each, and one control group with two samples. To simulate external resorption in group 2 and control, two defects were made on the buccal and lingual mid-root surfaces of each tooth with a diamond bur (1*1mm). Teeth were then submerged in 20% sulfuric acid for 4 days. Canals of 14 intact teeth in group 1, and 14 resorbed teeth in group 2 were filled with calcium hydroxide Ca(OH)2 while canals of resorbed teeth in control group were filled with saline. All teeth were then placed in a glass vial containing 15mL of deionized water (pH~7). The pH of water was measured at 0 and 1, 4, 7, 10, 14, 21 and 28 days using pH microelectrode. Independent t-test and repeated measured ANOVA analyzed the data. RESULTS: Except a mild decline at 7days and 14days, the average pH values showed increased during the time periods of this study. Day 28 showed the maximum pH average value in both groups (7.67-7.72) (P<0.05). Significant increase of pH values were detected at different time intervals compared with the baseline time (P<0.05). CONCLUSION: Diffusion of hydroxyl ions was similar in both resorbed and intact roots. In both groups pH values were significantly higher than the baseline pH at the various times. PMID- 24778689 TI - Osteoblastic cytokine response to gray and white mineral trioxide aggregate. AB - INTRODUCTION: The materials used for root-end filling and perforation repair are in direct contact with live tissues e.g. bone and connective tissue; their effects however, are uncertain. The aim of this ex vivostudy was to evaluate the osteoblastic secretory activity adjacent to gray and white mineral trioxide aggregate (MTA) and Intermediate Restorative Material (IRM). MATERIALS AND METHODS: The studied materials were prepared and placed in 24-wells plate. Human MG-63 osteoblasts were introduced to materials after their initial set. The supernatant fluid was collected after 1, 3, and 7 days and the level of interleukin-1beta was measured by ELISA test. A microscopic exam was also performed to assess proliferation and viability of the cells. Kruskal-Wallis and Tukey tests were used for analysis. RESULTS: T here were significant higher levels of interleukin-1beta in the gray and white MTA groups compared to IRM group (P<0.05). The difference in interleukin-1beta secretion level between two mineral trioxide aggregate groups was not significant (P>0.05).Morphologic appearance of osteoblasts adjacent to gray and white MTA was similar to normal osteoblasts in all observation periods, however cells adjacent to IRM were round, signifying cytotoxicity of the adjacent material. CONCLUSION: Human osteoblasts' has a favorable biologic response to white and gray MTA compared to IRM. PMID- 24778690 TI - Temperature Increase during Different Post Space Preparation Systems: An In Vitro Study. AB - INTRODUCTION: The purpose of this study was to evaluate external root surface temperature rise during post space preparation using LA Axxess bur, Beefill pack System, and Peeso Reamer drill. MATERIALS AND METHODS: The distal canals of forty five extracted human permanent mandibular first molars were instrumented in crown apical manner and obturated with lateral condensation technique. Teeth were then randomly divided into three groups according to post space preparation technique including: group 1. LA Axxess bur (Sybronendo Co., CA, USA), group 2 Beefill pack System (VD W Co., Munich, Germany) and group 3 Peeso Reamer drill (Mani Co., Tochigi-ken, Japan). Temperature was measured by means of digital thermometer MT 405 (Comercio Co., Sao Paulo, Brazil) which was installed on the root surfaces. Data was collected and submitted to one-way ANOVA and Post hoc analysis. RESULTS: Root surface temperatures were found to be significantly higher (7.3+/-2.7 vs. 4.3+/-2.1 and 4+/-2.4,) in samples of Beefill pack System compared with the two other groups (P<0.02). CONCLUSION: Using Beefill pack System during post space preparation may be potentially hazardous for periodontal tissues. PMID- 24778692 TI - Clinical utilization of cord blood over human health: experience of stem cell transplantation and cell therapy using cord blood in Korea. AB - Cord blood (CB) has been used as an important and ethical source for hematopoietic stem cell transplantation (SCT) as well as cell therapy by manufacturing mesenchymal stem cell, induced pleuripotential stem cell or just isolating mononuclear cell from CB. Recently, the application of cell-based therapy using CB has expanded its clinical utility, particularly, by using autologous CB in children with refractory diseases. For these purposes, CB has been stored worldwide since mid-1990. In this review, I would like to briefly present the historical development of clinical uses of CB in the fields of SCT and cell therapy, particularly to review the experiences in Korea. Furthermore, I would touch the recent banking status of CB. PMID- 24778691 TI - Evidence for adverse effect of perinatal glucocorticoid use on the developing brain. AB - The use of glucocorticoids (GCs) in the perinatal period is suspected of being associated with adverse effects on long-term neurodevelopmental outcomes for preterm infants. Repeated administration of antenatal GCs to mothers at risk of preterm birth may adversely affect fetal growth and head circumference. Fetal exposure to excess GCs during critical periods of brain development may profoundly modify the limbic system (primarily the hippocampus), resulting in long-term effects on cognition, behavior, memory, co-ordination of the autonomic nervous system, and regulation of the endocrine system later in adult life. Postnatal GC treatment for chronic lung disease in premature infants, particularly involving the use of dexamethasone, has been shown to induce neurodevelopmental impairment and increases the risk of cerebral palsy. In contrast to studies involving postnatal dexamethasone, long-term follow-up studies for hydrocortisone therapy have not revealed adverse effects on neurodevelopmental outcomes. In experimental studies on animals, GCs has been shown to impair neurogenesis, and induce neuronal apoptosis in the immature brains of newborn animals. A recent study has demonstrated that dexamethasone induced hypomyelination may result from the apoptotic degeneration of oligodendrocyte progenitors in the immature brain. Thus, based on clinical and experimental studies, there is enough evidence to advice caution regarding the use of GCs in the perinatal period; and moreover, the potential long-term effects of GCs on brain development need to be determined. PMID- 24778693 TI - Ten years of experience in the prevention of mother-to-child human immunodeficiency virus transmission in a university teaching hospital. AB - PURPOSE: Administration of antiretroviral drugs to mothers and infants significantly decreases mother-to-child human immunodeficiency virus (HIV) transmission; cesarean sections and discouraging breastfeeding further decreases this risk. The present study confirmed the HIV status of babies born to mothers infected with HIV and describes the characteristics of babies and mothers who received preventive treatment. METHODS: This study retrospectively analyzed medical records of nine infants and their mothers positive for HIV who gave birth at Korea University Ansan Hospital, between June 1, 2003, and May 31, 2013. Maternal parameters, including HIV diagnosis date, CD4+ count, and HIV ribonucleic acid (RNA) copy number, were analyzed. Infant growth and development, HIV RNA copy number, and HIV antigen/antibody test results were analyzed. RESULTS: Eight HIV-positive mothers delivered nine babies; all the infants received antiretroviral therapy. Three (37.5%) and five mothers (62.5%) were administered single- and multidrug therapy, respectively. Intravenous zidovudine was administered to four infants (50%) at birth. Breastfeeding was discouraged for all the infants. All the infants were negative for HIV, although two were lost to follow-up. Third trimester maternal viral copy numbers were less than 1,000 copies/mL with a median CD4+ count of 325/uL (92-729/uL). Among the nine infants, two were preterm (22.2%) and three had low birth weights (33.3%). CONCLUSION: This study concludes that prophylactic antiretroviral therapy, scheduled cesarean section, and prohibition of breastfeeding considerably decrease mother-to-child HIV transmission. Because the number of infants infected via mother-to-child transmission may be increasing, studies in additional regions using more variables are necessary. PMID- 24778694 TI - Long-term follow-up of Fanconi anemia: clinical manifestation and treatment outcome. AB - PURPOSE: The aim of this study was to characterize Korean patients with Fanconi anemia (FA), which is a rare but very challenging genetic disease. METHODS: The medical records of 12 FA patients diagnosed at Chonnam National University Hospital from 1991 to 2012 were retrospectively reviewed. RESULTS: The median age at diagnosis was 6.2 years. All patients showed evidence of marrow failure and one or more physical stigmata. Chromosome breakage tests were positive in 9 out of 11 available patients. The median follow-up duration was 69.5 months. The Kaplan-Meier (KM) survival of all patients was 83.3% at 10 years and 34.7% at 20 years, respectively. Seven patients underwent 9 stem cell transplantations (SCTs). Among them, 5 were alive by the end of the study. Ten-year KM survival after SCT was 71.4% with a median follow-up of 3.4 years. All 5 patients treated with supportive treatment alone died of infection or progression at the median age of 13.5 years, except for one with short follow-up duration. Acute leukemia developed in 2 patients at 15.4 and 18.1 years of age. Among 6 patients who are still alive, 3 had short stature and 1 developed insulin-dependent diabetes mellitus. CONCLUSION: We provide information on the long-term outcomes of FA patients in Korea. A nation-wide FA registry that includes information of the genotypes of Korean patients is required to further characterize ethnic differences and provide the best standard of care for FA patients. PMID- 24778695 TI - Outcomes of chronic dialysis in Korean children with respect to survival rates and causes of death. AB - PURPOSE: Adult Korean patients on chronic dialysis have a 9-year survival rate of 50%, with cardiovascular problems being the most significant cause of death. The 2011 annual report of the North American Pediatric Renal Trials and Collaborative Studies group reported 3-year survival rates of 93.4% and relatively poorer survival in younger patients. METHODS: In this study, we have reviewed data from Korean Pediatric Chronic Kidney Disease Registry from 2002 to 2010 to assess survival rates and causes of death in Korean children on chronic dialysis. RESULTS: The overall estimated patient survival rates were 98.4%, 94.4%, and 92.1% at 1, 3, and 5 years, respectively. No significant difference was observed in survival rates between patients on peritoneal dialysis and those on hemodialysis. Patients for whom dialysis was initiated before 2 years of age (n=40) had significantly lower survival rates than those for whom dialysis was initiated at 6-11 years of age (n=140). In all, 26 patients had died; the mortality rate was 19.9 per 1,000 patient years. The most common causes of death were infections and comorbidities such as malignancy and central nervous system (CNS) or liver diseases. CONCLUSION: The outcomes observed in this study were better than those observed in adults and comparable to those observed in pediatric studies in other countries. To improve the outcomes of children on chronic dialysis, it is necessary to prevent dialysis-related complications such as infection, congestive heart failure, or CNS hemorrhage and best control treatable comorbidities. PMID- 24778696 TI - Lowe syndrome: a single center's experience in Korea. AB - PURPOSE: Lowe syndrome is a rare, X-linked recessive disorder caused by mutations in the OCRL gene. It involves multiple anatomic systems, particularly the eyes, central nervous system, and kidneys, and leads to profound growth failure and global developmental delay. This study evaluated the clinical and genetic characteristics of Korean patients with Lowe syndrome. METHODS: The clinical findings and results of genetic studies were reviewed for 12 male patients diagnosed with Lowe syndrome at a single medical institution. RESULTS: The mean age of the patients at presentation was 2.2 months (range, 0-4 months), although the diagnosis was delayed by a mean of 2.8 years (range, 0-9.7 years). The mean follow-up period was 9.0 years (range, 0.6-16.7 years). Nine mutations in OCRL were identified in 11 patients (92%), with three novel mutations. The main presentation was congenital cataract in both eyes necessitating early cataract removal in the 11 patients with impaired visual acuity. Profound short stature and developmental delay were observed in all patients, and seizures occurred in 50% of the patients. All patients suffered from proximal renal tubular dysfunction, and one patient developed chronic renal failure. Other manifestations included pathologic fracture (50%), cutaneous cysts (42%), and cryptorchidism (42%). However, there was no bleeding tendency, and none of the patients died during the study period. CONCLUSION: This study describes the clinical and genetic characteristics of Korean patients with Lowe syndrome. The observations are helpful for understanding the natural courses of Lowe syndrome and for appropriate genetic counseling. PMID- 24778697 TI - Congenital muscular dystrophy type 1A with residual merosin expression. AB - Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder characterized by hypotonia, elevated serum creatine kinase level, delayed motor milestones, white matter changes observed by brain magnetic resonance imaging, and normal intelligence. A mutation in the laminin alpha2 (LAMA2) gene, located at 6q22-23, is a genetic cause of MDC1A. Patients have merosin (laminin alpha2) deficient skeletal muscles. However, the degree of merosin expression ranges from total absence to partial reduction. Patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency. We observed a Korean girl with MDC1A with residual merosin expression. Clinical presentation of this patient was typical except for late onset of the disease and external capsule involvement. Immunohistochemical staining of muscle fibers including merosin, is important to evaluate patients with hypotonia, delayed motor development, and abnormal white matter changes. PMID- 24778698 TI - Toxic epidermal necrolysis induced by lamotrigine treatment in a child. AB - Toxic epidermal necrolysis is an unpredictable and severe adverse drug reaction. In toxic epidermal necrolysis, epidermal damage appears to result from keratinocyte apoptosis. This condition is triggered by many factors, principally drugs such as antiepileptic medications, antibiotics (particularly sulfonamide), nonsteroidal anti-inflammatory drugs, allopurinol, and nevirapine. Lamotrigine has been reported potentially cause serious cutaneous reactions, and concomitant use of valproic acid with lamotrigine significantly increases this risk. We describe a case of an 11-year-old girl with tic and major depressive disorders who developed toxic epidermal necrolysis after treatment with lamotrigine, and who was diagnosed both clinically and pathologically. Children are more susceptible to lamotrigine-induced rash than adults, and risk of serious rash can be lessened by strict adherence to dosing guidelines. Unfortunately, in our case, the patient was administered a higher dose than the required regimen. Therefore, clinicians should strictly adhere to the dose regimen when using lamotrigine, especially in children. PMID- 24778699 TI - Alleviative Effects of a Kampo (a Japanese Herbal) Medicine "Maoto (Ma-Huang Tang)" on the Early Phase of Influenza Virus Infection and Its Possible Mode of Action. AB - A Kampo medicine, maoto, has been prescribed in an early phase of influenza-like illness and used for a treatment of influenza clinically in Japan these days. However, the efficacy of maoto against the virus infection remains to be elucidated. This study was conducted to evaluate the alleviative effects of maoto against early phase of influenza virus infection and its preliminary mode of actions through immune systems. When maoto (0.9 and 1.6 g/kg/day) was orally administered to A/J mice on upper respiratory tract infection of influenza virus A/PR/8/34 from 4 hours to 52 hours postinfection (p.i.) significant antipyretic effect was shown in comparison with water-treated control. Administration of maoto (0.8 and 1.3 g/kg/day) significantly decreased the virus titers in both nasal (NLF) and bronchoalveolar lavage fluids (BALF) at 52 hours p.i., and significantly increased the anti-influenza virus IgM, IgA, and IgG1 antibody titers in NLF, BALF, and serum, respectively. Maoto also increased significantly the influenza virus-bound IgG1 and IgM antibody titers in serum and the virus bound IgM antibody titer in even the BALF of uninfected A/J mice. These results indicate that maoto exerts antipyretic activity in influenza virus-infected mice and virus reducing effect at an early phase of the infection through probably augmentation of the virus-bound natural antibodies. PMID- 24778700 TI - Effects of Angiotensin-Converting Enzyme Inhibitor Derived from Tropaeolum majus L. in Rat Preimplantation Embryos: Evidence for the Dehydroepiandrosterone and Estradiol Role. AB - Although several studies have shown the inhibitory effects of Tropaeolum majus extracts (HETM) on angiotensin-converting enzyme (ACE) activity, no studies have been carried out during the beginning of pregnancy, when humoral and hormonal imbalance may affect zygote and early embryo transport. This study investigates whether HETM can affect embryonic development when administered during the one cell-blastocyst period. Pregnant Wistar rats received orally the HETM (3, 30, and 300 mg/kg/day) from the 1st to the 7th gestational day. Rats were killed on the 8th day of pregnancy and the following parameters were evaluated: clinical symptoms of toxicity (including organ weights), number of corpora lutea, implants per group, preimplantation losses ratio, and the serum levels of dehydroepiandrosterone (DHEA), estradiol, and progesterone. No clinical symptoms of maternal toxicity were evidenced. On the 8th day of pregnancy, the levels of DHEA and estradiol were increased and significant preimplantation losses were observed at all doses used. The present study reveals that the HETM can raise levels of DHEA and estradiol and induce difficulty in the embryo implantation in the early stages of pregnancy. The data contributes significantly to the safety aspects of using this natural product when trying to get pregnant or during pregnancy. PMID- 24778701 TI - Use of Ethnomedicinal Plants by the People Living around Indus River. AB - The objective of present study was to document and preserve ethnomedicinal knowledge use to treat different human ailments by traditional healers of Dera Ismail Khan region, Pakistan. Field work was conducted between February 2012 and January 2013 using semistructured questionnaires. Data was collected from 120 traditional healers through questionnaire survey. Traditional healers in the study area use 70 plant species mostly herbs (57%) for ethnomedicinal and other purposes. The highest FIC values (0.80) were obtained each for gastrointestinal and kidney problems followed by respiratory infections (0.72) and skin infections (0.73). There was a significant correlation (r (2) = 0.950; p < 0.01) between the age and traditional knowledge of respondent. Direct matrix ranking indicated Morus alba and Dalbergia sissoo as highly multipurpose and threatened species in the study area. The results showed high dependency of local inhabitants on medicinal plants in meeting their primary health care needs. Moreover, the traditional knowledge has been restricted to elder people. Protection measures should be taken in order to conserve precious multipurpose species that are facing overexploitation. Medicinal plants treating major ailments in the region may be subjected to phytochemical and pharmacological investigations for the identification of bioactive compounds. PMID- 24778702 TI - Targeting FASN in Breast Cancer and the Discovery of Promising Inhibitors from Natural Products Derived from Traditional Chinese Medicine. AB - Molecular targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells process a fundamental change in its bioenergetic metabolism from normal cells on an altered lipid metabolism, also known as the de novo fatty acid synthesis, for sustaining their high proliferation rates. Fatty acid synthesis is now associated with clinically aggressive tumor behavior and tumor cell growth and has become a novel target pathway for chemotherapy development. Although the underlying mechanisms of the altered de novo fatty acid synthesis still remains unclear, recent progress has shown that by targeting Fatty acid synthase (FASN), a key enzyme that catalyzes the synthesis of endogenous long chain fatty acid could be a critical target for drug discovery. However, relatively few FASN inhibitors have been discovered. With the long history of clinical practices and numerous histological case study reports, traditional Chinese medicine enjoys an important role in seeking bioactive anticancer natural compounds. Herein, we will give an overall picture of the current progress of molecular targeted therapy in cancer fatty acid synthesis, describe the advances in the research on natural products-derived FASN inhibitors and their potential for enhancing our understanding of fatty acids in tumor biology, and may provide new therapeutic moieties for breast cancer patient care. PMID- 24778703 TI - Beneficial effects of rikkunshito, a Japanese kampo medicine, on gastrointestinal dysfunction and anorexia in combination with Western drug: a systematic review. AB - Background. Kampo medicines are traditional herbal medicines which have been approved for medicinal use by the Japanese Ministry of Health and Welfare and are currently being used more and more, often in combination with Western drugs. Thus, the need for investigation of interactions between Kampo medicines and Western drugs is now widely recognized. Aim. To summarize the effects and drug interactions of rikkunshito, a Kampo medicine often prescribed for upper gastrointestinal disorders and anorexia. Methods. Animal and human studies were systematically reviewed to identify published data on rikkunshito. Results describing its effects were abstracted, with an emphasis on drug interactions. Results and Discussion. Rikkunshito ameliorates anorexia induced by anticancer drugs, improves quality of life scores, and can even prolong survival compared with monotherapy. Rikkunshito combined with proton pump inhibitor therapy is shown to be useful in the treatment of PPI-refractory gastroesophageal reflux disease patients and patients with gastrointestinal symptoms after endoscopic submucosal dissection. Rikkunshito reduces antidepressant-induced adverse events and improves quality of life without influencing antidepressant effects. Conclusions. Rikkunshito shows ameliorative effects on adverse reactions induced by various Western drugs and can achieve better results (e.g., anticancer drugs and proton pump inhibitor) without influencing the efficacy and bioavailability of Western drugs. PMID- 24778704 TI - Erratum to "shenqi fuzheng injection alleviates the transient worsening caused by steroids pulse therapy in treating myasthenia gravis". PMID- 24778705 TI - The Effects of Needling Fenglong (ST40) and Neiguan (PC6) on IL-17 of ApoE-Gene Knockout Mice's Liver. AB - The aim of the present paper was to observe the effects of needling ST40 and PC6 on IL-17 of ApoE(-/-) mice with fatty liver. Forty male ApoE(-/-) mice were randomized into Needling-Acupoint Group, Simvastatin Intragastric Administration Group, Needling Nonacupoint Group, and Model Group. Each was fed with high fat diet for 8 weeks since 16 weeks of age; after 8 weeks of intervention, mice were sacrificed and tested for various examinations. Result showed that the body weight, TC, and serum IL-17 in Needling-Acupoint Group decreased. Compared with Model Group, the immunohistochemical expressions of IL-17 in liver tissue were significantly decreased among the other three groups. In conclusion, acupuncture was able to lower the expression of IL-17 level both in serum and liver tissue in ApoE(-/-) mice, which is helpful to reduce the inflammation and defers the progress from fatty liver to cirrhosis. PMID- 24778706 TI - Treatment effects of xuebijing injection in severe septic patients with disseminated intravascular coagulation. AB - The treatment effects of Xuebijing (XBJ) injection in severe septic patients with disseminated intravascular coagulation (DIC) were investigated in this study. 171 severe septic patients with DIC were divided into the control group (n = 83) or intervention group (n = 88). Routine therapies were administered in both groups, and XBJ injection was administered additionally in the intervention group. Incidence of DIC, clinical severity scores, and coagulation parameters at 7 days after administration of XBJ injection were compared between the two groups, and short-term prognosis was evaluated by 28-day mortality. Compared with the control group, incidence of DIC in the intervention group was significantly lower at 7 days after administration of XBJ injection (P < 0.001). In addition, differences of platelet count and prothrombin time were significantly greater in the intervention group than in the control group (P all <0.05), and similar results were also found for differences of the Mortality in Emergency Department Sepsis score and Acute Physiology and Chronic Health Evaluation II score (P all <0.05). Furthermore, 28-day mortality was significantly lower in the intervention group (P = 0.034). These results demonstrate that XBJ injection can effectively treat DIC caused by severe sepsis and improve short-term prognosis of severe septic patients with DIC. PMID- 24778707 TI - A 12-Words-for-Life-Nurturing Exercise Program as an Alternative Therapy for Cervical Spondylosis: A Randomized Controlled Trial. AB - In this paper, we carried out a randomized controlled clinical trial to explore the effect of 12-words-for-life-nurturing exercise on patients presenting with cervical spondylosis. After exercise intervention, the mean VAS and NDI scores of the patients decreased significantly and the scores of BP, VT, and MH in SF-36 Health Questionnaire were significantly higher. Exercise therapy showed significant effect on relieving pain and improving vitality and mental health. The 12-words-for-life-nurturing exercise may be a potential effective therapy for patients with cervical spondylosis. PMID- 24778708 TI - Psychiatric staff on the wards does not share attitudes on aggression. AB - BACKGROUND: The concept of ward culture has been proposed as a reason for the often reported differences in treatment decisions when managing inpatient aggression. We therefore studied whether staff on wards actually shares similar perceptions and attitudes about aggression and whether the specialty of the ward on which the staff members work influences these opinions. METHODS: The Attitudes Towards Aggression Scale was used to assess attitudes towards aggression in 31 closed psychiatric wards. Altogether 487 staff members working on the study wards were asked to fill in the scale. Respondent's gender, age, educational level, working experience on the current ward, and specialty of this ward (acute, forensic, rehabilitation) served as background variables. RESULTS: Most of the variance found was due to differences between individuals. Belonging to the personnel of a particular ward did not explain much of the variance. CONCLUSIONS: Psychiatric staff on the wards does not share attitudes on aggression. As each staff member has his/her own opinion about aggression, training for dealing with aggression or violent incidents should be done, at least partly, on an individual level. We also suggest caution in using the concept of ward culture as an explanation for the use of restrictive measures on psychiatric wards. PMID- 24778710 TI - One-pot three-component synthesis and photophysical characteristics of novel triene merocyanines. AB - Novel triene merocyanines, i.e. 1-styryleth-2-enylidene and 4-(1,3,3 trimethylindolin-2-ylidene)but-2-en-1-ylideneindolones are obtained in good to excellent yields in a consecutive three-component insertion Sonogashira coupling addition sequence. The selectivity of either series is remarkable and has its origin in the stepwise character of the terminal addition step as shown by extensive computations on the DFT level. All merocyanines display intense absorption bands in solution and the film spectra indicate J-aggregation. While 1 styryleth-2-enylideneindolones show an intense deep red emission in films, 4 (1,3,3-trimethylindolin-2-ylidene)but-2-en-1-ylideneindolones are essentially nonemissive in films or in the solid state. TD-DFT computations rationalize the charge-transfer nature of the characteristic broad long-wavelength absorptions bands. PMID- 24778711 TI - New sesquiterpene hydroquinones from the Caribbean sponge Aka coralliphagum. AB - Four new sulfated sesquiterpene hydroquinones siphonodictyals E1-E4 (1-4) and cyclosiphonodictyol A (5) were isolated from a sample of the Caribbean sponge Aka coralliphagum collected off the coast of San Salvador in the Bahamas. The structures of the new compounds were elucidated on the basis of mass spectrometric and NMR spectroscopic analysis. Compounds 1-4 are derivatives of siphonodictyal E (9). Siphonodictyal E4 (4) exhibited mild antiproliferation activity against L929 mouse fibroblast, KB-31 epidermoid carcinoma, and MCF-7 breast cancer cell lines, while siphondictyal E3 (3) and cyclosiphonodictyol A (5) showed moderate activity against Gram-positive bacteria. PMID- 24778712 TI - Visible-light photoredox catalysis enabled bromination of phenols and alkenes. AB - A mild and efficient methodology for the bromination of phenols and alkenes has been developed utilizing visible light-induced photoredox catalysis. The bromine was generated in situ from the oxidation of Br(-) by Ru(bpy)3 (3+), both of which resulted from the oxidative quenching process. PMID- 24778713 TI - From porphyrin benzylphosphoramidate conjugates to the catalytic hydrogenation of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin. AB - Three new porphyrin aminoalkyl dibenzylphosphoramidates were synthesized by nucleophilic aromatic substitution of one p-fluorine atom of 5,10,15,20 tetrakis(pentafluorophenyl)porphyrin (TPPF 20 ) by primary aminoalkyl dibenzylphosphoramidates. The nucleophilic aromatic substitution was promoted by microwave irradiation in N-methyl-2-pyrrolidinone. Attempts to remove the benzyl groups of the phosphoramidate moiety by hydrogenolysis with 10% Pd/C led to the cleavage of the P-N bond and the reduction of the macrocycle to hydroporphyrin type derivatives. The extent of the effect of the catalytic hydrogenation to TPPF 20 with 10% Pd/C was then studied with a variety of solvents. The results showed that ethanol/DMF is the solvent of choice to produce chlorin TPCF 20 and an ethanol/DMF/NEt3 mixture is more adequate to produce isobacteriochlorin (TPIF 20 ). PMID- 24778709 TI - Current electroconvulsive therapy practice and research in the geriatric population. AB - Electroconvulsive therapy (ECT) is utilized worldwide for various severe and treatment-resistant psychiatric disorders. Research studies have shown that ECT is the most effective and rapid treatment available for elderly patients with depression, bipolar disorder and psychosis. For patients who suffer from intractable catatonia and neuroleptic malignant syndrome, ECT can be life saving. For elderly patients who cannot tolerate or respond poorly to medications and who are at a high risk for drug-induced toxicity or toxic drug interactions, ECT is the safest treatment option. Organic causes are frequently associated with late life onset of neuropsychiatric conditions, such as parkinsonism, dementia and stroke. ECT has proven to be efficacious even when these conditions are present. During the next decade, research studies should focus on the use of ECT as a synergistic therapy, to enhance other biological and psychological treatments, and prevent symptom relapse and recurrence. PMID- 24778714 TI - Synthesis of complex intermediates for the study of a dehydratase from borrelidin biosynthesis. AB - Herein, we describe the syntheses of a complex biosynthesis-intermediate analogue of the potent antitumor polyketide borrelidin and of reference molecules to determine the stereoselectivity of the dehydratase of borrelidin polyketide synthase module 3. The target molecules were obtained from a common precursor aldehyde in the form of N-acetylcysteamine (SNAc) thioesters and methyl esters in 13 to 15 steps. Key steps for the assembly of the polyketide backbone of the dehydratase substrate analogue were a Yamamoto asymmetric carbocyclisation and a Sakurai allylation as well as an anti-selective aldol reaction. Reference compounds representing the E- and Z-configured double bond isomers as potential products of the dehydratase reaction were obtained from a common precursor aldehyde by Wittig olefination and Still-Gennari olefination. The final deprotection of TBS ethers and methyl esters was performed under mildly acidic conditions followed by pig liver esterase-mediated chemoselective hydrolysis. These conditions are compatible with the presence of a coenzyme A or a SNAc thioester, suggesting that they are generally applicable to the synthesis of complex polyketide-derived thioesters suited for biosynthesis studies. PMID- 24778715 TI - Integration of enabling methods for the automated flow preparation of piperazine 2-carboxamide. AB - Here we describe the use of a new open-source software package and a Raspberry Pi((r)) computer for the simultaneous control of multiple flow chemistry devices and its application to a machine-assisted, multi-step flow preparation of pyrazine-2-carboxamide - a component of Rifater((r)), used in the treatment of tuberculosis - and its reduced derivative piperazine-2-carboxamide. PMID- 24778716 TI - Synthesis of chiral N-phosphinyl alpha-imino esters and their application in asymmetric synthesis of alpha-amino esters by reduction. AB - A variety of chiral N-phosphinyl alpha-imino esters have been synthesized for the first time from ketoesters and phosphinylamide, which were then reduced by L selectride to give the corresponding N-phosphinyl-protected alpha-amino esters. The reduction proceeded very well with excellent chemical yields (88-98%) as well as high diastereoselectivities (96:4 to 99:1). Some of these products could be obtained without column chromatography and recrystallization. The chiral phosphinyl auxiliary could be easily cleaved under acidic conditions. PMID- 24778717 TI - Conformation of dehydropentapeptides containing four achiral amino acid residues controlling the role of L-valine. AB - Structural studies of pentapeptides containing an achiral block, built from two dehydroamino acid residues (Delta(Z)Phe and DeltaAla) and two glycines, as well as one chiral L-Val residue were performed using NMR spectroscopy. The key role of the L-Val residue in the generation of the secondary structure of peptides is discussed. The obtained results suggest that the strongest influence on the conformation of peptides arises from a valine residue inserted at the C-terminal position. The most ordered conformation was found for peptide Boc-Gly-DeltaAla Gly-Delta(Z)Phe-Val-OMe (3), which adopts a right-handed helical conformation. PMID- 24778718 TI - Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non proteinogenic amino acid segment of the linear pentapeptide microginin. AB - A directed manipulation of the functional groups at C3 and C4 of D-glucose was demonstrated to synthesize naturally occurring (2S,3R)-alpha-hydroxy-beta aminodecanoic acid (AHDA, 2a) and its enantiomer 2b. The enantiomer of 2a is the N-terminal part of the natural linear pentapeptide microginin, which is used as an antihypertensive agent. PMID- 24778719 TI - Rapid pseudo five-component synthesis of intensively blue luminescent 2,5 di(hetero)arylfurans via a Sonogashira-Glaser cyclization sequence. AB - 2,5-Di(hetero)arylfurans are readily accessible in a pseudo five-component reaction via a Sonogashira-Glaser coupling sequence followed by a superbase mediated (KOH/DMSO) cyclization in a consecutive one-pot fashion. Besides the straightforward synthesis of natural products and biologically active molecules all representatives are particularly interesting due to their bright blue luminescence with remarkably high quantum yields. The electronic structure of the title compounds is additionally studied with DFT computations. PMID- 24778720 TI - End-group-functionalized poly(N,N-diethylacrylamide) via free-radical chain transfer polymerization: Influence of sulfur oxidation and cyclodextrin on self organization and cloud points in water. AB - In this work we report the synthesis of thermo-, oxidation- and cyclodextrin- (CD) responsive end-group-functionalized polymers, based on N,N-diethylacrylamide (DEAAm). In a classical free-radical chain transfer polymerization, using thiol functionalized 4-alkylphenols, namely 3-(4-(1,1-dimethylethan-1 yl)phenoxy)propane-1-thiol and 3-(4-(2,4,4-trimethylpentan-2-yl)phenoxy)propane-1 thiol, poly(N,N-diethylacrylamide) (PDEAAm) with well-defined hydrophobic end groups is obtained. These end-group-functionalized polymers show different cloud point values, depending on the degree of polymerization and the presence of randomly methylated beta-cyclodextrin (RAMEB-CD). Additionally, the influence of the oxidation of the incorporated thioether linkages on the cloud point is investigated. The resulting hydrophilic sulfoxides show higher cloud point values for the lower critical solution temperature (LCST). A high degree of functionalization is supported by (1)H NMR-, SEC-, FTIR- and MALDI-TOF measurements. PMID- 24778721 TI - Copper-phenanthroline catalysts for regioselective synthesis of pyrrolo[3',4':3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and of pyrrolo[1,2 a]phenanthrolines under mild conditions. AB - A new series of pyrrolo[3',4':3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and pyrrolo[1,2-a]phenanthrolines were efficiently built up from an 8 hydroxyquinoline derivative or phenanthroline via 1,3-dipolar cycloaddition reaction involving non-stabilized azomethine ylides, generated in situ from the parent furo[3,2-h]quinoliniums/phenanthroliums, in presence of a copper(II) chloride-phenanthroline catalytic system. The methodology combines general applicability with high yields. PMID- 24778722 TI - Chromatographically separable rotamers of an unhindered amide. AB - Surprisingly stable formamide rotamers were encountered in the tetrahydroisoquinoline and morphinan series of alkaloids. We investigated the hindered rotation around the amide bond by dynamic high-performance liquid chromatography (DHPLC) and kinetic measurements of the interconversion of the rotamers which can readily be separated by HPLC as well as TLC. The experimental results of the different methods were compared to each other as well as to results obtained by DFT calculations. PMID- 24778723 TI - Polyglycerol-functionalized nanodiamond as a platform for gene delivery: Derivatization, characterization, and hybridization with DNA. AB - A gene vector consisting of nanodiamond, polyglycerol, and basic polypeptide (ND PG-BPP) has been designed, synthesized, and characterized. The ND-PG-BPP was synthesized by PG functionalization of ND through ring-opening polymerization of glycidol on the ND surface, multistep organic transformations (-OH -> -OTs (tosylate) -> -N3) in the PG layer, and click conjugation of the basic polypeptides (Arg8, Lys8 or His8) terminated with propargyl glycine. The ND-PG BPP exhibited good dispersibility in water (>1.0 mg/mL) and positive zeta potential ranging from +14.2 mV to +44.1 mV at neutral pH in Milli-Q water. It was confirmed by gel retardation assay that ND-PG-Arg8 and ND-PG-Lys8 with higher zeta potential hybridized with plasmid DNA (pDNA) through electrostatic attraction, making them promising as nonviral vectors for gene delivery. PMID- 24778724 TI - Thermodynamically stable [4 + 2] cycloadducts of lanthanum-encapsulated endohedral metallofullerenes. AB - The [4 + 2] cycloaddition of o-quinodimethanes, generated in situ from the sultine 4,5-benzo-3,6-dihydro-1,2-oxathiin 2-oxide and its derivative, to La metal-encapsulated fullerenes, La2@C80 or La@C82, afforded the novel derivatives of endohedral metallofullerenes (3a,b, 4a,b and 5b). Molecular structures of the resulting compounds were elucidated using spectroscopic methods such as MALDI-TOF mass, optical absorption, and NMR spectroscopy. The [4 + 2] adducts of La2@C80 (3a,b, and 4a,b) and La@C82 (5b), respectively, retain diamagnetic and paramagnetic properties, as confirmed by EPR spectroscopy. Dynamic NMR measurements of 4a at various temperatures demonstrated the boat-to-boat inversions of the addend. In addition, 5b revealed remarkable thermal stability in comparison with the reported [4 + 2] cycloadduct of pentamethylcyclopentadiene and La@C82 (6). These findings demonstrate the utility of sultines to afford thermodynamically stable endohedral metallofullerene derivatives for the use in material science. PMID- 24778725 TI - A novel family of (1-aminoalkyl)(trifluoromethyl)- and (difluoromethyl)phosphinic acids - analogues of alpha-amino acids. AB - A series of novel (1-aminoalkyl)(trifluoromethyl)- and (difluoromethyl)phosphinic acids - analogues of proteinogenic and nonproteinogenic alpha-amino acids were prepared. The synthetic methodology was based on nucleophilic addition of (trifluoromethyl)phosphinic acid or (difluoromethyl)phosphinic acid or its ethyl ester to substrates with C=N or activated C=C double bonds. Analogues of glycine, phenylglycine, alanine, valine, proline, aminomalonic and aspartic acids were thus prepared. Three-component one pot reactions of (trifluoromethyl)phosphinic acid and dibenzylamine with aldehydes were also tested to prepare the title compounds. PMID- 24778726 TI - Phosphinate-containing heterocycles: A mini-review. AB - This review provides an overview of recent efforts towards the synthesis of phosphinate heterocycles R(1)R(2)P(O)(OR). Our laboratory and others' have been involved in this field and as a result new P-C, P-N, and P-O containing heterocyclic motifs are now available through a variety of methods. While developing rapidly, this area is still in its infancy so that biological testing of the compounds has not yet been conducted and applications are rare. The growing availability of synthetic methods will undoubtedly change this situation in the near future. PMID- 24778727 TI - Synthesis of fluorescent (benzyloxycarbonylamino)(aryl)methylphosphonates. AB - The synthesis of a library of structurally variable aromatic esters of (benzyloxycarbonylamino)(aryl)methylphosphonic acids is described by means of the Oleksyszyn reaction. The library was enlarged by the application of a Suzuki Miayra approach and by preparation of mixed esters. PMID- 24778728 TI - Group-assisted purification (GAP) chemistry for the synthesis of Velcade via asymmetric borylation of N-phosphinylimines. AB - A new approach to the anticancer drug Velcade was developed by performing asymmetric borylation of an imine anchored with a chiral N-phosphinyl auxiliary. Throughout the 7-step synthesis, especially in the imine's synthesis and in the asymmetric borylation reactions, operations and work-up were conducted in simple and easy ways without any column chromatographic purification, which defines the GAP (group-assisted purification) chemistry concept. It was found that the optically pure isomer (dr > 99:1) can be readily obtained by washing the crude mixture of the asymmetric borylation reaction with hexane; the chiral N phosphinyl auxiliary can be easily recovered after deprotection is finished. Several other N-phosphinylimines were also investigated for the asymmetric borylation reaction. The absolute configuration of the borylation product was confirmed by single crystal X-ray diffraction analysis. PMID- 24778729 TI - Use of activated enol ethers in the synthesis of pyrazoles: reactions with hydrazine and a study of pyrazole tautomerism. AB - Activated enol ethers derived from esters or the dinitrile of malonic acid, or from pentane-2,4-dione were treated with hydrazine hydrate. The structures of the obtained products - pyrazoles 5 - were studied with a focus on tautomerism and supramolecular structure. A reverse addition of the reagents led to the isolation of two novel products, namely bis-enehydrazines 6 with an unsymmetrical arrangement of the formally equivalent subunits. PMID- 24778730 TI - Asymmetric total synthesis of a putative sex pheromone component from the parasitoid wasp Trichogramma turkestanica. AB - Virgin females of the parasitoid wasp Trichogramma turkestanica produce minute amounts of a sex pheromone, the identity of which has not been fully established. The enantioselective synthesis of a putative component of this pheromone, (6S,8S,10S)-4,6,8,10-tetramethyltrideca-2E,4E-dien-1-ol (2), is reported as a contribution to this identification. Catalytic asymmetric conjugate addition of methylmagnesium bromide and stereoselective Horner-Wadsworth-Emmons olefinations are used as the key steps, and 2 was obtained in 16 steps with an overall yield of 4.4%. PMID- 24778731 TI - Structure elucidation of female-specific volatiles released by the parasitoid wasp Trichogramma turkestanica (Hymenoptera: Trichogrammatidae). AB - Females of the parasitoid wasp Trichogramma turkestanica produce the putative polydeoxypropionates (2E,4E,6S,8S,10S)-4,6,8,10-tetramethyltrideca-2,4-diene and (2E,4E,6S,8S,10S)-4,6,8,10-tetramethyltrideca-2,4-dien-1-ol or their enantiomers as sex specific volatiles. The structures were assigned on the basis of GC-MS investigations using synthetic reference compounds. PMID- 24778732 TI - Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability. AB - beta-Cyclodextrin (beta-CD) dimers have been prepared using the bioorthogonal Staudinger ligation for the first time. In addition to a known linker, methyl 2 (diphenylphosphanyl)terephthalate, a doubly active linker was specifically developed that enabled connection of two beta-CD units in a single step and in aqueous/organic media, under mild conditions and with good yields. A three-carbon spacer between the beta-CD torus and the azido group was required for facile dimer formation. The products, as studied by NMR spectroscopy, were found to adopt closed conformations by intramolecular self-inclusion. On the other hand, association via intermolecular binding was also observed in aqueous solution, confirmed by DOSY NMR experiments. Despite self-inclusion, the beta-CD cavities were capable of guest encapsulation, as shown by titration experiments: the binding constant with 1-adamantylamine was similar to that of natural beta-CD. Theoretical calculations for isolated molecules (PM3 level of theory) and in the presence of solvent [water, PM3(COSMO)] as well as DFT calculations suggested that the compounds prefer to adopt conformations which bring the phenyl groups either inside the beta-CD cavity (inclusion) or over its narrow side (vicinal). Thus, Staudinger ligation could be the method of choice for linking CDs exhibiting (i) ease of preparation in aqueous media, in short steps, under mild conditions and in good yields, (ii) satisfactory aqueous solubility and independent binding capacity of the cavities. PMID- 24778733 TI - Domino reactions of 2H-azirines with acylketenes from furan-2,3-diones: Competition between the formation of ortho-fused and bridged heterocyclic systems. AB - 3-Aryl-2H-azirines react with acylketenes, generated by thermolysis of 5 arylfuran-2,3-diones, to give bridged 5,7-dioxa-1-azabicyclo[4.4.1]undeca-3,8 diene-2,10-diones and/or ortho-fused 6,6a,12,12a-tetrahydrobis[1,3]oxazino[3,2 a:3',2'-d]pyrazine-4,10-diones. The latter compounds, with a new heterocyclic skeleton, are the result of the coupling of two molecules of azirine and two molecules of acylketene and can be prepared only from 3-aryl-2H-azirines having no electron-withdrawing groups in the aryl substituent. Calculations at the DFT B3LYP/6-31G(d) level for the various routes of bis[1,3]oxazino[3,2-a:3',2' d]pyrazine skeleton formation revealed a new domino reaction of 3-aryl-2H azirines occurring in the presence of furandiones: acid-catalyzed dimerization to dihydropyrazine followed by consecutive cycloaddition of the latter to two molecules of acylketenes. PMID- 24778734 TI - Unusual polymorphism in new bent-shaped liquid crystals based on biphenyl as a central molecular core. AB - Bent-shaped mesogens possessing a biphenyl as a central core have been synthesized and the role of the terminal chain and the orientation of the ester as a linkage group have been investigated. For the studied molecular core we have established that both parameters play an important role for the mesomorphic properties. The polyfluoroalkyl terminal chain supports the formation of mesophases, and the introduction of a chiral lactate terminal chain destabilizes mesophases for the first type of mutual orientation of ester groups, attached to the central core. On the contrary, for the opposite orientation of esters, the terminal chain has no effect on the mesomorphic properties, and columnar phases have been found for all compounds. A unique phase sequence has been found for the mesogen with the fluorinated chain. A generalized tilted smectics, SmCG, have been observed in a temperature interval between two different lamellar SmCP phases and characterized by X-ray and dielectric measurements. The dielectric spectroscopy data are unique and presented for the first time in the SmCG phase providing new information about the molecular dynamics. PMID- 24778735 TI - First synthesis of meso-substituted pyrrolo[1,2-a]quinoxalinoporphyrins. AB - A synthetic protocol for the construction of new meso-substituted pyrrolo[1,2 a]quinoxalinoporphyrins is described starting from 5-(4-amino-3-nitrophenyl) 10,15,20-triphenylporphyrin. The reaction of this porphyrin with 2,5 dimethoxytetrahydrofuran, followed by the reduction of the nitro group in the presence of NiCl2/NaBH4 afforded 5-(3-amino-4-(pyrrol-1-yl)phenyl)-10,15,20 triphenylporphyrin. This triphenylporphyrin underwent a Pictet-Spengler cyclization after the reaction with various aromatic aldehydes followed by in situ KMnO4 oxidation to form target porphyrin analogues in good yields. The structures of all synthesized products were established on the basis of spectral data and elemental analyses. PMID- 24778736 TI - Towards allosteric receptors - synthesis of beta-cyclodextrin-functionalised 2,2' bipyridines and their metal complexes. AB - Herein, we present three new 2,2'-bipyridines that carry two beta-cyclodextrin moieties in different substitution patterns. When coordinated by zinc(II) or copper(I) ions (or their complexes), these compounds undergo conformational changes and switch between "open" and "closed" forms and thereby bringing together or separating the cyclodextrin moieties from each other. PMID- 24778737 TI - Molecular recognition of isomeric protonated amino acid esters monitored by ESI mass spectrometry. AB - Two new 9,9'-spirobifluorene-derived crown ethers were prepared and used to recognise constitutionally isomeric amino acid derivatives. The performance of the receptors was evaluated by ESI-mass spectrometry using the isomer labelled guest method (ILGM). This method revealed the preferred binding of L-norleucine and L-leucine compared to L-isoleucine for both receptors. Furthermore, non covalent isotope effects demonstrate the relevance of dispersive interactions for the overall binding event. These effects also provide hints for the relative spatial orientation of the guest molecules within the host-guest complex, and thereby prove the importance of the spirobifluorene moiety for the observed binding of the protonated amino acid esters. PMID- 24778738 TI - Dimerisation, rhodium complex formation and rearrangements of N-heterocyclic carbenes of indazoles. AB - Deprotonation of indazolium salts at low temperatures gives N-heterocyclic carbenes of indazoles (indazol-3-ylidenes) which can be trapped as rhodium complexes (X-ray analysis). In the absence of Rh, the indazol-3-ylidenes spontaneously dimerize under ring cleavage of one of the N,N-bonds and ring closure to an indazole-indole spiro compound which possesses an exocyclic imine group. The E/Z isomers of the imines can be separated by column chromatography when methanol is used as eluent. We present results of a single crystal X-ray analysis of one of the E-isomers, which equilibrate in solution as well as in the solid state. Heating of the indazole-indole spiro compounds results in the formation of quinazolines by a ring-cleavage/ring-closure sequence (X-ray analysis). Results of DFT calculations are presented. PMID- 24778739 TI - Columnar/herringbone dual crystal packing of pyrenylsumanene and its photophysical properties. AB - A single crystal of pyrenylsumanene was found to exhibit both columnar and herringbone crystal packing. The sumanene moieties form unidirectional columnar structures based on pi-pi stacking while the pyrene moieties generate herringbone structures due to CH-pi interactions. The absorption and emission maxima of pyrenylsumanene were both red-shifted relative to those of sumanene and pyrene, owing to the extension of pi-conjugation. Monomer emission with high quantum yield (0.82) was observed for pyrenylsumanene in solution, while excimer-type red shifted emission was evident in the crystalline phase. PMID- 24778740 TI - Aza-Diels-Alder reaction between N-aryl-1-oxo-1H-isoindolium ions and tert enamides: Steric effects on reaction outcome. AB - The synthesis of 5-substituted 6,6a-dihydroisoindolo[2,1-a]quinolin-11(5H)-ones via [4 + 2] imino-Diels-Alder cyclization from N-aryl-3-hydroxyisoindolinones and N-vinyl lactams under Lewis acid-catalysed anhydrous conditions is reported. Reactions of N-(2-substituted-aryl)-3-hydroxyisoindolinones with N vinylpyrrolidone under identical conditions resulted in the formation of 2-(2 substitued-aryl)-3-(2-(2-oxopyrrolidin-1-yl)vinyl)isoindolin-1-one analogues indicating steric hinderance as the cause of deviation. The probable mechanism of the reaction based on the results from X-ray crystallography and molecular modelling is discussed. PMID- 24778741 TI - Cuevaenes C-E: Three new triene carboxylic derivatives from Streptomyces sp. LZ35DeltagdmAI. AB - Two pairs of geometrical isomers - cuevaenes A (1) and C (3) as well as cuevaenes D (4) and E (5) - and cuevaene B (2) were isolated from gdmAI-disrupted Streptomyces sp. LZ35. The constitution of cuevaene C (3) was found to be identical to cuevaene A (1) by means of NMR spectroscopy and high resolution mass spectrometry. However, the relative configurations of the triene side chain moieties were determined to be different. It was established on the basis of spectroscopic data that cuevaenes D (4) and E (5) are amides and geometrical isomers. Cuevaenes A-C (1-3) displayed moderate activity against Gram-positive bacteria (e.g., Bacillus subtilis strain ATCC 11060) and modest activity against fungi (e.g., Fusarium verticillioides strain S68 and Rhizoctonia solani strain GXE4). However, cuevaenes D (4) and E (5) showed no inhibitory activity against any of the tested microbes. PMID- 24778742 TI - Metal and metal-free photocatalysts: mechanistic approach and application as photoinitiators of photopolymerization. AB - In the present paper, the photoredox catalysis is presented as a unique approach in the field of photoinitiators of polymerization. The principal photocatalysts already reported as well as the typical oxidation and reduction agents used in both reductive or oxidative cycles are gathered. The chemical mechanisms associated with various systems are also given. As compared to classical iridium based photocatalysts which are mainly active upon blue light irradiation, a new photocatalyst Ir(piq)2(tmd) (also known as bis(1-phenylisoquinolinato-N,C (2'))iridium(2,2,6,6-tetramethyl-3,5-heptanedionate) is also proposed as an example of green light photocatalyst (toward the long wavelength irradiation). The chemical mechanisms associated with Ir(piq)2(tmd) are investigated by ESR spin-trapping, laser flash photolysis, steady state photolysis, cyclic voltammetry and luminescence experiments. PMID- 24778743 TI - Conformational analysis of 2,2-difluoroethylamine hydrochloride: double gauche effect. AB - The gauche effect in fluorinated alkylammonium salts is well known and attributed either to an intramolecular hydrogen bond or to an electrostatic attraction between the positively charged nitrogen and the vicinal electronegative fluorine atom. This work reports the effect of adding a fluorine atom in 2 fluoroethylamine hydrochloride on the conformational isomerism of the resulting 2,2-difluoroethylamine chloride (2). The analysis was carried out using NMR coupling constants in D2O solution, in order to mimic the equilibrium conditions in a physiological medium, in the gas phase and in implicit water through theoretical calculations. Despite the presence of sigmaCH->sigma*CF and sigmaCH >sigma*CN interactions, which usually rule the hyperconjugative gauche effect in 1,2-disubstituted ethanes, the most important forces leading to the double gauche effect ((+)NH3 in the gauche relationship with both fluorine atoms) in 2 are the Lewis-type ones. Particularly, electrostatic interactions are operative even in water solution, where they should be significantly attenuated, whereas hyperconjugation and hydrogen bond have secondary importance. PMID- 24778744 TI - Addition of H-phosphonates to quinine-derived carbonyl compounds. An unexpected C9 phosphonate-phosphate rearrangement and tandem intramolecular piperidine elimination. AB - The Abramov reaction, a base-catalyzed nucleophilic addition of dialkyl H phosphonates (phosphites) to carbonyl compounds, was performed with oxidized quinine derivatives as the substrates. Homologous aldehydes obtained from the vinyl group reacted in a typical way which led to alpha-hydroxyphosphonates, first reported compounds containing a direct P-C bond between the quinine carbon skeleton and a phosphorus atom. For the C9 ketones a phosphonate-phosphate rearrangement, associated with a tandem elimination of the piperidine fragment, was evidenced. PMID- 24778745 TI - Visible-light-induced, Ir-catalyzed reactions of N-methyl-N ((trimethylsilyl)methyl)aniline with cyclic alpha,beta-unsaturated carbonyl compounds. AB - N-Methyl-N-((trimethylsilyl)methyl)aniline was employed as reagent in visible light-induced, iridium-catalyzed addition reactions to cyclic alpha,beta unsaturated carbonyl compounds. Typical reaction conditions included the use of one equivalent of the reaction substrate, 1.5 equivalents of the aniline and 2.5 mol % (in MeOH) or 1.0 mol % (in CH2Cl2) [Ir(ppy)2(dtbbpy)]BF4 as the catalyst. Two major reaction products were obtained in combined yields of 30-67%. One product resulted from aminomethyl radical addition, the other product was a tricyclic compound, which is likely formed by attack of the intermediately formed alpha-carbonyl radical at the phenyl ring. For five-membered alpha,beta unsaturated lactone and lactam substrates, the latter products were the only products isolated. For the six-membered lactones and lactams and for cyclopentenone the simple addition products prevailed. PMID- 24778746 TI - Mindfulness Ameliorates the Relationship between Weight Concerns and Smoking Behavior in Female Smokers: A Cross-Sectional Investigation. AB - Weight concerns are common among female smokers and may interfere with smoking cessation. It is imperative to identify protective factors to lessen the likelihood that smoking-related weight concerns prompt smoking and hinder cessation efforts. Mindfulness is one potential protective factor that might prevent weight concerns from triggering smoking. In the current study, relationships among facets of trait mindfulness, smoking-related weight concerns, and smoking behavior were examined among 112 young adult female smokers (70.5% daily smokers; 83% Caucasian; mean age 20 [SD = 1.69]). After controlling for demographic variables, the Describing facet of trait mindfulness predicted lower smoking-related weight concerns. The mindfulness characteristics of Acting with Awareness, Nonreactivity, and Describing moderated the relationship between smoking-related weight concerns and smoking frequency, such that smoking-related weight concerns predicted greater smoking frequency in female smokers with low and medium levels of these mindfulness characteristics but did not in those with higher levels of mindfulness. These results suggest that mindfulness-based interventions may be effective for weight-concerned smokers. PMID- 24778747 TI - MR enterography imaging of Crohn's disease in pediatric patients. AB - BACKGROUND: Crohn disease (CD) is a chronic inflammatory process of gastrointestinal tract, which frequently affects children. Recent advances in Magnetic Resonance Imaging (MRI) technique have made small bowel imaging possible, what is extremely useful in pediatrics. The purpose of this article is to describe the characteristic MR enterography findings and to present the advantages of this modality in pediatric patients. MATERIAL/METHODS: A group of 40 patients referred from the Department of Pediatric Gastroenterology and Nutrition, Medical University of Warsaw was included in the analysis. The patients' age ranged from 7 to 18 years (mean age 14 years). Among the study participants, 28 patients were diagnosed with CD, whereas 12 patients had a history of ulcerative colitis or were strongly suspected of CD based on clinical data. The examinations were performed on GE Signa HD 1,5 T system. Small bowel distention was achieved by oral administration of 600-1000 ml of hyperosmotic solution of polyetylenglycol (PEG). Prior to the examination, 20-40 mg of a spasmolytic drug, hioscine-N-butylobromide (Buscolysin((r))), was administrated to reduce peristaltic movements. RESULTS: The abnormal small bowel segments were found in 21 patients and the features of colonic disease were detected in 5 patients. In 2 patients the lesions involved both small and large bowel. In 16 subjects mural changes were not found. Among studied patients, following signs of small bowel inflammation were fund: bowel wall thickening (n=21), submucosal edema (n=8), segment wall hyperenhancement (n=18), deep ulceration (n=6), fistula (n=3), stenosis (n=7), mesenteric signs such as hyperemia (n=9), fibrofatty proliferation (n=8) and lymphadenopathy (n=28). CONCLUSIONS: MR enterography is an excellent examination, which provides an accurate information about severity and activity of and complications related to CD. It is especially valuable in children, because of lack of the negative consequences of repeated exposure to ionizing radiation. PMID- 24778748 TI - [Evaluation of vaccination status against hepatitis B and HBsAg carriage among medical and paramedical staff of the Yaounde Central Hospital, Cameroon]. PMID- 24778749 TI - [Deep perineal endometriosis on episiotomy scar: about a rare case]. PMID- 24778750 TI - [Spinal cord compression revealing a vertebrobasilar spinal hydatid]. PMID- 24778751 TI - [Oral manifestations of systemic sclerosis]. PMID- 24778752 TI - [Epidemiology of infection Helicobacter pylori in Yaounde: specificity of the African enigma]. PMID- 24778753 TI - [A low back pain revealing a stiff-man syndrome]. PMID- 24778754 TI - Evaluation of antiretroviral therapy (ART) provision in an early cohort of patients initiating ART in Ghana. AB - INTRODUCTION: Against the background of Ghana's ART program which scaled up rapidly since inception in 2003, the study assessed outcomes of an early cohort of patients initiating ART. METHODS: THE STUDY UTILIZED THE FOLLOWING METHODS: a cross-sectional study involving patient interviews using a structured questionnaire, a review of records and a retrospective cohort analysis of adults initiating ART between 2003 and 2008 from four selected clinics. RESULTS: The 683 study participants consisted of 464 females (67.9%) and the mean age was 41 years. Mean duration of treatment was 25 months (SD =13). More than 95% were on a regimen as per national guidelines. Ninety-five (14.1%) of the respondents had one or two drugs substituted. Seventy-three% of the substitutions were due to adverse drug reactions. On at least one occasion, over half (350) had defaulted on a clinic appointment. In the 3 months preceding the survey, 21.4% (146) had missed treatment doses. About 49% (334) had challenges meeting financial obligations related to care. The median weight increased by 5.9 kg and 8.0 kg at 6 and 12 months after initiating ART respectively over the median baseline weight of 54 kg, (p-value = 0.001). The median CD4 count increased by 128, 170 and 256 cells/ul respectively at 6, 12 and 24 months from the median baseline of 125 cell/ul, (p-value = 0.035). CONCLUSION: This study of Ghanaian PLHIV on ART from four facilities showed encouraging immunological and clinical outcomes. There were however issues of appointment default, sub-optimum adherence to treatment and cost of care barriers needing attention. PMID- 24778755 TI - Branch retinal vein occlusion with sectoral cystoid macular edema in toxoplasmic chorioretinitis. PMID- 24778756 TI - Associated injuries in patients with facial fractures: a review of 604 patients. AB - Facial fractures may be associated with concomitant lesions of other parts of body with some of these injuries being life-threatening. This retrospective study reports the types of associated injury and the factors influencing their occurrence, in patients with facial fractures. In 18.2% of 604 patients, one associated injury at least was recorded. The most common associated injury was cranial trauma (9.9%), followed by limbs fractures (9.1%), chest trauma (2%), spine injury (0.5%) and eye ball rupture (0.5%). A poly trauma was recorded in 3.2% of the patients who had sustained a cerebral trauma, a spinal injury or a thoracic trauma. Death occurred in two patients (0.3%) who had respectively a spinal injury and a chest trauma. The occurrence of associated injuries correlated significantly with the fracture type with solitary mandibular fracture being a significant predictor of associated injuries. Although not statistically significant, multiple facial fractures and violence were more associated with concomitant injuries. The findings of this study recall the need for initial full examination of the trauma patients particularly victims of violence, patients presenting with multiple facial fractures or single facial bone fracture involving the mandible, the trauma patients? multidisciplinary management as well as trauma prevention. PMID- 24778757 TI - Occupational injuries and fatalities in a tanzanite mine: Need to improve workers safety in Tanzania. AB - INTRODUCTION: Work related injuries are common, and the mining industry accounts for a significant proportion of these injuries. Tanzania is among the countries with high rates of mining injuries, nevertheless pre-hospital care is almost non existant and health care service deliveries are poor. This study sought to identify factors associated with injuries and fatalities among miners in Mererani, Tanzania. METHODS: A Cross - Sectional study of miners who sustained injuries and seen at Mererani health centre between January 2009 and May 2012. RESULTS: In the selected period 248 injury patients were seen. All were males, and 54% were between 18 - 30 years age-group. Almost all (98.7%) didn't use protective gears at work, and worked for more than 12 hours daily. Falling rocks were the leading cause of injury (18.2%), and majority sustained multiple injuries (33%). Of the patients seen, 41.3% died. The following were more likely to die than others; Primary education (p = 0.04), Less than 5 years work experience (p = 0.000), unintentional injuries (p = 0.000), fall injuries (p = 0.000) and sustaining multiple injuries (p = 0.000). CONCLUSION: The burden of injuries and fatalities demonstrated in this study, point to the need for implementation and monitoring of the use of safety equipment and operating procedures of the mines by government and other regulatory authorities. Initiation of pre hospital care at the mines and improved emergency medical service delivery at health centers in Tanzania. PMID- 24778758 TI - Multitrait plant growth promoting (PGP) rhizobacterial isolates from Brassica juncea rhizosphere : Keratin degradation and growth promotion. AB - Plant growth promoting (PGP) rhizobacteria, a beneficial microbe colonizing plant roots, enhanced crop productivity and offers an attractive way to replace chemical fertilizers, pesticides, and supplements. The keratinous waste which comprises feathers, hairs, nails, skin and wool creates problem of solid waste management due to presence of highly recalcitrant keratin. The multi traits rhizobacteria effective to remove both keratine from the environment by producing keratinase enzyme and to eradicate the chemical fertilizer by providing different PGP activity is novel achievement. In the present study, the effective PM2 strain of PGPR was isolated from rhizospheric soil of mustard (Brassica juncea) field, Pantnagar and they were identified on the basis of different biochemical tests as belonging to Bacillus genera. Different plant growth promoting activity, feather degradation and keratinolytic activity was performed and found very effective toward all the parameters. Furthermore, the efficient strain PM2 was identified on the basis of 16s rRNA sequencing and confirmed as Bacillus cereus. The strain PM2 might be used efficiently for keratinous waste management and PGP activity. Therefore, the present study suggests that Bacillus cereus have multi traits activity which extremely useful for different PGP activity and biotechnological process involving keratin hydrolysis, feather biodegradation or in the leather industry. PMID- 24778759 TI - Tunneling nanotubes: Diversity in morphology and structure. AB - Tunneling nanotubes (TNTs) are recently discovered thin membranous tubes that interconnect cells. During the last decade, research has shown TNTs to be diverse in morphology and composition, varying between and within cell systems. In addition, the discovery of TNT-like extracellular protrusions, as well as observations of TNTs in vivo, has further enriched our knowledge on the diversity of TNT-like structures. Considering the complex molecular mechanisms underlying the formation of TNTs, as well as their different functions in intercellular communication, it is important to decipher how heterogeneity of TNTs is established, and to address what roles the compositional elements have in the execution of various functions. Here, we review the current knowledge on the morphological and structural diversity of TNTs, and address the relation between the formation, the structure, and the function of TNTs. PMID- 24778760 TI - Nrz but not zBcl-xL antagonizes Bcl-wav pro-apoptotic activity in zebrafish. AB - We recently identified a new highly divergent Bcl-2 related protein, named Bcl wav, with phylogenetic pattern restricted to aquatic anamniotes. In zebrafish gastrula, bclwav gene silencing resulted in calcium-dependent cytoskeleton remodeling leading to convergence and extension movements defaults and abnormal orientation of the larva notochord. Beyond its function in cell migration, Bcl wav was found to act as a pro-apoptotic Bcl-2 member inducing Bax/Bak dependent cell death. Here we show that, in zebrafish, pro-apoptotic Bcl-wav activity is selectively counteracted by the anti-apoptotic Nrz protein but not by zBcl-xL. Indeed Nrz but not zBcl-xL was able to decrease Bcl-wav dependent embryo mortality. Furthermore Nrz was able to prevent apoptosis induced by Bcl-wav ectopic expression in the embryo's head and tail. Finally co-immunoprecipitation experiments in HeLa cells showed that Bcl-wav directly interacts with Nrz. Overall these results expand our current knowledge about Bcl-2 family proteins interactome during early zebrafish development. PMID- 24778761 TI - Kin recognition by roots occurs in cycads and probably in conifers. AB - Kin recognition by the roots of Cycas edentata was recently demonstrated. Our extensive literature search revealed this to be the first report of kin recognition in any spermatophyte other than angiosperms. Based on this new validation that the phenomenon occurs among phylogenetically diverse taxa, we conclude that kin recognition by roots may be an ancient phenomenon. PMID- 24778762 TI - Switching off photosynthesis: The dark side of sacoglossan slugs. AB - Sometimes the elementary experiment can lead to the most surprising result. This was recently the case when we had to learn that so-called "photosynthetic slugs" survive just fine in the dark and with chemically inhibited photosynthesis. Sacoglossan sea slugs feed on large siphonaceous, often single-celled algae by ingesting their cytosolic content including the organelles. A few species of the sacoglossan clade fascinate researcher from many disciplines, as they can survive starvation periods of many months through the plastids they sequestered, but not immediately digested - a process known as kleptoplasty. Ever since the term "leaves that crawl" was coined in the 1970s, the course was set in regard to how the subject was studied, but the topics of how slugs survive starvation and what for instance mediates kleptoplast longevity have often been conflated. It was generally assumed that slugs become photoautotrophic upon plastid sequestration, but most recent results challenge that view and the predominant role of the kleptoplasts in sacoglossan sea slugs. PMID- 24778763 TI - Vps11, a subunit of the tethering complexes HOPS and CORVET, is involved in regulation of glycolipid degradation and retrograde toxin transport. AB - We recently reported that ERM (ezrin, radixin, moesin) proteins are involved in intracellular sorting of Shiga toxin (Stx) and its receptor globotriaosylceramide (Gb3), and that depletion of ezrin and moesin reduced retrograde Golgi transport of Stx. In the same study, we found that knockdown of Vps11, a core subunit of both the homotypic fusion and protein sorting (HOPS) complex and the class C core vacuole/endosome tethering factor (CORVET), increased retrograde transport of Stx and could counteract the inhibiting effect of moesin and ezrin knockdown. In this study we demonstrate that Vps11 knockdown also leads to increased Stx toxicity as well as increased retrograde transport and toxicity of ricin. Additionally, we show that knockdown of Vps11 restores the reduced Gb3 level observed after moesin depletion. PMID- 24778764 TI - Eco-evolutionary dynamics of complex social strategies in microbial communities. AB - Microbial communities abound with examples of complex social interactions that shape microbial ecosystems. One particularly striking example is microbial cooperation via the secretion of public goods. It has been suggested by theory, and recently demonstrated experimentally, that microbial population dynamics and the evolutionary dynamics of cooperative social genes take place with similar timescales, and are linked to each other via an eco-evolutionary feedback loop. We overview this recent evidence, and discuss the possibility that a third process may be also part of this loop: phenotypic dynamics. Complex social strategies may be implemented at the single-cell level by means of gene regulatory networks. Thus gene expression plasticity or stochastic gene expression, both of which may occur with a timescale of one to a few generations, can potentially lead to a three-way coupling between behavioral dynamics, population dynamics, and evolutionary dynamics. PMID- 24778765 TI - Tumor-derived exosomes: A message delivery system for tumor progression. AB - Intercellular communication is a key process in the development and progression of cancer. The dynamic and reciprocal interplays between the tumor and its microenvironment orchestrate events critical to the establishment of primary and metastatic niches and maintenance of a permissive environment at the tumor-stroma interface. Atay and colleagues found that gastrointestinal stromal tumor cells secrete vesicles known as exosomes. These exosomes contain oncogenic KIT and their transfer and uptake by surrounding smooth muscle cells lead to enhanced AKT and MAPK signaling and phenotypic modulation of several cellular processes, including morphological changes, expression of tumor-associated markers, secretion of matrix metalloproteinases, and enhanced tumor cell invasion. This provocative study emphasizes that exosome-mediated signaling within the tumor microenvironment acts as a positive feedback loop that contributes to invasiveness and that interfering with this message delivery system may represent promising therapeutic approaches, not only for GIST, but for other types of cancer. PMID- 24778766 TI - PTEN: A master regulator of neuronal structure, function, and plasticity. AB - PTEN (phosphatase and tensin homolog on chromosome ten) is a dual protein/lipid phosphatase that dephosphorylates PIP3, thereby inhibiting the AKT/mTOR pathway. This inhibition ultimately decreases protein translation, cell proliferation and cell growth. In the central nervous system, inhibition of PTEN leads to increased stem cell proliferation, somatic, dendritic and axonal growth, accelerated spine maturation, diminished synaptic plasticity, and altered intrinsic excitability. In agreement with these findings, patients carrying single-copy inactivating mutations of PTEN suffer from autism, macrocephaly, mental retardation, and epilepsy.(1) (-) (9) Understanding the mechanisms through which PTEN modulates the structure, function, and plasticity of cortical networks is a major focus of study. Preventing and reversing the changes induced by loss of Pten in model animals will pave the way for treatments in humans. PMID- 24778767 TI - Redox status and aging link in neurodegenerative diseases. PMID- 24778768 TI - Liver volumetry: Is imaging reliable? Personal experience and review of the literature. AB - The amount of the future liver remnant volume is fundamental for hepato-biliary surgery, representing an important potential risk-factor for the development of post-hepatectomy liver failure. Despite this, there is no uniform consensus about the amount of hepatic parenchyma that can be safely resected, nor about the modality that should be chosen for this evaluation. The pre-operative evaluation of hepatic volume, along with a precise identification of vascular and biliar anatomy and variants, are therefore necessary to reduce surgical complications, especially for extensive resections. Some studies have tried to validate imaging methods [ultrasound, computed tomography (CT), magnetic resonance imaging] for the assessment of liver volume, but there is no clear evidence about the most accurate method for this evaluation. Furthermore, this volumetric evaluation seems to have a certain degree of error, tending to overestimate the actual hepatic volume, therefore some conversion factors, which should give a more reliable evaluation of liver volume, have been proposed. It is widespread among non-radiologists the use of independent software for an off-site volumetric analysis, performed on digital imaging and communications in medicine images with their own personal computer, but very few studies have provided a validation of these methods. Moreover, while the pre-transplantation volumetric assessment is fundamental, it remains unclear whether it should be routinely performed in all patients undergoing liver resection. In this editorial the role of imaging in the estimation of liver volume is discussed, providing a review of the most recent literature and a brief personal series of correlations between liver volumes and resection specimens' weight, in order to assess the precision of the volumetric CT evaluation. PMID- 24778769 TI - Clinical decision support systems for brain tumor characterization using advanced magnetic resonance imaging techniques. AB - In recent years, advanced magnetic resonance imaging (MRI) techniques, such as magnetic resonance spectroscopy, diffusion weighted imaging, diffusion tensor imaging and perfusion weighted imaging have been used in order to resolve demanding diagnostic problems such as brain tumor characterization and grading, as these techniques offer a more detailed and non-invasive evaluation of the area under study. In the last decade a great effort has been made to import and utilize intelligent systems in the so-called clinical decision support systems (CDSS) for automatic processing, classification, evaluation and representation of MRI data in order for advanced MRI techniques to become a part of the clinical routine, since the amount of data from the aforementioned techniques has gradually increased. Hence, the purpose of the current review article is two fold. The first is to review and evaluate the progress that has been made towards the utilization of CDSS based on data from advanced MRI techniques. The second is to analyze and propose the future work that has to be done, based on the existing problems and challenges, especially taking into account the new imaging techniques and parameters that can be introduced into intelligent systems to significantly improve their diagnostic specificity and clinical application. PMID- 24778770 TI - Role of interventional radiology in the management of acute gastrointestinal bleeding. AB - Acute gastrointestinal bleeding (GIB) can lead to significant morbidity and mortality without appropriate treatment. There are numerous causes of acute GIB including but not limited to infection, vascular anomalies, inflammatory diseases, trauma, and malignancy. The diagnostic and therapeutic approach of GIB depends on its location, severity, and etiology. The role of interventional radiology becomes vital in patients whose GIB remains resistant to medical and endoscopic treatment. Radiology offers diagnostic imaging studies and endovascular therapeutic interventions that can be performed promptly and effectively with successful outcomes. Computed tomography angiography and nuclear scintigraphy can localize the source of bleeding and provide essential information for the interventional radiologist to guide therapeutic management with endovascular angiography and transcatheter embolization. This review article provides insight into the essential role of Interventional Radiology in the management of acute GIB. PMID- 24778772 TI - Orbital inflammatory disease: Pictorial review and differential diagnosis. AB - Orbital inflammatory disease (OID) represents a collection of inflammatory conditions affecting the orbit. OID is a diagnosis of exclusion, with the differential diagnosis including infection, systemic inflammatory conditions, and neoplasms, among other conditions. Inflammatory conditions in OID include dacryoadenitis, myositis, cellulitis, optic perineuritis, periscleritis, orbital apicitis, and a focal mass. Sclerosing orbital inflammation is a rare condition with a chronic, indolent course involving dense fibrosis and lymphocytic infiltrate. Previously thought to be along the spectrum of OID, it is now considered a distinct pathologic entity. Imaging plays an important role in elucidating any underlying etiology behind orbital inflammation and is critical for ruling out other conditions prior to a definitive diagnosis of OID. In this review, we will explore the common sites of involvement by OID and discuss differential diagnosis by site and key imaging findings for each condition. PMID- 24778773 TI - Lung cancer screening-don't forget the chest radiograph. AB - Lung cancer is a major health burden and early detection only bears the possibility of curative treatment. Screening with computed tomography (CT) recently demonstrated a mortality reduction in selected patients and has been incorporated in clinical guidelines. Problems of screening with CT are the excessive number of false positive findings, costs, radiation burden and from a global point of view shortage of CT capacity. In contrast, chest radiography could be an ideal screening tool in the early detection of lung cancer. It is widely available, easy to perform, cheap, the radiation burden is negligible and there is only a low rate of false positive findings. Large randomized controlled trials could not show a mortality reduction, but different large population-based cohort studies have shown a lung cancer mortality reduction. It has been argued that community-based cohort studies are more closely reflecting the "real world" of everyday medicine. Radiologists should be aware of the found mortality reduction and realize that early detection of lung cancer is possible when reading their daily chest radiographs. Offering a chest radiograph in selected scenarios for the early detection of lung cancer is therefore still justified. PMID- 24778771 TI - FMRI contributions to addressing autobiographical memory impairment in temporal lobe pathology. AB - Episodic autobiographical memory (AM) allows one, through the recollection of sensory-perceptual details, thoughts and feelings, to become aware of an event as belonging to one's own past as well as being able to project into one's future. Because AM provides a sense of self-continuity, contributes to the integrity of the self, and helps predicting future experiences, any deficit of AM may have debilitating consequences for everyday life functioning. Understanding AM failure and the underlying neural mechanisms has the potential to shed light on brain reorganization mechanisms and engagement of compensatory processes. Functional magnetic resonance imaging (fMRI) provides the most promising imaging method to tackle these issues. We reviewed evidence from the few studies that used fMRI to investigate the functionality of the residual tissue, the neural reorganization and compensatory mechanisms in patients with neurological conditions due to impaired medial temporal lobe. Overall, these studies highlight the importance of the left hippocampus, which when atrophied and not functional leads to AM deficits but its residual functionality may support relatively normal AM recollection. When damaged hippocampal tissue is not functional, other brain regions (e.g., the medial prefrontal cortex) may be involved to compensate impairment, but they appear generally ineffective to support detailed episodic recollection. PMID- 24778774 TI - Imaging of skeletal muscle in vitamin D deficiency. AB - Elderly people are prone to accidental falls and one of the main risk factor is considered muscle weakness. Several studies focused on muscle weakness and muscle morphology changes in the elderly that may be associated with vitamin D deficiency. The prevalence of vitamin D deficiency is higher than previously though representing an important issue for public health and prevention. There is an increased interest in vitamin D effects in skeletal muscle and imaging modalities are particularly involved in this field. In patients with vitamin D deficiency, ultrasound, computed tomography, densitometry and magnetic resonance imaging (MRI) can efficiently describe changes in muscle morphology and size. Moreover, new imaging modalities, such as MRI spectroscopy, may improve knowledge about the metabolic effects of vitamin D in skeletal muscle. In this narrative review we will discuss the role of skeletal muscle imaging in vitamin D-deficient individuals. The aim of this paper is to improve and encourage the role of radiologists in this field. PMID- 24778775 TI - Psoas muscle metastasis from cervical carcinoma: Correlation and comparison of diagnostic features on FDG-PET/CT and diffusion-weighted MRI. AB - Psoas muscle metastasis, though rare, is the commonest site of skeletal muscle involvement in cervical carcinoma. The appropriate clinical management of this condition, particularly of the pain related to malignant psoas syndrome, is still evolving and the diagnostic features on conventional morphological imaging modalities are often non specific, with the differential diagnosis lying between sarcoma, hematoma, and abscess. In this report, a comparison of various morphofunctional imaging modalities was made. Fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) was the first to suspect disease involvement of the psoas muscle, demonstrating intense FDG uptake (compared with the contralateral muscle), while ultrasound showed heterogeneous echotexture, and magnetic resonance imaging (MRI) showed subtle altered signal intensity in the right psoas muscle. Both anatomical imaging modalities and non contrast CT of the PET-CT examination demonstrated a bulky psoas muscle, without any focal abnormality. On diffusion-weighted imaging of MRI (DWI-MRI), restricted diffusion of the involved muscle was an important observation. The psoas muscle metastatic involvement was proven histopathologically. Thus, enhanced glucose metabolism and restricted diffusion in the newer non-invasive molecular imaging modalities (e.g., PET/CT and DWI-MRI) could serve as valuable adjunctive parameters in diagnosing this entity in the absence of a focal abnormality in the anatomical modalities. In the treatment response monitoring scenario, FDG-PET/CT demonstrated near complete resolution following administration of 3 cycles of systemic chemotherapy and local external radiotherapy. PMID- 24778776 TI - Influence of DNA extraction on oral microbial profiles obtained via 16S rRNA gene sequencing. AB - BACKGROUND AND OBJECTIVE: The advent of next-generation sequencing has significantly facilitated characterization of the oral microbiome. Despite great efforts in streamlining the processes of sequencing and data curation, upstream steps required for amplicon library generation could still influence 16S rRNA gene-based microbial profiles. Among upstream processes, DNA extraction is a critical step that could represent a great source of bias. Accounting for bias introduced by extraction procedures is important when comparing studies that use different methods. Identifying the method that best portrays communities is also desirable. Accordingly, the aim of this study was to evaluate bias introduced by different DNA extraction procedures on oral microbiome profiles. DESIGN: Four DNA extraction methods were tested on mock communities consisting of seven representative oral bacteria. Additionally, supragingival plaque samples were collected from seven individuals and divided equally to test two commonly used DNA extraction procedures. Amplicon libraries of the 16S rRNA gene were generated and sequenced via 454-pyrosequencing. RESULTS: Evaluation of mock communities revealed that DNA yield and bacterial species representation varied with DNA extraction methods. Despite producing the lowest yield of DNA, a method that included bead beating was the only protocol capable of detecting all seven species in the mock community. Comparison of the performance of two commonly used methods (crude lysis and a chemical/enzymatic lysis+column-based DNA isolation) on plaque samples showed no effect of extraction protocols on taxa prevalence but global community structure and relative abundance of individual taxa were affected. At the phylum level, the latter method improved the recovery of Actinobacteria, Bacteroidetes, and Spirochaetes over crude lysis. CONCLUSION: DNA extraction distorts microbial profiles in simulated and clinical oral samples, reinforcing the importance of careful selection of a DNA extraction protocol to improve species recovery and facilitate data comparison across oral microbiology studies. PMID- 24778777 TI - Impact of postdural puncture headache after diagnostic lumbar puncture. PMID- 24778778 TI - Are clinical measures influenced by various ethnic origins in Iranian patients with ankylosing spondylitis?A pilot study. AB - BACKGROUND: Ankylosing spondylitis (AS) may manifest with heterogeneous patterns according to ethnic origins. The purpose of this study was to describe the influence of various Iranian ethnic origins on clinical measures in patients with AS. METHODS: 0ne hundred sixty-three AS patients diagnosed by modified New York 1984 criteria were enrolled consecutively. The patients were classified into Fars, Turk, Kord, Lor and other ethnic origins. Several clinical measures were described and compared between the ethnic origins. RESULTS: The highest and the lowest finger to floor distance was observed for Fars ethnicity (20.4+/-14.8) and other ethnicities (5.9+/-8.1), respectively (P=0.04). The frequency of severe decrease in cervical slope was significantly different between various ethnicities (P=0.025). The most and the least frequency of severe decrease in cervical slope was observed in Fars patients (61.3%) and other ethnicities (20%), respectively. The frequency of severe thoracic kyphosis was significantly dissimilar between various ethnicities (P=0.006). The most and the least frequency of severe increase in thoracic kyphosis was observed in Fars (68.8%) and Lor patients (25%), respectively. A significant relationship was seen only between other ethnicities and finger to floor distance, lateral lumbar flexion, chest expansion and BASDAI (P<0.05). CONCLUSION: Clinical expression variations in AS disease might be influenced by various Iranian ethnic origins. A larger sample size with other Iranian ethnicities (Baluch, Arab, etc) is required to clear the definite relationship between Iranian ethnicities and clinical expression. PMID- 24778779 TI - Relationship between testosterone levels and depressive symptoms in older men in Amirkola, Iran. AB - BACKGROUND: Testosterone may be an important factor causing depression in the elderly men. The purpose of this study was to determine the relationship between testosterone levels and depressive symptoms in older men in Amirkola, Iran. METHODS: This cross- sectional study is a part of the Amirkola Health and Aging Project (AHAP) that involves people aged 60 and above living in Amirkola, a small town in northern Iran. The testosterone levels were measured using ELISA on morning blood samples (ngr / ml) and depressive symptoms were identified using Geriatric Depression Scale (GDS). The data were collected and analyzed. RESULTS: Eight hundred thirty elderly men with the mean age of 70.02+/-7.7 years were included. On the basis of GDS criteria, 593 individuals had no depressive symptoms and 237 had at least one of these symptoms. The mean serum testosterone level in men without symptoms of depression (4.94+/-4.22) ngr/ml and was higher than in those with such symptoms (4.19+/-3.65) ngr/ml (P=0.011). Also, there was a significant inverse correlation between the testosterone levels and number of depressive symptoms (P=0.015, r=-0.084). After adjusting with age and educational levels, and living alone (OR=2.6, 95% CI: 1.17-5.82, P=0.02), testosterone levels (OR=1.67, 95% CI: 1.03-2.72, P=0.038) had the greatest impact on the development of depression. CONCLUSION: The results of this study showed a significant inverse relationship between serum testosterone levels and depressive symptoms in elderly men. PMID- 24778780 TI - Psychological factors in patients with peptic ulcerand functional dyspepsia. AB - BACKGROUND: The role of psychological factors in peptic ulcer disease (PUD) and functional dyspepsia (FD) has not been clearly determined. In this study the role of conflict management styles, psychiatric symptoms, and alexithymia were assessed in patients with PUD and FD and in the healthy individuals. METHODS: Ninety subjects [30 PUD (15 women, 15 men), 30 FD (15 women, 15 men), and 30 healthy individuals (15 women, 15 men)] in two endoscopy wards of Babol University of Medical Sciences were evaluated. Three groups were matched with regard to demographic variables. Conflict management styles, psychiatric symptoms, and alexithymia were evaluated by appropriate questionnaires. RESULTS: The patients with PUD reported less mean scores on psychiatric symptoms than the FD patients (depression 12.6+/-7.5 vs 28+/-9.5, anxiety 8.2+/-5.9 vs 18.7+/-6. obsessive-compulsive disorder 15.7+/-7.5 vs 21.8+/-8.4, interpersonal sensitivity 9.5+/-7.4 vs 16+/-7, psychoticism 8.03+/-4.5 vs 14.3+/-6.3, somatization 12.5+/ 10.8 vs 20.7+/-8.1, and the total score of psychiatric symptoms 94.4+/-49.9 vs 160.1+/-46.6). The mean scores use of unconstructive conflict management styles in PUD patients were lower than FD (dominating 17.7+/-3.5 vs 20.2+/-2.7, avoiding 17.5+/-3 vs 23.8+/-4.4). Alexithymia symptoms were higher in FD patients than PUD individuals (difficulty in identifying feelings 23.5+/-6.3 vs 27.8+/-3.9, difficulty in describing feeling 16.5+/-4.4 vs 17.3+/-3.6). The PUD and FD patients had higher scores regarding these variables than the healthy subjects. CONCLUSION: The results show that both PUD and FD patients experienced more psychiatric symptoms, unconstructive conflict management styles, and alexithymia than the healthy subjects. FD patients had worse psychiatric problems than PUD. PMID- 24778781 TI - Are older women likely to use medicines than older men? (Results from AHAP study). AB - BACKGROUND: The health of elderly population in the world has been an important issue in recent century and the use of appropriate or inappropriate medications is challenging among them. The purpose of this study was to assess the pattern of medication in elderly population in Amirkola, northern of Iran. METHODS: This study was conducted on 1534 elderly subjects who participated in Amirkola Health and Ageing Project (AHAP) in 2013. The number of drugs that was used regardless of their indication in terms of age, level of education, disease, cognitive or depression and social support were recorded and compared in both sexes. RESULTS: The mean number of drugs used in men and women was 2.1+/-2.45 and 3.59+/-2.75, respectively (P=0.000). Concurrent use of > 4 drugs was seen in 16.5% of men and in 35.12% of women (P=0.000). The difference for using the number of drugs was significant between sexes with low educational level, but was similar in educated individuals. The use of polypharmacy was associated with the number of concurrent diseases (r=0.58, P=000), cognitive status (r=0.065, P=0.012), social support (r= 0.1, P=0.008), and depression (r=0.273, P=0.000). CONCLUSION: The results show that the use of polypharmacy in the elderly population in Amirkola is relatively high and they need to be educated. Considering the other indices, this problem highly manifested more in the elderly women. PMID- 24778782 TI - Comparative effect of thymus vulgaris and ibuprofen on primary dysmenorrhea: A triple-blind clinical study. AB - BACKGROUND: Dysmenorrhea is one of the most common medical problems in gynecology causing several problems in the personal and social life of women. This study was conducted to compare the effect of thymus vulgaris and ibuprofen on the treatment of primary dysmenorrhea Methods: This clinical study was conducted on 84 students of Babol University of Medical Sciences with primary dysmenorrhea. The students were randomly assigned to three groups receiving thymus vulgaris, ibuprofen and placebo. In all three groups, with the beginning of pain, 200 mg capsules and 25 drops of essential oil were given every 6 hours for two consecutive cycles. Pain intensity used the visual scale before and one hour after each dose for 48 hour after starting medication. The data were collected and analyzed. This study was registered in the Iranian Registry of Clinical Trial (www.irct.ir) with registration number ID: IRCT201101245683N1 RESULTS: The mean age of participants was 20.5+/-1.8 years. Both thymus vulgaris and ibuprofen were effective to reduce the pain severity of dysmenorrhea. Before treatment, the mean pain intensity in thymus vulgaris, ibuprofen and placebo groups were 6.57+/-2.02, 5.30+/-2.23 and 6.18+/-1.78, respectively and after treatment decreased to 1.21+/-1.06, 1.48+/ 1.62 and 3.54+/-2.26, respectively. Reduction of pain severity was not statistically significant between the two medications, however it was significant for each drug compared with placebo (p<0.001). CONCLUSION: The results suggest that thymus vulgaris as well as ibuprofen can be effective in reducing the severity of pain and spasm in primary dysmenorrhea. PMID- 24778783 TI - Ileocecal patch -low rectal anastomosis in total colectomy: New idea for the prevention of fecal incontinence. AB - BACKGROUND: Total colectomy is used in children with total colonic aganglionosis, Ulcerative colitis (UC) and familial adenomatous polyposis (FAP). The purpose of this study was to maintain ileocecal valve and rectal-sparing surgery for the prevention of fecal incontinence in these children. METHODS: From1990 to 2011, 14 children with diagnosis of UC, FAP and Hirschsprung's disease were operated. Total colectomy was done with the preservation of patch of cecum with ileocecal valve and half of the rectum with ileocecorectal anastomosis. Distal ileum designed as S shape pouch and ileocecal valve were preserved. In Hirschsprung's disease, posterior rectal myotomy was established. The data were collected and analyzed. RESULTS: The mean age of the patients was 54 months (ranged from 2 months to 18 years). Ten patients were male. Among 14 patients, Hirschsprung's disease, ulcerative colitis and FAP were seen in 10, 3, and one case, respectively. They were followed up annually. Clinical and endoscopic examinations were performed to evaluate the function of ileocecorectal anastomosis. They followed from 2 to 24 years. At first year, the patients experienced four to six bowel movements during the day and one at night. This frequency decreased over time. The main postoperative complications included recurrent enterocolitis (n=2), perianal fistula (n=2). Only 2 patients were suffering from some degree of fecal soiling. CONCLUSION: The results show that the Ileocecal patch- low rectal anastomosis in total colectomy leads to low complications and prevent fecal frequency and incontinence. It also increases absorptive function of ileum in children. PMID- 24778784 TI - Length of service and commitment of nurses in hospitalsof Social Security Organization (SSO) in Tehran. AB - BACKGROUND: A nurse's commitment is the most important factor that influences her performance and depends on other variables. The purpose of this research was to study the relationship between length of service of the nurses with the amount of occupational commitment and organizational commitment. METHODS: From Winter 2012 to Spring 2013, 266 nurses were chosen in selected hospitals of Social Security Organization (SSO). These nurses were randomly categorized into six different classes of service records including < 5, 5-9, 10-14, 15-19, 20-24, and 25-29 years. The length of service is related to the organizational, occupational, affective, continuance, and normative commitment. The data were collected and analyzed. RESULTS: Generally 84% of the responders were women and the rest were men of which 95% had a bachelor's degree and the rest had higher academic degrees. The length of service in 81% of nurses was <15 years and 19% were higher than 15 years. Significant correlation were seen between continuance and occupational commitments and length of service (r=0.23, P=0.04 and r=-0.26, P=0.02, respectively). There were not any significant differences regarding organizational, affective and normative commitments (P=0.12, P=0.33, P=0.47, respectively). CONCLUSION: The results show that the length of service was related to continuance and occupational commitment. So pre-retirement of the nurses after 20 years of work can result in an increase in average commitment of employees. PMID- 24778785 TI - Investigation of auditory thresholds in type 2 diabetic patients compared to non diabetic cases. AB - BACKGROUND: Hearing loss is one of the common complaints of diabetics. The aim of this study was to evaluate the hearing status of diabetic patients in Babol, North of Iran. METHODS: The hearing status of 50 type 2 diabetic patients (case group) and 50 healthy individuals (control group) were evaluated from October 2011 to September 2012. Audiometry was done with the frequencies of 250, 500, 1000, 2000, 4000, 6000, 8000 HZ and speech tests like SRT (speech reception threshold), SDS (speech discrimination score) were performed. The data were collected and analyzed. RESULTS: The mean age of case group was 50.1+/-3 and in control group was 49.9+/-3.2 years. Hearing thresholds were 10.55.6, 10.76.1, 15.27.1, 169.6, 21.213.5, 26.416.5, 28.32 db in the right ear of the case group and 11.25.3, 9.74.9, 127.1, 14.29.4, 20.913.3, 25.115.6, 27.620.2 db in control group with different frequencies (p<0.05). Similar results were obtained in the left ear of both groups. The mean SRT in the right ear of the case group was 15.77.7 and control group was 9.24.8 and 13.56.9 in case and 9.14 in the left ear of case group (P=0.0001). SDS was 94.33.7 and in 96.23.3 in the right ear for the case and control group, respectively (P=0.0001). For the left ear, these values were 94.44.4 and 95.93.2, respectively (P=0.023). CONCLUSION: The results show that hearing loss in different frequencies and speech reception threshold were higher in diabetic group but speech discrimination score was higher in normal individuals. Audiological monitoring is recommended in diabetic patients during therapy. PMID- 24778786 TI - Effects of 8 weeks resistance training on plasma vaspin and lipid profile levels in adult men with type 2 diabetes. AB - BACKGROUND: Vaspin is associated with decreased blood glucose concentration. In this study, we aimed to investigate the effects of resistance exercise training on plasma vaspin and lipid profile levels in patients with type 2 diabetes. METHODS: Thirty men were divided into 2 groups: control (n=15), and resistance exercise (n=15). The resistance group performed a resistance exercise consisting of 3 circuits of 8-15 repetitions of the 8 exercises. Lipid profiles and vaspin levels were measured at baseline and at the end of study. This study was registered in the Iranian Registry of Clinical Trial (www.irct.ir) with registration number ID: IRCT2013060911772N1. RESULTS: Intergroup study showed that after an 8-week of resistance training, resistance group had reductions in vaspin (330.50+/-82.51 ng/ml vs 251.62+/-107.28 ng/ml, p=0.03), and TC levels (185.21+/-47.51 mg/dL vs 171.10+/-37.91 mg/dL p= 0.02); but, had increase in HDL C levels (38.20+/-20.65 mg/dL vs 43.80+/-7.87 mg/dL p=0.01), whereas, vaspin levels significantly increased in control groups (344+/-78.64 ng/ml vs 436 +/- 70.47 ng/ml, p= 0.03). On the other hand, significant difference was seen in plasma vaspin levels between two groups. CONCLUSION: Our findings suggest that resistance training significantly decreased the level of vaspin without affecting the lipid profile level. PMID- 24778787 TI - Efficacy of multiplex PCR procedure for Iranian Streptococcus pneumoniae isolates. AB - BACKGROUND: Identifying regional types and evaluating the frequency of pneumococcal strains has become increasingly important especially in vaccination. The purpose of this study was the identification and frequency determination of our regional serotype and evaluation of the performance of recent type specific multiplex PCR for the diagnosis of streptococcus pneumonia serotypes. METHODS: All isolated S. pneumonia from suspected patients in Tehran and Isfahan Hospitals from June to December of 2012 were evaluated. All specimens and their serotypes were identified through a conventional method and specific antisera. Serotype specific multiplex PCR was applied and ran in seven reactions consisting of 34 S. pneumonia primer pairs plus a primer pair as an internal control for this purpose. RESULTS: Overall, 14 genotype specific serotypes (including two subtypes for 19 and 23) were detected and had identical results with stereotyping method except for serotype 28 and one of the identified serotype 23. The serotypes 19, 6 and 23 were dominant with the frequency of 51.8%. A cross reactivity was also observed between genotypes 1 and 9A/9V. CONCLUSION: Applied multiplex PCR format can be suitable and cost effective tool for identification of S. pneumonia serotypes. PMID- 24778788 TI - Glucose Tolerance and lipid profile changes after surgical menopause. AB - BACKGROUND: Bilateral salpingo-oophorectomy in women may lead to metabolic consequences in patients. This study was performed to determine the glucose tolerance and lipid profile after menopause resulting from bilateral salpingo oophorectomy. METHODS: From September 2011 to March 2013, 31 women participants aged 46-52 years who underwent hysterectomy and bilateral salpingo-oophorectomy for benign reasons were recruited. An oral glucose tolerance test (OGTT), triglyceride (TG), total cholesterol, low density lipoproteis (LDL), high density lipoprotein (HDL) was performed before and 6 months after surgery. Fasting insulin and 2-hour insulin levels, fasting insulin / glucose indexes and homeostasis model assessment HOMA indexes were also measured. RESULTS: The mean age of the patients was 48.6+/-2.9 years. The mean 2-h glucose level in OGTT changed from 26.7 before surgery to 111.1 uUnit/ml (P=0.030). The mean level of lipid profile before and after surgery for TG was 132.3 versus 181.2 mg/dl (P=0.005), total cholesterol 177.4 versus 206.7 mg/dl (P=0.0001) and LDL 98.4 versus 115.3 mg/dl (P=0.003). The other variables showed no significant difference. CONCLUSION: The results indicate that lipid profile changes like increase of TG, total cholesterol and LDL should be considered before removing the ovary during hysterectomy in premenopausal women. PMID- 24778789 TI - Nonspecific Interstitial pneumonia (NSIP)/ Overlap or Distinct Entity: A case report from the National Research Institute of Tuberculosis and Lung Disease (NRITLD). AB - BACKGROUND: In many cases of ILD (interstitial lung disease), overlap diagnosis is considered. Here, a few cases with diagnosis of a variety of ILDs, where eventual open lung biopsy has been performed are selected. Reference will be made to reliable sources to show that NSIP can still be a variant of UIP (Usual interstitial pneumonia) with better treatment response and prognosis. CASE PRESENTATION: In case 1, there is a difference between the HRCT(High Resolution Computed Tomography) result (NSIP pattern without fibrosis) and pathologic result (which includes fibrosing NSIP more closely related to UIP).Case 2 shows obvious discord between HRCT result (UIP pattern) and pathologic result (NSIP pattern). In case 3, there is again a discrepancy between HRCT report (very mild architectural distortion suggestive for ILD like NSIP) and pathology report (destructed lung tissue with interstitial fibrosis suggestive of HP (Hypersesitivity Pneumonitis) and not NSIP. CONCLUSION: In this paper, we demonstrate that although NSIP can be a distinct diagnosis in most cases, but in rare cases the distinction between the other kinds of ILD especially UIP and NSIP in spite of full workup including tissue assessment can be very difficult. PMID- 24778790 TI - Papillary fibroelastoma of a mitral valve chordae, presenting with atypical chest pain and palpitation: A case report and the literature. AB - BACKGROUND: Primary intra cardiac tumors are rare. In this article, we present papillary fibroelastoma of mitral valve chordae. CASE PRESENTATION: A 35-year old man presented with atypical chest pain and palpitation. Physical examination and electrocardiogram were normal. Transesophageal echocardiography (TEE) revealed a mass of 1015 mm attached to chordae of anteromedial papillary muscle of mitral valve. The tumor was completely resected and the mitral valve chordae tendineae was preserved successfully. The pathological diagnosis was papillary fibroelastoma. CONCLUSION: In any patient with atypical chest pain and palpitation, valvular tumor should be considered in differential diagnosis. PMID- 24778791 TI - Deep vein thrombosis as a rare complication of brucellosis. AB - BACKGROUND: Brucellosis can involve almost any organ system and may present with a broad spectrum of clinical presentations. In this study, we present a case of deep vein thrombosis due to human brucellosis. CASE PRESENTATION: A 15- year old boy presented with acute pain and swelling in his left thigh in June 2011, when he complained of fever, chills and lower extremity pain in which he could barely walk. In family history, his older brother had brucellosis 3 weeks ago and appropriate medication was given. The tubal standard agglutination test (wright test) and 2ME test were positive (in a titer of 1/1280 and 1/640, respectively). Peripheral venous doppler ultrasound of left lower extremity showed that common iliac, femoral, external iliac, superficial and deep femoral vein and popliteal vein were enlarged and contained with echogenous clot. He was treated with rifampicin 600 mg once a day, doxycycline 100 mg twice a day (both for three months) and amikacin 500 mg twice a day (for 2 weeks) accompanied with anti coagulant. Ten days after the onset of this treatment, thrombophlebitis was cured. The follow up of the patient showed no abnormality after approximately one year later. CONCLUSION: In brucellosis endemic areas, the clinicians who encounter patients with deep vein thrombosis and current history of a febrile illness, should consider the likelihood of brucellosis. PMID- 24778792 TI - Cycling performance decrement is greater in hypobaric versus normobaric hypoxia. AB - BACKGROUND: The purpose of this study was to determine whether cycling time trial (TT) performance differs between hypobaric hypoxia (HH) and normobaric hypoxia (NH) at the same ambient PO2 (93 mmHg, 4,300-m altitude equivalent). METHODS: Two groups of healthy fit men were matched on physical performance and demographic characteristics and completed a 720-kJ time trial on a cycle ergometer at sea level (SL) and following approximately 2 h of resting exposure to either HH (n = 6, 20 +/- 2 years, 75.2 +/- 11.8 kg, mean +/- SD) or NH (n = 6, 21 +/- 3 years, 77.4 +/- 8.8 kg). Volunteers were free to manually increase or decrease the work rate on the cycle ergometer. Heart rate (HR), arterial oxygen saturation (SaO2), and rating of perceived exertion (RPE) were collected every 5 min during the TT, and the mean was calculated. RESULTS: Both groups exhibited similar TT performance (min) at SL (73.9 +/- 7.6 vs. 73.2 +/- 8.2), but TT performance was longer (P < 0.05) in HH (121.0 +/- 12.1) compared to NH (99.5 +/- 18.1). The percent decrement in TT performance from SL to HH (65.1 +/- 23.6%) was greater (P < 0.05) than that from SL to NH (35.5 +/- 13.7%). The mean exercise SaO2, HR, and RPE during the TT were not different in HH compared to NH. CONCLUSION: Cycling time trial performance is impaired to a greater degree in HH versus NH at the same ambient PO2 equivalent to 4,300 m despite similar cardiorespiratory responses. PMID- 24778793 TI - Structural Reinforcement of Cell-Laden Hydrogels with Microfabricated Three Dimensional Scaffolds. AB - Hydrogels commonly used in tissue engineering are mechanically soft, thus often display structural weakness. Herein, we introduce a strategy for enhancing the structural integrity and fracture toughness of cell-laden hydrogels by incorporating a three-dimensional (3D) microfabricated scaffold as a structural element. A digital micromirror device projection printing (DMD-PP) system, a rapid prototyping technology which employs a layer-by-layer stereolithographic approach, was utilized to efficiently fabricate 3D scaffolds made from photocrosslinkable poly(ethylene glycol) diacrylate (PEGDA). The scaffold was incorporated into a photocrosslinkable gelatin hydrogel by placing it in a pre gel solution, and inducing in situ hydrogel formation. The resulting scaffold reinforced hydrogels demonstrated significant increase in ultimate stress and provided structural support for weak hydrogels. In addition, the scaffold did not affect the rigidity of hydrogels, as it was not involved in the crosslinking reaction to form the hydrogel. Therefore, the presented approach could avoid inadvertent and undesired changes in the hydrogel rigidity which is a known regulator of cellular activities. Furthermore, the biocompatibility of scaffold reinforced hydrogels was confirmed by evaluating the viability and proliferation of encapsulated fibroblasts. Overall, the strategy of incorporating 3D scaffolds into hydrogels as structural reinforcements presented in this study will be highly useful for enhancing the mechanical toughness of hydrogels for various tissue engineering applications. PMID- 24778794 TI - MRI-guided laser ablation of neuroendocrine tumor hepatic metastases. AB - BACKGROUND: Neuroendocrine tumors (NET) represent a therapeutically challenging and heterogeneous group of malignancies occurring throughout the body, but mainly in the gastrointestinal system. PURPOSE: To describe magnetic resonance imaging (MRI)-guided laser ablation of NET liver metastases and assess its role within the current treatment options and methods. MATERIAL AND METHODS: Two patients with NET tumor hepatic metastases were treated with MRI-guided interstitial laser ablation (LITT). Three tumors were treated. Clinical follow-up time was 10 years. RESULTS: Both patients were successfully treated. There were no local recurrences at the ablation site during the follow-up. Both patients had survived at 10-year follow-up. One patient is disease-free. CONCLUSION: MRI-guided laser ablation can be used to treat NET tumor liver metastases but combination therapy and a rigorous follow-up schedule are recommended. PMID- 24778795 TI - Pneumonia occurring after injection of Lipiodol to localize pulmonary nodules before fluoroscopy-aided thoracoscopic resection. AB - We report the case of a 33-year-old man with a testicular tumor and multiple lung metastases. After high orchiectomy, chemotherapy was administered. Subsequently, fluoroscopy-assisted thoracoscopic resection was performed for pulmonary lesions that had decreased in size after the chemotherapy but had persisted. Because four pulmonary lesions were too small to detect by fluoroscopy during the operation, Lipiodol marking was done before thoracoscopic resection. Sixteen days after the surgery, pneumonia after Lipiodol injection occurred on the lung contralateral to that injected with Lipiodol. Pneumonia improved rapidly after intravenous infusion of antibiotics. PMID- 24778796 TI - Arterial spin labeling perfusion-weighted MRI for long-term follow-up of a cerebral arteriovenous malformation after stereotactic radiosurgery. AB - We present a longitudinal series of arterial spin-labeling magnetic resonance imaging (ASL-MRI) in a patient with cerebral arteriovenous malformations (AVMs) treated by stereotactic radiosurgery (SRS). Pretreatment ASL-MRI showed high signal intensity in both the nidus and draining veins, and the latter signal abnormality gradually moved proximally by 14 months after SRS. At 24 months, the signal abnormalities finally disappeared, indicating complete obliteration of the nidus. The hemodynamic changes in the AVM were clearly visualized in the longitudinal ASL-MRI series, thus this non-invasive MR method may be useful not only for detecting AVMs but also for assessment of their response after SRS. PMID- 24778797 TI - Xanthogranulomatous pyelonephritis mimicking a renal cell carcinoma: a unique and challenging case. AB - We describe an unusual case of xanthogranulomatous pyelonephritis (XGPN) in a 73 year-old woman diagnosed after a blunt abdominal trauma. This case is unique because of the atypical presentation, with absence of symptoms, normal laboratory exams, and unusual computed tomography and magnetic resonance imaging findings. The patient underwent radical nephrectomy because a renal cystic tumor was suspected. Only the histopathological findings suggested the final diagnosis of XGPN. PMID- 24778798 TI - Imaging findings in uncorrected tetralogy of Fallot and pulmonary atresia with major aortopulmonary collateral arteries and septic embolism. AB - Tetralogy of Fallot (TOF) is one of the most common congenital heart malformations comprising a ventricular septal defect, right ventricular outflow tract obstruction, right ventricular hypertrophy, and overriding aorta. A rare variant includes pulmonary atresia and major aortopulmonary collateral arteries. Altered hemodynamics within the functional single-ventricle results in turbulent flow and predisposes to endocardial vegetation formation which may consequently lead to thromboembolic events. We present a rare case of an adult survivor of uncorrected TOF with pulmonary atresia. PMID- 24778799 TI - Malignant peripheral nerve sheath tumor of the distal phalanx of the fifth toe: a case report. AB - Malignant peripheral nerve sheath tumor (MPNST) involving bone is rare. We report a case of MPNST of the fifth toe. The lesion was located in the distal phalanx of the right fifth toe and extended into surrounding subcutaneous tissues. Findings on magnetic resonance imaging and histological features of the case are described and the literature is briefly reviewed. PMID- 24778800 TI - Latissimus dorsi free flap reconstruction of major abdominal defect in treatment of giant Marjolin's ulcer: a short report focused on preoperative imaging. AB - We present a case of a 56-year-old man with a giant carcinoma in the abdominal wall. Based on positron emission tomography/computed tomography (PET/CT) scan there were FDG-avid lymph nodes in the ipsilateral axillary and groin, suspicious for metastases. At contrast-enhanced CT the parietal peritoneum seemed free of tumor invasion, which was essential to radical surgery planning. The tumor was completely removed with clear margins of resection and no metastasis in the resected lymph nodes. The PET/CT scan was repeated after 4 months, showing no signs of recurrence. PMID- 24778801 TI - Endovascular recanalization techniques for popliteal arterial occlusive injury with limb-threatening ischemia secondary to trauma. AB - To date, no ideal endovascular strategy has been established for traumatic arterial occlusion. Here, we report the outcomes of a combination of endovascular recanalization techniques applied in two patients with high risk of leg amputation. A 33-year-old man with popliteal artery occlusion due to blunt trauma was treated by balloon angioplasty with long inflation time and aspiration thrombectomy. A 74-year-old woman with popliteal artery occlusion after total knee replacement was treated by aspiration thrombectomy and stent placement. In both cases, we achieved satisfactory recanalization, and peripheral ischemia was absent even 1 year later. PMID- 24778802 TI - Pulmonary intimal sarcoma: a rare differential diagnosis for arterial filling defects on a chest CT. AB - We present a rare case of pulmonary intimal sarcoma mimicking pulmonary embolism in a 40-year-old woman. Although extremely rare, these tumors must be considered in patients who present inappropriate imaging findings that suggest embolism. Chest computed tomography is the modality of choice to determine the extent of the tumor. We present a female patient with suspected embolism that was in fact found to be an endothelial sarcoma of the pulmonary arteries. PMID- 24778803 TI - Mandibular tori as an incidental finding in MRI. AB - TORI (SINGULAR: torus) are among the most common benign jaw lesions. The magnetic resonance imaging (MRI) characteristics have not been reported yet. We present a 72-year-old patient with mandibular tori, which were detected as an incidental finding on MRI and provide an overview of the imaging features of tori. PMID- 24778804 TI - Rare diagnosis of nodular lymphangitis caused by Mycobacterium marinum: MDCT imaging findings. AB - Mycobacterium marinum is an atypical mycobacterium that usually causes a solitary nodule on the hand ("fish tank granuloma") or less commonly, secondary erythematous channels and nodules spread along lymphatic drainage of the extremity, mimicking sporothricoid skin lesions of nodular lymphangitis. This report presents a case of this rare entity, a nodular lymphangitis caused by Mycobacterium marinum. Multidetector computed tomography (MDCT) imaging was very useful in determining the morphology (cellulitis with a few small subcutaneous nodules and channels) and the extension of the lesion. PMID- 24778805 TI - Magnetic resonance imaging in acute mastoiditis. AB - BACKGROUND: In cases of suspected mastoiditis, imaging is used to evaluate the extent of mastoid destruction and possible complications. The role of magnetic resonance imaging (MRI) in mastoiditis has not been systematically evaluated. PURPOSE: To assess the diagnostic performance of MRI in patients with suspected acute mastoiditis. MATERIAL AND METHODS: Twenty-three patients with suspected acute mastoiditis were included in this retrospective study (15 boys, 8 girls; mean age, 2 years 11 months). All patients were examined on a 1.5 T MRI system. The MRI examination included both enhanced and non-enhanced turbo spin echo (TSE), diffusion-weighted images, and venous time-of-flight magnetic resonance angiography (TOF MRA) for the evaluation of the venous sinuses. Surgical findings, as well as clinical and imaging follow-up were used as the standard of reference. The sensitivity and accuracy of MRI for mastoiditis and subperiosteal abscesses was calculated. RESULTS: Twenty (87%) of 23 patients had mastoiditis, and 12 (52%) of 23 patients had a subperiosteal abscess in addition to mastoiditis. Mastoiditis and subperiosteal abscesses were identified by MRI in all cases. Sensitivity for mastoiditis was 100%, specificity was 66%, and accuracy was 86%. Sensitivity for subperiosteal abscesses was 100% and accuracy was 100%. CONCLUSION: Multiparametric MRI has high accuracy for mastoiditis and subperiosteal abscesses. PMID- 24778806 TI - Retroperitoneal fibromatosis presenting as a presacral mass. AB - Aggressive fibromatosis arising from the retroperitoneum is extremely rare. It may occur in association with previous trauma, abdominal surgery, drugs, Gardner's syndrome, or familial adenomatous polyposis. We report a case of retroperitoneal fibromatosis presenting as a presacral mass with an infiltrating nature, relatively intense enhancement on enhanced computed tomography scanning, and low-signal intensity on T2-weighted magnetic resonance imaging in a patient with no significant medical or surgical history. PMID- 24778807 TI - Abdominopelvic actinomycosis: spectrum of imaging findings and common mimickers. AB - BACKGROUND: Actinomycosis is a rare suppurative disease that may mimic other inflammatory conditions on imaging. Its invasive nature may lead to mass formation and atypical presentation thus making accurate diagnosis quite difficult. PURPOSE: To describe the different aspects of abdominopelvic actinomycosis on cross-sectional imaging and indicate discriminative findings from other inflammatory or neoplastic diseases. MATERIAL AND METHODS: In our study we analyzed 18 patients (15 women, 3 men; age range, 25-75 years; mean age, 50 years) with pathologically proved abdominopelvic actinomycosis. Contrast enhanced abdominal computed tomography (CT) had been performed in all patients. Eleven patients had a history of using intrauterine contraceptive devices. Bowel site, wall thickness and enhancement degree, inflammatory infiltration, and features of peritoneal or pelvic mass were evaluated at CT. RESULTS: The sigmoid colon was most commonly involved. Most patients showed concentric bowel wall thickening, enhancing homogenously and inflammatory infiltration of pericolonic fat was mostly diffuse. In 11 patients, one or more pelvic abscesses were revealed, while a peritoneal or pelvic mass adjacent to the involved bowel segment was seen in three cases. Infiltration into the abdominal wall was seen in three cases while in one case there was thoracic dissemination. CONCLUSION: Actinomycosis is related not only to long-term use of intrauterine contraceptive devices and should be included in the differential diagnosis when cross-sectional imaging studies show concentric bowel wall-thickening, intense contrast enhancement, regional pelvic or peritoneal masses, and extensive inflammatory fat infiltration with abscess formation. PMID- 24778808 TI - The Effect of Residual Endotoxin Contamination on the Neuroinflammatory Response to Sterilized Intracortical Microelectrodes. AB - A major limitation to the use of microelectrode technologies in both research and clinical applications is our inability to consistently record high quality neural signals. There is increasing evidence that recording instability is linked, in part, to neuroinflammation. A number of factors including extravasated blood products and macrophage released soluble factors are believed to mediate neuroinflammation and the resulting recording instability. However, the roles of other inflammatory stimuli, such as residual endotoxin contamination, are poorly understood. Therefore, to determine the effect of endotoxin contamination we examined the brain tissue response of C57/BL6 mice to non-functional microelectrodes with a range of endotoxin levels. Endotoxin contamination on the sterilized microelectrodes was measured using a limulus amebocyte lysate test following FDA guidelines. Microelectrodes sterilized by autoclave, dry heat, or ethylene oxide gas, resulted in variable levels of residual endotoxins of 0.55 EU/mL, 0.22 EU/mL, and 0.11 EU/mL, respectively. Histological evaluation at two weeks showed a direct correlation between microglia/macrophage activation and endotoxin levels. Interestingly, astrogliosis, neuronal loss, and blood brain barrier dysfunction demonstrated a threshold-dependent response to bacterial endotoxins. However, at sixteen weeks, no histological differences were detected, regardless of initial endotoxin levels. Therefore, our results demonstrate that endotoxin contamination, within the range examined, contributes to initial but not chronic microelectrode associated neuroinflammation. Our results suggest that minimizing residual endotoxins may impact early recording quality. To this end, endotoxins should be considered as a potent stimulant to the neuroinflammatory response to implanted intracortical microelectrodes. PMID- 24778809 TI - Combinatorial delivery of immunosuppressive factors to dendritic cells using dual sized microspheres. AB - Microparticulate systems are beginning to show promise for delivery of modulatory agents for immunotherapeutic applications which modulate dendritic cell (DC) functions. Co-administration of multiple factors is an emerging theme in immune modulation which may prove beneficial in this setting. Herein, we demonstrate that localized, controlled delivery of multiple factors can be accomplished through poly (lactic-co-glycolic acid) (PLGA) microparticle systems fabricated in two size classes of phagocytosable and unphagocytosable microparticles (MPs). The immunosuppressive ability of combinatorial multi-factor dual MP systems was evaluated by investigating effects on DC maturation, DC resistance to LPS mediated maturation and proliferation of allogeneic T cells in a mixed lymphocyte reaction. Phagocytosable MPs (~2 MUm) were fabricated encapsulating either rapamycin (RAPA) or all-trans retinoic acid (RA), and unphagocytosable MPs (~30 MUm) were fabricated encapsulating either transforming growth factor beta-1 (TGF beta1) or interleukin-10 (IL-10). Combinations of these MP classes reduced expression of stimulatory/costimulatory molecules (MHC-II, CD80 and CD86) in comparison to iDC and soluble controls, but not necessarily to single factor MPs. Dual MP-treated DCs resisted LPS-mediated activation, in a manner driven by the single factor phagocytosable MPs used. Dendritic cells treated with dual MP systems suppressed allogeneic T cell proliferation, generally demonstrating greater suppression by combination MPs than single factor formulations, particularly for the RA/IL-10 MPs. This work demonstrates feasibility of simultaneous targeted delivery of immunomodulatory factors to cell surface receptors and intracellular locations, and indicates that a combinatorial approach can boost immunoregulatory responses for therapeutic application in autoimmunity and transplantation. PMID- 24778810 TI - A comparison of endoscopic ultrasound guided biopsy and positron emission tomography with integrated computed tomography in lung cancer staging. AB - BACKGROUND AND STUDY AIMS: Exact staging of patients with non-small-cell lung cancer (NSCLC) is important to improve selection of resectable and curable patients for surgery. Positron emission tomography with integrated computed tomography (PET/CT) and endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) are new and promising methods, but indications in lung cancer staging are controversial. Only few studies have compared the 2 methods. The aim of this study was to assess and compare the diagnostic values of PET/CT and EUS FNA for diagnosing advanced lung cancer in patients, who had both procedures performed. PATIENTS AND METHODS: 27 patients considered to be potential candidates for resection of NSCLC underwent PET/CT and EUS-FNA. Diagnoses were confirmed either by open thoracotomy, mediastinoscopy or clinical follow-up. Advanced lung cancer was defined as tumour-stage >= IIIA(N2), corresponding to T4 and/or N2-N3- and/or M1 disease. Diagnostic values of PET/CT and EUS-FNA, with regard to the diagnosis of advanced lung cancer, were assessed and compared. RESULTS: The sensitivity of PET/CT and EUS-FNA were respectively 60% and 60% for T4 disease, 56% versus 100% for N2-N3 disease (p=0.12) and 100% versus 33% for M1 disease (p=0.50). For diagnosing advanced lung cancer PET/CT had a sensitivity of 79%, specificity of 61%, positive predictive value (PPV) of 69%, negative predictive value (NPV) of 73%, and an accuracy of 70%. EUS-FNA had a sensitivity of 79%, specificity of 100%, PPV of 100%, NPV of 81%, and an accuracy of 89% for advanced lung cancer. CONCLUSIONS: PET/CT and EUS-FNA had a comparable sensitivity and NPV for diagnosing advanced lung cancer, but EUS-FNA had superior specificity and PPV. The two methods seem to complement each other. PMID- 24778811 TI - Diagnosis Performance of Different MR Imaging Signs of Cirrhosis: the Caudate to Right Lobe Ratio, the Posterior Right Hepatic Notch, and the Expanded Gallbladder Fossa. AB - Background & Aims The purpose of the study is to evaluate the accuracy of the C/RL, RPN, and EGF in diagnosing cirrhosis. Methods The study population included 95 cirrhotic patients in the cirrhosis group (56 men, 39 women, age range 14 76;mean age 52.3) and 57 subjects in the control group (26 men, 31 women, age range 18-83;mean age 51). All MR examinations were performed by using the same protocol. Two radiologists independently assessed data sets in two different reading sessions. The sensitivity, specificity, and accuracy and the relative risk of the signs in diagnosing cirrhosis were calculated. The diagnosis accuracy of the C/RL sign was calculated using the ROC curve. The statistical significance of any difference of each sign between different classes of cirrhosis was also calculated. Results The interobserver agreement between the readers was excellent (kappa>= 0.81;95% CI:0.92, 1.0). There was a significant statistical difference of the diagnostic value of C/RL, RPN, and EGF between cirrhotic patients and control group (p<0.001). The sensitivity, specificity, and accuracy of C/RL were 72%, 87%, and 78%; 67%, 87%, and 75% for RPN; and 49%, 91%, and 65% for EGF. C/RL (OR=18.95) and RPN (OR=14.74) showed a higher risk for cirrhosis compared to EGF (OR=14.74). There was a statistical significance difference between C/RL and EGF (p=0.002) and between RPN and EGF for Child A class of cirrhosis (p-0.037). Conclusion The C/RL and RPN have similar performance regarding the diagnosis of cirrhosis having a higher diagnostic performance compared to EGF in cirrhosis. PMID- 24778812 TI - Imaging of avascular necrosis of femoral head: familiar methods and newer trends. AB - Avascular necrosis of the femoral head (AVN) is an increasingly common cause of musculoskeletal disability, and it poses a major diagnostic and therapeutic challenge. Although patients are initially asymptomatic, AVN usually progresses to joint destruction, requiring total hip replacement, usually before the fifth decade. Avascular necrosis is characterized by osseous cell death due to vascular compromise. Avascular necrosis of bone results generally from corticosteroid use, trauma, pancreatitis, alcoholism, radiation, sickle cell disease, infiltrative diseases (e.g. Gaucher's disease), and Caisson disease. The most commonly affected site is the femoral head and patients usually present with hip and referred knee pain. The aim of diagnostic imaging procedures in avascular femoral head necrosis is to provide the patient with a stage-adapted therapy. Therefore, a differentiated diagnostic work-up is needed. Native radiography of the hip in two planes is still the first step. Over the past years, the diagnosis of femoral head necrosis has experienced tremendous improvement due to the use of MRI and CT scans. Because of these improvements the correct stage can be diagnosed early and the appropriate therapy can be initiated immediately. Today, MRI is the most sensitive diagnostic imaging procedure. CT scans can be particularly useful to exclude subchondral fractures. The use of bone scintigraphy is restricted to exceptional cases. In Europe, the ARCO classification of avascular femoral head necrosis has been widely accepted. In this overview, we describe the specific characteristics of the different diagnostic imaging procedures and illustrate them with appropriate imaging material. PMID- 24778813 TI - Assessment of Extracorporeal Shock Wave Lithotripsy (ESWL) Therapeutic Efficiency in Urolithiasis. AB - Extracorporeal shock wave lithotripsy (ESWL) revolutionized the treatment of urolithiasis and gradually became the favorite treatment option so that today it is considered to be the first line of treatment for more than 75% of the patients with urolithiasis. The purpose of this study was the assessment of the therapeutic efficiency, complications and limitations of ESWL in urolithiasis in the initial experience using a third generation electromagnetic lithotripter. Between 2007 and 2008 we performed ESWL for 167 patients with urolithiasis. We recorded 92 patients with single stone (55.1%) and 72 with multiple lithiasis (44.9%). Stone size varied between 7 and 24 mm with an average of 12.3+/-7.1 mm. Radioopac stones were found in 104 patients (62.3%) while radiolucent stones in 63 only (37.6%). Complete stone disintegration and clearance was achieved in most cases (86.2%). Complications were mostly minor and rare (transitory haematuria, renal colic). Severe complications (renal hematoma, steinstrasse) were diagnosed for a limited number of patients (3.6%) and their management was mostly nonsurgical or minimally invasive (retrograde ureteroscopy). ESWL is therefore the first line of treatment for urolithiasis with stone size smaller than 2.5 cm. It has an efficiency rate above 85%, low procedure time, high safety and good tolerability (new generation lithotripters do not require anesthesia) and minimal complications. PMID- 24778814 TI - Contributions on the study of the compressive strength of the light-cured composite resins. AB - The mechanical properties of the light-cured composite resins are related to the material composition, but also vary according to the light-source characteristics used for polymerization. In this study we followed the compressive strength variation for a light-cured composite resin according to the time of exposure to the curing light. With that end in view,18 test pieces were made from a light cured hybrid composite material (Filtek Z250). The test pieces where then submitted to a compressive force by a mechanical properties universal testing machine. Our results didn't show an increase of the compressive strength according to the light-curing time increasing, than only in the light-curing time limit indicated by the manufacturer. A longer light-curing time may induce a shrinkage polymerization growth with the formation of internal tensions inside the material. The composite materials light-curing in short layers as long as there is indicated by the manufacturer seems to be a safer method to make the best from a resin qualities, then an exaggerated increase of the light-curing time. The light-curing is indicated to be done in the direction of the compressive forces. To confirm this supposition other mechanical tests are also necessary. PMID- 24778815 TI - Endoscopic papillectomy into the treatment of neoplastic lesions of vater papilla. AB - Adenomas of the duodenal papilla are rare. The frequency of malignant adenomas is 15-30%. Villous adenoma is a premalignant lesion with the highest rate of transformation. Options for surgical treatment include endoscopic and ablation resection, transduodenal ampullectomy, duodeno-pancreatectomy. AIM: Evaluation of the efficacy and safety of endoscopic papillectomy for ampullary adenomas. MATERIAL AND METHOD: 12 patients were selected (F:M, 5:7, age range 37 - 68 years) with ampullary adenoma, treated by endoscopic papillectomy. Biliary sphincterotomy was performed in 6 cases; and pancreatic sphincterotomy was performed in 3 cases. Biliary stenting was performed in 2 cases; pancreatic stent was placed in 11 cases. RESULTS: En bloc resection was performed in 8 cases, and piecemeal resection in 4 cases. Complete resection R0 was noted in 10 cases. Pathology examination has show: tubulo-villous adenoma (5 patients); villous adenoma (4 patients), tubular adenoma (2 cases), adenocarcinoma (one case). Complications were immediate: bleeding (2 cases) and pancreatitis (1 case). Follow-up endoscopy reveals no ductal stenosis or recurrence. CONCLUSION: Endoscopic papillectomy is a safe and well-tolerated alternative to surgical treatment of ampullary adenoma. PMID- 24778816 TI - Clinical and Morphological Aspects of Warthin's Tumor. AB - The study includes 16 cases of Warthin's tumor in a period of 4 years (2004 2008). The tumors were diagnosed at patients of VII decade, most of them smoker. The studies of Warthin's tumor macroscopic morphological parameters allow us to establish the localization exclusive at parotid glands like solitary tumor and the tumoral volume oscillate mostly between 2-4 cm in diameter. Histopathologically we notice the prevalence of typical tumor forms, with balanced raport epithelium / stroma. In this study we have found in 10 cases typical forms, in 4 cases the prevalence of epithelium component and in 2 cases the prevalence of stroma component. PMID- 24778817 TI - Subdeltoideus bursitis manifested as gigantic cystic supraclavicular and lateralcervical tumour. AB - The authors present a case of a left gigantic supraclavicular and lateralcervical tumor with rapid growth, which has turned out to be a subdeltoideus bursitis. PMID- 24778818 TI - The differential diagnosis of chronic pancreatitis. AB - BACKGROUND Chronic pancreatitis is an inflammatory disease of the pancreas with a physiopathology that is yet to be fully understood, with a multifactorial etiology, of which alcohol abuse causes the majority of cases. PATIENTS AND METHOD We included 80 patients diagnosed with chronic pancreatitis, admitted in the Gastroenterology Clinic of the University of Medicine and Pharmacy Craiova. In each patient, demographic parameters, family and personal history were recorded. All patients were initially evaluated by transabdominal ultrasound. In selected cases other imagistic methods were used: computed tomography, endoscopic ultrasound with fine needle aspiration, endoscopic retrograde cholangiopancreatography. RESULTS The mean age in the studied group ranged between 26 and 76 years with a mean age of 52.9 years. The male to female ratio was 3.6:1. The most frequent presenting symptom was abdominal pain (93.75%), followed by fatigue (70%), anorexia (50%); fewer patients presented with emesis, loss of weight, diarrhea, meteorism and flatulence. The most frequent etiologic factor of chronic pancreatitis in the studied group was alcohol abuse. Using imaging methods the following complications of chronic pancreatitis were diagnosed in the studied group: complicated or uncomplicated pseudocysts (31.57%), pancreatic cancer (18.75%), obstructive jaundice (10%), segmental portal hypertension (2.5%), and pseudoaneurysm (1.25%).CONCLUSSIONS Transabdominal ultrasound is quite accurate in diagnosing chronic pancreatitis and its morbidities and its non-invasiveness makes it the method of choice in the initial assessment of the disease. EUS has the advantage of visualizing not just the modifications of the pancreatic ducts, but also the parenchyma. Moreover, it can be used as EUS-FNA in order to increase the sensitivity of the differential diagnosis between pseudotumoral chronic pancreatitis and pancreatic cancer. PMID- 24778819 TI - Immunohistochemical evaluation of hormone receptors with predictive value in mammary carcinomas. AB - AIMS. Immunohistochemical evaluation of hormone receptors (ER, PR) and correlation of immunohistochemical and morpho-clinical data. METHOD. The study was performed on paraffin-embedded and HE stained tissues originating from 100 cases of invasive mammary carcinoma. Monoclonal antibodies anti-estrogen and anti progesterone receptors were used for the immunohistochemical study. The detection system was EnVision HRP and the visualization system was 3-3' diaminobenzidine tetrahydrochloride (DAB). The evaluation of the result was performed using the Allred score. REZULTS. The majority of the studied cases (57%) expressed both types of hormone receptors and in 32% of the cases the hormone receptors were completely absent. The rest of the cases presented a heterogeneous phenotype: 7% presented the ER-/PR+ type and 4%, the ER+/PR- type. Compared with the classical phenotype (ER+/PR-), ER+/PR- tumors were more frequent at patients over 50 years. The tumors with ER+/PR- were larger than the ER+/PR+ and they were of the invasive ductal carcinoma type with an Allred score for ER under 6. CONCLUSION. The predictive value is amplified when the ER status is correlated with the PR status because the heterogeneous phenotypes are identified, especially the ER+/PR phenotype which have an aggressive behavior and the lowest response to tamoxifen therapy. PMID- 24778820 TI - Pseudomyxoma peritonei. AB - The authors report a case of a 60 years old Romanian male with peritoneal pseudomyxoma that was discovered to have a primary location in the greater omentum. Pseudomyxoma peritonei arising into the greater omentum is very rare. It is an original case report and the new data represents a well-balanced summary of a timely subject, with reference to the literature. This it is a significantly advance in our understanding of a particular disease etiology. Until now, only a few primary greater omentum pseudomyxoma peritonei have been described. Clinical and pathologic findings of this case are presented and the topic of primary location in the great omentum of pseudomyxoma peritonei was reviewed. Preoperative ultrasound examination showed the presence of an "eyes of net" tumoral-mass formation, in the greater omentum, and a fluid collection was found in the abdomen (Morrison space and the pouch of Douglas). Notwithstanding, diagnosis of pseudomyxoma was preoperatively considered less probable due to the rarity of the affection and the advanced age. During laparotomy, the presence of the large mass observed at the ultrasound examination was revealed. Mucinous ascites was present with invasive mucinous implants in the peritoneum and in the greater omentum. Operation consisted in the total removal of the mass followed by evacuation of the mucinous ascites. Histological examination confirmed the clinical diagnosis of pseudomyxoma peritonei. PMID- 24778821 TI - EUS Elastography in Evaluating Chronic Liver Disease. Why not from Inside? AB - Fibrosis is the liver's scarring response to injury, culminating in cirrhosis and its complications. Percutaneous liver biopsy with connective tissue stain is considered more likely a ''silver'', rather than a ''gold standard'' for assessing the degree of hepatic fibrosis. That's why new modalities were recently developed to accurately assess the stage of the liver disease. The term ''elastography'' describes an imaging technique that conveys information about a tissue's relative firmness in response to compression, meaning it is more akin to palpation than inspection. Real-time transabdominal elastography represents a new technology for measurement of tissue elasticity integrated in ultrasound systems and can be performed with conventional ultrasound probes during a routine sonography examination. Some of its limitations are that it cannot explore neither all the patients, nor a sufficient size of the liver. In order to overcome these, now that the technology exists, we propose an endoscopic approach from the "inside". PMID- 24778822 TI - Basal cell carcinomas - clinical-evolutional and histopahotologic aspects. AB - Basal cell carcinoma (BCC) is the most frequent cutaneous tumour. Having as aim the identification of the clinical-evolutional and histopathologic aspects of the basal cell carcinomas, we have undertaken a retrospective study for a period of 5 years, from 1st January 2004 to 31st December 2008, on 706 patients interned in the Dermatology Clinic of Craiova, whom indicated 738 tumours. A clinical data was drawn for the patients, containing the identification data, environment, profession, cancer localisation and history of the disease, clinical and histopathologic diagnosis. Results. In our lot, the most numerous cases were of pearly BCC (33.6%), nodular BCC (22.2%), respectively scar plane BCC (13.1%).Regarding the histopathologic type, the repartition was as it follows: solid BCC (33.7%), polymorph (19.2%), adenoid (13.1%), keratinised (11.8%), superficial (7.0%), cystic (3.8%), pigmented (3.8%), scleroderma form (2.2%), in situ (1.4%). PMID- 24778823 TI - Dissolution of pentoxifylline from extended release formulations. Researches concerning development of a biorelevant test. AB - This paper presents results of a pharmacokinetics study concerning pentoxifylline and its main metabolites after administration of extended release formulation of Trental 400 mg and correlation of this pharmacokinetics with in vitro dissolution test results of parent drug. In order to establish most relevant in vitro test, dissolution was performed in different experimental conditions (stirring rate and dissolution medium). Correlation was linear and very good. Generalization of correlation to rate of appearance of metabolites in plasma proved that this process could be well correlated with dissolution. Most relevant test was finally found to be the release in water medium, in conditions of a high stirring rate - 100 rpm. PMID- 24778825 TI - Neuroendocrine differentiation in prostate adenocarcinoma biopsies and its correlation to histological grading. AB - Prostate adenocarcinoma is frequently diagnosed on needle biopsies in early, organ-confined stages. New prognostic factors would help identifying at this stage patients at risk for unfavorable evolution, that would benefit from alternate therapy. This study aims to find correlations between the extent of neurocrine differentiation (NED), a feature commonly seen in prostate carcinoma, and known factors of disease evolution such as histological grade, malignant cell proliferation and serum PSA levels. Immunohistochemistry for choromogranin A and neuron-specific enaolase (NSE) was used to calculate expression scores in order to asses the extent of NED in prostate biopsies. Tumour proliferative activity was estimated by calculating percentages of Ki-67 immunoreactive cell nuclei. Results show that the presence of numerous clusters of chromogranin A positive cells is a feature that differentiate tumours with Gleason score 9 from those with a score of 6. Also, the same extended neuroendocrine differentiation is associated with high tumour proliferative activity. Multinomial regression analysis showed that high Ki indices, serum PSA values and NSE scores are predictive for moderately and poorly differentiated prostatic adenocarcinoma. PMID- 24778824 TI - Cytological and histopathological aspects concerning preinvasive squamous cervical lesions. AB - Our study was carried out on a total number of 158 patients, with a mean age of 32, all tested and identified cytologically (Pap-test) as presenting minor cellular abnormalities, respectively ASCUS (10) and LSIL (119), and major cellular abnormalities, respectively SIL-borderline (8) and HSIL (21), and who, either voluntarily or upon cytopathologists' recommendation, were colposcopically examined. Subsequently, they were subjected to cervical biopsy or excision therapy. In patients with ASCUS cytology, 6 cases were morphologically diagnosed with benign cervical lesions, 3 were diagnosed with LSIL, and one patient was diagnosed as HSIL (CIN 2). Out of 119 LSIL smears 108 were confirmed by histopathology, while 11 were diagnosed as HSIL (CIN 2). In SIL-borderline patients, 5 cases were screened as LSIL and 3 as HSIL. In patients with HSIL cytology, 18 were diagnosed histopathologically as HSIL (CIN 2 and CIN 3/CIS), while 3 were diagnosed as invasive squamous carcinoma. PMID- 24778826 TI - Study of nimesulide release from solid pharmaceutical formulations in tween 80 solutions. AB - Nimesulide is a weakly acidic non-steroidal anti-inflammatory drug (NSAIDs). Like many non-steroidal anti-inflammatory drugs, Nimesulide is very sparingly soluble in water (~ 0.01 mg/mL).The poor aqueous solubility and wettability of Nimesulide gives rise to difficulties in pharmaceutical formulations for oral or parenteral delivery, which may lead to variable bioavailability. Based on the Biopharmaceutical Classification System (BCS), Nimesulide is considered a BCS 2 drug (poorly soluble and highly permeable). Solubilization in surfactant solutions above critical micelle concentration (CMC) offers one approach to the formulation of poorly soluble drugs. Weakly acidic and basic drugs may be brought into solution by the solubilizing action of surfactants. In this study, different concentrations of Tween 80 was used in combination with buffer (pH 7.4) to increase the solubility of Nimesulide. The results show that the dependence of the released amount on the Tween concentration is not linear, very low Tween concentration showing a decrease of "solubility", probably connected to a critical micelle concentration at the interface Nimesulide solution. An "analytical" artefact connected to a decreasing ultraviolet absorption of Nimesulide because of Nimesulide precipitation, the formation of a colloidal solution is possible, and the phenomenon remains to be searched further. It is hard to explain that for an almost complete solubilization a significant Tween quantity is necessary and this should be more than that of other slightly soluble drugs. PMID- 24778827 TI - Colposcopic evaluation of neoplasic and preneoplasic lesions of the cervix - a retrospective study. AB - Based on observation sheets and the existing database in Obstetrics - Gynecology Department, we reviewed the outcome for patients diagnosed with neoplasic and preneoplasic lesions of the cervix that were examined in our clinic. Colposcopic diagnosis efficiency was analyzed retrospectively reported to the histopathologic diagnosis and to the results of other studies. Our results were similar to those presented in international literature, showing a carefull evaluation of cervical lesions in our colposcopy department. PMID- 24778828 TI - Simoultaneuos occurence of other diseases among prison inmates with tuberculosis. AB - Prison populations are considered to be at high risk for tuberculosis infections, and many of the cases encountered have initiated while the individuals were in prison. There are also studies that have estimated the occupational risk of exposure and infection for hospital-based and correctional healthcare workers. To our knowledge, data on the incidence and risk factors associated with tuberculosis are very scanty in Romania, and therefore the aim of this study was to determine the prevalence and associated risk factors for this infections among a sample of prison inmates stationed at Colibasi Hospital Prison. PMID- 24778829 TI - Occlusal screening as basis for the integration of conjunct gnato-prosthetic devices. AB - The functional disorders of the masticator apparatus impose the accomplishment of a phased assessment protocol which should permit the marking out and prefigure the future treatment plan, at the same time. The association of clinical data with therapeutic options and last but not least with the patient's "expectations" represent a particularly important stage within the final occlusal and aesthetic integration. In order to analyse the data collected through examination various assessment systems are available nowadays which permit the correlation of symptoms identified with adequate diagnoses. The planning of the therapy on the basis of clinical registrations associated with the challenges of the bio aesthetics shall impose a new conduct within the orofacial rehabilitation of patients. PMID- 24778830 TI - Clinical, epidemiological and histopathological prognostic factors in oral squamous carcinoma. AB - The study that was carried out was comprised of 117 cases of oral squamous carcinomas, selected in two years interval, between 2007-2008. The tumors were diagnosed especially at patients between the ages of 50 and 79 years, 96,6% being over 40 years old. It came out a clear predominance of the male sex in approximatively 90% of the cases. The main localisation was the lower lip and the tongue ( 67,5% ), in approximatively equal proportions ( 35% and 32,5% ). The histopathologically analisys releaved that 37,6% were well differentiated squamous carcinomas, 27,4% were moderately differentiated squamous carcinomas and 35% were poorly differentiated squamous carcinomas. Out of these 3,3% were microcarcinomas, 91,9% were non-metastatic invasive carcinomas and 4,8% were invasive carcinomas with metastatic adenopathy. PMID- 24778831 TI - Clinical and morphological aspects of sinovitis in early rheumatoid arthritis. AB - The earliest joint changes in rheumatoid arthritis occur in the synovial membrane, leading to development of an unsuppurated proliferative synovitis. This study is based on 33 cases of early rheumatoid arthritis for which we have investigated a series of clinical and morphological parameters. For the examined cases we found that the disease incidence reached its maximum in fifth and sixth decades of life, predominantly in females, over half of cases being diagnosed in the first six months from the onset of the disease. Histopathological study of synovial membrane samples showed characteristic morphological changes but unspecific for the disease, represented by the synoviocytes proliferation, inflammatory infiltrates, fibrinoid necrosis, fibroblasts proliferation and vascular changes. Reaching composite histological score may be useful by providing some information on the severity of the disease. PMID- 24778832 TI - Primary Small Cell Carcinoma of the Esophagus: Clinico- pathological Features and Therapeutic Options. AB - Primary esophageal small cell carcinoma (SmCC) is a rare disease with a poor prognosis despite agressive multimodality combination treatment. This article presents the case of a 76-year old women diagnosed with pimary esophageal SmCC. The diagnosis was established by upper gastrointestinal endoscopy with biopsies that confirmed an esophageal SmCC positive to synaptophysin, chromogranin, CD56, TTF-1, and cytokeratin 8/18. Further staging procedures included CT, PET and EUS, followed by combination chemotherapy and radiotherapy. Restaging was then performed, again with PET and CT of the thorax, abdomen and pelvis. This was then followed by salvage esophagectomy due to the presence of residual tumor. Surgical pathology confirmed a 3 cm SmCC, with invasion of the submucosa and lymphovascular invasion. In conclusion, the article describes the rare occurrence of esophageal SmCC, together with the algorithm of diagnosis and staging based on state-of-the-art imaging methods. This was followed by combination chemoradiotherapy and surgical esophagectomy as the standard of care in this aggressive disease. PMID- 24778833 TI - The outcome of patients with lupus nephritis and the impact of cardiovascular risk factors. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is the prototype of autoimmune connective tissue diseases. Renal disease is a frequent manifestation of SLE that influences the outcome of the patients. The aim of the current study was to determine and analyze the clinical features and subsequent outcome of 70 patients with LN, followed in our department over the past 5 years, focusing on the impact of cardiovascular risk factors in the renal outcome and mortality. PATIENTS AND METHODS: Our prospective study included 70 patients with SLE and LN and 70 patients with SLE without signs of renal involvement, all patients fulfilled the revised ACR (American College of Rheumatology) criteria for the classification of SLE. Demographical data, risk factors and comorbidities were recorded. RESULTS: Patients with lupus nephritis had a mean age of 37 years (range 15-65, SD 1.8). During the study, we had a rate of drop off of 15 patients with lupus nephritis (21%) and 19 patients without nephritis (26%). Patients with LN had a higher prevalence of positive anti-dsDNA antibodies (85.4% vs 49%, p<0.001, RR=2.2) and a lower percent of rheumatoid factor (FR) positive (5.45% vs 15.68%, p=0.03, RR=0.34) compared with the controls, a higher prevalence of corticosteroid treatment (65.45% vs 7.83%, p<0.001, RR=2.1) and immunosuppressive treatment (AZA 27.27% vs 3.92%, p=0.01, RR=1.71, CFM 34.54% vs 0%, p<0.001, RR=2.16), a higher frequency of hypertension (47.27% vs 9.8%, p<0.001, RR=2.4), hyperlipidaemia (49.09% vs 1.96%, p<0.001, RR=1.81) and anti-PL antibodies (49.09% vs 20%, p=0.001, RR=2.70),and a higher mortality (16% vs 2%, p=0.02, RR=1.76). 20 patients (36.36%) from the survival group (55 patients), evoluated to renal failure, 9.09% of these with end -stage renal failure, results that are similar with the ones in other studies. CONCLUSIONS: The study reveals the fact that cardiovascular risk factors such as hypertension, hyperlipidaemia and antiphospholipid syndrome are associated with a higer rate of mortality and an evolution to end-stage renal disease. PMID- 24778834 TI - A critical Evaluation of Surgical Treatment of Perforated Ulcer. AB - The treatment of perforated ulcer disease continues to evolve because of recent advances in pharmacology, bacteriology, and operative techniques. Despite antisecretory medication and Helicobacter pylori eradication, it is still the most common indication for emergency gastric surgery associated with high morbidity and mortality. A clinical study was carried out on patients with perforated gastric or duodenal ulcer, admitted in the 1st Surgery Department between 2002 and 2008. During the 7 years of study there were admitted 256 patients with perforated ulcer - 212 cases of duodenal and 44 cases of gastric perforated ulcer. The main surgical treatment option was simple closure with Graham patch, followed by ulcer excision and vagotomy with pyloroplasty. The second major objective was the topical treatment of peritonitis and consisted in the lavage of the peritoneal cavity and drainage. Distal gastric resection has now very limited indications. We recorded no complications postoperatively. In the modern treatment of ulcer, surgery is reserved for the acute (perforation and bleeding) and chronic complications (stenosis / penetration) and exceptionally or the patients with a prolonged history of uncomplicated ulcers with lack of response to conservative therapy. PMID- 24778835 TI - Considerations regarding the optical properties of the composite resin restorative materials. AB - The purpose of this study has been to investigate the effects of certain substances frequently used in alimentation on the color stability of the composite resin restorative materials. The research hypothesis was that color stability of the composite resin is affected by the type of composite material used and by the polishing procedure. 14 samples of 5X15X2mm have been prepared from seven universal light curing restorative composite resins. The materials have manipulated and cured using LA 500 Blue Light lamp. A first color determination was done before the introduction of the samples in the dyeing agent with the help of an Easy Shade device. The samples have been splited into two lots each with seven samples. The samples from the first lot have been sectioned into three equal segments. The samples from the second lot have also been sectioned into three equal segments, and in addition to the previous group, their exterior surfaces were processed with a diamond burr. For each type of composite we have introduced a sample in one of the three chosen dyes: red alimentary colorant, coffee and red wine. The color of the samples has been determined again using the Vita Easy Shade device. From clinical point of view the results of this study shows that there are three important factors that matter when we talk about durable aesthetic results: the type of composite resin used for the restoration, the finishing and polishing procedures and the pacients' alimentation habits. The composite resins with a good representation of the anorganic structure are easier to be polished, therefore they have only slight color modifications. Using plastic matrixes for shaping the exterior surface of the restoration is the best solution for obtaining a very smooth surface. The most significant color modifications have been done by the red wine. Coffee and to a smaller extent the red alimentary colorant have modified the color of the restoration material in a smaller degree. PMID- 24778836 TI - A cause of falsely high noise level in signal averaged electrocardiogram recordings. AB - Signal averaged electrocardiogram (SAECG) is a well-established noninvasive method of exploration in patients at risk for sudden cardiac death. The time domain SAECG analysis has a set of well-defined standards, including the value of accepted noise level. In very rare instances, the final noise level appears to remain unacceptably high even after carefully preparing the skin of the patient and averaging a great number of QRS complexes. We encountered three such cases in patients who had a SAECG done for a 40 Hz high-pass filter, which showed a high noise level in contrast with the visual impression of a good quality of the recording. PMID- 24778837 TI - The role of biliodigestive derivations in the treatment of choledocholithiasis. AB - The obstructive jaundice is a complex syndrome with both benign etiology (choledocholithiasis, hydatid cyst, chronic pancreatitis) and malignant (cancer of the pancreas, cholangiocarcinoma and gallbladder cancer) and it has a special place in biliopancreatic pathology, with up most importance due to changes in local and general status of the organism, difficult etiologic diagnostic problems for the clinician and whose solution requires teamwork, which involves both the surgeon, gastroenterologist, anesthesiologist etc. The introduction of laparoscopic approach and upper gastrointestinal endoscopy for gallstone disease giving the opportunity to solve choledocholithiasis only by laparoscopic approach or by combining laparoscopic cholecystectomy with extraction of the common bile duct stones using endoscopic retrograde cholangiopancreatography, which greatly restricted the classical surgical indications. In these circumstances, I consider appropriate to review the place and indications of biliodigestive derivations in obstructive jaundice caused by coledocholithiasis. PMID- 24778838 TI - The contribution and the importance of modern ultrasound techniques in the diagnosis of major structural abnormalities in the first trimester - case reports. AB - We describe a series of cases where modern ultrasound (US) techniques diagnosed major structural abnormalities of the fetus in the first trimester (FT), unapparent when using the basic protocol of US investigation. In some cases, major structural abnormalities can be revealed in the FT scan solely to specialized personnel. Perhaps early screening should be confined in specialized centers, because congenital abnormalities detailed diagnostic has a huge impact in counseling the couple and also in prenatal advice of future pregnancies. PMID- 24778839 TI - A pilot study of real time elastography in the differentiation of focal liver lesions. AB - INTRODUCTION: Real time-sonoelastography (RTE) is a new developed technique that reveals the physical properties of the tissue by characterizing the difference in hardness between diseased tissue and surrounding tissue. Elasticity measurements have been already reported to be useful for the diagnosis and differentiation of many tumors: breast lesions, prostate cancer, lymph nodes and pancreatic masses but there are only few studies for the focal liver lesions. The aim of the study was to analyze whether computer enhanced dynamic analysis of elastography images is able to better characterize and differentiate benign and malignant liver lesions. MATERIAL AND METHODS: The study group included, in total thirty nine liver tumors. RTE was performed by EUS or transabdominal ultrasound. ROC analysis for the mean hue obtained through histogram analysis of the region of interest (liver lesion) after averaging individual pixels over a 10-second elastography movies was used to assess the color information inside the region of interest and to consequently differentiate benign and malignant liver lesions. Based on a cutoff of 170 for the mean hue histogram values recorded on the region of interest, the sensitivity, specificity, and accuracy of differentiation of benign and malignant masses were 92.5%, 88.8%, and 88.6%, respectively. The positive and negative predictive values were 86.7% and 92.3%, respectively. In conclusion, real time sonoelastography is a promising technique that might improve the characterization and differentiation between benign and malignant focal liver lesions visualized during transabdominal or endoscopic ultrasound. PMID- 24778840 TI - Utility of endoscopic ultrasound multimodal examination with fine needle aspiration for the diagnosis of pancreatic insulinoma - a case report. AB - Insulinomas are benign insulin-secreting neuroendocrine tumors originating in the pancreatic beta cells. Symptoms are caused by hypoglycemia and clinical diagnosis is based on establishing their relationship to fasting, usually via a fasting test. The most conclusive imaging tests are endoscopic ultrasound (EUS) and CT. Surgery is the treatment of choice. A 33 year old male presented with a 2-year history of hunger which had intensified in the previous 6 months with added accompanying symptoms, culminating with an acute episode - loss of consciousness and seizures - which resolved after administering i.v. glucose. A fasting test was performed, with results suggestive for an insulinoma. Dual-phase CT showed a mass in the tail of the pancreas but no contrast enhancement. EUS was used for further assessment: B-mode showed a hypoechoic focal mass with a cystic component, on contrast enhancement the pattern was hypovascular, and elastography showed soft tissue. EUS fine needle aspiration (FNA) was performed and the immunohistochemistry (IHC) assay was conclusive for a neuroendocrine tumor of the pancreas. Treatment consisted of caudal pancreatectomy, with no recurrence after 1-year follow-up. Although this case started with a classic clinical presentation of an insulinoma, imaging studies related to tumor vascularization raised doubts about the actual diagnosis. Nevertheless, multimodal EUS assessment with FNA was considered to be the most appropriate diagnostic technique for detection, characterization and staging of the mass. EUS findings together with the IHC assay were able to offer the definite diagnosis of a benign neuroendocrine tumor and allowed us to refer the patient for appropriate treatment. PMID- 24778841 TI - The treatment of giant rhinophyma - Case Report. AB - The aim of the article is to present an update on the pathophysiology, clinical features and treatment of rhinophyma. A 56 years old patient, living in urban area, presented with a giant rhinophyma which caused him not only upper airways obstruction and difficulty in eating, but also aesthetic and psycho-social disadvantages.The treatment of the patient was a surgical intervention consisting in removal of the nasal tumor and split-thickness skin grafting of the defect. The aesthetic result after surgical intervention was very good, there were no postoperative complications or recurrences.Rhinophyma represents the most advanced form of acne rosacea. The diagnosis is easy to establish based on the clinical features of the disease. In advanced forms of rhinophyma, when the tumor is giant, the main method of treatment is surgery. PMID- 24778842 TI - Impaired arterial stiffness in systemic lupus ertythematosus - correlations with inflammation markers. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is an inflammatory disease caused by autoimmune dysregulation, which mainly affects young women, usually free from atherosclerosis. Accelerated atherosclerosis is a well established complication of SLE and it cannot be explained by Framingham risk factors alone, and has been attributed to complex interactions between traditional risk factors and factors associated with the disease per se, or its treatment. Arterial stiffness and endothelium function may serve as a valuable measure to be counted in the follow up of these patients prior to a potential cardiovascular event. The aim of the study was to evaluate atherosclerosis, inflammatory process, immune mediated, using imaging techniques and to identify the role of molecules known to be involved in inflammation, hsCRP, homocysteine, IL-6, ESR and fibrinogen, in the development and perpetuation of atherosclerosis in patients with systemic lupus erythematosus. Methods Our prospective study included 53 patients diagnosed with systemic lupus erythematosus and fulfilled the revised ACR (American College of Rheumatology) criteria for the classification of SLE. Exclusion criteria were <18 years of age, history of CVD, infections, diabetes mellitus, dyslipidemia. RESULTS: We enrolled 53 patients with SLE, 50 (94%) women and 3 (6%) men, with a mean age of 31,92 years (SD 5,55; limits 22-44) with no significant difference between sex (31,65+/-3,4 years in women and 37,33+/-4,05 years in men). The measurement of inflammation markers revealed increased values for all the variables: ESR had a mean value of 69,19+/- 14,18mm, fibrinogen 445,66 +/ 4,56mg%; IL-6 had a mean value of 11,209 +/-1,56pg/ml; homocysteine 17,721+/ 2,5374 umol/l and for hs CRP the mean value was 3,493+/-1,12 mg/l. The assesement of arterial stiffness showed a mean value of 23,32% (SD 5,82; 95%CI 21,716 - 24,925) for AIx and 9,1m/s (SD 0,49; 95%CI 8,971 - 9,244) for cfPWV. There was a positive, significant correlation between AIx and hsCRP (r=0,612; 95%CI 0,4104 - 0,7576; p<0,001), (r=0,526; 95% CI 0,2979 to 0,6971; p=0,0001), for AIx and homocysteine (r=0,526; 95%CI 0,2979 to 0,6971; p=0,0001). The correlation coefficient with AIx was similar for ESR and fibrinogen (r=0,63 and 0,60). IL-6 and AIx correlated correlated positively, (r=0,369; 95%CI 0,1097 - 0,5813), statistically significant (p=0,006), but the correlation was not powerful. hsCRP and cfPWV were related (r=0,652; 95%CI 0,4677-0,7862; p<0,001); cfPWV also correlated with IL-6 (r=0,6552; 95%CI 0,4677- 0,7862; p<0,0001), homocysteine (r=0,9174; 95%CI 0,8606- 0,9517; p<0,0001), ESR (r=0,74) and fibrinogen (r=0,64). CONCLUSIONS: In summary, our data suggest that arterial stiffness is related to the level of systemic inflammation, and that inflammation is involved in the early alteration of arterial wall. Increase in arterial stiffness can be detected by applanation tonometry, and may serve as an important predictor of future cardiovascular events, since an early diagnosis may have a significant value in preventing the development of major vascular disease. PMID- 24778843 TI - Post-myocardial infarction arrhythmia risk stratification using microvolt T-wave alternans. AB - Since its initial description, a number of studies have described the use of microvolt T-wave alternans (MTWA) as a predictor of the primary or secondary occurrence of ventricular arrhythmic events. These studies, however, have been limited by small sample sizes and disparate patient populations. Studies of MTWA in post-myocardial infarction (MI) patients are few in number, but hold predictive value for risk of ventricular arrhythmias. We performed a study of MTWA in post-myocardial infarction patients to clarify the predictive accuracy and usefulness of MTWA compared to other invasive and non-invasive techniques. We enrolled 120 patients (74 men, 46 women, mean age 62.3 +/- 15.2 years in men, and 64.2 +/- 13.8 years in women) with a history of myocardial infarction but no prior sustained ventricular arrhythmias. Patients were assessed by echocardiography, Holter, signal averaged ECG, MTWA, and electrophysiology study. Mean follow-up was 14 months. The MTWA test had a good negative predictive value for arrhythmic events in post-MI patients and can be used for risk stratification. We consider that in patients with positive MTWA further invasive evaluation, respectively electrophysiology study, is necessary. PMID- 24778845 TI - Opportunistic Screening for Ca PVU in Primary Health Care. AB - Majority of countries don't have an organized screening program.It is not conducted or is in form of opportunistic screening. An organized screening for cervical cancer in developed countries is resulted in significant decrease of incidence and mortality. In our country there is no an organized screening program. Even it is carried out,it is in form of opportunistic screening. Consequently,the number of cervical carcinoma (Ca PVU) is the largest in Europe. The goal of this research is accomplishing possibilities and limits of opportunistic screening in Velika Plana. PMID- 24778844 TI - The contribution of the video capsule endoscopy in establishing the indication of surgical treatment in the tumoral pathology of the small bowel. AB - BACKGROUND AND AIMS: Capsule endoscopy (CE) represents a novel method which allows safe, non-invasive and rapid exploration of the small bowel. Our aim was to determine the feasibility CE has in assessing tumoral pathology of the small bowel and aiding surgical teams in determining appropriate treatment. Material and Method Our study was conducted on 11 patients who presented tumoral pathology of the small bowel, from a total of 50 patients investigated by VCE. Malignancy was determined on the surgical resection piece, by histological exam. Statistic analysis of the data was conducted using Fisher's Exact Test. Results Tumoral pathology was represented by: 3 intestinal polyps, 2 benign stromal tumors, 2 malign stromal tumors, 2 adenocarcinomas, one neuroendocrine malign tumor and one duodenal papilla carcinoma. We followed the presence of malign tumors in regards to age. All malign tumors (n=6) were recorded in patients over 60 years old, while benign tumors were recorded in most cases (80%, n=4) in people under 60 years old. One case of benign tumor (intestinal polyp) was observed above 60 years old. Conclusion Capsule endoscopy represents a real help for the surgeon, as it allows identification of small bowel pathology, giving information regarding the approximate localization of lesions, their size and orienting on their nature. Tumoral pathology is encountered mainly with the old age population and can be presented under a multitude of forms. We believe that an efficient method for incipient detection and a protocol to establish malignity is necessary. PMID- 24778846 TI - Researches on the preparation and characterization of some tinctures from Silene albae herba and Silene pendulae herba. AB - Starting from the varied chemical composition of Silene species (Caryophyllaceae family), the pharmacological utilizations (homeopathy) and the cumulative toxicity for a long time administration, were performed researches concerning the preparation and characterization of tinctures from aerial parts of S. alba and S. pendula species. Tinctures were obtained, according to the Romanian Pharmacopoeia Xth edition, by percolation and characterized from physico-chemical point of view: color, taste, smell, relative density, refractive index, and quality conditions - content in iron and heavy metals, alcohol concentration and evaporation residue. Qualitative and quantitative analyses of tinctures were making for the flavonosids, using thin layer-chromatography, respectively VIS spectrophotometry. PMID- 24778847 TI - Socio-economic factors influencing the nutritional behaviour of pupils. AB - The purpose of the study was to evaluate the quality of morning nutrition of children in primary school, related to the residence environment and the family educational level. We included in our study 220 children in the age group 8-10, studying in urban and rural schools. They answered a 24-itemed questionnaire regarding their morning nutrition. Nutrition state, health state and school performance were evaluated. We found that 9.1% of all the children skip breakfast and midmorning snack. Most frequently they have margarine, salami, jam or cheese sandwiches and tea as breakfast. The free "milk and roll" are daily consumed by less than 45 % of the subjects. We did not find significant disorders in their nutrition and health state. Educational activities for a healthy nutrition are necessary. PMID- 24778848 TI - The failures of root canal preparation with hand ProTaper. AB - The failures of root canal preparation are due to some anatomical deviation (canal in "C" or "S") and some technique errors. The technique errors are usually present in canal root cleansing and shaping stage and are the result of endodontic treatment objectives deviation. OBJECTIVES: Our study was made on technique errors while preparing the canal roots with hand ProTaper. METHODOLOGY: Our study was made "in vitro" on 84 extracted teeth (molars, premolars, incisors and canines). The canal root of these teeth were cleansed and shaped with hand ProTaper by crown-down technique and canal irrigation with NaOCl(2,5%). The dental preparation control was made by X-ray. RESULTS: During canal root preparation some failures were observed like: canal root overinstrumentation, zipping and stripping phenomenon, discarded and/or fractured instruments. CONCLUSIONS: Hand ProTaper represents a revolutionary progress of endodontic treatment, but a deviation from accepted rules of canal root instrumentation can lead to failures of endodontic treatment. PMID- 24778849 TI - Whitening non vital teeth - a case report. AB - Commonly used in cosmetic dentistry teeth whitening can be used combined with other restorative techniques during dental treatment. Non-vital teeth whitening is necessary whenever we need an improvement of their aspect, as it's a known fact that these teeth can have a grey or pink-grey coloration when they are not correctly endodontical treated. PMID- 24778850 TI - Considerations on dental bridges' stability and balance for mandibulary teeth with coronary-root amputation. AB - Dental occlusion represent the function of dentomaxillary system at which realization participate all the components of that system holding the equilibrium between them. Setting up the treatment with dental bridges in partial edentuluous is rule by some principles that have aims like restore the morphology and functions change by edentuluous condition and also prevention disorders of remaining teeth and other structures and functions of dentomaxillary system. During the prosthetic treatment with fixed bridgeworks in clinical cases presents in this study , we used also terapeutical techniques specifically other dental domains like endodontology and oral surgery. For avoid the appearance of occlusal dysfunction is necessary a good knowledge and respecting the biomorphocinematic behaviour of dentomaxillary system structure under action of occlusal force during mastication and also biomechanical rules that influence the functional equilibrium of teeth and dental bridges. PMID- 24778851 TI - Emphysematous Cystitis. Case report and imaging features. AB - Emphysematous cystitis is a rare bacterial infection of the bladder which results in presence of gas in the bladder wall, lumen, and surrounding tissues. The most important factors involved in this disease are diabetes mellitus, dysuria and neurogenic bladder, with predominance of female gender.We present a case of a 64 years old female patient, with diabetes mellitus tip 2, who presented in our emergency department with fever, abdominal complaint, olyguria for the last one month. Abdominal CT (computer tomography) revealed gas in the bladder with thickening of bladder wall and formation of an air-fluid level. Laboratory test showed anemia and leukocytosis. Urine culture showed elevated growth of Escherichia coli (E. coli). The diagnosis was emphysematous cystitis and patient started the antibiotic specific therapy. PMID- 24778852 TI - GnRH Antagonist IVF Protocol in PCOS. AB - The aim of the present study was to compare the GnRH agonist long protocol with the flexible GnRH antagonist protocol in infertile PCOS women undergoing COS in terms of clinical pregnancy rate (CPR), with special reference to the incidence of OHSS. Materials and Methods. The study was conducted at the Hospital Obstetrics and Gynecology Cuza Voda Iasi and Fertility Reproductive Medical Center Omini Clinic Iasi from June 1, 2010, to September 31, 2012. PCOS as defined by the Rotterdam 2003 consensus, i.e. presence of two of the following three features: presence of oligo- and/ or anovulation, clinical and/or biochemical signs of hyperandrogenism, polycystic ovaries and exclusion of other endocrinopathies. Results. No differences were observed in clinical pregnancy rate (CPR) in the agonist and antagonist protocols, respectively. Incidence of OHSS was lower in the antagonist compared with agonist group (4% versus 28%). Duration of stimulation (13,80 + 1,4 vs 11,85 + 2,4 p < 0,001) and total gonadotrophin required (2435,5 + 884,5 versus 2005, 5 + 545,5 IU p < 0.003) were also lower in the antagonist compared with agonist protocol. Conclusions. The current study suggests that the flexible GnRH antagonist protocol is associated with a similar ongoing pregnancy rate, lower incidence of OHSS grade II, lower gonadotrophin requirement and shorter duration of stimulation, compared with GnRH agonist. The GnRH antagonist might be the treatment choice for patients with PCOS undergoing IVF. PMID- 24778853 TI - Clinical and therapeutic aspects in dento-alveolar disharmony (DAD) with crowding. AB - Dento-alveolar disharmony (DAD) with crowding represents a predispose factor for periodontal pathology installing, especially when septic inflammation is associated. In this context, the identification of integrity or presence of the periodontal structure modifications becomes essential, any discovered element of periodontal pathology transforming into an important factor for a correct and beneficial orthodontic or periodontal-orthodontic therapy setup. The purpose of our study was to reveal the relations between the DAD existence and periodontal modifications within a lot of 528 subjects of 7 to 19 years old wearing different DAD who asked for an orthodontic control, and also the effects of orthodontic therapy upon periodontal structures for the situations in which this therapy was instituted. 74,87% was the percentage for patients with DAD and crowding who accepted the initiation of an orthodontic treatment and 12,75% of them had a friable C type periodontium (with great possibility to evolve towards a periodontal pathology), 25,62% had chronic gingivitis, and in 15,43% there have been noticed gingival recessions more than 2 mm. The orthodontic treatment was finalized for 44,96% of the patients, in 13,43% we noticed the persistence of C type periodontium, in 8,95% of gingival recessions more than 2 mm, in 25,37% chronic gingivitis and in 22,38% hypertrophic gingivitis. CONCLUSION: it is important to initiate an exhaustive control of the patient with DAD before, during and after the orthodontic treatment, especially if the patient is susceptible to develop a periodontal pathology, and also to maintain a good oral hygiene along the treatment. PMID- 24778854 TI - Surface morphology of leukemic cells from chronic myeloid leukemia under atomic force microscopy. AB - Atomic force microscopy (AFM) represents an important instrument for measuring mechanical properties of biological materials ranging from single molecules to normal or malignant cells. AFM provides a 3D profile of the surface on a nanoscale, by measuring forces between a sharp probe (<10 nm), supported on a flexible cantilever, and surface at very short distance (0.2-10 nm probe-sample separation). The AFM tip "gently" touches the surface and records the small force between the probe and the surface. The patients were three normal human subjects and nine patients with chronic myeloid leukemia in different phases of disease. With atomic force microscope, numerous spicules were observed on the surface of leukemic cells, especially in blastic phase of CML. PMID- 24778855 TI - Purulent pericardial effusions with pericardial tamponade - diagnosis and treatment issues. AB - Purulent pericarditis is rarely encountered in the antibiotherapy era, mainly in immunosupressed patients, after cardiac operations, in septicemia. Diagnosis of purulent pericarditis is based upon the analysis of pericardial drainage, obtained through pericardiocentesis or preferably, through a surgical approach. The reported case has following peculiarities: clinical signs of false acute surgical abdomen; altered clinical and biological response to infection; Optimal treatment is early, efficient pericardial drainage, with low risk of tissue contamination and of pericardial constriction; Surgical subxyphoid pericardial drainage is prefered in patients with affected general status. Antero-(lateral) thoracic approach with associated anterior pericardiectomy ensures an efficient pericardial drainage and prevents pericardial constriction, with low risks for pleural contamination. PMID- 24778856 TI - Study on the frequency and values of sanguine eosinophilia in children admitted with parasitary diseases. AB - The authors carried out a retrospective study on the frequency, levels and relative and absolute mean values of sanguine eosinophily in children admitted with various parasitary diseases within the sanitary units in Craiova and in the Pediatric Clinic of Fundeni Clinical Institute, Bucharest, over a period of 12 years. The study group consisted of 2,198 children, aged 0-16 years: 1,226 with diseases caused by protozoa - 1,195 intestinal giardiasis and 31 acquired Toxoplasmosis; 754 with diseases caused by nematodes - 169 Ascaridiasis, 470 Oxyurasis, 23 Trichocephalosis and 92 Trichinellosis; 50 with diseases caused by cestodes - 23 Hydatidosis and 27 Himenolepidosis; 168 with different associated parasitoses. For processing the data we used statistical-mathematical methods: arithmetic mean (Am) and standard deviation (+/- Sd). PMID- 24778857 TI - Intrajejunal migration of adjustable gastric band: a case report. AB - Introduction. Laparoscopic gastric banding is a first line bariatric procedure that is performed worldwide and can achieve substantial weight loss. Despite its many advantages, as the least invasive bariatric procedure, it has several complications like gastric prolapse, stoma obstruction and migration of the gatstric band. Rarely are these complications life threatening, but re-operation is usually the only treatment. Case presentation. We report a rare case of intrajejunal migration of an adjustable gastric band that was placed laparoscopically four years ago. Conclusion. Gastric band migration is a rather common complication of laparoscopic gastric banding, but intrajejunal migration is very rare and requires high clinical suspicion, close follow-up and thorough pre-operative investigation so as to avoid intraoperative surprises and retrieve the displaced gastric band safely. PMID- 24778858 TI - Comparative aspects of microglia reaction in white and gray matter. AB - OBJECTIVES: Microglia are considered as the primary immune effector cells in the brain and have a critical role in all brain lesions. We wanted to find out if there is any difference in the way that white and gray matter microglia react to the same type of lesion. MATERIAL AND METHOD: We used 14-16 weeks old single transgenic CX3CR1-EGFP mice, whereon microglia were labeled by expression of the green fluorescent protein EGFP and the L1-L2 dorsal spinal columns were exposed. After 10 min of continuous base line image acquisition, we made a micro-lesion by focusing and raising the power of the laser and, than, we monitored it for an additional hour. Laser-lesion and image recording were also made in the right somato-sensory cortex. We quantified microglial response and compared white vs. grey matter. RESULTS: 5-10 min after the lesion, microglia already showed signs of polarization by extending their processes both in white and gray matter. Processes were sent by the microglial bodies situated at a distance of 50 to 100 um, depending on the lesion size. Microglial processes did not display a preferred target site from the lesion; in contrast, they formed a uniform "shielding" ring around the lesion. CONCLUSIONS: Microglia showed targeted responses to acute injuries in grey and white matter also; no major differences were observed besides the speed of the process, due probably to particular cortex and spine architecture. PMID- 24778859 TI - Retrorectal dermoid cyst: a rare clinical entity. AB - The retrorectal space represents the anatomical site at which level we identify the embryologic reminiscents in which it can develop liquid tumors - cysts or solid tumors - neoplasia. These tumors are rare but pose a diagnostic and therapeutic interest. This paper presents the case of a young 18 years-old diagnosed incidentally at a gynecological examination, with a palpable tumor developed, at the retrorectal space. Imaging examinations - transvaginal ultrasound and abdominal - pelvic computer tomographic exam - have supported the presence of a cystic tumor with a maximum diameter of 7.8 cm., in the space retrorectal. The lesion presented surgical indication, so it needed a posterior approach with resection of the coccyx enough for the control and safety of the operation. Histopathological examination revealed a dermoid cyst. Five years after surgery the patient is presented in good general condition, asymptomatic without clinical and imaging signs of local-regional recurrence. PMID- 24778860 TI - Renal anemia - risk factor for chronic kidney disease. AB - The purpose of this research was to analyze the influence of anemia on renal function in patients with chronic kidney disease. Were monitored for 12 months 165 patients with chronic kidney disease, 96 patients had anemia and a control group of 69 patients had no anemia. A value of hemoglobin under 120 g/L in women and under 130 g/L in men on admission defined anemia. Anemia was associated with a more severe renal damage, a lower residual diuresis, especially in the presence of other risk factors such as diabetes, inflammation or secondary hyperparathyroidism, so early diagnosis and correction of anemia is important for prognosis and evolution of these patients. PMID- 24778862 TI - The impact of C reactive protein on global cardiovascular risk on patients with coronary artery disease. AB - Introduction. Cardiovascular disease (CVD) is the major cause of premature death worldwide. Hundreds of risk factors have been associated with cardiovascular disease. Recent extensive evidence supports inflammation as a key pathogenetic mechanism in the development and progression of atherosclerosis and in triggering clinical atherothrombotic CVD events. C-reactive protein (CRP) is one possible marker of vascular inflammation and plays a direct role in promoting vascular inflammation, vessel damage and clinical CVD events. Material and method. The purpose of this study was to evaluate the correlation between CRP level and the global cardiovascular risk. We evaluated 100 patients with cardiovascular risk factors, using the systematic coronary risk evalution (SCORE) charts for high risk regions of Europe and we determined the CRP level, using the nephelometric method. Results. By their SCORE chart, 44% of the patients are in the moderate risk category, and almost 40% in the high risk category, the rest of them (16%) are in the low and very high risk category. A statistically significant p value (p<0.05) was observed between patients with CRP<10mg/L, who had a lower sistolic blood pressure than patients with CRP>=10mg/L, Conclusion. The CRP level over 10mg/L is correlated with an over 4% risk of developing a fatal CVD in 10 years. The acute phase reactant, CRP, a simple downstream marker of inflammation, has now emerged as a major cardiovascular risk factor. PMID- 24778861 TI - HBV influence on Response to Antiretroviral Therapy in Horizontally HIV-HBV Coinfected Patient during Early Childhood. AB - BACKGROUND: There are few studies on pediatric HIV-HBV coinfection, so evidences about relationships between the two viruses are scarce. OBJECTIVES: influence of HBV infection on virological and immunological response to antiretroviral therapy (ART) in antiretroviral-naive horizontally HIV-HBV coinfected subjects during early childhood. MATERIAL AND METHODS: observational study on 826 HIV+ subjects in evidence of Craiova Regional Centre (CRC); we analyzed the immunological and virological response at 6-12 months after starting first antiretroviral regimens compared in 2 groups: horizontally HIV-HBV coinfected subjects during early childhood (CoS) versus horizontally HIV infected subjects during early childhood without HBV infection (non-CoS). RESULTS: Number of subjects: CoS-66 subjects, non-CoS-132 subjects. Demographic data: CoS-gender ratio F:M=0.886, the majority lived in rural area (57.58%), mean age on diagnosis-9.288+/-4.607 years, non-CoS gender ratio F:M=0.859, the majority lived in urban area (53.79%), mean age on diagnosis-10.742+/-5.107 years. At baseline, HIV category was: CoS-A-1.52%, B 80.30%, C-18.18%, non-CoS-A-2.27%, B-70.45%, C-27.27% (p Chi(2)=0.332), the mean CD4+ cell count was: CoS-148.33+/-148.10 cells/ml, non-CoS-163.17+/-155.39 cells/ml (p Student=0.521) and the mean HIV viral load (HIV VL) was: CoS-5.06+/ 0.80 lgcopies/ml (for 29 subjects), non-CoS-5.04+/-0.84 lgcopies/ml (for 61 subjects) (p Student=0.978). At the end of the studied period, the mean increase in CD4+ cell count was: CoS-177.068+/-141.676 cells/ml, non-CoS-176.015+/-191.751 cells/ml (p Student=0.969) and the mean decrease in HIV VL was: CoS-5.04+/-0.79 lgcopies/ml, non-COS-4.69+/-2.04 lgcopies/ml (p Student=0.911). CONCLUSIONS: The presence of HBV coinfection does not influence immunological or virological response to ART. PMID- 24778863 TI - Chromatographic analysis of the flavonoids from robinia pseudoacacia species. AB - THE PURPOSE OF THIS STUDY WAS THE QUALITATIVE AND QUANTITATIVE ANALYSIS OF FLAVONOIDS FROM ROBINIA PSEUDOACACIA USING TWO DIFFERENT TECHNIQUES OF ANALYSIS: Thin Layer Chromatography (TLC) and TLC coupled with photo-densitometry. The results obtained by chromatographic analysis showed a higher concentration of flavonoids in flowers than in leaves. The flowers harvested in the plains have a higher concentration of hyperoside (0.9 mg/mL) compared with the flowers collected from the hills (0.54 mg/mL). The leaves are richer in ruthoside (0.98 mg/mL) compared with the flowers. PMID- 24778864 TI - Midterm experience of ipsilateral axillary-axillary arteriovenous loop graft as tertiary access for haemodialysis. AB - Objectives. To present a series of ipsilateral axillary artery to axillary vein loop arm grafts as an alternative vascular access procedure for haemodialysis in patients with difficult access. Design. Retrospective case series. Methods. Patients who underwent an axillary loop arteriovenous graft from September 2009 to September 2012 were included. Preoperative venous imaging to exclude central venous stenosis and to image arm/axillary veins was performed. A cuffed PTFE graft was anastomosed to the distal axillary artery and axillary vein and looped on the arm. Results. 25 procedures were performed on 22 patients. Median age was 51 years, with 9 males and 13 females. Median number of previous access procedures was 3 (range 0-7). Median followup was 16.4 months (range 1-35). At 3 months and 1 year, the primary and secondary patency rates were 70% and 72% and 36% and 37%, respectively. There were 11 radiological interventions in 6 grafts including 5 angioplasties and 6 thrombectomies. There were 19 surgical procedures in 10 grafts, including thrombectomy, revision, repair for bleeding, and excision. Conclusions. Our series demonstrates that the axillary loop arm graft yields acceptable early patency rates in a complex group of patients but to maintain graft patency required high rates of surgical and radiological intervention, in particular graft thrombectomy. PMID- 24778865 TI - Treatment of Corneal Neovascularization Using Anti-VEGF Bevacizumab. AB - Purpose. To evaluate antiangiogenic effect of local use of bevacizumab (anti-VEGF antibody) in patients with corneal neovascularization. Methods. Patients were divided into two groups. All patients suffered from some form of corneal neovascularization (NV). Patients in group A received 0.2-0.5 mL of bevacizumab solution subconjunctivally (concentration 25 mg/mL) in a single dose. Group A included 28 eyes from 27. Patients in group B applied bevacizumab eye drops twice daily (concentration 2.5 mg/mL) for two weeks. Group B included 38 eyes from 35 patients. We evaluated the number of corneal segments affected by NV, CDVA, and the incidence of complications and subjective complaints related to the treatment. The minimum follow-up period was six months. Results. By the 6-month follow-up, in group A the percentage reduction of the affected peripheral segments was 21.6% and of the central segments was 9.6%; in group B the percentage reduction of the central segments was 22.7% and of the central segments was 38.04%. In both groups we noticed a statistically significant reduction in the extent of NV. Conclusion. The use of bevacizumab seems to be an effective and safe method in the treatment of corneal neovascularization, either in the subconjunctival or topical application form. PMID- 24778866 TI - Age macular degeneration: etiology, prevention, individualized therapies, cell therapy, and tissue engineering. PMID- 24778867 TI - Clinical characteristics of alternaria keratitis. AB - Purpose. Alternaria spp. are an uncommon cause of mycotic keratitis. Previous studies on Alternaria keratitis have generally been limited to case reports. We examined the clinical characteristics of Alternaria keratitis in this study. Methods. The characteristics and outcomes of 7 patients with culture-proven Alternaria keratitis treated in our hospital were compared with 25 previously reported cases. Results. The risk factors for Alternaria keratitis were trauma in 5 patients and soft contact lenses in 1 patient. Six patients with early diagnosis (<2 weeks) were cured with medical antimicrobial treatment; a patch graft was required in 1 patient with perforation. When incorporated with previous reports on Alternaria keratitis (n = 32), 14 (44%) infections followed trauma, 10 (31%) were associated with preexisting corneal disease or previous ocular surgery, and 5 (16%) occurred in soft contact lens wearers. Successful medical treatment was achieved in 23 (72%) patients, including 10 out of 21 eyes (48%) treated with natamycin and/or amphotericin B. Therapeutic penetrating keratoplasty was performed in 9 (28%) cases. Conclusions. Alternaria keratitis is generally associated with specific risk factors and responds to medical treatment when early diagnosis is performed and prompt antifungal treatment is initiated. PMID- 24778868 TI - Aspirin for prevention of preeclampsia in lupus pregnancy. AB - Preeclampsia, the onset of hypertension and proteinuria during pregnancy, is a common medical disorder with high maternal and fetal mortality and morbidity. The underlying pathology remains poorly understood and includes inflammation, endothelial dysfunction, and an unbalanced thromboxane A2/prostacyclin ratio. For women with systemic lupus erythematosus (SLE), particularly those with preexisting renal disease or with active lupus, the risk of developing preeclampsia is up to 14% higher than it is among healthy individuals. The mechanism is still unknown and the data for preventing preeclampsia in lupus pregnancies are rare. Modulating the impaired thromboxane A2/prostacyclin ratio by administration of low-dose aspirin appears to be the current best option for the prevention of preeclampsia. After providing an overview of the pathogenesis of preeclampsia, preeclampsia in lupus pregnancies, and previous trials for prevention of preeclampsia with aspirin treatment, we recommend low-dose aspirin administration for all lupus patients starting prior to 16 weeks of gestation. Patients with SLE and antiphospholipid syndrome should receive treatment with heparin and low-dose aspirin during pregnancy. PMID- 24778869 TI - A Preliminary Study on the Relationship between Platelet Serotonin Transporter Functionality, Depression, and Fatigue in Patients with Untreated Chronic Hepatitis C. AB - Objective and Methods. Although the interaction between fatigue and depression in patients with chronic hepatitis C infection (HCV) has been recognized, the biological correlates of this observation have yet to be reported. We addressed this issue by examining serotonin transporter- (SERT-) driven [(14)C]-serotonin uptake rate (SUR) and serotonin content in platelets of 65 untreated HCV patients and 65 healthy control subjects (HCS). All patients completed report questionnaires for fatigue, depression, and general psychopathology. Structured interviews were conducted by a board-certified psychiatrist. Results. Whereas 36 of the patients experienced fatigue of moderate-to-severe intensity, only 16 reported symptoms of depression (BDI score > 10). Mean SUR in patients with depressive symptoms was significantly higher relative to the HCS, corresponding to a large Cohen's effect size of d = 1.45 (95% CI = 0.66-1.83). Patients who rated their fatigue to have a marked impact on mood and activity displayed a moderate relationship between the BDI score and SUR (n = 18, r = 0.563, P = 0.015), which becomes stronger after controlling for age, gender, and thrombocytopenia (r part = 0.710, P = 0.003). In the univariate analysis, high fatigue interference score, thrombocytopenia, and high SUR were all significant predictors of depression. Conclusions. High SERT activity could be implicated in the expression of depressive symptoms especially in a subgroup of HCV patients who are feeling fatigue as markedly distressing. PMID- 24778870 TI - Funding for postbariatric body-contouring (bariplastic) surgery in England: a postcode lottery. AB - Background. With the increase in bariatric surgery in the UK, there has been a substantial increase in patients undergoing massive weight loss (MWL) seeking postbariatric body-contouring (bariplastic) surgery. However, there is a wide variation of availability on the National Health Service (NHS). Aims. To (1) review the funding policies of Primary Care Trusts (PCTs) in England for bariplastic surgery and (2) analyse the number of procedures funded in two consecutive financial years. Methods. We sent out questionnaires to all PCTs in England regarding their funding policies for bariplastic surgery and requested the number of procedures funded in 2008-09 and 2009-10. Findings. 121/147 (82%) PCTs replied to our questionnaires. 73 (60%) excluded all bariplastic procedures. 106/121 (87.6%) PCTs had referral guidelines for plastic surgery. 46/121 (38%) PCTs provided the total number of funded abdominoplasty-apronectomy (A-A) in the two financial years: total number of A-A applicants rose from 393 to 531, but approval for funding fell from 24.2% to 19.6%. Only 3 (2%) PCTs indicated increase in their future spending on bariplastic procedures in the next 5 years, with 67% planning to decrease or unsure about future funding. Conclusion. There exists a postcode lottery for bariplastic surgery in England and we feel the need for guidelines on provision of bariplastic procedures following MWL. PMID- 24778871 TI - Seasonality of tuberculosis in delhi, India: a time series analysis. AB - Background. It is highly cost effective to detect a seasonal trend in tuberculosis in order to optimize disease control and intervention. Although seasonal variation of tuberculosis has been reported from different parts of the world, no definite and consistent pattern has been observed. Therefore, the study was designed to find the seasonal variation of tuberculosis in Delhi, India. Methods. Retrospective record based study was undertaken in a Directly Observed Treatment Short course (DOTS) centre located in the south district of Delhi. Six year data from January 2007 to December 2012 was analyzed. Expert modeler of SPSS ver. 21 software was used to fit the best suitable model for the time series data. Results. Autocorrelation function (ACF) and partial autocorrelation function (PACF) at lag 12 show significant peak suggesting seasonal component of the TB series. Seasonal adjusted factor (SAF) showed peak seasonal variation from March to May. Univariate model by expert modeler in the SPSS showed that Winter's multiplicative model could best predict the time series data with 69.8% variability. The forecast shows declining trend with seasonality. Conclusion. A seasonal pattern and declining trend with variable amplitudes of fluctuation were observed in the incidence of tuberculosis. PMID- 24778872 TI - Acceptance of Provider Initiated HIV Testing and Counseling among Tuberculosis Patients in East Wollega Administrative Zone, Oromia Regional State, Western Ethiopia. AB - Human immunodeficiency virus (HIV) is a powerful risk factor for the development of tuberculosis. This study assessed the acceptance and associated factors that can affect provider initiated HIV testing and counseling (PITC) among tuberculosis patients at the East Wollega administrative zone, Oromia regional state, western Ethiopia, from January to August, 2010. A single population proportion formula is used to calculate the total sample size of 406 and the cluster sampling technique was used to select 13 health centers that provide PITC services. The sample size was proportionally allocated to each health center. The study participants were selected using a simple random sampling technique using the lottery method. Structured questionnaire was used for collection of sociodemographic data. From the total of study subjects, 399 (98.2%) TB patients were initiated for HIV test and 369 (92.5%) patients accepted the initiation. Of those, 353 (95.5%) patients had taken HIV test and received their results. According to the reviewed documents, the prevalence of HIV among tuberculosis (TB) patients in the study area was 137 (33.7%). The logistic regression result showed the PITC was significantly associated with their knowledge about HIV (AOR = 3.22, 95% CI: 1.3-7.97), self-perceived risk (AOR = 2.93, 95% CI: 1.12-7.66), educational status (AOR = 3.51, 95% CI: 1.13-10.91), and knowledge on transmission of HIV/AIDS (AOR = 7.56, 95% CI: 1.14-40.35) which were significantly associated with the acceptance of PITC among TB patients. Therefore, this study's results showed, the prevalence of HIV among TB patient was high; to enhance the acceptance of PITC among TB patients, health extension workers must provide health education during home-to-home visiting. TB treatment supervisors also provide counseling intensively for all forms of TB patients during their first clinical encounter. PMID- 24778873 TI - Conceptualisation and development of a quality of life measure for parents of children with autism spectrum disorder. AB - Parents of children with autism spectrum disorder (ASD) tend to experience greater psychological distress than parents of typically developing children or children with other disabilities. Quality of Life (QoL) is increasingly recognised as a critical outcome measure for planning and treatment purposes in ASD. There is a need for ASD-specific QoL measures as generic measures may not capture all relevant aspects of living with ASD. This paper describes the conceptualisation and development of an autism-specific measure of QoL, the Quality of Life in Autism Questionnaire (QoLA) for parents and caregivers of children with ASD, that is suitable to clinical and research settings. Preliminary psychometric properties (reliability and validity) of the measure are also presented. The QoLA has 48 items in two subscales: one comprising QoL items and the second a parent report of how problematic their child's ASD symptoms are. A study involving 39 families suggested the QoLA has excellent internal consistency as well as good known-groups validity between parents of children with ASD and those who were typically developing. The QoLA also showed good convergent validity with other measures of QoL and ASD symptom severity, respectively. The QoLA may be a valuable assessment tool and merits further psychometric evaluation. PMID- 24778874 TI - Changes in renal function in elderly patients following intravenous iodinated contrast administration: a retrospective study. AB - Background. Contrast-induced nephropathy (CIN) is a recognised complication of intravascular administration of iodinated contrast media (ICM). Previous studies suggest a higher incidence in the elderly, but no large study has assessed this to date. We set out to assess changes in creatinine in elderly inpatients following computed tomography (CT) examination and compare those who received intravenous contrast to those who did not. Methods. Using the Radiology Information System in two teaching hospitals, inpatients over the age of seventy who had a CT examination and a baseline creatinine were identified and their follow-up creatinine levels were analysed. Elderly inpatients who underwent a noncontrast CT over the same period were used as controls. Results. 677 elderly inpatients who received ICM were compared with 487 controls. 9.2% of patients who received ICM developed acute kidney injury (AKI) compared to 3.5% of inpatient controls (P < 0.0001). Patients with higher baseline eGFR had a higher incidence of post-CT AKI. Conclusions. The incidence of post-CT AKI is higher in patients who received IV ICM compared to those who did not; the difference may be partly attributable to contrast-induced nephropathy. This suggests that the incidence of CIN in the elderly may not be as high as previously thought. PMID- 24778875 TI - Carotid Artery Stenosis: Comparison of 3D Time-of-Flight MR Angiography and Contrast-Enhanced MR Angiography at 3T. AB - Purpose. The aim of this study was to assess the correlation of 3D time-of-flight MR angiography (TOF MRA) and contrast-enhanced MR angiography (CEMRA) for carotid artery stenosis evaluation at 3T. Material and Methods. Twenty-three patients (5 f, 18 m; mean age 61 y, age range 45-78 y) with internal carotid artery stenosis detected with ultrasonography were examined on a 3.0T MR system. The MR examination included both 3D TOF MRA and CEMRA of the carotid arteries. MR images were evaluated independently by two board-certified radiologists. Stenosis evaluation was based on a five-point scale. Stenosis grades determined by TOF and CEMRA were compared using Spearman's rank correlation coefficient and the Wilcoxon test. Cohen's Kappa was used to evaluate interrater reliability. Results. CEMRA detected stenosis in 24 (52%) of 46 carotids evaluated, while TOF detected stenosis in 27 (59%) of 46 carotids. TOF MRA yielded significantly higher results for stenosis grade in comparison to CEMRA (P = 0.014). Interrater agreement was very good for both TOF MRA (kappa = 0.93) and CEMRA (kappa = 0.93). Conclusion. At 3T, 3D TOF MRA should not be used as replacement for contrast enhanced MRA of the carotid arteries, as it results in significantly higher stenosis grades. PMID- 24778876 TI - Prescription Practice for Diabetes Management among a Female Population in Primary Health Care. AB - Introduction. Prescription for diabetes care is an important practice in primary care. Methods. This is a descriptive study carried out on at primary care clinics over a five-month period at Al Imam Medical Complex, Riyadh, Saudi Arabia. It was cross-sectional study of 160 female diabetic patients, who visited the services between January and May, 2012. Data were collected from the medical records on the clinical characteristics and drugs prescribed for their diabetic management. Results. The majority of the sample population (82%) was older than 40 years old. Half of them had concomitant hypertension, hyperlipidemia, and obesity. There were 500 prescriptions for diabetes management. More than 57% of participants were on two or more drugs for hyperglycemia. Metformin was the most common drug prescribed. Metformin and sulphonylurea were the most common combined medications. Most of cases ( 70%) were on a combination of antihypertensive drugs. ACE or ARBs and diuretic was the most common combined prescriptions. Statins and aspirin were used by 41% and 23.8% of the research population, respectively. Conclusion. Polypharmacy is a feature in diabetes care. Most of the prescription practice for diabetic care follows the recommended guidelines for hyperglycemia and hypertension. Management of dyslipidemia among diabetic patients, however, is an area that needs to be developed. PMID- 24778877 TI - Clinical utility of cognistat in multiprofessional team evaluations of patients with cognitive impairment in Swedish primary care. AB - Background. Diagnostic evaluations of dementia are often performed in primary health care (PHC). Cognitive evaluation requires validated instruments. Objective. To investigate the diagnostic accuracy and clinical utility of Cognistat in a primary care population. Methods. Participants were recruited from 4 PHC centres; 52 had cognitive symptoms and 29 were presumed cognitively healthy. Participants were tested using the Mini-Mental State Examination (MMSE), the Clock Drawing Test (CDT), and Cognistat. Clinical diagnoses, based on independent neuropsychological examination and a medical consensus discussion in secondary care, were used as criteria for diagnostic accuracy analyses. Results. The sensitivity, specificity, positive predictive value, and negative predictive value were 0.85, 0.79, 0.85, and 0.79, respectively, for Cognistat; 0.59, 0.91, 0.90, and 0.61 for MMSE; 0.26, 0.88, 0.75, and 0.46 for CDT; 0.70, 0.79, 0.82, and 0.65 for MMSE and CDT combined. The area under the receiver operating characteristic curve was 0.82 for Cognistat, 0.75 for MMSE, 0.57 for CDT, and 0.74 for MMSE and CDT combined. Conclusions. The diagnostic accuracy and clinical utility of Cognistat was better than the other tests alone or combined. Cognistat is well adapted for cognitive evaluations in PHC and can help the general practitioner to decide which patients should be referred to secondary care. PMID- 24778878 TI - Nephrogenic systemic fibrosis risk and liver disease. AB - Objective. Evaluate the incidence of nephrogenic systemic fibrosis (NSF) in patients with liver disease in the peritransplant period. Materials and Methods. This IRB approved study retrospectively reviewed patients requiring transplantation for cirrhosis, hepatocellular carcinoma (HCC), or both from 2003 to 2013. Records were reviewed identifying those having gadolinium enhanced MRI within 1 year of posttransplantation to document degree of liver disease, renal disease, and evidence for NSF. Results. Gadolinium-enhanced MRI was performed on 312 of 837 patients, including 23 with severe renal failure (GFR < 30 mL/min/1.73 cm(2)) and 289 with GFR > 30. Two of 23 patients with renal failure developed NSF compared to zero NSF cases in 289 patients with GFR > 30 (0/289; P < 0.003). High dose gadodiamide was used in the two NSF cases. There was no increased incidence of NSF with severe liver disease (1/71) compared to nonsevere liver disease (1/241; P = 0.412). Conclusion. Renal disease is a risk factor for NSF, but in our small sample our evidence suggests liver disease is not an additional risk factor, especially if a low-risk gadolinium agent is used. Noting that not all patients received high-risk gadolinium, a larger study focusing on patients receiving high-risk gadolinium is needed to further evaluate NSF risk in liver disease in the peritransplant period. PMID- 24778879 TI - Features of atherosclerosis in the tunica adventitia of coronary and carotid arteries in a black kenyan population. AB - Introduction. Histologic changes which occur in the tunica adventitia during initiation, progression, and complications of atherosclerosis are seldom reported. This study aimed at describing the features of atherosclerosis in the tunica adventitia of two of the commonly afflicted arteries, namely, left anterior descending coronary and common carotid in black Kenyans. Materials and Methods. Specimens from 108 individuals [76 males and 32 females, mean age 34.6] were processed for paraffin embedding. Seven micron thick sections were stained with Mason's trichrome and Haematoxylin/Eosin and examined with a light microscope. Results. Features of atherosclerosis were present in the tunica adventitia of 14.8% of left anterior descending arteries and 11.1% of common carotid arteries. Increase in adventitial thickness was associated with increased density of vasa vasora in 8.3% of both arteries. In the left anterior descending and common carotid arteries, 6.5% and 3.7% of cases, respectively, the tunica adventitia thickened without intimal hyperplasia. Conclusion. Features of atherosclerosis occur in the tunica adventitia of coronary and carotid arteries in over 10% of the black Kenyans studied. These features often precede the intimo medial changes. Tunica adventitia should therefore be prioritized in evaluation for atherosclerosis, in individuals at risk. This may enhance early detection and intervention. PMID- 24778880 TI - E-bike injuries: experience from an urban emergency department-a retrospective study from Switzerland. AB - Background. Between 2005 and 2012, annual sales of E-bikes in Switzerland increased from 1,792 to 52,941. This continuous and rapid transition from human powered bicycles to an electric bicycle technology may indicate the increasing demand for low-cost transportation technology in combination with a healthy lifestyle. Material and Methods. In the present study, from April 2012 to September 2013, we retrospectively analysed E-bike accidents treated in the Emergency Department of our hospital by focusing on the following parameters: age, gender, time, period, and cause of the accident, as well as injury and outcome. Results. Patients were predominantly male. The mean age of injured E cyclists was 47.5 years. The main causes of injury were self-accident. Most injuries were to the head/neck. The mean ISS was 8.48. The outcome showed that 9 patients were treated as outpatients, 9 were inpatients, and 5 patients were kept in the Intensive Care Unit (ICU). Only six patients underwent surgery (S). Discussion. This is the first attempt to evaluate E-bike injuries in Switzerland in an acute hospital setting. Since there is increasing popular preference for E bikes as means of transportation and injuries to the head or neck are prevalent among E-cyclists, the hazard should not to be underestimated. PMID- 24778881 TI - Kojic Acid production from agro-industrial by-products using fungi. AB - A total of 278 different isolates of filamentous fungi were screened using synthetic medium for respective ability to produce kojic acid. Nineteen, six, and five isolates proved to be low, moderate, and high kojic acid producers, respectively. Levels of kojic acid produced were generally increased when shaking cultivation was used rather than those obtained using static cultivation. A trial for the utilization of 15 agro-industrial wastes or by-products for kojic acid production by the five selected higher kojic acid producer isolates was made. The best by-product medium recorded was molasses for kojic acid. A. flavus numbers 7 and 24 were able to grow and produce kojic acid on only 12 out of 15 wastes or by products media. The best medium used for kojic acid production by A. flavus number 7 was rice fragments followed by molasses, while the best medium used for kojic acid production by A. flavus number 24 was the molasses followed by orange, pea, and rice fragments. An attempt for production of kojic acid using a 1.5 L laboratory fermentor has been made. Aspergillus flavus number 7 was used and grown on molasses medium; maximum level (53.5 g/L) of kojic acid was obtained after eight days of incubation. PMID- 24778882 TI - Impact of minimal residual disease, detected by flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia. AB - In this retrospective study, we evaluated the impact of pre- and posttransplant minimal residual disease (MRD) detected by multiparametric flow cytometry (MFC) on outcome in 160 patients with ALL who underwent myeloablative allogeneic hematopoietic cell transplantation (HCT). MRD was defined as detection of abnormal B or T cells by MFC with no evidence of leukemia by morphology (<5% blasts in marrow) and no evidence of extramedullary disease. Among 153 patients who had pre-HCT flow data within 50 days before transplant, MRD pre-HCT increased the risk of relapse (hazard ratio (HR) = 3.64; 95% confidence interval (CI), 1.87 7.09; P = .0001) and mortality (HR = 2.39; 95% CI, 1.46-3.90, P = .0005). Three year estimates of relapse were 17% and 38% and estimated 3-year OS was 68% and 40% for patients without and with MRD pre-HCT, respectively. 144 patients had at least one flow value post-HCT, and the risk of relapse among those with MRD was higher than that among those without MRD (HR = 7.47; 95% CI, 3.30-16.92, P < .0001). The risk of mortality was also increased (HR = 3.00; 95% CI, 1.44-6.28, P = .004). These data suggest that pre- or post-HCT MRD, as detected by MFC, is associated with an increased risk of relapse and death after myeloablative HCT for ALL. PMID- 24778883 TI - The Association between Female Genital Cutting and Spousal HCV Infection in Egypt. AB - Objective. To identify the risk factors for HCV infection within married couples in Egypt. Methods. In 2008 Egypt conducted its first nationally representative survey of HCV prevalence. 11126 of the 12780 individuals aged 15-59 year who were sampled agreed to participate and provided information via a questionnaire about demographic and behavioural characteristics and blood for HCV antibody and RNA analysis. We assessed the risk factors for HCV infection in a subsample of 5182 married individuals via multivariate logistic regression. Results. Overall HCV antibody prevalence in the married couples was 18.2% (95% CI, 16.8-19.6). HCV antibody prevalence was higher in the husbands (23.7%) than the wives (12.1%; P < 0.001). Having a spouse who was infected with HCV was an independent risk factor for HCV infection with odds ratios of 2.1 (95% CI, 1.6-2.9) and 2.2 (95% CI, 1.6 3.1) for women and men, respectively. Husbands whose wives had experienced female genital cutting (FGC) had a higher prevalence of HCV and this relationship was driven by a strong association in urban areas. Amongst the women there was no association between FGC and HCV overall but in urban areas only women who had experienced FGC were HCV infected. Conclusions. This study provides additional evidence of the importance of intrafamilial transmission of HCV in Egypt. PMID- 24778884 TI - Patterns of antimicrobial resistance in the causative organisms of spontaneous bacterial peritonitis: a single centre, six-year experience of 1981 samples. AB - Background/Aims. Spontaneous bacterial peritonitis (SBP) is one of the leading causes of morbidity and mortality in patients with cirrhosis. This study aims to determine the microbial agents of SBP and the pattern of antibiotic resistance, in a large number of ascitic samples. Methodology. In a cross-sectional, single center, hospital based study, 1981 consecutive ascitic fluid samples were recruited from 2005 to 2011. Samples were dichotomized into three-year periods, in order to assess the trend of resistance to the first-line empirical antibiotics. Results. SBP was found in 482 (24.33%) of samples, of which 314 (65.15%) were culture positive. The most prevalent isolated pathogen was E. coli (33.8%), followed by staphylococcus aureus (8.9%) and Enterococcus (8.6%). No significant changes in the proportion of gram-negative/gram-positive infections occurred during this period. A percentage of resistant strains to cefotaxime (62.5%, 85.7%), ceftazidim (73%, 82.1%), ciprofloxacin (30, 59.8%), ofloxacin (36.8%, 50%), and oxacilin (35%, 51.6%) were significantly increased. E. coli was most sensitive to imipenem, piperacillin-tazobactam, amikacin, ceftizoxime, and gentamicin. Conclusions. The microbial aetiology of SBP remains relatively constant. However, the resistance rate especially to the first-line recommended antibiotics was significantly increased. This pattern must be watched closely and taken into account in empirical antibiotic treatment. PMID- 24778885 TI - Involvement of thalamus in initiation of epileptic seizures induced by pilocarpine in mice. AB - Studies have suggested that thalamus is involved in temporal lobe epilepsy, but the role of thalamus is still unclear. We obtained local filed potentials (LFPs) and single-unit activities from CA1 of hippocampus and parafascicular nucleus of thalamus during the development of epileptic seizures induced by pilocarpine in mice. Two measures, redundancy and directionality index, were used to analyze the electrophysiological characters of neuronal activities and the information flow between thalamus and hippocampus. We found that LFPs became more regular during the seizure in both hippocampus and thalamus, and in some cases LFPs showed a transient disorder at seizure onset. The variation tendency of the peak values of cross-correlation function between neurons matched the variation tendency of the redundancy of LFPs. The information tended to flow from thalamus to hippocampus during seizure initiation period no matter what the information flow direction was before the seizure. In some cases the information flow was symmetrically bidirectional, but none was found in which the information flowed from hippocampus to thalamus during the seizure initiation period. In addition, inactivation of thalamus by tetrodotoxin (TTX) resulted in a suppression of seizures. These results suggest that thalamus may play an important role in the initiation of epileptic seizures. PMID- 24778886 TI - Reduced Renshaw recurrent inhibition after neonatal sciatic nerve crush in rats. AB - Renshaw recurrent inhibition (RI) plays an important gated role in spinal motion circuit. Peripheral nerve injury is a common disease in clinic. Our current research was designed to investigate the change of the recurrent inhibitory function in the spinal cord after the peripheral nerve crush injury in neonatal rat. Sciatic nerve crush was performed on 5-day-old rat puppies and the recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSR) elicited from the sectioned dorsal roots and recorded either from the LG-S and MG nerves by antidromic stimulation of the synergist muscle nerve. Our results demonstrated that the MSR recorded from both LG-S or MG nerves had larger amplitude and longer latency after neonatal sciatic nerve crush. The RI in both LG-S and MG motoneuron pools was significantly reduced to virtual loss (15-20% of the normal RI size) even after a long recovery period upto 30 weeks after nerve crush. Further, the degree of the RI reduction after tibial nerve crush was much less than that after sciatic nerve crush indicatig that the neuron-muscle disconnection time is vital to the recovery of the spinal neuronal circuit function during reinnervation. In addition, sciatic nerve crush injury did not cause any spinal motor neuron loss but severally damaged peripheral muscle structure and function. In conclusion, our results suggest that peripheral nerve injury during neonatal early development period would cause a more sever spinal cord inhibitory circuit damage, particularly to the Renshaw recurrent inhibition pathway, which might be the target of neuroregeneration therapy. PMID- 24778887 TI - Congenital Arthrogryposis: An Extension of the 15q11.2 BP1-BP2 Microdeletion Syndrome? AB - The proximal 15q11-q13 region contains 5 breakpoints (BP1-BP5). The BP1-BP2 region spans approximately 500 kb and contains four evolutionarily conserved genes. The genes in this region are known to play a role in central nervous system development and/or function. Microdeletions within the 15q11.2 BP1-BP2 region have been reported in patients with neurological dysfunction, developmental delays, behavioral problems, and dysmorphic features. We report two unrelated subjects with the 15q11.2 BP1-BP2 microdeletion and presenting with congenital arthrogryposis, a feature which has not been previously reported as part of this newly recognized microdeletion syndrome. While arthrogryposis seen in these two subjects may be coincidental, we propose that congenital arthrogryposis may result from neurological dysfunction and involvement of the microdeletion of the 15q11.2 BP1-BP2 region, further expanding the phenotype of this microdeletion syndrome. We encourage others to report patients with this chromosome microdeletion and neurological findings to further characterize the clinical phenotype. PMID- 24778888 TI - Microduplication of 3p26.3 implicated in cognitive development. AB - We report here a 34-month-old boy with global developmental delay referred for molecular karyotyping and fragile X studies. Molecular karyotype analysis revealed a microduplication in the 3p26.3 region involving part of the CHL1 and CNTN6 genes. Several deletions, one translocation, and one duplication have previously been described in this region of chromosome 3. The CHL1 gene has been proposed as a dosage-sensitive gene with a central role in cognitive development, and so the microduplication reported here appears to be implicated in our patient's phenotype. PMID- 24778889 TI - A turner syndrome patient carrying a mosaic distal x chromosome marker. AB - A skin sample from a 17-year-old female was received for routine karyotyping with a set of clinical features including clonic seizures, cardiomyopathy, hepatic adenomas, and skeletal dysplasia. Conventional karyotyping revealed a mosaic Turner syndrome karyotype with a cell line containing a small marker of X chromosome origin. This was later confirmed on peripheral blood cultures by conventional G-banding, fluorescence in situ hybridisation and microarray analysis. Similar Turner mosaic marker chromosome cases have been previously reported in the literature, with a variable phenotype ranging from the mild "classic" Turner syndrome to anencephaly, agenesis of the corpus callosum, complex heart malformation, and syndactyly of the fingers and toes. This case report has a phenotype that is largely discordant with previously published cases as it lies at the severe end of the Turner variant phenotype scale. The observed cytogenetic abnormalities in this study may represent a coincidental finding, but we cannot exclude the possibility that the marker has a nonfunctioning X chromosome inactivation locus, leading to functional disomy of those genes carried by the marker. PMID- 24778890 TI - Subacromial impingement syndrome caused by a voluminous subdeltoid lipoma. AB - Subacromial impingement syndrome is a clinical diagnosis encompassing a spectrum of possible etiologies, including subacromial bursitis, rotator cuff tendinopathy, and partial- to full-thickness rotator cuff tears. This report presents an unusual case of subdeltoid lipoma causing extrinsic compression and subacromial impingement syndrome. The patient, a 60-year-old man, presented to our institution with a few years' history of nontraumatic, posteriorly localized throbbing pain in his right shoulder. Despite a well-followed 6-months physiotherapy program, the patient was still suffering from his right shoulder. The MRI scan revealed a well-circumscribed 6 cm * 2 cm * 5 cm homogenous lesion compatible with a subdeltoid intermuscular lipoma. The mass was excised en bloc, and subsequent histopathologic examination confirmed a benign lipoma. At 6-months follow-up, the patient was asymptomatic with a complete return to his activities. Based on this case and a review of the literature, a subacromial lipoma has to be included in the differential diagnosis of a subacromial impingement syndrome refractory to nonoperative treatment. Complementary imaging modalities are required only after a failed conservative management to assess the exact etiology and successfully direct the surgical treatment. PMID- 24778891 TI - Imaging features of periosteal chondroma manifesting as a subcutaneous mass in the index finger. AB - Periosteal chondroma is a rare benign hyaline cartilage neoplasm that occurs most commonly in the metaphases of long tubular bones. We present a unique case of periosteal chondroma arising in the proximal phalanx of the left index finger in a 12-year-old boy. Physical examination revealed a slightly protuberant, subcutaneous mass. Plain radiographs and computed tomography scans showed a periosteal lesion producing saucerization of the cortex and subjacent cortical sclerosis, without internal matrix calcification. On magnetic resonance imaging, the lesion exhibited intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Contrast-enhanced fat-suppressed T1 weighted images demonstrated peripheral and septal enhancement. The patient underwent a marginal excision with curettage of the underlying bone cortex. Histological examination confirmed the diagnosis of periosteal chondroma. There has been no evidence of local recurrence eight months after surgery. Periosteal chondroma can protrude into the subcutaneous soft tissue causing a palpable mass. Recognition of the typical radiological features can lead to an accurate diagnosis of this rare condition. PMID- 24778893 TI - Stone formation from nonabsorbable clip migration into the collecting system after robot-assisted partial nephrectomy. AB - We describe a case in which a Weck Hem-o-lok clip (Teleflex, Research Triangle Park, USA) migrated into the collecting system and acted as a nidus for stone formation in a patient after robot-assisted partial nephrectomy. The patient presented 2 years postoperatively with left-sided renal colic. Abdominal computed tomography scan showed a 10 millimeter renal calculus in the left middle pole. After using laser lithotripsy to fragment the overlying renal stone, a Weck Hem-o lok clip was found to be embedded in the collecting system. A laser fiber through a flexible ureteroscope was used to successfully dislodge the clip from the renal parenchyma, and a stone basket was used to extract the clip. PMID- 24778892 TI - Nephron sparing surgery for renal angiomyolipoma with inferior vena cava thrombus in tuberous sclerosis. AB - Introduction. Angiomyolipoma is a common benign renal tumor. It is associated with Tuberous Sclerosis Complex (TSC) in 20% of patients. Angiomyolipomas are classically multiple, bilateral, and growing; they may lead to complications such as Wunderlich syndrome or, in rare cases, to venous extension. Observation. a 74 year-old woman with TSC presented with an angiomyolipoma of the right kidney with inferior vena cava (IVC) fatty thrombus. She underwent partial nephrectomy and thrombectomy. After a 7-year follow-up there was no evidence of recurrence or metastasis and her renal function was preserved. Review of Literature. It is the 44th reported angiomyolipoma associated with IVC thrombus. The mean size of angiomyolipomas was 86.1 mm and 67.4% of patients were symptomatic. Pulmonary embolism was found in 6 patients. There were 2 cases of recurrence/metastatic outcome after radical nephrectomy and thrombectomy. They were associated with epithelioid form. The mean size of epithelioid tumors was significantly bigger than in classical angiomyolipomas (127.1 mm versus 82.6 mm, P = 0.037). With a median follow-up of 12 months, 91.3% of patients were recurrence and metastasis free, with 3 cases of nephron sparing surgery. Conclusion. Nephron sparing surgery for angiomyolipoma with IVC fatty thrombus can be safely performed in TSC, even in sporadic angiomyolipoma. PMID- 24778894 TI - Laparoscopic repair of a ureteric sciatic hernia: report of a case. AB - Ureteric sciatic hernias are extremely rare. Here we report a case of a 78-year old woman presented with colicky left abdominal pain. Computed tomography revealed a ureteric sciatic hernia, and drip infusion pyelography revealed dilated left ureter with herniation of the ureter into the sciatic foramen. The hernia was successfully repaired laparoscopically. We have described the diagnosis and management of the patient, followed by a review of the literature on sciatic hernias. PMID- 24778895 TI - The Effect of Mass Media Campaign on the Use of Insecticide-Treated Bed Nets among Pregnant Women in Nigeria. AB - Background. Malaria during pregnancy is a major public health problem in Nigeria especially in malaria-endemic areas. It increases the risk of low birth weight and child/maternal morbidity/mortality. This paper addresses the impact of radio campaigns on the use of insecticide-treated bed nets among pregnant women in Nigeria. Methods. A total of 2,348 pregnant women were interviewed during the survey across 21 of Nigeria's 36 states. Respondents were selected through a multistage sampling technique. Analysis was based on multivariate logistic regression. Results. Respondents who knew that sleeping under ITN prevents malaria were 3.2 times more likely to sleep under net (OR: 3.15; 95% CI: 2.28 to 4.33; P < 0.0001). Those who listened to radio are also about 1.6 times more likely to use ITN (OR: 1.56; 95% CI: 1.07 to 2.28; P = 0.020), while respondents who had heard of a specific sponsored radio campaign on ITN are 1.53 times more likely to use a bed net (P = 0.019). Conclusion. Pregnant women who listened to mass media campaigns were more likely to adopt strategies to protect themselves from malaria. Therefore, behavior change communication messages that are aimed at promoting net use and antenatal attendance are necessary in combating malaria. PMID- 24778896 TI - Cervical Cytology and Human Papillomavirus Testing in Adolescent Women: Implications in Management of a Positive HPV Test. AB - Objectives. Consensus guidelines establish that HPV testing should not be used to manage adolescents with atypical squamous cells of undetermined significance (ASC US). This study aimed to estimate the impact on follow-up of HPV testing after the first-time ASC-US diagnosis. Methods. From January 2009 to December 2010, all ASC-US diagnoses in adolescents were retrieved. Results. 1950 cervical cytologies were received from this population and 335 cases (17.1%) were reported as ASC-US. A total of 287 cases were included in the study. Cases were divided into control group (no HPV test; 46 cases) and case group (HPV test performed; 241 cases). On follow-up, in the control group, 43.4% patients had cytology, and 56.6% patients had no follow-up. The case group was divided into negative HPV (60 cases) and positive HPV (181 cases). In the negative-HPV group, 41.7% had cytology and 58.3% had no follow-up. In the positive-HPV group, 41% had cytology, 22% underwent colposcopy, and 37% had no follow-up. Patients with positive-HPV results were more likely to have follow-up than patients in the control and negative-HPV groups (63% versus 43.4% versus 41.7%, resp.). Conclusions. HPV infections are common in adolescents. A positive HPV test cannot predict which women will develop carcinoma. Adherence to current guidelines is recommended in this population. PMID- 24778897 TI - Can't and Won't. PMID- 24778898 TI - Location of maxillary intraosseous vascular anastomosis based on the tooth position and height of the residual alveolar bone: computed tomographic analysis. AB - PURPOSE: The aims of this study were to measure the distance of the intraosseous vascular anastomosis in the anterolateral wall of the maxillary sinus from different reference points, and to correlate the location of the intraosseous vascular anastomosis with the tooth position and the residual bone height of the maxilla. METHODS: Computed tomography (CT) images were taken from 283 patients undergoing dental implants placement in the posterior maxilla. Three horizontal lines were drawn at the ridge crest, maxillary sinus floor, and the position of the anastomosis. A vertical second line at the center of each tooth was drawn perpendicular to the horizontal lines. The distance from the ridge crest to the maxillary sinus floor and the distance from the maxillary sinus floor to the bony canal were measured from the intersections of the horizontal and vertical lines. The residual alveolar bone height was used to categorize three groups: group 1,<4 mm; group 2, between 4 and 8 mm; and group 3, >8 mm. RESULTS: The residual bone height values of different tooth positions were significantly different (P=0.0002). The distance from the maxillary sinus floor to the intraosseous vascular anastomosis was significantly different between groups 1 and 3 (P=0.0039). At the molar sites, a moderate negative correlation was found between the residual bone height and the distance from the maxillary sinus floor to the intraosseous anastomosis. The distances of the alveolar ridge crest and the maxillary sinus from the intraosseous vascular anastomosis were not significantly different between sexes. CONCLUSIONS: Within the limitations of this study, sites with a higher residual bone height in the molar regions were at a relatively high risk of artery damage during window osteotomy preparation; therefore, we recommend taking more precautions when using a lateral approach for sinus elevation. PMID- 24778899 TI - Impact of iron deficiency anemia on chronic periodontitis and superoxide dismutase activity: a cross-sectional study. AB - PURPOSE: Both chronic periodontitis (CP) and iron deficiency anemia (IDA) induce oxidative stress in the body and cause an imbalance between reactive oxygen species and antioxidants, such as superoxide dismutase (SOD). This study explored the SOD enzyme activity of saliva and serum in CP patients with and without IDA and analyzed the impact of IDA on CP. METHODS: A total of 82 patients were divided into four groups: control group (CG, 22), periodontally healthy IDA patients (IDA-PH, 20), CP patients (CP, 20), and IDA patients with CP (IDA-CP, 20). After clinical measurements and samplings, serum and salivary SOD levels were determined using an SOD assay kit. RESULTS: IDA-CP patients exhibited a higher gingival index, bleeding on probing, probing pocket depth, and percentage (%) of sites with a clinical attachment loss (CAL) of >=6 mm (P<0.008) than CP patients. The mean salivary and serum SOD levels were significantly lower in the IDA-PH, CP, and IDA-CP patients than in the CG group (P<0.008). A significant positive correlation between salivary and serum SOD activity was observed in IDA (P<0.05). Furthermore, serum and salivary SOD levels were significantly and negatively correlated with all periodontal parameters including the percentage of sites with CAL of 4-5 and >=6 mm (P<0.05) except the significant correlation between salivary SOD activity and mean CAL and the percentage of sites with CAL of 4-5 mm (P>0.05) in these patients. CONCLUSIONS: Within the limits of this study, it may be suggested that IDA patients with chronic periodontitis have more periodontal breakdowns than patients with chronic periodontitis. Serum and salivary SOD activity levels were lower in the IDA-PH, CP and IDA-CP groups than in the CG. Iron deficiency anemia influenced the serum SOD activity but did not seem to affect the salivary SOD activity in these patients. PMID- 24778900 TI - Effect of supportive periodontal therapy on the prevention of tooth loss in Korean adults. AB - PURPOSE: The purpose of this retrospective study was to evaluate the effect of patient compliance with supportive periodontal therapy (SPT) on tooth loss in Korean adults. METHODS: The periodontal records of 134 patients were reviewed for this study. They completed active periodontal treatment from 1999 to 2001 and were placed on a schedule of periodic follow-up visits for SPT. Patient compliance was classified into complete compliance (CC), erratic compliance (EC), and noncompliance (NC) groups. Re-examinations were carried out 11.0+/-0.8 years after the active periodontal treatment. The prognosis for each tooth was determined as good, questionable, or hopeless according to the bone loss observed in pretreatment radiographs. RESULTS: The rate of tooth loss of the CC group was significantly lower than that of the NC group. The tooth loss/patient and the tooth loss/patient/year were not significantly different between the three groups. The rates of tooth loss in the good, questionable, and hopeless prognosis groups were 6.7%, 9.5%, and 13.2%, respectively. For the teeth with a good prognosis, the rate of tooth loss of the CC group was significantly lower than that of the NC group (0.4% vs. 5.1%). For the teeth with a questionable prognosis, the CC group showed a significantly lower rate of tooth loss than did the EC group (4.1% vs. 30.7%) or the NC group (4.1% vs. 25.6%). For the teeth with a hopeless prognosis, the rates of tooth loss were not significantly different among the three groups. CONCLUSIONS: Within the limits of this study, the patients who showed a poor compliance with SPT were more likely to lose teeth than were the regularly compliant patients. However, the risk of tooth loss with a hopeless prognosis was high irrespective of the compliance. PMID- 24778901 TI - Herbal anti-inflammatory immunomodulators as host modulators in chronic periodontitis patients: a randomised, double-blind, placebo-controlled, clinical trial. AB - PURPOSE: Host modulatory therapy has been proposed as a treatment for periodontal diseases. A class of herbal medicines, known to be immunomodulators, alters the activity of immune function through the regulation of informational molecules such as cytokines. In the current study, we tested the hypothesis that herbal immunomodulator drugs act as an adjuvant to scaling and root planing (SRP) in alleviating periodontal inflammation by improving clinical and biochemical parameters. METHODS: Sixty healthy subjects (30 in each group) with moderate and severe chronic periodontitis were enrolled in a double-blind, placebo-controlled, double-masked randomised controlled trial. The control group was treated with SRP and a placebo, whereas the test group was treated with SRP followed by dietary supplementation of Septilin for 3 weeks. Periodontal clinical parameters and serum C-reactive protein (CRP) levels were evaluated for all patients at the baseline, 3 weeks, and 6 weeks. RESULTS: Improved gingival index scores found in the test group as compared to the control group were found to be statistically significant only after 3 weeks (P<0.001). In contrast, the decrease in the sulcus bleeding index and pocket depth scores was statistically highly significant in the test group as compared to the control group after 3 weeks and 6 weeks (P<0.001). However, reduced clinical attachment level and CRP scores, as reflected in the test group as compared to the control group, were not found to be statistically significant after both 3 weeks (P>0.05) and 6 weeks (P>0.05). CONCLUSIONS: The results of this clinical-biochemical study suggest that dietary supplementation with herbal immunomodulatory agents may be a promising adjunct to SRP and may aid in improving periodontal treatment outcomes. PMID- 24778902 TI - A periodontitis-associated multispecies model of an oral biofilm. AB - PURPOSE: While single-species biofilms have been studied extensively, we know notably little regarding multispecies biofilms and their interactions. The purpose of this study was to develop and evaluate an in vitro multispecies dental biofilm model that aimed to mimic the environment of chronic periodontitis. METHODS: Streptococcus gordonii KN1, Fusobacterium nucleatum ATCC23726, Aggregatibacter actinomycetemcomitans ATCC33384, and Porphyromonas gingivalis ATCC33277 were used for this experiment. The biofilms were grown on 12-well plates with a round glass slip (12 mm in diameter) with a supply of fresh medium. Four different single-species biofilms and multispecies biofilms with the four bacterial strains listed above were prepared. The biofilms were examined with a confocal laser scanning microscope (CLSM) and scanning electron microscopy (SEM). The minimum inhibitory concentrations (MIC) for four different planktonic single species and multispecies bacteria were determined. The MICs of doxycycline and chlorhexidine for four different single-species biofilms and a multispecies biofilm were also determined. RESULTS: The CLSM and SEM examination revealed that the growth pattern of the multispecies biofilm was similar to those of single species biofilms. However, the multispecies biofilm became thicker than the single-species biofilms, and networks between bacteria were formed. The MICs of doxycycline and chlorhexidine were higher in the biofilm state than in the planktonic bacteria. The MIC of doxycycline for the multispecies biofilm was higher than were those for the single-species biofilms of P. gingivalis, F. nucleatum, or A. actinomycetemcomitans. The MIC of chlorhexidine for the multispecies biofilm was higher than were those for the single-species biofilms of P. gingivalis or F. nucleatum. CONCLUSIONS: To mimic the natural dental biofilm, a multispecies biofilm composed of four bacterial species was grown. The 24-hour multispecies biofilm may be useful as a laboratory dental biofilm model system. PMID- 24778903 TI - Periodontitis among poor rural Indian mothers increases the risk of low birth weight babies: a hospital-based case control study. AB - PURPOSE: Low birth weight (LBW) is one of the major public health problems in India. Hence, there is a need to identify risk factors that, when modified, will reduce the burden of unhealthy children on the healthcare system. The objective of this study was to determine whether periodontitis among mothers in the rural population of India is a risk factor for LBW babies. METHODS: A hospital-based case control study was conducted among 340 postpartum mothers. The cases consisted of 170 women who had given birth to babies weighing <2,500 g, while the control group consisted of 170 women who had given birth to babies weighing >=2,500 g. Details of the mothers were taken from the hospital records and through a personal interview, and a full-mouth periodontal examination was performed postpartum, which included probing depth, clinical attachment level, and bleeding on probing on six sites per tooth. RESULTS: LBW cases had a significantly worse periodontal status than the controls, having an odds ratio (OR) of 2.94 (P=0.01). The multivariate logistic regression model demonstrated that periodontal disease is a significant independent risk factor with an adjusted odds ratio (aOR) of 2.85 for the LBW group (95% confidence interval [CI], 1.62-5.5). Other factors showing significant associations with LBW were pre eclampsia (aOR, 4.49; 95% CI, 1.4-14.7), preterm labor (aOR, 5.5; 95% CI, 3.2 9.9), and vaginal type of delivery (aOR, 2.74; 95% CI, 1.4-5.2). CONCLUSIONS: Periodontitis represents a strong, independent, and clinically significant risk factor for LBW. Periodontal therapy should form a part of the antenatal preventive care among rural women in India. PMID- 24778904 TI - Simultaneous placement of an interpositional free gingival graft with nonsubmerged implant placement. AB - PURPOSE: Various surgical techniques target achieving adequate keratinized tissue around dental implants; however, these techniques are usually performed before implant placement or upon the exposure of submerged implants. The aim of this case report is to describe a simultaneous placement of an interpositional free gingival graft (iFGG) with that of nonsubmerged implants in a patient lacking keratinized tissue and to assess the long-term outcome of this grafted gingiva. METHODS: A wedge-shaped free gingnival graft (FGG), including an epithelium connective tissue (E-C) portion and a connective-tissue-only (CT) portion, was harvested from the palate. The CT portion was inserted under the buccal flap, and the E-C portion was secured tightly around the implants and to the lingual flap. RESULTS: At the 8-year follow-up, the gingival graft remained firmly attached and was well maintained, with no conspicuous shrinkage or reported discomfort during oral hygiene procedures. The use of an iFGG at a nonsubmerged implant placement minimizes the required number of surgical steps and patient discomfort while providing adequate buccal keratinized tissue. CONCLUSIONS: Therefore, the technique could be considered an alternative method in increasing the keratinized tissue for cases that have a minimal amount of keratinized tissue. PMID- 24778905 TI - Sudden unexpected nocturnal death in Chiari type 1 malformation and potential role of opioid analgesics. AB - BACKGROUND: Chiari malformation type 1 (CM1) is a common congenital anomaly of the craniocervical junction. CM1 is reported to run a usually benign course and patients typically experience no symptoms or chronic, slowly progressive symptoms. However, recent reports indicate that a subset of patients with CM1 may present with acute deterioration and sudden unexpected death (SUD). We report a case of SUD during sleep in a young man with CM1, which we believe was related to the administration of common and therapeutic doses of narcotic analgesics for the management of pain. We will clarify the pathophysiology of acute deterioration and SUD in CM1 and the possibility that the adverse effects of opiate analgesics likely were the leading cause of death in our patient. CASE DESCRIPTION: In this review, we present a 29-year-old male with worsening headache secondary to previously diagnosed CM1. The patient died suddenly and unexpectedly after administration of common and therapeutic doses of narcotic analgesics for the management of pain. CONCLUSION: The mechanism(s) of acute neurological deterioration and sudden death in patients with CM1 remains poorly understood. We believe the rapid fatal deterioration in our patient following administration of opioids suggests that this category of medication may cause sudden unexpected "neurogenic" cardiac death in CM1 patients by inducing sleep-related breathing difficulties and associated hypercapnia. Hypercapnia by further increasing intracranial pressure can result in a sudden pressure-induced decompensation of the cardiopulmonary control centers in the brain stem and cause instantaneous cardiorespiratory arrest. PMID- 24778906 TI - Giant clival chordoma causing pathological laughter. AB - BACKGROUND: Chordomas are rare slowly growing tumors that originate from remnants of the notochord. They have a malignant local behavior, causing symptoms due to bone infiltration and compression of neurovascular structures. Only a few cases of brain tumors associated with pathological laughter have been reported in the literature. CASE DESCRIPTION: We report a case of a 42-year-old male patient with this atypical clinical presentation treated at our institution, and discuss the concerning literature. CONCLUSION: Although being a very rare presentation of chordomas, pathological laughter is usually expected to improve after brain stem decompression. PMID- 24778907 TI - Dural adhesion to porous cranioplastic implant: A potential safety concern. AB - BACKGROUND: Patient-specific implants are used for cranioplastic skull reconstruction when large bone flaps must be replaced or where there are complex or critical contours, especially near the face. These implants have a low complication rate, with poor fit and postoperative infection being the most common complications. We report here a potentially serious hazard that may arise from the use of porous implants. CASE DESCRIPTION: A 45-year-old woman sustained severe head trauma in a motor vehicle accident that required urgent surgical intervention. Because of progressive resorption of her native bone flap, she underwent replacement of her native flap with a hard tissue replacement/patient matched implant cranioplasty. Eight years later, she sustained a traumatic laceration over her vertex that necessitated removal of her cranioplastic implant because of persistent local infection. Intraoperatively, the dural flap was ingrowing and firmly adherent to the inside surface of the porous cranioplasty. After several failed attempts to remove the whole implant piecemeal, we attempted to dissect the dural flap from the brain surface to remove it together with the cranioplastic implant but exposure of the extensive cortical adhesions between the brain surface and the dural flap was compromised by the hard overlying cranioplastic implant. Despite our meticulous attempts to cut off these cortical adhesions, a perisylvian blood vessel was avulsed, resulting in intraparenchymal hemorrhage. CONCLUSION: In this case, dural adhesion and ingrowth to the underside of the cranioplasty implant led to disastrous bleeding when the implant needed to be removed years after initial implantation. PMID- 24778908 TI - Dolichoectasia of the vertebrobasilar complex causing neural compression. PMID- 24778909 TI - The overlooked issue in US unemployment. PMID- 24778910 TI - Thunderclap headache: It is always sub-arachnoid hemorrhage. Is it? - A case report and Review. AB - BACKGROUND: Spontaneous intracranial hypotension (SIH) is one of the relatively misdiagnosed pathophysiological entities by virtue of its presentation. SIH is a condition involving reduced intracranial pressure usually secondary to dural tear. There is recent increase in reporting of its varied presentation in literature. Critical care physicians and neurosurgeons are recognizing it in higher numbers than before. SIH is characterized by sudden onset of orthostatic headache and may be associated with neck stiffness, nausea, vomiting, tinnitus, deafness, and cognitive abnormalities. Since its imaging characteristics resemble classic subdural hematoma from other causes wrong diagnosis and intervention might have devastating outcome. CASE DESCRIPTION: Here we discuss a case presented to us with severe headache of sudden onset without any associated problems. Patient was initially being treated as sinusitis and later diagnosed as bilateral subdural hematoma and surgical intervention was being considered. Thorough history taking and physical examination lead to strong suspicion of intracranial hypotension (IH) and patient showed dramatic improvement with epidural blood patch. CONCLUSION: IH is a commonly misdiagnosed entity. A high index of suspicion is required for timely diagnosis, in order to minimize unwanted therapeutic interventions that can worsen the patient's condition and to help initiate early and simple interventions. PMID- 24778911 TI - Subtotal resection of an intradural mature teratoma in an adult presenting with difficulty initiating micturition. AB - BACKGROUND: Teratomas are tumors comprised of tissues from all three germ layers. Teratomas within the spine are exceedingly rare especially in the absence of either spinal dysraphism, congenital abnormalities of the spine, spinal surgery, or history of lumbar punctures. Virchow was the first to describe this occurrence in the spine in 1863 and since then, only a handful of cases have been reported. CASE DESCRIPTION: A 41-year-old male presented with a longstanding history of difficulty initiating micturition and lower back pain with recent onset of saddle paraesthesia and bilateral leg pain. He did not have a history suggestive of spinal trauma nor congenital abnormalities. Neurological examination was unremarkable. Magnetic resonance imaging (MRI) confirmed the presence of an intradural extra axial lesion in the region of the cauda equine. At surgery, the lesion was found to be densely adherent to the conus and a subtotal resection was performed. Histological examination confirmed the lesion to be a mature teratoma. Postoperatively, he made a good recovery and there is no evidence of recurrence at one year follow-up. CONCLUSION: This case demonstrates that a teratoma without immature elements can be subtotally excised to reduce the risk of neurological morbidity. PMID- 24778912 TI - Conservative surgery for osteoid osteoma of the lumbar vertebrae. AB - BACKGROUND: We present two patients with osteoid osteomas of the lumbar spine to highlight the delay in diagnosis and the utility of precise radiological localization enabling tumor resection without jeopardizing spinal stability. CASE DESCRIPTION: Two young patients with refractory back pain presented after having undergone a year of conservative treatment for presumed mechanical back pain. The presence of "red-flag" symptoms (e.g. rest and night pain, and transient pain relief with aspirin) led to the performance of an isotope bone scan, and subsequent computed tomography (CT), which were both consistent with the diagnosis of an osteoid osteoma. After accurate CT-based preoperative planning for tumor excision, a customized conservative surgical technique was utilized that included marginal en-bloc surgical resection of the tumors. As the intervertebral facet joints were also carefully preserved along with stability, no accompanying instrumented fusion was warranted. Both patients returned to full function with complete resolution of their long-standing back pain of more than 2 years. CONCLUSIONS: The diagnosis of osteoid osteoma of the spine requires a high index of clinical suspicion. Diagnostic evaluations should include thin-slice CT scan to assist in planning the most restricted/conservative en-bloc surgical resection while preserving vertebral stability with facet preservation, and thus avoiding instrumented fusions. Without the availability of percutaneous radiofrequency ablation, such restricted/conservative approaches to osteoid osteomas are viable options in countries with developing economies. PMID- 24778913 TI - Timing of cranioplasty after decompressive craniectomy for trauma. AB - BACKGROUND: The optimal timing of cranioplasty after decompressive craniectomy for trauma is unknown. The aim of this study was to determine if early cranioplasty after decompressive craniectomy for trauma reduces complications. METHODS: Consecutive cases of patients who underwent autologous cranioplasty after decompressive craniectomy for trauma at a single Level I Trauma Center were studied in a retrospective 10 year data review. Associations of categorical variables were compared using Chi-square test or Fisher's exact test. RESULTS: A total of 157 patients were divided into early (<12 weeks; 78 patients) and late (>=12 weeks; 79 patients) cranioplasty cohorts. Baseline characteristics were similar between the two cohorts. Cranioplasty operative time was significantly shorter in the early (102 minutes) than the late (125 minutes) cranioplasty cohort (P = 0.0482). Overall complication rate in both cohorts was 35%. Infection rates were lower in the early (7.7%) than the late (14%) cranioplasty cohort as was bone graft resorption (15% early, 19% late), hydrocephalus rate (7.7% early, 1.3% late), and postoperative hematoma incidence (3.9% early, 1.3% late). However, these differences were not statistically significant. Patients <18 years of age were at higher risk of bone graft resorption than patients >=18 years of age (OR 3.32, 95% CI 1.25-8.81; P = 0.0162). CONCLUSIONS: After decompressive craniectomy for trauma, early (<12 weeks) cranioplasty does not alter the incidence of complication rates. In patients <18 years of age, early (<12 weeks) cranioplasty increases the risk of bone resorption. Delaying cranioplasty (>=12 weeks) results in longer operative times and may increase costs. PMID- 24778914 TI - Unusual hemodynamic stroke related to an accessory middle cerebral artery: The usefulness of fusion images from three-dimensional angiography. AB - BACKGROUND: Ischemic stroke associated with an anomaly of the middle cerebral artery (MCA) is a rare occurrence. The diagnosis is very difficult when there are steno-occlusive lesions associated with an accessory middle cerebral artery (AMCA). CASE DESCRIPTION: A 77-year-old female with hypertension and hyperlipidemia experienced repeated transient ischemic attacks (TIAs) of motor aphasia and dysarthria. Although angiography showed only left intracranial occlusion, the fusion images of three-dimensional digital subtraction angiography (3-D DSA) showed complex steno-occlusive lesions and an AMCA related with the TIA. The cerebral blood flow (CBF) to the left frontal lobe was supplied by the AMCA, via the anterior communicating artery from the right internal carotid artery. The left temporal and parietal lobes were supplied by the stenotic MCA, via the left posterior communicating artery from the left posterior cerebral artery. Single-photon emission computed tomography showed a marked decrease in CBF to both the left frontal and temporal lobes. A left superficial temporal artery (STA)-to-left MCA double anastomosis was performed, in which each branch of the STA supplied branches of the AMCA and MCA. CONCLUSION: This is the first reported case of ischemic stroke in a patient with an AMCA. The exact diagnosis could be made only by using fusion images of 3-D DSA, which were useful for understanding the complicated CBF pattern and for the choice of recipient artery in bypass surgery. PMID- 24778915 TI - A case of Langerhans cell histiocytosis of the skull in which preoperative methionine positron emission tomography was useful in comprehending the spreading of the lesion. AB - BACKGROUND: The problem with treatments against skull lesions of Langerhans cell histiocytosis (LCH) is that invasions often reach the bones and dura mater, making it difficult to accurately comprehend the range thereof prior to surgery. We herein report that (11)C-methionine positron emission tomography (PET) (Met PET) carried out prior to surgery was useful in comprehending the spreading of the lesion. CASE DESCRIPTION: A 20-year-old female presented with swelling and dull pain on the left side of the head. A slightly heterogeneously reinforced tumor was observed inside the bone defect in the gadolinium-enhanced T1-wighted image upon magnetic resonance imaging (MRI) and the dura mater contacting the tumor was observed with an enhancing effect. Accumulation was poor in the center of the tumor upon Met-PET, and accumulation with a well-defined border was observed in the border thereof as well as the area adjacent to the brain. Surgical resection was performed; the pathological diagnosis was LCH. An invasion of tumor cells was observed in the dura mater with accumulation observed according to Met-PET. Moreover, the accumulation of tumor cells was observed in the area observed with accumulation inside the bone; however, the center part with poor accumulation lacked tumor cells, with fibrous tissue accounting for most parts. CONCLUSION: Met-PET was believed to be helpful in comprehending the spreading of the tumor in the surroundings of the brain surface for skull lesions. PMID- 24778916 TI - "Microbleeding" from intracranial aneurysms: Local hemosiderin deposition identified during microsurgical treatment of unruptured intracranial aneurysms. AB - BACKGROUND: During elective surgery for unruptured aneurysms, we have identified a group of patients with hemosiderin staining of the pial surface immediately adjacent to the aneurysm dome suggesting a remote and unrecognized history of microbleeding from the aneurysm. These cases form the basis for this report. METHODS: Medical records of 421 unruptured cerebral aneurysm patients treated surgically between January 2003 and September 2010 were retrospectively reviewed. Patients with a history of prior subarachnoid hemorrhage, craniotomy, or significant closed head injury were excluded from review. Records were reviewed for intraoperative descriptions of hemosiderin deposition in the vicinity of the aneurysm as well as history of headaches, time to presentation, comorbidities, aneurysm characteristics, procedures, and radiologic imaging. RESULTS: Local hemosiderin staining immediately adjacent to the aneurysm was identified intraoperatively in 13 cases. Each of these patients had a history of remote atypical headache prior to presentation. Eight of these patients (62%) had aneurysms described as particularly "thin-walled" at the time of surgery. Aneurysm locations included the internal carotid artery (ICA) (54%), middle cerebral artery (MCA) (23%), anterior communicating artery (ACOMMA) (15%), and the anterior cerebral artery (ACA) (8%). More than half (54%) of these patients had a history of smoking, while 31% had hypertension, and 23% had a history of alcohol abuse. Dyslipidemia and family history of aneurysms were present in 15% and hypercholesterolemia was noted in one patient (8%). CONCLUSION: We suggest this group of patients had suffered a "microbleed" resulting in local hemosiderin deposition next to the aneurysm. The origins and clinical implications of such microbleeds are unknown and warrant further investigation. PMID- 24778917 TI - Pilomyxoid astrocytoma of the cerebellar vermis in an elderly patient. AB - BACKGROUND: Pilomyxoid astrocytoma (PMA) has recently been accepted as an aggressive variant of pilocytic astrocytoma with distinct histopathological features. PMAs have been frequently described in the pediatric population with a predilection for the hypothalamic/chiasmatic region. CASE DESCRIPTION: A 72-year old African American male presented with 6 months of memory loss, difficulty expressing himself, and a progressively worsening gait. Magnetic resonance imaging of the brain demonstrated a heterogeneously enhancing cystic mass centered within the cerebellar vermis with mass effect on the fourth ventricle and ventriculomegaly. The patient underwent placement of a ventriculoperitoneal shunt followed by a surgical resection of the lesion, which after immunohistopathologic evaluation, was diagnosed as a World Health Organization grade II PMA. The patient refused further treatment of the lesion and expired 11 months after initial symptom presentation and 4 months after surgery. CONCLUSION: To our knowledge, this is the first report of PMA of the cerebellar vermis in a previously unreported age group. This case report describes the natural history of this type of tumor in a patient who refused adjuvant therapy following surgical resection. PMID- 24778918 TI - Long-term follow-up in two cases of intracranial Rosai-Dorfman Disease complicated by incomplete resection and recurrence. AB - BACKGROUND: Although intracranial Rosai-Dorfman disease is a principally benign lymphohistiocytosis, some patients run a relapsing or progressive course. However, reports about long-term follow-up are extremely rare. CASE DESCRIPTION: In two patients, initial tumor resection was incomplete or followed by recurrences over 3 years, which finally subsided after application of chemotherapy, and patients remained tumor-free for more than 7 years thereafter. CONCLUSION: Up to now there is no agreement on how to treat complicated cases of intracranial Rosai-Dorfman disease; our good experience with adjuvant chemotherapy and long-term follow-up will contribute to treatment planning in complicated cases. PMID- 24778919 TI - Synchronous multicentric glioblastoma with PNET and O subtypes: Possible pathogenesis. AB - BACKGROUND: Glioblastomas (GBM) are highly infiltrative, cellular and mitotically active tumors with large histologic variations within and between tumours. Several subtypes have been described including the GBM with oligodendroglial differentiation (GBM-O) and primitive neuroectodermal tumour components (GBM PNET). We report the first described case of a patient with synchronous multi centric GBM-O and GBM-PNET components. CASE DESCRIPTION: A patient, who presented with a short history of progressive headache and difficulty with memory recall, was found on MRI imaging to have two intracranial lesions. These showed heterogeneous enhancement and were found in the left frontal and left temporal regions. The patient underwent gross total resection of these two lesions which were found to show GBM-O and GBM-PNET differentiations. CONCLUSION: Although tumour cell migration in the context of GBM is a well-recognized phenomenon, the traditional hypothesis is not able to satisfactorily explain this case of multicentric GBM whereby the two lesions demonstrate different cell origins. More current understanding of the migratory pathways from the subventricular zone provide an alternate and plausible pathway that fits our patient's unusual diagnosis. PMID- 24778920 TI - Orbital tuberculosis with coexisting fungal (Aspergillus flavus) infection. AB - BACKGROUND: A coexisting invasive fungal and tubercular involvement of the skull base is a rare event. Co-infection has been reported with involvement of paranasal sinuses and middle ear cleft. CASE DESCRIPTION: We herein report a case of an elderly male diabetic patient who presented with gradually progressive visual loss, which on imaging showed an orbital lesion. Surgical decompression and microbiological evaluation showed growth of Mycobacterium tuberculosis and Aspergillus flavus. CONCLUSION: Rare combinations of such infections do exist and should be treated aggressively to achieve good outcomes in a losing battle with fastidious organisms in the backdrop of compromised immunity. PMID- 24778921 TI - Hemangioblastoma of the optic nerve producing bilateral optic tract edema in a patient with von Hippel-Lindau disease. AB - BACKGROUND: The authors present a novel case of a hemangioblastoma of the optic nerve producing bilateral optic tract edema in a patient with von Hippel-Lindau disease (VHL). This is the only case in the literature documenting optic tract edema secondary to a hemangioblastoma of the optic nerve. CASE DESCRIPTION: The patient was a 34-year-old female in whom this lesion was causing retro-orbital pain and proptosis. She had previously lost vision in the symptomatic eye secondary to a retinal hemangioblastoma. The optic nerve lesion was excised by sectioning the optic nerve both proximally and distally to the lesion. There were no complications and patient's symptoms resolved postoperatively. A follow-up magnetic resonance imaging (MRI) scan revealed complete excision of the mass and resolution of the optic tract edema. CONCLUSION: Optic nerve hemangioblastomas in patients with VHL are rare, but are manageable with meticulous microneurosurgery and with appropriate patient expectations. This is the first known case of an optic nerve hemangioblastoma producing bilateral optic tract edema, which resolved after resection of the prechiasmal tumor. Hemangioblastoma should remain in the differential diagnosis of optic nerve tumors, especially in the setting of VHL. PMID- 24778922 TI - Minimally invasive posterior cervical decompression using tubular retractor: The technical note and early clinical outcome. AB - BACKGROUND: The aim of this work is to present a novel decompression technique that approaches cervical spine posteriorly, but through minimal invasive method using tubular retractor avoiding detachment of posterior musculature. METHODS: Six patients underwent minimally invasive posterior cervical decompression using the tubular retractor system and surgical microscope. Minimally invasive access to the posterior cervical spine was performed with exposure through a paramedian muscle-splitting approach. With the assistance of a specialized tubular retraction system and deep soft tissue expansion mechanism, multilevel posterior cervical decompression could be accomplished. This approach also allows safe docking of the retractor system on the lateral mass, thus avoiding the cervical spinal canal during exposure. A standard operating microscope was used with *10 magnification and 400 mm focal length. The hospital charts, magnetic resonance imaging studies, and follow-up records of all the patients were reviewed. Outcome was assessed by neurological status and visual analog scale (VAS) for neck and arm pain. RESULTS: There was no significant complication related to operation. The follow-up time was 4-12 months (mean, 9 months). Muscle weakness improved in all patients; sensory deficits resolved in four patients and improved in two patients. Analysis of the mean VAS for radicular pain and VAS for neck pain showed significant improvement. CONCLUSIONS: The preliminary experiences with good clinical outcome seem to promise that this minimally invasive technique is a valid alternative option for the treatment of cervical spondylotic myelopathy. PMID- 24778923 TI - The extended supracerebellar transtentorial approach for resection of medial tentorial meningiomas. AB - BACKGROUND: The supracerebellar transtentorial (SCTT) approach has been established as a safe corridor to access the posteriomedial basal temporal region. Previous reports have demonstrated the efficacy of this route in the resection of intrinsic tumors and small arteriovenous malformations. Only one report in the English literature has described its use to resect a medial tentorial meningioma. METHODS: The authors discuss the relevant surgical anatomy of this approach and its advantages compared with more traditional routes, and illustrate its application to remove medial tentorial meningiomas through two operative cases with accompanying videos. RESULTS: In illustrative case one, the patient recovered from surgery with no deficits. All his preoperative symptoms had resolved at 3-month follow-up. At the 4-year follow-up, MRI did not demonstrate any growth of the residual tumor. In case two, gross total resection was achieved and the patient did not suffer any postoperative language or visual deficit. At 2-year follow-up, no tumor recurrence was present. CONCLUSION: The SCTT approach has a potential to safely access extra-axial lesions located around the medial tentorial incisura. As demonstrated in these two cases, the approach merits consideration in patients with tentorial meningiomas as an alternative to more widely utilized skull base approaches and subtemporal routes. PMID- 24778924 TI - STAT2 signaling and dengue virus infection. AB - Dengue virus (DENV) is an important human pathogen whose byzantine relationship with the immune response is poorly understood. DENV causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, diseases for which palliative care is the only treatment. DENV immunopathogenesis studies are complicated by the lack of an immunocompetent small-animal model, and this has hindered anti DENV drug and vaccine development. This review describes strategies that DENV uses to evade the type I interferon response and focuses on how data gained from the study of DENV NS5-mediated STAT2 degradation may be used to create immunocompetent DENV mouse models and design anti-DENV therapeutics. PMID- 24778925 TI - Integrating non-coding RNAs in JAK-STAT regulatory networks. AB - Being a well-characterized pathway, JAK-STAT signaling serves as a valuable paradigm for studying the architecture of gene regulatory networks. The discovery of untranslated or non-coding RNAs, namely microRNAs and long non-coding RNAs, provides an opportunity to elucidate their roles in such networks. In principle, these regulatory RNAs can act as downstream effectors of the JAK-STAT pathway and/or affect signaling by regulating the expression of JAK-STAT components. Examples of interactions between signaling pathways and non-coding RNAs have already emerged in basic cell biology and human diseases such as cancer, and can potentially guide the identification of novel biomarkers or drug targets for medicine. PMID- 24778926 TI - The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. AB - JAK-STAT3 signaling, while regulating many aspects of cancer development and progression, promotes invasion and metastasis through activation of key metastasis promoting genes such as WASF3. STAT3 promotes WASF3 expression and JAK2 independently activates it, which is required for invasion. JAK-STAT3 signaling is dependent on WASF3 function, since its inactivation in cells expressing JAK-STAT3 suppresses invasion. WASF3 overexpression leads to activation of NFkappaB and ZEB1 which also promote invasion through regulation of target genes involved in metastasis. NFkappaB frequently cooperates with STAT3 to upregulate metastasis promoting genes such as matrix metalloproteinases and cytokines, as well as to suppress microRNAs which can suppresses invasion. This better understanding of the complex role played by JAK-STAT3 in the regulation of cell movement, invasion, and metastasis provides opportunities to suppress this lethal aspect of cancer progression by not only targeting the JAK and STAT3 proteins directly, but also some of the downstream effectors of JAK-STAT3 signaling. PMID- 24778928 TI - Molecular regulation of macrophages in unleashing cancer-related inflammation. AB - It is unclear how tumor-associated macrophages (TAMs) contribute to the initiation of oncogenesis and how they are regulated at the molecular level. By using a lineage-specific deletion strategy, we found that heat shock protein 90kDa beta (Grp94), member 1 (HSP90B1), a master chaperone for Toll-like receptors and integrins also known as GP96, critically endows TAMs with the ability to promote genotoxic stress and colitis-associated colon cancer. PMID- 24778929 TI - GM-CSF facilitates the development of inflammation-associated colorectal carcinoma. AB - The granulocyte macrophage colony-stimulating factor (GM-CSF) is known to play a protective role in intestinal inflammation. However, the effects of GM-CSF on the progression of colitis to colorectal carcinoma have long remained unclear. We have recently demonstrated that GM-CSF produced by colonic epithelial cells promotes colorectal tumorigenesis by stimulating the secretion of vascular endothelial growth factor. PMID- 24778927 TI - Protein tyrosine phosphatases as wardens of STAT signaling. AB - Signaling by signal transducers and activators of transcription (STATs) is controlled at many levels of the signaling cascade. Protein tyrosine phosphatases (PTPs) regulate STAT activation at several layers, including direct pSTAT dephosphorylation in both cytoplasm and nucleus. Despite the importance of this regulation mode, many aspects are still incompletely understood, e.g., the identity of PTPs acting on certain members of the STAT family. After a brief introduction into the STAT and PTP families, we discuss here the current knowledge on PTP mediated regulation of STAT activity, focusing on the interaction of individual STATs with specific PTPs. Finally, we highlight open questions and propose important tasks of future research. PMID- 24778930 TI - The worm that lived: Evolution of rapid aging under high extrinsic mortality revisited. AB - Organisms age because of the "selection shadow"-the decline of the force of natural selection with age. Seemingly straightforward corollary of this theory is the Medawar-Williams prediction, which maintains that increased extrinsic (non aging) mortality will result in the evolution of accelerated aging and decreased longevity. Despite its centrality to modern thinking about the ultimate causes of aging, this prediction ignores the fact that mortality is often a non-random process depending on individual condition. Increased condition-dependent mortality inescapably results in increased selection for resistance against the agent of mortality. Provided that resistance to various stressors is commonly associated with increased longevity, the evolutionary outcome is no longer certain. We recently documented this experimentally by showing that populations of Caenorhabditis remanei evolved to live shorter under high extrinsic mortality, but only when mortality was applied haphazardly. On the contrary, when extrinsic mortality was caused by heat-shock, populations experiencing the same rate of increased mortality evolved greater longevities, notwithstanding increased "selection shadow." Intriguingly, stress-resistant and long-lived worms were also more fecund. We discuss these results in the light of recent theoretical developments, such as condition-environment interactions and hyperfunction theory of aging. PMID- 24778931 TI - Switch-like regulation of tissue-specific alternative pre-mRNA processing patterns revealed by customized fluorescence reporters. AB - Alternative processing of precursor mRNAs (pre-mRNAs), including alternative transcription start sites, alternative splicing and alternative polyadenylation, is the major source of protein diversity and plays crucial roles in development, differentiation and diseases in higher eukaryotes. It is estimated from microarray analyses and deep sequencing of mRNAs from synchronized worms that up to 25% of protein-coding genes in Caenorhabditis elegans undergo alternative pre mRNA processing and that many of them are subject to developmental regulation. Recent progress in visualizing the alternative pre-mRNA processing patterns in living worms with custom-designed fluorescence reporters has enabled genetic analyses of the regulatory mechanisms for alternative processing events of interest in vivo. Expression of the tissue-specific isoforms of actin depolymerising factor (ADF)/cofilin, UNC-60A and UNC-60B, is regulated by a combination of alternative splicing and alternative polyadenylation of pre-mRNA from a single gene unc-60. We recently found that muscle-specific splicing regulators ASD-2 and SUP-12 cooperatively switch the pre-mRNA processing patterns of the unc-60 gene in body wall muscles. Here I summarize the bichromatic fluorescence reporter system utilized for visualizing the tissue-specific alternative processing patterns of the unc-60 pre-mRNA. I also discuss the model for the coordinated regulation of the UNC-60B-type pre-mRNA processing in body wall muscles by ASD-2 and SUP-12. PMID- 24778932 TI - Regulation of TGFbeta superfamily signaling by two separable domains of glypican LON-2 in C. elegans. AB - Regulated intercellular signaling is critical for the normal development and maintenance of multicellular organisms. Glypicans have been shown to regulate signaling by TGFbetas, hedgehogs and Wnts, in several cellular contexts. Glypicans comprise a conserved family of heparan sulfated, glycosylphosphatidylinositol (GPI)-linked extracellular proteins. The structural complexity of glypicans may underlie their functional complexity. In a recent study(31), we built on previous findings that one of the two C. elegans glypicans, LON-2, specifically inhibits signaling by the TGFbeta superfamily member DBL-1. We tested the functional requirements of LON-2 protein core components and post-translational modifications for LON-2 activity. We provide the first evidence that two parts of a glypican can independently regulate TGFbeta superfamily signaling in vivo: the N-terminal furin protease product and a C-terminal region containing heparan sulfate attachment sites. Furthermore, we show a protein-protein interaction motif is crucial for LON-2 activity in the N terminal protein core, suggesting that LON-2 acts by serving as a scaffold for DBL-1 and an RGD-binding protein. In addition, we demonstrate specificity of glypican function by showing C. elegans GPN-1 does not functionally substitute for LON-2. This work reveals a molecular foundation for understanding the complexity and specificity of glypican function. PMID- 24778933 TI - The role of the formin gene fhod-1 in C. elegans embryonic morphogenesis. AB - During the second half of embryogenesis, the ellipsoidal Caenorhabditis elegans embryo elongates into a long, thin worm. This elongation requires a highly organized cytoskeleton composed of actin microfilaments, microtubules and intermediate filaments throughout the epidermis of the embryo. This architecture allows the embryonic epidermal cells to undergo a smooth muscle-like actin/myosin based contraction that is redundantly controlled by LET- 502/Rho kinase and MEL 11/myosin phosphatase in one pathway and FEM-2/PP2c phosphatase and PAK-1/p21 activated kinase in a parallel pathway(s). Although actin microfilaments surround the embryo, the force for contraction is generated mainly in the lateral (seam) epidermal cells whose actin microfilaments appear qualitatively different from those in their dorsal/ventral neighbors. We have identified FHOD-1, a formin family actin nucleator, which acts in the lateral epidermis. fhod-1 mutants show microfilament defects in the embryonic lateral epidermal cells and FHOD-1 protein is detected only in those cells. fhod-1 genetic interactions with let-502, mel 11, fem-2 and pak-1 indicate that fhod-1 preferentially regulates those microfilaments acting with let-502 and mel-11, and in parallel to fem-2 and pak 1. Thus, FHOD-1 may contribute to the qualitative differences in microfilaments found in the contractile lateral epidermal cells and their non-contractile dorsal and ventral neighbors. Different microfilament populations may be involved in the different contractile pathways. PMID- 24778934 TI - Deep sequencing strategies for mapping and identifying mutations from genetic screens. AB - The development of next-generation sequencing technologies has enabled rapid and cost effective whole genome sequencing. This technology has allowed researchers to shortcut time-consuming and laborious methods used to identify nucleotide mutations in forward genetic screens in model organisms. However, causal mutations must still be mapped to a region of the genome so as to aid in their identification. This can be achieved simultaneously with deep sequencing through various methods. Here we discuss alternative deep sequencing strategies for simultaneously mapping and identifying causal mutations in Caenorhabditis elegans from mutagenesis screens. Focusing on practical considerations, such as the particular mutant phenotype obtained, this review aims to aid the reader in choosing which strategy to adopt to successfully clone their mutant. PMID- 24778935 TI - The SAS-5 N-terminal domain is a tetramer, with implications for centriole assembly in C. elegans. AB - The centriole is a conserved microtubule-based organelle essential for both centrosome formation and cilium biogenesis. It has a unique 9-fold symmetry and its assembly is governed by at least five component proteins (SPD-2, ZYG-1, SAS 5, SAS-6 and SAS-4), which are recruited in a hierarchical order. Recently published structural studies of the SAS-6 N-terminal domain have greatly advanced our understanding of the mechanisms of centriole assembly. However, it remains unclear how the weak interaction between the SAS-6 N-terminal head groups could drive the assembly of a closed ring-like structure, and what determines the stacking of multiple rings on top one another in centriole duplication. We recently reported that SAS-5 binds specifically to a very narrow region of the SAS-6 central coiled coil through its C-terminal domain (CTD, residues 391-404). Here, we further demonstrate by both static light scattering and small angle X ray scattering that the SAS-5 N-terminal domain (NTD, residues 1-260) forms a tetramer. Specifically, we found that the tetramer is formed by SAS-5 residues 82 260, whereas residues 1-81 are intrinsically disordered. Taking these results together, we propose a working model for SAS-5-mediated assembly of the multi layered central tube structure. PMID- 24778936 TI - Complex RIA calcium dynamics and its function in navigational behavior. AB - Recently, we have reported novel and complex calcium dynamics in the RIA interneuron, which has been implicated in several navigational behaviors in C. elegans. Here, we review our findings on the compartmentalized and global calcium events in RIA and propose functional consequence as well as potential regulatory mechanisms of these intriguing calcium signals. PMID- 24778937 TI - Chaperoning myosin assembly in muscle formation and aging. AB - The activity and assembly of various myosin subtypes is coordinated by conserved UCS (UNC-45/CRO1/She4p) domain proteins. One founding member of the UCS family is the Caenorhabditis elegans UNC-45 protein important for the organization of striated muscle filaments. Our recent structural and biochemical results demonstrated that UNC-45 forms a protein chain with defined periodicity of myosin interaction domains. Intriguingly, the UNC-45 chain serves as docking platform for myosin molecules, which promotes ordered spacing and incorporation of myosin into contractile muscle sarcomeres. The physiological relevance of this observation was demonstrated in C. elegans by transgenic expression of UNC-45 chain formation mutants, which provokes defects in muscle structure and size. Collaborating with the molecular chaperones, Hsp70 and Hsp90, chain formation of UNC-45 links myosin folding with myofilament assembly. Here, we discuss our recent findings on the dynamic regulation of UNC-45 structure and stability in the context of muscle regeneration mechanisms that are affected in myopathic diseases and during aging. PMID- 24778938 TI - C. elegans fmi-1/flamingo and Wnt pathway components interact genetically to control the anteroposterior neurite growth of the VD GABAergic neurons. AB - During development, multiple environmental cues, e.g., growth factors, cell adhesion molecules, etc., interact to influence the pattern of outgrowth of axons and dendrites in a cell-specific fashion. As a result, individual neurons may receive similar signals, but make unique choices, leading to distinct wiring within the nervous system. C. elegans has been useful in identifying molecular cues that influence neuronal development, as well as the downstream mechanisms that allow individual neurons to make cell-specific responses. Recently, we described a role for the conserved cadherin domain-containing protein, FMI 1/flamingo, in multiple stages of neural development in C. elegans. During the initial phase of neurite outgrowth, FMI-1 seems to have a relatively cell specific effect on the VD neurons to promote the initial neurite formed to grow toward the anterior. In this capacity, FMI-1 appears to work coordinately with at least two Wnt ligands, EGL-20 and LIN-44, and multiple downstream Wnt signaling components (including LIN-17/Frizzled, DSH-1/Disheveled, and BAR-1/beta-catenin). Here I will discuss some of the ideas we considered about how FMI-1 could affect neurons as they acquire their morphology during development. PMID- 24778939 TI - Role of the CRL2(LRR-1) E3 ubiquitin-ligase in the development of the germline in C. elegans. AB - The ubiquitin-proteolytic system (UPS) regulates a variety of cellular and biological processes by controlling the stability of regulatory proteins, in space and time. Not surprisingly, defects in this system have been associated with various syndromes and pathologies, including cancer, illustrating the importance of understanding the regulation and the multiple functions of this system. C. elegans is a powerful model system to identify components of the UPS and to study their function during development in multicellular organisms. In C. elegans, the evolutionarily conserved CRL2(LRR-1) E3-ligase is critical for the development of the germline. Inactivation of the CUL-2 scaffold or the LRR-1 substrate-recognition subunit leads to a cell cycle arrest in germline stem cells resulting in sterility. Through a genetic screen, we have identified a cul-2 temperature-sensitive allele and we have used this allele to show that CUL-2 plays multiple roles in the development of the germline. CUL-2 (1) promotes germ cell proliferation, (2) influences the balance between mitotic proliferation and meiotic differentiation, and (3) inhibits the first step of meiotic prophase. Here, we discuss how CUL-2 regulates and coordinates these different processes. We suggest that ubiquitin-mediated protein degradation constitutes an important additional layer of regulation that contributes to the spatial organization of the germline. PMID- 24778940 TI - Filamin and Phospholipase C-epsilon are required for calcium signaling in the Caenorhabditis elegans Spermatheca. AB - Mechanical properties of the microenvironment are fundamental in orchestrating normal tissue function, disease progression, and organismal development. Studies of mechanotransduction in cultured cells on artificial substrates have revealed underlying principles, but the in vivo roles of mechanotransduction remain unclear. We recently reported that the Caenorhabditis elegans spermatheca-a myoepithelial tube composed of a cell monolayer-may be mechanosensitive. Live imaging with the genetically encoded calcium indicator GCaMP revealed that oocyte induced stretching of the spermatheca resulted in calcium oscillations and constriction of the tube. FLN-1/filamin, a mechanosensitive cytoskeletal scaffolding protein, is required to correctly trigger the calcium transients. PLC 1/phospholipase C-epsilon and ITR-1/IP3 receptor are required to produce the calcium transients, and may function downstream of filamin. In addition to providing important insights into the biology of C. elegans, our studies offer a novel and genetically tractable model for studying mechanotransduction in a myoepithelial tissue. PMID- 24778941 TI - A tale of two receptors: Dual roles for ionotropic acetylcholine receptors in regulating motor neuron excitation and inhibition. AB - Nicotinic or ionotropic acetylcholine receptors (iAChRs) mediate excitatory signaling throughout the nervous system, and the heterogeneity of these receptors contributes to their multifaceted roles. Our recent work has characterized a single iAChR subunit, ACR-12, which contributes to two distinct iAChR subtypes within the C. elegans motor circuit. These two receptor subtypes regulate the coordinated activity of excitatory (cholinergic) and inhibitory (GABAergic) motor neurons. We have shown that the iAChR subunit ACR-12 is differentially expressed in both cholinergic and GABAergic motor neurons within the motor circuit. In cholinergic motor neurons, ACR-12 is incorporated into the previously characterized ACR-2 heteromeric receptor, which shows non-synaptic localization patterns and plays a modulatory role in controlling circuit function.(1) In contrast, a second population of ACR-12-containing receptors in GABAergic motor neurons, ACR-12GABA, shows synaptic expression and regulates inhibitory signaling.(2) Here, we discuss the two ACR-12-containing receptor subtypes, their distinct expression patterns, and functional roles in the C. elegans motor circuit. We anticipate our continuing studies of iAChRs in the C. elegans motor circuit will lead to novel insights into iAChR function in the nervous system as well as mechanisms for their regulation. PMID- 24778943 TI - Sealing the ducts: Tight junctions of ductal epithelium. PMID- 24778942 TI - Cell invasion through basement membrane: The netrin receptor DCC guides the way. AB - Cell invasion through basement membrane is an essential part of normal development and physiology, and occurs during the pathological progression of human inflammatory diseases and cancer. F-actin-rich membrane protrusions, called invadopodia, have been hypothesized to be the "drill bits" of invasive cells, mediating invasion through the dense, highly cross-linked basement membrane matrix. Though studied in vitro for over 30 y, invadopodia function in vivo has remained elusive. We have recently discovered that invadopodia breach basement membrane during anchor cell invasion in C. elegans, a genetically and visually tractable in vivo invasion event. Further, we found that the netrin receptor DCC localizes to the initial site of basement membrane breach and directs invasion through a single gap in the matrix. In this commentary, we examine how the dynamics and structure of AC-invadopodia compare with in vitro invadopodia and how the netrin receptor guides invasion through a single basement membrane breach. We end with a discussion of our surprising result that the anchor cell pushes the basement membrane aside, instead of completely dissolving it through proteolysis, and provide some ideas for how proteases and physical displacement may work together to ensure efficient and robust invasion. PMID- 24778944 TI - Modeling and optimization of atomic layer deposition processes on vertically aligned carbon nanotubes. AB - Many energy conversion and storage devices exploit structured ceramics with large interfacial surface areas. Vertically aligned carbon nanotube (VACNT) arrays have emerged as possible scaffolds to support large surface area ceramic layers. However, obtaining conformal and uniform coatings of ceramics on structures with high aspect ratio morphologies is non-trivial, even with atomic layer deposition (ALD). Here we implement a diffusion model to investigate the effect of the ALD parameters on coating kinetics and use it to develop a guideline for achieving conformal and uniform thickness coatings throughout the depth of ultra-high aspect ratio structures. We validate the model predictions with experimental data from ALD coatings of VACNT arrays. However, the approach can be applied to predict film conformality as a function of depth for any porous topology, including nanopores and nanowire arrays. PMID- 24778945 TI - Atomic layer deposition, a unique method for the preparation of energy conversion devices. PMID- 24778946 TI - Extracellular biosynthesis of gadolinium oxide (Gd2O3) nanoparticles, their biodistribution and bioconjugation with the chemically modified anticancer drug taxol. AB - As a part of our programme to develop nanobioconjugates for the treatment of cancer, we first synthesized extracellular, protein-capped, highly stable and well-dispersed gadolinium oxide (Gd2O3) nanoparticles by using thermophilic fungus Humicola sp. The biodistribution of the nanoparticles in rats was checked by radiolabelling with Tc-99m. Finally, these nanoparticles were bioconjugated with the chemically modified anticancer drug taxol with the aim of characterizing the role of this bioconjugate in the treatment of cancer. The biosynthesized Gd2O3 nanoparticles were characterized by UV-vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoemission spectroscopy (XPS). The Gd2O3-taxol bioconjugate was confirmed by UV-vis spectroscopy and fluorescence microscopy and was purified by using high performance liquid chromatography (HPLC). PMID- 24778947 TI - Nanoscale patterning of a self-assembled monolayer by modification of the molecule-substrate bond. AB - The intercalation of Cu at the interface of a self-assembled monolayer (SAM) and a Au(111)/mica substrate by underpotential deposition (UPD) is studied as a means of high resolution patterning. A SAM of 2-(4'-methylbiphenyl-4-yl)ethanethiol (BP2) prepared in a structural phase that renders the Au substrate completely passive against Cu-UPD, is patterned by modification with the tip of a scanning tunneling microscope. The tip-induced defects act as nucleation sites for Cu-UPD. The lateral diffusion of the metal at the SAM-substrate interface and, thus, the pattern dimensions are controlled by the deposition time. Patterning down to the sub-20 nm range is demonstrated. The difference in strength between the S-Au and S-Cu bond is harnessed to develop the latent Cu-UPD image into a patterned binary SAM. Demonstrated by the exchange of BP2 by adamantanethiol (AdSH) this is accomplished by a sequence of reductive desorption of BP2 in Cu free areas followed by adsorption of AdSH. The appearance of Au adatom islands upon the thiol exchange suggests that the interfacial structures of BP2 and AdSH SAMs are different. PMID- 24778948 TI - Unlocking higher harmonics in atomic force microscopy with gentle interactions. AB - In dynamic atomic force microscopy, nanoscale properties are encoded in the higher harmonics. Nevertheless, when gentle interactions and minimal invasiveness are required, these harmonics are typically undetectable. Here, we propose to externally drive an arbitrary number of exact higher harmonics above the noise level. In this way, multiple contrast channels that are sensitive to compositional variations are made accessible. Numerical integration of the equation of motion shows that the external introduction of exact harmonic frequencies does not compromise the fundamental frequency. Thermal fluctuations are also considered within the detection bandwidth of interest and discussed in terms of higher-harmonic phase contrast in the presence and absence of an external excitation of higher harmonics. Higher harmonic phase shifts further provide the means to directly decouple the true topography from that induced by compositional heterogeneity. PMID- 24778949 TI - Frequency, amplitude, and phase measurements in contact resonance atomic force microscopies. AB - The resonance frequency, amplitude, and phase response of the first two eigenmodes of two contact-resonance atomic force microscopy (CR-AFM) configurations, which differ in the method used to excite the system (cantilever base vs sample excitation), are analyzed in this work. Similarities and differences in the observables of the cantilever dynamics, as well as the different effect of the tip-sample contact properties on those observables in each configuration are discussed. Finally, the expected accuracy of CR-AFM using phase-locked loop detection is investigated and quantification of the typical errors incurred during measurements is provided. PMID- 24778950 TI - Noncontact atomic force microscopy II. PMID- 24778951 TI - Effect of contaminations and surface preparation on the work function of single layer MoS2. AB - Thinning out MoS2 crystals to atomically thin layers results in the transition from an indirect to a direct bandgap material. This makes single layer MoS2 an exciting new material for electronic devices. In MoS2 devices it has been observed that the choice of materials, in particular for contact and gate, is crucial for their performance. This makes it very important to study the interaction between ultrathin MoS2 layers and materials employed in electronic devices in order to optimize their performance. In this work we used NC-AFM in combination with quantitative KPFM to study the influence of the substrate material and the processing on single layer MoS2 during device fabrication. We find a strong influence of contaminations caused by the processing on the surface potential of MoS2. It is shown that the charge transfer from the substrate is able to change the work function of MoS2 by about 40 meV. Our findings suggest two things. First, the necessity to properly clean devices after processing as contaminations have a great impact on the surface potential. Second, that by choosing appropriate materials the work function can be modified to reduce contact resistance. PMID- 24778952 TI - Challenges and complexities of multifrequency atomic force microscopy in liquid environments. AB - This paper illustrates through numerical simulation the complexities encountered in high-damping AFM imaging, as in liquid enviroments, within the specific context of multifrequency atomic force microscopy (AFM). The focus is primarily on (i) the amplitude and phase relaxation of driven higher eigenmodes between successive tip-sample impacts, (ii) the momentary excitation of non-driven higher eigenmodes and (iii) base excitation artifacts. The results and discussion are mostly applicable to the cases where higher eigenmodes are driven in open loop and frequency modulation within bimodal schemes, but some concepts are also applicable to other types of multifrequency operations and to single-eigenmode amplitude and frequency modulation methods. PMID- 24778953 TI - Interaction of iron phthalocyanine with the graphene/Ni(111) system. AB - Graphene grown on crystalline metal surfaces is a good candidate to act as a buffer layer between the metal and organic molecules that are deposited on top, because it offers the possibility to control the interaction between the substrate and the molecules. High-resolution angular-resolved ultraviolet photo electron spectroscopy (ARPES) is used to determine the interaction states of iron phthalocyanine molecules that are adsorbed onto graphene on Ni(111). The iron phthalocyanine deposition induces a quenching of the Ni d surface minority band and the appearance of an interface state on graphene/Ni(111). The results have been compared to the deposition of iron phthalocyanine on graphene/Ir(111), for which a higher decoupling of the organic molecule from the underlying metal is exerted by the graphene buffer layer. PMID- 24778954 TI - Near-infrared dye loaded polymeric nanoparticles for cancer imaging and therapy and cellular response after laser-induced heating. AB - BACKGROUND: In the past decade, researchers have focused on developing new biomaterials for cancer therapy that combine imaging and therapeutic agents. In our study, we use a new biocompatible and biodegradable polymer, termed poly(glycerol malate co-dodecanedioate) (PGMD), for the synthesis of nanoparticles (NPs) and loading of near-infrared (NIR) dyes. IR820 was chosen for the purpose of imaging and hyperthermia (HT). HT is currently used in clinical trials for cancer therapy in combination with radiotherapy and chemotherapy. One of the potential problems of HT is that it can up-regulate hypoxia-inducible factor-1 (HIF-1) expression and enhance vascular endothelial growth factor (VEGF) secretion. RESULTS: We explored cellular response after rapid, short-term and low thermal dose laser-IR820-PGMD NPs (laser/NPs) induced-heating, and compared it to slow, long-term and high thermal dose heating by a cell incubator. The expression levels of the reactive oxygen species (ROS), HIF-1 and VEGF following the two different modes of heating. The cytotoxicity of NPs after laser/NP HT resulted in higher cell killing compared to incubator HT. The ROS level was highly elevated under incubator HT, but remained at the baseline level under the laser/NP HT. Our results show that elevated ROS expression inside the cells could result in the promotion of HIF-1 expression after incubator induced-HT. The VEGF secretion was also significantly enhanced compared to laser/NP HT, possibly due to the promotion of HIF-1. In vitro cell imaging and in vivo healthy mice imaging showed that IR820-PGMD NPs can be used for optical imaging. CONCLUSION: IR820-PGMD NPs were developed and used for both imaging and therapy purposes. Rapid and short term laser/NP HT, with a low thermal dose, does not up-regulate HIF-1 and VEGF expression, whereas slow and long term incubator HT, with a high thermal dose, enhances the expression of both transcription factors. PMID- 24778955 TI - Thermal stability and reduction of iron oxide nanowires at moderate temperatures. AB - BACKGROUND: The thermal stability of iron oxide nanowires, which were obtained with a hard template method and are promising elements of Li-ion based batteries, has been investigated by means of thermogravimetry, infrared and photoemission spectroscopy measurements. RESULTS: The chemical state of the nanowires is typical of the Fe2O3 phase and the stoichiometry changes towards a Fe3O4 phase by annealing above 440 K. The shape and morphology of the nanowires is not modified by moderate thermal treatment, as imaged by scanning electron microscopy. CONCLUSION: This complementary spectroscopy-microscopy study allows to assess the temperature limits of these Fe2O3 nanowires during operation, malfunctioning or abuse in advanced Li-ion based batteries. PMID- 24778956 TI - Tensile properties of a boron/nitrogen-doped carbon nanotube-graphene hybrid structure. AB - Doping is an effective approach that allows for the intrinsic modification of the electrical and chemical properties of nanomaterials. Recently, a graphene and carbon nanotube hybrid structure (GNHS) has been reported, which extends the excellent properties of carbon-based materials to three dimensions. In this paper, we carried out a first-time investigation on the tensile properties of the hybrid structures with different dopants. It is found that with the presence of dopants, the hybrid structures usually exhibit lower yield strength, Young's modulus, and earlier yielding compared to that of a pristine hybrid structure. For dopant concentrations below 2.5% no significant reduction of Young's modulus or yield strength could be observed. For all considered samples, the failure is found to initiate at the region where the nanotubes and graphene sheets are connected. After failure, monatomic chains are normally observed around the failure region. Dangling graphene layers without the separation of a residual CNT wall are found to adhere to each other after failure with a distance of about 3.4 A. This study provides a fundamental understanding of the tensile properties of the doped graphene-nanotube hybrid structures, which will benefit the design and also the applications of graphene-based hybrid materials. PMID- 24778957 TI - Control theory for scanning probe microscopy revisited. AB - We derive a theoretical model for studying SPM feedback in the context of control theory. Previous models presented in the literature that apply standard models for proportional-integral-derivative controllers predict a highly unstable feedback environment. This model uses features specific to the SPM implementation of the proportional-integral controller to give realistic feedback behaviour. As such the stability of SPM feedback for a wide range of feedback gains can be understood. Further consideration of mechanical responses of the SPM system gives insight into the causes of exciting mechanical resonances of the scanner during feedback operation. PMID- 24778958 TI - A catechol biosensor based on electrospun carbon nanofibers. AB - Carbon nanofibers (CNFs) were prepared by combining electrospinning with a high temperature carbonization technique. And a polyphenol biosensor was fabricated by blending the obtained CNFs with laccase and Nafion. Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscope (FE-SEM) were, respectively, employed to investigate the structures and morphologies of the CNFs and of the mixtures. Cyclic voltammetry and chronoamperometry were employed to study the electrocatalysis of the catechol biosensor. The results indicated that the sensitivity of the biosensor was 41 uA.mM(-1), the detection limit was 0.63 uM, the linear range was 1-1310 uM and the response time was within 2 seconds, which excelled most other laccase-based biosensor reported. Furthermore, the biosensor showed good repeatability, reproducibility, stability and tolerance to interferences. This novel biosensor also demonstrated its promising application in detecting catechol in real water samples. PMID- 24778959 TI - Photoactivation of luminescence in CdS nanocrystals. AB - This paper presents the results of the research on the luminescence of cadmium sulfide nanocrystals (NCs) synthesized by colloid chemistry in a gelatinous matrix. The photostimulation of the short-wavelength emission band with lambdamax = 480 nm has been detected. It is shown that the determining factor of the photostimulation effect is the adsorption of the water molecules on the surface of NC. The observed effect is explained by the recombination mechanism that is responsible for the short-wavelength emission band. PMID- 24778960 TI - Dye-sensitized Pt@TiO2 core-shell nanostructures for the efficient photocatalytic generation of hydrogen. AB - Pt@TiO2 core-shell nanostructures were prepared through a hydrothermal method. The dye-sensitization of these Pt@TiO2 core-shell structures allows for a high photocatalytic activity for the generation of hydrogen from proton reduction under visible-light irradiation. When the dyes and TiO2 were co-excited through the combination of two irradiation beams with different wavelengths, a synergic effect was observed, which led to a greatly enhanced H2 generation yield. This is attributed to the rational spatial distribution of the three components (dye, TiO2, Pt), and the vectored transport of photogenerated electrons from the dye to the Pt particles via the TiO2 particle bridge. PMID- 24778961 TI - Exploring the complex mechanical properties of xanthan scaffolds by AFM-based force spectroscopy. AB - The polysaccharide xanthan has been extensively studied owing to its potential application in tissue engineering. In this paper, xanthan scaffold structures were investigated by atomic force microscope (AFM) in liquid, and the mechanical properties of the complex xanthan structures were investigated by using AFM-based force spectroscopy (FS). In this work, three types of structures in the xanthan scaffold were identified based on three types of FS stretching events. The fact that the complex force responses are the combinations of different types of stretching events suggests complicated intermolecular interactions among xanthan fibrils. The results provide crucial information to understand the structures and mechanical properties of the xanthan scaffold. PMID- 24778962 TI - Morphological characterization of fullerene-androsterone conjugates. AB - Here we report on the self-organization characteristics in water of two diastereomer pairs of fullerene-androsterone hybrids that have the hydrophobic C60 appendage in the A and D ring of the androsterone moiety, respectively. The morphology and particle size in aqueous solution were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS), with satisfactory agreement between both techniques. In general, these fullerene derivatives are shown to organize into spherical nano-scale structures with diameters in the ranges of 10-20 and 30-50 nm, respectively. PMID- 24778963 TI - One pot synthesis of silver nanoparticles using a cyclodextrin containing polymer as reductant and stabilizer. AB - A facile and one pot synthesis of silver nanoparticles with narrow size distributions using silver nitrate and a copolymer 1 from N-isopropylacrylamide (NIPAM) and mono-(1H-triazolylmethyl)-2-methylacryl-beta-cyclodextrin acting as reductant and stabilizer without using any additional reducing agent is reported. The reduction was carried out in aqueous solution under pH neutral conditions at room temperature. The results of dynamic light scattering analysis and transmission electron microscopy show adjustable particle sizes from 30-100 nm, due to variation of silver nitrate concentration, the polymeric reducing and stabilisation agent concentration or reaction time. The spherical structure of the silver nanoparticles has been confirmed by UV-vis spectroscopy and transmission electron microscopy. The optical properties of the nanoparticles have also been characterized by fluorescence spectroscopy. The formed spherical particles are stable in aqueous medium at room temperature over a period of several weeks. Furthermore the changes in the optical properties of the nanoparticles due to thermo induced volume phase transition behavior of the thermoresponsive cyclodextrin containing polymer 1 have been characterized by UV vis spectroscopy. PMID- 24778964 TI - Uncertainties in forces extracted from non-contact atomic force microscopy measurements by fitting of long-range background forces. AB - In principle, non-contact atomic force microscopy (NC-AFM) now readily allows for the measurement of forces with sub-nanonewton precision on the atomic scale. In practice, however, the extraction of the often desired 'short-range' force from the experimental observable (frequency shift) is often far from trivial. In most cases there is a significant contribution to the total tip-sample force due to non-site-specific van der Waals and electrostatic forces. Typically, the contribution from these forces must be removed before the results of the experiment can be successfully interpreted, often by comparison to density functional theory calculations. In this paper we compare the 'on-minus-off' method for extracting site-specific forces to a commonly used extrapolation method modelling the long-range forces using a simple power law. By examining the behaviour of the fitting method in the case of two radically different interaction potentials we show that significant uncertainties in the final extracted forces may result from use of the extrapolation method. PMID- 24778965 TI - Fullerenes as adhesive layers for mechanical peeling of metallic, molecular and polymer thin films. AB - We show that thin films of C60 with a thickness ranging from 10 to 100 nm can promote adhesion between a Au thin film deposited on mica and a solution deposited layer of the elastomer polymethyldisolaxane (PDMS). This molecular adhesion facilitates the removal of the gold film from the mica support by peeling and provides a new approach to template stripping which avoids the use of conventional adhesive layers. The fullerene adhesion layers may also be used to remove organic monolayers and thin films as well as two-dimensional polymers which are pre-formed on the gold surface and have monolayer thickness. Following the removal from the mica support the monolayers may be isolated and transferred to a dielectric surface by etching of the gold thin film, mechanical transfer and removal of the fullerene layer by annealing/dissolution. The use of this molecular adhesive layer provides a new route to transfer polymeric films from metal substrates to other surfaces as we demonstrate for an assembly of covalently-coupled porphyrins. PMID- 24778966 TI - Preparation of poly(N-vinylpyrrolidone)-stabilized ZnO colloid nanoparticles. AB - We propose a method for the synthesis of a colloidal ZnO solution with poly(N vinylpyrrolidone) (PVP) as stabilizer. Stable colloidal solutions with good luminescence properties are obtained by using PVP as stabilizer in the synthesis of ZnO nanoparticles by a sol-gel method assisted by ultrasound. Nanoparticles with sizes of 30-40 nm in a PVP matrix are produced as a solid product. The colloidal ZnO/PVP/methanol solution, apart from the most intense PL band at 356 nm coming from the PVP, exhibits a strong PL band at 376 nm (3.30 eV) which corresponds to the emission of the free exciton recombination in ZnO nanoparticles. PMID- 24778967 TI - Impact of thermal frequency drift on highest precision force microscopy using quartz-based force sensors at low temperatures. AB - In frequency modulation atomic force microscopy (FM-AFM) the stability of the eigenfrequency of the force sensor is of key importance for highest precision force measurements. Here, we study the influence of temperature changes on the resonance frequency of force sensors made of quartz, in a temperature range from 4.8-48 K. The sensors are based on the qPlus and length extensional principle. The frequency variation with temperature T for all sensors is negative up to 30 K and on the order of 1 ppm/K, up to 13 K, where a distinct kink appears, it is linear. Furthermore, we characterize a new type of miniaturized qPlus sensor and confirm the theoretically predicted reduction in detector noise. PMID- 24778968 TI - Neutral and charged boron-doped fullerenes for CO2 adsorption. AB - Recently, the capture and storage of CO2 have attracted research interest as a strategy to reduce the global emissions of greenhouse gases. It is crucial to find suitable materials to achieve an efficient CO2 capture. Here we report our study of CO2 adsorption on boron-doped C60 fullerene in the neutral state and in the 1e (-)-charged state. We use first principle density functional calculations to simulate the CO2 adsorption. The results show that CO2 can form weak interactions with the BC59 cage in its neutral state and the interactions can be enhanced significantly by introducing an extra electron to the system. PMID- 24778969 TI - Single-asperity contact mechanics with positive and negative work of adhesion: Influence of finite-range interactions and a continuum description for the squeeze-out of wetting fluids. AB - In this work, single-asperity contact mechanics is investigated for positive and negative work of adhesion Deltagamma. In the latter case, finite-range repulsion acts in addition to hard-wall constraints. This constitutes a continuum model for a contact immersed in a strongly wetting fluid, which can only be squeezed out in the center of the contact through a sufficiently large normal load F N. As for positive work of adhesion, two stable solutions can coexist in a finite range of normal loads. The competing solutions can be readily interpreted as contacts with either a load-bearing or a squeezed-out fluid. The possibility for coexistence and the subsequent discontinuous wetting and squeeze-out instabilities depend not only on the Tabor coefficient MUT but also on the functional form of the finite range repulsion. For example, coexistence and discontinuous wetting or squeeze out do not occur when the repulsion decreases exponentially with distance. For positive work of adhesion, the normal displacement mainly depends on F N, Deltagamma, and MUT but - unlike the contact area - barely on the functional form of the finite-range attraction. The results can benefit the interpretation of atomic force microscopy in liquid environments and the modeling of multi-asperity contacts. PMID- 24778970 TI - One-step synthesis of high quality kesterite Cu2ZnSnS4 nanocrystals - a hydrothermal approach. AB - The present work demonstrates a systematic approach for the synthesis of pure kesterite-phase Cu2ZnSnS4 (CZTS) nanocrystals with a uniform size distribution by a one-step, thioglycolic acid (TGA)-assisted hydrothermal route. The formation mechanism and the role of TGA in the formation of CZTS compound were thoroughly studied. It has been found that TGA interacted with Cu(2+) to form Cu(+) at the initial reaction stage and controlled the crystal-growth of CZTS nanocrystals during the hydrothermal reaction. The consequence of the reduction of Cu(2+) to Cu(+) led to the formation Cu2- x S nuclei, which acted as the crystal framework for the formation of CZTS compound. CZTS was formed by the diffusion of Zn(2+) and Sn(4+) cations to the lattice of Cu2- x S during the hydrothermal reaction. The as-synthesized CZTS nanocrystals exhibited strong light absorption over the range of wavelength beyond 1000 nm. The band gap of the material was determined to be 1.51 eV, which is optimal for application in photoelectric energy conversion device. PMID- 24778971 TI - The softening of human bladder cancer cells happens at an early stage of the malignancy process. AB - Various studies have demonstrated that alterations in the deformability of cancerous cells are strongly linked to the actin cytoskeleton. By using atomic force microscopy (AFM), it is possible to determine such changes in a quantitative way in order to distinguish cancerous from non-malignant cells. In the work presented here, the elastic properties of human bladder cells were determined by means of AFM. The measurements show that non-malignant bladder HCV29 cells are stiffer (higher Young's modulus) than cancerous cells (HTB-9, HT1376, and T24 cell lines). However, independently of the histological grade of the studied bladder cancer cells, all cancerous cells possess a similar level of the deformability of about a few kilopascals, significantly lower than non malignant cells. This underlines the diagnostic character of stiffness that can be used as a biomarker of bladder cancer. Similar stiffness levels, observed for cancerous cells, cannot be fully explained by the organization of the actin cytoskeleton since it is different in all malignant cells. Our results underline that it is neither the spatial organization of the actin filaments nor the presence of stress fibers, but the overall density and their 3D-organization in a probing volume play the dominant role in controlling the elastic response of the cancerous cell to an external force. PMID- 24778972 TI - Nanoscale particles in technological processes of beneficiation. AB - BACKGROUND: Cavitation is a rather common and important effect in the processes of destruction of nano- and microscale particles in natural and technological processes. A possible cavitation disintegration of polymineral nano- and microparticles, which are placed into a liquid, as a result of the interaction of the particles with collapsed cavitation bubbles is considered. The emphasis is put on the cavitation processes on the interface between liquid and fine solid particles, which is suitable for the description of the real situations. RESULTS: The results are illustrated for the minerals that are most abundant in gold ore. The bubbles are generated by shock loading of the liquid heated to the boiling temperature. Possibilities of cavitation separation of nano- and microscale monomineral fractions from polymineral nano- and microparticles and of the use of cavitation for beneficiation are demonstrated. CONCLUSION: The cavitation disintegration mechanism is important because the availability of high-grade deposits in the process of mining and production of noble metals is decreasing. This demands for an enhancement of the efficiency in developing low-grade deposits and in reprocessing ore dumps and tailings, which contain a certain amount of noble metals in the form of finely disseminated fractions. The cavitation processes occuring on the interface between liquid and fine solid particles are occasionally more effective than the bulk cavitation processes that were considered earlier. PMID- 24778973 TI - Plasma-assisted synthesis and high-resolution characterization of anisotropic elemental and bimetallic core-shell magnetic nanoparticles. AB - Magnetically anisotropic as well as magnetic core-shell nanoparticles (CS-NPs) with controllable properties are highly desirable in a broad range of applications. With this background, a setup for the synthesis of heterostructured magnetic core-shell nanoparticles, which relies on (optionally pulsed) DC plasma gas condensation has been developed. We demonstrate the synthesis of elemental nickel nanoparticles with highly tunable sizes and shapes and Ni@Cu CS-NPs with an average shell thickness of 10 nm as determined with scanning electron microscopy, high-resolution transmission electron microscopy and energy dispersive X-ray spectroscopy measurements. An analytical model that relies on classical kinetic gas theory is used to describe the deposition of Cu shell atoms on top of existing Ni cores. Its predictive power and possible implications for the growth of heterostructured NP in gas condensation processes are discussed. PMID- 24778974 TI - Applicability and costs of nanofiltration in combination with photocatalysis for the treatment of dye house effluents. AB - Nanofiltration (NF) is a capable method for the separation of dyes, which can support and even improve the applicability of photocatalysis in effluent treatment processes. The membrane process usually will need a special pre treatment to avoid precipitation and fouling on the membrane surface. Conceptually NF can be applied in the pre-treatment prior to the catalytic reactor or in connection with the reactor to separate the liquid phase from the reaction system and to recycle finely suspended catalysts and/or organic compounds. When concerning such reaction systems on a bigger scale, cost figures will prove the usefulness of those concepts. Different applications of photocatalysis on the lab-scale have been published in recent years. Membrane technology is used almost in all those processes and an overview will be given of those recently published systems that have been reported to be potentially useful for a further scale-up. NF membranes are mostly used for the more sophisticated separation step of these processes and the additional costs of the NF treatment, without any associated equipments, will be described and illustrated. The total specific costs of industrial NF treatment processes in usefully adjusted and designed plants range from 1 to 6 US$/m(3) treated effluent. Combination concepts will have a good precondition for further development and upscaling, if the NF costs discussed here in detail will be, together with the costs of photocatalysis, economically acceptable. PMID- 24778975 TI - Encapsulation of nanoparticles into single-crystal ZnO nanorods and microrods. AB - One-dimensional single crystal incorporating functional nanoparticles of other materials could be an interesting platform for various applications. We studied the encapsulation of nanoparticles into single-crystal ZnO nanorods by exploiting the crystal growth of ZnO in aqueous solution. Two types of nanodiamonds with mean diameters of 10 nm and 40 nm, respectively, and polymer nanobeads with size of 200 nm have been used to study the encapsulation process. It was found that by regrowing these ZnO nanorods with nanoparticles attached to their surfaces, a full encapsulation of nanoparticles into nanorods can be achieved. We demonstrate that our low-temperature aqueous solution growth of ZnO nanorods do not affect or cause degradation of the nanoparticles of either inorganic or organic materials. This new growth method opens the way to a plethora of applications combining the properties of single crystal host and encapsulated nanoparticles. We perform micro-photoluminescence measurement on a single ZnO nanorod containing luminescent nanodiamonds and the spectrum has a different shape from that of naked nanodiamonds, revealing the cavity effect of ZnO nanorod. PMID- 24778976 TI - Energy dissipation in multifrequency atomic force microscopy. AB - The instantaneous displacement, velocity and acceleration of a cantilever tip impacting onto a graphite surface are reconstructed. The total dissipated energy and the dissipated energy per cycle of each excited flexural mode during the tip interaction is retrieved. The tip dynamics evolution is studied by wavelet analysis techniques that have general relevance for multi-mode atomic force microscopy, in a regime where few cantilever oscillation cycles characterize the tip-sample interaction. PMID- 24778977 TI - Calibration of quartz tuning fork spring constants for non-contact atomic force microscopy: direct mechanical measurements and simulations. AB - Quartz tuning forks are being increasingly employed as sensors in non-contact atomic force microscopy especially in the "qPlus" design. In this study a new and easily applicable setup has been used to determine the static spring constant at several positions along the prong of the tuning fork. The results show a significant deviation from values calculated with the beam formula. In order to understand this discrepancy the complete sensor set-up has been digitally rebuilt and analyzed by using finite element method simulations. These simulations provide a detailed view of the strain/stress distribution inside the tuning fork. The simulations show quantitative agreement with the beam formula if the beam origin is shifted to the position of zero stress onset inside the tuning fork base and torsional effects are also included. We further found significant discrepancies between experimental calibration values and predictions from the shifted beam formula, which are related to a large variance in tip misalignment during the tuning fork assembling process. PMID- 24778978 TI - Genetics and smoking. AB - Regular smoking is the major risk factor for cardiovascular disease and cancers, and thus is one of the most preventable causes of morbidity and mortality worldwide. Intake of nicotine, its central nervous system effects, and its metabolism are regulated by biological pathways; some of these are well known, but others are not. Genetic studies offer a method for developing insights into the genes contributing to those pathways. In recent years, large genome-wide association study (GWAS) meta-analyses have consistently revealed that the strongest genetic contribution to smoking-related traits comes from variation in the nicotinic receptor subunit genes. Many other genes, including those coding for enzymes involved in nicotine metabolism, also have been implicated. However, the proportion of phenotypic variance explained by the identified genetic variants is very modest. This review intends to cover progress made in genetics and genetic epidemiology of smoking behavior in recent years, and focuses on studies revealing the nicotinic receptor gene cluster on chromosome 15q25. Evidence supporting the involvement of a novel pathway in the shared pathophysiology of nicotine dependence and schizophrenia is also briefly reviewed. A summary of the current knowledge on gene-environment interactions involved in smoking behavior is included. PMID- 24778979 TI - HYDROGEL-BASED NANOCOMPOSITES OF THERAPEUTIC PROTEINS FOR TISSUE REPAIR. AB - The ability to design artificial extracellular matrices as cell instructive scaffolds has opened the door to technologies capable of studying cell fates in vitro and to guide tissue repair in vivo. One main component of the design of artificial extracellular matrices is the incorporation of protein-based biochemical cues to guide cell phenotypes and multicellular organizations. However, promoting the long-term bioactivity, controlling the bioavailability and understanding how the physical presentations of these proteins impacts cellular fates are among the challenges of the field. Nanotechnolgy has advanced to meet the challenges of protein therapeutics. For example, the approaches to incorporating proteins into tissue repairing scaffolds have ranged from bulk encapsulations to smart nanodepots that protect proteins from degradations and allow opportunities for controlled release. PMID- 24778980 TI - Prevalence of mandibular fractures reported at C.S.M.S.S Dental College, aurangabad from february 2008 to september 2009. AB - AIM: The aim of this study is to determine the etiology, frequency of mandibular fractures among different age and sex, to determine the frequency of anatomic distribution, and to report the different modalities of treatment provided to the patients reported at our institution from February 2008 to September 2009. MATERIALS AND METHODS: All patients fulfilling the selection criteria and having mandible fracture were selected for the study. Patient information was collected by means of a medical data form specifically designed for the present study. The values were subjected to Z and Chi-square tests. RESULTS: Out of 35 patients, thirty one were males (88.57%) and four were females (11.43%) with a male:female ratio of 8:1. We found a peak occurrence in young adults, aged 21-30 years (n = 15, 42.86%). In case of etiology of fracture, road traffic accidents (RTAs) was the most common (n = 25, 71.43%) and condyle was most frequently involved site (n = 19, 38.78%). In most (n = 16, 45.71%) of the patients, an open reduction and rigid internal fixation using bone plate and screws was done. CONCLUSION: In the present study, the prevalence of mandible fractures was more prevalent in male patients, especially during the 3(rd) decade of life. The most common cause was road traffic accident and the more frequently affected region was condyle of the mandible. Open reduction and rigid internal fixation using miniplates and screws was the most commonly used treatment. PMID- 24778981 TI - Evaluation and co-relation of the Oratest, colorimetric Snyder's test and salivary Streptococcus mutans count in children of age group of 6-8 years. AB - AIM: Evaluation and co-relation of the caries susceptibility using Oratest, colorimetric Snyder's test and salivary Streptococcus mutans count amongst children in the age group of 6-8 years. MATERIALS AND METHODS: A total of 120 healthy children were grouped into control and test groups according to their dmft/DMFT scores. Snyder's test, salivary S. mutans count and Oratest were performed for each individual. RESULTS: The relationship of three caries activity tests with each other and with existing caries status was found out. CONCLUSION AND CLINICAL IMPLICATIONS: The present study has shown that Oratest has a definite clinical relationship with caries status and microbiological relationship with S. mutans count of the individual. PMID- 24778982 TI - Awareness and risk perception of hepatitis B infection among auxiliary healthcare workers. AB - CONTEXT: Auxiliary healthcare workers (AHCWs) have a higher risk of occupational exposure to hepatitis B virus infection than the general population. Daily handling and exposure to biomedical wastes, blood, and its products make the AHCWs vulnerable to blood borne diseases among which Hepatitis B is one of the world's most common and serious infectious diseases. AIMS: To evaluate the HBV infection related awareness and occupational risk perception among AHCWs. SETTINGS AND DESIGN: Survey. MATERIALS AND METHODS: A cross-sectional survey was carried out in M. S. Ramaiah Medical and Dental Hospitals among 300 auxiliary health workers which comprised of laboratory technicians, hygienists, laundry workers, and the housekeeping staff. After acquiring ethical clearance and informed written consent, they were explained about the objective of the study and were requested to fill a standard questionnaire. The data was compiled and subjected to statistical analysis using the Statistical Package for Social Sciences (SPSS) software. STATISTICAL ANALYSIS USED: SPSS Software Version 19. RESULTS: Our survey revealed that 90.03% of the respondents were aware of hepatitis B infection (HBI) and 67.2% answered questions correctly on risk perception. Only 37% of the respondents correctly answered questions on biomedical waste management. CONCLUSIONS: Overall, an adequate awareness and a moderate occupational risk perception about HBI were found among the study group. However, knowledge regarding hospital waste disposal was found to be insufficient. Our vision aims at a nation committed to combat silent epidemic of viral hepatitis infection. PMID- 24778983 TI - Knowledge, awareness and practices of dental care waste management among private dental practitioners in Tricity (Chandigarh, Panchkula and Mohali). AB - OBJECTIVE: The objective of this study is to assess the awareness and practices of dental care waste management among private dental practitioners in Tricity (Chandigarh, Panchkula and Mohali). MATERIALS AND METHODS: A cross-sectional study was conducted in 100 private dental practitioners selected by simple random sampling using a close-ended questionnaire. RESULTS: Amongst the total respondents 52% were males and 48% were females. Nearly 14% of the dental practitioners were not aware of the different categories of the waste generated in their clinics and 12% of the practitioners were not aware of the color coding used to dispose the waste. About 26% of them practiced wrong measures to dispose sharps and extracted tooth respectively. A majority 32% of Dentists did not disposed outdated and expired medicines properly. CONCLUSION: Majority of the dental practitioners was aware of categories and color coding used for disposal of different types of wastes yet they do not follow the same in their practice. Hence, strict prosecution laws should also be imposed under biomedical waste management act for the Dentists so that it should be implemented in daily practice. PMID- 24778984 TI - Assessment of relationship between body mass index and periodontal status among state government employees in Shimla, Himachal Pradesh. AB - BACKGROUND: The literature shows that an increased body mass index (BMI) may be a potential risk factor for periodontitis. Association between BMI and periodontitis has been ascribed to unhealthy dietary patterns with insufficient micronutrients and excess sugar and fat content. AIM: The present study intended to assess the relation between BMI and periodontal status among state government employees in Shimla city, Himachal Pradesh in India. MATERIALS AND METHODS: The study sample comprised 1,008 subjects aged 18-58 years, drawn by a proportional sample from 10,908 employees. BMI was calculated by the Quetelet index as the ratio of the subject's body weight (in kg) to the square of the height (in meters). Periodontal status was recorded using the Community Periodontal Index (CPI). Binary multiple logistic regression analysis was done to assess the relation between BMI and periodontal status. The dependent variable for logistic regression analysis was categorized into control group (scores 0-2 of the CPI) and periodontitis group (scores 3 and 4 of the CPI). RESULTS: The overall prevalence of periodontal disease was 98.9%. Score 2 (bleeding and calculus) was the highest score prevailing among the subjects. They had an increased risk of periodontitis by 56% for each 1 kg/m(2) increase in BMI, which means that a higher BMI could be a potential risk factor for periodontitis among the adults aged 18 to 58 years. CONCLUSION: BMI evaluation could be used in the assessment of periodontal risk. PMID- 24778985 TI - Dental health attitude in Indian society. AB - Every society provides a unique soil for a health-care programmer to build upon. Indian society is similarly unique in factors such as social mindset, prevalent beliefs and customs. These factors should not be given a passive glance and should be explored carefully giving an adequate weight to each factor's background and its progress to the present status in contemporary dental practice. Only a careful scientific analysis of society is therefore the need of the hour for oral health-care programmers. PMID- 24778986 TI - Comparison of different caries diagnostic thresholds under epidemiological and clinical settings among 7-15 year old school children from Bangalore city. AB - AIM: The aim of this study is to compare the different caries diagnostic thresholds under epidemiological and clinical settings among 7-15 year old school children. MATERIALS AND METHODS: A cross-sectional study was undertaken among 7 15 years old school children of Bangalore city. Total 738 children were enrolled in the study. General information was collected regarding oral hygiene practice and personal habits of the schoolchildren. Subsequently, examination was done under both the settings to record Decayed, missing and filled surfaces index for permanent teeth (DMFS) and Decayed, missing and filled surfaces index for deciduous teeth (dmfs) using the World Health Organization (WHO) and WHO + IL criteria. RESULTS: The present study showed that both the settings (clinical and epidemiological) and diagnostic thresholds (WHO and WHO + IL), could influence the detection of carious lesions. Mean Ds under WHO + Initial lesions (IL) criteria (3.92 + 3.49) was nearly double of WHO criteria (1.88 + 2.73,) and the influence observed was more in 14 years of age, where mean Ds under WHO + IL criteria (5.43 + 2.5) which was more than double of WHO criteria (2.02 + 1.9). CONCLUSION: The choice of a diagnostic threshold (WHO and WHO + IL) and the conditions of examination (epidemiological and clinical) are important for the detection of caries. PMID- 24778987 TI - Mandibular hypo-hyperdontia: A report of three cases. AB - Dental anomalies of tooth number in development of the permanent dentition are quite common than the primary dentition, however, the combined occurrence of hypodontia and hyperdontia is a rare phenomenon, especially in the same dental arch. The purpose of this report is to describe a case of concomitant hypo hyperdontia (CHH) in three patients (one girl and two boys) with missing mandibular central incisor and an erupted mandibular mesiodens. Three rare cases of mandibular CHH were observed during routine examination, where the two anomalies manifested in the anterior region of the mandible. Furthermore, these are the only cases exhibited taurodontism in association with mandibular CHH. PMID- 24778988 TI - Prevalence of malocclusion among adolescents in South Indian population. AB - OBJECTIVE: To record prevalence of malocclusion among 2,400 adolescents in Karnataka state, India and to define difference in malocclusion status in urban and rural population. DESIGN: Randomized cross-sectional study. SETTING: School students of Karnataka state, 24 August 2011 to 30 March 2012. PARTICIPANTS: School students in the age group of 13-17 years. MATERIALS AND METHODS: Each individual was assessed for occlusal traits - sagittal occlusion, overjet, overbite, crowding, midline diastema, and crossbite. STATISTICAL ANALYSIS USED: Examinations were computerized and analyzed using Statistical Package for Social Sciences version 16. Chi-square test was used for computing statistical significance. RESULTS: 87.79% of population had malocclusion. Out of which 89.45% had class I, 8.37% had class II, and 2.14% had class III malocclusion. Normal overjet and overbite was seen in 48.22 and 49.87% of subjects, respectively. Frequency of crowding was 58.12% and 15.43% of subjects had midline diastema. Anterior crossbite was present in 8.48% and posterior crossbite in 0.99%. Urban population had twice the class II sagittal occlusion, and increased overjet as compared to rural population. CONCLUSIONS: Malocclusion is widely spread among population of Karnataka state, with greater prevalence in urban population. Early exfoliation of deciduous teeth and refined diet can be considered as viable etiological factors. PMID- 24778989 TI - Effectiveness of oral health education programs: A systematic review. AB - In recent years, attention has been drawn toward assessing the effectiveness of oral health education programs. This is in line with demand for evidence based research and will help to inform policy makers on how to allocate resources. (1) Collect and collate all information on oral health education programs. (2) Assess the programs based on various coding criteria. (3) Assess effectiveness of oral health education programs on oral health status and knowledge, attitude and practice. A search of all published articles in Medline was done using the keywords "oral health education, dental health education, oral health promotion". The resulting titles and abstracts provided the basis for initial decisions and selection of articles. Out of the primary list of articles, a total number of 40 articles were selected as they fulfilled the following inclusion criteria: (1). Articles on oral health programs with an oral health education component (2). Articles published after the year 1990 (3). Articles published in English. The full text of the articles was then obtained from either the internet or libraries of dental research colleges and hospitals in and around Bangalore. A set of important variables were identified and grouped under five headings to make them amenable for coding. The coding variables were then described under various subheadings to allow us to compare the chosen articles. Oral health education is effective in improving the knowledge attitude and practice of oral health and in reducing plaque, bleeding on probing of the gingiva and caries increment. This study identifies a few important variables which contribute to the effectiveness of the programs. There is an indication in this review that the most successful oral health programs are labor intensive, involve significant others and has received funding and additional support. A balance between inputs and outputs and health care resources available will determine if the program can be recommended for general use. PMID- 24778990 TI - Optimal Time Intervals between Pre-Operative Radiotherapy or Chemoradiotherapy and Surgery in Rectal Cancer? AB - BACKGROUND: In rectal cancer therapy, radiotherapy or chemoradiotherapy (RT/CRT) is extensively used pre-operatively to (i) decrease local recurrence risks, (ii) allow radical surgery in non-resectable tumors, and (iii) increase the chances of sphincter-saving surgery or (iv) organ-preservation. There is a growing interest among clinicians and scientists to prolong the interval from the RT/CRT to surgery to achieve maximal tumor regression and to diminish complications during surgery. METHODS: The pros and cons of delaying surgery depending upon the aim of the pre-operative RT/CRT are critically evaluated. RESULTS: Depending upon the clinical situation, the need for a time interval prior to surgery to allow tumor regression varies. In the first and most common situation (i), no regression is needed and any delay beyond what is needed for the acute radiation reaction in surrounding tissues to wash out can potentially only be deleterious. After short course RT (5Gyx5) with immediate surgery, the ideal time between the last radiation fraction is 2-5 days, since a slightly longer interval appears to increase surgical complications. A delay beyond 4 weeks appears safe; it results in tumor regression including pathologic complete responses, but is not yet fully evaluated concerning oncologic outcome. Surgical complications do not appear to be influenced by the CRT-surgery interval within reasonable limits (about 4-12 weeks), but this has not been sufficiently explored. Maximum tumor regression may not be seen in rectal adenocarcinomas until after several months; thus, a longer than usual delay may be of benefit in well responding tumors if limited or no surgery is planned, as in (iii) or (iv), otherwise not. CONCLUSION: A longer time interval after CRT is undoubtedly of benefit in some clinical situations but may be counterproductive in most situations. After short-course RT, long-term results from the clinical trials are not yet available to routinely recommend an interval longer than 2-5 days, unless the tumor is non-resectable at diagnosis. PMID- 24778992 TI - Clonal non-malignant hematological disorders: unraveling molecular pathogenic mechanisms to develop novel targeted therapeutics. AB - Clonal non-malignant hematological disorders are a heterogeneous group of diseases that are particularly challenging for hematologists. Indeed, most obvious and frequent hematological diseases include a broad spectrum of malignancies, such as leukemias, lymphomas, myeloma, and other myeloproliferative or lymphoproliferative disorders. In recent years, all these diseases have been categorized by the WHO according to a novel classification of myeloid and lymphoid malignancies, which takes in account the outstanding progress in our understanding of molecular defects underlying hematological malignancies. Regardless of a number of novel technologies, hematologists continue to deal daily with conditions where a clear diagnosis of a malignancy is missing: this is the case of several clonal hematological disorders, which are considered bona fide non-malignant. Some myelodysplastic syndromes, chronic T and NK disorders of granular lymphocytes, myelofibrosis, monoclonal gammopathies, monoclonal B-cel lymphocytosis, mastocytosis and paroxysmal nocturnal hemoglobinuria are paradigmatic examples of how clonal disorders are clearly different from cancers, even if they may share with hematological malignancies similar molecular, genetic, epigenetic and immunological processes. Indeed, it is not entirely clear whether in individual conditions such pathogenic mechanisms may represent initial step(s) of malignant transformation, making a bridge between these clonal non malignant disorders and typical hematological cancers. Some of these non malignant disorders imply specific pathogenic mechanisms and/or clinical course, and so they have been definitely established with their own biological and clinical identity. However, the obvious question whether some of these clonal non malignant hematological diseases form some a kind of disease-continuum with their corresponding malignant counterpart is still to be answered. PMID- 24778991 TI - Perspectives on reprograming cancer-associated dendritic cells for anti-tumor therapies. AB - In recent years, the relevance of the tumor microenvironment (TME) in the progression of cancer has gained considerable attention. It has been shown that the TME is capable of inactivating various components of the immune system responsible for tumor clearance, thus favoring cancer cell growth and tumor metastasis. In particular, effects of the TME on antigen-presenting cells, such as dendritic cells (DCs) include rendering these cells unable to promote specific immune responses or transform them into suppressive cells capable of inducing regulatory T cells. In addition, under the influence of the TME, DCs can produce growth factors that induce neovascularization, therefore further contributing to tumor development. Interestingly, cancer-associated DCs harbor tumor antigens and thus have the potential to become anti-tumor vaccines in situ if properly reactivated. This perspective article provides an overview of the scientific background and experimental basis for reprograming cancer-associated DCs in situ to generate anti-tumor immune responses. PMID- 24778993 TI - Are T-LGL Leukemia and NK-Chronic Lymphoproliferative Disorder really two distinct diseases? AB - Mature Large Granular lymphocytes (LGL) disorders include a spectrum of conditions, ranging from polyclonal to clonal indolent and/or overt leukemic LGL proliferations. Most cases are represented by clonal expansions of TCRalpha/beta+ LGL displaying a CD8+ phenotype with expression of cytotoxic T-cell antigens (CD57, CD16, TIA-1, perforin and granzyme B). Proliferations of CD3-CD16+ NK cells with a restricted patter of NK receptors are less common, usually comprising 15% of the cases. Main features are cytopenias, splenomegaly and autoimmune phenomena. Morphology, immunophenotyping and molecular analyses are crucial to establish a correct diagnosis of disease. According to the 2008 WHO classification, two separate entities account for the majority of cases, T-LGL leukemia and Chronic Lymphoproliferative Disease of NK cell (this latter still provisional). Although these disorders are characterized by the expansion of different cells types i.e. T and NK cells, with specific genetic features and abnormalities, compelling evidence supports the hypothesis that a common pathogenic mechanism would be involved in both disorders. As a matter of fact, a foreign antigen driven clonal selection is considered the initial step in the mechanism ultimately leading to generation of both conditions. In this chapter we will discuss recent advances on the pathogenesis of chronic T and NK disorders of granular lymphocytes, challenging the current WHO classification on the opportunity to separate T and NK disorders, which are likely to represent two sides of the same coin. PMID- 24778994 TI - Discovering the meaning of monoclonal gammopathy of undetermined significance: current knowledge, future challenges. AB - Monoclonal gammopathy of undetermined significance (MGUS) is a non malignant plasma cell disorder with a relatively low risk of progression to Multiple Myeloma (MM) and to related Plasma cells disordes (lymphoplasmacellular neoplasms, Waldenstrom Macroglobulinemia or light chain amyloidosis). It is a quite common finding, especially in the population above the age of 50 and it can also present in association with many non malignant conditions. Differential diagnosis of symptomatic and asymptomatic forms is the determinant for starting therapy. Over the last few years many advances in the understanding of the biology of MGUS, together with large epidemiological studies, allowed to define risk models to estimate the risk of progression to MM according to MGUS isotype and, more recently, to peculiar flow cytometry findings. The goal of many recent studies aims at evaluating individual patients and their overall risk of progression, the detection of early signs of progression and the development of timely treatment strategies. PMID- 24778995 TI - Molecular pathogenesis of myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are a group of clonal hematologic disorders characterized by inefficient hematopoiesis, hypercellular bone marrow, dysplasia of blood cells and cytopenias. Most patients are diagnosed in their late 60s to early 70s. MDS is a risk factor for the development of acute myeloid leukemia which can occur in 10-15% of patients with MDS. A variety of pathophysiologic mechanisms contributes to the genesis and persistence of MDS including immunologic, epigenetic, cytogenetic and genetic factors. The only potential curative option for MDS is hematopoietic cell transplantation which is suitable for only a few patients. Currently approved therapeutic options for MDS, including lenalidomide, decitabine, and 5-azacytidine, are targeted to improve transfusion requirements and quality of life. Moreover, 5-azacytidine has also been demonstrated to improve survival in some patients with higher risk MDS. New ways to predict which patients will better gain benefit from currently available therapeutic agents are the primary challenges in MDS. In the last 10 years, chromosome scanning and high throughput technologies (single nucleotide polymorphism array genotyping, comparative genomic hybridization, and whole genome/ exome sequencing) have tremendously increased our knowledge of MDS pathogenesis. Indeed, the molecular heterogeneity of MDS supports the idea of different therapeutic approaches which will take into account the diverse morphologic and clinical presentations of MDS patients rather than a restricted therapeutic strategy. This review will summarize the molecular abnormalities in key relevant components of the biology and pathogenesis of MDS and will provide an update on the clinical impact and therapeutic response in MDS patients. PMID- 24778996 TI - Immunological derangement in hypocellular myelodysplastic syndromes. AB - Hypocellular or hypoplastic myelodysplastic syndromes (HMDS) are a distinct subgroup accounting for 10-15% of all MDS patients, that are characterized by the presence of bone marrow (BM) hypocellularity, various degree of dysmyelopoiesis and sometimes abnormal karyotype. Laboratory and clinical evidence suggest that HMDS share several immune-mediated pathogenic mechanisms with acquired idiopathic aplastic anemia (AA). Different immune-mediated mechanisms have been documented in the damage of marrow hematopoietic progenitors occurring in HMDS; they include oligoclonal expansion of cytotoxic T lymphocytes (CTLs), polyclonal expansion of various subtypes of T helper lymphocytes, overexpression of FAS-L and of the TNF related apoptosis-inducing ligand (TRAIL), underexpression of Flice-like inhibitory protein long isoform (FLIPL) in marrow cells as well as higher release of Th1 cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). It has also been documented that some HMDS patients have higher frequency of polymorphisms linked both to high production of proinflammatory cytokines such as TNF-alpha and transforming growth factor-beta and to the inhibition of T-cell mediated immune responses such as interleukin-10, further suggesting that immune-mediated mechanisms similar to those seen in AA patients may also operate in HMDS. Clinically, the strongest evidence for immune mediated hematopoietic suppression in some HMDS is the response to immunosuppression including mainly cyclosporine, anti-thymocyte globulin and/or cyclosporine, or alemtuzumab. Here we review all these immune mechanisms as well as the influence of this deranged cellular and humoral immunologic mileau on the initiation and possible progression of MDS. All these observations are pivotal not only for a better understanding of MDS pathophysiology, but also for their immediate clinical implications, eventually leading to the identification of MDS patients who may benefit from immunosuppression. PMID- 24778997 TI - Anti-Complement Treatment in Paroxysmal Nocturnal Hemoglobinuria: Where we Stand and Where we are Going. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal, non-malignant, hematological disorder characterized by the expansion of hematopoietic stem cells and progeny mature blood cells which are deficient in some surface proteins, including the two complement regulators CD55 and CD59. PNH is the paradigm of diseases implying complement dysregulation as main pathogenic mechanism; in fact, PNH erythrocytes are uncapable to modulate on their surface physiologic complement activation, which eventually leads to the typical clinical hallmark of PNH - the chronic complement-mediated intravascular anemia. Indeed, due to the lack of CD55 complement is continuously activated on erythrocyte surface, which subsequently enables the terminal lytic complement because of the lack of CD59, finally resulting in erythrocyte lysis. The availability of eculizumab as the first complement inhibitor for clinical use renewed the interest for this rare hematological disease. Indeed, in the last decad the anti-C5 monoclonal antibody has proven effective for the treatment of PNH, resulting in a sustained control of complement-mediated intravascular hemolysis, with a remarkable clinical benefit. Anti-complement treatment allowed transfusion independence in at least half of PNH patients receiving eculizumab, with adequate control of all hemolysis associated symptoms even in almost all remaining patients. In addition, the risk of thromboembolic events - an other clinical hallmark of PNH, which significantly affects prognosis and survival - seems substantially reduced on eculizumab treatment, apparently resulting in improved survival. Even with all these remarkable effects, eculizumab treatment does not result in hemoglobin normalization, and most patients remain anemic. It has been demonstrated that this is due to persistent activation of the early phases of complement activation (upstream the C5), leading to complement-mediated extravascular hemolysis. Ongoing researches are focusing on possible strategies to improve current anti complement therapies, aiming to develop second-generation complement therapeutics. Here we review PNH and its complement-mediated pathophysiology, summarizing available data on anti-complement treatment; we'll also discuss recent pathogenic insights which drive the development of novel strategies of complement inhibition. PMID- 24778998 TI - Molecular genetics of myelofibrosis and its associated disease phenotypes. AB - In 2005, the discovery of Janus kinase 2 (JAK2) V617F mutation in approximately half of patients with myelofibrosis (MF) marked an important milestone in our understanding of the pathophysiology of MF. This has broadened our understanding of the disease pathogenesis and became the foundation for the development and subsequent clinical use of JAK inhibitors for MF. However, it is clear that other pathogenetic modifiers contribute to the disease diversity and phenotypic variability of MF. Novel genome scanning technologies were useful in the identification of recurrent molecular mutations in other genes including MPL, TET2, IDH1/2, DNMT3A, SH3B2 (LNK) and CBL in MF pointing out that other pathways might be important in addition to the JAK/STAT pathway. The biologic role and clinical implications of these molecular mutations in MF is currently under investigation. The main challenge is to understand the mechanisms whereby molecular mutations whether alone or in combination with other genetic and non genetic events contribute to the pathogenesis of MF and eventually can explain the phenotypic variability among the MF patients. In the present review we will provide an overview of the molecular pathogenesis of MF describing past and recent discoveries in molecular markers and their possible relevance in disease phenotype. PMID- 24778999 TI - Current concepts on diagnosis and treatment of mastocytosis. AB - Mastocytosis is a heterogeneous group of disorders characterized by a clonal proliferation and accumulation of mast cells in one or more organ, primarily in the skin and bone marrow. The clinical spectrum of the disease varies from relatively benign forms with isolated skin lesions to very aggressive variants with extensive systemic involvement and poor prognosis. The growth and proliferation of clonal mast cells is caused by an activating mutation of the tyrosine kinase receptor Kit for Stem Cell Factor, the main growth factor for mast cells. Clinical symptoms are related to mast-cell mediator release, to the tissue mast cell infiltration or both. The degree of infiltration and cell activation determines the highly variable clinical and morphological features. Current treatment of mastocytosis includes symptomatic, antimediator drugs and cytoreductive targeted therapies. PMID- 24779000 TI - Monoclonal B-cell lymphocytosis. AB - Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition defined by the presence of a small (<5 x 10(9)/L) clonal B-cell population in the peripheral blood in the absence of lymph-node enlargement, cytopenias or autoimmune diseases. It is found in approximately 3-12% of normal persons depending on the accuracy of analytical techniques applied. According to the immunophenotypic profile of clonal B-cells, the majority of MBL cases (75%) are classified as chronic lymphocytic leukemia (CLL)-like. This form may progress into CLL at a rate of 1-2% per year. It is thought that CLL is always preceded by MBL. The remaining MBL cases are defined as atypical CLL-like (CD5+/CD20(bright)) and CD5(-) MBL. The MBL clone size is quite heterogenous. Accordingly, two forms of MBL are identified: i) high-count, or 'clinical' MBL, in which an evidence of lymphocytosis (<5 x 10(9)/L clonal B-cells) is seen, and ii) a low-count MBL, in which a normal leukocyte count is found and that is identified only in population screening studies. Both forms of MBL may carry the cytogenetic abnormalities that are the hallmark of CLL, including 13q-, 17p- and trisomy 12. Consistent with the indolent phenotype of this condition, genetic lesions, such as TP53, ATM, NOTCH1 and SF3B1 mutations, usually associated with high-risk CLL, are rarely seen. Overall, no prognostic indicator of evolution of MBL to overt CLL has been found at present time. However, taking into account this possibility, a clinical and lab monitoring (at least annually), is recommended. PMID- 24779002 TI - "PADding" My Career with Dr. Mary Ellen Avery. PMID- 24779003 TI - Boston bombings and resilience - what do we mean by this? PMID- 24779004 TI - Developing forensic mental healthcare in kosovo. AB - In many economically struggling societies, forensic psychiatry is still in its initial developmental stages and thus forensic patients pose an ongoing challenge for the healthcare and juridical systems. In this article, we present the various issues and problems that arose when establishing the first forensic psychiatric institute in Kosovo - a country whose population has constantly been reported as suffering from a high psychiatric morbidity due to long-lasting traumatic experiences during the war of 1999. The implementation of a new forensic psychiatric institute in the developing mental healthcare system of Kosovo, still characterized by considerable shortages, required substantial effort on various levels. On the policy and financial level, it was made possible by a clear intent and coordinated commitment of all responsible national stakeholders and authorities, such as the Ministries of Health and Justice, and by the financial contribution of the European Commission. Most decisive in terms of the success of the project was capacity building in human resources, i.e., the recruitment and training of motivated staff. Training included essential clinical and theoretical issues as well as clearly defined standard operation procedures, guidelines, and checklists to aid daily routine work and the management of challenging situations. PMID- 24779005 TI - Guideline concordant therapy prolongs survival in HER2-positive breast cancer patients: results from a large population-based cohort of a cancer registry. AB - Even though randomized controlled clinical trials demonstrated improved survival by adjuvant trastuzumab treatment of HER2-positive breast cancer patients, data on its effect in clinical routine are scarce. This study evaluated the use and efficacy of trastuzumab in routine treatment of HER2-positive breast cancer patients. Data from the clinical cancer registry Regensburg (Germany) were analyzed. The present study investigated 6,991 female patients with primary invasive breast cancer. In premenopausal HER2-positive patients a considerable increase of trastuzumab therapy was observed from 58.1% in 2006 to 90.9% in 2011, whereas in postmenopausal patients trastuzumab was rather used on a constant rate of 49.1%. Best overall survival (OS) was found in HER2/steroid hormone receptor positive patients receiving guideline concordant treatment with trastuzumab plus chemotherapy (CHT) plus antihormone therapy (AHT) with a 7-year OS rate of 96% compared to the non-trastuzumab group with a 7-year OS rate of 92%. In multivariable analysis, HER2-positive patients treated with CHT or AHT who did not get trastuzumab, had a worse 7-year OS (65%, P = 0.006 versus 79%, P = 0.017) than the control groups. This population-based study demonstrated that guideline concordant use of adjuvant trastuzumab improves OS for HER2-positive breast cancer patients treated in routine clinical care. PMID- 24779006 TI - Impact of MSWI bottom ash codisposed with MSW on landfill stabilization with different operational modes. AB - The aim of the study was to investigate the impact of municipal solid waste incinerator (MSWI) bottom ash (BA) codisposed with municipal solid waste (MSW) on landfill stabilization according to the leachate quality in terms of organic matter and nitrogen contents. Six simulated landfills, that is, three conventional and three recirculated, were employed with different ratios of MSWI BA to MSW. The results depicted that, after 275-day operation, the ratio of MSWI BA to fresh refuse of 1 : 10 (V : V) in the landfill was still not enough to provide sufficient acid-neutralizing capacity for a high organic matter composition of MSW over 45.5% (w/w), while the ratio of MSWI BA to fresh refuse of 1 : 5 (V : V) could act on it. Among the six experimental landfills, leachate quality only was improved in the landfill operated with the BA addition (the ratio of MSWI BA to fresh refuse of 1 : 5 (V : V)) and leachate recirculation. PMID- 24779007 TI - Cryopreservation of embryos and oocytes in human assisted reproduction. AB - Both sperm and embryo cryopreservation have become routine procedures in human assisted reproduction and oocyte cryopreservation is being introduced into clinical practice and is getting more and more widely used. Embryo cryopreservation has decreased the number of fresh embryo transfers and maximized the effectiveness of the IVF cycle. The data shows that women who had transfers of fresh and frozen embryos obtained 8% additional births by using their cryopreserved embryos. Oocyte cryopreservation offers more advantages compared to embryo freezing, such as fertility preservation in women at risk of losing fertility due to oncological treatment or chronic disease, egg donation, and postponing childbirth, and eliminates religious and/or other ethical, legal, and moral concerns of embryo freezing. In this review, the basic principles, methodology, and practical experiences as well as safety and other aspects concerning slow cooling and ultrarapid cooling (vitrification) of human embryos and oocytes are summarized. PMID- 24779008 TI - Evaluation and comparison of multiple aligners for next-generation sequencing data analysis. AB - Next-generation sequencing (NGS) technology has rapidly advanced and generated the massive data volumes. To align and map the NGS data, biologists often randomly select a number of aligners without concerning their suitable feature, high performance, and high accuracy as well as sequence variations and polymorphisms existing on reference genome. This study aims to systematically evaluate and compare the capability of multiple aligners for NGS data analysis. To explore this capability, we firstly performed alignment algorithms comparison and classification. We further used long-read and short-read datasets from both real-life and in silico NGS data for comparative analysis and evaluation of these aligners focusing on three criteria, namely, application-specific alignment feature, computational performance, and alignment accuracy. Our study demonstrated the overall evaluation and comparison of multiple aligners for NGS data analysis. This serves as an important guiding resource for biologists to gain further insight into suitable selection of aligners for specific and broad applications. PMID- 24779009 TI - A short-term incubation with high glucose impairs VASP phosphorylation at serine 239 in response to the nitric oxide/cGMP pathway in vascular smooth muscle cells: role of oxidative stress. AB - A reduction of the nitric oxide (NO) action in vascular smooth muscle cells (VSMC) could play a role in the vascular damage induced by the glycaemic excursions occurring in diabetic patients; in this study, we aimed to clarify whether a short-term incubation of cultured VSMC with high glucose reduces the NO ability to increase cGMP and the cGMP ability to phosphorylate VASP at Ser-239. We observed that a 180 min incubation of rat VSMC with 25 mmol/L glucose does not impair the NO-induced cGMP increase but reduces VASP phosphorylation in response to both NO and cGMP with a mechanism blunted by antioxidants. We further demonstrated that high glucose increases radical oxygen species (ROS) production and that this phenomenon is prevented by the PKC inhibitor chelerythrine and the NADPH oxidase inhibitor apocynin. The following sequence of events is supported by these results: (i) in VSMC high glucose activates PKC; (ii) PKC activates NADPH oxidase; (iii) NADPH oxidase induces oxidative stress; (iv) ROS impair the signalling of cGMP, which is involved in the antiatherogenic actions of NO. Thus, high glucose, via oxidative stress, can reduce the cardiovascular protection conferred by the NO/cGMP pathway via phosphorylation of the cytoskeleton protein VASP in VSMC. PMID- 24779010 TI - Autophagy in hepatic fibrosis. AB - Hepatic fibrosis is a leading cause of morbidity and mortality worldwide. Hepatic fibrosis is usually associated with chronic liver diseases caused by infection, drugs, metabolic disorders, or autoimmune imbalances. Effective clinical therapies are still lacking. Autophagy is a cellular process that degrades damaged organelles or protein aggregation, which participates in many pathological processes including liver diseases. Autophagy participates in hepatic fibrosis by activating hepatic stellate cells and may participate as well through influencing other fibrogenic cells. Besides that, autophagy can induce some liver diseases to develop while it may play a protective role in hepatocellular abnormal aggregates related liver diseases and reduces fibrosis. With a better understanding of the potential effects of autophagy on hepatic fibrosis, targeting autophagy might be a novel therapeutic strategy for hepatic fibrosis in the near future. PMID- 24779011 TI - Comparative genomic hybridization selection of blastocysts for repeated implantation failure treatment: a pilot study. AB - The aim of this study is to determine if the use of preimplantation genetic screening (PGS) by array comparative genomic hybridization (array CGH) and transfer of a single euploid blastocyst in patients with repeated implantation failure (RIF) can improve clinical results. Three patient groups are compared: 43 couples with RIF for whom embryos were selected by array CGH (group RIF-PGS), 33 couples with the same history for whom array CGH was not performed (group RIF NO PGS), and 45 good prognosis infertile couples with array CGH selected embryos (group NO RIF PGS). A single euploid blastocyst was transferred in groups RIF-PGS and NO RIF PGS. Array CGH was not performed in group RIF NO PGS in which 1-2 blastocysts were transferred. One monoembryonic sac with heartbeat was found in 28 patients of group RIF PGS and 31 patients of group NO RIF PGS showing similar clinical pregnancy and implantation rates (68.3% and 70.5%, resp.). In contrast, an embryonic sac with heartbeat was only detected in 7 (21.2%) patients of group RIF NO PGS. In conclusion, PGS by array CGH with single euploid blastocyst transfer appears to be a successful strategy for patients with multiple failed IVF attempts. PMID- 24779012 TI - Genetic analysis of diversity within a Chinese local sugarcane germplasm based on start codon targeted polymorphism. AB - In-depth information on sugarcane germplasm is the basis for its conservation and utilization. Data on sugarcane molecular markers are limited for the Chinese sugarcane germplasm collections. In the present study, 20 start codon targeted (SCoT) marker primers were designed to assess the genetic diversity among 107 sugarcane accessions within a local sugarcane germplasm collection. These primers amplified 176 DNA fragments, of which 163 were polymorphic (92.85%). Polymorphic information content (PIC) values ranged from 0.783 to 0.907 with a mean of 0.861. Unweighted pair group method of arithmetic averages (UPGMA) cluster analysis of the SCoT marker data divided the 107 sugarcane accessions into six clusters at 0.674 genetic similarity coefficient level. Relatively abundant genetic diversity was observed among ROC22, ROC16, and ROC10, which occupied about 80% of the total sugarcane acreage in China, indicating their potential breeding value on Mainland China. Principal component analysis (PCA) partitioned the 107 sugarcane accessions into two major groups, the Domestic Group and the Foreign Introduction Group. Each group was further divided based on institutions, where the sugarcane accessions were originally developed. The knowledge of genetic diversity among the local sugarcane germplasm provided foundation data for managing sugarcane germplasm, including construction of a core collection and regional variety distribution and subrogation. PMID- 24779013 TI - The regulation of autophagy by influenza A virus. AB - Influenza A virus is a dreadful pathogen of animals and humans, causing widespread infection and severe morbidity and mortality. It is essential to characterize the influenza A virus-host interaction and develop efficient counter measures against the viral infection. Autophagy is known as a catabolic process for the recycling of the cytoplasmic macromolecules. Recently, it has been shown that autophagy is a critical mechanism underlying the interaction between influenza A virus and its host. Autophagy can be induced by the infection with influenza A virus, which is considered as a necessary process for the viral proliferation, including the accumulation of viral elements during the replication of influenza A virus. On the other hand, influenza A virus can inhibit the autophagic formation via interaction with the autophagy-related genes (Atg) and signaling pathways. In addition, autophagy is involved in the influenza virus-regulated cell deaths, leading to significant changes in host apoptosis. Interestingly, the high pathogenic strains of influenza A virus, such as H5N1, stimulate autophagic cell death and appear to interplay with the autophagy in distinct ways as compared with low pathogenic strains. This review discusses the regulation of autophagy, an influenza A virus driven process. PMID- 24779014 TI - Lack of association between TLR4 genetic polymorphisms and diabetic nephropathy in a Chinese population. AB - OBJECTIVE: Toll-like receptor 4 (TLR4) plays a central role in innate immunity. Activation of innate immune response and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of diabetic nephropathy. In this study, we aimed to investigate whether TLR4 variants are associated with diabetic nephropathy in the Chinese population. METHODS: Seven tagging single nucleotide polymorphisms (SNPs) of TLR4 based on HapMap Chinese data were genotyped in 1,455 Chinese type 2 diabetic patients. Of these patients, 622 were diagnosed with diabetic nephropathy and 833 were patients with diabetes for over 5 years but without diabetic nephropathy. RESULTS: None of the SNPs and haplotypes showed significant association to diabetic nephropathy in our study. No association between the SNPs and quantitative traits was observed either. CONCLUSION: We concluded that common variants within TLR4 genes were not associated with diabetic nephropathy in the Chinese type 2 diabetes patients. PMID- 24779015 TI - The effect of bolus volume on hyoid kinematics in healthy swallowing. AB - Hyoid movement in swallowing is biomechanically linked to closure of the laryngeal vestibule for airway protection and to opening of the upper esophageal sphincter. Studies suggest that the range of hyoid movement is highly variable in the healthy population. However, other aspects of hyoid movement such as velocity remain relatively unexplored. In this study, we analyze data from a sample of 20 healthy young participants (10 male) to determine whether hyoid movement distance, duration, velocity, and peak velocity vary systematically with increases in thin liquid bolus volume from 5 to 20 mL. The temporal correspondence between peak hyoid velocity and laryngeal vestibule closure was also examined. The results show that maximum hyoid position and peak velocity increase significantly for 20 mL bolus volumes compared to smaller volumes, and that the timing of peak velocity is closely linked to achieving laryngeal vestibule closure. This suggests that generating hyoid movements with increased power is a strategy for handling larger volumes. PMID- 24779016 TI - BMP-4 genetic variants and protein expression are associated with platinum-based chemotherapy response and prognosis in NSCLC. AB - To explore the role of genetic polymorphisms of bone morphogenic proteins 4 (BMP 4) in the response to platinum-based chemotherapy and the clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC), 938 patients with stage III (A+B) or IV NSCLC were enrolled in this study. We found that the variant genotypes of 6007C > T polymorphisms significantly associated with the chemotherapy response. The 6007CC genotype carriers had a higher chance to be responder to chemotherapy (adjusted odd ratio = 2.77; 95% CI: 1.83-4.18; adjusted < 0.001). The 6007C > T polymorphisms and BMP-4 expression also affect the prognosis of NSCLC. Patients with high BMP-4 expression had a significantly higher chance to be resistant to chemotherapy than those with low BMP-4 expression (OR = 2.81; 95% CI: 1.23-6.44; P = 0.01). The hazard ratio (HR) for 6007TT was 2.37 times higher than 6007CC (P = 0.003). In summary, the 6007C > T polymorphism of BMP-4 gene and BMP-4 tissue expression may be used as potential predictor for the chemotherapy response and prognosis of advanced NSCLC. PMID- 24779017 TI - New strategies for evaluation and analysis of SELEX experiments. AB - Aptamers are an interesting alternative to antibodies in pharmaceutics and biosensorics, because they are able to bind to a multitude of possible target molecules with high affinity. Therefore the process of finding such aptamers, which is commonly a SELEX screening process, becomes crucial. The standard SELEX procedure schedules the validation of certain found aptamers via binding experiments, which is not leading to any detailed specification of the aptamer enrichment during the screening. For the purpose of advanced analysis of the accrued enrichment within the SELEX library we used sequence information gathered by next generation sequencing techniques in addition to the standard SELEX procedure. As sequence motifs are one possibility of enrichment description, the need of finding those recurring sequence motifs corresponding to substructures within the aptamers, which are characteristically fitted to specific binding sites of the target, arises. In this paper a motif search algorithm is presented, which helps to describe the aptamers enrichment in more detail. The extensive characterization of target and binding aptamers may later reveal a functional connection between these molecules, which can be modeled and used to optimize future SELEX runs in case of the generation of target-specific starting libraries. PMID- 24779019 TI - Acute and subacute toxicity in vivo of thermal-sprayed silver containing hydroxyapatite coating in rat tibia. AB - To reduce the incidence of implant-associated infection, we previously developed a novel coating technology using hydroxyapatite (HA) containing silver (Ag). This study examined in vivo acute and subacute toxicity associated with the Ag-HA coating in rat tibiae. Ten-week-old rats received implantation of HA-, 2% Ag-HA-, or 50% Ag-HA-coated titanium rods. Concentrations of silver in serum, brain, liver, kidneys, and spleen were measured in the acute phase (2-4 days after treatment) and subacute phase (4-12 weeks after treatment). Biochemical and histological examinations of those organs were also performed. Mean serum silver concentration peaked in the acute phase and then gradually decreased. Mean silver concentrations in all examined organs from the 2% Ag-HA coating groups showed no significant differences compared with the HA coating group. No significant differences in mean levels of glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, creatinine, or blood urea nitrogen were seen between the three groups and controls. Histological examinations of all organs revealed no abnormal pathologic findings. No acute or subacute toxicity was seen in vivo for 2% Ag-HA coating or HA coating. Ag-HA coatings on implants may represent biologically safe antibacterial biomaterials and may be of value for reducing surgical-site infections related to implantation. PMID- 24779018 TI - The function of CD3+CD56+ NKT-like cells in HIV-infected individuals. AB - CD3(+)CD56(+) NKT-like cells are one of the critical effectors in the immune response to viral infection and tumors, but the functional features of NKT-like cells in HIV infection have been rarely reported. In this study, we observed and described the state of NKT-like cell functions in primary HIV-infected individuals (PHIs), chronic HIV-infected individuals (CHIs), long-term nonprogressors (LTNPs), and HIV-negative controls (NCs). The results showed that the percentage of IFN-gamma(+)CD3(+)CD56(+) NKT-like cells was notably higher in LTNPs compared with CHIs, and the proportion of CD3(+)CD56(+) NKT-like cells with dual function (IFN-gamma(+)CD107a(+) NKT-like cells) in LTNPs was also much higher than in CHIs. Additionally, the percentages of IFN-gamma(+)CD107a(+) NKT like cells negatively correlated with viral load. Taken together, our data demonstrated that good functions of CD3(+)CD56(+) NKT-like cells in LTNPs likely occurred as a protective mechanism that slows down HIV disease progression. PMID- 24779020 TI - Effects of prepolymerized particle size and polymerization kinetics on volumetric shrinkage of dental modeling resins. AB - Dental modeling resins have been developed for use in areas where highly precise resin structures are needed. The manufacturers claim that these polymethyl methacrylate/methyl methacrylate (PMMA/MMA) resins show little or no shrinkage after polymerization. This study examined the polymerization shrinkage of five dental modeling resins as well as one temporary PMMA/MMA resin (control). The morphology and the particle size of the prepolymerized PMMA powders were investigated by scanning electron microscopy and laser diffraction particle size analysis, respectively. Linear polymerization shrinkage strains of the resins were monitored for 20 minutes using a custom-made linometer, and the final values (at 20 minutes) were converted into volumetric shrinkages. The final volumetric shrinkage values for the modeling resins were statistically similar (P > 0.05) or significantly larger (P < 0.05) than that of the control resin and were related to the polymerization kinetics (P < 0.05) rather than the PMMA bead size (P = 0.335). Therefore, the optimal control of the polymerization kinetics seems to be more important for producing high-precision resin structures rather than the use of dental modeling resins. PMID- 24779021 TI - Prognostic indices of poor nutritional status and their impact on prolonged hospital stay in a Greek university hospital. AB - BACKGROUND: To ascertain the potential contributors to nutritional risk manifestation and to disclose the factors exerting a negative impact on hospital length of stay (LOS), by means of poor nutritional status, in a nonselected hospitalized population. MATERIALS AND METHODS: NutritionDay project questionnaires were applied to 295 adult patients. Study parameters included anthropometric data, demographics, medical history, dietary-related factors, and self-perception of health status. Body Mass Index (BMI) and Malnutrition Universal Screening Tool (MUST) were calculated for each participant. MUST score was applied for malnutrition assessment, while hospital LOS constituted the outcome of interest. RESULTS: Of the total cohort, 42.3% were at nutritional risk and 21.4% malnourished. Age, gender, BMI, MUST score, autonomy, health quality, appetite, quantity of food intake, weight loss, arm or calf perimeter (P < 0.001, for all), and dietary type (P < 0.01) affected nutritional status. Poor nutrition status (P = 0.000), deteriorated appetite (P = 0.000) or food intake (P = 0.025), limited autonomy (P = 0.013), artificial nutrition (P = 0.012), weight loss (P = 0.010), and arm circumference <21 cm (P = 0.007) were the most powerful predictors of hospital LOS >7 days. CONCLUSION: Nutritional status and nutrition related parameters such as weight loss, quantity of food intake, appetite, arm circumference, dietary type, and extent of dependence confer considerable prognostic value regarding hospital LOS in acute care setting. PMID- 24779024 TI - Association of different primers and resin cements for adhesive bonding to zirconia ceramics. AB - PURPOSE: To evaluate the shear bond strength (SBS) to zirconia ceramics using different associations of primers and resin cements. MATERIALS AND METHODS: Two blocks of LAVA zirconia (3Y-TZP) were randomly submitted to an application of three different commercially available primers: Alloy Primer (AP), Z-Prime Plus (ZP), and Signum Zirconia Bond (SZB). Nonprimed specimens were considered controls. After treatment, the 80 specimens (5 mm * 5 mm * 2 mm) were randomly cemented with one of the resin cements: Panavia F, Multilink, seT, and NX3. For cementation, cylinders of resin cement were built on the ceramic surfaces using the SDI SBS apparatus. The specimens were submitted to the SBS test. Fractured surfaces were observed under stereomicroscopy to determine the failure mode, and mean bond strength values were analyzed using the Kruskal-Wallis and Mann-Whitney tests (alpha = 0.05). RESULTS: Signum Zirconia Bond had the highest SBS compared to all other primers and the control group, regardless of the resin cement used. The highest values were obtained when associating Panavia F with Signum Zirconia Bond. Alloy Primer increased bonding values when associated with seT cement only. When no primer was used, no statistical difference was observed among resin cements. All specimens fractured due to adhesive failure. CONCLUSION: Signum Zirconia Bond is capable of increasing bonding values of resin cements to zirconia ceramics. Its association with Panavia F shows enhanced results when considering short-term adhesion to zirconia. PMID- 24779023 TI - STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice. AB - When formulating a deep brain stimulation (DBS) treatment plan for a patient with Parkinson's disease (PD), two critical questions should be addressed: 1- Which brain target should be chosen to optimize this patient's outcome? and 2- Should this patient's DBS operation be unilateral or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the subthalamic nucleus (STN) and the globus pallidus internus (GPi). While the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all Parkinson's disease cases (Figure 1). This bilateral STN "one-size fits-all" approach was challenged by an editorial entitled "STN vs. GPi: The Rematch," which appeared in the Archives of Neurology in 2005. Since 2005, a series of well designed clinical trials and follow-up studies have addressed the question as to whether a more tailored approach to DBS therapy might improve overall outcomes. Such a tailored approach would include the options of targeting the GPi, or choosing a unilateral operation. The results of the STN vs. GPi 'rematch' studies support the conclusion that bilateral STN DBS may not be the best option for every Parkinson's disease surgical patient. Off period motor symptoms and tremor improve in both targets, and with either unilateral or bilateral stimulation. Advantages of the STN target include more medication reduction, less frequent battery changes, and a more favorable economic profile. Advantages of GPi include more robust dyskinesia suppression, easier programming, and greater flexibility in adjusting medications. In cases where unilateral stimulation is anticipated, the data favor GPi DBS. This review summarizes the accumulated evidence regarding the use of bilateral vs. unilateral DBS and the selection of STN vs. GPi DBS, including definite and possible advantages of different targets and approaches. Based on this evidence, a more patient tailored, symptom specific approach will be proposed to optimize outcomes of PD DBS therapy. Finally, the importance of an interdisciplinary care team for screening and effective management of DBS patients will be reaffirmed. Interdisciplinary teams can facilitate the proposed patient-specific DBS treatment planning and provide a more thorough analysis of the risk-benefit ratio for each patient. PMID- 24779022 TI - Cellular players in skeletal muscle regeneration. AB - Skeletal muscle, a tissue endowed with remarkable endogenous regeneration potential, is still under focused experimental investigation mainly due to treatment potential for muscle trauma and muscular dystrophies. Resident satellite cells with stem cell features were enthusiastically described quite a long time ago, but activation of these cells is not yet controlled by any medical interventions. However, after thorough reports of their existence, survival, activation, and differentiation there are still many questions to be answered regarding the intimate mechanism of tissue regeneration. This review delivers an up-to-date inventory of the main known key players in skeletal muscle repair, revealed by various models of tissue injuries in mechanical trauma, toxic lesions, and muscular dystrophy. A better understanding of the spatial and temporal relationships between various cell populations, with different physical or paracrine interactions and phenotype changes induced by local or systemic signalling, might lead to a more efficient approach for future therapies. PMID- 24779025 TI - A three-year prospective randomized study of silorane- and methacrylate-based composite restorative systems in class II restorations. AB - PURPOSE: To evaluate and compare the 3-year clinical performance of a silorane based composite with that of a methacrylate-based composite in Class II restorations. MATERIALS AND METHODS: Seventy-eight patients, each with two class II restorations under occlusion, were enrolled in this study. One hundred fifty six restorations were placed, 50% for each material: a silorane-based composite, Filtek P90/ P90 System Adhesive and a methacrylate-based resin composite, Quixfil/ Prime &Bond NT. A single operator placed all restorations according to the manufacturers' instructions. Immediately after placement, the restorations were finished/polished. Clinical evaluation was performed at baseline and at yearly intervals after placement by two other independent examiners using slightly modified USPHS criteria. The changes in the USPHS parameters during the three-year period were analyzed with the Friedman test. The baseline scores were compared with those at the recall visits using the Wilcoxon signed rank test. The level of significance was set at p < 0.05. RESULTS: All restorations were evaluated at 3 years. Post-operative sensitivity was observed in 6 patients (2 Filtek P90, 4 Quixfil) between 1 and 3 weeks. Seven failed restorations (4.5%) were observed during the follow up: 4 in the Filtek P90 (5.1%) and 3 in the Quixfil group (3.8%). This resulted in non-significantly different annual failure rates of 1.7% and 1.2%, respectively. Fracture of restoration was the main reason for failure. CONCLUSION: After 3 years, no significant difference was seen in overall clinical effectiveness between the silorane- based and methacrylate-based composite restorative systems. PMID- 24779026 TI - Evaluation of different restorative techniques for filling flared root canals: fracture resistance and bond strength after mechanical fatigue. AB - PURPOSE: To evaluate the fracture resistance (FR) and bond strength (BS) after mechanical fatigue (MF) of flared root canals restored with different restorative techniques for fiber post cementation. MATERIALS AND METHODS: The root canals of 84 single-rooted premolars were endodontically treated and prepared in order to simulate an oversized root canal, except for the positive control group (PC), in which a prefabricated fiber post (PFP) with a diameter compatible with the post cavity was cemented. In the oversized root canals, alternative restorative techniques for post cementation were tested, as follows: NC: negative control (PFP with a diameter smaller than that of the root canal); AP: PFP + accessory posts; RR: root reinforcement with composite resin; DAP: direct anatomical post; IAP: indirect anatomical post. After the luting procedures using Excite DSC and Variolink II, indirect composite crowns were cemented on composite resin cores and the specimens were mechanically fatigued (1.2 x 106 cycles, 40 N). From each group, 8 specimens were subjected to the push-out BS test and the others 6 specimens to the FR test. For both tests, the data were subjected to ANOVA and Scheffe's tests (alpha = 0.05). RESULTS: In terms of FR, all alternative techniques showed intermediate performance, being similar to both control groups. In terms of BS, only the groups DAP and IAP were similar to the well-adapted condition (positive control group). CONCLUSION: The use of DAP and IAP should be the first choice for fiber post cementation in oversized root canals. PMID- 24779027 TI - Mammalian protein glycosylation--structure versus function. AB - Carbohydrates fulfil many common as well as extremely important functions in nature. They show a variety of molecular displays--e.g., free mono-, oligo-, and polysaccharides, glycolipids, proteoglycans, glycoproteins, etc.--with particular roles and localizations in living organisms. Structure-specific peculiarities are so many and diverse that it becomes virtually impossible to cover them all from an analytical perspective. Hence this manuscript, focused on mammalian glycosylation, rather than a complete list of analytical descriptors or recognized functions for carbohydrate structures, comprehensively reviews three central issues in current glycoscience, namely (i) structural analysis of glycoprotein glycans, covering both classical and novel approaches for teasing out the structural puzzle as well as potential pitfalls of these processes; (ii) an overview of functions attributed to carbohydrates, covering from monosaccharide to complex, well-defined epitopes and full glycans, including post glycosylational modifications, and (iii) recent technical advances allowing structural identification of glycoprotein glycans with simultaneous assignation of biological functions. PMID- 24779028 TI - The adsorption behaviour of CH4 on microporous carbons: effects of surface heterogeneity. AB - The effects of chemical and structural surface heterogeneity on the CH4 adsorption behaviour on microporous carbons have been investigated using a hybrid theoretical approach, including the use of density functional theory (DFT), molecular dynamics (MD), and grand canonical Monte Carlo (GCMC) simulations. Bader charge analysis is first performed to analyze the surface atomic partial charges. The CH4 adsorption densities in defective and functionalized graphite slit pores are lower than that in the perfect pore according to the MD simulations. Finally, the CH4 adsorption isotherms for the perfect, defective and functionalized slit pores are analyzed using the GCMC simulations in combination with the DFT and MD results. For pores with a defective surface, the adsorption capacities decrease; the embedded functional groups decrease the adsorption capacity at low pressure and enhance it at high pressure. Our results demonstrate the significant effects of chemical and structural surface heterogeneity on the CH4 adsorption and provide a systematic approach to understand the gas adsorption behaviour. PMID- 24779029 TI - The non-covalent nature of the molecular structure of the benzene molecule. AB - The benzene molecule is one of the most emblematic systems in chemistry, with its structural features being present in numerous different compounds. We have carried out an analysis of the influence of quantum mechanical interference on the geometric features of the benzene molecule, showing that many of the characteristics of its equilibrium geometry are a consequence of non-covalent contributions to the energy. This result implies that quasi-classical reasoning should be sufficient to predict the defining aspects of the benzene structure such as its planarity and equivalence of its bond lengths. PMID- 24779030 TI - Dielectric measurements of aqueous DNA solutions up to 110 GHz. AB - A measurement system for broadband dielectric spectroscopy of biological samples for frequencies between 25 MHz and 110 GHz is presented. It is based on a vector network analyzer and a 1.19 mm-diameter open-ended coaxial probe. Complex reflection coefficients of aqueous Na-DNA solutions are measured in the frequency domain at a constant temperature of 25 degrees C. Complex permittivity spectra are analysed at various solute concentrations and two dispersions are observed. The first one is located at about 19 GHz and is due to the reorientation of water molecules. The second one is located at approximately 100 MHz and is interpreted as being caused by DNA counterion fluctuations. The relaxation frequency of free water in solutions appears to be practically unaffected by the presence of DNA. For the relaxation in the MHz region the dielectric loss maximum shifts to higher frequencies and the distribution of relaxation times becomes broader with increasing polymer concentration. PMID- 24779031 TI - Computational delineation of tyrosyl-substrate recognition and catalytic landscapes by the epidermal growth factor receptor tyrosine kinase domain. AB - The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which catalyzes protein phosphorylation reactions by transferring the gamma phosphoryl group from an ATP molecule to the hydroxyl group of tyrosine residues in protein substrates. EGFR is an important drug target in the treatment of cancers and a better understanding of the receptor function is critical to discern cancer mechanisms. We employ a suite of molecular simulation methods to explore the mechanism of substrate recognition and to delineate the catalytic landscape of the phosphoryl transfer reaction. Based on our results, we propose that a highly conserved region corresponding to Val852-Pro853-Ile854-Lys855 Trp856 in the EGFR tyrosine kinase domain (TKD) is essential for substrate binding. We also provide a possible explanation for the established experimental observation that protein tyrosine kinases (including EGFR) select substrates with a glutamic acid at the P - 1 position and a large hydrophobic amino acid at the P + 1 position. Furthermore, our mixed quantum mechanics/molecular mechanics (QM/MM) simulations show that the EGFR protein kinase favors the dissociative mechanism, although an alternative channel through the formation of an associative transition state is also possible. Our simulations establish some key molecular rules in the operation for substrate-recognition and for phosphoryl transfer in the EGFR TKD. PMID- 24779032 TI - Ambulatory quality indicators to prevent infection in sickle cell disease. AB - The purpose of this study was to identify rates of adherence for three outpatient quality indicators noted by Wang et al. (Pediatrics 2011;128:484-493): (1) influenza vaccine, (2) pneumococcal immunizations, and (3)penicillin prophylaxis in patients with sickle cell disease (SCD) in a Medicaid sample. These variables were chosen based on Wang and colleagues' suggestion that these variables are important for the assessment of the quality of care of children with SCD. We hypothesized that the overall rate of adherence would be poor with adults having worse rates of adherence than children. We conducted a retrospective cohort study using the Wisconsin State Medicaid database over a 5-year period to assess the preventative medication adherence of individuals with SCD. Preventative medication variables in this study included influenza vaccination,pneumococcal immunizations (PCV7, PPV23), and penicillin prophylaxis. As predicted, the 2003 2007 Wisconsin State Medicaid database showed patients with SCD had low adherence in terms of recommended influenza vaccinations (21.58% adherent), PPV23 pneumococcal immunizations (43.47% adherent), and penicillin prophylaxis (18.18% adherent). Pneumococcal immunizations for PCV7 were higher than expected (77.27%adherent). Although children tended to adhere to recommended preventative medications more than adults,overall adherence was low. Although we cannot explain why adherence is low, it is likely due to multiple factors at the patient and provider-level. We encourage patients and providers to create a partnership to meet adherence recommendations, and we describe our strategies for increasing adherence. PMID- 24779033 TI - Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. AB - Dasatinib is a second generation tyrosine kinase inhibitor, with activity in imatinib resistant Ph-positive ALL.We have treated 34 patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia(ALL) (n519) or lymphoid blast phase of chronic myelogenous leukemia (CML-LB) (n515) with the combination of dasatinib and the hyper CVAD regimen. Prior regimens included hyper CVAD plus imatinib(n511, 4 had transplant in first CR), other combination chemotherapy (n512), monotherapy with kinase inhibitors other than dasatinib (n59), and investigational agents (n52). Pretreatment ABL mutations were noted in 10 patients. The overall response rate was 91%, with 24 patients (71%) achieving complete response(CR), and 7(21%) CR with incomplete platelet recovery (CRp). Two patients died during induction and one had progressive disease. Twenty-six patients (84%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 patients (42%) achieved complete molecular response, and 11 patients (35%) had major molecular response (BCR-ABL/ABL<0.1%). Nine patients proceeded to allogeneic transplantation.Grades 3 and 4 toxicities included hemorrhage, pleural and pericardial effusions and infections. The median follow up for patients with CML-LB is 37.5 months (range, 7-70 months) with a 3-year overall survival of 70%;68% remained in CR at 3 years. For ALL patients, the median follow-up is 52 months (range, 45-59 months)with a 3-year survival of 26%; 30% remain in CR at 3 years. The combination of Hyper CVAD regimen with dasatinib is effective in patients with relapsed Ph-positive ALL and CML-LB. PMID- 24779034 TI - Partial dysfunction of Treg activation in sickle cell disease. AB - Sickle cell disease (SCD) is a chronic inflammatory disease associated with multiple organ damage, chronic anemia, and infections. SCD patients have a high rate of alloimmunization against red blood cells (RBCs) following transfusion and may develop autoimmune diseases. Studies in mouse models have suggested that regulatory T cells (Treg) play a role in alloimmunization against RBC antigens. We characterized the phenotype and function of the Treg cell population in a homogeneous cohort of transfused SCD patients. We found that the distribution of Treg subpopulations differed significantly between SCD patients and healthy blood donors. SCD patients have a particular Treg phenotype, with strong CTLA-4 and CD39 expression and weak HLA-DR and CCR7 expression. Finally, we show that this particular phenotype is related to SCD rather than alloimmunization status. Indeed, we observed no difference in Treg phenotype or function in vitro using autologous feeder cells between strong and weak responders to alloimmunization. PMID- 24779035 TI - Sickle-cell disease stroke throughout life: a retrospective study in an adult referral center. AB - Strokes are one of the most severe complications of sickle-cell disease. Most studies have been restricted to children with sickle-cell disease. To better understand the characteristics and follow-up of strokes occurring from childhood to adulthood, we undertook a retrospective cohort study of 69 stroke patients among the 2,875 patients consulting at the French Adult Sickle-Cell Disease Referral Center. Between 1970 and 2008, they had experienced 104 strokes: 80 ischemic, 22 hemorrhagic, and 2 intracranial sinus thromboses. Coma and/or fatal outcomes underscored the severity of strokes in sickle-cell disease patients.Hemorrhagic strokes occurred mostly in adults and carried a higher risk of death than ischemic stroke. The mechanisms underlying sickle-cell disease associated strokes were reevaluated and etiologies were determined for first stroke and recurrences, in childhood and adulthood. Sickle-cell disease vasculopathy concerned only SS patients and remains their most frequent stroke etiology. Cardioembolism, vaso-occlusive crisis and triggering factors were other etiologies identified in adults. Recurrences occurred in 19 SS patients only after a first ischemic stroke. SC patients' strokes occurred in adulthood and were associated with cardiovascular risk factors. Our findings provide novel information about cerebrovascular pathologies throughout the lives of sickle-cell disease patients and suggest the need for different diagnostic and therapeutic management approaches in those different settings. PMID- 24779036 TI - Involvement of primary mesenchymal precursors and hematopoietic bone marrow cells from chronic myeloid leukemia patients by BCR-ABL1 fusion gene. AB - For decades now, it is well established that chronic myeloid leukemia (CML) is a hematopoietic stem cell(HPC) disorder. However, it remains to be determined whether BCR-ABL1 gene rearrangement occurs in a HPC or at an earlier stem cell and whether the degree of involvement of hematopoiesis by the BCR-ABL1 fusion gene relates to the response to therapy. Here, we have investigated by interphase fluorescence in situ hybridization (iFISH) the distribution of BCR-ABL1 fusion gene in FACS-sorted bone marrow (BM) populations of mesenchymal precursor cells (MPC) and other hematopoietic cell populations from 18 newly diagnosed CML patients. Overall, our results showed systematic involvement at relatively high percentages of BM maturing neutrophils (97%615%), basophils (95%612%), eosinophils (90%68%), CD341 precursors cells (90%67%),monocytes (84%630%), nucleated red blood cells (87%624%), and mast cells (77%633%). By contrast, MPC(30%634%), B-cells (15%627%), T-lymphocytes (50%626%), and NK-cells (35%634%) were involved at lower percentages. In 8/18 CML patients, 2 tumor BCR-ABL11 subclones were detected by iFISH. Of note, all tumor cell subclones were systematically detected in CD341 cells, whereas MPC were only involved by the ancestral tumor cell subclone. In summary, here we confirm the presence at diagnosis of the BCR-ABL1 fusion gene inMPC, CD341 precursors, and other different BM hematopoietic myeloid cell lineages from CML patients,including also in a significant fraction of cases, a smaller percentage of T, B, and NK lymphocytes.Interestingly, involvement of MPC was restricted to the ancestral BCR ABL11 subclone. PMID- 24779037 TI - Anti-inflammatory effects of melatonin in a rat model of caerulein-induced acute pancreatitis. AB - The purpose of our study was to evaluate the protective effect of melatonin in a rat model of caerulein-induced acute pancreatitis. For the induction of experimental acute pancreatitis, four subcutaneous injections of caerulein (20 mgkg-1 body weight) were given to Wistar rats at 2-h intervals. Melatonin was injected intraperitoneally (25 mg kg-1 body weight) 30 min before each caerulein injection. After 12 h, rats were sacrificed by decapitation. Blood and pancreas samples were collected and processed for serological and histopathological studies,respectively. Lipase, a-amylase, corticosterone, total antioxidant power and cytokines interleukin (IL)-1b, IL-4 and tumour necrosis factor(TNF)-a were determined using commercial kits. ANOVA and Tukey tests (P<0.05) were performed for the statistical analysis of the results.Results showed that the administration of melatonin reduced histological damage induced by caerulein treatment as well as the hyperamylasemia and hyperlipidemia. Corticosterone and antioxidant total power were also reverted to basal activities. Furthermore, melatonin pre-treatment reduced pro-inflammatory cytokines IL-1b and TNF-a and increased the serum levels of anti-inflammatory cytokine IL-4. In conclusion,the findings suggest that the protective effect of melatonin in caerulein-induced acute pancreatitis is mediated by the anti-inflammatory ability of this indolamine. Thus, melatonin may have a protective effect against acute pancreatitis. PMID- 24779038 TI - Morphological aspects and expression of estrogen and progesterone receptors in the interdigital sinus in cyclic ewes. AB - Many species that belong to Artiodactyls order show an interdigital sinus (IS), as it occurs in sheep, in all four extremities. These are considered to be scent glands responsible for sexual communication having strong attractiveness to mature males at the peak of the breeding season. The aim of this study was to evaluate, in IS in cyclic ewes, the microscopic and ultrastructure (scanning and transmission electron microscopy) anatomy, secretion composition, and mRNA and protein expression of estrogen receptors a and b and progesterone receptors. Glandular sebaceous structures occupy a superficial area of the pouch. The other glands present in the IS show a coiled tubular structure and tall and polyhedral secretory cells with irregular luminal surface resulting from the secretory process. Protein and mRNA gene transcription studies were performed to determine the presence of ER (a and b) and P4r in IS. At the follicular phase, IS cell populations analyzed using flow cytometry expressed higher levels of ERb compared with ERa (P<0.05), whereas no difference was observed between them in the luteal phase. The IS amount of secretion was the highest in the follicular phase compared with luteal phase (P<0.05) or pregnancy (P<0.001).To the best of our knowledge, for the first time, the presence of ER (a and b) within the IS was demonstrated. As estrogen action is mediated by specific receptors in target cells, the presence of these receptors in IS might be needed to trigger signaling pathways involved in conspecific chemical (sexual) communication attributed to this area. PMID- 24779039 TI - Reply: To PMID 23689318. PMID- 24779040 TI - [Comparative study on condition and related factors of Keshan disease and dilated cardiomyopathy in Shandong province]. PMID- 24779041 TI - [Epidemiological characteristics of human plague in different age groups in China from 1950-2012]. PMID- 24779042 TI - [Molecular epidemiology characteristics of human enterovirus coxsackievirus A6 in Guangzhou, in 2011]. PMID- 24779043 TI - Reply: To PMID 23311739. PMID- 24779044 TI - The patient centered medical home. A systematic review. AB - BACKGROUND: The patient-centered medical home (PCMH) describes mechanisms for organizing primary care to provide high quality care across the full range of individuals' health care needs.It is being widely implemented by provider organizations and third party payers. PURPOSE: To describe approaches for PCMH implementation and summarize evidence for effects on patient and staff experiences,process of care, and clinical and economic outcomes. DATA SOURCES: PubMed (through 6 December 2011), Cumulative Index to Nursing & Allied Health Literature, and the Cochrane Database of Systematic Reviews (through 29 June 2012). STUDY SELECTION: English-language trials and longitudinal observational studies that met criteria for the PCMH, as defined by the Agency for Healthcare Research and Quality, and included populations with multiple conditions. DATA EXTRACTION: Information on study design, populations, interventions,comparators, financial models, implementation methods,outcomes, and risk of bias were abstracted by 1 investigator and verified by another. DATA SYNTHESIS: In 19 comparative studies, PCMH interventions had a small positive effect on patient experiences and small to moderate positive effects on the delivery of preventive care services(moderate strength of evidence). Staff experiences were also improved by a small to moderate degree (low strength of evidence).Evidence suggested a reduction in emergency department visits(risk ratio [RR], 0.81 [95% CI, 0.67 to 0.98]) but not in hospital admissions (RR, 0.96 [CI, 0.84 to 1.10]) in older adults (low strength of evidence). There was no evidence for overall cost savings. LIMITATION: Systematic review is challenging because of a lack of consistent definitions and nomenclature for PCMH. CONCLUSION: The PCMH holds promise for improving the experiences of patients and staff and potentially for improving care processes,but current evidence is insufficient to determine effects on clinical and most economic outcomes PMID- 24779048 TI - Sex change in plants and animals: a unified perspective. PMID- 24779049 TI - Environmental heterogeneity, multivariate sexual selection and genetic constraints on cuticular hydrocarbons in Drosophila simulans. AB - Sexual selection is responsible for the evolution of many elaborate traits, but sexual trait evolution could be influenced by opposing natural selection as well as genetic constraints. As such, the evolution of sexual traits could depend heavily on the environment if trait expression and attractiveness vary between environments. Here, male Drosophila simulans were reared across a range of diets and temperatures, and we examined differences between these environments in terms of (i) the expression of male cuticular hydrocarbons (CHCs) and (ii) which male CHC profiles were most attractive to females. Temperature had a strong effect on male CHC expression, whereas the effect of diet was weaker. Male CHCs were subject to complex patterns of directional, quadratic and correlational sexual selection, and we found differences between environments in the combination of male CHCs that were most attractive to females, with clearer differences between diets than between temperatures. We also show that genetic covariance between environments is likely to cause a constraint on independent CHC evolution between environments. Our results demonstrate that even across the narrow range of environmental variation studied here, predicting the outcome of sexual selection can be extremely complicated, suggesting that studies ignoring multiple traits or environments may provide an over-simplified view of the evolution of sexual traits. PMID- 24779050 TI - Evolution in the sabre-tooth cat, Smilodon fatalis, in response to Pleistocene climate change. AB - The late Pleistocene was a time of environmental change, culminating in an extinction event. Few fossil localities record a temporal series of carnivore fossil populations from this interesting interval as well as Rancho La Brea (RLB). We analysed mandibles of Smilodon fatalis from RLB using 2-D geometric morphometrics to examine whether, and how, mandibular shape changes through time. Smilodon fatalis shows mandibular evolution with oscillations between a small, ancestral-type morph in pits 77 (~37 Kybp) and 2051 (~26 Kybp), a larger, more derived morph in pits 91 (~28 Kybp) and 61-67 (~13.6 Kybp), and an intermediate morph from pit 13 (~17.7 Kybp). These oscillations end in pit 61-67, with greatest body size, and are estimated to have its widest gape and lowest bite force. Additionally, variation is lowest in pit 61-67, which was deposited concurrent with the Bolling-Allerod warming event, which may have important implications for the timing or conditions during the extinction event. Contra to a temporal Bergmann's rule, such rapid warming events appear to be correlated with larger, derived, morphologies whereas static, cooler, climates correlate with gracile, ancestral morphologies. PMID- 24779051 TI - New CEO takes the reins at the Gates Foundation. PMID- 24779052 TI - Canada's oil sands residents complain of health effects. PMID- 24779053 TI - Profile: Australia's Baker IDI Heart and Diabetes Institute. PMID- 24779054 TI - How do we tell the stories of medicine? PMID- 24779055 TI - Response to letter regarding article, "Four-variable risk model in men and women with heart failure". PMID- 24779056 TI - Vertically transmitted symbiont reduces host fitness along temperature gradient. AB - Parasites with exclusive vertical transmission from host parent to offspring are an evolutionary puzzle. With parasite fitness entirely linked to host reproduction, any fitness cost for infected hosts risks their selective elimination. Environmental conditions likely influence parasite impact and thereby the success of purely vertical transmission strategies. We tested for temperature-dependent virulence of Caedibacter taeniospiralis, a vertically transmitted bacterial symbiont of the protozoan Paramecium tetraurelia. We compared growth of infected and cured host populations at five temperatures (16 32 degrees C). Infection reduced host density at all temperatures, with a peak of -30% at 28 degrees C. These patterns were largely consistent across five infected Paramecium strains. Similar to Wolbachia symbionts, C. taeniospiralis may compensate fitness costs by conferring to the host a 'killer trait', targeting uninfected competitors. Considerable loss of infection at 32 degrees C suggests that killer efficacy is not universal and that limited heat tolerance restricts the conditions for persistence of C. taeniospiralis. PMID- 24779057 TI - [What can be learn from the last SUMER survey (medical surveillance of occupational risks) on carcinogenic exposures at work?]. PMID- 24779058 TI - Scientists. Excitement for a new era. PMID- 24779059 TI - Troubleshooting forum. SDS-page. What is the best way to separate proteins of similar molecular weight? (Thread 33111). PMID- 24779060 TI - If not Angelman, what is it? A review of Angelman-like syndromes. AB - Angelman syndrome (AS) is caused by a lack of expression of the maternally inherited UBE3A gene in the brain. However, about 10% of individuals with a clinical diagnosis of AS do not have an identifiable molecular defect. It is likely that most of those individuals have an AS-like syndrome that is clinically and molecularly distinct from AS. These AS-like syndromes can be broadly classified into chromosomal microdeletion and microduplication syndromes, and single-gene disorders. The microdeletion/microduplication syndromes are now easily identified by chromosomal microarray analysis and include Phelan-McDermid syndrome (chromosome 22q13.3 deletion), MBD5 haploinsufficiency syndrome (chromosome 2q23.1 deletion), and KANSL1 haploinsufficiency syndrome (chromosome 17q21.31 deletion). The single-gene disorders include Pitt-Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat-Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett (MECP2) syndrome. They also include disorders due to mutations in HERC2, adenylosuccinase lyase (ADSL), CDKL5, FOXG1, MECP2 (duplications), MEF2C, and ATRX. Although many of these single-gene disorders can be caused by chromosomal microdeletions resulting in haploinsufficiency of the critical gene, the individual disorders are often caused by intragenic mutations that cannot be detected by chromosomal microarray analysis. We provide an overview of the clinical features of these syndromes, comparing and contrasting them with AS, in the hope that it will help guide clinicians in the diagnostic work-up of individuals with AS-like syndromes. PMID- 24779061 TI - A remarkable effect of N,N-diethylamino functionality on the optoelectronic properties of a salicylimine-based probe for Al(3+). AB - A new live-cell permeable, fluorescent probe comprised of a simple salicylimine based Schiff base (SA1) has been developed for Al3+ with nano-molar sensitivity in aqueous media. SA1 was synthesized through a simple structural modification of a recently reported receptor SA2 by the incorporation of the N,Ndiethylamino (DEA) group as a fine controllable unit. This modification affects the performance of SA1 remarkably in terms of its sensitivity, water compatibility and efficiency as well as its mechanistic aspect. The presence of the DEA group in SA1 led to its dual channel emission due to the TICT state and at the same time its hydrophobic nature was also responsible for controlling the strong hydration of Al3+ ions in aqueous media which ultimately led to the high sensitivity of SA1 for Al3+. The structure of SA1 was confirmed by single crystal X-ray diffraction and its binding with Al3+ was studied in detail using UVvisible, fluorescence and 1H NMR spectral studies along with mass determination. The effort of getting a single crystal of Al3+-SA1 led to single crystals of Cl-/NO3 - complexes of protonated SA1 which were fully characterized by their XRD studies. PMID- 24779062 TI - Hereditary cerebral arteriopathy with subcortical infarcts and leucoencephalopathy. PMID- 24779063 TI - [Biological markers of respiratory diseases]. PMID- 24779064 TI - [New-onset chronic obstructive pulmonary disease and its clinical significance in patients with ST-segment elevation myocardial infarction]. AB - AIM: To estimate the prevalence of new-onset chronic obstructive pulmonary disease (COPD) and its clinical significance in patients with ST-segment elevation myocardial infarction (STEMI) on an electrocardiogram. SUBJECTS AND METHODS: The trial enrolled 154 patients with STEMI who underwent external respiratory function examination with a bronchodilatation test, as well as body plethysmography. The level of high-sensitivity C-reactive protein (CRP) was determined 10-14 days after the onset of clinical manifestations of STEMI. RESULTS: Thirty-four (22%) of the 154 patients were known to have a history of COPD. Our examination was first to reveal irreversible postbronchodilatation airway obstruction and to diagnose COPD in 24 (20%) of 120 patients having no evidence of lung pathology in the history. All patients with new-onset obstructive pulmonary disease had varying degrees of respiratory symptoms before this hospitalization; however, they did not seek medical advice. The patients with STEMI concurrent with COPD were recorded to have lower diffusing lung capacity, higher CRP levels, more frequent recurrences of myocardial infarction, early postinfarction angina, but the incidence rate of pneumonia in in-hospital myocardial infarction achieved significant differences. CONCLUSION: The trial has disclosed that screening spirometry should be performed to detect COPD in patients with ischemic lung disease, which will be able to reduce the risk of complications and to improve prognosis in this patient group. PMID- 24779065 TI - [Biochemical markers of endothelial dysfunction in chronic obstructive pulmonary disease concurrent with hypertensive disease or coronary heart disease]. AB - AIM: To evaluate the vascular endothelium in patients with cardiopulmonary disease, by studying the levels of endothelin-1 (ET-1) and C-type natriuretic peptide (CNP). SUBJECTS AND METHODS: Examinations were conducted in 212 dwellers of the Astrakhan Region, including 40 patients with chronic obstructive pulmonary disease (COPD) concurrent with hypertensive disease (HD), 40 patients with COPD concurrent with coronary heart disease (CHD), 27 somatically healthy individuals, 35 patients with Stage II HD, 35 patients with Functional Classes II and III CHD, and 35 patients with moderate and severe COPD. RESULTS: The patients with COPD concurrent with HD and CHD were found to have endothelial dysfunction manifesting itself in the overproduction of ET-1 and CNP. The level of CNP was statistically significantly higher in the COPD + HD group than in the HD and COPD groups whereas in the COPD + HD group the level of ET-1 remained comparable to that in the COPD and HD groups. This indicates that CNP is a more sensitive indirect marker of endothelial dysfunction and that nitric oxide deficiency is aggravated in the concurrence of COPD and HD as compared to a mononosological entity (HD, COPD). CONCLUSION: The concurrence of COPD and CHD is more unfavorable for the development and severity of endothelial dysfunction, which may lead to mutual aggravation syndrome, the rapider progression of the diseases, and the increased frequency of complications. PMID- 24779066 TI - [Cardiac comorbidity in patients with chronic obstructive pulmonary disease: diagnosis and economics]. AB - AIM: To provide a clinical and economic rationale for the comprehensive examination of patients with chronic obstructive pulmonary disease (COPD), by using functional and ultrasound methods for the early detection of cardiac comorbidity. SUBJECTS AND METHODS: Three hundred and sixteen patients (33 with COPD, 44 with COPD + hypertension, 73 with COPD + coronary heart disease (CHD), 36 with hypertension, 50 with CHD, 19 with asthma, and 28 with asthma + hypertension) and 33 apparently healthy individuals were examined using 611 indicators obtained directly or by calculation during echocardiography, carotid artery duplex scanning, and 24-hour electrocardiographic (ECG) and blood pressure (BP) monitoring. RESULTS: Cardiovascular diseases develop in patients with COPD in its early stages. In cardiac comorbidity, the length of hospital stay increases by 1-1.5 days in patients with COPD; the number of people admitted to hospital more than once every 3 years rises from 14 to 28%; the cost of a pharmacotherapy cycle is 1.35- and 2.95-fold higher when COPD is concurrent with hypertension and CHD, respectively. CONCLUSION: In addition to ECG and spirometry, the management standard for patients with COPD should include echocardiography, 24-hour ECG and BP monitoring, and, according to their results, carotid artery duplex scanning. PMID- 24779067 TI - [The clinical aspects of efficiency of the prevention of pneumococcal infection with vaccines in chronic obstructive pulmonary disease patients living in the West Siberian Region]. AB - AIM: To evaluate the impact of vaccination against pneumococcal infection on the clinical aspects of the underlying disease in patients with chronic obstructive pulmonary disease (COPD). SUBJECTS AND METHODS: The study conducted in the West Siberian Region (Omsk and Tyumen) enrolled 200 COPD patients aged 30 to 55 years, of whom 50 people in each city were vaccinated with Pneumo 23, as well as 50 unvaccinated persons in each city formed a comparison group. Physical examination, questionnaire survey, and medical history data collection were made during a year before vaccination and after it. Changes in the number of COPD exacerbations, hospital admissions, and disability days were compared in the groups of Pneumo 23-vaccinated and unvaccinated patients. RESULTS: In Pneumo 23 vaccinated patients with COPD, the number of its exacerbations, hospital admissions, and disability days within a year of starting the study were fewer than in the unvaccinated patients, with the more effect being seen in the Omsk dwellers, which had a beneficial effect on the clinical state of the vaccinated. CONCLUSION: Incorporation of pneumococcal vaccine along with antirecurrent, standard therapy may serve as one of the tools to alleviate COPD. PMID- 24779068 TI - [The features of risk factors, systemic inflammation, and endothelial dysfunction in patients with asthma concurrent with coronary heart disease]. AB - AIM: To identify risk factors (RFs), to evaluate the impact of systemic inflammation and endothelial dysfunction on the development of asthma concurrent with coronary heart disease (CHD), and to determine the degree of control of the disease. SUBJECTS AND METHODS: The clinical trial included 50 asthmatics aged 40 75 years with CHD. All the patients underwent external respiratory function (ERF) test, ECG, blood pressure and anthropometric measurements, and bicycle ergometry. Their medical and allergy history data were collected and RFs and basic therapy were assessed. Laboratory blood and urine values and endothelial function were estimated determining the brachial artery diameter and the time-averaged maximal linear velocity (TAMX) of blood flow in endothelium-dependent and endothelium independent vasodilation (VDV and VIDV). RESULTS: The development of asthma in the presence of CHD was found to be associated with RFs, such as female gender (66%), hereditary asthma (40%) and CHD (76%), hypertension (86%), obesity (42%), smoking (7%), occupational exposures (20%), and dyslipidemia. Laboratory tests in the asthmatic patients with CHD revealed a positive C-reactive protein reaction (CRP) in 16 (32%) patients and increased serum cholesterol levels. Reactive hyperemia and nitroglycerin tests in the patients with asthma concurrent with CHD showed that the BA diameter was significantly increased up to 4.27 +/- 0.3 and 4.54 +/- 0.03 mm, respectively, as compared to the baseline values (p < 0.01). Most patients were observed to have marked and frequent symptoms of the disease, frequent asthma exacerbations, and impaired ERF and to need "rescue" bronchodilators. CONCLUSION: RFs, such as female gender, family history, hypertension, obesity and dyslipidemia play an important role in the development of asthma concurrent with CHD. Impaired TAMX, VDV, and VIDV, hypercholesterolemia and higher CRP levels were detected. Basic therapy in the patients with asthma concurrent with CHD was not optimal or rather effective since disease control was not achieved in 70% of the patients. PMID- 24779069 TI - [Possibility of achieving and maintaining asthma control in patients with bronchial cold hyperreactivity]. AB - AIM: To evaluate the clinical efficiency of tactics to widen the scope of monotherapy with inhaled glucocorticosteroids (IGCS) in asthmatic patients with bronchial cold hyperreactivity (BCHR) during winter to achieve control of the disease in real clinical practice. SUBJECTS AND METHODS: An open-label longitudinal study was conducted in a cold period in 106 asthmatics divided into 2 groups: 1) those with BCHR and 2) those with unchanged bronchial reactivity to a cold stimulus. The study involved monitoring the symptoms by the asthma control test, peak expiratory flow rate (PEFR), and spirometry results before and after cold bronchoprovocation testing; assessment of the pattern of bronchial inflammation from the ratios of induced sputum (IS) cell populations; and estimation of the number of asthma exacerbations and emergency care recourses. Group 1 used a stepwise increase of the scope of basic therapy with beclomethasone dipropionate 1000 microg/day until asthma control was achieved, which was followed by the therapy with the stable dose. Group 2 received monotherapy with beclomethasone dipropionate as the stable dosage of < or = 500 microg/day. RESULTS: After the first 12 weeks of a follow-up, Group 1 showed the most marked positive changes in the intensity of clinical symptoms, forced expiratory volume in one second, and PEFR that remained within the following 12 weeks during the continued therapy with the stable dose of the drug. A preponderance of the eosinophilic and neutrophilic pattern of inflammation was seen in the patients of this group. By the end of the study, there was a decline in the number of IS inflammatory cells. A discriminant model was developed as a tool to predict asthma control achievement in patients with BCHR. CONCLUSION: A stepwise increase in the scope of IGCS monotherapy in asthmatic patients with BCHR during winter can yield the results of disease control and the incidence of exacerbations, which are similar to those seen in asthmatics with no signs of BCHR (53 and 49%, respectively). PMID- 24779070 TI - [Clinical manifestations of Legionella pneumonia in hematology patients]. AB - AIM: To detect the most common clinical manifestations of Legionella pneumonia (LP) in immunocompromized patients. SUBJECTS AND METHODS: Clinical manifestations, the results of investigation of bronchoalveolar lavage fluid (BALF) and urine, and the data of lung computed tomography (CT) were studied in patients with blood system diseases and acute respiratory failure (ARF). RESULTS: The diagnosis of LP was verified in 8 (10.5%) of 76 patients with blood system diseases and ARF. The disease manifested as fever, higher concentrations of inflammatory markers (procalcitonin, fibrinogen), ARF, hypoxemia, and infiltrative lung injury. Six of the 8 patients were switched to mechanical ventilation. Lung CT showed no pathognomonic signs. Five of the 8 patients were observed to have renal dysfunction. The diagnosis of LP was made on the basis of the results of BALF examination in 7 patients and urinary antigen detection in 1. The disease was caused by Legionella pneumophila serogroup 1 in 3 patients and by L. pneumophila of other serogroups in the other patients. Therapy with respiratory fluoroquinolones was performed in 5 patients. Three patients died from progressive ARF and hypoxemia. BALF results were obtained after their death and therapy for legionellosis was not initiated. CONCLUSION: The incidence of LP is 10.5% in hematology patients. The clinical manifestations of legionellosis are nonspecific; its diagnosis requires bacteriological and/or serological evidence. Due to the high risk of death, it is reasonable to preuse respiratory fluoroquinolones or macrolides in immunocompromized patients with progressive ARF and suspected Legionella pneumonia before diagnosis. PMID- 24779071 TI - [Clinical manifestations of anemia syndrome and its significance in the course of chronic heart failure in elderly patients]. AB - AIM: To define the practical significance of anemia in the course of chronic heart failure (CHF) in elderly outpatients. SUBJECTS AND METHODS: One hundred and sixty-four patients aged 60 to 85 years with NYHA classification Functional Class (FC) II--IV CHF due to coronary heart disease and arterial hypertension were examined. Clinical, laboratory, and echocardiographic parameters were assessed; admissions and fatal outcomes were recorded. The follow-up was 2.5 +/- 2.1 years. RESULTS: Anemia syndrome was recorded in 32.9% of the patients (women were 43.5% and men were 26.5%) (p = 0.024). There was an association between decreased hemoglobin levels and renal dysfunction (odds ratio (OR) 2.04; 95% confidence interval, 1.05 to 3.98; p = 0.036). In all the patients, anemia was mild and similar in its pattern and etiology, regardless of gender. Because of decompensated CHF, 46.3% of the patients with anemia and 22.7% of those without this condition were admitted to hospital (p = 0.002). The survival rates of the elderly CHF patients with and without anemia were equal (p = 0.549); however, comparison of only the patients with anemia showed a difference in male and female survival rates (p = 0.005). FC III--IV CHF (OR 4.37), chronic kidney disease (OR 2.27%), and a left ventricular ejection fraction of < 35% (OR 2.74) were predictors of a poor outcome in the elderly patients with CHF and anemia. CONCLUSION: Anemia was encountered in 32.9% of the elderly outpatients with CHF. Anemia was more common in the women than in the men and mild and similar in its pattern and etiology, regardless of gender. The disease prognosis was more favorable in the females than in the males. PMID- 24779072 TI - [Hemostasiological, lipidemic, and hemodynamic indicators associated with the risk of cardiovascular death in high- and very high-risk patients according to the SCORE scale]. AB - AIM: To identify lipidemic, hemostasiological, and hemodynamic indicators associated with the risk of cardiovascular death in high- and very high-risk patients. SUBJECTS AND METHODS: One hundred and forty-eight patients whose mean age was 50.8 +/- 4.4 years were examined. All the patients were divided into high (1 group) and very high (2 group) cardiovascular death risk groups according to the SCORE scale. Lipid metabolism, hemostatic system parameters (fibrinogen, time of ADP-induced platelet aggregation initiation, D-dimer), endothelial dysfunction markers (von Willebrand factor), and echocardiographic findings were studied. RESULTS: Multivariate regression analysis showed that the odds ratio for a cardiovascular death risk was 1.8 (95% confidence interval (CI), 1.1 to 4.2; p = 0.04) in patients with a D-dimer level of greater than 1 mg/ml, 0.77 (95% CI, 0.6 to 0.97; p = 0.03) in those with an ADP-induced platelet aggregation initiation time of 13.5 sec, 1.04 (95% CI, 1.01 to 1.07; p = 0.02) in those with an end diastolic volume of more than 123 ml, 1.1 (95% CI, 1.04 to 1.2; p = 0.003) in those with an end-diastolic dimension of more than 51 mm, 1.5 (95% CI, 1.1 to 2.0; p = 0.009) in those with a ventricular septal thickness of more than 11.5 mm, and 2.1 (95% CI, 1.03 to 3.2; p = 0.0032) in those with avon Willebrand factor level of more than 140%. CONCLUSION: The high levels of von Willebrand factor, D-dimer, ADP-induced platelet aggregation, triglycerides, end-diastolic volume, end-diastolic dimension, and ventricular septal thickness are independent predictors of cardiovascular death in very high-risk patients. These indicators bear out a close relationship between lipid metabolic and hemostatic disturbances and between endothelial dysfunction and intracardiac hemodynamic worsening in these patients. PMID- 24779073 TI - [Evaluation of coronary artery lesion in men with osteopenic syndrome and coronary artery disease]. AB - AIM: To examine the relation between coronary atherosclerosis (CA), coronary artery calcification (CAC), and bone mineral density (BMD) in men with coronary artery disease (CAD). SUBJECTS AND METHODS: The investigation included 74 males aged 60.1 (range, 55-70) years with verified CAD. All the patients underwent X ray contrast-enhanced selective coronary angiography and coronary artery calcium score (CS) and BMD measurements by osteodensitometry. The severity of a coronary artery lesion was evaluated using the SYNTAX score. According to the T score, the patients were divided into 3 groups: 1) 23 patients with osteoporosis (OP), 2) 30 patients with osteopenia, and 3) 21 patients with normal BMD. RESULTS: Osteopenic syndrome (OS) (OP and osteopenia) was found in 71.6% of the patients with angiographically confirmed CAD. Single-vessel lesion in the coronary bed (CB) was more frequently recorded in the normal BMD group than in the OP one (p = 0.023). Severe CB lesion was more common for the patients with OP (p = 0.029). There were statistically significant differences between the osteopenia and normal BMD groups in the severe degree of CB lesion (p = 0.042). Differences were noted in total CS between Groups 1 and 2 (p = 0.0122). CS significantly correlated with the severity of CA lesion according to the SYNTAX score (r = 0.53; p = 0.002). CONCLUSION: Severe CB lesion in males correlates with CAC and is associated with decreased BMD, suggesting the commonness of the pathogenetic components of AS and OS. PMID- 24779074 TI - [The specific features of the immunophenotype of blast cells in patients with de novo normal karyotype acute myeloid leukemia and FLT3-ITD mutation]. AB - AIM: To study the specific features of de novo acute myeloid leukemia (AML) with FLT3-ITD mutation. SUBJECTS AND METHODS: The results of examination were analyzed in 101 patients. Bone marrow morphological specimens were stained with Pappenheim stain. The karyotype was investigated using the standard GTG-banding method. Blast cells were immunotyped in a five-color analysis on a Cytomics FC 500 laser flow cytofluorometer. RESULTS: FLT3-ITD mutation was identified in 21 patients who had a varying morphological nature of blasts, different karyotype variants, and frequently additional NPM1 gene mutation. The distinctive property of 10 patients with normal karyotype and FLT3-ITD mutation (without NPM1 gene mutation) was the larger number of cases with high expression of HLA-DR and CD7 than in the control group that included 18 patients with normal karyotype AML without FLT3 ITD nutation: 50% versus 6.2% (p = 0.007) and 100% versus 55.6% (p = 0.014), respectively. CONCLUSION: Normal karyotype AML with FLT3-ITD mutation is a group that is homogeneous in the biological phenotype of leukemia cells. PMID- 24779075 TI - [Mechanisms of comorbidity in hemophilia patients]. AB - AIM: To study the somatic status of patients with varying degrees of hemophilia, the mechanisms of comorbidity from the results of studies of systemic microcirculation (MC), body composition, and key metabolic parameters. SUBJECTS AND METHODS: One hundred and twenty hemophilia patients were examined. The authors studied their viscera; MC by laser Doppler flowmetry; body composition parameters by bioelectrical impedance; and blood cholesterol, albumin, and iron levels. RESULTS: The incidence of chronic diseases of the kidney, digestive system, and myocardium (from electrocardiographic findings), and liver was found to be proportional to the severity of hemophilia. The number of diseases per patient with mild, moderate, or severe hemophilia was 1.0 +/- 0.02, 1.5 +/- 0.02, and 2.5 +/- 0.03, respectively. Four and two systems were ascertained to be commonly affected in patients with severe and mild hemophilia, respectively. The investigators studied the comorbidity mechanisms that included changed systemic MC; a decreased perfusion associated with excess fat mass; evolving iron deficiency; anemia; protein and mineral deficiencies; and a tendency to lower blood cholesterol levels, which reflected energoplastic wastes in hemophilia patients. CONCLUSION: The detection of comorbidity and mechanisms of its development in hemophilia makes it possible to improve the prevention of hemorrhage and visceral pathology in these patients and their quality of life. PMID- 24779076 TI - [Delirium in the clinical practice of a therapist]. AB - Delirium is a neuropsychiatric condition that may complicate any visceral disease. Its rate is especially high among patients with inflammatory diseases or metabolic disturbances and in the elderly. Brain injury concurrent with an abnormal stress response underlies the development of delirium. The clinical picture of delirium is characterized by clouding of consciousness accompanied by global cognitive and behavioral changes. According to the nature of changes in motor behavior, delirium is divided into hyperactive, hypoactive, and mixed subtypes. Special scales, such as Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), are used to identify delirium. Management of delirium includes specific therapy for the underlying disease and adequate care. Low-dose neuroleptics, haloperidol in particular, are recommended to correct behavioral changes. PMID- 24779077 TI - [Choice of novel endpoints in clinical trials evaluating the efficiency of drug therapy in patients with pulmonary hypertension]. AB - Pulmonary hypertension (PH) is characterized by a poor prognosis: the three-year survival rate in patients with PH is not greater than 60% as evidenced by current national registries. In the past decade, there have been drugs that are able to relieve symptoms of the disease, to slow down its progression, and improve quality of life. Historically, clinical trials dealing with PH have had a fixed and rather short-tern period and most commonly used the index "the change in the distance covered in the 6-minute walk test" as a primary endpoint. Further optimization of PH therapy requires that the efficacy of drugs and the strategies of therapy be evaluated with respect to their effects on morbidity and mortality, i.e. on prognosis. The SERAPHIN trial is now the only completed and published clinical trial using the combined index of morbidity and mortality as a primary endpoint. It demonstrates that that therapy with the novel drug macitentan causes a reduction in morbidity and mortality in patients with PH. PMID- 24779078 TI - [Eradication therapy for Helicobacter pylori infection: review of world trends]. AB - The literature review gives current views on the treatment of Helicobacter pylori infection. The rising antibiotic resistance of H. pylori in the first decade of the 21st century entailed the decreased efficiency of common eradication therapy (ET) regimens, by determining the higher interest in this problem. The paper summarizes data on the efficiency of current ET regimens in different regions of the world in the past 3 years. The prospects of alternative ET regimens are considered. The existing and promising ways of optimizing the current ET regimens are presented. PMID- 24779079 TI - [Role of probiotics in the prevention and treatment of diarrhea of various genesis: focus on linex]. AB - The paper gives an update on the role of the microbiota in the maintenance of human health and in the pathogenesis of diseases. There is evidence for the efficacy and safety of probiotics in the treatment and prevention of diarrhea of various genesis. The place of linex in the therapy of diarrhea syndrome is discussed on the basis of the results of clinical trials. PMID- 24779080 TI - [Metabolic syndrome and coronary heart disease]. PMID- 24779081 TI - [Sepsis markers. XXI century]. AB - Sepsis remains a leading cause of death in all age groups worldwide. Diagnosis, process monitoring, and timely appropriate treatment are all that are a fairly complex problem due to the heterogeneity of the disease itself. Diagnostic biomolecular markers could greatly simplify, accelerate, and objectify the entire healing process, from diagnosis and process monitoring to verification and timely correction of therapy. Today, as a result of technological development of laboratory studies, more than 100 biological units in the general concept of systemic inflammation and infection are being studied as diagnostic markers. The nature of sepsis still remains a mystery. PMID- 24779082 TI - Distal biceps brachii tendon rupture resulting in acute compartment syndrome. PMID- 24779083 TI - Current state and use of biological adhesives in orthopedic surgery. PMID- 24779084 TI - Diagnostic issues affecting the epidemiology of fetal alcohol spectrum disorders. AB - BACKGROUND: Epidemiological measures of the prevalence of fetal alcohol spectrum disorders (FASD) vary greatly in the literature. Irrespective of the methodology, the criteria to define a 'case' are set by the researchers. Hence, estimates of the prevalence of FASD primarily depend on the diagnostic criteria currently available. The problem lies therein - the aforementioned criteria are ill defined. MATERIALS & METHODS: A critical analysis of the diagnostic criteria from the Institute of Medicine, Hoyme, 4-Digit Diagnostic Code and Canadian guidelines was performed, with particular attention focused on the inconsistencies in specificities of the fetal alcohol syndrome (FAS) facial phenotype. RESULTS: To date, the Canadian guidelines represent the only guidelines that have pushed for a uniform diagnostic capacity through harmonizing the IoM and 4-Digit Diagnostic Code criteria. In the absence of a reliable biochemical marker of effect to confirm maternal drinking during pregnancy, the importance and dependence on diagnostic guidelines for FASD is understated. With the availability of four published guidelines for diagnoses across the spectrum of FASD, there is a need to reach a set standard globally. There are profound implications of relaxed and strict diagnostic approaches on FAS prevalence reporting in the literature. CONCLUSIONS: This review exposes the clinical burden of diagnosing the range of FASD with disputing diagnostic criteria. Discrepancies in the criteria pose a danger to the validity of FASD diagnoses with respect to inaccurate estimates of incidence and prevalence. In turn, these discrepancies risk compromising the future healthcare of affected individuals with regards to intervention, counselling and treatment. PMID- 24779085 TI - [Changes in diagnostic criteria and practice guidelines for primary osteoporosis]. PMID- 24779086 TI - Ten years of the CIHR Institute of Aging: building on strengths, addressing gaps, shaping the future. PMID- 24779087 TI - An endovascular procedure (stent graft) in the treatment of a recurrent secondary aortoduodenal fistula. AB - A secondary aortoenteric fistula is a complication of earlier aortic grafting due to anaortic abdominal aneurysm. A primary aortoduodenal fistula (ADF) is a rare clinical entity that usually causes gastrointestinal bleeding that can be occult, intermittent, or massive. This article presents the case of a 68-year-old man with acute onset of a massive hematemesis and hematochezia.Eight years earlier he had undergone the implantation of an aortobifemoral prosthesis to treat an aortic aneurysm. The patient's condition was unstable, and it was during emergency surgery that the diagnosis of an ADF was made. An infected graft was removed in its entirety,and a new prosthesis was implanted. An omentoplasty with a pedunculated flap was performed.After 8 months, the patient had a recurrent AD F. He underwent another operation, but hemorrhaging from the aortic anastomosis occurred, so he required emergency surgery. Eventration occurred on the 14th postoperative day. The resection of the transversal colon was performed with a cecostomy for the decompression of the end-to-end anastomosis. Three months later the patient suffered a recurrent AD F. An aortobifemoral stent graft was implanted. Periaortal flow drainage was established for the irrigation of the retroperitoneal space. A microjejunostomy tube was also inserted. The patient recovered without any complications. This case represents an example of a rare serious complication of aortic abdominal aneurysm. This case report covers pathophysiology, diagnostic evaluation, and management of an aortoenteric fistula. PMID- 24779088 TI - Inpatient glycemic control in 4 easy steps. PMID- 24779089 TI - All info is good info. Seek & incorporate all available patient information. PMID- 24779090 TI - Intellectual disability. PMID- 24779091 TI - Author Cynthia Goss, BA, MICP, responds. PMID- 24779092 TI - Millennials. Overcoming the generation gap. PMID- 24779093 TI - Put me back in, coach. Watch for concussions presenting subtly. PMID- 24779094 TI - Sugar smack. Thoroughly investigate & treat all reversible causes in head injury. PMID- 24779095 TI - Trauma overtriage. Who should pay the bill? PMID- 24779096 TI - Simple thoracostomy. Moving beyong needle decompression in traumatic cardiac arrest. PMID- 24779097 TI - Nitrous oxide. New delivery of an old drug. PMID- 24779098 TI - Under constant threat. Delivering critical care in Ciudad Juarez & on the U.S. Mexico border. PMID- 24779099 TI - International trauma system collaboration. A report on the 201 3 Korea-Arizona Trauma Summit. PMID- 24779100 TI - High index of suspicion. Recognizing & managing traumatic neck injuries. PMID- 24779101 TI - The lethal triad. Hypothermia, acidosis & coagulopathy create a deadly cycle for trauma patients. PMID- 24779102 TI - Leaving a legacy. Harnessing the real power in the classroom. PMID- 24779103 TI - Givers & takeers. Evolve with EMS, not against it. PMID- 24779104 TI - Microscope slides in the life sciences: material, epistemic and symbolic objects. PMID- 24779105 TI - "The living picture": on the circulation of microscope-slide knowledge in 1903. AB - Microscope slides allowed preparations to circulate among scientific and educational contexts. An extension of the circulation of microscope slides was how they became part of lantern exhibition culture. This article considers an early example of the adoption of microscope lantern show conventions by another medium, the cinema. E Martin Duncan, who was employed by Charles Urban to produce a series of popular-science films beginning in 1903, brought his experience with microphotography to bear on the challenge of adapting cinema to the purpose of public instruction. Duncan's first series of films, entitled "The Unseen World," demonstrated both profound links to the display tradition of the lantern lecture as well as the transformation of that tradition by the cinema's representational possibilities. PMID- 24779106 TI - Histopathology slides from medical research to medical practice in interwar Strasbourg. AB - Histopathologists have been interested in cancer since the beginning of cellular theory. Rudolf Virchow and Julius Cohnheim defined cancer as a disease due to specific changes in tissues; cancer was thus considered a "pathologist's disease." Virchow emphasized the principles of biopsy and its value in the diagnosis of malignant tumours, but he himself did not promote it as an instrument for diagnosis. In the nineteenth century, in fact, cancer was a pathologists' disease in research only, not in diagnosis. By the mid-twentieth century, pathologists figured in medical practice as mediators between alternative therapeutic solutions. Histopathology entered a new arena, medical practice. In this paper, the process through which microscope slides moved from histopathology research to medical practice will be explored in detail with the aim of understanding how medical research integrates routine medical practices. The quasi-inherent character of scientific knowledge as relevant to medical practice is not taken for granted here. Through a study of medical school laboratory records from the interwar period in Strasbourg, I argue that pathologists could direct patients to specific forms of therapy on the basis of microscopic slides of cancer cells because they had defined (and re-defined) cancers by contributing to establishing radiation therapy practices. PMID- 24779107 TI - Sex on a slide: Antoine Lacassagne and the search for a microscopic definition of masculinity and femininity. AB - In 1919, the French pathologist and pioneer of radiotherapy of cancer, Antoine Lacassagne, studied the case of a young man of indeterminate sexuality (a condition later named "intersex," and recently renamed, "disorders of sexual development"). Lacassagne's argument that the patient was a "true" hermaphrodite, that is, an individual who possesses at the same time male and female sexual glands, was grounded exclusively in his study of microscopic preparations. Such preparations were seen as the definitive proof of the "true biological sex" of a given person, seen as a fixed entity. On the other hand, Lacassagne's definition of biological, or rather histological sex, was dissociated from sexuality, sexual orientation and sex/gender identity. In the 1930s, the isolation of sex hormones made it possible to modulate specific sexual traits, thus destabilizing the concept of a fixed biological sex. It did not undermine, however, the central role of histological proofs. Sex on a slide continued to be seen as definitive evidence of the "true" sexual identity of an individual, but from the 1930s this proof was valid only for the time when a given microscopic preparation had been manufactured. PMID- 24779108 TI - Induction of visibility: reflections on histological slides, drawing visual hypotheses and aesthetic-epistemic actions. AB - This paper focuses on histological slides and on the strategies of visual transformation of Santiago Ramon y Cajal. His practices and concepts reveal that not only the slides as such and their images have cognitive and aesthetic values crucial to the epistemic gain about the original material, but also the processes that unveil and reassess these values during observation and imaging. Therefore, considering the nature of these processes contributes to--besides the inquiry about the slides themselves--disclosing their role as epistemic and cultural objects in the history of the life sciences. To be beneficial to this inquiry, however, a closer definition of these processes is needed. I propose to define these operations in terms of the notion of "induction of visibility," which specifies general concepts of "visualisation" or "making something visible" as an instrument generating and transporting visual knowledge. Processes of visibility induction, I argue, constitute a category of visual action in their own right, which derives from and generates aesthetic and epistemic operations likewise. For this category, I propose, therefore, the concept of "aesthetic-epistemic action". PMID- 24779109 TI - Changing the scale: slides and electron microscopy at the Virus Laboratory of the Pasteur Institute. AB - Slides are material objects, the daily existence of which cannot be diassociated from the practice of microscopy. But what happens to slides when the examination tool is no longer an optical apparatus but an electon microscope? This is the core issue this paper examines. The answer it proposes is that electron microscope slides are not slides in the classical sense of the word but complex arrangements of materials including plates, cards, photographs and notebooks, which constitute an imaginary "slide," an assemblage the status and existence of which is defined in reference to the heritage of optical microscopy. To illustrate this argument, the paper follows the experimental work of Odile Croissant, the first electron microscopist at the Pasteur Institute in Paris during the 1940s and 1950s when the practices of the new microscopy were introduced and calibrated. PMID- 24779110 TI - From scientific object to commemorated victim: the children of the Spiegelgrund. AB - The legacy of German medical research in the era of National Socialism remains contentious, as regards identification of victims, and the appropriate handling of scientific specimens. These questions are acutely posed by the scientific slides, brain sections, and other body parts of victims, who were killed for research. These slides continued to be held by Austrian and German scientific institutes in the second half of the twentieth century. That scientists continued research on these slides between 1945 and the late 1980s suggests a disassociation of guilt and responsibility for the deaths of the victims by the German scientific community. PMID- 24779111 TI - The afterlife of the slide: exploring emotional attachment to artefactualised bodily traces. AB - In this paper I explore the role of the slide, not as familiar scientific object, but rather as a fixed remnant that testifies to the lived experience of an individual. Returning to the scene of the public scandal that surrounded the unauthorised retention of children's organs and tissues at two British hospitals in the late 1990s, I investigate the emotional significance that here came to be attached to archived slides. In so doing I draw attention to the ways in which the facticity of the slide--its ability to testify to the fact, or the existence, not only of the person from whom it is drawn, but also, when created for histopathological reasons, the disease that ultimately killed them--acts to efface their presumed ephemerality. In the final section of the paper I turn to consider how the events that I describe have come to shape the ways in which this kind of highly artefactualised bodily material is now accommodated in the institutional setting of the tissue bank and with what implications for research and the wider dissemination of scientific knowledge. Specifically, I explore how and why slides have come to acquire a "personality" and, with it, something akin to legally constituted "personality rights" including rights relating to publicity and privacy. PMID- 24779112 TI - About the new significance and the contingent meaning of biological material and data in biobanks. AB - Since the end of the 1990s, the practice of biobanking--performed in and by actors called biobanks--has become a key practice for the life sciences and the biotechnologies, though the practice of biobanking is far from being something entirely new. Its significance, however, is indeed new, in the sense that the biological material and associated data collected in, and manipulated by, well organised and often highly specialised facilities is transformed into an (epistemic) object with biovalue. In other words, the practice of biobanking signifies not only the collection, manipulation, and distribution of biological material and associated data in an organised manner involving various actors that govern or use the services of a biobank. Rather, it produces biobanks as sites of co-production of data-driven scientific knowledge. My paper draws on case studies of the history and practices of Genethon DNA and Cell Bank, the Biobank of Picardie, and the Tumour Bank of the Saint-Louis Hospital in a comparative manner. It presents biobanking as both a contingent practice and of an open, experimental character and concludes that it is transforming into a data-driven practice pursued in an industrialized manner. PMID- 24779113 TI - Teamwork, communication, formula-one racing and the outcomes of cardiac surgery. AB - Most cardiac units achieve excellent results today, but the risk of cardiac surgery is still relatively high, and avoidable harm is common. The story of the Green Lane Cardiothoracic Unit provides an exemplar of excellence, but also illustrates the challenges associated with changes over time and with increases in the size of a unit and the complexity of practice today. The ultimate aim of cardiac surgery should be the best outcomes for (often very sick) patients rather than an undue focus on the prevention of error or adverse events. Measurement is fundamental to improving quality in health care, and the framework of structure, process, and outcome is helpful in considering how best to achieve this. A combination of outcomes (including some indicators of important morbidity) with key measures of process is advocated. There is substantial evidence that failures in teamwork and communication contribute to inefficiency and avoidable harm in cardiac surgery. Minor events are as important as major ones. Six approaches to improving teamwork (and hence outcomes) in cardiac surgery are suggested. These are: 1) subspecialize and replace tribes with teams; 2) sort out the leadership while flattening the gradients of authority; 3) introduce explicit training in effective communication; 4) use checklists, briefings, and debriefings and engage in the process; 5) promote a culture of respect alongside a commitment to excellence and a focus on patients; 6) focus on the performance of the team, not on individuals. PMID- 24779114 TI - Cardiac surgery, the brain, and inflammation. AB - Cognitive deterioration can reliably be measured after procedures requiring anesthesia and surgery. Cardiac surgery has had the spotlight because of the high reported incidence of postoperative cognitive dysfunction in early studies, but such effects occur after other surgical procedures as well. "Early" postoperative cognitive dysfunction should be considered as a different phenomenon, relating to acute pharmacological, physiological, and stress-related recovery. The focus should be on what is affecting patients at 3 months, 12 months, and 5 years later. Like with many other aspects of perioperative risk, a significant element is the patient's preoperative cognitive status. We now know that up to one-third of overtly "normal" elective cardiac surgical patients enter surgery with some degree of pre-existing cognitive impairment or, when applying psychogeriatric measures, mild cognitive impairment. The latter is a known prodrome or early stage of the amyloid associated Alzheimer's disease dementia. Inflammatory responses during cardiac surgery have been recognized for years, but our understanding of the complexity of systemic inflammatory response has grown significantly with the ability to assay neurohumoral markers such as interleukins. The blood-brain barrier is made vulnerable by both pre-existing disorders (mild cognitive impairment/amyloid; vascular disease) and by the inflammatory response to surgery and cardiopulmonary bypass. Inflammation affecting the brain at this time may set in motion accelerated neurological and hence cognitive decline that, despite an initial recovery and even functional improvement, may proceed to further long-term decline at an accelerated rate in susceptible individuals. Clinical data are emerging from longer-term studies to support this concern, but evidence for effective preventive or therapeutic strategies is limited. PMID- 24779115 TI - Meaningful outcome measures in cardiac surgery. AB - The most common cardiac surgical procedures are coronary artery bypass graft surgery and aortic or mitral valve repair or replacement. Underlying conditions include coronary artery disease and heart failure, manifesting as exertional angina, dyspnea, and poor exercise tolerance. The major goals of surgery are to alleviate symptoms and improve patient survival. These, therefore, should inform the choice of primary outcome measures in clinical studies enrolling patients undergoing cardiac surgery. Studies focusing on surrogate outcome measures are relied on all too often. Many are of questionable significance and often have no convincing relationship with patient outcome. Traditional "hard endpoint" outcome measures include serious complications and death with the former including myocardial infarction (MI) and stroke. Such serious adverse outcomes are commonly collected in registries, but because they occur infrequently, they need to be large to reliably detect true associations and treatment effects. For this reason, some investigators combine several outcomes into a single composite endpoint. Cardiovascular trials commonly use major adverse cardiac events (MACEs) as a composite primary endpoint. However, there is no standard definition for MACE. Most include MI, stroke, and death; others include rehospitalization for heart failure, revascularization, cardiac arrest, or bleeding complications. An influential trial in noncardiac surgery found that perioperative beta-blockers reduced the risk of MI but increased the risk of stroke and death. Such conflicting findings challenge the veracity of such composite endpoints and raise a far more important question: which of these endpoints, or even others that were unmeasured, are most important to a patient recovering from surgery? Given the primary aims of cardiac surgery are to relieve symptoms and improve good quality survival, it is disability-free survival that is the ultimate outcome measure. The question then becomes: what is disability and how should it be quantified after cardiac surgery? PMID- 24779116 TI - Fluid therapy and outcome: balance is best. AB - The use of intravenous fluids is routine in patients undergoing surgery or critical illness; however, controversy still exists regarding optimum fluid therapy. Recent literature has examined the effects of different types, doses, and timing of intravenous fluid therapy. Each of these factors may influence patient outcomes. Crystalloids consist of isotonic saline or balanced electrolyte solutions and widely distribute across extracellular fluid compartments, whereas colloids contain high-molecular-weight molecules suspended in crystalloid carrier solution and do not freely distribute across the extracellular fluid compartments. Colloids vary in composition and associated potential adverse effects. Recent evidence has highlighted safety and ethical concerns regarding the use of colloid solutions in critically ill patients, particularly the use of synthetic starch solutions, which have been associated with increased morbidity and mortality. Crystalloid solutions with a chloride-rich composition (e.g., isotonic saline) have been associated with metabolic acidosis, hyperchloremia, increased incidence of acute kidney injury, and increased requirement for renal replacement therapy. An optimum dose of intravenous fluids remains controversial with no definitive evidence to support restrictive versus liberal approaches. Further high-quality trials are needed to elucidate the optimum fluid therapy for patients, but currently a balanced approach to type, dose, and timing of fluids is recommended. PMID- 24779117 TI - Clinical microsystems: a critical framework for crossing the quality chasm. AB - Patients, payers, and the public have increased expectations concerning the quality, safety and costs of our health care delivery systems. Whether or not to redesign our complex delivery systems is no longer in question. In order to succeed in optimizing care and outcomes (clinical and financial) for our stakeholders, we must design and evaluate tests of change. This journey will require a fundamental shift in our traditional thinking about healthcare delivery systems, including how: (1) each of us relates (effectively or not) to one another, and (2) the value of our patient's care is impacted accordingly. With this challenge in mind, this article will provide insight to the reader concerning clinical microsystems, small groups of professionals who work together on a regular basis to provide care to discrete populations of patients. The reader will learn how to leverage these microsystems to meet our stakeholders' expectations, namely to optimize the quality, safety and costs of our health care delivery systems. PMID- 24779118 TI - Developing and executing quality improvement projects (concept, methods, and evaluation). AB - Continuous quality improvement, quality assurance, cycles of change--these words of often used to express the process of using data to inform and improve clinical care. Although many of us have been exposed to theories and practice of experimental work (e.g., randomized trial), few of us have been similarly exposed to the science underlying quality improvement. Through the lens of a single center quality improvement study, this article exposes the reader to methodology for conducting such studies. The reader will gain an understanding of these methods required to embark on such a study. PMID- 24779119 TI - Predicting adult perfusion practice trends and the adoption of evidence-based practice. AB - In an effort to provide optimal patient care, perfusionists should rely on information provided by current research. Present statistics, however, document a substantial underuse of evidence-based clinical practice and therapies not only in perfusion, but throughout the entire medical field. This investigation applied a statistical method--binomial proportion analysis--to aid in uncovering the trends in perfusion practice from 2004 to 2011. Through the analysis of national adult perfusion practice surveys, the feasibility of using binomial proportion statistical analysis is assessed in its ability to track adult perfusion practice proportional differentials over time and evaluate the adoption and attitudes toward the compliance of evidence-based practice within the field of perfusion. Surveys conducted in 2004 and 2006 on adult perfusion practice in the United States--although not published--are compared with data obtained by a similar survey distributed in 2011 through an international perfusion network system and perfusion mailing system, Perflist and Perfmail. The increase of perfusionists who practice retrograde and antegrade autologous priming (R/A AP) seen from 2004 to 2006 (35-50%) was statistically significant (Z(cal) = -2.30, p < .05) and from 2006 to 2011 (Z(calc) = -5.23; p < .05). Although the increase in biocompatible circuit (BC) use by perfusionists from 2004-2006 (53-64%) was not statistically significant (Z(calc) = -1.69, p < .05), the use of BCs did continue to increase (86%) significantly from 2006 to 2011 (Z(calc) = -9.15, p < .05). Other trends were observed; however, statistical significance was variable. This investigation demonstrates that binomial proportion statistical analysis is an effective method of evaluating perfusion practice trends and adoptions based on increasing or decreasing perfusion population proportion compliance over time. PMID- 24779120 TI - Can the oxygenator screen filter reduce gaseous microemboli? AB - Gaseous microemboli (GME) define small bubbles as < 200 microm in size. GME are reported to increase morbidity after cardiopulmonary bypass (CPB) and cardiac surgery. To prevent intrusion of GME into the systemic circulation during CPB, arterial line filtration is generally recommended. New trends in oxygenator design promote location of arterial filtration as an integral part of the oxygenator housing. The present experimental study aimed to evaluate the GME removal properties of an integrated arterial screen filter in a standard microporous oxygenator. The GME properties of Terumo Capiox FX25 with an integrated arterial screen filter was assessed in an experimental setup and compared with Capiox RX25, in which no arterial screen filter is present. A blood analog prime solution was recirculated using a roller pump at 4 and 6 L per minute flow rate, respectively, through a customized CPB circuit comprising oxygenator, reservoir, and connecting tubing. A controlled volume of air was introduced into the circuit. The GME activity was measured and computed using a Gampt BCC200 ultrasonic device placing one probe at the venous inlet and one other at the arterial outlet of the oxygenator. Transmembrane delta values of GME activity were used to calculate the removal efficacy based on counts and volume of GME. Use of screen filtration reduced the GME volume by 99.1% +/- .1% compared with 98.0% +/- .1% for controls at 4 L/min flow rate (p < .001). At 6 L/min, the reduction was 97.9% +/- .1% compared with 97.0% +/- .1% (p < .001). In contrast, the reduction of GME counts was less effective after screen filtration compared with controls: 89.6 +/- .6% versus 91.4 +/- .4% at 4 L/min and 55.6% +/- 1.6% versus 76.0% +/- 1.4% at 6 L/min, respectively (p < .001). The tested oxygenator with incorporated arterial screen filter reduced GME activity based on the calculated volume at the same time as counts of GME increased. PMID- 24779121 TI - Gaseous microemboli: do we finally start to comprehend how to remove them? PMID- 24779122 TI - Comparison of routine laboratory measures of heparin anticoagulation for neonates on extracorporeal membrane oxygenation. AB - Our objective was to determine the best measure of heparin anticoagulation in neonatal patients on extracorporeal membrane oxygenation. Activated clotting time (ACT), activated partial thromboplastin time (aPTT), and antifactor Xa levels, along with corresponding heparin infusion rates and heparin bolus volumes, were collected from neonates receiving ECMO at our institution from 2008 to 2013. After natural log transformation of antifactor Xa, ACT, and aPTT, overall correlations between antifactor Xa levels and either ACT or aPTT and correlations between these tests and heparin infusion rates were evaluated using linear mixed models that accounted for both within- and between-patient correlations. Twenty six neonates with an average weight of 3.4 kg (standard deviation .7) had a total of 27 separate ECMO runs during the study period. Within each patient, ACT (r = .40, p < .0001) and aPTT (r = .48, p < .0001) were both directly correlated with antifactor Xa levels. In contrast, between patients, only aPTT maintained a direct correlation with antifactor Xa (r = .61, p = .07), whereas ACT showed a statistically significant inverse correlation with antifactor Xa (r = -.48, p = .04). Compared with ACT, aPTT is more consistently reflective of the anticoagulation status both within each patient on ECMO and between patients treated with ECMO. Future efforts to develop standardized heparin infusion algorithms for patients on ECMO should consider using aPTT levels to monitor anticoagulation. PMID- 24779124 TI - Initial experience with recombinant antithrombin to treat antithrombin deficiency in patients on extracorporeal membrane oxygenation. AB - Acquired antithrombin (AT) deficiency has been associated with patients on extracorporeal membrane oxygenation (ECMO) as a result of hemodilution, blood coagulation activation, and the use of heparin. Replacement of AT has been typically utilized through the use of fresh-frozen plasma or AT concentrate. Antithrombin alfa (ATryn) is a recombinant form of AT (rAT) with an identical amino acid sequence as that of plasma-derived antithrombin. The primary objective of this study is to examine the relationship of rAT dose to measured plasma antithrombin activity in a small series of patients who received rAT while on ECMO. A retrospective chart review was performed of all patients at Medical City Children's Hospital who received ATryn while supported on ECMO between December 2011 and April 2012. Five patients were identified and the patients' weight, bolus dose of ATryn, drip rate of ATryn, and AT blood levels were collected for analysis. The median age of these patients was 1 month (range, 1 day to 3.75 years). Because no dosing guidelines exist for pediatric ECMO, a starting dose of ATryn was chosen based on the manufacturer's labeled indication (prevention of thromboembolic events in patients with AT hereditary deficiency). The median dose of rAT was 368 IU/kg/day (range, 104-520 IU/kg/day) to obtain AT activity level of 80-120%. The average time to reach the targeted AT activity level (80-120%) was 12.7 hours (range, 11-17 hours). Our findings suggest that the published ATryn dose may be inadequate to reach desired AT activity concentrations for pediatric patients on ECMO. Difference in patient population, use of extracorporeal circuits, and the use of heparin are likely explanations for this finding. We would also recommend frequent checking of AT levels while delivering this drug because making timely adjustments is necessary for achieving and maintaining the target AT activity level. PMID- 24779123 TI - Does removing Mannitol and Voluven from the priming fluid of the cardiopulmonary bypass circuit have clinical effects? AB - The Auckland Hospital cardiothoracic unit recently removed Mannitol and Voluven from its Plasma-lyte-based cardiopulmonary bypass (CPB) priming fluid. Like with any change to practice, a comprehensive audit should be performed to identify positive or negative effects. The aim of this retrospective analysis was to investigate the effect of changing the CPB prime constituents on fluid balance and clinical outcome parameters. Clinical records were reviewed for 100 consecutive patients undergoing primary, isolated coronary artery bypass grafting (CABG), 50 patients before the prime change and 50 after. All data were collated into a central database for analysis. Mean arterial pressure while on bypass was higher in the new prime group (61.5 mmHg versus 57.5 mmHg, p = .002). There was no significant difference in hematocrit, hemoglobin, serum sodium, serum potassium, or creatinine postoperatively between groups. In regard to important outcomes such as postoperative weight and fluid balance, time on ventilation, length of stay in the intensive care unit (ICU) or hospital, and mortality, there were no significant differences. Interestingly, new prime group spent a smaller proportion of their time in the ICU on mechanical ventilation (23% versus 36%, p = .022). Mannitol and Voluven, like with all drugs, carry their own potential adverse effects. This study demonstrates that removing Mannitol and Voluven from priming fluid did not have any detrimental effect on electrolytes, fluid status, and other important outcomes in this consecutive series of patients having primary isolated CABG surgery. The risk-benefit balance combined with the obvious economic benefit clearly favors removing Mannitol and Voluven from priming fluids. PMID- 24779125 TI - Membrane oxygenator heat exchanger failure detected by unique blood gas findings. AB - Failure of components integrated into the cardiopulmonary bypass circuit, although rare, can bring about catastrophic results. One of these components is the heat exchanger of the membrane oxygenator. In this compartment, unsterile water from the heater cooler device is separated from the sterile blood by stainless steel, aluminum, or by polyurethane. These areas are glued or welded to keep the two compartments separate, maintaining sterility of the blood. Although quality control testing is performed by the manufacturer at the factory level, transport presents the real possibility for damage. Because of this, each manufacturer has included in the instructions for use a testing procedure for testing the integrity of the heat exchanger component. Water is circulated through the heat exchanger before priming and a visible check is made of the oxygenator bundle to check for leaks. If none are apparent, then priming of the oxygenator is performed. In this particular case, this procedure was not useful in detecting communication between the water and blood chambers of the oxygenator. PMID- 24779126 TI - Bivalirudin in venovenous extracorporeal membrane oxygenation. AB - Optimal anticoagulation plays a pivotal role in successful outcome of extracorporeal membrane oxygenation (ECMO). Heparin has been the anticoagulant of choice owing to its advantages like easy monitoring and reversibility. However, if heparin resistance is encountered, one has to decide whether to treat heparin resistance with fresh-frozen plasma or antithrombin concentrates or to choose one of the heparin alternatives for anticoagulation. We report a case of heparin resistance resulting from antithrombin III deficiency in a patient on venovenous ECMO, in which anticoagulation was managed with bivalirudin. The dose of bivalirudin for anticoagulation in ECMO has not been standardized and different authors have reported different doses. We found a bivalirudin dose of .1-.2 mg/kg/h to be adequate to maintain a target activated clotting time of 200-220 seconds. Platelet counts were stable throughout and no major bleeding or thrombotic complications took place. We found bivalirudin to be a feasible and effective anticoagulant and safe to use for long durations in ECMO without any major complications. PMID- 24779127 TI - One-way valve malfunction in an extracorporeal membrane oxygenation priming circuit. AB - Developing technologies have changed both the components and the management style when extracorporeal membrane oxygenation (ECMO) is used to support critically ill cardiac and respiratory patients. The Cardiohelp system is a small, portable extracorporeal system just recently available within the United States. Manufacturing standards and quality processes have made mechanical failure and malfunction of extracorporeal components less common; however, there is still potential for mechanical failure or component malfunction before or during extracorporeal support. This case review describes the malfunction of a Retroguard unidirectional flow valve integrated into the priming setup of a Cardiohelp system during the priming process. PMID- 24779128 TI - Going beyond manufacturers' limitations is not in the best interest of our patients. PMID- 24779130 TI - Image resolution. PMID- 24779129 TI - Response to letter "Going beyond manufacturers' limitations is not in the best interests of our patients" by Gerard J. Myers. PMID- 24779131 TI - Calibration of temperature measurement by infrared pyrometry in microwave heating of powder materials: an exothermic reaction based approach. AB - Accurate temperature measurement remains a challenge for microwave heating of powder materials. We propose a temperature calibration method based on exothermic reactions and the resultant thermal runaway that occurs during microwave heating. The approach was demonstrated on microwave heating of four titanium alloys. Differential scanning calorimetry was used to determine the threshold reaction temperature for each selected titanium alloy. This served as a standard for the microwave heating of these titanium alloys. Infrared pyrometric temperature measurements were then calibrated by comparing the starting temperature of each thermal runaway event with the threshold reaction temperature. PMID- 24779132 TI - Microwave-assisted melt reaction method for the intercalation of carboxylic acid anions into layered double hydroxides. AB - Carboxylic acid anions intercalated layered double hydroxides are currently gaining increasing interest due to their potential applications in pharmaceutical field for controlled drug release in novel tunable drug delivery systems. In this work different aliphatic carboxylic acid anions were intercalated into the interlayers of commercial as well as synthetically prepared layered double hydroxides, through a novel microwave mediated melt reaction approach. The volumetric nature of microwave dielectric heating was exploited in order to rapidly heat the intimate mixture of the lamellar inorganic precursor and the appropriate organic acid, at the melting temperature of the particular mono- or dicarboxylic acid used, reaching the intercalation in approximately two hours treatment. PMID- 24779133 TI - Modeling of a thermo-chromatographic pulse (TCP) as radio-frequency (RF)-induced selective heating effect. AB - By utilizing the specific influence of water adsorption on the dielectric loss factor and, consequently, selective heating of the zeolite NaY in a radio frequency (RF) electromagnetic field, a hot zone moving through the packed bed can be realized initiated by water injection. While the effect of water adsorption on RF heating and the phenomenon of the thermo-chromatographic pulse (TCP) itself were described in a previous paper, the present study presents a detailed model for the description and explanation of this effect. It involves the complex dependence of dielectric loss on temperature and moisture content, a diffusion model considering both hopping and Knudsen mechanisms and a power balance for a representative segment of the packed bed. The developed model was successfully applied to adequately describe various experimental situations observed for selective RF heating in a NaY zeolite bed. PMID- 24779134 TI - Microwave ovens and food safety: preparation of Not-Ready-to-Eat products in standard and smart ovens. AB - The introduction of several Not-Ready-to-Eat (NRTE) products, beginning in 2007, has resulted in several recalls and has caused serious concerns about their safe cooking in microwave ovens. These products are not fully-thermally processed prior to sale but depend upon the consumer to finish cooking them to the safe minimum temperatures, defined by the USDA, in order to destroy any sources of foodborne illnesses. While microwave ovens are a primary means of this finish cooking step, they are known to cook foods unevenly in terms of temperature distribution, especially from a frozen state, and this may cause parts of the food to be below the required safe-temperature. Hence there are concerns regarding how reliably microwave ovens can provide the minimum required safe temperatures in order to avoid the possibility of foodborne illnesses. To determine this, temperature profiling tests were preformed upon three frozen NRTE entrees, heating them in eight new brand-name 1100-watt and 1200-watt microwave ovens in order to evaluate how well the minimum temperatures were reached throughout the products. By comparison, these same tests were repeated using three "smart" microwave ovens in which internal computer-control makes them user independent. In addition, a comparison was also made of the microwave output power claimed by the manufacturers of these ovens to that determined using the IEC procedures. PMID- 24779135 TI - Microwave-assisted extraction of essential oils from herbs. AB - Microwave-assisted extraction (MAE) has been recognized as a technique with several advantages over other extraction methods, such as reduction of costs, extraction time, energy consumption, and CO2 emissions. In this study, MAE was performed to obtain essential oils from two different herbs (basil and epazote). A factorial design was conducted in order to determine the effect of solvent quantity, power, and heating time on essential oil yields. Chemical composition, physical properties and yield percentage of essential oils from MAE were compared with essential oils obtained by steam distillation (SD). Amount of solvent and heating time significantly affected the yields (p < 0.05). Chemical composition and physical properties of the essential oils from basil and epazote were not affected by the extraction method (MAE or SD), with similar yielding obtained by both methods (p < 0.05). PMID- 24779136 TI - MW domestic ovens out of the kitchen. PMID- 24779137 TI - Physico-chemical characteristics of microwave-dried wheat distillers grain with solubles. AB - Laboratory-prepared samples of wheat distillers grain with solubles with varying condensed distillers solubles (CDS) content were dried under varying microwave power, and microwave convection settings using a domestic microwave oven to examine their effect on the chemical, structural, color, flow, compression, thermal, and frictional properties of the product, which is dried distillers grain with solubles (DDGS). As CDS level increased, protein and ash content increased, while fat and fiber content decreased in wheat-based DDGS. Fat content was also markedly effected by the microwave oven drying conditions. While CDS level, microwave power or microwave convection setting, and/or their interactions significantly effected a number of physical properties; results indicated that CDS level had a stronger influence compared to the other factors. DDGS samples with high CDS levels were significantly denser, finer but more differentiated in size, less flowable, and less dispersible. These also produced denser and stronger pellets. PMID- 24779138 TI - An efficient empirical model for microwave-induced average temperature of liquid cylindrical reactants. AB - Microwave-assisted chemical reactions have become very popular in preparative chemistry due to many advantages such as accelerated reaction rate, higher chemical yield and lower energy use. In dedicated equipment, however, the microwave units operate as "black boxes" keeping the role of the thermal effects in microwave-assisted chemical processes somewhat obscure. To address this issue, in this paper, we propose a simple mathematical model for computing microwave induced temperature in a three-media cylindrical structure representing a core element of a typical microwave reactor with the reactant assumed to be stirred by convection flows. The model determines the average temperature of the reactant for the known absorbed microwave power and heating time. To illustrate its functionality, the model is used to compute time-temperature characteristics of water, ethanol, and methanol heated in the batch reactor MiniFlow 200SS. The curve calculated for water appears to be in an excellent agreement with an experiment. This confirms the hypothesis on temperature homogenization in liquid reactants in batch reactors due to convection and suggests that modeling can be helpful in clarifying and quantifying the details of microwave-assisted chemical processes. PMID- 24779139 TI - Influence of low- and high-frequency electrical heating on biodegrading microorganisms in soil: soil respiration. AB - The influence of electrical heating on microbiological processes in soil has been studied to evaluate the potential for enhancing biodegradation of pollutants by controlling the temperature. A frequency of 50 Hz (power line frequency) was applied for resistive heating. Dielectric heating was realized using a frequency of 13.56 MHz (radio frequency). Both techniques were compared with conventional heating in a water bath. For experiments in laboratory and full scale, a model soil and a contaminated original soil were used. It was shown that under conditions capable for heating soil to 35 degrees C or even 60 degrees C, soil respiration as a measure for microbial activity was not hindered by electrical heating when temperature and moisture content were comparable with conventional heating. The variations of soil respiration were reversible upon temperature changes. Under certain conditions, periodical fluctuations of microbiological activity were observed. Several possible explanations including chronobiology are discussed without being able to provide an unambiguous interpretation for this effect. PMID- 24779140 TI - Temperature and moisture dependence of the dielectric properties of silica sand. AB - The major objective of this work was to investigate the effects of temperature and moisture content on the dielectric properties of silica sand. The dielectric properties of moist silica sand at five temperatures between 20 to 100 degrees C, covering different moisture content levels at a frequency of 2.45 GHz, were measured with an open-ended coaxial probe dielectric measurement system. The wave penetration depth was calculated based on the measured dielectric data. The results show moisture content to be the major influencing factor for the variation of dielectric properties. Dielectric constant, loss factor and loss tangent all increase linearly with increasing moisture content. Three predictive empirical models were developed to relate the dielectric constant, loss factor, loss tangent of silica sand as a linear function of moisture content. An increase in temperature between 20 to 100 degrees C was found to increase the dielectric constant and loss factor. The penetration depth decreased with increase in moisture content and temperature. Variation in penetration depth was found to vary linearly with decrease in moisture content. An predictive empirical model was developed to calculate penetration depth for silica sand. This study offers useful information on dielectric properties of silica sand for developing microwave drying applications in mineral processing towards designing better microwave sensors for measuring silica sand moisture content. PMID- 24779141 TI - Buoyancy driven mixing of miscible fluids by volumetric energy deposition of microwaves. AB - An experiment that seeks to investigate buoyancy driven mixing of miscible fluids by microwave volumetric energy deposition is presented. The experiment involves the use of a light, non-polar fluid that initially rests on top of a heavier fluid which is more polar. Microwaves preferentially heat the polar fluid, and its density decreases due to thermal expansion. As the microwave heating continues, the density of the lower fluid eventually becomes less than that of the upper, and buoyancy driven Rayleigh-Taylor mixing ensues. The choice of fluids is crucial to the success of the experiment, and a description is given of numerous fluid combinations considered and characterized. After careful consideration, the miscible pair of toluene/tetrahydrofuran (THF) was determined as having the best potential for successful volumetric energy deposition buoyancy driven mixing. Various single fluid calibration experiments were performed to facilitate the development of a heating theory. Thereafter, results from two fluid mixing experiments are presented that demonstrate the capability of this novel Rayleigh-Taylor driven experiment. Particular interest is paid to the onset of buoyancy driven mixing and unusual aspects of the experiment in the context of typical Rayleigh-Taylor driven mixing. PMID- 24779142 TI - Publications about microwaves. PMID- 24779143 TI - Improving heating uniformity of pathological tissue specimens inside a domestic microwave oven. AB - A 3D coupled electromagnetic thermal model was developed using COMSOL 4.0 to predict the electromagnetic field distribution and temperature profile in pathological tissue samples immersed in a reagent inside the oven cavity. The effect of the volume of reagent on the mean heating rate and heating uniformity within the tissue sample was investigated. Also, the effect of using a water load, as a method of temperature control, is emphasized. A well insulated K type thermocouple connected to a PC is used for model validation. Good agreement is found between experimental and simulated temperature profiles. Results show that as the volume of reagent increases, the mean heating rate decreases and temperature homogeneity increases. Also, it is possible to minimize overshooting temperature values inside the tissue sample and enhance tissue uniformity by about 27% using 100 ml of water load and 42.26% using 150 ml. Domestic microwave oven is a low cost economical tool that can speed up tissue processing steps. Achieving uniform heating inside the microwave oven is the key factor for improving workflow inside pathological labs and maintaining tissue quality and integrity. PMID- 24779144 TI - Highly luminescent PbS/ZnS nanoparticles synthesized by a microwave method. AB - Nanoparticles with PbS core of 12 nm and shell of approximately 3 nm were synthesized at PbS:ZnS ratios of 1.01:0.1 using Merca Ptopropionic Acid as stabilizing agent. PbS/ZnS nanoparticles present a dramatically increase of Photoluminescence intensity, confirming the confinement of the PbS core by increasing the Quantum Yield from 0.63 to 0.92 by the addition of the ZnS shell. In this case, the synthesis by microwave method allows obtaining nanoparticles with enhanced optical characteristics in shorter reaction time than those of nanoparticles synthesized by colloidal method. PMID- 24779145 TI - Preparation of modified semi-coke by microwave heating and adsorption kinetics of methylene blue. AB - Preparation of modified semi-coke has been achieved, using phosphoric acid as the modifying agent, by microwave heating from virgin semi-coke. Process optimization using a Central Composite Design (CCD) design of Response Surface Methodology (RSM) technique for the preparation of modifies semi-coke is presented in this paper. The optimum conditions for producing modified semi-coke were: concentration of phosphoric acid 2.04, heating time 20 minutes and temperature 587 degrees C, with the optimum iodine of 862 mg/g and yield of 47.48%. The textural characteristics of modified semi-coke were analyzed using scanning electron microscopy (SEM) and nitrogen adsorption isotherm. The BET surface area of modified semi-coke was estimated to be 989.60 m2/g, with the pore volume of 0.74 cm3/g and a pore diameter of 3.009 nm, with micro-pore volume contributing to 62.44%. The Methylene Blue monolayer adsorption capacity was found to be mg/g at K. The adsorption capacity of the modified semi-coke highlights its suitability for liquid phase adsorption application with a potential usage in waste water treatment. PMID- 24779146 TI - Design of dual band wearable antenna using metamaterials. AB - This paper presents two types of dual band (2.4 and 5.8 GHz) wearable planar dipole antennas, one printed on a conventional substrate and the other on a two dimensional metamaterial surface (Electromagnetic Bandgap (EBG) structure). The operation of both antennas is investigated and compared under different bending conditions (in E and H-planes) around human arm and leg of different radii. A dual band, Electromagnetic Band Gap (EBG) structure on a wearable substrate is used as a high impedance surface to control the Specific Absorption Rate (SAR) as well as to improve the antenna gain up to 4.45 dBi. The EBG inspired antenna has reduced the SAR effects on human body to a safe level (< 2W/Kg). I.e. the SAR is reduced by 83.3% for lower band and 92.8% for higher band as compared to the conventional antenna. The proposed antenna can be used for wearable applications with least health hazard to human body in Industrial, Scientific and Medical (ISM) band (2.4 GHz, 5.2 GHz) applications. The antennas on human body are simulated and analyzed in CST Microwave Studio (CST MWS). PMID- 24779147 TI - A new design of an S/X dual band circular slot antenna for radar applications. AB - A novel design of dual-band slot antenna with a circular patch for radar applications is presented and studied. It is fed by a micro-strip line and built on a FR-4 substrate with a whole size of 18 x 30 mm2. A dual band printed antenna is created by introducing slots on the radiating element. By this, two bandwidth, covering C and X band, are achieved. In order to obtain a good fundamental antenna design, the initial studies were carried out theoretically, using CST Microwave Studio simulation software. In this case, the frequency range at return loss < 10 dB is 5.24 - 6.16 GHz for low frequency and is 7.9 -11.7 GHz for high frequency. In addition, the proposed antenna has good radiation characteristics and stable gains over the whole operating bands. A prototype of antenna is fabricated and tested. Experimental data show good agreement between simulated and measured results. PMID- 24779148 TI - CAP in a capsule. PMID- 24779149 TI - Epidemiology of community-acquired pneumonia. PMID- 24779151 TI - General and radiological investigations. PMID- 24779150 TI - Community-acquired pneumonia: bacteriological profile and microbiological investigations. PMID- 24779152 TI - Importance of severity assessment: community-acquired pneumonia. AB - Pneumonia Severity Index and CURB 65 are the two most important prognostic scoring tools to predict mortality for patients with CAP. These tools accurately predict mortality but do not directly measure disease severity. The clinical assessment is still required to decide hospital admission or ICU care. Prognostic scoring systems have been used to assist in the site-of-care decisions, with limited success. PSI and CURB 65 are complementary to one another, as they identify different segments of the CAP population. The PSI developed to predict low-risk patients is complex to use. Also, its role in identifying critically ill individuals is limited because it may overestimate the mortality risk in old patients with comorbidity and may underestimate the need for ICU care in younger patients who have not been previously ill. The CURB 65 is simple and is particularly useful for clinicians in identifying vital sign abnormalities that defne severe illness. However, it is unable to detect patients with multiple comorbid illnesses effectively, particularly in the presence of decompensated illnesses associated with CAP. At best, these scoring systems are decision support tools, and cannot be used as 'rules' for site-of-care decisions. In future, biomarkers such as PCT are likely to be used to predict CAP mortality and to guide management decisions. Preliminary data indicate that measurement of PCT may be valuable and that the findings may complement the risk stratifcation results from prognostic scoring models. PMID- 24779153 TI - Management of community-acquired pneumonia. PMID- 24779154 TI - Antibiotic timing in community-acquired pneumonia patients. PMID- 24779155 TI - Atypical pneumonia. PMID- 24779156 TI - Modulating treatment according to resistance patterns and local epidemiology. PMID- 24779157 TI - Prevention of pneumonia through vaccination. PMID- 24779158 TI - [Confidentiality, an obligation]. PMID- 24779159 TI - [Resilience in the face of sexual offenses]. PMID- 24779160 TI - [A new cancer plan to reduce inequalities]. PMID- 24779161 TI - [Cooperation between professions and advanced practices]. PMID- 24779162 TI - [The family at the heart of care. Creating physical and psychological space]. PMID- 24779163 TI - [Parent-caregiver partnership in pediatrics]. AB - Hospital stays are becoming shorter and increasingly concern chronic diseases, meaning there is a need for heavy involvement from the parents in the care. They need a parent-caregiver partnership. Some obstacles could happen. Building a high quality alliance with the parents requires the teams to develop new skills to support them. PMID- 24779164 TI - [Encouraging the participation of parents]. AB - Despite legislation allowing them to be present with their child, parents are still too often sidelined during care procedures. However, having a family member close by helps the child to feel reassured, reducing their pain as well as their anxiety. Encouraging the presence of the parents during nursing procedures should be part of all team projects. PMID- 24779165 TI - [Welcoming families from all cultures]. AB - Caring for a child also involves contact with their family, with their culture, experience and own knowledge. Taking into account the place and role of everyone in the family facilitates the care relationship. PMID- 24779166 TI - [Parenthood and the birth of the family]. AB - A project to start a family can be knocked off course by a couple's infertility. While medical intervention frequently leads to the birth of a baby, it is not always enough to ensure that the child is "born" psychologically. This article presents a clinical situation which highlights issues surrounding unattainable parenthood then the birth of the family, the impossible weaning from the mother's body and family transmission. PMID- 24779167 TI - [The parents of a handicapped child, partners of the individualized care project]. AB - When a child is disabled, the family's dynamic undergoes a profound transformation, with a particular shift in priorities and values. Sometimes there is major upheaval in relationships with family members and friends. The parents need to construct their parenthood differently. Their participation in meetings regarding their child's personalised project can prove very beneficial in this difficult process. PMID- 24779168 TI - [Sibling therapy, a part of systemic family therapy]. AB - Sibling therapies are rarely used. They can however constitute an important part of the family therapy process, notably in psychiatry and in the context of a mental disorder. PMID- 24779169 TI - [The participation of the parent with the healthcare of their child]. AB - When a nursing procedure needs to be carried out, the child and his or her parents can adopt a comfortable position and participate as best as they can during the procedure. Explanation sheets and personal advice enable such procedures to be carried out in the best conditions for the families and caregivers. PMID- 24779170 TI - [Bibliography. The family at the heart of care]. PMID- 24779171 TI - [Hypnosis for chronic pain of children]. AB - A child or adolescent can suffer from chronic pain. Whatever the causes, it can trap the child in a specific process whereby they focus on the pain, fearing that it will appear and experiencing anxiety. Hypno-analgesia and hypnotherapy enable them to escape this process and find within themselves the capacity to face up to the pain. Moreover, these techniques offer them an autonomy which they can use in all areas of their life. PMID- 24779172 TI - [The role of pediatric nurses in health education]. AB - One of the main purposes of the child health nurse's activity is to promote children's and families' health. To this end, she sets up individual and collective activities relating to health education, in all health care and child care facilities. PMID- 24779173 TI - [Consequences preterm birth for the family]. AB - Current intensive care techniques enable more and more very preterm babies to survive. It is important to be aware of the nature and extent of the specific difficulties which the parents and any siblings may encounter following this birth, both in the long and medium-term. This understanding will also enable measures for improving the support of families to be offered. PMID- 24779174 TI - [Paradigm shift with the new American guidelines for lipid-lowering therapy]. PMID- 24779175 TI - [Physicians working for employment agencies risk tax blow]. PMID- 24779176 TI - [Equal key messages in guidelines for lipids for cardiovascular prevention. European and American recommendations are based on risk stratification]. PMID- 24779177 TI - [Environment and health is the challenge of the future]. PMID- 24779178 TI - [Imbalance in global environmental processes affects human health]. PMID- 24779179 TI - [An increasing number of diseases can be linked to air pollution]. PMID- 24779180 TI - [Heavy metals deserves continued vigilance]. PMID- 24779181 TI - [Good drugs at the wrong place can affect nature and lead to resistance]. PMID- 24779182 TI - [The health care system should prepare for a changing climate]. PMID- 24779183 TI - [Experiences from various hospitals--too unequal care in Sweden]. PMID- 24779184 TI - [Why were the colleagues silent in the Astrid Lindgren case?]. PMID- 24779186 TI - [Delirium in old age - a diagnostic challenge]. PMID- 24779185 TI - [Professional care at "run-down hostel"]. PMID- 24779187 TI - [Psychopharmalogical treatment of delirium in the elderly]. AB - Delirium is frequent in hospitalized elderly. Treatment of the medical problems causing delirium is paramount. Mostly antipsychotics are used for treatment of psychological and behavioral symptoms in delirium. Increased mortality of elderly and demented patients receiving antipsychotics suggests caution in prescribing antipsychotics for delirium. Standard treatment is low-dose haloperidol. If more sedation is needed, melperone or pipamperone can be used. In delirious Parkinsonian patients or if dementia with Lewy-bodies is suspected quetiapine is better tolerated. Other sedating antipsychotics like prothipendyl, promethazine or levomepromazin are considered inappropriate medication in the elderly due to their anticholinergic and orthostatic side effects. Cholinesterase inhibitors are not effective in delirium, except physostigmine for treatment of anticholinergic intoxication confined to intensive care. Benzodiazepines are effective in alcohol und benzodiazepine-withdrawal, but may induce delirium (paradox reaction). Clomethiazole is contraindicated in frequent pulmonal conditions in the elderly like COPD. Chloral hydrate is considered inappropriate medication in the elderly due to QTc-prolongation. On intensive care units clonidine and recently dexmedetomidine are useful. At the moment there are no data indicating melatonin being effective for treatment of delirium. PMID- 24779188 TI - [A healthy life style for toddlers]. AB - The first years of life are important for the development of a healthy life style. Therefore, parents should pay attention to nutrition and activity when caring for their toddlers. Current recommendations give advice about these issues and also address topics as vegan nutrition and food allergies. PMID- 24779189 TI - Gist of medicinal plants of Pakistan having ethnobotanical evidences to crush renal calculi (kidney stones). AB - Human civilization is facing the problem of kidney stones since ancient ages. Although mortality rate is not so high, yet it affects the victim's quality of life. The patient suffers from intense pain and many other symptoms modifying his life style and affecting his socioeconomic status. Many drugs and invasive methods have also been developed for the treatment, but these are highly costly and unaffordable for poor people and the rate of reoccurrence is also high. The use of medicinal plants is both affordable and effective in this respect. In this article, 35 medicinal plants of Pakistan origin and their crucial information have been enumerated in alphabetical order of plant's scientific name, family, place (distribution), part used, local name, habit, major constituents and references. It can also be seen that all parts are used for the treatment of kidney stones. Leaves represent 28% contribution, whole plants and seeds 12%, fruits and roots 11% contribution in this respect. Flowers contribute 8% in the treatment of kidney stone while branches, bark, bushes, buds, milk and shoots contribute only 3% in the removal of kidney stones. Habits of plants were also taken under consideration. It was noticed that herbs are the most useful life form in this regard which contributed 63% for the removal of kidney stone. Shrubs contributed 20%, trees 11% while bushes and weeds contributed 3% for the removal of kidney stones. PMID- 24779190 TI - Paracetamol: mechanism of action, applications and safety concern. AB - Paracetamol/acetaminophen is one of the most popular and most commonly used analgesic and antipyretic drugs around the world, available without a prescription, both in mono- and multi-component preparations. It is the drug of choice in patients that cannot be treated with non-steroidal anti-inflammatory drugs (NSAID), such as people with bronchial asthma, peptic ulcer disease, hemophilia, salicylate-sensitized people, children under 12 years of age, pregnant or breastfeeding women. It is recommended as a first-line treatment of pain associated with osteoarthritis. The mechanism of action is complex and includes the effects of both the peripheral (COX inhibition), and central (COX, serotonergic descending neuronal pathway, L-arginine/NO pathway, cannabinoid system) antinociception processes and "redox" mechanism. Paracetamol is well tolerated drug and produces few side effects from the gastrointestinal tract, however, despite that, every year, has seen a steadily increasing number of registered cases of paracetamol-induced liver intoxication all over the world. Given the growing problem of the safety of acetaminophen is questioned the validity of the sale of the drug without a prescription. This work, in conjunction with the latest reports on the mechanism of action of paracetamol, trying to point out that it is not a panacea devoid of side effects, and indeed, especially when is taken regularly and in large doses (> 4 g/day), there is a risk of serious side effects. PMID- 24779191 TI - Amphetamines in wastewater of the city Poznan (Poland)--estimation of drug abuse. AB - The aim of the study was to determine the profile of amphetamines consumed by a community in Poland. Amphetamine, methamphetamine and MDMA (ecstasy) were detected in wastewater samples collected from the main Wastewater Treatment Plant in the city of Poznan (about 687 000 people) using liquid chromatography/tandem mass spectrometry (LC-MS-MS). Back-calculations used in the sewage epidemiology approach were applied to estimate the level of consumption of the drugs being analyzed. These types of studies were carried out for the first time in Poland for a considerable period--from June 2009 to December 2010. The analysis of variance (ANOVA) confirmed significant monthly differences in amphetamine consumption. The concentration of amphetamine, methamphetamine and MDMA in wastewater samples and the levels of their consumption were lower than reported in other European countries, but unexpectedly, the ratio of consumed methamphetamine to MDMA and the consumption level of methamphetamine were relatively high. This study shows that sewage epidemiology is a promising tool, especially when combined with classical methods, to estimate illicit drugs use in a particular population. Therefore, efforts should be made to monitor the profiles and consumption levels of drugs and to extend the scope of the research to other illicit substances, especially cannabinoids and cocaine. PMID- 24779192 TI - 3,5-Dimethoxy-(4-methoxyphenyl)benzamide suppresses adipogenesis in 3T3-L1 cells. AB - In this study, the adipogenesis-suppressing effect of 3,5-dimethoxy(4 methoxyphenyl)benzamide (DMPB), a derivative of the anti-obesity substance resveratrol, was measured in 3T3-L1 cells. The results show that DMPB effectively suppressed the hormone-induced differentiation of 3T3-L1 cells, compared to resveratrol at the same concentration, and reduced the protein expression of fatty acid synthase and acetyl-CoA carboxylase. In addition, DMPB was observed to decrease the PPAR-gamma transcription activity, which was increased by rosiglitazone, in a concentration-dependent manner. From the above results, it is considered that DMPB shows strong potential as an anti-obesity substance. PMID- 24779193 TI - Antimicrobial peptides as potential tool to fight bacterial biofilm. AB - Recently, the topic of biofilm has met a huge interest of researchers owing to a significant role played by this microbial life form in severe infections. These well organised three-dimensional microbial communities are characterized by a strong resistance to antimicrobials. Biofilms significantly contribute to morbidity and mortality as related infections are very difficult to treat due to their tendency to relapse after the withdrawal of antibiotics. According to the literature, antimicrobial peptides (AMPs) have a high potential as future antibiofilm agents. AMPs can influence various stages of biofilm formation and exhibit antimicrobial activity against a broad spectrum of microorganisms including multi-drug resistant strains. The purpose of the present study was to determine the activity of antimicrobial peptides against biofilms formed by a variety of bacterial strains. To do this, the following antimicrobial peptides were synthesized: Citropin 1.1, Lipopeptides Palm-KK-NH2 and Palm-RR-NH2, Omiganan, Pexiganan and Temporin A. Antimicrobial activity of the compounds and conventional antibiotics was determined for planktonic cells and biofilms formed by reference strains of Gram-positive (Staphylococcus aureus, S. epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis) bacteria. AMPs exhibited a strong antibacterial activity against Gram-positive strains, while Gram-negative bacteria were less susceptible. Antimicrobial activity of the tested peptides against biofilms formed by Gram-positive organisms was significantly stronger as compared to that of conventional antimicrobials. PMID- 24779194 TI - Synthesis, pro-apoptotic activity and 2D-QSAR studies of new analogues of fluphenazine. AB - A series of 10 novel analogues of fluphenazine (FPh) were synthesized. Influence of the synthesized analogues of FPh on frequency of apoptosis and necrosis in cultures of human lymphocytes genotoxically damaged in vitro with benzo[a]pyrene (B[a]P; 7,5 microM, 48 h) was compared with the effect of FPh. Activity of the tested compounds was expressed by ED50 (pro-apoptotic activity) and TD50 (pro necrotic effect, cytotoxicity). It was noticed that compounds 3-9 and 12 exerted a pro-apoptotic effect markedly stronger than that of FPh. Additionally, compounds 3, 9 and 10 exhibited the weakest influence on frequency of necrotic lymphocyte in cultures. 2D-QSAR analysis was done in order to find quantitative relationship between structures of the tested analogues and their pro-apoptotic activity or pro-necrotic effect in B[a]P-damaged cell cultures. Several statistically significant QSAR models were generated. Information obtained from 2D-QSAR study will be used in further design of analogues of FPh more active in cancer chemoprevention. PMID- 24779195 TI - New renin inhibitors containing phenylalanylhistidyl-gamma-amino acid derivatives in P3 - P1' position. AB - Five potential inhibitors of renin have been designed and obtained. In the molecule position P3 - P1', crucial for indicating inhibitory activity, all contain phenylalanylhistidylaminoalcanoyl group, ready for interaction with the hydrophobic pocket S3 - S1 of renin molecule. The aminoalcanoyl fragment consists of pseudo-dipeptidic units derivative of gamma-amino acids: of 4-amino-3 hydroxybutanoic acid (AHBA) [26], 4-amino-5-(4-ethoxyphenyl)-3-hydroxypentanoic acid (AEPHPA) [13], 4-amino-5-cyclohexyl-3-hydroxypentanoic acid (ACHPA) (1) and 4-amino-3-hydroxynonanoic acid (AHNA) [21]. At the P3 - P2 position of obtained compounds an unnatural fragment, derivative of Phe-His dipeptide, was placed ande isoamyl amid of 6-amino-hexanoic acid was attached at the end of the molecule (epsilonAhx-Iaa). The preliminary in vitro tests indicated that all compounds were inactive. However, they provided valuable information on P3 - P2 fragment possible structure modification able to produce a resonable renin activity inhibition. All synthesized inhibitors were chymotrypsin-resistant. PMID- 24779196 TI - New lead structures in the isoxazole system: relationship between quantum chemical parameters and immunological activity. AB - Potential immunological activities of three compounds: RM54 and its two derivatives RM55 and RM56, were evaluated in several, selected in vitro and in vivo tests such as: mitogen-induced lymphocyte proliferation, cytokine production, the humoral immune response in vitro and carrageenan test. Leflunomide served as a reference drug. The studied compounds showed differential, generally immunosuppressive properties. RM56 exhibited stronger suppressive activities as compared to RM54 and RM55. In particular, RM56 displayed the strongest activity in suppression of the carrageenan inflammation that was correlated with strong suppression of the humoral immune response in vitro and lymphocyte proliferation. Density Functional Theory (DFT) was employed to shed a light on molecular properties of the investigated compounds. The geometrical parameters of the studied molecular structures were fully optimized at the B3LYP/6-311G(d,p) level. The atomic charges distribution derived on the base of the Mulliken population analysis was correlated with immunological activity of RM54, RM55 and RM56. The obtained relationships show that the isoxazole ring plays an important role in the observed immunological activities. We also suggest that due to strong anti-inflammatory and anti-proliferative properties of RM-56, potential therapeutic applications of this derivative can be broad. PMID- 24779197 TI - Phytate, inorganic and total phosphorus and their relations to selected trace and major elements in herbal teas. AB - Phytate phosphorus in 59 samples of herbal teas was determined within the range of 2.44-36.90 microg/mL. Extraction yield was statistically higher in extracts from the leaves than that found in extracts from other plant organs. Average total level of trace elements determined in medicinal herbs follows the order: Fe > Mn > Zn > Cu, for major elements the order is: Ca > Mg > Na > K. Correlation analysis revealed that relations of phytate P to other phosphorus forms and metals were statistically insignificant. However, there were several characteristic relations of inorganic phosphorus to water-extractable K, Zn and total Zn. Furthermore, positive relations were found between total and water extractable fractions of metals. Principal component analysis grouped the samples into separate clusters. It was also found that inorganic P, as well as water extractable Zn and Na, had a huge impact on differentiation of the studied plant material. PMID- 24779198 TI - Statistical optimization and in-vitro evaluation of hollow microcapsules of an anti-hypertensive agent. AB - The present work attempts to formulate and evaluate hollow microcapsules of an antihypertensive drug--ramipril, which will remain in vicinity of absorption site. The emulsion diffusion solvent evaporation method was employed for preparation of microspheres using Eudragit E100. Glycerol monostearate and sodium lauryl sulfate were used as surfactants, which showed good effect of film integrity. The different proportion of Eudragit E100 and ramipril at varying speed were employed for formulating hollow microspheres using 3(2) full factorial design. The formulated microspheres were subjected to evaluation of various parameters such as particle size analysis using motic microscope, drug loading efficiency and in vitro drug release. The main effect plot showed negative impact of polymer concentration and drug complex concentration, whereas positive impact of rotation speed on the % release of drug and drug encapsulation efficiency. The optimized batch of microcapsules was formulated as a hard gelatine capsule dosage form containing loading (plain drug) as well as sustained fraction of drug in form of microcapsules. It was found that dosage form also showed good in vitro release profile. PMID- 24779199 TI - Material and tableting properties of Azadirachta indica gum with reference to official acacia gum. AB - This study determined the material and tableting properties of Azadirachta indica gum (NMG) relative to acacia gum (ACA). The morphological properties were assessed with size and shape factors of aspect ratio, roundness, irregularity and equivalent-circle-diameter. The tableting properties of the gums were determined using compressional characteristics, tensile strength (TS), brittle fracture index (BFI) and crushing-strength-friability/disintegration-time ratio (CSFR/DT). The results suggest that NMG possesses larger, irregular and more elongated particles than ACA. The onset and amount of plastic deformation occurring in NMG was faster and higher, respectively, than in ACA. The result shows that, although ACA tablets were stronger, their tendency to cap/laminate was higher than in NMG tablets. The NMG tablets possess lower DT than those of ACA, while the CSFR/DT result suggests that a better balance exists between the strength and weakness of NMG tablets. The study concluded that NMG can be a useful excipient in tablet formulation. PMID- 24779200 TI - Surface activity of novel surface active compounds, products of catalytic oxyethylation of cholic acid and their micellar adducts with selected lipophilic therapeutic agents. AB - The aim of this study was to determine the surface activity parameters of novel surface active compounds, products of catalytic oxyethylation of cholic acid, and their micellar adducts with selected lipophilic therapeutic agents (diclofenac, loratadine, naproxen and rutin). High solubility of lipophilic naproxen was observed in the environment of aqueous solutions of the cholic acid oxyethylation products as suggested by determined factual solubility and the value of micellar partition coefficient (K(w)(m)). Determined surface activity of surfactants described by various physicochemical characteristics (gamma(cmc)(25), cmc, deltaG(m)(o) and A(m)) suggested their compatibility with physiological values of the surface activity of plasma (48.0-52.0 mJ/m2) and lacrimal fluid (46.0-52.0 mJ/m2). Calculated values of HLB(1)(HNMR) and n(TE) of the micellar adduct in solid phase (solid dispersion) corresponded to an increase in its hydrophilicity, and, therefore, suggested possible mechanisms and site of diclofenac, loratadine, naproxen and rutin solubilization in the micellar structure (core or palisadic layer). PMID- 24779201 TI - Nanoprecipitation with sonication for enhancement of oral bioavailability of furosemide. AB - Furosemide is a weakly acidic diuretic indicated for treatment of edema and hypertension. It has very poor solubility but high permeability through stomach and upper gastrointestinal tract (GIT). Due to its limited solubility it has poor and variable oral bioavailibility of 10-90%. The aim of this study was to enhance the oral bioavailibilty of furosemide by preparation of nanosuspensions. The nanosuspensions were prepared by nanoprecipitation with sonication using DMSO (dimethyl sulfoxide) as a solvent and water as an antisolvent (NA). The prepared nanosuspensions were sterically stabilized with polyvinyl acetate (PVA). These were characterized for particle size, zeta potential, polydispersity index, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X ray diffraction (XRD) pattern and release behavior. The average particle size of furosemide nanoparticles were found to be in the range of 150-300 nm. This was further confirmed by SEM photograph. The particle size varies with an increase in concentration of drug and stabilizer. The preparations showed negative zeta potential and polydispersity index in the range of 0.3 +/- 0.1. DSC and XRD studies indicated that the crystalline furosemide drug was converted to amorphous form upon precipitation into nanoparticles. The saturation solubility of prepared furosemide nanoparticles markedly increased compared to the original drug in simulated gastric fluid. The release profiles of nanosuspension formulation showed up to 81.2% release in 4 h. It may be concluded that the nanoprecipitation with ultrasonication have potential to formulate homogenous nanosuspensions with uniform sized amorphous nanoparticles of furosemide. Polyvinyl acetate can be used as a suitable steric stabilizer to prepare stable furosemide nanosuspensions. The enhanced saturation solubility in simulated gastric fluid may lead to enhanced absorption of furosemide. PMID- 24779202 TI - Interaction analysis of aspirin with selective amino acids. AB - This study was conducted to assess the compatibility of aspirin with selective amino acids by studying the effect of amino acids on the solubility of aspirin, so that the attention could be paid towards the use of proteinous foods along with aspirin. Two different types of dissolution media, i.e., 0.5% solution of each amino acid and 100 mL of distilled water (100 mL each), were prepared. Then, 1 g of aspirin was added in both media and shaked gently. Ten milliliters of sample was withdrawn at different time intervals, i.e., 10, 20, 30, 40, 50 and 60 min and analyzed spectrophotometrically at 265 nm. It is evident from results that the absorbance of aspirin increased with the addition of amino acids and this increase was significant (p < 0.05). Absorbance after adding amino acid like glycine, tyrosine, glutamic acid, tartaric acid and aspartic acid was observed to be 2.98, 2.96, 2.92, 3.23 and 3.28, respectively, as compared to that of aspirin alone. The increase in absorbance of aspirin in the presence of tartaric acid and aspartic acid was non-significantly (p > 0.05) greater than that in the presence of other amino acids like glycine, tyrosine and glutamic acid. The absorbance of aspirin in the presence of tartaric acid and aspartic acid was 3.23 and 3.28, respectively, while the absorbance of aspirin in the presence of glycine, tyrosine and glutamic acid was 2.98, 2.96 and 2.92, respectively. This study elaborates that the solubility of aspirin increases with concomitant administration of amino acids, thus the use of amino acids (proteinous foods) with aspirin should be prohibited or low dose of aspirin should be recommended in such situation. PMID- 24779203 TI - The impact of liposomes on transdermal permeation of naproxen--in vitro studies. AB - The possibility of applying liposomes as a topical drug delivery system is still a matter of intensive research. The purpose of this study was to determine the suitability of liposomes as carriers of naproxen and to prove their impact on the effectiveness of transdermal permeation of an active substance. The study was conducted with the use of Franz Diffusion Cell System by comparing the efficacy of a preparation containing 20% of phosphatidylcholine (PC) and 10% of naproxen with reference preparations, i.e., a formulation containing 10% of naproxen without PC and the commercial product Naproxen 10%, gel. The largest transdermal penetration flux of naproxen and the highest efficacy of naproxen permeation were obtained for the formulation containing 10% of naproxen and 20% of PC. The study of the influence of liposomes size and topology on the transdermal diffusion of naproxen (large unilamellar vesicle, LUV, multilamellar vesicle, MLV) showed that there was no statistically significant difference in the flux or total amounts of transdermally diffused naproxen between compared formulations. In conclusion, liposomes present in a formulation double the efficacy of the transdermal permeation of naproxen in vitro compared to reference preparations containing no carriers. Better permeation effect of a formulation was not related to the liposome type (LUV or MLV). PMID- 24779204 TI - Characterization of gliclazide release from Isabgol husk hydrogel beads by validated HPLC method. AB - Isabgol husk, a medicinally important natural polysaccharide was applied for fabrication of hydrogel beads by ionic gelation method to incorporate gliclazide. Different strengths of Isabgol husk and sodium alginate were utilized for assessing the process variables on formulation performance. Aqueous solution of calcium chloride in 2, 5 and 8% w/v strength was used as cross-linker for polymeric blends of Isabgol husk and sodium alginate. The formulations were characterized for various parameters such as particle size, swelling index, entrapment efficiency, in vitro release, and release kinetics. The quantification of gliclazide throughout the study was performed by HPLC method which was validated according to ICH guidelines for system suitability, linearity, accuracy, sensitivity, precession, robustness, and ruggedness. The surface morphology of beads was observed by scanning electron microscopy. The formed beads were brown, free flowing, spherical, and irregular in structure. The size in different formulations varied from 752.83 +/- 0.630 to 838.62 +/- 0.741 microm. The beads remained for 2-3 h in alkaline phosphate buffer (pH 7.4), after that they showed disintegration. The formulations released up to 95% of loaded gliclazide in phosphate buffer (pH 7.4) within 8 h. No significant difference was observed in parameters studied such as particle size, entrapment efficiency and swelling index for hydrogel beads during accelerated stability study (p > 0.05). The regression equation developed by HPLC method was linear (r5 > 0.9990) over the range 2.5 to 10 microg/mL. The limit of detection (LOD) and limit of quantification (LOQ) were 0.037619 microg/mL and 0.113997 microg/mL, respectively. The observed values for number of theoretical plates (N > or = 2000), tailing factor (T < or = 2), asymmetry factor (AF < or = 1), and relative standard deviation (RSD < or = 1%) of applied method showed the reliability for gliclazide estimation in Isabgol husk hydrogel beads. PMID- 24779205 TI - Stability evaluation of thermosensitive drug carrier systems based on Pluronic F 127 polymer. AB - The aim of this study was to evaluate the stability of thermosensitive systems based on Pluronic F-127 polymer, in aspects of their possible application in novel drug technology. A formulation was prepared without any active ingredient, consisting of 16% (w/w) of polymer dissolved in aqueous medium. Such preparation was autoclaved and then subjected to 3-month conditioning at elevated (40 degrees) and reduced (5 degrees C) temperature. Rheological parameters: viscosity, consistency and sol-gel transition characteristics were studied in 1 month interval. The significance of measured changes was evaluated by proper statistical analyses. Significant changes exceeding the established criteria (+/- 10% of every initial value) were observed during the study. Furthermore, total involution of sol-gel transition phenomenon was observed in samples stored at 40 degrees C. Results indicate the lack of stability in tested formulation at both of storage conditions. However, some regularity indicates that the stability at reduced temperature could be confirmed, if only the concentration of polymer and the measurements schedule were slightly modified. PMID- 24779206 TI - Legal instruments supporting the development of orphan medicinal products in the European Union. AB - Securing the freedoms of the Internal Market by the European Union entails an obligation to implement such mechanisms so that medicinal products placed on the market could be, on the one hand, widely available to the citizens of Member States and, on the other, so that medicinal products could be both safe and effective. The first aspect involves acting towards the improvement of public health and the prevention of human diseases and troubles, while the second- removing the sources of danger to human health. From this perspective, we need to highlight the problem of a deficit in the development, and thus a deficit in the availability of medicinal products authorized for marketing, which are intended for use in rare diseases. This paper aims to analyze the European Union pharmaceutical law in order to establish whether, and if yes--how the EU legal regulations support the development and availability of orphan medicinal products on the Internal Market. PMID- 24779207 TI - Prescription of evidence-based medicine drugs by general practitioners to patients after myocardial infarction: outcomes from the Czech Republic. AB - Ischemic heart disease is the most frequent cause of both serious morbidity and mortality of adult population in developed countries. The main aim of the study was to carry out the analysis of general practitioners (GP) prescription of evidence-based therapy in patients after myocardial infarction (MI). Data were retrospectively collected in 2011, by a single application with the help of software that GPs use in their surgeries. All patients of a particular GP who had MI in their history and who were at the time of data collection treated only by GPs (not by the specialists of internal medicine or cardiology) were always included. Four hundred ninety one patients were included in the study. The average age was 70.7 (+/- 11.6) and 69.2% of the involved patients were men. Seventy nine percent of patients used beta-blockers, 80% antiplatelet drugs, 77% statins and 79% used angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs). Forty four percent of patients used drugs from all four groups. The significant prescription decrease was proved in all four groups in dependence on patients' age (p < 0.05). Although the evidence-based medicine usage in patients after MI in the Czech Republic is comparable to other countries, it is not optimal. More intensive involvement of pharmacists in the care of patients after MI would further improve the situation. PMID- 24779209 TI - New abietatriene-type diterpenes linked with lanostenes from oleo-resin of Pinus roxburghii Sarg. PMID- 24779208 TI - Analysis of direct costs of hypertension treatment among adolescents in Poland. AB - In adolescents, arterial hypertension (AH) is diagnosed much more frequently than previously thought--it affects 3.2% of the population aged 11-18. In Poland, at present, there are no cost analyses of treatment arterial hypertension among adolescents. The aim of the conducted studies was to analyze direct medical and non-medical costs in the time horizon of one calendar year (2010) of AH treatment in adolescents in Poland. A retrospective study from the societal perspective was based on data from 480 patients medical history cards obtained from the archives of the hospital. From this group, according to the criteria for inclusion in the study, a research group was selected consisting of 36 patients aged 16-18 years, with a diagnosed and treated hypertension. Analysis covered direct medical costs (costs of pharmacotherapy, doctors' visits and laboratory tests, hospitalization) and direct non-medical costs (cost of transport to the outpatient clinic). Average annual cost of hypertension treatment per patient was 89.96 Euro. The largest part of the structure of total costs related with hypertension treatment in adolescents in Poland were the costs of medical consultation with lab tests and diagnostic examinations--35.04% and pharmacotherapy costs--32.95%, with hospital stays rating somewhat lower with 19.12%, and the smallest part were the costs of the patient's transportation to the hypertension outpatient clinic- 12.89%. Early identification of risk factors of such cardiovascular diseases as hypertension as early as in the developmental age, and their subsequent elimination, should be considered a good investment in the reduction of costs associated with hypertension treatment in adulthood. PMID- 24779210 TI - [Dislocation after total hip arthroplasty--the problem is still present, reasons and treatments]. AB - Dislocation after total hip replacement remains a significant problem in orthopedic practice. Despite the use of more modem implants risk of instability is estimated at a few percent for primary treatment and for several procedures. The standard procedure in case of the first dislocation is reduction of the prosthesis in general anesthesia. Further investigation is individual, each case must be thoroughly examined for proper execution of the original surgery and the risk of the next dislocation. Regardless of the subsequent procedures performed a key role in the event of instability prosthesis plays properly conducted rehabilitation and patient education. PMID- 24779211 TI - [Comparison of basic electrical features of ICD defibrillating leads implanted to right ventricular apex or right ventricular outflow track and septum]. AB - Automatic implantable cardioverter-defibrillators (ICDs) are nowadays an essential tool for reducing mortality due to sudden cardiac death. Technological advances in the miniaturization of devices and lead fixation, and the development of surgical techniques has led to more frequent implantation of the defibrillation leads outside the right ventricular apex (RVA), especially in those patients requiring cardiac pacing, as data from large clinical trials showed that chronic RVA pacing is harmful, especially in heart failure subjects, who are an important target for the ICD. Very few studies have been published comparing the electrical characteristics of leads placed in the RVA versus those implanted outside the RVA, mainly to right ventricular outflow tract of the heart (RVA), hence any subsequent analysis of this issue seems to be a valuable addition to the available information in this topic. The aim of this study was to compare the electrical parameters of ICD leads implanted into the right ventricular apex (RVA), to those placed in one of the alternative sites: the right ventricular outflow tract (RVOT), or the area of the interventricular septum (RVS). MATERIAL AND METHODS: Retrospective analysis of medical data from a single centre (teaching hospital), which included 132 patients with ICD implanted in 2010-2011, both in primary and secondary prevention of sudden cardiac death. We compared the most important electrical parameters of the ICD system, as the resistance of the pacing system, resistance of high-voltage coil, the amplitude of the sensed beats and pacing threshold. In addition, we compared the time of implantation, X-ray fluoroscopy time and X-ray exposure. RESULTS: There were no statistically significant differences between the two analysed groups in terms of pacing-system resistance (601.012 vs. 602.7omega, p = 0,499), high-energy coil resistance (63.7omega vs. 67.22, p = 0,201), amplitude of sensed R-waves (14,6mV vs. 15.3mV, p = 0, 710) and the pacing threshold energy (0,368 microJ vs. 0.259 microJ, p = 0,803). Also the duration of implantation (123, 3 min vs. 123, 9 min, p = 0,940), fluoroscopy time (11,0 minutes vs. 8,6 minutes, p = 0,06) and dose exposure (1594, 5cGy/cm2 vs. 2094, 4cGy/cm2, p = 0,069) were comparable in both groups. CONCLUSIONS: Implantation of ICD leads to the RVOT/RVS is a safe procedure, and the basic electrical parameters of such systems are comparable to ICDs with lead implanted to the RVA. PMID- 24779212 TI - [Patients with implanted pacemakers in the primary hospital and stay under the care of an outpatient cardiology clinic--differences in comparison with the reference center]. AB - The aim of the study was to find an answer for a question whether a newly created primary centre ensures the same level of safety as a reference centre in terms of complications of pacemaker implantation and whether the outpatient care of patients with an implanted pacemaker is as competent as in a reference centre. MATERIAL AND METHODS. The analysis of documentation of the patients (274 pts, 135 men, mean age = 74 + 9 years) who underwent implantation of a permanent single (VVI, 222pts) or dual-chamber (DDD, 52pts) pacemaker at the department of cardiology of the primary centre compared to the reference centre (80 pts) at the department of cardiology. The following data was analyzed: gender, age, length of hospitalization, type of pacemaker, type of electrode, place of pacing, indications for permanent pacing, co-existing diseases, periprocedural complications, complications, technique of electrode implantation and the type of electrode fixation. RESULTS: Patients who underwent implantation of a pacemaker in the primary centre were hospitalized longer than those treated in the reference centre, p < 0.001. The technique of subclavian venipuncture used to implant the passive endocardial electrode was more common in the primary centre, p = 0.034. The number of complications after implantation of pacemaker was not significantly statistically. The technique of electrode implantation has a statistically significant effect on the number of complications (OR = 0.11, p < 0.04). Subclavian venipuncture was associated with a statistically significantly higher incidence of pneumothorax (p < 0.019). The type of pacemaker, electrodes or indication for implantation did not have a statistically significant influence on the complications. The patients with ischemic heart disease and myocardial infarction are the most exposed to the complications (OR = 3.73, p < 0.03). All check-ups at the primary centre were carried out by a physician who used suitable programmers. Most visits in the reference centre were carried out by a technician who used the "IMPULS-BIS" set. Pacemaker implantation costs were directly connected with the duration of hospitalization. CONCLUSIONS. High percentage of ventricular stimulation, stimulation of the apex of the right ventricle, the application of passive electrode, avoiding the use of cephalic vein indicates further the need deepen cooperation between centers. Outpatient care of patients with an implanted pacemaker in the primary centre was as competent as in the reference centre. Pacemaker implantation costs are directly connected with the duration of hospitalisation. PMID- 24779213 TI - [B-type natriuretic peptide and high sensitivity troponin T as a marker of cardiac failure in patients after permanent cardiac pacing]. AB - Both B-type natriuretic peptide and high sensitivity troponin T play the role in the clinical practice now. Examination of this markers is important in ischaemic heart disease, chronic heart failure, pulmonary embolismus, after cardio pulmonary resuscitations,electrotherapy and renal insufficienty. The aim of this study was to demonstrate the impact of permanent cardiac pacing on selected biochemical parameters of the cardiovascular system, such as the B-type natriuretic peptide and high-sensitivity troponin levels, and usefulness of this biochemical parameters in daily practice. MATERIAL AND METHODS: The study involved 195 people. Finally, 117 patients completed the study. There were distinguished: group I--21 patients with pacemaker AAI/R, group II--59 patients with a pacemaker DDD/R, group III--37 patients with pacemaker VVI/R, a control group--48 healthy subjects of comparable age.In the treatment groups (group I, II, and III) peptide BNP, troponin T detected by high-sensitivity assay, were performed three times. In the control group the same tests were performed once. RESULTS: In the group II blood concentration of B-type natriuretic peptide 3 month after implantation DDD/R was elevated from 157.27 +/- 186.34 microg/1000 microl to 214.46 +/- 249.54 pg/1000microl and was statistical signification higher from the period before implantation ( p < 0.001). 6 month after implantation DDD/R blood concentration of B - type natriuretic peptide was 219.15 +/- 257.59 microg/1000 microl and was statistical significantly higher compared to period before implantation (p < 0.001). In the group II high sensitivity troponin T after implantation elevated from 10.42 +/- 12.81 ng/ml to 17.08 +/- 38.86 ng/ml (p < 0.05). CONCLUSIONS: In the group with DDD/R blood concentration of B-type natriuretic paptide and high sensitivity troponin T are elevated. Both B-type natriuretic peptide and high sensitivity troponin T play important role in examinations patients after cardiac pacing implantations. Cardiac examination after implantation pacing should be completed by B-type natriuretic peptide and high sensitivity troponin T examinations. PMID- 24779214 TI - [Preliminary results of research on a new marker of idiopathic membranous nephropathy: anti-PLA2R]. AB - Idiopathic membranous nephropathy (IMN) is a chronic glomerular disease. It is result of new discovery that the production of anti-PLA2R autoantibodies, reacting with phospholipase A2 receptor on the surface of podocytes. Specific antibodies occur in IMN patients blood in exacerbated of disease, and disappear during remission. It suggest that analyse of these parameter can prove quick diagnosis to recognize and monitoring treatment process. The aim of our work was to determine anti-PLA2R in patients with suspected IMN and persons during/after treatment in order to monitor the effectiveness of therapy. MATERIAL AND METHODS: The study group consisted of 22 patients. Patients were divided into two groups: Group A--patients with symptomatic nephrotic syndrome in the course of membranous nephropathy; Group B--patients diagnosed with IMN who monitored the effectiveness of therapy. We collected the serum samples for all patients and determined of anti-PLA2R autoantibodies by indirect immunofluorescence test. RESULTS: Antibodies were detected in 12 patients (54.54%): diagnosed (n = 5) and monitor (n = 7). All of patients with exacerbated disease process in monitored group had positive test results. CONCLUSIONS: Our data suggest that anti-PLA2R is a sensitive diagnostic method and good for monitoring of disease activity, but nevertheless a need for further research on a larger group of patients to confirm that the test is a reliable source of diagnostic information. PMID- 24779215 TI - [The early C4d urinary excretion and long-term kidney graft survival in patients treated with tacrolimus and mycophenolate mophetil]. AB - The C4d urinary excretion seems to increase with the risk of graft rejection or progression of chronic allograft nephropathy although its impact on long-term kidney transplant (KTx) outcomes remains unclear. Presently the most common maintenance immunosuppression schemes (IS) includes corticosteroids and cyclosporine or tacrolimus (Tac) with mycophenolane mophetil (MMF), and Tac combined with MMF is regarded to be superior to other schemes. The aim of the study was to determine whether the initial (1-3 months post KTx) level of C4d urinary excretion may help to predict long-term kidney allograft transplantation outcomes in patients treated with Tac+MMF as maintenance IS. MATERIAL AND METHODS: The study involved 66 patients who had undergone kidney allograft transplantation. The urine specimens taken from the morning urine portion was assessed by ELISA test for C4d excretion. To increase the objectivity of the assessment all measurements were divided by urinary creatinine excretion (ng/mgCr). The study population was grouped according the calculated Roc curve (the cut off value of the urinary C4d excretion 13.1 ng/mgCr; AUC 0.93; 95% CI 0.74-0.95) into LC4d and HC4d, C4d below or above 13.1 ng/mgCr. RESULTS: The mean C4d urinary excretion was 166.6 +/- 186.3 ng/mL (3.9 +/- 6.2 ng/mgCr), in LC4d and HC4d 34.8 +/- 102.2 ng/mL (1.1 +/- 6.4 ng/mgCr) and 347.3 +/- 255.7ng/mL (19.2 +/- 5.9 ng/mgCr), respectively. In accord with the division of study population, the statistically significant differences were seen between LC4d and HC4d in urinary C4d excretion Z = 4.4; p = 0.019 (Z = 4.9, p = 0.011 for excretion calculated per urinary creatinine). Kaplan-Meier curve analysis demonstrated a higher graft survival rate in LC4d than in HC4d group (p = 0.048 by log-rank) in ten years follow-up. CONCLUSIONS: In patients treated with tacrolimus and mycophenolate mophetil as a maintenance immunosuppression, the lower C4d urinary excretion in the early post-transplant period seems to be a low significance prognostic marker of a better long-term kidney allograft transplantation outcome. PMID- 24779216 TI - [Capsaicin inhalation cough challenge in an evaluation of cough threshold- preliminary study]. AB - Capsaicin inhalation cough challenge is one of the most important methods evaluating cough and is acknowledged not only in pharmacological, but also in scientific studies and clinical practice. However, it is not popular in Poland. The aim of the study was then introduction of capsaicin challenge into clinical and scientific practice, evaluation of cough threshold in healthy volunteers and assessment of the test reproducibility and safety. MATERIAL AND METHODS: Thirty healthy volunteers (18 women) were included. Cough was induced by inhalation of capsaicin aerosol in doubling concentrations (0.49-1000 microM), using single breath method and a compressed air-driven nebulizer controlled by a breath activated dosimeter. Cough was counted for 10 s after each inhalation to assess the capsaicin concentration evoking at least 2 (C2) and 5 coughs (C5). The reproducibility of cough challenge results was assessed on the ground of two tests performed in an at least 10 day interval. RESULTS: Basing on the previously published literature, we introduced the capsaicin inhalation cough challenge into clinical practice. No difference between cough threshold among men and women was observed. A negative correlation between the age of the subjects and log C2 value was found (r = -0.44, p = 0.025). Reproducibility of cough challenge was assessed in 14 subjects and no significant differences between log C2 and log C5 in both tests were observed. Correlation coefficient for log C2 and C5 was r = 0.89, p = 0.0000 and r = 0.79, p = 0.001, respectively. There was a better reproducibility of log C2 (kappa 0.654, SEM = 0.10) than C5 (kappa 0.420, SEM = 0.13). The most common symptom reported by the patients during the capsaicin challenge was throat irritation. No serious adverse events were observed. CONCLUSIONS: Access to previously published medical literature allows to introduce the capsaicin inhalation cough challenge into clinical practice. The test is safe, shows good tolerability and reproducibility of the results. PMID- 24779217 TI - [Estimation of volume of pleural fluid and its impact on spirometrical parameters]. AB - In the course of various diseases, there is an accumulation of fluid in the pleural cavities. Pleural fluid accumulation causes thoracic volume expansion and reduction of volume lungs, leading to formation of restrictive disorders. The aim of the study was to estimate the volume of pleural fluid by ultrasonography and to search for the relationship between pleural fluid volume and spirometrical parameters. MATERIAL AND METHODS: The study involved 46 patients (26 men, 20 women) aged 65.7 +/- 14 years with pleural effusions who underwent thoracentesis. Thoracentesis was preceded by ultrasonography of the pleura, spirometry test and plethysmography. The volume of the pleural fluid was calculated with the Goecke' and Schwerk' (GS) or Padykula (P) equations. RESULTS: The obtained values were compared with the actual evacuated volume. The median volume of the removed pleural fluid was 950 ml. Both underestimated the evacuated volume (the median volume 539 ml for GS and 648 ml for P, respectively). Pleural fluid removal resulted in a statistically significant improvement in VC (increase 0.20 +/- 0.35 ; p < 0.05), FEV1 (increase 0.16 +/- 0.32 l; p < 0.05), TLC (increase 0.30 +/- 0.58 l; p < 0.05) and PEF (0.37 +/- 1 l/s; p < 0.05) CONCLUSIONS: Pleural fluid removal causes a significant improvement in lung function parameters. The analyzed equations for fluid volume calculation do not correlate with the actual volume. PMID- 24779219 TI - [Futile medical care and euthanasia in the opinion of professional nurses]. AB - Futile medical care and euthanasia are hard to assess unequivocally and are becoming a frequent topic of social discussion. The problem requires both ethical and moral consideration as well as legal regulations. As a medical issue it has got both its supporters and opponents. The aim of the study was to evaluate of nurses' attitudes and knowledge concerning euthanasia and persistend therapy. MATERIAL AND METHODS: The survey group included 183 nurses aged 30-58. The diagnostic method poll was applied, the technique used was a questionnaire. RESULTS: Among the nurses participating in the survey, 83% is against providing futile medical care when it is known that it will not bring any effect, while increasing the suffering and prolonging dying. 45% of the respondents consider euthanasia unacceptable, 41% think that euthanasia could be performed in cases in which patient's suffering cannot be relieved. 49% of the surveyed think that euthanasia should remain strictly prohibited by the Polish law, while 31% think that Polish legal system should legalize euthanasia. CONCLUSIONS: The nurses are aware that futile medical care for terminally ill and dying patients does not lead to successful treatment but instead it prolongs dying and suffering, at the same time resulting in extremely high financial costs. In most cases they are advocates of its discontinuing. The surveyed nurses differ in their approach towards euthanasia, some of them supporting the idea, the other--opposing it. Most of them express the opinion that euthanasia should be forbidden in the Polish law and their personal approach towards euthanasia is negative. PMID- 24779218 TI - [The effect of neurorehabilitation on the functional state and muscle tone of upper limb in patients after ischaemic stroke]. AB - Rehabilitation of upper limb in patients after ischemic stroke is a major challenge for modern neurorehabilitation. Function of upper limb of patients after ischemic stroke returns on the end of the rehabilitation comparing with another parts of the body. Below presents two groups of patients after ischemic stroke who were rehabilitated with use of the following methods: kinesiotherapy combined with NDT- Bobath method and kinesiotherapy only. The aim of this study was to assess the impact of kinesiotherapy only and NDT- Bobath method combined with kinesiotherapy on the functional state and muscle tone of upper limb in patients after ischemic stroke. MATERIAL AND METHODS: The study involved a group of 40 patients after ischemic stroke with motor control and muscle tone problems of upper limb. Patients were divided into two groups, each of them included 20 people. Upper limb in group I was rehabilitated with the use of kinesiotherapy exercise however group II with the use of kinesiotherapy exercise combined with NDT- Bobath method (Neurodevelopmental Treatment Bobath). To evaluate the patients before and after rehabilitation muscle tone Asworth scale was used and to assess functional status Rivermead Motor Assessment (RMAIII) scale was used. RESULTS: After 5 weeks of rehabilitation in group II in majority patients were observed decrease of muscle tone and improvement in upper limb functional status. In group I the muscle tone were also decreased and functional status were better but in smaller impact than in II group. CONCLUSIONS: Classical kinesiotherapy combined with the NDT-Bobath method gives better results in neurorehabilitation of upper limb than the use of kinesiotherapy exercises only in patients after ischemic stroke. PMID- 24779220 TI - [Delayed HIV disease diagnosis, despite multiple hospitalizations--case report]. AB - Prevalence of human immunodeficiency virus (HIV) infection remains very low in Poland and is estimated to be 0.2%. The number of people undergoing HIV-testing is low. Only 10% population was ever tested and the HIV morbidity increases yearly in Poland. The percentage of late diagnoses is high and remains so in recent years. The aim of the current paper was to present a case of female patient, the partner intravenous drug user, who was hospitalized several times due to: aseptic meningitis, delivery, thrombocytopenia and was never offered a HIV testing. The disease was diagnosed at the late stage with CD4 count of 39 cells/microl (13%). Diagnosis of the disease at the advanced stage potentially reduces a chance for successful treatment and is associated with worse prognosis. Routine testing for HIV infection should be widely available in any health care facility and be directed in particular to people with specific indicator conditions or risky behaviors. PMID- 24779221 TI - [Influenza infection in intensive cardiac care unit patients]. AB - Infection with influenza type A virus may cause serious cardiovascular complications, such as myocarditis, heart failure, acute myocardial infarction. Also infection with influenza type AH1N1 may contribute to aggravation of cardiac disorders, i.e. acute coronary syndrome, heart failure, cardiogenic shock, severe ventricular arrythmias. One of the most fatal complication of influenza is pneumonia leading to acute respiratory insufficiency requiring artifitial ventilation. Symptoms of respiratory tract infections durnig influenza epidemy should always be treated with a high index of suspicion. Early diagnosis and adequate antiviral treatment may prevent those complications. A series of four cases of patients hospitalised in intensive cardiac care unit due to suspected cardiac dyspnea and finally diagnosed as a cardiac disease complicated by influenza pneumonia is presented. PMID- 24779222 TI - [Classification and etiology of hyperthyroidism]. AB - The prevalence of hyperthyroidism in women is between 0.5-2% and it is 10 times less common in men. The most common causes are Graves' disease, toxic multinodular goiter, and autonomously functioning thyroid adenoma. Rare causes of hyperthyroidisms are as follow: pituitary adenoma, autoimmune thyroiditis (Hashitoxicosis), levothyroxine overdose, inadequate iodine supplementation (including amiodaron induced hyperthyroidism, iodine-based contrast media), hCG excess (pregnancy, gestational trophoblastic disease, germ-cell tumors), drug induced hyperthyroidism, differentiated thyroid carcinomas and/or their metastases, struma ovarii, and familial nonautoimmune hyperthyroidism. This article focuses on the current data of etiopathogenesis of hyperthyroidisms. Genetic factors (like HLA-DR3,CD40, CTLA-4, PTPN22, FOXP3 CD25) and thyroid specific genes (thyroglobulin, TSHR, G(s)alpha) and environmental and endogenous factors (such as age, iodine, selenium, emotional stress, smoking, gender, pregnancy, sex hormones, fetal microchimerism, fetal growth, bacterial infections, viral infections, allergies, drugs (alemtuzumab, interferon alpha, iplimumab/tremelimumab, tyrosine kinase inhibitors, denileukindiftitox, thalidomide/lenalidomide, exposition to fallout and radiotherapy) have been described. PMID- 24779223 TI - [Influence of ethyl alcohol on diabetes pathogenesis type]. AB - Relations between metabolism of carbohydrates and ethyl alcohol consumption became a subject of many research because they occur very frequently amongst alcoholics. One of the most often and dangerous effects of abusing ethanol is hypoglycemia. It is caused by hepatic gluconeogenesis disturbed by ethyl alcohol. Chronic result of abusing alcohol is chronic pancreas inflammation (PZT), what causes disorders of exo- and endocrine function of pancreas. Endocrine function is secretion of insulin and the glucagon what regulates metabolism of absorbed compounds. Failure of beta cells of Langerhans islets causes diabetes demanding insulin therapy. The ethanol can cause recurring diabetes resulting from damage of cells of Langerhans islets but can be also the risk factor of diabetes type 2. PMID- 24779224 TI - [Metabolic syndrome in patients with psoriasis]. AB - Psoriasis is a chronic inflammatory disease of skin, nail plates and joints, which shares similarities with other chronic inflammatory diseases such as rheumatoid arthritis and atherosclerosis. Recent studies indicated that patients with psoriasis are at greater risk for cardiovascular co-morbidities and metabolic syndrome. Published data demonstrates that there is a correlation between the severity of skin changes, cardiovascular co-morbidities and features of metabolic syndrome. Recent research showed that psoriasis plaque shares striking histological features with atherosclerotic one. Both plaques have an elevated level of activated T helper 1 and T helper 17 cells. T helper 1 cells show an overproduction of proinflammatory cytokines such as: TNF-alpha, INF-gamma IL-6 which result in endothelial dysfunction. IL-17 produced by T helper 17 cells have been known to play an important role in the pathogenesis of psoriasis and trigger inflammation in various tissues and organs. In addition, elevated level of serum IL-17 have been observed in unstable coronary artery disease (CAD) as well as in acute myocardial infarction (MI). Physical activity was proved to play a protective role in prevalence of cardiovascular co-morbidities. Recent studies showed that increased physical activity in patients with psoriasis reduce inflammation and risk of cardiometabolic co-morbidities. PMID- 24779225 TI - International year of crystallography. PMID- 24779226 TI - Dielectric characterization of the seeds of invasive Chinese tallow tree. AB - Biofuels have the potential to replace a significant portion of the transportation needs of the USA and the world. Low-cost lipid feedstock (i.e. tallow tree seeds) can be used for production of biodiesel, but these seeds need to be dried. Microwave drying is utilized to dry various seeds and grain, but for this process to be most efficient the dielectric properties of the materials need to be known. This study presents, for the first time, the dielectric properties of the seeds of the Chinese tallow tree. The dielectric constant and dielectric loss factor were determined using a modified free-space method for different moisture contents at frequency ranges centered around 915 and 2450 MHz respectively. The dielectric constant decreased with frequency in those respective ranges, and increased linearly with increasing moisture content, from 1.96 at 0% m.c. to 2.3 at 7% m.c. at 915 MHz, and from 2.08 at 0% m.c. to 2.42 at 7.6% m.c. at 2450 MHz. The dielectric loss factor generally decreased with frequency in both frequency ranges, and increased linearly with moisture content from a low of 0.16 at 0% m.c. to 0.21 at 7.56% at 915 MHz, respectively from a low of 0.13 at 0% m.c. to 0.2 at 7.6% m.c. at 2450 MHz. These results can be used to design microwave processing operations and systems for drying of tallow tree seeds, as well as for non-destructive determination of theses seeds' moisture content. PMID- 24779227 TI - Calorimetry study of microwave absorption of some solid materials. AB - In practice, the dielectric constant of a material varies the applied frequency the material composition, particle size, purity, temperature, physical state (solid or liquid), and moisture content. All of these parameters might change during processing, therefore, it is difficult to predict how well a material will absorb microwave energy in a given process. When the temperature is measured by a digital thermometer, it could not accurately reflect the true temperature of the bulk materials, especially for mixed materials. Thus, in this paper we measured the microwave absorption characteristics of different materials by calorimetry. The microwave power levels, irradiation times, and masses of the materials were varied. It was difficult to predict the microwave energy absorption characteristics of reagent-grade inorganic compounds based on their color, metallic cation, or water stoichiometry. CuO, MnO2, Fe3O4, and MnSO4 x H2O (Taishan) strongly absorbed microwave energy. Most of the remaining inorganic compounds were poor absorbers, with silica hardly absorbing any microwave energy. Carbon-based materials had significantly different microwave absorption characteristics. Activated carbon and coke were especially sensitive to microwaves, but different types of coal were poor absorbers. The jamesonite concentrate absorbed microwave energy strongly, while the zinc concentrate was a poor absorber. PMID- 24779228 TI - Microwave sintering studies on low loss (Zn, Mg)TiO3 dielectric resonator materials. AB - Low dielectric loss Zn07Mg0.3TiO3 and MgTiO3 microwave dielectric resonators were prepared by the conventional solid state reaction method. The microwave interaction with these materials has been studied using both single-mode and multimode microwave furnaces operating at a frequency of 2.45 GHz. Microwave sintering could be achieved using a multimode microwave furnace only, whereas, interaction with a single-mode furnace showed plasma generation. Phase formation was observed by X-ray diffraction. Microwave dielectric characteristics such as dielectric constant (epsilon'), quality factor (Q x f) and temperature coefficient of resonant frequency (tauf) of microwave sintered samples were measured using a vector network analyzer and compared with conventional sintered ones. Microstructure of all the conventional and microwave sintered samples was observed using high resolution scanning electron microscope. Although epsilon' and tauf of the conventional and microwave sintered samples are found to be comparable, the quality factor (the vital characteristic of dielectric resonators) of microwave sintered samples are observed to be much lower than those obtained by conventional sintering. The difference in these values is discussed with respect to the grain size. PMID- 24779229 TI - Measurement of output power density from mobile phone as a function of input sound frequency. AB - Measurements of power density emitted by a mobile phone were carried out as a function of the sound frequency transmitted by a sound generator, ranging from 250 to 14000 Hz. Output power density was monitored by means of the selective radiation meter Narda SRM 3000 in spectrum analysis mode, and the octave frequency analysis of each tone used for the experimental design was acquired by the sound level meter Larson Davis LxT Wind. Vodafone providers were used for mobile phone calls with respect to various local base station in Southern-Italy. A relationship between the mobile phone microwaves power density and the sound frequencies transmitted by the sound generator was observed. In particular, microwaves power density level decreases significantly at sound frequency values larger than 4500 Hz. This result can be explained assuming that discontinuous transmission mode of global system for mobile communications is powered not only in silence-mode, but also at frequencies larger than 4500 Hz. PMID- 24779230 TI - Influence of low- and high-frequency heating on biodegrading microorganisms in soil: microbial degradation. AB - The influence of low-frequency (50 Hz) resistive and high-frequency (13.56 MHz, radio-frequency) dielectric heating in comparison to conventional heating on the microbial degradation of pollutants in soil was studied. The investigation of the biodegradation of model substances (benzoic acid, acetic acid, glucose, sodium acetate) added to a standard soil showed no significant influence of the electrical heating methods when compared with samples heated to the same temperature in a water bath. Therefore, a hindrance of the microbial degradation could be excluded as it was done for soil respiration in a previous study. This finding is especially relevant for the application of these electrical heating methods for thermally enhanced soil bioremediation as an option for making in situ or ex situ clean-up processes more efficient. PMID- 24779231 TI - Distinct types of uterine adenomyosis based on laparoscopic and histopathologic criteria. AB - PURPOSE: To analyze laparoscopically treated cases of adenomyosis based on intraoperative and histopathology findings and to correlate different types with patients' presenting symptoms and characteristics, as well as with the surgical approach. MATERIALS AND METHODS: Sixty-eight women who underwent laparoscopic treatment of adenomyosis at a referral center for gynecological laparoscopy. RESULTS: Four distinct types of adenomyosis could be identified: diffuse, sclerotic, nodular, and cystic (54.5%, 13%, 28%, and 4.5% of cases, respectively). Menorrhagia as the main presenting symptom was significantly more frequent in patients with the diffuse type (84%) compared to those with sclerotic (44%) and nodular (37%) types (p = 0.025 andp = 0.001, respectively). All cases of cystic and nodular adenomyosis were treated by laparoscopic excision of the lesion. Eighty-nine percent of patients with sclerotic adenomyosis were treated with wide laparoscopic excision of the abnormal tissue. Eighty-one percent of patients with diffuse adenomyosis were treated with laparoscopic hysterectomy. CONCLUSIONS: Adenomyosis can be classified in four distinct types with differences in the presenting symptoms, as well as in the ideal surgical approach. PMID- 24779232 TI - Microwave endometrial ablation for hypermenorrhea treatment: a new era in Japan. AB - An estimated six million women in Japan suffer from excessive menstruation and the treatment of this disorder has been undergoing dramatic changes recently. In April 2012, microwave endometrial ablation (MEA) was approved for insurance coverage as a K863-3: a hysteroscopic endometrial ablation (17,810 points). Since the introduction of MEA to Shimane University Hospital in August 2007, authors (KN, KM) have performed the procedure in 96 patients with excessive menstruation. They have also evaluated its safety and its efficacy, not only by comparing it to the existing surgical treatment but by quantifying patients' satisfaction levels and symptom improvement. The authors conclude that MEA is a safe, effective, a low-cost treatment, and they recommend that it be considered as a standard treatment for conservative therapy-resistant excessive menstruation. PMID- 24779233 TI - Survey and analysis on birth quality influence factors of 300 cases of newborns. AB - PURPOSE: Little research has been conducted to specifically identify the correlations of birth quality influence factors of newborns and hemoglobin of gravidae and puerperal with birth weight of newborns. To investigate the correlations of birth quality influence factors of newborns and hemoglobin of gravidae and puerperal with birth weight of newborns in order to provide a scientific basis for promoting health ofgravidae and their newborns. MATERIALS AND METHODS: Three hundred cases of gravidae and puerpera treated in the present hospital were randomly selected, and questionnaire survey method was used to survey their basic situations. Also, hemoglobin values in different pregnancy stages were detected. According to birth weight of newborns, gravidae were divided into several groups to compare antepartum hemoglobin levels of various groups of gravidae. In addition, logistic regression analysis was carried out for birth quality influence factors of newborns. RESULTS: Logistic regression analysis result showed that birth quality influence factors of newborns included age, nutrition situation and pregnancy healthcare education of gravidae and puerpera. In addition, birth weight of newborns was positively related to antepartum hemoglobin level of gravidae (r = 0.746, p < 0.01). CONCLUSIONS: It was feasible for promoting smooth delivery of gravidae and puerpera, reducing incidence rate of mother and baby complications and effectively enhancing health situations of newborns to strengthen health monitoring of gravidae and conduct health education intervention. PMID- 24779234 TI - The role of hysteroscopy in the diagnostic work-up of infertile asymptomatic patients. AB - PURPOSE OF INVESTIGATION: To demonstrate that office hysteroscopy has a key-role in the diagnostic work-up of infertile couples. MATERIALS AND METHODS: The entire database of hysteroscopies performed in 572 menstruated women from 2008 to 2011, was retrospectively analyzed. A two-dimensional correspondence analysis among endometrial patterns, age ranges, and indication for hysteroscopies was made. A main-effect hierarchical log-linear model was built to assess the goodness of the correspondences found. RESULTS: A clear cluster of aggregation appears in case of both primary and secondary infertility, with and without other indications for hysteroscopy, as well as in case of primary infertility with irregular menstrual bleeding. In such patients, chronic endometritis, normal pattern, and uterine malformations were frequently found. The most significant correspondence was found for normal pattern and chronic endometritis in case of secondary infertility and primary infertility, respectively. CONCLUSIONS: Office hysteroscopy should be reconsidered in the diagnostic work-up of infertile couples. It is able to assess or rule out endometrial factor for female infertility. PMID- 24779235 TI - Clinical analysis of diagnosis and treatment of 13 cases with cesarean scar pregnancy. AB - OBJECTIVE: To explore effective methods in diagnosing and treating cesarean scar pregnancy (CSP) after cesarean section. MATERIALS AND METHODS: The clinical data of 13 cases with CSP who were admitted to the present hospital from October 2009 to February 2012 were retrospectively analyzed. RESULTS: The agreement diagnostic rate was 92.3% (12/13). On the basis of transvaginal color Doppler ultrasonography 12 patients had medical therapy combined with uterine artery embolization (UAE) and curettage was successfully performed. One patient was diagnosed through an emergency setting due to symptomatology. CONCLUSION: Early accurate diagnosis of CSP is the key to perform proper and successful treatment. PMID- 24779236 TI - A deceiving disease in women for clinicians: peritoneal tuberculosis. AB - INTRODUCTION: Peritoneal tuberculosis (TB) is uncommon in developed countries, although there is an increase in incidence due to the patients with acquired immunodeficiency syndrome and in immigrants from countries with tuberculosis. The aim of the study was to identify characteristic features of peritoneal tuberculosis (TB), which may be useful for the clinical differential diagnosis and management of this deceiving disease. MATERIALS AND METHODS: For this retrospective study, 18 patients, who were diagnosed with peritoneal TB were identified after surgery. RESULTS: Initial presentation consisted of ascites, pelvic masses, and elevated levels of CA-125. All patients were initially misdiagnosed as ovarian carcinoma. Tissue biopsies obtained from laparoscopy or laparotomy revealed accurate diagnosis of peritoneal TB. CONCLUSION: Peritoneal TB should be included in the differential diagnosis ofascites and pelvic masses and can be accurately diagnosed by laparoscopic biopsy. PMID- 24779237 TI - Establishment of reference range for thyroid hormones in normal pregnant women in China's coastal area. AB - PURPOSE: The current study aims to establish reference ranges for thyroid hormones in normal pregnant women during their pregnancy period. MATERIALS AND METHODS: A one-time cross-sectional survey was conducted on 490 normal pregnant women and 51 nonpregnant women (control). The serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) levels were measured. RESULTS: The serum FT3 and FT4 levels in pregnant women decreased gradually from the first to the last three months of pregnancy (p < 0.01). The serum TSH level increased gradually during the whole pregnancy (p < 0.01), and was significantly lower than the control (p < 0.01) in the first three months. However, in the middle and last three months of pregnancy, TSH was higher than the control (p < 0.01). CONCLUSIONS: The thyroid hormone levels in normal pregnant women are different from those in non-pregnant women; significant differences exist among the three stages of pregnancy. PMID- 24779238 TI - Vitamin B12 and folic acid status of term pregnant women and newborns in the Antwerp region, Belgium. AB - OBJECTIVE: Descriptive study on maternal serum vitamin B12 and folic acid in term pregnancy and in umbilical cord blood that was performed in an inner city hospital with a mixed ethnic population in the region of Flanders in Belgium. MATERIALS AND METHODS: A prospective cohort study that took place from April 1 until May 31, 2011. Plasma folic acid and vitamin B12 were measured in maternal and umbilical cord blood from all term uncomplicated deliveries in a single regional hospital. Data on age, previous obstetric history, ethnicity, nutritional intake, and use of vitamin supplements were registered. RESULTS: Data were collected from 110 patients, mean maternal serum vitamin B12 was 243.9 pmol/l and mean folic acid level was 43.0 nmol/l. Using a cutoff of respectively 150 pmol/l for vitamin B12 and 7.1 nmol/l for folic acid, 13% of the women were classified as vitamin B12-deficient and 23% were deficient for folic acid. Vitamin B12 deficiency was only seen in autochthonous Belgian women. A correlation between the maternal and umbilical cord levels was noted (R = 0.7 for vitamin B12, R = 0.85 for folic acid), but none of the umbilical cord levels demonstrated deficiency. Number of previous pregnancies and intake of supplements had no influence. CONCLUSION: Pregnant women in Antwerp, Belgium, frequently show vitamin B12 and folic acid deficiency, although a correlation exists with lower umbilical cord levels, the present limited data did not demonstrate any case of deficiency in umbilical cord blood. The frequency is highest in the autochthonous population and is not influenced by intake of vitamin supplements. PMID- 24779239 TI - Clinical characteristics and reproductive outcome following hysteroscopic adhesiolysis of patients with intrauterine adhesion--a retrospective study. AB - The authors performed a retrospective clinical analysis of 153 patients with intrauterine ashesion (IUA) who underwent hysteroscopic adhesiolysis. A follow-up office hysteroscopy was performed in all cases after three months. On follow-up hysteroscopy, 22 patients showed reformation of adhesions and required a repeat procedure. The primary risk factor for IUA was uterine curettage associated with pregnancy termination. The follow-up study revealed that the rate of pregnancy after IUA treatment was 51%. The conception rate in women who had reformation of IUA was significantly lower than that of women who had a normal cavity following adhesiolysis. Therefore the authors conclude that prevention is more important than therapy in IUA. Increasing education about avoiding curettage is necessary to reduce the incidence of IUA. Outreach is particularly important for older women with less education. However, hysteroscopic adhesiolysis for IUA is a safe and effective method of choice for restoring menstrual function and fertility. PMID- 24779240 TI - Implications of premature ovarian failure on bone turnover markers and bone mineral density. AB - INTRODUCTION: Premature ovarian failure (POF) is the cessation of ovarian function before the age of 40. The loss of ovarian function, whether premature or not, has an overwhelming impact on female skeletal health, leading to an increased risk of developing osteoporosis because of the lengthened time of exposure to reduced estrogen. The objective of this study was to compare the implications of premature ovarian failure on bone turnover markers and bone mineral density in patients under the age of 40. MATERIALS AND METHODS: Sixty-one patients with a diagnosis of POF were selected for this prospective study. Patients were divided into two groups according to age, patients < 30 years old (n = 30), and patients > or = 30 years old (n = 31). RESULTS: Between the two age sub-groups (< 30 and > or = 30 years old), there was a significant difference in menopause rating scale (MRS), lumbar spine t-score, N-telopeptides crosslinks (NTx), and serum bone specific alkaline phosphatase (bALP) between the two age groups (10.93 +/- 7.79 vs 17.38 +/- 8.62; -1.84 +/- 1.47 vs -1.06 +/- 0.93; 58.80 +/- 21.32 vs 41.1 +/- 11.37; 48.99 +/- 42.16 vs 23.76 +/- 10.08, respectively). CONCLUSION: It is apparent that bone mineral density (BMD) is commonly less in women with POF than normal healthy women. Therefore, measurement of BMD is warranted. At this time, it is not clear how often the tests should be carried out to evaluate BMD. Further prospective studies are required to establish guidelines. However, it seems reasonable to monitor women with POF yearly for the presence of any endocrine dysfunction and to assess BMD at periodic intervals. PMID- 24779241 TI - The influence of mifepristone to caspase 3 expression in adenomyosis. AB - OBJECTIVE: To discuss the influence of mifepristone to caspase 3 expression in adenomyosis tissue. MATERIALS AND METHODS: Sixty patients were equally divided into four groups. Groups 1, 2, and 3 were treated with 5, 10, and 15 mg mifepristone, respectively and group 4 was treated with placebo. The expression of caspase 3 was examined by immunohistochemical method in both eutopic and ectopic endometria of the 40 cases. RESULTS: Compared with placebo group, the expression of caspase 3 in both eutopic endometrium and ectopic endometrium in the three treatment groups was significantly increased. There was no difference in the expression of caspase 3 in both eutopic and ectopic endometria between the ten and 25 mg treatment groups, while both the ten and 25 mg treatment groups had a higher expression intensity of caspase 3 in both eutopic and ectopic endometria, compared with the five mg treatment group (p < 0.01). CONCLUSION: Mifepristone can increase the expression of caspase 3 in both eutopic and ectopic endometria and initiate cell apoptosis in both eutopic and ectopic endometria. Therefore mifepristone can effectively inhibit the emergence and development of adenomyosis. PMID- 24779242 TI - Homeopathy for infertility treatment: a case series. AB - Homeopathy has been used in the past for treating a broad aspect of diseases. In gynecology, its use remains limited. Taking under consideration its clinical aspects, the authors attempted to use it for treating female sub fertility problems. With this study, the authors present five cases of female infertility treated successfully with the use of homeopathic treatment in a large obstetrics gynecology Hospital in Athens. PMID- 24779243 TI - Correlations of abnormal ultrasound audio-visual images of ovarian cortex surface and pelvic adhesion in infertile patients. AB - OBJECTIVE: The aim of this study was to evaluate the related factors between abnormal ultrasonic appearance of ovarian and pelvic adhesion in infertile women. MATERIALS AND METHODS: Forty-eight cases were examined with transvaginal ultrasonography (TVUS) if there was pelvic adhesion before surgery (experiment group), and the surgical group was used as control. The specificity of pelvic adhesion was evaluated. RESULTS: Thirty-nine cases were abnormal in experiment group and 38 cases were confirmed with surgery, while one case was normal. Nine cases were normal in study group and six cases were confirmed with surgery, while three cases were abnormal. There were 91.7% (44/48) in coincidence rate and 97.4% (38/39) in positive predictive value. CONCLUSION: Infertility in women with pelvic adhesion with abnormal ovarian appearance, may be examined specifically with TVUS. PMID- 24779244 TI - Does proteinura in preeclampsia have enough value to predict pregnancy outcome? AB - OBJECTIVE: Preeclampsia is defined by the new onset of elevated blood pressure and protienuria after 20 weeks of gestation. Protienuria is one of the essential criteria for the clinical definition of preeclampsia. The authors investigated the predictive value of proteinuria in the outcome of pregnancies with preeclampsia. MATERIALS AND METHODS: In this retrospective cohort study, they entered all pregnant women who were admitted with diagnosis of preeclampsia in Yahyanejad Hospital from 1998 to 2008. Patients' data such as age, gestational age, level of 24-hour urine protein, liver enzyme, blood urea nitrogen (BUN), creatinine, and other laboratory test. Also, prenatal and maternal outcome were studied. The data analyzed and compare with each other. RESULTS: Out of 289 patients, 5.9% (17) women had placental abruption, 13.1% (28) patients had intrauterine growth retardation (IUGR), 32.2% (96) had respiratory distress, and 26.6% (77) of the patients' infants were transferred to neonatal intensive care unit (NICU). Although the present study showed proteinurea cannot be a sufficient predictor for adverse consequences of preeclampsia, however, the incidence of pregnancy adverse effects increased in the patients with elevated 24-hour proteinuria. CONCLUSION: The authors concluded that proteinuria in patients with preeclampsia is associated with adverse outcome in pregnancy, although it is not an adequate predictor. PMID- 24779245 TI - The effects of magnesium sulphate on the contractile activity of uterus in an animal model of preeclampsia. AB - PURPOSE: This study was undertaken to evaluate the effects of magnesium sulfate (MgSO4) on the contractile activity of the uterus in a pregnant rat model of preeclampsia induced by N-nitro-arginine methyl ester (L-NAME). MATERIALS AND METHODS: Twenty-eight, 160-220 gram, three to four month old female Sprague Dawley rats were used in this study. After conception was confirmed by vaginal smears on the first day of pregnancy, the animals were allocated into four groups according to the chemicals fed in their drinking water as control (nothing administered), L-NAME (50 mg/kg L-NAME), MgSO4 (600 mg/kg MgSO4), and MgSO4 + L NAME group (600 mg/kg MgSO4 + 50 mg/kg L-NAME). The pregnant uterus strips were isolated on the 19th day and the contractile activity of uterus was examined by applying 0, 0.1, 0.2, 0.4, 0.8, and 2.5 mIU/ml oxytocin to each group and responses are recorded accordingly. RESULTS: There were no statistically significant differences regarding fetal parameters and peak amplitudes of the oxytocin stimulated pregnant rat myometrial strips among groups. In L-NAME group at 0 and 0.1 mIU/ml oxytocin, the contraction frequency in a ten-min period was statistically lower than the control group (Z = -2.850, p = 0.004; Z = -2.902, p = 0.004, respectively). In MgSO4 group only at 0 mIU/ml oxytocin, the frequencies of the contractions in ten-min period were statistically lower than the control group (Z = -2.973,p = 0.003). In L-NAME + MgSO4 group at 0, 0.1 and 0.2 mIU/ml oxytocin concentrations the frequencies of the contractions in ten-min period were statistically lower than the control group (Z = - 4.018, p = 0.000; Z = 3.237, p = 0.001; Z = -2.902, p = 0.004, respectively). In L-NAME + MgSO4 given group at each oxytocin concentrations, the frequencies of the contractions in ten min period were lower but not statistically different than the L-NAME group. CONCLUSION: MgSO4 has no significant effect on the amplitude of spontaneous or oxytocin induced myometrial contractions, but decreased the frequency of spontaneous contractions. At each doses of oxytocin, MgSO4 has no significant effect on the frequency of contraction in a pregnant rat model of preeclampsia induced by L-NAME. PMID- 24779246 TI - Alteration of T-cell subpopulations and lipid peroxidation in the blood of patients with vulvar non-neoplastic epithelial disorder. AB - OBJECTIVE: To determine the relationship between vulvar non-neoplastic epithelial disorder and thymus-dependent lymphyocyte levels and lipid peroxidation. MATERIALS AND METHODS: the authors measured the levels of CD3+, CD4+, CD8+, CD16+ T cell, and the concentration of superoxide dismutase (SOD) and malondialdehyde (MDA) in the blood of 62 patients with vulvar non-neoplastic epithelial disorder. A control group consisted of 30 normal women from the present hospitals. RESULTS: The level of CD4+/CD8+ T-lymphocytes and SOD in the blood of the patients with vulvar non-neoplastic epithelial disorder was significantly lower than that in control subjects, but the level of MDA was higher as compared with normal women. CONCLUSION: There is increased immune activation and lipid peroxidation in patients with vulvar non-neoplastic epithelial disorder, which could contribute to destruction of vulvar tissue. PMID- 24779247 TI - The association between inherited thrombophilia and recurrent pregnancy loss in Turkish women. AB - OBJECTIVE: To investigate the relation between recurrent pregnancy loss (RPL) and factor V Leiden, prothrombin G20210A, and C677T methylenetetrahydrofolate reductase (MTHFR) mutations. MATERIALS AND METHODS: A case-control study was conducted on 95 consecutive cases with RPL, and 40 age-matched controls who had no history of pregnancy loss and had at least one successful pregnancy. After application of exclusion criteria, 60 patients in the study group and 40 control cases were compared for thrombophilic factors. RESULTS: Thirteen out of 60 RPL cases and one out of 40 in the control group were carriers of factor V Leiden mutation. While six patients were carriers of prothrombin G20210A gene mutation, none in the control group carried this mutation. Twenty-nine out of 60 RPL cases and 17 out of 40 control cases had MTHFR mutation. CONCLUSION: The authors found a positive correlation between RPL and FVL and FII gene mutations, but no significant association between RPL and MTHFR gene mutation. PMID- 24779248 TI - Hypothyroidism and first-trimester spontaneous miscarriages. AB - OBJECTIVE: To evaluate the association between hypothyroidism and first-trimester spontaneous miscarriages and to explain the mechanism. MATERIALS AND METHODS: Patients admitted between October and May 2011 with threatened miscarriage in the first trimester were analyzed and levels of progesterone and thyroid hormones as T3, T4, and thyroid-stimulating hormone (TSH) were estimated. Once hypothyroidism was diagnosed, patients were treated with sodium levothyroxine (LT4) as substitution and outcomes were observed. RESULTS: Measurement of progesterone was useful for predicting the outcome of threatened miscarriage The results showed that progesterone (P) = 14.74 ng/ml is selected as predictive value to judge whether the fetal treatment was successfully or not. When serum P value is above 14.74 ng/ml before treatment, it may favour a miscarriage, if the serum P value is below 14.74 ng/ml, miscarriage is unlikely; its sensitivity and specificity are high. The risk for miscarriage in patients diagnosed with hypothyroidism in which LT4 substitution was similar to the level observed in the controls, and P between the two groups had no distinct difference. The mechanism explaining the risk of miscarriage increased by thyroid disorders remains unclear, which needs advanced research. CONCLUSION: Screening of thyroid disorders has important clinical significance in early pregnancy, and substitution of LT4 to those who are in the early pregnancy with hypothyroidism could reduce the risk of miscarriage. PMID- 24779249 TI - Prediction of pregnancy outcomes with combined ultrasound scanning of yolk sacs and serum CA125 determinations in early threatened abortion. AB - OBJECTIVES: To assess the predictive value of the combination of ultrasound scanning, yolk sacs and CA125 levels for pregnancy outcomes in early threatened abortion. MATERIALS AND METHODS: A total 196 pregnant women at less than 12 weeks gestation were enrolled. They were assigned into: (A) normal pregnancy (n = 61); (B) early threatened abortion but with favorable outcomes after active treatment (n = 56); (C) pregnancy with spontaneous miscarriage and threatened abortions (n = 79). The yolk sacs were examined and serum CA125 levels were measured. RESULTS: The visualization rate in groups A and B were significantly higher than that in group C. For the mean yolk sac diameter, there was a statistically significant difference between groups A and C (p < 0.05), B and C (p < 0.05), but no statistically significant differences were observed between A and B (p > 0.05). The mean serum CA125 levels were significantly different (p < 0.05) among three groups. The sensitivity, specificity, and Youden Index for predicting adverse outcomes using irregular shape, abnormal size, or non-visualization of the yolk sac were 81.01%, 85.71%, and 0.67, respectively. CONCLUSION: The combination of ultrasound scanning of yolk sacs and measurement of serum CA125 levels is of great value for predicting pregnancy outcomes. PMID- 24779250 TI - The serum level of C-reactive protein in patients undergoing GnRH agonist protocols for in vitro fertilization cycle. AB - BACKGROUND: The synchronization of the uterus and mature eggs at the molecular level is the key factor in embryo transfer, and the regulation of synchronization depends on a variety of cytokines. C-reactive protein (CRP), as the first acute phase reaction protein, is involved in the entire process of embryo transfer. The study is designed to investigate the correlation among CRP, sex hormone, controlled ovarian hyperstimulation (COH) cycle, and pregnancy outcome. MATERIALS AND METHODS: Ninety-two patients who accepted in vitro fertilization (IVF) treatment cycles because of tubal factor were included in the study. Seventy treated cases were included to complete final analysis with the full set of results. Respectively on the second day of the menstruation (Day-2) in gonadotropin-releasing hormone agonist (GnRH-a) short program treatment, on the morning in human chorionic gonadotropin (hCG) treatment (Day-hCG) and the embryo transplant day (Day-ET), plasma CRP level was tested by enzyme-linked immunosorbent assay (ELISA). The correlativity among CRP level, sex hormone, COH, and pregnancy outcome was analyzed by statistical methods. RESULTS: In the short program GnRH-a of 70 cases, there was no relationship between serum CRP level and the infertility age, gonadotropin (Gn) dosage, number of oocytes retrieved, the number of normal fertilization, and sex hormone. In the short program of GnRH-a, the change of serum CRP levels in Day-2, Day-hCG, Day-ET: serum CRP in Day-2 < Day-hCG < Day-ET and the level of serum CRP gradually increased in Day-2, Day hCG, and Day-ET in both the pregnant group and non-pregnant group. In non pregnant group, the ratio of hCG/D2 and ET/hCG-day were significantly higher than the pregnant group. The area under receiver operating characteristic (ROC) curve was 0.806, indicating the accuracy of diagnostic tests is medium, the authors chose the point which presents the ratio of CRP in Day-ET to Day-hCG which was less than 1.752 as a predictor of treatment outcome, the sensitivity of the experiment was 77.8%, and the specificity 75%. CONCLUSION: CRP as a sensitive inflammatory marker, CRP ratio of Day-ET/Day-hCG could be a predictor of treatment outcome by ROC curve analysis in COH program. PMID- 24779251 TI - Application of two-dimensional echocardiography combined with enhanced flow in diagnosing fetal heart malformation. AB - OBJECTIVE: The current study aims to evaluate the diagnostic accuracy of two dimensional echocardiography combined with enhanced flow (e-flow) imaging for fetal heart malformation. MATERIALS AND METHODS: A total of 1,639 pregnant women were enrolled. They were examined using fetal echocardiography combined e-flow. The obtained results were compared with those by postnatal examination or post induction autopsy. RESULTS: Complete data were obtained from 1,286 out of the 1,639 fetuses (78.46%). Two-dimensional echocardiography combined with e-flow imaging had sensitivity, specificity, a misdiagnosis rate, and a missed diagnosis rate of 98.0%, 99.3%, 2.0%, and 0.7%, respectively. It has a consistency evaluation Kappa value of 0.970 (p = 0.000). CONCLUSION: Two-dimensional echocardiography combined with e-flow is an accurate and reliable diagnostic method for fetal heart malformation. It has high sensitivity and specificity. PMID- 24779252 TI - Complete eradication of chronic long standing eczema and keratosis pilaris following treatment with dextroamphetamine sulfate. AB - PURPOSE: To present two other dermatologic conditions related to a disorder of sympathetic nervous system hypofunction common in women that respond to treatment with dextroamphetamine sulfate--chronic eczema and keratosis pilaris. MATERIALS AND METHODS: Case 1 was a patient with chronic eczema of 30 years duration was started on treatment for other conditions related to the sympathetic neural hyperalgesia edema syndrome, i.e., migraine headaches and chronic fatigue syndrome. Case 2 who also had chronic eczema also had a skin condition frequently associated with eczema--keratosis pilaris and he was started on dextroamphetamine sulfate for chronic fatigue syndrome. RESULTS: Not only did the headaches and chronic fatigue syndrome in both patients markedly improve following sympathomimetic amine therapy but so did the eczema and keratosis pilaris. CONCLUSIONS: Eczema and keratosis pilaris are two more chronic dermatologic conditions besides chronic urticaria and prurigo nodularis that respond extremely well to treatment with dextroamphetamine sulfate. Case 2 shows this condition is not restricted to females. PMID- 24779253 TI - Pregnancy management in Behcet's disease treated with uninterrupted infliximab. Report of a case with fetal growth restriction and mini-review of the literature. AB - BACKGROUND: The mutual impact of Behcet's disease (BD) and pregnancy is variable and still unclear. Among the safe drugs administered, the newer infliximab (IFX) was rarely experienced in pregnancy, particularly in the third trimester. CASE: The authors report a pregnancy with fetal growth restriction at 36 weeks in a 31 year-old primigravida with symptomatic BD, treated with uninterrupted monthly IFX and daily enoxaparin. The patient was induced at 38 weeks and had an uneventful vaginal delivery of a healthy baby. The postpartum period and following six months were uneventful for mother in terms of BD exacerbation, and newborn in terms of potential risks of neonatal BD and/or infections due to late immunosuppressive IFX administration. CONCLUSION: Because of the inconstant mutual impact, BD pregnancies should be precautionary considered at "potential high-risk" and need a careful and close monitoring by a multidisciplinary team with specific expertise. PMID- 24779254 TI - Dichorionic twin pregnancy discordant for anencephaly: two cases with different management. AB - BACKGROUND: Prevalence ofanencephaly in dichorionic twins is higher than in singleton pregnancies. The authors report two cases with two different management strategies. CASE 1: Spontaneous dichorionic diamniotic twin pregnancy with the second twin diagnosed with anencephaly at 12 weeks gestation. Selective feticide was performed at the age of 13.2 weeks. Vaginal delivery occurred at 39 weeks, and birth weight was 2,850 g. CASE 2: Dichorionic diamniotic twin pregnancy discordant for anencephaly in the second twin was diagnosed at 13 weeks gestation. An expectant management was decided. Preterm delivery occurred at 35 weeks due to hydramnios of the affected fetus, delivering a healthy newborn weighing 2,300 g and an anencephalic neonate who died immediately after delivery. CONCLUSION: Anencephaly should be diagnosed as soon as possible, idealistically at 11-13+6 weeks ultrasound (US) scan, in order to offer the most appropriate counselling to the parents, ranging from selective feticide or expectant management. This short series suggests that selective early feticide may increase gestational age and birth weight. PMID- 24779255 TI - Severe headaches from intracranial hypertension (pseudotumor cerebri) abrogated by treatment with dextroamphetamine sulfate. AB - PURPOSE: To determine if sympathomimetic amines may relieve migraine headache pain from pseudotumor cerebri (PTC) similar to its effect on helping other types of migraine headaches that were recalcitrant to other therapies. MATERIALS AND METHODS: A woman with severe migraine headaches which did not respond to treatment with acetazolamide was treated with dextroamphetamine sulfate sustained release capsules 25 mg daily. RESULTS: The patient demonstrated marked improvement within a month. The marked decrease in headache pain has persisted over a year. Her papilledema also completely disappeared. CONCLUSIONS: The sympathetic neural hyperalgesia edema syndrome can manifest as PTC. Besides headaches, other symptoms that the patient manifested were part of this syndrome including chronic fatigue, inability to lose weight despite dieting, and backache. All of these additional symptoms also improved with sympathomimetic amine therapy. PMID- 24779256 TI - Successful rescue hysteroscopic resection of a cervical ectopic pregnancy previously treated with methotrexate with no combined safety precautions. AB - BACKGROUND: Cervical pregnancy (CP) is a life-threatening condition that represents less than one percent of all ectopic pregnancies. Transvaginal sonography (TVS) is the gold standard for an accurate diagnosis. For hemodinamically stable women the available treatments involve a medical therapy, alone or in combination with interventional measures (hysteroscopy, angiographic embolization or laparoscopic ligation of uterine arteries). MATERIALS AND METHODS: The authors describe a CP unsuccessfully treated with methotrexate (MTX), but resolved with hysteroscopy. CASE REPORT: A nulliparous woman arrived with low abdominal pain without vaginal bleeding at six weeks of amenorrhea. TVS revealed a gestational sac implanted in the isthmic cervical region, with a serum beta-hCG of 1,100 mUI/ml, that raised to 4,274 mUI/ml in a week, despite one intrasaccular-MTX injections and two systemic doses. The authors arranged for a hysteroscopic resection with no previous dilatation of the cervix. They did not adopt any safety precautions to their procedure. CONCLUSION: It is difficult to define the exact role of hysteroscopy regarding CP. Despite some authors dispute on its complementary function to MTX, the authors believe that it could be used as a rescue method in case of MTX failure. The final aims of a proper management are to minimize the risk of haemorrhage and preserve women's fertility. PMID- 24779257 TI - Prenatal diagnosis of multiple fetal anomalies in naphthalene-addicted pregnant women: a case report. AB - BACKGROUND: Naphthalene is one of the abused inhalants. It has been associated with acute and chronic health problems. To the authors' knowledge, prenatal exposure to naphthalene has never been discussed in humans. CASE: The authors discuss a case of naphthalene-addicted pregnant women with multiple fetal anomalies. At 15 weeks gestation, ultrasound screening demostrated multiple fetal anomalies: anencephaly, scoliosis, diffuse subcutaneous edema, flexion contracture of lower extremities, and hypoplastic left ventricle. Four weeks later obstetrical ultrasonography revealed that there was no fetal cardiac activity. The patient had a medical abortion. CONCLUSION: A stronger knowledge basis regarding naphthalene-related fetal anomaly is required to ensure accurate direct link, however the probability of naphthalene-related fetal anomaly must be considered. PMID- 24779258 TI - Can laparoscopic removal of Essure device before embryo transfer correct poor reproductive outcome pattern in IVF? A case report. AB - OBJECTIVE: This report describes a successful surgical approach to multiple in vitro fertilization (IVF) failures in the setting of hydrosalpinges, which had been previously treated with Essure inserts. MATERIALS AND METHODS: A non-smoking 33-year-old Caucasian G2 P0020 (body mass index: BMI = 22) attended for second opinion. Her history was significant for bilateral hydrosalpinges having been noted on hysterosalpingogram two years earlier. This was managed by hysteroscopic placement of Essure inserts bilaterally. One year later, and now with Essure in situ, the patient completed three IVF cycles elsewhere. Her first and third IVF attempts resulted in biochemical pregnancy, while human chorionic gonadotropin (hCG) was negative after the second cycle. Upon presentation at the authors' center and before beginning a fourth IVF cycle, further testing and surgical removal of the Essure devices was recommended. RESULTS: Repeat hysteroscopy was unremarkable; laparoscopic bilateral salpingectomy and extirpation of Essure implants was accomplished without difficulty. Following menses, the patient initiated IVF with three embryos transferred. At day 60, a single intrauterine pregnancy was identified with positive cardiac activity (rate > 100/min). Her obstetrical course was uneventful; a healthy 4,195 gram male infant was delivered (breech) by Cesarean at 40 weeks' gestation. CONCLUSION: Essure inserts comprise inner fibers of polyethylene terephthalate, a stainless steel coil, and a nickel titanium coil. The product received FDA approval as a contraceptive in 2002 although its use for hydrosalpinx remains off-label. While successful outcomes with IVF following Essure placement have been reported, this is the first description of pregnancy and delivery from IVF after Essure removal. Essure may be considered for sterilization when laparoscopy is contraindicated, but experience with its use specifically for treating hydrosalpinges before IVF is limited. This observed association between prior poor IVF outcomes and Essure with subsequent delivery after surgical Essure removal is the first of its kind to be reported, and warrants further investigation. PMID- 24779259 TI - Premature ovarian failure in a 17-year-old woman. AB - INTRODUCTION: Premature ovarian failure (POF) in a healthy adolescent is a rare event. It is diagnosed by the presence of amenorrhea, hypoestrogenism, and elevated follicle-stimulating hormone (FSH) levels before the age of 40. CASE: The patient presented with amenorrhoea at 17 years after identifying a change from her regular to irregular and metrorrhagic cycles. No positive medical history was noted regarding smoking, chemotherapy, radiation or autoimmune diseases and the physical examination was normal. Her family history revealed that both her maternal aunt and grandmother were affected by POF, but the karyotype test was normal and the FMR1 screening premutation test was negative. The patient underwent an ovarian biopsy which revealed the absence of functional follicles. She began a replacement therapy with estroprogestogens and she was informed about the most successful means to start a family, including adoption and oocyte donation. CONCLUSION: POF is a heterogeneous, multifactorial, and poorly understood condition that involves medical concerns, psychological sphere, and sexuality of the affected patients. Management should be directed at symptoms resolution, bone protection, and psychosocial support for women facing this unexpected and devastating diagnosis. PMID- 24779260 TI - Amniotic band syndrome (ABS): can something be done during pregnancy in African poor countries? Three cases and review of the literature. AB - Amniotic band syndrome (ABS) is a fetal congenital malformation, affecting mainly the limbs, but also the craniofacial area and internal organs. Two mains pathogenic mechanisms are proposed in its genesis. Firstly the early amnion rupture (exogenous theory) leading to fibrous bands, which wrap up the fetal body; secondly, the endogenous theory privileges vascular origin, mesoblastic strings not being a causal agent. The authors believe that the second theory explain the occurrence of ABS. The outcome of the disease during pregnancy depends on the gravity of the malformations. Interruption of the pregnancy is usually proposed when diagnosis of severe craniofacial and visceral abnormalities is confirmed. Whereas minor limb defects can be repaired with postnatal surgery. In case of an isolated amniotic band with a constricted limb, in utero lysis of the band can be considered to avoid a natural amputation. In an African country, such treatment is not possible as far as the antenatal diagnosis. PMID- 24779261 TI - Partial agenesis of corpus callosum--case study. AB - Agenesis of the corpus callosum is an uncommon cerebral malformation usually of unknown etiology. It can be associated with other brain abnormalities, such as ventriculomegaly, or in combination with problems with other organs, such as congenital heart defect, as well as with chromosome anomalies. Diagnosis of this rare anomaly is important not only because of possible association with other developmental anomalies but also because of postnatal treatment and evaluation of children with this disorder. This paper presents prenatal diagnosis of partial agenesis of the posterior part of corpus callosum of a fetus detected in gestational week 33 by ultrasonography as an isolated developmental disorder, i.e., not accompanied by other morphological anomalies of the fetus or chromosome aberrations or other genetic defects. PMID- 24779263 TI - [Parity and menarche as risk factors for osteoporosis in postmenopausal women]. AB - BACKGROUND: Worldwide studies, even in our country, have thrown discrepant results about the relation between osteoporosis, parity and age of menarche. OBJECTIVE: To investigate the relation of osteoporosis in postmenopausal mexican women with multiparity and age of menarche. PATIENTS AND METHOD: Transversal, retrospective and analytical study. Non-probabilistic sampling technique was performing with users women of the IMSS in San Luis Potosi. Reproductive history and age of menarche were obtained by the addition of these items to the previously validated Albrand questionnaire. Women were divided into groups according to the number of pregnancies in: normal parity (0 to 3 childbirths) conformed by 112 patients (46%) and multiparity (> or = 4 pregnancies), 131 women (54%). In relation to menarche with an average of 12.98 years, from this number we divided them in: early menarche (before the age of 13) and late menarche (at 13 years of age or after). It was measured bone mineral density with dual distal forearm x-ray absorptiometry to all patients. RESULTS: 243 women were studied, with an average of age of 55.92, rank 31 to 80 years. Using the criteria, of the World Health Organization, 18% of posmenopausal women had osteoporosis, 39% had osteopenia and 41% had bone normality. No association was found between the number of deeds and osteoporosis. Additionally we observed that the women who had 4 or more children were older than the other women. average 57.42 against 54.16. Also there was significant negative correlation (r = -0.43) between age and densitometry. In addition we found that an age greater to 13 years in the appearance of the menarche was related to osteoporosis (OR 4.46; p = 0.035). CONCLUSIONS: In posmenopausal women a menarche at the age of 13 years or after is a risk factor for osteoporosis. PMID- 24779264 TI - [Some demographic aspects associated with ectopic pregnancy]. AB - BACKGROUND: The determination techniques of chorionic gonadotropin and transvaginal high resolution ultrasound have revolutionized the diagnosis of ectopic pregnancy. OBJECTIVE: Assess demographic aspects associated with ectopic pregnancy in Hospital Angeles del Pedregal over a 6 years period. MATERIALS AND METHODS: Descriptive and retrospective study. We reviewed 143 clinical records from March 1, 2006 to January 31, 2013, with diagnosis of ectopic pregnancy discharge. The analyzed variables were: age, history of ectopic pregnancy, method of family planning, pelvic inflammatory disease, smoking, weeks of gestation, clinical picture, localization of ectopic pregnancy, treatment and complications. RESULTS: Were analyzed 143 cases, diagnosed and corroborated with histopathological study, of ectopic pregnancy in Hospital Angeles del Pedregal during the period from 2006 to 2012. The average age at which pregnancies occurred was 32.4 +/- 5.4 years; 89% of patients were over 25 years old. 35% were primigravidous and 51 women had previous caesarean, 31 abortion and 22 childbirth. 10% had history of ectopic pregnancy and 39% had 5 weeks gestation; 72% not used contraceptives, 30% were smokers, and only 2% had suffered pelvic inflammatory disease. CONCLUSION: Despite the technological advances the correct evaluation of risk factors is essential for the diagnosis of ectopic pregnancy. PMID- 24779265 TI - [Diagnosis and prognosis of fetal ebstein anomaly]. AB - BACKGROUND: Fetal echocardiography is possible to confirm with great certainty the diagnosis, in utero, Ebstein's anomaly, as well as determine its perinatal prognosis. OBJECTIVE: Review the experience of 16 cases diagnosed with Ebstein's anomaly, using fetal echocardiography, analyzing "forecast echocardiographic parameters" set by Pavlova, Huhta and Barre. MATERIAL AND METHOD: retrospective and descriptive analysis. We analysed echocardiographic parameters and its correlation with the perinatal development of 16 cases diagnosed with Ebstein's anomaly. RESULTS: Maternal age of our patients was 27.94 +/- 5.7 years, gestational age 31.3 +/- 3.6.) Mortality: in-utero 37.5% (n = 6), neonatal 50% (n = 8), survived 12.5% (n = 2). Cardiothoracic index 0.61 +/- 0.074, relationship foramen oval/heart atrial 0.6 +/- 0.015; obstruction to the way out of the right ventricle in 14 cases (87.5%). The deceased 81% presented degree of valvular displacement > 2.5; relationship RV/LV 2.24 +/- 0.37). CONCLUSIONS: Cardiothoracic index fetal stage > 0.55, relationship oval foramen/interatrial septum < 0.3, obstruction to the way out and a degree of valvular displacement > 2.5, absence of back flow in arteriosus ductus and a ratio RV/LV > 2 are poor prognostic factors for Ebstein's anomaly. PMID- 24779266 TI - [Modified cesarean-hysterectomy technique for management of placenta accreta]. AB - BAKGROUND: Obstetric hemorrhage is a major cause of maternal morbidity. The increasing number of births via cesarean has increased the incidence of placenta accreta worldwide. As new techniques aimed at reducing maternal mortality and morbidity have emerged with varying results. OBJECTIVES: To describe the surgical technique used in our hospital for management of placenta accreta. Report outcomes and maternal complications. METHODS: Descriptive study, data were obtained from clinical records of patients diagnosed with placenta accreta and whose management was by our modified technique cesarean-hysterectomy by a multidisciplinary team. We included patients who were treated at the Hospital Civil de Guadalajara Dr. Juan I. Menchaca in the period from April 1, 2008 to November 1, 2012. RESULTS: 23 patients were included. The mean gestational age at Doppler ultrasound diagnosis was 31 +/- 3 weeks and for termination of pregnancy was 34 +/- 1 weeks of gestation. Only 5 patients were admitted to intensive care, one patient suffer bladder injury noticed and repaired. CONCLUSIONS: Our modified technique cesarean-hysterectomy for management of placenta accreta has reduced mortality and morbidity in our hospital as well as injuries to nearby organs and hospital stay. PMID- 24779267 TI - [Intrauterine contraception in nulliparous women as a strategy to reduce unplanned pregnancies in Latin America]. AB - Due high rates of unplanned pregnancy and unsafe abortion in young women in Latin America intrauterine contraception, by its great contraceptive efficacy, should be offered by the public services of health in a more generalized way. However, some negative prejudices prevail over the perception of its benefits. The aim of this article was to explore the most relevant myths around this contraceptive method in Latin America and make a review of the literature to allay the fears of their use by young and nulliparous women. METHODS: Descriptive and retrospective study. Search for information in Embase and PubMed with emphasis on clinical randomized studies, studies of cases and controls, meta-analyses and systematic reviews which show risks and benefits of intrauterine contraception. RESULTS: Evidence shows that intrauterine contraception has few contraindications for young women and nulliparous; for this reason it must be as an effective public health strategy to reduce unplanned pregnancies and unsafe abortions. CONCLUSIONS: We identified the major barriers to the use of intrauterine contraception in Latin America and evidence for each one of them in the bibliography. Doctors of first contact in health systems should now recognize that intrauterine contraception is safe and effective. PMID- 24779268 TI - [Clinical practice guideline for the diagnosis and treatment of hyperprolactinemia]. AB - BACKGROUND: Hyperprolactinemia is a common finding within clinical practice in both endocrinology and general practice fields, amongst other specialties. The general practitioner and other specialists must know the indications and serum prolactin determination parameters in order to, once detected, derive the patient for a correct assessment and begin treatment. OBJECTIVE: Formulate a clinical practice guideline evidence-based for the diagnosis and treatment of hyperprolactinemia. METHOD: It took the participation of eight gynecologists, two pathologists and a pharmacologist in the elaboration of this guideline due their experience and clinical judgement. These recommendations were based upon diagnostic criteria and levels of evidence from treatment guidelines previously established, controlled clinical trials and standardized guides for adolescent and adult population with hyperprolactinemia. RESULTS: During the conformation of this guideline each specialist reviewed and updated a specific topic and established the evidence existent over different topics according their field of best clinical expertise, being enriched by the opinion of other experts. At the end, all the evidence and decisions taken were unified in the document presented here. CONCLUSIONS: It is presented the recommendations established by the panel of experts for diagnosis and treatment of patients with high levels of prolactin; also the level of evidence for the diagnosis of hyperprolactinemia, handling drug induced hyperprolactinemia and prolactinomas in pregnant and non-pregnant patients. PMID- 24779269 TI - [Functionality and endometrial changes associated with induction ovulation with citrate of clomifene and recombinant FSH in infertile women]. AB - It has been reported that infertility affects approximately 20% of couples in reproductive age around the world. Although many factors involved, ovulatory dysfunction and particularly the hypothalamus pituitary dysfunction are quite common. The first line treatment for these pathologies consists on the administration of inducing ovulation agents such as recombinant gonadotropins and clomiphene citrate which it was obtained high rates of ovulation but not of pregnancy. So determine the effect of these treatments on the endometrium at morphological and molecular level is very important to understand the female reproductive physiology and optimize clinical strategies to obtain better pregnancy rates after treatments. In this paper we detailed the studies that have reported changes at the molecular and morphological level in human endometrium. PMID- 24779270 TI - [Prenatal diagnosis of right aortic arch. Types of presentation and postnatal evolution]. AB - BACKGROUND: Right aortic arch is the most common abnormality of the aortic arch, excluding aberrant right subclavian artery. Its importance lies in its association with genetic syndromes, another important congenital heart defects, and that may cause clinical symptons from vascular rings. OBJECTIVE: Was to describe the prenatal clinical presentation, the correlation with postnatal findings and postnatal development of the fetus. METHODS: Observational retrospective analysis of 18 cases of right aortic arch diagnosed prenatally between the years 2005-2011. RESULTS: 5 pregnancies were interrupted because of ultrasound findings associated with poor prognosis. In 13 cases were term infants, with a good correlation between prenatal and postnatal findings, and the prognosis was excellent in cases in which the prenatal diagnosis of right aortic arch was isolated. CONCLUSIONS: In our experience, right aortic arch is a rare condition, but it can be associated with important congenital heart defects (heart disease or vascular rings) and/or other morphological anomalies in the fetus, in which case it should be ruled out chromosomal or genetic syndrome. If prenatally is considered an isolated finding, after careful ultrasound assessment by obstetricians and pediatric cardiologists, it is likely that evolution will be favorable postnatally. PMID- 24779271 TI - [Prenatal exclusion of von Hippel-Lindau syndrome in a Mexican family carrying a novel VHL gene mutation]. AB - BACKGROUND: von Hippel-Lindau (VHL) disease is an autosomal dominant and familial multisystemic syndrome that is caused by the inactivation of the VHL gene and it is characterized by diverse types of high vasculated tumours of benign and malign nature. In this work we describe the clinical characteristics and the prenatal diagnosis of a woman with VHL. OBJECTIVE: Describe the first exclusion prenatal case by DNA analysis of the VHL syndrome in Latinoamerican population. MATERIAL AND METHODS: Analysis of a Mexican familial pedigree showed 5 affected subjects with VHL on 3 consecutive generations. The proband was a 7 weeks pregnancy woman who was referred to our service for familiar and personal history of this disease. Maternal DNA was obtained from peripheral blood leukocytes, while fetal DNA was isolated from amniotic liquid cells on the 15th week. The maternal and fetal DNA analysis were done by the Polymerase Chain reaction (PCR) and the direct nucleotide sequence of the VHL gene. RESULTS: A novel mutation (c. 161_168 dup GGAGGCCG) in the VHL gene was identified in maternal DNA. Fetal DNA analysis indicated that the fetus inherited the wild-type allele from the mother. CONCLUSION: A novel VHL gene mutation was identified in a familial case of the disease, expanding the mutational spectrum in this disorder. The molecular prenatal testing in the affected woman at 15 weeks of gestation, demonstrated that the fetus did nor inherited the mutated allele. To the best of our knowledge, this is the first example of prenatal-molecular exclusion on VHL syndrome in Latinoamerica population. PMID- 24779272 TI - [Normal values of gases in the vein of the umbilical cord during the postpartum period and postcesarea immediately in normal fetuses to term]. AB - BACKGROUND: To be able to diagnose and catalogue a patient with imbalance of the acid basic condition a gasometria must be realized. The pH and the gasometria of the blood of umbilical cord are useful tools to study the immediate situation of the newborn child. The values gasometricos in the vein and the artery of the umbilical cord change according to the geographical altitude. OBJECTIVE: To identify the normal values of the venous gases of the umbilical cord in the postpartum immediate one of normal fetuses to term, born by obstetric resolution, without hurt, in the Spanish Hospital of the Mexico City and to identify the difference with the considered normal values for other institutions of different conditions of the Mexican Republic located to different altitudes. MATERIAL AND METHOD: Transversal, prospective, descriptive and observacional study effected in the service of Obstetrics of the Hospital Espanol of Mexico (Maternidad Mundet). All the patients were included pregnant woman of term, with pregnancy of normal evolution, with an obstetric resolution without evidence of foetal hurt that they deposited with labor or for elective Caesarean. RESULTS: The average of the curves of normal distribution of the pH, of the PCO2, of the HCO3, of the PO2, of the base excess and of the foetal hemoglobin they were: 7.34, 39.3081, 20.66, 29.3529,-4.09 and 15.18, respectively.The distribution curves of the analyzed values were normal, in no.case there was asymmetry, with a not significant Kolmogorov. CONCLUSIONS: The gasometric of the cord is a simple, practical method and, especially I target to value the foetal condition intraparto. The values found in our analysis do not demonstrate statistically significant differences with the values of other studies effected to minor altitudes that that of the Mexico City. The analysis that here one presents is a partial check of the final sample that will belong 300 individuals. PMID- 24779273 TI - [Malignant ovarian germ cell tumors. Current status of diagnosis and treatment]. AB - Malignant ovarian germ cell tumors (MOGCT) are extremely aggressive and rapidly growing neoplasms, with a peak incidence occurring in adolescent girls and young women. Its incidence in Mexico is three times higher than the observed in Western countries and the United States. Dysgerminoma, immature teratoma, yolk salc tumor, and mixed germ cell tumors make up more than 90% of all MOGCT. PMID- 24779274 TI - [A case study of anaphylaxis in a pregnant woman]. AB - We report a case of anaphylaxis in a 35+5 week of pregnancy patient who came to the Emergency Room with shortness of breath, hypotension and loss on fetal wellbeing. Due to her medical history and given the clinical picture at that time, an anaphylactic shock was suggested as the most probable diagnose. The administration of dexchlorpheniramine and methylprednisolone resulted in an immediate and positive reaction. Simultaneously, an improvement in the fetus cardiotocographic record was objectified. The patient was hospitalized for 48 hours, after which she was discharged. In case of suspicion of anaphylaxis in a pregnant woman, four aspects should be handled: the severity of the anaphylaxis chart, individual complications regarding a pregnant woman, unfavorable effects of the regularly used treatment during that specific gestation, and the need of fetal extraction based of gestational age. PMID- 24779275 TI - [Modification of the obstetric hysterectomy in placental acretism]. AB - Acretismo is a condition of abnormal placentation, in which the villi invade the myometrium at the implantation site, Representing a risk of massive obstetric hemorrhage with possible alterations of the coagulation, besides to the damage to other organs. Moving forward even to his death, so it is a challenge for the obstetric services, to make a correct diagnosis and in a timely manner, along with the programming of the interruption of pregnancy, as well as the utilization of proper surgical techniques and the involvement of a multidisciplinary team to the possible complications. The following describes a surgical technique modified for patients with a diagnosis of acretismo placentario, used in the Hospital General de Occidente in Jalisco, Mexico from 1 year ago, presenting two clinical cases of patients who underwent surgery with this technique, considering it necessary to present up to the moment a significant decrease in the amount of bleeding, zero days stay of patients in intensive care, any complications in the mother as well as in the product, and more importantly, it has remained at the hospital with no maternal death by this pathology in the last year, considering the nature of being a referral hospital for the whole entity by the Servicios de Salud Jalisco. It is necessary to consider the risks/benefits in the short, medium and long term for the institution, the mother and the product, allowing present good practices that will impinge on the permanent reduction of the maternal death by this pathology. PMID- 24779276 TI - [Tuberculosis in perinatal stage. A challenge to the binomial care mother-son. Report of two cases]. AB - Case report of 18-year old female patient with clinical signs of pulmonary tuberculosis during pregnancy at beginning of fourth month into term, with airway impairment, as evidenced by dry cough, fever and night sweats, as well as a 6 kg. weightloss. Twenty-two days after giving birth, the patient was hospitalized with high fever and deteriorated health conditions, requiring treatment in the intensive care unit due to complications such as severe malnutrition, septic shock, pulmonary abscess, pachypleuritis, empyema and bronchopleural fistula. The tuberculosis diagnosis was established through ABF identification with Ziehl Neelsen stain of the pleural fluid. The patient was hospitalized for 42 days, including eleven days on a mechanical ventilator, before being discharged. Her newborn daughter was admitted to the Pediatric Intensive Care Unit on the 19th day of life due to coughing, fever, difficulty in breathing, liquid stool and rejecting food. The newborn was hospitalized in the newborn intensive care unit for twenty-two days, developing major sepsis and multiple organ failure, which complications led to her death. An autopsy was conducted, revealing granulomatous lesions consistent with tuberculosis in lungs, liver, small intestine, large intestine and peritoneum; additionally the PCR of bronchial aspirate was positive to Mycobacterium tuberculosis DNA. PMID- 24779277 TI - [Psychoprophylactic childbirth without pain. 20 personal observations. 1958]. PMID- 24779278 TI - Adolescents: which risks for their life and health? AB - This paper reviews emerging research findings related to the biological, behavioral, psychological and social processes that occur during adolescence. New research makes it possible to identify interactions among brain structures, hormonal production and behavioral impulses, that underpin and explain the connections with serious problems emerging during adolescence: behavioral disorders, substance abuse, risky sexual conduct, violence and other social disorders. PMID- 24779279 TI - Stress among medical Saudi students at College of Medicine, King Faisal University. AB - BACKGROUND: Sources of student stress can be academic pressures, social or personal issues and medical students have to face the challenge of rigorous curriculum and also have to learn how to deal with emotionally difficult experiences. AIM OF WORK: Determination of the prevalence of stress and to identify the risk factors of stress among Saudi medical students at Faculty of Medicine, King Faisal University, Saudi Arabia. METHODS: A survey study design was conducted among medical students at Faculty of Medicine, King Faisal University, Al Ahsaa Governorate, Eastern Province from February-May, 2013. Both male and female students were invited to participate in our study. The total number of students was 650 Saudi medical students, out of them 244 medical students were participated in the current study. All participants were provided a self administered questionnaire. A likert scale with 3 points for responses was used. Questionnaires were given to participants 2 month before end-semester examinations, to minimize the extra stress symptoms A score of stress was calculated. RESULTS: Prevalence of stress was 53% among Saudi students. Gender has no role in stress among medical students (p > 0.05). Logistic regression analysis revealed the most important risk factors of stress, having places for recreation at the University showed a relationship with stress among medical students with a p value = 0.000, there is a statistically significant relationship between stress and having optimal place for studying outside the university p = 0.001, while, comparing number of sleeping hours with stress, we could not find a statistically significant relationship among medical students, p = 0.744. Medical students who had close friends to share with them their stresses and concerns showed a highly statistically significant relationship between stressed and unstressed students p = 0.001. CONCLUSION: Medical students reported high levels of stress. The most frequently occurring stressors among the students were related to academic and psychosocial domains. The associations between stressed cases and gender, occurrence of academic and psychosocial stressors need to be further tested by prospective studies. PMID- 24779280 TI - Prevalence survey of healthcare-associated infections and antimicrobial use at the University Hospital "Paolo Giaccone", Palermo, Italy. AB - INTRODUCTION: Healthcare-associated infections (HAIs) and antimicrobial resistance are well known major public health threats. The first goal of our study was to describe the prevalence of HAI, while the second goal was to describe the antibiotic consumption at our University Hospital, "P. Giaccone" in Palermo, Italy. METHODS: A standardized methodology for a combined Point Prevalence Survey (PPS) on healthcare-associated infections (HAIs) and antimicrobial use in European acute care hospital developed by the European Centre for Disease Prevention and Control (ECDC) was piloted across Europe. The teaching Hospital "P. Giaccone" in Palermo, Italy, participated in the study. RESULTS: Out of 328 surveyed patients, 12 (3.6%) had an HAI and 159 (48.5%) were receiving at least one antimicrobial agent. Prevalence results were highest in intensive care units, with 17.6% patients with HAI. Bloodstream infections represented the most common type (50%) of HAI. Surgical prophylaxis was the indication for antimicrobial prescribing in 59 (37.1%) out of 159 patients and exceeded 24 hours in 54 (91.5%) cases. DISCUSSION: The results suggest that in our hospital there was a frequent and inappropriate use of antimicrobials, especially in the setting of surgical prophylaxis. PMID- 24779281 TI - Staphylococcus aureus infections in children in an Iranian referral pediatric hospital. AB - INTRODUCTION: Staphylococcus aureus is associated with various infections ranging from skin and soft tissues such as surgical site infections and abscesses to lower respiratory tracts and bloodstream. The aim of this study was to evaluate underlying condition of patients with S. aureus infections in an Iranian referral pediatric Hospital. MATERIAL AND METHODS: Information was extracted retrospectively from the medical records of patients who were diagnosed with S. aureus infections. Data obtained about the study subjects included basic demographics, reason for admission, culture site, length of hospital stay, and methicillin susceptibility. RESULTS: The underlyning condition of of patients with S. aureus infection during November 2011 and March 2013 were included in the study. The most frequent diagnosis in patients with S. aureus infection was jaundice (12%), abscess (10%), cellulitis (10%), wound infection (8%), septic arthritis (7%) and sezeire (5%). Wound was the most common infection sites among all subjects 34/98 (35%) following by blood (20/98, 20%) as well as skin and soft tissue (19/98, 19%). The proportion of MRSA infections among all S. aureus isolates was 79% (77/98) during the study period. In addition, 58/74 (78%) met the definition of Hospital-Associated Methicillin-Resistant S. aureus (HA-MRSA) infections and the rest; 20/24 patients (83%), were classified as Community Associated Methicillin-Resistant S. aureus (CA- MRSA). CONCLUSION: In our study, the high frequency of MRSA was found not only in HA S. aureus but also in CA S. aureus isolates; therefore, the strategic goals to optimize antimicrobial use including PMID- 24779282 TI - Social and interpersonal relationship modifications after renal transplant. A statistic and epidemiologic evaluation. AB - INTRODUCTION: Kidney and liver transplants are the most frequent transplantation procedures carried out in Italy. We report the result of an epidemiological study on kidney transplanted patients resident in the Province of Messina (Italy). METHODS: Seventy-five patients were enrolled between June 2010 march 2011, interviewed and evaluated using an adapted Italian version short-form 36. Socio economic characteristics, quality of life modifications and involvement in transplant-related charities were studied. The follow-up period was ranging between 52 and 356 months. All subjects gave written informed consent and all results were analysed by chi-square test. RESULTS: No statistically significant differences were found between sexes, social and interpersonal relationship modifications. DISCUSSION: The benefits obtained on quality of life after transplantation is the prerogative of a small percentage of patients and is related to medium and high socio-economic conditions. The possibility of avoiding the haemodialysis represents the primary benefit for the totality of patients. PMID- 24779283 TI - A study on occupational exposure of Sicilian farmers to Giardia and Cryptosporidium. AB - INTRODUCTION: A cross-sectional study was undertaken to determine the prevalence of Giardia and Cryptosporidium in calves of Palermo area (Sicily) and to evaluate the occupational risk associated with occurrence of zoonotic genotypes. METHODS: A total of 217 faecal samples, from 149 calves (between 2 and 240 days of age) and 68 farmers, were collected in 19 cattle-farms of Palermo area. A questionnaire regarding demographic characteristics and personal hygienic measures was submitted to all farmers. All faecal samples were analyzed by Immunofluorescence assay and Polimerase Chain Reaction (PCR); genotypes were determined by DNA sequencing of Triose Phosphate Isomerase gene for Giardia and Small Subunit Ribosomal RNA gene for Cryptosporidium. RESULTS: None farmer tested was positive for Giardia and Cryptosporidium, whereas these protozoa were respectively detected in 53 (including 5 with zoonotic G. duodenalis genotype A) and 17 (of which 1 with zoonotic C. ubiquitum) of the examined calves. DISCUSSION: The results indicate that the risk of transmitting both protozoa to farmers in Palermo area is negligible although it cannot be considered null because of identification of human genotypes/species in calves. PMID- 24779284 TI - Psychosocial predictors of barriers to cervical cancer screening among Iranian women: the role of attachment style and social demographic factors. AB - OBJECTIVES: Despite advances in screening and treatment during past several Decades, cervical cancer remains a major health problem for Iranian women. Recent researches have focused on factors related to development of health behavior in an effort to design effective early interventions. The current study aimed to investigate the role of attachment styles on cervix cancer screening barriers among women of Bandar Abbas-Iran. METHODS: In an analytic-cross sectional study, 681 women aged 21-65 referring to health centers were selected randomly and after completing written informed consents were investigated by Revised Adult Attachment Scale (RAAS) (Collins and Read), Pap smear screening barriers and demographic data questionnaire. The data were analyzed by Pearson correlation coefficient, linear regressions and chi-square test. RESULTS: The results showed significant association between attachment styles and screening barriers. There was a negative significant relation between secure attachment style and screening barriers and there was a positive significant association between insecure attachment style (anxiety and avoidant) and screening barriers. The regression analysis indicated that insecure attachment style (avoidant) were predictors of barriers to the Pap smear screening test in this regard. There was a significant association between age and residential area and participation in Pap smear test. CONCLUSIONS: Insecure attachment style is associated with hazardous risk behaviors and these results can be useful for health service providers in preventive planning of screening and identification of people susceptible to risk and the design of the intervention. PMID- 24779285 TI - Antimicrobial potential of Sicilian honeys against commensal Escherichia coli and pathogenic Salmonella serovar infantis. AB - INTRODUCTION: The purpose of this study was to investigate the antibacterial effect of 71 locally produced honeys from different botanical sources collected from apiarist's open markets in Sicily. METHODS: Antimicrobial activity was determined against Escherichia coli (ATCC 25922) and Salmonella serovar Infantis (ATCC 1523) by an agar-diffusion assay from the estimation of the diameter of the inhibition zone produced by the honeys. Statistically) significant differences (P < .000) regarding inhibition were observed for the honeys tested. RESULTS: The chestnut and polyfloral honey samples exhibited the largest and highest inhibition (diameter of the inhibition zone > 25 mm) against both E. coli and S. Infantis. The honey of oregano origin showed intermediate or low activity against E. coli and S. Infantis, respectively. Prickly pear and erica honeys showed no antimicrobial activity against the two reference strains. DISCUSSION: The results may partially suggest the usefulness of the Sicilian honeys on treating multi resistant enterobacteria. In light of the enormous potential for application of honey in the clinical practice, it is important that research continues not only into those honeys well recognized as antimicrobial, but also into other locally produced and yet untested honeys. PMID- 24779286 TI - Prospects application of polypyrrole-based immunosensor to Porphyromonas gingivalis quantification in subgingival plaque samples. AB - BACKGROUND: Periodontitis still poses a serious threat to oral and systemic health condition of humans. The proportion of the main pathogenic bacteria change in localized sites was associated with the initiation of the disease process. However, the limitations of microbiological diagnostic aids rendered the diagnosis of active periodontitis status point-of-care or chair-side based on microbiological data difficult. METHODS: Porphyromonas gingivalis, a major putative etiological agent in the initiation and progression of chronic periodontitis, was used as the experimental subject. An immunosensor based on polypyrrole-coated interdigitated array microelectrodes was developed to quantify Porphyromonas gingivalis in pure culture, gingival crevicular fluid and saliva samples. The regression equation for the normalized impedance change (NIC) versus Porphyromonas gingivalis concentration (C) was measured. The correlation between results of the immunosensor and quantitative real-time PCR method in quantifying Porphyromonas gingivalis in subgingival plaque samples was evaluated. RESULTS: Results of the study revealed that the lowest detection limits of the immunosensor was 1.9 x 10(4), 2.7 x 10(5), and 2.7 x 10(6) cells/mL in pure culture, gingival crevicular fluid, and saliva samples respectively. The values determined using the immunosensor strongly correlated with those obtained using quantitative real-time PCR method (R2 = 0.91, p < 0.05). The immunosensor did not require any labels and amplification steps, and the total detection time from sampling to measurement was less than one hour. CONCLUSIONS: The immunosensor developed in the present study offered some insight into monitoring the change in the number of periodontal bacteria chair-side during routine clinical practice. PMID- 24779287 TI - Clinical utility of a quantitative Rose Bengal slide agglutination test in the diagnosis of human brucellosis in an endemic region. AB - BACKGROUND: Brucellosis currently ranks as the most important zoonotic disease in the world. Brucellosis is difficult to diagnose because patients often have nonspecific clinical symptoms that can be attributed to a number of disease agents prevalent in the area. Thus, this has necessitated the dependency of clinicians on microbiological confirmation, very often by sero diagnostic methods. Early and accurate detection of brucellosis is important if specific antibiotic treatment is to be effective for the patients. The use of RBST as a qualitative means of diagnosis is quiet common. However, to date, there are only a handful of reports of the application of RBST as a quantitative diagnostic method in medical literature. The potential usefulness of quantitative Rose Bengal slide agglutination test (RBST) for suspected brucellosis was evaluated as a simple, inexpensive diagnostic tool to be used in clinical practice in an endemic region. METHODS: 200 consecutive patients who reported to Belgaum Institute of Medical Sciences (BIMS) Hospital, Belgaum, Karnataka (India) between June 2009 and December 2011 were studied. Standard RBST, quantitative RBST, standard tube agglutination test (SAT), 2-mercaptoethanol test (2-ME), and blood cultures were carried out on all patients. The case was confirmed as positive for brucellosis if any one of the tests was positive and the data was compared to the quantitative RBST considering blood culture result as gold standard. RESULTS: B. melitensis was cultured in only 28% of the patients in this study. In patients with negative blood cultures, serology was used for diagnosis. The sensitivities were 88.9% (standard RBST), 92.6% (SAT), and 57.4% (2ME). The specificities were found to be 87.7% (standard RBST), 86.2% (SAT), and 95.7% (2ME). RBST titers > or = 1:8 were detected in a majority of patients (50, 74%) with bacteriologically proven brucellosis thereby guiding clinician for prompt therapy. Prozone reaction with RBST observed in 4 patients was an interesting finding and these four true cases would have been underdiagnosed and denied therapy on the basis of qualitative/standard RBST alone. The possibility of prozone in patient's serum with high RBST antibody titers can be avoided by testing several dilutions. CONCLUSIONS: This technique has an immense value particularly for use in resource poor settings seen in rural areas. It can deliver definitive diagnosis in < 10 minutes to the clinician, which may in turn result in the early initiation of specific treatment and could be applied thus as a bedside methodology. It is not technically demanding and easy to interpret, does not involve heavy capital outlay, or trained personnel and, thus, is potentially useful in resource poor laboratories, particularly in developing regions. In addition, quantitative RBST demonstrates sensitivity and specificity equivalent to that achievable by performing SAT. It can readily be extended to screen a vast number of blood samples particularly in areas where brucellosis is hyperendemic. Quantitative RBST and 2ME have been noted to be of great value in therapeutic monitoring. Our data suggest that RBST titers in a range of 1:8 and 1:16 can undoubtedly be considered diagnostic of brucellosis in conjunction with compatible clinical and epidemiological evidence for the patients residing in areas endemic for the disease. Quantitative RBST is, therefore, recommended for routine use in clinical microbiology laboratories as an accurate and speedy diagnostic assay. PMID- 24779288 TI - Ultrasonic oscillation dialysis-graphite furnace atomic absorption spectrometer method for determination of "free" copper and exchangeable copper in serum. AB - BACKGROUND: The determination of copper (Cu) in human blood is important in medical diagnosis. However, its biological activities strongly depend on the chemical forms, and thus data for total Cu concentration is not sufficient for medical diagnosis or mechanism study. Therefore, analyses of copper species in serum have much more physiologically meaningful. METHODS: Ultrasonic oscillation dialysis procedure was introduced in the determination of "free" Cu, more precisely PBS dialysis Cu (DiaCu), and exchangeable Cu (EXCu) by graphite furnace atomic absorption spectrometry (GFAAS). Then the levels of serum "free" Cu and EXCu from hepatitis, liver cancer, and cervical cancer patients were determined. RESULTS: The accuracy of the method ranged from 92% - 97% for PBS DiaCu and 90% - 107% for EXCu when using a dialysis membrane pore size of 25 kDa. The regression equation of the calibration curve was expressed as y = bChi + a, with linear regression coefficients (r2) of 0.9999 for ultrapure water and 0.9998 for PBS buffer and EDTA buffer. The limit of detection is 0.76 microg/L. Application of this method to serum samples showed that the levels of"free" Cu and EXCu in serum changed in various pathophysiological conditions. CONCLUSIONS: Ultrasonic oscillation dialysis-GFAAS method described here for the speciation of "free" Cu and EXCu in serum is simple with good reproducibility and small sample volume. PMID- 24779289 TI - Effects of the C161T polymorphism in the gene of peroxisome proliferators activated receptor gamma on changes of plasma lipid and apolipoprotein ratios induced by a high carbohydrate diet in a healthy Chinese Han young population. AB - BACKGROUND: Changes in the ratios of plasma lipids and apolipoproteins may be associated with diets and the C161T polymorphism in the gene of peroxisome proliferators activated receptor gamma (PPARgamma). As a result, this study was to investigate the effects of this polymorphism on changes of the ratios induced by a high-carbohydrate (high-CHO) diet. METHODS: After a washout diet of 54% carbohydrate for 7 days, 56 healthy young adults (22.89 +/- 1.80 years old) were given the high-CHO diet of 70% carbohydrate for 6 days. Height, weight, waist circumference (WC), glucose, triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (apo) AI, and apoB100 at baseline and before and after the high-CHO diet were measured. Body mass index (BMI), TG/HDL-C, log (TG/HDL-C), TC/HDL-C, LDL-C/HDL-C, and apoB100/apoAI were calculated. PPARgamma C161T was detected by a PCR-RFLP method. The relationship between the polymorphism and the ratios were analyzed. RESULTS: The female T carriers had higher BMI and WC than the female CC homozygotes at baseline and before and after the diet, higher glucose, TG/HDL-C and log (TG/HDL-C) before the diet. In males, when compared to the T carriers, the CC homozygotes had higher TG/HDL-C, log (TG/HDL-C) and apoB100/apoAI at baseline and before and after the diet, higher glucose at baseline, higher LDL-C/HDL-C and TC/HDL-C before and after the diet. Compared with those before the high-CHO diet, TC/HDL-C and LDL-C/HDL-C decreased after the diet regardless of gender and the genotypes. Decreased BMI and WC were observed in the male CC homozygotes but only decreased BMI in the female T carriers. Notably, decreased apoB100/apoAI was observed in the male T carriers, while elevated TG/HDL-C and log (TG/HDL-C) in the female CC homozygotes, and reduced glucose in the female T carriers. CONCLUSIONS: The results suggest that the interplay of gender, the PPARgamma C161T polymorphism and the high-CHO diet can change not only the ratios of plasma lipids and apolipoproteins but also the association of the ratios with plasma glucose, WC, and BMI in healthy Chinese young adults. Once confirmed by larger sample size and multi-center trials, the findings will provide a new scientific basis for personalized dietary intervention for the subjects with different PPARgamma C161T genotypes to reduce risks of CAD, especially in a country with a quarter of the world's population. PMID- 24779290 TI - The role of N-terminal proBNP in the clinic scoring of heart failure due to dilated cardiomyopathy in children. AB - BACKGROUND: We aimed to show sensitivity and specificity of NT-ProBNP in demonstrating the degree of cardiac failure caused by dilated cardiomyopathy (DCMP). METHODS: From January 2006 to July 2012, thirty patients (2 - 168 months) who had DCMP with acute heart failure and 37 healthy children aged (1 - 168 months) were enrolled in this study. Clinical evaluation was done using a modified Ross scoring system. Ross scoring was done before and after treatment. Patients with a score of > 2 points were included in the study. Ross scoring, echocardiographic parameters, serum NT-ProBNP levels and cardiothoracic index (CTI) were measured before and on the 7th day of treatment. Patients were divided into 3 groups according to degree of heart failure. RESULTS: While the change in logNT-ProBNP in the patient group following one-week of treatment was significant (p < 0.05), there was no marked significance in the changes in EF, FS, LVEDD, LVMIz, and CTI. There was a statistically significant difference between logNT ProBNP levels each Ross clinical group not only before treatment but also on assessment on the 7th day of treatment in the patient group (p < 0.001, Tukey's and Tamhane's T2 post-hoc tests). No significant difference was detected between EF, FS, LVEDDs, LVMIz, and CTI and the stages of acute cardiac failure. The NT ProBNP levels of patients who became clinically asymptomatic after treatment but still had left ventricular systolic dysfunction were statistically significant when compared to the control group. The cut off value to distinguish healthy children from the patients with left ventricular systolic dysfunction caused by cardiomyopathy was found as 174.3 pg/mL. CONCLUSIONS: NT-ProBNP levels are more effective than conventional echocardiographic parameters for clinical determination of the stage of cardiac failures in children with left ventricular systolic dysfunction due to DCMP. Therefore, it can be used for determining the treatment and management of such patients. Furthermore, the test is simple and beneficial, because of its availability in most clinical chemistry laboratories and its advantage of allowing frequent measurements and assessments. PMID- 24779291 TI - Telbivudine during the second and third trimester of pregnancy interrupts HBV intrauterine transmission: a systematic review and meta-analysis. AB - BECKGROUND: Evaluate the efficacy and safety of telbivudine during the 2nd and 3rd trimester of pregnancy in intrauterine transmission of hepatitis B virus (HBV). Based on the principle of Cochrane systematic reviews, a database was constructed from Medline, EMBASE, Cochrane Library, the US National Science Digital Library (NSDL), the China Biological Medicine Database (CBM-disc), and contact with Chinese experts in the field from November 2006 to February 2013. METHODS: The Critical Appraisal Skills Programme (CASP) of Oxford, Cochrane Collaboration's tool, and Review Manager Version 5.0 (Rev-Man 5.0) for assessing the quality of clinical trials, risk of bias, and statistical analysis was used. We analyzed the effects and safety of telbivudine treatment on intrauterine mother-to-child transmission (MTCT) of HBV from HBsAg and HBV-DNA positive mothers. All newborns received an immune prophylaxis schedule consisting of simultaneous hepatitis B virus vaccine and hepatitis B immunoglobulin (HBIG) postpartum. Of 32 studies, 7 studies fulfilled the inclusion criteria in the study. RESULTS: Either the Mantel-Haenszel or Inverse Variance fixed-effects model or Mantel-Haenszel or Inverse Variance random-effects model was applied for all analyses indicated by odds ratio (OR) and 95% confidence interval (CI). The meta-analysis based on new onset of HBsAg seropositivity of infants at 6-12 months postpartum revealed that the control group had an intrauterine transmission rate of 8.25-42.31%. This rate was reduced to 0-14.29% in the telbivudine treatment group (OR 0.09, 95% CI 0.04-0.22, including seven trials, p < 0.001). The rates of intrauterine transmission based on new onset of HBV DNA seropositivity of infants at 6-12 months postpartum were 8.25-19.23% in the control group and 0 - 3.57% in the treatment group (OR 0.07, 95% CI 0.02-0.22, p < 0.001, including only five trials, since two trials had no data on HBV DNA in infants). With the exception of CK elevations, adverse effect frequencies were similar in both groups. CONCLUSIONS: Telbivudine is an effective and safe drug for preventing intrauterine transmission of HBV. PMID- 24779292 TI - Diagnostic accuracy of Golgi protein 73 in primary hepatic carcinoma using ELISA: a systematic review and meta-analysis. AB - BACKGROUND: Primary hepatic carcinoma (PHC) is currently one of the most common worldwide causes of cancer death. Golgi protein 73 (GP73) has been proposed as potential diagnostic marker. However, it is controversial because of inconsistent diagnostic accuracy in different studies. The aim of this study was to assess the diagnostic accuracy of GP73 for PHC. METHODS: All the studies relating to the diagnostic accuracy of GP73 for patients with PHC from 1978 to January 2013 were collected. Methodological quality was assessed by Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). The overall diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate the diagnostic accuracy of GP73 using Meta-DiSc statistical software. RESULTS: Altogether 5,637 subjects were included in the 25 selected studies. The sensitivity and specificity (95% confidence interval) of GP73 was 0.75 (0.73 0.76) and 0.84 (0.83 - 0.86), respectively. The area under the summary receiver operating characteristic curve (AUC) and Q* index of GP73 was 0.8616 and 0.8021. CONCLUSIONS: Serum GP73 has a relatively high diagnostic accuracy in primary hepatic carcinoma with better sensitivity and high specificity than AFP. PMID- 24779293 TI - Changes in oxidative stress parameters and antioxidant status in lung cancer: Western blot analysis of nitrotyrosine and protein carbonyls content. AB - INTRODUCTION: The source of many diseases, including tumors, lies in an increased generation of reactive oxygen species resulting in oxidative stress. We investigated the relationships between advanced oxidation protein products (AOPPs), nitrotyrosine (NT), protein carbonyls (PCO) content, and the prooxidant antioxidant balance (PAB) in patients with lung cancer. METHODS: A total of 14 age-matched healthy controls, 14 subjects with non-lung cancer pulmonary disease, and 41 patients with lung cancer were included in this study. Spectrophotometry was used to examine plasma AOPP, serum FRAP, and PAB, while serum PCO and NT were assessed with western blot analysis. RESULTS: A significant difference in AOPP levels were found between patients and controls (p < 0.01). Also, there was a highly significant difference in NT levels between patients and controls (p < 0.001). PAB showed negative correlation with albumin (r = -0.340, p = 0.011) and positive correlation with CRP (r = 0.342, p = 0.011). AOPP, albumin, gender, and smoking were the significant independent variables found by backward stepwise multiple logistic regression (MLR) analysis method. MLR analysis revealed that AOPP was the variable that had a significant effect on lung cancer [(p = 0.006, OR = 1.074, (95% CI) (1.020-1.131)]. CONCLUSIONS: The use of non-invasive diagnostic biochemical parameters would represent a very important contribution to our diagnostic armamentarium in lung cancer, considering the high incidence of this deadly disease. In this regard, AOPP and NT levels have appeared to play a prominent role, although further studies are certainly warranted. PMID- 24779294 TI - Detection of trisomy 4 and 10 in Egyptian pediatric patients with acute lymphoblastic leukemia. AB - BACKGROUND: Improvement in cure rates for children with acute lymphoblastic leukemia (ALL) has focused attention on better methods of identifying patients with increased or decreased risk of treatment failure. Chromosome aberrations have a major role in pediatric ALL risk assessment. The aim of this work is to detect the frequency of trisomy 4 and 10 in Egyptian pediatric ALL patients and to analyze their possible prognostic significance. METHODS: Forty newly diagnosed pediatric ALL patients were subjected to bone marrow aspirate morphological examination and immunophenotyping. Detection of copy number of chromosome 4 and 10 was done using Fluorescence In Situ Hybridization (FISH) technique using whole chromosome painting probes. RESULTS: Combined trisomy 4 and 10 was detected in 7 cases (17.5%), all of them were of B-ALL type. Single trisomy 4 or 10 was not detected in any case. Trisomy positive patients had a statistically significant lower total leucocytic count (p = 0.041), higher platelet count (p = 0.018), and lower blast percentage in peripheral blood (p = 0.016) at diagnosis. CONCLUSIONS: Combined trisomy 4 and 10 identifies a group of ALL patients that have good prognostic indicators. Screening of Egyptian pediatric ALL patients for trisomy 4 and 10 may help in "patients' stratification" aiming to develop a risk-adapted therapy in order to minimize therapy related morbidities particularly in children. PMID- 24779295 TI - Evaluation of nosocomial blood stream infections caused by Pseudomonas species in newborns. AB - BACKGROUND: Nosocomial blood stream infections (NBSI) are a significant hazard in health care facilities, exacting a tremendous toll and causing increased morbidity, mortality, and increased length of hospital stay and health care costs. METHODS: In this article, we report the results of a retrospective cohort study to describe the epidemiology of pseudomonas NBSI in infants admitted to one Turkish neonatal intensive care unit (NICU) during the 5-year period 2006-2010. In this period, Pseudomonas spp. were isolated from the blood cultures of 28 patients. RESULTS: Pseudomonas putida (n = 12) was a causative microorganism at 42.8% of these infants, while Pseudomonas aeruginosa (n = 9) was determined in 32%. Sixty-five percent (n = 18) of the infants were below 32 weeks. The median age at diagnosis was 7 days (4-16). Mechanical ventilation (> 48 hours) rate was 89.2% (n = 25) and umbilical catheterization rate (> 48 hours) was 29.2% (n = 9). Imipenem resistance was detected in 53.5% (n = 15) of all cases. Median length of hospital stay was 15 days (8-29) with a mortality rate of 28%. Five of the infants who died had associated disorders such as Di George syndrome, anal atresia, necrotizing enterocolitis, and respiratory distress syndrome. CONCLUSIONS: We may say that pseudomonas infections are still an important cause of nosocomial sepsis and mortality in NICUs. Low birth weight and invasive procedures may be predisposing factors for pseudomonas infections. Mortality was associated with underlying disorders. PMID- 24779296 TI - Suppression of T-type Ca2+ channels inhibited human laryngeal squamous cell carcinoma cell proliferation running title: roles of T-type Ca2+ channels in LSCC cell proliferation. AB - BACKGROUND: Despite the tight correlation between T-type Ca2+ channels and a great variety of tumors, the roles of alpha1G subunit of T-type Ca2+ channels in laryngeal squamous cell carcinoma (LSCC) have not yet been investigated. METHODS: In the present study, we examined the expression of alpha1G subunit of T-type Ca2+ channel in human LSCC tissues and cell lines. One human laryngeal squamous cell carcinoma cell line, Hep-2, was also examined for T-type channels using voltage-clamp recordings. Cell proliferation assays were performed in the presence or absence of T-type channel blocker mibefradil and alpha1G subunit sepcific siRNA. The cell cycle was determined by flow cytometry. RESULTS: Our results indicated that the a1G subunit of T-type Ca2+ channel is highly expressed in human laryngeal squamous cell carcinoma tissues and cell lines. alpha1G siRNA significantly down-regulated the protein expression of the alpha1G subunit. Both alpha1G siRNA and mibefradil inhibited Hep-2 cell proliferation and arrested cell cycle progression. CONCLUSIONS: Together, these findings suggest a functional role of T-type channels in certain laryngeal carcinomas, and that inhibition of T type channels reduces cell proliferation via cell cycle arrest, suggesting that the alpha1G subunit of T-type Ca2+ channel may be used as a therapeutic target for treating LSCC. PMID- 24779297 TI - Analysis of combined CSF biomarkers in AD diagnosis. AB - BACKGROUND: The new proposed diagnostic criteria for early diagnosis of Alzheimer's Disease (AD) underline the value of cerebrospinal fluid (CSF) biomarkers. The first aim of the study was to determine the diagnostic accuracy of CSF biomarker Abeta1-42, T-tau, and P-tau in differentiating AD patients in our cohort by means of "pure" biomarkers and in form of a combined analysis of these biomarkers. The second aim of the study was to determine the diagnostic accuracy of these markers for predicting incipient AD in patients with mild cognitive impairment (MCI). METHODS: We studied 102 CSF samples: 33 AD [mean age at baseline 71.2 (54-86)], 16 MCI [mean age at baseline 71.3 (57-78)], 24 non AD dementia, including 7 vascular dementia, 4 frontotemporal degeneration, 5 dementia with Lewy Body, and 8 with other dementia [mean age at baseline 72.7 (51 87)] and 32 non-demented neurological patients [mean age at baseline 71.3 (45-87) referred to as control (CO) later in the text]. A double sandwich ELISA (Innotest beta amyloid Abeta1-42, hTau and P-tau181 by Innogenetics, Gent, Belgium) was performed to quantify the concentration of the above biomarkers. The three biomarkers were then combined in the IATI index [(measured Ab1-42)/(240 + 1.18 *measured tau)], and in the ratios Abeta1-42/T-tau, Abeta1-42/P-tau, T-tau/Abeta1 42 and P-tau/Abeta1-42. RESULTS: Abeta1-42, T-tau and P-tau181 concentration showed statistically significant differences between AD and CO (327.2 pg/mL +/- 150.2 pg/mL and 659.4 pg/mL +/- 254.2 pg/mL; 508.2 pg/mL +/- 360.2 pg/mL and 305.3 pg/mL +/- 228.9 pg/mL; 82.2 pg/mL +/- 26.1 pg/mL and 45.3 pg/mL +/- 26.4 pg/mL, respectively, p < 0.05), while the difference between AD and MCI was statistically different only for Abeta1-42 (327.2 pg/mL +/- 150.2 pg/mL and 600.8 +/- 271.9 pg/mL, respectively, p < 0.05). The IATI index was 0.5 +/- 0.3 in AD, 0.9 +/- 0.6 in MCI, 1.37 +/- 0.9 in non AD dementia and 1.26 +/- 0.8 in non demented neurological patients. With a cut-off fixed at 1 the sensitivity and specificity of the IATI index in discriminating AD from CO was 84% and 52%, respectively. CONCLUSIONS: This study confirms the great significance of CSF biomarker measurements in AD diagnosis in clinical routine. It is understood that a clinical diagnostic work-up is necessary in the process. Moreover, a biochemical profile of CSF biomarkers requires further investigations. PMID- 24779298 TI - Evaluating the performance of urine conductivity as screening for early stage chronic kidney disease. AB - BACKGROUND: This study aimed to determine if urine conductivity (Cond) is better for screening early stage chronic kidney disease (CKD) instead of the currently routinely used parameters of urine creatinine (UCr), urine osmolality (Osmo), urine specific gravity (SpGr), and urine protein (UP). METHODS: One hundred and forty participants (86 male, 54 female) with eGFR > 60 were grouped as either early stage CKD (kidney damage longer than 3 months with either structural or functional abnormalities [n = 72]) or the control group (without CKD and without kidney damage or functional abnormalities [n = 681]). Sensitivty (Sn) and specificity (Sp) of UP and the ROC curves were calculated. The area under the curve (AUC) with 95% confidence interval (CI) was used to compare Cond, UCr, Osmo, and SpGr. Pearson's correlation was used to analyze the correlation between Cond and UCr, Osmo, and SpGr in the early stage CKD group. RESULTS: The Sn and Sp of UP were 22.2% and 92.6%, respectively. By ROC analysis, Cond had the largest AUC (0.752, 95% CI: 0.672-0.832), with 52.9% Sn and 86.1% Sp. Pearson's correlation showed that the coefficient (p < 0.01) of Cond to UCr, Osmo, and SpG were 0.696, 0.907, and 0.820, respectively. CONCLUSIONS: Cond has better screening ability than UP for early stage CKD and may be a potential surrogate parameter for Osmo, SpGr and UCr. PMID- 24779299 TI - Study of genetic variants of 8q21 and 8q24 associated with prostate cancer in Jing-Jin residents in northern China. AB - BACKGROUND: To identify the genetic risk of six genetic variants at 8q21 and 8q24 (including rs1512268, A; rs12543663, C; rs10086908, C; rs1016343, T; rs13252298, A, and rs6983561, C) associated with prostate cancer in Beijing and Tianjin (Jing jin) area residents in northern China. METHODS: 574 subjects were enrolled. Blood samples and clinical information were collected from histologically confirmed prostate cancer cases (n = 286) and clinically evaluated matched normal controls (n = 288) from Chinese men in northern China. Six SNPs at 8q21 and 8q24 were genotyped by high-resolution melt and sequencing in subjects. We compared statistical differences between the prevalence of risk genotypes with prostate cancer in cases and controls and analyzed the association between clinical covariates and risk loci in case groups to infer their relationship with aggressive prostate cancer. RESULTS: Three genotypes of rs10086908, CC (OR = 2.48; 95% CI = 1.02 - 5.98, p = 0.037) rs1016343, TT (OR = 1.64, 95% CI = 1.07 - 2.53, p = 0.023); and rs6983561, CC (OR = 1.91; 95% CI = 1.09 - 3.63, p = 0.044) at 8q24 were identified to be associated with prostate cancer risk in Jing-jin Chinese. The D' values of both two-locus haplotypes (T-A: rs1016343 vs. rs13252298; T-C: rs1016343 vs. rs6983561) were 0.907 and 0.859, respectively, the three-locus haplotype, only TAC constituted by the loci (rs1016343, T; rs13252298, A; rs6983561, C) was also associated with prostate cancer (p = 0.033), revealing rs1016343 vs. rs6983561 with significant differences between cases and controls. According to clinical covariates and odds ratios of risk genotypes relative to non-risk genotypes, rs6983561, CC was associated with age (OR = 2.5; 95% CI = 1.02 - 6.13, p = 0.039), and tumor aggressiveness (OR = 1.15; 95% Cl = 1.06 - 1.23, p = 0.013). CONCLUSIONS: The loci including rs10086908, rs1016343, and rs6983561 at 8q24 could be associated with prostate cancer in Jing jin residents in northern China. Our results suggest that these loci could influence susceptibility to prostate cancer in the northern Chinese population. PMID- 24779300 TI - Cancer antigen-125 and ICAM-1 are together responsible for ascites in liver cirrhosis. AB - BACKGROUND: Cancer antigen-125 is a high molecular weight glycoprotein used mainly for the diagnosis of ovarian carcinoma. However, elevation of cancer antigen-125 is observed in many benign conditions specially in liver cirrhosis but the reason behind the elevation remains unknown. Similarly intercellular adhesion molecule (ICAM-1) elevation is reported in liver cirrhosis but its role played in liver cirrhosis and ascites is unclear. METHODS: A total of 76 patients were involved in the study diagnosed with liver cirrhosis, Budd-Chairi syndrome, and tuberculous peritonitis. The degree of ascites was graded according to standard criteria into mild, moderate and severe. Cancer antigen-125 levels and sICAM-1 levels of all the patients were measured along with other liver parameters to evaluate the association of CA-125 and sICAM-1 with ascites. RESULTS: When cancer antigen-125 levels of liver cirrhosis patients were correlated with ascites a strong correlation was observed with the degree of ascites but no association was seen with liver function parameters. A significant difference was shown when liver cirrhosis patients with ascites were compared with liver cirrhosis patients without ascites (p < 0.05). All the patients with ascites had elevated levels of CA-125 (mean: 261.11 U/mL +/- 118.15 U/mL) whereas most of the patients without ascites had CA-125 levels under the normal range. A strong correlation (p < 0.05) is seen between CA-125 level and the degree of ascites. Elevated levels of sICAM-1 were observed in liver cirrhosis patients with ascites as well as in patients with other benign diseases with ascites (mean sICAM-1: 7.23 +/- 4.12 ng/mL and 6.67 +/- 2.99 ng/mL, respectively). When sICAM levels of liver cirrhosis patients with and without ascites were compared a significant difference (p < 0.05) is observed. CONCLUSIONS: The elevation of cancer antigen-125 in liver cirrhosis is specific to ascites. The mesothelial cells of the peritoneum chiefly contribute to the elevation of cancer antigen-125 along with the large surface area of the peritoneum. Therefore, CA-125 can be used as a good marker for early diagnosis of ascites and CA-125 has no relationship with the etiology of diseases in benign ascites. ICAM-1 plays a key role in the formation of ascites by influencing the endothelial-vascular permeability and therefore it along with CA-125 can be used as markers or alternative tools to diagnose ascites and to monitor the progression and severity of the disease. PMID- 24779301 TI - Frequency of hematological findings associated with severe plasma vitamin B12 deficiency in infants and adolescents. AB - BACKGROUND: The aim of this study was to determine the hematological status of severe vitamin B12 deficiency in infants and adolescents. METHODS: This study involved 95 infants and 117 adolescents with severe plasma vitamin B12 deficiency (< 120 pg/ mL) and normal plasma folate and ferritin. Infants were aged between one and 24 months. Adolescents were aged between 11 and 17 years. RESULTS: Macrocytic anemia was associated with nine (9.5%) out of 95 infants with severe vitamin B12 deficiency. Neutropenia was found in 16 (16.8%) out of 95 infants with severe vitamin B12 deficiency. Thrombocytopenia was not found in 95 infants with severe vitamin B12 deficiency. Macrocytic anemia was found in two (1.7%) out of 117 adolescents with a severe vitamin B12 deficiency. Neutropenia was associated in one (0.8%) out of 117 adolescents with severe vitamin B12 deficiency. Thrombocytopenia was not found in 117 adolescents with severe vitamin B12 deficiency. CONCLUSIONS: Low clinical or hematological findings for B12 deficiency in infants and adolescents living in regions at risk, such as those with low consumption of meat and other animal products warrant the measurement of vitamin B12 level. PMID- 24779302 TI - A case-control study on the association of common variants of CAPN10 gene and the risk of type 2 diabetes in an Iranian population. AB - BACKGROUND: Calpain-10 is a ubiquitously expressed protease that serves as an intracellular calcium-dependent cysteine protease and is regarded to be one of the candidate genes for type 2 diabetes mellitus (T2DM). We aimed to identify the association of the common variants of this gene and the risk of T2DM in the Kurdish ethnic group of Iran. METHODS: Study groups included 173 T2DM and 173 normoglycemic subjects. Genotyping was determined by PCR-RFLP. Genotypic and allelic frequencies were then evaluated. Data was analyzed using SPSS software. RESULTS: The allelic frequency of the A-allele of SNP-43 variant was significantly different (p = 0.01) between case and control groups (18% vs. 11%). The genotype frequencies for SNP-43 did not show any significant difference between case and control individuals. However, the dominant model of SNP-43 was found to be significantly associated with T2DM (OR = 1.75, 95% CI = 1.06 - 2.89, p < 0.029). The distribution and allele frequency of other SNPs (SNP-19 and -63) did not show any significant difference between the study groups. For SNP-43, fasting serum insulin (p = 0.043) and HOMA-IR (p = 0.026) were higher in the control subjects with the GA+AA genotype when compared with the GG genotype. Among the T2DM subjects, there was no significant difference in any of the clinical or biochemical parameters between the GG and GA+AA genotypes of SNP-43. Normoglycemic subjects carrying the 2R/3R+3R/3R genotypes of SNP-19 had significantly lower HDL-C (p = 0.034) as compared with those with the 2R/2R genotype. In T2DM subjects, no significant difference was found in any of the clinical or biochemical parameters between 2R/2R and 2R/3R+3R/3R genotypes. T2DM subjects carrying the CT+TT genotypes of SNP-63 variation had significantly higher LDL-C (p = 0.015) as compared with those with the CC genotype. In normoglycemic subjects, no significant difference was found in any of the clinical or biochemical parameters between CC and CT+TT genotypes. CONCLUSIONS: Our findings revealed that there is an association between the SNP-43, but not SNP-19 and -63, and T2DM in the Kurdish ethnic group of West Iran. PMID- 24779303 TI - Autoantibody detection: prevailing practices at a tertiary care hospital in Riyadh. AB - BACKGROUND: Anti-nuclear antibody (ANA) test as the first level investigation for detection of auto-immune rheumatic disease has been recommended in a number of international guidelines. This study was performed to evaluate the local practice and trends of auto-antibody laboratory requests. METHODS: Data were collected from 249 initial laboratory requests for first level auto-antibody detection between April 2012 and April 2013 in the Immunology Unit at King Khalid University Hospital, Riyadh. This group of patients included 151 females and 98 males (mean age 40.1 +/- 21; range 4-85 years). RESULTS: Of the total requests, ANA as a single first level investigation was requested by only 32 (13%) clinicians whereas the rest of the investigations included simultaneous testing of ANA and second level extractable nuclear antigen (ENA) auto-antibody tests. Anti-double stranded DNA (anti-dsDNA) antibody was simultaneously tested with ANA in 158 patients as first level test where both the tests were positive in 44 (27.8%) patients and in 24 (15.1%) patients a negative ANA test was associated with a positive anti-dsDNA antibody test. Rheumatoid factor (RF) tested positive in 04/53 (7.5%), anti-neutrophil cytoplasmic antibody (ANCA) in 01/48 (2%) and SS A and SS-B in 03/37 (8.1%) requests as first level tests with ANA. CONCLUSIONS: Using second level auto-antibody tests in conjunction with ANA as the first line investigation does not appear to be a cost effective approach, highlighting the importance of adherence to the guidelines. ANA negative and anti-dsDNA positive group of patients requires further assessment in a large scale study. PMID- 24779304 TI - HCV antigen testing for the diagnosis of hepatitis C infection: a cost-efficient algorithm. AB - BACKGROUND: In North America, diagnosis of active hepatitis C virus (HCV) infection is currently performed using RNA testing which is highly sensitive and specific but is associated with three major limitations: lability of RNA molecules, higher costs, and longer turn-around time as compared with commercially-available HCV core antigen testing. In the current study, a new HCV core antigen assay product was evaluated for the diagnosis of HCV infection and its cost reducing potential. METHODS: Ninety plasma specimens positive for HCV RNA along with 25 negative HCV specimens were used for HCV antigen assay. Twenty four specimens positive for a panel of agents were used for possible cross reactivity. Sixty-four HCV antibody-positive specimens with negative HCV RNA and indeterminate HCV immunoblot results were also employed. RESULTS: In the first group, 78/90 (86.6%) tested positive for HCV antigen with regression analysis showing no significant deviation from linearity. None of the prenatal specimens tested positive for HCV antigen. Non-specific reactions were not observed. In the HCV antibody-indeterminate group, only 2/64 (3.1%) were antigen positive. In the last group, none of the HCV antibody very-low-positive specimens tested positive for HCV antigen. Both inter- and intra-run reproducibility of 100% were noted. The cost analysis showed a minimum of 52.13% reduction in costs associated with qualitative RNA testing. CONCLUSIONS: Considering the complexity of HCV infection diagnosis and the significant cost and turn-around time burden it imposes on clinical laboratories, HCV antigen testing seems an attractive adjunct to the current battery of laboratory diagnosis that demands more attention. PMID- 24779305 TI - A case of diffuse large B-cell lymphoma complicated by hemophagocytic syndrome. AB - BACKGROUND: Hemophagocytic syndrome (HPS) is a fatal disease and T-cell lymphoma is a common cause of this syndrome. The authors describe a rare case of diffuse large B-cell lymphoma (DLBCL) with HPS. METHODS: Hematologic investigation, bone marrow aspirate and biopsy, cytogenetic analysis and lymph node biopsy were performed. RESULTS: The patient obtained transient complete remission with rituximab and chemotherapy but relapsed soon within the observation period. CONCLUSIONS: More aggressive therapy should be given in order to obtain a better therapeutic effect for the patients of DLBCL with HPS. PMID- 24779306 TI - Evaluation of immunoturbidimetric rheumatoid factor method from Diagam on Abbott c8000 analyzer: comparison with immunonephelemetric method. AB - Rheumatoid factor (RF) consists of autoantibodies and because of its heterogeneity its determination is not easy. Currently, nephelometry and Elisa method are considered as reference methods. Due to consolidation, many laboratories have fully automated turbidimetric apparatus, and specific nephelemetric systems are not always available. In addition, nephelemetry is more accurate, but time consuming, expensive, and requires a specific device, resulting in a lower efficiency. Turbidimetry could be an attractive alternative. The turbidimetric RF test from Diagam meets the requirements of accuracy and precision for optimal clinical use, with an acceptable measuring range, and could be an alternative in the determination of RF, without the associated cost of a dedicated instrument, making consolidation and saving blood possible. PMID- 24779307 TI - Changes in plasma intact parathyroid hormone levels following 24-hour incubation at room temperature as determined by Roche electrochemiluminescence PTH immunoassay. AB - BACKGROUND: Estimation of circulatory PTH is necessary for correct diagnosis of diseases related to the parathyroid gland, bone, and kidney. METHODS: Roche Electrochemiluminescence PTH immunoassay was used to measure changes in plasma iPTH concentration in 100 random samples following a 24 hours incubation at room temperature. RESULTS: Low to normal iPTH concentration individuals showed higher decrease in iPTH concentration as compared to individuals with elevated PTH and the rate of PTH degradation was significantly higher (p < 0.05) in the low to normal PTH group. CONCLUSIONS: Blood samples from suspected hypo- or normo parathyroid subjects should be analyzed as soon as possible as a little degradation of PTH at room temperature could influence their clinical interpretation. PMID- 24779308 TI - Urinalysis: comparison between microscopic analysis and a new automated microscopy image-based urine sediment instrument. AB - BACKGROUND: Urinalysis is a high demand procedure, with a large amount of manual labor and poorly standardized. Recently a new walk-away automated urine analyzer has been introduced. The aim of this study was to evaluate the performance of UriSed as an alternative to the microscopic analysis of urine samples. METHODS: Four hundred mid-stream urine samples from patients with several clinical conditions were analyzed by bright field microscopy and by UriSed. The validation protocol included studies of precision, carryover, and comparison with the gold standard microscopy. RESULTS: Our data showed that UriSed is a precise method. Repeatability and reproducibility ranged from 8 to 15%. Carryover was negligible. All the elements showed good agreement between both methods, with an extremely high correlation between the erythrocyte and leukocyte counts (r > 0.95) CONCLUSIONS: UriSed is a precise and accurate alternative to microscopy that allows a better workflow and may significantly improve turnaround time. PMID- 24779309 TI - Cold agglutinins in celiac disease: a new biomarker or an innocent bystander? PMID- 24779310 TI - [Single-donor (apheresis) platelets and pooled whole-blood-derived platelets- significance and assessment of both blood products]. AB - The transfusion efficacy of ATK, which contain fully functional platelets, is beyond all doubt. The equivalence of ATK and PTK has been subject of many studies. Some of those studies show the superiority of ATK's, while others do not, but there have been no studies that demonstrated a superiority of PTK's. The superiority of platelets stored in plasma and in third generation additive solution was demonstrated in clinical studies; therefore, it cannot be said that all the platelet concentrates on the German market are equivalent in efficacy. Of decisive importance, above all, is the risk of transfusion-transmitted infections with known pathogens, or those not yet discovered. This risk is different for ATK compared to PTK. Taking this difference in risk and the difference in donor exposure of transfused patients into account, it can definitely be said that ATK and PTK are not equivalent. In 2012, the Robert-Koch-Institute (RKI) published a mathematical risk model for different platelet concentrates and assessed the risk of transmitting known pathogens such as HIV, HCV, and HBV. The risk was higher for PTK compared to ATK. The relative risks for PTK derived from 4BCs were 2.2 (95%--CI: 2.1-2.4) for HIV, 2.7 (95%--CI: 2.5-3.0) for HCV, and 2.2 (95%--CI: 2.8 3.7) for HBV. At the present time, these are the relative risks of transfusion transmitted infections with the traditional pathogens for PTK compared to ATK. In addition to the RKI assessed risks, there is the theoretical risk of a new, unknown agent, transmitted through blood exposure. The magnitude of this risk is hardly predictable for PTK. The experience gathered so far, especially in the last three decades, with the emergence of HIV, prions, and West Nil virus, shows that the biological nature of a next transfusion-transmissible infectious agent cannot be predictable. This agent, if we think at a conventional sexually transmissible agent with nucleic acid and long latent period, would spread first in areas with high population density and thereby reduce the theoretical advantage of ATK (but definitely would not nullify it!). It is equally plausible, however, that this agent would behave like a prion, non-sexual transmission, or like a West-Nil virus, a non-contagious vector-transmitted agent. For PTK this would mean a relative risk up to 4 times (PTK from 4 BCs) or 5 times (PTK from 5 BCs) higher than the risk estimated by the Robert-Koch-Institute. If, taking the passive surveillance data and the changing variables (donor frequency, donor population, and donor location) into account, the risk of transmission of an infection via ATK (exposure to 1 donor) with HIV, HCV, and HBV moves closer to the higher risk of PTK (exposure to 4 or 8 donors, in case of double ATK per patient), this result of the risk model calculation by no means indicates any equivalency between PTK and ATK with respect to the risk of transmission of infection. The modifiable variables of donor frequency, donor population, and donor location need to be modified, as scientific deductions, in such a way that the avoidable risk of ATK which is influenced by these variables can be corrected to the minimum risk of a transmission of infection of HIV, HBV, and HCV via ATK in comparison to PTK. The minimum risk of a possible transmission of infection via ATK (exposure to 1 donor) is the basic intrinsic risk of each individual blood donation. The basic intrinsic risk increases relative to the number of blood donations or exposure to donors (PtK has an unalterable, production dependent exposure to 4 or 8 donors). Let us consider a 1:1.000 prevalence for a new pathogen, which is spread equally in each donor population (apheresis and whole blood) and the present case of approximately 500,000 transfused platelet concentrates in Germany. This means that for the production of 4 PTK about 2 million donations are processed, 2,000 infectious Buffy-Coats are obtained and, thereby, 2,000 infectious PTK. In the case of ATK, considering five (5) donations per year, theoretically, it would mean 100 donors infected and 500 infectious ATK. Considering 15 apheresis donations per donor per year, this would mean that 33 donors are infected, but still 500 infectious ATK would be produced. The prion is an example of a pathogen that, although its existence is well known, cannot be proven or pathogen-reduced. In addition, it has a very long incubation period compared to the donation intervals. Due to the manufacturing process, PTK has a 4 fold higher donor exposure and therefore a 4-fold higher risk for transfusion transmitted infections compared to ATK. If a patient needs the transfusion of two platelet concentrates, by transfusing a double-ATK from the same donor the risk of transfusion-transmitted infections will remain the same. On the other hand, the risk will increase by 8-fold by transfusing two PTK. The only current possibility to prevent or to minimize the risk of infection with prions is to minimize the donor exposure by transfusing ATK instead of PTK. Hypothetical risk scenarios carry significant weight in law. This can be seen in the constant rulings of the German Federal Supreme Court (Bundesgerichtshofs (BGH)) on the so called hypothetical risk explanations (BGH, NJW 1996, 776, 777; 2000, 1784, 1787; 2005, 2614, 2616). Therefore, a risk does not need to be confirmed to be subject to compulsory explanation. It is sufficient that serious voices in the medical scientific community point to specific risks, which cannot be set aside as insignificant outside opinions, but must be viewed as serious warnings. According to the rulings, patients must even be informed of rare and often extremely rare risks, which could, should they come true, significantly impact daily life and, despite their rarity, are specific to the treatment and are startling for the ordinary person (BGH, 15.02.2000- VI ZR 48199 -; BGH, 30.11.2004 - VI ZR 209104 ; OLG Hamm, 29.09.2010 - 1-3 V 169109). These conditions have been fulfilled for PTK according to current knowledge, especially since, in the meantime in several rulings, the federal supreme court has required the reference to as yet unknown risks (refer to BGH, 13.06.2006 - VI ZR 323104 - for the use of new medical treatment methods, BGH, 27.06.2007 - VI ZR 55105 for experimental therapy using new, unapproved medication BGH, 06.07.2010 - VI ZR 198109 - for unknown risks cannot be excluded, for example based on anatomical conditions). ATK and PTK are therapeutic alternatives with the same range of indications for treatment using thrombocytes, however, with differing risks of infection, with different exposures to donors, and with different efficacy. ATK and PTK. ATK and PTK are therapeutic alternatives in terms of pharmaceutical law based on the different risks and the different quality. Patients must be informed of therapeutic alternatives such as ATK and PTK according to the patient rights law. Denial of reimbursement for additional fees for ATK by individual insurance companies (or paying authorities) deviates blatantly, as seen in the ruling of the Social Court of of the Saarland in this matter, from the basic requirement of the Transfusion Law (Transfusionsgesetz (TFG)) and is legally incorrect. The legality of the question whether the transfusion of ATK is indicated or if PTK had sufficed, is not allowable within the context of an MDK-Test according to subsection 275 ff. SGB V. The denial is a direct infringment on the treatment authority of the attending hospital physician and is illegal according to subsection 275 Abs. 5 SGBV. It is certainly possible to establish a full ATK supply and can be immediately realized by increasing donation rates from 5 to 8.3 apheresis donations per year in the current scenario of apheresis structure and donor population. The donation interval between two apheresis donations would be 49 days. A complete supply with ATK can also be immediately implemented by enlarging the donor population, keeping the current apheresis donation frequency. The donor pool must be increased by 24,576 donors, which means a 67% increase of the existing donor population. A transition to an ATK supply that can cover the entire demand can certainly be realized in a short period of time, while assuring a complete supply with PTK is not a realistic option. All existing studies advise taking extreme caution with any alternative to the current German gold standard for the treatment of hyporegenerative thrombocytopenia. A prophylactic transfusion of a non-pathogen-inactivated platelet concentrate with on average 3 x 10(11) platelets is recommended when the platelet count drops below the threshold of 10,000/microL. All other alternatives to this strategy show an increase in intracranial bleeding events. The existing studies on platelet dose (PLADO-Trial and StoP-Trial) do not recommend deviating from 3 x 10(11) platelets per unit. On the contrary, these studies demonstrate that the only practicable way is to individually correlate every platelet transfusion to the patient body surface. Considering the current knowledge, it is not justified to lower the standard dose and, for certain patient groups, to switch from prophylaxis to therapeutic platelet transfusion. Applying ATK or PTK with a lower platelet content and only for therapeutic purposes, could considerably increase the bleeding risk, especially for WHO grades III and IV. This will also affect all the patients who receive an induction treatment. Through pathogen reduction, in parallel with platelet loss (Apoptosis), the function of the treated platelets is impaired. Alternatively, the cell destruction caused during this process could result in a release of platelet microRNA directly into the supernatant or in microvesicles. This reduction of microRNA will affect the storage of the platelets. (ABSTRACT TRUNCATED) PMID- 24779311 TI - Evaluation of certain food additives and contaminants. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives and a food contaminant with a view to concluding as to safety concerns and to preparing specifications for identity and purity. The first part of the report contains a general discussion of the principles governing the toxicological evaluation of and assessment of dietary exposure to food additives. A summary follows of the Committee's evaluations of technical, toxicological and dietary exposure data for seven food additives (advantame; glucoamylase from Trichoderma reesei expressed in Trichoderma reesei; glycerol ester of gum rosin; glycerol ester of tall oil rosin; glycerol ester of wood rosin; nisin; and octenyl succinic acid modified gum arabic) and an assessment of dietary exposure to cadmium from cocoa and cocoa products. Specifications for the following food additives were revised: annatto extracts (solvent-extracted bixin and solvent-extracted norbixin); Benzoe tonkinensis; food additives containing aluminium and/or silicon; mineral oil (medium viscosity); modified starches; paprika extract; phosphates (analytical methods for the determination of phosphorus and revision of specifications); 3 phytase from Aspergillus niger expressed in Aspergillus niger; potassium aluminium silicate; and potassium aluminium silicate-based pearlescent pigments. Annexed to the report are tables summarizing the Committee's recommendations for dietary exposures to and toxicological evaluations of the food additives and contaminant considered. PMID- 24779312 TI - Ethically optimal interventions with impaired patients. AB - It may be difficult to imagine having a severe impairment such as quadriplegia or being dependent on a respirator. There is evidence that when careproviders make treatment decisions for patients who are in these situations, we imagine the patients are worse-off than they report they are -- most patients with even very severe impairments report that they greatly value being alive. This misperception may cause us to make treatment decisions for patients with impairments that we might not make for other patients. In this article I describe how to provide better care for patients who have impairments. This includes not presupposing that the patients' quality of life is decreased, considering with patients how outside factors may be limiting their functioning, and seeking to help offset these factors, if we can, when they exist, to avoid allowing patients' impairments to result in their being truly "disabled". PMID- 24779313 TI - DNR and ECMO: a paradox worth exploring. AB - Extracorporeal membrane oxygenation (ECMO) provides continuous circulation and/or oxygenation to adults with cardiac failure, pulmonary dysfunction, or both. The technology is similar to the traditional heart-lung bypass machines used during surgical procedures, however ECMO may be used outside the confines of the operating room and for extended periods of time. This paper explores the complexities, both clinical and ethical, of a do-not-resuscitate (DNR) order for patients with cardiopulmonary failure on veno-arterial (VA-ECMO), a type of ECMO that provides resuscitation superior to the chest compressions that DNR is intended to prevent. Clinically, a DNR order has limited utility for patients on VA-ECMO and its presence can serve to create confusion. Symbolically, however, the designation may serve as a stepping-stone for surrogates facing difficult end of-life decisions. The paper concludes by suggesting that it is prudent to avoid DNR discussions in the context of VA-ECMO PMID- 24779314 TI - Defending the jurisdiction of the clinical ethicist. AB - In this essay I suggest that the bioethics profession's jurisdiction over healthcare ethics consultation is in need of reinforcement. I argue that as the profession becomes more successful, competitors will challenge the profession to justify its ethical claims and ask whose ethics the profession represents. This challenge will come more quickly as the profession tries to influence the ethics of healthcare organizations. I propose a method of bolstering jurisdiction that will make the profession less vulnerable to challenge in the future. PMID- 24779315 TI - Can the social sciences save bioethics? AB - John Evans proposes some ways in which the social sciences can improve bioethics: by recognizing that it is a profession, that it embrace the four principles advanced by Beauchamp and Childress over the years, and that ethical commissions and committees make use of social science research to determine and use the values of the public. All three of these proposals are challenged. PMID- 24779316 TI - Clinical ethicists: consultants or professionals? AB - John H. Evans's views on the multiple roles of healthcare ethics consultants are based on his claim that bioethics is a "distinct profession" that has a "system of abstract knowledge." This response to Professor Evans disputes both of his claims. It is argued that clinical ethicists are consultants but not professionals. Their roles as consultants require more than one abstract form of knowledge (principlism). Instead, clinical ethicists rely upon a variety of ethical perspectives and other skills to help resolve conflicts and facilitate healthcare decisions and policy making, whether it is in clinical, research, policy, or organizational contexts. The credibility and effectiveness of clinical ethicists depend upon their knowledge of ethics, their practical experience, and personal abilities, not one form of abstract knowledge. PMID- 24779317 TI - Response to Callahan and Winslade. AB - I respond to commentaries by Daniel Callahan and William J. Winslade on my article, "Defending the Jurisdiction of the Clinical Ethicist," all of which are in this issue of JCE. PMID- 24779318 TI - The desire to die: making treatment decisions for suicidal patients who have an advance directive. AB - This article enumerates and critically examines the potential grounds on which we might treat the case of a patient with an advance directive who attempted suicide, differently from one whose injuries were the result of an accident. Grounds for differentiation are distilled into two potential justifications. The first addresses the concern that withholding or withdrawing care from a patient with self-inflicted injuries would be aiding and abetting suicide.The second examines concerns about the patient's decisionmaking capacity. Ultimately, it is argued that while there might be legitimate reasons to hold the advance directive of a suicidal patient to a different standard of scrutiny, the fact that the patient's medical state was self-inflicted should not, in and of itself, necessarily invalidate the guidance of the directive. Finally, four practical recommendations are offered for negotiating similar cases. PMID- 24779319 TI - Beyond privacy: benefits and burdens of e-health technologies in primary care. AB - In this mixed methods study we identify and assess ethical and pragmatic issues and dilemmas surrounding e-health technologies in the context of primary care, including what is already in the literature. We describe how primary healthcare professionals can access reliable and accurate data, improve the quality of care for patients, and lower costs while following institutional guidelines to protect patients. Using qualitative and quantitative methodologies we identify several underlying ethical and pragmatic burdens and benefits of e-health technologies.The 41 study participants reported more burdens than benefits, and were generally ambivalent about their level of satisfaction with their institutions' e-health technologies, their general knowledge about the technologies, and whether e-health can improve team-based communication and collaboration. Participants provided recommendations to improve e-health technologies in primary care settings. PMID- 24779320 TI - The side-effects of the "Facebook effect": challenging Facebook's "organ donor" application. AB - A recent study published in the American Journal of Organ Transplantation proposes that an organ donor application in Facebook can increase the rates at which individuals donate organs. While I offer support for the use of social media mechanisms in the service of the promotion of organ donation public health initiatives, there are several ethical concerns surrounding informed consent. While Facebook has made a noble effort to aid public health initiatives focused on organ donation, the current application does not promote decisions that are based on individuals' personal values and goals. Without an intervention that promotes an understanding and appreciation of a decision for or against donation, the application does not obtain informed consent. Without first ensuring that a Facebook member has registered with her or his own state donor registry, this social media mechanism may create more confusion than clarity about an individual's organ donor status. If Facebook desires to have a positive impact on the rates of organ donation, it must do so in a manner that obtains proper consent and promotes ethically informed decisions. PMID- 24779321 TI - Legal briefing: voluntarily stopping eating and drinking. AB - This issue's "Legal Briefing" column covers recent legal developments involving voluntarily stopping eating and drinking (VSED). Over the past decade, clinicians and bioethicists have increasingly recognized VSED as a medically and ethically appropriate means to hasten death. Most recently, in September 2013, the National Hospice and Palliative Care Organization (NHPCO) called on its 2,000 member hospices to develop policies and guidelines addressing VSED. And VSED is getting more attention not only in healthcare communities, but also in the general public. For example, VSED was recently highlighted on the front page of the New York Times and in other national and local media. Nevertheless, despite the growing interest in VSED, there remains little on-point legal authority and only sparse bioethics literature analyzing its legality.This article aims to fill this gap. Specifically, we focus on new legislative, regulatory, and judicial acts that clarify the permissibility of VSED. We categorize these legal developments into the following seven categories: 1. Definition of VSED. 2. Uncertainty Whether Oral Nutrition and Hydration Are Medical Treatment. 3. Uncertainty Regarding Providers' Obligations to Patients Who Choose VSED. 4. Judicial Guidance from Australia. 5. Judicial Guidance from the United Kingdom. PMID- 24779322 TI - Absence of left ventricular hypertrophy in severe isolated aortic stenosis and preserved left ventricular systolic function. AB - BACKGROUND AND AIM OF THE STUDY: Recent evidence challenges the paradigm that left ventricular hypertrophy (LVH) is required to preserve left ventricular systolic performance in severe aortic stenosis (AS). The study aims were to determine the clinical, echocardiographic and prognostic implications in a cohort of patients with symptomatic severe AS, a preserved left ventricular ejection fraction (LVEF), and an absence of LVH. METHODS: Echocardiographic, clinical, aortic valve replacement (AVR)-related and all-cause death data were analyzed in 512 patients (253 males, 259 females; mean age 78.4 +/- 10.3 years) with severe AS and a preserved LVEF. Of these patients, 21% were enrolled prospectively, and the mean follow up was 40.4 +/- 32.5 months. RESULTS: By using the American Society of Echocardiography equation for left ventricular mass calculation, LVH was shown to be present in 330 patients (63%) and absent from 182 (36%). Typically, patients without LVH had a larger body surface area, were more often male, had a larger aortic valve area index (AVAi), and had similar LVEFs and rates of AVR as compared to those with LVH. A total of 59 deaths (32.4%) occurred among patients without LVH, and 134 (40.6%) among those with LVH (p = 0.07). When the left ventricular mass index (LVMi) was analyzed as a continuous variable, in both unadjusted and adjusted models for demographics, clinical characteristics, medications, AVAi, LVEF, and systemic vascular resistance, no association was found between LVMi and survival (p = 0.26). However, only patients with a normal LVMi and relative wall thickness had a survival benefit when compared to those with any pattern of abnormal left ventricular geometry (p = 0.01). CONCLUSION: LVH was absent in more than one-third of patients with severe AS, and was not associated with worse outcomes. A normal left ventricular geometry was associated with lower mortality rates, while AVR was associated with prolonged survival, regardless of LVMi. Mechanisms other than compensatory hypertrophy appear capable of offsetting the adverse effects of afterload excess in AS. PMID- 24779323 TI - Comparison of different surgical techniques in 112 consecutive patients with aortic root operations: when should the valve be spared? AB - BACKGROUND AND AIM OF THE STUDY: The benefit of valve-sparing aortic root replacement compared to conventional aortic root replacement surgery remains unclear. METHODS: Between February 2009 and November 2010, a total of 112 patients underwent aortic root surgery at the Department of Cardiovascular and Thoracic Surgery, Heinrich-Heine-University, Dusseldorf, Germany. The valve sparing technique was used when leaflets were grossly normal. In cases where the valve could not be saved, a prosthetic or biological substitute was used for the aortic root, according to existing guidelines. The patients were allocated to three groups: (i) valve-sparing aortic root replacement group using the David technique (VSR-David; n = 47); (ii) valve-replacing aortic root surgery with a prosthetic conduit using the Bentall-Kuchucus technique (VRR-Prosthetic; n = 31); and (iii) valve-replacing aortic root surgery with a biological stentless valve with the full root technique (VRR-Bio; n = 34). RESULTS: Intraoperative data revealed that, in the VSR-David group, the cardiopulmonary bypass and cross-clamp times were significantly longer (207 +/- 68 min and 140 +/- 38 min respectively; both p = 0.001). The VRR-Prosthetic patients were at highest risk (mean EuroSCORE 15.9%) compared to the VSR-David and VRR-Bio groups (10.8% and 10.4%, respectively). Postoperative analysis showed that patients in the VRR-Bio group had the lowest number of perioperative heart failures (p = 0.004). The perioperative 30-day mortality was significantly higher in the VRR-Prosthetic group (22.6%; p = 0.004). Transaortic flow velocities were significantly lower in the VSR-David group, followed by the VRR-Bio group and VRR-Prosthetic group (1.66 +/- 0.54, 1.98 +/- 0.45, and 2.29 +/- 0.39 m/s, respectively; p = 0.012). The univariate and multivariate analyses of perioperative risk factors showed that only open distal anastomosis was strongly associated with negative results, but not the valve-sparing technique. CONCLUSION: Aortic valve-sparing root replacement must be considered as an excellent alternative for young patients requiring aortic root replacement when a biological valve is clinically indicated. For patients aged >65 years, or with a decreased life expectancy, the full root technique with a stentless valve should be used, given its technical simplicity and excellent postoperative results. PMID- 24779324 TI - Aortic wall thickness: an independent risk factor for aortic dissection? AB - BACKGROUND AND AIM OF THE STUDY: Aortic aneurysm size is known to portend a higher likelihood of aortic complications in patients with connective tissue disorders (CTD), but other objective tools are needed to determine which patients are at greatest risk of dissection, especially those which reflect the structural integrity and strength of the aortic wall. METHODS: The aortic wall pathology was evaluated in CTD patients with and without acute aortic dissection to identify parameters that affect the risk of dissection. A retrospective review was performed of aneurysm pathology from patients with Marfan syndrome (MFS; n = 53) without dissection undergoing prophylactic aortic root surgery, and acute type A aortic dissection patients (AAAoD; n = 16). Patients without a cardiovascular cause of death (n = 19) served as controls. The minimal aortic medial wall thickness was measured, and medial myxoid degeneration (MMD) and the degree of elastin loss and fragmentation were graded. RESULTS: The mean minimal aortic wall thickness was 1,625 +/- 364 microm in controls, and 703 +/- 256 microm and 438 +/ 322 microm for MFS and AAAoD patients, respectively. Aortic root diameters did not correlate with aortic wall thickness. A comparison of aortic medial thickness showed that the media was significantly thinner among acute dissection patients than either elective surgical patients (p = 0.02) or controls (p < 0.001). Aortic size, degree of MMD, and elastin loss did not vary significantly between CTD patients. CONCLUSION: A diminished aortic wall medial thickness may be linked to aortic dissection. High-resolution imaging techniques in the future may lead to the morphological assessment of aortic medial wall thickness in vivo becoming a reality which, in theory, could provide a more refined risk prognostication for acute aortic dissection. PMID- 24779325 TI - The aortic root: simple as possible, but not simpler. AB - During the past decades, replacement of the aortic valve (AVR) was considered a straightforward treatment of aortic valve disease. The technique is simple, with a relatively low perioperative mortality and morbidity (3-5%) and, as such, does not require a detailed knowledge of aortic root anatomy. However, with the renaissance of reconstructive procedures on the aortic root, an increased use of biological aortic valve prostheses (especially of stentless devices) and, finally, the revival of the Ross procedure, a more detailed understanding of aortic root function and morphology was required in the operating room. PMID- 24779326 TI - Enlargement of the aortic annulus during aortic valve replacement: a review. AB - The main goal of aortic valve replacement (AVR) is to obtain relief from the fixed left ventricular (LV) obstruction by replacing the aortic valve with a prosthesis, either mechanical or biological, of adequate size. Most currently available prostheses provide satisfactory hemodynamic performance, but small sized prostheses may be associated with high transvalvular gradients and suboptimal effective orifice area that result in prosthesis-patient mismatch (PPM), and thus are far from ideal for use in young, active patients. The avoidance of PPM is advisable as it has been repeatedly associated with increased mortality, decreased exercise tolerance and an impaired regression of LV hypertrophy after AVR for severe aortic stenosis. Enlargement of the aortic annulus (EAA) has proved to be a valuable method to prevent PPM in the presence of a diminutive aortic root. This review outlines the various techniques described for EAA, presenting technical details, long-term results and major procedure-related complications, and discussing the current role of EAA in patients requiring AVR. PMID- 24779327 TI - Physicochemical and micro-tomographic characterization of inorganic deposits associated with aortic stenosis. AB - BACKGROUND AND THE AIM OF THE STUDY: A major feature of aortic stenosis is massive mineralization of the aortic valve, though the mechanism of the process remains unclear. The study aim was to characterize the chemical composition and morphology of inorganic deposits from surgically excised natural aortic valves and to seek similarities to minerals in bones and teeth. METHODS: Mineral deposits from 30 surgically excised natural aortic valves were examined. The control group consisted of autopsy samples (aortic valves, vertebral bodies) and teeth obtained after extraction. Micro-computed tomography (micro-CT) was used to describe the morphology and density of the minerals. X-ray fluorescence and Fourier transform infrared spectroscopy were applied to determine the chemical composition. RESULTS: A poorly crystalline, B-type carbonate-containing hydroxyapatite (HAP) was found to constitute the mineral phase of the aortic valve leaflets. No other chemical compounds were identified. The elemental composition of the minerals in aortic valves and bone/tooth did not differ markedly, except that the Mg concentration was fourfold higher in valve material. The aortic valve deposits were irregular in shape and occupied ca. 40% of the leaflet volume. The volume of the deposits were spread over a broad range (0.001 0.3 mm3), while the density ranged from that of dentine to enamel (average value 2.2 g/cm3), slightly higher than that of compact bone. CONCLUSION: The aortic valve deposits were identified as B-type carbonate-containing HAP, and were not identical to those found in bones and teeth, the main difference being a fourfold elevated Mg content. Mg may have been deposited as a separate compound, as micro CT results suggested that the formation of mineral deposits in aortic valves was a multi-factorial process. The morphological parameters and densities of the valve deposits were spread over a broad range (factor approximately 300). An unequivocal identification of the mechanism responsible for the aortic valve pathological calcification was not possible, however. PMID- 24779328 TI - Mitral valve repair for severe organic mitral regurgitation in the elderly. AB - BACKGROUND AND AIM OF THE STUDY: Although mitral valve repair has become the standard surgical procedure for mitral regurgitation (MR), the procedure does not necessarily apply to elderly patients aged > 75 years because of high morbidity and mortality. METHODS: A total of 104 patients aged > 75 years who underwent mitral valve repair between January 1991 and December 2011 was reviewed retrospectively. The mean age was 78 years, and the mean follow up was 3.7 years. Possible risk factors for hospital death and morbidity were identified, and valve related events during the follow up period were analyzed. RESULTS: The overall hospital mortality rate was 4.8% (5/104). Multivariate logistic regression analysis identified serum creatinine level > 2.0 mg/dl as the only independent predictor of hospital mortality. A total of 33 patients had postoperative complications. Infective endocarditis was the only independent predictor of hospital morbidity. Actual survival at five years was 85.6 +/- 4.1%. By Cox regression analysis, age (HR 1.195; p <0.012) proved to be a negative predictor of late survival, whereas the absence of chronic obstructive pulmonary disease (HR 0.129; p <0.014) was a positive predictor. Rates of freedom from thromboembolic events and bleeding at five years were 87.9 +/- 4.2% and 97.9 +/- 1.5%, respectively. Rates of freedom from moderate-to-severe MR and reoperation at five years were 80.3 +/- 6.5% and 97.5 +/- 2.5%, respectively. CONCLUSION: Late survival and freedom from valve-related events were favorable, in addition to hospital outcome, in patients aged > 75 years. Mitral valve repair is an acceptable surgical procedure in terms of hospital mortality/morbidity and freedom from valve-related events. PMID- 24779329 TI - Systemic and local levels of fetuin-a in calcified mitral valves of rheumatic heart disease. AB - BACKGROUND AND AIM OF THE STUDY: Fetuin-A is a circulating glycoprotein that inhibits ectopic calcification. The study aim was first, to assess serum fetuin-A level in patients with calcified rheumatic mitral valve disease (RMVD), and second, to demonstrate the presence of fetuin-A by immunohistochemistry (IHC) in calcified RMVD which, to date, has not been verified in other studies. METHODS: The study group comprised 68 adult patients with isolated RMVD and normal renal function. Of these patients, 34 (27 males, seven females; mean age 33.44 +/- 9.0 years) had severe calcification (Wilkins calcium score 3 or 4) and 34 (25 males, nine females; mean age 30.8 +/- 8.5 years) had mild calcification (Wilkins calcium score 1 or 2). A group of 32 age- and gender-matched healthy subjects (25 males, seven females; mean age 29.5 +/- 4.6 years) served as controls. Baseline serum fetuin-A levels were measured using an enzyme-linked immunosorbent assay (ELISA), while Wilkins calcium scores were assessed using either transthoracic or transesophageal echocardiography. Serum levels of calcium, phosphorus and alkaline phosphatase were assessed in all subjects. Histopathological examinations of ten severely calcific rheumatic mitral valves were made and compared with 10 non-calcified rheumatic mitral valves, all of which had undergone mitral valve replacement. RESULTS: Serum fetuin-A levels were significantly lower in RMVD patients than in controls (108.83 +/- 7.1 versus 114.46 +/- 3.32 ng/ml; p = 0.014). However, there was no significant difference in fetuin-A level between patients with severe (C3/C4) versus mild calcification (C1/C2) (108.84 +/- 7.82 versus 108.82 +/- 6.36 ng/ml; p = NS). No correlation of fetuin-A was seen with serum high-sensitivity C-reactive protein, calcium, phosphorus and alkaline phosphatase, or with Wilkins' calcium score. IHC analyses revealed the presence of fetuin-A in the mesenchymal matrix and calcified area of calcific valves, while minimal to absent fetuin-A deposition was detected in the mesenchymal matrix of non-calcified mitral valves. CONCLUSION: Serum fetuin-A levels were significantly decreased in patients with calcific RMVD. The present study was the first to demonstrate fetuin-A in the calcified mitral valve of rheumatic etiology, and suggests its possible role in the pathophysiology of calcific mitral valve disease. Further studies are required, however, to determine therapeutic implications. PMID- 24779330 TI - Long-term results of mitral valve repair with semi-rigid posterior band annuloplasty. AB - BACKGROUND AND AIM OF THE STUDY: Optimal repair of the mitral valve involves the implantation of an annuloplasty device to geometrically reshape and/or stabilize the annulus and improve long-term durability. It has been reported previously that trigone-to-trigone semi-rigid posterior band (PB) annuloplasty is associated with excellent short-term outcomes, physiologic motion of the anterior mitral annulus and leaflet, and lower postoperative transvalvular gradients compared to complete ring (CR) annuloplasty. The aim of this retrospective study was to compare the long-term effectiveness of PB and CR annuloplasty in patients with degenerative mitral valve regurgitation (MR). METHODS: Between 1993 and 2010, a total of 1,612 patients with degenerative MR underwent mitral valve repair (MVr) with either PB (n = 1,101) or CR (n = 511). Initially, CR was the annuloplasty device of choice, but after 2001 PB was preferred. A retrospective review of clinical and echocardiographic follow up was performed on these patients. The eight-year cumulative freedom from adverse events were determined by life-table analysis. RESULTS: Hospital mortality was 1.9% overall (n = 30/1612), but 1.3% (12/939) for isolated MVr, and 2.7% (18/673) for MVr with concomitant procedures (p = 0.04). Hospital mortality was similar for both PB (1.9%; 21/1101) and CR (1.8%; 9/511) (p = 0.8). The mean MR grade was reduced from 3.9 +/- 0.3 preoperatively to 0.6 +/- 0.9 at follow up using PB (p < 0.01), and from 3.9 +/- 0.4 to 0.9 +/- 0.9 using CR (p < 0.01). PB was associated with a similar long term freedom from death (77 +/- 0.03% versus 83 +/- 0.02%; p = 0.4), reoperation (95 +/- 0.01% versus 92 +/- 0.01%; p = 0.06), and reoperation or recurrent severe MR (91 +/- 0.02% versus 92 +/- 0.01%; p = 0.7), and slightly greater freedom from valve-related complications compared to CR (91 +/- 0.02% versus 87 +/- 0.02%; p = 0.02). CONCLUSION: The long-term outcome of mitral valve annuloplasty with PB was comparable to that with CR for degenerative disease. Anterior annuloplasty was found to be unnecessary in this patient population. PMID- 24779331 TI - Neurocognitive deficit and quality of life after mitral valve repair. AB - BACKGROUND AND AIM OF THE STUDY: Postoperative cognitive dysfunction (POCD) is a relevant complication after cardiac surgery that affects patient outcome. The study aims was to prospectively evaluate neurocognitive functions, quality of life (QoL) and psychological distress following minimally invasive mitral valve (MV) repair. METHODS: A total of 98 consecutive patients (64 males, 34 females; mean age 53.7 +/- 10.3 years; mean logistic EuroSCORE 3.23 +/- 2.90) who underwent MV repair through a Hearthport Port-Access system was enrolled in the study. Neurocognitive evaluations were performed using the Mini-Mental State Examination, Trail-Making Test (TMT-A and -B) and digit span shortly before surgery, at hospital discharge, and at three months postoperatively. Measures of QoL (Medical Outcomes, Study Short Form, SF-36) and psychological distress (Hospital Anxiety and Depression Scale, HADS) were also undertaken. RESULTS: The large degree of POCD referred to in other studies was not observed; rather, a clear sign of improvement was observed when considering TMT-B (p <0.001) and digit span forward (p < 0.05) tests at the three-month follow up. These results also agreed with the QoL and mood state indices, which showed improvements (p < 0.05) in all SF-36 and HADS scores. No significant relationship was found between neurocognitive impairment and the cross-clamp and cardiopulmonary bypass times. CONCLUSION: The study results highlighted the low risk of neurocognitive deficits after MV repair. A substantial improvement in the patients' neurocognitive assessment and QoL, from the preoperative condition to the three-month follow up after surgery, was observed. However, the small number of patients demonstrating a clear cognitive decline made it difficult to identify causative factors for POCD. PMID- 24779332 TI - Impact of mitral valve geometry on hemodynamic efficacy of surgical repair in secondary mitral regurgitation. AB - BACKGROUND AND AIM OF THE STUDY: Mitral valve geometry is significantly altered secondary to left ventricular remodeling in non-ischemic and ischemic dilated cardiomyopathies. Since the extent of remodeling and asymmetry of dilatation of the ventricle differ significantly between individual patients, the valve geometry and tethering also differ. The study aim was to determine if mitral valve geometry has an impact on the efficacy of surgical repairs to eliminate regurgitation and restore valve closure in a validated experimental model. METHODS: Porcine mitral valves (n = 8) were studied in a pulsatile heart simulator, in which the mitral valve geometry can be precisely altered and controlled throughout the experiment. Baseline hemodynamics for each valve were measured (Control), and the valves were tethered in two distinct ways: annular dilatation with 7 mm apical papillary muscle (PM) displacement (Tether 1, symmetric), and annular dilatation with 7 mm apical, 7 mm posterior and 7 mm lateral PM displacement (Tether 2, asymmetric). Mitral annuloplasty was performed on each valve (Annular Repair), succeeded by anterior leaflet secondary chordal cutting (Sub-annular Repair). The efficacy of each repair in the setting of a given valve geometry was quantified by measuring the changes in mitral regurgitation (MR), leaflet coaptation length, tethering height and area. RESULTS: At baseline, none of the valves was regurgitant. Significant leaflet tethering was measured in Tether 2 over Tether 1, but both groups were significantly higher compared to baseline (60.9 +/- 31 mm2 for Control versus 129.7 +/- 28.4 mm2 for Tether 1 versus 186.4 +/- 36.3 mm2 for Tether 2). Consequently, the MR fraction was higher in Tether 2 group (23.0 +/- 5.7%) than in Tether 1 (10.5 +/- 5.5%). Mitral annuloplasty reduced MR in both groups, but remnant regurgitation after the repair was higher in Tether 2. After chordal cutting a similar trend was observed with trace regurgitation in Tether 1 group at 3.6 +/- 2.8%, in comparison to 18.6 +/- 4.2% in the Tether 2 group. CONCLUSION: In this experimental model, the tethering geometry of the mitral valve impacts the valve hemodynamics after annuloplasty and chordal cutting. The quantitative assessment of valve geometry may help in tailoring a repair to the specific tethering pattern. PMID- 24779333 TI - Extended posterior leaflet extension for mitral regurgitation in giant left atrium. AB - Giant left atrium is a rare condition, with a reported incidence of 0.3%, that is normally caused by rheumatic mitral valve disease but very rarely is caused by other etiologies. In such patients, annular dilatation with tenting and reduced height of the posterior leaflet result in significant mitral regurgitation. At surgery, the posterior leaflet was incised from the posterior mitral annulus, starting the incision at the mid portion of the mitral annulus and, if necessary, extending it to the anterolateral portion of the mitral annulus and the posteromedial portion of the mitral annulus. An autologous pericardial patch was harvested, depending on the incision. Herein is reported a surgical technique for posterior leaflet extension in patients with giant left atrium, without rheumatic disease. PMID- 24779334 TI - Intermediate results of transaortic edge-to-edge repair of the mitral valve in patients undergoing aortic valve replacement. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the safety and efficacy of a transaortic edge-to-edge mitral valve repair in patients undergoing aortic valve replacement (AVR) who were considered to be at high risk for double valve surgery. METHODS: All patients deemed to be at high surgical risk for standard double-valve surgery, and who instead underwent AVR with transaortic edge-to-edge mitral valve repair between September 2008 and October 2012 at the authors' institution, were analyzed retrospectively. Intraoperative transesophageal and follow-up transthoracic echocardiography were performed to evaluate adequacy of the repair and to assess for any recurrence of mitral regurgitation (MR). RESULTS: A total of 55 patients (mean age 78.4 +/- 8.4 years) was identified (45 minimally invasive, 10 median sternotomy). All patients were in NYHA class III-IV. The aortic valve lesion was classified as stenosis (n = 45), insufficiency (n = 6), or prosthetic valve insufficiency (n = 4), and the mitral valve lesion as functional (n = 16), degenerative calcification (n = 27), or rheumatic (n = 12). There were four deaths (7%). The median total hospital length of stay was 7 days (IQR 6-11 days). The median preoperative versus postoperative MR grade was moderate-to-severe (3+) (IQR 3-4+) versus 0 (IQR 0-1+) (p < 0.001). The median time to follow up echocardiography was 6.5 months (IQR 0.8-12 months). The median preoperative and postoperative versus follow up MR grades were 3+ (IQR 3-4+) versus 1+ (IQR 0-1+) (p < 0.001), and 0 (IQR 0-1+) versus 1+ (IQR 0-1+) (p = 0.004), respectively. CONCLUSION: In high-risk patients undergoing AVR with grade 3-4+ MR, a transaortic edge-to-edge mitral valve repair may be a safe and effective alternative to conventional double-valve surgery. However, longer-term data are needed to verify this proposal. PMID- 24779335 TI - Early hemodynamic performance of the BioValsalva valved conduit after aortic root replacement. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to examine the hemodynamic performance of the BioValsalva porcine aortic valve conduit in the aortic root position. METHODS: Between February 2007 and April 2012, a total of 223 patients underwent aortic root replacement at the authors' institution. The BioValsalva valved conduit was implanted in 131 patients, and 86 of these patients (mean age 64.7 +/- 9.7 years) consented to participate in the present study. The parameters assessed to evaluate prosthetic valve function included mean pressure gradient (MPG) as measured by transthoracic Doppler echocardiography, and the effective orifice area (EOA) by means of the continuity equation. Hemodynamic data were obtained from all 86 patients within 10 days and six months postoperatively. RESULTS: The mean aortic cross-clamp time was 103 +/- 30 min. Concomitant procedures were performed in 50 patients (56.5%). Four patients developed valve dysfunction due to endocarditis, and underwent a reoperation without the need to perform a redo Bentall. The early MPG across the implanted valve was 12 +/- 4.6 mmHg (range: 4-24.8 mmHg), and the early mean EOA was 1.81 +/- 0.6 cm2 (range: 0.9-3.2 cm2). After six months the MPG was 11.6 +/- 4.6 mmHg (range: 2.2-25.5 mmHg) and the EOA was 1.69 +/- 0.43 cm2 (range: 0.8-2.6 cm2). CONCLUSION: Based on its special design with a stentless valve, which is not incorporated into the proximal suture line, the BioValsalva conduit has an advantage over intraoperatively prepared conduits in cases of reoperation. Besides simplified intraoperative handling, the BioValsalva conduit exhibits good systolic hemodynamic performance with large EOAs. PMID- 24779336 TI - Long-term outcomes following Medtronic Open Pivot valved conduit. AB - BACKGROUND AND AIM OF THE STUDY: Aortic root replacement is a complex procedure, though subsequent modifications of the original Bentall procedure have made surgery more reproducible. The study aim was to examine the outcomes of a modified Bentall procedure, using the Medtronic Open PivotTM valved conduit. Whilst short-term data on the conduit and long-term data on the valve itself are available, little is known of the long-term results with the valved conduit. METHODS: Patients undergoing aortic root replacement between February 1999 and February 2010, using the Medtronic Open Pivot valved conduit were identified from the prospectively collected Cardiothoracic Register at The Prince Charles Hospital, Brisbane, Australia. All patients were followed up echocardiographically and clinically. The primary end-point was death, and a Cox proportional model was used to identify factors associated.with survival. Secondary end-points were valve-related morbidity (as defined by STS guidelines) and postoperative morbidity. Predictors of morbidity were identified using logistic regression. RESULTS: A total of 246 patients (mean age 50 years) was included in the study. The overall mortality was 12%, with actuarial 10-year survival 79% and a 10-year estimate of valve-related death of 0.04 (95% CI: 0.004, 0.07). Preoperative myocardial infarction (p = 0.004, HR 4.74), urgency of operation (p = 0.038, HR 2.8) and 10% incremental decreases in ejection fraction (p = 0.046, HR 0.69) were predictive of mortality. Survival was also affected by the valve gradients, with a unit increase in peak gradient reducing mortality (p = 0.021, HR 0.93). Valve-related morbidity occurred in 11 patients. Urgent surgery (p <0.001, OR 4.12), aortic dissection (p = 0.015, OR 3.35), calcific aortic stenosis (p = 0.016, OR 2.35) and Marfan syndrome (p 0.009, OR 3.75) were predictive of postoperative morbidity. The reoperation rate was 1.2%. CONCLUSION: The Medtronic Open Pivot valved conduit is a safe and durable option for aortic root replacement, and is associated with low morbidity and 10-year survival of 79%. However, further studies are required to determine the effect of valve gradient on survival. PMID- 24779337 TI - Early and mid-term functional and hemodynamic evaluation of the St. Jude Medical Regent 17 mm aortic valve mechanical prosthesis. AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to report the early and mid term clinical and hemodynamic results of a prospective trial investigating the clinical performance of the St. Jude Medical Regent 17 mm mechanical aortic valve prosthesis (SJMR-17). METHODS: Between January 2001 and January 2009, 20 patients (18 females, two males; mean age 69.2 +/- 7.3 years) with aortic valve stenosis underwent first-time aortic valve replacement (AVR) with the SJMR-17. The mean body surface area (BSA) was 1.68 +/- 0.2 m2, and the mean follow up was 18.7 +/- 9.2 months (range: 10-32 months). All patients were monitored with serial echocardiography; the first study was performed preoperatively, while subsequent controls were at two and six months, and within one year, respectively. All survivors underwent dobutamine stress testing (DSE) at one year after surgery. RESULTS: There was one death. At the six-month follow up the mean NYHA class was 1.3 +/- 0.6, and was significantly lower than preoperatively 2.75 +/- 0.86 (p < 0.0001). The peak and mean transprosthetic gradient (TPG) was 29 +/- 6.8 and 17.5 +/- 4.5 mmHg respectively, significantly lower than preoperatively. The left ventricular mass (LVM; g) and indexed left ventricular mass (LVMi; g/m2) were 191.0 +/- 22.6 g and 114.5 +/- 10.6 g/m2, respectively, and were significantly lower than preoperative values (258.0 +/- 40.0 g, p < 0.0001; and 157.0 +/- 26.0 g/m2, p = 0.00002). The mean TPG correlated well with the LVMi reduction (p = 0.033). During DSE, the peak and mean TPGs were increased significantly to 73.8 +/- 17.7 mmHg and 37 +/- 10.7 mmHg, respectively, significantly higher than at the basal (resting) state. Multivariate regression analysis identified the effective orifice area index, BSA, age and postoperative LVMi as strong predictors for a higher mean TPG. CONCLUSION: The SJMR-17 prosthesis might be employed with satisfactory postoperative clinical and hemodynamic outcome in patients with a small aortic annulus, especially in elderly patients, as an alternative to other valves, or to other surgical strategies such as annulus enlargement. PMID- 24779338 TI - In-vitro study of a porcine quadricuspid aortic valve. AB - BACKGROUND AND AIM OF THE STUDY: Quadricuspid aortic valve (QAV) is an extremely rare congenital defect in which the valve features an additional fourth cusp. It is often associated with an alteration in valve functionality such as valve regurgitation, stenosis and coronary disease. These associated pathologies entail surgical correction in about 50% of patients at a mean age of 50 years. METHODS: A swine QAV was studied in a pulsatile mock loop in the laboratory. Rest (70 bpm) and exercise (100 bpm) conditions were simulated, and opening and closing kinematics were evaluated from a high-speed video. Short- and long-axis echocardiograms were recorded. The pressure drop across the valve, valve competence and effective orifice area were evaluated and compared to data from healthy samples tested in the same experimental apparatus. RESULTS: Hemodynamic quantities were physiologic-like, despite the QAV showing an altered kinematics (longer closing and opening times compared to healthy samples) and an asynchronous closing phase (the extra cusps reached the closed configuration at the end of systole systematically earlier with respect to the other three cusps). Echocardiographic data showed an increased coaptation height between the left and right coronary cusps, and a mismatch between the lunule of the extra cusp and the non-coronary cusp. CONCLUSION: The altered kinematics, together with incorrect coaptation, can alter the biomechanics of the structure, inducing an anomalous distribution of local stress which could lead to structural failure over time. PMID- 24779339 TI - Bentall operation in 375 patients: long-term results and predictors of death. AB - BACKGROUND AND AIM OF THE STUDY: The Bentall operation is a 40-year-old standardized procedure for treating aortic valve diseases and aneurysms involving the aortic root. The study aim was to analyze the results and predictors of long term outcome after the Bentall procedure for aortic root diseases. METHODS: Between January 1990 and December 2007, a total of 375 patients (296 males, 79 females) underwent the Bentall operation at the authors' institution. Bicuspid aortic valve (BAV) was present in 91 patients, and Marfan syndrome in 13. Thirty six patients were treated as emergencies, and 30 for acute dissection. A concomitant surgical procedure was performed in 78 patients. The operative procedure included both classic Bentall and button techniques. Follow up data were obtained from hospital and office records and from telephone contacts. Kaplan-Meier survival analysis and Cox regression analysis were performed to investigate the predictors of long-term outcome. RESULTS: The overall in-hospital mortality was 4.5%, and after elective operations was 2.3%. A 20-year long-term follow up included 32 late deaths, of which 14 were cardiac-related. Freedom from late all-cause mortality at 5, 10, and 15 years was 97.1%, 81.9%, and 53.9%, respectively. At univariate analysis, long-term mortality was associated with age, diabetes, BAV, NYHA class III/IV, emergency treatment, cardiopulmonary bypass time, and coronary artery bypass grafting. Independent predictors of long term mortality were age (OR 1.16; CI: 1.08-1.23), emergency surgery (OR 28; CI: 4 192) and BAV (OR 3; CI: 1.3-6.9). CONCLUSION: The Bentall procedure is a safe and durable operation, with a very good early and long-term results and a low rate of reoperation. In the present series, age, BAV and emergency surgery were important independent predictors of mortality. PMID- 24779340 TI - Aortic transection with superior biatrial trans-septal approach for triple valve re-do procedures. AB - The repair of atrioventricular valves requires optimal valve exposure through even unconventional surgical approaches. This is especially true in the situation of multiple re-do valve surgeries, where extensive adhesions may prevent adequate valve exposure. When multiple valve surgeries are contemplated, an extensive incisional approach is required without causing damage to any surrounding crucial structures. Re-do surgeries are described in patients with prosthetic valve endocarditis where the correction of all valves involved is necessary, as is the correction of underlying ventricular pathologies such as sinuses and atrioventricular tunnels. As several surgical approaches have been attempted in these situations, a technique is described which involves a superior biatrial approach after transecting the aorta, which addresses the mitral, tricuspid and aortic valves and allows the correction of associated ventricular pathologies. PMID- 24779341 TI - Simultaneous transapical paraprosthetic leak occlusion and valve-in-valve implantation into a degenerated mitral bioprosthesis. AB - Transcatheter valve-in-valve implantation is an emerging treatment option for high-risk patients with failing mitral bioprostheses. The presence of a paravalvular leak is considered a contraindication to this procedure that would leave the patient with significant residual regurgitation. The case is described of a patient with a severely degenerated 29 mm Carpentier-Edwards mitral bioprosthesis successfully treated by simultaneous transapical transcatheter valve-in-valve implantation and paraprosthetic leak occlusion. The potential advantages of this approach are discussed. PMID- 24779342 TI - Dynamic tricuspid valve stenosis induced with a pacemaker lead: a case report. AB - Isolated severe tricuspid valve stenosis due to an endocardial pacemaker lead is extremely rare, and is usually caused by either fibrosis of a perforated or lacerated leaflet, or fibrotic adherence between the lead and the valvular apparatus. Reported cases typically include clinical manifestations of both systemic venous stasis and low cardiac output. The case is presented of a 20-year old female with a surgically repaired congenital heart disease who developed severe tricuspid stenosis at six years after the implantation of a DDD pacemaker. Unexpectedly, the patient had no signs of venous stasis and suffered only from exercise intolerance. Right heart catheterization under fluoroscopic guidance revealed an atrial lead forming a loop at the level of the tricuspid valve. A paradoxical inspiratory decrease in the transvalvular diastolic gradient, caused by the caudal heart motion and straightening of the loop during inspiration, was noted. Such a dynamic nature with a temporary inspiratory relief of the obstruction may explain the partial clinical presentation of tricuspid stenosis in this case. The lead was removed and the tricuspid valve repaired surgically, after which the patient's recovery was uneventful with normalization of exercise tolerance. PMID- 24779343 TI - Multifunctional ultrasound contrast agents for imaging guided photothermal therapy. AB - Among all the imaging techniques, ultrasound imaging has a unique advantage due to its features of real-time, low cost, high safety, and portability. Ultrasound contrast agents (UCAs) have been widely used to enhance ultrasonic signals. One of the most exciting features of UCAs for use in biomedicine is the possibility of easily putting new combinations of functional molecules into microbubbles (MBs), which are the most routinely used UCAs. Various therapeutic agents and medical nanoparticles (quantum dots, gold, Fe3O4, etc.) can be loaded into ultrasound-responsive MBs. Hence, UCAs can be developed as multifunctional agents that integrate capabilities for early detection and diagnosis and for imaging guided therapy of various diseases. The current review will focus on such state of-the-art UCA platforms that have been exploited for multimodal imaging and for imaging guided photothermal therapy. PMID- 24779344 TI - Predicting geogenic arsenic contamination in shallow groundwater of south Louisiana, United States. AB - Groundwater contaminated with arsenic (As) threatens the health of more than 140 million people worldwide. Previous studies indicate that geology and sedimentary depositional environments are important factors controlling groundwater As contamination. The Mississippi River delta has broadly similar geology and sedimentary depositional environments to the large deltas in South and Southeast Asia, which are severely affected by geogenic As contamination and therefore may also be vulnerable to groundwater As contamination. In this study, logistic regression is used to develop a probability model based on surface hydrology, soil properties, geology, and sedimentary depositional environments. The model is calibrated using 3286 aggregated and binary-coded groundwater As concentration measurements from Bangladesh and verified using 78 As measurements from south Louisiana. The model's predictions are in good agreement with the known spatial distribution of groundwater As contamination of Bangladesh, and the predictions also indicate high risk of As contamination in shallow groundwater from Holocene sediments of south Louisiana. Furthermore, the model correctly predicted 79% of the existing shallow groundwater As measurements in the study region, indicating good performance of the model in predicting groundwater As contamination in shallow aquifers of south Louisiana. PMID- 24779346 TI - What is the risk of aluminium as a neurotoxin? AB - Aluminium is neurotoxic. Its free ion, Al(3+) (aq), is highly biologically reactive and uniquely equipped to do damage to essential cellular (neuronal) biochemistry. This unequivocal fact must be the starting point in examining the risk posed by aluminium as a neurotoxin in humans. Aluminium is present in the human brain and it accumulates with age. The most recent research demonstrates that a significant proportion of individuals older than 70 years of age have a potentially pathological accumulation of aluminium somewhere in their brain. What are the symptoms of chronic aluminium intoxication in humans? What if neurodegenerative diseases such as Alzheimer's disease are the manifestation of the risk of aluminium as a neurotoxin? How might such an (outrageous) hypothesis be tested? PMID- 24779347 TI - Life cycle GHG emissions from microalgal biodiesel--a CA-GREET model. AB - A life cycle assessment (LCA) focused on greenhouse gas (GHG) emissions from the production of microalgal biodiesel was carried out based on a detailed engineering and economic analysis. This LCA applies the methodology of the California Low Carbon Fuel Standard (CA LCFS) and uses life cycle inventory (LCI) data for process inputs, based on the California-Modified Greenhouse Gases, Regulated Emissions, and Energy use in Transportation (CA GREET) model. Based on detailed mass and energy balances, calculated GHG emissions from this algal biodiesel system are 70% lower than those of conventional diesel fuel, meeting the minimum 50% GHG reduction requirements under the EPA RFS2 and 60% for the European Union Renewable Energy Directive. This LCA study provides a guide to the research and development objectives that must be achieved to meet both economic and environmental goals for microalgae biodiesel production. PMID- 24779345 TI - Immunocompetent murine models for the study of glioblastoma immunotherapy. AB - Glioblastoma remains a lethal diagnosis with a 5-year survival rate of less than 10%. (NEJM 352:987-96, 2005) Although immunotherapy-based approaches are capable of inducing detectable immune responses against tumor-specific antigens, improvements in clinical outcomes are modest, in no small part due to tumor induced immunosuppressive mechanisms that promote immune escape and immuno resistance. Immunotherapeutic strategies aimed at bolstering the immune response while neutralizing immunosuppression will play a critical role in improving treatment outcomes for glioblastoma patients. In vivo murine models of glioma provide an invaluable resource to achieving that end, and their use is an essential part of the preclinical workup for novel therapeutics that need to be tested in animal models prior to testing experimental therapies in patients. In this article, we review five contemporary immunocompetent mouse models, GL261 (C57BL/6), GL26 (C57BL/6) CT-2A (C57BL/6), SMA-560 (VM/Dk), and 4C8 (B6D2F1), each of which offer a suitable platform for testing novel immunotherapeutic approaches. PMID- 24779348 TI - An investigation of G-quadruplex structural polymorphism in the human telomere using a combined approach of hydrodynamic bead modeling and molecular dynamics simulation. AB - Guanine-rich oligonucleotides can adopt noncanonical tertiary structures known as G-quadruplexes, which can exist in different forms depending on experimental conditions. High-resolution structural methods, such as X-ray crystallography and NMR spectroscopy, have been of limited usefulness in resolving the inherent structural polymorphism associated with G-quadruplex formation. The lack of, or the ambiguous nature of, currently available high-resolution structural data, in turn, has severely hindered investigations into the nature of these structures and their interactions with small-molecule inhibitors. We have used molecular dynamics in conjunction with hydrodynamic bead modeling to study the structures of the human telomeric G-quadruplex-forming sequences at the atomic level. We demonstrated that molecular dynamics can reproduce experimental hydrodynamic measurements and thus can be a powerful tool in the structural study of existing G-quadruplex sequences or in the prediction of new G-quadruplex structures. PMID- 24779349 TI - High resolution metabolite imaging in the hippocampus following neonatal exposure to the environmental toxin BMAA using ToF-SIMS. AB - The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is suggested to be linked with neurodegenerative disease. In a rat model, neonatal exposure to BMAA induced selective uptake in the hippocampus and caused cell loss, mineralization and astrogliosis as well as learning and memory impairments in adulthood. Moreover, neonatal exposure resulted in increased protein ubiquitination in the cornus ammonis 1 (CA1) region of the adult hippocampus indicating that BMAA may induce protein aggregation. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) based imaging is a powerful technology for spatial profiling of small molecular weight compounds in biological tissues with high chemical specificity and high spatial resolution. The aim of this study was to characterize neurochemical changes in the hippocampus of six month-old rats treated neonatally (postnatal days 9-10) with BMAA. Multivariate data analysis of whole section ToF-SIMS scans was performed to delineate anatomical regions of interest based on their chemical distribution pattern. Further analysis of spectral data obtained from the outlined anatomical regions, including CA1 and dentate gyrus (DG) revealed BMAA-induced long-term changes. Increased levels of phospholipids and protein fragments in the histopathologically altered CA1 region as well as phosphate depletion in the DG were observed. Moreover, high resolution SIMS imaging revealed a specific localization of phosphatidylcholine lipids, protein signals and potassium in the histopathologically altered CA1. These findings demonstrate that ToF-SIMS based imaging is a powerful approach for probing biochemical changes in situ and might serve as promising technique for investigating neurotoxin-induced brain pathology. PMID- 24779350 TI - Role of vascular endothelial growth factor in the pathophysiology of intracranial arteriovenous malformations. PMID- 24779351 TI - Response to "Role of surgical versus endovascular embolectomy for the treatment of acute large vessel occlusion". PMID- 24779352 TI - Genetic Diversity, Reassortment, and Recombination in Alfalfa mosaic virus Population in Spain. AB - The variability and genetic structure of Alfalfa mosaic virus (AMV) in Spain was evaluated through the molecular characterization of 60 isolates collected from different hosts and different geographic areas. Analysis of nucleotide sequences in four coding regions--P1, P2, movement protein (MP), and coat protein (CP)- revealed a low genetic diversity and different restrictions to variation operating on each coding region. Phylogenetic analysis of Spanish isolates along with previously reported AMV sequences showed consistent clustering into types I and II for P1 and types I, IIA, and IIB for MP and CP regions. No clustering was observed for the P2 region. According to restriction fragment length polymorphism analysis, the Spanish AMV population consisted of seven haplotypes, including two haplotypes generated by reassortment and one involving recombination. The most frequent haplotypes (types for P1, MP, and CP regions, respectively) were I-I-I (37%), II-IIB-IIB (30%), and one of the reassortants, II-I-I (17%). Distribution of haplotypes was not uniform, indicating that AMV population was structured according to the geographic origin of isolates. Our results suggest that agroecological factors are involved in the maintenance of AMV genetic types, including the reassortant one, and in their geographic distribution. PMID- 24779353 TI - Melanin-independent accumulation of turgor pressure in appressoria of Phakopsora pachyrhizi. AB - Appressoria of some plant-pathogenic fungi accumulate turgor pressure that produces a mechanical force enabling the direct penetration of hyphae through the epidermis. Melanin functions as an impermeable barrier to osmolytes, which allows appressoria to accumulate high turgor pressure. Deficiency of melanin in appressoria reduces turgor pressure and compromises the infection process. In Phakopsora pachyrhizi, the soybean rust pathogen, the appressoria are hyaline. Our objective was to ensure the absence of a melanin layer specifically between the appressorial cell wall and plasma membrane, as well as to determine the turgor pressure of P. pachyrhizi appressoria. We demonstrated that two melanin biosynthesis inhibitors neither reduced turgor pressure nor compromised the infection process. Transmission electron microscopy also showed the absence of a melanin layer between the appressorial cell wall and plasma membrane. In addition, the turgor pressure of P. pachyrhizi appressoria was 5 to 6 MPa, based on extracellular osmolytes used to simulate different osmotic pressures. This is the first report showing that turgor pressure accumulation of P. pachyrhizi appressoria was independent of melanin. PMID- 24779354 TI - Virulence and Molecular Analyses Support Asexual Reproduction of Puccinia striiformis f. sp. tritici in the U.S. Pacific Northwest. AB - Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici, occurs every year and causes significant yield losses in the U.S. Pacific Northwest (PNW). A large number of P. striiformis f. tritici races are identified every year and predominant races have changed rapidly. Barberry and mahonia plants, which have been identified under controlled conditions as alternate hosts for the fungus, are found in the region. However, whether sexual reproduction occurs in the P. striiformis f. sp. tritici population under natural conditions is not clear. To determine the reproduction mode of the P. striiformis f. sp. tritici population using virulence and molecular markers, a systematic collection of leaf samples with a single stripe of uredia was made in 26 fields in the PNW in 2010. In total, 270 isolates obtained from the PNW collection, together with 66 isolates from 20 other states collected in the same year, were characterized by virulence tests and simple sequence repeat (SSR) markers. In total, 21 races and 66 multilocus genotypes (MLGs) were detected, of which 15 races and 32 MLGs were found in the PNW. Cluster analysis with the SSR marker data revealed two genetic groups, which were significantly correlated to the two virulence groups. The analyses of genotype/individual ratio, multilocus linkage disequilibrium, and heterozygosity strongly supported asexual reproduction for the pathogen population in the PNW, as well as other regions of the United States. PMID- 24779355 TI - Fusarium graminearum Possesses Virulence Factors Common to Fusarium Head Blight of Wheat and Seedling Rot of Soybean but Differing in Their Impact on Disease Severity. AB - Fusarium graminearum is a toxigenic fungal pathogen that causes Fusarium head blight (FHB) and crown rot on cereal crops worldwide. This fungus also causes damping-off and crown and root rots at the early stage of crop development in soybean cultivated in North and South America. Several F. graminearum genes were investigated for their contribution to FHB in cereals but no inherent study is reported for the dicotyledonous soybean host. In this study we determined the disease severity on soybean seedlings of five single gene disrupted mutants of F. graminearum, previously characterized in wheat spike infection. Three of these mutants are impaired on a specific function as the production of deoxynivalenol (DON, Deltatri5), lipase (DeltaFgl1), and xylanase (Deltaxyl03624), while the remaining two are MAP kinase mutants (DeltaFgOS-2, Deltagpmk1), which are altered in signaling pathways. The mutants that were reduced in virulence (Deltatri5, DeltaFgl1, and DeltaFgOS-2) or are avirulent (Deltagpmk1) on wheat were correspondently less virulent or avirulent in soybean seedlings, as shown by the extension of lesions and seedling lengths. The Deltaxyl03624 mutant was as virulent as the wild type mirroring the behavior observed in wheat. However, a different ranking of symptom severity occurred in the two hosts: the DeltaFgOS-2 mutant, that infects wheat spikelets similarly to Deltatri5 and DeltaFgl1 mutants, provided much reduced symptoms in soybean. Differently from the other mutants, we observed that the DeltaFgOS-2 mutant was several fold more sensitive to the glyceollin phytoalexin suggesting that its reduced virulence may be due to its hypersensitivity to this phytoalexin. In conclusion, lipase and DON seem important for full disease symptom development in soybean seedlings, OS-2 and Gpmk1 MAP kinases are essential for virulence, and OS-2 is involved in conferring resistance to the soybean phytoalexin. PMID- 24779356 TI - A simple and inexpensive point-of-care test for hepatitis B surface antigen detection: serological and molecular evaluation. AB - Early identification of chronic hepatitis B is important for optimal disease management and prevention of transmission. Cost and lack of access to commercial hepatitis B surface antigen (HBsAg) immunoassays can compromise the effectiveness of HBV screening in resource-limited settings and among marginalized populations. High-quality point-of-care (POC) testing may improve HBV diagnosis in these situations. Currently available POC HBsAg assays are often limited in sensitivity. We evaluated the NanoSign((r)) HBs POC chromatographic immunoassay for its ability to detect HBsAg of different genotypes and with substitutions in the 'a' determinant. Thirty-seven serum samples from patients with HBV infection, covering HBV genotypes A-G, were assessed for HBsAg titre with the Roche Elecsys HBsAg II quantification assay and with the POC assay. The POC assay reliably detected HBsAg at a concentration of at least 50 IU/mL for all genotypes, and at lower concentrations for some genotypes. Eight samples with substitutions in the HBV 'a' determinant were reliably detected after a 1/100 dilution. The POC strips were used to screen serum samples from 297 individuals at risk for HBV in local clinical settings (health fairs and outreach events) in parallel with commercial laboratory HBsAg testing (Quest Diagnostics EIA). POC testing was 73.7% sensitive and 97.8% specific for detection of HBsAg. Although the POC test demonstrated high sensitivity over a range of genotypes, false negatives were frequent in a clinical setting. Nevertheless, the POC assay offers advantages for testing in both developed and resource-limited countries due to its low cost (0.50$) and immediately available results. PMID- 24779357 TI - Experimental selection of long-term intracellular mycobacteria. AB - Some intracellular bacteria are known to cause long-term infections that last decades without compromising the viability of the host. Although of critical importance, the adaptations that intracellular bacteria undergo during this long process of residence in a host cell environment remain obscure. Here, we report a novel experimental approach to study the adaptations of mycobacteria imposed by a long-term intracellular lifestyle. Selected Mycobacterium bovis BCG through continuous culture in macrophages underwent an adaptation process leading to impaired phenolic glycolipids (PGL) synthesis, improved usage of glucose as a carbon source and accumulation of neutral lipids. These changes correlated with increased survival of mycobacteria in macrophages and mice during re-infection and also with the specific expression of stress- and survival-related genes. Our findings identify bacterial traits implicated in the establishment of long-term cellular infections and represent a tool for understanding the physiological states and the environment that bacteria face living in fluctuating intracellular environments. PMID- 24779358 TI - Effects of methyl jasmonate and salicylic acid on tanshinone production and biosynthetic gene expression in transgenic Salvia miltiorrhiza hairy roots. AB - Tanshinone is a group of active diterpenes, which are widely used in the treatment of cardiovascular disease. In this study, methyl jasmonate (MJ) and salicylic acid (SA) were used to investigate their effects on tanshinone accumulation and biosynthetic gene expression in the hairy roots of geranylgeranyl diphosphate synthase (SmGGPPS) overexpression line (G50) in Salvia miltiorrhiza. High-performance liquid chromatography analysis showed that total tanshinone content in G50 was obviously increased by 3.10-fold (11.33 mg/g) with MJ at 36 H and 1.63 times (5.95 mg/g) after SA treatment for 36 H in comparison with their mimic treatment control. Furthermore, quantitative reverse transcription PCR analysis showed that the expression of isopentenyl-diphosphate delta-isomerase (SmIPPI), SmGGPPS, copalyl diphosphate synthase (SmCPS), and kaurene synthase-like (SmKSL) increased significantly with MJ treatment. However, the expression of SmIPPI reached the highest level at 144 H, whereas those of SmGGPPS, SmCPS, and SmKSL only increased slightly with SA treatment. The two elicitor treatments suggested that tanshinone accumulation positively correlated to the expression of key genes such as SmGGPPS, SmCPS, and SmKSL. Meanwhile, the study also indicated that it was a feasible strategy to combine elicitor treatment with transgenic technology for the enhancement of tanshinone, which paved the way for further metabolic engineering of tanshinone biosynthesis. PMID- 24779359 TI - Comparative study of the enological potential of different winemaking byproducts: implications in the antioxidant activity and color expression of red wine anthocyanins in a model solution. AB - Different white winemaking byproducts (pomace, skins, seeds, and stems) were compared as natural sources of phenolic compounds having biological and sensory properties of enological interest. Antioxidant and copigmentation effects of these byproducts were studied in a wine-like model solution. RRLC-DAD was used to establish differences in the phenolic composition, and the ABTS method was used to compare the antioxidant activities. Spectrophotometric and colorimetric analyses were performed to assess the magnitude of copigmentation and the changes induced in the color expression of red wine anthocyanins. Antioxidant and copigmentation properties significantly varied depending on the type of byproduct, which was related to their qualitative and quantitative phenolic composition. Seeds and pomace showed the highest antioxidant potential, whereas skins and pomace led to the strongest and visually perceptible color effects on red wine anthocyanins by multiple copigmentation (darker, more saturated, and vivid bluish colors). Results open the possibility of technological applications for the wine industry based on reusing winemaking byproducts to improve the biological value and color characteristics of red wines. PMID- 24779360 TI - Experiences of employees with arm, neck or shoulder complaints: a focus group study. AB - BACKGROUND: Many people suffer from complaints of the arm, neck or shoulder (CANS). CANS causes significant work problems, including absenteeism (sickness absence), presenteeism (decreased work productivity) and, ultimately, job loss. There is a need for intervention programs for people suffering from CANS. Management of symptoms and workload, and improving the workstyle, could be important factors in the strategy to deal with CANS. The objective of this study is to evaluate the experienced problems of employees with CANS, as a first step in an intervention mapping process aimed at adaptation of an existing self management program to the characteristics of employees suffering from CANS. METHODS: A qualitative study comprising three focus group meetings with 15 employees suffering from CANS. Based on a question guide, participants were asked about experiences in relation to continuing work despite their complaints. Data were analysed using content analysis with an open-coding system. During selective coding, general themes and patterns were identified and relationships between the codes were examined. RESULTS: Participants suffering from CANS often have to deal with pain, disability, fatigue, misunderstanding and stress at work. Some needs of the participants were identified, i.e. disease-specific information, exercises, muscle relaxation, working with pain, influence of the work and/or social environment, and personal factors (including workstyle). CONCLUSIONS: Employees suffering from CANS search for ways to deal with their complaints in daily life and at work. This study reveals several recurring problems and the results endorse the multi-factorial origin of CANS. Participants generally experience problems similar to those of employees with other types of complaints or chronic diseases, e.g. related to their illness, insufficient communication, working together with healthcare professionals, colleagues and management, and workplace adaptations. These topics will be addressed in the adaptation of an existing self-management program to the characteristics of employees suffering from CANS. PMID- 24779361 TI - Is sexual function in female partners of men with premature ejaculation compromised? AB - The authors enrolled 32 female partners of sexually active men with premature ejaculation to investigate their sexual functions. An age-matched sample of the same number women whose partners had no sexual dysfunction was also included. Premature ejaculation was defined for all participants as ejaculation that nearly always occurs before or within 2 min of vaginal penetration. An invitation letter was given to men with premature ejaculation to ask whether their female partners could be contacted about completing a questionnaire to measure female sexual status. On the basis of the Female Sexual Function Index, the average sexual function score was significantly lower in partners of men with premature ejaculation (21.8 +/- 7.6) compared with that in healthy controls (25.9 +/- 6.6). Female sexual dysfunction was diagnosed in 78% of women who has a male partner with premature ejaculation, while 40% of female partner of healthy men. All of the domain scores of Female Sexual Function Index, except the desire and pain levels, were significantly lower in female partners of men with premature ejaculation group than those of healthy subjects. PMID- 24779363 TI - Abstracts of the 9th International Conference on Cryptococcus and Cryptococcosis, 15-19 May, 2014, Amsterdam, the Netherlands. PMID- 24779362 TI - The tyrosine kinase inhibitor bafetinib inhibits PAR2-induced activation of TRPV4 channels in vitro and pain in vivo. AB - BACKGROUND AND PURPOSE: Protease-activated receptor 2 (PAR2) is expressed on nociceptive neurons, and can sensitize transient receptor potential (TRP) ion channels to amplify neurogenic inflammation and pain. The mechanisms by which this occurs are not fully understood. PAR2 causes receptor-operated activation of TRPV4 channels and TRPV4 null mice have attenuated PAR2-stimulated neurogenic inflammation and mechanical hyperalgesia. Here we investigate the intracellular signalling mechanisms underlying PAR2-induced TRPV4 channel activation and pain. EXPERIMENTAL APPROACH: Responses of non-transfected and TRPV4-transfected HEK293 cells to agonists of PAR2 (trypsin and SLIGRL) and TRPV4 channels (GSK1016790A) were determined using calcium imaging. Inhibitors of TRPV4 channels (HC067047), sarcoendoplasmic reticulum calcium transport ATPase (thapsigargin), Galphaq (UBO QIC), tyrosine kinases (bafetinib and dasatinib) or PI3 kinases (wortmannin and LY294002) were used to investigate signalling mechanisms. In vivo effects of tyrosine kinase inhibitors on PAR2 -induced mechanical hyperalgesia were assessed in mice. KEY RESULTS: In non-transfected HEK293 cells, PAR2 activation transiently increased intracellular calcium ([Ca(2+) ]i ). Functional expression of TRPV4 channels caused a sustained increase of [Ca(2+) ]i , inhibited by HC067047, bafetinib and wortmannin; but not by thapsigargin, UBO-QIC, dasatinib or LY294002. Bafetinib but not dasatinib inhibited PAR2-induced mechanical hyperalgesia in vivo. CONCLUSIONS AND IMPLICATIONS: This study supports a role for tyrosine kinases in PAR2-mediated receptor-operated gating of TRPV4 channels, independent of Galphaq stimulation. The ability of a tyrosine kinase inhibitor to diminish PAR2-induced activation of TRPV4 channels and consequent mechanical hyperalgesia identifies bafetinib (which is in development in oncology) as a potential novel analgesic therapy. PMID- 24779364 TI - Lymphocytic ganglioneuritis secondary to intervertebral disc extrusion in a dog. AB - This study presents a case of lymphocytic ganglioneuritis in a dog secondary to intervertebral disc extrusion that mimicked a peripheral nerve sheath tumour on magnetic resonance imaging. A four-year-old spayed female dachshund with lumbar pain was imaged via magnetic resonance. A tubular, space-occupying, contrast enhancing lesion was noted in the right intervertebral foramen at L6 to L7. This was presumed to represent focal enlargement of the right sixth lumbar spinal nerve. A right-sided haemilaminectomy was performed at L6 to L7 and material that grossly resembled extruded nucleus pulposus was removed. The right L6 dorsal root ganglion, dorsal nerve root and proximal spinal nerve were severely enlarged and a partial thickness biopsy was collected from the dorsal root ganglion. Results of histopathological examination of the submitted tissue samples were consistent with extruded disc material and lymphocytic ganglioneuritis. To the author's knowledge, this is the first published report of lymphocytic ganglioneuritis secondary to intervertebral disc disease in a dog. PMID- 24779365 TI - Cytotoxicity and activation of the Wnt/beta-catenin pathway in mouse embryonic stem cells treated with four GSK3 inhibitors. AB - BACKGROUND: Small membrane-permeable molecules are now widely used during maintenance and differentiation of embryonic stem cells of different species. In particular the glycogen synthase kinase 3 (GSK3) is an interesting target, since its chemical inhibition activates the Wnt/beta-catenin pathway. In the present comparative study four GSK3 inhibitors were characterized. METHODS: Cytotoxicity and potential to activate the Wnt/beta-catenin pathway were tested using the commonly used GSK3 inhibitors BIO, SB-216763, CHIR-99021, and CHIR-98014. Wnt/beta-catenin-dependent target genes were measured by quantitative PCR to confirm the Wnt-reporter assay and finally EC50-values were calculated. RESULTS: CHIR-99021 and SB-216763 had the lowest toxicities in mouse embryonic stem cells and CHIR-98014 and BIO the highest toxicities. Only CHIR-99021 and CHIR-98014 lead to a strong induction of the Wnt/beta-catenin pathway, whereas BIO and SB 216763 showed a minor or no increase in activation of the Wnt/beta-catenin pathway over the natural ligand Wnt3a. The data from the Wnt-reporter assay were confirmed by gene expression analysis of the TCF/LEF regulated gene T. CONCLUSIONS: Out of the four tested GSK3 inhibitors, only CHIR-99021 and CHIR 98014 proved to be potent pharmacological activators of the Wnt/beta-catenin signaling pathway. But only in the case of CHIR-99021 high potency was combined with very low toxicity. PMID- 24779366 TI - RECLU: a pipeline to discover reproducible transcriptional start sites and their alternative regulation using capped analysis of gene expression (CAGE). AB - BACKGROUND: Next generation sequencing based technologies are being extensively used to study transcriptomes. Among these, cap analysis of gene expression (CAGE) is specialized in detecting the most 5' ends of RNA molecules. After mapping the sequenced reads back to a reference genome CAGE data highlights the transcriptional start sites (TSSs) and their usage at a single nucleotide resolution. RESULTS: We propose a pipeline to group the single nucleotide TSS into larger reproducible peaks and compare their usage across biological states. Importantly, our pipeline discovers broad peaks as well as the fine structure of individual transcriptional start sites embedded within them. We assess the performance of our approach on a large CAGE datasets including 156 primary cell types and two cell lines with biological replicas. We demonstrate that genes have complicated structures of transcription initiation events. In particular, we discover that narrow peaks embedded in broader regions of transcriptional activity can be differentially used even if the larger region is not. CONCLUSIONS: By examining the reproducible fine scaled organization of TSS we can detect many differentially regulated peaks undetected by previous approaches. PMID- 24779368 TI - Orthostatic hypotension in older adults with dementia. AB - Orthostatic hypotension (OH) in older adults with dementia is associated with increased confusion, dizziness, syncope, and falls. These problems may result in a negative, downward spiral accompanied by high morbidity and mortality. The literature supports that nonpharmacological interventions are effective in the reduction of symptoms and prevention of orthostasis. The purpose of this quality improvement project was to increase staff knowledge and skill in the assessment, documentation, and care of residents with OH in dementia care units within a continuing care retirement community. An in-service program using a protocol based on clinical practice guidelines was presented to RNs, licensed practical nurses, therapists, and unlicensed caregivers. Assessments, documentation of assessments, and interventions for residents with OH increased following the in service program. As staff continue to apply their knowledge in care routines, it is expected that this evidence-based practice will reduce symptoms of OH and increase safety and quality of life within this specific population. PMID- 24779367 TI - TGF-beta signalling in the adult neurogenic niche promotes stem cell quiescence as well as generation of new neurons. AB - Members of the transforming growth factor (TGF)-beta family govern a wide range of mechanisms in brain development and in the adult, in particular neuronal/glial differentiation and survival, but also cell cycle regulation and neural stem cell maintenance. This clearly created some discrepancies in the field with some studies favouring neuronal differentiation/survival of progenitors and others favouring cell cycle exit and neural stem cell quiescence/maintenance. Here, we provide a unifying hypothesis claiming that through its regulation of neural progenitor cell (NPC) proliferation, TGF-beta signalling might be responsible for (i) maintaining stem cells in a quiescent stage, and (ii) promoting survival of newly generated neurons and their functional differentiation. Therefore, we performed a detailed histological analysis of TGF-beta1 signalling in the hippocampal neural stem cell niche of a transgenic mouse that was previously generated to express TGF-beta1 under a tetracycline regulatable Ca-Calmodulin kinase promoter. We also analysed NPC proliferation, quiescence, neuronal survival and differentiation in relation to elevated levels of TGF-beta1 in vitro and in vivo conditions. Finally, we performed a gene expression profiling to identify the targets of TGF-beta1 signalling in adult NPCs. The results demonstrate that TGF-beta1 promotes stem cell quiescence on one side, but also neuronal survival on the other side. Thus, considering the elevated levels of TGF beta1 in ageing and neurodegenerative diseases, TGF-beta1 signalling presents a molecular target for future interventions in such conditions. PMID- 24779369 TI - Return visits to the emergency department: what can we learn from older adults' experiences? AB - Unscheduled return visits to the emergency department (ED) represent a considerable segment of older adults' total visits to the ED. This study explores the factors that led to early return visits to the ED by older adults. Using a qualitative descriptive design, semi-structured interviews were conducted in a large teaching hospital with 15 older adults who returned to the ED within 2 weeks after an initial visit. From the interviews, three major themes emerged as precipitants that led older adults to return to the ED. These were Managing the Symptoms, Care Curing the Initial ED Visit, and Who I Am. The findings suggest that the main reason for older adults' return to the ED is the severity of the symptoms they experienced. Ensuring the timeliness of follow-up appointments and the provision of resources to support the transition home are identified as interventions that would improve the care provided in EDs. PMID- 24779370 TI - Myocardial perfusion and oxygenation are impaired during stress in severe aortic stenosis and correlate with impaired energetics and subclinical left ventricular dysfunction. AB - BACKGROUND: Left ventricular (LV) hypertrophy in aortic stenosis (AS) is characterized by reduced myocardial perfusion reserve due to coronary microvascular dysfunction. However, whether this hypoperfusion leads to tissue deoxygenation is unknown. We aimed to assess myocardial oxygenation in severe AS without obstructive coronary artery disease, and to investigate its association with myocardial energetics and function. METHODS: Twenty-eight patients with isolated severe AS and 15 controls underwent cardiovascular magnetic resonance (CMR) for assessment of perfusion (myocardial perfusion reserve index-MPRI) and oxygenation (blood-oxygen level dependent-BOLD signal intensity-SI change) during adenosine stress. LV circumferential strain and phosphocreatine/adenosine triphosphate (PCr/ATP) ratios were assessed using tagging CMR and 31P MR spectroscopy, respectively. RESULTS: AS patients had reduced MPRI (1.1 +/- 0.3 vs. controls 1.7 +/- 0.3, p < 0.001) and BOLD SI change during stress (5.1 +/- 8.9% vs. controls 18.2 +/- 10.1%, p = 0.001), as well as reduced PCr/ATP (1.45 +/ 0.21 vs. 2.00 +/- 0.25, p < 0.001) and LV strain (-16.4 +/- 2.7% vs. controls 21.3 +/- 1.9%, p < 0.001). Both perfusion reserve and oxygenation showed positive correlations with energetics and LV strain. Furthermore, impaired energetics correlated with reduced strain. Eight months post aortic valve replacement (AVR) (n = 14), perfusion (MPRI 1.6 +/- 0.5), oxygenation (BOLD SI change 15.6 +/- 7.0%), energetics (PCr/ATP 1.86 +/- 0.48) and circumferential strain (-19.4 +/- 2.5%) improved significantly. CONCLUSIONS: Severe AS is characterized by impaired perfusion reserve and oxygenation which are related to the degree of derangement in energetics and associated LV dysfunction. These changes are reversible on relief of pressure overload and hypertrophy regression. Strategies aimed at improving oxygen demand-supply balance to preserve myocardial energetics and LV function are promising future therapies. PMID- 24779371 TI - Cardiovascular case fatality in rheumatoid arthritis is decreasing; first prospective analysis of a current low disease activity rheumatoid arthritis cohort and review of the literature. AB - BACKGROUND: Previous studies found increased case fatality after myocardial infarction and more frequent sudden death in RA patients compared to non-RA subjects. The RA associated CV risk might be explained by the combined effects of chronic systemic inflammation and increased lifestyle associated cardiovascular risk factors, and modified by the use of medication such as non steroidal anti inflammatory drugs, corticosteroids and disease modifying anti-rheumatic drugs. Trends in case fatality rate in RA after the introduction of potent anti inflammatory biologic therapies and treat-to-target treatment strategies aiming at remission are not known. This study was performed to examine the cardiovascular fatality rate in current low disease activity RA, and to evaluate trends in RA associated CV case fatality over time. METHODS: Prospective study to determine the incidence of fatal and nonfatal CV events in 480 RA patients included in the ACT-CVD cohort between February 2009 and December 2011. Patients with prior CV disease were excluded. Cox regression analysis was performed to determine CV event risk and contributing risk factors over time. The results of the cohort analysis were put into the context of a review of the literature to evaluate trends in RA associated CV fatality rate over time. RESULTS: The study included 480 RA patients, 72.3% female with median disease duration of 4.2 years, 72.1% being in clinical remission (Disease Activity Score in 28 joints). During a mean follow up of 2.9 years 29 patients (6%) experienced a first CV event, 2 fatal and 27 non-fatal, corresponding to a 6.9% case fatality rate. Comparison with previous studies in cohorts with successive enrolment periods shows a trend towards a decrease in CV case fatality in RA from 52.9% in 1998 to 6.9% in our study. CONCLUSION: CV case fatality in current low disease activity RA is importantly lower than in previous studies, and a trend towards decreasing CV fatality in RA is suggested. PMID- 24779373 TI - Apropos: 'Preliminary evaluation on the efficiency of the kit Platelia Dengue NS1 Ag-ELISA to detect dengue virus in dried Aedes aegypti: a potential tool to improve dengue surveillance'. AB - Only simple, point-of-care, assay formats of the Platellia Dengue NS1 Ag-ELISA would be suitable to identify Dengue virus in Aedes aegypti mosquitoes in dengue endemic areas lacking sophisticated laboratory infrastructure and trained laboratory personnel. PMID- 24779372 TI - Applying genome-wide gene-based expression quantitative trait locus mapping to study population ancestry and pharmacogenetics. AB - BACKGROUND: Gene-based analysis has become popular in genomic research because of its appealing biological and statistical properties compared with those of a single-locus analysis. However, only a few, if any, studies have discussed a mapping of expression quantitative trait loci (eQTL) in a gene-based framework. Neither study has discussed ancestry-informative eQTL nor investigated their roles in pharmacogenetics by integrating single nucleotide polymorphism (SNP) based eQTL (s-eQTL) and gene-based eQTL (g-eQTL). RESULTS: In this g-eQTL mapping study, the transcript expression levels of genes (transcript-level genes; T genes) were correlated with the SNPs of genes (sequence-level genes; S-genes) by using a method of gene-based partial least squares (PLS). Ancestry-informative transcripts were identified using a rank-score-based multivariate association test, and ancestry-informative eQTL were identified using Fisher's exact test. Furthermore, key ancestry-predictive eQTL were selected in a flexible discriminant analysis. We analyzed SNPs and gene expression of 210 independent people of African-, Asian- and European-descent. We identified numerous cis- and trans-acting g-eQTL and s-eQTL for each population by using PLS. We observed ancestry information enriched in eQTL. Furthermore, we identified 2 ancestry informative eQTL associated with adverse drug reactions and/or drug response. Rs1045642, located on MDR1, is an ancestry-informative eQTL (P = 2.13E-13, using Fisher's exact test) associated with adverse drug reactions to amitriptyline and nortriptyline and drug responses to morphine. Rs20455, located in KIF6, is an ancestry-informative eQTL (P = 2.76E-23, using Fisher's exact test) associated with the response to statin drugs (e.g., pravastatin and atorvastatin). The ancestry-informative eQTL of drug biotransformation genes were also observed; cross-population cis-acting expression regulators included SPG7, TAP2, SLC7A7, and CYP4F2. Finally, we also identified key ancestry-predictive eQTL and established classification models with promising training and testing accuracies in separating samples from close populations. CONCLUSIONS: In summary, we developed a gene-based PLS procedure and a SAS macro for identifying g-eQTL and s eQTL. We established data archives of eQTL for global populations. The program and data archives are accessible at http://www.stat.sinica.edu.tw/hsinchou/genetics/eQTL/HapMapII.htm. Finally, the results from our investigations regarding the interrelationship between eQTL, ancestry information, and pharmacodynamics provide rich resources for future eQTL studies and practical applications in population genetics and medical genetics. PMID- 24779374 TI - Validation of quantitative magnetic resonance imaging-based apparent bone volume fraction in peri-articular tibial bone of cadaveric knees. AB - BACKGROUND: In the knee, high-resolution magnetic resonance (MR) imaging has demonstrated that increased apparent bone volume fraction (trabecular bone volume per total volume; BV/TV) in the peri-articular proximal medial tibia is associated with joint space narrowing and the presence of bone marrow lesions. However, despite evidence of construct validity, MR-based apparent BV/TV has not yet been cross-validated in the proximal medial tibia by comparison with a gold standard (e.g., micro-computed tomography [microCT]). In this cadaveric validation study we explored the association between MR-based apparent BV/TV and microCT-based BV/TV in the proximal peri-articular medial tibia. METHODS: Fresh cadaveric whole knee specimens were obtained from individuals 51 to 80 years of age with no knee pathology other than osteoarthritis. Ten knees were collected from five cadavers within 10 hours of death and underwent a 3-Tesla MR exam including a coronal-oblique 3-dimensional fast imaging with steady state precession (3D FISP) sequence within 36 hours of death. The specimens were placed in a 4% paraformaldehyde in phosphate buffer within 58 hours of death. After preservation, a subchondral region from the tibial plateau was collected and underwent microCT imaging with a voxel size of 9 MUm x 9 MUm x 9 MUm. A single reader analyzed the microCT images in a similar volume of interest as selected in the MR measures. A different reader analyzed the MR-based trabecular morphometry using a custom analysis tool. To analyze the MR-based trabecular morphometry, a rectangular region of interest (ROI) was positioned on the 20 central images in the proximal medial tibial subchondral bone. The primary outcome measures were MR based and microCT-based trabecular BV/TV in the proximal medial tibia. RESULTS: The MR-based apparent BV/TV was strongly correlated with microCT-based BV/TV (r=0.83, confidence interval=0.42 to 0.96), despite the MR-based apparent BV/TV being systematically lower than measured using microCT. CONCLUSIONS: MR-based apparent BV/TV in the proximal peri-articular medial tibia has good construct validity and may represent an alternative for CT-based BV/TV. PMID- 24779375 TI - Diverse molecular signatures for ribosomally 'active' Perkinsea in marine sediments. AB - BACKGROUND: Perkinsea are a parasitic lineage within the eukaryotic superphylum Alveolata. Recent studies making use of environmental small sub-unit ribosomal RNA gene (SSU rDNA) sequencing methodologies have detected a significant diversity and abundance of Perkinsea-like phylotypes in freshwater environments. In contrast only a few Perkinsea environmental sequences have been retrieved from marine samples and only two groups of Perkinsea have been cultured and morphologically described and these are parasites of marine molluscs or marine protists. These two marine groups form separate and distantly related phylogenetic clusters, composed of closely related lineages on SSU rDNA trees. Here, we test the hypothesis that Perkinsea are a hitherto under-sampled group in marine environments. Using 454 diversity 'tag' sequencing we investigate the diversity and distribution of these protists in marine sediments and water column samples taken from the Deep Chlorophyll Maximum (DCM) and sub-surface using both DNA and RNA as the source template and sampling four European offshore locations. RESULTS: We detected the presence of 265 sequences branching with known Perkinsea, the majority of them recovered from marine sediments. Moreover, 27% of these sequences were sampled from RNA derived cDNA libraries. Phylogenetic analyses classify a large proportion of these sequences into 38 cluster groups (including 30 novel marine cluster groups), which share less than 97% sequence similarity suggesting this diversity encompasses a range of biologically and ecologically distinct organisms. CONCLUSIONS: These results demonstrate that the Perkinsea lineage is considerably more diverse than previously detected in marine environments. This wide diversity of Perkinsea-like protists is largely retrieved in marine sediment with a significant proportion detected in RNA derived libraries suggesting this diversity represents ribosomally 'active' and intact cells. Given the phylogenetic range of hosts infected by known Perkinsea parasites, these data suggest that Perkinsea either play a significant but hitherto unrecognized role as parasites in marine sediments and/or members of this group are present in the marine sediment possibly as part of the 'seed bank' microbial community. PMID- 24779376 TI - Canine heartworm disease (Dirofilaria immitis) in Western Europe: survey of veterinary awareness and perceptions. AB - BACKGROUND: This survey examines the experience and opinion of veterinarians with canine heartworm (HW; Dirofilaria immitis) infection in non-endemic and endemic areas of Europe. METHODS: A questionnaire was distributed by e-mail to veterinary practitioners within non-endemic countries including UK, Germany, and Netherlands,non-endemic regions of France, Spain, Italy and endemic regions of France, Spain and Italy. The main questions were about the HW cases seen in the last 12 months, if the number of cases had changed over the last 5 years and practitioner awareness of the ESCAAP Guidelines on HW. Additional questions examined practitioner perception regarding the risk of HW for pets travelling in endemic areas and the use of preventatives including veterinary perception of pet owner compliance. RESULTS: Overall 584 responses, 389 from non-endemic countries and regions and 195 from endemic regions were obtained. Most of the cases were seen in endemic regions, although in Germany 20% of veterinarians reported cases of HW infection. Overall, 10% of practitioners in non-endemic areasand 12% in endemic areas, respectively, reported an increasing number of cases. The practitioner awareness of ESCCAP guidelines is low. Veterinarians responded that preventative drugs were prescribed to most client dogs in endemic areas and most practitioners rated owner compliance as good or excellent in following the veterinarian's guidance for HW prevention. Overall 63% of veterinarians responded that owners are more or less aware of the HW risk traveling with their dogs in endemic areas. Forty four percent of responders in non-endemic regions considered it somewhat likely to very likely that HW infection will become endemic in their regions. CONCLUSIONS: In both non-endemic and endemic countries at least 1 responding practitioner admitted seeing a case of canine HW infection and has shown awareness regarding infection. Ten percent of practitioners stated that the number of cases is increasing. Although the number of owners traveling with their dogs was low, the perception of surveyed veterinarians was that owners were quite aware of the HW risk for their dogs. Several veterinary practitioners believe that HW infection could become endemic in their non-endemic area within the next 10 years. PMID- 24779378 TI - Evaluation of four ionic liquids for pretreatment of lignocellulosic biomass. AB - BACKGROUND: Lignocellulosic biomass is highly recalcitrant and various pretreatment techniques are needed to facilitate its effective enzymatic hydrolysis to produce sugars for further conversion to bio-based chemicals. Ionic liquids (ILs) are of interest in pretreatment because of their potential to dissolve lignocellulosic materials including crystalline cellulose. RESULTS: Four imidazolium-based ionic liquids (ILs) ([C=C2C1im][MeCO2], [C4C1im][MeCO2], [C4C1im][Cl], and [C4C1im][HSO4]) well known for their capability to dissolve lignocellulosic species were synthesized and then used for pretreatment of substrates prior to enzymatic hydrolysis. In order to achieve a broad evaluation, seven cellulosic, hemicellulosic and lignocellulosic substrates, crystalline as well as amorphous, were selected. The lignocellulosic substrates included hybrid aspen and Norway spruce. The monosaccharides in the enzymatic hydrolysate were determined using high-performance anion-exchange chromatography. The best results, as judged by the saccharification efficiency, were achieved with [C4C1im][Cl] for cellulosic substrates and with the acetate-based ILs for hybrid aspen and Norway spruce. After pretreatment with acetate-based ILs, the conversion to glucose of glucan in recalcitrant softwood lignocellulose reached similar levels as obtained with pure crystalline and amorphous cellulosic substrates. IL pretreatment of lignocellulose resulted in sugar yields comparable with that obtained with acidic pretreatment. Heterogeneous dissolution with [C4C1im][HSO4] gave promising results with aspen, the less recalcitrant of the two types of lignocellulose included in the investigation. CONCLUSIONS: The ability of ILs to dissolve lignocellulosic biomass under gentle conditions and with little or no by-product formation contributes to making them highly interesting alternatives for pretreatment in processes where high product yields are of critical importance. PMID- 24779377 TI - Specific NuRD components are required for fin regeneration in zebrafish. AB - BACKGROUND: Epimorphic regeneration of a missing appendage in fish and urodele amphibians involves the creation of a blastema, a heterogeneous pool of progenitor cells underneath the wound epidermis. Current evidence indicates that the blastema arises by dedifferentiation of stump tissues in the vicinity of the amputation. In response to tissue loss, silenced developmental programs are reactivated to form a near-perfect copy of the missing body part. However, the importance of chromatin regulation during epimorphic regeneration remains poorly understood. RESULTS: We found that specific components of the Nucleosome Remodeling and Deacetylase complex (NuRD) are required for fin regeneration in zebrafish. Transcripts of the chromatin remodeler chd4a/Mi-2, the histone deacetylase hdac1/HDAC1/2, the retinoblastoma-binding protein rbb4/RBBP4/7, and the metastasis-associated antigen mta2/MTA were specifically co-induced in the blastema during adult and embryonic fin regeneration, and these transcripts displayed a similar spatial and temporal expression patterns. In addition, chemical inhibition of Hdac1 and morpholino-mediated knockdown of chd4a, mta2, and rbb4 impaired regenerative outgrowth, resulting in reduction in blastema cell proliferation and in differentiation defects. CONCLUSION: Altogether, our data suggest that specialized NuRD components are induced in the blastema during fin regeneration and are involved in blastema cell proliferation and redifferentiation of osteoblast precursor cells. These results provide in vivo evidence for the involvement of key epigenetic factors in the cellular reprogramming processes occurring during epimorphic regeneration in zebrafish. PMID- 24779379 TI - Characteristics of extracurricular physical activity and cognitive performance in adolescents. The AVENA study. AB - The aim of this report was to examine the associations between some characteristics (i.e., structure and number) of extracurricular physical activity (EPA) and cognitive performance in adolescents. A total of 1662 adolescents (880 girls; 13.0-18.5 years) from 5 Spanish cities (Granada, Madrid, Murcia, Santander and Zaragoza) were included in this study. Structure (organised and non organised) and number of EPAs, and participation at vigorous intensity during EPA were self-reported. Cognitive performance (verbal, numeric and reasoning abilities, and an overall score) was measured with the "SRA-Test of Educational Ability". Results showed that vigorous EPA was positively associated with all cognitive variables. Adolescents who practiced an organised EPA had higher scores in 3 of the 4 cognitive variables than those who practiced a non-organised EPA (all P < 0.05). Likewise, the group who participated in more than one EPA had higher cognitive performance in all variables than the group who participated in only one EPA (all P < 0.05). Regardless of potential confounder variables, including vigorous EPA, both structure and number of EPAs were each other independently associated with cognitive performance. Therefore, structure and number of EPAs may positively influence cognitive performance in adolescents. Participating in multiple, organised EPA may have benefits for cognitive performance. PMID- 24779380 TI - Blastocystis sp. in splenic cysts: causative agent or accidental association? A unique case report. AB - BACKGROUND: Blastocystis sp. is one of the most prevalent parasites found in human stool and has been recently considered an opportunistic emerging pathogen in immunocompromised individuals. However, cases of invasive intestinal infections and skin rashes have been attributed to infection by Blastocystis sp in immunocompetent individuals, suggesting that it is an emerging parasite with pathogenic potential. FINDINGS: We present a case of a 22 year old female patient who complained of pain in the left hypochondrium. Ultrasonography and abdominal computed tomography scans showed two splenic cysts. The cyst fluid analysis demonstrated numerous Blastocystis sp.; PCR and DNA sequencing analyses confirmed the presence of Blastocystis subtype 3. CONCLUSIONS: This is, to our knowledge, the first case report of the presence of Blastocystis subtype 3 in extra intestinal organs and is strong evidence that Blastocystis sp. is potentially pathogenic and invasive. However, further studies are required to determine the pathogenicity of the parasite. PMID- 24779382 TI - The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder. AB - The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients, caregivers, and society and accounts for the largest part of the morbidity-mortality of the illness. Lurasidone is an atypical antipsychotic with a potent binding affinity as antagonist for D2, 5-HT2A, 5-HT7, and partial agonist at 5-HT1A receptors. Affinity for other receptors as H1 and muscarinic were negligible. Lurasidone was approved in 2010 for the treatment of schizophrenia and recently, 2013, for bipolar depression in monotherapy and an adjunct to lithium or valproate. Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the QT interval. Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment, in patients with bipolar II disorders, and versus other antipsychotic agents. PMID- 24779381 TI - Diversity of Greek meningococcal serogroup B isolates and estimated coverage of the 4CMenB meningococcal vaccine. AB - BACKGROUND: Serogroup B meningococcal (MenB) isolates currently account for approximately 90% of invasive meningococcal disease (IMD) in Greece with ST-162 clonal complex predominating. The potential of a multicomponent meningococcal B vaccine (4CMenB) recently licensed in Europe was investigated in order to find whether the aforementioned vaccine will cover the MenB strains circulating in Greece. A panel of 148 serogroup B invasive meningococcal strains was characterized by multilocus sequence typing (MLST) and PorA subtyping. Vaccine components were typed by sequencing for factor H-binding protein (fHbp), Neisserial Heparin Binding Antigen (NHBA) and Neisseria adhesin A (NadA). Their expression was explored by Meningococcal Antigen Typing System (MATS). RESULTS: Global strain coverage predicted by MATS was 89.2% (95% CI 63.5%-98.6%) with 44.6%, 38.5% and 6.1% of strains covered by one, two and three vaccine antigens respectively. NHBA was the antigen responsible for the highest coverage (78.4%), followed by fHbp (52.7%), PorA (8.1%) and NadA (0.7%). The coverage of the major genotypes did not differ significantly. The most prevalent MLST genotype was the ST-162 clonal complex , accounting for 44.6% of the strains in the panel and with a predicted coverage of 86.4%, mainly due to NHBA and fHbp. CONCLUSIONS: 4CMenB has the potential to protect against a significant proportion of Greek invasive MenB strains. PMID- 24779383 TI - Patterns of hand preference in Italian adolescent high-school students. AB - The Annett Hand Preference Questionnaire (AHPQ) is amongst the most widely used self-report measures of handedness. The psychometric properties of the AHPQ have been rarely evaluated outside the Anglo-Saxon culture where the majority of the studies on the AHPQ were done. In this study, 1,023 students (males=49.5%) from four large high schools operating in the district of Cagliari (Italy) were invited to fill in the Italian version of the AHPQ. The AHPQ was proved to measure a unidimensional latent trait, and the questionnaire was good at assessing deviation from right-handedness with high discrimination between subjects. Some items were more informative than others, and in particular the non equivalence between the primary and the non-primary actions was confirmed by both the confirmatory factor and the item response theory analysis. The use of the rule of thumb that classifies subjects on the basis of the primary actions was supported for the distinction between consistent right- and left-handed. However, the mixed-handed group identified on the basis of the rule of thumb was not entirely consistent with the mixed-handed class predicted by the latent class analysis. Males were about twice as likely as females to be in the mixed-handed class. PMID- 24779385 TI - Sexual function of women suffering from anorexia nervosa and bulimia nervosa. AB - The cross-sectional study aimed at examining the sexual function of young adult women suffering from eating disorders. The authors interviewed 53 women (26 with anorexia nervosa and 27 with bulimia nervosa) and 58 female students. Each participant was administered the Female Sexual Function Index, the Eating Attitudes Test, the Body Shape Questionnaire, and the Beck Depression Inventory. Comparisons among the 3 groups showed that patients with anorexia nervosa scored lower in each Female Sexual Function Index subscale than did healthy controls. There was no significant difference between bulimia nervosa and healthy controls. Sexual functionality of patients with anorexia nervosa was correlated only with body mass index (r = 0.5, p =.01). Sexual functionality of patients with bulimia nervosa was correlated only with the Beck Depression Inventory (r = -0.4, p =.03) Patients with anorexia nervosa had more disturbed sexual function than did controls. Sexual function can be related to the level of starvation and symptoms of depression. PMID- 24779384 TI - Reporting funding source or conflict of interest in abstracts of randomized controlled trials, no evidence of a large impact on general practitioners' confidence in conclusions, a three-arm randomized controlled trial. AB - BACKGROUND: Systematic reporting of funding sources is recommended in the CONSORT Statement for abstracts. However, no specific recommendation is related to the reporting of conflicts of interest (CoI). The objective was to compare physicians' confidence in the conclusions of abstracts of randomized controlled trials of pharmaceutical treatment indexed in PubMed. METHODS: We planned a three arm parallel-group randomized trial. French general practitioners (GPs) were invited to participate and were blinded to the study's aim. We used a representative sample of 75 abstracts of pharmaceutical industry-funded randomized controlled trials published in 2010 and indexed in PubMed. Each abstract was standardized and reported in three formats: 1) no mention of the funding source or CoI; 2) reporting the funding source only; and 3) reporting the funding source and CoI. GPs were randomized according to a computerized randomization on a secure Internet system at a 1:1:1 ratio to assess one abstract among the three formats. The primary outcome was GPs' confidence in the abstract conclusions (0, not at all, to 10, completely confident). The study was planned to detect a large difference with an effect size of 0.5. RESULTS: Between October 2012 and June 2013, among 605 GPs contacted, 354 were randomized, 118 for each type of abstract. The mean difference (95% confidence interval) in GPs' confidence in abstract findings was 0.2 (-0.6; 1.0) (P = 0.84) for abstracts reporting the funding source only versus no funding source or CoI; -0.4 (-1.3; 0.4) (P = 0.39) for abstracts reporting the funding source and CoI versus no funding source and CoI; and -0.6 (-1.5; 0.2) (P = 0.15) for abstracts reporting the funding source and CoI versus the funding source only. CONCLUSIONS: We found no evidence of a large impact of trial report abstracts mentioning funding sources or CoI on GPs' confidence in the conclusions of the abstracts. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01679873. PMID- 24779386 TI - Strain-engineering the anisotropic electrical conductance of few-layer black phosphorus. AB - Newly fabricated few-layer black phosphorus and its monolayer structure, phosphorene, are expected to be promising for electronic and optical applications because of their finite direct band gaps and sizable but anisotropic electronic mobility. By first-principles simulations, we show that this unique anisotropic free-carrier mobility can be controlled by using simple strain conditions. With the appropriate biaxial or uniaxial strain (4-6%), we can rotate the preferred conducting direction by 90 degrees . This will be useful for exploring unusual quantum Hall effects and exotic electronic and mechanical applications based on phosphorene. PMID- 24779387 TI - Animal models of intracranial aneurysms: targeting the extracranial versus intracranial circulation. PMID- 24779388 TI - Endoscopic imaging of intracranial tumour cavities. PMID- 24779389 TI - Malignant irreversible global cerebral edema as a complication of fourth ventricular arachnoid cyst. AB - Arachnoid cysts are benign congenital lesions of the central nervous system accounting for 1% of all intracranial masses. Intraventricular location of arachnoid cyst especially in the fourth ventricle is rare. Fenestration or marsupialization of these "innocent-looking" benign cysts can lead to dreadful life-threatening complications. We report a rare case of development of malignant irreversible global cerebral edema in a 21-year-old lady following surgical decompression of fourth ventricular arachnoid cyst. PMID- 24779390 TI - The biology of bacterial peptidoglycans and their impact on host immunity and physiology. AB - Peptidoglycans (PGN) are a constituent of the bacterial cell wall, and are shed as bacteria divide. The presence of PGN is therefore a marker of bacterial activity that has been exploited by both plants and animals to induce defence mechanisms. Pattern recognition receptors that recognize PGN are extremely well conserved throughout evolution and shown to play important and diverse role in the development, homeostasis and activation of the immune system. In addition, PGN can be detected beyond mucosal surfaces, and their receptor can be expressed in tissues and cells that are far from the niches where bacteria reside. Thus, PGN affects not only the host's immunity, but also more generally the host's physiology. In this review, we discuss the biochemistry and biology of PGN, and their intriguing effects on the development of the immune system and the host physiology. PMID- 24779392 TI - The complementary niches of anthropocentric and biocentric conservationists. AB - A divergence of values has become apparent in recent debates between conservationists who focus on ecosystem services that can improve human well being and those who focus on avoiding the extinction of species. These divergent points of view fall along a continuum from anthropocentric to biocentric values, but most conservationists are relatively closer to each other than to the ends of the spectrum. We have some concerns with both positions but emphasize that conservation for both people and all other species will be most effective if conservationists focus on articulating the values they all share, being respectful of divergent values, and collaborating on common interests. The conservation arena is large enough to accommodate many people and organizations whose diverse values lead them to different niches that can, with good will and foresight, be far more complementary than competitive. PMID- 24779391 TI - MAPT rs242562 and GSK3B rs334558 are associated with Parkinson's Disease in central China. AB - BACKGROUND: Microtubule-associated protein tau (MAPT) is a neuronal protein involved in the pathogenesis of several neurodegenerative diseases including Parkinson's Disease (PD). Glycogen synthase kinase 3 beta (GSK3B) catalyzes phosphorylation in multiple sites of tau protein. However, whether or not there is any association between the GSK3B gene alteration, MAPT haplotype and PD remains unexplored in Chinese population, especially in central Chinese population. RESULTS: Here, we aimed at studying the effect of MAPT rs242562 and GSK3B rs334558 on the risk of PD by performing a case-control association study in central China. Our data showed that all PD patients and controls were of MAPT H1/H1 diplotype in our study, thus confirming that the distribution of the MAPT H1 haplotype is common in China. GG genotype of MAPT rs242562 serves protection effect on PD risk in central Chinese population, while genotype of GSK3B rs334558 showed no difference between PD patients and controls. CONCLUSIONS: We conclude that the MAPT rs242562 is associated with PD in central China in the background of MAPT H1/H1 diplotype. The GG genotype of rs242562 displays protection against PD in subgroup with GSK3B rs334558 T carrier. PMID- 24779393 TI - Formation of neutral In(m)C(n) clusters under C60 ion bombardment of indium. AB - The formation of neutral gas phase indium carbide clusters under C60(+) ion bombardment of solid indium was investigated using laser based postionization prior to mass spectrometric detection. Two different postionization methods were used and shown to provide saturated photoionization efficiency, thereby delivering nearly the same information about the composition of the sputtered material. The resulting size distributions of neutral In(m)C(n) clusters are compared with those of the corresponding cationic secondary cluster ions and discussed in terms of calculated cluster properties. Investigating the dependence on C60(+) ion fluence, we demonstrate that clusters containing only one carbon atom are formed in single impact events, whereas the formation of more carbon rich clusters results from carbon accumulation at the bombarded surface. PMID- 24779395 TI - Protein folding thermodynamics: a new computational approach. AB - Folding free energy is the fundamental thermodynamic quantity characterizing the stability of a protein. Yet, its accurate determination based on computational techniques remains a challenge in physical chemistry. A straightforward brute force approach would be to conduct molecular dynamics simulations and to estimate the folding free energy from the equilibrium population ratio of the unfolded and folded states. However, this approach is not sensible at physiological conditions where the equilibrium population ratio is vanishingly small: it is extremely difficult to reliably obtain such a small equilibrium population ratio due to the low rate of folding/unfolding transitions. It is therefore desirable to have a computational method that solely relies on simulations independently carried out for the folded and unfolded states. Here, we present such an approach that focuses on the probability distributions of the effective energy (solvent averaged protein potential energy) in the folded and unfolded states. We construct these probability distributions for the protein villin headpiece subdomain by performing extensive molecular dynamics simulations and carrying out solvation free energy calculations. We find that the probability distributions of the effective energy are well-described by the Gaussian distributions for both the folded and unfolded states due to the central limit theorem, which enables us to calculate the protein folding free energy in terms of the mean and the width of the distributions. The computed protein folding free energy (-2.5 kcal/mol) is in accord with the experimental result (ranging from -2.3 to -3.2 kcal/mol depending on the experimental methods). PMID- 24779394 TI - NPY/Y1 receptor-mediated vasoconstrictory and proliferative effects in pulmonary hypertension. AB - BACKGROUND AND PURPOSE: Pulmonary arteries (PAs) are innervated, but little is known about the role of neuronal axis in pulmonary hypertension (PH). Here, we have examined the role of the neuropeptide Y (NPY) and its Y1 receptor in PH pathogenesis. EXPERIMENTAL APPROACH: NPY was localized by immunofluorescence. Expression of NPY and Y1 receptor were determined by quantitative PCR. Cellular response to NPY stimulation was assessed by Western blotting, thymidine incorporation and calcium imaging. Wire myography and isolated perfused mouse lung were applied to study pulmonary vasoactive effects of NPY. Selective receptor antagonists were used to assess the contribution of receptor subtypes in mediating NPY effects. KEY RESULTS: Samples from PH patients showed increased NPYergic innervation within the PA wall and higher Y1 receptor expression, compared with donors. However, NPY levels were unchanged in both PA and serum. In the chronic hypoxic mouse model, Y1 receptor were up-regulated, while expression of both NPY and Y1 receptor was increased in the lungs of monocrotaline and SU5416-hypoxia rats. On a functional level, NPY acutely increased intracellular calcium levels and enhanced vasoconstriction of lung vessels preconstricted with adrenaline. Furthermore, NPY stimulated proliferation of human pulmonary arterial smooth muscle cells and activated p38 and PKD pathways. Correspondingly, higher phosphorylation of PKD was observed in remodelled vessels from PH patients. The selective Y1 receptor antagonist, BIBO 3304, concentration-dependently inhibited vasoconstrictive and proliferative effects of NPY. CONCLUSIONS AND IMPLICATIONS: NPY and Y1 receptor are possible mediators of both vasoconstriction and pulmonary vascular remodelling in PH. PMID- 24779396 TI - Isotopic variation across the Audubon's-myrtle warbler hybrid zone. AB - Differences in seasonal migratory behaviours are thought to be an important component of reproductive isolation in many organisms. Stable isotopes have been used with success in estimating the location and qualities of disjunct breeding and wintering areas. However, few studies have used isotopic data to estimate the movements of hybrid offspring in species that form hybrid zones. Here, we use stable hydrogen to estimate the wintering locations and migratory patterns of two common and widespread migratory birds, Audubon's (Setophaga auduboni) and myrtle (S. coronata) warblers, as well as their hybrids. These two species form a narrow hybrid zone with extensive interbreeding in the Rocky Mountains of British Columbia and Alberta, Canada, which has been studied for over four decades. Isotopes in feathers grown on the wintering grounds or early on migration reveal three important patterns: (1) Audubon's and myrtle warblers from allopatric breeding populations winter in isotopically different environments, consistent with band recovery data and suggesting that there is a narrow migratory transition between the two species, (2) most hybrids appear to overwinter in the south-eastern USA, similar to where myrtle warblers are known to winter, and (3) some hybrid individuals, particularly those along the western edge of the hybrid zone, show Audubon's-like isotopic patterns. These data suggest there is a migratory divide between these two species, but that it is not directly coincident with the centre of the hybrid zone in the breeding range. We interpret these findings and discuss them within the context of previous research on hybrid zones, speciation and migratory divides. PMID- 24779397 TI - Measuring hypoxia-induced RNA in maternal blood: a new way to identify critically hypoxic fetuses in utero? AB - Severe fetal hypoxia causes stillbirth and permanent childhood disability. Unfortunately, none of the current tests is precise at determining the degree of fetal hypoxia in utero. We recently showed that hypoxia-induced RNA abundance in the maternal circulation (of likely fetoplacental origin) was tightly correlated with the degree of fetal hypoxia, suggesting it may be possible to generate a maternal blood test to more precisely determine the severity of fetal hypoxia. Such a test could drastically improve outcomes and decrease stillbirth rates. We are running a large prospective study to validate this test, and will use microarrays, RNA-seq and digital PCR to identify RNA transcripts that best correlate with the severity of fetal hypoxia. Finally, we note our data hints at the possibility of measuring dynamic changes in the fetoplacental transcriptome, measured in serial maternal blood samples. This could afford exciting new insights into the pathology of major obstetric diseases. PMID- 24779398 TI - Improved measures for the cross-national comparison of age profiles of internal migration. AB - We develop and demonstrate the application of a concise set of measures intended to encapsulate key features of the age profile of internal migration and highlight the significant differences that exist between nations in these profiles. Model schedules have been the most common method of comparing internal migration patterns but issues related to the estimation and interpretation of their parameters hinder their use for cross-national comparison. We demonstrate that the interpretation of exponential coefficients as rates of ascent and descent does not best reflect the slopes of migration age profiles, and we propose more consistent measures based on the rate of change in migration intensity. We demonstrate, through correlation and factor analysis, that most of the inter-country variance in migration age profiles is captured by the age at and intensity of peak migration. The application of these two indicators to 25 countries reveals significant differences between regions. PMID- 24779399 TI - The left perceptual bias for adult and infant faces in adults and 5-year-old children: face age matters. AB - A large number of studies have shown that adults rely more heavily on information conveyed by the left side of the face in judging emotional state, gender and identity. This phenomenon, called left perceptual bias (LPB), suggests a right hemisphere lateralization of face processing mechanisms. Although specialization of neural mechanisms for processing over-experienced face categories begins during the first year of life, little is known about the developmental trajectory of the LPB and whether or when the bias becomes selective for specific face categories as a result of experience. To address these questions we tested adults (Experiment 1) and 5-year-old children (Experiment 2) with null or limited experience with infants in an identity matching-to-sample task with chimeric adult and infant faces, for which both adults and children have been shown to manifest differential processing abilities. Results showed that 5-year-olds manifest a leftward bias selective for adult faces, and the magnitude of the bias is larger for adult compared to infant faces in adults. This evidence is in line with earlier demonstrations of a perceptual processing advantage for adult faces in adults and children and points to the role of experience in shaping neurocognitive specialization for face processing. PMID- 24779400 TI - The Lives Saved Tool (LiST) as a model for diarrhea mortality reduction. AB - BACKGROUND: Diarrhea is a leading cause of morbidity and mortality among children under five years of age. The Lives Saved Tool (LiST) is a model used to calculate deaths averted or lives saved by past interventions and for the purposes of program planning when costly and time consuming impact studies are not possible. DISCUSSION: LiST models the relationship between coverage of interventions and outputs, such as stunting, diarrhea incidence and diarrhea mortality. Each intervention directly prevents a proportion of diarrhea deaths such that the effect size of the intervention is multiplied by coverage to calculate lives saved. That is, the maximum effect size could be achieved at 100% coverage, but at 50% coverage only 50% of possible deaths are prevented. Diarrhea mortality is one of the most complex causes of death to be modeled. The complexity is driven by the combination of direct prevention and treatment interventions as well as interventions that operate indirectly via the reduction in risk factors, such as stunting and wasting. Published evidence is used to quantify the effect sizes for each direct and indirect relationship. Several studies have compared measured changes in mortality to LiST estimates of mortality change looking at different sets of interventions in different countries. While comparison work has generally found good agreement between the LiST estimates and measured mortality reduction, where data availability is weak, the model is less likely to produce accurate results. LiST can be used as a component of program evaluation, but should be coupled with more complete information on inputs, processes and outputs, not just outcomes and impact. SUMMARY: LiST is an effective tool for modeling diarrhea mortality and can be a useful alternative to large and expensive mortality impact studies. Predicting the impact of interventions or comparing the impact of more than one intervention without having to wait for the results of large and expensive mortality studies is critical to keep programs focused and results oriented for continued reductions in diarrhea and all-cause mortality among children under five years of age. PMID- 24779401 TI - Cross-communication between histone H3 and H4 acetylation and Akt-mTOR signalling in prostate cancer cells. AB - Molecular tumour targeting has significantly improved anti-cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of Rapamycin (mTOR) and histone deacetylase (HDAC) inhibition has been shown not only to enhance anti tumour potential, but also to prevent resistance development seen under mono-drug therapy. This investigation was designed to evaluate whether cross-communication exists between mTOR signalling and epigenetic events regulated by HDAC. DU-145 prostate cancer cells were treated with insulin-like growth factor (IGF) to activate the Akt-mTOR cascade or with the HDAC-inhibitor valproic acid (VPA) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, mTOR, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between mTOR and the epigenetic machinery. IGF activated mTOR, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGFr blockade and knock down blocked the Akt-mTOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up-regulated histone acetylation, but also activated mTOR-Akt signalling. HDAC1 and 2 knock-down revealed that the interaction with the mTOR system is initiated by histone H3 acetylation. HDAC-mTOR communication, therefore, is apparent whereby tumour-promoting (Akt/mTOR(high), aH3/aH4(low)) and tumour-suppressing signals (Akt/mTOR(low) , aH3/aH4(high)) are activated in parallel. Combined use of an HDAC- and mTOR inhibitor might then diminish pro tumour effects triggered by the HDAC- (Akt/mTOR(high)) or mTOR inhibitor (aH3/aH4(low)) alone. PMID- 24779402 TI - Co-ligand and solvent effects on the spin-crossover behaviors of PtS-type porous coordination polymers. AB - In our previous work ( Chen , X.-Y. ; Chem. Commun. 2013 , 49 , 10977 - 10979 ), we have reported the crystal structure and spin-crossover properties of a compound [Fe(NCS)2(tppm)].S [1.S, tppm = 4,4',4",4'''-tetrakis(4-pyridylethen-2 yl)tetraphenylmethane, S = 5CH3OH.2CH2Cl2]. Here, its analogues [Fe(X)2(tppm)].S [X = NCSe(-), NCBH3(-), and N(CN)2(-) for compounds 2.S, 3.S, and 4.S, respectively] have been synthesized and characterized by variable-temperature X ray diffraction and magnetic measurements. The crystal structure analyses of 2.S and 3.S reveal that both compounds possess the same topologic framework (PtS type) building from the tetrahedral ligand tppm and planar unit FeX2; the framework is two-fold self-interpenetrated to achieve one-dimensional open channels occupied by solvent molecules. Powder X-ray diffraction study indicates the same crystal structure for 4. The average values of Fe-N distances observed, respectively, at 100, 155, and 220 K for the Fe1/Fe2 centers are 1.969/2.011, 1.970/2.052, and 2.098/2.136 A for 2.S, whereas those at 110, 175, and 220 K are 1.972/2.013, 1.974/2.056, and 2.100/2.150 A for 3.S, indicating the presence of a two-step spin crossover in both compounds. Temperature-dependent magnetic susceptibilities (chiMT) confirm the two-step spin-crossover behavior at 124 and 200 K in 2.S, 151 and 225 K in 3.S, and 51 and 126 K in 4.S, respectively. The frameworks of 2-4 are reproducible upon solvent exchange and thereafter undergo solvent-dependent spin-crossover behaviors. PMID- 24779403 TI - Predictors of long-term nursing home placement under competing risk: evidence from the Health and Retirement Study. AB - OBJECTIVES: To examine predictors of long-term nursing home placement (LTNHP) while controlling for mortality as a competing risk event. DESIGN: Longitudinal. SETTING: Health and Retirement Study, 1998-2010. PARTICIPANTS: Nationally representative sample of community-living older adults (N = 10,385). MEASUREMENTS: Longitudinal data were used with a maximum follow-up of 12 years. First, a traditional Cox proportional hazards model was estimated treating death as an uninformative censoring event. A joint cause-specific hazards model that accounts for the competing risk of mortality in estimating the risk of LTNHP was then estimated. RESULTS: The effect of adjusting for competing risk of mortality is evident for nearly all predictors of LTNHP. Predictors were over- or underestimated in the traditional Cox model, and several predictors changed in the direction of the association, whereas others changed in magnitude. For example, after controlling for mortality, women aged 85 and older had more than twice the risk (hazard ratio = 7.23, 95% confidence interval = 5.18-10.10) of LTNHP than evidenced in the traditional Cox model. CONCLUSION: Whenever possible, the competing risk of mortality should be recognized and adjusted in developing screening tools and predictive risk models for LTNHP. PMID- 24779404 TI - Twitter as a tool to enhance student engagement during an interprofessional patient safety course. AB - Twitter and other social media forums are gaining popularity in both the academic and conference arenas as tools to increase participant engagement, attention and interaction. While Twitter has been used successfully to engage college students, it has not been explored for use in an interprofessional curriculum. We sought to explore it as a method to foster student engagement. During a weeklong interprofessional patient safety course we invited students and faculty to participate in a Twitter conversation. It was found that this form of social media successfully captured a "behind the scenes" conversation and the experiences of the students which would have not been otherwise captured. This information is guiding future interprofessional educational programming in both the medical and nursing schools. PMID- 24779405 TI - Perceptions of, and assistance provided to, a hypothetical rape victim: differences between rape disclosure recipients and nonrecipients. AB - OBJECTIVE: Undergraduate rape disclosure recipients' and nonrecipients' sociodemographic and life experience variables, attitudes towards rape, and responses to a hypothetical rape disclosure were compared to determine differences between them. PARTICIPANTS: One hundred ninety-two undergraduates at 3 universities participated in this online survey between November 2011 and April 2012. METHODS: Participants reported on their rape myth acceptance (RMA) and personal direct and indirect (ie, disclosure receipt) experiences with sexual assault. Participants also responded to a hypothetical rape disclosure. RESULTS: Disclosure recipients were more likely to report a victimization history, and less confusion and perceived ineffectiveness in helping the hypothetical victim. RMA and nonrecipient status predicted perceived victim responsibility; these variables and childhood victimization predicted confusion about helping. RMA also predicted perceived ineffectiveness of one's helping behaviors. Victimization history and female gender predicted victim empathy. CONCLUSIONS: These findings can inform sexual assault-related programming for undergraduates through the provision of targeted assistance and corrective information. PMID- 24779406 TI - Analysis of gold(I/III)-complexes by HPLC-ICP-MS demonstrates gold(III) stability in surface waters. AB - Understanding the form in which gold is transported in surface- and groundwaters underpins our understanding of gold dispersion and (bio)geochemical cycling. Yet, to date, there are no direct techniques capable of identifying the oxidation state and complexation of gold in natural waters. We present a reversed phase ion pairing HPLC-ICP-MS method for the separation and determination of aqueous gold(III)-chloro-hydroxyl, gold(III)-bromo-hydroxyl, gold(I)-thiosulfate, and gold(I)-cyanide complexes. Detection limits for the gold species range from 0.05 to 0.30 MUg L(-1). The [Au(CN)2](-) gold cyanide complex was detected in five of six waters from tailings and adjacent monitoring bores of working gold mines. Contrary to thermodynamic predictions, evidence was obtained for the existence of Au(III)-complexes in circumneutral, hypersaline waters of a natural lake overlying a gold deposit in Western Australia. This first direct evidence for the existence and stability of Au(III)-complexes in natural surface waters suggests that Au(III)-complexes may be important for the transport and biogeochemical cycling of gold in surface environments. Overall, these results show that near MUg L(-1) enrichments of Au in environmental waters result from metastable ligands (e.g., CN(-)) as well as kinetically controlled redox processes leading to the stability of highly soluble Au(III)-complexes. PMID- 24779407 TI - Dinitrogen splitting and functionalization in the coordination sphere of rhenium. AB - [ReCl3(PPh3)2(NCMe)] reacts with pincer ligand HN(CH2CH2PtBu2)2 (HPNP) to five coordinate rhenium(III) complex [ReCl2(PNP)]. This compound cleaves N2 upon reduction to give rhenium(V) nitride [Re(N)Cl(PNP)], as the first example in the coordination sphere of Re. Functionalization of the nitride ligand derived from N2 is demonstrated by selective C-N bond formation with MeOTf. PMID- 24779408 TI - Controlled doping of carbon nanotubes with metallocenes for application in hybrid carbon nanotube/Si solar cells. AB - There is considerable interest in the controlled p-type and n-type doping of carbon nanotubes (CNT) for use in a range of important electronics applications, including the development of hybrid CNT/silicon (Si) photovoltaic devices. Here, we demonstrate that easy to handle metallocenes and related complexes can be used to both p-type and n-type dope single-walled carbon nanotube (SWNT) thin films, using a simple spin coating process. We report n-SWNT/p-Si photovoltaic devices that are >450 times more efficient than the best solar cells of this type currently reported and show that the performance of both our n-SWNT/p-Si and p SWNT/n-Si devices is related to the doping level of the SWNT. Furthermore, we establish that the electronic structure of the metallocene or related molecule can be correlated to the doping level of the SWNT, which may provide the foundation for controlled doping of SWNT thin films in the future. PMID- 24779409 TI - Phase-contrast and magnification radiography at diagnostic X-ray energies using a pseudo-microfocus X-ray source. AB - OBJECTIVE: To investigate the use of conventional diagnostic X-ray tubes for applications in which specialist microfocus sources are normally required. METHODS: A conventional diagnostic X-ray tube was used in conjunction with a range of apertures to investigate improvements in spatial resolution using a line pairs test object. Phase-contrast effects were investigated by varying source-to object and object-to-receptor distances using a 2-French catheter as a clinically realistic test object. RESULTS: For magnification radiography using a computed radiography receptor and conventional X-ray tube with a 1-mm nominal focus size, the limiting spatial resolution was improved from 3.55 line-pairs per millimetre, for a conventional contact image, to 5.6 line-pairs per millimetre, for a *2 magnified view with a 250-um aperture. For inline phase-contrast radiography, phase contrast enhancement of a 2-French catheter was demonstrated, and the expected trends with variations in source-to-object and object-to-receptor distances were found. Images of a neonatal phantom demonstrated a subtle improvement in visibility of a superimposed 1-French catheter simulating a percutaneously inserted central catheter for no increase in patient radiation dose. CONCLUSION: Spatial resolution improvement and visible phase contrast can be produced in clinically relevant objects using a pseudo-microfocus geometry at X-ray energies in the normal diagnostic range, using conventional diagnostic X ray tubes and image receptors. The disadvantages of the proposal are the large distances required to produce phase contrast and limitations imposed by the resulting tube loading. ADVANCES IN KNOWLEDGE: It is possible to use conventional diagnostic X-ray equipment in applications that normally require microfocus X-ray sources. This presents some possibilities for clinical applications. PMID- 24779410 TI - Peri-infarct ischaemia assessed by cardiovascular MRI: comparison with quantitative perfusion single photon emission CT imaging. AB - OBJECTIVE: To develop a new method for the cardiac MR (CMR) quantification of peri-infarct ischaemia using fused perfusion and delayed-enhanced images and to evaluate this method using quantitative single photon emission CT (SPECT) imaging as a reference. METHODS: 40 patients presenting with peri-infarct ischaemia on a routine stress (99m)Tc-SPECT imaging were recruited. Within 8 days of the SPECT study, myocardial perfusion was evaluated using stress adenosine CMR. Using fused perfusion and delayed-enhanced images, peri-infarct ischaemia was quantified as the percentage of myocardium with stress-induced perfusion defect that was adjacent to and larger than a scar. This parameter was compared with both the percent myocardium ischaemia (SD%) and the ischaemic total perfusion deficit (TPD). The diagnostic performance of CMR in detection of significant coronary artery stenosis (of >=70%) was also determined. RESULTS: On SPECT imaging, in addition to peri-infarct ischaemia, reversible perfusion abnormalities were detected in a remote zone in seven patients. In the 33 patients presenting with only peri-infarct ischaemia, the agreement between CMR peri-infarct ischaemia and both SD% and ischaemic TPD was excellent [intraclass coefficient of correlation (ICC) = 0.969 and ICC = 0.877, respectively]. CMR-defined peri-infarct ischaemia for the detection of a significant coronary artery stenosis showed an areas under receiver-operating characteristic curve of 0.856 (95% confidence interval, 0.680 0.939). The best cut-off value was 8.1% and allowed a 72% sensitivity, 96% specificity, 60% negative predictive value and 97% positive predictive value. CONCLUSION: This proof-of-concept study shows that CMR imaging has the potential as a test for quantification of peri-infarct ischaemia. ADVANCES IN KNOWLEDGE: This study demonstrates the proof of concept of a commonly known intuitive idea, that is, evaluating the peri-infarct ischaemic burden by subtracting delayed enhancement from first-pass perfusion imaging on CMR. PMID- 24779411 TI - Secondary structure of corona proteins determines the cell surface receptors used by nanoparticles. AB - Nanoparticles used for biological and biomedical applications encounter a host of extracellular proteins. These proteins rapidly adsorb onto the nanoparticle surface, creating a protein corona. Poly(ethylene glycol) can reduce, but not eliminate, the nonspecific adsorption of proteins. As a result, the adsorbed proteins, rather than the nanoparticle itself, determine the cellular receptors used for binding, the internalization mechanism, the intracellular transport pathway, and the subsequent immune response. Using fluorescence microscopy and flow cytometry, we first characterize a set of polystyrene nanoparticles in which the same adsorbed protein, bovine serum albumin, leads to binding to two different cell surface receptors: native albumin receptors and scavenger receptors. Using a combination of circular dichroism spectroscopy, isothermal titration calorimetry, and fluorescence spectroscopy, we demonstrate that the secondary structure of the adsorbed bovine serum albumin protein controls the cellular receptors used by the protein-nanoparticle complexes. These results show that protein secondary structure is a key parameter in determining the cell surface receptor used by a protein-nanoparticle complex. We expect this link between protein structure and cellular outcomes will provide a molecular basis for the design of nanoparticles for use in biological and biomedical applications. PMID- 24779412 TI - Defining the impact of non-native species. AB - Non-native species cause changes in the ecosystems to which they are introduced. These changes, or some of them, are usually termed impacts; they can be manifold and potentially damaging to ecosystems and biodiversity. However, the impacts of most non-native species are poorly understood, and a synthesis of available information is being hindered because authors often do not clearly define impact. We argue that explicitly defining the impact of non-native species will promote progress toward a better understanding of the implications of changes to biodiversity and ecosystems caused by non-native species; help disentangle which aspects of scientific debates about non-native species are due to disparate definitions and which represent true scientific discord; and improve communication between scientists from different research disciplines and between scientists, managers, and policy makers. For these reasons and based on examples from the literature, we devised seven key questions that fall into 4 categories: directionality, classification and measurement, ecological or socio-economic changes, and scale. These questions should help in formulating clear and practical definitions of impact to suit specific scientific, stakeholder, or legislative contexts. PMID- 24779413 TI - The focal complex of epithelial cells provides a signalling platform for interleukin-8 induction in response to bacterial pathogens. AB - Bacterial pathogens can induce an inflammatory response from epithelial tissues due to secretion of the pro-inflammatory chemokine interleukin-8 (IL-8). Many bacterial pathogens manipulate components of the focal complex (FC) to induce signalling events in host cells. We examined the interaction of several bacterial pathogens with host cells, including Campylobacter jejuni, to determine if the FC is required for induction of chemokine signalling in response to bacterial pathogens. Our data indicate that secretion of IL-8 is triggered by C. jejuni, Helicobacter pylori and Salmonella enterica serovar Typhimurium in response to engagement of beta1 integrins. Additionally, we found that the secretion of IL-8 from C. jejuni infected epithelial cells requires FAK, Src and paxillin, which in turn are necessary for Erk 1/2 recruitment and activation. Targeting the FC component paxillin with siRNA prevented IL-8 secretion from cells infected with several bacterial pathogens, including C. jejuni, Helicobacter pylori, Salmonella enterica serovar Typhimurium, Staphylococcus aureus, Pseudomonas aeruginosa, and Vibrio parahaemolyticus. Our findings indicate that maximal IL-8 secretion from epithelial cells in response to bacterial infection is dependent on the FC. Based on the commonality of the host response to bacterial pathogens, we propose that the FC is a signalling platform for an epithelial cell response to pathogenic organisms. PMID- 24779414 TI - Personality in women and associations with mortality: a 40-year follow-up in the population study of women in Gothenburg. AB - BACKGROUND: The question of whether personality traits influence health has long been a focus for research and discussion. Therefore, this study was undertaken to examine possible associations between personality traits and mortality in women. METHODS: A population-based sample of women aged 38, 46, 50 and 54 years at initial examination in 1968-69 was followed over the course of 40 years. At baseline, 589 women completed the Cesarec-Marke Personality Schedule (the Swedish version of the Edwards Personal Preference Schedule) and the Eysenck Personality Inventory. Associations between personality traits and mortality were tested using Cox proportional hazards models. RESULTS: No linear associations between personality traits or factor indices and mortality were found. When comparing the lowest (Q1) and highest quartile (Q4) against the two middle quartiles (Q2 + Q3), the personality trait Succorance Q1 versus Q2 + Q3 showed hazard ratio (HR) = 1.37 (confidence interval (CI) = 1.08-1.74), and for the factor index Aggressive non-conformance, both the lowest and highest quartiles had a significantly higher risk of death compared to Q2 + Q3: for Q1 HR = 1.32 (CI = 1.03-1.68) and for Q4 HR = 1.36 (CI = 1.06-1.77). Neither Neuroticism nor Extraversion predicted total mortality. CONCLUSIONS: Personality traits did not influence long term mortality in this population sample of women followed for 40 years from mid- to late life. One explanation may be that personality in women becomes more circumscribed due to the social constraints generated by the role of women in society. PMID- 24779416 TI - Single-case experimental designs: reflections on conduct and analysis. AB - In this editorial discussion we reflect on the issues addressed by, and arising from, the papers in this special issue on Single-Case Experimental Design (SCED) study methodology. We identify areas of consensus and disagreement regarding the conduct and analysis of SCED studies. Despite the long history of application of SCEDs in studies of interventions in clinical and educational settings, the field is still developing. There is an emerging consensus on methodological quality criteria for many aspects of SCEDs, but disagreement on what are the most appropriate methods of SCED data analysis. Our aim is to stimulate this ongoing debate and highlight issues requiring further attention from applied researchers and methodologists. In addition we offer tentative criteria to support decision making in relation to the selection of analytical techniques in SCED studies. Finally, we stress that large-scale interdisciplinary collaborations, such as the current Special Issue, are necessary if SCEDs are going to play a significant role in the development of the evidence base for clinical practice. PMID- 24779415 TI - A combined linkage and regional association mapping validation and fine mapping of two major pleiotropic QTLs for seed weight and silique length in rapeseed (Brassica napus L.). AB - BACKGROUND: Seed weight (SW) and silique length (SL) are important determinants of the yield potential in rapeseed (Brassica napus L.). However, the genetic basis of both traits is poorly understood. The main objectives of this study were to dissect the genetic basis of SW and SL in rapeseed through the preliminary mapping of quantitative trait locus (QTL) by linkage analysis and fine mapping of the target major QTL by regional association analysis. RESULTS: Preliminary linkage mapping identified thirteen and nine consensus QTLs for SW and SL, respectively. These QTLs explained 0.7-67.1% and 2.1-54.4% of the phenotypic variance for SW and SL, respectively. Of these QTLs, three pairs of SW and SL QTLs were co-localized and integrated into three unique QTLs. In addition, the significance level and genetic effect of the three co-localized QTLs for both SW and SL showed great variation before and after the conditional analysis. Moreover, the allelic effects of the three QTLs for SW were highly consistent with those for SL. Two of the three co-localized QTLs, uq.A09-1 (mean R(2) = 20.1% and 19.0% for SW and SL, respectively) and uq.A09-3 (mean R(2) = 13.5% and 13.2% for SW and SL, respectively), were detected in all four environments and showed the opposite additive-effect direction. These QTLs were validated and fine mapped (their confidence intervals were narrowed down from 5.3 cM to 1 cM for uq.A09-1 and 13.2 cM to 2.5 cM for uq.A09-3) by regional association analysis with a panel of 576 inbred lines, which has a relatively rapid linkage disequilibrium decay (0.3 Mb) in the target QTL region. CONCLUSIONS: A few QTLs with major effects and several QTLs with moderate effects might contribute to the natural variation of SW and SL in rapeseed. The meta-, conditional and allelic effect analyses suggested that pleiotropy, rather than tight linkage, was the genetic basis of the three pairs of co-localized of SW and SL QTLs. Regional association analysis was an effective and highly efficient strategy for the direct fine mapping of target major QTL identified by preliminary linkage mapping. PMID- 24779418 TI - Fusion of ligand-coated nanoparticles with lipid bilayers: effect of ligand flexibility. AB - Amphiphilic, monolayer-protected gold nanoparticles (AuNPs) have recently been shown to insert into and fuse with lipid bilayers, driven by the hydrophobic effect. The inserted transmembrane state is stabilized by the "snorkeling" of charged ligand end groups out of the bilayer interior. This snorkeling process is facilitated by the backbone flexibility of the alkanethiol ligands that comprise the monolayer. In this work, we show that fusion is favorable even in the absence of backbone flexibility by modeling the ligands as rigid rods. For rigid ligands, snorkeling is still accommodated by rotations of the ligand with respect to the grafting point, but the process incurs a more significant free energy penalty than if the backbone were fully flexible. We show that the rigid rod model predicts similar trends in the free energy change for insertion as the previous flexible model when the size of the AuNPs is varied. However, the rigidity of the ligand backbone reduces the overall magnitude of the free energy change compared to that of the flexible model. These results thus generalize previous findings to systems with hindered backbone flexibility due to either structural constraints or low temperature. PMID- 24779417 TI - Mapping the trajectory of socioeconomic disparity in working memory: parental and neighborhood factors. AB - Working memory (WM) is positively correlated with socioeconomic status (SES). It is not clear, however, if SES predicts the rate of WM development over time or whether SES effects are specific to family rather than neighborhood SES. A community sample of children (n = 316) enrolled between ages 10 and 13 completed four annual assessments of WM. Lower parental education, but not neighborhood disadvantage, was associated with worse WM performance. Neither measure of SES was associated with the rate of developmental change. Consequently, the SES disparity in WM is not a developmental lag that narrows or an accumulating effect that becomes more pronounced. Rather, the relation between family SES and WM originates earlier in childhood and is stable through adolescence. PMID- 24779421 TI - An experimental manipulation of social comparison in social anxiety. AB - Negative self-appraisal is thought to maintain social anxiety particularly when comparing oneself to others. Work on social comparison suggests that gender may moderate the effects of social comparison in social anxiety. Self-appraisals of the desirability of one's personality may be more important to women, whereas self-appraisal of signs of anxiety may be more important to men. Within each gender, those with high social anxiety are expected to report more negative self appraisal when comparing themselves to someone else described as high achieving. This study is the first we are aware of that examined gender-based interactive effects after a social comparison manipulation. Participants read a bogus profile of a fellow student's adjustment to college. They were randomly assigned to read a profile suggesting that the fellow student was "high achieving" or more normative in his/her achievements. When comparing to a "high achieving" individual, men with high social anxiety reported the most negative self appraisals of their signs of anxiety. In addition, greater social anxiety was associated with a poorer self-appraisal of personality only among men. The implications of the findings for conceptualizing the role of social comparison in social anxiety are discussed. PMID- 24779419 TI - Huntington's disease (HD): degeneration of select nuclei, widespread occurrence of neuronal nuclear and axonal inclusions in the brainstem. AB - Huntington's disease (HD) is a progressive polyglutamine disease that leads to a severe striatal and layer-specific neuronal loss in the cerebral neo-and allocortex. As some of the clinical symptoms (eg, oculomotor dysfunctions) suggested a degeneration of select brainstem nuclei, we performed a systematic investigation of the brainstem of eight clinically diagnosed and genetically confirmed HD patients. This post-mortem investigation revealed a consistent neuronal loss in the substantia nigra, pontine nuclei, reticulotegmental nucleus of the pons, superior and inferior olives, in the area of the excitatory burst neurons for horizontal saccades, raphe interpositus nucleus and vestibular nuclei. Immunoreactive intranuclear neuronal inclusions were present in all degenerated and apparently spared brainstem nuclei and immunoreactive axonal inclusions were observed in all brainstem fiber tracts of the HD patients. Degeneration of brainstem nuclei can account for a number of less well-understood clinical HD symptoms (ie, cerebellar, oculomotor and vestibular symptoms), while the formation of axonal aggregates may represent a crucial event in the cascades of pathological events leading to neurodegeneration in HD. PMID- 24779420 TI - Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus. AB - GPI-anchoring is a universal and critical post-translational protein modification in eukaryotes. In fungi, many cell wall proteins are GPI-anchored, and disruption of GPI-anchored proteins impairs cell wall integrity. After being synthesized and attached to target proteins, GPI anchors undergo modification on lipid moieties. In spite of its importance for GPI-anchored protein functions, our current knowledge of GPI lipid remodelling in pathogenic fungi is limited. In this study, we characterized the role of a putative GPI lipid remodelling protein, designated PerA, in the human pathogenic fungus Aspergillus fumigatus. PerA localizes to the endoplasmic reticulum and loss of PerA leads to striking defects in cell wall integrity. A perA null mutant has decreased conidia production, increased susceptibility to triazole antifungal drugs, and is avirulent in a murine model of invasive pulmonary aspergillosis. Interestingly, loss of PerA increases exposure of beta-glucan and chitin content on the hyphal cell surface, but diminished TNF production by bone marrow-derived macrophages relative to wild type. Given the structural specificity of fungal GPI-anchors, which is different from humans, understanding GPI lipid remodelling and PerA function in A. fumigatus is a promising research direction to uncover a new fungal specific antifungal drug target. PMID- 24779422 TI - Mouse mammary tumor virus-based vector transduces non-dividing cells, enters the nucleus via a TNPO3-independent pathway and integrates in a less biased fashion than other retroviruses. AB - BACKGROUND: Mouse mammary tumor virus (MMTV) is a complex, milk-born betaretrovirus, which preferentially infects dendritic cells (DC) in the gastrointestinal tract and then spreads to T and B lymphocytes and finally to the mammary gland. It is not clear how the prototypic betaretrovirus infects mucosal DCs and naive lymphocytes as these cells are considered to be non-proliferative. Studies of MMTV biology have been hampered by the difficulty of obtaining sufficient virus/vector titers after transfection of a molecular clone in cultured cells. To surmount this barrier we developed a novel MMTV-based vector system with a split genome design containing potent posttranscriptional regulatory functions. RESULTS: Using this system, vector particles were produced to markedly greater titers (>1000-fold) than those obtained previously. The titers (>106 transduction units /ml) were comparable to those achieved with lentiviral or gammaretroviral vectors. Importantly, the vector transduced the enhanced green fluorescence protein gene into the chromosomes of non-dividing cells, such as cells arrested at the G2/M phase of the cell cycle and unstimulated hematopoietic progenitor cells, at an efficiency similar to that obtained with the HIV-1-based vector. In contrast to HIV-1, MMTV transductions were not affected by knocking down the expression of a factor involved in nuclear import of the HIV-1 pre-integration complexes, TNPO3. In contrast to HIV-1, the MMTV-based vector did not preferentially integrate in transcription units. Additionally, no preference for integration near transcription start sites, the regions preferentially targeted by gammaretroviral vectors, was observed. The vector derived from MMTV exhibits a random integration pattern. CONCLUSIONS: Overall, the betaretroviral vector system should facilitate molecular virology studies of the prototypic betaretrovirus as well as studies attempting to elucidate fundamental cellular processes such as nuclear import pathways. Random integration in cycling and non-cycling cells may be applicable in unbiased gene delivery. PMID- 24779423 TI - Williams syndrome: ophthalmological examination and review of systemic manifestations. AB - PURPOSE: To evaluate the frequency and severity of ophthalmic manifestations and associated diseases, as well as the epidemiological data in patients with Williams syndrome. METHODS: The authors prospectively studied 30 patients clinically diagnosed as having Williams syndrome as confirmed by the fluorescence in situ hybridization test. Patient history included gender, age, race, education level, previous illnesses, and surgeries. The ophthalmologic examination included best-corrected visual acuity, dynamic and static refraction, extraocular motility test, stereopsis test (Titmus and Lang), and direct and indirect funduscopy. RESULTS: Thirty patients were included in this study. The mean age was 14.5 +/- 1.38 years (range: 7 to 26 years). Fifty percent of the patients were male and 50% were female. Among the children examined, 77% had a refractive error. Hyperopia and astigmatism were noted in 67% and 20% of the patients, respectively, and myopia in 7%. Only one case of amblyopia was noted. On external examination, 23% of children had epicanthus; via biomicroscopy, 3 children with stellate patterns of the irides were observed. Eleven patients (36.6%) had measurable strabismus, 9 (82%) had esotropia, and 2 (18%) had exotropia. Binocular vision was abnormal in 43% of patients. Diffuse arteriovenous tortuosity on funduscopy was observed in 27% of patients. CONCLUSIONS: Williams syndrome is rare and is associated with multiple phenotypes and diseases that are susceptible to treatment. Multidisciplinary clinical management is critical and, in some cases, surgical intervention is required. PMID- 24779424 TI - Ophthalmologic features of Vici syndrome. AB - PURPOSE: To report and compile the ophthalmological features critical to diagnosis of Vici syndrome, a rare congenital disorder characterized principally by agenesis of the corpus callosum, cataracts, cardiomyopathy, immune defects, and hypopigmentation. METHODS: A child with Vici syndrome (OMIM 242840) is reported with emphasis on the ophthalmologic evaluation. Ophthalmologic assessments including fundus examination, visual evoked potentials (VEPs), and ocular coherence tomography are presented. These findings are compared with those identified in other published cases of children with Vici syndrome. RESULTS: Ophthalmologic findings included bilateral nuclear and anterior polar cataracts, bilateral optic nerve atrophy, and mild fundus hypopigmentation. Evoked potentials recorded across the mid-occipital scalp demonstrated misrouting of optic pathways typical of albinism. Optical coherence tomography exhibited a poorly defined fovea demonstrating a lesser degree of foveal depression also consistent with ocular albinism. Review of reported children with Vici syndrome identifies bilateral cataracts, nystagmus, fundus hypopigmentation, visual impairment, and optic nerve hypoplasia as common ophthalmologic features. CONCLUSIONS: Ophthalmologic findings are critical to the diagnosis of Vici syndrome. Most common are bilateral cataracts and relative fundus hypopigmentation. VEPs can identify misrouting of optic pathways typical of ocular albinism, thereby establishing the diagnosis in challenging cases. PMID- 24779425 TI - Towards personalized treatment of depression: a candidate gene approach. AB - The causal pathways leading to depression involve a combination of genetic and environmental risk factors and the relative contribution of these factors differ across patients. In addition, patients vary in the way they respond to treatment. The aim of this article is to discuss a candidate gene approach (5-HTTLPR) in the treatment of depression and how it may be implemented to individualize treatment plans for patients. First, we examine the role of 5-HTTLPR polymorphisms in biased emotion processing and in the interplay between emotion regulation and cognitive control. An intriguing finding is that the low expression short allele variant of 5-HTTLPR is best conceived as a gene that affects malleability or plasticity rather than specific vulnerability to depression. A shift from vulnerability to susceptibility has the potential to translate into new perspectives on individualized treatment of depression. The interplay between therapeutic intervention and genotype is a special case of gene-environment interactions (GxE). Within this new field, recently named "therapygenetics," a small number of studies have so far provided preliminary but provocative evidence of an association between the low expression 5-HTTLPT short allele and response to psychological treatment. Future research should expand into randomized controlled trial (RCT) designs to examine the likelihood of response to psychotherapy versus pharmacotherapy in the individual patient. PMID- 24779426 TI - Oxychloride-hydroxychloride-trihydroxide phase relationships of rare earths in aqueous solution. AB - Phase studies were undertaken with PbFCl-type rare earth oxychlorides (REOCls), where RE = La-Dy and Y. Specifically, equilibria in REOCl-H2O systems were investigated in an effort to describe the interrelationship of the oxychloride, hydroxychloride, and trihydroxide phases of rare earths in water. When lighter rare earths were employed, REOCls were generally stable in basic media, while acidic solutions readily yielded RE(OH)3 by hydrolysis. However, the systematics of equilibrium established in sufficient amounts of water did not continue across the rare earth series and were not particularly relevant to cases in which the oxychloride phase was added to a volume of water smaller than the critical quantity. Difficulties encountered during initial attempts to investigate the hydrolysis of REOCl required that a special parameter, the dilution ratio (D = volume of water/weight of powder), be used for REOCl-RE2(OH)5Cl.nH2O-RE(OH)3 phase relationships in water at different temperatures. The equilibration of REOCl in solutions of low dilution ratios (D <= 0.5 mL/mg) yielded all three phases depending on the nature of the RE, dilution ratio, and temperature. Interestingly, the addition of salt (NaCl) to systems at similar dilution ratios markedly increased the stability of RE2(OH)5Cl.nH2O phases. In contrast, the essential feature of YOCl-water equilibria in the range 0.1 <= D <= 1.0 mL/mg was characterized by spatial stability of the Y2(OH)5Cl.nH2O structure. In conclusion, the present investigation provides systematic phase diagrams for rare earth oxychloride-water systems that can be used as guidelines for the preparation and application of REOCls and RE2(OH)5Cl.nH2O phases in aqueous media. PMID- 24779427 TI - Polyethylenimine-enhanced electrocatalytic reduction of CO2 to formate at nitrogen-doped carbon nanomaterials. AB - Nitrogen-doped carbon nanotubes are selective and robust electrocatalysts for CO2 reduction to formate in aqueous media without the use of a metal catalyst. Polyethylenimine (PEI) functions as a co-catalyst by significantly reducing catalytic overpotential and increasing current density and efficiency. The co catalysis appears to help in stabilizing the singly reduced intermediate CO2(*-) and concentrating CO2 in the PEI overlayer. PMID- 24779428 TI - A/H1N1 vaccine intentions in college students: an application of the theory of planned behavior. AB - OBJECTIVE: To test the applicability of the Theory of Planned Behavior (TPB) in college students who have not previously received the A/H1N1 vaccine. PARTICIPANTS: Undergraduate communication students at a metropolitan southern university. METHODS: In January-March 2010, students from voluntarily participating communication classes completed a hardcopy survey assessing TPB and clinically significant constructs. Hierarchical regression equations predicted variance in vaccine intentions of students who had not received a flu shot (N=198; 70% Caucasian). RESULTS: The TPB model explained 51.7% (p<.001) of variance in vaccine intentions. Controlling for side effects, self-efficacy and perceived comparative susceptibility predicted intentions when entered in the first block, whereas attitudes, subjective norms, and perceived behavioral control significantly contribute when entered in the second block. CONCLUSIONS: For students who have not previously received a flu vaccine, vaccine communication should utilize self-efficacy and perceived comparative susceptibility to employ the TPB to promote vaccine intentions. PMID- 24779429 TI - Sclerostin in institutionalized elderly women: associations with quantitative bone ultrasound, bone turnover, fractures, and mortality. AB - OBJECTIVES: To evaluate the association between levels of circulating sclerostin (an emerging biomarker and important regulator of bone formation) and laboratory parameters of bone and mineral metabolism, bone mineral density and quality measured using quantitative ultrasound (QUS), fracture risk, and mortality. DESIGN: Prospective cohort study. SETTING: Austrian nursing homes (N = 95). PARTICIPANTS: Female nursing home residents aged 70 and older (mean 84 +/- 6; N = 539). MEASUREMENTS: Serum sclerostin, bone turnover markers, and bone mineral density and quality were measured at baseline. Participants were followed for clinical fractures and all-cause mortality. RESULTS: Partial correlation analysis adjusted for age, weight, and renal function revealed a significant positive correlation between sclerostin levels and calcaneal stiffness and radial and phalangeal speed of sound (all P < .01) and a significant negative correlation between sclerostin levels and osteocalcin, serum C-terminal telopeptide of type I collagen, and parathyroid hormone (PTH; P < .05). After a mean follow-up of 27 +/ 8 months, 139 participants (26%) had died and 64 had a hip or other nonvertebral fracture (12%). Sclerostin was not predictive of mortality. In women with a negative fracture history, it was significantly but not linearly associated with fracture risk. CONCLUSION: In institutionalized elderly women, there is a significant relationship between serum sclerostin levels and QUS indices, bone turnover, and PTH, but sclerostin was not strongly associated with important clinical outcomes. Thus, it remains unclear whether sclerostin is a clinically useful predictor of fractures or mortality, at least in this setting. PMID- 24779430 TI - Synthesis and reactivity of 1,2-dioxolanes from beta,gamma-epoxy ketones. AB - Five-membered ring peroxides were prepared in one step in 31-86% yield from readily accessible beta,gamma-epoxy ketones and H2O2. The reaction proceeded via a tetrahydrofuran, which was converted to the thermodynamically favored 1,2 dioxolane. The product contains a leaving group, which can be displaced to synthesize analogues of the plakinic acid natural products. PMID- 24779432 TI - Dynamics in crowded environments: is non-Gaussian Brownian diffusion normal? AB - The dynamics of colloids and proteins in dense suspensions is of fundamental importance, from a standpoint of understanding the biophysics of proteins in the cytoplasm and for the many interesting physical phenomena in colloidal dispersions. Recent experiments and simulations have raised questions about our understanding of the dynamics of these systems. Experiments on vesicles in nematic fluids and colloids in an actin network have shown that the dynamics of particles can be "non-Gaussian"; that is, the self-part of the van Hove correlation function, Gs(r,t), is an exponential rather than Gaussian function of r, in regimes where the mean-square displacement is linear in t. It is usually assumed that a linear mean-square displacement implies a Gaussian Gs(r,t). In a different result, simulations of a mixture of proteins, aimed at mimicking the cytoplasm of Escherichia coli, have shown that hydrodynamic interactions (HI) play a key role in slowing down the dynamics of proteins in concentrated (relative to dilute) solutions. In this work, we study a simple system, a dilute tracer colloidal particle immersed in a concentrated solution of larger spheres, using simulations with and without HI. The simulations reproduce the non-Gaussian Brownian diffusion of the tracer, implying that this behavior is a general feature of colloidal dynamics and is a consequence of local heterogeneities on intermediate time scales. Although HI results in a lower diffusion constant, Gs(r,t) is very similar to and without HI, provided they are compared at the same value of the mean-square displacement. PMID- 24779431 TI - The impact of severe traumatic brain injury on a novel base deficit- based classification of hypovolemic shock. AB - BACKGROUND: Recently, our group has proposed a new classification of hypovolemic shock based on the physiological shock marker base deficit (BD). The classification consists of four groups of worsening BD and correlates with the extent of hypovolemic shock in severely injured patients. The aim of this study was to test the applicability of our recently proposed classification of hypovolemic shock in the context of severe traumatic brain injury (TBI). METHODS: Between 2002 and 2011, patients >=16 years in age with an AIShead >= 3 have been retrieved from the German TraumaRegister DGU((r)) database. Patients were classified into four strata of worsening BD [(class I (BD <= 2 mmol/l), class II (BD > 2.0 to 6.0 mmol/l), class III (BD > 6.0 to 10 mmol/l) and class IV (BD > 10 mmol/l)] and assessed for demographic and injury characteristics as well as blood product transfusions and outcomes. The cohort of severely injured patients with TBI was compared to a population of all trauma patients to assess possible differences in the applicability of the BD based classification of hypovolemic shock. RESULTS: From a total of 23,496 patients, 10,201 multiply injured patients with TBI (AIShead >= 3) could be identified. With worsening of BD, a consecutive increase of mortality rate from 15.9% in class I to 61.4% in class IV patients was observed. Simultaneously, injury severity scores increased from 20.8 (+/ 11.9) to 41.6 (+/-17). Increments in BD paralleled decreasing hemoglobin, platelet counts and Quick's values. The number of blood units transfused correlated with worsening of BD. Massive transfusion rates increased from 5% in class I to 47% in class IV. Between multiply injured patients with TBI and all trauma patients, no clinically relevant differences in transfusion requirement or massive transfusion rates were observed. CONCLUSION: The presence of TBI has no relevant impact on the applicability of the recently proposed BD-based classification of hypovolemic shock. This study underlines the role of BD as a relevant clinical indicator of hypovolaemic shock during the initial assessment in respect to haemostatic resuscitation and transfusion requirements. PMID- 24779434 TI - Strengthening of palliative care as a component of integrated treatment throughout the life course. AB - In December 2013, the World Health Organization Executive Board generated a report entitled: Strengthening of palliative care as a component of integrated treatment throughout the life course. The contents of that report are presented. PMID- 24779433 TI - Flagellin/TLR5 signalling activates renal collecting duct cells and facilitates invasion and cellular translocation of uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) colonizing kidneys is the main cause of acute pyelonephritis. TLR5 that senses flagellin was shown to be highly expressed in the bladder and to participate in host defence against flagellated UPEC, although its role in kidneys still remains elusive. Here we show that TLR5 is expressed in renal medullary collecting duct (MCD) cells, which represent a preferential site of UPEC adhesion. Flagellin, like lipopolysaccharide, stimulated the production of the chemoattractant chemokines CXCL1 and CXCL2, and subsequent migration capacity of neutrophils in cultured wild-type (WT) and Tlr4( /-) MCDs, but not in Tlr5(-/-) MCDs. UPEC can translocate across intact MCD layers without altering tight junctions. Strikingly, the invasion capacity and transcellular translocation of the UPEC strain HT7 were significantly lower in Tlr5(-/-) than in WT MCDs. The non-motile HT7DeltafliC mutant lacking flagellin also exhibited much lower translocation capacities than the HT7 isolates. Finally, Tlr5(-/-) kidneys exhibited less infiltrating neutrophils than WT kidneys one day after the transurethral inoculation of HT7, and greater delayed renal bacterial loads in the day 4 post-infected Tlr5(-/-) kidneys. Overall, these findings indicate that the epithelial TLR5 participates to renal antibacterial defence, but paradoxically favours the translocation of UPEC across intact MCD cell layers. PMID- 24779435 TI - Resonance: offering. PMID- 24779436 TI - Nonadherence with analgesic medications: implications and strategies. PMID- 24779437 TI - Impact of the functional status of saeRS on in vivo phenotypes of Staphylococcus aureus sarA mutants. AB - We investigated the in vivo relevance of the impact of sarA and saeRS on protease production using derivatives of the USA300 strain LAC. The results confirmed that mutation of saeRS or sarA reduces virulence in a bacteremia model to a comparable degree. However, while eliminating protease production restored virulence in the sarA mutant, it had little impact in the saeRS mutant. Additionally, constitutive activation of saeRS (saeRS(C)) enhanced the virulence of LAC and largely restored virulence in the isogenic sarA mutant. Based on these results, together with our analysis of the representative virulence factors alpha toxin, protein A (Spa), and extracellular nucleases, we propose a model in which the attenuation of saeRS mutants is defined primarily by decreased production of such factors, while constitutive activation of saeRS increases virulence, and reverses the attenuation of sarA mutants, because it results in both increased production and decreased protease-mediated degradation of these same factors. This regulatory balance was also apparent in a murine model of catheter-associated infection, with the results suggesting that the impact of saeRS on nuclease production plays an important role during the early stages of these infections that is partially offset by increased protease production in sarA mutants. PMID- 24779438 TI - Evaluation of a complex intervention to improve activities of daily living of disabled cancer patients: protocol for a randomised controlled study and feasibility of recruitment and intervention. AB - BACKGROUND: Many cancer patients have problems performing activities of daily living (ADL). A randomised controlled trial was designed to examine the effects of an ADL intervention in addition to standard treatment and care in a hospital setting. The objective of this article was to present the study and to analyse the feasibility of the recruitment process and the intervention. METHODS: Adult disabled cancer patients at Naestved Hospital in Denmark were enrolled between 1 March 2010 and 30 June 2011 and randomised into an ADL intervention or to a control group. The intervention was performed by occupational therapists. The feasibility of the recruitment was analysed with regard to success in achieving the estimated number of participants and identification of barriers, and feasibility of the intervention was based on calculations of patient attendance and patient acceptability. The primary outcome of the randomised controlled trial was patients' health-related quality of life 2 and 8 weeks after baseline. RESULTS: A total of 118 disabled cancer patients were enrolled in the study over a time span of 16 months. Very few meetings between occupational therapist and patient were cancelled. Time spent on the intervention varied considerably, but for the majority of patients, time consumption was between 1-3 hours. CONCLUSIONS: Despite difficulties with recruitment, participation was considered feasible and the intervention was accepted among patients. Missing data in the follow-up period were mostly due to death among participants. Very few participants declined to complete questionnaires during follow-up. PMID- 24779439 TI - Single macroscopic pillars as model system for bioinspired adhesives: influence of tip dimension, aspect ratio, and tilt angle. AB - The goal of our study is to better understand the design parameters of bioinspired dry adhesives inspired by geckos. For this, we fabricated single macroscopic pillars of 400 MUm diameter with different aspect ratios and different tip shapes (i.e., flat tips, spherical tips with different radii, and mushroom tips with different diameters). Tilt-angle-dependent adhesion measurements showed that although the tip shape of the pillars strongly influences the pull-off force, the pull-off strength is similar for flat and mushroom-shaped tips. We found no tilt-angle dependency of adhesion for spherical tip structures and, except for high tilt angle and low preload experiments, no tilt-angle effect for mushroom-tip pillars. For flat-tip pillars, we found a strong influence of tilt angle on adhesion, which decreased linearly with increasing aspect ratio. The experiments show that for the tested aspect ratios between 1 and 5, a linear decrease of tilt-angle dependency is found. The results of our studies will help to design bioinspired adhesives for application on smooth and rough surfaces. PMID- 24779441 TI - Assembly line polyketide synthases: mechanistic insights and unsolved problems. AB - Two hallmarks of assembly line polyketide synthases have motivated an interest in these unusual multienzyme systems, their stereospecificity and their capacity for directional biosynthesis. In this review, we summarize the state of knowledge regarding the mechanistic origins of these two remarkable features, using the 6 deoxyerythronolide B synthase as a prototype. Of the 10 stereocenters in 6 deoxyerythronolide B, the stereochemistry of nine carbon atoms is directly set by ketoreductase domains, which catalyze epimerization and/or diastereospecific reduction reactions. The 10th stereocenter is established by the sequential action of three enzymatic domains. Thus, the problem has been reduced to a challenge in mainstream enzymology, where fundamental gaps remain in our understanding of the structural basis for this exquisite stereochemical control by relatively well-defined active sites. In contrast, testable mechanistic hypotheses for the phenomenon of vectorial biosynthesis are only just beginning to emerge. Starting from an elegant theoretical framework for understanding coupled vectorial processes in biology [Jencks, W. P. (1980) Adv. Enzymol. Relat. Areas Mol. Biol. 51, 75-106], we present a simple model that can explain assembly line polyketide biosynthesis as a coupled vectorial process. Our model, which highlights the important role of domain-domain interactions, not only is consistent with recent observations but also is amenable to further experimental verification and refinement. Ultimately, a definitive view of the coordinated motions within and between polyketide synthase modules will require a combination of structural, kinetic, spectroscopic, and computational tools and could be one of the most exciting frontiers in 21st Century enzymology. PMID- 24779442 TI - Genetic analysis of the response to eleven Colletotrichum lindemuthianum races in a RIL population of common bean (Phaseolus vulgaris L.). AB - BACKGROUND: Bean anthracnose is caused by the fungus Colletotrichum lindemuthianum (Sacc. & Magnus) Lams.- Scrib. Resistance to C. lindemuthianum in common bean (Phaseolus vulgaris L.) generally follows a qualitative mode of inheritance. The pathogen shows extensive pathogenic variation and up to 20 anthracnose resistance loci (named Co-), conferring resistance to specific races, have been described. Anthracnose resistance has generally been investigated by analyzing a limited number of isolates or races in segregating populations. In this work, we analyzed the response against eleven C. lindemuthianum races in a recombinant inbred line (RIL) common bean population derived from the cross Xana * Cornell 49242 in which a saturated linkage map was previously developed. RESULTS: A systematic genetic analysis was carried out to dissect the complex resistance segregations observed, which included contingency analyses, subpopulations and genetic mapping. Twenty two resistance genes were identified, some with a complementary mode of action. The Cornell 49242 genotype carries a complex cluster of resistance genes at the end of linkage group (LG) Pv11 corresponding to the previously described anthracnose resistance cluster Co-2. In this position, specific resistance genes to races 3, 6, 7, 19, 38, 39, 65, 357, 449 and 453 were identified, with one of them showing a complementary mode of action. In addition, Cornell 49242 had an independent gene on LG Pv09 showing a complementary mode of action for resistance to race 453. Resistance genes in genotype Xana were located on three regions involving LGs Pv01, Pv02 and Pv04. All resistance genes identified in Xana showed a complementary mode of action, except for two controlling resistance to races 65 and 73 located on LG Pv01, in the position of the previously described anthracnose resistance cluster Co-1. CONCLUSIONS: Results shown herein reveal a complex and specific interaction between bean and fungus genotypes leading to anthracnose resistance. Organization of specific resistance genes in clusters including resistance genes with different modes of action (dominant and complementary genes) was also confirmed. Finally, new locations for anthracnose resistance genes were identified in LG Pv09. PMID- 24779443 TI - Two hundred years of local avian extinctions in eastern Amazonia. AB - Local, regional, and global extinctions caused by habitat loss, degradation, and fragmentation have been widely reported for the tropics. The patterns and drivers of this loss of species are now increasingly well known in Amazonia, but there remains a significant gap in understanding of long-term trends in species persistence and extinction in anthropogenic landscapes. Such a historical perspective is critical for understanding the status and trends of extant biodiversity as well as for identifying priorities to halt further losses. Using extensive historical data sets of specimen records and results of contemporary surveys, we searched for evidence of local extinctions of a terra firma rainforest avifauna over 200 years in a 2500 km(2) eastern Amazonian region around the Brazilian city of Belem. This region has the longest history of ornithological fieldwork in the entire Amazon basin and lies in the highly threatened Belem Centre of Endemism. We also compared our historically inferred extinction events with extensive data on species occurrences in a sample of catchments in a nearby municipality (Paragominas) that encompass a gradient of past forest loss. We found evidence for the possible extinction of 47 species (14% of the regional species pool) that were unreported from 1980 to 2013 (80% last recorded between 1900 and 1980). Seventeen species appear on the International Union for Conservation of Nature Red List, and many of these are large-bodied. The species lost from the region immediately around Belem are similar to those which are currently restricted to well-forested catchments in Paragominas. Although we anticipate the future rediscovery or recolonization of some species inferred to be extinct by our calculations, we also expect that there are likely to be additional local extinctions, not reported here, given the ongoing loss and degradation of remaining areas of native vegetation across eastern Amazonia. PMID- 24779445 TI - My intention was a child but I was very afraid: fertility intentions and HIV risk perceptions among HIV-serodiscordant couples experiencing pregnancy in Kenya. AB - We sought to understand fertility intentions and HIV risk considerations among Kenyan HIV-serodiscordant couples who became pregnant during a prospective study. We conducted individual in-depth interviews (n = 36) and focus group discussions (n = 4) and performed qualitative data analysis and interpretation using an inductive approach. Although most of the couples were aware of the risk of horizontal and vertical HIV transmission, almost all couples reported that they had intended to become pregnant and that the desire for children superseded HIV risk considerations. Motivations for pregnancy were numerous and complex: satisfying desired family size, desire for biological children, maintaining stability of the union, and sociocultural pressures. Couples desired strategies to reduce HIV risk during conception, but expressed hesitation toward assisted reproductive technologies as unnatural. HIV prevention programs should therefore address conception desires and counsel about coordinated periconception risk reduction strategies. PMID- 24779446 TI - Different dynamical effects in mesophilic and hyperthermophilic dihydrofolate reductases. AB - The role of protein dynamics in the reaction catalyzed by dihydrofolate reductase from the hyperthermophile Thermotoga maritima (TmDHFR) has been examined by enzyme isotope substitution ((15)N, (13)C, (2)H). In contrast to all other enzyme reactions investigated previously, including DHFR from Escherichia coli (EcDHFR), for which isotopic substitution led to decreased reactivity, the rate constant for the hydride transfer step is not affected by isotopic substitution of TmDHFR. TmDHFR therefore appears to lack the coupling of protein motions to the reaction coordinate that have been identified for EcDHFR catalysis. Clearly, dynamical coupling is not a universal phenomenon that affects the efficiency of enzyme catalysis. PMID- 24779447 TI - Picturing objects in infancy. AB - Infants' transfer of information from pictures to objects was tested by familiarizing 9-month-olds (N = 31) with either a color or black-and-white photograph of an object and observing their preferential reaching for the real target object versus a distractor. One condition tested object recognition by keeping both objects visible, and the other tested object representation by hiding both objects. On visible trials, infants reached more for the distractor, indicating they recognized the target object from its picture. On hidden trials, infants reached more for the target object, suggesting they formed a continued representation of the object based on its picture. Photograph color had no effect. Infants thus show picture-to-object transfer by 9 months with preferential reaching, even with black-and-white pictures. PMID- 24779448 TI - Relativistic four-component potential energy curves for the lowest 23 covalent states of molecular bromine (Br2). AB - The covalent excited states and ground state of the Br2 molecule has been investigated by using four-component relativistic COSCI and MRCISD methods. These methods were performed for all covalent states in the representation Omega((+/ )). Calculated potential energy curves (PECs) were obtained at the four-component COSCI level, and spectroscopic constants (R(e), D(e), D0, omega(e), omega(e)x(e), omega(e)y(e), B(e), alpha(e), gamma(e), Te, Dv) for bounded states are reported. The vertical excitations for all covalent states are reported at COSCI, MRCISD, and MRCISD+Q levels. We also present spectroscopic constants for two weakly bounded states (A':(1)2u and B':(1)0(-)u) not yet reported in the literature, as well as accurate analytical curves for all five relativistic molecular bounded sates [the ground state X:0 g(+) and the excited states A:(1)1(u), B:(1)0(u)(+), C:(2)1(u), and B':(1)0(u)(-)] found in this work. PMID- 24779444 TI - Phylogenetic and antigenic characterization of reassortant H9N2 avian influenza viruses isolated from wild waterfowl in the East Dongting Lake wetland in 2011 2012. AB - BACKGROUND: Wild waterfowl are recognized as the natural reservoir for influenza A viruses. Two distinct lineages, the American and Eurasian lineages, have been identified in wild birds. Gene flow between the two lineages is limited. The H9N2 virus has become prevalent in poultry throughout Eurasia, and mainly circulates in wild ducks and shorebirds in North America. METHODS: In this study, 22 H9N2 avian influenza viruses were isolated from wild waterfowl feces in East Dongting Lake Nature Reserve in November 2011 and March 2012. The phylogenetic, molecular, and antigenic characteristics of these viruses were analyzed based on analyses of the whole genome sequence of each isolate. RESULTS: Phylogenetic analyses indicated that these H9N2 viruses were generated by reassortment events. The HA, NA, PA, and NS genes were derived from the American gene pool, and the other four genes were derived from the Eurasian gene pool. Antigenic analyses indicated that these viruses were significantly different from the Eurasian lineage viruses. CONCLUSIONS: This study presents the isolation of novel intercontinental recombinant H9N2 viruses from wild waterfowl in the East Dongting Lake wetland. The novel genotype H9N2 virus has not been detected in poultry in the region yet, and may be transmitted to naive birds in poultry farms. Therefore, our results highlight the need for ongoing surveillance of wild birds and poultry in this region. PMID- 24779450 TI - Intramolecular hydrogen transfer reaction: menthon from isopulegol. AB - The flavor menthon (isomeric mixture of (-)-menthon and (+)-isomenthon) was obtained in good yields and selectivities by a solventless ruthenium catalyzed isomerization of the homoallylic alcohol (-)-isopulegol. In contrast to most previous assumptions on such "isomerization" reactions, this reaction follows an intermolecular pathway, with menthol and pulegon being the central intermediates in this transformation. PMID- 24779449 TI - Late-life factors associated with healthy aging in older men. AB - OBJECTIVES: To identify potentially modifiable late-life biological, lifestyle, and sociodemographic factors associated with overall and healthy survival to age 85. DESIGN: Prospective longitudinal cohort study with 21 years of follow-up (1991-2012). SETTING: Hawaii Lifespan Study. PARTICIPANTS: American men of Japanese ancestry (mean age 75.7, range 71-82) without baseline major clinical morbidity and functional impairments (N = 1,292). MEASUREMENTS: Overall survival and healthy survival (free from six major chronic diseases and without physical or cognitive impairment) to age 85. Factors were measured at late-life baseline examinations (1991-1993). RESULTS: Of 1,292 participants, 1,000 (77%) survived to 85 (34% healthy) and 309 (24%) to 95 (<1% healthy). Late-life factors associated with survival and healthy survival included biological (body mass index, ankle brachial index, cognitive score, blood pressure, inflammatory markers), lifestyle (smoking, alcohol use, physical activity), and sociodemographic factors (education, marital status). Cumulative late-life baseline risk factor models demonstrated that age-standardized (at 70) probability of survival to 95 ranged from 27% (no factors) to 7% (>= 5 factors); probability of survival to 100 ranged from 4% (no factors) to 0.1% (>= 5 factors). Age-standardized (at 70) probability of healthy survival to 90 ranged from 4% (no factors) to 0.01% (>= 5 factors). There were nine healthy survivors at 95 and one healthy survivor at 100. CONCLUSION: Several potentially modifiable risk factors in men in late life (mean age 75.7) were associated with markedly greater probability of subsequent healthy survival and longevity. PMID- 24779451 TI - TWIST overexpression predicts biochemical recurrence-free survival in prostate cancer patients treated with radical prostatectomy. AB - OBJECTIVE: The aim of this study was to determine whether TWIST and androgen receptor (AR) expression can predict the outcome in radical prostatectomy (RP) patients. MATERIAL AND METHODS: Samples from different tumour areas of 181 prostate cancer patients were analysed for TWIST and AR expression, and the results were correlated with known clinicopathological data and biochemical recurrence-free survival (BFS). RESULTS: TWIST overexpression in the margin area of the tumour (M-TWIST) was related to positive surgical margin (p = 0.047), capsule invasion (p = 0.006) and biochemical recurrence (BCR) (p = 0.004). AR expression in the margin area of the tumour (M-AR) was associated with high Gleason score (p = 0.004), positive surgical margin (p = 0.004) and BCR (p = 0.05). M-TWIST overexpression was clearly associated with M-AR expression (p < 0.0001). Four parameters, i.e. M-TWIST overexpression (p < 0.0001), positive surgical margin (p = 0.003), high Gleason score (p < 0.0001) and M-AR expression (p = 0.008), predicted BFS. In the multivariate analysis, M-TWIST overexpression (p = 0.011) and Gleason score (p = 0.002) were the only independent predictors of BFS. CONCLUSIONS: M-TWIST overexpression is associated with clinicopathological prognosis factors and M-AR overexpression and is a powerful independent predictor of BFS in conjunction with the Gleason score in prostate cancer patients treated with RP. PMID- 24779452 TI - Ketamine cystitis: practical considerations in management. AB - OBJECTIVE: The aim of this study was to investigate and report the clinical spectrum and practical problems in the management of a cohort of patients presenting with lower urinary tract symptoms (LUTS) related to abuse of ketamine. MATERIAL AND METHODS: The clinical presentation, cystoscopic findings, radiological features and outcomes of patients presenting with LUTS related to ketamine abuse between January 2008 and April 2013 were retrospectively reviewed and analysed. RESULTS: In total, 34 patients were seen during this period. All patients had LUTS, haematuria and abdominal pain to varying degrees. Two patients (7%) had a concomitant urinary tract infection. Upper tract imaging was carried out in 18 out of 34 patients and bilateral hydronephrosis was found in two cases (6%). Cystoscopy showed a small inflamed bladder (capacity 60-350 ml) in 14 out of the 16 cases where this was performed. Bladder biopsies showed denudation of urothelium and infiltration of submucosa with lymphocytes and eosinophils with no increase in mast cells. Fifty-nine per cent of patients did not attend their clinic, imaging and/or cystoscopy appointments. One patient underwent a subtotal cystectomy and bladder reconstruction. CONCLUSIONS: Ketamine cystitis is a complex problem whose exact pathological mechanism and natural history remain unknown. The only known effective treatment is to abstain from the drug. Urologists need to recognize the condition early and work together with the local substance misuse service, focusing on drug cessation therapy to reduce complications. PMID- 24779453 TI - Perceived discrimination and its associations with mental health and substance use among Asian American and Pacific Islander undergraduate and graduate students. AB - OBJECTIVES: Racial discrimination experiences can negatively affect health. This study examined perceived discrimination and its relationship with mental health and substance use among Asian American and Pacific Islander (API) undergraduate and graduate students. PARTICIPANTS: A total of 113 API students aged 18-35 completed the study during February-June, 2011. METHODS: The authors conducted a cross-sectional, anonymous survey online. Dependent variables included mental health (depressive, anxiety, and somatic symptoms) and substance use (alcohol problems, use of tobacco, marijuana or hashish, and other illegal drugs). RESULTS: Students' perceived discrimination were significantly, positively associated with depressive, anxiety, and somatic symptoms, but not with substance use. Ethnic identity moderated the relationship between perceived discrimination and somatic symptoms, but not depressive or anxiety symptoms. CONCLUSIONS: These findings suggested the negative effect of racial discrimination on API students' mental health. The buffering effect of ethnic identity may increase resilience in these students when they face racial discrimination. PMID- 24779454 TI - The quality of internal medicine hospital care during summer holiday season. AB - RATIONALE, AIMS AND OBJECTIVES: The July/August Phenomenon is a period when the quality of care in hospitals is thought to decrease due to summer vacation stand ins and new staff. The results of studies on the veracity of this claim have been conflicting. This study investigates the situation in internal medicine. METHODS: Registry data of patients treated in internal medicine wards between 1 July 2000 and 30 November 2009 were obtained and analysed. RESULTS: There were no differences in mortality during the July admissions compared with those in November when adjusting for age, diagnosis, gender and year [for the overall data risk ratio (RR) = 1.10, 95% confidence interval (CI) 1.00-1.23, P = 0.06; for the university hospitals RR = 1.10, 95% CI 0.91-1.33, P = 0.34; for the non university hospitals RR = 1.10, 95% CI 0.97-1.26, P = 0.13]. The duration of admission (overall mean 4.5, standard deviation 6.0) was equal between July and November when adjusted for age, diagnosis, gender and year in all groups (overall data: RR = 1.00, 95% CI 0.99-1.02, P = 0.83; university hospitals RR = 1.02, 95% CI 0.99-1.04, P = 0.13; non-university hospitals RR = 1.00, 95% CI 0.98-1.01, P = 0.67). CONCLUSIONS: The quality of care in Finnish internal medicine wards in July seems to equal November. Our results do not support the existence of a July Phenomenon in Finland. PMID- 24779456 TI - Unique genome replication mechanism of the archaeal virus AFV1. AB - The exceptional genomic content and genome organization of the Acidianus filamentous virus 1 (AFV1) that infects the hyperthermophilic archaeon Acidianus hospitalis suggest that this virus might exploit an unusual mechanism of genome replication. An analysis of replicative intermediates of the viral genome by two dimensional (2D) agarose gel electrophoresis revealed that viral genome replication starts by the formation of a D-loop and proceeds via strand displacement replication. Characterization of replicative intermediates using dark-field electron microscopy, in combination with the 2D agarose gel electrophoresis data, suggests that recombination plays a key role in the termination of AFV1 genome replication through the formation of terminal loops. A terminal protein was found to be attached to the ends of the viral genome. The results allow us to postulate a model of genome replication that relies on recombination events for initiation and termination. PMID- 24779455 TI - A home-based method for the detection of impaired glucose tolerance in hypertensive primary care patients. AB - OBJECTIVE: The aim of this project was to compare an oral glucose tolerance test (OGTT) partly performed in the patient's home (OGTTh) with a clinic-obtained OGTT with regard to the ability of the tests to identify patients with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM-2). DESIGN: A method comparison. SETTING: The study was completed at two primary health care centres. SUBJECTS: Fifty-one patients with hypertension aged 50-79 years completed both OGTT tests. MAIN OUTCOME MEASURES: Values for capillary P-glucose obtained two hours after a glucose load were compared between the two OGTT tests. Fasting plasma glucose (fP-glucose) and HbA1c were also measured. RESULTS: Thirty-seven patients were classified in the same group (normal/IGT/DM-2) by the two tests. The index of validity based on the test's ability to identify normal or pathological values (>= 8.9 mmol/l) was 0.75. The value for kappa was 0.66 with a sensitivity of 0.54 and a specificity of 0.82. CONCLUSION: OGTTh may be a useful screening method for IGT in risk groups such as hypertensive patients. PMID- 24779457 TI - Descriptive epidemiology of detected anthrax outbreaks in wild wood bison (Bison bison athabascae) in northern Canada, 1962-2008. AB - We inventoried and assessed historical anthrax outbreak data from 1962-2008 in wild wood bison (Bison bison athabascae) in Wood Buffalo National Park and the Slave River Lowlands (SRL), Northwest Territories, Canada. We compared these results with a 2010 outbreak in the SRL. Anthrax outbreaks have occurred in 12 of the years between 1962 and 2008 in wild wood bison with 1,515 anthrax deaths detected. The average number of carcasses found each outbreak year was 126 (range 1-363), though local averages varied. The numbers of animals found dead per outbreak declined over the past four decades. Outbreaks varied in duration from 16-44 days (average length 25.5 days). The length of an outbreak was not a determinant of the number of dead bison found, but outbreaks starting in July had more deaths than those staring in June. Males were more likely to be detected in an outbreak, outbreaks were likely not random events, and there was no relationship between outbreak size or length and location. Future surveillance activities may benefit from targeting bulls and planning surveillance activities for more than 3 wk after outbreak detection. Coordinating data collecting and recording efforts between jurisdictions may overcome historical challenges in inconsistent record keeping. PMID- 24779458 TI - Serologic, molecular, and pathologic survey of pseudorabies virus infection in hunted wild boars (Sus scrofa) in Italy. AB - To investigate pseudorabies-virus (PrV) -antibody and viral-DNA prevalence, we collected blood, nasal and genital swabs, and tonsillar and lymph-node tissue samples from 139 wild boars (Sus scrofa; 39 piglets, 30 juveniles, and 70 adults), during the hunting season of 2010-2011 in Tuscany, Central Italy. We performed immunohistochemistry with anti-PrV monoclonal antibodies on selected tissue samples. Forty-three of 139 (30.9%) boars were PrV-antibody positive and a 1,954-base-pair PrV-specific product was amplified from nine nasal (6.5%) and 26 genital (18.7%) swabs. Sequence analysis of PrV-positive PCR products revealed identity scores of 99-100% with Suid herpesvirus 1 strain Becker (JF797219) and confirmed the identification of PrV DNA in tested swabs. There was significantly higher antibody prevalence in adults than in juveniles and in piglets than in juveniles. The prevalence of viral DNA was significantly higher in genital swabs than in nasal specimens. The percentage of positive nasal swabs did not differ among age classes. Piglets had a higher percentage of PCR-positive genital swabs than juvenile and adult subjects (30.8% vs. 13.3% and 14.3%, respectively). Results confirmed that PrV infection is widespread in the wild boar population in the study area. The presence of anti-PrV antibodies and of the PrV virus in piglets could be related to vertical transmission of the virus. This hypothesis was also supported by a higher presence of viral genome in genital swabs than in nasal swabs. This field study supports the importance of vertical transmission of PrV, and the high prevalence of virus in genital swabs supports venereal transmission in adult feral boars. PMID- 24779459 TI - Origin of Dermacentor albipictus (Acari: Ixodidae) on elk in the Yukon, Canada. AB - Winter ticks (Dermacentor albipictus) on elk (Cervus elaphus canadensis) have recently increased in numbers in the Yukon, Canada, potentially posing risks to other indigenous host species in the region. To evaluate the regional source of winter ticks in the Yukon, we sequenced one nuclear (ITS-2) and two mitochondrial (16SrRNA and COI) genes, and genotyped 14 microsatellite loci from 483 winter tick specimens collected across North America. We analyzed genetic variation across the geographic and host ranges of this tick species with the use of variance partitioning, Bayesian clustering, and standard population genetic analyses. Based on our results, winter ticks on elk in the Yukon could have originated either by translocation from central Alberta or by northward range expansion of more geographically proximate populations in northern Alberta and British Columbia. Although there was some genetic structuring of winter ticks on different hosts in the same region, we found little evidence of host specificity in winter ticks from five ungulate host species, suggesting that the winter ticks on elk in the Yukon could potentially become established on other locally available host species such as moose (Alces alces). PMID- 24779460 TI - Evaluation of monkeypox virus infection of black-tailed prairie dogs (Cynomys ludovicianus) using in vivo bioluminescent imaging. AB - Monkeypox (MPX) is a re-emerging zoonotic disease that is endemic in Central and West Africa, where it can cause a smallpox-like disease in humans. Despite many epidemiologic and field investigations of MPX, no definitive reservoir species has been identified. Using recombinant viruses expressing the firefly luciferase (luc) gene, we previously demonstrated the suitability of in vivo bioluminescent imaging (BLI) to study the pathogenesis of MPX in animal models. Here, we evaluated BLI as a novel approach for tracking MPX virus infection in black tailed prairie dogs (Cynomys ludovicianus). Prairie dogs were affected during a multistate outbreak of MPX in the US in 2003 and have since been used as an animal model of this disease. Our BLI results were compared with PCR and virus isolation from tissues collected postmortem. Virus was easily detected and quantified in skin and superficial tissues by BLI before and during clinical phases, as well as in subclinical secondary cases, but was not reliably detected in deep tissues such as the lung. Although there are limitations to viral detection in larger wild rodent species, BLI can enhance the use of prairie dogs as an animal model of MPX and can be used for the study of infection, disease progression, and transmission in potential wild rodent reservoirs. PMID- 24779461 TI - Evidence of an Oxyspirura petrowi epizootic in northern bobwhites (Colinus virginianus), Texas, USA. AB - We captured 36 Northern Bobwhites (Colinus virginianus) in Mitchell County, Texas in June-September 2013, and examined them for the eyeworm Oxyspirura petrowi. We recovered 334 eyeworms from 28 of 29 adult bobwhites (97%); infections ranged from 1-40 worms and mean (+/- SD) abundance of 11.9 +/- 13.0. Three of seven juveniles were infected, and those infected had one eyeworm each. Prevalence of eyeworms was similar among months. However, mean abundance of eyeworms peaked in July and August (3.3 +/- 2.1, 13.5 +/- 15.0, and 16.9 +/- 15.5), and decreased in September (6.3 +/- 3.0). We suggest that several previous studies may underreport prevalence and abundance because in those studies only the eye surface and nictitating membrane were examined, and not eye-associated tissue, ducts, glands, or sinuses. PMID- 24779462 TI - Health evaluation and survey of zoonotic pathogens in free-ranging capybaras (Hydrochoerus hydrochaeris). AB - Capybaras (Hydrochoerus hydrochaeris) are the world's largest rodents and play an epidemiologic role in the transmission of zoonotic pathogens, including the causative agents of Brazilian spotted fever, leptospirosis, and others. We surveyed the health of 31 free-ranging capybaras at the Alberto Lofgren State Park, Sao Paulo, Brazil using a variety of diagnostic methods. Hematology and serum chemistry were consistent with mild malnutrition and parasitism but did not indicate severe physiologic imbalance or disease. All animals were serologically negative for Rickettsia rickettsii, Leishmania spp., and Trypanosoma sp., but antibodies against rabies virus (71%), Leptospira sp. (26%), and Toxoplasma sp. (23%) were detected. Salmonella sp. was not cultured from fecal samples. Frequently cultured enterobacteria included Escherichia coli (61%), Enterococcus casseiflavus (35%), Enterococcus faecalis (35%), Enterobacter aerogenes (32%), Klebisella pneumoniae (32%), and Serratia marcescens (32%). No potentially pathogenic fungi were cultured from hair samples. Fecal parasitology revealed infection by Protozoophaga sp. (58%), Viannella spp. (23%), Strongyloides spp. (10%), and Ancilostomatidae (10%). A total of 218 ticks was retrieved from the animals: Amblyomma sp. larvae and nymphs (43%), A. dubitatum adults (52%), and A. cajennense adults (5%). The capybaras were free from most potentially zoonotic pathogens evaluated; however, the presence of Amblyomma spp. ticks (potential vectors of Rickettsia spp.) and indirect evidence of exposure to the rabies virus, Leptospira sp., and Toxoplasma sp. warrant the maintenance of public health programs and wildlife health monitoring. PMID- 24779463 TI - Avian bornavirus in free-ranging waterfowl: prevalence of antibodies and cloacal shedding of viral RNA. AB - We surveyed free-ranging Canada Geese (Branta canadensis), Trumpeter Swans (Cygnus buccinator), Mute Swans (Cygnus olor), and Mallards (Anas platyrhynchos) to estimate the prevalence of antibodies to avian bornavirus (ABV) and of cloacal shedding of ABV RNA in southern Ontario, Canada. Blood samples and cloacal swabs were collected from 206 free-ranging Canada Geese, 135 Trumpeter Swans, 75 Mute Swans, and 208 Mallards at 10 main capture sites between October 2010 and May 2012. Sera were assessed for antibodies against ABV by enzyme-linked immunosorbent assay and swabs were evaluated for ABV RNA using real-time reverse transcription PCR. Serum antibodies were detected in birds from all four species and at each sampling site. Thirteen percent of the geese caught on the Toronto Zoo site shed ABV RNA in feces compared with 0% in geese sampled at three other locations. The proportions of shedders among Mute Swans, Trumpeter Swans, and Mallards were 9%, 0%, and 0%, respectively. Birds that were shedding viral RNA were more likely to have antibodies against ABV and to have higher antibody levels than those that were not, although many birds with antibodies were not shedding. We confirmed that exposure to, or infection with, ABV is widespread in asymptomatic free-ranging waterfowl in Canada; however, the correlation between cloacal shedding, presence of antibodies, and presence of disease is not fully understood. PMID- 24779464 TI - Antibodies to rabies virus in terrestrial wild mammals in native rainforest on the north coast of Sao Paulo State, Brazil. AB - Rabies causes thousands of human and animal deaths worldwide each year. The emergent importance of rabies in wild animals demonstrates the necessity of epidemiologic studies of infection in these species toward the development of better strategies for prevention and control of rabies. We analyzed the circulation of rabies virus among wildlife species from a native rainforest in Sao Paulo State, Brazil. We used the rapid fluorescent focus inhibition test (RFFIT) to test for rabies virus-neutralizing antibodies in 139 captured terrestrial mammals and the fluorescent antibody test (FAT), mouse inoculation test (MIT), and reverse-transcriptase (RT)-PCR to test for virus in samples from the central nervous system of 53 animals found dead. The percentage of samples positive by RFFIT was 10.8%. All samples tested by FAT, MIT, and RT-PCR were negative. Research should be continued to obtain a better understanding of the role of wildlife in the circulation and transmission of rabies virus. PMID- 24779465 TI - Mass mortality of Eurasian Tree Sparrows (Passer montanus) from Salmonella Typhimurium dt40 in Japan, winter 2008-09. AB - An outbreak of salmonellosis in wild passerines caused mass mortality of Eurasian Tree Sparrows (Passer montanus) in Hokkaido, Japan, 2005-06; however, the etiology was poorly understood. In winter 2008-09, sparrow mortality again occurred in Hokkaido, and 202 deaths in 100 incidents at 94 sites were reported. We conducted a comprehensive investigation to evaluate the cause and impact on sparrow populations. We collected 26 carcasses at 13 sites, including a zoological park. In addition, Salmonella screening of zoo animals was conducted as a biosecurity measure. Salmonella Typhimurium was isolated from multiple organs in all examined sparrows; they were diagnosed with septicemic salmonellosis. Eleven sites (85%) were related to wild bird feeding and six of eight sparrow fecal samples, including from the zoo, were S. Typhimurium positive. No infection was detected in zoo animals. Isolates belonged to three phage types: DT40 (88%), DT110 (8%), and DT120 (4%). Pulsed-field gel electrophoresis patterns were the same in all isolates, regardless of phage type. Biochemical characteristics and antibiotic-resistance profiles of DT40 were similar in all isolates, indicating a single origin. The mortality was likely associated with that in 2005-06 because the isolates had the same profiles. Tissue levels of sodium, calcium, and magnesium (the main components of chemical deicer suspected to be the major cause of poisoning deaths in 2005-06 mortality) were not higher in the affected sparrows. We conclude that an emerging epidemic infection with S. Typhimurium DT40 related to bird feeding was the cause of sparrow mortality in 2008-09 and suggest that this causative strain is host adapted to sparrows in Japan. The mortality might have had some impact on the local population, but its influence was limited. PMID- 24779466 TI - Pathogens in water deer (Hydropotes inermis) in South Korea, 2010-12. AB - Water deer (Hydropotes inermis) are among the most common wildlife to approach farmhouses and livestock barns in Korea. We collected 305 water deer from Gangwon (n=168), South Chungcheong (n=89), and Gyeongsang (n=48) provinces in 2010-12 and used PCR and serologic tests to screen the deer for pathogens. In 2010, tests for bovine viral diarrhea virus (BVDV), rotavirus, and Brucella abortus were positive in 8% (5/60), 2% (1/60), and 59% (33/56) of the animals, respectively. In 2010, the water deer were negative for foot-and-mouth disease virus, coronaviruses, and Mycobacterium bovis. All samples collected in 2011 and 2012 were negative for all pathogens analyzed. These results suggest that at least two of the investigated pathogens, BVDV and B. abortus, circulate among water deer in South Korea. PMID- 24779467 TI - Increased Contracaecum osculatum infection in Baltic cod (Gadus morhua) livers (1982-2012) associated with increasing grey seal (Halichoerus gryphus) populations. AB - Grey seals (Halichoerus gryphus), the main final host of the gastric parasitic nematode Contracaecum osculatum in the Baltic, have recently recolonized the southwestern Baltic Sea. This colonization could lead to an increase in prevalence and intensity of third-stage larvae of C. osculatum in livers of Baltic cod (Gadus morhua), which serve as transport host for this helminth. We performed a parasitologic study of cod in spring 2012 and compared the results with previously unpublished data from 1982/1983. Additionally, grey seals were counted annually from 2000 to 2011 at three haul-out sites in the southwestern Baltic. Of 97 cod livers examined in the 1982/1983 survey, 22% harbored C. osculatum larvae, whereas 55.1% of the examined cod livers (n=185) were infected in 2012; the mean intensity and mean abundance increased from 4.3 and 0.9 to 20.2 and 11.1, respectively. Molecular identification (PCR) confirmed the identity of the larvae. The grey seal population increased markedly during the 12-yr period. We suggest that the elevated parasitism of cod livers is associated with the successful re-establishment of grey seals in the southwestern Baltic. PMID- 24779468 TI - Seasonal prevalence of antibodies to Leptospira interrogans in Antillean manatees from a landlocked lake in Tabasco, Mexico. AB - Factors that alter the dynamics of ecologic systems can influence transmission of infectious diseases and may lead to decreases in natural populations. Leptospirosis is a cosmopolitan disease of zoonotic importance that affects most mammals. At the southern Gulf of Mexico, Antillean manatees (Trichechus manatus manatus) inhabit highly variable environments, with extended floods during the rainy season and drought conditions during the dry season that affect food availability and the thermal environment for manatees. We tested for changes in prevalence and titers of antibodies to 12 serovars of Leptospira interrogans in manatees between dry and rainy seasons. We determined titers for L. interrogans through microscopic agglutination tests (MAT) from 10 manatees, six during the dry season (DS), and six during the rainy season (RS) in Laguna de las Ilusiones, a landlocked lake hosting a population of about 20 manatees. All individuals were antibody positive (titers >= 100) to at least one serovar. The serovars bataviae, bratislava, canicola, and icterohaemorrhagiae had overall prevalences >= 50%; bataviae, bratislava, and canicola had prevalences >= 50% during both seasons. Serovars icterohaemorrhagiae and pyrogenes had prevalences >= 50% during DS and pomona, tarassovi, wolfii, and autumnalis during RS. Significant differences in prevalence between seasons were found for pomona, tarassovi, and autumnalis. Titers of tarassovi, wolfii, autumnalis, and bataviae were significantly higher during RS. There was a high prevalence of L. interrogans during the RS independent of high availability of plant foods, coinciding with the epizootiology of the bacteria that are endemic to tropical regions. Another factor possibly influencing prevalence is high anthropogenic pressure at the lake, causing an increase in potential sources of infection. Because of possible cross-reaction in MAT, further research is needed on the molecular discrimination of serovars in animals in the lake. PMID- 24779469 TI - Influence of aqueous precursor chemistry on the growth process of epitaxial SrTiO3 buffer layers. AB - In this Article, epitaxial thin films of SrTiO3 were prepared on single crystalline (100) LaAlO3 by an aqueous chemical solution deposition method. By using different chelating agents to stabilize the metal ions in water, the impact of the precursor chemistry on the microstructural and crystalline properties of the films was studied. Thorough investigation of the precursor by means of infrared and Raman spectroscopy as well as thermogravimetric analysis revealed that stable precursors can be obtained in which strontium ions can be either free in the solution or stabilized by one of the chelating agents. This stabilization of strontium ions appeared to be essential in order to obtain single phase SrTiO3 films. Precursors in which Sr(2+) remained as free ions showed SrO microcrystal segregation. Precursors in which both metal ions were stabilized gave rise to strongly textured, dense, and terraced SrTiO3 films, allowing subsequent deposition of YBa2Cu3O7-delta with superior superconducting performances. PMID- 24779470 TI - Assessment of phosphorylation in Toxoplasma glideosome assembly and function. AB - Members of the phylum Apicomplexa possess a highly conserved molecular motor complex anchored in the parasite pellicle and associated with gliding motility, invasion and egress from infected cells. This machinery, called the glideosome, is structured around the acylated gliding-associated protein GAP45 that recruits the motor complex composed of myosin A and two associated myosin light chains (TgMLC1 and TgELC1). This motor is presumably firmly anchored to the inner membrane complex underneath the plasma membrane via an interaction with two integral membrane proteins, GAP50 and GAP40. To determine if the previously mapped phosphorylation sites on TgGAP45 and TgMLC1 have a direct significance for glideosome assembly and function, a series of phospho-mimetic and phospho-null mutants were generated. Neither the overexpression nor the allelic replacement of TgMLC1 with phospho-mutants impacted on glideosome assembly and parasite motility. TgGAP45 phosphorylation mutants were functionally investigated using a complementation strategy in a TgGAP45 inducible knockout background. The loss of interaction with TgGAP50 by one previously reported GAP45-mutant appeared to depend only on the presence of a remaining competing wild type copy of TgGAP45. Accordingly, this mutant displayed no phenotype in complementation experiments. Unexpectedly, GAP45 lacking the region encompassing the cluster of twelve phosphorylation sites did not impact on its dual function in motor recruitment and pellicle integrity. Despite the extensive phosphorylation of TgMLC1 and TgGAP45, this post-translational modification does not appear to be critical for the assembly and function of the glideosome. PMID- 24779471 TI - Shape dependent synthesis and field emission induced rectification in single ZnS nanocrystals. AB - We report on the synthesis of shape controlled ZnS nanocrystals designed into nanodots, nanorods, and nanowires retaining the same diameter and crystallographic phase. We used UHV scanning tunneling microscopy and spectroscopy to study rectification behavior from single nanocrystals. The nanorod and nanowire show large tunneling current at the negative bias in comparison to the positive bias demonstrating current rectification, while the nanodot shows symmetric current-voltage behavior. We proposed a tunneling mechanism where direct tunneling is followed by resonant tunneling mechanism through ZnS nanocrystal at lower applied bias voltages. Stimulation of field emission in Fowler-Nordheim tunneling regime at higher negative bias voltages enables the rectification behavior from the ZnS nanorod or nanowire. Absence of rectification from the ZnS nanodot is associated with spherical shape where the field emission becomes less significant. Realizing functional electronic component from such shape dependent single ZnS nanocrystal may provide a means in realizing nanocrystal based miniaturized devices. PMID- 24779472 TI - Specificity determinants for autoproteolysis of LexA, a key regulator of bacterial SOS mutagenesis. AB - Bacteria utilize the tightly regulated stress response (SOS) pathway to respond to a variety of genotoxic agents, including antimicrobials. Activation of the SOS response is regulated by a key repressor-protease, LexA, which undergoes autoproteolysis in the setting of stress, resulting in derepression of SOS genes. Remarkably, genetic inactivation of LexA's self-cleavage activity significantly decreases acquired antibiotic resistance in infection models and renders bacteria hypersensitive to traditional antibiotics, suggesting that a mechanistic study of LexA could help inform its viability as a novel target for combating acquired drug resistance. Despite structural insights into LexA, a detailed knowledge of the enzyme's protease specificity is lacking. Here, we employ saturation and positional scanning mutagenesis on LexA's internal cleavage region to analyze >140 mutants and generate a comprehensive specificity profile of LexA from the human pathogen Pseudomonas aeruginosa (LexAPa). We find that the LexAPa active site possesses a unique mode of substrate recognition. Positions P1-P3 prefer small hydrophobic residues that suggest specific contacts with the active site, while positions P5 and P1' show a preference for flexible glycine residues that may facilitate the conformational change that permits autoproteolysis. We further show that stabilizing the beta-turn within the cleavage region enhances LexA autoproteolytic activity. Finally, we identify permissive positions flanking the scissile bond (P4 and P2') that are tolerant to extensive mutagenesis. Our studies shed light on the active site architecture of the LexA autoprotease and provide insights that may inform the design of probes of the SOS pathway. PMID- 24779474 TI - Seventy-one important questions for the conservation of marine biodiversity. AB - The ocean provides food, economic activity, and cultural value for a large proportion of humanity. Our knowledge of marine ecosystems lags behind that of terrestrial ecosystems, limiting effective protection of marine resources. We describe the outcome of 2 workshops in 2011 and 2012 to establish a list of important questions, which, if answered, would substantially improve our ability to conserve and manage the world's marine resources. Participants included individuals from academia, government, and nongovernment organizations with broad experience across disciplines, marine ecosystems, and countries that vary in levels of development. Contributors from the fields of science, conservation, industry, and government submitted questions to our workshops, which we distilled into a list of priority research questions. Through this process, we identified 71 key questions. We grouped these into 8 subject categories, each pertaining to a broad component of marine conservation: fisheries, climate change, other anthropogenic threats, ecosystems, marine citizenship, policy, societal and cultural considerations, and scientific enterprise. Our questions address many issues that are specific to marine conservation, and will serve as a road map to funders and researchers to develop programs that can greatly benefit marine conservation. PMID- 24779475 TI - Modeling nitrate at domestic and public-supply well depths in the Central Valley, California. AB - Aquifer vulnerability models were developed to map groundwater nitrate concentration at domestic and public-supply well depths in the Central Valley, California. We compared three modeling methods for ability to predict nitrate concentration >4 mg/L: logistic regression (LR), random forest classification (RFC), and random forest regression (RFR). All three models indicated processes of nitrogen fertilizer input at the land surface, transmission through coarse textured, well-drained soils, and transport in the aquifer to the well screen. The total percent correct predictions were similar among the three models (69 82%), but RFR had greater sensitivity (84% for shallow wells and 51% for deep wells). The results suggest that RFR can better identify areas with high nitrate concentration but that LR and RFC may better describe bulk conditions in the aquifer. A unique aspect of the modeling approach was inclusion of outputs from previous, physically based hydrologic and textural models as predictor variables, which were important to the models. Vertical water fluxes in the aquifer and percent coarse material above the well screen were ranked moderately high-to-high in the RFR models, and the average vertical water flux during the irrigation season was highly significant (p < 0.0001) in logistic regression. PMID- 24779477 TI - Claims-based algorithms for identifying Medicare beneficiaries at high estimated risk for coronary heart disease events: a cross-sectional study. AB - BACKGROUND: Databases of medical claims can be valuable resources for cardiovascular research, such as comparative effectiveness and pharmacovigilance studies of cardiovascular medications. However, claims data do not include all of the factors used for risk stratification in clinical care. We sought to develop claims-based algorithms to identify individuals at high estimated risk for coronary heart disease (CHD) events, and to identify uncontrolled low-density lipoprotein (LDL) cholesterol among statin users at high risk for CHD events. METHODS: We conducted a cross-sectional analysis of 6,615 participants >=66 years old using data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study baseline visit in 2003-2007 linked to Medicare claims data. Using REGARDS data we defined high risk for CHD events as having a history of CHD, at least 1 risk equivalent, or Framingham CHD risk score >20%. Among statin users at high risk for CHD events we defined uncontrolled LDL cholesterol as LDL cholesterol >=100 mg/dL. Using Medicare claims-based variables for diagnoses, procedures, and healthcare utilization, we developed algorithms for high CHD event risk and uncontrolled LDL cholesterol. RESULTS: REGARDS data indicated that 49% of participants were at high risk for CHD events. A claims-based algorithm identified high risk for CHD events with a positive predictive value of 87% (95% CI: 85%, 88%), sensitivity of 69% (95% CI: 67%, 70%), and specificity of 90% (95% CI: 89%, 91%). Among statin users at high risk for CHD events, 30% had LDL cholesterol >=100 mg/dL. A claims-based algorithm identified LDL cholesterol >=100 mg/dL with a positive predictive value of 43% (95% CI: 38%, 49%), sensitivity of 19% (95% CI: 15%, 22%), and specificity of 89% (95% CI: 86%, 90%). CONCLUSIONS: Although the sensitivity was low, the high positive predictive value of our algorithm for high risk for CHD events supports the use of claims to identify Medicare beneficiaries at high risk for CHD events. PMID- 24779478 TI - Proteomic analysis of insect molting fluid with a focus on enzymes involved in chitin degradation. AB - Cuticular chitin degradation is extremely important for insect growth and development, which has not been fully understood thus far. One obstacle to understanding this mechanism is the lack of a systematic analysis of the chitinolytic enzymes involved in cuticular chitin degradation. In this study, we used the silkmoth Bombyx mori as a model organism and compared proteomic analyses for larval-pupal (L-P) and pupal-adult (P-A) molting fluids using tandem mass tag quantitative mass spectrometry. There were 195 proteins identified from both L-P and P-A molting fluids. A total of 170 out of 195 proteins were deduced to be secretory and were enriched for GO terms associated with chitin metabolism and proteolysis by using AgriGO. Although the chitinolytic enzymes are encoded by many insect genes, the proteomics analysis unexpectedly showed that only four chitinolytic enzymes with the combination "211" were abundant in both molting fluids, namely, two insect GH18 Chitinase family members (ChtI and ChtII), one bacterial-type GH18 Chitinase (Chi-h), and one insect GH20 hexosaminidase (Hex1). A tissue-specific and stage-specific gene expression pattern verified that the "211" enzymes are involved in cuticular chitin degradation. This work first demonstrates that specific enzymes ChtI, ChtII, Chi-h, and Hex1 can be assigned to cuticular chitin degradation. PMID- 24779476 TI - Predictors of positive response to cardiac resynchronization therapy. AB - BACKGROUND: Approximately 30% of patients treated with cardiac resynchronization therapy (CRT) do not achieve favourable response. The purpose of the present study was to identify echocardiographic and clinical predictors of a positive response to CRT. METHODS: The study included 82 consecutive heart failure (HF) patients in New York Heart Association (NYHA) functional class III or IV with left bundle branch block (LBBB), QRS duration >= 120 ms and left ventricular ejection fraction (LVEF) <= 35%. Statistical analysis was performed using IBM SPSS statistical software (SPSS v.21.0 for Mac OS X). A p value < 0.05 was considered statistically significant. RESULTS: Echocardiographic response was established in 81.6% and clinical response was achieved in 82.9% of patients. Significant univariate predictors of favourable echocardiographic response after 12 months were smaller left ventricular end-diastolic diameter (LVEDD) (odds ratio [OR] 0.89; 95% confidence interval [CI] 0.82 - 0.97, p = 0.01), and smaller left ventricular end-systolic diameter (LVESD) (OR 0.91; 95% CI 0.85 - 0.98, p = 0.01). Lower uric acid concentration was associated with better echocardiographic response (OR 0.99; 95% CI 0.99 - 1.0, p = 0.01). Non-ischemic HF etiology (OR 4.89; 95% CI 1.39 - 17.15, p = 0.01) independently predicted positive clinical response. Multiple stepwise regression analysis demonstrated that LVEDD lower than 75 mm (OR 5.60; 95% confidence interval [CI] 1.36 - 18.61, p = 0.01) was the strongest independent predictor of favourable echocardiographic response. CONCLUSIONS: Smaller left ventricular end-diastolic and end-systolic diameters and lower serum uric acid concentration were associated with better response to CRT. Left ventricular end-diastolic diameter and non-ischemic heart failure etiology were the strongest independent predictors of positive response to CRT. PMID- 24779479 TI - Gold catalysis coupled with visible light stimulation: syntheses of functionalized indoles. AB - A judicious combination of Au-catalysis and synergistic visible-light stimulation formulates an exceptionally simple and mild reaction system capable of directly coupling anilines and alkynes to form multifunctionalized indoles. PMID- 24779480 TI - "Helping" versus "being a helper": invoking the self to increase helping in young children. AB - Can a subtle linguistic cue that invokes the self motivate children to help? In two experiments, 3- to 6-year-old children (N = 149) were exposed to the idea of "being a helper" (noun condition) or "helping" (verb condition). Noun wording fosters the perception that a behavior reflects an identity-the kind of person one is. Both when children interacted with an adult who referenced "being a helper" or "helping" () and with a new adult (), children in the noun condition helped significantly more across four tasks than children in the verb condition or a baseline control condition. The results demonstrate that children are motivated to pursue a positive identity. Moreover, this motivation can be leveraged to encourage prosocial behavior. PMID- 24779481 TI - Financial consequences of the implementation of a rapid response system on a surgical ward. AB - RATIONALE, AIMS AND OBJECTIVES: Rapid response systems (RRSs) are recommended by the Institute for Healthcare Improvement and implemented worldwide. Our study on the effects of an RRS showed a non-significant decrease in cardiac arrest and/or unexpected death from 0.5% to 0.25%. Unplanned intensive care unit (ICU) admissions increased significantly from 2.5% to 4.2% without a decrease in APACHE II scores. In this study, we estimated the mean costs of an RRS per patient day and tested the hypothesis that admitting less severely ill patients to the ICU reduces costs. METHODS: A cost analysis of an RRS on a surgical ward, including costs for implementation, a 1-day training programme for nurses, nursing time for extra vital signs observation, medical emergency team (MET) consults and differences in unplanned ICU days before and after RRS implementation. To test the hypothesis, we performed a scenario analysis with a mean APACHE II score of 14 points instead of the empirical 17.6 points for the unplanned ICU admissions, including 33% extra MET consults and 22% extra unplanned ICU admissions. RESULTS: Mean RRS costs were ?26.87 per patient-day: implementation ?0.33 (1%), training ?0.90 (3%), nursing time spent on extended observation of vital signs ?2.20 (8%), MET consults ?0.57 (2%) and increased number of unplanned ICU days after RRS implementation ?22.87 (85%). In the scenario analysis mean costs per patient-day were ?10.18. CONCLUSIONS: The costs for extra unplanned ICU days were relatively high but the remaining RRS costs were relatively low. The 'APACHE II 14' scenario confirmed the hypothesis that costs for the number of unplanned ICU days can be reduced if less severely ill patients are referred to the ICU. Based upon these findings, our hospital stimulates earlier referral to the ICU, although further implementation strategies are needed to achieve these aims. PMID- 24779482 TI - Self-management behaviors in older adults with asthma: associations with health literacy. AB - OBJECTIVES: To examine self-management behaviors, including medication adherence and inhaler technique, in older adults with asthma and their association with health literacy. DESIGN: Observational cohort study. SETTING: Primary care and pulmonary specialty practices in two tertiary academic medical centers and three federally qualified health centers in New York, New York, and Chicago, Illinois. PARTICIPANTS: Adults with moderate or severe persistent asthma aged 60 and older (N = 433). MEASUREMENTS: Outcomes were adherence to asthma controller medications, metered dose inhaler (MDI) and dry powder inhaler (DPI) techniques, having a usual asthma physician, and avoidance of four common triggers. Health literacy was assessed using the Short Test of Functional Health Literacy in Adults. RESULTS: The mean age was 67, and 36% of participants had marginal or low health literacy. Adherence was low (38%) overall and worse in individuals with low health literacy (22%) than in those with adequate literacy (47%, P < .001) and after adjusting for demographic factors and health status (odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.31-0.73). Similarly, inhaler technique was poor; only 38% and 54% had good MDI and DPI technique, respectively. Technique was worse in those with low health literacy (MDI technique: OR = 0.57, 95% CI = 0.38-0.85; DPI technique: OR = 0.42, 95% CI = 0.25-0.71). Asthma self-monitoring and avoidance of triggers occurred infrequently but were less consistently associated with low health literacy. CONCLUSION: Adherence to medications and inhaler technique are poor in older adults with asthma and worse in those with low health literacy. Clinicians should routinely assess controller medication adherence and inhaler technique and use low-literacy communication strategies to support self-management in older adults with asthma. PMID- 24779483 TI - Contagiousness under antiretroviral therapy and stigmatization toward people with HIV. AB - Perceived contagiousness is a major dimension underlying HIV-related stigmatization. Antiretroviral therapy (ART) can diminish contagiousness by reducing viral load levels in HIV-infected individuals. To test the assumption that reductions in contagiousness can lead to a decrease in stigmatizing reactions, we conducted an experimental online study. A sample of 752 participants (50.9% female) read a short vignette depicting an HIV-positive individual with either a high or a low viral load and were either given or not given information about the association between viral load and contagiousness. Subsequently, participants were asked to rate their willingness to stigmatize this individual by responding to two measures of social and physical distance. Differences between the low and the high viral load information groups and the combined no-information groups (forming a quasi-control group) were analyzed using analysis of covariance (ANCOVA), controlling for gender and baseline perceptions of contagiousness. The covariates, perceived contagiousness at baseline and gender, were associated with social and physical distancing, but the viral load/information factor was only significant in physical distancing. Planned contrast analyses confirmed that physical distancing in the informed group was lower in the low viral load condition compared to the high viral load condition and to the control group. We thus found evidence for the significant role of perceived contagiousness in the HIV-related stigma and were able to experimentally demonstrate the potential of ART to reduce HIV-related stigmatization by lowering viral load and contagiousness, when these changes are accompanied by a decreased perception of contagiousness. PMID- 24779484 TI - SHIV susceptibility changes during the menstrual cycle of pigtail macaques. AB - BACKGROUND: Hormonal changes during menstrual cycling may affect susceptibility to HIV. METHODS: We determined the simian human immunodeficiency virus (SHIV) acquisition time point in 43 cycling pigtail macaques infected by repeated vaginal virus exposures initiated randomly in the cycle. RESULTS: SHIV infection was first detected in the follicular phase in 38 macaques (88%), and in the luteal phase in five macaques (12%), indicating a statistically significant timing difference. Assuming a 7-day eclipse phase, most infections occurred during or following a high-progesterone period associated with menstruation, vaginal epithelium thinning, and suppressed mucosal immunity. CONCLUSIONS: This raises questions whether other high-progesterone conditions (pregnancy, hormonal contraception) similarly affect HIV risk. PMID- 24779485 TI - Flourishing: exploring predictors of mental health within the college environment. AB - OBJECTIVE: To explore the predictive factors of student mental health within the college environment. PARTICIPANTS: Students enrolled at 7 unique universities during years 2008 (n=1,161) and 2009 (n=1,459). METHODS: Participants completed survey measures of mental health, consequences of alcohol use, and engagement in the college environment. RESULTS: In addition to replicating previous findings related to Keyes' Mental Health Continuum, multiple regression analysis revealed several predictors of college student mental health, including supportive college environments, students' sense of belonging, professional confidence, and civic engagement. However, multiple measures of engaged learning were not found to predict mental health. CONCLUSIONS: Results suggest that supportive college environments foster student flourishing. Implications for promoting mental health across campus are discussed. Future research should build on exploratory findings and test confirmatory models to better understand relationships between the college environment and student flourishing. PMID- 24779486 TI - Sensitivity to the two-peptide bacteriocin lactococcin G is dependent on UppP, an enzyme involved in cell-wall synthesis. AB - Most bacterially produced antimicrobial peptides (bacteriocins) are thought to kill target cells by a receptor-mediated mechanism. However, for most bacteriocins the receptor is unknown. For instance, no target receptor has been identified for the two-peptide bacteriocins (class IIb), whose activity requires the combined action of two individual peptides. To identify the receptor for the class IIb bacteriocin lactococcin G, which targets strains of Lactococcus lactis, we generated 12 lactococcin G-resistant mutants and performed whole-genome sequencing to identify mutations causing the resistant phenotype. Remarkably, all had a mutation in or near the gene uppP (bacA), encoding an undecaprenyl pyrophosphate phosphatase; a membrane protein involved in peptidoglycan synthesis. Nine mutants had stop codons or frameshifts in the uppP gene, two had point mutations in putative regulatory regions and one caused an amino acid substitution in UppP. To verify the receptor function of UppP, it was shown that growth of non-sensitive Streptococcus pneumoniae could be inhibited by lactococcin G when L. lactis uppP was expressed in this bacterium. Furthermore, we show that the related class IIb bacteriocin enterocin 1071 also uses UppP as receptor. The approach used here should be broadly applicable to identify receptors for other bacteriocins as well. PMID- 24779487 TI - Enhanced microwave absorption property of reduced graphene oxide (RGO)-MnFe2O4 nanocomposites and polyvinylidene fluoride. AB - MnFe2O4 nanoparticles have been synthesized on a large scale by a simple hydrothermal process in a wild condition, and the RGO/MnFe2O4 nanocomposites were also prepared under ultrasonic treatment based on the synthesized nanoparticles. The absorption properties of MnFe2O4/wax, RGO/MnFe2O4/wax and the RGO/MnFe2O4/PVDF (polyvinylidene fluoride) composites were studied; the results indicated that the RGO/MnFe2O4/PVDF composites show the most excellent wave absorption properties. The minimum reflection loss of RGO/MnFe2O4/PVDF composites with filler content of 5 wt % can reach -29.0 dB at 9.2 GHz, and the bandwidth of frequency less than -10 dB is from 8.00 to 12.88 GHz. The wave absorbing mechanism can be attributed to the dielectric loss, magnetic loss and the synergetic effect between RGO+MnFe2O4, RGO+PVDF and MnFe2O4+PVDF. PMID- 24779488 TI - An application of the health action process approach to physiotherapy rehabilitation adherence. AB - This study tested the utility of an extended version of the health action process approach (HAPA) to explain the attitudinal and behavioural processes contributing to rehabilitation adherence and ultimately rehabilitation outcomes in physiotherapy patients. The HAPA focuses on self-efficacy, action and coping planning and their relationships to behavioural intentions and actual behaviour. A one group prospective design was employed in which 20 participants with soft tissue injuries of the shoulder were followed for the first four weeks of their clinic- and home-based physiotherapy. Participants enrolled in the study after their first physiotherapy clinic appointment, at which time they completed questionnaires measuring the motivational HAPA constructs and shoulder function. Action and coping plans were then made with assistance of the researcher. Adherence behaviours were measured throughout the study, and at the end the volitional stage HAPA constructs, action self-efficacy and shoulder function were assessed. Moderate to strong correlations occurred between the self-efficacies and behavioural intentions, behavioural intentions and adherence behaviours, and adherence behaviours and post-study shoulder function. These findings support the extension of the HAPA model to include the functional outcomes for soft tissue injuries of the shoulder. Its true value will nevertheless only be realized in a longer duration study with a larger sample size. PMID- 24779489 TI - Therapeutic neuroscience education via e-mail: a case report. AB - Therapeutic neuroscience education (TNE) aims to alter a patient's thoughts and beliefs about pain and has shown efficacy in treating chronic pain. To date, TNE sessions mainly consist of one-on-one verbal communication. This approach limits availability of TNE to pain patients in remote areas. A 32-year-old patient with chronic low back pain (CLBP) who underwent surgery for thoracic outlet syndrome (TOS) attended a single clinic one-on-one TNE session followed by TNE via electronic mail (e-mail), pacing and graded exposure over a 4-month period. A physical examination, Numeric Rating Scale (NRS), Oswestry Disability Index (ODI), the Disabilities of Arm, Shoulder and Hand (DASH), and Fear-Avoidance Beliefs Questionnaire (FABQ) were assessed during her initial physical therapy visit as well as 1 and 4 months later. Pre-TNE, the patient reported: NPRS (arm) = 7/10; NPRS (leg) = 4/10; ODI = 10.0%; DASH = 36.7%; FABQ-W = 24; and FABQ-PA = 17. After 5 e-mail sessions all outcome measures improved, most noticeably NRS (arm) = 2/10; NRS (leg) = 0/10; DASH = 16.7%; FABQ-W = 8; and FABQ-PA = 7. TNE can potentially be delivered to suffering pain patients in remote areas or to individuals who have time and financial constraints, and likely at a significant reduced cost via e-mail. PMID- 24779490 TI - Special issue on culture and substance use. PMID- 24779491 TI - The impact of acculturation and acculturative stress on alcohol use across Asian immigrant subgroups. AB - Acculturation and acculturative stress are examined as predictors of alcohol use among Asian immigrants, using the 2004 National Latino and Asian Americans Survey (NLAAS). Separate regression analyses were conducted for Chinese (n = 600), Filipino (n = 508), and Vietnamese (n = 520) immigrants. Alcohol use varied for the three groups. English proficiency was associated with drinking for all groups. Family conflict was associated with drinking for Chinese immigrants. General acculturative stress and discrimination were associated with drinking for Vietnamese immigrants. Results underscore acculturation and acculturative stress as being contributors to alcohol consumption, and the importance of considering the heterogeneity of Asian immigrants in research on their alcohol use. The study's limitations are noted. PMID- 24779492 TI - The role of immigration status in heavy drinking among Asian Americans. AB - We examined the role of Asian Americans' immigration status in their heavy drinking, using a national sample of 3,574 Asian American adults during 2008 to 2011 when surveyed by the National Health Interview Survey. Our results, with relevant social structural factors controlled, show that U.S.-born Asian Americans exhibited the highest heavy-drinking levels, followed by long-time resident Asian immigrants, then recent-resident Asian immigrants (our three main subsamples). The higher heavy-drinking levels characterizing U.S.-born Asians who were male and younger, as compared to immigrant Asians who were male and younger, helped explain differential heavy-drinking levels across subsamples. The study's limitations are noted. PMID- 24779493 TI - From "Kickeando las malias" (kicking the withdrawals) to "Staying clean": The impact of cultural values on cessation of injection drug use in aging Mexican American men. AB - Drug use among older adults is a growing concern, particularly for the burgeoning Hispanic population. Older adults seeking drug treatment will double over the next decade to almost 6 million. Cultural factors influence drug use, and more specifically, Hispanic cultural values influence heroin use. This study explored Mexican-American injection drug users' adherence to traditional Hispanic cultural values and their impact on cessation. Ethnographic interviews endorsed contextualized influences of values on heroin use. Cultural values functioned dichotomously, influencing both initiation and cessation. Understanding the impact of cultural values on substance abuse is critical given the changing demographics in American society. PMID- 24779495 TI - New drug use among agricultural workers. AB - Research on drug use onset rarely examines the spatial dimensions of onset, owing to a literature that is overwhelming from urban areas of an industrialized country (United States). Narrative interviews from drug-using agricultural workers in contrast reveal another side of drug use onset, where influence of familiarity with place becomes evident, despite the expectation that the novelty and/or adventure within a lifestyle of seasonal employment and migratory labor that requires overnight accommodations on-the-season is likely to push/pull one into the first use of a new drug or the first drug that an individual has ever used. PMID- 24779497 TI - Measuring ethnic identity in Latino adolescents with substance use disorders. AB - The Multigroup Ethnic Identity Measure (MEIM) is a frequently used instrument to assess the level of ethnic identity in adolescents. The factor structure of the MEIM has extensively been studied in diverse nonclinical samples, while research with clinical samples of adolescents is lacking. The purpose of the current study is to identify the factor structure of the MEIM in a clinical sample of Latino adolescents (N = 106) with substance use disorders. A confirmatory factor analysis was used to test three competing factor structure models of the MEIM. Results indicated that a six-item two-factor model best fit the data for Latino adolescents in this study. Implications of these results and suggestions for further research are discussed. PMID- 24779496 TI - "A cool little buzz": alcohol intoxication in the dance club scene. AB - In recent years, there has been increasing concern about youthful "binge" drinking and intoxication. Yet the meaning of intoxication remains under theorized. This paper examines intoxication in a young adult nightlife scene, using data from a 2005-2008 National Institute on Drug Abuse-funded project on Asian American youth and nightlife. Analyzing in-depth qualitative interview data with 250 Asian American young adults in the San Francisco area, we examine their narratives about alcohol intoxication with respect to sociability, stress, and fun, and their navigation of the fine line between being "buzzed" and being "wasted." Finally, limitations of the study and directions for future research are noted. PMID- 24779498 TI - "PMA sounds fun": negotiating drug discourses online. AB - In 2007, a young woman, Annabel Catt, died after consuming a capsule sold as "ecstasy" that contained para-methoxyamphetamine. In this paper, we describe how this death was depicted in online drug-user communities and illustrate how the meanings of drug use are negotiated in online settings. News articles, public online discussions, and online fieldwork formed the data. This paper demonstrates how dominant drug discourses may be resisted by drug users, drawing on theories of health resistance and Kane Race's concept of counterpublic health. Online environments may offer ways of engaging people who use drugs that acknowledge both pleasure and safety. The study's limitations are noted. PMID- 24779499 TI - Understanding alcohol use among U.S. Cambodians: how useful is the concept of cultural norms? AB - Observed differences in substance use are frequently attributed to cultural norms, which in turn are often interpreted as fixed properties of ethnically defined groups. During a community-based participatory research study (2009 2011), U.S. Cambodian women identified community-specific drinking behaviors and beliefs. To test how widely other U.S. Cambodians shared their views, we formulated them into a series of normative statements and surveyed local community members (N = 172). We identified few consensualized norms, which suggests that (A) norms may not be reducible to normative statements; and/or (B) norms may not be shared by all group members; and (C) if neither A nor B holds, then the attribution of observed drinking patterns to cultural norms lacks internal validity. Study's limitations were noted. PMID- 24779500 TI - Associations between ethnic labels and substance use among Hispanic/Latino adolescents in Los Angeles. AB - Self-identification with ethnic-specific labels may indicate successful ethnic identity formation, which could protect against substance use. Alternatively, it might indicate affiliation with oppositional subcultures, a potential risk factor. This study examined longitudinal associations between ethnic labels and substance use among 1,575 Hispanic adolescents in Los Angeles. Adolescents who identified as Cholo or La Raza in 9th grade were at increased risk of past-month substance use in 11th grade. Associations were similar across gender and were not confounded by socioeconomic status, ethnic identity development, acculturation, or language use. Targeted prevention interventions for adolescents who identify with these subcultures may be warranted. PMID- 24779501 TI - Self-management of buprenorphine/naloxone among online discussion board users. AB - BACKGROUND: Buprenorphine/naloxone is an effective medication used to treat opioid dependence. Patients in treatment and those using it illegally without prescriptions have discussed using buprenorphine/naloxone anonymously on Internet discussion boards. Their beliefs about self-treatment and efforts to self-treat are not well known. OBJECTIVES: To identify facilitators of self-treatment by online buprenorphine/naloxone users. METHODS: A qualitative, retrospective study of discussion board postings from September 2010 to November 2012 analyzed 121 threads from 13 discussion boards using grounded theory. RESULTS: Facilitators of self-management themes that emerged included: (1) a ready supply of buprenorphine/naloxone from a variety of sources; (2) distrust of buprenorphine prescribers and pharmaceutical companies; (3) the declaration that buprenorphine/naloxone is a "bad-tasting" medicine; (4) the desire to adopt a different delivery method other than sublingually; and (5) a desire to become completely "substance-free." The sublingual film formulation appears to be an important facilitator in self-treatment because it can more easily be apportioned to extend the medication because of limited supply, cost, or to taper. CONCLUSIONS/IMPORTANCE: The findings indicate a range of self-management activities ranging from altering the amount taken to modifying the physical medication composition or changing the administration route; some of these behaviors constitute problematic extra-medical use. Contributors to discussion boards seem to trust each other more than they trust pharmacists and prescribing physicians. The shared knowledge and behaviors of this understudied online community are important to healthcare providers because of the previously unknown precautions and risks taken to self-treat. PMID- 24779502 TI - Problematic substance use among Hispanic adolescents and young adults: implications for prevention efforts. AB - Using data collected between 2005 and 2012 from a longitudinal study of acculturation patterns and substance use among Hispanic youth in Southern California (N = 2722), we fit multivariate logistic regression models to estimate the association of type and frequency of drug use, friend and parent drug use, cultural orientation (measured by the ARSMA-II), and psychological distress (CES D score) in 10th grade with problematic substance use (measured with the RAPI) in (i) 11th grade and (ii) young adulthood. We conclude that future intervention efforts with Hispanic adolescents and young adults should target polysubstance and problem users and emphasize inter-individual, structural, and cultural processes as they relate to problematic substance use. PMID- 24779503 TI - Determinants of problem drinking and depression among Latino Day laborers. AB - Little is known about alcohol misuse and depression among Latino day laborers despite the fact that they encounter multiple stressors (e.g., job instability, unsafe work environments). A structural equation model tested the relationships among laborer stress, social support, health status, current alcohol misuse, and depression. A sample of 89 male, urban Latino day laborers completed measures assessing these constructs in 2011. Stress was negatively related to physical health status, which was associated with depression. Findings suggest that stressors specific to being a day laborer resulting from their work and living conditions generate and maintain health disparities in this vulnerable population. PMID- 24779504 TI - The interaction of drug use, sex work, and HIV among transgender women. AB - Transgender women have a higher prevalence of drug use, HIV, drug use, and sex work than the general population. This article explores the interaction of these variables and discusses how sex work and drug use behaviors contribute to the high rates of HIV. A model predicting HIV rates with sex work and drug use as well as these behaviors in the transgender woman's social network is presented. Challenges to intervening with transgender women, as well as suggestions and criteria for successful interventions, are discussed. PMID- 24779505 TI - Place matters in perceived tobacco exposure among Korean American young adults: mixed methods approach. AB - A sequential mixed methods study was conducted to identify factors influencing perceived norms about smoking and to examine the association of acculturative contexts and normative beliefs among Korean American young adults (KAYA) who face increased risk of smoking. Content analysis of data from 67 participants in 10 focus groups in 2010 led to the development of an online survey in 2012 (N = 475). KAYA overestimated smoking prevalence, reporting Korean-owned businesses (KOB) as primary places of exposure. Our findings revealed that visits to KOB predicted perceived norms about smoking. Modifying perceptions about social norms and involuntary tobacco exposure may be critical in reducing smoking among KAYA. The study's limitations are noted. PMID- 24779506 TI - A primer for using meta-analysis to consolidate research. AB - The article provides an introduction to interpreting meta-analysis in the context of synthesizing results of studies that examine the role of culture on drug use behaviors. Topics reviewed include using effect size to indicate the strength of a relationship in a primary study, combining effects in weighted models to yield a summary effect, and understanding how study-level moderators help to explain the heterogeneity in effect dispersion across investigations. The advantages of meta-analytic procedures for consolidating preexisting knowledge are highlighted. PMID- 24779507 TI - Does diversity matter? The need for longitudinal research on adolescent alcohol and drug use trajectories. AB - The existing research aimed at understanding alcohol and drug (AOD) use patterns from early to late adolescence typically does not examine samples with substantial racial and ethnic diversity. This is a critical research gap because studies have suggested that non-white adolescents often have worse health outcomes compared to white adolescents, even with less AOD use. In this paper, we discuss the need for future research on this topic, given demographic shifts in the racial and ethnic composition of the USA. We also outline how this research can provide information on what periods might be most relevant for each racial/ethnic group, and suggest measures that epidemiological studies on early substance use should assess to capture the underlying cultural, acculturation, psychosocial, and contextual factors that explain racial/ethnic differences in AOD trajectories. PMID- 24779508 TI - Surveying the literature on acculturation and alcohol use among Hispanic college students: we're not all on the same page. AB - During the past several years, a steadily growing body of literature examining acculturation and alcohol use among Hispanic college students has emerged. A review of this literature suggests that there have been (and continues to be) mixed findings regarding the association between acculturation and alcohol use in this population. Thus, the exact nature of this association is not clear. This paper provides an overview of this literature and outlines recommendations for future research that will help to elucidate the complexities inherent in this line of work. PMID- 24779510 TI - Preparation of N,N-dialkylcarbamato lanthanide complexes by extraction of lanthanide ions from aqueous solution into hydrocarbons. AB - Lanthanides are easily extracted as N,N-dibutylcarbamato complexes from aqueous solutions of their chlorides into heptane solutions of dibutylamine saturated with CO2. The products are recovered in high yields and are soluble in hydrocarbons. The derivatives [Ln(O2CNBu2)3]n [Ln = Nd (1), Eu (2), Tb (3)], [NH2Bu2]2[Ln4(CO3)(O2CNBu2)12] [Ln = Tb (4), Sm (5), Eu (6)], and [Sm4(CO3)(O2CNBu2)10], 7, have thus been obtained. The crystal and molecular structure of 4 has been solved; the samarium and europium complexes 5 and 6 were found to be isostructural. Mass spectra of the complexes 1-3, 4, and 7 (in MeCN/toluene) reveal that equilibria are present in solution. Compound 2 has been reacted in toluene with NHBz2 in the presence of CO2 affording [NH2Bz2][Eu(O2CNBz2)4], 8, through a ligand exchange process. By thermal treatment, 8 afforded [Eu(O2CNBz2)3]n, 9. With a similar procedure [Sm(O2CNBz2)3]n, 10, was obtained from 5. According to the photoluminescence study carried out on solid samples of 2, 4, 5, 7, and 8, the metal centered f-f transitions represent the only effective way to induce lanthanide luminescence in these complexes. PMID- 24779511 TI - Highly site-selective direct C-H bond functionalization of phenols with alpha aryl-alpha-diazoacetates and diazooxindoles via gold catalysis. AB - An unprecedented direct C-H bond functionalization of unprotected phenols with alpha-aryl alpha-diazoacetates and diazooxindoles was developed. A tris(2,4-di tert-butylphenyl) phosphite derived gold complex promoted the highly chemoselective and site-selective C-H bond functionalization of phenols and N acylanilines with gold-carbene generated from the decomposition of diazo compounds, furnishing the corresponding products in moderate to excellent yields at rt. The salient features of this reaction include readily available starting materials, unprecedented C-H functionalization rather than X-H insertion, good substrate scope, mild conditions, high efficiency, and ease in further transformation. To the best of our knowledge, this is the first example of C-H functionalization of unprotected phenols with diazo compounds. PMID- 24779512 TI - Computational tests of quantum chemical models for excited and ionized states of molecules with phosphorus and sulfur atoms. AB - Time-dependent density functional theory (TD-DFT) and electron propagator theory (EPT) are used to calculate the electronic transition energies and ionization energies, respectively, of species containing phosphorus or sulfur. The accuracy of TD-DFT and EPT, in conjunction with various basis sets, is assessed with data from gas-phase spectroscopy. TD-DFT is tested using 11 prominent exchange correlation functionals on a set of 37 vertical and 19 adiabatic transitions. For vertical transitions, TD-CAM-B3LYP calculations performed with the MG3S basis set are lowest in overall error, having a mean absolute deviation from experiment of 0.22 eV, or 0.23 eV over valence transitions and 0.21 eV over Rydberg transitions. Using a larger basis set, aug-pc3, improves accuracy over the valence transitions via hybrid functionals, but improved accuracy over the Rydberg transitions is only obtained via the BMK functional. For adiabatic transitions, all hybrid functionals paired with the MG3S basis set perform well, and B98 is best, with a mean absolute deviation from experiment of 0.09 eV. The testing of EPT used the Outer Valence Green's Function (OVGF) approximation and the Partial Third Order (P3) approximation on 37 vertical first ionization energies. It is found that OVGF outperforms P3 when basis sets of at least triple zeta quality in the polarization functions are used. The largest basis set used in this study, aug-pc3, obtained the best mean absolute error from both methods 0.08 eV for OVGF and 0.18 eV for P3. The OVGF/6-31+G(2df,p) level of theory is particularly cost-effective, yielding a mean absolute error of 0.11 eV. PMID- 24779513 TI - Chemerin and CMKLR1 expression in human arteries and periadventitial fat: a possible role for local chemerin in atherosclerosis? AB - BACKGROUND: Depending on their anatomical location, different fat depots have a different capacity to produce bioactive peptides, called adipokines. Adipokines produced by periadventitial fat have been implicated in the pathogenesis of vascular disease, including atherosclerosis. Chemerin is an adipokine with an established role in immunity, adipose tissue function and metabolism, acting in autocrine, paracrine and endocrine manners. We investigated the protein expression of chemerin and its receptor, CMKLR1, in human aortas, coronary vessels and the respective periadventitial adipose tissue and correlated their expression with the presence of atherosclerosis. METHODS: Immunohistochemistry for chemerin and CMKLR1 was performed on human aortic and coronary artery samples including the periadventitial adipose tissue. Aortic and coronary atherosclerotic lesions were assessed using the AHA classification. RESULTS: Chemerin immunopositivity was noticed in both periadventitial fat depots, in vascular smooth muscle cells and foam cells in atherosclerotic lesions. Periadventitial fat and foam cell chemerin immunopositivity was statistically significantly correlated with the severity of atherosclerosis in both locations. CMKLR1 was expressed in vascular smooth muscle cells and foam cells in aortic and coronary vessels with atherosclerotic lesions. CMKLR1 immunostaining in foam cells was statistically significantly correlated with aortic atherosclerosis. CONCLUSIONS: Our results lend some support to a presumable role of locally produced chemerin in the progression of atherosclerotic lesions, possibly acting through its CMKLR1 receptor. Further research will elucidate the role of chemerin signaling in atherosclerosis. PMID- 24779514 TI - Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. AB - Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose limiting adverse effects that have been attributed, at least in part, to the off target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications. PMID- 24779515 TI - Effective autodissemination of pyriproxyfen to breeding sites by the exophilic malaria vector Anopheles arabiensis in semi-field settings in Tanzania. AB - BACKGROUND: Malaria vector control strategies that target adult female mosquitoes are challenged by the emergence of insecticide resistance and behavioural resilience. Conventional larviciding is restricted by high operational costs and inadequate knowledge of mosquito-breeding habitats in rural settings that might be overcome by the juvenile hormone analogue, Pyriproxyfen (PPF). This study assessed the potential for Anopheles arabiensis to pick up and transfer lethal doses of PPF from contamination sites to their breeding habitats (i.e. autodissemination of PPF). METHODS: A semi-field system (SFS) with four identical separate chambers was used to evaluate PPF-treated clay pots for delivering PPF to resting adult female mosquitoes for subsequent autodissemination to artificial breeding habitats within the chambers. In each chamber, a tethered cow provided blood meals to laboratory-reared, unfed female An. arabiensis released in the SFS. In PPF-treated chambers, clay pot linings were dusted with 0.2 - 0.3 g AI PPF per pot. Pupae were removed from the artificial habitats daily, and emergence rates calculated. Impact of PPF on emergence was determined by comparing treatment with an appropriate control group. RESULTS: Mean (95% CI) adult emergence rates were (0.21 +/- 0.299) and (0.95 +/- 0.39) from PPF-treated and controls respectively (p < 0.0001). Laboratory bioassay of water samples from artificial habitats in these experiments resulted in significantly lower emergence rates in treated chambers (0.16 +/- 0.23) compared to controls 0.97 +/- 0.05) (p < 0.0001). In experiments where no mosquitoes introduced, there were no significant differences between control and treatment, indicating that transfer of PPF to breeding sites only occurred when mosquitoes were present; i.e. that autodissemination had occurred. Treatment of a single clay pot reduced adult emergence in six habitats to (0.34 +/- 0.13) compared to (0.98 +/- 0.02) in the controls (p < 0.0001), showing a high level of habitats coverage amplification of the autodissemination event. CONCLUSION: The study provides proof of principle for the autodissemination of PPF to breeding habitats by malaria vectors. These findings highlight the potential for this technique for outdoor control of malaria vectors and call for the testing of this technique in field trials. PMID- 24779516 TI - Conservation success as a function of good alignment of social and ecological structures and processes. AB - How to create and adjust governing institutions so that they align (fit) with complex ecosystem processes and structures across scales is an issue of increasing concern in conservation. It is argued that lack of such social ecological fit makes governance and conservation difficult, yet progress in explicitly defining and rigorously testing what constitutes a good fit has been limited. We used a novel modeling approach and data from case studies of fishery and forest conservation to empirically test presumed relationships between conservation outcomes and certain patterns of alignment of social-ecological interdependences. Our approach made it possible to analyze conservation outcome on a systems level while also providing information on how individual actors are positioned in the complex web of social-ecological interdependencies. We found that when actors who shared resources were also socially linked, conservation at the level of the whole social-ecological system was positively affected. When the scales at which individual actors used resources and the scale at which ecological resources were interconnected to other ecological resources were aligned through tightened feedback loops, conservation outcome was better than when they were not aligned. The analysis of individual actors' positions in the web of social-ecological interdependencies was helpful in understanding why a system has a certain level of social-ecological fit. Results of analysis of positions showed that different actors contributed in very different ways to achieve a certain fit and revealed some underlying difference between the actors, for example in terms of actors' varying rights to access and use different ecological resources. PMID- 24779517 TI - Shagenes A and B, new tricyclic sesquiterpenes produced by an undescribed Antarctic octocoral. AB - The isolation and characterization of two new tricyclic sesquiterpenoids, shagenes A (1) and B (2) are presented. These compounds were isolated from an undescribed soft coral collected from the Scotia Arc in the Southern Ocean. One- and two-dimensional NMR spectroscopy and mass spectrometry provided the data necessary to characterize the compounds and their relative stereochemical configurations. Exploration of the bioactivity of shagenes A and B found 1 active against the visceral leishmaniasis causing parasite, Leishmania donovani, with no cytotoxicity against the mammalian host. PMID- 24779518 TI - Significance of an increase in the Child-Pugh score after radiotherapy in patients with unresectable hepatocellular carcinoma. AB - BACKGROUND: We attempted to analyze the effects of an increase in the Child-Pugh (CP) score on the overall survival of patients with unresectable hepatocellular carcinoma (HCC) after radiotherapy (RT). METHODS: From March 2006 to February 2012, 103 patients received RT using the TomoTherapy Hi-Art at Incheon St. Mary's Hospital and Seoul St. Mary's Hospital. The dose per fraction was 1.8-5 Gy, and the total dose was 40-60 Gy (median, 50 Gy). We considered an increase of at least 2 points in the CP score within 3 months after RT to be clinically important radiation-induced hepatic toxicity and analyzed the effects of an increased CP score on overall survival. RESULTS: The median follow-up duration was 11.6 months (range, 3.5-85.3 months). The median survival time was 11.6 months. In multivariate analysis, planning target volume and an increase in the CP score after RT were found to be a statistically significant factors (p = 0.010 and 0.015, respectively). In a comparison of cases with and without an increase in the CP score, there was an 11.0-month difference in the median survival time (6.9 vs. 17.9 months), and the relative risk of mortality was 1.8. CONCLUSION: An increase of at least 2 points in the CP score within 3 months of RT completion is an important on-treatment factor that affects overall survival. To minimize such increases, careful patient selection and a more sophisticated radiation treatment plan are imperative. PMID- 24779519 TI - Genetic perspectives on northern population cycles: bridging the gap between theory and empirical studies. AB - Many key species in northern ecosystems are characterised by high-amplitude cyclic population demography. In 1924, Charles Elton described the ecology and evolution of cyclic populations in a classic paper and, since then, a major focus has been the underlying causes of population cycles. Elton hypothesised that fluctuations reduced population genetic variation and influenced the direction of selection pressures. In concordance with Elton, present theories concern the direct consequences of population cycles for genetic structure due to the processes of genetic drift and selection, but also include feedback models of genetic composition on population dynamics. Most of these theories gained mathematical support during the 1970s and onwards, but due to methodological drawbacks, difficulties in long-term sampling and a complex interplay between microevolutionary processes, clear empirical data allowing the testing of these predictions are still scarce. Current genetic tools allow for estimates of genetic variation and identification of adaptive genomic regions, making this an ideal time to revisit this subject. Herein, we attempt to contribute towards a consensus regarding the enigma described by Elton almost 90 years ago. We present nine predictions covering the direct and genetic feedback consequences of population cycles on genetic variation and population structure, and review the empirical evidence. Generally, empirical support for the predictions was low and scattered, with obvious gaps in the understanding of basic population processes. We conclude that genetic variation in northern cyclic populations generally is high and that the geographic distribution and amount of diversity are usually suggested to be determined by various forms of context- and density-dependent dispersal exceeding the impact of genetic drift. Furthermore, we found few clear signatures of selection determining genetic composition in cyclic populations. Dispersal is assumed to have a strong impact on genetic structuring and we suggest that the signatures of other microevolutionary processes such as genetic drift and selection are weaker and have been over-shadowed by density-dependent dispersal. We emphasise that basic biological and demographical questions still need to be answered and stress the importance of extensive sampling, appropriate choice of tools and the value of standardised protocols. PMID- 24779520 TI - Phosphatase activity of the histidine kinases ensures pathway specificity of the ChrSA and HrrSA two-component systems in Corynebacterium glutamicum. AB - The majority of bacterial genomes encode a high number of two-component systems controlling gene expression in response to a variety of different stimuli. The Gram-positive soil bacterium Corynebacterium glutamicum contains two homologous two-component systems (TCS) involved in the haem-dependent regulation of gene expression. Whereas the HrrSA system is crucial for utilization of haem as an alternative iron source, ChrSA is required to cope with high toxic haem levels. In this study, we analysed the interaction of HrrSA and ChrSA in C. glutamicum. Growth of TCS mutant strains, in vitro phosphorylation assays and promoter assays of P(hrtBA) and P(hmuO) fused to eyfp revealed cross-talk between both systems. Our studies further indicated that both kinases exhibit a dual function as kinase and phosphatase. Mutation of the conserved glutamine residue in the putative phosphatase motif DxxxQ of HrrS and ChrS resulted in a significantly increased activity of their respective target promoters (P(hmuO) and P(hrtBA) respectively). Remarkably, phosphatase activity of both kinases was shown to be specific only for their cognate response regulators. Altogether our data suggest the phosphatase activity of HrrS and ChrS as key mechanism to ensure pathway specificity and insulation of these two homologous systems. PMID- 24779521 TI - Development of an electronic medical record-based algorithm to identify patients with unknown HIV status. AB - Individuals with unknown HIV status are at risk for undiagnosed HIV, but practical and reliable methods for identifying these individuals have not been described. We developed an algorithm to identify patients with unknown HIV status using data from the electronic medical record (EMR) of a large health care system. We developed EMR-based criteria to classify patients as having known status (HIV-positive or HIV-negative) or unknown status and applied these criteria to all patients seen in the affiliated health care system from 2008 to 2012. Performance characteristics of the algorithm for identifying patients with unknown HIV status were calculated by comparing a random sample of the algorithm's results to a reference standard medical record review. The algorithm classifies all patients as having either known or unknown HIV status. Its sensitivity and specificity for identifying patients with unknown status are 99.4% (95% CI: 96.5-100%) and 95.2% (95% CI: 83.8-99.4%), respectively, with positive and negative predictive values of 98.7% (95% CI: 95.5-99.8%) and 97.6% (95% CI: 87.1-99.1%), respectively. Using commonly available data from an EMR, our algorithm has high sensitivity and specificity for identifying patients with unknown HIV status. This algorithm may inform expanded HIV testing strategies aiming to test the untested. PMID- 24779522 TI - Frontal EEG asymmetry as predictor of physiological responses to aversive memories. AB - Evidence suggests that asymmetry in frontal electrical activity predicts responses to aversive experiences, such that higher left-sided activity might dampen responses to trauma reminders. We measured frontal asymmetry at rest and during viewing of a trauma film, and assessed startle responses to film-reminder images. To explore potential moderators, we compared two films (Study 1; N = 64) and modulated reappraisal (Study 2; N = 72). As expected, left frontal activation during film viewing predicted dampened responses in individuals who viewed a staged road accident. However, this effect tended to be reversed when a genocide documentary was used. In Study 2, all participants viewed the genocide film. Left frontal activity at rest again predicted higher startle responses, while reappraisal did not moderate the effects. Thus, the type of trauma film plays a crucial role in the effects of frontal asymmetry, which warrants further critical investigation. PMID- 24779523 TI - Effects of an inpatient rehabilitation program after temporal lobe epilepsy surgery and other factors on employment 2 years after epilepsy surgery. AB - OBJECTIVE: To evaluate the effects of a postsurgical rehabilitation program on employment status 2 years after temporal lobe epilepsy surgery in relation to other predictors. METHODS: Employment outcome 2 years after temporal lobe resection in a group of 232 adult patients with the offer of a 3-week inpatient rehabilitation program immediately after surgery ("Reha group") was compared to a group of 119 patients who had surgery before such a rehabilitation program existed. One hundred thirty-nine (59.9%) of the Reha group patients attended the rehabilitation program. Further predictors for employment outcome were analyzed using multivariate logistic regression analysis. RESULTS: Preoperatively, the groups did not differ significantly in variables relevant for employment, including employment rate. Two years after surgery, the rate of those not being employed had decreased in the Reha group from 38.4% to 27.6% (p < 0.001, McNemar test), and slightly increased in the control group (37.8-42.0%; n.s.), resulting in a difference of 14.4% in favor of the Reha group (p = 0.008). General unemployment rates during the two observation periods were similar. In addition to the offer of rehabilitation support ("Reha group") and preoperative employment, the following other variables were shown as significant predictors of employment post surgery in multivariate regression analysis: seizure outcome, diagnosis of a personality disorder preoperatively, and age at surgery (all, p < 0.01; Nagelkerkes R(2) = 0.59). SIGNIFICANCE: Independently from other factors, a 3-week inpatient rehabilitation program after temporal lobe epilepsy surgery seems to improve employment status 2 years after surgery. PMID- 24779525 TI - Effect of Au nanorods on potential barrier modulation in morphologically controlled Au@Cu2O core-shell nanoreactors for gas sensor applications. AB - In this work, Au@Cu2O core-shell nanoparticles (NPs) were synthesized by simple solution route and applied for CO sensing applications. Au@Cu2O core-shell NPs were formed by the deposition of 30-60 nm Cu2O shell layer on Au nanorods (NRs) having 10-15 nm width and 40-60 nm length. The morphology of Au@Cu2O core-shell NPs was tuned from brick to spherical shape by tuning the pH of the solution. In the absence of Au NRs, cubelike Cu2O NPs having ~200 nm diameters were formed. The sensor having Au@Cu2O core-shell layer exhibited higher CO sensitivity compared to bare Cu2O NPs layer. Tuning of morphology of Au@Cu2O core-shell NPs from brick to spherical shape significantly lowered the air resistance. Transition from p- to n-type response was observed for all devices below 150 degrees C. It was demonstrated that performance of sensor depends not only on the electronic sensitization of Au NRs but also on the morphology of the Au@Cu2O core shell NPs. PMID- 24779524 TI - An electronic health record-based intervention to increase follow-up office visits and decrease rehospitalization in older adults. AB - OBJECTIVES: To assess the effect of an electronic health record-based transitional care intervention involving automated alerts to primary care providers and staff when older adults were discharged from the hospital. DESIGN: Randomized controlled trial. SETTING: Large multispecialty group practice. PARTICIPANTS: Individuals aged 65 and older discharged from hospital to home. INTERVENTION: In addition to notifying primary care providers about the individual's recent discharge, the system provided information about new drugs added during the inpatient stay, warnings about drug-drug interactions, recommendations for dose changes and laboratory monitoring of high-risk medications, and alerts to the primary care provider's support staff to schedule a posthospitalization office visit. MEASUREMENTS: An outpatient office visit with a primary care provider after discharge and rehospitalization within 30 days after discharge. RESULTS: Of the 1,870 discharges in the intervention group, 27.7% had an office visit with a primary care provider within 7 days of discharge. Of the 1,791 discharges in the control group, 28.3% had an office visit with a primary care provider within 7 days of discharge. In the intervention group, 18.8% experienced a rehospitalization within the 30-day period after discharge, compared with 19.9% in the control group. The hazard ratio for an office visit with a primary care physician did not significantly differ between the intervention and control groups. The hazard ratio for rehospitalization in the 30-day period after hospital discharge in the intervention versus the control group was 0.94 (95% confidence interval = 0.81 1.1). CONCLUSION: This electronic health record-based intervention did not have a significant effect on the timeliness of office visits to primary care providers after hospitalization or risk of rehospitalization. PMID- 24779526 TI - Long-acting injectable risperidone and oral antipsychotics in patients with schizophrenia: results from a prospective, 1-year, non-interventional study (InORS). AB - OBJECTIVE: To explore differences in outcomes for patients with schizophrenia treated with risperidone long-acting treatment (RLAT) or oral antipsychotics (oAP). METHODS: The International Observational Registry on Schizophrenia (InORS) explored flexible doses of newly initiated RLAT and oAPs for adults with schizophrenia, exploring 6-month retrospective hospitalization data and 12-month prospective medication use, outcomes, and tolerability. Efficacy outcomes included hospitalizations, the Clinical Global Impression of Schizophrenia (CGI SCH), and the Global Assessment of Functioning (GAF). Medication switch patterns were also analysed. RESULTS: Data were analysed from 1083 patients (561 RLAT, 522 oAP). At baseline, RLAT patients had higher symptom severity, greater functional impairment, and poorer compliance. Percentages of patients hospitalized were similar between groups, and median duration per hospitalization decreased after RLAT initiation and with oAP. The difference in duration of hospitalization between the retrospective and prospective period was significantly better with RLAT (P = 0.002). Mean CGI-SCH change from baseline was significantly better for RLAT vs. oAP patients for overall, positive, and negative symptom scores (P < 0.05). Mean functional improvement from baseline was significantly higher with RLAT vs. oAP (P < 0.001). CONCLUSIONS: Hospitalizations and symptomatic and functional outcomes were better with RLAT vs. oAP; frequent medication switches were associated with less favourable outcomes. PMID- 24779527 TI - Intensive care unit readmission prevention checklist: is it worth the effort? AB - RATIONALE, AIMS AND OBJECTIVES: Checklists have been adopted by various institutions to improve patient outcomes. In particular, readmission prevention checklists may be of potential value to improve patient care and reduce medical costs. As a result, a prior quality improvement study was conducted to create an intensive care unit readmission prevention checklist. The previous pilot demonstrated zero readmissions when the readmission prevention checklist was utilized but yielded low compliance (30%). Thus, a subsequent quality initiative was undertaken to refine the readmission prevention checklist with the primary aim of improved compliance while maintaining a reduced readmission rate that was observed with the original quality improvement study. METHOD: A single-centre, cross-sectional study for assessing baseline data and a prospective observational study to assess the effectiveness of a refined readmission prevention checklist tool in a 20-bed tertiary medical-surgical intensive care unit at an academic medical centre in Rochester, MN was conducted. Medical patients admitted through the emergency department, upon direct transfer from outside facility, and post operative surgical patients at our institution were included. A refined readmission prevention checklist tool was administered during an 8-week pilot period for medical and post-operative surgical patients. RESULTS: The refined readmission prevention checklist resulted in an even lower compliance (10.5%) from the initial phase likely resulting from utilization of a paper readmission prevention checklist in an electronic medical environment. Moreover, the refined readmission prevention checklist demonstrated a 22% unplanned readmission rate for patients in which the tool was utilized. CONCLUSIONS: In conclusion, the findings of the current quality improvement study may serve to rethink the process of health care delivery that applies paper tools in an electronic medical environment. PMID- 24779528 TI - Field-effect transistors built from all two-dimensional material components. AB - We demonstrate field-effect transistors using heterogeneously stacked two dimensional materials for all of the components, including the semiconductor, insulator, and metal layers. Specifically, MoS2 is used as the active channel material, hexagonal-BN as the top-gate dielectric, and graphene as the source/drain and the top-gate contacts. This transistor exhibits n-type behavior with an ON/OFF current ratio of >10(6), and an electron mobility of ~33 cm(2)/V.s. Uniquely, the mobility does not degrade at high gate voltages, presenting an important advantage over conventional Si transistors where enhanced surface roughness scattering severely reduces carrier mobilities at high gate fields. A WSe2-MoS2 diode with graphene contacts is also demonstrated. The diode exhibits excellent rectification behavior and a low reverse bias current, suggesting high quality interfaces between the stacked layers. In this work, all interfaces are based on van der Waals bonding, presenting a unique device architecture where crystalline, layered materials with atomically uniform thicknesses are stacked on demand, without the lattice parameter constraints. The results demonstrate the promise of using an all-layered material system for future electronic applications. PMID- 24779529 TI - The lived experience of the wound care nurse in caring for patients with pressure ulcers. AB - The aim of the study was to report the lived experience of the wound care nurse (WCN) in caring for patients with pressure ulcers (PU). WCN play an important role in caring for patients with PU, but the effect on caring for individuals with such wounds is poorly understood. A descriptive and interpretative study on the life worlds of spatiality, temporality, relationality and corporeality was carried out. Utilising the hermeneutic Heideggerian phenomenology, data were collected over a 3-month period in 2012 using in-depth interviews with five WCN. The interviews revealed eight themes: 'challenge', 'making sense of it all', 'coping and self-care', 'advocate of mine/making a difference', 'knowledge and technology', 'we have seen what can happen', 'holistic caring' and 'frustration'. Twenty-five sub-themes were also identified. WCN experienced a demanding and rewarding role of caring, influenced by the environment and the challenges with individuals living with PU. This study demonstrated an enriching yet challenging role. Recommendations for WCN, health care authorities and education providers include raising awareness of the importance of self-care, greater recognition of the effect of this role on patients with PU and changing education to include reflective practice and resilience strategies. PMID- 24779530 TI - Editorial: emerging clones of bacterial epidemics in the genomic area. PMID- 24779531 TI - Unleashing the quadratic nonlinear optical responses of graphene by confining white-graphene (h-BN) sections in its framework. AB - In an attempt to diversify the options in designing graphene-based systems bearing large second order nonlinear optical (NLO) responses of octupolar and/or dipolar character, the subject of the quadratic NLO properties of hybrid boron nitride (BN) graphene flakes is opened up. State of the art ab initio and density functional theory methods applied on a toolbox of book-text octupolar and arbitrary dipolar planar hybrid h-BN-graphene nanosized systems reveal that by confining finite h-BN sections in the internal network of graphene, the capacity of the pi-electron network of graphene species in delivering giant second order NLO responses could be fully exploited. Configuration interaction (CIS) and time dependent density functional (TD) computations, within the sum-overstate (SOS) perturbational approach, expose that the prevailing (hyper)polarization mechanism, lying under the sizable computed octupolar hyperpolarizabilities, is fueled by alternating positive and negative atomic charges located in the internal part of the hybrid flakes, and more precisely at the BN/graphene intersections. This type of charge transfer mechanism distinguishes, in fact, the elemental graphene dipoles/octupoles we report here from other conventional NLO dipoles or octupoles. More interestingly, it is shown that by controlling the shape, size, and covering area of the h-BN domain (or domains), one can effectively regulate "a volonte" both the magnitudes and types of the second order NLO responses switching from dipolar to octupolar and vice versa. Especially in the context of the latter class of NLO properties, this communication brings into surface novel, graphene-based, octupolar planar or quasiplanar motifs. The take home message of this communication is summarized as follows: When the right BN segment is incorporated in the right section of the right graphene flake, systems of giant quadratic NLO octupolar and/or dipolar responses may emerge. PMID- 24779532 TI - The English version of the four-dimensional symptom questionnaire (4DSQ) measures the same as the original Dutch questionnaire: a validation study. AB - BACKGROUND: Translations of questionnaires need to be carefully validated to assure that the translation measures the same construct(s) as the original questionnaire. The four-dimensional symptom questionnaire (4DSQ) is a Dutch self report questionnaire measuring distress, depression, anxiety and somatization. OBJECTIVE: To evaluate the equivalence of the English version of the 4DSQ. METHODS: 4DSQ data of English and Dutch speaking general practice attendees were analysed and compared. The English speaking group consisted of 205 attendees, aged 18-64 years, in general practice, in Canada whereas the Dutch group consisted of 302 general practice attendees in the Netherlands. Differential item functioning (DIF) analysis was conducted using the Mantel-Haenszel method and ordinal logistic regression. Differential test functioning (DTF; i.e., the scale impact of DIF) was evaluated using linear regression analysis. RESULTS: DIF was detected in 2/16 distress items, 2/6 depression items, 2/12 anxiety items, and 1/16 somatization items. With respect to mean scale scores, the impact of DIF on the scale level was negligible for all scales. On the anxiety scale DIF caused the English speaking patients with moderate to severe anxiety to score about one point lower than Dutch patients with the same anxiety level. CONCLUSION: The English 4DSQ measures the same constructs like the original Dutch 4DSQ. The distress, depression and somatization scales can employ the same cut-off points as the corresponding Dutch scales. However, cut-off points of the English 4DSQ anxiety scale should be lowered by one point to retain the same meaning as the Dutch anxiety cut-off points. PMID- 24779533 TI - Rapidly increasing prescribing of proton pump inhibitors in primary care despite interventions: a nationwide observational study. AB - BACKGROUND: Guideline and reimbursement modifications have been introduced to optimize prescribing of antisecretory medication in Danish general practice. Impacts of the interventions have not been evaluated. OBJECTIVES: To analyse developments in prescribing of antisecretory medication in Denmark 2001-2011 and to assess the impacts of interventions on prescribing of antisecretory medication. METHODS: Register-based cohort study covering the entire Danish population of currently 5.5 million inhabitants. Developments in the prescribing of antisecretory medication over time in Denmark between 2001 and 2011 and association with age and gender of users along with the impact of interventions on the prescribing of drug subgroups are analysed. RESULTS: 96.8% of all antisecretory drugs sold are proton pump inhibitors (PPIs) and 94.4% of the PPIs are prescribed in primary care. Prescribing of PPIs has increased substantially during the past decade. Both number of users and the average individual use have increased. The prescribing of ulcerogenic drugs to the elderly has stagnated in the same time range. Reimbursement modifications and scientific guidelines do not seem to have had a substantial influence on the steadily increasing prescribing of PPIs. CONCLUSION: Use of PPIs has increased substantially during the past decade, without a change in indications for use of PPIs in the same time range. Interventions to enhance adherence to guidelines and promote rational use of PPIs do not seem to have had a substantial influence on the overall prescribing rate. PMID- 24779534 TI - A method for estimating wage, using standardised occupational classifications, for use in medical research in the place of self-reported income. AB - BACKGROUND: Income is predictive of many health outcomes and is therefore an important potential confounder to control for in studies. However it is often missing or poorly measured in epidemiological studies because of its complexity and sensitivity. This paper presents and validates an alternative approach to the survey collection of reported income through the estimation of a synthetic wage measure based on occupation. METHODS: A synthetic measure of weekly wage was calculated using a multilevel random effects model of wage predicted by a Standard Occupational Classification (SOC) fitted in data from the UK Labour Force Survey (years 2001-2010)a. The estimates were validated and tested by comparing them to reported income and then contrasting estimated and reported income's association with measures of health in the Scottish Health Survey (SHS) 2003 and wave one (2009) of the UK Household Longitudinal Study (UKHLS). RESULTS: The synthetic estimates provided independent and additional explanatory power within models containing other traditional proxies for socio-economic position such as social class and small area based measures of socio-economic position. The estimates behaved very similarly to 'real', reported measures of both household and individual income when modelling a measure of 'general health'. CONCLUSIONS: The findings suggest that occupation based synthetic estimates of wage are as effective in capturing the underlying relationship between income and health as survey reported income. The paper argues that the direct survey measurement of income in every study may not actually be necessary or indeed optimal. PMID- 24779535 TI - Supramolecular ionic liquid gels for quasi-solid-state dye-sensitized solar cells. AB - A 1-propyl-3-methylimidazolium iodide based supramolecular ionic liquid gel was prepared through the host-guest interactions between a host of beta-cyclodextrin and a room temperature ionic liquid type guest, 1-ethyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)imide, which contains bis(trifluoromethylsulfonyl)imide as the guest group. The gel-to-sol phase transition temperature of the prepared supramolecular ionic liquid gel could be tuned by the ratio of host to guest. The synthesized supramolecular ionic liquid gel was further applied in quasi-solid-state electrolyte dye-sensitized solar cells, which showed a power conversion efficiency of 4.79% under the simulated air mass 1.5 solar spectrum illumination at 100 mW cm(-2) and excellent long-term stability. PMID- 24779536 TI - Recognizing World Elder Abuse Awareness Day 2014. PMID- 24779537 TI - Rosalie Wolf Memorial Lecture: Reconsidering assumptions regarding men as elder abuse perpetrators and as elder abuse victims. AB - From research findings and practice experiences, it is concluded that abuse of older men is especially invisible and underreported, compared to abuse of older women. It is proposed that attention should be directed not to gender, but to those conditions in different countries and cultures leading to abuse of both older men and women, including (but not limited to) economic problems, few alternatives to family care of the elderly, violence, changing characteristics of the family, ageism, and sexism. Advocates for the prevention of elder abuse should work together in combating, reducing, and eliminating the problem of elder abuse of both older men and older women. PMID- 24779538 TI - Older people's conceptualization of elder abuse and neglect. AB - This qualitative study used data from eight focus groups involving 58 people aged over 65 years in both urban and rural settings across Northern Ireland and the Republic of Ireland. Following training, four older people assisted in facilitation and analysis as peer researchers. Increasing lack of respect within society was experienced as abusive. The vulnerability of older people to abuse was perceived as relating to the need for help and support, where standing up for themselves might have repercussions for the person's health or safety. Emotional abusiveness was viewed as underpinning all forms of abuse, and as influencing its experienced severity. Respondents' views as to whether an action was abusive required an understanding of intent: some actions that professionals might view as abusive were regarded as acceptable if they were in the older person's best interests. Preventing abuse requires a wide-ranging approach including rebuilding respect for older people within society. Procedures to prevent elder abuse need to take into account the emotional impact of family relationships and intent, not just a description of behaviors that have occurred. PMID- 24779539 TI - Elder mistreatment, culture, and help-seeking: a cross-cultural comparison of older Chinese and Korean immigrants. AB - This study explored and compared the salient sociocultural characteristics that influenced elder mistreatment and help-seeking behaviors among older Chinese and Korean immigrants. Results from qualitative, in-depth focus groups with 30 participants revealed that elder mistreatment is a culturally laden construct, and core values of traditional culture and acculturation are significant contextual factors that profoundly affect the perceptions of elder abuse and receptivity of interventions. Older Korean participants, compared to their Chinese counterparts, demonstrated stronger influence of hierarchy and cultural beliefs in exclusive family ties and gender norms, and were less likely to disclose abuse. Implications for culturally based interventions are also discussed. PMID- 24779540 TI - Financial abuse of older people by a family member: a difficult terrain for service providers in Australia. AB - Financial abuse by a family member is the most common form of abuse experienced by older Australians, and early intervention is required. National online surveys of 228 chief executive officers and 214 aged care service providers found that, while they were well placed to recognize financial abuse, it was often difficult to intervene successfully. Problems providers encountered included difficulties in detecting abuse, the need for consent before they could take action, the risk that the abusive family member would withdraw the client from the service, and a lack of resources to deal with the complexities inherent in situations of financial abuse. PMID- 24779541 TI - Elder abuse and neglect: a survey of Irish general practitioners. AB - The objective of this study was to survey general practitioners (GPs) in Ireland regarding their experience with elder abuse. A random sample of 800 GPs were mailed a survey in March 2010, with a reminder in May 2010, yielding a 24% response rate. The majority, 64.5%, had encountered elder abuse, with 35.5% encountering a case in the previous year. Most were detected during a home visit. Psychological abuse and self-neglect were most common. Most GPs in Ireland have encountered cases of elder abuse, most were willing to get involved beyond medical treatment, and 76% cited a need for more education. PMID- 24779542 TI - Neglect and abuse of older people in Nepal: a commentary on "A baseline study on reported cases of elder abuse in Nepali press". AB - Little is known about elder abuse in Nepal. To gain further insights, the National Human Rights Commission in association with the Geriatric Center in Nepal published a report that analyzes all cases of older people's abuse published in two daily newspapers in Nepal over a 2-year period. This commentary discusses the main findings of the report, as well as future directions. PMID- 24779543 TI - Elder abuse and neglect vs. parricide: a letter from Russia. AB - In Russia, elder abuse is rarely discussed in the professional literature and the media. However, it is posited that parricide can be considered a form of elder abuse in Russia, as the line between elder abuse and parricide can be vague. Instances of parricide can appear trivial, hardly realized as such by victims and the social environment. Borderline cases can include involving older people in binge drinking, denying them help, and manipulating them to commit suicide. The perpetrators are often nonpsychotic, although sometimes exhibiting abnormal personality traits. Anger toward the victim can be absent on the part of the perpetrator, with their actions often driven by economic desires. A concluding point is that for better prevention of parricide and, therefore, elder abuse, it should not be considered only an unusual horrific crime committed by the mentally ill. PMID- 24779544 TI - Surface imprinting approach for preparing specific adsorbent for IgG separation. AB - In this study, we focused our attention on preparing of a new adsorbent for specific separation of immunoglobulin G (IgG). In this respect, we applied core shell surface imprinting approach. Silica microspheres were selected as core material to prepare specific surface imprinted polymer against IgG. Silica surface was activated via acidic treatment and modified with 3 methacryloyloxypropyl trimethoxysilane (MPTMS). Then, IgG molecules were imprinted on the surface of microspheres by using N-methacryloyl-L-aspartic acid as complexing/functional monomer. The core-shell silica microspheres were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, thermo gravimetric analysis and zeta size analysis. Then, the microspheres were used for the separation of IgG from aqueous solution to evaluate/optimize conditions. The effect of parameters such as concentration, pH, ionic strength, and temperature on the separation of IgG were evaluated in their relevant ranges. The maximum IgG adsorption capacities of IgG-imprinted and non imprinted core-shell silica microspheres were found to be 15.43 and 9.43 mg/g, respectively, at pH 6.0 phosphate buffer. 1.0 M NaCl was used as a desorption agent. Selectivity of the imprinted microspheres was also investigated by using human serum albumin and haemoglobin as competitor molecules. PMID- 24779545 TI - Antenatal care visit attendance, intermittent preventive treatment during pregnancy (IPTp) and malaria parasitaemia at delivery. AB - BACKGROUND: The determinants and barriers for delivery and uptake of IPTp vary with different regions in sub-Saharan Africa. This study evaluated the determinants of ANC clinic attendance and IPTp-SP uptake among parturient women from Mount Cameroon Area and hypothesized that time of first ANC clinic attendance could influence uptake of IPTp-SP/dosage and consequently malaria parasite infection status at delivery. METHODS: Two cross sectional surveys were carried out at the Government Medical Centre in the Mutengene Health Area, Mt Cameroon Area from March to October 2007 and June 2008 to April 2009. Consented parturient women were consecutively enrolled in both surveys. In 2007, socio demographic data, ANC clinic attendance, gestational age, fever history and reported use/dosage of IPTp-SP were documented using a structured questionnaire. In the second survey only IPT-SP usage/dosage was recorded. Malaria parasitaemia at delivery was determined by blood smear microscopy and placental histology. RESULTS AND DISCUSSION: In 2007, among the 287 women interviewed, 2.2%, 59.7%, and 38.1% enrolled in the first, second and third trimester respectively. About 90% of women received at least one dose SP but only 53% received the two doses in 2007 and by 2009 IPTp-two doses coverage increased to 64%. Early clinic attendance was associated (P = 0.016) with fever history while being unmarried (OR = 2.2; 95% CI: 1.3-3.8) was significantly associated with fewer clinic visits (<4visits). Women who received one SP dose (OR = 3.7; 95% CI: 2.0-6.8) were more likely not to have attended >= 4visits. A higher proportion (P < 0.001) of women with first visit during the third trimester received only one dose, meanwhile, those who had an early first ANC attendance were more likely (OR = 0.4; 95% CI = 0.2 - 0.7) to receive two or more doses. Microscopic parasitaemia at delivery was frequent (P = 0.007) among women who enrolled in the third trimester and had received only one SP dose than in those with two doses. CONCLUSION: In the study area, late first ANC clinic enrolment and fewer clinic visits may prevent the uptake of two SP doses and education on early and regular ANC clinic visits can increase IPTp coverage. PMID- 24779546 TI - Evaluation of three different methods of distance learning for postgraduate diagnostic imaging education: A pilot study. AB - Objective : The purpose of this study was to evaluate the perceived effectiveness and learning potential of 3 Web-based educational methods in a postgraduate radiology setting. Methods : Three chiropractic radiology faculty from diverse geographic locations led mini-courses using asynchronous discussion boards, synchronous Web conferencing, and asynchronous voice-over case presentations formatted for Web viewing. At the conclusion of each course, participants filled out a 14-question survey (using a 5-point Likert scale) designed to evaluate the effectiveness of each method in achieving specified course objectives and goals and their satisfaction when considering the learning potential of each method. The mean, standard deviation, and percentage agreements were tabulated. Results : Twenty, 15, and 10 participants completed the discussion board, Web conferencing, and case presentation surveys, respectively. All educational methods demonstrated a high level of agreement regarding the course objective (total mean rating >4.1). The case presentations had the highest overall rating for achieving the course goals; however, all but one method still had total mean ratings >4.0 and overall agreement levels of 70%-100%. The strongest potential for interactive learning was found with Web conferencing and discussion boards, while case presentations rated very low in this regard. Conclusions : The perceived effectiveness in achieving the course objective and goals was high for each method. Residency-based distance education may be a beneficial adjunct to current methods of training, allowing for international collaboration. When considering all aspects tested, there does not appear to be a clear advantage to any one method. Utilizing various methods may be most appropriate. PMID- 24779547 TI - Giving the early fossil record of sponges a squeeze. AB - Twenty candidate fossils with claim to be the oldest representative of the Phylum Porifera have been re-analysed. Three criteria are used to assess each candidate: (i) the diagnostic criteria needed to categorize sponges in the fossil record; (ii) the presence, or absence, of such diagnostic features in the putative poriferan fossils; and (iii) the age constraints for the candidate fossils. All three criteria are critical to the correct interpretation of any fossil and its placement within an evolutionary context. Our analysis shows that no Precambrian fossil candidate yet satisfies all three of these criteria to be a reliable sponge fossil. The oldest widely accepted candidate, Mongolian silica hexacts from c. 545 million years ago (Ma), are here shown to be cruciform arsenopyrite crystals. The oldest reliable sponge remains are siliceous spicules from the basal Cambrian (Protohertzina anabarica Zone) Soltanieh Formation, Iran, which are described and analysed here in detail for the first time. Extensive archaeocyathan sponge reefs emerge and radiate as late as the middle of the Fortunian Stage of the Cambrian and demonstrate a gradual assembly of their skeletal structure through this time coincident with the evolution of other metazoan groups. Since the Porifera are basal in the Metazoa, their presence within the late Proterozoic has been widely anticipated. Molecular clock calibration for the earliest Porifera and Metazoa should now be based on the Iranian hexactinellid material dated to c. 535 Ma. The earliest convincing fossil sponge remains appeared at around the time of the Precambrian-Cambrian boundary, associated with the great radiation events of that interval. PMID- 24779549 TI - Electronic structure of low-dimensional 4d(5) oxides: interplay of ligand distortions, overall lattice anisotropy, and spin-orbit interactions. AB - The electronic structure of the low-dimensional 4d(5) oxides Sr2RhO4 and Ca3CoRhO6 is herein investigated by embedded-cluster quantum chemistry calculations. A negative tetragonal-like t2g splitting is computed in Sr2RhO4 and a negative trigonal-like splitting is predicted for Ca3CoRhO6, in spite of having positive tetragonal distortions in the former material and cubic oxygen octahedra in the latter. Our findings bring to the foreground the role of longer-range crystalline anisotropy in generating noncubic potentials that compete with local distortions of the ligand cage, an issue not addressed in standard textbooks on crystal-field theory. We also show that sizable t2g(5)-t2g(4)eg(1) couplings via spin-orbit interactions produce in Sr2RhO4 ?Z? = ?Sigma(i)l(i).s(i)? ground-state expectation values significantly larger than 1, quite similar to theoretical and experimental data for 5d(5) spin-orbit-driven oxides such as Sr2IrO4. On the other hand, in Ca3CoRhO6, the ?Z? values are lower because of larger t2g-eg splittings. Future X-ray magnetic circular dichroism experiments on these 4d oxides will constitute a direct test for the ?Z? values that we predict here, the importance of many-body t2g-eg couplings mediated by spin-orbit interactions, and the role of low-symmetry fields associated with the extended surroundings. PMID- 24779548 TI - Burden of disease from inadequate water, sanitation and hygiene in low- and middle-income settings: a retrospective analysis of data from 145 countries. AB - OBJECTIVE: To estimate the burden of diarrhoeal diseases from exposure to inadequate water, sanitation and hand hygiene in low- and middle-income settings and provide an overview of the impact on other diseases. METHODS: For estimating the impact of water, sanitation and hygiene on diarrhoea, we selected exposure levels with both sufficient global exposure data and a matching exposure-risk relationship. Global exposure data were estimated for the year 2012, and risk estimates were taken from the most recent systematic analyses. We estimated attributable deaths and disability-adjusted life years (DALYs) by country, age and sex for inadequate water, sanitation and hand hygiene separately, and as a cluster of risk factors. Uncertainty estimates were computed on the basis of uncertainty surrounding exposure estimates and relative risks. RESULTS: In 2012, 502,000 diarrhoea deaths were estimated to be caused by inadequate drinking water and 280,000 deaths by inadequate sanitation. The most likely estimate of disease burden from inadequate hand hygiene amounts to 297,000 deaths. In total, 842,000 diarrhoea deaths are estimated to be caused by this cluster of risk factors, which amounts to 1.5% of the total disease burden and 58% of diarrhoeal diseases. In children under 5 years old, 361,000 deaths could be prevented, representing 5.5% of deaths in that age group. CONCLUSIONS: This estimate confirms the importance of improving water and sanitation in low- and middle-income settings for the prevention of diarrhoeal disease burden. It also underscores the need for better data on exposure and risk reductions that can be achieved with provision of reliable piped water, community sewage with treatment and hand hygiene. PMID- 24779550 TI - Oestradiol-induced synapse formation in the female hippocampus: roles of oestrogen receptor subtypes. AB - During the oestrus cycle, varying spine synapse density correlates positively with varying local synthesis of oestradiol in the hippocampus. In this context, the roles of the oestrogen receptor (ER) subtypes ERalpha and beta are not fully understood. In the present study, we used neonatal hippocampal slice cultures from female rats because these cultures synthesise oestradiol and express both receptor subtypes, and inhibition of oestradiol synthesis in these cultures results in spine synapse loss. Using electron microscopy, we tested the effects on spine synapse density in response to agonists of both ERalpha and ERbeta. Application of agonists to the cultures had no effect. After inhibition of oestradiol synthesis, however, agonists of ERalpha induced spine synapse formation, whereas ERbeta agonists led to a reduction in spine synapse density in the CA1 region of these cultures. Consistently, up-regulation of ERbeta in the hippocampus of adult female aromatase-deficient mice is paralleled by hippocampus specific spine synapse loss in this mutant. Finally, we found an increase in spine synapses in the adult female ERbeta knockout mouse, but no effect in the adult female ERalpha knockout mouse. Our data suggest antagonistic roles of ERbeta and ERalpha in spine synapse formation in the female hippocampus, which may contribute to oestrus cyclicity of spine synapse density in the hippocampus. PMID- 24779551 TI - On uncertain sightings and inference about extinction. AB - The extinction of many species can only be inferred from the record of sightings of individuals. Solow et al. (2012, Uncertain sightings and the extinction of the Ivory-billed Woodpecker. Conservation Biology 26:180-184) describe a Bayesian approach to such inference and apply it to a sighting record of the Ivory-billed Woodpecker (Campephilus principalis). A feature of this sighting record is that all uncertain sightings occurred after the most recent certain sighting. However, this appears to be an artifact. We extended this earlier work in 2 ways. First, we allowed for overlap in time between certain and uncertain sightings. Second, we considered 2 plausible statistical models of a sighting record. In one of these models, certain and uncertain sightings that are valid arise from the same process whereas in the other they arise from independent processes. We applied both models to the case of the Ivory-billed Woodpecker. The result from the first model did not favor extinction, whereas the result for the second model did. This underscores the importance, in applying tests for extinction, of understanding what could be called the natural history of the sighting record. PMID- 24779553 TI - An interview with: Jorge J. Rodriguez, MD, PhD; Unit Chief, Mental Health and Substance Use; Pan American Health Organization. PMID- 24779552 TI - Taking the temperature of the interiors of magnetically heated nanoparticles. AB - The temperature increase inside mesoporous silica nanoparticles induced by encapsulated smaller superparamagnetic nanocrystals in an oscillating magnetic field is measured using a crystalline optical nanothermometer. The detection mechanism is based on the temperature-dependent intensity ratio of two luminescence bands in the upconversion emission spectrum of NaYF4:Yb(3+), Er(3+). A facile stepwise phase transfer method is developed to construct a dual-core mesoporous silica nanoparticle that contains both a nanoheater and a nanothermometer in its interior. The magnetically induced heating inside the nanoparticles varies with different experimental conditions, including the magnetic field induction power, the exposure time to the magnetic field, and the magnetic nanocrystal size. The temperature increase of the immediate nanoenvironment around the magnetic nanocrystals is monitored continuously during the magnetic oscillating field exposure. The interior of the nanoparticles becomes much hotter than the macroscopic solution and cools to the temperature of the ambient fluid on a time scale of seconds after the magnetic field is turned off. This continuous absolute temperature detection method offers quantitative insight into the nanoenvironment around magnetic materials and opens a path for optimizing local temperature controls for physical and biomedical applications. PMID- 24779554 TI - The role of the trans double bond in skin barrier sphingolipids: permeability and infrared spectroscopic study of model ceramide and dihydroceramide membranes. AB - Dihydroceramides (dCer) are members of the sphingolipid family that lack the C4 trans double bond in their sphingoid backbone. In addition to being precursors of ceramides (Cer) and phytoceramides, dCer have also been found in the extracellular lipid membranes of the epidermal barrier, the stratum corneum. However, their role in barrier homeostasis is not known. We studied how the lack of the trans double bond in dCer compared to Cer influences the permeability, lipid chain order, and packing of multilamellar membranes composed of the major skin barrier lipids: (d)Cer, fatty acids, cholesterol, and cholesteryl sulfate. The permeability of the membranes with long-chain dCer was measured using various markers and was either comparable to or only slightly greater than (by up to 35%, not significant) that of the Cer membranes. The dCer were less sensitive to acyl chain shortening than Cer (the short dCer membranes were up to 6-fold less permeable that the corresponding short Cer membranes). Infrared spectroscopy showed that long dCer mixed less with fatty acids but formed more thermally stable ordered domains than Cer. The key parameter explaining the differences in permeability in the short dCer and Cer was the proportion of the orthorhombic phase. Our results suggest that the presence of the trans double bond in Cer is not crucial for the permeability of skin lipid membranes and that dCer may be underappreciated members of the stratum corneum lipid barrier that increase its heterogeneity. PMID- 24779555 TI - Intramolecular charge transfer of push-pull pyridinium salts in the singlet manifold. AB - The solvent effect on the photophysical and photochemical properties of the iodides of three trans (E) isomers of 2-D-vinyl,1-methylpyridinium, where D is a donor group (4-dimethylaminophenyl, 3,4,5-trimethoxyphenyl and 1-pyrenyl), was studied by stationary and transient absorption techniques. The results obtained allowed the negative solvatochromism and relaxation pathways of the excited states in the singlet manifold to be reasonably interpreted. Resorting to ultrafast absorption techniques and DFT calculations allowed information on the excited state dynamics and the role of the solvent-controlled intramolecular charge transfer (ICT) processes to be obtained. The structure-dependent excited state dynamics in nonpolar solvents, where the ICT is slower than solvent rearrangement, and in polar solvents, where an opposite situation is operative, was thus explained. The push-pull character of the three compounds, particularly the anilino-derivative, suggests their potential application in optoelectronics. PMID- 24779556 TI - Activity, reduced toxicity, and scale-up synthesis of amphotericin B-conjugated polysaccharide. AB - Amphotericin B (AMB) arabinogalactan (AG) conjugate was synthesized by the conjugation of AMB to oxidized AG by reductive amination. The conjugate was evaluated for in vitro antifungal activity and in vivo toxicity. Optimization of the conjugation process was investigated using large batches of 100 g, which are 20 times larger than previously reported for AMB-AG conjugation. The efficacy of AMB-AG conjugates was studied as a function of reaction conditions and time, aldehyde/reducing agent mole ratio, and purification procedure. The most potent AMB-AG conjugate having low minimal inhibitory concentration (MIC) and high maximal tolerated dose (MTD) was obtained following reduction with NaBH4 at 1:2 mol ratio (AG units/NaBH4) at 25 degrees C for 24 h. AMB-AG conjugate prepared under these conditions demonstrated MIC of 0.5 mg/L (equiv of AMB) in Candida albicans, and an MTD of 60 mg/kg (equiv of AMB) in mice, while AMB clinical formulation (Fungizone) demonstrated high toxicity (MTD = 3 mg/kg). These findings confirm the simplicity and reproducibility of the conjugation allowing this method to be applied on larger scale production. PMID- 24779557 TI - Isolation and complete structural assignment of Lycopodium alkaloid cernupalhine A: theoretical prediction and total synthesis validation. AB - Cernupalhine A (1) is a trace Lycopodium alkaloid (0.7 mg) possessing a new C17N skeleton with an unusual hydroxydihydrofuranone motif newly isolated from Palhinhaea cernua L. Its complete structural assignment, including absolute stereochemistry, was established through a combination of high-field NMR techniques and computational methods and further unequivocal confirmation by the first asymmetric total synthesis. Following the first total synthesis of lobscurinine (3), 1 was achieved via regio- and stereoselective cyanide ion addition and subsequent acid treatment. PMID- 24779558 TI - Effects of the professional identity development programme on the professional identity, job satisfaction and burnout levels of nurses: A pilot study. AB - The aim of this study was to evaluate the effects of the Professional Identity Development Program on the professional identity, job satisfaction and burnout levels of registered nurses. This study was conducted as a quasi-experimental one with 63 nurses working in a university hospital. Data were gathered using the Personal Information Questionnaire, the Professional Self Concept Inventory, Minnesota Job Satisfaction Inventory and the Maslach Burnout Inventory. The Professional Identity Development Program which consists of ten sessions was implemented to the study group once a week. The Program significantly improved the professional identity of the nurses in the study group compared to that of the control group. During the research period, burnout levels significantly decreased in the study group while those of the control group increased. The programme did not create any significant differences in the job satisfaction levels of the nurses. The programme had a positive impact on the professional identity of the nurses. It is recommended that the programme should be implemented in different hospitals with different samples of nurses, and that its effectiveness should be evaluated. PMID- 24779559 TI - Association between hearing impairment and self-reported difficulty in physical functioning. AB - OBJECTIVES: To determine whether hearing impairment, defined by using objective audiometry, is associated with multiple categories of self-reported physical functioning in a cross-sectional, nationally representative sample of older adults. DESIGN: Multivariate secondary analysis of cross-sectional data. SETTING: The 2005-06 and 2009-10 cycles of the National Health and Nutrition Examination Survey. PARTICIPANTS: Adults aged 70 and older who completed audiometric testing (N = 1,669). MEASUREMENTS: Hearing was measured using pure-tone audiometry. Physical functioning was assessed using a structured interview. RESULTS: In a model adjusted for age and demographic and cardiovascular risk factors, greater hearing impairment (per 25 dB hearing level (HL)) was associated with greater odds of physical disability in activities of daily living (odds ratio (OR) = 1.4, 95% confidence interval (CI) = 1.1-1.9), instrumental activities of daily living (OR = 1.6, 95% CI = 1.2-2.2), leisure and social activities (OR = 1.5, 95% CI = 1.1-2.0), lower extremity mobility (OR = 1.4, 95% CI = 1.1-1.7), general physical activities (OR = 1.3, 95% CI = 1.1-1.6), work limitation (OR = 1.4, 95% CI = 1.0 1.9), walking limitation (OR = 1.6, 95% CI = 1.3-2.0), and limitation due to memory or confusion (OR = 1.4, 95% CI = 1.1-1.8). Hearing impairment was not associated with limitations in amount or type of work done (OR = 1.2, 95% CI = 1.0-1.6). CONCLUSION: Hearing impairment in older adults is independently associated with greater disability and limitations in multiple self-reported categories of physical functioning. PMID- 24779560 TI - Nano-proniosomes enhancing the transdermal delivery of mefenamic acid. AB - Mefenamic acid (MA) is a BCS II class NSAID drug. It is available only in the form of tablets, capsules, and pediatric suspensions. Oral administration of MA is associated with severe gastrointestinal side effects. The aim of this study was to develop a convenient and low-cost transdermal drug delivery system for MA using proniosome as a novel carrier without the addition of penetration enhancers. The formulation factors, such as the presence of cholesterol, types of lecithin, and surfactants were investigated for their influence on the entrapment efficiency, rate of hydration, vesicle size, and zeta potential, in vitro drug release and skin permeation in order to optimize the proniosomal formulations with the minimum dose of the drug. Furthermore, the in vivo anti-inflammatory effect was evaluated on a formalin-induced rat paw edema model. The results showed that the type of surfactants had higher impact on the entrapment efficiency than the type of lecithins, with the highest in Span 80 (82.84%). The release of MA from Span 80 proniosomal gel was significantly affected by the type of lecithin used. The addition of cholesterol significantly increased both the drug release and the skin permeation flux of MA. Zeta potential showed a stable A4 noisomal suspension. DSC revealed the molecular dispersion of MA into the loaded proniosomes. In vivo study of the treatment group with MA proniosome gel showed a significant inhibition of rat paw edema compared with the same gel without the drug (control). The results of this study suggest that proniosomes are promising nano vesicular carriers and safe alternatives to enhance the transdermal delivery of MA. PMID- 24779561 TI - Single-particle study of Pt-modified Au nanorods for plasmon-enhanced hydrogen generation in visible to near-infrared region. AB - Pt-modified Au nanorods (NRs) synthesized by anisotropic overgrowth were used for producing H2 under visible and near-infrared light irradiation. The Pt-tipped sample exhibited much higher activity compared with fully covered samples. Using single-particle spectroscopies combined with transmission electron microscopy, we observed obvious quenching phenomena for photoluminescence and light scattering from individual Pt-tipped NRs. The analysis of energy relaxation of plasmon generated hot electrons indicates the electron transfer from the excited Au to Pt. PMID- 24779563 TI - Cancer biology, toxicology and alternative methods development go hand-in-hand. AB - Toxicological research faces the challenge of integrating knowledge from diverse fields and novel technological developments generally in the biological and medical sciences. We discuss herein the fact that the multiple facets of cancer research, including discovery related to mechanisms, treatment and diagnosis, overlap many up and coming interest areas in toxicology, including the need for improved methods and analysis tools. Common to both disciplines, in vitro and in silico methods serve as alternative investigation routes to animal studies. Knowledge on cancer development helps in understanding the relevance of chemical toxicity studies in cell models, and many bioinformatics-based cancer biomarker discovery tools are also applicable to computational toxicology. Robotics-aided, cell-based, high-throughput screening, microscale immunostaining techniques and gene expression profiling analyses are common tools in cancer research, and when sequentially combined, form a tiered approach to structured safety evaluation of thousands of environmental agents, novel chemicals or engineered nanomaterials. Comprehensive tumour data collections in databases have been translated into clinically useful data, and this concept serves as template for computer-driven evaluation of toxicity data into meaningful results. Future 'cancer research inspired knowledge management' of toxicological data will aid the translation of basic discovery results and chemicals- and materials-testing data to information relevant to human health and environmental safety. PMID- 24779562 TI - Effect of diabetes on brain structure: the action to control cardiovascular risk in diabetes MR imaging baseline data. AB - PURPOSE: To investigate the association of characteristics of type 2 diabetes mellitus (duration and biochemical severity of diabetes) to brain structure measured on magnetic resonance (MR) images, specifically testing whether more severity in metrics of diabetes is inversely correlated with brain volumes and positively correlated with ischemic lesion volumes. MATERIALS AND METHODS: This study protocol was approved by the institutional review board of each center and participants provided written informed consent. Baseline severity of diabetes was evaluated by testing fasting plasma glucose levels, hemoglobin A1c levels, and duration of diabetes. MR imaging was performed with fluid-attenuated inversion recovery, proton-density, T2-weighted, and T1-weighted sequences, which were postprocessed with an automated computer algorithm that classified brain tissue as gray or white matter and as normal or ischemic. Separate linear regression models adjusted for potential confounding factors were used to investigate the relationship of the diabetes measures to MR imaging outcomes in 614 participants (mean age, 62 years; mean duration of type 2 diabetes mellitus, 9.9 years). RESULTS: The mean volumes of total gray matter (463.9 cm(3)) and total white matter (463.6 cm(3)) were similar. The mean volume of abnormal tissue was 2.5 cm(3), mostly in the white matter (81% white matter, 5% gray matter, 14% deep gray and white matter). Longer duration of diabetes and higher fasting plasma glucose level were associated with lower normal (beta = -0.431 and -0.053, respectively; P < .01) and total gray matter volumes (beta = -0.428 and -0.053, respectively; P < .01). Fasting plasma glucose was also inversely correlated with ischemic lesion volume (beta = -0.006; P < .04). Hemoglobin A1c level was not associated with any MR imaging measure. CONCLUSION: Longer duration of diabetes is associated with brain volume loss, particularly in the gray matter, possibly reflecting direct neurologic insult; biochemical measures of glycemia were less consistently related to MR imaging changes. Contrary to common clinical belief, in this sample of patients with type 2 diabetes mellitus, there was no association of diabetes characteristics with small vessel ischemic disease in the brain. PMID- 24779564 TI - Comparison of perceived quality amongst migrant and local patients using primary health care delivered by community health centres in Shenzhen, China. AB - BACKGROUND: Providing good quality primary health care to all inhabitants is one of the Chinese Government's health care objectives. However, information is scarce regarding the difference in quality of primary health care delivered to migrants and local residents respectively. This study aimed to compare patients' perceptions of quality of primary health care between migrants and local patients, and their willingness to use and recommend primary health care to others. METHODS: A cross-sectional survey was conducted. 787 patients in total were chosen from four randomly drawn Community Health Centers (CHCs) for interviews. RESULTS: Local residents scored higher than migrants in terms of their satisfaction with types of drugs available (3.62 vs. 3.45, p=0.035), attitude of health workers (4.41 vs. 4.14, p=0.042) and waiting time (4.30 vs. 3.86, p<0.001). Even though there was no significant difference in overall satisfaction between local residents and migrants (4.16 vs. 3.91, p=0.159), migrants were more likely to utilize primary health care as the first choice for their usual health problems (94.1% vs. 87.1%, p=0.032), while local residents were more inclined to recommend Traditional Chinese Medicine to others (65.6% vs. 56.6%, p=0.026). CONCLUSIONS: Quality of primary health care given to migrants is less satisfactory than to local residents in terms of attitude of health workers and waiting time. Our study suggests quality of care could be improved through extending opening hours of CHCs and strengthening professional ethics education. Considering CHCs as the first choice by migrants might be due to their health insurance scheme, while locals' recommendations for traditional Chinese medicine were possibly because of cultural differences. PMID- 24779565 TI - Validity and relative validity of a novel digital approach for 24-h dietary recall in athletes. AB - BACKGROUND: We developed a digital dietary analysis tool for athletes (DATA) using a modified 24-h recall method and an integrated, customized nutrient database. The purpose of this study was to assess DATA's validity and relative validity by measuring its agreement with registered dietitians' (RDs) direct observations (OBSERVATION) and 24-h dietary recall interviews using the USDA 5 step multiple-pass method (INTERVIEW), respectively. METHODS: Fifty-six athletes (14-20 y) completed DATA and INTERVIEW in randomized counter-balanced order. OBSERVATION (n = 26) consisted of RDs recording participants' food/drink intake in a 24-h period and were completed the day prior to DATA and INTERVIEW. Agreement among methods was estimated using a repeated measures t-test and Bland Altman analysis. RESULTS: The paired differences (with 95% confidence intervals) between DATA and OBSERVATION were not significant for carbohydrate (10.1%, -1.2 22.7%) and protein (14.1%, -3.2-34.5%) but was significant for energy (14.4%, 1.2 29.3%). There were no differences between DATA and INTERVIEW for energy (-1.1%, 9.1-7.7%), carbohydrate (0.2%, -7.1-8.0%) or protein (-2.7%, -11.3-6.7%). Bland Altman analysis indicated significant positive correlations between absolute values of the differences and the means for OBSERVATION vs. DATA (r = 0.40 and r = 0.47 for energy and carbohydrate, respectively) and INTERVIEW vs. DATA (r = 0.52, r = 0.29, and r = 0.61 for energy, carbohydrate, and protein, respectively). There were also wide 95% limits of agreement (LOA) for most method comparisons. The mean bias ratio (with 95% LOA) for OBSERVATION vs. DATA was 0.874 (0.551-1.385) for energy, 0.906 (0.522-1.575) for carbohydrate, and 0.895(0.395-2.031) for protein. The mean bias ratio (with 95% LOA) for INTERVIEW vs. DATA was 1.016 (0.538-1.919) for energy, 0.995 (0.563-1.757) for carbohydrate, and 1.031 (0.514-2.068) for protein. CONCLUSION: DATA has good relative validity for group-level comparisons in athletes. However, there are large variations in the relative validity of individuals' dietary intake estimates from DATA, particularly in athletes with higher energy and nutrient intakes. DATA can be a useful athlete-specific, digital alternative to conventional 24-h dietary recall methods at the group level. Further development and testing is needed to improve DATA's validity for estimations of individual dietary intakes. PMID- 24779566 TI - Baseline levels of melamine in food items sold in Canada. I. Dairy products and soy-based dairy replacement products. AB - A variety of dairy and soy-based dairy replacement products (n = 246) purchased from Canadian retail outlets were analysed for baseline levels of melamine (MEL) using a sensitive LC-MS/MS method (method quantification limit = 4 ug/kg). MEL was infrequently detected; only 14% of the items analysed contained quantifiable levels of MEL. The concentrations observed, aside from one recalled sample of candy, ranged from 0.00435 to 0.276 mg/kg, and were at least 10 times lower than the 2.5 mg/kg interim standard for melamine in products containing milk and milk derived ingredients established by Health Canada. The consumption of foods containing these low levels of MEL does not constitute a health risk for consumers. PMID- 24779567 TI - Baseline levels of melamine in food items sold in Canada. II. Egg, soy, vegetable, fish and shrimp products. AB - A variety of egg-containing, soy-based, fish, shrimp and vegetable products sold in Canada were analysed for melamine (MEL) using a sensitive solid-phase extraction LC-MS/MS analytical method. MEL was detected above the method quantification limit of 0.004 mg/kg in 98 of the 378 samples analysed. Concentrations in the various food product groups ranged 0.00507-0.247 mg/kg (egg containing items), 0.00408-0.0479 mg/kg (soy-based meat substitutes), 0.00409 1.10 mg/kg (fish and shrimp products), and 0.00464-0.688 mg/kg (vegetable products). MEL was detected less frequently in egg- and soy-containing products. The presence of MEL in most of the Canadian Total Diet Study shrimp composites collected after 2001 suggested the residues in shrimp were caused by a relatively recent exposure to MEL. All concentrations of MEL reported were lower than the 2.5 mg/kg interim standard established for MEL in items containing milk and milk derived ingredients and the respective maximum residue limits for cyromazine and its metabolite, melamine, in vegetables set by the Canadian Government (2009; http://www.hc-sc.gc.ca/fn-an/securit/chem-chim/melamine/qa-melamine-qr-eng.php#8 ). The consumption of foods containing these low levels of MEL does not constitute a health risk for consumers. PMID- 24779568 TI - Colour additives in snack foods consumed by primary school children in Hong Kong. AB - The objective of the present study was to assess synthetic colours in common snack foods consumed by children and the accuracy of labelling. Dietary exposure to synthetic colours was estimated using food frequency questionnaire data obtained from primary school children in Hong Kong. The concentration of synthetic colours in food items consumed was determined by HPLC with photodiode array detection. Dietary exposure to synthetic colours for an average primary school student was considerably lower than the acceptable daily intake for their age. Estimates fell below the maximum acceptable daily intake established by the Food and Agriculture Organization/World Health Organization (FAO/WHO) and European Food Safety Authority (ESFA). However, data from HPLC analyses showed that several synthetic colours, which were labelled as being present in the food, were not detected and vice versa. PMID- 24779569 TI - Streptomycin and dihydrostreptomycin residues in bovine milk from the Brazilian retail market. AB - Pasteurised bovine milk from retail markets in the State of Sao Paulo, Brazil, was analysed for the presence of streptomycin (STP) and dihydrostreptomycin (DHSTP) residues. An ELISA kit was used for screening and a LC-APCI-MS/MS QToF method for confirmatory analysis. Both methods were intra-laboratory validated and found suitable for screening and confirmatory testing, respectively, for STP and DHSTP residues in pasteurised bovine milk at concentration levels below the maximum residue limit (MRL) established for these substances (200 ug kg(-1) expressed as the sum of the concentrations of STP and DHSTP). No residues of STP and DHSTP at detectable levels were found in the analysed samples (n = 299). PMID- 24779570 TI - Survey of trace element composition of commercial infant formulas in the Nigerian market. AB - Concentrations of zinc (Zn), copper (Cu), cadmium (Cd), lead (Pb), iron (Fe), nickel (Ni), chromium (Cr), vanadium (V) and cobalt (Co) were measured in 190 samples covering 19 different brands of popular baby foods in Nigeria to assess whether the intakes complied with the recommended desired levels for essential metals and permissible levels for toxic elements. The mean concentrations of Zn, Cu, Cd, Pb, Fe, Ni, Cr, V and Co in different types of infant foods were found to vary from 1.8-7.8; <0.001-0.1; <0.001-0.02; 0.01-0.1; 4.4-25.8; 0.03-0.06; 0.1 1.6; <0.001-0.1 to <0.001-0.1 ug g(-1), respectively. The average concentrations of these metals were higher in soy-based formulas than milk-based infant foods. The estimated average daily intakes of metals through the consumption of these brands of infant foods for ages 0-6 and 7-12 months were 118.6 and 163.5; 1.0 and 1.9; 0.2 and 0.3; 1.3 and 1.8; 294.8 and 530.6; 1.0 and 1.1; 15.1 and 20.6; and 0.8 and 4.0 ug kg(-1) body weight (bw) day(-1) for Zn, Cu, Pb, Cd, Fe, Ni, Cr and Co, respectively. The daily intakes of non-essential elements of these metals through baby foods are well below the recommended tolerable levels. Similarly, the daily intake levels of essential elements (e.g. Zn, Co, Cu and Fe) were also significantly lower than the recommended desirable levels in infant foods. PMID- 24779571 TI - Survey of arsenic, cadmium, copper, mercury and lead in kidney of cattle, horse, sheep and pigs from rural areas in Croatia. AB - Trace element (As, Cd, Cu, Hg, Pb) concentrations were determined in the kidney of cattle, sheep, horses and pigs from rural areas of Croatia. Arsenic concentrations in kidney tissues ranged from 0.013 to 0.5 mg kg(-1). No significant differences in As kidney levels were observed among species. The highest levels of Cd and Hg were found in horses and ranged 0.029-47.4 and 0.009 0.13 mg kg(-1), respectively. The European Union maximum levels for Cd in kidney were exceeded by 92.3% of horses, 14% of cattle and 16% of sheep. The highest mean Cu levels were found in sheep and horse (8.53 and 8.45 mg kg(-1)). Mean Hg concentrations in kidney of cattle, sheep, horses and pigs were 0.051, 0.011, 0.034 and 0.094 mg kg(-1), respectively, and the highest levels of Pb were found in cattle (1.71 mg kg(-1)). Significant differences in Cd, Pb and Hg concentrations between animal species were observed. PMID- 24779572 TI - Survey of pesticide residues in maize, cowpea and millet from northern Cameroon: part I. AB - In northern Cameroon, the misuse of pesticides for pest control is common among small-scale farmers. Therefore, monitoring of pesticide residues was carried out on stored maize, cowpea and millet from eight localities. The determination of residues of organochlorines (lindane, alpha-endosulfan and beta-endosulfan), organophosphorus compounds (malathion and pirimiphos-methyl), synthetic pyrethroids (permethrin) and carbamates (carbufuran) was performed using GC ECD/NPD and GC-MS for confirmation. Organochlorine pesticides were detected more frequently and in higher concentrations, ranging from 0.02 +/- 0.01 mg kg(-1) for beta-endosulfan in millet to 9.53 +/- 4.00 mg kg(-1) lindane in maize, than organophosphorus compounds, with concentrations varying from 0.04 +/- 0.03 mg kg( 1) for pirimiphos methyl to 0.23 +/- 0.38 mg kg(-1) for malathion in maize. Permethrin was found only in maize at 0.39 +/- 0.23 mg kg(-1). No carbofuran was found. More than 75% of samples contained pesticide residues above the maximum residue limit (MRL); showing a potential human dietary risk related to consumption of these grains. PMID- 24779573 TI - Aflatoxins and ochratoxin A in pistachios sampled in Spain: occurrence and presence of mycotoxigenic fungi. AB - A survey of the fungal contamination and occurrence of aflatoxins and ochratoxin A (OTA) in 50 pistachio nut samples collected from commercial stores around Catalonia (Spain) was carried out. Aspergillus flavus was found in 30% of samples, whereas Aspergillus section Nigri, Aspergillus ochraceus, and Penicillium verrucosum were found in 40%, 2% and 26% of samples, respectively. A total of 204 fungal isolates were obtained; 70.8% of A. flavus isolates were able to produce aflatoxin B1 and B2, whereas OTA production capacity was detected in 54.4% of the A. section Nigri biseriate isolates. Aflatoxins were detected in five samples (10% of total), all exceeding the maximum legal limit set for aflatoxin B1 (2 ug kg(-1)) or for total aflatoxins (4 ug kg(-1)), with one sample having a very high level of contamination (1134.5 ug kg(-1)). Only one sample of pistachio showed OTA contamination at 0.67 ug kg(-1). Simultaneous contamination by aflatoxins and OTA was not observed in these samples. It was concluded that the frequency of aflatoxins and OTA contamination in pistachio samples available in the Spanish market is relatively low. Thus, no significant contribution to health risk should be expected from aflatoxin consumption through pistachios among healthy consumers. However, the existence of single samples with an extremely high aflatoxin concentration reinforces the need for effective prevention strategies in pistachio processing and commercialization. PMID- 24779574 TI - Aflatoxin M1 in Spanish infant formulae: occurrence and dietary intake regarding type, protein-base and physical state. AB - The incidence of aflatoxin M1 (AFM1) in 69 different infant formulae marketed in Spain between 2007 and 2008 was studied and dietary intake estimated. Samples were analysed using an HPLC method coupled with fluorescence detection after immunoaffinity column clean-up. The toxin was detected in 26 formulae (37.7%) at levels below the permissible limit set by EC legislation, giving a range of 0.6 11.6 ng kg(-1) with a mean value of 3.1 ng kg(-1). Increasing occurrence was found in those formulae produced by the less complex manufacturing processes affecting casein/whey protein ratio: pre-term, 14.3%; starter, 35.3%; follow-up, 42.1%; toddler 87.6%; while hypoallergenic and lactose-free were totally exempt. Additionally, the influence of main protein source and physical state (powdered and ready-to-use formula) on AFM1 occurrence was evaluated leading to similar conclusions. Dietary AFM1 weekly intake was observed to be stable around 1 ng kg( 1) bw for standard formula and 0.1 ng kg(-1) bw for pre-term feeding. PMID- 24779575 TI - Extended-release naltrexone and harm reduction counseling for chronically homeless people with alcohol dependence. AB - BACKGROUND: Abstinence-based alcohol interventions are minimally desirable to and effective for chronically homeless individuals with alcohol dependence who have multimorbidity and high publicly funded service utilization and associated costs. Lower-barrier, patient-centered combined pharmacobehavioral interventions may more effectively treat this population. Harm reduction counseling involves a nonjudgmental, empathic style and patient-driven goal setting that requires neither abstinence nor use reduction. Extended-release naltrexone (XR-NTX), a monthly injectable formulation of an opioid receptor antagonist, reduces craving, is safe and effective for active drinkers, and may thereby support harm reduction goal setting. The aims of this 12-week, single-arm pilot were to initially document some aspects of feasibility, acceptability, and alcohol outcomes following XR-NTX administration and harm reduction counseling for chronically homeless individuals with alcohol dependence. METHODS: Participants were currently/formerly chronically homeless, alcohol-dependent individuals (N = 31) from 2 community-based agencies in the US Pacific Northwest. Measures included self-reported alcohol craving, quantity/frequency, problems, and biomarkers (ethyl glucuronide [EtG], liver transaminases). XR-NTX and harm reduction counseling were administered monthly over the 3-month treatment course. RESULTS: Of the 45 individuals approached, 43 were interested in participation. The first injection was received by 31 participants, and 24 complied with all study procedures. Participants reported the treatment was acceptable. Participants evinced decreases in alcohol craving (33%), typical (25%) and peak (34%) use, frequency (17%), problems (60%), and EtG from the baseline to the 12-week follow up (Ps < .05). CONCLUSIONS: XR-NTX and harm reduction counseling are promising means of supporting reductions in alcohol use and alcohol-related harm among chronically homeless, alcohol-dependent individuals. PMID- 24779576 TI - Extraordinary reinforcement effect of three-dimensionally nanoporous cellulose gels in poly(epsilon-caprolactone) bionanocomposites. AB - Three-dimensionally nanoporous cellulose gels (NCG) were prepared by dissolution and coagulation of cellulose from aqueous alkali hydroxide-urea solution, and used to fabricate NCG/poly(epsilon-caprolactone) (PCL) nanocomposites by in situ ring-opening polymerization of epsilon-CL monomer in the NCG. The NCG content of the NCG/PCL nanocomposite could be controlled between 7 and 38% v/v by changing water content of starting hydrogel by compression dewatering. FT-IR and solid state (13)C NMR showed that the grafting of PCL onto cellulose are most likely occurred at the C6-OH groups and the grafting percentage of PCL is 25 wt % for the nanocomposite with 7% v/v NCG. (1)H NMR, XRD, and DSC results indicate that the number-average molecular weight and crystal formation of PCL in the nanocomposites are remarkably restricted by the presence of NCG. AFM images confirm that the interconnected nanofibrillar cellulose network structure of NCG are finely distributed and preserved well in the PCL matrix after polymerization. DMA results show remarkable increase in tensile storage modulus of the nanocomposites above glass transition and melting temperatures of the PCL matrix. The percolation model was used to evaluate the mechanical properties of the nanocomposites, in which stress transfer among the interconnected nanofibrillar network is facilitated through strong intermolecular hydrogen bonding and entanglement of cellulose nanofibers. PMID- 24779577 TI - Influence of dietary docosahexaenoic acid supplementation on the overall rumen microbiota of dairy cows and linkages with production parameters. AB - The rumen microbiota contributes to greenhouse gas emissions and has an impact on feed efficiency and ruminant product fatty acid composition. Dietary fat supplements have shown promise in reducing enteric methane production and in altering the fatty acid profiles of ruminant-derived products, yet in vivo studies on how these impact the rumen microbiota are limited. In this study, we investigated the rumen bacterial, archaeal, fungal, and ciliate protozoan communities of dairy cows fed diets supplemented with 4 levels of docosahexaenoic acid (DHA) (0, 25, 50, and 75 g.cow(-1).day(-1)) and established linkages between microbial communities and production parameters. Supplementation with DHA significantly (P < 0.05) altered rumen bacterial and archaeal, including methanogenic archaeal, communities but had no significant (P > 0.05) effects on rumen fungal or ciliate protozoan communities. Rumen bacterial communities of cows receiving no DHA were correlated with increased saturated fatty acids (C18:0 and C11:0) in their milk. Furthermore, rumen bacterial communities of cows receiving a diet supplemented with 50 g DHA.cow(-1).day(-1) were correlated with increases in monounsaturated fatty acids (C20:1n-9) and polyunsaturated fatty acids (C22:5n-3; C22:6n-3; C18:2 cis-9, trans-11; C22:3n-6; and C18:2n-6 trans) in their milk. The significant diet-associated changes in rumen archaeal communities observed did not result in altered enteric methane outputs in these cows. PMID- 24779578 TI - Current practice and future prospects for social data in coastal and ocean planning. AB - Coastal and ocean planning comprises a broad field of practice. The goals, political processes, and approaches applied to planning initiatives may vary widely. However, all planning processes ultimately require adequate information on both the biophysical and social attributes of a planning region. In coastal and ocean planning practice, there are well-established methods to assess biophysical attributes; however, less is understood about the role and assessment of social data. We conducted the first global assessment of the incorporation of social data in coastal and ocean planning. We drew on a comprehensive review of planning initiatives and a survey of coastal and ocean practitioners. There was significantly more incorporation of social data in multiuse versus conservation oriented planning. Practitioners engaged a wide range of social data, including governance, economic, and cultural attributes of planning regions and human impacts data. Less attention was given to ecosystem services and social ecological linkages, both of which could improve coastal and ocean planning practice. Although practitioners recognize the value of social data, little funding is devoted to its collection and incorporation in plans. Increased capacity and sophistication in acquiring critical social and ecological data for planning is necessary to develop plans for more resilient coastal and ocean ecosystems and communities. We suggest that improving social data monitoring, and in particular spatial social data, to complement biophysical data, is necessary for providing holistic information for decision-support tools and other methods. Moving beyond people as impacts to people as beneficiaries, through ecosystem services assessments, holds much potential to better incorporate the tenets of ecosystem-based management into coastal and ocean planning by providing targets for linked biodiversity conservation and human welfare outcomes. PMID- 24779579 TI - Excellent antimicrobial properties of silver-loaded mesoporous silica SBA-15. AB - AIMS: To synthesize silver-loaded mesoporous silica SBA-15 (Ag/SBA-15) materials and examine their antimicrobial action and antimicrobial mechanism. METHODS AND RESULTS: Ag/SBA-15 materials were prepared by means of incipient wetness impregnation, impregnation and direct hydrothermal synthesis methods. The antimicrobial activity of Ag/SBA-15 was investigated using Escherichia coli as an indicator bacterium, and the antimicrobial mechanism was explored. The properties and Ag(+) release behaviour of Ag/SBA-15 materials were compared. Experimental results showed that Ag/SBA-15 materials resulted in 7.5 log inactivation of E. coli for only 60 min, which exhibited very high antimicrobial activities at room temperature without using any light or electrical power input. The cell wall and cell membrane were destroyed in the antimicrobial process, leading to leakage of intracellular components. The formation of extracellular reactive oxygen species (ROS) involved in the bactericidal process was confirmed. Production of intracellular ROS was also discovered. CONCLUSIONS: Ag/SBA-15 exhibited high antimicrobial activity against E. coli. This antimicrobial effect was a synergistic action between extracellular ROS and the toxicity of Ag(+) , which induced intracellular ROS production and subsequent cell death. SIGNIFICANCE AND IMPACT OF THE STUDY: This study revealed for the first time the antimicrobial activities and mechanisms of Ag/SBA-15 materials prepared with different methods. PMID- 24779580 TI - Membrane disruption and anti-quorum sensing effects of synergistic interaction between Lavandula angustifolia (lavender oil) in combination with antibiotic against plasmid-conferred multi-drug-resistant Escherichia coli. AB - AIM: The aim of this study was to investigate the mode of action of the lavender essential oil (LV) on antimicrobial activity against multi-drug-resistant Escherichia coli J53 R1 when used singly and in combination with piperacillin. METHOD AND RESULTS: In the time-kill analysis, a complete killing of bacteria was observed based on colony counts within 4 h when LV was combined with piperacillin during exposure at determined FIC concentrations. Analysis of the membrane permeabilizing effects of LV on treated cultures through their stability against sodium dodecyl sulphate revealed that the LV played a role in disrupting the bacterial cell membrane. The finding is further supported by scanning electron microscopy analysis and zeta potential measurement. In addition, reduction in light production expression of E. coli [pSB1075] by the LV showed the presence of potential quorum sensing (QS) inhibitors. CONCLUSIONS: These results indicated that the LV has the potential to reverse bacterial resistance to piperacillin in E. coli J53 R1. It may operate via two mechanisms: alteration of outer membrane permeability and inhibition of bacterial QS. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings offer a novel approach to develop a new option of phytopharmaceuticals against multi-drug-resistant E. coli. PMID- 24779581 TI - Antiviral efficacy and mechanisms of action of oregano essential oil and its primary component carvacrol against murine norovirus. AB - AIMS: To investigate the antiviral efficacy of oregano oil and its primary active component, carvacrol, against the nonenveloped murine norovirus (MNV), a human norovirus surrogate. METHODS AND RESULTS: Along with an observed loss in cell culture infectivity, the antiviral mechanisms of action were determined in side by-side experiments including a cell-binding assay, an RNase I protection assay and transmission electron microscopy (TEM). Both antimicrobials produced statistically significant reductions (P <= 0.05) in virus infectivity within 15 min of exposure (c. 1.0-log10). Despite this, the MNV infectivity remained stable with increasing time exposure to oregano oil (1.07-log10 after 24 h), while carvacrol was far more effective, producing up to 3.87-log10 reductions within 1 h. Based on the RNase I protection assay, both antimicrobials appeared to act directly upon the virus capsid and subsequently the RNA. Under TEM, the capsids enlarged from <=35 nm in diameter to up to 75 nm following treatment with oregano oil and up to 800 nm with carvacrol; with greater expansion, capsid disintegration could be observed. Virus adsorption to host cells did not appear to be affected by either antimicrobial. CONCLUSIONS: Our results demonstrate that carvacrol is effective in inactivating MNV within 1 h of exposure by acting directly on the viral capsid and subsequently the RNA. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides novel findings on the antiviral properties of oregano oil and carvacrol against MNV and demonstrates the potential of carvacrol as a natural food and surface (fomite) sanitizer to control human norovirus. PMID- 24779582 TI - Lactobacillus gasseri K7 modulates the blood cell transcriptome of conventional mice infected with Escherichia coli O157:H7. AB - AIMS: As the immune cells underlying the intestinal barrier sense luminal microbial signals, blood cell transcriptomics may identify subclinical changes triggered by gut bacteria that may otherwise not be detected. We have therefore investigated how Lactobacillus gasseri K7 and enterohemorrhagic Escherichia coli O157:H7 modulate the blood cell transcriptome of mice possessing an intact microbiota. METHODS AND RESULTS: We have analysed the transcriptome of five groups of C57BL/6J mice: (i) control, (ii) inoculated with a single dose of E. coli, (iii) inoculated during 2 weeks with Lact. gasseri, (iv) co-inoculated with E. coli and Lact. gasseri, (v) inoculated with Lact. gasseri prior to E. coli infection. The transcriptome could distinguish between the five treatment groups. Gene characteristics of bacterial infection, in particular inflammation, were upregulated in the mice inoculated with E. coli. Lact. gasseri had only mild effects on the transcriptome but modified the gene expression induced by E. coli. CONCLUSIONS: The transcriptome differentiates mice inoculated orally with E. coli, Lact. gasseri and combinations of these two strains. SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggest that the blood cell transcriptome can be used as a source of biomarkers to monitor the impact of probiotics in subclinical models of infectious disease. PMID- 24779583 TI - Pathogen exclusion properties of canine probiotics are influenced by the growth media and physical treatments simulating industrial processes. AB - AIMS: Manufacturing process used in preparation of probiotic products may alter beneficial properties of probiotics. The effect of different growth media and inactivation methods on the protective properties of canine-originated probiotic bacteria against adhesion of canine enteropathogens was investigated. METHODS AND RESULTS: Three established dog probiotics, Lactobacillus fermentum VET9A, Lactobacillus plantarum VET14A and Lactobacillus rhamnosus VET16A, and their mixture were assessed using the dog mucus pathogen exclusion model. The pathogens used were Enterococcus canis, Salmonella enterica serovar Typhimurium and Clostridium perfringens. The effect of growth media, one reflecting laboratory and the other manufacture conditions, and viability (viable and heat inactivated, 80 degrees C per 30 min) on the pathogen exclusion properties of probiotics were characterized. Greater pathogen exclusion percentages were noted for probiotics growing in conditions reflecting manufacture when compared to laboratory (P < 0.05). Inactivation of probiotics by heat (80 degrees C per 30 min) increased pathogen exclusion compared with their viable forms (P < 0.05). CONCLUSIONS: Manufacturing process conditions such as growth media, incubation temperature and pretreatment methods may significantly affect the protective properties of the tested strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Growing conditions and pretreatment methods should be carefully considered when designing new probiotics to reduce the risk of common infections in dogs. The studied probiotics are promising potential feed additives for dogs. PMID- 24779584 TI - Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals. AB - Neutrophil extracellular traps (NETs) are a recently discovered addition to the defensive armamentarium of neutrophils, assisting in the immune response against rapidly dividing bacteria. Although older adults are more susceptible to such infections, no study has examined whether aging in humans influences NET formation. We report that TNF-alpha-primed neutrophils generate significantly more NETs than unprimed neutrophils and that lipopolysaccharide (LPS)- and interleukin-8 (IL-8)-induced NET formation exhibits a significant age-related decline. NET formation requires generation of reactive oxygen species (ROS), and this was also reduced in neutrophils from older donors identifying a mechanism for reduced NET formation. Expression of IL-8 receptors (CXCR1 and CXCR2) and the LPS receptor TLR4 was similar on neutrophils from young and old subjects, and neutrophils challenged with phorbol-12-myristate-13-acetate (PMA) showed no age associated differences in ROS or NET production. Taken together, these data suggest a defect in proximal signalling underlies the age-related decline in NET and ROS generation. TNF-alpha priming involves signalling through p38 MAP kinase, but activation kinetics were comparable in neutrophils from young and old donors. In a clinical setting, we assessed the capacity of neutrophils from young and older patients with chronic periodontitis to generate NETs in response to PMA and hypochlorous acid (HOCL). Neutrophil extracellular trap generation to HOCL, but not PMA, was lower in older periodontitis patients but not in comparison with age matched controls. Impaired NET formation is thus a novel defect of innate immunity in older adults but does not appear to contribute to the increased incidence of periodontitis in older adults. PMID- 24779585 TI - Polyacrylonitrile-chalcogel hybrid sorbents for radioiodine capture. AB - Powders of a Sn2S3 chalcogen-based aerogel (chalcogel) were combined with powdered polyacrylonitrile (PAN) in different mass ratios (SnS33, SnS50, and SnS70; # = mass% of chalcogel), dissolved in dimethyl sulfoxide, and added dropwise to deionized water to form pellets of a porous PAN-chalcogel hybrid material. These pellets, along with pure powdered (SnSp) and granular (SnSg) forms of the chalcogel, were then used to capture iodine gas under both dynamic (dilute) and static (concentrated) conditions. Both SnSp and SnSg chalcogels showed very high iodine loadings at 67.2 and 68.3 mass%, respectively. The SnS50 hybrid sorbent demonstrated a high, although slightly reduced, maximum iodine loading (53.5 mass%) with greatly improved mechanical rigidity. In all cases, X ray diffraction results showed the formation of crystalline SnI4 and SnI4(S8)2, revealing that the iodine binding in these materials is mainly due to a chemisorption process, although a small amount of physisorption was observed. PMID- 24779586 TI - Toward design of synergistically active carbon-based catalysts for electrocatalytic hydrogen evolution. AB - Replacement of precious Pt catalyst with cost-effective alternatives would be significantly beneficial for hydrogen production via electrocatalytic hydrogen evolution reaction (HER). All candidates thus far are exclusively metallic catalysts, which suffer inherent corrosion and oxidation susceptibility during acidic proton-exchange membrane electrolysis. Herein, based on theoretical predictions, we designed and synthesized nitrogen (N) and phosphorus (P) dual doped graphene as a nonmetallic electrocatalyst for sustainable and efficient hydrogen production. The N and P heteroatoms could coactivate the adjacent C atom in the graphene matrix by affecting its valence orbital energy levels to induce a synergistically enhanced reactivity toward HER. As a result, the dual-doped graphene showed higher electrocatalytic HER activity than single-doped ones and comparable performance to some of the traditional metallic catalysts. PMID- 24779587 TI - Changes in glutamate concentration, glucose metabolism, and cerebral blood flow during focal brain cooling of the epileptogenic cortex in humans. AB - OBJECTIVE: Recently, focal brain cooling (FBC) was proposed as a method for treating refractory epilepsy. However, the precise influence of cooling on the molecular basis of epilepsy has not been elucidated. Thus the aim of this study was to assess the effect of FBC on glutamate (Glu) concentration, cerebral blood flow (CBF), and glucose metabolism in patients with intractable epilepsy. METHODS: Nine patients underwent FBC at 15 degrees C for 30 min prior to cortical resection (n = 6) or hippocampectomy (n = 3). Measurement of metabolites and CBF, as well as electrocorticography (ECoG), was performed. RESULTS: Epileptic discharge (ED), as observed by ECoG, disappeared in the cooling period and reappeared in the rewarming period. Glu concentrations were high during the precooling period and were reduced to 51.2% during the cooling period (p = 0.025). Glycerol levels showed a similar decrease (p = 0.028). Lactate concentration was high during the precooling period and was reduced during the cooling period (21.3% decrease; p = 0.005). Glucose and pyruvate levels were maintained throughout the procedure. Changes in CBF were parallel to those observed by ECoG. SIGNIFICANCE: FBC reduced EDs and concentrations of Glu and glycerol. This demonstrates the neuroprotective effect of FBC. Our findings confirm that FBC is a reasonable and optimal treatment option for patients with intractable epilepsy. PMID- 24779588 TI - Redox-active porous coordination polymers prepared by trinuclear heterometallic pivalate linking with the redox-active nickel(II) complex: synthesis, structure, magnetic and redox properties, and electrocatalytic activity in organic compound dehalogenation in heterogeneous medium. AB - Linking of the trinuclear pivalate fragment Fe2CoO(Piv)6 by the redox-active bridge Ni(L)2 (compound 1; LH is Schiff base from hydrazide of 4 pyridinecarboxylic acid and 2-pyridinecarbaldehyde, Piv(-) = pivalate) led to formation of a new porous coordination polymer (PCP) {Fe2CoO(Piv)6}{Ni(L)2}1.5 (2). X-ray structures of 1 and 2 were determined. A crystal lattice of compound 2 is built from stacked 2D layers; the Ni(L)2 units can be considered as bridges, which bind two Fe2CoO(Piv)6 units. In desolvated form, 2 possesses a porous crystal lattice (SBET = 50 m(2) g(-1), VDR = 0.017 cm(3) g(-1) estimated from N2 sorption at 78 K). At 298 K, 2 absorbed a significant quantity of methanol (up to 0.3 cm(3) g(-1)) and chloroform. Temperature dependence of molar magnetic susceptibility of 2 could be fitted as superposition of chiMT of Fe2CoO(Piv)6 and Ni(L)2 units, possible interactions between them were taken into account using molecular field model. In turn, magnetic properties of the Fe2CoO(Piv)6 unit were fitted using two models, one of which directly took into account a spin-orbit coupling of Co(II), and in the second model the spin-orbit coupling of Co(II) was approximated as zero-field splitting. Electrochemical and electrocatalytic properties of 2 were studied by cyclic voltammetry in suspension and compared with electrochemical and electrocatalytic properties of a soluble analogue 1. A catalytic effect was determined by analysis of the catalytic current dependency on concentrations of the substrate. Compound 1 possessed electrocatalytic activity in organic halide dehalogenation, and such activity was preserved for the Ni(L)2 units, incorporated into the framework of 2. In addition, a new property occurred in the case of 2: the catalytic activity of PCP depended on its sorption capacity with respect to the substrate. In contrast to homogeneous catalysts, usage of solid PCPs may allow selectivity due to porous structure and simplify separation of product. PMID- 24779590 TI - Multiplexing natural orientation: oppositely directed self-assembling peptides. AB - We explore here the possibility that polypeptide chains with directional multiplicity might provide for the control of peptide self-assembly processes. We tested this new possibility using an oppositely directed peptide (ODP) supramolecular system. The ODP could make it possible to form a betaalphabeta motif with antiparallel beta-sheets, which does not exist in nature. Furthermore, the designed ODPs were able to self-assemble into discrete, homogeneous, and structured protein-like controlled nano-objects. ODPs represent a simple but powerful unnatural self-assembling peptide system that can become a basic scaffold for fabricating more complex and elaborate artificial nanostructures. PMID- 24779589 TI - Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening. AB - The lack of effective therapies for bone metastatic prostate cancer (PCa) underscores the need for accurate models of the disease to enable the discovery of new therapeutic targets and to test drug sensitivities of individual tumors. To this end, the patient-derived xenograft (PDX) PCa model using immunocompromised mice was established to model the disease with greater fidelity than is possible with currently employed cell lines grown on tissue culture plastic. However, poorly adherent PDX tumor cells exhibit low viability in standard culture, making it difficult to manipulate these cells for subsequent controlled mechanistic studies. To overcome this challenge, we encapsulated PDX tumor cells within a three-dimensional hyaluronan-based hydrogel and demonstrated that the hydrogel maintains PDX cell viability with continued native androgen receptor expression. Furthermore, a differential sensitivity to docetaxel, a chemotherapeutic drug, was observed as compared to a traditional PCa cell line. These findings underscore the potential impact of this novel 3D PDX PCa model as a diagnostic platform for rapid drug evaluation and ultimately push personalized medicine toward clinical reality. PMID- 24779591 TI - Changes in sleep-wake rhythms, subjective sleep quality and pain among patients undergoing total hip arthroplasty. AB - We evaluated nocturnal sleep-wake rhythms and subjective sleep quality on the first postoperative night compared with the preoperative night in 34 patients who had total hip arthroplasty (mean age: 61.9 years; 82.4% female) under spinal anaesthesia. We also examined secondary factors related to sleep disturbances after surgery. Patients wore an accelerometer (actigraph) during the preoperative period and the first postoperative night to track sleep-wake rhythms. Secondary end-points were postsurgical pain and low back pain. Sleep parameters were measured objectively by actigraphy, and subjective sleep quality was measured by the Oguri-Shirakawa-Azumi Sleep Inventory, Middle-Aged and Aged Version and found to worsen significantly after surgery. Actigram data showed a reduction in actual sleep time from 353.7 +/- 121.2 min preoperatively to 263.8 +/- 104.4 min postoperatively. The data indicate that normalized continuous sleep time is important for patient healing and well-being and that postoperative sleep disturbance is related to low back pain more than to postsurgical pain. PMID- 24779592 TI - The complete mitochondrial genome of Rhinogobio typus (Teleostei, Cyprinidae, Gobioninae). AB - In the present study, the complete mitochondrial genome sequence of Rhinogobio typus (Teleostei, Cyprinidae, Gobioninae) was obtained using a PCR-based method. The total length of the mitochondrial genome is 16,608 bp, including 22 transfer RNA genes, 2 ribosomal RNA genes, 13 protein-coding genes, and a non-coding control region (D-loop), which is similar to that observed in many other reported fishes. The overall-based composition is 31.3% A, 26.6% T, 15.9% G and 26.2% C, with high A + T content (57.9%). These results will provide a useful tool for species identification, evolutionary and population genetic studies of R. typus and its related species. PMID- 24779593 TI - Droplet digital PCR technology promises new applications and research areas. AB - Digital Polymerase Chain Reaction (dPCR) is used to quantify nucleic acids and its applications are in the detection and precise quantification of low-level pathogens, rare genetic sequences, quantification of copy number variants, rare mutations and in relative gene expressions. Here the PCR is performed in large number of reaction chambers or partitions and the reaction is carried out in each partition individually. This separation allows a more reliable collection and sensitive measurement of nucleic acid. Results are calculated by counting amplified target sequence (positive droplets) and the number of partitions in which there is no amplification (negative droplets). The mean number of target sequences was calculated by Poisson Algorithm. Poisson correction compensates the presence of more than one copy of target gene in any droplets. The method provides information with accuracy and precision which is highly reproducible and less susceptible to inhibitors than qPCR. It has been demonstrated in studying variations in gene sequences, such as copy number variants and point mutations, distinguishing differences between expression of nearly identical alleles, assessment of clinically relevant genetic variations and it is routinely used for clonal amplification of samples for NGS methods. dPCR enables more reliable predictors of tumor status and patient prognosis by absolute quantitation using reference normalizations. Rare mitochondrial DNA deletions associated with a range of diseases and disorders as well as aging can be accurately detected with droplet digital PCR. PMID- 24779594 TI - Complete mitochondrial genome of Eumeces elegans (Squamata: Scincidae). AB - Eumeces elegans is a kind of blue-tailed lizard in the genus Eumeces, and widely distributed in southern provinces of China. We sequenced and characterized the complete mitochondrial genome of Eumeces elegans. The total length of the complete mitochondrial genome was 17,304 bp with 13 protein-coding genes, 22 tRNAs, two rRNAs and a control regions. The overall base composition of Eumeces elegans was 31.0% A, 15.0% G, 29.8% C, and 24.2% T. ND6 subunit gene and eight tRNA genes were encoded on the L-stand, and other genes were distributed on the H strand. PMID- 24779595 TI - The complete mitochondrial genome of the bean pod borer, Maruca testulalis (Lepidoptera: Crambidae: Spilomelinae). AB - In this study, the complete mitochondrial genome of Maruca testulalis was determined (GenBank accession number KJ623250). It is 15,110 bp in length, and included 13 PCGs, 2 rRNA gens, 22 tRNA genes, and a A + T-rich region. Its gene order and orientation are identical to other crambid species. The AT-skew and GC skew of the entire mitogenome are negative and the nucleotide composition is biased toward A + T nucleotides (80.6%). All PCGs begin with ATN codons, except for COI which is initiated by CGA. All the 22 tRAN genes can be fold into the typical clover-leaf secondary structure except for tRNA(ser)(AGN). The 335 bp long A + T-rich region is located between srRNA and tRNA(Met) and contains some common features of the other lepidopterans, including the motif ATAGT followed by 14 bp poly-T stretches and a microsatellite-like (AT)11 elements preceded by the ATTTA motif. PMID- 24779596 TI - The complete mitochondrial genome of Hoeven's mullet-goby Hemigobius hoevenii (Bleeker) (Teleostei, Gobiidae). AB - In this study, the complete mitochondrial genome of Hoeven's mullet-goby Hemigobius hoevenii (Bleeker, 1851) collected from Malay Peninsula has been amplified and sequenced. The complete mitochondrial genome is 16,469 base pairs (bp) in total length, had the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding genes, 2 rRNAs, 22 tRNAs, 1 control region (CR) and 1 light-strand replication origin (OL). The overall base composition of H. hoevenii is 27.1% for A, 26.6% for T, 29.0% for C, 17.3% for G, with higher AT content 53.7%. This study will contribute for understanding the phylogenetic approach of Hemigobius species as well as the related genera of gobiid fishes. PMID- 24779597 TI - Complete mitochondrial genome of Ostrea denselamellosa (Bivalvia, Ostreidae). AB - The complete mitochondrial (mt) genome of the flat oyster, Ostrea denselamellosa, was determined using Long-PCR and genome walking techniques in this study. The total length of the mt genome sequence of O. denselamellosa was 16,227 bp, which is the smallest reported Ostreidae mt genome to date. It contained 12 protein coding genes (lacking of ATP8), 23 transfer RNA genes, and two ribosomal RNA genes. A bias towards a higher representation of nucleotides A and T (60.7%) was detected in the mt genome of O. denselamellosa. The rrnL was split into two fragments (3' half, 711 bp; 5' half, 509 bp), which seems to be the unique characteristics of Ostreidae mt genomes. PMID- 24779598 TI - Complete mitochondrial genome of the mulberry white caterpillar Rondotia menciana (Lepidoptera: Bombycidae). AB - The mulberry white caterpillar, Rondotia menciana, belongs to the lepidopteran family Bombycidae, in which the domestic silkworm, Bombyx mori is included. In this study, we describe the complete mitochondrial genome of R. menciana in terms of general genomic features and characteristic features found in the A+T-rich region. The 15,364 bp long genome consisted of a typical set of genes (13 protein coding genes [PCGs], 2 rRNA genes, and 22 tRNA genes) and 1 major non-coding A+T rich region, with the typical arrangement found in Lepidoptera. Twelve of the 13 PCGs started with typical ATN codons, except for the COI, which began with CGA and twelve of 13 PCGs had complete stop codons, except for the COII, which ended with a single T. The 360 bp long A+T-rich region harbored the conserved sequence blocks typically found in lepidopteran insects. Additionally, the A+T-rich region of R. menciana contained one tRNA(Met)-like structure, which had a proper anticodon and secondary structure. PMID- 24779599 TI - The complete mitochondrial genome of the Korean minnow Nipponocypris koreanus (Cypriniformes, Cyprinidae). AB - The complete mitochondrial genome of the Korean minnow Nipponocypris koreanus (Kim et al., 2005) which is endemic to Korean Peninsula has been amplified and sequenced in this study. The complete mitochondrial genome is 16,615 base pairs (bp) in total length, had the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding genes, 2 rRNAs, 22 tRNAs, 1 control region (CR) and 1 light-strand replication origin (OL). The overall base composition of N. koreanus is 30.0% for A, 26.8% for T, 26.1% for C, 17.1% for G, with higher AT content 56.8%. This study will be rather beneficial for understanding the phylogenetic approach of Nipponocypris species and other related genera of cyprinid fishes. PMID- 24779600 TI - The complete mitogenome of Pampus argenteus (Perciformes: Stromateidae). AB - Long PCR and primer walking methods are employed for determining the complete mitochondrial genome sequence of Pampus argenteus. The mitogenome is a circular molecule of 16,544 bp in length including the structure of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 2 non-coding regions (L strand replication origin and control region). Within the control region, we identify the termination-associated sequence domain (TAS), central conserved domain (CSB-F, CSB-E and CSB-D), and three conserved sequence blocks (CSB-1, CSB 2 and CSB-3). PMID- 24779601 TI - The complete mitogenome of the Murray Cod, Maccullochella peelii (Mitchell, 1838) (Teleostei: Percichthyidae). AB - The complete mitochondrial genome of the iconic Australian freshwater fish, the Murray Cod, Maccullochella peelii, was recovered from partial genome sequencing data using the HiSeq platform (Illumina, San Diego, CA). The mitogenome consists of 16,442 bp (58% A + T content) containing 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs, and a 768 bp non-coding AT-rich region. This is the first mitogenome sequence for the genus Maccullochella, and the fourth for the family Percichthyidae. PMID- 24779602 TI - Complete mitochondrial genome of the Mold Mite, Tyrophagus putrescentiae (Acari: Acaridae). AB - In this study, the first complete mitochondrial genome (mitogenome) of the mold mite, Tyrophagus putrescentiae was determined by long PCR and primer walking methods. The mitogenome was 13,288 bp in length, including 13 typical invertebrate protein-coding genes, 18 transfer RNA genes and 2 ribosomal RNA genes. The overall base composition of the heavy strand is 22.5% A, 48.2% T, 13.2% C and 16.1% G, with a A+T bias. Stop codon was incomplete for ND4 gene and ND2. Gene overlaps were observed between 12 pairs of the contiguous genes in T. putrescentiae. The study also displayed that four tRNAs were missed for T. putrescentiae. Researches on mitogenome would further contribute to resolving phylogenetic position and interrelationships of Tyrophagus. PMID- 24779603 TI - Complete mitochondrial genome of Paracanthobrama guichenoti. AB - In this study, we sequenced the complete mitochondrial genome of Paracanthobrama guichenoti. This mitochondrial genome, consisting of 16,607 base pairs, encoded 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and a non-coding control region as those found in other vertebrates, with the gene synteny identical to that of typical vertebrates. Control region (D-Loop), of 932 bp in length, is located between tRNA(Phe) and tRNA(Leu). The overall base composition of the heavy strand shows T 28.4%, C 24.6%, A 31.2% and G 15.7%, with an AT bias of 59.6%. PMID- 24779604 TI - Complete mitochondrial genome of the longfin mako shark, Isurus paucus (Chondrichthyes, Lamnidae). AB - Here we describe the complete mitochondrial genome sequence of the longfin mako, Isurus paucus, which is a pelagic shark found in temperate and tropical waters. The circle genome (16,704 bp) consists of 13 protein coding, 22 tRNA, 2 rRNA genes and 1 control region. It has the typical vertebrate mitochondrial gene arrangement. PMID- 24779605 TI - The complete mitogenome of the whale shark parasitic copepod Pandarus rhincodonicus norman, Newbound & Knott (Crustacea; Siphonostomatoida; Pandaridae) -a new gene order for the copepoda. AB - The complete mitochondrial genome of the parasitic copepod Pandarus rhincodonicus was obtained from a partial genome scan using the HiSeq sequencing system. The Pandarus rhincodonicus mitogenome has 14,480 base pairs (62% A+T content) made up of 12 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs, and a putative 384 bp non-coding AT-rich region. This Pandarus mitogenome sequence is the first for the family Pandaridae, the second for the order Siphonostomatoida and the sixth for the Copepoda. PMID- 24779606 TI - Mitochondrial genome of the longtail butterfly ray Gymnura poecilura (Myliobatiformes: Gymnuridae). AB - The complete mitogenome the longtail butterfly ray (Gymnura poecilura) was first presented in this study. It is 17,874 bp in length, contains 37 genes with the typical gene order and transcriptional direction in vertebrates. The overall base composition is: 28.5% A, 26.5% T, 15.0% G and 30.1% C. There are 26 bp overlaps and 41 bp short intergenic spaces located in 7 and 16 gene junctions, respectively. Two start codons (ATG and GTG) and two stop codons (TAG and TAA/T) were used in protein-coding genes. The origin of L-strand replication (OL) was found between tRNA-Asn and tRNA-Cys genes. The control region has the same A and C contents (28.8%). PMID- 24779607 TI - Ventricular assist devices in heart failure: how to support the heart but prevent atrophy? AB - Ventricular assist devices (VAD) have recently established themselves as an irreplaceable therapeutic modality of terminal heart failure. Because of the worldwide shortage of donors, ventricular assist devices play a key role in modern heart failure therapy. Some clinical data have revealed the possibility of cardiac recovery during VAD application. On the other hand, both clinical and experimental studies indicate the risk of the cardiac atrophy development, especially after prolonged mechanical unloading. Little is known about the specific mechanisms governing the unloading-induced cardiac atrophy and about the exact ultrastructural changes in cardiomyocytes, and even less is known about the ways in which possible therapeutical interventions may affect heart atrophy. One aim of this review was to present important aspects of the development of VAD related cardiac atrophy in humans and we also review the most significant observations linking clinical data and those derived from studies using experimental models. The focus of this article was to review current methods applied to alleviate cardiac atrophy which follows mechanical unloading of the heart. Out of many pharmacological agents studied, only the selective beta2 agonist clenbuterol has been proved to have a significantly beneficial effect on unloading-induced atrophy. Mechanical means of atrophy alleviation also seem to be effective and promising. PMID- 24779608 TI - Pharmacogenetic analysis of captopril effects on blood pressure: possible role of the Ednrb (endothelin receptor type B) candidate gene. AB - The objective of the current study was to search for genetic determinants associated with antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitor captopril. Linkage and correlation analyses of captopril-induced effects on blood pressure (BP) with renal transcriptome were performed in the BXH/HXB recombinant inbred (RI) strains derived from spontaneously hypertensive rat (SHR) and Brown Norway (BN-Lx) progenitors. Variability of blood pressure lowering effects of captopril among RI strains was continuous suggesting a polygenic mode of inheritance. Linkage analysis of captopril-induced BP effects revealed a significant quantitative trait locus (QTL) on chromosome 15. This QTL colocalized with cis regulated expression QTL (eQTL) for the Ednrb (endothelin receptor type B) gene in the kidney (SHR allele was associated with increased renal expression) and renal expression of Ednrb correlated with captopril-induced BP effects. These results suggest that blood pressure lowering effects of ACE inhibitor captopril may be modulated by the variants at the Ednrb locus. PMID- 24779609 TI - The contractile response of isolated small pulmonary arteries induced by activated macrophages. AB - To test whether macrophages can play any role in hypoxic pulmonary vasoconstriction, we tested the in vitro response of rings from small pulmonary arteries to the activation of macrophages by FMLP, a substance stimulating predominantly membrane-bound NADPH oxidase. A small vessel myograph was used to measure the responses of rings from small pulmonary arteries (300-400 microm) isolated from rat lungs. Rings from 5 rats were placed into both chambers of the myograph. The vessels were stabilized for 40 min and then normalized by automatic stretching to a wall tension equivalent to the intravascular pressure 30 mm Hg. At the start of each experiment, vessels were exposed to 80 mM K+ to obtain maximal contractile response, which was used to normalize subsequent contractile responses. 2x10(6) viable macrophages, obtained by peritoneal lavage, were added into one chamber, then 5 microM FMLP was administrated to both chambers and the tension measurement was started. The hydrogen peroxide concentration produced by stimulated macrophages was measured luminometrically. The concentrations of H2O2 in specimens from chambers containing activated macrophages rose from 3.5+/-1.5 nM to 110+/-28 nM within 25 min of stimulation, while FMLP itself didn't increase the H2O2 concentration from the baseline value (4.5+/-3 nM) in samples from control chambers. After FMLP administration, the tension of the vessel rings in the presence of macrophages reached 0.23+/-0.07 of maximal contractile response, it did not change in controls. The addition of ROS scavenger 4-hydroxy-TEMPO blocked the contractile response to the activation of macrophages. We conclude that the activation of macrophages stimulates the contraction of small pulmonary arteries and that this contraction is probably mediated by reactive oxygen species. PMID- 24779610 TI - Shuttle-cargo fusion molecules of transport peptides and the hD2/3 receptor antagonist fallypride: a feasible approach to preserve ligand-receptor binding? AB - To determine if the conjugation of a small receptor ligand to a peptidic carrier to potentially facilitate transport across the blood-brain barrier (BBB) by "molecular Trojan horse" transcytosis is feasible, we synthesized several transport peptide-fallypride fusion molecules as model systems and determined their binding affinities to the hD2 receptor. Although they were affected by conjugation, the binding affinities were found to be still in the nanomolar range (between 1.5 and 64.2 nM). In addition, homology modeling of the receptor and docking studies for the most potent compounds were performed, elucidating the binding modes of the fusion molecules and the structure elements contributing to the observed high receptor binding. Furthermore, no interaction between the hybrid compounds and P-gp, the main excretory transporter of the BBB, was found. From these results, it can be inferred that the approach to deliver small neuroreceptor ligands across the BBB by transport peptide carriers is feasible. PMID- 24779611 TI - Warped functional analysis of variance. AB - This article presents an Analysis of Variance model for functional data that explicitly incorporates phase variability through a time-warping component, allowing for a unified approach to estimation and inference in presence of amplitude and time variability. The focus is on single-random-factor models but the approach can be easily generalized to more complex ANOVA models. The behavior of the estimators is studied by simulation, and an application to the analysis of growth curves of flour beetles is presented. Although the model assumes a smooth latent process behind the observed trajectories, smootheness of the observed data is not required; the method can be applied to irregular time grids, which are common in longitudinal studies. PMID- 24779612 TI - Does the type of creatinine assay affect creatinine clearance determination? AB - BACKGROUND: A creatinine clearance (CrCl) is still often requested to estimate the glomerular filtration rate (GFR) in clinical practice. However, the diversity of serum and urine creatinine (Scr, Ucr) assays leads to different CrCl-results which are here compared with each other and with the CKD-EPI eGFR-formula. METHODS: We collected information on urine volume, Ucr and Scr using Roche's enzymatic (E), compensated Jaffe (CJ) and Jaffe (J) assay for 589 patients. To allow comparison with the CKD-EPI prediction results, CrCl was normalized for body surface area. RESULTS: Differences between CrCl-E and CrCl-CJ are rather small as opposed to the large differences with CrCl-J. However, two compensating errors in the CrCl-J calculation result in a closer agreement with CKD-EPI eGFR, than between CrCl-CJ or CrCl-E and CKD-EPI eGFR. The explained variance R(2) in all three cases is smaller than 0.66, demonstrating the very large scatter of the data around the regression line. CONCLUSIONS: CrCl determination is very assay dependent. Although many clinical labs have switched to ID-GC/MS-standardized assays (E and CJ) for the determination of Scr and Ucr to improve analytical accuracy, the increased deviation of the normalized CrCl from the CKD-EPI prediction illustrates that the use of CrCl remains questionable for clinical practice. When a CrCl is requested, we would even recommend clinical labs who work with compensated Jaffe assays not to compensate the Scr-J value. PMID- 24779613 TI - Fundus autofluorescence imaging in a patient with the juvenile form of galactosialidosis. AB - The authors report the characteristics of fundus autofluorescence (FAF) images in a patient with galactosialidosis who presented with a macular cherry-red spot ophthalmoscopically. The cherry-red spot in the macula was hyperreflective in the FAF images. Optical coherence tomography (OCT) revealed an abnormally hyperreflective region in the retinal ganglion cell layer; however, the boundary between hyperreflective and normal regions was not clear. The findings indicate that FAF may be a more useful method to detect macular lesions than conventional funduscopic examination and OCT imaging in patients with lysosomal storage diseases presenting with a macular cherry-red spot. PMID- 24779614 TI - Individuals receiving specialized treatment for drug and alcohol dependence and gambling disorder in Israel--characteristics and implications for prevalence estimates. AB - BACKGROUND: Substance dependence is one of the main factors contributing to morbidity and mortality worldwide. Gambling disorder has recently been included as an addictive disorder in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) and is associated with substantial psychiatric comorbidity and respective disability. Nevertheless, the vast majority of those suffering from these disorders do not receive treatment. In Israel, prevalence of substance dependence has traditionally been estimated to be lower than those in high-income countries, though prevalence estimates from the recent decade are lacking. Moreover, characteristics of individuals seeking treatment for substance dependence and gambling disorder have not been published. METHODS: In this study, the authors analyzed data from the Israel National Addiction Registry, a computerized database that includes sociodemographic characteristics of all individuals treated in specialized public facilities for substance dependence and gambling disorders in the years 2003-2012. RESULTS: The prevalence of treatment utilization for drug and alcohol dependence and gambling disorders were 0.2%, 0.1%, and 0.01%, respectively. These rates generally remained stable throughout the last decade. Individuals seeking treatment for alcohol dependence were in the lower socioeconomic status (SES) cluster, whereas those seeking treatment for drug dependence were in the midrange SES clusters, findings that are generally in concurrence with characteristics of treatment seekers in high-income countries. CONCLUSIONS: Prevalence estimates based on reports indicating that approximately 10% of individuals with substance dependence seek treatment suggest rates of alcohol dependence in Israel that are substantially higher those previously published, though still lower than most high-income countries. Nationwide epidemiologic studies exploring current rates of substance dependence and gambling disorder in Israel are urgently needed, and treatment options should be planned and funded accordingly. Potential reasons for these apparent low rates of treatment utilization for these disorders in Israel should be explored in order to improve services provided for this population. PMID- 24779615 TI - A rule-based expert system for chemical prioritization using effects-based chemical categories. AB - A rule-based expert system (ES) was developed to predict chemical binding to the estrogen receptor (ER) patterned on the research approaches championed by Gilman Veith to whom this article and journal issue are dedicated. The ERES was built to be mechanistically transparent and meet the needs of a specific application, i.e. predict for all chemicals within two well-defined inventories (industrial chemicals used as pesticide inerts and antimicrobial pesticides). These chemicals all lack structural features associated with high affinity binders and thus any binding should be low affinity. Similar to the high-quality fathead minnow database upon which Veith QSARs were built, the ERES was derived from what has been termed gold standard data, systematically collected in assays optimized to detect even low affinity binding and maximizing confidence in the negatives determinations. The resultant logic-based decision tree ERES, determined to be a robust model, contains seven major nodes with multiple effects-based chemicals categories within each. Predicted results are presented in the context of empirical data within local chemical structural groups facilitating informed decision-making. Even using optimized detection assays, the ERES applied to two inventories of >600 chemicals resulted in only ~5% of the chemicals predicted to bind ER. PMID- 24779616 TI - Effects-based chemical category approach for prioritization of low affinity estrogenic chemicals. AB - Regulatory agencies are charged with addressing the endocrine disrupting potential of large numbers of chemicals for which there is often little or no data on which to make decisions. Prioritizing the chemicals of greatest concern for further screening for potential hazard to humans and wildlife is an initial step in the process. This paper presents the collection of in vitro data using assays optimized to detect low affinity estrogen receptor (ER) binding chemicals and the use of that data to build effects-based chemical categories following QSAR approaches and principles pioneered by Gilman Veith and colleagues for application to environmental regulatory challenges. Effects-based chemical categories were built using these QSAR principles focused on the types of chemicals in the specific regulatory domain of concern, i.e. non-steroidal industrial chemicals, and based upon a mechanistic hypothesis of how these non steroidal chemicals of seemingly dissimilar structure to 17beta-estradiol (E2) could interact with the ER via two distinct binding types. Chemicals were also tested to solubility thereby minimizing false negatives and providing confidence in determination of chemicals as inactive. The high-quality data collected in this manner were used to build an ER expert system for chemical prioritization described in a companion article in this journal. PMID- 24779619 TI - Colour and label evaluation of commercial pasteurised red juices and related drinks. AB - Despite growing demand by consumers for healthy beverages, artificial colours are still widely used. Levels of anthocyanins and artificial colours were determined by HPLC with UV-Vis detection in red orange juices and other red beverages (nectar, juice-based, health, carbonated and sports drinks). The contribution of pigments to the visible colour of the beverage was calculated. Red orange juice samples contained about 34 mg l(-1) of anthocyanins, which were responsible for about 92% of the visible colour. Red juice-based drinks, containing from 0% to 30% of red orange, berry, grape or pomegranate juices, had low levels of anthocyanins (about 7 mg l(-1)) and high levels of E129 (about 32 mg l(-1)), which were responsible for about 90.7% of the colour of these beverages. Red health drinks, enriched with vitamins and polyphenols, contained from 3% to 50% of red fruit juices. Also in this case the E129 levels were higher (about 22 mg l(-1)) than anthocyanins (about 9 mg l(-1)), and were responsible for the colour of the beverages (76.1%). High levels of artificial colours were found in red orange carbonated drinks, but in comparable amounts with those found in the other beverage samples, while anthocyanins were only present in trace amounts. Although all of the beverages claimed to contain red fruits on the labels, no correlation was found between the level of anthocyanins and the declared percentage of red fruits. These labels generally conformed with the requirements of the law, but food product labels can often be misleading to consumers about the real characteristics of the product. PMID- 24779618 TI - Modern technologies for retinal scanning and imaging: an introduction for the biomedical engineer. AB - This review article is meant to help biomedical engineers and nonphysical scientists better understand the principles of, and the main trends in modern scanning and imaging modalities used in ophthalmology. It is intended to ease the communication between physicists, medical doctors and engineers, and hopefully encourage "classical" biomedical engineers to generate new ideas and to initiate projects in an area which has traditionally been dominated by optical physics. Most of the methods involved are applicable to other areas of biomedical optics and optoelectronics, such as microscopic imaging, spectroscopy, spectral imaging, opto-acoustic tomography, fluorescence imaging etc., all of which are with potential biomedical application. Although all described methods are novel and important, the emphasis of this review has been placed on three technologies introduced in the 1990's and still undergoing vigorous development: Confocal Scanning Laser Ophthalmoscopy, Optical Coherence Tomography, and polarization sensitive retinal scanning. PMID- 24779617 TI - Predicting the occurrence of embolic events: an analysis of 1456 episodes of infective endocarditis from the Italian Study on Endocarditis (SEI). AB - BACKGROUND: Embolic events are a major cause of morbidity and mortality in patients with infective endocarditis. We analyzed the database of the prospective cohort study SEI in order to identify factors associated with the occurrence of embolic events and to develop a scoring system for the assessment of the risk of embolism. METHODS: We retrospectively analyzed 1456 episodes of infective endocarditis from the multicenter study SEI. Predictors of embolism were identified. Risk factors identified at multivariate analysis as predictive of embolism in left-sided endocarditis, were used for the development of a risk score: 1 point was assigned to each risk factor (total risk score range: minimum 0 points; maximum 2 points). Three categories were defined by the score: low (0 points), intermediate (1 point), or high risk (2 points); the probability of embolic events per risk category was calculated for each day on treatment (day 0 through day 30). RESULTS: There were 499 episodes of infective endocarditis (34%) that were complicated by >= 1 embolic event. Most embolic events occurred early in the clinical course (first week of therapy: 15.5 episodes per 1000 patient days; second week: 3.7 episodes per 1000 patient days). In the total cohort, the factors associated with the occurrence of embolism at multivariate analysis were prosthetic valve localization (odds ratio, 1.84), right-sided endocarditis (odds ratio, 3.93), Staphylococcus aureus etiology (odds ratio, 2.23) and vegetation size >= 13 mm (odds ratio, 1.86). In left-sided endocarditis, Staphylococcus aureus etiology (odds ratio, 2.1) and vegetation size >= 13 mm (odds ratio, 2.1) were independently associated with embolic events; the 30-day cumulative incidence of embolism varied with risk score category (low risk, 12%; intermediate risk, 25%; high risk, 38%; p < 0.001). CONCLUSIONS: Staphylococcus aureus etiology and vegetation size are associated with an increased risk of embolism. In left-sided endocarditis, a simple scoring system, which combines etiology and vegetation size with time on antimicrobials, might contribute to a better assessment of the risk of embolism, and to a more individualized analysis of indications and contraindications for early surgery. PMID- 24779620 TI - Pilot survey of hen eggs consumed in the metropolitan area of Rio de Janeiro, Brazil, for polyether ionophores, macrolides and lincosamides residues. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, which has recently been developed and validated, was used for the identification and quantification of polyether ionophore, macrolide and lincosamide residues in commercial eggs sold in the metropolitan area of Rio de Janeiro, Brazil. The method was applied to 100 samples and the results showed a high incidence of polyether ionophore residues (25%). Salinomycin was detected in 21% of samples, but only two non-compliant results (5.3 and 53 ug kg(-1)) were found if maximum limits (tolerances) established by European Union were adopted in Brazil and if a method decision limit (CCalpha) of 3.4 ug kg(-1) was considered. In 8% of analyzed samples, more than one studied coccidiostat was found. The lincosamide, lincomycin, and the macrolide, tylosin, were detected at trace levels in 4 and 1% of the samples, respectively. Lasalocid, clarithromycin and erythromycin were not found. PMID- 24779621 TI - Pilot survey of commercial pasteurized milk consumed in the metropolitan area of Rio de Janeiro, Brazil, for tetracyclines residues, including the 4-epimers of oxytetracycline, tetracycline and chlortetracycline. AB - This pilot survey aimed to assess the occurrence of tetracyclines and the 4 epimers of oxytetracycline, tetracycline and chlortetracycline in commercial pasteurized milks sold in the metropolitan area of Rio de Janeiro, Brazil, between October 2009 and March 2010. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, developed and validated in our laboratory, was used. All 100 analyzed samples were compliant, but 14 contained oxytetracycline in concentrations ranging from the method limit of detection (3.7 ug l(-1)) to the method limit of quantification (12.2 ug l(-1)). One sample contained oxytetracycline and tetracycline simultaneously (at a concentration slightly higher than method limit of quantification, 7.0 ug l(-1)). The presence of 4 epioxytetracycline and 4-epitetracycline in contaminated samples with the parent drugs could not be confirmed as traces were detected only in the quantification MRM transition. No other tetracyclines were detected. PMID- 24779622 TI - Survey and risk assessment of trace elements in foods from Taiwan containing red mould rice (Monascus) by ICP-MS. AB - The concentrations of seven trace elements (As, Cd, Cr, Pb, Se, Cu and Zn) in 93 red mould rice (Monascus) food samples in Taipei, Taiwan, were determined by inductively coupled plasma-mass spectrometry (ICP-MS) after wet digestion. The results, calculated in mg kg(-1) (wet weight) for each sample, revealed the general scenario of food safety in Taiwan: As (0.005-12.04), Cd (<0.0005-2.22), Cr (0.014-6.95), Cu (0.012-8.70), Pb (0.001-0.64), Se (<0.001-1.29) and Zn (0.020 67.02). Three food samples were identified with As concentrations higher than regulatory limits: a dietary supplement sample and a seaweed sample with As concentrations that exceeded the limit of Taiwan's health food standard of 2 mg kg(-1), and a canned eel sample with an As concentration that exceeded the limit of Canada's fish standard of 3.5 mg kg(-1). This study suggests that the estimated intakes of these seven trace elements from the consumption of foods containing Monascus pose little risk, as the trace element contents in the majority of samples were lower than the permissible/tolerable intakes per week according to the guidelines recommended by the Food and Agricultural Organization/World Health Organization (FAO/WHO). Moreover, their concentrations in foods containing Monascus differ widely for different food varieties, suggesting that external contaminants and raw materials are the main sources of trace elements. This study shows that ICP-MS is a simple method proposed for the determination of As, Cd, Cr, Pb, Se, Cu, and Zn in foods containing Monascus. PMID- 24779623 TI - Estimation of methylmercury intake from the 2007 Chinese Total Diet Study. AB - Methylmercury intake for adult males of twelve provinces in China was estimated by means of the 2007 Chinese Total Diet Study. Methylmercury levels were measured in twelve food groups of each province of four regions and was only found in the aquatic food groups. The range for methylmercury contents of aquatic foods was 3.29-31.60 ug kg(-1), being 50-87% of total mercury. Methylmercury intakes from aquatic foods for adult males of twelve provinces ranged from 0.003 to 0.138 ug kg(-1) bw week(-1) with average of 0.041 ug kg(-1) bw week(-1), which were estimated according to methylmercury contents and corresponding aquatic food consumption. Methylmercury intakes for the Chinese population were far below the corresponding provisional tolerable weekly intake (PTWI), which was established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Consequently, there was little health risk from methylmercury exposure for the average Chinese population. PMID- 24779624 TI - Elemental composition of commercial sea cucumbers (holothurians). AB - Toxic and essential elements in 11 different sea cucumber species were determined and compared with daily intake recommendations and maximum allowed levels. The contents of macro-elements contents in dried sea cucumber samples were found to be 25,000-152,000 mg kg(-1) for Na, 4000-8600 mg kg(-1) for Mg, 1100-5200 mg kg( 1) for K, 15,000-68,000 mg kg(-1) and 36,300-251,000 mg kg(-1) for Cl. Trace element concentrations in dried sea cucumber samples were found to be 11-100 mg kg(-1) for Zn, 41-660 mg kg(-1) for Fe, 3-74 mg kg(-1) for Cu, 1.1-16 mg kg(-1) for Mn, 1.4-3.7 mg kg(-1) for Se, 1.1-9.6 mg kg(-1) for Cr, and 0.3-5.1 mg kg(-1) for Ni. All sea cucumber species were rich sources of Na, Cl, Mg, Ca, Fe, Cu, Se and Cr for human consumption. Regarding contaminants, As, Cd and Pb concentrations in dried sea cucumbers were in the ranges of 1.1-6.1, 0.03-0.06 and 0.11-0.69 mg kg(-1), respectively. Moreover, Hg values of 11 sea cucumbers were below the detection limit (0.01 mg kg(-1)). PMID- 24779625 TI - Survey of 13 trace elements of toxic and nutritional significance in rice from Brazil and exposure assessment. AB - Twenty-seven rice samples from Brazil, four parboiled brown, seventeen white and six parboiled white were analysed by ICP-MS for trace element determination. Concentrations of arsenic varied from 58.8 to 216.9 ng g(-1), for cadmium from 6.0 to 20.2 ng g(-1), for antimony from 0.12 to 1.28 ng g(-1), and for uranium from 0.025 to 1.28 ng g(-1). The estimated daily intake through rice consumption was 9.5 ug for As, 2.4 ug for Cd, 0.029 ug for Sb, 0.013 ug for U, 3.1 ug for Co, 0.2 ug for Cu, 85.6 mg for Mg, 1.9 mg for Mn, 333 mg for P, 3.0 ug for Se, 1.6 mg for Zn, 0.9 mg for Rb, and 0.3 ug for V. Found values represent a considerable percentage of the dietary reference intakes and provisional tolerable daily intake for essential and toxic elements, respectively. PMID- 24779626 TI - Survey of aflatoxins in rice from Iran using immunoaffinity column clean-up and HPLC with fluorescence detection. AB - A study was undertaken to determine levels of aflatoxins in rice. A total of 261 rice samples were analyzed by HPLC using a method was based on the extraction of 50 g of finely ground rice plus 5 g NaCl with 200 ml of 80% methanol. After filtration and immunoaffinity clean-up, 20 ul was injected onto the HPLC. HPLC analysis was carried out using a Genesis RP C18 column (250 * 4.6, 4 um I.D.) and a mobile phase with a linear gradient of water/methanol/acetonitrile (6 : 2 : 2 v/v) over 16 min. Aflatoxins were determined after post-column derivatisation with iodine by fluorescence detection at excitation and emission wavelengths of 365 and 445 nm, respectively. It was found that 68.9% of the rice samples contained aflatoxin B1 at levels greater than 0.2 ng g(-1). PMID- 24779627 TI - Survey of aflatoxins in chillies from Pakistan produced in rural, semi-rural and urban environments. AB - Chilli peppers from Pakistan are consumed locally and also exported. Their quality is compromised by aflatoxins (AF) contamination. AF in chillies from rural, semi-rural and urban areas of the Punjab region of Pakistan were determined. Twenty-three (52.3%), 22 (50%) and 29 (65.9%) samples from rural, semi-rural and urban areas respectively, contained levels of aflatoxins which exceeded the European Union limits of >5 ug kg(-1) for AFB1 and >10 ug kg(-1) for total AF that apply to spices. Mean values for AFB1 in ground samples were 23.8, 14.8 and 14.0 ug kg(-1) for rural, semi-rural and urban areas, respectively. Mean total AF in ground samples were 27.7, 17.7 and 16.2 ug kg(-1) from equivalent locations. Eleven (50%), 12 (54.5%) and 14 (63.6%) whole samples from rural, semi rural and urban areas, respectively, contained total levels of AF that exceeded European Union limits. The data indicate that individual localities have particular problems. In conclusion, the concentrations were often greater than the statutory limits set by the European Union. PMID- 24779628 TI - Aflatoxin levels and exposure assessment of Spanish infant cereals. AB - Aflatoxins (AFB1, AFB2, AFG1 and AFG2) are immunosuppressant, mutagenic, teratogenic and carcinogenic agents with a widespread presence in foodstuffs. Since human exposure to aflatoxins occurs primarily by contaminated food intake, and given the greater susceptibility of infants to their adverse effects, the quantification of these mycotoxins in infant food based on cereals is of relevance. Aflatoxin levels were determined in 91 Spanish infant cereals classified in terms of non- and organically produced and several types from 10 different manufacturers, using a extraction procedure followed by inmunoaffinity column clean-up step and HPLC with fluorescence detection (FLD) and post-column derivatisation (Kobra Cell system). Daily aflatoxin intake was also assessed. Preliminary analysis showed a valuable incidence of detected infant cereal samples at an upper concentration level than the detection limit for total aflatoxin (66%), corresponding to a 46, 40, 34 and 11% for AFB1, AFB2, AFG1 and AFG2, respectively. Lower aflatoxin values (median, Q1, Q3) in conventional infant cereal (n = 74, AFB1: =10, p < 0.001). However, there was no significant correlation between LDH levels and severities of pectus excavatum. The symmetric subgroup had significantly higher LDH level than the asymmetric subgroup (p < 0.001) and there was a significant decrease of LDH level after correction of deformity (p = 0.017). CONCLUSION: In conclusion, only LDH, one of the routine laboratory tests, was significantly elevated than normal value, which was thought to be caused by etiologies of pectus excavatum and the compression of the internal organs. Further studies on LDH including isoenzyme studies in patients with pectus excavatum will be needed, and these studies will provide a deeper and wider comprehension of pectus excavatum. PMID- 24779632 TI - Two samples for blood transfusion: single centre experience. AB - OBJECTIVES: The aim of this study was to evaluate the introduction of two-sample policy for transfusion at our hospital and reduction of the risk of ABO incompatible transfusion. BACKGROUND: ABO incompatible transfusion can be a fatal but avoidable event. Wrong blood in tube is a cause of ABO incompatible transfusion and there are various strategies available to try and expunge this event. METHODS: Survey of policy/practice before and after the introduction of a two-sample policy. RESULTS: Staff training is inadequate in reducing the risk of ABO incompatible transfusion. A two-sample policy was introduced and does not significantly increase workload or use of group O blood and does not compromise patient safety by causing delay in blood provision. Post hoc analysis confirms good understanding of the policy by medical staff. Observation of medical staff taking transfusion samples demonstrated consistent deviation from policy, enforcing the need for confirmatory samples. CONCLUSION: A two-sample policy adds an extra layer of safety to transfusion practice and can be introduced without creating new problems. PMID- 24779633 TI - Aromaticity from the viewpoint of molecular geometry: application to planar systems. PMID- 24779634 TI - Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation. AB - We detail the phenotype of a novel form of neuronal ceroid lipofuscinosis due to a homozygous progranulin gene mutation (c.813_816del; CLN11 MIM #614706). The symptoms appeared in two young adult siblings, and included progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction. Long-lasting episodes of palinopsia were a recurring symptom and associated with polyphasic visual-evoked potential waveform that suggested hyperexcitability of the occipital cortex. Electroencephalography showed rare spike-wave paroxysms, and magnetic resonance imaging revealed selective cerebellar atrophy. Skin biopsy revealed fingerprint storage and the absence of progranulin protein. Electron microscopy of peripheral blood leukocytes showed fingerprint profiles in 1/100 lymphocytes. These findings define a novel phenotype and provide clues for better understanding of progranulin function. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24779635 TI - Digital memory versatility of fully pi-conjugated donor-acceptor hybrid polymers. AB - The fully pi-conjugated donor-acceptor hybrid polymers Fl-TPA, Fl-TPA-TCNE, and Fl-TPA-TCNQ, which are composed of fluorene (Fl), triphenylamine (TPA), dimethylphenylamine, alkyne, alkyne-tetracyanoethylene (TCNE) adduct, and alkyne 7,7,8,8-tetracyanoquinodimethane (TCNQ) adduct, were synthesized. These polymers are completely amorphous in the solid film state and thermally stable up to 291 409 degrees C. Their molecular orbital levels and band gaps vary with their compositions. The TCNE and TCNQ units, despite their electron-acceptor characteristics, were found to enhance the pi-conjugation lengths of Fl-TPA-TCNE and Fl-TPA-TCNQ (i.e., to produce red shifts in their absorption spectra and significant reductions in their band gaps). These changes are reflected in the electrical digital memory behavior of the polymers. Moreover, the TCNE and TCNQ units were found to diversify the digital memory modes and to widen the active polymer layer thickness window. In devices with aluminum top and bottom electrodes, the Fl-TPA polymer exhibits stable unipolar permanent memory behavior with high reliability. The Fl-TPA-TCNE and Fl-TPA-TCNQ devices exhibit stable unipolar permanent memory behavior as well as dynamic random access memory behavior with excellent reliability. These polymer devices were found to operate by either hole injection or hole injection along with electron injection, depending on the polymer composition. Overall, this study demonstrated that the incorporation of pi-conjugated cyano moieties, which control both the pi conjugation length and electron-accepting power, is a sound approach for the design and synthesis of high-performance digital memory polymers. The TCNE and TCNQ polymers synthesized in this study are highly suitable active materials for the low-cost mass production of high-performance, polarity-free, programmable, volatile, and permanent memory devices that can be operated with very low power consumption, high ON/OFF current ratios, and high reliability. PMID- 24779636 TI - Assessing multiregion avian benefits from strategically targeted agricultural buffers. AB - Mounting evidence of wildlife population gains from targeted conservation practices has prompted the need to develop and evaluate practices that are integrated into production agriculture systems and targeted toward specific habitat objectives. However, effectiveness of targeted conservation actions across broader landscapes is poorly understood. We evaluated multiregion, multispecies avian densities on row-crop fields with native grass field margins (i.e., buffers) as part of the first U.S. agricultural conservation practice designed to support habitat and population recovery objectives of a national wildlife conservation initiative. We coordinated breeding season point transect surveys for 6 grassland bird species on 1151 row-crop fields with and without native grass buffers (9-37 m) in 14 U.S. states (10 ecoregions) from 2006 to 2011. In most regions, breeding season densities of 5 of 6 targeted bird species were greater in the 500-m surrounding survey points centered on fields with native grass buffers than in landscapes without buffers. Relative effect sizes were greatest for Northern Bobwhite (Colinus virginianus), Dickcissel (Spiza americana), and Field Sparrow (Spizella pusilla) in the Mississippi Alluvial Valley and Eastern Tallgrass Prairie regions. Other species (e.g., Eastern Meadowlark [Sturnella magna], Grasshopper Sparrow [Ammodramus savannarum]) exhibited inconsistent relative effect sizes. Bird densities on fields with and without buffers were greatest in the Central Mixed-grass Prairie region. Our results suggest that strategic use of conservation buffers in regions with the greatest potential for relative density increases in target species will elicit greater range-wide population response than diffuse, uninformed, and broadly distributed implementation of buffers. We recommend integrating multiple conservation practices in broader agricultural landscapes to maximize conservation effectiveness for a larger suite of species. PMID- 24779638 TI - Curiosities in drug metabolism. AB - 1. It is inevitable that during some xenobiotic biotransformation studies, a certain metabolite or degradation product arises of which the identity is uncertain, the route of formation is ambiguous, or it is just a plain mystery. 2. The following communication draws attention to three drugs reported in the literature, chlorphentermine, phenothiazine and aminopyrine, where after many years of investigation there still exists uncertainty over some of their metabolites. Noticeably, these three examples probably involve (potential) interaction of a nitrogen centre within the drug molecule. 3. It is hoped that the resurrection and assemblage of these data will offer interesting reading and that these examples may prove sufficiently intriguing to motivate further exploration and some resolution of these lingering concerns. PMID- 24779637 TI - Versatile RNA interference nanoplatform for systemic delivery of RNAs. AB - Development of nontoxic, tumor-targetable, and potent in vivo RNA delivery systems remains an arduous challenge for clinical application of RNAi therapeutics. Herein, we report a versatile RNAi nanoplatform based on tumor targeted and pH-responsive nanoformulas (NFs). The NF was engineered by combination of an artificial RNA receptor, Zn(II)-DPA, with a tumor-targetable and drug-loadable hyaluronic acid nanoparticle, which was further modified with a calcium phosphate (CaP) coating by in situ mineralization. The NF can encapsulate small-molecule drugs within its hydrophobic inner core and strongly secure various RNA molecules (siRNAs, miRNAs, and oligonucleotides) by utilizing Zn(II) DPA and a robust CaP coating. We substantiated the versatility of the RNAi nanoplatform by demonstrating effective delivery of siRNA and miRNA for gene silencing or miRNA replacement into different human types of cancer cells in vitro and into tumor-bearing mice in vivo by intravenous administration. The therapeutic potential of NFs coloaded with an anticancer drug doxorubicin (Dox) and multidrug resistance 1 gene target siRNA (siMDR) was also demonstrated in this study. NFs loaded with Dox and siMDR could successfully sensitize drug resistant OVCAR8/ADR cells to Dox and suppress OVCAR8/ADR tumor cell proliferation in vitro and tumor growth in vivo. This gene/drug delivery system appears to be a highly effective nonviral method to deliver chemo- and RNAi therapeutics into host cells. PMID- 24779639 TI - Modulatory effects of extracts of vinegar-baked Radix Bupleuri and saikosaponins on the activity of cytochrome P450 enzymes in vitro. AB - 1. In this article, the modulatory effects of extracts from vinegar-baked Radix Bupleuri (VBRB) and saikosaponins on the activity of CYP1A2, CYP2C9 and CYP3A4 were investigated in vitro. 2. Microsomal in vitro incubation method was utilized to simulate metabolic reaction under physiological environment by incubating the marker with liver microsomes in the absence or presence of VBRB and saikosaponins. The contents of 4-acetamidophenol, 6beta-hydroxyltestosterone and 4-hydroxydiclofenac, the metabolites of phenacetin, testosterone and diclofenac, which were selected as specific probe drugs of CYP1A2, CYP2C9 and CYP3A4, respectively, were analyzed by high-performance liquid chromatography. 3. The production of the metabolites was incubation time dependent. The modulatory effects of different VBRB extracts and saikosaponins on CYP isoforms increased with concentration. Among all the extracts studied, BC1 has a strong inhibition effect compared to the three CYP isoforms tested, while the others have only significant inhibition on the activity of CYP2C9. 4. This in vitro study demonstrated that various extracts of VBRB tested in this study have negligible potential to interfere with CYP1A2- and CYP3A4-metabolized drugs; risk of herb drug interaction might occur when VBRB is concurrently taken with CYP2C9 substrates. PMID- 24779640 TI - Identifying genetic loci controlling neonatal passive transfer of immunity using a hybrid genotyping strategy. AB - Colostrum intake is critical to a piglet's survival and can be measured by precipitating out the gamma-immunoglobulins from serum with ammonium sulfate (immunocrit). Genetic analysis of immunocrits on 5312 piglets indicated that the heritabilities (se) for direct and maternal effects were 0.13 (0.06) and 0.53 (0.08) respectively. To identify QTL for direct genetic effects, piglets with the highest and lowest immunocrits from 470 litters were selected. Six sets of DNA pools were created based on sire of the litter. These 12 DNA pools were applied to Illumina Porcine SNP60 BeadChips. Normalized X and Y values were analyzed. Three different SNP selection methods were used: deviation of the mean from high vs. low pools, the deviation adjusted for variance based on binomial theory and ANOVA. The 25 highest ranking SNPs were selected from each evaluation for further study along with 12 regions selected based on a five-SNP window approach. Selected SNPs were individually genotyped in the 988 piglets included in pools as well as in 524 piglets that had intermediate immunocrits. Association analyses were conducted fitting an animal model using the estimated genetic parameters. Nineteen SNPs were nominally associated (P < 0.01) with immunocrit values, of which nine remained significant (P < 0.05) after Bonferroni correction, located in 16 genomic regions on 13 chromosomes. In conclusion, the pooling strategy reduced the cost to scan the genome by more than 80% and identified genomic regions associated with a piglet's ability to acquire gamma-immunoglobulin from colostrum. Each method to rank SNPs from the pooled analyses contributed unique validated markers, suggesting that multiple analyses will reveal more QTL than a single analysis. PMID- 24779641 TI - Enantioselective inclusion of alcohols by solvent-controlled assembled flexible metal-organic frameworks. AB - Through judicious choice of the ligands and patient regulation of the solvent conditions, three unique chiral coordination polymeric isomers have been synthesized. Their structures, gas adsorption, and structural interconversion have been studied. One of the isomers displays dynamic behavior, and its use in the enantioselective separation of chiral alcohols has also been reported. PMID- 24779642 TI - Nanometer-resolved radio-frequency absorption and heating in biomembrane hydration layers. AB - Radio-frequency (RF) electromagnetic fields are readily absorbed in biological matter and lead to dielectric heating. To understand how RF radiation interacts with macromolecular structures and possibly influences biological function, a quantitative description of dielectric absorption and heating at nanometer resolution beyond the usual effective medium approach is crucial. We report an exemplary multiscale theoretical study for biomembranes that combines (i) atomistic simulations for the spatially resolved absorption spectrum at a single planar DPPC lipid bilayer immersed in water, (ii) calculation of the electric field distribution in planar and spherical cell models, and (iii) prediction of the nanometer resolved temperature profiles under steady RF radiation. Our atomistic simulations show that the only 2 nm thick lipid hydration layer strongly absorbs in a wide RF range between 10 MHz and 100 GHz. The absorption strength, however, strongly depends on the direction of the incident wave. This requires modeling of the electric field distribution using tensorial dielectric spectral functions. For a spherical cell model, we find a strongly enhanced RF absorption on an equatorial ring, which gives rise to temperature gradients inside a single cell under radiation. Although absolute temperature elevation is small under conditions of typical telecommunication usage, our study points to hitherto neglected temperature gradient effects and allows thermal RF effects to be predicted on an atomistically resolved level. In addition to a refined physiological risk assessment of RF fields, technological applications for controlling temperature profiles in nanodevices are possible. PMID- 24779643 TI - Streptomyces-induced resistance against oak powdery mildew involves host plant responses in defense, photosynthesis, and secondary metabolism pathways. AB - Rhizobacteria are known to induce defense responses in plants without causing disease symptoms, resulting in increased resistance to plant pathogens. This study investigated how Streptomyces sp. strain AcH 505 suppressed oak powdery mildew infection in pedunculate oak, by analyzing RNA-Seq data from singly- and co-inoculated oaks. We found that this Streptomyces strain elicited a systemic defense response in oak that was, in part, enhanced upon pathogen challenge. In addition to induction of the jasmonic acid/ethylene-dependent pathway, the RNA Seq data suggests the participation of the salicylic acid-dependent pathway. Transcripts related to tryptophan, phenylalanine, and phenylpropanoid biosynthesis were enriched and phenylalanine ammonia lyase activity increased, indicating that priming by Streptomyces spp. in pedunculate oak shares some determinants with the Pseudomonas-Arabidopsis system. Photosynthesis-related transcripts were depleted in response to powdery mildew infection, but AcH 505 alleviated this inhibition, which suggested there is a fitness benefit for primed plants upon pathogen challenge. This study offers novel insights into the mechanisms of priming by actinobacteria and highlights their capacity to activate plant defense responses in the absence of pathogen challenge. PMID- 24779644 TI - Muchimangins G-J, fully substituted xanthones with a diphenylmethyl substituent, from Securidaca longepedunculata. AB - Four highly oxygenated xanthones, muchimangins G-J (1-4), have been isolated from the roots of Securidaca longepedunculata collected in Democratic Republic of Congo. Their structures were elucidated by analyses of spectroscopic data to be fully substituted xanthones with a diphenylmethyl substituent at C-2. PMID- 24779645 TI - Characterization of the spectrum of Korean inflammatory demyelinating diseases according to the diagnostic criteria and AQP4-Ab status. AB - BACKGROUND: The relative frequencies of demyelinating diseases among Korean patients with idiopathic inflammatory demyelinating disease of the central nervous system (IIDD) have not been sufficiently studied. We therefore describe a cohort of 203 patients with IIDD from three centers in Korea whose syndromes were identified precisely according to international clinical criteria and autoantibody to aquaporin 4 (AQP4-Ab) status. METHODS: In total, 260 consecutive patients were screened and 203 were included from three hospitals in Korea. All were tested for AQP4-Ab by using a cell-based assay. Patients who met the criteria for definite neuromyelitis optica (NMO) or had a positive AQP4-Ab test result were defined as the NMO group. Among the others, patients were assessed if they had acute disseminated encephalomyelitis, multiple sclerosis (MS), acute transverse myelitis, optic neuritis, or other demyelinating disease as a clinically isolated syndrome of the brain. RESULTS: Eighteen percent of patients were classified as the NMO group, 2% as acute disseminated encephalomyelitis, 18% as MS, 41% as acute transverse myelitis, 11% as optic neuritis, and 8% as other clinically isolated syndrome of the brain. AQP4-Ab was positive in 18% of patients and the relative frequency of NMO to MS (NMO/MS ratio) was 1.06. The mean duration of follow up in our patients was 64 months. CONCLUSIONS: Among Korean patients with idiopathic inflammatory demyelinating diseases, the incidence of NMO may be similar to that of MS, and the overall positivity of AQP4 Ab could be lower than previously reported. In addition, acute transverse myelitis that is not associated with MS or NMO can be relatively common in these patients. Further population-based studies with AQP4-Ab are needed to determine the exact incidence of NMO and other idiopathic inflammatory demyelinating diseases in Korea. PMID- 24779646 TI - Role of parathyroid hormone estimation in needle washing of parathyroid aspiration biopsy in localising 99mTc-sestamibi-negative primary hyperparathyroidism: a series of seventeen patients: Our experience. PMID- 24779648 TI - An electrophysiological investigation of discourse coherence in healthy adults. AB - This study used event-related potentials (ERPs) to investigate discourse coherence processing. Because there are scant data on ERP indices of discourse coherence in typical adults, it is important to study a non-clinical population before examining clinical populations. Twelve adults listened to a story with sentences in a coherent versus incoherent order. Sequences of nonsense syllables served as a control. ERPs in the 200-400 ms time window, reflecting phonological and lexical processing, and in the 600-900 ms time window, reflecting later discourse processing for integration, were investigated. Results revealed a right anterior and posterior positivity that was greater for coherent than for incoherent discourse during the 600-900 ms time window. These findings point to an index of discourse coherence and further suggest that ERPs can be used as a clinical tool to study discourse-processing disorders in populations with brain damage, such as aphasia and traumatic brain injury. PMID- 24779647 TI - Redox potential ultrasensitive nanoparticle for the targeted delivery of camptothecin to HER2-positive cancer cells. AB - Ideal "smart" nanoparticles for drug delivery should enhance therapeutic efficacy without introducing side effects. To achieve that, we developed a drug delivery system (HCN) based on a polymer-drug conjugate of poly[2-(pyridin-2 yldisulfanyl)]-graft-poly(ethylene glycol) and camptothecin with an intracellularly cleavable linker and human epidermal growth factor receptor 2 (HER2) targeting ligands. An in vitro drug release study found that HCN was stable in the physiological environment and supersensitive to the stimulus of elevated intracellular redox potential, releasing all payloads in less than 30 min. Furthermore, confocal microscopy revealed that HCN could specifically enter HER2-positive cancer cells. As a consequence, HCN could effectively kill HER2 positive cancer cells while not affecting HER2-negative cells. PMID- 24779649 TI - Developing with ring 14 syndrome: a survey in different countries. AB - This study aimed to assess the communicative skills of children and young adults with ring 14 syndrome and linear 14q deletions, investigating the relationships among their language development and their genetic, clinical, psychomotor and behavioural characteristics. Participants were 36 individuals with chromosome 14 aberrations whose parents completed a questionnaire, specifically developed in five languages, to assess their son's/daughter's development. Data analysis showed that chronological age does not account for the high individual variability found in the participants' skills. The comparison between participants with ring 14 syndrome and participants with 14q linear deletions showed that the former were characterised by a higher occurrence of epilepsy, abnormalities of the retina and autism. The participants with smaller amounts of deleted genetic material were those who had a higher level of language development. Because ring 14 syndrome is a rare genetic disease, the collection of data from a large group of individuals could be helpful to create expectations about the possible developmental outcomes of these children. PMID- 24779650 TI - Aripiprazole in difficult-to-treat delusional disorder with co-morbid epilepsy. PMID- 24779651 TI - Screening and selection of peptides specific for esophageal cancer cells from a phage display peptide library. AB - BACKGROUND: Esophageal cancer is a common malignant tumor of the gastrointestinal tract and is typically diagnosed at an advanced stage due to the absence of early clinical symptoms. Although surgery, chemotherapy, and radiotherapy represent the major treatment methods employed for this cancer, the prognosis of esophageal cancer remains poor. METHODS: A Ph.D.-12TM Phage Display Peptide Library was screened using an esophageal cancer cell line, Eca109, and a normal esophageal epithelial cell line to identify novel ligands that selectively bind the surface of esophageal cancer cells with high affinity. RESULTS: Two polypeptides were isolated that exhibited higher binding affinities and specificity for the Eca109 cells. These peptides were further validated using enzyme-linked immunosorbent assays (ELISAs), immunofluorescence assays, and immunohistochemistry assays. CONCLUSION: Two polypeptides with high binding affinities to esophageal cancer cells were isolated from the Ph.D.-12 Phage Display Peptide Library. Further studies are needed to characterize the biological effects of these polypeptides and to explore the potential for these peptides to be used for the early screening of esophageal cancer or for cell-targeted therapies that would reduce the toxic side effects of cancer treatment. PMID- 24779652 TI - Nighttime cross-coverage is associated with decreased intensive care unit mortality. A single-center study. AB - RATIONALE: Cross-coverage is associated with medical errors caused by miscommunication during handoffs. However, no direct evidence links handoffs to outcomes, or explains the mechanisms leading to outcomes. Furthermore, the previous literature may overestimate the impact of handoffs because of hindsight bias. OBJECTIVES: To explore the effects of nighttime cross-coverage on mortality and decision making in critically ill patients. METHODS: Observational cohort of 629 consecutive critically ill admissions, admitted for at least 48 hours, and critical care fellows in an academic hospital. MEASUREMENTS AND MAIN RESULTS: Intensive care unit (ICU) mortality and nighttime decisions. Our exposure variable was cross-covering status of fellows. We observed a decrease in ICU mortality (odds ratio, 0.77 per 1 d; 0.60-0.99; P = 0.04), a higher number of nighttime decisions (19.3 vs. 10.4%; odds ratio, 2.02; 95% confidence interval [CI], 1.03-3.95; P = 0.04), an increase in fentanyl equivalents administered to patients at night (difference, +10.2 MUg/h; 95% CI, +1.4 to +19.0; P = 0.02), and an increase in transfusions at night (difference, +465 ml; 95% CI, +98 to +832; P = 0.01) when fellows were cross-covering. CONCLUSIONS: In this single-center study exposure to cross-covering fellows was associated with a decrease in ICU mortality and with more nighttime decisions. Our findings contradict the dominant hypothesis that cross-coverage is associated with worse outcomes, and suggest that a "second look" by cross-covering fellows may mitigate cognitive errors. Future interventions to improve patient safety in ICUs should focus both on the quality of handoffs and on strategies to decrease cognitive errors. PMID- 24779653 TI - Lessons from sexual and reproductive health voucher program design and function: a comprehensive review. AB - BACKGROUND: Developing countries face challenges in financing healthcare; often the poor do not receive the most basic services. The past decade has seen a sharp increase in the number of voucher programs, which target output-based subsidies for specific services to poor and underserved groups. The dearth of literature that examines lessons learned risks the wheel being endlessly reinvented. This paper examines commonalities and differences in voucher design and implementation, highlighting lessons learned for the design of new voucher programmes. METHODOLOGY: The methodology comprised: discussion among key experts to develop inclusion/exclusion criteria; up-dating the literature database used by the DFID systematic review of voucher programs; and networking with key contacts to identify new programs and obtain additional program documents. We identified 40 programs for review and extracted a dataset of more than 120 program characteristics for detailed analysis. RESULTS: All programs aimed to increase utilisation of healthcare, particularly maternal health services, overwhelmingly among low-income populations. The majority contract(ed) private providers, or public and private providers, and all facilitate(d) access to services that are well defined, time-limited and reflect the country's stated health priorities. All voucher programs incorporate a governing body, management agency, contracted providers and target population, and all share the same incentive structure: the transfer of subsidies from consumers to service providers, resulting in a strong effect on both consumer and provider behaviour. Vouchers deliver subsidies to individuals, who in the absence of the subsidy would likely not have sought care, and in all programs a positive behavioural response is observed, with providers investing voucher revenue to attract more clients. A large majority of programs studied used targeting mechanisms. CONCLUSIONS: While many programs remain too small to address national-level need among the poor, large programs are being developed at a rate of one every two years, with further programs in the pipeline. The importance of addressing inequalities in access to basic services is recognized as an important component in the drive to achieve universal health coverage; vouchers are increasingly acknowledged as a promising targeting mechanism in this context, particularly where social health insurance is not yet feasible. PMID- 24779654 TI - Estimating peer effects in longitudinal dyadic data using instrumental variables. AB - The identification of causal peer effects (also known as social contagion or induction) from observational data in social networks is challenged by two distinct sources of bias: latent homophily and unobserved confounding. In this paper, we investigate how causal peer effects of traits and behaviors can be identified using genes (or other structurally isomorphic variables) as instrumental variables (IV) in a large set of data generating models with homophily and confounding. We use directed acyclic graphs to represent these models and employ multiple IV strategies and report three main identification results. First, using a single fixed gene (or allele) as an IV will generally fail to identify peer effects if the gene affects past values of the treatment. Second, multiple fixed genes/alleles, or, more promisingly, time-varying gene expression, can identify peer effects if we instrument exclusion violations as well as the focal treatment. Third, we show that IV identification of peer effects remains possible even under multiple complications often regarded as lethal for IV identification of intra-individual effects, such as pleiotropy on observables and unobservables, homophily on past phenotype, past and ongoing homophily on genotype, inter-phenotype peer effects, population stratification, gene expression that is endogenous to past phenotype and past gene expression, and others. We apply our identification results to estimating peer effects of body mass index (BMI) among friends and spouses in the Framingham Heart Study. Results suggest a positive causal peer effect of BMI between friends. PMID- 24779655 TI - Ethyl carbamate levels in wine and spirits from markets in Hebei Province, China. AB - Ethyl carbamate (EC) in wine, grain spirits and wine sauce (145 samples) was analysed using solid-phase extraction and stable isotope dilution GC/MS. Samples were obtained from markets in eight areas (Shijiazhuang, Baoding, Handan, Qinhuangdao, Langfang, Zhangjiakou, Xingtai and Cangzhou) of Hebei Province, China. The method had a limit of detection of 2 ug kg-1, with recoveries varying from 95.7 to 102% and RSD ranging 2.3-5.6%. The average concentrations of ethyl carbamate in wines, grain spirits and wine sauce were 14.7 (<2.0-44.5) ug kg-1, 33.8 (2.9-129) ug kg-1 and 8.7 (<2.0-63.3) ug kg-1, respectively. The results led to the development of limit standards that can be used to predict the concentration of ethyl carbamate in Chinese fermented wines. PMID- 24779656 TI - Concentrations of selected trace elements in mineral and spring bottled waters on the Serbian market. AB - Eight selected trace elements, which are generally included in regulations, were analyzed in 23 types of bottled waters. Ten mineral and seven spring bottled waters were from the Serbian market and six mineral bottled waters were obtained in different EU countries. For the purpose of comparison, selected tap waters were also analyzed. Inductively coupled plasma mass spectrometry (ICP-MS) was used for the analysis of trace elements (arsenic, cadmium, copper, manganese, nickel, lead and antimony). Results were compared with the Serbian regulations for bottled water, EU regulations and guideline values set by the World Health Organization for drinking water. With few exceptions, the trace element levels of most bottled waters were below the guideline values. However, a higher content of antimony was observed in waters from polyethylene terephthalate (PET) containers, indicating a potential leaching of this element from the plastic packaging. PMID- 24779657 TI - Organic and total mercury levels in bigeye tuna, Thunnus obesus, harvested by Taiwanese fishing vessels in the Atlantic and Indian Oceans. AB - Muscle samples of 121 and 110 bigeye tuna (Thunnus obesus) caught by Taiwanese long-line fishing vessels in the Atlantic and Indian Oceans, respectively, were used to analyze total mercury (THg) and organic mercury (OHg) content. The overall THg and OHg concentrations were 0.786 +/- 0.386 (0.214-3.133) and 0.595 +/- 0.238 (0.143-2.222) mg kg-1 wet weight, respectively, similar to the results of previous studies. Our findings, however, reflected the highest THg and OHg concentrations for the species in each ocean among the published data. Mean THg and OHg concentrations in Atlantic tuna were significantly (p < 0.05) higher than those in Indian tuna. Two of 121 samples of tuna from the Atlantic Ocean, but no samples from the Indian Ocean, had levels of OHg above 2 mg kg-1 wet weight set by the Department of Health Taiwan, and 13 of 121 samples of tuna from the Atlantic Ocean and three of 110 samples from the Indian Ocean had levels of OHg above 1 mg kg-1 wet weight set by US FDA and WHO. Accordingly, for adult Taiwanese men and women with average body weight of 65 and 55 kg, respectively, the maximum allowable weekly intake of bigeye tuna is suggested to be 170 and 145 g, respectively. PMID- 24779658 TI - Concentrations of selected metals in candies and chocolates consumed in southern Nigeria. AB - Results are presented for the determination of levels of Ca, Cd, Ni, Cr, Cu, Pb, Mn, Zn Fe, Co and Mg in candies and chocolates consumed in southern Nigeria. Mean concentrations of metals in both confectionaries ranged 7.7-1405.2 ug/g1 for Ca, <0.001-0.2 ug/g for Cd, 1.4-7.9 ug/g for Ni, 0.4-3.0 ug/g for Cr, <0.08-2.3 ug/g for Pb, 0.4-12.6 ug/g for Mn, 0.6-8.0 ug/g for Zn, 1.7-12.3 ug/g for Fe, <0.05 1.49 ug/g for Co, and 8.4-576.1 ug/g for Mg. The data showed that that these metals are not present at harmful levels. Concentrations of nickel and chromium were slightly elevated but were comparable to levels reported in similar food items elsewhere in the world. PMID- 24779659 TI - Lead, cadmium, arsenic, mercury and copper levels in Chinese Yunnan Pu'er tea. AB - The Yunnan region of China produces a distinctive variety of Pu'er tea, which is consequently labeled as a Chinese geographic indication product. In this study, the safety of Chinese Yunnan Pu'er tea with regard to heavy metal content was evaluated in 30 different brands of Pu'er tea, including 150 commercial samples. Metal levels in the Pu'er tea samples followed the order: copper (12-22 ug/g) > lead (0.26-3.2 ug/g) > arsenic (0.035-0.24 ug/g) > cadmium (0.0059-0.085 ug/g) > mercury (<0.010 ug/g). Mercury was not detected in 17 of the brands of Pu'er tea. Metal-to-metal correlation studies showed that there were no significant correlation between metal pairs. Based on current safety standards, the low levels of metals detected in these Pu'er tea samples mean they are safe for human consumption. PMID- 24779660 TI - Nitrate and nitrite levels in commonly consumed vegetables in Hong Kong. AB - Levels of nitrate and nitrite in 73 different vegetables, a total of 708 individual samples grouped into leafy, legumes, root and tuber, and fruiting vegetables, which are traded mainly in Hong Kong, were measured. Where available, five samples of each vegetable type were purchased from different commercial outlets during the winter of 2008 and summer of 2009. Levels of nitrate and nitrite were determined by ion chromatography and flow injection analysis, respectively. Nitrate and nitrite levels of all samples ranged <4-6300 and <0.8 9.0 mg kg-1, respectively. Nitrate concentrations for the different groups, in descending order, were leafy > root and tuber > fruiting and legume vegetables. More than 80% of vegetables had mean nitrate concentrations less than 2000 mg kg 1, but mean nitrate concentrations of three types of leafy vegetables, namely Chinese spinach, Shanghai cabbage and Chinese white cabbage, were >3500 mg kg-1. On the other hand, nitrite concentrations were generally low - <1 mg kg-1 on average. Nitrate in vegetables (i.e. Chinese flowering cabbage, Chinese spinach and celery) can be reduced significantly (12-31%) after blanching for 1-3 min, but not after soaking. PMID- 24779661 TI - Survey of aflatoxins in maize tortillas from Mexico City. AB - In Mexico, maize tortillas are consumed on a daily basis, leading to possible aflatoxin exposure. In a survey of 396 2-kg samples, taken over four sampling days in 2006 and 2007 from tortilla shops and supermarkets in Mexico City, aflatoxin levels were quantified by HPLC. In Mexico, the regulatory limit is 12 ug kg-1 total aflatoxins for maize tortillas. In this survey, 17% of tortillas contained aflatoxins at levels of 3-385 ug kg-1 or values below the limit of quantification (12 ug kg-1 and 87% were below the regulatory limit. Average aflatoxin concentrations in 56 contaminated samples were: AFB1 (12.1 ug kg-1); AFB2 (2.7 ug kg-1); AFG1 (64.1 ug kg-1) and AFG2 (3.7 ug kg-1), and total AF (20.3 ug kg-1). PMID- 24779662 TI - Occurrence of ochratoxin A in wine and beer samples from China. AB - A total of 125 wine and beer samples, including 42 white, 63 red wine and 20 beer samples, originating from several areas of China were analyzed for ochratoxin A (OTA). An analytical method based on immunoaffinity column (IAC) for clean-up and high performance liquid chromatography with fluorescence detection (HPLC-FD) was used to determine OTA. Positive results were further confirmed by LC-MS-MS. OTA was detected in 22 (17.6%) samples at levels of 0.02-1.18 ng/ml, which were below the EU maximum limit. The mean OTA concentration in red wine was slightly higher than in white wine. This study showed that OTA occurs in wine and beer in China but at levels that pose no danger of significant human exposure to OTA from this source. PMID- 24779663 TI - Survey of aflatoxin M1 in cheese from the North-east region of Sao Paulo, Brazil. AB - In the present study, 24 samples of Minas Frescal cheese and 24 samples of Minas Padrao cheese produced in the North-east region of the state of Sao Paulo, Brazil, were analysed for aflatoxin M1 (AFM1) by high-performance liquid chromatography (HPLC) between March and August 2008. AFM1 was detected in 13 (27.1%) samples at concentrations ranging from 0.037 to 0.313 ng g-1. The mean concentrations of AFM1 in positive samples of Minas Frescal and Minas Padrao cheese were 0.142 +/- 0.118 and 0.118 +/- 0.054 ng g-1, respectively. It is concluded that the incidence of AFM1 in Minas cheese may contribute to an increase in the overall ingestion of aflatoxins in the diet, hence indicating the need for the adoption of a tolerance limit for AFM1 in cheese in Brazil. PMID- 24779664 TI - A survey of ochratoxin A occurence in Greek wines. AB - A total of 150 wines, including 123 dry wines (64 red, 49 white and 10 rose) and 27 dessert wines (14 red and 13 white), were obtained from various viticulture and oenological practices across Greece during the period 1999-2006 and analyzed for ochratoxin a (OTA) using immunoaffinity clean-up and HPLC with fluorescence detection. There was a high frequency of OTA in commercially available wines (69% positive samples). However, the level of contamination was relatively low, with only one sample marginally reaching the EU permitted maximum level (2.0 ug l-1). A total of 91% of the samples had OTA concentrations <1.0 ug l-1. The higher concentrations were found in wines from the southern regions, especially in dessert-type wines. There were no significant differences based on wine color or production years. Furthermore, there was no difference between conventional or organic cropping systems in terms of OTA presence. PMID- 24779665 TI - Survey of ochratoxin A in rice from Iran using affinity column cleanup and HPLC with fluorescence detection. AB - This paper records the occurrence and levels of ochratoxin A (OTA) in rice using a HPLC technique preceded by an immunoaffinity clean-up step. The method was based on the extraction of finely ground rice sample with an acetonitrile/water (60 : 40, v/v) solution. Recovery was 98.9% while the limit of detection (LOD) was 0.2 ng g-1. A total of 182 rice samples were analyzed with a frequency of contamination of 6%. Levels of OTA in positive samples ranged 0.2-4.8 ng g-1, with an average contamination of all analyzed samples of 1.6 ng g-1. PMID- 24779666 TI - Deoxynivalenol and zearalenone in Fusarium-contaminated wheat in Mexico City. AB - Fusarium spp. invasion causes head blight, a destructive disease in the world's main wheat-growing areas, and deoxynivalenol (DON) and zearalenone (ZEA) contamination in cereal-based products. No data are available on the relationship between Fusarium spp. on commercial wheat samples in Mexico City and the presence of mycotoxins. A total of 30 wheat samples were subject to a PCR method involving genes of the trichothecene and zearalenone biosynthesis pathways to detect the presence of Fusarium. Detection and quantification of DON and ZEA was performed using liquid chromatography coupled to UV detection. PCR indicated the presence of the Tri5 and PKS4 genes in 16.7 and 23.3% of samples, respectively. DON and ZEA contamination was found in 51.2 and 71.4% of samples, respectively, where a positive amplification was obtained. This work presents up-to-date information on mycotoxin contamination in Mexico, where improved contamination/exposure data and firm control/monitoring measures are needed. PMID- 24779668 TI - Ion scattering studies of molecular structure at liquid surfaces with applications in industrial and biological systems. PMID- 24779667 TI - Demographic, risk factors and motivations among blood donors with reactive serologic tests for syphilis in Sao Paulo, Brazil. AB - OBJECTIVE: To identify the demographic characteristics, risk factors and motivations for donating among blood donors with reactive serologic tests for syphilis. BACKGROUND: Post-donation interviews with syphilis seropositive blood donors improve recruitment and screening strategies. METHODS: This case-control study compares 75 Venereal Disease Research Laboratory (VDRL) > 8, EIA+ (enzyme immunoassay) and FTA-ABS+ (fluorescent treponemal antibody); 80 VDRL-, EIA+ and FTA-ABS+; and 34 VDRL- and EIA- donors between 2004 and 2009. Donors were assessed by their demographic characteristics, sexual behaviour, history of alcohol and illicit drugs use, and motivations to donate. RESULTS: Donors with VDRL > 8 were more likely to be divorced [AOR = 12.53; 95% confidence interval (CI) 1.30-120.81], to have had more than six sexual partners (AOR=7.1; 95% CI 1.12-44.62) and to report male-male-sex in the past 12 months (AOR=8.18; 95% CI 1.78-37.60). Donors with VDRL-, EIA+ and FTA-ABS+ were less likely to be female (AOR=0.26; 95% CI 0.07-0.96), more likely to be older (AOR=10.2; 95% CI 2.45 42.58 >= 39 and <60 years old) and to have had more than six sexual partners in the past 12 months (AOR = 8.37; 95% CI 1.49-46.91). There was no significant difference among groups regarding illicit drugs use; 30.7% (VDRL > 8) and 12.5% (VDRL-, EIA+ and FTA-ABS+) of donors reported that they had been at risk for HIV infection (P = 0.004). One-third of donors came to the blood bank to help a friend or a relative who needed blood. CONCLUSION: Although donors exposed to syphilis reported and recognised some high risk behaviour, most were motivated by direct appeal to donate blood. Monitoring the risk profile of blood donors can benefit public health and improve blood safety. PMID- 24779669 TI - Everolimus with low-dose tacrolimus in simultaneous pancreas and kidney transplantation. AB - The efficacy and safety of everolimus (EVR) in simultaneous pancreas and kidney transplantation (SPKT) is unclear. We retrospectively evaluated 25 consecutive SPKT recipients at our center from November 2011 to March 2013. All patients received dual induction (Thymoglobulin/basiliximab) and low-dose tacrolimus plus corticosteroids. Nine patients who received EVR were compared with 14 patients who received enteric-coated mycophenolate sodium (EC-MPS); two patients who received sirolimus were excluded from the analysis. With a median follow-up of 14 months, the pancreas graft survival rate was 100% in both groups, and the kidney graft survival rate was 100% and 93% in EVR and EC-MPS patients, respectively. One EC-MPS patient lost her kidney graft from proteinuric kidney disease. Another EC-MPS patient received treatment for clinically diagnosed pancreas and kidney graft rejection. No rejection was observed in EVR patients. Serum creatinine and HbA1c levels were similar between the groups. There was no significant difference of surgical or medical complications. In conclusion, EVR seems to provide comparable short-term outcome to EC-MPS when combined with low-dose tacrolimus/steroids and dual induction therapy. A larger study with a longer follow-up is required to further assess this combination. PMID- 24779670 TI - Health care utilization and receipt of preventive care for patients seen at federally funded health centers compared to other sites of primary care. AB - OBJECTIVE: To compare utilization and preventive care receipt among patients of federal Section 330 health centers (HCs) versus patients of other settings. DATA SOURCES: A nationally representative sample of adults from the Medical Expenditure Panel Survey (2004-2008). STUDY DESIGN: HC patients were defined as those with >=50 percent of outpatient visits at HCs in the first panel year. Outcomes included utilization and preventive care receipt from the second panel year. We used negative binomial and logistic regression models with propensity score adjustment for confounding differences between HC and non-HC patients. PRINCIPAL FINDINGS: Compared to non-HC patients, HC patients had fewer office visits (adjusted incidence rate ratio [aIRR], 0.63) and hospitalizations (aIRR, 0.43) (both p < .001). HC patients were more likely to receive breast cancer screening than non-HC patients (adjusted odds ratio [aOR] 2.78, p < .01). In subgroup analyses, uninsured HC patients had fewer outpatient and emergency room visits and were more likely to receive dietary advice and breast cancer screening compared to non-HC patients. CONCLUSIONS: Health centers add value to the health care system by providing socially and medically disadvantaged patients with care that results in lower utilization and maintained or improved preventive care. PMID- 24779671 TI - Repeated exclusive enteral nutrition in the treatment of paediatric Crohn's disease: predictors of efficacy and outcome. AB - BACKGROUND: Exclusive enteral nutrition (EEN) induces remission and mucosal healing in children with active Crohn's disease (CD). AIM: To compare short- and long-term outcomes of the first vs. second courses of EEN, and to identify predictors of sustained remission. METHODS: Retrospective single centre analysis of all patients with CD (6-18 years) treated with EEN over 7.5 years. Patients were excluded if exposed to anti-TNFalpha or corticosteroids 3 months prior to EEN. Data included disease phenotype, activity, NOD2 genotype, laboratory indices and anthropometrics. Remission and relapse were defined by mathematically weighted Paediatric Crohn's Disease Activity Index (wPCDAI) with 1-year follow up. RESULTS: Of 94 patients treated with EEN, 52 fulfilled inclusion criteria (31 male, mean age 13.2 years). Azathioprine was started within the first month in 33/52 patients; 26/52 received a second EEN course. First compared to second EEN revealed higher wPCDAI at start (59 vs. 40, P < 0.0001), tended to higher remission rates after 3 months (92% vs. 77%, n.s.), but showed comparable 1-year relapse rates (67% vs. 70%, median time 231 vs. 145 days, n.s.). Disease activity, weight gain and inflammatory markers showed better improvement with first EEN. Faecal calprotectin >200 MUg/g during EEN was associated with shorter remission (median time 157 vs. 287 days, n.s.). Certain NOD2 genotypes were related to higher relapse rates (92% R702W or G908R vs. 50% 1007fs vs. 60% wild type, P < 0.01). CONCLUSIONS: Exclusive enteral nutrition induces remission in active Crohn's disease, but efficacy tends to decrease with the second course. Despite early azathioprine use, 1-year relapse rates are high, but may be related to NOD2 genotype. PMID- 24779672 TI - Fast solution-combustion synthesis of nitrogen-modified Li4Ti5O12 nanomaterials with improved electrochemical performance. AB - A series of nitrogen-modified Li4Ti5O12 (N-LTO) nanomaterials with hierarchical micro/nanoporous structures are first synthesized via a facile one-step combustion process using thermal decomposition of urea. Successful deposition of a TiN thin layer onto the LTO surface was confirmed by transmission electron microscopy with energy-dispersive X-ray analysis, X-ray photoelectron spectroscopy, Raman spectroscopy, and thermogravimetric measurements. The electrochemical performances of the N-LTO nanomaterials are also investigated in this work. Compared with pristine LTO, the N-LTO nanomaterial with 1.1 wt % nitrogen exhibits a higher rate capability and better reversibility. At charge/discharge rates of 1, 2, 8, and 15 C, the discharge capacities of the N LTO electrode were 159, 150, 128, and 108 mAh g(-1), respectively. After 200 cycles at 1 C, its capacity retention was 98.5% with almost no capacity fading. PMID- 24779673 TI - REAL-flection: Genuine reflection on real experiences. PMID- 24779674 TI - Prepregnancy body mass index and risk of preterm birth: association heterogeneity by preterm subgroups. AB - BACKGROUND: To evaluate the association between prepregnancy body mass index (BMI) is associated with early vs. late and medically-induced vs. spontaneous preterm birth (PTB) subtypes. METHODS: Using data from the Boston Birth Cohort, we examined associations of prepregnancy BMI with 189 early (<34 completed weeks) and 277 late (34-36 completed weeks) medically-induced PTBs and 320 early and 610 late spontaneous PTBs vs. 3281 term births (37-44 weeks) in multinomial regression. To assess for mediation by important pregnancy complications, we performed sequential models with and without hypertensive disorders of pregnancy, chorioamnionitis, and gestational diabetes. RESULTS: Prevalence of prepregnancy obesity (BMI >= 30.0 kg/m2) was 28% among mothers with medically-induced PTBs, 18% among mothers with spontaneous PTBs, and 18% among mothers with term births (p = <0.001). After adjustment for demographic and known risk factors for PTB, prepregnancy obesity was associated with higher odds of both early [OR 1.78 (1.19, 2.66)] and late [OR 1.49 (1.09, 2.04)] medically-induced PTB. These effect estimates were attenuated with inclusion of hypertensive disorders of pregnancy and gestational diabetes. For spontaneous deliveries, prepregnancy obesity was associated with decreased odds of PTB (0.76 [0.58, 0.98]) and underweight was nearly associated with increased odds of PTB (1.46 [0.99, 2.16]). CONCLUSION: Prepregnancy obesity is associated with higher risk of medically-induced, but not spontaneous PTB. Hypertensive disorders of pregnancy and gestational diabetes appear to partially explain the association between prepregnancy obesity and early and late medically-induced PTB. PMID- 24779675 TI - Uniform fluorescent nanobioprobes for pathogen detection. AB - Manipulating biochemical reactions in living cells to synthesize nanomaterials is an attractive strategy to realize their synthesis that cannot take place in nature. Yeast cells have been skillfully utilized to produce desired nanoparticles through spatiotemporal coupling of intracellular nonrelated biochemical reaction pathways for formation of fluorescent CdSe quantum dots. Here, we have successfully transformed Staphylococcus aureus cells into cellular beacons (fluorescing cells), all of which are highly fluorescent and photostable with perfect uniformity. Importantly, on the basis of such cells, we efficiently fabricated fluorescent nanobioprobes by a specific interaction between the protein A expressed on the S. aureus surface and the Fc fragment domain of antibodies, avoiding the use of other common methods for cell surface modifications, such as molecular covalent connection or more difficult genetic and metabolic engineering. Coupled with immunomagnetic beads, the resulting fluorescent-biotargeting bifunctional cells, i.e., biotargeting cellular beacons, can be employed as nanobioprobes for detection of viruses, bacteria, and tumor cells. With this method, H9N2 AIV can be detected specifically with a limit of 8.94 ng/mL (based on protein content). Furthermore, diverse probes for detection of different pathogens or for other biomedical applications can be easily obtained by simply changing the antibody conjugated to the cell surface. PMID- 24779676 TI - First evidence of subclinical renal tubular injury during sickle-cell crisis. AB - BACKGROUND: The pathophysiologic mechanisms classically involved in sickle-cell nephropathy include endothelial dysfunction and vascular occlusion. Arguments demonstrating that ischemia-reperfusion injury-related kidney damage might coincide with vaso-occlusive crisis (VOC) are lacking. METHODS: In this prospective study, we sought to determine whether tubular cells and glomerular permeability might be altered during VOC. Urine neutrophil gelatinase-associated lipocalin (NGAL) levels and albumin-excretion rates (AER) of 25 patients were evaluated prospectively during 25 VOC episodes and compared to their steady state (ST) values. RESULTS: During VOC, white blood-cell counts (WBC) and C-reactive protein (CRP) were significantly higher than at ST but creatinine levels were comparable. Urine NGAL levels were significantly increased during VOC vs ST (P = 0.007) and remained significant when normalized to urine creatinine (P = 0.004), while AER did not change significantly. The higher urine NGAL concentration was not associated with subsequent (24-48 hour) acute kidney injury. Univariate analysis identified no significant correlations between urine NGAL levels and laboratory parameters during VOC. CONCLUSIONS: These results demonstrated that subclinical ischemia-reperfusion tubular injury is common during VOC and highlight the importance of hydroelectrolyte monitoring and correction during VOC. PMID- 24779677 TI - Lactoferrin-modified poly(ethylene glycol)-grafted BSA nanoparticles as a dual targeting carrier for treating brain gliomas. AB - In this study, a dual-targeting drug delivery system based on bovine serum albumin nanoparticles (BSA-NPs) modified with both lactoferrin (Lf) and mPEG2000 loading doxorubicin (DOX) was designed, and its blood-brain barrier (BBB) penetration and brain glioma cells targeting properties were explored. BSA-NPs were prepared by a desolvation technique, and mPEG2000 was incorporated onto the surface of BSA-NPs by reacting with the free amino-group of BSA to form mPEG2000 modified BSA-NPs (P2000-NPs). Finally, Lf-modified P2000-NPs (Lf-NPs) was obtained by absorbing Lf onto the surface of P2000-NPs via the positive and negative charges interaction at physiological pH. Three levels of mPEG2000 and Lf modified NPs were prepared and characterized, respectively. The uptake and potential cytotoxicity of different DOX preparations in vitro by the primary brain capillary endothelial cells (BCECs) and glioma cells (C6) were investigated. The dual-targeting effects were studied on the BBB model in vitro, BCECs/C6 glioma coculture model in vitro, and C6 glioma-bearing rats in vivo, respectively. The results exhibited that, with the increase of the amount of both mPEG2000 and Lf, the particle size of NPs increased and its zeta potential decreased. The in vivo pharmacokinetics study in healthy rats exhibited that P2000-NPs with a high level of mPEG2000 (P2000H-NPs) had longer circulation time in vivo. Compared to other NPs, Lf-NPs with high level of both Lf and mPEG2000 (LfH-NPs) showed the strongest cytotoxicity and the highest effectiveness in the uptake both in BCECs and C6 as well as improved the dual-targeting effects. Body distribution of DOX in different formulations revealed that LfH-NPs could significantly increase the accumulation of DOX in the brain, especially at 2 h postinjection (P < 0.05). In conclusion, Lf-NPs were a prospective dual-targeting drug delivery system for effective targeting therapy of brain gliomas. PMID- 24779678 TI - Successful Treatment of Chronic Hepatitis E After an Orthotopic Liver Transplant With Ribavirin Monotherapy. AB - OBJECTIVES: Hepatitis E virus infection is increasingly reported as a cause of chronic hepatitis in organ transplant recipients. Besides reduction of immunosuppressive therapy or pegylated-interferon therapy, promising results have been reported for ribavirin monotherapy of hepatitis E virus after kidney transplant. To our knowledge, this is the first report of a successful ribavirin monotherapy for chronic hepatitis E virus infection after and orthotopic liver transplant. MATERIALS AND METHODS: This is a case report of a 55-year-old man with a diagnosis of chronic hepatitis E (genotype 3f) 26 months after an orthotopic liver transplant. A reduction of immunosuppressive therapy was not tolerated, and the patient did not qualify for pegylated-interferon therapy. Because of progressively elevated liver transaminases accompanied by histologic changes in the liver allograft, ribavirin monotherapy was undertaken for 16 weeks. RESULTS: We saw a decrease in liver enzymes after 1 week of ribavirin monotherapy. Hepatitis E virus RNA anti-HEV-IgM were tested after 8 weeks of ribavirin therapy, and were both negative. Antiviral therapy was continued for 16 weeks, and hepatitis E virus RNA remained undetectable; there also was a significant decrease in liver transaminases levels to normal values. In the 8 week and 8-month follow-ups at the end of antiviral therapy, the patient presented with normal liver enzymes and no detectable hepatitis E virus RNA. CONCLUSIONS: In conclusion, successful therapy of chronic hepatitis E after an orthotopic liver transplant may be achieved by ribavirin monotherapy and should be considered in patients who are sensitive to a reduction of immunosuppressive therapy or pegylated-interferon therapy. PMID- 24779679 TI - Regional abundance of on-premise outlets and drinking patterns among Swiss young men: district level analyses and geographic adjustments. AB - INTRODUCTION AND AIMS: This study investigated the associations of alcohol outlet density with specific alcohol outcomes (consumption and consequences) among young men in Switzerland and assessed the possible geographically related variations. DESIGN AND METHODS: Alcohol consumption and drinking consequences were measured in a 2010-2011 study assessing substance use risk factors (Cohort Study on Substance Use Risk Factors) among 5519 young Swiss men. Outlet density was based on the number of on- and off-premise outlets in the district of residence. Linear regression models were run separately for drinking level, heavy episodic drinking (HED) and drinking consequences. Geographically weighted regression models were estimated when variations were recorded at the district level. RESULTS: No consistent association was found between outlet density and drinking consequences. A positive association between drinking level and HED with on premise outlet density was found. Geographically weighted regressions were run for drinking level and HED. The predicted values for HED were higher in the southwest part of Switzerland (French-speaking part). DISCUSSION AND CONCLUSIONS: Among Swiss young men, the density of outlets and, in particular, the abundance of bars, clubs and other on-premise outlets was associated with drinking level and HED, even when drinking consequences were not significantly affected. These findings support the idea that outlet density needs to be considered when developing and implementing regional-based prevention initiatives. PMID- 24779680 TI - Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. AB - RATIONALE: Daily azithromycin decreases acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but long-term side effects are unknown. OBJECTIVES: To identify the types of exacerbations most likely to be reduced and clinical subgroups most likely to benefit from azithromycin, 250 mg daily, added to usual care. METHODS: Enrollment criteria included irreversible airflow limitation and AECOPD requiring corticosteroids, emergency department visit, or hospitalization in the prior year or use of supplemental oxygen. Recurrent events and cumulative incidence analyses compared treatment received for AECOPD by randomization group, stratified by subgroups of interest. Cox proportional hazards models estimated treatment effects in subgroups adjusted for age, sex, smoking status, FEV1% predicted, concomitant COPD medications, and oxygen use. MEASUREMENTS AND MAIN RESULTS: Azithromycin was most effective in reducing AECOPD requiring both antibiotic and steroid treatment (n = 1,113; cumulative incidence analysis, P = 0.0002; recurrent events analysis, P = 0.002). No difference in treatment response by sex (P = 0.75), presence of chronic bronchitis (P = 0.19), concomitant inhaled therapy (P = 0.29), or supplemental oxygen use (P = 0.23) was observed. Older age and milder Global Initiative for Chronic Obstructive Lung Disease stage were associated with better treatment response (P = 0.02 and 0.04, respectively). A significant interaction between treatment and current smoking was seen (P = 0.03) and azithromycin did not reduce exacerbations in current smokers (hazard ratio, 0.99; 95% confidence interval, 0.71-1.38; P = 0.95). CONCLUSIONS: Azithromycin is most effective in preventing AECOPD requiring both antibiotic and steroid treatment. Adjusting for confounders, we saw no difference in efficacy by sex, history of chronic bronchitis, oxygen use, or concomitant COPD therapy. Greater efficacy was seen in older patients and milder Global Initiative for Chronic Obstructive Lung Disease stages. We found little evidence of treatment effect among current smokers. Clinical trial registered with www.clinicaltrials.gov (NCT0011986 and NCT00325897). PMID- 24779682 TI - Prospective cohort study on change in weight status and occurrence of habitual snoring in children. AB - OBJECTIVE: To determine the association between the change in weight status and newly developed snoring in children. DESIGN: This was a prospective cohort study. SETTING: Structured interviews were conducted at participants' homes, and physical examinations were performed at The-pa Community Hospital in Southern Thailand. PARTICIPANTS: Cohort subjects (n = 1076) were recruited from children born over a 1-year period between November 2000 and October 2001 in The-pa District of Songkhla Province, Southern Thailand. Data collection was performed when the child was 5 and 8.5 years old. MAIN OUTCOME MEASURES: The child's snoring, weight, height and tonsillar size were examined. The change in weight status was categorised into four groups: not obese, became not obese, became obese and persistently obese. RESULTS: Of 1076, 983 subjects (91.4%) completed both surveys. The overall prevalence of habitual snoring decreased from 13% at age 5 to 10.9% at age 8.5 years. Of the 855 children who reported not snoring in the first survey, 61 (7.1%) had become habitual snorers. After adjusting for tonsillar size, children who had become obese or were persistently obese had a significant association with becoming a new snorer with an odds ratio of 5.8 (Confidence interval, CI, 1.3-25.8) and 11.7 (CI, 2.5-54.9), respectively. CONCLUSIONS: Children with newly developed obesity at 8.5 years old were strongly associated with new snoring occurrence, which is similar to the findings of long term follow-up studies in adults. Our findings support the idea that the patterns of changes in weight status and snoring development in adults begin as early as the primary school years. PMID- 24779681 TI - Function of RasGRP3 in the formation and progression of human breast cancer. AB - INTRODUCTION: Ras guanine nucleotide exchange factors (RasGEFs) mediate the activation of the Ras signaling pathway that is over activated in many human cancers. The RasGRP3, an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types. Here, we investigated the putative alteration of expression and potential function of RasGRP3 in the formation and progression of human breast cancer. METHODS: The RasGRP3 and phosphoRasGRP3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT-474, JIMT 1, MCF7, SK-BR-3, MDA-MB-453, T-47D) both in mRNA (Q-PCR) and protein (Western blot; immunohistochemistry) levels. To explore the biological function of the protein, RasGRP3 knockdown cultures were established. To assess the role of RasGRP3 in the viability of cells, annexin-V/PI staining and MitoProbeTM DilC1 (5) assay were performed. To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance, CyQuant assay was performed. To observe the RasGRP3 function in tumor formation, the Severe combined immunodeficiency (SCID) mouse model was used. To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed. RESULTS: RasGRP3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines. Down regulation of RasGRP3 expression in breast cancer cells decreased cell proliferation, induced apoptosis in MCF7 cells, and sensitized T-47D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin). Gene silencing of RasGRP3 reduced tumor formation in mouse xenografts as well. Inhibition of RasGRP3 expression also reduced Akt, ERK1/2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor-I (IGF-I) or epidermal growth factor (EGF) stimulation confirming the functional role of RasGRP3 in the altered behavior of these cells. CONCLUSIONS: Taken together, our results suggest that the Ras activator RasGRP3 may have a role in the pathological behavior of breast cancer cells and may constitute a therapeutic target for human breast cancer. PMID- 24779683 TI - Probability-enhanced sufficient dimension reduction for binary classification. AB - In high-dimensional data analysis, it is of primary interest to reduce the data dimensionality without loss of information. Sufficient dimension reduction (SDR) arises in this context, and many successful SDR methods have been developed since the introduction of sliced inverse regression (SIR) [Li (1991) Journal of the American Statistical Association 86, 316-327]. Despite their fast progress, though, most existing methods target on regression problems with a continuous response. For binary classification problems, SIR suffers the limitation of estimating at most one direction since only two slices are available. In this article, we develop a new and flexible probability-enhanced SDR method for binary classification problems by using the weighted support vector machine (WSVM). The key idea is to slice the data based on conditional class probabilities of observations rather than their binary responses. We first show that the central subspace based on the conditional class probability is the same as that based on the binary response. This important result justifies the proposed slicing scheme from a theoretical perspective and assures no information loss. In practice, the true conditional class probability is generally not available, and the problem of probability estimation can be challenging for data with large-dimensional inputs. We observe that, in order to implement the new slicing scheme, one does not need exact probability values and the only required information is the relative order of probability values. Motivated by this fact, our new SDR procedure bypasses the probability estimation step and employs the WSVM to directly estimate the order of probability values, based on which the slicing is performed. The performance of the proposed probability-enhanced SDR scheme is evaluated by both simulated and real data examples. PMID- 24779684 TI - Special needs dentistry: perception, attitudes and educational experience of Malaysian dental students. AB - A compromised oral health condition amongst patients with special health care needs (SHCN) has been associated with the reluctance and shortage of skills of dental professionals in managing such patients. Lack of training and experience at the undergraduate level are reported barriers to the provision of care for this patient cohort. Undergraduate education therefore, plays an important role in producing professionals with the knowledge, skills and positive attitude in treating patients with SHCN. This study aims to determine the level of knowledge, comfort and attitudes of Malaysian undergraduate dental students towards caring for patients with SHCN, as well as their perception on education in this field. A self-administered questionnaire was administered in the classroom style to final year undergraduate dental students in Malaysian public dental schools. Most students were aware of Special Needs Dentistry (SND) as a specialty after being informed by academic staff. The majority of the students demonstrated poor knowledge in defining SND and felt uncomfortable providing care for such patients. They perceived their undergraduate training in SND as inadequate with most students agreeing that they should receive didactic and clinical training at undergraduate level. A high percentage of students also expressed interest in pursuing postgraduate education in this area of dentistry despite the lack of educational exposure during undergraduate years. The study supports a need for educational reform to formulate a curriculum that is more patient-centred, with earlier clinical exposure in various clinical settings for students to treat patients with special health care needs, applying the concept of holistic care in a variable clinical condition. PMID- 24779686 TI - Mechanisms of pathogenesis in allergic asthma: role of interleukin-23. AB - Asthma is a chronic airway inflammatory disease characterized by intense leukocyte and eosinophilic infiltration accompanied by mucus hypersecretion and tissue hyperresponsiveness. Recent evidence suggests that T-helper (Th)2 cells and their cytokine products orchestrate the pathology of asthma. In addition, Th17 cells are implicated in the pathogenesis of antigen-induced airway inflammation. The Th17 related cytokine interleukin (IL)-23 plays important roles in many immunological diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Several reports describe the role of IL-23 in the pathogenesis of allergic asthma in both human and mice. IL-23 leads to neutrophil infiltration in the airway of asthmatic mice, which is characteristic of severe asthma resulting from Th17 development and subsequently IL-17 secretion. IL-23 can also promote eosinophil infiltration in the airway, which is a hallmark of allergic asthma. These studies suggest that IL-23 could be a promoting factor in the development of allergic asthma and likewise would be a target for asthma therapy. In support of this view, trials of anti-IL-23 therapy have been attempted in human and mouse asthma models with encouraging outcomes. This review presents the role of IL-23 in asthma according to recent clinical trials and animal model studies. The proposed mechanisms of IL-23-induced airway inflammation and the agents currently being tested that target IL-23 related pathways are discussed. PMID- 24779687 TI - Survey of polycyclic aromatic hydrocarbons in marine products in Korea using GC/MS. AB - This study investigates polycyclic aromatic hydrocarbons (PAHs) in marine products on the Korean market. A total of 280 samples of fish (n = 100), shellfish (n = 80), cephalopod (n = 60) and crustacea (n = 40) were collected for analyses of PAHs (naphthalene, acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthene, pyrene, benz[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthene, benzo[a]pyrene, indeno[1,2,3 c,d]pyrene, dibenz[a,h]anthracene and benzo[g,h,i]perylene). The analytical procedure was based on the matrix solid-phase dispersion on Florisil cartridges and extraction with hexane/dichloromethane (3:1, v/v). The PAHs were determined by gas chromatography with mass spectrometric detection using selective ion monitoring. Average recoveries for all the PAHs studied were in the range 58-79%. The sum of 16 PAHs concentrations in fish, shellfish, cephalopod/crustacea were in the range 0.2-0.5, 1.2-1.6 and 0.8-1.9 ug/kg, respectively. PMID- 24779688 TI - Aflatoxin in raw walnut kernels marketed in Tehran, Iran. AB - The occurrence of aflatoxin in 35 samples of raw walnuts, which were randomly collected from Iranian supermarkets in Tehran, was examined. Analysis of aflatoxin was performed by solvent extraction and immunoaffinity clean-up followed by determination using high-performance liquid chromatography with fluorescence detection. Limits of detection (LOD) for the aflatoxins were 0.03 0.25 ng g-1. Limits of quantification (LOQ) were 0.12-0.80 ng g-1. Total aflatoxin concentrations in the samples ranged from 0 to 112.8 ng g-1. About 74.3% of the samples were contaminated with aflatoxins, of which 20.0% exceeded the maximum tolerable limit of 15 ng g-1 set by Codex. PMID- 24779685 TI - Diffusion tensor imaging as a predictor of locomotor function after experimental spinal cord injury and recovery. AB - Traumatic spinal cord injury (SCI) causes long-term disability with limited functional recovery linked to the extent of axonal connectivity. Quantitative diffusion tensor imaging (DTI) of axonal integrity has been suggested as a potential biomarker for prognostic and therapeutic evaluation after trauma, but its correlation with functional outcomes has not been clearly defined. To examine this application, female Sprague-Dawley rats underwent midthoracic laminectomy followed by traumatic spinal cord contusion of differing severities or laminectomy without contusion. Locomotor scores and hindlimb kinematic data were collected for 4 weeks post-injury. Ex vivo DTI was then performed to assess axonal integrity using tractography and fractional anisotropy (FA), a numerical measure of relative white matter integrity, at the injury epicenter and at specific intervals rostral and caudal to the injury site. Immunohistochemistry for tissue sparing was also performed. Statistical correlation between imaging data and functional performance was assessed as the primary outcome. All injured animals showed some recovery of locomotor function, while hindlimb kinematics revealed graded deficits consistent with injury severity. Standard T2 magnetic resonance sequences illustrated conventional spinal cord morphology adjacent to contusions while corresponding FA maps indicated graded white matter pathology within these adjacent regions. Positive correlations between locomotor (Basso, Beattie, and Bresnahan score and gait kinematics) and imaging (FA values) parameters were also observed within these adjacent regions, most strongly within caudal segments beyond the lesion. Evaluation of axonal injury by DTI provides a mechanism for functional recovery assessment in a rodent SCI model. These findings suggest that focused DTI analysis of caudal spinal cord should be studied in human cases in relationship to motor outcome to augment outcome biomarkers for clinical cases. PMID- 24779689 TI - Natural occurrence of aflatoxins (B1 and M1) in feed, plasma and raw milk of lactating dairy cows in Beja, Tunisia, using ELISA. AB - Beja is an agricultural area in northwest Tunisia. It contributes to national needs by offering cereals and milk to the market for human and animal consumption. A small number of studies on mycotoxin occurrence in feedstuffs and raw milk from lactating dairy cows in this region are available. Therefore, 226 samples were collected from farms and local markets during November 2008 until April 2010. Samples consisted of 112 raw cow milk, 56 blood from lactating cows and 58 feed destined for dairy cows. Plasma and feed were analysed for aflatoxin B1 (AFB1). Milk samples were analysed for aflatoxin M1 (AFM1). All samples were treated using a simultaneous methanolic-aqueous extraction, followed by immunoaffinity column clean-ups and were investigated by competitive enzyme linked immunoabsorbent assay (ELISA). Recoveries were 80%-95% and 81%-92% for AFB1 and AFM1, respectively, while the limit of detection (LOD) was 0.01 ug/kg or ug/l for both mycotoxins. Results revealed the presence of AFB1 in 84.4% of the feed samples (mean 18.7 +/- 1.4 ug/kg), and 39.2% of the plasma-examined samples (median 7.1 +/- 1.0 ug/l) were found to be contaminated at levels higher than the Tunisian and the European Union (EU) limit for dairy animals, which are 20 and 5 ug/kg in animal feed, respectively. AFM1 was detected in 60.7% of the cow raw milk samples examined (median 13.6 +/- 1.4 ug/l). Contaminated levels were higher than the EU limit of 0.05 ug/l. It was concluded that more precaution should be taken on hygiene controls in order to prevent fungal contamination. PMID- 24779690 TI - Selenium levels in breads from Sakarya, Turkey. AB - Selenium (Se) is an important trace element for human and animal health. It accumulates in wheat and corn, which is consumed mostly as bread. The Turkish population consumes mainly white wheat, whole wheat (brown bread) and corn breads. In this study, samples of these breads were collected from six different bakeries in the city of Sakarya, and their selenium levels were determined by ICP OES after a chemical digestion. It was found that average selenium levels in white wheat, whole wheat and corn breads were 1149, 1204 and 2023 ug/kg, respectively. The results are compared with daily recommended intake and upper tolerable levels for selenium. PMID- 24779691 TI - Determination of acrylamide in Thai-conventional snacks from Nong Mon market, Chonburi using GC-MS technique. AB - Acrylamide in Thai-conventional snacks was analysed by GC/MS with a linear response ranged of 5-50 ug and r2 > 0.99. The limit of detection (s/n = 3) and limit of quantification (s/n = 10) were 4 and 15 ug kg-1, respectively, and RSD < 2%. Acrylamide in 19 food samples ranged from <15 ug kg-1 to 1.26 mg kg-1 with highest concentrations in Kanom Jak. Moderate levels (150-500 ug kg-1) were detected mostly in deep-fried products, especially sweet potato and taro crisps, Kanom Kai Hong, banana fritters, durian chips and spring rolls. Thai-conventional snacks possessed low concentrations (<150 ug kg-1) including Khao Larm, Pa Tong Koo, sweet banana crisps and deep-fried Chinese wonton. Acrylamide was lowest (<15 ug kg-1) in fish strips, rice crackers, Hoi Jor and fried fish balls. Dietary habits by 400 tourists indicate a daily intake of acrylamide <150 ng, well below a toxic dose. PMID- 24779692 TI - Determination of PDE-5 inhibitors and appetite suppressants in adulterated dietary supplements using LC/PDA and LC/MS. AB - There have been a number of reports of dietary supplements contaminated with illegal adulterants that threaten consumers' health because of their adverse pharmacological effects. In the present study, a convenient and economic method was developed to detect illegal pharmaceutics, such as PDE-5 inhibitor and appetite suppressants, using liquid chromatography (LC)/photodiode array (PDA) for screening and LC/mass spectrometry (MS) for successive confirmation. Target peaks were identified by comparison of their chromatographic retention times and PDA spectra with those of synthetic standards and finally confirmed by LC/MS. As a result, tadalafil, a PDE-5 inhibitor, and N-desmethylsibutramine, a derivative of sibutramine, were detected in various dietary supplements at concentrations of 13.5-21.9 mg and 3.0 mg per single dose, respectively. The present study will contribute to the development of an analytical method enabling rapid screening of a variety of health foods, and the result suggests that consumers should be aware of serious health risks related to these illegal compounds. PMID- 24779693 TI - Aluminium in food and daily dietary intake estimate in Greece. AB - Aluminium content of foods, as well as dietary aluminium intake of the Greek adult population, was determined using graphite furnace atomic absorption spectroscopy after microwave sample digestion and food consumption data. Al content ranged from 0.02 to 741.2 mg kg-1, with spices, high-spice foods, cereal products, vegetables and pulses found to be high in Al. Differences in aluminium content were found between different food classes from Greece and those from some other countries. Aluminium intake of Greeks is 3.7 mg/day based on DAFNE Food Availability Databank, which uses data from the Household Budget Surveys. On the other hand, according to the per capita food consumption data collected by both national and international organisations, Al intake is 6.4 mg day-1. Greek adult population has an Al intake lower than the Provisional Tolerable Weekly Intake of 7 mg kg-1 body weight established by EFSA. Cereals and vegetables are the main Al contributors, providing 72.4% of daily intake. PMID- 24779694 TI - Determination of tetracycline residues in chicken meat by liquid chromatography tandem mass spectrometry. AB - Analysis of residual levels of tetracyclines (TCs) in chicken meat was performed using a validated liquid chromatography coupled with a tandem mass spectrometry (LC-MS/MS) technique. Overall, the recoveries for TCs ranged from 56.9% to 101.2%, with standard deviations of 4.5-13.2%. Detection limits ranged from 7.9 to 14.6 ug kg-1. In four of 60 samples, doxycycline (DXC) was determined in a range from 19.9 to 35.6 ug kg-1; and in one sample tetracycline was detected at 17.2 ug kg-1. Chlortetracycline (CTC) and oxytetracycline (OTC) were not detected in any of the tested samples. This study indicates that chicken meat sold in Bursa, Turkey, contained some residues of TCs. Therefore, stricter regulations for the use of antibiotics in the poultry industry and the monitoring of drug residues in chicken meat prior to marketing are needed. Finally, this method has been applied successfully for the confirmation of TCs in chicken meat. PMID- 24779695 TI - Levels of selected heavy metals in canned tomato paste sold in Ghana. AB - Sixty-one samples of canned tomato paste comprising seven brands originating from three countries and sold in local markets in the Kumasi Metropolis of Ghana were analysed for levels of iron (Fe), zinc (Zn), manganese (Mn), cadmium (Cd) and lead (Pb) by flame atomic absorption spectrophotometry and for levels of mercury (Hg) by direct mercury analyzer. Mean heavy metal concentrations varied by brand, ranging from below the limit of detection (Cd) to a maximum concentration range of 1.68 +/- 1.63 to 58.6 +/- 14.5 ug g-1 (Fe). Estimated mean ranges of other heavy metals are 2.06 +/- 0.62 to 8.52 +/- 0.68 ug g-1 (Zn), 2.62 +/- 0.33 to 5.75 +/- 0.47 ug g-1 (Mn), 0.070 +/- 0.003 to 0.116 +/- 0.012 ug g-1 (Pb) and 0.011 +/- 0.001 to 0.102 +/- 0.001 ug g-1 (Hg). Assessed metal levels in five brands were below the WHO/FAO permissible levels. Results of the one-way analysis of variance (ANOVA) conducted on the data suggested no significant variations (P > 0.05) in the concentrations of the metals in the same brands of canned tomatoes. PMID- 24779696 TI - Zearalenone occurrence in surface waters in central Illinois, USA. AB - Zearalenone (ZEN) is an estrogenic secondary metabolite produced by certain fungi that commonly infest important cereal crops. The ability of ZEN to move from contaminated crops to surface waters has been demonstrated previously. This article reports the development and application of a method for the measurement of ZEN in surface waters from the central part of Illinois, USA. The method uses a cleanup procedure based on tandem reverse-phase disks and immunoaffinity columns, separation by liquid chromatography and detection by a combination of absorbance and fluorescence. ZEN was frequently found in samples of waters from lakes, streams and a field ditch. Although the frequency of detection was high (32% above the limit of detection, 0.4 ng L-1), the levels found were low, with the highest sample having 5.7 ng L-1. Therefore, although fungi can contribute to the exposure to environmental estrogens, the contribution from zearalenone in water is likely small. PMID- 24779697 TI - Survey of total mercury in infant formulae and oral electrolytes sold in Canada. AB - Total mercury (Hg) was measured in 150 infant formula products (as sold) and oral electrolyte solutions purchased in Canada in 2003. Results less than the limit of detection (LOD) were reported as the numeric value of the LOD. Electrolytes contained the lowest concentrations, averaging 0.026 ng/g. Average levels in milk based ready-to-use, concentrated liquid and powdered concentrate were 0.028, 0.069 and 0.212 ng/g, respectively. In soy-based formulae, the respective mean concentrations were 0.049, 0.101 and 0.237 ng/g. These concentrations cannot be considered on an absolute basis because 76% of sample concentrations fell below the limit of detection. Despite the inability to measure many of the actual background concentrations, the method was sufficiently sensitive to identify clear cases of low-level Hg contamination (up to 1.5 ng/g) of individual lots of powdered formula. Also, all the different lots of one brand of concentrated liquid infant formulae had significantly higher concentrations of Hg than those of all other concentrated liquid products. After dilution with preparation water, the Hg concentrations in all products would be lower than the Canadian Drinking Water Guideline for Hg of 1 ng/mL and too low to impact on health. PMID- 24779698 TI - Natural occurrence of ochratoxin A in wolfberry fruit wine marketed in China. AB - Wolfberry fruit wine (WFW) is widely used as a global functional food to improve the immune system and prevent human disease. A total of 36 bottled WFWs were randomly collected in China between 2005 and 2010. Samples were analysed for the presence of ochratoxin A (OTA) using immunoaffinity column (IAC) clean-up and high-performance liquid chromatography with fluorescence detection (HPLC-FLD). Positive results were confirmed by liquid chromatography-electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS). The limit of detection (LOD), based on a signal-to-noise ratio of 3, was 0.05 ng mL-1. Recoveries ranged from 78.3% to 94.7% and relative standard deviations from 1.1% to 4.3% within the spiking range of 0.2-20 ng mL-1. OTA was detected in one sample, below the maximum allowable limit as established by the European community. PMID- 24779699 TI - The influence of industrial-scale canning on cadmium and lead levels in sardines and anchovies from commercial fishing centres of the Mediterranean Sea. AB - The current study encompassed a survey on the levels of toxic trace elements in two highly consumed fish species in commercial fishing centres of western, central and eastern Mediterranean Sea. A Zeeman GTA-AAS graphite furnace atomic absorption spectrometry system was used throughout the study. Toxicological evaluation of the samples revealed a low Cd content in the raw samples, ranging between 0.003 and 0.027 mg kg-1. Pb presented significantly higher values, from 0.037 to 0.297 mg kg-1, occasionally reaching the limit of 0.3 mg kg-1. Heavy metal levels were particularly higher in bones, thus raising queries about the safe consumption of fish intended to be eaten as a whole, a very common practice for small fish and canned products. The influence of industrial-scale canning showed that canning enhanced heavy metal levels by 35%-80%. The effect of canning depended on metal type and reduction of moisture loss after the steam-roasting step of the canning procedure. PMID- 24779700 TI - Cannabinoid CB2 receptor as a new phototherapy target for the inhibition of tumor growth. AB - The success of targeted cancer therapy largely relies upon the selection of target and the development of efficient therapeutic agents that specifically bind to the target. In the current study, we chose a cannabinoid CB2 receptor (CB2R) as a new target and used a CB2R-targeted photosensitizer, IR700DX-mbc94, for phototherapy treatment. IR700DX-mbc94 was prepared by conjugating a photosensitizer, IR700DX, to mbc94, whose binding specificity to CB2R has been previously demonstrated. We found that phototherapy treatment using IR700DX-mbc94 greatly inhibited the growth of CB2R positive tumors but not CB2R negative tumors. In addition, phototherapy treatment with nontargeted IR700DX did not show significant therapeutic effect. Similarly, treatment with IR700DX-mbc94 without light irradiation or light irradiation without the photosensitizer showed no tumor-inhibitory effect. Taken together, IR700DX-mbc94 is a promising phototherapy agent with high target-specificity. Moreover, CB2R appears to have great potential as a phototherapeutic target for cancer treatment. PMID- 24779701 TI - Impact of states' nurse work hour regulations on overtime practices and work hours among registered nurses. AB - OBJECTIVES: To examine the degree to which states' work hour regulations for nurses-policies regarding mandatory overtime and consecutive work hours-decrease mandatory overtime practice and hours of work among registered nurses. METHODS: We analyzed a nationally representative sample of registered nurses from the National Sample Survey of Registered Nurses for years 2004 and 2008. We obtained difference-in-differences estimates of the effect of the nurse work hour policies on the likelihood of working mandatory overtime, working more than 40 hours per week, and working more than 60 hours per week for all staff nurses working in hospitals and nursing homes. PRINCIPAL FINDINGS: The mandatory overtime and consecutive work hour regulations were significantly associated with 3.9 percentage-point decreases in the likelihood of working overtime mandatorily and 11.5 percentage-point decreases in the likelihood of working more than 40 hours per week, respectively. CONCLUSIONS: State mandatory overtime and consecutive work hour policies are effective in reducing nurse work hours. The consecutive work hour policy appears to be a better regulatory tool for reducing long work hours for nurses. PMID- 24779702 TI - Triboelectrification based motion sensor for human-machine interfacing. AB - We present triboelectrification based, flexible, reusable, and skin-friendly dry biopotential electrode arrays as motion sensors for tracking muscle motion and human-machine interfacing (HMI). The independently addressable, self-powered sensor arrays have been utilized to record the electric output signals as a mapping figure to accurately identify the degrees of freedom as well as directions and magnitude of muscle motions. A fast Fourier transform (FFT) technique was employed to analyse the frequency spectra of the obtained electric signals and thus to determine the motion angular velocities. Moreover, the motion sensor arrays produced a short-circuit current density up to 10.71 mA/m(2), and an open-circuit voltage as high as 42.6 V with a remarkable signal-to-noise ratio up to 1000, which enables the devices as sensors to accurately record and transform the motions of the human joints, such as elbow, knee, heel, and even fingers, and thus renders it a superior and unique invention in the field of HMI. PMID- 24779703 TI - Detection rate and outcome of colonic serrated epithelial changes in patients with ulcerative colitis or Crohn's colitis. AB - BACKGROUND: Chronic ulcerative colitis (CUC) and colonic Crohn's disease (CD) increase colorectal neoplasia (CRN) risk. While sessile serrated polyp (SSP) is a known cancer precursor, serrated epithelial changes (SEC) are of uncertain prevalence and neoplastic risk. AIM: To assess the serrated lesion detection rates in CUC and CD and documented incidence of subsequent CRN in a retrospective, single-centre cohort study. METHODS: Patients were identified by a central diagnostic index and pathology review confirmed SEC, SSP, CUC and CD diagnoses from 2006-12. Matched controls were identified from among all CUC and CD patients having colonoscopy during the second half of the time period. All were followed for incident CRN, estimated by the Kaplan-Meier method. RESULTS: Between 2006 and 2012, 79 SEC and 10 SSP cases were identified. Detection rates were estimated to be 10/1000 and 2/1000 patients, for SEC and SSP respectively, among 4208 unique CUC or CD patients having colonoscopy from 2010-12. With only 10 cases, SSP patients were not further analysed. Cumulative incidence of subsequent CRN at 1 and 3 years was 12% (95% CI, 0-30%) and 30% (3-57%), respectively, in SEC patients compared to 4% (0-12%) and 9% (0-23%), respectively, in CUC or CD controls (P = 0.047, log-rank). However, this statistical difference was not significant after patients were stratified for history of prior or synchronous dysplasia (P = 0.09). CONCLUSIONS: Serrated epithelial changes and sessile serrated polyps are uncommonly detected by colonoscopy in chronic ulcerative colitis and Crohn's disease patients. Histology with changes of serrated epithelium may be associated with risk of subsequent colorectal neoplasia, however further studies are needed to explore this relationship. PMID- 24779704 TI - The survival and the long-term trends of patients with gastric cancer in Shanghai, China. AB - BACKGROUND: Gastric cancer remains a major health issue and a leading cause of death worldwide. This study presented a long-term survival data of gastric cancer registered in Shanghai of China from 1972-2003, with aims to describe the trends as well as the age, sex, stage and tumor sites specific characteristics. METHODS: The main source of information on cancer cases was the notification card sending to the registry. The residential status of cancer cases was confirmed by home visits. The methods of follow-up have been a mixture of both active and passive ones. RESULTS: We observed an increased trend of survival probability during the last decades. Patients diagnosed during 1972-1976 had a 5-years relative survival rate at 12% for males and 11% for females, respectively, which had dramatically increased to 30% for male and 32% for female patients respectively during the period of 2002-2003. Among the patients diagnosed in 2002-2003, the overall survival probability declined with patient's age at the time of diagnosis. The lowest survival rate was observed among the oldest group, with the median survival time of 0.8 years. Patients diagnosed with stage I had a higher relative survival rate. Patients with cardia cancer had the worst prognosis, with the 5 year relative survival rate of 29%. CONCLUSIONS: The survival probability of patients with gastric cancer in Shanghai has improved significantly during the last decades. Age, stage and site of tumor have an impact on prognosis. PMID- 24779706 TI - Impaired fasting glucose and body mass index as determinants of mortality in ALLHAT: is the obesity paradox real? AB - Emerging literature suggests that obesity may be "protective" against mortality and cardiovascular outcomes, while dysglycemia may worsen outcomes regardless of obesity. The authors measured the association of weight, smoking, and glycemia with mortality in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Among 5423 ALLHAT participants without established diabetes or cardiovascular disease, 3980 (73%) had normal fasting glucose and 1443 (27%) had impaired fasting glucose (IFG) levels at study entry. After a median of 4.9 years follow-up, 554 (10%) had died (37% cardiovascular). IFG was associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02-1.50), while obesity was associated with lower all cause mortality (adjusted HR, 0.76; 95% CI, 0.60-0.96). However, after excluding underweight individuals (body mass index [BMI] <22 kg/m(2) ) and smokers, neither obesity nor IFG was associated with all-cause mortality [corrected]. Although obesity appeared protective against mortality, this association was not significant in never-smokers or after exclusion of BMI <22 kg/m(2) . The obesity paradox may result from confounding by a sicker, underweight referent population and smoking. PMID- 24779707 TI - Suture of the right internal jugular vein catheter in a mitral valve replacement: a case report. AB - INTRODUCTION: Central venous catheterization can be necessary for patients undergoing a cardiac operation. Accidental suturing of the catheter to the heart is a rare complication that is difficult to correct; excessive traction force on the central venous catheter can lead to heart breakage or even death. CASE PRESENTATION: We describe the case of a 56-year-old Han Chinese woman who was scheduled to undergo mitral valve replacement. The central venous catheter placed into her right internal jugular vein was accidentally sutured to the left atrial suture line during the operation. The stuck catheter was successfully removed without having to perform a cardiopulmonary bypass. CONCLUSIONS: Attaching a catheter to the heart by cardiac sutures can occur when the tip of the catheter locates directly above the atrial-caval junction. Care should be taken when closing the cephalad end of a left atrial incision in a mitral valve replacement. Although rare, accidental suturing of the central venous catheter must be kept in mind, and an approach should be chosen to remove the catheter that best avoids additional insult to the heart function. PMID- 24779709 TI - In silico prediction and automatic LC-MS(n) annotation of green tea metabolites in urine. AB - The colonic breakdown and human biotransformation of small molecules present in food can give rise to a large variety of potentially bioactive metabolites in the human body. However, the absence of reference data for many of these components limits their identification in complex biological samples, such as plasma and urine. We present an in silico workflow for automatic chemical annotation of metabolite profiling data from liquid chromatography coupled with multistage accurate mass spectrometry (LC-MS(n)), which we used to systematically screen for the presence of tea-derived metabolites in human urine samples after green tea consumption. Reaction rules for intestinal degradation and human biotransformation were systematically applied to chemical structures of 75 green tea components, resulting in a virtual library of 27,245 potential metabolites. All matching precursor ions in the urine LC-MS(n) data sets, as well as the corresponding fragment ions, were automatically annotated by in silico generated (sub)structures. The results were evaluated based on 74 previously identified urinary metabolites and lead to the putative identification of 26 additional green tea-derived metabolites. A total of 77% of all annotated metabolites were not present in the Pubchem database, demonstrating the benefit of in silico metabolite prediction for the automatic annotation of yet unknown metabolites in LC-MS(n) data from nutritional metabolite profiling experiments. PMID- 24779708 TI - The mitochondrial cardiolipin remodeling enzyme lysocardiolipin acyltransferase is a novel target in pulmonary fibrosis. AB - RATIONALE: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. OBJECTIVES: To define a role for LYCAT in human and murine models of pulmonary fibrosis. METHODS: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. MEASUREMENTS AND MAIN RESULTS: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. CONCLUSIONS: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID- 24779710 TI - Chemistry, biology, and medicine of fluorescent nanomaterials and related systems: new insights into biosensing, bioimaging, genomics, diagnostics, and therapy. PMID- 24779711 TI - Prognostic evaluation of patients undergoing living-donor liver transplant by APACHE II and MELD scores. AB - OBJECTIVES: We hypothesized that the combination of APACHE II and Model for End Stage Liver Disease systems would work satisfactorily in patients admitted to intensive care unit after living-donor liver transplant. MATERIALS AND METHODS: Data were retrospectively collected from the database of our surgical team. The study included 38 patients (hepatitis B virus cirrhosis, 47.4%; hepatocellular carcinoma, 28.9%; other diseases, 23.7%). Laboratory values were obtained. Vital signs, Glasgow Coma scale scores, and urine output were abstracted. Variables included age, sex, acute physiology score, APACHE II score, APACHE II-predicted intensive care unit and hospital mortality, predicted length of intensive care unit, and hospital stay. Patients' actual length of intensive care unit and hospital stays, intensive care unit and hospital discharge status, and discharge location were recorded. Standardized mortality ratios were calculated. Discrimination and calibration of APACHE II were assessed. All patients were divided into 3 groups: Model for End-Stage Liver Disease score: >25, 18 to 25, and <18. Predicted hospital mortality was calculated and compared. RESULTS: Mean APACHE II scores of survivors and non-survivors were 13.03 and 23.67. Mean risk of death was 7.05% and 25.07%. APACHE II scores and risk of death between survivors and non-survivors was significantly different (P <.001). The cutoff value of APACHE II score and Model for End-Stage Liver Disease score in the receiving operating characteristic curve was 20 and 25. Patients with APACHE II scores greater than 20 or Model for End-Stage Liver Disease scores greater than 25 had higher predicted hospital mortality after living-donor liver transplant. CONCLUSIONS: The modified APACHE II model provides an accurate prognosis of patients receiving a living-donor liver transplant. The combined application of Model for End-Stage Liver Disease score and APACHE II score can improve the predictive accuracy. PMID- 24779713 TI - Nurses' perceptions of education on invasive mechanical ventilation. AB - BACKGROUND: Intensive care units (ICUs) encompass advanced clinical management and technology, mandating continuing education for nurses to maintain competency. This study examined nurses' perceptions of current education on invasive mechanical ventilation in an Australian ICU. METHODS: Qualitative data were obtained from five optional open-ended questions as part of a larger 30-item cross-sectional survey of 160 ICU nurses. Content analysis was used to code the data, developing concepts and themes. RESULTS: Fifty nurses (31%) completed at least one open-ended question. Content analysis identified five major themes: advanced knowledge, in-service education, practical structured education, interactive bedside teaching, and practicing safe care. Respondents' perceived continuing education on invasive mechanical ventilation to be more focused on novice than experienced ICU nurses and recommended practical, structured bedside teaching as the preferred method of education. CONCLUSION: Respondents recognized the need for interactive, practical, bedside education sessions to transfer learning into the everyday work environment. PMID- 24779712 TI - Cisplatin intrastrand adducts sensitize DNA to base damage by hydrated electrons. AB - The oligonucleotide TTTTTGTGTTT with or without a cisplatin adduct was reacted with hydrated electrons generated by ionizing radiation. Hydroxyl radicals were quenched with ethylenediaminetetraacetic acid (EDTA), and the solutions were bubbled with wet nitrogen to eliminate oxygen, a scavenger of hydrated electrons. Prior to irradiation, the structure of the initial cisplatin adduct was identified by mass spectrometry as G-cisplatin-G. Radiation damage to DNA bases was quantified by high-performance liquid chromatography (HPLC), after enzymatic digestion of the TTTTTGTGTTT-cisplatin complex to deoxyribonucleosides. The masses of the platinum adducts following digestion and separation by HPLC were measured by mass spectrometry. Our results demonstrate that hydrated electrons induce damage to thymines as well as detachment of the cisplatin moiety from both guanines in the oligonucleotide. This detachment regenerates both unmodified guanine and damaged guanine, in equimolar amounts. At 1000 Gy, a net average of 2.5 thymines and 1 guanine are damaged for each platinum lost from the oligonucleotide. Given the extensive base damage that occurs for each cisplatin adduct lost, it is clear that, prior to undergoing detachment, these adducts must catalyze several cycles of reactions of hydrated electrons with DNA bases. It is likely that a single reaction leads to the loss of the cisplatin adduct and the damage observed on the guanine base; however, the damage to the thymine bases must require the continued presence of the cisplatin adduct, acting as a catalyst. To our knowledge, this is the first time that platinum-DNA adducts have been shown to have catalytic activity. We propose two pathways for the interaction of hydrated electrons with TTTTTGTGTTT-cisplatin: (1) the hydrated electron is initially captured by a thymine base and transferred by base to base electron hopping to the guanine site, where the cisplatin moiety detaches from the oligonucleotide via dissociative electron attachment, and (2) the hydrated electron interacts directly with the platinum-guanine adduct and induces detachment of the cisplatin moiety via dissociative electron attachment. Although the precise mechanism remains to be elucidated, our results provide important insights into the radiosensitization of DNA by cisplatin. PMID- 24779714 TI - Career coaching: innovative academic-practice partnership for professional development. AB - This article describes an academic-practice partnership that uses career coaching to support the health care system's strategic plans to increase nurses' educational level. Nurses and other employees seek coaching to explore their career path and create an educational plan to accomplish their goal. Career coaching by nursing faculty provides a unique service as they have expert knowledge of various educational programs as well as methods for achieving academic success. The academic-practice partnership is a win-win-win; the health care system achieves advancement of professional nursing practice, employees are supported to advance their education and professional nursing practice, and faculty benefit from immersion in current professional concerns and issues. PMID- 24779715 TI - Preparing new nurse graduates for practice in multiple settings: a community based academic-practice partnership model. AB - Responding to local and national concerns about the nursing workforce, the California Institute for Nursing and Health Care worked with private and public funders and community health care partners to establish community-based transition-to-practice programs for new RN graduates unable to secure nursing positions in the San Francisco Bay Area. The goals were to retain new RN graduates in nursing and further develop their skills and competencies to increase their employability. Leaders from academic and inpatient, ambulatory, and community-based practice settings, as well as additional community partners, collaboratively provided four 12- to 16-week pilot transition programs in 2010 2011. A total of 345 unemployed new nurse graduates enrolled. Eighty-four percent of 188 respondents to a post-program survey were employed in inpatient and community settings 3 months after completion. Participants and clinical preceptors also reported increases in confidence and competence. PMID- 24779716 TI - Examination of the teaching styles of nursing professional development specialists, part I: best practices in adult learning theory, curriculum development, and knowledge transfer. AB - The American Nurses Association advocates for nursing professional development (NPD) specialists to have an earned graduate degree, as well as educational and clinical expertise. However, many NPD specialists have limited exposure to adult learning theory. Limited exposure to adult learning theory may affect NPD educational practices, learning outcomes, organizational knowledge transfer, and subsequently, the professional development of the nurses they serve and quality of nursing care. An examination of current teaching practices may reveal opportunities for NPD specialists to enhance educational methods to promote learning, learning transfer, and organizational knowledge and excellence. This article, the first in a two-part series, examines best practices of adult learning theories, nursing professional development, curriculum design, and knowledge transfer. Part II details the results of a correlational study that examined the effects of four variables on the use of adult learning theory to guide curriculum development for NPD specialists in hospitals. PMID- 24779717 TI - Comparison of hybrid and completely online RN-to-BSN curricula: aspects of program structure that lead to success. AB - The large increase in the number of RN-to-BSN programs has occurred in the context of the expansion of Internet-based resources. This article expands on an earlier reported evaluation of a program based on community-derived needs. Several dimensions were identified that appear to contribute to student success in a blended-hybrid and completely online curricula. Students move through a synchronous cohort curriculum. The graduation rate for both programs was above the national average for all programs (80%), and graduation rate for the blended hybrid program (92%) exceeded the online program (88%). Social support theory framed the important factors in a way that paralleled the factors reported by students as leading to their success. PMID- 24779719 TI - Features of an effective operative dentistry learning environment: students' perceptions and relationship with performance. AB - OBJECTIVE: Students' perceptions of their learning environment influence the quality of outcomes they achieve. Learning dental operative techniques in a simulated clinic environment is characterised by reciprocal interactions between skills training, staff- and student-related factors. However, few studies have examined how students perceive their operative learning environments and whether there is a relationship between their perceptions and subsequent performance. Therefore, this study aimed to clarify which learning activities and interactions students perceived as supporting their operative skills learning and to examine relationships with their outcomes. METHODS: Longitudinal data about examples of operative laboratory sessions that were perceived as effective or ineffective for learning were collected twice a semester, using written critical incidents and interviews. Emergent themes from these data were identified using thematic analysis. Associations between perceptions of learning effectiveness and performance were analysed using chi-square tests. RESULTS: Students indicated that an effective learning environment involved interactions with tutors and peers. This included tutors arranging group discussions to clarify processes and outcomes, providing demonstrations and constructive feedback. Feedback focused on mistakes, and not improvement, was reported as being ineffective for learning. However, there was no significant association between students' perceptions of the effectiveness of their learning experiences and subsequent performance. CONCLUSIONS: It was clear that learning in an operative technique setting involved various factors related not only to social interactions and observational aspects of learning but also to cognitive, motivational and affective processes. Consistent with studies that have demonstrated complex interactions between students, their learning environment and outcomes, other factors need investigation. PMID- 24779718 TI - microRNA 31 functions as an endometrial cancer oncogene by suppressing Hippo tumor suppressor pathway. AB - BACKGROUND: We aimed to investigate whether MIR31 is an oncogene in human endometrial cancer and identify the target molecules associated with the malignant phenotype. METHODS: We investigated the growth potentials of MIR31 overexpressing HEC-50B cells in vitro and in vivo. In order to identify the target molecule of MIR31, a luciferase reporter assay was performed, and the corresponding downstream signaling pathway was examined using immunohistochemistry of human endometrial cancer tissues. We also investigated the MIR31 expression in 34 patients according to the postoperative risk of recurrence. RESULTS: The overexpression of MIR31 significantly promoted anchorage independent growth in vitro and significantly increased the tumor forming potential in vivo. MIR31 significantly suppressed the luciferase activity of mRNA combined with the LATS2 3'-UTR and consequently promoted the translocation of YAP1, a key molecule in the Hippo pathway, into the nucleus. Meanwhile, the nuclear localization of YAP1 increased the transcription of CCND1. Furthermore, the expression levels of MIR31 were significantly increased (10.7-fold) in the patients (n = 27) with a high risk of recurrence compared to that observed in the low-risk patients (n = 7), and this higher expression correlated with a poor survival. CONCLUSIONS: MIR31 functions as an oncogene in endometrial cancer by repressing the Hippo pathway. MIR31 is a potential new molecular marker for predicting the risk of recurrence and prognosis of endometrial cancer. PMID- 24779720 TI - Diffusion tensor imaging findings in semi-acute mild traumatic brain injury. AB - The past 10 years have seen a rapid increase in the use of diffusion tensor imaging to identify biomarkers of traumatic brain injury (TBI). Although the literature generally indicates decreased anisotropic diffusion at more chronic injury periods and in more severe injuries, considerable debate remains regarding the direction (i.e., increased or decreased) of anisotropic diffusion in the acute to semi-acute phase (here defined as less than 3 months post-injury) of mild TBI (mTBI). A systematic review of the literature was therefore performed to (1) determine the prevalence of different anisotropic diffusion findings (increased, decreased, bidirectional, or null) during the semi-acute injury phase of mTBI and to (2) identify clinical (e.g., age of injury, post-injury scan time, etc.) and experimental factors (e.g., number of unique directions, field strength) that may influence these findings. Results from the literature review indicated 31 articles with independent samples of semi-acute mTBI patients, with 13 studies reporting decreased anisotropic diffusion, 11 reporting increased diffusion, 2 reporting bidirectional findings, and 5 reporting null findings. Chi squared analyses indicated that the total number of diffusion-weighted (DW) images was significantly associated with findings of either increased (DW >= 30) versus decreased (DW <= 25) anisotropic diffusion. Other clinical and experimental factors were not statistically significant for direction of anisotropic diffusion, but these results may have been limited by the relatively small number of studies within each domain (e.g., pediatric studies). In summary, current results indicate roughly equivalent number of studies reporting increased versus decreased anisotropic diffusion during semi-acute mTBI, with the number of unique diffusion images being statistically associated with the direction of findings. PMID- 24779721 TI - Using estimated true safety event rates versus flagged safety event rates: does it change hospital profiling and payment? AB - OBJECTIVE: To assess whether use of the AHRQ Patient Safety Indicator (PSI) composite measure versus modified composite measures leads to changes in hospital profiles and payments. DATA SOURCES/STUDY SETTING: Retrospective analysis of 2010 Veterans Health Administration discharge data. STUDY DESIGN: We used the AHRQ PSI software (v4.2) to obtain PSI-flagged events and composite scores for all 151 hospitals in the database (n = 517,814 hospitalizations). We compared the AHRQ PSI composite to two modified composites that estimated "true safety events" from previous chart abstraction findings: one with modified numerators based on the positive predictive value (PPV) of each PSI, and one with similarly modified numerators but whose denominators were based on the expected fraction of PSI eligible cases that remained after removing those PSIs that were present-on admission (POA). PRINCIPAL FINDINGS: Although a small percentage (5-6 percent) of hospitals changed outlier status based on modified PSI composites, some of these changes were substantial; 30 and 19 percent of hospitals changed >=20 ranks after adjustment for PPVs and POA flags, respectively. We estimate that 33 percent of hospitals would see a change of at least 10 percent in performance payments. CONCLUSIONS: Changes in hospital profiles and payments would be substantial for some hospitals if the PSI composite score used weights reflecting the relative prevalence of true versus flagged events. PMID- 24779722 TI - The association between employee obesity and employer costs: evidence from a panel of U.S. employers. AB - PURPOSE: To estimate the employer costs associated with employee obesity. DESIGN: The study used cross-sectional analysis of employee health-risk assessment, disability, workers' compensation, and medical claims data from 2006 to 2008. SETTING: The study took place in the United States from 2006 to 2008. SUBJECTS: A panel database with 29,699 employees drawn from a panel of employers and observed for 3 years each (N = 89,097) was used. MEASURES: Workdays lost owing to illness and disability; the cost of medical, short-term disability, and workers' compensation claims; and employees' adjusted body mass indices (BMI) were measured. ANALYSIS: We model the number and probability of workdays lost from illness, short-term disability, and workers' compensation events; short-term disability and workers' compensation payments; and health care spending as a function of BMI. We estimate spline regression models and fit results using a third-degree fractional polynomial. RESULTS: Probability of disability, workers' compensation claims, and number of days missed owing to any cause increase with BMI above 25, as do total employer costs. The probability of a short-term disability claim increases faster for employees with hypertension, hyperlipidemia, or diabetes. Normal weight employees cost on average $3830 per year in covered medical, sick day, short-term disability, and workers' compensation claims combined; morbidly obese employees cost more than twice that amount, or $8067, in 2011 dollars. CONCLUSION: Obesity is associated with large employer costs from direct health care and insurance claims and indirect costs from lost productivity owing to workdays lost because of illness and disability. PMID- 24779723 TI - Internet and video game use in relation to overweight in young adults. AB - PURPOSE: To examine the relationship between interactive media use (Internet and video games) and overweight risk in young adults. DESIGN: Prospective cohort study. SETTING: France (TEMPO study). SUBJECTS: Community sample of 674 young adults aged 22 to 35 in 2009 (response rate to the original mail out: 44.3%). MEASURES: Data were collected through mail-based questionnaires from study participants in 1999 (juvenile overweight, juvenile TV use) and 2009 (overweight, Internet and video game use, regular physical activity), and from their parents who participated in the GAZEL study from 1989 to 2009 (parental overweight). ANALYSIS: Logistic regression. RESULTS: Participants who engaged in regular video game use (>1 time/wk) were more likely to be overweight than those who did not (odds ratio [OR] 2.20, 95% confidence interval [CI] 1.42-3.42). Adjusting for sex, regular athletic activity, juvenile overweight, juvenile TV use, and parental overweight, the OR associated with video game use decreased but remained statistically significant (OR 1.94, 95% CI 1.15-3.28). We found no significant association between Internet use and overweight. CONCLUSION: Video game use may be a relevant target for interventions aiming to decrease the burden of overweight and associated consequences in young adults. PMID- 24779725 TI - Editor's desk: The performance issue. PMID- 24779726 TI - Should we have extended his life with medical care or helped him have a good death? PMID- 24779727 TI - Noninvasive Imaging of PSMA in prostate tumors with (89)Zr-Labeled huJ591 engineered antibody fragments: the faster alternatives. AB - Engineered antibody fragments offer faster delivery with retained tumor specificity and rapid clearance from nontumor tissues. Here, we demonstrate that positron emission tomography (PET) based detection of prostate specific membrane antigen (PSMA) in prostatic tumor models using engineered bivalent antibodies built on single chain fragments (scFv) derived from the intact antibody, huJ591, offers similar tumor delineating properties but with the advantage of rapid targeting and imaging. (89)Zr-radiolabeled huJ591 scFv (dimeric scFv-CH3; (89)Zr Mb) and cysteine diabodies (dimeric scFv; (89)Zr-Cys-Db) demonstrated internalization and similar Kds (~2 nM) compared to (89)Zr-huJ591 in PSMA(+) cells. Tissue distribution assays established the specificities of both (89)Zr-Mb and (89)Zr-Cys-Db for PSMA(+) xenografts (6.2 +/- 2.5% ID/g and 10.2 +/- 3.4% ID/g at 12 h p.i. respectively), while minimal accumulation in PSMA(-) tumors was observed. From the PET images, (89)Zr-Mb and (89)Zr-Cys-Db exhibited faster blood clearance than the parent huJ591 while tumor-to-muscle ratios for all probes show comparable values across all time points. Ex vivo autoradiography and histology assessed the distribution of the probes within the tumor. Imaging PSMA-expressing prostate tumors with smaller antibody fragments offers rapid tumor accumulation and accelerated clearance; hence, shortened wait periods between tracer administration and high-contrast tumor imaging and lower dose-related toxicity are potentially realized. PMID- 24779729 TI - Hospital stay following complex major head and neck resection: what factors play a role? AB - OBJECTIVES: Identify factors which have an impact on the length of postoperative hospital stay in patients undergoing major surgical resection for head and neck cancer. DESIGN: Retrospective study using hospital case notes. SETTING: Tertiary centre. PARTICIPANTS: One hundred and eighty-four patients who underwent 191 major head and neck resections between 2006 and 2010 were identified from the head and neck oncology database. An additional cohort of 52 patients from a second centre was used to externally validate the model. METHODS: Data collected on 13 variables including age, preoperative haemoglobin level, body mass index, timing of surgery (primary or recurrent tumour), category of surgical procedure (clean, clean-contaminated, contaminated, dirty), tracheostomy (yes or no) and duration of the operation were analysed using a multiple linear regression. RESULTS: In the 13 parameter model, the four variables that were found to significantly (P < 0.05) prolong length of stay (LOS) were surgical wound type (clean-contaminated, P = 2.19 * 10(-6) versus clean), tracheostomy (P = 0.0034), operation time (P = 0.011) and American Society of Anaesthesiologists (ASA) grades 3 and 4 (P = 0.0067) versus 1 and 2. The statistically significant variables were used to generate a preoperative submodel without the operative time and a postoperative submodel with all four variables. Overall, the best model based on adjusted R(2) was the postoperative model. When fitted on the external data set, there was no significant difference in the residuals, indicating that the models generalise across centres. CONCLUSION: Clean contaminated wound was the most significant factor affecting the LOS, with others being ASA grades 3 and 4, longer duration of surgery and presence of a tracheostomy. Using these parameters, it is possible to predict the LOS in patients undergoing major surgical resection for head and neck cancer. PMID- 24779728 TI - Formation of highly structured cubic micellar lipid nanoparticles of soy phosphatidylcholine and glycerol dioleate and their degradation by triacylglycerol lipase. AB - Lipid nanoparticles of reversed internal phase structures, such as cubic micellar (I2) structure show good drug loading ability of peptides and proteins as well as some small molecules. Due to their controllable small size and inner morphology, such nanoparticles are suitable for drug delivery using several different administration routes, including intravenous, intramuscular, and subcutaneous injection. A very interesting system in this regard, is the two component soy phosphatidylcholine (SPC)/glycerol dioleate (GDO) system, which depending on the ratio of the lipid components form a range of reversed liquid crystalline phases. For a 50/50 (w/w) ratio in excess water, these lipids have been shown to form a reversed cubic micellar (I2) phase of the Fd3m structure. Here, we demonstrate that this SPC/GDO phase, in the presence of small quantities (5-10 wt %) of Polysorbate 80 (P80), can be dispersed into nanoparticles, still with well defined Fd3m structure. The resulting nanoparticle dispersion has a narrow size distribution and exhibit good long-term stability. In pharmaceutical applications, biodegradation pathways of the drug delivery vehicles and their components are important considerations. In the second part of the study we show how the structure of the particles evolves during exposure to a triacylglycerol lipase (TGL) under physiological-like temperature and pH. TGL catalyzes the lipolytic degradation of acylglycerides, such as GDO, to monoglycerides, glycerol, and free fatty acids. During the degradation, the interior phase of the particles is shown to undergo continuous phase transitions from the reversed I2 structure to structures of less negative curvature (2D hexagonal, bicontinuous cubic, and sponge), ultimately resulting in the formation of multilamellar vesicles. PMID- 24779730 TI - Mechanisms and origins of switchable regioselectivity of palladium- and nickel catalyzed allene hydrosilylation with N-heterocyclic carbene ligands: a theoretical study. AB - The mechanisms and origins for the Pd- and Ni-catalyzed regioselective hydrosilylation of allene have been investigated by means of density functional theory (DFT) calculations. The free-energy profiles of Pd- and Ni-catalyzed reactions with small and bulky N-heterocyclic carbene (NHC) ligands are calculated to determine the mechanism for regioselectivities. The calculation results show that different metals (Ni vs Pd) lead to regiochemical reversals for the hydrosilylation of allene. The allylsilane is the major product via palladium catalysis with small NHC ligand, while the vinylsilane is the major product via nickel catalysis with bulky NHC ligand. Both electronic and steric factors play a key role in the regioselectivities for the hydrosilylation of allene via Pd and Ni catalysts. The calculation results are in good agreement with observed regioselectivities and could provide insights into the design of new catalysts for the regioselectivity of hydrosilylation reactions. PMID- 24779732 TI - Nickel-iron oxyhydroxide oxygen-evolution electrocatalysts: the role of intentional and incidental iron incorporation. AB - Fe plays a critical, but not yet understood, role in enhancing the activity of the Ni-based oxygen evolution reaction (OER) electrocatalysts. We report electrochemical, in situ electrical, photoelectron spectroscopy, and X-ray diffraction measurements on Ni(1-x)Fe(x)(OH)2/Ni(1-x)Fe(x)OOH thin films to investigate the changes in electronic properties, OER activity, and structure as a result of Fe inclusion. We developed a simple method for purification of KOH electrolyte that uses precipitated bulk Ni(OH)2 to absorb Fe impurities. Cyclic voltammetry on rigorously Fe-free Ni(OH)2/NiOOH reveals new Ni redox features and no significant OER current until >400 mV overpotential, different from previous reports which were likely affected by Fe impurities. We show through controlled crystallization that beta-NiOOH is less active for OER than the disordered gamma NiOOH starting material and that previous reports of increased activity for beta NiOOH are due to incorporation of Fe-impurities during the crystallization process. Through-film in situ conductivity measurements show a >30-fold increase in film conductivity with Fe addition, but this change in conductivity is not sufficient to explain the observed changes in activity. Measurements of activity as a function of film thickness on Au and glassy carbon substrates are consistent with the hypothesis that Fe exerts a partial-charge-transfer activation effect on Ni, similar to that observed for noble-metal electrode surfaces. These results have significant implications for the design and study of Ni(1-x)Fe(x)OOH OER electrocatalysts, which are the fastest measured OER catalysts under basic conditions. PMID- 24779731 TI - Evaluating marker-guided treatment selection strategies. AB - A potential venue to improve healthcare efficiency is to effectively tailor individualized treatment strategies by incorporating patient level predictor information such as environmental exposure, biological, and genetic marker measurements. Many useful statistical methods for deriving individualized treatment rules (ITR) have become available in recent years. Prior to adopting any ITR in clinical practice, it is crucial to evaluate its value in improving patient outcomes. Existing methods for quantifying such values mainly consider either a single marker or semi-parametric methods that are subject to bias under model misspecification. In this article, we consider a general setting with multiple markers and propose a two-step robust method to derive ITRs and evaluate their values. We also propose procedures for comparing different ITRs, which can be used to quantify the incremental value of new markers in improving treatment selection. While working models are used in step I to approximate optimal ITRs, we add a layer of calibration to guard against model misspecification and further assess the value of the ITR non-parametrically, which ensures the validity of the inference. To account for the sampling variability of the estimated rules and their corresponding values, we propose a resampling procedure to provide valid confidence intervals for the value functions as well as for the incremental value of new markers for treatment selection. Our proposals are examined through extensive simulation studies and illustrated with the data from a clinical trial that studies the effects of two drug combinations on HIV-1 infected patients. PMID- 24779733 TI - Reply: To PMID 24383789. PMID- 24779735 TI - Aflatoxin levels in raw and processed hazelnuts in Turkey. AB - Aflatoxin levels in hazelnut samples obtained from exporter companies were monitored over a 3-year period. A total of 3188 samples of raw and processed hazelnuts were analysed using an HPLC method. The total aflatoxin content of the contaminated samples was in the range of 0.02-78.98 ug kg(-1) for hazelnut kernels, 0.07-43.59 ug kg(-1) for roasted hazelnut kernels, 0.02-39.17 ug kg(-1) for roasted sliced hazelnut kernels, and 0.02-11.20 ug kg(-1) for hazelnut purees, respectively, showing that the variations of aflatoxin contamination were very high. The results of aflatoxin analysis revealed that the aflatoxin contamination in the hazelnut samples was at a tolerable level. A total of 3147 samples were contaminated with aflatoxins, although below the legal limits. However, the aflatoxin contents of 41 samples exceeded the legal limits. Therefore, aflatoxin contents of hazelnuts should be monitored regularly to minimise the risk of aflatoxin hazard, and pre- and post-harvest strategies should be developed to prevent aflatoxin formation. PMID- 24779734 TI - Metabolic activity of the tongue in obstructive sleep apnea. A novel application of FDG positron emission tomography imaging. AB - RATIONALE: The metabolic activity of the tongue is unknown in patients with obstructive sleep apnea (OSA). Tongue electromyographic (EMG) activity is increased in patients with OSA. This increase in tongue EMG activity is thought to be related to either increased neuromuscular compensation or denervation with subsequent reinnervation of the muscle fibers. Increased glucose uptake in the tongue would support increased neuromuscular compensation, whereas decreased glucose uptake in the tongue would support denervation with subsequent reinnervation of the muscle fibers. OBJECTIVES: To investigate the metabolic activity of the genioglossus and control upper airway muscles in obese patients with sleep apnea compared with obese control subjects. METHODS: Obese subjects with and without OSA underwent a standard overnight sleep study to determine an apnea-hypopnea index. Each subject had a positron emission tomography with [(18)F]-2-fluoro-2-deoxy-D-glucose scan in addition to noncontrast computed tomography or magnetic resonance imaging. Glucose uptake was quantified within upper airway tissues with the standardized uptake value. MEASUREMENTS AND MAIN RESULTS: We recruited 30 obese control subjects (apnea-hypopnea index, 4.7 +/- 3.1 events per hour) and 72 obese patients with sleep apnea (apnea-hypopnea index, 43.5 +/- 28.0 events per hour). Independent of age, body mass index, sex, and race, patients with OSA had significantly reduced glucose uptake in the genioglossus (P = 0.03) in comparison with obese normal subjects. No differences in standardized uptake value were found in the control muscles (masseter [P = 0.38] and pterygoid [P = 0.70]) and subcutaneous fat deposits (neck [P = 0.44] and submental [P = 0.95]) between patients with OSA and control subjects. CONCLUSIONS: There was significantly reduced glucose uptake in the genioglossus of patients with sleep apnea in comparison with obese normal subjects with [(18)F]-2-fluoro-2-deoxy-D-glucose positron emission tomography imaging. The reduction in glucose uptake was likely secondary to alterations in tongue muscle fiber-type or secondary to chronic denervation. The reduced glucose uptake argues against the neuromuscular compensation hypothesis explaining the increase in tongue EMG activity in obese patients with OSA. PMID- 24779736 TI - Monitoring dithiocarbamate fungicide residues in greenhouse and non-greenhouse tomatoes in Iran by HPLC-UV. AB - The simultaneous analysis of dithiocarbamate fungicide residues on greenhouse and non-greenhouse tomatoes was performed by high-performance liquid chromatography with UV detection. A calibration curve with spiked samples was plotted to determine dithiocarbamate residues in tomato samples. Limits of detection and quantification were approximately 0.05 and 0.2 ug g(-1), respectively. The ranges of mean recoveries at five spiking levels for all dithiocarbamates of interest were between 88.2%-95.7% and 99.5%-100.8% in standards and spiked samples, respectively. In this study, 40 greenhouse and 40 non-greenhouse tomato samples were analysed. None of the samples analysed contained dithiocarbamates in excess of the maximum residue levels established by the Codex Committee on Pesticide Residues, except for one greenhouse sample, with ethylenebisdithiocarbamates at 3.2 ug g(-1). PMID- 24779737 TI - Nitrate content in dandelion (Taraxacum officinale) and lettuce (Lactuca sativa) from organic and conventional origin: intake assessment. AB - To estimate the actual intake of nitrate by consumption of different lettuce varieties, 52 samples of lettuce of different origins and dandelion from 15 different areas of northeast Slovenia were analysed. For determination of actual nitrate content, a continuous flow method was used. The lowest nitrate content was detected in dandelion, with a mean value of 195 mg kg(-1) (ranging 47-487 mg kg(-1)). Nitrate content in lettuce of different origins ranged 85-3237 mg kg( 1), with a mean value of 1196 mg kg(-1). The mean nitrate content in organically cultivated lettuce was 890 mg kg(-1), which was considerably lower than the nitrate level in conventionally cultivated lettuce (1298 mg kg(-1)). Consumption of 100 g of dandelion would result in a maximal nitrate intake corresponding to 22% of the acceptable daily intake (ADI), with values up to seven times higher for lettuce. PMID- 24779738 TI - LC-MS/MS determination of acrylamide in instant noodles from supermarkets in the Hebei province of China. AB - Acrylamide (AA) concentrations in instant noodles (90 samples, covering 10 different brands) from Hebei Province of China were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The instant noodles were sampled from the southern and northern areas of Hebei Province (Shijiazhuang and Tangshan, respectively). The average content of AA for all 10 instant noodle brands was 6-145 ug/kg. The average content of AA in fried instant noodles was 4.47 times of those in non-fried ones, indicating the influence of the frying process. The average content of AA in instant noodles from Shijiazhuang was 1.64 times that of the samples from Tangshan (56 ug/kg). Eighty-four percent of the instant noodle samples in Hebei were contaminated with AA, with an average content of 80 ug/kg. These observations will be helpful for evaluating individual exposure to AA from instant noodles in China. PMID- 24779739 TI - Determination of heavy metals in different honey brands from Iranian markets. AB - A variety of elements are present in honey at different concentrations. Although some of these heavy metals and trace elements are useful nutrition, at higher levels they could cause health problems. In order to achieve confidence about food safety, regular monitoring of food quality is necessary. In this study, heavy metals and trace element contents were determined by inductively coupled plasma atomic emission spectrometer in 10 different honey brands from Iranian markets. All heavy metal contents in these samples were within ranges as reported in literature, except for Hg, Al and As. Compared with recommended daily intakes, it is concluded that heavy metals or trace elements intoxication following honey consumption in Iran is unlikely. PMID- 24779740 TI - Co-occurrence of mycoflora, aflatoxins and fumonisins in maize and rice seeds from markets of different districts in Cairo, Egypt. AB - The mycoflora and mycotoxins contamination of commercial maize and rice grains collected from local markets of the major five zones of the province of Cairo, Egypt, represented by 20 different districts were studied. A total number of about 23 species belonging to 12 different genera of fungi were isolated and identified. About 70% of the samples were infected with Aspergillus flavus and Aspergillus niger, with percentages of 33%, 40% recovered from maize and 46%, 27% recovered from rice, respectively. The percentages of infection of maize ranged from 16% to 142%. The percentages of infection of rice seeds ranged from 6% to 93%. Total aflatoxins and fumonisins detected in maize averaged 9.75 and 33 ug/kg, respectively. Total aflatoxins and fumonisins detected in rice averaged 5.15 and 1014 ug/kg, respectively. PMID- 24779741 TI - Occurrence of aflatoxins in export-quality Pakistani rice. AB - A survey was conducted to assess the extent of aflatoxin B1, B2, G1 and G2 contamination of export-quality rice. Five hundred and nineteen batches of rice (including white, brown and sella rice) from various exporters were analysed for aflatoxins using Mycosep column clean-up and quantification with high-performance liquid chromatography, during the year 2010. Mean concentrations for aflatoxin B1 (AFB1) and aflatoxin B2 (AFB2) were 0.56 ug kg(-1) and 0.03 ug kg(-1) for brown rice, 0.49 ug kg(-1) and 0.03 ug kg(-1) for white rice and 0.73 ug kg(-1) and 0.02 ug kg(-1) for sella rice, with an overall positive (>= the limit of detection of 0.1 ug kg(-1) for AFB1 and AFG1; and 0.05 ug kg(-1) for AFB2 and AFG2) incidence of 49%. Out of all analysed samples, only 1.9% was found positive for aflatoxin G1. Highly contaminated samples were found in the month of August, with findings for aflatoxin B1 (AFB1) and aflatoxin B2 (AFB2) of 16.65 ug kg(-1) and 2.64 ug kg(-1), respectively. During the whole year, monitoring aflatoxin concentrations exhibited a distinct variation according to the climatic conditions, with relatively high levels during March, July and August, which could be related to favourable environmental conditions. PMID- 24779742 TI - Determination of essential and non-essential elements in various tea leaves and tea infusions consumed in Turkey. AB - Tea is one of the most popular beverages in the world. Thus, the chemical components in tea are of great interest, especially in relation to health. In this study, 12 tea samples (10 black, 1 white and 1 green) and 5 herbal tea samples were purchased from supermarkets in Izmir, Turkey. Sample preparation has been performed using wet and microwave digestion procedures. The elemental content (Fe, Zn, Cu, Mn, Ni, Na and K) in the digests and infusions has been analysed. Generally, elemental contents in tea leaves were found to be higher than those in tea infusions. The accuracy of the method was checked and confirmed by standard reference material analyses. The comparison of wet and microwave digestion has not shown significantly different results. Therefore, the microwave digestion procedure was preferred because it is less laborious. The elemental intake related to tea consumption has also been studied. PMID- 24779743 TI - Evaluation of total aflatoxin, nitrate and nitrite levels in layer feed samples of companies producing their own feed in Edincik and Bandirma province of Turkey. AB - Feed contamination by fungi can lead to nutrient losses and detrimental effects on animal health and production. The presence of nitrates and nitrites in food can be harmful to both people and animals. The aim of this study was to determine total aflatoxin, nitrate and nitrite levels in layer feed samples from companies producing their own feed in Edincik and Bandirma provinces in Turkey and to discuss the potential risk to animal health. The results of the analyses indicated that mean total aflatoxin (AFT) ranged from 0.4 to 36.8 ug kg(-1) and from 0.45 to 47.0 ug kg(-1) in the year 2007 and the year 2008 samples, respectively. It was determined that nitrate levels were 2.4-10 and 1.7-13 ug kg( 1) and that nitrite levels were 0-2.4 ug kg(-1) and 0-2.6 ug kg(-1) in these years, respectively. The levels of total aflatoxin, nitrate and nitrite in the layer samples could not be considered a risk to poultry health and productivity. PMID- 24779744 TI - Monitoring of mercury, arsenic, cadmium and lead in Ayurvedic formulations marketed in Delhi by flame AAS and confirmation by ICP-MS. AB - The quality and safety of Ayurvedic formulations has become a serious issue, as this Indian system of medicine is used by 80% of the Indian population. Hence, the present study was performed to evaluate heavy metals contents by flame atomic absorbance spectroscopy (AAS) measurements and confirmation by inductive coupled plasma-mass spectroscopy (ICP-MS). A total of 78 formulations (56 herbal, 19 herbometallic and 3 metallic) were sampled. In herbal formulations, lead in 19.6% (11/56), cadmium in 21.4% (12/56), mercury and arsenic in 5.3% (3/56) were above the limit. Lead in 52.6% (10/19) of samples, cadmium in 26.3% (5/19) and mercury and arsenic contained in one herbometallic sample was above the limit. Heavy metals in all metal formulations were above the WHO limit. Significant batch variation was observed. The analytical results of flame AAS and ICP-MS did not differ significantly in the range of measurements in this study, which proves that both methods are satisfactory for estimation of heavy metals in these type of samples. PMID- 24779745 TI - Seasonal patterns of aflatoxin M1 contamination in commercial pasteurised milk from different areas in Thailand. AB - Aflatoxin M1 (AFM1) levels were determined in pasteurised milk from five commercial trademarks produced in different areas in Thailand. One hundred and twenty milk samples were collected from local markets in Chiang Mai province, Thailand, to evaluate AFM1 concentrations using immunoaffinity columns and high performance liquid chromatography with fluorescence detection. The overall median AFM1 level was 0.023 ug L(-1) ranging from 0.004 to 0.293 ug L(-1). All trademarks had average AFM1 concentrations lower than 0.05 ug L(-1), with those in Trademarks 3 to 5 being higher than Trademarks 1 and 2 (P < 0.01). All trademarks had different seasonal patterns of AFM1, even though operating in the same area. However, only Trademark 3 showed significant differences of AFM1 levels between seasons. The results suggested that farm management factors, rather than environment factors, were likely to be the main cause of AFM1 contamination in dairy products. PMID- 24779746 TI - Masticatory efficiency in complete denture wearers with reduced dental arches--a randomised cross-over study. AB - One obstacle to placing artificial posterior teeth in manufacturing complete dentures is a reduction of the space between the maxilla and the mandible. Occasionally, second molar placement is not performed, as it does not affect aesthetics, phonetics or comfort. The aim of this study was to compare the masticatory efficiency between patients wearing maxillary and mandibular complete dentures with reduced dental arches (without second molars) (WSM) and with full dental arches (FDA). Twenty subjects were divided into two groups and randomly received new complete dentures. Patients in Group 1 were given dentures WSM, and those in Group 2 were given dentures with FDA. After the post-placement visits, an initial masticatory efficiency test was performed with Optocal, an artificial test food. Fifteen days later, second molars were placed in Group 1 and removed from Group 2, and a new test was performed. Comminuted material was treated and sieved under vibration. The mean and standard deviation of masticatory efficiency with FDA were 10.4 and 8.1, respectively. In the tests WSM, the mean and standard deviation were 8.4 and 3.3, respectively. After removing the second molars in Group 2 and adding them in Group 1, the mean and standard deviation were 15.7 and 14.7 for Group 1 and 12.5 and 10.4 for Group 2, respectively. Within the limitations of this study, placing artificial teeth up to the first molars can be performed when needed without compromising masticatory efficiency. PMID- 24779747 TI - Transarterial infusion chemotherapy with cisplatin plus S-1 for hepatocellular carcinoma treatment: a phase I trial. AB - BACKGROUND: In Japan, transarterial infusion chemotherapy using cisplatin (CDDP TAI) is frequently used for advanced hepatocellular carcinoma (HCC). Moreover, oral chemotherapy with S-1, an oral fluoropyrimidine derivative, has also elicited promising responses in HCC patients. We determined the recommended dosage for CDDP-TAI plus S-1 combination therapy for advanced HCC. METHODS: Twelve Child-Pugh class A or B patients with advanced HCC who met the eligibility criteria were enrolled in this phase I trial. Patients received CDDP-TAI (infusion, day 1) plus S-1 (oral administration, days 1-21) every 5 weeks until disease progression. RESULTS: Cisplatin (65 mg/m(2)) was administered with S-1 at 50 mg . m(-2) day-1 (level 1, 3 patients), 60 mg . m(-2) day-1 (level 2, 3 patients), or 80 mg . m(-2) day-1 (level 3, 6 patients). The total number of treatment courses was 25 (median, 2 courses/patient; range, 1-6 courses). Dose limiting toxicity was not observed in any patient at any level; therefore, the recommended dosage for cisplatin and S-1 in combination was level 3. Grade 3 adverse events were elevated alanine aminotransferase levels (2 patients), elevated aspartate aminotransferase levels (2 patients), anemia (1 patient), and decreased platelet counts (1 patient). Median progression-free survival and overall survival were 73 days and 328 days, respectively. The disease control rate was 58% (7/12); 17% (2/12) of patients achieved partial response and 42% (5/12) achieved stable disease. CDDP-TAI plus S-1 is safe for the treatment of HCC. CONCLUSION: The recommended dosage for further evaluation of this combination therapy in phase II studies is 65 mg/m(2) CDDP and 80 mg/m(2) S-1. TRIAL REGISTRATION: UMIN; number: UMIN000003113. PMID- 24779748 TI - Effects of moderate aerobic exercise training on vascular health and blood pressure in African Americans. AB - As healthcare progresses toward individualized medicine, understanding how different racial groups respond to lifestyle interventions is valuable. It is established that African Americans have disproportionate levels of cardiovascular disease and impaired vascular health, and clinical practice guidelines suggest lifestyle interventions as the first line of treatment. Recently, the authors reported that 6 months of aerobic exercise improved inflammatory markers, flow mediated dilation (FMD), and levels of circulating endothelial microparticles (EMPs) in African American adults. This study is a subgroup analysis of the aerobic exercise-induced changes in vascular health and blood pressure (BP) measures, including carotid artery intima-media thickness (IMT), nitroglycerin mediated dilation (NMD), ambulatory BP, and office BP. Sedentary African American adults (53.4+/-6.2 years; 21 women and 5 men) showed improved vascular health but no change in BP. Carotid artery IMT decreased 6.4%, plasma nitric oxide levels increased 76.6%, plasma EMP levels decreased, percentage of FMD increased 59.6%, and FMD/NMD ratio increased 36.2% (P<.05 for all). Six months of aerobic exercise training is sufficient to elicit improvements in vascular structure and function in African Americans, even without improvements in BP measures or NMD (ie, smooth muscle function). To our knowledge, this is the first study to report such findings in African Americans. PMID- 24779749 TI - The use of acellular dermal matrix membrane for vertical soft tissue augmentation during submerged implant placement: a case series. AB - OBJECTIVE: To evaluate the efficiency of acellular dermal matrix membrane to augment vertical peri-implant soft tissue thickness during submerged implant placement. MATERIAL AND METHODS: Forty acellular dermal matrix-derived allogenic membranes (AlloDerm, BioHorizons, Birmingham, AL, USA) and 42 laser-modified surface internal hex implants (BioHorizons Tapered Laser Lok, Birmingham, AL, USA) were placed in submerged approach in 40 patients (15 males and 25 females, mean age 42.5 +/- 1.7) with a thin vertical soft tissue thickness of 2 mm or less. After 3 months, healing abutments were connected to implants, and the augmented soft tissue thickness was measured with periodontal probe. The gain in vertical soft tissue volume was calculated. Mann-Whitney U-test was applied and significance was set to 0.05. RESULTS: All 40 allografts healed successfully. Thin soft tissue before augmentation had an average thickness of 1.54 +/- 0.51 mm SD (range, 0.5-2.0 mm, median 1.75 mm), and after soft tissue augmentation with acellular dermal matrix, thickness increased to 3.75 +/- 0.54 mm SD (range, 3.0 5.0 mm, median 4.0 mm) at 3 months after placement. This difference between medians was found to be statistically significant (P < 0.001). Mean increase in soft tissue thickness was 2.21 +/- 0.85 mm SD (range, 1.0-4.5 mm, median 2.0 mm). CONCLUSIONS: It can be concluded that acellular dermal matrix membrane can be successfully used for vertical soft tissue augmentation. PMID- 24779750 TI - Miniaturization of NMR systems: desktop spectrometers, microcoil spectroscopy, and "NMR on a chip" for chemistry, biochemistry, and industry. PMID- 24779751 TI - Pregnancy in a unicornuate uterus: a case report. AB - INTRODUCTION: A unicornuate uterus accounts for 2.4 to 13% of all Mullerian anomalies. A unicornuate uterus with a non-communicating rudimentary horn may be associated with gynecological and obstetric complications such as infertility, endometriosis, hematometra, urinary tract anomalies, abortions, and preterm deliveries. It has a poor reproductive outcome and pregnancy management is still unclear. CASE PRESENTATION: We report a case of a 26-year-old Caucasian woman presenting with a unicornuate uterus with a non-communicating rudimentary horn. The diagnosis of the anomaly was based on two-dimensional and three-dimensional sonography. The excision of her symptomatic rudimentary horn and her ipsilateral fallopian tube was performed laparoscopically. The growth of the fetus was normal. At 20 weeks' pregnancy, her cervix started shortening and a tocolytic therapy was started. A cesarean delivery was successfully performed at 39 weeks and 4 days' gestation. CONCLUSIONS: Although the reproductive outcome of women with unicornuate uterus is poor, a successful pregnancy is possible. Routine excision of the rudimentary horn should be undertaken during non-pregnant state laparoscopically, and it would be necessary to screen such pregnancies for the development of intrauterine growth retardation with serial ultrasound assessments of the estimated fetal weight and the cervix length. PMID- 24779752 TI - Mayday message for senior nurses. PMID- 24779754 TI - Health service plays it safe. PMID- 24779761 TI - Using a national guideline to prevent and manage pressure ulcers. AB - Developing pressure ulcers is a painful and distressing event for patients, and one that can be prevented. The National Institute for Health and Care Excellence pressure ulcer guideline has recently been updated to cover the prevention and management of this condition. This article focuses on the recommendations that are relevant to nurses, covering areas such as risk assessment, skin assessment, repositioning, pressure-redistributing devices, dressings, patient and carer information, and training and education. It also identifies what senior nurses and nurse managers must do to ensure their staff can prevent and manage pressure ulcers effectively. PMID- 24779762 TI - Development of a community nursing drug chart. AB - In April 2011, three providers of community services in Brent and Ealing, in London, and Harrow, in Middlesex, integrated with an acute NHS provider, Ealing Hospital. As part of a newly merged integrated care organisation, the community health services pharmacist undertook an extensive review of all medicines management processes and activities to ensure that they were safe. One of the recommendations of the review was to harmonise processes, practices, policies and guidance documents between the three community services providers. This article describes the process of developing a community nursing drug chart, which involved auditing drug administration in community nursing sites across the three boroughs, consulting a focus group of nursing service leads and assessing how the chart compared with national standards. The aim of the article is to share the process and the drug chart with other community service providers. PMID- 24779763 TI - Leadership support for ward managers in acute mental health inpatient settings. AB - This article shares findings of work undertaken with a group of mental health ward managers to consider their roles through workshops using an action learning approach. The tensions between the need to balance the burden of administrative tasks and act as clinical role models, leaders and managers are considered in the context of providing recovery-focused services. The group reviewed their leadership styles, broke down the administrative elements of their roles using activity logs, reviewed their working environments and considered how recovery focused they believed their wards to be. Findings support the notion that the ward manager role in acute inpatient settings is at times unmanageable. Administration is one aspect of the role for which ward managers feel unprepared and the high number of administrative tasks take them away from front line clinical care, leading to frustration. Absence from clinical areas reduces opportunities for role modeling good clinical practice to other staff. Despite the frustrations of administrative tasks, overall the managers thought they were supportive to their staff and that their wards were recovery focused. PMID- 24779764 TI - The RAFAELA system: a workforce planning tool for nurse staffing and human resource management. AB - The RAFAELA system was developed in Finland during the 1990s to help with the systematic and daily measurement of nursing intensity (NI) and allocation of nursing staff. The system has now been rolled out across almost all hospitals in Finland, and implementation has started elsewhere in Europe and Asia. This article describes the system, which aims to uphold staffing levels in accordance with patients' care needs, and its structure, which consists of three parts: the Oulu Patient Classification instrument; registration of available nursing resources; and the Professional Assessment of Optimal Nursing Care Intensity Level method, as an alternative to classical time studies. The article also highlights the benefits of using a systematic measurement of NI. PMID- 24779765 TI - Efficient peroxydisulfate activation process not relying on sulfate radical generation for water pollutant degradation. AB - Peroxydisulfate (PDS) is an appealing oxidant for contaminated groundwater and toxic industrial wastewaters. Activation of PDS is necessary for application because of its low reactivity. Present activation processes always generate sulfate radicals as actual oxidants which unselectively oxidize organics and halide anions reducing oxidation capacity of PDS and producing toxic halogenated products. Here we report that copper oxide (CuO) can efficiently activate PDS under mild conditions without producing sulfate radicals. The PDS/CuO coupled process is most efficient at neutral pH for decomposing a model compound, 2,4 dichlorophenol (2,4-DCP). In a continuous-flow reaction with an empty-bed contact time of 0.55 min, over 90% of 2,4-DCP (initially 20 MUM) and 90% of adsorbable organic chlorine (AOCl) can be removed at the PDS/2,4-DCP molar ratio of 1 and 4, respectively. Based on kinetic study and surface characterization, PDS is proposed to be first activated by CuO through outer-sphere interaction, the rate limiting step, followed by a rapid reaction with 2,4-DCP present in the solution. In the presence of ubiquitous chloride ions in groundwater/industrial wastewater, the PDS/CuO oxidation shows significant advantages over sulfate radical oxidation by achieving much higher 2,4-DCP degradation capacity and avoiding the formation of highly chlorinated degradation products. This work provides a new way of PDS activation for contaminant removal. PMID- 24779766 TI - Antitumorigenic potential of linalool is accompanied by modulation of oxidative stress: an in vivo study in sarcoma-180 solid tumor model. AB - Coriander, used as a common food seasoning, contains linalool as the main constituent of its essential oil. In this study, we tested the effect of linalool vis-a-vis that of a conventional chemotherapeutic drug, cyclophosphamide, against solid S-180 tumor-bearing Swiss albino mice. Tumor volume, cell count, cell cycle phase distribution, apoptosis, and proliferation markers indicate that linalool has potent antitumor activity. In vitro and in vivo data suggest that induction of oxidative stress might be responsible for the anticancer effect of linalool. However, interestingly, unlike cyclophosphamide, linalool did not induce myelosuppression or hepatotoxicity in mice as evident from bone marrow cell count, status of hepatic oxidative stress/antioxidant enzymes, and histopathology. Thus, linalool exerted prooxidant effect in tumor tissue and an antioxidant effect in liver. This is also supported by the expression of Nrf-2 and p21, which are considered to be important players in response to oxidative stress. Moreover, administration of linalool modulated the proliferation of spleen cells in tumor-bearing mice challenged with lipopolysaccharide. Finally, the detection of linalool in sera and tumor tissues by HPLC confirmed its bioavailability. In conclusion, linalool showed differential cytotoxicity towards tumor and normal cells in contrast to cyclophosphamide, which is uniformly toxic to both. PMID- 24779767 TI - Chitosan-based thermoreversible hydrogel as an in vitro tumor microenvironment for testing breast cancer therapies. AB - Breast cancer is a major health problem for women worldwide. Although in vitro culture of established breast cancer cell lines is the most widely used model for preclinical assessment, it poorly represents the behavior of breast cancers in vivo. Acceleration of the development of effective therapeutic strategies requires a cost-efficient in vitro model that can more accurately resemble the in vivo tumor microenvironment. Here, we report the use of a thermoreversible poly(ethylene glycol)-g-chitosan hydrogel (PCgel) as an in vitro breast cancer model. We hypothesized that PCgel could provide a tumor microenvironment that promotes cultured cancer cells to a more malignant phenotype with drug and immune resistance. Traditional tissue culture plates and Matrigel were applied as controls in our studies. In vitro cellular proliferation and morphology, the secretion of angiogenesis-related growth factors and cytokines, and drug and immune resistance were assessed. Our results show that PCgel cultures promoted tumor aggregate formation, increased secretion of various angiogenesis- and metastasis-related growth factors and cytokines, and increased tumor cell resistance to chemotherapeutic drugs and immunotherapeutic T cells. This PCgel platform may offer a valuable strategy to bridge the gap between standard in vitro and costly animal studies for a wide variety of experimental designs. PMID- 24779768 TI - Comparative analysis of Arabidopsis UGT74 glucosyltransferases reveals a special role of UGT74C1 in glucosinolate biosynthesis. AB - The study of glucosinolates and their regulation has provided a powerful framework for the exploration of fundamental questions about the function, evolution, and ecological significance of plant natural products, but uncertainties about their metabolism remain. Previous work has identified one thiohydroximate S-glucosyltransferase, UGT74B1, with an important role in the core pathway, but also made clear that this enzyme functions redundantly and cannot be the sole UDP-glucose dependent glucosyltransferase (UGT) in glucosinolate synthesis. Here, we present the results of a nearly comprehensive in vitro activity screen of recombinant Arabidopsis Family 1 UGTs, which implicate other members of the UGT74 clade as candidate glucosinolate biosynthetic enzymes. Systematic genetic analysis of this clade indicates that UGT74C1 plays a special role in the synthesis of aliphatic glucosinolates, a conclusion strongly supported by phylogenetic and gene expression analyses. Finally, the ability of UGT74C1 to complement phenotypes and chemotypes of the ugt74b1-2 knockout mutant and to express thiohydroximate UGT activity in planta provides conclusive evidence for UGT74C1 being an accessory enzyme in glucosinolate biosynthesis with a potential function during plant adaptation to environmental challenge. PMID- 24779769 TI - Determinants of coverage decisions in health insurance marketplaces: consumers' decision-making abilities and the amount of information in their choice environment. AB - OBJECTIVE: To investigate the determinants and quality of coverage decisions among uninsured choosing plans in a hypothetical health insurance marketplace. STUDY SETTING: Two samples of uninsured individuals: one from an Internet-based sample comprised largely of young, healthy, tech-savvy individuals (n = 276), and the other from low-income, rural Virginians (n = 161). STUDY DESIGN: We assessed whether health insurance comprehension, numeracy, choice consistency, and the number of plan choices were associated with participants' ability to choose a cost-minimizing plan, given their expected health care needs (defined as choosing a plan costing no more than $500 in excess of the total estimated annual costs of the cheapest plan available). DATA COLLECTION: Primary data were collected using an online questionnaire. PRINCIPAL FINDINGS: Uninsured who were more numerate showed higher health insurance comprehension; those with more health insurance comprehension made choices of health insurance plans more consistent with their stated preferences; and those who made choices more concordant with their stated preferences were less likely to choose a plan that cost more than $500 in excess of the cheapest plan available. CONCLUSIONS: Increasing health insurance comprehension and designing exchanges to facilitate plan comparison will be critical to ensuring the success of health insurance marketplaces. PMID- 24779771 TI - Structure and stability of an azoreductase with an FAD cofactor from the strict anaerobe Clostridium perfringens. AB - Azoreductase enzymes present in many microorganisms exhibit the ability to reduce azo dyes, an abundant industrial pollutant, to produce carcinogenic metabolites that threaten human health. All biochemically-characterized azoreductases, around 30 to date, have been isolated from aerobic bacteria, except for AzoC, the azoreductase of Clostridium perfringens, which is from a strictly anaerobic bacterium. AzoC is a recently biochemically-characterized azoreductase. The lack of structural information on AzoC hinders the mechanistic understanding of this enzyme. In this paper, we report on the biophysical characterization of the structure and thermal stability of AzoC by using a wide range of biophysical tools: Liquid Chromatography-Mass Spectrometry (LC-MS), Circular Dichroism Spectroscopy, Fourier-transform Infrared (FTIR) Spectroscopy, SDS-PAGE, Size Exclusion Chromatography, MALDI-TOF and UV-visible spectroscopy. We found that the flavin cofactor of AzoC is FAD, while all other structurally-known azoreductases employ FMN as a cofactor. The secondary structure of AzoC has 16% less alpha-helix structures, 5% more beta-sheet structures and 11% more turn and unordered than the average of structurally-known azoreductase that have 10-14% sequence similarities with AzoC. We also found that oxidized AzoC is trimeric, which is unique amongst structurally known azoreductases. In contrast, reduced AzoC is monomeric, despite similarities in catalytic activity and thermal stability of oxidized and reduced AzoC. Our results show that the use of FTIR spectroscopy is crucial for characterization of the beta-sheet content in AzoC, illustrating the need for complementary biophysical tools for secondary structural characterization of proteins. PMID- 24779770 TI - The Bcl-2/xL inhibitor ABT-263 increases the stability of Mcl-1 mRNA and protein in hepatocellular carcinoma cells. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the major causes of mortality. ABT-263 is a newly synthesized, orally available Bcl-2/xL inhibitor that shows promising efficacy in HCC therapy. ABT-263 inhibits the anti-apoptotic activity of Bcl-2 and Bcl-xL, but not Mcl-1. Previous reports have shown that ABT 263 upregulates Mcl-1 in various cancer cells, which contributes to ABT-263 resistance in cancer therapy. However, the associated mechanisms are not well known. METHODS: Western blot, RNAi and CCK-8 assays were used to investigate the relationship between Mcl-1 upregulation and ABT-263 sensitivity in HCC cells. Real-time PCR and Western blot were used to detect Mcl-1 mRNA and protein levels. Luciferase reporter assay and RNA synthesis inhibition assay were adopted to analyze the mechanism of Mcl-1 mRNA upregulation. Western blot and the inhibition assays for protein synthesis and proteasome were used to explore the mechanisms of ABT-263-enhanced Mcl-1 protein stability. Trypan blue exclusion assay and flow cytometry were used to examine cell death and apoptosis. RESULTS: ABT-263 upregulated Mcl-1 mRNA and protein levels in HCC cells, which contributes to ABT 263 resistance. ABT-263 increased the mRNA level of Mcl-1 in HCC cells by enhancing the mRNA stability without influencing its transcription. Furthermore, ABT-263 increased the protein stability of Mcl-1 through promoting ERK- and JNK induced phosphorylation of Mcl-1Thr163 and increasing the Akt-mediated inactivation of GSK-3beta. Additionally, the inhibitors of ERK, JNK or Akt sensitized ABT-263-induced apoptosis in HCC cells. CONCLUSIONS: ABT-263 increases Mcl-1 stability at both mRNA and protein levels in HCC cells. Inhibition of ERK, JNK or Akt activity sensitizes ABT-263-induced apoptosis. This study may provide novel insights into the Bcl-2-targeted cancer therapeutics. PMID- 24779772 TI - Identifying structural features related to the biological activity of a series of AT1 antagonists from fragment-based drug design. AB - Antagonists of AT1 receptor are interesting substances to develop drugs that can be used for the treatment of hypertension and other diseases that affect the cardiovascular system. This study investigates the main interactions between various AT1 antagonists and the biological target by applying fragment-based drug design (Hologram QSAR - HQSAR). The proposed HQSAR model yielded significant correlation coefficients (q(2) = 0.764 and r(2) = 0.914), indicating that the method is rigorous and reliable. All models were externally validated using a test set and the results showed good agreement between the experimental and predicted data (r(2) test = 0.740). Therefore, our model can positively contribute to understand the structural features involved in the main interactions between the AT1 antagonists and the residues of the binding site. PMID- 24779773 TI - Fatty acid-binding proteins at a glance. AB - Fatty acid-binding proteins (FABPs) are extensively expressed in animals, involved in the metabolism of fatty acids. FABPs share a much conserved secondary structure though they have 20% ~ 70% identities at the amino acid level. In addition to the role in lipid metabolism, FABPs are closely associated with cytokine production in immune cells and tumor growth and angiogenesis. Increasing studies are broadening our understanding of biological roles of FABPs beyond lipid trafficking and storage. PMID- 24779774 TI - Defect-induced enhancement and quenching control of photocurrent in few-layer graphene photodetectors. AB - A novel approach is presented for achieving an enhanced photoresponse in a few layer graphene (FLG) based photodetector that is realized by introducing defect sites in the FLG. Fabrication induced wrinkle formation in graphene presented a four-fold enhancement in the photocurrent when compared to unfold FLG. Interestingly, it was observed that the addition of few multiwalled carbon nanotubes to an FLG improves the photocurrent by two-fold along with a highly stable response as compared to FLG alone. PMID- 24779775 TI - Pro-oxidative and antioxidative controls and signaling modification of polyphenolic phytochemicals: contribution to health promotion and disease prevention? AB - Polyphenolic phytochemicals (PPs) have been extensively studied as potential nutriceuticals for maintenance of health and treatment of cancer, inflammation, and neurodegeneration. However, the reported beneficial outcomes are inconsistent. The biological activities of PPs have been attributed to their pro oxidative and antioxidative actions and effects on signaling mechanisms and epigenomic modifications. These diversified properties were described or postulated on the basis of a variety of experimental studies using cell culture and animal models, even though most have not been replicated and results are not validated. This review attempts to give an overview of biological properties of PPs, based on the coherent results from relevant studies, and evaluate critically the experimental conditions and possible artifacts. Complicated molecular mechanisms and multitargeting genomic interactions of PPs are discussed, with a view that reasonable mechanistic propositions are usually obtained from well designed in vivo studies. PMID- 24779776 TI - The relationship between lysine 4 on histone H3 methylation levels of alcohol tolerance genes and changes of ethanol tolerance in Saccharomyces cerevisiae. AB - We evaluated whether epigenetic changes contributed to improve ethanol tolerance in mutant populations of Saccharomyces cerevisiae (S. cerevisiae). Two ethanol tolerant variants of S. cerevisiae were used to evaluate the genetic stability in the process of stress-free passage cultures. We found that acquired ethanol tolerance was lost and transcription level of some genes (HSP104, PRO1, TPS1, and SOD1) closely related to ethanol tolerance decreased significantly after the 10th passage in ethanol-free medium. Tri-methylation of lysine 4 on histone H3 (H3K4) enhanced at the promoter of HSP104, PRO1, TPS1 and SOD1 in ethanol-tolerant variants of S. cerevisiae was also diminished after tenth passage in stress-free cultures. The ethanol tolerance was reacquired when exogenous SOD1 transferred in some tolerance-lost strains. This showed that H3K4 methylation is involved in phenotypic variation with regard to ethanol tolerance with respect to classic breeding methods used in yeast. PMID- 24779777 TI - Plerixafor-augmented peripheral blood stem cell mobilization in AL amyloidosis with cardiac involvement: a case series. AB - Nearly half of AL amyloidosis patients have cardiac involvement, an independent predictor of poor prognosis. High-dose melphalan and autologous stem-cell transplantation (HDM/SCT) can induce complete hematologic responses and prolong survival in AL amyloidosis. Granulocyte colony-stimulating factor (G-CSF)-induced mobilization of peripheral blood stem cell (PBSC) in AL amyloidosis patients is associated with volume overload, arrhythmias and capillary leak syndrome. Plerixafor has a different mechanism of action and has non-overlapping toxicities with G-CSF. We describe our experience in five patients with AL amyloidosis and cardiac involvement who received plerixafor with G-CSF for PBSC mobilization. Median age was 56 years; two patients had undergone heart transplantation within the year prior to HDM/SCT. Three patients received plerixafor after an initial trial of mobilization with G-CSF alone. No patient had any significant toxicities during mobilization and PBSC collection. The median total yield of PBSCs collected was 5.9 * 10(6) CD34+ cells/kg; the median number of leukapheresis days was 2. Neutrophil engraftment after HDM/SCT occurred at a median of nine days, platelet engraftment at a median of 13 days. Plerixafor was effective and well tolerated when used upfront or as rescue for PBSC mobilization in AL amyloidosis patients with cardiac involvement. PMID- 24779778 TI - Comparison of peripheral venous and arterial blood gas analyses. PMID- 24779779 TI - A comparison of contents of group A and B trichothecenes and microbial counts in different cereal species. AB - Concentrations of trichothecenes and the amounts of microbial biomass were compared in grain of bread wheat, durum wheat, triticale, rye, oat and barley. Grain samples came from lines regionalised in Poland grown under identical climatic and agricultural conditions in 2007. Among the six analysed cereals, the highest mean concentration of toxic metabolites of 151.89 ug/kg was found for grain of Triticum durum, whereas the lowest was for barley grain (25.56 ug/kg). The highest contamination with microscopic fungi was recorded in case of barley and rice grain (mean concentrations of ergosterol were 12.53 mg/kg and 11.24 mg/kg, respectively). In case of the analysed cereals, the total microbial biomass expressed in the amount of ATP turned out to be the highest (4.7 * 105 relative light units [RLU]) for rye and oat (3.2 * 105 RLU). The results of the applied classical discrimination analysis indicate a significant diversification of species in terms of all the 11 analysed metabolites. PMID- 24779780 TI - Undeclared allergenic ingredients in foods from animal origin: survey of an Italian region's food market, 2007-2009. AB - Several EC Directives have been promulgated to protect allergic individuals but no rule has been established with regard to allergen cross-contamination caused by shared transport vehicles or common processing equipment. The aim of this research was to quantify, by enzyme-linked immunosorbent assay (ELISA) or real time polymerase chain reaction, the presence in meat- or fish-based foods of four allergens (milk, egg, crustaceans and molluscs) that was not indicated either in the list of ingredients or in the label alert. In the time frame of 2007-2009, a total of 723 samples were subjected to 1983 analyses. The percentage of samples scoring positive ranged between 1.8% and 6.8% over the 3 years, and the concentrations of undeclared allergens found were 0.3-13.3 mg kg-1 for milk (beta lactoglobulin) and 0.21-12 mg kg-1 for egg white proteins. On this basis, the possibility of cross-contamination serious enough to raise public health concern cannot be dismissed. PMID- 24779781 TI - Pesticide residues in raspberries (Rubus idaeus L.) and dietary risk assessment. AB - The aim of this study was to evaluate the residues of 140 pesticides in raspberries from north-eastern Poland (2005-2010). Gas chromatography with electron capture detector (GC-ECD) and nitrogen phosphorous detector (GC-NPD) was used. Among the 128 samples, 66 (51.6%) were found to detect residues: 14.1% contained one pesticide and around 38% multiple pesticide residues. The most frequently detected were pyrimethanil residues (36.0%). Twenty-seven (21.1%) raspberry samples exceeded the maximum residue limits. The estimated daily intakes ranged from 0.003% to 3.183% of the acceptable daily intake (ADI) for adults 0.008% and 9.7% for toddlers, respectively. The most critical case is procymidone, the acute risk was 180.9% of acute reference dose (ARfD) for toddlers and for adults (83% of ARfD) which is high. PMID- 24779782 TI - Toxic and essential elements in Lebanese cheese. AB - Concentrations of 20 minor, trace and ultratrace elements relevant to human health (Ag, Al, As, Cd, Co, Cr, Cu, Fe, Hg, Li, Mn, Mo, Ni, Pb, Sb, Se, Si, Sn, V) were determined in four different varieties of the most consumed cheese in Lebanon (Halloumi, Double Creme, Baladi, Labneh) sampled at five different provinces (Grand Beirut, South of Lebanon, North of Lebanon, Mount of Lebanon and Beka'a) during the wet and dry seasons. The analyses were carried out by double focussing sector field inductively coupled plasma-mass spectrometry (ICP-MS) in order to avoid errors due to polyatomic interferences. Levels of toxic elements (As, Cd, Pb) were generally below the WHO permissible levels in dairy products. Concentrations of most elements were considerably affected by the type of cheese, the geographical site and the season of sampling. PMID- 24779783 TI - Determination of methylmercury in marine fish from coastal areas of Zhejiang, China. AB - The concentration of methylmercury (MMC) and total mercury (TMC) in marine fishes (five species) frequently consumed in the coastal areas of Zhejiang province, China, was determined. The method of high-performance liquid chromatography atomic fluorescence spectrometry (HPLC-AFS) with the microwave-assisted extraction was used for the MMC determination. TMC was analysed by a direct mercury analyser. MMC and TMC concentrations in five fish species ranged from 53 to 158 ug kg-1 and 60 to 172 ug kg-1, respectively. The proportion of MMC levels in TMC was greater than 80%. The highest MMC and TMC levels were found in Hairtail. PMID- 24779784 TI - Organic and conventional fertilisation procedures on the nitrate, antioxidants and pesticide content in parts of vegetables. AB - Different parts of plant foods are generally discarded by consumers such as peel, stalk and leaves, which could however possess a nutritional value. However, few studies have analysed the composition of these marginal foods. The phenolic compound, flavonoid, polyamine, nitrate and pesticide contents of parts of vegetables that are usually discarded--but which were cultivated according to conventional and non-conventional procedures--were analysed to provide suggestions on how to improve the consumption of these parts and to reduce the production of urban solid waste. Few, but significant, differences between the two manuring procedures were observed. Higher nitrate content and the presence of organochlorine pesticides were found in conventional cultivated papaya peel, lemon balm leaves, jack fruit pulp, and beet stalk and peel. Discarded parts of plant foods such as stalk, leaves and peels can be used as a source of antioxidant compounds, such as phenolic compounds. PMID- 24779785 TI - Mercury and selenium concentrations in muscle tissue of different species of predatory freshwater fish and correlation between these elements. AB - Concentrations of total mercury and selenium were determined in 49 and 42 muscle tissue samples, respectively, of six species of predatory freshwater fish, dace (Leuciscus leuciscus), pike perch (Sander lucioperca), pike (Esox lucius), European catfish (Silurus glanis), rainbow trout (Oncorhynchus mykiss) and asp (Aspius aspius). Muscle selenium concentration did not correlate with the corresponding total mercury concentration (R2 < 0.198) in all examined predatory fish species. There was an inverse correlation between the ratio Se/Hg content and the total mercury content in the muscle tissues of dace, pike perch, pike, European catfish and asp. The muscle tissue of rainbow trout exhibits a linear correlation between the ratio Se/Hg content and the total mercury content. The total mercury concentration of all examined samples did not exceed the hygienic limit for Hg for predatory fish. PMID- 24779786 TI - A survey of aflatoxin in cotton seed in Iran by HPLC with on-line photochemical derivatisation and fluorescence detection. AB - The aflatoxins content of 140 cotton seed samples were determined using high performance liquid chromatography. Samples were obtained from wholesalers in Iran between May 2010 and June 2011. Aflatoxin B1 gave the highest incidence of contamination and was found in 129 of the 139 samples. The highest concentration of aflatoxin was 14.4 ng g-1. Thirteen cotton seed samples (9.35%) were above one of the regulatory limits of the European Union (5 ng g-1), but no sample was above the highest EU limit and the safety limit recommended by the FDA (20 ng g 1) and regulatory limits of Iran (50 ng g-1) for total aflatoxin. PMID- 24779787 TI - Ochratoxin A in wines from 2002 to 2008 harvest marketed in Rio de Janeiro, Brazil. AB - The occurrence of ochratoxin A (OTA) in wine from 2002 to 2008 harvest, traded in Rio de Janeiro State, was evaluated by analysing 43 national and 37 imported wines from Argentina (32) and Chile (5), adding up to 80 samples in total. OTA determination was performed using immunoaffinity columns and high-performance liquid chromatography. In 80 wine samples analysed, 25 (31.3%) were positive, presenting levels greater than 0.020 ng OTA mL-1. It was not detected in imported wines. Within national wines, 58.1% of the samples were contaminated, with levels ranging from 0.020 to 0.050 ng mL-1. The toxin was detected in 18 (69.2%) of 26 samples analysed of red table wine. Wines from 2008 harvest presented 84.6% of samples contaminated in 13 samples analysed. Despite the levels found in this study, they are below Brazilian tolerance limits. Nevertheless, the presence of OTA as found contributes to the human exposure to this toxin. PMID- 24779788 TI - Occurrence of fumonisins and aflatoxins in cereals from markets of Hebei Province of China. AB - Fumonisins B1, B2 and B3 (FB1, FB2 and FB3) and aflatoxins B1 (AFB1), B2 (AFB2), G1 (AFG1) and G2 (AFG2) are both major mycotoxins of food concern, because of their wide range of concentration and possible co-occurrence. Therefore, a contamination survey in corn and wheat flour by liquid chromatography-tandem mass spectrometry was carried out. Quantification of fumonisins and aflatoxins was based on internal calibration (by the use of 13C34-fumonisin) and external calibration, respectively. Fumonisins were detected in 95% of corn samples and in 7% of wheat flour samples, with the mean level (FB1 + FB2 + FB3) of 441 ug kg-1 and 0.09 ug kg-1, respectively. Low levels of aflatoxins were detected in 37% of the samples with a mean level (B1 + B2 + G1 + G2) of 0.12 ug kg-1. Fumonisins and aflatoxins were not detected in 29% of the samples analysed. Simultaneous occurrence of fumonisins and aflatoxins was observed in 12% of samples. PMID- 24779789 TI - Trends in monitoring residues of prohibited pharmacologically active substances in primary products of animal origin in Lithuania and the European Union from 1999 to 2008. AB - Group A pharmacologically active substances monitoring data in the Republic of Lithuania (LR) during the period 1999-2008 are presented. Peer review is based on data taken from residue monitoring plans of the years 1999-2008 and the National Food and Veterinary Risk Assessment Institute (NFVRAI) reports on analyses performed in various foods. The data were analysed with the SPSS statistical package, using descriptive statistics and generalised linear modelling methods. Retrospective analysis of residue monitoring results showed that food processed from animal products presented no risk to consumers as regards to substances of Group A1, A2, A3, A4 and A5. One substance of Group A6 (chloramphenicol) was detected in bovine milk in 2003 (9%), 2006 (2%) and 2008 (1.4%). The decreasing trend is confirmed by statistical data analyses, where year of monitoring (P <= 0.0001), product (P <= 0.1) and their interaction (P <= 0.0001) proved the positive effect of the monitoring system. PMID- 24779790 TI - BTES and aldehydes analysis in PET-bottled water in Lebanon. AB - The aim of this study was to determine benzene, toluene, ethylbenzene, styrene (BTES), formaldehyde, acetaldehyde and benzaldehyde in Lebanese polyethylene terephthalate (PET)-bottled water. Aldehydes were analysed by high-performance liquid chromatography with ultraviolet-visible detection (HPLC/UV-vis) after 2,4 dinitrophenylhydrazine (DNPH) derivatisation and solid phase extraction (SPE) concentration, whereas headspace trap gas chromatograph-flame ionisation detector (GC/FID) was used for BTES determination. Both methods were validated according to the NF XP 90-210 and showed good linearity ranging from 3 (limit of quantification [LOQ]) to 15 ug L-1 for BTES and from 20 (LOQ) to 900 ug L-1 for aldehydes. No quantified contamination with BTES, acetaldehyde and benzaldehyde was determined in all analysed fresh Lebanese PET-bottled waters. Formaldehyde was quantified in 3 of the 15 samples at concentrations lower than the maximum contaminant level set by the US Environmental Protection Agency and the World Health Organisation. The samples' exposure to sunlight during 5 months increases the migration of formaldehyde and acetaldehyde. Similar migration increase was observed when the samples were incubated at 40 degrees C during 10 days. PMID- 24779791 TI - Fumaric acid esters in psoriasis and multiple sclerosis. AB - Fumaric acid esters (FAEs) are effective in patients with moderate to severe psoriasis. Recent studies also report the efficacy of one FAE component, dimethylfumarate, in relapsing forms of multiple sclerosis (MS). We describe the case of a patient with MS who developed severe plaque psoriasis during interferon beta-1a treatment for MS. The psoriasis was unresponsive to usual topical treatments and phototherapy. The patient was started on FAE 720 mg daily, with complete remission of the psoriatic lesions and neurological stabilization at follow-up at 24 months. Our case suggests that FAEs could represent a therapeutic option for patients with MS who develop plaque psoriasis following exposure to immune-modulating agents. PMID- 24779792 TI - President's message. PMID- 24779794 TI - Identifying the ideal body size and shape characteristics associated with children's physical performance tests in Peru. AB - We used allometric models to identify the optimal body size/shape characteristics associated with physical and motor performance tests in Peruvian schoolchildren. The sample consisted of 3624 subjects (1669 boys and 1955 girls) aged 11-17 years from 31 public schools belonging to four cities located in the three natural regions in central Peru. Motor performance included 12-min run, standing long jump, grip strength, curl-ups, shuttle run, and sit and reach. The reciprocal Ponderal index (RPI), a characteristic sometimes referred to as the somatotype "ectomorphy," was found to be the most suitable body shape indicator associated with 12-min run, standing long jump, curl-up, and shuttle run performance. A positive maturation offset parameter was also associated with greater standing long jump, grip strength, shuttle run, and sit-and-reach performances. With the exception of the sit-and-reach flexibility, sex differences are pervasive in all tests favoring boys. Rainforest schoolchildren are best performers in the power and flexibility tests, whereas those from high altitude were superior in the 12 min endurance test even after taking their much lighter body size characteristics into account. This latter finding suggests that living at high altitude in Peru benefits children's endurance performance both before and even after controlling for differences in the confounding variable of body size/shape. PMID- 24779795 TI - Vinyl epoxides in organic synthesis. PMID- 24779793 TI - Phospho-kinase profile of triple negative breast cancer and androgen receptor signaling. AB - BACKGROUND: The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer. In triple negative breast cancer (TNBC) a gene expression classification has described different subgroups including a luminal androgen subtype. The AR can be controlled by several mechanisms like the activation of membrane tyrosine kinases and downstream signaling pathways. However little is known in TNBC about how the AR is modulated by these mechanisms and the potential therapeutic strategists to inhibit its expression. METHODS: We used human samples to evaluate the expression of AR by western-blot and phospho-proteomic kinase arrays that recognize membrane tyrosine kinase receptors and downstream mediators. Western-blots in human cell lines were carried out to analyze the expression and activation of individual proteins. Drugs against these kinases in different conditions were used to measure the expression of the androgen receptor. PCR experiments were performed to assess changes in the AR gene after therapeutic modulation of these pathways. RESULTS: AR is present in a subset of TNBC and its expression correlates with activated membrane receptor kinases-EGFR and PDGFRbeta in human samples and cell lines. Inhibition of the PI3K/mTOR pathway in TNBC cell lines decreased notably the expression of the AR. Concomitant administration of the anti-androgen bicalutamide with the EGFR, PDGFRbeta and Erk1/2 inhibitors, decreased the amount of AR compared to each agent given alone, and had an additive anti-proliferative effect. Administration of dihydrotestosterone augmented the expression of AR that was not modified by the inhibition of the PI3K/mTOR or Erk1/2 pathways. AR expression was posttranscriptionally regulated by PI3K or Erk1/2 inhibition. CONCLUSION: Our results describe the expression of the AR in TNBC as a druggable target and further suggest the combination of bicalutamide with inhibitors of EGFR, PDGFRbeta or Erk1/2 for future development. PMID- 24779796 TI - Leading nurses highlight the truth about nursing. PMID- 24779798 TI - Managers used 'emotional blackmail' to persuade trust staff to have flu jab. PMID- 24779800 TI - New workforce plan will emphasise skills as much as numbers. PMID- 24779799 TI - High numbers of mature students 'bring commitment and experience'. PMID- 24779801 TI - Contact your MPs in fight for fair pay, says Peter Carter. PMID- 24779804 TI - NICE issues guidance on pressure ulcer prevention and management. PMID- 24779805 TI - Drive to develop leaders in learning disability nursing. PMID- 24779807 TI - Home visits to new mothers could improve child outcomes. PMID- 24779808 TI - Put foot care first, urges Diabetes UK. PMID- 24779810 TI - Case examiners could speed up FtP process. PMID- 24779811 TI - Insulin pump therapy service revolutionises diabetes care. PMID- 24779812 TI - Scottish independence and NMC revalidation top congress debates. PMID- 24779813 TI - Lack of career progression and job cuts behind exodus of senior nurses. PMID- 24779819 TI - Dementia: early diagnosis. PMID- 24779820 TI - Brian's breakthrough in cancer diagnosis. PMID- 24779821 TI - Caring nurses hit by a quality storm. PMID- 24779834 TI - There is no 'one size fits all' solution for treating mental health conditions. PMID- 24779835 TI - Familiar routines are helpful for stroke as well as dementia. PMID- 24779836 TI - A range of views on anxiety, its medicalisation and seriousness. PMID- 24779837 TI - Is herpes zoster vaccine free for nurses or will we have to pay? PMID- 24779838 TI - Handheld devices could help to diagnose asthma more efficiently. PMID- 24779840 TI - Rehabilitation care for a close friend proved to be abysmal. PMID- 24779841 TI - Mentoring nursing students in the sexual health setting. AB - The sexual health setting provides many opportunities for nursing students to meet the competencies set out in the Nursing and Midwifery Council's Standards for Pre-Registration Nursing Education. However, students who are daunted by the setting may adopt a passive, observer role. Mentors may find it a challenge to facilitate the learning of pre-registration nursing students in this setting. This article explores several strategies that mentors can adopt to make learning active and relevant for nursing students. These strategies may also be relevant to other nursing fields and to midwifery students. PMID- 24779842 TI - Writing a journal article: guidance for novice authors. AB - This article focuses on writing for journal publication. The purpose of writing is explored, paying particular attention to the message to be conveyed and the readership to which that message is addressed.The process of drafting and revising an article for publication is outlined, after which attention is turned to the peer-review process, what peer reviewers are looking for in an article, and what might then be required of the author in redrafting the article to meet the expectations of the journal. Prospective authors are encouraged to research the journal to which they plan to submit their work, and to then target their writing to the readership of that publication. PMID- 24779843 TI - Ethical practice. PMID- 24779844 TI - Factors affecting cost-effectiveness in wound care decision making. AB - With increasing health service cutbacks, cost-effectiveness is a central issue in many wound care decisions. Clinicians are frequently required to justify clinical decision making in terms of health benefits obtained and the cost to health service providers. However, few clinicians have the skills to accurately interpret cost in more than local health economic terms, and the disjointed structures that exist in healthcare provision mean that even those who monitor health expenditure have little concept of the global cost of care provision. This article focuses on the pressures placed on healthcare providers to achieve cost effectiveness in care, specifically in relation to wound care and the effect that pain at dressing change has on the cost of care. PMID- 24779845 TI - Pressure ulcer treatment in a patient with spina bifida. AB - Pressure ulcers can have a significant effect on patients' health and quality of life. They may also be associated with increased treatment-related costs, including product selection, length of interventions, prolonged hospitalisation, and resources and time required to care for patients. Pressure ulcers may be more common in patients with comorbidities. This article presents a case study of a man with spina bifida who was admitted to hospital with a pressure ulcer on his chest. It examines the clinical and social issues that affected the patient's wound healing, with the aim of identifying appropriate assessment and management of such patients. PMID- 24779846 TI - Personalised approach. PMID- 24779847 TI - Brokering better outcomes. PMID- 24779849 TI - Cherry-pick the best bits. PMID- 24779850 TI - Student life--South American challenge. PMID- 24779852 TI - Systematic review of health-related quality of life in older people following percutaneous coronary intervention. AB - People aged over 60 years represent an increasingly high proportion of the population undergoing percutaneous coronary intervention. While risks are greater for older people in terms of major adverse cardiovascular events and higher mortality for this treatment, it is unclear if the benefits of health-related quality of life outcomes may outweigh risks. A search of the PubMed, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica, and Cochrane databases was conducted for the period from January 1999 to June 2012 using key words "percutaneous coronary intervention"/"angioplasty," "older," "elderly," and "quality of life"/"health-related quality of life." Using a systematic review approach, data from 18 studies were extracted for description and synthesis. Findings revealed that everyone regardless of age reported better health-related quality of life, primarily from the relief of angina and improved physical and mental function. Age itself did not have an independent predictive effect when other factors such as comorbid conditions were taken into account. Assessment of older peoples' health status following percutaneous coronary intervention by nurses and other health professionals is therefore important for the provision of quality care. PMID- 24779851 TI - Ganglioneuroma presenting as an adrenal incidentaloma: a case report. AB - INTRODUCTION: Ganglioneuromas are rare benign tumors arising from the neural crest tissue and are most commonly located in the posterior mediastinum and retroperitoneum; they are rarely found in the adrenal gland. This tumor is usually asymptomatic and in the majority of cases is detected incidentally. Although the characteristics of adrenal ganglioneuroma on computerized tomography and magnetic resonance imaging have been well described, the exact diagnosis is difficult. Histopathological examination is currently the mainstay of diagnosis. Ganglioneuromas have a very good prognosis with surgical removal. We report the case of a male patient with an incidentally identified adrenal ganglioneuroma with high standardized uptake values in a positron emission tomography scan. CASE PRESENTATION: An 18-year-old Turkish male patient with no previous comorbidities was admitted to our hospital with lower-quadrant pain. He had no significant past medical or surgical history. A physical examination did not reveal any signs and the results of routine laboratory tests were all within the normal ranges. Our patient underwent computed tomography of his abdomen, which showed a relatively homogenous left adrenal tumor measuring 5.2 * 4.3 * 7.1cm. On a positron emission tomography scan, the left adrenal gland disclosed a standardized uptake value of 4.1. Our patient underwent an exploratory laparotomy with left adrenalectomy without any related complications. CONCLUSION: Ganglioneuroma may sometimes be similar to other adrenal malignancies. Careful evaluation with endocrine tests and imaging procedures is necessary to provide an accurate diagnosis. Definitive diagnosis can be made by histological examination. The prognosis is very good with surgical removal. PMID- 24779853 TI - Building and characterizing regional and global emission inventories of toxic pollutants. AB - To define consistent strategies for managing the environmental sustainability of chemicals, it is important to quantify the magnitude of their emissions and their associated impacts. Not all countries monitor and report emissions related to their activities. This is particularly the case for chemical emissions, whose toxic impacts on human health and ecosystems cannot be readily determined because of gaps in the available data. Emission data that can be retrieved from publicly available databases are typically restricted to a limited number of toxic substances, for a few countries, or for aggregated regions. Extrapolation strategies are thus needed to fill in those data gaps and to move from the consideration of single countries or regions to the world scale. Little is known about how effective these strategies are in extrapolating emissions. With the use of emission data available in public databases in the world, the current work explores different opportunities to compile representative inventories of toxic emissions. In this study, we build global and European emission inventories using three extrapolation proxies, namely the gross domestic product, the emissions of carbon dioxide, and the emissions of mercury. The three proxies are compared and their efficacies are tested statistically to identify the best performer for specific classes of substances. The potential impacts associated with the emissions in the European and global inventory are further tested by using an impact system adopted for the comparative assessment of chemicals in the field of life cycle assessment. PMID- 24779854 TI - Episodic ozone exposure in adult and senescent Brown Norway rats: acute and delayed effect on heart rate, core temperature and motor activity. AB - Setting exposure standards for environmental pollutants may consider the aged as a susceptible population but the few published studies assessing susceptibility of the aged to air pollutants are inconsistent. Episodic ozone (O3) is more reflective of potential exposures occurring in human populations and could be more harmful to the aged. This study used radiotelemetry to monitor heart rate (HR), core temperature (T(c)) and motor activity (MA) in adult (9-12 months) and senescent (20-24 months) male, Brown Norway rats exposed to episodic O3 (6 h/day of 1 ppm O3 for 2 consecutive days/week for 13 weeks). Acute O3 initially led to marked drops in HR and T(c). As exposures progressed each week, there was diminution in the hypothermic and bradycardic effects of O3. Senescent rats were less affected than adults. Acute responses were exacerbated on the second day of O3 exposure with adults exhibiting greater sensitivity. During recovery following 2 d of O3, adult and senescent rats exhibited an elevated T(c) and HR during the day but not at night, an effect that persisted for at least 48 h after O3 exposure. MA was elevated in adults but not senescent rats during recovery from O3. Overall, acute effects of O3, including reductions in HR and T(c), were attenuated in senescent rats. Autonomic responses during recovery, included an elevation in T(c) with a pattern akin to that of a fever and rise in HR that were independent of age. An attenuated inflammatory response to O3 in senescent rats may explain the relatively heightened physiological response to O3 in younger rats. PMID- 24779855 TI - Cocultures of mesenchymal stem cells and endothelial cells as organotypic models of prostate cancer metastasis. AB - In spite of recognized limitations in capturing species-specific responses and high costs, rodent models remain commonly used in prostate cancer metastasis research, due largely to the lack of available alternatives. We aim to develop an in vitro culture system to study prostate cancer response to a simulated bone microenvironment, which may be used to understand early events in prostate metastasis to bone or for drug screening applications. To achieve this, mesenchymal stem cells and endothelial cells were isolated and cocultured to form a vascularized bone analogue. Endothelial cells were found to exert osteopotentiating effects on mesenchymal stem cell differentiation, and reciprocal effects by the stromal cells were found to stimulate vasculogenic responses, suggesting the possible utility of this system to elicit three-way interactions between endothelial, mesenchymal, and prostate cancer cells. We further developed the use of fluorescently labeled cells which could be used to concurrently track cellular migration, proliferation, and morphometric analysis. We demonstrate the concurrent, real-time visualization of prostate cancer and endothelial cells, which may be useful for evaluation of spatiotemporal changes at a single-cell level. When prostate cancer cell proliferation on various substrates was measured, it was found that the use of coculture systems may provide a better reflection of conditions in vivo, highlighting the potential utility as a model system. PMID- 24779856 TI - Intermolecular potential for binding of protonated peptide ions with perfluorinated hydrocarbon surfaces. AB - An analytic potential energy function was developed to model both short-range and long-range interactions between protonated peptide ions and perfluorinated hydrocarbon chains. The potential function is defined as a sum of two-body potentials of the Buckingham form. The parameters of the two-body potentials were obtained by fits to intermolecular potential energy curves (IPECs) calculated for CF4, which represents the F and C atoms of a perfluoroalkane chain, interacting with small molecules chosen as representatives of the main functional groups and atoms present in protonated peptide ions: specifically, CH4, NH3, NH4(+), and HCOOH. The IPECs were calculated at the MP2/aug-cc-pVTZ level of theory, with basis set superposition error (BSSE) corrections. Good fits were obtained for an energy range extending up to about 400 kcal/mol. It is shown that the pair potentials derived from the NH3/CF4 and HCOOH/CF4 fits reproduce acceptably well the intermolecular interactions in HCONH2/CF4, which indicates that the parameters obtained for the amine and carbonyl atoms may be transferable to the corresponding atoms of the amide group. The derived potential energy function may be used in chemical dynamics simulations of collisions of peptide-H(+) ions with perfluorinated hydrocarbon surfaces. PMID- 24779857 TI - Thiamine pyrophosphate stimulates acetone activation by Desulfococcus biacutus as monitored by a fluorogenic ATP analogue. AB - Acetone can be degraded by aerobic and anaerobic microorganisms. Studies with the strictly anaerobic sulfate-reducing bacterium Desulfococcus biacutus indicate that acetone degradation by these bacteria starts with an ATP-dependent carbonylation reaction leading to acetoacetaldehyde as the first reaction product. The reaction represents the second example of a carbonylation reaction in the biochemistry of strictly anaerobic bacteria, but the exact mechanism and dependence on cofactors are still unclear. Here, we use a novel fluorogenic ATP analogue to investigate its mechanism. We find that thiamine pyrophosphate is a cofactor of this ATP-dependent reaction. The products of ATP cleavage are AMP and pyrophosphate, providing first insights into the reaction mechanism by indicating that the reaction proceeds without intermediate formation of acetone enol phosphate. PMID- 24779858 TI - The chromatin landscape of the moss Physcomitrella patens and its dynamics during development and drought stress. AB - The moss Physcomitrella patens is an important model organism for evo-devo studies. Here, we determined the genome-wide chromatin landscape of five important histone three (H3) modifications (H3K4me3, H3K27me3, H3K27Ac, H3K9Ac and H3K9me2) and describe the changes to these histone marks in two contrasted situations, developmental transition and abiotic (drought) stress. Integrative analysis of these histone H3 modifications revealed their preferential association into 15 chromatin states (CS) in genic regions of the P. patens genome. Synergistic relationships that influence expression levels were revealed for the three activating marks H3K4me3, H3K27Ac and H3K9Ac, while an antagonistic relationship was found between CS containing the H3K27me3 and H3K27Ac marks, suggesting that H3K27 is a key indexing residue regarding transcriptional output. Concerning the alteration of histone marks in response to developmental transition (juvenile to adult) and drought stress, the three activating marks H3K4me3, H3K27Ac and H3K9Ac show significant changes in both situations. However, changes to H3K27me3 are central only for genes differentially expressed during development. Interestingly, genes induced during drought stress show significant histone mark toggling during developmental transition. This situation suggests that drought induced adult (gametophore expressed) genes are primed to respond to this stress during the juvenile to adult transition. PMID- 24779859 TI - Structural changes from native waxy maize starch granules to cold-water-soluble pyrodextrin during thermal treatment. AB - The structural changes occurring during the thermal conversion of insoluble native waxy maize starch granules to cold-water-soluble pyrodextrin under acidic conditions have been investigated by multiple techniques, including synchrotron small-angle X-ray scattering (SAXS), wide-angle X-ray scattering, differential scanning calorimetry, and gel permeation chromatography. In a mixture of water/glycerol (20/80, w/w), the SAXS characteristic peak at ca. 0.6 nm(-1) decreased in intensity as pyrodextrin solubility increased. The peak disappeared as pyrodextrin solubility reached 100%. Starch crystal size, its associated melting enthalpy, and pyrodextrin molecular size decreased as solubility increased. Although starch structure changed during thermal conversion, the pyrodextrins appeared identical to the native starch when observed in glycerol under a normal and polarized light microscope. It is proposed that the starch backbone is hydrolyzed by acid in the amorphous region and the crystalline region with starch molecules being hydrolyzed into small molecular fractions but persisting in a radial arrangement. PMID- 24779860 TI - Experience of gratitude, awe and beauty in life among patients with multiple sclerosis and psychiatric disorders. AB - BACKGROUND: Feelings of gratitude and awe facilitate perceptions and cognitions that go beyond the focus of illness and include positive aspects of one's personal and interpersonal reality, even in the face of disease. We intended to measure feelings of gratitude, awe, and experiences of beauty in life among patients with multiple sclerosis and psychiatric disorders, particularly with respect to their engagement in specific spiritual/religious practices and their life satisfaction. METHODS: We conducted a cross-sectional survey with standardized questionnaires to measure engagement in various spiritual practices (SpREUK-P) and their relation to experiences of Gratitude, Awe and Beauty in Life and life satisfaction (BMLSS-10). In total, 461 individuals (41 +/- 13 years; 68% women) with multiple sclerosis (46%) and depressive (22%) or other psychiatric disorders (32%) participated. RESULTS: Among participants, 23% never, 43% rarely, 24% often, and 10% frequently experienced Gratitude. In contrast, 41% never, 37% rarely, 17% often, and 6% frequently experienced Awe. Beauty in Life was never experienced by 8% of the sample, and 28% rarely, 46% often, and 18% frequently experienced it. Gratitude (F = 9.2; p = .003) and Beauty in Life (F = 6.0; p = .015) were experienced significantly more often by women than men. However, the experience of Awe did not differ between women and men (F = 2.2; n.s.). In contrast to our hypothesis, Gratitude/Awe cannot explain any relevant variance in patients' life satisfaction (R2 = .04). Regression analyses (R2 = .42) revealed that Gratitude/Awe can be predicted best by a person's engagement in religious practices, followed by other forms of spiritual practices and life satisfaction. Female gender was a weak predictor and underlying disease showed no effect. CONCLUSIONS: Gratitude/Awe could be regarded as a life orientation towards noticing and appreciating the positive in life--despite the symptoms of disease. Positive spirituality/religiosity seems to be a source of gratitude and appreciation in life, whereas patients with neither spiritual nor religious sentiments (R-S-) seem to have a lower awareness for these feelings. PMID- 24779861 TI - Biochemical analysis of TssK, a core component of the bacterial Type VI secretion system, reveals distinct oligomeric states of TssK and identifies a TssK-TssFG subcomplex. AB - Gram-negative bacteria use the Type VI secretion system (T6SS) to inject toxic proteins into rival bacteria or eukaryotic cells. However, the mechanism of the T6SS is incompletely understood. In the present study, we investigated a conserved component of the T6SS, TssK, using the antibacterial T6SS of Serratia marcescens as a model system. TssK was confirmed to be essential for effector secretion by the T6SS. The native protein, although not an integral membrane protein, appeared to localize to the inner membrane, consistent with its presence within a membrane-anchored assembly. Recombinant TssK purified from S. marcescens was found to exist in several stable oligomeric forms, namely trimer, hexamer and higher-order species. Native-level purification of TssK identified TssF and TssG as interacting proteins. TssF and TssG, conserved T6SS components of unknown function, were required for T6SS activity, but not for correct localization of TssK. A complex containing TssK, TssF and TssG was subsequently purified in vitro, confirming that these three proteins form a new subcomplex within the T6SS. Our findings provide new insight into the T6SS assembly, allowing us to propose a model whereby TssK recruits TssFG into the membrane-associated T6SS complex and different oligomeric states of TssK may contribute to the dynamic mechanism of the system. PMID- 24779862 TI - [123I]FP-CIT SPECT (DaTSCAN) may be a useful tool to differentiate between Parkinson's disease and vascular or drug-induced parkinsonisms: a meta-analysis. AB - BACKGROUND AND PURPOSE: Differentiating idiopathic Parkinson's disease from secondary parkinsonian syndromes is crucial since their management and prognosis differ considerably. Functional imaging of the dopaminergic pathway by means of [123I]FP-CIT SPECT (DaTSCAN) might be useful in this regard, but its role is still controversial. The accuracy of DaTSCAN in the differential diagnosis between Parkinson's disease and vascular or drug-induced parkinsonism was therefore systematically reviewed. METHODS: MEDLINE and CENTRAL were searched for studies aiming to determine accuracy measures (sensitivity, specificity, diagnostic odds ratio, positive and negative likelihood ratios) of DaTSCAN in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism. RESULTS: Five studies were included. Pooled accuracy measures in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism were relatively high, with sensitivity and specificity values above 85% and 80%, respectively. CONCLUSIONS: DaTSCAN might accurately differentiate between early Parkinson's disease and secondary parkinsonian conditions, namely vascular or drug-induced, in patients with clinically unclear parkinsonism. However, all the studies reviewed here show several methodological limits, which prevent definitive conclusions on the role of DaTSCAN being drawn in this context. Further studies are needed to confirm our results and definitely evaluate the utility of DaTSCAN in differentiating between Parkinson's disease and vascular or drug-induced parkinsonism. PMID- 24779863 TI - Construction of leaky strains and extracellular production of exogenous proteins in recombinant Escherichia coli. AB - In this study, a strategy of the construction of leaky strains for the extracellular production of target proteins was exploited, in which the genes mrcA, mrcB, pal and lpp (as a control) from Escherichia coli were knocked out by using single- and/or double-gene deletion methods. Then the recombinant strains for the expression of exogenous target proteins including Trx-hPTH (human parathyroid hormone 1-84 coupled with thioredoxin as a fusion partner) and reteplase were reconstructed to test the secretory efficiency of the leaky strains. Finally, the fermentation experiments of the target proteins from these recombinant leaky strains were carried out in basic media (Modified R media) and complex media (Terrific Broth media) in flasks or fermenters. The results demonstrated that the resultant leaky strains were genetically stable and had a similar growth profile in the complex media as compared with the original strain, and the secretory levels of target proteins into Modified R media from the strains with double-gene deletion (up to 88.9%/mrcA lpp-pth) are higher than the excretory levels from the strains with single-gene deletion (up to 71.1%/lpp-pth) and the host E. coli JM109 (DE3) (near zero). The highest level of extracellular production of Trx-hPTH in fermenters is up to 680 mg l(-1). PMID- 24779864 TI - Two cases of severe intoxication associated with analytically confirmed use of the novel psychoactive substances 25B-NBOMe and 25C-NBOMe. AB - CONTEXT: A new group of novel psychoactive substance, the N-methoxybenzyl (NBOMe) derivatives of substituted phenethylamine, has recently emerged on the drug market, among which 25I-NBOMe and 25B-NBOMe have previously been implicated in clinical intoxications and fatalities. We report two cases of acute intoxication associated with these substances. CASE DETAILS: Two male patients (17 and 31 years of age) had ingested drugs labelled as 'NBOMe' or 'Holland film' and developed confusion, agitation, hypertension, tachycardia, hyperthermia, sweating and dilated pupils. Other features included convulsion, rhabdomyolysis and deranged liver function. The patients required benzodiazepines and other drugs for the control of symptoms. Urine samples from both patients were analysed using liquid-chromatography tandem mass spectrometry (LC-MS/MS) following glucuronidase digestion and solid-phase extraction. Identification was based upon comparison of the retention time and enhanced product ion scan with reference standards. In both urine samples, 25B-NBOMe was detected. Additionally, 25C-NBOMe was identified in one of the urine samples. DISCUSSION: The NBOMe compounds are highly potent 5HT2A receptor agonists and are also agonists at alpha-adrenergic receptors, which likely account for their serotonergic and sympathomimetic symptoms. The clinical testing of NBOMe drugs is not commonly available. Clinicians as well as laboratory staff play an important role in facilitating the detection of this group of potentially dangerous emerging drugs. PMID- 24779865 TI - Organophosphate-pyrethroid combination pesticides may be associated with increased toxicity in human poisoning compared to either pesticide alone. AB - BACKGROUND: Organophosphate (OP) poisoning results in significant toxicity while pyrethroid poisoning is associated with extremely low fatality. OPs can inhibit the detoxification of pyrethroid and increase the toxicity of the combination. We assessed whether mixed OP-pyrethroid poisoning impacted outcome in human poisoning. METHODS: Patients were identified from a prospectively collected institutional poisoning database that incorporates demographic and outcome data of patients presenting with poisoning. RESULTS: Of the 1177 poisoned patients admitted over 2 years, 32 presented with OP-pyrethroid (50% chlorpyrifos-5% cypermethrin mixture) poisoning (Group 1), 26 consumed 20% chlorpyrifos (Group 2), and 32 took 15% cypermethrin (Group 3). Seizures occurred in 15.6% (n = 5) with chlorpyrifos-cypermethrin poisoning, 18.8% (n = 6) with cypermethrin poisoning, and 3.9% (n = 1) with chlorpyrifos poisoning. Ventilatory requirements were 53.5% (17/32), 42.3% (11/26), and 15.7% (5/32) in Groups 1-3, respectively. Ventilator-free days (Mean +/- SD) was significantly lower (p < 0.006) in Group 1 (20.9 +/- 9.3 days) than those in Group 2 (26.1 +/- 4.4 days) or 3 (27.8 +/- 0.6). The median (inter-quartile range) hospital stay was 5.5 (4-19.5), 5 (5-6), and 1 (0.65-1.5) days, respectively, in the three groups. Four patients died in Group 1 (13%). None died in the other groups. CONCLUSION: Although confounded by the varying quantity of chlorpyrifos and cypermethrin in the different formulations, patients with mixed poisoning appear to have shorter ventilator free days than patients poisoned by either of the pesticides alone. Further studies are required comparing patients poisoned by formulations with similar quantities of OP and pyrethroid or with analysis of blood pesticide concentration on admission. PMID- 24779866 TI - Two cases of aggressive nontumoral folliculotropic mycosis fungoides with visceral involvement. AB - Mycosis fungoides (MF) is the most common type of primary cutaneous T-cell lymphoma (CTCL), and folliculotropic MF (FMF) is one clinical variant of classic MF. MF generally has a good prognosis with an indolent clinical course, but for FMF greater therapeutic resistance is suggested. Visceral involvement is very rare in these two clinical forms. We report two exceptional cases of FMF with pulmonary and hepatic involvement. Five years after their initial diagnoses, patient 1 presented with a pulmonary localization of his FMF, and patient 2 with liver involvement, without lymph node or T-cell clones in the blood. These two patients had FMF corresponding to stage T2N0M1B0. These two cases highlight the aggressiveness of this rare variant of MF. They suggest that the T lymphocytes found in the folliculotropic form of CTCL could be characterized by greater visceral tropism. They raise the question of the molecular and functional characteristics of these T lymphocytes, and the possibility of a common target in the hair follicles and certain organs. Studies have shown that chemokine receptors are likely to be involved in the skin tropism that characterizes CTCL. These two cases show the aggressiveness of FMF and point to the interest in comparing the molecular characteristics of T lymphocytes in the folliculotropic and nonfolliculotropic forms of CTCL. PMID- 24779867 TI - Methods for constructing and assessing propensity scores. AB - OBJECTIVES: To model the steps involved in preparing for and carrying out propensity score analyses by providing step-by-step guidance and Stata code applied to an empirical dataset. STUDY DESIGN: Guidance, Stata code, and empirical examples are given to illustrate (1) the process of choosing variables to include in the propensity score; (2) balance of propensity score across treatment and comparison groups; (3) balance of covariates across treatment and comparison groups within blocks of the propensity score; (4) choice of matching and weighting strategies; (5) balance of covariates after matching or weighting the sample; and (6) interpretation of treatment effect estimates. EMPIRICAL APPLICATION: We use data from the Palliative Care for Cancer Patients (PC4C) study, a multisite observational study of the effect of inpatient palliative care on patient health outcomes and health services use, to illustrate the development and use of a propensity score. CONCLUSIONS: Propensity scores are one useful tool for accounting for observed differences between treated and comparison groups. Careful testing of propensity scores is required before using them to estimate treatment effects. PMID- 24779868 TI - Catamenial dermatoses: has anyone ever considered prostaglandins? AB - Catamenial dermatoses are unusual, cyclic, perimenstrual reactions to hormones produced during the menstrual cycle. They occur in a variety of clinical presentations, including urticaria, eczema, fixed drug eruptions, erythema multiforme and anaphylaxis. Autoimmune progesterone dermatitis is the most common, and is caused by an autoimmune response to endogenous progesterone in women of reproductive age. We report a case of catamenial dermatosis in a 42-year old Jamaican woman with a 10-year history of cyclic blistering and ulcerative eruptions of her mouth and limbs. Her symptoms were fully in keeping with a Stevens-Johnson-type reaction, and were associated with production of prostaglandins occurring during her menstrual cycle. PMID- 24779869 TI - Study protocol: imaging brain development in the Childhood to Adolescence Transition Study (iCATS). AB - BACKGROUND: Puberty is a critical developmental phase in physical, reproductive and socio-emotional maturation that is associated with the period of peak onset for psychopathology. Puberty also drives significant changes in brain development and function. Research to date has focused on gonadarche, driven by the hypothalamic-pituitary-gonadal axis, and yet increasing evidence suggests that the earlier pubertal stage of adrenarche, driven by the hypothalamic-pituitary adrenal axis, may play a critical role in both brain development and increased risk for disorder. We have established a unique cohort of children who differ in their exposure to adrenarcheal hormones. This presents a unique opportunity to examine the influence of adrenarcheal timing on brain structural and functional development, and subsequent health outcomes. The primary objective of the study is to explore the hypothesis that patterns of structural and functional brain development will mediate the relationship between adrenarcheal timing and indices of affect, self-regulation, and mental health symptoms collected across time (and therefore years of development). METHODS/DESIGN: Children were recruited based upon earlier or later timing of adrenarche, from a larger cohort, with 128 children (68 female; M age 9.51 years) and one of their parents taking part. Children completed brain MRI structural and functional sequences, provided saliva samples for adrenarcheal hormones and immune biomarkers, hair for long-term cortisol levels, and completed questionnaires, anthropometric measures and an IQ test. Parents completed questionnaires reporting on child behaviour, development, health, traumatic events, and parental report of family environment and parenting style. DISCUSSION: This study, by examining the neurobiological and behavioural consequences of relatively early and late exposure to adrenarche, has the potential to significantly impact our understanding of pubertal risk processes. PMID- 24779870 TI - Printing ink compounds in foods: UK survey results. AB - Three hundred and fifty foodstuffs packaged in printed paper/board were purchased from UK retail outlets. Solvent extracts of all foods and associated quality assurance samples were analysed by gas chromatography-mass spectrometry (GC-MS) to determine the presence and concentrations of 20 printing ink compounds: benzophenone, 4-methylbenzophenone, 2-methylbenzophenone, 3-methylbenzophenone, 4 hydroxybenzophenone, 2-hydroxybenzophenone, 4-phenylbenzophenone, methyl-2 benzoylbenzoate, 1-hydroxycyclohexyl phenyl ketone, 2-isopropylthioxanthone, 4 isopropylthioxanthone, 2,4-diethyl-9H-thioxanthen-9-one, 2,2-dimethoxy-2 phenylacetophenone, 2-methyl-4'-(methylthio)-2-morpholinopropiophenone, 4-(4 methylphenylthio)benzophenone, ethyl-4-dimethylaminobenzoate, 2-ethylhexyl-4 (dimethylamino)benzoate, N-ethyl-p-toluene-sulphonamide, triphenyl phosphate and di-(2-ethylhexyl) fumarate. The presence of one or more of the compounds benzophenone, 4-phenylbenzophenone, methyl-2-benzoylbenzoate, 1-hydroxycyclohexyl phenyl ketone, 2,2-dimethoxy-2-phenylacetophenone, 4-(4 methylphenylthio)benzophenone, ethyl-4-dimethylaminobenzoate, 2-ethylhexyl-4 dimethylaminobenzoate and triphenyl phosphate was confirmed in some food samples. Analysis of the associated packaging material was also carried out to confirm whether or not it was likely that the occurrence of these compounds in the foods was due to migration from the printed paper/board packaging. With the exception of triphenyl phosphate, detected in one foodstuff, all the packaging material contained the substance(s) found in the food. PMID- 24779871 TI - Occurrence of several main antibiotic residues in raw milk in 10 provinces of China. AB - In the present study, 199 raw milk samples were analysed for beta-lactams, tetracyclines, sulfonamides and quinolones. They were obtained from collection tanks of milk routes in 10 provinces of China. The occurrence and concentration range of the four antibiotics were investigated by competitive enzyme-linked immunosorbent assay methods. At the detectable level, 0.5%, 47.2% and 20.1% of samples were positive for beta-lactams, quinolones and sulfonamides, respectively. No sample was positive for tetracyclines. Beta-lactams were positive only in Beijing while quinolones and sulfonamides were positive in all provinces. One (0.5%) sample for beta-lactams was above the maximum residue limits (MRLs, regulated by EU, CAC and China). The maximum concentrations for sulfonamides and quinolones were 16.28 ug kg-1 and 23.25 ug kg-1 which were under their maximum residue limits. More precaution should be taken on antibiotic controls because of the high detection rate of some antibiotics. PMID- 24779872 TI - Feed additives diclazuril and nicarbazin in egg and liver samples from Croatian farms. AB - In total 307 egg and 275 liver samples were examined for nicarbazin and 365 eggs for diclazuril over a 30-month period. Enzyme-linked immunosorbent assay methods used for quantification were validated according to European Commission Decision 2002/657/EC. Non-compliant samples were confirmed by LC-MS/MS. Mean diclazuril concentrations in egg samples were 0.31 ug kg-1, which is below the MRL. In only one egg sample, 2.26 ug kg-1 was determined by enzyme-linked immunosorbent assay, although confirmation by LC-MS/MS gave a value of 1.6 ug kg(-1). Mean nicarbazin levels determined were 1.85 ug kg-1 in egg and 21.1 ug kg-1 in liver samples. Four samples, one egg and three livers, yielded elevated concentrations of nicarbazin, but only in the egg sample the LC-MS/MS method confirmed nicarbazin (106 ug kg-1) above the MRL value. PMID- 24779873 TI - Cadmium in meat and edible offal of free-range reared Swallow-belly Mangulica pigs from Vojvodina (northern Serbia). AB - The aim of this study was to determine the cadmium concentration in four muscles and 10 edible offal items of 15 free-range reared Swallow-belly Mangulica pigs from Vojvodina, by flame atomic absorption spectrometry after mineralisation by dry ashing. All individual concentrations in muscles and heart, tongue, spinal cord, back fat and leaf fat were below the limit of detection (LOD = 0.050 mg/kg). In lungs, spleen and brain, cadmium concentrations ranked from below LOD, 0.055 and 0.058 to 0.057, 0.065 and 0.074 mg/kg, respectively. The concentration of cadmium in liver and kidney ranged from 0.089 to 0.116 mg/kg and from 0.204 to 0.440 mg/kg, respectively. Cadmium concentrations in liver and kidney of free range reared Swallow-belly Mangulica pigs slaughtered at about 20 months of age were lower than in liver and kidney of commercial pigs from Vojvodina, slaughtered at about 6 months of age. PMID- 24779874 TI - T-2 and HT-2 toxins in cereals and cereal-based products in South Korea. AB - A total of 214 samples, consisting of brown rice, barley, mixed grains, corn, wheat and wheat flour were analysed for T-2 and HT-2 toxins using high performance liquid chromatography with fluorescence detection. Recovery and repeatability were 79.9%-107.5% and 4.9%-14.5% for T-2, and 74.0%-106.1% and 5.0% 17.9% for HT-2, respectively. T-2 toxin was detected in 11 (5.1%) of all samples. The highest incidence was found in corn (21.7%) followed by mixed grains and brown rice. Mean of all samples was 1.5-4.1 ug kg-1, the maximum level being 41.5 ug kg-1 in corn. HT-2 toxin was detected in 126 (58.9%) of all samples, and the mean values were 26.4-59.2 ug kg-1. The estimated daily intakes for the sum of T 2 and HT-2 toxins were 2.56, 3.22, 2.53, 0.03, 0.01 and 2.45 ng (kg bw)-1 day-1 in brown rice, barley, mixed grains, corn, wheat and wheat flour, respectively. PMID- 24779875 TI - Survey of aflatoxin M1 in raw milk in the five provinces of China. AB - Aflatoxin M1 (AFM1) is the only mycotoxin that has a legal limit in milk all over the world. In the present study, 360 raw milk samples were collected from Beijing, Hebei, Shanxi, Shanghai and Guangdong provinces in China in September 2010, and their AFM1 levels were determined by using enzyme-linked immunosorbent assay (ELISA). More than three-fourths (78.1%) of the 360 raw milk samples contained AFM1 at concentrations of 5-123 ng L-1. AFM1 contents in all positive samples were far below the Chinese and US legal limit of 500 ng L-1, but 10% of the raw milk samples exceeded the EU legal limit of 50 ng L-1. Moreover, both incidence and content of AFM1 in milk collected from the southern provinces, including Shanghai and Guangdong, were higher than those collected from the northern provinces, including Beijing, Hebei and Shanxi. PMID- 24779876 TI - T-2 toxin, zearalenone and fumonisin B1 in feedstuffs from China. AB - A total of 420 feedstuff samples were collected from China to determine and quantify T-2 toxin (T-2), zearalenone (ZEN) and fumonisin B1 (FB1). The contents of mycotoxins were determined by reverse-phase high-performance liquid chromatography with three-step cleanup and fluorescence detection. The mean recoveries of mycotoxins in spiked feedstuffs ranged from 72.2% to 95%. The limits of detection and quantification ranged from 1.8 to 5.7 and 6 to 19 ug/kg, respectively. Of the 420 analysed feedstuff samples, the incidence of T-2, ZEN and FB1 was 79.5%, 85.2% and 96.1%, respectively; levels detected ranged from 10 735, 35-1478 and 20-6568 ug/kg, respectively. The results suggest a risk for domestic animals and humans. Further, the procedure was found to be suitable for determination of mycotoxins in feedstuffs and can be used for routine analysis. This is the first report in China on natural contamination of feedstuffs with these mycotoxins. PMID- 24779878 TI - Aflatoxins in black tea in Iran. AB - Aflatoxins (AFs) are highly toxic, and carcinogenic secondary fungal metabolites and have been detected in various food commodities. In this regard, 40 black tea samples including domestic and imported black tea were analysed for aflatoxin contamination by high-performance liquid chromatography using a post-column derivatisation procedure (Kobra cell) with fluorescence detection. Samples were randomly collected in 2010 from Tehran markets. The results revealed that 30 among 40 samples were contaminated with aflatoxins (27.5% of the total). Mean AFB1 content was 10.0 ng/g and mean of aflatoxin total was 12.07 ng/g for the 11 contaminated samples. PMID- 24779877 TI - Heavy metal content of black teas consumed in Iran. AB - Tea (Camellia sinensis) is the most widely consumed beverage in several parts of the world. Tea consumption is a major component of the traditional Iranian diet; however, limited data are available indicating heavy metals content of this beverage. This study aimed to assess concentrations of heavy metals, including copper, lead, cadmium, chromium and mercury as well as minerals like zinc and iron in black tea samples. Atomic absorption spectrometry was used to determine the elements of interest in 20 brands of black tea that are widely consumed among Iranians. The mean concentrations were 28.8 for Zn, 135.2 for Fe, 15.9 for Cu and 8.2 for Cr (mg kg-1) and 134.5 for Cd, 209.5 for Pb and 40 for Hg (ug kg-1). It is concluded that tea consumption can be a possible source of some heavy metal intake for the Iranian population. PMID- 24779879 TI - Metal levels in organically and conventionally produced animal and vegetable products in Turkey. AB - Lead, cadmium, copper, zinc and iron levels were determined in organically and conventionally produced wheat, green lentils, flower honey and eggs that are supplied on different markets in Ankara, Turkey. Their toxicological and nutritional values were compared with national and international limits and literature data. The levels of cadmium and lead in conventionally and organically produced wheat, green lentils, honey and egg were below the limit of detection (LOD), whereas the level of copper was only below LOD in honey and eggs. The levels of Zn and Cu were found to be higher in conventionally produced wheat samples than organically produced ones; whereas the level of Fe in organic products was found to be higher than the conventional products. PMID- 24779880 TI - Heavy metals in Mugil cephalus (Mugilidae) from the Ligurian Sea (North-West Mediterranean, Italy). AB - Pb, Cd and Hg in muscles of flathead mullet (Mugil cephalus), collected from Bocca di Magra, La Spezia (Ligurian Sea, Mediterranean Sea, Italy), were determined using graphite furnace atomic absorption spectrometry after microwave digestion for Pb and Cd and direct mercury analyser for Hg. Average Pb concentrations varied in the range 0.20-0.24 mg/kg, whereas Cd and Hg levels were negligible. None of the tested 200 samples exceeded the European regulatory limits as set by EC 1881/2006 and 420/2011. Metal concentrations in fish muscles were assessed for human consumption according to provisional tolerable weekly intake. The estimated values of Pb, Cd and Hg in M. cephalus's edible parts in this study were below the values established by the Joint WHO/FAO Expert Committee on Food Additives. Therefore, it can be concluded that there is no health problem in human consumption. PMID- 24779881 TI - Fusariotoxins in Russian Federation 2005-2010 grain harvests. AB - Monitoring results of food grain contamination with fusariotoxins-deoxynivalenol (DON), zearalenone (ZEN), fumonisins (FB1&FB2), T-2 and HT-2 toxins-are presented. Harvests of 2005-2010 in different regions of Russia were investigated. The occurrence of DON in wheat was 8%, barley 9%, oats 4%, rye 2% and maize 2%. The highest frequency of ZEN contamination was found in oats, the lowest in wheat. Calculated average daily intake of DON varied from 0.066 to 0.096 ug/kg body weight, the highest being found in the Southern region, but substantially lower than the provisional maximum tolerable daily intake. The results of enzyme-linked immunosorbent assay and high-performance liquid chromatography-mass spectrometry analysis demonstrated the presence of T-2 toxin in 14% and HT-2 toxin in 17% of all samples. The maximum level of T-2 toxin was exceeded only in one sample of barley. Relatively high frequency and levels of FB1&FB2 contamination were found in maize. PMID- 24779882 TI - Lead and cadmium in functional health foods and Korean herbal medicines. AB - Lead (Pb) and cadmium (Cd) in functional health foods (FHF) and Korean herbal medicines (KHM) were analysed by the standard addition method with inductively coupled plasma-mass spectrometry. A total of 672 samples were collected from 2347 people (1015 adults, 557 students and 775 infants and children) who lived in Korea. Pb and Cd concentrations were analysed in the samples (FHF, n = 535; KHM, n = 50). Method validation was carried out using standard reference material (SRM), recovery rate and limits of detection and quantification. Recovery rates for Pb and Cd using three SRMs were 94.9%-101.6% and 96.7%-115.2%, respectively. Mean Pb values in FHF and KHM were 0.146 and 0.349 mg kg-1, respectively. Mean Cd levels in FHF and KHM were 0.035 and 0.056 mg kg-1, respectively. Mean values in Spirulina and yeast products were the highest in the FHF samples (0.940 mg kg-1 for Pb in Spirulina products and 0.115 mg kg-1 for Cd in yeast products). PMID- 24779883 TI - In silico analysis of TTR gene (coding and non-coding regions, and interactive network) and its implications in transthyretin-related amyloidosis. AB - INTRODUCTION: Transthyretin (TTR)-related amyloidosis is a life-threatening disease. Currently, several questions about the pathogenic mechanisms of TTR related amyloidosis remain unanswered. METHODS: We have investigated various TTR related issues using different in silico approaches. RESULTS: Using an amino acid similarity-based analysis, we have indicated the most relevant TTR secondary structures in determining mutation impact. Our amyloidogenic propensity analysis of TTR missense substitutions has highlighted a similar pattern for wild-type and mutated TTR amino beta acid sequences. However, some mutations present differences with respect to the general distribution. We have identified non coding variants in cis-regulatory elements of the TTR gene, and our analysis on V122I-related haplotypes has indicated differences in non-coding regulatory variants, suggesting differences among V122I carriers. The analysis of methylation status indicated CpG sites that may affect TTR expression. Finally, our interactive network analysis revealed functional partners of TTR that may play a modifier role in the pathogenesis of TTR-related amyloidosis. DISCUSSION AND CONCLUSION: Our data provided new insights into the pathogenesis of TTR related amyloidosis that, if they were to be confirmed through experimental investigations, could significantly improve our understanding of the disease. PMID- 24779884 TI - Social inequalities in teenage fertility outcomes: childbearing and abortion trends of three birth cohorts in Finland. AB - CONTEXT: Teenagers of low socioeconomic status are more likely to get pregnant, and less likely to choose abortion, than more privileged teenagers. Few studies have used longitudinal data to examine whether these differences persist as overall teenage pregnancy rates decline. METHODS: Nationally representative register data from 259,242 Finnish women in three birth cohorts (1955-1959, 1965 1969 and 1975-1979) were analyzed using Cox regression to assess socioeconomic differences in teenagers' risks of pregnancy and abortion. Binary logistic regression was used to assess socioeconomic differences in the odds of pregnant teenagers' choosing abortion. RESULTS: Socioeconomic differences in abortion risk did not change substantially across cohorts; however, differences in the risk of childbirth rose between the first two cohorts and then returned to their earlier level. In all cohorts, teenagers from upper-level employee backgrounds, the most privileged group, had the lowest risks of abortion and childbirth (44-53% and 53 69% lower, respectively, than those for manual workers' children). Teenagers whose parents were lower-level employees or farmers also had reduced risks of both outcomes in all cohorts; results for other socioeconomic groups were less consistent. Pregnant teenagers from upper-level employee backgrounds had 2-3 times the odds of abortion of manual workers' children; the largest difference was found in the 1950s cohort. CONCLUSIONS: Despite the declining overall teenage pregnancy rate, poorer background continues to be associated with a higher risk of conceiving and of giving birth. PMID- 24779885 TI - Mutagenic potential of 8-oxo-7,8-dihydro-2'-deoxyguanosine bypass catalyzed by human Y-family DNA polymerases. AB - One of the most common lesions induced by oxidative DNA damage is 8-oxo-7,8 dihydro-2'-deoxyguanosine (8-oxodG). Replicative DNA polymerases poorly traverse this highly mutagenic lesion, suggesting that the replication fork may switch to a polymerase specialized for translesion DNA synthesis (TLS) to catalyze 8-oxodG bypass in vivo. Here, we systematically compared the 8-oxodG bypass efficiencies and fidelities of the TLS-specialized, human Y-family DNA polymerases eta (hPoleta), iota (hPoliota), kappa (hPolkappa), and Rev1 (hRev1) either alone or in combination. Primer extension assays revealed that the times required for hPoleta, hRev1, hPolkappa, and hPoliota to bypass 50% of the 8-oxodG lesions encountered (t50(bypass)) were 0.58, 0.86, 108, and 670 s, respectively. Although hRev1 bypassed 8-oxodG efficiently, hRev1 failed to catalyze the extension step of TLS, and a second polymerase was required to extend the lesion bypass products. A high-throughput short oligonucleotide sequencing assay (HT-SOSA) was used to quantify the types and frequencies of incorporation errors produced by the human Y-family DNA polymerases at and near the 8-oxodG site. Although hPoleta bypassed 8-oxodG most efficiently, hPoleta correctly incorporated dCTP opposite 8 oxodG within only 54.5% of the sequences analyzed. In contrast, hPoliota bypassed the lesion least efficiently but correctly incorporated dCTP at a frequency of 65.8% opposite the lesion. The combination of hRev1 and hPolkappa was most accurate opposite 8-oxodG (92.3%), whereas hPolkappa alone was the least accurate (18.5%). The t50(bypass) value and correct dCTP incorporation frequency in the presence of an equal molar concentration of all four Y-family enzymes were 0.60 s and 43.5%, respectively. These values are most similar to those of hPoleta alone, suggesting that hPoleta outcompetes the other three Y-family polymerases to catalyze 8-oxodG bypass in vitro and possibly in vivo. PMID- 24779886 TI - The osteogenic effects of swimming, jumping, and vibration on the protection of bone quality from disuse bone loss. AB - We assessed and compared the effects of swimming, jumping, and vibration therapies on the prevention of bone loss because of unloading. Eighty Wistar rats were randomly divided into eight groups: S, permanent hind limb-suspended rats; CON, control rats; S + Swim, unloading interrupted by swimming exercise; S + C(Swim), suspension interrupted by regular weight-bearing with the same duration as in the S + Swim protocol; S + Jump, unloading interrupted by jumping exercise; S + C(Jump), suspension interrupted for regular weight-bearing as in the S + Jump group; S + Vibr, unloading interrupted by vibration; and S + C(Vibr), suspension with interruptions for regular weight-bearing with the same protocol as that used for the S + Vibr rats. At the end of the experiment, the bone mineral density, bone strength, histomorphometric parameters, and serum levels of the bone markers were analyzed. The hind limb-suspended rats exhibited bone quality loss. In contrast, the trained rats showed a significant increase in bone mass, bone strength, bone formation, and serum levels of bone markers compared with the respective controls. Although we did not find a significant difference among the three physical exercises, the osteogenic effect of vibration was slightly lower than that of swimming and jumping. Thus, all physical exercises were efficient in preventing bone loss because of unloading and preserving bone quality. PMID- 24779887 TI - Mini Implants Supporting Fixed Partial Dentures in the Posterior Mandible: A Retrospective. AB - Small-diameter, or mini, dental implants have been successfully used to support removable and fixed oral prostheses. These implants impart about twice the per square-millimeter force on the supporting bone and this should be addressed during treatment planning. In the posterior jaws, bite forces are of a higher magnitude than in the anterior jaws and may induce an overload of the supporting bone and failure of the osseointegration. Thus there should not be occlusal contact in functional excursions that induce off axial loads. The cases presented herein demonstrate that mini dental implants may be used successfully to support fixed partial dentures in mandibular sites in highly selected patients. Attention should be given to the bone density of the site, very slow seating rotation of the implant with intermissions or cooling during insertion, observation of a 4 month healing time, flapless placement, treatment of any existing periodontitis, an insoluble cement, and exclusion of occlusal contact in functional excursions. Importantly, a narrow, rounded occlusal table should be used to minimize off axial loads and an insoluble luting cement should be used to prevent loosening of the crowns due to dissolution of the cement and an overload of the retained implant with any residual cement-retained in the retainer. The implant that supports the cement retained retainer will be subjected to leveraged rotation that may destroy the osseointegration and result in exfoliation of the implant. PMID- 24779888 TI - Effects of Mn(II) on UO2 dissolution under anoxic and oxic conditions. AB - Groundwater composition and coupled redox cycles can affect the long-term stability of U(IV) products from bioremediation. The effects of Mn(II), a redox active cation present at uranium-contaminated sites, on UO2 dissolution in both oxic and anoxic systems were investigated using batch and continuous-flow reactors. Under anoxic conditions Mn(II) inhibited UO2 dissolution, which was probably due to adsorption of Mn(II) and precipitation of MnCO3 that decreased exposure of U(IV) surface sites to oxidants. In contrast, Mn(II) promoted UO2 dissolution under oxic conditions through Mn redox cycling. Oxidation of Mn(II) by O2 produced reactive Mn species, possibly short-lived Mn(III) in solution or at the surface, that oxidatively dissolved the UO2 more rapidly than could the O2 alone. At pH 8 the Mn cycling was such that there was no measurable accumulation of particulate Mn oxides. At pH 9 Mn oxides could be produced and accumulate, while they were continuously reduced by UO2, with Mn(II) returning to the aqueous phase. With the rapid turnover of Mn in the redox cycle, concentrations of Mn as low as 10 MUM could maintain an enhanced UO2 dissolution rate. The presence of the siderophore desferrioxamine B (a strong Mn(III)-complexing ligand) effectively decoupled the redox interactions of uranium and manganese to suppress the promotional effect of Mn(II). PMID- 24779889 TI - Risk factors for nasopharyngeal carriage of Streptococcus pneumoniae and effects of a hygiene intervention: repeated cross-sectional cohort study at day care centres. AB - BACKGROUND: Day care attendance and antibiotic consumption are major risk factors for carriage of antibiotic-susceptible and non-susceptible pneumococci. We describe the nasopharyngeal carriage of antibiotic-susceptible and non susceptible pneumococci among children at day care centres (DCCs), analyse the association of potential risk factors with carriage, and examine the effects of a hygiene intervention on carriage. METHODS: Thirty DCCs in 2 communities were included in a cohort intervention trial. Nasopharyngeal cultures and information on the children were obtained every 6 months. The study lasted 2.5 y and the hygiene intervention was introduced at half of the DCCs during the last 1.5 y of the study. The results were analysed using a mixed effects logistic regression model. RESULTS: A total of 5663 cultures were obtained from 2399 children, of which 55.6% grew pneumococci. Of the pneumococci, 27.9% were penicillin-non susceptible (PNSP). The hygiene intervention was associated with a decreased risk of pneumococcal carriage, but this did not reach statistical significance for PNSP carriage. Pneumococcal and PNSP carriage was negatively associated with age, varied significantly between DCCs, and was positively associated with the number of preceding colds. Individual antibiotic use (mainly penicillin/amoxicillin) at the time of sampling and/or during the preceding month was associated with a decreased risk of pneumococcal and PNSP carriage. Individual use of cephalosporins was associated with an increased risk of carriage of penicillin and TMP-SMX-non-susceptible pneumococci. CONCLUSION: The hygiene intervention at the DCCs reduced the risk of pneumococcal carriage and the individual use of antibiotics was found to affect carriage in a complex manner. PMID- 24779890 TI - Extracellular matrix protein 1 is correlated to carcinogenesis and lymphatic metastasis of human gastric cancer. AB - BACKGROUND: Tumor-induced lymphangiogenesis is a crucial step in malignant invasion and metastasis. Extracellular matrix protein 1 (ECM1) was recently reported to play a role in lymphangiogenesis. In the present work, we aimed to evaluate the role of ECM1 in gastric cancer and examined whether aberrant expression of ECM1 increased the tumorigenic and metastatic potential of human gastric cancer. METHODS: The mRNA and protein expression of ECM1 in gastric cancer specimen and the noncancerous counterparts from 77 patients were detected by real-time PCR and immunohistochemistry staining. Lymphatic microvessel density (LMVD) in the corresponding serial sections was assessed by counting the lymphatic microvessels labelled by D2-40. The correlations between ECM1 expression, LMVD, and the clinicopathological parameters were examined. RESULTS: ECM1 protein expression was detected in 70.1% (54/77) of gastric cancer specimen, significantly higher than that in the corresponding counterparts (P<0.01). ECM1 mRNA in tumor specimen was also dramatically amplified. Elevated LMVD and ECM1 were positively correlated (P<0.01). In addition, ECM1 protein expression was also closely associated with depth of tumor invasion and TNM stage (P<0.05, respectively). CONCLUSIONS: ECM1 expression is aberrant elevated in tumor specimen and is closely related to the tumorigenic and metastatic potential of human gastric cancer. Thus, carrying out the protein examination may be beneficial to predict carcinogenesis and metastatic spread of human gastric cancer. PMID- 24779892 TI - Supramolecular dendritic polymers: from synthesis to applications. AB - CONSPECTUS: Supramolecular dendritic polymers (SDPs), which perfectly combine the advantages of dendritic polymers with those of supramolecular polymers, are a novel class of non-covalently bonded, highly branched macromolecules with three dimensional globular topology. Because of their dynamic/reversible nature, unique topological structure, and exceptional physical/chemical properties (e.g., low viscosity, high solubility, and a large number of functional terminal groups), SDPs have attracted increasing attention in recent years in both academic and industrial fields. In particular, the reversibility of non-covalent interactions endows SDPs with the ability to undergo dynamic switching of structure, morphology, and function in response to various external stimuli, such as pH, temperature, light, stress, and redox agents, which further provides a flexible and robust platform for designing and developing smart supramolecular polymeric materials and functional supramolecular devices. The existing SDPs can be systematically classified into the following six major types according to their topological features: supramolecular dendrimers, supramolecular dendronized polymers, supramolecular hyperbranched polymers, supramolecular linear-dendritic block copolymers, supramolecular dendritic-dendritic block copolymers, and supramolecular dendritic multiarm copolymers. These different types of SDPs possess distinct morphologies, unique architectures, and specific functions. Benefiting from their versatile topological structures as well as stimuli responsive properties, SDPs have displayed not only unique characteristics or advantages in supramolecular self-assembly behaviors (e.g., controllable morphologies, specific performance, and facile functionalization) but also great potential to be promising candidates in various fields. In this Account, we summarize the recent progress in the synthesis, functionalization, and self assembly of SDPs as well as their potential applications in a wide range of fields. A variety of synthetic methods using non-covalent interactions have been established to prepare different types of SDPs based on varied mono- or multifunctionalized building blocks (e.g., monomer, dendron, dendrimer, and hyperbranched polymer) with homo- or heterocomplementary units. In addition, SDPs can be further endowed with excellent functionalities by employing different modification approaches involving terminal, focal-point, and backbone modification. Similar to conventional dendritic polymers, SDPs can self-assemble into diverse supramolecular structures such as micelles, vesicles, fibers, nanorings, tubes, and many hierarchical structures. Finally, we highlight some typical examples of recent applications of SDP-based systems in biomedical fields (e.g., controlled drug/gene/protein delivery, bioimaging, and biomimetic chemistry), nanotechnology (e.g., nanoreactors, catalysis, and molecular imprinting), and functional materials. The current research on SDPs is still at the very early stage, and much more work needs to be done. We anticipate that future studies of SDPs will focus on developing multifunctional, hierarchical supramolecular materials toward their practical applications by utilization of cooperative non-covalent interactions. PMID- 24779891 TI - Defending the fort: a role for defensin-2 in limiting Rickettsia montanensis infection of Dermacentor variabilis. AB - The importance of tick defensins is evidenced by their expression in a wide variety of tick tissues and prevalence across many tick genera. To date, the functional and biological significance of defensin-2 as a rickettsiastatic or rickettsiacidal antimicrobial peptide has not been addressed. In a previous study, defensin-2 transcription was shown to increase in Dermacentor variabilis ticks challenged with Rickettsia montanensis. In the present study, the hypothesis that defensin-2 is functional as a rickettsiastatic and/or rickettsiacidal antimicrobial peptide is tested. We show that defensin-2 plays a role in reducing burden after acquisition of Rickettsia montanensis through capillary feeding. Moreover, defensin-2 is shown to associate with R. montanensis in vitro and in vivo, causing cytoplasmic leakiness. PMID- 24779893 TI - Insights into the structural changes occurring upon photoconversion in the orange carotenoid protein from broadband two-dimensional electronic spectroscopy. AB - Carotenoids play an essential role in photoprotection, interacting with other pigments to safely dissipate excess absorbed energy as heat. In cyanobacteria, the short time scale photoprotective mechanisms involve the photoactive orange carotenoid protein (OCP), which binds a single carbonyl carotenoid. Blue-green light induces the photoswitching of OCP from its ground state form (OCPO) to a metastable photoproduct (OCPR). OCPR can bind to the phycobilisome antenna and induce fluorescence quenching. The photoswitching is accompanied by structural and functional changes at the level of the protein and of the bound carotenoid. Here, we use broadband two-dimensional electronic spectroscopy to study the differences in excited state dynamics of the carotenoid in the two forms of OCP. Our results provide insight into the origin of the pronounced vibrational lineshape and oscillatory dynamics observed in linear absorption and 2D electronic spectroscopy of OCPO and the large inhomogeneous broadening in OCPR, with consequences for the chemical function of the two forms. PMID- 24779894 TI - High headache-related disability in patients with systemic lupus erythematosus and primary Sjogren's syndrome. AB - BACKGROUND AND PURPOSE: It is often argued that patients with systemic lupus erythematosus (SLE) have more headaches than healthy subjects, but this association remains controversial. Thus the magnitude and severity of headaches in SLE were evaluated in comparison with another autoimmune disease, namely primary Sjogren's syndrome (pSS). METHODS: Sixty-seven patients with SLE, 71 pSS patients and 108 healthy subjects were included. The International Classification of Headache Disorders, Headache Impact Test-6 (HIT-6), and the Migraine Disability Assessment (MIDAS) questionnaire were used to classify and assess headache-related disability. RESULTS: Primary headaches were more prevalent in SLE patients than in healthy subjects (82% vs. 69%, P = 0.01). Amongst the headache sufferers, SLE patients (N = 55) and pSS patients (N = 51) had higher HIT-6 scores (median 51, range 36-67, and median 54, range 36-72, respectively) than healthy subjects (N = 69) (median 46, range 36-72; P = 0.02 and P = 0.0009, respectively). Also, MIDAS scores were higher in SLE (median 0, range 0-110) and pSS patients (median 1, range 0-40) than in healthy subjects (median 0, range 0 10; P = 0.04 and P = 0.003, respectively). CONCLUSION: Patients with SLE and pSS have a higher burden from headaches and more severe headaches than headache sufferers without these diseases. However, evidence of a specific bothersome SLE headache was not possible to identify as the headaches had the same characteristics and similar impact and severity in pSS patients. Depressive mood significantly influenced headache severity. PMID- 24779895 TI - Peripheral blood cells chimerism after unrelated cord blood transplantation in children: kinetics, predictive factors and impact on post-transplant outcome. AB - This study aimed to describe kinetics of complete donor chimerism occurrence (cDC, >99.9% donor) after unrelated cord blood transplantation (UCBT), to identify its predictive factors and its impact on post-transplant outcome. Ninety four children who received single UCBT after a myeloablative conditioning regimen had blood chimerism evaluation at predefined post-transplant dates, using a real time polymerase chain reaction method with 0.1% sensitivity. Cumulative incidence of cDC at 1 year post-transplantation was 61.8%. Three predictive factors were identified in multivariate analysis: history of malignant disease (P = 0.03), older age (above 2.16 years, the first quartile of age, P = 0.0055) and higher level of cord/recipient human leucocyte antigen mismatch (4/6 vs. 5-6/6, P < 0.001) increased the probability of post-transplant cDC. Although graft cell dose had a strong impact on haematological recovery, it did not apparently influence cDC occurrence. Early cDC (i.e. more than 99.9% donor chimerism on days 15-30 post-transplant) appeared useful to predict engraftment (P = 0.003) as well as acute and chronic graft-versus-host disease (GvHD). Severe acute or chronic GvHD never occurred in patients with DC <=99.9%, suggesting than even minimal residual host haematopoiesis is associated with a very low risk of GvHD after UCBT. PMID- 24779896 TI - In-vitro/in-vivo characterization of trans-resveratrol-loaded nanoparticulate drug delivery system for oral administration. AB - OBJECTIVES: The current studies entail successful formulation of systematically optimized (OPT) nanoparticulate drug delivery system to increase the oral bioavailability using Eudragit RL 100 of trans-resveratrol (t-RVT), and evaluate their in-vitro/in-vivo performance. METHODS: t-RVT-loaded Eudragit RL 100 nanoparticles (t-RVT NPs) were prepared by nanoprecipitation method. The nanoparticles (NPs) were systematically optimized using 3(2) central composite design and the OPT formulation located using overlay plot. The pharmacokinetic and in-vivo biodistribution of t-RVT NPs were investigated in rats, and various levels of in-vitro/in-vivo correlation (IVIVC) were established. KEY FINDINGS: The OPT formulation (mean particle size: 180 nm) indicated marked improvement in drug release profile vis-a-vis pure drug and marketed formulation (MKT). Augmentation in the values of Ka (5.64-fold) and AUC0-24 (7.25-fold) indicated significant enhancement in the rate and extent of bioavailability by the optimized trans-resveratrol-loaded Eudragit RL 100 nanoparticles (OPT-t-RVT NPs) compared with pure drug. Level A of IVIVC was successfully established. OPT-t-RVT NPs showed 4.11-fold rose in the values of t-RVT concentrations in liver. In-situ single pass intestinal perfusion studies construed remarkable enhancement in the absorptivity and permeability parameters of OPT-t-RVT NPs. CONCLUSIONS: The results, therefore, insight into the role of solubility enhancement and trounce enterohepatic recirculation for improving the oral bioavailability of t-RVT. PMID- 24779897 TI - Total mercury in infant food, occurrence and exposure assessment in Portugal. AB - Commercial infant food labelled as from organic and conventional origin (n = 87) was analysed for total mercury content using a direct mercury analyser (DMA). Median contents of mercury were 0.50, 0.50 and 0.40 MUg kg-1 for processed cereal based food, infant formulae and baby foods, respectively, with a maximum value of 19.56 MUg kg-1 in a baby food containing fish. Processed cereal-based food samples showed statistically significant differences for mercury content between organic and conventional analysed products. Consumption of commercial infant food analysed did not pose a risk to infants when the provisionally tolerable weekly intake (PTWI) for food other than fish and shellfish was considered. By the contrary, a risk to some infants could not be excluded when using the PTWI for fish and shellfish. This is the first study reporting contents of total mercury in commercial infant food from both farming systems and the first on exposure assessment of children to mercury in Portugal. PMID- 24779898 TI - Heavy metals in raw cow and ewe milk from north-east Iran. AB - The presence of toxic metals in milk may create significant health problems for the population. In this study, 1440 raw cow and ewe milk samples from 18 townships in north-east Iran were analysed in four different seasons. Lead, cadmium and mercury levels were determined using atomic absorption spectrophotometry. Mean concentration of lead, cadmium and mercury in cow milk samples was 12.9 +/- 6.0, 0.3 +/- 0.3 and 3.1 +/- 0.3 ng g-1, respectively, and in ewe milk samples, these mean values were 14.9 +/- 7.8, 1.6 +/- 1.2 and 3.1 +/- 0.3 ng g-1, respectively. Statistical analyses showed that lead and cadmium concentrations in ewe milk were significantly higher than in cow milk. Concentrations of these metals in ewe milk varied significantly with different seasons. As the concentrations did not exceed the safety limits, they could not pose a serious danger to public health. PMID- 24779899 TI - 3-Monochloro-1,2-propandiol (3-MCPD) in soy sauce from the Bulgarian market. AB - The 3-monochloro-1,2-propandiol (3-MCPD) levels in soy sauces which contained hydrolysed vegetable protein were evaluated for the Bulgarian market. For analysis of 3-MCPD, a gas chromatography-mass spectrometry (GC-MS) method was applied with a linear range of 0.03-2.00 MUg mL-1 and a limit of detection (LOD) of 2.3 MUg kg-1 and a limit of quantification (LOQ) of 3.4 MUg kg-1. At these levels, the standard deviation was 5.1%, with recoveries between 81% and 102%. The method was applied to the analysis of 21 samples of soy sauce from the Bulgarian market. Results ranged from 3.7 to 185.6 MUg kg-1. Soy sauces produced from hydrolysed soy protein contained higher levels of 3-MCPD than naturally fermented sauces. In 38.4% of samples of Bulgarian origin, the 3-MCPD content was above the EU limit of 20 MUg kg-1. In all analysed samples, 33.3% had a 3-MCPD content above the EU limit. PMID- 24779900 TI - Natural co-occurrence of fungi and mycotoxins in poultry feeds from Entre Rios, Argentina. AB - A total of 120 pelleted poultry feed samples from Entre Rios Province, Argentina, were evaluated. The aims were to investigate (1) the presence of relevant toxigenic fungi, as well as to determine the ability to produce aflatoxins (AFs) by Aspergillus section Flavi isolated strains; and (2) the natural co-occurrence of AFs, fumonisins (FBs), gliotoxin, diacetoxyscirpenol (DAS), HT-2 and T-2 toxin by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Total fungal counts were below the established value (1 * 104 CFU g-1). Aspergillus flavus and A. parasiticus were the only aflatoxigenic species isolated. Co-occurrence of fumonisin B1 (FB1), HT-2 and T-2 toxin was detected in 100% of the feeds, with mean levels from 4502 to 5813; 6.7 to 21.6 and 19.6 to 30.3 ug kg-1, respectively. A large number of starter samples were co contaminated with aflatoxin B1 (AFB1), FB1, HT-2 and T-2 toxins. Gliotoxin and DAS were not found in this survey. PMID- 24779901 TI - Mercury contamination in commercial fresh and salt water fish of the Zabol Chahnimeh reservoirs and the Gulf of Oman (Iran). AB - In order to investigate bioaccumulation of mercury in Iranian coastal waters fish, tiger tooth croaker (Otolithes ruber) and yellowspotted trevally (Carangoides fulvoguttatus) from the Gulf of Oman and grass carp (Ctenopharyngodon idella) and silver carp (Hypophthalmichthys molitrix) from Zabol Chahnimeh reservoirs were sampled in May 2012. In these ecosystems, total mercury concentrations were measured in muscle and gill of these four fish species. Both regions did not reveal a significant difference. In H. molitrix and O. ruber, mercury concentrations in gill increased with increasing length (H. molitrix, r = 0.94, p < 0.005; O. ruber, r = 0.94, p > 0.005) and weight (H. molitrix, r = 0.94, p < 0.005; O. ruber, r = 0.82, p > 0.04). Generally, mercury levels in the analysed fish samples were higher than WHO, FDA and US-EPA legal limits. PMID- 24779902 TI - Aflatoxin M1 in raw, UHT milk and dairy products in Sicily (Italy). AB - A survey on 73 milk samples from different animal breeds and 24 dairy products samples from Sicily, Italy, was carried out for the presence of aflatoxin M1 (AFM1) by LC-fluorescence detection after immunoaffinity cleanup. AFM1 was detected in 48% and 42% of the milk and dairy samples at concentration ranges between <5.0-16.0 and <5.0-18.0 ng L-1, respectively. Within the raw milk samples, 92% had an AFM1 content below 5.0 ng L-1, in 7% of the cases it was in the range 5.0-10.0 ng L-1 and 1% was contaminated between 10.0 and 20.0 ng L-1. For the dairy products, ultra-high-temperature treated (UHT) milk, milk cream and cheese, the incidence was 42%, of which 83% contained less than 5.0 ng L-1 and 17% contained 10.0-20.0 ng L-1 AFM1. The levels of contamination found justify continuous monitoring for public health and to reduce consumer exposure. PMID- 24779903 TI - Trends in monitoring residues of pharmacologically active group B substances in products of animal origin in Lithuania from 1999 to 2008. AB - Monitoring data of group B pharmacologically active substances in the Republic of Lithuania during the period 1999-2008 are presented. Peer review is based on data taken from residue-monitoring plans of the years 1999-2008 and the National Food and Veterinary Risk Assessment Institute reports on analyses performed in various foods. The data were analysed with the SPSS statistical package. Analysis of group B pharmacologically active substances residues monitoring results from the years 1999-2008 revealed that 25,030 samples were tested to detect 421 (1.68%) non-compliant samples in three groups of substances: antibacterials, anthelmintics and non-steroidal anti-inflammatory drugs. Most residues (88.3%) were found in milk, and were far less in beef, pork, sheep and goat meat. PMID- 24779904 TI - Antibiotics in South Indian coastal sea and farmed prawns (Penaeus monodon). AB - Sulphonamides and chloramphenicol antibiotics were analysed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in sea and farmed prawn (Penaeus monodon) samples obtained from the coastal region of southern India during 2011-2012. Average recoveries were 77-99% and precision was between 1% and 8%. The results revealed that in sea prawn samples neither of the two antibiotics was detected, but in farmed samples from coastal Andhra Pradesh some sulphonamides were detected in a concentration range greater than the maximum residual limit as set by Council Directive 2377/90 EC. PMID- 24779905 TI - Ochratoxin A in several grains in Iran. AB - Ochratoxin A content in 100 grain and derived products were determined by high performance liquid chromatography with immunoaffinity column clean-up and fluorometric detection. Ochratoxin A was detected in 32% of green gram, 13.3% of chickpea, 10% of lentil and 17.5% of wheat flour. Ochratoxin contamination was below the regulatory limits of the European Union and of Iran. Recovery was 97% and the limit of detection was 0.12 ng g-1. PMID- 24779906 TI - LC-TOF/MS determination of phthalates in edible salts from food markets in Korea. AB - Residual quantities of 12 phthalates have been monitored in edible salts (raw salts, refined salts, refined salts with additives and baked salts) available in Korean food markets. Liquid-liquid extraction followed by liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) was used to analyse the samples. The method was validated and showed linear correlation (R2 > 0.996) in the range 0.5 100 ng g-1 for all target analytes. Recoveries were 85.9-108.4%, except for diethyl phthalate (DEP). Relative standard deviations (RSDs) were 2.7-6.0% and the limits of detection (LODs) were 1.2-2.8 ng g-1. Although the contamination of phthalates in salt would be trivial in comparison to those of other main foods and below the reference dose of the Chronic Oral Exposure recommended by US-EPA, the availability of reference data could be valuable for food chemists and salt manufacturers. PMID- 24779907 TI - Sorbate and benzoate in Turkish retail foodstuffs. AB - From 2008 to 2011, surveys were conducted to determine the levels of benzoic and sorbic acids and their respective salts in 983 retail food samples which included sauces, vegetable and fruit preparations, flavoured syrups, food supplements, cereals, bakery products, jelly, synthetic cream, sprays, mustards, jam and preserves, molasses, chewing gum, confectionery, non-alcoholic beverages, tea, wine, vinegar, brine and beers. The analysis involved methanol extraction of the foodstuff and direct determination by HPLC with UV detection. Quality assurance was employed with each batch of samples. Accuracy was ensured through regular participation in proficiency tests. Over this four-year period, a total of 23 samples (2.3%), some syrups, tomato sauces and fruit contained individual or combined levels of sorbic and benzoic acids above regulatory limits. Unauthorised use of benzoic acid was also detected in a syrup sample, bakery products and fruit preserves. PMID- 24779908 TI - A survey of levels of ethyl carbamate in alcoholic beverages in 2009-2012, Hebei Province, China. AB - Results of a survey of levels of ethyl carbamate (EC) (urethane) in alcoholic beverages carried out in four successive years from 2009 to 2012 by gas chromatography-mass spectrometry (GC/MS) are presented. The beverages were purchased for sampling from Hebei Province of China, including eight main areas of production. The samples comprised wines (n = 212), grain spirits (n = 143) and wine sauces (n = 164). The data show that the average EC content in these kinds of alcoholic beverages remains nearly constant over the years. The results provide valuable data for food authorities to establish maximum limits for EC in China. PMID- 24779909 TI - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in fish, seafood products and fish oil in Spain. AB - A total of 84 samples of wild and farmed fish, cephalopods and fish oils for animal feeding, traded in Spain, were analysed for polychlorinated dibenzo-p dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl PCBs) in 2009-2012, by gas chromatography-ion trap tandem mass spectrometry (GC MS-MS). The method was optimised for screening at moderate costs, allowing PCDD/Fs determination at 1 pg World Health Organization-toxic equivalent quantities (WHO-TEQ) g-1 wet weight (w w) and dl-PCBs at 0.02 pg WHO-TEQ g-1 w w. Concentrations in fish and cephalopods ranged from values below the limit of detection to 1.7 pg g-1 WHO-TEQ sum PCDD/Fs and dl-PCBs, considered as safe with regard to EU legislation. Higher levels were found in cod livers (5.4-54.2) and fish oils (3.3-30.7), with one noncompliant sample in each group. PMID- 24779910 TI - Senile plaques and cerebral amyloid angiopathy in an aged California sea lion (Zalophus californianus). AB - Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) consisting of beta amyloid (Abeta) are major features in the brain of Alzheimer's disease (AD) patients and elderly humans and animals. In this study, we report the finding of SPs and CAA in an aged sea lion (30 years), which is the first demonstration of AD-related pathological changes in a marine animal. Histologically, SPs were observed at the cerebral cortex, most frequently at the frontal lobe, with two morphologically different types: the small round type and the large granular type. Only the small round SPs were positive for Congo red staining. The SPs were equally immunoreactive to Abeta40 and Abeta42 and were mainly composed of Abeta with an N-terminal pyroglutamate residue at position 3. Amyloid depositions at vessel walls were noted at the meninges and within the parenchyma. Interestingly, double immunofluorescence staining for Abeta40 and Abeta42 showed that the two subtypes were deposited segmentally in different parts of the vessel walls. The lesions observed in the sea lion suggest that Abeta deposition is widely present in various animal species, including marine mammals; however, the peculiar deposits similar to cotton wool plaques and the specific pattern of CAA are characteristic features of this animal. PMID- 24779912 TI - Does a magnetic blanket induce changes in muscular blood flow, skin temperature and muscular tension in horses? AB - REASONS FOR PERFORMING STUDY: Static magnetic blankets are often claimed to induce increases in blood flow, reduce muscle tension and tenderness, and be beneficial in both prevention and treatment of musculoskeletal injuries in horses. However, there are no studies that confirm alleged beneficial effects of magnets on muscles of the back in healthy horses. OBJECTIVES: To investigate whether static magnets sewn into a blanket affect back muscle blood flow, skin temperature, mechanical nociceptive threshold (MNT) and behaviour in healthy horses. STUDY DESIGN: Prospective, randomised, blinded, placebo-controlled crossover study. METHODS: The following outcome measurements of the back of 10 healthy horses were performed; blood flow by photoplethysmography, skin temperature by use of thermistors in conjunction with digital infrared thermography, and MNTs by algometry. The horses' behaviour was filmed during the procedure and scored on an ethogram. Measurements were performed repeatedly for a 30 min baseline period. Thereafter a blanket with active, static magnets (900 gauss) or placebo magnets was placed on the horse and measurements were performed for a 60 min treatment period and a 30 min post treatment period. The study procedure was repeated on the consecutive day, when the horse received the alternative treatment. RESULTS: Blood flow in muscle, skin temperatures, MNTs and behavioural traits did not differ between active and placebo magnetic blankets. Skin temperature increased similarly during both active and placebo blanket treatment. CONCLUSIONS: In healthy horses, magnetic blankets did not induce additional significant effects on muscle blood flow, skin temperature, MNTs and behaviour when compared with nonmagnetic blankets. PMID- 24779911 TI - The stem cell adjuvant with Exendin-4 repairs the heart after myocardial infarction via STAT3 activation. AB - The poor survival of cells in ischaemic myocardium is a major obstacle for stem cell therapy. Exendin-4 holds the potential of cardioprotective effect based on its pleiotropic activity. This study investigated whether Exendin-4 in conjunction with adipose-derived stem cells (ADSCs) could improve the stem cell survival and contribute to myocardial repairs after infarction. Myocardial infarction (MI) was induced by the left anterior descending artery ligation in adult male Sprague-Dawley rats. ADSCs carrying double-fusion reporter gene [firefly luciferase and monomeric red fluorescent protein (fluc-mRFP)] were quickly injected into border zone of MI in rats treated with or without Exendin 4. Exendin-4 enhanced the survival of transplanted ADSCs, as demonstrated by the longitudinal in vivo bioluminescence imaging. Moreover, ADSCs adjuvant with Exendin-4 decreased oxidative stress, apoptosis and fibrosis. They also improved myocardial viability and cardiac function and increased the differentiation rates of ADSCs into cardiomyocytes and vascular smooth muscle cells in vivo. Then, ADSCs were exposed to hydrogen peroxide/serum deprivation (H(2)O(2)/SD) to mimic the ischaemic environment in vitro. Results showed that Exendin-4 decreased the apoptosis and enhanced the paracrine effect of ADSCs. In addition, Exendin-4 activated signal transducers and activators of transcription 3 (STAT3) through the phosphorylation of Akt and ERK1/2. Furthermore, Exendin-4 increased the anti apoptotic protein Bcl-2, but decreased the pro-apoptotic protein Bax of ADSCs. In conclusion, Exendin-4 could improve the survival and therapeutic efficacy of transplanted ADSCs through STAT3 activation via the phosphorylation of Akt and ERK1/2. This study suggests the potential application of Exendin-4 for stem cell based heart regeneration. PMID- 24779913 TI - Combined inhibition of caspase 3 and caspase 7 by two highly selective DARPins slows down cellular demise. AB - Caspases play important roles during apoptosis, inflammation and proliferation. The high homology among family members makes selective targeting of individual caspases difficult, which is necessary to precisely define the role of these enzymes. We have selected caspase-7-specific binders from a library of DARPins (designed ankyrin repeat proteins). The DARPins D7.18 and D7.43 bind specifically to procaspase 7 and active caspase 7, but not to other members of the family. Binding of the DARPins does not affect the active enzyme, but interferes with its activation by other caspases. The crystal structure of the caspase 7-D7.18 complex elucidates the high selectivity and the mode of inhibition. Combining these caspase-7-specific DARPins with the previously reported caspase-3 inhibitory DARPin D3.4S76R reduces the activity of caspase 3 and 7 in double transfected HeLa cells during apoptosis. In addition, these cells showed less susceptibility to TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand)-induced apoptosis in living cell experiments. D7.18 and D7.43 are therefore novel tools for in vitro studies on procaspase 7 activation as well as for clarifying the role of its activation in different cellular processes. If applied in combination with D3.4S76R, they represent an excellent instrument to increase our understanding of these enzymes during various cellular processes. PMID- 24779914 TI - Psychological consequences and associated risk factors among adult survivors of the 2008 Wenchuan earthquake. AB - BACKGROUND: In 2008, a devastating earthquake measuring 8.0 on the Richter scale struck Wenchuan, China. Following this disaster, several studies were conducted which assessed the degree of mental disorders in the affected population, but very few considered that several disorders may occur at the same time. This paper aims to investigate the psychological effects and risk factors among adult survivors one-year after the earthquake event. METHODS: 2080 adult earthquake survivors from 19 counties in the affected areas were interviewed. A stratified sampling strategy was used to collect the information. Earthquake survivors completed self-report questionnaires, which included a post-traumatic stress disorder (PTSD) checklist, a self-rating depression scale and a self-rating anxiety scale. RESULTS: Fifty nine percent of the participants were male. The prevalence of probable PTSD in the sample was 40.1% (based on the DSM-IV criteria). Significant differences in the demographic variables were found in the levels of anxiety, depression, and PTSD. Anxiety levels were found to be positively correlated with depression (r = 0.438, p < 0.01) and PTSD (r = 0.322, p < 0.01). Risk factors for each symptom were also identified. Being female, having a low income level and having a low perceived level of social support were found to be the risk factors associated with anxiety, depression, and PTSD. There appeared to be no obvious relationship between the distance from the epicenter of the earthquake event and the severity of the psychological problems. CONCLUSIONS: PTSD, anxiety, and depression were prevalent among the survivors. Most findings on the predictors were found to be consistent with current research. Positive adjustment and social support were found to be needed for the highest-risk population. PMID- 24779915 TI - Fracture Strength of Zirconia and Alumina Ceramic Crowns Supported by Implants. AB - Due to the brittleness and limited tensile strength of the veneering glass ceramic materials, the methods that combine strong core material (as zirconia or alumina) are still under debate. The present study aims to evaluate the fracture strength and the mechanism of failure through fractographic analysis of single all-ceramic crowns supported by implants. Forty premolar cores were fabricated with CAD/CAM technology using alumina (n = 20) and zirconia (n = 20). The specimens were veneered with glass-ceramic, cemented on titanium abutments, and subjected to loading test until fracture. SEM fractographic analysis was also performed. The fracture load was 1165 (+/-509) N for alumina and 1638 (+/-662) N for zirconia with a statistically significant difference between the two groups (P = 0.026). Fractographic analysis of alumina-glass-ceramic crowns, showed the presence of catastrophic cracks through the entire thickness of the alumina core; for the zirconia-glass-ceramic crowns, the cracks involved mainly the thickness of the ceramic veneering layer. The sandblast procedure of the zirconia core influenced crack path deflection. Few samples (n = 3) showed limited microcracks of the zirconia core. Zirconia showed a significantly higher fracture strength value in implant-supported restorations, indicating the role played by the high resistant cores for premolar crowns. PMID- 24779916 TI - Origin of arsenic in groundwater from the multilayer aquifer in Cremona (northern Italy). AB - An analysis of 70 wells that tap groundwater from depths of up to 260 m in and around the town of Cremona, N. Italy, shows that 50 of them contain more than 10 MUg/L of arsenic. Concentrations of As >10 ppb are accompanied by concentrations of Fe ranging from <0.1 to 6 mg/L and high concentrations of NH4 and Mn (<19 and <1.3 mg/L, respectively). The associations suggest that the mechanism of mobilization of As is the reductive dissolution of Fe oxides driven by the degradation of peat, which is commonly found in the aquifer system. Groundwater in the aquifer has a component of downward flow via leakage through aquitards and flow through lateral discontinuities in them. Along these flow paths, As is released by reductive dissolution of Fe oxides in shallow and intermediate aquifers (0-85 m below surface), reaching up to 183 MUg/L, and is attenuated (<95 MUg/L) at greater depths (100-150 m). Coprecipitation in iron sulfides could play an important role in As attenuation at these depths. The lower As concentration (<37 MUg/L) in the deepest aquifer (160-260 m) is less related to the As concentration of the overlying aquifers because the groundwater here has a component of upward flow. PMID- 24779917 TI - Frequency of spontaneous pulsations of the central retinal vein in the paediatric population. PMID- 24779918 TI - An autopsy case of meningeal carcinomatosis with parenchymal invasion through the cranial and spinal nerve roots. AB - Meningeal carcinomatosis is a well-known complication of malignant neoplasms. We report a case of meningeal carcinomatosis of 2 months' duration in a 22-year-old man, in whom the initial symptom was gradually worsening headache. Postmortem examination revealed infiltrating adenocarcinoma of the stomach. Carcinoma cells showed diffuse spread to the subarachnoid space of the brain and spinal cord. In many places, subarachnoid tumor cells had infiltrated to the cranial and spinal nerves. Moreover, carcinoma cells in the nerve roots extended to the parenchyma of the brain and spinal cord beyond the CNS-peripheral nervous system junction. These findings suggest that cranial and spinal nerve roots can be a possible route of parenchymal invasion in meningeal carcinomatosis. PMID- 24779920 TI - Narrow tuning of an odorant receptor to plant volatiles in Spodoptera exigua (Hubner). AB - Olfaction plays an important role in insects in recognizing volatile compounds, which are used to find food and mates, as well as avoid danger, predators and pathogens. The key players in the detection of volatile compounds are olfactory receptor (OR) proteins, which are located within the dendritic membrane of sensory neurons and extend into the lymph of sensilla on insect antennae. In the present study, we identify an OR gene, named SexiOR3, which is expressed in adult antenna in both sexes, but with female bias, in the beet armyworm moth Spodoptera exigua. Further in situ hybridization analysis revealed that SexiOR3 was mainly located in short trichoid sensilla. In in vitro heterologous expression experiments, SexiOR3 was narrowly tuned to E-beta-farnesene and several compounds of related structure, among 62 different compounds tested in this study. Furthermore, SexiOR3 responds to E-beta-farnesene at a low concentration of 10( 9) M, comparable to that of pheromone receptors (PRs) responding to the pheromones. This is a very interesting finding for a general OR, indicating that high specificity is a feature of at least one general OR and not only the PRs. The results suggest that the OR3 gene may play an important role in the moth olfactory system, and underpins important insect behaviour. PMID- 24779919 TI - Genetic variant in IL33 is associated with susceptibility to rheumatoid arthritis. AB - INTRODUCTION: Interleukin (IL)-33 is a proinflammatory cytokine contributing to the pathogenesis of rheumatoid arthritis (RA). The gene encoding IL-33 may serve as a genetic factor and be associated with the risk of RA. To investigate the potential association between IL33 and RA, we performed a case-control study based on Chinese Han population. METHODS: A three-stage case-control study was performed. Two tag single-nucleotide polymorphisms (SNPs) (rs7044343 and rs10975514), mapping to the IL33 gene, were first genotyped in the discovery population. We further genotyped rs7044343 and rs10975514 in the validation and replication population. The associations between the two tag SNPs and phenotypic subgroups of RA and levels of serum IL-33 were assessed with a logistic regression model. RESULTS: In the discovery population, the CC genotype of rs7044343 was associated with RA patients (odds ratio (OR) = 0.777, 95% confidence interval (CI), 0.611 to 0.988; P = 0.040). After anti-citrullinated peptide antibody (ACPA) stratification, the CC genotype of rs7044343 was also shown to be a protective genotype in RA without ACPA (OR = 0.610; 95% CI, 0.379 to 0.982; P = 0.042). In the validation population and replication population, the association between rs7044343 and RA, especially ACPA-negative RA, was still significant. A meta-analysis of discovery, validation, and replication panels confirmed the association between CC genotype of rs7044343 and RA (Pcombined = 0.0004; ORcombined = 0.77; 95% CI, 0.67 to 0.89). No evidence was found for heterogeneity between three sample sets (Phet = 0.99; I2 = 0%). Similar results were also obtained in ACPA-negative RA (Pcombined = 0.0002; ORcombined = 0.57; 95% CI, 0.43 to 0.77). No association was detected between rs10975514 polymorphism and RA susceptibility in the discovery and validation population. The serum levels of IL-33 were significantly lower in the patients with the rs7044343 CC genotype. CONCLUSION: The CC genotype of rs7044343 in IL33 is associated with RA patients and downregulates IL-33 expression in RA. PMID- 24779922 TI - Nanodiscs and electrospray ionization mass spectrometry: a tool for screening glycolipids against proteins. AB - Electrospray ionization-mass spectrometry (ESI-MS) is extensively employed to detect and quantify protein-carbohydrate interactions in vitro and is increasingly used to screen carbohydrate libraries against target proteins. However, current ESI-MS methods are limited to carbohydrate ligands that are relatively soluble in water and are, therefore, not generally suitable for studying protein interactions with glycolipids, an important class of cellular receptors. Here, we describe a catch-and-release (CaR)-ESI-MS assay, which exploits nanodiscs (NDs) to solubilize glycolipids and mimic their natural cellular environment, suitable for screening libraries of glycosphingolipids (GSL) against proteins to identify specific interactions and to rank their relative affinities. Using the B subunit homopentamers of cholera toxin and heat labile toxin as model GSL-binding proteins, the CaR-ESI-MS was applied to NDs containing mixtures of gangliosides. The results demonstrate that the CaR-ESI-MS assay can simultaneously detect both high and low affinity GSL ligands using either a library of NDs that each contains one GSL or incorporating a mixture of GSLs into a single ND. Moreover, the relative abundances of the released ligands appear to reflect their relative affinities in solution. Application of the CaR ESI-MS assay using NDs containing gangliosides extracted from porcine brain led to the discovery of a neolacto GSL as a cholera toxin ligand, highlighting the power of the assay for identifying specific protein-glycolipid interactions from biologically relevant mixtures. PMID- 24779921 TI - Phenolic composition of vinegars over an accelerated aging process using different wood species (acacia, cherry, chestnut, and oak): effect of wood toasting. AB - Wood shavings are widely employed in vinegar making to reduce aging time. Accordingly, this study aims to evaluate the effects of using shavings from different wood species (acacia, cherry, chestnut, and oak) and of toasting on the release of phenolic compounds into vinegar during the aging process. The study involved aging vinegars using previously toasted shavings and untoasted ones, at 0.5% and 1% (w/v), and collecting samples at 15 and 30 days. The phenolic compounds were analyzed by LC-DAD during the aging process. As a result, wood markers naringenin and kaempferol (cherry), robinetin and fustin (acacia), and isovanillin (oak) were identified for the first time in vinegars. The results also showed that toasting wood shavings decreases the concentration of most flavonoid wood markers (e.g., (+)-taxifolin, naringenin, and fustin) in vinegar, but that it is essential for the highest releases of aldehyde compounds (syringaldehyde, protocatechualdehyde, and vanillin). Remarkably, 15 days was sufficient to obtain the highest increases of most polyphenol compounds in the vinegar. Statistical analysis (linear discriminant analysis) proved that the phenolic compounds identified in vinegars are useful for discriminating vinegars regarding the wood species of the shavings used to accelerate aging. PMID- 24779923 TI - Dentate nuclei T2 relaxometry is a reliable neuroimaging marker in Friedreich's ataxia. AB - BACKGROUND AND PURPOSE: In Friedreich's ataxia (FRDA), frataxin deficiency results in iron redistribution in the dentate nuclei (DNC). Clusters of iron cause inhomogeneities in a magnetic field and result in a reduction in T2 relaxation time (T2). METHODS: T2 was prospectively evaluated in DNC, putamen, substantia nigra (SN), cerebellar white matter (CWM) and caudate and the correlation with clinical parameters was investigated. Thirty-five patients (range 9-51 years) and 44 controls (12-49 years) underwent T2 multi-echo sequence in a 3T scanner. Twenty-three patients (12-50 years) and 19 controls (14-49 years) were reassessed after 1 year. T2 was evaluated using specialized software (Aftervoxel) and severity of disease was quantified with the Friedreich Ataxia Rating Scale (FARS). RESULTS: T2 of both DNC was significantly shorter in the FRDA group at baseline (right, 58.6 +/- 8.3 ms vs. 63.7 +/- 8.1 ms, P = 0.013; left, 56.7 +/- 7.7 ms vs. 62.6 +/- 6.8 ms, P = 0.001). No significant difference was found between groups regarding the SN, putamen, CWM and caudate T2. DNC T2 values correlated with age, FARS total score and FARS III subscore on both sides. Prospectively, there was a significant reduction of T2 in FRDA patients in right and left DNC (P = 0.001 and 0.009) but not in other structures. Amongst controls, none of the regions significantly changed after 1 year. DNC T2 change over time correlated with GAA expansions and clinical deterioration (expressed by a change in FARS scores). CONCLUSIONS: DNC T2 values are abnormal in FRDA, progress over time and correlate with ataxia severity. These results strongly suggest that DNC relaxometry can be a useful neuroimaging marker in FRDA. PMID- 24779924 TI - S-allylcysteine prevents cisplatin-induced nephrotoxicity and oxidative stress. AB - OBJECTIVES: Cisplatin (CP) is an antineoplastic agent that induces nephrotoxicity and oxidative stress. S-allylcysteine (SAC) is a garlic-derived antioxidant. This study aims to explore whether SAC protects against CP-induced nephrotoxicity in rats. METHODS: In the first stage, the SAC protective dose was determined by measuring renal damage and the oxidative stress markers malondialdehyde, oxidized proteins and glutathione in rats injected with CP. In the second stage, the effect of a single dose of SAC on the expression of nuclear factor-erythroid 2 related factor-2 (Nrf2), protein kinase C beta 2 (PKCbeta2) and nicotinamide adenine dinucleotide phosphate oxidase subunits (p47(phox) and gp91(phox) ) was studied. In addition, the effect of SAC on oxidative stress markers and on the activity of catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) in isolated proximal and distal tubules were evaluated. KEY FINDINGS: SAC (25 mg/kg) prevented the CP-induced renal damage and attenuated CP induced decrease in Nrf2 levels and increase in PKCbeta2, p47(phox) and gp91(phox) expression in renal cortex and oxidative stress and decrease in the activity of CAT, GPx and GR in proximal and distal tubules. CONCLUSIONS: These data suggest that SAC provides renoprotection by attenuating CP-induced oxidative stress and decrease in the activity of CAT, GPx and GR. PMID- 24779925 TI - Low pH overrides the need of calcium ions for the shape-function relationship of calmodulin: resolving prevailing debates. AB - Calmodulin (CaM) regulates numerous cellular functions by sensing Ca(2+) levels inside cells. Although its structure as a function of the Ca(2+)-bound state remains hotly debated, no report is available on how pH independently or in interaction with Ca(2+) ions regulates shape and function of CaM. From SAXS data analysis of CaM at different levels of Ca(2+)-ion concentration and buffer pH, we found that (1) CaM molecules possess a Gaussian-chain-like shape in solution even in the presence of Ca(2+) ion or at low pH, (2) the global shape of apo CaM is very similar to its NMR structure rather than the crystal structures, (3) about 16 Ca(2+) ions or more are required per CaM molecule in solution to achieve the four-Ca(2+)-bound crystal structure, (4) low pH alone can impart shape changes in CaM similar to Ca(2+) ions, and (5) at different [Ca(2+)]/[CaM] ratio or pH values, the predominant shape of CaM is essentially a weighted average of its apo and fully activated shape. Results were further substantiated by analysis of sedimentation coefficient values from analytical ultracentrifugation and peptide binding assays using two peptides, each known to preferentially bind the apo or the Ca(2+)-activated state. PMID- 24779926 TI - Effect of N-butylscopolammonium bromide on equine ileal smooth muscle activity in an ex vivo model. AB - REASONS FOR PERFORMING STUDY: N-butylscopolammonium bromide (NBB) is an anticholinergic agent used to treat spasmodic colic in horses. Intestinal smooth muscle spasm also occurs in horses with intraluminal intestinal obstructions, such as ileal impactions. The antispasmodic effects of NBB may be useful in managing ileal impactions, but the effects of NBB on equine ileal smooth muscle are unknown. OBJECTIVES: To investigate the effects of NBB on spontaneous and induced contraction of the equine ileum in an ex vivo model. STUDY DESIGN: Ex vivo biomechanical study assessing contractile properties in isolate equine ileal smooth muscle with and without exposure to NBB. METHODS: Ileal tissue was collected from 6 healthy horses after euthanasia, and isolated circular and longitudinal smooth muscle strips were connected to isometric force transducers in organ baths. After equilibration, the effect of NBB (1 nmol/l to 100 MUmol/l) on spontaneous and carbachol-induced contraction was determined and compared with responses in control tissue. RESULTS: At >=30 MUmol/l, NBB inhibited spontaneous contractions in all muscle strips that exhibited spontaneous activity. N butylscopolammonium bromide pre-treatment inhibited carbachol-induced contraction in circular (NBB-treated half maximal effective concentration [EC50] 0.530 * 10( 8) mol/l vs. control EC50 41.57 * 10(-8) mol/l) and longitudinal muscle strips (NBB-treated EC50 0.243 * 10(-8) mol/l vs. control EC50 90.84 * 10(-8) mol/l). Abolition of carbachol-induced contraction with NBB was observed at lower concentrations in circular than longitudinal muscle strips. Pretreatment with NBB significantly inhibited carbachol-induced contractions; NBB-treated tissue required greater carbachol concentrations to produce sustained contractions than control muscle strips. Histamine-evoked contraction was not affected by NBB. CONCLUSIONS: N-butylscopolammonium bromide inhibits spontaneous and cholinergically mediated contraction in equine ileal smooth muscle strips ex vivo. Thus, NBB might reduce intestinal spasm in equine ileal impactions and could be useful for medical management of these cases, although further study is needed to confirm these effects in vivo. PMID- 24779928 TI - Dose-dependent behavioral response of the mosquito Aedes albopictus to floral odorous compounds. AB - The value of using plant volatiles as attractants for trapping and spatial repellents to protect hosts against mosquitoes has been widely recognized. The current study characterized behavioral responses of Aedes albopictus (Skuse) (Diptera: Culicidae) to different concentrations, ranging from 6 to 96%, of several common floral odorous compounds, including linalool, geraniol, citronellal, eugenol, anisaldehyde, and citral, using a wind tunnel olfactometer system. The results indicated that female mosquitoes reacted differently to different concentrations of the tested compounds, and the reactions also were different when those chemicals were tested alone or in the presence of human host odor. When tested alone, anisaldehyde was attractive at all tested concentrations, eugenol was attractive only at concentrations of 48-96%, while citronellal, linalool, citral, and geraniol were attractive at lower concentrations and repellent at higher concentrations. When tested in the presence of a human host, all compounds except for anisaldehyde at all tested concentrations showed host-seeking inhibition to certain degrees. Based on the results, it was concluded that anisaldehyde was effective in attracting Ae. albopictus when used alone but could also remarkably inhibit the host-seeking ability at a concentration of 96%, while citral, geraniol, linalool, citronellal, and eugenol are suitable as spatial repellents. PMID- 24779927 TI - Curcumin attenuates angiogenesis in liver fibrosis and inhibits angiogenic properties of hepatic stellate cells. AB - Hepatic fibrosis is concomitant with sinusoidal pathological angiogenesis, which has been highlighted as novel therapeutic targets for the treatment of chronic liver disease. Our prior studies have demonstrated that curcumin has potent antifibrotic activity, but the mechanisms remain to be elucidated. The current work demonstrated that curcumin ameliorated fibrotic injury and sinusoidal angiogenesis in rat liver with fibrosis caused by carbon tetrachloride. Curcumin reduced the expression of a number of angiogenic markers in fibrotic liver. Experiments in vitro showed that the viability and vascularization of rat liver sinusoidal endothelial cells and rat aortic ring angiogenesis were not impaired by curcumin. These results indicated that hepatic stellate cells (HSCs) that are characterized as liver-specific pericytes could be potential target cells for curcumin. Further investigations showed that curcumin inhibited VEGF expression in HSCs associated with disrupting platelet-derived growth factor-beta receptor (PDGF-betaR)/ERK and mTOR pathways. HSC motility and vascularization were also suppressed by curcumin associated with blocking PDGF-betaR/focal adhesion kinase/RhoA cascade. Gain- or loss-of-function analyses revealed that activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) was required for curcumin to inhibit angiogenic properties of HSCs. We concluded that curcumin attenuated sinusoidal angiogenesis in liver fibrosis possibly by targeting HSCs via a PPAR-gamma activation-dependent mechanism. PPAR-gamma could be a target molecule for reducing pathological angiogenesis during liver fibrosis. PMID- 24779929 TI - Trace elements and heavy metals in poultry and livestock meat in Taiwan. AB - Trace elements and heavy metals were determined in poultry and livestock meat by inductively coupled plasma mass spectrometry after graphite block digestion. Samples were collected from markets in Taiwan and included beef (20), mutton (20), pork (30), chicken (30), duck (10) and goose (10). Mean concentrations of Mn, Co, As, Se, Mo, Cd, Sb and Pb in meat samples were 0.106-0.365 MUg/g, 0.002 0.033 MUg/g, 0.005-0.035 MUg/g, 0.108-0.349 MUg/g, 0.029-0.140 MUg/g, <0.002 0.003 MUg/g, <0.002-0.004 MUg/g and 0.009-0.046 MUg/g, respectively. Arsenic concentrations in both pork and chicken were higher than in other meat. Lead concentrations were higher in duck. Risk assessment from these data did not indicate harm for public health. PMID- 24779930 TI - Investigations on Fusarium spp. and their mycotoxins causing Fusarium ear rot of maize in Kosovo. AB - After wheat, maize (Zea mays L.) is the second most important cereal crop in Kosovo and a major component of animal feed. The purpose of this study was to analyse the incidence and identity of the Fusarium species isolated from naturally infected maize kernels in Kosovo in 2009 and 2010, as well as the mycotoxin contamination. The disease incidence of Fusarium ear rot (from 0.7% to 40% diseased ears) on maize in Kosovo is high. The most frequently Fusarium spp. identified on maize kernels were Fusarium subglutinans, F. verticillioides/F. proliferatum and F. graminearum. Maize kernel samples were analysed by LC-MS/MS and found to be contaminated with deoxynivalenol (DON), DON-3-glucoside, 3-acetyl DON, 15-acetyl-DON, zearalenone, zearalenone-14-sulphate, moniliformin, fumonisin B1 and fumonisin B2. This is the first report on the incidence and identification of Fusarium species isolated from naturally infected maize as well as the mycotoxin contamination in Kosovo. PMID- 24779931 TI - Total mercury content, weight and length relationship in swordfish (Xiphias gladius) in Sri Lanka. AB - Mercury (Hg) is a global environmental pollutant that has been the cause of many public health concerns. It is transferred through trophic level and bio magnification in the food chain. Total Hg level was measured by cold vapour atomic absorption spectrometry in muscle tissue of 176 Swordfish (Xiphiasgladius) samples ranging from 11.8-112.0 kg total weight and 45-278 cm total length, collected from major fish landing sites in Sri Lanka during July 2009 to March 2010. Total Hg concentration varied between 0.18-2.58 mg/kg wet weight (ww), with a mean value +/- standard deviation of 0.90 +/- 0.52 mg/kg ww. Of the investigated samples 32% exceeded Hg limits as set by the European Union and Sri Lankan legislation (1 mg/kg, ww). Hg concentration of swordfish showed a significant positive relationship (P value < 0.05) with the fish length and weight. Consequently, consumption of larger fish leads to an increase in the exposure level for consumers. PMID- 24779932 TI - Cadmium, lead and some other trace elements in Larch Bolete mushrooms (Suillus grevillei) (Klotzsch) Sing., collected from the same site over two years. AB - The aim of this study was to examine the status of some trace metals accumulated in the flesh of Suillus grevillei mushrooms collected from the same site over two successive years. Total Ag, Al, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, Pb, Rb, Sr and Zn contents of fruiting bodies were determined by inductively coupled plasma atomic emission spectroscopy (ICP-AES) with ultrasonic cross-flow nebuliser. A difference (p < 0.05) was found in the contents of Cd, Cr, Cu, Fe, K, Na, Ni, Pb, Rb and Sr in caps and Fe, Na, P and Rb (p < 0.05) in stipes (Ag, Cd, Co, Cr, Ni and Pb were not determined in stipes). Natural fluctuations in trace elements' content of Suillus grevillei collected from the same site over time is a variable that needs to be considered when assessing minerals' nutritional status of mushrooms. PMID- 24779933 TI - Aflatoxins in selected Thai commodities. AB - Aflatoxin (AF) B1, B2, G1 and G2 were determined in 120 samples of selected Thai commodities including unpolished rice, unpolished glutinous rice, chilli powder, whole dried chilli pods and raw peanut. The mean concentrations of the total AFs for analysed samples were 0.16, 25.43, 14.18, 6.62 and 1.43 ug kg(-1) with positive incidences of 4%, 20%, 97%, 37% and 30%, respectively. Quantitative analysis was performed using HPLC equipped with post-column derivatisation and fluorescence detection. Sample clean-up was carried out using immunoaffinity columns for selective enrichment of AFs. The method was validated by using certified reference material, which showed recoveries over 85%. The limit of detections (LODs) and limit of quantifications (LOQs) were in a range between 0.01-0.11 ug kg(-1) and 0.03-0.38 ug kg(-1), respectively. The results clearly demonstrated that AFs were detectable in different matrices. Chilli powder was found to have the highest level of AFs contamination followed by chilli pods, peanut and rice, respectively. However, among the selected commodities, unpolished rice contained only trace levels of AFB1 and AFB2. With regard to the fact that AFs are a natural contaminant in commodities, this report calls to attention the regular monitoring and effective control of food commodities to prevent health hazards. PMID- 24779934 TI - Aflatoxins in various food from Istanbul, Turkey. AB - The present work reports the total aflatoxin and aflatoxin B1 levels in 62 food samples from Istanbul, Turkey. The total aflatoxin content in dried American cucumber, squash, tomato, okra and saffron samples was found to be 1.7 MUg/kg. AFB1 levels in five dried vegetables (red bell pepper, American cucumber, squash, tomato and okra), two tea (linden and jasmine flower) and three spice samples (cardamom, galangal and saffron) were 1 MUg/kg. Of the tested samples, 76% exceeded legal limits of total aflatoxin. The highest levels were determined in chestnut (232.9 MUg/kg), nutmeg (206.1 MUg/kg) and sumac (182.5 MUg/kg). These findings confirm the existing knowledge that food should be regularly and effectively controlled. PMID- 24779935 TI - Ochratoxin A in dried grapes and grape-derived products in Turkey. AB - Ochratoxin A (OTA) is a naturally occurring mycotoxin and widespread food contaminant which results in a probable human exposure. A total of 85 samples (50 dried grapes, 10 grape juices and 25 pekmez (boiled and concentrated grape juices) were collected from different supermarkets and traditional bazaars in Istanbul during 2008-2009. An analytical method based on immuno-affinity column for clean-up and high-performance liquid chromatography equipped with fluorescence detection was used to determine the OTA. Contamination frequencies were 8%, 20% and 88% with mean concentrations of positive samples of 1.15, 1.40 and 2.04 ug/kg for dried grapes, grape juices and pekmez samples, respectively. These levels were lower than the maximum levels as set by the European Commission (EC). However, 12 of 25 pekmez samples had higher levels than permitted by the European Union (EU) for safe consumption. PMID- 24779936 TI - Natural occurrence of fumonisins B1 and B2 in corn in four provinces of China. AB - Fumonisin B1 (FB1) and fumonisin B2 (FB2) are the most abundant fumonisins (FBs) occurring worldwide in maize, infected mainly by Fusarium verticillioides and F. proliferatum. A total of 307 corn kernel samples were collected from 45 districts of Gansu, Shandong, Ningxia and the Inner Mongolia provinces of the north and northwest China. The samples were analysed for FB1 and FB2 by high-performance liquid chromatography. The FBs (FB1+ FB2) incidence rate in samples from Gansu, Shandong, Ningxia and Inner Mongolia were 31.5%, 81.1%, 46.2% and 53.6%, respectively. Average FBs concentration was 703 MUg/kg and the concentrations ranged from <=11 to 13,110 MUg kg(-1). Results were compared with the European Commission (EC) regulation for FB1+ FB2 in unprocessed maize for human consumption of 4 mg kg(-1). Contamination in 17 samples was higher than these levels. More than 80% of the samples from Liaocheng county, which is located in the Shandong province, were contaminated with FBs, with a mean total FB concentration of 2496 MUg/kg. The result was significantly different from that of the Inner Mongolia (1399 MUg/kg), Ningxia (373 MUg/kg) and Gansu (175 MUg/kg). Average exposure to FBs (0.12 MUg/kg body weight/day) is within the provisional maximum tolerable daily intake of 2.0 mg/kg of body weight set by the Joint Food and Agriculture Organization and World Health Organization Expert Committee on Food Additives. PMID- 24779937 TI - Cadmium in locally grown rice (Oryza sativa) in Nigeria. AB - Cadmium levels were determined in locally grown rice samples in Nigeria and any potential risk involved in their consumption was assessed. The dried samples were digested with a 1:1 HNO3:HClO4 mixture and analysed with atomic absorption spectrophotometer (AAS). Mean cadmium values (mg/kg) were: Adamawa (0.50 +/- 0.02), Benue (0.63 +/- 0.05), Nasarawa (0.48 +/- 0.10), Taraba (0.48 +/- 0.10), Anambra (0.49 +/- 0.09), Ebonyi (0.60 +/- 0.08) and Enugu (0.59 +/- 0.10). All samples exceeded the Codex Alimentarius maximum limit for cadmium in rice. The dietary intake for a 60 kg adult ranges from 235 to 309 ug/week in the northern region and 240-294 ug/week in the south-eastern region. The target hazard quotient (THQ) ranged from 0.54 to 0.71, which is less than 1, indicating that the population will not be exposed to a potential health risk from dietary cadmium. However, the measured cadmium levels in rice should be of concern. PMID- 24779938 TI - Mercury and methylmercury in Korean herbal medicines and functional health foods. AB - Total mercury (Hg) and methyl mercury (MeHg) were analysed in functional health foods (FHFs) and in Korean herbal medicines (KHMs). A total of 560 samples (FHFs, n = 511; KHMs, n = 49) were collected. The levels of total Hg in 416 samples were lower than the limit of detection. MeHg analysis was conducted in 45 samples and the ranges of MeHg levels in samples were less than the LOD of 38.92 ng g(-1). Weekly intake per body weight (WIPBW) values of total Hg in FHFs and KHMS were 0.89 and 11.77 ng kg(-1) BW, respectively. The margins of exposure (MOEs) of total Hg for FHFs and KHMS were 598,753 and 36,503, respectively. The WIPBW values of MeHg for FHFs and KHMS were 0.22 and 0.01 ng kg(-1) BW, respectively. MOE values of MeHg for FHFs and KHMS were 412,276 and 517,363, respectively. PMID- 24779939 TI - Nitrite in hamburgers in Arak, Iran. AB - Nitrite and nitrate are used as additives in meat products to provide colour, taste and protection against micro-organisms, but excessive use of these substances can be toxic and can cause carcinogenesis in man. Natural and organic foods are not permitted to use chemical preservatives, the traditional curing agents used for cured meats, and so nitrate and/or nitrite cannot be added to hamburgers. This study aimed to measure nitrite in hamburgers sold in Arak city, in the centre of Iran, in 2011. For this purpose, 105 samples were randomly selected and analysed according to Official AOAC Method 973. The residual nitrite in the samples was 30-100 mg/kg (p < 0.001). In 85.7% of the samples, presence of nitrite was demonstrated, which suggests unfavourable production conditions and poor sodium nitrite standards at hamburger factories. PMID- 24779940 TI - Chromium level and intake from Chinese made tea. AB - Tea is a popular drink around the world. It is also one of the sources of metal intake. The objectives of this study were to assess chromium (Cr) intake from popular green, oolong, black and Pu-erh tea. In total, 128 Chinese made teas were analysed and concentration differences among four types of tea were explored. Black tea contained highest total Cr, which varied between 0.63 and 17.60 mg/kg. The lowest content was found in the green tea samples, between 0.26 and 1.30 mg/kg. Cr(III) and Cr(VI) in black tea were higher than in other types of tea. Cr(III), Cr(VI) and total Cr concentration in different tea infusions were also analysed. The results suggest that drinking tea is an effective way for Cr intake and the risk of adults and children being chronically intoxicated by tea infusions is low. PMID- 24779941 TI - Mycotoxins and fungal metabolites in groundnut- and maize-based snacks from Nigeria. AB - This exploratory study was aimed at investigating the spectrum of fungal metabolites in the processed food and snacks. Twenty types of snacks made separately from groundnut (n = 10), maize (n = 8) and a combination of groundnut and maize (n = 2) were analysed for naturally occurring mycotoxins and other fungal metabolites by a liquid chromatography-tandem mass spectrometric multi mycotoxin method. A total of 18, 21 and 32 metabolites were detected and quantified in the groundnut-, groundnut/maize- and maize-based snacks, respectively. Aflatoxins contaminated 2, 3 and 5 of the groundnut/maize-, groundnut- and maize-based snacks at concentrations up to 14, 1041 and 74 ug kg( 1), respectively. Thus, the National Agency for Food and Drug Administration and Control (NAFDAC) recommended limit of 20 ug kg(-1) for aflatoxins was exceeded in 6 of the 20 snacks. Fumonisins contaminated all the maize- and groundnut/maize based snacks with higher concentrations in the maize-based snacks (mean = 218.7 ug kg(-1)) compared with the groundnut/maize-based snacks (mean = 178.5 ug kg( 1)). Up to 26 different metabolites were found to co-occur in the same samples, thus posing an additional threat to the consumers due to possible additive and/or synergistic effects. PMID- 24779942 TI - Metal levels in Trachurus trachurus and Cyprinus carpio in Turkey. AB - Concentrations of five toxic metals were determined in two fish species from Turkish cities during 2010-2011. The obtained lead concentrations for all of the studied Trachurus trachurus (mean 777 MUg kg(-1)) and Cyprinus carpio (mean 439 MUg kg(-1)) samples were found to be higher than the maximum level (ML) of 300 MUg kg(-1), while Cd concentrations in the same samples were lower than the ML. Mean chromium (501 MUg kg(-1)), Ni (272 MUg kg(-1)) and Cu (785 MUg kg(-1)) concentrations in T. trachurus were significantly higher than in C. carpio (336 MUg Cr kg(-1), 229 MUg Ni kg(-1) and 394 MUg Cu kg(-1)), similar to those of Pb and Cd. Measured Pb concentrations in T. trachurus tissues are significantly higher than the ML, while those of Cd in both T. trachurus and C. carpio species were lower than the ML values. PMID- 24779944 TI - Body mass index predicts outcome of ureteroscopy-assisted retrograde nephrostomy for percutaneous nephrolithotomy. AB - INTRODUCTION: Several clinical series of retrograde nephrostomy for percutaneous nephrolithotomy (PCNL) have been published over the past 30 years demonstrating good outcomes and safety. We previously reported our adaptation of the Lawson technique, wherein we deploy the puncture wire through a flexible ureteroscope. We herein aim to clarify the performance characteristics of this nephrostomy creation technique. MATERIALS AND METHODS: Institutional Review Board approval and informed consent were obtained. A ureteroscopy-assisted retrograde nephrostomy (UARN) procedure was performed as described previously. Data were collected prospectively. Multiple patient and operative factors were evaluated for association with UARN success and nephrostomy creation time: body mass index (BMI), skin-to-stone distance, Guy's score, Clinical Research of the Endourological Society nephrolithometric score, hydronephrosis, stone burden, location of nephrostomy, exit from a stone-bearing calix, and use of holmium laser to access calix. RESULTS: Nephrostomy was successful in 49/52 UARN procedures (94%). Only single access was placed: upper-18, mid-27, and lower-7. Median BMI was 29 kg/m(2) and median time for nephrostomy creation was 39 minutes. Fluoroscopy time for the entire PCNL including nephrostomy creation was 84 and 16 seconds for case numbers 1-25 and 26-52, respectively. By stepwise linear regression, variables correlating with nephrostomy creation time were BMI (r(2)=0.219), stone burden (r(2)=0.094), use of holmium laser to access calix (r(2)=0.104), and total r(2) linear=0.416. CONCLUSIONS: UARN is an intuitive safe procedure that offers dramatic reductions in fluoroscopy times. UARN is best suited to cases requiring only one nephrostomy tract. Upper pole access is commonly performed with a subcostal technique to navigate the puncture wire below the ribs. Increasing BMI best predicts longer nephrostomy creation times; procedure failure was associated with BMI exceeding 40 kg/m(2). UARN is a robust technique for nephrostomy creation in appropriately selected patients. PMID- 24779945 TI - Benzobisoxazole cruciforms as fluorescent sensors. AB - CONSPECTUS: Cross-conjugated molecular cruciforms are intriguing platforms for optoelectronic applications. Their two intersecting pi-conjugated arms allow independent modulation of the molecules' HOMO and LUMO levels and guarantee a well-defined optical response to analyte binding. In addition, the rigid cross conjugated geometries of these molecules allow their organization in two- and three-dimensional space with long-range order, making them convenient precursors for the transition from solution-based to the more practical solid-state- and surface-based devices. Not surprisingly, a number of molecular cruciform classes have been explored because of these appealing properties. These include tetrakis(arylethynyl)benzenes, tetrastyrylbenzenes, distyrylbis(arylethynyl)benzenes, tetraalkynylethenes, biphenyl-based "swivel" cruciforms, and benzobisoxazole-based cruciforms. In this Account, we summarize our group's work on benzobisoxazole molecular cruciforms. The heterocyclic central core of these molecules forces their HOMOs to localize along the vertical bisethynylbenzene axis; the HOMO localization switches to the horizontal benzobisoxazole axis only in cases when that axis bears electron-rich 4-(N,N dimethylamino)phenyl substituents and the vertical axis does not. In contrast, the LUMOs are generally delocalized across the entire molecule, and their localization occurs only in cruciforms with donor-acceptor substitution. Such spatially isolated frontier molecular orbitals (FMOs) of the benzobisoxazole cruciforms make their response to protonation very predictable. Benzobisoxazole cruciforms are highly solvatochromic, and their fluorescence quantum yields reach 80% in nonpolar solvents. Solutions of cruciforms in different solvents change emission colors upon addition of carboxylic and boronic acid analytes. These changes are highly sensitive to the analyte structure, and the emission color responses permit qualitative discrimination among structurally closely related species. In self-assembled complexes with boronic acids, benzobisoxazole fluorophores switch their analyte preferences and become responsive to Lewis basic species: phenoxides, amines, ureas, and small organic and inorganic anions. These sensing complexes allow the decoupling of the sensor's two functions: a nonfluorescent boronic acid does the chemistry through the exchange of its labile B-O bonds for other nucleophiles, and it can be optimized for solubility and analyte specificity; the benzobisoxazole fluorophore senses the electronic changes on the boron and reports them to the operator through changes in its emission colors, allowing this sensing element to be kept constant across a broad range of analytes. We have recently expanded our studies to benzimidazole-based "half-cruciforms", which are L-shaped rigid fluorophores that maintain most of the spatial separation of FMOs observed in benzobisoxazole cruciforms. Unlike benzobisoxazoles, benzimidazoles are acidic on account of their polar N-H bonds, and this feature allows them to respond to a broader range of pH values than their benzobisoxazole counterparts. The deprotonated benzimidazolate anions maintain their fluorescence, which makes them promising candidates for incorporation into solid-state sensing materials known as zeolithic imidazolate frameworks. PMID- 24779946 TI - Consolidated Standards of Reporting Trials (CONSORT): answering the call for JOI's endorsement. PMID- 24779947 TI - The effect of different implant-abutment connections on screw joint stability. AB - Dental implants with an internal connection have been designed to establish a better stress distribution when lateral external forces act on the prosthesis and minimize the forces transmitted to the fastening screw. In the present study, 10 externally and 10 internally hexed implants were tested with a compressive force applied with an Instron Universal machine. Four cycles of loading-unloading were applied to each specimen to achieve displacements of 0.5, 1, 2, and 2.5 mm. The mean loads for the first cycle were 256.70 N for the external connection and 256 N for the internal connection implants. The independent t test did not reveal any significant differences among the 2 tested groups (P = .780). For the second cycle, the mean loads needed for a displacement of 1 mm were 818.19 N and 780.20 N for the external connection and the internal connection implants, respectively. The independent t test revealed significant differences among the 2 tested groups (P < .001). In the third cycle, the mean load values for a 2-mm displacement were 1394.10 N and 1225.00 N. The independent t test revealed significant differences among the 2 tested groups (P < .001). The mean loads for the fourth cycle were 1488.00 N for the external connection and 1029.00 N for the internal connection implants. These loads were required for a displacement of 2.5 mm. The independent t test revealed significant differences among the 2 tested groups (P < .001). The results of this in vitro study suggest that the internal connection design of the examined implant system could not prevent screw loosening during overloading. No implant or prosthesis failure was noticed in either group. PMID- 24779948 TI - Effects of pH and elevated glucose levels on the electrochemical behavior of dental implants. AB - Implant failure is more likely to occur in persons with medically compromising systemic conditions, such as diabetes related to high blood glucose levels and inflammatory diseases related to pH levels lower than those in healthy people. The aim of this study was to investigate the effects of lower pH level and simulated- hyperglycemia on implant corrosion as these effects are critical to biocompatibility and osseointegration. The electrochemical corrosion properties of titanium implants were studied in four different solutions: Ringer's physiological solution at pH = 7.0 and pH = 5.5 and Ringer's physiological solution containing 15 mM dextrose at pH = 7 and pH = 5.5. Corrosion behaviors of dental implants were determined by cyclic polarization test and electrochemical impedance spectroscopy. Surface alterations were studied using a scanning electron microscope. All test electrolytes led to apparent differences in corrosion behavior of the implants. The implants under conditions of test exhibited statistically significant increases in I(corr) from 0.2372 to 1.007 MUAcm(-2), corrosion rates from 1.904 to 8.085 mpy, and a decrease in polarization resistances from 304 to 74 Omega. Implants in dextrose-containing solutions were more prone to corrosion than those in Ringer's solutions alone. Increasing the acidity also yielded greater corrosion rates for the dextrose containing solutions and the solutions without dextrose. PMID- 24779949 TI - Finite element analysis of provisional structures of implant-supported complete prostheses. AB - The use of provisional resin implant-supported complete dentures is a fast and safe procedure to restore mastication and esthetics of patients soon after surgery and during the adaptation phase to the new denture. This study assessed stress distribution of provisional implant-supported fixed dentures and the all on-4 concept using self-curing acrylic resin (Tempron) and bis-acrylic resin (Luxatemp) to simulate functional loads through the three-dimensional finite element method. Solidworks software was used to build three-dimensional models using acrylic resin (Tempron, model A) and bis-acrylic resin (Luxatemp, model B) for denture captions. Two loading patterns were applied on each model: (1) right unilateral axial loading of 150 N on the occlusal surfaces of posterior teeth and (2) oblique loading vector of 150 N at 45 degrees . The results showed that higher stress was found on the bone crest below oblique load application with a maximum value of 187.57 MPa on model A and 167.45 MPa on model B. It was concluded that model B improved stress distribution on the denture compared with model A. PMID- 24779950 TI - Saliva versus peri-implant inflammation: quantification of IL-1beta in partially and totally edentulous patients. AB - The aim of this study was to investigate the potential use of salivary IL1beta in early-stage diagnostics of peri-implant inflammation in partially and totally edentulous patients rehabilitated with dental implants. Patients were classified according to peri-implant probing depth and bleeding upon probing in groups of healthy individuals or in groups of individuals with peri-implant inflammation. Data on plaque index, clinical attachment loss, suppuration, and mobility were also assessed. Saliva was collected without stimulation, and the levels of IL 1beta were determined by ELISA. Healthy groups demonstrated significantly lower levels of IL-1beta compared with the inflammation groups. No difference in IL 1beta levels was observed between partially edentulous or totally edentulous patients. Salivary IL-1beta may be useful for the diagnosis and monitoring of early peri-implant inflammation, particularly in edentulous patients. PMID- 24779951 TI - An alternative approach for augmenting the anterior maxilla using autogenous free gingival bone graft for implant retained prosthesis. AB - Numerous factors may keep surgeons from placing implants in the anterior maxilla in order to avoid suboptimal restorative outcomes. This paper describes a technique of an autogenous-free gingival-bone block graft, which allows bone and gingival augmentation and a primary seal to be achieved simultaneously. Additionally, it describes a technique for achieving primary soft tissue closure of maxillary extraction sockets using a rotated pedicle palatal connective tissue flap. PMID- 24779952 TI - Nasopalatine duct cyst, a delayed complication to successful dental implant placement: diagnosis and surgical management. AB - The dental literature reports frequently on both the success and survival of dental implants, whereby the focus remains on the biological response of hard and soft tissue to the implants. The predication and anticipation of adverse implant events can then lead to the preemption of implant loss. However, biological situations can arise that are outside the control of the clinician. The author reports a case history of the late manifestation of a nasopalatine duct cyst in close proximity to a dental implant and its subsequent surgical management. PMID- 24779953 TI - The Custom Endosteal Implant: histology and case report of a retrieved maxillary custom osseous-integrated implant nine years in service. AB - The Custom Endosteal Implant (CEI) is a custom-cast osseo-integrated implant that has evolved to replace the "old" fibro-integrated subperiosteal variant. This newly developed implant achieves osseous integration by utilizing a hydroxyapatite (HA) coating, and a specialized grafting technique that produces much improved success rates relative to its fibro-integrated subperiosteal predecessor. This case reported here represents a maxillary CEI implant that was placed and in functional service for 9 years before being retrieved and processed for histologic examination subsequent to the patient's demise. In addition, due to infection that occurred shortly after placement, an early provisional procedure with fluoridated HA was also performed. Histologic analysis of the postmortem specimen revealed a fully integrated new bone formation intimately surrounding the previously dehisced implant strut. The latter had previously been decontaminated and grafted with a thin layer of fluorapatite (FA) material. Results including histologic analysis confirmed complete osseo-integration of the implant following successful FA graft revision. PMID- 24779954 TI - Use of stress analysis methods to evaluate the biomechanics of oral rehabilitation with implants. AB - Because the biomechanical behavior of dental implants is different from that of natural tooth, clinical problems may occur. The mechanism of stress distribution and load transfer to the implant/bone interface is a critical issue affecting the success rate of implants. Therefore, the aim of this study was to conduct a brief literature review of the available stress analysis methods to study implant supported prosthesis loading and to discuss their contributions in the biomechanical evaluation of oral rehabilitation with implants. Several studies have used experimental, analytical, and computational models by means of finite element models (FEM), photoelasticity, strain gauges and associations of these methods to evaluate the biomechanical behavior of dental implants. The FEM has been used to evaluate new components, configurations, materials, and shapes of implants. The greatest advantage of the photoelastic method is the ability to visualize the stresses in complex structures, such as oral structures, and to observe the stress patterns in the whole model, allowing the researcher to localize and quantify the stress magnitude. Strain gauges can be used to assess in vivo and in vitro stress in prostheses, implants, and teeth. Some authors use the strain gauge technique with photoelasticity or FEM techniques. These methodologies can be widely applied in dentistry, mainly in the research field. Therefore, they can guide further research and clinical studies by predicting some disadvantages and streamlining clinical time. PMID- 24779955 TI - Prediction of high- and low-affinity quinol-analogue-binding sites in the aa3 and bo3 terminal oxidases from Bacillus subtilis and Escherichia coli1. AB - Haem-copper oxidases are the terminal enzymes in both prokaryotic and eukaryotic respiratory chains. They catalyse the reduction of dioxygen to water and convert redox energy into a transmembrane electrochemical proton gradient during their catalytic activity. Haem-copper oxidases show substantial structure similarity, but spectroscopic and biochemical analyses indicate that these enzymes contain diverse prosthetic groups and use different substrates (i.e. cytochrome c or quinol). Owing to difficulties in membrane protein crystallization, there are no definitive structural data about the quinol oxidase physiological substrate binding site(s). In the present paper, we propose an atomic structure model for the menaquinol:O2 oxidoreductase of Bacillus subtilis (QOx.aa3). Furthermore, a multistep computational approach is used to predict residues involved in the menaquinol/menaquinone binding within B. subtilis QOx.aa3 as well as those involved in quinol/quinone binding within Escherichia coli QOx.bo3. Two specific sequence motifs, R70GGXDX4RXQX3PX3FX[D/N/E/Q]X2HYNE97 and G159GSPX2GWX2Y169 (B. subtilis numbering), were highlighted within QOx from Bacillales. Specific residues within the first and the second sequence motif participate in the high- and low-affinity substrate-binding sites respectively. Using comparative analysis, two analogous motifs, R71GFXDX4RXQX8[Y/F]XPPHHYDQ101 and G163EFX3GWX2Y173 (E. coli numbering) were proposed to be involved in Enterobacteriales/Rhodobacterales/Rhodospirillales QOx high- and low-affinity quinol-derivative-binding sites. Results and models are discussed in the context of the literature. PMID- 24779956 TI - Effectiveness of combined exercise training to improve functional fitness in older adults: A randomized controlled trial. AB - AIM: The present randomized controlled trial evaluated the impact of different exercise training modalities on functional fitness responses in apparently healthy older men. METHODS: A total of 59 community-dwelling older men were randomly assigned to an aerobic training group (ATG, n=19), a combined aerobic and resistance training group (CTG, n=20) or a control group (n=20). Both exercise training programs were moderate-to-vigorous intensity, 3 days/week for 9 months. Six independent functional fitness tests (back scratch, chair sit-and reach, 30-s chair stand, arm curl, 8-ft up-and-go, 6-min walk) were measured on five different occasions. The data were analyzed using a mixed-model ANOVA. RESULTS: ANOVA showed a significant main effect of group (P<0.001) for all functional fitness tests, with significant differences between both training groups and controls. However, the ATG only improved the chair sit-and-reach and the 30-s chair stand performance, whereas CTG improved in all functional fitness tests. ANOVA also identified a significant main effect of time for 8-ft up-and-go (P=0.031) in the CTG. CONCLUSIONS: Only the combined exercise program was effective in improving all functional fitness components related to daily living activities. PMID- 24779957 TI - (135)Cs/(137)Cs isotopic ratio as a new tracer of radiocesium released from the Fukushima nuclear accident. AB - Since the Fukushima Daiichi nuclear power plant (FDNPP) accident in 2011, intensive studies of the distribution of released fission products, in particular (134)Cs and (137)Cs, in the environment have been conducted. However, the release sources, that is, the damaged reactors or the spent fuel pools, have not been identified, which resulted in great variation in the estimated amounts of (137)Cs released. Here, we investigated heavily contaminated environmental samples (litter, lichen, and soil) collected from Fukushima forests for the long-lived (135)Cs (half-life of 2 * 10(6) years), which is usually difficult to measure using decay-counting techniques. Using a newly developed triple-quadrupole inductively coupled plasma tandem mass spectrometry method, we analyzed the (135)Cs/(137)Cs isotopic ratio of the FDNPP-released radiocesium in environmental samples. We demonstrated that radiocesium was mainly released from the Unit 2 reactor. Considering the fact that the widely used tracer for the released Fukushima accident-sourced radiocesium in the environment, the (134)Cs/(137)Cs activity ratio, will become unavailable in the near future because of the short half-life of (134)Cs (2.06 years), the (135)Cs/(137)Cs isotopic ratio can be considered as a new tracer for source identification and long-term estimation of the mobility of released radiocesium in the environment. PMID- 24779958 TI - Inter-laboratory discordance of beta-2 microglobulin results: impact on the validity of the international staging system for multiple myeloma. PMID- 24779959 TI - Longitudinal analysis of minority women's perceptions of cohesion: the role of cooperation, communication, and competition. AB - BACKGROUND: Interaction in the form of cooperation, communication, and friendly competition theoretically precede the development of group cohesion, which often precedes adherence to health promotion programs. The purpose of this manuscript was to explore longitudinal relationships among dimensions of group cohesion and group-interaction variables to inform and improve group-based strategies within programs aimed at promoting physical activity. METHODS: Ethnic minority women completed a group dynamics-based physical activity promotion intervention (N = 103; 73% African American; 27% Hispanic/Latina; mage = 47.89 + 8.17 years; mBMI = 34.43+ 8.07 kg/m2) and assessments of group cohesion and group-interaction variables at baseline, 6 months (post-program), and 12 months (follow-up). RESULTS: All four dimensions of group cohesion had significant (ps < 0.01) relationships with the group-interaction variables. Competition was a consistently strong predictor of cohesion, while cooperation did not demonstrate consistent patterns of prediction. CONCLUSIONS: Facilitating a sense of friendly competition may increase engagement in physical activity programs by bolstering group cohesion. PMID- 24779960 TI - Determination of respiratory gas flow by electrical impedance tomography in an animal model of mechanical ventilation. AB - BACKGROUND: A recent method determines regional gas flow of the lung by electrical impedance tomography (EIT). The aim of this study is to show the applicability of this method in a porcine model of mechanical ventilation in healthy and diseased lungs. Our primary hypothesis is that global gas flow measured by EIT can be correlated with spirometry. Our secondary hypothesis is that regional analysis of respiratory gas flow delivers physiologically meaningful results. METHODS: In two sets of experiments n = 7 healthy pigs and n = 6 pigs before and after induction of lavage lung injury were investigated. EIT of the lung and spirometry were registered synchronously during ongoing mechanical ventilation. In-vivo aeration of the lung was analysed in four regions of-interest (ROI) by EIT: 1) global, 2) ventral (non-dependent), 3) middle and 4) dorsal (dependent) ROI. Respiratory gas flow was calculated by the first derivative of the regional aeration curve. Four phases of the respiratory cycle were discriminated. They delivered peak and late inspiratory and expiratory gas flow (PIF, LIF, PEF, LEF) characterizing early or late inspiration or expiration. RESULTS: Linear regression analysis of EIT and spirometry in healthy pigs revealed a very good correlation measuring peak flow and a good correlation detecting late flow. PIFEIT = 0.702 . PIFspiro + 117.4, r(2) = 0.809; PEFEIT = 0.690 . PEFspiro-124.2, r(2) = 0.760; LIFEIT = 0.909 . LIFspiro + 27.32, r(2) = 0.572 and LEFEIT = 0.858 . LEFspiro-10.94, r(2) = 0.647. EIT derived absolute gas flow was generally smaller than data from spirometry. Regional gas flow was distributed heterogeneously during different phases of the respiratory cycle. But, the regional distribution of gas flow stayed stable during different ventilator settings. Moderate lung injury changed the regional pattern of gas flow. CONCLUSIONS: We conclude that the presented method is able to determine global respiratory gas flow of the lung in different phases of the respiratory cycle. Additionally, it delivers meaningful insight into regional pulmonary characteristics, i.e. the regional ability of the lung to take up and to release air. PMID- 24779961 TI - Advice to follow a low-carbohydrate diet has a favourable impact on low-grade inflammation in type 2 diabetes compared with advice to follow a low-fat diet. AB - BACKGROUND: Inflammation may play an important role in type 2 diabetes. It has been proposed that dietary strategies can modulate inflammatory activity. METHODS: We investigated the effects of diet on inflammation in type 2 diabetes by comparing a traditional low-fat diet (LFD) with a low-carbohydrate diet (LCD). Patients with type 2 diabetes were randomized to follow either LFD aiming for 55 60 energy per cent (E%) from carbohydrates (n = 30) or LCD aiming for 20 E% from carbohydrates (n = 29). Plasma was collected at baseline and after 6 months. C reactive protein (CRP), interleukin-1 receptor antagonist (IL-1Ra), IL-6, tumour necrosis factor receptor (TNFR) 1 and TNFR2 were determined. RESULTS: Both LFD and LCD led to similar reductions in body weight, while beneficial effects on glycaemic control were observed in the LCD group only. After 6 months, the levels of IL-1Ra and IL-6 were significantly lower in the LCD group than in the LFD group, 978 (664-1385) versus 1216 (974-1822) pg/mL and 2.15 (1.65-4.27) versus 3.39 (2.25-4.79) pg/mL, both P < 0.05. CONCLUSIONS: To conclude, advice to follow LCD or LFD had similar effects on weight reduction while effects on inflammation differed. Only LCD was found significantly to improve the subclinical inflammatory state in type 2 diabetes. PMID- 24779962 TI - Cross-talk between the circadian clock and the cell cycle in cancer. AB - The circadian clock is an endogenous timekeeper system that controls the daily rhythms of a variety of physiological processes. Accumulating evidence indicates that genetic changes or unhealthy lifestyle can lead to a disruption of circadian homeostasis, which is a risk factor for severe dysfunctions and pathologies including cancer. Cell cycle, proliferation, and cell death are closely intertwined with the circadian clock, and thus disruption of circadian rhythms appears to be linked to cancer development and progression. At the molecular level, the cell cycle machinery and the circadian clocks are controlled by similar mechanisms, including feedback loops of genes and protein products that display periodic activation and repression. Here, we review the circadian rhythmicity of genes associated with the cell cycle, proliferation, and apoptosis, and we highlight the potential connection between these processes, the circadian clock, and neoplastic transformations. Understanding these interconnections might have potential implications for the prevention and therapy of malignant diseases. PMID- 24779963 TI - DNA methylation in obesity and type 2 diabetes. AB - To elucidate the mechanisms related to the development of type 2 diabetes (T2D) and other degenerative diseases at a molecular level, a better understanding of the changes in the chromatin structure and the corresponding functional changes in molecular pathways is still needed. For example, persons with low birth weight are at a high risk for development of T2D later in life, suggesting that the intrauterine environment contributes to the disease. One of the hypotheses is that epigenetic regulation, including changes in DNA methylation leading to modifications in chromatin structure, are behind metabolic alterations, e.g. leading to the phenomenon termed metabolic memory. Altered DNA methylation has been shown to affect healthy aging and also to promote age-related health problems. There is suggestive evidence that lifestyle changes including weight loss can have an impact on DNA methylation and consequently gene expression. In this review we provide an overview of human studies investigating DNA methylation in obesity and T2D and associated risk factors behind these diseases. PMID- 24779964 TI - Effect of intensive care after cardiac arrest on patient outcome: a database analysis. AB - INTRODUCTION: The study aimed to determine the impact of treatment frequency, hospital size, and capability on mortality of patients admitted after cardiac arrest for postresuscitation care to different intensive care units. METHODS: Prospectively recorded data from 242,588 adults consecutively admitted to 87 Austrian intensive care units over a period of 13 years (1998 to 2010) were analyzed retrospectively. Multivariate analysis was used to assess the effect of the frequency of postresuscitation care on mortality, correcting for baseline parameters, severity of illness, hospital size, and capability to perform coronary angiography and intervention. RESULTS: In total, 5,857 patients had had cardiac arrest and were admitted to an intensive care unit. Observed hospital mortality was 56% in the cardiac-arrest cohort (3,302 nonsurvivors). Patients treated in intensive care units with a high frequency of postresuscitation care generally had high severity of illness (median Simplified Acute Physiology Score (SAPS II), 65). Intensive care units with a higher frequency of care showed improved risk-adjusted mortality. The SAPS II adjusted, observed-to-expected mortality ratios (O/E-Ratios) in the three strata (<18; 18 to 26; >26 resuscitations per ICU per year) were 0.869 (95% confidence interval, 0.844 to 894), 0.876 (0.850 to 0.902), and 0.808 (0.784 to 0.833). CONCLUSIONS: In this database analysis, a high frequency of post-cardiac arrest care at an intensive care unit seemed to be associated with improved outcome of cardiac-arrest patients. We were able to identify patients who seemed to profit more from high frequency of care, namely, those with an intermediate severity of illness. Considering these findings, cardiac-arrest care centers might be a reasonable step to improve outcome in this specific population of cardiac-arrest patients. PMID- 24779965 TI - Genetic variants in mammary development, prolactin signalling and involution pathways explain considerable variation in bovine milk production and milk composition. AB - BACKGROUND: The maintenance of lactation in mammals is the result of a balance between competing signals from mammary development, prolactin signalling and involution pathways. Dairy cattle are an interesting case study to investigate the effect of polymorphisms that affect the function of genes in these pathways. In dairy cattle, lactation yields and milk composition (for example protein percentage and fat percentage) are routinely recorded, and these vary greatly between individuals. In this study, we test 8058 single nucleotide polymorphisms in or close to genes in these pathways for association with milk production traits and determine the proportion of variance explained by each pathway, using data on 16 812 dairy cattle, including Holstein-Friesian and Jersey bulls and cows. RESULTS: Single nucleotide polymorphisms close to genes in the mammary development, prolactin signalling and involution pathways were significantly associated with milk production traits. The involution pathway explained the largest proportion of genetic variation for production traits. The mammary development pathway also explained additional genetic variation for milk volume, fat percentage and protein percentage. CONCLUSIONS: Genetic variants in the involution pathway explained considerably more genetic variation in milk production traits than expected by chance. Many of the associations for single nucleotide polymorphisms in genes in this pathway have not been detected in conventional genome-wide association studies. The pathway approach used here allowed us to identify some novel candidates for further studies that will be aimed at refining the location of associated genomic regions and identifying polymorphisms contributing to variation in lactation volume and milk composition. PMID- 24779966 TI - Asiatic acid ameliorates hepatic lipid accumulation and insulin resistance in mice consuming a high-fat diet. AB - Effects of asiatic acid (AA) at 10 or 20 mg/kg/day upon hepatic steatosis in mice consuming a high-fat diet (HFD) were examined. AA intake decreased body weight, water intake, feed intake, epididymal fat, and plasma and hepatic triglyceride levels in HFD-treated mice (P < 0.05). HFD enhanced 2.85-fold acetyl coenzyme A carboxylase (ACC1), 3.34-fold fatty acid synthase (FAS), 3.71-fold stearoyl CoA desaturase (SCD)-1, 3.62-fold 3-hydroxy-3-methylglutaryl coenzyme A reductase, 2.91-fold sterol regulatory element-binding protein (SREBP)-1c, and 2.75-fold SREBP-2 expression in liver (P < 0.05). Compared with HFD groups, AA intake at two doses reduced 18.9-45.7% ACC1, 25.1-49.8% FAS, 24.7-57.1% SCD-1, and 21.8 53.3% SREBP-1c protein expression (P < 0.05). Histological results indicated AA intake at two doses reduced hepatic lipid accumulation and inflammatory infiltrate. HFD increased hepatic production of reactive oxygen species, interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, as well as decreased hepatic glutathione content and glutathione peroxidase and catalase activities (P < 0.05). AA intake at two doses reversed these alterations (P < 0.05). AA intake suppressed 32.4-58.8% nuclear factor kappa (NF-kappa)B p65 and 24.2-56.7% p-p38 expression (P < 0.05) and at high dose down-regulated 29.1% NF kappaB p50 and 40.7% p-JNK expression in livers from HFD-treated mice. AA intake at two doses lowered plasma insulin secretion and HOMR-IR (P < 0.05). These results suggest that AA is a potent hepatic protective agent against HFD-induced hepatic injury. PMID- 24779967 TI - Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients. AB - BACKGROUND AND PURPOSE: Visual impairments are frequent in multiple sclerosis (MS). Optic neuritis can directly reduce retinal nerve fiber layer (RNFL) thickness. Our objectives were to evaluate associations of the RNFL thickness (RNFLT) of MS patients with magnetic resonance imaging (MRI) measures of regional brain atrophy and tissue injury in the post-chiasmatic deep gray matter (GM) section of the visual pathway. METHODS: Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT) in 96 relapsing-remitting MS (RR-MS) patients and 46 controls. MRI was obtained within +/-3 months of OCT. RNFLT associations with MRI measures from diffusion tensor imaging and regional and tissue specific atrophy were assessed. RESULTS: In RR-MS, lower RNFLT was associated with lower white matter volume and lower whole brain volume. Lower RNFLT was associated with lower total deep gray matter volume and lower thalamus volume. Lower RNFLT was associated with greater mean diffusivity (MD) in normal appearing (NA) brain tissue and NA gray matter. Trends were found for lower RNFLT with greater MD in NA white matter and thalamus. RNFLT in controls was not associated with MD. CONCLUSIONS: Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR-MS. PMID- 24779968 TI - Vitamin D deficiency and level of asthma control in women from North of Jordan: a case-control study. AB - INTRODUCTION: Reduced vitamin-D levels in patients with asthma have been associated with impaired lung function, increased airway hyper-responsiveness, and reduced glucocorticoid responsiveness. Nationwide studies revealed a considerable prevalence of vitamin-D deficiency (VDD) in Jordanian women. OBJECTIVE: A case-control study was conducted to determine the relationship between serum vitamin A and D levels and asthma among women in North of Jordan. METHODS: Sixty-eight asthmatics, age range between 14 and 65 years and 77 healthy women, age range between 19 and 51 years, were enrolled. Asthma severity was classified using Global Initiative for Asthma (GINA) guidelines and Asthma Control Test (ACT) questionnaire. Serum vitamin-A and 25-hydroxyvitamin-D (25(OH)D3) levels were measured using high-performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods, respectively. RESULTS: The prevalence of VDD (<15 ng/ml) was higher but not statistically significant for women with asthma compared with controls (95.6% vs. 87.0%; p = 0.070). The severity of VDD correlated with the number of asthma medications (p = 0.020). 25(OH)-D3 serum levels directly correlated with asthma control level using ACT score (p = 0.012) and GINA classification (p = 0.046). After adjusting for age, the odds of having VDD for asthmatic women were 35.9 times higher than that for women with no asthma. There was no difference in serum vitamin-A level between healthy and asthmatic women (p = 0.214) and none had vitamin-A deficiency (<200 ug/dl). CONCLUSIONS: VDD is prevalent in women with asthma in northern Jordan. The severity of VDD correlated with poor asthma control and a need for more medications to control asthma. There was no association between vitamin-A and asthma. PMID- 24779969 TI - Sorption of H2 to open metal sites in a metal-organic framework: a symmetry adapted perturbation theory analysis. AB - Metal-organic frameworks (MOFs) show considerable promise as materials for gas storage and separation. Many MOF structures have open metal sites, which allow for coordination of gas molecules to the metal centers. In this work, we use coupled-cluster and symmetry-adapted perturbation theory to probe the interaction between hydrogen gas and unsaturated metal sites in mimic structures based on the MOF HKUST-1. The interactions are of a mixed electrostatic/dispersive nature, with the relative magnitudes of these components dependent on the metal center. The strongest binding was found for magnesium- and zinc-containing MOFs, with an overall interaction energy of -4.5 kcal mol(-1). PMID- 24779970 TI - Aflatoxins contamination and prevention in red chillies (Capsicum annuum L.) in Pakistan. AB - During 2006-2011, 331 red chilli samples (226 whole, 69 powdered and 36 crushed) were collected from all over Pakistan for the estimation of total aflatoxins (AFs = AFB1 + AFB2 + AFG1 + AFG2) contamination by thin layer chromatography (TLC). Mean AFs levels in whole, powdered and crushed chillies were 11.7, 27.8 and 31.2 ug kg(-1), respectively. AFs levels in 62.4% of whole, 26.1% of powdered and 19.4% of crushed chillies were found lower than the maximum limit (ML = 10 ug kg( 1)) as assigned by the European Union. Furthermore, whole (27.9%), powdered (28%) and crushed (27.8%) chillies showed AFs contamination which ranged between 10 and 20 ug kg(-1). However, 9.7% of whole, 46% of powdered and 52.8% of crushed chillies showed AFs levels beyond the ML of 20 ug kg(-1) as assigned by the USDA. It was concluded that AFs contamination in chillies requires further investigation, monitoring and routine analysis. Furthermore, proper harvesting, drying, handling, storage and transport conditions need to be employed. PMID- 24779971 TI - Aflatoxin M1 in buffalo and cow milk in Afyonkarahisar, Turkey. AB - Potential hazardous human exposure to aflatoxin M1 (AFM1) via consumption of milk and milk products has been demonstrated by many researchers. The aim of this study was to investigate the presence of this mycotoxin in buffalo and cow milk samples in the city of Afyonkarahisar, Turkey. For this purpose, 126 buffalo and 124 cow milk samples were collected from dairy farms in Afyonkarahisar province. AFM1 levels were determined by high-performance liquid chromatography with tandem mass spectrometric detection. Although AFM1 was not detected in cow milk samples, AFM1 was found above the limit of detection (<0.008-0.032 ug/L) in 27% (34 out of 126) of the buffalo milk samples. The results of this study indicated the importance of continuous surveillance of commonly consumed milk or milk product samples for AFM1 contamination in Turkey. PMID- 24779972 TI - Occurrence of aflatoxin B1 and ochratoxin A in dried vine fruits from Greek market. AB - Twenty-six samples of dried vine fruits from Athens and Thebes (Central Greece) market were simultaneously extracted and cleaned up by immunoaffinity columns and analysed for aflatoxin B1 (AFB1) and ochratoxin A (OTA). A combination of ELISA and HPLC methods was applied for the determination of AFB1. Recovery was 97.6%, RSD 6.46%, while the limit of detection (LOD) and limit of quantification (LOQ) were 0.05 MUg kg(-1) and 0.09 MUg kg(-1), respectively. OTA concentrations were only estimated by ELISA. Results revealed the presence of AFB1 in 23% of the samples (mean 1.4 MUg AFB1 kg(-1)), but none exceeded the EU limit (2 MUg AFB1 kg(-1)). However, OTA was detected in 100% of the samples (mean 47.2 MUg OTA kg( 1)). Six samples were found to be contaminated at high levels (median 120.6 MUg OTA kg(-1)) and 18 exceeded the EU limit (10 MUg OTA kg(-1)). PMID- 24779973 TI - Aflatoxin M1 in milk from urban and rural farmhouses of Punjab, Pakistan. AB - Aflatoxin M1 (AFM1) was determined in 107 milk samples collected from urban and rural farmhouses from Punjab, Pakistan, by HPLC with fluorescence detection. An incidence rate of 64% (38/59) in milk samples from urban farmhouses was found, with a mean concentration of 0.064 +/- 0.023 MUg L(-1). In rural samples about 52% (25/48) of milk samples were contaminated with AFM1, with a mean of 0.04 +/- 0.034 MUg L(-1). About 42% of milk samples from urban and 27% from rural farmhouses were well above the limit permitted by the European Union (EU). However, only 15% and 8% of milk samples from urban and rural farmhouses, respectively, exceeded the limit of USDA/Codex regulations. The results showed that the contamination of milk with AFM1 from Punjab, Pakistan, when compared with Codex limit is present and needs continuous monitoring. The awareness and education among dairy farmers on the potential health risks associated with aflatoxins should be communicated. PMID- 24779974 TI - Aflatoxin M1 in raw cow and buffalo milk in Shush city of Iran. AB - Aflatoxin M1 (AFM1) contamination is evaluated in 120 samples of raw milk from cow and buffalo (60 each), collected randomly in the Shush (southwest Iran). Enzyme-linked immunoabsorbent assay (ELISA) was applied to analyse AFM1 in the samples. AFM1 was detected in 44 (69%) raw cow milk samples with a mean of 55 ng/l at a range of 3.6-419 ng/l) and in 46 (79%) raw buffalo milk samples with a mean of 116 ng/l at a range of 13-423 ng/l. In all samples, the AFM1 concentration was lower than the Iranian national standard and FDA limit of 500 ng/l. According to the European Union and Codex Alimentarius Commission, 18 (28%) and 32 (52%) of cow and buffalo raw milk samples are above the 50 ng/l limit, respectively. Results showed that AFM1 contamination of raw milk could pose a problem for public health, since all age groups, including infants and children, consume this product. PMID- 24779975 TI - Biogenic amines in commercially produced Yulu, a Chinese fermented fish sauce. AB - Seven biogenic amines were determined in 35 commercially produced Yulu samples from three provinces of China by pre-column derivatisation with dansyl chloride (Dns-Cl) and high-performance liquid chromatography with fluorescence detection (HPLC-FLD). Putrescine, cadaverine, histamine and tyramine were the major biogenic amines (more than 100 mg kg(-1)), while tryptamine, spermidine and spermine were regarded as minor biogenic amines (less than 25 mg kg(-1)). Twenty samples contained more than 50 mg kg(-1) histamine (the limit for histamine in seafood products as suggested by the Food and Drug Administration). Twenty-one samples contained more than 100 mg kg(-1) tyramine and 10 contained more than 1000 mg kg(-1) total biogenic amines. This study provided data on biogenic amine levels in Chinese fermented fish sauce. The results suggested that biogenic amine content should be monitored in commercially produced Yulu. PMID- 24779976 TI - Essential and toxic metals in tea (Camellia sinensis) imported and produced in Ethiopia. AB - Sixteen samples of packed tea leaves (Camellia sinensis) were purchased from supermarkets in Addis Ababa, Ethiopia for metal analysis. Elements were measured by FAAS and graphite furnace atomic absorption spectrometer (GFAAS) employing external calibration curves. The levels in mg/kg dried weight basis varied from Cu: 4.7-12.9; Cd: 0.02-2.83; Pb: <0.01-2.29; Zn: 8.6-198.3; Mn: 81.7-962.2; Al: 3376.4-10,369.3; K: 7667.7-10,775; Li: 0.2-0.62; Ba: 9.4-1407.1; Mg: 1145.6 1834.1; Fe: 286.4-880.9; Ca: 1414.2-2646.0; Na: 147.1-557.7. Levels of exposure to the investigated metals by drinking tea were checked with the recommended daily allowance (RDA) of the WHO/FAO. Considering the average daily consumption rate of tea alone, the possible daily intakes of Al, Ba and Mn surpass the amenability to the side effects associated with these elements like Alzheimer's disease, kidney damage and Parkinson's disease, respectively, for which drinking tea should cause awareness. The other investigated elements are in the acceptable range. PMID- 24779977 TI - Ochratoxin A in grape pekmez (grape molasses) consumed in Turkey. AB - In this study, ochratoxin A (OTA) in 55 home-made, 20 commercial and 7 organic grape pekmez (grape molasses) produced in Turkey was investigated. OTA was detected in 73% of home-made pekmez samples, in 35% of commercial pekmez samples and in 71% of organic pekmez samples. Eleven per cent of the samples had OTA levels higher than 10 ug/l. The highest OTA level (31 ug/l) was detected in organic pekmez. The maximum OTA levels were 15 ug/l and 12 ug/l in home-made and commercial pekmez samples, respectively. Mean OTA levels were 3.5 ug/l, 1.4 ug/l and 9.2 ug/l in home-made, commercial and organic pekmez samples, respectively. Organic pekmez samples and home-made pekmez samples had higher OTA contamination than commercial pekmez samples. Results confirm OTA contamination in grape pekmez samples, indicating that the OTA level in grape pekmez could be a potential risk for consumers. PMID- 24779978 TI - Aflatoxins in animal feed in Iran. AB - One hundred and forty-six samples of animal feed (barley, n = 60; wheat bran, n = 22; wheat dry pulp, n = 29; and canola meal, n = 35) were collected in 2011 from Mashhad (Khorasan, Iran). Aflatoxins (AFs) were determined in these samples after immunoaffinity column clean-up by high-performance liquid chromatography (HPLC) with fluorescence detection. Aflatoxin B1 (AFB1) contamination was found in 28 samples: in five of the barley samples (8.3%) at a mean level of 0.48 ug.kg(-1), in two wheat bran samples (9.0%) at a mean level of 0.88 ug.kg(-1), in 10 wheat dry pulp samples (34.5%) at a mean level of 0.30 ug.kg(-1) and in 11 canola meal samples (31.4%) at a mean level of 0.92 ug.kg(-1). AFB1 levels were below the maximum levels of Iran regulations (5 ug.kg(-1)) and the EU maximum limit (5 ug.kg(-1)). PMID- 24779979 TI - Furan in canned sardines and other fish. AB - Thirty-seven different samples of canned sardines and other fish sold in the United Kingdom were analysed for their furan content using a validated automated headspace gas chromatography-mass spectrometry procedure. All 37 samples contained detectable furan, with an average level of 26 MUg kg(-1). The maximum furan content was in canned fish containing tomato sauce, which had an average of 49 MUg kg(-1) and in canned fish packed with lemon which had an average of 55 MUg kg(-1). All fish in brine or in oil contained less than 20 MUg kg(-1) furan. Furan levels recorded in fish packed in extra virgin olive oil were low with an average of 2 MUg kg(-1). PMID- 24779980 TI - Fumonisin B1 in cereal mixtures marketed in Brazil. AB - The aim of this study was to detect and quantify fumonisin B1 (FB1) in cereal mixtures marketed in Brazil. Fifteen samples from different lots were acquired each month by internet from supermarkets during seven months, adding up to 105 analysed samples. The unit sample constituted of an original package with a minimum of 250 g. Extraction and clean-up of samples for FB1 determination were carried out using immunoaffinity columns. Identification and quantification of FB1 were performed by high performance liquid chromatography. Eighty-eight (83.8%) samples were contaminated with FB1 and four (3.8%) presented levels above 500 ug kg(-1) (634, 703, 1269 and 1876 ug kg(-1)). Maximum FB1 + FB2 levels allowed by Brazilian regulations will reach 1500 ug kg(-1) for corn flour in 2016 and 1000 ug kg(-1) for others corn products. This study showed that even at levels below the legislative limits, human exposure to this toxin can occur constantly. PMID- 24779981 TI - Toxic and essential elements in butter from the Black Sea region, Turkey. AB - In this study, 88 randomly selected samples of butter produced in the Black Sea region of Turkey were purchased from different retail markets during different periods and investigated for toxic and essential elements content. Quantitative analyses of elements in the samples were performed using an inductively coupled plasma-mass spectroscopy (ICP-MS). Mean concentrations of As, Cr, Cu, Fe, Mn, Ni, Pb, Se and Zn in the butter samples were 18.93, 100.32, 384.66, 4199.1, 887.47, 168.64, 56.13, 16.34 and 384.66 ug kg(-1), respectively. Cd and Co were detected in 19 (mean content 0.29 ug kg(-1)) and 81 (mean content 3.81 ug kg(-1)) samples of 88 butter samples, respectively. However, the dietary intake of these elements by the population of the Black Sea region is currently well below the dietary reference intake (DRI) and provisional tolerable weekly intake (PTWI) levels of essential and toxic elements. PMID- 24779982 TI - Total arsenic in rice milk. AB - Rice milk and its by-products were tested for total arsenic concentration. Total arsenic concentration was determined using graphite-furnace atomic absorption spectrometry. The arsenic concentrations ranged from 2.7 +/- 0.3 to 17.9 +/- 0.5 ug L(-1). Rice milk and its by-products are not clearly defined as food, water or milk substitute. The US Environmental Protection Agency (EPA), the European Union (EU) and the World Health Organization (WHO) have set a level of 10 ug L(-1) for total arsenic concentrations in drinking water. The EU and the US regulatory agencies do not provide any guidelines on total arsenic concentrations in foods. This study provides us with a starting point to address this issue in the State of Mississippi, USA. PMID- 24779983 TI - Aflatoxins and ochratoxin A in maize of Punjab, Pakistan. AB - Aflatoxin and ochratoxin levels were determined in maize samples collected from store houses of 15 districts belonging to three agro-ecological zones of Punjab, Pakistan. Toxins were extracted by Aflaochra immunoaffinity columns and analysed by high-performance liquid chromatography (HPLC). Mean moisture content of maize kernels was recorded above the safe storage level of 15%. Results indicated that aflatoxin B1 and B2 contamination was found in 97.3% and 78.9% of the collected samples, respectively. Aflatoxin G1, aflatoxin G2 and ochratoxin A were not detected in any sample. Among positive samples, 77.3% contained aflatoxin B1 and 28% aflatoxin B2, exceeding the legal limits as set by the European Union (EU) and the United States Food and Drug Administration (USFDA). It was concluded that a significant number of samples contained aflatoxin B1 and B2 above the legal limits. PMID- 24779984 TI - Toxic and micronutrient elements in organic, brown and polished rice in Brazil. AB - Concentration levels of As, Cd, Hg, Pb, Tl, Sn, Sb Co, Cu, Mn, Se, Zn, Cr, Ni and Mo in different types of rice cultivated in irrigated fields in Brazil were evaluated. Arsenic, Cd, Pb, Zn, Mn and Cu were found in higher concentrations in brown rice samples, suggesting the prevalence of these elements in the bran. Meanwhile, lower concentrations of Pb, Mo, Cr, Se and Co were found in parboiled rice. Organic rice did not differ of cultivated conventionally rice. Thallium, Hg and Sb were not detected in any rice sample whose limits of detection were 0.7 MUg kg(-1), 2.5 MUg kg(-1) and 8 MUg kg(-1), respectively. The concentrations of the investigated elements were compared with those reported for polished rice and brown rice from other countries, unveiling concentrations in general at the same level for rice produced at non-contaminated sites. PMID- 24779985 TI - Aflatoxin in pistachio nuts used as ingredients in Gaz sweets produced in Isfahan, Iran. AB - In Isfahan province of Iran, pistachio and almond are used specifically as ingredients to produce Gaz sweets, which are a typical product of Isfahan and exported to many countries. In this survey, 112 samples were gathered from different corresponding Gaz producers from 2007 to 2012 to evaluate the occurrence of aflatoxins (AF) in these products. Samples were analysed for AFB1, AFB2, AFG1 and AFG2 using immunoaffinity column clean-up (IC) and quantified by high-performance liquid chromatography (HPLC) with fluorescence detection. Among the samples analysed, AFB1 was detected in 13.4% of the samples above the maximum limit (ML) as set in Iran (5 ug/kg). Total AF (AFT) was above the ML in 9.8% of the samples. This study showed that full consideration is equally essential for nuts used as ingredients in special food products such as the Gaz sweets as for nuts for direct human consumption. It suggests a need for modifying the current trend of supervision. PMID- 24779986 TI - Evaluation of heavy metals contamination in Iranian foodstuffs: canned tomato paste and tomato sauce (ketchup). AB - One hundred and thirty-five samples of canned tomato paste and 30 tomato sauces (ketchup) samples (23 and 10 brands, respectively) purchased from wholesale markets in the Tehran, Iran, during the period 2010-2013 were analysed. Levels of lead and cadmium were determined by graphite furnace atomic absorption spectrophotometer (GF-AAS) and arsenic by hydride vapour generation (HG-AAS or VGA). Average concentration of arsenic found in the tomato paste and ketchup samples was 62 +/- 14 and 48 +/- 12 ng g(-1), respectively. Cadmium values in 7% of tomato paste and 10% of ketchup samples were below the limit of quantification (LOQ). Lead concentrations were below LOQ in 75% of tomato paste and 77% of ketchup samples. Values obtained for these heavy metals in all samples were lower than the limits of national and international standards. PMID- 24779987 TI - Association of XRCC1 gene polymorphisms with susceptibility to gastric cancer in Chinese Han population. AB - OBJECTIVES: Gastric cancer is one of the most frequently causing cancer-related deaths worldwide. The X-ray repair complementing group 1 gene (XRCC1) is an important candidate gene for influencing gastric cancer risk. This study aimed to evaluate the associations between XRCC1 genetic variants and gastric cancer susceptibility in Chinese Han population. METHODS: Four hundred twenty-four gastric cancer patients and 430 cancer-free controls were enrolled. Two genetic variants (c.1254C>T and c.1779C>G) of XRCC1 gene were genotyped by created restriction site-polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism methods, respectively. KEY FINDINGS: Results from this study indicated that the allele and genotype frequencies of these two genetic variants were statistically different between gastric cancer patients and cancer-free controls. The association analyses suggested that these two genetic variants were statistically associated with the increased risk of gastric cancer (for c.1254C>T, T versus C: odds ratio (OR) = 1.44, 95% confidence interval (CI) 1.17 1.77; for c.1779C>G, G versus C: OR = 1.51, 95% CI 1.22-1.86). The allele-T of c.1254C>T and allele-G c.1779C>G genetic variants may contribute to the susceptibility to gastric cancer in Chinese Han population. CONCLUSION: Our data suggest that these two genetic variants might be used as molecular markers for evaluating the susceptibility to gastric cancer. PMID- 24779988 TI - Immunohistochemical analysis of cyclooxygenase-2 and brain fatty acid binding protein expression in grades I-II meningiomas: correlation with tumor grade and clinical outcome after radiotherapy. AB - This study was done to evaluate the association of cyclooxygenase 2 (COX-2) and brain fatty acid binding protein (BFABP) with tumor grade and outcome of grades I II meningiomas treated with radiotherapy. From 1996 to 2008, 40 patients with intracranial grades I-II meningiomas were treated with radiotherapy. Immunohistochemical staining for COX-2 and BFABP were performed on formalin-fixed paraffin-embedded tissues. COX-2 expression was significantly associated with BFABP status and both COX-2 (P < 0.01) and BFABP (P = 0.01) expression were stronger in the grade II meningiomas than in grade I tumors. Among the clinicopathologic factors, age and COX-2 status were prognostic in progression free survival. Patients with moderate or strong COX-2 expression had worse outcome than those with negative or weak COX-2 expression (P = 0.03) after controlling for potential confounders. Our results suggest that the molecular biomarker COX-2 has prognostic significance in intracranial grades I-II meningiomas following radiotherapy. PMID- 24779989 TI - 'How do we know if this is the best?' Mental health-care professionals' views on national guidelines for psychosocial interventions. AB - National guidelines are released regularly, and professionals are expected to adopt and implement them. However, studies dealing with mental health-care professionals' views about guidelines are sparse. The aim of the present study was to highlight mental health-care staff's views on the Swedish national guidelines for 'psychosocial interventions for schizophrenia or schizophrenia type symptoms' and their implementation. The study took place in the southeast parts of Sweden, and data were collected through five group interviews consisting of 16 professionals working either in the county council or in the municipalities. The transcribed text was analysed by content analysis, revealing two categories. The first category 'a challenge to the practice of care as known' reflected that the release of guidelines could be perceived as a challenge to prevailing care and culture. The second category 'anticipating change to come from above' mirrored views on how staff expected the implementation process to flow from top to bottom. To facilitate working in accordance with guidelines, we suggest that future guidelines should be accompanied by an implementation plan, where the educational needs of frontline staff are taken into account. There is also a need for policy makers and managers to assume responsibility in supporting the implementation of evidence-based practice. PMID- 24779990 TI - Improving the physical health of people with severe mental illness: boundaries of care provision. AB - There is compelling evidence that the physical health of people with severe mental illness is poor. Health-promotion guidelines have been recommended as a mechanism for improving the physical health of this population. However, there are significant barriers to the adoption of evidence-based guidelines in practice. The purpose of this research was to apply existing implementation theories to examine the capability of the health system to integrate physical health promotion into mental health service delivery. Data were collected within a regional city in Queensland, Australia. Fifty participants were interviewed. The core theme that emerged from the data was that of 'care boundaries' that influenced the likelihood of guidelines being implemented. Boundaries existed around the illness, care provision processes, sectors, the health-care system, and society. These multilevel boundaries, combined with participants' ways of responding to them, impacted on capability (i.e. the ability to integrate physical health promotion into existing practices). Participants who were able to identify strategies to mediate these boundaries were better positioned to engage with physical health-promotion practice. Thus, the implementation of evidence based guidelines depended heavily on the capability of the workforce to develop and adopt boundary-mediating strategies. PMID- 24779991 TI - Catheter-based closure of paravalvular leak. AB - Paravalvular leak (PVL) is a serious complication from surgical and percutaneous valve replacement procedures. The most common manifestations include congestive heart failure and hemolytic anemia, which may cause considerable morbidity and mortality. Repeat surgery for PVL closure is often complicated and carries a reduced probability of success. As such, catheter-based techniques to eliminate PVL have been developed. Percutaneous PVL closure procedures rely heavily on multimodality imaging techniques such as echocardiography, fluoroscopy and computed tomography for diagnosis, technical planning and procedural guidance. Evidence demonstrates that catheter-based closure of PVL boasts high procedural success rates and favorable clinical outcomes. Given the rapidly advancing nature of this field, this review summarizes the contemporary diagnosis of PVL, common techniques used for percutaneous closure and the latest data on patient outcomes following this procedure. PMID- 24779992 TI - Common occurrence of a positive delta53Cr shift in Central European waters contaminated by geogenic/industrial chromium relative to source values. AB - Carcinogenic effects of hexavalent chromium in waters are of concern in many countries worldwide. We explored Cr isotope systematics at 11 sites in the Czech Republic and Poland. Geogenic Cr pollution was associated with serpentinite bodies at former convergent plate margins, while anthropogenic Cr pollution resulted from electroplating, tanning, and the chemical industry. Cr(VI) concentration in geogenic waters was less than 40 ppb. Anthropogenic waters contained up to 127,000 ppb Cr(VI). At both geogenic and anthropogenic sites, where known, the source of pollution had a low delta53Cr (<10/00). delta53Cr of geogenic and anthropogenic waters was up to 3.9 and 5.80/00, respectively. At both serpentinite-dominated and industrial sites, delta53Cr(VI)aq was shifted toward higher values, compared to the pollution source. At the industrial sites, this positive delta53Cr shift was related to Cr(VI) reduction, a process known to fractionate Cr isotopes. At geogenic sites, the origin of high delta53Cr(VI)aq is tentatively ascribed to preferential release of 53Cr during oxidation of soil Cr(III) and its mobilization to water. delta53Cr(VI) of industrially contaminated waters was significantly higher (p<0.001) compared to delta53Cr of waters carrying geogenic Cr(VI), implying that either the effective fractionation factor or process extent was greater for Cr(VI) reduction than for Cr(III) oxidation. PMID- 24779993 TI - A probabilistic model to evaluate population dietary recommendations. AB - Food-based dietary recommendations (FBR) play an essential role in promoting a healthy diet. To support the process of formulating a set of population-specific FBR, a probabilistic model was developed specifically to predict the changes in the percentage of a population at risk of inadequate nutrient intakes after the adoption of alternative sets of FBR. The model simulates the distribution of the number of servings per week from food groups or food items at baseline and after the hypothetical successful adoption of alternative sets of FBR, while ensuring that the population's energy intake distribution remains similar. The simulated changes from baseline in median nutrient intakes and the percentage of the population at risk of inadequate nutrient intakes are calculated and compared across the alternative sets of FBR. The model was illustrated using a hypothetical population of 12- to 18-month-old breast-feeding children consuming a cereal-based diet low in animal source foods. PMID- 24779994 TI - Highly sensitive and homogeneous detection of membrane protein on a single living cell by aptamer and nicking enzyme assisted signal amplification based on microfluidic droplets. AB - Membrane proteins play vital roles in numerous physiological functions. Recently, they have been considered as candidate biomarkers for cancer and recognized as major drug targets. So, accurate, sensitive, and high-throughput quantitative detection of the membrane proteins is crucial for better understanding their roles in cancer cells and further validating their function in clinical research. Here, we report a highly sensitive and homogeneous detection of membrane protein on single living cells by aptamer and nicking enzyme assisted fluorescence signal amplification in microfluidic droplets. The homogeneous reaction based on the membrane protein-triggered conformation alteration of hairpin probe can improve the detection accuracy with elimination of several washing and separation steps. The microfluidic system provides a high-throughput platform for the detection of a single cell, and the highly monodisperse droplet can function as an independent microreactor for the aptamer and nicking enzyme assisted fluorescence signal amplification, coordinating with the small volume of the confined space (a droplet), increased reaction rate, and highly sensitive detection of membrane protein on single cell can be reached. PMID- 24779995 TI - Our eclectic adventures in the slower eras of photosynthesis: from New England Down Under to biosphere 2 and beyond. AB - This is a tale of a career in plant physiological ecology that enjoyed the freedom to address photosynthetic physiology and biochemistry in leaves of plants from diverse environments. It was supported by block funding (now sadly a thing of the past) for research at the Australian National University, by grants during appointments in the United States and in Germany, and by Columbia University. It became a "career experiment" in which long-term, high-trust support for curiosity driven plant biology in Australia, and at times in the United States, led to surprisingly innovative results. Although the rich diversity of short-term competitive grant opportunities in the United States sustained ongoing research, it proved difficult to mobilize support for more risky long-term projects. A decade after the closure of the Biosphere 2 Laboratory, this article highlights the achievements of colleagues in experimental climate change research from 1998 to 2003. PMID- 24779996 TI - Gene expression regulation in photomorphogenesis from the perspective of the central dogma. AB - Depending on the environment a young seedling encounters, the developmental program following seed germination could be skotomorphogenesis in the dark or photomorphogenesis in the light. Light signals are interpreted by a repertoire of photoreceptors followed by sophisticated gene expression networks, eventually resulting in developmental changes. The expression and functions of photoreceptors and key signaling molecules are highly coordinated and regulated at multiple levels of the central dogma in molecular biology. Light activates gene expression through the actions of positive transcriptional regulators and the relaxation of chromatin by histone acetylation. Small regulatory RNAs help attenuate the expression of light-responsive genes. Alternative splicing, protein phosphorylation/dephosphorylation, the formation of diverse transcriptional complexes, and selective protein degradation all contribute to proteome diversity and change the functions of individual proteins. PMID- 24779997 TI - Posttranslationally modified small-peptide signals in plants. AB - Cell-to-cell signaling is essential for many processes in plant growth and development, including coordination of cellular responses to developmental and environmental cues. Cumulative studies have demonstrated that peptide signaling plays a greater-than-anticipated role in such intercellular communication. Some peptides act as signals during plant growth and development, whereas others are involved in defense responses or symbiosis. Peptides secreted as signals often undergo posttranslational modification and proteolytic processing to generate smaller peptides composed of approximately 10 amino acid residues. Such posttranslationally modified small-peptide signals constitute one of the largest groups of secreted peptide signals in plants. The location of the modification group incorporated into the peptides by specific modification enzymes and the peptide chain length defined by the processing enzymes are critical for biological function and receptor interaction. This review covers 20 years of research into posttranslationally modified small-peptide signals in plants. PMID- 24779998 TI - Geographic distribution, phylogeny, and genetic diversity of the fruit- and blood feeding moth Calyptra thalictri Borkhausen (Insecta: Lepidoptera: Erebidae). AB - Facultative blood feeding on live animals or carrion is widespread within Lepidoptera. Male moths within the genus Calyptra are known to use their fruit piercing mouthparts to occasionally feed on mammalian blood. The Palearctic species Calyptra thalictri is known to exhibit differential feeding behaviors that appear to be based on geographic location. This species is known to pierce fruit throughout its range but has recently been reported to also feed on human blood under experimental conditions in the Russian Far East. Here we document the distribution of this widespread species, reconstruct its evolutionary history, and calculate its genetic diversity for the first time. Recently collected samples are combined with museum specimens to model suitable environments for this taxon. Our findings suggest that while the blood-feeding populations are not monophyletic, there is geographical structure. Our analysis of macroclimate variables suggests that altitude and precipitation are the environmental variables most critical to habitat suitability in this lineage. PMID- 24779999 TI - Unique sodium phosphosilicate glasses designed through extended topological constraint theory. AB - Sodium phosphosilicate glasses exhibit unique properties with mixed network formers, and have various potential applications. However, proper understanding on the network structures and property-oriented methodology based on compositional changes are lacking. In this study, we have developed an extended topological constraint theory and applied it successfully to analyze the composition dependence of glass transition temperature (Tg) and hardness of sodium phosphosilicate glasses. It was found that the hardness and Tg of glasses do not always increase with the content of SiO2, and there exist maximum hardness and Tg at a certain content of SiO2. In particular, a unique glass (20Na2O-17SiO2 63P2O5) exhibits a low glass transition temperature (589 K) but still has relatively high hardness (4.42 GPa) mainly due to the high fraction of highly coordinated network former Si((6)). Because of its convenient forming and manufacturing, such kind of phosphosilicate glasses has a lot of valuable applications in optical fibers, optical amplifiers, biomaterials, and fuel cells. Also, such methodology can be applied to other types of phosphosilicate glasses with similar structures. PMID- 24780000 TI - Functional DNA-containing nanomaterials: cellular applications in biosensing, imaging, and targeted therapy. AB - CONSPECTUS: DNA performs a vital function as a carrier of genetic code, but in the field of nanotechnology, DNA molecules can catalyze chemical reactions in the cell, that is, DNAzymes, or bind with target-specific ligands, that is, aptamers. These functional DNAs with different modifications have been developed for sensing, imaging, and therapeutic systems. Thus, functional DNAs hold great promise for future applications in nanotechnology and bioanalysis. However, these functional DNAs face challenges, especially in the field of biomedicine. For example, functional DNAs typically require the use of cationic transfection reagents to realize cellular uptake. Such reagents enter the cells, increasing the difficulty of performing bioassays in vivo and potentially damaging the cell's nucleus. To address this obstacle, nanomaterials, such as metallic, carbon, silica, or magnetic materials, have been utilized as DNA carriers or assistants. In this Account, we describe selected examples of functional DNA containing nanomaterials and their applications from our recent research and those of others. As models, we have chosen to highlight DNA/nanomaterial complexes consisting of gold nanoparticles, graphene oxides, and aptamer micelles, and we illustrate the potential of such complexes in biosensing, imaging, and medical diagnostics. Under proper conditions, multiple ligand receptor interactions, decreased steric hindrance, and increased surface roughness can be achieved from a high density of DNA that is bound to the surface of nanomaterials, resulting in a higher affinity for complementary DNA and other targets. In addition, this high density of DNA causes a high local salt concentration and negative charge density, which can prevent DNA degradation. For example, DNAzymes assembled on gold nanoparticles can effectively catalyze chemical reactions even in living cells. And it has been confirmed that DNA nanomaterial complexes can enter cells more easily than free single-stranded DNA. Nanomaterials can be designed and synthesized in needed sizes and shapes, and they possess unique chemical and physical properties, which make them useful as DNA carriers or assistants, excellent signal reporters, transducers, and amplifiers. When nanomaterials are combined with functional DNAs to create novel assay platforms, highly sensitive biosensing and high-resolution imaging result. For example, gold nanoparticles and graphene oxides can quench fluorescence efficiently to achieve low background and effectively increase the signal-to background ratio. Meanwhile, gold nanoparticles themselves can be colorimetric reporters because of their different optical absorptions between monodispersion and aggregation. DNA self-assembled nanomaterials contain several properties of both DNA and nanomaterials. Compared with DNA-nanomaterial complexes, DNA self assembled nanomaterials more closely resemble living beings, and therefore they have lower cytotoxicity at high concentrations. Functional DNA self-assemblies also have high density of DNA for multivalent reaction and three-dimensional nanostructures for cell uptake. Now and in the future, we envision the use of DNA bases in making designer molecules for many challenging applications confronting chemists. With the further development of artificial DNA bases using smart organic synthesis, DNA macromolecules based on elegant molecular assembly approaches are expected to achieve great diversity, additional versatility, and advanced functions. PMID- 24780001 TI - New frontiers in obstructive sleep apnoea. AB - OSA (obstructive sleep apnoea), the most common respiratory disorder of sleep, is caused by the loss of upper airway dilating muscle activity during sleep superimposed on a narrow upper airway. This results in recurrent nocturnal asphyxia. Termination of these events usually requires arousal from sleep and results in sleep fragmentation and hypoxaemia, which leads to poor quality sleep, excessive daytime sleepiness, reduced quality of life and numerous other serious health consequences. Furthermore, patients with untreated sleep apnoea are at an increased risk of hypertension, stroke, heart failure and atrial fibrillation. Although there are many predisposing risk factors for OSA, including male gender, endocrine disorders, use of muscle relaxants, smoking, fluid retention and increased age, the strongest risk factor is obesity. The aim of the present review is to focus on three cutting-edge topics with respect to OSA. The section on animal models covers various strategies used to simulate the physiology or the effects of OSA in animals, and how these have helped to understand some of the underlying mechanisms of OSA. The section on diabetes discusses current evidence in both humans and animal models demonstrating that intermittent hypoxia and sleep fragmentation has a negative impact on glucose tolerance. Finally, the section on cardiovascular biomarkers reviews the evidence supporting the use of these biomarkers to both measure some of the negative consequences of OSA, as well as the potential benefits of OSA therapies. PMID- 24780002 TI - The ins and outs of fibroblast growth factor receptor signalling. AB - FGFR (fibroblast growth factor receptor) signalling plays critical roles in embryogensis, adult physiology, tissue repair and many pathologies. Of particular interest over recent years, it has been implicated in a wide range of cancers, and concerted efforts are underway to target different aspects of FGFR signalling networks. A major focus has been identifying the canonical downstream signalling pathways in cancer cells, and these are now relatively well understood. In the present review, we focus on two distinct but emerging hot topics in FGF biology: its role in stromal cross-talk during cancer progression and the potential roles of FGFR signalling in the nucleus. These neglected areas are proving to be of great interest clinically and are intimately linked, at least in pancreatic cancer. The importance of the stroma in cancer is well accepted, both as a conduit/barrier for treatment and as a target in its own right. Nuclear receptors are less acknowledged as targets, largely due to historical scepticism as to their existence or importance. However, increasing evidence from across the receptor tyrosine kinase field is now strong enough to make the study of nuclear growth factor receptors a major area of interest. PMID- 24780003 TI - Detection of vascular endothelial growth factor in colon cancer xenografts using bevacizumab based near infrared fluorophore conjugate. AB - BACKGROUND: The aim of this study was to develop the near infrared fluorescence (NIRF)-based imaging agent for the visualization of vascular endothelial growth factor (VEGF) in colon cancer. AlexaFluor 750 conjugating with bevacizumab, and injected intravenously into nude mice bearing VEGF over-expressing HT29 human colorectal cancer. Optical imaging was performed at 15 min, 24 h and 48 h post injection. Immunofluorescences staining of the tumor sections were performed. HT29 colorectal cancer xenografts were clearly visualized with bevacizumab AlexaFluor 750. RESULTS: Ex vivo analysis showed 2.1 +/- 0.4%, 37.6 +/- 6.3% and 38.5 +/- 6.2% injected dose/g accumulated in the tumors at 15 min, 24 h and 48 h respectively. Tumor uptake was significantly decreased in pretreated with excess of bevacizumab (p = 0.002). Immunofluorescence analysis showed strong staining of anti-CD 31 antibody around the blood vessels. Anti-VEGF-A and bevacizumab showed heterogeneous expression throughout the tumor. CONCLUSIONS: Current study successfully detected the VEGF expression in HT29 colorectal cancer xenografts, signifying as a potential agent for non-invasive imaging of VEGF expression, which may be applied in clinical practice. PMID- 24780004 TI - Immunomodulation by fish-oil containing lipid emulsions in murine acute respiratory distress syndrome. AB - INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care units. Patients with ARDS often require parenteral nutrition with lipid emulsions as essential components. Besides being an energy supply, these lipid emulsions might display differential modulatory effects on lung integrity and inflammation. METHODS: In a pre-emptive strategy, we investigated the impact of three different intravenously infused lipid emulsions on lung morphology, leukocyte invasion, protein leakage and cytokines in a murine model of ARDS. Mice received an infusion of normal saline solution, a pure long chain triglycerides (LCT) emulsion, a medium-chain triglycerides (MCT) containing mixed emulsion (LCT/MCT), or a fish oil (FO) containing mixed emulsion (LCT/MCT/FO) before lipopolysaccharide (LPS) challenge. RESULTS: Mice pre-infused with fish oil-containing lipid emulsion showed decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in their alveolar space after LPS challenge compared to mice receiving LCT or LCT/MCT. In line with these findings, lung morphology assessed by histological staining after LPS-induced lung injury improved faster in the LCT/MCT/FO group. Concerning the above mentioned parameters, no significant difference was observed between mice infused with LCT or the combination of LCT and MCT. CONCLUSION: Fish oil containing lipid emulsions might exert anti-inflammatory and pro-resolving effects in the murine model of acute lung injury. Partial replacement of n-6 fatty acids with n-3 fatty acids may thus be of benefit for critically ill patients at risk for ARDS which require parenteral nutrition. PMID- 24780006 TI - Provision of human immunodeficiency virus infection following cord blood transplantation. PMID- 24780005 TI - Bone marrow mesenchymal stem cells protected post-infarcted myocardium against arrhythmias via reversing potassium channels remodelling. AB - Bone marrow mesenchymal stem cells (BMSCs) emerge as a promising approach for treating heart diseases. However, the effects of BMSCs-based therapy on cardiac electrophysiology disorders after myocardial infarction were largely unclear. This study was aimed to investigate whether BMSCs transplantation prevents cardiac arrhythmias and reverses potassium channels remodelling in post-infarcted hearts. Myocardial infarction was established in male SD rats, and BMSCs were then intramyocardially transplanted into the infarcted hearts after 3 days. Cardiac electrophysiological properties in the border zone were evaluated by western blotting and whole-cell patch clamp technique after 2 weeks. We found that BMSCs transplantation ameliorated the increased heart weight index and the impaired LV function. The survival of infarcted rats was also improved after BMSCs transplantation. Importantly, electrical stimulation-induced arrhythmias were less observed in BMSCs-transplanted infarcted rats compared with rats without BMSCs treatment. Furthermore, BMSCs transplantation effectively inhibited the prolongation of action potential duration and the reduction of transient and sustained outward potassium currents in ventricular myocytes in post-infarcted rats. Consistently, BMSCs-transplanted infarcted hearts exhibited the increased expression of K(V)4.2, K(V)4.3, K(V)1.5 and K(V)2.1 proteins when compared to infarcted hearts. Moreover, intracellular free calcium level, calcineurin and nuclear NFATc3 protein expression were shown to be increased in infarcted hearts, which was inhibited by BMSCs transplantation. Collectively, BMSCs transplantation prevented ventricular arrhythmias by reversing cardiac potassium channels remodelling in post-infarcted hearts. PMID- 24780007 TI - Resistin as a factor in osteoarthritis: synovial fluid resistin concentrations correlate positively with interleukin 6 and matrix metalloproteinases MMP-1 and MMP-3. AB - OBJECTIVES: Resistin is an adipocytokine that has been related to inflammation and insulin resistance. Following knee injury, elevated levels of resistin have been found in synovial fluid (SF) while very little is known about the role of resistin in osteoarthritis (OA). The aim of the present study was to investigate resistin levels in OA joints and to determine if it is associated with inflammatory and catabolic factors in the joints. METHOD: SF, plasma, and cartilage samples were collected from 88 OA patients undergoing knee replacement surgery. Resistin levels were measured by enzyme-linked immunosorbent assay (ELISA) in SF, plasma, and cartilage culture media. RESULTS: Significant levels of resistin [0.75 (0.67) ng/mL; median (IQR)] were found in SF from OA patients. Resistin correlated positively with interleukin (IL)-6 (r = 0.39, p < 0.001) and with matrix metalloproteinases MMP-1 (r = 0.31, p = 0.004) and MMP-3 (r = 0.24, p = 0.024) in SF. Resistin was also released from cultured OA cartilage and it correlated with resistin levels in SF (r = 0.39, p < 0.001). In addition, resistin levels in plasma correlated positively with those in SF (r = 0.44, p < 0.001). There were no differences in SF or plasma resistin concentrations between females and males or between non-diabetic and diabetic patients, and resistin did not correlate with body mass index (BMI). CONCLUSIONS: Resistin is present in OA joints and is released from OA cartilage. Levels of resistin in SF are associated with inflammatory and catabolic factors, suggesting that resistin has a role to play in the pathogenesis of, and as a possible drug target in, OA. PMID- 24780008 TI - Raman enhancement effect on two-dimensional layered materials: graphene, h-BN and MoS2. AB - Realizing Raman enhancement on a flat surface has become increasingly attractive after the discovery of graphene-enhanced Raman scattering (GERS). Two-dimensional (2D) layered materials, exhibiting a flat surface without dangling bonds, were thought to be strong candidates for both fundamental studies of this Raman enhancement effect and its extension to meet practical applications requirements. Here, we study the Raman enhancement effect on graphene, hexagonal boron nitride (h-BN), and molybdenum disulfide (MoS2), by using the copper phthalocyanine (CuPc) molecule as a probe. This molecule can sit on these layered materials in a face-on configuration. However, it is found that the Raman enhancement effect, which is observable on graphene, hBN, and MoS2, has different enhancement factors for the different vibrational modes of CuPc, depending strongly on the surfaces. Higher-frequency phonon modes of CuPc (such as those at 1342, 1452, 1531 cm(-1)) are enhanced more strongly on graphene than that on h-BN, while the lower frequency phonon modes of CuPc (such as those at 682, 749, 1142, 1185 cm(-1)) are enhanced more strongly on h-BN than that on graphene. MoS2 demonstrated the weakest Raman enhancement effect as a substrate among these three 2D materials. These differences are attributed to the different enhancement mechanisms related to the different electronic properties and chemical bonds exhibited by the three substrates: (1) graphene is zero-gap semiconductor and has a nonpolar C-C bond, which induces charge transfer (2) h-BN is insulating and has a strong B-N bond, while (3) MoS2 is semiconducting with the sulfur atoms on the surface and has a polar covalent bond (Mo-S) with the polarity in the vertical direction to the surface. Therefore, the different Raman enhancement mechanisms differ for each material: (1) charge transfer may occur for graphene; (2) strong dipole-dipole coupling may occur for h-BN, and (3) both charge transfer and dipole-dipole coupling may occur, although weaker in magnitude, for MoS2. Consequently, this work studied the origin of the Raman enhancement (specifically, chemical enhancement) and identifies h-BN and MoS2 as two different types of 2D materials with potential for use as Raman enhancement substrates. PMID- 24780009 TI - Kappa-opioid receptor antagonism: a mechanism for treatment of relief drinking? PMID- 24780010 TI - Common or rare variants for complex traits? PMID- 24780011 TI - The answer you get depends on the question you ask. PMID- 24780012 TI - Microwave liver ablation and dark urine. AB - Microwave assisted liver resection is a useful technique, especially when haemostasis could be difficult to achieve with conventional methods. However, prolonged administration of microwaves can be responsible for intraoperative haemoglobinuria. We describe the first case of acute haemolysis secondary to microwave assisted liver resection. PMID- 24780013 TI - Thymic teratoma masquerading as a thyroid lump. AB - Teratomas are germ cell tumours commonly found in the sacrococcygeal region, ovary, testicle or, infrequently, the mediastinum. In very rare circumstances, these tumours are found in the neck. This case represents a thymic teratoma presenting as what appeared to be an intrathyroid lesion. This has not been described previously and demonstrates an unusual presentation of a neck lump necessitating two operations and a multidisciplinary approach for management. We would also like to highlight that while patients undergo imaging to guide surgery, the surgeon must always be prepared for the unexpected and recognise situations where the operation should be converted to an exploratory procedure instead of full resection. Often, combined surgical care is the best option for difficult congenital cases. PMID- 24780014 TI - Facial nerve injury during temporal artery biopsy. AB - Temporal artery biopsy is considered the gold standard investigation of giant cell arteritis and is recommended in suspected cases despite a sensitivity of 81 91%. This review highlights the potential risk of facial nerve injury during temporal artery biopsy and introduces recent advances in the emerging role of imaging modalities. When these non-invasive techniques are used in conjunction with American College of Rheumatology scoring, which includes clinical features and biochemical test results, temporal artery biopsy may be avoided in selected cases. PMID- 24780015 TI - Surgical management of presacral bleeding. AB - INTRODUCTION: Presacral venous bleeding is an uncommon but potentially life threatening complication of rectal surgery. During the posterior rectal dissection, it is recommended to proceed into the plane between the fascia propria of the rectum and the presacral fascia. Incorrect mobilisation of the rectum outside the Waldeyer's fascia can tear out the lower presacral venous plexus or the sacral basivertebral veins, causing what may prove to be uncontrollable bleeding. METHODS: A systematic search of the MEDLINE((r)) and EmbaseTM databases was performed to obtain primary data published in the period between 1 January 1960 and 31 July 2013. Each article describing variables such as incidence of presacral venous bleeding, surgical approach, number of cases treated and success rate was included in the analysis. RESULTS: A number of creative solutions have been described that attempt to provide good tamponade of the presacral haemorrhage, eliminating the need for second operation. However, few cases are reported in the literature. CONCLUSIONS: As conventional haemostatic measures often fail to control this type of haemorrhage, several alternative methods to control bleeding definitively have been described. We propose a practical comprehensive classification of the available techniques for the management of presacral bleeding. PMID- 24780016 TI - A nine-year review of medicolegal claims in neurosurgery. AB - INTRODUCTION: Neurosurgery remains among the highest malpractice risk specialties. This study aimed to identify areas in neurosurgery associated with litigation, attendant causes and costs. METHODS: Retrospective analysis was conducted of 42 closed litigation cases treated by neurosurgeons at one hospital between March 2004 and March 2013. Data included clinical event, timing and reason for claim, operative course and legal outcome. RESULTS: Twenty-nine claims were defended out of court and twelve were settled out of court. One case required court attendance and was defended. Of the 42 claims, 28, 13 and 1 related to spinal (0.3% of caseload), cranial (0.1% of caseload) and peripheral nerve (0.07% of caseload) surgery respectively. The most common causes of claims were faulty surgical technique (43%), delayed diagnosis/misdiagnosis (17%), lack of information (14%) and delayed treatment (12%), with a likelihood of success of 39%, 29%, 17% and 20% respectively. The highest median payouts were for claims against faulty surgical technique (L230,000) and delayed diagnosis/misdiagnosis (L212,650). The mean delay between clinical event and claim was 664 days. CONCLUSIONS: Spinal surgery carries the highest litigation risk versus cranial and peripheral nerve surgery. Claims are most commonly against faulty surgical technique and delayed diagnosis/misdiagnosis, which have the highest success rates and payouts. In spinal surgery, the most common cause of claims is faulty surgical technique. In cranial surgery, the most common cause is lack of information. Claims may occur years after the clinical event, necessitating thorough contemporaneous documentation for adequate future defence. We emphasise thorough patient consultation and meticulous surgical technique to minimise litigation in neurosurgical practice. PMID- 24780017 TI - Successful closure of gastrocutaneous fistulas using the Surgisis((r)) anal fistula plug. AB - INTRODUCTION: Gastrocutaneous fistulas remain an uncommon complication of upper gastrointestinal surgery. Less common but equally problematic are gastrocutaneous fistulas secondary to non-healing gastrostomies. Both are associated with considerable morbidity and mortality. Surgical repair remains the gold standard of care. For those unfit for surgical intervention, results from conservative management can be disappointing. We describe a case series of seven patients with gastrocutaneous fistulas who were unfit for surgical intervention. These patients were managed successfully in a minimally invasive manner using the Surgisis((r)) (Cook Surgical, Bloomington, IN, US) anal fistula plug. METHODS: Between September 2008 and January 2009, seven patients with gastrocutaneous fistulas presented to Wishaw General Hospital. Four gastrocutaneous fistulas represented non-healing gastrostomies, two followed an anastomotic leak after an oesophagectomy and one following an anastomotic leak after a distal gastrectomy. All patients had poor nutritional reserve with no other identifiable reason for failure to heal. All were deemed unfit for surgical intervention. Five gastrocutaneous fistulas were closed successfully using the Surgisis((r)) anal fistula plug positioned directly into the fistula tract under local anaesthesia and two gastrocutaneous fistulas were closed successfully using the Surgisis((r)) anal fistula positioned endoscopically using a rendezvous technique. RESULTS: For the five patients with gastrocutaneous fistulas closed directly under local anaesthesia, oral alimentation was reinstated immediately. Fistula output ceased on day 12 with complete epithelialisation occurring at a median of day 26. For the two gastrocutaneous fistulas closed endoscopically using the rendezvous technique, oral alimentation was reinstated on day 5 with immediate cessation of fistula output. Follow-up upper gastrointestinal endoscopy confirmed re epithelialisation at eight weeks. In none of the cases has there been fistula recurrence (range of follow-up duration: 30-59 months). CONCLUSIONS: Surgisis((r)) anal fistula plugs can be used safely and effectively to close gastrocutaneous fistulas in a minimally invasive manner in patients unfit for surgical intervention. PMID- 24780018 TI - A comparative study of the iron status of patients with oesophageal adenocarcinoma to determine suitability for a clinical trial of iron chelation therapy. AB - INTRODUCTION: The incidence of oesophageal adenocarcinoma (OAC) is rising dramatically and overall survival remains extremely poor. Iron has been shown to potentiate tumourigenesis in OAC, and iron chelation therapy demonstrates promise in vivo as an adjunct to neoadjuvant and palliative chemotherapy. OAC, however, has traditionally been associated with iron deficiency anaemia. The aim of this study was therefore to formally quantify the iron status of OAC patients in order to guide the design of future clinical trials involving iron chelation therapy. METHODS: Demographic and cancer specific data were collected prospectively from all patients presenting with OAC and gastric adenocarcinoma (GAC). Patients had haemoglobin, serum iron, serum ferritin and serum transferrin receptor (sTfR) levels measured to assess systemic iron status. In addition, the sTfR/log ferritin (sTfR-F) index was calculated. RESULTS: Average haemoglobin, serum iron, serum ferritin, sTfR and sTfR-F index values for all patients presenting with OAC were within normal sex specific reference ranges. No statistical difference in iron status was observed between OAC patients presenting with resectable and advanced OAC. Patients with OAC are relatively iron replete compared with those presenting with GAC. Iron parameters were not significantly altered by standard neoadjuvant chemotherapy. CONCLUSIONS: Patients presenting with resectable or advanced OAC could be considered as candidates for a clinical trial of iron chelation therapy as an addition to standard neoadjuvant or palliative treatments. PMID- 24780019 TI - Single-visit endovenous laser treatment and tributary procedures for symptomatic great saphenous varicose veins. AB - INTRODUCTION: Endovenous ablation of saphenous varicose veins has decreased morbidity and recovery time compared with open surgery. This study assessed the outcome and mid-term patient satisfaction of single-visit endovenous laser treatment (EVLT) alone, EVLT combined with phlebectomies and endovenous chemical ablation. METHODS: A retrospective review was conducted of all patients (n=91) in 2008-2009 who underwent single-visit day-case EVLT using local anaesthesia under a single surgeon. Postoperative venous ultrasonography at 2 and 14 months was reviewed. A telephone questionnaire was carried out to assess recurrence of symptoms and quality of life at 42 months. RESULTS: Overall, 124 limbs underwent day-case EVLT under local anaesthesia using an 810nm diode laser at a continuous setting of 14W. Forty-eight of these underwent EVLT alone while fifty underwent EVLT with phlebectomies and twenty-six underwent EVLT with endovenous chemical ablation. Ninety-one per cent of limbs underwent two-month postoperative imaging. All had satisfactory great saphenous vein (GSV) ablation (anterior thigh vein patency: n=1). The majority (84%) of limbs underwent 14-month imaging with a 98% GSV ablation rate. Three per cent had anterior thigh vein and saphenofemoral junction incompetence. Recurrence of GSV patency and reflux was <1%. The response rate to the questionnaire was 60%: 95% of respondents confirmed improvement following treatment, 62% remained symptom free at 42 months while 65% of patients with a return of symptoms deemed them mild. The questionnaire was scored out of 56 for symptoms and quality of life. Those with symptoms scored significantly higher. CONCLUSIONS: At 42 months, the majority of limbs remained asymptomatic. The short-term GSV ablation rates were excellent. Overall mid-term review of patients has shown a well received single-visit service with concomitant phlebectomy or endovenous ablation, and good ablation and patient satisfaction rates. PMID- 24780020 TI - Thyroid surgery as a 23-hour stay procedure. AB - INTRODUCTION: The main barriers to short stay thyroidectomy are haemorrhage, bilateral recurrent laryngeal nerve palsy causing respiratory compromise and hypocalcaemia. This study assessed the safety and effectiveness of thyroidectomy as a 23-hour stay procedure. METHODS: All patients undergoing total or completion thyroidectomy were prescribed calcium and vitamin D3 supplements following surgery. Retrospective analysis identified patients admitted for longer than 23 hours and any readmissions. RESULTS: A total of 164 patients were admitted for 23 hour stay thyroid surgery over a 25-month period between 2008 and 2010. Four patients (2%) required admission for longer than 23 hours. No patients required emergency intervention for postoperative haemorrhage or airway compromise. Biochemical hypocalcaemia (despite calcium supplements) was detected in one patient when measured at the outpatient clinic two weeks following surgery. Twelve patients (7.3%) attended the accident and emergency department following discharge; four required admission for intravenous antibiotics for wound infection and one for biochemical hypocalcaemia. CONCLUSIONS: This single centre UK experience demonstrates that thyroidectomy can be carried out both safely and effectively as a 23-hour stay procedure. Prophylactic prescription of calcium and vitamin D3 reduces hypocalcaemia, and thereby also prolonged admission and readmission due to hypocalcaemia. Supplements are an acceptable, cost effective method of reducing hypocalcaemia and shortening postoperative length of stay. PMID- 24780021 TI - The yield of colorectal cancer among fast track patients with normocytic and microcytic anaemia. AB - INTRODUCTION: We receive fast track referrals on the basis of iron deficiency anaemia (IDA) for patients with normocytic anaemia or for patients with no iron studies. This study examined the yield of colorectal cancer (CRC) among fast track patients to ascertain whether awaiting confirmation of IDA is necessary prior to performing bowel investigations. METHODS: A review was undertaken of 321 and 930 consecutive fast track referrals from Centre A and Centre B respectively. Contingency tables were analysed using Fisher's exact test. Logistic regression analyses were performed to investigate significant predictors of CRC. RESULTS: Overall, 229 patients were included from Centre A and 689 from Centre B. The odds ratio for microcytic anaemia versus normocytic anaemia in the outcome of CRC was 1.3 (95% confidence interval [CI]: 0.5-3.9) for Centre A and 1.6 (95% CI: 0.8 3.3) for Centre B. In a logistic regression analysis (Centre B only), no significant difference in CRC rates was seen between microcytic and normocytic anaemia (adjusted odds ratio: 1.9, 95% CI: 0.9-3.9). There was no statistically significant difference in the yield of CRC between microcytic and normocytic anaemia (p=0.515, Fisher's exact test) in patients with anaemia only and no colorectal symptoms. Finally, CRC cases were seen in both microcytic and normocytic groups with or without low ferritin. CONCLUSIONS: There is no significant difference in the yield of CRC between fast track patients with microcytic and normocytic anaemia. This study provides insufficient evidence to support awaiting confirmation of IDA in fast track patients with normocytic anaemia prior to requesting bowel investigations. PMID- 24780022 TI - Prompt laparoscopic cholecystectomy would reduce morbidity and save hospital resources. AB - INTRODUCTION: Limited resources and organisational problems often result in significant waiting times for patients presenting with an indication for cholecystectomy. This study investigated the potential false economy of such practice. METHODS: Retrospective analysis of all patients on a waiting list for cholecystectomy between July 2007 and October 2010 was performed. The hospital computer document management system and patients' notes were used to collect data. RESULTS: A total of 1,021 patients were included in the study; 701 were listed from clinic and 320 were listed following an emergency admission. The median time on a waiting list before surgery was 96 days (range: 5-381 days). Eighty-seven patients (8.5%) had an emergency admission with a gallstone related problem while on a waiting list. This resulted in 488 cumulative inpatient days. There was a significant correlation between increased time spent on the waiting list and increased chance of an emergency admission (p=0.01). Patients added to the waiting list from emergency admissions were more likely to be admitted with complications than those listed from clinic (15.3% vs 5.4%, p<0.01). There was no association between age (p=0.53) or sex (p=0.23) and likelihood of emergency admission while on a waiting list. CONCLUSIONS: Prompt elective surgery and same admission emergency laparoscopic cholecystectomy can reduce waiting list patient morbidity and is likely to save resources in the long term. PMID- 24780023 TI - Low energy fractures of the acetabulum. AB - INTRODUCTION: Acetabular fractures due to high energy injuries are common and well documented; those secondary to low energy mechanisms are less well described. We undertook a retrospective study of the acetabular fracture referrals to our unit to evaluate the proportion of injuries resulting from a low energy mechanism. METHODS: A total of 573 acetabular fractures were evaluated from 1 January 2005 to 31 December 2008. The plain radiography and computed tomography of those sustaining a low energy fracture were assessed and the fracture patterns classified. RESULTS: Of the 573 acetabular fractures, 71 (12.4%) were recorded as being a result of a low energy mechanism. The male-to female ratio was 2.4:1 and the mean patient age was 67.0 years (standard deviation: 19.1 years). There was a significantly higher number of fractures (p<0.001) involving the anterior column (with or without a posterior hemitransverse component) than in a number of previously conducted large acetabular fracture studies. CONCLUSIONS: Our results demonstrate that low energy fractures make up a considerable proportion of acetabular fractures with a distinctly different fracture pattern distribution. With the continued predicted rise in the incidence of osteoporosis, life expectancy and an aging population, it is likely that this type of fracture will become increasingly more common, posing difficult management decisions and leading to procedures that are technically more challenging. PMID- 24780024 TI - Postoperative pain following primary lower limb arthroplasty and enhanced recovery pathway. AB - INTRODUCTION: Enhanced recovery is a concept that has become increasingly popular for arthroplasty surgery over the last ten years. This study was designed to assess the analgesia requirements, pain levels and time to discharge for patients having primary arthroplasty in the enhanced recovery pathway. METHODS: A multidisciplinary prospective cohort study was carried out between January 2012 and March 2012. Data were collected for patients undergoing primary arthroplasty in one hospital during this time. Details of anaesthesia, local infiltration, additional medications and analgesia were recorded. A visual analogue scale pain score was obtained from each patient at time of mobilisation on days 0, 1, 2 and 3 postoperatively. RESULTS: Ninety-six patients were included in the study. Of these, 34 underwent total hip arthroplasty and 62 total knee arthroplasty (TKA). Pain was the greatest contributor for delayed discharge in TKA patients. The patients who had TKA and did not receive non-steroidal anti-inflammatory drugs (NSAIDs) had significantly higher pain scores (day 0, p<0.01; day 1, p<0.001; day 2, p<0.01) and significantly increased opiate demands compared with those patients who did receive NSAIDs. CONCLUSIONS: There are unacceptably high pain scores in patients undergoing TKA without the use of NSAIDs. There should be focused intervention with this group of patients to improve their pain scores and reduce their length of stay. PMID- 24780025 TI - The rising rate of admissions for tonsillitis and neck space abscesses in England, 1991-2011. AB - INTRODUCTION: Sore throats and tonsillitis represent a considerable health burden as well as a significant source of expenditure for the National Health Service (NHS). As part of the recent NHS savings drive, the introduction of 'procedures of low clinical effectiveness' (PoLCE) lists has reinforced a large reduction in the number of tonsillectomies performed. We carried out a cross-sectional study of trends in emergency sore throat admissions in the context of the number of tonsillectomies performed. METHODS: Hospital Episode Statistics (HES) data were extracted. Office for National Statistics data were also used. RESULTS: Between 1991 and 2011, the overall tonsillectomy rate fell by 44%. In the same time, the admission rate for tonsillitis rose by 310% (Pearson's r=-0.67, p=0.01). The peritonsillar abscess admission rate rose by 31% (r=-0.79, p<0.01). Between 1996 and 2011, the overall tonsillectomy rate fell by 41% and the retro and parapharyngeal abscess admission rate rose by 39% (r=-0.55, p=0.026). There was a 14% overall increase in tonsillectomy and sore throat associated bed days. This was despite the large fall in tonsillectomy numbers and the reduction in length of hospital stay. CONCLUSIONS: Efforts to reduce the tonsillectomy rate are correlated with a significant rise in emergency admissions. The rise in the retro and parapharyngeal abscess rate is perhaps most alarming given the very high mortality of these conditions. Bed day data suggest that no net saving has been made despite the new measures. PMID- 24780026 TI - Wound dressing following debridement for Fournier's gangrene. PMID- 24780027 TI - A simple technique to improve venting of the femur. PMID- 24780028 TI - A consistent and reliable technique for tensioning a suture button syndesmosis fixation system. PMID- 24780029 TI - Custom made articulating hip spacer for staged revision in Birmingham hip resurfacing. PMID- 24780030 TI - Metal frame for identification of bone graft harvest position. PMID- 24780031 TI - A technique for minimally invasive long bone biopsy. PMID- 24780032 TI - Infrapatellar fat pad: an aid in revision total knee arthroplasty. PMID- 24780033 TI - Establishing the entry point for in situ pinning of slipped upper femoral epiphysis. PMID- 24780034 TI - Handheld modification of the laparoscopic hook using the Trewavis((c)) arthroscopic lateral release hook. PMID- 24780035 TI - An inexpensive alternative method in the management of paediatric forearm fractures. PMID- 24780036 TI - Calcaneal pull-down technique in the management of resistant equinus associated with congenital club foot. PMID- 24780037 TI - A 'TAD' easier to calculate! PMID- 24780038 TI - Nebulised local anaesthesia technique for fish bone removal. PMID- 24780039 TI - A drill technique to suture to the calcified abdominal aorta. PMID- 24780041 TI - Hepatobiliary cystadenomas. PMID- 24780042 TI - A novel way to secure a chest drain. PMID- 24780043 TI - Blunted day-night changes in luteinizing hormone pulse frequency in girls with obesity: the potential role of hyperandrogenemia. AB - CONTEXT: Puberty is marked by sleep-associated changes in LH pulse frequency and amplitude. Early pubertal girls with obesity exhibit blunted day-to-night changes in LH secretion; whether this occurs in late pubertal obese girls is unknown. OBJECTIVE: The objective of the study was to test two hypotheses: 1) blunted day to-night changes in LH secretion occur in both early and late pubertal obese girls, and 2) such alterations are specifically associated with hyperandrogenemia. DESIGN: This was a cross-sectional analysis. SETTING: The study was conducted at a clinical research center. PATIENTS OR OTHER PARTICIPANTS: Twenty-seven early pubertal, premenarcheal girls (12 of whom were obese) and 63 late pubertal (postmenarcheal) girls (27 of whom were obese) participated in the study. INTERVENTION: Blood samples were taken every 10 minutes from 7:00 pm to 7:00 am. MAIN OUTCOME MEASURE: Change in LH pulse frequency [LH interpulse interval (IPI)] from daytime hours (7:00 pm-11:00 pm, while awake) to nighttime hours (11:00 pm to 7:00 am, while generally asleep). RESULTS: Both nonobese and obese postmenarcheal girls demonstrated significant day-to-night decreases in LH pulse frequency (IPI increases of 33% and 16%, respectively), but day-to-night changes were blunted in obese girls (P = .004, obese vs nonobese). Day-to-night LH pulse frequency decreased significantly in postmenarcheal obese subjects with normal T concentrations (26% IPI increase) but not in those with hyperandrogenemia. Similar differences were evident for LH pulse amplitude. Nonobese and obese early pubertal girls exhibited nonsignificant differences in day-night LH pulse frequency (day to night IPI increase of 26% vs decrease of 1%, respectively). CONCLUSIONS: Day-to-night changes in LH pulse secretion are blunted in postmenarcheal obese adolescent girls. This phenomenon may in part reflect hyperandrogenemia. PMID- 24780044 TI - An independent study of a gene expression classifier (Afirma) in the evaluation of cytologically indeterminate thyroid nodules. AB - CONTEXT: Molecular markers hold the promise of improved diagnostic yield in thyroid fine-needle biopsy. The Afirma gene expression classifier (GEC), available commercially, reports a negative predictive value of 94% in the diagnosis of benign nodules after indeterminate cytology. However, there are currently no independent studies of the performance of this assay. OBJECTIVE: The aim was to assess the performance of the Afirma GEC in an academic medical center. DESIGN: Samples for the GEC were collected according to the manufacturer's recommended protocol from patients undergoing thyroid fine-needle aspiration. We requested GEC analysis on nodules reported cytologically as follicular neoplasm or atypia or follicular lesion of undetermined significance from patients willing to defer surgery. PATIENTS: All patients undergoing thyroid fine-needle aspiration during the study period, whose cytology was reported as follicular neoplasm or atypia of undetermined significance/follicular lesion of undetermined significance, were offered access to the test and recruited to this study. INTERVENTION: PATIENTS whose GEC was "benign" were offered ultrasound follow-up in lieu of surgery. Those with a "suspicious" GEC were advised to undergo diagnostic lobectomy. SETTING: The study was conducted at a large academic medical center. MAIN OUTCOME MEASURE: We measured the rate of benign and suspicious calls from the Afirma GEC and histological diagnosis after surgery. RESULTS: A total of 72 nucleic acid samples were sent for GEC analysis. In 12 (17%) of these samples, there was insufficient mRNA, leaving 60 Afirma results for analysis. Of these, 16 (27%) were benign, whereas 44 (73%) were suspicious. The rate of confirmed malignancy in GEC-suspicious nodules was only 17%. CONCLUSION: The Afirma GEC demonstrates a lower than expected rate of benign reports in follicular or Hurthle cell neoplasm and a lower than anticipated malignancy rate within GEC-suspicious nodules. These data suggest that the positive predictive value of the GEC is lower than previously reported and call into question the performance of the test when applied in the context of specialized academic cytopathology. PMID- 24780045 TI - Impact of successful treatment of acromegaly on overnight heart rate variability and sleep apnea. AB - BACKGROUND: Successful treatment of acromegaly improves disease-related cardiovascular mortality and morbidity, but its effects on autonomic modulation of the heart rate are unknown. OBJECTIVES: We documented treatment-induced changes in time-domain heart rate variability, taking into account the confounding effects of obstructive sleep apnea. PATIENTS AND METHODS: Sixteen consecutive patients (12 males, aged 43 +/- 12 y) with newly diagnosed acromegaly underwent overnight (12:00-7:00 am) cardiac Holter recordings coupled with polysomnography. Data were obtained before and 10 +/- 6 months after successful treatment of acromegaly. RESULTS: IGF-1 levels fell from 807 +/- 333 to 207 +/- 69 MUg/L and normalized in all patients. Seven patients (44%) had obstructive sleep apnea (apnea-hypopnea index 33 +/- 21/h) at baseline. Treatment had no significant effect on polysomnographic indices. After treatment, increases were noted in the normal-to-normal heart period (NN), SD-NN, the percentage of NN differing from the previous NN by greater than 50 msec, and the root mean square of successive differences in NN (each P < .05). These heart rate variability results were not influenced by the type of treatment, and there was no relationship between changes in NN and changes in the apnea-hypopnea index (P = .58). CONCLUSION: Early after successful treatment of acromegaly, we observed increased parasympathetic modulation/decreased sympathetic modulation of the nighttime heart rate, an effect that seems unrelated to changes in sleep apnea status. Treatments aimed at normalizing IGF-1 may improve cardiovascular homeostasis through improved cardiac autonomic nervous system modulation. PMID- 24780046 TI - High-sensitivity BRAF mutation analysis: BRAF V600E is acquired early during tumor development but is heterogeneously distributed in a subset of papillary thyroid carcinomas. AB - CONTEXT: The homogeneous distribution of BRAF V600E in papillary thyroid carcinoma (PTC) has been called into question by recent reports. These studies claim that BRAF V600E is heterogeneous and is limited to tumor cell subsets in the majority of PTCs. OBJECTIVE: The objective of the study was to understand the allele distribution of BRAF V600E by evaluating the percentage of mutated neoplastic cells in a group of PTCs using two different highly sensitive analytical approaches: allele-specific locked nucleic acid PCR and 454 next generation sequencing targeted to BRAF exon 15. STUDY DESIGN: BRAF V600E was investigated using allele-specific locked nucleic acid PCR on 155 consecutive samples of PTC. Mutated cases were reanalyzed by 454 next-generation sequencing and immunohistochemistry. Because the evaluation of genetic heterogeneity in tumor samples can be profoundly biased by contamination with normal cells, all mutation frequency data were normalized to the real amount of neoplastic cells within each tumor. RESULTS: Eighty-five of 155 PTCs (54.8%) were BRAF V600E mutated. The distribution of mutated neoplastic cells within the tumor was as follows: greater than 80% in 37 of 85 (43.5%), 30-80% in 39 of 85 (45.9%), and less than 30% in 9 of 85 (10.6%). In most of the PTCs with less than 80% BRAF V600E-positive neoplastic cells, the mutation was present in large neoplastic cell subpopulations. Tumors with less than 30% mutated neoplastic cells were smaller than tumors with a percentage of mutated cells greater than 80% or between 30% and 80% (P < .05). CONCLUSIONS: BRAF V600E is heterogeneously distributed in some PTCs. The large BRAF V600E neoplastic cell subpopulations found in mutated cases is consistent with the view that the BRAF V600E is acquired early during PTC development. PMID- 24780047 TI - Association between metabolic syndrome, radiographic knee osteoarthritis, and intensity of knee pain: results of a national survey. AB - CONTEXT: Although osteoarthritis (OA) has been suggested as another component of metabolic syndrome (MetS), weight-independent associations between MetS and knee OA or intensity of arthritic knee pain remain unclear. OBJECTIVE: The objective of the study was to evaluate the above associations and suggest possible mechanisms. DESIGN AND SETTING: This was a cross-sectional study using the fifth Korean National Health and Nutrition Examination Survey (2010). PARTICIPANTS: A total of 2363 adults (>=50 y of age) who had completed both laboratory examinations and an evaluation for radiographic knee OA participated in the study. MAIN OUTCOME AND MEASURES: Radiographic knee OA was defined as a Kellgren/Lawrence grade of 2 or greater, and the intensity of arthritic knee pain was assessed using a self-reported numeric rating scale. MetS was diagnosed based on National Cholesterol Education Program-Adult Treatment Panel III criteria, and insulin resistance was evaluated using the homeostasis model assessment-estimated insulin resistance index. RESULTS: In a multivariable logistic regression analysis, MetS was associated with radiographic knee OA (adjusted odds ratio 1.49; 95% confidence interval 1.23-1.79; P < .001). This association was not changed significantly after further adjusting for homeostasis model assessment estimated insulin resistance but became nonsignificant after adjusting for weight or body mass index. Age-, sex-, and weight (or body mass index)-adjusted mean score of knee pain was significantly higher in subjects with more components of MetS (P for trend = .010 or .035, respectively). CONCLUSIONS: The association between MetS and radiographic knee OA can be largely explained by an excessive weight but not by insulin resistance, a key pathophysiology of MetS. Because accumulation of MetS components appears to be associated with a higher intensity of knee pain, independently of weight, appropriate treatment for MetS may be helpful for subjects with knee pain. PMID- 24780048 TI - Adipocyte size threshold matters: link with risk of type 2 diabetes and improved insulin resistance after gastric bypass. AB - CONTEXT: Adipocyte volume has been associated with insulin resistance and type 2 diabetes. OBJECTIVE: Our purpose was to identify an adipocyte volume threshold linked with increased insulin resistance risk, and to examine its association with insulin resistance improvement after bariatric surgery. SETTING AND DESIGN: We investigated two cohorts of Caucasian women, candidates for bariatric surgery, from two institutional centers in France (age 42.0 +/- 11.5 years; body mass index, 47.6 +/- 6.9 kg/m(2)) and Germany (age 41.3 +/- 11.2 years; body mass index, 49.5 +/- 8.1 kg/m(2)). 38% of the subjects had gastric bypass surgery and were followed for 6 months after the intervention. We defined a group of subjects with type 2 diabetes or at risk of type 2 diabetes (DRD) and investigated the relations between adipocyte volume and this status before and after surgery. RESULTS: In both cohorts, subjects with DRD presented enlarged adipocytes (France, P = 3*10(-4); Germany, P =3*10(-10)) and we were able to determine thresholds in each cohort above which diabetes risk was potentially increased (France: 1003+/-42 pL, Germany: 798+/-32 pL). Subjects above those adipocyte thresholds were less prone to disappearance of the DRD status after bypass surgery (France, risk ratio = 2.1, P = .024; Germany, risk ratio = 1.3, P = .05). CONCLUSIONS: We show in two cohorts of morbidly obese subjects that a specific adipocyte volume threshold may predict an increased risk for obesity-associated type 2 diabetes. However, this threshold might be established for each specific investigation site. Having a high adipocyte size is associated with a lower improvement of insulin resistance after bypass surgery in both cohorts. PMID- 24780049 TI - Implication of circulating irisin levels with brown adipose tissue and sarcopenia in humans. AB - CONTEXT: Irisin is an exercise-induced novel myokine that drives brown-fat-like conversion of white adipose tissue and has been suggested to be a promising target for the treatment of obesity-related metabolic disorders. OBJECTIVE: To assess the association of circulating irisin concentrations with brown adipose tissue (BAT) and/or sarcopenia in humans. SETTING AND DESIGN: We examined irisin levels in 40 BAT-positive and 40 BAT-negative women detected by (18)F fluorodeoxyglucose positron emission tomography ((18)FDG-PET). In a separate study, we also examined 401 subjects with or without sarcopenia defined by skeletal muscle mass index (SMMI) and appendicular skeletal muscle (ASM)/height(2) using dual-energy x-ray absorptiometry. RESULTS: Among 6877 consecutive (18)FDG-PET scans in 4736 subjects, 146 subjects (3.1%) had positive BAT scans. The BAT-detectable group and the matched BAT-undetectable group did not differ in circulating irisin levels measured using two different ELISA kits (P = .747 and P = .160, respectively). Serum irisin levels were not different between individuals with sarcopenia and those without sarcopenia using either kit (P = .305 and P = .569, respectively). Also, serum irisin levels were not different between groups defined by ASM/height(2) using either kit (P = .352 and P = .134, respectively). Although visceral fat area and skeletal muscle mass showed significant difference according to tertiles of SMMI levels, irisin concentrations did not differ. CONCLUSIONS: Circulating irisin levels were not different in individuals with detectable BAT or those with sarcopenia compared with control subjects and were not correlated with SMMI. PMID- 24780050 TI - Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. AB - CONTEXT: Chronic supraphysiological glucocorticoid therapy controls the androgen excess of 21-hydroxylase deficiency (21OHD) but contributes to the high prevalence of obesity, glucose intolerance, and reduced bone mass in these patients. Abiraterone acetate (AA) is a prodrug for abiraterone, a potent CYP17A1 inhibitor used to suppress androgens in the treatment of prostate cancer. OBJECTIVE: The objective of the study was to test the hypothesis that AA added to physiological hydrocortisone and 9alpha-fludrocortisone acetate corrects androgen excess in women with 21OHD without causing hypertension or hypokalemia. DESIGN: This was a phase 1 dose-escalation study. SETTING: The study was conducted at university clinical research centers. PARTICIPANTS: We screened 14 women with classic 21OHD taking hydrocortisone 12.5-20 mg/d to enroll six participants with serum androstenedione greater than 345 ng/dL (>12 nmol/L). INTERVENTION: AA was administered for 6 days at 100 or 250 mg every morning with 20 mg/d hydrocortisone and 9alpha-fludrocortisone acetate. MAIN OUTCOME MEASURE: The primary endpoint was normalization of mean predose androstenedione on days 6 and 7 (< 230 ng/dL [<8 nmol/L)] in greater than 80% of participants. Secondary end points included serum 17-hydroxyprogesterone and testosterone (T), electrolytes, plasma renin activity, and urine androsterone and etiocholanolone glucuronides. RESULTS: With 100 mg/d AA, mean predose androstenedione fell from 764 to 254 ng/dL (26.7-8.9 nmol/L). At 250 mg/d AA, mean androstenedione normalized in five participants (83%) and decreased from 664 to 126 ng/dL (23.2-4.4 nmol/L), meeting the primary end point. Mean androstenedione declined further during day 6 to 66 and 38 ng/dL (2.3 and 1.3 nmol/L) at 100 and 250 mg/d, respectively. Serum T and urinary metabolites declined similarly. Abiraterone exposure was strongly negatively correlated with mean androstenedione. Hypertension and hypokalemia were not observed. CONCLUSION: AA 100-250 mg/d added to replacement hydrocortisone normalized several measures of androgen excess in women with classic 21OHD and elevated serum androstenedione. PMID- 24780052 TI - Photic hypersensitivity in the premonitory phase of migraine--a positron emission tomography study. AB - BACKGROUND AND PURPOSE: Sensitivity to light (photophobia) is a common ill understood symptom of migraine, whose neurobiology is important in understanding the disorder. METHODS: Patients reporting premonitory symptoms before migraine headache were infused with nitroglycerin (GTN) at a first visit. Patients who responded with premonitory symptoms followed by a delayed headache resembling their migraine had positron emission tomography (PET) scans at least 1 week later, during which GTN infusion was repeated. H2 (15) O PET scans were performed during baseline (pain free), premonitory phase (pain free) and migraine headache. Patients were divided into two groups, with and without photophobia in the premonitory phase. The differences between the premonitory and baseline scans were analysed within groups and between groups using statistical parametric mapping. RESULTS: Thirteen patients participated in the PET study, 10 of whom had at least one PET scan during the premonitory phase in the absence of pain. Data from these 10 patients were included in the final analysis. Five patients had photophobia and five patients did not have photophobia in the premonitory phase. Comparing the premonitory scans to baseline scans, there was activation of extrastriate visual cortex (BA18) in patients with photophobia. This activation was significantly greater than in the patients without photophobia. CONCLUSION: Our findings indicate that photic hypersensitivity is linked to activation of the visual cortex during the premonitory phase of migraine in the absence of headache. PMID- 24780051 TI - Sexual dimorphisms in the associations of BMI and body fat with indices of pubertal development in girls and boys. AB - CONTEXT: The effect of obesity and concomitant insulin resistance on pubertal development is incompletely elucidated. OBJECTIVE: To determine how measures of adiposity and insulin resistance are associated with pubertal maturation in boys and girls. SETTING AND DESIGN: Breast and pubic hair Tanner stage and testicular volume by orchidometry were determined by physical examination in 1066 children. Ovarian volume was estimated by trans-abdominal ultrasound. Fat mass, skeletal age, and fasting serum for insulin and glucose, total T, estradiol, estrone, dehydroepiandrosterone-sulfate, and androstenedione were measured at the National Institutes of Health Clinical Research Center. Convenience sample; 52% obese, 59% female. RESULTS: Logistic regression identified a significant interaction between sex and obesity for prediction of pubertal development (P <= .01). There was a negative association between boys' testicular volume and body mass index (BMI)/fat mass but a positive association between girls' breast stage and BMI/fat mass. Ovarian volume in girls was positively associated with insulin resistance but not with BMI/fat mass. There was a positive association between obesity and measures of estrogen exposure (breast development and skeletal age) in both sexes. Positive correlations were seen for girls between BMI and pubic hair development and between insulin resistance and T production, whereas adiposity was negatively associated with pubic hair in boys. CONCLUSIONS: Significant sexual dimorphisms in the manifestations of pubertal development are seen in obese girls and boys. Two known effects of obesity, increased peripheral conversion of low-potency androgens to estrogens by adipose tissue-aromatase and increased insulin resistance, may be in large part responsible for these differences. PMID- 24780053 TI - Phenolic compounds and carotenoids from four fruits native from the Brazilian Atlantic Forest. AB - Fruits from the Atlantic Forest have received increasing interest because they contain high levels of bioactive compounds with notable functional properties. The composition of carotenoids and phenolic compounds from fruits found in the Atlantic Forest (jussara, uvaia, araca, and grumixama) was determined by high performance liquid chromatography coupled to diode array and mass spectrometry detectors. Uvaia showed the highest levels of carotenoids (1306.6 MUg/100 g fresh matter (f.m.)). Gallic acid was the major phenolic compound in araca (12.2 mg GAE/100 g f.m.) and uvaia (27.5 mg GAE/100 g f.m.). In grumixama, eight quercetin derivatives were found; the main carotenoids included all-trans-beta cryptoxanthin (286.7 MUg/100 g f.m.) and all-trans-lutein (55.5 MUg/100 g f.m.). Uvaia and grumixama contain high amounts of carotenoids, while jussara showed greater levels of phenolic compounds (415 mg GAE/100 g f.m.), particularly anthocyanins (cyanidin 3-rutinoside: 179.60 mg/100 g f.m.; cyanidin 3-glucoside: 47.93 mg/100 g f.m.). PMID- 24780055 TI - A review on ethnobotany, phytochemistry and pharmacology of plant genus Caralluma R. Br. AB - OBJECTIVES: Caralluma is a xerophytic genus used as traditional medicine for the treatment of diabetes, inflammation, leprosy, obesity and rheumatism. Objectives of this review are to establish a relationship between traditional uses and scientific studies by critically evaluating the available fragmented literature on ethnobotany, pharmacology, phytochemistry and toxicology of genus Caralluma. KEY FINDINGS: Ethnomedical uses of Caralluma have been recorded from various countries such as China, India, Iran and Pakistan for six major classes of diseases including diabetes and gastrointestinal disorders. This review indicated the efficacy of genus Caralluma in several in vitro and in vivo pharmacological properties such as antimicrobial, antioxidant and anticancer activity. These bioactivity might be due to the presence of certain classes of compounds in genus Caralluma including pregnane glycosides, flavonoid glycosides and flavones. SUMMARY: Traditional uses and scientific evaluation of Caralluma indicates that it is one of the most widely used genus in some parts of the world. Further studies on the structural activity relationship of some of the isolated compound may improve their biological potency as well as scientific exploitation of traditional uses of the genus. PMID- 24780054 TI - The ability of an attaching and effacing pathogen to trigger localized actin assembly contributes to virulence by promoting mucosal attachment. AB - Enterohaemorrhagic Escherichia coli (EHEC) colonizes the intestine and causes bloody diarrhoea and kidney failure by producing Shiga toxin. Upon binding intestinal cells, EHEC triggers a change in host cell shape, generating actin 'pedestals' beneath bound bacteria. To investigate the importance of pedestal formation to disease, we infected genetically engineered mice incapable of supporting pedestal formation by an EHEC-like mouse pathogen, or wild type mice with a mutant of that pathogen incapable of generating pedestals. We found that pedestal formation promotes attachment of bacteria to the intestinal mucosa and vastly increases the severity of Shiga toxin-mediated disease. PMID- 24780056 TI - Production of nitrous oxide from anaerobic digester centrate and its use as a co oxidant of biogas to enhance energy recovery. AB - Coupled Aerobic-anoxic Nitrous Decomposition Operation (CANDO) is a new process for wastewater treatment that removes nitrogen from wastewater and recovers energy from the nitrogen in three steps: (1) NH4(+) oxidation to NO2(-); (2) NO2( ) reduction to N2O gas; and (3) N2O conversion to N2 with energy production. In this work, we optimize Steps 1 and 2 for anaerobic digester centrate, and we evaluate Step 3 for a full-scale biogas-fed internal combustion engine. Using a continuous stirred reactor coupled to a bench-scale sequencing batch reactor, we observed sustained partial oxidation of NH4(+) to NO2(-) and sustained (3 months) partial reduction of NO2(-) to N2O (75-80% conversion, mass basis), with >95% nitrogen removal (Step 2). Alternating pulses of acetate and NO2(-) selected for Comamonas (38%), Ciceribacter (16%), and Clostridium (11%). Some species stored polyhydroxybutyrate (PHB) and coupled oxidation of PHB to reduction of NO2(-) to N2O. Some species also stored phosphorus as polyphosphate granules. Injections of N2O into a biogas-fed engine at flow rates simulating a full-scale system increased power output by 5.7-7.3%. The results underscore the need for more detailed assessment of bioreactor community ecology and justify pilot- and full scale testing. PMID- 24780057 TI - Structural analysis of an intact monoclonal antibody by online electrochemical reduction of disulfide bonds and Fourier transform ion cyclotron resonance mass spectrometry. AB - Structural confirmation and quality control of recombinant monoclonal antibodies (mAbs) by top-down mass spectrometry is still challenging due to the size of the proteins, disulfide content, and post-translational modifications such as glycosylation. In this study we have applied electrochemistry (EC) to overcome disulfide bridge complexity in top-down analysis of mAbs. To this end, an electrochemical cell was coupled directly to an electrospray ionization (ESI) source and a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer (MS) equipped with a 15 T magnet. By performing online EC-assisted reduction of interchain disulfide bonds in an intact mAb, the released light chains could be selected for tandem mass spectrometry (MS/MS) analysis without interference from heavy-chain fragments. Moreover, the acquisition of full MS scans under denaturing conditions allowed profiling of all abundant mAb glycoforms. Ultrahigh resolution FTICR-MS measurements provided fully resolved isotopic distributions of intact mAb and enabled the identification of the most abundant adducts and other interfering species. Furthermore, it was found that reduction of interchain disulfide bonds occurs in the ESI source dependent on capillary voltage and solvent composition. This phenomenon was systematically evaluated and compared with the results obtained from reduction in the electrochemical cell. PMID- 24780058 TI - The case for measuring anti-drug antibodies in people with multiple sclerosis. AB - The advent of biopharmaceuticals (BPs) has led to significant improvements in the treatment of many chronic inflammatory diseases, and the number of BPs on the market and of diseases treated reflects their success. However, repetitive parenteral administration and intrinsic immunogenic properties of the drug can elicit an immune response, leading to production of anti-drug antibodies (ADA). This is a major limitation of the use of BPs and has to be taken into consideration in clinical practice and during drug development. With increasing knowledge about the immunogenicity of BPs and regular ADA testing in patients, we ensure optimized long-term treatment for the individual and thus optimal use of health care resources. This field has already been extensively investigated in the treatment of multiple sclerosis with IFN-beta, but there is a clear need for consensus from academia, health care providers and the BP industry in managing ADA across all BPs and diseases. PMID- 24780059 TI - Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: a pan-Canadian epidemiological study. AB - Timely diagnosis and care are major determinants of the outcome in acute promyelocytic leukaemia (APL), a malignancy whose incidence may be increasing. The Canadian Cancer Registry (CCR) and health system represent valuable settings to study APL epidemiology. We analysed the CCR, which contains data on all Canadians with APL. To provide clinical information lacking in the CCR, we obtained data from five leukaemia referral centres during a similar time period. Between 1993 and 2007, there were 399 APL in Canada. Age-standardized incidence was 0.083/100,000 and was stable over time. The early death (ED) rate was 21.8% (10.6% in patients <50 years old and 35.5% for those aged >50 years), with no improvement over time. Five-year overall survival (OS) was 54.6% (73.3% in patients <50 years; 29.1% older patients). In the referral cohort, 131 patients were diagnosed between 1999 and 2010. ED was 14.6% and 2-year OS was 76.5%. Within this cohort, ED and OS improved over time, although advanced patient age remained an adverse determinant of OS. In Canada, APL incidence is unexpectedly low and temporally stable. ED was higher than reported in clinical trials, but similar to reports from other registries. In contrast, ED was lower in referral centres and improved with time. PMID- 24780060 TI - Supramolecular polymerization of benzene-1,3,5-tricarboxamide: a molecular dynamics simulation study. AB - Supramolecular polymerization in the family of benzene-1,3,5-tricarboxamide (BTA) has been investigated using atomistic molecular dynamics (MD) simulations. Gas phase calculations using a nonpolarizable force field reproduce the cooperativity in binding energy and intermolecular structure seen in quantum chemical calculations. Both quantum chemical and force field based calculations suggest that the ground state structure of the BTA dimer contains two donor hydrogen bonds and one acceptor hydrogen bond rather than the conjectured three-donor and zero-acceptor hydrogen-bonded state. MD simulations of BTA molecules in a realistic solvent, n-nonane, demonstrate the self-assembly process. The free energy (FE) of dimerization and of solvation has been determined. The solvated dimer of BTA with hexyl tails is more stable than two monomers by about 13 kcal/mol. Furthermore, the FE of association of a BTA molecule to an oligomer exhibits a dependence on the oligomer size, which is a robust signature of cooperative self-assembly. PMID- 24780061 TI - Review: the impacts of circulating 25-hydroxyvitamin D levels on cancer patient outcomes: a systematic review and meta-analysis. AB - CONTEXT: Circulating levels of 25-hydroxyvitamin D [25(OH)D] may affect the prognosis of cancer patients; however, the epidemiological results are not consistent. OBJECTIVE: To perform a meta-analysis of all published studies to assess the associations of circulating 25(OH)D levels measured at or near the time of diagnosis and outcomes for cancer patients. DATA SOURCES: Searches of the PubMed and MEDLINE databases were performed and updated to December 2013. STUDY SELECTION: Studies reporting an association between circulating 25(OH)D levels at or near the time of diagnosis and outcomes for the patients were included. DATA EXTRACTION: Data extraction was performed independently by two authors, and conflicts were resolved by a third investigator. DATA SYNTHESIS: Included in the meta-analysis were 25 studies with 17 332 cases. Significant associations between circulating 25(OH)D levels at or near the time of diagnosis and the outcomes for cancer patients were found. The pooled hazard ratio for the highest vs the lowest quartile of circulating 25(OH)D levels was 0.55 (95% confidence interval [CI] = 0.33-0.91) for overall survival of colorectal cancer patients, 0.63 (95% CI = 0.51-0.77) for breast cancer patients, and 0.48 (95% CI = 0.36-0.64) for lymphoma patients. Higher 25(OH)D levels were significantly associated with reduced cancer specific mortality for patients with colorectal cancer (P = .005) and lymphoma (P < .001) and improved disease-free survival for patients with breast cancer (P < .001) or lymphoma (P < .05). A 10-nmol/L increment in circulating 25(OH)D levels conferred a hazard ratio of 0.96 (95% CI = 0.95-0.97) for overall survival of the cancer patients. CONCLUSIONS: The results indicate that cancer patients with higher circulating 25(OH)D levels at or near the time of diagnosis have better outcomes. PMID- 24780062 TI - The World Health Organization Fracture Risk Assessment Tool (FRAX) underestimates incident and recurrent fractures in consecutive patients with fragility fractures. AB - CONTEXT: The World Health Organization Fracture Risk Assessment tool (FRAX) was developed to identify patients at risk of sustaining a fragility fracture (FF). OBJECTIVE: The objective of the study was to evaluate estimated FRAX probabilities of FF at the time of a FF and to compare them with the observed incidence of recurrent FF. METHODS: A prospective cohort included men and women older than 50 years at the time of a FF. FRAX scores without bone mineral density [FRAX-body mass index (BMI)] were calculated prior to and after the inclusion FF. Recurrent FFs were recorded over a 4-year follow-up. Determinants associated with recurrent FF were determined by univariate and multivariate analyses. RESULTS: FRAX-BMI scores were available in 1399 of the 1409 recruited patients. A high risk FRAX-BMI score was present in only 42.7% patients before and 56.4% after the incident FF. Most FF patients at low or moderate risk before their initial FF were men, younger than 65 years, or without previous FF. Over a median follow-up of 3 years, recurrent FF occurred in 108 patients (2.69 per 100 patient-years). The overall sensitivity of post-FF FRAX to predict a recurrent FF was 71.3% and was specifically lower in patients younger than 65 years (13%) and without previous FF (63%) at inclusion. CONCLUSIONS: The FRAX-BMI scores were below the Canadian threshold for treatment in more than half the patients at the time of a FF and in close to a third of patients with recurrent FF. FRAX-BMI severely underestimates the FF risk in patients younger than 65 years old and after a single FF. PMID- 24780063 TI - Lexical tone perception in native speakers of Cantonese. AB - PURPOSE: This study aimed at investigating (1) tone perception development among typically-developing Cantonese speakers and (2) the hierarchy of tone perception difficulty among the 15 tone contrasts. METHOD: Two-hundred typically-developing children aged 3-10 and a group of 25 normal hearing adults were recruited. They were tested on a pool of 75-item calibrated recorded speech signals. Participants responded to each stimulus by pointing at the corresponding picture displayed on a computer screen from a choice of four. RESULT: There was a gradual increase in tone perception accuracy from children aged 3-6. After age 6, tone perception accuracy was similar to adults with an average error rate of 3-8%. The two tone contrasts that listeners consistently found difficult to distinguish were T2T5 (high-rising vs low-rising) and T3T6 (mid-level vs low-level). In addition, all children groups also showed difficulty in T4T6 identification (low-falling vs low level). CONCLUSION: Tone perception is not error-free even among native Cantonese speaking adults. Overall tone identification performance improved steadily from age 3 to age 6. Based on the participants' performance, a three-tier set of tone groups, with an increasing level of difficulty for identification, is proposed for rehabilitation purposes. These tone groups are (1) Easy: T1T2, T1T3, T1T4, T1T5, T1T6, and T2T3, (2) Medium: T2T4, T2T6, T3T4, and T4T5, and (3) Hard: T2T5, T3T5, T3T6, T4T6, and T5T6. PMID- 24780064 TI - Transcript mapping based on dRNA-seq data. AB - BACKGROUND: RNA-seq and its variant differential RNA-seq (dRNA-seq) are today routine methods for transcriptome analysis in bacteria. While expression profiling and transcriptional start site prediction are standard tasks today, the problem of identifying transcriptional units in a genome-wide fashion is still not solved for prokaryotic systems. RESULTS: We present RNAseg, an algorithm for the prediction of transcriptional units based on dRNA-seq data. A key feature of the algorithm is that, based on the data, it distinguishes between transcribed and un-transcribed genomic segments. Furthermore, the program provides many different predictions in a single run, which can be used to infer the significance of transcriptional units in a consensus procedure. We show the performance of our method based on a well-studied dRNA-seq data set for Helicobacter pylori. CONCLUSIONS: With our algorithm it is possible to identify operons and 5'- and 3'-UTRs in an automated fashion. This alleviates the need for labour intensive manual inspection and enables large-scale studies in the area of comparative transcriptomics. PMID- 24780066 TI - The influence of glucose load on metabolism during minor surgery using remifentanil-induced anesthesia. AB - BACKGROUND: During perioperative fasting, lipid metabolism gradually increases, resulting in free fatty acids (FFA) and/or ketone bodies. Suppression of surgical stress by remifentanil may allow the safe administration of glucose infusions, avoiding both hyperglycemia and ketogenesis. The effects of glucose infusion on glucose and lipid metabolism were therefore investigated in patients undergoing minor surgery with remifentanil anesthesia. METHODS: Thirty-four patients were randomized 1 : 1 to receive no glucose (0G group) or low-dose glucose (0.1 g/kg/h for 1 h followed by 0.05 g/kg/h for 1 h; LG group). The concentrations of glucose, adrenocorticotropic hormone (ACTH), 3-methylhistidine (3-MH), insulin, cortisol, FFA, creatinine (Cr), and ketone bodies were measured before anesthetic induction, 1 and 2 h after glucose infusion, at the end of surgery, and the next morning. RESULTS: The concentrations of cortisol and ACTH decreased during surgery in both groups when compared with the concentrations before anesthesia and at the end of surgery (P < 0.05). Glucose and insulin concentrations were significantly higher in the LG than in the 0G group at 1 and 2 h after infusion. No patient experienced hyperglycemia. The concentrations of FFA and ketone bodies were lower in the LG than in the 0G group during surgery, but there were no significant between group differences in 3-MH/Cr. CONCLUSION: Infusion of low dose glucose attenuated fat catabolism without causing hyperglycemia, indicating that infusion of low-dose glucose during remifentanil-induced anesthesia may be safe for patients. PMID- 24780067 TI - MicroRNA-221 targeting PI3-K/Akt signaling axis induces cell proliferation and BCNU resistance in human glioblastoma. AB - MicroRNAs (miRNAs) are short regulatory RNAs that negatively regulate protein biosynthesis at the post-transcriptional level and participate in the pathogenesis of different types of human cancers, including glioblastoma. In particular, the levels of miRNA-221 are overexpressed in many cancers and miRNA 221 exerts its functions as an oncogene. Nevertheless, the roles of miRNA-221 in carmustine (BCNU)-resistant glioma cells have not been totally elucidated. In the present study, we explored the effects of miRNA-221 on BCNU-resistant glioma cells and the possible molecular mechanisms by which miRNA-221 mediated the cell proliferation, survival, apoptosis and BCNU resistance were investigated. We found that miR-221 was overexpressed in glioma cells, including BCNU-resistant cells. Moreover, we found that miR-221 regulated cell proliferation and BCNU resistance in glioma cells. Overexpression of miR-221 led to cell survival and BCNU resistance and reduced cell apoptosis induced by BCNU, whereas knockdown of miR-221 inhibited cell proliferation and prompted BCNU sensitivity and cell apoptosis. Further investigation revealed that miR-221 down-regulated PTEN and activated Akt, which resulted in cell survival and BCNU resistance. Overexpression of PTEN lacking 3'UTR or PI3-K/Akt specific inhibitor wortmannin attenuated miR-221-mediated BCNU resistance and prompted cell apoptosis. We propose that miR-221 regulated cell proliferation and BCNU resistance in glioma cells by targeting PI3-K/PTEN/Akt signaling axis. Our findings may provide a new potential therapeutic target for treatment of glioblastoma. PMID- 24780068 TI - Dietary vitamin D2--a potentially underestimated contributor to vitamin D nutritional status of adults? AB - It has been suggested that vitamin D2 is not very prevalent in the human food chain. However, data from a number of recent intervention studies suggest that the majority of subjects had measurable serum 25-hydroxyvitamin D2 (25(OH)D2) concentrations. Serum 25(OH)D2, unlike 25(OH)D3, is not directly influenced by exposure of skin to sun and thus has dietary origins; however, quantifying dietary vitamin D2 is difficult due to the limitations of food composition data. Therefore, the present study aimed to characterise serum 25(OH)D2 concentrations in the participants of the National Adult Nutrition Survey (NANS) in Ireland, and to use these serum concentrations to estimate the intake of vitamin D2 using a mathematical modelling approach. Serum 25(OH)D2 concentration was measured by a liquid chromatography-tandem MS method, and information on diet as well as subject characteristics was obtained from the NANS. Of these participants, 78.7 % (n 884) had serum 25(OH)D2 concentrations above the limit of quantification, and the mean, maximum, 10th, 50th (median) and 90th percentile values of serum 25(OH)D2 concentrations were 3.69, 27.6, 1.71, 2.96 and 6.36 nmol/l, respectively. To approximate the intake of vitamin D2 from these serum 25(OH)D2 concentrations, we used recently published data on the relationship between vitamin D intake and the responses of serum 25(OH)D concentrations. The projected 5th to 95th percentile intakes of vitamin D2 for adults were in the range of 0.9 1.2 and 5-6 MUg/d, respectively, and the median intake ranged from 1.7 to 2.3 MUg/d. In conclusion, the present data demonstrate that 25(OH)D2 concentrations are present in the sera of adults from this nationally representative sample. Vitamin D2 may have an impact on nutritional adequacy at a population level and thus warrants further investigation. PMID- 24780070 TI - Causal prophylactic efficacy of primaquine, tafenoquine, and atovaquone-proguanil against Plasmodium cynomolgi in a rhesus monkey model. AB - Since the 1940s, the large animal model to assess novel causal prophylactic antimalarial agents has been the Plasmodium cynomolgi sporozoite-infected Indian origin rhesus monkey. In 2009 the model was reassessed with 3 clinical standards: primaquine (PQ), tafenoquine (TQ), and atovaquone-proguanil. Both control monkeys were parasitemic on day 8 post-sporozoite inoculation on day 0. Primaquine at 1.78 mg base/kg/day on days (-1) to 8 protected 1 monkey and delayed parasitemia patency of the other monkey to day 49. Tafenoquine at 6 mg base/kg/day on days ( 1) to 1 protected both monkeys. However, atovaquone-proguanil at 10 mg atovaquone/kg/day on days (-1) to 8 did not protect either monkey and delayed patency only to days 18-19. Primaquine and TQ at the employed regimens are proposed as appropriate doses of positive control drugs for the model at present. PMID- 24780069 TI - Association of the variants in the BUD13-ZNF259 genes and the risk of hyperlipidaemia. AB - The single nucleotide polymorphisms (SNPs) in the BUD13 homolog (BUD13) and zinc finger protein 259 (ZNF259) genes have been associated with one or more serum lipid traits in the European populations. However, little is known about such association in the Chinese populations. Our objectives were to determine the association of the BUD13/ZNF259 SNPs and their haplotypes with hypercholesterolaemia (HCH)/hypertriglyceridaemia (HTG) and to identify the possible gene-gene interactions among these SNPs. Genotyping of 6 SNPs was performed in 634 hyperlipidaemic and 547 normolipidaemic participants. The ZNF259 rs2075290, ZNF259 rs964184 and BUD13 rs10790162 SNPs were significantly associated with serum lipid levels in both HCH and non-HCH populations (P < 0.008 0.001). On single locus analysis, only BUD13 rs10790162 was associated with HCH (OR: 2.23, 95% CI: 1.05, 4.75, P = 0.015). The G-G-A-A-C-C haplotype, carrying rs964184-G-allele, was associated with increased risk of HCH (OR: 1.35, 95% CI: 1.10, 1.66, P = 0.005) and HTG (OR: 1.75, 95% CI: 1.39, 2.21, P = 0.000). The A-C G-G-C-C and A-C-A-G-T-C haplotypes, carrying rs964184-C-allele, were associated with reduced risk of HCH (OR: 0.77, 95% CI: 0.61, 0.99, P = 0.039 and OR: 0.66, 95% CI: 0.47, 0.94, P = 0.021 respectively). On multifactor dimensionality reduction analyses, the two- to three-locus models showed a significant association with HCH and HTG (P < 0.01-0.001). The BUD13/ZNF259 SNPs, which were significant in the European populations, are also replicable in the Southern Chinese population. Moreover, inter-locus interactions may exist among these SNPs. However, further functional studies are required to clarify how these SNPs and genes actually affect the serum lipid levels. PMID- 24780071 TI - Dehydration is an independent predictor of discharge outcome and admission cost in acute ischaemic stroke. AB - BACKGROUND AND PURPOSE: Our aim was to investigate the influence of admission dehydration on the discharge outcome in acute ischaemic and hemorrhagic stroke. METHODS: Between January 2009 and December 2011, 4311 ischaemic and 1371 hemorrhagic stroke patients from the stroke registry of Chang Gung healthcare system were analyzed. The eligible patients were identified according to inclusion/exclusion criteria. In total, 2570 acute ischaemic and 573 acute hemorrhagic stroke patients were finally recruited. According to the blood urea nitrogen (BUN) to creatinine (Cr) ratio (BUN/Cr), these patients were divided into dehydrated (BUN/Cr >= 15) and non-dehydrated (BUN/Cr < 15) groups. Demographics, admission costs and discharge outcomes including modified Rankin scale (mRS) and Barthel index (BI) were examined. Data were analyzed using multivariate analysis of two-stage least squares including logistic and linear regression. RESULTS: Acute ischaemic stroke with admission dehydration had higher infection rates (P = 0.006), worse discharge BI (62.8 +/- 37.4 vs. 73.4 +/- 32.4, P < 0.001, adjusted P < 0.001), worse mRS (2.7 +/- 1.6 vs. 2.3 +/- 1.5, P < 0.001, adjusted P = 0.009) and higher admission costs (2470.8 +/- 3160.8 vs. 1901.2 +/- 2046.8 US dollars, P < 0.001, adjusted P = 0.013) than those without dehydration. However, acute hemorrhagic stroke with or without admission dehydration showd no difference in admission costs (P = 0.618) and discharge outcomes (BI, P = 0.058; mRS, P = 0.058). CONCLUSION: Admission dehydration is associated with worse discharge outcomes and higher admission costs in acute ischaemic stroke but not in hemorrhagic stroke. PMID- 24780072 TI - Public and stakeholder participation for managing and reducing the risks of shale gas development. AB - Emerging technologies pose particularly strong challenges for risk governance when they have multidimensional and inequitable impacts, when there is scientific uncertainty about the technology and its risks, when there are strong value conflicts over the perceived benefits and risks, when decisions must be made urgently, and when the decision making environment is rife with mistrust. Shale gas development is one such emerging technology. Drawing on previous U.S. National Research Council committee reports that examined risk decision making for complex issues like these, we point to the benefits and challenges of applying the analytic-deliberative process recommended in those reports for stakeholder and public engagement in risk decision making about shale gas development in the United States. We discuss the different phases of such a process and conclude by noting the dangers of allowing controversy to ossify and the benefits of sound dialogue and learning among publics, stakeholders, industry, and regulatory decision makers. PMID- 24780073 TI - Community responses of arthropods to a range of traditional and manipulated grazing in shortgrass steppe. AB - Responses of plants to grazing are better understood, and more predictable, than those of consumers in North American grasslands. In 2003, we began a large-scale, replicated experiment that examined the effects of grazing on three important arthropod groups-beetles, spiders, and grasshoppers-in shortgrass steppe of north central Colorado. We investigated whether modifications of the intensity and seasonality of livestock grazing alter the structure and diversity of macroarthropod communities compared with traditional grazing practices. Treatments represented a gradient of grazing intensity by cattle and native herbivores: long-term grazing exclosures; moderate summer grazing (the traditional regime); intensive spring grazing; intensive summer grazing; and moderately summer-grazed pastures also inhabited by black-tailed prairie dogs (Cynomys ludovicianus Ord). Beetles and spiders were the most common groups captured, comprising 60% and 21%, respectively, of 4,378 total pitfall captures. Grasshopper counts were generally low, with 3,799 individuals observed and densities <4 m(-2). Two years after treatments were applied, vegetation structure differed among grazing treatments, responding not only to long-term grazing conditions, but also to the short-term, more-intensive grazing manipulations. In response, arthropods were, in general, relatively insensitive to these grazing induced structural changes. However, species-level analyses of one group (Tenebrionidae) revealed both positive and negative effects of grazing treatments on beetle richness and activity-density. Importantly, these responses to grazing were more pronounced in a year when spring-summer rainfall was low, suggesting that both grazing and precipitation-which together may create the greatest heterogeneity in vegetation structure-are drivers of consumer responses in this system. PMID- 24780074 TI - Synthesis of rotenone-O-monosaccharide derivatives and their phloem mobility. AB - Six monosaccharide derivatives of rotenone were designed and synthesized to assess whether rotenone could become phloem mobile by the addition of a monosaccharide group. Phloem mobility experiments showed that only D-glucose conjugates exhibit phloem transport properties in castor bean (Ricinus communis L.) seedlings. Two D-glucose conjugates, 2-O-beta-D glucopyranosyldemethylrotenone and 6'-O-beta-D-glucopyranosyldalpanol, had significantly obtained systemicity compared with that of rotenone, and 6'-O-beta D-glucopyranosyldalpanol was more mobile than 2-O-beta-D glucopyranosyldemethylrotenone. Coupling with a monosaccharide core is a reasonable method for conferring phloem mobility on insecticides, but phloem mobility is also affected by the parent molecule and the position of the monosaccharide. PMID- 24780075 TI - Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy. AB - BACKGROUND: Environmental and genetic factors predispose an individual to the development of Graves' disease (GD). In an expression study of intraorbital tissue, adipocyte-related immediate early genes (IEGs) and immunomodulatory genes were found to be overexpressed in patients with Graves' ophthalmopathy (GO). We hypothesized that genetic variations in these genes could be associated with GD and/or GO. METHODS: A total of 98 single nucleotide polymorphisms (SNPs) in 12 genes were genotyped in 594 GD patients with (n=267) or without (n=327) GO and 1147 sex- and ethnicity-matched controls from Malmo, Sweden. RESULTS: Ten SNPs in four genes (BTG family, member 2 [BTG2], cysteine-rich, angiogenic inducer 61 [CYR61], zinc finger protein 36, C3H type, homolog mouse [ZFP36], and stearoyl coenzyme A desaturase [SCD]) showed an association with GD and/or GO. SNPs rs12136280 (odds ratio [OR] 1.29, p=0.002), rs6663606 (OR 1.26, p=0.004), and rs17534202 (OR 1.21, p=0.02) in BTG2 and rs3753793 (OR 1.21, p=0.03) in CYR61 were associated with GD. An association with GO was shown for SNPs rs3753793 (OR 1.45, p=0.008), rs6682848 (OR 1.55, p=0.03), rs12756618 (OR 1.77, p=0.049), and rs1378228 (OR 1.29, p=0.049) in CYR61, rs1057745 (OR 1.56, p=0.03) and rs11083522 (OR 1.32, p=0.04) in ZFP36, and rs1393491 (OR 1.38, p=0,048) in SCD. Smoking and CYR61 rs12756618 interacted to increase the risk of GO. CONCLUSIONS: We found associations of SNPs in IEGs and SCD with GD and/or GO; however, confirmation in a different population is required. PMID- 24780076 TI - Electroejaculation as a method of fertility preservation in boys diagnosed with cancer: a single-center experience and review of the literature. AB - OBJECTIVE: To evaluate the feasibility of electroejaculation to perform semen cryopreservation in pubertal boys before gonadotoxic therapy and to review the literature on this topic. DESIGN: Retrospective cohort study and review of the literature. SETTING: Academic children's hospital. PATIENT(S): Boys diagnosed with cancer to whom sperm cryopreservation was offered before the start of gonadotoxic therapy. INTERVENTION(S): We studied the outcome of electroejaculation, including patient characteristics, hormone levels, and pretreatment semen parameters. MAIN OUTCOME MEASURE(S): Semen cryopreservation. RESULT(S): Pretreatment semen samples were obtained by masturbation in 106/114 boys with cancer, of which 78/106 were adequate for preservation. Electroejaculation was offered to 11 boys, of which three of 11 samples appeared adequate for preservation. Reviewing all reported electroejaculation cases in children with cancer in the literature, 13/29 (45%) cases were successful. Testosterone levels were higher in patients with successful sperm yield obtained by electroejaculation (median, 8.3 nmol/L [5.2-42.4] in successful harvests, vs. median 1.7 nmol/L [0.01-17.9] in unsuccessful harvests). CONCLUSION(S): Semen cryopreservation should be offered to all pubertal boys diagnosed with cancer. If masturbation fails, electroejaculation can be considered as a useful option for semen cryopreservation and leads to adequate material for cryopreservation in about half of the cases. PMID- 24780077 TI - Protein-specific prediction of mRNA binding using RNA sequences, binding motifs and predicted secondary structures. AB - BACKGROUND: RNA-binding proteins interact with specific RNA molecules to regulate important cellular processes. It is therefore necessary to identify the RNA interaction partners in order to understand the precise functions of such proteins. Protein-RNA interactions are typically characterized using in vivo and in vitro experiments but these may not detect all binding partners. Therefore, computational methods that capture the protein-dependent nature of such binding interactions could help to predict potential binding partners in silico. RESULTS: We have developed three methods to predict whether an RNA can interact with a particular RNA-binding protein using support vector machines and different features based on the sequence (the Oli method), the motif score (the OliMo method) and the secondary structure (the OliMoSS method). We applied these approaches to different experimentally-derived datasets and compared the predictions with RNAcontext and RPISeq. Oli outperformed OliMoSS and RPISeq, confirming our protein-specific predictions and suggesting that tetranucleotide frequencies are appropriate discriminative features. Oli and RNAcontext were the most competitive methods in terms of the area under curve. A precision-recall curve analysis achieved higher precision values for Oli. On a second experimental dataset including real negative binding information, Oli outperformed RNAcontext with a precision of 0.73 vs. 0.59. CONCLUSIONS: Our experiments showed that features based on primary sequence information are sufficiently discriminating to predict specific RNA-protein interactions. Sequence motifs and secondary structure information were not necessary to improve these predictions. Finally we confirmed that protein-specific experimental data concerning RNA-protein interactions are valuable sources of information that can be used for the efficient training of models for in silico predictions. The scripts are available upon request to the corresponding author. PMID- 24780078 TI - Association between TLR1 polymorphisms and alopecia areata. AB - Toll-like receptors (TLRs) may contribute to the process of autoimmune attacks on hair follicles. To investigate whether the TLR1 gene polymorphisms are associated with the development and clinical features of alopecia areata (AA), a case control comparison of two single nucleotide polymorphisms (SNPs) (rs4833095, Asn248Ser and rs5743557, -414C > T) of TLR1 were studied in 239 AA patients and 248 controls. Using multiple logistic regression model, odds ratios, 95% confidence intervals and corresponding p values were estimated. Clinical features were analyzed based on the age of onset, family history, type of AA, nail involvement and body hair involvement. The missense SNP rs4833095 was significantly associated with the development of AA (codominant2, p = 0.002; recessive, p = 0.001; log-additive, p = 0.0071; and allele frequency, p = 0.0066). The promoter SNP rs5743557 was weakly associated with the development of AA (codominant2, p = 0.019; recessive, p = 0.032; log-additive, p = 0.020; and allele frequency, p = 0.03). In the clinical features, rs4833095 was only weakly associated with age of onset between 15 and 50 years (codominant2, p = 0.043 and recessive, p = 0.022). The results suggest that rs4833095 of TLR1 may be associated with the susceptibility for AA in the Korean population. PMID- 24780079 TI - A rapid and sensitive UFLC-MS/MS method for the simultaneous determination of gentiopicroside and swertiamarin in rat plasma and its application in pharmacokinetics. AB - OBJECTIVES: Radix Gentianae is a traditional Chinese medicine derived from medicinal plants of the family Gentianaceae. Its pharmacological effects have been primarily attributed to the presence of a number of secoiridoid glycosides, in particular gentiopicroside and swertiamarin. In this study, a rapid and sensitive method based on ultrafast liquid chromatography-tandem mass spectrometry has been developed for the simultaneous determination of gentiopicroside and swertiamarin in rat plasma using paeoniflorin as internal standard (IS). METHODS: After liquid-liquid extraction with ethyl acetate isopropanol (95 : 5, v/v), separation was achieved on a Shim-pack XR-ODS C18 column (75 mm * 3.0 mm, 2.2 MUm) with a mobile phase consisting of methanol : 0.1% formic acid (30 : 70, v/v) at a flow rate of 0.4 ml/min. Detection on an API 3200 QTRAP mass spectrometer equipped with an electrospray ionization source operated in the negative ionization mode was performed by multiple reaction monitoring of the precursor-to-product ion transitions of gentiopicroside, swertiamarin and IS at m/z 401.0 -> 179.0, 419.0 -> 179.1 and 525.1 -> 121.0 respectively. The calibration curves were linear over the concentration range of 20-10 000 and 2-1000 ng/ml for gentiopicroside and swertiamarin with corresponding lower limits of quantification of 20 and 2 ng/ml. The limits of detection were 4 and 0.5 ng/ml for gentiopicroside and swertiamarin, respectively. The intraday and interday precisions were below 11.9% for gentiopicroside and below 9.5% for swertiamarin in terms of relative standard deviation, and the accuracy was within +/-8.3% for gentiopicroside and within +/ 10.2% for swertiamarin in terms of relative error. Extraction recovery, matrix effect and stability were satisfactory in rat plasma. The method was fully validated and applied to a pharmacokinetic study involving oral administration of a Radix Gentianae extract to groups of male and female rats. KEY FINDINGS: Results showed that in female rats, both compounds were absorbed to a greater extent and eliminated more slowly than in male rats, although the rate of absorption was similar in the two groups. CONCLUSIONS: There were remarkable differences in pharmacokinetic properties of gentiopicroside and swertiamarin between male and female rats. The results will provide helpful information for the development of suitable dosage forms and clinical references on rational administration. PMID- 24780081 TI - Distal deep vein thrombosis--a benign disease? PMID- 24780080 TI - Inhibition of COX-2-mediated eicosanoid production plays a major role in the anti inflammatory effects of the endocannabinoid N-docosahexaenoylethanolamine (DHEA) in macrophages. AB - BACKGROUND AND PURPOSE: N-docosahexaenoylethanolamine (DHEA) is the ethanolamine conjugate of the long-chain polyunsaturated n-3 fatty acid docosahexaenoic (DHA; 22: 6n-3). Its concentration in animal tissues and human plasma increases when diets rich in fish or krill oil are consumed. DHEA displays anti-inflammatory properties in vitro and was found to be released during an inflammatory response in mice. Here, we further examine possible targets involved in the immune modulating effects of DHEA. EXPERIMENTAL APPROACH: Antagonists for cannabinoid (CB)1 and CB2 receptors and PPARgamma were used to explore effects of DHEA on NO release by LPS-stimulated RAW264.7 cells. The possible involvement of CB2 receptors was studied by comparing effects in LPS-stimulated peritoneal macrophages obtained from CB2 (-/-) and CB2 (+/+) mice. Effects on NF-kappaB activation were determined using a reporter cell line. To study DHEA effects on COX-2 and lipoxygenase activity, 21 different eicosanoids produced by LPS stimulated RAW264.7 cells were quantified by LC-MS/MS. Finally, effects on mRNA expression profiles were analysed using gene arrays followed by Ingenuity((r)) Pathways Analysis. KEY RESULTS: CB1 and CB2 receptors or PPARs were not involved in the effects of DHEA on NO release. NF-kappaB and IFN-beta, key elements of the myeloid differentiation primary response protein D88 (MyD88)-dependent and MyD88 independent pathways were not decreased. By contrast, DHEA significantly reduced levels of several COX-2-derived eicosanoids. Gene expression analysis provided support for an effect on COX-2-mediated pathways. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that the anti-inflammatory effects of DHEA in macrophages predominantly take place via inhibition of eicosanoids produced through COX-2. LINKED ARTICLES: This article is part of a themed section on Cannabinoids 2013 published in volume 171 issue 6. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2014.171.issue-6/issuetoc. PMID- 24780082 TI - Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors. AB - Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addition to low HDAC potency and selectivity observed, poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here we report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compounds based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compound to feed back into the design process. A total of 17 compounds were evaluated, revealing molecules with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivatives exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivatives showed high BBB penetration (~0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate molecules for small molecule probes and drugs. PMID- 24780083 TI - Accelerated adaptive integration method. AB - Conformational changes that occur upon ligand binding may be too slow to observe on the time scales routinely accessible using molecular dynamics simulations. The adaptive integration method (AIM) leverages the notion that when a ligand is either fully coupled or decoupled, according to lambda, barrier heights may change, making some conformational transitions more accessible at certain lambda values. AIM adaptively changes the value of lambda in a single simulation so that conformations sampled at one value of lambda seed the conformational space sampled at another lambda value. Adapting the value of lambda throughout a simulation, however, does not resolve issues in sampling when barriers remain high regardless of the lambda value. In this work, we introduce a new method, called Accelerated AIM (AcclAIM), in which the potential energy function is flattened at intermediate values of lambda, promoting the exploration of conformational space as the ligand is decoupled from its receptor. We show, with both a simple model system (Bromocyclohexane) and the more complex biomolecule Thrombin, that AcclAIM is a promising approach to overcome high barriers in the calculation of free energies, without the need for any statistical reweighting or additional processors. PMID- 24780084 TI - Random monoallelic expression: regulating gene expression one allele at a time. AB - Monoallelic gene expression is a remarkable process in which transcription occurs from only one of two homologous alleles in a diploid cell. Interestingly, between 0.5% and 15% of autosomal genes exhibit random monoallelic gene expression, in which different cells express only one allele independently of the underlying genomic sequence, in a cell type-specific manner. Recently, genome-wide studies have increased our understanding of the cell type-specific incidence of random monoallelic gene expression, and how the imbalance in allelic expression is distinguished within the cell and potentially maintained across cell generations. Monoallelic gene expression is likely generated through stochastic independent regulation of the two alleles upon differentiation, and has varied implications for the cell and organism, in particular with respect to disease. PMID- 24780086 TI - Evolutionary constraints in variable environments, from proteins to networks. AB - Environmental changes can not only trigger a regulatory response, but also impose evolutionary pressures that can modify the underlying regulatory network. Here, we review recent approaches that are beginning to disentangle this complex interplay between regulatory and evolutionary responses. Systematic genetic reconstructions have shown how evolutionary constraints arise from epistatic interactions between mutations in fixed environments. This approach is now being extended to more complex environments and systems. The first results suggest that epistasis is affected dramatically by environmental changes and, hence, can profoundly affect the course of evolution. Thus, external environments not only define the selection of favored phenotypes, but also affect the internal constraints that can limit the evolution of these phenotypes. These findings also raise new questions relating to the conditions for evolutionary transitions and the evolutionary potential of regulatory networks. PMID- 24780085 TI - Mechanisms of epigenetic memory. AB - Although genetics has an essential role in defining the development, morphology, and physiology of an organism, epigenetic mechanisms have an essential role in modulating these properties by regulating gene expression. During development, epigenetic mechanisms establish stable gene expression patterns to ensure proper differentiation. Such mechanisms also allow organisms to adapt to environmental changes and previous experiences can impact the future responsiveness of an organism to a stimulus over long timescales and even over generations. Here, we discuss the concept of epigenetic memory, defined as the stable propagation of a change in gene expression or potential induced by developmental or environmental stimuli. We highlight three distinct paradigms of epigenetic memory that operate on different timescales. PMID- 24780087 TI - Gene regulation by structured mRNA elements. AB - The precise temporal and spatial coordination of gene activity, based on the integration of internal and external signals, is crucial for the accurate functioning of all biological processes. Although the basic principles of gene expression were established some 60 years ago, recent research has revealed a surprising complexity in the control of gene activity. Many of these gene regulatory mechanisms occur at the level of the mRNA, including sophisticated gene control tasks mediated by structured mRNA elements. We now know that mRNA folds can serve as highly specific receptors for various types of molecules, as exemplified by metabolite-binding riboswitches, and interfere with pro- and eukaryotic gene expression at the level of transcription, translation, and RNA processing. Gene regulation by structured mRNA elements comprises versatile strategies including self-cleaving ribozymes, RNA-folding-mediated occlusion or presentation of cis-regulatory sequences, and sequestration of trans-acting factors including other RNAs and proteins. PMID- 24780088 TI - Osteosarcomas of jaw: experience of a single centre. AB - Although osteosarcoma is the most common primary malignant tumour of bone, osteosarcomas of jaw are rare. In osteosarcomas of jaw, evaluating the clinicopathological factors affecting the prognosis is not easy because of different approaches to diagnosis, treatment, and follow-up. This study reviewed 14 cases of JOS that were diagnosed between 1990-2010, in terms of age, gender, site, clinical history, histopathologic type and histopathologic grade, treatment, and prognosis. Median age was 35 years, while male:female ratio was 1.8:1. Eight tumours were located in the mandible. Osteoblastic differentiation was the predominant feature in seven cases followed by chondroid osteosarcoma (four cases), fibroblastic osteosarcoma, low-grade (parosteal) osteosarcoma associated with fibrous dysplasia, and postradiation osteosarcoma (one cases each). During follow-up, recurrence was seen in four patients at least once and they all died. In conclusion, early diagnosis and complete resection seems to be effective in prognosis. Therefore, clinicians and pathologists should be aware of its characteristics and main differential diagnosis to avoid late recognition. PMID- 24780089 TI - New molecular diagnostic kit to assess Y-chromosome deletions in the Japanese population. AB - OBJECTIVES: Deletions in the azoospermia factor regions are the most common known molecular genetic cause of human male infertility involving spermatogenetic failure. Testing for these deletions in Japanese DNA samples using conventional sequence-tagged site probes occasionally lead to considerable non-specific or faint products in the Japanese population. The aim of the present study was to evaluate the sensitivity and specificity of a newly developed kit for the detection of azoospermia factor microdeletions in the Japanese population. METHODS: Sequence-tagged site probes were reselected and the Luminex suspension array assay was carried out. Validation was retrospectively carried out with 2014 DNA sequences with known microdeletions, which were divided into four categories. RESULTS: Category 1 deletions that corresponded to the conventional classification of azoospermia factor deletion were present in 83 men (4.2%), which can result in intrachromosomal homologous recombination. Kit data confirmed the presence of deletions of this type in DNA sequences known to harbor the azoospermia factor deletions. Category 2 deletions involved cytogenetic abnormalities in 28 men (1.4%), whereas category 3 deletions in 759 men (37.7%) were atypical classifications including the gr/gr deletion. As these deletions are thought to be a result of palindromic units and non-homologous recombination, these microdeletions might impact in the interpretation of some clinical findings. The rest of the 1145 cases (56.8%) were assigned to category 4 as normal variants (polymorphism/no deletion). CONCLUSIONS: The present findings show that this new kit offers good sensitivity and specificity with the advantage of saving in terms of cost and time. PMID- 24780090 TI - LDL-cholesterol-lowering effect of plant sterols and stanols across different dose ranges: a meta-analysis of randomised controlled studies. AB - Phytosterols (PS, comprising plant sterols and plant stanols) have been proven to lower LDL-cholesterol concentrations. The dose-response relationship for this effect has been evaluated in several meta-analyses by calculating averages for different dose ranges or by applying continuous dose-response functions. Both approaches have advantages and disadvantages. So far, the calculation of averages for different dose ranges has not been done for plant sterols and stanols separately. The objective of the present meta-analysis was to investigate the combined and separate effects of plant sterols and stanols when classified into different dose ranges. Studies were searched and selected based on predefined criteria. Relevant data were extracted. Average LDL-cholesterol effects were calculated when studies were categorised by dose, according to random-effects models while using the variance as weighing factor. This was done for plant sterols and stanols combined and separately. In total, 124 studies (201 strata) were included. Plant sterols and stanols were administered in 129 and fifty-nine strata, respectively; the remaining used a mix of both. The average PS dose was 2.1 (range 0.2-9.0) g/d. PS intakes of 0.6-3.3 g/d were found to gradually reduce LDL-cholesterol concentrations by, on average, 6-12%. When plant sterols and stanols were analysed separately, clear and comparable dose-response relationships were observed. Studies carried out with PS doses exceeding 4 g/d were not pooled, as these were scarce and scattered across a wide range of doses. In conclusion, the LDL-cholesterol-lowering effect of both plant sterols and stanols continues to increase up to intakes of approximately 3 g/d to an average effect of 12%. PMID- 24780091 TI - Real life study of three years omalizumab in patients with difficult-to-control asthma. AB - BACKGROUND: Even though there are multiple options for the treatment of asthma, there still exists a fair group of patients with difficult-to-control asthma. We describe for the first time the real-world effects of three-year omalizumab treatment on patients with difficult-to-control asthma, seen in a social security hospital in a Latin American country. METHODS: Difficult-to-control asthmatic patients from the out-patient clinic of a regional hospital were recruited to receive a three-year omalizumab course. Efficacy parameters were asthma control test (ACT) score; FEV1; daily beclomethasone maintenance dose; and unplanned visits for asthma exacerbations (emergency room (ER), hospitalisations, intensive care). RESULTS: 52 patients were recruited, 47 completed the three-year treatment (42 female, 15-67 years, mean age 43.5). Comparing efficacy parameters of the year before omalizumab with the 3rd year of omalizumab: mean ACT improved from 12.4 to 20.5, mean FEV1 from 66.3% (standard deviation (SD) 19.1%) to 88.4% (SD 16.2%) of predicted, while mean beclomethasone dose reduced from 1750 to 766 mcg/day and there was a significant reduction in patients experiencing ER visits (from 95% to 19%, p<0.0001), hospitalisation (38% to 2%, p<0.0001) and intensive care (4% to 0, NS). Five patients discontinued omalizumab, two because of an adverse event (anaphylaxis, severe headache, both resolved without sequelae). CONCLUSION: Omalizumab improved most clinical parameters of Mexican patients with difficult-to-control asthma. Especially the rates of ER visits and hospitalisation were significantly reduced, thus reducing costs. Omalizumab was generally well tolerated. PMID- 24780092 TI - Early-onset Alzheimer's disease: a global cross-sectional analysis. AB - BACKGROUND AND PURPOSE: Little is known about factors associated with early-onset Alzheimer's disease (EOAD), which occurs before 65 years of age. The identification of factors of EOAD might provide insights into Alzheimer's disease (AD) pathogenesis. METHODS: Data from over 3000 subjects with AD from C-Path Online Data Repository were used to compare demographics, comorbidities and prescribed medications between EOAD and late-onset Alzheimer's disease (LOAD). The generalized estimating equations binomial model was used to identify factors associated with EOAD, allowing for within-trials correlation (multiple patients from one single trial). RESULTS: Despite the similar proportions in White, Asian and Black between EOAD and LOAD, a significantly higher proportion of EOAD population was from other races: Native American Indian, Alaskan and Hawaiian and other minorities (including Hispanics) (P < 0.0001); and were more likely to have anxiety or depression (P < 0.0001). A high proportion of the LOAD population reported a history of AD from any relative (70% vs. 58%); atrial fibrillation, hypertension, heart disease, stroke, hypercholesterolaemia and hypothyroidism were over-represented in LOAD (P < 0.01). LOAD patients used more risperidone and donepezil (P < 0.01). The multivariable model results showed that, compared with LOAD, EOAD patients were more frequently from other races and were more likely to have anxiety or depression, with less hypertension, stroke and atrial fibrillation. CONCLUSION: Early-onset Alzheimer's disease is found more frequently in Native American Indians, Alaskans, Hawaiians and other minorities, including Hispanics; patients with EOAD have more anxiety or depression. EOAD occurs independently of hypertension, stroke and atrial fibrillation. PMID- 24780093 TI - Maintenance of the enteric stem cell niche by bacterial lipopolysaccharides? Evidence and perspectives. AB - The enteric nervous system (ENS) has to respond to continuously changing microenvironmental challenges within the gut and is therefore dependent on a neural stem cell niche to keep the ENS functional throughout life. In this study, we hypothesize that this stem cell niche is also affected during inflammation and therefore investigated lipopolysaccharides (LPS) effects on enteric neural stem/progenitor cells (NSPCs). NSPCs were derived from the ENS and cultured under the influence of different LPS concentrations. LPS effects upon proliferation and differentiation of enteric NSPC cultures were assessed using immunochemistry, flow cytometry, western blot, Multiplex ELISA and real-time PCR. LPS enhances the proliferation of enteric NSPCs in a dose-dependent manner. It delays and modifies the differentiation of these cells. The expression of the LPS receptor toll-like receptor 4 on NSPCs could be demonstrated. Moreover, LPS induces the secretion of several cytokines. Flow cytometry data gives evidence for individual subgroups within the NSPC population. ENS-derived NSPCs respond to LPS in maintaining at least partially their stem cell character. In the case of inflammatory disease or trauma where the liberation and exposure to LPS will be increased, the expansion of NSPCs could be a first step towards regeneration of the ENS. The reduced and altered differentiation, as well as the induction of cytokine signalling, demonstrates that the stem cell niche may take part in the LPS-transmitted inflammatory processes in a direct and defined way. PMID- 24780095 TI - Research on floral timing by ambient temperature comes into blossom. AB - The floral transition is an essential process in the life cycle of flower-bearing plants, because their reproductive success depends on it. To determine the right moment of flowering, plants respond to many environmental signals, including day length, light quality, and temperature. Small changes in ambient temperature also affect the flowering process, although our knowledge of the genetic and molecular mechanisms underlying this flowering pathway is limited. However, recent advances in Arabidopsis (Arabidopsis thaliana) have uncovered multiple molecular mechanisms controlling ambient temperature regulation of flowering, which modulate both repressing and activating factors of flowering time. At a time when temperatures are rising worldwide, understanding how plants integrate ambient temperature signals can be crucial for crop production. PMID- 24780094 TI - Association of perioperative blood transfusion with oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma. AB - BACKGROUND: To test the hypothesis that perioperative blood transfusion (PBT)impacts oncologic outcomes of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS: Retrospective analysis of 2492 patients with UTUC treated at 23 institutions with RNU between 1987 and 2007.Cox regression models addressed the association of PBT with disease recurrence, cancer-specific mortality and any-cause mortality. RESULTS: A total of 510 patients (20.5%) patients received PBT. Within a median follow-up of 36 months (Interquartile range: 55 months), 663 (26.6%) patients experienced disease recurrence, 545 patients (21.9%) died of UTUC and 884 (35.5%) patients died from any cause. Patients who received PBT were at significantly higher risk of disease recurrence, cancer-specific mortality and overall mortality than patients not receiving PBT in univariable Cox regression analyses. In multivariable Cox regression analyses that adjusted for the effects of standard clinicopathologic features, PBT did not remain associated with disease recurrence (HR: 1.11; 95% CI 0.92-1.33, p = 0.25), cancer-specific mortality (HR: 1.09; 95% CI 0.89-1.33, p = 0.41) or overall mortality (HR: 1.09; 95% CI 0.93 1.28, p = 0.29). CONCLUSIONS: In patients undergoing RNU for UTUC, PBT is associated with disease recurrence, cancer-specific survival or overall survival in univariable, but not in multivariable Cox regression analyses. PMID- 24780096 TI - Evaluating electrophysiological and behavioral responses to volatiles for improvement of odor-baited trap tree management of Conotrachelus nenuphar (Coleoptera: Curculionidae). AB - Plum curculio, Conotrachelus nenuphar (Herbst), one of the most important pests of apple in eastern and central North America, is usually managed in New England apple orchards by multiple full-block insecticide applications. Efforts to reduce insecticide inputs against plum curculio include using an "attract and kill" approach: odor-baited trap trees deployed in the perimeter row of apple orchards. The standard approach is based on baiting apple trees with two olfactory stimuli, the fruit volatile benzaldehyde and the aggregation pheromone of plum curculio, grandisoic acid. We attempted to improve attraction, aggregation, and retention of adult plum curculios within specific baited trap tree canopies within apple orchards using an additional host plant volatile found to be highly stimulating in electroantennogram studies, trans-2-hexenal. We also attempted to increase aggregation using increased release rates of grandisoic acid. We found that trans 2-hexenal did not provide increased aggregation when deployed as an additional attractant within trap trees or when conversely deployed as a "push" component or repellent in perimeter trees lateral to the baited trap tree. Although increasing the release rate of grandisoic acid 5* actually appeared to increase overall aggregation within trap trees, it was not significantly different than that obtained using the standard dose. Therefore, we believe that the standard olfactory stimuli are sufficient to provide aggregation within trap trees, but that other means should be used to manage them after their arrival. PMID- 24780097 TI - Anti-human immunodeficiency virus type 1 agent alpha-hydroxy glycineamide enters the target cells via a mechanism of passive diffusion. AB - OBJECTIVES: Alpha-hydroxy glycineamide (alphaHGA) is the active antiviral metabolite of tri-peptide glycyl-prolyl-glycine-amide (GPG-NH2 ). alphaHGA inhibits the replication of HIV-1 in vitro by interfering with the capsid formation. It has also an effect on viral gp160 envelope protein. Since drug transport is an important aspect of drug function, we investigated the mechanism of [(14) C] alphaHGA uptake by a human T cell line. METHODS: H9 cells were incubated with defined amounts of radiolabelled alphaHGA for definite time durations. After harvesting the cells and removal of radiolabelled material, the radioactivity associated with the cells was assayed. Experiments were also designed to address the effect of metabolic inhibitors, temperature and extra unlabelled compound as potential competitor on the cellular uptake of alphaHGA. KEY FINDINGS: Uptake of alphaHGA into H9 cells was time- and dose-dependent. The uptake properties showed a low temperature dependency (Q10 < 2). Moreover the uptake was not inhibited by increasing concentrations of cold competitors. There was no effect on cellular uptake of alphaHGA by known metabolic inhibitors, NaN3 and NaF. CONCLUSIONS: Kinetic analysis of compound uptake, metabolic inhibition studies, saturation studies and the Q10 value of alphaHGA uptake indicate that the compound enters H9 cells by a mechanism of passive diffusion. PMID- 24780098 TI - Nucleoside transporters and human organic cation transporter 1 determine the cellular handling of DNA-methyltransferase inhibitors. AB - BACKGROUND AND PURPOSE: Inhibitors of DNA methyltransferases (DNMTs), such as azacytidine, decitabine and zebularine, are used for the epigenetic treatment of cancer. Their action may depend upon their translocation across the plasma membrane. The aim of this study was to identify transporter proteins contributing to DNMT inhibitor action. EXPERIMENTAL APPROACH: Drug interactions with selected hCNT and hENT proteins were studied in transiently transfected HeLa and MDCK cells. Interaction with human organic cation transporters (hOCTs) was assessed in transiently transfected HeLa cells and Xenopus laevis oocytes. KEY RESULTS: Zebularine uptake was mediated by hCNT1, hCNT3 and hENT2. Decitabine interacted with but was not translocated by any nucleoside transporter (NT) type. hCNT expression at the apical domain of MDCK cells promoted net vectorial flux of zebularine. Neither hOCT1 nor hOCT2 transported decitabine, but both were involved in the efflux of zebularine, suggesting these proteins act as efflux transporters. hOCT1 polymorphic variants, known to alter function, decreased zebularine efflux. CONCLUSIONS AND IMPLICATIONS: This study highlights the influence of human NTs and hOCTs on the pharmacokinetics and pharmacodynamics of selected DNMT inhibitors. As hOCTs may also behave as efflux transporters, they could contribute either to chemoresistance or to chemosensitivity, depending upon the nature of the drug or combination of drugs being used in cancer therapy. PMID- 24780099 TI - Transportin-1 and Transportin-2: protein nuclear import and beyond. AB - Nearly 20 years after its identification as a new beta-karyopherin mediating the nuclear import of the RNA-binding protein hnRNP A1, Transportin-1 is still commonly overlooked in comparison with its best known cousin, Importin-beta. Transportin-1 is nonetheless a considerable player in nucleo-cytoplasmic transport. Over the past few years, significant progress has been made in the characterization of the nuclear localization signals (NLSs) that Transportin-1 recognizes, thereby providing the molecular basis of its diversified repertoire of cargoes. The recent discovery that mutations in the Transportin-dependent NLS of FUS cause mislocalization of this protein and result in amyotrophic lateral sclerosis illustrates the importance of Transportin-dependent import for human health. Besides, new functions of Transportin-1 are emerging in processes other than nuclear import. Here, we summarize what is known about Transportin-1 and the related beta-karyopherin Transportin-2. PMID- 24780100 TI - Evolving renorrhaphy technique for retroperitoneal laparoscopic partial nephrectomy: single-surgeon series. AB - OBJECTIVES: To evaluate renorrhaphy techniques and to analyze surgical outcomes in retroperitoneal laparoscopic partial nephrectomy. METHODS: A retrospective study from January 2008 to December 2011 analyzed 526 patients with renal tumors in whom renorrhaphy was changed from one layer, interrupted, figure-of-eight (n = 228) suture to two layers, continuous, unknotted (n = 298) suture. All procedures were carried out by the same laparoscopic surgeon (XZ). Patient demographics, tumor characteristics, operative outcomes and perioperative renal function were compared. RESULTS: Median follow up for one layer, interrupted, figure-of-eight suture and two layers, continuous, unknotted suture was 31 and 28 months, respectively. The two layers, continuous, unknotted suture group had shorter warm ischemia time (P = 0.021), faster removal of Jackson-Pratt drains (P = 0.029) and shorter hospital stay (P = 0.037) than the one layer, interrupted, figure-of eight suture group. There was a trend towards a better preservation of glomerular filtration rates in the two layers, continuous, unknotted suture group (P = 0.045). In a multivariable model, the two layers, continuous, unknotted suture technique was a statistically significant independent predictor of warm ischemia time (P = 0.01), hospital stay (P = 0.001) and estimated glomerular filtration rates (P = 0.043). CONCLUSIONS: Two layers, continuous, unknotted suture renorrhaphy allows better outcomes than one layer, interrupted, figure-of-eight suture renorrhaphy in retroperitoneal laparoscopic partial nephrectomy. A longer clinical follow-up evaluation is warranted. PMID- 24780101 TI - Quality by design development of brivanib alaninate tablets: degradant and moisture control strategy. AB - A quality by design approach was applied to the development of brivanib alaninate tablets. Brivanib alaninate, an ester pro-drug, undergoes hydrolysis to its parent compound, BMS-540215. The shelf-life of the tablets is determined by the rate of the hydrolysis reaction. Hydrolysis kinetics in the tablets was studied to understand its dependence on temperature and humidity. The BMS-540215 amount versus time profile was simulated using a kinetic model for the formation of BMS 540215 as function of relative humidity in the environment and a sorption desorptiom moisture transfer model for the relative humidity inside the package. The combined model was used to study the effect of initial tablet water content on the rate of degradation and to identify a limit for initial tablet water content that results in acceptable level of the degradant at the end of shelf life. A strategy was established for the moisture and degradant control in the tablet based on the understanding of its stability behavior and mathematical models. The control strategy includes a specification limit on the tablet water content and manufacturing process controls that achieve this limit at the time of tablet release testing. PMID- 24780102 TI - Theoretical and experimental study of charge transfer through DNA: impact of mercury mediated T-Hg-T base pair. AB - DNA-Hg complexes may play an important role in sensing DNA defects or in detecting the presence of Hg in the environment. A fundamental way of characterizing DNA-Hg complexes is to study the way the electric charge is transferred through the molecular chain. The main goal of this contribution was to investigate the impact of a mercury metal cation that links two thymine bases in a DNA T-T mismatched base pair (T-Hg-T) on charge transfer through the DNA molecule. We compared the charge transfer efficiencies in standard DNA, DNA with mismatched T-T base pairs, and DNA with a T-Hg(II)-T base pair. For this purpose, we measured the temperature dependence of steady-state fluorescence and UV-vis of the DNA molecules. The experimental results were confronted with the results obtained employing theoretical DFT methods. Generally, the efficiency of charge transfer was driven by mercury changing the spatial overlap of bases. PMID- 24780103 TI - Growth and lipid accumulation properties of microalgal Phaeodactylum tricornutum under different gas liquid ratios. AB - In this study, the effects of gas liquid ratio (GLR) on growth, lipid and fatty acid production of Phaeodactylum tricornutum were investigated. The positive linear relationships among specific growth rate, lipid content, fatty acid methyl ester content and GLR were built. GLR of 1.5vvm was considered as the optimum GLR for P. tricornutum growth and yielding oil, with highest biomass productivity (227.09mgL(-1)d(-1)), highest lipid productivity (48.48mgL(-1)d(-1)) and considerable amount fatty acids of saturated (50.16%) and monounsaturated (48.79%), which gave the finest compromise between oxidative stability and cold flow properties. pH variation was good controlled by the air bubbling velocity and algal photosynthesis. CO3(2-)/HCO3(-) ratio influenced the fatty acids synthesis, especially the component of C16:1. The average value of the most favorable composition C16:1 was 48.36%, which is comparable with other reports. PMID- 24780104 TI - Changes in children's food group intake from age 3 to 7 years: comparison of a FFQ with an online food record. AB - Few studies have investigated the relative validity of FFQ in young children and no study has investigated the relative validity of changes in children's food intake in a longitudinal context. The aim of the present study was to compare the FFQ of the longitudinal Family Influences on Food Intake study, assessing children's food intake in the previous 3 months, with a 3 d online food record when children were 3 and 7 years old, as well as to investigate the relative validity of changes in food group intake over a 4-year period. Parents (n 89) completed the FFQ and an online food record over three non-consecutive days on two separate occasions (January-April 2008 and 2012). Wilcoxon signed-rank tests and Spearman's correlations were used to compare food group intake and changes in intake assessed using both methods. In 2008, the intake of eleven of the twenty two food groups was overestimated and that of four food groups underestimated in the FFQ in comparison with the online tool; in 2012, the intake of four food groups was overestimated and that of seven food groups underestimated. Nevertheless, changes in intake did not differ significantly between the two methods for eighteen food groups. Correlations in 2008 and 2012 were, on average, 0.47; correlations between the changes in dietary intake were, on average, 0.26. The results suggest that despite the significant differences between the two methods for a number of food groups at both baseline and/or follow-up, the FFQ can be used to monitor changes in dietary intake for groups of young children. PMID- 24780105 TI - Menstrual cycle length in reproductive age women is an indicator of oocyte quality and a candidate marker of ovarian reserve. AB - OBJECTIVE: The menstrual cycle is a finely tuned biological process comprising a precisely orchestrated sequence of events: follicular growth, selection and ovulation, extensive endometrial changes, corpus luteum (CL) growth and maturation, and luteolysis. Differences in the length of the menstrual cycle (MCL) have been associated with variable female fecundity. However, the reason for these differences is so far unknown. The donor-recipient model, separating uterine from ovarian factors, allows clarifying the origin of MCL-associated fecundity variations. STUDY DESIGN: We analyzed retrospectively 2015 oocyte donation cycles, resulting in 3427 embryo transfers (ET) and pregnancy follow-up. RESULTS: Surprisingly, we found that oocyte donors MCL of 34-35 days were strongly associated with significantly higher biochemical, clinical and ongoing pregnancy rates in woman who received the embryos, compared to the reference group of MCL of 27-29 days. Moreover, donors with longer MCL presented higher ovarian response to stimulation and lower amount of hormonal stimulation needed to achieve multifollicular growth. Conversely, MCL of <25 days were associated with a poorer ovarian response to stimulation, less cumulus oocyte complexes (COCs) and less mature oocytes (MII) retrieved; however, the quality of oocytes in these women is not associated to their ovarian response, as evidenced by the pregnancy rates obtained when transferred into an adequately prepared endometrium. CONCLUSIONS: We conclude that oocyte quality, rather than natural endometrial preparation, is the main reason for the reported higher fecundity of women with longer MCL. This result is further confirmed by our data on bleeding length in the donor pool. Response to ovarian stimulation is the definitive test of ovarian reserve; moreover, since different MCLs result from varying length of the follicular phase, longer MCL should be associated with a higher number of follicular recruitment events. We hypothesize that MCL is associated with - and a marker of - ovarian reserve in healthy reproductive age women. PMID- 24780106 TI - The biomechanical effect of a lateral meniscus posterior root tear with and without damage to the meniscofemoral ligament: efficacy of different repair techniques. AB - PURPOSE: To evaluate the effect of the meniscofemoral ligament (MFL) in maintaining lateral-compartment contact pressures after injury to the posterior root of the lateral meniscus, and to measure the ability to restore intra articular loads to normal by repairing the posterior root to the tibia after transection of the posterior root and the MFL. METHODS: Ten human cadaveric knee joints were axially loaded to 100 N. A digital pressure sensor measured the contact pressure in the lateral compartment. Five different conditions were tested: intact, after release of the posterior root of the lateral meniscus, after transection of the MFL along with release of the posterior root, refixation of the posterior root of the lateral meniscus to the tibia using an anatomic transosseous tunnel, and refixation of the root of the lateral meniscus using a tibial anterior cruciate ligament (ACL) tunnel. RESULTS: After transection of the posterior lateral meniscus root, the contact pressure did not increase significantly. The additional transection of the MFL led to a significant increase in the contact pressure. Anatomic fixation of the meniscus posterior horn reduced the femorotibial pressure to nearly pre-sectioning values. The reattachment of the meniscus posterior horn through a tibial ACL tunnel was equivalent to an anatomic fixation. CONCLUSIONS: In the case of a root tear of the lateral meniscus, the MFL maintains meniscus function and stabilizes the pressure in the lateral compartment. A complete detachment of the posterior meniscus horn (MFL and root tear) leads to an increase in the intra-articular pressure. A root repair normalizes the pressure down to normal values. The tibial ACL tunnel is suitable to perform the repair and to lead out the suture. CLINICAL RELEVANCE: In the case of a complete detachment of the meniscus posterior horn, fixation of the posterior root is necessary to restore the meniscus function and to guarantee an equal pressure distribution in the lateral compartment. It can be combined with an ACL reconstruction. PMID- 24780107 TI - Forehead sympathetic skin responses in determining autonomic involvement in Parkinson's disease. AB - OBJECTIVE: The purpose of this study was to evaluate forehead sympathetic skin response (SSR) and demonstrate any differences with extremity SSR in determining autonomic nervous system (ANS) involvement in patients with Parkinson's disease (PD). METHODS: Twenty early stage, 20 advanced stage idiopathic PD patients and 20 healthy controls participated in this study. SSR of forehead, hands and feet, heart rate variability (HRV), orthostatic intolerance, QT intervals and dysautonomic symptoms were evaluated. RESULTS: Absent forehead SSR was determined unilaterally in 4, bilaterally in 7 early stage patients, and unilaterally in 4, bilaterally in 8 advanced stage PD patients; there was significant difference between early and advanced stage PD and control groups in terms of the lack of SSR (p=0.000). Absent extremity SSR was determined in at least 1 extremity of 3 advanced stage PD patients, and none of the early stage PD patients. No difference was noted in HRV at rest between early and advanced stage PD and control groups (p=0.218); but HRV at deep breathing was lower in both early and advanced PD patients compared to controls (p=0.014, p=0.002, respectively). CONCLUSION: Forehead SSR is more sensitive in determining ANS dysfunction not only in late but also in early stage of PD. SIGNIFICANCE: With further supportive research, forehead SSR might be used as a simple diagnostic electrophysiological test in the early diagnosis of ANS dysfunction enabling proper treatment and increasing the quality of life of PD patients. PMID- 24780108 TI - Electroencephalographic correlates of working memory deficits in children with Fetal Alcohol Spectrum Disorder using a single-electrode pair recording device. AB - OBJECTIVE: Children with Fetal Alcohol Spectrum Disorder (FASD) exhibit cognitive deficits that can be probed using eye movement tasks. We employed a recently developed, single-sensor electroencephalographic (EEG) recording device in measuring EEG activity during the performance of an eye movement task probing working memory in this population. METHODS: Children with FASD (n=18) and typically developing children (n=19) performed a memory-guided saccade task requiring the participant to remember the spatial location of one, two or three stimuli. We hypothesized that children with FASD would (i) exhibit performance deficits, particularly at greater mnemonic loads; and (ii) display differences in theta (4-8Hz) and alpha (8-12Hz) frequency band power compared with controls. RESULTS: Children with FASD failed to perform the task correctly more often than controls when presented with two or three stimuli, and demonstrated related reductions in alpha and theta power. CONCLUSION: These data suggest that the memory-guided task is sensitive to working memory deficits in children with FASD. SIGNIFICANCE: Simultaneous recording of EEG activity suggest differing patterns of underlying neural recruitment in the clinical group, consistent with previous literature indicating more cognitive resources are required by children with FASD in order to complete complex tasks correctly. PMID- 24780109 TI - Identification of a protein phosphatase 2A family member that regulates cell cycle progression in Trypanosoma brucei. AB - The cell cycle consists of an orderly sequence of events, whose purpose is to faithfully replicate and segregate cellular components. Many events in the cell cycle are triggered by protein kinases and counteracting phosphoprotein phosphatases (PPP). In Trypanosoma brucei, RNAi has been used to characterize numerous regulatory kinases, while the role of protein phosphatases has primarily been deduced with inhibitors such as okadaic acid and calyculin. In the present study, we identify for the first time a protein phosphatase 2A family member (TbPP2A-1) whose knockdown with RNAi phenocopies the effects of okadaic acid (OKA). In bloodstream forms (BF) and insect stage procyclic forms (PF) RNAi of TbPP2A-1 generates a cell population characterized by: an inhibition of cell growth, a block in cytokinesis; continued synthesis of nuclear DNA leading to aneuploidy; continued mitosis leading to cells with N>2, and an unusual phenotype where number of kinetoplasts (and flagella) is less than the number of nuclei. An engineered cell line was constructed to further study TbPP2A-1 and to facilitate the discovery of other cell cycle regulatory genes. PMID- 24780110 TI - Stage distribution and performance status of newly diagnosed patients in a UK regional mesothelioma centre. PMID- 24780111 TI - Efficacy of epidermal growth factor receptor inhibitors versus chemotherapy as second-line treatment in advanced non-small-cell lung cancer with wild-type EGFR: a meta-analysis of randomized controlled clinical trials. AB - BACKGROUND: EGFR mutation status is closely related to the efficacy of EGFR-TKIs in advanced non-small cell lung cancer (NSCLC). EGFR-TKIs have become the standard first-line treatment for advanced EGFR-mutation NSCLC, while for EGFR wild-type tumors, the preferred first-line treatment is chemotherapy. However, the efficacy of EGFR-TKIs as second-line treatment in EGFR wild-type NSCLC remains controversial. We sought to evaluate the effectiveness of EGFR-TKI as second-line treatment in EGFR wild-type NSCLC. METHODS: Randomized controlled trials that compared EGFR-TKIs with chemotherapy in previously treated advanced NSCLC with wild-type EGFR were included. We performed a meta-analysis to evaluate the effectiveness of EGFR-TKIs compared with standard chemotherapy. The endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: Six randomized controlled trials with a total of 990 patients with wild-type EGFR were included: 499 in the EGFR-TKIs group and 491 in the chemotherapy group. The results indicated that in the second-line treatment of EGFR wild-type advanced NSCLC, PFS was significantly inferior in the EGFR-TKIs group versus the chemotherapy group (HR=1.37, 95% CI=1.20-1.56, P<0.00001). However, this significant difference did not translate into OS (HR=1.02, 95% CI=0.87-1.20, P=0.81). ORR tended to favor chemotherapy but there was no significant difference compared with EGFR-TKI (RR=1.77, 95% CI=0.90-3.50, P=0.10). CONCLUSIONS: Chemotherapy improves PFS significantly but not OS, compared with EGFR-TKIs as a second-line treatment in advanced NSCLC with wild type EGFR. Whether EGFR-TKIs should be used in EGFR wild-type patients should be considered carefully. PMID- 24780113 TI - Hypodontia: prevalence and pattern amongst the living Druze population - a Near Eastern genetic isolate. AB - The Druze population is a small-sized Near Eastern genetic isolate with high rates of consanguineous marriages. The present study aimed at investigating prevalence, pattern and distribution of hypodontia in the permanent dentition, excluding wisdom teeth, amongst this population. Panoramic radiographs, dental casts, and anamnestic records of 85 un-admixed Druze schoolchildren (45 males, 40 females; age range=14-18 years, mean age=16 years, SD=0.5 years) were examined for evidence of hypodontia. Those with any type of facial clefts or craniofacial syndromes were excluded. Hypodontia prevalence was 11.8% (11.1% for males, 12.5% for females) with no statistically significant difference between sexes. The average number of missing teeth per child was 1.4 (1.2 for males, 1.6 for females). The majority (90%) of affected individuals exhibited minor hypodontia (one or two teeth missing). The most commonly missing teeth were upper lateral incisors and canines, followed by lower and upper second premolars. Asymmetrical hypodontia was more prevalent. Maxillary, left side, and anterior segment predominance were observed. The distinct features of hypodontia among the Druze population are the relatively high prevalence of minor hypodontia, and the upper lateral incisors and canines being the most commonly missing teeth. PMID- 24780112 TI - Neoadjuvant chemo-immunotherapy modifies CD4(+)CD25(+) regulatory T cells (Treg) in non-small cell lung cancer (NSCLC) patients. AB - BACKGROUND: Regulatory T cells (Treg) are critical for cancer immune evasion; whereas natural killer (NK) cells are central for effective anti-tumor immunity including antibody-induced cellular cytotoxicity (ADCC). The predictive role of Treg levels for clinical response to chemo-immunotherapy in non-small cell lung cancer (NSCLC) as well as therapy-induced Treg changes remain to be defined. PATIENTS AND METHODS: The impact of Treg on NK-mediated cetuximab-dependent cellular cytoxicity was tested in vitro. Frequency and functional activity of Treg was analyzed in 31 NSCLC stage IB-IIIA patients treated by neoadjuvant Cetuximab/Docetaxel/Cisplatin prior to surgery. Data were correlated with clinical outcome variables and Treg tumor infiltration. RESULTS: Treg potently inhibit NK-mediated and cetuximab-induced ADCC in vitro. In addition, a significant correlation between Treg reduction and clinical response was seen. However, the grade of tumor infiltrating Treg in resected tumors did not correlate with peripheral Treg levels. Moreover, Treg levels at diagnosis did not predict clinical response to chemo-immunotherapy. CONCLUSIONS: The drop of Treg levels during neoadjuvant chemo-immunotherapy in NSCLC patients significantly correlates with clinical response. However, Treg at diagnosis are not linked to inferior clinical response to chemo-immunotherapy in NSCLC in vivo even though Treg efficiently inhibit ADCC in vitro. PMID- 24780114 TI - A comparison of Bt transgene, hybrid background, water stress, and insect stress effects on corn leaf and ear injury and subsequent yield. AB - Experimentally manipulated water and insect stresses were applied to field-grown corn with different Bacillus thuringiensis (Bt) transgenes and no Bt transgenes, and different nontransgenic hybrid backgrounds (2011 and 2012, Corpus Christi, TX). Differences in leaf injury, ear injury, and yield were detected among experimental factors and their interactions. Under high and low water stress, injury from noctuid larvae (Lepidoptera: Noctuidae) on leaves during vegetative growth (primarily from fall armyworm, Spodoptera frugiperda J.E. Smith) and on developing ears (primarily from corn earworm, Helicoverpa zea [Boddie]) was lowest on more recent releases of Bt hybrids (newer Bt hybrids) expressing Cry1A.105+Cry2Ab2 and Cry 3Bb1, compared with earlier Bt hybrids (older Bt hybrids) expressing Cry1Ab and Cry3Bb1 and non-Bt hybrids. High water stress led to increased leaf injury under substantial fall armyworm feeding pressure in 2011 (as high as 8.7 on a 1-9 scale of increasing injury). In contrast, ear injury by corn earworm (as high as 20 cm(2) of surface area of injury) was greater in low water stress conditions. Six hybrid backgrounds did not influence leaf injury, while ear injury differences across hybrid backgrounds were detected for non-Bt and older Bt hybrid versions. While newer Bt hybrids expressing Cry1A.105+Cry2Ab2 and Cry 3Bb1 had consistent low leaf injury and high yield and low but less consistent ear injury across six hybrid backgrounds, water stress was a key factor that influenced yield. Bt transgenes played a more variable and lesser role when interacting with water stress to affect yield. These results exemplify the interplay of water and insect stress with plant injury and yield, their interactions with Bt transgenes, and the importance of these interactions in considering strategies for Bt transgene use where water stress is common. PMID- 24780115 TI - Effects of repeated transvaginal ultrasound-guided aspirations performed in anestrous and cyclic mares on P4 and E2 plasma levels and luteal function. AB - The aim of the present study was to verify how repeated ovum pick-up (OPU), performed in anestrous and cyclic mares, affect ovarian activity, measured by progesterone (P4) and 17beta-estradiol (E2) plasma levels. Ovum pick-up of all visible follicles was performed every 9 to 12 days, and four sessions were carried out during anestrous (A) and breeding season (BS). The number of aspirated follicles per mare at each session was not significantly different between the two periods (BS: 6.1 +/- 2.4; A: 7.5 +/- 4.4; P > 0.05), but the mean follicular diameter was significantly higher during BS (16.0 +/- 7.1 vs. 10.2 +/- 5.1 mm; P < 0.05); during A the number of aspirated follicles less than 15 mm in diameter resulted significantly higher than that registered in BS (5.1 +/- 2.7 vs. 3.0 +/- 1.8; P < 0.05). The total mean value of P4 was higher in BS than in A (6.3 +/- 4.4 vs. 0.3 +/- 1.8 ng/mL; P < 0.05), whereas the total mean level of E2 was not different between the two periods (3.8 +/- 3.4 vs. 2.5 +/- 2.7 pg/mL; P > 0.05). Estradiol plasma values resulted positively correlated, in A and BS, with diameter of follicles detected on the ovaries (R = 0.345 and R = 0.331, respectively), whereas a negative correlation was observed between P4 and follicular diameter in BS (R = -0.162). Both E2 and P4 presented a high individual variability during BS; in particular, in three of seven mares, P4 trend was compatible with a normal estrous cycle, and the interval between two consecutive peaks was 21 days. In two of seven mares, with CL at first OPU, P4 concentrations remained more than 3 ng/mL throughout the entire treatment period. Finally, in two of seven animals, P4 levels initially showed a similar pattern to that of a normal estrous cycle, then, after the second aspiration, they remained consistently higher than 3 ng/mL. When the procedure was carried out in cyclic animals, the influence of this technique on ovarian activity seemed to be related to individual variability although, according to progesterone values, structures observed on the ovaries after aspirations presented luteal function. Furthermore, the resumption of normal ovarian activity, after repeated OPU sessions, occurred in a period not much longer than the duration of a normal estrous cycle (25.4 +/- 5.2 days). Data recorded during nonbreeding period showed that repeated OPU in anestrous mares do not affect ovarian activity and do not anticipate the resumption of ovarian cyclicity. However, based on the number of aspirated follicles in anestrous and cyclic mares, both types of subjects could be considered as oocyte donors. PMID- 24780116 TI - Distinct susceptibility of induction of methylation of p16ink4a and p19arf CpG islands by X-radiation and chemical carcinogen in mice. AB - Inactivation of the tumor suppressor genes p16(ink4a) and p19(arf)/p14(arf) by hypermethylation of promoter CpG islands occurs frequently in various tumors. The aim of this study is to investigate the difference of susceptibility of methylation induced by carcinogens between p16(ink4a) and p19(arf). The methylation status of both genes was analyzed by denaturing high performance liquid chromatography (DHPLC) and bisulfite-sequencing, respectively. The expression level of P16 protein was analyzed by immunohistochemistry. Results showed that p16(ink4a) methylation was detected in the glandular stomach, small intestine and other organs of mice following X-radiation and subsequent bone marrow transplantation (BMT), but not in mock control mice. We found that the intestinal tract was the most sensitive organ for X-ray induced p16(ink4a) methylation. Loss of P16 protein expression was observed in the intestinal tissues of X-irradiated mice, but not in the mock control mice. Interestingly, p19(arf) methylation was not observed in the gastrointestinal tissues of the negative control mice following X-radiation/BMT. However, administration of N nitrosomethylurea and/or Helicobacter felis infection promoted methylation of p19(arf) CpG islands in the gastrointestinal tracts, but did not promote p16(ink4a) methylation. In addition, p16(ink4a) methylation was detected not only in the X-irradiated GFP-negative tissue cells, but also in the GFP-positive bone marrow-derived cells that were transplanted into the BMT mice after X-radiation. In conclusion, the methylation susceptibility of p16(ink4a) and p19(arf) to carcinogen treatments was remarkably different: X-radiation indirectly induces systemic p16(ink4a) methylation, especially in the intestine; whereas N nitrosomethylurea and/or H. felis infection induce p19(arf) methylation in their target organs. PMID- 24780117 TI - Nuclear and cytoplasmic changes in erythrocytes of p53-deficient medaka fish (Oryzias latipes) after exposure to gamma-radiation. AB - Previous studies have examined the effects of gamma-radiation on Japanese fish, in particular medaka (Oryzias latipes). In the present work, alterations in erythrocytes were recorded as haematological bio-indicators of exposure to gamma radiation. After exposure of medaka fish to two different doses of radiation (2 Gy and 10 Gy), many malformations in red blood cells were observed in the irradiated fish compared with control fish. These malformations included acanthocytes, crenated cells, amoeboid cells, and sickle cells. More malformations were seen at the higher radiation dose. No micronuclei were seen in any group, but nuclear abnormalities were observed. We conclude that gamma radiation causes morphological malformations of erythrocytes and is harmful to medaka fish. PMID- 24780118 TI - Identification of arginine vasotocin (AVT) neurons activated by acute and chronic restraint stress in the avian septum and anterior diencephalon. AB - Effects of acute and chronic psychological stress in the brain of domestic avian species have not been extensively studied. Experiments were performed using restraint stress to determine groups of neurons activated in the septum and diencephalon of chickens. Using FOS immunoreactivity six brain structures were shown activated by acute stress including: the lateral hypothalamic area (LHy), ventrolateral thalamic nucleus (VLT), lateral septum (LS), lateral bed nucleus of the stria terminalis (BSTL), nucleus of the hippocampal commissure (NHpC) and the core region of the paraventricular nucleus (PVNc). Additionally, the LHy and PVNc showed increased FOS immunoreactive (-ir) cells in the birds chronically stressed when compared to controls. In contrast, the NHpC showed decreased FOS-ir cells following the 10day chronic stress imposed. Thereafter, restraint stress experiments were performed to identify activated arginine vasotocin (AVT) neurons (parvocellular or magnocellular) using immunocytochemistry. Of the six FOS activated structures, the PVN was known to contain distinct size groups of AVT-ir neurons, parvocellular (small), medium sized and magnocellular (large). Using dual immunostaining (AVT/FOS), AVT-ir parvocellular neurons in the PVNc were found activated in both acute and chronic stress. To determine whether these AVT ir parvocellular neurons are co-localized with corticotropin releasing hormone (CRH), an attempt was made to visualize CRH-ir neurons using colchicine. Although AVT-ir and CRH-ir parvocellular neurons occur in the PVNc, only a few neurons were shown co-localized with AVT and CRH after acute restraint stress. Results of this study suggest that the NHpC, LS, VLT, BSTL, LHy and AVT-ir parvocellular neurons in the PVNc are associated with psychological stress in birds. PMID- 24780119 TI - Trenbolone acetate metabolites promote ovarian growth and development in adult Japanese medaka (Oryzias latipes). AB - Trenbolone acetate, a synthetic androgen, has been used as a growth promoter in beef cattle in the US since 1987. While several teleost studies have investigated the masculinization effects of the metabolite 17beta-trenbolone, few have focused on the reproductive impacts of all three trenbolone acetate (TBA) metabolites including trendione. Adult female medaka (Oryzias latipes) were exposed to TBA metabolites (10, 100, and 1000ng/L) for 14days (n=3). Histological examination revealed that TBA metabolites (1000ng/L) significantly reduced the percentage of primary ovarian follicles and increased the percentage of vitellogenic follicles compared to control fish. 17alpha-Trenbolone significantly increased whereas trendione reduced whole body levels of estradiol-17beta. Testosterone was significantly reduced by trendione treatment and only the highest dose of 17beta trenbolone and lowest dose of trendione altered 11-ketotestosterone. Additionally, TBA metabolites may be further broken down and/or metabolized or converted by the animal influencing both sex steroid levels and ovarian development. PMID- 24780120 TI - Three new anti-proliferative Annonaceous acetogenins with mono-tetrahydrofuran ring from graviola fruit (Annona muricata). AB - Bioassay-guided fractionation of the fruit powder of graviola (Annona muricata) yielded three novel compounds: muricins J, K, and L. The compounds are all C35 Annonaceous acetogenins with a mono-tetrahydrofuran ring and four hydroxyls. Their structures were elucidated by spectral methods and chemical modification after isolation via chromatographic techniques and HPLC purification. These three acetogenins demonstrated an antiproliferative against human prostate cancer PC-3 cells. PMID- 24780121 TI - Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors. AB - The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110 nM) demonstrated a reduction in CSF Abeta in wild type rats after a single dose. PMID- 24780122 TI - Study of enzyme activities and protein content of beluga (Huso huso) semen before and after cryopreservation. AB - Knowledge gained regarding the biochemical processes that occur during sperm collection, processing and freezing-thawing might improve current sperm cryopreservation techniques. In our present study, we determined the effect of cryopreservation on the total protein concentration (TP) and the activities of certain enzymes in semen samples from the beluga (Huso huso). The TP content of the seminal plasma of fresh semen was 0.47 +/- 0.026 g/l, and the TP after cryopreservation was 1.86 +/- 0.6 g/l. The activities of acid phosphatase (0.82 +/- 0.042 U/l), lactate dehydrogenase (234.4 +/- 19.4 U/l), arylsulfatase (143.1 +/- 32.5 U/l) and beta-N-acetylglucosaminidase (58.39 +/- 4.14 U/l) in the seminal plasma of fresh semen were significantly lower than those in the supernatant of frozen-thawed semen samples (7.43 +/- 0.64, 3224.6 +/- 167.2, 422.6 +/- 21.3 and 90.2 +/- 5.37 U/l respectively). These parameters may be useful as biomarkers for estimating damage to the cell membrane of spermatozoa caused by freezing-thawing. PMID- 24780123 TI - Analysis of trajectory entropy for continuous stochastic processes at equilibrium. AB - The analytical expression for the trajectory entropy of the overdamped Langevin equation is derived via two approaches. The first route goes through the Fokker Planck equation that governs the propagation of the conditional probability density, while the second method goes through the path integral of the Onsager Machlup action. The agreement of these two approaches in the continuum limit underscores the equivalence between the partial differential equation and the path integral formulations for stochastic processes in the context of trajectory entropy. The values obtained using the analytical expression are also compared with those calculated with numerical solutions for arbitrary time resolutions of the trajectory. Quantitative agreement is clearly observed consistently across different models as the time interval between snapshots in the trajectories decreases. Furthermore, analysis of different scenarios illustrates how the deterministic and stochastic forces in the Langevin equation contribute to the variation in dynamics measured by the trajectory entropy. PMID- 24780124 TI - Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations. AB - The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signalling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient- and energy-dependent signals. It activates PKC-alpha and Akt and regulates the actin cytoskeleton. Deregulation of the mTOR-signalling pathway (PI3K amplification/mutation, PTEN loss of function, Akt overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signalling pathway. PMID- 24780126 TI - Hydrogen and methane emissions from beef cattle and their rumen microbial community vary with diet, time after feeding and genotype. AB - The aims of the present study were to quantify hydrogen (H2) and methane (CH4) emissions from beef cattle under different dietary conditions and to assess how cattle genotype and rumen microbial community affected these emissions. A total of thirty-six Aberdeen Angus-sired (AAx) and thirty-six Limousin-sired (LIMx) steers were fed two diets with forage:concentrate ratios (DM basis) of either 8:92 (concentrate) or 52:48 (mixed). Each diet was fed to eighteen animals of each genotype. Methane (CH4) and H2 emissions were measured individually in indirect respiration chambers. H2 emissions (mmol/min) varied greatly throughout the day, being highest after feed consumption, and averaged about 0.10 mol H2/mol CH4. Higher H2 emissions (mol/kg DM intake) were recorded in steers fed the mixed diet. Higher CH4 emissions (mol/d and mol/kg DM intake) were recorded in steers fed the mixed diet (P< 0.001); the AAx steers produced more CH4 on a daily basis (mol/d, P< 0.05) but not on a DM intake basis (mol/kg DM intake). Archaea (P= 0.002) and protozoa (P< 0.001) were found to be more abundant and total bacteria (P< 0.001) less abundant (P< 0.001) on feeding the mixed diet. The relative abundance of Clostridium cluster IV was found to be greater (P< 0.001) and that of cluster XIVa (P= 0.025) lower on feeding the mixed diet. The relative abundance of Bacteroides plus Prevotella was greater (P= 0.018) and that of Clostridium cluster IV lower (P= 0.031) in the LIMx steers. There were no significant relationships between H2 emissions and microbial abundance. In conclusion, the rate of H2 production immediately after feeding may lead to transient overloading of methanogenic archaea capacity to use H2, resulting in peaks in H2 emissions from beef cattle. PMID- 24780127 TI - Arrhythmogenic right ventricular cardiomyopathy: contribution of different electrocardiographic techniques. AB - Arrhythmogenic right ventricular cardiomyopathy, also known as arrhythmogenic right ventricular dysplasia, is a condition in which myocardium is replaced by fibrous or fibrofatty tissue, predominantly in the right ventricle. It is clinically characterized by potentially lethal ventricular arrhythmias, and is a leading cause of sudden cardiac death. Its prevalence is not known exactly but is estimated at approximately 1:5000 in the adult population. Diagnosis can be on the basis of structural and functional alterations of the right ventricle, electrocardiographic abnormalities (including depolarization and repolarization alterations and ventricular arrhythmias) and family history. Diagnostic criteria facilitate the recognition and interpretation of non-specific clinical features of this disease. The authors present a case in which the diagnosis of arrhythmogenic right ventricular cardiomyopathy was prompted by the suspicion of right ventricular disease on transthoracic echocardiography. This was confirmed by detection of epsilon waves on analysis of the ECG, which generally go unnoticed but in this case were the key to the diagnosis. Their presence was also shown by non-conventional ECG techniques such as modified Fontaine ECG. The course of the disease culminated in the occurrence of ventricular tachycardia, which prompted placement of an implantable cardioverter-defibrillator. PMID- 24780125 TI - Secretion of bacterial lipoproteins: through the cytoplasmic membrane, the periplasm and beyond. AB - Bacterial lipoproteins are peripherally anchored membrane proteins that play a variety of roles in bacterial physiology and virulence in monoderm (single membrane-enveloped, e.g., gram-positive) and diderm (double membrane-enveloped, e.g., gram-negative) bacteria. After export of prolipoproteins through the cytoplasmic membrane, which occurs predominantly but not exclusively via the general secretory or Sec pathway, the proteins are lipid-modified at the cytoplasmic membrane in a multistep process that involves sequential modification of a cysteine residue and cleavage of the signal peptide by the signal II peptidase Lsp. In both monoderms and diderms, signal peptide processing is preceded by acylation with a diacylglycerol through preprolipoprotein diacylglycerol transferase (Lgt). In diderms but also some monoderms, lipoproteins are further modified with a third acyl chain through lipoprotein N acyl transferase (Lnt). Fully modified lipoproteins that are destined to be anchored in the inner leaflet of the outer membrane (OM) are selected, transported and inserted by the Lol (lipoprotein outer membrane localization) pathway machinery, which consists of the inner-membrane (IM) ABC transporter-like LolCDE complex, the periplasmic LolA chaperone and the OM LolB lipoprotein receptor. Retention of lipoproteins in the cytoplasmic membrane results from Lol avoidance signals that were originally described as the "+2 rule". Surface localization of lipoproteins in diderms is rare in most bacteria, with the exception of several spirochetal species. Type 2 (T2SS) and type 5 (T5SS) secretion systems are involved in secretion of specific surface lipoproteins of gamma-proteobacteria. In the model spirochete Borrelia burgdorferi, surface lipoprotein secretion does not follow established sorting rules, but remains dependent on N-terminal peptide sequences. Secretion through the outer membrane requires maintenance of lipoproteins in a translocation-competent unfolded conformation, likely through interaction with a periplasmic holding chaperone, which delivers the proteins to an outer membrane lipoprotein flippase. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey. PMID- 24780129 TI - Pheochromocytoma diagnosed after anticoagulation for atrial fibrillation ablation procedure: a giant in disguise. AB - Pheochromocytoma is a rare catecholamine-producing tumor, discovered incidentally in 50% of cases. We present the case of a 44-year-old male with a history of paroxysmal palpitations. Baseline ECG, transthoracic echocardiogram and ECG stress test showed no relevant alterations. Paroxysmal atrial fibrillation was detected on 24-hour Holter ECG. After antiarrhythmic therapy, the patient remained symptomatic, and was accordingly referred for electrophysiological study and atrial fibrillation ablation. Anticoagulation was initiated before the procedure. After ablation and still anticoagulated, he complained of hematospermia. The abdominal and pelvic imaging study showed a 10-cm left adrenal mass, predominantly cystic, compatible with pheochromocytoma, which was confirmed after biochemical tests (increased urine metanephrines and plasma catecholamines). Metaiodobenzylguanidine scintigraphy scanning confirmed localized disease in the adrenal gland, excluding other uptake foci. Following appropriate preoperative management, surgical resection of the giant mass was performed successfully and without complications. PMID- 24780128 TI - Myocardial and anti-inflammatory effects of chronic bosentan therapy in monocrotaline-induced pulmonary hypertension. AB - INTRODUCTION AND OBJECTIVES: Endothelin-1 antagonists are increasingly used in the treatment of pulmonary hypertension despite the lack of knowledge of their myocardial and systemic effects. We assessed the right ventricular myocardial and systemic effects of endothelin-1 antagonists in monocrotaline-induced pulmonary hypertension. METHODS: Male Wistar rats (180-200 g, n=57) randomly received 60 mg/kg monocrotaline or vehicle subcutaneously. Two days later, bosentan was randomly started (300 mg/kg/day) by oral route in a subgroup of monocrotaline injected rats, while the other monocrotaline-injected and control rats received vehicle. At 25-30 days, invasive hemodynamic assessment was performed under anesthesia, arterial blood samples were collected for gas analysis and plasma was extracted for quantification of endothelin-1, cytokines, nitrates and 6-keto prostaglandin F1alpha. Right ventricular myocardium was collected for assessment of cyclooxygenase and nitric oxide synthase activity and gene expression. RESULTS: The monocrotaline group developed pulmonary hypertension, low cardiac output, right ventricular hypertrophy and dilation, changes in gene expression and inflammatory activation that were attenuated in the group treated with bosentan. From a functional point of view, this group had improved right ventricular function and preserved ventriculo-vascular coupling, without deterioration in arterial gas parameters or systemic hypotension. In molecular terms, they showed reduced endothelin-1 and cytokine levels, decreased right ventricular inducible nitric oxide synthase and cyclooxygenase-2 activity and increased nitrate plasma levels compared with the non-treated group. CONCLUSIONS: In this study we demonstrate that besides attenuating pulmonary hypertension, bosentan has beneficial hemodynamic, myocardial and anti-inflammatory effects. PMID- 24780130 TI - A spiderweb in the heart. PMID- 24780131 TI - Thin and open vessel windows for intra-vital fluorescence imaging of murine cochlear blood flow. AB - Normal microvessel structure and function in the cochlea is essential for maintaining the ionic and metabolic homeostasis required for hearing function. Abnormal cochlear microcirculation has long been considered an etiologic factor in hearing disorders. A better understanding of cochlear blood flow (CoBF) will enable more effective amelioration of hearing disorders that result from aberrant blood flow. However, establishing the direct relationship between CoBF and other cellular events in the lateral wall and response to physio-pathological stress remains a challenge due to the lack of feasible interrogation methods and difficulty in accessing the inner ear. Here we report on new methods for studying the CoBF in a mouse model using a thin or open vessel-window in combination with fluorescence intra-vital microscopy (IVM). An open vessel-window enables investigation of vascular cell biology and blood flow permeability, including pericyte (PC) contractility, bone marrow cell migration, and endothelial barrier leakage, in wild type and fluorescent protein-labeled transgenic mouse models with high spatial and temporal resolution. Alternatively, the thin vessel-window method minimizes disruption of the homeostatic balance in the lateral wall and enables study CoBF under relatively intact physiological conditions. A thin vessel-window method can also be used for time-based studies of physiological and pathological processes. Although the small size of the mouse cochlea makes surgery difficult, the methods are sufficiently developed for studying the structural and functional changes in CoBF under normal and pathological conditions. PMID- 24780132 TI - Association between glaucoma and sleep apnea in a large French multicenter prospective cohort. AB - OBJECTIVE: Several reports suggest that glaucoma may be linked to obstructive sleep apnea (OSA). Herein, we investigated this hypothesis in the largest reported sample to date. METHODS: Data were from the French multicenter prospective cohort study including OSA-suspected patients from private practice, general and teaching hospitals. Demographics, history, comorbidities and sleep studies from patients aged >50 years were analyzed. Univariate and multivariate logistic regression were used to predict the odds ratio of prevalent glaucoma depending on sleep apnea status and other potential anthropometric, metabolic, cardiovascular and respiratory confounders. RESULTS: A total of 9580 patients aged >50 years were included. Among these patients, 6754 had sleep apnea and 330 had glaucoma. Glaucoma prevalence was 3.55% in patients with OSA and 3.14% in patients without OSA. OSA diagnosis did not significantly influence the risk of glaucoma in univariate analysis (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.87-1.47). The variables significantly influencing the odds of glaucoma with multivariate regression were age >61.4 years (OR, 1.55; 95% CI, 1.23-1.95), body mass index <30 kg/m2 (OR, 1.58; 95% CI, 1.26-1.99), female gender (OR, 1.40; 95% CI, 1.11-1.78), arterial hypertension (OR, 1.32; 95% CI, 1.05-1.67), high triglyceride levels (OR, 2.03; 95% CI, 1.43-2.88) and thyroid dysfunction (OR, 1.52; 95% CI, 1.09-2.11). CONCLUSIONS: When confounders are taken into account, patients with OSA do not have higher odds of glaucoma compared with patients who do not have OSA in a large multicenter prospective cohort. PMID- 24780133 TI - Delayed diagnosis of narcolepsy: characterization and impact. AB - Narcolepsy, a chronic neurologic condition resulting from dysregulation of the sleep-wake cycle, usually has an onset at an early age. However, a long delay until diagnosis has been consistently reported in the literature across countries and several publications have focused on characterizing this delay. Most studies report a mean delay to diagnosis of up to 15 years, with individual cases of >60 years, although a trend over time toward a shorter diagnostic delay has been suggested. While variables associated with this delay have been identified, a lack of symptom recognition resulting in misdiagnosis prior to reaching the narcolepsy diagnosis is the likely underlying reason. This lack of symptom recognition is especially relevant considering the high comorbidity burden that has been shown in patients with narcolepsy as some disorders manifest with symptoms that overlap with narcolepsy. A consequence of delayed diagnosis is delayed treatment, which affects the burden of disease. Substantial detrimental effects on health-care resource utilization, employment, and quality of life have been described after narcolepsy onset and prior to the diagnosis of narcolepsy. This review highlights the importance of closing the diagnostic gap by expanding awareness of narcolepsy and its symptoms. PMID- 24780134 TI - Rapid eye movement sleep behaviour disorder in young- and older-onset Parkinson disease: a questionnaire-based study. AB - BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) is common in Parkinson disease (PD). OBJECTIVES: To determine the frequency of clinically probable RBD (cpRBD) in young-onset (21 to < or =40 years; YOPD) and older-onset PD (>40 years; OOPD) and characterize its pattern. METHODS: A total of 156 patients with PD (YOPD-51, OOPD-105) were clinically examined and the presence of RBD was diagnosed using the minimal criteria for diagnosis of RBD (International Classification of Sleep Disorders, ICSD-1). RBD screening questionnaire based on the minimal criteria was used. The bed-partners were also interviewed with Mayo sleep questionnaire. Other scales included Unified Parkinson Disease Rating Scale part III (UPDRS III), Hoehn & Yahr stage, Mini Mental Status Examination, Pittsburgh Sleep Quality Index, Parkinson Disease Sleep Scale, Epworth Sleep Scale, Hamilton Anxiety Rating Scale and Hamilton Depression Rating Scale. RESULTS: cpRBD was diagnosed in 30 (19.2%) patients, majority being OOPD rather than YOPD (86.7% vs. 13.3%; P=0.01). The frequency of RBD was significantly higher (P=0.016) in OOPD (24.8%) compared to those with YOPD (7.8%). Most often (72.4%) RBD occurred after the onset of parkinsonian symptoms. RBD was independently associated with higher global PSQI scores, total ESS scores and total PDSS scores after adjusting for the effects of age, gender, Hoehn & Yahr stage and duration of illness. CONCLUSIONS: Patients with RBD were older with later-onset motor symptoms, a more advanced stage, poorer sleep quality, and more frequent daytime sleepiness. Older-onset PD had a higher frequency of RBD than young-onset PD. PMID- 24780135 TI - Disturbed dreaming during the third trimester of pregnancy. AB - OBJECTIVE: The majority of women develop sleep impairments during pregnancy, but alterations in dream experiences remain poorly understood. This study aimed to assess prospectively and comparatively the recall of dreaming and of disturbed dreaming in late pregnancy. METHODS: Fifty-seven nulliparous, third-trimester pregnant women (mean age+/-SD, 28.7+/-4.06 years) and 59 non-pregnant controls (mean age+/-SD, 26.8+/-4.21 years) completed demographics and psychological questionnaires. A 14-day prospective home log assessed sleep and dream characteristics and the Sleep Disorders Questionnaire measured retrospective dream and disturbed dream recall. RESULTS: Even though pregnant and non-pregnant women showed similar prospective dream recall (P=0.47), pregnant women reported prospectively more bad dreams (P=0.004). More pregnant women (21%) than non pregnant women (7%) reported a nightmare incidence exceeding moderately severe pathology (>1/week) (P=0.03). Pregnant women also reported overall lower sleep quality (P=0.007) and more night awakenings (P=0.003). Higher prospective recall of bad dreams (r = -0.40, P=0.002) and nightmares (r = -0.32, P=0.001) both correlated with lower sleep quality in pregnant women. CONCLUSIONS: Late pregnancy is a period of markedly increased dysphoric dream imagery that may be a major contributor to impaired sleep at this time. Further polysomnographic assessments of pregnant women are needed to clarify relationships between sleep and disturbed dream production in this population. PMID- 24780136 TI - The structured diagnostic interview for sleep patterns and disorders: rationale and initial evaluation. AB - OBJECTIVES: We aimed to describe and report the initial validity of a newly developed structured interview for sleep disorders (Diagnostic Interview for Sleep Patterns and Disorders [DISP]) administered by trained lay interviewers. METHODS: A total of 225 patients with various sleep disorders were recruited from two nationally recognized sleep centers in the United States. The International Classification of Sleep Disorders, second edition (ICSD-2) criteria, were used to classify sleep disorders (e.g., delayed sleep phase disorder, hypersomnia, narcolepsy with cataplexy [NC], restless legs syndrome [RLS], periodic limb movement disorder [PLMD], insomnia, rapid eye movement sleep behavior disorder [RBD], and obstructive sleep apnea [OSA]). Interview diagnoses were compared with final diagnoses by sleep specialists (reference diagnosis based on clinical history, examination, and polysomnography [PSG] when indicated). RESULTS: DISP diagnoses had fair to substantial concordance with clinician diagnoses for various sleep disorders, with area under the receiver operator characteristic curves (AUC) ranging from 0.65 to 0.84. Participants classified by the clinician as having a sleep disorder were moderately well-detected (sensitivity ranging from 0.50 for RBD disorder to 0.87 for insomnia). Substantial specificity (>0.8) also was seen for five of the eight sleep disorders (i.e., delayed sleep phase, hypersomnia, NC, PLMD, and RBD). Interviews were more likely than clinicians to detect disorders secondary to the primary sleep problem. CONCLUSIONS: The DISP provides an important tool for the detection of a wide range of sleep disorders in clinical settings and is particularly valuable in the detection of secondary disorders that were not the primary referral diagnosis. PMID- 24780137 TI - Smoking effect on chemokines of the human chronic periodontitis. AB - AIM: Evaluate the effects of smoking on chemokines of the human chronic periodontitis (CP). MATERIALS AND METHODS: Gingival samples were obtained from 23 smokers (S) and 20 non-smokers (NS) diagnosed with CP. Periodontal examination was performed. The CCL2, CCL3, CCL5, CCL19, CCL20, and CXCL8 chemokine levels were measured in gingival tissues using enzyme-linked immunosorbent assay. Chemokines were compared between S and NS, and were correlated with the number of cigarettes per day (C/day) and time of the smoking habit in years (SH/years). RESULTS: CCL3 and CXCL8 of S were significantly smaller than that found in NS subjects, whereas the CCL5 levels increased in the S group. Negative correlations could be observed between CCL19 levels and SH/year. CONCLUSION: Smoking suppresses the immune response which may contribute to an increased susceptibility to periodontal disease in smokers. PMID- 24780138 TI - Insights about echinostomiasis by paleomolecular diagnosis. AB - Echinostomiasis is a zoonosis caused by intestinal trematodes and transmitted by the ingestion of mollusks, crustaceans, fish, amphibians, and reptiles, either raw or poorly cooked. Today human infection is endemic in Southeast Asia and the Far East, but has been reported more recently in other regions of the world. Interestingly eggs identified as Echinostoma sp. were found in coprolites from a mummified body human in Brazil, dated 560 +/- 40 BP (before present). However, the specific diagnosis based on morphology of the eggs has not been resolved at the species level. As a follow-up to the previous finding, the current study now aims to standardize the methodology for molecular diagnosis and apply it to the coprolite, using current Echinostoma paraensei-positive feces as the reference, and also the same fecal material dried in a stove as an experimental coprolite model. Isolated eggs of E. paraensei and adult worm were included to verify the sensibility and as positive control, respectively. An adult worm of E. luisreyi was used for comparison. PCR using primers in-house for ITS1 region (126 bp) and cox1 (123 bp) of Echinostoma spp. and subsequent nucleotide sequencing were performed. This is the first molecular paleoparasitological diagnosis for echinostomiasis. The methodology was able to amplify specific DNA fragments for the genus Echinostoma sp. in all samples: adult worm, feces, and a single egg of the parasite, in both the experimental coprolite and archaeological sample. Additionally we observed that ancient DNA can also be retrieved without rehydrating the material. The nucleotide sequences from E. paraensei and E. luisreyi are very similar in the fragment analyzed that difficult the differentiation these species, but DNA sequence analysis recovered in the parasite found in the mummy showed more similarity with the species E. paraensei. PMID- 24780139 TI - Molecular and phylogenetic characterizations of an Eimeria krijgsmanni Yakimoff & Gouseff, 1938 (Apicomplexa: Eimeriidae) mouse intestinal protozoan parasite by partial 18S ribosomal RNA gene sequence analysis. AB - Previously, we characterized an undocumented strain of Eimeria krijgsmanni by morphological and biological features. Here, we present a detailed molecular phylogenetic analysis of this organism. Namely, 18S ribosomal RNA gene (rDNA) sequences of E. krijgsmanni were analyzed to incorporate this species into a comprehensive Eimeria phylogeny. As a result, partial 18S rDNA sequence from E. krijgsmanni was successfully determined, and two different types, Type A and Type B, that differed by 1 base pair were identified. E. krijgsmanni was originally isolated from a single oocyst, and thus the result show that the two types might have allelic sequence heterogeneity in the 18S rDNA. Based on phylogenetic analyses, the two types of E. krijgsmanni 18S rDNA formed one of two clades among murine Eimeria spp.; these Eimeria clades reflected morphological similarity among the Eimeria spp. This is the third molecular phylogenetic characterization of a murine Eimeria spp. in addition to E. falciformis and E. papillata. PMID- 24780140 TI - Seroprevalence of Toxoplasma gondii infection in cattle, horses, pigs and chickens in Japan. AB - The presence of antibodies to Toxoplasma gondii in livestock and poultry was investigated by latex agglutination tests; samples that agglutinated at dilutions of 1:64 or higher were regarded as positive. Sera were collected from fattening beef cattle (102 Japanese black, 105 crossbreeds and 114 castrated Holstein), culled dairy cattle (101 Holstein), 100 horses, 115 fattening pigs and 235 chickens (163 free-range and 72 broilers) at abattoirs in Gifu Prefecture, Japan, from August 2012 to August 2013. Antibodies to T. gondii were found in 7.3% (31/422) in cattle, 5.2% (8/155) in pigs, but not in horses or chickens. These results suggest that toxoplasmosis may be transmitted to humans via consumption of T. gondii-infected raw beef in Japan. PMID- 24780141 TI - First detection of Echinococcus multilocularis infection in two species of nonhuman primates raised in a zoo: a fatal case in Cercopithecus diana and a strongly suspected case of spontaneous recovery in Macaca nigra. AB - The causative parasite of alveolar echinococcosis, Echinococcus multilocularis, maintains its life cycle between red foxes (Vulpes vulples, the definitive hosts) and voles (the intermediate hosts) in Hokkaido, Japan. Primates, including humans, and some other mammal species can be infected by the accidental ingestion of eggs in the feces of red foxes. In August 2011, a 6-year-old zoo-raised female Diana monkey (Cercopithecus diana) died from alveolar echinococcosis. E. multilocularis infection was confirmed by histopathological examination and detection of the E. multilocularis DNA by polymerase chain reaction (PCR). A field survey in the zoo showed that fox intrusion was common, and serodiagnosis of various nonhuman primates using western blotting detected a case of a 14-year old female Celebes crested macaque (Macaca nigra) that was weakly positive for E. multilocularis. Computed tomography revealed only one small calcified lesion (approximately 8mm) in the macaque's liver, and both western blotting and enzyme linked immunosorbent assay (ELISA) showed a gradual decline of antibody titer. These findings strongly suggest that the animal had recovered spontaneously. Until this study, spontaneous recovery from E. multilocularis infection in a nonhuman primate had never been reported. PMID- 24780142 TI - Mass trapping Popillia quadriguttata using Popillia japonica (Coleoptera: Scarabaeidae) pheromone and floral lures in northeastern China. AB - Popillia quadriguttata (F.) has caused extensive damage to ?20 families and 25 species of plants in Asia, especially in China and Korea. Adult feeding causes serious damage to soybean leaves, and larvae develop on the roots of soybean, turf, and horticultural crops. As Japanese beetle (Popillia japonica Newman) lures have been used for trapping P. quadriguttata in a previous study, mass trapping this pest with various densities of the Japanese beetle pheromone, Japonilure, and floral lure, alone and in combination, were carried out during 2012-2013 in a northeastern China soybean field. Mass trapping in 2012 with Japonilure gave the best results with 72 and 75% adult and larval reduction, respectively. In 2013, mass trapping (30 traps per hectare) with Japonilure, floral lure, or the combination resulted in a 93, 70, and 74% reduction of adults trapped, and a 90, 77, and 93% reduction of overwintering larvae, respectively. In addition, field tests showed that almost twice as many beetles approached the lure combination compared with the floral lure alone, and the pheromone residual was ?80% of the initial dosage after 30 d. Because reduction of overwintering larvae is the most critical parameter indicating treatment efficacy, the results here indicate that the lure or lure combinations can be recommended for use by Chinese soybean farmers. PMID- 24780143 TI - Sexual dimorphism in oxytocin responses to health perception and disgust, with implications for theories on pathogen detection. AB - In response to a recent hypothesis that the neuropeptide oxytocin might be involved in human pathogen avoidance mechanisms, we report the results of a study in which we investigate the effect of intranasal oxytocin on two behaviors serving as proxies for pathogen detection. Participants received either oxytocin or a placebo and were asked to evaluate (1) the health of Caucasian male computer generated pictures that varied in facial redness (an indicator of hemoglobin perfusion) and (2) a series of pictures depicting disgusting scenarios. Men, but not women, evaluated all faces, regardless of color, as less healthy when given oxytocin compared to a placebo. Women, on the other hand, expressed decreased disgust when given oxytocin compared to a placebo. These results suggest that intranasal oxytocin administration does not facilitate pathogen detection based on visual cues, but instead reveal clear sex differences in the perception of health and sickness cues. PMID- 24780144 TI - Regulatory mechanisms for the development of the migratory phenotype: roles for photoperiod and the gonad. AB - This article is part of a Special Issue "Energy Balance". Male white-crowned sparrows, Zonotrichia leucophrys gambelii, were studied to investigate roles of natural day length and the testes in regulating development and expression of the vernal migration phenotype. Previous work suggested that a pulse of androgen during winter months followed by the vernal increase in photoperiod promotes fueling (fat deposition) to support long distance flight; however, other traits required for successful migration remain untested. To investigate these points, birds were captured on their wintering grounds and castrated prior to winter solstice following Mattocks (1976). A subset of the castrates received 8mm Silastic implants of testosterone (T-castrates) and others blank implants (Blank castrates) for 16 days in February. Shams were surgical controls. Migratory traits measured were as follows: 24h locomotor activity, prenuptial molt, body mass, fat score, flight muscle profile, cloacal protuberance (CPL) and plasma androgens measured over 28 weeks divided into 3 experimental periods (pre implant, implant, and post-implant). Under short day lengths, castration increased diurnal locomotor activity over Shams. Testosterone implants temporarily enhanced CPL, plasma androgens and flight muscle enlargement, but failed to induce migratory restlessness. Whereas all groups exhibited seasonal increases in mass, fat score and muscle profile, only Shams showed timely onset and completion of prenuptial molt and migratory restlessness. Thus, for castrated males exposed to naturally increasing day lengths, the organizational effects of a transient testosterone surge were not sufficient to actuate a timely spring molt and migratory behavior. A fully functional testis that can organize central processes is required for the entire expression of the spring migratory phenotype. PMID- 24780146 TI - Sleep patterns in children with and without autism spectrum disorders: developmental comparisons. AB - The present study examined age-related changes in the sleep of children with autism spectrum disorders (ASD) compared to age-related changes in the sleep of typically developing (TD) children. Participants were 108 mothers of children with ASD and 108 mothers of TD children. Participants completed a questionnaire on children's overall sleep quality that also tapped specific sleep-domains (i.e., bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night wakings, parasomnias, disordered breathing, daytime sleepiness). Results confirm significantly poorer sleep quantity and quality in children with ASD, particularly children age 6-9 years. Unlike TD children, the sleep problems of children with ASD were unlikely to diminish with age. Our findings suggest that it is important to exam specific domains of sleep as well as overall sleep patterns. Finding of significant age-related interactions suggests that the practice of combining children from wide age-ranges into a single category obfuscates potentially important developmental differences. PMID- 24780145 TI - Evaluation of reference genes for quantitative real-time PCR in the brain, pituitary, and gonads of songbirds. AB - Quantitative real-time PCR (qPCR) is becoming a popular tool for the quantification of gene expression in the brain and endocrine tissues of songbirds. Accurate analysis of qPCR data relies on the selection of appropriate reference genes for normalization, yet few papers on songbirds contain evidence of reference gene validation. Here, we evaluated the expression of ten potential reference genes (18S, ACTB, GAPDH, HMBS, HPRT, PPIA, RPL4, RPL32, TFRC, and UBC) in brain, pituitary, ovary, and testis in two species of songbirds: zebra finch and white-throated sparrow. We used two algorithms, geNorm and NormFinder, to assess the stability of these reference genes in our samples. We found that the suitability of some of the most popular reference genes for target gene normalization in mammals, such as 18S, depended highly on tissue type. Thus, they are not the best choices for brain and gonad in these songbirds. In contrast, we identified alternative genes, such as HPRT, RPL4 and PPIA, that were highly stable in brain, pituitary, and gonad in these species. Our results suggest that the validation of reference genes in mammals does not necessarily extrapolate to other taxonomic groups. For researchers wishing to identify and evaluate suitable reference genes for qPCR in songbirds, our results should serve as a starting point and should help increase the power and utility of songbird models in behavioral neuroendocrinology. PMID- 24780148 TI - A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. AB - The muscular dystrophies are a broad group of hereditary muscle diseases with variable severity. Population-based prevalence estimates have been reported but pooled estimates are not available. We performed a systematic review of worldwide population-based studies reporting muscular dystrophies prevalence and/or incidence using MEDLINE and EMBASE databases. The search strategy included key terms related to muscular dystrophies, incidence, prevalence and epidemiology. Two reviewers independently reviewed all abstracts, full text articles and abstracted data using standardized forms. Pooling of prevalence estimates was performed using random effect models. 1104 abstracts and 167 full text articles were reviewed. Thirty-one studies met all eligibility criteria and were included in the final analysis. The studies differed widely in their approaches to case ascertainment, resulting in significant methodological heterogeneity and varied data quality. The pooled prevalence of DMD and BMD was 4.78 (95% CI 1.94-11.81) and 1.53 (95% CI 0.26-8.94) per 100,000 males respectively. The incidence of DMD ranged from 10.71 to 27.78 per 100,000. This is the first meta-analysis of worldwide prevalence estimates for muscular dystrophies. There is a need for more epidemiological studies addressing global estimates on incidence and prevalence of muscular dystrophies, utilizing standardized diagnostic criteria as well as multiple sources of case ascertainment. PMID- 24780149 TI - Influence of a two-year steroid treatment on body composition as measured by dual X-ray absorptiometry in boys with Duchenne muscular dystrophy. AB - Steroids are nowadays routinely used as a long-term treatment in Duchenne muscular dystrophy (DMD). Their effects on body composition were assessed using dual X-ray absorptiometry. The study followed over 2 years 29 genetically confirmed DMD patients: 21 in the steroid-treated group and 8 in the steroid naive group. After 2 years of steroid treatment, the lean tissue mass values increased significantly (p<0.0001), the percentage of body fat mass remained practically constant (p=0.94) in comparison with the initial visit. In the steroid-naive patients, there were no significant increases in the lean tissue mass but deterioration in body composition confirmed by a significant increase in the percentage of body fat mass. Besides, significant negative correlations were found between the percentage of body fat mass and the MFM total score (R=-0.79, n=76, p<0.0001). A 2-year steroid treatment improves significantly body composition of boys with DMD through a significant increase in lean tissue mass. We suggest that a thorough check of body composition should be carried out before steroid treatment discontinuation in case of overweight gain. PMID- 24780147 TI - Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder. AB - The aim of the present study was to evaluate the association of dopaminergic gene variants with emotion dysregulation (EMD) and attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3'-UTR 9/10 VNTR, rs27072 in the 3'-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on a priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. A sample of 110 children with ASD was assessed with a rigorously validated DSM-IV-referenced rating scale. Global EMD severity (parents' ratings) was associated with DAT1 intron8 (etap(2)=.063) and rs2283265 (etap(2)=.044). Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety (etap(2)=.065) and depression (etap(2)=.059), and for DRD2 rs2283265, depression (etap(2)=.053). DRD2 rs2283265 was associated with teachers' global ratings of ADHD (etap(2)=.052). DAT1 intron8 was associated with parent-rated hyperactivity (etap(2)=.045) and both DAT1 9/10 VNTR (etap(2)=.105) and DRD2 rs2283265 (etap(2)=.069) were associated with teacher-rated inattention. These findings suggest that dopaminergic gene polymorphisms may modulate EMD and ADHD symptoms in children with ASD but require replication with larger independent samples. PMID- 24780150 TI - Detachment and flow cytometric quantification of seagrass-associated bacteria. AB - A new protocol was developed to detach bacteria from seagrass tissue and subsequently enumerate cells using flow cytometry (FCM). A method involving addition of the surfactant Tween 80 and vortexing resulted in maximum detachment efficiency of seagrass attached bacteria, providing a robust protocol for precisely enumerating seagrass-associated bacteria with FCM. Using this approach we detected cell concentrations between 2.0*10(5) and 8.0*10(6)cells mg(-1) DW tissue. PMID- 24780151 TI - Single-nucleotide polymorphism PCR for the detection of Mycoplasma pneumoniae and determination of macrolide resistance in respiratory samples. AB - The aim of this study was to develop a single-nucleotide polymorphism (SNP) PCR assay to be performed directly on respiratory samples for the simultaneous detection of Mycoplasma pneumoniae and its 23S rRNA gene mutations, which are responsible for macrolide resistance. For multiplex SNP PCR, two outer primers for amplification of the 23S rRNA gene and two mutant-specific primers for the discrimination of single base changes were designed. A total of 73M. pneumoniae positive samples and 100M. pneumoniae-negative samples were analyzed using this assay. By SNP PCR, we detected two mutations conferring high-level macrolide resistance in 22 samples (A2063G from 20 and A2064G from 2 samples); these results are identical to those produced by the 23S rRNA gene sequencing of M. pneumoniae-positive samples. Thus, this assay can be used as a practical method for the simultaneous detection of M. pneumoniae and mutations associated with macrolide resistance directly from respiratory samples. PMID- 24780152 TI - Molecular biodiversity and recent analytical developments: a marriage of convenience. AB - Nature has developed an outstanding bio- and molecular diversity as a result of billion years of evolution resulting in a tremendous number of secondary metabolites. Among them a small part has been so far explored for discovery of lead compounds. The lead discovery from natural sources is a technological challenge for the pharmaceutical industry. The bio- and molecular diversity in plants, animals and microorganisms, as sources for new leads, and the remarkable recent developments in NMR, mass spectrometry coupled with advanced separation techniques (LC and GC), high throughput screening, and structure-based virtual screening are discussed in this article. PMID- 24780153 TI - Advances in the biotechnological glycosylation of valuable flavonoids. AB - The natural flavonoids, especially their glycosides, are the most abundant polyphenols in foods and have diverse bioactivities. The biotransformation of flavonoid aglycones into their glycosides is vital in flavonoid biosynthesis. The main biological strategies that have been used to achieve flavonoid glycosylation in the laboratory involve metabolic pathway engineering and microbial biotransformation. In this review, we summarize the existing knowledge on the production and biotransformation of flavonoid glycosides using biotechnology, as well as the impact of glycosylation on flavonoid bioactivity. Uridine diphosphate glycosyltransferases play key roles in decorating flavonoids with sugars. Modern metabolic engineering and proteomic tools have been used in an integrated fashion to generate numerous structurally diverse flavonoid glycosides. In vitro, enzymatic glycosylation tends to preferentially generate flavonoid 3- and 7-O glucosides; microorganisms typically convert flavonoids into their 7-O-glycosides and will produce 3-O-glycosides if supplied with flavonoid substrates having a hydroxyl group at the C-3 position. In general, O-glycosylation reduces flavonoid bioactivity. However, C-glycosylation can enhance some of the benefits of flavonoids on human health, including their antioxidant and anti-diabetic potential. PMID- 24780154 TI - Do furanic and phenolic compounds of lignocellulosic and algae biomass hydrolyzate inhibit anaerobic mixed cultures? A comprehensive review. AB - Nowadays there is a growing interest on the use of both lignocellulosic and algae biomass to produce biofuels (i.e. biohydrogen, ethanol and methane), as future alternatives to fossil fuels. In this purpose, thermal and thermo-chemical pretreatments have been widely investigated to overcome the natural physico chemical barriers of such biomass and to enhance biofuel production from lignocellulosic residues and, more recently, marine biomass (i.e. macro and microalgae). However, the pretreatment technologies lead not only to the conversion of carbohydrate polymers (ie cellulose, hemicelluloses, starch, agar) to soluble monomeric sugar (ie glucose, xylose, arabinose, galactose), but also the generation of various by-products (i.e. furfural and 5-HMF). In the case of lignocellulosic residues, part of the lignin can also be degraded in lignin derived by-products, mainly composed of phenolic compounds. Although the negative impact of such by-products on ethanol production has been widely described in literature, studies on their impact on biohydrogen and methane production operated with mixed cultures are still very limited. This review aims to summarise and discuss literature data on the impact of pre-treatment by-products on H2-producing dark fermentation and anaerobic digestion processes when using mixed cultures as inoculum. As a summary, furanic (5-HMF, furfural) and phenolic compounds were found to be stronger inhibitors of the microbial dark fermentation than the full anaerobic digestion process. Such observations can be explained by differences in process parameters: anaerobic digestion is performed with more complex mixed cultures, lower substrate/inoculum and by-products/inoculum ratios and longer batch incubation times than dark fermentation. Finally, it has been reported that, during dark fermentation process, the presence of by-products could lead to a metabolic shift from H2-producing pathways (i.e. acetate and butyrate) to non-H2-producing pathways (i.e. lactate, ethanol and propionate) and whatever the metabolic route, metabolites can be all further converted into methane, but at different rates. PMID- 24780155 TI - The transport and mediation mechanisms of the common sugars in Escherichia coli. AB - Escherichia coli can uptake and utilize many common natural sugars to form biomass or valuable target bio-products. Carbon catabolite repression (CCR) will occur and hamper the efficient production of bio-products if E. coli strains are cultivated in a mixture of sugars containing some preferred sugar, such as glucose. Understanding the transport and metabolism mechanisms of the common and inexpensive sugars in E. coli is important for further improving the efficiency of sugar bioconversion and for reducing industrial fermentation costs using the methods of metabolic engineering, synthetic biology and systems biology. In this review, the transport and mediation mechanisms of glucose, fructose, sucrose, xylose and arabinose are discussed and summarized, and the hierarchical utilization principles of these sugars are elucidated. PMID- 24780156 TI - Yarrowia lipolytica and pollutants: Interactions and applications. AB - Yarrowia lipolytica is a dimorphic, non-pathogenic, ascomycetous yeast species with distinctive physiological features and biochemical characteristics that are significant in environment-related matters. Strains naturally present in soils, sea water, sediments and waste waters have inherent abilities to degrade hydrocarbons such as alkanes (short and medium chain) and aromatic compounds (biphenyl and dibenzofuran). With the application of slow release fertilizers, design of immobilization techniques and development of microbial consortia, scale up studies and in situ applications have been possible. In general, hydrocarbon uptake in this yeast is mediated by attachment to large droplets (via hydrophobic cell surfaces) or is aided by surfactants and emulsifiers. Subsequently, the internalized hydrocarbons are degraded by relevant enzymes innately present in the yeast. Some wild-type or recombinant strains also detoxify nitroaromatic (2,4,6-trinitrotoluene), halogenated (chlorinated and brominated hydrocarbons) and organophosphate (methyl parathion) compounds. The yeast can tolerate some metals and detoxify them via different biomolecules. The biomass (unmodified, in combination with sludge, magnetically-modified and in the biofilm form) has been employed in the biosorption of hexavalent chromium ions from aqueous solutions. Yeast cells have also been applied in protocols related to nanoparticle synthesis. The treatment of oily and solid wastes with this yeast reduces chemical oxygen demand or value-added products (single cell oil, single cell protein, surfactants, organic acids and polyalcohols) are obtained. On account of all these features, the microorganism has established a place for itself and is of considerable value in environment-related applications. PMID- 24780157 TI - Engineered whole-cell biocatalyst-based detoxification and detection of neurotoxic organophosphate compounds. AB - The development of efficient tools is required for the eco-friendly detoxification and effective detection of neurotoxic organophosphates (OPs). Although enzymes have received significant attention as biocatalysts because of their high specific activity, the uneconomic and labor-intensive processes of enzyme production and purification make their broad use in practical applications difficult. Because whole-cell systems offer several advantages compared with free enzymes, including high stability, a reduced purification requirement, and low preparation cost, they have been suggested as promising biocatalysts for the detoxification and detection of OPs. To develop efficient whole-cell biocatalysts with enhanced activity and a broad spectrum of substrate specificity, several factors have been considered, namely the selected strains, the chosen OP hydrolyzing enzymes, where enzymes are localized in a cell, and which enhancer will assist the expression, function, and folding of the enzyme. In this article, we review the current investigative progress in the development of engineered whole-cell biocatalysts with excellent OP-hydrolyzing activity, a broad spectrum of substrate specificity, and outstanding stability for the detoxification and detection of OPs. PMID- 24780158 TI - Does host immunity influence helminth egg hatchability in the environment? AB - Transmission success for helminths with free-living stages depends on the ability of eggs and larvae to develop and survive once in the environment. While environmental conditions are often suggested to influence egg phenology and hatching rate, immunity against parasite eggs might also play a role. We examined this hypothesis using the gastrointestinal helminths Trichostrongylus retortaeformis and Graphidium strigosum, two common infections of the European rabbit. Changes in egg hatching rate and volume were examined in relation to specific antibodies in the serum and bound to eggshells, using eggs shed in host faeces over a 15-week period. Hatching rate was consistently higher for T. retortaeformis than G. strigosum and no changes were observed between weeks. Egg volume increased for G. strigosum but decreased for T. retortaeformis. We did find evidence of egg-specific antibody responses and fewer antibodies were bound to eggs of T. retortaeformis compared to G. strigosum. Little to no association was found between antibodies and hatchability, or volume, for both helminths. We suggest that host antibodies play a relatively minor role in the egg hatching rate of these gastrointestinal helminths. PMID- 24780159 TI - Optimal second order sliding mode control for nonlinear uncertain systems. AB - In this paper, a chattering free optimal second order sliding mode control (OSOSMC) method is proposed to stabilize nonlinear systems affected by uncertainties. The nonlinear optimal control strategy is based on the control Lyapunov function (CLF). For ensuring robustness of the optimal controller in the presence of parametric uncertainty and external disturbances, a sliding mode control scheme is realized by combining an integral and a terminal sliding surface. The resulting second order sliding mode can effectively reduce chattering in the control input. Simulation results confirm the supremacy of the proposed optimal second order sliding mode control over some existing sliding mode controllers in controlling nonlinear systems affected by uncertainty. PMID- 24780160 TI - GPI based velocity/force observer design for robot manipulators. AB - In many applications involving a robot in contact with a surface it is important to control the interaction between the manipulator and its environment, usually by employing force sensors. However, sometimes it is desirable to remove them due to a variety of reasons, e.g. high costs, noisy measurements and a narrow bandwidth. To overcome these drawbacks, in this work it is proposed as a velocity/force observer based on the Generalized Proportional Integral (GPI) technique. Joint velocities and contact forces are estimated with only position measurements and then used in a force/position control scheme. Ultimate boundedness of the observation errors is formally proven and an arbitrarily small ultimate bound is then achieved. Simulation results are used to validate the proposed approach. PMID- 24780161 TI - Infections with multiple Cryptosporidium species and new genetic variants in young dairy calves on a farm located within a drinking water catchment area in New Zealand. AB - Several Cryptosporidium species are known to infect cattle. However, the occurrence of mixed infections with more than one species and the impact of this phenomenon on animal and human health are poorly understood. Therefore, to detect the presence of mixed Cryptosporidium infections, 15 immunofluorescence-positive specimens obtained from 6-week-old calves' faeces (n=60) on one dairy farm were subjected to PCR-sequencing at multiple loci. DNA sequences of three Cryptosporidium species: C. parvum (15/15), C. bovis (3/15) and C. andersoni (1/15), and two new genetic variants were identified. There was evidence of mixed infections in five specimens. C. parvum, C. bovis and C. andersoni sequences were detected together in one specimen, C. parvum and C. bovis in two specimens, and C. parvum and C. parvum-like variants in the remaining two specimens. Sequencing of gp60 amplicons identified the IIaA19G4R1 (8/15) and IIaA18G3R1 (4/15) C. parvum subgenotypes. This study provides evidence of endemic mixed infections with the three main Cryptosporidium species of cattle and new genetic variants, in calves at the transition age of six weeks. The results add to the body of evidence describing Cryptosporidium isolates as genetically heterogeneous populations, and highlight the need for iterative genotyping to explore their genetic makeup. PMID- 24780162 TI - New insights on metastrongyloid lungworms infecting cats of Sardinia, Italy. AB - In addition to the well-known Aelurostrongylus abstrusus (Strongylida: Angiostrongylidae), Troglostrongylus brevior (Strongylida: Crenosomatidae) has recently been diagnosed as a causative agent of bronco-pulmonary infections of cats in Spain and Italy. However, information concerning the impact of this species of lungworm on feline population is limited to a few case reports. From July 2011 to May 2013 an epidemiological survey was carried out on Sardinia island (Italy), where 107 individual faecal samples were examined by Baermann technique, and first-stage larvae were identified based on their morphology and characterization of molecular markers. The 29.9% (32/107) of cats examined were infested by broncho-pulmonary nematodes and, although A. abstrusus was the most frequently detected (n=27; 25.2%), larvae of T. brevior were also found (n=7; 6.5%). In addition, two cats (1.9%) were co-infested by both species. Overall metastrongyloid infection was higher in female cats (n=22; 38.6%) than in males (n=10; 20%) (chi(2)=4.39; p=0.036). The mean age of positive animals was 21.1 (+/ 29.8) months, being infected animals from 2 months to 10 years of age. Of the 32 animals that scored positive for lungworms only 6 (18.8%) displayed a respiratory condition associated with lungworm infestations. Biomolecular characterization confirmed the morphological diagnosis of A. abstrusus. Positive samples that were identified at genus level as Troglostrongylus spp. were molecularly characterized as T. brevior. This study represents the first epidemiological survey on metastrongyloid lungworms of domestic cats in Sardinia and the first report of T. brevior on this island. PMID- 24780163 TI - [Massive lipomatous hypertrophy of the interatrial septum: Diagnosis by real-time 3-dimensional transesophageal echocardiography. A case report and review of literature]. PMID- 24780164 TI - Infective endocarditis and caseous calcification of the mitral annulus: the odd couple. AB - Caseous calcification of the mitral annulus is an infrequent echocardiographic finding. The differential diagnosis includes other entities like tumors, abscess or thrombus. Both cardiac CT and cardiac MRI may be useful for its definitive diagnosis. PMID- 24780165 TI - Effect of the interplay between protein and surface on the properties of adsorbed protein layers. AB - Although protein adsorption to surface is a common phenomenon, investigation of the process is challenging due to the complexity of the interplay between external factors, protein and surface properties. Therefore experimental approaches have to measure the properties of adsorbed protein layers with high accuracy in order to achieve a comprehensive description of the process. To this end, we used a combination of two biosensing techniques, dual polarization interferometry and quartz crystal microbalance with dissipation. From this, we are able to extract surface coverage values, layer structural parameters, water content and viscoelastic properties to examine the properties of protein layers formed at the liquid/solid interface. Layer parameters were examined upon adsorption of proteins of varying size and structural properties, on surfaces with opposite polarity. We show that "soft" proteins such as unfolded alpha synuclein and high molecular weight albumin are highly influenced by the surface polarity, as they form a highly diffuse and hydrated layer on the hydrophilic silica surface as opposed to the denser, less hydrated layer formed on a hydrophobic methylated surface. These layer properties are a result of different orientations and packing of the proteins. By contrast, lysozyme is barely influenced by the surface polarity due to its intrinsic structural stability. Interestingly, we show that for a similar molecular weight, the unfolded alpha synuclein forms a layer with the highest percentage of solvation not related to surface coverage but resulting from the highest water content trapped within the protein. Together, these data reveal a trend in layer properties highlighting the importance of the interplay between protein and surface for the design of biomaterials. PMID- 24780166 TI - Immune responses to vaccines involving a combined antigen-nanoparticle mixture and nanoparticle-encapsulated antigen formulation. AB - Many physicochemical characteristics significantly influence the adjuvant effect of micro/nanoparticles; one critical factor is the kinetics of antigen exposure to the immune system by particle-adjuvanted vaccines. Here, we investigated how various antigen-nanoparticle formulations impacted antigen exposure to the immune system and the resultant antigen-specific immune responses. We formulated antigen with poly(lactic-co-glycolic acid) (PLGA) nanoparticles by encapsulating antigen within nanoparticles or by simply mixing soluble antigen with the nanoparticles. Our results indicated that the combined formulation (composed of antigen encapsulated in nanoparticles and antigen mixed with nanoparticles) induced more powerful antigen-specific immune responses than each single-component formulation. Mice immunized with the combined vaccine formulation displayed enhanced induction of antigen-specific IgG antibodies with high avidity, increased cytokine secretion by splenocytes, and improved generation of memory T cell. Enhanced immune responses elicited by the combined vaccine formulation might be attributed to the antigen-depot effect at the injection site, effective provision of both adequate initial antigen exposure and long-term antigen persistence, and efficient induction of dendritic cell (DC) activation and follicular helper T cell differentiation in draining lymph nodes. Understanding the effect of antigen-nanoparticle formulations on the resultant immune responses might have significant implications for rational vaccine design. PMID- 24780167 TI - Long term mesenchymal stem cell culture on a defined synthetic substrate with enzyme free passaging. AB - Mesenchymal stems cells (MSCs) are currently the focus of numerous therapeutic approaches in tissue engineering/repair because of their wide multi-lineage potential and their ability to modulate the immune system response following transplantation. Culturing these cells, while maintaining their multipotency in vitro, currently relies on biological substrates such as gelatin, collagen and fibronectin. In addition, harvesting cells from these substrates requires enzymatic or chemical treatment, a process that will remove a multitude of cellular surface proteins, clearly an undesirable process if cells are to be used therapeutically. Herein, we applied a high-throughput 'hydrogel microarray' screening approach to identify thermo-modulatable substrates which can support hES-MP and ADMSC growth, permit gentle reagent free passaging, whilst maintaining multi-lineage potential. In summary, the hydrogel substrate identified, poly(AEtMA-Cl-co-DEAA) cross-linked with MBA, permitted MSCs to be maintained over 10 passages (each time via thermo-modulation), with the cells retaining expression of MSC associated markers and lineage potency. This chemically defined system allowed the passaging and maintenance of cellular phenotype of this clinically important cell type, in the absence of harsh passaging and the need for biological substrates. PMID- 24780168 TI - Simulation and analysis of cellular internalization pathways and membrane perturbation for graphene nanosheets. AB - Clarifying the mechanisms of cellular interactions of graphene family nanomaterials is an urgent issue to the development of guidelines for safer biomedical applications and to the evaluation of health and environment impacts. By combining large-scale computer simulations, theoretical analysis, and experimental discussions, here we present a systematic study on the interactions of graphene nanosheets having various oxidization degrees with a model lipid bilayer membrane. In the mesoscopic simulations, we investigate the detailed translocation pathways of these materials across a 56 * 56 nm(2) membrane patch which allows us to fully consider the role of membrane perturbation during this process. A phase diagram regarding the transmembrane translocation mechanisms of graphene nanosheets is thereby obtained in the space of oxidization degree and particle size. Then, we propose a theoretical approach to analyze the effects of various initial equilibrium states of graphene nanosheets with membrane on their following cellular uptake process. Finally, we demonstrate that the simulation and theoretical results reproduce some important experimental findings towards the mechanisms of cytotoxicity and antibacterial activity of graphene materials. These results not only provide new insight into the cellular internalization mechanism of graphene-based nanomaterials but also offer fundamental understanding on their physicochemical properties which can be precisely tailored for safer biomedical and environment applications. PMID- 24780169 TI - Induced pluripotent stem cell-derived hepatocytes and endothelial cells in multi component hydrogel fibers for liver tissue engineering. AB - Liver tissue engineering requires a suitable cell source, methodologies to assemble the cells within their niche microenvironments in a spatially defined manner, and vascularization of the construct in vivo for maintenance of hepatocyte viability and function. Recently, we have developed methods of encapsulating cells within separate domains in multi-component hydrogel fibers and methods of assembling fibers to form 3D-patterned tissue constructs. In the present work, we have combined these approaches to encapsulate hepatocytes and endothelial cells within their specific niches, and to assemble them into endothelialized liver tissue constructs. The hepatocytes and endothelial cells were obtained in parallel by differentiating human recombinant protein-induced human pluripotent stem cells, resulting in a construct which contained genetically identical endothelial and parenchymal elements. We were able to demonstrate that the presence of endothelial cells in the scaffold significantly improved hepatocyte function in vitro and facilitated vascularization of the scaffold when implanted in a mouse partial hepatectomy model. The in vivo studies further asserted that integration of the scaffold with host vasculature had occurred, as demonstrated by the presence of human albumin in the mouse serum. PMID- 24780170 TI - Optimizing human embryonic stem cells differentiation efficiency by screening size-tunable homogenous embryoid bodies. AB - Human embryonic stem cells (hESCs) are generally induced to differentiate by forming spherical structures termed embryoid bodies (EBs) in the presence of soluble growth factors. hEBs are generated by suspending small clumps of hESC colonies; however, the resulting hEBs are heterogeneous because this method lacks the ability to control the number of cells in individual EBs. This heterogeneity affects factors that influence differentiation such as cell-cell contact and the diffusion of soluble factors, and consequently, the differentiation capacity of each EB varies. Here, we fabricated size-tunable concave microwells to control the physical environment, thereby regulating the size of EBs formed from single hESCs. Defined numbers of single hESCs were forced to aggregate and generate uniformly sized EBs with high fidelity, and the size of the EBs was controlled using concave microwells of different diameters. Differentiation patterns in H9- and CHA15-hESCs were affected by EB size in both the absence and presence of growth factors. By screening EB size in the presence of various BMP4 concentrations, a two-fold increase in endothelial cell differentiation was achieved. Because each hESC line has unique characteristics, the findings of this study demonstrate that concave microwells could be used to screen different EB sizes and growth factor concentrations to optimize differentiation for each hESC line. PMID- 24780171 TI - Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. AB - RATIONALE: In cardiomyocytes from failing hearts, insufficient mitochondrial Ca(2+) accumulation secondary to cytoplasmic Na(+) overload decreases NAD(P)H/NAD(P)(+) redox potential and increases oxidative stress when workload increases. These effects are abolished by enhancing mitochondrial Ca(2+) with acute treatment with CGP-37157 (CGP), an inhibitor of the mitochondrial Na(+)/Ca(2+) exchanger. OBJECTIVE: Our aim was to determine whether chronic CGP treatment mitigates contractile dysfunction and arrhythmias in an animal model of heart failure (HF) and sudden cardiac death (SCD). METHODS AND RESULTS: Here, we describe a novel guinea pig HF/SCD model using aortic constriction combined with daily beta-adrenergic receptor stimulation (ACi) and show that chronic CGP treatment (ACi plus CGP) attenuates cardiac hypertrophic remodeling, pulmonary edema, and interstitial fibrosis and prevents cardiac dysfunction and SCD. In the ACi group 4 weeks after pressure overload, fractional shortening and the rate of left ventricular pressure development decreased by 36% and 32%, respectively, compared with sham-operated controls; in contrast, cardiac function was completely preserved in the ACi plus CGP group. CGP treatment also significantly reduced the incidence of premature ventricular beats and prevented fatal episodes of ventricular fibrillation, but did not prevent QT prolongation. Without CGP treatment, mortality was 61% in the ACi group <4 weeks of aortic constriction, whereas the death rate in the ACi plus CGP group was not different from sham operated animals. CONCLUSIONS: The findings demonstrate the critical role played by altered mitochondrial Ca(2+) dynamics in the development of HF and HF associated SCD; moreover, they reveal a novel strategy for treating SCD and cardiac decompensation in HF. PMID- 24780173 TI - Programmed death-1 pathway in cancer and autoimmunity. AB - Programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. A major functional role of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune diseases. Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-1 pathway has become an attractive target in cancer therapy. Recent clinical trials have shown that anti-PD-1 agents have profound effects on solid tumor regression. Current approaches include six agents that are either PD 1 and PD-L1 targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-1 blockade in variety of tumor types. In this review we will highlight the basic biology of the PD-1 system and discuss its potential roles in both autoimmunity and cancer. We propose that future research on PD-1 may lead to the translation of fundamental regulatory pathways into the development of practical new approaches for the treatment of autoimmune diseases and cancer. PMID- 24780172 TI - Diverse cellular and molecular modes of axon degeneration. AB - The elimination of large portions of axons is a widespread event in the developing and diseased nervous system. Subsets of axons are selectively destroyed to help fine-tune neural circuit connectivity during development. Axonal degeneration is also an early feature of nearly all neurodegenerative diseases, occurs after most neural injuries, and is a primary driver of functional impairment in patients. In this review we discuss the diversity of cellular mechanisms by which axons degenerate. Initial molecular characterization highlights some similarities in their execution but also argues that unique genetic programs modulate each mode of degeneration. Defining these pathways rigorously will provide new targets for therapeutic intervention after neural injury or in neurodegenerative disease. PMID- 24780174 TI - Unusual late lung metastasis from leiomyosarcoma of the uterus. PMID- 24780175 TI - Who uses the emergency department for dermatologic care? A statewide analysis. AB - BACKGROUND: Emergency department (ED) visits for skin symptoms are on the rise. The nature of these visits is not yet well characterized. OBJECTIVE: We sought to conduct a longitudinal analysis comparing patients discharged from the ED with dermatologic primary diagnoses to those with nondermatologic primary diagnoses. METHODS: Using the California State ED Database, we compared demographic variables and visit characteristics of patients discharged with dermatologic primary diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification codes 680-709) to those of patients discharged with nondermatologic primary diagnoses from 2005 to 2011. RESULTS: Patients given dermatologic primary diagnoses in the ED were more likely to be male, aged 18 to 54 years, white or Native American, and low income. They tended to be self-pay patients or have Medicaid, to live in less populous areas, and to visit the ED on the weekend. LIMITATIONS: Results from California may not be generalizable nationally. The databases we used were based on administrative records, which have limited clinical detail. CONCLUSION: The population of patients discharged home from the ED with dermatologic primary diagnoses appears to differ significantly from the population receiving nondermatologic primary diagnoses. PMID- 24780176 TI - Diet and psoriasis, part II: celiac disease and role of a gluten-free diet. AB - Patients with psoriasis have been shown to have a higher prevalence of other autoimmune diseases including celiac disease, a condition marked by sensitivity to dietary gluten. A number of studies suggest that psoriasis and celiac disease share common genetic and inflammatory pathways. Here we review the epidemiologic association between psoriasis and celiac disease and perform a meta-analysis to determine whether patients with psoriasis more frequently harbor serologic markers of celiac disease. We also examine whether a gluten-free diet can improve psoriatic skin disease. PMID- 24780177 TI - Diet and psoriasis, part III: role of nutritional supplements. AB - Patients with psoriasis are increasingly turning to the use of alternative and complementary medicine to manage their psoriasis. Patients often inquire about what dietary supplements may be beneficial, including the use of oral vitamin D, vitamin B12, selenium, and omega-3 fatty acids in fish oils. In this review we examine the extent to which each of these common nutritional interventions has been studied for the treatment of psoriasis. We weighed evidence from both controlled and uncontrolled prospective trials. The evidence of benefit was highest for fish oils. For other supplements, there is need for additional large, randomized clinical trials to establish evidence of efficacy. PMID- 24780178 TI - Experimental anisakid infections in mice. AB - Anisakidosis is a human parasitic disease caused by infections with members of the Anisakidae family. Accidental infection after fish intake affects the gastrointestinal tract as a consequence of mechanical damage caused by migrating larvae. Infections can also trigger allergies, hives, severe asthma or anaphylaxis with angioedema. Although mouse models of intraperitoneal antigenic stimulation exist, enabling immunological studies, few models using gastric introduction of live larvae are available for the study of immunological and gastrointestinal damage in mice. This study was designed to characterize serum reactivity against Anisakis spp. and Contracaecum spp. in Balb/c mice following orogastric inoculation and to assess gastrointestinal damage. These anisakid species were classified at the Universidade Federal Fluminense (UFF) School of Veterinary Medicine and materials for live larval inoculation were developed at the UFF Immunobiology laboratory. Live larvae were inoculated following injection with a NaCl solution. Blood samples were collected and sera screened for immunoglobulin (Ig)E and IgG anti-larva responses to both nematodes, specific for somatic and excretory/secretory antigens, by enzyme-linked immunosorbent assay (ELISA). The means of the optical densities were analysed using analysis of variance (ANOVA) with Tukey's post-hoc test and the general linear model. This analysis identified the presence of anti-IgG seroreactivity to both somatic and excretory/secretory Anisakis antigens in inoculated animals compared with controls (P< 0.001), and no gastric or intestinal damage was observed. These experiments demonstrated that introduction of live Contracaecum spp. into the gastrointestinal tract did not elicit serum sensitization in animals. PMID- 24780179 TI - Contradictions and dialectics in the palliative dialogue: enhancing the palliative dialogue by dialectical principles. AB - The application of required communication skills in the palliative dialogue necessitates a significant transition from the paternalistic medical approach to the holistic psychosocial approach that focuses on the patient and views the individual as a whole entity. Understanding the evolution of a therapeutic relationship in terms of entrance into the relationship, development, maintenance, and leave taking as well as the adoption of dialectical ideas gives palliative caregivers flexibility in the dialogue with patients and families. Accepting the principles of dialectics, in which the existence of contradictions is seen as an inherent part of a reality that is undergoing constant change, gives the caregiver the flexibility to interpret dichotomic thoughts and emotions as a dialectic failure and, in accordance, to move toward a synthesis of the ideas of living and dying. This approach provides caregivers the means to promote the palliative dialogue, implement varied communication skills to clarify the patient's goals, and implement a therapeutic plan to realize them. PMID- 24780180 TI - Mindfulness-oriented recovery enhancement ameliorates the impact of pain on self reported psychological and physical function among opioid-using chronic pain patients. AB - CONTEXT: Chronic pain impacts one-third of the U.S. population, and its effects are debilitating for individuals and costly to the medical system. Although opioids are commonly prescribed to address chronic pain, they confer risk for misuse and addiction in some patients and may not fully restore life function particularly with regard to psychosocial factors. Because of the multiplicity of impacts that chronic pain may have on daily functioning, broad-spectrum behavioral interventions are needed. OBJECTIVES: The purpose of this study was to conduct follow-up analyses from a pilot randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE) to assess specific effects of MORE on various biopsychosocial aspects of pain-related impairment. METHODS: Chronic pain patients (N = 115; mean age, 48 +/- 14 years; 68% female) were randomly assigned to either eight weeks of MORE or a support group. Domains of pain-related functional interference were measured with the Brief Pain Inventory at pre- and post-treatment and at a three-month follow-up. Treatment effects were analyzed with multivariate intention-to-treat models. RESULTS: MORE participants reported significantly greater reductions in functional interference than support group participants at post-treatment across all domains, including general activity, mood, walking ability, normal work, relationships, sleep, and enjoyment of life. These effects were largely maintained by the three-month follow-up; however, general activity level and walking ability were no longer significant, indicating differential long-term effects between physiological and psychological functioning. CONCLUSION: Findings demonstrate preliminary efficacy of MORE as a treatment for pain-related functional impairments and suggest that effects may be more pronounced and durable for aspects of psychological function. PMID- 24780181 TI - Experience of advanced chronic obstructive pulmonary disease: metasynthesis of qualitative research. AB - CONTEXT: Chronic obstructive pulmonary disease (COPD) is a life-limiting illness. Despite best available treatments, individuals continue to experience symptom burden and have high health care utilization. OBJECTIVES: To increase understanding of the experience and ongoing needs of individuals living with COPD. METHODS: Medline, PsycINFO, CINAHL, and Sociological Abstracts were searched for articles published between January 1990 and June 2013. Metasynthesis of qualitative data followed the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Metasyntheses are increasingly used to gain understandings of complex research questions through synthesizing data from individual qualitative studies. Descriptive and analytical themes were developed through thematic synthesis and expert panel discussion of extracted primary quotes, not the primary data themselves. RESULTS: Twenty-two studies were included. Four hundred twenty-two free codes were condensed into seven descriptive themes: better understanding of condition, breathlessness, fatigue, frailty, anxiety, social isolation, and loss of hope and maintaining meaning. These seven themes were condensed further into three analytical themes that described the experience and ongoing needs of individuals with COPD: the need for better understanding of condition, sustained symptom burden, and the unrelenting psychological impact of living with COPD. CONCLUSION: Combining discrete qualitative studies provided a useful perspective of the experience of living with COPD over the past two decades. Further studies into the ongoing needs of individuals with COPD are unlikely to add to this well-established picture. Future research should focus on solutions through the development of interventions that address patients' ongoing needs. PMID- 24780182 TI - How do follow-up care instructions and treatment summaries relate to cancer survivors' cancer-related pain? AB - CONTEXT: Cancer-related pain is a problem for many cancer survivors. Treatment summaries (TS) and follow-up care instructions (FCI) provided after cancer treatment could reduce pain for cancer survivors. OBJECTIVES: This study sought to determine how TS and FCI received by cancer survivors relate to cancer survivors' cancer-related pain after treatment completion. METHODS: Data were from 2010, Behavioral Risk Factor Surveillance System, Cancer Survivorship module, completed by 10 U.S. states and entities. RESULTS: Pain was reported by 9% of survivors. TS (P = 0.02) and FCI (P < 0.001) were associated with pain. Compared with cancer survivors who had not received TS or FCI, those who received TS had greater odds of pain (odds ratio, 1.57; 95% confidence interval, 1.08 2.28) and those who received FCI had more than twice the odds of pain (odds ratio, 2.36; 95% confidence interval, 1.52-3.67). CONCLUSION: FCI and TS were related to pain but in the opposite direction than predicted. Those who received TS and FCI were more likely to report pain than those who did not receive FCI and TS. This may be explained by the severity of cancer treatment. It is possible that those who undergo more severe cancer treatments are more likely to receive FCI and TS. Testing this relationship is a logical next step. PMID- 24780183 TI - Polypharmacy in patients with advanced cancer and pain: a European cross sectional study of 2282 patients. AB - CONTEXT: Patients with advanced cancer need multiple drugs to control symptoms and to treat cancer and concomitant diseases. At the same time, the goal of treatment changes as life expectancy becomes limited. This results in a risk for polypharmacy, maintained use of unneeded drugs, and drug-drug interactions (DDIs). OBJECTIVES: The aim of the study was to analyze the use of medications and to identify unneeded drugs, and drugs and drug combinations with a risk for DDIs in a cohort of advanced cancer pain patients, defined by a need for a World Health Organization analgesic ladder Step III opioid. METHODS: All drugs taken within a study day by cancer patients receiving opioids for moderate or severe pain (Step III opioids) were analyzed. Nonopioids and adjuvants were analyzed for their use across countries. Unneeded medications and drugs and drug combinations with a risk for pharmacodynamic and pharmacokinetic DDIs were identified on the basis of published literature and electronic resources. RESULTS: In total, 2282 patients from 17 centers in 11 European countries were included. They received a mean of 7.8 drugs (range 1-20). Over one-quarter used 10 or more medications. The drugs and drug classes most frequently coadministered with opioids were proton pump inhibitors, laxatives, corticosteroids, paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, metoclopramide, benzodiazepines, anticoagulants, antibiotics, anticonvulsants, diuretics, and antidepressants. The use of nonopioids and essential adjuvants varied across countries. Approximately 45% of patients received unnecessary or potentially unnecessary drugs, and about 7% were given duplicate or antagonizing agents. Exposures to DDIs were frequent and increased the risk of sedation, gastric ulcerations, bleedings, and neuropsychiatric and cardiac complications. Many patients were exposed to pharmacokinetic DDIs involving cytochrome P450, including about 58% who used a Step III opioid CYP3A4 (izoenzyme of cytochrome P450) substrate, and more than 10% who were given major CYP3A4 inhibitors or inducers. CONCLUSION: Patients with cancer treated with a World Health Organization Step III opioid use a high number of drugs. Nonopioid analgesics and corticosteroids are frequently used, but different patterns of use between countries were found. Many patients receive unneeded drugs and are at risk of serious DDIs. These findings demonstrate that drug therapy in these patients needs to be evaluated continuously. PMID- 24780184 TI - Legal barriers in accessing opioid medicines: results of the ATOME quick scan of national legislation of eastern European countries. AB - CONTEXT: Overregulation of controlled medicines is one of the factors contributing to limited access to opioid medicines. OBJECTIVES: The purpose of this study was to identify legal barriers to access to opioid medicines in 12 Eastern European countries participating in the Access to Opioid Medication in Europa project, using a quick scan method. METHODS: A quick scan method to identify legal barriers was developed focusing on eight different categories of barriers. Key experts in 12 European countries were requested to send relevant legislation. Legislation was quick scanned using World Health Organization guidelines. Overly restrictive provisions and provisions that contain stigmatizing language and incorrect definitions were identified. The selected provisions were scored into two categories: 1) barrier and 2) uncertain, and reviewed by two authors. A barrier was recorded if both authors agreed the selected provision to be a barrier (Category 1). RESULTS: National legislation was obtained from 11 of 12 countries. All 11 countries showed legal barriers in the areas of prescribing (most frequently observed barrier). Ten countries showed barriers in the areas of dispensing and showed stigmatizing language and incorrect use of definitions in their legislation. Most barriers were identified in the legislation of Bulgaria, Greece, Lithuania, Serbia, and Slovenia. The Cypriot legislation showed the fewest total number of barriers. CONCLUSION: The selected countries have in common as main barriers prescribing and dispensing restrictions, the use of stigmatizing language, and incorrect use of definitions. The practical impact of these barriers identified using a quick scan method needs to be validated by other means. PMID- 24780185 TI - Family conferences in palliative care: a survey of health care providers in France. AB - CONTEXT: Family conferences are conducted to assist with end-of-life discussions and discharge planning. OBJECTIVES: This study describes the current practices of family conferences in palliative care units (PCUs) in France. METHODS: A cross sectional descriptive survey was sent to each PCU in France (n = 113). Members of the interdisciplinary health care team (palliative care physician, nurse, psychologist, and social worker) who were active in each PCU at the time of the survey were asked to respond. RESULTS: Two hundred seventy-six of 452 responses (61%) were obtained from members of the health care team in 91 units (81%). Two hundred seventy-two of 276 health care providers (HCPs) (99%) reported conducting family conferences in their clinical practice. Only 13 participants (5%) reported that they followed a structured protocol. Most respondents completed the questionnaire: palliative care physicians (n = 225; 82%), nurses (n = 219; 79%), and psychologists (n = 181; 66%). The three primary goals of family conferences were to allow family members to express their feelings (n = 240; 87%), identify family caregivers (n = 233; 84%), and discuss the patient's plan of care (n = 219; 79%). The primary reasons for conducting a family conference were: the patient's illness was terminal (n = 216; 78%), family caregivers requested a conference (n = 208; 75%), or terminal sedation was required (n = 189; 69%). One hundred six of 452 HCPs (38%) reported that patients were not invited to participate. The primary indications and goals for a family conference were significantly different among the four health care disciplines. CONCLUSION: Most HCPs in our study conducted family conferences. However, most of the family conferences had no structured protocol, half of the participants preferred no patient participation, and a significant variation was noted in the primary indications and goals among disciplines. PMID- 24780186 TI - MicroRNA-152 targets ADAM17 to suppress NSCLC progression. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been suggested to play an essential role in tumorigenesis. In this study, we show that miR-152 is significantly downregulated in non-small cell lung cancer (NSCLC) tissues and cell lines. Restoration of miR-152 significantly reduces proliferation, colony formation, migration and invasion of NSCLC cells. In addition, ADAM metallopeptidase domain 17 (ADAM17) is identified as a target of miR-152 in NSCLC cells, and miR-152-induced suppression of cell proliferation, colony formation, migration and invasion is partially mediated by silencing of ADAM17 expression. Furthermore, ADAM17 inversely correlates with miR-152 in NSCLC tissues. Collectively, our findings indicate that miR-152 acts as tumor suppressor in NSCLC partially via targeting ADAM17. PMID- 24780187 TI - Infection in long term care facility in the kingdom of Bahrain. AB - Infections in long term care facilities (LTCF) are common and are considered a major cause of mortality and morbidity. Endemic infections and outbreaks are observed in LTCF. Of particular concern is the growth of multi-drug resistant organisms. A study was conducted in the Kingdom of Bahrain concerning infections among the residents in a LTCF. The aim was to define the rate, type and outcomes of institutional infections. The different treatment modalities and antimicrobials used were evaluated. Our facility cares for the elderly and a heterogeneous group of patients from different populations (e.g., mentally retarded, bedbound due to various disabilities and other forms of consciousness impairment such as post stroke disability, cerebral palsy and anoxic brain damage). The initial span of six months was changed to seven months to increase the sample size and improve the data analysis. This was a prospective study conducted in Muharaq Geriatric Hospital in the Kingdom of Bahrain. The study was conducted over seven months from January 2013 to July 2013 on 104 patients. During that period, patients with new positive cultures from different sites were included. The clinical features, microbiological features and outcomes of the bacteremic episodes were included. The information was collected by a questionnaire created by the research team. From a total of 104 patients staying in the LTFC, 19 had positive cultures from different sites at different times. The study showed that infections are common, especially urinary tract infections. PMID- 24780188 TI - Effects of polymorphisms in immunity-related genes on the immune system and successful aging. AB - Aging is associated with the dysregulation of immune system. Despite a progressive decline in immune function resulting in hyporesponsiveness to infection and vaccination, aging is also characterized by a chronic, low-grade, pro-inflammatory condition. An elderly individual with a systemic inflammation is at an increased risk of age-related diseases. Polymorphisms in the genes coding for inflammatory or anti-inflammatory molecules associated with immune related processes can affect the balance between the pro-inflammatory and anti inflammatory networks. An improved understanding of the interactions among endogenous and environmental factors and genetic polymorphisms in anti inflammatory and immune-related genes will increase the possibility of treating major age-related diseases to achieve longevity. The major challenge is to fully understand the complex interactions between genetic variations and multiple factors and their relative contributions to immunosenescence and age-related diseases in various populations. The results of studies that examined polymorphisms in immune-related genes associated with successful aging are reviewed here. PMID- 24780189 TI - Experimental infection of Opisthorchis viverrini cercariae to the cyprinid fish, Barbonymus gonionotus. AB - Opisthorchis viverrini is an important public health problem, a major cause of cholangiocarcinoma in the Greater Mekong subregion including Lao PDR, Cambodia, Vietnam and Thailand. Humans acquire the infection by consumption of raw, fermented or partially cooked freshwater cyprinid fish containing infective metacercariae. This study examined the effect of cercarial infection dosage (25 200 cercariae), age (1-60 day) and size (1-24mm) of Barbonymus gonionotus fish on infection success of O. viverrini cercariae. Additionally, the site of cyst formation of O. viverrini cercariae and subsequent development to the metacercariae was examined. The result showed that cercarial infection dose (F4,95=8.52, P<0.001) age (P<0.001, lambdaLR(2)=954.72) and size (P<0.001, lambdaLR(2)=1204.84) were significantly associated with number of O. viverrini metacercariae recovery with in every additional fish age, the O. viverrini metacercarial recovery rate increased by 5.4% (P<0.001). Most metacercariae were found in the body of the fish (81.4%). We concluded that O. viverrini cercarial infection dosage, and age and size of fish were important determinants for a successful infection to fish. PMID- 24780191 TI - Role of Bacopa monnieri in the temporal regulation of oxidative stress in clock mutant (cryb) of Drosophila melanogaster. AB - Accruing evidences imply that circadian organization of biochemical, endocrinological, cellular and physiological processes contribute to wellness of organisms and in the development of pathologies such as malignancy, sleep and endocrine disorders. Oxidative stress is known to mediate a number of diseases and it is notable to comprehend the orchestration of circadian clock of a model organism of circadian biology, Drosophila melanogaster, under oxidative stress. We investigated the nexus between circadian clock and oxidative stress susceptibility by exposing D. melanogaster to hydrogen peroxide (H2O2) or rotenone; the reversibility of rhythms following exposure to Bacopa monnieri extract (ayurvedic medicine rich in antioxidants) was also investigated. Abolishment of 24h rhythms in physiological response (negative geotaxis), oxidative stress markers (protein carbonyl and thiobarbituric acid reactive substances) and antioxidants (superoxide dismutase, catalase, glutathione-S transferase and reduced glutathione) were observed under oxidative stress. Furthermore, abolishment of per mRNA rhythm in H2O2 treated wild type flies and augmented susceptibility to oxidative stress in clock mutant (cry(b)) flies connotes the role of circadian clock in reactive oxygen species (ROS) homeostasis. Significant reversibility of rhythms was noted following B. monnieri treatment in wild type flies than cry(b) flies. Our experimental approach revealed a relationship involving oxidative stress and circadian clock in fruit fly and the utility of Drosophila model in screening putative antioxidative phytomedicines prior to their use in mammalian systems. PMID- 24780193 TI - Is the great NHS sell-off under way? PMID- 24780194 TI - Burns following attempted electrosurgical tattoo removal. PMID- 24780192 TI - Developmental and cross-modal plasticity in deafness: evidence from the P1 and N1 event related potentials in cochlear implanted children. AB - Cortical development is dependent on extrinsic stimulation. As such, sensory deprivation, as in congenital deafness, can dramatically alter functional connectivity and growth in the auditory system. Cochlear implants ameliorate deprivation-induced delays in maturation by directly stimulating the central nervous system, and thereby restoring auditory input. The scenario in which hearing is lost due to deafness and then reestablished via a cochlear implant provides a window into the development of the central auditory system. Converging evidence from electrophysiologic and brain imaging studies of deaf animals and children fitted with cochlear implants has allowed us to elucidate the details of the time course for auditory cortical maturation under conditions of deprivation. Here, we review how the P1 cortical auditory evoked potential (CAEP) provides useful insight into sensitive period cut-offs for development of the primary auditory cortex in deaf children fitted with cochlear implants. Additionally, we present new data on similar sensitive period dynamics in higher-order auditory cortices, as measured by the N1 CAEP in cochlear implant recipients. Furthermore, cortical re-organization, secondary to sensory deprivation, may take the form of compensatory cross-modal plasticity. We provide new case-study evidence that cross-modal re-organization, in which intact sensory modalities (i.e., vision and somatosensation) recruit cortical regions associated with deficient sensory modalities (i.e., auditory) in cochlear implanted children may influence their behavioral outcomes with the implant. Improvements in our understanding of developmental neuroplasticity in the auditory system should lead to harnessing central auditory plasticity for superior clinical technique. PMID- 24780195 TI - Influence of partial cutting on parasitism of endemic spruce budworm (Lepidoptera: Tortricidae) populations. AB - Silvicultural treatments such as thinning have been suggested as management tools against the spruce budworm, Choristoneura fumiferana (Clemens) (Lepidoptera: Tortricidae). Among other things, parasitoids are also proposed to be influenced by silvicultural procedures, but the effect of thinning on spruce budworm's natural enemies has not been tested yet. In this study, the influence of partial cutting on parasitism of endemic spruce budworm populations has been investigated in mature balsam fir-white birch forests. Two intensities of partial cutting (25 and 40% stand basal area reduced) were conducted in 2009 and parasitism of introduced spruce budworm larvae and pupae was determined during the 3 yr after these treatments. Pupal parasitism was too low for comparison between treatments. However, 2 yr after treatments, parasitism of the fourth- and fifth-instar larvae was significantly reduced in plots with both intensities of partial cutting, which was attributed to the parasitoid Tranosema rostrale (Brischke). Three years after treatments, no significant influence of partial cutting on parasitism of spruce budworm larvae was found. This study suggests that the influence of partial cutting on parasitism of endemic spruce budworm populations is not consistent, but that under certain circumstances parasitism is reduced by partial cutting. PMID- 24780196 TI - High concentraction of taurocholic acid induced apoptosis in HTR-8/SVneo cells via overexpression of ERp29 and activation of p38. AB - INTRODUCTION: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disease associated with a significant risk of fetal complications. Our previous study using an iTRAQ-based proteomics approach showed that ERp29 was overexpressed in the placenta tissue of ICP patients, which was an apoptosis related protein and has not been investigated in the pathogenesis of ICP. The aim of this study was to explore the role of ERp29 in the mechanism of apoptosis in the placenta of ICP. METHODS: HTR-8/SVneo cells were cultured and treated with different concentrations of taurocholic acid (TCA) (0, 10, 50 and 100 MUM). The apoptotic index and cell cycle were detected by flow cytometry; furthermore, the expression levels of ERp29 and p-p38 were detected by western blot. The ERp29 siRNA was also used to confirm the role of ERp29 in TCA induced-apoptosis. RESULTS: ERp29 expression and the apoptotic index were significantly increased in HTR-8/SVneo cells exposed to 100 MUM TCA; so were p-p38 and caspase-3 activity, compared with the 50 MUM, 10 MUM TCA groups and negative control group (P < 0.05, respectively). The induction of apoptosis by TCA and the expression of p-p38 were reduced in HTR-8/SVneo cells after treatment with ERp29-siRNA, compared with controls (P < 0.05, respectively). CONCLUSIONS: This study suggested that overexpression of ERp29 may play a key role in TCA-induced apoptosis in HTR 8/SVneo cells via activation of p38, which may participate in the pathogenesis of ICP and may represent a novel target for ICP treatment. PMID- 24780197 TI - Inhibition of Delta-like 4 mediated signaling induces abortion in mice due to deregulation of decidual angiogenesis. AB - OBJECTIVE: To explore whether the Dll4/Notch1 pathway plays a key role in regulating the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) driven decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype. METHODS: Progesterone-replaced ovariectomized pregnant mice received a single injection of YW152F (Dll4 blocking antibody, BAb) or placebo at embryonic day (E) 4.5. Animals were sacrificed at different time points; blood and uterus were collected for further analysis. Number of embryos and implantation site, uteri weight, and serum progesterone levels were assessed. Alterations in the tip/stalk phenotype were determined by quantitative immunofluorescent analysis of vascularization, Dll4 expression, cellular proliferation and apoptosis in uterine sections. RESULTS: Abrogation of Dll4 signaling leads to a promiscuous expression of Dll4, increased cell proliferation, apoptosis and vascularization at E 6.5. Such an abrogation was associated with a dramatic disruption of embryo growth and development starting at E 9.5. DISCUSSION: The observed promiscuous expression of Dll4 and the increase in cell proliferation, apoptosis and vascularization are events compatible with loss of the tip/stalk phenotype. Excessive (although very likely defective) decidual angiogenesis due to such vascular alterations is the most likely cause of subsequent interruption of embryo development and related pregnancy in Dll4 treated mice. CONCLUSIONS: Dll4 plays a key role in regulating decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype. PMID- 24780198 TI - JunB/cyclin-D1 imbalance in placental mesenchymal stromal cells derived from preeclamptic pregnancies with fetal-placental compromise. AB - INTRODUCTION: In the present study, we characterized the expression of Activating Protein 1 (AP-1) factors, key cell cycle regulators, in primary placental mesenchymal stromal cells (PDMSCs) derived from normal and preeclamptic (PE) pregnancies with fetal-placental compromise. METHODS: PDMSCs were isolated from control (n = 20) and preeclamptic (n = 24) placentae. AP-1 expression was determined by semi-quantitative RT-PCR (sqRT-PCR), Real Time PCR and Western Blot assay. PDMSCs were plated and JunB siRNA was performed. JunB and Cyclin-D1 expression were assessed by Real Time and Western Blot analyses. RESULTS: JunB expression was significantly increased while Cyclin-D1 expression was significantly down-regulated in PE relative to control PDMSCs. JunB siRNA was accompanied by JunB down-regulation and increased Cyclin-D1 in normal PDMSCs. CONCLUSIONS: We described, for the first time, AP-1 expression in PDMSCs derived from physiological and PE placentae. Importantly, we demonstrated that JunB over expression in PE-PDMSCs affects Cyclin-D1 regulation. Our data suggest a possible contribution of these pathological placental cells to the altered cell cycle regulation typical of preeclamptic placentae. PMID- 24780199 TI - Persistent and acute chlamydial infections induce different structural changes in the Golgi apparatus. AB - Chlamydia trachomatis causes a wide range of diseases that have a significant impact on public health. Acute chlamydial infections can cause fragmentation of the Golgi compartment ensuring the lipid transportation from the host cell. However, the changes that occur in the host cell Golgi apparatus after persistent infections are unclear. Here, we examined Golgi-associated gene (golga5) transcription and expression along with the structure of the Golgi apparatus in cells persistently infected with Chlamydia trachomatis. The results showed that persistent infections caused little fragmentation of the Golgi. The results also revealed that Golgi fragmentation might be associated with the suppression of transcription of the gene golga5. PMID- 24780201 TI - The association between T-stage and clinical nodal metastasis In HPV-positive oropharyngeal cancer. AB - PURPOSE: To evaluate the association between T-stage and primary tumor subsite with clinical nodal metastasis in HPV-positive oropharyngeal squamous cell carcinomas. STUDY DESIGN: Retrospective medical record review. MATERIALS AND METHODS: A retrospective analysis of all previously untreated patients with HPV positive oropharyngeal squamous cell carcinoma evaluated by the senior author in a tertiary-care center over a 5-year period was performed. Medical records were evaluated for HPV status, clinical T-stage, clinical nodal stage, and anatomic location of primary oropharyngeal subsite. RESULTS: 83% (59/71) of patients presented with clinical nodal disease. T-stage was not associated with the absence of regional disease (cN0) in tonsillar complex or base of tongue cancers. However, early T1/T2 tonsillar complex cancers were less likely to present with cN2c disease compared to T3/T4 lesions (0% vs. 18-33%, p=0.03). Further, base of tongue cancers were more likely to present with cN2c disease compared to tonsillar complex tumors (35% vs. 7%, p=0.01). CONCLUSION: In HPV-positive tonsillar complex cancers, T-stage does not appear to predict the presence of clinical nodal metastasis (N0 vs. N1-N3), but may predict the extent of metastasis when present. This association does not appear to affect base of tongue cancers. Further, base of tongue cancers have a greater incidence of cN2c disease compared to tonsillar complex cancers. PMID- 24780200 TI - Validation of the short-form McGill pain questionnaire-2 in younger and older people with cancer pain. AB - Pain is among the most common symptoms of cancer. Because cancer can occur at any age, it is imperative that pain assessment tools are valid for use across the adult lifespan. The Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2) is a valid and reliable tool for the assessment of the multidimensional qualities of pain in people with chronic nonmalignant pain, but its psychometric properties in people with cancer pain and in older versus younger people require investigation. This study evaluated age differences in the validity, reliability, and use of the SF MPQ-2 in 244 people with advanced cancer and pain. We confirmed the previously reported 4-factor solution in older (>= 60 years) and younger (<60 years) patients. Internal consistency reliability and convergent validity were similar across age groups, although the SF-MPQ-2 sensory subscales were correlated with mental health quality of life in older, but not younger, patients. Older and younger patients selected the same words with the same intensity to describe their pain. The most commonly selected words in both age groups were aching, tiring-exhausting, sharp, and dull. These results demonstrate that the SF-MPQ-2 is appropriate for use across the adult lifespan in people with cancer pain. PERSPECTIVE: This study demonstrated that the SF-MPQ-2 is valid for use in older and younger people with advanced cancer and pain. This measure could improve cancer pain assessment across the adult lifespan, which may lead to improved pain management. PMID- 24780202 TI - Consistency of gait characteristics as determined from acceleration data collected at different trunk locations. AB - Estimates of gait characteristics may suffer from errors due to discrepancies in accelerometer location. This is particularly problematic for gait measurements in daily life settings, where consistent sensor positioning is difficult to achieve. To address this problem, we equipped 21 healthy adults with tri-axial accelerometers (DynaPort MiniMod, McRoberts) at the mid and lower lumbar spine and anterior superior iliac spine (L2, L5 and ASIS) while continuously walking outdoors back and forth (20 times) over a distance of 20 m, including turns. We compared 35 gait characteristics between sensor locations by absolute agreement intra-class correlations (2, 1; ICC). We repeated these analyses after applying a new method for off-line sensor realignment providing a unique definition of the vertical and, by symmetry optimization, the two horizontal axes. Agreement between L2 and L5 after realignment was excellent (ICC>0.9) for stride time and frequency, speed and their corresponding variability and good (ICC>0.7) for stride regularity, movement intensity, gait symmetry and smoothness and for local dynamic stability. ICC values benefited from sensor realignment. Agreement between ASIS and the lumbar locations was less strong, in particular for gait characteristics like symmetry, smoothness, and local dynamic stability (ICC generally<0.7). Unfortunately, this lumbar-ASIS agreement did not benefit consistently from sensor realignment. Our findings show that gait characteristics are robust against limited repositioning error of sensors at the lumbar spine, in particular if our off-line realignment is applied. However, larger positioning differences (from lumbar positions to ASIS) yield less consistent estimates and should hence be avoided. PMID- 24780203 TI - Five year results of the first US FDA-approved hip resurfacing device. AB - A prospective, multi-center postmarket approval study has been ongoing since May 2006 to assess safety and efficacy of the first US FDA approved hip resurfacing implant. 265 patients have been enrolled at five study sites. The average age of the patients is 51.3 years. There have been 7 revisions (2.4%) in the cohort to date. K-M survival curves for the cohort are 97.6% at 5 years. There is a trend toward a gender difference in implant survivorship, with 98.6% of men and 94.7% of women free from revision. Metal ion analysis revealed median cobalt and chromium levels of 1.5 ppb and 1.7 ppb at 1 year. In this prospective US study, the Birmingham Hip Resurfacing implant is demonstrating results comparable to those in the literature. PMID- 24780204 TI - The 50 highest cited papers in hip and knee arthroplasty. PMID- 24780205 TI - Determinants of heat generation in patients treated with therapeutic hypothermia following cardiac arrest. AB - BACKGROUND: Therapeutic hypothermia (TH) is recommended to reduce ischemic brain injury after cardiac arrest. The variables that predict heat generation by patients receiving TH are uncertain, as is how this heat generation relates to neurologic outcome. We hypothesized that patient characteristics, medication use, inflammation, and organ injury would be associated with heat generation. We further hypothesized that neurologic outcome would be most strongly associated with heat generation. METHODS AND RESULTS: Surface and intravascular cooling devices were used to provide TH in 57 consecutive cardiac arrest patients. Device water temperatures during the maintenance (33 degrees C) phase were collected. Patient heat generation was quantified as the "heat index" (HI), which was the inverse average water temperature over a minimum of 2 hours of maintenance hypothermia. Variables measuring reduced ischemic injury and improved baseline health were significantly associated with HI. After controlling for presenting rhythm, a higher HI was independently associated with favorable disposition (OR=2.2; 95% CI 1.2 to 4.1; P=0.014) and favorable Cerebral Performance Category (OR=1.8; 95% CI 1.0 to 3.1; P=0.035). Higher HI predicted favorable disposition (receiver-operator area under the curve 0.71, P=0.029). HI was linearly correlated with arteriovenous CO2 (r=0.69; P=0.041) but not O2 (r=0.13; P=0.741) gradients. CONCLUSIONS: In cardiac arrest patients receiving TH, greater heat generation is associated with better baseline health, reduced ischemic injury, and improved neurologic function, which results in higher metabolism. HI can control for confounding effects of patient heat generation in future clinical trials of rapid TH and offers early prognostic information. PMID- 24780206 TI - Association of comorbidity burden with abnormal cardiac mechanics: findings from the HyperGEN study. AB - BACKGROUND: Comorbidities are common in heart failure (HF), and the number of comorbidities has been associated with poor outcomes in HF patients. However, little is known about the effect of multiple comorbidities on cardiac mechanics, which could impact the pathogenesis of HF. We sought to determine the relationship between comorbidity burden and adverse cardiac mechanics. METHODS AND RESULTS: We performed speckle-tracking analysis on echocardiograms from the HyperGEN study (n=2150). Global longitudinal, circumferential, and radial strain, and early diastolic (e') tissue velocities were measured. We evaluated the association between comorbidity number and cardiac mechanics using linear mixed effects models to account for relatedness among subjects. The mean age was 51 +/- 14 years, 58% were female, and 47% were African American. Dyslipidemia and hypertension were the most common comorbidities (61% and 58%, respectively). After adjusting for left ventricular (LV) mass index, ejection fraction, and several potential confounders, the number of comorbidities remained associated with all indices of cardiac mechanics except global circumferential strain (eg, beta=-0.32 [95% CI -0.44, -0.20] per 1-unit increase in number of comorbidities for global longitudinal strain; beta=-0.16 [95% CI -0.20, -0.11] for e' velocity; P <= 0.0001 for both comparisons). Results were similar after excluding participants with abnormal LV geometry (P<0.05 for all comparisons). CONCLUSIONS: Higher comorbidity burden is associated with worse cardiac mechanics, even in the presence of normal LV geometry. The deleterious effect of multiple comorbidities on cardiac mechanics may explain both the high comorbidity burden and adverse outcomes in patients who ultimately develop HF. PMID- 24780207 TI - Prognostic value of left ventricular diastolic dysfunction in a general population. AB - BACKGROUND: New techniques of Tissue Doppler Imaging (TDI) enable the measurement of myocardial velocities and provide information about left ventricular (LV) diastolic function. Recent studies explored the prognostic role of TDI-derived indexes. However, these studies considered only total mortality and did not provide information on cardiovascular mortality and morbidity. Therefore, we investigated in continuous and categorical analyses whether Doppler diastolic indexes contained any prognostic information over and beyond traditional cardiovascular risk factors in a general population. METHODS AND RESULTS: We measured early and late diastolic peak velocities of mitral inflow (E and A) by conventional Doppler, and the mitral annular velocities (e' and a') by TDI in 793 participants (mean age 50.9 years). We calculated multivariable-adjusted hazard ratios for conventional and TDI Doppler indexes, while accounting for family cluster and cardiovascular risk factors. Median follow-up was 4.8 years (5th to 95th percentile, 3.0 to 5.4). With adjustments applied for covariables, e' velocity was a significant predictor of fatal and nonfatal cardiovascular (n=59; P=0.004) and cardiac events (n=40; P=0.001). TDI e' yielded a net reclassification improvement of 54.2% for cardiovascular and 64.0% for cardiac events. Hazard ratios of all cardiovascular (2.21; P=0.042) and cardiac (4.50; P=0.002) events were significantly elevated in participants with increased LV filling pressure compared with subjects with normal diastolic function. CONCLUSIONS: TDI e' velocity is a significant predictor of fatal and nonfatal cardiovascular events in a general population. Furthermore, we observed an increase in all cardiovascular events in the diastolic dysfunction group characterized by elevated LV filling pressure. PMID- 24780208 TI - An unusual cause of epigastric pain after stent placement for bariatric surgery leak. PMID- 24780209 TI - Low FODMAP diet in the treatment of irritable bowel syndrome: is it the end of the road or the beginning of a journey? PMID- 24780210 TI - An unresectable Klatskin's tumor? PMID- 24780211 TI - Reply: To PMID 24076059. PMID- 24780212 TI - Uncommon case of ulcerative esophagitis. PMID- 24780213 TI - Staging for hepatocellular carcinoma: complex and confusing. PMID- 24780215 TI - Re: Halmos et al, A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. PMID- 24780214 TI - The anti-inflammasome effect of lactate and the lactate GPR81-receptor in pancreatic and liver inflammation. PMID- 24780216 TI - Toxicity of cylindrospermopsin in human lymphocytes: proliferation, viability and cell cycle studies. AB - The global expansion of cylindrospermopsin (CYN) producing cyanobacteria in surface freshwater increases the risk of human exposure and poisoning. Following ingestion, CYN is transported with blood in general circulation to the liver and kidneys, and can potentially interact with immune system cells. In the present study, we investigated whether CYN (0.01-1.0 MUg ml(-1)) can alter the function of human peripheral blood lymphocytes isolated from healthy donors. It was found that CYN demonstrates significant antiproliferative activity in lymphocytes during different phases of their activation. The most remarkable effects (decrease by>90%) were observed in lymphocytes exposed to 1 MUg ml(-1) CYN at the beginning of activation. Further analyses revealed a cell-cycle arrest at G0/G1 and prolonged S phase in lymphocytes undergoing activation and significant apoptosis inducement in activated cells. Reduced abilities to fight pathogenic microorganisms or malignant cells should be taken into consideration in CYN exposure and risk assessments. PMID- 24780217 TI - Yessotoxin triggers ribotoxic stress. AB - This work tests the hypothesis that the marine algal toxin yessotoxin (YTX) can trigger ribotoxic stress response in L6 and BC3H1 myoblast cells. YTX exposure at a concentration of 100 nM displays the characteristics of a ribotoxic stress response in such cells. The exposure leads to activation of the p38 mitogen activated protein kinase, the stress-activated protein kinase c-jun, and the double-stranded RNA-activated protein kinase (PKR). YTX treatment also causes ribosomal RNA cleavage and inhibits protein synthesis. These observations support the idea that YTX can act as a ribotoxin. PMID- 24780218 TI - Cytotoxicity of cinnamon-flavored electronic cigarette refills: are the results truly applicable to electronic cigarette use? PMID- 24780219 TI - Two Perkinsus spp. infect Crassostrea gasar oysters from cultured and wild populations of the Rio Sao Francisco estuary, Sergipe, northeastern Brazil. AB - Brazilian production of bivalve molluscs is small but expanding, especially in the northeastern region where the native oysters Crassostrea rhizophorae and C. gasar are abundant, and tropical weather promotes their rapid growth. Studies on bivalve pathology are scarce in Brazil, with only a few employing techniques for detecting protozoan pathogens listed by the World Organisation for Animal Health (OIE). In 2008, a Perkinsus sp. was reported for the first time in Brazil, infecting C. rhizophorae oysters from a wild population in Ceara state, NE Brazil. Recently P. marinus was detected in the same oyster species in nearby Paraiba state. These findings highlighted the need to expand knowledge on the presence and impacts of Perkinsus spp. on Brazilian oyster populations. The current investigation evaluated Perkinsus sp. infections among wild and cultured C. gasar mangrove oysters from the estuary of the Rio Sao Francisco, Sergipe state, NE Brazil. Our results show that Perkinsus sp. infections occurred commonly in oysters of both groups, at prevalences that were frequently higher among cultured oysters. Prevalences varied seasonally, with maximum values during summer (January) of 57% and 80% for wild and cultured oysters respectively, and minimum values during winter (July). Results of DNA sequencing, in situ hybridization assays, and phylogenetic analyses showed dual- and single-pathogen infections by P. marinus and/or P. olseni in the tested oysters. PMID- 24780220 TI - A simple colorimetric DNA detection by target-induced hybridization chain reaction for isothermal signal amplification. AB - A novel DNA detection method is presented based on a gold nanoparticle (AuNP) colorimetric assay and hybridization chain reaction (HCR). In this method, target DNA hybridized with probe DNA modified on AuNP, and triggered HCR. The resulting HCR products with a large number of negative charges significantly enhanced the stability of AuNPs, inhibiting aggregation of AuNPs at an elevated salt concentration. The approach was highly sensitive and selective. Using this enzyme free and isothermal signal amplification method, we were able to detect target DNA at concentrations as low as 0.5 nM with the naked eye. Our method also has great potential for detecting other analytes, such as metal ions, proteins, and small molecules, if the target analytes could make HCR products attach to AuNPs. PMID- 24780221 TI - Cold-microwave enhanced enzyme-linked immunosorbent assays--a path to high throughput clinical diagnostics. AB - The enzyme-linked immunosorbent assay (ELISA) constitutes an important clinical diagnostic approach. However, the prolonged incubation times involved lead to turnaround times of typically ?1 day, potentially delaying a definitive diagnosis or an adequate treatment plan for individual patients. Here cold-microwave technology (CMT) was employed to significantly reduce the times required for diagnostic ELISAs. The new approach was validated and compared to a conventional ELISA setup measuring canine calprotectin (cCP). Canine serum and fecal specimens were used for the analytical validation of cCP ELISA by conventional and CMT ELISA. Cross-validation of both ELISA methods consisted of the determination of analytic sensitivity, linearity, accuracy, precision, and reproducibility. The long-term stability of antibody-coated ELISA plates was also evaluated up to 33 days. The ELISA approaches were comparable to each other. The observed-to expected ratios for linearity and accuracy were 100.2+/-11.8 and 98.1+/-10.8% (mean+/-standard deviation), respectively. Precision and reproducibility were ?17.2%. For samples run on precoated ELISA plates over 33 days %CVs were ?12.5%. While both ELISA approaches were analytically sensitive, linear, accurate, precise, and reproducible with measurements of cCP concentrations, CMT-ELISA offered a reduction in incubation times by 90-95%, facilitating a very fast turnaround time and suggesting CMT-ELISA for improved human and veterinary clinical diagnostics. PMID- 24780222 TI - Quantitative real-time kinetics of optogenetic proteins CRY2 and CIB1/N using single-molecule tools. AB - In this work we evaluate the interaction of two optogenetic protein variants (CIB1, CIBN) with their complementary protein CRY2 by single-molecule tools in cell-free extracts. After validating the blue light induced co-localization of CRY2 and CIB1/N by Forster resonance energy transfer (FRET) in live cells, a fluorescence correlation spectroscopy (FCS) based method was developed to quantitatively determine the in vitro association of the extracted proteins. Our experiments suggest that CIB1, in comparison with CIBN, possesses a better coupling efficiency with CRY2 due to its intact protein structure and lower diffusion rate within 300s detection window. PMID- 24780223 TI - A minimum variance method for genome-wide data-driven normalization of quantitative real-time polymerase chain reaction expression data. AB - Advances in multiplex qRT-PCR have enabled increasingly accurate and robust quantification of RNA, even at lower concentrations, facilitating RNA expression profiling in clinical and environmental samples. Here we describe a data-driven qRT-PCR normalization method, the minimum variance method, and evaluate it on clinically derived Mycobacterium tuberculosis samples with variable transcript detection percentages. For moderate to significant amounts of nondetection (~50%), our minimum variance method consistently produces the lowest false discovery rates compared to commonly used data-driven normalization methods. PMID- 24780224 TI - Extremozymes--biocatalysts with unique properties from extremophilic microorganisms. AB - Extremozymes are enzymes derived from extremophilic microorganisms that are able to withstand harsh conditions in industrial processes that were long thought to be destructive to proteins. Heat-stable and solvent-tolerant biocatalysts are valuable tools for processes in which for example hardly decomposable polymers need to be liquefied and degraded, while cold-active enzymes are of relevance for food and detergent industries. Extremophilic microorganisms are a rich source of naturally tailored enzymes, which are more superior over their mesophilic counterparts for applications at extreme conditions. Especially lignocellulolytic, amylolytic, and other biomass processing extremozymes with unique properties are widely distributed in thermophilic prokaryotes and are of high potential for versatile industrial processes. PMID- 24780225 TI - Laparoscopic diaphragm rupture repair (with video). PMID- 24780226 TI - Burkholderia vietnamiensis C09V as the functional biomaterial used to remove crystal violet and Cu(II). AB - Burkholderia vietnamiensis C09V (B.V. C09V) was used to remove both crystal violet (CV) and Cu(II) because dye effluents often contain dyes and metal ions. Inhibiting the strain's growth through the biosorption of Cu(II) on B.V. C09V and promoting its growth by using CV as a carbon source led to the degradation of CV (30mg/L). It fell to 36.9 percent and the amount of Cu(II) (50mg/L) removed rose to 34.9 percent in the presence of both CV and Cu(II). This outcome is comparable to the single presence of CV and Cu(II). EDS analysis showed that Cu(II) was adsorbed onto the strain (the atomic percentage of Cu(II) was 1.9 percent), while kinetic studies indicated that firstly, the decolorization of CV fitted well to the pseudo first-order degradation kinetic model and secondly, the biosorption of Cu(II) fitted well to the pseudo second-order kinetic model. The degradation rate constants of CV were stable in the 0.101-0.0068/h range and R(2) was both higher than 0.981 when Cu(II) concentrations were present. Furthermore, the biosorption capacity of Cu(II) ranged from 38.8 to 20.3mg/g at the CV concentration of 30mg/L (both R(2)>0.96). This suggests that the strain has the potential to degrade CV and facilitate the biosorption of Cu(II) in dye effluent. PMID- 24780227 TI - Identification of heavy metal sources in the reclaimed farmland soils of the pearl river estuary in China using a multivariate geostatistical approach. AB - Heavy metals in the reclaimed farmland soils of the Pearl River Estuary in China have attracted much attention because of the health risk posed to local residents. The identification of heavy metal sources in these soils is necessary to reduce their health risk. Reclaimed farmland soil samples were collected from 144 sites in the Pearl River Estuary and the contents of heavy metals (Cd, Pb, Cr, Ni, Cu, and Zn) were determined. All these heavy metals showed concentrations substantially higher than their background values, indicating possible anthropogenic pollution. The results of a multivariate geostatistical method demonstrate that grouped Cd, Cr, and Cu were mainly controlled by chemical fertilizers. Grouped Pb and Zn were the most severely impacted by atmospheric deposition from Guangzhou and Foshan, and Ni was primarily impacted by electroplating factories' wastewater discharge. PMID- 24780228 TI - gamma-H2AX as a biomarker for DNA double-strand breaks in ecotoxicology. AB - The visualisation of DNA damage response proteins enables the indirect measurement of DNA damage. Soon after the occurrence of a DNA double-strand break (DSB), the formation of gamma-H2AX histone variants is to be expected. This review is focused on the potential use of the gamma-H2AX foci assay in assessing the genotoxicity of environmental contaminants including cytostatic pharmaceuticals, since standard methods may not be sensitive enough to detect the damaging effect of low environmental concentrations of such drugs. These compounds are constantly released into the environment, potentially representing a threat to water quality, aquatic organisms, and, ultimately, human health. Our review of the literature revealed that this method could be used in the biomonitoring and risk assessment of aquatic systems affected by wastewater from the production, usage, and disposal of cytostatic pharmaceuticals. PMID- 24780229 TI - Overexpression of Iris. lactea var. chinensis metallothionein llMT2a enhances cadmium tolerance in Arabidopsis thaliana. AB - Metallothioneins (MTs) are cysteine-rich, low molecular weight, heavy metal binding protein molecules. Here, a full-length cDNA homologue of MT2a (type 2 metallothionein) was isolated from the cadmium-tolerant species Iris. lactea var. chinensis (I. lactea var. chinensis). Expression of IlMT2a in I. lactea var. chinensis roots and leaves was up-regulated in response to cadmium stress. When the gene was constitutively expressed in Arabidopsis thaliana (A. thaliana), root length of transgenic lines was longer than that of wild-type under 50MUM or 100MUM cadmium stress. However, there was no difference of cadmium absorption between wild-type and trangenic lines. Histochemical staining by 3,3 diaminobenzidine (DAB) and nitroblue tetrazoliu (NBT) clearly demonstrated that transgenic lines accumulated remarkably less H2O2 and O2(-) than wild-type. Together, IlMT2a may be a promising gene for the cadmium tolerance improvement. PMID- 24780230 TI - CombiSimilarity, an innovative method to compare environmental and health data sets with different attribute sizes example: eighteen Organochlorine Pesticides in soil and human breast milk samples. AB - Human health and the health of the environment have entwined. In this paper we underpin this position by presenting a modeling approach named CombiSimilarity, which has been developed by the first author in the software tool PyHasse comprising a wide variety of partial ordering tools. A case study of 18 Organochlorine Pesticides (OCPs) detected in soil as well as in human breast milk samples in the Taurus Mountains in Turkey is carried out. Seven soil samples and 44 breast milk samples were measured. We seek to answer the question whether the contamination pattern in breast milk is associated with the contamination pattern in soil by studying the mutual quantitative relationships of the chemicals involved. We could demonstrate that there is a similarity with respect to the concentration profiles between the soil and breast milk pollution. Therefore the hypothesis may be formulated that the concentrations of chemicals in the milk samples are strongly related to the soil contamination. This supports the concept that soil could be a surrogate for human exposure at background locations. PMID- 24780231 TI - Sulfur metabolism: different tolerances of two aquatic macrophytes exposed to arsenic. AB - The toxicity of arsenic (As) and the mechanisms of response to this pollutant were analyzed in two aquatic plant species, one sensitive and one tolerant to the pollutant, Salvinia minima and Lemna gibba, respectively. The plants, grown in nutrient solution at pH 6.5, were exposed to As concentrations of 0.0 and 1.0mgL( 1) for 3 days. Both species accumulated As in their tissues, which resulted in increases in H2O2 production. L. gibba accumulated eleven times more As than S. minima. However, L. gibba was more tolerant, as shown by the absence of cell membrane damage and, despite greater accumulation, smaller growth reduction than S. minima. Indeed, the index of tolerance to As was twenty percent higher in L. gibba than in S. minima, which most likely results from the presence of a more efficient defense system. This defense system in L. gibba is most likely based on sulfate absorption, assimilation and metabolism. L. gibba showed an increase in sulfate absorption and adenosine-5'-triphosphate (ATP) sulfurylase activity (the first enzyme of the inorganic sulfate assimilation pathway) following exposure to As. Consequently, the plant produced greater concentrations of sulfur-containing compounds that are involved in cellular detoxification, such as glutathione and non-protein thiols, and demonstrated greater enzymatic activity of gamma glutamylcysteine synthetase, glutathione S-transferase and glutathione reductase. Therefore, the plant's ability to increase absorption, assimilation and metabolism of sulfur are key steps for tolerance to oxidative stress triggered by metals. PMID- 24780232 TI - Development of a non-lethal method for evaluating transcriptomic endpoints in Arctic grayling (Thymallus arcticus). AB - With increases in active mining and continued discharge associated with former mine operations, evaluating the health of watersheds in the Canadian Yukon Territory is warranted. Current environmental assessment approaches often employ guidelines established using sentinel species not relevant to Arctic monitoring programs. The present study focused on the successful development of a quantitative real-time polymerase chain reaction (qPCR) assay directed towards the indigenous Arctic grayling (Thymallus arcticus) and examines the feasibility of using non-lethal sampling from the caudal fin as a means for evaluation of mRNA abundance profiles reflective of environmental conditions. In a proof of concept study performed blind, qPCR results from animals in an area with elevated water concentrations of cadmium (Cd) and zinc (Zn) and higher body burdens of Cd, Zn, and lead (Pb) were compared to a reference location in the Yukon Territory. Lower condition factor and a higher abundance of hepatic and caudal fin gene transcripts encoding the metallothionein isoforms (mta/mtb), in addition to elevated heat shock protein 70 (hsp70) and catalase (cat) mRNAs in liver, were observed in fish from the test site. The strong positive correlation between metal body burden and caudal fin mta/mtb mRNA abundance demonstrates a high potential for use of the Arctic grayling assay in non-lethal environmental monitoring programs. PMID- 24780233 TI - Ferret-mouse differences in interkinetic nuclear migration and cellular densification in the neocortical ventricular zone. AB - The thick outer subventricular zone (OSVZ) is characteristic of the development of human neocortex. How this region originates from the ventricular zone (VZ) is largely unknown. Recently, we showed that over-proliferation-induced acute nuclear densification and thickening of the VZ in neocortical walls of mice, which lack an OSVZ, causes reactive delamination of undifferentiated progenitors and invasion by these cells of basal areas outside the VZ. In this study, we sought to determine how VZ cells behave in non-rodent animals that have an OSVZ. A comparison of mid-embryonic mice and ferrets revealed: (1) the VZ is thicker and more pseudostratified in ferrets. (2) The soma and nuclei of VZ cells were horizontally and apicobasally denser in ferrets. (3) Individual endfeet were also denser on the apical (ventricular) surface in ferrets. (4) In ferrets, apicalward nucleokinesis was less directional, whereas basalward nucleokinesis was more directional; consequently, the nuclear density in the periventricular space (within 16 MUm of the apical surface) was smaller in ferrets than in mice, despite the nuclear densification seen basally in ferrets. These results suggest that species-specific differences in nucleokinesis strategies may have evolved in close association with the magnitudes and patterns of nuclear stratification in the VZ. PMID- 24780234 TI - Charting the course of pediatric nursing research: the SPN Delphi study. AB - In order to inform the care of children at this pivotal time in the history of healthcare, the Society of Pediatric Nurses (SPN) sought to identify priorities for nursing research and key challenges facing pediatric nursing. A three round Delphi study was conducted electronically with SPN members. The top 10 priorities and challenges were identified and will serve as a valuable guide for pediatric nursing practice, education, policy and administration over the coming decade. PMID- 24780235 TI - Hygienic conditions in child-care facilities in North Carolina and South Carolina: an integrated microbial and observational study. AB - BACKGROUND: In the United States almost one-quarter (23%) of children younger than age 5 years participate in some form of out-of-home child care; these children are 2.3-3.5 times more likely to contract acute gastrointestinal illness. METHODS: Observational investigations were done to understand the hygienic conditions and practices of 40 child-care facilities in North Carolina and South Carolina. These data were compared with microbiological indicator data (aerobic plate counts and coliform counts) collected from selected surfaces in each facility. Results from the two data sets were analyzed using nonparametric statistical methods to reveal potential risk factors for enteric disease transmission. RESULTS: Statistically significant differences (P <= .05) in surface microbial counts were observed when comparing family child-care homes versus centers and between facilities participating in the Child and Adult Care Food Program and those that do not participate. Facilities without written surface cleaning or food preparation policies had statistically significantly higher microbial counts on surfaces. CONCLUSIONS: Our unique study, which combined observational and microbiological data, provided revealing information about the relationship between hygiene indicators and sanitary practices in child care facilities in the southeastern United States. PMID- 24780236 TI - Elevated blood Hg at recommended seafood consumption rates in adult seafood consumers. AB - Mercury (Hg) exposure from seafood continues to be a public health concern due to health effects from elevated exposure, increasing worldwide seafood consumption, and continued Hg inputs into the environment. Elevated Hg exposure can occur in populations with specialized diets of sport-caught freshwater fish. However, we need a better understanding of Hg exposure from seafood, the most common exposure source, and from specific seafood types. We examined Hg exposure in avid seafood consumers, and the seafood items and consumption frequency that confer the largest Hg exposure. Adult, avid seafood consumers, in Long Island, NY, USA, with blood total Hg concentrations predicted to exceed the USEPA reference concentration that is considered safe (5.8 MUg L(-1)), were eligible for the study; 75% of self-reported avid seafood consumers were eligible to participate. We measured blood total Hg concentrations and seafood consumption in 285 participants. We examined relationships between Hg and seafood consumption using multiple linear regression. Seafood consumption rate for our population (14.4 kg yr(-1)) was >2 times that estimated for the U.S. (6.8 kg yr(-1)), and lower than the worldwide estimate (18.4 kg yr(-1)). Mean blood Hg concentration was 4.4 times the national average, and 42% of participants had Hg concentrations exceeding 5.8 MUg L(-1). Elevated Hg exposures occurred at all seafood consumption frequencies, including the recommended frequency of 2 meals per week. Blood Hg concentrations were positively associated with weekly tuna steak or sushi intake (beta=6.30 change in blood Hg, MUg L(-1)) and monthly (beta=2.54) or weekly (beta=9.47) swordfish, shark or marlin intake. Our findings show that seafood consumers in this population have elevated Hg exposures even at relatively low seafood consumption rates that are at or below current dietary recommendations. Further study should examine health risks and benefits of avid seafood consumption, and consider modifying guidelines to include recommendations for specific seafood types. PMID- 24780237 TI - Elevation of serum lactate dehydrogenase at posterior reversible encephalopathy syndrome onset in chemotherapy-treated cancer patients. AB - The pathophysiology of posterior reversible encephalopathy syndrome (PRES) is incompletely understood; however, an underlying state of immune dysregulation and endothelial dysfunction has been proposed. We examined alterations of serum lactate dehydrogenase (LDH), a marker of endothelial dysfunction, relative to the development of PRES in patients receiving chemotherapy. A retrospective Institutional Review Board approved database of 88 PRES patients was examined. PRES diagnosis was confirmed by congruent clinical diagnosis and MRI. Clinical features at presentation were recorded. Serum LDH values were collected at three time points: prior to, at the time of, and following PRES diagnosis. Student's t test was employed. LDH values were available during the course of treatment in 12 patients (nine women; mean age 57.8 years [range 33-75 years]). Chemotherapy associated PRES patients were more likely to be normotensive (25%) versus the non chemotherapy group (9%). LDH levels at the time of PRES diagnosis were higher than those before and after (p=0.0263), with a mean difference of 114.8 international units/L. Mean time intervals between LDH measurement prior to and following PRES diagnosis were 44.8 days and 51.4 days, respectively. Mean elapsed time between last chemotherapy administration and PRES onset was 11.1days. In conclusion, serum LDH, a marker of endothelial dysfunction, shows statistically significant elevation at the onset of PRES toxicity in cancer patients receiving chemotherapy. Our findings support a systemic process characterized by endothelial injury/dysfunction as a factor, if not the prime event, in the pathophysiology of PRES. PMID- 24780239 TI - Withdraw Saatchi's quackery bill. PMID- 24780238 TI - Cell-based delivery of dATP via gap junctions enhances cardiac contractility. AB - The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC CMs) is a promising strategy to treat myocardial infarction and reverse heart failure, but to date the contractile benefit in most studies remains modest. We have previously shown that the nucleotide 2-deoxyadenosine triphosphate (dATP) can substitute for ATP as the energy substrate for cardiac myosin, and increasing cellular dATP content by globally overexpressing ribonucleotide reductase (R1R2) can dramatically enhance cardiac contractility. Because dATP is a small molecule, we hypothesized that it would diffuse readily between cells via gap junctions and enhance the contractility of neighboring coupled wild type cells. To test this hypothesis, we performed studies with the goals of (1) validating gap junction mediated dATP transfer in vitro and (2) investigating the use of R1R2 overexpressing hPSC-CMs in vivo as a novel strategy to increase cardiac function. We first performed intracellular dye transfer studies using dATP conjugated to fluorescein and demonstrated rapid gap junction-mediated transfer between cardiomyocytes. We then cocultured wild type cardiomyocytes with either cardiomyocytes or fibroblasts overexpressing R1R2 and saw more than a twofold increase in the extent and rate of contraction of wild type cardiomyocytes. Finally, we transplanted hPSC-CMs overexpressing R1R2 into healthy uninjured rat hearts and noted an increase in fractional shortening from 41+/-4% to 53+/-5% just five days after cell transplantation. These findings demonstrate that dATP is an inotropic factor that spreads between cells via gap junctions. Our data suggest that transplantation of dATP-producing hPSC-CMs could significantly increase the effectiveness of cardiac cell therapy. PMID- 24780240 TI - Cultivable gut bacteria of scarabs (Coleoptera: Scarabaeidae) inhibit Bacillus thuringiensis multiplication. AB - The entomopathogen Bacillus thuringiensis is used to control various pest species of scarab beetle but is not particularly effective. Gut bacteria have diverse ecological and evolutionary effects on their hosts, but whether gut bacteria can protect scarabs from B. thuringiensis infection remains poorly understood. To investigate this, we isolated 32 cultivable gut bacteria from Holotrichia oblita Faldermann, Holotrichia parallela Motschulsky, and Anomala corpulenta Motschulsky, and analyzed their effect on B. thuringiensis multiplication and Cry toxin stability. 16S rDNA analysis indicated that these gut bacteria belong to the Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes phyla. A confrontation culture analyses of the 32 isolates against three scarab-specific B. thuringiensis strains showed that the majority of the scarab gut bacteria had antibacterial activity against the B. thuringiensis strains. The Cry toxin stability analysis results showed that while several strains produced proteases capable of processing the scarab-specific toxin Cry8Ea, none were able to completely degrade it. These results suggest that gut bacteria can potentially affect the susceptibility of scarabs to B. thuringiensis and that this should be considered when considering future control measures. PMID- 24780241 TI - Application of PCR-based methods for diagnosis of intestinal parasitic infections in the clinical laboratory. AB - For many years PCR- and other DNA-based methods of pathogen detection have been available in most clinical microbiology laboratories; however, until recently these tools were not routinely exploited for the diagnosis of parasitic infections. Laboratories were initially reluctant to implement PCR as incorporation of such assays within the algorithm of tools available for the most accurate diagnosis of a large variety of parasites was unclear. With regard to diagnosis of intestinal parasitic infections, the diversity of parasites that one can expect in most settings is far less than the parasitological textbooks would have you believe, hence developing a simplified diagnostic triage is feasible. Therefore the classical algorithm based on population, patient groups, use of immuno-suppressive drugs, travel history etc. is also applicable to decide when to perform and which additional techniques are to be used, if a multiplex PCR panel is used as a first-line screening diagnostic. PMID- 24780242 TI - Endocarditis 2014: an update. AB - The epidemiology of infective endocarditis is changing due to a number of factors, including more frequent and varied antibiotic use, the emergence of resistant microorganisms, and an increase in the implantation of cardiovascular devices. This review outlines and consolidates the most recent guidelines, including the 2007 and 2010 AHA/ACC guidelines and scientific statements for the prevention and management of infective endocarditis and for the management of cardiovascular device infections. The evidence-based guidelines, including the 2009 HRS consensus document, for the treatment of patients with cardiovascular device-related infections are also reviewed. Only patients with prosthetic valves, patients with prior endocarditis, cardiac transplant patients with a valvulopathy, and certain congenital heart disease patients now require endocarditis prophylaxis. There is an increasing incidence of cardiovascular device-related infections due to the higher frequency of implanted devices and higher morbidity and mortality rates in older patients. PMID- 24780243 TI - Membrane permeability of the human pluripotent stem cells to Me2SO, glycerol and 1,2-propanediol. AB - Due to the unlimited capacity of self-renew and ability to differentiate into derivatives of three germ layers, human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), have a great potential in regenerative medicine. A major challenge we are facing during the long-term storage of human pluripotent stem cells with the conventional slow cooling rate is the low cell recovery rate after cryopreservation which cannot meet the requirements for the future clinical applications. Evaluating the cell membrane permeability and the corresponding activation energy of hESCs and hiPSCs for water and different cryoprotective agents (CPA), including dimethyl sulfoxide (Me2SO), 1,2-propandiol and glycerol, is important for facilitating the development of cryopreservation protocol to enhance cell recovery after the cryopreservation. The osmotically inactive volume of hESCs and hiPSCs determined using the Boyle-van't Hoff model was 0.32V0 and 0.42V0, respectively. The membrane permeability was assessed from the volume changes of cells exposed to Me2SO, 1,2-propanediol and glycerol at the temperatures ranging from 8 to 30 degrees C. These results showed the biophysical differences between hESCs and hiPSCs. Their activation energy for water and CPAs extrapolated from the Arrhenius relationship indicated that the water transport was probably not through the channel-mediated mechanism. PMID- 24780244 TI - Effect of temperature, pH and heme ligands on the reduction of Cygb(Fe(3+)) by ascorbate. AB - Cytoglobin (Cygb) plays a role in regulating vasodilation in response to changes in local oxygen concentration by altering the rate of nitric oxide (NO) metabolism. Because the reduction of Cygb(Fe(3+)) by a reductant is the control step for Cygb-mediated NO metabolism, we examined the effects of temperature, pH, and heme ligands on the Cygb(Fe(3+)) reduction by ascorbate (Asc) under anaerobic conditions. The standard enthalpy of Cygb(Fe(3+)) reduction by Asc was determined to be 42.4 +/- 3.1 kJ/mol. The rate of Cygb(Fe(3+)) reduction increased ~6% per degrees C when temperature varied from 35 degrees C to 40 degrees C. The yield and the rate of Cygb(Fe(3+)) reduction significantly increases with pH (2-3 times per pH unit), paralleling the formation of the Asc ion (A(2-)) and the increased stability of reduced state of heme iron at high pH values. Heme ligand cyanide (CN(-)) decreased the yield and the rate of Cygb(Fe(3+)) reduction, but ligands CO and NO allowed the process of Cygb(Fe(3+)) reduction to continue to completion. Critical information is provided for modeling and prediction of the process of Cygb-mediated NO metabolism in vessels in a range of temperature and pH values. PMID- 24780246 TI - Causal link between vitamin D deficiency and ill health still possible. PMID- 24780247 TI - Alterations of the biomarker S-100B and NSE in patients with acute vertebral spine fractures. AB - BACKGROUND CONTEXT: Although several publications concerning the use of the biomarkers S100B and neuron-specific enolase (NSE) in vertebral spine fractures in animal experimental studies have proven their usefulness as early indicators of injury severity, there are no clinical reports on their effectiveness as indicators in patients with spinal injuries. As these biomarkers have been examined, with promising results, in patients with traumatic brain injury, there is a potential for their implementation in patients with vertebral spine fractures. PURPOSE: To investigate the early serum measurement of S100B and NSE in patients with vertebral spine fractures compared with those in patients with acute fractures of the proximal femur. STUDY DESIGN: Prospective longitudinal cohort study. PATIENT SAMPLE: A cohort of 34 patients admitted over an 18-month period to a single medical center for suspected vertebral spine trauma. Twenty nine patients were included in the control group. OUTCOME MEASURES: S100B and NSE serum levels were assessed in different types of vertebral spine fractures. METHODS: We included patients older than 16 years with vertebral spine fractures whose injuries were sustained within 24 hours before admission to the emergency room and who had undergone a brief neurologic examination. Spinal cord injuries (SCIs) were classified as being paresthesias, incomplete paraplegias, or complete paraplegias. Blood serum was obtained from all patients within 24 hours after the time of injury. Serum levels of S100B and NSE were statistically analyzed using Wilcoxon signed-rank test. RESULTS: S100B serum levels were significantly higher in patients with vertebral spine fractures (p=.01). In these patients, the mean S100B serum level was 0.75 MUg/L (standard deviation [SD] 1.44, 95% confidence interval [CI] 0.24, 1.25). The mean S100B serum level in control group patients was 0.14 MUg/L (SD 0.11, 95% CI 0.10, 0.19). The 10 patients with neurologic deficits had significantly higher S100B serum levels compared with the patients with vertebral fractures but without neurologic deficits (p=.02). The mean S100B serum level in these patients was 1.18 MUg/L (SD 1.96). In the 26 patients with vertebral spine fractures but without neurologic injury, the mean S100B serum level was 0.42 MUg/L (SD 0.91, 95% CI 0.08, 0.76). The analysis revealed no significant difference in NSE levels. CONCLUSIONS: We observed a significant correlation not only between S100B serum levels and vertebral spine fractures but also between S100B serum levels and SCIs with neurologic deficit. These results may be meaningful in clinical practice and to future studies. PMID- 24780245 TI - Updates of reactive oxygen species in melanoma etiology and progression. AB - Reactive oxygen species (ROS) play crucial roles in all aspects of melanoma development, however, the source of ROS is not well defined. In this review we summarize recent advancement in this rapidly developing field. The cellular ROS pool in melanocytes can be derived from mitochondria, melanosomes, NADPH oxidase (NOX) family enzymes, and uncoupling of nitric oxide synthase (NOS). Current evidence suggests that Nox1, Nox4 and Nox5 are expressed in melanocytic lineage. While there is no difference in Nox1 expression levels in primary and metastatic melanoma tissues, Nox4 expression is significantly higher in a subset of metastatic melanoma tumors as compared to the primary tumors; suggesting distinct and specific signals and effects for NOX family enzymes in melanoma. Targeting these NOX enzymes using specific NOX inhibitors may be effective for a subset of certain tumors. ROS also play important roles in BRAF inhibitor induced drug resistance; hence identification and blockade of the source of this ROS may be an effective way to enhance efficacy and overcome resistance. Furthermore, ROS from different sources may interact with each other and interact with reactive nitrogen species (RNS) and drive the melanomagenesis process at all stages of disease. Further understanding ROS and RNS in melanoma etiology and progression is necessary for developing new prevention and therapeutic approaches. PMID- 24780248 TI - Limitations of administrative databases in spine research: a study in obesity. AB - BACKGROUND CONTEXT: The use of national inpatient databases for spine surgery research has been increasing. Unfortunately, without firsthand knowledge of each specific database, it can be difficult to judge the validity of such studies. Large databases that rely on administrative data, such as International Classification of Diseases, Ninth Revision (ICD-9) codes, may misrepresent patient information and could thus affect the results of studies that use these data. PURPOSE: The present study uses obesity, an easily quantified and objective variable, as an example comorbidity to assess the accuracy of ICD-9 codes in the setting of their continued use in spine database studies. STUDY DESIGN/SETTING: A cross-sectional study at a large academic medical center. PATIENT SAMPLE: All patients spending at least one night in the hospital as an inpatient between April 1, 2013 and April 16, 2013. Obstetrics and gynecology, psychiatry, and pediatric patients were excluded. OUTCOME MEASURES: Proportion of patients for whom ICD-9 obesity diagnosis codes assigned at hospital discharge match chart documented body mass index (BMI). METHODS: The medical record was reviewed for each patient, and obesity ICD-9 codes were directly compared with documented BMI. RESULTS: The study included 2,075 patients. Of 573 "obese" patients (calculated BMI 30-39.9), only 109 received the correct code (278.00), giving this ICD-9 code a sensitivity of 0.19. Of 174 "morbidly obese" patients (calculated BMI >40), only 84 received the correct code (278.01), giving this ICD-9 code a sensitivity of 0.48. CONCLUSIONS: Using obesity as an example, this study highlights the potential errors inherent to using ICD-9-coded databases for spine surgery research. Should a study based on such data use "obesity" as a variable in any analyses, the reader should interpret these results with caution. We further suggest that obesity is likely not the only comorbidity to which these results apply. As database research continues to represent an increasing proportion of publications in the field of spine surgery, it is important to realize that study outcomes can be skewed by data accuracy, and, thus, should not be blindly accepted simply by virtue of large sample sizes. PMID- 24780249 TI - Cost-effective studies in spine surgeries: a narrative review. AB - BACKGROUND CONTEXT: Although the pathologic processes that affect the spine remain largely unchanged, our techniques to correct them continue to evolve with the development of novel medical and surgical interventions. Although the primary purpose of new technologies is to improve patients' quality of life, the economic impact of such therapies must be considered. PURPOSE: To review the available peer-reviewed literature on spine surgery that addresses the cost-effectiveness of various treatments and technologies. STUDY DESIGN: A narrative literature review. METHODS: Articles published between January 1, 2000 and December 31, 2012 were selected from two Pubmed searches using keywords cost-effectiveness AND spine (216 articles) and cost analysis AND spine (358 articles). Relevant articles on cost analyses and cost-effectiveness were selected by the authors and reviewed. RESULTS: Cervical and lumbar surgeries (anterior cervical discectomy and fusion, standard open lumbar discectomy, and standard posterior lumbar laminectomy) are reasonably cost effective at 2 years after the procedure (<100,000 US dollars per quality-adjusted life years gained) and become more cost effective with time because of sustained clinical improvements with relatively low additional incurred costs. The usage of transfusion avoidance technology is not cost effective because of the low risk of complications associated with allogenic transfusions. Although intraoperative neuromonitoring and imaging modalities are both cost saving and cost-effective, their cost-effectiveness is largely dependent on the baseline rate of neurologic complications and implant misplacement, respectively. More rigorous studies are needed to evaluate the cost effectiveness of recombinant bone morphogenetic protein. CONCLUSIONS: An ideal new technology should be able to achieve maximal improvement in patient health at a cost that society is willing to pay. The cost-effectiveness of technologies and treatments in spine care is dependent on their durability and the rate and severity of the baseline clinical problem that the treatment was designed to address. PMID- 24780250 TI - Low doses of flagellin-L2 multimer vaccines protect against challenge with diverse papillomavirus genotypes. AB - Genetically modified bacterial flagellin (Fla), a Toll-like receptor-5 (TLR5) ligand, was evaluated as a fusion partner for human papillomavirus (HPV) L2-based immunogens in two animal challenge models; either cutaneous inoculation of rabbits with HPV 'quasivirions' containing cottontail rabbit papillomavirus (CRPV) genomes that induce warts, or intra-vaginal inoculation of mice with HPV 'pseudovirions' encapsidating a luciferase reporter plasmid and measurement of bioluminescence to determine infectivity. An Escherichia coli production system was developed for flagellin-L2 (Fla-L2) fusions containing either monomeric HPV 16 L2 a.a. 11(*11-200) or oligomeric L2 comprising a fusion of the a.a. 11-88 peptides of five (Fla~5*11-88) or eight (Fla~8*11-88) genital HPV types. Immunogenicity and bioactivity of Fla-L2 constructs were assessed using an in vitro neutralization and cell-based TLR-5 binding assay, respectively. Efficacy was evaluated following active immunization of rabbits or mice administered 3 intramuscular doses of Fla-L2 recombinants without exogenous adjuvant, followed by challenge. In addition, passive immunization studies of naive rabbits with serial dilutions of pooled immune sera were used to determine End-Point Protection Titers (EPPT) for each formulation against a broader spectrum of HPV quasivirions. Efficacy was assessed for up to 10 weeks on the basis of wart volume induced following challenge and results compared to licensed L1-VLP vaccines (Gardasil and Cervarix). Following active immunization at doses as low as 1 MUg, Fla-L2 fusions afforded complete protection against infection (mice) and disease (rabbits) following either homologous or heterologous HPV challenge. Passive immunization with anti-L2 immune sera discriminated between the different vaccine candidates under evaluation, demonstrated the protective role of antibody and suggested the superiority of this oligomeric L2-TLR5 agonist fusion approach compared to L1-based vaccines in its ability to cross-protect against non-vaccine HPV types. PMID- 24780251 TI - Enhancement of recombinant adenovirus vaccine-induced primary but not secondary systemic and mucosal immune responses by all-trans retinoic acid. AB - Vaccination is an important tool for enhancing immune responses against mucosal pathogens. Intramuscularly administered adenovirus (Ad) vectors have been demonstrated to be strong inducers of both systemic and mucosal immune responses. Further enhancement of immune responses following Ad vaccination is highly desirable. All-trans retinoic acid (ATRA), a biologically active vitamin A metabolite, has been explored as an adjuvant for primary immune responses following vaccination. In this study, we investigated the effect of ATRA on a heterologous Ad prime boost regimen. ATRA co-administration during priming increased mucosal and systemic antibody responses as well as mucosal but not systemic CD8(+) T cell responses. However, this effect was no longer apparent after boosting regardless of whether ATRA was administered at the time of priming, at the time of boosting, or at both immunizations. Our findings confirm ATRA as an adjuvant for primary immune responses and suggest that the adjuvant effect does not extend to secondary immune responses. PMID- 24780252 TI - TRPA1 receptor stimulation by hydrogen peroxide is critical to trigger hyperalgesia and inflammation in a model of acute gout. AB - Acute gout attacks produce severe joint pain and inflammation associated with monosodium urate (MSU) crystals leading to oxidative stress production. The transient potential receptor ankyrin 1 (TRPA1) is expressed by a subpopulation of peptidergic nociceptors and, via its activation by endogenous reactive oxygen species, including hydrogen peroxide (H2O2), contributes to pain and neurogenic inflammation. The aim of this study was to investigate the role of TRPA1 in hyperalgesia and inflammation in a model of acute gout attack in rodents. Inflammatory parameters and mechanical hyperalgesia were measured in male Wistar rats and in wild-type (Trpa1(+/+)) or TRPA1-deficient (Trpa1(-/-)) male mice. Animals received intra-articular (ia, ankle) injection of MSU. The role of TRPA1 was assessed by receptor antagonism, gene deletion or expression, sensory fiber defunctionalization, and calcitonin gene-related peptide (CGRP) release. We found that nociceptor defunctionalization, TRPA1 antagonist treatment (via ia or oral administration), and Trpa1 gene ablation abated hyperalgesia and inflammatory responses (edema, H2O2 generation, interleukin-1beta release, and neutrophil infiltration) induced by ia MSU injection. In addition, we showed that MSU evoked generation of H2O2 in synovial tissue, which stimulated TRPA1 producing CGRP release and plasma protein extravasation. The MSU-elicited responses were also reduced by the H2O2-detoxifying enzyme catalase and the reducing agent dithiothreitol. TRPA1 activation by MSU challenge-generated H2O2 mediates the entire inflammatory response in an acute gout attack rodent model, thus strengthening the role of the TRPA1 receptor and H2O2 production as potential targets for treatment of acute gout attacks. PMID- 24780253 TI - Effect of serine phosphorylation and Ser25 phospho-mimicking mutations on nuclear localisation and ligand interactions of annexin A2. AB - Annexin A2 (AnxA2) interacts with numerous ligands, including calcium, lipids, mRNAs and intracellular and extracellular proteins. Different post-translational modifications participate in the discrimination of the functions of AnxA2 by modulating its ligand interactions. Here, phospho-mimicking mutants (AnxA2-S25E and AnxA2-S25D) were employed to investigate the effects of Ser25 phosphorylation on the structure and function of AnxA2 by using AnxA2-S25A as a control. The overall alpha-helical structure of AnxA2 is not affected by the mutations, since the thermal stabilities and aggregation tendencies of the mutants differ only slightly from the wild-type (wt) protein. Unlike wt AnxA2, all mutants bind the anxA2 3' untranslated region and beta-gamma-G-actin with high affinity in a Ca(2+)-independent manner. AnxA2-S25E is not targeted to the nucleus in transfected PC12 cells. In vitro phosphorylation of AnxA2 by protein kinase C increases its affinity to mRNA and inhibits its nuclear localisation, in accordance with the data obtained with the phospho-mimicking mutants. Ca(2+) dependent binding of wt AnxA2 to phosphatidylinositol, phosphatidylinositol-3 phosphate, phosphatidylinositol-4-phosphate and phosphatidylinositol-5-phosphate, as well as weaker but still Ca(2+)-dependent binding to phosphatidylserine and phosphatidylinositol-3,5-bisphosphate, was demonstrated by a protein-lipid overlay assay, whereas binding of AnxA2 to these lipids, as well as its binding to liposomes, is inhibited by the Ser25 mutations. Thus, introduction of a modification (mutation or phosphorylation) at Ser25 appears to induce a conformational change leading to increased accessibility of the mRNA- and G-actin binding sites in domain IV independent of Ca(2+) levels, while the Ca(2+) dependent binding of AnxA2 to phospholipids is attenuated. PMID- 24780254 TI - Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology. AB - Tau pathology found in Alzheimer's disease (AD) is crucial in cognitive decline. Epidemiologic evidences support that habitual caffeine intake prevents memory decline during aging and reduces the risk to develop Alzheimer's disease. So far, experimental studies addressed the impact of caffeine in models mimicking the amyloid pathology of AD. However, in vivo effects of caffeine in a model of AD like tauopathy remain unknown. Here, we evaluated effects of chronic caffeine intake (0.3 g/L through drinking water), given at an early pathologic stage, in the THY-Tau22 transgenic mouse model of progressive AD-like tau pathology. We found that chronic caffeine intake prevents from the development of spatial memory deficits in tau mice. Improved memory was associated with reduced hippocampal tau phosphorylation and proteolytic fragments. Moreover, caffeine treatment mitigated several proinflammatory and oxidative stress markers found upregulated in the hippocampus of THY-Tau22 animals. Together, our data support that moderate caffeine intake is beneficial in a model of AD-like tau pathology, paving the way for future clinical evaluation in AD patients. PMID- 24780255 TI - Estrogenic compounds determination in water samples by dispersive liquid-liquid microextraction and micellar electrokinetic chromatography coupled to mass spectrometry. AB - In this work, a group of 12 estrogenic compounds, i.e., four natural sexual hormones (estrone, 17beta-estradiol, 17alpha-estradiol and estriol), an exoestrogen (17alpha-ethynylestradiol), a synthetic stilbene (dienestrol), a mycotoxin (zearalenone) and some of their major metabolites (2-methoxyestradiol, alpha-zearalanol, beta-zearalanol, alpha-zearalenol and beta-zearalenol) have been separated and determined by micellar electrokinetic chromatography (MEKC) coupled to electrospray ion trap mass spectrometry. For this purpose, a background electrolyte containing an aqueous solution of 45 mM of perfluorooctanoic acid (PFOA) adjusted to pH 9.0 with an ammonia solution, as MS friendly surfactant, and methanol (10% (v/v)), as organic modifier, was used. To further increase the sensitivity, normal stacking mode was applied by injecting the sample dissolved in an aqueous solution of 11.5mM of ammonium PFO (APFO) at pH 9.0 containing 10% (v/v) of methanol for 25s. Dispersive liquid-liquid microextraction, using 110 MUL of chloroform and 500 MUL of acetonitrile as extraction and dispersion solvents, respectively, was employed to extract and preconcentrate the target analytes from different types of environmental water samples (mineral, run-off and wastewater) containing 30% (w/v) NaCl and adjusted to pH 3.0 with 1M HCl. The limits of detection achieved were in the range 0.04 1.10 MUg/L. The whole method was validated in terms of linearity, precision, recovery and matrix effect for each type of water, showing determination coefficients higher than 0.992 for matrix-matched calibration and absolute recoveries in the range 43-91%. PMID- 24780256 TI - Fast determination of 22 sulfonamides from chicken breast muscle using core-shell nanoring amino-functionalized superparamagnetic molecularly imprinted polymer followed by liquid chromatography-tandem mass spectrometry. AB - A novel, simple and sensitive method was developed for the simultaneous determination of 22 sulfonamides (SAs) in chicken breast muscle by using the dispersive micro-solid-phase extraction (d-MU-SPE) procedure combined with ultra fast liquid chromatography-tandem quadrupole mass spectrometry (UFLC-MS/MS). The excellent core-shell nanoring amino-functionalized superparamagnetic molecularly imprinted polymer (CS-NR-Mag-MIP) was used as sorbent, and the main factors affecting the extraction efficiency were investigated in detail. All target compounds showed good linearities in the tested range with correlation coefficients (r) higher than 0.9980. The mean recoveries were in the range of 85.0-112.2% at low, medium and high concentration levels (0.1, 1.0 and 5.0 ng/g). The intra-day and inter-day relative standard deviations (RSDs) were lower than 6.0% and 8.9%, respectively. The limits of quantification for the 22 SAs were between 0.013 and 0.099 ng/g. The developed d-MU-SPE-UFLC-MS/MS method had been successfully applied to the chicken breast muscle samples for food-safety risk monitoring in Zhejiang Province, China. The results showed sulfamethazine, sulfamethoxazole and sulfaquinoxaline in five out of three hundred collected samples were detected with concentrations of 0.418-2.28, 16.4 and 2.93 ng/g, respectively. It was confirmed that the CS-NR-Mag-MIP was a kind of highly effective d-MU-SPE materials used for the SAs analyses. PMID- 24780257 TI - Evaluation of 13C- and 2H-labeled internal standards for the determination of amphetamines in biological samples, by reversed-phase ultra-high performance liquid chromatography-tandem mass spectrometry. AB - Stable isotope-labeled internal standards (SIL-ISs) are often used when applying liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze for legal and illegal drugs. ISs labeled with (13)C, (15)N, and (18)O are expected to behave more closely to their corresponding unlabeled analytes, compared with that of the more classically used (2)H-labeled ISs. This study has investigated the behavior of amphetamine, (2)H3-, (2)H5, (2)H6-, (2)H8-, (2)H11-, and (13)C6 labeled amphetamine, during sample preparation by liquid-liquid extraction and LC MS/MS analyses. None or only minor differences in liquid-liquid extraction recoveries of amphetamine and the SIL-ISs were observed. The chromatographic resolution between amphetamine and the (2)H-labeled amphetamines increased with the number of (2)H-substitutes. For chromatographic studies we also included seven additional (13)C6-amphetamines and their analytes. All the (13)C6-labeled ISs were co-eluting with their analytes, both when a basic and when an acidic mobile phase were used. MS/MS analyses of amphetamine and its SIL-ISs showed that the ISs with the highest number of (2)H-substitutes required more energy for fragmentation in the collision cell compared with that of the ISs with a lower number. The findings, in this study, support those of previous studies, showing that (13)C-labeled ISs are superior to (2)H-labeled ISs, for analytical purposes. PMID- 24780258 TI - Stability of the proteasome inhibitor bortezomib in cell based assays determined by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. AB - Bortezomib represents the first clinically approved proteasome inhibitor for multiple myeloma. Research conducted on its intracellular kinetics in target cells and on possibly related mechanisms of resistance is sparse so far. We therefore developed and validated a highly sensitive ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) method for bortezomib quantification within cultured myeloma cells and media. Fast gradient UPLC based on a BEH C18 column (1.7 MUm particle size) with aqueous formic acid and acetonitrile as mobile phase. Selective extraction procedures using protein precipitation extraction (PPE) and liquid-liquid extraction (LLE) were established and compared. Extracted bortezomib was quantified by positive electrospray tandem mass spectrometry using deuterated D8-bortezomib as internal standard. The calibrated ranges were 0.5-2500 pg per sample. For LLE, overall accuracies varied between 99.2% and 112% (medium) and 89.9% and 111% (cells), while overall precision ranged from 1.13% to 13.0% (medium) and 2.80% to 12.7% (cells), respectively. Recovery rates (cells/medium) were >77%/>65% for LLE and >89%/63% for PPE. Matrix effects were generally lower for LLE compared to PPE. Regardless of the extraction method, retrievable amounts of bortezomib were considerably reduced after 24h of incubation (0.2, 1, 5, and 25 nM). Revealing greater dependence on the extent of acidification, retrieval of bortezomib can be increased distinctly in acidified solution or acidified culture medium. Thus, particular attention needs to be paid to the occurring bortezomib degradation in neutral culture medium since correct quantification of intracellular bortezomib can only be achieved in relation to the corresponding extracellular concentration. PMID- 24780259 TI - Three dimensionally honeycomb layered double hydroxides framework as a novel fiber coating for headspace solid-phase microextraction of phenolic compounds. AB - A new solid phase microextraction (SPME) fiber based on high-temperature three dimensionally honeycomb layered double hydroxide (TDH-LDH) material is presented. The fiber coating can be prepared easily, it is mechanically stable and exhibits relatively high thermal stability. This study shows that three dimensionally honeycomb layered double hydroxide generated porous morphology. The TDH-LDH material was tested for the extraction of some phenolic and polycyclic aromatic hydrocarbon compounds from aqueous sample solutions in combination with gas chromatography-mass spectrometry (GC-MS). The TDH-LDH fiber contains polar groups and its efficiency for non-polar polycyclic aromatic hydrocarbon compounds was lower than phenolic compounds. On the other hand, a high tendency towards the adsorption of polar phenolic compounds was observed for the proposed fiber. The effects of the extraction and desorption parameters including extraction temperature, extraction time, ionic strength, stirring rate, pH and desorption temperature and time have been studied. In optimum conditions, the repeatability for one fiber (n=5), expressed as relative standard deviation (R.S.D. %), was between 2.8% and 7.1% for the phenolic compounds. The detection limits for the studied phenolic compounds were between 0.02 and 5.8 ng mL(-1). The developed method offers the advantage of being simple to use, with shorter analysis time, lower cost of equipment, thermal stability of fiber and high relative recovery in comparison to conventional methods of analysis. PMID- 24780260 TI - Synthesis and characterization of poly[N-isopropylacrylamide-co-1-(N,N-bis carboxymethyl)amino-3-allylglycerol] grafted to magnetic nano-particles for the extraction and determination of fluvoxamine in biological and pharmaceutical samples. AB - In this research, a novel method is reported for the surface grafting of N isopropylacrylamide as a thermosensitive agent and 1-(N,N-bis-carboxymethyl)amino 3-allylglycerol with an affinity toward fluvoxamine onto magnetic nano-particles modified by 3-mercaptopropyltrimethoxysilane. The grafted nano-particles were characterized by Fourier transform infrared spectroscopy, elemental analysis, and thermogravimetric analysis. The surface morphology was studied with scanning electron microscopy and transmission electron microscopy. The resulting grafted nano-particles were used in solid phase extraction and determining of trace fluvoxamine in biological human fluids and pharmaceutical samples. The profile of the fluvoxamine uptake by the modified magnetic nano-particles indicated good accessibility of the active sites in the grafted copolymer. It was found that the adsorption behavior could be fitted by the Freundlich adsorption isotherm model. It was observed that a maximum amount of fluvoxamine was released at a temperature above the lower critical solution temperature of the polymer. PMID- 24780261 TI - Separations by gradient elution: why are steep gradient profiles distorted and what is their impact on resolution in reversed-phase liquid chromatography. AB - The formation of a concentration shock layer of either methanol or acetonitrile used as the modifier in steep RPLC aqueous/organic gradients was predictable from their excess adsorption isotherm and was directly observed from their elution profiles recorded in UV absorption. A discontinuity of the concentration profile of the organic modifier arises and grows along the column. Its effects on the peak shapes and the resolution levels achieved in steep gradient chromatography were measured in the recorded chromatograms of a sample mixture containing 14 different analytes uniformly distributed across the gradient retention window. The results showed severe peak shape deformation for some compounds and a significant degradation of the baseline resolution of weakly (when using acetonitrile) and moderately (when using methanol) retained analytes. Solutions to limit this loss of resolution may lie in changing the initial gradient conditions or in adjusting the curvature of the gradient profile at the column inlet. PMID- 24780262 TI - Supported liquid membrane-protected molecularly imprinted beads for micro-solid phase extraction of sulfonamides in environmental waters. AB - In this work, molecularly imprinted polymer (MIP) beads have been prepared and evaluated for the development of a supported liquid membrane-protected micro solid phase extraction method for the analysis of sulfonamides (SAs) in aqueous samples. The performance of MIP beads was firstly evaluated in cartridges by conventional solid-phase extraction for the simultaneous analysis of SAs. Afterward, beads were packed into a polypropylene hollow fiber protected by an organic solvent immobilized in the pores of the capillary wall. During the process, the analytes were extracted from the aqueous sample to the immobilized organic solvent and then selectively retained by the MIP beads located inside the capillary. The effect of various experimental parameters as sample pH, time and stirring-rate among others, were studied for the establishment of optimum rebinding conditions. Relative recoveries for all sulfonamides tested in river and reservoir water samples by the proposed method using 100mL water sample spiked with 50MUg L-1 of each sulfonamide were within 70-120%, with a relative standard deviation (RSD) <10% (n=3). The detection limits (LODs) were within 0.2 3MUgL(-1), depending upon the sulfonamide and the type of water used. PMID- 24780263 TI - "Programmed packaging" for gene delivery. AB - We report on the development of a multifunctional envelope-type nano device (MEND) based on our packaging concept "Programmed packaging" to control not only intracellular trafficking but also the biodistribution of encapsulated compounds such as nucleic acids/proteins/peptides. Our strategy for achieving this is based on molecular mechanisms of cell biology such as endocytosis, vesicular trafficking, etc. In this review, we summarize the concept of programmed packaging and discuss some of our recent successful examples of using MENDs. Systematic evolution of ligands by exponential enrichment (SELEX) was applied as a new methodology for identifying a new ligand toward cell or mitochondria. The delivery of siRNA to tumors and the tumor vasculature was achieved using pH sensitive lipid (YSK05), which was newly designed and optimized under in vivo conditions. The efficient delivery of pDNA to immune cells such as dendritic cells has also been developed using the KALA ligand, which can be a breakthrough technology for DNA vaccine. Finally, ss-cleavable and pH-activated lipid-like surfactant (ssPalm) which is a lipid like material with pH-activatable and SS cleavable properties is also introduced as a proof of our concept. PMID- 24780264 TI - Multifunctional mesoporous bioactive glasses for effective delivery of therapeutic ions and drug/growth factors. AB - Regeneration of large-size bone defects represents a significant challenge clinically, which requires the use of scaffolds with multifunction, such as anti bacterial activity, and stimulation of osteogenesis and angiogenesis. It is known that functional ions or drug/growth factors play an important role to stimulate tissue regeneration. Mesoporous bioactive glasses (MBG) possess excellent bioactivity and drug-delivery ability as well as effective ionic release in the body fluids microenvironment due to its specific mesoporous structure and large surface area. For these reasons, functional ions (e.g. lithium (Li), strontium (Sr), Copper (Cu) and Boron (B)) and drug/growth factors (e.g. dexamethasone, vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)) have been incorporated into MBG, which shows high loading efficiency and effective release. The release of therapeutic ions and drug/growth factors from MBG offers it multifunctional properties, such as improved osteogenesis, angiogenesis, anti-bacterial/cancer activity. However, there is no a systematic review about delivery of therapeutic ions and drugs/growth factors from MBG for the functional effect on the tissue regeneration despite that significant progress has been achieved in the past five years. Therefore, in this review, we mainly focused on the new advances for the functional effect of delivering therapeutic ions and drugs/growth factors on the ostegeogenesis, angiogenesis and antibacterial activity. It is expected that the review will offer new concept to develop multifunctional biomaterials for bone regeneration by the synergistic effect of therapeutic ions and drug/growth factors. PMID- 24780265 TI - Coaxial electrospinning for encapsulation and controlled release of fragile water soluble bioactive agents. AB - Coaxial electrospinning is a robust technique for one-step encapsulation of fragile, water-soluble bioactive agents, including growth factors, DNA and even living organisms, into core-shell nanofibers. The coaxial electrospinning process eliminates the damaging effects due to direct contact of the agents with organic solvents or harsh conditions during emulsification. The shell layer serves as a barrier to prevent the premature release of the water-soluble core contents. By varying the structure and composition of the nanofibers, it is possible to precisely modulate the release of the encapsulated agents. Promising work has been done with coaxially electrospun non-woven mats integrated with bioactive agents for use in tissue engineering, in local delivery and in wound healing, etc. This paper reviews the origins of the coaxial electrospinning method, its updated status and potential future developments for controlled release of the class of fragile, water-soluble bioactive agents. PMID- 24780266 TI - Safety, efficacy, and molecular mechanism of claudin-1-specific peptides to enhance blood-nerve-barrier permeability. AB - The blood-nerve barrier consists of the perineurium and endoneurial vessels. The perineurial barrier is composed of a basal membrane and a layer of perineurial cells sealed by tight junction proteins preventing e.g. application of analgesics for selective regional pain control. One of the barrier-sealing proteins in the blood-nerve barrier is claudin-1. Therefore, the claudin-1-peptidomimetics (C1C2), derived from the first extracellular loop (ECL1) on claudin-1 was developed. In this study, we further evaluated the expression of tight junction proteins in the perineurium in Wistar rats and characterized the specificity, in vivo applicability, mechanism of action as well as the biocompatibility of C1C2. In the perineurium, claudin-19, tricellulin and ZO-1, but no claudin-2, 3, 8 and 11 were expressed. C1C2 specifically bound to the ECL1 of claudin-1 and fluorescent 5,6-carboxytetramethylrhodamine-C1C2 was rapidly internalized. Opening the perineurium with C1C2 reduced the mRNA and protein expression of claudin-1 and increased small and macromolecule permeability into the peripheral nerve. Application of C1C2 facilitated regional analgesia using MU-opioid receptor agonists like DAMGO or morphine without motor impairment in naive rats as well as rats with hind paw inflammation. In contrast the control peptide C2C2 derived from ECL1 on claudin-2 did neither open the barrier nor facilitated opioid-mediated regional analgesia. C1C2 delivery was well tolerated and caused no morphological and functional nerve damage. C1C2 effects could be reversed by interference with the wnt-signal-transduction pathway, specifically the homeobox transcription factor cdx2, using a glycogen-synthase-kinase-3 inhibitor. In summary, we describe the composition of and a pathway to open the perineurial barrier employing a peptide to deliver hydrophilic substances to the peripheral nerve. PMID- 24780267 TI - Enhancement of efficiency of chitosan-based complexes for gene transfection with poly(gamma-glutamic acid) by augmenting their cellular uptake and intracellular unpackage. AB - As a cationic polysaccharide, chitosan (CS) has been identified for its potential use as a non-viral vector for exogenous gene transfection. However, owing to their electrostatic interactions, CS complexes may cause difficulties in gene release upon their arrival at the site of action, thus limiting their transfection efficiency. In this work, an attempt is made to facilitate the release of a gene by incorporating a negatively-charged poly(gamma-glutamic acid) (gammaPGA) into CS complexes in order to diminish their attractive interactions. The mechanisms of exploiting gammaPGA to enhance the transfection efficiency of CS complexes are elucidated. The feasibility of using this CS/gammaPGA-based system for DNA or siRNA transfer is explored as well. Additionally, potential of the CS/gammaPGA formulation to deliver disulfide bond-conjugated dual PEGylated siRNAs for multiple gene silencing is also examined. Moreover, the genetic use of pKillerRed-mem, delivered using complexes of CS and gammaPGA, to express a membrane-targeted KillerRed as an intrinsically generated photosensitizer for photodynamic therapy is described. PMID- 24780269 TI - Theranostic nanoparticles for future personalized medicine. AB - The concept of personalized medicine has recently emerged as a promising way to address unmet medical needs. Due to the limitations of standard diagnostic and therapeutic strategies, the disease treatment is moving towards tailored treatment for individual patients, considering the inter-individual variability in therapeutic response. Theranostics, which involves the combination of therapy and diagnostic imaging into a single system, may fulfill the promise of personalized medicine. By integrating molecular imaging functionalities into therapy, theranostic approach could be advantageous in therapy selection, treatment planning, objective response monitoring and follow-up therapy planning based on the specific molecular characteristics of a disease. Although the field of therapy and imaging of its response have been independently developed thus far, developing imaging strategies can be fully exploited to revolutionize the theranostic systems in combination with the therapy modality. In this review, we describe the recent advances in molecular imaging technologies that have been specifically developed to evaluate the therapeutic efficacy for theranostic purposes. PMID- 24780270 TI - Efficient calcium lactate production by fermentation coupled with crystallization based in situ product removal. AB - Lactic acid is a platform chemical with various industrial applications, and its derivative, calcium lactate, is an important food additive. Fermentation coupled with in situ product removal (ISPR) can provide more outputs with high productivity. The method used in this study was based on calcium lactate crystallization. Three cycles of crystallization were performed during the fermentation course using a Bacillus coagulans strain H-1. As compared to fed batch fermentation, this method showed 1.7 times higher average productivity considering seed culture, with 74.4% more L-lactic acid produced in the fermentation with ISPR. Thus, fermentation coupled with crystallization-based ISPR may be a biotechnological alternative that provides an efficient system for production of calcium lactate or lactic acid. PMID- 24780268 TI - Protein polymer nanoparticles engineered as chaperones protect against apoptosis in human retinal pigment epithelial cells. AB - alphaB-Crystallin is a protein chaperone with anti-apoptotic and anti inflammatory activity that is apically secreted in exosomes by polarized human retinal pigment epithelium. A 20 amino acid mini-peptide derived from residues 73 92 of alphaB-crystallin protects human retinal pigment epithelial (RPE) cells from oxidative stress, a process involved in the progression of age-related macular degeneration (AMD). Unfortunately, due to its small size, its development as a therapeutic requires a robust controlled release system. To achieve this goal, the alphaB-crystallin peptide was re-engineered into a protein polymer nanoparticle/macromolecule with the purpose of increasing the hydrodynamic radius/molecular weight and enhancing potency via multivalency or an extended retention time. The peptide was recombinantly fused with two high molecular weight (~40kDa) protein polymers inspired by human tropoelastin. These elastin like polypeptides (ELPs) include the following: (i) a soluble peptide called S96 and (ii) a diblock copolymer called SI that assembles multivalent nanoparticles at physiological temperature. Fusion proteins, cryS96 and crySI, were found to reduce aggregation of alcohol dehydrogenase and insulin, which demonstrates that ELP fusion did not diminish chaperone activity. Next their interaction with RPE cells was evaluated under oxidative stress. Unexpectedly, H2O2-induced stress dramatically enhanced cellular uptake and nuclear localization of both cryS96 and crySI ELPs. Accompanying uptake, both fusion proteins protected RPE cells from apoptosis, as indicated by reduced caspase 3 activation and TUNEL staining. This study demonstrates the in vitro feasibility of modulating the hydrodynamic radius for small peptide chaperones by seamless fusion with protein polymers; furthermore, they may have therapeutic applications in diseases associated with oxidative stress, such as AMD. PMID- 24780271 TI - Development, validation and application of specific primers for analyzing the clostridial diversity in dark fermentation pit mud by PCR-DGGE. AB - In this study, a Clostridia-specific primer set SJ-F and SJ-R, based on the available 16S rRNA genes sequences from database, was successfully designed and authenticated by theoretical and experimental evaluations. It targeted 19 clostridial families and unclassified_Clostridia with different coverage rates. The specificity and universality of novel primer set was tested again using the dark fermentation pit mud (FPM). It was demonstrated that a total of 13 closest relatives including 12 species were affiliated with 7 clostridial genera, respectively. Compared to the well-accepted bacterial universal primer pair P2/P3, five unexpected clostridial genera including Roseburia, Tissierella, Sporanaerobacter, Alkalibacter and Halothermothrix present in the FPM were also revealed. Therefore, this study could provide a good alternative to investigate the clostridial diversity and monitor their population dynamics rapidly and efficiently in various anaerobic environments and dark fermentation systems in future. PMID- 24780272 TI - A C-14 labeled Py-Im polyamide localizes to a subcutaneous prostate cancer tumor. AB - In an effort to quantitate Py-Im polyamide concentrations in vivo, we synthesized the C-14 radioactively labeled compounds 1-3, and investigated their tumor localization in a subcutaneous xenograft model of prostate cancer (LNCaP). Tumor concentrations were compared with representative host tissues, and exhibited a certain degree of preferential localization to the xenograft. Compound accumulation upon repeated administration was measured. Py-Im polyamide 1 was found to accumulate in LNCaP tumors at concentrations similar to the IC50 value for this compound in cell culture experiments. PMID- 24780273 TI - Exploring bacterial lignin degradation. AB - Plant biomass represents a renewable carbon feedstock that could potentially be used to replace a significant level of petroleum-derived chemicals. One major challenge in its utilization is that the majority of this carbon is trapped in the recalcitrant structural polymers of the plant cell wall. Deconstruction of lignin is a key step in the processing of biomass to useful monomers but remains challenging. Microbial systems can provide molecular information on lignin depolymerization as they have evolved to break lignin down using metalloenzyme dependent radical pathways. Both fungi and bacteria have been observed to metabolize lignin; however, their differential reactivity with this substrate indicates that they may utilize different chemical strategies for its breakdown. This review will discuss recent advances in studying bacterial lignin degradation as an approach to exploring greater diversity in the environment. PMID- 24780274 TI - Computational tools for designing and engineering enzymes. AB - Protein engineering strategies aimed at constructing enzymes with novel or improved activities, specificities, and stabilities greatly benefit from in silico methods. Computational methods can be principally grouped into three main categories: bioinformatics; molecular modelling; and de novo design. Particularly de novo protein design is experiencing rapid development, resulting in more robust and reliable predictions. A recent trend in the field is to combine several computational approaches in an interactive manner and to complement them with structural analysis and directed evolution. A detailed investigation of designed catalysts provides valuable information on the structural basis of molecular recognition, biochemical catalysis, and natural protein evolution. PMID- 24780275 TI - CAZyme discovery and design for sweet dreams. AB - Development of synthetic routes to complex carbohydrates and glyco-conjugates is often hampered by the lack of enzymes with requisite properties or specificities. Indeed, assembly or degradation of carbohydrates requires carbohydrate-active enzymes (CAZymes) able to act on a vast range of glycosidic monomers, oligomers or polymers in a regio-specific or stereo-specific manner in order to produce the desired structure. Sequence-based analyses allow finding the most original enzymes. Novel screening methods have emerged that enable a more efficient exploitation of the CAZyme diversity found in the microbial world or generated by protein engineering. Computational biology methods also play a prominent role in the success of CAZyme design. Such progress allows circumventing current limitations of carbohydrate synthesis and opens new opportunities related to the synthetic biology field. PMID- 24780276 TI - Engineering aldolases as biocatalysts. AB - Aldolases are seen as an attractive route to the production of biologically important compounds due to their ability to form carbon-carbon bonds. However, for many industrial reactions there are no naturally occurring enzymes, and so many different engineering approaches have been used to address this problem. Engineering methods have been used to alter the stability, substrate specificity and stereospecificity of aldolases to produce excellent enzymes for biocatalytic processes. Recently greater understanding of the aldolase mechanism has allowed many successes with both rational engineering approaches and computational design of aldolases. Rational engineering approaches have produced desired enzymes quickly and efficiently while combination of computational design with laboratory methods has created enzymes with activity approaching that of natural enzymes. PMID- 24780277 TI - Heme uptake in bacterial pathogens. AB - Iron is an essential nutrient for the survival of organisms. Bacterial pathogens possess specialized pathways to acquire heme from their human hosts. In this review, we present recent structural and biochemical data that provide mechanistic insights into several bacterial heme uptake pathways, encompassing the sequestration of heme from human hemoproteins to secreted or membrane associated bacterial proteins, the transport of heme across bacterial membranes, and the degradation of heme within the bacterial cytosol to liberate iron. The pathways for heme transport into the bacterial cytosol are divergent, harboring non-homologous protein sequences, novel structures, varying numbers of proteins, and different mechanisms. Congruously, the breakdown of heme within the bacterial cytosol by sequence-divergent proteins releases iron and distinct degradation products. PMID- 24780278 TI - Interfacial metal coordination in engineered protein and peptide assemblies. AB - Metal ions are frequently found in natural protein-protein interfaces, where they stabilize quaternary or supramolecular protein structures, mediate transient protein-protein interactions, and serve as catalytic centers. Paralleling these natural roles, coordination chemistry of metal ions is being increasingly utilized in creative ways toward engineering and controlling the assembly of functional supramolecular peptide and protein architectures. Here we provide a brief overview of this emerging branch of metalloprotein/peptide engineering and highlight a few select examples from the recent literature that best capture the diversity and future potential of approaches that are being developed. PMID- 24780279 TI - Social networks as the context for understanding employment services utilization among homeless youth. AB - Little is known about the factors associated with use of employment services among homeless youth. Social network characteristics have been known to be influential in motivating people's decision to seek services. Traditional theoretical frameworks applied to studies of service use emphasize individual factors over social contexts and interactions. Using key social network, social capital, and social influence theories, this paper developed an integrated theoretical framework that capture the social network processes that act as barriers or facilitators of use of employment services by homeless youth, and understand empirically, the salience of each of these constructs in influencing the use of employment services among homeless youth. We used the "Event based approach" strategy to recruit a sample of 136 homeless youth at one drop-in agency serving homeless youth in Los Angeles, California in 2008. The participants were queried regarding their individual and network characteristics. Data were entered into NetDraw 2.090 and the spring embedder routine was used to generate the network visualizations. Logistic regression was used to assess the influence of the network characteristics on use of employment services. The study findings suggest that social capital is more significant in understanding why homeless youth use employment services, relative to network structure and network influence. In particular, bonding and bridging social capital were found to have differential effects on use of employment services among this population. The results from this study provide specific directions for interventions aimed to increase use of employment services among homeless youth. PMID- 24780280 TI - Applying complexity theory: a review to inform evaluation design. AB - Complexity theory has increasingly been discussed and applied within evaluation literature over the past decade. This article reviews the discussion and use of complexity theory within academic journal literature. The aim is to identify the issues to be considered when applying complexity theory to evaluation. Reviewing 46 articles, two groups of themes are identified. The first group considers implications of applying complexity theory concepts for defining evaluation purpose, scope and units of analysis. The second group of themes consider methodology and method. Results provide a starting point for a configuration of an evaluation approach consistent with complexity theory, whilst also identifying a number of design considerations to be resolved within evaluation planning. PMID- 24780281 TI - Evolutionary Evaluation: implications for evaluators, researchers, practitioners, funders and the evidence-based program mandate. AB - Evolutionary theory, developmental systems theory, and evolutionary epistemology provide deep theoretical foundations for understanding programs, their development over time, and the role of evaluation. This paper relates core concepts from these powerful bodies of theory to program evaluation. Evolutionary Evaluation is operationalized in terms of program and evaluation evolutionary phases, which are in turn aligned with multiple types of validity. The model of Evolutionary Evaluation incorporates Chen's conceptualization of bottom-up versus top-down program development. The resulting framework has important implications for many program management and evaluation issues. The paper illustrates how an Evolutionary Evaluation perspective can illuminate important controversies in evaluation using the example of the appropriate role of randomized controlled trials that encourages a rethinking of "evidence-based programs". From an Evolutionary Evaluation perspective, prevailing interpretations of rigor and mandates for evidence-based programs pose significant challenges to program evolution. This perspective also illuminates the consequences of misalignment between program and evaluation phases; the importance of supporting both researcher-derived and practitioner-derived programs; and the need for variation and evolutionary phase diversity within portfolios of programs. PMID- 24780282 TI - Cross-saturation and transferred cross-saturation experiments. AB - Structural analyses of protein-protein interactions are required to reveal their functional mechanisms, and accurate protein-protein complex models, based on experimental results, are the starting points for drug development. In addition, structural information about proteins under physiologically relevant conditions is crucially important for understanding biological events. However, for proteins such as those embedded in lipid bilayers and transiently complexed with their effectors under physiological conditions, structural analyses by conventional methods are generally difficult, due to their large molecular weights and inhomogeneity. We have developed the cross-saturation (CS) method, which is an nuclear magnetic resonance measurement technique for the precise identification of the interfaces of protein-protein complexes. In addition, we have developed an extended version of the CS method, termed transferred cross-saturation (TCS), which enables the identification of the residues of protein ligands in close proximity to huge (>150 kDa) and heterogeneous complexes under fast exchange conditions (>0.1 s(-1)). Here, we discuss the outline, basic theory, and practical considerations of the CS and TCS methods. In addition, we will review the recent progress in the construction of models of protein-protein complexes, based on CS and TCS experiments, and applications of TCS to in situ analyses of biologically and medically important proteins in physiologically relevant states. PMID- 24780283 TI - The use of health services among elderly patients with stage IV prostate cancer in the initial period following diagnosis. AB - OBJECTIVE: Information regarding variability in the type and extent of health services used by elderly patients with advanced prostate cancer (PCa) in the initial period following diagnosis is limited. We evaluated health services utilization among elderly men with stage IV PCa with (M1) and without (M0) distant metastasis during the year following diagnosis. METHODS: We evaluated patients aged 66 and older with incident stage IV PCa during 2005-2007 using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Measures included skilled nursing facility (SNF) stay, hospice stay, and hospitalization. Multivariable logistic regression models were estimated to determine the association between M1 PCa and each health service. Poisson regression was used to assess hospital length of stay. RESULTS: The final sample included 3379 patients (20% M0; 80% M1). In the year following diagnosis, M1 patients had greater use of SNF (M0: 8%; M1: 22%), hospice (M0: 5%; M1: 20%), and hospitalization (M0: 43%; M1: 61%). Compared to M0 patients, M1 patients had statistically significantly higher adjusted odds of SNF use (OR=1.89; 95% CI=1.38 2.59), hospice use (OR=3.22; 95% CI=2.19-4.72), and hospitalization (OR=1.45; 95% CI=1.20-1.75). Among those hospitalized, M1 patients had 24% longer length of stay (p<0.01). CONCLUSIONS: There is 2- to 3-fold greater use of SNF and hospice, and higher hospitalization among M1 compared to M0 patients. Elderly patients with advanced PCa face significant clinical burden within the first year after their diagnosis. Greater understanding of the relationship between clinical disease burden and health services utilization can improve healthcare delivery in this population. PMID- 24780285 TI - Median survival of cancer patients has risen from one to 10 years over past 40 years. PMID- 24780284 TI - Autism as a sequence: from heterochronic germinal cell divisions to abnormalities of cell migration and cortical dysplasias. AB - The considerable heterogeneity in the number and severity of symptoms observed in autism spectrum disorders (ASD) has been regarded as an obstacle to any future research. Some authors believe that clinical heterogeneity results from the complex interplay of the many genetic and environmental factors that themselves define a condition as multifactorial. However, it is important to note that neuropathological findings in both idiopathic and syndromic autism suggests a single pathophysiological mechanism acting during brain development: the heterochronic division of germinal cells and subsequent migrational abnormalities of daughter cells to their target fields. Multiple exogenous (e.g., viruses, drugs) and endogenous (e.g., genetic mutations) factors are known to disrupt the division of germinal cells and provide for an autism phenotype. The variety of endogenous and exogenous factors, their timing of action during brain development, and the genetic susceptibility of affected individuals (a Triple Hit hypothesis) may all account for the clinical heterogeneity of ASD. PMID- 24780286 TI - Policy, phylogeny, and the parasite. AB - Animal diseases gain political attention by their inclusion on lists of global bodies such as those of the World Organisation for Animal Health (OIE). Inclusion requires national governments to report outbreaks promptly but may lead to trading restrictions between nations in an attempt to limit spread. Detection therefore has consequences that may have direct impact from farm to state levels. We consider here current approaches to discriminating listed parasites from related but unlisted counterparts. We outline necessary drivers for the discrimination of important taxa and how these may be influenced by national policies. Further, we propose a set of 'best practice' measures, broadly based upon current taxonomic philosophies for protists and metazoans, that should be applied when defining taxa for listing as notifiable. PMID- 24780287 TI - Short-term and long-term causes of death in patients with alcoholic hepatitis in Denmark. AB - BACKGROUND & AIMS: The incidence of acute alcoholic hepatitis is increasing, and mortality is high. However, causes of death among patients with alcoholic hepatitis have not been systematically recorded. We investigated causes of death in a population-based cohort of patients with alcoholic hepatitis who were followed for as long as 10 years. METHODS: We used the Danish National Registry of Patients to identify all patients with a first-time episode of alcoholic hepatitis from 1999 through 2008. We collected and analyzed data on 1951 patients, identifying causes of death, diagnoses of cirrhosis, and alcohol abuse. RESULTS: Of the 1951 patients, 401 died within the first 84 days after admission, and 600 died later (through December 31, 2008). Most deaths within the first 84 days after admission resulted from liver failure (40%), infections (20%), or hepatorenal syndrome (11%). Beyond 84 days, causes of deaths differed between patients with and without cirrhosis; most patients without cirrhosis (n = 326) died of causes related to alcohol abuse, whereas most patients with cirrhosis (n = 675) died of liver failure (34%), infections (16%), or variceal bleeding (11%). Cirrhosis was present in 51% of patients diagnosed with alcoholic hepatitis. Among patients without cirrhosis, 24% developed cirrhosis within 10 years; continued alcohol abuse was a strong risk factor for cirrhosis (hazard ratio, 2.14; 95% confidence interval, 1.50-3.05). The 10-year risk of a second episode of alcoholic hepatitis was 12%. CONCLUSIONS: On the basis of a study of the Danish population, the most common causes of death among patients with alcoholic hepatitis, within 84 days and within 10 years, are liver-related events and infections. Strategies are to identify and treat these complications and to reduce alcoholism. PMID- 24780288 TI - Sleep duration affects risk for ulcerative colitis: a prospective cohort study. AB - BACKGROUND & AIMS: Sleep deprivation is associated with production of inflammatory cytokines. Disturbed sleep quality has been associated with increased risk of disease flare in patients with Crohn's disease (CD) or ulcerative colitis (UC). However, the association between sleep and risk of incident CD and UC has not been previously examined. METHODS: We conducted a prospective study of women who were enrolled in the Nurses' Health Study (NHS) I since 1976 and NHS II since 1989 and followed through detailed biennial questionnaires with >90% follow-up. We examined the association of sleep duration reported in 1986 in NHS I and 2001 in NHS II with incident CD and UC, diagnosed through 2010, in NHS I and 2009 in NHS II. Cox proportional hazards models adjusting for potential confounders were used to calculate hazard ratios and 95% confidence intervals (CIs). RESULTS: Among 151,871 women, we confirmed 191 cases of CD (incidence, 8/100,000 person-years) and 230 cases of UC (incidence, 10/100,000 person-years) over 2,292,849 person-years. Compared with women with reported usual sleep durations of 7-8 h/day (incidence, 8/100,000 person-years), women with reported sleep duration <6 h/day (11/100,000 person-years) or >9 h/day (20/100,000 person-years) had a higher incidence of UC (P < .05). The multivariate hazard ratios for UC were 1.51 (95% CI, 1.10-2.09) for sleep durations <6 h/day and 2.05 (95% CI, 1.44-2.92) for sleep durations >9 h/day, compared with sleep durations of 7-8 h/day. In contrast, sleep duration did not modify risk of CD. Duration of rotating night shift work was not associated with CD or UC. CONCLUSIONS: On the basis of data from the NHS I and II, less than 6 hours sleep/day and more than 9 hours sleep/day are each associated with an increased risk of UC. Further studies are needed to evaluate sleep as a modifiable risk factor in the pathogenesis and progression of IBD. PMID- 24780289 TI - Upper extremity kinematics and muscle activation patterns in subjects with facioscapulohumeral dystrophy. AB - OBJECTIVE: To compare the kinematics and muscle activity of subjects with facioscapulohumeral dystrophy (FSHD) and healthy control subjects during the performance of standardized upper extremity tasks. DESIGN: Exploratory case control study. SETTING: A movement laboratory. PARTICIPANTS: Subjects (N=19) with FSHD (n=11) and healthy control subjects (n=8) were measured. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Kinematic data were recorded using a 3 dimensional motion capturing system. Muscle activities, recorded using electromyography, were obtained from 6 superficial muscles around the glenohumeral joint. Shoulder elevation and elbow flexion angles, and maximum electromyographic activity during the movements as a percentage of maximum voluntary contraction (MVC) were calculated. RESULTS: Kinematic differences between the FSHD group and the healthy control group were found in the shoulder elevation angle during single shoulder movements and both reaching tasks. In general, subjects with FSHD had higher percentages of muscle activation. The median activity of the trapezius was close to the MVC activity during the single shoulder movements. Moreover, deltoid and pectoralis muscles were also highly active. CONCLUSIONS: Higher activation of the trapezius in subjects with FSHD indicates a mechanism that could help relieve impaired shoulder muscles during arm elevation around shoulder height. Compared with healthy subjects, persons with FSHD activated their shoulder muscles to a greater extent during movements that required arm elevation. PMID- 24780291 TI - Vitamin D supplements do not reduce mortality risk. PMID- 24780290 TI - Cardiopulmonary exercise testing is well tolerated in people with Alzheimer related cognitive impairment. AB - OBJECTIVE: To retrospectively assess whether cardiopulmonary exercise testing would be well tolerated in individuals with Alzheimer disease (AD) compared with a nondemented peer group. DESIGN: We retrospectively reviewed 575 cardiopulmonary exercise tests (CPETs) in individuals with and without cognitive impairment caused by AD. SETTING: University medical center. PARTICIPANTS: Exercise tests (N=575) were reviewed for nondemented individuals (n=340) and those with AD related cognitive impairment (n=235). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The main outcome measure for this study was reporting the reason for CPET termination. The hypothesis reported was formulated after data collection. RESULTS: We found that in cognitively impaired individuals, CPETs were terminated because of fall risk more often, but that overall test termination was infrequent 5.5% versus 2.1% (P=.04) in peers without cognitive impairment. We recorded 6 cardiovascular and 7 fall risk events in those with AD, compared with 7 cardiovascular and 0 fall risk events in those without cognitive impairment. CONCLUSIONS: Our findings support using CPETs to assess peak oxygen consumption in older adults with cognitive impairment caused by AD. PMID- 24780292 TI - Acquisition and structuring of midgut bacterial communities in gypsy moth (Lepidoptera: Erebidae) larvae. AB - Insects are associated with a diversity of bacteria that colonize their midguts. The extent to which these communities reflect maternal transmission, environmental acquisition, and subsequent structuring by the extreme conditions within the insect gut are poorly understood in many species. We used gypsy moth (Lymantria dispar L.) as a model to investigate interactions between egg mass and environmental sources of bacteria on larval midgut communities. Egg masses were collected from several wild and laboratory populations, and the effects of diet, initial egg mass community, and internal host environment were evaluated using 454 16S-rRNA gene pyrosequencing. Wild populations were highly diverse, while laboratory-maintained egg masses were associated with few operational taxonomic units. As larvae developed, their midgut bacterial communities became more similar to each other and the consumed diet despite initial differences in egg mass-associated bacteria. Subsequent experiments revealed that while midgut membership was more similar to bacteria associated with diet than with egg mass associated bacteria, we were unable to detect distinct, persistent differences attributable to specific host plants. The differences between foliar communities and midgut communities of larvae that ingested them were owing to relative changes in populations of several bacteria phylotypes. We conclude that gypsy moth has a relatively characteristic midgut bacterial community that is reflective of, but ultimately distinct from, its foliar diet. This work demonstrates that environmental acquisition of diverse microbes can lead to similar midgut bacterial assemblages, underscoring the importance of host physiological environment in structuring bacterial communities. PMID- 24780293 TI - Optional games on cycles and complete graphs. AB - We study stochastic evolution of optional games on simple graphs. There are two strategies, A and B, whose interaction is described by a general payoff matrix. In addition, there are one or several possibilities to opt out from the game by adopting loner strategies. Optional games lead to relaxed social dilemmas. Here we explore the interaction between spatial structure and optional games. We find that increasing the number of loner strategies (or equivalently increasing mutational bias toward loner strategies) facilitates evolution of cooperation both in well-mixed and in structured populations. We derive various limits for weak selection and large population size. For some cases we derive analytic results for strong selection. We also analyze strategy selection numerically for finite selection intensity and discuss combined effects of optionality and spatial structure. PMID- 24780294 TI - Variability in assessing treatment response: metastatic colorectal cancer as a paradigm. AB - PURPOSE: The cutoff values currently used to categorize tumor response to therapy are neither biologically based nor tailored for measurement reproducibility with contemporary imaging modalities. Sources and magnitudes of discordance in response assessment in metastatic colorectal cancer (mCRC) are unknown. EXPERIMENTAL DESIGN: A subset of patients' CT images of chest, abdomen, and pelvis were randomly chosen from a multicenter clinical trial evaluating insulin like growth factor receptor type 1-targeted therapy in mCRC. Using Response Evaluation Criteria in Solid Tumors (RECIST), three radiologists selected target lesions and measured "uni" (maximal diameter), "bi" (product of maximal diameter and maximal perpendicular diameter), and "vol" (volume) on baseline and 6-week posttherapy scans in the following ways: (i) each radiologist independently selected and measured target lesions and (ii) one radiologist's target lesions were blindly remeasured by the others. Variability in relative change of tumor measurements was analyzed using linear mixed effects models. RESULTS: Three radiologists independently selected 138, 101, and 146 metastatic target lesions in the liver, lungs, lymph nodes, and other organs (e.g., peritoneal cavity) in 29 patients. Of 198 target lesions total, 33% were selected by all three, 28% by two, and 39% by one radiologist. With independent selection, the variability in relative change of tumor measurements was 11% (uni), 19% (bi), and 22% (vol), respectively. When measuring the same lesions, the corresponding numbers were 8%, 14%, and 12%. CONCLUSIONS: The relatively low variability in change of mCRC measurements suggests that response criteria could be modified to allow more accurate and sensitive CT assessment of anticancer therapy efficacy. PMID- 24780295 TI - Importance of EGFR/ERCC1 interaction following radiation-induced DNA damage. AB - PURPOSE: The epidermal growth factor receptor (EGFR) plays an important role in cellular response to chemotherapy and radiotherapy through modulation of DNA repair. EGFR activates DNA-dependent protein kinase (DNA-PK) stimulating repair of DNA strand breaks (SB) and interstrand crosslinks (ICL). We investigated the role of EGFR in repair of ionizing radiation (IR)-induced SB independently of DNA PK. EXPERIMENTAL DESIGN: The EGFR interactome was investigated via mass spectrometry. IR-induced EGFR-ERCC1 binding was validated biochemically and via proximity ligation assay in different cell lines including the M059K and M059J glioma cell lines, proficient and deficient for the expression of DNAPKcs, respectively. EGFR-ERCC1 functional significance following IR-induced SB was investigated in knockdown experiments with the Comet and gammaH2AX foci assays. The effect of this interaction was tested with EGFR-ERCC1 knockdown in combination with gefitinib and NU7026 using the MTT and apoptosis assays. RESULTS: This study demonstrates that EGFR inhibition further impairs IR-induced DNA repair in cells lacking expression of DNAPKcs or in combination with the DNAPK inhibitor NU7026. Our data suggest a role for EGFR in DNA repair independent of DNAPKcs but dependent on ERCC1. Alkaline comet and gammaH2AX foci assays in cells depleted of EGFR, ERCC1, or EGFR-ERCC1 expression demonstrated involvement of this interaction in DNA repair. Cellular survival and apoptosis data correlate with levels of residual DNA damage underlying the importance of this complex following SB. CONCLUSION: These data emphasize the importance of understanding the various mechanisms by which EGFR modulates DNA repair to optimize targeted therapy for patients with cancer. PMID- 24780297 TI - Hexokinase 2 regulates G1/S checkpoint through CDK2 in cancer-associated fibroblasts. AB - Hexokinase 2 (HK2), a pivotal glycolytic enzyme, is often overexpressed in tumor cells and contributes to glycolysis. Emerging evidence has suggested that glycolysis is also enhanced in cancer-associated fibroblasts (CAF). However, it is not clear whether HK2 is involved in enhanced glycolysis in CAFs or what role HK2 plays in the CAFs. In this study, both time course experiments and dose response experiments demonstrated that the protein and mRNA levels of HK2 increase in CAF cells, according to western blot and quantitative PCR analyses, respectively. Additionally, miR-182 targets the 3' UTR of HK2, and its overexpression results in the degradation of HK2 mRNA, which eventually reduces the level of HK2 protein. On the other hand, knockdown of miR-182 increased the expression of HK2. Most importantly, HK2 regulated the protein level and T14 phosphorylation of CDK2, and knockdown of HK2 resulted in a G1 phase cell cycle arrest. These observations suggest that HK2 plays important roles in glycolysis regulation and in cell cycle checkpoint activation. PMID- 24780296 TI - Old drug new use--amoxapine and its metabolites as potent bacterial beta glucuronidase inhibitors for alleviating cancer drug toxicity. AB - PURPOSE: Irinotecan (CPT-11) induced diarrhea occurs frequently in patients with cancer and limits its usage. Bacteria beta-glucuronidase (GUS) enzymes in intestines convert the nontoxic metabolite of CPT-11, SN-38G, to toxic SN-38, and finally lead to damage of intestinal epithelial cells and diarrhea. We previously reported amoxapine as a potent GUS inhibitor in vitro. To further understand the molecular mechanism of amoxapine and its potential for treatment of CPT-11 induced diarrhea, we studied the binding modes of amoxapine and its metabolites by docking and molecular dynamics simulation, and tested the in vivo efficacy on mice in combination with CPT-11. EXPERIMENTAL DESIGN: The binding of amoxapine, its metabolites, 7-hydroxyamoxapine and 8-hydroxyamoxapine, and a control drug loxapine with GUS was explored by computational protocols. The in vitro potencies of metabolites were measured by Escherichia coli GUS enzyme and cell-based assay. Low-dosage daily oral administration was designed to use along with CPT-11 to treat tumor-bearing mice. RESULTS: Computational modeling results indicated that amoxapine and its metabolites bound in the active site of GUS and satisfied critical pharmacophore features: aromatic features near bacterial loop residue F365' and hydrogen bond toward E413. Amoxapine and its metabolites were demonstrated as potent in vitro. Administration of low dosages of amoxapine with CPT-11 in mice achieved significant suppression of diarrhea and reduced tumor growth. CONCLUSIONS: Amoxapine has great clinical potential to be rapidly translated to human subjects for irinotecan-induced diarrhea. PMID- 24780299 TI - Is popularity associated with aggression toward socially preferred or marginalized targets? AB - This study was designed to test whether aggression toward easy or challenging targets is more likely to be associated with popularity. More specifically, we tested two alternative hypotheses with a sample of 224 adolescents (12- and 13 year-olds): (a) whether aggression toward highly disliked peers is associated with popularity (the easy target hypothesis) or (b) whether aggression toward highly liked peers is associated with popularity (the challenging target hypothesis). Support was found only for the challenging target hypothesis. In particular, our results indicate that aggressiveness toward peers who are liked by many others has social benefits in the form of greater popularity (particularly for highly preferred adolescents) without social costs (i.e., is unrelated to social preference). In contrast, aggressiveness toward peers who are disliked by many others is associated with lower social preference but bears no association with popularity. These results highlight the importance of studying contextualized aggression in order to understand the conditions under which aggression is most, and least, likely to be associated with social power and dominance. PMID- 24780298 TI - PEG spacers of different length influence the biological profile of bombesin based radiolabeled antagonists. AB - INTRODUCTION: The gastrin-releasing peptide receptor (GRPR) was shown to be expressed with high density on several types of cancers. Radiolabeled peptides for imaging and targeted radionuclide therapy have been developed. In this study, we evaluated the potential of statine-based bombesin antagonists, conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) through oligoethyleneglycol spacers, labeled with (177)Lu and we determined the effect of polyethyleneglycol (PEG) spacer length on in vitro and in vivo properties. METHODS: The bombesin antagonists were synthesized on solid phase using Fmoc chemistry; the spacers Fmoc-dPEGx-OH (x=2, 4, 6 and 12) and the DOTA(tBu)3 were coupled using a standard procedure. The peptides were labeled with (177)Lu and evaluated in vitro (lipophilicity, serum stability, internalization and binding affinity assays). Biodistribution studies were performed in PC-3 tumor-bearing nude mice. RESULTS: The solid-phase synthesis was straightforward with an overall yield ranging from 30% to 35% based on the first Fmoc cleavage. The hydrophilicity increased with spacer length (logD: -1.95 vs -2.22 of PEG2 and PEG12 analogs, respectively). There is a tendency of increased serum stability by increasing the spacer length (T1/2=246+/-4 and 584+/-20 for PEG2 and PEG6 analogs, respectively) which seems to reverse with the PEG12 analog. The IC50 values are similar with the only significant difference of the PEG12 analog. The (177)Lu-labeled PEG4 and PEG6 conjugates showed similar pharmacokinetic with high tumor uptake and excellent tumor-to-kidney ratios (7.8 and 9.7 at 4h for the PEG4 and PEG6 derivatives, respectively). The pancreas uptake was relatively high at 1h but it shows fast washout (0.46%+/-0.02% IA/g and 0.29%+/-0.08% IA/g already at 4h). CONCLUSION: Among all the studied analogs the PEG4 and PEG6 showed significantly better properties. The very high tumor-to-non-target organ ratios, in particular tumor-to-kidney ratios, already at early time point will be important in regard to safety concerning kidney toxicity. PMID- 24780300 TI - "The ladder of the law has no top and no bottom": how therapeutic jurisprudence can give life to international human rights. AB - In the past two decades, therapeutic jurisprudence (TJ) has become one of the most important theoretical approaches to the law. But, there has, as of yet, been puzzlingly little written about the relationship between TJ and international human rights law. To be sure, there has been some preliminary and exploratory work on the relationship between TJ and international law in general, but virtually nothing on its relationship to international human rights law in a mental disability law context. This paper seeks to focus on this lack of consideration, to speculate as to why that might be, and to offer some suggestions as to how to infuse some new vitality and vigor into this important area of law and social policy. In this article, first, I offer a brief explanation of TJ. Next, I discuss, also briefly, the impact (and the potential future greater impact) of the recently-ratified United Nations Convention on the Rights of Persons with Disabilities (CRPD) on this area. Then, I consider the sparse commentary currently available on the intersection between TJ and international law in general, and will speculate as to why this is so sparse. Then, I offer some thoughts as to the TJ/international human rights law connection, looking specifically at three questions that require far more attention from this perspective (access to counsel, the use of state-sanctioned psychiatry as a tool of political oppression, and the potential redemptive power of the CRPD), and describe a research agenda that scholars might turn to in furtherance of the investigation of the relationships between therapeutic jurisprudence, international human rights law and mental disability law. I conclude by calling on scholars, activists, advocates and practitioners to begin to take this connection seriously in their future work. PMID- 24780301 TI - Cost-effectiveness of upcoming treatments for hepatitis C: we need to get the models right. PMID- 24780302 TI - Effect of thrombocytopenia on treatment tolerability and outcome in patients with chronic HCV infection and advanced hepatic fibrosis. AB - BACKGROUND & AIMS: Pegylated interferon is still the backbone of hepatitis C treatment and may cause thrombocytopenia, leading to dose reductions, early discontinuation, and eventually worse clinical outcome. We assessed associations between interferon-induced thrombocytopenia and bleeding complications, interferon dose reductions, early treatment discontinuation, as well as SVR and long-term clinical outcome. METHODS: All consecutive patients with chronic HCV infection and biopsy-proven advanced hepatic fibrosis (Ishak 4-6) who initiated interferon-based therapy between 1990 and 2003 in 5 large hepatology units in Europe and Canada were included. RESULTS: Overall, 859 treatments were administered to 546 patients. Baseline platelets (in 10(9)/L) were normal (?150) in 394 (46%) treatments; thrombocytopenia was moderate (75-149) in 324 (38%) and severe (<75) in 53 (6%) treatments. Thrombocytopenia-induced interferon dose reductions occurred in 3 (1%); 46 (16%), and 15 (30%) treatments respectively (p<0.001); interferon was discontinued due to thrombocytopenia in 1 (<1%), 8 (3%), and in 8 (16%) treatments respectively (p<0.001). In total, 104 bleeding events were reported during 53 treatments. Only two severe bleeding complications occurred. Multivariate analysis showed that cirrhosis and a platelet count below 50 were associated with on-treatment bleeding. Within thrombocytopenic patients, patients attaining SVR had a lower occurrence of liver failure (p<0.001), hepatocellular carcinoma (p<0.001), liver related death or liver transplantation (p<0.001), and all-cause mortality (p=0.001) compared to patients without SVR. CONCLUSIONS: Even in thrombocytopenic patients with chronic HCV infection and advanced hepatic fibrosis, on-treatment bleedings are generally mild. SVR was associated with a marked reduction in cirrhosis-related morbidity and mortality, especially in patients with baseline thrombocytopenia. PMID- 24780303 TI - KIR2DL3+NKG2A- natural killer cells are associated with protection from productive hepatitis C virus infection in people who inject drugs. AB - BACKGROUND & AIMS: Despite continuous high-risk behavior, a subgroup among people who inject drugs (PWID) remains seronegative for hepatitis C virus (HCV) suggesting that a state of "natural resistance" to HCV Infection may exist. Homozygosity for KIR2DL3 and its ligand HLA-C1 group alleles has been associated with control of HCV infection, however, the mechanism mediating this protective effect remained unclear. METHODS: Peripheral NK cells from PWID (n=104) were phenotypically and functionally characterized by multicolor flow cytometry. Expression levels of the NK cell receptor ligands were analysed in liver biopsies and primary human hepatocytes. RESULTS: HCV seronegative PWID (n=34) had increased levels of KIR2DL3(+)NKG2A(-) NK cells compared to healthy controls (n=10; p<0.001) and PWID with chronic (n=38; p<0.001) or resolved infection (n=37; p<0.001). There was an inverse correlation between the frequency of KIR2DL3(+) and NKG2A(+) NK cells (r=-0.53; p<0.0001). Importantly, expression of HLA-E, the ligand for NKG2A, was significantly upregulated in liver biopsies of HCV infected patients (n=51) compared to HBV infected patients (n=22; p<0.01) and correlated with HCV viral load (r=0.32; p<0.0029). In functional analyses KIR2DL3(-)NKG2A(+) NK cells but not KIR2DL3(+)NKG2A(-) NK cells were significantly inhibited by HLA-E ligation. Accordingly, interferon gamma secretion of NK cells from PWID with chronic infection but not from HCV seronegative PWID was significantly suppressed in the presence of HLA-E. CONCLUSIONS: KIR2DL3(+)NKG2A(-) NK cells are not sensitive to HLA-E-mediated inhibition and may thereby control early HCV infection prior to seroconversion and result in an apparent state of "natural resistance" to HCV in PWID. PMID- 24780304 TI - Painful tic convulsif as manifestation of vertebrobasilar dolichoectasia and aneurysm. PMID- 24780305 TI - [Aetiology and treatment of vocal fold paralysis: retrospective study of 108 patients]. AB - OBJECTIVES: To review the aetiology and treatment of laryngeal paralysis diagnosed at our hospital and to describe the available therapeutic options. METHODS: Retrospective review of medical records of 108 patients diagnosed with unilateral and bilateral vocal fold paralysis between 2000 and 2012, identifying the cause of paralysis and its treatment. RESULTS: Of the 108 cases analysed, 70% had unilateral vocal fold immobility and 30% bilateral immobility. The most frequent aetiology in both cases was trauma (represented mainly by surgical injury), followed by tumours in unilateral paralysis and medical causes in bilateral paralysis. Half of the patients with unilateral paralysis (38) were treated surgically, with medialization thyroplasty. In bilateral vocal fold immobility, the treatment consisted of tracheostomy in patients with threatened airway (40%). We planned to widen the air passage in 9 patients (27%), performing cordectomy in most of them. CONCLUSIONS: The aetiology observed in our patients is similar to that described in the literature. In cases of unilateral vocal fold paralysis, we believe thyroplasty is the procedure of choice. In bilateral paralysis, it is possible to perform cordectomy in selected patients once the airway has been secured. PMID- 24780306 TI - Balancing formal and informal care for older persons: how case managers respond. AB - This study examined how front-line home and community-care (H&CC) case managers view the role of informal caregivers, and the factors that contribute to H&CC managers' resource allocation decisions. The study research used two methods of data collection: (a) secondary analysis of the results from balance of care (BoC) simulations conducted in nine regions of Ontario, and (b) in-depth follow-up interviews with participating BoC case managers. Results suggest that case managers unanimously agree that the unit of care in the H&CC sector is not confined to the individual, as in acute care, but encompasses both the individual and the caregiver. We found, however, considerable variation in the mix and volume of H&CC services recommended by case managers. We conclude that variability in decision making may reflect the lack of regulations, best practices, and accountability guidelines in the H&CC sector. PMID- 24780307 TI - Optimal heating conditions for forming a mouthguard using a circle tray: effect of different conditions on the thickness and fit of formed mouthguards. AB - PURPOSE: The aim of this study was to determine the optimal heating conditions for sheet forming using a circle tray by comparing the thickness and fit of mouthguards formed under different conditions. METHODS: Mouthguards were fabricated using ethylene vinyl acetate sheets (4.0mm thick) and a vacuum forming machine. The working model was trimmed to a height of 20mm at the incisor and 15 mm at the first molar. Two forming conditions were compared: square sheets were pinched by the clamping frame attached to the forming machine; and round sheets were pinched at the top and bottom and stabilized by a circle tray. Each condition was defined when the sheet sagged by 10-mm or 15-mm below the level of the clamp. The thickness of the sheet was determined for the incisal and molar portion. Additionally, the difference in fit according to the forming conditions was measured by examining the cross section. Differences in the thickness or the fit due to forming conditions were analyzed using two-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparison tests. RESULTS: The thickness after formation was thicker at the 10-mm condition than that of 15-mm, and the fit at the 15-mm condition was better when that of 10-mm with square and round sheets. CONCLUSION: Within the limitation of this study, it was suggested that when forming a mouthguard using a 4.0-mm EVA sheet and a circle tray on a vacuum forming machine, the sheet should be formed at a sagging distance of 10 mm. PMID- 24780309 TI - A framework to facilitate self-directed learning, assessment and supervision in midwifery practice: a qualitative study of supervisors' perceptions. AB - BACKGROUND: Self-directed learning is an educational concept that has received increasing attention. The recent workplace literature, however, reports problems with the facilitation of self-directed learning in clinical practice. We developed the Midwifery Assessment and Feedback Instrument (MAFI) as a framework to facilitate self-directed learning. In the present study, we sought clinical supervisors' perceptions of the usefulness of MAFI. METHODS: Interviews with fifteen clinical supervisors were audio taped, transcribed verbatim and analysed thematically using Atlas-Ti software for qualitative data analysis. RESULTS: Four themes emerged from the analysis. (1) The competency-based educational structure promotes the setting of realistic learning outcomes and a focus on competency development, (2) instructing students to write reflections facilitates student centred supervision, (3) creating a feedback culture is necessary to achieve continuity in supervision and (4) integrating feedback and assessment might facilitate competency development under the condition that evidence is discussed during assessment meetings. Supervisors stressed the need for direct observation, and instruction how to facilitate a self-directed learning process. CONCLUSION: The MAFI appears to be a useful framework to promote self-directed learning in clinical practice. The effect can be advanced by creating a feedback and assessment culture where learners and supervisors share the responsibility for developing self-directed learning. PMID- 24780310 TI - A quarter of reported waiting times for elective care are probably wrong, MPs say. PMID- 24780308 TI - Gender and race/ethnicity differences for initiation of alcohol-related service use among persons with alcohol dependence. AB - BACKGROUND: Prior studies on treatment for alcohol-related problems have yielded mixed results with respect to gender and race/ethnicity disparities. Additionally, little is known about gender and racial differences in time to first alcohol-related service contact amongst persons with alcohol dependence. This study explored gender and race/ethnicity differences for first alcohol related service utilization in a population-based sample. METHODS: Primary analyses were restricted to Blacks, Whites and Hispanics, ages 18-44, with lifetime alcohol dependence (n=3311) in Wave 1 of the National Epidemiologic Survey on Alcohol and Related Conditions. We compared time to service use among men and women within and across race/ethnicity strata using multivariable Cox proportional hazard methods. RESULTS: In the sample of individuals age <45 with alcohol dependence, only 19.5% reported alcohol-related service use. Overall, women were less likely than men to receive alcohol-related services in their lifetime. However, women who did receive treatment were younger at first service utilization and had a shorter interval between drinking onset and service use than men. Gender differences were consistent across racial/ethnic groups but only statistically significant for Whites. There were no appreciable race/ethnicity differences in hazard ratios for alcohol-related service use or time from drinking initiation to first service contact. Results of sensitivity analyses for persons >=45 years old are discussed. CONCLUSIONS: There are important gender differences in receipt of and time from drinking initiation to service utilization among persons with alcohol dependence. Increased recognition of these differences may promote investigation of factors underlying differences and identification of barriers to services. PMID- 24780311 TI - A DNA-based nano-immunoassay for the label-free detection of glial fibrillary acidic protein in multicell lysates. AB - We have developed a quantitative approach to eventually enable precise and multiplexing protein analysis of very small systems, down to a single or a few cells. Through DNA-directed immobilization of DNA-protein conjugates we immobilized antibodies specific for a certain protein of interest, on a complementary DNA nanoarray fabricated by means of nanografting, a nanolithography technique based on atomic force microscopy (AFM). The proof of concept was realized for glial fibrillary acidic protein (GFAP), a biomarker crucial in cell's differentiation of astrocytes, and functional to grade classification of gliomas, the most common of primary malignant brain tumors. The efficiency of the nano-immuno sensing was tested by obtaining the immobilization of purified recombinant GFAP protein at different concentration in a standard solution then in a cellular lysate. A comparison of sensitivity between our technique and conventional ELISA assays is provided at the end of the paper. FROM THE CLINICAL EDITOR: This team developed a quantitative approach to enable precise and multiplexing protein analysis of very small systems, down to a single or a few cells, demonstrating the utility of this DNA-based nano-immunoassay in the detection of GFAP. PMID- 24780312 TI - microRNAs control of in vivo toxicity from graphene oxide in Caenorhabditis elegans. AB - The molecular basis for in vivo graphene oxide (GO) toxicity is still largely unclear. We here used Caenorhabditis elegans to investigate the microRNAs (miRNAs) control of GO toxicity. With the aid of SOLiD sequencing, we identified 23 up-regulated and 8 down-regulated miRNAs in GO-exposed nematodes. Gene ontology and KEGG pathway database analysis implied that these identified miRNAs might be involved in control of many biological processes, and some of them suggest the possible new functions of GO. Functions of the identified miRNAs in regulating the GO toxicity on lifespan were confirmed in the available miRNAs mutants. Moreover, we provide the evidence to raise a hypothesis that GO may reduce lifespan through influencing the functions of insulin/IGF signaling, TOR signaling, and germline signaling pathways controlled by miRNAs. Our results will be helpful for understanding the molecular basis for GO toxicity, and finding clues for useful surface modifications to reduce GO toxicity. From the clinical editor: In this study, toxicity of graphene oxide is studied in a Caenorhabditis elegans model via microRNA analysis. The authors report that multiple important pathways are influenced by GO and raise a hypothesis that GO may reduce lifespan through influencing the functions of insulin/IGF signaling, TOR signaling, and germline signaling pathways. PMID- 24780313 TI - Functional and molecular characterization of plastid terminal oxidase from rice (Oryza sativa). AB - The plastid terminal oxidase (PTOX) is a plastohydroquinone:oxygen oxidoreductase that shares structural similarities with alternative oxidases (AOX). Multiple roles have been attributed to PTOX, such as involvement in carotene desaturation, a safety valve function, participation in the processes of chlororespiration and setting the redox poise for cyclic electron transport. We have investigated a homogenously pure MBP fusion of PTOX. The protein forms a homo-tetrameric complex containing 2 Fe per monomer and is very specific for the plastoquinone head group. The reaction kinetics were investigated in a soluble monophasic system using chemically reduced decyl-plastoquinone (DPQ) as the model substrate and, in addition, in a biphasic (liposomal) system in which DPQ was reduced with DT diaphorase. While PTOX did not detectably produce reactive oxygen species in the monophasic system, their formation was observed by room temperature EPR in the biphasic system in a [DPQH2] and pH-dependent manner. This is probably the result of the higher concentration of DPQ achieved within the partial volume of the lipid bilayer and a higher Km observed with PTOX-membrane associates which is ~47mM compared to the monophasic system where a Km of ~74MUM was determined. With liposomes and at the basic stromal pH of photosynthetically active chloroplasts, PTOX was antioxidant at low [DPQH2] gaining prooxidant properties with increasing quinol concentrations. It is concluded that in vivo, PTOX can act as a safety valve when the steady state [PQH2] is low while a certain amount of ROS is formed at high light intensities. PMID- 24780314 TI - The bacterial-type [4Fe-4S] ferredoxin 7 has a regulatory function under photooxidative stress conditions in the cyanobacterium Synechocystis sp. PCC 6803. AB - Ferredoxins function as electron carrier in a wide range of metabolic and regulatory reactions. It is not clear yet, whether the multiplicity of ferredoxin proteins is also reflected in functional multiplicity in photosynthetic organisms. We addressed the biological function of the bacterial-type ferredoxin, Fed7 in the cyanobacterium Synechocystis sp. PCC 6803. The expression of fed7 is induced under low CO2 conditions and further enhanced by additional high light treatment. These conditions are considered as promoting photooxidative stress, and prompted us to investigate the biological function of Fed7 under these conditions. Loss of Fed7 did not inhibit growth of the mutant strain Deltafed7 but significantly modulated photosynthesis parameters when the mutant was grown under low CO2 and high light conditions. Characteristics of the Deltafed7 mutant included elevated chlorophyll and photosystem I levels as well as reduced abundance and activity of photosystem II. Transcriptional profiling of the mutant under low CO2 conditions demonstrated changes in gene regulation of the carbon concentrating mechanism and photoprotective mechanisms such as the Flv2/4 electron valve, the PSII dimer stabilizing protein Sll0218, and chlorophyll biosynthesis. We conclude that the function of Fed7 is connected to coping with photooxidative stress, possibly by constituting a redox-responsive regulatory element in photoprotection. In photosynthetic eukaryotes domains homologous to Fed7 are exclusively found in chloroplast DnaJ-like proteins that are likely involved in remodeling of regulator protein complexes. It is conceivable that the regulatory function of Fed7 evolved in cyanobacteria and was recruited by Viridiplantae as the controller for the chloroplast DnaJ-like proteins. PMID- 24780315 TI - Multifunctional HER2-antibody conjugated polymeric nanocarrier-based drug delivery system for multi-drug-resistant breast cancer therapy. AB - Nanotechnology-based medical approaches have made tremendous potential for enhancing the treatment efficacy with minimal doses of chemotherapeutic drugs against cancer. In this study, using tamoxifen (Tam), biodegradable antibody conjugated polymeric nanoparticles (NPs) was developed to achieve targeted delivery as well as sustained release of the drug against breast cancer cells. Poly(D,L-lactic-co-glycolic acid) (PLGA) NPs were stabilized by coating with poly(vinyl alcohol) (PVA), and copolymer polyvinyl-pyrrolidone (PVP) was used to conjugate herceptin (antibody) with PLGA NPs for promoting the site-specific intracellular delivery of Tam against HER2 receptor overexpressed breast cancer (MCF-7) cells. The Tam-loaded PVP-PLGA NPs and herceptin-conjugated Tam-loaded PVP-PLGA NPs were characterized in terms of morphology, size, surface charge, and structural chemistry by dynamic light scattering (DLS), Transmission electron microscopy (TEM), zeta potential analysis, 1H nuclear magnetic resonance (NMR), and Fourier transform infrared (FT-IR) spectroscopy. pH-based drug release property and the anticancer activity (in vitro and in vivo models) of the herceptin conjugated polymeric NPs were evaluated by flow cytometry and confocal image analysis. Besides, the extent of cellular uptake of drug via HER2 receptor mediated endocytosis by herceptin-conjugated Tam-loaded PVP-PLGA NPs was examined. Furthermore, the possible signaling pathway of apoptotic induction in MCF-7 cells was explored by Western blotting, and it was demonstrated that drug loaded PLGA NPs were capable of inducing apoptosis in a caspase-dependent manner. Hence, this nanocarrier drug delivery system (DDS) not only actively targets a multidrug-resistance (MDR) associated phenotype (HER2 receptor overexpression) but also improves therapeutic efficiency by enhancing the cancer cell targeted delivery and sustained release of therapeutic agents. PMID- 24780316 TI - Overexpression of inducible nitric oxide synthase impairs the survival of bone marrow stem cells transplanted into rat infarcted myocardium. AB - AIMS: Inducible nitric oxide synthase (iNOS) over-expression is considered critical to the death of transplanted cells in infarcted myocardium. The present study was to investigate the effect of iNOS on the survival of transplanted bone marrow mesenchymal stem cells (BMSCs) in infarcted myocardium. MAIN METHODS AND KEY FINDINGS: Male rat BMSCs were injected into the infarct region of female rat hearts at 1 hour (H1, group A), day 3 (D3, group B), and day 7 (D7, group C) after coronary artery ligation, and harvested on D7 after transplantation. Myocardial iNOS expression was significantly increased shortly after coronary ligation with its peak on D3, and returned to baseline at D7. The cell survival rates were 6.2%, 2.1%, and 8.3% in group A, B, and C, respectively, one week after transplantation as assessed by detecting the Y-chromosome sry sequence in the infarct region. There was no significant difference in the survival rates between D7 and week 6 after cell transplantation in group A. Treating the animals in group B with the selective iNOS inhibitor 1400 W significantly increased the survival rate (from 1.8% to 4.2%). Apoptosis level of the transplanted cells was also significantly reduced with 1400 W treatment in group B. SIGNIFICANCE: BMSC transplantation on H1 and D7 after coronary ligation might be the optimal time for cell survival. The loss of transplanted BMSCs in the infarcted myocardium was partially due to increased apoptosis and iNOS overexpression. Selective iNOS inhibition early in myocardial infarction may increase the cell viability. PMID- 24780318 TI - Tocopherol inhibits the relaxing effect of terbutaline in the respiratory and reproductive tracts of the rat: the role of the oxidative stress index. AB - AIMS: Reactive oxygen species play a role in the signal transduction of beta adrenergic receptors. We investigated whether an antioxidant (tocopherol) can reduce the effect of terbutaline in beta-2-adrenergic receptor (beta2-AR) regulated smooth muscles. MAIN METHODS: Contractility of the tissues from nonpregnant (trachea) and 22-day-pregnant (myometrium and cervix) rats was investigated in an isolated organ bath. The tracheal and uterine beta2-AR expressions were increased by 17-beta-estradiol valerate (E2) and progesterone (P4), respectively. The accumulation of cyclic-AMP (cAMP), and the total oxidant (TOS) and total antioxidant status (TAS) were also measured. The oxidative stress index (OSI) was defined as the ratio of TOS and TAS. KEY FINDINGS: Terbutaline (10(-10)-10(-5)M) decreased the contractions in the nontreated and the P4 pretreated myometria, but tocopherol (10(-7)M) did not alter these actions. Terbutaline (10(-6)M) increased the cervical resistance both in the nontreated and in the P4-treated samples, while tocopherol reduced this action only in the P4-treated cervices. Terbutaline (10(-9)-10(-4)M) reduced the tracheal tones both in the nontreated and in the E2-treated tissues, while tocopherol reduced these effects. The changes in the intracellular cAMP levels of the tissues were in harmony with the isolated organ results. The OSI was highest in the trachea and lowest in the pregnant myometrium. SIGNIFICANCE: A higher OSI is linked to a higher tocopherol sensitivity of beta-mimetic-induced relaxation. Our results suggest that the antiasthmatic effect of beta-mimetics may worsen, while their tocolytic effect may remain unchanged during parallel tocopherol administration. PMID- 24780319 TI - Sustained reduction in blood pressure from electrical activation of the baroreflex is mediated via the central pathway of unmyelinated baroreceptors. AB - AIMS: This study aims to identify the contribution of myelinated (A-fiber) and unmyelinated (C-fiber) baroreceptor central pathways to the baroreflex control of sympathetic nerve activity and arterial pressure. MAIN METHODS: Two binary white noise stimulation protocols were used to electrically stimulate the aortic depressor nerve and activate reflex responses from either A-fiber (3 V, 20-100 Hz) or C-fiber (20 V, 0-10 Hz) baroreceptor in anesthetized Sprague-Dawley rats (n=10). Transfer function analysis was performed between stimulation and sympathetic nerve activity (central arc), sympathetic nerve activity and arterial pressure (peripheral arc), and stimulation and arterial pressure (Stim-AP arc). KEY FINDINGS: The central arc transfer function from nerve stimulation to splanchnic sympathetic nerve activity displayed derivative characteristics for both stimulation protocols. However, the modeled steady-state gain (0.28 +/- 0.04 vs. 4.01 +/- 0.2%.Hz(-1), P<0.001) and coherence at 0.01 Hz (0.44 +/- 0.05 vs. 0.81 +/- 0.03, P<0.05) were significantly lower for A-fiber stimulation compared with C-fiber stimulation. The slope of the dynamic gain was higher for A-fiber stimulation (14.82 +/- 1.02 vs. 7.21 +/- 0.79 dB.decade(-1), P<0.001). The steady state gain of the Stim-AP arc was also significantly lower for A-fiber stimulation compared with C-fiber stimulation (0.23 +/- 0.05 vs. 3.05 +/- 0.31 mmHg.Hz(-1), P<0.001). SIGNIFICANCE: These data indicate that the A-fiber central pathway contributes to high frequency arterial pressure regulation and the C fiber central pathway provides more sustained changes in sympathetic nerve activity and arterial pressure. A sustained reduction in arterial pressure from electrical stimulation of arterial baroreceptor afferents is likely mediated through the C-fiber central pathway. PMID- 24780317 TI - Endothelin-1 and its role in the pathogenesis of infectious diseases. AB - Endothelins are potent regulators of vascular tone, which also have mitogenic, apoptotic, and immunomodulatory properties (Rubanyi and Polokoff, 1994; Kedzierski and Yanagisawa, 2001; Bagnato et al., 2011). Three isoforms of endothelin have been identified to date, with endothelin-1 (ET-1) being the best studied. ET-1 is classically considered a potent vasoconstrictor. However, in addition to the effects of ET-1 on vascular smooth muscle cells, the peptide is increasingly recognized as a pro-inflammatory cytokine (Teder and Noble, 2000; Sessa et al., 1991). ET-1 causes platelet aggregation and plays a role in the increased expression of leukocyte adhesion molecules, the synthesis of inflammatory mediators contributing to vascular dysfunction. High levels of ET-1 are found in alveolar macrophages, leukocytes (Sessa et al., 1991) and fibroblasts (Gu et al., 1991). Clinical and experimental data indicate that ET-1 is involved in the pathogenesis of sepsis (Tschaikowsky et al., 2000; Goto et al., 2012), viral and bacterial pneumonia (Schuetz et al., 2008; Samransamruajkit et al., 2002), Rickettsia conorii infections (Davi et al., 1995), Chagas disease (Petkova et al., 2000, 2001), and severe malaria (Dai et al., 2012; Machado et al., 2006; Wenisch et al., 1996a; Dietmann et al., 2008). In this minireview, we will discuss the role of endothelin in the pathogenesis of infectious processes. PMID- 24780320 TI - Curcumin-primed exosomes mitigate endothelial cell dysfunction during hyperhomocysteinemia. AB - AIM: Exosomes, the nano-units (<200 nm), released from diverse cell types in the extracellular body fluid, possess non-immunogenic property and ability to cross the blood-brain barrier (BBB). Since exosomes carry biological information from their cells of origin, we hypothesize that priming cells with potential therapeutic agents release improved cellular contents through exosomes. Curcumin possesses anti-oxidative and anti-inflammatory properties and provides a promising treatment for cerebral diseases and therefore, the aim of the study is to establish that mouse brain endothelial cells (MBECs) when primed with curcumin (7.5 MUM), release an alleviated exosome population that can help recover the endothelial cell (EC) layer permeability. MAIN METHODS: Homocysteine is a well known causative factor of BBB disruption; therefore, homocysteine-treated ECs were used as a model of BBB disruption and curcumin-primed exosomes were utilized to check their potential for mitigating EC disruption. MBECs were treated with curcumin and exosomes were isolated by using ultracentrifugation and immunoprecipitation. Expression levels of junction proteins were detected by Western blot and immunocytochemistry assays. Endothelial cell permeability was analyzed with Fluorescein isothiocyanate-Bovine serum albumin (FITC-BSA) leakage assay using transwell permeable supports. KEY FINDINGS: Exosomes derived from curcumin-treated (primed) cells (CUR-EXO) alleviated oxidative stress, tight junctions (ZO-1, claudin-5, occludin), adherent junction (VE-cadherin) proteins and EC layer permeability induced during EC damage due to high homocysteine levels (hyperhomocysteinemia). SIGNIFICANCE: In conclusion, the study potentiates the use of CUR-EXO for cerebral diseases where drug delivery is still a challenge. The results also pave the way to novel translational therapies for cerebral diseases by maintaining and establishing therapeutic conservatories via primed exosomes. PMID- 24780321 TI - Correlation of over-expressions of miR-21 and Notch-1 in human colorectal cancer with clinical stages. AB - AIM: The aim of the study was to identify expressions of Notch-1, microRNA-21 (miR-21), and phosphatase and tensin homolog (PTEN) in colorectal cancer (CRC), and to explore their relationship with clinical stages and metastatic status of CRC. MAIN METHODS: 102 CRC patients were enrolled and clinical data were analyzed. Expressions of Notch-1 and miR-21 in CRC and adjacent non-tumor tissues of these patients were measured by real time-PCR. Protein expressions of Notch-1 and PTEN of 12 paired tissues were determined by Western blot and immunohistochemistry. The correlations between gene expressions in different clinical stages as well as metastatic status were evaluated by linear regression. KEY FINDINGS: Notch-1 was over-expressed in 86.27% (88/102) CRC tissues, particularly in advanced stages, while miR-21 expression was increased to 74.51% (76/102) in CRC tissues compared with matched adjacent non-tumor tissues. The expressions of Notch-1 and miR-21 were positively correlated with CRC development, especially in advanced-stages (r(2)=0.3839, p<0.01). Expressions of PTEN were significantly down-regulated in CRC tissues and negatively correlated with expressions of Notch-1 (r(2)=0.5207, p<0.01) and miR-21 (r(2)=0.6996, p<0.01). SIGNIFICANCE: These data indicate that the crosstalk between Notch-1 and miR-21 is involved in CRC development through degradation of PTEN. PMID- 24780322 TI - Editor in chief's reply to Nguyen-Van-Tam. PMID- 24780323 TI - Responding to bioterror concerns by increasing milk pasteurization temperature would increase estimated annual deaths from listeriosis. AB - In a 2005 analysis of a potential bioterror attack on the food supply involving a botulinum toxin release into the milk supply, the authors recommended adopting a toxin inactivation step during milk processing. In response, some dairy processors increased the times and temperatures of pasteurization well above the legal minimum for high temperature, short time pasteurization (72 degrees C for 15 s), with unknown implications for public health. The present study was conducted to determine whether an increase in high temperature, short time pasteurization temperature would affect the growth of Listeria monocytogenes, a potentially lethal foodborne pathogen normally eliminated with proper pasteurization but of concern when milk is contaminated postpasteurization. L. monocytogenes growth during refrigerated storage was higher in milk pasteurized at 82 degrees C than in milk pasteurized at 72 degrees C. Specifically, the time lag before exponential growth was decreased and the maximum population density was increased. The public health impact of this change in pasteurization was evaluated using a quantitative microbial risk assessment of deaths from listeriosis attributable to consumption of pasteurized fluid milk that was contaminated postprocessing. Conservative estimates of the effect of pasteurizing all fluid milk at 82 degrees C rather than 72 degrees C are that annual listeriosis deaths from consumption of this milk would increase from 18 to 670, a 38-fold increase (8.7- to 96-fold increase, 5th and 95th percentiles). These results exemplify a situation in which response to a rare bioterror threat may have the unintended consequence of putting the public at increased risk of a known, yet severe harm and illustrate the need for a paradigm shift toward multioutcome risk benefit analyses when proposing changes to established food safety practices. PMID- 24780324 TI - Internalization and fate of Escherichia coli O157:H7 in leafy green phyllosphere tissue using various spray conditions. AB - In the past decade, leafy greens have been implicated in several outbreaks of foodborne illness, and research has focused on contamination during preharvest operations. Concerns have been raised that internalization of pathogens into the edible tissue occurs where postharvest chemical interventions would be ineffective. This study was initiated to measure the degree and fate of Escherichia coli O157:H7 internalized in the phyllosphere tissue of leafy greens when spray conditions, inoculum level, and type of leafy green were varied. Two spraying treatments were applied: (i) spraying individual spinach or lettuce leaves on plants once with a high dose (7 to 8 log CFU/ml) of E. coli O157:H7 and (ii) spraying spinach, lettuce, or parsley plants repeatedly (once per minute) with a low dose (2.7 to 4.2 log CFU/ml) of E. coli O157:H7 over a 10- to 20-min period. With the high-dose spray protocol, no significant differences in the prevalence of internalization occurred between Shiga toxin-negative E. coli O157:H7 isolates and virulent isolates (P > 0.05), implying that the Shiga toxin virulence factors did not influence internalization or the subsequent fate of those populations under these test conditions. Significantly greater internalization of E. coli O157:H7 occurred in spinach leaves compared with lettuce leaves when leaves were sprayed once with the high-dose inoculum (P < 0.05), whereas internalization was not observed in lettuce leaves but continued to be observed in spinach and parsley leaves following repeated spraying of the low-dose inoculum. Based on these results, it is surmised that a moisture film was generated when spraying was repeated and this film assisted in the mobilization of pathogen cells to plant apertures, such as stomata. E. coli O157:H7 cells that were internalized into spinach tissue using a low-dose repeat spray protocol were temporary residents because they were not detected 2 days later, suggesting that plant-microbe interactions may be responsible. PMID- 24780325 TI - Shiga toxin-producing Escherichia coli distribution and characterization in a pasture-based cow-calf production system. AB - Shiga toxin-producing Escherichia coli (STEC) strains are commonly found in cattle gastrointestinal tracts. In this study, prevalence and distribution of E. coli virulence genes (stx1, stx2, hlyA, and eaeA) were assessed in a cow-calf pasture-based production system. Angus cows (n = 90) and their calves (n = 90) were kept in three on-farm locations, and fecal samples were collected at three consecutive times (July, August, and September 2011). After enrichment of samples, stx1, stx2, eaeA, and hlyA were amplified and detected with a multiplex PCR (mPCR) assay. Fecal samples positive for stx genes were obtained from 93.3% (84 of 90) of dams and 95.6% (86 of 90) of calves at one or more sampling times. Age class (dam or calf), spatial distribution of cattle (farm locations B, H, K), and sampling time influenced prevalence and distribution of virulence genes in the herd. From 293 stx-positive fecal samples, 744 E. coli colonies were isolated. Virulence patterns of isolates were determined through mPCR assay: stx1 was present in 41.9% (312 of 744) of the isolates, stx2 in 6.5% (48 of 744), eaeA in 4.2% (31 of 744), and hlyA in 2.4% (18 of 744). Prevalence of non-O157 STEC was high among the isolates: 33.8% (112 of 331) were STEC O121, 3.6% (12 of 331) were STEC O103, and 1.8% (6 of 331) were STEC O113. One isolate (0.3%) was identified as STEC O157. Repetitive element sequence-based PCR (rep-PCR) fingerprinting was used to study genetic diversity of stx-positive E. coli isolates. Overall, rep-PCR fingerprints were highly similar, supporting the hypothesis that strains are transmitted between animals but not necessarily from a dam to its calf. Highly similar STEC isolates were obtained at each sampling time, but isolates obtained from dams were more diverse than those from calves, suggesting that strain differences in transference may exist. Understanding the transfer of E. coli from environmental and animal sources to calves may aid in developing intervention strategies to reduce E. coli colonization of young cattle. PMID- 24780326 TI - Fecal shedding of non-O157 serogroups of Shiga toxin-producing Escherichia coli in feedlot cattle vaccinated with an Escherichia coli O157:H7 SRP vaccine or fed a Lactobacillus-based direct-fed microbial. AB - The objectives of this study were to determine whether fecal shedding of non-O157 Shiga toxin-producing Escherichia coli (STEC) in feedlot cattle was affected by the use of an E. coli O157:H7 vaccine or a direct-fed microbial (DFM) and whether the shedding of a particular non-O157 STEC serogroup within feces was associated with shedding of O157 or other non-O157 STEC serogroups. A total of 17,148 cattle in 40 pens were randomized to receive one, both, or neither (control) of the two interventions: a vaccine based on the siderophore receptor and porin proteins (E. coli SRP vaccine, two doses) and a DFM product (low-dose Bovamine). Fresh fecal samples (30 samples per pen) were collected weekly from pen floors for four consecutive weeks beginning approximately 56 days after study allocation. DNA extracted from enriched samples was tested for STEC O157 and non-O157 serogroups O26, O45, O103, O111, O121, and O145 and for four major virulence genes (stx1, stx2, eae, and ehxA) using an 11-gene multiplex PCR assay. Generalized linear mixed models were used to analyze the effects of treatments and make within sample comparisons of the presence of O-serogroup-specific genes. Results of cumulative prevalence measures indicated that O157 (14.6%), O26 (10.5%), and O103 (10.3%) were the most prevalent STEC O serogroups. However, the vaccine, DFM, or both had no significant effect (P > 0.05) on fecal prevalence of the six non-O157 STEC serogroups in feedlot cattle. Within-sample comparisons of the presence of STEC serogroup-specific genes indicated that fecal shedding of E. coli O157 in cattle was associated with an increased probability (P < 0.05) of fecal shedding of STEC O26, O45, O103, and O121. Our study revealed that neither the E. coli O157:H7 vaccine, which reduced STEC O157 fecal shedding, nor the DFM significantly affected fecal shedding of non-O157 STEC serogroups, despite the fact that the most prevalent non-O157 STEC serogroups tended to occur concurrently with O157 STEC strains within fecal samples. PMID- 24780327 TI - A mixture of Lactobacillus casei, Lactobacillus lactis, and Paenibacillus polymyxa reduces Escherichia coli O157:H7 in finishing feedlot cattle. AB - A direct-fed microbial (DFM) containing Paenibacillus polymyxa, Lactobacillus casei, and Lactobacillus lactis was fed to cattle (n = 120) to determine impacts on shedding and survival of Escherichia coli O157:H7 in feces. Cattle were individually penned and fed diets containing 0 (control), 4 * 10(7) CFU (DFM-4), 8 * 10(7) CFU (DFM-8), or 1.2 * 10(8) CFU (DFM-12) lactobacilli per kg of dietary dry matter over 84-day fall-winter growing and 140-day spring-summer finishing periods. Fecal grab samples were collected from cattle at 28-day intervals, E. coli O157:H7 was detected by immunomagnetic separation, and isolates were compared by pulsed-field gel electrophoresis. During the growing period, feces negative for E. coli O157 from each dietary treatment were inoculated with 10(5) CFU/g nalidixic acid-resistant E. coli O157:H7 and were incubated at 4 and 22(u) C for 11 weeks. Fecal pH and fecal dry matter were measured on days 0, 1, 3, and 7 and weekly thereafter, with E. coli O157:H7 enumerated through dilution plating. Treatment with DFMs did not affect survival of E. coli O157:H7 in feces or fecal pH (P > 0.05). Only one steer was positive for E. coli O157:H7 during the growing period, but during the finishing period, DFM-8 and DFM-12 reduced the prevalence of E. coli O157:H7 in feces (P < 0.05). Feeding DFMs also reduced the frequency of individual steers shedding E. coli O157:H7 during finishing (P < 0.05), with control steers shedding E. coli O157:H7 up to four times, whereas DFM 12 steers shed E. coli O157:H7 a maximum of twice. Treatment with DFMs influenced pulsed-field gel electrophoresis profiles; steers that were fed DFM-8 and DFM-12 shed more diverse subtypes of E. coli O157:H7 than did control or DFM-4 steers. Because a companion study found linear improvement in performance with increasing dosage of DFMs in the first 28 days of the growing period, targeted use of DFM-12 during this time and for the final 1 or 2 weeks prior to slaughter may optimize performance and reduce E. coli O157:H7 while minimizing feed costs. PMID- 24780328 TI - Effects of in-plant interventions on reduction of enterohemorrhagic Escherichia coli and background indicator microorganisms on veal calf hides. AB - Enterohemorrhagic Escherichia coli (EHEC) serotypes in veal have recently been recognized as a problem. Because hides are considered to be the principal source of EHEC and hide interventions have been shown to be very efficacious in the control of EHEC in beef processing plants, various hide-directed intervention strategies have been implemented in several veal processing plants to mitigate contamination. We evaluated the effectiveness of three different hide interventions used at veal processing plants: A, a water rinse followed by a manual curry comb of the hide; B, application of 200 ppm of chlorine followed by a hot water rinse; and C, a 5-min treatment with chlorine foam followed by a rinse with 180 to 200 ppm of acidified sodium chlorite. The levels of total aerobic bacteria, Enterobacteriaceae, coliforms, and E. coli, as well as the prevalence of Salmonella, E. coli O157:H7, and non-O157 EHEC, were determined on hides pre- and postintervention. Interventions A, B, and C reduced indicator organisms (P < 0.05) by 0.8 to 3.5 log CFU, 2.1 to 2.7 log CFU, and 1.0 to 1.5 log CFU, respectively. No Salmonella was detected on hides prior to intervention. E. coli O157:H7 prevalence was observed at only one plant, so comparison was not possible. Other non-O157 EHECs (O26, O103, and O111) were observed for all interventions studied. Interventions A and B reduced culture-confirmed non-O157 EHEC by 29 and 21 % , respectively, whereas intervention C did not reduce non O157 EHEC. Our results show that the most effective veal hide intervention for reducing indicator organisms and EHECs was the application of 200 ppm of chlorine followed by hot water rinse. These data provide options that veal processors can consider in their EHEC control program. PMID- 24780329 TI - Salmonella internalization in mung bean sprouts and pre- and postharvest intervention methods in a hydroponic system. AB - Mung bean sprouts, typically consumed raw or minimally cooked, are often contaminated with pathogens. Internalized pathogens pose a high risk because conventional sanitization methods are ineffective for their inactivation. The studies were performed (i) to understand the potential of internalization of Salmonella in mung bean sprouts under conditions where the irrigation water was contaminated and (ii) to determine if pre- and postharvest intervention methods are effective in inactivating the internalized pathogen. Mung bean sprouts were grown hydroponically and exposed to green fluorescence protein-tagged Salmonella Typhimurium through maturity. One experimental set received contaminated water daily, while other sets received contaminated water on a single day at different times. For preharvest intervention, irrigation water was exposed to UV, and for postharvest intervention-contaminated sprouts were subjected to a chlorine wash and UV light. Harvested samples were disinfected with ethanol and AgNO3 to differentiate surface-associate pathogens from the internalized ones. The internalized Salmonella Typhimurium in each set was quantified using the plate count method. Internalized Salmonella Typhimurium was detected at levels of 2.0 to 5.1 log CFU/g under all conditions. Continuous exposure to contaminated water during the entire period generated significantly higher levels of Salmonella Typhimurium internalization than sets receiving contaminated water for only a single day (P < 0.05). Preintervention methods lowered the level of internalized Salmonella by 1.84 log CFU/g (P < 0.05), whereas postintervention methods were ineffective in eliminating internalized pathogens. Preintervention did not completely inactivate bacteria in sprouts and demonstrated that the remaining Salmonella Typhimurium in water became more resistant to UV. Because postharvest intervention methods are ineffective, proper procedures for maintaining clean irrigation water must be followed throughout production in a hydroponic system. PMID- 24780330 TI - Physicochemical, mechanical, and molecular properties of nonlysogenic and p22 lysogenic Salmonella typhimurium treated with citrus oil. AB - The aim of this study was to evaluate the phenotypic and genotypic properties of nonlysogenic Salmonella Typhimurium (ST(P22-)) and lysogenic Salmonella Typhimurium (ST(P22+)) in the presence of sublethal concentrations (SLC2D) of citrus essential oils (CEOs), which were used to evaluate antimicrobial susceptibility, cell surface hydrophobicity, autoaggregation ability, bacterial motility, lysogenic conversion, gene expression patterns, and antibiofilm formation. The SLC2D values of non-heat-treated (N-CEO) and heat-treated (H-CEO) CEO in an autoclave at 121 degrees C for 20 min were 2.0 to 2.1 mg/ml against ST(P22-) and 1.7 to 1.9 mg/ml against STP(22+). The rates of injured ST(P22-) and ST(P22+) cells treated with SLC2D of N-CEO and H-CEO ranged from 67 to 83%. The hydrophobicity and autoaggregation were decreased to 2.5 and 19.5% for ST(P22-) and 4.7 and 21.7% for ST(P22+), respectively, in the presence of N-CEO. A noticeable reduction in the swarming motility was observed in ST(P22-) with N-CEO (14.5%) and H-CEO (13.3%). The numbers of CEO-induced P22 were 5.40 log PFU/ml for N-CEO and 5.65 log PFU/ml for H-CEO. The relative expression of hilA, hilC, hilD, invA, invC, invE, invF, sirA, and sirB was down-regulated in ST(P22-) and ST(P22+) with N-CEO and H-CEO. The numbers of adherent ST(P22-) and ST(P22+) were effectively reduced by more than 1 log in the presence of CEO. These results suggest that CEO has potential to be used to control bacterial attachment, colonization, and invasion. PMID- 24780331 TI - Listeria monocytogenes transfer during mechanical dicing of celery and growth during subsequent storage. AB - The transfer of Listeria monocytogenes to previously uncontaminated product during mechanical dicing of celery and its growth during storage at various temperatures were evaluated. In each of three trials, 275 g of retail celery stalks was immersed in an aqueous five-strain L. monocytogenes cocktail to obtain an average of 5.6 log CFU/g and then was diced using a hand-operated dicer, followed by sequential dicing of 15 identical 250-g batches of uninoculated celery using the same dicer. Each batch of diced celery was examined for numbers of Listeria initially and after 3 and 7 days of storage at 4, 7, and 10 degrees C. Additionally, the percentage by weight of inoculated product transferred to each of 15 batches of uninoculated celery was determined using inoculated red stems of Swiss chard as a surrogate. Listeria transfer to diced celery was also assessed after removing the Swiss chard. L. monocytogenes transferred from the initial batch of inoculated celery to all 15 batches of uninoculated celery during dicing, with populations decreasing from 5.2 to 2.0 log CFU/g on the day of processing. At 10 degrees C, Listeria reached an average population of 3.4 log CFU/g in all batches of uninoculated celery. Fewer batches of celery showed significant growth during storage at 4 and 7 degrees C (P < 0.05). Swiss chard pieces were recovered from all 15 batches of celery, with similar amounts seen in batches 2 to 15 (P > 0.05). L. monocytogenes was also recovered from each batch of uninoculated celery after the removal of Swiss chard, with populations decreasing from 4.7 to 1.7 log CFU/g. Storing the diced celery at 10 degrees C yielded a L. monocytogenes generation time of 0.87 days, with no significant growth observed during storage at 4 or 7 degrees C. Consequently, mitigation strategies during dicing and proper refrigeration are essential to minimizing potential health risks associated with diced celery. PMID- 24780332 TI - Delivery of selective agents via time-delayed release tablets improves recovery of Listeria monocytogenes injured by acid and nitrite. AB - Listeria selective enrichment media are designed to enhance the isolation of the organism and increase the chances of detection. Drawbacks include the requirements for prolonged sample incubation (48 to 72 h) and manual addition of selective agents, which may be a source of contamination. Modified Listeria recovery broth (mLRB) is a proprietary enrichment medium formulated to facilitate the recovery of injured cells; its selective agents are incorporated into a format that allows delayed release until 6 h of incubation. We evaluated the change in cell populations over time for acid- and nitrite-injured Listeria monocytogenes in mLRB with the selective agents added manually at 0 h (mLRBS0) and 6 h (mLRBS6). Recovery of injured cells in mLRB plus time-delayed tablets (mLRBTD) was also compared with that in enrichment media recommended by the U.S. Department of Agriculture (University of Vermont broth), the U.S. Food and Drug Administration (buffered Listeria enrichment broth), and the International Organization for Standardization (demi-Fraser broth). Nitrite- or acid-injured Listeria at approximately 10 CFU/ml were inoculated into each broth medium, and Listeria populations were enumerated at various times from 12 to 48 h of incubation at 37 degrees C. Analysis of variance revealed that acid-injured Listeria populations in mLRBS6 at 24 h were significantly higher (P < 0.05) than those in mLRBS0; however, the differences in populations on these two media were not significant for nitrite-injured cells. Cell populations of four strains of Listeria inoculated into mLRBTD were significantly higher at 24 h than when those strains were enriched in buffered Listeria enrichment broth, demi-Fraser broth, and University of Vermont broth. Comparison between artificially contaminated milk and meat samples with a four-strain cocktail of Listeria resulted in cell populations that were significantly higher (P < 0.05) at 24 h on mLRBTD for contaminated meat than on mLRB for contaminated milk. Delivery of selective agents via time-delayed release tablets into mLRB maximizes recovery of acid- and nitrite-injured Listeria and saves analyst time during food sample analysis. PMID- 24780333 TI - Effects of different nitrite concentrations from a vegetable source with and without high hydrostatic pressure on the recovery of Listeria monocytogenes on ready-to-eat restructured ham. AB - Sodium nitrite exerts an inhibitory effect on the growth of Listeria monocytogenes. The objective of this study was to investigate the effects of various nitrite concentrations from a vegetable source with and without high hydrostatic pressure (HHP) on the recovery and growth of L. monocytogenes on ready-to-eat restructured ham. A preconverted celery powder was used as the vegetable source of nitrite. Targeted concentrations of natural nitrite investigated were 0, 50, and 100 mg/kg. HHP treatments evaluated were 400 MPa for 4 min and 600 MPa for 1 or 4 min at 12 +/- 2 degrees C (initial temperature of the pressurization fluid). Viable L. monocytogenes populations were monitored on modified Oxford medium and thin agar layer medium through 98 days of storage at 4 +/- 1 degrees C. Populations on both media did not differ. The HHP treatment at 600 MPa for 4 min resulted in L. monocytogenes populations below the detection limit of our sampling protocols throughout the storage period regardless of the natural nitrite concentration. The combination of HHP at 400 MPa for 4 min or 600 MPa for 1 min with natural nitrite resulted in initial inhibition of viable L. monocytogenes. Ham formulations that did not contain natural nitrite allowed faster growth of L. monocytogenes than did those with nitrite, regardless of whether they were treated with HHP. The results indicate that nitrite from a vegetable source at the concentrations used in this study resulted in slower growth of this microorganism. HHP treatments enhanced the inhibitory effects of natural nitrite on L. monocytogenes growth. Thus, the combination of natural nitrite plus HHP appears to have a synergistic inhibitory effect on L. monocytogenes growth. PMID- 24780334 TI - Pickled egg production: effect of brine acetic acid concentration and packing conditions on acidification rate. AB - U.S. federal regulations require that acidified foods must reach a pH of 4.6 or lower within 24 h of packaging or be kept refrigerated until then. Processes and formulations should be designed to satisfy this requirement, unless proper studies demonstrate the safety of other conditions. Our objective was to determine the effect of brine acetic acid concentration and packing conditions on the acidification rate of hard-boiled eggs. Eggs were acidified (60/40 egg-to brine ratio) at various conditions of brine temperature, heat treatment to filled jars, and postpacking temperature: (i) 25 degrees C/none/25 degrees C (cold fill), (ii) 25 degrees C/none/2 degrees C (cold fill/refrigerated), (iii) 85 degrees C/none/25 degrees C (hot fill), and (iv) 25 degrees C/100 degrees C for 16 min/25 degrees C (water bath). Three brine concentrations were evaluated (7.5, 4.9, and 2.5% acetic acid) and egg pH values (whole, yolk, four points within egg) were measured from 4 to 144 h, with eggs equilibrating at pH 3.8, 4.0, and 4.3, respectively. Experiments were conducted in triplicate, and effects were considered significant when P < 0.05. Multiple linear regression analysis was conducted to evaluate the effect on pH values at the center of the yolk. Regression analysis showed that brine concentration of 2.5% decreased the acidification rate, while packing conditions of the hot fill trial increased it. Inverse prediction was used to determine the time for the center of the yolk and the total yolk to reach a pH value of 4.6. These results demonstrate the importance of conducting acidification studies with proper pH measurements to determine safe conditions to manufacture commercially stable pickled eggs. PMID- 24780335 TI - Effects of salt concentration on biogenic amine formation and quality changes in grass carp (Ctenopharyngodon idellus) fillets stored at 4 and 20 degrees C. AB - The effects of different salt concentrations on the quality changes of grass carp (Ctenopharyngodon idella) fillets were evaluated in terms of biogenic amines, adenosine triphosphate and its related compounds, sensory attributes, total volatile basic nitrogen (TVB-N), and total viable counts during 4 and 20 degrees C storage. Grass carp fillets were brined in solutions of 2% NaCl (T1) and 10% NaCl (T2), and unsalted carp fillets were used as controls (CK). T1 and T2 showed higher sensory scores than CK. According to the TVB-N values, CK, T1, and T2 could maintain the freshness of carp for approximately 9, 12, and 27 days, respectively, when stored at 4 degrees C. The higher salt concentration had better inhibitory effect on the accumulation of some biogenic amines, such as tryptamine (TRM), 2-phenylethylamine (PHE), putrescine (PUT), and cadaverine (CAD). TVB-N of untreated grass carp fillets showed a significant (P < 0.05) correlation with TRM, PHE, PUT, and CAD during storage. PUT and CAD showed a significant (P < 0.05) correlation with TVB-N for T2 at 20 degrees C and T1 at 4 degrees C. PMID- 24780336 TI - Analyses of black Aspergillus species of peanut and maize for ochratoxins and fumonisins. AB - The genus Aspergillus section Nigri, or the black aspergilli, represents genetically closely related species that produce the mycotoxins, ochratoxins and the fumonisins. Fumonisin B1 (FB1) is of an added concern because it is also a virulence factor for maize. Our preliminary data indicated that black aspergilli could develop asymptomatic infections with maize and peanuts plants. Symptomless infections are potential problems, because under favorable conditions, there is a potential for accumulation of ochratoxins and the fumonisins in contaminated postharvest crops. In the present report, the ability of black aspergilli from peanuts and maize to produce ochratoxin A and FB1 on maize kernels was assessed. One hundred fifty strains from peanuts and maize were isolated from several southeastern and midwestern states. Aspergillus nigri (A. nigri var. nigri) was the dominant species (87%), while Aspergillus foetidus, Aspergillus japonicus, Aspergillus tubingensis, and Aspergillus carbonarius were infrequently isolated. None of the wild isolates produced detectable amounts of ochratoxins. However, we do report the occurrence of the fumonisins B1, B2, and B3. Of 54 field isolates, 30% (n = 16) produced FB1, 61% (n = 33) produced FB2, and 44% (n = 24) produced FB3. The amounts of fumonisins produced during the test period of 30 days suggest that these strains might be weak to moderate producers of fumonisin on maize. To our knowledge, this is a first report of FB1 and FB3 production by isolates of black aspergilli from an American cereal and legume. PMID- 24780337 TI - A toxin isolated from Sarcocystis fayeri in raw horsemeat may be responsible for food poisoning. AB - Food poisoning has been reported after the consumption of raw horsemeat in Japan. Diarrhea with a short incubation period is a common symptom in such cases of food poisoning. Cysts found in horsemeat ingested by patients have been identified as Sarcocystis fayeri based on morphological and genetic evaluation and findings from experimental feeding of cysts to dogs, which resulted in the excretion of sporocysts. The extracts of the horsemeat containing the cysts produced a positive enterotoxic response in the rabbit ileal loop test. Intravenous injection of a 15-kDa protein isolated from the cysts induced diarrhea and lethal toxicity in rabbits, and the protein produced enterotoxicity in the ileal loop test as did the extracts of the horsemeat containing the cysts. The partial amino acid sequence of the 15-kDa protein was homologous to the actin-depolymerizing factor of Toxoplasma gondii and Eimeria tenella. These findings indicate that the 15-kDa protein of S. fayeri is a toxin that causes food poisoning after consumption of parasitized horsemeat. PMID- 24780338 TI - Prevalence and diversity of enterotoxigenic Escherichia coli strains in fresh produce. AB - Analysis of fresh produce showed that enterotoxigenic Escherichia coli (ETEC) strains are most often found in cilantro and parsley, with prevalence rates of approximately 0.3%. Some ETEC strains also carried Shiga toxigenic E. coli (STEC) genes but had no STEC adherence factors, which are essential to cause severe human illness. Most ETEC strains in produce carried stable toxin and/or labile toxin genes but belonged to unremarkable serotypes that have not been reported to have caused human illnesses. PMID- 24780339 TI - Sampling by sponge wipe or skin excision for recovery of inoculated Salmonella and Campylobacter from defeathered broiler carcasses. AB - Broilers may carry Salmonella and Campylobacter on inner and outer surfaces upon arrival at the slaughter plant, and carcasses can be further contaminated during commercial processing. A sensitive, nondestructive, repeatable sampling method would be useful to test carcasses for levels of bacteria before and after specific processing steps to measure either contamination or efficacy of intervention techniques. Blending of excised skin is accepted as an effective sampling method but requires damage to the carcass; this makes repeated measurements on the same carcass difficult. Herein we compare sponge sampling to skin excision to recover inoculated Salmonella and Campylobacter from broiler carcasses. In each of three replications, broiler carcass breast skin was inoculated with approximately 6.0 log antimicrobial-resistant Salmonella and Campylobacter, allowed to dry for 60 s, and sampled by either sponge, skin excision, or sponge followed by skin excision. Antimicrobial-resistant Salmonella and Campylobacter were enumerated from all samples. Skin excision allowed recovery of 0.1 to 0.2 log more inoculated bacteria than did sponge sampling. When excision was used on the same skin previously sampled by sponging, the combination of both methods did not significantly improve recovery compared with sponging alone. Skin excision is slightly more sensitive than sponge sampling; however, for repeated nondestructive sampling of broiler carcasses during processing, sponge sampling may be preferable to recover Salmonella and Campylobacter within 60 s of a contamination event. PMID- 24780340 TI - Evaluation of the thin agar layer method for the recovery of pressure-injured and heat-injured Listeria monocytogenes. AB - A sublethally injured bacterial cell has been defined as a cell that survives a stress such as heating, freezing, acid treatment, or other antimicrobial intervention but can repair the cellular damage exerted by the stressor and later regain its original ability to grow. Consequently, sublethally injured cells are not likely to be included in conventional enumeration procedures, which could result in unrealistically low counts unless efforts are made to encourage recovery of the injured cells before enumeration. The objective of this study was to evaluate the use of the thin agar layer (TAL) method for the recovery of pressure-injured and heat-injured Listeria monocytogenes in a tryptic soy broth with 0.6% yeast extract system. Pressure injury consisted of treatment of a culture of mixed L. monocytogenes strains with high hydrostatic pressure at 400 or 600 MPa for 1 s, 2 min, 4 min, or 6 min at a process temperature of 12+/-2 degrees C. Heat injury consisted of treatment of a culture of mixed L. monocytogenes strains at 60+/-1 degrees C for 3, 6, or 9 min. Growth media were tryptic soy agar (TSA) with 0.6% yeast extract, modified Oxford medium (MOX), and TAL, which consisted of a 7-ml layer of TSA overlaid onto solidified MOX. Counts of viable L. monocytogenes on TAL were higher than those on MOX in the heat injury experiment but not in the pressure-injury experiment. Therefore, the effectiveness of the TAL method may be specific to the type of injury applied to the microorganism and should be investigated in a variety of cellular injury scenarios. PMID- 24780341 TI - Survival of Listeria monocytogenes on fresh blueberries (Vaccinium corymbosum) stored under controlled atmosphere and ozone. AB - Listeria monocytogenes is a foodborne pathogen that represents a high risk for consumers because it can grow under refrigeration conditions and can also develop acid tolerance. Fresh blueberries are hand-picked, packed, and transported under refrigeration without receiving a microbial inactivation treatment. The aim of this work was to study the survival of L. monocytogenes in fresh highbush blueberries stored at 4 or 12 degrees C under different controlled atmosphere conditions, including air (control); 5% O2, 15% CO2, 80% N2 (controlled atmosphere storage [CAS]); or ozone gas (O3), 4 ppm at 4 degrees C or 2.5 ppm at 12 degrees C, at high relative humidity (90 to 95%) for a total of 10 days. Fresh blueberries inside a plastic clamshell were spot inoculated with the bacteria and were stored at 4 or 12 degrees C in isolated cabinets under air, CAS, and O3 atmospheric conditions. Samples were evaluated on days 0, 1, 4, 7, and 10 for microbial growth using modified Oxford agar. CAS did not delay or inhibit L. monocytogenes growth in fresh blueberries after 10 days. O3 achieved 3 and 2-log reductions when compared with air treatment at 4 and 12 degrees C, respectively. Low concentrations of O3 together with proper refrigeration temperature can ensure product safety throughout transportation. O3 is a strong antimicrobial that safely decomposes to oxygen and water without leaving residues and can be used as an alternative method to prevent bacterial growth during a long transport period. PMID- 24780342 TI - Anti-Listeria starters: in vitro selection and production plant evaluation. AB - Anti-Listeria bacterial starters are highly demanded by the meat industry. Novel bioprotective anti-Listeria starters were searched among Lactobacillus species strains isolated from artisanal sausages. The screening confirmed that anti Listeria activity is a strain-specific property and yielded only 1 strain (of 36) exhibiting a satisfactory level of inhibition, L. delbrueckii WC0286. This strain was compared with two commercial bioprotective starters, SafePro B-SF-43 and SafePro B-LC-20, in a model simulating in vitro the first step of the fermentation process. The presence of the bioprotective starters did not modify the pH in such a way that could affect the safety or organoleptic properties of the product. Both SafePro B-SF-43 and SafePro B-LC-20 effected an important reduction of Listeria counts (0.56 and 0.72 log CFU g(-1), respectively, in 72 h), while the anti-Listeria effect of L. delbrueckii WC0286 was minor (0.15 log CFU g(-1)). These results discouraged the utilization of L. delbrueckii WC0286 for a challenge test in a pilot salami production, in favor of the best performing bioprotective starter, SafePro B-LC-20. The test confirmed that SafePro B-LC-20 did not alter the acidification trend of sausages and was capable of inhibiting Listeria, which decreased by 1.21 log CFU g(-1). This information is relevant to address research activity toward the development of new bioprotective starters. The data herein presented demonstrate that the efficacy in Listeria control of potentially bioprotective bacterial starters requires further validation in real meat matrixes, possibly by using in vitro meat fermentation experiments to narrow down the list of candidates before pilot scale challenge tests. PMID- 24780343 TI - Effect of cooling rates and temperatures on quality and safety of quahog clams (Mercenaria mercenaria). AB - The model ordinance in the National Shellfish Sanitation Program's Guide for the Control of Molluscan Shellfish was initially established for oysters; however, the clam industry also follows the protocol. Rapid cooling during periods when the growing waters exceed 80 degrees F (26.7 degrees C) results in cold shock, which causes unacceptable mortalities in clams. The clam industry was looking for a procedure to lower the clams to the standard temperature while minimizing shell shock mortalities during the warm summer months. Three tempering treatments were examined, and total aerobic plate counts (APCs) and most-probable-number (MPN) counts of Vibrio, V. parahaemolyticus, and fecal coliforms were enumerated. In treatment 1 (control), clams were harvested, held for 5 h at 90 degrees F (32.2 degrees C), and then moved to 45 degrees F (7.2 degrees C) for storage. In treatment 2, clams were harvested and held for 5 h at 90 degrees F (32.2 degrees C), followed by 12 h at 65 degrees F (18.3 degrees C) and 12 h at 55 degrees F (12.8 degrees C), and then were moved to 45 degrees F (7.2 degrees C) for long-term storage. In treatment 3, clams were harvested and held for 5 h at 90 degrees F (32.2 degrees C), followed by 24 h at 55 degrees F (12.8 degrees C) before being moved to 45 degrees F (7.2 degrees C) for long-term storage. Three replicate trials were performed with triplicate analyses during late June through early to mid-August. The current National Shellfish Sanitation Program standard is treatment 1; it contained statistically (P <= 0.05) higher total APCs than treatments 2 and 3 throughout the 21-day storage period. APCs ranged from 2.3 * 10(4) immediately after harvest to 2.7 * 10(6), 1.6 * 10(5), and 4.8 * 10(5) for treatments 1, 2, and 3, respectively, after 14 days of storage. A statistical analysis showed that treatments 2 and 3 had significantly lower total MPN per gram Vibrio than treatment 1 on day 7 but were equal to treatment 1 on days 1 and 14. MPN per gram for V. parahaemolyticus was statistically lower in treatments 2 and 3 than in treatment 1 on storage days 1 and 7. However, on day 14, treatment 3 was significantly lower than treatments 1 and 2. There was no statistical difference for fecal coliforms. The greatest mortality occurred in treatment 1 (87.4%), followed by treatment 2 (83.3%) and treatment 3 (66.0%). The outcome of this research clearly shows that treatments 2 and 3 can cool clams to a temperature of 45 degrees F (7.2 degrees C) without compromising quality or safety and can reduce the number of dead clams introduced into the marketplace. PMID- 24780344 TI - Detection of Mycobacterium tuberculosis complex by PCR in fresh cheese from local markets in Hidalgo, Mexico. AB - The objective of this study was to identify the presence of Mycobacterium tuberculosis complex bacterial DNA in samples extracted from fresh cheeses; 95 samples of fresh cheese were obtained from municipal markets in the state of Hidalgo, in central Mexico, and were analyzed in triplicate. The exogenous control for the amplification was the mitochondrial gene for cytochrome b (cyt b). M. tuberculosis complex DNA was detected by nested-PCR amplification of a fragment of the mpb70 gene in six samples, four of which were obtained from regions with enzootic bovine tuberculosis. These results suggest that cheeses prepared with raw milk contaminated with M. bovis are being sold and consumed by humans, which may cause tuberculosis. PMID- 24780345 TI - Incidence of deoxynivalenol in Serbian wheat and barley. AB - One hundred thirty-nine small-grain cereal (wheat and barley) samples collected during the 2010 harvest in Serbia were tested for deoxynivalenol (DON) contamination. Samples were classified into four different groups and then analyzed by analytical methods based on cleanup by solid-phase extraction and detection by liquid chromatography after the validation. Limits of detection of DON were 18 and 22 MUg/kg for wheat and barley, respectively, and limits of quantification were 60 and 73 MUg/kg for wheat and barley, respectively. Obtained recovery values for wheat and barley samples ranged from 93.7 to 105.8% and from 84.7 to 89.2%, respectively. Analysis of 128 wheat samples showed that 100 (78.1%) of them were contaminated with DON at the levels ranging from 64 to 4,808 MUg/kg. The contamination level of even 16 (12.5%) samples was above the established maximum tolerable limits adopted by the European Commission (EC) and Serbian regulation. In the 11 examined barley samples, DON was found in 3 (27.3%), with the levels ranging from 118 to 355 MUg/kg, although none of the samples were contaminated above the limit for this cereal. The results obtained were analyzed as a function of climatic conditions and compared with the previous data on the presence of DON in Serbia. PMID- 24780346 TI - Evaluation of a sensitive reverse transcription PCR-enzymelinked immunosorbent assay for detection of hepatitis A virus in oysters (Saccostrea glomerata) on the east coast of the Gulf of Thailand. AB - Hepatitis A virus (HAV) contamination in food can lead to major health problems. We developed a combination reverse transcription (RT) PCR method plus enzyme linked immunosorbent assay (ELISA) to detect HAV in fresh oysters harvested along the east coast of the Gulf of Thailand. Viral nucleic acid was extracted via the glycine-arginine-polyethylene glycol method followed by RT-PCR amplification with specifically designed primers against HAV and an ELISA to detect the digoxigenin labeled RT-PCR products. The ELISA in concert with the RT-PCR protocol further increased the detection sensitivity by 100-fold for the HAV genome and 10-fold in artificially contaminated oysters. The overall sensitivity of the RT-PCR in combination with the ELISA was 31.88 pg and 16 PFU/g, respectively. The ELISA increases the specificity of the RT-PCR assay for detecting naturally occurring HAV in oysters. This combined RT-PCR-ELISA approach is a practical and sensitive method for HAV detection and can be utilized in routine screening for HAV in shellfish. PMID- 24780347 TI - Investigating the cost to ongoing tasks not associated with prospective memory task requirements. AB - The purpose of the current study was to investigate the relationship between prospective memory (PM) and consciousness by examining cost to ongoing activities, with cost assumed to reflect a direction of conscious resources away from the ongoing task in service of the PM task. Ongoing task blocks in which the PM task was relevant or irrelevant were alternated to achieve three aims: determine if cost would persist in irrelevant blocks when relevant and irrelevant blocks were clearly demarcated and irrelevant stimuli were incompatible with the PM task; investigate if costs would be greatest at the start of irrelevant blocks; and determine whether costs would occur when the irrelevant block preceded any relevant blocks. Costs were found in irrelevant blocks and greater cost at the start of the irrelevant blocks suggest the cost may be due in part to participants making decisions about the engagement of conscious resources at transition points. PMID- 24780348 TI - On the link between mind wandering and task performance over time. AB - Here we test the hypothesis that fluctuations in subjective reports of mind wandering over time-on-task are associated with fluctuations in performance over time-on-task. In Study 1, we employed a singleton search task and found that performance did not differ prior to on- and off-task reports, nor did individual differences in mind wandering predict differences in performance (so-called standard analytic methods). Importantly however, we find that fluctuations in mind wandering over time are strongly associated with fluctuations in behavior. In Study 2, we provide a replication of the relation between mind wandering and performance over time found in Study 1, using a Flanker interference task. These data indicate (1) a tight coupling between mind wandering and performance over time and (2) that a temporal-analytic approach can reveal effects of mind wandering on performance in tasks where standard analyses fail to do so. The theoretical and methodological implications of these findings are discussed. PMID- 24780349 TI - Associations between child emotional eating and general parenting style, feeding practices, and parent psychopathology. AB - Emotional eating is the tendency to eat in response to negative emotions. Prior research has identified a relationship between parenting style and child emotional eating, but this has not been examined in clinical samples. Furthermore, the relationship between specific parenting practices (e.g., parent feeding practices) and child emotional eating has not yet been investigated. The current study examined relationships between child emotional eating and both general and specific parenting constructs as well as maternal symptoms of depression and binge eating among a treatment-seeking sample of overweight children. Participants included 106 mother-child dyads who attended a baseline assessment for enrollment in a behavioral intervention for overeating. Ages of children ranged from 8 to 12 years old. Mothers completed self-report measures of their child's emotional eating behavior, their own feeding practices, and symptoms of depression and binge eating. Children completed a self-report measure of their mothers' general parenting style. A stepwise regression analysis was conducted to identify the parent variable that was most strongly related to child emotional eating, controlling for child age and gender. Emotional feeding behavior (i.e., a tendency to offer food to soothe a child's negative emotions) was the parent factor most significantly related to child emotional eating. Findings suggest that emotional feeding practices in parents may be related to emotional eating in children. Treatment with overweight children who engage in emotional eating may be improved by targeting parent feeding practices. PMID- 24780350 TI - Three-dimensional v/s standard titanium miniplate fixation in the management of mandibular fractures--a randomized clinical study. AB - PURPOSE: The aim of this study was to compare treatment outcomes using three dimensional and standard titanium miniplates in the management of mandibular fractures. MATERIAL AND METHODS: A prospective study of 30 patients with mandibular fractures. Patients were randomly categorized into 2 groups with 15 patients in each group; patients in Group I were treated with 2.0 mm 3 dimensional titanium miniplate and screws and patients in Group II were treated with 2.0 mm standard plates and screws. Clinical parameters evaluated were: intra operative assessment of reduction, intra-operative and post-operative assessment of stability of occlusion, mobility of fracture fragments and need for intermaxillary fixation. Radiographic parameters included pre-operative evaluation of displacement of fracture fragments and post-operative evaluation of bone union and plate fracture at different time intervals. RESULTS: In Group I, 3 patients (20%) and in Group II, 8 patients (53%) had gap between fracture fragments during reduction. Six patients (40%) in Group I and 8 patients (53%) in Group II had mildly deranged occlusion on the 7th post-operative day. Two patients (13%) in Group I and 6 patients (40%) in Group II needed IMF till the end of the 1st month. No patients showed tissue dehiscence at the end of 1st and 3rd month post-operatively. Infection was not observed in any patient post operatively. Five patients (33%) from Group I had displaced fracture fragments and 10 patients (67%) had severely displaced fracture fragments pre-operatively. Seven (47%) patients from Group II had displaced fracture fragments and 8 (53%) had severely displaced fracture fragments pre-operatively. Nine patients (60%) in Group I and 6 patients (40%) in Group II showed radiographic evidence of bone union after the 3rd month post-operatively. CONCLUSION: The use of 3D miniplate is a viable option for fixation of mandibular fractures routinely. 3D titanium miniplates showed comparable results compared to standard titanium miniplates. PMID- 24780351 TI - Stability study of total temporomandibular joint replacement on sheep. AB - OBJECTIVE: To evaluate the stability of our custom-made prosthesis by establishing the model of sheep total temporomandibular joint (TMJ) replacement. METHODS: Six sheep were included in our study. Spiral computed tomography (CT) data of all sheep was obtained and transformed into 3-dimensional model by surgicase5.0 software preoperatively. Total TMJ prostheses were made based on the skull model. Ultra-high molecular weight polyethylene was used to make glenoid fossa lining, while titanium alloy to prefabricate mandibular retention handle and titanium plate over glenoid fossa. Cobalt-chromium-molybdenum alloy was also used to prefabricate the condyle. The right sides of all sheep, as the experimental group, were carried out total TMJ replacement, while the left sides were as the control group. The bone in both experimental and control side were excised after 3 and 6 months. Scanning electron microscope (SEM) was used to observe the interface between bone and prosthesis. Van Gieson staining and immunohistochemical staining (IHC) were used respectively to observe the interface of titanium screw and bone and the expression of alkaline phosphatase (ALP). RESULTS: SEM and Van Gieson staining showed that there was immature bone and osteoid formed in the interface of prosthesis and bone after 3 months. While after 6 months, there was osseointegration between them. IHC showed that the expression of ALP in the experimental side was much higher than in the control side after 3 months and its expression decreased after 6 months with no difference from the control side. CONCLUSION: The custom-made TMJ prosthesis which was designed and manufactured by ourselves has good stability after total TMJ replacement. PMID- 24780352 TI - A scanning electron microscope characterisation of biofilm on failed craniofacial osteosynthesis miniplates. AB - INTRODUCTION: Between 3 and 18% of craniofacial osteosynthesis plates are removed due to chronic infection. Removal of the plate is necessary to manage the chronic infective state i.e. miniplate removal results in resolution of the infection. These observations are suggestive of a biofilm-related infection. The aim of this retrospective study was to characterise the presence of biofilm on the removed miniplates from oral and maxillofacial surgery. MATERIALS AND METHODS: A total of 12 plates and associated screws were recovered from eleven patients suffering from persistent, trauma site infection. The recovered plates plus 1 control plate were imaged using scanning electron microscopy (SEM). One recovered plate was also imaged using confocal microscopy (CM) for comparative purposes. RESULTS: Of the 12 plates, 3 (25%) demonstrated highly localised polymicrobial biofilms, five (42%) demonstrated coccal biofilms, one possessed a filamentous biofilm and one showed attached yeast. Overall, 75% of the plates and 82% of the patients exhibited evidence of biofilm to varying degrees. All of the infections resolved following removal of the plates and antibiotic treatment. CONCLUSION: Microbial biofilms can explain the clinical course of chronic infections associated with miniplates. PMID- 24780353 TI - Influence of epidermal growth factor receptor expression on the cetuximab and panitumumab response rates of head and neck carcinoma cells. AB - OBJECTIVES: To examine the impact of epidermal growth factor receptor (EGFR) expression level on the efficacy of monoclonal antibodies against the EGFR. METHODS: In four human head and neck carcinoma cell lines, epidermal growth factor expression was knocked down by lentiviral RNA interference. Next, the efficacies of cetuximab and panitumumab at concentrations of 4, 40, and 400 MUg/ml were measured by real time cell analysis for a 48-h duration. Finally, the different response rates to the drugs were statistically analyzed. RESULTS: The lentiviral EGFR knockdown efficiency ranged from 18 to 54 % across all of the cell lines. All original cell lines exhibited rather poor or inverse responses with regard to EGFR-AB treatment. In contrast, inhibiting EGFR expression in the same cell lines yielded statistically significant better responses to cetuximab or panitumumab treatment. CONCLUSIONS: The cell lines used in this study responded poorly to cetuximab and panitumumab. Better anti-EGFR treatment efficacy was related to lower EGFR expression in head and neck cancer cell lines. These findings might influence the selection of patients to receive cetuximab and panitumumab treatment for head and neck cancer. PMID- 24780354 TI - Subcranial craniotomy approach for frontobasal fracture correction. AB - OBJECTIVE: Frontobasilar fracture types and the outcome of patients after management with the subcranial approach technique were evaluated. MATERIAL AND METHODS: A retrospective analysis of 48 patients (45 males, mean age 38,5 years; range 16-82 years) who had a subcranial approach for frontal base fracture correction between April 1996 and April 2011 at a tertiary care academic hospital in Turku, Finland. RESULTS: Sixteen (33%) patients had fractures including all frontobasilar fracture types (Type I-IV) i.e. fractures that involved frontal sinuses, orbital roofs, ethmoidal region, cribriform plate and sphenoidal region. Twenty-seven (56%) patients were considered to have had brain damage at presentation. Forty percent of patients were suffering from synchronous trauma. Peroperatively, 31 (65%) patients had exposure or defect of the dura due to bone dehiscence but only two patients suffered from cerebrospinal fluid (CSF) fistula following surgery. CSF fistulae were covered by pericranium in most of the cases (68%). There was no postoperative meningitis. Thirty-eight percent of the patients needed further operation with a subcranial craniotomy following primary reconstruction. At the last follow-up visit 35% were suffering from permanent neurological problems following brain injury. CONCLUSIONS: Subcranial approach seemed successful in the management of all frontobasilar fractures in this series with reasonably low complication rate. Therefore, we would recommend it as the technique of choice in multiple and even in the most complicated frontal base fractures. PMID- 24780355 TI - Three-dimensional natural head position reproduction using a single facial photograph based on the POSIT method. AB - We developed a new method to record and reproduce the three-dimensional natural head position (NHP) from a single photograph of a patient's face using a pose from orthography and scaling with iterations (POSIT) algorithm. We attached 4-mm spherical ceramic markers to the patient's face as feature points. A frontal photograph of the patient's NHP was taken using an ordinary digital camera parallel to the global horizon. Computed tomography (CT) was then performed on the patient with the markers. The ceramic marker positions were determined in the 2D image and corresponded to points in the 3D model. The 3D rotation matrix determined using the feature points via the POSIT method was applied to the CT model to reproduce the NHP. A skull phantom was used to evaluate the accuracy and reproducibility of the developed method. The degree difference ( degrees ) between the true and POSIT orientations in the roll, pitch, and yaw directions was quantified as the error. The mean accuracy was -0.04 +/- 0.15 degrees , -0.17 +/- 0.50 degrees , and -0.02 +/- 0.37 degrees in the roll, pitch, and yaw directions, respectively. The method developed was highly reproducible during intra-observer and inter-observer variation analyses. The accuracy of the method was clinically acceptable, and the procedure was time- and cost-effective. This method is accurate and inexpensive; additionally, it does not affect the patient's lip position, and we expect it to be routinely used during orthognathic surgery. PMID- 24780356 TI - Prognostic value of echocardiographic changes in patients with pulmonary arterial hypertension receiving parenteral prostacyclin therapy. AB - BACKGROUND: It is unknown whether the echocardiographic changes observed after treatment of patients with pulmonary arterial hypertension have prognostic value. METHODS: Subjects with pulmonary arterial hypertension, confirmed by right heart catheterization, who underwent Doppler echocardiography before (baseline) and after 1 year of treatment (follow-up) with parenteral prostacyclin analogues were retrospectively identified. Echocardiographic parameters were measured offline by two investigators. RESULTS: A total of 48 patients were included (mean age, 45 +/ 14 years; 83% women). Compared with baseline, follow-up echocardiography showed reductions in right atrial area (mean percentage change, 12 +/- 25%; P < .001), right ventricular (RV) basal and middle cavity dimensions (mean percentage change, 8.5 +/- 14% [P < .001] and 6.8 +/- 17% [P = .005], respectively), and peak tricuspid regurgitant velocity (mean percentage change, 10 +/- 14%; P < .001). Tricuspid annular plane systolic excursion (mean percentage change, 36 +/- 43%; P < .001) and RV outflow tract time-velocity integral (mean percentage change, 48 +/- 66%; P < .001) increased. During a median follow-up period of 52.5 months (interquartile range, 20.5-80 months), 18 patients (37.5%) died, mostly (n = 15 [83%]) from progression of pulmonary arterial hypertension. The changes in RV end-diastolic area (hazard ratio [HR per 10% decrease, 0.73; 95% confidence interval [CI], 0.57-0.93), tricuspid valve regurgitation velocity (HR per 10 cm/sec decrease, 0.58; 95% CI, 0.37-0.89), RV outflow tract velocity-time integral (HR per 10% increase, 0.90; 95% CI, 0.83-0.98), and subjective RV function (HR per 1 unit of improvement [e.g., from moderate to mild], 0.55; 95% CI, 0.31-0.96) were associated with overall mortality. CONCLUSIONS: Echocardiographic parameters that estimate RV systolic pressure and assess RV morphology and function improve after 1 year of prostacyclin analogue treatment, and the degree of change has prognostic implications. PMID- 24780357 TI - Characterization of circulating and endothelial progenitor cells in patients with extreme-duration type 1 diabetes. AB - OBJECTIVE: We characterized and correlated endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) with lack of vascular complications in the Joslin Medalist Study in patients with type 1 diabetes for 50 years or longer. RESEARCH DESIGN AND METHODS: EPC and CPC levels were ascertained by flow cytometry and compared among Medalists (n = 172) with or without diabetic retinopathy (DR; n = 84 of 162), neuropathy (n = 94 of 165), diabetic nephropathy (DN; n = 18 of 172), cardiovascular disease (CVD; n = 63 of 168), age-matched controls (n = 83), type 2 diabetic patients (n = 36), and younger type 1 diabetic patients (n = 31). Mitogens, inflammatory cytokines, and oxidative markers were measured in blood or urine. Migration of cultured peripheral blood mononuclear cells (PBMCs) from Medalists and age-matched controls were compared. RESULTS: Medalists' EPC and CPC levels equaled those of their nondiabetic age-matched controls, were 10% higher than those in younger type 1 diabetic patients, and were 20% higher than those in age-matched type 2 diabetic patients. CPC levels were 15% higher in Medalists without CVD and nephropathy than in those affected, whereas EPC levels were significantly higher in those without peripheral vascular disease (PVD) than those with PVD. Stromal-derived factor 1 (SDF-1) levels were higher in Medalists with CVD, DN, and DR than in those not affected and their controls. IGF-I levels were lower in Medalists and correlated inversely with CPC levels. Additionally, cultured PBMCs from Medalists migrated more than those from nondiabetic controls. CONCLUSIONS: Normal levels of EPC and CPC in the Medalists, unlike other groups with diabetes, especially those without CVD, support the idea that endogenous factors exist to neutralize the adverse effects of metabolic abnormalities of diabetes on vascular tissues. PMID- 24780358 TI - Effects of sodium fluoride on MAPKs signaling pathway in the gills of a freshwater teleost, Cyprinus carpio. AB - Exposure to elevated levels of fluoride can cause a variety of adverse effects in fish. Previously we showed that fluoride causes injuries and apoptosis in the gills of Cyprinus carpio. In this study, the effects of fluoride on caspase-3 activity and on accumulation of proteins in the MAPKs pathways were evaluated using Western blotting and immunohistochemistry methods in vivo and in vitro. In vivo experiments showed that the caspase-3 activity increased with fluoride exposure level in a dose-dependent pattern Western blotting and immunohistochemistry results indicated that ERK relative activation tended to decrease as a function of fluoride exposure concentration. In contrast, relative activation of JNK increased with fluoride exposure level. Fluoride exposure did not appear to affect p38 activation. Furthermore, pretreatment of branchial cells with MAPK-specific inhibitors effectively prevented JNK induction and ERK inhibition, respectively, as well as reversed caspase-3 activity in fluoride treated branchial cells. Our results indicate that activation of JNK and inactivation of ERK were caused by increased ROS and decreased antioxidant capacity in the gills of chronically exposed C. carpio described previously, which eventually caused the observed apoptosis in the fluoride-exposed gills and cells in C. carpio. JNK activation and ERK inactivation mechanism play a crucial role in gill impairment induced by chronic fluorosis. These findings contribute to a better understanding of the initial molecular and cellular events in the gill of fish chronically exposed to fluoride. PMID- 24780359 TI - Mechanisms of hexabromocyclododecanes induced developmental toxicity in marine medaka (Oryzias melastigma) embryos. AB - Hexabromocyclododecanes (HBCDs) are widely used as additive brominated flame retardants, and are now ubiquitous contaminants in the environmental media and biota, including the marine environment and marine organisms. However, the impacts of HBCDs on marine fish are not well known. In this study the embryos of marine medaka (Oryzias melastigma) were used to assess the developmental toxicity of HBCDs. Freshly fertilized marine medaka embryos were exposed to various concentrations of technical HBCD (tHBCD, 0, 5, 20 and 50MUg/L) until the first fry stage, and hatch success, morphology and cardiac function were examined. In all the exposure groups (5, 20 and 50MUg/L) tHBCD significantly increased the embryo heart beats. The measurement of sinus venosus-bulbus arteriosus (SV-BA) distance indicated that tHBCD significantly enlarged the SV-BA distance at exposure concentrations of 20 and 50MUg/L. The malformation rate at the first fry stage was also induced by tHBCD in a dose dependent manner, with the formation of pericardial edema and yolk sac edema as the most frequently observed malformation. In addition, the concentrations of total HBCD isomers (SigmaHBCDs) in embryos in the current study were comparative with environmental levels and increased with increasing exposure duration. Furthermore, exposure to tHBCD also induced the level of 8-oxodG, a representative oxidative DNA damage. The mechanisms of HBCD-induced developmental toxicity were further explored by TUNEL assay, gel-based quantitative proteomic approach and measurement of the expression of several stress responsive genes, such as p53, TNF-alpha, IL-1beta, CYP1A, COX-1 and COX-2, together with the activities of caspases. The results suggested that HBCDs exposure at environmentally realistic concentrations induced oxidative stress and apoptosis, and suppressed nucleotide and protein synthesis, which all together resulted in developmental toxicity, particularly in the cardiovascular system, in the embryos of O. melastigma. PMID- 24780360 TI - Sports medicine and sports science contributions to football. PMID- 24780361 TI - Assessment of sexual risk behaviors and perception of vulnerability to sexually transmitted diseases/acquired immunodeficiency syndrome in women, 1999-2012: a population based survey in a medium-sized Brazilian city. AB - Sexual behavior is a key factor for susceptibility to sexually transmitted diseases. An evaluation of the sexual behavior of women at reproductive age was conducted in 1999. A replication of this study aims to evaluate the current situation and identify changes in sexual behavior, 13 years later. This is a population-based cross-sectional study, conducted with 1071 women in Pelotas, Brazil. Compared to the 1999 study, a 14% increase in early sexual debut and an 8% decrease in the non-use of condoms were observed in 2012. The proportion of women who reported anal sex doubled between these periods. There was no trend of increase or decrease in the prevalence of behaviors with distinct patterns being observed for each of them. Reduction of non-use of condoms may be an indicator of the effectiveness of campaigns to promote safe sex. However, the increased prevalence of early sexual debut and anal sex indicates the need for campaigns to continue and to expand their focus, especially among vulnerable groups. PMID- 24780362 TI - Survival of HIV patients with tuberculosis started on simultaneous or deferred HAART in the THRio cohort, Rio de Janeiro, Brazil. AB - BACKGROUND: The timing of highly active antiretroviral therapy (HAART) after a tuberculosis diagnosis in HIV-infected patients can affect clinical outcomes and survival. We compared survival after tuberculosis diagnosis in HIV-infected adults who initiated HAART and tuberculosis therapy simultaneously to those who delayed the start of HAART for at least two months. METHODS: The THRio cohort includes 17,983 patients receiving HIV care in 29 public clinics in Rio de Janeiro, Brazil. HAART-naive patients at the time of a new TB diagnosis between September 2003 and June 2008 were included. Survival was measured in days from diagnosis of TB. We compared survival among patients who initiated HAART within 60 days of TB treatment (simultaneous - ST) to those who started HAART >60 days of TB treatment or never started (deferred - DT). Kaplan-Meier plots and Cox proportional hazards regression analyses were conducted. RESULTS: Of 947 patients diagnosed with TB, 572 (60%) were HAART naive at the time of TB diagnosis; 135 were excluded because of missing CD4 count results. Among the remaining 437 TB patients, 56 (13%) died during follow-up: 25 (10%) among ST patients and 31 (16%) in DT group (p=0.08). ST patients had lower median CD4 counts at TB diagnosis than DT patients (106 vs. 278, p<0.001). Cox proportional hazards utilizing propensity score analysis showed that DT patients were more likely to die (adjusted HR=1.89; 95% CI: 1.05-3.40; p=0.03). CONCLUSION: HAART administered simultaneously with TB therapy was associated with improved survival after TB diagnosis. HAART should be given to patients with HIV-related TB as soon as clinically feasible. PMID- 24780363 TI - Comparison among the BED capture enzyme immunoassay test and AxSYM avidity index assay for determining recent HIV infection and incidence in two Voluntary Counselling and Testing Centres in Northeast Brazil. AB - The aims of this study were to compare the automated AxSYM avidity assay index with the BED capture enzyme immunoassay test and to calculate the HIV-1 incidence using the BED capture enzyme immunoassay and AxSYM avidity assay index algorithms within a population seeking the Voluntary Counselling and Testing Centres in two municipalities in the Metropolitan Region of Recife, Northeast of Brazil. An analysis was conducted in 365 samples that tested positive for HIV infection from frozen serum collected during the period 2006-2009. There was a similar proportion of males and females; most patients were heterosexual (86%) with a median age of 29 years. Of the 365 samples, 102 (28%) and 66 (18.1%) were identified as recent infections by BED capture enzyme immunoassay and AxSYM avidity assay index, respectively. The HIV-1 total incidence in the BED capture enzyme immunoassay and AxSYM avidity assay index algorithms were: 0.79 (95% CI: 0.60-0.98) and 0.34 (95% CI: -0.04 to 0.72), respectively. Incidence was higher among men. There was good agreement between the tests, with a kappa of 0.654 and a specificity of 95.8%. AxSYM avidity assay index may be helpful in improving the quality of the estimates of recent HIV infection and incidence, particularly when used in a combined algorithm with BED capture enzyme immunoassay. PMID- 24780364 TI - Assessment of antioxidants status and superoxide dismutase activity in HIV infected children. AB - OBJECTIVE: This study aims to assess the nutritional status of selenium, copper and zinc; and also the erythrocyte superoxide dismutase activity of HIV-infected children compared to a control group. METHODS: A cross-sectional study was carried out with prepubertal HIV-infected children (n=51) and their healthy siblings (n=32). All biochemical measurements including plasma selenium, serum copper levels, serum and erythrocyte zinc levels and erythrocyte superoxide dismutase activity were evaluated according to dietary, clinical and biochemical parameters. RESULTS: Compared to the control group, the HIV-infected children had lower z-score values for height-for-age (p=0.0006), higher prevalence of stunting (11.8%) (p=0.047), lower selenium levels (p=0.0006) and higher copper levels (p=0.019). No difference was found concerning superoxide dismutase activity (p>0.05). The HIV-infected group presented a higher proportion (45.1%) of children with zinc intakes below the estimated average requirement (p=0.014); however, no association with zinc biochemical parameters was found. CONCLUSION: HIV-infected children have an inadequate selenium and copper nutritional status, which could influence the progression to AIDS. An adequate micronutrient status could improve the clinical conditions in these patients and minimize free radical production and cellular oxidative stress. PMID- 24780365 TI - Tropical pruritus. PMID- 24780366 TI - The rapid and sustained responses of dendritic cells to influenza virus infection in a non-human primate model. AB - Dendritic cells (DCs) are readily infected by influenza viruses and play a crucial role in regulating host innate and adaptive immune responses to viral infection. The aims of this study are to characterize the dynamic changes in the numbers and maturation status of dendritic cells present in the lung and lung associated lymph nodes (LALNs) in the model of a non-human primate (NHP) infected by influenza A virus (IAV). Cynomolgus macaques were infected with influenza A virus (H3N2) via bronchoscopy. Flow cytometry was used to analyze the DC numbers, maturation status and subsets during the time of acute infection (days 1, 2, 3, 4, 7) and the resolution phase (day 30). A dramatic increase in the numbers of influenza A virus-infected CD11c+CD14- myeloid dendritic cells (mDCs) and CD11c CD123+ plasmacytoid dendritic cells (pDCs) were observed from day 1 to day 4 and peak up from day 7 post-infection. In lung and lung-associated lymph nodes, the numbers and maturation status of myeloid dendritic cells and plasmacytoid dendritic cells increased more slowly than those in the lung tissues. On day 30 post-infection, influenza A virus challenge increased the number of myeloid dendritic cells, but not plasmacytoid dendritic cells, compared with baseline. These findings indicate that dendritic cells are susceptible to influenza A virus infection, with the likely purpose of increasing mature myeloid dendritic cells numbers in the lung and lung and lung-associated lymph nodes, which provides important new insights into the regulation of dendritic cells in a non-human primate model. PMID- 24780367 TI - Effect of pulmonary hypertension on outcome of pulmonary tuberculosis. AB - BACKGROUND: This study performed at the National Research Institute of Tuberculosis and Lung Disease, Tehran, Iran, aimed to evaluate the effect of concomitant pulmonary hypertension on the outcome of pulmonary tuberculosis. METHODS: New cases of pulmonary tuberculosis were recruited for the study. Pulmonary hypertension was defined as systolic pulmonary arterial pressure >= 35 mm Hg estimated by transthoracic Doppler echocardiography. We assessed the relationship between pulmonary hypertension and mortality during the six-month treatment of tuberculosis. RESULTS: Of 777 new cases of pulmonary tuberculosis, 74 (9.5%) had systolic pulmonary arterial pressure >= 35 mm Hg. Ten of them (13.5%) died during treatment compared to 5% of cases with pulmonary arterial pressure less than 35 mm Hg (p=0.007). Logistic regression analysis showed that pulmonary hypertension and drug abuse remained independently associated with mortality (OR=3.1; 95% CI: 1.44-6.75 and OR=4.4; 95% CI: 2.35-8.17, respectively). CONCLUSION: A significant association was found between mortality and presence of pulmonary hypertension and drug abuse among new cases of pulmonary tuberculosis. PMID- 24780368 TI - Safety, tolerability and side effects of human papillomavirus vaccines: a systematic quantitative review. AB - Recently, many studies have evaluated HPV vaccine safety and adverse effects. Two vaccines have been recently evaluated in randomized controlled trials: the bivalent vaccine for HPV 16 and 18 (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) and the quadrivalent vaccine for HPV 6, 11, 16, and 18 (Gardasil, Merck and Co., Inc., Whitehouse Station, NJ). We have performed a systematic review of all randomized controlled trials in which HPV vaccines were compared with placebo regarding safety, tolerability and adverse effects. Studies were searched up to March 2013 in the databases: Pubmed, Embase, Scielo and Cancerlit. Odds Ratios (OR) of most incident adverse effects were obtained. Twelve reports, involving 29,540 subjects, were included. In the HPV 16/18 group, the most frequently reported events related to the vaccine were pain (OR 3.29; 95% CI: 3.00-3.60), swelling (OR 3.14; 95% CI: 2.79-3.53) and redness (OR 2.41; 95% CI: 2.17-2.68). For the HPV 6/11/16/18 group the events were pain (OR 2.88; 95% CI: 2.42-3.43) and swelling (OR 2.65; 95% CI: 2.0-3.44). Concerning the HPV 16/18 vaccine, pain was the most common outcome detected. These effects can be due to a possible VLP-related inflammation process. Fatigue was the most relevant general effect observed followed by fever, gastrointestinal symptoms, and headache. In the HPV 6/11/16/18 group, only general symptoms, pain and swelling were observed. Pain and swelling were the most frequent. Comparing HPV 16/18 to HPV 6/11/16/18 vaccines, the former presented more adverse effects, perhaps because there are many more trials evaluating the bivalent vaccine. Other studies are needed to clarify this issue. PMID- 24780369 TI - The usefulness of ultrasound imaging in digital and extradigital glomus tumors. AB - Recent years have witnessed an increase in the use of ultrasound imaging of the skin in the field of dermatology, as the technique reveals details of vessels and other structures that cannot be detected on physical examination. Extradigital glomus tumors are rarely seen in clinical practice and can pose a diagnostic challenge for dermatologists. We report on 4 patients with a clinical suspicion of extradigital glomus tumor and on 1 patient with a clinical suspicion of subungual glomus tumor. All 5 patients underwent ultrasound examination in B mode and color and pulsed-wave Doppler prior to surgical excision of the tumor and histologic examination, which confirmed the diagnosis in each case. Ultrasound imaging of the skin, combined with clinical findings, provided a simple, noninvasive way of making a prompt diagnosis and identifying the exact location of the lesion for surgical removal. PMID- 24780370 TI - Thoracic dual energy CT: acquisition protocols, current applications and future developments. AB - Thanks to a simultaneous acquisition at high and low kilovoltage, dual energy computed tomography (DECT) can achieve material-based decomposition (iodine, water, calcium, etc.) and reconstruct images at different energy levels (40 to 140keV). Post-processing uses this potential to maximise iodine detection, which elicits demonstrated added value for chest imaging in acute and chronic embolic diseases (increases the quality of the examination and identifies perfusion defects), follow-up of aortic endografts and detection of contrast uptake in oncology. In CT angiography, these unique features are taken advantage of to reduce the iodine load by more than half. This review article aims to set out the physical basis for the technology, the acquisition and post-processing protocols used, its proven advantages in chest pathologies, and to present future developments. PMID- 24780371 TI - Effect of posterior pelvic tilt taping in women with sacroiliac joint pain during active straight leg raising who habitually wore high-heeled shoes: a preliminary study. AB - OBJECTIVE: The purpose of this study was to assess whether a 1-day application of posterior pelvic tilt taping (PPTT) using a kinesiology tape would decrease anterior pelvic tilt and active straight leg raising test scores in women with sacroiliac joint who habitually wore high-heeled shoes. METHODS: Sixteen women (mean age, 23.63 +/- 3.18 years) were enrolled in this study. Anterior pelvic tilt was measured using a palpation meter before PPTT application, immediately after PPTT application, 1 day after PPTT application, and immediately after PPTT removal after 1 day of application. Active straight leg raising scores were measured at the same periods. Posterior pelvic tilt taping was applied in the target position (posterior pelvic tilt position). RESULTS: The anterior pelvic tilt was decreased during and after 1 day of PPTT application (before and after kinesiology tape removal) compared with the initial angle (all P < .05). Active straight leg raising scores were decreased during and 1 day after PPTT application (before and after kinesiology tape removal) compared with the initial score (all P < .05). CONCLUSION: The results of this preliminary study suggests that PPTT may temporarily decrease anterior pelvic tilt and active straight leg raising score in women with sacroiliac joint pain who habitually wear high-heeled shoes. PMID- 24780372 TI - Longitudinal changes in ventral and dorsal neck muscle layers during loading against gravity in healthy volunteers using speckle tracking. AB - OBJECTIVE: This study aimed to describe and compare the longitudinal mechanical activity, deformation, and deformation rate of the different layers of dorsal and ventral neck muscles in healthy volunteers during head lifts against gravity. METHODS: The cross-sectional study included 19 healthy volunteers (mean age, 28 years; SD, 7 years). Ultrasound with speckle-tracking analysis was used to investigate longitudinal mechanical activation, deformation, and deformation rate of dorsal and ventral neck muscles in real time during a head lift. Significance levels were set as P = .025 or P = .0125, depending on the number of comparisons. RESULTS: The dorsal neck muscles did not significantly differ in deformation (P > .04); however, the multifidus had a higher deformation rate than all other dorsal muscles (P < .003). The sternocleidomastoid had significantly higher deformation than the longus capitis (P = .005) and colli (P = .001) but a lower deformation rate than the longus colli (P = .02). CONCLUSION: The sternocleidomastoid deformed more than the deeper muscles, but it did significantly slower than the longus colli. Among the dorsal muscles, the deepest (the multifidus) had the highest deformation rate. PMID- 24780373 TI - Regulatory roles of c-jun in H5N1 influenza virus replication and host inflammation. AB - The cytokine storm which is a great burden on humanity in highly pathogenic influenza virus infections requires activation of multiple signaling pathways. These pathways, such as MAPK and JNK, are important for viral replication and host inflammatory response. Here we examined the roles of JNK downstream molecule c-jun in host inflammatory responses and H5N1 virus replication using a c-jun targeted DNAzyme (Dz13). Transfection of Dz13 significantly reduced H5N1 influenza virus replication in human lung epithelial cells. Concomitantly, there was a decreased expression of pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interferon (IFN)-beta and interleukin (IL)-6) in c-jun suppressed cells, while the expression of anti-inflammatory cytokines, such as IL-10, was increased. In vivo, compared with control groups, suppression of c-jun improved the survival rate of mice infected with H5N1 virus (55.5% in Dz13 treated mice versus <=11% of control mice) and decreased the CD8(+) T cell proliferation. Simultaneously, the pulmonary inflammatory response and viral burden also decreased in the Dz13 treated group. Thus, our data demonstrated a critical role for c-jun in the establishment of H5N1 infection and subsequent inflammatory reactions, which suggest that c-jun may be a potential therapeutic target for viral pneumonia. PMID- 24780374 TI - Lysylated phospholipids stabilize models of bacterial lipid bilayers and protect against antimicrobial peptides. AB - Aminoacylated phosphatidylglycerols are common lipids in bacterial cytoplasmic membranes. Their presence in Staphylococcus aureus has been linked to increased resistance to a number of antibacterial agents, including antimicrobial peptides. Most commonly, the phosphatidylglycerol headgroup is esterified to lysine, which converts anionic phosphatidylglycerol into a cationic lipid with a considerably increased headgroup size. In the present work, we investigated the interactions of two well-studied antimicrobial peptides, cecropin A and mastoparan X, with lipid vesicles composed of 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and 1 palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), containing varying fractions of an aminoacylated phosphatidylethanolamine, a stable analog of the corresponding phosphatidylglycerol-derivative. To differentiate between the effects of headgroup size and charge on peptide-lipid interactions, we synthesized two different derivatives. In one, the headgroup was modified by the addition of lysine, and in the other, by glutamine. The modification by glutamine results in a phospholipid with a headgroup size comparable to that of the lysylated version. However, whereas lysyl-phosphatidylethanolamine (Lys-PE) is cationic, glutaminyl phosphatidylethanolamine (Gln-PE) is zwitterionic. We found that binding of mastoparan X and cecropin A was not significantly altered if the content of aminoacylated phosphatidylethanolamines did not exceed 20mol.%, which is the concentration found in bacterial membranes. However, a lysyl phosphatidylethanolamine content of 20mol% significantly inhibits dye release from lipid vesicles, to a degree that depends on the peptide. In the case of mastoparan X, dye release is essentially abolished at 20mol.% lysyl phosphatidylethanolamine, whereas cecropin A is less sensitive to the presence of lysyl-phosphatidylethanolamine. These observations are understood through the complex interplay between peptide binding and membrane stabilization as a function of the aminoacylated lipid content. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID- 24780375 TI - Peptide entry inhibitors of enveloped viruses: the importance of interfacial hydrophobicity. AB - There are many peptides known that inhibit the entry of enveloped viruses into cells, including one peptide that is successfully being used in the clinic as a drug. In this review, we discuss the discovery, antiviral activity and mechanism of action of such peptides. While peptide entry inhibitors have been discovered by a wide variety of approaches (structure-based, accidental, intentional, rational and brute force) we show here that they share a common physical chemical property: they are at least somewhat hydrophobic and/or amphipathic and have a propensity to interact with membrane interfaces. We propose that this propensity drives a shared mechanism of action for many peptide entry inhibitors, involving direct interactions with viral and cellular membranes, as well as interactions with the complex hydrophobic protein/lipid interfaces that are exposed, at least transiently, during virus-cell fusion. By interacting simultaneously with the membrane interfaces and other critical hydrophobic surfaces, we hypothesize that peptide entry inhibitors can act by changing the physical chemistry of the membranes, and the fusion protein interfaces bridging them, and by doing so interfere with the fusion of cellular and viral membranes. Based on this idea, we propose that an approach that focuses on the interfacial hydrophobicity of putative entry inhibitors could lead to the efficient discovery of novel, broad spectrum viral entry inhibitors. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova. PMID- 24780376 TI - Effect of cytochrome c on the phase behavior of charged multicomponent lipid membranes. AB - We studied the effect of submicromolar concentrations of cytochrome c (cyt c) on the phase behavior of ternary lipid membranes composed of charged dioleoylphosphatidylglycerol, egg sphingomyelin and cholesterol. The protein was found to induce micron-sized domains in membranes belonging to the single-fluid phase region of the protein-free ternary mixture and, as a result, to expand the region of coexistence of liquid ordered (Lo) and liquid disordered (Ld) phases. Direct observations on individual vesicles revealed that protein adsorption increases the area of Ld domains. Measurements using a fluorescent analog of cyt c showed that the protein preferentially adsorbs onto domains belonging to the Ld phase. The adsorption was quantitatively characterized in terms of partitioning ratios between the Ld and the Lo phases. The protein was also found to induce vesicle leakage even at relatively low concentrations. In eukaryotic cells under normal physiological conditions, cyt c is localized within the intermembrane space of mitochondria. During cell apoptotis, cyt c is released into the cytosol and its adsorption to intracellular membranes may strongly perturb the lipid distribution within these membranes as suggested by our results. PMID- 24780377 TI - Integrity of the actin cytoskeleton of host macrophages is essential for Leishmania donovani infection. AB - Visceral leishmaniasis is a vector-borne disease caused by an obligate intracellular protozoan parasite Leishmania donovani. The molecular mechanism involved in internalization of Leishmania is poorly understood. The entry of Leishmania involves interaction with the plasma membrane of host cells. We have previously demonstrated the requirement of host membrane cholesterol in the binding and internalization of L. donovani into macrophages. In the present work, we explored the role of the host actin cytoskeleton in leishmanial infection. We observed a dose-dependent reduction in the attachment of Leishmania promastigotes to host macrophages upon destabilization of the actin cytoskeleton by cytochalasin D. This is accompanied by a concomitant reduction in the intracellular amastigote load. We utilized a recently developed high resolution microscopy-based method to quantitate cellular F-actin content upon treatment with cytochalasin D. A striking feature of our results is that binding of Leishmania promastigotes and intracellular amastigote load show close correlation with cellular F-actin level. Importantly, the binding of Escherichia coli remained invariant upon actin destabilization of host cells, thereby implying specific involvement of the actin cytoskeleton in Leishmania infection. To the best of our knowledge, these novel results constitute the first comprehensive demonstration on the specific role of the host actin cytoskeleton in Leishmania infection. Our results could be significant in developing future therapeutic strategies to tackle leishmaniasis. PMID- 24780378 TI - Cholesterol modulates function of connexin 43 gap junction channel via PKC pathway in H9c2 cells. AB - It has been shown that cholesterol modulates activity of protein kinase C (PKC), and PKC phosphorylates connexin 43 (Cx43) to regulate its function, respectively. However, it is not known whether cholesterol modulates function of Cx43 through regulating activity of PKC. In the present study, we demonstrated that cholesterol enrichment reduced the dye transfer ability of Cx43 in cultured H9c2 cells. Western blot analysis indicated that cholesterol enrichment enhanced the phosphorylated state of Cx43. Immunofluorescent images showed that cholesterol enrichment made the Cx43 distribution from condensed to diffused manner in the interface between the cells. In cholesterol enriched cells, PKC antagonists partially restored the dye transfer ability among the cells, downregulated the phosphorylation of Cx43 and redistributed Cx43 from the diffused manner to the condensed manner in the cell interface. In addition, reduction of cholesterol level suppressed PKC activity to phosphorylate Cx43 and restored Cx43 function in PKC agonist-treated cells. Furthermore, we demonstrated that cholesterol enrichment upregulated the phosphorylated state of Cx43 at Ser368, while PKC antagonists reversed the effect. Taken together, cholesterol level in the cells plays important roles in regulating Cx43 function through activation of the PKC signaling pathway. PMID- 24780379 TI - Effects of amphetamine on delay discounting in rats depend upon the manner in which delay is varied. AB - Whether stimulant drugs like amphetamine increase or decrease choice of larger delayed reinforcers over smaller immediately available reinforcers under delay discounting procedures can depend on several factors, including the order in which delay is presented. This study examined whether the order of delay presentation impacts drug effects on discounting in rats (n = 8) trained and tested under an ascending order, a descending order, as well as under a fixed delay condition. Responses on one lever delivered 1 food pellet immediately and responses on the other lever delivered 3 food pellets immediately or after a delay (4-32 s). In Experiment 1, the delay to the larger reinforcer varied within session and the order of delay presentation (ascending or descending) varied across conditions. In Experiment 2, the same delay value was presented in all blocks of the session (i.e., delay was fixed), and delay varied across conditions. Under the ascending order of delay, amphetamine (0.32-1.78 mg/kg) increased choice of the larger reinforcer in some rats and decreased choice in others. In the same rats responding under the descending and fixed delay conditions, amphetamine markedly decreased choice of the larger reinforcer even in the component associated with no delay. In some subjects, the effects of amphetamine differed depending on the manner in which delay was presented, indicating that drug-induced changes in performance were due, in part, to mechanisms other than altered sensitivity to reinforcer delay. These results also suggest that a history of responding under both orders of delay presentation can modulate drug effects. This article is part of the Special Issue entitled 'CNS Stimulants'. PMID- 24780380 TI - Necessary, but not sufficient: insights into the mechanisms of mGluR mediated long-term depression from a rat model of early life seizures. AB - Using the rat model of early life seizures (ELS), which has exaggerated mGluR mediated long-term depression of synaptic strength (mGluR-LTD) in adulthood, we probed the signaling cascades underlying mGluR-LTD induction. Several inhibitors completely blocked mGluR-LTD in control but not in ELS rats: the proteasome, the mammalian target of rapamycin (mTOR), S6 kinase (S6K), or L-type voltage-gated calcium channels (L-type VGCC). Inhibition of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) resulted in a near complete block of mGluR-LTD in control rats and a slight reduction of mGluR-LTD in ELS rats. "Autonomous" CaMKII was found to be upregulated in ELS rats, while elevated S6K activity, which is stimulated by mTOR, was described previously. Thus, modulation of each of these factors was necessary for mGluR-LTD induction in control rats, but even their combined, permanent activation in the ELS rats was not sufficient to individually support mGluR-LTD induction following ELS. This implies that while these factors may act sequentially in controls to mediate mGluR-LTD, this is no longer the case after ELS. In contrast, activated ERK was found to be significantly down regulated in ELS rats. Inhibition of MEK/ERK activation in control rats elevated mGluR-LTD to the exaggerated levels seen in ELS rats. Together, these results elucidate both the mechanisms that persistently enhance mGluR-LTD after ELS and the mechanisms underlying normal mGluR-LTD by providing evidence for multiple, convergent pathways that mediate mGluR-LTD induction. With our prior work, this ties these signaling cascades to the ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization. PMID- 24780381 TI - The protective effect of astaxanthin on fetal alcohol spectrum disorder in mice. AB - Astaxanthin is a strong antioxidant with the ability of reducing the markers of inflammation. To explore the protective effect of astaxanthin on maternal ethanol induced embryonic deficiency, and to investigate the underlying mechanisms, we detected the morphology, expression of neural marker genes, oxidative stress indexes, and inflammatory factors in mice model of fetal alcohol spectrum disorder with or without astaxanthin pretreatment. Our results showed that astaxanthin blocked maternal ethanol induced retardation of embryonic growth, and the down-regulation of neural marker genes, Otx1 and Sox2. Moreover, astaxanthin also reversed the increases of malondialdehyde (MDA), hydrogen peroxide (H2O2), and the decrease of glutathione peroxidase (GPx) in fetal alcohol spectrum disorder. In addition, maternal ethanol induced up-regulation of toll-like receptor 4 (TLR4), and the down-streaming myeloid differentiation factor 88 (MyD88), NF-kappaB, TNF-alpha, and IL-1beta in embryos, and this was inhibited by astaxanthin pretreatment. These results demonstrated a protective effect of astaxanthin on fetal alcohol spectrum disorder, and suggested that oxidative stress and TLR4 signaling associated inflammatory reaction are involved in this process. PMID- 24780382 TI - Electric motorized morcellator versus transvaginal extraction for myoma retrieval after laparoscopic myomectomy: a propensity-matched analysis. AB - STUDY OBJECTIVE: To compare surgery-related outcomes of electric motorized morcellator (EMM) and transvaginal extraction (TVE) for myoma retrieval after laparoscopic myomectomy. DESIGN: A retrospective propensity-matched analysis of prospectively collected data (Canadian Task Force classification II-2). SETTING: A university teaching hospital. PATIENTS: One hundred women undergoing laparoscopic myomectomy. INTERVENTIONS: Laparoscopic myomectomy followed by myoma retrieval via TVE or EMM. MEASUREMENTS AND MAIN RESULTS: Fifty propensity-matched patient pairs (100 patients) undergoing laparoscopic myomectomy followed by myoma retrieval via TVE or EMM were studied. No significant differences were observed in baseline patient characteristics. Operative times were similar between groups (66 vs 73 minutes in the TVE and EMM group, respectively, p = .19). However, patients undergoing TVE experienced lower specimen retrieval time than patients undergoing extraction via EMM (5 [3-30] vs 7 [3-35] minutes, p < .001). Blood loss, transfusion, and complication rates were similar between groups. One retrieval-related complication occurred in the EMM group (bleeding from an incision using a morcellator requiring resuture). The need for an analgesic rescue dose was lower in the TVE group compared with patients in the EMM group (p = .03). Although overall satisfaction levels were similar between groups, TVE is related to higher cosmetic outcomes compared with EMM (9.5 [+/-0.6] vs 8.5 [+/ 1], p < .001). CONCLUSION: TVE upholds the effectiveness of EMM, minimizing the operative time and potentially postoperative pain. Further large prospective studies are needed. PMID- 24780383 TI - Vaginal versus robotic hysterectomy and concomitant pelvic support surgery: a comparison of postoperative vaginal length and sexual function. AB - STUDY OBJECTIVE: To compare the change from pre- to postoperative total vaginal length (TVL) in women who underwent either a total vaginal hysterectomy (TVH) with uterosacral ligament suspension (USLS) or a robotic hysterectomy (RH) with colpopexy (SCP). Secondary objectives included comparing sexual function, pelvic floor function, and prolapse recurrence between routes of surgery. DESIGN: This was a retrospective cohort study (Canadian Task Force classification II-2). SETTING: This was conducted at 1 tertiary academic medical center over a 2-year period. PATIENTS: Women who underwent either TVH/USLS or RH/SCP. INTERVENTIONS: Baseline and postoperative POP-Q Pelvic Organ Prolapse Quantification exams were recorded as well as postoperative validated questionnaires. Twenty-nine subjects were needed in each group to detect a 1.5-cm difference in TVL. MEASUREMENTS AND MAIN RESULTS: There were 38 TVH/USLS and 46 RH/SCP participants. RHs were either total (28/46 [61%]) or supracervical (18/46 [39%]). The mean postoperative follow up was 9.5 +/- 3.1 months. For the primary outcome, women in the TVH/USLS group had a decrease in TVL, whereas women in the RH/SCP group had an increase in TVL ( 0.6 +/- 1.0 cm vs 0.5 +/- 0.8 cm, p < .001). Among sexually active women (55/84, 65.5%), there was no difference in postoperative sexual function between groups based on Pelvic Organ Prolapse/Urinary incontinence Sexual Function Questionnaire short form scores, with good sexual function in both groups (32.6 +/- 6.2 TVH/USLS vs 35.1 +/- 7.3 RH/SCP, p = .22). Although both groups showed good postoperative apical support, the TVH/USLS group had a slightly lower mean C point compared with the RH/SCP group (-6.8 +/- 1.2 vs -7.7 +/- 1.8, p = .02). Both groups showed good postoperative pelvic floor function, with no difference in mean postoperative Pelvic Organ Prolapse Distress Inventory scores (42.2 +/- 45.4 vs 52.7 +/- 46.6, p = .44). Recurrent prolapse (defined as any prolapse at or beyond the hymen) was not different between groups (13.2% for TVH/USLS vs 6.5% for RH/SCP, p = .46). CONCLUSION: Vaginal length decreased after vaginal hysterectomy with pelvic support surgery compared with RH with pelvic support surgery, with no differences in postoperative sexual function or pelvic floor function between groups. PMID- 24780384 TI - Dienogest was effective in treating hemorrhagic ascites caused by endometriosis: a case report. AB - Hemorrhagic ascites caused by endometriosis is extremely rare, and its treatment is under discussion. We report a case of recurrent endometriosis-related ascites treated with dienogest (DNG). A 35-year-old nulliparous Japanese woman with a history of infertility presented with worsening dysmenorrhea and abdominal distention caused by massive ascites. The patient underwent exploratory laparotomy, and hemorrhagic ascites (5500 mL) was drained. She had a normal-sized uterus, and the bilateral ovaries could not be observed because of extensive adhesion in the abdominal cavity. Endometriosis was diagnosed by histopathological evaluation of the omental biopsy, and this was considered to be the cause of ascites. After laparotomy, she had recurrence of ascites. For the next 8 years, the patient was treated conservatively with gonadotropin-releasing hormone agonist therapy and drainage during the intermittent periods followed by DNG administration. She has been treated continuously with DNG for 1 year with no recurrence of ascites. DNG could be an effective treatment for recurrent ascites associated with endometriosis, especially when surgical therapy is undesirable. PMID- 24780385 TI - Right temporal activation differs between melancholia and nonmelancholic depression: a multichannel near-infrared spectroscopy study. AB - The aim of this study was to determine whether melancholia differs from nonmelancholic depression in frontotemporal functioning by means of multichannel near-infrared spectroscopy. We recruited 32 major depressive disorder (MDD) patients with melancholic features (MDD-MF), 28 MDD patients with nonmelancholic features (MDD-NMF), and 24 healthy controls. Regional hemodynamic changes induced by a verbal fluency task (VFT) were monitored, and their correlations with depressive symptoms were examined. In comparison with the controls, significant differences were observed in mean oxygenated hemoglobin (oxy-Hb) changes induced by VFT in patients with MDD-MF in 25 channels (p = 0.000-0.047) and in those with MDD-NMF in 12 channels (p = 0.000-0.023). Moreover, patients with MDD-MF had significantly smaller mean oxy-Hb changes than those with MDD-NMF in 8 channels of the right temporal region (p = 0.001-0.048). No significant correlations were observed between mean oxy-Hb changes and the Hamilton rating scale for depression (HAMD) 17 total score in both groups of patients with MDD. On examining each item of HAMD17, psychomotor retardation in patients with MDD-MF showed a significant positive correlation with mean oxy-Hb changes in the right temporal region (ch43; rho = 0.55; p = 0.001), whereas that in patients with MDD-NMF showed a significant negative correlation with mean oxy-Hb changes in the frontal and left temporal regions in 3 channels (rho = -0.60 to -0.53; p = 0.000-0.004). In conclusion, our results indicate that melancholia is qualitatively distinct from nonmelancholic depression both clinically and biologically. PMID- 24780386 TI - UVR8 mediated plant protective responses under low UV-B radiation leading to photosynthetic acclimation. AB - The UV-B photoreceptor UVR8 regulates the expression of several genes leading to acclimation responses in plants. Direct role of UVR8 in maintaining the photosynthesis is not defined but it is known to increase the expression of some chloroplastic proteins like SIG5 and ELIP. It provides indirect protection to photosynthesis by regulating the synthesis of secondary metabolites and photomorphogenesis. Signaling cascades controlled by UVR8 mediate many protective responses thus promotes plant acclimation against stress and secures its survival. PMID- 24780387 TI - The spatial diffusion of norovirus epidemics over three seasons in Tokyo. AB - We studied the spatial trend of norovirus (NoV) epidemics using sentinel gastroenteritis surveillance data for patients aged <15 years (n = 140) in the Tokyo area for the 2006-2007 to 2008-2009 seasons utilizing the kriging method of geographical information system (GIS). This is the first study of the spreading pattern of NoV epidemics using sentinel surveillance data. Correlations of sentinel cases between the seasons and with demographic data were examined to identify the trend and related factors. A similar pattern of diffusion was observed over the seasons, and its mean correlation between seasons was significantly high. A higher number of cases were found in the peripheral area, which surrounds the most populated central area, and showed a correlation with the ratio of the children population (r = 0.321, P < 0.01) and the ratio of residents in larger families (r = 0.263, P < 0.01). While NoV susceptibility remained, the results suggest a transmission route in the local community as a possible epidemic factor. Prevention with focus on the peripheral area is desirable. PMID- 24780388 TI - Medical professionalism and abuse of detainees in the war on terror. PMID- 24780389 TI - Identification of the ghrelin-GHSR 1 system and its influence in the modulation of induced ocular hypertension in rabbit and rat eyes. AB - Recent studies evidenced a decrease in ghrelin's aqueous humor levels in patients with glaucoma. The goal of our investigation was to study the effect of the ghrelin-GHSR-1a system in the modulation of intraocular pressure in acute ocular hypertension models and its expression and distribution in ocular tissues. Two animal models of acute ocular hypertension were used to study the effect of the ghrelin-GHSR-1a system in the modulation of intraocular pressure: the rabbit and the rat. Ocular hypertension was induced by an intravitreal injection of 20% NaCl. Ghrelin or des-acyl ghrelin were delivered subconjunctivally and the intraocular pressure was assessed by a rebound tonometer that was calibrated for each species. In addition, we have studied the influence of nitric oxide and prostaglandins on ghrelin's effect in the rabbit animal model. Finally, we determined by immunofluorescence the expression of ghrelin and GHSR-1 in the rat's ocular tissue. Ghrelin decreased the intraocular pressure in both animal models (maximum decrease: 43.8+/-12.0% in the rabbit and 29.0+/-7.46% in the rat). In the rabbit, this effect was blunted in the presence of l-NAME and ketorolac. Des-acyl ghrelin only decreased the intraocular pressure in the rat (maximum decrease: 34.9+/-8.15%). Ghrelin expression was detected in the ciliary processes and GHSR-1 expression was detected in the trabecular meshwork and ciliary body. The ghrelin-GHSR-1 system is expressed in the anterior segment of the eye. Ghrelin and des-acyl ghrelin are responsible for a hypotensive effect in acute ocular hypertension animal models. PMID- 24780390 TI - Vitamin D has a greater impact on cancer mortality rates than on cancer incidence rates. PMID- 24780391 TI - Extracorporeal photopheresis for paediatric patients experiencing graft-versus host disease (GVHD). AB - Extracorporeal photopheresis (ECP) is broadly used in adults with cutaneous T cell lymphoma, acute or chronic graft-versus-host disease (GVHD), rejection of solid organ transplants, and a variety of autoimmune, cell-mediated diseases. The predominant use of ECP in children and adolescents is for treating GVHD. Children pose specific challenges to ECP, due to their unique physiology and to patient's size. Herein, we will focus on current clinical trials with ECP in children with GVHD, with an emphasis on technical and clinical issues that are peculiar to the paediatric setting. PMID- 24780392 TI - Extracorporeal photopheresis in acute and chronic graft-versus-host disease. AB - Graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation causing significant morbidity and mortality. Corticosteroids are the established first-line treatment of GvHD. Patients not responding to corticosteroids have a dismal prognosis. Extracorporeal photopheresis (ECP) has objective activity in the treatment of both acute and chronic corticosteroid-refractory GvHD patients, has an excellent safety profile and is internationally well-established. ECP has been recommended by a significant number of renowned scientific organizations as an efficient treatment option for patients with GvHD. ECP has a proven corticosteroid-sparing effect and favourably impacts on survival and quality of life of responding patients. PMID- 24780393 TI - Improving the electrical properties of lanthanum silicate films on ge metal oxide semiconductor capacitors by adopting interfacial barrier and capping layers. AB - The electrical properties of La-silicate films grown by atomic layer deposition (ALD) on Ge substrates with different film configurations, such as various Si concentrations, Al2O3 interfacial passivation layers, and SiO2 capping layers, were examined. La-silicate thin films were deposited using alternating injections of the La[N{Si(CH3)3}2]3 precursor with O3 as the La and O precursors, respectively, at a substrate temperature of 310 degrees C. The Si concentration in the La-silicate films was further controlled by adding ALD cycles of SiO2. For comparison, La2O3 films were also grown using [La((i)PrCp)3] and O3 as the La precursor and oxygen source, respectively, at the identical substrate temperature. The capacitance-voltage (C-V) hysteresis decreased with an increasing Si concentration in the La-silicate films, although the films showed a slight increase in the capacitance equivalent oxide thickness. The adoption of Al2O3 at the interface as a passivation layer resulted in lower C-V hysteresis and a low leakage current density. The C-V hysteresis voltages of the La-silicate films with Al2O3 passivation and SiO2 capping layers was significantly decreased to ~0.1 V, whereas the single layer La-silicate film showed a hysteresis voltage as large as ~1.0 V. PMID- 24780394 TI - Is it time to train neurologists in the management of mood and anxiety disorders? PMID- 24780395 TI - Priming of Toll-like receptor 4 pathway in mesenchymal stem cells increases expression of B cell activating factor. AB - Mesenchymal stem cells (MSCs) can be polarized into two distinct populations, MSC1 and MSC2, by activation of different Toll-like receptors (TLRs). TLR4-primed MSC1 expressed proinflammatory factors, whereas TLR3-primed MSC2 expressed suppressive factors. However, little is known about the function of TLRs on B lymphocyte-related immune modulation. In this study, we investigated the expression of B cell activating factor (BAFF), a member of the tumor necrosis factor ligand superfamily with notable stimulating activity on B cells, in human MSCs (hMSCs) and in murine MSCs (mMSCs) after activation of TLRs. BAFF was increasingly expressed in presence of TLR4 agonist (lipopolysaccharide, LPS), while TLR2 agonist (Zymosan) and TLR3-agonist (polyinocinic-polycytidykic acid, poly I:C) had no effect on BAFF expression. In addition, we demonstrated that signaling pathways of NF-kappaB, p38 MAPK, and JNK were involved in TLR4-primed BAFF expression. Our results suggested that TLR4 and downstream pathways in MSCs exert an important function in B lymphocyte-related immune regulation. Further defining a homogeneous population of MSCs should provide insight into MSC-based immune-modulating therapy. PMID- 24780396 TI - Rice BiP3 regulates immunity mediated by the PRRs XA3 and XA21 but not immunity mediated by the NB-LRR protein, Pi5. AB - Plant innate immunity is mediated by pattern recognition receptors (PRRs) and intracellular NB-LRR (nucleotide-binding domain and leucine-rich repeat) proteins. Overexpression of the endoplasmic reticulum (ER) chaperone, luminal binding protein 3 (BiP3) compromises resistance to Xanthomonas oryzae pv. oryzae (Xoo) mediated by the rice PRR XA21 [12]. Here we show that BiP3 overexpression also compromises resistance mediated by rice XA3, a PRR that provides broad spectrum resistance to Xoo. In contrast, BiP3 overexpression has no effect on resistance mediated by rice Pi5, an NB-LRR protein that confers resistance to the fungal pathogen Magnaporthe oryzae (M. oryzae). Our results suggest that rice BiP3 regulates membrane-resident PRR-mediated immunity. PMID- 24780397 TI - Functional analysis of iPSC-derived myocytes from a patient with carnitine palmitoyltransferase II deficiency. AB - INTRODUCTION: Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited disorder involving beta-oxidation of long-chain fatty acids (FAO), which leads to rhabdomyolysis and subsequent acute renal failure. The detailed mechanisms of disease pathogenesis remain unknown; however, the availability of relevant human cell types for investigation, such as skeletal muscle cells, is limited, and the development of novel disease models is required. METHODS: We generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of a Japanese patient with CPT II deficiency. Mature myocytes were differentiated from the patient-derived hiPSCs by introducing myogenic differentiation 1 (MYOD1), the master transcriptional regulator of myocyte differentiation. Using an in vitro acylcarnitine profiling assay, we investigated the effects of a hypolipidemic drug, bezafibrate, and heat stress on mitochondrial FAO in CPT II deficient myocytes and controls. RESULTS: CPT II-deficient myocytes accumulated more palmitoylcarnitine (C16) than did control myocytes. Heat stress, induced by incubation at 38 degrees C, leads to a robust increase of C16 in CPT II-deficient myocytes, but not in controls. Bezafibrate reduced the amount of C16 in control and CPT II-deficient myocytes. DISCUSSION: In this study, we induced differentiation of CPT II-deficient hiPSCs into mature myocytes in a highly efficient and reproducible manner and recapitulated some aspects of the disease phenotypes of CPT II deficiency in the myocyte disease models. This approach addresses the challenges of modeling the abnormality of FAO in CPT II deficiency using iPSC technology and has the potential to revolutionize translational research in this field. PMID- 24780398 TI - Enhanced prostacyclin formation and Wnt signaling in sclerostin deficient osteocytes and bone. AB - We show that prostacyclin production is increased in bone and osteocytes from sclerostin (Sost) knockout mice which have greatly increased bone mass. The addition of prostacyclin or a prostacyclin analog to bone forming osteoblasts enhances differentiation and matrix mineralization of osteoblasts. The increase in prostacyclin synthesis is linked to increases in beta-catenin concentrations and activity as shown by enhanced binding of lymphoid enhancer factor, Lef1, to promoter elements within the prostacyclin synthase promoter. Blockade of Wnt signaling reduces prostacyclin production in osteocytes. Increased prostacyclin production by osteocytes from sclerostin deficient mice could potentially contribute to the increased bone formation seen in this condition. PMID- 24780399 TI - Down regulation of brain cellular prion protein in an animal model of insulin resistance: possible implication in increased prevalence of stroke in pre diabetics/diabetics. AB - The risk of stroke is drastically increased in diabetic and pre-diabetic patients. The worldwide spread of obesity and insulin resistance increases the incidence of stroke. The direct effect of insulin resistance, as it pertains to stroke, on the central nervous system is not well understood. Since one of the physiological functions of the cellular prion protein (PrP(C)) is neuroprotection, we studied effects of brain insulin resistance on the expression of PrP(C) in fructose-fed rats as an animal model of prediabetes. Compared with control chow-fed animals, rats fed a high-fructose diet (FF), exhibited compromised tyrosine phosphorylation of insulin receptor beta subunit (IRbeta) and reduced serine phosphorylation of Akt, PI3K activity, and decreased PIP3 levels in cortices indicating the induction of brain insulin resistance. We also observed that both mRNA and protein expression of the PrP(C) was significantly decreased whereas protein level of NR2B subunit of NMDA glutamate receptors profoundly increased in the brain of fructose-fed rats compared to control chow fed rats. Considering a neuroprotective role for PrP(C) and the involvement of NR2B subunit in the excitotoxicity-induced neuronal apoptosis, these phenomena may contribute to the severity and poor prognosis of ischemic stroke in diabetes/prediabetes. PMID- 24780400 TI - New role of lupeol in reticence of angiogenesis, the cellular parameter of neoplastic progression in tumorigenesis models through altered gene expression. AB - There is a major unmet medical need for effective and well tolerated treatment options for cancer. The search now seeks to identify active biomolecules with multiple targets. Lupeol, an important dietary triterpenoid known as anticarcinogen by inducing apoptosis. But it is still more to reveal the potency of lupeol in the inhibition of neovascularization in cancer context. The study aimed to explore the efficacy of the lupeol in targeting angiogenesis. In this study, the inhibition of neovessel formation was assessed by preliminary antiangiogenesis assays like chorio allontoic membrane (CAM) and rat corneal micro pocket models. Further, validated for the micro vessel density (MVD) in histological sections of peritoneum, solid tumor and xenograft tumor by immunostaining with anti CD31 antibody. Antitumor potency was verified in ascites carcinoma, solid lymphoma and human nueroblastoma xenograft in CAM. Altered angiogenic gene expression by RT-PCR, ELISA and gelatin zymography. Lupeol significantly inhibits the neovessel formation in CAM and in the rat cornea. The similar effect was ascertained in mice and human xenograft tumor models with the regressed growth. Eventually reflecting on the differential transcription of angiogenic genes like MMP-2 & 9, HIF-1alpha, VEGFa and Flt-1 was noteworthy. It is now evident from our studies that, a new avenue of dietary triterpenoid lupeol by targeting angiogenesis, potentially inferring the multimode action in cancer prevention. PMID- 24780401 TI - Dye and its removal from aqueous solution by adsorption: a review. AB - In this review article the authors presented up to-date development on the application of adsorption in the removal of dyes from aqueous solution. This review article provides extensive literature information about dyes, its classification and toxicity, various treatment methods, and dye adsorption characteristics by various adsorbents. One of the objectives of this review article is to organise the scattered available information on various aspects on a wide range of potentially effective adsorbents in the removal of dyes. Therefore, an extensive list of various adsorbents such as natural materials, waste materials from industry, agricultural by-products, and biomass based activated carbon in the removal of various dyes has been compiled here. Dye bearing waste treatment by adsorption using low cost alternative adsorbent is a demanding area as it has double benefits i.e. water treatment and waste management. Further, activated carbon from biomass has the advantage of offering an effected low cost replacement for non-renewable coal based granular activated carbon provided that they have similar or better adsorption on efficiency. The effectiveness of various adsorbents under different physico-chemical process parameters and their comparative adsorption capacity towards dye adsorption has also been presented. This review paper also includes the affective adsorption factors of dye such as solution pH, initial dye concentration, adsorbent dosage, and temperature. The applicability of various adsorption kinetic models and isotherm models for dye removal by wide range of adsorbents is also reported here. Conclusions have been drawn from the literature reviewed and few suggestions for future research are proposed. PMID- 24780402 TI - Nanofluidics of thin polymer films: linking the slip boundary condition at solid liquid interfaces to macroscopic pattern formation and microscopic interfacial properties. AB - If a thin liquid film is not stable, different rupture mechanisms can be observed causing characteristic film morphologies: spinodal dewetting and dewetting by nucleation of holes. This rupturing entails liquid flow and opens new possibilities to study microscopic phenomena. Here we use this process of dewetting to gain insight on the slip boundary condition at the solid-liquid interface. Having established hydrodynamic models that allow for the determination of the slip length in a dewetting experiment based on nucleation, we move on to the quantification and molecular description of slip effects in various systems. For the late stage of the dewetting process involving the Rayleigh-Plateau instability, several distinct droplet patterns can be observed. We describe the importance of slip in determining what pattern may be found. In order to control the slip length, we use polymeric liquids on different hydrophobic coatings of silicon wafers. We find that subtle changes in the coating can lead to large changes in the slip length. Thus, we gain insight into the question of how the structure of the substrate affects the slip length. PMID- 24780403 TI - SAR studies of o-hydroxychalcones and their cyclized analogs and study them as novel inhibitors of cathepsin B and cathepsin H. AB - Cathepsins have emerged as a potential target for anti-cancer drug development. In the present study, we have synthesized three structurally related series of flavanoids i.e., 2'-hydroxychalcones, flavanones and flavones and assayed in vitro to study their inhibitory potency against cathepsin B and H, promising drug candidate for cancer therapy. Enzyme kinetics studies were carried out in presence of these compounds after preliminary proteolytic studies on endogenous protein substrates. SAR studies suggested that open chain flavanoids were better inhibitors as compared to their cyclized analogs. The most potent inhibitors among the three series were nitro substituted compounds 1g, 2g and 3g with Ki values of ~6.18*10(-8) M, 4.8*10(-7) M and 7.85*10(-7) M for cathepsin B and Ki values of ~2.8*10(-7) M, 31.8*10(-6) M and 33.7*10(-6) M for cathepsin H, respectively. The relationship between chalcone, flavanones and flavone structures interpreted by docking studies on cathepsin B and H also provided useful insights. PMID- 24780404 TI - Access to treatment and educational inequalities in cancer survival. AB - The public health care systems in the Nordic countries provide high quality care almost free of charge to all citizens. However, social inequalities in health persist. Previous research has, for example, documented substantial educational inequalities in cancer survival. We investigate to what extent this may be driven by differential access to and utilization of high quality treatment options. Quasi-experimental evidence based on the establishment of regional cancer wards indicates that (i) highly educated individuals utilized centralized specialized treatment to a greater extent than less educated patients and (ii) the use of such treatment improved these patients' survival. PMID- 24780405 TI - Clinically meaningful nocebo effect occurs in acupuncture treatment: a systematic review. AB - OBJECTIVE: To investigate the nocebo effect using randomized acupuncture trials that include sham and no-treatment groups. STUDY DESIGN AND SETTING: Electronic databases were searched to retrieve eligible trials from their inception until June 2013. Risk differences were then calculated using the acupuncture and sham groups to determine the treatment effect and the sham and no-treatment groups to determine the nocebo effect. RESULTS: In total, 58 eligible trials were analyzed. On the basis of the rate of patients with any adverse event in 31 trials reporting available data, the treatment effect was 0.012 (95% confidence interval [CI]: 0.003, 0.021), with a number needed to harm (NNH) of 83 (95% CI: 48, 333). The nocebo effect was 0.049 (95% CI: 0.012, 0.086), with an NNH of 20 (95% CI: 12, 83). By contrast, the rate of dropouts due to adverse events in 39 trials reporting available data showed no differences for both effects. In addition, nearly 70% of the trials reported zero dropouts in the sham and no-treatment groups. CONCLUSION: Our findings suggest that (1) the nocebo effect of acupuncture is clinically meaningful and (2) the rate of patients with any adverse event may be a more appropriate indicator of the nocebo effect. PMID- 24780406 TI - Re: Yamane et al.: Sutureless 27-gauge needle-guided intrascleral intraocular lens implantation with lamellar scleral dissection (Ophthalmology 2014;121:61-6). PMID- 24780407 TI - High-dose subconjunctival cyclosporine a implants do not affect corneal neovascularization after high-risk keratoplasty. AB - PURPOSE: To test whether subconjunctival cyclosporine A (CsA) implants affect the incidence and the degree of corneal neovascularization occurring after penetrating keratoplasty. DESIGN: Prospective, randomized, multicenter, controlled phase 2/3 clinical trial. The study comprised 43 trial sites in Germany, India, and the United States. PARTICIPANTS: Enrolled patients (n = 97) were randomized to 1 of 3 groups: treatment group A (n = 36), treatment group B (n = 40), and the control group (n = 21). METHODS: Patients from each group received either of 2 doses of subconjunctival CsA (group A, low-dose CsA; group B, high-dose CsA) or placebo (carrier only) implants at the time of high-risk penetrating keratoplasty. MAIN OUTCOME MEASURES: The incidence and degree of corneal neovascularization occurring after penetrating keratoplasty were evaluated in a substudy (LX201-01 study: NCT00447187). A web-based image upload system was developed. Standardized digital slit-lamp pictures were quantitatively and objectively evaluated using Cell^F morphometry software. RESULTS: No statistically significant difference in incidence and degree of corneal neovascularization developing after penetrating keratoplasty was found between treatment groups and placebo group. Mean corneal neovascularization area at week 52 (visit 12) was 2.32+/-1.79% in treatment group A versus placebo (2.79+/-2.11%; P = 0.45) and 2.74+/-2.22% in treatment group B versus placebo (2.79+/-2.11%; P = 0.94). CONCLUSIONS: High-dose subconjunctival CsA implants do not significantly affect corneal neovascularization after high-risk penetrating keratoplasty. This suggests that local CsA has negligible antiangiogenic effects in the human cornea, at least in the transplant setting. PMID- 24780408 TI - Author reply: To PMID 24148655. PMID- 24780409 TI - Urine 6-sulfatoxymelatonin levels are inversely associated with arterial stiffness in post-menopausal women. AB - OBJECT: The secretion of melatonin, a pleiotropic hormone mainly synthesized by the pineal gland, typically decreases with age and may be associated with the development of aging-related pathologic conditions such as cardiovascular disease. Atherosclerosis is an aging-related disease, the pathogenesis of which involves chronic inflammation and increased oxidative stress. Since melatonin has both anti-oxidant and anti-inflammatory properties, it may be associated with atherosclerosis. Therefore, we investigated the relationship between urine concentrations of 6-sulfatoxymelatonin (aMT6s) and arterial stiffness in post menopausal women. METHODS: A total of 66 post-menopausal women participated in the study. Melatonin secretion was estimated by measuring aMT6s levels in first morning urine samples. The cardio-ankle vascular index (CAVI) was used as an indicator of arterial stiffness. RESULTS: Estimated mean CAVI decreased gradually with increasing aMT6s quartiles. The multivariate logistic regression analysis showed that the fourth aMT6s quartile was associated with a high CAVI with an adjusted odds ratio of 0.03 (95% confidence interval, 0.01-0.47). CONCLUSION: Our study revealed an inverse relationship between urine aMT6s and arterial stiffness as determined by CAVI. Although it is impossible to determine causality, our results suggest that melatonin may have a beneficial role in the pathogenesis of atherosclerosis. Further prospective studies are required to establish the clinical significance of our study. PMID- 24780410 TI - Strontium ranelate lives to fight another day. PMID- 24780411 TI - Glucose feeding during development aggravates the toxicity of the organophosphorus insecticide Monocrotophos in the nematode, Caenorhabditis elegans. AB - Several studies have demonstrated that high glucose feeding induced oxidative stress and apoptosis thereby affecting growth, fertility, aging and lifespan in Caenorhabditis elegans. Earlier studies from our laboratory had clearly established the propensity of monocrotophos, an OPI to alter the physiological and behavioral responses of C. elegans. The present study was aimed to investigate the effect of monocrotophos (MCP) on physiological/behavioral and biochemical responses in C. elegans that were maintained on high glucose diet. We exposed the worms through development to high glucose diet (2%) and then treated with sublethal concentrations of MCP (0.5, 0.75, 1.5mM). We measured the behavioral responses in terms of locomotion, physiological responses in terms of egg laying, brood size, lifespan; morphological alterations; and biochemical responses including glucose content. The worms exposed from egg stage through development to high glucose diet showed enhanced toxic outcome of MCP in terms of physiological, behavioral and biochemical responses. Our studies showed that C. elegans is a good model to study glucose-OPI interactive neurotoxicity since all the responses could be studied at ease in this organism and the outcome could be well extrapolated to those that one would expect in higher animals. PMID- 24780412 TI - Telmisartan reduces progressive oxidative stress and phosphorylated alpha synuclein accumulation in stroke-resistant spontaneously hypertensive rats after transient middle cerebral artery occlusion. AB - Telmisartan is an angiotensin receptor blocker with high lipid solubility, also called metabosartan, which exerts a special protective effect on both acute brain damage and chronic neurodegeneration. We examined the effects of telmisartan on oxidative stress by advanced glycation end product (AGE) and 4-hydroxynonenal (4 HNE) assays and the accumulation of phosphorylated alpha-synuclein (pSyn) in the brain of stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 12 weeks, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups: the vehicle group, the low-dose telmisartan group (.3 mg/kg/day), and the high-dose telmisartan group (3 mg/kg/day, postoperatively). Immunohistologic analysis was performed when rats were 6, 12, and 18 months old. AGE, 4-HNE, and pSyn-positive cells (per square millimeter) increased with age in the cerebral cortex and hippocampus of the vehicle group, in the low-dose telmisartan group, these parameters decreased without lowering blood pressure (BP), and in the high-dose telmisartan group, these parameters increased with lowering BP. The present study suggests that a persistent hypertension after tMCAO caused a progressive oxidative stress with the abnormal accumulation of pSyn, and that telmisartan reduced oxidative stress and the accumulation of pSyn without lowering BP (low dose) or improved these conditions with a reduction in BP (high dose) via its pleiotropic effects through a potential peroxisome proliferator-activated receptor gamma stimulation in the brain of SHR-SR. PMID- 24780413 TI - In mouse oocytes the mitochondrion-originated germinal body-like structures accumulate mouse Vasa homologue (MVH) protein. AB - Mouse Vasa homologue (MVH) antibodies were applied to mouse Graafian oocytes to clarify if mitochondrion-originated germinal body-like structures, described previously by conventional electron microscopy, were associated with the germ plasm. It was found that both the mitochondrion-like structures with cristae and the germinal body-like structures that lacked any signs of cristae were labelled specifically by the anti-MVH antibody. Moreover, some granules were MVH-positive ultrastructural hybrids of the mitochondria and germinal body-like structures, the presence of which clearly supported the idea of a mitochondrial origin for the germinal body-like structures. This finding is the first evidence that mitochondrion-originated germinal body-like granules represent mouse germ plasm. PMID- 24780414 TI - Superparamagnetic iron oxide magnetic nanomaterial-labeled bone marrow mesenchymal stem cells for rat liver repair after hepatectomy. AB - BACKGROUND: Superparamagnetic iron oxide magnetic nanomaterials (SPIO) are tracers used for treatment of central nervous and cardiovascular system complications in animal models. The present study investigated survival and proliferation of SPIO-labeled bone marrow mesenchymal stem cells (BMSCs) to determine their potential therapeutic value in liver repair. METHODS: Surface antigens of BMSCs were measured using flow cytometry. BMSCs viability, growth curve, and SPIO (0-100 MUg/mL) labeling rate were evaluated using trypan blue staining, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and Prussian blue staining, respectively. SPIO-labeled BMSCs were transplanted via liver or spleen injection in rats undergoing 70% hepatectomy. Distribution of SPIO-labeled BMSCs in liver and spleen, and liver repair were evaluated by magnetic resonance imaging (MRI), and serum alanine aminotransferase, aspartate aminotransferase, albumin, and total bilirubin levels. RESULTS: CD29(+)/CD90(+)/CD45(-) BMSCs were successfully isolated from rats. Labeling rate of SPIO in 25 MUg/mL was 94.9%. SPIO labeling did not affect BMSCs survival and proliferation. MRI showed that BMSCs colonized in the liver, whether via spleen or liver injection. Serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin in the transplanted rats were significantly lower than in the hepatectomy group at days 1, 3, and 7 after hepatectomy (all P < 0.05), whereas serum albumin levels were significantly higher in the transplanted rats on posthepatectomy day 3 (both P < 0.05). These indicators were not significantly different between the spleen and liver injection approaches. CONCLUSIONS: BMSCs transplantation via liver or spleen injection could significantly accelerate liver healing. In vivo MRI of SPIO-labeled BMSCs can be used to trace real-time liver healing during clinical treatment after hepatectomy. PMID- 24780415 TI - Imaging techniques for the pre-surgical diagnosis of adnexal tumours. AB - A correct diagnosis of any adnexal mass is essential to triage women to appropriate treatment pathways. Several imaging techniques are available that may be used to provide an assessment of a mass before treatment, such as transvaginal ultrasonography, magnetic resonance imaging, computed tomography, and positron emission tomography combined with computed tomography. In this chapter, we focus in depth on the role of transvaginal ultrasonography, as current evidence suggests it is the most appropriate initial imaging investigation to identify and characterise any mass if present in women suspected of having adnexal pathology. Subjective assessment by an experienced ultrasound examiner is the optimal approach to diagnose masses, followed by risk models and rules developed by the International Ovarian Tumor Analysis study. A group of tumours has proven difficult to classify with transvaginal ultrasound, and remain a diagnostic challenge for which accurate second-stage tests would be of value. Some studies suggest that magnetic resonance imaging (MRI), compared with other imaging modalities, may play a role in the assessment of this cohort of 'difficult to classify' adnexal masses. These studies, however, did not report quality of transvaginal ultrasonography (i.e. experience level of the examiner) and lacked uniformity in describing the criteria used to define such 'difficult' masses. On the basis of standardised terminology developed by the International Ovarian Tumor Analysis study to describe adnexal masses, as well as prediction models and rules developed in the course of the study, we propose new criteria that we can use to clearly define complex or 'difficult to classify' adnexal masses to focus the role for second-line imaging tests, such as conventional magnetic resonance imaging combined with dynamic contrast-enhanced or diffusion-weighted sequences on masses where further tests other than ultrasonography would be of value. PMID- 24780416 TI - Robotic thoracic surgery: technical considerations and learning curve for pulmonary resection. AB - Retrospective series indicate that robot-assisted approaches to lung cancer resection offer comparable radicality and safety to video-assisted thoracic surgery or open surgery. More intuitive movements, greater flexibility, and high definition three-dimensional vision overcome limitations of video-assisted thoracic surgery and may encourage wider adoption of robotic surgery for lung cancer, particularly as more early stage cases are diagnosed by screening. High capital and running costs, limited instrument availability, and long operating times are important disadvantages. Entry of competitor companies should drive down costs. Studies are required to assess quality of life, morbidity, oncologic radicality, and cost effectiveness. PMID- 24780417 TI - VATS-based approach for robotic lobectomy. AB - Lobectomy with systematic lymph node sampling or dissection remains the mainstay of treatment of early stage non-small cell lung cancer. The use of video-assisted thoracic surgery (VATS) to perform lobectomy was first reported in 1992. Advantages of VATS include less trauma and pain, shorter chest drainage duration, decreased hospital stay, and preservation of short-term pulmonary function. However, VATS is characterized by loss of binocular vision and a limited maneuverability of thoracoscopic instruments, an unstable camera platform, and poor ergonomics for the surgeon. To overcome these limitations, robotic systems were developed during the last decades. This article reviews the technical aspects of robotic lobectomy using a VATS-based approach. PMID- 24780418 TI - Total port approach for robotic lobectomy. AB - Robotic surgery is safe and efficient, with similar survival rates to the open and video-assisted thoracoscopic surgery (VATS) approaches. The surgeon can provide an R0 resection in patients with cancer. Technical modifications lead to decreased operative times and may improve the ability to teach. The capital cost, service contract costs, and equipment costs have to be carefully considered and studied, and patient selection is critical. There are few achievable benefits of using a robotic system compared with VATS when performing a sympathotomy for patients with hyperhidrosis or a pulmonary wedge resection for tissue diagnosis for patients with interstitial lung disease. PMID- 24780419 TI - Robotic lobectomy for non-small cell lung cancer: long-term oncologic results. AB - Robotic lobectomy is a feasible, safe, and oncologically sound surgical treatment of early-stage lung cancer. The technique is reproducible across multiple centers and in the long-term yields results consistent with the best seen with conventional video-assisted thoracic surgery (VATS) and thoracotomy. Lymphadenectomy may reduce inadequate staging of the hilar and mediastinal nodes during curative, anatomic resection. Differences between robotic versus VATS versus thoracotomy approaches to thoracic diseases should be evaluated to define the appropriate role of each approach. PMID- 24780420 TI - Robot-assisted lung anatomic segmentectomy: technical aspects. AB - Anatomic lung segmentectomy is a possible alternative to lobectomy for small (<2 cm) primary lung cancers. Interest in anatomic lung segmentectomy has increased further after the adoption of high-resolution computed tomography and the implementation of lung cancer screening studies, which are increasing the detection rate of small lung cancers. Robotic surgery seems well suited to the precise dissection required for anatomic segmentectomy. Initial experience of robotic anatomic segmentectomy in patients with a single primary or metastatic lung lesion is highly encouraging. The introduction of robotic staplers, aspirators, and 5-mm lung forceps will further increase precision. PMID- 24780421 TI - Robotic pneumonectomy. AB - Pneumonectomy is indicated for centrally placed tumors when a lung-preserving operation cannot be performed for oncologic reasons. The technique of robotic pneumonectomy is still undergoing development and modification. Several pioneering surgeons have determined it to be feasible but more data are required to determine the benefits and disadvantages of robotic pneumonectomy. PMID- 24780422 TI - Thoracoscopic versus robotic approaches: advantages and disadvantages. AB - The overall advantages of thoracoscopy over thoracotomy in terms of patient recovery have been fairly well established. The use of robotics, however, is a newer and less proven modality in the realm of thoracic surgery. Robotics offers distinct advantages and disadvantages in comparison with video-assisted thoracoscopic surgery. Robotic technology is now used for a variety of complex cardiac, urologic, and gynecologic procedures including mitral valve repair and microsurgical treatment of male infertility. This article addresses the potential benefits and limitations of using the robotic platform for the performance of a variety of thoracic operations. PMID- 24780423 TI - Robotic thymectomy for myasthenia gravis. AB - Robotic thymectomy with the da Vinci robotic system is the latest development in the surgery of thymic gland. Thymectomy for myasthenia gravis is best offered to patients with seropositive acetylcholine receptor antibodies and who are seronegative for muscle-specific kinase protein. The robotic operation technique is indicated in all patients with myasthenia gravis in association with a resectable thymoma, typically Masaoka-Koga stages I and II. PMID- 24780424 TI - Robotic thymectomy for thymic neoplasms. AB - Robotic thymectomy has been well described for the management of myasthenia gravis and thymic masses. Both short- and long-term safety and efficacy have been demonstrated. Surgical approaches vary, but the technique for thymic dissection and excision is universal. PMID- 24780425 TI - Robotic esophagectomy: modified McKeown approach. AB - This article describes a robotic 2-stage 3-field esophagolymphadenectomy. Techniques highlighted include thoracic esophagectomy; cervical, wide thoracic, and abdominal lymphadenectomy; thoracic duct ligation; gastric tube creation; esophagogastric anastomosis in the left neck; and jejunostomy feeding tube placement. PMID- 24780426 TI - Robotic-assisted minimally invasive esophagectomy: the Ivor Lewis approach. AB - Robotic-assisted minimally invasive esophagectomy (RAMIE) is emerging as a potential alternative approach to standard minimally invasive esophagectomy (MIE). However, early reports vary widely in operative approach, method, and reporting of outcomes, including operative complications. A formal, prospective academic program to evaluate RAMIE was initiated at the authors' institution, with the primary goal of maximizing patient safety during the introduction of new technology into the operating room. The standardized RAMIE Ivor Lewis approach developed through this program is described in detail. The available literature is reviewed, with early reports suggesting outcomes similar to those of MIE and standard open esophagectomy. PMID- 24780427 TI - Robotic benign esophageal procedures. AB - Robotic master-slave devices can assist surgeons to perform minimally invasive esophageal operations with approaches that have already been demonstrated using laparoscopy and thoracoscopy. Robotic-assisted surgery for benign esophageal disease is described for the treatment of achalasia, epiphrenic diverticula, refractory reflux, paraesophageal hernias, duplication cysts, and benign esophageal masses, such as leiomyomas. Indications and contraindications for robotic surgery in benign esophageal disease should closely approximate the indications for laparoscopic and thoracoscopic procedures. Given the early application of the technology and paucity of clinical evidence, there are currently no procedures for which robotic esophageal surgery is the clinically proven preferred approach. PMID- 24780428 TI - Robotic surgery. PMID- 24780429 TI - Genetic characterization of a novel G3P[14] rotavirus strain causing gastroenteritis in 12 year old Australian child. AB - A genotype G3P[14] rotavirus strain was identified in a 12year old child presenting to the Emergency Department of the Royal Children's Hospital, Melbourne, with gastroenteritis. G3P[14] strains have been previously identified in rabbits in Japan, China, the USA and Italy and a single lapine-like strain from a child in Belgium. Full genome sequence analysis of RVA/Human wt/AUS/RCH272/2012/G3P[14] (RCH272) revealed that the strain contained the novel genome constellation G3-P[14]-I2-R3-C3-M3-A9-N2-T6-E2-H3. The genome was genetically divergent to previously characterized lapine viruses and the genes were distantly related to a range of human bovine-like strains and animal strains of bovine, bat and canine/feline characteristics. The VP4, VP6, NSP2, NSP3, NSP4 and NSP5 genes of RCH272 clustered within bovine lineages in the phylogenetic analysis and shared moderate genetic similarity with an Australian bovine-like human strain RVA/Human-tc/AUS/MG6/1993/G6P[14]. Bayesian coalescent analysis suggested these genes of RCH272 and RVA/Human-tc/AUS/MG6/1993/G6P[14] were derived from a population of relatively homogenous bovine-like ancestral strains circulating between 1943 and 1989. The VP7, VP1, VP2 and NSP1 genes shared moderate genetic similarity with the Chinese strain RVA/Bat tc/CHN/MSLH14/2011/G3P[3] and the VP3 gene clustered within a lineage comprised of canine and feline strains. This strain may represent the direct transmission from an unknown host species or be derived via multiple reassortment events between strains originating from various species. The patient lived in a household containing domesticated cats and dogs and in close proximity to a colony of Gray-headed Flying-foxes. However, without screening numerous animal populations it is not possible to determine the origins of this strain. PMID- 24780430 TI - Coenzyme Q10 treatment ameliorates cognitive deficits by modulating mitochondrial functions in surgically induced menopause. AB - The mechanisms associated with cognitive decline in post-menopausal state driven by loss of ovarian function and reduced estrogen levels are not well understood. The aim of the present study is to investigate the role of mitochondrial dysfunctions in cognitive impairment in post-menopausal state and to evaluate the protective effect of Coenzyme Q10 (CoQ10). A significant decline in cognitive functions was observed in mice after four weeks of ovariectomy as assessed by morris water maze and elevated plus maze. Administration of CoQ10 (10 mg/kg body weight, orally) daily for 4 weeks was found to reverse cognitive deficits observed in ovariectomized (Ovx) mice. The activity of mitochondrial electron transport chain components; NADH: cytochrome c reductase, succinate dehydrogenase and cytochrome c oxidase was significantly reduced in the brain of Ovx mice. This was accompanied by higher levels of ROS, protein carbonyls, lipid peroxidation, mitochondrial swelling and reduced activity of aconitase. The levels of GSH were observed to be significantly lowered resulting in reduced redox ratio (GSH/GSSG) in brain of Ovx mice. Activities of antioxidant enzymes; superoxide dismutase and catalase were also found to be reduced in brain of Ovx animals. CoQ10 supplementation to Ovx mice mitigated the mitochondrial dysfunctions and oxidative stress. Thus, the data indicates that CoQ10 improves cognitive decline in post-menopausal state by modulating mitochondrial functions and oxidative stress. PMID- 24780432 TI - Too many Germans are addicted to alcohol or tobacco, says report. PMID- 24780433 TI - Temperature-responsive peptide-mimetic coating based on poly(N-methacryloyl-l leucine): properties, protein adsorption and cell growth. AB - Poly(N-methacryloyl-l-leucine) (PNML) coatings were successfully fabricated via polymerization from peroxide initiator grafted to premodified glass substrate. Chemical composition and thickness of PNML coatings were determined using time of flight-secondary ion mass spectrometry (TOF- SIMS) and ellipsometry, respectively. PNML coatings exhibit thermal response of the wettability, between 4 and 28 degrees C, which indicates a transition between hydrated loose coils and hydrophobic collapsed chains. Morphology of the PNML coating was observed with the AFM, transforming with increasing temperature from initially relatively smooth surface to rough and more structured surface. Protein adsorption observed by fluorescence microscopy for model proteins (bovine serum albumin and lentil lectin labeled with fluorescein isothiocyanate) at transition from 5 to 25 degrees C, showed high affinity of PNML coating to proteins at all investigated temperatures and pH. Thus, PNML coating have significant potential for medical and biotechnological applications as protein capture agents or functional replacements of antibodies ("plastic antibodies"). The high proliferation growth of the human embryonic kidney cell (HEK 293) onto PNML coating was demonstrated, indicating its excellent cytocompatibility. PMID- 24780434 TI - Concentration effects on peptide elution from pendant PEO layers. AB - In earlier work, we have provided direction for development of responsive drug delivery systems based on modulation of structure and amphiphilicity of bioactive peptides entrapped within pendant polyethylene oxide (PEO) brush layers. Amphiphilicity promotes retention of the peptides within the hydrophobic inner region of the PEO brush layer. In this work, we describe the effects of peptide surface density on the conformational changes caused by peptide-peptide interactions, and show that this phenomenon substantially affects the rate and extent of peptide elution from PEO brush layers. Three cationic peptides were used in this study: the arginine-rich amphiphilic peptide WLBU2, the chemically identical but scrambled peptide S-WLBU2, and the non-amphiphilic homopolymer poly l-arginine (PLR). Circular dichroism (CD) was used to evaluate surface density effects on the structure of these peptides at uncoated (hydrophobic) and PEO coated silica nanoparticles. UV spectroscopy and a quartz crystal microbalance with dissipation monitoring (QCM-D) were used to quantify changes in the extent of peptide elution caused by those conformational changes. For amphiphilic peptides at sufficiently high surface density, peptide-peptide interactions result in conformational changes which compromise their resistance to elution. In contrast, elution of a non-amphiphilic peptide is substantially independent of its surface density, presumably due to the absence of peptide-peptide interactions. The results presented here provide a strategy to control the rate and extent of release of bioactive peptides from PEO layers, based on modulation of their amphiphilicity and surface density. PMID- 24780435 TI - Effect of ZrO(2) additions on the crystallization, mechanical and biological properties of MgO-CaO-SiO(2)-P(2)O(5)-CaF(2) bioactive glass-ceramics. AB - A series of ZrO(2) doped MgO-CaO-SiO(2)-P(2)O(5)-CaF(2) bioactive glass-ceramics were obtained by sintering method. The crystallization behavior, phase composition, morphology and structure of glass-ceramics were characterized. The bending strength, elastic modulus, fracture toughness, micro-hardness and thermal expansion coefficient (TEC) of glass-ceramics were investigated. The in vitro bioactivity and cytotoxicity tests were used to evaluate the bioactivity and biocompatibility of glass-ceramics. The sedimentation mechanism and growth process of apatites on sample surface were discussed. The results showed that the mainly crystalline phases of glass-ceramics were Ca(5)(PO4)3F (fluorapatite) and beta-CaSiO(3). (beta-wollastonite). m-ZrO(2) (monoclinic zirconia) declined the crystallization temperatures of glasses. t-ZrO(2) (tetragonal zirconia) increased the crystallization temperature of Ca(5)(PO4)(3)F and declined the crystallization temperature of beta-CaSiO(3). t-ZrO(2) greatly increased the fracture toughness, bending strength and micro-hardness of glass-ceramics. The nanometer apatites were induced on the surface of glass-ceramic after soaking 28 days in SBF (simulated body fluid), indicating the glass-ceramic has good bioactivity. The in vitro cytotoxicity test demonstrated the glass-ceramic has no toxicity to cell. PMID- 24780436 TI - Structural and morphological investigations of beta-cyclodextrin-coated silver nanoparticles. AB - This paper describes the synthesis of silver nanoparticles using an aqueous silver nitrate solution in the presence of glucose as a reducing agent, sodium hydroxide as a reaction catalyst and beta-CD as a stabilizer. The structure and the morphology associated to the stabilizing layer around the silver nanoparticles were investigated. Raman spectroscopy confirmed the nanoparticle surface modification by beta-CD, demonstrating the interaction between the beta CD rim hydroxyl groups and the AgNP surface. Transmission electron microscopy images showed an average 28.0nm diameter pseudo-spherical nanoparticles. Apart from this, a novel characterization of the beta-CD layer surrounding the nanoparticles was carried out by using complementary analytical electron microscopy based on electron spectroscopy imaging in the transmission microscope. Mapping images revealed the presence of carbon and oxygen, demonstrating the existence of a uniform and interacting beta-CD layer covering the nanoparticles. The antibacterial activity was also investigated and the beta-CD-coated silver nanoparticles showed a promising bactericidal activity against the microorganism Escherichia coli. PMID- 24780437 TI - Associations among gestational weight gain, physical activity, and pre-pregnancy body size with varying estimates of pre-pregnancy weight. AB - OBJECTIVES: the purpose of this study was to examine associations among gestational weight gain (GWG) and pregnancy leisure-time physical activity (LTPA), within pre-pregnancy body mass index (BMI) categories, while utilising two different estimates of pre-pregnancy weight. DESIGN: a cohort study. Data were collected via questionnaire and abstraction from birth certificate as a part of a larger study. SETTING: three antenatal clinics in Lansing, Michigan, USA. PARTICIPANTS: a subset of women who participated in the Archive for Research on Child Health (ARCH) study and delivered a singleton, term infant (n=135). Participants were enroled prior to 14 weeks' gestation. MEASUREMENTS: pre pregnancy BMI was categorised as normal, overweight and obese (excluded underweight). GWG was calculated by subtracting pre-pregnancy weight from weight at childbirth (obtained from birth certificate) and classified as 'excess' or 'not excess' using the upper limit of the 2009 IOM recommended range. These two variables were constructed twice, first by using pre-pregnancy weight self reported at enrolment and second, by using pre-pregnancy weight recorded on birth certificates. LTPA, also self-reported at enrolment, was modelled using two thresholds, moderate LTPA, and vigorous LPTA. FINDINGS: overall, 56-60% of our sample experienced excess GWG, depending on the source used for pre-pregnancy weight. Overweight and obese women had significantly higher odds of excess GWG (compared to normal weight women; Odds Ratio (OR)=2.48-5.34). LTPA level did not differ among pre-pregnancy BMI categories and was not related to appropriateness of GWG. KEY CONCLUSIONS: regardless of the source of pre-pregnancy weight, overweight and obese women were more likely to experience excess GWG (compared to normal weight women) and LTPA was not significantly related to the appropriateness of GWG. IMPLICATIONS FOR PRACTICE: findings highlight the need for practitioners to effectively communicate GWG recommendations and counsel women about the importance of achieving appropriate GWG. Although GWG counselling has traditionally been focused on obese women, these results suggest overweight women are in need of GWG counselling as well. PMID- 24780438 TI - Paroxysmal dysarthria-ataxia in remitting-relapsing Bickerstaff's-like encephalitis. AB - Paroxysmal dysarthria-ataxia is a rare neurological condition due to ephaptic transmission, generally appearing in multiple sclerosis patients characterized by stereotyped attacks of slurred speech usually accompanied by ataxia, appearing many times a day. Here we describe a patient with an unusual remitting-relapsing form of Bickerstaff's-like brainstem encephalitis who manifested PDA after a relapse with the involvement of a peculiar region below the red nuclei and benefited from lamotrigine. PMID- 24780439 TI - Role of glutathione S-transferases in the spinocerebellar ataxia type 2 clinical phenotype. AB - Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative and incurable hereditary disorder caused by a CAG repeat expansion mutation on ATXN2 gene. The identification of reliable biochemical markers of disease severity is of paramount significance for the development and assessment of clinical trials. In order to evaluate the potential use of glutathione-S-transferase (GST) activity as a biomarker for SCA2, a case-control study in 38 affected, presymptomatic individuals or healthy controls was conducted. An enlarged sample of 121 affected individuals was set to assess the impact of GST activity on SCA2 clinical expression. There was a significant increase in GST activity in affected individuals relative to controls, although sensibility and specificity were not high. GST activity was not significantly influenced by sex, age, disease duration or CAG repeat size and did not significantly influence disease severity markers. These findings show a disruption of in vivo GST activity in SCA2, suggesting a role for oxidative stress in the neurodegenerative process. PMID- 24780440 TI - Co-encapsulation of resveratrol and curcumin in lipid-core nanocapsules improves their in vitro antioxidant effects. AB - Resveratrol and curcumin are natural antioxidants found in the human diet that have been used in the prevention and treatment of different diseases associated with oxidative stress. Aiming to improve the antioxidant effects of resveratrol and curcumin, lipid-core nanocapsules containing the combination of both polyphenols were developed. Physicochemical characteristics were evaluated and compared to the formulations containing each polyphenol individually. Co encapsulation did not influence nanotechnological characteristics, and all formulations presented mean diameter around 200 nm, low polydispersity index, and encapsulation efficiency close to 100%. Nanoencapsulation increases the photostability of resveratrol and curcumin, and co-encapsulation improves resveratrol photostability. The in vitro antioxidant activity of polyphenols against HO radicals was enhanced by nanoencapsulation, and a better effect was observed after their co-nanoencapsulation. Also, nanocapsules exhibited controlled release profile, for both polyphenols. The results showed that the strategy to co-encapsulate resveratrol and curcumin is a promising approach to improve the performance of medicines used to prevent and treat diseases associated with oxidative stress. PMID- 24780441 TI - Adenosine dry powder inhalation for bronchial challenge testing, part 2: proof of concept in asthmatic subjects. AB - Adenosine is an indirect stimulus to assess bronchial hyperresponsiveness (BHR(2)) in asthma. Bronchial challenge tests are usually performed with nebulised solutions of adenosine 5'-monophosphate (AMP(3)). The nebulised AMP test has several disadvantages, like long administration times and a restrictive maximum concentration that does not result in BHR in all patients. In this study, we investigated the applicability of dry powder adenosine for assessment of BHR in comparison to nebulised AMP. Dry powder adenosine was prepared in doubling doses (0.01-80 mg) derived from the nebulised AMP test with addition of two higher doses. Five asthmatic subjects performed two bronchial challenge tests, one with nebulised AMP following the 2-min tidal breathing method; the second with dry powder adenosine administered with an investigational inhaler and single slow inhalations (inspiratory flow rate 30-40 L/min). All subjects reached a 20% fall in FEV1(4) with the new adenosine test (PD20(5)) compared to four subjects with the AMP test (PC20(6)). Dry powder adenosine was well tolerated by all subjects and better appreciated than nebulised AMP. In conclusion, this new bronchial challenge test appears to be a safe and convenient alternative to the nebulised AMP test to assess BHR in asthmatic subjects. PMID- 24780442 TI - Interpersonal Processes and Attachment in Voice-Hearers. AB - BACKGROUND: Studies of both clinical and non-clinical voice hearers suggest that distress is rather inconsistently associated with the perceived relationship between voice and hearer. It is also not clear if their beliefs about voices are relevant. AIMS: This study investigated the links between attachment anxiety/avoidance, interpersonal aspects of the voice relationship, and distress whilst considering the impact of beliefs about voices and paranoia. METHOD: Forty four voice-hearing participants completed a number of self-report measures tapping attachment, interpersonal processes in the voice relationship, beliefs about voices, paranoia, distress and depression. RESULTS: Attachment avoidance was related to voice intrusiveness, hearer distance and distress. Attachment anxiety was related to voice intrusiveness, hearer dependence and distress. A series of simple mediation analyses were conducted that suggest that the relationship between attachment and voice related distress may be mediated by interpersonal dynamics in the voice-hearer relationship, beliefs about voices and paranoia. CONCLUSIONS: Beliefs about voices, the hearer's relationship with their voices, and the distress voices sometimes engender appear to be meaningfully related to their attachment style. This may be important to consider in therapeutic work. PMID- 24780444 TI - Authors' reply to Grant and Garland and to Bolland and colleagues. PMID- 24780443 TI - Posterior polymorphous corneal dystrophy 3 is associated with agenesis and hypoplasia of the corpus callosum. AB - Posterior polymorphous corneal dystrophy (PPCD) is a dominantly inherited disorder of the corneal endothelium that has been associated with mutations in the zinc-finger E-box binding homeobox 1 gene (ZEB1) gene in approximately one third of affected families. While the corneal dystrophies have traditionally been considered isolated disorders of the corneal endothelium, we have recently identified two cases of maldevelopment of the corpus callosum in unrelated individuals with PPCD. The proband of the first family was diagnosed shortly after birth with agenesis of the corpus callosum and several other developmental abnormalities. Karyotype, FISH and whole genome copy number variant analyses were normal. She was subsequently diagnosed with PPCD, prompting screening of the ZEB1 gene, which identified a novel deletion (c.449delG; p.(Gly150Alafs*36)) present in the heterozygous state that was not identified in either unaffected parent. The proband of the second family was diagnosed several months after birth with thinning of the corpus callosum and PPCD. Whole genome copy number variant analysis revealed a 1.79 Mb duplication of 17q12 in the proband and her father and brother, neither of whom had PPCD. ZEB1 sequencing identified a novel deletion (c.1913-1914delCA; p.(Ser638Cysfs*5)) present in the heterozygous state, which was also identified in the proband's affected mother. Thus, we report the first two cases of the association of PPCD with a developmental abnormality of the brain, in this case maldevelopment of the corpus callosum. PMID- 24780445 TI - Development of a selective S1P1 receptor agonist, Syl930, as a potential therapeutic agent for autoimmune encephalitis. AB - Sphingosine-1-phosphate receptor subtype 1 (S1P1) is essential for lymphocyte egress from secondary lymphoid organs and is a validated drug target for the treatment of autoimmune disorders. However, during the preclinical and clinical trials of S1P1 modulators, the undesired activation of S1P3, a subtype of sphingosine 1-phosphate (S1P) receptors family, by S1P1 modulators often results in bradycardia in patients. Thus, we designed and synthesized a new series of selective S1P1 agonists. One of them, Syl930 (the prodrug), is preference to activate S1P1 but not S1P3. In this study, we further investigated the therapeutic potential of Syl930 on an experimental autoimmune encephalomyelitis (EAE) model in Lewis rats. We found that Syl930 can activate and internalize S1P1 receptors and effectively decreased the periphery blood lymphocytes (PBL) in SD rats, and subsequently rendered PBL insensitive to egress signal from secondary lymphoid organs (SLO). Intriguingly, the treatment of Syl930 did not bring any side effect on heart rate of the tested rats. Furthermore, the suppressed PBL caused by Syl930 was able to recover within 3 days after the last dose of treatment, which is correlated to the relatively short elimination half-life of Syl930. In the rat EAE model, therapeutic treatment with Syl930 significantly inhibited the progression of EAE and EAE-associated histological changes in brain and spinal cord of Lewis rats. These results illustrate that, as a selective S1P1 agonist, Syl930 exhibits a profound and rapidly reversible suppression of lymphocyte trafficking and it has the potential to serve as a therapeutic agent for autoimmune encephalitis. PMID- 24780446 TI - Salvianolic acid B protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways. AB - The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H2O2)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H2O2 induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H2O2 induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases. PMID- 24780448 TI - Overarousal interacts with a sense of fearlessness about death to predict suicide risk in a sample of clinical outpatients. AB - Converging evidence suggests that acute states of overarousal are common prior to suicidal behavior. Yet, there has been very little theory-driven research of these phenomena. We consider two competing theoretical perspectives. The first is consistent with the interpersonal theory of suicide, which suggests that the prospect of engaging in lethal suicidal behavior should elicit some degree of arousal; however, the effect of arousal will be particularly relevant when considered in the context of an individual's capability for suicide. The second perspective draws from escape-based models, which would suggest that arousal alone should result in increased suicide risk, given the distress associated with high arousal states. Results indicated that the interaction of overarousal and capability for suicide was associated with suicidal symptoms. As overarousal increased, suicidal symptoms increased among high capability individuals and decreased among low capability individuals. These effects were observed beyond the effects of depression, anxiety, age, gender, and marital status. There was no significant main effect of overarousal. Results support a perspective in line with the interpersonal theory, suggesting that overarousal states may be particularly dangerous for individuals who have developed the capability for suicide. PMID- 24780447 TI - Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. AB - Basic pharmacological/transgenic studies have clearly demonstrated a cause-effect relationship between the induction and activation of matrix metalloproteinases (MMPs) and adverse changes in the structure and function of the left ventricle (LV). Thus, regulation of MMP induction and/or activation would appear to be a potential therapeutic target in the context of cardiovascular disease, such as following myocardial infarction (MI). However, pharmacological approaches to inhibit MMPs have yet to be realized for clinical applications. The endogenous inhibitors of the MMPs (TIMPs) constitute a set of 4 small molecules with unique functionality and specificity. Thus, improved understanding on the function and roles of individual TIMPs may provide important insight into the design and targets for pharmacological applications in LV remodeling processes, such as MI. Therefore, the purpose of this review will be to briefly examine biological functions and relevance of the individual TIMPs in terms of adverse LV remodeling post-MI. Second is to examine the past outcomes and issues surrounding clinical trials targeting MMPs in the post MI context and how new insights into TIMP biology may provide new pharmacological targets. This review will put forward the case that initial pharmacological attempts at MMP inhibition were over-simplistic and that future strategies must recognize the diversity of this matrix proteolytic system and that lessons from TIMP biology may lead to future therapeutic strategies. PMID- 24780449 TI - The prognostic significance of early remission of positive symptoms in first treated psychosis. AB - We examine the relationship between achieving remission of positive symptoms within 3 months in first episode psychosis and outcomes 5 years later. Time to remission of positive symptoms, other early characteristics and 5 year outcomes were assessed in a prospective study of 132 patients being treated for the first time for a psychotic disorder. Just under 60% of patients showed remission of positive symptoms within 3 months. In comparison to later remitters, they showed lower levels of positive symptoms, greater likelihood of competitive employment and less likelihood of collecting a disability pension at 5 years. Earlier remission of positive symptoms may have prognostic significance for longer term outcomes. PMID- 24780450 TI - A clinical and economic evaluation of Control of Hyperglycaemia in Paediatric intensive care (CHiP): a randomised controlled trial. AB - BACKGROUND: Early research in adults admitted to intensive care suggested that tight control of blood glucose during acute illness can be associated with reductions in mortality, length of hospital stay and complications such as infection and renal failure. Prior to our study, it was unclear whether or not children could also benefit from tight control of blood glucose during critical illness. OBJECTIVES: This study aimed to determine if controlling blood glucose using insulin in paediatric intensive care units (PICUs) reduces mortality and morbidity and is cost-effective, whether or not admission follows cardiac surgery. DESIGN: Randomised open two-arm parallel group superiority design with central randomisation with minimisation. Analysis was on an intention-to-treat basis. Following random allocation, care givers and outcome assessors were no longer blind to allocation. SETTING: The setting was 13 English PICUs. PARTICIPANTS: Patients who met the following criteria were eligible for inclusion: >= 36 weeks corrected gestational age; <= 16 years; in the PICU following injury, following major surgery or with critical illness; anticipated treatment > 12 hours; arterial line; mechanical ventilation; and vasoactive drugs. Exclusion criteria were as follows: diabetes mellitus; inborn error of metabolism; treatment withdrawal considered; in the PICU > 5 consecutive days; and already in CHiP (Control of Hyperglycaemia in Paediatric intensive care). INTERVENTION: The intervention was tight glycaemic control (TGC): insulin by intravenous infusion titrated to maintain blood glucose between 4.0 and 7.0 mmol/l. CONVENTIONAL MANAGEMENT (CM): This consisted of insulin by intravenous infusion only if blood glucose exceeded 12.0 mmol/l on two samples at least 30 minutes apart; insulin was stopped when blood glucose fell below 10.0 mmol/l. MAIN OUTCOME MEASURES: The primary outcome was the number of days alive and free from mechanical ventilation within 30 days of trial entry (VFD-30). The secondary outcomes comprised clinical and economic outcomes at 30 days and 12 months and lifetime cost-effectiveness, which included costs per quality-adjusted life-year. RESULTS: CHiP recruited from May 2008 to September 2011. In total, 19,924 children were screened and 1369 eligible patients were randomised (TGC, 694; CM, 675), 60% of whom were in the cardiac surgery stratum. The randomised groups were comparable at trial entry. More children in the TGC than in the CM arm received insulin (66% vs. 16%). The mean VFD-30 was 23 [mean difference 0.36; 95% confidence interval (CI) -0.42 to 1.14]. The effect did not differ among prespecified subgroups. Hypoglycaemia occurred significantly more often in the TGC than in the CM arm (moderate, 12.5% vs. 3.1%; severe, 7.3% vs. 1.5%). Mean 30 day costs were similar between arms, but mean 12-month costs were lower in the TGC than in CM arm (incremental costs -L3620, 95% CI -L7743 to L502). For the non cardiac surgery stratum, mean costs were lower in the TGC than in the CM arm (incremental cost -L9865, 95% CI -L18,558 to -L1172), but, in the cardiac surgery stratum, the costs were similar between the arms (incremental cost L133, 95% CI L3568 to L3833). Lifetime incremental net benefits were positive overall (L3346, 95% CI -L11,203 to L17,894), but close to zero for the cardiac surgery stratum ( L919, 95% CI -L16,661 to L14,823). For the non-cardiac surgery stratum, the incremental net benefits were high (L11,322, 95% CI -L15,791 to L38,615). The probability that TGC is cost-effective is relatively high for the non-cardiac surgery stratum, but, for the cardiac surgery subgroup, the probability that TGC is cost-effective is around 0.5. Sensitivity analyses showed that the results were robust to a range of alternative assumptions. CONCLUSIONS: CHiP found no differences in the clinical or cost-effectiveness of TGC compared with CM overall, or for prespecified subgroups. A higher proportion of the TGC arm had hypoglycaemia. This study did not provide any evidence to suggest that PICUs should stop providing CM for children admitted to PICUs following cardiac surgery. For the subgroup not admitted for cardiac surgery, TGC reduced average costs at 12 months and is likely to be cost-effective. Further research is required to refine the TGC protocol to minimise the risk of hypoglycaemic episodes and assess the long-term health benefits of TGC. TRIAL REGISTRATION: Current Controlled Trials ISRCTN61735247. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 26. See the NIHR Journals Library website for further project information. PMID- 24780451 TI - Diabetic kidney disease: an ACEI (or an ARB) in the hole. PMID- 24780452 TI - The changing landscape of diabetic kidney disease: new reflections on phenotype, classification, and disease progression to influence future investigative studies and therapeutic trials. PMID- 24780453 TI - Epidemiology and risk factors for diabetic kidney disease. AB - Prevalence rates of diabetic kidney disease (DKD) are increasing in parallel with the incidence rates of diabetes mellitus. DKD has already become a significant health problem worldwide. Without radical improvements in prevention and treatment, DKD prevalence will continue to climb. The pathogenesis of DKD is complex and multifactorial, with genetic and environmental factors involved. Several nonmodifiable risk factors contribute to DKD, including genetics, sex, age, age at onset, and duration of diabetes. However, there are also several modifiable risk factors that have a strong effect on the risk of DKD. Traditional modifiable factors include glycemic control, blood pressure, lipids, and smoking. Other recently discovered modifiable risk factors include chronic low-grade inflammation, advanced glycation end products, and lack of physical activity. Efficient management of these modifiable risk factors may improve the prognosis of diabetic patients at risk of DKD. PMID- 24780454 TI - Natural history and clinical characteristics of CKD in type 1 and type 2 diabetes mellitus. AB - The nature of CKD in diabetes is changing. Diabetic glomerulosclerosis remains the cause of CKD in most type 1 diabetic individuals. However, the rate of progression of diabetic nephropathy has slowed because of improving glucose and blood pressure control. Most individuals with type 2 diabetes and 5% to 30% of those with type 1 diabetes with progressive CKD have normal urine albumin excretion or low-level microalbuminuria (albumin-to-creatinine ratio approximately <100 mg/g), which does not progress despite the decline in glomerular filtration. People with progressive CKD but normal albuminuria have predominantly interstitial or vascular changes with much less glomerular changes. It seems likely that these histological abnormalities relate to blood pressure, aging, obesity, and intrarenal vascular disease. Initial studies suggested that 85% to 100% of diabetic individuals with microalbuminuria (Kidney Disease Improving Global Outcomes [KDIGO] CKD albuminuria A2) progressed to proteinuria (KDIGO CKD albuminuria A3). Recent data demonstrate that even after 2 to 3 years of persistent microalbuminuria, most will revert to normal albumin excretion (KDIGO CKD albuminuria A1). Regression is more likely at lower levels of microalbuminuria and with improved glucose, blood pressure, and lipid control. Thus, low levels of microalbuminuria cannot be considered as established diabetic nephropathy. PMID- 24780455 TI - Cardiovascular complications of diabetic kidney disease. AB - Diabetic nephropathy is the most common cause of CKD and represents a large and ominous public health problem. Patients with diabetic kidney disease have exceptionally high rates of cardiovascular morbidity and mortality. In fact, the excess mortality among patients with diabetes appears to be largely limited to the subgroup with kidney disease and explained by their high burden of cardiovascular disease. The mechanisms underlying the strong association between diabetic kidney disease and various forms of cardiovascular disease are poorly understood. Traditional risk factors for cardiovascular disease, although prevalent among those with diabetes, do not fully account for the heightened risk observed. Despite their susceptibility to cardiovascular disease, patients with CKD are less likely to receive appropriate risk factor modification than the general population. Moreover, because patients with CKD have commonly been excluded from major cardiovascular trials, the evidence for potential treatments remains limited. The mainstays of treatment for diabetic kidney disease currently include blockade of the renin-angiotensin-aldosterone system and control of hypertension, hyperglycemia, and dyslipidemia. Increased awareness of the vulnerability of this patient population and more timely interventions are likely to improve outcomes while large evidence gaps are filled with newer studies. PMID- 24780457 TI - Genetic and epigenetic risk factors for diabetic kidney disease. AB - Diabetes is increasing at daunting rates worldwide, and approximately 40% of affected individuals will develop kidney complications. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and there are significant healthcare costs providing appropriate renal replacement therapies to affected individuals. For several decades, investigators have sought to discover inherited risk factors and biomarkers for DKD. In recent years, advances in high-throughput laboratory techniques and computational analyses, coupled with the establishment of multicenter consortia, have helped to identify genetic loci that are replicated across multiple populations. Several genome-wide association studies (GWAS) have been conducted for DKD with further meta-analysis of GWAS and comprehensive "single gene" meta-analyses now published. Despite these efforts, much of the inherited predisposition to DKD remains unexplained. Meta-analyses and integrated-omics pathway studies are being used to help elucidate underlying genetic risks. Epigenetic phenomena are increasingly recognized as important drivers of disease risk, and several epigenome-wide association studies have now been completed. This review describes key findings and ongoing genetic and epigenetic initiatives for DKD. PMID- 24780456 TI - Blood pressure, hypertension, RAAS blockade, and drug therapy in diabetic kidney disease. AB - Type 2 diabetes is the most common cause of CKD and ESRD in the United States and the Western world. Hypertension is prevalent in this cohort, and control of blood pressure is perhaps the most important risk factor to reduce CKD progression. The most recent blood pressure target recommended by the Kidney Disease: Improving Global Outcomes and Kidney Disease Outcomes Quality Initiative guideline committees is less than 140/90 mmHg for all patients with CKD. There is some evidence for those with 1 g or more of albuminuria, albeit weak, to support a blood pressure target of less than 130/80 mmHg. Multiple studies demonstrate that renin-angiotensin-aldosterone system (RAAS) blockers are important in reducing cardiovascular risk and progression of CKD in those with advanced proteinuric nephropathy. However, there is no evidence that they prevent nephropathy or that reduction in microalbuminuria alone is associated with slowed nephropathy progression. The purpose of this article is to review the major studies that have evaluated cardiovascular and kidney endpoints in patients with diabetes and the role of RAAS blockers in the treatment of this disease. PMID- 24780458 TI - Glomerular and tubular function in the diabetic kidney. AB - Diabetes mellitus with its attendant complications is a significant cause of morbidity and mortality with diabetic nephropathy being the leading cause of end stage renal disease in the Western world. Characteristic structural and functional changes in the kidney early in the course of diabetes have been shown to have enduring effects on the progression of disease. A better understanding of the mechanisms underlying these changes is imperative to the development of new therapeutic strategies. Renal hypertrophy and hyperfiltration along with proximal tubular hyperreabsorption are among the distinctive features of early diabetic nephropathy. Additionally, there are particular alterations in the sensitivity of the glomerular and tubular function to dietary salt intake in early diabetes. Herein, we focus on these early physiologic changes and discuss some of the primary and secondary mechanisms discovered in recent years which lead to these alterations in kidney function. PMID- 24780460 TI - Glycemic exposure, glycemic control, and metabolic karma in diabetic complications. AB - Diabetes continues to cast a long shadow over the lives of many people. It is now clear that even transient hyper- or hypoglycemia or increased glycemic variability around healthy mean glucose levels can have long-lasting and long term effects on the development and progression of diabetic complications, including cardiovascular disease, kidney disease, retinopathy, and neuropathy. Even after glycemic control has been achieved and maintained for many years, it appears hard to undo the changes that are instilled, including epigenetic programming, compositional changes, post-translational modifications, or simply lead time toward an inevitable fate. This phenomenon has become known as "metabolic memory" or the "legacy effect," but it may be better characterized as "metabolic karma," in which the intent and actions of an individual (with respect to metabolic control) influence the future health of that individual. This "bad karma" has been used to explain many clinical observations surrounding diabetes and its management, including the lack of benefits in many short- and intermediate-term trials, and the potential utility of early intensive glycemic control. Further understanding the molecular basis of a metabolic legacy in diabetes will certainly provide new targets for intervention. PMID- 24780461 TI - New insights into the use of biomarkers of diabetic nephropathy. AB - Diabetic nephropathy (DN) is a major microvascular complication of diabetes characterized by increasing albuminuria and progressive loss of kidney function. Increased excretion of albumin into the urine is a key feature of DN, and its assessment is considered to be an early marker predicting the onset and progression of DN. However, albuminuria has certain limitations; therefore, the quest for more reliable renal biomarkers with higher sensitivity and specificity are needed for early prediction of the onset and monitoring of the progression of DN. Furthermore, such biomarkers may also provide a better insight into identifying the complex pathophysiological processes responsible for DN. This article aims to provide a comprehensive and critical review of the current literature on relevant biomarkers of kidney injury, including markers of renal fibrosis, inflammation, and oxidative stress, as well as addressing contemporary proteomic approaches. PMID- 24780459 TI - Podocytes, signaling pathways, and vascular factors in diabetic kidney disease. AB - Alterations and injury to glomerular podocytes play a key role in the initiation and progression of diabetic kidney disease (DKD). Multiple factors in diabetes cause abnormalities in podocyte signaling that lead to podocyte foot process effacement, hypertrophy, detachment, loss, and death. Alterations in insulin action and mammalian target of rapamycin activation have been well documented to lead to pathology. Reduced insulin action directly leads to albuminuria, increased glomerular matrix accumulation, thickening of the glomerular basement membrane, podocyte apoptosis, and glomerulosclerosis. In addition, podocytes generate factors that alter signaling in other glomerular cells. Prominent among these is vascular endothelial growth factor-A, which maintains glomerular endothelium viability but causes endothelial cell pathology when generated at too high a level. Finally, circulating vascular factors (eg, activated protein C) have a profound effect on podocyte stability and survival. This cytoprotective factor is critical for podocyte health, and its deficiency promotes podocyte injury and apoptosis. Thus, the podocyte sits in the center of a network of paracrine and hormonal signaling systems that in health keep the podocyte adaptable and viable, but in diabetes they can lead to pathologic changes, detachment, and death. PMID- 24780462 TI - Inside plant: biotrophic strategies to modulate host immunity and metabolism. AB - Filamentous plant pathogens that establish biotrophic interactions need to avoid plant immune responses. Recent findings from different pathosystems suggest that sufficient suppression of host immunity is based on the modulation of a rather limited number of host targets. Microbial strategies to target host physiology dependent on the duration of biotrophy, the style of host tissue colonization and the degree of interference with plant development. In this article, we present current concepts in biotrophic virulence strategies and discuss mechanisms of pathogen adaptation and effector specialization. PMID- 24780463 TI - The effect of distal humeral hemiarthroplasty on articular contact of the elbow. AB - BACKGROUND: Hemiarthroplasty is a treatment option for selected distal humerus fractures. The purpose of this study was to determine the effect of distal humeral hemiarthroplasty and implant size on elbow articular contact. We hypothesized that implants of varying sizes produce different contact patterns compared with the native elbow. METHODS: Eight cadaveric arms were tested in an elbow simulator and the kinematics recorded. Three-dimensional reconstructions of bones and cartilage were generated from computed-tomography images to determine contact patterns. The native articulation was compared to optimal, oversized, and undersized implants (Latitude Anatomic Hemiarthroplasty). Changes in contact patterns relative to the native articulation were measured using total contact area and contact patch agreement scores, defined as the sum of distance between contact patches*area, indicating how well contact patches agree with the native contact pattern. FINDINGS: The native articulation had significantly lower ulnohumeral contact patch agreement scores compared to all tested implants (P<0.05). Mean ulnohumeral and radiocapitellar contact area decreased an average 44% (P=0.03) and 4% (P=0.07) following placement of an optimally sized implant. There was no effect of implant size on contact area or contact patch agreement score (P>0.05). INTERPRETATION: Shape differences of elbow implants relative to the native joint may be responsible for altered contact patterns and could be improved with design modifications. These changes may predispose the elbow to arthritis. The lack of influence of implant size suggests that implant shape and materials may be more important than implant sizing during surgery. PMID- 24780466 TI - Dimethylarginines ADMA and SDMA: the real water-soluble small toxins? AB - Uremia occurs if the kidney loses the ability to eliminate toxic compounds at a sufficient rate into the urine. In 1970, N-N, N-G- and N-G,N'-G-dimethyl-arginine (asymmetric dimethylarginine [ADMA] and symmetric dimethylarginine) were isolated from human urine. It was anticipated that both substances might be important in the pathophysiology and for the diagnosis of various pathologic states. It took 22 years, however, before this idea materialized when it was found that ADMA, which is increased in hemodialysis patients, inhibits the synthesis of the endothelial-derived relaxing factor, identified as nitric oxide. ADMA correlates with traditional and nontraditional cardiovascular risk factors and is a strong predictor of cardiovascular events and death in both patients with chronic kidney disease and in the general population. It also seems to mediate adverse cardiovascular effects of drugs such as proton pump inhibitors. To date, we have no specific pharmacologic therapy at hand to neutralize the deleterious effects of ADMA, curbing the enthusiasm for this marker and mediator of cardiovascular disease. PMID- 24780467 TI - Protein-bound molecules: a large family with a bad character. AB - Many small solutes excreted by the kidney are bound to plasma proteins, chiefly albumin, in the circulation. The combination of protein binding and tubular secretion allows the kidney to reduce the free, unbound concentrations of such solutes to lower levels than could be obtained by tubular secretion alone. Protein-bound solutes accumulate in the plasma when the kidneys fail, and the free, unbound levels of these solutes increase more than their total plasma levels owing to competition for binding sites on plasma proteins. Given the efficiency by which the kidney can clear protein-bound solutes, it is tempting to speculate that some compounds in this class are important uremic toxins. Studies to date have focused largely on two specific protein-bound solutes: indoxyl sulfate and p-cresyl sulfate. The largest body of evidence suggests that both of these compounds contribute to cardiovascular disease, and that indoxyl sulfate contributes to the progression of chronic kidney disease. Other protein-bound solutes have been investigated to a much lesser extent, and could in the future prove to be even more important uremic toxins. PMID- 24780468 TI - The peptidic middle molecules: is molecular weight doing the trick? AB - Chronic kidney disease (CKD) is characterized by a gradual endogenous intoxication caused by the progressive accumulation of bioactive compounds that in normal conditions would be excreted and/or metabolized by the kidney. Uremic toxicity now is understood as one of the potential causes for the excess of cardiovascular disease and mortality observed in CKD. An important family of uremic toxins is that of the peptidic middle molecules, with a molecular weight ranging between 500 and 60,000 Da, which makes them, as a consequence, difficult to remove in the process of dialysis unless the dialyzer pore size is large enough. This review provides an overview of the main and best-characterized peptidic middle molecules and their role as potential culprits of the cardiometabolic complications inherent to CKD patients. PMID- 24780469 TI - Gases as uremic toxins: is there something in the air? AB - The field of uremic toxicity comprises the study of a large number of different substances, classified in relation to various characteristics, for example, protein-binding, dimensions, and so forth. The endogenous compounds of a gaseous nature have received much attention lately from the scientific community because of their increasingly recognized importance in health and disease. Among these substances, some are uremic toxins per se, others are related to uremic toxins, or can become toxic under some circumstances. We divided them into two broad categories: organic and inorganic compounds. Among the organic compounds are phenols, indols, 2-methoxyresorcinol, p-hydroxy hippuric acid and phenyl acetic acid, trimethylamine, and dimethylamine; among the inorganic solutes are ammonia, nitric oxide, carbon monoxide, and hydrogen sulfide. In this article, these substances are described in relation to the elements that they affect or by which they are affected in uremia, which are the blood, breath, stools, and the gastrointestinal tract. In addition, the effect of the dialysis procedure on exhaled gases are described. PMID- 24780470 TI - Laboratory abnormalities in CKD-MBD: markers, predictors, or mediators of disease? AB - Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and an array of laboratory abnormalities. The latter classically include disturbances in the parathyroid hormone/vitamin D axis. More recently, fibroblast growth factor 23 (FGF23) and klotho also have been identified as important regulators of mineral metabolism. Klotho deficiency and high circulating FGF23 levels precede secondary hyperparathyroidism in CKD patients. Levels of FGF23 and parathyroid hormone increase along the progression of CKD to maintain mineral homeostasis and to overcome end-organ resistance. It is hard to define when the increase of both hormones becomes maladaptive. CKD-MBD is associated with adverse outcomes including cardiovascular disease and mortality. This review summarizes the complex pathophysiology of CKD-MBD and outlines which laboratory abnormalities represent biomarkers of disease severity, which laboratory abnormalities are predictors of cardiovascular disease, and which laboratory abnormalities should be considered (direct) uremic toxins exerting organ damage. This information may help to streamline current and future therapeutic efforts. PMID- 24780471 TI - Clinical studies and chronic kidney disease: what did we learn recently? AB - This article summarizes relevant clinical studies that recently were devoted to the role of uremic toxins in outcomes of patients with chronic kidney disease and uremia. We summarize observational data linking uremic toxins (phosphate, the dimethylarginines, uric acid, and several large peptidic middle molecules and protein-bound solutes) to outcomes in observational studies. Interventional studies that evaluate the impact of different removal strategies on uremic toxin concentration in end-stage renal disease are then summarized along with clinical outcome studies with different dialysis strategies. Finally, we focuse on interventions in chronic kidney disease patients who are not yet on dialysis. We conclude that although there are more and more data on how to better remove uremic toxins by dialysis and nondialysis strategies, convincing evidence of the impact of these strategies on hard outcomes is much scarcer. PMID- 24780472 TI - Proteomics and metabolomics as tools to unravel novel culprits and mechanisms of uremic toxicity: instrument or hype? AB - The development of proteomic and metabolomic technologies holds the promise to significantly impact patient management by improving diagnosis, unraveling more appropriate therapeutic targets, and enabling more precise prognosis of disease development. Proteomics and metabolomics have been applied with the aim of improving dialysis, defining uremic toxins, and unraveling their origin. Ideally, these technologies should inform us which proteomic or metabolomic compounds are subject to significant alterations of concentration or structure as a result of failing kidney function, and thus can be considered as potential uremic toxins. After a few years of applying these technologies in the area of uremic toxicity studies we are now in a position where we can estimate how and what they can contribute to the field. In this review we critically examine the current literature on the application of proteomics and metabolomics in the context of dialysis and uremic toxins. We highlight the most promising findings, indicate where we see the current need, and which future developments consequently are to be expected, given the technological constraints that undoubtedly exist. PMID- 24780473 TI - The kidney and uremic toxin removal: glomerulus or tubule? AB - Chronic kidney disease (CKD) is a condition that affects approximately 10% of the adult population in developed countries. In patients with CKD adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also known as uremic toxins, are a heterogeneous group of organic compounds, many are too large to be filtered (middle molecules) or are protein-bound. Tubular secretion shifts the binding and allows for active secretion of such solutes. To mediate urinary solute excretion, renal proximal tubules are equipped with a range of transporters that cooperate in basolateral uptake and luminal excretion. These putative uremic toxins are poorly filtered across dialysis membranes because they are protein bound and current dialysis therapy does not correct the full spectrum of uremic toxicity. Residual renal function, which may represent an important contribution of solutes secreted by the proximal tubule rather than unreabsorbed filtrate, is an important predictor of survival of CKD patients. Many of the transporters that mediate the renal excretion of uremic retention solutes were first recognized as mediators of drug trafficking and drug-drug interactions, and a considerable amount of literature concerning the actions of these transporters antedates the recognition of their importance in the proximal renal tubular transport of uremic retention solutes. These transporters include members belonging to the organic cation/anion/zwitterion solute carrier family, such as the organic anion transporters (OAT)1, OAT3, and OATP4C1, and to the adenosine triphosphate binding cassette superfamily of transmembrane transporters, including the multidrug resistance proteins and breast cancer resistance protein. This article draws on this body of information to describe the renal tubular clearance mechanisms for uremic toxins, as well as the intracellular events associated with their accumulation, involving activation of the aryl hydrocarbon receptor, disturbance of mitochondrial functioning, and competition with metabolizing enzymes. PMID- 24780474 TI - Extracorporeal removal of uremic toxins: can we still do better? AB - Improving outcomes by manipulating the prescription of renal replacement therapy to increase the removal of uremic toxins has had limited success. Failure to achieve better outcomes can be attributed to the heterogenic nature of uremic toxins, the complex distribution of some toxins in the body, and the predominant regimen of thee times weekly, in-center hemodialysis. This review summarizes the various mechanisms and kinetics of removal for the three major classes of uremic toxin-small water-soluble solutes, middle molecules, and protein-bound solutes from both a theoretical and an experimental perspective. Taken together, the available data suggest that contemporary dialyzers are not a significant impediment to the removal of water-soluble uremic toxins, particularly when combined with commonly used blood and dialysis fluid flow rates and in online convective therapies. Enhancing the removal of those solutes will require a change in paradigm to longer and more frequent treatment sessions. Whether or not such a strategy also would improve the removal of protein-bound uremic toxins is less clear; that goal might require the development of different, more complex devices than those currently used for renal replacement therapy. PMID- 24780475 TI - Nonextracorporeal methods for decreasing uremic solute concentration: a future way to go? AB - The uremic milieu is consequential to a disrupted balance between availability of retention solutes and the excretory capacity of the kidneys. Although metabolism is the prime contributor to the internal milieu, a significant fraction of uremic retention solutes originates from other sources. The main route of entrance is via the intestinal tract, directly from the diet and indirectly from commensal microbial metabolism. This latter dynamic interplay between the intestines and kidney has been coined the gut-kidney axis. This review summarizes current understanding of the gut-kidney axis and explores the impact of dietary and other nonextracorporeal therapeutic interventions in patients with chronic kidney disease. PMID- 24780476 TI - Sublingual immunotherapy approved for grass pollen allergies. PMID- 24780477 TI - FDA defends generic drug labeling plan. PMID- 24780478 TI - Hospital earns financial rewards for inpatient MTM services. PMID- 24780479 TI - Direct engagement as part of collaborative practice improves diabetes care. PMID- 24780480 TI - The Aurora theater shooting: lessons learned in a department of pharmacy. PMID- 24780481 TI - Low back pain induced by i.v. amiodarone. PMID- 24780482 TI - Sustained virological response after taking crushed elvitegravir-cobicistat emtricitabine-tenofovir tablets. PMID- 24780483 TI - Verifying information in pharmacy residency applications. PMID- 24780484 TI - Verifying information in pharmacy residency applications. PMID- 24780485 TI - New practitioner engagement in continuous professional development. PMID- 24780486 TI - A common vision. PMID- 24780487 TI - Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, dosage, administration, and current role in therapy of a recently approved agent for controlling methotrexate toxicity are reviewed. SUMMARY: Glucarpidase is a bacterial enzyme useful in reversing toxicity induced by the widely used antineoplastic agent methotrexate. Glucarpidase gained U.S. marketing approval in 2012 for reducing serum methotrexate concentrations greater than 1 MUM/L in patients with delayed methotrexate clearance due to impaired renal function. In clinical trials, glucarpidase has been administered to a total of 3887 patients receiving high-dose methotrexate (i.e., doses of >=500 mg/m(2)), including pediatric patients. Patients treated with glucarpidase in addition to standard supportive care (hydration, urinary alkalization, leucovorin rescue, and, in some cases, hemodialysis) had a mean reduction in serum methotrexate levels of greater than 88%, with reductions occurring in a median of 15 minutes; however, up to 4.4% of adult patients and up to 6% of pediatric patients in clinical trial cohorts died despite glucarpidase use, suggesting the agent might not confer a survival advantage over supportive care alone. Glucarpidase is well tolerated; the most common adverse effects are flushing, nausea, vomiting, hypotension, and headache, which are typically grade 1 or 2 in severity and resolve without intervention. CONCLUSION: Glucarpidase is a well-tolerated and effective treatment for reducing serum methotrexate concentrations greater than 1 MUM/L in patients with impaired renal function. While there are few adverse effects associated with treatment, there may be little or no impact on methotrexate associated mortality. PMID- 24780488 TI - The art of team leadership. PMID- 24780489 TI - Care transitions service: a pharmacy-driven program for medication reconciliation through the continuum of care. AB - PURPOSE: A quality-improvement program at University of New Mexico Hospital (UNMH) encompassing admission, discharge, and postdischarge medication reconciliation activities is described, with a report on initial assessments of the program's impact on rates of medication-related problems (MRPs). METHODS: Pharmacists conducted a five-month evaluation of the UNMH Care Transitions Service (CTS), which serves inpatients admitted to the hospital's family medicine service, providing medication reconciliation and targeted MRP interventions. Selected patients who received CTS services from November 2012 through March 2013 (n = 191) were included in the analysis. The study endpoints were the rates and types of MRPs identified, the most commonly implicated medication classes, and predictors of MRPs. Postdischarge MRP rates during a two-month trial of CTS services at a UNMH outpatient clinic were also evaluated. RESULTS: During the five-month evaluation of inpatient CTS services, a total of 1140 MRPs were identified (an average of 6 per patient), about 70% of which were resolved independently of provider review using pharmacy-driven protocols. During the two month pilot test of CTS outpatient services (n = 16), a total of 28 MRPs were identified; in over 80% of cases, there was a decline in the number of MRPs from the admission to the postdischarge medication reconciliation. CONCLUSION: MRPs were identified through the continuum of care. The majority of MRPs identified in both the inpatient and outpatient settings involved patient variables and patient nonadherence. Seventy percent of inpatient MRPs were resolved independently by the CTS team under pharmacy-driven protocols. PMID- 24780491 TI - The pea seedling mitochondrial Nepsilon-lysine acetylome. AB - Posttranslational lysine acetylation is believed to occur in all taxa and to affect thousands of proteins. In contrast to the hundreds of mitochondrial proteins reported to be lysine-acetylated in non-plant species, only a handful have been reported from the plant taxa previously examined. To investigate whether this reflects a biologically significant difference or merely a peculiarity of the samples thus far examined, we immunoenriched and analyzed acetylated peptides from highly purified pea seedling mitochondria using mass spectrometry. Our results indicate that a multitude of mitochondrial proteins, involved in a variety of processes, are acetylated in pea seedlings. PMID- 24780490 TI - Gene markers of cellular aging in human multipotent stromal cells in culture. AB - INTRODUCTION: Human multipotent stromal cells (MSCs) isolated from bone marrow or other tissue sources have great potential to treat a wide range of injuries and disorders in the field of regenerative medicine and tissue engineering. In particular, MSCs have inherent characteristics to suppress the immune system and are being studied in clinical studies to prevent graft-versus-host disease. MSCs can be expanded in vitro and have potential for differentiation into multiple cell lineages. However, the impact of cell passaging on gene expression and function of the cells has not been determined. METHODS: Commercially available human MSCs derived from bone marrow from six different donors, grown under identical culture conditions and harvested at cell passages 3, 5, and 7, were analyzed with gene-expression profiling by using microarray technology. RESULTS: The phenotype of these cells did not change as reported previously; however, a statistical analysis revealed a set of 78 significant genes that were distinguishable in expression between passages 3 and 7. None of these significant genes corresponded to the markers established by the International Society for Cellular Therapy (ISCT) for MSC identification. When the significant gene lists were analyzed through pathway analysis, these genes were involved in the top scoring networks of cellular growth and proliferation and cellular development. A meta-analysis of the literature for significant genes revealed that the MSCs seem to be undergoing differentiation into a senescent cell type when cultured extensively. Consistent with the differences in gene expression at passage 3 and 7, MSCs exhibited a significantly greater potential for cell division at passage 3 in comparison to passage 7. CONCLUSIONS: Our results identified specific gene markers that distinguish aging MSCs grown in cell culture. Confirmatory studies are needed to correlate these molecular markers with biologic attributes that may facilitate the development of assays to test the quality of MSCs before clinical use. PMID- 24780492 TI - Synthetic lethality by co-targeting mitochondrial apoptosis and PI3K/Akt/mTOR signaling. AB - Small-molecule inhibitors that antagonize anti-apoptotic Bcl-2 proteins such as BH3 mimetics are currently considered as promising cancer therapeutics to engage the mitochondrial pathway of apoptosis in cancer cells. However, BH3 mimetics may be effective as monotherapy only in cancers that critically depend on anti apoptotic Bcl-2 proteins for their survival. Since most cancers have evolved multiple strategies to evade programmed cell death, concomitant targeting of several signaling transduction pathways becomes more and more relevant. The current review highlights the potential of combined inhibition of anti-apoptotic Bcl-2 proteins together with the PI3K/Akt/mTOR signaling cascade to trigger apoptosis in cancer cells. PMID- 24780493 TI - Mineral oil in human tissues, Part I: concentrations and molecular mass distributions. AB - Of 37 subjects aged 25-91 y (mean 67 y), mineral oil hydrocarbons were measured in subcutaneous abdominal fat tissue, mesenteric lymph nodes (MLN), spleen, liver and lung, for some of them also in kidney, heart and brain. No mineral oil aromatic hydrocarbons (MOAH) were detected. The mean concentration of mineral oil saturated hydrocarbons (MOSH) in the mesenteric lymph nodes was 223 mg/kg, in liver 131 mg/kg, in fat tissue 130 mg/kg, in spleen 93 mg/kg and in lung 12 mg/kg. They were clearly lower in kidney, heart and brain. The maxima, found in MLN and spleen, were 1390 and 1400 mg/kg, respectively. For a quarter of the subjects a total amount of MOSH in the body above 5 g was calculated. The MOSH composition in the fat tissue and the MLN appeared virtually identical and varied little between the subjects. It was centered on the n-alkanes C23-C24, ranged from C16 to C35 and included hydrocarbons of plant origin. The MOSH in spleen and liver had almost the same composition for a given subject, but varied somewhat between subjects. They were centered between C25 and C27, ranged from C18 to beyond C45 and were without hydrocarbons of plant origin. Part of the MOSH seem to be strongly accumulated, resulting in far higher concentrations in human tissues related to exposure than observed in shorter term animal experiments. The composition of the accumulated MOSH does not support that Class I mineral oils, sometimes termed "food grade", are less accumulated in the human body than Class II and III oils, which questions the present classification. PMID- 24780495 TI - Pathology of gliomas and developments in molecular testing. AB - Advances in technology are allowing a molecular characterisation of human brain tumours that is providing a wealth of new information. In this short overview, a summary of the histopathology of the common gliomas is integrated with some molecular data. In some instances, the data are proving clinically relevant with conventional therapies. Some single histological entities are being found to contain a number of molecular subtypes, whereas in others, different histological entities are found to be molecularly similar. The introduction of targeted therapies will necessitate a complete reassessment of the way we characterise tumours, and particularly the adequacy of our pathology reports in a new clinical environment. PMID- 24780494 TI - The spatiotemporal association of non-prescription retail sales with cases during the 2009 influenza pandemic in Great Britain. AB - OBJECTIVE: To assess whether retail sales of non-prescription products can be used for syndromic surveillance and whether it can detect influenza activity at different spatial scales. A secondary objective was to assess whether changes in purchasing behaviour were related to public health advice or levels of media or public interest. SETTING: The UK. PARTICIPANTS: National and regional influenza case estimates and retail sales from a major British supermarket. OUTCOME MEASURES: Weekly, seasonally adjusted sales of over-the-counter symptom remedies and non-pharmaceutical products; recommended as part of the advice offered by public health agencies; were compared with weekly influenza case estimates. Comparisons were made at national and regional spatial resolutions. We also compared sales to national measures of contemporaneous media output and public interest (Internet search volume) related to the pandemic. RESULTS: At a national scale there was no significant correlation between retail sales of symptom remedies and cases for the whole pandemic period in 2009. At the regional scale, a minority of regions showed statistically significant positive correlations between cases and sales of adult 'cold and flu' remedies and cough remedies (3.2%, 5/156, 3.8%, 6/156), but a greater number of regions showed a significant positive correlation between cases and symptomatic remedies for children (35.6%, 55/156). Significant positive correlations between cases and sales of thermometers and antiviral hand gels/wash were seen at both spatial scales (Cor 0.477 (95% CI 0.171 to 0.699); 0.711 (95% CI 0.495 to 0.844)). We found no significant association between retail sales and media reporting or Internet search volume. CONCLUSIONS: This study provides evidence that the British public responded appropriately to health messaging about hygiene. Non-prescription retail sales at a national level are not useful for the detection of cases. However, at finer spatial scales, in particular age-groups, retail sales may help augment existing surveillance and merit further study. PMID- 24780496 TI - Two-step grafting significantly enhances the survival of foetal dopaminergic transplants and induces graft-derived vascularisation in a 6-OHDA model of Parkinson's disease. AB - Following transplantation of foetal primary dopamine (DA)-rich tissue for neurorestaurative treatment of Parkinson's disease (PD), only 5-10% of the functionally relevant DAergic cells survive both in experimental models and in clinical studies. The current work tested how a two-step grafting protocol could have a positive impact on graft survival. DAergic tissue is divided in two portions and grafted in two separate sessions into the same target area within a defined time interval. We hypothesized that the first graft creates a "DAergic" microenvironment or "nest" similar to the perinatal substantia nigra that stimulates and protects the second graft. 6-OHDA-lesioned rats were sequentially transplanted with wild-type (GFP-, first graft) and transgenic (GFP+, second graft) DAergic cells in time interims of 2, 5 or 9days. Each group was further divided into two sub-groups receiving either 200k (low cell number groups: 2dL, 5dL, 9dL) or 400k cells (high cell number groups: 2dH, 5dH, 9dH) as first graft. During the second transplantation, all groups received the same amount of 200k GFP+ cells. Controls received either low or high cell numbers in one single session (standard protocol). Drug-induced rotations, at 2 and 6weeks after grafting, showed significant improvement compared to the baseline lesion levels without significant differences between the groups. Rats were sacrificed 8weeks after transplantation for post-mortem histological assessment. Both two-step groups with the time interval of 2days (2dL and 2dH) showed a significantly higher survival of DAergic cells compared to their respective standard control group (2dL, +137%; 2dH, +47%). Interposing longer intervals of 5 or 9days resulted in the loss of statistical significance, neutralising the beneficial two step grafting effect. Furthermore, the transplants in the 2dL and 2dH groups had higher graft volume and DA-fibre-density values compared to all other two-step groups. They also showed intense growth of GFP+ vessels - completely absent in control grafts - in regions where the two grafts overlap, indicating second-graft derived angiogenesis. In summary, the study shows that two-step grafting with a 2days time interval significantly increases DAergic cell survival compared to the standard protocol. Furthermore, our results demonstrate, for the first time, a donor-derived neoangiogenesis, leading to a new understanding of graft survival and development in the field of cell-replacement therapies for neurodegenerative diseases. PMID- 24780497 TI - Ketamine administered to pregnant rats in the second trimester causes long lasting behavioral disorders in offspring. AB - Commonly used anesthetic agents, e.g. ketamine, may be neurotoxic to the developing brain but there has been little attention to the neurobehavioral consequences for offspring when used for maternal anesthesia. We hypothesize that treatment of pregnant rats with ketamine during the second trimester would affect brain development of the offspring. Pregnant rats on gestational day 14, about equal to midtrimester pregnancy in humans, received a sedative dose of ketamine intravenously for 2h. Brain hippocampal morphology of their pups at postnatal days 0 (P0) and P30 was examined by Nissl-staining and the characteristics of dendrites were determined using the Golgi-Cox staining, while cell proliferation in subventricular zone (SVZ) and dentate gyrus (DG) was labeled with bromodeoxyuridine (BrdU). Their neurobehavioral functions were tested at P25-30 after which the NR1 and NR2 subunits of N-methyl-d-aspartate (NMDA) receptor, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD 95) in the hippocampus were analyzed by western blot. When pregnant rats were exposed to ketamine, there was neuronal loss, pyramidal neuronal abnormality and reduced cell proliferation in the hippocampus of offspring. These morphological abnormalities were associated with depression- and anxiety-like behaviors, and impaired memory up to young adult age. The treatment further caused NR2A receptor subunit up-regulation and NR2B receptor subunit, BDNF and PSD-95 down-regulation. These data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits. PMID- 24780498 TI - Neuroprotective effects of leptin in the context of obesity and metabolic disorders. AB - As the population of the world ages, the prevalence of neurodegenerative disease continues to rise, accompanied by increases in disease burden related to obesity and metabolic disorders. Thus, it will be essential to develop tools for preventing and slowing the progression of these major disease entities. Epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. Experimentally, the fat derived hormone leptin has been shown to act as a neuroprotective agent in various animal models of dementia, toxic insults, ischemia/reperfusion, and other neurodegenerative processes. Specifically, leptin minimizes neuronal damage induced by neurotoxins and pro-apoptotic conditions. Leptin has also demonstrated considerable promise in animal models of obesity and metabolic disorders via modulation of glucose homeostasis and energy intake. However, since obesity is known to induce leptin resistance, we hypothesize that resistance to the neuroprotective effects of leptin contributes to the pathogenesis of obesity associated neurodegenerative diseases. This review aims to explore the literature pertinent to the role of leptin in the protection of neurons from the toxic effects of aging, obesity and metabolic disorders, to investigate the physiological state of leptin resistance and its causes, and to consider how leptin might be employed therapeutically in the prevention and treatment of neurodegenerative disease. PMID- 24780499 TI - EFFORTLESS S-ICD registry: another step in the right direction. PMID- 24780500 TI - Impact of anatomical and functional severity of coronary atherosclerotic plaques on the transmural perfusion gradient: a [15O]H2O PET study. AB - BACKGROUND: Myocardial ischaemia occurs principally in the subendocardial layer, whereas conventional myocardial perfusion imaging provides no information on the transmural myocardial blood flow (MBF) distribution. Subendocardial perfusion measurements and quantification of the transmural perfusion gradient (TPG) could be more sensitive and specific for the detection of coronary artery disease (CAD). The current study aimed to determine the impact of lesion severity as assessed by the fractional flow reserve (FFR) on subendocardial perfusion and the TPG using [(15)O]H2O positron emission tomography (PET) imaging in patients evaluated for CAD. METHODS AND RESULTS: Sixty-six patients with anginal chest pain were prospectively enrolled and underwent [(15)O]H2O myocardial perfusion PET imaging. Subsequently, invasive coronary angiography was performed and FFR obtained in all coronary arteries irrespective of the PET imaging results. Thirty (45%) patients were diagnosed with significant CAD (i.e. FFR <=0.80), whereas on a per vessel analysis (n = 198), 53 (27%) displayed a positive FFR. Transmural hyperaemic MBF decreased significantly from 3.09 +/- 1.16 to 1.67 +/- 0.57 mL min(-1) g(-1) (P < 0.001) in non-ischaemic and ischaemic myocardium, respectively. The TPG decreased during hyperaemia when compared with baseline (1.20 +/- 0.14 vs. 0.94 +/- 0.17, P < 0.001), and was lower in arteries with a positive FFR (0.97 +/- 0.16 vs. 0.88 +/- 0.18, P < 0.01). A TPG threshold of 0.94 yielded an accuracy to detect CAD of 59%, which was inferior to transmural MBF with an optimal cutoff of 2.20 mL min(-1) g(-1) and an accuracy of 85% (P < 0.001). Diagnostic accuracy of subendocardial perfusion measurements was comparable with transmural MBF (83 vs. 85%, respectively, P = NS). CONCLUSION: Cardiac [(15)O]H2O PET imaging is able to distinguish subendocardial from subepicardial perfusion in the myocardium of normal dimensions. Hyperaemic TPG is significantly lower in ischaemic myocardium. This technique can potentially be employed to study subendocardial perfusion impairment in more detail. However, the diagnostic accuracy of subendocardial hyperaemic perfusion and TPG appears to be limited compared with quantitative transmural MBF, warranting further study. PMID- 24780502 TI - Activities of 2-phthalimidethanol and 2-phthalimidethyl nitrate, phthalimide analogs devoid of the glutarimide moiety, in experimental models of inflammatory pain and edema. AB - The reintroduction of thalidomide in the pharmacotherapy greatly stimulated the interest in the synthesis and pharmacological evaluation of phthalimide analogs with new and improved activities and also greater safety. In the present study, we evaluated the activities of two phthalimide analogs devoid of the glutarimide ring, namely 2-phthalimidethanol (PTD-OH) and 2-phthalimidethyl nitrate (PTD-NO), in experimental models of inflammatory pain and edema in male C57BL/6J mice. Intraplantar (i.pl.) injection of carrageenan (300 MUg) induced mechanical allodynia and this response was inhibited by previous per os (p.o.) administration of PTD-OH and PTD-NO (750 mg/kg) and also by thalidomide (500 or 750 mg/kg). The edema induced by carrageenan was also inhibited by previous p.o. administration of PTD-OH (500 and 750 mg/kg) and PTD-NO (125, 250, 500 or 750 mg/kg), but not by thalidomide. Carrageenan increased tumor necrosis factor (TNF) alpha and CXCL1 concentrations and also the number of neutrophils in the paw tissue. Previous p.o. administration of PTD-NO (500 mg/kg) reduced all the parameters, while PTD-OH (500 mg/kg) reduced only the accumulation of neutrophils. Thalidomide, on the other hand, was devoid of effect on these biochemical parameters. Plasma concentrations of nitrite were increased after p.o. administration of the phthalimide analog coupled to a NO donor, PTD-NO (500 mg/kg), but not after administration of PTD-OH or thalidomide. In conclusion, our results show that small molecules, structurally much simpler than thalidomide or many of its analogs under investigation, exhibit similar activities in experimental models of pain and inflammation. Finally, as there is evidence that the glutarimide moiety contributes to the teratogenic effect of many thalidomide analogs, our results indicate that phthalimide analogs devoid of this functional group could represent a new class of analgesic and anti-inflammatory candidates with potential greater safety. PMID- 24780501 TI - Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. AB - AIM: High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. OBJECTIVE: To investigate the effects of an HDL mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). DESIGN AND SETTING: A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. PATIENTS: Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. INTERVENTION: Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. MAIN OUTCOME MEASURES: The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. RESULTS: The nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, 0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. CONCLUSION: CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study. Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; TRIAL REGISTRATION NUMBER: NCT01201837. PMID- 24780503 TI - Spatial learning in the Morris water maze in mice genetically different in the predisposition to catalepsy: the effect of intraventricular treatment with brain derived neurotrophic factor. AB - Hereditary catalepsy in mice is accompanied with volume reduction of some brain structures and high vulnerability to inflammatory agents. Here an association between hereditary catalepsy and spatial learning deficit in the Morris water maze (MWM) in adult mouse males of catalepsy-resistant AKR, catalepsy-prone CBA and AKR.CBA-D13Mit76 (D13) strains was studied. Recombinant D13 strain was created by means of the transfer of the CBA-derived allele of the major gene of catalepsy to the AKR genome. D13 mice showed a low MWM performance in the acquisition test and high expression of the gene coding proinflammatory interleukin-6 (Il-6) in the hippocampus and cortex compared with mice of the parental AKR and CBA strains. An acute ivc administration of 300 ng of brain derived neurotrophic factor (BDNF) normalized the performance in the MWM, but did not decrease the high Il-6 gene expression in the brain of D13 mice. These results indicated a possible association between the hereditary catalepsy, MWM performance, BDNF and level of Il-6 mRNA in the brain, although the relation between these characteristics seems to be more complex. D13 recombinant mice with deficit of spatial learning is a promising model for study of the genetic and molecular mechanisms of learning disorders as well as for screening potential cognitive enhancers. PMID- 24780504 TI - Experimental evidence for involvement of nitric oxide in low frequency magnetic field induced obsessive compulsive disorder-like behavior. AB - It is well documented that extremely low frequency magnetic field (ELF MF) produced effects on the function of nervous system in humans and laboratory animals. Dopaminergic and serotonergic pathways have been implicated in obsessive compulsive disorder (OCD). Recently involvement of nitric oxide (NO) in OCD-like behavior is suggested. Hence, the present study was carried out to understand the involvement of dopamine, serotonin and NO in ELF MF induced OCD-like behavior. Swiss albino mice were exposed to ELF MF (50 Hz, 10G) for 8 h/day for 7, 30, 60, 90 and 120 days by subjecting them to Helmholtz coils. OCD-like behavior was assessed in terms of marble burying behavior (MBB) test. Results revealed that ELF MF induced time dependant MBB, on 7th, 30th, 60th, 90th, and 120th exposure day. Further, levels of dopamine, serotonin and NO after 120 days of ELF MF exposure were determined in the regions of the brain. The neurohumoral studies revealed that exposure to ELF MF increased NO levels in cortex, hippocampus and hypothalamus, and levels of dopamine and serotonin remain unaffected. As OCD-like behavior after ELF MF exposure was associated with higher levels of NO with no significant change in serotonin and dopamine. The effect of such exposure was studied in groups concurrently treated with NO modulators, NO precursor, L-ARG (400 mg/kg) or NOS inhibitor, L-NAME (15.0mg/kg) or 7-NI (10.0 mg/kg). These treatments revealed that NO precursor exacerbated and NOS inhibitors attenuated ELF MF induced OCD-like behavior with corresponding changes in the levels of NO. PMID- 24780505 TI - Facilitation of high-rate NADH electrocatalysis using electrochemically activated carbon materials. AB - Electrochemical activation of glassy carbon, carbon paper and functionalized carbon nanotubes via high-applied-potential cyclic voltammetry leads to the formation of adsorbed, redox active functional groups and increased active surface area. Electrochemically activated carbon electrodes display enhanced activity toward nicotinamide adenine dinucleotide (NADH) oxidation, and more importantly, dramatically improved adsorption of bioelectrochemically active azine dyes. Adsorption of methylene green on an electroactivated carbon electrode yields a catalyst layer that is 1.8-fold more active toward NADH oxidation than an electrode prepared using electropolymerized methylene green. Stability studies using cyclic voltammetry indicate 70% activity retention after 4000 cycles. This work further facilitates the electrocatalysis of NADH oxidation for bioconversion, biosensor and bioenergy processes. PMID- 24780506 TI - The role of eating frequency on total energy intake and diet quality in a low income, racially diverse sample of schoolchildren. AB - OBJECTIVE: The relationship of meal and snacking patterns with overall dietary intake and relative weight in children is unclear. The current study was done to examine how eating, snack and meal frequencies relate to total energy intake and diet quality. DESIGN: The cross-sectional associations of eating, meal and snack frequencies with total energy intake and diet quality, measured by the Healthy Eating Index 2005 (HEI-2005), were examined in separate multivariable mixed models. Differences were examined between elementary school-age participants (9 11 years) and adolescents (12-15 years). SETTING: Two non-consecutive 24 h diet recalls were collected from children attending four schools in the greater Boston area, MA, USA. SUBJECTS: One hundred and seventy-six schoolchildren, aged 9-15 years. RESULTS: Overall, 82% of participants consumed three daily meals. Eating, meal and snack frequencies were statistically significantly and positively associated with total energy intake. Each additional reported meal and snack was associated with an 18.5% and a 9.4% increase in total energy intake, respectively (P<0.001). The relationships of eating, meal and snack frequencies with diet quality differed by age category. In elementary school-age participants, total eating occasions and snacks increased HEI-2005 score. In adolescents, each additional meal increased HEI-2005 score by 5.40 points (P=0.01), whereas each additional snack decreased HEI-2005 score by 2.73 points (P=0.006). CONCLUSIONS: Findings suggest that snacking increases energy intake in schoolchildren. Snacking is associated with better diet quality in elementary school-age children and lower diet quality in adolescents. Further research is needed to elucidate the role of snacking in excess weight gain in children and adolescents. PMID- 24780508 TI - A milestone-based approach to breast imaging instruction for residents. AB - Residency is historically an apprenticeship, learning through observation and instruction with varying degrees of structure. Since July 2013, the Next Accreditation System (NAS) of the ACGME has required the use of progressive milestones for each radiology residency rotation. The authors describe how a breast imaging curriculum can be structured to comply with the NAS. The breast imaging rotations move from basic recognition and management of suspicious findings, through the detection of more subtle findings and learning of biopsy skills, and finally to the synthesis and management of more advanced findings. Likewise, patient communication moves from sharing imaging findings to the more challenging situation of breaking the bad news of a cancer diagnosis. This progression of skills mirrors the objectives of levels 1 to 4 of the NAS. Learning objectives have been adapted to form very specific milestones for each rotation, which results in a shared responsibility between residents and faculty members. Using clear expectations may improve the uniformity of teaching, resident satisfaction, and facilitate performance review for residents who are struggling. Didactic lectures, case-based conferences, teaching file cases, and assigned readings provide different approaches to education, allowing variation in learning styles. Performance on the breast imaging section on the ACR Diagnostic Radiology In-Training examination at our institution has risen from below the 50th percentile to around the 80th percentile beginning in 2011. PMID- 24780507 TI - Tryps and trips: cell trafficking across the 100-year-old blood-brain barrier. AB - One hundred years ago, Edwin E. Goldmann discovered the blood-brain barrier (BBB) using trypan dyes. These dyes were developed and named by Paul Ehrlich during his search for drugs to kill African trypanosomes (extracellular parasites that cause sleeping sickness) while sparing host cells. For Ehrlich, this was the first strategy based on the 'chemotherapy' concept he had introduced. The discovery of the BBB revealed, however, the difficulties in drug delivery to the brain. Mechanisms by which parasites enter, dwell, and exit the brain currently provide novel views on cell trafficking across the BBB. These mechanisms also highlight the role of pericytes and endocytosis regulation in BBB functioning and in disrupted BBB gating, which may be involved in the pathogenesis of neurodegeneration. PMID- 24780509 TI - The scope and distribution of imaging services at critical access hospitals. AB - PURPOSE: The purpose of this study was to better understand the availability and scope of imaging services at critical access hospitals (CAHs) throughout the United States. METHODS: Recent American Hospital Association (AHA) annual survey data (containing 1,063 variables providing comprehensive information on organizational characteristics and availability of various services at 6,317 hospitals nationwide) and US census data were merged. Imaging survey data included mammography, ultrasound, CT, MRI, single photon emission CT, and combined PET/CT. Availability and characteristics of imaging services at the 1,060 CAHs in 45 states for which sufficient data were available were studied. RESULTS: Mammography, ultrasound, and some form of CT were the most widely available of all imaging services, but were available in all CAHs in only 13%, 33%, and 56% of all states, respectively. In no states were >=64-slice CT, MRI, single photon emission CT, and combined PET/CT available in all CAHs. CONCLUSIONS: An overall scarcity of access to imaging services exists at CAHs throughout the United States. With 19.3% of the US population residing in rural areas and almost entirely dependent on CAHs for health services, the policy implications for imaging access could be profound. Further research is necessary to investigate the effect of imaging access on CAH patient outcomes. PMID- 24780510 TI - Authors' reply. PMID- 24780511 TI - A three-tier framework for monitoring antiretroviral therapy in high HIV burden settings. AB - The provision of antiretroviral therapy (ART) in low and middle-income countries is a chronic disease intervention of unprecedented magnitude and is the dominant health systems challenge for high-burden countries, many of which rank among the poorest in the world. Substantial external investment, together with the requirement for service evolution to adapt to changing needs, including the constant shift to earlier ART initiation, makes outcome monitoring and reporting particularly important. However, there is growing concern at the inability of many high-burden countries to report on the outcomes of patients who have been in care for various durations, or even the number of patients in care at a particular point in time. In many instances, countries can only report on the number of patients ever started on ART. Despite paper register systems coming under increasing strain, the evolution from paper directly to complex electronic medical record solutions is not viable in many contexts. Implementing a bridging solution, such as a simple offline electronic version of the paper register, can be a pragmatic alternative. This paper describes and recommends a three-tiered monitoring approach in low- and middle-income countries based on the experience implementing such a system in the Western Cape province of South Africa. A three tier approach allows Ministries of Health to strategically implement one of the tiers in each facility offering ART services. Each tier produces the same nationally required monthly enrolment and quarterly cohort reports so that outputs from the three tiers can be aggregated into a single database at any level of the health system. The choice of tier is based on context and resources at the time of implementation. As resources and infrastructure improve, more facilities will transition to the next highest and more technologically sophisticated tier. Implementing a three-tier monitoring system at country level for pre-antiretroviral wellness, ART, tuberculosis and mother and child health services can be an efficient approach to ensuring system-wide harmonization and accurate monitoring of services, including long term retention in care, during the scale-up of electronic monitoring solutions. PMID- 24780512 TI - International Alzheimer's Disease Research Portfolio (IADRP) aims to capture global Alzheimer's disease research funding. AB - Alzheimer's disease (AD) is a recognized international public health crisis. There is an urgent need for public and private funding agencies around the world to coordinate funding strategies and leverage existing resources to enhance and expand support of AD research. To capture and compare their existing investments in AD research and research-related resources, major funding organizations are starting to utilize the Common Alzheimer's Disease Research Ontology (CADRO) to categorize their funding information. This information is captured in the International Alzheimer's Disease Research Portfolio (IADRP) for further analysis. As of January, 2014, over fifteen organizations from the US, Canada, Europe and Australia have contributed their information. The goal of the IADRP project is to enable funding organizations to assess the changing landscape of AD research and coordinate strategies, leverage resources, and avoid duplication of effort. PMID- 24780513 TI - Factors determining the total serum antioxidant capacity in men with coronary heart disease--the powerful effect of treatment with thienopyridines. PMID- 24780514 TI - Potassium-rich diet and risk of stroke: updated meta-analysis. AB - Recently a few prospective population studies provided additional and heterogeneous information concerning the reported statistical associations between potassium (K) intake and stroke risk. Therefore, we updated our previous meta-analysis of K intake and risk of cerebrovascular events. Three studies were added to the previous analysis, and the results of the comparison between the event rate in the two extreme categories of K intake were used. Pooled analysis of 14 cohorts (overall 333,250 participants and 10,659 events) showed an inverse and significant association between K intake and risk of stroke (Relative Risk: 0.80; 95% CI: 0.72-0.90). Our results indicated a favorable effect of higher K intake on risk of stroke. These results confirm the appropriateness of worldwide recommendations for a population increased consumption of potassium-rich foods to prevent cardiovascular disease. PMID- 24780516 TI - Putting the diabetes risk due to statins in perspective: a re-evaluation using the complementary outcome. AB - AIMS: Statins are used extensively to treat dyslipidemia and have been associated with significant clinical benefit that increases with dose. However, recent studies have associated statins with an excess risk of developing diabetes mellitus, which may offset the clinical benefit to patients. Adverse events related to intensive-dose statin therapy were revisited in light of recent data regarding the use of relative risks. DATA SYNTHESIS: A meta-analysis was replicated with the event of interest redefined as the complementary outcome (no onset of diabetes). Five randomised controlled trials that compared the risk of intense-dose with moderate-dose of statin therapy for the onset of diabetes with a follow-up greater than 12 months were included in the analysis. A reduction in the risk for no-onset of diabetes was found when intensive-dose statin therapy was compared with moderate-dose statin therapy, revealing a relative risk of 0.9908 (95%CI: 0.9849-0.99679). Over two years, one more patient was harmed by diabetes onset for every 237 patients exposed to intensive-dose statin therapy (95%CI: 123-3847) compared with standard dose statin therapy. CONCLUSIONS: Statins are associated with only a very small increase in risk of diabetes mellitus. Previous research selected the outcomes with the lower baseline risks and therefore the actual risk associated with statins has been largely over estimated. PMID- 24780515 TI - Chronic kidney disease in type 2 diabetes: lessons from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study. AB - The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study is an ongoing observational survey that examines the role of estimated glomerular filtration rate (eGFR) as an independent predictor of cardiovascular and renal outcomes in 15,773 Italian subjects with type 2 diabetes. The analysis of data collected at the enrollment visit provided a picture of chronic kidney disease (CKD) and its association with other complications, risk factors for cardiovascular disease (CVD) and treatments in a large contemporary cohort. Main results of this analysis were that (a) non-albuminuric renal impairment is the predominant clinical phenotype in patients, particularly women, with reduced eGFR; (b) concordance between CKD and diabetic retinopathy is low, with only a minority of patients with renal dysfunction presenting with any or advanced retinal lesions; (c) the non-albuminuric form is associated with a significant prevalence of CVD, especially at the level of the coronary vascular bed; (d) CKD is associated with hemoglobin (Hb) A1c variability more than with average HbA1c, whereas retinopathy and CVD are not; (e) in elderly individuals with moderate-to severe eGFR reduction, use of agents which are not recommended, such as sulphonylureas and metformin, is still frequent; and (f) though complications are generally more prevalent in men (except non-albuminuric renal impairment) women show a less favorable CVD risk profile and achieve therapeutic targets to a lesser extent than men, despite the fact that treatment intensity is not lower. These data update existing information on the natural history of CKD in patients with type 2 diabetes. PMID- 24780517 TI - When to say when. PMID- 24780518 TI - Reply to letter: Re: Use of rapid sequence intubation predicts improved survival among patients intubated after out-of-hospital cardiac arrest. PMID- 24780519 TI - Re: Use of rapid sequence intubation predicts improved survival among patients intubated after out-of-hospital cardiac arrest. PMID- 24780520 TI - Authors' reply to Boucher. PMID- 24780521 TI - Enrichment of cells with TALEN-induced mutations using surrogate reporters. AB - Targeted gene knockout using engineered nucleases such as transcription activator like-effector nucleases (TALENs) is a gold standard for investigating the functions of a gene of interest. Although most TALENs can cleave chromosomal DNA efficiently, the activities of designed TALENs are not always high enough to allow the efficient derivation of cells containing TALEN-driven mutations. Thus, simple methods to enrich cells containing TALEN-directed mutations would facilitate the use of TALENs. Here we describe the enrichment of such cells using surrogate episomal reporters coupled with flow cytometric sorting, magnetic separation, or hygromycin selection. PMID- 24780522 TI - The application of transcription activator-like effector nucleases for genome editing in C. elegans. AB - The nematode Caenorhabditis elegans has been a powerful model system for biomedical research in the past decades, however, the efficient genetic tools are still demanding for gene knockout, knock-in or conditional gene mutations. Transcription activator-like effector nucleases (TALENs) that comprise a sequence specific DNA-binding domain fused to a FokI nuclease domain facilitate the targeted genome editing in various cell types or organisms. Here we summarize the recent progresses and protocols using TALENs in C. elegans that generate gene mutations and knock-ins in the germ line and the conditional gene knockout in somatic tissues. PMID- 24780525 TI - Comments on "Modeled PM2.5 removal by trees in ten U.S. cities and associated health effects" by Nowak et al. (2013). PMID- 24780523 TI - Methodological considerations for heat shock of the nematode Caenorhabditis elegans. AB - Stress response pathways share commonalities across many species, including humans, making heat shock experiments valuable tools for many biologists. The study of stress response in Caenorhabditis elegans has provided great insight into many complex pathways and diseases. Nevertheless, the heat shock/heat stress field does not have consensus as to the timing, temperature, or duration of the exposure and protocols differ extensively between laboratories. The lack of cohesiveness makes it difficult to compare results between groups or to know where to start when preparing your own protocol. We present a discussion of some of the major hurdles to reproducibility in heat shock experiments as well as detailed protocols for heat shock and hormesis experiments. PMID- 24780526 TI - Behavior change and reducing health disparities. AB - The mission of the National Institutes of Health,"... is science in pursuit of fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability". A wide range of factors contribute to longer life and to less illness. Although estimates vary, most analyses suggest that only about 10% of the variation in health outcome is attributable to medical care. Further, medical care is most effective in addressing and preventing infectious disease and acute illnesses. Recent large randomized clinical trials often fail to demonstrate that medical care lengthens life expectancy. International comparisons suggest that life expectancy in the United States is increasing, but the rate of increase is falling behind that of other wealthy countries. Strategies for improving health outcomes include better dissemination and implementation of proven evidence-based interventions. Further, reduction of services that use resources but do not offer health benefits must be considered. The final section of this paper reviews evidence relevant to factors outside the health care system that may enhance life expectancy and reduce illness and the disability. The relationship between educational attainment and life expectancy is used as a case example. The potential of behavioral and social interventions for increasing life expectancy may be orders of magnitude greater than traditional medial interventions. However, considerably more research is necessary in order to provide persuasive evidence for the benefits of these programs. PMID- 24780527 TI - Tobacco control environment in the United States and individual consumer characteristics in relation to continued smoking: differential responses among menthol smokers? AB - OBJECTIVE: We used a consumer panel augmented with state-specific measures of tobacco control activities to examine the main effects and interactions among consumer behaviors, particularly menthol cigarette smoking, and tobacco control environment on cessation over a six-year period. METHODS: We used the Nielson Homescan Panel, which tracks consumer purchasing behaviors, and tobacco control information matched to panelist zip code. We focused on 1582 households purchasing >=20 packs from 2004 to 2009. Our analysis included demographics; purchasing behavior including menthol versus nonmenthol use (>=80% of cigarettes purchased being menthol), quality preferences (average price/pack), purchase recency, and nicotine intake (nicotine levels of cigarettes purchased); and tobacco control metrics (taxation, anti-tobacco advertising, smoke-free policies). RESULTS: Menthol smoking (Hazard Ratio [HR]=0.79, 95% Confidence Interval [CI] 0.64, 0.99), being African American (HR=0.67, CI 0.46, 0.98), being male (HR=0.46, CI 0.28, 0.74), higher quality premium preferences (HR=0.80, CI 0.77, 0.91), lower recency (HR=1.04, CI 1.02, 1.05), and higher nicotine intake rates (HR=0.99, CI 0.99, 0.99) were related to continued smoking. No significant interactions were found. CONCLUSION: While there were no interactions between menthol use and effects of tobacco control activities, we did find additional support for the decreased cessation rates among menthol cigarette smokers, particularly in the African American population. PMID- 24780528 TI - Robustness and management adaptability in tropical rangelands: a viability-based assessment under the non-equilibrium paradigm. AB - Rangelands provide the main forage resource for livestock in many parts of the world, but maintaining long-term productivity and providing sufficient income for the rancher remains a challenge. One key issue is to maintain the rangeland in conditions where the rancher has the greatest possibility to adapt his/her management choices to a highly fluctuating and uncertain environment. In this study, we address management robustness and adaptability, which increase the resilience of a rangeland. After reviewing how the concept of resilience evolved in parallel to modelling views on rangelands, we present a dynamic model of rangelands to which we applied the mathematical framework of viability theory to quantify the management adaptability of the system in a stochastic environment. This quantification is based on an index that combines the robustness of the system to rainfall variability and the ability of the rancher to adjust his/her management through time. We evaluated the adaptability for four possible scenarios combining two rainfall regimes (high or low) with two herding strategies (grazers only or mixed herd). Results show that pure grazing is viable only for high-rainfall regimes, and that the use of mixed-feeder herds increases the adaptability of the management. The management is the most adaptive with mixed herds and in rangelands composed of an intermediate density of trees and grasses. In such situations, grass provides high quantities of biomass and woody plants ensure robustness to droughts. Beyond the implications for management, our results illustrate the relevance of viability theory for addressing the issue of robustness and adaptability in non-equilibrium environments. PMID- 24780529 TI - Evolution of droplets in subsea oil and gas blowouts: development and validation of the numerical model VDROP-J. AB - The droplet size distribution of dispersed phase (oil and/or gas) in submerged buoyant jets was addressed in this work using a numerical model, VDROP-J. A brief literature review on jets and plumes allows the development of average equations for the change of jet velocity, dilution, and mixing energy as function of distance from the orifice. The model VDROP-J was then calibrated to jets emanating from orifices ranging in diameter, D, from 0.5 mm to 0.12 m, and in cross-section average jet velocity at the orifice ranging from 1.5 m/s to 27 m/s. The d50/D obtained from the model (where d50 is the volume median diameter of droplets) correlated very well with data, with an R(2)=0.99. Finally, the VDROP-J model was used to predict the droplet size distribution from Deepwater Horizon blowouts. The droplet size distribution from the blowout is of great importance to the fate and transport of the spilled oil in marine environment. PMID- 24780531 TI - Congenital muscular dystrophy and generalized epilepsy caused by GMPPB mutations. AB - The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (alpha-DG). Alpha dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutations were recently linked to eight cases of alpha dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. This article is part of a Special Issue entitled RNA Metabolism 2013. PMID- 24780532 TI - Combusted but not smokeless tobacco products cause DNA damage in oral cavity cells. AB - The aim of this work was to investigate genomic DNA damage in human oral cavity cells after exposure to different tobacco product preparations (TPPs). The oral carcinoma cell line 101A, gingival epithelial cells HGEC, and gingival fibroblasts HGF were exposed to TPM (total particulate matter from 3R4F cigarettes), ST/CAS (2S3 smokeless tobacco extract in complete artificial saliva), and NIC (nicotine). Treatments were for 24 h using TPM at its EC-50 doses, ST/CAS and NIC at doses with equi-nicotine units, and high doses for ST/CAS and NIC. Comet assays showed that TPM, but not ST/CAS or NIC, caused substantial DNA breaks in cells; only the high ST/CAS dose caused weak DNA damage. These results were confirmed by immunofluorescence for gamma-H2AX protein. These data revealed that the combusted TPP caused substantial DNA damage in all cell types, whereas the two non-combusted TPPs exerted no or only minimal DNA damage. They support epidemiologic evidence on the relative risk associated with consumption of non-combusted versus combusted tobacco products, and help to understand potential genotoxic effects of such products on oral cavity cells. PMID- 24780530 TI - Altered serine/threonine kinase activity in schizophrenia. AB - Converging evidence implicates alterations in multiple signaling pathways in the etiology of schizophrenia. Previously, these studies were limited to the analysis of one or a few phosphoproteins at a time. Here, we use a novel kinase array platform to simultaneously investigate the convergence of multiple signaling cascades implicated in schizophrenia. This technology uses consensus peptide substrates to assess activity levels of a large number (>100) of serine/threonine protein kinases. 19 peptide substrates were differentially phosphorylated (>15% change) in the frontal cortex in schizophrenia. These peptide substrates were examined using Ingenuity Pathway Analysis to group them according to the functions and to identify processes most likely affected in schizophrenia. Pathway analysis placed 14 of the 19 peptides into cellular homeostatic pathways, 10 into pathways governing cytoskeletal organization, and 8 into pathways governing ion homeostasis. These data are the first to simultaneously investigate comprehensive changes in signaling cascades in a severe psychiatric disorder. The examination of kinase activity in signaling pathways may facilitate the identification of novel substrates for drug discovery and the development of safer and more effective pharmacological treatment for schizophrenia. PMID- 24780533 TI - Potential matrix metalloproteinase inhibitors from edible marine algae: a review. AB - Matrix metalloproteinases are endopeptidases which belong to the group of metalloproteinases that contribute for the extra-cellular matrix degradation, and several tissue remodeling processes. An imbalance in the regulation of these endopeptidases eventually leads to several severe pathological complications like cancers, cardiac, cartilage, and neurological related diseases. Hence inhibitory substances of metalloproteinases (MMPIs) could prove beneficial in the management of above specified pathological conditions. The available synthetic MMPIs that have been reported until now have few shortcomings and thus many of them could not make to the final clinical trials. Hence a growing interest among researchers on screening of MMPIs from different natural resources is evident and especially natural products from marine origin. As there has been an unparalleled contribution of several biologically active compounds from marine resources that have shown profound applications in nutraceuticals, cosmeceuticals, and pharmaceuticals, we have attempted to discuss the various MMPIs from edible sea weeds. PMID- 24780534 TI - The effect of glyphosate, its metabolites and impurities on erythrocyte acetylcholinesterase activity. AB - Glyphosate [N-(phosphonomethyl)glycine] is used all over the world to protect agricultural and horticultural crops. According to initial reports, glyphosate has been considered to be safe for humans and animals; nevertheless, recent investigations had proven its toxicity. Extensive use of glyphosate and the conviction of its low toxicity leads to a situation in which it is used in excessive amounts in agriculture. That is why, we have investigated the effect of the most commonly used pesticide: glyphosate, its metabolites and impurities on acetylcholinesterase (AChE) activity (in vitro) in human erythrocytes, which is biochemically similar to acetylcholinesterase present in neural synapses. The analysis of noxious effects of metabolites and impurities of pesticides seems to be very important to evaluate toxicological risk that is associated with the effect of pesticide formulations (requirement of the EU regulations 1107/200/EC). The erythrocytes were incubated with xenobiotics at concentrations range from 0.01 to 5 mM for 1 and 4 h. Statistically significant decrease in AChE activity (about 20%) was observed only at high concentrations of the compounds (0.25-5 mM), which enter body only as a result of acute poisoning. There were no statistically significant differences in the effect of the investigated compounds, while the changes caused by them were similar after 1 and 4 h incubation. The investigated metabolites and impurities did not cause stronger changes in AChE activity than glyphosate itself. It may be concluded that the compounds studied (used in the concentrations that are usually determined in the environment) do not disturb function of human erythrocyte acetylcholinesterase. PMID- 24780535 TI - Surface structures of gill, scale and erythrocyte of Anabas testudineus exposed to sublethal concentration of cypermethrin. AB - The present study was undertaken to assess the toxicity of sublethal concentrations (0.015, 0.030 and 0.045 ppm) of cypermethrin on the gills, scales and erythrocytes of Anabas testudineus for 21 days. The morphological changes on the gills, scales and erythrocytes of the A. testudineus were observed using scanning electron microscope (SEM). The SEM studies on all the three treated groups revealed several kinds of gills, scales and erythrocytes alterations and modifications with abnormal morphology. Gill alterations included highly active mucous cells, epithelial hyperplasia, fusion of secondary lamellae and epithelial lifting. The scales showed damaged lepidonts. Abnormal erythrocytes (shrunken cells), oozed out cytoplasmic content and lobopodial projections were observed in the erythrocytes of fish after exposure to cypermethrin. PMID- 24780536 TI - Diagnosing dying: an integrative literature review. AB - BACKGROUND: To ensure patients and families receive appropriate end-of-life care pathways and guidelines aim to inform clinical decision making. Ensuring appropriate outcomes through the use of these decision aids is dependent on timely use. Diagnosing dying is a complex clinical decision, and most of the available practice checklists relate to cancer. There is a need to review evidence to establish diagnostic indicators that death is imminent on the basis of need rather than a cancer diagnosis. AIM: To examine the evidence as to how patients are judged by clinicians as being in the final hours or days of life. DESIGN: Integrative literature review. DATA SOURCES: Five electronic databases (2001-2011): Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, PsycINFO and CINAHL. The search yielded a total of 576 hits, 331 titles and abstracts were screened, 42 papers were retrieved and reviewed and 23 articles were included. RESULTS: Analysis reveals an overarching theme of uncertainty in diagnosing dying and two subthemes: (1) 'characteristics of dying' involve dying trajectories that incorporate physical, social, spiritual and psychological decline towards death; (2) 'treatment orientation' where decision making related to diagnosing dying may remain focused towards biomedical interventions rather than systematic planning for end-of-life care. CONCLUSIONS: The findings of this review support the explicit recognition of 'uncertainty in diagnosing dying' and the need to work with and within this concept. Clinical decision making needs to allow for recovery where that potential exists, but equally there is the need to avoid futile interventions. PMID- 24780537 TI - Jet lag. AB - INTRODUCTION: Jet lag is a syndrome caused by disruption of the 'body clock', and affects most air travellers crossing five or more time zones; it is worse on eastward than on westward flights. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions to prevent or minimise jet lag? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found five studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: hypnotics, lifestyle and environmental adaptations, and melatonin. PMID- 24780538 TI - Thrombus in transit: a link between pulmonary embolism and neurological embolic events. PMID- 24780539 TI - "Double takotsubo": first description of the sequence of classical followed by inverted type in a young woman. PMID- 24780540 TI - Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus. AB - BACKGROUND: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. METHODS AND RESULTS: A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. CONCLUSIONS: The current data suggest that in selected patients and support out of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made. PMID- 24780541 TI - Low fasting plasma glucose level predicts morbidity and mortality in symptomatic adults with congenital heart disease. AB - BACKGROUND: Adults with complex congenital heart disease (ACHD) have a high prevalence of abnormal glucose regulation (AGR: impaired glucose tolerance and diabetes mellitus). However, the impact of AGR on the prognosis remains unclear. PURPOSE: Our purpose was to clarify the prognostic value of AGR in ACHD. METHODS AND RESULTS: We performed a 75 g oral glucose tolerance test in 438 consecutive patients with ACHD (age 26 +/- 8 years), including 38 unrepaired, 148 Fontan, 252 biventricular, and 27 healthy subjects and investigated associations between AGR and clinical events that required hospitalization or caused deaths from all causes. When compared with the healthy group, fasting blood glucose level (FPG, mg/dl) was lower in the unrepaired and Fontan subjects (p<0.05-0.01) and the prevalence of low FPG (<= 80 mg/dl) was also higher in the unrepaired (58%), Fontan (47%), and biventricular group (33%) than in the healthy control (11%) (p<0.0001). Postprandial hyperglycemia (area under the curve of glucose: PG-AUC) was higher in all ACHD groups (p<0.0001 for all). New York Heart Association class and lower FPG independently predicted the hospitalization (FPG <= 84 mg/dl) and mortality (FPG <= 80 mg/dl) (p<0.05-0.0001), while the PG-AUC was not an independent predictor. When compared with the asymptomatic ACHD, symptomatic ACHD with lower FPG had high hazard ratios of 2.2 (95% confidence interval [CI]: 1.3 3.8, p<0.002) and 3.3 (95% CI: 1.2-11.9, p<0.03) for the hospitalizations and all cause mortality, respectively. CONCLUSIONS: Low FPG is not uncommon in ACHD and the low FPG predicts the morbidity and all-cause mortality in symptomatic ACHD. PMID- 24780542 TI - Vascular access complications in patients with continuous-flow left ventricle assist device undergoing percutaneous invasive procedures: a word of caution. PMID- 24780543 TI - Takotsubo cardiomyopathy in the setting of necrotizing myopathy. PMID- 24780544 TI - The rebound phenomenon after aspirin cessation: the biochemical evidence. PMID- 24780545 TI - An unusual defibrillator lead complication identified at explant. PMID- 24780546 TI - Abnormal hemostatic parameters in patients with myocardial infarction but angiographically normal coronary arteries. PMID- 24780547 TI - Use of optical coherence tomography in acute clinical settings. PMID- 24780548 TI - Remote ICD-monitoring in detection and follow-up of triggers of idiopathic ventricular fibrillation: implications for the clinical management of IVF patients. PMID- 24780549 TI - The status of IRBs/ECs, ICFs and trial registration in clinical trials of traditional Chinese medicine for stable angina. PMID- 24780550 TI - Protective role of peroxisome proliferator-activated receptor beta/delta in acute lung injury induced by prolonged hyperbaric hyperoxia in rats. AB - Peroxisome proliferator-activated receptor (PPAR)-beta/delta is a transcription factor that belongs to the PPAR family, but the role of PPAR-beta/delta in acute lung injury (ALI) induced by hyperbaric oxygen is unknown. In this study we investigated if PPAR-beta/delta activation protects from hyperoxia-induced ALI in a rat model. ALI was induced by prolonged hyperbaric oxygen (HBO2) (2.3ATA, 100% O2) for 8h. Administration of PPAR-beta/delta agonist GW0742 (0.3mg/kg, i.p.) at 1 and 6h prior to HBO2 exposure significantly reduced the (1) lung injury, (2) proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6), (3) apoptosis (Bax/Bcl-2, cleaved-caspase-3 and TUNEL), (4) nuclear factor (NF)-kappaB expression level and DNA binding activity in the nucleus, and (5) extracellular signal-regulated kinase (ERK)1/2 phosphorylation and markedly elevated (6) superoxide dismutase and glutathione peroxidase activities as well as (7) IkappaB expression. However, administration of the PPAR-beta/delta antagonist GSK0660 abolished these protective effects. These findings indicate that activation of PPAR-beta/delta ameliorates hyperoxia-induced ALI in rats by up-regulating antioxidant enzyme activity as well as suppressing inflammation and apoptosis. PMID- 24780551 TI - Heme oxygenase-1 (HO-1) mediated respiratory responses to hypoxia in the goldfish, Carassius auratus. AB - In this study we investigated the role of heme oxygenase-1 (HO-1) in modulating the hypoxic and hyperoxic ventilatory responses of goldfish (Carassius auratus) acclimated to 7 and 25 degrees C. HO-1 was present in the neuroepithelial cells (NECs; putative branchial O2 chemoreceptors) of fish acclimated to 7 degrees C only. Hypoxia exposure increased gill HO-1 activity in 7 degrees C fish (14.0+/ 1.4 to 42.5+/-3.2pmolbilirubinmin(-1)mgprotein(-1)). Inhibition of HO-1 activity with zinc protophorphyrin IX (ZnPPIX) increased the ventilation frequency response to acute hypoxia (30mmHg); frequency increased from 48.3+/-5.1 to 137.4+/-16.0 breaths per min (BPM) in hypoxic 7 degrees C fish treated with ZnPPIX compared to 46.2+/-4.2 to 77.9+/-5.3 BPM in control fish. Unlike in the control (untreated) 7 degrees C fish exposed to hyperoxia, fish injected with ZnPPIX did not significantly decrease breathing frequency. Inhibiting HO-1 activity was without effect on the hypoxic or hyperoxic ventilatory responses of fish acclimated to 25 degrees C. Based on these observations, we suggest that HO 1 plays an inhibitory role in regulating breathing frequency but only in goldfish acclimated to 7 degrees C. PMID- 24780552 TI - Tobacco exposure in children and adolescents with chronic kidney disease: parental behavior and knowledge. A study from the Midwest Pediatric Nephrology Consortium. AB - AIM: The incidence of cardiovascular disease (CVD) in children with chronic kidney disease (CKD) is high. Exposure to second hand smoke (SHS) is a known risk factor for CVD. Due to a recent report of high incidence of SHS in children with CKD, we sought to investigate via questionnaire the smoking behaviors of caregivers of children with CKD. MATERIAL AND METHODS: A cross sectional study was conducted in which caregivers of children and adolescents with CKD were asked to complete a single anonymous self-administered survey. RESULTS: Almost 40% of children and adolescents lived with one or more smokers. Over half of smokers smoked in the presence of their children and in the car. Smokers were significantly less aware of the detrimental effect of SHS exposure on the renal health of their children. Among smokers, almost 70% reported they had not been advised by their child's nephrologist to quit tobacco use. CONCLUSION: There is a high prevalence of SHS exposure among children and adolescents with CKD, which may contribute to CVD. Caregivers are not fully aware of the detrimental effects of SHS exposure on the renal health of their children. PMID- 24780553 TI - Cognition may be related to arterial pulsatility index in HD patients. AB - AIMS: Hemodialysis (HD) patients have a heavy burden of subclinical cerebrovascular disease and cognitive changes consistent with a vascular etiology. Pulsatility index is associated with microangiopathy of cerebral blood vessels and an increased risk of cerebral infarction. The proposed study was to determine common carotid artery pulsatility index (CCAPI) and its relation to cognition in well-dialyzed HD patients with no history of stroke or dementia and matched controls. METHODS: Observational, cross-sectional study of CCAPI and cognition in 37 hemodialysis outpatients and 18 matched controls with normal kidney function. Non-parametric analyses were used to compare variables between groups. Multiple regression and ANOVA models were used to adjust for risk factor differences. RESULTS: Controls had a lower CCAPI than the HD group (1.7 +/- 0.3 vs. 2.1 +/- 0.4 cm/s, p = 0.006). HD patients scored significantly lower on all cognitive domains. Attention correlated with CCAPI in HD patients, independent of hypertension, diabetes, hyperlipidemia, and years on HD (r2 = -0.36, p = 0.01). CCAPI correlated with years on HD, independent of traditional cardiovascular risk factors. (r2 = 0.26, p = 0.04). CONCLUSION: In well-dialyzed hemodialysis patients with no history of stroke or dementia, CCAPI may correlate with cognitive function and represent a marker for underlying cerebral microvascular disease. PMID- 24780554 TI - Evaluation of acid-base control, electrolyte balance, and filter patency of a Prismaflex-based regional citrate anticoagulation protocol for pre-dilution continuous veno-venous hemodiafiltration. AB - BACKGROUND: Regional citrate anticoagulation (RCA) is increasingly used in patients requiring continuous renal replacement therapy (CRRT). This study evaluated a new RCA protocol based on the Prismaflex(r) dialysis device and an isotonic citrate solution (prismocitrate) for pre-dilution continous veno-venous hemodiafiltration. METHODS: The Prismaflex(r)/Prismocitrate-based protocol involved an AN69ST(r) membrane (Prisma Flex ST100), a blood flow of 120 mL/min, 1.8 L/h Prismocitrate (10 mmol/L citrate/2 mmol/L citric acid) substitution fluid in pre-dilution mode, and 0.8 L/h dialysate flow (PrismOcal) at the start. In parallel, infusions of potassium, calcium, and magnesium were initiated. Blood pH, bicarbonate, base excess, and ionized calcium levels were measured in 6 hours intervals and magnesium levels every 24 hours. Scheduled hemofilter run time was 72 hours. RESULTS: A consecutive series of 25 continuous renal replacement treatments was analyzed in 15 patients. After at least 6h of RRT, 69.9% of bicarbonate concentrations and 84.6% base excess (BE) calculations were below normal range. During CRRT, mean bicarbonate decreased from 22.9 to 20.2 mmol/L and mean BE from -1.5 to -4.2 mmol/L. In addition, 66.3% of ionized systemic calcium concentrations were out of the normal range, while 54.1% of the magnesium readings were above normal range. Five filters reached the scheduled run time of 72 hours, 19 treatments stopped prematurely because of RRT related reasons (5 filter clottings, 2 severe metabolic disarrangements, 12 major Prismaflex(r) hardware or software handling problems). One patient was switched to intermittent hemodialysis. CONCLUSIONS: The evaluated Prismaflex(r)/ Prismocitrate-based citrate anticoagulation protocol provides insufficient control of blood acid-base and electrolyte balance. PMID- 24780555 TI - Myeloma progression and urinary gammaglobulin affect the urinary cystatin C to diagnose acute kidney injury in multiple myeloma. AB - AIMS: Urinary cystatin C has been suggested as a useful biomarker for diagnosis of acute kidney injury (AKI). Multiple myeloma is often complicated by AKI. Therefore, we investigated whether the urinary cystatin C was available for diagnosis of AKI in multiple myeloma. MATERIALS AND METHODS: This study included 39 patients with monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma. We reviewed the medical records retrospectively and investigated whether urinary gamma-globulin and myeloma progression had effects on urinary cystatin C excretion. RESULTS: Spearman's correlation analysis showed that serum beta2-microglobulin and serum cystatin C had a significant positive correlation with the urinary cystatin C excretion (r = 0.513, p = 0.001, r = 0.659, p < 0.001) and FEcystatinC (r = 0.585, p = 0.002, r = 0.711, p < 0.001). The GFRcr also had a significant negative correlation with the urinary cystatin C excretion (r = -0.582, p < 0.001) and FEcystatinC (r = -0.474, p = 0.002). In addition, the urinary gamma-globulin had a significant positive correlation with the urinary cystatin C excretion (r = 0.678, p < 0.001) and FEcystatinC (r = 0.731, p < 0.001). Urinary gamma-globulin was the most significant factor to influence urinary cystatin C excretion in multiple regression test. CONCLUSION: These results indicate that urinary gamma-globulin and myeloma progression can increase the fractional and total excretion of urinary cystatin C. Therefore, it is believed that the urinary cystatin C can be affected by urinary gamma-globulin and myeloma progression in the diagnosis of AKI in multiple myeloma. In addition, urinary gamma-globulin is believed to be the most significant factor to influence on urinary cystatin C. PMID- 24780556 TI - Recovery of oxygenated ignitable liquids by zeolites, Part I: Novel extraction methodology in fire debris analysis. AB - The recovery of low molecular weight oxygenates in fire debris samples is severely compromised by the use of heated passive headspace concentration with an activated charcoal strip, as outlined in ASTM E-1412. The term "oxygenate" is defined herein as a small, polar, organic molecule, such as acetone, methanol, ethanol, or isopropanol, which can be employed as an ignitable liquid and referred to in the ASTM classification scheme as the "oxygenated solvents" class. Although a well accepted technique, the higher affinity of activated carbon strips for heavy molecular weight products over low molecular weight products and hydrocarbons over oxygenated products, it does not allow for efficient recovery of oxygenates such as low molecular weight alcohols and acetone. The objective of this study was to develop and evaluate a novel method for the enhanced recovery of oxygenates from fire debris samples. By optimizing conditions of the heated passive headspace technique, the utilization of zeolites allowed for the successful collection and concentration of oxygenates. The results demonstrated that zeolites increased the recovery of oxygenates by at least 1.5-fold compared to the activated carbon strip and may complement the currently used extraction technique. PMID- 24780557 TI - Reprint of "The clinical impact of deficiency in DNA non-homologous end-joining". AB - DNA non-homologous end-joining (NHEJ) is the major DNA double strand break (DSB) repair pathway in mammalian cells. Defects in NHEJ proteins confer marked radiosensitivity in cell lines and mice models, since radiation potently induces DSBs. The process of V(D)J recombination functions during the development of the immune response, and involves the introduction and rejoining of programmed DSBs to generate an array of diverse T and B cells. NHEJ rejoins these programmed DSBs. Consequently, NHEJ deficiency confers (severe) combined immunodeficiency - (S)CID - due to a failure to carry out V(D)J recombination efficiently. NHEJ also functions in class switch recombination, another step enhancing T and B cell diversity. Prompted by these findings, a search for radiosensitivity amongst (S)CID patients revealed a radiosensitive sub-class, defined as RS-SCID. Mutations in NHEJ genes, defining human syndromes deficient in DNA ligase IV (LIG4 Syndrome), XLF-Cernunnos, Artemis or DNA-PKcs, have been identified in such patients. Mutations in XRCC4 or Ku70,80 in patients have not been identified. RS SCID patients frequently display additional characteristics including microcephaly, dysmorphic facial features and growth delay. Here, we overview the clinical spectrum of RS-SCID patients and discuss our current understanding of the underlying biology. PMID- 24780558 TI - Base excision repair: a critical player in many games. AB - This perspective reviews the many dimensions of base excision repair from a 10,000 foot vantage point and provides one person's view on where the field is headed. Enzyme function is considered under the lens of X-ray diffraction and single molecule studies. Base excision repair in chromatin and telomeres, regulation of expression and the role of posttranslational modifications are also discussed in the context of enzyme activities, cellular localization and interacting partners. The specialized roles that base excision repair play in transcriptional activation by active demethylation and targeted oxidation as well as how base excision repair functions in the immune processes of somatic hypermutation and class switch recombination and its possible involvement in retroviral infection are also discussed. Finally the complexities of oxidative damage and its repair and its link to neurodegenerative disorders, as well as the role of base excision repair as a tumor suppressor are examined in the context of damage, repair and aging. By outlining the many base excision repair-related mysteries that have yet to be unraveled, hopefully this perspective will stimulate further interest in the field. PMID- 24780559 TI - Mitochondrial genome maintenance in health and disease. AB - Human mitochondria harbor an essential, high copy number, 16,569 base pair, circular DNA genome that encodes 13 gene products required for electron transport and oxidative phosphorylation. Mutation of this genome can compromise cellular respiration, ultimately resulting in a variety of progressive metabolic diseases collectively known as 'mitochondrial diseases'. Mutagenesis of mtDNA and the persistence of mtDNA mutations in cells and tissues is a complex topic, involving the interplay of DNA replication, DNA damage and repair, purifying selection, organelle dynamics, mitophagy, and aging. We briefly review these general elements that affect maintenance of mtDNA, and we focus on nuclear genes encoding the mtDNA replication machinery that can perturb the genetic integrity of the mitochondrial genome. PMID- 24780561 TI - Neural imaginaries and clinical epistemology: Rhetorically mapping the adolescent brain in the clinical encounter. AB - The social work of brain images has taken center stage in recent theorizing of the intersections between neuroscience and society. However, neuroimaging is only one of the discursive modes through which public representations of neurobiology travel. This article adopts an expanded view toward the social implications of neuroscientific thinking to examine how neural imaginaries are constructed in the absence of visual evidence. Drawing on ethnographic fieldwork conducted over 18 months (2008-2009) in a United States multidisciplinary pediatric pain clinic, I examine the pragmatic clinical work undertaken to represent ambiguous symptoms in neurobiological form. Focusing on one physician, I illustrate how, by rhetorically mapping the brain as a therapeutic tool, she engaged in a distinctive form of representation that I call neural imagining. In shifting my focus away from the purely material dimensions of brain images, I juxtapose the cultural work of brain scanning technologies with clinical neural imaginaries in which the teenage brain becomes a space of possibility, not to map things as they are, but rather, things as we hope they might be. These neural imaginaries rely upon a distinctive clinical epistemology that privileges the creative work of the imagination over visualization technologies in revealing the truths of the body. By creating a therapeutic space for adolescents to exercise their imaginative faculties and a discursive template for doing so, neural imagining relocates adolescents' agency with respect to epistemologies of bodily knowledge and the role of visualization practices therein. In doing so, it provides a more hopeful alternative to the dominant popular and scientific representations of the teenage brain that view it primarily through the lens of pathology. PMID- 24780563 TI - TLR2 signaling directs NO-dependent MMP-9 induction in mouse microglia. AB - Microglia are neural immune cells that produce pro-inflammatory proteins in the central nervous system. Dysregulation of microglia gene expression is linked to the chronic brain inflammation and the neurological disorders. Matrix metalloproteinase-9 (MMP-9) is a pro-inflammatory protease that regulates the neurotoxicity of glial cells in the brain and spinal cord. Recent studies showed the accumulation of MMP-9 at microglia-rich plaques associates with neurodegenerative diseases. However, the regulatory mechanism of MMP-9 expression in microglia inflammation is still unknown. Here we show that oxidized low density lipoprotein (oxLDL) induces the expression and secretion of Pro-MMP-9 (92kDa) via TLR2 signaling pathway in mouse microglial cells. Depletion of TLR2 or its signaling mediators MyD88/TRAF6 blocks the agonist-induced MMP-9 expression. In addition, TLR2-dependent nitric oxide (NO) synthesis is also required for endogenous Pro-MMP-9 expression and secretion. Cell death assay indicates that the neurotoxicity of microglia is regulated by endogenous NO and TLR2 signaling pathway. Our findings establish a pathophysiological link between oxLDL and MMP-9 expression in microglia-related neuroinflammation. PMID- 24780562 TI - Dynorphin release by the lateral olivocochlear efferents may inhibit auditory nerve activity: a cochlear drug delivery study. AB - Dynorphin (dyn) is suggested to excite the auditory nerve (AN) when released by the lateral olivocochlear (LOC) efferents. However, previous studies evaluated either intravenously delivered dyn-like agents, raising the potential for systemic (central) effects, or agent concentrations unlikely to be achieved via endogenous cochlear release. This study tested the hypothesis that biologically relevant increases in dyn levels in the cochlea achieved via diffusion of the drug of (-)pentazocine across the round window membrane enhances AN firing. In general, amplitude of the cochlear whole-nerve action potential (CAP) was depressed following drug application. These results suggest that dyn released by the LOC neurons would likely act as an inhibitory transmitter substance in the LOC system; neurotransmission is one of the LOC system's vast unknowns. PMID- 24780564 TI - Discharge properties of neurons recorded in the parvalbumin-positive (PV1) nucleus of the rat lateral hypothalamus. AB - This study reports for the first time the extracellular activity recorded, in anesthetized rats, from cells located in an identified cluster of parvalbumin (PV)-positive neurons of the lateral hypothalamus forming the PV1-nucleus. Random like firing characterized the majority (21/30) of the cells, termed regular cells, with a median firing rate of 1.7 spikes/s, Fano factor equal to 1, and evenly distributed along the rostro-caudal axis. Four cells exhibiting an oscillatory activity in the range 1.6-2.1Hz were observed only in the posterior part of the PV1-nucleus. The asynchronous activity of PV1 neurons is likely to produce a "network-driven" effect on their main target within the periaqueductal gray matter. The hypothesis is raised that background random-like firing of PV1 nucleus is associated with functional network activity likely to contribute dynamic information related to condition transitions of awareness and non conscious perception. PMID- 24780560 TI - Inter-individual variation in DNA repair capacity: a need for multi-pathway functional assays to promote translational DNA repair research. AB - Why does a constant barrage of DNA damage lead to disease in some individuals, while others remain healthy? This article surveys current work addressing the implications of inter-individual variation in DNA repair capacity for human health, and discusses the status of DNA repair assays as potential clinical tools for personalized prevention or treatment of disease. In particular, we highlight research showing that there are significant inter-individual variations in DNA repair capacity (DRC), and that measuring these differences provides important biological insight regarding disease susceptibility and cancer treatment efficacy. We emphasize work showing that it is important to measure repair capacity in multiple pathways, and that functional assays are required to fill a gap left by genome wide association studies, global gene expression and proteomics. Finally, we discuss research that will be needed to overcome barriers that currently limit the use of DNA repair assays in the clinic. PMID- 24780565 TI - Dependence of ethanol effects on protein charges. AB - Ethanol is used as a conventional disinfectant solution. It is highly effective against enveloped viruses due to its effects on virus membranes. It also confers inactivation of non-enveloped viruses, which can be ascribed to conformational changes or changes in association state of the viral proteins induced by ethanol. We have examined here the effects of pH and hence the charged state of proteins on the ethanol-induced conformational changes and self-association of model proteins, i.e., bovine serum albumin (BSA) and ribonuclease A (RNase A). Both proteins showed qualitatively different aggregation behavior and structure changes by ethanol at pH 4.0 and 7.0, at which BSA has opposite charges and RNase A has different degree of net positive charges. PMID- 24780566 TI - Expression of mRNA and protein-protein interaction of the antiviral endoribonuclease RNase L in mouse spleen. AB - The interferon-inducible, 2',5'-oligoadenylate (2-5A)-dependent endoribonuclease, RNase L is a unique antiviral RNA-degrading enzyme involved in RNA-metabolism, translational regulation, stress-response besides its anticancer/tumor-suppressor and antibacterial functions. RNase L represents complex cellular RNA-regulations in mammalian cells but diverse functions of RNase L are not completely explained by its 2-5A-regulated endoribonuclease activity. We hypothesized that RNase L has housekeeping function(s) through interaction with cellular proteins. We investigated RNase L mRNA expression in mouse tissues by RT-PCR and its protein protein interaction in spleen by GST-pulldown and immunoprecipitation assays followed by proteomic analysis. RNase L mRNA is constitutively and differentially expressed in nine different mouse tissues, its level is maximum in immunological tissues (spleen, thymus and lungs), moderate in reproductive tissues (testis and prostate) and low in metabolic tissues (kidney, brain, liver and heart). Cellular proteins from mouse spleen [fibronectin precursor, beta-actin, troponin I, myosin heavy chain 9 (non-muscle), growth-arrest specific protein 11, clathrin light chain B, a putative uncharacterized protein (Ricken cDNA 8030451F13) isoform (CRA_d) and alanyl tRNA synthetase] were identified as cellular RNase L interacting proteins. Thus our results suggest for more general cellular functions of RNase L through protein-protein interactions in the spleen for immune response in mammals. PMID- 24780567 TI - Adsorption of arsenic by activated carbon, calcium alginate and their composite beads. AB - The present investigation deals with preparation of three different adsorbent materials namely; potassium hydroxide activated carbon based apricot stone (C), calcium alginate beads (G) and calcium alginate/activated carbon composite beads (GC) were used for the removal of arsenic. The prepared adsorbent materials were characterized by scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR), N2-adsorption at -196 degrees C and point of zero charge. From the obtained results, it was found that the porosity, surface area and total pore volume of the adsorbent material C>GC>G respectively, however, the G adsorbent has more acidic function group than the other adsorbents. The influence of pH, time, temperature and initial concentration of arsenic(V) were studied and optimized. GC exhibits the maximum As(V) adsorption (66.7mg/g at 30 degrees C). The adsorption of arsenic ions was observed to follow pseudo-second order mechanism as well as the thermodynamic parameters confirm also the endothermic spontaneous and a physisorption process. PMID- 24780568 TI - [The gut microbiota in sickness and health]. AB - The human gut microbiota, formerly known as 'gut flora', may be regarded as an external organ with many physiological functions in metabolism, development of the immune system and defense against pathogens. The adult gut microbiota consist of 1013-1014 micro-organisms. The aggregate genome of these, known as the microbiome, is 100 times larger than the human genome. The gut microbiotica may be involved in the pathogenesis of a range of syndromes, such as inflammatory bowel disease, obesity, diabetes mellitus and atopic disorders. It should be noted that until now most of the studies conducted have been association studies, without proof of causality. This increasing insight has led to identification of new therapeutic strategies, which are currently being investigated in clinical studies. Although the implications of this knowledge for individual patients have yet to become clear, various interventions are conceivable, such as supplementation of nutritional elements, prebiotics or probiotics and feces transplantation. PMID- 24780569 TI - [Skin disorders associated with monoclonal gammopathies]. AB - A monoclonal gammopathy is a condition in which a monoclonal immunoglobulin (M protein, formerly known as paraprotein) produced by a clonal proliferation of plasma cells is present in the blood. The spectrum of monoclonal gammopathies includes monoclonal gammopathy of uncertain significance (MGUS), multiple myeloma, Waldenstrom disease, plasmacytoma and primary amyloidosis. Various skin diseases are associated with monoclonal gammopathies. These are often rare skin diseases which are not easily recognised. This association is important to be known, in order to screen these patients for M-proteins and if necessary refer them to a haematologist. We present a 62-year-old male with cryoglobulinaemia and MGUS, a 64-year-old male with lichen myxoedematosus and MGUS and a 74-year-old male with necrobiotic xanthogranuloma and probably MGUS. PMID- 24780570 TI - [Pulmonary oedema in pregnancy: myocardial infarction as a possible cause]. AB - BACKGROUND: Pulmonary oedema in pregnancy may have various causes. A systematic approach to a pregnant woman with pulmonary oedema is important. Acute myocardial infarction should be considered during the differential diagnosis. CASE DESCRIPTION: A 30-year-old primigravida, who had been admitted with pre eclampsia, complained of increasing shortness of breath at 28 weeks and 5 days gestation. She had pulmonary oedema, which was considered to be consistent with pre-eclampsia. A caesarean section was performed at 28 weeks and 6 days gestation because of increasing oxygen dependency. Following the caesarean section the patient was transferred to the ICU because of imminent respiratory failure, and a semi-acute anterior infarction was diagnosed by means of an ECG (estimated ejection fraction: 30%). The patient was discharged in a reasonable condition 8 days after the caesarean section. CONCLUSION: Differential diagnosis of pulmonary oedema during pregnancy is wide. Consultation with a cardiologist is recommended if a possible cardiac cause is suspected. Determination of troponin levels, ECG and an electrocardiogram should be the first diagnostic tools of choice in a pregnant patient. PMID- 24780571 TI - [Gene expression classifiers in the prognosis of breast cancer]. AB - Gene expression classifiers such as the 70-gene signature that reflect the biology of breast tumours have started to find their way into daily clinical practice. Several retrospective validation studies in breast cancer have established the prognostic value of the 70-gene signature (MammaPrint). The prospective observational RASTER study shows excellent 5-year distant recurrence free intervals in 98.4% of patients who had a high clinical risk but who according to the 70-gene signature had a low risk. Particularly in patients aged 45 years or older with an oestrogen receptor (ER)-positive, HER2-negative tumour, diameter 1-2 cm, grade 2 there is prospective evidence that the 70-gene signature can make a useful contribution towards decision-making on adjuvant chemotherapy. PMID- 24780573 TI - [Lithium: only acceptable with careful monitoring]. AB - In the Netherlands, lithium is the mood stabilizer of choice for patients with bipolar disorder. Long-term treatment with lithium can only be implemented safely with frequent and appropriate monitoring of serum lithium concentrations. Here we use 3 cases to illustrate that severe complications can arise when careful monitoring is not performed: a 47-year-old woman with symptoms of a lithium intoxication with therapeutic plasma levels; a 73-year-old woman with chronic lithium intoxication; and a 56-year-old woman with end-stage renal failure after many years of probable toxic lithium levels. PMID- 24780574 TI - [Diarrhoea and malabsorption due to olmesartan use]. AB - BACKGROUND: The differential diagnosis of diarrhoea in combination with villous atrophy is broad. Coeliac disease heads the list but medication-induced villous atrophy should also be taken into consideration. CASE DESCRIPTION: We report the case of a 63-year-old man presenting with recurrent secretory diarrhoea, acute renal failure and metabolic acidosis. Initial work-up revealed total villous atrophy (Marsh stage IIIC) with intraepithelial lymphocytosis. A gluten-free diet did not have any effect on the diarrhoea. During several periods of hospitalization antihypertensive medications were temporarily stopped due to dehydration; this resulted in reduction of his symptoms. Eventually an association between the enteropathy and the antihypertensive olmesartan was suspected. Indeed, permanent withdrawal of olmesartan resulted in permanent clinical improvement. CONCLUSION: Olmesartan is frequently prescribed in the Netherlands and it should be included in the differential diagnosis of diarrhoea accompanying villous atrophy. PMID- 24780575 TI - [The danger of unpublished trial results]. AB - Unpublished and selectively published trial results may lead to distortion of the effectiveness and the profile of side effects of interventions. This jeopardizes patient safety and leads to unnecessary costs. Between 25 and 50% of all clinical trials remain unpublished. Primary outcomes, as originally defined in study protocols, often differ from those in the final publication. Positive trial results are almost 3 times as likely to be published as negative results. Commercial sponsorship is strongly associated with the publication of results that promote the interests of that sponsor, but non-publication and selective reporting is also frequent among non-commercial trials. Existing solutions, such as the requirement for prospective registration of trial protocols and the mandatory publication of trial results within 1 year after completion of the trial will only be successful if their compliance is more strictly monitored. PMID- 24780576 TI - [A man with a swelling in the palm of his hand]. AB - A 41-year-old man had a palpable mass on the volar side of his hand. X-ray, ultrasound and MRI showed an inhomogeneous tumour with calcification. Histologic examination ruled out the suspicion of a liposarcoma. The surgeon successfully excised the ossifying lipoma, which is a rare variant of a common lipoma and can clinically and radiologically mimic malignant neoplasms. PMID- 24780577 TI - [Is one single exposure to asbestos life-threatening?]. AB - The media occasionally reports on possible asbestos exposure during demolition of houses in an urban setting. The risk for the development of any asbestos-related cancer in these settings is considered to be lower than for that in occupational exposure. Offermans et al. examined a Dutch cohort of 58,279 workers in the period from 1986 to 2007. They concluded that the risk of lung cancer, laryngeal cancer and mesothelioma increased with exposure to asbestos. The risk of development of lung cancer was higher for anyone with increased years of exposure to asbestos fibre combined with a smoking habit. The study was well conducted, but exact data on fibre concentration and type of asbestos are lacking. We suggest that occasional exposure to asbestos poses hardly any risk for the general population. However, rules and regulations for the removal of asbestos containing material remain important as asbestos exposure remains a serious health risk, especially in smokers. PMID- 24780578 TI - Prognostic performance of high-sensitivity cardiac troponin T kinetic changes adjusted for elevated admission values and the GRACE score in an unselected emergency department population. AB - PURPOSE: The aim of this study was to test the prognostic performance of rising and falling kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) and the GRACE score. METHODS: Rising and falling hs-cTnT changes in an unselected emergency department population were compared. RESULTS: 635 patients with a hs cTnT >99th percentile admission value were enrolled. Of these, 572 patients qualified for evaluation with rising patterns (n=254, 44.4%), falling patterns (n=224, 39.2%), or falling patterns following an initial rise (n=94, 16.4%). During 407days of follow-up, we observed 74 deaths, 17 recurrent AMI, and 79 subjects with a composite of death/AMI. Admission values >14ng/L were associated with a higher rate of adverse outcomes (OR, 95%CI:death:12.6, 1.8-92.1, p=0.01, death/AMI:6.7, 1.6-27.9, p=0.01). Neither rising nor falling changes increased the AUC of baseline values (AUC: rising 0.562 vs. 0.561, p=ns, falling: 0.533 vs. 0.575, p=ns). A GRACE score >=140 points indicated a higher risk of death (OR, 95%CI: 3.14, 1.84-5.36), AMI (OR, 95%CI: 1.56, 0.59-4.17), or death/AMI (OR, 95%CI: 2.49, 1.51-4.11). Hs-cTnT changes did not improve the prognostic performance of a GRACE score >=140 points (AUC, 95%CI: death: 0.635, 0.570-0.701 vs. 0.560, 0.470-0.649 p=ns, AMI: 0.555, 0.418-0.693 vs. 0.603, 0.424-0.782, p=ns, death/AMI: 0.610, 0.545-0.676 vs. 0.538, 0.454-0.622, p=ns). Coronary angiography was performed earlier in patients with rising than with falling kinetics (median, IQR [hours]:13.7, 5.5-28.0 vs. 20.8, 6.3-59.0, p=0.01). CONCLUSION: Neither rising nor falling hs-cTnT changes improve the prognostic performance of elevated hs-cTnT admission values or the GRACE score. However, rising values are more likely associated with the decision for earlier invasive strategy. PMID- 24780579 TI - Pediatric reference intervals for thyroglobulin using the Beckman Coulter Access 2 immunoassay. PMID- 24780580 TI - Authors reply: estimated glomerular filtration rate by two equations and their relationship with metabolic syndrome. PMID- 24780582 TI - The role of surface electrostatics on the stability, function and regulation of human cystathionine beta-synthase, a complex multidomain and oligomeric protein. AB - Human cystathionine beta-synthase (hCBS) is a key enzyme of sulfur amino acid metabolism, controlling the commitment of homocysteine to the transsulfuration pathway and antioxidant defense. Mutations in hCBS cause inherited homocystinuria (HCU), a rare inborn error of metabolism characterized by accumulation of toxic homocysteine in blood and urine. hCBS is a complex multidomain and oligomeric protein whose activity and stability are independently regulated by the binding of S-adenosyl-methionine (SAM) to two different types of sites at its C-terminal regulatory domain. Here we study the role of surface electrostatics on the complex regulation and stability of hCBS using biophysical and biochemical procedures. We show that the kinetic stability of the catalytic and regulatory domains is significantly affected by the modulation of surface electrostatics through noticeable structural and energetic changes along their denaturation pathways. We also show that surface electrostatics strongly affect SAM binding properties to those sites responsible for either enzyme activation or kinetic stabilization. Our results provide new insight into the regulation of hCBS activity and stability in vivo with implications for understanding HCU as a conformational disease. We also lend experimental support to the role of electrostatic interactions in the recently proposed binding modes of SAM leading to hCBS activation and kinetic stabilization. PMID- 24780581 TI - Multiple facets of TPP1 in telomere maintenance. AB - Telomeres are nucleoprotein complexes that cap the ends of all linear chromosomes and function to prevent aberrant repair and end-to-end chromosome fusions. In somatic cells, telomere shortening is a natural part of the aging process as it occurs with each round of cell division. In germ and stem cells, however, the enzyme telomerase synthesizes telomere DNA to counter-balance telomere shortening and help maintain cellular proliferation. Of the primary telomere end-binding proteins, TPP1 has recently emerged as a primary contributor in protecting telomere DNA and in recruiting telomerase to the telomere ends. In this review, we summarize the current knowledge regarding the role of TPP1 in telomere maintenance. PMID- 24780583 TI - Low resolution X-ray structure of gamma-glutamyltranspeptidase from Bacillus licheniformis: opened active site cleft and a cluster of acid residues potentially involved in the recognition of a metal ion. AB - gamma-Glutamyltranspeptidases (gamma-GTs) cleave the gamma-glutamyl amide bond of glutathione and transfer the released gamma-glutamyl group to water (hydrolysis) or acceptor amino acids (transpeptidation). These ubiquitous enzymes play a key role in the biosynthesis and degradation of glutathione, and in xenobiotic detoxification. Here we report the 3A resolution crystal structure of Bacillus licheniformis gamma-GT (BlGT) and that of its complex with l-Glu. X-ray structures confirm that BlGT belongs to the N-terminal nucleophilic hydrolase superfamily and reveal that the protein possesses an opened active site cleft similar to that reported for the homologous enzyme from Bacillus subtilis, but different from those observed for human gamma-GT and for gamma-GTs from other microorganisms. Data suggest that the binding of l-Glu induces a reordering of the C-terminal tail of BlGT large subunit and allow the identification of a cluster of acid residues that are potentially involved in the recognition of a metal ion. The role of these residues on the conformational stability of BlGT has been studied by characterizing the autoprocessing, enzymatic activity, chemical and thermal denaturation of four new Ala single mutants. The results show that replacement of Asp568 with an Ala affects both the autoprocessing and structural stability of the protein. PMID- 24780584 TI - The role of radiology in active middle ear implantation. AB - Active middle ear implants (AMEIs) have been available for a number of years and yet most radiologists have never heard of them. Some bear a striking resemblance to cochlear implants whereas others are more similar to conventional hearing aids. The aims of this review are to provide an introduction as to the types of implants available, how they work and when they are indicated. Also, to highlight important pre-operative imaging features that can influence surgery and to consider the role of imaging in the post-operative setting. As patient choice increases, it becomes more likely that radiologists will encounter these devices in daily practice and knowledge of them may prove useful. PMID- 24780585 TI - Age, diet, and season do not affect longevity-related differences in peroxidation index between Spisula solidissima and Arctica islandica. AB - The susceptibility of membrane lipids to peroxidation (peroxidation index [PI]) increases with the double bond content of fatty acids and is inversely correlated to longevity in mammals, birds, and bivalve molluscs. In molluscs, membrane polyunsaturated fatty acids content can be affected by temperature, nutrition, and the individual's age. In this study, we evaluated how these three parameters may alter correlations between PI and longevity. We determined the fatty acid and dimethyl acetal compositions of phospholipids from gill mitochondrial and nonmitochondrial preparations from the short-lived Spisula solidissima (maximum longevity = 37 years) and the long-lived Arctica islandica (maximum longevity = 507 years) exposed to diet abundance and temperature (season) treatments. We also evaluated the effect of individual age on PI in S. solidissima (from 6 to 23 years). The temperature increase from winter to summer (2 to 12 degrees C) coincided with decreases in values of PI, proportions of eicosapentaenoic acid, and dimethyl acetals. Higher microalgae supplementation increased polyunsaturated fatty acids and PI and decreased dimethyl acetals; age did not affect the PI in S. solidissima. Our finding that the PI of A. islandica remained significantly lower than that of S. solidissima in corresponding fractions throughout treatments suggests that longevity-related differences in PI are resilient to environmental conditions. PMID- 24780586 TI - Towards an agroecological assessment of dairy systems: proposal for a set of criteria suited to mountain farming. AB - Ruminant production systems have been facing the sustainability challenge, namely, how to maintain or even increase production while reducing their environmental footprint, and improving social acceptability. One currently discussed option is to encourage farmers to follow agroecological principles, that is, to take advantage of ecological processes to reduce inputs and farm wastes, while preserving natural resources, and using this diversity to increase system resilience. However, these principles need to be made more practical. Here, we present the procedure undertaken for the collaborative construction of an agroecological diagnostic grid for dairy systems with a focus on the mountain farming relying on the use of semi-natural grasslands. This diagnosis will necessarily rely on a multicriteria evaluation as agroecology is based on a series of complementary principles. It requires defining a set of criteria, based on practices to be recommended, that should be complied with to ensure agroecological production. We present how such agroecological criteria were identified and organized to form the architecture of an evaluation model. As a basis for this work, we used five agroecological principles already proposed for animal production systems. A group of five experts of mountain production systems and of their multicriteria evaluation was selected, with a second round of consultation with five additional experts. They first split up each principle into three to four generic sub-principles. For each principle, they listed three to eight categories of state variables on which the fulfilment of the principle should have a positive impact (e.g. main health disorders for the integrated health management principle). State variables are specific for a given production, for example, dairy farms. Crossing principles with state variables enabled experts to build five matrices, with 75 cells relevant for dairy systems. In each cell, criteria are specific to the local context, for example, mountain dairy systems in this study. Finally, we discuss the opportunities offered by our methodology, and the steps remaining for the construction of the evaluation model. PMID- 24780587 TI - Expert consultation on risk factors for introduction of infectious pathogens into fish farms. AB - An expert consultation was conducted to provide quantitative parameters required to inform risk-based surveillance of aquaculture holdings for selected infectious hazards. The hazards were four fish diseases endemic in some or several European countries: infectious salmon anaemia (ISA), viral haemorrhagic septicaemia (VHS), infectious haematopoietic necrosis (IHN), and koi herpes virus disease (KHD). Experts were asked to provide estimates for the relative importance of 5 risk themes for the hazard to be introduced into and infect susceptible fish at the destination. The 5 risk themes were: (1) live fish and egg movements; (2) exposure via water; (3) on-site processing; (4) short distance mechanical transmission and (5) distance independent mechanical transmission. The experts also provided parameter estimates for hazard transmission pathways within the themes. The expert consultation was undertaken in a 2 step approach: an online survey followed by an expert consultation meeting. The expert opinion indicated that live fish movements and exposure via water were the major relevant risk themes. Experts were recruited from several European countries and thus covered a range of farming systems. Therefore, the outputs from the expert consultation have relevance for the European context. PMID- 24780589 TI - Spectrum of genes involved in a unique case of Potocki Schaffer syndrome with a large chromosome 11 deletion. PMID- 24780590 TI - Single-step antibody-based affinity cryo-electron microscopy for imaging and structural analysis of macromolecular assemblies. AB - Single particle cryo-electron microscopy (cryo-EM) is an emerging powerful tool for structural studies of macromolecular assemblies (i.e., protein complexes and viruses). Although single particle cryo-EM requires less concentrated and smaller amounts of samples than X-ray crystallography, it remains challenging to study specimens that are low-abundance, low-yield, or short-lived. The recent development of affinity grid techniques can potentially further extend single particle cryo-EM to these challenging samples by combining sample purification and cryo-EM grid preparation into a single step. Here we report a new design of affinity cryo-EM approach, cryo-SPIEM, that applies a traditional pathogen diagnosis tool Solid Phase Immune Electron Microscopy (SPIEM) to the single particle cryo-EM method. This approach provides an alternative, largely simplified and easier to use affinity grid that directly works with most native macromolecular complexes with established antibodies, and enables cryo-EM studies of native samples directly from cell cultures. In the present work, we extensively tested the feasibility of cryo-SPIEM with multiple samples including those of high or low molecular weight, macromolecules with low or high symmetry, His-tagged or native particles, and high- or low-yield macromolecules. Results for all these samples (non-purified His-tagged bacteriophage T7, His-tagged Escherichiacoli ribosomes, native Sindbis virus, and purified but low concentration native Tulane virus) demonstrated the capability of cryo-SPIEM approach in specifically trapping and concentrating target particles on TEM grids with minimal view constraints for cryo-EM imaging and determination of 3D structures. PMID- 24780591 TI - Molecular dynamics investigation of the active site dynamics of mycobacterial cyclopropane synthase during various stages of the cyclopropanation process. AB - Mycobacterial cyclopropane synthase 1 (CmaA1) is one of the most important drug targets in anti tuberculosis drug discovery as it is responsible for cis cyclopropanation at the distal position of unsaturated mycolates, which is an essential step for the pathogenicity, persistence and drug resistance. Five representative models of CmaA1 which correspond to different stages in the cyclopropanation process have been studied using molecular dynamics (MD) simulations. The MD simulations and structural analyses provide a detailed account of the structural changes in the active sites of CmaA1. CmaA1 has two distinct binding sites, i.e., cofactor binding site (CBS) and acyl substrate binding site (ASBS). The apo state of CmaA1 corresponds to a closed conformation where the CBS is inaccessible due to the existence of H-bond between Pro202 of loop10 (L10) and Asn11 of N-terminal alpha1 helix. However, cofactor binding leads to the breaking of this H-bond and thus the H-bond is absent in the holo form. The hydrophobic side chains orient towards the inner side of the ASBS upon cofactor binding to create a hydrophobic environment for the substrate. The cofactor and substrate tend to come close to each other facilitated by opening of L10 to exchange the methyl group from the cofactor to the substrate. The MD study also revealed that the system tends to regain the apo conformation within 40ns after releasing the product. PMID- 24780592 TI - Design, synthesis, and biological evaluation of novel FAK scaffold inhibitors targeting the FAK-VEGFR3 protein-protein interaction. AB - Focal adhesion kinase (FAK) and vascular endothelial growth factor receptor 3 (VEGFR3) are tyrosine kinases, which function as key modulators of survival and metastasis signals in cancer cells. Previously, we reported that small molecule chlorpyramine hydrochloride (C4) specifically targets the interaction between FAK and VEGFR3 and exhibits anti-tumor efficacy. In this study, we designed and synthesized a series of 1 (C4) analogs on the basis of structure activity relationship and molecular modeling. The resulting new compounds were evaluated for their binding to the FAT domain of FAK and anti-cancer activity. Amongst all tested analogs, compound 29 augmented anti-proliferative activity in multiple cancer cell lines with stronger binding to the FAT domain of FAK and disrupted the FAK-VEGFR3 interaction. In conclusion, we hope that this work will contribute to further studies of more potent and selective FAK-VEGFR3 protein-protein interaction inhibitors. PMID- 24780593 TI - Design and synthesis of novel 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4 oxadiazoles as selective COX-2 inhibitors with potent anti-inflammatory activity. AB - A novel series of 2-phenyl-5-(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4-oxadiazoles were designed and synthesized for selective COX-2 inhibition with potent anti inflammatory activity. Among the compounds tested, 9g (2-(3-(4-nitrophenyl)-1 phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazole) was found to be the most potent inhibitor of COX-2 with IC50 of 0.31 MUM showing promising degree of anti inflammatory activity in the carrageenan-induced rat paw edema model with ED50 of 74.3 mg/kg. The lead compound 9g further showed suppression of acetic acid induced writhes comparable to that of aspirin and gastro-sparing profile superior to the aspirin. Molecular docking analysis displayed higher binding affinity of ligands towards COX-2 than COX-1. PMID- 24780594 TI - Multifunctional nanoliposomes with curcumin-lipid derivative and brain targeting functionality with potential applications for Alzheimer disease. AB - With the objective to formulate multifunctional nanosized liposomes to target amyloid deposits in Alzheimer Disease (AD) brains, a lipid-PEG-curcumin derivative was synthesized and characterized. Multifunctional liposomes incorporating the curcumin derivative and additionally decorated with a Blood Brain Barrier (BBB) transport mediator (anti-Transferin antibody) were prepared and characterized. The fluorescence intensity of curcumin derivative was found to increase notably when the curcumin moiety was in the form of a diisopropylethylamine (DIPEA) salt. Both curcumin-derivative liposomes and curcumin-derivative Anti-TrF liposomes showed a high affinity for the amyloid deposits, on post-mortem brains samples of AD patients. The ability of both liposomes to delay Abeta1-42 peptide aggregation was confirmed by Thioflavin assay. However, the decoration of the curcumin-derivative liposomes with the Anti TrF improved significantly the intake by the BBB cellular model. Results verify that the attachment of an antibody on the curcumin-liposome surface does not block deposit staining or prevention of Abeta aggregation, while the presence of the curcumin-PEG-lipid conjugate does not reduce their brain-targeting capability substantially, proving the potential of such multifunctional NLs for application in Alzheimer disease treatment and diagnosis. PMID- 24780595 TI - Synthesis of novel 1,2,3-triazole substituted-N-alkyl/aryl nitrone derivatives, their anti-inflammatory and anticancer activity. AB - A series of novel 1,2,3-triazole substituted N-phenyl nitrone derivatives 5a-e were prepared in three steps starting from 1-substituted-1,2,3-triazole-4 carbaldehydes 2 via Schiff's base formation, reduction followed by oxidation. Similarly, 1,2,3-triazole substituted N-alkyl nitrone derivatives 6a-p were prepared in single step starting from compound 2 on reaction with N-alkyl hydroxylamine hydrochlorides. All the final compounds were screened for anti inflammatory and anticancer activity against various cancer cell lines. Among the compounds tested, the compounds 5a, 5d, 6a, 6b, 6m and 6o exhibited significant inhibition of IL-1beta secretion as a measure of anti-inflammatory activity. Compound 5b, 5c, 6h, 6i and 6o exhibited significant activity against all the cell lines (A549, COLO 205, MDA-MB 231 and PC-3) at IC50 values of <15 MUM. PMID- 24780596 TI - Synthesis, molecular structure, DNA-binding, cytotoxicity, apoptosis and antioxidant activity of compounds containing aryloxazole. AB - Three novel aryloxazole compounds 1-3 were synthesized and characterized. The crystal structures of compounds 2 and 3 show that N atom locates at beta-position and O atom at alpha-position in naphthalene cycle. The DNA binding constants for compounds 1-3 are 4.44 * 10(3), 5.31 * 10(3) and 2.64 * 10(3) M(-1), respectively. The viscosity measurements indicate that these compounds intercalate between the DNA base pairs. Upon irradiation, compounds 1-3 can effectively cleave pBR322 DNA. The cytotoxicity of the compounds against BEL 7402, A549, MG-63 and SKBR-3 were assayed by MTT method. The apoptosis and cell cycle arrest were investigated towards A549 cells. The antioxidant activities of the compounds against hydroxyl radicals were also explored. PMID- 24780597 TI - Synthesis of 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs and their biological evaluation as anticancer agents: mTOR inhibitors. AB - A microwave assisted strategy for synthesis of series of 1H-pyrazolo[4,3 d]pyrimidin-7(6H)-ones has been developed and their biological evaluation as anticancer agents is described. The synthetic protocol involves simple procedure by oxidative coupling of 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide with different aldehydes in presence of K2S2O8 offering 5-substituted-1H-pyrazolo[4,3 d]pyrimidin-7(6H)-one compounds in excellent yields. The in vitro anticancer activity screening against human cancer cell lines HeLa, CAKI-I, PC-3, MiaPaca-2, A549 gave good results. The in detailed mechanistic correlation studies of compound 3m revealed that the compound shows anticancer activity through apoptosis mechanism and also inhibits mTOR with nonomolar potency. The design was based on docking with mTOR protein. The concentration dependent cell cycle analysis, western blotting experiment and nuclear cell morphology studies have been described. PMID- 24780598 TI - Synthesis and biological evaluation of some new pyrazoline substituted benzenesulfonylurea/thiourea derivatives as anti-hyperglycaemic agents and aldose reductase inhibitors. AB - Seventeen new pyrazoline substituted benzenesulfonylurea/thiourea derivatives (2a q) were synthesized and characterized by elemental analysis and various spectroscopic techniques viz; IR, (1)H NMR, (13)C NMR, and MS data. Thirteen compounds showed moderate to good anti-hyperglycaemic activity in glucose fed hyperglycaemic normal rats at the dose of 0.05 mM/kg b.w. On the basis of docking results nine compounds (2a, 2c, 2e, 2h, 2k, 2l, 2n, 2o and 2q) were evaluated for their ability to inhibit rat lens aldose reductase. Out of these six compounds (2h, 2k, 2l, 2n, 2o and 2q) were found more effective than the known ARI sorbinil. Five compounds (2h, 2k, 2l, 2n and 2o) showed significant dual action (anti-hyperglycaemic and aldose reductase inhibition). PMID- 24780599 TI - Synthesis, antiproliferative activity and DNA binding properties of novel 5 aminobenzimidazo[1,2-a]quinoline-6-carbonitriles. AB - The synthesis of 5-amino substituted benzimidazo[1,2-a]quinolines prepared by microwave assisted amination from halogeno substituted precursor was described. The majority of compounds were active at micromolar concentrations against colon, lung and breast carcinoma cell lines in vitro. The N,N-dimethylaminopropyl 9 and piperazinyl substituted derivative 19 showed the most pronounced activity towards all of the three tested tumor cell lines, which could be correlated to the presence of another N heteroatom and its potential interactions with biological targets. The DNA binding studies, consisting of UV/Visible absorbency, melting temperature studies, and fluorescence and circular dichroism titrations, revealed that compounds 9, 19 and 20 bind to DNA as strong intercalators. The cellular distribution analysis, based on compounds' intrinsic fluorescence, showed that compound 20 does not enter the cell, while compounds 9 and 19 do, which is in agreement with their cytotoxic effects. Compound 9 efficiently targets the nucleus whereas 19, which also showed DNA intercalating properties in vitro, was mostly localised in the cytoplasm suggesting that the antitumor mechanism of action is DNA-independent. PMID- 24780600 TI - Dual inhibition of the alpha-glucosidase and butyrylcholinesterase studied by molecular field topology analysis. AB - A striking dual inhibition of enzymes alpha-glucosidase and butyrylcholinesterase by small drug-like molecules, including 1,4-disubstituted-1,2,3-triazoles, chalcones, and benzothiazepines, was rationalized with the help of Molecular Field Topology Analysis, a 3D QSAR technique similar to CoMFA. A common pharmacophore supported the concept of a link existing between type-2 diabetes mellitus and Alzheimer's disease. These findings will be instrumental for rational design of drug candidates for both of these conditions. PMID- 24780602 TI - Autosomal recessive primary microcephalies (MCPH). AB - Autosomal recessive primary microcephaly (MCPH) is a genetically heterogeneous disease characterized by a pronounced reduction in volume of otherwise architectonical normal brains and intellectual deficit. Here, we summarize the genetic causes of MCPH types 1-12 known to date. PMID- 24780601 TI - Lead optimization of dual tubulin and Hsp27 inhibitors. AB - Tubulin and heat shock protein 27 (Hsp27) are well-characterized molecular targets for anti-cancer drug development. We previously identified lead compounds that inhibited both Hsp27 and tubulin. These compounds exhibited extensive anti cancer activities against the proliferation of various human cancer cell lines. In the current study, a systematic ligand based structural optimization led to new analogs that significantly inhibited the growth of a panel of breast cancer cell lines. Furthermore, the most potent compounds were examined with tubulin polymerization assay and Hsp27 chaperone activity assay. The compounds showed potent tubulin polymerization inhibition but no Hsp27 inhibitory effect. The structural optimization dissected the dual activity and improved the selectivity of the compounds for tubulin. The results revealed several structural moieties of the lead compounds that are critical for Hsp27 inhibition. The modification of these structural fragments eliminated Hsp27 inhibition, but did not harm tubulin targeting effects of the compounds. This result further defined the structure activity relationship between the tubulin and Hsp27 effects of these compounds. PMID- 24780603 TI - Long-term follow-up in children with benign convulsions associated with gastroenteritis. AB - BACKGROUND: The outcome of benign convulsions associated with gastroenteritis (CwG) has generally been reported as being excellent. However, these data need to be confirmed in studies with longer follow-up evaluations. AIM: To assess the long-term neurological outcome of a large sample of children presenting with CwG. METHODS: We reviewed clinical features of 81 subjects presenting with CwG (1994 2010) from three different Italian centers with a follow-up period of at least 3 years. RESULTS: Follow-up period ranged from 39 months to 15 years (mean 9.8 years). Neurological examination and cognitive level at the last evaluation were normal in all the patients. A mild attention deficit was detected in three cases (3.7%). Fourteen children (17.3%) received chronic anti-epileptic therapy. Interictal EEG abnormalities detected at onset in 20 patients (24.7%) reverted to normal. Transient EEG epileptiform abnormalities were detected in other three cases (3.7%), and a transient photosensitivity in one (1.2%). No recurrence of CwG was observed. Three patients (3.7%) presented with a febrile seizure and two (2.5%) with an unprovoked seizure, but none developed epilepsy. CONCLUSIONS: The long-term evaluation of children with CwG confirms the excellent prognosis of this condition, with normal psychomotor development and low risk of relapse and of subsequent epilepsy. PMID- 24780604 TI - Maternal viral infection during pregnancy impairs development of fetal serotonergic neurons. AB - BACKGROUND: Maternal viral infection during pregnancy induces morphological abnormalities in the fetus and may cause emotional and psychological problems in offspring through unknown mechanisms. We have previously shown that prenatal exposure of rats to chemicals such as thalidomide causes an autistic-like phenotype in offspring, indicating that prenatal events affecting serotonergic development may cause developmental disorder. METHODS: We investigated whether prenatal viral infection altered the expression of neurotransmitters involved in the emotional or psychological status of offspring. We here took advantage of the polyriboinosinic:polyribocytidylic acid (poly I:C) system, the synthetic double stranded RNA, which is often used in animal models of viral infection. RESULTS: Ten mg/kg of poly I:C was intraperitoneally injected on gestational day (GD) 9 and counted the numbers of serotonin-immunopositive cells on GD15 using flat whole-mount preparation method, resulting 11.1% of increase in the number of serotonergic neurons in poly I:C group. Furthermore, there was a significant decrease in hippocampal serotonin content in offspring by postnatal day 50 following poly I:C administration by high-performance liquid chromatography. DISCUSSION AND CONCLUSION: Since serotonin is known to link with behavior and emotion after birth, these results suggest that maternal viral infection might cause, in addition to morphological abnormalities, serotonin-related pathogenesis such as neurodevelopmental disorders including autism spectrum disorders. PMID- 24780605 TI - Principal author of PRIDE study responds to news story in The BMJ claiming that the study was based on "flawed" analysis. PMID- 24780606 TI - Quality of life assessment in patients after mandibular resection and free fibula flap reconstruction. AB - PURPOSE: The aim of the present study was to assess patients' quality of life (QOL) after mandibular resection and reconstruction with the free fibula flap (FFF). MATERIALS AND METHODS: We performed a retrospective study of all patients who underwent segmental mandibular resection and FFF reconstruction at the Division of Oral and Maxillofacial Surgery, McGill University Health Center. The patients were contacted and asked to complete a QOL assessment at least 1 year after surgery. The patients' photographs were taken and evaluated for the esthetic outcomes after surgery by 2 dental health professionals using a visual analog scale and compared with the patients' self-evaluations. A descriptive analysis was used for data analysis. RESULTS: Seventeen patients underwent segmental mandibular resection and reconstruction with a FFF, and 11 completed the QOL questionnaire. Two patients were deceased at the start of the study, 1 refused to complete the QOL questionnaire, and 3 had developed disease recurrence and were not asked to complete the QOL questionnaire. Of the 11 patients who completed the QOL assessment, 8 rated their overall QOL as outstanding, very good, or good and 3 reported it to be fair. No significant correlation was found between the patients' self-reported esthetic evaluation and the third-party evaluations. CONCLUSIONS: Most patients who underwent mandibular resection and FFF reconstruction reported satisfaction with their overall QOL. We did not find a correlation between the patients' perceived esthetic outcome and the dental healthcare professionals' assessment. PMID- 24780607 TI - Orbital fractures and ocular injury: is a postoperative ophthalmology examination necessary? AB - PURPOSE: To determine whether formal ophthalmology evaluation is necessary after operative repair of orbital fractures and the association of an ocular injury to the severity of facial injury. PATIENTS AND METHODS: This was a retrospective cohort study of patients with orbital fractures undergoing operative repair from 2005 to 2013. Subjects were included if they had undergone reconstruction of orbital floor fractures and had data from pre- and postoperative examinations by the oral and maxillofacial surgery and ophthalmology services available. The predictor variables included the service performing the ocular examination (oral and maxillofacial surgery or ophthalmology) and the number of fractures present. The outcome variables were the presence of pre- and postoperative ocular injuries. Logistic regression models were used to determine the relationship of the fracture number to ocular injury. RESULTS: A total of 28 subjects had undergone repair of orbital fractures with preoperative and postoperative examinations performed by both services. Preoperative ocular injuries were found in 17 of the 28 subjects. Those detected by oral and maxillofacial surgeons were limited to changes in visual acuity, pupillary response, and extraocular muscle dysfunction in 11 subjects. Two subjects had new postoperative ocular findings that were considered minor and did not alter management. An increasing number of facial fractures was associated with an increased risk of ocular trauma. Those with 3 or more fractures had an odds ratio of 14.625 (95% confidence interval, 2.191 to 97.612, P = .006) for the presence of ocular injury. CONCLUSIONS: Operative repair of orbital fractures did not lead to new ocular injuries that would change the management. Thus, those without preoperative ocular injuries will not require a formal postoperative ophthalmology examination. However, the subjects with more fractures had an increased likelihood of ocular injuries. PMID- 24780608 TI - Lymphoma mimics obstructive sialadenitis: three cases. AB - Obstructive sialadenitis is a common salivary gland disorder usually secondary to viral or bacterial infections, sialolithiasis, duct stricture, or mucous plug. The differential diagnosis also should include dehydration, trauma, and scarring secondary to oral mucosal surgical procedures or neoplasm. It is important to consider neoplasm in these patients, especially when symptoms do not resolve as expected after treatment for obstruction. In a series of 591 cases referred to the Massachusetts General Hospital Oral and Maxillofacial Surgery Service for "obstructive sialadenitis" from 2009 through 2012, 3 patients had obstruction secondary to low-grade follicular lymphoma. PMID- 24780609 TI - Validation of mandibular genioplasty using a stereolithographic surgical guide: in vitro comparison with a manual measurement method based on preoperative surgical simulation. AB - PURPOSE: Stereolithographic guidance, increasingly used in orthognathic surgery, has not been completely verified for genioplasty. This study compared the accuracy of manual measurement with that of a stereolithographic guide in vitro. MATERIALS AND METHODS: Thirty rapid prototype (RP) mandibular models (15 pairs) were included in the experimental (stereolithographic) and control (manual) groups (15 each). Surgical simulation was performed in the 2 groups by advancing the chin 5 mm and then vertically reducing the chin 5 mm using Mimics software. In the stereolithographic group, genioplasty was performed on mandibular RP models using a 3-dimensionally printed surgical guide based on surgical simulation results. In the control group, it was performed using an osteotomy line drawn according to simulation measurements. For the 2 groups, anterior horizontal transverse error and anterior and posterior vertical errors were compared, as were data from the osteotomized chin segment and the preoperative surgical simulation. Positional difference error was calculated and the differences were evaluated with t tests. RESULTS: For advancement genioplasty, the absolute anterior transverse error value was 0.47 +/- 0.35 (mean +/- standard deviation) with the stereolithographic guide, less than with the manual method (0.77 +/- 0.45; P = .001). For reduction genioplasty, the absolute anterior vertical error value was 0.27 +/- 0.23 mm with the stereolithographic guide versus 0.58 +/- 0.49 mm with the manual method (P < .001). CONCLUSION: Use of a stereolithographic surgical guide increased accuracy, but the difference in mean error values between methods was only approximately 0.3 mm. The superior accuracy may not be compelling in favor of stereolithographic surgical guides. PMID- 24780610 TI - Running exercise alleviates trabecular bone loss and osteopenia in hemizygous beta-globin knockout thalassemic mice. AB - A marked decrease in beta-globin production led to beta-thalassemia, a hereditary anemic disease associated with bone marrow expansion, bone erosion, and osteoporosis. Herein, we aimed to investigate changes in bone mineral density (BMD) and trabecular microstructure in hemizygous beta-globin knockout thalassemic (BKO) mice and to determine whether endurance running (60 min/day, 5 days/wk for 12 wk in running wheels) could effectively alleviate bone loss in BKO mice. Both male and female BKO mice (1-2 mo old) showed growth retardation as indicated by smaller body weight and femoral length than their wild-type littermates. A decrease in BMD was more severe in female than in male BKO mice. Bone histomorphometry revealed that BKO mice had decreases in trabecular bone volume, trabecular number, and trabecular thickness, presumably due to suppression of osteoblast-mediated bone formation and activation of osteoclast mediated bone resorption, the latter of which was consistent with elevated serum levels of osteoclastogenic cytokines IL-1alpha and -1beta. As determined by peripheral quantitative computed tomography, running increased cortical density and thickness in the femoral and tibial diaphyses of BKO mice compared with those of sedentary BKO mice. Several histomorphometric parameters suggested an enhancement of bone formation (e.g., increased mineral apposition rate) and suppression of bone resorption (e.g., decreased osteoclast surface), which led to increases in trabecular bone volume and trabecular thickness in running BKO mice. In conclusion, BKO mice exhibited pervasive osteopenia and impaired bone microstructure, whereas running exercise appeared to be an effective intervention in alleviating bone microstructural defect in beta-thalassemia. PMID- 24780612 TI - Osseointegration of short titan implants: A pilot study in pigs. AB - Reduced vertical bone level in the implantation area is often considered one of the limiting factors before implant insertion. Inserting implants of reduced length might be useful in order to avoid vertical bone augmentation prior to implantation. To the present day, no official guidelines exist as to the optimal length for these implants. It is nevertheless well known that the stability of an implant depends primarily on its osseointegration, which could otherwise be influenced by modifying implant surface texture. The aim of our study was to evaluate osseointegration in correlation with implant length and surface texture. Three different variations of titan implants (n=5) were compared: two types, each with an acid-etched and ceramic blasted surface, were inserted in the upper jaw of adult female minipigs at different lengths (tioLogic ST Shorty, 5mm length; tioLogic ST, 9mm length) and were compared to a control group (tioLogic ST, 9mm length, ceramic blasted surface). Eight weeks after unloaded healing, bone tissue specimens containing the implants were processed, stained with Masson-Goldner trichrome and analyzed histologically. Regardless of implant length and surface texture, new bone formation with no signs of inflammation could be detected in the area of the threads. Implants with a modified surface showed no statistically significant difference in bone-implant-contact (BIC) (tioLogic ST Shorty, 56.5%; tioLogic((c))ST; 77.2%), but a statistically significant difference could be found, when the 9mm implants were compared to the control group (BIC 48.9%). Surface modification could positively influence osseointegration as well as contribute to overcoming the adverse effects of length reduction. PMID- 24780611 TI - Central adiponectin administration reveals new regulatory mechanisms of bone metabolism in mice. AB - Adiponectin (APN), the most abundant adipocyte-secreted adipokine, regulates energy homeostasis and exerts well-characterized insulin-sensitizing properties. The peripheral or central effects of APN regulating bone metabolism are beginning to be explored but are still not clearly understood. In the present study, we found that APN-knockout (APN-KO) mice fed a normal diet exhibited decreased trabecular structure and mineralization and increased bone marrow adiposity compared with wild-type (WT) mice. APN intracerebroventricular infusions decreased uncoupling protein 1 (UCP1) expression in brown adipose tissue, epinephrine and norepinephrine serum levels, and osteoclast numbers, whereas osteoblast osteogenic marker expression and trabecular bone mass increased in APN KO and WT mice. In addition, centrally administered APN increased hypothalamic tryptophan hydroxylase 2 (TPH2), cocaine- and amphetamine-regulated transcript (CART), and 5-hydroxytryptamine (serotonin) receptor 2C (Htr2C) expressions but decreased hypothalamic cannabinoid receptor-1 expression. Treatment of immortalized mouse neurons with APN demonstrated that APN-mediated effects on TPH2, CART, and Htr2C expression levels were abolished by downregulating adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper motif (APPL)-1 expression. Pharmacological increase in sympathetic activity stimulated adipogenic differentiation of bone marrow stromal cells (BMSC) and reversed APN-induced expression of the lysine-specific demethylases involved in regulating their commitment to the osteoblastic lineage. In conclusion, we found that APN regulates bone metabolism via central and peripheral mechanisms to decrease sympathetic tone, inhibit osteoclastic differentiation, and promote osteoblastic commitment of BMSC. PMID- 24780613 TI - Evaluating the efficacy of mineralocorticoid receptor antagonism in patients with STEMI without heart failure. PMID- 24780615 TI - Randomized trial comparing ferric carboxymaltose vs oral ferrous glycine sulphate for postoperative anaemia after total knee arthroplasty. AB - BACKGROUND: Despite preoperative anaemia treatment, a risk of postoperative anaemia remains. This randomized, controlled study evaluated the efficacy of i.v. ferric carboxymaltose (FCM) as postoperative anaemia treatment after total knee arthroplasty (TKA). METHODS: TKA patients with postoperative anaemia [haemoglobin (Hb) 8.5-12.0 g dl(-1)] without prior transfusions were randomly assigned to FCM [700-1000 mg iron (according to calculate iron deficit on postoperative day 2)] or ferrous glycine sulphate (FS; 100 mg iron daily from day 7 onwards) and followed for Hb, iron status, quality-of-life (EQ-5D), and performance (6 min walk test) until day 30. RESULTS: Of 161 preoperatively non-anaemic patients, 122 (75.8%) developed anaemia after operation (within 24 h) and were enrolled in this study (60 FCM, 62 FS). Hb substantially decreased until day 4 in both groups, and partly recovered by day 30. FCM-treated patients achieved Hb >=12.0 g dl(-1) more frequently (42.3% vs 23.5%; P=0.04) and showed a trend towards higher Hb increase from day 4 to day 30 [+1.7 (1.2) vs +1.3 (1.0); P=0.075] compared with FS-treated patients. Patients with postoperative Hb <10 g dl(-1) experienced better Hb increase with FCM [+2.4 (0.3) g dl(-1)] than FS [+1.1 (0.4) g dl(-1); P=0.018]. Patients being iron-deficient at enrolment (56.7%) had a higher Hb increase with FCM [+1.9 (0.3) g dl(-1)] than FS [+1.2 (0.2) g dl(-1); P=0.03]. Total EQ-5D and performance outcomes were comparable between the groups, but FCM was associated with better scores for 'usual activities'. No i.v. iron-related adverse events were reported. CONCLUSIONS: Preoperatively non-anaemic TKA patients are at high risk of postoperative anaemia. Postoperative i.v. FCM provided significant benefit over oral FS, particularly in patients with preoperative iron deficiency, severe postoperative anaemia, or both. CLINICAL TRIAL REGISTRATION: EudraCT 2010 023038-22; ClinicalTrials.gov NCT01913808. PMID- 24780616 TI - Frequent mutation of rs13281615 and its association with PVT1 expression and cell proliferation in breast cancer. AB - The q24 band of chromosome 8 (8q24) is frequently amplified in human cancers including breast cancer, and several SNPs (single nucleotide polymorphisms) at 8q24, including rs13281615, have been identified for their association with cancer risks. These SNPs are in a "gene desert" region, and their functions in cancer development remain to be illustrated, although several of the SNPs appear to influence the genes in the "desert" in a long-range manner, including the v myc avian myelocytomatosis viral oncogene homolog (MYC) and the non-protein coding plasmacytoma variant translocation 1 (PVT1), both of which have been implicated in human cancers. In the current study, we examined rs13281615 for its potential role in breast cancer using normal and cancer tissues from 121 Chinese women with breast cancer. In addition to confirming the association of the GG genotype of rs13281615 with breast cancer risk, we found that germline GG genotype was significantly associated with estrogen receptor (ER) positivity, higher tumor grade and higher proliferation index. We also found frequent somatic mutations (22/121 or 18.2%) of this SNP in breast cancer. Interestingly, the majority of the mutations (17/22 or 77%) involved a G->A change, resulting in a decrease in the number of cancers with the GG risk genotype and subsequent loss of GG association with higher tumor grade and proliferation index in cancers. Furthermore, PVT1 expression was increased in cancers, and the increase was associated with the GG genotype of rs13281615. These results suggest that the GG genotype of SNP rs13281615 plays a role in breast cancer likely by influencing PVT1 expression, and that during oncogenesis, "protective" mutations could occur. PMID- 24780614 TI - Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study. AB - AIMS: We aimed to assess the impact of eplerenone on cardiovascular (CV) outcomes in STEMI without known heart failure, when initiated within 24 h of symptom onset. METHODS AND RESULTS: In this randomized, placebo-controlled, double-blind trial, we assigned 1012 patients with acute STEMI and without a history of heart failure to receive either eplerenone (25-50 mg once daily) or placebo in addition to standard therapy. The primary endpoint was the composite of CV mortality, re hospitalization, or, extended initial hospital stay, due to diagnosis of HF, sustained ventricular tachycardia or fibrillation, ejection fraction <=40%, or elevated BNP/NT-proBNP at 1 month or more after randomization. BNP elevation was defined as BNP levels or values above 200 pg/mL or NT-proBNP values above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or above 1800 pg/mL (patients older than 75). After a mean follow-up of 10.5 months, the primary endpoint occurred in 92 patients (18.2%) in the eplerenone group and in 149 patients (29.4%) in the placebo group [adjusted hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.76; P < 0.0001]. The primary endpoint was driven by a high BNP/NT-proBNP level (adjusted HR, 0.60; 95% CI, 0.45-0.79; P < 0.0003). Adverse event rates were similar in both groups. Serum potassium levels exceeded 5.5 mmol/L in 5.6 vs. 3.2% (P = 0.09) and were below 3.5 mmol/L in 1.4 vs. 5.6% of patients (P = 0.0002), in the eplerenone and placebo groups, respectively. CONCLUSION: The addition of eplerenone during the acute phase of STEMI was safe and well tolerated. It reduced the primary endpoint over a mean 13 months follow up mostly because of significantly lower BNP/NT-proBNP levels. Additional studies are needed to clarify the role of early use of MRAs in STEMI patients without heart failure. CLINICAL TRIAL REGISTRATION: NCT01176968. PMID- 24780617 TI - Genetic analysis of 17 children with Hunter syndrome: identification and functional characterization of four novel mutations in the iduronate-2-sulfatase gene. AB - Mucopolysaccharidosis type II (MPS II) is a rare X-linked disorder caused by alterations in the iduronate-2-sulfatase (IDS) gene. In this study, IDS activity in peripheral mononuclear blood monocytes (PMBCs) was measured with a fluorimetric enzyme assay. Urinary glycosaminoglycans (GAGs) were quantified using a colorimetric assay. All IDS exons and intronic flanks were bidirectionally sequenced. A total of 15 mutations (all exonic region) were found in 17 MPS II patients. In this cohort of MPS II patients, all alterations in the IDS gene were caused by point nucleotide substitutions or small deletions. Mutations p.Arg88His and p.Arg172* occurred twice. All mutations were inherited except for p.Gly489Alafs*7, a germline mutation. We found four new mutations (p.Ser142Phe, p.Arg233Gly, p.Glu430*, and p.Ile360Tyrfs*31). In Epstein-Barr virus (EBV)-immortalized PMBCs derived from the MPS II patients, no IDS protein was detected in case of the p.Ser142Phe and p.Ile360Tyrfs*31 mutants. For p.Arg233Gly and p.Glu430*, we observed a residual expression of IDS. The p.Arg233Gly and p.Glu430* mutants had a residuary enzymatic activity that was lowered by 14.3 and 76-fold, respectively, compared with healthy controls. This observation may help explain the mild disease phenotype in MPS II patients who had these two mutations whereas the p.Ser142Phe and p.Ile360Tyrfs*31 mutations caused the severe disease manifestation. PMID- 24780618 TI - Molecular cytogenetic characterization of a wheat - Leymus mollis 3D(3Ns) substitution line with resistance to leaf rust. AB - Leymus mollis (Trin.) Pilger (NsNsXmXm, 2n = 28), a wild relative of common wheat, possesses many potentially valuable traits that could be transferred to common wheat during breeding programs. In this study, the karyotypic constitution of a wheat - L. mollis 3D(3Ns#1) disomic substitution line isolated from the F5 progeny of octoploid Tritileymus M842-16 * Triticum durum cv. D4286, which was designated as 10DM57, was determined using genomic in situ hybridization (GISH), fluorescent in situ hybridization (FISH), SSR markers, and EST-STS markers. Screening of mitosis and meiosis showed that 10DM57 had a chromosome karyotype of 2n = 42 = 21II. GISH indicated that 10DM57 was a line with 40 chromosomes from wheat and two of the Ns chromosomes from L. mollis, which formed a ring bivalent in pollen mother cells at metaphase I. FISH analysis showed that the chromosome 3D may be replaced by 3Ns#1 in 10DM57. DNA markers, including SSR and EST-STS primers, showed that the pair of wheat chromosome 3D in 10DM57 was substituted by the pair of chromosome 3Ns#1 from L. mollis. Evaluation of the agronomic traits showed that, compared with its common wheat relative 7182, 10DM57 was resistant to leaf rust while the spike length and number of spikes per plant were improved significantly, which correlated with a higher wheat yield. The new germplasm, 10DM57, could be exploited as an intermediate material in wheat genetic and breeding programs. PMID- 24780619 TI - Mutagenesis at specific genomic loci of amphioxus Branchiostoma belcheri using TALEN method. PMID- 24780620 TI - Egg-derived tyrosine phosphatase as a potential biomarker for muscle ageing and degeneration in Drosophila melanogaster. PMID- 24780621 TI - The role of autophagy during development of the oomycete pathogen Phytophthora infestans. PMID- 24780622 TI - The magnitude of nocebo effects in pain: a meta-analysis. AB - The investigation of nocebo effects is evolving, and a few literature reviews have emerged, although so far without quantifying such effects. This meta analysis investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term "nocebo." Only studies that investigated nocebo effects as the effects that followed the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen's d and Hedges' g. The overall magnitude of the nocebo effect was moderate to large (lowest g=0.62 [0.24-1.01] and highest g=1.03 [0.63 1.43]) and highly variable (range of g=-0.43 to 4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d=0.81) in mechanistic studies. In studies in which nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g=0.76 [0.39-1.14] and highest g=1.17 [0.52-1.81]) than in studies in which nocebo effects were induced by verbal suggestions alone (lowest g=0.64 [-0.25 to 1.53] and highest g=0.87 [0.40-1.34]). These findings are similar to those in the placebo literature. As the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates the importance of minimizing nocebo effects in clinical practice. PMID- 24780624 TI - Evolution of specific immunity in shrimp - a vaccination perspective against white spot syndrome virus. AB - Invertebrates lack true adaptive immunity and it solely depends on the primitive immunity called innate immunity. However, various innate immune molecules and mechanisms are identified in shrimp that plays potential role against invading bacterial, fungal and viral pathogens. Perceiving the shrimp innate immune mechanisms will contribute in developing effective vaccine strategies against major shrimp pathogens. Hence this review intends to explore the innate immune molecules of shrimp with suitable experimental evidences together with the evolution of "specific immune priming" of invertebrates. In addition, we have emphasized on the development of an effective vaccine strategy against major shrimp pathogen, white spot syndrome virus (WSSV). The baculovirus displayed rVP28 (Bac-VP28), a major envelope protein of WSSV was utilized to study its vaccine efficacy by oral route. A significant advantage of this baculovirus expression cassette is the use of WSSV-immediate early 1 (ie1) promoter that derived the abundant expression of rVP28 protein at the early stage of the infection in insect cell. The orally vaccinated shrimp with Bac-VP28 transduced successfully in the shrimp cells as well as provided highest survival rate. In support to our vaccine efficacy we analysed Pattern Recognition Proteins (PRPs) beta-1,3 glucan lipopolysaccharides (LGBP) and STAT gene profiles in the experimental shrimp. Indeed, the vaccination of shrimp with Bac-VP28 demonstrated some degree of specificity with enhanced survival rate when compared to control vaccination with Bac-wt. Hence it is presumed that the concept of "specific immune priming" in relevant to shrimp immunity is possible but may not be common to all shrimp pathogens. PMID- 24780623 TI - Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions: a systematic review and meta-analysis. AB - Recent systematic reviews have reported a positive, although modest, effect of probiotics in terms of preventing common cold symptoms. In this systematic review, the effect of probiotics, specifically Lactobacillus and Bifidobacterium strains, on the duration of acute respiratory infections in otherwise healthy children and adults was evaluated. To identify relevant trials, eight databases, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Science Citation Index (SCI) and OAISTER, were searched from inception to 20 July 2012. Details regarding unpublished studies/databases were also obtained from probiotic manufacturers. Study selection, data extraction and quality assessment were carried out by two reviewers. Risk of bias was assessed using criteria adapted from those published by the Centre for Reviews and Dissemination. In this review, twenty randomised controlled trials (RCT) were included, of which twelve were considered to have a low risk of bias. Meta-analysis revealed significantly fewer numbers of days of illness per person (standardised mean difference (SMD) - 0.31 (95% CI - 0.41, - 0.11), I2= 3%), shorter illness episodes by almost a day (weighted mean difference - 0.77 (95% CI - 1.50, - 0.04), I2= 80%) (without an increase in the number of illness episodes), and fewer numbers of days absent from day care/school/work (SMD - 0.17 (95% CI - 0.31, - 0.03), I2= 67%) in participants who received a probiotic intervention than in those who had taken a placebo. Reasons for heterogeneity between the studies were explored in subgroup analysis, but could not be explained, suggesting that the effect sizes found may differ between the population groups. This systematic review provides evidence from a number of good-quality RCT that probiotics reduce the duration of illness in otherwise healthy children and adults. PMID- 24780625 TI - Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. AB - Mutations in the Huntington locus (htt) have devastating consequences. Gain-of poly-Q repeats in Htt protein causes Huntington's disease (HD), while htt(-/-) mutants display early embryonic lethality. Despite its importance, the function of Htt remains elusive. To address this, we compared more than 3700 compounds in three syngeneic mouse embryonic stem cell (mESC) lines: htt(-/-), extended poly-Q (Htt-Q140/7), and wild-type mESCs (Htt-Q7/7) using untargeted metabolite profiling. While Htt-Q140/7 cells did not show major differences in cellular bioenergetics, we find extensive metabolic aberrations in htt(-/-) mESCs, including (i) complete failure of ATP production despite preservation of the mitochondrial membrane potential; (ii) near-maximal glycolysis, with little or no glycolytic reserve; (iii) marked ketogenesis; (iv) depletion of intracellular NTPs; (v) accelerated purine biosynthesis and salvage; and (vi) loss of mitochondrial structural integrity. Together, our findings reveal that Htt is necessary for mitochondrial structure and function from the earliest stages of embryogenesis, providing a molecular explanation for htt(-/-) early embryonic lethality. PMID- 24780626 TI - Delayed transition to new cell fates during cellular reprogramming. AB - In many embryos specification toward one cell fate can be diverted to a different cell fate through a reprogramming process. Understanding how that process works will reveal insights into the developmental regulatory logic that emerged from evolution. In the sea urchin embryo, cells at gastrulation were found to reprogram and replace missing cell types after surgical dissections of the embryo. Non-skeletogenic mesoderm (NSM) cells reprogrammed to replace missing skeletogenic mesoderm cells and animal caps reprogrammed to replace all endomesoderm. In both cases evidence of reprogramming onset was first observed at the early gastrula stage, even if the cells to be replaced were removed earlier in development. Once started however, the reprogramming occurred with compressed gene expression dynamics. The NSM did not require early contact with the skeletogenic cells to reprogram, but the animal cap cells gained the ability to reprogram early in gastrulation only after extended contact with the vegetal halves prior to that time. If the entire vegetal half was removed at early gastrula, the animal caps reprogrammed and replaced the vegetal half endomesoderm. If the animal caps carried morpholinos to either hox11/13b or foxA (endomesoderm specification genes), the isolated animal caps failed to reprogram. Together these data reveal that the emergence of a reprogramming capability occurs at early gastrulation in the sea urchin embryo and requires activation of early specification components of the target tissues. PMID- 24780627 TI - A gene expression atlas of early craniofacial development. AB - We present a gene expression atlas of early mouse craniofacial development. Laser capture microdissection (LCM) was used to isolate cells from the principal critical microregions, whose development, differentiation and signaling interactions are responsible for the construction of the mammalian face. At E8.5, as migrating neural crest cells begin to exit the neural fold/epidermal ectoderm boundary, we examined the cranial mesenchyme, composed of mixed neural crest and paraxial mesoderm cells, as well as cells from adjacent neuroepithelium. At E9.5 cells from the cranial mesenchyme, overlying olfactory placode/epidermal ectoderm, and underlying neuroepithelium, as well as the emerging mandibular and maxillary arches were sampled. At E10.5, as the facial prominences form, cells from the medial and lateral prominences, the olfactory pit, multiple discrete regions of underlying neuroepithelium, the mandibular and maxillary arches, including both their mesenchymal and ectodermal components, as well as Rathke's pouch, were similarly sampled and profiled using both microarray and RNA-seq technologies. Further, we performed single cell studies to better define the gene expression states of the early E8.5 pioneer neural crest cells and paraxial mesoderm. Taken together, and analyzable by a variety of biological network approaches, these data provide a complementing and cross validating resource capable of fueling discovery of novel compartment specific markers and signatures whose combinatorial interactions of transcription factors and growth factors/receptors are responsible for providing the master genetic blueprint for craniofacial development. PMID- 24780628 TI - Foxi3 is necessary for the induction of the chick otic placode in response to FGF signaling. AB - Vertebrate cranial sensory organs are derived from region at the border of the anterior neural plate called the pre-placodal region (PPR). The otic placode, the anlagen of the inner ear, is induced from PPR ectoderm by FGF signaling. We have previously shown that competence of embryonic ectoderm to respond to FGF signaling during otic placode induction correlates with the expression of PPR genes, but the molecular basis of this competence is poorly understood. Here, we characterize the function of a transcription factor, Foxi3 that is expressed at very early stages in the non-neural ectoderm and later in the PPR of chick embryos. Ablation experiments showed that the underlying hypoblast is necessary for the initiation of Foxi3 expression. Mis-expression of Foxi3 was sufficient to induce markers of non-neural ectoderm such as Dlx5, and the PPR such as Six1 and Eya2. Electroporation of Dlx5, or Six1 together with Eya1 also induced Foxi3, suggesting direct or indirect positive regulation between non-neural ectoderm genes and PPR genes. Knockdown of Foxi3 in chick embryos prevented the induction of otic placode markers, and was able to prevent competent cranial ectoderm from expressing otic markers in response to FGF2. In contrast, Foxi3 expression alone was not sufficient to confer competence to respond to FGF on embryonic ectoderm. Our analysis of PPR and FGF-responsive genes after Foxi3 knockdown at gastrula stages suggests it is not necessary for the expression of PPR genes at these stages, nor for the transduction of FGF signals. The early expression but late requirement for Foxi3 in ear induction suggests it may have some of the properties associated with pioneer transcription factors. PMID- 24780629 TI - Rab23 regulates Nodal signaling in vertebrate left-right patterning independently of the Hedgehog pathway. AB - Asymmetric fluid flow in the node and Nodal signaling in the left lateral plate mesoderm (LPM) drive left-right patterning of the mammalian body plan. However, the mechanisms linking fluid flow to asymmetric gene expression in the LPM remain unclear. Here we show that the small GTPase Rab23, known for its role in Hedgehog signaling, plays a separate role in Nodal signaling and left-right patterning in the mouse embryo. Rab23 is not required for initial symmetry breaking in the node, but it is required for expression of Nodal and Nodal target genes in the LPM. Microinjection of Nodal protein and transfection of Nodal cDNA in the embryo indicate that Rab23 is required for the production of functional Nodal signals, rather than the response to them. Using gain- and loss-of function approaches, we show that Rab23 plays a similar role in zebrafish, where it is required in the teleost equivalent of the mouse node, Kupffer's vesicle. Collectively, these data suggest that Rab23 is an essential component of the mechanism that transmits asymmetric patterning information from the node to the LPM. PMID- 24780630 TI - Genotype-phenotype relationship in a child with 2.3 Mb de novo interstitial 12p13.33-p13.32 deletion. AB - Microdeletion 12p13.33, though very rare, is an emerging condition associated with variable phenotype including a specific speech delay sound disorder, labelled childhood apraxia of speech (CAS), intellectual disability (ID) and neurobehavioral problems. Here we report a de novo 2.3 Mb interstitial 12p13.33 p13.32 deletion in a 5 year-old child with mild ID, speech delay, microcephaly, muscular hypotonia, and joint laxity. In contrast to previously reported patients with 12p13.33 monosomy, our patient's interstitial deletion spans the 12p13.33 12p13.32 region with the distal breakpoint within intron 12 of CACNA1C. Phenotype genotype comparison between our case, previously reported patients, and subjects with 12p13.33 deletions led us to propose that haploinsufficiency of CACNA1C may influence the variability of the patients' phenotype, since the gene resulted disrupted or entirely deleted in the majority of reported patients. In addition, phenotypic features such as microcephaly, muscular hypotonia, and joint laxity are mainly present in patients with monosomy of 12p13.33 extending to the 12p13.32 portion. A common region of ~300 kb, harbouring EFCAB4B and PARP11, is deleted in patients with microcephaly while a second region of ~700 kb, including TSPAN9 and PMTR8, could be associated with muscle hypotonia and joint laxity. These data reinforce the hypothesis that multiple haploinsufficient genes and age dependent observation may concur to generate the variable phenotype associated with 12p13.33 deletion. PMID- 24780631 TI - Body weight and body composition of depot medroxyprogesterone acetate users. AB - OBJECTIVES: Weight gain is a concern with the contraceptive depot medroxyprogesterone acetate (DMPA); however, this issue remains controversial. The objective of this study was to compare body weight (BW) and body composition (BC) in DMPA and copper intrauterine device (IUD) users at baseline and after one year of use. STUDY DESIGN: We enrolled new DMPA users and age and weight matched new IUD users into this prospective study. Weight and height were measured, BC (fat and lean mass) was evaluated using dual-energy X-ray absorptiometry, and physical activity was assessed at baseline and at 12 months. Student's paired t test and the Wilcoxon paired test for matched samples were used. RESULTS: Ninety seven women were enrolled for the study; 26 matched pairs continued using the initial method for at least one year, and completed the baseline and 12 month assessments. An increase of 1.9 kg occurred in BW (p=.02) in DMPA users at 12 months of use, resulting from an increase in fat mass of 1.6 kg (p=.03). Weight remained stable in IUD users; however, there was an increase in lean mass at 12 months of use (p=.001). The number of women practicing physical activity increased in this group. There was a significant difference between the groups regarding the variation in the percentage of central fat (p=.04). CONCLUSION: Weight gain in the DMPA group after the first year of use resulted from an increase in fat mass. Weight remained stable in the IUD group; however, an increase in lean mass and a reduction in localized abdominal fat mass occurred, possibly because more users were practicing physical activity. IMPLICATIONS STATEMENT: There was a greater increase in body weight in DMPA users compared to TCu380A IUD users in the first year of use of the contraceptive method. Furthermore, the weight increase in users of DMPA occurred principally as the result of an increase in fat mass. Physical activity probably could increase the lean mass in the users of TCu380A IUD. PMID- 24780632 TI - Exploring aspects of physiotherapy care valued by breast cancer patients. AB - OBJECTIVE: To explore the reported value of physiotherapy care received by patients who had accessed a Specialist Breast Care Physiotherapy Service. DESIGN: Exploratory qualitative study using in-depth interviews to explore aspects of physiotherapy care valued by breast cancer patients. Thematic network analysis was used to interpret the data and bring together the different experiences of the participants and identify common themes. SETTING: Physiotherapy Department at a NHS Foundation Trust Teaching Hospital. PARTICIPANTS: Nineteen participants were recruited and three were selected to take part in the in-depth interviews. All participants had received physiotherapy care from a Specialist Breast Care Physiotherapy Service and had been discharged within the last six months. RESULTS: Participants valued a patient-centred holistic approach to care and access to a Specialist Service with an experienced clinician. In particular the importance of the therapeutic alliance and the value of psychological, emotional and educational support emerged, with the participants feeling empowered in their recovery. CONCLUSION AND CLINICAL IMPLICATIONS: Participants reported an overall positive experience of their physiotherapy care. This study supports the need for service providers to evaluate their current physiotherapy provision and subsequently develop Specialised Services to meet the physiotherapy needs of breast cancer patients throughout all stages of their treatment pathway from the delivery of pre-operative care through to post-treatment follow-up. PMID- 24780633 TI - Evidence-based practice in physiotherapy: a systematic review of barriers, enablers and interventions. AB - BACKGROUND: Despite clear benefits of the Evidence-Based Practice (EBP) approach to ensuring quality and consistency of care, its uptake within physiotherapy has been inconsistent. OBJECTIVES: Synthesise the findings of research into EBP barriers, facilitators and interventions in physiotherapy and identify methods of enhancing adoption and implementation. DATA SOURCES: Literature concerning physiotherapists' practice between 2000 and 2012 was systematically searched using: Academic Search Complete, Cumulative Index of Nursing and Allied Health Literature Plus, American Psychological Association databases, Medline, Journal Storage, and Science Direct. Reference lists were searched to identify additional studies. STUDY SELECTION: Thirty-two studies, focusing either on physiotherapists' EBP knowledge, attitudes or implementation, or EBP interventions in physiotherapy were included. DATA EXTRACTION AND SYNTHESIS: One author undertook all data extraction and a second author reviewed to ensure consistency and rigour. Synthesis was organised around the themes of EBP barriers/enablers, attitudes, knowledge/skills, use and interventions. RESULTS: Many physiotherapists hold positive attitudes towards EBP. However, this does not necessarily translate into consistent, high-quality EBP. Many barriers to EBP implementation are apparent, including: lack of time and skills, and misperceptions of EBP. LIMITATIONS: Only studies published in the English language, in peer-reviewed journals were included, thereby introducing possible publication bias. Furthermore, narrative synthesis may be subject to greater confirmation bias. CONCLUSION AND IMPLICATIONS: There is no "one-size fits all" approach to enhancing EBP implementation; assessing organisational culture prior to designing interventions is crucial. Although some interventions appear promising, further research is required to explore the most effective methods of supporting physiotherapists' adoption of EBP. PMID- 24780634 TI - Contextual regulation of pancreatic cancer stem cell phenotype and radioresistance by pancreatic stellate cells. AB - BACKGROUND AND PURPOSE: Progression of pancreatic ductal adenocarcinoma (PDAC) is promoted by desmoplasia induced by pancreatic stellate cells (PSC). Contributory to this progression is epithelial mesenchymal transition (EMT), which shares many characteristics with the cancer stem cell (CSC) hypothesis. We investigated the role of these processes on the radioresponse and tumorigenicity of pancreatic cancer cells. MATERIALS AND METHODS: We used an in vitro sphere model and in vivo xenograft model to examine the role of PSC in EMT and CSC processes. RESULTS: We demonstrated that PSC enhanced the CSC phenotype and radioresistance of pancreatic cancer cells. Furthermore, the expression of several EMT and CSC markers supported enhanced processes in our models and that translated into remarkable in vivo tumorigenicity. Multi-dose TGFbeta neutralizing antibody inhibited the EMT and CSC processes, sensitized cells to radiation and reduced in vivo tumorigenicity. A proteomic screen identified multiple novel factors that were regulated by PSC in pancreatic cells. CONCLUSION: These results are critical in highlighting the role of PSC in tumor progression and radioresistance by manipulating the EMT and CSC processes. TGFbeta and the novel factors identified are important targets for better therapeutic outcome in response to PSC mediated mechanisms. PMID- 24780635 TI - Pattern of occult nodal relapse diagnosed with (18)F-fluoro-choline PET/CT in prostate cancer patients with biochemical failure after prostate-only radiotherapy. AB - INTRODUCTION: The purpose of this study was to describe the pattern of nodal relapse with (18)F-fluoro-choline (FCH) Positron Emission Tomography/Computerized Tomography (PET/CT) in prostate cancer patients after radiotherapy. MATERIALS AND METHODS: Eighty-three patients had a FCH PET/CT at time of biochemical failure. Of 65 patients with positive findings, 33 had positive nodes. This analysis included 31 patients who had undergone prior prostate-only radiotherapy with or without a prior radical prostatectomy. Each FCH positive node was assigned to a lymph node station with respect to the CTV defined by the RTOG guidelines (CTVRTOG). 3D mapping was performed after each node was manually placed in a reference planning CT scan after automatic co-registration of the two scans based on bone anatomy. Eighteen patients (58%) underwent focal salvage FCH PET-guided stereotactic radiotherapy with no hormones. RESULTS: Fourteen patients (45.2%) had a relapse outside the CTVRTOG. Of the 17 patients with a positive node inside the CTVRTOG, 15 had a single node (88.2%) while seven patients out of the 13 evaluable patients (53.9%) who had a relapse outside the CTVRTOG had ?2 positive nodes on FCH PET/CT (OR=8.75, [95% CI: 1.38-54.80], p=0.020). Relapses that occurred outside the CTVRTOG involved the proximal common iliac (19.3%) and lower periaortic nodes (19.3%) up to L2-L3. CONCLUSION: 3D mapping of nodal relapses evaluated with FCH PET/CT suggests that with IMRT the upper field limit of pelvic radiotherapy could be extended to L2-L3 safely to cover 95% of nodal stations at risk of an occult relapse. PMID- 24780636 TI - Structural change of N-glycan exposes hydrophobic surface of human transferrin. AB - Transferrin is an iron-transport protein which possesses N-glycans at Asn432 and Asn630 in humans. Transferrin glycoforms Tf-1 and Tf-2, previously identified in human cerebrospinal fluid, are defined as the lower and upper bands in gel electrophoresis, respectively. Importantly, the Tf-2/Tf-1 ratio is raised in idiopathic normal pressure hydrocephalus patients and is useful as a clinical marker. In order to gain insight into the relationship between transferrin glycoform and biological function, we performed comparative characterization of Tf-1, Tf-2 and serum transferrin (sTf). Mass spectrometric analyses confirmed that Tf-2 is modified with disialylated biantennary glycans at both of the two N glycosylation sites, which are similar to the N-glycans of sTf. On the other hand, Tf-1 is site-specifically modified: Asn630 has biantennary agalacto-complex type glycan with bisecting N-acetylglucosamine (GlcNAc) and core fucose while Asn432 is modified with complex/high mannose-type glycans and possibly single GlcNAc. Size exclusion chromatography and fluorescence correlation spectroscopy analysis revealed that the hydration volume of Tf-1 is slightly smaller than that of sTf. Our striking finding is that Tf-1 has an exposed hydrophobic surface as monitored by the fluorescence intensity and wavelength of a hydrophobic probe, 1 anilino-8-naphthalene sulfonate, whereas Tf-2 does not. These results suggest that the different N-glycan structure of Tf-1 lowers the apparent hydration volume and reveals a patch of hydrophobic surface on transferrin which is otherwise covered with sialoglycan in sTf and Tf-2. The carbohydrate deficiency in certain pathological conditions may also expose hydrophobic surface which may modulate the function and/or stability of transferrin. PMID- 24780637 TI - Use, fate and ecological risks of antibiotics applied in tilapia cage farming in Thailand. AB - The use, environmental fate and ecological risks of antibiotics applied in tilapia cage farming were investigated in the Tha Chin and Mun rivers in Thailand. Information on antibiotic use was collected through interviewing 29 farmers, and the concentrations of the most commonly used antibiotics, oxytetracycline (OTC) and enrofloxacin (ENR), were monitored in river water and sediment samples. Moreover, we assessed the toxicity of OTC and ENR on tropical freshwater invertebrates and performed a risk assessment for aquatic ecosystems. All interviewed tilapia farmers reported to routinely use antibiotics. Peak water concentrations for OTC and ENR were 49 and 1.6 MUg/L, respectively. Antibiotics were most frequently detected in sediments with concentrations up to 6908 MUg/kg d.w. for OTC, and 2339 MUg/kg d.w. for ENR. The results of this study indicate insignificant short-term risks for primary producers and invertebrates, but suggest that the studied aquaculture farms constitute an important source of antibiotic pollution. PMID- 24780638 TI - Use of propofol for short duration procedures in children with long chain 3 hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiencies. AB - The medication propofol, commonly used for anesthesia, has been avoided in patients with mitochondrial fatty acid oxidation disorders (FAODs) due to concerns that it contains long-chain fatty acids (LCFAs), and because of reports of severe side effects in some critically ill patients receiving high-dose propofol infusions that mimic some of the symptoms regularly found in FAOD patients. In this secondary analysis, we examined the outcomes of 8 children with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency or trifunctional protein (TFP) deficiency who were repeatedly sedated for an electroretinogram (ERG) as part of a longitudinal study of the progression of chorioretinopathy commonly found in this population. A total of 39 sedated ERG procedures were completed using propofol for sedation. The propofol dosing, estimated total energy needs of the subject, and inpatient dietary intake recording were completed in 32 of these procedures. The LCFAs in the propofol provided approximately 1.0% of the average total daily energy needs. The sedation with propofol resulted in no adverse side effects and was safely used in this short duration procedure. PMID- 24780639 TI - Identification and differential expression of hepatopancreas microRNAs in red swamp crayfish fed with emodin diet. AB - Using high-throughput Illumina Solexa system, the differential miRNA expressions from hepatopancreas in red swamp crayfish (Procambarus clarkii) fed with diets containing 0 (control) and 75 mg emodin kg(-1) (trial) were identified, respectively. As a result, 13,335,928 raw reads from the control sample and 14,938,951 raw reads from the trial sample were obtained while 13,053,344 (98.77%) and 14,517,522 (98.34%) small RNA were identified, respectively. 106 mature miRNAs (belonging to 68 miRNA gene families) were identified. 35 miRNAs displayed significantly differential expressions between two libraries. Of these, comparing to the control library, 6 miRNAs were significantly up-regulated and 29 miRNAs were significantly down-regulated. Moreover, 5 novel miRNAs (2 from control sample, 3 from trial sample) and target genes were predicted. GO analysis suggested that these miRNAs might be involved in innate immune response, growth, metabolism, cellular process, biological regulation and stimulus response. Our knowledge from this study could contribute to a better understanding of the miRNAs roles in regulating innate immune response and the study of miRNA function in crayfish. PMID- 24780640 TI - Multiple protein stationary phases: a review. AB - Cellular membrane affinity chromatography stationary phases have been extensively used to characterize immobilized proteins and provide a direct measurement of multiple binding sites, including orthosteric and allosteric sites. This review will address the utilization of immobilized cellular and tissue fragments to characterize multiple transmembrane proteins co-immobilized onto a stationary phase. This approach will be illustrated by demonstrating that multiple transmembrane proteins were immobilized from cell lines and tissue fragments. In addition, the immobilization of individual compartments/organelles within a cell will be discussed and the changes in the proteins binding/kinetics based on their location. PMID- 24780641 TI - Which proportion of extended-spectrum beta-lactamase producing strains could be treated by non-carbapenem beta-lactams? PMID- 24780642 TI - Molecular characterization of a novel proto-type antimicrobial protein galectin-1 from striped murrel. AB - In this study, we reported a molecular characterization of a novel proto-type galectin-1 from the striped murrel Channa striatus (named as CsGal-1). The full length CsGal-1 was identified from an established striped murrel cDNA library and further we confirmed the sequence by cloning. The complete cDNA sequence of CsGal 1 is 590 base pairs (bp) in length and its coding region encoded a poly peptide of 135 amino acids. The polypeptide contains a galactoside binding lectin domain at 4-135. The domain carries a sugar binding site at 45-74 along with its signatures (H(45)-X-Asn(47)-X-Arg(49) and Trp(69)-X-X-Glu(72)-X-Arg(74)). CsGal-1 shares a highly conserved carbohydrate recognition domain (CRD) with galectin-1 from other proto-type galectin of teleosts. The mRNA expressions of CsGal-1 in healthy and various immune stimulants including Aphanomyces invadans, Aeromonas hydrophila, Escherchia coli lipopolysaccharide and poly I:C injected tissues of C. striatus were examined using qRT-PCR. CsGal-1 mRNA is highly expressed in kidney and is up-regulated with different immune stimulants at various time points. To understand its biological activity, the coding region of CsGal-1 gene was expressed in an E. coli BL21 (DE3) cloning system and its recombinant protein was purified. The recombinant CsGal-1 protein was agglutinated with mouse erythrocytes at a concentration of 4MUg/mL in a calcium independent manner. CsGal 1 activity was inhibited by d-galactose at 25mM(-1) and d-glucose and d-fructose at 100mM(-1). The results of microbial binding assay showed that the recombinant CsGal-1 protein agglutinated only with the Gram-negative bacteria. Interestingly, we observed no agglutination against Gram-positive bacteria. Overall, the study showed that CsGal-1 is an important immune gene involved in the recognition and elimination of pathogens in C. striatus. PMID- 24780643 TI - Cardiovascular responses to the ingestion of sugary drinks using a randomised cross-over study design: Does glucose attenuate the blood pressure-elevating effect of fructose? AB - Overconsumption of sugar-sweetened beverages has been implicated in the pathogenesis of CVD. The objective of the present study was to elucidate acute haemodynamic and microcirculatory responses to the ingestion of sugary drinks made from sucrose, glucose or fructose at concentrations similar to those often found in commercial soft drinks. In a randomised cross-over study design, twelve young healthy human subjects (seven men) ingested 500 ml tap water in which was dissolved 60 g of either sucrose, glucose or fructose, or an amount of fructose equivalent to that present in sucrose (i.e. 30 g fructose). Continuous cardiovascular monitoring was performed for 30 min before and at 60 min after ingestion of sugary drinks, and measurements included beat-to-beat blood pressure (BP) and impedance cardiography. Additionally, microvascular endothelial function testing was performed after iontophoresis of acetylcholine and sodium nitroprusside using laser Doppler flowmetry. Ingestion of fructose (60 or 30 g) increased diastolic and mean BP to a greater extent than the ingestion of 60 g of either glucose or sucrose (P< 0.05). Ingestion of sucrose and glucose increased cardiac output (CO; P< 0.05), index of contractility (P< 0.05) and stroke volume (P< 0.05), but reduced total peripheral resistance (TPR; P< 0.05), which contrasts with the tendency of fructose (60 and 30 g) to increase resistance. Microvascular endothelial function did not differ in response to the ingestion of various sugary drinks. In conclusion, ingestion of fructose, but not sucrose, increases BP in healthy human subjects. Although sucrose comprises glucose and fructose, its changes in TPR and CO are more related to glucose than to fructose. PMID- 24780644 TI - Nuclear translocation of heparan sulfate proteoglycans and their functional significance. AB - BACKGROUND: Heparan sulfate proteoglycans (HSPGs) are important constituents of the cell membrane and they act as co-receptors for cellular signaling. Syndecan 1, glypican and perlecan also translocate to the nucleus in a regulated manner. Similar nuclear transport of growth factors and heparanase indicate a possible co regulation and functional significance. SCOPE OF REVIEW: In this review we dissect the structural requirement for the nuclear translocation of HSPGs and their functional implications.s MAJOR CONCLUSIONS: The functions of the nuclear HSPGs are still incompletely understood. Evidence point to possible functions in hampering cell proliferation, inhibition of DNA topoisomerase I activity and inhibition of gene transcription. GENERAL SIGNIFICANCE: HSPGs influence the behavior of malignant tumors in many different ways. Modulating their functions may offer powerful tools to control fundamental biological processes and provide the basis for subsequent targeted therapies in cancer. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. PMID- 24780646 TI - Comparative autoradiographic in vitro investigation of melanin concentrating hormone receptor 1 ligands in the central nervous system. AB - The MCHR1 is an interesting pharmacological and pharmaceutical target, due to its involvement in pathologies as diabetes, gut inflammation and adiposity. in vivo PET-studies of the MCHR1 in energy homeostasis and diabetes could be of great value for deeper understanding of endocrinological hormone status and consequential pharmacological interactions. Furthermore, PET-tracers would facilitate compound dose selection of MCHR1 antagonists for treatment. Therefore, we developed two potential PET-tracers, [(11)C]SNAP-7941 and [(18)F]FE@SNAP, for the in vivo visualization of this receptor. Aim of this study was a preclinical in vitro evaluation of both unlabeled ligands. Therefore, a comparative autoradiographic investigation on CNS (coronal rat brain and 4 different human brain regions) and peripheral tissues (rat tongue as target and rat testes as non target region) was conducted. Competition experiments, using the two radioligands [(125)I]-MCH and [(125)I]-S36057, were performed with selective and specific MCHR1 ligands as PMC-3886, a MCHR1 agonist, SNAP-7941 and FE@SNAP, two MCHR1 antagonists. Additionally, immunohistochemical staining with a specific MCHR1 antibody was performed. Specific binding was found in all tissues known to express the MCHR1 as human and rat CNS and peripheral rat tongue tissue. No specific binding was found in the non-target region of rat testes. MCHR1 antibody staining complemented the outcome of the autoradiographic experiments. The compounds SNAP-7941 and FE@SNAP were generally comparable with PMC-3886. Hence, the in vitro autoradiographic study of the unlabeled compounds SNAP-7941 and FE@SNAP further qualifies the potential of the PET-tracers [(11)C]SNAP-7941 and [(18)F]FE@SNAP as useful MCHR1 PET-tracers. PMID- 24780645 TI - The cytochrome P450 genes of channel catfish: their involvement in disease defense responses as revealed by meta-analysis of RNA-Seq data sets. AB - BACKGROUND: Cytochrome P450s (CYPs) encode one of the most diverse enzyme superfamily in nature. They catalyze oxidative reactions of endogenous molecules and exogenous chemicals. METHODS: We identified CYPs genes through in silico analysis using EST, RNA-Seq and genome databases of channel catfish. Phylogenetic analyses and conserved syntenic analyses were conducted to determine their identities and orthologies. Meta-analysis of RNA-Seq databases was conducted to analyze expression profile of CYP genes following bacterial infection. RESULTS: A full set of 61 CYP genes was identified and characterized in channel catfish. Phylogenetic tree and conserved synteny provided strong evidence of their identities and orthorlogy. Lineage-specific gene duplication was evident in a number of clans in channel catfish. CYP46A1 is missing in the catfish genome as observed with syntenic analysis and RT-PCR analysis. Thirty CYPs were found up- or down-regulated in liver, while seven and eight CYPs were observed regulated in intestine and gill following bacterial infection. CONCLUSION: We systematically identified and characterized a full set of 61 CYP genes in channel catfish and studied their expression profiles after bacterial infection. While bacterial challenge altered the expression of large numbers of CYP genes, the mechanisms and significance of these changes are not known. GENERAL SIGNIFICANCE: This work provides an example to systematically study CYP genes in non-model species. Moreover, it provides a basis for further toxicological and physiological studies in channel catfish. PMID- 24780647 TI - Specific inhibitory effects of the NO donor MAHMA/NONOate on human platelets. AB - Nitric oxide (NO) is a physiological inhibitor of platelet function and has vaso dilating effects. Therefore, synthesized NO releasing agents are used e.g. in cardiovascular medicine. The aim of this study was to characterise specific effects of the short living agent MAHMA/NONOate, a NO donor of the diazeniumdiolate class, on human platelets. Whole blood was obtained from healthy volunteers. In washed human platelets, the MAHMA/NONOate induced phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) and cyclic nucleotide production were studied by Western Blot and by enzyme immunoassay kits. Agonist induced aggregation was measured in platelet rich plasma. Paired Student's t-test was used for statistical analysis. MAHMA/NONOate significantly stimulated platelet VASP phosphorylation in a concentration dependent manner and increased intracellular cGMP, but not cAMP levels, transiently. ODQ, a specific inhibitor of the soluble guanylyl cyclase, completely prevented VASP phosphorylation induced by low MAHMA/NONOate concentrations (5nM-15nM). The effects of higher concentrations (30-200nM) were only partially inhibited by ODQ. MAHMA/NONOate reduced platelet aggregation induced by low doses of agonists (2uM ADP, 0.5ug/mL collagen, 5uM TRAP-6) in a concentration dependent manner. MAHMA/NONOate leads to a rapid and transient activation of platelet inhibitory systems, accompanied by decreased platelet aggregation induced by low dose agonists. At low MAHMA/NONOate concentrations, the effects are cGMP dependent and at higher concentrations additionally cGMP independent. The substance could be of interest for clinical situations requiring transient and subtotal inhibition of platelet function. PMID- 24780648 TI - Paradoxical action of reactive oxygen species in creation and therapy of cancer. AB - A great number of comprehensive literature believe that reactive oxygen species (ROS) and their products play a significant role in cell homeostasis maintenance, tissue protection against further insults by controlling cells proliferation through inducing apoptosis, and defending against cancer. ROS is believed to be like a potential double-edged sword in both cancer progression and prevention. Although at low and moderate levels ROS affect some of the most essential mechanisms of cell survival such as proliferation, angiogenesis and tumor invasion, at higher levels these agents can expose cells to detrimental consequences of oxidative stress including DNA damage and apoptosis that result in therapeutic effects on cancer. Understanding the new aspects on molecular mechanisms and signaling pathways modulating creation and therapy of cancers by ROS is critical in development of therapeutic strategies for patients suffering from cancer. This paper presents a general overview and rationale of paradoxical action of ROS in creation and therapy of cancer, tests to be used, and examples of how it may be applied. PMID- 24780649 TI - Priming and testing silicon patch-clamp neurochips. AB - We report on the systematic and automated priming and testing of silicon planar patch-clamp chips after their assembly in Plexiglas packages and sterilization in an air plasma reactor. We find that almost 90% of the chips are successfully primed by our automated setup, and have a shunt capacitance of between 10 pF and 30 pF. Blocked chips are mostly due to glue invasion in the well, and variability in the manual assembly process is responsible for the distribution in shunt capacitance value. Priming and testing time with our automated setup is less than 5 min per chip, which is compatible with the production of large series for use in electrophysiology experiments. PMID- 24780650 TI - [Acute respiratory distress syndrome: a review of the Berlin definition]. AB - Acute Respiratory Distress Syndrome (ARDS) is due to many causes. The absence of a universal definition up until now has led to a series of practical problems for a definitive diagnosis. The incidences of ARDS and Acute Lung Injury (ALI) vary widely in the current literature. The American-European Consensus Conference definition has been applied since its publication in 1994 and has helped to improve knowledge about ARDS. However, 18 years later, in 2011, the European Intensive Medicine Society, requested a team of international experts to meet in Berlin to review the ARDS definition. The purpose of the Berlin definition is not to use it as a prognostic tool, but to improve coherence between research and clinical practice. PMID- 24780651 TI - Long-term admission to the intensive care unit: a cost-benefit analysis. AB - OBJECTIVE: To assess outcomes in long-term ICU patients, with follow-ups carried out at one year post discharge, in order to calculate the costs incurred by the hospital in relation to the benefits gained. MATERIAL: Of 3639 patients consecutively admitted over the course of three years to ICU, 235 (6.5%) were assessed for the purposes of the study, having spent a period exceeding 20 days in intensive care. METHOD: The survey tool used was the Spanish Minimum Data Set (MDS). The length of ICU stay and hospital stay following discharge from ICU were calculated, and one year post discharge the patient/next of kin was contacted in order to carry out a follow-up survey on survival and functional status (according to GOS-E scale). RESULTS: The 235 study patients had a mean stay of 37 days, occupied 34% of ICU beds available and consumed 29% of the ICU's economic resources ($14,400,175). Their stay on hospital wards was (mean) 33 days. Mortality in ICU and on hospital wards was 40% higher amongst older patients, and those with a higher APACHE II and Charlson index score. Mortality rates were three times higher among neurosurgical patients: mortality at follow-up was 25%, and only 21% recovered an acceptable functional status. CONCLUSIONS: Mortality rates in long-term ICU patients are high, both during their hospital stay and in the first year post discharge. Surviving patients do not exhibit a good level of recovery, and consume a large proportion of economic resources. PMID- 24780652 TI - Importance of "acknowledging and reducing treatment uncertainty" in appraisal and revalidation. PMID- 24780653 TI - Pasteurella multocida infected total knee arthroplasty: a case report and review of the literature. AB - Pasteurella multocida is a rare cause of prosthetic joint infection. This infection generally follows significant animal contact, usually licks and scratches. We report a case of P multocida infection that was treated with linezolid with salvage of the implant. Linezolid is generally active against Gram positive organisms only with the exception of Pasteurella, which is Gram negative. We extensively review the previous reported cases of implant infection with P multocida. PMID- 24780654 TI - Pharyngeal angiosarcoma following multimodal treatment for oropharyngeal squamous cell carcinoma. AB - It is well established that angiosarcoma can develop following radiotherapy. We present an unusual case of angiosarcoma of the pharynx that developed three years after treatment with surgery and adjuvant chemoradiotherapy for a T2N2bM0 squamous cell carcinoma of the oropharynx. The patient was tumour free until developing dysphagia, which was found to be caused by an angiosarcoma. The patient underwent surgery of the pharyngeal angiosarcoma by laryngopharyngectomy, tongue base resection, selective neck dissection and radial forearm microvascular free flap reconstruction. Angiosarcoma following head and neck malignancy is rare but must be considered as part of the differential diagnosis in patients with new symptoms after radiotherapy. PMID- 24780655 TI - Surgical resection of hepatic and cardiac neuroendocrine metastases from a caecal primary tumour. AB - A 66-year-old patient had an incidentally detected caecal neuroendocrine tumour that had metastasised to the liver and left atrium. He was asymptomatic with regard to this tumour and did not have carcinoid syndrome. Resection of the primary tumour and the metastatic deposits (with the ablation of one lesion) is thought to be curative. PMID- 24780656 TI - Two case reports of perineal hernia after laparoscopic abdominoperineal resection with a proposed modification to the operative technique. AB - Perineal hernia is a rare complication following laparoscopic abdominoperineal resection (APR) for rectal cancer. We present two case reports of perineal hernia following laparoscopic APR and discuss their management. We suggest that they developed because the pelvic peritoneum was left open during laparoscopic APR and propose that closure of the pelvic peritoneum should be routine in this operation. PMID- 24780657 TI - Septic arthritis in the era of immunosuppressive treatments. AB - Immunosuppressants have been the mainstay of treatment for certain inflammatory joint conditions for many years. Developments in this field, namely biological treatments, have led to a change in the classical presentation of acute bone, joint and soft tissue infections. The normal findings of severe pain and tenderness on examination may be absent or simply mimic a typical exacerbation of the chronic joint condition. A minimally raised white cell count and elevated C reactive protein in the absence of systemic signs of infection may be interpreted as further evidence for the diagnosis of an exacerbation of inflammatory arthritis. We present a unique case of recurrent polyarticular septic arthritis in a patient treated with immunosuppression for refractory rheumatoid arthritis. We hope this article will enable doctors to appreciate and recognise the changing face of septic arthritis in the modern era of immunosuppressant treatments. PMID- 24780658 TI - Intracortical haematogenous osteomyelitis. AB - We present an unusual case of haematogenous osteomyelitis in the diaphysis of the tibia of an adult leading to a subacute presentation with an extracortical abscess. Fluid from the abscess grew methicillin resistant Staphylococcus aureus (MRSA) on culture; MRSA with the same antibiogram had been grown from the patient's blood seven years earlier following a bowel resection. Drainage of the abscess and curettage of the bone lesion together with appropriate antibiotic therapy led to resolution of the osteomyelitis. PMID- 24780659 TI - Conservative management of renal artery pseudoaneurysm following partial nephrectomy. AB - A bleeding renal artery pseudoaneurysm is a recognised complication occurring after partial nephrectomy. The bleeding is usually suspected when a patient presents with haematuria following the procedure and the reported management is with radiologically guided embolisation. We report a case of renal artery pseudoaneurysm successfully managed conservatively, giving another potential management option in non-torrential haemorrhage. PMID- 24780660 TI - Stiff fingers as an unwanted side effect of intravascular tadalafil gel abuse. AB - The internet provides the public with unregulated access to a wide range of medications. We present the case of a 43-year-old man who purchased oral tadalafil gel on the internet and injected it into his left radial artery. He presented 48 hours after injection with signs of ischaemia distal to the injection site requiring a combination of medical and surgical treatment. This unique case highlights the potential dangers of unregulated access to medication and the consequences of intravascular injection of oral gels. PMID- 24780661 TI - Intrathoracic migration of an unbent Steinmann pin. AB - Steinmann pins are known to be used as a shoulder stabilisation device in recurrent dislocation. Although rare, their potential to migrate within the thorax has been reported. We present the case of an 87-year-old man who was treated for recurrent left shoulder dislocation with pinning using a Steinmann pin. He presented eight days postoperatively with the pin impaling the aortic adventitia. To our knowledge, this is only the fifth case report of such an event. Awareness of this complication and attempts to prevent its occurrence are critical as the outcome can be fatal. PMID- 24780662 TI - A systematic review of patient reported outcomes and patient experience in enhanced recovery after orthopaedic surgery. AB - INTRODUCTION: Orthopaedic enhanced recovery after surgery (ERAS) providers are encouraged to estimate the actual benefit of ERAS according to the patient's opinion by using patient generated data alongside traditional measures such as length of stay. The aim of this paper was to systemically review the literature on the use of patient generated information in orthopaedic ERAS across the whole perioperative pathway. METHODS: Publications were identified using Embase(TM), MEDLINE((r)), AMED, CINAHL((r)) (Cumulative Index to Nursing and Allied Health Literature), the Cochrane Library and the British Nursing Index. Search terms related to experiences, acceptance, satisfaction or perception of ERAS and quality of life (QoL). FINDINGS: Of the 596 abstracts found, 8 papers were identified that met the inclusion criteria. A total of 2,208 patients undergoing elective hip and knee arthroplasty were included. Patient satisfaction was reported in 6 papers. Scores were high in all patients and not adversely affected by length of stay. QoL was reported in 2 papers and showed that QoL scores continued to increase up to 12 months following ERAS. Qualitative methods were used in one study, which highlighted problems with support following discharge. There is a paucity of data reporting on patient experience in orthopaedic ERAS. However, ERAS does not compromise patient satisfaction or QoL after elective hip or knee surgery. The measurement of patient experience should be standardised with further research. PMID- 24780663 TI - Retraction of unreliable publication. PMID- 24780664 TI - Pain after laparoscopic antireflux surgery. AB - INTRODUCTION: The benefits of antireflux surgery are well established. Laparoscopic techniques have been shown to be generally safe and effective. The aim of this paper was to review the subject of pain following laparoscopic antireflux surgery. METHODS: A systematic review of the literature was conducted using the PubMed database to identify all studies reporting pain after laparoscopic antireflux surgery. Publications were included for the main analysis if they contained at least 30 patients. Operations in children, Collis gastroplasty procedures, endoluminal fundoplication and surgery for paraoesophageal hernias were excluded. The frequency of postoperative pain was calculated and the causes/management were reviewed. An algorithm for the investigation of patients with pain following laparoscopic fundoplication was constructed. RESULTS: A total of 17 studies were included in the main analysis. Abdominal pain and chest pain following laparoscopic fundoplication were reported in 24.0% and 19.5% of patients respectively. Pain was mild or moderate in the majority and severe in 4%. Frequency of pain was not associated with operation type. The authors include their experience in managing patients with persistent, severe epigastric pain following laparoscopic anterior fundoplication. CONCLUSIONS: Pain following laparoscopic antireflux surgery occurs in over 20% of patients. Some have an obvious complication or a diagnosis made through routine investigation. Most have mild to moderate pain with minimal effect on quality of life. In a smaller proportion of patients, pain is severe, persistent and can be disabling. In this group, diagnosis is more difficult but systematic investigation can be rewarding, and can enable appropriate and successful treatment. PMID- 24780665 TI - The constrictor knot is the best ligature. AB - INTRODUCTION: An ideal ligature should tighten readily and remain tight. Ligature failure can be a critical complication of invasive procedures in human and veterinary surgical practice. Previous studies have tested various knots but not the constrictor knot. METHODS: A new test bench was employed to compare six ligatures using four suture materials. As tension in a ligature is not readily measured, the study employed a surrogate measurement: the force required to slide a ligature along a rod. Benchmark values tested each suture material wrapped around the rod to establish the ratio between this force and the ligature tension for each material. Each ligature was tested first during tightening and then again afterwards. The benchmark ratios were employed to calculate the tensions to evaluate which ligature and which suture material retained tension best. RESULTS: The model provided consistent linear relationships between the tension in the suture and the force required to pull the ligature along the rod. The constrictor knot retained tension in the ligature best (55-107% better than the next best ligature). Among the suture materials, polydioxanone had the greatest ability to retain the tension in a ligature and polyglactin the least. CONCLUSIONS: The constrictor knot showed superior characteristics for use as a ligature, and should be introduced into teaching and clinical practice for human and veterinary surgery. The new test bench is recommended for future testing of ligatures as well as objective comparison of suture materials. PMID- 24780666 TI - Fracture healing following high energy tibial trauma: Ilizarov versus Taylor Spatial Frame. AB - INTRODUCTION: The optimal treatment of high energy tibial fractures remains controversial and a challenging orthopaedic problem. The role of external fixators for all these tibial fractures has been shown to be crucial. METHODS: A five-year consecutive series was reviewed retrospectively, identifying two treatment groups: Ilizarov and Taylor Spatial Frame (TSF; Smith & Nephew, Memphis, TN, US). Fracture healing time was the primary outcome measure. RESULTS: A total of 112 patients (85 Ilizarov, 37 TSF) were identified for the review with a mean age of 45 years. This was higher in women (57 years) than in men (41 years). There was no significant difference between frame types (p=0.83). The median healing time was 163 days in both groups. There was no significant difference in healing time between smokers and non-smokers (180 vs 165 days respectively, p=0.07), open or closed fractures (p=0.13) or age and healing time (Spearman's r=0.12, p=0.18). There was no incidence of non-union or re-fracture following frame removal in either group. CONCLUSIONS: Despite the assumption of the rigid construct of the TSF, the median time to union was similar to that of the Ilizarov frame and the TSF therefore can play a significant role in complex tibial fractures. PMID- 24780667 TI - A preliminary study of manipulation under anaesthesia for secondary frozen shoulder following breast cancer treatment. AB - INTRODUCTION: The aim of this paper is to present the results of manipulation under anaesthesia (MUA) and injection of local anaesthetic and corticosteroid followed by a physiotherapy regime for secondary frozen shoulder after breast cancer treatment (surgery, radiotherapy), and to compare them with a control group. METHODS: Patients referred to the senior author for secondary frozen shoulder following breast cancer treatment over a ten-year period were investigated. Recorded data included age, treatment for breast cancer, length of symptoms, Oxford shoulder score (OSS) and range of motion before and after shoulder MUA. These data were compared with a control group of patients with frozen shoulder. RESULTS: A total of 263 patients were referred with 281 frozen shoulders. Of these, 7 patients (7 shoulders) had undergone previous breast cancer treatment and the remaining 256 patients (274 shoulders) formed the control group. None of the patients were diabetic. The mean preoperative OSS was 31 for the study group and 27 for the control group, improving to 43 for both groups following MUA. Forty-two per cent of the study group and fifteen per cent of the control group had a second MUA subsequently. At the long-term follow-up appointment, 71% of the study group patients were satisfied with their result. CONCLUSIONS: The results of this preliminary study suggest that MUA, corticosteroid injection and subsequent physiotherapy have achieved good final results in a series of patients with frozen shoulder secondary to breast cancer treatment. Members of the multidisciplinary team looking after breast cancer patients should be aware of this management option and, on manifestation of this pathology, should refer the patient to an orthopaedic surgeon. PMID- 24780668 TI - Survey of management of common iliac artery aneurysms by members of the Vascular Society of Great Britain and Ireland. AB - INTRODUCTION: The aim of this study was to determine whether the current management of common iliac artery aneurysms (CIAAs) by vascular surgeons is in tune with existing guidelines for referral. METHODS: This was a postal survey of members of the Vascular Society of Great Britain and Ireland. The main outcome measures were relative frequency of ruptured CIAA, respondents' size threshold for surveillance versus intervention, and their management strategies for isolated unilateral CIAAs, bilateral CIAAs and aortoiliac aneurysms. RESULTS: Two hundred and eighty-four (anonymous) replies were received (48% response rate). Respondents estimated that a ruptured abdominal aortic aneurysm (AAA) was 25 times more common than a ruptured CIAA. Most surgeons (64%) would wait until a CIAA reached 4 cm in diameter before considering intervention. This threshold was not affected by other scenarios such as the presence of a bilateral CIAA or a small (4 cm) AAA. Eighty per cent of surgeons would treat a non-ruptured CIAA by stenting, where possible. The majority of surgeons felt that ultrasonography surveillance should be commenced when a CIAA exceeds 1.5 cm, with a surveillance interval of 1 year but with more frequent surveillance for CIAAs wider than 3 cm. CONCLUSIONS: Existing guidelines that recommend referral for possible intervention for non-ruptured CIAAs at a diameter of 3 cm are out of tune with current practice. Most surgeons in this survey would wait until the diameter was 4 cm. PMID- 24780669 TI - Patterns of arteriosclerotic lesions of the lower extremity in a West Indian population based on angiographic findings and ethnicity. AB - INTRODUCTION: This study aimed to determine whether ethnic differences show different patterns of arterial disease in the lower limb. METHODS: A prospective analysis of 100 consecutive patients with 160 lower limb arteriograms was performed looking at the pattern of disease with relation to ethnicity in Trinidad and Tobago. RESULTS: There were 53 male and 47 female patients with an age range of 43-90 years (mean: 66 years). Of the 100 patients, 45 were of East Indian descent, 36 of Afro-Caribbean descent, 14 of mixed descent and 5 had other backgrounds. There were 32 smokers and 69 diabetics. The most commonly affected artery in East Indians was the anterior tibial artery (ATA, 70%) followed by the peroneal artery (60%), superficial femoral artery (SFA, 60%), posterior tibial artery (PTA, 57%) and tibioperoneal trunk (TPT, 39%). In Afro-Caribbeans, the most commonly affected artery was the ATA (79%) followed by the PTA (74%), peroneal artery (66%) and TPT (55%). The mixed group showed the PTA (85%) to be most diseased followed by the peroneal artery (75%), ATA (70%), SFA (70%), dorsalis pedis artery (DPA, 60%) and TPT (50%). Overall, the most diseased vessel in all groups was the ATA (73%) followed by the PTA (66%), peroneal artery (64%), SFA (59%), TPT (46%), DPA (38%), popliteal artery (31%) and medial plantar artery (MPA, 29%), with the proximal vessels not being affected severely. CONCLUSIONS: Ethnic divisions were only statistically significant (p<0.05) with East Indians showing worse disease in the profunda femoris artery and Afro-Caribbeans showing worse disease in the PTA, DPA and MPA. This suggests that environmental factors may play a significant role in the disease process including smoking and dietary factors rather than purely genetics. PMID- 24780670 TI - Perioperative tranexamic acid in day-case paediatric tonsillectomy. AB - INTRODUCTION: Tranexamic acid has been used for many years to minimise blood loss during surgery and, more recently, to reduce morbidity after major trauma. While small studies have confirmed reduction in blood loss during tonsillectomy with its use, the rate of primary haemorrhage following tonsillectomy has not been reported. In the UK, less than 50% of children having a tonsillectomy are managed as day cases, partly because of concerns about bleeding during the initial 24 hours following surgery. METHODS: A retrospective review of clinical records between January 2007 and January 2013 produced 476 children between the ages of 3 and 16 years who underwent CoblationTM tonsillectomy, with or without adenoidectomy and/or insertion of ventilation tubes. All children were ASA (American Society of Anesthesiologists) grade 1 or 2 and anaesthetised using a standard day surgery protocol. Following induction of anaesthesia, all received intravenous tranexamic acid at a dose of 10-15 mg/kg. RESULTS: Two children (0.4%) had minor bleeding within two hours of surgery. Both returned to theatre for haemostasis and were discharged home later the same day with no further complications. The expected rate for primary haemorrhage in the UK using this technique for tonsillectomy is 1%. CONCLUSIONS: Perioperative tranexamic acid in a single, parenteral dose might reduce the incidence of primary haemorrhage following paediatric tonsillectomy, facilitating discharge on the day of surgery. The results from this observational study indicate a potential benefit and need for a large, prospective, multicentre, randomised controlled trial. PMID- 24780671 TI - Assessment of recurrent laryngeal nerve function during thyroid surgery. AB - INTRODUCTION: There is disparity in the reported incidence of temporary and permanent recurrent laryngeal nerve (RLN) palsy following thyroidectomy. Much of the disparity is due to the method of assessing vocal cord function. We sought to identify the incidence and natural history of temporary and permanent vocal cord palsy following thyroid surgery. The authors wanted to establish whether intraoperative nerve monitoring and stimulation aids in prognosis when managing vocal cord palsy. METHODS: Prospective data on consecutive thyroid operations were collected. Intraoperative nerve monitoring and stimulation, using an endotracheal tube mounted device, was performed in all cases. Endoscopic examination of the larynx was performed on the first postoperative day and at three weeks. RESULTS: Data on 102 patients and 123 nerves were collated. Temporary and permanent RLN palsy rates were 6.1% and 1.7%. Most RLN palsies were identified on the first postoperative day with all recognised at the three-week review. No preoperative clinical risk factors were identified. Although dysphonia at the three-week follow-up visit was the only significant predictor of vocal cord palsy, only two-thirds of patients with cord palsies were dysphonic. Intraoperative nerve monitoring and stimulation did not predict outcome in terms of vocal cord function. CONCLUSIONS: Temporary nerve palsy rates were consistent with other series where direct laryngoscopy is used to assess laryngeal function. Direct laryngoscopy is the only reliable measure of cord function, with intraoperative monitoring being neither a reliable predictor of cord function nor a predictor of eventual laryngeal function. The fact that all temporary palsies recovered within four months has implications for staged procedures. PMID- 24780672 TI - Favourable outcomes of coccygectomy for refractory coccygodynia. AB - INTRODUCTION: Coccygodynia is a condition associated with severe discomfort in the region of the coccyx. While traditional procedures had poor outcomes and high complication rates, recent literature suggests better outcomes and lower complication rates with coccygectomy. METHODS: Data were collected retrospectively from clinical notes. A questionnaire was used to evaluate the outcomes. The outcome measures included pain analogue score (PAS) in sitting and during daily activities as well as patients' overall pain relief. Overall improvement in pain and complications were documented. RESULTS: Between 2000 and 2010, 14 patients underwent total coccygectomy for refractory coccygodynia. All patients were available for follow-up appointments and the follow-up duration ranged from 24 to 132 months (mean: 80 months). The aetiology was traumatic in eight patients and non-traumatic in six. The PAS improved from a median of 9 to 4 for sitting and from 7.5 to 2.5 for daily activities. One patient had mild discharge for more than two weeks. No patients required further surgery. Twelve patients (85.7%) had excellent or good pain relief. Only one patient was unsatisfied. A Wilcoxon signed-rank test revealed significant improvement in pain when sitting (p<0.05) and during activities of daily living (p<0.05) at the final follow-up visit. A Mann-Whitney U test did not show a significant difference in improvement in PAS between the traumatic and non-traumatic groups (p=0.282 and 0.755). CONCLUSIONS: In our series, total coccygectomy offered satisfactory relief of pain in the majority of patients with a low wound complication rate. PMID- 24780673 TI - Obesity and recurrent intervertebral disc prolapse after lumbar microdiscectomy. AB - INTRODUCTION: The primary aim of this study was to investigate the relationship between obesity and recurrent intervertebral disc prolapse (IDP) following lumbar microdiscectomy. METHODS: A retrospective review of case notes from 2008 to 2012 was conducted for all patients who underwent single level lumbar microdiscectomy performed by a single surgeon. All patients were followed up at two weeks and six weeks following surgery, and given an open appointment for a further six months. RESULTS: A total of 283 patients were available for analysis: 190 (67%) were in the non-obese group and 93 (32.9%) in the obese group. There was no statistical difference in postoperative infection, dural tear or length of stay between the non-obese and obese groups. Recurrent symptomatic IDP was seen in 27 patients (9.5%) confirmed by magnetic resonance imaging. Nineteen (10.0%) were in the non obese group and eight (8.6%) in the obese group (p>0.8). CONCLUSIONS: In our study, obesity was not a predictor of recurrent IDP following lumbar microdiscectomy. Our literature review confirmed that this study reports the largest series to date analysing the relationship between obesity and recurrent IDP following lumbar microdiscectomy in the British population. PMID- 24780674 TI - YouTubeTM as a source of patient information for lumbar discectomy. AB - INTRODUCTION: YouTubeTM contains more than 60% of all videos on the internet. Its popularity has increased, and it has now become a source of patient education and information. It is unregulated for the quality of its videos. This project was designed to assess the quality of videos on YouTubeTM on lumbar discectomy. METHODS: A systematic search of YouTubeTM was performed. The search terms used were 'lumbar' and 'discectomy'. The first ten pages were reviewed. Information was recorded relating to the date of publishing, the publisher and the number of viewings. The content was reviewed using criteria based on recommendations from the British Association of Spine Surgeons website. Content was assessed and points were awarded for information relating to management options, description of the procedure (including anaesthetic, likely recovery and outcome) and complications as well as information relating to the author and his or her institute. An overall rating of 'inadequate', 'poor', 'average' or 'good' was given. RESULTS: Overall, 81 videos were identified. The total number of viewings was 2,722,964 (range: 139-111,891), with an average number of 34,037 viewings per video. There were 16 with a rating of 'good', 25 with a rating of 'average' and 40 with a rating of 'poor' or 'inadequate'. The most common missing information related to anaesthesia or complications. Most videos (69/81) were broadcast by surgeons or surgical institutes. CONCLUSIONS: The quality of YouTubeTM videos is variable and we believe this represents the unregulated nature of broadcasts on YouTubeTM. Thought should be given to information in videos prior to placement. PMID- 24780675 TI - Splenectomy results from an 18-year single centre experience. AB - INTRODUCTION: Splenectomy is performed both as an emergency procedure following trauma and electively when indicated for haematological disease. Postsplenectomy patients receive immunotherapy vaccines and continuous antibiotic prophylaxis. Despite well documented concerns regarding complications and overwhelming postsplenectomy infection (OPSI) risk, there appears to be only a small amount of consistent data on long-term outcomes. The authors therefore present their postsplenectomy patient outcomes over an 18-year follow-up period. METHODS: One hundred and five postsplenectomy patients operated on between 1991 and 2011 were identified from pathology codes and their case notes were reviewed. Eighty-eight patients (83.8%) were followed up for at least five years or until death. RESULTS: Of the 105 splenectomy patients (58 were male), the median age was 54 years (range: 10-87 years) and the median survival was 80 months. Operative morbidity and mortality rates were 21.0% (n=22) and 8.6% (n=9) respectively. Thirty-seven patients (27 males) underwent an emergency splenectomy with a median age, operative morbidity and operative mortality of 51 years, 13.5% and 21.6% (n=8) respectively. This compares with 68 patients (35 males) undergoing an elective splenectomy with the same parameters respectively of 55 years, 25.0% and 1.5% (n=1). Excluding operative deaths, multivariate analysis revealed age (p=0.002) as the only significant and independent prognostic indicator. Immunotherapy and antibiotic prophylaxis rates for the emergency cohort were 92.6% and 88.9% respectively, compared with 90.2% and 93.4% for the elective cohort. At follow-up, no patients were readmitted with OPSI. CONCLUSIONS: Over an 18-year period and a diverse indication for splenectomy, we have identified no evidence of OPSI. However, a significant operative mortality was associated with traumatic splenic rupture. PMID- 24780676 TI - A single surgeon's series of transthoracic oesophageal resections. AB - INTRODUCTION: Significant controversy persists over the optimum surgical management of oesophageal carcinoma. The authors report on a consecutive personal series of open transthoracic oesophageal resections. METHODS: Data relating to resections performed between mid-1993 and the end of 2010 were analysed. Patient and tumour assessment evolved over this period. Preoperative chemotherapy in appropriate cases was introduced in 2002. A laparotomy and right lateral thoracotomy approach (Ivor-Lewis) was used. In all cases the pylorus was not interfered with, no attempt was made to perform a radical lymphadenectomy but surgical strategy was focused on producing an R0 resection and a hand sewn anastomosis was fashioned. RESULTS: A total of 165 resections were performed; 130 patients (80%) were male. The median age was 66 years (range: 31-82 years). Eighty per cent had an adenocarcinoma. Sixty-four per cent of the tumours were T3/T4 and sixty-two per cent node positive. Forty patients (24%) had an involved circumferential resection margin (CRM). Five patients (3.0%) had no resection and a quarter (26%) developed morbidity of some form. There was one clinical anastomotic leak (0.6%) and three benign strictures requiring dilation (1.8%). In hospital mortality was 3.0% (5 patients). Disease specific survival at one, two and five years was 77%, 42% and 36% respectively. Neither CRM involvement nor preoperative chemotherapy influenced survival significantly. No patient required intervention to disrupt the pylorus. CONCLUSIONS: Excellent outcomes are achievable following open transthoracic oesophagectomy without radical lymphadenectomy using a hand sewn gastro-oesophageal anastomosis and without disrupting the pylorus. PMID- 24780677 TI - Clinical guidelines: too much of a good thing. PMID- 24780678 TI - Recent NICE guidance of interest to surgeons. PMID- 24780680 TI - A novel technique for manipulation of the gallbladder with an impacted stone in Hartmann's pouch during laparoscopic cholecystectomy. PMID- 24780681 TI - Bone wax following proximal femoral osteotomy in total hip replacement. PMID- 24780682 TI - Tying a surgical mask to prevent fogging. PMID- 24780683 TI - An improvised amplification device for smartphone loudspeakers. PMID- 24780684 TI - Optimisation of intramedullary nail alignment. PMID- 24780685 TI - Mirroring dynamic gallbladder retraction of conventional laparoscopic cholecystectomy at the transumbilical approach. PMID- 24780686 TI - Reduction of paraphimosis in children: the EMLA(r) glove technique. PMID- 24780687 TI - Wound protector/retractor for improved access in infrainguinal vascular surgery. PMID- 24780688 TI - A useful aid in navigating the tortuous ureter. PMID- 24780689 TI - Avoiding port site bleeding in laparoscopic cholecystectomy. PMID- 24780690 TI - Securing the dressing after circumcision in adults. PMID- 24780691 TI - A novel simulation for transanal endoscopic operation training. PMID- 24780692 TI - Endonasal dacryocystorhinostomy with and without stenting. PMID- 24780693 TI - Retained surgical sponges, needles and instruments. PMID- 24780694 TI - Metrical assessment of cutmarks on bone: is size important? AB - Extrapolating type of blade from a bone lesion has always been a challenge for forensic anthropologists: literature has mainly focused on the morphological characteristics of sharp force lesions, whereas scarce indications are available concerning the metrical assessment of cut marks and their correlation with the size of blade. The present study aims at verifying whether it is possible to reconstruct the metrical characteristics of the blade from the measurements taken from the lesion. Eleven blades with different thickness, height and shape were used for this study. A metallic structure was built, in order to simulate incised wounds and reiterate hits with the same energy. Perpendicular and angled tests were performed on fragments of pig femurs, in order to produce 110 lesions (10 for each blade). Depth, height and angle were measured and compared with metrical characteristics of each blade. Results showed a wide superimposition of metrical characteristics of width and angle of lesions regardless the type and the orientation of blade: for symmetric blades a high correlation index was observed between the depth of the lesion and the angle of the blade in perpendicular tests (0.89) and between the angle of lesion and the height of the blade in angled tests (-0.76); for asymmetric blades in both the tests a high correlation was observed between the angle of the blade and angle and width of the lesion (respectively 0.90 and 0.76 for perpendicular tests, and 0.80 and 0.90 for angled ones). This study provides interesting data concerning the interpretation of cutmarks on bone and suggests caution in assessing the size of weapons from the metrical measurements of lesions. PMID- 24780695 TI - Quantitative analysis of 3,4-dimethylmethcathinone in blood and urine by liquid chromatography-tandem mass spectrometry in a fatal case. AB - We report here the quantitative analysis of cathinone-type designer drug 3,4 dimethylmethcathinone (3,4-DMMC) in blood and urine using liquid chromatography tandem mass spectrometry (LC-MS/MS) in a fatal case. Abuse of 3,4-DMMC is widespread and a global issue. However, to date, there have been no reports of 3,4-DMMC-related deaths. We encountered a death in which 3,4-DMMC was thought to play a causative role, and successfully identified this designer drug from biological samples by using LC-MS/MS and QuEChERS (quick, easy, cheap, effective, rugged and safe) extraction method. For standard samples, detection of 3,4-DMMC in human blood and urine samples in the calibration range (5-400 ng/mL) was successful with recoveries of 85.9-89.4% (blood) and 95.8-101% (urine), limits of detection of 1.03 (blood) and 1.37 ng/mL (urine) and limits of quantification of 5.00 (blood) and 5.38 ng/mL (urine). The concentrations of 3,4-DMMC in blood (external iliac vein) and urine in the case were 27 mg/L and 7.6 mg/L, respectively. Some metabolites, including 3,4-dimethylcathione (DMC) and beta ketone reduced metabolites (beta-OH-DMMC and beta-OH-DMC), were detected in both blood and urine. PMID- 24780696 TI - Robust, accurate and fast automatic segmentation of the spinal cord. AB - Spinal cord segmentation provides measures of atrophy and facilitates group analysis via inter-subject correspondence. Automatizing this procedure enables studies with large throughput and minimizes user bias. Although several automatic segmentation methods exist, they are often restricted in terms of image contrast and field-of-view. This paper presents a new automatic segmentation method (PropSeg) optimized for robustness, accuracy and speed. The algorithm is based on the propagation of a deformable model and is divided into three parts: firstly, an initialization step detects the spinal cord position and orientation using a circular Hough transform on multiple axial slices rostral and caudal to the starting plane and builds an initial elliptical tubular mesh. Secondly, a low resolution deformable model is propagated along the spinal cord. To deal with highly variable contrast levels between the spinal cord and the cerebrospinal fluid, the deformation is coupled with a local contrast-to-noise adaptation at each iteration. Thirdly, a refinement process and a global deformation are applied on the propagated mesh to provide an accurate segmentation of the spinal cord. Validation was performed in 15 healthy subjects and two patients with spinal cord injury, using T1- and T2-weighted images of the entire spinal cord and on multiecho T2*-weighted images. Our method was compared against manual segmentation and against an active surface method. Results show high precision for all the MR sequences. Dice coefficients were 0.9 for the T1- and T2-weighted cohorts and 0.86 for the T2*-weighted images. The proposed method runs in less than 1min on a normal computer and can be used to quantify morphological features such as cross-sectional area along the whole spinal cord. PMID- 24780697 TI - Brain activity and prosocial behavior in a simulated life-threatening situation. AB - To study the neuronal basis of altruistic behavior, we investigated functional connectivity within brain networks of participants who exhibited either a self benefit behavior or an altruistic one in a life-threatening situation simulated in a virtual environment. In particular, participants were asked to evacuate a virtual building on fire and, without being previously informed, they were faced with a decision on whether to stop and help a trapped virtual human, at the possible cost of losing their own life in the virtual experience. Group independent component analysis (gICA) applied on blood-oxygen-level-dependent (BOLD) functional images revealed significant differences between the group of participants who showed selfish behavior and those who acted prosocially. Specifically, an increased functional connectivity in the salience network, comprising the anterior insula (AI) and the anterior mid cingulate cortex (aMCC), was observed in the selfish group compared to the prosocial one. Conversely, higher ICA weights in the medial prefrontal cortex and temporo-parietal junction (TPJ), were observed in the prosocial group. The findings show that an increased functional connectivity of the salience network, which suggests an enhanced sensitivity to the threatening situation and potential danger for the individual, resulted in more selfish choices, while the engagement of the medial prefrontal and temporo-parietal cortices subserved prosocial behavior, possibly due to their role in perspective-taking. The study provides the first online neurophysiological measurement of prosocial decision-making during threatening situations, opening new avenues to the investigation of neuronal substrates of complex social behaviors. PMID- 24780698 TI - Signal contributions to heavily diffusion-weighted functional magnetic resonance imaging investigated with multi-SE-EPI acquisitions. AB - Diffusion-weighted (DW) functional magnetic resonance imaging (fMRI) signal changes have been noted as a promising marker of neural activity. Although there is no agreement on the signal origin, the blood oxygen level dependent (BOLD) effect has figured as one of the most likely sources. In order to investigate possible BOLD and non-BOLD contributions to the signal, DW fMRI was performed on normal volunteers using a sequence with two echo-planar acquisitions after pulsed gradient spin-echo. Along with the changes to the signal amplitude (DeltaS/S) measured at both echo-times, this sequence allowed changes to the transverse relaxation rate (DeltaR2) to be estimated for multiple b-values during hypercapnia (HC) and visual stimulation (VS). DeltaS/S and DeltaR2 observed during HC were relatively insensitive to increasing b-value. On the other hand, DeltaS/S demonstrated a clear dependence on b-value at both echo-times for VS. In addition, DeltaR2 during the latter half of VS was significantly more negative at b=1400s/mm(2) than for the time-courses at lower b-value, but DeltaR2 during the post-stimulus undershoot was independent of b-value. The results have been discussed in terms of two models: the standard intravascular-extravascular model for fMRI and a three-compartment model (one intra- and two extravascular compartments). Within these interpretations the results suggest that the majority of the response is linked to changes in transverse relaxation, but possible contributions from other sources may not be ruled out. PMID- 24780699 TI - IRES-incorporated lactococcal bicistronic vector for target gene expression in a eukaryotic system. AB - Plasmid DNAs isolated from lactic acid bacteria (LAB) such as Lactococcus lactis (L. lactis) has been gaining more interests for its positive prospects in genetic engineering-related applications. In this study, the lactococcal plasmid, pNZ8048 was modified so as to be able to express multiple genes in the eukaryotic system. Therefore, a cassette containing an internal ribosome entry site (IRES) was cloned between VP2 gene of a very virulent infectious bursal disease (vvIBDV) UPM 04190 of Malaysian local isolates and the reporter gene, green fluorescent protein (GFP) into pNZ:CA, a newly constructed derivative of pNZ8048 harboring the cytomegalovirus promoter (Pcmv) and polyadenylation signal. The new bicistronic vector, denoted as pNZ:vig was subjected to in vitro transcription/translation system followed by SDS-PAGE and Western blot analysis to rapidly verify its functionality. Immunoblotting profiles showed the presence of 49 and 29kDa bands that corresponds to the sizes of the VP2 and GFP proteins respectively. This preliminary result shows that the newly constructed lactococcal bicistronic vector can co-express multiple genes in a eukaryotic system via the IRES element thus suggesting its feasibility to be used for transfection of in vitro cell cultures and vaccine delivery. PMID- 24780700 TI - Application of optimized dispersive liquid-liquid microextraction for determination of melatonin by HPLC-UV in plasma samples. AB - Melatonin (N-acetyl-3-(2-aminoethyl)-5-methoxyindole) is biologically active as a neurohormone and antioxidant agent. The optimized dispersive liquid-liquid microextraction (DLLME) followed by high-performance liquid chromatography-ultra violet detection (HPLC-UV) was used for the analysis of melatonin in human plasma. Influence variables such as volume of extracting (carbon tetrachloride: CCl4) and dispersing solvents (acetonitrile: ACN), pH and ionic strength, extraction time and centrifugation time were screened in a 2(6-2) fractional factorial design (FFD) and then the significant variables were optimized by using a central composite design (CCD). At optimum conditions values of variables set as pH 6.0, 1.5 mL ACN, 140 MUL CCl4, 1.0 min extraction time and 3.0 min centrifugation at 4,500 rpm. At optimum conditions method has linear response over 2.0-500.0 ng mL(-1) with detection limit of 0.5 ng mL(-1) with relative standard deviations (RSDs) less than 5.0%. The values of intra-day and inter-day RSD were 4.3% and 8.5%, respectively. The method was applied successfully for the analysis of melatonin in plasma sample. PMID- 24780701 TI - Microwave-assisted derivatization: application to steroid profiling by gas chromatography/mass spectrometry. AB - Gas chromatography-mass spectrometry (GC-MS) remains as the gold-standard technique for the study of the steroid metabolome. A main limitation is the need of performing a derivatization step since incubation with strong silylations agents for long periods of time (usually 16 h) is required for the derivatization of hindered hydroxyls present in some steroids of interest. In the present work, a rapid, simple and reproducible microwave-assisted derivatization method was developed. In the method, 36 steroids already treated with methoxyamine (2% in pyridine) were silylated with 50 MUl of N-trimethylsilylimidazole by using microwave irradiation, and the formed methyloxime-trimethylsilyl derivatives were analyzed by GC-MS. Microwave power and derivatization time silylation conditions were optimized being the optimum conditions 600 W and 3 min respectively. In order to evaluate the usefulness of this technique, the urine steroid profiles for 20 healthy individuals were analyzed. The results of a comparison of microwave irradiation with the classical heating protocol showed similar derivatization yields, thus suggesting that microwave-assisted silylation is a valid tool for the rapid steroid metabolome study. PMID- 24780702 TI - Determination and pharmacokinetic study of the novel anti-tumor candidate drug DG 7 in rat plasma by liquid chromatography-tandem mass spectrometry. AB - DG-7 (11,14-dihydroxy-7,20-epoxy-20-O-derivative of ent-kaurene diterpenoid) is a novel anti-tumor candidate drug. A sensitive and specific liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantification of DG-7 in rat plasma. An aliquot of 50 MUL plasma sample was prepared by liquid-liquid extraction with ethyl acetate. Chromatographic separation was accomplished on a Waters XTerra C18 column (2.1 mm * 150 mm, 5 MUm) with an isocratic elution system consisting of methanol and water. Detection was performed by multiple reaction monitoring (MRM) mode using electrospray ionization in the positive ion mode. The optimized fragmentation transitions for MRM were m/z 590.1->m/z 260.0 for DG-7 and m/z 180.3->m/z 110.1 for phenacetin (internal standard). The method was linear over the concentration range of 5 2,500 ng/mL. The intra- and inter-day precisions were less than 7.9% and the accuracy was within +/- 9.0%. The mean recovery of DG-7 ranged from 76.8% to 79.2%. The validated method has been successfully applied to a pharmacokinetic study in rats after intravenous administration of DG-7. PMID- 24780703 TI - Development, validation and application of an HPLC-MS/MS method for the determination of fentanyl and nor-fentanyl in human plasma and saliva. AB - Monitoring fentanyl concentration in saliva and plasma may be useful in pharmacokinetic/pharmacodynamic studies. Salivettes((r)) have been used widely for collecting saliva samples. However due to its lipophilicity, fentanyl adsorbs to the cotton dental bud (CDB) used in this device. Furthermore, due to dry mouth being a common adverse effect seen in patients treated with opioids, obtaining enough saliva for analysis is often a challenge. Hence, a simple simultaneous method to quantify fentanyl and its metabolite in both human plasma and saliva was developed and validated. A novel extraction method was also developed and validated to recover fentanyl in saliva directly from the CDB. This extraction method utilises acetonitrile to recover the fentanyl directly from the CDB rather than recovery by centrifugation, which is not always possible. Reverse phase chromatographic separation was performed on a Shimadzu LC 20A HPLC system using gradient elution. The electrospray ion source (ESI) was operated in positive ion mode using an Applied Biosystems API 3200 LC/MS/MS as detector. Deuterated fentanyl (D5) and nor-fentanyl (D5) were used as internal standards (IS). The retention times for fentanyl and nor-fentanyl were 3.70 min and 3.20 min respectively. The lower limit of quantitation (LLOQ) was determined to be 0.030 MUg/L in plasma and 0.045 in saliva for fentanyl and nor-fentanyl. Acceptable linearity for fentanyl and nor-fentanyl in both plasma and saliva was demonstrated from 0.02 to 10 MUg/L (R(2) 0.9988-0.9994). Accuracy for fentanyl and nor-fentanyl in both plasma and saliva samples was between 96% and 108%. Total imprecision expressed as the co-efficient of variation was between 1.0 and 15.5% for both analytes in both matrices. The validated method was applied successfully in 11 paired plasma and saliva samples obtained from patients with cancer pain receiving transdermal fentanyl (Duragesic((r))) at doses from 25 MUg to 100 MUg. PMID- 24780705 TI - [Quality of life. Do we know what we are doing?]. PMID- 24780704 TI - Component analysis and structure identification of active substances for anti gastric ulcer effects in Radix Astragali by liquid chromatography and tandem mass spectrometry. AB - This study provided a comprehensive component analysis and structure identification of active substances for the anti-gastric ulcer effects of Radix Astragali. The data were generated by organically combining the results from in vivo pharmacodynamic experiments, a cell growth-promoting assay, structure identification, content determination, fingerprinting, and correlation analyses. The fingerprints from high-performance liquid chromatography coupled with a diode array detector (HPLC-DAD) and from HPLC coupled with evaporative light scattering detectors (ELSD) from 95% ethanol extracts of Radix Astragali (ERA) were determined using HPLC-DAD-ELSD. The structures of 16 compounds were identified using ultra-pressure liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS). The contents of these 16 compounds were simultaneously determined in a single run using HPLC-DAD-ELSD. The strength of the anti ulceration effect of each of the 16 compounds was correlated to its content in the HPLC spectrum using gray relation statistics. The sequence of the contribution from each of the 16 compounds to the anti-gastric ulcer effect was determined. The results showed that ononin, astragalosideIII, and astragalosideIV contributed most to the observed anti-gastric ulcer effects and that these three compounds also exhibited strong growth-promoting effects in cultured GES-1 cells. The results of this study can be used to evaluate the quality of Radix Astragali and to provide a theoretical foundation for its further study. PMID- 24780706 TI - [The concept of quality of life in medicine: its history and current relevance]. AB - This paper attempts to review 40 years of quality-of-life research. The increasing recognition of the topic is obvious from the number of publications and its representation in academic discussions. Despite a rather weak theoretical foundation, methods of quality-of-life assessment have been developed successfully. Both the number and the quality of assessment tools have increased over the years so that there is now a broad spectrum of instruments for adults and children available, which is used from epidemiological studies to health services research, and especially in quality assurance and comparative benchmarking. Assessment is still underrepresented in clinical trials, which is why only few meta-analyses and reviews are available. Also, implementation of results in recommendations for treatment and in guidelines has just started. Implications for clinical practice also relate to the patient orientation in the physician-patient communication. A future perspective is the widespread use of available instruments, provided that relevant information is gained, which depends on the study design as well as the interpretation and dissemination of results. Consequences for the healthcare systems are expected if improvements in quality of life can be attributed to benefits of treatment and surrounding services. PMID- 24780707 TI - [Measuring quality of life: as simple as possible and as detailed as necessary]. AB - Numerous instruments for measuring health-related quality of life have been developed over the past decades. Explicit methodological criteria should be used to select an instrument to use in a given study. Based on a list of such methodological criteria, this paper provides guidance for choosing appropriate quality of life instruments. Special emphasis will be given to the advantages and disadvantages of using generic and disease-specific instruments as these are the main types of quality of life measures. Finally, the development and the use of short forms of existing instruments will be discussed. PMID- 24780708 TI - [Methodology for analysing quality-of-life data in the benefit assessment of pharmaceuticals]. AB - Early benefit assessment aims to prove a benefit of a new pharmaceutical over the appropriate comparator based on patient-relevant endpoints. In addition to mortality and morbidity, quality of life is a patient-relevant endpoint. Thus, phase III clinical trials are the basis of evidence. But HTA and health authorities attach different importance to quality of life. Using the example of oncology, the challenges with study design and analysis will be discussed. A particular challenge to the analysis of quality-of-life data is varying observation times in treatment arms with different effectiveness. Based on the example of Crizotinib possible solutions will be presented. PMID- 24780709 TI - [Valuation of health-related quality of life and utilities in health economics]. AB - Measuring health-related quality of life is an important aspect in economic evaluation of health programmes. The development of utility-based (preference based) measures is advanced by the discipline of health economics. Different preference measures are applied for valuing health states to produce a weighted health state index. Those preference weights should be derived from a general population sample in case of resource allocation on a collective level (as in current valuation studies of the EuroQol group). PMID- 24780710 TI - [Is it quality of life that patients really want? Assessment from a general practitioner's perspective]. AB - The multidimensional, complex construct of 'quality of life' as a patient reported outcome is used in medicine as a measurable indicator of health and illness. But do we know what we do when we measure 'quality of life'? Can we grasp how the patient with his individual concept of disease really feels when we use instruments that were designed, administered and analysed by professionals? Do we know the meaning of what we have measured? Is it not shortsighted to focus on health-related quality of life? And is it really quality of life that patients actually want? From a general practitioner's perspective, these questions will be asked of three patients. PMID- 24780711 TI - [The significance of quality of life from a socio-legal perspective]. AB - Only rarely is the term quality of life explicitly mentioned in the Social Security Code (Sozialgesetzbuch, SGB). In the statutory health insurance law (Book V of the Social Security Code, SGB V), the term is explicitly regulated within the context of the entitlement to pharmaceuticals. While there are pharmaceuticals that have the priority to increase the quality of life but are excluded from the provision of healthcare (Section 34 (1) Sentence 7 SGB V), the improvement of the quality of life has to be taken into account for the cost benefit assessment (Section 35b SGB V) as well as for the early pharmaceutical benefit assessment (Section 35a SGB V) and for the formation of reference price groups (Section 35 SGB V) for and in the case of an entitlement to benefits in the event of illness. PMID- 24780712 TI - [The significance of quality of life--an ethical approach]. AB - Quality of life is highly appreciated as an evaluation criterion and a goal of interventions in medicine, but it is insufficiently applied. There is no unanimous definition of "quality of life". From a philosophical point of view, subjectivistic concepts can be differentiated from objectivistic ones. In medicine there are the three concepts of general, health-related and disease specific quality of life. In this paper it is argued that a general and subjectivistic account of quality of life is of prevailing ethical significance, due to patient orientation and patient autonomy reasons. The normative function of quality of life should be given much more consideration by the responsible players in clinical research, healthcare and allocation decisions within the healthcare system. PMID- 24780713 TI - [Quality of life and the healthcare system: do we know what we are doing? On the importance of quality of life from the perspective of patients]. AB - "Healthcare" is not an exact term but an abstract representation of a system which itself is unable to create quality of life. The term "quality of life" is a general term. Every human being is part of the world he or she lives in (his or her "lifeworld", "Lebenswelt"). Health and disease have a direct and, through individual system components, significantly different effect. Is there a healthcare system? Which resources are available to this healthcare system and the individual persons themselves? There are numerous and quite different components influencing a patient's individual quality of life. These components also include the professional philosophy of physicians, their professional practice and their communication skills in dealing with their patients. The disease-related quality of life can be categorised into the groups "occasional diseases," "chronic, incurable diseases," "diseases leading to disability," or "fatal diseases". In each group, the factors influencing quality of life are subject to a different individual assessment. Disease does not stop at the doctor's office, but becomes an integral part of life, which is especially true of predestined, life-long chronic diseases such as, for example, psoriasis, a chronic skin condition. Diagnosis und limiting factors in treatment have an impact on the patient's quality of life, too, and must be conceived of as "indication-related". Also, support from outside the professional healthcare system, in particular from patient self-help organisations, contributes to assisting patients with maintaining a high level of individual quality of life. Self-help is not only effective, but useful as well, as has been demonstrated by initial studies in Germany. PMID- 24780714 TI - [The relevance of quality of life for the work of the Federal Joint Committee]. AB - As the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany, the Federal Joint Committee (G-BA) is responsible for determining the catalogue of benefits for those insured by statutory health insurance (SHI) funds. The G-BA uses patient relevant, health-related quality of life outcomes as a decision criterion in the assessment of new examination or treatment methods, the benefit assessment of new pharmaceuticals, the quality assurance of services, and in determining treatment goals for disease management programmes and special forms of care. But the data generally available on quality of life are considered insufficient by the G-BA. Studies submitted for methods assessments or the benefit assessments of pharmaceuticals often lack findings on quality of life, or the data are of limited value due to methodological shortcomings. Because the burden of disease is shifting more and more towards chronic and oncological diseases due to demographic changes, the G-BA considers an improvement in the data available on health-related quality of life to be urgently necessary. PMID- 24780715 TI - [Does ethics pay off? Need and perspectives of value management in hospitals]. AB - The economic pressure on German hospitals has increased considerably over the last years, mainly because of the introduction of a flat-rate payment system, and it will most likely further increase under the current demographic and political conditions. The growing dominance of economics in the inpatient sector increases the pressure on hospital staff and results in an increased volume of care (with sometimes inappropriate overtreatment) and uncontrolled rationing and a continuous struggle to maintain the quality of patient care. This development is not only alarming from an ethical perspective, but also impairs the hospital's economic performance. To counter the increasing economic pressure with "more ethics" does--according to the line of reasoning adopted in this article--not appear to be very successful. Rather, central ethical values in inpatient care have to become an integral part of hospital management. This value management first requires a clear definition of the normative standards, e.g. within a mission statement. Second, the realisation of the normative standards in routine inpatient care has to be systematically assessed, evaluated and managed. Since normative standards are difficult to measure objectively and on a quantitative scale, (repeated) surveys among hospital staff are the central instrument to secure the "internal quality" of the hospital. It appears very likely that more ethics in the hospital will pay off by improving its economic performance. The empirical proof for this conceptually extremely plausible hypothesis has yet to be provided. PMID- 24780716 TI - [Survey on evidence-based medicine teaching activities in the German-speaking area: a target-group specific analysis]. AB - INTRODUCTION: A survey conducted in 2011/12 on evidence-based medicine teaching activities in Germany, Austria and Switzerland shows an apparent increase of undergraduate and postgraduate teaching activities addressing different target groups. The potential target-group specific or generalised nature of teaching activities in EbM were explored by comparing the contents and structures of educational offers in order to detect differences and commonalities. METHODS: First, several large institutions of the healthcare system were contacted. In addition, the participants of the EbM Academy were consulted as key informants, and the members of the German-speaking colleges of general practitioners and the German Network for EBM were asked to identify potential providers of EbM teaching activities. In the second step pretested detailed questionnaires were sent out that allowed a target-group specific analysis of contents, structures and didactic methods. RESULTS: Altogether, 185 teaching activities in EbM are described; 117 (6.8%) of these address students, 70 (37.8%) physicians and 55 (29.7%) caregivers and members of other healthcare professions. Further target groups include people interested in the healthcare system with a total of 38 (i.e., 20.5%) and patients with 18 (9.7%) teaching activities (multiple responses allowed). Students are mainly taught in obligatory seminars, courses or lectures with a high number of participants, whereas teaching activities addressing other target groups are mostly offered to small groups of participants in the form of optional seminars, courses or workshops lasting a similar length of time. As regards the content, attendees from all target groups with only little previous knowledge are taught the first three steps of EbM according to Sackett. Specialised contents are not distributed evenly and reveal some adaptation to the respective target groups. DISCUSSION: Structural differences between the target groups are most likely attributed to distinct framework conditions in education and career. Parallels in content demonstrate high rates of conformity concerning the teaching of basic knowledge, though, while individually selecting particular focus areas of special expertise. PMID- 24780717 TI - Acute COPD exacerbation: 3 T MRI evaluation of pulmonary regional perfusion- preliminary experience. AB - OBJECTIVES: To compare pulmonary perfusion parameters by means of dynamic perfusion magnetic resonance in patients affected by chronic obstructive pulmonary disease (COPD), during and after acute exacerbation. METHODS: Fifteen patients were successfully evaluated with perfusional MRI during an acute exacerbation of COPD and upon clinical stabilization. Inclusion criteria were a PaCO2 > 45 mmHg and respiratory acidosis (arterial blood pH < 7.35) at admittance. RESULTS: In the acute phase a reduction of pulmonary blood flow (PBF) and pulmonary blood volume (PBV), and a significant prolonging of the mean transit time (MTT) and time to peak (TTP) were observed in all patients. In the stabilization phase a significant increase of PBF and PBV and a significant reduction of MTT and TTP were observed in 6 patients; no significant variations were observed in the other 9 patients. CONCLUSION: 3D time-resolved contrast enhanced MRI allows quantitative evaluation of pulmonary regional perfusion in patients affected by COPD, identifying patients in which perfusion defects are resolved in the clinical-stabilization phase. This technique might allow the identification of patients in whom vasospasm may be the main responsible of pulmonary hypoperfusion during acute COPD exacerbation, with potential advantages on the clinical management of these patients. PMID- 24780718 TI - The burden of idiopathic pulmonary fibrosis: an unmet public health need. AB - Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease of unknown cause characterized by relentlessly progressive restrictive-ventilatory limitation, hypoxia, dyspnea, and cough. Both the incidence and prevalence of IPF appears to be increasing, with little impact on its dismal 3-year median survival, despite two decades of clinical trials. Increasingly recognized are the serious associated comorbid illnesses, including pulmonary hypertension, chronic obstructive pulmonary disease, gastroesophageal reflux disease, obstructive sleep apnea, obesity, lung cancer, and depression that further contribute to the substantial rise in the use of IPF-related healthcare resources. At present, lung transplantation remains the sole viable treatment for the few who qualify. Pharmacologic interventions targeting lung function and survival have remained largely disappointing, and very few investigations have specifically targeted comorbid conditions, symptoms, quality-of-life, and healthcare resource utilization. In reviewing the burden of illness associated with IPF, including the epidemiology, comorbidities, quality-of-life and the physical, psychosocial, and economic costs of this devastating disease, we hope to highlight some of the unmet medical needs associated with IPF, and encourage both public support and further investigations into these and other patient-centered outcomes and not just that of survival and lung function. PMID- 24780719 TI - Quantifying preferences for asthma control in parents and adolescents using best worst scaling. AB - BACKGROUND: Understanding the views of parents and children is critical to designing effective asthma management programs. It was hypothesized that parents and adolescents would exhibit heterogenous preferences with regard to asthma control. METHODS: Fifty parents of children with asthma and 51 adolescents with asthma participated in a best-worst scaling study to quantify preferences regarding night-time symptoms, wheezing/chest tightening, changes in asthma medications, emergency visits and physical activity limitations. RESULTS: A latent class analysis revealed heterogeneity inherent in the preferences of parents and adolescents. Two classes of parents emerged from the analysis that displayed significantly different preferences. The first displayed strong preferences for averting night-time symptoms, wheezing/chest tightening, physical activity limitations and emergency room visits with odds ratios (OR) of 42 (95% CI 24, 72), 40 (95% CI 23, 68), 26 (95% CI 15, 44) and 21 (95% CI 12, 35), respectively, compared to an OR of 1 for 10 physical activity limitations per month. A second smaller parent class displayed more balanced preferences. Most adolescents displayed similar preferences for averting night-time symptoms, wheezing/chest tightening, physical activity limitations and emergency room visits, with ORs of 28 (95% CI 16, 48), 25 (95% CI 14, 44), 27 (95% CI 15, 46) and 20 (95% CI 11, 34) respectively. CONCLUSIONS: This study revealed the importance placed on averting night-time symptoms, wheezing and chest tightening, emergency room visits and physical activity limitations by parents and adolescents alike, with greater emphasis on symptom aversion by parents. Preference heterogeneity exists and should be considered in customized asthma management programs. PMID- 24780720 TI - An electronic health record driven algorithm to identify incident antidepressant medication users. AB - OBJECTIVE: We validated an algorithm designed to identify new or prevalent users of antidepressant medications via population-based drug prescription records. PATIENTS AND METHODS: We obtained population-based drug prescription records for the entire Olmsted County, Minnesota, population from 2011 to 2012 (N=149,629) using the existing electronic medical records linkage infrastructure of the Rochester Epidemiology Project (REP). We selected electronically a random sample of 200 new antidepressant users stratified by age and sex. The algorithm required the exclusion of antidepressant use in the 6 months preceding the date of the first qualifying antidepressant prescription (index date). Medical records were manually reviewed and adjudicated to calculate the positive predictive value (PPV). We also manually reviewed the records of a random sample of 200 antihistamine users who did not meet the case definition of new antidepressant user to estimate the negative predictive value (NPV). RESULTS: 161 of the 198 subjects electronically identified as new antidepressant users were confirmed by manual record review (PPV 81.3%). Restricting the definition of new users to subjects who were prescribed typical starting doses of each agent for treating major depression in non-geriatric adults resulted in an increase in the PPV (90.9%). Extending the time windows with no antidepressant use preceding the index date resulted in only modest increases in PPV. The manual abstraction of medical records of 200 antihistamine users yielded an NPV of 98.5%. CONCLUSIONS: Our study confirms that REP prescription records can be used to identify prevalent and incident users of antidepressants in the Olmsted County, Minnesota, population. PMID- 24780721 TI - Evaluation of medication alerts in electronic health records for compliance with human factors principles. AB - INTRODUCTION: Increasing the adoption of electronic health records (EHRs) with integrated clinical decision support (CDS) is a key initiative of the current US healthcare administration. High over-ride rates of CDS alerts strongly limit these potential benefits. As a result, EHR designers aspire to improve alert design to achieve better acceptance rates. In this study, we evaluated drug-drug interaction (DDI) alerts generated in EHRs and compared them for compliance with human factors principles. METHODS: We utilized a previously validated questionnaire, the I-MeDeSA, to assess compliance with nine human factors principles of DDI alerts generated in 14 EHRs. Two reviewers independently assigned scores evaluating the human factors characteristics of each EHR. Rankings were assigned based on these scores and recommendations for appropriate alert design were derived. RESULTS: The 14 EHRs evaluated in this study received scores ranging from 8 to 18.33, with a maximum possible score of 26. Cohen's kappa (kappa=0.86) reflected excellent agreement among reviewers. The six vendor products tied for second and third place rankings, while the top system and bottom five systems were home-grown products. The most common weaknesses included the absence of characteristics such as alert prioritization, clear and concise alert messages indicating interacting drugs, actions for clinical management, and a statement indicating the consequences of over-riding the alert. CONCLUSIONS: We provided detailed analyses of the human factors principles which were assessed and described our recommendations for effective alert design. Future studies should assess whether adherence to these recommendations can improve alert acceptance. PMID- 24780723 TI - The CD95/CD95L signaling pathway: a role in carcinogenesis. AB - Apoptosis is a fundamental process that contributes to tissue homeostasis, immune responses, and development. The receptor CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance, and various lineages of malignant cells exhibit loss-of-function mutations in this pathway; therefore, CD95 was initially classified as a tumor suppressor gene. However, more recent data indicate that in different pathophysiological contexts, this receptor can transmit non-apoptotic signals, promote inflammation, and contribute to carcinogenesis. A comparison with the initial molecular events of the TNF-R signaling pathway leading to non-apoptotic, apoptotic, and necrotic pathways reveals that CD95 is probably using different molecular mechanisms to transmit its non-apoptotic signals (NF-kappaB, MAPK, and PI3K). As discussed in this review, the molecular process by which the receptor switches from an apoptotic function to an inflammatory role is unknown. More importantly, the biological functions of these signals remain elusive. PMID- 24780722 TI - pSCANNER: patient-centered Scalable National Network for Effectiveness Research. AB - This article describes the patient-centered Scalable National Network for Effectiveness Research (pSCANNER), which is part of the recently formed PCORnet, a national network composed of learning healthcare systems and patient-powered research networks funded by the Patient Centered Outcomes Research Institute (PCORI). It is designed to be a stakeholder-governed federated network that uses a distributed architecture to integrate data from three existing networks covering over 21 million patients in all 50 states: (1) VA Informatics and Computing Infrastructure (VINCI), with data from Veteran Health Administration's 151 inpatient and 909 ambulatory care and community-based outpatient clinics; (2) the University of California Research exchange (UC-ReX) network, with data from UC Davis, Irvine, Los Angeles, San Francisco, and San Diego; and (3) SCANNER, a consortium of UCSD, Tennessee VA, and three federally qualified health systems in the Los Angeles area supplemented with claims and health information exchange data, led by the University of Southern California. Initial use cases will focus on three conditions: (1) congestive heart failure; (2) Kawasaki disease; (3) obesity. Stakeholders, such as patients, clinicians, and health service researchers, will be engaged to prioritize research questions to be answered through the network. We will use a privacy-preserving distributed computation model with synchronous and asynchronous modes. The distributed system will be based on a common data model that allows the construction and evaluation of distributed multivariate models for a variety of statistical analyses. PMID- 24780724 TI - Proteomic analysis of the venom from the scorpion Mesobuthus martensii. AB - The scorpion Mesobuthus martensii is the most populous species in eastern Asian countries, and several toxic components have been identified from their venoms. Nevertheless, a complete proteomic profile of the venom of M. martensii is still not available. In this study, the venom of M. martensii was analyzed by comprehensive proteomic approaches. 153 fractions were isolated from the M. martensii venom by 2-DE, SDS-PAGE and RP-HPLC. The ESI-Q-TOF MS results of all fractions were used to search the scorpion genomic and transcriptomic databases. Totally, 227 non-redundant protein sequences were unambiguously identified, composed of 134 previously known and 93 previously unknown proteins. Among 134 previously known proteins, 115 proteins were firstly confirmed from the M. martensii crude venom and 19 toxins were confirmed once again, involving 43 typical toxins, 7 atypical toxins, 12 venom enzymes and 72 cell associated proteins. In typical toxins, 7 novel-toxin sequences were identified, including 3 Na(+)-channel toxins, 3K(+)-channel toxins and 1 no-annotation toxin. These results increased 230% (115/50) venom components compared with previous studies from the M. martensii venom, especially 50% (24/48) typical toxins. Additionally, a mass fingerprint obtained by MALDI-TOF MS indicated that the scorpion venom contained more than 200 different molecular mass components. BIOLOGICAL SIGNIFICANCE: This work firstly gave a systematic investigation of the M. martensii venom by combined proteomics strategy coupled with genomics and transcriptomics. A large number of protein components were unambiguously identified from the venom of M. martensii, most of which were confirmed for the first time. We also contributed 7 novel-toxin sequences and 93 protein sequences previously unknown to be part of the venom, for which we assigned potential biological functions. Besides, we obtained a mass fingerprint of the M. martensii venom. Together, our study not only provides the most comprehensive catalog of the molecular diversity of the M. martensii venom at the proteomic level, but also enriches the composition information of scorpion venom. PMID- 24780725 TI - Proteomic characterization of the venom and transcriptomic analysis of the venomous gland from the Mexican centipede Scolopendra viridis. AB - This communication reports the results of proteomic, transcriptomic, biochemical and electrophysiological analysis of the soluble venom and venom glands of the Mexican centipede Scolopendra viridis Say (here thereafter abbreviated S. viridis). Separation of the soluble venom permitted to obtain 54 different fractions, from which a mass finger printing analysis permitted the identification of at least 86 components, where 70% of the molecules have low molecular masses. Two-dimensional electrophoretic separation of this venom revealed the presence of about forty proteins with molecular weights ranging from 17 to 58kDa. The novo sequencing of 149 peptides obtained by LC-MS/MS from the 2D gels showed the presence of proteins with amino acid sequences similar to several enzymes and venom allergens type 3. Furthermore, a total of 180 sequences were obtained from a cDNA library prepared with two venomous glands. From this, 155 sequences correspond to complete genes containing more than 200 base pairs each. Comparative sequence analyses of these sequences indicated the presence of different types of enzymes and toxin-like genes. Two proteins with molecular weights around 37,000 and 42,000Da were shown to contain hyaluronidase activity. Electrophysiological assays performed with soluble venom show that it decreases mammalian sodium channel currents. BIOLOGICAL SIGNIFICANCE: Animal venoms of Scolopendra species have been scarcely studied, although they have been reported to contain several bioactive compounds, some of which with potential therapeutic interest. The Mexican centipede S. viridis contains a powerful venom, capable of inflicting immediate effects on their preys. This communication is focused on the identification and description of a proteomic and transcriptomic analysis of the protein components of this venom. Several amino acid sequences similar to reported enzymes are the principal components in the S. viridis venom, but also a low number of toxins were identified. This knowledge should contribute to the understanding of the pharmacological effects caused by bites of this centipede species. PMID- 24780726 TI - Absolute quantification of apolipoproteins and associated proteins on human plasma lipoproteins. AB - Lipoprotein-associated proteins form an intrinsic part of the major plasma lipoprotein classes. There is increasing evidence that the quantity of these proteins per lipoprotein particle determines lipoprotein function including redox, inflammatory and thrombotic properties and may impact on lipoprotein related risks for developing heart disease. However, only limited information on the relative quantity of these proteins has been published and no comprehensive absolute quantitative data providing the stoichiometry of proteins associated with lipoproteins is available to date. To address this, we performed extensive absolute quantification by mass spectrometry of 17 lipoprotein-associated proteins on VLDL, LDL, Lp(a) and HDL from healthy subjects. For the first time we show the exact stoichiometry of apolipoproteins on different lipoprotein classes. The most distinct differences were seen in the abundance of all apoCs, apoE and apoF. We further revealed strong variations between individual samples, which indicates the complexity of the protein complement of lipoproteins and can provide additional insights into lipoprotein-related risk factors. This approach has the potential to determine alterations in the protein profiles of lipoproteins in disease states such as CVD or diabetes and, if performed on large cohorts, to translate into a tool for identifying new candidate biomarkers for risk of disease. BIOLOGICAL SIGNIFICANCE: A more comprehensive picture about the protein complement on individual lipoprotein classes is the goal of lipoprotein proteomics analyses. Despite many such studies, there is a lack of absolute quantitative data on lipoproteins isolated from individual subjects. The stoichiometry of lipoprotein-associated proteins rather than their presence or absence could provide insights into an individual's predisposition for disease such as heart disease or diabetes. Our study provides a comprehensive overview of the absolute quantity of proteins on the major apolipoprotein classes VLDL, LDL, Lp(a) and HDL. PMID- 24780727 TI - Differential proteomic approach for identification and verification of aberrantly glycosylated proteins in adenocarcinoma lung cancer (ADLC) plasmas by lectin capturing and targeted mass spectrometry. AB - To investigate quantitative differences in aberrant glycosylation of target glycoproteins between noncancerous group and patient group with adenocarcinoma lung cancer (ADLC), differential proteomic approach was developed by cooperatively using comparative lectin-capturing, targeted mass spectrometry (MRM MS), and antibody/lectin sandwich ELISA. Plasma samples comparatively prepared from 3 ADLC patients and 3 controls, with and without lectin-fractionation using fucose-specific Aleuria aurantia lectin (AAL), were trypsin-digested and analyzed for target glycoproteins, alpha-1-acid glycoprotein (AGP) and ceruloplasmin (CP), by MRM MS. From the MRM MS data the abundance levels of AAL-captured glycoforms of both targets were significantly higher in ADLC cases compared to controls, although the levels in total protein abundance were comparable between ADLC and control groups. This difference between ADLC and control groups in the fucosylated glycoform levels was originated mainly from aberrant fucosylation on the targets in ADLC plasmas rather than change in total protein abundance of the targets, and also confirmed by sandwich ELISA. AGP and CP were further verified to be biomarker candidates by MRM-based analysis of AAL-captured plasmas (30 ADLC cases, 30 controls), with AUROC 0.758 and 0.847 respectively. This differential proteomic approach can be useful for identifying and verifying biomarker candidate involved in aberrant protein glycosylation. BIOLOGICAL SIGNIFICANCE: The present paper introduces an efficient differential proteomic method to investigate quantitative differences in aberrant protein glycosylation of serological glycoproteins between noncancerous group and lung cancer patient group. This differential proteomic approach consisting of the targeted MRM MS of comparatively lectin-captured plasma fractions and the antibody/lectin sandwich ELISA-based assay was evaluated to be useful for identification of aberrantly fucosylated glycoproteins AGP and CP in lung cancer plasmas. In addition, we have demonstrated that the MRM MS-based differential proteomic approach is also useful for high-throughput verification of the aberrantly fucosylated glycoproteins AGP and CP using the large number of individual plasmas. Therefore, the present MRM MS-based differential proteomic strategy with lectin-capturing can be a powerful tool for high-throughput verification of aberrantly glycosylated biomarker candidates, identified preliminary by mass profiling experiments in proteomic fields but requiring further validation using a large number of cohorts. PMID- 24780728 TI - The effect of dried plum on serum levels of receptor activator of NF-kappaB ligand, osteoprotegerin and sclerostin in osteopenic postmenopausal women: a randomised controlled trial. AB - Although several studies have confirmed the bone-protective properties of dried plum, its exact mechanisms of action remain unclear. Recent research has shown that osteocytes may control bone formation via the production of sclerostin and bone resorption via the receptor activator of NF-kappaB ligand (RANKL) and its inhibitor osteoprotegerin (OPG). To investigate the mechanism of action of dried plum in reversing bone loss, we measured serum levels of RANKL, OPG and sclerostin in osteopenic postmenopausal women (n 160). Participants were randomly assigned to the treatment group of either 100 g dried plum/d or 75 g dried apple/d (comparative control) for 1 year. All participants received 500 mg Ca plus 400 IU (10 MUg) vitamin D daily. Bone mineral densities (BMD) of the lumbar spine, forearm, hip and whole body were assessed at baseline and at the end of the study using dual-energy X-ray absorptiometry. Blood samples were collected at baseline and after 12 months to assess bone biomarkers. Dried plum significantly increased the BMD of the ulna and spine in comparison with the control group. In comparison with corresponding baseline values, dried plum increased the RANKL levels by only +1.99 v. +18.33% and increased the OPG levels by +4.87 v. - 2.15% in the control group. Serum sclerostin levels were reduced by - 1.12% in the dried plum group v. +3.78% in the control group. Although percentage changes did not reach statistical significance (P<= 0.05), these preliminary data may indicate that the positive effects of dried plum on bone are in part due to the suppression of RANKL production, the promotion of OPG and the inhibition of sclerostin. PMID- 24780729 TI - Comment on "self-expandable metal stents for malignant colonic obstruction: data from a retrospective regional SIED-AIGO study" by R. Di Mitri, F. Mocciaro, M. Traina et al. [Digestive and Liver Disease 2014;46:279-82]. PMID- 24780730 TI - New patterns and architectures. PMID- 24780731 TI - Evolving locomotion with Hoxc9. AB - Limb innervation is established by opposing Hox-dependent activities. In this issue of Developmental Cell, Jung et al. (2014) show that Hoxc9 restriction of Foxp1, high levels of which specify limb-innervating motor neurons, first appeared in vertebrates concomitantly with paired appendages. Spatial control of this activity shapes neural networks controlling locomotion patterns. PMID- 24780732 TI - Genome reactivation after the silence in mitosis: recapitulating mechanisms of development? AB - Transcription is silenced during mitosis and reactivated at mitotic exit. The dynamics and identities of "bookmarking" transcription factors and chromatin marks that mediate reactivation often recapitulate those observed during cell identity establishment in development. Thus, features of postmitotic gene reactivation can provide insights into mechanisms of developmental cell fate establishment. PMID- 24780733 TI - Determining physical principles of subcellular organization. AB - Recent advances have transformed our understanding of cell biology, but we are still unable to predict the behaviors of these systems. One difficulty is that we lack an understanding of the physical principles of subcellular organization. Combining quantitative experiments with new theoretical insights may allow such principles to be developed. PMID- 24780735 TI - Do endothelial cells dream of eclectic shape? AB - Endothelial cells (ECs) exhibit dramatic plasticity of form at the single- and collective-cell level during new vessel growth, adult vascular homeostasis, and pathology. Understanding how, when, and why individual ECs coordinate decisions to change shape, in relation to the myriad of dynamic environmental signals, is key to understanding normal and pathological blood vessel behavior. However, this is a complex spatial and temporal problem. In this review we show that the multidisciplinary field of Adaptive Systems offers a refreshing perspective, common biological language, and straightforward toolkit that cell biologists can use to untangle the complexity of dynamic, morphogenetic systems. PMID- 24780734 TI - Keeping at arm's length during regeneration. AB - Regeneration of a lost appendage in adult amphibians and fish is a remarkable feat of developmental patterning. Although the limb or fin may be years removed from its initial creation by an embryonic primordium, the blastema that emerges at the injury site fashions a close mimic of adult form. Central to understanding these events are revealing the cellular origins of new structures, how positional identity is maintained, and the determinants for completion. Each of these topics has been advanced recently, strengthening models for how complex tissue pattern is recalled in the adult context. PMID- 24780736 TI - Exploring the function of cell shape and size during mitosis. AB - Dividing cells almost always adopt a spherical shape. This is true of most eukaryotic cells lacking a rigid cell wall and is observed in tissue culture and single-celled organisms, as well as in cells dividing inside tissues. While the mechanisms underlying this shape change are now well described, the functional importance of the spherical mitotic cell for the success of cell division has been thus far scarcely addressed. Here we discuss how mitotic rounding contributes to spindle assembly and positioning, as well as the potential consequences of abnormal mitotic cell shape and size on chromosome segregation, tissue growth, and cancer. PMID- 24780737 TI - Global quantification of tissue dynamics in the developing mouse kidney. AB - Although kidneys of equal size can vary 10-fold in nephron number at birth, discovering what regulates such variation has been hampered by a lack of quantitative parameters defining kidney development. Here we report a comprehensive, quantitative, multiscale analysis of mammalian kidney development in which we measure changes in cell number, compartment volumes, and cellular dynamics across the entirety of organogenesis, focusing on two key nephrogenic progenitor populations: the ureteric epithelium and the cap mesenchyme. In doing so, we describe a discontinuous developmental program governed by dynamic changes in interactions between these key cellular populations occurring within a previously unappreciated structurally stereotypic organ architecture. We also illustrate the application of this approach to the detection of a subtle mutant phenotype. This baseline program of kidney morphogenesis provides a framework for assessing genetic and environmental developmental perturbation and will serve as a gold standard for the analysis of other organs. PMID- 24780739 TI - Polarized Wnt signaling regulates ectodermal cell fate in Xenopus. AB - How cells convert polarity cues into cell fate specification is incompletely understood. Here, we show that Wnt/beta-catenin and Wnt/PCP signaling cooperate in this process in early Xenopus embryos. We find that the Wnt coreceptor Lrp6 is asymmetrically localized to the basolateral membrane in ectodermal blastomeres. Lrp6 asymmetry is controlled by Wnt/PCP signaling, indicating that this pathway regulates not only planar- but also apicobasal cell polarity. Following asymmetric cell division, Lrp6 preferentially sorts to the deep ectodermal cell layer and becomes depleted in the epithelial cell layer. This is accompanied by elevated Wnt/beta-catenin signaling in deep cells, which in turn promotes their differentiation into ciliated cells. We conclude that coordinated Wnt/PCP and Wnt/beta-catenin signaling convert apicobasal polarity information to specify ectodermal cell fate. PMID- 24780738 TI - In situ imaging in C. elegans reveals developmental regulation of microtubule dynamics. AB - Microtubules (MTs) are cytoskeletal polymers that undergo dynamic instability, the stochastic transition between growth and shrinkage phases. MT dynamics are required for diverse cellular processes and, while intrinsic to tubulin, are highly regulated. However, little is known about how MT dynamics facilitate or are regulated by tissue biogenesis and differentiation. We imaged MT dynamics in a smooth muscle-like lineage in intact developing Caenorhabditis elegans. All aspects of MT dynamics change significantly as stem-like precursors exit mitosis and, secondarily, as they differentiate. We found that suppression, but not enhancement, of dynamics perturbs differentiated muscle function in vivo. Distinct ensembles of MT-associated proteins are specifically required for tissue biogenesis versus tissue function. A CLASP family MT stabilizer and the depolymerizing kinesin MCAK are differentially required for MT dynamics in the precursor or differentiated cells, respectively. All of these multidimensional phenotypic comparisons were facilitated by a data display method called the diamond graph. PMID- 24780740 TI - Accelerated heart function recovery after therapeutic plasma exchange in patient treated with biventricular mechanical circulatory support for severe peripartum cardiomyopathy. AB - We describe a case of severe peripartum cardiomyopathy treated with biventricular mechanical circulatory support, where rapid haemodynamic recovery was observed after therapeutic plasma exchange, used as an adjunct to the inhibition of prolactin release. The patient recovered and after 2 months was discharged from the hospital without clinical symptoms of heart disease. PMID- 24780741 TI - Aggressive multiple surgical interventions to pulmonary artery sarcoma. AB - We describe our experience with a patient who had metastasized pulmonary artery sarcoma, but survived 7 years after diagnosis. A 61-year-old man was diagnosed with pulmonary artery intimal sarcoma after resection of metastatic tumours to the bilateral lungs. The primary lesion in the pulmonary artery trunk extending into the bilateral branches was treated by tumour endoarterectomy followed by chemotherapy. He underwent resections of lung metastases two more times before detection of recurrent obstructive pulmonary artery sarcoma 4 years after the tumour endoarterectomy. En bloc resection of the tumour including the pulmonary artery trunk, valve and interventricular septum was performed, and the right ventricular out flow tract was reconstructed with a stentless pulmonary valve and equine pericardium. He died of the disease soon after an operation for metastatic brain tumour 3 years later. Pulmonary artery sarcoma has a dismal prognosis, but aggressively repeated surgical interventions may lengthen survival. PMID- 24780742 TI - Pathobiont hypnotises enterocytes to promote tumour development. PMID- 24780743 TI - The PRSS1 c.623G>C (p.G208A) mutation is the most common PRSS1 mutation in Korean children with hereditary pancreatitis. PMID- 24780744 TI - In vivo anticancer synergy mechanism of doxorubicin and verapamil combination treatment is impaired in BALB/c mice with metastatic breast cancer. AB - The development of resistance to anticancer drugs is a major unsolved problem in the chemotherapy treatment of metastatic breast cancer. We have shown that increased expression of P-glycoprotein (P-gp) prevented nuclear entry of the doxorubicin molecules into murine breast cancer cells (4T1-R) leading to doxorubicin chemoresistance. This study was performed to test whether inhibition of P-gp using verapamil could overcome doxorubicin chemoresistance and eliminate multiorgan metastasis 4T1-R cells in BALB/c mouse. The 4T1-R cells were treated with doxorubicin alone, verapamil alone, and a combination of both. Multiorgan metastasis of 4T1-R cells in the presence and in the absence of combination treatment was determined in the BALB/c mouse model. Verapamil induced nuclear translocation of doxorubicin, G2-phase growth arrest and synergistically induced 100% cytotoxicity in 4T1-R cells in culture. However, the combination treatment using verapamil and doxorubicin did not improve the overall survival of BALB/c mice with metastatic breast cancer. Our results indicate that the combination treatment of verapamil and doxorubicin did not inhibit tumor growth in the lungs and liver indicating that the anticancer synergy mechanism of verapamil and doxorubicin is impaired in vivo in BALB/c mouse model with metastatic breast cancer. We propose that understanding the mechanisms as to why the combination of doxorubicin and verapamil treatment was impaired in the mouse model should allow novel approaches to improve chemotherapy response of metastatic breast cancer. PMID- 24780745 TI - Aberrant miRNA profiles associated with chronic benzene poisoning. AB - Chronic occupational benzene exposure is associated with an increased risk of hematological malignancies. To gain an insight into the new biomarkers and molecular mechanisms of chronic benzene poisoning, miRNA profiles and mRNA expression pattern from the peripheral blood mononuclear cells of chronic benzene poisoning patients and health controls matched age and gender without benzene exposure were performed using the Exiqon miRNA PCR ARRAY and Gene Chip Human Gene 2.0ST Arrays, respectively. Totally, 6 up-regulated miRNAs (miR-34a, miR-205, miR 10b, let-7d, miR-185 and miR-423-5p-2) and 7 down-regulated miRNAs (miR-133a, miR 543, hsa-miR-130a, miR-27b,miR-223, miR-142-5p and miR-320b) were found in chronic benzene poisoning group compared to health controls (P <= 0.05). By integrating miRNA and mRNA expression data, these differential miRNAs were mainly involved in regulation of transcription from RNA polymerase II promoter, axon guidance, regulation of transcription, DNA-dependent, nervous system development, and regulation of actin cytoskeleton organization. Further, pathway analysis indicated that SMAD4, PLCB1, NFAT5, GNAI2, PTEN, VEGFA, BCL2, CTNNB1 and CCND1 were key target genes of differential miRNAs which were implicated in Adherens junction, TGF-beta signaling pathway, Wnt signaling pathway, tight junction and Pathways in cancer. In conclusion, the aberrant miRNAs might be a potential biomarker of chronic benzene poisoning. PMID- 24780746 TI - The relationship between central hemodynamics, morning blood pressure surge, glycemic control and sodium intake in patients with type 2 diabetes and essential hypertension. AB - AIMS: The current study aimed to investigate the relationship between morning blood pressure surge (MBPS), hemodynamic parameters, glycemic control and 24-h urinary sodium excretion (USE) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: MBPS and central hemodynamic parameters were assessed from ambulatory blood pressure measurements. In addition to routine biochemistry, 24h urine collection was performed to measure protein, albumin and sodium excretion. RESULTS: There were 146 (38%) patients with T2DM and 238 (72%) patients without T2DM (control group). Patients with T2DM had statistically higher MBPS compared with patients without T2DM (P<0.0001). In patients with T2DM, MBPS was correlated with HbA1c (rho=0.311, P<0.0001), 24h urinary sodium excretion (USE) (rho=0.292, P=0.004) and various hemodynamic parameters. Additionally, regression analysis showed that being male (P=0.006), the presence of coronary artery disease (P=0.023), HbA1c (P=0.012), and 24h USE (P=0.001) were independently related with log MBPS in T2DM patients. CONCLUSION: This study demonstrated that T2DM was an independent risk factor for increased MBPS and MBPS was associated with central hemodynamic parameters. Additionally poor glycemic control and sodium intake were associated with worse MBPS in T2DM. PMID- 24780747 TI - Molecular evolution of calcification genes in morphologically similar but phylogenetically unrelated scleractinian corals. AB - Molecular phylogenies of scleractinian corals often fail to agree with traditional phylogenies derived from morphological characters. These discrepancies are generally attributed to non-homologous or morphologically plastic characters used in taxonomic descriptions. Consequently, morphological convergence of coral skeletons among phylogenetically unrelated groups is considered to be the major evolutionary process confounding molecular and morphological hypotheses. A strategy that may help identify cases of convergence and/or diversification in coral morphology is to compare phylogenies of existing "neutral" genetic markers used to estimate genealogic phylogenetic history with phylogenies generated from non-neutral genes involved in calcification (biomineralization). We tested the hypothesis that differences among calcification gene phylogenies with respect to the "neutral" trees may represent convergent or divergent functional strategies among calcification gene proteins that may correlate to aspects of coral skeletal morphology. Partial sequences of two nuclear genes previously determined to be involved in the calcification process in corals, "Cnidaria-III" membrane-bound/secreted alpha-carbonic anhydrase (CIII-MBSalpha-CA) and bone morphogenic protein (BMP) 2/4, were PCR amplified, cloned and sequenced from 31 scleractinian coral species in 26 genera and 9 families. For comparison, "neutral" gene phylogenies were generated from sequences from two protein-coding "non-calcification" genes, one nuclear (beta tubulin) and one mitochondrial (cytochrome b), from the same individuals. Cloned CIII-MBSalpha-CA sequences were found to be non-neutral, and phylogenetic analyses revealed CIII-MBSalpha-CAs to exhibit a complex evolutionary history with clones distributed between at least 2 putative gene copies. However, for several coral taxa only one gene copy was recovered. With CIII-MBSalpha-CA, several recovered clades grouped taxa that differed from the "non-calcification" loci. In some cases, these taxa shared aspects of their skeletal morphology (i.e., convergence or diversification relative to the "non-calcification" loci), but in other cases they did not. For example, the "non-calcification" loci recovered Atlantic and Pacific mussids as separate evolutionary lineages, whereas with CIII-MBSalpha-CA, clones of two species of Atlantic mussids (Isophyllia sinuosa and Mycetophyllia sp.) and two species of Pacific mussids (Acanthastrea echinata and Lobophyllia hemprichii) were united in a distinct clade (except for one individual of Mycetophyllia). However, this clade also contained other taxa which were not unambiguously correlated with morphological features. BMP2/4 also contained clones that likely represent different gene copies. However, many of the sequences showed no significant deviation from neutrality, and reconstructed phylogenies were similar to the "non-calcification" tree topologies with a few exceptions. Although individual calcification genes are unlikely to precisely explain the diverse morphological features exhibited by scleractinian corals, this study demonstrates an approach for identifying cases where morphological taxonomy may have been misled by convergent and/or divergent molecular evolutionary processes in corals. Studies such as this may help illuminate our understanding of the likely complex evolution of genes involved in the calcification process, and enhance our knowledge of the natural history and biodiversity within this central ecological group. PMID- 24780748 TI - Evolutionary pattern of rDNA following polyploidy in Leymus (Triticeae: Poaceae). AB - Ribosomal ITS polymorphism and its ancestral genome origin of polyploid Leymus were examined to infer the evolutionary outcome of rDNA gene following allopolyploid speciation and to elucidate the geographic pattern of ITS variation. The results demonstrated that different polyploids have experienced varying fates, including maintenance or homogenization of divergent arrays, occurrence of chimeric repeats and potential pseudogenes. Our data suggested that (1) the Ns, P/F, and St genomic types in Leymus were originated from Psathyrostachys, Agropyron/Eremopyrum, and Pseudoroegneria, respectively; (2) the occurrence of a higher proportion of Leymus species with predominant uniparental rDNA type might associate with the segmental allopolyploid origin, nucleolar dominance of alloploids, and rapid radiation of Leymus; (3) maintenance of multiple parental ITS types in allopolyploid might result from long generation times associated to vegetative multiplication, number and chromosomal location of ribosomal loci and/or recurrent hybridization; (4) the rDNA genealogical structure of Leymus species might associate with the geographic origins; and (5) ITS sequence clade shared by Leymus species from Central Asia, North America, and Nordic might be an outcome of ancestral ITS homogenization. Our results shed new light on understanding evolutionary outcomes of rDNA following allopolyploid speciation and geographic isolation. PMID- 24780749 TI - Interspecific relationships and the evolution of sexual dimorphism in pygmy sunfishes (Centrarchidae: Elassoma). AB - The genus Elassoma represents a small but unique component of the aquatic biodiversity hotspot in southeastern North America. We present the first phylogeny of the seven described species, corroborated by sequence data from mitochondrial and nuclear protein coding genes. This analysis reveals a Coastal Plain clade sister to the geographically isolated, and federally protected, Elassoma alabamae. The Coastal Plain clade contains the widespread E. zonatum, which is sister to a clade primarily restricted to lowland Neogene subprovinces. We analyzed morphometric data in a phylogenetic context to illustrate the evolution of sexual shape dimorphism within the genus. Sixteen univariate and three multivariate traits were tested for significant sexual dimorphism for each species, and relative transformation rates were inferred from the time tree. A simple index of interspecific sexual dimorphism revealed greater disparity among sympatric species comparisons than among allopatric comparisons. Results implicate geology as a primary factor influencing ecological diversification, and sexual selection as a mechanism reinforcing reproductive isolation in areas of secondary contact. We discuss putative roles of geological history and sexual selection in the generation and maintenance of the aquatic biodiversity gradient in southeastern North America. PMID- 24780750 TI - What's missing from avian global diversification analyses? AB - The accumulation of vast numbers of molecular phylogenetic studies has contributed to huge knowledge gains in the evolutionary history of birds. This permits subsequent analyses of avian diversity, such as how and why diversification varies across the globe and among taxonomic groups. However, available genetic data for these meta-analyses are unevenly distributed across different geographic regions and taxonomic groups. To comprehend the impact of this variation on the interpretation of global diversity patterns, I examined the availability of genetic data for possible biases in geographic and taxonomic sampling of birds. I identified three main disparities of sampling that are geographically associated with latitude (temperate, tropical), hemispheres (East, West), and range size. Tropical regions, which host the vast majority of species, are substantially less studied. Moreover, Eastern regions, such as the Old World Tropics and Australasia, stand out as being disproportionately undersampled, with up to half of communities not being represented in recent studies. In terms of taxonomic discrepancies, a majority of genetically undersampled clades are exclusively found in tropical regions. My analysis identifies several disparities in the key regions of interest of global diversity analyses. Differential sampling can have considerable impacts on these global comparisons and call into question recent interpretations of latitudinal or hemispheric differences of diversification rates. Moreover, this review pinpoints understudied regions whose biota are in critical need of modern systematic analyses. PMID- 24780751 TI - Rapid radiation and dispersal out of the Qinghai-Tibetan Plateau of an alpine plant lineage Rhodiola (Crassulaceae). AB - Rhodiola L. (Crassulaceae) is a mid-sized plant genus consisting of about 70 species, with most species distributed on the Qinghai-Tibetan Plateau (QTP) and the adjacent areas, and several species in north-east Asia, Europe, and North America. This study explored the origin and diversification history of Rhodiola and tested the biogeographic relationships between the QTP and other regions of the Northern Hemisphere. We sequenced the nuclear ribosomal internal transcribed spacers and eight plastid DNA fragments representing 55 species of Rhodiola, and reconstructed phylogenetic relationships with maximum parsimony, maximum likelihood and Bayesian inference. Several instances of incongruence between the nuclear and the plastid data sets were revealed, which can best be explained by reticulate evolution. Species of Rhodiola and Pseudosedum form a well-supported clade sister to Phedimus. Dating analysis suggested that the origin and diversification times of this group are largely correlated with the extensive uplifts of the Qinghai-Tibetan Plateau. Ancestral state reconstruction supports the hypothesis that Rhodiola originated on the QTP, and then dispersed to other regions of the Northern Hemisphere. Our findings highlight the importance of the uplifts of the Qinghai-Tibetan Plateau in promoting species diversification and the possible role of reticulate evolution in the diversification process. Our results also suggest the biogeographic significance of QTP as the source area in alpine plant evolution in the Northern Hemisphere. PMID- 24780753 TI - Ion-binding of glycine zwitterion with inorganic ions in biologically relevant aqueous electrolyte solutions. AB - The ion-binding between inorganic ions and charged functional groups of glycine zwitter-ion in NaCl(aq), KCl(aq), MgCl2(aq), and CaCl2(aq) has been investigated over a wide salt concentration range by using integral equation theory in the 3D RISM approach. These systems mimic biological systems where binding of ions to charged residues at protein surfaces is relevant. It has been found that the stability of ion pairs formed by the carboxylate group and added inorganic cations decreases in the sequence Mg(2+)>Ca(2+)>Na(+)>K(+). However, all formed ion pairs are weak and decrease in stability with increasing salt concentration. On the other hand, at a given salt concentration the stability of (-NH3(+):Cl( ))aq ion pairs is similar in all studied systems. The features of ion-binding and the salt concentration effect on this process are discussed. PMID- 24780752 TI - Understanding photoreceptor outer segment phagocytosis: use and utility of RPE cells in culture. AB - RPE cells are the most actively phagocytic cells in the human body. In the eye, RPE cells face rod and cone photoreceptor outer segments at all times but contribute to shedding and clearance phagocytosis of distal outer segment tips only once a day. Analysis of RPE phagocytosis in situ has succeeded in identifying key players of the RPE phagocytic mechanism. Phagocytic processes comprise three distinct phases, recognition/binding, internalization, and digestion, each of which is regulated separately by phagocytes. Studies of phagocytosis by RPE cells in culture allow specifically analyzing and manipulating these distinct phases to identify their molecular mechanisms. Here, we compare similarities and differences of primary, immortalized, and stem cell derived RPE cells in culture to RPE cells in situ with respect to phagocytic function. We discuss in particular potential pitfalls of RPE cell culture phagocytosis assays. Finally, we point out considerations for phagocytosis assay development for future studies. PMID- 24780754 TI - Towards understanding knee joint laxity: errors in non-invasive assessment of joint rotation can be corrected. AB - The in vivo quantification of rotational laxity of the knee joint is of importance for monitoring changes in joint stability or the outcome of therapies. While invasive assessments have been used to study rotational laxity, non invasive methods are attractive particularly for assessing young cohorts. This study aimed to determine the conditions under which tibio-femoral rotational laxity can be assessed reliably and accurately in a non-invasive manner. The reliability and error of non-invasive examinations of rotational joint laxity were determined by comparing the artefact associated with surface mounted markers against simultaneous measurements using fluoroscopy in five knees including healthy and ACL deficient joints. The knees were examined at 0 degrees , 30 degrees , 60 degrees and 90 degrees flexion using a device that allows manual axial rotation of the joint. With a mean RMS error of 9.6 degrees , the largest inaccuracy using non-invasive assessment was present at 0 degrees knee flexion, whereas at 90 degrees knee flexion, a smaller RMS error of 5.7 degrees was found. A Bland and Altman assessment indicated that a proportional bias exists between the non-invasive and fluoroscopic approaches, with limits of agreement that exceeded 20 degrees . Correction using average linear regression functions resulted in a reduction of the RMS error to below 1 degrees and limits of agreement to less than +/-1 degrees across all knees and flexion angles. Given the excellent reliability and the fact that a correction of the surface mounted marker based rotation values can be achieved, non-invasive evaluation of tibio femoral rotation could offer opportunities for simplified devices for use in clinical settings in cases where invasive assessments are not justified. Although surface mounted marker based measurements tend to overestimate joint rotation, and therefore joint laxity, our results indicate that it is possible to correct for this error. PMID- 24780755 TI - The influence of an unilateral carotid artery stenosis on brain oxygenation. AB - We study the impact of varying degrees of unilateral stenoses of an carotid artery on pulsatile blood flow and oxygen transport from the heart to the brain. For the numerical simulation a model reduction approach is used involving non linear 1-D transport equation systems, linear 1-D transport equations and 0-D models. The haemodynamic effects of vessels beyond the outflow boundaries of the 1-D models are accounted for using a 0-D lumped three element windkessel model. At the cerebral outflow boundaries the 0-D windkessel model is extended by metabolic autoregulation, based on the cerebral oxygen supply. Additionally lumped parameter models are applied to incorporate the impact of the carotid stenosis. Our model suggests that for a severe unilateral stenosis in the right carotid artery the partial pressure of oxygen in the brain area at risk can only be restored, if the corresponding cerebral resistance is significantly decreased and if the circle of Willis (CoW) is complete. PMID- 24780757 TI - Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15. AB - The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGFbeta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15 expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. PMID- 24780756 TI - Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. AB - In recent years, immune-based therapies have become an increasingly attractive treatment option for patients with cancer. Cancer immunotherapy is often used in combination with conventional chemotherapy for synergistic effects. The alkylating agent cyclophosphamide (CTX) has been included in various chemoimmunotherapy regimens because of its well-known immunostimulatory effects. Paradoxically, cyclophosphamide can also induce suppressor cells that inhibit immune responses. However, the identity and biologic relevance of these suppressor cells are poorly defined. Here we report that cyclophosphamide treatment drives the expansion of inflammatory monocytic myeloid cells (CD11b(+)Ly6C(hi)CCR2(hi)) that possess immunosuppressive activities. In mice with advanced lymphoma, adoptive transfer (AT) of tumor-specific CD4(+) T cells following cyclophosphamide treatment (CTX+CD4 AT) provoked a robust initial antitumor immune response, but also resulted in enhanced expansion of monocytic myeloid cells. These therapy-induced monocytes inhibited long-term tumor control and allowed subsequent relapse by mediating functional tolerization of antitumor CD4(+) effector cells through the PD-1-PD-L1 axis. PD-1/PD-L1 blockade after CTX+CD4 AT therapy led to persistence of CD4(+) effector cells and durable antitumor effects. Depleting proliferative monocytes by administering low-dose gemcitabine effectively prevented tumor recurrence after CTX+CD4 AT therapy. Similarly, targeting inflammatory monocytes by disrupting the CCR2 signaling pathway markedly potentiated the efficacy of cyclophosphamide-based therapy. Besides cyclophosphamide, we found that melphalan and doxorubicin can also induce monocytic myeloid suppressor cells. These findings reveal a counter-regulation mechanism elicited by certain chemotherapeutic agents and highlight the importance of overcoming this barrier to prevent late tumor relapse after chemoimmunotherapy. PMID- 24780760 TI - Meta-analysis of side effects of statins shows need for trial transparency. PMID- 24780758 TI - Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30. AB - Natural killer (NK) cells are potent immune effector cells capable of mediating antitumor responses. Thus, during immunoediting, tumor cell populations evolve strategies to escape NK-cell-mediated recognition. In this study, we report a novel mechanism of immune escape involving tumor cell shedding of B7-H6, a ligand for the activating receptor NKp30 that mediates NK-cell binding and NK-cell mediated killing. Tumor cells from different cancer entities released B7-H6 by ectodomain shedding mediated by the cell surface proteases "a disintegrin and metalloproteases" (ADAM)-10 and ADAM-17, as demonstrated through the use of pharmacologic inhibitors or siRNA-mediated gene attenuation. Inhibiting this proteolytic shedding process increased the levels of B7-H6 expressed on the surface of tumor cells, enhancing NKp30-mediated activation of NK cells. Notably, we documented elevated levels of soluble B7-H6 levels in blood sera obtained from a subset of patients with malignant melanoma, compared with healthy control individuals, along with evidence of elevated B7-H6 expression in melanoma specimens in situ. Taken together, our results illustrated a novel mechanism of immune escape in which tumor cells impede NK-mediated recognition by metalloprotease-mediated shedding of B7-H6. One implication of our findings is that therapeutic inhibition of specific metalloproteases may help support NK-cell based cancer therapy. PMID- 24780761 TI - Reaction kinetics and oxidation products formation in the degradation of ciprofloxacin and ibuprofen by ferrate(VI). AB - The treatment of ciprofloxacin (CIP) and ibuprofen (IBU) in test solutions by ferrate(VI) was investigated in this study. A series of jar test was performed in bench-scale at pH 6-9 and ferrate(VI) dose of 1-5 mg L(-1). Results demonstrated that ferrate(VI) removed CIP from test solutions efficiently, with above 70% of reduction under study conditions. In contrary, the removal rates of IBU were very low, less than 25% in all conditions. Raising ferrate(VI) dose improved the treatment performance, while the influence of solution pH was not significant at pH 6-9 compared with that of ferrate(VI) dose. In addition, kinetic studies of ferrate(VI) with both compounds were carried out at pH 8 and pH 9 (20 degrees C). Ferrate(VI) had a much higher reactivity with CIP than IBU at pH 8 and pH 9, with CIP's apparent second-order rate constants of 113.7+/-6.3 M(-1) s(-1) and 64.1+/-1.0 M(-1) s(-1), respectively. The rate constants of ferrate(VI) with IBU were less than 0.2 M(-1) s(-1) at pH 8 and pH 9. Furthermore, seven oxidation products (OPs) were formed during CIP degradation by ferrate(VI). The attack on the piperazinyl ring of the CIP by ferrate(VI) appeared to lead to the cleavage or hydroxylation of the rings, and the attack on the quinolone moiety by ferrate(VI) might lead to the cleavage of the double bond at the six-member heterocyclic ring. No OPs of IBU were detected during ferrate(VI) oxidation due to very small part of IBU was degraded by ferrate(VI). PMID- 24780762 TI - Household food waste separation behavior and the importance of convenience. AB - Two different strategies aiming at increasing household source-separation of food waste were assessed through a case-study in a Swedish residential area (a) use of written information, distributed as leaflets amongst households and (b) installation of equipment for source-segregation of waste with the aim of increasing convenience food waste sorting in kitchens. Weightings of separately collected food waste before and after distribution of written information suggest that this resulted in neither a significant increased amount of separately collected food waste, nor an increased source-separation ratio. After installation of sorting equipment in households, both the amount of separately collected food waste as well as the source-separation ratio increased vastly. Long-term monitoring shows that results where longstanding. Results emphasize the importance of convenience and existence of infrastructure necessary for source segregation of waste as important factors for household waste recycling, but also highlight the need of addressing these aspects where waste is generated, i.e. already inside the household. PMID- 24780763 TI - Ceftolozane/tazobactam activity tested against aerobic Gram-negative organisms isolated from intra-abdominal and urinary tract infections in European and United States hospitals (2012). AB - Ceftolozane/tazobactam is under clinical development for treatment of complicated intra-abdominal infections (IAI), complicated urinary tract infections (UTI) and ventilator-associated pneumonia. We evaluated the in vitro activity of ceftolozane/tazobactam and comparator agents tested against Gram-negative aerobic bacteria causing IAI and healthcare-associated UTI (HCA-UTI). The organisms were consecutively collected from January to December 2012 from 59 medical centers located in the United States (USA) and 15 European countries by the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS). The collection included 809 organisms from IAI and 2474 organisms from HCA-UTI, and susceptibility testing was performed by reference broth microdilution methods as described by the Clinical and Laboratory Standards Institute (CLSI) M07-A9 document. Overall, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were the most frequently isolated pathogens from both infection types. Ceftolozane/tazobactam was very active against E. coli (MIC50/90, 0.25/0.5 mg/L; 98.5-99.9% inhibited at an MIC of <=8 mg/L) and retained activity against many of the multidrug-resistant (MDR; MIC50/90, 0.5/2->32 mg/L) and ESBL-phenotype strains (MIC50/90, 0.5/2-32 mg/L). Ceftolozane/tazobactam was active against most K. pneumoniae strains (MIC50/90, 0.25/16 mg/L, 88.9-89.6% inhibited at an MIC of <=8 mg/L), but some ESBL-phenotype (MIC50/90, 4-8/>32 mg/L) and MDR (MIC50/90, 16/>32 mg/L) isolates exhibited elevated MIC values. Ceftolozane/tazobactam was the most active agent tested against P. aeruginosa (MIC50/90, 0.5/4 mg/L; 93.4-95.7% inhibited at <=8 mg/L) and retained potency against many MDR (MIC50/90, 2-4/>32 mg/L), ceftazidime nonsusceptible (MIC50/90, 2-4/>32 mg/L) and meropenem-nonsusceptible (MIC50/90, 2/>32 mg/L) strains. Ceftolozane/tazobactam was also active against Klebsiella oxytoca (MIC50/90, <=0.12-0.25/0.5-1 mg/L), Enterobacter spp. (MIC50/90, 0.25 0.5/4-8 mg/L), Citrobacter spp. (MIC50/90, 0.25/2-32 mg/L), Proteus mirabilis (MIC50/90, 0.5/0.5 mg/L), indole-positive Proteae (MIC50/90, 0.25/0.5-1 mg/L), and Serratia spp. (MIC50/90, 0.5/1-2 mg/L). In summary, ceftolozane/tazobactam demonstrated potent in vitro activity when tested against contemporary aerobic Gram-negative pathogens causing IAI and HCA-UTI in USA and European medical centers. PMID- 24780764 TI - Bacteraemia with rifampin-resistant Staphylococcus aureus and the potential role of cross-resistance between rifampin and rifaximin. PMID- 24780765 TI - A prospective study of community-associated Clostridium difficile infections: the role of antibiotics and co-infections. AB - OBJECTIVES: This prospective study was performed to determine the incidence, risk factors, severity and outcomes of community-associated Clostridium difficile infection (CA-CDI) in the SE of Scotland. METHODS: All patients (335) diagnosed with laboratory confirmed CDI in the city of Edinburgh, East Lothian and Midlothian regions of Scotland between August 2010 and July 2011 were followed up for one year after diagnosis. Clinical details and laboratory markers were recorded. Stool samples were tested for C. difficile, other bacterial pathogens and norovirus. Molecular epidemiology of C. difficile isolates was studied by PCR ribotyping. RESULTS: Of the total 335 confirmed CDI cases, PCR-ribotype 001 was the commonest (14.1%), followed by PCR-ribotypes 078 (12.9%) and 015 (11.7%), respectively. CA-CDI represented 12.5% of the cases. In these, PCR-ribotype 078 was the commonest (19.0%), followed by PCR-ribotypes 014/020 (16.7%), PCR ribotype 015 (14.3% and PCR-ribotype 001 (11.9%). A lower Charlson co-morbidity index and a lower age was observed in the CA-CDI group as was total number of different antibiotic classes whereas age >75 was more common in the HA-CDI group. On multivariable analysis presence of PCR-ribotype 078 was significantly associated with community acquisition (p = 0.006) whereas a greater proportion of immunosuppressed patients and those on antibiotics 8 weeks preceding diagnosis (p = 0.035 and p = 0.005 respectively) were found among HA-CDI cases. Charlson co morbidity index, number of different antibiotics given in the eight weeks preceding onset, severity of infection and rural residence were not significantly different between the two groups. CONCLUSION: This study demonstrates that patients with CA-CDI may also present with severe infection, are less likely to receive antibiotics prior to CDI, more likely to be younger in age and have a greater proportion of PCR-ribotype 078 compared with CDI acquired in a hospital setting. Hence a high level of vigilance must be maintained to detect CDI cases which present in the community without the traditional predisposing factors. PMID- 24780767 TI - Effects of exercise on mitochondrial function, neuroplasticity and anxio depressive behavior of mice. AB - The present study was aimed at analyzing the effects of physical exercise on mitochondrial physiology, anxio-depressive-like behaviors and neuroplasticity in mice. Adult C57BL/6J male mice were isolated in home cages equipped or not with free-running wheels. After 6weeks of exercise, mice were tested in various behavioral paradigms to evaluate anxiety- and depressive-like behaviors. The hippocampi were dissected for neurochemical assays, including mitochondrial activity, monoamines content and the expression of genes involved in energy metabolism and brain-derived neurotrophic factor (BDNF) regulation. Exercise decreased anxiety-like behaviors in the open field and elevated plus maze, and exerted antidepressant-like effects in the tail suspension test. Exercise stimulated brain mitochondrial activity and increased resistance against rotenone, an inhibitor of complex I activity. Furthermore, mRNA expression of Bdnf, Gdnf, Tfam (mitochondrial transcription factor A), and Ndufa6 (mitochondrial I subunit) genes, as well as the phosphorylation of cAMP response element-binding protein were increased after exercise. In summary, exercise appears to engage mitochondrial pathways and to potentiate neuroplasticity and might be associated to mood improvement. PMID- 24780766 TI - Serotonin modulates electrosensory processing and behavior via 5-HT2-like receptors. AB - Efficient sensory processing of the environment is a critical function for any organism to survive and is accomplished by having neurons adapt their responses to stimuli based on behavioral context in part through neuromodulators such as serotonin (5-HT). We have recently shown that one critical function of the serotonergic system in weakly electric fish is to enhance sensory pyramidal neuron responses within the electrosensory lateral line lobe (ELL) to stimuli caused by same sex conspecifics, thereby enhancing their perception. This enhancement is accomplished by making pyramidal neurons more excitable through downregulation of potassium channels. However, the nature of the 5-HT receptors that mediate this effect is not known. Here we show that the 5-HT2 receptor antagonist ketanserin (ket) can effectively block the effects of 5-HT on pyramidal neuron excitability in vitro. Indeed, 5-HT application subsequent to ket application did not cause any significant changes in neuron excitability and responses to current injection. We further show that ket applied in vivo can block the effects of 5-HT on behavioral responses. Thus, our results strongly suggest that the previously observed effects of 5-HT on sensory processing within ELL and their consequences for behavior are mediated by 5-HT2 receptors. PMID- 24780769 TI - Physical exercise training and neurovascular unit in ischemic stroke. AB - Physical exercise could exert a neuroprotective effect in both clinical studies and animal experiments. A series of related studies have indicated that physical exercise could reduce infarct volume, alleviate neurological deficits, decrease blood-brain barrier dysfunction, promote angiogenesis in cerebral vascular system and increase the survival rate after ischemic stroke. In this review, we summarized the protective effects of physical exercise on neurovascular unit (NVU), including neurons, astrocytes, pericytes and the extracellular matrix. Furthermore, it was demonstrated that exercise training could decrease the blood brain barrier dysfunction and promote angiogenesis in cerebral vascular system. An awareness of the exercise intervention benefits pre- and post stroke may lead more stroke patients and people with high-risk factors to accept exercise therapy for the prevention and treatment of stroke. PMID- 24780768 TI - Extracellular pH modulates GABAergic neurotransmission in rat hypothalamus. AB - Changes in extracellular pH have a modulatory effect on GABAA receptor function. It has been reported that pH sensitivity of the GABA receptor is dependent on subunit composition and GABA concentration. Most of previous investigations focused on GABA-evoked currents, which only reflect the postsynaptic receptors. The physiological relevance of pH modulation of GABAergic neurotransmission is not fully elucidated. In the present studies, we examined the influence of extracellular pH on the GABAA receptor-mediated inhibitory neurotransmission in rat hypothalamic neurons. The inhibitory postsynaptic currents (IPSCs), tonic currents, and the GABA-evoked currents were recorded with whole-cell patch techniques on the hypothalamic slices from Sprague-Dawley rats at 15-26 postnatal days. The amplitude and frequency of spontaneous GABA IPSCs were significantly increased while the external pH was changed from 7.3 to 8.4. In the acidic pH (6.4), the spontaneous GABA IPSCs were reduced in amplitude and frequency. The pH induced changes in miniature GABA IPSCs (mIPSCs) similar to that in spontaneous IPSCs. The pH effect on the postsynaptic GABA receptors was assessed with exogenously applied varying concentrations of GABA. The tonic currents and the currents evoked by sub-saturating concentration of GABA ([GABA]) (10 MUM) were inhibited by acidic pH and potentiated by alkaline pH. In contrast, the currents evoked by saturating [GABA] (1mM) were not affected by pH changes. We also investigated the influence of pH buffers and buffering capacity on pH sensitivity of GABAA receptors on human recombinant alpha1beta2gamma2 GABAA receptors stably expressed in HEK 293 cells. The pH influence on GABAA receptors was similar in HEPES- and MES-buffered media, and not dependent on protonated buffers, suggesting that the observed pH effect on GABA response is a specific consequence of changes in extracellular protons. Our data suggest that the hydrogen ions suppress the GABAergic neurotransmission, which is mediated by both presynaptic and postsynaptic mechanisms. PMID- 24780770 TI - Developmental study of the distribution of hypoxia-induced factor-1 alpha and microtubule-associated protein 2 in children's brainstem: comparison between controls and cases with signs of perinatal hypoxia. AB - Perinatal asphyxia and hypoxia are common causes of morbidity in neonates. Prenatal birth associated with hypoxemia often results in several disorders because of the lack of oxygen in the brain. Survival rates from perinatal hypoxia have improved, but appropriate treatments for recovery are still limited, with great impact on patients, their families, society in general and health systems. The aim of this work is to contribute to a better understanding of the cellular mechanisms underlying the brainstem responses to hypoxia. For this purpose, distributions of two proteins, hypoxia-inducible factor-1 alpha (HIF-1alpha) and microtubule-associated protein 2 (MAP-2) were analyzed in brainstems of 11 children, four of them showing neuropathological evidence of brain hypoxia. They were included in control or hypoxic groups, and then in several subgroups according to their age. Immunohistochemical labeling for these proteins revealed only cell bodies containing HIF-1alpha, and both cell bodies and fibers positive for MAP-2 in the children's brainstems. The distribution of HIF-1alpha was more restricted than that of MAP-2, and it can be suggested that the expression of HIF 1alpha increased with age. The distribution pattern of MAP-2 in the medulla oblongata could be more due to age-related changes than to a response to hypoxic damage, whereas in the pons several regions, such as the nucleus ambiguus or the solitary nucleus, showed different immunolabeling patterns in controls and hypoxic cases. The distribution patterns of these two proteins suggest that some brainstem regions, such as the reticular formation or the central gray, could be less affected by conditions of hypoxia. PMID- 24780771 TI - The high cost of endovascular neurosurgery therapies and the need to sustain quality on limited resources. PMID- 24780772 TI - Aneurysm wall composition may determine rupture risk and endovascular treatment failure. PMID- 24780773 TI - Allograft AlloDerm((r)) tissue for laparoscopic transabdominal preperitoneal groin hernia repair: A case report. AB - INTRODUCTION: Synthetic mesh is the prosthetic material used for most inguinal hernioplasties. However, when left in contact with intra-abdominal viscera, it often becomes associated with infection and migration, particularly in irradiated tissues, contaminated fields, immunosuppressed individuals, and patients with intestinal obstruction or fistula. AlloDerm((r)) Regenerative Tissue Matrix (LifeCell Corporation, Branchburg, NJ) is derived from human cadaver skin and may be associated with fewer visceral adhesions and more durability in infected fields than synthetic mesh. PRESENTATION OF CASE: We report the first case in which AlloDerm was used in a laparoscopic transabdominal preperitoneal repair of a multiple recurrent right inguinal hernia, a left femoral hernia, and an umbilical hernia in the same patient. Use of AlloDerm greatly enhanced the maneuverability during laparoscopic hernia repair due to its pliability and strength and eliminated the need to cover the prosthetic with peritoneum. DISCUSSION: Previous pelvic radiation and multiple previous groin repairs can render the peritoneum friable, resulting in obstacles to successful closure. AlloDerm is a reasonable choice for groin hernia repairs when such factors are present. CONCLUSION: The long-term durability of AlloDerm for laparoscopic groin hernia repairs is yet to be determined, but based on current data it seems prudent to use this technique in laparoscopic repair of complex groin hernias where infection is suspected or inadequate prosthetic coverage with peritoneum is anticipated. PMID- 24780774 TI - Relapse of acute myeloid leukemia manifested by cholecystitis: A case report and review of the literature. AB - INTRODUCTION: AML is the most common form of leukemia in adults. In rare circumstances AML may present in the form of extra-medullary disease. Gallbladder infiltration with myeloblasts is rare and only a few cases exist in the literature describing this entity. PRESENTATION OF CASE: We present a rare case of AML relapse in the form of extramedullary infiltration of the gallbladder in a 50-year-old male patient. The leukemic infiltration presented as symptomatic cholecystitis and sepsis. A laparoscopic cholecystectomy was performed and the gallbladder was pathologically examined. Histopathologic examination demonstrated multiple scattered, highly atypical single cells admixed with some plasma cells, small lymphocytes and macrophages consistent with leukemic infiltration. The abnormal cells demonstrated immunohistochemical staining for CD68, CD33 and CD117. The patient did well post-operatively but the relapse precluded him from bone marrow transplantation. DISCUSSION: Although AML is relatively common, 3 cases per 100,000 population, extramedullary disease in the form of gallbladder infiltration is exceedingly rare. An extensive review of the literature revealed only four cases of myeloid infiltration of the gallbladder. To our knowledge this is the only case of relapsing disease in the form of gallbladder infiltration presenting as symptomatic cholecystitis in a pre-bone marrow transplantation patient. CONCLUSION: This case highlights the importance of maintaining a high index of suspicion of atypical manifestations of AML when managing refractory sepsis. Extramedullary manifestations of AML in the form of gallbladder infiltration must be considered in the differential diagnosis of patients with a history of myeloid malignancies and for patients whom fail conventional non operative management. PMID- 24780775 TI - Comment on: Conservative management of an infected laparoscopic hernia mesh: A case study. AB - INTRODUCTION: We recently published an article in this journal describing the successful conservative treatment of a patient with an infected laparoscopically inserted hernia mesh using gentamycin flushes via a pig-tail drain and long term oral antibiotics. This prevented the need for major reconstructive surgery. However, 3 months after we published our report, the patient re-presented with symptoms of a recurrence of infection. PRESENTATION OF CASE: Seven months after stopping oral antibiotics, our patient represented with fever and swelling and redness over his left sided inguinal hernia mesh. This mesh had to be surgically removed. The procedure was laparoscopic and showed infection confined to the central 5cm of the mesh. Microbiology culture results were the same as on initial presentation. DISCUSSION: The microbiology results suggest that it is likely that the infection was never fully eradicated and that our intervention merely kept the infection at bay. Once long term antibiotics were stopped it is likely that the infection was able to eventually recur. CONCLUSION: Consequently, we have been unable to show that our method of conservative management of infected hernia meshes is effective to prevent long term recurrence of infection. PMID- 24780776 TI - Endoscopic ultrasonography allowing expectant management of pancreatic haemangioma. AB - Pancreatic haemangiomas are rare benign tumours that can affect both adults and children. They have an unknown incidence and only 15 adult cases have been reported, all from histological examination. Patients present with vague symptoms relating to tumour mass or they are detected incidentally. Cross-sectional imaging is the mainstay of investigation and may reveal arterially enhancing cystic lesions but in the case presented here, it was non-diagnostic. The use of endoscopic ultrasonography confirmed the nature of the benign lesion, allowing a conservative approach as opposed to operative resection. PMID- 24780777 TI - The misleading appearance of silver nitrate on plain radiography. AB - Cauterisation with silver nitrate is commonly used to treat overgranulation. Silver nitrate has a high density and a high mass attenuation coefficient, and it is therefore highly radio-opaque. We present a case in which its topical application to an area of overgranulation was interpreted as a bony fragment by the reporting radiologist in a patient with a supracondylar humeral fracture whose radiograph after removal of K-wires showed a large radio-opaque lesion. Although not a new phenomenon, it is one not widely known, and it can lead to confusion and unnecessary further imaging. PMID- 24780778 TI - Seeking responsibility for the lost swab? Search elsewhere. AB - This article explores the possibility that the surgeon's control over his or her environment is not complete and that, in certain circumstances, the final swab count can be distinguished from the 'normal course of events'. We readily accept that most swabs and instruments are left inside patients simply as a result of substandard care but we cannot accept that this is invariably the case, and lessons from the common law are cited to illustrate the reasons why. We hope to persuade defendant lawyers that it might be worthwhile to tease out from surgeons under scrutiny how these factors may have influenced their practice on the day that a swab was retained. PMID- 24780779 TI - The aetiology and current management of prepubertal epididymitis. AB - INTRODUCTION: The aim of this study was to review the published evidence on the pathogenesis and management of acute epididymitis (AE) in prepubertal boys after the authors encountered an unexpectedly large number of such cases in their institution. METHODS: Using MEDLINE((r)), a literature search was performed for articles in English with the words "pre-pubertal" OR "boys" OR "p(a)ediatric" OR "children" AND "epididymitis" OR "epididymo-orchitis". RESULTS: The literature suggests that it is rare to find a bacterial infection or anatomical anomaly as a cause for AE in this population. A postviral infectious phenomenon is the most likely explanation. The management should be supportive and antibiotics reserved for those with pyuria or positive cultures. Urodynamic studies and renal tract ultrasonography have been advocated for those with recurrent epididymitis. CONCLUSIONS: AE in prepubertal boys is more common than believed previously. A careful history for recent viral illnesses should be included. Antibiotics, urinary tract imaging and functional studies should be used in selected cases. PMID- 24780780 TI - Meta-analysis of retrojugular versus antejugular approach for carotid endarterectomy. AB - INTRODUCTION: The retrojugular approach for carotid endarterectomy (CEA) has been reported to have the advantages of shorter operative time and ease of dissection, especially in high carotid lesions. Controversial opinion exists with regard to its safety and benefits over the conventional antejugular approach. METHODS: A systematic review of electronic information sources was conducted to identify studies comparing outcomes of CEA performed with the retrojugular and antejugular approach. Synthesis of summary statistics was undertaken and fixed or random effects models were applied to combine outcome data. FINDINGS: A total of 6 studies reporting on a total of 740 CEAs (retrojugular approach: 333 patients; antejugular approach: 407 patients) entered our meta-analysis models. The retrojugular approach was found to be associated with a higher incidence of laryngeal nerve damage (odds ratio [OR]: 3.21, 95% confidence interval [CI]: 1.46 7.07). No significant differences in the incidence of hypoglossal or accessory nerve damage were identified between the retrojugular and antejugular approach groups (OR: 1.09 and 11.51, 95% CI: 0.31-3.80 and 0.59-225.43). Cranial nerve damage persisting during the follow-up period was similar between the groups (OR: 2.96, 95% CI: 0.79-11.13). Perioperative stroke and mortality rates did not differ in patients treated with the retrojugular or antejugular approach (OR: 1.26 and 1.28, 95% CI: 0.31-5.21 and 0.25-6.50). CONCLUSIONS: Currently, there is no conclusive evidence to favour one approach over the other. Proof from a well designed randomised trial would help determine the role and benefits of the retrojugular approach in CEA. PMID- 24780781 TI - Ionising radiation exposure in paediatric trauma. AB - INTRODUCTION: Trauma remains the highest cause of paediatric morbidity and mortality. These trauma patients incur radiation exposure during intraoperative management. Medical personnel have the responsibility to ensure observation of the 'as low as reasonably achievable' principle, a practice mandate that minimises ionising radiation exposure. The aim of this study was to quantify the difference in the amount of ionising radiation used by operating surgeons of different grades in paediatric trauma surgery. METHODS: Intraoperative imaging in paediatric trauma surgery between 2008 and 2010 at a UK trauma centre was analysed retrospectively, recording injury demographics, surgeon grade, radiation exposure (dose area product [DAP]) and screening time. A mobile image intensifier was used in all cases and the lowest dose rate was selected for all screening. RESULTS: A total of 782 trauma cases were analysed: 304 procedures (39%) were carried out by consultants, 127 (16%) by senior registrars and 351 (45%) by junior registrars. The mean screening time for consultants was 0.23 minutes (standard deviation [SD]: 0.21 minutes) while for senior registrars it was 0.24 minutes (SD: 0.27 minutes) and for junior registrars 0.47 minutes (SD: 1.5 minutes). The mean DAP for consultants was 58.49Gycm(2) (SD: 53.66Gycm(2)). For senior registrars it was 87.2Gycm(2) (SD: 126.64Gycm(2)) and for junior registrars it was 90.46Gycm(2) (SD: 180.02Gycm(2)). This equates to a 51% increase in screening time and a 35% increase in DAP by a junior registrar compared with a consultant. CONCLUSIONS: Significantly lower screening times and radiation exposure was found in procedures performed by consultants compared with registrars (p<0.001). Given the harmful and unknown long-term effects of ionising radiation exposure in children, we recommend increasing consultant presence in paediatric trauma theatres. PMID- 24780782 TI - Managing the open abdomen in a district general hospital. AB - INTRODUCTION: The need to manage an open abdomen is becoming more common in general surgical practice and a variety of methods of temporary abdominal closure (TAC) are available. The evidence for the efficacy of the various forms of TAC as well as the subsequent definitive fascial closure (DFC) rates and complications comes mainly from large trauma series in the US, which represent a different patient population to those in the UK in whom TAC is usually required. METHODS: All cases of open abdomen management in our hospital over a five-year period were reviewed to ascertain the methods of TAC used, our success in achieving DFC and the applicability of managing such cases in a district hospital environment. RESULTS: Nineteen patients underwent TAC, with two deaths (10.5%) and an overall DFC rate at hospital discharge of 12/17 (70.6%). The median lengths of critical care and hospital stays were 19.5 and 38.0 days respectively. Thirteen out of seventeen survivors had at least one significant complication. CONCLUSIONS: The management of the open abdomen can be achieved safely in a district general hospital setting with acceptable outcomes for the non-trauma patients commonly seen in UK practice but it is a resource intensive and expensive undertaking. PMID- 24780783 TI - Axillary lymph node clearance in patients with positive sentinel lymph node biopsy. AB - INTRODUCTION: The use of adjuvant radiotherapy is standard practice following breast conserving surgery and mastectomy in selected patients. Prospective clinical trials are currently being designed to assess the effect of omitting axillary lymph node clearance (ALNC) in selected patients. The aim of this study was to identify the percentage of patients understaged and not considered for postmastectomy radiotherapy (PMRT) and/or supraclavicular fossa radiotherapy (SCFRT) with positive sentinel lymph node (SLN) macrometastasis if the proposed prospective trial inclusion/exclusion protocols are followed. METHODS: A total of 38 women who were found negative for axillary metastases preoperatively but positive at SLN biopsy and who had ALNC were analysed. PMRT or SCFRT was offered to patients if >=4 positive lymph nodes (including sentinel nodes) were positive for macrometastasis and/or a tumour size of >=5cm was detected. Fisher's exact test was used to determine the statistical significance of omitting ALNC. RESULTS: The mean age of the 38 patients was 55 years. A fifth (21.1%) of patients had T1, 76.3% had T2 and 2.6% had T3 disease. The percentage of positive SLNs was 52.6% (1 node), 34.2% (2 nodes) and 13.1% (3 nodes). The number of positive nodes at clearance was 0-3. If the inclusion criteria for trials that consider omitting ALNC are followed (eg POSNOC trial), 23.7% of patients (p=0.0001) with >=4 positive nodes (including SLNs) would not be offered SCFRT and PMRT. Similarly, if multicentric disease were to be excluded from the trial criteria, the proportion of undertreated patients would reduce by 15.7%. CONCLUSIONS: Our study has shown a significant risk of missing patients for PMRT or SCFRT if no ALNC is offered in the presence of SLN macrometastasis. Tumour multicentricity is an important factor in predicting high axillary nodal involvement. Consequently, exclusion of T2 tumours with multicentric involvement in trials considering omitting ALNC may be more appropriate. PMID- 24780784 TI - Ultrasonography alone for diagnosis of breast cancer in women under 40. AB - INTRODUCTION: Recent guidelines suggest that ultrasonography should be used as the primary imaging modality in women under 40 years of age with mammography being offered if further imaging is required. The aim of this study was to assess the adequacy of ultrasonography and the utility of mammography in this patient group by reviewing the role these imaging techniques had in the diagnosis of breast cancer in our unit. METHODS: All breast cancers diagnosed in patients 39 years or younger from June 2009 to June 2011 were reviewed. This was a retrospective review of presentation, clinical findings, imaging modality (ultrasonography, mammography, magnetic resonance imaging [MRI]) and histology. Mammography was the primary imaging modality until May 2011 in women between 35 and 39 years of age. Both invasive and intraductal carcinoma were included in the study but lobular carcinoma in situ was excluded. RESULTS: A total of 2,495 patients were referred to the symptomatic breast clinic in this age group during the study period. Thirty women were identified with either invasive cancer (n=27) or ductal carcinoma in situ (n=3). Twenty-eight patients underwent mammography, graded as uncertain, suspicious or malignant in the majority. Malignancy was missed in one patient. All 30 patients underwent ultrasonography, reported as uncertain, suspicious or malignant, an indication for diagnostic core biopsy. Ultrasonography alone did not miss any cancers but did fail to detect multifocal disease in one patient. CONCLUSIONS: In this study group, ultrasonography was reliable as the primary imaging modality for women under 40, identifying all cancers in this cohort. Mammography and/or MRI remain essential adjuncts to accurately determine multifocality and/or the extent of disease. PMID- 24780785 TI - Clinical significance of incidental findings on staging positron emission tomography for oesophagogastric malignancies. AB - INTRODUCTION: The aim of this retrospective study was to determine the clinical significance of incidental findings detected on positron emission tomography (PET) in patients undergoing staging of oesophagogastric malignancies. METHODS: Patients with oesophagogastric malignancies who underwent PET between June 2007 and May 2012 were included in the study. PET was performed according to hospital protocol. All imaging was interpreted by two consultant radiologists in nuclear medicine. Incidental findings that were unrelated to the primary malignancy were recorded and patients were recommended to have further investigations (imaging, endoscopy and biopsy). RESULTS: Overall, 333 patients (240 male, 93 female; mean age: 67 years) with upper gastrointestinal malignancies were eligible for inclusion in the study. Eighty-nine of these patients had PET demonstrating one or more incidental findings. Two patients were found to have a second primary malignancy. One patient had a distant metastasis of his primary cancer and six patients had a premalignant lesion. CONCLUSIONS: In this study, incidental findings were discovered in 26.7% of patients with known oesophagogastric cancer. A second primary cancer or premalignant lesion was found in 8.4% of patients with incidental findings. Patients with these findings should be investigated to rule out further malignancy. There were a high proportion of false positive results in our study. It is recommended that each patient is considered on an individual basis and assessed with simultaneous PET and computed tomography. PMID- 24780786 TI - The influence of FDG PET-CT on the detection of extrahepatic disease in patients being considered for resection of colorectal liver metastasis. AB - INTRODUCTION: The aim of this study was to evaluate the influence of flurodeoxyglucose positron emission tomography computed tomography (FDG PET-CT), as an adjunct to conventional CT staging, in the detection of extrahepatic disease in patients with potentially resectable colorectal liver metastasis. METHODS: Overall, 133 consecutive patients with colorectal liver metastases staged with CT and PET-CT referred to the East Lancashire regional hepatobiliary multidisciplinary team over a two-year period were included in this study. Abnormal findings on PET-CT were correlated with follow-up imaging and/or histology. All imaging was reviewed by specialist hepatobiliary radiologists for the presence/absence of extrahepatic disease. The influence of the PET-CT findings was categorised for each patient in relation to operability and other significant findings. RESULTS: PET-CT had a major impact on staging of extra hepatic disease in 20% of patients, in comparison with the initial CT. Six per cent of patients were upstaged from operable CT findings to inoperable findings on PET-CT because of the discovery of inoperable occult extrahepatic disease. Five per cent had operable local regional nodal disease detected on PET-CT. A further 3% had premalignant colorectal lesions detected on PET-CT. Six per cent of patients were downstaged from indeterminate or suspected inoperable CT findings to operable findings on PET-CT. CONCLUSIONS: The use of PET-CT in this setting may prevent futile operations, guide the resection of local regional nodal disease and downstage a number of patients thought to have extrahepatic disease on conventional imaging. This study has shown similar results to other recent studies and supports the use of PET-CT as a necessary staging modality in patients with potentially resectable colorectal liver metastases. PMID- 24780787 TI - Methods for siting emergency stomas in the absence of a stoma therapist. AB - INTRODUCTION: Stomas often have to be sited in emergencies by trainees who may have had little training in this. Emergency stomas and stomas where the site has not been marked preoperatively by a stoma therapist are more prone to complications. These complications may severely affect a patient's quality of life. Advice in the literature on how to best site stomas is conflicting. We compared two easy anatomical methods of siting stomas to sites chosen by a stoma therapist and looked at how this site was affected by the patients' body mass index (BMI). METHODS: Patients undergoing elective colorectal surgery were seen either pre or postoperatively. Each patient's BMI was recorded and the positions of three different potential stoma positions (site G: the gold standard, marked by a stoma therapist; site S: marked using a pair of scissors against the umbilicus; site H: halfway between the umbilicus and anterior superior iliac spine) were compared. RESULTS: The two fixed anatomical methods described (method S and method H) both gave poor results. The most common reason for poor siting was the proximity of a skin crease. There was a statistically significant correlation between the patient's BMI and the laterality of the gold standard site. CONCLUSIONS: The two simple anatomical methods described here do not provide a shortcut to effective siting. A more effective method may be calculating the laterality of the site using the patient's BMI, and then moving up/down to avoid a skin crease and improve the patient's view for changing the bag. This deserves further study. PMID- 24780788 TI - Incidence and predictors of post-thyroidectomy hypocalcaemia in a tertiary endocrine surgical unit. AB - BACKGROUND: Post-thyroidectomy hypocalcaemia is a common complication with significant short and long term morbidity. The aim of this study was to determine the incidence and predictors of post-thyroidectomy hypocalcaemia (as defined by a corrected calcium <2.1 mmol/l) in a tertiary endocrine surgical unit. METHODS: A total of 238 consecutive patients who underwent completion or bilateral thyroid surgery between 2008 and 2011 were included in this retrospective study. Clinical and biochemical data were obtained from electronic and hard copy medical records. RESULTS: The incidence of post-thyroidectomy hypocalcaemia on first postoperative day (POD1) was 29.0%. There was variation in the incidence of hypocalcaemia depending on the timing of measurement on the first postoperative day. At six months following surgery, 5.5% of patients were on calcium and/or vitamin D supplementation. Factors associated with post-thyroidectomy hypocalcaemia were lower preoperative corrected calcium (p=0.005) and parathyroid gland (PTG) auto transplant (p=0.001). Other clinical factors such as central lymph node dissection, inadvertent PTG excision, ethnicity, preoperative diagnosis and Lugol's iodine were not associated with post-thyroidectomy hypocalcaemia. CONCLUSION: The incidence of post-thyroidectomy hypocalcaemia was underestimated by 6% when only POD1 measurements were considered. The timing of measurement on POD1 has an impact on the incidence of post-thyroidectomy hypocalcaemia. Auto transplantation and lower preoperative calcium were associated with post thyroidectomy hypocalcaemia. PMID- 24780789 TI - Serology and ultrasound for diagnosis of choledocholithiasis. AB - INTRODUCTION: Magnetic resonance cholangiopancreatography (MRCP) is not a routine investigation to exclude choledocholithiasis unless there is clinical or biochemical suspicion of common bile duct (CBD) stones. This study attempted to determine which radiological or serological parameters best predicted CBD stones. METHODS: All patients undergoing MRCP from 2005 to 2011 were selected. Patients with pancreatitis were excluded. Liver function tests (LFTs) at admission and prior to MRCP were recorded, as was abdominal ultrasonography and MRCP results. Parameters measured routinely on LFTs included alkaline phosphatase (ALP), alanine transaminase (ALT) and bilirubin. Receiver operating characteristic curve area analysis (area under the curve [AUC]) and chi-squared analysis were undertaken. RESULTS: Overall, 195 patients were identified, 71 of whom had CBD stones on MRCP. Raised ALP levels on admission demonstrated a correlation with CBD stones (AUC: 0.619, odds ratio [OR]: 3.16, p=0.06). At ultrasonography, a dilated CBD (OR: 3.76, p<0.001) and intrahepatic duct dilation (OR: 5.56, p<0.001) were highly significant predictors. However, only 37% of patients had a dilated CBD on ultrasonography. Ongoing elevation of LFT parameters, particularly ALP (AUC: 0.707, OR: 4.64, p<0.001) and ALT (AUC: 0.646, OR: 5.40, p<0.001), displayed a significant correlation with CBD stones. CONCLUSIONS: Ongoing (even if minor) elevations of liver function test parameters should prompt the need to exclude CBD stones even in the presence of a normal CBD diameter on ultrasonography. PMID- 24780790 TI - Patient outcomes after treatment with percutaneous cholecystostomy for biliary sepsis. AB - INTRODUCTION: Acute cholecystitis is among the most common general surgical presentations. There is a cohort of patients who develop systemic sepsis and complications of acute cholecystitis. These patients are often elderly and co morbid. Conservative management with percutaneous cholecystostomy has been shown to be a safe and effective management option in the acute setting. However, there is currently no consensus for the further management of these patients. In particular, there is a paucity of data on readmission rates and subsequent operative or non-operative management. METHODS: A retrospective study was carried out of patients treated with a percutaneous cholecystostomy for biliary sepsis over a three-year period in a UK teaching hospital. Outcome measures were subsequent operative or conservative management, conversion rates, operative complications and readmission rates. RESULTS: Twenty-five patients had a percutaneous cholecystostomy for the treatment of acute biliary sepsis. The median follow-up duration was 35 months. Thirteen patients (52%) had operative treatment. In the operative group, 6/13 had a laparoscopic cholecystectomy, 2/13 had a planned open cholecystectomy, 2/13 had abandoned procedures and 3/13 had a converted procedure. Complications in the operative group included: postoperative mortality (1/13), common bile duct injury requiring drainage and endoscopic stenting (1/13) and one patient required readmission with recurrent pain. In the non-operative group, 5/12 patients were readmitted with biliary sepsis, 5/12 had no readmissions, 1/12 died in the community and 1/12 was readmitted with biliary colic. CONCLUSIONS: Percutaneous cholecystostomy is a recognised treatment modality for elderly, co-morbid patients with biliary sepsis. Nevertheless, the readmission rate in this group is relatively high at 5/12 (42%). Patients who undergo subsequent operative management have a conversion rate of 3/13 (23%) and a significant complication rate of 2/13 (15%). The further management of patients having undergone percutaneous cholecystostomy requires careful consideration on an individual case basis. The P-POSSUM (Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) may aid decision making. PMID- 24780791 TI - The use of computed tomography in identifying radiologically occult hip fractures in the elderly. AB - INTRODUCTION: Fractured neck of femur (NOF) is a cause of significant morbidity and mortality. Approximately 4% of patients with an initial normal hip x-ray in the emergency department (ED) will in fact have an occult fracture. In cases where there is ongoing clinical suspicion of NOF fracture despite a normal hip x ray, alternative imaging should be used. Although available evidence supports the use of magnetic resonance imaging (MRI) for this, it is often not readily accessible from the ED. In our department, it is common practice to request computed tomography (CT). METHODS: A historical review was undertaken of all patients who presented between October 2007 and January 2011 who had CT requested by ED staff. Patients included in the study were those who presented following low impact trauma in whom fractured NOF was suspected despite a normal x-ray. RESULTS: Of the 65 included patients, fractures (pelvic and hip) were identified in 38 patients on CT. Fractured NOFs were found in 13 patients. Acetabular fractures were found in nine patients, five of whom required further orthopaedic management. One patient went on to have MRI to confirm the diagnosis of an impacted NOF fracture, suspected both on x-ray and CT. Further review was undertaken of the medical notes of discharged patients to identify any who reattended or required further imaging. No such cases were found. CONCLUSIONS: This review has shown the use of CT to be a practical approach to improving the care of patients with occult hip fractures. PMID- 24780792 TI - A simple technique for double ligation of the vas deferens during vasectomy. PMID- 24780793 TI - The use of alginate dressing on grafted donor sites in burns. PMID- 24780794 TI - Reverse tissue expansion. PMID- 24780795 TI - A novel method for community monitoring of flexion contracture in Dupuytren's disease. PMID- 24780796 TI - The 'do-it-yourself' silastic ring for the silastic ring Roux-en-Y gastric bypass. PMID- 24780797 TI - The silent assistant in elbow surgery. PMID- 24780798 TI - Innovative postoperative bra for patients with drains following breast surgery. PMID- 24780799 TI - Preventing damage to the femoral trunion during acetabular revision. PMID- 24780800 TI - Use of a template to improve placement of volar splints on an injured hand. PMID- 24780801 TI - The Derby parallax technique for marking levels in thoracic spinal surgery. PMID- 24780802 TI - Accurate screw arthrodesis of the distal interphalangeal joint. PMID- 24780803 TI - Presurgical preparation using static electricity. PMID- 24780804 TI - The modified mallet splint for closed central slip injuries. PMID- 24780805 TI - Fishing method of appendix extraction during laparoscopy. PMID- 24780806 TI - Using a cartilage butterfly graft to repair a damaged bony canal wall in combined approach tympanoplasty surgery. PMID- 24780807 TI - An adjunct to safe cement removal in revision shoulder arthroplasty. PMID- 24780808 TI - A simple, safe and effective bedside technique to achieve haemostasis in serious colorectal anastomotic bleeding. PMID- 24780809 TI - Safe suction during laparoscopic surgery. PMID- 24780810 TI - A method for the placement of the ceramic liner in an uncemented cup. PMID- 24780811 TI - The diagnostic value of fine needle aspiration in parotid lumps. PMID- 24780812 TI - Minimally invasive endoscopic therapy for the management of Boerhaave's syndrome. PMID- 24780813 TI - Twist-over: stainless steel suture technique for skin graft applications. PMID- 24780814 TI - Streptococcal toxic shock syndrome following total thyroidectomy. PMID- 24780815 TI - A secure retraction technique for exposing the internal mammary vessels. PMID- 24780816 TI - Traditional Chinese Medicine (TCM) for fibrotic liver disease: hope and hype. PMID- 24780817 TI - Whole-body PET/MRI: the effect of bone attenuation during MR-based attenuation correction in oncology imaging. AB - PURPOSE: In combined PET/MRI standard PET attenuation correction (AC) is based on tissue segmentation following dedicated MR sequencing and, typically, bone tissue is not represented. We evaluate PET quantification in whole-body (WB)-PET/MRI following MR-AC without considering bone attenuation and then investigate different strategies to account for bone tissue in clinical PET/MR imaging. To this purpose, bone tissue representation was extracted from separate CT images, and different bone representations were simulated from hypothetically derived MR based bone classifications. METHODS: Twenty oncology patients referred for a PET/CT were injected with either [18F]-FDG or [18F]-NaF and imaged on PET/CT (Biograph TruePoint/mCT, Siemens) and PET/MRI (mMR, Siemens) following a standard single-injection, dual-imaging clinical WB-protocol. Routine MR-AC was based on in-/opposed-phase MR imaging (orgMR-AC). PET(/MRI) images were reconstructed (AW OSEM, 3 iterations, 21 subsets, 4mm Gaussian) following routine MR-AC and MR-AC based on four modified attenuation maps. These modified attenuation maps were created for each patient by non-linear co-registration of the CT images to the orgMR-AC images, and adding CT bone mask values representing cortical bone: 1200HU (cortCT), spongiosa bone: 350HU (spongCT), average CT value (meanCT) and original CT values (orgCT). Relative difference images of the PET following AC using the modified attenuation maps were compared. SUVmean was calculated in anatomical reference regions and for PET-positive lesions. RESULTS: The relative differences in SUVmean across patients following orgMR-AC and orgCT in soft tissue lesions and in bone lesions were similar (range: 0.0% to -22.5%), with an average underestimation of SUVmean of 7.2% and 10.0%, respectively when using orgMR-AC. In bone lesions, spongCT values were closest to orgCT (median bias of 1.3%, range: -9.0% to 13.5%) while the overestimation of SUVmean with respect to orgCT was highest for cortCT (40.8%, range: 1.5% to 110.8%). For soft tissue lesions the bias was highest using cortCT (13.4%, range: -2.3% to 17.3%) and lowest for spongCT (-2.2%, range: 0.0% to -13.7%). CONCLUSIONS: In PET/MR imaging using standard MR-AC PET uptake values in soft lesions and bone lesions are underestimated by about 10%. In individual patients this bias can be as high as 22%, which is significant during clinical follow-up exams. If bone segmentation is available, then assigning a fixed attenuation value of spongious bone to all bone structures appears reasonable and results in only a minor bias of 5%, or less in uptake values of soft tissue and bone lesions. PMID- 24780818 TI - Paediatric ultrasonography of the liver, hepatobiliary tract and pancreas. AB - In the field of paediatric radiology ultrasonography (US) is the most versatile imaging tool available. Children in general, by virtue of their body composition, are excellent candidates for US exams in whom abdominal anatomy and pathology can be visualised in great detail. The fact that during the US study a clinical history can be obtained strongly adds to the value of the US exam. This does require investment in time and expertise and ideally a paediatric radiologist performing the exam. In this review the role of ultrasonography (US) of the liver, biliary tract and pancreas in children is discussed. PMID- 24780819 TI - Cellular contractility changes are sufficient to drive epithelial scattering. AB - Epithelial scattering occurs when cells disassemble cell-cell junctions, allowing individual epithelial cells to act in a solitary manner. Epithelial scattering occurs frequently in development, where it accompanies epithelial-mesenchymal transitions and is required for individual cells to migrate and invade. While migration and invasion have received extensive research focus, how cell-cell junctions are detached remains poorly understood. An open debate has been whether disruption of cell-cell interactions occurs by remodeling of cell-cell adhesions, increased traction forces through cell substrate adhesions, or some combination of both processes. Here we seek to examine how changes in adhesion and contractility are coupled to drive detachment of individual epithelial cells during hepatocyte growth factor (HGF)/scatter factor-induced EMT. We find that HGF signaling does not alter the strength of cell-cell adhesion between cells in suspension, suggesting that changes in cell-cell adhesion strength might not accompany epithelial scattering. Instead, cell-substrate adhesion seems to play a bigger role, as cell-substrate adhesions are stronger in cells treated with HGF and since rapid scattering in cells treated with HGF and TGFbeta is associated with a dramatic increase in focal adhesions. Increases in the pliability of the substratum, reducing cells ability to generate traction on the substrate, alter cells' ability to scatter. Further consistent with changes in substrate adhesion being required for cell-cell detachment during EMT, scattering is impaired in cells expressing both active and inactive RhoA mutants, though in different ways. In addition to its roles in driving assembly of both stress fibers and focal adhesions, RhoA also generates myosin-based contractility in cells. We therefore sought to examine how RhoA-dependent contractility contributes to cell-cell detachment. Inhibition of Rho kinase or myosin II induces the same effect on cells, namely an inhibition of cell scattering following HGF treatment. Interestingly, restoration of myosin-based contractility in blebbistatin-treated cells results in cell scattering, including global actin rearrangements. Scattering is reminiscent of HGF-induced epithelial scattering without a concomitant increase in cell migration or decrease in adhesion strength. This scattering is dependent on RhoA, as blebbistatin-induced scattering is reduced in cells expressing dominant-negative RhoA mutants. This suggests that induction of myosin-based cellular contractility may be sufficient for cell-cell detachment during epithelial scattering. PMID- 24780820 TI - miR-34a expands myeloid-derived suppressor cells via apoptosis inhibition. AB - Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population and show significant expansion under pathological conditions. microRNA plays important roles in many biological processes, whether microRNAs have a function in the expansion of MDSCs is still not very clear. In this study, miR-34a overexpression can induce the expansion of MDSCs in bone marrow chimera and transgenic mice model. The experimental results suggest that miR-34a inhibited the apoptosis of MDSCs but did not affect the proliferation of MDSCs. The distinct mRNA microarray profiles of MDSCs of wild type and miR-34a over-expressing MDSCs combined with the target prediction of miR-34a suggest that miR-34a may target genes such as p2rx7, Tia1, and plekhf1 to inhibit the apoptosis of MDSCs. Taken together, miR 34a contributes to the expansion of MDSCs by inhibiting the apoptosis of MDSCs. PMID- 24780821 TI - Inhibition of transforming growth factor-beta signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor. AB - Interaction between tumor cells and stromal fibroblasts plays essential roles in tumor progression. However, its detailed molecular mechanism remains unclear. To understand the mechanism, we investigated molecules mediating this interaction using the three-dimensional (3D) co-culture system of Panc-1 pancreatic carcinoma cells with normal fibroblasts. When the two kinds of cells were placed on the top of collagen gel, the tumor cells scattered into the fibroblast layer, apparently undergoing epithelial-mesenchymal transition. When fibroblasts were placed within collagen gel, Panc-1 cells actively invaded into the collagen gel, extending a microtubule-based long protrusion. Although transforming growth factor-beta (TGF beta) and hepatocyte growth factor (HGF) individually stimulated the tumor cell invasion into collagen gel without fibroblasts, TGF-beta signaling inhibitors (SB431542 and LY2157299) significantly enhanced the Panc-1 cell invasion in the 3D co-culture with fibroblasts. Experiments with HGF/Met signaling inhibitors or with the fibroblast conditioned medium revealed that HGF was a major invasion promoting factor secreted from fibroblasts and SB431542 increased the HGF secretion by blocking the HGF-suppressing activity of cancer cell-derived TGF beta. These results indicate that HGF and TGF-beta are critical regulators for both tumor-stroma interaction and tumor invasion. The results also suggest that TGF-beta signaling inhibitors may promote tumor progression under some pathological conditions. PMID- 24780822 TI - Methamphetamine use is an independent predictor of poor outcome after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Clinical outcomes of methamphetamine users with aneurysmal subarachnoid hemorrhage (aSAH) are unknown. OBJECTIVE: To analyze differences in presentation, in-hospital morbidity, and outcomes between methamphetamine users and non-users. METHODS: All 472 patients included in the Barrow Ruptured Aneurysm Trial from 2003 to 2007 were reviewed. Patients with 1- and 3-year follow-up were included in this analysis (n=398). Methamphetamine users were identified as patients who provided a history of methamphetamine use on admission or tested positive on urine toxicology testing. Methamphetamine users were compared with non-users using univariate analysis. Outcomes were then analyzed using multivariate logistic regression models for demographic characteristics, medical comorbidities, radiographic and clinical presentation, and vasospasm. RESULTS: Thirty-one patients (7.8%) were identified as methamphetamine users in this cohort. Methamphetamine users were younger than non-users (mean age 42.8 vs 55 years, p<0.001). In multivariate logistic regression models, methamphetamine use was an independent predictor of poor Glasgow Outcome Scale score at both 1 year (OR=5.02; 95% CI 1.03 to 24.48; p<0.05) and 3 years (OR=7.18; 95% CI 1.73 to 29.87; p=0.007). Other independent predictors in this model included older age, clinical vasospasm, diabetes, and aneurysm size. Cocaine and tobacco use were not significantly associated with poor outcome in our cohort. Methamphetamine use was not significantly associated with vasospasm, higher Fisher or Hunt and Hess grade, or intraparenchymal hemorrhage/intraventricular hemorrhage. CONCLUSIONS: Methamphetamine users have significantly worse outcomes at 1 and 3 years following aSAH. Further analysis is necessary to understand the pathological response associated with methamphetamine use in this setting. PMID- 24780823 TI - Utilization rates of hip arthroplasty in OECD countries. AB - BACKGROUND: Hip arthroplasty and revision surgery is growing exponentially in OECD countries, but rates vary between countries. METHODS: We extracted economic data and utilization rates data about hip arthroplasty done in OECD countries between 1990 and 2011. Absolute number of implantations and compound annual growth rates were computed per 100,000 population and for patients aged 65 years old and over and for patients aged 64 years and younger. RESULTS: In the majority of OECD countries, there has been a significant increase in the utilization of total hip arthroplasty in the last 10 years, but rates vary to a great extent: In the United States, Switzerland, and Germany the utilization rate exceeds 200/100,000 population whereas in Spain and Mexico rates are 102 and 8, respectively. There is a strong correlation between gross domestic product (GDP) and health care expenditures per capita with utilization rate. Utilization rates in all age groups have continued to rise up to present day. A seven fold higher growth rate was seen in patients aged 64 years and younger as compared to older patients. CONCLUSION: We observed a 38-fold variation in the utilization of hip arthroplasty among OECD countries, correlating with GDP and health care expenditures. Over recent years, there has been an increase in the utilization rate in most countries. This was particularly evident in the younger patients. Due to increasing life expectancy and the disproportionally high use of arthroplasty in younger patients we expect an exponential increase of revision rate in the future. PMID- 24780824 TI - Systematic review of factors associated with depression and anxiety disorders among older adults with Parkinson's disease. AB - Depression and anxiety disorders have a substantial impact on the quality of life, the functioning and mortality of older adults with Parkinson's disease (PD). The purpose of this systematic review was to examine the factors associated with the prevalence of depression and anxiety disorders among individuals with PD aged 60 years and older. Following a literature search in PubMed, PsycINFO, CINAHL, and EMBASE, 5 articles met the inclusion criteria (adults aged 60 years and older, individuals with PD, and with depression and anxiety disorders, and English-language peer reviewed articles) and were included in this review. These studies were conducted in the U.S (n = 3), in Italy (n = 1) and the U.K (n = 1). Findings indicated that autonomic symptoms, motor fluctuations, severity and frequency of symptoms, staging of the disease, and PD onset and duration were associated with the prevalence of depression and anxiety disorders among older adults suffering from PD. Despite the limited number of studies included in the review, depression and anxiety disorders are often unrecognized and untreated and the comorbidity greatly exacerbates PD symptoms. The identification of factors associated with the development of depression and anxiety disorders could help in designing preventive interventions that would decrease the risk and burden of depression and anxiety disorders among older adults with PD. PMID- 24780825 TI - Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder. AB - Data on immunohistochemical expression of novel and traditional urothelial markers in the wide range of urothelial carcinoma variants have so far been very limited. In this study, whole tissue sections from 130 bladder urothelial carcinoma and variants were stained with a panel of novel and traditional immunomarkers supportive of urothelial lineage. The positivity rates were as follows: (a) urothelial carcinomas with or without divergent differentiation: GATA3 (50%), S-100P (86%), uroplakin III (20%), thrombomodulin (40%), cytokeratin 7 (CK7) (80%), CK20 (55%), p63 (87%), and high molecular weight cytokeratin (HMCK) (89%); (b) urothelial carcinoma variants (micropapillary, plasmacytoid, nested, clear cell, and microcystic): GATA3 (88%), S-100P (96%), uroplakin III (33%), thrombomodulin (49%), CK7 (95%), CK20 (61%), p63 (69%), and HMCK (96%); and (c) undifferentiated carcinomas (lymphoepithelioma-like carcinoma, small cell carcinoma, sarcomatoid carcinoma and carcinoma with rhabdoid and giant cells): GATA3 (28%), S-100P (31%), uroplakin III (0%), thrombomodulin (22%), CK7 (50%), CK20 (3%), p63 (50%), and HMCK (49%). In urothelial carcinoma with squamous differentiation, GATA3 expression was lower (20%) in contrast to p63 and S-100P. In urothelial carcinoma with glandular differentiation, GATA3 (50%) and p63 (60%) expression was lower than S-100P (100%). p63 expression was relatively lower in micropapillary (54%) and plasmacytoid (50%) variants compared with the other urothelial carcinoma variants. This study provides comprehensive data for novel and traditionally used markers to support urothelial lineage in urothelial carcinoma variants. Our findings show that GATA3, S-100P, CK7, CK20, HMCK, and p63, in the appropriate differential diagnostic setting, are useful to support urothelial lineage of variant morphologies. PMID- 24780826 TI - Prognostic value of myogenic differentiation in undifferentiated pleomorphic sarcomas of soft tissue. AB - Patients with pleomorphic soft tissue sarcomas with myogenic differentiation (MD) are thought to have a worse prognosis than those without MD. In this study, we sought to determine the prognostic significance of MD in a restricted cohort of patients with high-grade undifferentiated pleomorphic sarcoma (UPS) of the extremities or trunk that were uniformly treated at a single institution. Thirty eight patients met the inclusion criteria: (1) extremity or truncal soft tissue UPS, (2) histologic high grade, (3) size of 8 cm or more, (4) received protocol treatment. Immunohistochemical stains were performed on each tumor for 3 muscle markers: muscle-specific actin, smooth muscle actin, and desmin. A tumor was classified as having MD if it showed positive staining for at least 1 muscle marker. We correlated the line of differentiation with outcome using chi(2) and Kaplan-Meier analysis. MD was identified in 15 tumors and non-MD in 23 tumors. There were no significant differences between the myogenic and nonmyogenic groups in terms of age, sex, tumor size, tumor grade, or follow-up. The overall survival (OS) and disease-specific survival (DSS) were both 86.7% for patients with myogenic sarcomas. The OS and DSS were both 91.3% for those with nonmyogenic sarcomas. There was no significant difference between groups for OS or DSS in chi(2) testing (P = .649) or on Kaplan-Meier curve/log-rank testing (P = .541). In this homogenous group of patients with large, high-grade, extremity or truncal UPS who received neoadjuvant chemoradiotherapy, MD did not predict a worse survival than non-MD. PMID- 24780827 TI - Severe domestic squalor: Time to sort out the mess. PMID- 24780828 TI - [More evidence in favor of generics!]. PMID- 24780829 TI - [Anaphylaxis to protamine during cardiovascular surgery]. AB - Protamine is a polypeptide with low molecular weights that is used widely to reverse heparin anticoagulation during cardiac surgery. Protamine, efficient and relatively sure, can produce multiple adverse reactions after intravenous administration, including pulmonary hypertension, or systemic hypotension leading at times to cardiovascular collapse and death. Physiopathologic mechanisms, underlying these reactions, are not clear. Immunologic and non-immunologic pathways are suggested. Some risk factors expose to protamine's adverse reactions. Preoperative identification of these factors should prompt specific preventive measures. The anesthesiologist and the cardiac surgeon must be vigilant when administrating protamine. Reheparinization and reinstitution of cardiopulmonary bypass should be considered in patients with refractory shock. PMID- 24780830 TI - Continuous infusion of piperacillin/tazobactam in patients with severe infections: A possible pharmacokinetic optimisation? AB - Piperacillin/Tazobactam is a time-dependent antimicrobial combination (beta lactam/beta-lactamase inhibitor) commonly used in the treatment of severe Gram negative infections. The optimisation of its time-dependent bactericidal activity via continuous infusion could improve clinical outcomes. Several studies have been realized on the relevance of a continuous infusion, but, to date, no definitive position can be adopted on the matter and a well-designed randomized controlled trial is warranted. In other articles, continuous infusion regimens are also more cost efficient. This article is an update, including the most recent trials about this subject. PMID- 24780831 TI - [Clinical pharmacy and surgery: Review]. AB - Clinical pharmacy has been developed and evaluated in various medical hospital activities. Reviews conducted in this area reported a higher value of this discipline. In surgical services, evenly adverse drug events may occur, so clinical pharmacy activities must also help to optimize the management of drug's patient. The objectives of this literature review is to determine the profile of clinical pharmacy activities developed in surgical services and identify indicators. The research was conducted on Pubmed((r)) database with the following keywords (2000-2013), "surgery", "pharmacy", "pharmacist", "pharmaceutical care", "impact" and limited to French or English papers. Studies dealing on simultaneously medical and surgical areas were excluded. Twenty-one papers were selected. The most frequently developed clinical pharmacy activities were history and therapeutic drug monitoring (antibiotics or anticoagulants). Two types of indicators were identified: activity indicators with the number of pharmaceutical interventions, their description and clinical signification, the acceptance rate and workload. Impact indicators were mostly clinical and economic impacts. The development of clinical pharmacy related to surgical patients is documented and appears to have, as for medical patients, a clinical and economical value. PMID- 24780832 TI - Methylphenidate-risperidone combination in child psychiatry: A retrospective analysis of 44 cases. AB - INTRODUCTION: Psychotimulant-antipyschotic combinations are frequently used in child psychiatry, but have been rarely described in the literature. METHOD AND PATIENTS: We propose here a retrospective study of 44 children who received the combination methylphenidate (MPH)-risperidone (RIS). The sample is composed of children who received either MPH (n=28) or RIS (n=16) as primary treatment. A vast majority of the children had a comorbid attention deficit hyperactivity disorder (ADHD) diagnosis. RESULTS: For over 60% of patients, regardless of their initial monotherapy, bitherapy decreased the symptoms of ADHD and conduct disorder, sleep disorders and anxiety. Concerning the safety of the bitherapy, a compensation effect on weight gain and appetite was respectively observed in 70% and 50% of patients. Even though iatrogenic tachycardia can be encountered with both drugs, it has never been reported when they are associated and we have reported a total of 3 cases in our study. We have also observed a case of dyskinesia resolved with the discontinuation of the treatment. DISCUSSION/CONCLUSION: MPH-RIS bitherapy appears to be particularly effective in ADHD with conduct disorder symptoms. Although tolerance may limit its use, the benefit/risk ratio seems favourable for a number of children. PMID- 24780833 TI - Generic vancomycin products: Analysis of serum concentrations in patients with acute myeloid leukemia. AB - Concerns have recently emerged about the quality of generic vancomycin products. Our aim is to analyze serum vancomycin concentrations measured 48 hours after the start of an empirical treatment regimen in patients with acute myeloid leukemia (AML) who received one of the two generic vancomycin products available in France. PATIENTS AND METHODS: Seventy-nine AML patients treated with vancomycin during two study periods were included in the study. Our vancomycin dosing regimen was based on the patients' total body weight adjusted for renal clearance. RESULTS: A total of 93 serum vancomycin concentrations were collected: 31 in period 1 and 62 in period 2. In bivariate analysis, the mean serum vancomycin concentrations were not significantly different (19.9 +/- 11.2 mg/L in period 1 vs 18.9 +/- 6.0 mg/L in period 2, P=0.64). In the final generalized estimating equations model, serum vancomycin concentrations correlated statistically with a positive coefficient for age (P<0.001) and with negative coefficients for male sex (P=0.001) and hemoglobin level (P=0.021). CONCLUSION: Serum vancomycin concentrations measured 48 hours after the start of an empirical treatment were not influenced by the nature of the generic product but correlated with age, sex and hemoglobin level in AML patients. PMID- 24780834 TI - [Role of clinical pharmacist in the therapeutical optimization in geriatric outpatient hospital]. AB - SETTING: Cares in outpatient hospital for elderly patients is a period of interest for multidisciplinary reassessment and pharmaceutical care of the prescription. The objective is to present the implementation of the pharmaceutical care activity at the outpatient hospital. METHODS: Between August and October 2011, elderly patients hospitalized in the outpatient hospital for a brief appraisal had a pharmaceutical care. The clinician introduced pharmaceutical reviews in the synthesis letter for general practitioner. An analysis of the activity was carried out over 3 months. RESULTS: A pharmaceutical care had been realized for 67 patients, mean age of 81.7 years. Among medical related problems identified, 39.6% were for potentially unnecessary medication. A stop was proposed for 44% of pharmaceutical interventions. A total of 91 pharmaceutical interventions and 13 recommendations were made and 34% of patients had potentially inappropriate medication. CONCLUSION: According to the objective to reduce the therapeutics contributing to the iatrogenesis, this approach allowed us to undertake a multidisciplinary collaboration oriented toward the relay between hospital and city cares. PMID- 24780835 TI - [Parmentier hygiene and public health]. AB - The legend about Parmentier is quite reductive when it limits his activity to the promotion of potato. This military pharmacist intended mainly to make science serve human being, whatever could be his various activities. Actor of the foundation of food chemistry, reorganizer of military pharmacy, he has always been highly concerned with hygiene and public health. He then studied the quality of water, particularly in the case of river Seine, or the purity of air, especially in hospitals. The affair of Dunkerque exhumations or that of cesspools, or the utilisation of human excrements in agriculture were parts of the occurrences for which he had the opportunity to find a scientific approach allowing to solve the difficult questions that were asked to him, for the best benefit of public health. The exhaustive study he published in "Bulletin de pharmacie" for the conservation of meat shows that he did not ignore anything about freezing of food in order to preserve it. It is necessary not to forget the important role he played, as soon as he were informed of Jenner's discovery, for the diffusion of vaccination in France. It is simply astounding to observe how modern were the questions he solved and how intense was his spirit of dedication to the public good, when exerting his functions in "Comite de Salubrite de la Seine" or "Conseil de Sante des Armees", as well as outside these prestigious institutions. PMID- 24780836 TI - [Determinants of the evolution of hospital pharmacy in France and Quebec: Perception of hospital pharmacists]. AB - BACKGROUND: Hospital pharmacy practice has evolved differently between France and Quebec. While this development is part of broader systems, French and Quebec hospitals have undergone significant changes over the years to cope with challenges, among others, the economic and demographic realities. PURPOSE: The main objective is to evaluate and compare the perception of French and Quebec hospital pharmacists about the factors that have contributed to the evolution of pharmacy practice in their respective context. METHODS: This is a descriptive cross-sectional study. The study focuses on a sample of experienced hospital pharmacists in France and Quebec. We targeted a convenience sample of 50 respondents per country. An online questionnaire with 15 pharmaceutical activities to which are connected nine factors that may have influenced the implementation of each of these activities in each country was used. The mean score was calculated for each of the nine factors for each activity. The perception of French and Quebec hospital pharmacists was then compared. A P value less than 0.05 was considered statistically significant. RESULTS: Two hundred and sixty hospital pharmacists were directly contacted in France and 79 in Quebec. Seventy-eight French pharmacists and 77 Quebec pharmacists responded to the survey, that is a respective response rate of 30% and 97%, respectively. The hierarchy of factors that contributed to the evolution of pharmacy practice was similar between the two countries, legislative and regulatory factors as well as the concern for risk management and quality dominate; scientific human, economic factors and training have a relatively similar position. For cons, the news factor (6th in France against the 10th position in Quebec) and the academic factor (10th position in France against the 6th position in Quebec) obtained inverse scores between France and Quebec. CONCLUSION: There are few data on the determinants of the evolution of hospital pharmacy in France and Quebec. The hierarchy of factors that contributed to the evolution of pharmacy practice is similar between the two countries, although differences of rank were found for the news and academic factors. Further studies are needed to better understand the factors that influence the evolution of pharmacy practice in health care institutions. PMID- 24780838 TI - Rescue of defective MC4R cell-surface expression and signaling by a novel pharmacoperone Ipsen 17. AB - Melanocortin 4 receptor (MC4R) is a key factor in regulating energy homeostasis, and null mutations occurring in the gene encoding MC4R cause severe early-onset morbid obesity in humans. Many obesity-causing mutations affecting MC4R clinically identified so far lead to failure of mutant receptors to shuttle to the plasma membrane. In this study, we show that a novel human MC4R antagonist, Ipsen 17, acted as an pharmacological chaperone of human MCR4. As tested with 12 obesity-causing human MC4R variants including S58C, E61K, N62S, I69T, P78L, C84R, G98R, T162I, R165W, W174C, C271Y, and P299H, Ipsen 17 was found to be the most universal pharmacological chaperone of MC4R reported so far because it can completely rescue nearly all mutant receptors (except P299H) with the highest potency (an EC50 value of approximately 10(-8) M) and efficiency when compared with results for other tested pharmacological chaperones of MC4R including ML00253764, PBA, MTHP, PPPone, MPCI, DCPMP, and NBP described in the literature. Once restored to the plasma membrane, defective human MC4R variants responded to alpha-MSH stimulation with an EC50 value of approximately 10(-8) M and displayed dramatically enhanced signaling ability (except for G98R) in a mutant-specific efficacy and potency profile. Taken together, these results indicate that Ipsen 17 represents a candidate for the development of a targeted treatment of severe early-onset morbid obesity caused by a large subset of inherited mutations in the human MC4R gene. PMID- 24780837 TI - p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene. AB - STAR/StarD1, part of a protein complex, mediates the transport of cholesterol from the outer to inner mitochondrial membrane, which is the rate-limiting step for steroidogenesis, and where steroid hormone synthesis begins. Herein, we examined the role of oxidant-sensitive p38 MAPKs in the regulation of STAR gene transcription, using model steroidogenic cell lines. Our data indicate that oxidant activation of p38 MAPK exhibits a negative regulatory role in the induction of functional expression of STAR, as evidenced by enhanced induction of STAR (mRNA/protein) expression and increased steroidogenesis during pharmacological inhibition of p38 MAPK or in cells with increased transient overexpression of a dominant-negative (dn) form of p38 MAPKalpha or p38 MAPKbeta. Studies with rat Star-promoter demonstrated that overexpression of p38 MAPKalpha wt, -beta, or -gamma significantly reduced both basal and cAMP-sensitive promoter activity. In contrast, overexpression of p38 MAPKalpha-dn, -beta, or -gamma enhanced the Star promoter activity under basal conditions and in response to cAMP stimulation. Use of various constitutively active and dn constructs and designer knock-out cell lines demonstrated that MKK3 and MKK6, the upstream activators of p38 MAPKs, play a role in p38 MAPKalpha-mediated inhibition of Star promoter activity. In addition, our studies raised the possibility of CREB being a potential target of the p38 MAPK inhibitory effect on Star promoter activity. Collectively, these data provide novel mechanistic information about how oxidant sensitive p38 MAPKs, particularly p38 MAPKalpha, contribute to the negative regulation of Star gene expression and inhibit steroidogenesis. PMID- 24780839 TI - PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells. AB - Phorbol 12-myristate 13-acetate (PMA) induces cellular apoptosis in prostate cancer cells, the growth of which is governed by androgen/androgen receptor (AR) signaling, but the mechanism by which PMA exerts this effect remains unknown. Therefore, in this study, we investigated the mechanistic action of PMA in prostate cancer cells with regard to AR. We showed that PMA decreased E2F1 as well as AR expression in androgen-dependent prostate cancer LNCaP cells. Furthermore, PMA activated JNK and p53 signaling, resulting in the induction of cellular apoptosis. In LNCaP cells, androgen deprivation and a novel anti androgen enzalutamide (MDV3100) augmented cellular apoptosis induced by PMA. Moreover, castration-resistant prostate cancer (CRPC) C4-2 cells were more sensitive to PMA compared with LNCaP cells and were sensitized to PMA by enzalutamide. Finally, the expression of PKC, E2F1, and AR was diminished in PMA resistant cells, indicating that the gain of independence from PKC, E2F1, and AR functions leads to PMA resistance. In conclusion, PMA exerted its anti-cancer effects via the activation of pro-apoptotic JNK/p53 and inhibition of pro proliferative E2F1/AR in prostate cancer cells including CRPC cells. The therapeutic effects of PMA were augmented by androgen deletion and enzalutamide in androgen-dependent prostate cancer cells, as well as by enzalutamide in castration-resistant cells. Taken together, PMA derivatives may be promising therapeutic agents for treating prostate cancer patients including CRPC patients. PMID- 24780840 TI - Somatostatin system: molecular mechanisms regulating anterior pituitary hormones. AB - The somatostatin (SRIF) system, which includes the SRIF ligand and receptors, regulates anterior pituitary gland function, mainly inhibiting hormone secretion and to some extent pituitary tumor cell growth. SRIF-14 via its cognate G-protein coupled receptors (subtypes 1-5) activates multiple cellular signaling pathways including adenylate cyclase/cAMP, MAPK, ion channel-dependent pathways, and others. In addition, recent data have suggested SRIF-independent constitutive SRIF receptor activity responsible for GH and ACTH inhibition in vitro. This review summarizes current knowledge on ligand-dependent and independent SRIF receptor molecular and functional effects on hormone-secreting cells in the anterior pituitary gland. PMID- 24780841 TI - The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells. AB - Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues. Although COUP-TFII-deficient mice had Leydig cell dysfunction and impaired fertility, it remained unknown whether Insl3 expression was directly regulated by COUP-TFII. In this study, we observed a significant decrease in Insl3 mRNA levels in MA-10 Leydig cells depleted of COUP TFII. Furthermore, a -1087 bp mouse Insl3 promoter was activated fourfold by COUP TFII in MA-10 Leydig cells. Using 5' progressive deletions, the COUP-TFII responsive element was located between -186 and -79 bp, a region containing previously uncharacterised direct repeat 0-like (DR0-like) and DR3 elements. The recruitment and direct binding of COUP-TFII to the DR0-like element were confirmed by chromatin immunoprecipitation and DNA precipitation assay respectively. Mutation of the DR0-like element, which prevented COUP-TFII binding, significantly decreased COUP-TFII-mediated activation of the -1087 bp Insl3 reporter in CV-1 fibroblast cells but not in MA-10 Leydig cells. Finally, we found that COUP-TFII cooperates with the nuclear receptor steroidogenic factor 1 (SF1) to further enhance Insl3 promoter activity. Our results identify Insl3 as a target for COUP-TFII in Leydig cells and revealed that COUP-TFII acts through protein-protein interactions with other DNA-bound transcription factors, including SF1, to activate Insl3 transcription in these cells. PMID- 24780843 TI - Association of occupational pesticide exposure with accelerated longitudinal decline in lung function. AB - Cross-sectional studies have shown that occupational exposure to vapors, gases, dusts, and fumes (VGDF) and pesticides is associated with a lower level of lung function. These associations seem to be stronger in ever smokers. In the current study, we aimed to assess whether occupational exposure to VGDF and pesticides is associated with longitudinal decline in lung function. We used 12,772 observations from 2,527 participants in the Vlagtwedde-Vlaardingen Study, a general-population-based cohort study that followed subjects for 25 years, from 1965 to the last survey in 1989/1990. Job-specific exposure was estimated with the ALOHA+ job exposure matrix. Associations between exposures and annual changes in forced expiratory volume in 1 second (FEV1) and FEV1 as a percentage of inspiratory vital capacity (FEV1%VC) were assessed with linear mixed-effect models including sex, age, and level of lung function at the first measurement and pack-years of smoking at the last measurement. We tested for interaction between smoking and occupational exposure and assessed associations separately for never smokers and ever smokers. Exposure to VGDF was not associated with accelerated lung function decline after adjustment for co-exposure to pesticides. Exposure to pesticides, both in the last-held job and as a cumulative measure, was associated with accelerated decline in FEV1 and FEV1%VC, especially among ever smokers, where we found an excess change in FEV1 of -6.9 mL/year (95% confidence interval: -10.2, -3.7) associated with high pesticide exposure. PMID- 24780844 TI - Mating behavior and its morphological correlates in two color morphs of Girardinus metallicus (Pisces: Poeciliidae), a species previously thought not to exhibit courtship display. AB - Girardinus metallicus is a Cuban poeciliid fish whose social behavior has been little studied. The only account involves a colorless morph that is sexually monochromatic and does not exhibit courtship display. We describe the behavior of two other morphs (black and yellow) that exhibit sexual dichromatism. We observed courtship displays in black but not yellow males. Contrary to the pattern in most poeciliids, black males exhibit long gonopodia and courtship; typically, longer gonopodia evolve in species without courtship, because they facilitate coercive mating but circumvent female choice. We focused on the black morph to address whether morphological traits are favored by sexual selection. Larger males with longer gonopodia courted and attempted copulations more often. Black area was not associated with intersexual interactions, but was positively associated with aggressiveness. Dominant males attempted more copulations, consistent with the idea that black coloration may be a badge of status. Black males may possess long gonopodia because the gonopodium itself is a target of female choice. However, there was no difference in gonopodium length between black and yellow males, although the latter do not court. We discuss processes that may maintain the polymorphism and prospects for future studies in this intriguing system. PMID- 24780842 TI - Association between informal caregiving and cellular aging in the survey of the health of wisconsin: the role of caregiving characteristics, stress, and strain. AB - The pathophysiological consequences of caregiving have not been fully elucidated. We evaluated how caregiving, stress, and caregiver strain were associated with shorter relative telomere length (RTL), a marker of cellular aging. Caregivers (n = 240) and some noncaregivers (n = 98) in the 2008-2010 Survey of the Health of Wisconsin, comprising a representative sample of Wisconsin adults aged 21-74 years, reported their sociodemographic, health, and psychological characteristics. RTL was assayed from blood or saliva samples. Median T and S values were used to determine the telomere-to-single copy gene ratio (T/S) for each sample, and log(T/S) was used as the dependent variable in analyses. Multivariable generalized additive models showed that RTL did not differ between caregivers and noncaregivers (difference in log(T/S) = -0.03; P > 0.05), but moderate-to-high levels of stress versus low stress were associated with longer RTL (difference = 0.15; P = 0.04). Among caregivers, more hours per week of care, caring for a young person, and greater strain were associated with shorter RTL (P < 0.05). Caregivers with discordant levels of stress and strain (i.e., low perceived stress/high strain) compared with low stress/low strain had the shortest RTL (difference = -0.24; P = 0.02, Pinteraction = 0.13), corresponding to approximately 10-15 additional years of aging. Caregivers with these characteristics may be at increased risk for accelerated aging. Future work is necessary to better elucidate these relationships and develop interventions to improve the long-term health and well-being of caregivers. PMID- 24780845 TI - On the controversy over non-human culture: the reasons for disagreement and possible directions toward consensus. AB - In recent decades, animal behaviorists have been using the term culture in relation to non-human animals, starting a controversy with social scientists that is still far from cooling down. I investigated the meanings of the term culture as used by social and cultural anthropologists, and also its recent use by ethologists, in order to better understand this controversy and identify possible paths that might lead to a consensus. I argue that disagreements in the level of theories involve definitions of culture and theories of behavioral development, while disagreements in the level of worldviews include the acceptance or rejection of the idea of a radical distinction between humans and other animals. Reaching a synthetic approach to (human and non-human) animal behavior depends on constructing a consensus in both levels. It is also necessary to discuss how to include symbolic communication in a comparative perspective. I conclude that this might lead to the abandonment or reconstruction of the related dichotomies of nature-culture, innate-acquired and gene-environment. This article is part of a Special Issue entitled: Neotropical Behaviour. PMID- 24780846 TI - Editorial overview: environmental biotechnology. PMID- 24780848 TI - Metabolic actions of natriuretic peptides and therapeutic potential in the metabolic syndrome. AB - Natriuretic peptides (NPs) are a group of peptide-hormones mainly secreted from the heart, signaling via c-GMP coupled receptors. NP are well known for their renal and cardiovascular actions, reducing arterial blood pressure as well as sodium reabsorption. Novel physiological functions have been discovered in recent years, including activation of lipolysis, lipid oxidation, and mitochondrial respiration. Together, these responses promote white adipose tissue browning, increase muscular oxidative capacity, particularly during physical exercise, and protect against diet-induced obesity and insulin resistance. Exaggerated NP release is a common finding in congestive heart failure. In contrast, NP deficiency is observed in obesity and in type-2 diabetes, pointing to an involvement of NP in the pathophysiology of metabolic disease. Based upon these findings, the NP system holds the potential to be amenable to therapeutical intervention against pandemic diseases such as obesity, insulin resistance, and arterial hypertension. Various therapeutic approaches are currently under development. This paper reviews the current knowledge on the metabolic effects of the NP system and discusses potential therapeutic applications. PMID- 24780849 TI - Relationship between the type and amount of physical activity and low back pain in Koreans aged 50 years and older. AB - OBJECTIVES: To examine the association between the type and amount of physical activity (PA) and low back pain (LBP) in people aged >=50 years. DESIGN: Cross sectional study. SETTING: A nationwide survey. PARTICIPANTS: Data were obtained from the Fifth Korea National Health and Nutrition Examination Survey, which was conducted in 2010 and 2011. Overall, 1796 men and 2198 women aged >=50 years were included. METHODS: PA was categorized as vigorous, moderate, walking, strength exercises, or flexibility exercises. The total amount of PA was presented as quartiles of the total metabolic equivalent (MET)-minutes/week based on the PA questionnaire. Multivariate logistic regression analysis was performed to examine associations between LBP and the type and amount of PA. MAIN OUTCOME MEASUREMENTS: Odds ratio for LBP according to the type of PA and the quartiles of the total MET-minutes/week. RESULTS: After adjusting for age and body mass index, vigorous and moderate PA were associated with an increased risk of LBP in both men and women, whereas strength exercises were associated with a reduced risk of LBP. These associations were maintained after adjusting for all potential confounders. Subgroup analysis according to age revealed that these trends were most significantly demonstrated in women aged >=65 years. The PA quartiles for total MET-minutes/week for men showed a U-shaped association with LBP, whereas only the fourth PA quartile for women showed an increased risk of LBP compared with the second quartile. CONCLUSIONS: These results suggest that both the type and amount of PA affect the development of LBP in people aged >=50 years and thus activity modification might be helpful for prevention and management of LBP. PMID- 24780850 TI - Intradiskal methylene blue treatment for diskogenic low back pain. AB - BACKGROUND: Low back pain is a leading cause of pain and disability. The intervertebral disk has been identified as the most common source of chronic low back pain. Although prior treatments directed at intervertebral disks have been disappointing, recent studies show promising improvement of pain and function after a single intradiskal injection of methylene blue. OBJECTIVE: To assess changes in pain and function in patients with diskogenic low back pain, diagnosed by diskography, after an intradiskal injection of methylene blue. STUDY DESIGN: Prospective trial. METHODS: Patients diagnosed with diskogenic pain by diskography underwent a single treatment of intradiskal injection of methylene blue, determined by prior provocation diskography. MAIN OUTCOME MEASURES: Pain and function measurements were completed at baseline and 1, 2, and 6 months after treatment. Treatment was considered a categorical success based on a 30% improvement in pain according to a visual analog scale (VAS) and function on the Oswestry Disability Index (ODI). Treatment was considered a categorical failure if less than 30% improvement in pain and function was achieved or if the patient pursued other invasive treatment options during the trial period. RESULTS: Sixteen patients received the intradiskal methylene blue injection. Eleven patients received a single-level injection, 4 patients received a 2-level injection, and one patient received injections at 3 levels. For the VAS, at 1, 2, and 6 months after the injection, the categorical success rates were 25%, 21%, and 25%, respectively. For the ODI, at 1, 2 and 6 months after the injection, the categorical success rates were 25%, 21%, and 33%, respectively. The overall categorical success rates at 1, 2, and 6 months after the injection were 19%, 21%, and 25%, respectively. CONCLUSION: This small trial did not demonstrate overall clinical success of intradiskal methylene blue injection for patients diagnosed with diskogenic pain by diskography. PMID- 24780851 TI - Noninvasive treatments for pediatric complex regional pain syndrome: a focused review. AB - This is a review of current literature of noninvasive treatments for pediatric complex regional pain syndrome (CRPS). There are a variety of noninvasive approaches to the treatment of pain, but few pediatric-focused studies have been published in regard to CRPS. In comparison with adult CRPS, there is a greater need for behavioral approaches in children to enable coping with difficult symptoms. Current gaps in knowledge include mechanisms triggering CRPS, pediatric focused diagnostic criteria, validated tests that are diagnostically specific, definitive treatment protocols, age-based medication recommendations, and validation of specific noninvasive treatments in pediatric populations. Intensive multidisciplinary treatment is supported by high recovery rates and a family centered approach that allows continuation of goals into the community environment. PMID- 24780852 TI - Falls, fear of falling, self-reported impairments, and walking limitations in persons with late effects of polio. AB - OBJECTIVE: To investigate fall frequency during the past year, circumstances relating to falls, fear of falling, self-reported impairments, and walking limitations in persons with mild to moderate late effects of polio. DESIGN: A cross-sectional postal survey. PARTICIPANTS: A total of 325 persons with clinically and electrophysiologically verified late effects of polio (175 women and 150 men; mean age 70 years). METHOD: Data regarding demographics, fall frequency during the past year, and circumstances relating to falls were obtained through a questionnaire. Fear of falling when performing daily activities was assessed with the Falls Efficacy Scale-International (FES-I), impairments were assessed with the Self-Reported Impairments in Persons with Late Effects of Polio (SIPP), and walking limitations were assessed with the Walking Impact Scale (Walk 12). RESULTS: Of the 325 respondents, 62% reported at least one fall during the past year. Most of the falls were reported in the afternoon (68%) and when walking outdoors (53%). Persons who fell reported significantly higher (P < .001) mean scores than did the persons who did not fall in the FES-I (35.8 points versus 29.2 points), SIPP (28.2 points versus 25.0 points), and Walk-12 (63% versus 43%). CONCLUSIONS: Falls are common in people with mild to moderate late effects of polio, especially later in the day and while walking outdoors. Fear of falling, self-reported impairments, and walking limitations were greater among the persons who fell than in the persons who did not fall. To reduce falls and fear of falling in persons with late effects of polio and to increase their activity level and participation in various life situations, evidence-based interdisciplinary fall management programs are needed. PMID- 24780853 TI - Hyperglycemia promotes vasculogenesis in choroidal neovascularization in diabetic mice by stimulating VEGF and SDF-1 expression in retinal pigment epithelial cells. AB - To investigate the influence of hyperglycemia on the severity of choroidal neovascularization (CNV) in diabetic mice, especially the involvement of bone marrow-derived cells (BMCs) and underlying molecular mechanisms. The mice were randomly divided into control group, diabetes group and diabetes treated with insulin group, which were laser treated to induce CNV. The CNV severity was evaluated by fundus fluorescein angiography, HE staining and choroidal flatmount. The BMCs recruitment and differentiation in CNV were examined in GFP chimeric mice by choroidal flatmount and immunofluorescence. The bone marrow-derived mesenchymal stem cells (BMSCs) recruitment and migration were tested in vivo and in vitro. VEGF and SDF-1 production in vivo and in vitro were tested by realtime PCR and ELISA. The CNV severity and expression of VEGF and SDF-1 were enhanced in DM mice compared with control mice and that insulin treatment decreased CNV severity in DM mice. The DM mice demonstrated more BMCs and bone marrow-derived mesenchymal stem cells (BMSCs) recruited and incorporated into CNV, increased ratio of BMCs expressing endothelial cell marker or macrophage marker, and up regulated expression of VEGF and SDF-1 in CNV. Human BMSCs migration and expression of VEGF and SDF-1 in retinal pigment epithelial (RPE) cells increased when cultured under high glucose. This study suggested that hyperglycemia enhanced the expression of VEGF and SDF-1 in RPE cells, and promoted recruitment and incorporation of BMCs and affected differentiation of BMCs in CNV, which led to more severe CNV in diabetic mice. PMID- 24780854 TI - Population genetics of 30 insertion-deletion polymorphisms in two Chinese populations using Qiagen Investigator(r) DIPplex kit. AB - Insertion-deletion polymorphisms (INDELs) are short length diallelic polymorphisms caused by the insertion or deletion of several bases. INDEL markers can serve as useful supplementary or stand-alone assays for human identification. The Qiagen Investigator((r)) DIPplex kit multiplexes 30 autosomal INDELs plus amelogenin for forensic use. The objective of this study was to estimate genetic diversity of 30 INDEL markers in the Han (the largest ethnic group of China, n=565) and She population (almost the smallest ethnic group of China, n=119), and to evaluate their usefulness in forensic genetics. In the Han and She, the mean observed heterozygosity values were 0.4133 and 0.3896, and the combined matching probability values were 1.80*10(-11) and 3.17*10(-11), respectively. Furthermore, the allele frequencies for each locus were compared with those in other reported Chinese subpopulations, and the forensic efficacy was compared between this kit and in-house developed INDEL assay. This study demonstrates that the Investigator((r)) DIPplex kit can be used as a supplementary tool for human identity testing in China. PMID- 24780855 TI - Enhanced sorption of mercury from compact fluorescent bulbs and contaminated water streams using functionalized multiwalled carbon nanotubes. AB - Three different functionalized multiwalled carbon nanotubes were prepared, namely, oxidized CNTs (CNT-OX), iodide incorporated MWCNT (CNT-I) and sulfur incorporated MWCNT (CNT-S). The as prepared adsorbents were structurally characterized by various spectral techniques like scanning electron microscopy (SEM), energy dispersive X-ray (EDAX), Brunauer, Emmett, and Teller (BET) surface area analyzer, Fourier transform infra red (FTIR) and Raman spectroscopy. Loading of iodide and sulfur was evident from the EDAX graphs. The adsorption properties of Hg(2+) as a function of pH, contact time and initial metal concentration were characterized by Cold vapor AAS. The adsorption kinetics fitted the Pseudo second order kinetics and equilibrium was reached within 90 min. The experimental data were modeled with Langmuir, Freundlich, Dubinin-Redushkevich and Temkin isotherms and various isotherm parameters were evaluated. It was found that the mercury adsorption capacity for the prepared adsorbents were in the order of CNT-S>CNT I>CNT-OX>CNT. Studies have been conducted to demonstrate the applicability of the sorbent toward the removal of Hg(0) from broken compact fluorescent light (CFL) bulbs and Hg(II) from contaminated water streams. PMID- 24780856 TI - Amino siloxane oligomer-linked graphene oxide as an efficient adsorbent for removal of Pb(II) from wastewater. AB - A high performance sorbent, oligomer-linked graphene oxide (GO) composite, was prepared through simple cross-linking reactions between GO sheets and poly3 aminopropyltriethoxysilane (PAS) oligomers as crosslinking agents. The three dimensional PAS oligomers prevented GO sheets from aggregation, provided foreign molecules with easier access, and introduced a large amount of amino functional groups. The morphology, structure and property of the PAS-GO composite were determined by scanning electron microscope (SEM), transmission electron microscope (TEM), Fourie transform infrared (FTIR), X-ray diffractometer (XRD), thermogravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS). The adsorption performance of PAS-GO was investigated in removing Pb(II) ions from water. Compared to 3-aminopropyltriethoxysilane functionalized GO (AS-GO) which was prepared by the direct reaction between 3-aminopropyltriethoxysilane and GO, PAS-GO exhibited much higher adsorptivity toward Pb(II) with the maximum adsorption capacity of 312.5mg/g at 303 K and furthermore the maximum adsorption capacity increased with increasing temperature. The adsorption could be conducted in a wide pH range of 4.0-7.0. Importantly, PAS-GO had a priority tendency to adsorb Pb, Cu and Fe from a mixed solution of metal ions, especially from a practical industrial effluent. PMID- 24780857 TI - Haloactamides versus halomethanes formation and toxicity in chloraminated drinking water. AB - In this study we quantified the concentrations of nine haloacetamides (HAcAms) and nine halomethanes (HMs) in the final waters of five drinking water treatment plants (DWTPs) that use either chlorination or chloramination for disinfection and evaluated the toxicity of dichloroacetamide (DCAcAm) and dichloromethane (DCM) in normal rat kidney (NRK) cells using four in vitro toxicity assays. All the DWTPs final waters contained primarily di-HAcAms, followed by tri- and mono HAcAms, and DCAcAm was the most abundant species of the 9 HAcAms, regardless of chlorination or chloramination being applied. In the final waters of DWTPs using chlorination, tri-HMs (trihalomethanes, THMs) accounted for the majority of HMs, whereas chloramination resulted in more di-HMs (especially DCM) than THMs. All four in vitro toxicity assays indicated that the NRK cell chronic cytotoxicity and acute genotoxicity of DCAcAm were substantially higher than that of DCM. In view of observed occurrence concentrations and quantified toxicity levels, the findings of this study suggest that DCAcAm represents a higher toxicity risk than DCM in chloraminated drinking waters. PMID- 24780858 TI - Oncogenic programmes and Notch activity: an 'organized crime'? AB - The inappropriate Notch signalling can influence virtually all aspect of cancer, including tumour-cell growth, survival, apoptosis, angiogenesis, invasion and metastasis, although it does not do this alone. Hence, elucidating the partners of Notch that are active in cancer is now the focus of much intense research activity. The genetic toolkits available, coupled to the small size and short life of the fruit fly Drosophila melanogaster, makes this an inexpensive and effective animal model, suited to large-scale cancer gene discovery studies. The fly eye is not only a non-vital organ but its stereotyped size and disposition also means it is easy to screen for mutations that cause tumours and metastases and provides ample opportunities to test cancer theories and to unravel unanticipated nexus between Notch and other cancer genes, or to discover unforeseen Notch's partners in cancer. These studies suggest that Notch's oncogenic capacity is brought about not simply by increasing signal strength but through partnerships, whereby oncogenes gain more by cooperating than acting individually, as in a ring 'organized crime'. PMID- 24780859 TI - Description of two new thermophilic species of the genus Rubrobacter, Rubrobacter calidifluminis sp. nov. and Rubrobacter naiadicus sp. nov., and emended description of the genus Rubrobacter and the species Rubrobacter bracarensis. AB - Four isolates, designated, RG-1(T), RG-3(T), RG-6 and RG-8 with optimum growth temperatures around 60 degrees C were recovered from a hot stream near Ribeira Grande on the Island of Sao Miguel in the Azores. These strains were strictly aerobic, catalase and oxidase positive. The organisms could be divided into two groups; one comprising strains RG-1(T) and RG-6, the other formed by strains RG 3(T) and RG-8, with distinctive phenotypic and chemotaxonomic characteristics. Major fatty acids varied between the groups, but all contained iso-branched components such as iso-C16:0 10-methyl and iso-C17:0 10-methyl. Analysis of the 16S rRNA gene shows the strains to cluster with species of the genus Rubrobacter, specifically with Rubrobacter xylanophilus to which they have pairwise sequence similarity in the range of 98.4-98.6%. The DNA-DNA hybridization result show that strains RG-1(T) and RG-3(T) share 72% reassociation. Strains RG-1(T) and RG-3(T) displayed extreme tolerance to desiccation when compared to other species of the genus. Based on genotypic, physiological and biochemical characteristics we describe two new species: Rubrobacter calidifluminis sp. nov., represented by strain RG-1(T) (=CECT 8308(T) =JCM 19154(T)) and Rubrobacter naiadicus sp. nov. represented by strain RG-3(T) (=CECT 8310(T)=JCM 19155(T)). The description of the species Rubrobacter bracarensis[16] is emended to correct the fatty acid composition of these organisms. The discovery of new fatty acids in these species requires emendation of the description of the genus Rubrobacter. PMID- 24780860 TI - Proteomics meets blue biotechnology: a wealth of novelties and opportunities. AB - Blue biotechnology, in which aquatic environments provide the inspiration for various products such as food additives, aquaculture, biosensors, green chemistry, bioenergy, and pharmaceuticals, holds enormous promise. Large-scale efforts to sequence aquatic genomes and metagenomes, as well as campaigns to isolate new organisms and culture-based screenings, are helping to push the boundaries of known organisms. Mass spectrometry-based proteomics can complement 16S gene sequencing in the effort to discover new organisms of potential relevance to blue biotechnology by facilitating the rapid screening of microbial isolates and by providing in depth profiles of the proteomes and metaproteomes of marine organisms, both model cultivable isolates and, more recently, exotic non cultivable species and communities. Proteomics has already contributed to blue biotechnology by identifying aquatic proteins with potential applications to food fermentation, the textile industry, and biomedical drug development. In this review, we discuss historical developments in blue biotechnology, the current limitations to the known marine biosphere, and the ways in which mass spectrometry can expand that knowledge. We further speculate about directions that research in blue biotechnology will take given current and near-future technological advancements in mass spectrometry. PMID- 24780861 TI - Docosahexaenoic acid and human brain development: evidence that a dietary supply is needed for optimal development. AB - Humans evolved a uniquely large brain among terrestrial mammals. Brain and nervous tissue is rich in the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). Docosahexaenoic acid is required for lower and high order functions in humans because of understood and emerging molecular mechanisms. Among brain components that depend on dietary components, DHA is limiting because its synthesis from terrestrial plant food precursors is low but its utilization when consumed in diet is very efficient. Negligible DHA is found in terrestrial plants, but in contrast, DHA is plentiful at the shoreline where it is made by single-celled organisms and plants, and in the seas supports development of very large marine mammal brains. Modern human brains accumulate DHA up to age 18, most aggressively from about half-way through gestation to about two years of age. Studies in modern humans and non-human primates show that modern infants consuming infant formulas that include only DHA precursors have lower DHA levels than for those with a source of preformed DHA. Functional measures show that infants consuming preformed DHA have improved visual and cognitive function. Dietary preformed DHA in the breast milk of modern mothers supports many-fold greater breast milk DHA than is found in the breast milk of vegans, a phenomenon linked to consumption of shore-based foods. Most current evidence suggests that the DHA-rich human brain required an ample and sustained source of dietary DHA to reach its full potential. PMID- 24780862 TI - Involvement of S. cerevisiae Rpb4 in subset of pathways related to transcription elongation. AB - Yeast Rpb4, a subunit of RNA pol II is not essential for viability but is involved in multiple cellular phenotypes such as temperature sensitivity, enhanced pseudohyphal morphology, and decreased sporulation. Both in vivo and in vitro studies strongly support involvement of Rpb4 in transcription initiation, while its role in transcription elongation is not entirely consistent. Here we show that Rpb4 is not required for recruitment of RNA pol II on the coding region of YLR454w, a representative long gene. Yet we find strong genetic interaction of rpb4? with mutants in many transcription elongation factors such as Paf1, Spt4, Dst1, Elp3 and Rpb9. We demonstrate that, Rpb4 interacts functionally with Paf1 to affect the transcription elongation of the FKS1 gene. Our results suggest that while Rpb4 is not required for general transcription elongation, it could support transcription elongation for specific of class of genes by interaction with other elongation factors. PMID- 24780863 TI - Differential expression profiles of poplar MAP kinase kinases in response to abiotic stresses and plant hormones, and overexpression of PtMKK4 improves the drought tolerance of poplar. AB - Mitogen-activated protein kinase (MAPK) cascades are universal signal transduction modules that play essential roles in plant growth, development and stress response. MAPK kinases (MAPKKs), which link MAPKs and MAPKK kinases (MAPKKKs), are integral in mediating various stress responses in plants. However, to date few data about the roles of poplar MAPKKs in stress signal transduction are available. In this study, we performed a systemic analysis of poplar MAPKK gene family expression profiles in response to several abiotic stresses and stress-associated hormones. Furthermore, Populus trichocarpa MAPKK4 (PtMKK4) was chosen for functional characterization. Transgenic analysis showed that overexpression of the PtMKK4 gene remarkably enhanced drought stress tolerance in the transgenic poplar plants. The PtMKK4-overexpressing plants also exhibited much lower levels of H2O2 and higher antioxidant enzyme activity after exposure to drought stress compared to the wide type lines. Besides, some drought marker genes including PtP5CS, PtSUS3, PtLTP3 and PtDREB8 exhibited higher expression levels in the transgenic lines than in the wide type under drought conditions. This study provided valuable information for understanding the putative functions of poplar MAPKKs involved in important signaling pathways under different stress conditions. PMID- 24780864 TI - The phylogeny of Ephemeroptera in Pterygota revealed by the mitochondrial genome of Siphluriscus chinensis (Hexapoda: Insecta). AB - The mayfly species Siphluriscus chinensis (Siphluriscidae) has valuable structures useful for phylogeny reconstruction, given its putative basal position within the Ephemeroptera. Here its nearly complete mitochondrial genome is sequenced. We built phylogenetic trees through multiple analytical strategies with some other insect mitogenomes. Structurally, the obtained mitochondrial genome of S. chinensis is 16,616 bp in length,(1) containing 37 genes and an extra trnK-like (trnK2 (AAA)) gene. The 12 PCGs start with typical ATN codons, except the nad1 gene which starts with an unnormalized TTG. Like other known mayfly mitogenomes, the strand bias has negative AT-skew and negative GC-skew. Phylogenetically, our topologies suggest that Odonata is the basally diverged clade in Pterygota; Ephemeroptera is the sister group of the Neoptera; and S. chinensis is indeed the most basal mayfly branch. PMID- 24780865 TI - The murine serotonin syndrome - evaluation of responses to 5-HT-enhancing drugs in NMRI mice. AB - In humans, the ingestion of the combination of two or more serotonin (5-HT) enhancing drugs but also of a single drug in overdose can induce serious adverse effects, which are characteristics of the serotonin syndrome (SS). In mice, acute administration of direct and indirect 5-HT agonists also leads to behavioral and autonomic responses, but in literature different responses are thought to be essential. In order to detect common behavioral SS responses induced by 5-HT enhancing drugs with different mechanisms of action, we investigated the effects of the 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), and the monoaminooxidase (MAO) inhibitor tranylcypromine (TCP) in male NMRI mice. The drugs were administered alone or in combination to investigate additive effects or drug potentiation. Moreover, we compared the 5-HT responses to the effects induced by the dopamine, noradrenaline, and cholinergic agonists, apomorphine (APO), atomoxetine (ATO), and oxotremorine (OXO). Our results show that the studied 5-HT-enhancing drugs induced a different number of concomitant responses. The following five responses consistently and dose-dependently occurred in NMRI mice: flat body posture, hindlimb abduction, piloerection, tremor, and decreased rearings. Like in humans, the combination of 5-HT-enhancing drugs leads to a potentiation of drug effects. With the exception of flat body posture the responses are not specific for serotonergic hyperactivity. The findings demonstrate that the SS in NMRI mice is a suitable animal model for preclinical research, if it is taken into account that the spectrum of typical responses to 5-HT enhancing drugs may differ depending on drug and mouse strain and that some responses might be evoked by activation of other transmission systems, too. PMID- 24780866 TI - Conditioned saccharin avoidance induced by infusion of amphetamine in the nucleus accumbens shell and morphine in the ventral tegmental area: behavioral and biochemical study. AB - Drugs of abuse possess the seemingly paradoxical property of conditioning rats to avoid from drinking a saccharin solution that had been predictively paired with their systemic administration (conditioned saccharin avoidance, CSA). CSA is dependent upon an intact dopamine (DA) transmission but the locus, central or peripheral, and eventually the brain area from which this effect originates and its relationship with the rewarding properties of the drug is debated. In order to clarify this issue we tested the ability of amphetamine and morphine to induce CSA after infusion at the same dose-range and in the same areas from which these drugs induce conditioned place preference (CPP). Drugs were infused intracerebrally immediately after saccharin drinking in two acquisition trials and CSA was tested on a two bottle saccharin/water choice. Amphetamine (10 and 20 MUg/0.5 MUl) induced CSA after infusion in the NAc shell but was ineffective in the NAc core. Morphine (0.5 and 1 MUg/0.5 MUl) induced CSA from the VTA at both doses tested. Amphetamine (20 MUg/0.5 MUl) and morphine (1 MUg/0.5 MUl) failed to induce CSA after infusion 1.2mm dorsal the NAc shell and the VTA respectively. Finally, morphine (1 MUg/0.5 MUl), infused in the VTA, elicited a selective increase in dialysate DA in the NAc shell. These results indicate that drugs of abuse induce CSA from the same intracerebral sites and at the same doses at which they induce CPP. These observations are consistent with the existence of a strong relationship between CSA and drug reward related to their ability to stimulate DA transmission in the NAc shell. PMID- 24780867 TI - Perceived location specificity in perceptual separation-induced but not fear conditioning-induced enhancement of prepulse inhibition in rats. AB - Prepulse inhibition (PPI) is the suppression of the startle reflex when the startling stimulus is shortly preceded by a non-startling stimulus (the prepulse). Previous studies have shown that both fear conditioning of a prepulse and precedence-effect-induced perceptual separation between the conditioned prepulse and a noise masker facilitate selective attention to the prepulse and consequently enhance PPI with a remarkable prepulse-feature specificity. This study investigated whether the two types of attentional enhancements of PPI in rats also exhibit a prepulse-location specificity. The results showed that when a prepulse was delivered by each of the two spatially separated loudspeakers, fear conditioning of the prepulse at a particularly perceived location (left or right to the tested rat) enhanced PPI without exhibiting any perceived-location specificity. However, when a noise masker was presented, the precedence-effect induced perceptual separation between the conditioned prepulse and the noise masker further enhanced PPI when the prepulse was perceived as coming from the location that was conditioned but not the location without being conditioned. Moreover, both conditioning-induced and perceptual separation-induced PPI enhancements were eliminated by extinction learning, whose effect could be blocked by systemic injection of the selective antagonist of metabotropic glutamate receptor subtype 5 (mGluR5), 2-methyl-6-(phenylethynyl)-pyridine (MPEP). Thus, fear conditioning of a prepulse perceived at a particular location not only facilitates selective attention to the conditioned prepulse but also induces a learning-based spatial gating effect on the spatial unmasking of the conditioned prepulse, leading to that the perceptual separation-induced PPI enhancement becomes perceived-location specific. PMID- 24780868 TI - Autism-related behavioral phenotypes in an inbred rat substrain. AB - Behavioral and genetic differences among Wistar-Kyoto (WKY) rats from different vendors and different breeders have long been observed, but generally overlooked. In our prior work, we found that two closely related WKY substrains, the WKY/NCrl and WKY/NHsd rats, differ in a small percentage of their genome which appeared to be highly enriched for autism risk genes. Although both substrains have been used widely in studies of hypertension, attention deficit/hyperactivity disorder (ADHD) and depression, they have not been tested for any autism-related behavioral phenotypes. Furthermore, these two substrains have often been used interchangeably in previous studies; no study has systematically examined the phenotypic differences that could be attributed by their small yet potentially meaningful genetic differences. In this paper we compared these two substrains on a battery of neurobehavioral tests. Although two substrains were similar in locomotor activity, WKY/NCrl rats were significantly different from WKY/NHsd rats in the elevated plus maze test, as well as measures of social interaction and ultrasonic vocalization. These strains were also compared with Sprague Dawley (SD) rats, a common outbred strain, and spontaneous hypertensive rats (SHR), an inbred rat model for ADHD and hypertension, which were derived from the same ancestor strain as the WKY strains. Our behavioral findings suggest that WKY/NCrl rats may be useful as a model autism spectrum disorders due to their lower social interest, lower ultrasonic vocalization and higher anxiety levels when WKY/NHsd rats are used as the control strain. Given the small genetic difference between the two inbred substrains, future studies to identify the exact gene and sequence variants that differ between the two may be useful for identifying the genetic mechanisms underlying these behaviors. PMID- 24780869 TI - Ultrasound stethoscope is not a substitute of physical examination: reply. PMID- 24780870 TI - Transapical transcatheter aortic valve replacement with simultaneous paravalvular leakage closure in a patient with severely degenerated aortic valve bioprosthesis. PMID- 24780871 TI - Progression of coronary atherosclerosis in stable patients with ultrasonic features of high-risk plaques. AB - AIM: Large plaque burden, expansive vascular remodelling, and spotty calcification have been considered as important morphologies of high-risk plaques causing acute coronary events. Although non-occlusive rupture of high-risk plaques has been proposed as a mechanism for disease progression in post-mortem studies, the natural history of coronary atherosclerosis in stable patients with high-risk plaques has not been fully elucidated. We sought to evaluate coronary atheroma progression in stable patients with greyscale intravascular ultrasound (IVUS)-derived high-risk plaques. METHODS AND RESULTS: We analysed 4477 patients with stable coronary artery disease underwent serial greyscale IVUS imaging in eight clinical trials. We compared volumetric intravascular ultrasound (IVUS) data in the non-culprit segments between patients with and without high-risk plaques, defined as the combination of per cent atheroma volume (PAV) >63%, positive remodelling and spotty calcification. High-risk plaques were observed in 201 (4.5%) of patients. Patients with high-risk plaques exhibited a greater PAV (47.1 +/- 8.4 vs. 37.7 +/- 8.7%, P < 0.001) at baseline. On serial evaluation, however, regression of PAV (-0.26 +/- 0.39 vs. 0.24 +/- 0.32%, P = 0.03) was observed. In patients with high-risk plaques, the non-statin use was associated with the accelerated atheroma progression, whereas atheroma regression was observed under statin therapy (change in PAV: 1.87 +/- 0.68% vs. -0.83 +/- 0.53%, P = 0.01). CONCLUSIONS: Patients with high-risk plaques exhibit extensive atheroma burden, which is modifiable with anti-atherosclerotic therapies. These findings underscore risk modification using a statin in patients with high-risk plaques. PMID- 24780872 TI - Ultrasound stethoscope is not a substitute of physical examination. PMID- 24780873 TI - Real-time three-dimensional transoesophageal echocardiography for diagnosing the extent of dehiscence of Starr-Edward valve prosthesis in the mitral position. PMID- 24780875 TI - Epidemiology and mortality of hip fracture among patients on dialysis: Taiwan National Cohort Study. AB - Chronic kidney disease increases the risk for hip fractures. Hip fractures are associated with increased mortality, decreased quality of life, and higher economic burden. To determine whether dialysis modality is associated with a higher incidence of hip fractures in patients with end-stage renal disease (ESRD), we used the Taiwan National Health Insurance Research Database to examine the records of 51,473 patients who began dialysis between 1999 and 2005. The patients were followed until death, transplantation, dialysis cessation, or 31 December 2008. The follow-up period was (mean+/-SD) 4.14+/-2.48 years. The cumulative incidence rate of hip fracture was calculated using Kaplan-Meier methods. Predictors of hip fracture were determined using Cox models. During the study period, 1903 patients had a hip fracture. The overall incidence rate of hip fracture was 89.21/10,000 patient-years. Patients on hemodialysis (HD) had a 31% higher incidence of hip fracture than those on peritoneal dialysis (PD) (HR 1.31, 95% CI: 1.01-1.70). Patients >=65 years old had more than 13 times the risk of a hip fracture than did those 18-44 years old (HR: 13.65; 95% CI: 10.12-18.40). Other factors that increased the risk of a hip fracture were a prior hip fracture (HR: 1.44; 95% CI: 1.15-1.80), osteoporosis (HR: 1.24; 95% CI: 1.07-1.45), DM (HR: 1.66; 95% CI: 1.51-1.83), and liver cirrhosis (HR: 1.37, 95% CI: 1.15-1.64). The overall in-hospital mortality rate was 3.2%. The cumulative survival rates after a hip fracture were 74.6% at one year and only 29.6% at seven years. Our findings supported the notion that being on HD is a risk for hip fracture. Additionally, old age, female gender, a prior hip fracture, osteoporosis, DM and liver cirrhosis were also risk factors for hip fracture in patients with ESRD and undergoing dialysis. PMID- 24780874 TI - Genetic variants of the LIN28B gene predict severe radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy. AB - BACKGROUND: LIN28 is an RNA-binding protein that not only plays key roles in multiple cellular developmental processes and tumourigenesis, but also is involved in tissue inflammatory response. However, no published study has investigated associations between genetic variants in LIN28 and radiation-induced pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with definitive radiation therapy. METHODS: We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of LIN28A (rs11247946 T>C, rs3811464 C>T, rs11581746 T>C, and rs12728900 G>A) and LIN28B (rs314280 G>A, rs12194974 G>A, rs17065417 A>C and rs314276 C>A) in 362 patients with NSCLC, who received definitive radio(chemo)therapy. The associations between RP risk and genotypes were assessed by hazards ratio (HR) in Cox proportional hazards regression analysis with time to event considered with and without adjustment for potential confounders. RESULTS: Multivariate analyses found that patients carrying LIN28B rs314280 AG and AA/AG or rs314276 AC and AA/AC genotypes had a higher risk of grade ?3 RP (for rs314280 AG and AA/AG versus GG, adjusted HR=2.97 and 2.23, 95% confidence interval (CI)=1.32-6.72 and 1.01-4.94, P=0.009 and 0.048, respectively; for rs314276 AC and AA/AC versus CC, adjusted HR=2.30 and 2.00, 95% CI=1.24-4.28 and 1.11-3.62, and P=0.008 and 0.022, respectively). Further stratified analyses showed a more consistent and profound risk in the subgroups of age <65years, males, stage III/IV, ever smokers, having radio-chemotherapy and mean lung dose (MLD) ?19.0Gy. CONCLUSION: Genetic variants of LIN28B, but not LIN28A, may be biomarkers for susceptibility to severe RP in NSCLC patients. Large, prospective studies are needed to confirm our findings. PMID- 24780876 TI - Association between use of antiepileptic drugs and fracture risk: a systematic review and meta-analysis. AB - BACKGROUND: It has been shown that antiepileptic drugs (AEDs) may have a detrimental effect on bone health and translate into an increased risk of bone fracture. We aimed to comprehensively evaluate the association between use of AEDs and fracture risk. METHODS: We searched NCBI (PubMed), ISI Web of Science, the Cochrane Library and EMBASE databases for studies reporting fracture risk among users of AEDs. Random-effects meta-analysis was used to pool results across studies. RESULTS: Twenty-two studies met the inclusion criteria. Overall, there was a significant increase in fracture risk among users of AEDs involving 1,292,910 participants, with a mean/median age of 36-82 years (relative risk (RR)=1.86; 95% confidence interval (CI) 1.62-2.12). When we limited the studies to those on osteoporosis-related fractures, the RR was still significant. Both liver enzyme-inducing antiepileptic drugs (LEI AEDs) and non-LEI AEDs were associated with an increase in fracture risk, although the estimate for LEI AEDs was higher than that of non-LEI AEDs (RR=1.18; 95% CI 1.11-1.25). For some specific AEDs, use of phenobarbiturate (PB), topiramate (TPM) and phenytoin (PHT) suggested an increase in fracture risk of 78%, 39% and 70%, respectively. CONCLUSIONS: The study suggests a robust association between use of AEDs and fracture risk (particularly for LEI AEDs). It also suggests that several specific AEDs such as PB, TPM and PHT may be associated with an increased risk of fracture. PMID- 24780877 TI - Disrupting the intrinsic growth potential of a suture contributes to midfacial hypoplasia. AB - Children with unoperated cleft palates have nearly normal growth of their faces whereas patients who have had early surgical repair often exhibit midfacial hypoplasia. Surgical repair is responsible for the underlying bone growth arrest but the mechanisms responsible for these surgical sequelae are poorly understood. We simulated the effect of cleft palate repair by raising a mucoperiosteal flap in the murine palate. Three-dimensional micro-CT reconstructions of the palate along with histomorphometric measurements, finite element (FE) modeling, immunohistochemical analyses, and quantitative RT-PCR were employed to follow the skeletal healing process. Inflammatory bone resorption was observed during the first few days after denudation, which destroyed the midpalatal suture complex. FE modeling was used to predict and map the distribution of strains and their associated stresses in the area of denudation and the magnitude and location of hydrostatic and distortional strains corresponded to sites of skeletal tissue destruction. Once re-epithelialization was complete and wound contracture subsided, the midpalatal suture complex reformed. Despite this, growth at the midpalatal suture was reduced, which led to palatal constriction and a narrowing of the dental arch. Thus the simple act of raising a flap, here mimicked by denuding the mucoperiosteum, was sufficient to cause significant destruction to the midpalatal suture complex. Although the bone and cartilage growth plates were re-established, mediolateral skeletal growth was nonetheless compromised and the injured palate never reached its full growth potential. These data strongly suggest that disruption of suture complexes, which have intrinsic growth potential, should be avoided during surgical correction of congenital anomalies. PMID- 24780878 TI - Cathepsin S controls adipocytic and osteoblastic differentiation, bone turnover, and bone microarchitecture. AB - Cathepsin S is a cysteine protease that controls adipocyte differentiation and has been implicated in vascular and metabolic complications of obesity. Considering the inverse relation of osteoblasts and adipocytes and their mutual precursor cell, we hypothesized that cathepsin S may also affect osteoblast differentiation and bone remodeling. Thus, the fat and bone phenotypes of young (3 months old) and aged (12 or 18 months old) cathepsin S knock-out (KO) and wild type (WT) mice were determined. Cathepsin S KO mice had a normal body weight at both ages investigated, even though the amount of subscapular and gonadal fat pads was reduced by 20%. Further, cathepsin S deficiency impaired adipocyte formation (-38%, p<0.001), which was accompanied by a lower expression of adipocyte-related genes and a reduction in serum leptin, IL-6 and CCL2 (p<0.001). Micro-CT analysis revealed an unchanged trabecular bone volume fraction and density, while tissue mineral density was significantly lower in cathepsin S KO mice at both ages. Aged KO mice further had a lower cortical bone mass (-2.3%, p<0.05). At the microarchitectural level, cathepsin S KO mice had thinner trabeculae (-8.3%), but a better connected trabecular network (+24%). Serum levels of the bone formation marker type 1 procollagen amino-terminal-propeptide and osteocalcin were both 2-3-fold higher in cathepsin S KO mice as was the mineralized surface. Consistently, osteogenic differentiation was increased 2 fold along with an increased expression of osteoblast-specific genes. Interestingly, serum levels of C-terminal telopeptide of type I collagen were also higher (+43%) in cathepsin S KO mice as were histological osteoclast parameters and ex vivo osteoclast differentiation. Thus, cathepsin S deficiency alters the balance between adipocyte and osteoblast differentiation, increases bone turnover, and changes bone microarchitecture. Therefore, bone and fat metabolisms should be monitored when using cathepsin S inhibitors clinically. PMID- 24780879 TI - Embryonic stem cell therapy improves bone quality in a model of impaired fracture healing in the mouse; tracked temporally using in vivo micro-CT. AB - In the current study, we used an estrogen-deficient mouse model of osteoporosis to test the efficacy of a cell-generated bone tissue construct for bone augmentation of an impaired healing fracture. A reduction in new bone formation at the defect site was observed in ovariectomized fractures compared to the control group using repeated measures in vivo micro-computed tomography (MUCT) imaging over 4 weeks. A significant increase in the bone mineral density (BMD), trabecular bone volume ratio, and trabecular number, thickness and connectivity were associated with fracture repair in the control group, whereas the fractured bones of the ovariectomized mice exhibited a loss in all of these parameters (p<0.001). In a separate group, ovariectomized fractures were treated with murine embryonic stem (ES) cell-derived osteoblasts loaded in a three-dimensional collagen I gel and recovery of the bone at the defect site was observed. A significant increase in the trabecular bone volume ratio (p<0.001) and trabecular number (p<0.01) was observed by 4 weeks in the fractures treated with cell-loaded collagen matrix compared to those treated with collagen I alone. The stem cell derived osteoblasts were identified at the fracture site at 4 weeks post implantation through in situ hybridization histochemistry. Although this cell tracking method was effective, the formation of an ectopic cellular nodule adjacent to the knee joints of two mice suggested that alternative in vivo cell tracking methods should be employed in order to definitively assess migration of the implanted cells. To our knowledge, this study is the first of its kind to examine the efficacy of stem cell therapy for fracture repair in an osteoporosis related fracture model in vivo. The findings presented provide novel insight into the use of stem cell therapies for bone injuries. PMID- 24780880 TI - Heat-related mortality and adaptation to heat in the United States. AB - BACKGROUND: In a changing climate, increasing temperatures are anticipated to have profound health impacts. These impacts could be mitigated if individuals and communities adapt to changing exposures; however, little is known about the extent to which the population may be adapting. OBJECTIVE: We investigated the hypothesis that if adaptation is occurring, then heat-related mortality would be decreasing over time. METHODS: We used a national database of daily weather, air pollution, and age-stratified mortality rates for 105 U.S. cities (covering 106 million people) during the summers of 1987-2005. Time-varying coefficient regression models and Bayesian hierarchical models were used to estimate city specific, regional, and national temporal trends in heat-related mortality and to identify factors that might explain variation across cities. RESULTS: On average across cities, the number of deaths (per 1,000 deaths) attributable to each 10 degrees F increase in same-day temperature decreased from 51 [95% posterior interval (PI): 42, 61] in 1987 to 19 (95% PI: 12, 27) in 2005. This decline was largest among those >= 75 years of age, in northern regions, and in cities with cooler climates. Although central air conditioning (AC) prevalence has increased, we did not find statistically significant evidence of larger temporal declines among cities with larger increases in AC prevalence. CONCLUSIONS: The population has become more resilient to heat over time. Yet even with this increased resilience, substantial risks of heat-related mortality remain. Based on 2005 estimates, an increase in average temperatures by 5 degrees F (central climate projection) would lead to an additional 1,907 deaths per summer across all cities. PMID- 24780881 TI - A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome. AB - BACKGROUND: Usher syndrome (USH) is a heterogeneous group of inherited retinitis pigmentosa (RP) and sensorineural hearing loss (SNHL) caused by mutations in at least 12 genes. Our aim is to identify additional USH-related genes. METHODS: Clinical examination included visual acuity test, funduscopy and electroretinography. Genetic analysis included homozygosity mapping and whole exome sequencing (WES). RESULTS: A combination of homozygosity mapping and WES in a large consanguineous family of Iranian Jewish origin revealed nonsense mutations in two ciliary genes: c.3289C>T (p.Q1097*) in C2orf71 and c.3463C>T (p.R1155*) in centrosome-associated protein CEP250 (C-Nap1). The latter has not been associated with any inherited disease and the c.3463C>T mutation was absent in control chromosomes. Patients who were double homozygotes had SNHL accompanied by early-onset and severe RP, while patients who were homozygous for the CEP250 mutation and carried a single mutant C2orf71 allele had SNHL with mild retinal degeneration. No ciliary structural abnormalities in the respiratory system were evident by electron microscopy analysis. CEP250 expression analysis of the mutant allele revealed the generation of a truncated protein lacking the NEK2 phosphorylation region. CONCLUSIONS: A homozygous nonsense CEP250 mutation, in combination with a heterozygous C2orf71 nonsense mutation, causes an atypical form of USH, characterised by early-onset SNHL and a relatively mild RP. The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins. PMID- 24780884 TI - Water fluoridation could save NHS millions every year. PMID- 24780882 TI - Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. AB - BACKGROUND: The most common spinocerebellar ataxias (SCA)--SCA1, SCA2, SCA3, and SCA6--are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset. METHODS: We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age. RESULTS: For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (-0.105+/-0.005 and -0.056+/-0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: -0.049+/ 0.002 and -0.090+/-0.009, respectively; normal: +0.013+/-0.005 and -0.029+/ 0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age. CONCLUSIONS: These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies. CLINICALTRIALSGOV, NUMBER: NCT01037777 and NCT00136630 for the French patients. PMID- 24780883 TI - Comparative analysis of virulence and resistance profiles of Salmonella Enteritidis isolates from poultry meat and foodborne outbreaks in northern Jordan. AB - This study was conducted to isolate Salmonella Enteritidis from poultry samples and compare their virulence and antibiotic resistance profiles to S. Enteritidis isolated from outbreaks in northern Jordan. Two hundred presumptive isolates were obtained from 302 raw poultry samples and were subjected to further analysis and confirmation. A phylogenic tree based on 16S rRNA sequencing was constructed and selected isolates representing each cluster were further studied for their virulence in normal adult Swiss white mice. The most virulent strains were isolated from poultry samples and had an LD 50 of 1.55 * 10 (5) CFU, while some of the outbreak isolates were avirulent in mice. Antibiotic resistance profiling revealed that the isolates were resistant to seven of eight antibiotics screened with each isolate resistant to multiple antibiotics (from two to six). Of the poultry isolates, 100%, 88.9%, 77.8%, 66.7%, and 50% showed resistance to nalidixic acid, ciprofloxacin, ampicillin, cephalothin, and cefoperazone, respectively. Two outbreak isolates were sensitive to all tested antibiotics, while 71.4% were resistant to cefoperazone and only 28.6% showed resistance to nalidixic acid. Salmonella outbreak isolates were genetically related to poultry isolates as inferred from the 16S rRNA sequencing, yet were phenotypically different. Although outbreak strains were similar to poultry isolates, when tested in the mouse model, some of the outbreak isolates were highly virulent while others were avirulent. This might be due to a variation in susceptibility of the mouse to different S. Enteritidis isolates. PMID- 24780885 TI - Disease location and severity may predict vitamin D deficiency in Crohn's. PMID- 24780887 TI - Transcriptomic profiles of Aspergillus flavus CA42, a strain that produces small sclerotia, by decanal treatment and after recovery. AB - Aspergillus flavus is a ubiquitous saprophyte and is capable of producing many secondary metabolites including the carcinogenic aflatoxins. The A. flavus population that produces small sclerotia (S strain) has been implicated as the culprit for persistent aflatoxin contamination in field crops. We investigated how the plant volatile decanal, a C10 fatty aldehyde, affected the growth and development of the S strain A. flavus. Decanal treatment yielded fluffy variants lacking sclerotia and conidia and exhibiting a dosage-dependent radial colony growth. We used RNA-Seq analysis to examine transcriptomic changes caused by decanal and after removal of decanal. Mature sclerotia contained only 80% of the total transcripts detected in all samples in comparison to 94% for the decanal treated culture. Gene ontology (GO) analysis showed that decanal treatment increased expression of genes involved in oxidoreductase activity, cellular carbohydrate metabolism, alcohol metabolism and aflatoxin biosynthesis. The treatment affected cellular components associated with cell wall, and gene expression of glucanases, alpha-amylases, pectinesterase and peptidase required for its biosynthesis was increased. After decanal was removed, the culture resumed sclerotial production. Moreover, its GO terms significantly overlapped with those of the untreated culture; five of the enriched molecular functions, oxidoreductase activity, monooxygenase activity, electron carrier activity, heme binding, and iron binding were found in the untreated culture. The GO term of cellular component enriched was mainly integral protein constituents of the membrane. The results suggested that decanal halted development at the vegetative state rendering the fungus unable to produce conidia and sclerotia. The induced fluffy phenotype could be related to lower transcript abundance of flbB, flbD, and flbE but not to veA expression. Increased abundance of the laeA transcript in the treated culture correlated with early transcriptional activation of aflatoxin and kojic acid biosynthesis gene clusters. Expression profiles revealed subtle differences in timing of activation of the respective 55 secondary metabolite gene clusters. PMID- 24780888 TI - Dissection of genetic factors associated with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal late onset neurological disorder characterized by motor neuron degeneration in the primary motor cortex, brainstem and spinal cord. The majority of cases are sporadic (SALS) and only 5-10% have a family history (FALS). FALS cases show a high heritability and this has enabled the identification of several genetic triggers, of which mutations in SOD1, FUS, TARDBP and C9ORF72 are the most frequent. While such advances have contributed to our current understanding of the causes of most cases of FALS and their underlying pathophysiological consequences, they only explain a small fraction of SALS with the etiology of most SALS cases remaining unexplained. Here, we review past and current methods used for the identification of FALS and SALS associated genes and propose a risk-based classification for these. We also discuss how the growing number of whole exome/genome sequencing datasets prepared from SALS cases, and control individuals, may reveal novel insights into the genetic etiology of SALS; for instance through revealing increased mutation burden rates across genes or genomic regions that were not previously associated with ALS or through allowing the examination of a potential "oligogenic" mechanism of the disease. Finally we summarize the three most recently discovered 'high risk' genes in ALS. PMID- 24780890 TI - Serum gamma-glutamyl transferase: a novel biomarker for coronary artery disease. AB - BACKGROUND: Atherosclerosis is a chronic inflammatory process, in which oxidative stress is the key event. Gamma-glutamyl transferase (GGT) is a cellular production of oxidants. We aimed to elucidate the relationship of serum GGT levels and coronary artery disease (CAD) in a Chinese population. MATERIAL AND METHODS: A total of 513 adult subjects who had undergone coronary angiography were enrolled in the study. Clinical characteristics, coronary angiography, and serum samples were collected from all the patients and analyzed for the serum GGT, blood lipids, and cardiovascular risk factors. RESULTS: Subjects with CAD had significantly increased activity of serum GGT (p=0.003). Serum GGT levels exhibited positive correlations with alcohol intake (beta=0.177, p<0.001), coronary complexity (beta=0.068, p<0.001), and triacylglycerol (beta=0.058, p<0.001). High-density lipoprotein cholesterol levels (beta=0.157, p=0.008) and age (beta=0.004, p=0.002) were negatively correlated with serum GGT in the CAD group. The coronary complexity presented a negative correlation with Ig apolipoprotein AI (beta=-2.517, p=0.001) and positive correlations with smoking (beta=0.640, p<0.001), Ig-GGT (beta=0.613, p=0.004), Ig high sensitivity-C reactive protein (beta=0.320, p<0.001), and hypertension (beta=0.286, p<0.026). CONCLUSIONS: The study showed a positive correlation between serum GGT and CAD in a Chinese population. Serum GGT levels may be a potential biomarker for CAD. PMID- 24780891 TI - Combination of conventional blood cultures and the SeptiFast molecular test in patients with suspected sepsis for the identification of bloodstream pathogens. AB - We evaluated performances of the molecular test SeptiFast (SF) for the detection of agents of bloodstream infection (BSI) in patients with suspected sepsis, the majority of them under antibiotic treatment and at high prevalence of HIV-1 infection (10.5%). Matched SF and blood culture (BC) samples (n=1186) from 1024 patients were studied. Two hundred fifty-one episodes of BSI out of 1144 were identified with the combined methods (22%). SF identified more episodes of BSI than BC: 206 versus 176 (chi(2)=7.008, P=0.0081) and a significantly higher number of Gram-negative bacteria than BC (77 versus 53, chi(2)=9.12; P=0.0025), as well as of polymicrobial infections (chi(2)=4.50, P=0.0339). In conclusion, SF combined with BC improved the diagnosis of sepsis, especially in immunocompromised patients. PMID- 24780892 TI - Magnetic Resonance Imaging Findings in the Symptomatic Hips of Younger Retired National Football League Players. AB - BACKGROUND: American football players have an increased level of risk for hip injuries because of the high level of contact, biomechanical load, and anatomic strain placed on the hip joint. Many injuries are attributed to soft tissue injury rather than intra-articular lesions. However, because of improved imaging and increased knowledge, physicians are attributing unexplained hip pain to intra articular lesions with increasing frequency. PURPOSE: To assess the prevalence of pathologic intra-articular hip lesions in a younger, retired National Football League (NFL) player cohort evaluated for persistent hip pain. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A retrospective chart review was performed of magnetic resonance imaging (MRI) on retired NFL players evaluated at an orthopaedic clinic for persistent hip pain. All MRIs were performed at the same location and reviewed by the same independent radiologist. The study included 62 hips; MRI was used to evaluate 27 hips, and MRI arthrogram was used to evaluate 35 hips. Images were assessed for labral tears, chondral lesions, ligamentum teres (LT) tears, bone cysts, osteophytes, loose bodies, trochanteric bursitis, and alpha angle. Player demographics, including position and seasons played, were recorded. RESULTS: From February 2011 to December 2012, a total of 50 retired players from the NFL (average age, 33 years; range, 27-39 years) received impairment evaluations assessing all symptomatic joints. Thirty-eight (76%) players had hip complaints and underwent a dedicated hip MRI. Twenty-four players (63%) had bilateral hip pain, for a total of 62 hips evaluated. There were 55 (89%) labral tears, 61 (98%) chondral lesions, and 50 (81%) partial or complete LT tears identified on MRI. Additional findings included 3 (5%) hips with osteophytes, 9 (14.5%) with subchondral bone cysts, and 3 (5%) with paralabral cysts. None of the players were found to have trochanteric bursitis or loose bodies. Fifty-eight of 62 alpha angles could be measured, for a mean of 59 degrees (range, 39 degrees -77 degrees ). The majority of players were defensive players (63%), while the remainder were offensive players (34%) and 1 special teams player. Position breakdown was as follows: 29% were defensive backs, 16% played the defensive line, 18% were linebackers, 13% were fullbacks, 11% were wide receivers, 5% played the offensive line, and the remaining 8% were kickers, running backs, and quarterbacks. CONCLUSION: This study demonstrated a high incidence of intra-articular pathologic lesions of the hip in a younger cohort of retired NFL players. The majority of players had bilateral hip pain. The most common finding was chondral lesions, followed by labral tears. Future research is needed to further elucidate incidence and treatment outcomes using prospective studies examining active and retired players with hip-related injuries. PMID- 24780893 TI - Sports and Activity Levels After Open Surgical Treatment of Femoroacetabular Impingement. AB - BACKGROUND: Several studies indicate that professional athletes can successfully return to competition after surgical treatment of femoroacetabular impingement (FAI). However, little is known about sports and activity levels after FAI surgery in the general patient population. HYPOTHESIS/PURPOSE: The purpose was to determine the sports behavior, satisfaction with sports ability, and activity levels in a consecutive cohort of patients with FAI who were treated by surgical hip dislocation. The hypothesis was that the majority of patients (>75%) would be active in sports at follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This retrospective study included 153 patients (mean age, 30.0 years; 40.5% female) with 192 hips treated. Sports behavior and satisfaction were determined at a mean follow-up of 59.4 months with the use of a questionnaire. Activity levels at follow-up were assessed by the Hip Sports Activity Scale (HSAS) and the University of California, Los Angeles (UCLA) activity scale. RESULTS: Of 126 patients who were regularly active in sports before surgery, 107 (85%) were so at follow-up. Nineteen patients (12.4%) stopped participating in regular sports, and 8 (5.2%) commenced with sports after the operation. The most popular activities before surgery were skiing (22%), cycling (22%), jogging (20%), and soccer (13%). At follow-up, most patients were engaged in cycling (23%), fitness/weight training (20%), skiing (18%), and jogging (11%). Of all patients, 75% were satisfied with their sports ability, and 25% were not. Moreover, 60.3% stated that their sports ability had improved after surgery, 20.5% declared no change, and 19.2% were subjectively deteriorated. The mean pain level during sports was rated to be 2.1 according to the visual analog scale. The mean HSAS score was 3.5 (range, 0-8), and the mean UCLA score was 7.7 (range, 3 10); male patients reported significantly higher scores than did female patients on the HSAS (4.1 vs 2.7, respectively) and UCLA scale (8.2 vs 7.0, respectively). CONCLUSION: The vast majority of patients with FAI who are treated by surgical hip dislocation return to sports activities, and most patients are satisfied with their sports ability at midterm follow-up. Activity levels are significantly higher in male patients, but this does not yield higher satisfaction rates. PMID- 24780894 TI - Expression of phosphorylated cyclic AMP response element-binding protein in melanin-concentrating hormone neurons and orexin neurons in male and female rats during ad-libitum feeding. AB - Using phosphorylated cyclic AMP response element-binding protein (pCREB) as a marker of neural activity, we previously suggested that orexin neurons and melanin-concentrating hormone (MCH) neurons play distinct roles in feeding behavior. In the present study, we examined the expression of pCREB during ad libitum feeding; previously, only fasted animals were examined. MCH neurons, but not orexin neurons, expressed pCREB during spontaneous food intake. The induction of pCREB expression did not differ by sex, but attenuation seemed to occur faster in females than in males. On the basis of the results of the present study, we speculate that MCH neurons respond to nutrition-related feeding, but the feeding related activity of orexin was not evident unless hunger was accompanied by stress, such as the stress caused by the absence of food in the case of fasting. Therefore, the desire to eat under normal conditions does not drive orexin neurons, but it does drive MCH neurons. We tested this hypothesis by examining the effects of consuming glucose or saccharin, a nonmetabolized sweetener, in fasted male and female rats. Glucose and saccharin were equally effective in reducing pCREB expression in the orexin neurons of female rats. In MCH neurons, glucose attenuated the expression of pCREB, but saccharin had no effect, irrespective of sex. Taken together, the results indicate that MCH and orexin peptides play physiologically distinct roles in feeding behavior. PMID- 24780895 TI - Effects of ipsilateral and bilateral auditory stimuli on audiovisual integration: a behavioral and event-related potential study. AB - We used event-related potential measures to compare the effects of ipsilateral and bilateral auditory stimuli on audiovisual (AV) integration. Behavioral results showed that the responses to visual stimuli with either type of auditory stimulus were faster than responses to visual stimuli only and that perceptual sensitivity (d') for visual detection was enhanced for visual stimuli with ipsilateral auditory stimuli. Furthermore, event-related potential components related to AV integrations were identified over the occipital areas at ~180-200 ms during early-stage sensory processing by the effect of ipsilateral auditory stimuli and over the frontocentral areas at ~300-320 ms during late-stage cognitive processing by the effect of ipsilateral and bilateral auditory stimuli. Our results confirmed that AV integration was also elicited, despite the effect of bilateral auditory stimuli, and only occurred at later stages of cognitive processing in response to a visual detection task. Furthermore, integration from early-stage sensory processing was observed by the effect of ipsilateral auditory stimuli, suggesting that the integration of AV information in the human brain might be particularly sensitive to ipsilaterally presented AV stimuli. PMID- 24780896 TI - Motor cortex stimulation for neuropathic pain syndromes: a case series experience. AB - Neuropathic pain is a chronic condition lacking effective management and responding poorly to standard treatment protocols. Motor cortex stimulation has emerged as a new and promising therapeutic tool with outcomes potentially affected by the specific causes and location. In this study we report a series of eight cases in the neurosurgery practice of one of the authors (R.J.B.), including neuropathic pain syndromes of trigeminal or thalamic origin with or without anesthesia dolorosa. Pain relief was evaluated on the basis of comparison of Visual Analog scores at baseline and at 3 months after surgery. In addition, we assessed differences in pain relief outcomes between cases with trigeminal neuralgia and thalamic stroke, as well as cases with or without anesthesia dolorosa (i.e. pain with numbness of the affected area). Visual Analog Scale scores showed a statistically significant decrease of 4.19 (P=0.002) at 3 months follow-up compared with baseline. Pain relief levels in four of five patients in the subgroup with facial pain were higher than 50%, and none of the patients in the subgroup with thalamic and phantom limb pain showed such a good outcome. Furthermore, we found larger pain relief levels in facial pain conditions with versus without anesthesia dolorosa. These results point to utility of motor cortex stimulation in relieving neuropathic pain, as well as better outcomes for patients with facial pain and anesthesia dolorosa. Future studies should incorporate methods to noninvasively trial those patients who may benefit from surgical implantation to predict the outcomes and maximize their negative predictive value. PMID- 24780897 TI - Serotonin 2A receptor agonist binding in the human brain with [11C]Cimbi-36. AB - [(11)C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT(2A)) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [(11)C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT(2A) receptors with [(11)C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [(11)C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [(11)C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT(2A) receptor antagonist ketanserin before a second PET scan significantly decreased [(11)C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [(11)C]Cimbi-36 binding is selective for 5-HT(2A) receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT(2A) receptors in the human brain. Thus, we here describe [(11)C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT(2A) receptors in the human brain. PMID- 24780898 TI - The impact of Ly6Clow monocytes after cerebral hypoxia-ischemia in adult mice. AB - After an ischemic stroke, mononuclear phagocytic cells such as microglia, macrophages, and monocytes migrate to the lesion site and coordinate an immune response. Monocytes, which are recruited from the bloodstream after ischemic brain injury, can be categorized into two subsets in mice: inflammatory and patrolling monocytes. Although inflammatory monocytes (Ly6C(hi)) seem to have a protective role in stroke progression, the impact of patrolling monocytes (Ly6C(low)) is unknown. To address the role of Ly6C(low) monocytes in stroke, we generated bone marrow chimeric mice in which their hematopoietic system was replaced by Nr4a1(-/-) cells, allowing the complete and permanent ablation of Ly6C(low) monocytes without affecting the Ly6C(hi) subset. We then subjected adult mice to cerebral hypoxia-ischemia using the Levine/Vannucci model. Functional outcomes after stroke such as body weight change, neurologic score, motor functions and spatial learning were not affected. Moreover, depletion in Ly6C(low) monocytes did not change significantly the total infarct size, cell loss, atrophy, the number, or the activation state of microglia/macrophages at the lesion site. These data suggest that Ly6C(low) patrolling monocytes are redundant in the progression and recovery of ischemic stroke. PMID- 24780899 TI - Early small vessel disease affects frontoparietal and cerebellar hubs in close correlation with clinical symptoms--a resting-state fMRI study. AB - Cerebral small vessel disease, mainly characterized by white matter lesions and lacunes, has a high clinical impact as it leads to vascular dementia. Recent studies have shown that this disease impairs frontoparietal networks. Here, we apply resting-state magnetic resonance imaging and data-driven whole-brain imaging analysis methods (eigenvector centrality) to investigate changes of the functional connectome in early small vessel disease. We show reduced connectivity in frontoparietal networks, whereas connectivity increases in the cerebellum. These functional changes are closely related to white matter lesions and typical neuropsychological deficits associated with small vessel disease. PMID- 24780900 TI - Endothelial progenitor cells augment collateralization and hemodynamic rescue in a model of chronic cerebral ischemia. AB - Surgical flow augmentation for treatment of cerebral hemodynamic impairment remains controversial. Here, we investigated the benefit of endothelial progenitor cell (EPC) treatment in a rat model of chronic cerebral hypoperfusion. At repeated time points after 3-vessel occlusion (3-VO), animals were treated with 1 * 10(6) DiI-labeled (a) ex vivo-expanded embryonic-EPC (e-EPC), (b) cyclic AMP-differentiated embryonic-endothelial progenitor-derived cells (e-EPDC as biologic control) or, (c) saline. The cerebrovascular reserve capacity (CVRC) was assessed immediately before and on days 7 and 21 after 3-VO. Structural effects were assessed by latex perfusion, immunohistochemistry, and intravital fluorescence video microscopy on day 21. Three-vessel occlusion resulted in a significant impairment of the CVRC with better functional recovery after treatment with e-EPC (16.4+/-8%) compared with e-EPDC (3.7+/-8%) or saline (6.4+/ 9%) by day 21 (P<0.05), which was paralleled by a significant increase in the vessel diameters of the anterior Circle of Willis, a significantly higher number of leptomeningeal anastomoses and higher parenchymal capillary density in e-EPC treated animals. Interestingly, despite in vivo interaction of e-EPC with the cerebral endothelium, e-EPC incorporation into the cerebral vasculature was not observed. Our results suggest that EPC may serve as a novel therapeutic agent in clinical trials for nonsurgical treatment of chronic cerebral hemodynamic impairment. PMID- 24780901 TI - Lipocalin-2 deficiency attenuates neuroinflammation and brain injury after transient middle cerebral artery occlusion in mice. AB - Lipocalin-2 (LCN2) is a secreted protein of the lipocalin family, but little is known about the expression or the role of LCN2 in the central nervous system. Here, we investigated the role of LCN2 in ischemic stroke using a rodent model of transient cerebral ischemia. Lipocalin-2 expression was highly induced in the ischemic brain and peaked at 24 hours after reperfusion. After transient middle cerebral artery occlusion, LCN2 was predominantly expressed in astrocytes and endothelial cells, whereas its receptor (24p3R) was mainly detected in neurons, astrocytes, and endothelial cells. Brain infarct volumes, neurologic scores, blood-brain barrier (BBB) permeabilities, glial activation, and inflammatory mediator expression were significantly lower in LCN2-deficient mice than in wild type animals. Lipocalin-2 deficiency also attenuated glial neurotoxicity in astrocyte/neuron cocultures after oxygen-glucose deprivation. Our results indicate LCN2 has a critical role in brain injury after ischemia/reperfusion, and that LCN2 may contribute to neuronal cell death in the ischemic brain by promoting neurotoxic glial activation, neuroinflammation, and BBB disruption. PMID- 24780902 TI - The contribution of ketone bodies to basal and activity-dependent neuronal oxidation in vivo. AB - The capacity of ketone bodies to replace glucose in support of neuronal function is unresolved. Here, we determined the contributions of glucose and ketone bodies to neocortical oxidative metabolism over a large range of brain activity in rats fasted 36 hours and infused intravenously with [2,4-(13)C2]-D-beta hydroxybutyrate (BHB). Three animal groups and conditions were studied: awake ex vivo, pentobarbital-induced isoelectricity ex vivo, and halothane-anesthetized in vivo, the latter data reanalyzed from a recent study. Rates of neuronal acetyl CoA oxidation from ketone bodies (V(acCoA-kbN)) and pyruvate (V(pdhN)), and the glutamate-glutamine cycle (V(cyc)) were determined by metabolic modeling of (13)C label trapped in major brain amino acid pools. V(acCoA-kbN) increased gradually with increasing activity, as compared with the steeper change in tricarboxylic acid (TCA) cycle rate (V(tcaN)), supporting a decreasing percentage of neuronal ketone oxidation: ~100% (isoelectricity), 56% (halothane anesthesia), 36% (awake) with the BHB plasma levels achieved in our experiments (6 to 13 mM). In awake animals ketone oxidation reached saturation for blood levels >17 mM, accounting for 62% of neuronal substrate oxidation, the remainder (38%) provided by glucose. We conclude that ketone bodies present at sufficient concentration to saturate metabolism provides full support of basal (housekeeping) energy needs and up to approximately half of the activity-dependent oxidative needs of neurons. PMID- 24780903 TI - Small vessel disease and the resting functional architecture of the brain. AB - Small vessel disease (SVD) is linked to cognitive impairment and dementia, yet little is known regarding functional activation in patients with SVD. Resting fMRI recordings suggest reduced connectivity in prefrontal, parietal and cingulate nodes and reciprocally increased connectivity in cerebellum, alterations which predicted neuropsychological test performance. Together with diffusion tensor tensor imaging studies, these data support of a model of disrupted connectivity as a systems-level approach to the cognitive disturbances seen in SVD. PMID- 24780904 TI - Bolus arrival time and cerebral blood flow responses to hypercarbia. AB - The purpose of this study was to evaluate how cerebral blood flow and bolus arrival time (BAT) measures derived from arterial spin labeling (ASL) MRI data change for different hypercarbic gas stimuli. Pseudocontinuous ASL (pCASL) was applied (3.0T; spatial resolution=4 * 4 * 7 mm(3); repetition time/echo time (TR/TE)=3,600/11 ms) sequentially in healthy volunteers (n=12; age=30+/-4 years) for separate experiments in which (i) normocarbic normoxia (i.e., room air), hypercarbic normoxia (i.e., 5% CO2/21% O2/74% N2), and hypercarbic hyperoxia (i.e., carbogen: 5% CO2/95% O2) gas was administered (12 L/minute). Cerebral blood flow and BAT changes were quantified using models that account for macrovascular signal and partial volume effects in all gray matter and regionally in cerebellar, temporal, occipital, frontal, and parietal lobes. Regional reductions in BAT of 4.6% to 7.7% and 3.3% to 6.6% were found in response to hypercarbic normoxia and hypercarbic hyperoxia, respectively. Cerebral blood flow increased by 8.2% to 27.8% and 3.5% to 19.8% for hypercarbic normoxia and hypercarbic hyperoxia, respectively. These findings indicate that changes in BAT values may bias functional ASL data and thus should be considered when choosing appropriate experimental parameters in calibrated functional magnetic resonance imaging or ASL cerebrovascular reactivity experiments that use hypercarbic gas stimuli. PMID- 24780905 TI - The size of blood-brain barrier opening induced by focused ultrasound is dictated by the acoustic pressure. AB - Focused ultrasound (FUS) in combination with microbubbles (MBs) has been successfully used in the delivery of various-size therapeutic agents across the blood-brain barrier (BBB). This study revealed that FUS-induced BBB opening size, defined by the size of the largest molecule that can permeate through the BBB, can be controlled by the acoustic pressure as dictated by cavitational mechanisms. Focused ultrasound was applied onto the mouse hippocampus in the presence of systemically administered MBs for trans-BBB delivery of fluorescently labeled dextrans with molecular weights 3 to 2,000 kDa (hydrodynamic diameter: 2.3 to 54.4 nm). The dextran delivery outcomes were evaluated using ex vivo fluorescence imaging. Cavitation detection was employed to monitor the MB cavitation activity associated with the delivery of these agents. It was found that the BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa). These findings indicate that the BBB opening size can be controlled by the acoustic pressure and predicted using cavitation detection. PMID- 24780907 TI - Functional and haemodynamic assessment of mild-to-moderate pulmonary valve stenosis at rest and during exercise. AB - OBJECTIVE: In adult patients with mild-to-moderate pulmonary valve (PV) stenosis, exercise capacity and haemodynamics have not been extensively studied, although regular exercise is recommended. Therefore, we aimed to assess exercise capacity to study the increase in PV gradient during exercise and to evaluate the impact of this increased pressure load on the RV. METHODS: Nineteen patients (8 female; 29+/-6.4 years) with isolated mild-to-moderate PV stenosis and no prior cardiac interventions were consecutively enrolled from the outpatient clinic of adult congenital heart disease. All patients underwent cardiopulmonary exercise testing, transthoracic echocardiography and bicycle stress echocardiography. Results for exercise testing were compared with age-matched and gender-matched control patients. RESULTS: In the studied population, resting heart rate (89+/-11 vs 75+/-14 bpm; p=0.001), peak power (199+/-66 vs 263+/-68 W; p=0.006); peak VO2 (31.2+/-9.9 vs 39+/-7.4 mL/kg/min; p=0.011); oxygen uptake efficiency slope (2430+/-913 vs 3292+/-943(mL/min)/(L/min); p=0.007) and VE/VCO2 slope (26.8+/-5.2 vs 22.6+/-4.3; p=0.01) differed significantly from controls. A linear increase of peak PV gradient with increasing flow was observed in the pooled dataset (Pearson's R=0.947; p<0.0001) and slopes identical as for control patients were obtained for the oxygen pulse-workload relationship. Right heart morphology and function were preserved in the studied patients. CONCLUSIONS: Patients with mild to-moderate PV stenosis have decreased exercise capacity. A linear increase in PV gradient with flow suggests a fixed valve area throughout the exercise. Although systolic RV pressure load increases during exercise, good ventricular performance was observed without signs of functional or morphological changes of the right heart. CLINICAL TRIAL NUMBER: NCT01444222. PMID- 24780908 TI - Quantification of mitral regurgitation by echocardiography. PMID- 24780906 TI - Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age related macular degeneration. AB - Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD. PMID- 24780909 TI - Adjusting parameters of aortic valve stenosis severity by body size. AB - BACKGROUND: Adjustment of cardiac dimensions by measures of body size appears intuitively convincing and in patients with aortic stenosis, aortic valve area (AVA) is commonly adjusted by body surface area (BSA). However, there is little evidence to support such an approach. OBJECTIVE: To identify the adequate measure of body size for the adjustment of aortic stenosis severity. METHODS: Parameters of aortic stenosis severity (jet velocity, mean pressure gradient (MPG) and AVA) and measures of body size (height, weight, BSA and body mass index (BMI)) were analysed in 2843 consecutive patients with aortic stenosis (jet velocity >=2.5 m/s) and related to outcomes in a second cohort of 1525 patients from the Simvastatin/Ezetimibe in Aortic Stenosis (SEAS) study. RESULTS: Whereas jet velocity and MPG were independent of body size, AVA was significantly correlated with height, weight, BSA and BMI (Pearson correlation coefficient (r) 0.319, 0.281, 0.317 and 0.126, respectively, all p<0.001) to the effect that larger patients presented with larger AVA (less severe stenosis). Of the anthropometric measures used for linear adjustment, BSA was most effective in eliminating the correlation between AVA and body size (r=0.007), rivalled only by allometric (non linear) models, findings that are confirmed in 1525 prospectively followed patients from the SEAS study. Predictive accuracy for aortic valve events and cardiovascular death during 46 months of follow-up was unchanged by adjusting AVA, regardless of measure of body size (area under the receiver operating curve for AVA 0.72 (CI 0.58 to 0.87) versus, for example, AVA/BSA 0.75 (CI 0.61 to 0.88), p=0.22). CONCLUSIONS: In the assessment of aortic stenosis, linear adjustment of AVA by BSA improves comparability between patients with diverging body size without, however, increasing the predictive accuracy for clinical events in a population with mild to moderate stenosis. PMID- 24780910 TI - RV stroke work in children with pulmonary arterial hypertension: estimation based on invasive haemodynamic assessment and correlation with outcomes. AB - BACKGROUND: RV performance is an important determinant of outcomes in children with pulmonary arterial hypertension (PAH). RV stroke work (RVSW), the product of mean pulmonary artery pressure and stroke volume, integrates contractility, afterload and ventricular-vascular coupling. RVSW has not been evaluated in children with PAH. We tested the hypothesis that RVSW would be a predictor of outcomes in children with PAH. METHODS: Patients in the Children's Hospital Colorado PAH database were evaluated retrospectively, and those with idiopathic PAH and those with minor or repaired congenital heart disease were included. Haemodynamic data were obtained by catheterisation and echocardiography, performed within 3 months. RVSW was calculated: mean pulmonary arterial pressure * stroke volume, and indexed to body surface area. Statistics included Kruskal Wallis, Wilcoxon rank sum, and Spearman correlation. RESULTS: Fifty patients were included. Median age of the cohort was 9.5 (6.0, 15.7) years, with a median indexed pulmonary vascular resistance (PVRi) of 6.5 (3.7, 11.6) WU m(2). RVSW had a significant association with PVRi (r=0.6, p<0.0001), tricuspid annular systolic plane excursion (r=0.55, p=0.0001), and RV fractional area change (r=-0.4, p=0.005). Grouped by WHO class, there was a significant difference in RVSW (p=0.04). Need for atrial septostomy and death were associated with higher RVSW (p=0.04 and p=0.03, respectively). CONCLUSIONS: RVSW can be estimated in children with PAH, and is significantly associated with abnormal WHO class, the need for septostomy, as well as mortality. Indices accounting for RV performance as well as ventricular-vascular coupling may be useful in the prognosis and, hence, management of children with PAH. PMID- 24780911 TI - The Manchester Acute Coronary Syndromes (MACS) decision rule for suspected cardiac chest pain: derivation and external validation. AB - OBJECTIVE: We aimed to derive and validate a clinical decision rule (CDR) for suspected cardiac chest pain in the emergency department (ED). Incorporating information available at the time of first presentation, this CDR would effectively risk-stratify patients and immediately identify: (A) patients for whom hospitalisation may be safely avoided; and (B) high-risk patients, facilitating judicious use of resources. METHODS: In two sequential prospective observational cohort studies at heterogeneous centres, we included ED patients with suspected cardiac chest pain. We recorded clinical features and drew blood on arrival. The primary outcome was major adverse cardiac events (MACE) (death, prevalent or incident acute myocardial infarction, coronary revascularisation or new coronary stenosis >50%) within 30 days. The CDR was derived by logistic regression, considering reliable (kappa>0.6) univariate predictors (p<0.05) for inclusion. RESULTS: In the derivation study (n=698) we derived a CDR including eight variables (high sensitivity troponin T; heart-type fatty acid binding protein; ECG ischaemia; diaphoresis observed; vomiting; pain radiation to right arm/shoulder; worsening angina; hypotension), which had a C-statistic of 0.95 (95% CI 0.93 to 0.97) implying near perfect diagnostic performance. On external validation (n=463) the CDR identified 27.0% of patients as 'very low risk' and potentially suitable for discharge from the ED. 0.0% of these patients had prevalent acute myocardial infarction and 1.6% developed MACE (n=2; both coronary stenoses without revascularisation). 9.9% of patients were classified as 'high risk', 95.7% of whom developed MACE. CONCLUSIONS: The Manchester Acute Coronary Syndromes (MACS) rule has the potential to safely reduce unnecessary hospital admissions and facilitate judicious use of high dependency resources. PMID- 24780912 TI - A proteomic approach to investigate AuNPs effects in Balb/3T3 cells. AB - Although gold nanoparticles (AuNPs) are currently used in several industrial products and biomedical applications, information about their biological effects is very limited. Thus, it is becoming crucial to assess their safety and adequately investigate the complexity of cell-nanoparticles interactions. In this work, the Balb/3T3 mouse fibroblast cell line was selected as an in vitro model to study the effects of AuNPs. Alteration of cellular processes and biochemical pathways caused by AuNPs exposure was investigated by analysing the differentially expressed proteome. Of interest was the difference observed in the protein pattern expression of cells exposed to AuNPs. It was found that 88 and 83 proteins were de-regulated after exposure to 5 and 15nm AuNPs, respectively. Analysis of the proteome revealed that AuNPs triggers several pathways related to cellular growth and proliferation, cell morphology, cell cycle regulation, cellular function and maintenance, oxidative stress, and inflammatory response. Moreover, SPR analysis showed an increase of ECM proteins biosynthesis in cells exposed to AuNPs. We observed by TEM analysis that NPs are internalized and confined mainly in autophagosomes. Endoplasmic reticulum stressed and modification at mitochondrial level occurred. This study aims to improve existing knowledge necessary for a correct assessment of the balance between AuNPs potential adverse and beneficial effects and might have important implications for biomedical applications (e.g. nanomedicine). To conclude proteomics link to system biology analysis is a valuable tool to understand and predict nanoparticles' toxicity, furthermore it has the potential to reveal pathways that may not be immediately evident with classical toxicological assays. PMID- 24780913 TI - Expression alterations of genes on both neuronal and glial development in rats after developmental exposure to 6-propyl-2-thiouracil. AB - The present study was performed to determine target gene profiles associated with pathological mechanisms of developmental neurotoxicity. For this purpose, we selected a rat developmental hypothyroidism model because thyroid hormones play an essential role in both neuronal and glial development. Region-specific global gene expression analysis was performed at postnatal day (PND) 21 on four brain regions representing different structures and functions, i.e., the cerebral cortex, corpus callosum, dentate gyrus and cerebellar vermis of rats exposed to 6 propyl-2-thiouracil in the drinking water at 3 and 10ppm from gestational day 6 to PND 21. Expression changes of gene clusters of neuron differentiation and development, cell migration, synaptic function, and axonogenesis were detected in all four regions. Characteristically, gene expression profiles suggestive of affection of ephrin signaling and glutamate transmission were obtained in multiple brain regions. Gene clusters suggestive of suppression of myelination and glial development were specifically detected in the corpus callosum and cerebral cortex. Immunohistochemically, immature astrocytes immunoreactive for vimentin and glial fibrillary acidic protein were increased, and oligodendrocytes immunoreactive for oligodendrocyte lineage transcription factor 2 were decreased in the corpus callosum. Immunoreactive intensity of myelin basic protein was also decreased in the corpus callosum and cerebral cortex. The hippocampal dentate gyrus showed downregulation of Ptgs2, which is related to synaptic activity and neurogenesis, as well as a decrease of cyclooxygenase-2-immunoreactive granule cells, suggesting an impaired synaptic function related to neurogenesis. These results suggest that multifocal brain region-specific microarray analysis can determine the affection of neuronal or glial development. PMID- 24780914 TI - The free energy of nanopores in tense membranes. AB - Membrane nanopores are central players for a range of important cellular membrane remodeling processes as well as membrane rupture. Understanding pore formation in tense membranes requires comprehension of the molecular mechanism of pore formation and the associated free energy change as a function of the membrane tension. Here we propose a scheme to calculate the free energy change associated with the formation of a nanometer sized pore in molecular dynamics simulations as a function of membrane tension, which requires the calculation of only one computationally expensive potential of mean force. We show that membrane elastic theory can be used to estimate the pore formation free energy at different tension values from the free energy change in a relaxed membrane and the area expansion curves of the membranes. We have computed the pore formation free energy for a dipalmitoyl-phosphatidylcholine (DPPC) membrane at two different lateral pressure values, 1 bar and -40 bar, by calculating the potential of mean force acting on the head group of a single lipid molecule. Unrestrained simulations of the closing process confirm that the intermediate states along this reaction coordinate are reasonable and show that hydrophilic indentations spanning half the bilayer connected by a hydrophobic pore segment represent the corresponding high energy transition state. A comparison of the stability of simulated membranes to experiment at high loading rates show that, contrary to expectation, pores form too easily in small simulated membrane patches. This discrepancy originates from a combination of the absence of ions in the simulations and the small membrane size. PMID- 24780915 TI - Possible role of non-muscle alpha-actinins in muscle cell mechanosensitivity. AB - The main hypothesis suggested that changes in the external mechanical load would lead to different deformations of the submembranous cytoskeleton and, as a result, dissociation of different proteins from its structure (induced by increased/decreased mechanical stress). The study subjects were fibers of the soleus muscle and cardiomyocytes of Wistar rats. Changes in external mechanical conditions were reconstructed by means of antiorthostatic suspension of the animals by their tails for 6, 12, 18, 24 and 72 hours. Transversal stiffness was measured by atomic force microscopy imaging; beta-, gamma-actin, alpha-actinin 1 and alpha-actinin 4 levels in membranous and cytoplasmic fractions were quantified by Western blot analysis; expression rates of the corresponding genes were studied using RT-PCR. RESULTS: In 6 hours, alpha-actinin 1 and alpha-actinin 4 levels decreased in the membranous fraction of proteins of cardiomyocytes and soleus muscle fibers, respectively, but increased in the cytoplasmic fraction of the abovementioned cells. After 6-12 hours of suspension, the expression rates of beta-, gamma-actin, alpha-actinin 1 and alpha-actinin 4 were elevated in the soleus muscle fibers, but the alpha-actinin 1 expression rate returned to the reference level in 72 hours. After 18-24 hours, the expression rates of beta actin and alpha-actinin 4 increased in cardiomyocytes, while the alpha-actinin 1 expression rate decreased in soleus muscle fibers. After 12 hours, the beta- and gamma-actin content dropped in the membranous fraction and increased in the cytoplasmic protein fractions from both cardiomyocytes and soleus muscle fibers. The stiffness of both cell types decreased after the same period of time. Further, during the unloading period the concentration of nonmuscle actin and different isoforms of alpha-actinins increased in the membranous fraction from cardiomyocytes. At the same time, the concentration of the abovementioned proteins decreased in the soleus muscle fibers. PMID- 24780917 TI - High prevalence of Candida dubliniensis in lower respiratory tract secretions from cystic fibrosis patients may be related to increased adherence properties. AB - OBJECTIVES: We identified Candida spp isolated from lower respiratory tract secretions obtained from cystic fibrosis (CF) patients, by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), with the aim of determining the most prevalent causative agent. We also sought to determine their adhesive properties in order to understand their biology related to CF. METHODS: Twenty-five clinical samples were collected from a cohort of 20 CF patients. Twenty-six isolates of Candida spp were isolated and identified by MALDI-TOF MS method. Adherence assays were performed using the Fluxion BioFlux 200, a flow apparatus that allows for the visualization of adhering cells. RESULTS: MALDI-TOF MS analysis revealed C. dubliniensis to be the most prevalent species (n=18, 69%), followed by C. albicans (n=4), C. tropicalis (n=3), and C. glabrata (n=1). C. dubliniensis showed the strongest adherence under constant flow when compared to the other species of Candida. In the majority of cases, C. dubliniensis was isolated in combination with Pseudomonas aeruginosa and Staphylococcus aureus. C. dubliniensis appears to be able to survive in the CF lung and coexist with bacteria. CONCLUSIONS: The data presented here show that the presence of C. dubliniensis in the lower airways of CF patients may be related to increased adherence properties. PMID- 24780918 TI - Estimation of secondary measles transmission from a healthcare worker in a hospital setting. AB - Measles among healthcare workers (HCWs) is associated with a significant risk of nosocomial transmission to susceptible patients. When a measles case occurs in the healthcare setting, most guidelines recommend exhaustive measures. To evaluate the effects of measures against measles transmission in the healthcare setting precisely, it is essential to determine whether secondary transmission generally occurs. This study describes, for the first time, the actual secondary transmission rate for a measles-infected HCW in a ward with no special air ventilation capacity. The routine treatment of a number of immunocompromised patients occurs in this ward, and thus patients as well as HCWs have a thorough understanding and practice of standard and extended precautions. Our paired serum sample study revealed that none of the people in the ward exposed to the HCW at the catarrhal stage over a period of 4 days exhibited elevated levels of antibodies against measles. We suggest that strict adherence to standard and expanded precautions among patients and HCWs may be effective for preventing the transmission of a highly airborne disease, such as measles. PMID- 24780919 TI - Antioxidants: potential antiviral agents for Japanese encephalitis virus infection. AB - Japanese encephalitis (JE) is prevalent throughout eastern and southern Asia and the Pacific Rim. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. Despite the importance of JE, little is known about its pathogenesis. The role of oxidative stress in the pathogenesis of viral infections has led to increased interest in its role in JEV infections. This review focuses mainly on the role of oxidative stress in the pathogenesis of JEV infection and the antiviral effect of antioxidant agents in inhibiting JEV production. First, this review summarizes the pathogenesis of JE. The pathological changes include neuronal death, astrocyte activation, and microglial proliferation. Second, the relationship between oxidative stress and JEV infection is explored. JEV infection induces the generation of oxidants and exhausts the supply of antioxidants, which activates specific signaling pathways. Finally, the therapeutic efficacy of a variety of antioxidants as antiviral agents, including minocycline, arctigenin, fenofibrate, and curcumin, was studied. In conclusion, antioxidants are likely to be developed into antiviral agents for the treatment of JE. PMID- 24780920 TI - Grand-paternal age and the development of autism-like symptoms in mice progeny. AB - Advanced paternal age (APA) contributes to the risk of autism spectrum disorders (ASDs) in children. In this study, we used a mouse model to investigate the effects of APA on behavioral features related to autistic syndromes (that is, social deficits, communication impairments and stereotypic/repetitive behaviors). We also examined whether such effects are transmitted across generations. To do this, males aged 15 months (APA) and 4 months (control) were bred with 4-month old females, and the resulting offspring (F1) and their progeny (F2; conceived by 4-month-old parents) were tested for the presence and severity of ASD-like behaviors. Our results indicate that APA resulted in offspring that displayed distinctive symptoms of ASD. We found that both F1 conceived from old fathers and F2 derived from old grandfathers displayed increased ultrasound vocalization (USV) activity, decreased sociability, increased grooming activity and increased anxiety-like responses. Moreover, such abnormalities were partially transmitted to the second generation of mice, having APA grandfathers. In conclusion, our study suggests that the risk of ASD could develop over generations, consistent with heritable mutations and/or epigenetic alterations associated with APA. PMID- 24780922 TI - Management of chronic venous disorders of the lower limbs - guidelines according to scientific evidence. PMID- 24780921 TI - Pavlovian conditioning and cross-sensitization studies raise challenges to the hypothesis that overeating is an addictive behavior. AB - Elevated glucocorticoid levels and sign tracking (ST) in Pavlovian conditioning are potential biomarkers of compulsive behaviors such as addiction. As overeating is sometimes viewed as a form of addictive behavior, we hypothesized that murine Pavlovian sign trackers would have a greater propensity to overeat and develop obesity. Using a food reward in the classical conditioning paradigm, we show that ST behavior is a robust conditioned response but not a predictor of eating and growth trajectories in mice, thus challenging the view that the development of obesity and drug addiction depend on identical mechanisms. This interpretation was supported by experiments which showed that overweight mice do not display cross-sensitization to an addictive drug (morphine), and conversely, that overweight morphine-sensitized animals do not overconsume a highly rewarding food. Although the rewarding/motivational effects of both food and drugs of abuse are mediated by similar neurochemical mechanisms, obesity and drug addiction represent a summation of other dysfunctional input and output pathways that lead to the emergence of two distinct disorders, each of which would deserve a specific pharmacotherapeutic approach. PMID- 24780923 TI - Modelling of UPLC behaviour of acylcarnitines by quantitative structure-retention relationships. AB - In the present work, the retention time (RT) of acylcarnitines, collected by ultra-performance liquid-chromatography after formation of butyl esters, is modelled by quantitative structure-retention relationship (QSRR) method. The investigated set consists of free carnitine and 46 different acylcarnitines, including the isomers commonly monitored in screening metabolic disorders. To describe the structure of (butylated) acylcarnitines, a large number of computational molecular descriptors generated by software Dragon are subjected to variable selection methods aimed at identifying a small informative subset. The QSRR model is established using two different approaches: the multi linear regression (MLR) combined with a genetic algorithm (GA) variable selection and the partial least square (PLS) regression after iterative stepwise elimination (ISE) of useless descriptors. Predictive performance of both models is evaluated using an external set consisting of 10 representative acylcarnitines, and, successively, by repeated random data partitions between the calibration and prediction sets. Finally, a principal component analysis (PCA) is performed on the model variables to facilitate the interpretation of the established QSRRs. A PLS model based on seven latent variables extracted from 20 molecular descriptors selected by ISE permits to calculate/predict the retention time of acylcarnitine with accuracy better than 5%, whereas a 6-dimensional model identified by GA-MLR provides a slightly worse performance. PMID- 24780924 TI - Development of a microdialysis system to monitor lamivudine in blood and liver for the pharmacokinetic application in herbal drug interaction and the gene expression in rats. AB - The aim of study is to develop a novel multiple microdialysis technique coupled to a validated chromatographic system for the measurement of protein-unbound form lamivudine and investigation of its herb-drug interaction in rat blood and liver. Furthermore, gene expression changes of drug metabolizing enzymes in rat were evaluated by microarray analysis after being treated with a traditional Chinese herbal formulation, Long-Dan-Xie-Gan-Tang (LDXGT). The analyte was separated by a reverse-phase C18 column using the mobile phase comprising methanol and 10mM KH2PO4 (15:85, v/v, adjusted to pH 6.0 with NaOH) with the flow rate of 0.8mL/min, and the UV wavelength was set at 270nm. The processes of method validation followed Food and Drug Administration (FDA) guidelines. The pharmacokinetic data demonstrated that the area under the concentration-time curve (AUC) of the lamivudine alone and the LDXGT pretreated group were 532+/ 37.6 and 550+/-44.2minMUg/mL in rat blood after lamivudine administration (10mg/kg, i.v.) and 682+/-196 and 642+/-153minMUg/mL in rat liver, respectively. The herb-drug pharmacokinetic interaction showed that with either lamivudine alone or in combination with pretreated with LDXGT, the pharmacokinetic parameters were not significantly changed except the apparent volume of distribution (Vd) at a high dose of lamivudine (30mg/kg). In addition, microarray analysis showed that among 70 altered genes (selection criteria: |Fold change|?2 and p<0.05), only 11 genes were involved in drug metabolism and indicated that a relatively small portion of drug metabolizing genes in liver were altered at the genome level after the therapeutic dose of LDXGT treatment. In conclusion, these studies provide constructive information to interpret the herb-drug interactions between lamivudine and a popular Chinese herbal formulation. PMID- 24780925 TI - Simultaneous determination of oral antidiabetic drugs in human plasma using microextraction by packed sorbent and high-performance liquid chromatography. AB - In this study, a simple method using microextraction by packed sorbent and high performance liquid chromatography with ultraviolet detection for simultaneous determination of chlorpropamide, gliclazide and glimepiride in human plasma was developed and validated. A fractional factorial design and a complete factorial design were applied to evaluate the parameters which could affect the extraction and desorption steps, respectively. All parameters in the extraction step (pH, sample volume, sample dilution and number of aspiration/ejection cycles) and in the desorption step (percentage of acetonitrile in the elution solvent and number of aspirations of elution solvent through the device) were statistically significant (p>0.05) when recovery was used as response. The developed method allowed the use of small volumes of sample and solvents and rapid separation by using a fused core column (only 2.2min were needed). This method was fully validated showing selectivity, precision, accuracy and linearity over the range 1.0-50.0MUgmL(-1) for chlorpropamide, 1.0-10.0MUgmL(-1) for gliclazide and 0.1 1.0MUgmL(-1) for glimepiride. Finally, the validated method was applied in the analysis of samples from volunteers containing the three tested analytes. PMID- 24780926 TI - Quaternization and oxidation reactions of cyclodiphosphazane derivatives and their copper(I) and gold(I) complexes. AB - The reactions of cyclodiphosphazane derivatives cis-{(t)BuN(H)P(MU N(t)Bu)2PN(H)(t)Bu} (1), cis-{MeN(C4H8N)P(MU-N(t)Bu)2P(NC4H8Me)} (2) and {(Me2NCH2CH2O)P(MU-N(t)Bu)2P(OCH2CH2NMe2)} (3) with methyl iodide and methyl triflate and their subsequent reactions with elemental sulfur and selenium are reported. Interestingly, the reactions of 1-3 with an excess of methyl iodide resulted in quaternising only one phosphorus atom in cis-[{(t)BuNHP(MU N(t)Bu)2P(CH3)NH(t)Bu}](I) (4), two exocyclic nitrogen atoms and one of the phosphorus atoms in cis-{(Me2NC4H8N)P(MU-N(t)Bu)2P(CH3)(NC4H8NMe2)}](I)3 (7) and only two exocyclic nitrogen atoms in cis-[{(Me3NCH2CH2O)P(MU N(t)Bu)2P(OCH2CH2NMe3)}](I)2 (8). The reaction of 1 with one equiv. of methyl triflate produced cis-[{(t)BuN(H)P(MU-N(t)Bu)2P(CH3)N(H)(t)Bu}]OTf (5), whereas the same reaction in a 1 : 2 molar ratio afforded cis-{(t)BuN(H)P(CH3)(MU N(t)Bu)2P(CH3)N(H)(t)Bu}(OTf)2 (6). Compounds 4 and 5 showed poor solubility in water, whereas 7 and 8 were high melting crystalline solids with moderate to good water solubility. Treatment of 4 with either elemental sulfur or selenium gave both cis- and trans-chalcogenide derivatives. Similar reactions of 7 and 8 produced both mono- and bischalcogenides. Reactions between 4 or 7 and CuI yielded dinuclear complexes, cis-[{Cu2(MU-I)3((t)BuN(H)P)(MU N(t)Bu)2(P(CH3)N(H)(t)Bu)]2}(I)] (15) and cis-[{Cu2(MU-I)3[(Me2NC4H8N)P(MU N(t)Bu)2P(CH3)(NC4H8NMe2)]2}(I)5] (16), while the reaction of 8 with CuI produced a coordination polymer [{Cu2(MU-I)3(MU-N(t)BuP)2(OCH2CH2NMe3)2}I]infinity (17), containing triiodo-bridged [Cu2(MU-I)3] linkers. The molecular structures of several of these compounds were confirmed by single crystal X-ray diffraction studies. The Cu(I)...Cu(I) distance of 2.55 A in 15 is quite short and is the same as that found in copper metal and also in complexes containing [Cu2(MU-I)3] linkers. All the metal complexes exhibit strong intra-, inter- or both intra- and inter-molecular hydrogen bonding interactions. PMID- 24780927 TI - Spin Hall voltages from a.c. and d.c. spin currents. AB - In spin electronics, the spin degree of freedom is used to transmit and store information. To this end the ability to create pure spin currents--that is, without net charge transfer--is essential. When the magnetization vector in a ferromagnet-normal metal junction is excited, the spin pumping effect leads to the injection of pure spin currents into the normal metal. The polarization of this spin current is time-dependent and contains a very small d.c. component. Here we show that the large a.c. component of the spin currents can be detected efficiently using the inverse spin Hall effect. The observed a.c.-inverse spin Hall voltages are one order of magnitude larger than the conventional d.c. inverse spin Hall voltages measured on the same device. Our results demonstrate that ferromagnet-normal metal junctions are efficient sources of pure spin currents in the gigahertz frequency range. PMID- 24780928 TI - Role of ROS and HMGB1 in contact allergen-induced IL-18 production in human keratinocytes. AB - Keratinocytes have a key role in all phases of allergic contact dermatitis. We have recently identified the possibility to use IL-18 production for the in vitro identification of contact allergens. The purpose of this study was to characterize the molecular mechanisms underlying allergen-induced IL-18 production, in order to identify the cellular source of reactive oxygen species (ROS) and the danger signals involved. The NCTC2544 cell line was exposed to three contact allergens, namely p-phenylenediamine (PPD), 2,4 dinitrochlorobenzene (DNCB), and citral, in the presence or absence of diphenylene iodonium (DPI), allopurinol, and rotenone to identify the source of ROS, and to anti-Toll-like receptor 4 antibody and glycirrizic acid to characterize the danger-associated molecular pattern molecules. In the case of PPD, the induction of IL-18 can be modulated by rotenone, allopurinol, and DPI. In the case of DNCB, rotenone completely prevents the induction of IL-18, whereas for citral, DPI completely prevents the induction of IL-18. We demonstrated the ability of all allergens tested to induce the release of high-mobility group protein B1 (HMGB1). Its sequester by glycirrizic acid significantly modulates PPD induced IL-18 production and completely prevents DNCB- and citral-induced IL-18. We found that different intracellular sources of ROS are triggered by contact allergens, and an important role for HMGB1 in chemical allergen-induced IL-18 production was demonstrated. PMID- 24780929 TI - Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo. AB - Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL. PMID- 24780930 TI - Abnormal epidermal barrier recovery in uninvolved skin supports the notion of an epidermal pathogenesis of psoriasis. PMID- 24780932 TI - Trials of autologous bone marrow stem cells for heart disease. PMID- 24780931 TI - Trichohyalin-like proteins have evolutionarily conserved roles in the morphogenesis of skin appendages. AB - S100 fused-type proteins (SFTPs) such as filaggrin, trichohyalin, and cornulin are differentially expressed in cornifying keratinocytes of the epidermis and various skin appendages. To determine evolutionarily conserved, and thus presumably important, features of SFTPs, we characterized nonmammalian SFTPs and compared their amino acid sequences and expression patterns with those of mammalian SFTPs. We identified an ortholog of cornulin and a previously unknown SFTP, termed scaffoldin, in reptiles and birds, whereas filaggrin was confined to mammals. In contrast to mammalian SFTPs, both cornulin and scaffoldin of the chicken are expressed in the embryonic periderm. However, scaffoldin resembles mammalian trichohyalin with regard to its expression in the filiform papillae of the tongue and in the epithelium underneath the forming tips of the claws. Furthermore, scaffoldin is expressed in the epithelial sheath around growing feathers, reminiscent of trichohyalin expression in the inner root sheath of hair. The results of this study show that SFTP-positive epithelia function as scaffolds for the growth of diverse skin appendages such as claws, nails, hair, and feathers, indicating a common evolutionary origin. PMID- 24780933 TI - Intramolecular folding of triblock copolymers via quadrupole interactions between poly(styrene) and poly(pentafluorostyrene) blocks. AB - beta-Hairpin formation is one of the fundamental folding actions in biomacromolecules. We present a linear triblock copolymer synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, that is able to mimic on a very basic level hairpin formation by using pi-pi stacking interactions between phenyl and 2,3,4,5,6-pentafluorophenyl residues. PMID- 24780934 TI - Adherence to self-monitoring via interactive voice response technology in an eHealth intervention targeting weight gain prevention among Black women: randomized controlled trial. AB - BACKGROUND: eHealth interventions are effective for weight control and have the potential for broad reach. Little is known about the use of interactive voice response (IVR) technology for self-monitoring in weight control interventions, particularly among populations disproportionately affected by obesity. OBJECTIVE: This analysis sought to examine patterns and predictors of IVR self-monitoring adherence and the association between adherence and weight change among low income black women enrolled in a weight gain prevention intervention. METHODS: The Shape Program was a randomized controlled trial comparing a 12-month eHealth behavioral weight gain prevention intervention to usual care among overweight and obese black women in the primary care setting. Intervention participants (n=91) used IVR technology to self-monitor behavior change goals (eg, no sugary drinks, 10,000 steps per day) via weekly IVR calls. Weight data were collected in clinic at baseline, 6, and 12 months. Self-monitoring data was stored in a study database and adherence was operationalized as the percent of weeks with a successful IVR call. RESULTS: Over 12 months, the average IVR completion rate was 71.6% (SD 28.1) and 52% (47/91) had an IVR completion rate >=80%. At 12 months, IVR call completion was significantly correlated with weight loss (r =-.22; P=.04) and participants with an IVR completion rate >=80% had significantly greater weight loss compared to those with an IVR completion rate <80% (-1.97 kg, SE 0.67 vs 0.48 kg, SE 0.69; P=.01). Similar outcomes were found for change in body mass index (BMI; mean difference -0.94 kg, 95% CI -1.64 to -0.24; P=.009). Older, more educated participants were more likely to achieve high IVR call completion. Participants reported positive attitudes toward IVR self-monitoring. CONCLUSIONS: Adherence to IVR self-monitoring was high among socioeconomically disadvantaged black women enrolled in a weight gain prevention intervention. Higher adherence to IVR self-monitoring was also associated with greater weight change. IVR is an effective and useful tool to promote self-monitoring and has the potential for widespread use and long-term sustainability. TRIAL REGISTRATION: Clinicaltrials.gov NCT00938535; http://www.clinicaltrials.gov/ct2/show/NCT00938535. PMID- 24780935 TI - BIR2 affects complex formation of BAK1 with ligand binding receptors in plant defense. AB - BAK1 is a multifunctional leucine-rich repeat receptor kinase (LRR-RLK) that exerts its function by interacting with multiple ligand binding receptors and thereby influences diverse processes varying from brassinosteroid perception via PAMP and DAMP perception to cell death control. We recently identified a new BAK1 interacting protein, BIR2, that is also a LRR-RLK but, in contrast to BAK1, negatively regulates BAK1-dependent PAMP responses. While brassinosteroid responses are not affected by BIR2, cell death is negatively regulated as described for BAK1. BIR2 is released from BAK1 after ligand perception, increasing the pool of free BAK1 that is available to form complexes with activated ligand binding receptors. Individual ligands can only partially release BAK1 from BIR2. After exposition to a cocktail of ligands, almost the complete amount of BAK1 can be released indicating that BAK1 exists, together with BIR2, in subpools that can be individually addressed by specific ligands. These data support the idea that BAK1 exists in preformed complexes with its ligand binding receptor partners. Overexpression of BIR2 results in reduced complex formation of BAK1 with FLS2, showing that BIR2 negatively regulates BAK1 complex formation with ligand binding receptors. PMID- 24780936 TI - Defining young in the context of prostate cancer. AB - The experience of prostate cancer is for most men a major life stress with the psychological burden of this disease falling more heavily on those who are younger. Despite this, being young as it applies to prostate cancer is not yet clearly defined with varied chronological approaches applied. However, men's responses to health crises are closely bound to life course and masculinities from which social roles emerge. This paper applied qualitative methodology (structured focus groups and semistructured interviews with expert informants) using interpretative phenomenological analysis to define what it means to be young and have prostate cancer. Structured focus groups were held with 26 consumer advisors (men diagnosed with prostate cancer who provide support to other men with prostate cancer or raise community awareness) and health professionals. As well, 15 men diagnosed with prostate cancer and in their 40s, 50s, or 60s participated in semi-structured interviews. Participants discussed the attributes that describe a young man with prostate cancer and the experience of being young and diagnosed with prostate cancer. Chronological definitions of a young man were absent or inconsistent. Masculine constructions of what it means to be a young man and life course characteristics appear more relevant to defining young as it applies to prostate cancer compared with chronological age. These findings have implications for better understanding the morbidities associated with this illness, and in designing interventions that are oriented to life course and helping young men reconstruct their identities after prostate cancer. PMID- 24780937 TI - Disparities in preventive health behaviors among non-Hispanic White men: heterogeneity among foreign-born Arab and European Americans. AB - The objectives of this study were to estimate and compare the age-adjusted prevalence of not receiving a flu vaccine, pneumonia vaccine, or prostate cancer screening among U.S.- and foreign-born White men by region of birth (Europe/Russia and the Arab Nations) and examine these associations while controlling for potential confounders. Twelve years of restricted data from the National Health Interview Survey (NHIS) including 91,636 U.S.- and foreign-born men were used. Chi-squares were used to compare descriptive statistics, and odds ratios (ORs; 95% confidence intervals [CIs]) were used for inferential statistics. In crude and adjusted analyses, foreign-born Arab American men were less likely to report receiving a flu (OR = 0.38; 95% CI = 0.21, 0.67) and pneumonia (OR = 0.33; 95% CI = 0.16, 0.70) vaccine compared with U.S.-born White men. There were no statistically significant differences for PSA testing between Arab American and White men. This national study examining uptake of flu and pneumonia vaccines suggests estimates are lower for foreign-born Arab American men compared with U.S.-born White men. Future studies should collect qualitative data that assesses the cultural context surrounding prevention and screening behaviors among Arab Americans. PMID- 24780938 TI - Use of topical liposomes containing meglumine antimoniate (Glucantime) for the treatment of L. major lesion in BALB/c mice. AB - Treatment of cutaneous leishmaniasis (CL) is a dream for the patients, health care authorities and scientists. The aim of this study was to develop a topical liposomal meglumine antimoniate (MA, GlucantimeTM) (Lip-MA) formulation and evaluate the therapeutic effects of the preparation on lesion induced by Leishmania major in BALB/c mice. Liposomes containing 22.5% MA (6.4% Sb(+5)) with and without oleic acid (LMA-OA and LMA) were formulated using fusion method plus homogenization and characterized for the size and encapsulation efficiency. The penetration of MA from the LMA-OA and LMA formulations through and into the skin was checked in vitro using Franz diffusion cells fitted with mouse skin at 37 degrees C for 8h. The in vitro permeation data showed that almost 1.5% of formulations applied in the mouse skin were penetrated and the amount retained in the skin was about 65%. The 50% effective dose of LMA and LMA-OA against amastigotes of L. major was 46.36 and 41.01 MUg/ml, respectively. LMA or LMA-OA was used topically twice a day for 4 weeks to treat the lesion induced by L. major in susceptible BALB/c mice. The results showed a significantly (P<0.001) smaller lesion size in the treated groups of mice compared to the control groups which received either empty liposomes or phosphate-buffered saline (PBS). The spleen parasite burden was significantly (P<0.001) lower in the treated groups compared to the control groups receiving either empty liposomes or PBS at the end of the treatment period. However, when the treatment was stopped, the lesion size progressed and spleen parasite burden increased in LMA and LMA-OA groups, but still was significantly less than the control groups (P<0.05). There was no significant difference between the two formulations of LMA and LMA-OA. The results suggested that topical liposomes containing MA might be an appropriate choice for clinical trials for the treatment of CL. PMID- 24780939 TI - Avoid loss of time. PMID- 24780940 TI - In reply: avoid loss of time. PMID- 24780941 TI - Saddle-splay screening and chiral symmetry breaking in toroidal nematics. AB - We present a theoretical study of director fields in toroidal geometries with degenerate planar boundary conditions. We find spontaneous chirality: despite the achiral nature of nematics the director configuration shows a handedness if the toroid is thick enough. In the chiral state the director field displays a double twist, whereas in the achiral state there is only bend deformation. The critical thickness increases as the difference between the twist and saddle-splay moduli grows. A positive saddle-splay modulus prefers alignment along the meridian of the bounding torus, and hence promotes a chiral configuration. The chiral-achiral transition mimics the order-disorder transition of the mean-field Ising model. The role of the magnetisation in the Ising model is played by the degree of twist. The role of the temperature is played by the aspect ratio of the torus. Remarkably, an external field does not break the chiral symmetry explicitly, but shifts the transition. In the case of toroidal cholesterics, we do find a preference for one chirality over the other - the molecular chirality acts as a field in the Ising analogy. PMID- 24780942 TI - Trends in healthcare and the role of the anesthesiologist in the perioperative surgical home - the US perspective. AB - PURPOSE OF REVIEW: Although advances in science are important, changes in population structure and developments in health policy have equally critical roles in shaping the future of anesthesia practice. Therefore, it is important for anesthesiologists to be aware of these trends and their implications. RECENT FINDINGS: As in other industrialized nations, population aging implies that patients presenting for elective surgery in future decades will be older and sicker. Nevertheless, in part for economic reasons, the fraction of surgeries performed in the ambulatory environment will continue to increase. Furthermore, the gradual elimination of fee-for-service care in favor of bundled payments will place additional risk on providers to prevent costly complications. In the USA, the American Society of Anesthesiologists has offered the 'surgical home' as a new model for perioperative care delivery in which the anesthesiologist serves as the coordinator of care from the preoperative through the postoperative phase. The purpose is not only to increase patient-centeredness but also to find opportunities for cost savings and increased efficiencies. SUMMARY: Global demographic and health policy trends are calling for new models of healthcare delivery. Anesthesiologists have much experience in the fields of risk assessment and quality improvement. They are well positioned to become leaders in the perioperative care environment of the future. PMID- 24780943 TI - The argument against reimbursing physicians for value. PMID- 24780944 TI - Can dietary integrators provide a clinical benefit in the treatment of functional dyspepsia? results from a prospective study with TUBES Gastro. AB - AIM: Given the limited efficacy of conventional medical therapy for functional dyspepsia, patients frequently seek alternative medical approaches. The use of suc h alternative therapies has dramatically increased during the last decades. The scope of this prospective study was to provide evidence of the clinical benefit of the treatment of functional dyspepsia with a dietary integrator composed by sodium alginate, sodium bicarbonate, bromelin and essential oils. METHODS: This study enrolled a total of 100 patients affected by functional dyspepsia diagnosed primarily on the basis of typical symptoms and the exclusion of non-functional gastrointestinal diseases (negative upper gastrointestinaltract endoscopy and negative for H. pylori infections, including acid-related diseases), non-gastrointestinal diseases, and psychiatric illness. All patients enrolled were categorized in two symptom-predominant subgroups: dysmotility-like dyspepsia (N.=60) and reflux-like dyspepsia (N.=40). Patients were treated with TUBES Gastro (0.80 g oral tablets bid after main meals) for 4 weeks, on top of their current treatment with proton pump inhibitors or not. Efficacy was measured by a Numerical Rating Scale (NRS) at baseline and after 14 and 28 days of treatment with TUBES Gastro while safety and tolerability were evaluated based on the adverse event reporting from the patients. RESULTS: Sixty patients were diagnosed with dysmotility-like dyspepsia and were enrolled into the study; the majority was females (68%) with a mean age of 48.5 years (19-81). The mean baseline NRS score was 5.7 (4-8). A high statistically significant reduction of the NRS score was observed at 14 and 28 days: -1.5 (-26.3%) and -3.4 (-59.6%), respectively (P<0.0001). Forty patients were diagnosed with reflux-like dyspepsia and were enrolled into the study; the majority was males (70%) with a mean age of 49.1 years (24-80). The mean baseline NRS score was 6.8 (5-9). A high statistically significant reduction of the NRS score was observed at 14 and 28 days: -2.8 (-41.2%) and -4.8 (70.6%), respectively (P<0.0001). No side effects were collected during the study duration. CONCLUSION: The data obtained from this four-week study indicate that TUBES Gastro treatment was effective and well tolerated in reducing the symptomatology of patients affected by functional dysmotility-like and reflux-like dyspepsia. PMID- 24780945 TI - Liver transplantation of hepatitis B surface antigen positive donors to hepatitis B core antibody recipients: analysis of 27 patients. AB - AIM: Shortage of donor livers is the major limiting factor for liver transplantation (LT). While livers from patients with past infection of Hepatitis B (HBcAb+) are commonly used as donors, scant data exists on outcomes following transplantation of HBsAg+ donor livers. The impact of donor HBsAg positivity on recipient survival is currently analyzed. METHODS: Post hoc analysis of all adults undergoing LT from October 1987-September 2010 registered in United Network for Organ Sharing/Organ Procurement and Transplantation Network, a concurrent, limited access database of all American LT recipients. Only recipients who were HBcAb+ were analyzed. LTs with missing donor or recipient serologic parameters for Hepatitis-B were excluded. Significant predictors of survival were determined by univariate analysis. Cox proportional hazards model was used to determine independent risk predictors in the multivariate analysis. RESULTS: The population consisted of 13,329 LT recipients. The mean age of donors and recipients were 40+/-16 years and 52+/-9 years respectively. The mean follow up was 3.7 years. Study population included 27 recipients transplanted with HBsAg+ grafts, of whom 7 (28%) died. Outcomes were adjusted for donor age, recipient age, donor gender, recipient gender, type of LT, MELD score, HCV status, previous LT, and cold ischemic time. On multivariate analysis, LT recipient outcomes were not significantly different for HBsAg+ donors versus donors without prior hepatitis B infection (HR: 1.14, 95% CI: 0.93-1.39, P=0.17). Kaplan-Meier curves revealed no significant survival difference between the two groups. CONCLUSION: These results suggest that donor HBsAg positivity did not affect overall survival of LT recipients. These findings could potentially expand the pool of liver donors. PMID- 24780946 TI - Hypolipidic diet and phytosubstance supplement in hypercholesterolemia. AB - AIM: This study aimed to evaluate the effects of phyto-supplements on hyperlipidemia. METHODS: For this study 191 patients, affected by hyperlipidemia, attending the Outpatient Clinics of Clinical Medicine Department, were recruited. The patients were divided in two groups. The first group (80) has been treated with hypolipidic diet for six months (group D). The second one (111) has been administered with hypolipidic diet and supplement (red yeast, guggulsterones, flavonoid, sylimarin) (group E). Anthropometric measurements and bioimpedance analysis were evaluated before and after treatment. Moreover, total cholesterol, LDL, HDL, triglycerides (TG) and hepatic transaminases (AST, ALT) were measured before, after 3 and 6 months of treatment. RESULTS: D group showed a significant reduction in BMI (32.6 +/- 0.7 vs. 34.3 +/- 0.7 kg/m2), waist circumference (104.4 +/- 1.6 vs. 108.3 +/- 1.5 cm), hip circumference (107.9 +/- 1.1 vs. 111.2 +/- 1.1 cm), total cholesterol (214.2 +/- 3.7 vs. 236.6 +/- 2.2 mg/dL, -9.4 +/- 68.2%), LDL cholesterol (133 +/- 3 vs. 152.9 +/- 2.8 mg/dL, -13 +/- 7.1%). E group showed a significant reduction in BMI (30.2 +/- 0.7 vs. 32.6 +/- 0.6 kg/m2), waist circumference (94.5 +/- 1.6 vs. 101.3 +/- 1.3 cm), hip circumference (106.6 +/- 1.1 vs. 110.5 +/- 1 cm), total cholesterol (212.4 +/- 3.7 vs. 256.9 +/- 2.1 mg/dL, -17.3 +/- 76.2%), LDL cholesterol (133.4 +/- 3.4 vs. 168.4 +/- 2.3 mg/dL, -20.8 +/- 47.8%). CONCLUSION: Low fat diet, associated to phyto-substance supplement, have been proven useful to decrease serum cholesterol level and to improve nutritional status. PMID- 24780947 TI - Peroral cholangioscopy facilitates targeted tissue acquisition in patients with suspected cholangiocarcinoma. AB - AIM: Biliary strictures that are suspicious for cholangiocarcinoma (CCA) are commonly encountered in clinical practice in patients with and without primary sclerosing cholangitis (PSC). A definitive histologic diagnosis of CCA via endoscopic retrograde cholangiography (ERCP) is often not obtainable with standard biliary brush cytology. Peroral cholangioscopy is an additional tool to help provide a diagnosis of CCA in patients with suspicious biliary strictures. Aim of the study was to assess the use of peroral cholangioscopy in patients with and without PSC and indeterminate biliary strictures. METHODS: Retrospective study. RESULTS: 25 patients were included in the study. All patients underwent ERCP with peroral cholangioscopy. Tissue samples obtained included routine cytology, fluorescent in-situ hybridization, and cholangioscopic-directed forceps biopsies. The operating characteristics of cholangioscopy to detect malignancy in 18 PSC patients with suspected cholangiocarcinoma were a sensitivity of 75%, specificity of 55%, and a positive predictive value (PPV) of 23%, and a negative predictive value of 92%. In 7 non-PSC patients with suspected cholangiocarcinoma these values sensitivity=100%, 25%, 50%, and NPV=100%, respectively. The overall operating characteristics of cholangioscopy to detect malignancy in all 25 patients with suspected cholangiocarcinoma were: sensitivity of 86%, specificity of 50%, PPV of 32%, and NPV of 93%. CONCLUSION: Cholangioscopy helps identify sites for tissue acquisition in PSC and non-PSC patients with biliary strictures suspicious for malignancy. PMID- 24780948 TI - Technical tips and issues of biliary stenting, focusing on malignant hilar obstruction. AB - In patients with inoperable hilar cholangiocarcinoma (HCCA), palliative endoscopic or percutaneous drainage provides benefits in terms of symptomatic improvement and quality of life. Endoscopic biliary stent placement is considered the gold standard, with metal stents preferred over plastic stents in patients with more than three months of life expectancy. However, the endoscopic management of advanced hilar obstruction is often more challenging and complex than distal malignant biliary obstructions. Recently, the Asia-Pacific working group on hepatobiliary cancers produced consensus recommendations on the use of endoscopic vs. percutaneous drainage and unilateral vs. bilateral drainage in the management of HCCA. However, these guidelines must be weighed against context specific information, such as the volume of liver drainage required, life expectancy of the patient, and the available expertise. In this literature review, we describe the issues commonly encountered during endoscopic biliary stenting for malignant hilar obstruction and provide technical guidance to improve success rates and patient outcomes. PMID- 24780949 TI - Irritable bowel syndrome: new findings in pathophysiological and therapeutic field. AB - Irritable bowel syndrome (IBS) is a high prevalence disease, whose symptoms are reported by a large number of young adults with significant effects on quality of life and social costs. Traditionally, IBS has been treated with dietary and lifestyle modification, fiber supplementation, psychological and pharmacological therapy. Since its complex and multifactorial etiopathogenesis is only partially known, therapeutic choices may be difficult and not always effective. New research efforts focused on the role of relationship between central nervous system and gut disorders (brain-gut axis), altered composition of gut microbiota (e.g. an eight times increased risk for IBS after Salmonella infection), immune activation with an increased number of T lymphocytes and mast cells associated with mucosa as well as an increased level of pro-inflammatory cytokines (IL-10 and IL-12, suggesting Th1 polarization), visceral hypersensitivity causing perception of pain even for minimal abdominal distension. Based on these findings, new possibilities of treatment are emerging with encouraging outcomes. Attention is directed to drugs that showed good tolerability profile and poor systemic absorption, which may make them suitable for repeated or long term treatments, as frequently required in patients with IBS. They have been successfully used drugs such as tachykinin receptors antagonists, tryptophan hydroxylase inhibitors, bile acid sequestrants, u agonist and delta antagonist opioid receptors. Recent studies are discussed in this review, focusing both on new therapeutic approaches and innovative adaptation of previously available treatments. PMID- 24780951 TI - [Malignant lymphomas in children and adolescents. Practical knowledge for diagnosis]. AB - Malignant lymphomas are very rare in childhood. Therefore in Germany and Europe wide the diagnosis and treatment of these diseases and research into them are carried out in multicenter-study groups and registries that provide central clinical consulting as well as histopathological, genetic, and molecular diagnoses. Despite these central structures, the diagnosis of these aggressive lymphomas is usually made initially outside these specialized centers. Therefore, in clinical situations that are often quite critical, every pathologist may be required to make the initial diagnosis and decide on the initial therapy regimen. Specific features related to the incidence, biology, and clinical presentation of pediatric lymphomas strongly influence the diagnostic workup and require a different diagnostic procedure from that employed in adults. In this paper, we will try to provide the most important information required for a tissue-saving initial diagnosis of the most common pediatric lymphomas. The proposed procedures allow reliable differentiation into the main lymphoma categories and, thus, provide the necessary information for the first therapeutic regimens, although the final subtyping will remain the responsibility of specialists. The most relevant histopathological features, appropriate immunohistochemical stains, and diagnostic pitfalls are demonstrated. As examples of the most common entities, special attention is paid to Burkitt lymphoma, diffuse large B-cell lymphoma, precursor T- and B-cell lymphoma, and anaplastic large-cell lymphoma. PMID- 24780953 TI - Mixed pial-dural fistula development after ventricular shunting. PMID- 24780952 TI - A gacS deletion in Pseudomonas aeruginosa cystic fibrosis isolate CHA shapes its virulence. AB - Pseudomonas aeruginosa, a human opportunistic pathogen, is capable of provoking acute and chronic infections that are associated with defined sets of virulence factors. During chronic infections, the bacterium accumulates mutations that silence some and activate other genes. Here we show that the cystic fibrosis isolate CHA exhibits a unique virulence phenotype featuring a mucoid morphology, an active Type III Secretion System (T3SS, hallmark of acute infections), and no Type VI Secretion System (H1-T6SS). This virulence profile is due to a 426 bp deletion in the 3' end of the gacS gene encoding an essential regulatory protein. The absence of GacS disturbs the Gac/Rsm pathway leading to depletion of the small regulatory RNAs RsmY/RsmZ and, in consequence, to expression of T3SS, while switching off the expression of H1-T6SS and Pel polysaccharides. The CHA isolate also exhibits full ability to swim and twitch, due to active flagellum and Type IVa pili. Thus, unlike the classical scheme of balance between virulence factors, clinical strains may adapt to a local niche by expressing both alginate exopolysaccharide, a hallmark of membrane stress that protects from antibiotic action, host defences and phagocytosis, and efficient T3S machinery that is considered as an aggressive virulence factor. PMID- 24780954 TI - Stroke associated with giant cell arteritis: a population-based study. AB - BACKGROUND: Giant cell arteritis (GCA) is the most common vasculitis in people >=50 years and can be associated with stroke. We aimed to evaluate the epidemiology and characteristics of stroke in patients with GCA. METHODS: All patients with a biopsy-proven diagnosis of GCA were identified among residents of the city of Dijon, France (152 000 inhabitants), between 2001 and 2012 using a prospective database. Among these, patients who suffered from stroke were retrieved by crossing data from the population-based Dijon Stroke Registry. Demographics and clinical features were recorded. We considered that the stroke was GCA-related if the stroke revealed GCA or occurred between the onset of symptoms and 4 weeks after the start of treatment. RESULTS: Among the 57 biopsy proven patients with GCA (incidence rate 10.9/100 000/year in individuals >=50 years), 4 (7.0%) experienced a GCA-related stroke. Three were men and all had >=2 vascular risk factors and were >=80 years. The stroke was vertebrobasilar for 3/4 patients and undetermined for the remaining one. The incidence rate of GCA related stroke in patients >=50 years was 0.76/100 000/year (95% CI 0 to 2.47), 1.36/100 000/year in men (95% CI 0 to 3.63) and 0.33/100 000/year (95% CI 0 to 1.45) in women. CONCLUSIONS: This population-based study demonstrated that GCA related stroke essentially affects the vertebrobasilar territory and mainly occurs in old men with associated vascular risk factors. Although rare, GCA symptoms must be searched for in elderly patients with stroke, and optimal vascular prevention must be conducted carefully in patients with GCA with a high vascular risk before initiating GCA treatment. PMID- 24780955 TI - Immediate effect of spinal magnetic stimulation on camptocormia in Parkinson's disease. AB - OBJECTIVES: Spinal cord stimulation is a potential therapeutic option for the treatment of Parkinson's disease (PD)-associated symptoms. Repetitive trans spinal magnetic stimulation (rTSMS) is a non-invasive and safe alternative for stimulation of spinal pathways that has not been studied for therapeutic efficacy in PD. We assessed the benefits of rTSMS on camptocormia, an often treatment resistant postural abnormality observed in PD patients. METHODS: We compared rTSMS to sham stimulation in PD patients with camptocormia in a single-centre, randomised, single-blind, crossover, placebo-controlled study. PD patients with camptocormia were administered a single trial of rTSMS (a train of 40 stimuli) or sham treatment followed 1 week later by the alternate treatment. Primary outcome measure was thoracolumbar spine flexion angle in the standing position immediately after the trial. RESULTS: Of 320 PD patients examined, 37 had concomitant camptocormia and were randomly assigned to either the rTSMS first group (n=19) or sham first group (n=18). Flexion angle in the standing position decreased by a mean of 10.9 degrees (95% CI 8.1 to 13.65) after rTSMS but remained unchanged after sham stimulation (mean, -0.1 degrees ; 95% CI -0.95 to 0.71). The flexion angle while sitting (secondary outcome) decreased by 8.1 degrees (95% CI 5.89 to 10.25) after rTSMS, whereas sham treatment had no significant effect (mean, -0.8 degrees ; 95% CI -1.62 to 0.05). CONCLUSIONS: We found an immediate beneficial effect of rTSMS on camptocormia in PD patients. Although the effect was transient, this successful trial justifies further studies to test if repeated rTSMS treatments can induce longer term improvements in camptocormia associated with PD. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000011495. PMID- 24780957 TI - Why am I not cited? PMID- 24780958 TI - [Re: Questionable justification for the possibility of conscientious objection]. PMID- 24780959 TI - [A. Eriksen replies]. PMID- 24780960 TI - [Re: Rarity--a separate criterion used in prioritization?]. PMID- 24780961 TI - [A. Heiberg and colleagues reply]. PMID- 24780962 TI - [Re: The intoxication in words]. PMID- 24780963 TI - [E. Hem replies]. PMID- 24780964 TI - [Re: Conscientious objection and the liberal dilemma]. PMID- 24780965 TI - [Re: Conscientious objection and the liberal dilemma]. PMID- 24780968 TI - [Re: Physicians' private referral practices]. PMID- 24780969 TI - [Re: Woman in her 30s with chronic fatigue]. PMID- 24780970 TI - [Re: Chiropractic education in Norway now!]. PMID- 24780971 TI - [Re: Are the guidelines for treatment of myocardial infarction followed?]. PMID- 24780972 TI - [J. Jortveit and colleagues reply]. PMID- 24780973 TI - [Re: Brachytherapy for malignant uveal melanoma]. PMID- 24780974 TI - [J. Krohn and colleagues reply]. PMID- 24780975 TI - [Re: Limited malignancy screening of patients with idiopathic venous thromboembolism]. PMID- 24780976 TI - [Re: Aphasia--when the system fails at least as much as the language]. PMID- 24780977 TI - [Can new anticoagulants be more risky than previously assumed?]. PMID- 24780978 TI - [Freedom of speech ought to take place]. PMID- 24780979 TI - Biosimilar medicines in inflammatory bowel disease. PMID- 24780981 TI - Porphyrias in Norway. AB - BACKGROUND: Porphyria is an umbrella term for a group of largely hereditary diseases that are due to defective haem synthesis. The diseases have a varied and partly overlapping range of symptoms and presentations. The commonest forms of porphyria are porphyria cutanea tarda, acute intermittent porphyria and erythropoietic protoporphyria. The purpose of this study is to provide an overview of the prevalence and pathological manifestations of porphyrias in Norway. MATERIAL AND METHOD: Information on all patients registered with the Norwegian Porphyria Centre (NAPOS) up to 2012 was used to estimate the prevalence and incidence of porphyrias in Norway. Figures on symptoms, precipitating factors and follow-up routines were obtained from the Norwegian Porphyria Registry, which includes 70% of Norwegians registered with NAPOS as having porphyria. RESULTS: The prevalence of porphyria cutanea tarda was approximately 10 : 100,000 and that of acute intermittent porphyria approximately 4 : 100,000. The total incidence of all porphyrias was approximately 0.5-1 : 100,000 per year. Diagnostic delay, i.e. the time passing between the onset of symptoms and diagnosis, varied from 1-17 years depending on the type of porphyria. There was wide variation in the frequency with which patients with the various types of porphyria went for medical check-ups. INTERPRETATION: The prevalence of acute intermittent porphyria and porphyria cutanea tarda appears to be higher in Norway than in most other countries. Data from the Norwegian Porphyria Registry makes it possible to demonstrate differences in treatment and follow-up of porphyria patients and may be used to initiate necessary measures. PMID- 24780982 TI - Maternal deaths in Norway 2005-2009. AB - BACKGROUND: Norway has low maternal mortality, but such deaths are underreported even in high-income countries. Our goal was to identify the exact number of maternal deaths, the causes of death and the potential for improvement through medical care in Norway. MATERIAL AND METHOD: We traced maternal deaths in the period from 1 January 2005 to 31 December 2009 by linking the Medical Birth Registry and the Cause of Death Registry, supplemented with data from maternity clinics. We identified the cause of death and the lessons that could be learned by a meticulous review of each case. RESULTS: We found 26 maternal deaths during the period, 14 of which were due to direct causes and 12 to indirect causes. The maternal mortality ratio was 8.7/100,000 live births. Fourteen of the deaths were registered in official statistics. Of the 12 deaths that were not included in the statistics, 11 were found through matching the registers and one had been reported directly by the hospital. The most common causes of death were hypertensive disorders during pregnancy (n = 6), thromboembolism (n = 4) and mental illness (n = 4). None of the deaths due to thromboembolism appeared in official statistics. The same applied to nine of the 12 indirect maternal deaths. We found a potential for improved medical care in 14 of 26 cases. Half of these were deaths due to hypertensive disorders during pregnancy or thromboembolism. INTERPRETATION: Maternal death was considerably underreported in Norwegian official statistics during the period studied. Greater attention should be given to better blood-pressure treatment, stabilisation and timely delivery in the case of hypertension during pregnancy, and to screening for possible pulmonary embolism. The same applies to mental illness and internal medical disorders in pregnant women. PMID- 24780983 TI - [The use of diuretics in kidney disease]. AB - BACKGROUND: Diuretics are an important part of the therapy for a number of medical conditions such as heart, liver and kidney failure and hypertension. This article presents updated knowledge on the use of diuretics in kidney disease. METHOD: The article is based on a literature search in PubMed, information obtained from textbooks on neurophysiology and kidney disease and on the authors' clinical experience. RESULTS: Kidney disease affects the pharmacokinetics and pharmacodynamics of diuretics, and this must be taken into account when selecting a drug and determining the dosage. This applies particularly to nephrotic syndrome and severe chronic renal disease (GFR < 30 ml/min/1.73 m2). INTERPRETATION: Knowledge of the pharmacology of diuretics is crucial to the rational use of diuretics in renal disease. Dose titration under close clinical monitoring and an optimal dosage interval make it possible to find the lowest possible effective dose and reduce the occurrence of side effects. PMID- 24780984 TI - Corrosive burns from wet cement. PMID- 24780985 TI - Stimulation of motor cortex for pain relief. PMID- 24780986 TI - [A four-month-old boy with inadequate weight gain]. PMID- 24780987 TI - [When the patient refuses blood transfusion]. PMID- 24780988 TI - [What should non-inferiority studies be called in Norwegian?]. PMID- 24781001 TI - Increased Na+/Ca2+ exchanger expression/activity constitutes a point of inflection in the progression to heart failure of hypertensive rats. AB - Spontaneously hypertensive rat (SHR) constitutes a genetic model widely used to study the natural evolution of hypertensive heart disease. Ca2+-handling alterations are known to occur in SHR. However, the putative modifications of Ca2+-handling proteins during the progression to heart failure (HF) are not well established. Moreover, the role of apoptosis in SHR is controversial. We investigated intracellular Ca2+, Ca2+-handling proteins and apoptosis in SHR vs. control Wistar rats (W) from 3 to 15 months (mo). Changes associated with the transition to HF (i.e. lung edema and decrease in midwall fractional shortening), occurred at 15 mo in 38% of SHR (SHRF). In SHRF, twitch and caffeine-induced Ca2+ transients, significantly decreased relative to 6/9 mo and 15 mo without HF signs. This decrease occurred in association with a decrease in the time constant of caffeine-Ca2+ transient decay and an increase in Na+/Ca2+ exchanger (NCX) abundance (p<0.05) with no changes in SERCA2a expression/activity. An increased Ca2+-calmodulin-kinase II activity, associated with an enhancement of apoptosis (TUNEL and Bax/Bcl2) was observed in SHR relative to W from 3 to 15 mo. CONCLUSIONS: 1. Apoptosis is an early and persistent event that may contribute to hypertrophic remodeling but would not participate in the contractile impairment of SHRF. 2. The increase in NCX expression/activity, associated with an increase in Ca2+ efflux from the cell, constitutes a primary alteration of Ca2+-handling proteins in the evolution to HF. 3. No changes in SERCA2a expression/activity are observed when HF signs become evident. PMID- 24781002 TI - An examination of traditional foods and cigarette smoking as cadmium sources among the nine First Nations of Eeyou Istchee, Northern Quebec, Canada. AB - Cadmium (Cd), a nonessential toxic metal present in the environment, accumulates in the organs of herbivorous mammals which typically are consumed by Aboriginal populations. The relative contribution of this potential exposure source to concentrations of blood Cd was investigated in 1429 participants (age >7 years) residing in the nine Cree First Nations communities of Eeyou Istchee, northern Quebec, Canada. Analysis of variance identified significant Cd concentration differences between communities, sex, and age groups, although these were complicated by significant 2-way interactions. The percentage of participants with Cd concentrations within the adopted health-based guideline categories of 'acceptable', 'concern' and 'action' pertaining to kidney damage was 56.2%, 38.3%, and 5.5%, respectively. Partial correlations (controlling for age as a continuous variable) did not show a significant association between consumption of traditional foods and Cd concentrations (r = 0.014, df = 105, p = 0.883). A significant and positive partial correlation (r = 0.390, df = 105, p < 0.001) was observed between Cd concentrations and number of cigarettes smoked daily. Analysis of covariance (with mean daily organ meat consumption over the year as a covariate) confirmed that smokers had significantly higher levels of blood Cd than non-smokers (F1,1109 = 1918.2, p < 0.001), and that traditional food consumption was not a good predictor of Cd exposure. Our findings suggest that consumption of traditional foods should not be restricted in Eeyou Istchee for fear of increased Cd exposure risk. Further studies of smoking prevalence among the Cree First Nations and additional public health initiatives to reduce smoking are recommended. PMID- 24781003 TI - Activity of colistin in combination with tigecycline or rifampicin against multidrug-resistant Stenotrophomonas maltophilia. AB - The antimicrobial treatment of Stenotrophomonas maltophilia infections is complicated by intrinsic multidrug resistance and a lack of reliable susceptibility data. We assessed the activity of colistin (COL), rifampicin (RIF) and tigecycline (TGC) alone and in combination using a range of in vitro susceptibility testing methodologies and a simple invertebrate model of S. maltophilia infection (Galleria mellonella). Synergy [fractional inhibitory concentration indices (FICIs) <=0.5] between COL and either RIF or TGC was observed against 92 % and 88 % of 25 S. maltophilia isolates, respectively, despite resistance to one or another of the single agents alone. In time-kill assays, COL combined with either RIF or TGC was superior to single agents, but only the COL/RIF regimen was reliably bactericidal. The in vitro findings correlated with treatment outcomes in G. mellonella, with heightened survival observed for larvae treated with COL/RIF or COL/TGC compared with COL, RIF or TGC alone. COL combined with RIF was the most effective combination overall in both in vitro and in vivo (p < 0.05) assays. Given the difficulty in selecting appropriate therapy for S. maltophilia infections, regimens consisting of COL combined with RIF or TGC could be considered for clinical use. PMID- 24781004 TI - Clostridium difficile infection diagnosis in a paediatric population: comparison of methodologies. AB - The increasing incidence of Clostridium difficile infection (CDI) in paediatric hospitalised populations, combined with the emergence of hypervirulent strains, community-acquired CDI and the need for prompt treatment and infection control, makes the rapid, accurate diagnosis of CDI crucial. We validated commonly used C. difficile diagnostic tests in a paediatric hospital population. From October 2011 to January 2012, 150 consecutive stools were collected from 75 patients at a tertiary paediatric hospital in Perth, Western Australia. Stools were tested using: C. Diff Quik Chek Complete, Illumigene C. difficile, GeneOhm Cdiff, cycloserine cefoxitin fructose agar (CCFA) culture, and cell culture cytotoxin neutralisation assay (CCNA). The reference standard was growth on CCFA or Cdiff Chromagar and PCR on isolates to detect tcdA, tcdB, cdtA, and cdtB. Isolates were PCR ribotyped. The prevalence of CDI was high (43 % of patients). Quik Chek Complete glutamate dehydrogenase (GDH) demonstrated a low negative predictive value (NPV) (93 %). Both CCNA and Quik Chek Complete toxin A/B had poor sensitivity (33 % and 29 % respectively). Molecular methods both had 89 % sensitivity. Algorithms using GDH + Illumigene or GeneOhm reduced the sensitivity to 85 % and 83 % respectively. Ribotype UK014/20 predominated. GDH NPV and GeneOhm and Illumigene sensitivities were reduced compared with adult studies. Quik Chek Complete and CCNA cannot reliably detect toxigenic CDI. A GDH first algorithm showed reduced sensitivity. In a high prevalence paediatric population, molecular methods alone are recommended over the use of GDH algorithm or culture and CCNA, as they demonstrate the best test performance characteristics. PMID- 24781005 TI - Analytical issues possibly affecting the performance of commercial human cytomegalovirus IgG avidity assays. AB - In the majority of cytomegalovirus (CMV) immunoglobulin G (IgG) avidity assays, avidity determination can be performed on the entire CMV IgG measurable positive concentration range. However, in some exceptional samples with very low IgG levels, inappropriately low avidity indexes have been described. In this study, we addressed some possible causes and the clinical importance of these inappropriately low avidity indexes. We compared VIDAS (bioMerieux), Liaison (DiaSorin), and Architect (Abbott) CMV IgG avidity assays on 129 samples from patients with past CMV infections, focusing on samples with low IgG levels. Inappropriately low avidity samples were further evaluated using seven different urea-based IgG avidity assays. We confirmed that inappropriately low avidity indexes in samples with very low IgG levels occur, but are rare. We could show that this phenomenon is not confined to a single assay and that assays employing chaotropic agents are affected more frequently and profoundly. In situations where the CMV IgG avidity is performed on CMV immunoglobulin M (IgM)-negative samples, the avidity index should be interpreted cautiously in cases of very low CMV IgG levels, whatever the technique used. PMID- 24781006 TI - Increased risk of pulmonary tuberculosis among patients with appendectomy in Taiwan. AB - The aim of this study was to determine whether there is a relationship between appendectomy and pulmonary tuberculosis in Taiwan. We designed a case-control study by analyzing the database from the Taiwan National Health Insurance Program. In total, we found 11,366 individuals (aged 20 years and older) with newly diagnosed pulmonary tuberculosis as the case group and 45,464 individuals without pulmonary tuberculosis as the control group from 1998 to 2011. The case group and the control group were matched on sex, age, and index year of diagnosing pulmonary tuberculosis. Using the multivariable unconditional logistic regression model, we measured the odds ratio (OR) and 95 % confidence interval (CI) for the risk of pulmonary tuberculosis associated with appendectomy and other comorbidities. After controlling for covariables, the multivariable unconditional logistic regression model disclosed that the OR of pulmonary tuberculosis was 1.4 in appendectomized patients (95 % CI = 1.13, 1.75) when compared to individuals without appendectomy. In further analysis, comorbidity with chronic obstructive pulmonary diseases (OR = 4.63, 95 % CI = 3.21, 6.68), pneumoconiosis (OR = 7.80, 95 % CI = 1.43, 42.5), chronic kidney diseases (OR = 5.65, 95 % CI = 1.79, 17.8), or diabetes mellitus (OR = 2.11, 95 % CI = 1.30, 3.44) increased the risk of pulmonary tuberculosis in appendectomized patients. Individuals with appendectomy are at a 1.4-fold increased risk of pulmonary tuberculosis. Comorbidities, including chronic obstructive pulmonary disease, pneumoconiosis, chronic kidney diseases, and diabetes mellitus, enhance the risk of pulmonary tuberculosis. PMID- 24781007 TI - Effect of amide bonds on the self-assembly of gemini surfactants. AB - This study provides an insight into the micellar aggregation properties in aqueous solutions of various gemini surfactants bearing one or more amide groups at the side chains and/or in the spacer by conductivity and small angle neutron scattering (SANS) studies. The amide functionality was found to enhance the surfactant aggregation properties as compared to the surfactants having no amide bond. Furthermore, the aggregation properties of the gemini surfactants bearing amide groups were found to strongly depend on the position and number of amide bonds. With the increase in the number of amide bonds, the aggregation number (N) and the size of the micelles increased. Additionally, the size and shape of the micelles were also found to depend both on the hydrocarbon chain length and the spacer chain length. It was also found that the aggregation number and the size of the micelles increased with an increase in concentration and decreased with an increase in temperature. The critical micellar concentration (CMC) values of the gemini surfactants obtained by a conductometric method were found to vary greatly with variation in the hydrocarbon chain. PMID- 24781008 TI - Role of nuclear medicine in neuroHIV: PET, SPECT, and beyond. AB - HIV-associated neurocognitive disorders (HAND) remain among the most common clinical disorders encountered in people infected with HIV despite widespread use of antiretroviral therapy. There is an enormous need for further evaluation and early diagnosis of HAND. The variety of PET agents such as FDG, C-PiB and [C]-R PK11195 as well as SPECT agents Tc-HMPAO, I-FP-CIT and I-IBZM have been investigated for the diagnosis of HAND, for distinguishing between demented and nondemented HIV patients, for differentiation between HAND and nonHIV related dementia, as well as for assessing the influence of coinfection with the other viral pathogens on the brain functionality. In spite of some interesting results, none of these tracers have been specifically created for HAND and none can be recommended for HAND diagnosis. Specialized tracers need to be developed for better diagnosis and management of HAND. The potential role of therapeutic nuclear medicine as part of the curative strategies for HIV is also discussed. PMID- 24781009 TI - Nuclear medicine in the management of patients with heart failure: guidance from an expert panel of the International Atomic Energy Agency (IAEA). AB - Heart failure is increasing worldwide at epidemic proportions, resulting in considerable disability, mortality, and increase in healthcare costs. Gated myocardial perfusion single photon emission computed tomography or PET imaging is the most prominent imaging modality capable of providing information on global and regional ventricular function, the presence of intraventricular synchronism, myocardial perfusion, and viability on the same test. In addition, I-mIBG scintigraphy is the only imaging technique approved by various regulatory agencies able to provide information regarding the adrenergic function of the heart. Therefore, both myocardial perfusion and adrenergic imaging are useful tools in the workup and management of heart failure patients. This guide is intended to reinforce the information on the use of nuclear cardiology techniques for the assessment of heart failure and associated myocardial disease. PMID- 24781010 TI - Utility of 18F-FDG uptake in various regions of Waldeyer's ring to differentiate benign from malignant lesions in the midline roof of the nasopharynx. AB - PURPOSE: Lymphoid hyperplasia is not uncommon in the midline roof of the nasopharynx. Most nasopharyngeal carcinoma patients present with primary tumors in the midline of the nasopharynx. The aim of this study was to evaluate the efficacy of 2-[fluorine-18] fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/computed tomography (CT) to differentiate between benign and malignant lesions in the midline roof of the nasopharynx. MATERIALS AND METHODS: The data from the (18)F FDG PET/CT images of 4846 participants were analyzed. Visual uptake, the lesions' standard uptake values (SUVs), and any abnormalities on the PET/CT images were evaluated. RESULTS: Sixty-six individuals with benign lesions and 25 with nasopharyngeal carcinoma were included in the analysis. The participants with benign and malignant lesions displayed increased (18)F-FDG uptake (SUV; mean+/ SD) in the midline roof of the nasopharynx (4.16+/-1.92 and 6.65+/-2.81, respectively), with SUVs significantly differing between the two types of lesions (P<0.001). An associated increased (18)F-FDG uptake in Waldeyer's ring and the salivary glands occurred in benign but not in malignant lesions. The ratio of uptake in the midline roof of the nasopharynx and the palatine tonsil in the benign lesions (0.92+/-0.42) was significantly lower than that in the malignant lesions (1.76+/-0.93) (P<0.001). CONCLUSION: The analysis of the intensity and patterns of (18)F-FDG uptake in various regions of Waldeyer's ring provides a feasible modality for the differentiation between benign lesions and malignant nasopharyngeal midline roof lesions. PMID- 24781011 TI - Two-day lymphoscintigraphic imaging for melanoma. AB - OBJECTIVES: Sentinel lymph node mapping has a long history of successful use in the staging and management of cutaneous melanoma. Most practitioners inject the primary site with radiocolloid the evening before or on the day of lymphoscintigraphy. We have found that imaging the day after lymphoscintigraphic injection is quite feasible; it decreases background radioactivity and makes scheduling easier. We aimed to determine whether 2-day lymphoscintigraphy is as effective at defining nodes as 1-day lymphoscintigraphy. MATERIALS AND METHODS: We reviewed the records of 172 patients who underwent lymphoscintigraphy over a 6 year period, all of whom had a diagnosis of melanoma and had undergone 2-day lymphoscintigraphy with imaging on both the day of injection and the day immediately after. The number of basins and the basin pattern were then examined when a discrepancy was seen in the reports in order to decide whether an actual discrepancy between images was present. The number of nodes on same-day and next day imaging was then evaluated as well. RESULTS: On same-day imaging, the number of basins identified was three node basins (NBs) in five patients, two NBs in 42 patients, one NB in 123 patients and no NB in two patients. On next-day imaging, the number of basins identified was three NBs in five patients, two NBs in 36 patients, one NB in 129 patients and no NB in two patients. The difference in the number of basins between same-day and next-day imaging was not significant once cases such as iliac, para-aortic and pelvic nodes, which do not affect surgical planning, were excluded (P=0.08). The pattern of nodes within the basin was also examined, and the presence or disappearance of disappearing nodes correlated with timing of the next-day images. All cases of disappearing nodes occurred at least 19 h after injection, and cases of disappearance of significant nodes occurred at at least 22 h. The absolute number of nodes declined in 45 cases, remained the same in 124 and increased in three. CONCLUSION: Overall, the same number of basins and, usually, nodes can be detected on the day after injection, as long as the time after injection does not significantly exceed 19 h. PMID- 24781012 TI - FoxO proteins restrain osteoclastogenesis and bone resorption by attenuating H2O2 accumulation. AB - Besides their cell-damaging effects in the setting of oxidative stress, reactive oxygen species (ROS) play an important role in physiological intracellular signalling by triggering proliferation and survival. FoxO transcription factors counteract ROS generation by upregulating antioxidant enzymes. Here we show that intracellular H2O2 accumulation is a critical and purposeful adaptation for the differentiation and survival of osteoclasts, the bone cells responsible for the resorption of mineralized bone matrix. Using mice with conditional loss or gain of FoxO transcription factor function, or mitochondria-targeted catalase in osteoclasts, we demonstrate this is achieved, at least in part, by downregulating the H2O2-inactivating enzyme catalase. Catalase downregulation results from the repression of the transcriptional activity of FoxO1, 3 and 4 by RANKL, the indispensable signal for the generation of osteoclasts, via an Akt-mediated mechanism. Notably, mitochondria-targeted catalase prevented the loss of bone caused by loss of oestrogens, suggesting that decreasing H2O2 production in mitochondria may represent a rational pharmacotherapeutic approach to diseases with increased bone resorption. PMID- 24781014 TI - Effect of FTY720 on the SET-PP2A complex in acute myeloid leukemia; SET binding drugs have antagonistic activity. PMID- 24781015 TI - PRPF8 defects cause missplicing in myeloid malignancies. AB - Mutations of spliceosome components are common in myeloid neoplasms. One of the affected genes, PRPF8, encodes the most evolutionarily conserved spliceosomal protein. We identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 15/447 and 24/450 cases, respectively. Fifty percent of PRPF8 mutant and del(17p) cases were found in AML and conveyed poor prognosis. PRPF8 defects correlated with increased myeloblasts and ring sideroblasts in cases without SF3B1 mutations. Knockdown of PRPF8 in K562 and CD34+ primary bone marrow cells increased proliferative capacity. Whole-RNA deep sequencing of primary cells from patients with PRPF8 abnormalities demonstrated consistent missplicing defects. In yeast models, homologous mutations introduced into Prp8 abrogated a block experimentally produced in the second step of the RNA splicing process, suggesting that the mutants have defects in proof-reading functions. In sum, the exploration of clinical and functional consequences suggests that PRPF8 is a novel leukemogenic gene in myeloid neoplasms with a distinct phenotype likely manifested through aberrant splicing. PMID- 24781016 TI - Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. AB - After allogeneic stem cell transplantation, graft-versus-host disease (GvHD) occurs through recognition of histocompatibility mismatches by donor T lymphocytes. The same mechanism operates in eliminating malignant cells (the graft-versus-tumor or GvT effect). We hypothesized that comparing the correlation between GvHD and relapse might provide a surrogate marker for the susceptibility of diseases to allo-immune effects. We studied 48 111 first allogeneic transplants performed between 1998 and 2007. In chronic myeloid leukemia (CML), the relapse risk declined clearly and proportionally to severity of acute and chronic GvHD. Acute lymphoblastic leukemia and BCR-ABL-negative myeloproliferative neoplasias were comparably sensitive to GvHD as CML, whereas myelodysplastic syndromes and lymphoproliferative disorders showed intermediate sensitivity. GvHD was only associated with modest reductions in relapse risk in acute myeloid leukemia (AML) and plasma cell disorders (PCDs). Except for PCD, hazard rates for relapse decreased to almost 0 at 48 months of follow-up in all diseases. These data confirm observations of potent GvT effects associated with GvHD. The strength of the GvHD/GvT correlation differs significantly between hematological malignancies. The parallel drop of relapse rates in different diseases despite differences in GvHD/GvT ratios suggests that GvT effects might operate in the absence of GvHD, particularly in AML. PMID- 24781017 TI - A revised definition for cure of childhood acute lymphoblastic leukemia. AB - With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse). PMID- 24781018 TI - The gamma-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells. AB - Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the gamma-secretase inhibitor PF 03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine mediated activation of nuclear factor-kappaB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients. PMID- 24781019 TI - Characteristics and molecular phylogeny of Fasciola flukes from Bangladesh, determined based on spermatogenesis and nuclear and mitochondrial DNA analyses. AB - This study aimed to precisely discriminate Fasciola spp. based on DNA sequences of nuclear internal transcribed spacer 1 (ITS1) and mitochondrial nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 1 (nad1) gene. We collected 150 adult flukes from the bile ducts of cattle, buffaloes, sheep, and goats from six different regions of Bangladesh. Spermatogenic status was determined by analyzing stained seminal vesicles. The ITS1 types were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The nad1 haplotypes were identified based on PCR and direct sequencing and analyzed phylogenetically by comparing with nad1 haplotypes of Fasciola spp. from other Asian countries. Of the 127 aspermic flukes, 98 were identified as Fg type in ITS1, whereas 29 were identified as Fh/Fg type, indicating a combination of ITS1 sequences of Fasciola hepatica and Fasciola gigantica. All the 127 aspermic flukes showed Fsp-NDI-Bd11 in nad1 haplotype with nucleotide sequences identical to aspermic Fasciola sp. from Asian countries. Further, 20 spermic flukes were identified as F. gigantica based on their spermatogenic status and Fg type in ITS1. F. gigantica population was thought to be introduced into Bangladesh considerably earlier than the aspermic Fasciola sp. because 11 haplotypes with high haplotype diversity were detected from the F. gigantica population. However, three flukes from Bangladesh could not be precisely identified, because their spermatogenic status, ITS1 types, and nad1 haplotypes were ambiguous. Therefore, developing a robust method to distinguish aspermic Fasciola sp. from other Fasciola species is necessary in the future. PMID- 24781020 TI - Feconomics(r); a new and more convenient method, the routine diagnosis of intestinal parasitic infections. AB - Direct wet mount examination and concentration are the most commonly used methods for detecting intestinal parasites from fecal samples. Concentration methods are used when there are fewer protozoan cyst, coccidian oocyst, microsporidial spore, helminth egg, and larvae in the fecal samples. Early detection of the causative intestinal parasites plays a significant role in implementing timely and correct treatment, which relieves the patients' symptoms and also prevents recurrences. Formalin-ethyl acetate concentration (FEAC) is believed to be a gold standard method to detect most intestinal parasites. Thus, in this study, we evaluated the diagnostic value of Feconomics(r) [manufactured by Salubris Inc, Boston, USA. Patent application number (TR): 2010/07549] which is a simple, new, and rapid fecal concentration method for the detection of the intestinal parasites in human beings. We also compared the FEAC with Feconomics(r) and direct wet mount examination. A total of 918 fecal samples were collected from the patients suspected to have intestinal parasitic infection. Samples were examined with the direct wet mount, FEAC, and Feconomics(r) methods. Different parasite species 15.9% (146/918) with Feconomics(r), 13.3% (122/918) with FEAC, and 9.8% (90/918) with direct wet mount examination, Feconomics(r) > FEAC > direct wet mount examinations were detected. They were statistically compared considering FEAC as the gold standard for parasitological diagnosis; the sensitivity and specificity of Feconomics(r) were calculated as 96 and 97%, respectively. Blastocystis hominis was found to be the most common parasite, followed by Giardia lamblia with direct wet mount examination, FEAC, and Feconomics(r) methods. Feconomics(r) proved to be better than not only FEAC in concentrating parasite egg and cyst forms as well as in maintaining characteristic morphology but it is also better in direct wet mount examination. Feconomics(r) eliminates the need for centrifugation by using absorbent beads that help the homogenization and concentration of the sample. Feconomics(r) in this study was considerably better than FEAC in detecting the trophozoites of Giardia lamblia. We suggest that Feconomics(r) be used for the routine diagnosis of intestinal parasitic infection in rural areas of developing countries due to the fact that a centrifuge is not required and it eliminates large stool particles. PMID- 24781021 TI - The isolation of Balamuthia mandrillaris from environmental sources from Peru. AB - Balamuthia mandrillaris is an opportunistic free-living amoeba that has been reported to cause skin lesions and the fatal Balamuthia amoebic encephalitis (BAE) in humans and other animals. Currently, around 200 human BAE cases have been reported worldwide, although this number is considered to be underestimated. The highest number of BAE cases has been reported in the American continent, mainly in the southwest of the USA. Peru seems to be another hotspot for BAE with around 55 human cases having been identified, usually involving cutaneous infection, especially lesions in the central face area. The isolation of Balamuthia from environmental sources has been reported on only three prior occasions, twice from Californian soils and once from dust in Iran and so it seems that this amoeba is relatively rarely encountered in samples from the environment. We investigated that possibility of finding the amoebae in soil samples from different regions where clinical cases have been reported in Peru. Twenty-one samples were cultured in non-nutrient agar plates and were checked for the presence of B. mandrillaris-like trophozoites and/or cysts. Those samples that were positive for these amoebae by microscopic criteria were then confirmed by PCR amplification and DNA sequencing of the mitochondrial 16S rDNA gene of B. mandrillaris. We have detected the presence of B. mandrillaris in four samples collected in the regions of Piura (3) and Lima (1) where infection cases have been previously reported. We hypothesize that B. mandrillaris is present in Peru in soil and dust which therefore constitutes a source of the infection for the BAE cases previously reported in this country. Further studies should be carried out in the area to confirm the generality of this finding. PMID- 24781022 TI - Selective and universal primers for trematode barcoding in freshwater snails. AB - Trematodes are significant pathogens of high medical, veterinary, and environmental importance. They are hard to isolate from their intermediate hosts, and their early life stages are difficult to identify morphologically. Therefore, primers were developed for trematodes to create a species barcoding system and allow selective PCR amplification in mixed samples. The specific oligonucleotide primer was universal for trematodes that infected several freshwater snail species in Israel. The diagnostic tool is based on the 18S rDNA gene. In contrast to morphological identification, trematode barcoding is rapid as it is based on a sequence of only 800 bp, and it classifies species accurately due to high polymorphism between conserved areas. PMID- 24781023 TI - Assessment of gastrointestinal parasites in wild chimpanzees (Pan troglodytes troglodytes) in southeast Cameroon. AB - We tested 114 faecal samples from wild simian immunodeficiency virus (SIV) positive (n = 43) and SIV-negative (n = 71) chimpanzees (Pan troglodytes troglodytes) in southeast Cameroon for the presence of gastrointestinal parasites by direct smear. We observed cysts from different protozoa (Entamoeba coli and Entamoeba histolytica / Entamoeba dispar, Endolimax nana, Iodamoeba butschlii, Chilomastix mesnili, Balantidium coli and Blastocystis cells) and trophozoites from Troglodytella abrassarti and Balantidium coli. Eggs from different helminths (strongylids, Ascaris lumbricoides, Abbreviata caucasica, Trichuris sp., Capillaria sp., Enterobius anthropopeci, Bertiella sp., Hymenolepis diminuta and an undetermined fluke) were also observed. Finally, we observed eggs that could not be properly identified and classified. We did not observe any differences between the SIV+ and SIV- samples except for the unidentified eggs. The studied chimpanzees were highly parasitised by strongylid (85.1% of prevalence), Troglodytella (43.8%) and Blastocystis (2.9%), and the frequency of the other parasites ranged from 0.9 to 8.8%. These high levels of parasite infections could represent an additional burden in a population where there is a high rate of the SIV virus in circulation. PMID- 24781024 TI - Incidence and molecular diversity of Acanthamoeba species isolated from public baths in Hungary. AB - Hungary has a large number of thermal baths and spa facilities which attract hundreds of thousands of tourists annually. Until recently, however, the free living amoebae were not of public health concern. Genotyping of Acanthamoeba species, potential agents of keratitis and granulomatous encephalitis, was carried out in 20 Hungarian public baths for the first time to assess the incidence and molecular diversity of the genus in the country. Our results show that 6.7% of the samples were positive for Acanthamoeba. Of these positive samples, 6.5 and 7% was from sterilized and unsterilized pools, respectively. The 18S rRNA gene investigation of the nine Acanthamoeba strains found reveals that seven belong to the hazardous T4 genotype. The remaining two samples were of the T15 type. All the strains kept growing at 36 degrees C. Our results underline the need to develop a control system for free-living amoebae and supervise the disinfection of Hungarian public baths. PMID- 24781025 TI - Spirocerca lupi infection in a dog from southern Italy: an "old fashioned" disease? AB - Canine spirocercosis caused by Spirocerca lupi is a life-threatening helminthic disease featured by severe clinical signs and potential development of oesophageal neoplasia. This infection is considered fairly frequent in Europe but almost unknown in Italy, from where only few reports have been published in local journals at the beginning of the XXI century. In the present study, an autochthonous case of canine spirocercosis in a 2-year-old dog from southern Italy is described. The animal was admitted to a private veterinary clinic in the municipality of Potenza (Basilicata region) due to persistent dyspnoea, vomiting, and regurgitation. At the abdominal ultrasound, a mass (1.3 * 2 cm) was observed and, thereafter, surgically removed from the apical part of the stomach. A female specimen of S. lupi was morphologically identified during the histological examination of the nodule and its eggs were detected in the faeces. In addition, the morphological identification was confirmed by molecular amplification and sequencing of partial cox2 gene sequence of S. lupi. Veterinarians should be aware of the potential risks derived from infection with this spirurid, which requires specific diagnostic and preventive measures. PMID- 24781026 TI - Essential oils with insecticidal activity against larvae of Aedes aegypti (Diptera: Culicidae). AB - Insecticidal activity of the essential oils (EOs) isolated from Tagetes lucida, Lippia alba, Lippia origanoides, Eucalyptus citriodora, Cymbopogon citratus, Cymbopogon flexuosus, Citrus sinensis, Swinglea glutinosa, and Cananga odorata aromatic plants, grown in Colombia (Bucaramanga, Santander), and of a mixture of L. alba and L. origanoides EOs were evaluated on Aedes (Stegomyia) aegypti Rockefeller larvae. The EOs were extracted by microwave-assisted hydrodistillation and characterized by gas chromatography-mass spectrometry (GC MS). The main components of the EOs were identified using their linear retention indices and mass spectra. The lethal concentrations (LCs) of the EOs were determined between the third and fourth instar of A. aegypti. LC50 was determined by probit analysis using mortality rates of bioassays. All essential oils tested showed insecticidal activity. The following values were obtained for C. flexuosus (LC50 = 17.1 ppm); C. sinensis (LC50 = 20.6 ppm); the mixture of L. alba and L. origanoides (LC50 = 40.1 ppm); L. alba (LC50 = 42.2 ppm); C. odorata (LC50 = 52.9 ppm); L. origanoides (LC50 = 53.3 ppm); S. glutinosa (LC50 = 65.7 ppm); T. lucida (LC50 = 66.2 ppm); E. citriodora (LC50 = 71.2 ppm); and C. citratus (LC50 = 123.3 ppm). The EO from C. flexuosus, with citral (geranial + neral) as main component, showed the highest larvicidal activity. PMID- 24781028 TI - Quantification of viable Giardia cysts and Cryptosporidium oocysts in wastewater using propidium monoazide quantitative real-time PCR. AB - Real-time PCR (qPCR) is a rapid tool to quantify pathogens in the aquatic environment; however, it quantifies all pathogens, including both viable and nonviable. Propidium monoazide (PMA) is a membrane-impairment dye that penetrates only membrane-damaged cells. Once inside the cell, PMA is covalently cross-linked to DNA through light photoactivation, and PCR amplification is strongly inhibited. The goal of this study was to evaluate PMA-qPCR assays for rapid quantification of viable and heat-treated Giardia cysts and Cryptosporidium oocysts in wastewater. We observed a reduction in detection of heat-treated Giardia duodenalis cysts of 83.2, 89.9, 98.2, or 97% with PMA-qPCR assays amplifying a 75 base-pair (bp) beta-giardin target, 77-bp triosephosphate isomerase (tpi), 133-bp glutamate dehydrogenase (GDH), and 143-bp beta-giardin gene target, respectively. Thus, the exclusion of dead cysts was more effective when qPCR assays that produced larger amplicons were used. The PMA treatment of Cryptosporidium oocysts plus/minus heat treatment abolished the fluorescent signal for dead oocysts with a PMA-qPCR assay amplifying a Cryptosporidium parvum (150-bp) oocyst wall protein (COWP) gene. The PMA-qPCR 143-bp beta-giardin assay for Giardia and the PMA-qPCR 150-bp COWP assay for Cryptosporidium accurately quantified live oo(cysts), and failed to detect dead oo(cysts), when phosphate buffered saline and tertiary effluent wastewater were spiked with concentrations of 10(3) or 10(2) dead oo(cysts), respectively. Therefore, these assays are suitable for the detection of viable parasites that are typically present in tertiary wastewater effluents at concentrations of <10(3) oo(cysts)/l and can provide rapid risk assessments of environmental water. PMID- 24781029 TI - Synergistic contributions by decreasing overpotential and enhancing charge transfer in alpha-Fe2O3/Mn3O4/graphene catalysts with heterostructures for photocatalytic water oxidation. AB - A novel nanocomposite consisting of alpha-Fe2O3, Mn3O4 and reduced graphene oxide (r-GO) has been facilely synthesized through a two-step method: solvothermal reaction for Mn3O4-modified alpha-Fe2O3 (alpha-Fe2O3/Mn3O4) and self-assembly process for combining alpha-Fe2O3/Mn3O4 with r-GO (alpha-Fe2O3/Mn3O4/r-GO). The morphology and structure of the nanocomposite were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM) and X-ray photoelectron spectroscopy (XPS). The results demonstrated that rod-like hematite was modified by Mn3O4 and dispersed on the surface of r-GO. Raman and Fourier transform infrared spectra (FTIR) showed superior interfacial contacts between alpha-Fe2O3/Mn3O4 and r-GO. Ultraviolet-visible diffuse reflectance spectroscopy (DRS) and photoelectrochemical characterization revealed a high light-harvesting efficiency, a lowered overpotential for water oxidation and an excellent charge transfer performance of alpha-Fe2O3/Mn3O4/r-GO nanocomposite with heterostructures. The photocatalytic oxygen evolution from the optimized photocatalyst was up to 1406.2 MUmol g(-1) in 10 h of UV-vis light irradiation and the quantum yield was ca. 4.35% at 365 nm. Our investigation suggests that constructing a catalyst with heterostructures is a promising method to enhance photocatalytic activity. PMID- 24781027 TI - Experimental infection of Calomys callosus with atypical strains of Toxoplasma gondii shows gender differences in severity of infection. AB - There is a significant genetic diversity of Toxoplasma gondii in Brazil. Two parasite isolates were recently obtained from chickens in Uberlandia, Minas Gerais state, Brazil, namely, TgChBrUD1 and TgChBrUD2. In this study, we investigated Calomys callosus susceptibility to these atypical T. gondii strains. Male and female animals were intraperitoneally infected with tachyzoites and monitored to evaluate body weight change, morbidity, and mortality. Immunohistochemical assay and qPCR were performed to determine the parasitism in liver, spleen, and brain. Our data showed that TgChBrUD2-infected males died earlier than TgChBrUD1-infected males and 100% of mortality was observed after 10 and 12 days of infection, respectively. Also, TgChBrUD1-infected females died earlier than TgChBrUD1-infected males and 100% of mortality was observed after 9 and 12 days of infection, respectively. Both strains were able to induce a decrease in body weight of males, but only the TgChBrUD1 strain induced an increase in body weight of females. TgChBrUD2-infected females had significantly higher parasite load in both liver and spleen in comparison to TgChBrUD1-infected females, but no significant difference was found between genders or strains when males were infected. There was higher parasitism in the liver than the brain from both males and females infected with either strain. In conclusion, C. callosus specimens are susceptible to both T. gondii atypical strains with differences between males and females in severity of infection. These findings open new prospects for understanding different aspects of T. gondii infection, including reinfection and vertical transmission with these atypical strains when utilizing this experimental model. PMID- 24781030 TI - Regulation of Rad51 promoter. AB - The DNA double-strand break repair and homologous recombination protein Rad51 is overexpressed in the majority of human cancers. This correlates with therapy resistance and decreased patient survival. We previously showed that constructs containing Rad51 promoter fused to a reporter gene are, on average, 850-fold more active in cancer cells than in normal cells. It is not well understood what factors and sequences regulate the Rad51 promoter and cause its high activity in cancerous cells. Here we characterized regulatory regions and examined genetic requirements for oncogenic stimulation of the Rad51 promoter. We identified specific regions responsible for up- and downregulation of the Rad51 promoter in cancerous cells. Furthermore, we show that Rad51 expression is positively regulated by EGR1 transcription factor. We then modeled the malignant transformation process by expressing a set of oncoproteins in normal human fibroblasts. Expression of different combinations of SV40 large T antigen, oncogenic Ras and SV40 small T antigen resulted in step-wise increase in Rad51 promoter activity, with all the 3 oncoproteins together leading to a 47-fold increase in expression. Cumulatively, these results suggest that Rad51 promoter is regulated by multiple factors, and that its expression is gradually activated as cells progress toward malignancy. PMID- 24781031 TI - Microvascular obstruction in patients with non-ST-elevation myocardial infarction: a contrast-enhanced cardiac magnetic resonance study. AB - The aim of the study was to assess the frequency and predictive factors of microvascular obstruction (MVO) in patients with non-ST-segment elevation myocardial infarction (NSTEMI). This study included 190 consecutive patients with NSTEMI who underwent percutaneous coronary intervention (PCI) within 24 h after admission and cardiac magnetic resonance (CMR) imaging, 4.1 days after angiography. MVO was defined using the CMR criteria. MVO was detected 26 of 190 patients (13.8%). Patients with MVO had higher peak high-sensitivity troponin T, creatine-kinase and creatine kinase-myocardial band levels and higher proportions of those with baseline thrombolysis in myocardial infarction (TIMI) flow grade 0 1, absence of collateral circulation, post-PCI TIMI flow grade <3, myocardial blush grade <3 and angiographic no-reflow than patients without MVO. Patients with MVO had larger initial area at risk [median (25th-75th percentiles), 23.9% (17.4-33.9%) vs. 16.1% (7.8-27.7%), P = 0.018] and infarct size [11.4% (6.6 19.2%) vs. 1.4% (0-4.7%) of the left ventricle, P < 0.001] than patients without MVO. In multivariable analysis, the culprit lesion localization in the circumflex coronary artery [adjusted odds ratio (OR) 13.71, 95% confidence interval 2.91 64.58, P < 0.001] and the infarct size [adjusted OR 3.37 (1.80-6.29), P < 0.001, for each 5% of the left ventricle] were independently associated with the increased risk for MVO. In patients with NSTEMI undergoing early PCI, the MVO defined by CMR imaging was present in 13.8 % of the patients. The localization of culprit lesion in the circumflex coronary artery and larger infarct size were independently associated with the increased risk for MVO. PMID- 24781032 TI - Atrial longitudinal strain parameters predict left atrial reverse remodeling after mitral valve surgery: a speckle tracking echocardiography study. AB - Volume overload in chronic severe mitral regurgitation (MR) causes left atrial (LA) remodeling. Volume overload generally diminishes after mitral valve surgery and LA size and shape are expected to recover. The recovery of LA functions named as reverse remodeling is said to be related with prognosis and mortality. A few clinical and echocardiographic parameters have been reported to be associated with LA reverse remodeling. In this study, we investigated the relationship between LA peak longitudinal strain (reservoir strain) assessed with 2 dimensional speckle tracking echocardiography (2D STE) and LA reverse remodeling. 53 patients (24 females and 29 males, mean age: 45.7 +/- 13.5 years) with severe MR and preserved left ventricular systolic function were included in the study. All patients had normal sinus rhythm. The etiology of MR was mitral valve prolapse (MVP) in 37 patients and rheumatic valvular disease in 16 patients. Mitral valve repair was performed in 30 patients while 23 underwent mitral valve replacement. Echocardiography was performed before the surgery and 6 months later. LA peak atrial longitudinal strain (PALS) was assessed with speckle tracking imaging. LA reverse remodeling was defined as a percent of decrease in LA volume index (LAVI). Left atrial volume index significantly decreased after surgery (58.2 +/- 16.6 vs. 43.9 +/- 17.2 ml/m2, p <= 0.001). Mean LAVI reduction was 22.5 +/- 27.2%. There was no significant difference in LAVI reduction between mitral repair and replacement groups (22.1 +/- 22.6 vs. 23.1 +/- 32.8 %, p = 0.9). Although the decrease in LAVI was higher in MVP group than rheumatic group, it was not statistically significant (24.4 +/- 26.8 vs. 18.2 +/- 28.9%, p = 0.4). Correlates of LAVI reduction were preoperative LAVI (r 0.28, p = 0.039), PALS (r 0.36, p = 0.001) and age (r -0.36, p = 0.007). Furthermore, in multivariate linear regression analysis (entering models), preoperative LAVI, age and PALS were all significant predictors of LA reverse remodeling (p <= 0.001, p = 0.04, p = 0.001 respectively). Left atrial peak longitudinal strain measured by 2D STE, in conjunction with preoperative LAVI and age is a predictor of LA reverse remodeling in patients undergoing surgery for severe MR. We suggest that in this patient population, PALS may also be used as a preoperative prognostic marker. PMID- 24781033 TI - Accurate image analysis of the retina using hessian matrix and binarisation of thresholded entropy with application of texture mapping. AB - In this paper, we demonstrate a comprehensive method for segmenting the retinal vasculature in camera images of the fundus. This is of interest in the area of diagnostics for eye diseases that affect the blood vessels in the eye. In a departure from other state-of-the-art methods, vessels are first pre-grouped together with graph partitioning, using a spectral clustering technique based on morphological features. Local curvature is estimated over the whole image using eigenvalues of Hessian matrix in order to enhance the vessels, which appear as ridges in images of the retina. The result is combined with a binarized image, obtained using a threshold that maximizes entropy, to extract the retinal vessels from the background. Speckle type noise is reduced by applying a connectivity constraint on the extracted curvature based enhanced image. This constraint is varied over the image according to each region's predominant blood vessel size. The resultant image exhibits the central light reflex of retinal arteries and veins, which prevents the segmentation of whole vessels. To address this, the earlier entropy-based binarization technique is repeated on the original image, but crucially, with a different threshold to incorporate the central reflex vessels. The final segmentation is achieved by combining the segmented vessels with and without central light reflex. We carry out our approach on DRIVE and REVIEW, two publicly available collections of retinal images for research purposes. The obtained results are compared with state-of-the-art methods in the literature using metrics such as sensitivity (true positive rate), selectivity (false positive rate) and accuracy rates for the DRIVE images and measured vessel widths for the REVIEW images. Our approach out-performs the methods in the literature. PMID- 24781034 TI - Central nervous system manifestation of IgG4-related disease. AB - IMPORTANCE: IgG4-related disease (IgG4-RD) is characterized by an inflammatory reaction rich in IgG4-positive plasma cells. Head and brain involvement is rare in IgG4-RD, and brain parenchyma involvement has never been reported. OBSERVATION: A man in his mid-50s with multiorgan IgG4-RD developed progressive spastic hemiparesis and dementia. Magnetic resonance imaging of the brain revealed several cortical and subcortical lesions. Pathologic findings in the brain were consistent with IgG4-related central nervous system involvement. The patient was treated with high-dose corticosteroids followed by rituximab, and his cognitive and motor functions improved significantly. CONCLUSIONS AND RELEVANCE: IgG4-RD should be considered in patients with unusual neurologic manifestations suggestive of autoimmune disease. PMID- 24781035 TI - The efficacy of sulodexide in the prevention of postthrombotic syndrome. AB - AIM: The aim of this open, observational registry was to evaluate the effects of antithrombotic treatment on the development of postthrombotic syndrome (PTS): the effects of "standard management" (SM; according to International Union of Angiology guidelines) were compared to SM in association with sulodexide or aspirin. METHODS: Postthrombotic syndrome occurrence was observed in 3 nonparallel groups after deep venous thrombosis (DVT); the registry started after the end of the anticoagulation period. The target was to observe the occurrence of PTS in 5 years. Three possible options were suggested to the patients, and the patients and their caregivers defined the type of management. A group of 167 patients was involved in the SM with reevaluation every 6 months; the sulodexide group included 124 patients and the aspirin group included 48 patients. RESULTS: The 3 groups were clinically similar and comparable for age and sex distribution. Of the 167 patients in the SM group, 154 patients completed 60 months of follow up. The percentage of patients with PTS in the SM group ranged from 14.9% (1 year after the end of anticoagulation) to 19.5% (60 months). In the nonparallel group using sulodexide (124 comparable patients at inclusion; 115 at 60 months), the percentage of PTS was variable from 8.8% (1 year after anticoagulants) to 12.17% at 60 months. These percentages are significantly lower than those observed with SM. In the nonparallel aspirin group (48 patients at inclusion and 34 at 54 months), there was a PTS incidence of 23.5% at 54 months (vs 12.17% in the sulodexide group and 18.23% in the SM group). The incidence of PTS was significantly higher in comparison with the other 2 groups. The incidence of PTS was lower in the sulodexide group in comparison with the 2 other groups. CONCLUSIONS: Sulodexide administration after DVT appears to be effective in preventing PTS in association with recommended management and a number of recurrent DVTs. Modalities of treatment, dosages, and timing of administration should be explored in more comprehensive and complete studies. PMID- 24781036 TI - Local and transient permeation events are associated with local melting of giant liposomes. AB - We reveal that the gel to fluid phase transition causes spherical membrane vesicles to release a finite number of molecules in several consecutive and localized events. By locally melting Giant Unilamellar lipid Vesicles (GUVs), using an optically trapped gold nanoparticle (AuNP) as a local heat source, we establish a local phase transition on the spherical GUV membrane clearly visualized using a phase sensitive fluorescent marker. We measure transient permeation events through this transition zone visualized as de-quenching of calcein as it escapes the interior of the GUV. Since biological membranes share several features with melting membranes, like nanoscale domain formation and critical density fluctuations, similar passive membrane transport could potentially be abundant in living cells. PMID- 24781037 TI - Combined effects of smoking and alcohol on metabolic syndrome: the LifeLines cohort study. AB - INTRODUCTION: The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. METHODS: 64,046 participants aged 18-80 years from the LifeLines Cohort study were categorized into three body mass index (BMI) classes (BMI<25, normal weight; BMI 25-30, overweight; BMI>=30 kg/m2, obese). MetS was defined according to the revised criteria of the National Cholesterol Education Program's Adult Treatment Panel III (NCEP ATP III). Within each BMI class and smoking subgroup (non-smoker, former smoker, <20 and >=20 g tobacco/day), the cross-sectional association between alcohol and individual MetS components was tested using regression analysis. RESULTS: Prevalence of MetS varied greatly between the different smoking-alcohol subgroups (1.7-71.1%). HDL cholesterol levels in all alcohol drinkers were higher than in non-drinkers (0.02 to 0.29 mmol/L, P values<0.001). HDL cholesterol levels were lower when they were also a former or current smoker (<20 and >=20 g tobacco/day). Consumption of <=1 drink/day indicated a trend towards lower triglyceride levels (non-significant). Concurrent use alcohol (>1 drink/day) and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. CONCLUSION: Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS. PMID- 24781038 TI - Chemomodulatory efficacy of lycopene on antioxidant enzymes and carcinogen induced cutaneum carcinoma in mice. AB - Oxidative stress has been implicated in various pathological processes, including skin tumourigenesis. Cutaneum carcinoma is commonly responsible for considerable morbidity and mortality, and treatments have not progressed substantially in recent years. Alternative strategies, such as chemoprevention, are being considered. In this study, we investigated the chemomodulatory potential of lycopene against 9,10-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced oxidative stress and skin carcinogenesis in female ICR mice. Pretreatment with lycopene at various doses significantly delayed tumour formation and growth. These treatments markedly reduced the tumour incidence and tumour volume. Moreover, lycopene inhibited the formation of reactive oxygen species and malondialdehyde, prevented the loss of glutathione, and affected the activities of a battery of oxidant enzymes in the skin of mice. Furthermore, mice that were administered lycopene exhibited higher levels of translocation of nuclear-factor-erythroid-2-related factor 2 into the nucleus compared with the vehicle-treated and model mice. Collectively, these results indicated that lycopene exerts a protective effect against DMBA/TPA-induced cutaneum carcinoma through antioxidant defence. PMID- 24781039 TI - Octreotide LAR treatment of acromegaly in "real life": long-term outcome at a tertiary care center. AB - OBJECTIVE: To report our day-to day experience with the long-term use of octreotide LAR in the treatment of acromegaly. PATIENTS AND METHODS: Patients with acromegaly managed between 2003 and 2012 with octreotide LAR for a median of 27 months (interquartile ranges 12-60) and who had not received radiation therapy or concomitant treatment with cabergoline were retrospectively evaluated. Both primarily treated patients (n = 33) and patients who received octreotide after failed pituitary surgery (adjunctive treatment, n = 124) were included. Full biochemical response was defined as the achievement of a GH <2.5 ng/mL and an IGF 1 <1.2 times the upper limit of normal (* ULN); we also evaluated efficacy using a GH cut off of <1 ng/mL. RESULTS: Over 60% of the patients achieved a GH of <2.5 ng/mL. The combined GH (<2.5 ng/mL) and IGF-1 (<1.2 * ULN) target was achieved by 35.5 and 33.6% of the patients treated primarily and adjunctively, respectively; these figures dropped to 22.6 and 23% when using a GH target of <1 ng/mL. All patients reported a significant improvement in acromegalic symptoms. Lower pretreatment GH and IGF-1 levels were both associated with a higher probability of achieving the composite biochemical target. CONCLUSION: Currently recommended GH and IGF-1 targets are reached by <36% of patients treated with octreotide LAR in a day-to day practice context. Nevertheless, in most instances a clinical benefit and an improvement in biochemical markers can be clearly documented. PMID- 24781040 TI - Trainee GP is struck off after concocting "frankly ridiculous" story to explain missing data. PMID- 24781041 TI - Glycogen phosphorylase BB levels are associated with haemodynamic parameters in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt insertion. AB - BACKGROUND: Transjugular intrahepatic portosystemic shunts (TIPS) have become a widely accepted tool in the treatment of patients with symptomatic portal hypertension. The aim of our study was to assess glycogen phosphorylase BB (GPBB) concentration in relation to echocardiographic and haemodynamic parameters in patients before and after TIPS insertion. METHODS: The study population consisted of 55 patients (38 men and 17 women, age 55.6+/-8.9 years, range 37-74 years) with liver cirrhosis treated with transjugular portosystemic shunting. GPBB, echocardiographic, and haemodynamic parameters were measured before TIPS insertion and 24 h after the procedure. GPBB concentrations were assessed using the Cardiac Array for Evidence Investigator protein biochip. Correlation between parameters was assessed using the Spearman's coefficient. RESULTS: Serum post procedural GPBB concentrations were increased in comparison with baseline (5.58 vs. 2.67 MUg/L, P<0.001). GPBB concentration after TIPS significantly correlated with baseline systemic vascular resistence (r=0.330; P=0.017) and cardiac index (r=0.313; P=0.025). CONCLUSION: GPBB concentration measurement may be a useful tool for monitoring myocardial ischemia during a TIPS procedure. PMID- 24781042 TI - The etiology of occupational pulmonary aluminosis--the past and the present. AB - BACKGROUND: The authors review pulmonary aluminosis caused by exposure to dust containing aluminium and its compounds, mainly oxides. Special attention is paid to various factors of occupational exposure as to an important etiologic issue. The condition has a rich and interesting history dating back to the 1930s. The most significant occupational exposures are associated with processes in bauxite smelting, the use of fine aluminium powder, exposure to aluminium welding fumes, grinding and polishing of aluminium materials. METHODS AND RESULTS: A literature search for relevant scientific studies in English was performed using the following internet databases: relevant sections of The Cochrane Library, EBSCO Discovery Service, Ovid, ProQuest Science Journals, PubMed, ScienceDirect, Scopus and Web of Knowledge. The initial clinical manifestations of pulmonary aluminosis are exertional dyspnea with dry, non-productive cough. Depending on the type and length of the occupational exposure, ventilatory defects may vary considerably from restrictive to obstructive pattern. Radiographic findings commonly showing nodular or slightly irregular opacities are predominantly located in the upper, less frequently in the lower lung fields, or can have a diffuse pattern. In advanced stages, severe pulmonary fibrosis with honeycombing occured. CONCLUSIONS: Although pulmonary aluminosis is a very rare disease, it still occurs. Since the industrial importance and use of aluminium continue to rise, lung damage from exposure to respirable aluminium particles should not be overlooked but monitored and prevented. Even today, the pathophysiology of pulmonary aluminosis has not been explained as yet. PMID- 24781043 TI - Xanthomas: clinical and pathophysiological relations. AB - BACKGROUND: Xanthomas are well circumscribed lesions in the connective tissue of the skin, tendons or fasciae that predominantly consist of foam cells; these specific cells are formed from macrophages as a result of an excessive uptake of low density lipoprotein (LDL) particles and their oxidative modification. RESULTS: Until recently, xanthelasma was considered to be only a cosmetic lesion; however, according to the results of recent prospective studies it is connected with an increased cardiovascular risk and reduced average lifespan. Pathogenetic mechanisms involved in the development of xanthomas resemble early stages of atherogenesis. In clinical practice, xanthomas can signalise various congenital or acquired dyslipidemias. The most prevalent form of xanthomas is xanthelasma palpebrarum. Tendinous and tuberous xanthomas are typical for autosomal dominant hypercholesterolemia, as well as for some rare conditions, such as cerebrotendinous xanthomatosis and familial beta-sitosterolemia. In patients with familial hypercholesterolemia, the presence of tendinous xanthomas has been shown to be associated with a two to four times higher risk for cardiovascular disease. Eruptive xanthomas are skin manifestations of a severe hypertriglyceridemia and implicate an elevated risk for acute pancreatitis or type 2 diabetes mellitus. Xanthoma striatum palmare is pathognomic for primary dysbetalipoproteinemia, whereas diffuse plane xanthomas are frequently associated with paraproteinemia and lymphoproliferative disorders. CONCLUSION: Thorough familiarity with the clinical presentation of xanthomas helps in the diagnosis and follow-up of different forms of dyslipidemia. Moreover, xanthelasma palpebrarum, the most prevalent form of xanthomas, is connected with increased risk of atherothrombotic disease independently of conventional cardiovascular risk factors. To fully understand the pathogenesis, further experimental and clinical research is required. PMID- 24781044 TI - Significance of serum mesothelin in an asbestos-exposed population in the Czech Republic. AB - AIMS: Pleural mesothelioma is a highly aggressive and difficult-to-treat form of cancer induced by asbestos in 80-90% of cases. The population group most at risk of the condition are asbestos-exposed workers. Mesothelin or soluble mesothelin related protein (SMRP) is studied as a potential marker of mesothelioma in the at risk population. METHODS: The study comprised 239 subjects with a mean duration of occupational exposure to asbestos of 19.9 years. In all of them, a complete medical history was taken, focused on exposure duration and a physical examination, a chest X-ray or other imaging investigations and a lung function test were performed. Their serum SMRP levels were measured and biopsy samples were taken to diagnose pleural disease. Based on the above examinations, the subjects were classified into subgroups and serum SMRP concentrations were statistically analyzed with respect to individual parameters. RESULTS: In asbestos-exposed individuals, mesothelin levels were significantly higher in those with pathological X-ray findings than in those with normal X-ray results (0.78 +/- 0.63 vs. 0.50 +/- 0.35, P<0.0001). The group of patients with benign disease had statistically significantly higher mesothelin levels than those with normal X-ray findings (0.755 +/- 0.543 vs. 0.50 +/- 0.35, P<0.001). In the group with present malignant processes, mesothelin levels were higher than in individuals with benign disease (1.19 +/- 0.89 vs. 0.76 +/- 0.54, P=0.015). Only a weak correlation was found between mesothelin levels and asbestos exposure duration. There were relatively high sensitivity and high specificity (75% and 90.6%, respectively) of serum mesothelin for pleural mesothelioma. However, given the small number of mesothelioma cases in the group, the results cannot be considered as statistically significant. CONCLUSIONS: In persons followed up for asbestos exposure, increased mesothelin levels signalize pathological processes in the chest and correlate with severity of the disease. The study suggests that mesothelin cannot be considered a reliable marker for the early stage of malignant degeneration of pleural disease but only an additional criterion for examination of the followed-up individuals. PMID- 24781045 TI - A new twist in neuroendocrine tumor research: Pacak-Zhuang syndrome, HIF-2alpha as the major player in its pathogenesis and future therapeutic options. AB - Backround. There is increasing evidence of the role of hypoxia or pseudohypoxia in tumorigenesis, including pheochromocytoma (PHEO) and paraganglioma (PGL). (Pseudo)hypoxia leads to activation of hypoxia-inducible transcription factors (HIFs) and thus, promotes the transcription of hypoxia-responsive genes which are involved in tumorigenesis. Recently identified is a new syndrome consisting of multiple and recurrent PGLs or PHEOs, somatostatinoma, and congenital polycythemia, due to somatic hypoxia-inducible factor 2alpha gene (HIF2A) mutations. METHODS AND RESULTS: PubMed and Web of Science online databases were used to search reviews and original articles on the HIF, PHEO/PGL, and Pacak Zhuang syndrome. CONCLUSIONS: The novel somatic and germline gain-of-function HIF2A mutations described latterly emphasize the role of the HIF-2alpha in the PHEO/PGL development and these findings designate HIF, especially HIF-2alpha, as a promising treatment target. PMID- 24781047 TI - Communication: the good, the bad, and the ugly. PMID- 24781046 TI - Na(+)/K(+)-ATPase inhibition by cisplatin and consequences for cisplatin nephrotoxicity. AB - AIMS: Cisplatin is a widely used chemotherapeutic. However, it is associated with numerous adverse effects. The aim of our study was examination of cisplatin interaction with Na(+)/K(+)-ATPase (NKA, the sodium pump). This enzyme is of crucial importance for all animal cells and particularly for the kidney, which is frequently damaged during chemotherapy. METHODS: The entire NKA was isolated from porcine kidney. Its large cytoplasmic segment connecting transmembrane helices 4 and 5 (C45), was heterologously expressed in E.coli (wild-type or C367S mutant). The ATPase activity was evaluated according to the inorganic phosphate production and the interaction of isolated C45 with cisplatin was studied using chronopotentiometry and mass spectrometry. RESULTS: Our experiments revealed that cisplatin can inhibit NKA. The finding that other platinum-based drugs with a low nephrotoxicity, carboplatin and oxaliplatin, did not inhibit NKA, suggested that NKA/cisplatin interaction is an important factor in cisplatin adverse effects. The inhibitory effect of cisplatin could be prevented by preincubation of the enzyme with reduced glutathione or DTT. Using chronopotentiometry and mass spectrometry, we found that cisplatin is bound to C45. However, our mutagenesis experiment did not confirm that the suggested Cys367 could be the binding site for cisplatin. CONCLUSION: Unintended interactions of drugs present serious limitations to treatment success. Although a large number of membrane pumps have been identified as potential targets of cisplatin, vis-a-vis nephrotoxicity, NKA inhibition seems to be of crucial importance. Experiments with isolated large cytoplasmic segment C45 revealed that it is the main target of cisplatin on NKA and that the reaction with cysteine residues plays an important role in cisplatin/NKA interactions. However, further experiments must be performed to identify the interacting amino acid residues more precisely. PMID- 24781048 TI - Transient ischemic attack: heed the warning. PMID- 24781049 TI - Quantum-chemical insights into mixed-valence systems: within and beyond the Robin Day scheme. AB - In mixed-valence (MV) systems essentially identical, more or less electronically coupled, redox centres are brought into formally different oxidation states by removal or addition of an electron. Depending on the strength of electronic coupling, an electron or a hole is either concentrated on one of the redox centres, or it is symmetrically delocalised onto several sites, or the situation is somewhere in between, which leads to the classification system for MV systems introduced by Melvin Robin and Peter Day. These different characteristics are of fundamental importance for the understanding of electron transfer processes. Applications of quantum-chemical methods to aid the classification and to unravel the nature of the electronic structure and spectroscopic data of both organic and transition-metal MV systems, have gained tremendous importance over the last two decades. In this review, we emphasise the prerequisites the quantum-chemical methods need to fulfill to successfully describe MV systems close to the borderline between Robin-Day classes II and III. These are, in particular, a balanced treatment of exchange, dynamical and non-dynamical correlation effects, as well as consideration of the crucial influence of the (solvent or solid-state) environment on the partial localisation of charge. A large variety of applications of quantum-chemical methods to both organic and inorganic MV systems are critically appraised here in view of these prerequisites. Practical protocols based on a combination of suitable density functional methods with continuum or non-continuum solvent models provided good agreement with experimental data for the ground states and the electronic excitations of a large range of MV systems close to the borderline. Recent applications of such methods have highlighted the crucial importance of conformational effects on electronic coupling, all the way to systems where conformational motion may cause a thermal mixing of class II and class III situations in one system. PMID- 24781050 TI - Differential effect of vitamin D on NOD2- and TLR-induced cytokines in Crohn's disease. AB - Accumulating evidence implicates defective innate immunity in the pathogenesis of Crohn's disease (CD). Ineffectual NOD2 (nucleotide-binding oligomerization domain 2) is the most common susceptibility gene contributing to CD. Vitamin D (vD), a potent modulator of innate and adaptive immunity, induces NOD2 gene expression and its downstream function. We hypothesized that the hormonal form of vD (1,25D) could beneficially modulate innate immune function in CD. Using peripheral mononuclear cells and monocyte-derived dendritic cells (Mo-DCs) from CD, it was found that 1,25D decreased Toll-like receptor (TLR)-induced cytokine production and enhanced cytokine levels induced by muramyl dipeptide (MDP), the NOD2 ligand. 1,25D increased the synergistic effect provided by NOD2 and TLR co-activation on interleukin (IL)-10, IL-23, and tumor necrosis factor-alpha (TNF-alpha). Whereas 1,25D inhibits Mo-DC TLR-induced cytokines, co-stimulation of NOD2 results in increased IL-10 and IL-23. IL-12p70 was completely abrogated by 1,25D. 1,25D similarly modulated cytokine production by immune cells in ulcerative colitis patients and healthy controls. Mo-DCs from CD patients heterozygous for NOD2 mutations had a response similar to those from patients without NOD2 mutations. Immune cells from patients homozygous for the 1007 fs mutation were unresponsive to MDP and 1,25D. Our in vitro data support 1,25D as a potential modulator of immunity. However, these results cannot be extrapolated to CD patients without further controlled studies. PMID- 24781051 TI - Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice. AB - T cells have a critical role in immune surveillance at mucosal surfaces. SHIP1(-/ ) mice succumb to mucosal inflammatory disease that afflicts the lung and small intestine (SI). The basis of this condition has not been defined. Here we show that SHIP1 is required for the normal persistence and survival of T cells in mucosal tissues. We find that CD4 and CD8 effector T cells are reduced; however, Treg cells are increased in the SI and lungs of SHIP1(-/-) and CD4CreSHIP(flox/flox) mice. Furthermore, a subset of T cells in the SI of SHIP1( /-) mice are FasL(+) and are more susceptible to extrinsic cell death. Mechanistic analyses showed that SHIP1 associates with the death receptor CD95/Fas and treatment with a Caspase 8 inhibitor prevents SHIP1 inhibitor mediated T-cell death. Notably, mucosal inflammation in SHIP1(-/-) mice is reduced by treatment with a Caspase 8 inhibitor. We also find that the incidence of Crohn's disease (CD) and pneumonia is significantly increased in mice with dual T and myeloid lineage SHIP1 deletion but not in single lineage-deleted mice. Thus, by promoting survival of protective T cells, thereby preventing an inflammatory myeloid response, SHIP1 maintains an appropriate balance of innate immune function at mucosal surfaces necessary for immune homeostasis. PMID- 24781053 TI - Erratum to: surface alterations of zirconia and titanium substrates after Er, Cr:YSGG irradiation. PMID- 24781052 TI - T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes. AB - Intestinal T helper type 2 (Th2) immunity in food allergy results in IgG1 and IgE production, and antigen re-exposure elicits responses such as anaphylaxis and eosinophilic inflammation. Although interleukin-4 (IL-4) is critically required for allergic sensitization, the source and control of IL-4 during the initiation of Th2 immunity in vivo remains unclear. Non-intestinal and non-food allergy systems have suggested that natural killer-like T (NKT) or gammadelta T-cell innate lymphocytes can supply the IL-4 required to induce Th2 polarization. Group 2 innate lymphoid cells (ILCs) are a novel IL-4-competent population, but their contribution to initiating adaptive Th2 immunity is unclear. There are also reports of IL-4-independent Th2 responses. Here, we show that IL-4-dependent peanut allergic Th2 responses are completely intact in NKT-deficient, gammadelta T-deficient or ILC-deficient mice, including antigen-specific IgG1/IgE production, anaphylaxis, and cytokine production. Instead, IL-4 solely from CD4(+) Th cells induces full Th2 immunity. Further, CD4(+) Th cell production of IL-4 in vivo is dependent on OX40L, a costimulatory molecule on dendritic cells (DCs) required for intestinal allergic priming. However, both Th2 cells and ILCs orchestrated IL-13-dependent eosinophilic inflammation. Thus, intestinal Th2 priming is initiated by an autocrine/paracrine acting CD4(+) Th cell-intrinsic IL 4 program that is controlled by DC OX40L, and not by NKT, gammadelta T, or ILC cells. PMID- 24781054 TI - Acupuncture combined with an antidepressant for patients with depression in hospital: a pragmatic randomised controlled trial. AB - OBJECTIVE: To assess the effectiveness of acupuncture combined with selective serotonin reuptake inhibitors (SSRIs) for patients with depression in hospital using a pragmatic randomised controlled trial. METHODS: 76 patients with depression were randomly divided into two groups (randomisation ratio 2:1 for treatment and control groups (CGs), respectively) and 71 patients completed the study. The 45 patients in the treatment group (TG) underwent acupuncture and received an SSRI and the 26 patients in the CG received an SSRI only. The 17-item Hamilton Depression Rating Scale (HDRS-17) was used to quantitatively assess patients after 1, 2, 4 and 6 weeks of treatment. RESULTS: The mean (SD) baseline total HDRS scores were 22.2 (0.60) and 22.1 (0.33) in the TG and CG, respectively. After the first week of treatment the HDRS score for the TG was reduced to 15.6 (0.81), significantly different from the score of 18.3 (0.55) for the CG, p<0.05. This significant difference was maintained to the end of the 6 week treatment period, when HDRS scores had fallen to 6.3 (0.49) and 8.2 (0.35) for the TG and CG, respectively. CONCLUSIONS: Acupuncture combined with an SSRI showed a statistically significant benefit for patients with depression in hospital over the 6-week period compared with SSRIs alone. This reduction in symptoms started in the first week and continued throughout the 6 weeks of treatment. PMID- 24781056 TI - Inhibitors of the glyoxylate cycle enzyme ICL1 in Candida albicans for potential use as antifungal agents. AB - Candida albicans is an opportunistic pathogen that causes candidiasis in humans. In recent years, metabolic pathways in C. albicans have been explored as potential antifungal targets to treat candidiasis. The glyoxylate cycle, which enables C. albicans to survive in nutrient-limited host niches and its. Key enzymes (e.g., isocitrate lyase (ICL1), are particularly attractive antifungal targets for C. albicans. In this study, we used a new screening approach that better reflects the physiological environment that C. albicans cells experience during infection to identify potential inhibitors of ICL. Three compounds (caffeic acid (CAFF), rosmarinic acid (ROS), and apigenin (API)) were found to have antifungal activity against C. albicans when tested under glucose-depleted conditions. We further confirmed the inhibitory potential of these compounds against ICL using the ICL enzyme assay. Lastly, we assessed the bioavailability and toxicity of these compounds using Lipinski's rule-of-five and ADMET analysis. PMID- 24781057 TI - Managing infections in pregnancy. AB - PURPOSE OF REVIEW: The management of infection in pregnancy aims mainly at improving the diagnosis and prognosis of congenital infections. Over 400 publications have dealt with this issue over the last 2 years, taking advantage of progress made not only in the epidemiological knowledge of infections but also neonatal treatment and prenatal diagnosis and interventions. The focus remains largely on viral and parasitic infections, namely cytomegalovirus (CMV) and toxoplasmosis, with the appearance of influenza as part of recent and severe outbreaks. RECENT FINDINGS: The prevalence of CMV infection is stable. The prediction of foetal infection from primary maternal infection is becoming more accurate and therapeutic approaches are promising, including the development of a vaccine in the near future. The prevalence of toxoplasmosis is decreasing markedly in Europe weakening the effect of preventive measures and questioning the rationale for screening. In addition, the efficacy of prenatal treatment is still under scrutiny, although no appropriate randomized controlled trial (RCT) has been undertaken. SUMMARY: Accurate dating of maternal primary infection is key to prenatal management including foetal and perinatal surveillance and therapy. Heightened prenatal surveillance following influenza infection in early pregnancy is warranted by an apparent increased risk of nonchromosomal congenital malformations in large epidemiological studies, likely as an effect of maternal hyperthermia. PMID- 24781059 TI - Interstellar H adsorption and H2 formation on the crystalline (010) forsterite surface: a B3LYP-D2* periodic study. AB - The physisorption/chemisorption of atomic hydrogen on a slab model of the Mg2SiO4 forsterite (010) surface mimicking the interstellar dust particle surface has been modeled using a quantum mechanical approach based on periodic B3LYP-D2* density functional calculations (DFT) combined with flexible polarized Gaussian type basis sets, which allows a balanced description of the hydrogen/surface interactions for both minima and activated complexes. Physisorption of hydrogen is barrierless, very weak and occurs either close to surface oxygen atoms or on Mg surface ions. The contribution of dispersion interactions accounts for almost half of the adsorption energy. Both the hydrogen adsorption energy and barrier to hydrogen jump between equivalent surface sites are overestimated compared to experimental results meant to simulate the interstellar conditions in the laboratory. The hydrogen atom exclusively chemisorbs at the oxygen site of the forsterite (010) surface, forming a SiOH surface group and its spin density being entirely transferred to the neighboring Mg ion. Barrier for chemisorption allows rapid attachment of H at the surface at 100 K, but prevents the same process from occurring at 10 K. From this H-chemisorbed state, the second hydrogen chemisorption mainly occurs on the neighboring Mg ion, thus forming a Mg-H surface group, giving rise to a surface species stabilized by favorable electrostatic interactions between the OHH-Mg pair. The formation of molecular hydrogen at the (010) forsterite surface adopting a Langmuir-Hinshelwood mechanism takes place either starting from two physisorbed H atoms with an almost negligible kinetic barrier through a spin-spin coupling driven reaction or from two chemisorbed H atoms with a barrier surmountable even at T higher than 10 K. We also suggest that a nanosized model of the interstellar dust built from a replica of the forsterite unit cell is able to adsorb half the energy released by the H2 formation by increasing its temperature by about 50 K which could then radiate in about 0.02 s. PMID- 24781060 TI - Development of a complete set of monosomic alien addition lines between Brassica napus and Isatis indigotica (Chinese woad). AB - KEY MESSAGE: A complete set of monosomic alien addition lines of Brassica napus with one of the seven chromosomes of Isatis indigotica and the recombinant mitochondria was developed and characterized. Monosomic alien addition lines (MAALs) are valuable for elucidating the genome structure and transferring the useful genes and traits in plant breeding. Isatis indigotica (Chinese woad, 2n = 14, II) in Isatideae tribe of Brassicaceae family has been widely cultivated as a medicinal and dye plant in China. Herein, the intertribal somatic hybrid (2n = 52, AACCII) between B. napus cv. Huashuang 3 (2n = 38, AACC) and I. indigotica produced previously was backcrossed recurrently to parental B. napus, and 32 MAAL plants were isolated. Based on their phenotype, 5S and 45S rDNA loci and chromosome-specific SSR markers, these MAALs were classified into seven groups corresponding to potential seven types of MAALs carrying one of the seven I. indigotica chromosomes. One of the MAALs could be distinguishable by expressing the brown anthers of I. indigotica, other two hosted the chromosome with 5S or 45S rDNA locus, but the remaining four were identifiable by SSR markers. The simultaneous detection of the same SSR maker and gene locus in different MAALs revealed the paralogs on the chromosomes involved. The recombinant mitochondrial genome in MAALs was likely related with their male sterility with carpellody stamens, while the MAAL with normal brown anthers probably carried the restoring gene for the male sterility. The complete set of MAALs should be useful for exploiting the I. indigotica genome and for promoting the introgression of valuable genes to B. napus. PMID- 24781061 TI - Optofluidic laser for dual-mode sensitive biomolecular detection with a large dynamic range. AB - Enzyme-linked immunosorbent assay (ELISA) is a powerful method for biomolecular analysis. The traditional ELISA employing light intensity as the sensing signal often encounters large background arising from non-specific bindings, material autofluorescence and leakage of excitation light, which deteriorates its detection limit and dynamic range. Here we develop the optofluidic laser-based ELISA, where ELISA occurs inside a laser cavity. The laser onset time is used as the sensing signal, which is inversely proportional to the enzyme concentration and hence the analyte concentration inside the cavity. We first elucidate the principle of the optofluidic laser-based ELISA, and then characterize the optofluidic laser performance. Finally, we present the dual-mode detection of interleukin-6 using commercial ELISA kits, where the sensing signals are simultaneously obtained by the traditional and the optofluidic laser-based ELISA, showing a detection limit of 1 fg ml(-1) (38 aM) and a dynamic range of 6 orders of magnitude. PMID- 24781062 TI - [Complex application of laparoscopic vagotomy in case of hard scarring ulcers after gastroduodenal bleeding]. AB - 654 patients with ulcerative gastroduodenal bleeding from duodenum were under observation. It was done the meta-analysis of treatment results of 111 patients with hard scarring duodenal ulcers. It was discovered high efficiency of organ preserving operations such aslaparoscopic vagotomy and proton pump inhibitors in these observations. PMID- 24781063 TI - [Indications for surgical treatment of hard scarring gastric ulcers]. AB - It was done the comparative analysis of the morphofunctional state of the upper gastrointestinal tract between 350 patients with effective conservative treatment and 104 patients with hard scarring gastric ulcers. The analysis identified the predictors of ineffective medical treatment and led to deliver the indications for timely surgical treatment. It was identified the next indications for planned organ-preserving surgical treatment of patients with hard scarring gastric ulcers: penetrating and non-healing ulcers with large or gigantic size in case of the adequate medical therapy, high-grade dysplasia and colonic metaplasia of the gastric epithelium in the borders or fundus of the ulcer,ulcers combination with fixed cardio-fundal or fundo-corporal hiatal hernias; hypotonic-hypokinetic type of the gastric and duodenal activity with the development of gastrostasis and pronounced duodenogastric reflux. PMID- 24781064 TI - [Low level of 25-OH-vitamin D as a marker of critical ischemia in case of diabetic foot syndrome]. AB - It was done the prospective study of the examination results of 40 patients with diabetes mellitus. All patients were divided into 2 groups for study of 25-OH vitamin D effect, cholesterol, triglycerides in blood serum on the nature of diabetes mellitus. The first group included patients with ulcero-necrotic injuries in case of neuro-ischemic forms of diabetic foot syndrome. The second group included patients without such injuries. It was significantly determined that there was more neuro-ischemic injuries in case of 25-OH-vitamin D level less than 30 nmol/l. Injuries are connected with reduction of arterial inflow because of osslusive-stenotic lesions of arteries. 25-OH-vitamin D level less than 30 nmol/l is a marker of neuro-ischemic injuries of foot in case of diabetes mellitus. This indication is more specific than cholesterol and triglycerides levels. PMID- 24781065 TI - [The impact of antisecretory therapy on gastroduodenal ulcers healing after acute bleeding]. AB - In this paper we compared the efficacy of proton pump inhibitors (PPIs) and H2 receptor antagonists on the morphogenesis of the marginal zone of gastric and duodenal ulcers in 56 patients withacute gastroduodenal bleeding. It is shown that the antisecretory drugs in the treatment of patients with acute ulcerative bleedingnot only affect on the secretory activity of the glands in gastroduodenal zone, but it also modulates inflammatory reparative process and the status of mucous and bicarbonate barrier. A greater anti-inflammatory effect of PPI in comparison with H2-receptor antagonists has been proved. Appointment of PPIs had more pronounced stimulation of angiogenesis and cell proliferation of the surface epithelium. PMID- 24781066 TI - [Ultrasound scanning of the distraction regenerate in case of multilocus elongation of the fragments in patients with defects of long bones]. AB - It was done ultrasound examination of distraction regenerates in patients with defect of bone tissue. The first group included 4 patients who had the size of congenital bone tissue defect 15.8+/-8.1 cm; the second group (3 patients) included posttraumatic defects with defect size 11.75+/-3.6 cm; the third group (4 patients) included posttraumatic defects with defect size 11+/-5.3 cm. It was discovered the particularities of distraction regenerate structural condition in case of low level of reparative osteogenesis. In the first group "ischemic" regenerate was characterized by slow formation of bone trabecules. In the second group "ischemic" regenerate had one or two hypo-echogenic cystic-like formations in the intermediate regenerate area. All patients of the third group had organotypic remodeling of the regenerate according to terms of distraction and fixation. PMID- 24781067 TI - [The particularities of acute surgical diseases treatment of abdominal cavity organs in patients with haemophilia]. AB - The experience of treatment of 366 patients with haemophilia who were urgently hospitalized in hematological Scientific Center over the last 10 years is presented in the article. There were 114 (31.1%) patients with acute diseases of abdominal cavity organs, 150 (41%) patients with bleeding from upper gastrointestinal tract, 102 (27.9%) patients with acute hematomas of retroperitoneal space. Urgent operations were performed in 48 (22.2%) patients who were hospitalized with clinical symptoms of acute abdomen syndrome. It was developed the criteria of diagnosis and choice of treatment tactic on the basis of the received results. Application of presented algorithms led to improve the quality of urgent surgical care to patients with haemophilia. PMID- 24781068 TI - [Comparative effectiveness of different treatment methods of liver failure]. AB - It was analyzed the results of treatment of 217 patients (139 men, 78 women) with chronic liver failure in case of liver cirrhosis of various etiology for study of degree of hepatic encephalopathyregression. All patients were divided into 3 groups. In the first group the drug therapy was used. In the second group additionallyplasma exchange was performed, in the third group - alsomolecular absorbent recirculating system was used (effectiveness of MARS-therapy).The results showed that the use of extracorporeal treatment techniques can effectively reduce the severity of hepatic encephalopathy in patients with liver cirrhosis. MARS-therapy improved the neurological status of patientsmore significantly in this case. It is considered that the inclusion of MARS-therapy in the combined treatment of patients leads to a significant reduction of hepatic encephalopathyseverity (1-2 points), in comparison with other methods of treatment. PMID- 24781069 TI - [Opportunities of computed tomographic colonography in detecting of colon neoplasms]. AB - The computed tomographic colonoscopy (CTC) was performed in 212 patients on the multislice computed tomography Siemens Open in low-dose mode during the period from 2010 to 2013. CTC was tolerated well by 80% of patients. 20% of patients complained of mild discomfort during the study. The optical colonoscopy with biopsy was done in 53 (25%) of 212 patients after CPC. This is due to the fact that it was not detected the significant endoluminal structures in other observations or small polyps were found in elderly patients. In these cases the risk of colonoscopy was not justified. Sensitivity and specificity of CTC was 55 and 91% respectively for the detection of polyps with diameter less than 5 mm; for polyps 5-9 mm - 85 and 93%; for polyps with diameter greater than 10 mm - 100 and 92%. PMID- 24781070 TI - [Hemorrhoidal disease accompanied by anal prolapsus and its treatment methods]. AB - The objective of this research is to evaluate specifications of the surgery, its post-operative period and complications in patients with traditional hemorrhoidectomy which is a procedure performed by using a linear stapler along with a circular resection of prolapsed mucosal and sub-mucosal layers of lower rectal ampulla with the utilization of Longo technique. The study was conducted with the participation of 398 patients with the hemorrhoidal disease accompanied by anal prolapsus of which 338 (84%) were composed of males and 65 (16%) of females. Out of 398 patients, 308 (77%) underwent stapler hemorrohidectomy using linear stapler, 74 (19%) patients had conventional hemorrhoidectomy with the utilization of electric coagulation and 16 (4%) of them received circular hemorroidopexy using Longo technique. According to the data obtained during this research linear stapler use in the treatment of hemorroidal desease, accompanied by anal prolapses is an effective and technically simple solution to the problem. This method is implemented quickly, allows to cover greater part of abnormally changed cavernous tissue and conduct persist lifting of anal canal mucosal layer. It is also a safe method without any disease relapses. PMID- 24781071 TI - [Venous thromboembolic complications in patients with intracranial hemorrhage and tumors of the central nervous system]. AB - It was analyzed the results of diagnosis and prevention of venous thromboembolic complications in 248 patients with intracranial hemorrhages of different etiology (hemorrhagic stroke, subarachnoid hemorrhage, craniocerebral injury, hemorrhages in the tumors of brain and spinal cord). The overall frequency of venous thrombosis in the vessels of the inferior vena cava pool was 24.6% (in 61 patients), the majority of patients had the asymptomatic thrombosis. The crural veins were the main localization of venous thrombosis. Also it was the main origin of thromboembolic complications (60.7%). Surgical treatment in different amount was an independent predictor of venous thromboembolic complications in neurosurgical patients according to the multivariate variance analysis. The frequency of thrombosis was significantly higher in the group of operated patients in comparison with non-operated group (37.1 vs. 17.6% (p=0.008). Early prevention by geparin (the use of direct anticoagulants for 2-4-th day of the founding of an intracranial hematoma) did not reduce the frequency of venous thrombosis in operated patients, but significantly reduced the frequency of fatal pulmonary embolism: 0 vs. 9.1% (p=0.002). Patients with intracranial hemorrhage are the one of the most unfavorable groups in terms of their venous thromboembolic complications. PMID- 24781072 TI - [Endovascular treatment of post-traumatic arteriovenous fistula of the splenic artery]. PMID- 24781073 TI - [Gastrointestinal bleeding from pancreatoduodenal artery with arrosion by ligature]. PMID- 24781074 TI - Novel Approaches for Preventing or Limiting Events (NAPLES III) Trial: randomised comparison of bivalirudin versus unfractionated heparin in patients at high risk of bleeding undergoing elective coronary stenting throught the femoral approach. rationale and design. AB - PURPOSE: Bivalirudin (Angiox, The Medicine's Company, Parsippany, NJ), a synthetic direct thrombin inhibitor, when compared with standard antithrombotic therapy (including unfractionated heparin [UFH] alone or plus a glycoprotein IIb/IIIa inhibitor) determines a significant decrease of major and minor bleeding and similar protection against ischemic events both in elective and in urgent percutaneous coronary intervention (PCI). There is a lack of prospective clinical trial assessing the safety and the efficacy of bivalirudin compared with UFH alone in the subset of biomarker negative patients at high risk of bleeding undergoing to elective PCI through the femoral approach. METHODS: This is a single-center, investigator-driven, randomized, double-blind, controlled trial ( www.clinicaltrial.gov registration: NCT01465503). Consecutive patients at high bleeding risk (score >=10 according to Nikolsky et al.) undergoing elective PCI through the femoral approach will be screened for eligibility. Included patients will be randomized (ratio 1.1) to bivalirudin (Bivalirudin group) and UFH (UFH group). The primary endpoint will be the rate of major bleeding (REPLACE 2 criteria). We expect a major bleeding rate >=5 % in the UFH group versus a <=3 % event rate in the Bivalirudin group. Aiming for a 0.05 alpha and 0.80 power, a total of 662 patients will be needed. This number will be increased by about 25 % (leading to a total of ~830 patients) because of uncertainty about expected endpoint rates. CONCLUSIONS: The present trial will give important information on what is the best anticoagulation regimen when performing PCI through the femoral approach in patients at high risk for bleeding. PMID- 24781075 TI - Mapping of Yr62 and a small-effect QTL for high-temperature adult-plant resistance to stripe rust in spring wheat PI 192252. AB - KEY MESSAGE: This manuscript reports a new gene (Yr62) and a small-effect QTL for potentially durable resistance to stripe rust and usefulness of Yr62 markers for marker-assisted selection. Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a devastating disease of wheat worldwide. Spring wheat germplasm PI 192252 showed a high level of high-temperature adult-plant (HTAP) resistance to stripe rust in germplasm evaluation over 8 years in the State of Washington. To elucidate the genetic basis of resistance, PI 192252 was crossed with 'Avocet susceptible'. A mapping population of 150 F5 recombinant inbred lines was developed using single-seed descent. Stripe rust tests were conducted with selected Pst races in a greenhouse and in field conditions under natural infections. The relative area under the disease progress curve (rAUDPC) data showed continuous distributions, indicating that HTAP resistance of PI 192252 was controlled by quantitative trait loci (QTL). Two QTL were identified in PI 192252, explaining 74.2 % of the total phenotypic variation for rAUDPC. These two QTL were mapped to chromosomes 4BL (QYrPI192252.wgp-4BL) and 5BS (QYrPI192252.wgp 5BS) with SSR and SNP markers and explained 40-60 and 22-27 %, respectively, of the phenotypic variation across the four environments. Because the major-effect QTL on 4BL is different from previously named Yr genes and inherited as a single gene, it is named Yr62. The SSR marker alleles Xgwm192 222 and Xgwm251 133 flanking Yr62 were different from the alleles in various wheat varieties, suggesting that these markers could be useful in marker-assisted selection for incorporating Yr62 into commercial cultivars. PMID- 24781076 TI - Epidemiological association between migraine and lipoprotein(a): a systematic review. AB - Migraine is a relatively frequent and disabling condition, which poses a large clinical and economical burden on human society. Since there is now emerging evidence that the risk of cardiovascular diseases may be significantly increased in patients with migraine, and that lipoprotein(a) is a powerful, independent cardiovascular risk factor, we performed an electronic searched on Medline, Scopus and Web of Science using the keywords "migraine" and "lipoprotein(a)" or "apolipoprotein(a)" or "Lp(a)" or "apo(a)", with no language or date restriction. The electronic search produced four cross-sectional studies which reported original data about the epidemiological association between lipoprotein(a) and migraine, and used standardized criteria for diagnosing migraine. In only one out of the four studies the concentration of lipoprotein(a) was found to be higher in migraineurs than in controls, whereas in the remaining three investigations lipoprotein(a) levels were found to be virtually identical between cases and controls. This analysis suggests that if any epidemiological and clinical link exists between migraine and cardiovascular disease, a direct involvement of lipoprotein(a) seems unlikely according to the available epidemiological evidence. PMID- 24781077 TI - The reliability of intraoperative electrocorticography in magnetic resonance imaging-negative temporal lobe epilepsy: spikes mark the spot. PMID- 24781078 TI - Stroke literature synopses: basic science. PMID- 24781079 TI - White matter hyperintensities and their penumbra lie along a continuum of injury in the aging brain. AB - BACKGROUND AND PURPOSE: Aging is accompanied by clinically silent cerebral white matter injury identified through white matter hyperintensities (WMHs) on fluid attenuated inversion recovery (FLAIR)- and diffusion tensor imaging-based measures of white matter integrity. The temporal course of FLAIR and diffusion tensor imaging changes within WMHs and their less-injured periphery (ie, their penumbra), however, has not been fully studied. We used longitudinal diffusion tensor imaging and FLAIR to explore these changes. METHODS: One hundred fifteen participants, aged 73.7+/-6.7 years, received clinical evaluations and MRIs on 2 dates. WMHs and fractional anisotropy (FA) maps were produced from FLAIR and diffusion tensor imaging and coregistered to a standardized space. Each distinct WMH was categorized as growing, stagnant, or noncontiguous incident. The penumbra of each WMH was similarly categorized as corresponding to a stagnant, growing, or noncontiguous incident WMH. Linear mixed-effect models were used to assess whether FA and FLAIR measurements changed between baseline and follow-up and differed between tissue categories. RESULTS: Baseline FA differed significantly by tissue category, with the following ordering of categories from highest to lowest FA: penumbra of noncontiguous incident, then stagnant, then growing WMHs; noncontiguous incident, then stagnant, then growing WMHs. Despite differences in baseline values, all tissue categories experienced declines in FA over time. Only noncontiguous incident WMHs showed significant FLAIR signal increases over time, and FLAIR signal significantly decreased in stagnant WMHs. CONCLUSIONS: WMHs and their penumbra vary in severity and together span a continuous spectrum of white matter injury that worsens with time. FLAIR fails to capture this continuous injury process fully but does identify a subclass of lesions that seem to improve over time. PMID- 24781081 TI - Intravenous thrombolysis of basilar artery occlusion: thrombus length versus recanalization success. AB - BACKGROUND AND PURPOSE: In middle cerebral artery occlusion, probability of recanalization after intravenous tissue-type plasminogen activator thrombolysis (IVT) was reported to drop <1% for thrombi exceeding 8 mm. We aimed to evaluate the effect of thrombus length and location on success of recanalization after IVT in basilar artery occlusion. METHODS: We evaluated 164 consecutive patients with angiography-proven basilar artery occlusion and available thrombus length. We excluded 24 patients who underwent endovascular treatment. All included patients (n=140) received IVT. Thrombolysis in myocardial infarction 2 to 3 was considered as successful recanalization. RESULTS: Of the 140 included patients, 37 (26.4%) lacked post-treatment angiography, mostly because of early death. Of the remaining 103 patients, those with recanalization had shorter thrombi (median, 5.5 mm and mean, 9.7 mm) when compared with those with nonrecanalized (median, 15.0 mm and mean, 16.6 mm; P<0.001). Thrombi shorter than 10 mm had 70% to 80% probability of recanalization, whereas 10 to 20 mm, 20 to 30 mm, and >30 mm long thrombi had probabilities of 50% to 70%, 30% to 50%, and 20% to 30%, respectively. Patients with thrombi <10 mm (n=52) and recanalization had more frequently top-of-the basilar (92.5%) and less frequently caudal or midbasilar (7.5%) clot location (P=0.01). In multivariable analysis, thrombus length was independently associated with recanalization (P=0.001). Their relationship remained linear across all lengths. CONCLUSIONS: Although recanalization of basilar artery occlusion with IVT depends on thrombus length, its probability even in patients with thrombi >30 mm (20%-30%) was substantially higher than minimal recanalization of middle cerebral artery thrombi exceeding 8 mm. There was no threshold length, beyond which basilar artery occlusion recanalization with IVT could ad hoc be deemed hopeless. PMID- 24781080 TI - Age of collagen in intracranial saccular aneurysms. AB - BACKGROUND AND PURPOSE: The chronological development and natural history of cerebral aneurysms (CAs) remain incompletely understood. We used (14)C birth dating of a main constituent of CAs, that is, collagen type I, as an indicator for biosynthesis and turnover of collagen in CAs in relation to human cerebral arteries to investigate this further. METHODS: Forty-six ruptured and unruptured CA samples from 43 patients and 10 cadaveric human cerebral arteries were obtained. The age of collagen, extracted and purified from excised CAs, was estimated using (14)C birth dating and correlated with CA and patient characteristics, including the history of risk factors associated with atherosclerosis and potentially aneurysm growth and rupture. RESULTS: Nearly all CA samples contained collagen type I, which was <5 years old, irrespective of patient age, aneurysm size, morphology, or rupture status. However, CAs from patients with a history of risk factors (smoking or hypertension) contained significantly younger collagen than CAs from patients with no risk factors (mean, 1.6+/-1.2 versus 3.9+/-3.3 years, respectively; P=0.012). CAs and cerebral arteries did not share a dominant structural protein, such as collagen type I, which would allow comparison of their collagen turnover. CONCLUSIONS: The abundant amount of relatively young collagen type I in CAs suggests that there is an ongoing collagen remodeling in aneurysms, which is significantly more rapid in patients with risk factors. These findings challenge the concept that CAs are present for decades and that they undergo only sporadic episodes of structural change. PMID- 24781082 TI - Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy. AB - BACKGROUND AND PURPOSE: Accumulation of amyloid-beta in cerebral blood vessels occurs in familial and sporadic forms of cerebral amyloid angiopathy and is a prominent feature of Alzheimer disease. However, the functional correlates of the vascular pathology induced by cerebral amyloid angiopathy and the mechanisms involved have not been fully established. METHODS: We used male transgenic mice expressing the Swedish, Iowa, and Dutch mutations of the amyloid precursor protein (Tg-SwDI) to examine the effect of cerebral amyloid angiopathy on cerebrovascular structure and function. Somatosensory cortex cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized Tg-SwDI mice and wild type littermates equipped with a cranial window. RESULTS: Tg-SwDI mice exhibited reductions in cerebral blood flow responses to whisker stimulation, endothelium dependent vasodilators, or hypercapnia at 3 months when compared with wild-type mice, whereas the response to adenosine was not attenuated. However, at 18 and 24 months, all cerebrovascular responses were markedly reduced. At this time, there was evidence of cerebrovascular amyloid deposition, smooth muscle fragmentation, and pericyte loss. Neocortical superfusion with the free radical scavenger manganic(I-II)meso-tetrakis(4-benzoic acid) porphyrin rescued endothelium dependent responses and functional hyperemia completely at 3 months but only partially at 18 months. CONCLUSIONS: Tg-SwDI mice exhibit a profound age dependent cerebrovascular dysfunction, involving multiple regulatory mechanisms. Early in the disease process, oxidative stress is responsible for most of the vascular dysfunction, but with advancing disease structural alterations of the vasomotor apparatus also play a role. Early therapeutic interventions are likely to have the best chance to counteract the deleterious vascular effects of cerebral amyloid angiopathy. PMID- 24781083 TI - Psychological associations of poststroke fatigue: a systematic review and meta analysis. AB - BACKGROUND AND PURPOSE: Fatigue is common after stroke but has no effective treatments. Psychological interventions improve fatigue in other conditions by targeting psychological factors such as mood. If psychological factors correlate with fatigue in stroke, this would justify the development of similar interventions for poststroke fatigue (PSF). We used systematic review and meta analysis to determine psychological associations of PSF. METHODS: We systematically searched for studies that reported psychological associations of PSF. We used odds ratios (ORs) to estimate the strength of associations and random-effects modeling to calculate summary estimates of ORs. We used stratified meta-analysis to investigate the impact of study design and conducted sensitivity analyses limited to studies that excluded patients with clinical depression and to studies that used depression scales without fatigue items. RESULTS: Thirty five studies (n=9268) reported the association between PSF and >=1 psychological factor. For PSF and depressive symptoms, we identified 19 studies (n=6712; pooled OR=4.14; 95% confidence interval, 2.73-6.27); this association existed in patients without clinical depression (pooled OR=1.39; 95% confidence interval, 1.27-1.53) and in studies using depression scales without fatigue items (pooled OR=5.41; 95% confidence interval, 1.54-18.93). For PSF and anxiety, we identified 4 studies (n=3884; pooled OR=2.34; 95% confidence interval, 0.98-5.58). Two studies (n=123) found an association with poor coping styles and 1 study (n=167) with loss of control. Six studies (n=1978) reported other emotional or behavioral associations. CONCLUSIONS: PSF is associated with depressive symptoms, anxiety, poor coping, loss of control, emotional, and behavioral symptoms. These factors are potential targets for treatment of PSF. PMID- 24781084 TI - Influence of stroke infarct location on functional outcome measured by the modified rankin scale. AB - BACKGROUND AND PURPOSE: In the early days after ischemic stroke, information on structural brain damage from MRI supports prognosis of functional outcome. It is rated widely by the modified Rankin Scale that correlates only moderately with lesion volume. We therefore aimed to elucidate the influence of lesion location from early MRI (days 2-3) on functional outcome after 1 month using voxel-based lesion symptom mapping. METHODS: We analyzed clinical and MRI data of patients from a prospective European multicenter stroke imaging study (I-KNOW). Lesions were delineated on fluid-attenuated inversion recovery images on days 2 to 3 after stroke onset. We generated statistic maps of lesion contribution related to clinical outcome (modified Rankin Scale) after 1 month using voxel-based lesion symptom mapping. RESULTS: Lesion maps of 101 patients with middle cerebral artery infarctions were included for analysis (right-sided stroke, 47%). Mean age was 67 years, median admission National Institutes of Health Stroke Scale was 11. Mean infarct volumes were comparable between both sides (left, 37.5 mL; right, 43.7 mL). Voxel-based lesion symptom mapping revealed areas with high influence on higher modified Rankin Scale in regions involving the corona radiata, internal capsule, and insula. In addition, asymmetrically distributed impact patterns were found involving the right inferior temporal gyrus and left superior temporal gyrus. CONCLUSIONS: In this group of patients with stroke, characteristic lesion patterns in areas of motor control and areas involved in lateralized brain functions on early MRI were found to influence functional outcome. Our data provide a novel map of the impact of lesion localization on functional stroke outcome as measured by the modified Rankin Scale. PMID- 24781085 TI - Shades of white: separating degrees of injury in the aging brain. PMID- 24781086 TI - Co-expression of anti-rotavirus proteins (llama VHH antibody fragments) in Lactobacillus: development and functionality of vectors containing two expression cassettes in tandem. AB - Rotavirus is an important pediatric pathogen, causing severe diarrhea and being associated with a high mortality rate causing approximately 500 000 deaths annually worldwide. Even though some vaccines are currently available, their efficacy is lower in the developing world, as compared to developed countries. Therefore, alternative or complementary treatment options are needed in the developing countries where the disease burden is the largest. The effect of Lactobacillus in promoting health and its use as a vehicle for delivery of protein and antibody fragments was previously shown. In this study, we have developed co-expression vectors enabling Lactobacillus paracasei BL23 to produce two VHH fragments against rotavirus (referred to as anti-rotavirus proteins 1 and 3, ARP1 and ARP3) as secreted and/or surface displayed products. ARP1 and ARP3 fragments were successfully co-expressed as shown by Western blot and flow cytometry. In addition, engineered Lactobacillus produced VHH antibody fragments were shown to bind to a broad range of rotavirus serotypes (including the human rotavirus strains 69M, Va70, F45, DS1, Wa and ST3 and simian rotavirus strains including RRV and SA11), by flow cytometry and ELISA. Hereby, we have demonstrated for the first time that when RRV was captured by one VHH displayed on the surface of co-expressor Lactobacillus, targeting other epitope was possible with another VHH secreted from the same bacterium. Therefore, Lactobacillus producing two VHH antibody fragments may potentially serve as treatment against rotavirus with a reduced risk of development of escape mutants. This co-expression and delivery platform can also be used for delivery of VHH fragments against a variety of mucosal pathogens or production of other therapeutic molecules. PMID- 24781087 TI - Homozygous truncating PTPRF mutation causes athelia. AB - Athelia is a very rare entity that is defined by the absence of the nipple-areola complex. It can affect either sex and is mostly part of syndromes including other congenital or ectodermal anomalies, such as limb-mammary syndrome, scalp-ear nipple syndrome, or ectodermal dysplasias. Here, we report on three children from two branches of an extended consanguineous Israeli Arab family, a girl and two boys, who presented with a spectrum of nipple anomalies ranging from unilateral hypothelia to bilateral athelia but no other consistently associated anomalies except a characteristic eyebrow shape. Using homozygosity mapping after single nucleotide polymorphism (SNP) array genotyping and candidate gene sequencing we identified a homozygous frameshift mutation in PTPRF as the likely cause of nipple anomalies in this family. PTPRF encodes a receptor-type protein phosphatase that localizes to adherens junctions and may be involved in the regulation of epithelial cell-cell contacts, peptide growth factor signaling, and the canonical Wnt pathway. Together with previous reports on female mutant Ptprf mice, which have a lactation defect, and disruption of one allele of PTPRF by a balanced translocation in a woman with amastia, our results indicate a key role for PTPRF in the development of the nipple-areola region. PMID- 24781088 TI - [Bibliometric study of scientific output published by the Revista Panamericana de Salud Publica/Pan American Journal of Public Health from 1997-2012]. AB - OBJECTIVE: To characterize the scientific output of the Revista Panamericana de Salud Publica/Pan American Journal of Public Health (RPSP) as a scientific publication of reference in the public health sector in the Americas. METHODS: A descriptive cross-sectional study was conducted based on the articles published in the RPSP from 1997-2012. Bibliometric indicators of productivity (documents published, languages, authorship, and indices of productivity and collaboration); impact (impact factor according to the SciELO Network, Journal Citation Report and SCImago); key words; and bibliographic references, their structure (document type and main nucleus of Bradford) and degree of obsolescence (Burton and Kebler half-life, and Price index), were analyzed. RESULTS: A total of 2 815 articles with a median of 3 authors and 2 institutions per article were published. The percentage of original research articles increased in 2008-2012 compared to 2003 2007 and 1997-2002 (P < 0.001). The predominant language was Spanish, displaced by English in the last 5 years. A total of 88.76% of the key words referred to the Health Sciences Descriptors (DeCS) and had a public health and community orientation related to the Americas. The Burton and Kebler half-life of bibliographic references was 8 years, although it decreased to 5 years in 2012. The Price index was 20.47% and the nucleus of Bradford was made up of 20 mainstream journals. The percentage of self-citation was low (2.07%). CONCLUSIONS: The RPSP is an international publication with bibliometric indicators similar to those of the most representative Latin American health science journals, with improvements in the recent years studied that lead it to fully meet international publishing criteria. PMID- 24781089 TI - Mortality inequality among older adults in Mexico: the combined role of infectious and chronic disease. AB - OBJECTIVE: To assess the effects of education and chronic and/or infectious disease, and the interaction between both variables, on the risk of dying among Mexicans 60 years and older. METHODS: Using data from the Mexican Health and Aging Study (MHAS), logistic regressions were performed to estimate the risk of mortality for older Mexicans between 2001 and 2003. Estimated mortality risks associated with chronic disease, infectious disease, and a combination of both were used to estimate additional life expectancy at age 60. RESULTS: Compared to the group with some schooling, the probability of dying over the twoyear inter wave period was 26% higher among those with no schooling. Not having at least one year of formal education translated into a shorter additional life expectancy at age 60 by 1.4-2.0 years. Having chronic and/or infectious disease also increased the risk of mortality during the same period CONCLUSIONS: These results indicate that 1) a mixed epidemiological regime (the presence of both chronic and infectious disease) adds to the mortality health burden experienced by older people, and 2) there are persistent inequalities in mortality risks based on socioeconomic status. PMID- 24781090 TI - [School meals: planning, production, distribution, and adequacy]. AB - OBJETIVE: To evaluate the planning, production, distribution, and nutritional adequacy of meals served at city schools. METHODS: This descriptive cross sectional study was conducted between March 2011 and April 2012 and included a representative sample (n = 42 schools) of extended shift city schools from Belo Horizonte, Minas Gerais, Brazil. Five meals from each school were randomly selected and analyzed by direct weighing. Production indicators and nutritional adequacy were evaluated in contrast to the recommendations of the city food security bureau and the Brazilian National Program of School Meals (PNAE). RESULTS: Seventy-nine percent of the analyzed meals did not meet the recommendations of the city food security bureau. The rate of waste (food left on plates) was acceptable at 4,90%, but the rates of cooked and not served food (7,06%) and counter leftovers (5,30%) were high. Both the city planned meals and the meals served in the schools were nutritionally inadequate in terms of the PNAE, particularly for children aged 11-15 years. There was a relationship between consumption by school staff and the amount of food that was cooked (r = 0.353; P < 0.001) and the rate of cooked and not served food (r = 0.138; P = 0.045). Waste was positively correlated with the rate of counter leftovers (r = 0.145; P = 0.035), and inversely correlated with fiber intake (r = -0.143; P = 0.038). CONCLUSIONS: The results indicate the importance of monitoring the planning, production, and distribution of school meals and of food and nutrition education in order to improve the quality of food and to reduce waste in schools. PMID- 24781091 TI - [Child malnutrition in children under 5 years of age in Peru: trends and determinants]. AB - OBJECTIVE: Analyze malnutrition and anemia trends in Peruvian children under 5 years of age and their association with determinants in the 2000-2011 period. METHODS: Nutritional indicators for children under 5 years of age from the 2011 Demographic and Family Health Survey (ENDES), and their evolution based on data from the 2000, 2005, and 2008 ENDES, were analyzed. Chronic malnutrition (CM) (height/age <= 2 SD), acute malnutrition (AM), (height/weight <= 2 SD), and anemia trends were estimated. Associations were found with factors such as sex, age, area of residence (urban or rural), region of residence, mother's education, wealth quintile, availability of public water system, sewer availability, altitude, presence of other children in household, birth order, presence of diarrhea in previous 15 days, and presence of cough in previous 15 days. RESULTS: AM, CM, and anemia in Peruvian children under 5 years of age decreased from 2000 2011. This reduction was not uniform for the three conditions, with decreases of 1.1% to 0.4% recorded for AM, 31.6% to 19.6% for CM, and 50.4% to 30.7% for anemia. Although the factors analyzed were related to the prevalence of these three illnesses, calculation of the adjusted odds ratios showed significant differences for CM (mother's education, Sierra region, altitude greater than 2 500 m above sea level, presence of two or more children in household, and being the third or successive child) and anemia (child sex [higher in males], children under 2 years of age, Resto de costa region and Selva region, altitude greater than 2 500 m above sea level, availability of public water system, sewer availability, presence of two or more children in household, and presence of diarrhea within 15 days prior to the survey). For AM, differences were observed according to some factors but they were not significant in the adjusted model. CONCLUSIONS: In the 2000-2011 period, Peru achieved reduction of its CM, AM, and anemia rates. AM rates decreased to almost one-third, with overall figures remaining fairly low, and affecting to a greater extent highly localized areas and groups of the country. However, the current rates of chronic malnutrition and anemia continue to be very high, which represents a true challenge for public policy, as occurs in other countries of the region. In order to overcome this challenge it will be necessary to change the approach, no longer conceiving of child malnutrition exclusively as a nutritional problem and instead placing greater emphasis on the related determinants. Finally, comprehensive and integrated initiatives should be encouraged and strengthened in the poorest communities. PMID- 24781092 TI - Maternal health and health-seeking behaviors among indigenous Mam mothers from Quetzaltenango, Guatemala. AB - OBJECTIVE: To obtain background information about maternal health and health seeking behaviors among indigenous mothers living in rural Mam-Mayan communities of Quetzaltenango, Guatemala. METHODS: A cross-sectional analysis of 100 pregnant and breastfeeding women in four communities was performed to determine prevalence and determinants of service utilization. RESULTS: Extreme poverty, poor education, and poor access to basic resources were prevalent. Out of 100 women 14 41 years old, 33% did not use the formal health care sector for antenatal care; the majority consulted a traditional birth attendant. Only 13% delivered in a hospital. Lower socioeconomic status, lack of fluency in Spanish, and no ownership of a motorized vehicle were associated with the highest likelihood of poor utilization of services. CONCLUSIONS: A variety of factors affect utilization of maternal health services by indigenous women in rural Quetzaltenango. These include socioeconomic disparities, ethnic and linguistic differences, and poor access to basic resources. The current reproductive needs of women should be addressed to improve their health and increase their chance of having healthy children. PMID- 24781093 TI - [Effect of avoidable and non-avoidable deaths on life expectancy in Mexico, 1998 2000 and 2008-2010]. AB - OBJECTIVE: Estimate the changes in life expectancy related to avoidable and nonavoidable deaths in Mexico between the three-year periods from 1998-2000 and 2008-2010 by sex and age group. METHODS: A descriptive cross-sectional study was conducted. Data from official sources on deaths recorded from 0-74 years of age and population estimates (Mexican and worldwide) for the three-year periods from 1998-2000 and 2008-2010 was used. The crude and standardized death rates and years of life expectancy lost in the periods studied were calculated. Estimates were made of the effect of avoidable and non-avoidable deaths on life expectancy from 0-74 years of age, using the Arriaga method, and temporary life expectancy by age group. RESULTS: Mortality due to avoidable causes increased by 2.1% whereas mortality related to non-avoidable causes decreased by 2.3%, with differences according to sex. Life expectancy at birth was 74.2 years in the three-year period from 1998-2000 and 75.1 years in the three-year period from 2008-2010. Temporary life expectancy from 0-74 years of age remained nearly the same at about 68.6 years. CONCLUSIONS: Years of life expectancy can be gained through actions that promote health and disease prevention, mainly by reducing deaths due to avoidable causes. Cross-sectional population-based interventions and strategies should be developed, focusing on specific subgroups, from a gender and generational perspective, and adjusted for the specific geographical, socioeconomic, and cultural features of the target population. PMID- 24781094 TI - [Social determinants of exclusion from health services and medicines in three Central American countries]. AB - OBJECTIVE: Examine the social determinants that affect population behavior with regard to the search for and acquisition of medicines, and their relationship to exclusion from health services based on aggregate data from three Central American countries: Guatemala, Honduras, and Nicaragua. METHODS: A descriptive, observational cross-sectional study was conducted by administration of a household survey. The study sample was selected in accordance with the conglomerate method. Data was analyzed with the SPSS(r) V.17 program using descriptive statistics, bivariate, multivariate, and principal components analysis (PCA). RESULTS: Although the majority of the persons could access health care, health exclusion (odds ratio [OR] 4.10; 95% confidence interval [95% CI]) was the main determinant of lack of access to medicines. The characteristics of housing (OR 0.747, 95% CI), formal employment of head of the household (OR 0.707, 95% CI), and socioeconomic status of the household (OR 0.462, 95% CI) were also important determinants of lack of access to medicines. CONCLUSIONS: The phenomena of lack of access to health services and medicines are not independent from one another. It was corroborated that the health system, as an intermediate social determinant of health, is an important factor for improvement of access to medicines. Public policies that aim to achieve universal coverage should consider this relationship in order to be effective. PMID- 24781095 TI - Geographic information system and multilevel analysis: gingival status among 12 year-old schoolchildren in Sao Paulo, Brazil. AB - OBJECTIVE: To evaluate gingival and calculus status among schoolchildren 12 years of age using a geographic information system and multilevel analysis. METHODS: A total of 1 002 schoolchildren were selected from 18 municipal districts by means of cluster sampling, from among 25 public and private schools in Piracicaba, Sao Paulo, Brazil, in 2005. Examinations were carried out by a single calibrated examiner utilizing the criteria of the World Health Organization, as well as the Community Periodontal Index. Social, economic, and behavioral variables were recorded with the use of a questionnaire and were used in the individual analysis (first level). The variables "percentage of heads of families without income" and "percentage of illiterate heads of families" were used in the contextual analysis (second level). RESULTS: A geographic information system was constructed for mapping the distribution of gingival bleeding. The variables were visually distinguished in the maps and demonstrated a tendency toward better gingival health in the central areas of the city, which are recognized as more privileged. On the contextual level, only the "percentage of illiterate heads of families" was significantly associated to gingival bleeding. CONCLUSIONS: The study confirms better oral health status among schoolchildren from privileged families, but does not confirm the data regarding "income." The individuals from areas in which the heads of family did not have income were not associated to a higher prevalence of gingival problems. This suggests that these individuals are reasonably protected from the impact of social privation due to the actions of public health care services in the municipality. PMID- 24781096 TI - [User embracement in the Family Health Strategy in Brazil: an integrative review]. AB - OBJECTIVE: To review the literature regarding the application of the notion of user embracement and to identify the contributions of this concept for primary health care practices in Brazil. METHOD: We carried out an integrative review of the literature regarding primary health care. The following databases were searched: LILACS, SciELO, and MEDLINE, covering the period from 2006 to 2010. The following search terms were used in LILACS and SciELO: "acolhimento" and "programa saude da familia" and "saude". For MEDLINE, the terms "user embracement" and "family health program" and "health" were used. The review was performed in November 2010. RESULTS: We identified 21 articles meeting the inclusion criteria, all of which described studies carried out in Brazil. The articles were divided into three empirical categories: integration and embracement; primary care work process; and evaluation of services. These are complementary categories that converge to two main views of embracement: the first sees embracement as a means of reorganizing the primary health care environment, and the second sees embracement as an attitude towards users. The review also shows that embracement may be a management tool that supports the Unified Health System and is associated with the principles of comprehensiveness and universality. CONCLUSIONS: Embracement is able to create a bond between health care workers and users. It promotes self-care, a better understanding of disease, as well as user co-responsibility for treatment. In addition, it facilitates universal access, strengthens multiprofessional and intersectoral work, qualifies care, humanizes practices, and encourages actions to combat prejudice. Nevertheless, the perspective of health care users regarding embracement deserves more attention and should be the focus of future studies. PMID- 24781097 TI - [Community-based participatory research in public health: potentials and challenges]. AB - A change in the research paradigm towards a method that more readily allows the translation of scientific knowledge into more community-oriented health actions and policies has been advocated in the field of public health. Special attention has been paid to community-based participatory research, which has the potential to allow the production of deeper knowledge of complex health issues. The present essay reflects on the contributions of participatory research in health, analyzing its theoretical perspectives, principles, and strengths. Some key aspects relating to the implementation of participatory research are also examined, underscoring possible strategies to face this challenge. Participatory research integrates a collaborative approach with involvement of communities, professionals, political decision-makers, and academics to produce knowledge, incorporating the different perspectives and experiences of these stakeholders. This approach facilitates acceptance of the project and engagement of communities, and consequently enhances the quality of the data collected. Participatory research may work in and of itself as an intervention: the involvement of communities may increase their awareness about the importance of the research themes and serve as training to define and address health issues, promoting empowerment. Nevertheless, researchers face challenges in applying this approach. Such challenges are related to the establishment and maintenance of research partnerships, the sharing of decision-making control, and the reconciliation of the motivations and interests of partners. More evidence regarding the process of implementation of participatory research will strengthen the method's theoretical framework and provide further understanding regarding its potential and limitations to address various problems, contexts, and populations, and clarify its beneficial role for communities. PMID- 24781098 TI - [Effectiveness of border screening for detecting Influenza in arriving airline travelers]. AB - OBJECTIVES: We measured symptom and influenza prevalence, and the effectiveness of symptom and temperature screening for identifying influenza, in arriving international airline travelers. METHODS: This cross-sectional study collected data from travelers to Christchurch International Airport, New Zealand, in winter 2008, via a health questionnaire, temperature testing, and respiratory sampling. RESULTS: Forms were returned by 15 976 (68%) travelers. Of these, 17% reported at least 1 influenza symptom, with runny or blocked nose (10%) and cough (8%) most common. Respiratory specimens were obtained from 3769 travelers. Estimated prevalence of influenza was 1.1% (4% among symptomatic, 0.2% among asymptomatic). The sensitivity of screening criteria ranged from 84% for "any symptom" to 3% for a fever of 37.8 AoC or greater. The positive predictive value was low for all criteria. CONCLUSIONS: Border screening using self-reported symptoms and temperature testing has limitations for preventing pandemic influenza from entering a country. Using "any symptom" or cough would lead to many uninfected people being investigated, yet some infected people would remain undetected. If more specific criteria such as fever were used, most infected people would enter the country despite screening. PMID- 24781099 TI - Ion coordination significantly enhances the photocatalytic activity of graphitic phase carbon nitride. AB - Here we report a facile surface modification route, metal ion coordination, to improve the photoactivity of carbon nitride. The metal ions coordinating into the plane of g-C3N4 significantly contribute to a drastic increase of the photocatalytic activity in solar hydrogen production as well as in the photodegradation of organic pollutants. PMID- 24781100 TI - Elevating sampling. AB - Sampling--the process of collecting, preparing, and introducing an appropriate volume element (voxel) into a system--is often underappreciated and pushed behind the scenes in lab-on-a-chip research. What often stands in the way between proof of-principle demonstrations of potentially exciting technology and its broader dissemination and actual use, however, is the effectiveness of sample collection and preparation. The power of micro- and nanofluidics to improve reactions, sensing, separation, and cell culture cannot be accessed if sampling is not equally efficient and reliable. This perspective will highlight recent successes as well as assess current challenges and opportunities in this area. PMID- 24781101 TI - Pilocytic astrocytoma of the cerebellopontine angle in a child presenting with auditory neuropathy spectrum disorder. PMID- 24781102 TI - Favorable prognostic factors for long-term postoperative hearing results after canal tympanoplasty for congenital aural stenosis. AB - OBJECTIVE: We aimed to determine favorable prognostic factors for long-term postoperative hearing results after canal tympanoplasty for congenital aural stenosis (CAS). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Canal tympanoplasty for CAS was performed in 25 ears. INTERVENTION: Primary repair of CAS. MAIN OUTCOME MEASURES: The influences of the following factors on the success of surgery were assessed by univariate and multivariate logistic regression analyses: modified Jahrsdoerfer grading system total score; age at surgery; patterns of presentation (whether sporadic or syndromic); presence of external auditory canal (EAC) cholesteatoma; presence of ossicular fixation, including the malleus bar; presence of a partial atretic plate; exposure of the facial nerve at the tympanic portion; type of tympanoplasty; and each component of the modified Jahrsdoerfer grading system. RESULTS: The univariate analysis revealed that the absence of EAC cholesteatoma (p = 0.029) and the presence of a partial atretic plate (p = 0.040) were significant predictive factors for favorable hearing prognosis, whereas the multivariate logistic regression analysis showed that an absence of EAC cholesteatoma was the most significant favorable predictive factor (p = 0.011), followed by anterolateral position of the malleus/incus complex with respect to the stapes as the second-most favorable factor (p = 0.021). CONCLUSION: The absence of EAC cholesteatoma and anterolateral position of the malleus/incus complex with respect to the stapes are considered useful in predicting long-term favorable hearing results after canal tympanoplasty for CAS. PMID- 24781103 TI - Acceptance of neurotology board certification among leaders in the field. AB - INTRODUCTION: Neurotology board certification was born a decade ago and is available to otolaryngologists who specialize in clinical neurotology. The degree of participation in this voluntary program among leaders in the field has not been previously assessed. METHODS: The Web sites of ACGME accredited otolaryngology programs were used to identify chairpersons who self-identified as neurotologists. Past presidents of the American Neurotology Society (ANS) since 1997 were also evaluated. The participation of both groups in neurotology board certification (NC) was ascertained using the search tool available on the American Board of Otolaryngology Web site (aboto.org). RESULTS: Of the 26 chairmen (all were men) identified as neurotologists, 18 (69%) participated in NC. Ten of 13 past presidents (77%) of the ANS participated in NC. Combining the 2 groups, 28 (72%) of 39 leaders in neurotology in the United States participated in NC. CONCLUSION: Adoption of the NC process among leaders in the field of neurotology in the United States has been robust, despite the significant costs entailed in participation. PMID- 24781104 TI - Delayed facial nerve weakness after intact canal wall tympanomastoidectomy. AB - OBJECTIVE: To find the etiology, frequency, and prognosis of delayed facial nerve weakness (DFW) in our department after intact canal wall tympanomastoidectomy for a tubotympanic (TT) type of chronic suppurative otitis media (CSOM) without cholesteatoma. STUDY DESIGN: Retrospective case review. SETTING: Tertiary care center. SUBJECTS AND METHODS: A total of 315 patients who underwent intact canal wall tympanomastoidectomy for TT type of CSOM without cholesteatoma in our department for the past 3 years were selected. Patients with facial nerve weakness after 72 hours of surgery were noted and assessed for a history of herpes zoster virus infection. There were 6 patients who developed DFW; of these, blood samples of 4 patients for serum antibody titers to varicella zoster virus and herpes simplex type 1 were sent on the 3rd day of developing DFW. Blood samples of each of the remaining 2 patients were sent on the 13th day and 1st day of developing DFW. All 6 patients were treated with prednisolone and acyclovir, and their prognosis was assessed. MAIN OUTCOME MEASURE: House-Brackmann facial nerve grading system and serum antibody titers for varicella zoster virus and herpes simplex type 1. RESULTS: Six patients (1.9%) developed DFW in this study. All patients had a history of herpes zoster virus infection. Serology results of 4 patients showed positive immunoglobulins M and G for varicella zoster virus and had significantly elevated titers of serum immunoglobulin G for varicella zoster virus, thus confirming the etiology. CONCLUSION: The incidence of DFW after tympanomastoidectomy is low and is due to viral reactivation, that is, varicella zoster. The overall prognosis seems impressive because all of the patients' facial nerve function improved by the end of 6 weeks. This study also illustrates the medicolegal importance of informing the patients with a history of herpes zoster virus infection the chance of developing DFW after undergoing tympanomastoidectomy. PMID- 24781105 TI - A step further in vestibular testing for patients with vestibular schwannoma. PMID- 24781106 TI - The semi-lunar meatoplasty. AB - Stenosis of the external auditory meatus is known to be problematic for the otolaryngologist. Establishment of an adequate meatoplasty is important to restore normal otologic physiologic function, whether the meatoplasty is performed as a primary operation or as an adjuvant procedure. Numerous techniques have been devised for performing a meatoplasty. A new technique to create a large and patent meatoplasty is described using a semi-lunar incision in the conchal bowl. PMID- 24781107 TI - Capturing thermal, mechanical, and acoustic effects of the diode (980 nm) laser in stapedotomy. AB - INTRODUCTION: The diode laser, with a wavelength of 980 nm, has promising characteristics for being used for the fenestration during stapedotomy. It is known that at this wavelength absorption in pigmented tissues is high, and absorption in water is relatively low compared with medical lasers in the infrared, making it theoretically an applicable laser for stapes surgery in patients with otosclerosis. Another important advantage is that, with respect to other lasers, this device is relatively inexpensive. Despite the potential advantages, the available literature only shows limited reports of this laser being used in stapes surgery. The present article evaluates the thermal, mechanical, and acoustic properties of the diode laser during stapes surgery. METHODS: For the mechanical effects, high-speed imaging with a frame rate up to 4000 f/s (=250 MUs resolution) was performed in an inner ear model. For thermal effects, the high-speed Schlieren technique was used. Acoustics were recorded by a hydrophone, incorporated in the model. Pulse settings were 100 ms, 3 W, which are the same settings used during stapes surgery. RESULTS: The application of the diode laser resulted in limited mechanical and thermal effects. Impulse noise was low with an average of 52 (SD, 7.8) dB (A). Before carbonization of the tip of the delivery laser, fiber enhances ablation of the footplate. CONCLUSION: The 980 nm diode laser is a useful tool for laser-assisted stapedotomy in patients with otosclerosis. Mechanical, thermal, and acoustic effects are limited and well within the safety limits. PMID- 24781108 TI - Intralabyrinthine schwannomas: a case series with discussion of the diagnosis and management. PMID- 24781110 TI - The slow death of lethal injection. PMID- 24781111 TI - Atypical age-related cortical thinning in episodic migraine. AB - BACKGROUND: Prior studies demonstrate reduced cortical thickness and volume in migraineurs. However, the effect of age on cortical thickness has not been assessed in migraineurs. In this study we investigated whether the process of aging on cortical thickness affects migraineurs differently compared to age matched healthy controls, i.e. whether aging exacerbates cortical thinning in migraineurs. METHODS: Cortical thickness was estimated using a general linear model vertex-by-vertex approach for 32 healthy controls (mean age=35.3 years; SD=11.6) and 27 episodic migraine patients (mean age=33.6 years; SD=12.3). Results were modeled using a main effect analysis to estimate the effect of age on cortical thickness for each group separately, and an age-by-group analysis to estimate differences in age-related cortical thinning between migraine patients and normal controls. RESULTS: Although migraineurs and normal controls both have expected age-related thinning in many regions along the cortical mantle, migraineurs have age-related thinning of regions that do not thin in healthy controls, including: bilateral postcentral, right fusiform, and right temporal pole areas. Cortical thinning of these regions is more prominent with advancing age. CONCLUSION: Results suggest that migraine is associated with atypical cortical aging, suggesting that the migraine disease process interacts with aging to affect cortical integrity. PMID- 24781109 TI - Toxoplasma effector MAF1 mediates recruitment of host mitochondria and impacts the host response. AB - Recent information has revealed the functional diversity and importance of mitochondria in many cellular processes including orchestrating the innate immune response. Intriguingly, several infectious agents, such as Toxoplasma, Legionella, and Chlamydia, have been reported to grow within vacuoles surrounded by host mitochondria. Although many hypotheses have been proposed for the existence of host mitochondrial association (HMA), the causes and biological consequences of HMA have remained unanswered. Here we show that HMA is present in type I and III strains of Toxoplasma but missing in type II strains, both in vitro and in vivo. Analysis of F1 progeny from a type II*III cross revealed that HMA is a Mendelian trait that we could map. We use bioinformatics to select potential candidates and experimentally identify the polymorphic parasite protein involved, mitochondrial association factor 1 (MAF1). We show that introducing the type I (HMA+) MAF1 allele into type II (HMA-) parasites results in conversion to HMA+ and deletion of MAF1 in type I parasites results in a loss of HMA. We observe that the loss and gain of HMA are associated with alterations in the transcription of host cell immune genes and the in vivo cytokine response during murine infection. Lastly, we use exogenous expression of MAF1 to show that it binds host mitochondria and thus MAF1 is the parasite protein directly responsible for HMA. Our findings suggest that association with host mitochondria may represent a novel means by which Toxoplasma tachyzoites manipulate the host. The existence of naturally occurring HMA+ and HMA- strains of Toxoplasma, Legionella, and Chlamydia indicates the existence of evolutionary niches where HMA is either advantageous or disadvantageous, likely reflecting tradeoffs in metabolism, immune regulation, and other functions of mitochondria. PMID- 24781112 TI - Development of an AP-FRET based analysis for characterizing RNA-protein interactions in myotonic dystrophy (DM1). AB - Forster Resonance Energy Transfer (FRET) microscopy is a powerful tool used to identify molecular interactions in live or fixed cells using a non-radiative transfer of energy from a donor fluorophore in the excited state to an acceptor fluorophore in close proximity. FRET can be a very sensitive tool to study protein-protein and/or protein-nucleic acids interactions. RNA toxicity is implicated in a number of disorders; especially those associated with expanded repeat sequences, such as myotonic dystrophy. Myotonic dystrophy (DM1) is caused by a (CTG)n repeat expansion in the 3' UTR of the DMPK gene which results in nuclear retention of mutant DMPK transcripts in RNA foci. This results in toxic gain-of-function effects mediated through altered functions of RNA-binding proteins (e.g. MBNL1, hnRNPH, CUGBP1). In this study we demonstrate the potential of a new acceptor photobleaching assay to measure FRET (AP-FRET) between RNA and protein. We chose to focus on the interaction between MBNL1 and mutant DMPK mRNA in cells from DM1 patients due to the strong microscopic evidence of their co localization. Using this technique we have direct evidence of intracellular interaction between MBNL1 and the DMPK RNA. Furthermore using the AP-FRET assay and MBNL1 mutants, we show that all four zinc-finger motifs in MBNL1 are crucial for MBNL1-RNA foci interactions. The data derived using this new assay provides compelling evidence for the interaction between RNA binding proteins and RNA foci, and mechanistic insights into MBNL1-RNA foci interaction demonstrating the power of AP-FRET in examining RNA-Protein interactions in DM1. PMID- 24781113 TI - STM/BP-Like KNOXI Is Uncoupled from ARP in the Regulation of Compound Leaf Development in Medicago truncatula. AB - Class I KNOTTED-like homeobox (KNOXI) genes are critical for the maintenance of the shoot apical meristem. The expression domain of KNOXI is regulated by ASYMMETRIC LEAVES1/ROUGHSHEATH2/PHANTASTICA (ARP) genes, which are associated with leaf morphology. In the inverted repeat-lacking clade (IRLC) of Fabaceae, the orthologs of LEAFY (LFY) function in place of KNOXI to regulate compound leaf development. Here, we characterized loss-of-function mutants of ARP (PHAN) and SHOOTMERISTEMLESS (STM)- and BREVIPEDICELLUS (BP)-like KNOXI in the model IRLC legume species Medicago truncatula. The function of ARP genes is species specific. The repression of STM/BP-like KNOXI genes in leaves is not mediated by PHAN, and no suppression of PHAN by STM/BP-like KNOXI genes was observed either, indicating that STM/BP-like KNOXI genes are uncoupled from PHAN in M. truncatula. Furthermore, comparative analyses of phenotypic output in response to ectopic expression of KNOXI and the M. truncatula LFY ortholog, SINGLE LEAFLET1 (SGL1), reveal that KNOXI and SGL1 regulate parallel pathways in leaf development. We propose that SGL1 probably functions in a stage-specific manner in the regulation of the indeterminate state of developing leaves in M. truncatula. PMID- 24781114 TI - The H+-ATPase HA1 of Medicago truncatula Is Essential for Phosphate Transport and Plant Growth during Arbuscular Mycorrhizal Symbiosis. AB - A key feature of arbuscular mycorrhizal symbiosis is improved phosphorus nutrition of the host plant via the mycorrhizal pathway, i.e., the fungal uptake of Pi from the soil and its release from arbuscules within root cells. Efficient transport of Pi from the fungus to plant cells is thought to require a proton gradient across the periarbuscular membrane (PAM) that separates fungal arbuscules from the host cell cytoplasm. Previous studies showed that the H+ ATPase gene HA1 is expressed specifically in arbuscule-containing root cells of Medicago truncatula. We isolated a ha1-2 mutant of M. truncatula and found it to be impaired in the development of arbuscules but not in root colonization by Rhizophagus irregularis hyphae. Artificial microRNA silencing of HA1 recapitulated this phenotype, resulting in small and truncated arbuscules. Unlike the wild type, the ha1-2 mutant failed to show a positive growth response to mycorrhizal colonization under Pi-limiting conditions. Uptake experiments confirmed that ha1-2 mutants are unable to take up phosphate via the mycorrhizal pathway. Increased pH in the apoplast of abnormal arbuscule-containing cells of the ha1-2 mutant compared with the wild type suggests that HA1 is crucial for building a proton gradient across the PAM and therefore is indispensible for the transfer of Pi from the fungus to the plant. PMID- 24781115 TI - A H+-ATPase That Energizes Nutrient Uptake during Mycorrhizal Symbioses in Rice and Medicago truncatula. AB - Most plant species form symbioses with arbuscular mycorrhizal (AM) fungi, which facilitate the uptake of mineral nutrients such as phosphate from the soil. Several transporters, particularly proton-coupled phosphate transporters, have been identified on both the plant and fungal membranes and contribute to delivering phosphate from fungi to plants. The mechanism of nutrient exchange has been studied in plants during mycorrhizal colonization, but the source of the electrochemical proton gradient that drives nutrient exchange is not known. Here, we show that plasma membrane H+-ATPases that are specifically induced in arbuscule-containing cells are required for enhanced proton pumping activity in membrane vesicles from AM-colonized roots of rice (Oryza sativa) and Medicago truncatula. Mutation of the H+-ATPases reduced arbuscule size and impaired nutrient uptake by the host plant through the mycorrhizal symbiosis. Overexpression of the H+-ATPase Os-HA1 increased both phosphate uptake and the plasma membrane potential, suggesting that this H+-ATPase plays a key role in energizing the periarbuscular membrane, thereby facilitating nutrient exchange in arbusculated plant cells. PMID- 24781116 TI - ABORTED MICROSPORES Acts as a Master Regulator of Pollen Wall Formation in Arabidopsis. AB - Mature pollen is covered by durable cell walls, principally composed of sporopollenin, an evolutionary conserved, highly resilient, but not fully characterized, biopolymer of aliphatic and aromatic components. Here, we report that ABORTED MICROSPORES (AMS) acts as a master regulator coordinating pollen wall development and sporopollenin biosynthesis in Arabidopsis thaliana. Genome wide coexpression analysis revealed 98 candidate genes with specific expression in the anther and 70 that showed reduced expression in ams. Among these 70 members, we showed that AMS can directly regulate 23 genes implicated in callose dissociation, fatty acids elongation, formation of phenolic compounds, and lipidic transport putatively involved in sporopollenin precursor synthesis. Consistently, ams mutants showed defective microspore release, a lack of sporopollenin deposition, and a dramatic reduction in total phenolic compounds and cutin monomers. The functional importance of the AMS pathway was further demonstrated by the observation of impaired pollen wall architecture in plant lines with reduced expression of several AMS targets: the abundant pollen coat protein extracellular lipases (EXL5 and EXL6), and CYP98A8 and CYP98A9, which are enzymes required for the production of phenolic precursors. These findings demonstrate the central role of AMS in coordinating sporopollenin biosynthesis and the secretion of materials for pollen wall patterning. PMID- 24781118 TI - [Micromorphology of decayed tooth tissues covered with artificial crown]. AB - Pathomorphological changes in dentine covered with artificial crown were studied in 40 decalcified teeth extracted from patients aged 35-61 years. The study of the decayed dentin microscopic structure revealed the uniform mineralization of dentinal tubules in 20% of cases, while in the absence of visually apparent caries it was present in 80% of cases. Irregular dentin structure was seen in 45% of caries cases and in 30% of observations with no signs of caries. Predentine distrophy and odontoblasts elimination in the decayed teeth was found in 55% of the observations while in the absence of caries lesions these features were seen in 70% of cases. PMID- 24781117 TI - EARLY FLOWERING3 Regulates Flowering in Spring Barley by Mediating Gibberellin Production and FLOWERING LOCUS T Expression. AB - EARLY FLOWERING3 (ELF3) is a circadian clock gene that contributes to photoperiod dependent flowering in plants, with loss-of-function mutants in barley (Hordeum vulgare), legumes, and Arabidopsis thaliana flowering early under noninductive short-day (SD) photoperiods. The barley elf3 mutant displays increased expression of FLOWERING LOCUS T1 (FT1); however, it remains unclear whether this is the only factor responsible for the early flowering phenotype. We show that the early flowering and vegetative growth phenotypes of the barley elf3 mutant are strongly dependent on gibberellin (GA) biosynthesis. Expression of the central GA biosynthesis gene, GA20oxidase2, and production of the bioactive GA, GA1, were significantly increased in elf3 leaves under SDs, relative to the wild type. Inhibition of GA biosynthesis suppressed the early flowering of elf3 under SDs independently of FT1 and was associated with altered expression of floral identity genes at the developing apex. GA is also required for normal flowering of spring barley under inductive photoperiods, with chemical and genetic attenuation of the GA biosynthesis and signaling pathways suppressing inflorescence development under long-day conditions. These findings illustrate that GA is an important floral promoting signal in barley and that ELF3 suppresses flowering under noninductive photoperiods by blocking GA production and FT1 expression. PMID- 24781119 TI - [Improvement of light-cured indirect inlays durability by means of electromagnetic field]. AB - The main strength characteristics of light-cured resins used for replacement of dental hard tissues defects are destructive stress by compression, microhardness, resistance to abrasion, impact and water absorption. The study focuses on some strength features of composite materials for inlays processed by electromagnetic field. Four sample series of light cured resin (Charisma, Heraus Kulzer, Germany) were used to assess strength features changes in various curing methods: 10 control samples were polymerized by conventional light-curing device, while 30 were additionally processed by electromagnetic field of various intensity (60, 80 and 100 Oe, 10 samples for each group). The obtained results confirm the positive effects of electromagnetic field on strength features of light-cured resins which improves the quality of inlays. PMID- 24781120 TI - [Specific features of materials for initial pulpitis treatment]. AB - The aim of the current study was to assess antibacterial and cytotoxic properties of Biodentine (Septodont), Rootdent (TehnoDent) and adhesive Futurabond NR (Voco). Two lines of experiments were carried out using cements water solutions and firm tablet-like samples (made by means of special pattern). Citotoxic activity was tested on NCTC L929 mice line fibroblasts culture. All the examined materials showed antibacterial activity against E. coli, S. aureus, C. albisans, St. faecalis, mostly evident in Futurabond and the poorest in Biodentine samples. As for cytotoxic properties, Biodentine proved not to suppress metabolic activity stimulating odontotropic impact. The results confirm the analyzed materials to be a useful tool for deep caries lesions and initial pulpitis treatment. PMID- 24781121 TI - [Structural changes of toothbrush bristles by brushing in patients with dental implants]. AB - Lack of proper oral hygiene practices can lead to treatment failure in patients with implant-retained restorations. Structural changes of toothbrush bristles were studied using scanning electron microscopy and correlated with cleaning efficiency which was assessed at baseline and after 3 months of use of various toothbrushes types in 146 patients with implant-retained restorations. Oral hygiene was valued according to several indices (Approximal Plaque-Index (API), the Turesky index (PI), a modified superstructure plaque index Silness-Loe (PLIsk). Ultrasound toothbrush provided the best and the most efficient cleaning outcome in patients with implant-retained restorations. Scanning electron microscopy proved ultrasonic toothbrush bristles to be more resistant to abrasion during the three-month use. PMID- 24781122 TI - [Sensory disorders in inferior alveolar nerve after sagittal split osteotomy of the mandible]. AB - Methodology of the sagittal split osteotomy of the mandible improved from year to year. However, there is still the problem of neurosensory disorders of inferior alveolar nerve in the early and late postoperative period is widely covered in the foreign literature. The incidence of these disorders ranges from 40 to 55%. During 2009-2013 years in Central Research Institute of Stomatology and Maxillofacial Surgery were operated 127 patients with associated deformities of the jaws: 102 according to traditional methods, 25 - by improved methods. Assessment of lower alveolar nerve conducted by electric teeth pulp test methods, blink reflex, computed tomography in 3D mode and the questionnaire. The results showed that the improved method of the sagittal split osteotomy of the mandible by using piezoelectric bone surgery saw during cutting of the cortical bone of the mandible and special splitters with replacing of damaging factors makes it possible to reduce the incidence of neurosensory disorders of inferior alveolar nerve and reduce the time of rehabilitation. PMID- 24781123 TI - [Defensins level in patients with inflammatory diseases of maxillofacial area]. AB - Molecular study of congenital immune factors was conducted in 45 patients with inflammatory diseases of maxillofacial area. The study focused on expression of cationic low-molecular peptides alpha- and Beta-defensines in oral mucosa. These peptides are involved in antibacterial activity and regulation of immune reactions. The results showed 20-fold increase in defensines expression in oral mucosa of patients with inflammatory diseases of maxillofacial area when compared to control group (12 healthy individuals) thus proving an important role they play in the development of the disease. Therapy with cytokines may be indicated in these cases. PMID- 24781124 TI - [Clinical and anatomical rationale for transanthral approach in orbital floor fractures. Part I]. AB - The rationale for transanthral approach in orbital floor fractures was formulated according to authors' treatment experience. The study included 525 patients aged 13 to 72 years with orbital floor fractures history (278 with posttraumatic deformities and 247 with recent fractures). Reposition and internal fixation was performed via transanthral approach in all cases. The paper summarizes treatment results, complications as well as pearls and pitfalls of the surgical technique. It is emphasized that transanthral approach reduces surgery time and enophthalmos or diplopy corrections are rarely indicated. PMID- 24781125 TI - [Shockwave lithotripsy in sialolithiasis patients]. AB - Shockwave lithotripsy was performed by various appliances in sialolithiasis patients. The best results were obtained by means of miniature appliances. Lithotripsy proved to be useful safe alternative for sialolithiasis treatment. PMID- 24781126 TI - [Cleft palate surgery with ENT-pathology correction]. AB - The article presents the cases of cleft palate surgical treatment with simultaneous intervention in ENT organs (bypass of the tympanic cavity, segmental or total adenotomy, etc.) with the restoration of vomer anatomy and hard palate reconstruction by means of super-elastic low-profile nickel titanium implant. The article describes the advantages of the method in comparison with the conventional ones. PMID- 24781127 TI - [Practical advices in choosing local anesthesia tools in dentistry. Management of carpule's quality in local anesthesia in dentistry]. AB - The equipment for local anesthesia is described in this article. Practical recommendations for the selection of the injection needle length, size, bevel type is given. Using dental needle for local anesthesia should be guided by the "one injection - one needle" rule, as a needle tends to deform by even the slightest contact with jawbone. Some of the shortcomings of carpule quality may be detected before use: signs of cup corrosion, the presence of sediment, air bubbles, rubber plunger disposition. In the case of such defects being identified all the package should not be used. The use of such carpule in clinical practice is unsafe. PMID- 24781128 TI - [Marginal fit changes in implant-supported prosthetic bars by electroerosive processing]. AB - The aim of the study was to evaluate the marginal fit changes in implant supported prosthetic bars by electroerosive processing. The experimental model included 9 bars supported by 2, 4 and 6 implant analogues (3 bars for each number of supports). Marginal gap size was assessed by digital microscopy before and after electroerosive processing conducted in 3 stages (10, 8 and 5 minutes long). Electroerosive processing proved to be useful tool for marginal fit correction. PMID- 24781129 TI - [Efficiency of teeth local anesthesia by articaine-containing formulation with adrenaline and clonidine in pediatric dentistry]. AB - The study evaluated duration and depth of the local infiltration anesthesia by articaine with different combinations of epinephrine and clonidine : articaine (4%) + epinephrine (1: 200 000), articaine (4%) + clonidine (1:100 000), articaine (4%) + epinephrine (1:200 000) + clonidine (1:100 000), articaine (4%) + epinephrine (1: 400 000) + clonidine (1:100, 000) in pediatric dental practice. It was revealed that the replacement of the vasoconstrictor epinephrine on clonidine associated with reduced depth and duration of analgesia. This increased efficiency is provided by inclusion of epinephrine (1:200 000), and clonidine (1:100 000) into anesthetic solution, which provided statistically significant increase in depth and duration of anesthesia. PMID- 24781130 TI - [Some aspects of terminology, classification and incidence of hypodontia]. AB - The paper presents the data of literature review on epidemiology, patterns and prevalence of hypodontia depending on race, nationality and gender of the patients. Correlation between congenital absence of the temporary and permanent teeth are discussed as well as the matters of the terminology and classification depending on the severity of this abnormality. PMID- 24781131 TI - [Class II malocclusion: some aspects of diagnostics and complex orthodontic and surgical treatment]. AB - Class II malocclusions are of interest to the practicing orthodontists since they constitute a significant percentage of the cases they treat. The process of establishing a treatment plan requires an assessment of therapeutic modifiability. The purpose of this article is to provide a perspective on the characteristics, development, etiology and broad treatment consideration in Class II malocclusions. PMID- 24781132 TI - [Method for prevention of tissue atrophy after teeth extraction]. AB - Modern approach to teeth loss treatment anticipates two main goals - both functional and esthetic rehabilitation. Smile esthetic depends not only on teeth shape, size and color but also on gingival volume and position (pink esthetic). The paper describes the method of optimal tissue preservation after frontal teeth extraction including free tissue transfer in the site of extraction performed in 24 patients. Palatal free autograft was positioned to refill the defect and sutured to gingival margin. Sutured were removed in 7 days. The method proved to be efficient and may be recommended for use in in-patient oral surgery units. PMID- 24781133 TI - [Dental implantation and prosthetics in Sjogren's syndrome]. AB - The author discusses the methods and conditions for the successful outcome of implantation in patients with Sjogren's syndrome. Considers it no alternative orthopedic and psychological rehabilitation of the patient with objective xerostomia. Examines implantation in patients with Sjogren's syndrome as a specialized form of surgical care. PMID- 24781134 TI - Information on quantum states pervades the visible spectrum of the ubiquitous Au144(SR)60 gold nanocluster. AB - Absorption spectra of very small metal clusters exhibit individual peaks that reflect the discreteness of their localized electronic states. With increasing size, these states develop into bands and the discrete absorption peaks give way to smooth spectra with, at most, a broad localized surface-plasmon resonance band. The widely accepted view over the last decades has been that clusters of more than a few dozen atoms are large enough to have necessarily smooth spectra. Here we show through theory and experiment that for the ubiquitous thiolate cluster compound Au144(SR)60 this view has to be revised: clearly visible individual peaks pervade the full near-IR, VIS and near-UV ranges of low temperature spectra, conveying information on quantum states in the cluster. The peaks develop well reproducibly with decreasing temperature, thereby highlighting the importance of temperature effects. Calculations using time-dependent density functional theory indicate the contributions of different parts of the cluster ligand compound to the spectra. PMID- 24781135 TI - The presence of enterovirus, adenovirus, and parvovirus B19 in myocardial tissue samples from autopsies: an evaluation of their frequencies in deceased individuals with myocarditis and in non-inflamed control hearts. AB - PURPOSE: Multiple viruses have been detected in cardiac tissue, but their role in causing myocarditis remains controversial. Viral diagnostics are increasingly used in forensic medicine, but the interpretation of the results can sometimes be challenging. In this study, we examined the prevalence of adenovirus, enterovirus, and parvovirus B19 (PVB) in myocardial autopsy samples from myocarditis related deaths and in non-inflamed control hearts in an effort to clarify their significance as the causes of myocarditis in a forensic material. METHODS: We collected all autopsy cases diagnosed with myocarditis from 1992 to 2010. Eighty-four suicidal deaths with morphologically normal hearts served as controls. Polymerase chain reaction was used for the detection of the viral genomes (adenovirus, enterovirus, and PVB) in myocardial tissue specimens. The distinction between acute and persistent PVB infection was made by the serological determination of PVB-specific immunoglobulins M and G. RESULTS: PVB was detected in 33 of 112 (29 %) myocarditis cases and 37 of 84 (44 %) control cases. All of the samples were negative for the presence of adenovirus and enterovirus. Serological evidence of an acute PVB infection, determined by the presence of immunoglobulin M, was only present in one case. In the remaining cases, PVB was considered to be a bystander with no or limited association to myocardial inflammation. CONCLUSION: In this study, adenovirus, enterovirus, and PVB were found to be rare causes of myocarditis. The detection of PVB in myocardial autopsy samples most likely represents a persistent infection with no or limited association with myocardial inflammation. The forensic investigation of myocardial inflammation demands a thorough examination, including special attention to non-viral causes and requires a multidisciplinary approach. PMID- 24781137 TI - Distribution and transport of PAHs in soil profiles of different water irrigation areas in Beijing, China. AB - Vertical distribution characteristics and transport mechanisms of polycyclic aromatic hydrocarbons (PAHs) in soil profiles (0-5.5 m) of different water irrigation areas in the southeast suburb of Beijing were analyzed and compared. 16 priority PAHs on the United States Environmental Protection Agency (US EPA) list were analyzed using gas chromatography and mass spectrometry (GC-MS). The relationship between the properties of soil and PAHs was also studied by statistical analyses. The results showed that total PAH concentrations in the topsoils of the wastewater irrigation (WWI) area, reclaimed water irrigation (RWI) area, groundwater irrigation (GWI) area were much higher than those in the deep soils, with the concentrations of 726.0, 206.8 and 42.8 MUg kg(-1) (dry wt), respectively. The low molecular weight (LMW) PAHs (2-3 ring) including naphthalene (Nap), phenanthrene (Phe), fluorene (Fl) dominated the layers (0.5 5.5 m) underneath the surfaces. The migration of LMW PAHs was faster than that of high molecular weight (HMW) PAHs and LMW PAHs were transported in dissolved matter. The different soil textures of three sites caused the differences in the variation ranges of PAHs in the profiles. The statistical analyses showed a significant linear positive correlation between PAHs and total organic carbon (TOC). The 2-4 ring PAHs were detected in the wastewater and reclaimed waters, which was consistent with those in the soil profiles. The presence of PAHs in the soil profiles was mainly due to the irrigation of wastewater. Wastewater reuse guidelines and standards for irrigation should be established urgently. PMID- 24781136 TI - Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. AB - Some recombinant adeno-associated viruses (rAAVs) can cross the neonatal blood brain barrier (BBB) and efficiently transduce cells of the central nervous system (CNS). However, in the adult CNS, transduction levels by systemically delivered rAAVs are significantly reduced, limiting their potential for CNS gene therapy. Here, we characterized 12 different rAAVEGFPs in the adult mouse CNS following intravenous delivery. We show that the capability of crossing the adult BBB and achieving widespread CNS transduction is a common character of AAV serotypes tested. Of note, rAAVrh.8 is the leading vector for robust global transduction of glial and neuronal cell types in regions of clinical importance such as cortex, caudate-putamen, hippocampus, corpus callosum, and substantia nigra. It also displays reduced peripheral tissue tropism compared to other leading vectors. Additionally, we evaluated rAAVrh.10 with and without microRNA (miRNA)-regulated expressional detargeting from peripheral tissues for systemic gene delivery to the CNS in marmosets. Our results indicate that rAAVrh.8, along with rh.10 and 9, hold the best promise for developing novel therapeutic strategies to treat neurological diseases in the adult patient population. Additionally, systemically delivered rAAVrh.10 can transduce the CNS efficiently, and its transgene expression can be limited in the periphery by endogenous miRNAs in adult marmosets. PMID- 24781138 TI - Rapidly growing mycobacteria among pediatric hematopoietic cell transplant patients traced to the hospital water supply. AB - BACKGROUND: Rapidly growing mycobacteria (RGM) have a predilection for those with immunocompromised states. We report increased isolation of RGM among pediatric hematopoietic cell transplant patients that was traced to the hospital water supply. METHODS: Cases of RGM-positive patients were differentiated based on whether they were community-acquired or nosocomial, colonized or infected based on predefined criteria. Medical records of all RGM-positive patients were reviewed and data extracted. Infection control outbreak measures were instituted and an environmental investigation was conducted. RESULTS: Between July 2011 and April 2012, 16 RGM isolates were identified among 15 hematopoietic cell transplant patients, compared with none in the preceding year. After environmental samples were initially grown on media for heterotrophic counts and further speciated, RGM species were identified in the hospital water supply. CONCLUSIONS: This outbreak of RGM was traced to an environmental source and was successfully controlled through institution of infection control measures. PMID- 24781139 TI - Influence of nanoparticle shape on charge transport and recombination in polymer/nanocrystal solar cells. AB - A key consideration for the efficient operation of hybrid solar cells based upon conjugated polymers and inorganic semiconductor nanocrystals is charge transport in the nanocrystal phase. Here we report the results of a study into the charge transport kinetics of polymer/nanocrystal solar cells based on blends poly(3 hexylthiophene) (P3HT) with either CdSe nano-dots or CdSe nano-tetrapods. Transient photocurrent measurements reveal significant differences in the charge transport kinetics of nano-dot and nano-tetrapod hybrid cells, with the charge collection of the P3HT/CdSe nano-dot device severely limited by charge trapping. In comparison the nano-tetrapod cell exhibits significantly reduced charge trapping compared to the nano-dot cell accounting for the improved fill-factor and overall device efficiency. Transient photovoltage measurements have also been employed that demonstrate slower recombination rates in the P3HT/CdSe tetrapod device compared to the P3HT/CdSe dot device. These observations directly identify nanoparticle shape as a critical factor influencing the charge transport and hence recombination in this benchmark hybrid system, confirming the hypothesis that the use of tetrapods improves device performance through an improvement in electron transport in the nanocrystal phase. PMID- 24781142 TI - Arsenic and cadmium are inhibitors of cyanobacterial dinitrogenase reductase (nifH1) gene. AB - The enzyme nitrogenase complex is a key component conferring nitrogen fixation in all known diazotrophs. This study for the first time examines the impact of As, Na, Cd, Cu and butachlor on component II (dinitrogenase reductase, nifH1) of nitrogenase from diazotrophic cyanobacterium Anabaena sp. PCC7120 using in silico and wet lab approaches. The nifH1 of Anabaena is a glycine-rich stable protein having DNA-binding properties and shows close similarity with free living compared with symbiotic diazotrophs. Phylogenetic tree revealed an adverse effect of the selected stresses on close homologs across the diazotroph community. The protein interaction network demonstrated the presence of nirA, glnA, glnB, alr4255 and alr2485 proteins besides nif proteins, suggesting their involvement in nitrogen fixation along with nifH1. Homology modelling and docking under As, Na, Cd, Cu and butachlor revealed an interaction between stressors and nifH1 protein which was further validated by a transcript of the gene through quantitative real-time PCR (qRT-PCR). Presence of binding sites for As, Na, Cd and Cu on oxyR promoter attested their adverse affects on nifH1. Maximum down regulation of nifH1 in Cd and As followed by salt, copper and butachlor revealed that arsenic and cadmium were most potential inhibitors of nitrogenase of diazotrophic community, which might negatively affect crop yield. PMID- 24781144 TI - MAF1 sequesters mitochondria for Toxoplasma gondii. PMID- 24781145 TI - Emerging beta-amyloid pathology and accelerated cortical atrophy. AB - IMPORTANCE: The effect of beta-amyloid (Abeta) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. OBJECTIVE: To test the hypothesis that the development of Abeta pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Abeta42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Abeta42 data and included 13 stable Abeta negative (normal baseline Abeta42 levels, with less than the median reduction over time), 13 declining Abeta negative (normal baseline Abeta42 levels, with greater than the median reduction over time), and 21 Abeta positive (pathologic baseline Abeta42 levels). All 15 patients with AD dementia were Abeta positive. MAIN OUTCOMES AND MEASURES: Group effects on regional gray matter volumes at baseline and over time, tested by linear mixed-effects models. RESULTS: Baseline gray matter volumes were similar among the CN Abeta groups, but atrophy rates were increased in frontoparietal regions in the declining Abeta-negative and Abeta-positive groups and in amygdala and temporal regions in the Abeta-positive group. Abeta-positive patients with AD dementia had further increased atrophy rates in hippocampus and temporal and cingulate regions. CONCLUSIONS AND RELEVANCE: Emerging Abeta pathology is coupled to increased frontoparietal (but not temporal) atrophy rates. Atrophy rates peak early in frontoparietal regions but accelerate in hippocampus, temporal, and cingulate regions as the disease progresses to dementia. Early-stage Abeta pathology may have mild effects on local frontoparietal cortical integrity while effects in temporal regions appear later and accelerate, leading to the atrophy pattern typically seen in AD. PMID- 24781146 TI - Expression and localization of SerpinB11 in mouse uteri during peri-implantation and the estrous cycle. AB - Serine protease inhibitor (Serpin) B11 has been identified as a novel serine protease inhibitor but the biological functions of SerpinB11 in female reproduction are unknown. Therefore, we investigate the spatiotemporal expression and regulation of SerpinB11 during the peri-implantation period. SerpinB11 mRNA and protein were detected in the uteri of pregnant mice on days 1-8 (day 1 = presence of a vaginal plug). SerpinB11 protein was localized in the embryonic implantation site on day 5 when embryo implantation occurred and was also strongly expressed in the primary decidual zone on day 6 and secondary decidual zone on days 7 and 8. The expression of SerpinB11 was induced by the activated blastocyst (based on patterns of expression during pseudopregnancy and delayed implantation) and by artificially induced decidualization. Moreover, expression of SerpinB11 was regulated by estradiol and progesterone in ovariectomized mice. The results were further supported by data from the estrous cycle. Thus, SerpinB11 is probably involved in embryo implantation and decidualization. PMID- 24781148 TI - Histone variants: key players of chromatin. AB - Histones are fundamental structural components of chromatin. Eukaryotic DNA is wound around an octamer of the core histones H2A, H2B, H3, and H4. Binding of linker histone H1 promotes higher order chromatin organization. In addition to their structural role, histones impact chromatin function and dynamics by, e.g., post-translational histone modifications or the presence of specific histone variants. Histone variants exhibit differential expression timings (DNA replication-independent) and mRNA characteristics compared to canonical histones. Replacement of canonical histones with histone variants can affect nucleosome stability and help to create functionally distinct chromatin domains. In line with this, several histone variants have been implicated in the regulation of cellular processes such as DNA repair and transcriptional activity. In this review, we focus on recent progress in the study of core histone variants H2A.X, H2A.Z, macroH2A, H3.3, and CENP-A, as well as linker histone H1 variants, their functions and their links to development and disease. PMID- 24781147 TI - Human mesenchymal stem cell spheroids in fibrin hydrogels exhibit improved cell survival and potential for bone healing. AB - Mesenchymal stem cells (MSCs) have great therapeutic potential for the repair of nonhealing bone defects, because of their proliferative capacity, multilineage potential, trophic factor secretion and lack of immunogenicity. However, a major challenge to the translation of cell-based therapies into clinical practice is ensuring their survival and function upon implantation into the defect site. We hypothesize that forming MSCs into more physiologic three-dimensional spheroids, rather than employing dissociated cells from two-dimensional monolayer culture, will enhance their survival when exposed to a harsh microenvironment but maintain their osteogenic potential. MSC spheroids were formed by using the hanging drop method with increasing cell numbers. Compared with larger spheroids, the smallest spheroids, which contained 15,000 cells, exhibited increased metabolic activity, reduced apoptosis and the most uniform distribution of proliferating cells. Spheroids were then entrapped in fibrin gels and cultured in serum-free medium and 1 % oxygen. Compared with identical numbers of dissociated MSCs in fibrin gels, spheroids exhibited significantly reduced apoptosis and secreted up to 100 fold more vascular endothelial growth factor. Moreover, fibrin gels containing spheroids and those containing an equivalent number of dissociated cells exhibited similar expression levels of early and late markers of osteogenic differentiation. Thus, MSC spheroids exhibit greater resistance to apoptosis and enhanced proangiogenic potential while maintaining similar osteogenic potential to dissociated MSCs entrapped in a clinically relevant biomaterial, supporting the use of MSC spheroids in cell-based approaches to bone repair. PMID- 24781149 TI - Calcium signaling in Parkinson's disease. AB - Calcium (Ca(2+)) is an almost universal second messenger that regulates important activities of all eukaryotic cells. It is of critical importance to neurons, which have developed extensive and intricate pathways to couple the Ca(2+) signal to their biochemical machinery. In particular, Ca(2+) participates in the transmission of the depolarizing signal and contributes to synaptic activity. During aging and in neurodegenerative disease processes, the ability of neurons to maintain an adequate energy level can be compromised, thus impacting on Ca(2+) homeostasis. In Parkinson's disease (PD), many signs of neurodegeneration result from compromised mitochondrial function attributable to specific effects of toxins on the mitochondrial respiratory chain and/or to genetic mutations. Despite these effects being present in almost all cell types, a distinguishing feature of PD is the extreme selectivity of cell loss, which is restricted to the dopaminergic neurons in the ventral portion of the substantia nigra pars compacta. Many hypotheses have been proposed to explain such selectivity, but only recently it has been convincingly shown that the innate autonomous activity of these neurons, which is sustained by their specific Cav1.3 L-type channel pore forming subunit, is responsible for the generation of basal metabolic stress that, under physiological conditions, is compensated by mitochondrial buffering. However, when mitochondria function becomes even partially compromised (because of aging, exposure to environmental factors or genetic mutations), the metabolic stress overwhelms the protective mechanisms, and the process of neurodegeneration is engaged. The characteristics of Ca(2+) handling in neurons of the substantia nigra pars compacta and the possible involvement of PD-related proteins in the control of Ca(2+) homeostasis will be discussed in this review. PMID- 24781152 TI - The effect of sex and genotype on growth performance, feed efficiency, and carcass traits of local sheep group Pantaneiro and Texel or Santa Ines crossbred finished on feedlot. AB - This study aimed to assess and compare the growth performance, feed efficiency, and carcass traits of Pantaneiro sheep and their Texel and Santa Ines crossbreds. Ninety-six lambs, fifty-one males, and forty-five females, with a mean weaning weight of 15.21 +/- 1.25 kg and 78 +/- 13 days of age, were slaughtered at a 32 kg body weight. The results showed better production efficiency from males compared with females. Texel-crossed lambs had a better growth performance than the other genotypes. The Texel * Pantaneiro lambs were more efficient with a better feedlot performance, higher ribeye muscle area, and better carcass characteristics with an adequate amount of fat cover. Pantaneiro lambs and their crosses with meat breeds could be useful in meat production systems under Savanna environmental conditions. PMID- 24781151 TI - Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance. AB - AIMS/HYPOTHESIS: Pantothenate kinase (PANK) is the first enzyme in CoA biosynthesis. Pank1-deficient mice have 40% lower liver CoA and fasting hypoglycaemia, which results from reduced gluconeogenesis. Single-nucleotide polymorphisms in the human PANK1 gene are associated with insulin levels, suggesting a link between CoA and insulin homeostasis. We determined whether Pank1 deficiency (1) modified insulin levels, (2) ameliorated hyperglycaemia and hyperinsulinaemia, and (3) improved acute glucose and insulin tolerance of leptin (Lep)-deficient mice. METHODS: Serum insulin and responses to glucose and insulin tolerance tests were determined in Pank1-deficient mice. Levels of CoA and regulating enzymes were measured in liver and skeletal muscle of Lep-deficient mice. Double Pank1/Lep-deficient mice were analysed for the diabetes-related phenotype and global metabolism. RESULTS: Pank1-deficient mice had lower serum insulin and improved glucose tolerance and insulin sensitivity compared with wild type mice. Hepatic and muscle CoA was abnormally high in Lep-deficient mice. Pank1 deletion reduced hepatic CoA but not muscle CoA, reduced serum glucose and insulin, but did not normalise body weight or improve acute glucose tolerance or protein kinase B phosphorylation in Lep-deficient animals. Pank1/Lep double deficient mice exhibited reduced whole-body metabolism of fatty acids and amino acids and had a greater reliance on carbohydrate use for energy production. CONCLUSIONS/INTERPRETATION: The results indicate that Pank1 deficiency drives a whole-body metabolic adaptation that improves aspects of the diabetic phenotype and uncouples hyperglycaemia and hyperinsulinaemia from obesity in leptin deficient mice. PMID- 24781153 TI - Enhancing milk and fertility performances using selection index developed for Indian Murrah buffaloes. AB - Selection for genetically superior Murrah buffaloes under Network Project on Buffalo Improvement, India, is presently based on milk yield, and it was observed that even in the absence of any direct selection pressure applied on fertility, there has been a downward trend in fertility associated with the selection for milk yield. The aim of the study was to develop selection indices which include fertility besides milk yield in Murrah buffaloes. Data pertaining to 1,224 lactation records spread over a period of 19 years were recorded and analyzed in the study. The negative association of pregnancy rate (fertility) with a 305-day milk yield (-0.08 +/- 0.04) and wet average (-0.12 +/- 0.02) indicated the importance of incorporating fertility trait in the construction of selection index. Four types of selection indices were constructed and evaluated. Two indices were developed using expected producing ability 305-days milk yield (EPAMY) with 6.5 and 4% fat in milk along with expected fertilizing ability (EFA). The other two indices developed consist of expected producing ability wet average (EPA WA) and EFA. The index involving (EPA WA and EFA) was found to be a more effective selection criterion in our herd, as the accuracy of index was more (0.61), in comparison to the index involving EPA MY and EFA. The robustness of selection index was assessed by increasing the relative economic values of included traits by 25 and 50%, and accuracy of the index remains almost stable without much change. The developed selection strategy involving EPA WA and EFA should be considered for the genetic evaluation of Murrah buffaloes, as it has a potential for maximizing the lifetime reproduction and production performances of the breed. PMID- 24781154 TI - Neospora caninum versus Brucella spp. exposure among dairy cattle in Ethiopia: a case control study. AB - This case-control study aimed at assessing the relative association of Neospora caninum and Brucella species exposure with reproductive disorders. The study was carried out between October 2011 and June 2012 on 731 dairy cows sampled from 150 dairy farms in selected 17 conurbations of Ethiopia. Two hundred sixty-six of the cows were categorized as cases based on their history of abortion or stillbirth while the remaining 465 were controls. The presence of antibody to N. caninum was screened using indirect ELISA, while Brucella spp. exposure was assayed serially using Rose Bengal Plate Test and Complement Fixation Test. Exposure to N. caninum was more frequently observed among cases (23.8%) than controls (12.7%), while no significant difference (p > 0.05) was noted for Brucella exposure between the two groups. Moreover, the proportion of cows with disorders like retention of fetal membrane, endometritis and increased inter-calving period were significantly higher (p < 0.05) among Neospora seropositive cows. In conclusion, the finding discloses the strong association of N. caninum with reproductive disorders compared to Brucella spp. exposure. However, neither N. caninum nor Brucella spp. could explain the majority (73.2%) of the reported abortions and stillbirths in cattle. Hence, this observation underscores the need for more intensive investigation on the identification of causes of the aforementioned disorders in dairy cattle of Ethiopia. PMID- 24781156 TI - Lung remodeling in a mouse model of asthma involves a balance between TGF-beta1 and BMP-7. AB - A key event in chronic allergic asthma is the TGF-beta-induced activation of fibroblasts into alpha-SMA-positive myofibroblasts which synthesize type-I collagen. In the present study we investigated the effect of the anti-fibrotic molecule BMP-7 in asthma. Balb/c mice were immunized i.p. with ovalbumin in alum and challenged every 2 days with ovalbumin aerosol (two or six challenges for acute and chronic protocols, respectively). The lung was evaluated for: alpha-SMA and type-I collagen by immunohistochemistry; BMP-7 and TGF- beta1 gene expression by qRT-PCR; type-I collagen and Smads 2 and 3 by immunoblotting; mucus by PSA staining. Type-I collagen around bronchi, alpha-SMA, mucus secretion, TGF- beta1 and BMP-7 gene expression were all increased in asthma. The TGF- beta1/BMP-7 ratio was higher in the chronic group and correlated with higher levels of collagen. Fibroblasts isolated from asthmatic and healthy lungs produced type-I collagen upon stimulation with TGF- beta1 via phosphorylation of Smad-2, Smad-3. Pre-treatment of the fibroblasts with BMP-7 reduced collagen production and Smads phosphorylation. Intranasal treatment of asthmatic mice with recombinant BMP-7 during the immunization protocol reduced lung inflammation and type I collagen deposition. These results suggest a protective role for BMP-7 in lung allergic inflammation, opposing the pro-fibrotic effects of TGF- beta1. PMID- 24781158 TI - Evolution in surgical training: what can we learn from professional coaches and elite athletes? PMID- 24781157 TI - Small-molecule axon-polarization studies enabled by a shear-free microfluidic gradient generator. AB - A deep understanding of the mechanisms behind neurite polarization and axon path finding is important for interpreting how the human body guides neurite growth during development and response to injury. Further, it is of great clinical importance to identify diffusible chemical cues that promote neurite regeneration for nervous tissue repair. Despite the fast development of various types of concentration gradient generators, it has been challenging to fabricate neuron friendly (i.e. shear-free and biocompatible for neuron growth and maturation) devices to create stable gradients, particularly for fast diffusing small molecules, which typically require high flow and shear rates. Here we present a finite element analysis for a polydimethylsiloxane/polyethylene glycol diacrylate (PDMS/PEG-DA) based gradient generator, describe the microfabrication process, and validate its use for neuronal axon polarization studies. This device provides a totally shear-free, biocompatible microenvironment with a linear and stable concentration gradient of small molecules such as forskolin. The gradient profile in this device can be customized by changing the composition or width of the PEG DA barriers during direct UV photo-patterning within a permanently bonded PDMS device. Primary rat cortical neurons (embryonic E18) exposed to soluble forskolin gradients for 72 h exhibited statistically significant polarization and guidance of their axons. This device provides a useful platform for both chemotaxis and directional guidance studies, particularly for shear sensitive and non-adhesive cell cultures, while allowing fast new device design prototyping at a low cost. PMID- 24781159 TI - Learning from preventable deaths: exploring case record reviewers' narratives using change analysis. AB - OBJECTIVE: To determine if applying change analysis to the narrative reports made by reviewers of hospital deaths increases the utility of this information in the systematic analysis of patient harm. DESIGN: Qualitative analysis of causes and contributory factors underlying patient harm in 52 case narratives linked to preventable deaths derived from a retrospective case record review of 1000 deaths in acute National Health Service Trusts in 2009. PARTICIPANTS: 52 preventable hospital deaths. SETTING: England. MAIN OUTCOME MEASURES: The nature of problems in care and contributory factors underlying avoidable deaths in hospital. RESULTS: The change analysis approach enabled explicit characterisation of multiple problems in care, both across the admission and also at the boundary between primary and secondary care, and illuminated how these problems accumulate to cause harm. It demonstrated links between problems and underlying contributory factors and highlighted other threats to quality of care such as standards of end of life management. The method was straightforward to apply to multiple records and achieved good inter-rater reliability. CONCLUSION: Analysis of case narratives using change analysis provided a richer picture of healthcare-related harm than the traditional approach, unpacking the nature of the problems, particularly by delineating omissions from acts of commission, thus facilitating more tailored responses to patient harm. PMID- 24781160 TI - The friends and family test: a qualitative study of concerns that influence the willingness of English National Health Service staff to recommend their organisation. AB - OBJECTIVES: The views of practitioners at the 'sharp end' of care provision are increasingly recognised as important indicators of quality of care. The National Health Service (NHS) Staff Survey in England has quantified employees' views on how far they would be happy with the standard of care provided by their organisation if a friend or family member needed treatment. We aimed to characterise the concerns that might affect the willingness of staff to recommend their own organisations. DESIGN: Qualitative study involving semi-structured interviews. Data analysis based on the constant comparative method. PARTICIPANTS: Members of clinical and managerial staff in four NHS organisations (n = 70), and senior stakeholders across the NHS including clinicians, managers and others with a strategic or senior-level perspective (n = 98). SETTING: One hundred and sixty eight interviews were conducted: 70 in four case study organisations and 98 across the wider English NHS. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Asking study participants the 'if a friend...' question offered insider views on the quality of care. Some staff had no concerns, but others, identified significant problems with consistency, reliability and behaviour of staff. Participants identified reasons for poor care that included inadequate organisational systems; structural problems of understaffing and under resourcing; weaknesses in professional cultures and professional competence and failure to deal with problems such as unacceptable conduct. Participants emphasised that staff were not always able to deliver high-quality care because they worked in difficult conditions. CONCLUSIONS: Asking staff to give accounts of their willingness to recommend their organisation to family and friends elicits important insights into quality and safety of care. Such accounts might be able to provide warning signs that could signal organisational decline and avert healthcare scandals, but use outside a research context requires further evaluation. PMID- 24781161 TI - Bleeding gastroesophageal varices: what the Umbo Embo can do for you. PMID- 24781163 TI - Increased rates of duodenal obstruction in pancreatic cancer patients receiving modern medical management. AB - BACKGROUND: Duodenal obstruction from pancreatic cancer historically occurs in 2 25 % of patients without surgery, but with new advances in chemotherapy and radiation therapy, the life expectancy of pancreatic cancer has increased. AIM: The aim of the study was to determine the rate of development of duodenal obstruction requiring intervention in patients with pancreatic head adenocarcinoma who do not undergo surgical resection, but receive modern chemoradiation. METHODS: It is a retrospective single center study. Inclusion criteria were patients with pancreatic cancer who underwent ERCP with metal biliary stent and then chemoradiation who subsequently developed symptomatic duodenal obstruction and underwent either metal duodenal stent placement or surgical duodenal bypass. RESULTS: Twenty-four of 63 patients (38 %, 95 % CI 26 50 %) with unresectable pancreatic cancer and biliary stents who received chemotherapy and/or radiation therapy developed duodenal obstruction. The average length of time from diagnosis of pancreatic adenocarcinoma to development of outlet obstruction was 11.4 +/- 4.9 months (range 1.5-40 months). Average length of time from development of duodenal obstruction to death was 4.8 +/- 2.1 months (range 0.5-60 months). Average survival time from diagnosis to death was 16.6 +/- 5.6 months (range 4.5-58 months). CONCLUSION: Thirty-eight percent of patients with unresectable pancreatic head adenocarcinoma and metal biliary stents who receive chemotherapy and/or radiation therapy eventually develop symptomatic duodenal obstruction requiring duodenal stent or surgical bypass. This rate of duodenal obstruction is nearly twice that of previous reports using older oncologic therapy and will likely increase as patients survive longer with advances in medical therapy for pancreatic cancer. PMID- 24781164 TI - [Auditory neuropathy (auditory neuropathy spectrum disorders): the approaches to diagnostics and rehabilitation]. AB - Auditory neuropathies (auditory neuropathy spectrum disorders, ANSD) may be a consequence of dysfunction of inner hair cells and/or of synapses between these cells and auditory nerve fibers. Another cause of these disorders is supposed to be pathological changes in the auditory nerve itself. The outcome of the rehabilitative treatment of the patients presenting with this disorder depends on the quality of diagnosis and precise location of the pathological process. The present study involved 82 patients with auditory neuropathies. The audiological data obtained in the course of this work were compared with the results of other authors published during the recent years. The objective audiological examination included electrocochleography, registration of auditory brainstem response (ABR) and otoacoustic emission of short-latency and long-latency evoked auditory nerve action potentials. High-amplitude cochlear microphonic and transient evoked otoacoustic emission (TEOAE) potentials were recorded in 82 patients. In 17 (20.7%) patients, otoacoustic emission disappeared in the course of time even though the microphonic potential remained stable. It was shown that the results of electrical acoustic correction in the patients exhibiting long-latency evoked auditory action potentials and positive ABR to electrical stimulation (positive promontory test) were better than in the remaining cases. The outcome of cochlear implantation to a large extent depended on the localization of the pathological process. Specifically, the results of the treatment of the patients with high amplitude summation potentials, prolonged latency, and positive auditory action potentials in response to electrical stimulation (typical of pre-synaptic localization of the pathological process) were better than in the patients with normal summation potentials, pathological auditory nerve action potentials, TEOAE, and negative ABR to electrical stimulation (indicative of post-synaptic localization of the pathological process). In the latter group of patients, the results of cochlear implantation were far from being satisfactory. It is concluded that additional information facilitating categorization of the pathological process can be obtained by the identification of the genetic mutations responsible for the development of auditory neuropathies. PMID- 24781162 TI - Temporal and spatial dependence of inflammatory biomarkers and suppression by fluvastatin in dextran sodium sulfate-induced rat colitis model. AB - BACKGROUND: Dextran sodium sulfate (DSS)-induced colitis in rats is widely used as an experimental model for elucidating the etiology of ulcerative colitis (UC) and developing its novel remedy. We investigated the temporal and spatial changes in inflammatory mediators such as tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS) in the regions of rectum and distal colon and examined whether statins, which were designed to lower plasma cholesterol levels, influenced those mediators. METHODS: Colitis was induced in rats by oral administration of 5 % DSS for 5 days, followed by 2 % DSS for 10 days. 5 % DSS rats were treated with fluvastatin (20 mg/kg) concomitantly for 5 days. The expression of inflammatory mediators of a sequence of four regions in rectum (R) and distal colon (D0, D1, and D2) was determined by quantitative RT-PCR. RESULTS: The peak of colitic damage, which was confirmed clinically and histopathologically, was found on days 4-6. The expression of TNF-alpha, iNOS, cytokine-induced neutrophil chemoattractant-1, interleukin (IL)-1beta, and IL-6 mRNA increased in R time dependently, showing the peak on days 4-6, and then decreased thereafter. The levels of mRNAs reduced from R to D0, D1, and D2 region dependently. Fluvastatin decreased the expression of these markers in addition to the prevention of DSS-induced damage. CONCLUSIONS: Results demonstrated that the expression of inflammatory biomarkers had time and region specificity and was markedly inhibited by fluvastatin. To obtain a precise drug effect for UC, it is important to elucidate the temporal and spatial dependence of inflammatory biomarkers in DSS colitis model. PMID- 24781165 TI - [The evolution of surgical interventions for cochlear implantation at the Russian Research and Practical Centre of Audiology and Hearing Rehabilitation]. AB - The objective of the present study was to estimate and analyse the effectiveness and labour intensity of the methods of surgical intervention for cochlear implantation. The analysis of the surgical stage of cochlear implantation was based on the examination of 2073 children and adults during the period from 1991 to 2013. The age of the patients varied between 6 months to 71 years. The cause of deafness was meningitis and an injury in 11% and 6% of the patients respectively. The cochlear implants from Advanced Bionics were inserted in 495 patients, those from Med-El in 9 ones , and from Neurelec in 20, and Nucleus devices from Cochlear in the remaining patents (n=1549) including 37 double-array electrodes and a Hybrid implant for electroacoustic correction of hearing . The implants with a straight and perimodiolar electrode were placed in a roughly equal number of the patients. The rationale for the performance of selected components of the surgical stage of cochlear implantation was developed along with the technical procedures for the purpose applied at this Centre since 1991. The original methods for the fixation and covering of the receiver-stimulator and also for the choice of the place of the electrode array insertion into the cochlea are described. They allowed to significantly decrease the frequency of complications, duration and extent of the surgical intervention as well as to reduce to a minimum post-operative manipulations. PMID- 24781166 TI - [The current tendencies and prospects of the neural response telemetry in the rehabilitation of the patients after cochlear implantation]. AB - The objective of the present study was to estimate the potential of the modern technique for telemetry of the neural response during rehabilitation of the patients following cochlear implantation. The methods for the purpose included comparison of the results of intra- and postoperative registration on neural response telemetry (NRT) and evaluation of the influence of perimodiolar localization of electrodes of cochlear implants on the threshold level of stimulation and propagation of excitation inside the cochlea. The results of the study confirm the possibility of using the registration of the electrically evoked auditory nerve potential for fitting the speech processor of the cochlear implant. In addition, it was shown that the application of the perimodiolar electrode significantly narrows the intracochlear excitation distribution profile which enhances the rehabilitative effectiveness of cochlear implantation. PMID- 24781167 TI - [The effectiveness of rehabilitation following bilateral cochlear implantation]. AB - The Russian Federation similar to many other countries witnesses the continuous rise in the number of patients undergoing bilateral cochlear implantation. The objective of the present study was to estimate the effectiveness of rehabilitation following bilateral cochlear implantation. A total of 28 patients admitted to the Russian Research and Practical Centre of Audiology and Hearing Rehabilitation between 2011 and 2012 were available for the examination with the use of tonal threshold audiometry. Twenty one patient underwent sequential cochlear implantation, simultaneous implantation was effected in the remaining 7 ones. The patients were tested by a speech therapist. The tonal threshold audiometry in the free sound field showed that the auditory thresholds corresponded to grade I hearing impairment. Free-field sound perception threshold in the bilaterally implanted patients with two active speech processors was significantly better than in those having one speech processor. All the patients exhibited binaural summation effect. Surdopedagogical testing revealed positive dynamics of the speech development. The positive dynamics was especially well apparent pronounced in the patients operated simultaneously or when the period between two implantations did not exceed 1 year. A reduction of the duration of the period between two surgical interventions resulted in the decreased difference between sound perception in two ears, improvement of sound localization, and acceleration of speech development. All the patients showed good speech recognition in the complex acoustic environment and the ability to locate sounds. PMID- 24781168 TI - [The experience of the work of a regional cochlear implantation center]. AB - The objective of the present study was to determine the main lines of the development of a regional cochlear implantation centre and to estimate the effectiveness of rehabilitation of the children treated with the use of cochlear implantation. Analysis of the results of the work of the branch of the Russian Research and Practical Centre of Audiology and Hearing Rehabilitation based at Voronezh Regional Children's Clinical Hospital No 1 provided materials for the establishment of the principle directions of activities of the regional cochlear implantation centre where a total of 161 children have been kept under observation during the last years. Fifty six of the 138 children at the age varying from 1 to 12 years were given the surgical treatment. The patients were followed up within two and more years after connection of the speech processor. The study group was comprised only of the pre-lingually deaf children. It is concluded that the performance of most cochlear implantation procedures based at local centres allows to reduce the cost of rehabilitation and makes the high-tech medical aid more readily available to the patients; moreover, the practical introduction of remote speech processor programming software into the work of regional cochlear implantation centres enhances the effectiveness of the rehabilitative measures based at local medical facilities. PMID- 24781169 TI - [Novel possibilities for the rehabilitation of patients presenting with congenital external and middle ear malformations]. AB - The objective of the present study was to estimate the advantages of cochlear Baha BIA 400 abutments in the intraoperative and early postoperative periods. A total of 10 implantations of the systems with the use of hydroxyapatite bone cement were performed in 9 patients of different age. Stability of the implants and intensity of skin reactions were evaluated. The data obtained indicate that the use of cochlear Baha BIA 400 abutments significantly simplifies and shortens the surgical stage of rehabilitation producing a good cosmetic result. The use of the Osstell instrument made it possible to estimate stability of the implants intraoperatively and evaluate the effectiveness of osteointegration during the follow-up period. Analysis of the results of the study provided a basis on which to improve the quality and shorten duration of the rehabilitative treatment of the patients presenting with congenital external and middle ear malformations. Moreover, the data obtained can be used to develop practical recommendations for the further work in this area. PMID- 24781170 TI - [The audiological phenotype and the prevalence of GJB2-related sensorineural loss of hearing in the infants suffering acoustic disturbances]. AB - The objective of the present work was to study specific features of the audiological phenotype and the prevalence of GJB2-related sensorineural hearing loss (SNHL) in the infants suffering acoustic disturbances. The study included 264 children with bilateral non-syndromic sensorineural loss of hearing diagnosed during the first year of life by means of detailed audiological examination that included tympanometry, registration of short-latency auditory action potentials (SLAAP), delayed evoked otoacoustic emission (DEOAE), distortion product frequency otoacoustic emission (DPFOAE), and auditory brain-stem response (ABR). In addition, stationary acoustically evoked responses (SAER) were recorded in 38 children presenting with hearing impairment associated with GJB2-related sensorineural loss of hearing. The follow-up dynamic study involved 113 children subjected to repeated audiological examination. The study revealed the genotype with pathological mutations in 182 (69.0%) children including 171 (64.8%) ones with biallelic mutations and 11 (4.2%) with a single mutation (heterozygous genotype). Eighty two (31.0%) children had genotype without mutations. A total of 21 different mutations and 30 different genotypes were identified. Analysis of the family histories of the children showed that neither the absence of relatives suffering from hearing impairment nor the presence of risk factors of acquired hearing impairment excludes the possibility of GJB2-related sensorineural loss of hearing in the infants. Otoacoustic emission fails to be registered in the majority of the children with the altered genotype (87%) during the stay in the maternity house. Mutations in the GJB2 gene are most frequently diagnosed in the patients with the moderate, moderately severe, and severe loss of hearing. At the same time, almost half of the infants presenting with the mild loss of hearing were found to exhibit changes in the GJB2 gene. The thresholds of registration of short-latency auditory action potentials remain stable in 90.0% of the children presenting with GJB2-related sensorineural loss of hearing which makes it possible to choose the strategy of their rehabilitative treatment (the use of hearing aids or cochlear implantation) during the very first months of life and predict the favourable outcome of cochlear implantation and hearing aid measures. The results of the present work illustrate the importance and practical significance of genetic studies (GJB2 gene tresting) of the infants suffering sensorineural loss of hearing and other acoustic disturbances for the elucidation of etiology of these conditions, prognosis of the disease, and the choice of the strategy for its treatment. PMID- 24781171 TI - [The new regulations for diagnostics of occupational hearing impairment]. AB - The author presents information about the new regulations for diagnostics of occupational hearing impairment included in the technical documentation of the Russian Ministry of Health and Social Development and Ministry of Health governing provision of medical assistance to the subjects suffering from occupational hearing impairment and establishing the new rules for the compulsory prophylactic examination (preliminary and periodic) of the candidates for employment in the noisy environment. In addition, the newly-established criteria for the estimation of hearing impairment and occupational fitness of the subjects presenting with this condition are considered. The advantages of the new regulations are discussed along with their drawbacks that require further correction. PMID- 24781172 TI - [The universal audiological screening of newborn infants: achievements and challenges]. AB - The objective of the present study was to estimate the effectiveness of universal audiological screening of newborn infants in Russia based on the results of this procedure obtained in 2011-2012 by the analysis of the activities of surdological centres in 15 regions of the country. It was shown, that the main indicators of the effectiveness of the screening are the technical equipment of maternity houses, newborn coverage at the first stage of screening, and its continuity. The study revealed 3.14% of the infants who failed to be involved in the first stage of screening. Hearing impairment was diagnosed in two of each 1,000 newborn infants at the second stage of screening, the frequency of severe forms of hearing impairment was estimated as three cases per 10,000 infants. The disadvantages of the current system of identification of newborn infants suffering congenital loss of hearing are discussed. The importance of the improvement of data collection methods is emphasized. PMID- 24781173 TI - [The prevalence of hearing impairment among the elementary school pupils in the city of Sana, the capital of Yemen]. AB - The present study was designed to estimate the prevalence of hearing impairment among the elementary school pupils. The portable tone audiometer in conjunction with otoscopy was used to examine 2.200 children aged from 6 to 9 years attending 12 elementary schools in the city of Sana. The children with negative results of the tests were referred to the University Clinic for the more comprehensive examination. Risk factors were revealed by the questionnaire study involving the parents. As many as 11.6% of the total number of children failed to pass the test. Their number decreased to 10.6% after cleaning the external auditory canal. Conductive hearing impairment was the commonest pathological condition while exudative otitis was its most frequent cause (6% of all cases). The prevalence of hearing impairment among the elementary school pupils in Yemen was shown to exceed that in the developed countries. The high risk of development of this pathology is attributable to the low socio-economic living standards. The importance of audiological screening of elementary school pupils is emphasized. PMID- 24781174 TI - [New method for analysis and visualization of the fine temporal structure of the transient evoked otoacoustic emission signal]. AB - We have developed the new method for the analysis and visualization of the fine temporal structure of the transient evoked otoacoustic emission signal. The method consists of the presentation of the signal in the form of a set of tone components with a rapidly changing amplitude and relatively stable frequency. It is based on the combination of three spectrograms differing in frequency and temporal resolution by means of fuzzy logic amplitude estimation with subsequent frequency refining with the use of the least square procedure, reduction of the number of the insignificant components, and final re-ordering of the results for the simplification of further data processing. The new method was named Pitch Envelope Analysis (PEA). For data representation, a new type of diagram named componentogram was designed. The proposed method can be used for the real time processing of the continuous data stream especially for speech processing. PMID- 24781175 TI - [The analysis of disability caused by ear pathology in the adult population of Moscow during the period from 2007 to 2010]. AB - Disability due to the loss of hearing is one of the main challenges to public health services and social protection of the population. The results of analysis performed by the author indicate the necessity of the comprehensive approach to the solution of disability problems for all social groups of the population. Special attention should be paid to the subpopulation of the able-bodied subjects with hearing disorders who need special medical and social rehabilitative measures to be developed and applied. PMID- 24781176 TI - [Clinical peculiarities of diagnostics of sensorineural loss of hearing and deafness in children]. AB - The clinical features of various subjective and objective methods for the study of the hearing function were evaluated based on the results of examination of 46 children presenting with sensorineural hearing loss and deafness. The factors that influence the effectiveness and quality of diagnostics of sensorineural loss of hearing in the children were elucidated. PMID- 24781177 TI - [On the necessity of standardization of objective methods for the study of hearing function in children presenting with acute inflammatory diseases of the middle ear at the level of outpatient treatment]. AB - The objective of the present study was to standardize the frequency of objective evaluation of the hearing function in the children presenting with acute inflammatory diseases of the middle ear at the level of the outpatient treatment. The studies carried out to this effect with the use of modern and readily available audiological method revealed functional disorders in the middle ear of more than 50% of the children suffering from acute non-perforative otitis even after the elimination of the clinical signs of inflammation. The complete restoration of the functional state of the middle ear was documented in all the patients following the rehabilitative treatment. The authors proposed the algorithm for the examination of the children presenting with acute inflammatory diseases of the middle ear with special reference to the optimal frequency of diagnostic studies. PMID- 24781178 TI - [Effectiveness of a herbal preparation tonsilgon N for the treatment of children presenting with chronic adenoiditis]. AB - The objective of the present study was to estimate the effectiveness of the herbal preparation tonsilgon N exhibiting the anti-inflammatory and immunostimulating properties for the treatment of the children presenting with pathology of a pharyngeal tonsil. A total of 62 children at the age varying from 3 to 11 years with chronic adenoiditis (CA) were available for the examination. The study group was comprised of 32 children, the control one included 30 patients. The study has demonstrated the improvement of daytime nasal breathing in the study group compared with the control patients by 15% on day 5, by 30% on day 7, and by 73% on day 9 after the onset of the treatment. The intensity of rhinorrhea in the children treated with the herbal preparation decreased sooner than in the control group. Nasal breathing at night improved as soon as day 5 after the onset of therapy. However, the difference between the treated and control children was statistically significant only on day 7 whereas night-time nasal breathing on day 9 improved in the study group by 1.4 times compared with the control one. It is concluded that the inclusion of therapy with tonsilgon N in the combined treatment of the children presenting with chronic adenoiditis increases its effectiveness and accelerates the process of reconvalescence. Tonsilgon N is a safe medication suitable for the prolonged application. PMID- 24781179 TI - [The role of biofilms in pathogenesis of chronic bacterial rhinosinusitis]. AB - The objective of the present work was to study the contribution of biofilms to the development of chronic bacterial rhinosinusitis. A total of 50 patients with this pathology were available for the examination. Mucosal swabs were taken from the middle nasal passages of all the patients to be used for the detection of biofilms by luminescence microscopy. The lactoferrine content in mucosal secretion from the nasal cavity was determined by an immunoenzymatic assay. Two groups of the patients presenting with bacterial rhinosinusitis were distinguished in the study of impression smears from nasal cavity mucosa by luminescence microscopy; one of them was comprised of biofilm-positive patients the other of biofilm-negative ones (56% and 44% respectively). The patients showing biofilms over nasal cavity mucosa had the lactoferrine content in mucosal secretion on the order of 0.0033+/-0.0008 mg/l compared with 0.0068+/-0.00075 mg/l in the biofilm-negative patients and 0.55+/-0.0005 mg/l in the healthy volunteers (controls). In other words, the biofilm-positive patients presenting with chronic bacterial rhinosinusitis had two times lower content of lactoferrine in mucosal secretion from the middle nasal passages than those in the biofilm negative group and 126 times lower content of lactoferrine than in the control group. PMID- 24781180 TI - [Allergic rhinitis: allergist's point of view]. AB - Allergic rhinitis is a serious medical and social problem associated with the continuously increasing morbidity level and imposing a high economic burden on the healthcare delivery system for the management of this condition. In accordance with the concept of "personalized medicine", the prescription of intranasal or oral antihistaminic agents, intranasal glucocorticosteroids and oral antagonists of antileukotrienic medicines as well as decongestants and therapeutic preparations of other classes for the treatment of allergic rhinitis should be well substantiated and based on an individual approach to a patient in every particular case. PMID- 24781181 TI - [Therapeutic modalities for the management of cough associated with acute respiratory viral infection, effective in an otolaryngologist's practice]. AB - The objective of the present study was to evaluate the effectiveness ascoril therapy in comparison with the treatment using the mucoactive agent lasolvan in the adult patients suffering from productive cough associated with acute viral respiratory infection. Patients and methods. The study included 120 patients suffering from productive cough associated with acute viral respiratory infection. They were divided into two groups. The patients comprising group 1 (n=6.) were treated with ascoril, those in group 2 (n=60) were given lasolvan. Results. The effectiveness of the treatment of cough in group 1 was found to be higher compared with that in group 2 (p<0.05); moreover, it was associated with better dynamics of certain indicators of the quality of life, such as the social activity level, vitality, and general health (p<0.05). The safety of the proposed treatment was confirmed by the absence of the adverse events throughout the entire treatment period. PMID- 24781182 TI - [Johanson-Blizzard syndrome: audiological features and results of cochlear implantation]. AB - Johanson-Blizzard syndrome is a rare congenital autosomal recessive disease characterized by the association of congenital deficiency of the exocrine pancreatic function and multiple malformations. One of the most common manifestations of this pathology is sensorineural hearing loss of different severity and anomalous development of the inner ear. The case of cochlear implantation in the patient presenting with bilateral sensorineural deafness, congenital malformation of the inner ear, and stenosis of the internal auditory canal is reported. PMID- 24781183 TI - [Cochlear implantation in immunocompromised patients]. AB - This paper reports a clinical case that gives evidence of the possibility of cochlear implantation after liver transplantation. Patient K. aged 3 years 10 months was admitted to the Russian Research and Practical Centre of Audiology and Hearing Rehabilitation with the diagnosis of type IB glycogenosis after maternal liver transplantation associated with chronic neutropenia, chronic cutaneous and mucosal infection, partial symptomatic partial epilepsy, retarded psycho-motor development, and complaints of the absence of auditory response. The audiological examination provided materials for the diagnosis of grade IV bilateral sensorineural hearing loss tending toward deafness. Cochlear implantation recommended to the patient was performed on February 20, 2013 using the HiRes 90 K implant with the HiFocus Helix electrode (Advanced Bionics, USA). The surgical intervention and the postoperative period passed without complications. The speech processor was activated one month after surgery. The results of surdopedagogical testing gave evidence of successful rehabilitation promising the further improvement. It is concluded that immunosuppressive therapy is not an absolute contraindication for cochlear implantation, but this procedure requires detailed examination and thorough preparation for the forthcoming surgery. PMID- 24781184 TI - Abnormal neurons in teratomas in NMDAR encephalitis. AB - IMPORTANCE: Ovarian teratomas are frequently described in patients with N-methyl d-aspartate receptor (NMDAR) encephalitis, yet NMDAR encephalitis is rarely described in patients with ovarian teratomas. Understanding why a minority of patients with teratomas are seen with autoimmune encephalitis may improve the management of NMDAR encephalitis and other teratoma-associated autoimmune diseases. OBJECTIVE: To characterize the unique organization of neuroglial elements within ovarian teratomas resected from patients with NMDAR encephalitis. DESIGN: Case-control study comparing the pathological features of ovarian teratomas resected from consecutively accrued cases with NMDAR encephalitis between January 1, 2009, and December 15, 2013, and ovarian teratomas resected from controls between June 1, 2012, and June 30, 2013. SETTING: Pathology tissue database at a tertiary academic care center. PARTICIPANTS: Five cases with teratoma-associated NMDAR encephalitis and serum or cerebrospinal fluid autoantibodies against central nervous system (CNS) NMDAR and 38 controls (39 ovarian teratomas) without neurological symptoms or signs. EXPOSURES: Formalin fixed, paraffin-embedded ovarian teratomas were examined for the presence of CNS tissue and inflammatory infiltrates using direct microscopy, enhanced with standard histopathological and immunological stains. MAIN OUTCOMES AND MEASURES: Frequency of detection of atypical (dysplastic) CNS neuronal elements in ovarian teratomas resected from cases vs controls, as well as characterization of the relationship between atypical neurons and immune infiltrates. RESULTS: Central nervous system neuronal elements were detected in 4 of 5 teratomas resected from cases with NMDAR encephalitis and in 20 of 39 controls (P = .36). Atypical neurons were seen within teratomas resected from 4 of 5 cases but not in 39 controls, reliably distinguishing teratomas associated with NMDAR encephalitis (P < .001). If found within the CNS, these histological abnormalities would have received the diagnosis of gangliogliomas (n = 3) and ganglioneuroblastoma (n = 1). Reactive changes were present in teratomas from controls, including ferruginated neurons and Rosenthal fibers. Abnormal neuroglial elements were closely related to immune infiltrates in teratomas resected from 4 of 4 cases. Inflammatory infiltrates were not associated with neuroglial tissue in 20 controls, further differentiating these populations (P < .001). CONCLUSIONS AND RELEVANCE: Abnormal neurons within teratomas distinguish cases with NMDAR encephalitis from controls and may promote the development of autoimmunity. PMID- 24781185 TI - Dissecting active ingredients of Chinese medicine by content-weighted ingredient target network. AB - Chinese medicine has been widely used in clinical practice, but its mode of action often remains obscure. This has seriously hindered further development and better clinical applications of Chinese medicine. Among the most critical questions to be addressed, the identification of active ingredients is an important one requiring more research. Existing methods are only concerned the potential pharmacological effects of the individual purified chemical ingredients without consideration of the contents of these ingredients, which is critical to the comprehensive effect of Chinese medicine. A novel approach was proposed here to integrate network pharmacology analysis and ingredient content in Chinese medicine to identify active ingredients. The therapeutic action of Xuesaitong (XST) injection on myocardial infarction was analyzed as an example in this study. Firstly, we built a cardiovascular disease (CVD) related protein-protein interaction (PPI) network. Secondly, the potential targets of the ingredients of XST were identified by integrating microarray data, text mining and pharmacophore model-based prediction. The target-ingredient relationships were then mapped to the network. Topological attributes related to the targets of these ingredients, together with the ingredients' contents, were combined to calculate a composition weighted index for integrative evaluation of ingredient efficacy. Our results indicated that major active ingredients in XST were notoginsenoside R1, ginsenoside Rg1, Rb1, Rd and Re, which was further validated on myocardial infarction rat models. In conclusion, this study presented a novel approach to identify active ingredients in Chinese medicine. PMID- 24781187 TI - Cockayne syndrome protein A is a transcription factor of RNA polymerase I and stimulates ribosomal biogenesis and growth. AB - Mutations in the Cockayne syndrome A (CSA) protein account for 20% of Cockayne syndrome (CS) cases, a childhood disorder of premature aging and early death. Hitherto, CSA has exclusively been described as DNA repair factor of the transcription-coupled branch of nucleotide excision repair. Here we show a novel function of CSA as transcription factor of RNA polymerase I in the nucleolus. Knockdown of CSA reduces pre-rRNA synthesis by RNA polymerase I. CSA associates with RNA polymerase I and the active fraction of the rDNA and stimulates re initiation of rDNA transcription by recruiting the Cockayne syndrome proteins TFIIH and CSB. Moreover, compared with CSA deficient parental CS cells, CSA transfected CS cells reveal significantly more rRNA with induced growth and enhanced global translation. A previously unknown global dysregulation of ribosomal biogenesis most likely contributes to the reduced growth and premature aging of CS patients. PMID- 24781188 TI - Highly efficient carrier multiplication in PbS nanosheets. AB - Semiconductor nanocrystals are promising for use in cheap and highly efficient solar cells. A high efficiency can be achieved by carrier multiplication (CM), which yields multiple electron-hole pairs for a single absorbed photon. Lead chalcogenide nanocrystals are of specific interest, since their band gap can be tuned to be optimal to exploit CM in solar cells. Interestingly, for a given photon energy CM is more efficient in bulk PbS and PbSe, which has been attributed to the higher density of states. Unfortunately, these bulk materials are not useful for solar cells due to their low band gap. Here we demonstrate that two-dimensional PbS nanosheets combine the band gap of a confined system with the high CM efficiency of bulk. Interestingly, in thin PbS nanosheets virtually the entire excess photon energy above the CM threshold is used for CM, in contrast to quantum dots, nanorods and bulk lead chalcogenide materials. PMID- 24781186 TI - The retromer complex is required for rhodopsin recycling and its loss leads to photoreceptor degeneration. AB - Rhodopsin mistrafficking can cause photoreceptor (PR) degeneration. Upon light exposure, activated rhodopsin 1 (Rh1) in Drosophila PRs is internalized via endocytosis and degraded in lysosomes. Whether internalized Rh1 can be recycled is unknown. Here, we show that the retromer complex is expressed in PRs where it is required for recycling endocytosed Rh1 upon light stimulation. In the absence of subunits of the retromer, Rh1 is processed in the endolysosomal pathway, leading to a dramatic increase in late endosomes, lysosomes, and light-dependent PR degeneration. Reducing Rh1 endocytosis or Rh1 levels in retromer mutants alleviates PR degeneration. In addition, increasing retromer abundance suppresses degenerative phenotypes of mutations that affect the endolysosomal system. Finally, expressing human Vps26 suppresses PR degeneration in Vps26 mutant PRs. We propose that the retromer plays a conserved role in recycling rhodopsins to maintain PR function and integrity. PMID- 24781189 TI - Proteomic analysis of cerebrospinal fluid: toward the identification of biomarkers for gliomas. AB - Gliomas are the most common primary brain tumors in adults and, despite advances in the understandings of glioma pathogenesis in the genetic era, they are still ineradicable, justifying the need to develop more reliable diagnostic and prognostic biomarkers for this malignancy. Because changes in cerebrospinal fluid (CSF) are suggested to be capable of sensitively reflecting pathological processes, e.g., neoplastic conditions, in the central nervous system, CSF has been deemed a valuable source for potential biomarkers screening in this era of proteomics. This systematic review focused on the proteomic analysis of glioma CSF that has been published to date and identified a total of 19 differentially expressed proteins. Further functional and protein-protein interaction assessments were performed by using Protein Analysis Through Evolutionary Relationships (PANTHER) website and Ingenuity Pathway Analysis (IPA) software, which revealed several important protein networks (e.g., IL-6/STAT-3) and four novel focus proteins (IL-6, galanin (GAL), HSPA5, and WNT4) that might be involved in glioma pathogenesis. The concentrations of these focus proteins were subsequently determined by enzyme-linked immunosorbent assay (ELISA) in an independent set of CSF and tumor cyst fluid (CF) samples. Specifically, glioblastoma (GBM) CF had significantly lower GAL, HSPA5, and WNT4 levels than CSF from different grades of glioma. In contrast, IL-6 level was significantly higher in GBM CF when compared with CSF and, among different CSF groups, was highest in GBM CSF. Therefore, these candidate protein biomarkers, identified from both the literatures and in silico analysis, may have potentials in clinical diagnosis, prognosis evaluation, treatment response monitoring, and novel therapeutic targets identification for patients with glioma. PMID- 24781190 TI - Anatomy of the superior petrosal veins and their exposure and management during petrous apex meningioma surgery using the lateral suboccipital retrosigmoid approach. AB - During surgeries in the upper cerebellopontine angle (CPA), the superior petrosal veins (SPVs) often act as obstacles; and their sectioning sometimes causes serious complications. In this study, we introduced a classification system for the SPVs wherein their tributaries were classified into four groups on the basis of their courses and draining areas. We furthermore explained the detailed anatomy of the vein of the cerebellopontine fissure, which is the largest tributary. In surgeries of petrous apex meningioma, the knowledge of the displacement pattern of the vein is very helpful for avoiding major venous complications. Therefore, we elucidated its anatomical situation in relation to the original portion of the meningioma and the natural draining point of the vein into the superior petrosal sinus (SPS) in each patient. In addition, we described the methods and techniques used to expose and manage the vein of the cerebellopontine fissure during surgery using the lateral suboccipital retrosigmoid approach. Presenting two illustrative cases, we recommend that the initial exposure of the tumor should be performed through the infratentorial lateral supracerebellar route and that the suprafloccular cistern is the best area to find the vein of the cerebellopontine fissure. We emphasized the importance of the preservation of the vein of the cerebellopontine fissure and also proposed the order for exposure of SPV tributaries during upper CPA surgery using the retrosigmoid approach. PMID- 24781191 TI - Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Proliferation and Tumor Growth In Vivo. AB - Alterations in cellular metabolism and bioenergetics are vital for cancer cell growth and motility. Here, the role of the mitochondrial protein voltage dependent anion channel (VDAC1), a master gatekeeper regulating the flux of metabolites and ions between mitochondria and the cytoplasm, in regulating the growth of several cancer cell lines was investigated by silencing VDAC1 expression using small interfering RNA (siRNA). A single siRNA specific to the human VDAC1 sequence at nanomolar concentrations led to some 90% decrease in VDAC1 levels in the lung A549 and H358, prostate PC-3, colon HCT116, glioblastoma U87, liver HepG2, and pancreas Panc-1 cancer cell lines. VDAC1 silencing persisted 144 hours post-transfection and resulted in profound inhibition of cell growth in cancer but not in noncancerous cells, with up to 90% inhibition being observed over 5 days that was prolonged by a second transfection. Cells expressing low VDAC1 levels showed decreased mitochondrial membrane potential and adenoside triphosphate (ATP) levels, suggesting limited metabolite exchange between mitochondria and cytosol. Moreover, cells silenced for VDAC1 expression showed decreased migration, even in the presence of the wound healing accelerator basic fibroblast growth factor (bFGF). VDAC1-siRNA inhibited cancer cell growth in a Matrigel-based assay in host nude mice. Finally, in a xenograft lung cancer mouse model, chemically modified VDAC1-siRNA not only inhibited tumor growth but also resulted in tumor regression. This study thus shows that VDAC1 silencing by means of RNA interference (RNAi) dramatically inhibits cancer cell growth and tumor development by disabling the abnormal metabolic behavior of cancer cells, potentially paving the way for a more effective pipeline of anticancer drugs. PMID- 24781192 TI - RNAi-mediated Gene Silencing of Mutant Myotilin Improves Myopathy in LGMD1A Mice. AB - Recent progress suggests gene therapy may one day be an option for treating some forms of limb girdle muscular dystrophy (LGMD). Nevertheless, approaches targeting LGMD have so far focused on gene replacement strategies for recessive forms of the disease. In contrast, no attempts have been made to develop molecular therapies for any of the eight dominantly inherited forms of LGMD. Importantly, the emergence of RNA interference (RNAi) therapeutics in the last decade provided new tools to combat dominantly inherited LGMDs with molecular therapy. In this study, we describe the first RNAi-based, preclinical gene therapy approach for silencing a gene associated with dominant LGMD. To do this, we developed adeno-associated viral vectors (AAV6) carrying designed therapeutic microRNAs targeting mutant myotilin (MYOT), which is the underlying cause of LGMD type 1A (LGMD1A). Our best MYOT-targeted microRNA vector (called miMYOT) significantly reduced mutant myotilin mRNA and soluble protein expression in muscles of LGMD1A mice (the TgT57I model) both 3 and 9 months after delivery, demonstrating short- and long-term silencing effects. This MYOT gene silencing subsequently decreased deposition of MYOT-seeded intramuscular protein aggregates, which is the hallmark feature of LGMD1A. Histological improvements were accompanied by significant functional correction, as miMYOT-treated animals showed increased muscle weight and improved specific force in the gastrocnemius, which is one of the most severely affected muscles in TgT57I mice and patients with dominant myotilin mutations. These promising results in a preclinical model of LGMD1A support the further development of RNAi-based molecular therapy as a prospective treatment for LGMD1A. Furthermore, this study sets a foundation that may be refined and adapted to treat other dominant LGMD and related disorders. PMID- 24781193 TI - Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin. AB - Monocytes rapidly infiltrate inflamed tissues and differentiate into CD209(+) inflammatory dendritic cells (DCs) that promote robust immunity or, if unregulated, inflammatory disease. Previous studies in experimental animal models indicate that inflammatory DC depletion through systemic elimination of their monocyte precursors with clodronate-loaded liposomes ameliorates the development of psoriasis and other diseases. However, translation of systemic monocyte depletion strategies is difficult due to the importance of monocytes during homeostasis and infection clearance. Here, we describe a strategy that avoids the monocyte intermediates to deplete inflammatory DCs through antibody-loaded toxin. Mice with an abundance of inflammatory DCs as a consequence of lipopolysaccharide exposure were treated with anti-CD209 antibody conjugated to saporin, a potent ribosome inactivator. The results demonstrate depletion of CD209(+) DCs. This strategy could prove useful for the targeted reduction of inflammatory DCs in disease. PMID- 24781194 TI - Regulatory T cells and their roles in immune dysregulation and allergy. AB - The main function of the immune system is to fight off potential infections, but also to maintain its activity below a level that would trigger self-reactivity. Regulatory T cells (Tregs) such as forkhead box P3(+) (FOXP3) Tregs and type 1 regulatory T cells (Tr1) play an essential role in this active process, using several distinct suppressive mechanisms. A wide range of pathologies have been associated with altered Treg cell function. This is best exemplified by the impact of mutations of genes essential for Treg function and the associated autoimmune syndromes. This review summarizes the main features of different subtypes of Tregs and focuses on the clinical implications of their altered function in human studies. More specifically, we discuss abnormalities affecting FOXP3(+) Tregs and Tr1 cells that will lead to autoimmune manifestations and/or allergic reactions, and the potential therapeutic use of Tregs. PMID- 24781195 TI - Clinical impact of H-Y alloimmunity. AB - H-Y antigens are a group of minor histocompatibility antigens encoded on the Y chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity. PMID- 24781196 TI - A betasatellite-dependent begomovirus infects ornamental rose: characterization of begomovirus infecting rose in Pakistan. AB - The Begomovirus genus of the family Geminiviridae comprises the largest group of geminiviruses. The list of begomoviruses is continuously increasing as a result of improvement in the methods for identification. Ornamental rose plants (Rosa chinensis) with highly stunted growth and leaf curling were found in Faisalabad, Pakistan. Plants were analyzed for begomovirus infection, through rolling circle amplification and PCR methods. Based on complete genome sequence homologies with other begomoviruses, a new begomovirus species infecting the rose plants was discovered. In this paper, we propose a new species name, Rose leaf curl virus (RoLCuV), for the virus. RoLCuV showed close identity (83 %) with Tomato leaf curl Pakistan virus, while associated betasatellite showed 96 % identity with Digera arvensis yellow vein betasatellite (DiAYVB), justifying a new isolate for the betasatellite. Recombination analysis of newly identified begomovirus revealed it as a recombinant of tomato leaf curl Pakistan virus from its coat protein region. The infectious molecules for virus/satellite were prepared and inoculated through Agrobacterium tumefaciens to N. benthamiana plants. RoLCuV alone was unable to induce any level of symptoms on N. benthamiana plants, but co inoculation with cognate betasatellite produced infection symptoms. Further investigation to understand the trans-replication ability of betasatellites revealed their flexibility to interact with Rose leaf curl virus. PMID- 24781198 TI - Cancer Research UK will increase its research spending by 50% over the next five to 10 years. PMID- 24781197 TI - Glucan, Water Dikinase Exerts Little Control over Starch Degradation in Arabidopsis Leaves at Night. AB - The first step on the pathway of starch degradation in Arabidopsis (Arabidopsis thaliana) leaves at night is the phosphorylation of starch polymers, catalyzed by glucan, water dikinase (GWD). It has been suggested that GWD is important for the control of starch degradation, because its transcript levels undergo strong diel fluctuations, its activity is subject to redox regulation in vitro, and starch degradation is strongly decreased in gwd mutant plants. To test this suggestion, we analyzed changes in GWD protein abundance in relation to starch levels in wild type plants, in transgenic plants in which GWD transcripts were strongly reduced by induction of RNA interference, and in transgenic plants overexpressing GWD. We found that GWD protein levels do not vary over the diel cycle and that the protein has a half-life of 2 d. Overexpression of GWD does not accelerate starch degradation in leaves, and starch degradation is not inhibited until GWD levels are reduced by 70%. Surprisingly, this degree of reduction also inhibits starch synthesis in the light. To discover the importance of redox regulation, we generated transgenic plants expressing constitutively active GWD. These plants retained normal control of degradation. We conclude that GWD exerts only a low level of control over starch degradation in Arabidopsis leaves. PMID- 24781199 TI - A paper microfluidic cartridge for automated staining of malaria parasites with an optically transparent microscopy window. AB - A paper microfluidic cartridge for the automated staining of malaria parasites (Plasmodium) with acridine orange prior to microscopy is presented. The cartridge enables simultaneous, sub-minute generation of both thin and thick smears of acridine orange stained parasites. Parasites are stained in a cellulose matrix, after which the parasites are ejected via capillary forces into an optically transparent chamber. The unique slanted design of the chamber ensures that a high percentage of the stained blood will be of the required thickness for a thin smear, without resorting to spacers or other methods that can increase production cost or require tight quality controls. A hydrophobic snorkel facilitates the removal of air bubbles during filling. The cartridge contains both a thin smear region, where a single layer of cells is presented unobstructed, for ease of species identification, and a thick smear region, containing multiple cell layers, for enhanced limit of detection. PMID- 24781200 TI - Understanding the degradation mechanism of rechargeable lithium/sulfur cells: a comprehensive study of the sulfur-graphene oxide cathode after discharge-charge cycling. AB - Lithium/sulfur (Li/S) cells have attracted much attention due to their higher theoretical specific capacity and energy compared to those of current lithium-ion cells. However, the application of Li/S cells is still hampered by short cycle life. Sulfur-graphene oxide (S-GO) nanocomposites have shown promise as cathode materials for long-life Li/S cells because oxygen-containing functional groups on the surface of graphene oxide were successfully used as sulfur immobilizers by forming weak bonds with sulfur and polysulfides. While S-GO showed much improved cycling performance, the capacity decay still needs to be improved for commercially viable cells. In this study, we attempt to understand the capacity fading mechanism based on an ex situ study of the structural and chemical evolution of S-GO nanocomposite cathodes with various numbers of cycles using scanning electron microscopy (SEM), near edge X-ray absorption fine structure (NEXAFS) and X-ray photoelectron spectroscopy (XPS). It is found that both the surface morphologies and chemical structures of the cathode materials change considerably with increasing number of cycles. These changes are attributed to several unexpected chemical reactions of lithium with S-GO nanocomposites occurring during the discharge-charge processes with the formation of Li2CO3, Li2SO3, Li2SO4, and COSO2Li species. These reactions result in the loss of recyclable active sulfur on the surface of the electrode, and thus capacity fades while coulombic efficiency is near 100%. Moreover, the reaction products accumulate on the cathode surface, forming a compact blocking insulating layer which may make the diffusion of Li ions into/out of the cathode difficult during the discharge-charge process and thus lead to lower utilization of sulfur at higher rates. We think that these two observations are significant contributors to the capacity and rate capability degradation of the Li/S-GO cells. Therefore, for the rechargeable Li/S-GO cells, we suggest that the content of oxygen containing functional groups on GO should be optimized and more stable functional groups need to be identified for further improvement of the cycling performance. The information we gain from this study may provide general insights into the fundamental understanding of the degradation mechanisms of other rechargeable Li/S cells using similar oxygen-containing functional groups as sulfur immobilizers. PMID- 24781201 TI - Validation of a brief step-test protocol for estimation of peak oxygen uptake. AB - BACKGROUND: Physical exercise capacity has been shown to predict cardiovascular disease incidence and is increasingly measured in epidemiological studies. However, direct measurement of peak oxygen uptake is too time consuming in large scale studies. We therefore investigated whether a brief 3-minute step-test protocol can be used to estimate peak oxygen uptake in these settings. DESIGN AND METHODS: A group of 97 subjects performed the YMCA step test and a maximal treadmill test with continuous measurement of oxygen uptake. Correlation and linear regression analyses were used to identify VO2peak predictors obtained from the step test and to develop models for VO2peak estimation. RESULTS: The YMCA model, including the 1-minute heart beat count, predicted VO2peak with R = 0.83. A novel simplified model based on the heart rate at 45 s of recovery performed comparable (R = 0.83). However, models based on heart rate measures were only valid in subjects who completed the test according to protocol, but not in subjects who terminated prematurely. For the applicability in subjects with low exercise capacity, a new model including gas exchange analysis enabled prediction of VO2peak (R = 0.89). All models were validated in an independent sample (r = 0.86-0.91). Exercise time of the step test was less than one-hird of standard ergospirometry (treadmill test: 654 +/- 151 s, step test: 180 s, p < 0.001). CONCLUSION: In large-scale epidemiological studies with limited time slots for exercise testing and significant proportions of subjects with low exercise capacity a modified version of the YMCA step test may be used to predict VO2peak. PMID- 24781202 TI - Interaction between diabetes and a high ankle-brachial index on mortality risk. AB - OBJECTIVE: Low ankle-brachial index (ABI) is a predictor of increased mortality. The impact of a high ABI on mortality is less studied. Moreover, diabetes is frequently associated with high ABI and, because of specific mechanisms in diabetic vascular diseases, the relationship with prognosis may be unique. Therefore, our aim was to compare mortality in individuals with and without diabetes according to abnormally low and high ABI. DESIGN AND METHODS: We studied the association between ABI and all-cause and cardiovascular mortality in 6986 participants from the REACH registry, a cohort of 45 years and older stable outpatients at high cardiovascular risk (2875 (41.1%) with diabetes) followed for 4 years. RESULTS: ABI was normal (0.91-1.29) in 49.5%, low (<=0.9) in 47.5%, and high (>=1.3) in 2.9% of participants. During follow up, 9.9% of participants died (6.5% from cardiovascular causes). A low ABI was associated with cardiovascular mortality (adjusted hazard ratio, HR, 1.98, 95% CI 1.62-2.41) and all-cause mortality (HR 2.01, 95% CI 1.72-2.36), without heterogeneity according to diabetes. In contrast, high ABI was associated with higher risk of all-cause mortality in individuals with diabetes (HR 2.11, 95% CI 1.16-3.84), but not without diabetes (HR 0.82, 95% CI 0.36-1.85; p-value for interaction 0.07). The trend was similar for cardiovascular mortality (HR 2.13, 95% CI 1.03-4.44 and HR 1.05, 95% CI 0.43-2.59 with and without diabetes, respectively; p-value for interaction 0.24). CONCLUSIONS: In the REACH registry, low ABI was associated with mortality, similarly in individuals without and with diabetes, whereas the association with high ABI was only observed in patients with diabetes. PMID- 24781205 TI - Should we relax the definition of death or the dead donor rule? PMID- 24781204 TI - The first mouse mutants of D14Abb1e (Fam208a) show that it is critical for early development. AB - An ENU mutagenesis screen to identify novel epigenetic modifiers was established in mice carrying a multi-copy GFP transgene, which is expressed in a variegated manner in erythrocytes and is highly sensitive to epigenetic silencing. The screen has produced mouse mutants of both known modifiers of epigenetic state, such as Dnmt1 and Smarca5, and novel modifiers, such as Smchd1 and Rlf. Here we report two mouse lines generated from the screen, MommeD6 and MommeD20, with point mutations in D14Abb1e. These are the first mouse mutants of D14Abb1e (also known as Fam208a), a gene about which little is known. Heterozygous intercrosses show that homozygous mutants from both the MommeD6 and MommeD20 lines are not viable beyond gastrulation, demonstrating an important role for D14Abb1e in development. We demonstrate that haploinsufficiency for D14Abb1e effects transgene expression at the RNA level. Analysis of the predicted D14Abb1e protein sequence reveals that it contains putative nuclear localisation signals and a domain of unknown function, DUF3715. Our studies reveal that D14Abb1e is localised to the nucleus and is expressed in skin and testes. PMID- 24781206 TI - Evaluation of microbial triglyceride oil purification requirements for the CelTherm process: an efficient biochemical pathway to renewable fuels and chemicals. AB - CelTherm is a biochemical process to produce renewable fuels and chemicals from lignocellulosic biomass. The present study's objective was to determine the level of treatment/purity of the microbial triacylglyceride oil (TAG) necessary to facilitate fuel production. After a unique microbe aerobically synthesizes TAG from biomass-derived sugars, the microbes were harvested and dried then crude TAG was chemically extracted from the residual biomass. Some TAGs were further purified to hydrotreating process requirements. Both grades were then noncatalytically cracked into a petroleum-like intermediate characterized by gas chromatography. Experiments were repeated using refined soybean oil for comparison to previous studies. The products from crude microbial TAG cracking were then further refined into a jet fuel product. Fuel tests indicate that this jet fuel corresponds to specifications for JP-8 military turbine fuel. It was thus concluded that the crude microbial TAG is a suitable feedstock with no further purification required, demonstrating CelTherm's commercial potential. PMID- 24781207 TI - A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. AB - Editing of the pre-mRNA for the serotonin receptor 2C (5-HT2CR) by site-specific adenosine deamination (A-to-I pre-mRNA editing) substantially increases the functional plasticity of this key neurotransmitter receptor and is thought to contribute to homeostatic mechanisms in neurons. 5-HT2CR mRNA editing generates up to 24 different receptor isoforms. The extent of editing correlates with 5 HT2CR functional activity: more highly edited isoforms exhibit the least function. Altered 5-HT2CR editing has been reported in postmortem brains of suicide victims. We report a comparative analysis of the connections among 5 HT2CR editing, genome-wide gene expression and DNA methylation in suicide victims, individuals with major depressive disorder and non-psychiatric controls. The results confirm previous findings of an overrepresentation of highly edited mRNA variants (which encode hypoactive 5-HT2CR receptors) in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected. This signature set of editing-associated genes is significantly enriched for genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. Notably, we report that the link between 5-HT2CR editing and gene expression is disrupted in suicide victims. The results suggest that the postulated homeostatic function of 5-HT2CR editing is dysregulated in individuals who committed suicide. PMID- 24781208 TI - Rapid depletion of muscle progenitor cells in dystrophic mdx/utrophin-/- mice. AB - Duchenne muscular dystrophy (DMD) patients lack dystrophin from birth; however, muscle weakness becomes apparent only at 3-5 years of age, which happens to coincide with the depletion of the muscle progenitor cell (MPC) pools. Indeed, MPCs isolated from older DMD patients demonstrate impairments in myogenic potential. To determine whether the progression of muscular dystrophy is a consequence of the decline in functional MPCs, we investigated two animal models of DMD: (i) dystrophin-deficient mdx mice, the most commonly utilized model of DMD, which has a relatively mild dystrophic phenotype and (ii) dystrophin/utrophin double knock-out (dKO) mice, which display a similar histopathologic phenotype to DMD patients. In contrast to age-matched mdx mice, we observed that both the number and regeneration potential of dKO MPCs rapidly declines during disease progression. This occurred in MPCs at both early and late stages of myogenic commitment. In fact, early MPCs isolated from 6-week-old dKO mice have reductions in proliferation, resistance to oxidative stress and multilineage differentiation capacities compared with age-matched mdx MPCs. This effect may potentially be mediated by fibroblast growth factor overexpression and/or a reduction in telomerase activity. Our results demonstrate that the rapid disease progression in the dKO model is associated, at least in part, with MPC depletion. Therefore, alleviating MPC depletion could represent an approach to delay the onset of the histopathologies associated with DMD patients. PMID- 24781210 TI - The genetic landscape of infantile spasms. AB - Infantile spasms (IS) is an early-onset epileptic encephalopathy of unknown etiology in ~40% of patients. We hypothesized that unexplained IS cases represent a large collection of rare single-gene disorders. We investigated 44 children with unexplained IS using comparative genomic hybridisation arrays (aCGH) (n = 44) followed by targeted sequencing of 35 known epilepsy genes (n = 8) or whole exome sequencing (WES) of familial trios (n = 18) to search for rare inherited or de novo mutations. aCGH analysis revealed de novo variants in 7% of patients (n = 3/44), including a distal 16p11.2 duplication, a 15q11.1q13.1 tetrasomy and a 2q21.3-q22.2 deletion. Furthermore, it identified a pathogenic maternally inherited Xp11.2 duplication. Targeted sequencing was informative for ARX (n = 1/14) and STXBP1 (n = 1/8). In contrast, sequencing of a panel of 35 known epileptic encephalopathy genes (n = 8) did not identify further mutations. Finally, WES (n = 18) was very informative, with an excess of de novo mutations identified in genes predicted to be involved in neurodevelopmental processes and/or known to be intolerant to functional variations. Several pathogenic mutations were identified, including de novo mutations in STXBP1, CASK and ALG13, as well as recessive mutations in PNPO and ADSL, together explaining 28% of cases (5/18). In addition, WES identified 1-3 de novo variants in 64% of remaining probands, pointing to several interesting candidate genes. Our results indicate that IS are genetically heterogeneous with a major contribution of de novo mutations and that WES is significantly superior to targeted re-sequencing in identifying detrimental genetic variants involved in IS. PMID- 24781209 TI - Developmental transcriptome analysis of human erythropoiesis. AB - To globally survey the changes in transcriptional landscape during terminal erythroid differentiation, we performed RNA sequencing (RNA-seq) on primary human CD34(+) cells after ex vivo differentiation from the earliest into the most mature erythroid cell stages. This analysis identified thousands of novel intergenic and intronic transcripts as well as novel alternative transcript isoforms. After rigorous data filtering, 51 (presumptive) novel protein-coding transcripts, 5326 long and 679 small non-coding RNA candidates remained. The analysis also revealed two clear transcriptional trends during terminal erythroid differentiation: first, the complexity of transcript diversity was predominantly achieved by alternative splicing, and second, splicing junctional diversity diminished during erythroid differentiation. Finally, 404 genes that were not known previously to be differentially expressed in erythroid cells were annotated. Analysis of the most extremely differentially expressed transcripts revealed that these gene products were all closely associated with hematopoietic lineage differentiation. Taken together, this study will serve as a comprehensive platform for future in-depth investigation of human erythroid development that, in turn, may reveal new insights into multiple layers of the transcriptional regulatory hierarchy that controls erythropoiesis. PMID- 24781211 TI - Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models. AB - Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of Survival Motor Neuron-1 (SMN1). In all SMA patients, a nearly identical copy gene called SMN2 is present, which produces low levels of functional protein owing to an alternative splicing event. To prevent exon-skipping, we have targeted an intronic repressor, Element1 (E1), located upstream of SMN2 exon 7 using Morpholino-based antisense oligonucleotides (E1(MO)-ASOs). A single intracerebroventricular injection in the relatively severe mouse model of SMA (SMNDelta7 mouse model) elicited a robust induction of SMN protein, and mean life span was extended from an average survival of 13 to 54 days following a single dose, consistent with large weight gains and a correction of the neuronal pathology. Additionally, E1(MO)-ASO treatment in an intermediate SMA mouse (SMN(RT) mouse model) significantly extended life span by ~700% and weight gain was comparable with the unaffected animals. While a number of experimental therapeutics have targeted the ISS-N1 element of SMN2 pre-mRNA, the development of E1 ASOs provides a new molecular target for SMA therapeutics that dramatically extends survival in two important pre-clinical models of disease. PMID- 24781212 TI - Ocular surface displacement with and without contact lenses during non-contact tonometry. AB - PURPOSE: To evaluate the displacement of the central ocular surface during non contact tonometry with and without soft contact lenses and determine the factors associated with the displacement of the central ocular surface and intraocular pressure (IOP) reading changes caused by wearing soft contact lenses (CLs). METHODS: One eye each in 21 subjects was studied. The cornea was photographed using a high-speed camera at 5,000 frames/sec during non-contact tonometry without contact lenses (NCL), with -5.0 diopters (D), -0.5 D and +5.0 D CL. The displacement of the ocular surface and the factors affecting displacement at the IOP reading and maximum displacement time were investigated. RESULTS: The IOP readings while wearing +5 D CL were significantly higher than those obtained while wearing -5 D CL. The ocular surface displacement between +5 D CL and other groups were significantly different. A significant positive correlation was found between the ocular surface displacement of subjects at the IOP reading time and the IOP obtained with the non-contact tonometer. A significant negative correlation was found between the ocular surface curvature and the IOP obtained using the non-contact tonometer. The radius of curvature of the ocular surface affected the displacement during the IOP reading and maximum displacement time. CONCLUSIONS: Our results indicate that soft contact lens use changes the ocular surface behavior and IOP readings during non-contact tonometry. The radius of curvature of the eye affects the ocular surface displacement and IOP readings in this situation. PMID- 24781213 TI - Relationship between periphyton biomarkers and trace metals with the responses to environment applying an integrated biomarker response index (IBR) in estuaries. AB - Estuaries are under great anthropogenic pressure. The presence of contaminants such as trace metals, organics and organometallics in the Haihe basin, Baohai Bay China indicates a deterioration of environmental quality. In this study the ecological status of three estuaries in Haihe basin was evaluated in relation to the presence of trace metals. An integrated biomarker response index (IBR) method was applied that combined biomarker responses in natural periphyton present on surface sediment with general "stress index". Sediment samples were collected at 11 sites throughout three estuaries of Haihe basin (Luanhe, Haihe and Zhangweixin) during three seasons. The IBR values indicated that the temporal variation of biological status was autumn (3.35) < spring (3.38) < summer (4.07) (The higher the value, the worse the biological status), while the spatial variation was Zhangweixin (0.73) < Luanhe (3.31) < Haihe (6.96) in spring and autumn, and Luanhe (1.79) < Zhangweixin (3.64) < Haihe (7.69) in summer. The risk quotients of trace metals in sediment samples were calculated based on the corresponding Effects Rang Low values. The temporal variation of risk quotients was autumn (10.76) < spring (11.78) < summer (15.99), while the estuarine variation was Luanhe (8.47) < Zhangweixin (12.29) < Haihe (19.42). The IBR values and risk quotients were fitted into cubic regression equations. It is proven that the good assessment of periphyton integrated biomarker responses to biological status and contaminated risk in estuarine zones. PMID- 24781214 TI - Far-red and near infrared BODIPY dyes: synthesis and applications for fluorescent pH probes and bio-imaging. AB - Far-red and near infrared (NIR) emissive dyes have advantages in the development of fluorescent probes and labelling for bio-imaging in living systems since fluorescence in the long-wavelength region would generate minimum photo-toxicity to biological components, deep tissue penetration and minimal background from auto-fluorescence by bio-molecules. BODIPY dyes are attractive due to their excellent photo-physical properties and potential for fluorescence-based sensing and bio-imaging applications. Thus, numerous research papers have emerged to develop BODIPY-based dyes with absorption and emission in the long-wavelength spectral region (650-900 nm). This review summarizes the general strategies to obtain far-red and NIR BODIPYs. Moreover, their applications for fluorescent pH probes and imaging or labelling in living systems are highlighted. PMID- 24781215 TI - Mutations in the PQBP1 gene prevent its interaction with the spliceosomal protein U5-15 kD. AB - A loss-of-function of polyglutamine tract-binding protein 1 (PQBP1) induced by frameshift mutations is believed to cause X-linked mental retardation. However, the mechanism by which structural changes in PQBP1 lead to mental retardation is unknown. Here we present the crystal structure of a C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5-15 kD. The U5-15 kD hydrophobic groove recognizes a YxxPxxVL motif in PQBP1, and mutations within this motif cause a loss-of-function phenotype of PQBP1 in vitro. The YxxPxxVL motif is absent in all PQBP1 frameshift mutants seen in cases of mental retardation. These results suggest a mechanism by which the loss of the YxxPxxVL motif could lead to the functional defects seen in this type of mental retardation. PMID- 24781218 TI - The path to personalised medicine in COPD. AB - Our understanding of chronic obstructive pulmonary disease (COPD) has changed dramatically over the past two decades. We have moved from an airflow limitation centric view to the realisation that COPD is a complex and heterogeneous disease, which leads inevitably to the need for personalising the assessment and treatment of patients with COPD. This review provides a brief perspective of the extraordinary transition that the COPD field has experienced in the last two decades, and speculates on how it should/can move forward in the near future in order to really achieve the goal of personalising COPD medicine in the clinic. PMID- 24781217 TI - Nocturnal non-invasive ventilation in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-group study. AB - INTRODUCTION: The effectiveness of non-invasive positive pressure ventilation (NIV) in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure (ARF) remains unclear. We investigated if nocturnal NIV in these patients prolongs the time to readmission for respiratory causes or death (primary endpoint) in the following 12 months. METHODS: 201 COPD patients admitted to hospital with ARF and prolonged hypercapnia >48 h after termination of ventilatory support were randomised to NIV or standard treatment. Secondary outcomes were daytime arterial blood gasses, transcutaneous PCO2 during the night, lung function, health-related quality-of-life (HRQL), mood state, daily activities and dyspnoea. RESULTS: 1 year after discharge, 65% versus 64% of patients (NIV vs standard treatment) were readmitted to hospital for respiratory causes or had died; time to event was not different (p=0.85). Daytime PaCO2 was significantly improved in NIV versus standard treatment (PaCO2 0.5 kPa (95% CI 0.04 to 0.90, p=0.03)) as was transcutaneous PCO2 during the night. HRQL showed a trend (p=0.054, Severe Respiratory Insufficiency questionnaire) in favour of NIV. Number of exacerbations, lung function, mood state, daily activity levels or dyspnoea was not significantly different. DISCUSSIONS: We could not demonstrate an improvement in time to readmission or death by adding NIV for 1 year in patients with prolonged hypercapnia after an episode of NIV for ARF. There is no reason to believe the NIV was not effective since daytime PaCO2 and night-time PCO2 improved. The trend for improvement in HRQL favouring NIV we believe nevertheless should be explored further. TRIAL REGISTRATION NUMBER: NTR1100. PMID- 24781216 TI - Interictal scalp electroencephalography and intraoperative electrocorticography in magnetic resonance imaging-negative temporal lobe epilepsy surgery. AB - IMPORTANCE: Scalp electroencephalography (EEG) and intraoperative electrocorticography (ECoG) are routinely used in the evaluation of magnetic resonance imaging-negative temporal lobe epilepsy (TLE) undergoing standard anterior temporal lobectomy with amygdalohippocampectomy (ATL), but the utility of interictal epileptiform discharge (IED) identification and its role in outcome are poorly defined. OBJECTIVES: To determine whether the following are associated with surgical outcomes in patients with magnetic resonance imaging-negative TLE who underwent standard ATL: (1) unilateral-only IEDs on preoperative scalp EEG; (2) complete resection of tissue generating IEDs on ECoG; (3) complete resection of opioid-induced IEDs recorded on ECoG; and (4) location of IEDs recorded on ECoG. DESIGN, SETTING, AND PARTICIPANTS: Data were gathered through retrospective medical record review at a tertiary referral center. Adult and pediatric patients with TLE who underwent standard ATL between January 1, 1990, and October 15, 2010, were considered for inclusion. Inclusion criteria were magnetic resonance imaging-negative TLE, standard ECoG performed at the time of surgery, and a minimum follow-up of 12 months. Univariate analysis was performed using log-rank time-to-event analysis. Variables reaching significance with log-rank testing were further analyzed using Cox proportional hazards. MAIN OUTCOMES AND MEASURES: Excellent or nonexcellent outcome at time of last follow-up. An excellent outcome was defined as Engel class I and a nonexcellent outcome as Engel classes II through IV. RESULTS: Eighty-seven patients met inclusion criteria, with 48 (55%) achieving an excellent outcome following ATL. Unilateral IEDs on scalp EEG (P = .001) and complete resection of brain regions generating IEDs on baseline intraoperative ECoG (P = .02) were associated with excellent outcomes in univariate analysis. Both were associated with excellent outcomes when analyzed with Cox proportional hazards (unilateral-only IEDs, relative risk = 0.31 [95% CI, 0.16-0.64]; complete resection of IEDs on baseline ECoG, relative risk = 0.39 [95% CI, 0.20-0.76]). Overall, 25 of 35 patients (71%) with both unilateral-only IEDs and complete resection of baseline ECoG IEDs had an excellent outcome. CONCLUSIONS AND RELEVANCE: Unilateral-only IEDs on preoperative scalp EEG and complete resection of IEDs on baseline ECoG are associated with better outcomes following standard ATL in magnetic resonance imaging-negative TLE. Prospective evaluation is needed to clarify the use of ECoG in tailoring temporal lobectomy. PMID- 24781219 TI - It's a MALDI but it's a goodie: MALDI-TOF mass spectrometry for microbial identification. AB - The last few years have witnessed a revolution in the diagnostic microbiology laboratory with the emergence of matrix assisted laser desorption/ionisation time of-flight mass spectrometry (MALDI-TOF MS) as an indispensible tool in microbial identification. In many laboratories this has superseded biochemical profiling. A mass spectrum is acquired from an unknown micro-organism and this proteomic fingerprint is then compared with a database of reference spectra to ascertain the likely genus and species identity. The reproducibility of this method is facilitated by the analysis of continually produced, highly abundant proteins (mainly ribosomal proteins) in the mass range 2000 to 20 000 Da. MALDI-TOF MS is reliable and rapid and has the ability to determine the identity of an isolate from culture in a matter of minutes rather than the hours or days required by more traditional methods. In addition to microbial identification of cultured isolates, work is underway to extend the utility of MALDI-TOF MS to include bacterial identification directly from clinical samples as well as providing timely information regarding antibiotic resistance and typing of different micro organisms. PMID- 24781220 TI - [Remissions in affective disorders: epidemiology, psychopathology, clinical and social prognosis, treatment]. AB - OBJECTIVE: Although there is some evidence on heterogeneity of remissions in affective disorders (partial and full), many aspects of their comparative epidemiology, psychopathology, comorbidity and treatment are still unclear. According to our hypothesis, partial/symptomatic and full/syndromal remissions are not just consecutive stages of disease with spontaneous or treatment related interchange, but independent clinical entities with different essence. The distinction reflects a predominant pattern of disease development, based on interaction of two comorbid axes -- recurrent depression and personality disorder (PD). METHODS: A random epidemiological sample of 450 subjects (314 women and 136 men) with affective disorders was examined cross-sectionally and retrospectively. RESULTS: In the epidemiological sample, the prevalence was distributed as follows: verified remissions -- 36.2% (n=163): partial -- 27.5% (n=124), full - 8.7% (n=39). It has been shown that partial remission is a result of overlapping of recurrent depression and PD with affective diathesis (cycloid, hyperthymic, borderline) or PD prone to close interrelations with affective disorders (avoidant, obsessive-compulsive, narcissistic, histrionic). Thus, most residual symptoms (RS) reflect the association and are heterogeneous -- combined, affective, personal. Combined RS (dysthymic, phobic/anxious, somatoform) are "joint" presentations of depression and PD. Affective RS are depressive "blips" or brief depressive flares. Personal RS are pathological postdepressive personality traits (depressive, hypochondriacal, avoidant, dependent, histrionic), emerged or enhanced after depression. Full remission develops in "dissociation" of recurrent depression and PD without affective diathesis (schizotypal, schizoid, obsessive-compulsive, histrionic). Some common personality dimensions are relevant here: perfectionism, work addiction, hyperactivity, and psychological detachment from vital depressive symptoms ("alexithymia for depression"). CONCLUSIONS: The discussed remissions division suggests different prognosis and treatment approach. PMID- 24781221 TI - [Brain and spine cord lesions caused by syphilis]. AB - OBJECTIVE: To analyze clinical features of the nervous system damage in syphilis taking into account the changes in the content of cerebrospinal fluid and clinical/anatomical brain damages of the brain. METHODS: The study was based on the analysis of 47 case histories of patients hospitalized in 1995-2001. The group included 47 patients, aged from 17 to 60 years. RESULTS: Syphilitic meningitis, syphilitic meningoneuritis, syphilitic menongoencephalitis, syphilitic meningovasculitis, cerebral gummas, syphilitic meningomyelitis and mental changes caused by syphilis are reviewed. CONCLUSIONS: The pathogenesis of different clinical forms of syphilitic damages of the brain and terminological issues are discussed. PMID- 24781222 TI - [Neurometabolic therapy in secondary prevention of stroke]. AB - OBJECTIVE: To study the efficacy of mexidol in secondary prevention of stroke. MATERIAL AND METHODS: We analyzed 3400 patients with stroke which were stratified into 7 groups: patients with cryptogenic ischemic stroke (II), arterial hypertension, atrial fibrillation, metabolic syndrome, syndrome of sleep-induced obstructive apnea/hypnea, diabetes mellitus, vasculitis. The assessment of efficacy was based on the absence of repeated II within 5 years of therapy. RESULTS: Mexidol reduced the frequency of repeated II both in patients without concomitant diseases and in those with arterial hypertension, syndrome of sleep induced obstructive apnea/hypnea, vasculitis, diabetes mellitus, atrial fibrillation and metabolic syndrome. CONCLUSION: The reliable efficacy of mexidol in secondary prevention of stroke was found out. PMID- 24781223 TI - [Effectiveness of different biofeedback therapies of tension headache]. AB - OBJECTIVE: To explore the effectiveness of treatment using biofeedback (BFB training) technology in patients with tension headache. METHODS: Respiratory training and EEG-BFB-therapy were used to reduce pain syndrome. Two groups of patients with different characteristics of the autonomic nervous system, according to R.M. Baevsky, during Holter monitoring of heart rate variability in the awakening period, presence of autonomic dysfunction that reflected migraine chronification were studied. RESULTS: The statistically significant difference in the effectiveness of treatment of tension headache using respiratory or EEF parameters of BFB in regard to autonomic nervous system function and the presence of autonomic dysfunction syndrome was demonstrated. PMID- 24781224 TI - [The use of aripiprazole in the treatment of obesity associated with the administration of neuroleptics of the second generation in patients with schizophrenia]. AB - OBJECTIVE: To investigate the advisability of using aripiprazole in schizophrenic patients with weight gain associated with treatment with atypical neuroleptics. MATERIAL AND METHODS: We studied 62 patients with schizophrenia in therapeutic remission. In all patients, weight gain was associated with the administration of atypical neuroleptics of the second generation. The treatment was stopped in 32 patients and 30 patients continued to receive atypical neuroleptics. RESULTS: Aripiprazole prevented exacerbations of disease and led to the significant reduction of the severity of negative symptoms. Switching patients to aripiprazole resulted in the considerable decrease in body mass up to its normalization. Side-effects included only mild akathisia. CONCLUSION: Comparison of results to literature values revealed that body mass decreased to the same degree as in patients treated with low doses of atypical neuroleptics. However, the use of first generation neuroleptics can not reduce the severity of negative symptoms and tolerability of these drugs is worse. PMID- 24781225 TI - [Effect of immunomodulatory therapy on circulatory immune complexes in patients with recurrent depressive disorders]. AB - OBJECTIVES: To study an effect of immunomodulatory therapy with cycloferon on some immunological parameters in patients with depression. MATERIALS AND METHODS: It was examined 192 patients with recurrent depressive disorders. All patients were randomized into two groups -- main group (98 patients) and comparison group (94 patients). Both groups received standard treatment with antidepressants and antipsychotics in ambulatory conditions. Patients of the main group additionally received cycloferon. RESULTS: Before treatment, there was an increase in concentrations of circulatory immune complexes (CIC), mainly due to most pathogenic average molecular (11S-19S) and small molecular (<11S) fractions, in both groups of the patients. A direct correlation between the degree of the severity of the disease and the degree of changes in immunological parameters was noted. CONCLUSIONS: Inclusion of cycloferon in the complex treatment had a positive effect on immunological parameters and led to the normalization of CIC levels and their fraction content. PMID- 24781226 TI - [Features of the immune system and the risk of endogenous psychosis at juvenile age]. AB - OBJECTIVE: To study an immunological profile at prodromal and manifesting stages of endogenous juvenile psychosis. METHODS: Authors studied 77 patients, aged from 16 to 25 years. Patients were stratified into 2 groups. The first group included 39 patients without psychotic symptoms (prodromal group) and the second one -- 38 patients with the first episode of psychosis (psychotic group). A complex of immunological parameters included phagocyte activity, cytotoxic activity, natural killer lymphocytes, production of interleukins (IL-1, IL-4, IL-10 and gamma interferon), content of circulating immune complexes. These parameters were measured at baseline and after treatment. RESULTS: The changes in the immune system emerged at the very early stages of the disease. There was the activation of proinflammatory and anti-inflammatory interleukins, decrease in the phagocyte index and cytotoxic activity of natural killer lymphocytes. The high activity of IL-10 production, decreased levels of the cytotoxic activity of natural killer lymphocytes and reduced phagocyte index as well as the accumulation of circulating immune complexes are maintained during psychosis. CONCLUSIONS: The authors recommend to use immunomodulating drugs, along with psychotropics, at the very early stages of the disease to prevent poor outcome. PMID- 24781227 TI - [Circadian changes of heart function in absence epilepsy]. AB - OBJECTIVE: To study circadian regulation of a cardiac rhythm and functionality of the heart. METHODS: An experimental study was carried out in rats WAG/Rij with a genetically determined absence epilepsy. RESULTS: The maximum number of spike wave discharges (SWD) occurred at night, early in the morning and evening, and the minimum number was observed from 8 a.m. to 16 p.m. The night functional capabilities of heart were reduced. CONCLUSIONS: The decrease in the number of SWD and spike-wave index in the daytime contributes to the realization of opportunities of the central mechanisms of autonomic regulation of the heart. At night, when the seizure activity is increased, these opportunities are limited. PMID- 24781228 TI - [In vitro effect of psychotropic drugs on the activity of leukocyte elastase]. AB - OBJECTIVE: To investigate the effect of the neuroleptic aminazine (chlorpromazine) and the antidepressant melipramine on the activity of leukocyte elastase (LE). METHODS: The LE activity was measured on a spectrophotometer. Different doses of aminazine and melipramine in terms of therapeutic doses were added to the pooled blood serum sampled from 7 healthy people. RESULTS: Aminazine and melipramine inhibited the LE activity. CONCLUSIONS: The dose-dependent inhibiting effect of aminazine and melipramine was shown. PMID- 24781229 TI - [Recommendations for diagnosis and treatment of tuberous sclerosis]. PMID- 24781230 TI - [Cranial neuropathy due to persistent herpes viral infection]. PMID- 24781231 TI - [Non-convulsive status epilepticus with a phenomenon of transitory amnesia]. AB - This article describes clinical cases of 13 year old boy with two non-convulsive status epilepticus which had transient epileptic amnesia as a clinical implication. Status EEG pattern in form of diffuse epileptic activity "benign epileptiform discharge of childhood" type was registered. PMID- 24781232 TI - [Anorexia nervosa in a female patient with diabetes mellitus type 1]. PMID- 24781233 TI - [Confusion assessment method for intensive care unit (CAM-ICU)]. AB - Delirium is a serious complication of disorders of nervous system and requires early detection for successful treatment. Confusion assessment method for intensive care unit (CAM-ICU) is a fast and reliable tool for detection of delirium. We performed screening for delirium among patients of neurological ward using CAM-ICU. Our experience showed that CAM-ICU could be used for the identification of delirium in neurological patients excluding those who suffer from severe aphasia. PMID- 24781234 TI - [Asymptomatic cerebral infarctions: risk factors and cognitive impairment]. AB - Objectives. To study the risk factors of asymptomatic cerebral infarctions (AI) and their effect on cognitive functions. Material and methods. We examined 114 patients, aged from 53 to 88 years, including 58 patients with AI (group 1), 32 women and 26 men (mean age 66.5+/-7.3 yeas), and 56 patients with chronic cerebral ischemia (CCI) without a history of stroke and transitory ischemic attacks, (group 2), 36 women and 20 men (mean age 64.2+/-6.6 yeas). Results. Cardiovascular risk factors (arterial hypertension, diabetes mellitus, ischemic heart disease, atrial fibrillation) were more frequent in group 1. The results of neuropsychological testing revealed worse cognitive performance in patients with AI. Conclusions. The results confirmed the negative effect of AI on cognitive functioning and higher risk of CCI progression. PMID- 24781235 TI - [Endoscopic surgery of hemorrhagic stroke]. AB - Objectives. Demonstration and analysis of possibilities of video-endoscopy in the surgical treatment of hypertensive hemorrhages Materials and methods. We analyzed the results of surgical treatment of 35 patients with hypertensive intracranial hematomas which were removed using endoscopic method. Twenty-eight patients had putamen, 3 thalamic, 3 cerebellar and 1 subcortical hematoma; the volume of hematomas ranged from 14 to 84 cm3. Results. Neurological lesions completely disappeared in 7 patients, 6 patients had moderate and 17 severe disability. Five (14%) patients died. Outcome of treatment was significantly (p<0.05) correlated with the level of consciousness before surgery, localization of the hemorrhage, presence and degree of transverse brain dislocation, repeated hemorrhages. Risk factors for poor outcome were depressed consciousness, recurrent hemorrhages, the transverse dislocation >6 mm and deep intracranial hematoma. Conclusions. The efficacy of endoscopic aspiration of hematomas is comparable to open surgical interventions but less traumatic. PMID- 24781236 TI - [Surgical prevention of stroke in patients with carotid stenosis]. AB - Objectives. To study the cerebral and central hemodynamics in patients with stenotic lesions of inner carotid arteries (ICA) before and after reconstructive surgery. Material and methods. Fifty-nine patients, aged from 46 to 78 years, with >50% atherosclerotic stenosis of ICA who underwent preventive carotid endarterectomy (CEAE) were examined. The isolate stenosis of ICA was identified in 13.6% of patients, concomitant lesions of brachiocephalic arteries in 86.4%. Atherosclerotic lesions of coronary arteries were found in 91.1% of patients and those of arteries of lower extremities in 45.8%. In 25.5% of patients, the heart surgery was performed before the current hospitalization. Heterogeneous atherosclerotic plaques with dense or hyperdense components were more frequents in symptomatic stenosis (63.3%). The maximal stenosis was identified in heterogeneous hyperechogenic plaques, the minimal ones in homogenous hypoechogenic plaques. Parameters of central hemodynamics were better in patients with 2nd stage of reconstructive surgeries. The emission fraction decreased proportionally to the degree of stenosis. The parameters of cerebral hemodynamics were significantly decreased in ICA stenosis and improved in the early post surgery period. Results. CEAE promoted the improvement of cognitive functions and the recovery of motor functions. The best positive dynamics was recorded in asymptomatic ICA stenosis. Poor outcome (transitory ischemic attacks, urgent surgery, restenosis) was found in patients with low levels of central and cerebral hemodynamics 12-24 months after the discharge. Moreover, smoking and the degree of stenosis predicted poor outcome. Conclusions. Surgical treatment in combination with the complex pharmacotherapy (hypotensive drugs, antiaggregants and statins) had the maximal effect, including the remote period. PMID- 24781237 TI - [Blood serum cytokines as predictors of hemorrhagic transformation of ischemic stroke]. AB - Objectives. Authors studied the levels of pro- (IL-1Beta, TNF-alpha, IL-6, IL-8, IFN-gamma) and anti-inflammatory cytokines (IL-1Ra, IL-10, IL-4) in the blood serum at 1st and 2nd day of acute period of ischemic stroke with hemorrhagic transformation (IS HT). Material and methods. We compared cytokines levels in the blood serum of patients with IS HT and in patients with ischemic (IS) and hemorrhagic stroke (HT). Results. In patients with IS HT, significantly lower levels of IL-1Beta, TNO-alpha and higher levels of IL-6 were noted at 1st and 2nd day compared to patients with IS and HS. Significantly lower levels of IFN-gamma and IL-10 with increased levels of IL-4 were noted at 1st and 2nd day of IS HT compared to IS. There were no differences in concentrations of IFN-gamma, IL-10 and IL-4 between IS HT and HS groups. Conclusion. Cytokines are not only involved in the development of HT in IS but can be predictors of HT. PMID- 24781238 TI - [The effect of magnesium nitrate on the outcome of experimental acute ischemic stroke]. AB - Objectives. To explore the effect of inorganic forms of magnesium (magnesium nitrate, magnesium sulfate, magnesium chloride) on the course of experimental ischemic stroke (II). Material and methods. The experimental ischemic stroke caused by the occlusion of two carotid arteries in Wistar rats was studied. Animals were divided into 6 case (n=168) and 2 control groups (n=56). In case groups, magnesium was injected 1h before the occlusion of both carotid arteries and 1-2h after the brain ischemia. Control groups received physiological solution in the same periods. Results. Magnesium nitrate, regardless of the period of injection, had the significant positive effect on the dynamics of neurological lesions and mortality of animals. Conclusions. Magnesium nitrate meets the majority of criteria required for ideal pharmacological drugs: it is inexpensive, easy available, easy injectable and does not cause any serious adverse effects. PMID- 24781239 TI - [Revascularization of the brain in the acute stage of ischemic stroke]. AB - A literature review on the early surgical revascularization using carotid endarterectomy in the acute stage of ischemic stroke is presented. Special attention is drawn to criteria of patient selection and time of surgery. A history of the problem is given. PMID- 24781240 TI - [Theoretical and practical aspects of treatment and prevention of acute cerebral blood cerculation disorders]. AB - Stroke is an important medical and social problem. Views about etiology, pathogenetic mechanisms and therapy of patients with stroke have undergone significant changes. In this work, we elucidate contemporary theoretical and practical aspects of stroke treatment and prevention based on the results of multicenter clinical trials and experience of leading foreign and native specialists. Much attention is devoted to the pharmacotherapy of patients with stroke. It has been shown that neuroprotective drugs, in particular, antihypoxants with pleiotropic action (mexidol), play an important role in treatment of ischemic stroke. PMID- 24781241 TI - [Mechanisms of neurotrophic and neuroprotective effects of cerebrolysin in cerebral ischemia]. AB - Cerebrolysin is the drug which contains peptides derived from the brain of a pig. It is used in neurological practice for recovery of stroke patients and treatment of dementia. Despite the evidence-basis and some experimental studies, the distinct mechanisms of pharmacological action of this drug remain unclear for most neurologists. In this paper, we present results of a molecular-biological analysis of peptide content of cerebrolysin. We have demonstrated the presence of active peptide fragments of nerve growth factor, enkephalins, orexin, halanin. The results of current clinical and experimental studies of cerebrolysin have been compared. The activity of above-mentioned neuropeptides explain experimental and clinical details of all known effects (neurotrophic, neuroprotective and immunomodulating) of cerebrolysin in ischemic and neurodegenerative CNS injuries. The analysis allowed to make conclusions about mechanisms of cerebrolysin action that were important for increasing the efficacy of this drug in clinical practice. PMID- 24781242 TI - [A method for predicting probability of stroke]. AB - Objectives. To develop a mathematical model of stroke probability in the individual patient and social groups. Material and methods. A large amount of laboratory research was performed in a hospital of Karaganda city. Correlations between the event "stroke"and 35 risk factors were determined. A regression model "stroke-risk factors"was developed using logistic regression method. Results and sonclusions. The equations obtained in the study allow to predict the probability of stroke. Since the regression equation is inherently close to the determined one, it can be differentiated. First derivative of the probability of each of the risk factors allowed us to determine the rate of increase of probability. This provision is new. PMID- 24781243 TI - [Prediction of outcome of the acute period of ischemic stroke in young and middle aged patients]. AB - Objectives. To find out cardiovascular risk factors and the effect of atherosclerotic lesions of carotid arteries on the level of disability of young and middle-aged patients to the end of the acute period of ischemic stroke (II). Material and methods. A study included 266 patients, aged from 25 to 59 years, with a first-ever II in the carotid system. Risk for cerebrovascular diseases (arterial hypertension, smoking, auricular fibrillation, diabetes mellitus, hypercholesterolemia, high atherogenic index, excessive body mass, hypodynamia, a family history for cerebrovascular diseases, a history of transitory ischemic attacks, heart diseases (ischemic heat disease, myocardial infarction, reduced left ventricular ejection fraction) were analyzed. Results and conclusions. The prognostic effect of previous myocardial infarction, diabetes mellitus type 2, smoking, hemodinamically significant stenosis of carotid arteries, multifocal atherosclerotic lesions in three arterial basins was found. PMID- 24781244 TI - [Work experience of a stroke center in the Western region of Kazakhstan]. AB - Objectives. To analyze results of the work of a regional stroke center in Aktobe city opened in Kazakhstan according to a state program of Health Care development for 2011-2015 years "Healthy Kazakhstan". Material and methods. In total 1177 stroke patients were hospitalized, including 721 patients (61.2%) with ischemic stroke, 268 (22.8%) patients with hemorrhagic stroke, 108 (9.2%) with transitory disturbances of cerebral blood circulation, 26 (2.2%) with subarachnoid hemorrhage and 54 (4.6%) with unspecified stroke. Results. The use of thrombolytic therapy (TLT), a highly specialized method of treatment of ischemic stroke, was analyzed. Other aspects of the work, including the measures of early and continued rehabilitation, are presented. During the first day after TLT, a significant reduction in neurological disorders was observed in 22 patients (84.6%). The partial recovery was seen in 3 patients (11.5%). One patient (3.8%) had hemorrhagic transformation. Conclusions. The use of TLT in the acute stage of ischemic stroke allows to achieve the complete recovery of neurological functions so patients can return to work and full life. PMID- 24781245 TI - Non-operative treatment versus percutaneous fixation for minimally displaced scaphoid waist fractures in high demand young manual workers. AB - BACKGROUND: Managing minimally displaced scaphoid fractures in young individuals doing physically demanding work remains an issue of debate due to duration of immobilisation and time required off work. Therefore, early diagnosis and appropriate treatment are important to avoid short- and long-term consequences. The literature lacks the exact definition of minimally displaced scaphoid waist fractures. The objective of this review article was to discuss nonoperative and minimally invasive treatment (percutaneous screw fixation) for minimally displaced scaphoid waist fractures and to systematically review the literature, focussing on young workers with physically demanding employment. MATERIALS AND METHODS: We searched for articles through the most commonly used portals using appropriate terminologies to identify the most relevant articles in the English language comparing nonoperative and percutaneous fixation methods for these fractures in patients between 16 and 40 years of age. Strict inclusion and exclusion criteria were observed. RESULTS: Sixty relevant published articles were found. Twenty-one of these were considered valid for inclusion and comprised five randomised controlled trials, three prospective studies, four systematic reviews, three meta-analyses, and six retrospective studies. These studies provided a reasonable account of information on the managing undisplaced and minimally displaced scaphoid waist fractures, with satisfactory clinical and statistical analysis. However, it was difficult to assess the outcomes of minimally displaced fractures in isolation. Furthermore, few of these studies relied on plain radiographs for assessing union and did not report on patients' work status. CONCLUSION: Cast treatment has the disadvantages of longer immobilisation time, joint stiffness, reduced grip strength, and longer time to return to manual work. Percutaneous fixation is aimed at reducing damage to the blood supply and soft tissues, allowing early mobilisation of the wrist and early return to manual work. The best available evidence for percutaneous screw fixation versus cast treatment suggests that percutaneous fixation allows a faster time to union by 5 weeks and an earlier return to manual work by 7 weeks, with similar union rates. This systematic review indicates a potential requirement for a prospective randomised controlled trial to compare these two treatment modalities for minimally displaced scaphoid waist fractures in workers with physically demanding jobs in order to objectively assess functional outcomes, time to union and time to return to work. LEVEL OF EVIDENCE: Level 3. PMID- 24781248 TI - Amyloid-based nanosensors and nanodevices. AB - Self-assembling amyloid-like peptides and proteins give rise to promising biomaterials with potential applications in many fields. Amyloid structures are formed by the process of molecular recognition and self-assembly, wherein a peptide or protein monomer spontaneously self-associates into dimers and oligomers and subsequently into supramolecular aggregates, finally resulting in condensed fibrils. Mature amyloid fibrils possess a quasi-crystalline structure featuring a characteristic fiber diffraction pattern and have well-defined properties, in contrast to many amorphous protein aggregates that arise when proteins misfold. Core sequences of four to seven amino acids have been identified within natural amyloid proteins. They are capable to form amyloid fibers and fibrils and have been used as amyloid model structures, simplifying the investigations on amyloid structures due to their small size. Recent studies have highlighted the use of self-assembled amyloid-based fibers as nanomaterials. Here, we discuss the latest advances and the major challenges in developing amyloids for future applications in nanotechnology and nanomedicine, with the focus on development of sensors to study protein-ligand interactions. PMID- 24781247 TI - Modifiable etiological factors and the burden of stroke from the Rotterdam study: a population-based cohort study. AB - BACKGROUND: Stroke prevention requires effective treatment of its causes. Many etiological factors for stroke have been identified, but the potential gain of effective intervention on these factors in terms of numbers of actually prevented strokes remains unclear because of the lack of data from cohort studies. We assessed the impact of currently known potentially modifiable etiological factors on the occurrence of stroke. METHODS AND FINDINGS: This population-based cohort study was based on 6,844 participants of the Rotterdam Study who were aged >=55 y and free from stroke at baseline (1990-1993). We computed population attributable risks (PARs) for individual risk factors and for risk factors in combination to estimate the proportion of strokes that could theoretically be prevented by the elimination of etiological factors from the population. The mean age at baseline was 69.4 y (standard deviation 6.3 y). During follow-up (mean follow-up 12.9 y, standard deviation 6.3 y), 1,020 strokes occurred. The age- and sex-adjusted combined PAR of prehypertension/hypertension, smoking, diabetes mellitus, atrial fibrillation, coronary disease, and overweight/obesity was 0.51 (95% CI 0.41 0.62) for any stroke; hypertension and smoking were the most important etiological factors. C-reactive protein, fruit and vegetable consumption, and carotid intima-media thickness in combination raised the total PAR by 0.06. The PAR was 0.55 (95% CI 0.41-0.68) for ischemic stroke and 0.70 (95% CI 0.45-0.87) for hemorrhagic stroke. The main limitations of our study are that our study population comprises almost exclusively Caucasians who live in a middle and high income area, and that risk factor awareness is higher in a study cohort than in the general population. CONCLUSIONS: About half of all strokes are attributable to established causal and modifiable factors. This finding encourages not only intervention on established etiological factors, but also further study of less well established factors. Please see later in the article for the Editors' Summary. PMID- 24781249 TI - African clawed toads (Xenopus laevis) sense the distance of lateral line stimuli. AB - Sighted African clawed toads use their lateral lines to detect stimulus distance, although accuracy and precision are poorer than for stimulus direction. Single surface wave trains elicited discrete turns and/or swims towards the wave origin. Most responses were brief, ending with the toad stationary (70% overall; 54-86% individual toads) or pausing before turning away (11%; 1-24%). Lunges or capturing movements with the arms (13%; 10-22%) also indicated where toads expected to find prey. Overall, 94% (88-100%) of oriented responses had well defined endpoints. Swim distance--measured as means, medians, and upper and lower quartiles--and the number of bilateral leg kicks increased with stimulus distance. Swim distance also depended upon stimulus angle due to features of turning. Most responses (81%; 62-92%) ended short of the wave origin. Regression slopes were 0.45 +/- 0.04 mm/mm for stimulus distances up to 85 mm (ca. 2-3x body lengths), 0.16 +/- 0.07 mm/mm for distances of 85-130 mm, and non-significant for larger distances to 220 mm. Slopes were steeper for responses that included lunges or capture movements. In only 15% (3-26%) of responses were both turn direction and swim distance sufficiently accurate for the toad to sweep through the wave origin. PMID- 24781251 TI - Evaluation of a fixed, weight-based dose of 3-factor prothrombin complex concentrate without adjunctive plasma following warfarin-associated intracranial hemorrhage. AB - INTRODUCTION: Data regarding use of prothrombin complex concentrate (PCC) for international normalization ratio (INR) reversal in warfarin-associated intracranial hemorrhage (wICH) is variable with regards to dosages, adjunctive agents, and product choice. In 2012, we implemented a fixed, weight-based [30 IU/kg] dosing protocol of 3-factor PCC (3PCC) utilizing a rapid infusion rate and no requirement for fresh frozen plasma (FFP) following factor product administration. We aimed to evaluate the impact of this protocol on immediate and delayed INR reversal in patients admitted with wICH in the absence of FFP co administration. METHODS: We conducted a retrospective review of patients receiving 3PCC following wICH between January 1, 2012 and December 10, 2013. The primary objective was to determine the percentage of patients achieving goal INR (<=1.4) following 3PCC administration. Patients were excluded if their bleed was not intracranial in origin, received a dose outside of the specified protocol, or were given FFP as an adjunctive agent. RESULTS: We included 35 patients with a mean presenting INR of 3.2 +/- 1.3. Thirty patients (85.7%) achieved goal INR (<=1.4) following one dose of 3PCC. The mean INR after infusion of 3PCC was 1.3 +/- 0.2. The median duration between 3PCC infusion and subsequent INR was 48.0 min (30-70.1 min). Vitamin K was utilized in 33 (94.3%) patients. No patient experienced a thromboembolic event within 7 days of 3PCC administration. CONCLUSIONS: Fixed, weight-based dosing of 3PCC without adjunctive FFP resulted in high rates of complete INR reversal without significant adverse events. PMID- 24781250 TI - Geographic population structure analysis of worldwide human populations infers their biogeographical origins. AB - The search for a method that utilizes biological information to predict humans' place of origin has occupied scientists for millennia. Over the past four decades, scientists have employed genetic data in an effort to achieve this goal but with limited success. While biogeographical algorithms using next-generation sequencing data have achieved an accuracy of 700 km in Europe, they were inaccurate elsewhere. Here we describe the Geographic Population Structure (GPS) algorithm and demonstrate its accuracy with three data sets using 40,000-130,000 SNPs. GPS placed 83% of worldwide individuals in their country of origin. Applied to over 200 Sardinians villagers, GPS placed a quarter of them in their villages and most of the rest within 50 km of their villages. GPS's accuracy and power to infer the biogeography of worldwide individuals down to their country or, in some cases, village, of origin, underscores the promise of admixture-based methods for biogeography and has ramifications for genetic ancestry testing. PMID- 24781253 TI - Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm. AB - Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5alpha- and 5beta-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5beta-DHT was more potent for relaxing KCl induced contraction, while TES and 5alpha-DHT were more potent for CCh- and OVA induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K(+) channels. These data indicate the absence of involvement of the epithelium-, NO- and K(+) channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca(2+)]i increment. 5beta-DHT was the most potent at decreasing KCl-induced [Ca(2+)]i increment and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca(2+) influx through L-type Ca(2+)channels but additional Ca(2+) entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action. PMID- 24781252 TI - Preferential expression of PAPPA in human preadipocytes from omental fat. AB - Fat distribution differs between individuals, and those with visceral fat predominance develop metabolic profiles that increase the risk of adverse cardiovascular events. This is due, in part, to the proinflammatory state associated with visceral obesity as well as depot-specific adipogenesis. The IGF system is important in adipose tissue development and metabolic function. Pregnancy-associated plasma protein A (PAPPA) is a novel zinc metalloproteinase that regulates local IGF availability. The first aim of this study was to characterize PAPPA mRNA and protein expression in primary cultures of human preadipocytes isolated from omental, mesenteric, and subcutaneous depots. PAPPA expression was significantly increased in omental preadipocytes compared with mesenteric and subcutaneous preadipocytes. The second aim of this study was to investigate the factors regulating PAPPA expression, focusing on proinflammatory cytokines and resveratrol that have been shown to have negative and positive effects, respectively, on metabolism and diet-induced obesity. Treatment of cultured primary human preadipocytes with tumor necrosis factor alpha and interleukin 1beta led to significant increases in PAPPA expression. Activated pathways mediating cytokine-induced PAPPA expression include the nuclear factor kappaB pathway and the MAPK family, particularly c-Jun NH2-terminal kinase and p38 MAPK. Resveratrol, a polyphenolic compound with beneficial cardiometabolic effects, significantly downregulated PAPPA expression under basal and stimulated conditions. Effects of resveratrol on PAPPA appeared to be mediated through pathways independent of silent mating type information regulation 2 homolog 1 (SIRT1) and AMP kinase activation. Depot-specific PAPPA expression in human preadipocytes may contribute to a depot-specific function. PMID- 24781254 TI - Application of microRNAs in diabetes mellitus. AB - MicroRNAs (miRNAs) are small molecules negatively regulating gene expression by diminishing their target mRNAs. Emerging studies have shown that miRNAs play diverse roles in diabetes mellitus. Type 1 diabetes (T1D) and T2D are two major types of diabetes. T1D is characterized by a reduction in insulin release from the pancreatic beta-cells, while T2D is caused by islet beta-cell dysfunction in response to insulin resistance. This review describes the miRNAs that control insulin release and production by regulating cellular membrane electrical excitability (ATP:ADP ratio), insulin granule exocytosis, insulin synthesis in beta-cells, and beta-cell fate and islet mass formation. This review also examines miRNAs involved the insulin resistance of liver, fat, and skeletal muscle, which change insulin sensitivity pathways (insulin receptors, glucose transporter type 4, and protein kinase B pathways). This review discusses the potential application of miRNAs in diabetes, including the use of gene therapy and therapeutic compounds to recover miRNA function in diabetes, as well as the role of miRNAs as potential biomarkers for T1D and T2D. PMID- 24781255 TI - Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules. AB - Cardiotonic steroids have been used for the past 200 years in the treatment of congestive heart failure. As specific inhibitors of membrane-bound Na(+)/K(+) ATPase, they enhance cardiac contractility through increasing myocardial cell calcium concentration in response to the resulting increase in intracellular Na concentration. The half-minimal concentrations of cardiotonic steroids required to inhibit Na(+)/K(+) ATPase range from nanomolar to micromolar concentrations. In contrast, the circulating levels of cardiotonic steroids under physiological conditions are in the low picomolar concentration range in healthy subjects, increasing to high picomolar levels under pathophysiological conditions including chronic kidney disease and heart failure. Little is known about the physiological function of low picomolar concentrations of cardiotonic steroids. Recent studies have indicated that physiological concentrations of cardiotonic steroids acutely stimulate the activity of Na(+)/K(+) ATPase and activate an intracellular signaling pathway that regulates a variety of intracellular functions including cell growth and hypertrophy. The effects of circulating cardiotonic steroids on renal salt handling and total body sodium homeostasis are unknown. This review will focus on the role of low picomolar concentrations of cardiotonic steroids in renal Na(+)/K(+) ATPase activity, cell signaling, and blood pressure regulation. PMID- 24781256 TI - Interplay between diet-induced obesity and chronic stress in mice: potential role of FKBP51. AB - While it is known that stress promotes obesity, the effects of stress within an obesogenic context are not so clear and molecular targets at the interface remain elusive. The FK506-binding protein 51 (FKBP51, gene: Fkbp5) has been identified as a target gene implicated in the development of stress-related psychiatric disorders and is a possible candidate for involvement in stress and metabolic regulation. The aims of the current study are to investigate the interaction between chronic stress and an obesogenic context and to additionally examine whether FKBP51 is involved in this interaction. For this purpose, male C57BL/6 mice were exposed to a high-fat diet for 8 weeks before being challenged with chronic social defeat stress. Herein, we demonstrate that chronic stress induces hypophagia and weight loss, ultimately improving features arising from an obesogenic context, including glucose tolerance and levels of insulin and leptin. We show that Fkbp5 expression is responsive to diet and stress in the hypothalamus and hippocampus respectively. Furthermore, under basal conditions, higher levels of hypothalamic Fkbp5 expression were related to increased body weight gain. Our data indicate that Fkbp5 may represent a novel target in metabolic regulation. PMID- 24781257 TI - Browning of white fat: does irisin play a role in humans? AB - The discovery of irisin as an exercise-regulated myokine inducing browning of WAT has gained interest as a potential new strategy to combat obesity and its associated disorders, such as type 2 diabetes. However, there are inconsistencies regarding the relevance of irisin in humans. The regulation of FNDC5 mRNA expression by exercise and contraction could not be reproduced by a number of human studies using several exercise protocols and in vitro approaches. Furthermore, the nature of FNDC5 fragments and the presence of irisin in humans are questionable and probably contribute to conflicting data obtained with commercially available ELISA kits. Most importantly, the information regarding the concentration of circulating irisin in humans is not clear, as different studies using different kits measure irisin levels in a wide range. Data about the role of irisin in states of human obesity and metabolic diseases are conflicting and, in some cases, changes in irisin levels have been observed; they were only moderate in 10-20%. Independent of the presence and regulation of FNDC5/irisin in humans, the application of recombinant irisin could still represent a therapeutic strategy to fight obesity. However, the current data obtained from human cell models reveal that FNDC5/irisin has no effect on browning of the major WAT depots in humans and is likely to selectively target a small subpopulation of adipocytes, which are located in classical BAT regions, such as the supraclavicular adipose tissue. Thus, other candidates, such as BMP7 or CNPs, seem to be more prominent candidates as inducers of browning in humans. PMID- 24781258 TI - Automated image analysis of a glomerular injury marker desmin in spontaneously diabetic Torii rats treated with losartan. AB - Diabetic nephropathy is a major complication in diabetes and a leading cause of end-stage renal failure. Glomerular podocytes are functionally and structurally injured early in diabetic nephropathy. A non-obese type 2 diabetes model, the spontaneously diabetic Torii (SDT) rat, is of increasing preclinical interest because of its pathophysiological similarities to human type 2 diabetic complications including diabetic nephropathy. However, podocyte injury in SDT rat glomeruli and the effect of angiotensin II receptor blocker treatment in the early stage have not been reported in detail. Therefore, we have evaluated early stages of glomerular podocyte damage and the beneficial effect of early treatment with losartan in SDT rats using desmin as a sensitive podocyte injury marker. Moreover, we have developed an automated, computational glomerulus recognition method and illustrated its specific application for quantitatively studying glomerular desmin immunoreactivity. This state-of-the-art method enabled automatic recognition and quantification of glomerular desmin-positive areas, eliminating the need to laboriously trace glomerulus borders by hand. The image analysis method not only enabled assessment of a large number of glomeruli, but also clearly demonstrated that glomerular injury was more severe in the juxtamedullary region than in the superficial cortex region. This applied not only in SDT rat diabetic nephropathy but also in puromycin aminonucleoside induced nephropathy, which was also studied. The proposed glomerulus image analysis method combined with desmin immunohistochemistry should facilitate evaluations in preclinical drug efficacy studies as well as elucidation of the pathophysiology of diabetic nephropathy. PMID- 24781264 TI - More work needed to protect children but promising trend data on exposure to violence. PMID- 24781266 TI - Uptake and accumulation of B-group vitamers in Saccharomyces cerevisiae in ethanol-stat fed-batch culture. AB - The uptake and accumulation of the B-group vitamins thiamine, riboflavin, nicotinamide, pantothenic acid and pyridoxine in Saccharomyces cerevisiae was studied by gradually increasing the specific dosage of vitamins in an ethanol stat fed-batch culture. Thiamine, nicotinamide, pantothenic acid, and pyridoxine were almost completely taken up at low vitamin dosages. Thiamine was determined to be the major accumulating form of vitamin B1 while most of the assimilated nicotinamide and pantothenic acid accumulated in cofactor forms. Despite the obvious uptake of pyridoxine, accumulation of B6 vitamers was not observed. In contrast with the other vitamins studied, riboflavin began accumulating in the culture medium immediately after vitamin addition was initiated. By the end of the experiment, the apparent uptake of all vitamins exceeded their accumulation in the cells. Variations in the growth rate of yeast at different vitamin dosages demonstrate the importance of balancing the vitamins in the media during cultivation. PMID- 24781265 TI - Natural solution to antibiotic resistance: bacteriophages 'The Living Drugs'. AB - Antibiotics have been a panacea in animal husbandry as well as in human therapy for decades. The huge amount of antibiotics used to induce the growth and protect the health of farm animals has lead to the evolution of bacteria that are resistant to the drug's effects. Today, many researchers are working with bacteriophages (phages) as an alternative to antibiotics in the control of pathogens for human therapy as well as prevention, biocontrol, and therapy in animal agriculture. Phage therapy and biocontrol have yet to fulfill their promise or potential, largely due to several key obstacles to their performance. Several suggestions are shared in order to point a direction for overcoming common obstacles in applied phage technology. The key to successful use of phages in modern scientific, farm, food processing and clinical applications is to understand the common obstacles as well as best practices and to develop answers that work in harmony with nature. PMID- 24781267 TI - Association of miR-146a rs2910164 with childhood IgA nephropathy. AB - BACKGROUND: Micro-RNAs (miRNAs) play important roles in the regulation of immune response and inflammation. The purpose of this study was to investigate the association between three single nucleotide polymorphisms (SNPs) (mir-146a rs2910164, let-7a-2 rs1143770, miR-196a2 rs11614913) and susceptibility to and severity of childhood immunoglobulin A (IgA) nephropathy (IgAN). METHODS: We genotyped three miRNA SNPs in two independent Han Chinese populations composed of 158 patients and 265 controls (discovery set), and 246 patients and 446 controls (validation set), respectively. RESULTS: We found that rs2910164 was significantly associated with IgAN in the discovery but not the validation set. Combined analysis revealed that rs2910164 CC and CG genotypes were associated with increased risk of IgAN compared with the GG genotype [adjusted odds ratios (OR) = 1.684, 95 % confidence interval (CI)1.190-2.384, P = 0.003; adjusted OR = 1.472, 95 % CI 1.079-2.007, P = 0.015, respectively). We also found that the frequency of the rs2910164 CC genotype was significantly higher in patients with Haas grade III-V than in those with Haas grade I-II for all study populations (P < 0.05). The expression of miR-146a in normal renal tissues with CC genotype was lower than in those with a G allele (P = 0.038). CONCLUSIONS: These results indicated that rs2910164 may affect the susceptibility and severity of pediatric IgAN. Further studies are needed to validate these findings. PMID- 24781268 TI - In memoriam of Clark Darwin West, MD July 4, 1918-January 11, 2014. PMID- 24781269 TI - Poiseuille's law in polyuria. PMID- 24781270 TI - Criminalising healthcare professionals is disproportionate and unlikely to work. PMID- 24781271 TI - Preoperative glucose level has different effects on the endogenous extracellular matrix-related gene expression in saphenous vein of type 2 diabetic patients undergoing coronary surgery. AB - BACKGROUND: Type 2 diabetes mellitus (DM) severely reduces the benefits of coronary artery bypass grafting (CABG). However, few studies investigated the correlation between preoperative glucose level and endogenous extracellular matrix (ECM)-related gene expression of saphenous vein (SV) conduits in diabetic patients. METHODS: A total of 130 patients were divided into high-glucose (HG), low-glucose (LG) and control group according to the preoperative level of blood glucose. The expression of ECM-related genes was analysed by microarray. RESULTS: Compared with control group, 30 genes showed at least a threefold change in expression in HG group; up-regulation was observed in 24 genes. However, there were only 21 ECM-related genes showed at least a threefold change in expression between the LG and control group. Compared with HG group, matrix metalloproteinases' (MMPs) expression was significantly decreased in LG and control groups. In contrast to the decrease in MMPs' expression, expression of tissue inhibitors of metalloproteinases (TIMPs) was increased. CONCLUSION: This study suggested that different preoperative diabetic status affected the expression of ECM-related genes in SV. ECM-related genes were more significantly imbalanced in diabetic patients with uncontrolled preoperative blood glucose than those with well-controlled preoperative blood glucose. PMID- 24781273 TI - Analysis of patient-reported anterior knee pain scale: implications for scale development in children and adolescents. AB - PURPOSE: The purpose of this investigation was to estimate and document the reliability and validity of the Anterior Knee Pain Scale (AKPS) and to estimate its relative prediction accuracy of anterior knee pain in young females. METHODS: Data from a prospective, epidemiologic study to diagnose patellofemoral knee pain among female athletes (n = 499) using the Anterior Knee Pain Scale (AKPS). Data were treated in 4 phases (descriptive phase, reliability phase, scale refinement phase) and a final validation stage that was focused on an effort to test and document the validation of the AKPS short form and perform head-to-head comparisons of the 6-item short form with the original, 13-item form. RESULTS: The AKPS was reduced from 13 items (alphaCoeff = 0.77, sigmaSEM = 0.004) to 6 items (alphaCoeff = 0.78, sigmaSEM = 0.004). Point-biserial correlations with patellofemoral pain diagnosis were comparable: r [498] = 0.70 (R(2) = 0.49, short form) and r [498] = 0.71 (R(2) = 0.51, long form), as was sensitivity: 84% (short form) and 80% (long form), and specificity: 89% (short form) and 90% (long form; AUC = 0.94 both). CONCLUSION: The current analyses indicate that a subset of measures from the AKPS is responsive to patellofemoral pain symptoms and may support screening for related diagnoses. A simpler and quicker scale optimized for diagnostic accuracy could reduce the demand on patients, clinicians and research teams focused on the identification and management of patellofemoral pain. LEVEL OF EVIDENCE: III. PMID- 24781274 TI - NexGen(r) LPS mobile bearing total knee arthroplasty: 10-year results. AB - PURPOSE: Mobile bearing (MB) knee prostheses were designed to improve the performances of the total knee arthroplasties (TKA). The clinical superiority of MB prosthesis compared to its fixed bearing counterpart has remained elusive. This study prospectively evaluates the cumulative survivorship, clinical, radiographic results, and complications of a large series of MB TKAs in relation to patient age, sex, severity of arthritis, and patellar resurfacing. METHODS: This study evaluates the 5- to 10-year cumulative survival rate of the NexGen((r)) LPS MB. Between 2000 and 2005, we performed a consecutive series of 332 MB, posterior-stabilized TKA in 249 patients (mean age 71.2 years, SD 6.9). The implants were clinically evaluated with the Hospital Special Surgery Knee Score (HSS-KS) and radiographically with the Knee Society Roentgenographic Evaluation System (KS-RES). The mean follow-up was 76.3 months (minimum 5 years). RESULTS: The HSS-KS improved from 55 pre-operatively to 86 at the end of follow up. According to the KS-RES, the implants were anatomically aligned and progressive radiolucent lines appeared in four knees (1.2 %). The patella was selectively resurfaced in 162 of 332 knees. Patients with the patella resurfaced had better clinical results compared to those not resurfaced, but there was no difference in terms of survival. The cumulative survival rate was 98.4 % at 10 years (Kaplan-Meier's analysis). CONCLUSIONS: This MB implant provided reliable and durable clinical results with a survivorship of over 98 % at 10 years, in unselected patients regardless of age, sex, severity of disease, and patellar treatment. PMID- 24781275 TI - Dynamic versus static reconstruction of the medial patellofemoral ligament for recurrent lateral patellar dislocation. AB - PURPOSE: To compare clinical and radiological outcomes of static and dynamic medial patellofemoral ligament (MPFL) reconstruction techniques. METHODS: In a retrospective, matched-paired, cohort analysis, 30 patients surgically treated for recurrent lateral patellar dislocation were divided into two groups of 15 patients matched for inclusion and exclusion criteria. The static technique group underwent rigid fixation of the gracilis tendon at the anatomic femoral MPFL insertion and the superomedial border of the patella; the dynamic technique group underwent detachment of the gracilis tendon at the pes anserinus with fixation to the proximal medial patellar margin via tunnel transfer obliquely through the patella. Kujala, Lysholm, and Tegner scores; pain level; and pre- and postoperative radiographic changes of patellar height, patellar tilt, and bisect offset were compared. RESULTS: No significant between-group differences were found in mean Kujala, Tegner, Lysholm, or visual analogue scale scores or radiographic parameters. One case of resubluxation was observed in the dynamic group. All but one patient in each group would have been willing to undergo the procedure again. CONCLUSIONS: Both techniques provided satisfactory short-term outcomes. LEVEL OF EVIDENCE: III. PMID- 24781276 TI - Tuning the surface Fermi level on p-type gallium nitride nanowires for efficient overall water splitting. AB - Solar water splitting is one of the key steps in artificial photosynthesis for future carbon-neutral, storable and sustainable source of energy. Here we show that one of the major obstacles for achieving efficient and stable overall water splitting over the emerging nanostructured photocatalyst is directly related to the uncontrolled surface charge properties. By tuning the Fermi level on the nonpolar surfaces of gallium nitride nanowire arrays, we demonstrate that the quantum efficiency can be enhanced by more than two orders of magnitude. The internal quantum efficiency and activity on p-type gallium nitride nanowires can reach ~51% and ~4.0 mol hydrogen h(-1) g(-1), respectively. The nanowires remain virtually unchanged after over 50,000 MUmol gas (hydrogen and oxygen) is produced, which is more than 10,000 times the amount of photocatalyst itself (~4.6 MUmol). The essential role of Fermi-level tuning in balancing redox reactions and in enhancing the efficiency and stability is also elucidated. PMID- 24781278 TI - Double-layer CVD graphene as stretchable transparent electrodes. AB - The stretchability of CVD graphene with a large area is much lower than that of mechanically exfoliated pristine graphene owing to the intrinsic and extrinsic defects induced during its synthesis, etch-out of the catalytic metal, and the transfer processes. This low stretchability is the main obstacle for commercial application of CVD graphene in the field of flexible and stretchable electronics. In this study, artificially layered CVD graphene is suggested as a promising candidate for a stretchable transparent electrode. In contrast to single-layer graphene (SLG), multi-layer graphene has excellent electromechanical stretchability owing to the strain relaxation facilitated by sliding among the graphene layers. Macroscopic and microscopic electromechanical tensile tests were performed to understand the key mechanism for the improved stretchability, and crack generation and evolution were systematically investigated for their dependence on the number of CVD graphene layers during tensile deformation using lateral force microscopy. The stretchability of double-layer graphene (DLG) is much larger than that of SLG and is similar to that of triple-layer graphene (TLG). Considering the transmittance and the cost of transfer, DLG can be regarded as a suitable candidate for stretchable transparent electrodes. PMID- 24781277 TI - Alanine aminotransferase and risk of the metabolic syndrome: a linear dose response relationship. AB - BACKGROUND: Elevated baseline circulating alanine aminotransferase (ALT) level has been demonstrated to be associated with an increased risk of the metabolic syndrome (MetS), but the nature of the dose-response relationship is uncertain. METHODS: We performed a systematic review and meta-analysis of published prospective cohort studies to characterize in detail the nature of the dose response relationship between baseline ALT level and risk of incident MetS in the general population. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science up to December 2013. Prospective studies in which investigators reported relative risks (RRs) of MetS for 3 or more categories of ALT levels were eligible. A potential nonlinear relationship between ALT levels and MetS was examined using restricted cubic splines. RESULTS: Of the 489 studies reviewed, relevant data were available on 29,815 non overlapping participants comprising 2,125 incident MetS events from five prospective cohort studies. There was evidence of a linear association (P for nonlinearity=0.38) between ALT level and risk of MetS, characterised by a graded increase in MetS risk at ALT levels 6-40 U/L. The risk of MetS increased by 14% for every 5 U/L increment in circulating ALT level (95% CI: 12-17%). Evidence was lacking of heterogeneity and publication bias among the contributing studies. CONCLUSIONS: Baseline ALT level is associated with risk of the MetS in a linear dose-response manner. Studies are needed to determine whether the association represents a causal relationship. PMID- 24781279 TI - Measuring the configurational temperature of a binary disc packing. AB - Jammed packings of granular materials differ from systems normally described by statistical mechanics in that they are athermal. In recent years a statistical mechanics of static granular media has emerged where the thermodynamic temperature is replaced by a configurational temperature X which describes how the number of mechanically stable configurations depends on the volume. Four different methods have been suggested to measure X. Three of them are computed from properties of the Voronoi volume distribution, the fourth takes into account the contact number and the global volume fraction. This paper answers two questions using experimental binary disc packings: first we test if the four methods to measure compactivity provide identical results when applied to the same dataset. We find that only two of the methods agree quantitatively. This implies that at least two of the four methods are wrong. Secondly, we test if X is indeed an intensive variable; this becomes true only for samples larger than roughly 200 particles. This result is shown to be due to recently measured correlations between the particle volumes [Zhao et al., Europhys. Lett., 2012, 97, 34004]. PMID- 24781280 TI - Oral co-administration of elacridar and ritonavir enhances plasma levels of oral paclitaxel and docetaxel without affecting relative brain accumulation. AB - BACKGROUND: The intestinal uptake of the taxanes paclitaxel and docetaxel is seriously hampered by drug efflux through P-glycoprotein (P-gp) and drug metabolism via cytochrome P450 (CYP) 3A. The resulting low oral bioavailability can be boosted by co-administration of P-gp or CYP3A4 inhibitors. METHODS: Paclitaxel or docetaxel (10 mg/kg) was administered to CYP3A4-humanised mice after administration of the P-gp inhibitor elacridar (25 mg kg(-1)) and the CYP3A inhibitor ritonavir (12.5 mg kg(-1)). Plasma and brain concentrations of the taxanes were measured. RESULTS: Oral co-administration of the taxanes with elacridar increased plasma concentrations of paclitaxel (10.7-fold, P<0.001) and docetaxel (four-fold, P<0.001). Co-administration with ritonavir resulted in 2.5 fold (paclitaxel, P<0.001) and 7.3-fold (docetaxel, P<0.001) increases in plasma concentrations. Co-administration with both inhibitors simultaneously resulted in further increased plasma concentrations of paclitaxel (31.9-fold, P<0.001) and docetaxel (37.4-fold, P<0.001). Although boosting of orally applied taxanes with elacridar and ritonavir potentially increases brain accumulation of taxanes, we found that only brain concentrations, but not brain-to-plasma ratios, were increased after co-administration with both inhibitors. CONCLUSIONS: The oral availability of taxanes can be enhanced by co-administration with oral elacridar and ritonavir, without increasing the brain penetration of the taxanes. PMID- 24781281 TI - Comment on 'The latency period of mesothelioma among a cohort of British asbestos workers (1978-2005)': methodological problems with case-only survival analysis. PMID- 24781282 TI - Hanging drop cultures of human testis and testis cancer samples: a model used to investigate activin treatment effects in a preserved niche. AB - BACKGROUND: Testicular germ cell tumours of young adults, seminoma or non seminomas, are preceded by a pre-invasive precursor, carcinoma in situ (CIS), understood to arise through differentiation arrest of embryonic germ cells. Knowledge about the malignant transformation of germ cells is currently limited by the lack of experimental models. The aim of this study was to establish an experimental tissue culture model to maintain normal and malignant germ cells within their niche and allow investigation of treatment effects. METHODS: Human testis and testis cancer specimens from orchidectomies were cultured in 'hanging drops' and effects of activin A and follistatin treatment were investigated in seminoma cultures. RESULTS: Testis fragments with normal spermatogenesis or CIS cells were cultured for 14 days with sustained proliferation of germ cells and CIS cells and without increased apoptosis. Seminoma cultures survived 7 days, with proliferating cells detectable during the first 5 days. Activin A treatment significantly reduced KIT transcript and protein levels in seminoma cultures, thereby demonstrating a specific treatment response. CONCLUSIONS: Hanging drop cultures of human testis and testis cancer samples can be employed to delineate mechanisms governing growth of normal, CIS and tumorigenic germ cells retained within their niche. PMID- 24781283 TI - Mechanical behavior of abdominal aorta aneurysm in rat model treated by cell therapy using mesenchymal stem cells. AB - Regenerative medicine to substitute conventional surgery or an endovascular stent constitutes currently a challenge to treat abdominal aneurysm artery (AAA). The present paper addresses the following question: Can a cellular therapy from mesenchymal stem cells reestablish the mechanical properties of damaged abdominal aorta? For that, the xenograft rat model that mimics arterial dilatation due to aneurysmal disease is used to study the effects of the proposed cellular therapy. To investigate the changes in the mechanical behavior of the arterial wall, the artery is assumed to be made of a hyperelastic and incompressible material characterized by a strain energy function fitted to the average data set of uniaxial tests of AAA tissue samples. In order to compute the stresses in the artery by using an analytical approach, the aneurysm is represented as a "parabolic-exponential" thin membrane. Thus, when compared to healthy, untreated and treated arteries, the obtained results demonstrate that the cellular therapy stabilizes the geometry of AAAs, improves the stiffness of the tissue and decreases stress variations in the arterial wall. PMID- 24781284 TI - Identical lesion morphology in primary progressive and relapsing-remitting MS--an ultrahigh field MRI study. AB - Potential differences between primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g., perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI. PMID- 24781285 TI - An ex vivo comparison of cooled-radiofrequency and bipolar-radiofrequency lesion size and the effect of injected fluids. AB - BACKGROUND AND OBJECTIVES: Radiofrequency (RF) neuroablation is a common therapy for alleviating chronic pain. Larger lesion volumes lead to higher chance of ablating small sensory nerves; therefore, bipolar-RF and cooled-RF are improved alternatives to conventional monopolar-RF. This work provides an ex vivo comparison of bipolar-RF to cooled-RF lesioning in the presence of bone structure using some conventional temperature and time programs and in conjunction with injection of a variety of clinically used substances. METHODS: Studies were performed using chicken muscle near a bone structure. Cooled-RF was applied using standard parameters at 60 degrees C for 150 seconds and perpendicular to the bone. Bipolar-RF was applied using interelectrode distances (IEDs) of 5, 10, or 15 mm at 80 degrees C for 90 or 150 seconds with the electrodes positioned either paralleled between the bone and muscle or perpendicular to the bone. The effect of injection of various fluids (sterile water, 0.9% saline, 7.3% saline, 2% lidocaine, 0.25% bupivacaine, lidocaine/methylprednisolone (Depo-Medrol), or lidocaine/betamethasone (Celestone) on lesion size was compared with no fluid injected in the muscle. Temperature profiles of lesioning were also obtained using an infrared camera. RESULTS: The volume of bipolar-RF lesions is dependent on IED, being more favorable at IED equals 10 mm. The injection of some fluids induces significant (P < 0.05) changes in bipolar-RF lesion volume, although the changes are dependent on IED. Cooled-RF induces larger lesions than bipolar-RF, with no changes in volume induced by injecting fluids. CONCLUSIONS: Cooled-RF yields larger lesions than bipolar-RF under the conditions used in this study. The spherical shape of cooled-RF lesions provides larger volume coverage than lesions obtained with bipolar-RF at IED equals 5, 10, or 15 mm under similar electrode tip temperature and lesioning time. PMID- 24781286 TI - Ultrasound-guided injection of the intrapelvic portion of the obturator internus in a cadaver model. AB - BACKGROUND AND OBJECTIVES: Musculoskeletal dysfunction of the pelvic floor is common. One of the intrapelvic muscles, the obturator internus (OI), can be substantially stressed during its sharply angulated exit from the pelvis. However, there may be considerable overlap between symptoms and signs arising from the OI and other potential pain generators including the levator ani in the pelvic region. Accurate diagnosis for the OI might permit more efficient treatment combined with OI-specific exercise and behavior modification. Therefore, we hypothesized that ultrasound (US)-guided needle insertion in the intrapelvic portion of the OI would be accurate when a pararectal approach is used for diagnostic and therapeutic purposes. METHODS: Bilateral US-guided intramuscular injections in the pelvic area were performed using 6 fresh, nonembalmed male cadavers. When the needle was positioned in the targeted muscle, 0.5 mL of green filler was injected. After the injection procedure, each specimen was dissected to evaluate the accuracy of US-guided injection into the intrapelvic portion of the OI. RESULTS: Twelve injections were made into the targeted muscles in the 6 cadaveric specimens. All injections placed filler into the OI muscles just medial to the inferior pubic ramus. There was no case in which a needle passed through unintended structures, such as neurovascular structures. CONCLUSIONS: The newly developed US-guided pararectal approach allowed accurate insertion of a needle into the intrapelvic portion of the OI. This US-guided method facilitated a more precise approach to the intrapelvic portion of the OI and may help differentiate conditions or symptoms caused by other structures. PMID- 24781287 TI - High-frequency transcutaneous electrical nerve stimulation attenuates postsurgical pain and inhibits excess substance P in rat dorsal root ganglion. AB - BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is a common therapeutic modality for pain management, but its effectiveness in skin/muscle incision and retraction (SMIR)-evoked pain is unknown. We aimed to examine the effects of TENS on postoperative pain and the levels of substance P (SP), N methyl-D-aspartate receptor 1 (NR1), and interleukin 1beta (IL-1beta) in rat dorsal root ganglion (DRG). METHODS: High-frequency (100 Hz) TENS was administered daily beginning on postoperative day 1 (POD1) and continued until animal subjects were killed for tissues. Mechanical sensitivity to von Frey stimuli (6g and 15g) and the levels of NR1, SP, and IL-1beta in DRG were assessed in the sham-operated, SMIR-operated, TENS after SMIR surgery, and placebo-TENS after SMIR surgery groups. RESULTS: Skin/muscle incision and retraction rats exhibited a significant hypersensitivity to von Frey stimuli on POD3. In contrast with SMIR rats, SMIR-operated rats receiving TENS therapy demonstrated a rapid recovery of mechanical hypersensitivity. The SMIR-operated rats showed an up regulation of NR1, SP, and IL-1beta in DRG on PODs 14 and 28, whereas the SMIR operated rats after TENS administration reversed this up-regulation. By contrast, the placebo-TENS after SMIR operation did not alter postsurgical pain nor the levels of NR1, SP, and IL-1beta. CONCLUSIONS: Our data demonstrated that TENS intervention reduced persistent postoperative pain caused by SMIR operation. Up regulation of NR1, SP, and IL-1beta in DRG, activated after SMIR surgery, is important in the development of prolonged postincisional pain. The TENS pain relief may be related to the suppression of NR1, SP, and IL-1beta in DRG of SMIR rats. PMID- 24781288 TI - Mistreatment of students and residents: why can't we just be nice? PMID- 24781289 TI - Considerations for flipping the classroom in medical education. PMID- 24781290 TI - Considerations for flipping the classroom in medical education. PMID- 24781291 TI - In reply to Goldberg and to Hurtubise et al. PMID- 24781292 TI - Cost must be a theme in our measurement of accountability. PMID- 24781293 TI - In reply to Walsh. PMID- 24781294 TI - Population health management: an approach to improve the integration of the health care and public health systems. PMID- 24781295 TI - The ah(a) moment. PMID- 24781296 TI - Artist's Statement: Night Rounds. PMID- 24781297 TI - Medicine and the arts. Sticky, a painting by Margaret Sutherland. Commentary. PMID- 24781299 TI - A missed miracle. PMID- 24781300 TI - Morning report. PMID- 24781301 TI - AM last page: funding of academic research in clinical medicine in the United Kingdom. PMID- 24781302 TI - Mesenteric liposarcoma: report of two cases with review of literature. PMID- 24781303 TI - An unusual case of oesophageal adenocarcinoma presenting with subcutaneous metastases. PMID- 24781304 TI - Assessing metal pollution in ponds constructed for controlling runoff from reclaimed coal mines. AB - Constructing ponds to protect downstream ecosystems is a common practice in opencast coal mine reclamation. As these ponds remain integrated in the landscape, it is important to evaluate the extent of the effect of mine pollution on these ecosystems. However, this point has not been sufficiently addressed in the literature. The main objective of this work was to explore the metal pollution in man-made ponds constructed for runoff control in reclaimed opencast coal mines over time. To do so, we evaluated the concentration of ten heavy metals in the water, sediment, and Typha sp. in 16 runoff ponds ranging from 1 to 19 years old that were constructed in reclaimed opencast coal mines of northeastern Spain. To evaluate degree of mining pollution, we compared these data to those from a pit lake created in a local unreclaimed mine and to local streams as an unpolluted reference, as well as comparing toxicity levels in aquatic organisms. The runoff ponds showed toxic concentrations of Al, Cu, and Ni in the water and As and Ni in the sediment, which were maintained over time. Metal concentrations in runoff ponds were higher than in local streams, and macrophytes showed high metal concentrations. Nevertheless, metal concentrations in water and sediment in runoff ponds were lower than those in the pit lake. This study highlights the importance of mining reclamation to preserve the health of aquatic ecosystems and suggests the existence of chronic metal toxicity in the ponds, potentially jeopardizing pond ecological functions and services. PMID- 24781305 TI - Retrospective monitoring of persistent organic pollutants, including PCBs, PBDEs, and polycyclic musks in blue mussels (Mytilus edulis) and sediments from New Bedford Harbor, Massachusetts, USA: 1991-2005. AB - Blue mussels (Mytilus edulis) and sediments collected from 1991 to 2005 from New Bedford Harbor (NBH), MA, were analyzed for two polycyclic musks (HHCB or Galaxolide(r) and AHTN or Tonalide(r)), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs). HHCB and AHTN were found in mussel tissues at mean concentrations of 836 and 376 ng/g lipid weight (lw), respectively, which were two- to seven-fold higher than those found at a reference site. Mean concentrations of HHCB and AHTN in NBH sediments were 12 and 6.3 ng/g dry weight (dw), respectively. Four- and five-ringed PAHs, such as phenanthrene, anthracene, fluoranthene, and pyrene, collectively accounted for 61 % of the ?PAHs concentrations in mussels from NBH. Mean SigmaPCB concentrations in mussels from upper and lower NBH were 942 and 182 MUg/g lw, respectively, and were dominated by tetra- and penta-chlorobiphenyl congeners, collectively accounting for 61 % of the SigmaPCB concentrations. The mean concentration of ?PBDEs in mussels from NBH was 277 ng/g lw, and no significant difference existed in the concentrations between upper and lower NBH. DDTs were the major OCP found in mussels, found at a mean concentration of 778 ng/g lw. The concentrations of HHCB, AHTN, SigmaPBDEs, SigmaPAHs, and DDTs in mussels decreased significantly (r (2) >= 0.56, p <= 0.052) from 1991 to 2005. The concentrations of PCBs and chlordanes did not exhibit a decreasing trend in mussel tissues (r (2) < 0.50; p > 0.076) from 1991 to 2005. Based on the temporal trends in the concentrations of HHCB, AHTN, ?PAHs, and ?PBDEs found in mussels from NBH, it was estimated that between 5.5 and 12 years were required for the concentrations of these compounds to decrease by half (i.e., environmental halving time) of the levels found in 1991. PMID- 24781307 TI - Ru-NO and Ru-NO2 bonding linkage isomerism in cis-[Ru(NO)(NO)(bpy)2](2+/+) complexes - a theoretical insight. AB - Ruthenium nitrosyl complexes have received considerable attention due to the fact that they are able to store, transfer and release NO in a controlled manner. It is well-known that the NO reactivity of ruthenium nitrosyl complexes can be modulated with the judicious choice of equatorial and axial ligands. In this piece of research we elucidate the nature of the Ru-NO and Ru-NO2 bonding in a cis-[Ru(NO)(NO2)(bpy)2](2+) complex energy decomposition (Su-Li EDA) and topological (e.g., QTAIM) and natural bond orbital analysis. It was observed that the strength of these bonds is directly correlated with the relative stability of isomers involved in nitro-nitrito and nitrosyl-isonitrosyl isomerism, as described previously by Coppens and Ooyama. PMID- 24781306 TI - The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. AB - Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo(11)C-acetate and PET-CT scanning to show that colonic acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through (13)C high-resolution magic-angle-spinning that (13)C acetate from fermentation of (13)C-labelled carbohydrate in the colon increases hypothalamic (13)C acetate above baseline levels. Hypothalamic (13)C acetate regionally increases the (13)C labelling of the glutamate-glutamine and GABA neuroglial cycles, with hypothalamic (13)C lactate reaching higher levels than the 'remaining brain'. These observations suggest that acetate has a direct role in central appetite regulation. PMID- 24781308 TI - Lack of association between peri-procedural myocardial damage and CYP2C19 gene variant in elective percutaneous coronary intervention. AB - Peri-procedural myocardial damage (MD) is associated with increased risk of major in-hospital complications and adverse clinical events. The aim of this study was to evaluate the effects of on-clopidogrel platelet aggregation and CYP2C19 reduced-function gene variants on elective percutaneous coronary intervention (PCI)-related MD. We measured changes in serum high-sensitive troponin T (hs-TnT) levels, CYP2C19 genotype, and on-clopidogrel platelet aggregation (PA) using VerifyNow((r)) P2Y12 system in 91 patients who received stent implantation (stent group). The control group comprised 30 patients who did not receive PCI. Blood samples were obtained before and 24 h after PCI or coronary angiography (CAG). Patients of the stent group were divided into high and low MD groups based on the median value of hs-TnT level at 24 h after PCI. Serum hs-TnT levels were significantly higher 24 h after PCI (86.8 +/- 121.5 pg/ml) compared with before PCI (9.4 +/- 5.3, p < 0.001), whereas the levels were identical before and 24 h after CAG in the control group. Simple logistic regression analysis demonstrated that MD correlated with age (p = 0.014), estimated GFR (p = 0.003), hemoglobin A1c (p = 0.015), baseline serum hs-TnT (p = 0.049), and stent length (p < 0.001). Multiple logistic regression analysis identified old age, high hemoglobin A1c level, and long stent, but not CYP2C19 reduced-function allele or high on clopidogrel PA, as independent predictors of elective PCI-related MD. The present study demonstrated no significant relation between peri-procedural MD and high on clopidgrel PA associated with CYP2C19 reduced-function allele in patients undergoing elective PCI. PMID- 24781309 TI - Is string esophageal capsule endoscopy really better than esophageal capsule endoscopy in the right supine position for Z-line examination? PMID- 24781310 TI - String-mounted double-headed capsule and Z-line detection: is string really the thing? PMID- 24781311 TI - Is British gastroenterology research in decline? PMID- 24781312 TI - Reply to: Telaprevir-induced acute kidney injury during treatment of chronic hepatitis C. PMID- 24781314 TI - Potential use of pulse oximetry for the diagnosis of testicular torsion. PMID- 24781315 TI - Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). AB - BACKGROUND: Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used. METHODS AND FINDINGS: The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines. We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%-4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3-3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1-10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1-13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1-8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7-5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication. CONCLUSIONS: We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV. Please see later in the article for the Editors' Summary. PMID- 24781316 TI - Spatio-temporal distribution of the timing of start and end of growing season along vertical and horizontal gradients in Japan. AB - We detected the spatio-temporal variability in the timing of start (SGS) and end of growing season (EGS) in Japan from 2003 to 2012 by analyzing satellite observed daily green-red vegetation index with a 500-m spatial resolution. We also examined the characteristics of SGS and EGS timing in deciduous broadleaf and needleleaf forests along vertical and horizontal gradients and then evaluated the relationship between their timing and daily mean air temperature. We found that for the timing of SGS and EGS, changes along the vertical gradient in deciduous broadleaf forest tended to be larger than those in deciduous needleleaf forest. For both forest types, changes along the vertical and horizontal gradients in the timing of EGS tended to be smaller than those of SGS. Finally, in both forest types, the sensitivity of the timing of EGS to air temperature was much less than that of SGS. These results suggest that the spatio-temporal variability in the timing of SGS and EGS detected by satellite data, which may be correlated with leaf traits, photosynthetic capacity, and environment conditions, provide useful ground-truthing information along vertical and horizontal gradients. PMID- 24781317 TI - Faded promises: the challenge of deadopting low-value care. PMID- 24781318 TI - Current evidence shows no place for antiviral drug distribution in a flu pandemic. PMID- 24781319 TI - Anisotropic thermal conductivity of graphene wrinkles. AB - In this paper, the anisotropic thermal conductivity characteristics of graphene wrinkles are observed for the first time using a non-equilibrium molecular dynamics method. Our results reveal that the wrinkling level has little effect on the thermal conductivity along the wrinkling direction. However, the wrinkling level plays an important role in the reduction of thermal conductivity along the texture direction, which results from the contributions of increased bond length, von Mises stress, broadening of phonon modes and G-band redshift. These results indicate that graphene wrinkles can be a promising candidate to modulate thermal conductivity properties in nanoscale thermal managements and thermoelectric devices. PMID- 24781320 TI - Cell-line authentication demystified. PMID- 24781321 TI - Discovering enhancers directly by activity. PMID- 24781322 TI - A synthetic approach to abiogenesis. AB - Synthetic biology seeks to probe fundamental aspects of biological form and function by construction (resynthesis) rather than deconstruction (analysis). Here we discuss how such an approach could be applied to assemble synthetic quasibiological systems able to replicate and evolve, illuminating universal properties of life and the search for its origins. PMID- 24781323 TI - Large-scale de novo DNA synthesis: technologies and applications. AB - For over 60 years, the synthetic production of new DNA sequences has helped researchers understand and engineer biology. Here we summarize methods and caveats for the de novo synthesis of DNA, with particular emphasis on recent technologies that allow for large-scale and low-cost production. In addition, we discuss emerging applications enabled by large-scale de novo DNA constructs, as well as the challenges and opportunities that lie ahead. PMID- 24781325 TI - Programming biological operating systems: genome design, assembly and activation. AB - The DNA technologies developed over the past 20 years for reading and writing the genetic code converged when the first synthetic cell was created 4 years ago. An outcome of this work has been an extraordinary set of tools for synthesizing, assembling, engineering and transplanting whole bacterial genomes. Technical progress, options and applications for bacterial genome design, assembly and activation are discussed. PMID- 24781326 TI - Structural basis for the immunomodulatory function of cysteine protease inhibitor from human roundworm Ascaris lumbricoides. AB - Immunosuppression associated with infections of nematode parasites has been documented. Cysteine protease inhibitor (CPI) released by the nematode parasites is identified as one of the major modulators of host immune response. In this report, we demonstrated that the recombinant CPI protein of Ascaris lumbricoides (Al-CPI) strongly inhibited the activities of cathepsin L, C, S, and showed weaker effect to cathepsin B. Crystal structure of Al-CPI was determined to 2.1 A resolution. Two segments of Al-CPI, loop 1 and loop 2, were proposed as the key structure motifs responsible for Al-CPI binding with proteases and its inhibitory activity. Mutations at loop 1 and loop 2 abrogated the protease inhibition activity to various extents. These results provide the molecular insight into the interaction between the nematode parasite and its host and will facilitate the development of anthelmintic agents or design of anti-autoimmune disease drugs. PMID- 24781327 TI - Filter materials for metal removal from mine drainage--a review. AB - A large number of filter materials, organic and inorganic, for removal of heavy metals in mine drainage have been reviewed. Bark, chitin, chitosan, commercial ion exchangers, dairy manure compost, lignite, peat, rice husks, vegetal compost, and yeast are examples of organic materials, while bio-carbons, calcareous shale, dolomite, fly ash, limestone, olivine, steel slag materials and zeolites are examples of inorganic materials. The majority of these filter materials have been investigated in laboratory studies, based on various experimental set-ups (batch and/or column tests) and different conditions. A few materials, for instance steel slag materials, have also been subjects to field investigations under real life conditions. The results from these investigations show that steel slag materials have the potential to remove heavy metals under different conditions. Ion exchange has been suggested as the major metal removal mechanisms not only for steel slag but also for lignite. Other suggested removal mechanisms have also been identified. Adsorption has been suggested important for activated carbon, precipitation for chitosan and sulphate reduction for olivine. General findings indicate that the results with regard to metal removal vary due to experimental set ups, composition of mine drainage and properties of filter materials and the discrepancies between studies renders normalisation of data difficult. However, the literature reveals that Fe, Zn, Pb, Hg and Al are removed to a large extent. Further investigations, especially under real-life conditions, are however necessary in order to find suitable filter materials for treatment of mine drainage. PMID- 24781324 TI - Principles of genetic circuit design. AB - Cells navigate environments, communicate and build complex patterns by initiating gene expression in response to specific signals. Engineers seek to harness this capability to program cells to perform tasks or create chemicals and materials that match the complexity seen in nature. This Review describes new tools that aid the construction of genetic circuits. Circuit dynamics can be influenced by the choice of regulators and changed with expression 'tuning knobs'. We collate the failure modes encountered when assembling circuits, quantify their impact on performance and review mitigation efforts. Finally, we discuss the constraints that arise from circuits having to operate within a living cell. Collectively, better tools, well-characterized parts and a comprehensive understanding of how to compose circuits are leading to a breakthrough in the ability to program living cells for advanced applications, from living therapeutics to the atomic manufacturing of functional materials. PMID- 24781328 TI - Assessment of metal pollution associated with an alteration area: Old Gumushane, NE Black Sea. AB - The objective of this study was to determine the potential environmental risks associated with the Kirkpavli (Old Gumushane in northern Turkey) alteration area by quantifying pollution in soil. The Kirkpavli (Old Gumushane) alteration area is situated at the south of the deposit with the same name of gold-silver-bearing lead, zinc, and copper in the southern part of the Black Sea Tectonic Unit (Eastern Pontides). In this study, 28 soil samples acquired from the alteration area were analyzed for contents of some main elements including lead (Pb), copper (Cu), zinc (Zn), cadmium (Cd), cobalt (Co), manganese (Mn), nickel (Ni), and arsenic (As). Contents of the elements in the area were determined, and high values were obtained such as 1,171 mg/kg for As, 12.4 mg/kg for Cd, 77.3 mg/kg for Co, 341 mg/kg for Cu, 1,172 mg/kg for Mn, 51.9 mg/kg for Ni, 3,725 mg/kg for Pb, and 880 mg/kg for Zn. Soil contamination was appraised on the basis of Geoaccumulation Index (I geo), Enrichment Factor (EF), Pollution Index, and Integrated Pollution Index. The calculated results of I geo, EF, and PI of the elements can be shown in descending order of parameters as As > Pb > Cd > Zn > Cu > Co > Mn. The parameters for some of these elements indicated extremely high contamination (I geo > 5), extremely high enrichment (EF > 40), and high pollution (PI > 3). High I geo, EF, and PI values of As, Pb, and Cd in the soil samples mean that soil pollution is typically associated with alteration area. Considering its location and the results of this study, the Kirkpavli alteration area is a significant source of pollution and may have ecotoxicological effects on terrestrial, groundwater, and aquatic ecosystems in the region. PMID- 24781329 TI - Influence of environmental factors on net N2 and N2O production in sediment of freshwater rivers. AB - Denitrification is an important N removal process in aquatic systems but is also implicated as a potential source of global N2O emissions. However, the key factors controlling this process as well as N2O emissions remain unclear. In this study, we identified the main factors that regulate the production of net N2 and N2O in sediments collected from rivers with a large amount of sewage input in the Taihu Lake region. Net N2 and N2O production were strongly associated with the addition of NO3(-)-N and NH4(+)-N. Specifically, NO3(-)-N controlled net N2 production following Michaelis-Menten kinetics. The maximum rate of net N2 production (V max) was 116.3 MUmol N2-N m(-2) h(-1), and the apparent half saturation concentration (k m) was 0.65 mg N L(-1). N2O to N2 ratios increased from 0.18 +/- 0.03 to 0.68 +/- 0.16 with the addition of NO3(-)-N, suggesting that increasing NO3(-)-N concentrations favored the production of N2O more than N2. The addition of acetate enhanced net N2 production and N2O to N2 ratios, but the ratios decreased by about 59.5% when acetate concentrations increased from 50 to 100 mg C L(-1), suggesting that the increase of N2O to N2 ratios had more to do with the net N2 production rate rather than acetate addition in this experiment. The addition of Cl(-) did not affect the net N2 production rates, but significantly enhanced N2O to N2 ratios (the ratios increased from 0.02 +/- 0.00 to 0.10 +/- 0.00), demonstrating that the high salinity effect might have a significant regional effect on N2O production. Our results suggest that the presence of N-enriching sewage discharges appear to stimulate N removal but also increase N2O to N2 ratios. PMID- 24781330 TI - Effects of peat fires on the characteristics of humic acid extracted from peat soil in Central Kalimantan, Indonesia. AB - When peat forest fires happen, it leads to burn soil and also humic acids as a dominant organic matter contained in peat soil as well as the forest. The structure and properties of humic acids vary depending on their origin and environment, therefore the transformation of humic acid is also diverse. The impacts of the peat fires on peat soil from Central Kalimantan, Indonesia were investigated through the characterization of humic acids, extracted from soil in burnt and unburnt sites. The characterization of humic acids was performed by elemental composition, functional groups, molecular weight by HPSEC, pyrolysate compounds by pyrolysis-GC/MS, fluorescence spectrum by 3DEEM spectrofluorometer, and thermogravimetry. The elemental composition of each humic substance indicated that the value of H/C and O/C of humic acids from burnt sites were lower than that from unburnt sites. The molecular weight of humic acids from burnt sites was also lower than that from unburnt sites. Pyrolysate compounds of humic acids from unburnt sites differed from those of humic acids from burnt soil. The heating experiment showed that burning process caused the significant change in the properties of humic acids such as increasing the aromaticity and decreasing the molecular weight. PMID- 24781331 TI - Assessment of the ozone tolerance of two soybean cultivars (Glycine max cv. Sambaiba and Tracaja) cultivated in Amazonian areas. AB - Brazilian soybean cultivars (Glycine max Sambaiba and Tracaja) routinely grown in Amazonian areas were exposed to filtered air (FA) and filtered air enriched with ozone (40 and 80 ppb, 6 h/day for 5 days) to assess their level of tolerance to this pollutant by measuring changes in key biochemical, physiological, and morphological indicators of injury and in enzymatic and non-enzymatic antioxidants. Sambaiba plants were more sensitive to ozone than Tracaja plants, as revealed by comparing indicator injury responses and antioxidant stimulations. Sambaiba exhibited higher visible leaf injury, higher stomatal conductance, and a severe decrease in the carbon assimilation rate. Higher ozone level (80 ppb) caused an increase in cell death in both cultivars. Levels of malondialdehyde and hydrogen peroxide also increased in Tracaja exposed under 80 ppb. Sambaiba plants exhibited decreases in ascorbate and glutathione levels and in enzymatic activities associated with these antioxidants. The higher tolerance of the Tracaja soybean appeared to be indicated by reduced physiological injuries and lower stomatal conductance, which might decrease the influx of ozone and enhance oxidation-reduction reactions involving catalase, ascorbate peroxidase, ascorbate, and glutathione, most likely stimulated by higher hydrogen peroxide. PMID- 24781332 TI - A real-time, dynamic early-warning model based on uncertainty analysis and risk assessment for sudden water pollution accidents. AB - A real-time, dynamic, early-warning model (EP-risk model) is proposed to cope with sudden water quality pollution accidents affecting downstream areas with raw water intakes (denoted as EPs). The EP-risk model outputs the risk level of water pollution at the EP by calculating the likelihood of pollution and evaluating the impact of pollution. A generalized form of the EP-risk model for river pollution accidents based on Monte Carlo simulation, the analytic hierarchy process (AHP) method, and the risk matrix method is proposed. The likelihood of water pollution at the EP is calculated by the Monte Carlo method, which is used for uncertainty analysis of pollutants' transport in rivers. The impact of water pollution at the EP is evaluated by expert knowledge and the results of Monte Carlo simulation based on the analytic hierarchy process. The final risk level of water pollution at the EP is determined by the risk matrix method. A case study of the proposed method is illustrated with a phenol spill accident in China. PMID- 24781333 TI - Effect of sulfide on the cytotoxicity of arsenite and arsenate in human hepatocytes (HepG2) and human urothelial cells (UROtsa). AB - Arsenic, a common poison, is known to react with sulfide in vivo, forming thioarsenates. The acute toxicity of the inorganic thioarsenates is currently unknown. Our experiments showed that a fourfold sulfide excess reduced acute arsenite cytotoxicity in human hepatocytes (HepG2) and urothelial cells (UROtsa) significantly, but had little effect on arsenate toxicity. Speciation analysis showed immediate formation of thioarsenates (up to 73 % of total arsenic) in case of arsenite, but no speciation changes for arsenate. Testing acute toxicity of mono- and trithioarsenate individually, both thioarsenates were found to be more toxic than their structural analogue arsenate, but less toxic than arsenite. Toxicity increased with the number of thio groups. The amount of cellular arsenic uptake after 24 h corresponded to the order of toxicity of the four compounds tested. The dominant to almost exclusive intracellular arsenic species was arsenite. The results imply that thiolation is a detoxification process for arsenite in sulfidic milieus. The mechanism could either be that thioarsenates regulate the amount of free arsenite available for cellular uptake without entering the cells themselves, or, based on their chemical similarity to arsenate, they could be taken up by similar transporters and reduced rapidly intracellularly to arsenite. PMID- 24781334 TI - Design and study of the efflux function of the EGFP fused MexAB-OprM membrane transporter in Pseudomonas aeruginosa using fluorescence spectroscopy. AB - Multidrug membrane transporters (efflux pumps) can selectively extrude a variety of structurally and functionally diverse substrates (e.g., chemotoxics, antibiotics), leading to multidrug resistance (MDR) and ineffective treatment of a wide variety of diseases. In this study, we have designed and constructed a fusion gene (egfp-mexB) of N-terminal mexB with C-terminal egfp, inserted it into a plasmid vector (pMMB67EH), and successfully expressed it in the DeltaMexB (MexB deletion) strain of Pseudomonas aeruginosa to create a new strain that expresses MexA-(EGFP-MexB)-OprM. We characterized the fusion gene using gel electrophoresis and DNA sequencing, and determined its expression in live cells by measuring the fluorescence of EGFP in single live cells using fluorescence microscopy. Efflux function of the new strain was studied by measuring its accumulation kinetics of ethidium bromide (EtBr, a pump substrate) using fluorescence spectroscopy, which was compared with cells (WT, DeltaMexM, DeltaABM, and nalB1) with various expression levels of MexAB-OprM. The new strain shows 6-fold lower accumulation rates of EtBr (15 MUM) than DeltaABM, 4-fold lower than DeltaMexB, but only 1.1 fold higher than WT. As the EtBr concentration increases to 40 MUM, the new strain has nearly the same accumulation rate of EtBr as DeltaMexB, but 1.4-fold higher than WT. We observed the nearly same level of inhibitory effect of CCCP (carbonyl cyanide-m-chlorophenylhydrazone) on the efflux of EtBr by the new strain and WT. Antibiotic susceptibility study shows that the minimum inhibitory concentrations (MICs) of aztreonam (AZT) and chloramphenicol (CP) for the new strain are 6-fold or 3-fold lower than WT, respectively, and 2-fold higher than those of DeltaMexB. Taken together, the results suggest that the fusion protein partially retains the efflux function of MexAB-OprM. The modeled structure of the fusion protein shows that the position and orientation of the N-terminal fused EGFP domain may either partially block the translocation pore or restrict the movement of the individual pump domains, which may lead to partially restricted efflux activity. PMID- 24781336 TI - Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC. AB - We determined the expression of epithelial-mesenchymal transition (EMT) indicator proteins, E-cadherin (E-cad), vimentin (VIM), mucin 1 (MUC1) and S100 calcium binding protein A4 (S100A4) in hepatocellular carcinoma (HCC) patient tissue samples. We also investigated the relationship between the expression of these proteins and clinicopathologic factors in HCC. Finally, we assessed the potential value of these markers as prognostic indicators of survival in HCC patients. The expression of E-cad, VIM, MUC1 and S100A4 EMT indicator proteins was assessed in tissue microarray HCC tissue sections and corresponding peritumoral normal tissues by immunohistochemistry. In addition, the expression for the four EMT indicator proteins was correlated with clinicopathological features of HCC and patient outcome. Comparison of clinicopathological characteristics and immunohistochemistry by chi(2) analysis revealed that downregulation of E-cad in HCC was significantly associated with later TNM cancer stage (P = 0.012), gross classification (P = 0.018), regional lymph node metastasis (P = 0.036) and liver cirrhosis (P = 0.028). Increased S100A4 expression in HCC was significantly associated with differentiation (P = 0.032), tumor with a complete fibrous capsule (P = 0.031) and portal vein invasion (P = 0.038). High VIM expression in HCC was significantly associated with high serum alpha-fetoprotein levels (P = 0.016). We also observed that low E-cad expression was significantly associated with overexpression of VIM (P = 0.001). Kaplan-Meier survival and Cox regression analysis revealed that low E-cad expression (HR = 0.164, 95 % CI 0.072 to 0.373, P < 0.001) and high serum alpha-fetoprotein levels (HR = 2.202, 95 % CI 1.054 to 4.598, P = 0.036) were independent prognostic factors in HCC. Our study demonstrates that high S100A4 and VIM expression and low E-cad expression correlate with an aggressive, malignant phenotype in HCC. These results also support a role for E-cad as a prognostic factor in HCC. PMID- 24781337 TI - Higher miR-21 expression in invasive breast carcinomas is associated with positive estrogen and progesterone receptor status in patients from Serbia. AB - MicroRNAs play essential role in breast carcinoma progression and invasion. Our principal goals were to assess clinicopathological and prognostic correlations of microRNA-21 (miR-21) expression levels in a group of 39 Serbian breast cancer patients with invasive lobular (ILC), ductal (IDC), or mixed (ILC-IDC) breast carcinomas and in order to discover the role of miR-21 in potential novel form of stratification of the patients with different estrogen receptor (ER) and progesterone receptor (PR) status. MiR-21 expression levels were measured by stem loop real-time RT-PCR using TaqMan technology. ER, PR, human epidermal growth factor 2 receptor (Her-2), and proliferative index (Ki-67) were evaluated by immunohistochemistry. MiR-21 levels do not vary among ILC, IDC, and ILC-IDC subgroups. MiR-21 expression levels varied significantly in the age, tumor size, Ki-67, and different grade (p = 0.030, p = 0.036, p = 0.027 and p = 0.032, respectively) subgroups. ER+ and PR+ showed higher miR-21 levels than their negative receptor status paired groups ER- and PR- with p = 0.012 and p = 0.018, respectively. MiR-21 positively correlated with ER and PR status (p = 0.018, rho = 0.379 and p = 0.034, rho = 0.345, respectively). Our findings suggest that miR 21 emulates transitional form of expression and that the levels of expression might be useful for stratification of the patients with different receptor status with the purpose to seek for new therapy approaches especially for the patients with the lack of response to conventional endocrine therapy. PMID- 24781338 TI - Survival following primary androgen deprivation therapy for localized intermediate- or high-risk prostate cancer: comparison with the life expectancy of the age-matched normal population. AB - The representative guidelines do not recommend androgen deprivation therapy (ADT) as a primary treatment for localized prostate cancer. However, in clinical practice, the use of primary ADT for localized prostate cancer has been widespread, especially among older patients. We performed a retrospective review of the efficacy of primary ADT for localized prostate cancer and compared their outcomes with the life expectancy of the normal population. The study cohort consisted of 410 men diagnosed with localized intermediate- or high-risk prostate cancer over the period 1992-2012 at five institutions. All patients underwent ADT as a primary cancer therapy, and mean follow-up was 6.0 years. Their progression free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) rates were calculated. Patients' expected survival rates were estimated by the Hakulinen method. Multivariate analysis demonstrated that Gleason score >=8 and cT3a were independent risk factors for all of PFS, CSS, and OS. In patients who have none or one of these risk factors, minimum OS rates were not inferior to the expected survival curves of the normal population. Meanwhile, in patients with both risk factors, the OS curve fell below the expected survival rates, especially after 6 years of follow-up. We conclude that primary ADT might be one of the therapeutic options for localized intermediate- and high-risk prostate cancer. However, for high-risk cases with Gleason score >=8 and cT3a, the choice of primary ADT should be deliberated carefully because the OS of these cases was inferior to the expected survival, especially at a late time point. PMID- 24781340 TI - Do we treat individuals as patients or as potential donors? A phenomenological study of healthcare professionals' experiences. AB - BACKGROUND: Organ donation and transplantation have made it possible to both save life and to improve the quality of life for a large number of patients. In the last years there has been an increasing gap between the number of patients who need organs and organs available for transplantation, and the focus worldwide has been on how to meet the organ shortage. This also rises some ethical challenges. OBJECTIVE: The objective of this study was to explore healthcare professionals' experience of ethics related to care and interaction with critically ill patients with severe brain injuries and their families. RESEARCH DESIGN: A hermeneutic phenomenological approach was used to explore the participants' experiences. Methods for collecting data were a combination of participant observations and in depth interviews. PARTICIPANTS AND RESEARCH CONTEXT: Two ICUs in a Norwegian university hospital were recruited for data collection. A total of 12 cases were observed, and 32 of the healthcare professionals involved were interviewed. ETHICAL CONSIDERATIONS: The study was approved by the Regional Committee for Research Ethics. Permission to the study in the ICUs was obtained from the Chief Physician in the two ICUs respectively. The right of the participants was ensured by written, voluntary, and informed consent. FINDINGS: From the thematic analysis, a structure of the participants' experiences emerged as a process. While the patients' condition was clarified through phases of prognostic ambiguity, gradual clarification and prognostic certainty, interaction with the families was characterized by ambiguity that involved withholding. The prognostic process had a great impact on how the healthcare professionals interacted with the family. The interaction challenged the participants' caring values in various ways and captured an important structure in their experiences of the ethical interaction with the patients' families. These challenges distinguish caring for families in donation situations from caring for relatives of critically ill patients in general. DISCUSSION: In the discussion we have illuminated how professional ethics may be threatened by more pragmatic and utilitarian arguments contained in regulations and transplant act. CONCLUSION: Ethical questions should be discussed more both in educations of healthcare professionals and in clinical practice. PMID- 24781341 TI - Efficacy and Tolerability of Palliative Split-Course Thoracic Chemoradiotherapy for Symptomatic Non-Small Cell Lung Cancer. AB - INTRODUCTION: To assess the efficacy and tolerability of palliative split-course concurrent thoracic chemoradiotherapy (CRT) in patients with incurable locally advanced and metastatic non-small cell lung cancer. METHODS: All patients with incurable non-small cell lung cancer and symptomatic thoracic disease treated with palliative split-course CRT between March 2006 and February 2013 at a single institution were included in this retrospective study. The primary endpoint was improvement in presenting thoracic symptoms. Secondary endpoints included toxicity, overall survival, and the cumulative incidence of locoregional failure. RESULTS: Fifty-five patients were identified, of whom 89% had distant metastatic disease at the initiation of treatment. The median radiotherapy dose delivered was 40 Gy over 20 fractions. Over 90% of patients were able to complete at least 2 cycles of chemotherapy, and 89% of patients completed the prescribed course of radiotherapy. Forty percent of patients had improvement in all presenting symptoms and 78% experienced improvement in at least 1 symptom. Nine and 2 patients, respectively, experienced grade 1 and 2 esophagitis and 1 patient experienced grade 2 pneumonitis. There were no cases of grade 3 toxicity. With a median follow-up for surviving patients of 4.5 months, the estimated actuarial 6 , 12-, and 24-month overall survival was 56%, 25%, and 13%, respectively. The actuarial 6-, 12-, and 24-month cumulative incidence of locoregional failure was 6%, 14%, and 22%, respectively. DISCUSSION: Split-course CRT allows for early introduction of systemic therapy while providing durable locoregional control with tolerable morbidity and significant improvement in chest symptomatology. This paradigm is a viable model for chest palliation in selected patients with intact performance status. PMID- 24781339 TI - Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems. AB - Gastrointestinal illnesses are a significant health burden for the US population, with 40 million office visits each year for gastrointestinal complaints and nearly 250,000 deaths. Acute and chronic inflammations are a common element of many gastrointestinal diseases. Inflammatory processes may be initiated by a chemical injury (acid reflux in the esophagus), an infectious agent (Helicobacter pylori infection in the stomach), autoimmune processes (graft versus host disease after bone marrow transplantation), or idiopathic (as in the case of inflammatory bowel diseases). Inflammation in these settings can contribute to acute complaints (pain, bleeding, obstruction, and diarrhea) as well as chronic sequelae including strictures and cancer. Research into the pathophysiology of these conditions has been limited by the availability of primary human tissues or appropriate animal models that attempt to physiologically model the human disease. With the many recent advances in tissue engineering and primary human cell culture systems, it is conceivable that these approaches can be adapted to develop novel human ex vivo systems that incorporate many human cell types to recapitulate in vivo growth and differentiation in inflammatory microphysiological environments. Such an advance in technology would improve our understanding of human disease progression and enhance our ability to test for disease prevention strategies and novel therapeutics. We will review current models for the inflammatory and immunological aspects of Barrett's esophagus, acute graft versus host disease, and inflammatory bowel disease and explore recent advances in culture methodologies that make these novel microphysiological research systems possible. PMID- 24781342 TI - The Impact of Cancer on the Clinical Outcome of Patients After Inferior Vena Cava Filter Placement: A Retrospective Cohort Study. AB - OBJECTIVES: Inferior vena cava (IVC) filters are placed to prevent pulmonary embolism, however, some studies have suggested that IVC filters are associated with exacerbated risks of deep vein/IVC thrombosis in cancer patients. The purpose of this study is to determine if cancer patients develop higher than expected rates of venous thromboembolism complications after filter placement compared with noncancer patients. MATERIALS AND METHODS: A retrospective cohort study of consecutive patients who received filters (2002 to 2006) at Johns Hopkins was conducted. Exposures and outcomes were obtained by chart review. Relative risks (RR, 95% confidence interval [CI]) for outcomes in cancer versus noncancer patients were estimated using multistate models. RESULTS: The cohort included 702 patients-246 with cancer and 456 without cancer. Cancer patients were older, more likely to be white and have filters placed for contraindications to anticoagulation (P<0.01). The most common cancers were lung (11.8%) and colorectal (10.6%). Cancer patients had an increase in venous thromboembolism (RR 1.9 [95% CI, 1.1, 3.2]) due to more deep venous thrombosis/IVC thrombosis (RR 1.7 [95% CI, 1.0, 3.0]). Higher pulmonary embolism rates in cancer were not statistically significant (RR 2.2 [95% CI, 0.8, 5.8]). CONCLUSIONS: Cancer patients have elevated risks of thrombotic complications compared with noncancer patients; however, these risks are not higher than expected based on historical controls. PMID- 24781343 TI - Radiotherapy and Male Breast Cancer: A Population-based Registry Analysis. AB - BACKGROUND: The local-regional management of female breast cancer has been extensively investigated worldwide. The optimal approach for males diagnosed with breast cancer is less clear. We have analyzed the treatment of male breast cancer using a population-based national registry to determine the impact of surgery and radiation therapy on survival. MATERIALS AND METHODS: The Surveillance Epidemiology and End Results (SEER) database was queried to identify males with invasive ductal carcinoma of the breast who underwent primary surgical resection (radical mastectomy, modified radical mastectomy, total mastectomy, or segmental) for the years 1983 to 2002. Demographic, clinical, and pathologic data were culled and analyzed to determine the impact of radiation therapy (RT) following resection. Survival rates were estimated using the Kaplan-Meier method and significance was determined using the log-rank test (P<0.05). Multivariate analysis with the Cox proportional hazards model was performed to determine factors significant for overall (OS) and cause-specific survival (CSS). RESULTS: A total of 1337 patients met the eligibility criteria and were analyzed. Median follow-up was 7.3 years (range, 1 mo to 25 y). Most men underwent modified radical mastectomy (n=1062) with a minority undergoing segmental (n=113). About 329 men received postoperative external beam RT. The median rates of OS and CSS for all men were 10.5 years and not yet reached, respectively. The surgical procedure did not significantly associate with OS or CSS. By stage, RT was associated with improved OS for stage I (P=0.03). There was a trend for improved survival with stage II (P=0.21) and III (P=0.15). RT was not associated with improved CSS by stage. RT improved rates of OS and CSS in N2 patients without reaching statistical significance (P=0.10 and 0.22). On multivariate analysis, advancing age, stage and grade, and no postoperative RT predicted for worse OS. However, when controlled for those with known hormone receptor status (n=978), only the factors of advancing age, stage, grade, and hormone receptor negativity predicted for worse OS. Advancing age, stage, and grade were the only predictors of CSS irrespective of the cohort analyzed. CONCLUSIONS: The primary surgical procedure did not ultimately influence OS or CSS in this population-based registry of males with breast cancer. A statistically nonsignificant improvement with postoperative RT was observed in men with lymph node involvement, larger tumor size, or higher stage. When controlled for age, stage, and grade in multivariate analysis, postoperative RT predicted for improved OS but not CSS. These data suggest a beneficial effect of RT in the postoperative setting. A prospective study is necessary to further elucidate appropriate treatment strategies for men with breast cancer. PMID- 24781344 TI - Siple Dome ice reveals two modes of millennial CO2 change during the last ice age. AB - Reconstruction of atmospheric CO2 during times of past abrupt climate change may help us better understand climate-carbon cycle feedbacks. Previous ice core studies reveal simultaneous increases in atmospheric CO2 and Antarctic temperature during times when Greenland and the northern hemisphere experienced very long, cold stadial conditions during the last ice age. Whether this relationship extends to all of the numerous stadial events in the Greenland ice core record has not been clear. Here we present a high-resolution record of atmospheric CO2 from the Siple Dome ice core, Antarctica for part of the last ice age. We find that CO2 does not significantly change during the short Greenlandic stadial events, implying that the climate system perturbation that produced the short stadials was not strong enough to substantially alter the carbon cycle. PMID- 24781345 TI - Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies. AB - The succinate dehydrogenase (SDH) complex exerts a fundamental role in mitochondrial cellular respiration and mutations in its encoding genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHx) lead to a number of inherited endocrine cancer predisposition syndromes, including familial paraganglioma/pheochromocytoma. Recent studies suggest a possible role for the SDH complex and other mitochondrial enzymes in the pathogenesis of hematological malignancy. Our aim was to search and identify pedigrees of patients affected by germline SHDx mutations treated at our institution for endocrine and other tumors, and seek to identify cases of hematological malignancy. We also analyzed cancer genome databases for reported cases of SDHx mutations outside of endocrine neoplasms. We report of two unrelated pedigrees carrying SDHx mutations with members affected by lymphomas. Sequencing data revealed one case of chronic lymphocytic leukemia with a SDHB mutation. This novel set of observations demonstrates the need for collaborative databases of patients with endocrine cancers with SDHx mutations, and the investigation of their role in hematological (lymphoid) malignancy. PMID- 24781346 TI - A case of congenital pyloric atresia with dystrophic epidermolysis bullosa. AB - Pyloric atresia with epidermolysis bullosa (EB) dystrophica is a rare entity that may not be immediately recognized. We describe the fourth confirmed case of pyloric atresia associated with the dystrophic subtype of EB diagnosed by standard pathologic measures, and discuss the clinical disease features and recent advances in the pathophysiology. PMID- 24781347 TI - Most older women recover baseline functional status following pelvic organ prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: To evaluate postoperative functional status changes in older women undergoing pelvic organ prolapse (POP) surgery and determine predictors for nonrecovery of baseline status. METHODS: We enrolled women >= 65 years in whom POP surgery was planned and measured functional status using the Katz Activities of Daily Living (ADL) and Lawton Instrumental Activities of Daily Living (IADL) scales at baseline, 1 week, 2 weeks, and 3 months postoperatively. We used logistic regression modeling to identify predictors of postoperative nonrecovery of functional status (score < baseline) and calculated score change over time. RESULTS: Sixty-six women were enrolled and 3-month data were complete for 53. Subjects had a mean age of 72 +/- 5 years, were all Caucasian, and had predominantly undergone vaginal surgery (70 %). At baseline 31% were ADL dependent and 12% were IADL-dependent. Both ADL and IADL scores changed significantly over time (p <0.001). At 3 months postoperatively, 19% of women failed to return to baseline ADLs and 25% failed to return to baseline IADLs. At all time points ADL dependence was almost entirely attributable to lack of continence, while IADL dependence was commonly due to the inability to independently perform activities outside the home. Age, number of comorbidities, depression, and baseline functional status were not significant predictors of IADL nonrecovery. In a model controlling for baseline IADL status, age, and BMI, higher baseline Colorectal-Anal Distress Inventory (CRADI) score significantly predicted IADL nonrecovery (AOR 1.13, 95% CI 1.00,1.27, p = 0.04). CONCLUSIONS: Most older women with baseline functional status independence undergoing POP surgery can expect to regain independence by 3 months postoperatively. PMID- 24781348 TI - Breaking the silence on viral hepatitis. PMID- 24781349 TI - Weight labeling and obesity: a longitudinal study of girls aged 10 to 19 years. PMID- 24781350 TI - [(Me)2NH2][BiGeS4]: the first organically directed bismuth thiogermanate with Rb+ ion exchange property. AB - The first organically directed bismuth thiogermanate, namely [(Me)2NH2][BiGeS4] (), has been solvothermally synthesized and characterized. The structure features a two-dimensional anionic network of [BiGeS4]n(n-), with dimethylammonium as a counterion and a structure-directing agent. is able to undergo ion exchange with Rb(+) ions. PMID- 24781351 TI - Autonomic testing of women with interstitial cystitis/bladder pain syndrome. AB - PURPOSE: Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by urinary urgency, frequency, nocturia, pain worse as the bladder fills and improved after emptying. These features might suggest abnormal autonomic bladder control mechanisms. We compared the structural integrity of the autonomic nervous system (ANS) in IC/BPS and control subjects. METHODS: IRB-approved study at University Hospitals Case Medical Center, Cleveland, OH to evaluate the structural integrity of the ANS in adult females. Testing included cardiovascular response to deep breathing, Valsalva maneuver, 30 min head up tilt, and sudomotor test. RESULTS: Differences in ANS integrity for IC/BPS subjects and controls were determined by modified Composite Autonomic Severity Score (CASS) that includes sudomotor, adrenergic and cardiovascular indices. Baseline heart rate (HR) and HRs from each of three 10 min upright segments of a tilt test were compared and trend analyses performed using t tests. Healthy and IC/BPS subjects were demographically similar. The two groups did not differ in modified-CASS scores but elevated average peak heart rate was evident during baseline (supine; p = 0.057) for IC/BPS subjects prior to a tilt test. Difference at baseline was maintained at each interval during the tilt, with nearly identical slopes across intervals. The preliminary nature of this report denotes a small sample size and important differences may not be detected. CONCLUSIONS: The findings show no structural ANS abnormalities in IC/BPS subjects. Higher baseline HR supports the concept of functional rather than structural change in the ANS, such as abnormality of sympathetic/parasympathetic balance that will require further evaluation. PMID- 24781352 TI - Safety of pediatric HIV elimination: the growing population of HIV- and antiretroviral-exposed but uninfected infants. AB - Lynne Mofenson and Heather Watts discuss the context and implications of the study by J. Sibuide and colleagues, which provides a detailed analysis of birth defects in infants with in utero antiretroviral drug exposure in the French Perinatal Cohort. Please see later in the article for the Editors' Summary. PMID- 24781354 TI - Bottom-up synthesis of nitrogen-doped graphene sheets for ultrafast lithium storage. AB - A facile bottom-up strategy was developed to fabricate nitrogen-doped graphene sheets (NGSs) from glucose using a sacrificial template synthesis method. Three main types of nitrogen dopants (pyridinic, pyrrolic and graphitic nitrogens) were introduced into the graphene lattice, and an inimitable microporous structure of NGS with a high specific surface area of 504 m(2) g(-1) was obtained. Particularly, with hybrid features of lithium ion batteries and Faradic capacitors at a low rate and features of Faradic capacitors at a high rate, the NGS presents a superior lithium storage performance. During electrochemical cycling, the NGS electrode afforded an enhanced reversible capacity of 832.4 mA h g(-1) at 100 mA g(-1) and an excellent cycling stability of 750.7 mA h g(-1) after 108 discharge-charge cycles. Furthermore, an astonishing rate capability of 333 mA h g(-1) at 10,000 mA g(-1) and a high rate cycle performance of 280.6 mA h g(-1) even after 1200 cycles were also achieved, highlighting the significance of nitrogen doping on the maximum utilization of graphene-based materials for advanced lithium storage. PMID- 24781353 TI - Oral and dental late effects in survivors of childhood cancer: a Children's Oncology Group report. AB - PURPOSE: Multi-modality therapy has resulted in improved survival for childhood malignancies. The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers provide practitioners with exposure- and risk-based recommendations for the surveillance and management of asymptomatic survivors who are at least 2 years from completion of therapy. This review outlines the pathophysiology and risks for oral and dental late effects in pediatric cancer survivors and the rationale for oral and dental screening recommended by the Children's Oncology Group. METHODS: An English literature search for oral and dental complications of childhood cancer treatment was undertaken via MEDLINE and encompassed January 1975 to January 2013. Proposed guideline content based on the literature review was approved by a multi disciplinary panel of survivorship experts and scored according to a modified version of the National Comprehensive Cancer Network "Categories of Consensus" system. RESULTS: The Children's Oncology Group oral-dental panel selected 85 relevant citations. Childhood cancer therapy may impact tooth development, salivary function, craniofacial development, and temporomandibular joint function placing some childhood cancer survivors at an increased risk for poor oral and dental health. Additionally, head and neck radiation and hematopoietic stem cell transplantation increase the risk of subsequent malignant neoplasms in the oral cavity. Survivors require routine dental care to evaluate for potential side effects and initiate early treatment. CONCLUSIONS: Certain childhood cancer survivors are at an increased risk for poor oral and dental health. Early identification of oral and dental morbidity and early interventions can optimize health and quality of life. PMID- 24781355 TI - Correlation of biochemical markers and HCV RNA titers with fibrosis stages and grades in chronic HCV-3a patients. AB - INTRODUCTION: Hepatitis C virus (HCV) is one of the most important causes of chronic liver diseases, which include inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. Several factors have been proposed to determine the clinical outcome of HCV infection. The accurate mechanism by which HCV damages the liver remains poorly understood. In chronic hepatitis C patients, the relation between serum biochemical markers, HCV RNA titers and histological liver injury remain controversial. OBJECTIVES: The aim of this study was to investigate the relation between serum biochemical markers, HCV RNA titers and the degree of liver damage in patients with chronic HCV. MATERIALS AND METHODS: Liver biopsies were performed on 79 of a total of 100 enrolled patients. The histological activity was evaluated by the METAVER scoring system. HCV RNA quantification was performed by quantitative real-time PCR, and HCV genotyping was performed by nested PCR. Biochemical markers were measured with biochemical instruments. RESULTS: HCV RNA titers were significantly correlated with aspartate aminotransferase (AST) (P=0.004), alkaline phosphatase (ALP) (P=0.001) and total bilirubin (P=0.012) levels. HCV RNA titers were also significantly correlated with a progression of the fibrosis stage (P=0.000), but no correlation was observed with the change in inflammatory grades. It was observed that bilirubin levels were higher in later fibrosis stages as compared with the initial stage (P=0.000). Results revealed that in different fibrosis stages, the levels of AST (P=0.000), ALP (P=0.000) and alanine aminotransferase (ALT) (P=0.008), the age at diagnosis (P=0.000), the present age (P=0.000) and the BMI (P=0.009) were statistically significant. In the case of the inflammatory grade, levels of bilirubin (P=0.000), ALP (P=0.000), AST (P=0.016) and ALT (P=0.000) were statistically different between the inflammatory grades. CONCLUSION: Serum HCV RNA titers were correlated with AST, ALP and total bilirubin. Levels of ALT, AST, ALP and bilirubin had significant relation with the liver fibrosis stage and the inflammatory grade in genotype 3a. Hence, our study suggests that AST, ALP and ALT may correlate with liver damage. PMID- 24781357 TI - Does curricular change improve faculty perceptions of student experiences with the educational environment? A preliminary study in an institution undergoing curricular change. AB - PURPOSE: College of Medicine, Gulf Medical University, United Arab Emirates, underwent a major curriculum change from a discipline-based to an organ system based integrated curriculum. However, it was not known how the faculty perceived the changes in the educational environment as experienced by the students. In this context, we aimed to compare the faculty perceptions of the student experiences in the discipline-based curriculum with those in the organ system based integrated curriculum. METHODS: The Dundee Ready Education Environment Measure (DREEM) questionnaire was modified to assess faculty perceptions of the student experiences, pilot-tested, and administered to all faculty members (n=28) involved in the discipline-based curriculum (FDC) in January 2009. In the subsequent year, data were collected from the same faculty involved in the new integrated curriculum (FIC). Collected data were transferred to Predictive Analytics Software version 18. Total, domain, and individual statement scores were assessed with the Wilcoxon signed rank test. Percentage agreement, disagreement, and uncertainty were assessed by the McNemar's test for proportion. RESULTS: The mean total DREEM score was significantly higher (P<0.001) for FIC (139/200) as compared to FDC (119/200). The FIC perceived significantly more positive student experiences with the educational environment as indicated by the domain scores and statement scores. The differences in proportions of agreement between FIC and FDC also reinforced that the FIC perceived more positive student experiences with the educational environment. CONCLUSION: The study showed that the faculty perceived the organ system-based integrated curriculum as providing a better educational environment for the students than the discipline based curriculum. PMID- 24781358 TI - Role of calmodulin in thermotolerance. AB - Nitric oxide (NO) and hydrogen peroxide (H 2O 2) are 2 key elements in heat shock (HS) signaling pathway. Our experiments indicate the existence of a cross talk among H 2O 2, NO, Ca 2+ channels, and the activation of calmodulin (CaM) to stimulate the DNA-binding activity of HS transcription factors as well as the accumulation of HS proteins so as to confer thermotolerance. CaM can bind to target proteins to alter their function, acting as part of a calcium signal transduction pathway. However, only a few of its target proteins had been reported by now. Herein we are discussing them and conclude that in order to obtain a more profound understanding of CaM signaling, further research will be needed in the future. PMID- 24781359 TI - [Compression or expansion of morbidity? Development of health among the older population]. AB - BACKGROUND: Within the context of demographic change, the development of morbidity among the older population has increasingly gained importance. In this respect, three different scenarios of the development of morbidity are discussed: the compression of morbidity, the dynamic equilibrium, and the expansion of morbidity. OBJECTIVES: This paper investigates in which way subjective and functional health have developed among the older population between 1997 and 2010. MATERIALS AND METHODS: Using German Socio-Economic Panel (GSOEP) data, the developments of subjective and functional health are examined in cross-sectional comparisons. The age groups between 65 and 89 are considered. Analyses are stratified according to gender and age. RESULTS: In comparing different cohorts, men and women from younger cohorts report better subjective and functional health compared to people born before them. Concerning subjective health, this trend mostly affects younger people (65-74 years). Elderly subjects (aged 75-89 years) in the cohort comparison between 1997 and 2010 report no improvements in subjective health. In contrast, functional health between the cohorts affected all age groups in a similar manner. CONCLUSION: Results for subjective and functional health are consistent with the compression of morbidity and the dynamic equilibrium and they do not point towards an expansion of morbidity. PMID- 24781360 TI - [Drug therapy in the elderly]. PMID- 24781361 TI - The BMJ's activism will ultimately harm its reputation. PMID- 24781362 TI - Hydrochromic conjugated polymers for human sweat pore mapping. AB - Hydrochromic materials have been actively investigated in the context of humidity sensing and measuring water contents in organic solvents. Here we report a sensor system that undergoes a brilliant blue-to-red colour transition as well as 'Turn On' fluorescence upon exposure to water. Introduction of a hygroscopic element into a supramolecularly assembled polydiacetylene results in a hydrochromic conjugated polymer that is rapidly responsive (<20 MUs), spin-coatable and inkjet compatible. Importantly, the hydrochromic sensor is found to be suitable for mapping human sweat pores. The exceedingly small quantities (sub-nanolitre) of water secreted from sweat pores are sufficient to promote an instantaneous colorimetric transition of the polymer. As a result, the sensor can be used to construct a precise map of active sweat pores on fingertips. The sensor technology, developed in this study, has the potential of serving as new method for fingerprint analysis and for the clinical diagnosis of malfunctioning sweat pores. PMID- 24781363 TI - Wide-field Raman imaging of dental lesions. AB - Detection of dental caries at the onset remains as a great challenge in dentistry. Raman spectroscopy could be successfully applied towards detecting caries since it is sensitive to the amount of Raman active mineral crystals, the most abundant component of enamel. Effective diagnosis requires full examination of a tooth surface via Raman mapping. Point-scan Raman mapping is not clinically relevant (feasible) due to lengthy data acquisition time. In this work, a wide field Raman imaging system was assembled based on a high-sensitivity 2D CCD camera for imaging the mineralization status of teeth with lesions. Wide-field images indicated some lesions to be hypomineralized and others to be hypermineralized. The observations of wide-field Raman imaging were in agreement with point-scan Raman mapping. Therefore, sound enamel and lesions can be discriminated by Raman imaging of the mineral content. In conclusion, wide-field Raman imaging is a potentially useful tool for visualization of dental lesions in the clinic. PMID- 24781365 TI - Geriatric oncology for the 21st century: a call for action. PMID- 24781366 TI - Involvement of the family physician in the care of chemotherapy-treated patients with cancer: patients' perspectives. AB - PURPOSE: Increasing numbers of patients receive active ambulatory oncology treatment over prolonged periods of time. Many of these patients suffer from additional comorbidities and require comprehensive medical care. We aimed to assess the perception of patients with cancer regarding the role of the family physician and the oncologist in their care during times of active cancer treatment. PATIENTS AND METHODS: A survey was conducted among 265 consecutive chemotherapy-treated patients at the daycare oncology clinic. RESULTS: All the patients were affiliated with one of four Israeli health maintenance organizations, 96% had a regular family physician, and 70% had met with him during the preceding month. Only one third of the patients thought their family physician was trained to or was willing to treat medical problems that occurred during chemotherapy treatment. Yet most patients, irrespective of clinical or socioeconomic variables, stated that involvement of the family physician was important to them. Only 30% stated that the oncologist communicated with the family physician. Accordingly, 72% of the patients stated that in the case of an urgent problem they would turn first to the oncology clinic; only 9% would consult their family physician. CONCLUSIONS: Our data point to a lack of communication between team members and inadequate medical training as major barriers for comprehensive medical care for chemotherapy-treated patients with cancer. Communication between treating teams may improve medical care for oncology patients with multiple treating practitioners. PMID- 24781367 TI - Provider-based research networks demonstrate greater hospice use for minority patients with lung cancer. AB - PURPOSE: The Community Clinical Oncology Program (CCOP) and Minority-Based Community Clinical Oncology Program (MBCCOP) are provider-based research networks (PBRN) that improve minority enrollment in cancer-focused clinical trials. We hypothesized that affiliation with a PBRN may also mitigate racial differences in hospice enrollment for patients with lung cancer. METHODS: We used the SEER Medicare data, linked to the National Cancer Institute's CCOP program data, to identify all patients (>= age 65 years) with lung cancer, diagnosed from 2001 to 2007. We defined clinical treatment settings as CCOP, MBCCOP, academic, or community-affiliated and used multivariable logistic regression analysis to determine factors associated with hospice enrollment. RESULTS: Forty-one thousand eight hundred eighty-five (55.1%) patients with lung cancer enrolled in hospice before death. Approximately 55% of CCOP, 57% of MBCCOP, 57% of academic, and 52% of community patients enrolled. Patients who were more likely to enroll were female (odds ratio [OR], 1.36; 95% CI, 1.31 to 1.40); >= age 79 years (OR, 1.11; 95%CI, 1.06 to 1.16); white; lived in more educated areas; had minimal comorbidities; and had distant disease. Asian and black patients in academic (41.1% and 50.4%, respectively) and community practices (35.2% and 43.4%, respectively) were less likely to enroll in hospice compared with white patients (academic, 58.8%; community, 53.1%). However, hospice enrollment was equivalent for black and white patients in MBCCOP (59.5% v 57.2%) and CCOP (52.2% v 56.3%) practices. CONCLUSION: Minority patients with lung cancer receiving treatment in cancer-focused PBRN- affiliated practices have greater hospice enrollment than those treated in academic and community practices. PMID- 24781368 TI - Pregnancy outcome following in utero exposure to lithium: a prospective, comparative, observational study. AB - OBJECTIVE: The authors conducted a prospective, comparative observational study to evaluate the risk of major anomalies following exposure to lithium during pregnancy. METHOD: A total of 183 lithium-exposed pregnancies of women who contacted the Israeli Teratology Information Service were followed up (90.2% in the first trimester) and compared with 72 disease-matched and 748 nonteratogenic exposed pregnancies. RESULTS: There were significantly more miscarriages (adjusted odds ratio=1.94, 95% CI=1.08-3.48) and elective terminations of pregnancy (17/183 [9.3%] compared with 15/748 [2.0%]) in the lithium-exposed group compared with the nonteratogenic exposure group. The rate of major congenital anomalies after exclusion of genetic or cytogenetic anomalies was not significantly different between the three groups (lithium-exposed in the first trimester: 8/123 [6.5%]; bipolar: 2/61 [3.3%]; nonteratogenic: 19/711 [2.7%]). Cardiovascular anomalies occurred more frequently in the lithium group exposed during the first trimester when compared with the nonteratogenic exposure group (5/123 [4.1%] compared with 4/711 [0.6%]) but not after excluding anomalies that spontaneously resolved (3/123 [2.4%] compared with 2/711 [0.3%]). Ebstein's anomaly was diagnosed in one lithium-exposed fetus and in two retrospective lithium cases that were not included because contact with the information service was made after the prenatal diagnosis by ultrasound. The rate of noncardiovascular anomalies was not significantly different between the groups. The rate of preterm deliveries was higher in the lithium group compared with the nonteratogenic exposure group (18/131 [13.7%] compared with 41/683 [6.0%]). CONCLUSIONS: Lithium treatment in pregnancy is associated with a higher rate of cardiovascular anomalies. Women who are treated with lithium during organogenesis should undergo fetal echocardiography and level-2 ultrasound. PMID- 24781369 TI - A biochemical and physicochemical comparison of two recombinant enzymes used for enzyme replacement therapies of hunter syndrome. AB - Mucopolysaccharidosis II (MPS II, Hunter syndrome; OMIM 309900) is an X-linked lysosomal storage disease caused by a deficiency in the enzyme iduronate-2 sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs). For enzyme replacement therapy (ERT) of Hunter syndrome, two recombinant enzymes, idursulfase (Elaprase((r)), Shire Human Genetic Therapies, Lexington, MA) and idursulfase beta (Hunterase((r)), Green Cross Corporation, Yongin, Korea), are currently available in Korea. To compare the biochemical and physicochemical differences between idursulfase and idursulfase beta, we examined the formylglycine (FGly) content, specific enzyme activity, mannose-6-phosphate (M6P) content, sialic acid content, and in vitro cell uptake activity of normal human fibroblasts of these two enzymes.The FGly content, which determines the enzyme activity, of idursulfase beta was significantly higher than that of idursulfase (79.4 +/- 0.9 vs. 68.1 +/- 2.2 %, P < 0.001). In accordance with the FGly content, the specific enzyme activity of idursulfase beta was significantly higher than that of idursulfase (42.6 +/- 1.1 vs. 27.8 +/- 0.9 nmol/min/MUg protein, P < 0.001). The levels of M6P and sialic acid were not significantly different (2.4 +/- 0.1 vs 2.4 +/- 0.3 mol/mol protein for M6P and 12.3 +/- 0.7 vs. 12.4 +/- 0.4 mol/mol protein for sialic acid). However, the cellular uptake activity of the normal human fibroblasts in vitro showed a significant difference (Kuptake, 5.09 +/- 0.96 vs. 6.50 +/- 1.28 nM protein, P = 0.017).In conclusion, idursulfase beta exhibited significantly higher specific enzyme activity than idursulfase, resulting from higher FGly content. These biochemical differences may be partly attributed to clinical efficacy. However, long-term clinical evaluations of Hunter syndrome patients treated with these two enzymes will be needed to demonstrate the clinical implications of significant difference of the enzyme activity and the FGly content. PMID- 24781370 TI - Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. AB - Growing evidence indicates that bone marrow-derived mesenchymal stem cells (BM MSCs) enhance wound repair via paracrine. Because the extent of environmental oxygenation affects the innate characteristics of BM-MSCs, including their stemness and migration capacity, the current study set out to elucidate and compare the impact of normoxic and hypoxic cell-culture conditions on the expression and secretion of BM-MSC-derived paracrine molecules (e.g., cytokines, growth factors and chemokines) that hypothetically contribute to cutaneous wound healing in vivo. Semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses of normoxic and hypoxic BM-MSCs and their conditioned medium fractions showed that the stem cells expressed and secreted significantly higher amounts of basic fibroblast growth factor (bFGF),vascular endothelial growth factor A (VEGF-A) interleukin 6 (IL-6) and interleukin 8 (IL-8) under hypoxic conditions. Moreover, hypoxic BM-MSC-derived conditioned medium (hypoCM) vs. normoxic BM-MSC-derived conditioned medium (norCM) or vehicle control medium significantly enhanced the proliferation of keratinocytes, fibroblasts and endothelial cells, the migration of keratinocytes, fibroblasts, endothelial cells and monocytes, and the formation of tubular structures by endothelial cells cultured on Matrigel matrix. Consistent with these in vitro results, skin wound contraction was significantly accelerated in Balb/c nude mice treated with topical hypoCM relative to norCM or the vehicle control. Notably increased in vivo cell proliferation, neovascularization as well as recruitment of inflammatory macrophages and evidently decreased collagen I, and collagen III were also found in the hypoCM treated group. These findings suggest that BM-MSCs promote murine skin wound healing via hypoxia-enhanced paracrine. PMID- 24781371 TI - Electroencephalographic Data Analysis With Visibility Graph Technique for Quantitative Assessment of Brain Dysfunction. AB - Usual techniques for electroencephalographic (EEG) data analysis lack some of the important properties essential for quantitative assessment of the progress of the dysfunction of the human brain. EEG data are essentially nonlinear and this nonlinear time series has been identified as multi-fractal in nature. We need rigorous techniques for such analysis. In this article, we present the visibility graph as the latest, rigorous technique that can assess the degree of multifractality accurately and reliably. Moreover, it has also been found that this technique can give reliable results with test data of comparatively short length. In this work, the visibility graph algorithm has been used for mapping a time series-EEG signals-to a graph to study complexity and fractality of the time series through investigation of its complexity. The power of scale-freeness of visibility graph has been used as an effective method for measuring fractality in the EEG signal. The scale-freeness of the visibility graph has also been observed after averaging the statistically independent samples of the signal. Scale freeness of the visibility graph has been calculated for 5 sets of EEG data patterns varying from normal eye closed to epileptic. The change in the values is analyzed further, and it has been observed that it reduces uniformly from normal eye closed to epileptic. PMID- 24781372 TI - What we know and what we don't know about preventing stroke. AB - Consulting Editor Druin Burch and the PLOS Medicine Editors discuss implications of research by Bos and colleagues, which finds that a high proportion of strokes in a European cohort are not attributable to known risk factors. Please see later in the article for the Editors' Summary. PMID- 24781373 TI - Good things come in small packages: exosomes, immunity and cancer. PMID- 24781374 TI - Long-term benefits of an early online problem-solving intervention for executive dysfunction after traumatic brain injury in children: a randomized clinical trial. AB - IMPORTANCE: Executive dysfunction after traumatic brain injury (TBI) in children is common and leads to significant short- and long-term problems in functioning across multiple settings. We hypothesized that improvements in short-term executive function would be maintained to 24 months after injury and that improvements would increase over time in a counselor-assisted problem-solving (CAPS) intervention. OBJECTIVE: To evaluate the efficacy of a CAPS intervention administered within 7 months of complicated mild to severe TBI compared with an Internet resource condition in improving long-term executive dysfunction. DESIGN, SETTING, AND PARTICIPANTS: Multisite, assessor-blinded, randomized clinical trial at 3 tertiary pediatric hospitals and 2 tertiary general medical centers. Participants included 132 adolescents aged 12 to 17 years who sustained a moderate to severe TBI 1 to 7 months before study enrollment. INTERVENTION: Web based CAPS intervention. MAIN OUTCOMES AND MEASURES: The primary outcome was the parent-reported Global Executive Composite (GEC) of the Behavior Rating Inventory of Executive Function. Secondary outcomes included the Behavioral Regulation Index (BRI) and Metacognition Index (MI) of the GEC. RESULTS: In older (>14 to 17 years) adolescents, the CAPS intervention was associated with lower GEC ratings at 12 (beta = -0.46; P = .03) and 18 (beta = -0.52; P = .02) months after enrollment. Trends were also observed for older adolescents toward lower GEC ratings at 6 months (beta = -0.40; P = .05), lower BRI ratings at 12 (beta = 0.40; P = .06) and 18 (beta = -0.47; P = .04) months, and lower MI ratings at 6 (beta = -0.41; P = .05), 12 (beta = -0.46; P = .03), and 18 (beta = -0.50; P = .03) months. In younger (12-14 years) adolescents, no group differences were found on the GEC, BRI, or MI ratings. CONCLUSIONS AND RELEVANCE: Delivery of the CAPS intervention early after TBI in older adolescents improves long-term executive function. This trial is, to our knowledge, one of the few large, randomized clinical treatment trials performed in pediatric TBI to demonstrate the efficacy of an intervention for management of executive dysfunction and long term benefits of an intervention delivered soon after injury. Use of the CAPS intervention clinically should be considered; however, further research should explore ways to optimize delivery. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00409448. PMID- 24781375 TI - Interactions between a wild Bornean orang-utan and a Philippine slow loris in a peat-swamp forest. AB - All documented orang-utan-loris interactions have been from Sumatra, where lorises were opportunistically preyed upon by orang-utans. In this paper, we describe two accounts of the Bornean orang-utan (Pongo pygmaeus wurmbii) interacting with the Philippine slow loris (Nycticebus menagensis). The interactions were by two adolescent female orang-utans. No attempts to catch the loris were observed on either occasion. Neither interaction was hostile. During the second observation, which was more detailed, we considered the behaviour to be play rather than aggression or attempted predation. Based upon the lack of interest from the adult females during these rare encounters, we propose that the behaviour represents play or non-aggressive exploration rather than predation. PMID- 24781377 TI - Neglected tropical diseases: prevalence and risk factors for schistosomiasis and soil-transmitted helminthiasis in a region of Minas Gerais State, Brazil. AB - BACKGROUND: Among the neglected tropical diseases (NTDs), schistosomiasis and the three main soil-transmitted helminthiases (STHs), i.e., ascariasis, trichuriasis and hookworm infection, represent the most common infections in developing countries. In Brazil, there is a lack of epidemiological data in many parts of the country, which favors the unawareness of the real situation concerning these diseases. Due to this, we investigated the occurrence of schistosomiasis and STHs in a region of Minas Gerais State, Brazil. METHODS: One stool sample was collected from 503 individuals, whose ages ranged from 0.1 to 91.2 years, and screened using both the Kato-Katz and the Formol-Ether methods. In parallel, a malacological survey was carried out in the main water bodies of the district, and Biomphalaria susceptibility assays and kernel-based techniques were also performed. RESULTS: No individual was found infected with Ascaris lumbricoides or hookworm. Schistosoma mansoni was the most common parasite found (1.6%). The prevalence was higher in males and the chance of acquiring the disease increased by 43.35 times with contact with a body of water. None of the Biomphalaria tenagophila and B. glabrata specimens were found naturally infected, but B. glabrata was highly susceptible to infection with Schistosoma mansoni. Using kernel-based techniques, clusters of Biomphalaria were found near the households where the infected individuals lived. CONCLUSIONS: Schistosomiasis was the most prevalent parasitic infection found. Our findings show that the occurrence of this disease has been underestimated by the local health care service, and highlight the importance of epidemiological surveillance in areas of low prevalence for schistosomiasis. PMID- 24781376 TI - The bacterial aetiology of adult community-acquired pneumonia in Asia: a systematic review. AB - BACKGROUND: Community-acquired pneumonia (CAP) is a major cause of adult mortality in Asia. Appropriate empirical treatment depends on knowledge of the pathogens commonly responsible. However, assessing the aetiological significance of identified organisms is often difficult, particularly with sputum isolates that might represent contamination with oropharyngeal flora. METHODS: A systematic review of all adult CAP aetiology studies from Asia, excluding the Middle East, published in English between 1 January 1990 and 1 March 2012 was conducted. Forty-eight studies reporting on 10 423 patients were included, representing data from China, India, Indonesia, Japan, Malaysia, The Philippines, Singapore, South Korea, Taiwan, Thailand and Vietnam. Data from large parts of Asia were unavailable and there was substantial heterogeneity in methodology. RESULTS: As in western studies, Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella spp. and Haemophilus influenzae were all significant pathogens. However, compared with western studies, S. pneumoniae was of less relative importance. Gram-negative bacilli and Mycobacterium tuberculosis were more important, and in northeast Thailand Burkholderia pseudomallei was a major pathogen. CONCLUSION: These data have major implications for diagnostic strategies and empirical treatment. Narrow-spectrum antibiotics targeting S. pneumoniae may be inappropriate in many Asian settings, and agents active against TB may lead to partial response and delayed TB diagnosis. PMID- 24781378 TI - Physical activity throughout adolescence and bone mineral density in early adulthood: the 1993 Pelotas (Brazil) Birth Cohort Study. AB - Association between three physical activity (PA) measurements throughout adolescence and bone density at 18 years of age was investigated. PA was associated with both lumbar spine and femoral neck bone mineral density (BMD) in early adulthood independent of type of PA used in the analysis. The results were more consistent in boys. INTRODUCTION: This study amis to evaluate if PA during adolescence could influence BMD later in life. METHODS: A population-based birth cohort study was carried out. PA was assessed at 11 and 15 years of age by questionnaire and included sports performed while BMD (lumbar spine and femoral neck) was measured by dual-energy X-ray absorptiometry at 18 years. A peak strain score was generated based on ground reaction forces of different PA. PA was measured as peak strain score, peak strain score multiplied by minutes/week and minutes/week. Unadjusted and adjusted analyses were performed using linear regression. RESULTS: Overall, 3,811 adolescents were studied (1,866 boys and 1,945 girls). The peak strain score at 11 and 15 years was associated with lumbar and femoral neck BMD at 18 years in boys. Among girls, high-impact PA at 11 years was positively associated with lumbar and femoral BMD (p = 0.01; p < 0.001). After adjusted analysis, weekly minutes of PA at 11 years were not associated with lumbar spine but were associated with femoral neck BMD (p < 0.001); at 15 years, weekly minutes of PA were positively associated with BMD at both sites. Regardless of PA status at 11 years of age, attaining the recommendations of PA (300 min/week) at 15 years appears to be important for BMD at 18 years in both sites in boys and girls. The results Appeared to be more consistent in boys. CONCLUSIONS: PA during adolescence was positively associated with both lumbar spine and femoral neck BMD in early adulthood independent of type of PA used in the analysis. PMID- 24781379 TI - Characterizing microarchitectural changes at the distal radius and tibia in postmenopausal women using HR-pQCT. AB - Limited prospective evidence exists regarding bone microarchitectural deterioration. We report annual changes in trabecular and cortical bone microarchitecture at the distal radius and tibia in postmenopausal women. Lost trabeculae with corresponding increase in trabecular thickness at the radius and thinning tibial cortex indicated trabecularization of the cortex at both sites. INTRODUCTION: Osteoporosis is characterized by low bone mass and the deterioration of bone microarchitecture. However, limited prospective evidence exists regarding bone microarchitectural changes in postmenopausal women: a population prone to sustaining osteoporotic fractures. Our primary objective was to characterize the annual change in bone area, density, and microarchitecture at the distal radius and distal tibia in postmenopausal women. METHODS: Distal radius and tibia were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline and 1 year later in 51 women (mean age +/- SD, 77 +/- 7 years) randomly sampled from the Saskatoon cohort of the Canadian Multicentre Osteoporosis Study (CaMos). We used repeated measures analysis of variance (ANOVA) with Bonferroni adjustment for multiple comparisons to characterize the mean annual change in total density, cortical perimeter, trabecular and cortical bone area, density, content, and microarchitecture. Significant changes were accepted at P < 0.05. RESULTS: At the distal radius in women without bone-altering drugs, total density (-1.7%) and trabecular number ( 6.4%) decreased, while trabecular thickness (+6.0%), separation (+8.6%), and heterogeneity (+12.1%) increased. At their distal tibia, cortical area (-4.5%), density (-1.9%), content (-6.3%), and thickness (-4.4%) decreased, while trabecular area (+0.4%) increased. CONCLUSIONS: The observed loss of trabeculae with concomitant increase in trabecular size at the distal radius and the declined cortical thickness, density, and content at the distal tibia indicated a site-specific trabecularization of the cortical bone in postmenopausal women. PMID- 24781380 TI - Dynamic cervical myelopathy in young adults. AB - PURPOSE: Non-traumatic cervical chronic joint instability in young adults is a rare and underexplored entity. We assessed the diagnostic relevance of dynamic MRI, and the clinical and radiological outcome after anterior cervical interbody fusion (ACIF) in these cases. METHODS: Six young patients (mean age 34 years) with cervical myelopathy without compression on static imaging had a dynamic MRI. Joint instability was defined by a reduction of the canal diameter on dynamic sequences. Clinical and radiological outcomes were assessed after surgery by examination, cervical X-rays, static and dynamic MRI. RESULTS: All the patients had joint instability. Four patients underwent surgery. Clinical status improved 1 year after surgery. All patients had a satisfactory fusion at 6-month follow-up and no residual compression at 1 year. CONCLUSION: Dynamic MRI can help detect a joint instability in young patients with cervical myelopathy without compression. ACIF seems to be efficient in these cases. PMID- 24781384 TI - A real time affinity biosensor on an insulated polymer using electric impedance spectroscopy in dielectric microchips. AB - This paper presents development of real time monitoring of binding events on flexible plastic in microchips. Two planar carbon microelectrodes are integrated into an insulated polyethylene terephthalate microchip without direct electrical contact with the solution in the microchannel. It has been possible to probe the electric impedance changes through the interface constituted by the microelectrode/PET microchannel/solution when a biomolecular interaction takes place on the polymer surface. This new transduction for biosensing was demonstrated for the molecular recognition of BSA immobilized on the polymer microchannel surface using the corresponding rabbit anti-BSA antibodies as an analyte in the flow microchannel at the nanomolar range concentration. The equilibrium association constant was determined for the affinity reaction between both ligands and was obtained equal to 5 * 10(7) M(-1). The promising results obtained with this new device make it a competitive biosensor. PMID- 24781383 TI - Maternal nutrition at conception modulates DNA methylation of human metastable epialleles. AB - In experimental animals, maternal diet during the periconceptional period influences the establishment of DNA methylation at metastable epialleles in the offspring, with permanent phenotypic consequences. Pronounced naturally occurring seasonal differences in the diet of rural Gambian women allowed us to test this in humans. We show that significant seasonal variations in methyl-donor nutrient intake of mothers around the time of conception influence 13 relevant plasma biomarkers. The level of several of these maternal biomarkers predicts increased/decreased methylation at metastable epialleles in DNA extracted from lymphocytes and hair follicles in infants postnatally. Our results demonstrate that maternal nutritional status during early pregnancy causes persistent and systemic epigenetic changes at human metastable epialleles. PMID- 24781382 TI - Inhibition of the activation and recruitment of microglia-like cells protects against neomycin-induced ototoxicity. AB - One of the most unfortunate side effects of aminoglycoside (AG) antibiotics such as neomycin is that they target sensory hair cells (HCs) and can cause permanent hearing impairment. We have observed HC loss and microglia-like cell (MLC) activation in the inner ear (cochlea) following neomycin administration. We focused on CX3CL1, a membrane-bound glycoprotein expressed on neurons and endothelial cells, as a way to understand how the MLCs are activated and the role these cells play in HC loss. CX3CL1 is the exclusive ligand for CX3CR1, which is a chemokine receptor expressed on the surface of macrophages and MLCs. In vitro experiments showed that the expression levels of CX3CL1 and CX3CR1 increased in the cochlea upon neomycin treatment, and CX3CL1 was expressed on HCs, while CX3CR1 was expressed on MLCs. When cultured with 1 MUg/mL exogenous CX3CL1, MLCs were activated by CX3CL1, and the cytokine level was increased in the cochleae leading to apoptosis in the HCs. In CX3CR1 knockout mice, a significantly greater number of cochlear HCs survived than in wild-type mice when the cochlear explants were cultured with neomycin in vitro. Furthermore, inhibiting the activation of MLCs with minocycline reduced the neomycin-induced HC loss and improved the hearing function in neomycin-treated mice in vivo. Our results demonstrate that CX3CL1-induced MLC activation plays an important role in the induction of HC death and provide evidence for CX3CL1 and CX3CR1 as promising new therapeutic targets for the prevention of hearing loss. PMID- 24781385 TI - Hierarchical growth of SnO2 nanostructured films on FTO substrates: structural defects induced by Sn(II) self-doping and their effects on optical and photoelectrochemical properties. AB - Direct hydrothermal growth of Sn(II)-doped SnO2 films on fluorine-doped tin oxide (FTO) substrates results in the formation of upstanding SnO2 nanosheet arrays covered by hierarchical SnO2 nanoflowers. The n-type semiconductor films show extended photoresponse in the visible spectrum arising from the coexistence of Sn(II) dopant ions and oxygen vacancies in these hierarchical SnO2 nanostructures, which leads to a narrowed bandgap. Photoluminescence spectroscopy revealed that the emission in the UV, blue and red spectral ranges is related to the evolution of Sn(II) dopants and oxygen vacancies with annealing temperature, whereas oxygen vacancies are mostly responsible for visible emission. The Sn(II) doped SnO2 films show higher photocurrent when sensitized with narrow bandgap CdS nanoparticles, serving as efficient electron acceptors. PMID- 24781386 TI - Single-port pancreatectomy: ready for prime time. PMID- 24781387 TI - Thalidomide and refractory Crohn's disease: what is in the future? PMID- 24781388 TI - Rosiglitazone, a PPAR-gamma agonist, fails to attenuate CLA-induced milk fat depression and hepatic lipid accumulation in lactating mice. AB - Our objective was to investigate the combination of rosiglitazone (ROSI) and conjugated linoleic acid (CLA) on mammary and hepatic lipogenesis in lactating C57Bl/6 J mice. Twenty-four lactating mice were randomly assigned to one of four treatments applied from postpartum day 6 to day 10. Treatments included: (1) control diet, (2) control plus 1.5 % dietary CLA (CLA) substituted for soybean oil, (3) control plus daily intra-peritoneal (IP) rosiglitazone injections (10 mg/kg body weight) (ROSI), and (4) CLA plus ROSI (CLA-ROSI). Dam food intake and milk fat concentration were depressed with CLA. However, no effects were observed with ROSI. The CLA-induced milk fat depression was due to reduced expression for mammary lipogenic genes involved in de-novo fatty acid (FA) synthesis, FA uptake and desaturation, and triacyglycerol synthesis. Liver weight (g/100 g body weight) was increased by CLA due to an increase in lipid accumulation triggering a compensatory reduction in mRNA abundance of hepatic lipogenic enzymes, including acetyl-CoA carboxylase I and stearoyl-CoA desaturase I. On the contrary, no effects were observed with ROSI on hepatic and mammary lipogenic gene and enzyme expression. Overall, feeding CLA to lactating mice induced milk fat depression and increased hepatic lipid accumulation, probably due to the presence of trans-10, cis-12 CLA isomer, while ROSI failed to significantly attenuate both hepatic steatosis and reduction in milk fat content. PMID- 24781389 TI - Adult diagnostic and functional outcomes of DSM-5 disruptive mood dysregulation disorder. AB - OBJECTIVE: Disruptive mood dysregulation disorder (DMDD) is a new disorder for DSM-5 that is uncommon and frequently co-occurs with other psychiatric disorders. Here, the authors test whether meeting diagnostic criteria for this disorder in childhood predicts adult diagnostic and functional outcomes. METHOD: In a prospective, population-based study, individuals were assessed with structured interviews up to six times in childhood and adolescence (ages 10 to 16 years; 5,336 observations of 1,420 youths) for symptoms of DMDD and three times in young adulthood (ages 19, 21, and 24-26 years; 3,215 observations of 1,273 young adults) for psychiatric and functional outcomes (health, risky/illegal behavior, financial/educational functioning, and social functioning). RESULTS: Young adults with a history of childhood DMDD had elevated rates of anxiety and depression and were more likely to meet criteria for more than one adult disorder relative to comparison subjects with no history of childhood psychiatric disorders (noncases) or individuals meeting criteria for psychiatric disorders other than DMDD in childhood or adolescence (psychiatric comparison subjects). Participants with a history of DMDD were more likely to have adverse health outcomes, be impoverished, have reported police contact, and have low educational attainment as adults compared with either psychiatric or noncase comparison subjects. CONCLUSIONS: The long-term prognosis of children with DMDD is one of pervasive impaired functioning that in many cases is worse than that of other childhood psychiatric disorders. PMID- 24781390 TI - UV and visible light active aqueous titanium dioxide colloids stabilized by surfactants. AB - Attempts to increase the stability of photocatalytically active nanodispersions of titanium dioxide over a wide range of pH (3-10) were undertaken. Polyethylene glycols (PEGs) with different molecular weights and polyoxyethylenesorbitan monooleate (Tween(r) 80) were tested as stabilizing agents of TiO2 nanoparticles. The results of DLS measurements proved the stabilizing effect of Tween(r) 80 while the systems involving PEGs, independently of the polymer concentration, showed a tendency to form aggregates in neutral solutions. The colloids stabilized with Tween(r) 80 were photosensitized with 2,3-naphthalenediol (nd) or 2-hydroxy-3-naphthoic acid (hn) or catechol (cat). The photocatalytic activity of such colloids has been assessed in an azure B degradation reaction using both UV and visible light. The nd@TiO2 + Tween colloid appeared particularly photoactive upon visible light irradiation. Moreover, the comparison of activities of nd@TiO2 + Tween and TiO2 + Tween revealed a significantly better performance of the former nanodispersion, independently of the irradiation conditions (UV or visible light). This effect has been explained by different structures of micelles formed in the case of TiO2 and nd@TiO2 stabilized with Tween(r) 80. PMID- 24781391 TI - Toward a Predictive Assessment of Stab-Penetration Forces. AB - Collaborative research between the disciplines of forensic pathology and biomechanics was undertaken to investigate the hyperelastic properties of human skin, to determine the force required for sharp instrument penetration of skin, and to develop a finite element model, which reflects the mechanisms of sharp instrument penetration. These studies have led to the development of a "stab metric," based on simulations, to describe the force magnitudes in stabbing incidents. Such a metric should, in time, replace the crudely quantitative descriptors of stabbing forces currently used by forensic pathologists. PMID- 24781392 TI - The postman always rings twice: two cases of shotgun deaths associated with an unconventional home security alarm system. AB - Injury and death cases caused by booby traps are not common in forensic medicine practice. Besides, installation of booby traps including firearms is generally for suicidal and rarely for homicidal purposes. Although few patents were described about home security alarm system that were created by firearms in the United States, 1 sample of injury with a similar unconventional mechanism of home safety system was reported by Asirdizer and Yavuz in 2009. In the published case report, the story of an electrical technician who was invited to a summer house by the homeowner to check the home security alarm system was reported. In the so called report, he was stated to be injured by the shotgun attached to the unconventional home security alarm system while checking the system. As a result, the homeowner was convicted of a possible intent to cause a life-threatening injury to the technician.The so-called homeowner and his wife died by the same shotgun attached to the same unconventional home security alarm system 4 years on from the first event. In the present case report, we have aimed to present the findings of the crime scene and the autopsies of these unusual 2 deaths and to discuss individual and legal factors in paving the way for the deaths of 2 people. PMID- 24781393 TI - Cardiac arrhythmia and death of teenager linked to rare genetic disorder diagnosed at autopsy. AB - A 17-year-old male adolescent sustained cardiac arrest after participating in a wrestling match, where he was thrown down. He had no pulse, and cardiopulmonary resuscitation was immediately initiated along with application of an automatic external defibrillator. Upon arrival of emergency medical services, an electrocardiogram showed the patient to be in ventricular tachycardia, torsades, and ventricular fibrillation. The patient was ultimately transported to the hospital and, with ACLS protocol being performed, was resuscitated to a junctional rhythm with bradycardia and borderline prolonged QT. His hospital stay was characterized by refractory cardiac failure, and 2 days after the incident, a decision was made to remove him from life support. At autopsy, there were no external or internal injuries that could be considered a contributing cause of death. On external examination, observations were made about the decedent's facial features including his nose, eyes, ears, fingers, and toes. A careful review of the decedent's medical history was initiated to reveal birth defects including syndactyly of the third and fourth digit of the upper extremity as well as complete lack of dental enamel. A tentative diagnosis of oculodentodigital dysplasia was made and confirmed by genetic testing of heart muscle taken from the decedent. This case report examines the rare association of oculodentodigital dysplasia with cardiac arrhythmia as well as places emphasis on the features of the disorder that can aid in its diagnosis. PMID- 24781394 TI - Can forensic pathologists diagnose pulmonary thromboembolism on postmortem computed tomography pulmonary angiography? AB - Postmortem computed tomography (CT) scanning is a routine examination in the medicolegal death investigation of every deceased person admitted to the Victorian Institute of Forensic Medicine. Pulmonary CT angiography is a standard clinical investigation for suspected pulmonary thromboembolism. To the best of our knowledge, a study of postmortem CT pulmonary angiography has not been previously reported in the English-speaking forensic literature. We present our findings on 13 cases of suspected massive pulmonary thromboembolism where forensic pathologists assessed postmortem CT pulmonary angiography, which were then correlated with conventional postmortem examinations. PMID- 24781395 TI - DNA analysis of fingernail clippings: an unusual case report. AB - The case of an unusual DNA analysis of fingernail clippings is described. A 20 year-old woman died of strangulation, and her former boyfriend entered the police's sight as suspect through rapid investigation and inspection. Genomic DNA from debris scraped underneath the suspect's fingernail was extracted 2 days after the incident using the modified DNA pretreatment method. Finally, mixed DNA profiles were observed from the suspect's fingernail clippings, one of them originating from the victim, which is consistent with the result of criminal investigation. With the support of strong evidence, the suspect soon confessed. In this case, it was really unusual in practice that fingernail debris extracted from the suspect was used to accuse the suspect himself. This case demonstrates the usefulness of the modified DNA pretreatment method and the possibility of getting DNA profiles from fingernail clippings with 2 days' lapse between the incident and recovery of the evidential material. PMID- 24781396 TI - Different whole-genome amplification methods as a preamplification tool in Y chromosome Loci analysis. AB - Degraded and low template DNA is often analyzed in forensic genetics laboratories. Reliable analysis of degraded and low template DNA is of great importance, because its results impact the quality and reliability of expert testimonies. Recently, a number of whole-genome amplification (WGA) methods have been proposed as preamplification tools improving quantity and quality of DNA. We chose, investigated, and compared 7 WGA methods to evaluate their ability to "recover" degraded and nondegraded DNA. These methods include degenerate oligonucleotide primed polymerase chain reaction, primer extension preamplification (PEP) polymerase chain reaction, GenomePlex WGA (Sigma), multiple displacement amplification, GenomiPhi Amplification Kit (Amersham Biosciences), restriction and circularization aided rolling circle amplification, and blunt-end ligation-mediated WGA. Recently, we have described the comparison of these methods' efficiency and reliability using SGMPlus kit. However, Y chromosome profiling is also often used in analysis of both nondegraded and degraded DNA. This includes criminal cases and investigation of kinship in male linage. Here we demonstrate the impact of WGA methods on Y-chromosome loci (Yfiler) reactivation.The best results for nondegraded DNA were obtained with GenomiPhi kit and PEP method. In the case of degraded DNA (200 base pairs), the most complete profiles were obtained with GenomePlex kit and PEP method. None of the analyzed methods allowed full reactivation of degraded (200 base pairs) DNA in terms of Y-chromosome loci profiling. PMID- 24781397 TI - Homicide or suicide? Gunshot wound interpretation: a Bayesian approach. AB - Many studies have been published examining various features of fatal gunshot wounds such as type of firearm, range of fire, number of shots, and wound location as a way of determining between homicidal and suicidal deaths. Pathologists frequently have to give evidence in court, and may have their opinion about probable manner of death challenged or be questioned about how sure they can be. In the literature, the features are always discussed in isolation, but in practice, the pathologist has to consider such details in combination. Using pooled data from a systematic review to obtain large data sets, this study shows how Bayesian analysis can be applied to consideration of combined features and can thus provide a quantified degree of confidence to support the pathologist's opinion through the use of likelihood ratios. Case examples are provided to illustrate the impact of different features. PMID- 24781398 TI - Body mass index and suicide. AB - It has been suggested that there is a connection between depression and an increased body mass index (BMI). As depression is related to suicide, a South Australian cohort study was performed to test whether a high BMI may also characterize victims of suicide. Body mass indexes from 100 consecutive cases of suicide (male-to-female ratio, 1:1) taken from the files of Forensic Science South Australia in Adelaide, Australia, were compared with BMIs from 100 sex- and age-matched control cases, where deaths were due to accidents, homicides, or natural diseases. No significant differences in BMIs and BMI categories were found between the 2 groups. However, when cases were subclassified according to the method used, BMIs were noted to be considerably lower in hangings than in both the control group as well as in victims who died of alternative means of suicide (P < 0.001). An association between an increased BMI and suicide could not be substantiated in this local study. However, the reasons for the decreased BMIs in hangings require further consideration that may assist in understanding more about particular victim subgroups. PMID- 24781399 TI - Fluid in the airway of nontraumatic death on postmortem computed tomography: relationship with pleural effusion and postmortem elapsed time. AB - To evaluate radiographic features of endotracheal/endobronchial fluid in the airway (FA) observed on postmortem computed tomography (PMCT). We studied 164 subjects who died at our hospital between April 2009 and September 2012. Fluid in the airway was considered positive when fluid was identified in the lumen of 1 of the 2 main bronchi in continuity with a segmental bronchus. Pleural effusion and atelectasis/consolidation of the lung lower lobes were also evaluated. Fluid in the airway was observed in 60 (71%) of 84 subjects with unilateral or bilateral pleural effusion, and in 44 (55%) of 80 subjects without pleural effusion (P = 0.029). Of the latter, 41 (93%) had atelectasis/consolidation of the lower lung lobes. Among subjects without pleural effusion, average times after death to PMCT of subjects with and without FA were 501 and 314 minutes, respectively (P = 0.01). Time-course analysis showed that cases with FA on PMCT largely correlated with time after death (R = 0.7966). Fluid in the airway is frequently observed on PMCT in subjects with pleural effusion or atelectasis/consolidation of the lung. No FA in subjects without pleural effusion correlated to shorter times after death. In addition, FA frequency on PMCT increased over time after death. PMID- 24781400 TI - To hold or not to hold: medicolegal death investigation practices during unexpected child death investigations and the experiences of next of kin. AB - The purpose of this study was to identify the current practices within the medicolegal death investigation system, as well as the experience of bereaved parents due to sudden unexpected child death with regard to viewing, memorial keepsakes, and communication during the death investigation. Convenience samples of 197 professionals and 156 bereaved parents participated. Respondents were asked to participate in an online survey. Results show that the majority of professional respondents (96.5%) allow the next of kin (NOK) to view his/her child before transport to the morgue while holding the infant/child was somewhat less commonplace (68.9%). The majority of professional respondents (70.4%) would also permit memorial keepsakes to be made. Additional factors are explored that both hinder and promote these common family requests. Furthermore, professional practices and NOK experiences in regard to communicating preliminary and final cause of death information to the NOK were highly variable. This article provides a snapshot at the current death investigative practices in the United States, as well as how these practices are received by NOK along with their recommendations for change. These results may be used to further inform future guidelines to improve comprehensive and efficient death investigations that support the emotional needs of the newly bereaved. PMID- 24781401 TI - The study on telomere length for age estimation in a Thai population. AB - Age is one of the key parameters in establishing a physical characteristic profile of an individual. For biological evidence left in crime scenes such as blood, saliva, hair, etc, the evidence owner's age can be determined only by DNA extracted from these materials. Previous researches have found that there are certain DNA regions with specialized characteristic and function called telomere being able to predict age. The present study was to determine the correlation between telomere length and age as well as the effect of sex on the correlation and to create linear regression equation for age estimation in Thai population for forensic purposes. Blood samples obtained from unrelated healthy Thai fresh cadavers without anatomical organ abnormalities were used in this study. All cadaver subjects underwent the postmortem examination in jurisdiction of the Department of Forensic Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, and Institute of Forensic Medicine, Police General Hospital. Fifty blood samples from both sexes of all ages divided into 6 groups for equal age distribution (0-11, 12-23, 24-35, 36-47, 48-59, and 60 years old and older) were collected for a total of 100 samples. The extracted genomic DNA samples were then subjected to telomere length estimation by terminal restriction fragment (TRF) assay. The results showed that the mean TRF length was inversely correlated with age (r = -0.625), and sex did not have a statistically significant influence on the association between age and mean TRF length (P > 0.05). The obtained linear regression equation was y = 113.538 +/- 9.604 - 0.012 * (R = 0.391; P < 0.001). However, the correlation was too low to be used for age estimation with high certainty and a possible reason for this in part would be the postmortem DNA degradation at some level, even using fresh cadaver blood, and other biological factors such as ethnicity and DNA sources. Roughly, those individuals who had a mean TRF length longer than 6.3 kilobase (kb), between 5.5 and 6.3 kb, and shorter than 5.5 kb aged younger than 28 years, 30 to 44 years, and older than 46 years, respectively (P < 0.01). As a preliminary study, this study highlighted that telomere length could act as a useful biomarker of aging in human population and might be used for rough age estimation in a Thai population. However, further studies with a larger sample size and/or in living human bloods as well as other cell types are recommended to support the results of this study. PMID- 24781402 TI - Sudden death from ruptured choroid plexus arteriovenous malformation. AB - Brain vascular malformations are recognized as having potential to produce hemorrhage, but leading to sudden death in children is uncommon. Arteriovenous malformations may be situated in any region of the brain, but very rarely, they can be restricted to the choroid plexus. We report here a rare case of sudden death in a child, caused by a ruptured vascular malformation with an unusual location, which was not identified grossly but only on histological examination. The size and the location of the lesion, as well as the age of our patient, were contributing factors of the massive bleeding. Autopsy remains an important tool because it provides valuable information about the etiology of such bleedings, improves knowledge about these lesions, and enhances epidemiologic data. PMID- 24781403 TI - Synovial fluid: an alternative toxicologic specimen? AB - Although blood is the most commonly used specimen in forensic toxicology, it is not always available. In those cases, alternative samples are sought on which to perform toxicology testing. The current study assessed the usefulness of synovial fluid for postmortem cocaine and opiate/opioid testing. One hundred four cases were sampled, with 98 cases being tested representing 24 negative controls and 74 cases positive for cocaine, benzoylecgonine, morphine, 6-monoacetylmorphine, hydrocodone, and/or oxycodone. Synovium demonstrated excellent correlation and predictability when compared with blood, although it was not as sensitive for 6 monoacetylmorphine as either vitreous or urine. The authors recommend further study to assess the usefulness of synovial fluid in postmortem toxicology to include the evaluation of its utilize for more drugs and the development of further assays to use its potential even in limited quantities. PMID- 24781404 TI - Compression asphyxia in upright suspended position. AB - In compression asphyxia, the respiration is prevented by external pressure on the body. It is usually due to external force compressing the trunk due to heavy weight over chest/abdomen and is associated with internal injuries. In the present case, the victim was suspended in an upright position owing to wedging of the chest and the abdomen in the gap between 2 parallel bridges undergoing construction. There was neither any heavy weight over the body, nor was any external force applied over the trunk. Moreover, there was neither any severe blunt force injury nor any significant pathological natural disease contributing to the cause of death. The body was wedged in the gap between 2 static hard surfaces. The victim was unable to extricate himself from the position owing to impairment of cognitive responses and coordination due to influence of alcohol. The victim died as a result of "static" asphyxia due to compression of the chest and the abdomen. Compression asphyxia in upright suspended position under this circumstance is very rare and not reported previously to the best of our knowledge. PMID- 24781405 TI - Peripheral postmortem redistribution of morphine. AB - It is known that postmortem drug concentrations can vary depending on the sampling site and that, in general, central sites have higher drug concentrations than do peripheral sites. It has also been suggested that clamping the femoral vessel before drawing the sample may eliminate possible contribution from central sites. Morphine is a commonly prescribed and commonly encountered opiate medication that is often found in postmortem examinations, both as a cause of death and also as an incidental finding. It is important to understand the degree of postmortem redistribution of morphine to peripheral sites and whether clamping the femoral vessel can eliminate postmortem redistribution of morphine to ensure the correct interpretation of postmortem morphine concentrations. Morphine drug concentrations were evaluated in clamped and unclamped femoral vein blood samples at 3 different times before autopsy, and no significant change in either the clamped or the unclamped femoral vein morphine concentration was seen over time. Furthermore, no significant difference was found between the clamped and unclamped blood concentrations at any period. Therefore, it can be concluded that for morphine, unclamped femoral blood samples do not show significant redistribution from central sites within the first 24 hours after death in bodies kept refrigerated at 4 degrees C. PMID- 24781406 TI - Fatal gunshot wound to the head with lack of immediate incapacitation. AB - Investigation of deaths caused by penetrating gunshot wounds to the head often raises the possibility of foul play. The forensic pathologist may be asked if the victim was able to perform certain acts after the gunshot, and how quickly this person might have become incapacitated. The possibility of a suicidal act can depend on these answers. We report the case of a 45-year-old woman whose body was found with a right temporal entrance wound. A shotgun was found 60 ft from the body location. The question of knowing if this woman had been able to shoot herself in the head and then walk a distance of 60 ft before dying was essential for the investigation, as suicide was the first hypothesis. The autopsy and a careful neuropathology investigation allowed to answer this question. In the literature, multiple publications report cases of victims who were able to act following penetrating ballistic head injury. PMID- 24781407 TI - An autopsy case of iatrogenic tracheoesophageal fistula secondary to tracheostomy. AB - Tracheoesophageal fistula (TEF) is an uncommon but life-threatening sequel of prolonged use of a cuffed tracheostomy tube. We describe a patient who developed a TEF after a tracheostomy done for management of head injury due to a road traffic mishap. The patient subsequently died of sepsis after bilateral bronchopneumonia. To the best of our knowledge, this is the first autopsy case of iatrogenic TEF after tracheal intubation reported in forensic literature. PMID- 24781408 TI - Crosstalk between adipocytes and immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. AB - Recent findings, notably on adipokines and adipose tissue inflammation, have revised the concept of adipose tissues being a mere storage depot for body energy. Instead, adipose tissues are emerging as endocrine and immunologically active organs with multiple effects on the regulation of systemic energy homeostasis. Notably, compared with other metabolic organs such as liver and muscle, various inflammatory responses are dynamically regulated in adipose tissues and most of the immune cells in adipose tissues are involved in obesity mediated metabolic complications, including insulin resistance. Here, we summarize recent findings on the key roles of innate (neutrophils, macrophages, mast cells, eosinophils) and adaptive (regulatory T cells, type 1 helper T cells, CD8 T cells, B cells) immune cells in adipose tissue inflammation and metabolic dysregulation in obesity. In particular, the roles of natural killer T cells, one type of innate lymphocyte, in adipose tissue inflammation will be discussed. Finally, a new role of adipocytes as antigen presenting cells to modulate T cell activity and subsequent adipose tissue inflammation will be proposed. PMID- 24781410 TI - Patient feedback as a way to improve quality of care. PMID- 24781409 TI - Shear stress and atherosclerosis. AB - Hemodynamic shear stress, the frictional force acting on vascular endothelial cells, is crucial for endothelial homeostasis under normal physiological conditions. When discussing blood flow effects on various forms of endothelial (dys)function, one considers two flow patterns: steady laminar flow and disturbed flow because endothelial cells respond differently to these flow types both in vivo and in vitro. Laminar flow which exerts steady laminar shear stress is atheroprotective while disturbed flow creates an atheroprone environment. Emerging evidence has provided new insights into the cellular mechanisms of flow dependent regulation of vascular function that leads to cardiovascular events such as atherosclerosis, atherothrombosis, and myocardial infarction. In order to study effects of shear stress and different types of flow, various models have been used. In this review, we will summarize our current views on how disturbed flow-mediated signaling pathways are involved in the development of atherosclerosis. PMID- 24781411 TI - Stability and change of ODD, CD and ADHD diagnosis in referred preschool children. AB - Longitudinal studies have shown that preschool children's diagnosis of Oppositional Defiant Disorder (ODD), Conduct Disorder (CD) and Attention Deficit/Hyperactivity Disorder (ADHD) are likely to persist into school age. However, limited attention has been paid to instability of diagnosis. The aim of the present study, therefore, was to investigate both stability and change of ODD, CD and ADHD diagnosis in children aged 3.5-5.5 years. For diagnosing these disorders, a semi-structured diagnostic parent interview, i.e., the Kiddie Disruptive Behavior Disorder Schedule (K-DBDS), was used at the first assessment and at follow-up assessments (9 and 18 months). Five diagnostic stability groups (chronic, partial remission, full remission, new onset, no diagnosis) were compared with regard to impairment and number of symptoms. Participants were referred preschool children with externalizing behavioral problems (N = 193; 83% male) and typically developing (TD) children (N = 58; 71% male). Follow-up assessments allowed to distinguish children belonging to the chronic group of ODD, CD or ADHD from those belonging to one of the remission groups. In addition, there was a substantial number of children with a new onset diagnosis. In conclusion, as a complement to studies showing stability of ODD, CD and ADHD diagnosis into school age, present findings point to changes of diagnosis in the preschool and early school period. Diagnostic reassessments therefore are needed in this age group. PMID- 24781412 TI - Estimating child sleep from parent report of time in bed: development and evaluation of adjustment approaches. AB - OBJECTIVE: To develop and evaluate adjustment factors to convert parent-reported time in bed to an estimate of child sleep time consistent with objective measurement. METHODS: A community sample of 217 children aged 4-9 years (mean age = 6.6 years) wore actigraph wristwatches to objectively measure sleep for 7 days while parents completed reports of child sleep each night. After examining the moderators of the discrepancy between parent reports and actigraphy, 3 adjustment factors were evaluated. RESULTS: Parent report of child sleep overestimated nightly sleep duration by ~24 min per night relative to actigraphy. Child age, gender, and sleep quality all had small or nonsignificant associations with correspondence between parent report and actigraph. Empirically derived adjustment factors significantly reduced the discrepancy between parent report and objective measurement. CONCLUSIONS: Simple adjustment factors can enhance the correspondence and utility of parent reports of child sleep duration for clinical and research purposes. PMID- 24781414 TI - Reply: Regulatory T cells-an important target for cancer immunotherapy. PMID- 24781417 TI - Regulatory T cells-an important target for cancer immunotherapy. PMID- 24781421 TI - Diagnostic and prognostic validity of different biomarkers in patients with suspected myocarditis. AB - BACKGROUND: Myocarditis might be associated with increased markers of myocardial injury. However, data on novel biomarkers, such as high-sensitive Troponin T (hs TnT) or Copeptin, are lacking. This study aimed to determine the diagnostic and prognostic utility of biomarkers in patients with suspected myocarditis. METHODS: Seventy patients with clinically suspected myocarditis (age 43.4 +/- 14 years, 76 % male, ejection fraction 36.9 +/- 17.8) underwent endomyocardial biopsy (EMB) and were followed for 7.5 (2-21) months. At the time of EMB, blood samples to evaluate concentrations of hs-TnT, Copeptin, NT-proBNP and mid-regional pro adrenomedullin (MR-proADM) were collected. RESULTS: According to EMB, 6 patients were diagnosed with acute myocarditis (AM) and 36 patients with chronic myocarditis (CM). In 28 patients, EMB revealed no myocardial inflammation (NM). Acute myocarditis was associated with the highest concentrations of hs-TnT compared to other groups (AM 262.9 pg/ml (61.4-884.2); CM 20.4 pg/ml (15.6-20.4); NM 19.5 pg/ml (13.8-50.7); p < 0.0001). No significant differences existed in the Copeptin, NT-proBNP, and MR-proADM concentrations between the groups. The concentration of hs-TnT was significantly higher in myocarditis when myocardial viral genome was detected (37.4 pg/ml (21.9-163.6) vs. 20 pg/ml (14-44.4); p = 0.042). During follow-up, only NT-proBNP in the highest quartile (>4,225 ng/ml) was predictive for cardiac death or heart transplantation (hazard ratio 9.2; 95% confidence interval 1.7-50; p = 0.011). CONCLUSIONS: Biopsy-proven acute and viral myocarditis is associated with elevated concentrations of hs-TnT. Elevated hs-TnT is highly suggestive of acute myocarditis, if other causes of increased myocardial necrosis markers such as myocardial infarction have been systematically excluded. PMID- 24781423 TI - Reply: GnRH agonist triggering in high-risk patients. PMID- 24781424 TI - GnRH agonist triggering in high-risk patients. PMID- 24781426 TI - High-throughput sperm differential proteomics suggests that epigenetic alterations contribute to failed assisted reproduction. AB - STUDY QUESTION: Are there quantitative alterations in the proteome of normozoospermic sperm samples that are able to complete IVF but whose female partner does not achieve pregnancy? SUMMARY ANSWER: Normozoospermic sperm samples with different IVF outcomes (pregnancy versus no pregnancy) differed in the levels of at least 66 proteins. WHAT IS KNOWN ALREADY: The analysis of the proteome of sperm samples with distinct fertilization capacity using low throughput proteomic techniques resulted in the detection of a few differential proteins. Current high-throughput mass spectrometry approaches allow the identification and quantification of a substantially higher number of proteins. STUDY DESIGN, SIZE, DURATION: This was a case-control study including 31 men with normozoospermic sperm and their partners who underwent IVF with successful fertilization recruited between 2007 and 2008. PARTICIPANTS/MATERIALS, SETTING, METHODS: Normozoospermic sperm samples from 15 men whose female partners did not achieve pregnancy after IVF (no pregnancy) and 16 men from couples that did achieve pregnancy after IVF (pregnancy) were included in this study. To perform the differential proteomic experiments, 10 no pregnancy samples and 10 pregnancy samples were separately pooled and subsequently used for tandem mass tags (TMT) protein labelling, sodium dodecyl sulphate-polyacrylamide gel electrophoresis, liquid chromatography tandem mass spectrometry (LC-MS/MS) identification and peak intensity relative protein quantification. Bioinformatic analyses were performed using UniProt Knowledgebase, DAVID and Reactome. Individual samples (n = 5 no pregnancy samples; n = 6 pregnancy samples) and aliquots from the above TMT pools were used for western blotting. MAIN RESULTS AND THE ROLE OF CHANCE: By using TMT labelling and LC-MS/MS, we have detected 31 proteins present at lower abundance (ratio no pregnancy/pregnancy < 0.67) and 35 at higher abundance (ratio no pregnancy/pregnancy > 1.5) in the no pregnancy group. Bioinformatic analyses showed that the proteins with differing abundance are involved in chromatin assembly and lipoprotein metabolism (P values < 0.05). In addition, the differential abundance of one of the proteins (SRSF protein kinase 1) was further validated by western blotting using independent samples (P value < 0.01). LIMITATIONS, REASONS FOR CAUTION: For individual samples the amount of recovered sperm not used for IVF was low and in most of the cases insufficient for MS analysis, therefore pools of samples had to be used to this end. WIDER IMPLICATIONS OF THE FINDINGS: Alterations in the proteins involved in chromatin assembly and metabolism may result in epigenetic errors during spermatogenesis, leading to inaccurate sperm epigenetic signatures, which could ultimately prevent embryonic development. These sperm proteins may thus possibly have clinical relevance. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Spanish Ministry of Economy and Competitiveness (Ministerio de Economia y Competividad; FEDER BFU 2009-07118 and PI13/00699) and Fundacion Salud 2000 SERONO13-015. There are no competing interests to declare. PMID- 24781425 TI - A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques. AB - STUDY QUESTION: Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? SUMMARY ANSWER: This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. WHAT IS KNOWN ALREADY: The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus-oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. STUDY DESIGN, SIZE, DURATION: First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3-4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3-4 animals/treatment; >=3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests and blood lipid profiles. MAIN RESULTS AND THE ROLE OF CHANCE: Several mRNAs encoding proteins involved in PGE2 synthesis, metabolism and signaling increase (P < 0.05) in the periovulatory follicle after administration of an ovulatory hCG bolus. PGE2 signaling through PTGER2 induces cumulus cell expansion and production of hyaluronic acid, which are critical events for fertilization. Moreover, chronic administration of a selective PTGER2 antagonist resulted in a significant (P < 0.05 versus vehicle-treated controls) contraceptive effect without altering steroid hormone patterns or menstrual cyclicity during a 5 months contraceptive trial. Fertility recovered as early as 1 month after ending treatment. LIMITATIONS, REASONS FOR CAUTION: This is a proof-of-concept study in a non-human primate model. Further investigations are warranted to elucidate the mechanism(s) of PTGER2 antagonist action in the primate ovary. Although PTGER2 antagonist treatment did not produce any obvious undesirable effects, improvements in the mode of administration, as well as the efficacy of these compounds, are necessary to consider such a contraceptive for women. WIDER IMPLICATIONS OF THE FINDINGS: Monitoring as well as improving the efficacy and safety of female contraceptives is an important public health activity. Even though hormonal contraceptives are effective for women, concerns remain regarding their side-effects and long-term use because of the widespread actions of such steroidal products in many tissues. Moreover, some women cannot take hormones for medical reasons. Thus, development of non-hormonal contraceptives for women is warranted. STUDY FUNDING/COMPETING INTEREST(S): Supported by Bayer HealthCare Pharmaceuticals, The Eunice Kennedy Shriver NICHD Contraceptive Development and Research Center (U54 HD055744), NIH Office of the Director (Oregon National Primate Research Center P51 OD011092), and a Lalor Foundation Postdoctoral Basic Research Fellowship (MCP). The use of the Leica confocal was supported by grant number S10RR024585. Some of the authors (N.B., A.R., K.-H.F., U.F., B.B. and B.L.) are employees of Bayer Healthcare Pharma. PMID- 24781427 TI - Individualized embryo transfer training: timing and performance. AB - STUDY QUESTION: How long is the individualized training and the stability of competence for the embryo transfer (ET) technique? SUMMARY ANSWER: The embryo transfer technique is easy-to-learn, hardly unlearned, and training should be individualized by monitoring with learning curve-cumulative summation (LC-CUSUM) curves. WHAT IS KNOWN ALREADY: Like many medical procedures, embryo transfer is an operator-dependent technique. Individualized or standardized training of these medical procedures should be monitored to determine when competence is acquired. STUDY DESIGN, SIZE, DURATION: This prospective, monocentric study involving five embryo transfer trainees was carried out between August 2011 and November 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was carried out in a large private clinic. Five gynaecologist trainees during their first year of assisted reproduction subspecialty performed embryo transfer for patients undergoing either fresh IVF, oocyte donor IVF, or frozen embryo transfer. There were 586 embryo transfers performed in 96 sessions of 3-10 embryo transfers each. An embryo transfer was considered successful if it gave rise to a positive pregnancy test 14 days later. LC-CUSUM and cumulative summation (CUSUM) curves were used to determine when competence was acquired and whether it was maintained over time, respectively. The length of time between two consecutive sessions was assessed for an effect on consolidation of the acquired competence. MAIN RESULTS AND THE ROLE OF CHANCE: We observed that all five trainees became proficient in embryo transfer by procedure 15 (after procedure 15, 9, 7, 13 and 9, respectively). Once competence was achieved, one of the five trainees showed a loss of proficiency. After having acquired competence, the median pregnancy rate per embryo transfer session was significantly lower when the interval between consecutive embryo transfer sessions was >=10 days compared with <10 days (20.0 versus 46.7%; P = 0.006). LIMITATIONS, REASONS FOR CAUTION: The patient groups included in the study were heterogeneous (IVF, oocyte donor IVF and frozen embryo transfer) and their outcomes are very variable; thus the distribution and proportion of these groups can determine the timing of competence acquisition. Our data show that low numbers of embryo transfer are needed to acquire competence, but since a relative high percentage of embryo transfers in our practice are from oocyte donor IVF, extrapolation of the findings to other clinical context should be done with caution. WIDER IMPLICATIONS OF THE FINDINGS: Personalized embryo transfer training is feasible and useful, allowing clinics, on one hand, to offer a maximum chances of pregnancy with fully trained personnel, and the other hand, to avoid the superfluous and costly overtraining of already proficient trainees. Furthermore, it is advisable to maintain a short interval of time between consecutive embryo transfer sessions after a trainee has acquired competence, to avoid a significant drop in the resulting pregnancy rate. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by funding from Fundacio Privada EUGIN. There are no conflicts of interest to declare. PMID- 24781429 TI - Adherence to reporting guidelines in observational studies concerning exposure to persistent organic pollutants and effects on semen parameters. AB - STUDY QUESTION: Are studies on semen quality in men exposed to persistent pesticides reported according to the 'strengthening the reporting of observational studies in epidemiology' (STROBE) recommendations and the guidelines for the appraisal of semen quality studies (SEMQUA)? SUMMARY ANSWER: Most studies of the impact of pesticides on semen quality do not follow the STROBE and SEMQUA guidelines, thus adherence is low, especially in methodological aspects. WHAT IS KNOWN ALREADY: Much of the controversy about reduced semen quality in recent decades arises from a lack of standardization in the methodology applied, despite the existence of several validated instruments for evaluating the quality of reporting. Indeed, SEMQUA was purpose-designed for the particular characteristics of semen quality studies. STUDY DESIGN, SIZE, DURATION: A structured literature search identified eligible articles reporting on persistent pesticides and human semen quality, published in English before 1 September 2012. Opinion articles and reviews were excluded. We assessed the adherence to reporting guidelines of the articles, using and comparing the STROBE statement and the SEMQUA guidelines, in both cases with indicators relevant to observational studies of semen quality. PARTICIPANTS/MATERIALS, SETTING, METHODS: A comprehensive bibliographic search in various electronic literature databases using the key words 'sperm' and 'pesticide' obtained 1179 papers, of which 46 were valid for our purposes. The papers examined occupational (26) and environmental exposure (20). Two of the present authors independently piloted the data extraction form for this review. The articles were then evaluated by two researchers using the STROBE and SEMQUA checklists. MAIN RESULTS AND THE ROLE OF CHANGE: Although no significant differences were found between the overall degree of compliance with STROBE and SEMQUA (47.0 +/- 18.5% versus 43.1 +/- 11.6%), there were significant differences when only methodological aspects were considered (48.4 +/- 21.0% versus 39.5 +/- 17.4%; P < 0.001). We observed an increase over time in the degree of compliance, for SEMQUA (r = 0.61 and P < 0.001) and STROBE (r = 0.45 and P < 0.01). The papers that reported a negative effect of exposure to persistent pesticides on sperm concentration presented a lower level of compliance to SEMQUA (42.1 +/- 18.3% versus 57.6 +/- 14.2%; P < 0.01) and STROBE (40.2 +/- 10.3% versus 49.5 +/- 11.6%; P < 0.05) than those which recorded no such influence. The year of publication and the observed effect on sperm concentration were the only candidate variables included in the model of stepwise multiple regression model for the 'degree of compliance' variables of SEMQUA and STROBE. LIMITATIONS, REASONS FOR CAUTION: Other characteristics of reporting quality, such as legibility, were not evaluated. WIDER IMPLICATIONS OF THE FINDINGS: The low degree of compliance observed is consistent with that observed in other studies of reproductive medicine and highlights the need to improve the design of studies of semen quality. SEMQUA proved to be a more specific tool than STROBE for the field of semen quality. Editors, reviewers and authors should be aware of SEMQUA and apply it when assessing papers on semen quality. STUDY FUNDING/COMPETING INTEREST(S): No research funding was received and none of the authors have any conflict of interests. PMID- 24781428 TI - Phthalate exposure and pubertal development in a longitudinal study of US girls. AB - STUDY QUESTION: Does phthalate exposure during early childhood alter the timing of pubertal development in girls? SUMMARY ANSWER: Urinary concentrations of high molecular weight phthalate (high-MWP) metabolites are associated with later pubarche. WHAT IS KNOWN ALREADY: Phthalates are anti-androgenic environmental agents known to alter early development, with possible effects on pubertal onset. STUDY DESIGN, SIZE, AND DURATION: This multi-ethnic study included 1239 girls from New York City, greater Cincinnati, and the San Francisco Bay Area who were 6 8 years old at enrollment (2004-2007) and who were followed until 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS Phthalate metabolites were measured in urine collected at enrollment from 1170 girls; concentrations ranged from <1 to >10,000 ug/l. Breast and pubic hair stages and body size were assessed one to two times annually to determine the age at transition from stage 1 to 2 for breast and pubic hair development. Associations between exposures and pubertal ages were estimated using Cox proportional hazard ratios (HR) with 95% confidence intervals (CI) and survival analyses. Associations were examined with respect to age specific body mass-index percentile, one of the strongest predictors of pubertal onset. MAIN RESULTS AND THE ROLE OF CHANCE: Urinary concentrations of high-MWP including di(2-ethylhexyl) phthalate (SigmaDEHP) metabolites were associated with later pubic hair development during 7 years of observation. The relationship was linear and was stronger among normal-weight girls. Among normal-weight girls, age at pubic hair stage 2 (PH2) was 9.5 months older for girls in the fifth compared with the first quintile of urinary SigmaDEHP (medians: 510 and 59 ug/g creatinine, respectively; adjusted HR 0.70, CI 0.53-0.93, P-trend 0.005. Age at first breast development was older for fifth quintile of mono-benzyl phthalate versus first (HR 0.83, CI 0.68-1.02; P-trend 0.018). No associations were observed between low-molecular weight phthalate urinary metabolite concentrations and age at pubertal transition in adjusted analyses. LIMITATIONS, REASONS FOR CAUTION: While there is evidence that phthalate exposures are fairly consistent over time, the exposure measure in this study may not reflect an earlier, more susceptible window of exposure. We investigated alternative explanations that might arise from exposure misclassification or confounding. WIDER IMPLICATIONS OF THE FINDINGS: Phthalates are widespread, hormonally active pollutants that may alter pubertal timing. Whether exposures delay or accelerate pubertal development may depend on age at exposure as well as other factors such as obesity and exposures earlier in life. Whether exposures act independently or as part of real life mixtures may also change their effects on maturation from birth through childhood. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the US National Institutes of Health, Environmental Protection Agency, New York State Empire Clinical Research Investigator Program and the Avon Foundation. L.H.K. is employed by Kaiser Permanente. The remaining authors declare they have no actual or potential competing financial interests. PMID- 24781430 TI - A population-based cohort study of the effect of Caesarean section on subsequent fertility. AB - STUDY QUESTION: Is there an association between Caesarean section and subsequent fertility? SUMMARY ANSWER: There is no or only a slight effect of Caesarean section on future fertility. WHAT IS KNOWN ALREADY: Previous studies have reported that delivery by a Caesarean section is associated with fewer subsequent pregnancies and longer inter-pregnancy intervals. The interpretation of these findings is difficult because of significant weaknesses in study designs and analytical methods, notably the potential effect of the indication for Caesarean section on subsequent delivery. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 1 047 644 first births to low-risk women using routinely collected, national administrative data of deliveries in English maternity units between 1 April 2000 and 31 March 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Primiparous women aged 15-40 years who had a singleton, term, live birth in the English National Health Service were included. Women with high-risk pregnancies involving placenta praevia, pre-eclampsia, eclampsia (gestational or pre existing), hypertension or diabetes were excluded from the main analysis. Kaplan Meier analyses and Cox proportional hazard models were used to assess the effect of mode of delivery on time to subsequent birth, adjusted for age, ethnicity, socio-economic deprivation and year of index delivery. MAIN RESULTS AND THE ROLE OF CHANCE: Among low-risk primiparous women, 224 024 (21.4%) were delivered by Caesarean section. The Kaplan-Meier estimate of the subsequent birth rate at 10 years for the cohort was 74.7%. Compared with vaginal delivery, subsequent birth rates were marginally lower after elective Caesarean for breech (adjusted hazard ratio, HR 0.96, 95% CI 0.94-0.98). Larger effects were observed after elective Caesarean for other indications (adjusted HR 0.81, 95% CI 0.78-0.83), and emergency Caesarean (adjusted HR 0.91, 95% CI 0.90-0.93). The effect was smallest for elective Caesarean for breech, and this was not statistically significant in women younger than 30 years of age (adjusted HR 0.98, 95% CI 0.96-1.01). LIMITATIONS, REASONS FOR CAUTION: We used birth cohorts from maternity units with good quality parity information. The data are likely to be nationally representative because the characteristics of the deliveries in included and omitted units were similar. There may be residual bias in our adjusted results due to unmeasured maternal factors such as obesity and voluntary absence of conception. Any residual bias would lead to an overestimate of the effect of Caesarean section on fertility, and the true effect is therefore likely to be smaller than the effect reported in our study. WIDER IMPLICATIONS OF THE FINDINGS: Our results provide strong evidence that there is no or only a slight effect of Caesarean section on future fertility. The clinical and social circumstances leading to the Caesarean section have a greater effect on future fertility than the Caesarean section itself. This finding is important in light of rising Caesarean section rates. STUDY FUNDING/COMPETING INTEREST(S): IG-U is supported by the Lindsay Stewart R&D Centre, Royal College of Obstetricians and Gynaecologists, UK. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: n/a. PMID- 24781432 TI - Towards graphene bromide: bromination of graphite oxide. AB - Halogenated graphene derivatives are interesting for their outstanding physical and chemical properties. In this paper, we present various methods for the synthesis of brominated graphene derivatives by the bromination of graphite oxides. Graphite oxides, prepared according to either the Hummers or Hofmann method, were brominated using bromine or hydrobromic acid under reflux or in an autoclave at elevated temperatures and pressures. The influence of both graphite oxide precursors on the resulting brominated graphenes was investigated by characterization of the graphenes, which was carried out using various techniques, including SEM, SEM-EDS, high-resolution XPS, FTIR, STA and Raman spectroscopy. In addition, the resistivity of the brominated graphenes was measured and the electrochemical properties were investigated by cyclic voltammetry. Although the brominated graphenes were structurally similar, they had remarkably different bromine concentrations. The most highly brominated graphene (bromine concentration above 26 wt%) exhibited a C/O ratio above 44 and partial hydrogenation. Brominated graphenes with such properties could be used for reversible bromine storage or as a starting material for further chemical modifications. PMID- 24781431 TI - Trends in children's exposure to violence, 2003 to 2011. AB - IMPORTANCE: The study suggests that years of public policy designed to reduce the burden of violence and victimization among youths is having some success. OBJECTIVE: To identify trends in children's exposure to violence, crime, and abuse from 2003 through 2011. DESIGN, SETTING, AND PARTICIPANTS: Three national telephone surveys of representative samples of children and caregivers from 2003, 2008, and 2011 were compared, all obtained using the Juvenile Victimization Questionnaire; samples included parents of children 2 to 9 years old and youth 10 to 17 years old. EXPOSURES: Direct and indirect experiences of violence, abuse, and victimization during the previous year. MAIN OUTCOMES AND MEASURES: Change in rates between 2003 and 2011 and between 2008 and 2011. RESULTS: Of 50 trends in exposure examined, there were 27 significant declines and no significant increases between 2003 and 2011. Declines were particularly large for assault victimization, bullying, and sexual victimization. There were also significant declines in the perpetration of violence and property crime. For the recession period between 2008 and 2011, there were 11 significant declines and no increases for 50 specific trends examined. Dating violence declined, as did one form of sexual victimization and some forms of indirect exposure. CONCLUSIONS AND RELEVANCE: Victimization surveys with general population samples confirm patterns seen in police data and adult surveys. Crime and violence have been declining in the child and youth population as well. PMID- 24781433 TI - Higher sweat chloride levels in patients with asthma: a case-control study. AB - OBJECTIVES: To screen asthmatic patients by sweat chloride test to identify proportion with Cystic Fibrosis (CF); (Sweat chloride level >60 mmol/L). Also, to compare sweat chloride levels between cases of bronchial asthma and age and sex matched healthy children aged 5 mo-15 y. METHODS: The present case-control study was conducted in a tertiary care hospital in India. Cases of bronchial asthma, diagnosed by GINA guideline 2008, and age matched healthy controls were included. Case to control ratio was 2:1. Sweat Chloride test was done by Pilocarpine Iontophoresis method. RESULTS: From April 2010 through May 2012, 216 asthmatics and 112 controls were recruited. Among asthmatics, there was no case of Cystic Fibrosis. Mean sweat chloride levels in asthmatics was 22.39 +/- 8.45 mmol/L (inter-quartile range - 15-28 mmol/L) and in controls 19.55 +/- 7.04 mmol/L (inter-quartile range - 15-23.5 mmol/L) (p value = 0.048). CONCLUSIONS: No Cystic Fibrosis case was identified among asthmatics. Mean sweat chloride levels were higher in asthmatics as compared to controls. PMID- 24781434 TI - Effect of delayed cord clamping on hemoglobin level of newborns. PMID- 24781435 TI - The multiple mechanistic faces of a pure volume overload: implications for therapy. AB - : Mitral regurgitation and other conditions marked by a pure isolated volume overload (VO) of the heart result in a progressive form of eccentric left ventricular remodeling and dysfunction. As opposed to the more extensively studied pressure overload, there are no approved medical therapies because an understanding of the underlying pathological mechanisms at work in VO is lacking. Over the past 20 years, our laboratory has identified multiple key biological functions involved in the pathological remodeling in VO. Specifically, we have noted perturbed matrix homeostasis, detrimental adrenergic signaling, increased intracellular reactive oxygen species and an intense inflammatory response that implicates mast cells and their product chymase, which seems to cause extensive remodeling both inside and outside the cardiomyocyte. How these multiple pathways intersect over the course of VO and their response to various single and combined interventions are now the subject of intense investigation. PMID- 24781436 TI - Intractable ascites, changes in serum vascular endothelial growth factor levels and thalidomide treatment in POEMS syndrome. PMID- 24781437 TI - Selective serotonin reuptake inhibitors exposure during pregnancy and neonatal outcomes. PMID- 24781438 TI - Paradoxes of US psychopharmacology practice in 2013: undertreatment of severe mental illness and overtreatment of minor psychiatric problems. PMID- 24781439 TI - Sexual dysfunction in clinically stable patients with bipolar disorder receiving lithium. AB - There is limited data on the prevalence of sexual dysfunction in patients with bipolar disorder receiving lithium. This study aimed to evaluate the prevalence of sexual dysfunction in patients with bipolar disorder receiving lithium and to study the correlates of sexual dysfunction. One hundred clinically stable patients with bipolar disorder (Global Assessment for Functioning score of >70, Hamilton Depression Rating Scale score of <=7 and Young Mania Rating Scale score of <=7, and no change in medications at least in the last 3 months) receiving lithium were evaluated on Arizona Sexual Experience Scale and Brief Adherence Rating Scale. The mean age of study sample was 44.3 years. The mean Hamilton Depression Rating Scale score was 1.06 (SD, 1.7) and the mean Young Mania Rating Scale score was 0.1 (SD, 0.5) and the mean Global Assessment for Functioning scale score was 84 (SD, 6.0). The mean duration of lithium use was approximately 119.62 (SD, 99.6) months, and the mean dose of lithium was 799.5 (SD, 251.4) mg/d. Of the 100 patients, approximately one third of the patients (n = 37) were found to have sexual dysfunction as per Arizona Sexual Experience Scale. Compared with those without sexual dysfunction, those with sexual dysfunction were older (t value = 3; P = 0.003). Those with sexual dysfunction had lower level of functioning (Global level of functioning score of 81.7 vs 85.5; t value = 3.2; P = 0.002), higher number of other adverse effects with lithium (total number of other adverse effects, 2.9 vs 1.4; t value = 4.2; P < 0.001), and poor medication compliance. To conclude, the present study suggests that approximately one third of the patients receiving lithium experience sexual dysfunction, and it is associated with poor medication adherence. PMID- 24781440 TI - Amenorrhea associated with duloxetine: two case reports. PMID- 24781441 TI - Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia. AB - We compared long-term treatment effectiveness of monthly olanzapine long-acting injection (LAI) with that of oral olanzapine. Outpatients with 2 or more episodes of psychotic worsening in the past 24 months with Positive and Negative Syndrome Scale total score of lower than 70 were randomized to 405 mg/4 weeks of olanzapine LAI (n = 264) or 10 mg/d of oral olanzapine (n = 260) for 2 years of open-label treatment. Dosing thereafter was flexible (150-405 mg/4 weeks of LAI vs 5-20 mg/d of oral). Primary outcome was time to all-cause discontinuation. At baseline, patients were clinically stable (mean Positive and Negative Syndrome Scale total score of 57). Seventeen percent of patients had been psychiatrically hospitalized in the previous 6 months, and 4.6% were rated nonadherent in the month before study entry. The groups did not differ significantly in median time to all-cause discontinuation (645 days for LAI, 678 days for oral; P = 0.61), discontinuation rate (53.8% for LAI, 51.2% for oral; P = 0.60), or relapse rate (20.1% for LAI, 18.5% for oral; P = 0.66). Postbaseline psychiatric hospitalization rate was low for both groups (7.6% for LAI, 9.2% for oral), but mean hospitalization duration was significantly longer for oral patients (1.80 days [20 for those hospitalized] vs 0.43 days [6 for those hospitalized], P = 0.02). There were no clinically significant group differences in adverse events or safety measures. No post-injection delirium/sedation syndrome events occurred. In conclusion, olanzapine LAI and oral olanzapine were similarly effective and well tolerated for up to 2 years of treatment in patients with schizophrenia. Treatment discontinuation for olanzapine LAI was similar to that of oral olanzapine, despite the 3-hour post-injection observation period and other precautionary procedures related to risk of post-injection delirium/sedation syndrome. PMID- 24781442 TI - Dose and dosing frequency of long-acting injectable antipsychotics: a systematic review of PET and SPECT data and clinical implications. AB - Brain imaging data of antipsychotics have mainly been derived from oral antipsychotic drugs, which hampers our understanding of the requirement of dose/dosing frequency of long-acting injectable (LAI) antipsychotics for the maintenance treatment of schizophrenia. A systematic literature search was performed to identify positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies that assessed dopamine D2 receptor occupancy levels with LAI antipsychotic drugs in humans, using PubMed, EMBASE, and PsycINFO (last search, February 2013). Twenty studies (15 PET and 5 SPECT studies) were identified. The most investigated drug in these PET and SPECT studies was haloperidol decanoate (44 subjects; 11 studies), followed by risperidone LAI (24 subjects; 3 studies), olanzapine pamoate (14 subject; 1 study), and fluphenazine decanoate (12 subjects; 3 studies). The data have demonstrated high and continuous D2 receptor blockade with LAIs; the effects of LAI first-generation antipsychotics on the central nervous system may persist for several months. The prospective and cross-sectional studies showed that continuous dopamine D2 receptor blockade above 65% (ie, the lower end of the established therapeutic window for the acute phase treatment) was not always necessary for maintenance treatment for at least some of the patients. In conclusion, because of the limited brain imaging data on LAI antipsychotics, we still do not know the best way to dose them. Still, the currently available brain imaging data raises a possibility that the dosing interval of LAI antipsychotics may be extended beyond the currently indicated range in some patients. PMID- 24781443 TI - Generation of 10(20) W cm(-2) hard X-ray laser pulses with two-stage reflective focusing system. AB - Intense X-ray fields produced with hard X-ray free-electron laser (XFEL) have made possible the study of nonlinear X-ray phenomena. However, the observable phenomena are still limited by the power density. Here, we present a two-stage focusing system consisting of ultra-precise mirrors, which can generate an extremely intense X-ray field. The XFEL beam, enlarged with upstream optics, is focused with downstream optics that have high numerical aperture. A grating interferometer is used to monitor the wavefront to achieve optimum focusing. Finally, we generate an extremely small spot of 30 * 55 nm with an extraordinary power density of over 1 * 10(20) W cm(-2) using 9.9 keV XFEL light. The achieved power density provides novel opportunities to elucidate unexplored nonlinear phenomena in the X-ray region, which will advance development on quantum X-ray optics, astronomical physics and high-energy density science. PMID- 24781444 TI - Genetic variability of porcine circovirus 2 in vaccinating and non-vaccinating commercial farms. AB - Vaccines against porcine circovirus 2 (PCV2) are now widely used to control the diseases caused by the virus. Although the vaccines protect pigs against the disease, they do not lead to sterilizing immunity and therefore infections with PCV2 continue in farms. It is expected that, due to its high evolutionary rate, PCV2 can adapt quickly to environmental pressures such as vaccination. The goal of this study was to elucidate the molecular variation of PCV2 in relation to vaccination. PCV2 variability was investigated from samples of infected pigs from five farms where vaccination had never been applied and two farms where pigs had been vaccinated for at least 2 years. For the genetic analysis, full PCV2 genomes were amplified and subsequently pooled by vaccination status from serum of eight vaccinated, infected pigs and 16 non-vaccinated, infected pigs. Variability of viral populations was quantified using next-generation sequencing and subsequent bioinformatics analysis. The number of segregating sites was similar in the non vaccinated (n=109) and vaccinated pools (n=96), but the distribution of these sites in the genome differed. Most notably, in the capsid gene, the number of segregating sites was observed only in the non-vaccinated population. Based on the structural analysis, it is expected that some low-frequency amino acids result in biologically low-fit viruses. On the contrary, D294 in replicase represents a novel amino acid which was dominant and unique in the vaccinated pool. This work showed that variable PCV2 populations were circulating in commercial farms, and that this variability was different in samples obtained from vaccinating and non-vaccinating farms. PMID- 24781445 TI - Chinese herbal medicine suppresses invasion-promoting capacity of cancer associated fibroblasts in pancreatic cancer. AB - Pancreatic cancer remains one of the leading causes of cancer-related deaths, due to aggressive growth, high metastatic rates during the early stage and the lack of an effective therapeutic approach. We previously showed that Qingyihuaji (QYHJ), a seven-herb Chinese medicine formula, exhibited significant anti-cancer effects in pancreatic cancer, associated with modifications in the tumor microenvironment, particularly the inhibition of cancer-associated fibroblast (CAF) activation. In the present study, we generated CAF and paired normal fibroblast (NF) cultures from resected human pancreatic cancer tissues. We observed that CAFs exhibited an enhanced capacity for inducing pancreatic cancer cell migration and invasion compared with NFs, while QYHJ-treated CAFs exhibited decreased migration and invasion-promoting capacities in vitro. The results of further analyses indicated that compared with NFs, CAFs exhibit increased CXCL1, 2 and 8 expression, contributing to the enhanced invasion-promoting capacities of these cells, while QYHJ treatment significantly suppressed CAF proliferation activities and the production of CAF-derived CXCL1, 2 and 8. These in vitro observations were confirmed in mice models of human pancreatic cancer. Taken together, these results suggested that suppressing the tumor-promoting capacity of CAFs through Chinese herbal medicine attenuates pancreatic cancer cell invasion. PMID- 24781447 TI - Gray matter abnormalities in childhood maltreatment: a voxel-wise meta-analysis. AB - OBJECTIVE: Childhood maltreatment acts as a severe stressor that produces a cascade of physiological and neurobiological changes that lead to enduring alterations in brain structure. However, structural neuroimaging findings have been inconsistent. The authors conducted a meta-analysis of published whole-brain voxel-based morphometry studies in childhood maltreatment to elucidate the most robust volumetric gray matter abnormalities relative to comparison subjects to date. METHOD: Twelve data sets were included, comprising 331 individuals (56 children/adolescents and 275 adults) with a history of childhood maltreatment and 362 comparison subjects (56 children/adolescents and 306 adults). Anisotropic effect size-signed differential mapping, a voxel-based meta-analytic method, was used to examine regions of smaller and larger gray matter volumes in maltreated individuals relative to comparison subjects. RESULTS: Relative to comparison subjects, individuals exposed to childhood maltreatment exhibited significantly smaller gray matter volumes in the right orbitofrontal/superior temporal gyrus extending to the amygdala, insula, and parahippocampal and middle temporal gyri and in the left inferior frontal and postcentral gyri. They had larger gray matter volumes in the right superior frontal and left middle occipital gyri. Deficits in the right orbitofrontal-temporal-limbic and left inferior frontal regions remained in a subgroup analysis of unmedicated participants. Abnormalities in the left postcentral and middle occipital gyri were found only in older maltreated individuals relative to age-matched comparison subjects. CONCLUSIONS: The findings demonstrate that the most consistent gray matter abnormalities in individuals exposed to childhood maltreatment are in relatively late-developing ventrolateral prefrontal-limbic-temporal regions that are known to mediate late-developing functions of affect and cognitive control, which are typically compromised in this population. PMID- 24781446 TI - The influence of ezetimibe on classical and alternative activation pathways of monocytes/macrophages isolated from patients with hypercholesterolemia. AB - Macrophages are crucial for the development of atherosclerotic plaques. Classically activated macrophages contribute to plaque growth and destabilization, while alternatively activated macrophages increase plaque stability. Here, we assessed the influence of ezetimibe on the activation of monocyte-derived macrophages isolated from patients with hypercholesterolemia (total cholesterol 263.4 +/- 12.5 mg/dl, low-density lipoprotein cholesterol 179.7 +/- 11.3 mg/dl, triglycerides 123.9 +/- 11.4 mg/dl). Cells were stimulated with 1 MUg/ml lipopolysaccharide (LPS) or 1 MUg/ml LPS plus 22 ng/ml ezetimibe. Control cells were left unstimulated. The expression of classical activation markers (interleukin-1beta (IL-1beta), nitric oxide (NO), and inducible nitric oxide synthase (iNOS)) and alternative activation markers (mannose receptor (MR) and arginase-1 (Arg1)) was determined after 48 h. The employed analytical methods included enzyme-linked immunosorbent assay, Griess reaction, real-time polymerase chain reaction, and Western blotting. LPS increased the secretion of IL-1beta and NO and the expression of iNOS mRNA, iNOS protein, and Arg1 protein. It did not affect the expression of MR or Arg1 mRNA. In comparison to LPS stimulation, co stimulation with ezetimibe decreased the secretion of IL-1beta and the expression of iNOS mRNA and protein, while it increased MR mRNA and protein expression. Co stimulation with ezetimibe did not change the secretion of NO or the expression of Arg1. The results suggest that ezetimibe in inflammatory in vitro conditions contributes to the suppression of classical and promotion of the alternative macrophage activation. PMID- 24781448 TI - Polycatenar pyrazole and pyrazolate ligands as building blocks of new columnar Pd(II) metallomesogens. AB - Dicatenar pyridine-functionalised pyrazole ligands [Hpz(R(n,n)py)] (R(n,n) = C6H3(OCnH2n+1)2, n = 4, 6, 8, 10, 12, 14, 16, 18) have been strategically synthesised to be used as new building blocks for designing discotic liquid crystalline materials. Their coordination to Pd(II) fragments has allowed to achieve two novel families of metallomesogens, [Pd(pz(R(n,n)py))2] () and [PdCl2(Hpz(R(n,n)py))] (), in which the ligand is coordinated in the anionic form as pyrazolate or in the neutral form as pyrazole, respectively. Thermal studies showed that the ligands with n = 14 and 16 carbon atoms, as well as all the palladium complexes, display discotic mesophases in the temperature range of 68 141 degrees C. The results indicate that the coordination environment around the metal is a determining factor which allows control of the supramolecular arrangement of the mesophase. Disc-like molecules from complexes pack themselves into cylindrical structures that result in hexagonal columnar phases (Colh), while the half-disc shaped molecules from self-assemble into a layer with an antiparallel dimeric disposition which generates lamellar columnar phases (ColL). Schematic models based on X-ray powder diffraction (XRD) experiments are proposed to illustrate the molecular organisation of these Pd metallomesogens in the columnar mesophases. PMID- 24781450 TI - Hypertriglyceridemia and hyperglycemia induced by capecitabine: a report of two cases and review of the literature. AB - BACKGROUND: Capecitabine is a tumor-activated oral fluoropyrimidine used in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature. METHODS: Two patients with colorectal carcinoma who developed capecitabine-induced hypertriglyceridemia (including a patient who developed hyperglycemia concurrently) were described, treatment modalities were discussed, and the literatures were reviewed. RESULTS: The first patient, a 43-year-old man, developed hyperlipidemia and hyperglycemia after two cycles of XELOX regimen chemotherapy for colorectal cancer. His triglyceride was 2.47 mmol/L (normal range 0.34-1.7 mmol/L) and total cholesterol was 6.93 mmol/L (normal range 3.12-5.9 mmol/L), while blood glucose was abnormal (fasting blood glucose was 10.58-11.9 mmol/L and 2 h postprandial glucose was 14.5-17.2 mmol/L) and glucose was positive in the urine(3+). The second patient, a 47-year-old woman, developed abnormalities in the lipid profile after the sixth cycle of XELOX regimen chemotherapy for colorectal cancer. Her serum triglyceride was 2.41 mmol/L (normal range 0.34-1.7 mmol/L), while the cholesterol level was 7.73 mmol/L (normal range 3.12-5.9 mmol/L). The profile of lipid improved gradually with reduced doses of capecitabine and was well restored after chemotherapy without any lipid-lowering agents. The Naranjo score for capecitabine-induced hypertriglyceridemia was 9 (definite). An analysis of the underlying pathogenic mechanisms was provided. CONCLUSION: It is important of physicians and pharmacists to be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia induced by capecitabine. PMID- 24781449 TI - Essential role of TEA domain transcription factors in the negative regulation of the MYH 7 gene by thyroid hormone and its receptors. AB - MYH7 (also referred to as cardiac myosin heavy chain beta) gene expression is known to be repressed by thyroid hormone (T3). However, the molecular mechanism by which T3 inhibits the transcription of its target genes (negative regulation) remains to be clarified, whereas those of transcriptional activation by T3 (positive regulation) have been elucidated in detail. Two MCAT (muscle C, A, and T) sites and an A/T-rich region in the MYH7 gene have been shown to play a critical role in the expression of this gene and are known to be recognized by the TEAD/TEF family of transcription factors (TEADs). Using a reconstitution system with CV-1 cells, which has been utilized in the analysis of positive as well as negative regulation, we demonstrate that both T3 receptor (TR) beta1 and alpha1 inhibit TEAD-dependent activation of the MYH7 promoter in a T3 dose dependent manner. TRbeta1 bound with GC-1, a TRbeta-selective T3 analog, also repressed TEAD-induced activity. Although T3-dependent inhibition required the DNA-binding domain (DBD) of TRbeta1, it remained after the putative negative T3 responsive elements were mutated. A co-immunoprecipitation study demonstrated the in vivo association of TRbeta1 with TEAD-1, and the interaction surfaces were mapped to the DBD of the TRbeta1 and TEA domains of TEAD-1, both of which are highly conserved among TRs and TEADs, respectively. The importance of TEADs in MYH7 expression was also validated with RNA interference using rat embryonic cardiomyocyte H9c2 cells. These results indicate that T3-bound TRs interfere with transactivation by TEADs via protein-protein interactions, resulting in the negative regulation of MYH7 promoter activity. PMID- 24781451 TI - Tolerability of Velcade (Bortezomib) subcutaneous administration using a maximum volume of 3 mL per injection site. AB - Subcutaneous injection is now commonly used as a standard for bortezomib administration. The bortezomib (Velcade((r))) product monograph recommends that intravenous injections be prepared at a concentration of 1 mg/mL, while subcutaneous injections may be prepared at a concentration of 2.5 mg/mL. Many institutions and subcutaneous administration guidelines use 2 mL as the maximum volume for subcutaneous injection. Using 2 mL as the maximum volume for injection would mean that many patients receiving bortezomib will receive two injections during each visit with common dosing parameters. In this prospective study evaluating a change to subcutaneous administration, bortezomib 1 mg/mL was administered subcutaneously at a higher maximum of 3 mL per injection site. For 57 individual patients, 339 doses were administered. Skin reactions were noted in 42% with all reactions being Grade 1 or 2. Patients tolerated subcutaneous injections well and only four patients were switched back to intravenous route. This is the first time that subcutaneous bortezomib of a volume up to a maximum of 3 mL (bortezomib 3 mg) per injection site has been reported. This higher single dose is well tolerated with limited skin reactions, no significant hypotension and facilitates ease of administration with only 5 patients needing two injections per visit. If the maximum volume for injection was kept at 2 mL, a total of 46 patients would have received two injections per visit. PMID- 24781453 TI - Safety of inadvertent administration of overdose of intrathecal Cytarabine in a pediatric patient. AB - PURPOSE: To describe a medication error of intrathecal Cytarabine overdose that was managed conservatively with no apparent toxicities. SUMMARY: An 11-year-old girl was diagnosed with bone marrow relapsed precursor B-cell acute lymphoblastic leukemia. According to her chemotherapy protocol, she was started on triple intrathecal chemotherapy consisting of Methotrexate, Cytarabine and Hydrocortisone on day 1 of the protocol. After the intrathecal therapy being administered to the patient, the pharmacist who checked the medication realized that the wrong formulation of Cytarabine was used to prepare the intrathecal therapy; this error resulted in five times overdose of Cytarabine. The patient was then managed conservatively without cerebrospinal fluid exchange. Our patient remained clinically and neurologically stable without apparent toxicities and was discharged safely from hospital. CONCLUSION: Supportive care without the need for invasive procedures such as cerebrospinal fluid exchange may be adequate for managing intrathecal Cytarabine overdose. PMID- 24781452 TI - Evaluating the effectiveness and safety of hydrocortisone therapy in cancer patients with septic shock. AB - PURPOSE: To evaluate the effectiveness and safety of hydrocortisone (HC) in cancer patients with septic shock. METHODS: This was a retrospective study of adult cancer patients with septic shock who received low-dose HC therapy (200 mg/day). The effectiveness of HC was assessed by determining the proportion of patients with reversal of septic shock, time to reversal, and mortality. The safety was assessed by determining the incidences of hyperglycemia, hypernatremia, and secondary infections, using a case-control approach. RESULTS: During the study period, 96 patients were enrolled. Reversal of septic shock was reported in 46 (47.9%) patients, median time to reversal was 1.9 days (range 0.2 7.6), ICU mortality was reported in 62 (65.26%) patients, and 28-day mortality in 64 (66.7%) patients. The incidence of secondary infections was higher in patients who received HC therapy, compared to patients who did not receive HC during septic shock: 44.8% vs 27.4%, P = 0.028. CONCLUSIONS: HC therapy was associated with resolution of septic shock in about half of the patients and a high incidence of secondary infections. Prospective studies are needed to fully assess the efficacy and safety of HC in cancer patients with septic shock. PMID- 24781454 TI - The role of demineralized allograft subchondral bone in the treatment of talar cystic OCD lesions that have failed microfracture. AB - Cystic talar shoulder defects are particularly challenging osteochondral lesions. A retrospective chart review was performed on 13 adults that previously failed microfracture, presented with medial cystic osteochondral lesions of the talus, and were treated with malleolar osteotomy and subchondral allograft reconstruction. The aim of the study was to evaluate the effect of a medial malleolar osteotomy and allograft subchondral bone plug on pain and function. We hypothesized that following surgery, pain and function would significantly improve. Compared with preoperative measures, pain (first step in the morning, during walking, at the end of the day) and function (descending the stairs, ascending the stairs, and ambulating up to 4 blocks) improved postoperatively at 6 and 12 months (P <= .001). During each activity, pain improved postoperatively from 6 to 12 months (P <= .006). Postoperatively, from 6 to 12 months, the level of disability improved while descending the stairs (P = .004), and the level of disability experienced while ascending the stairs and ambulating up to 4 blocks was maintained (P >= .02). Multiple regression analyses identified body mass index as a predictor of preoperative function (R(2) = .34, P = .04). No variables were identified as significant predictors of postoperative pain or function. With all osteotomies healing, no graft rejection, and a single deep venous thrombosis, allograft subchondral plugs appear to successfully treat osteochondral lesions of the talus with improvements in pain and function as well as an acceptable complication rate. LEVEL OF EVIDENCE: Therapeutic, Level IV: Retrospective Case Series. PMID- 24781455 TI - Native electrospray mass spectrometry of DNA G-quadruplexes in potassium solution. AB - A commonly used electrolyte in electrospray mass spectrometry (ESI-MS) of biomolecules is ammonium acetate (NH4OAc). Although some nucleic acid structures such as duplexes require only proper physiological ionic strength (whatever the monovalent ions) to be properly folded in ESI-MS conditions, the folding of some other nucleic acid structures such as DNA G-quadruplexes also depends on direct binding of specific cations. Here, we developed ESI-MS compatible conditions that allow one to observe DNA G-quaduplexes with K(+) ions specifically bound between G-quartets. NH4OAc was replaced with trimethylammonium acetate (TMAA), at concentrations up to 150 mM to provide physiological ionic strength, and the solution was doped with KCl at concentrations up to 1 mM. The trimethylammonium ion is too large to coordinate between G-quartets, where only K(+) ions bind. Compared with the equivalent NH4OAc/KCl mixtures, the TMAA/KCl mixtures provide cleaner spectra by suppressing the nonspecific adducts, and favor the formation of similar stacking arrangements as in 100 mM KCl (physiologically relevant cation) for the polymorphic human telomeric DNA G-quadruplexes. This new sample preparation method can be exploited to determine the number of potassium binding sites in new sequences, to screen ligand binding to the structures favored in potassium, and to transfer potassium-bound G-quadruplexes to the mass spectrometer for gas-phase structural probing, as illustrated herein with ion mobility spectrometry experiments. PMID- 24781456 TI - Detailed study of cyanobacterial microcystins using high performance tandem mass spectrometry. AB - Microcystins (MC) are a large group of toxic cyclic peptides, produced by cyanobacteria in eutrophic water systems. Identification of MC variants mostly relies on liquid chromatography (LC) combined with collision-induced dissociation (CID) mass spectrometry. Deviations from the essential amino acid complement are a common feature of these natural products, which makes the CID analysis more difficult and not always successful. Here, both CID and electron capture dissociation (ECD) were applied in combination with ultra-high resolution Fourier transform ion cyclotron resonance mass spectrometry to study a cyanobacteria strain isolated from the Salto Grande Reservoir in Sao Paulo State, Brazil, without prior LC separation. CID was shown to be an effective dissociation technique for quickly identifying the MC variants, even those that have previously been difficult to characterize by CID. Moreover, ECD provided even more detailed and complementary information, which enabled us to precisely locate metal binding sites of MCs for the first time. This additional information will be important for environmental chemists to study MC accumulation and production in ecosystems. PMID- 24781457 TI - Imidate-based cross-linkers for structural proteomics: increased charge of protein and peptide ions and CID and ECD fragmentation studies. AB - Chemical cross-linking is an attractive low-resolution technique for structural studies of protein complexes. Distance constraints obtained from cross-linked peptides identified by mass spectrometry (MS) are used to construct and validate protein models. Amidinating cross-linkers such as diethyl suberthioimidate (DEST) have been used successfully in chemical cross-linking experiments. In this work, the application of a commercial diimidate cross-linking reagent, dimethyl suberimidate (DMS), was evaluated with model peptides and proteins. The peptides were designed with acetylated N-termini followed by random sequences containing two Lys residues separated by an Arg residue. After cross-linking reactions, intra- and intermolecular cross-linked species were submitted to CID and ECD dissociations to study their fragmentation features in the gas phase. Fragmentation of intramolecular peptides by collision induced dissociation (CID) demonstrates a unique two-step fragmentation pathway involving formation of a ketimine as intermediate. Electron capture and electron transfer dissociation (ECD and ETD) experiments demonstrated that the cyclic moiety is not dissociated. Intermolecular species demonstrated previously described fragmentation behavior in both CID and ECD experiments. The charge state distributions (CSD) obtained after reaction with DMS were compared with those obtained with disuccinimidyl suberate (DSS). CSDs for peptides and proteins were increased after their reaction with DMS, owing to the higher basicity of DMS modified species. These features were also observed in LC-MS experiments with bovine carbonic anhydrase II (BCA) after cross-linking with DMS and tryptic proteolysis. Cross-linked peptides derived from this protein were identified at high confidence and those species were in agreement with the crystal structure of BCA. PMID- 24781458 TI - High-energy collision-induced dissociation by MALDI TOF/TOF causes charge-remote fragmentation of steroid sulfates. AB - A method for structural elucidation of biomolecules dating to the 1980s utilized high-energy collisions (~10 keV, laboratory frame) that induced charge-remote fragmentations (CRF), a class of fragmentations particularly informative for lipids, steroids, surfactants, and peptides. Unfortunately, the capability for high-energy activation has largely disappeared with the demise of magnetic sector instruments. With the latest designs of tandem time-of-flight mass spectrometers (TOF/TOF), however, this capability is now being restored to coincide with the renewed interest in metabolites and lipids, including steroid-sulfates and other steroid metabolites. For these metabolites, structure determinations are required at concentration levels below that appropriate for NMR. To meet this need, we explored CRF with TOF/TOF mass spectrometry for two groups of steroid sulfates, 3 sulfates and 21-sulfates. We demonstrated that the current generation of MALDI TOF/TOF instruments can generate charge-remote fragmentations for these materials. The resulting collision-induced dissociation (CID) spectra are useful for positional isomer differentiation and very often allow the complete structure determination of the steroid. We also propose a new nomenclature that directly indicates the cleavage sites on the steroid ring with carbon numbers. PMID- 24781459 TI - Structural distinction of diacyl-, alkylacyl, and alk-1-enylacyl glycerophosphocholines as [M - 15]- ions by multiple-stage linear ion-trap mass spectrometry with electrospray ionization. AB - We describe a linear ion-trap (LIT) multiple-stage (MS(n)) mass spectrometric approach towards differentiation of alkylacyl, alk-1-enylacyl- and diacyl glycerophoscholines (PCs) as the [M - 15]- ions desorbed by electrospray ionization (ESI) in the negative-ion mode. The MS4 mass spectra of the [M - 15 - R2'CH = CO]- ions originated from the three PC subfamilies are readily distinguishable, resulting in unambiguous distinction of the lipid classes. This method is applied to two alkyl ether rich PC mixtures isolated from murine bone marrow neutrophils and kidney, respectively, to explore its utility in the characterization of complex PC mixture of biological origin, resulting in the realization of the detailed structures of the PC species, including various classes and many minor isobaric isomers. PMID- 24781460 TI - Matrix segregation as the major cause for sample inhomogeneity in MALDI dried droplet spots. AB - The segregation in dried droplet MALDI sample spots was analyzed with regard to the matrix-to-sample ratio using optical microscopy, MALDI imaging mass spectrometry (MALDI MSI) and IR imaging spectroscopy. In this context, different polymer/matrix/solvent systems usually applied in the analysis of synthetic polymers were investigated. The use of typical matrix concentrations (10 mg mL-1) in almost every case resulted in ring patterns, whereas higher concentrated matrix solutions always led to homogeneous sample spot layers. The data revealed that segregation is predominantly caused by matrix transport in the drying droplet, whereas polymer segregation seems to be only secondary. PMID- 24781493 TI - Initial dose of antidepressant and suicidal behavior in youth: start low, go slow. PMID- 24781494 TI - Lung-protective ventilation in the operating room: time to implement? PMID- 24781495 TI - Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance. AB - BACKGROUND: Recent studies suggest that the transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remain unclear. METHODS: The authors explored the effects of genetic disruption of TRPM2 on mortality (n = 15), bacterial clearance (n = 6), organ injury, and systemic inflammation during cecal ligation and puncture-induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis. RESULTS: After cecal ligation and puncture, Trpm2-knockout mice had increased mortality compared with wild-type mice (73.3 vs. 40%, P = 0.0289). The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. TRPM2-mediated Ca influx plays an important role in lipopolysaccharide or cecal ligation and puncture-induced heme oxygenase-1 (HO-1) expression in macrophage. HO-1 up-regulation decreased bacterial burden both in wild-type bone marrow-derived macrophages and in cecal ligation and puncture-induced septic wild-type mice. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow-derived macrophages. Pretreatment of Trpm2-knockout bone marrow-derived macrophages with HO-1 inducer markedly increased HO-1 expression and decreased bacterial burden. Pretreatment of Trpm2-knockout mice with HO-1 inducer reversed the susceptibility of Trpm2-knockout mice to sepsis by enhancing the bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 messenger RNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 messenger RNA levels. TRPM2 levels correlated with HO-1 levels in septic patients (r = 0.675, P = 0.001). CONCLUSION: The study data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis possibly by regulating HO-1 expression. PMID- 24781496 TI - Blocking the mineralocorticoid receptor improves effectiveness of steroid treatment for low back pain in rats. AB - BACKGROUND: Localized inflammation of lumbar dorsal root ganglia (DRG) may contribute to low back pain. Local injections of corticosteroids used for low back pain are sometimes ineffective. Many corticosteroids activate not only the target glucocorticoid receptor (GR) but also the mineralocorticoid receptor (MR), which may have proinflammatory effects countering the effects of GR activation. METHODS: A low back pain model was implemented in rats (n = 6 to 10 per group) by locally inflaming the L5 DRG. Sensory neuron excitability and mechanical hypersensitivity of the hind paws were measured. Tested steroids were applied locally to the inflamed DRG or orally. RESULTS: The selective MR blocker eplerenone reduced pain behaviors when given orally starting at the time of surgery, or starting 7 days later. The highly GR-selective agonist fluticasone, applied locally to the inflamed DRG, was much more effective in reducing mechanical hypersensitivity. The MR/GR agonist 6-alpha methylprednisolone, commonly injected for low back pain, reduced mechanical hypersensitivity when applied locally to the DRG but was less effective than fluticasone. Its effectiveness was improved by combining it with local eplerenone. All tested steroids reduced hyperexcitability of myelinated sensory neurons (n = 71 to 220 cells per group) after inflammation, particularly abnormal spontaneous activity. CONCLUSIONS: This preclinical study indicates the MR may play an important role in low back pain involving inflammation. Some MR effects may occur at the level of the sensory neuron. It may be useful to consider the action of clinically used steroids at the MR as well as at the GR. PMID- 24781497 TI - Relationship between preventable hospital deaths and other measures of safety: an exploratory study. AB - OBJECTIVE: To explore associations between the proportion of hospital deaths that are preventable and other measures of safety. DESIGN: Retrospective case record review to provide estimates of preventable death proportions. Simple monotonic correlations using Spearman's rank correlation coefficient to establish the relationship with eight other measures of patient safety. SETTING: Ten English acute hospital trusts. PARTICIPANTS: One thousand patients who died during 2009. RESULTS: The proportion of preventable deaths varied between hospitals (3-8%) but was not statistically significant (P = 0.94). Only one of the eight measures of safety (Methicillin-resistant Staphylococcus aureus bacteraemia rate) was clinically and statistically significantly associated with preventable death proportion (r = 0.73; P < 0.02). There were no significant associations with the other measures including hospital standardized mortality ratios (r = -0.01). There was a suggestion that preventable deaths may be more strongly associated with some other measures of outcome than with process or with structure measures. CONCLUSIONS: The exploratory nature of this study inevitably limited its power to provide definitive results. The observed relationships between safety measures suggest that a larger more powerful study is needed to establish the inter relationship of different measures of safety (structure, process and outcome), in particular the widely used standardized mortality ratios. PMID- 24781499 TI - Gorlos-Phos for palladium-catalyzed borylation of aryl chlorides. AB - Using a readily available form of the mono-phosphine ligand, Gorlos-Phos.HBF4, Pd catalyzed borylation of aryl chlorides afforded aryl boronates in high yields. A variety of functional groups are well compatible with this palladium catalyzed borylation reaction. PMID- 24781498 TI - A review of the quality of behaviorally-based intervention research to improve social interaction skills of children with ASD in inclusive settings. AB - Students with autism spectrum disorders (ASDs) often have difficulties in social interaction skills, which may prevent their successful inclusion in general education placements. Behaviorally-based social skills interventions have been shown to be effective in attenuating such difficulties in these environments. In light of the increasing number of children with ASD being educated in inclusive settings and requirements for the use of research-based interventions in schools, this paper (1) analyzes the quality of single-case research using behaviorally based interventions to improve social interaction skills of children with ASD in inclusive settings and (2) evaluates whether such interventions can be considered an evidence-based practice. Characteristics and components of the interventions are summarized, and their implications for practice and future research are discussed. PMID- 24781500 TI - Apoptotic pathways of U937 leukemic monocytes investigated by infrared microspectroscopy and flow cytometry. AB - Apoptosis is a strictly regulated cell death mechanism that plays a pivotal role in the normal evolution of multicellular organisms. Its misregulation has been associated with many diseases, making its early and reliable detection a key point for modern cellular biology. In this paper, we propose the use of infrared microspectroscopy (IRMS) as a label-free methodology for the detection of apoptotic-related biochemical processes induced on U937 leukemic monocytes by serum starvation and CCCP-exposure. The spectroscopic results are in agreement with parallel Flow Cytometry (FC) experiments, where plasma membrane integrity and mitochondrial activity were assessed. Spectroscopic outcomes complement FC data and allow drawing a more complete picture of the apoptotic pathways. In particular, we established that the two apoptosis-inducing treatments, cell starvation and CCCP exposure, affect the cell cycle in a different way. With the former, cell death is preceded by a cell cycle arrest, whereas the latter causes an increased cell cycle progression. Spectral data demonstrate that for both conditions apoptosis proceeds through the accumulation of lipid droplets within cells. Moreover, we were able to establish a spectral marker for DNA condensation/fragmentation: the enhancement of the PhI band component centred at ~1206 cm(-1), which is more sensitive than the relative intensity of the PhII band to which phospholipids and carbohydrates also contribute significantly. In conclusion, we demonstrate that the intrinsic multi-parametric nature of IRMS and its application on cells under physiological conditions can be well exploited for the investigation of apoptotic pathways. PMID- 24781502 TI - G-protein stimulatory subunit alpha and Gq/11alpha G-proteins are both required to maintain quiescent stem-like chondrocytes. AB - Round chondrocytes in the resting zone of the growth plate provide precursors for columnar chondrocytes and have stem-like properties. Here we demonstrate that these stem-like chondrocytes undergo apoptosis in the absence of the receptor (PPR) for parathyroid hormone-related protein. We examine the possible roles of heterotrimeric G-proteins activated by the PPR. Inactivation of the G-protein stimulatory alpha-subunit (G(s)alpha) leads to accelerated differentiation of columnar chondrocytes, as seen in the PPR knockout, but a remnant of growth cartilage remains, in contrast to disappearance of the growth cartilage in the PPR knockout. Stem-like chondrocytes lose their quiescence and proliferate upon G(s)alpha ablation. Inactivation of G(s)alpha in mice with a mutant PPR that cannot activate G proteins, Gq and G11, leads to a PPR knockout-like phenotype. Thus, G(s)alpha is the major mediator of the anti-differentiation action of the PPR, while activation of both G(s)alpha and Gq/11alpha is required for quiescence of stem-like chondrocytes. PMID- 24781504 TI - Identification of risk and prognostic factors for patients with clonorchiasis associated intrahepatic cholangiocarcinoma. AB - BACKGROUND: Intrahepatic cholangiocarcinoma caused by clonorchiasis (CICC) has a poor prognosis, and there have been insufficient studies regarding risk and prognostic factors. We aimed to identify CICC-associated factors. METHODS: A retrospective analysis of 127 eligible patients with CICC was performed with 254 clonorchiasis cases used as matched controls to identify risk factors for CICC. The main outcomes analyzed included overall survival (OS) and disease-free survival (DFS). RESULTS: Out of 127 surgeries, R0 resection was performed in 61 patients, R1 in 32 patients, and R2 in 22 patients; nonresection surgery was performed in 12 patients. Median OS for the entire cohort was 29.5 months. Median OS and DFS for 61 patients with R0 resection were 52.4 months and 41.5 months, respectively. We found independent risk factors for CICC were duration of raw fish consumption of >=28 years (p < 0.001) and hepatitis B virus infection (p = 0.040). R0 resection (p < 0.001), well or moderately differentiated tumor (p = 0.019), and stage I to II tumor (p < 0.001) predicted improved OS for CICC. Serum carcinoembryonic antigen level of <=5 ng/ml (p = 0.029) and stage I to II tumor (p < 0.001) predicted improved DFS. CONCLUSIONS: Duration of raw fish consumption >=28 years and hepatitis B virus infection were significant risk factors for CICC in patients with clonorchiasis. For patients with CICC, curative resection is an effective treatment. Higher tumor differentiation and earlier American Joint Committee on Cancer stage predicted good prognosis. Serum carcinoembryonic antigen level was found to predict the possibility of recurrence after curative resection. PMID- 24781505 TI - Validation of accuracy in image co-registration with computed tomography and magnetic resonance imaging in Gamma Knife radiosurgery. AB - The latest version of Leksell GammaPlan (LGP) is equipped with Digital Imaging and Communication in Medicine (DICOM) image-processing functions including image co-registration. Diagnostic magnetic resonance imaging (MRI) taken prior to Gamma Knife treatment is available for virtual treatment pre-planning. On the treatment day, actual dose planning is completed on stereotactic MRI or computed tomography (CT) (with a frame) after co-registration with the diagnostic MRI and in association with the virtual dose distributions. This study assesses the accuracy of image co-registration in a phantom study and evaluates its usefulness in clinical cases. Images of three kinds of phantoms and 11 patients are evaluated. In the phantom study, co-registration errors of the 3D coordinates were measured in overall stereotactic space and compared between stereotactic CT and diagnostic CT, stereotactic MRI and diagnostic MRI, stereotactic CT and diagnostic MRI, and stereotactic MRI and diagnostic MRI co-registered with stereotactic CT. In the clinical study, target contours were compared between stereotactic MRI and diagnostic MRI co-registered with stereotactic CT. The mean errors of coordinates between images were < 1 mm in all measurement areas in both the phantom and clinical patient studies. The co-registration function implemented in LGP has sufficient geometrical accuracy to assure appropriate dose planning in clinical use. PMID- 24781506 TI - Posterior thoracic osteotomies. AB - Spinal osteotomies are used to treat partially flexible and fixed deformities. Fixed thoracic spinal deformities have been traditionally treated with anterior release and posterior correction with fusion. In recent decades, it has been shown that posterior-only osteotomies might be sufficient to achieve proper deformity correction with lower complication rates than with combined anterior and posterior procedures. Different types of osteotomies have been described to treat spinal deformities through a single posterior approach. These include posterior column osteotomies such as the Smith-Petersen osteotomy and the Ponte osteotomy, and three-column osteotomies such as the pedicle subtraction osteotomy, the posterior vertebral column resection and the posterior vertebral column decancellation. In general, three-column osteotomies are most commonly performed in the lumbar spine, where the vast majority of reports have focused on. They can also be performed in the thoracic spine in the setting of rigid thoracic deformity. A progressive increase in complications has been reported with more aggressive osteotomies. The aim of this article was to describe the most common posterior spinal osteotomies used to treat adult thoracic spinal deformities, with special emphasis on the technical aspects, complications and outcomes, based on current publications and European Spine Study Group (ESSG) data. PMID- 24781507 TI - Hypertension in India. PMID- 24781508 TI - Improving risk prediction performance for a better guidelines application. PMID- 24781509 TI - Can fetal vascular morphology at 30 weeks of gestation have impact on cardiovascular outcomes in childhood? PMID- 24781510 TI - Assessment of drug effects on blood pressure variability: which method and which index? PMID- 24781511 TI - Are the effects of telmisartan more marked in hypertensive patients? PMID- 24781512 TI - Obesity and blood pressure control. PMID- 24781513 TI - Obesity and blood pressure control. PMID- 24781514 TI - Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [11C]NNC112. AB - RATIONALE: Schizotypal personality disorder (SPD) is associated with working memory (WM) impairments that are similar to those observed in schizophrenia. Imaging studies have suggested that schizophrenia is associated with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder. OBJECTIVES: The aim of this study was to characterize prefrontal D1 receptor availability and its relation to WM performance in SPD. METHODS: We used positron emission tomography (PET) and the radiotracer [(11)C]NNC112 with 18 unmedicated SPD and 21 healthy control participants; as an index of D1 receptor availability, binding potential (BP) measures (BPF, BPND, and BPP) were calculated for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addition Test (PASAT). RESULTS: There were no significant group differences in PFC BP. BPF and BPP in the medial PFC were significantly negatively related to PASAT performance (r s = -0.551, p = .022 and r s = 0.488, p = .047, respectively), but BP was not related to 2-back performance. CONCLUSIONS: In contrast to what has been found in schizophrenia, SPD was not associated with significant alterations in prefrontal D1 receptor availability. Similar to previous schizophrenia findings, however, higher prefrontal D1 receptor availability was associated with poorer WM performance (as measured by the PASAT) in SPD. These findings suggest that schizophrenia and SPD may share a common pathophysiological feature related to prefrontal dopamine functioning that contributes to WM dysfunction, but that in SPD, alterations in D1 may occur only in a subset of individuals and/or to an extent that is minor relative to what occurs in schizophrenia. PMID- 24781515 TI - 5alpha-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients. AB - RATIONALE: The implications of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20 one [allopregnanolone (Allo)] in neuropsychiatric disorders have been highlighted in several recent clinical investigations. For instance, Allo levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants [i.e., selective brain steroidogenic stimulants (SBSSs)], including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms. Allo positively and allosterically modulates GABA action at postsynaptic and extrasynaptic GABAA receptors. It is synthesized in both the human and rodent brain cortices by principal glutamatergic pyramidal neurons from progesterone by the sequential action of 5alpha-reductase type I (5alpha-RI), which is the rate-limiting step enzyme in Allo biosynthesis, and 3alpha hydroxysteroid dehydrogenase (3alpha-HSD), which converts 5alpha dehydroprogesterone into Allo. HYPOTHESIS: We thus hypothesized that decreased CSF levels of Allo in depressed patients could reflect a brain dysfunction of 5alpha-RI. METHODS: In a pilot study of samples from six patients per group [six depressed patients and six nonpsychiatric subjects (NPS)], we studied the expression of 5alpha-RI messenger RNA (mRNA) in prefrontal cortex Brodmann's area 9 (BA9) and cerebellum from depressed patients obtained from the Maryland Brain Collection at the Maryland Psychiatric Research Center (Baltimore, MD) that were age-matched with NPS. RESULTS: The levels of 5alpha-RI mRNA were decreased from 25 +/- 5.8 in NPS to 9.1 +/- 3.1 fmol/pmol neuronal specific enolase (NSE) (t1,10 = 2.7, P = 0.02) in depressed patients. These differences are absent in the cerebellum of the same patients. The levels of neurosteroids were determined in the prefrontal cortex BA9 of depressed patients obtained from the Stanley Foundation Brain Bank Neuropathology Consortium, Bethesda (MD). The BA9 levels of Allo in male depressed patients failed to reach statistical difference from the levels of NPS (1.63 +/- 1.01 pg/mg, n = 8, in NPS and 0.82 +/- 0.33 pg/mg, n = 5, in nontreated depressed patients). However, depressed patients who had received antidepressant treatment (three patients SSRI and one TCA) exhibited increased BA9 Allo levels (6.16 +/- 2.5 pg/mg, n = 4, t1,9 = 2.4, P = 0.047) when compared with nontreated depressed patients. CONCLUSIONS: Although in a small number of patients, this finding is in-line with previous reports in the field that have observed an increase of Allo levels in CSF and plasma of depressed patients following antidepressant treatment. Hence, the molecular mechanisms underlying major depression may include a GABAergic neurotransmission deficit caused by a brain Allo biosynthesis downregulation, which can be normalized by SBSSs. PMID- 24781517 TI - Comparison of nicotine oral soluble film and nicotine lozenge on efficacy in relief of smoking cue-provoked acute craving after a single dose of treatment in low dependence smokers. AB - RATIONALE: Pilot study results suggested that a new form of nicotine oral soluble film relieved smoking cue-provoked acute craving faster than nicotine lozenge or gum. The new nicotine film may provide smokers another choice to relieve acute craving. OBJECTIVES: This study compared the efficacy of the 2.5 mg nicotine oral soluble film to 2 mg nicotine lozenge for acute relief of smoking cue-provoked craving. METHODS: A randomized, open label, active comparator controlled, parallel group study was conducted with 322 smokers enrolled. After 4 h of abstinence from smoking, eligible subjects were exposed to smoking cues as provocation. Immediately after the post-provocation baseline craving assessment using a 0-100 mm visual analogue scale (VAS), subjects took a randomized single dose of either the 2.5 mg nicotine film or the 2 mg nicotine lozenge. Craving assessments were completed at 50 s, 3 min, 5 min, 7 min, 15 min, 20 min, 25 min and 30 min after drug administration. RESULTS: Both treatments reduced cue induced craving and had similar maximum effects on craving relief. However, the 2.5 mg nicotine film relieved cue-induced craving to a greater degree than the 2 mg nicotine lozenge at 50 s (mean difference: -4.9, p = 0.014), 3 min (mean difference: -6.7, p = 0.011), and 5 min (mean difference: -5.6, p = 0.049) post treatment. CONCLUSIONS: The study confirmed the results from the pilot study. The 2.5 mg nicotine film relieved cue-provoked craving much quicker than the 2 mg nicotine lozenge while both having similar maximum effects. Nicotine film could be useful to provide quick craving relief for low dependence smokers. PMID- 24781516 TI - Involvement of pregnane xenobiotic receptor in mating-induced allopregnanolone formation in the midbrain and hippocampus and brain-derived neurotrophic factor in the hippocampus among female rats. AB - RATIONALE: Given that the pregnane neurosteroid, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), is increased following behavioral challenges (e.g., mating), and that there is behavioral-induced biosynthesis of 3alpha,5alpha-THP in midbrain and mesocorticolimbic structures, 3alpha,5alpha-THP likely has a role in homeostasis and motivated reproduction and reproduction-related behaviors (e.g., affect, affiliation). The role of pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism, for these effects is of continued interest. OBJECTIVES: We hypothesized that there would be differences in brain levels of 3alpha,5alpha THP following varied behavioral experiences, an effect abrogated by knockdown of PXR in the midbrain. METHODS: Proestrous rats were infused with PXR antisense oligonucleotides (AS-ODNs) or vehicle to the ventral tegmental area before different behavioral manipulations and assessments. Endpoints were expression levels of PXR in the midbrain, 3alpha,5alpha-THP, and ovarian steroids (estradiol, progesterone, dihydroprogesterone) in the midbrain, striatum, hippocampus, hypothalamus, prefrontal cortex, and plasma. RESULTS: Across experiments, knocking down PXR reduced PXR expression and 3alpha,5alpha-THP levels in the midbrain and hippocampus. There were differences in terms of the behavioral manipulations, such that paced mating had the most robust effects to increase 3alpha,5alpha-THP levels and reduce open field exploration and social interaction. An additional question that was addressed is whether brain-derived neurotrophic factor (BDNF) is a downstream factor for regulating effects of behavioral-induced 3alpha,5alpha-THP biosynthesis. Rats infused with PXR AS-ODNs had lower levels of BDNF in the hippocampus. CONCLUSION: Thus, PXR may be a regulator of mating-induced 3alpha,5alpha-THP formation and behavioral changes and neural plasticity, such as BDNF. PMID- 24781518 TI - Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus. AB - RATIONALE: Monoamine reuptake inhibitors can stimulate expression of brain derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is upregulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI), reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression. OBJECTIVES: We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BDNF by testing for region-specific changes in areas CA1, CA3, and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP. METHODS: Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme linked immunosorbent assay (ELISA) and Western blotting. RESULTS: LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected. CONCLUSIONS: LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium influx. PMID- 24781519 TI - Adrenal steroid hormones and ethanol self-administration in male rhesus macaques. AB - RATIONALE: Hypothalamic-pituitary-adrenal (HPA) axis hormones have neuroactive metabolites with receptor activity similar to ethanol. OBJECTIVES: The present study related HPA hormones in naive monkeys to ethanol self-administration. METHODS: Morning plasma adrenocorticotropic hormone (ACTH), cortisol, deoxycorticosterone (DOC), aldosterone, and dehydroepiandrosterone-sulfate (DHEA S) were measured longitudinally in male rhesus macaques (Macaca mulatta) induced to drink ethanol followed by access to ethanol (4 % w/v, in water) and water 22 h/day for 12 months. RESULTS: During ethanol access, DOC increased among non heavy (average intake over 12 months <=3.0 g/kg/day, n = 23) but not among heavy drinkers (>3.0 g/kg/day, n = 9); aldosterone was greater among heavy drinkers after 6 months. The ratio of DOC/aldosterone decreased only among heavy drinkers after 6 or12 months of ethanol self-administration. ACTH only correlated significantly with DHEA-S, the ratio of cortisol/DHEA-S and DOC after the onset of ethanol access, the former two just in heavy drinkers. Baseline hormones did not predict subsequent ethanol intake over 12 months, but baseline DOC correlated with average blood-ethanol concentrations (BECs), among all monkeys and heavy drinkers as a group. During ethanol access, aldosterone and DOC correlated and tended to correlate, respectively, with 12-month average ethanol intake. CONCLUSIONS: Ethanol self-administration lowered ACTH and selectively altered its adrenocortical regulation. Mineralocorticoids may compensate for adrenocortical adaptation among heavy drinkers and balance fluid homeostasis. As DOC was uniquely predictive of future BEC and not water intake, to the exclusion of aldosterone, GABAergic neuroactive metabolites of DOC may be risk factors for binge drinking to intoxication. PMID- 24781520 TI - Structure-activity relationship studies on neuroactive steroids in memory, alcohol and stress-related functions: a crucial benefit from endogenous level analysis. AB - RATIONALE: New research findings in the field of neuroactive steroids strongly suggest that to understand their role in physiopathology, it is essential to accurately measure their tissue levels. Through his broad chemical expertise and extensive knowledge of steroids, Dr. Robert H. Purdy pioneered structure-activity relationship studies on these compounds and developed innovative detection assays that are essential to assess their function in biological tissues. OBJECTIVE: The goal of the present paper is to point out the specific contributions of Dr. Purdy and his collaborators to the current knowledge on the role of neuroactive steroids in the modulation of memory and alcohol- and stress-related effects with particular emphasis on the detection assays he developed to assess their endogenous levels. Reviewed here are the major results as well as the original and valuable methodological strategies issued by the long-term collaboration between Dr Purdy and many scientists worldwide on the investigation of the structure-activity relationship of neuroactive steroids. RESULTS: Altogether, the data presented herein put forward the original notion that knowledge of the chemical structure of steroids is essential for their detection and the understanding of their role in physiological and pathological conditions, including the stress response. CONCLUSIONS: The current challenge is to identify and quantify using appropriate methods neuroactive steroids in the context of both animal and clinical studies in order to reveal how their levels change under physiological and disease states. Dr. Purdy passed away in September 2012, but scientists all over the world will always be grateful for his pioneering work on steroid chemistry and for his great enthusiasm in research. PMID- 24781522 TI - It's timely and time for the change: comments on Peck and Ranaldi. PMID- 24781521 TI - Compromised frontocerebellar circuitry contributes to nonplanning impulsivity in recovering alcoholics. AB - RATIONALE: Degradation of frontocerebellar circuitry is a principal neural mechanism of alcoholism-related executive dysfunctions affecting impulse control and cognitive planning. OBJECTIVE: We tested the hypothesis that alcoholic patients would demonstrate compromised dorsal anterior cingulate cortex (dACC) cerebellar functional connectivity when adjusting their strategies to accommodate uncertain conditions and would recruit compensatory brain regions to overcome ineffective response patterns. METHODS: Twenty-six alcoholics and 26 healthy participants underwent functional MRI in two sequential runs while performing a decision-making task. The first run required a response regardless of level of ambiguity of the stimuli; the second run allowed a PASS option (i.e., no response choice), which was useful on ambiguous trials. RESULTS: Healthy controls demonstrated strong synchronous activity between the dACC and cerebellum while planning and executing a behavioral strategy. By contrast, alcoholics showed synchronous activity between the dACC and the premotor cortex, perhaps enabling successful compensation for accuracy and reaction time in certain conditions; however, a negative outcome of this strategy was rigidity in modifying response strategy to accommodate uncertain conditions. Compared with the alcoholic group, the control group had lower nonplanning impulsiveness, which correlated with using the option PASS to respond in uncertain conditions. CONCLUSION: These findings suggest that compromised dACC-cerebellar functional circuitry contributes to recruitment of an alternative network-dACC-premotor cortex- to perform well under low-risk, unambiguous conditions. This compensatory network, however, was inadequate to enable the alcoholics to avert making poor choices in planning and executing an effective behavioral strategy in high-risk, uncertain conditions. PMID- 24781523 TI - PP2A delays APC/C-dependent degradation of separase-associated but not free securin. AB - The universal triggering event of eukaryotic chromosome segregation is cleavage of centromeric cohesin by separase. Prior to anaphase, most separase is kept inactive by association with securin. Protein phosphatase 2A (PP2A) constitutes another binding partner of human separase, but the functional relevance of this interaction has remained enigmatic. We demonstrate that PP2A stabilizes separase associated securin by dephosphorylation, while phosphorylation of free securin enhances its polyubiquitylation by the ubiquitin ligase APC/C and proteasomal degradation. Changing PP2A substrate phosphorylation sites to alanines slows degradation of free securin, delays separase activation, lengthens early anaphase, and results in anaphase bridges and DNA damage. In contrast, separase associated securin is destabilized by introduction of phosphorylation-mimetic aspartates or extinction of separase-associated PP2A activity. G2- or prometaphase-arrested cells suffer from unscheduled activation of separase when endogenous securin is replaced by aspartate-mutant securin. Thus, PP2A-dependent stabilization of separase-associated securin prevents precocious activation of separase during checkpoint-mediated arrests with basal APC/C activity and increases the abruptness and fidelity of sister chromatid separation in anaphase. PMID- 24781524 TI - Open versus laparoscopic abdominal rectopexy: an examination of early postoperative outcomes. AB - BACKGROUND: Abdominal rectopexy is used to treat full thickness rectal prolapse and obstructed defecation syndrome, with good outcomes. Use of a laparoscopic approach may reduce morbidity. The current study assessed short-term operative outcomes for patients undergoing laparoscopic or open rectopexy. METHODS: Rectopexy cases were identified from theater logs in two tertiary referral centers. Patient demographics, intra-operative details and early postoperative outcomes were examined. RESULTS: There were 62 patients included over 10 years, a third of whom underwent laparoscopic rectopexy. Laparoscopy was associated with a longer operative time (195.9 versus 129.6 min, p = 0.003), but this did not affect postoperative outcomes, with no significant differences found for complication rates and length of stay between the two groups. Univariable analysis found no influence of laparoscopic approach on the likelihood of postoperative complications, and no factor achieved significance with multivariable analysis. This study included the first laparoscopic cases performed in the involved institutions, and a "learning curve" existed as seen with a decreasing operative duration per case over time (p = 0.002). CONCLUSIONS: Laparoscopic rectopexy has similar short-term outcomes to open rectopexy. PMID- 24781525 TI - Arthroscopic anatomic study of posteromedial joint capsule in knee joint associated with popliteal cyst. AB - PURPOSE: The purpose of this study was to examine the arthroscopic anatomy of posteromedial capsule and magnetic resonance imaging (MRI) findings in internal derangement of the knee joint and to analyze the relationship between popliteal cysts and the posteromedial capsule. METHODS: From 2011 to 2012, a prospective study included 194 knees of consecutive arthroscopic surgeries for assorted knee problems. The anatomy of the posteromedial joint capsule was evaluated arthroscopically and divided into three types by the presence of capsular fold and opening: no capsular fold and no opening (type I), capsular fold without opening (type II), capsular fold with opening (type III). The presence and size of popliteal cyst were documented by MRI. RESULTS: Type I was observed in 160 knees (82.5 %), type II in 10 (5.1 %) and type III in 24 (12.4 %). Popliteal cysts were found in 25 knees (12.9 %) by MRI. Of these cases, symptomatic popliteal cysts were identified in 12 knees (6.9 %). On 160 knees demonstrated to be type I, only 3 knees (1.9 %) had popliteal cysts in MRI, 6 knees (60 %) in 10 knees of type II and 16 knees (66.7 %) in 24 knees of type III. Therefore, there was a statistically significant relationship between the type of anatomy in the posteromedial capsule and the popliteal cyst (p < 0.001). CONCLUSION: An association between popliteal cyst and arthroscopic anatomy of posteromedial capsule was demonstrated. Comprehensive understanding and knowledge of the arthroscopic anatomy of posteromedial capsule would contribute to the arthroscopic approach in understanding the pathogenesis of popliteal cyst. STUDY DESIGN: Development of diagnostic criteria on basis of consecutive patients. LEVEL OF EVIDENCE: 2. PMID- 24781526 TI - Digital droplet PCR (ddPCR) for the precise quantification of human T lymphotropic virus 1 proviral loads in peripheral blood and cerebrospinal fluid of HAM/TSP patients and identification of viral mutations. AB - An elevated human T cell lymphotropic virus 1 (HTLV)-1 proviral load (PVL) is the main risk factor for developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-1 infected subjects, and a high cerebrospinal fluid (CSF) to peripheral blood mononuclear cell (PBMC) PVL ratio may be diagnostic of the condition. However, the standard method for quantification of HTLV-1 PVL-real time PCR-has multiple limitations, including increased inter-assay variability in compartments with low cell numbers, such as CSF. Therefore, in this study, we evaluated a novel technique for HTVL-1 PVL quantification, digital droplet PCR (ddPCR). In ddPCR, PCR samples are partitioned into thousands of nanoliter-sized droplets, amplified on a thermocycler, and queried for fluorescent signal. Due to the high number of independent events (droplets), Poisson algorithms are used to determine absolute copy numbers independently of a standard curve, which enables highly precise quantitation. This assay has low intra-assay variability allowing for reliable PVL measurement in PBMC and CSF compartments of both asymptomatic carriers (AC) and HAM/TSP patients. It is also useful for HTLV-1-related clinical applications, such as longitudinal monitoring of PVL and identification of viral mutations within the region targeted by the primers and probe. PMID- 24781528 TI - Ni2+ chemistry in pathogens--a possible target for eradication. AB - The survival of all urease and/or hydrogenase containing pathogens depends on the proper homeostasis of nickel. In the scope of this perspectives paper, details of Ni(2+) metabolism of Helicobacter pylori, a widespread stomach-ulcer causing bacterium, are described. Nickel binding proteins and thermodynamics of such metal complexes are discussed in detail and special focus is given to potential nickel binding sequences in this metal's chaperones and regulators. A list of potential Ni(2+) binding sites in various pathogens is presented, which points out numerous examples of nickel interactions that still need to be understood. PMID- 24781527 TI - Erlotinib in African Americans with advanced non-small cell lung cancer: a prospective randomized study with genetic and pharmacokinetic analyses. AB - Prospective studies on epidermal growth factor receptor (EGFR) inhibitors in African Americans with non-small cell lung cancer (NSCLC) have not previously been performed. In this phase II randomized study, 55 African Americans with NSCLC received 150 mg/day erlotinib or a body weight-adjusted dose with subsequent escalations to the maximum-allowable dose, 200 mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower than those observed in previous studies, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics showed only two EGFR mutations, EGFR amplification in 17/47 samples, eight KRAS mutations, and five EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Low incidence of toxicity and low erlotinib exposure suggest standardized and maximum-allowable dosing may be suboptimal in African Americans. PMID- 24781529 TI - A pilot genome-scale profiling of DNA methylation in sporadic pituitary macroadenomas: association with tumor invasion and histopathological subtype. AB - Pituitary adenomas (PAs) are neoplasms that may cause a variety of neurological and endocrine effects. Although known causal contributors include heredity, hormonal influence and somatic mutations, the pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic PAs remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation profiling and RNA sequencing. PA samples clustered into subgroups according to functional status. Compared with hormonally-active PAs, nonfunctional PAs exhibited global DNA hypermethylation (mean beta-value 0.47 versus 0.42, P = 0.005); the most significant site of differential DNA methylation was within the promoter region of the potassium voltage-gated channel KCNAB2 (FDR = 5.11*10-10). Pathway analysis of promoter-associated CpGs showed that nonfunctional PAs are potentially associated with the ion-channel activity signal pathway. DNA hypermethylation tended to be negatively correlated with gene expression. DNA methylation analysis may be used to identify candidate genes involved in PA function and may potentially complement current standard immunostaining classification in sporadic PAs. DNA hypermethylation of KCNAB2 and downstream ion channel activity signal pathways may contribute to the endocrine-inactive status of nonfunctional PAs. PMID- 24781530 TI - A simple model of ostracism formation. AB - We study formation of ostracism in a society from a game theoretical perspective. The dynamics of group formation is complicated in that the choices of the individuals and the form of the groups mutually affect each other in the process. A suggested simple model shows that individual efforts to increase his/her own sense of belonging is responsible for both growth of groups and creation of an outcast. Once a person happens to get behind in synchronizing with others, tendency to alienate him may grow among others, possibly making him left out in the end. Alienating minority occurs even when there is a penalty for disliking and people are encouraged to favor others. Considering that the target is accidentally picked, we can understand ostracism as an inherent part of the group formation, rather than a result of specific discrepancy among people. Another finding is that a single individual who seeks for unconditional unification of the society ("philanthropist") likely invites his/her own isolation from the society, while the existence of such person generally promotes coalition of others. PMID- 24781531 TI - A liquid crystalline chirality balance for vapours. AB - Chiral discrimination of vapours plays an important role in olfactory perception of biological systems and its realization by artificial sensors has been an intriguing challenge. Here, we report a simple method that tangibly visualizes the chirality of a diverse variety of molecules dissolved from vapours with high sensitivity, by making use of a structural change in a periodic microstructure of a nematic liquid crystal confined in open microchannels. This microstructure is accompanied by a topological line defect of a zigzag form with equal lengths of 'zig' and 'zag.' We find that a tiny amount of vapour of chiral molecules injected onto the liquid crystal induces the imbalance of 'zig' and 'zag' depending on its enantiomeric excess within a few seconds. Our liquid-crystal based 'chirality balance' offers a simple, quick and versatile chirality-sensing/ screening method for gas-phase analysis (for example, for odours, environmental chemicals or drugs). PMID- 24781532 TI - Use of input impedance to determine changes in the resistance of arterial vessels at different levels in feline femoral bed. AB - In many studies, the functional state of vessels of different caliber was determined by fitting the lumped parameters of a mathematical model of the bed in order to fit the vascular input impedance (Z in) data. However, reliability of the results obtained in such a way remains uncertain. In this study, we employed a mathematical model with seven lumped parameters and Z in experimental data to analyze the distribution of resistance across the arterial bed of the hind limb in anesthetized cats, to test reliability of this distribution and to describe the process of ascending arterial dilation followed occlusion of iliac artery. The vascular bed was divided into three segments: large arteries, medium-sized arterial vessels and precapillary resistance vessels together with venous part of the bed. Based on the data of Z in measured in a wide frequency range (from 0 to 150 Hz) we showed that pharmacologically induced constriction and dilation of the arterial microvessels were reflected in the model by the changes in the resistance of distal precapillary vessels only, whereas the local constriction or dilation of femoral and iliac arteries as well as artificial stenosis of the femoral artery resulted exclusively in the changes of the resistance describing the state of large arteries. Using the input impedance method we could demonstrate and quantitatively describe the process of ascending arterial dilation during the post-occlusion (reactive) hyperemia. All these results prove that the model of vascular bed with seven lumped elements used in combination with input hydraulic impedance data can be an effective tool permitted to quantitatively analyze the functional state of arterial vessels of different caliber and to describe the changes in resistance of arterial vessels during vascular reactions. PMID- 24781533 TI - Improving value is improving health care, not rationing. PMID- 24781534 TI - Survival-rate analysis of surface treated dental zirconia (Y-TZP) ceramics. AB - The role of surface preparation, hydrothermal ageing exposure and subsequent cyclic fatigue testing on the biaxial strength of a dental Y-TZP material are investigated. The initial strength and survival rate of a dental Y-TZP ceramic material to fatigue testing was found to be highly dependent upon surface preparation more so than exposure to various hydrothermal exposure conditions. The results suggest that the monoclinic phase generated by either surface damage (especially sandblasting) and to a lesser extent hydrothermal exposure does appear to mitigate strength and fatigue degradation. The results are discussed in terms of the size of defects generated following various surface treatments and the role of cyclic fatigue induced crack growth. A critical ratio is established between the monotonic strength and fatigue stress survival. From the specimens that failed and exhibited reduced strength after cycling a plot of averaged crack growth rate versus max cyclic stress intensity factor was established which closely matched existing results for Y-TZP ceramics. PMID- 24781535 TI - The risks of methodology aversion in drug regulation. AB - Decisions made by drug regulatory agencies require a high level of expertise in statistical methodologies. Without urgent efforts to enhance the level of such expertise in European regulatory agencies, there is a risk that they will not be able to meet emerging challenges such as quantitative modelling of benefit-risk profiles, wider use of innovative trial designs and greater public transparency of clinical trial data. PMID- 24781536 TI - Cancer charity sees success re-prioritizing industry's shelved compounds. PMID- 24781537 TI - Zinc-finger nucleases make the cut in HIV. PMID- 24781541 TI - Trial watch: personalized medicines in late-stage development. PMID- 24781542 TI - 18 months sliced off Celebrex's patent protection. PMID- 24781544 TI - Anticancer drugs: A new weapon against metastatic melanoma. PMID- 24781545 TI - Heart Failure: Targeting miRNA pathology in heart disease. PMID- 24781551 TI - Design and synthesis of 3,3'-biscoumarin-based c-Met inhibitors. AB - A library of biscoumarin-based c-Met inhibitors was synthesized, based on optimization of 3,3'-biscoumarin hit 3, which was identified as a non-ATP competitive inhibitor of c-Met from a diverse library of coumarin derivatives. Among these compounds, 38 and 40 not only showed potent enzyme activities with IC50 values of 107 nM and 30 nM, respectively, but also inhibited c-Met phosphorylation in BaF3/TPR-Met and EBC-1 cells. PMID- 24781552 TI - Severe asthma: novel advances in the pathogenesis and therapy. AB - Asthma affects an estimated 300 million people worldwide and is severe in approximately 10% of sufferers. Asthma, especially severe asthma, is a heterogeneous disease that results from complex host-environment interactions. This review article outlines recent advances in both the understanding of pathogenesis and novel therapies. The pathogenesis of severe asthma can be broadly thought of in four domains: T(H)2 inflammation, non -T(H)2 inflammation, airway remodeling, and airway smooth muscle dysfunction. They can develop independently or partly as a consequence of each other. Interactions between these domains, their causation, and consequent impact upon disordered airway physiology and clinical expression are poorly understood. Recent advances in specific T(H)2- and non -T(H2)-targeted therapy, bronchial thermoplasty targeting airway remodeling and advances in therapies for airway smooth muscle dysfunction present new opportunities for treatment and inform our understanding of asthma pathogenesis. As our understanding of the pathogenesis increases, the need for individualized investigation, treatment, and management of asthma becomes more apparent. PMID- 24781553 TI - Prevalence and progression of chronic kidney disease in adult patients with sickle cell disease. AB - AIM: We evaluated the prevalence and progression of chronic kidney disease (CKD) during the 5-year period in a cohort of patients with sickle cell disease (SCD) aged 18 years and older. METHODS: We studied 98 patients with SCD. Chronic kidney disease stages I through V were defined based on estimated glomerular filtration rate (eGFR), and albuminuria grades were defined based on spot urine protein-to creatinine ratio according to the 2012 Kidney Disease Improving Global Outcomes recommendations. In patients with eGFR of greater than 60 mL/min per 1.73 m(2), CKD was diagnosed if grade A2 or A3 albuminuria was present. Chronic kidney disease progression was defined as an increase in CKD stage with an additional eGFR reduction of more than 25% from baseline. RESULTS: At baseline, 28.6% of patients had CKD. After a mean follow-up of 5.0 (SD, 0.9) years, 17 patients developed new CKD and the overall CKD prevalence increased to 41.8%. In addition, 8 patients experienced CKD progression. The following baseline variables were associated with the development and progression of CKD in univariate analysis: older age (P = 0.003), higher systolic blood pressure (BP; P = 0.003), lower eGFR (P = 0.001), higher serum creatinine (P = 0.001), and A3 albuminuria (P = 0.008). In multivariate analysis, baseline A3 albuminuria (adjusted odds ratio, 5.0; 95% confidence interval, 1.1-24.3; P = 0.048) and each 1-mm Hg increase in systolic BP (adjusted odds ratio, 1.04; 95% confidence interval, 1.0-1.07; P = 0.039) predicted CKD development and progression. CONCLUSIONS: Chronic kidney disease is common in patients with SCD and its prevalence increases with age. Several baseline modifiable and nonmodifiable factors were associated with the development and progression of CKD in patients with SCD. Strategies targeting BP control and proteinuria may be beneficial for individuals with SCD. PMID- 24781554 TI - Tripodal molecules for the promotion of phosphoester hydrolysis. AB - A series of low molecular weight tripodal amide/histidine-containing compounds (1 2) have been synthesised and shown to increase the rate of bis-(p-nitrophenyl) phosphate (BNPP) and soman (GD) breakdown in buffered aqueous solution. PMID- 24781555 TI - Anesthesia & Analgesia's collection on the perioperative surgical home. PMID- 24781550 TI - Therapeutic modulation of Notch signalling--are we there yet? AB - The Notch signalling pathway is evolutionarily conserved and is crucial for the development and homeostasis of most tissues. Deregulated Notch signalling leads to various diseases, such as T cell leukaemia, Alagille syndrome and a stroke and dementia syndrome known as CADASIL, and so strategies to therapeutically modulate Notch signalling are of interest. Clinical trials of Notch pathway inhibitors in patients with solid tumours have been reported, and several approaches are under preclinical evaluation. In this Review, we focus on aspects of the pathway that are amenable to therapeutic intervention, diseases that could be targeted and the various Notch pathway modulation strategies that are currently being explored. PMID- 24781556 TI - The anesthesiologist-directed perioperative surgical home: a great idea that will succeed only if it is embraced by hospital administrators and surgeons. PMID- 24781557 TI - Cognitive outcome of surgery: is there no place like home? PMID- 24781558 TI - Enhanced recovery after surgery versus perioperative surgical home: is it all in the name? PMID- 24781559 TI - Sedation depth and mortality: a large randomized trial is required. PMID- 24781560 TI - Bispectral index, sedation, spinal anesthesia and mortality: time to put the jigsaw puzzle together? PMID- 24781561 TI - Perioperative renin-angiotensin blockade: to continue or discontinue, that is the question! PMID- 24781562 TI - Perineural dexamethasone and multimodal perineural analgesia: how much is too much? PMID- 24781563 TI - Education and management case reports. PMID- 24781564 TI - The rationale and development of an adult cardiac anesthesia module to supplement the society of thoracic surgeons national database: using data to drive quality. PMID- 24781565 TI - TEG(r) functional fibrinogen analysis may overestimate fibrinogen levels. AB - Fibrinogen is of crucial importance in patients with ongoing bleeding. In this study, we compared fibrinogen concentration measured by thrombelastography (TEG(r)) with fibrinogen plasma concentration determined by Clauss. Sixty-three surgical patients and 38 healthy controls were included. For the whole group (patients and controls, n = 101), TEG(r) functional fibrinogen was on average 1.0 g/L higher than the plasma fibrinogen concentration (3.5 vs 2.5 g/L, 95% confidence interval for difference 0.8 to 1.2 g/L, P < 0.0001). Similar patterns were observed when patients and healthy controls were analysed separately. The fibrinogen level may be overestimated when assessed using TEG(r) compared with the fibrinogen plasma concentration measured by the conventional method. PMID- 24781566 TI - Thrombomodulin improved liver injury, coagulopathy, and mortality in an experimental heatstroke model in mice. AB - BACKGROUND: Heatstroke is a life-threatening illness and causes high mortality due to multiple organ injuries. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that plays an important role in the regulation of intravascular coagulation. In this study, we investigated the effect of TM on the inflammatory process, liver function, coagulation status, and mortality in experimental heatstroke. METHODS: Male C3H/HeN (8-10 weeks) mice were randomly assigned to the TM-treated group (TG-Pre) or nontreated heatstroke group (HS). In group TG-Pre, mice were treated with recombinant soluble TM (1 mg/kg, intraperitoneally) before heat exposure. In some experiments, recombinant soluble TM was administrated during heat exposure (TG-Delay). Heatstroke was induced by exposure to ambient temperature of 38 degrees C for 4 hours. After heat exposure, the levels of tumor necrosis factor-alpha, interleukin-6, and plasma high mobility group box 1 (HMGB1), liver function, plasma aspartate aminotransferase and alanine aminotransferase concentrations, and immunohistochemical and histopathological characteristics of the livers were determined. The coagulation status, plasma protein C levels, and thrombin-antithrombin complex levels were also measured. RESULTS: In group HS, plasma cytokines and HMGB1 concentrations increased after heat exposure. Plasma aspartate aminotransferase and alanine aminotransferase concentrations increased after heat exposure. In group HS livers, strong and extensive immunostaining for HMGB1 was observed. In addition, there was extensive hepatocellular necrosis and collapse of nuclei observed. In group HS, plasma protein C levels were suppressed and plasma thrombin antithrombin complex levels increased. In group TG-Pre, plasma cytokines and HMGB1 concentrations were suppressed after heat exposure compared with group HS. Liver injury, coagulopathy, and mortality also improved in group TG-Pre. Furthermore, recombinant soluble TM treatment decreased mortality even with delayed treatment. CONCLUSIONS: This study demonstrated that recombinant soluble TM suppressed plasma cytokines and HMGB1 concentrations after heat exposure. Recombinant soluble TM also improved liver injury and coagulopathy. Recombinant soluble TM treatment improved mortality even with delayed treatment. Recombinant soluble TM may be a beneficial treatment for heatstroke patients. PMID- 24781567 TI - Sedation depth during spinal anesthesia and survival in elderly patients undergoing hip fracture repair. AB - Low intraoperative Bispectral Index (BIS) values may be associated with increased mortality. In a previously reported trial to prevent delirium, we randomized patients undergoing hip fracture repair under spinal anesthesia to light (BIS >80) or deep (BIS approximately 50) sedation. We analyzed survival of patients in the original trial. Among all patients, mortality was equivalent across sedation groups. However, among patients with serious comorbidities (Charlson score >4), 1 year mortality was reduced in the light (22.2%) vs deep (43.6%) sedation group (hazard ratio [HR], 0.43; 95% confidence interval, 0.19-0.97; P = 0.04) during spinal anesthesia. Similarly, among patients with Charlson score >6, 1-year mortality was reduced in the light (28.6%) vs deep (52.6%) sedation group (HR 0.33; 95% confidence interval, 0.12-0.94; P = 0.04) during spinal anesthesia. Further research on reduced mortality after light sedation during spinal anesthesia is needed. PMID- 24781568 TI - A pilot study for a prospective, randomized, double-blind trial of the influence of anesthetic depth on long-term outcome. AB - BACKGROUND: Deep general anesthesia has been associated with increased mortality in 5 observational studies. The association may be causal or an epiphenomenon due to increased anesthetic sensitivity in high-risk patients. We conducted a pilot study to assess the feasibility of performing a definitive randomized controlled trial. The aims of the study were to determine whether anesthetic depth targeting in a high-risk group was feasible and to document anesthetic doses and arterial blood pressures associated with "deep" and "light" general anesthesia. METHODS: ASA physical status III and IV patients, aged >=60 years, having surgery lasting >=2 hours, with expected hospital stay >=2 days, and receiving general anesthesia were randomly allocated to a Bispectral Index (BIS) or spectral entropy (SE) target of 35 ("low" group) or 50 ("high" group). The primary end point was mean BIS or SE. Secondary end points were postanesthesia care unit length of stay and pain scores, quality of recovery score, hospital length of stay, postoperative complications, and death. A composite end point of postoperative complications (pneumonia, myocardial infarction, stroke, pulmonary embolism, heart failure, and death) was determined at 1 year. RESULTS: One hundred twenty-five patients were recruited. The mean of the median BIS/SE values for each patient during the maintenance phase of anesthesia in the low and high groups was significantly different: 39 vs 48 (mean difference 8 [95% confidence interval {CI95}, 6 to 10], P < 0.001). There was also a significant difference in mean volatile anesthetic administration (minimum alveolar concentration): 0.98 vs 0.64 (mean difference 0.35 [CI95, -0.44 to -0.26], P < 0.001) and target propofol concentrations: 4.0 vs 3.1 MUg/mL (mean difference -0.8 [CI95, -1.2 to -0.3], P = 0.004). Intraoperative mean arterial blood pressures were similar (85 vs 87 mm Hg; mean difference 2 [CI95, -2 to 6], P = 0.86), and there were no differences in short term recovery characteristics or hospital length of stay. There was a significant difference in the incidence of wound infection at 30 days (13% vs 3%; risk difference -10% [CI95, -21 to -0.1], P = 0.04). At 1 year, the composite rates of complications in the low and high groups were 28% and 17% (risk difference -11 [CI95, -25 to 4], P = 0.15) and mortality rates were 12% and 9%, respectively (risk difference -2 [CI95, -14 to 9], P = 0.70). CONCLUSIONS: This pilot study demonstrated that depth of anesthesia targeting with BIS or SE was achievable in a high-risk population with adequate separation of processed electroencephalogram monitor targets. The expected incidence of postoperative complications and mortality occurred. We conclude that a large, multicenter, randomized controlled trial is feasible. PMID- 24781569 TI - The association between ASA status and other risk stratification models on postoperative intensive care unit outcomes. AB - BACKGROUND: There is limited medical literature investigating the association between perioperative risk stratification methods and surgical intensive care unit (SICU) outcomes. Our hypothesis contends that routine assessments such as higher ASA physical status classification, surgical risk as defined by American College of Cardiology/American Heart Association guidelines, and simplified Revised Cardiac Index (SRCI) can reliably be associated with SICU outcomes. METHODS: We performed a chart review of all patients 18 years or older admitted to the SICU between October 1, 2010, and March 1, 2011. We collected demographic and preoperative clinical data: age, sex, ASA physical status class, surgical risk, and SRCI. Outcome data included our primary end point, SICU length of stay, and secondary end points: mechanical ventilation and vasopressor treatment duration, number of acquired organ dysfunctions (NOD), readmission to the intensive care unit (ICU) within 7 days, SICU mortality, and 30-day mortality. Regression analysis and nonparametric tests were used, and P < 0.05 was considered significant. RESULTS: We screened 239 patients and included 220 patients in the study. The patients' mean age was 58 +/- 16 years. There were 32% emergent surgery and 5% readmissions to the SICU within 7 days. The SICU mortality and the 30-day mortality were 3.2%. There was a significant difference between SICU length of stay (2.9 +/- 2.1 vs 5.9 +/- 7.4, P = 0.007), mechanical ventilation (0.9 +/- 2.0 vs 3.4 +/- 6.8, P = 0.01), and NOD (0 [0-2] vs 1 [0-5], P < 0.001) based on ASA physical status class (<= 2 vs >= 3). Outcomes significantly associated with ASA physical status class after adjusting for confounders were: SICU length of stay (incidence rate ratio [IRR] = 1.79, 95% confidence interval [CI], 1.35-2.39, P < 0.001), mechanical ventilation (IRR = 2.57, 95% CI, 1.69-3.92, P < 0.001), vasopressor treatment (IRR = 3.57, 95% CI, 1.84-6. 94, P < 0.001), NOD (IRR = 1.71, 95% CI, 1.46-1.99, P < 0.001), and readmission to ICU (odds ratio = 3.39, 95% CI, 1.04-11.09, P = 0.04). We found significant association between surgery risk and NOD (IRR = 1.56, 95% CI, 1.29 1.89, P < 0.001, and adjusted IRR = 1.31, 95% CI, 1.05-1.64, P = 0.02). SRCI was not significantly associated with SICU outcomes. CONCLUSIONS: Our study revealed that ASA physical status class is associated with increased SICU length of stay, mechanical ventilation, vasopressor treatment duration, NOD, readmission to ICU, and surgery risk is associated with NOD. PMID- 24781570 TI - The Society for Obstetric Anesthesia and Perinatology consensus statement on the management of cardiac arrest in pregnancy. AB - This consensus statement was commissioned in 2012 by the Board of Directors of the Society for Obstetric Anesthesia and Perinatology to improve maternal resuscitation by providing health care providers critical information (including point-of-care checklists) and operational strategies relevant to maternal cardiac arrest. The recommendations in this statement were designed to address the challenges of an actual event by emphasizing health care provider education, behavioral/communication strategies, latent systems errors, and periodic testing of performance. This statement also expands on, interprets, and discusses controversial aspects of material covered in the American Heart Association 2010 guidelines. PMID- 24781571 TI - A novel method for ultrasound-guided radial arterial catheterization in pediatric patients. AB - BACKGROUND: Radial arterial catheterization in pediatric patients is occasionally difficult despite ultrasound guidance. We therefore assessed the factors affecting catheterization and tested an intervention designed to improve its success. METHODS: For initial assessment, we performed multiple logistic regression analyses using 102 pediatric patients. Dependent variables included first-attempt and overall success or failure; independent variables were systolic blood pressure, weight, ASA physical status, trisomy 21, arterial diameter, and subcutaneous depth of the radial artery (<2, 2-4, >=4 mm). The effect of subcutaneous arterial depth on cannulation success was assessed using Kaplan Meier curves with log-rank and Dunn tests. We then assessed catheterization success in 60 patients who were randomized to no treatment or subcutaneous saline injection, as necessary, to increase the subcutaneous arterial depth from <2 to 2 to 4 mm. RESULTS: Subcutaneous arterial depth of 2 to 4 mm was derived as a significant independent predictor of initial and overall success from the multiple logistic regression analyses. The 2 to 4 mm group had a significantly shorter catheterization time compared with the other 2 groups in the log-rank test (2-4 vs <2 mm group; P = 0.01, 2-4 vs >=4 mm group; P < 0.001), and higher success rate in the first attempt (<2 [43.8%] vs 2-4 mm [76.9%], P = 0.02; 2-4 [76.9%] vs >=4.0 mm [19.4%], P < 0.001), and the overall attempt (<2 [62.5%] vs 2 4 mm [89.7%], P = 0.04; 2-4 [89.7%] vs >=4.0 mm [51.6%], P = 0.002). Injecting subcutaneous saline to bring arterial depth from <2 mm to 2 to 4 mm significantly shortened catheterization time (P = 0.002), and improved the success rate in the first-attempt (saline injection [85.0%] vs <2 mm [30.0%], P < 0.001), and the overall attempt (saline injection [90.0%] vs <2 mm [55.0%], P = 0.02). CONCLUSIONS: Ultrasound-guided radial artery catheterization in pediatric patients was fastest and most reliable when the artery was 2 to 4 mm below the skin surface. For arteries located <2 mm below the skin surface, increasing the depth to 2 to 4 mm by subcutaneous saline injection reduced catheterization time and improved the success rate. PMID- 24781572 TI - Cognitive dysfunction after fast-track hip and knee replacement. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is reported to occur after major surgery in as many as 20% of patients, elderly patients may especially experience problems in the weeks and months after surgery. Recent studies vary greatly in methods of evaluation and diagnosis of POCD, and the pathogenic mechanisms are still unclear. We evaluated a large uniform cohort of elderly patients in a standardized approach, after major joint replacement surgery (total hip and knee replacement). Patients were in an optimized perioperative approach (fast track) with multimodal opioid-sparing analgesia, early mobilization, and short length of stay (LOS <=3 days) and discharged to home. METHODS: In a prospective multicenter study, we included 225 patients aged >=60 years undergoing well-defined fast-track total hip or total knee replacement. Patients had neuropsychological testing preoperatively and 1 to 2 weeks and 3 months postoperatively. LOS, pain, opioid use, inflammatory response, and sleep quality were recorded. The practice effect of repeated cognitive testing was gauged using data from a healthy community-dwelling control group (n = 161). RESULTS: Median LOS was 2 days (interquartile range 2-3). The incidence of POCD at 1 to 2 weeks was 9.1% (95% confidence interval [CI], 5.4%-13.1%) and 8.0% (95% CI, 4.5%-12.0%) at 3 months. There was no statistically significant difference between patients with and without early POCD, regarding pain, opioid use, sleep quality, or C reactive protein response, although the CIs were wide. Patients with early POCD had a higher Mini Mental State Examination score preoperatively (difference in medians 0.5 [95% CI, -1.0% to 0.0%]; P = 0.034). If there was an association between early POCD and late POCD, the sample size was unfortunately too small to verify this (23.6% of patients with early POCD had late onset vs 6.7% in non-POCD group; risk difference 16.9 (95% CI, -2.1% to 41.1%; P = 0.089). CONCLUSIONS: The incidence of POCD early after total hip and knee replacement seems to be lower after a fast-track approach than rates previously reported for these procedures, but late POCD occurred with an incidence similar to that in previous studies of major noncardiac elective surgery. No association between early and late POCD could be verified. PMID- 24781573 TI - The antiapoptotic effect of remifentanil on the immature mouse brain: an ex vivo study. AB - BACKGROUND: The use of remifentanil in a context of potential prematurity led us to explore ex vivo the opioid effects on the immature mouse brain. Remifentanil enhances medullary glutamatergic N-methyl-D-aspartate (NMDA) receptor activity. Furthermore, in neonatal mouse cortex, NMDA was previously shown to exert either excitotoxic or antiapoptotic effects depending on the cortical layers. With the use of a model of acute cultured brain slices, we evaluated the potential necrotic and apoptotic effects of remifentanil, alone or associated with its glycine vehicle (commercial preparation of remifentanil, C.P. remifentanil), on the immature brain. METHODS: Cerebral slices from postnatal day 2 mice were treated up to 5 hours with the different compounds, incubated alone or in the presence of NMDA. The necrotic effect was studied by measuring lactate dehydrogenase activity and 7-Aminoactinomycin D labeling. Apoptotic death was evaluated by measurement of caspase-3 activity and cleaved caspase-3 protein levels, using Western blot and immunohistochemistry. Extrinsic and intrinsic apoptotic pathways were investigated by measuring caspase-8, caspase-9 activities, Bax protein levels, and mitochondrial integrity. RESULTS: C.P. remifentanil was ineffective on necrotic death, whereas it significantly reduced caspase-3 activity and cortical cleaved caspase-3 levels. C.P. remifentanil inhibited cortical Bax protein expression, caspase-9 activity, and preserved mitochondrial integrity, whereas it had no effect on caspase-8 activity. Its action targeted the neocortex superficial layers, and it was reversed by the opioid receptors antagonist naloxone and the NMDA antagonist MK801. Remifentanil and glycine acted synergistically to inhibit apoptotic death. In addition, C.P. remifentanil enhanced the antiapoptotic effect of NMDA, whereas it did not improve NMDA excitotoxicity in brain slices. CONCLUSION: The present data indicate that at a supraclinical concentration C.P. remifentanil had no pronecrotic effect but exerted ex vivo antiapoptotic action on the immature mouse brain, involving the opioid and NMDA receptors, and the mitochondrial-dependent apoptotic pathway. Assessment of the impact of the antiapoptotic effect of remifentanil in in vivo neonatal mouse models of brain injury will also be essential to measure its consequences on the developing brain. PMID- 24781574 TI - Reduced length of hospital stay in colorectal surgery after implementation of an enhanced recovery protocol. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) is a multimodal approach to perioperative care that combines a range of interventions to enable early mobilization and feeding after surgery. We investigated the feasibility, clinical effectiveness, and cost savings of an ERAS program at a major U. S. teaching hospital. METHODS: Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, before and after implementation of an ERAS protocol. Data collected included patient demographics, operative, and perioperative surgical and anesthesia data, need for analgesics, complications, inpatient medical costs, and 30-day readmission rates. RESULTS: There were 99 patients in the traditional care group, and 142 in the ERAS group. The median length of stay (LOS) was 5 days in the ERAS group compared with 7 days in the traditional group (P < 0.001). The reduction in LOS was significant for both open procedures (median 6 vs 7 days, P = 0.01), and laparoscopic procedures (4 vs 6 days, P < 0.0001). ERAS patients had fewer urinary tract infections (13% vs 24%, P = 0.03). Readmission rates were lower in ERAS patients (9.8% vs 20.2%, P = 0.02). DISCUSSION: Implementation of an enhanced recovery protocol for colorectal surgery at a tertiary medical center was associated with a significantly reduced LOS and incidence of urinary tract infection. This is consistent with that of other studies in the literature and suggests that enhanced recovery programs could be implemented successfully and should be considered in U.S. hospitals. PMID- 24781575 TI - Strategies for net cost reductions with the expanded role and expertise of anesthesiologists in the perioperative surgical home. AB - The Perioperative Surgical Home is a model adopted by the American Society of Anesthesiologists to increase quality and patient safety and to decrease costs. This Special Article is about the latter topic. Using narrative review, we show that there are two principal opportunities for net cost reduction. One opportunity is to reduce unnecessary interventions that do not have potential to benefit patients (e.g., preoperative laboratory studies in healthy patients undergoing low-risk surgery and use of substantial fresh gas flows with volatile anesthetics). The other opportunity is to optimize staff scheduling, case scheduling, and staff assignment. These two are the same as the principal ways that a positive return on investment can be achieved from use of an anesthesia information management system. Three other opportunities are much less likely to achieve as large (if any) net cost reduction among all patients but may at some hospitals. These are to reduce cancellations, operating room times, and/or hospital postoperative lengths of stay. PMID- 24781576 TI - Implementation of a total joint replacement-focused perioperative surgical home: a management case report. AB - BACKGROUND: The perioperative setting in the United States is noted for variable and fragmented care that increases the chance for errors and adverse outcomes as well as the overall cost of perioperative care. Recently, the American Society of Anesthesiologists put forward the Perioperative Surgical Home (PSH) concept as a potential solution to this problem. Although the PSH concept has been described previously, "real-life" implementation of this new model has not been reported. METHODS: Members of the Departments of Anesthesiology and Perioperative Care and Orthopedic Surgery, in addition to perioperative hospital services, developed and implemented a series of clinical care pathways defining and standardizing preoperative, intraoperative, postoperative, and postdischarge management for patients undergoing elective primary hip (n = 51) and knee (n = 95) arthroplasty. We report on the impact of the Total Joint Replacement PSH on length of hospital stay (LOS), incidence of perioperative blood transfusions, postoperative complications, 30-day readmission rates, emergency department visits, mortality, and patient satisfaction. RESULTS: The incidence of major complication was 0.0 (0.0-7.0)% and of perioperative blood transfusion was 6.2 (2.9-11.4)%. In hospital mortality was 0.0 (0.0-7.0)% and 30-day readmission was 0.7 (0.0-3.8)%. All Surgical Care Improvements Project measures were at 100.0 (93.0-100.0)%. The median LOS for total knee arthroplasty and total hip arthroplasty, respectively, was (median (95% confidence interval [interquartile range]) 3 (2-3) [2-3] and 3 (2-3) [2-3] days. Approximately half of the patients were discharged to a location other than their customary residence (70 to skilled nursing facility, 1 to rehabilitation, 39 to home with organization health services, and 36 to home). CONCLUSIONS: We believe that our experience with the Total Joint Replacement PSH program provides solid evidence of the feasibility of this practice model to improve patient outcomes and achieve high patient satisfaction. In the future, the impact of LOS on cost will have to be better quantified. Specifically, future studies comparing PSH to traditional care will have to include consideration of postdischarge care, which are drivers of the perioperative costs. PMID- 24781577 TI - The effects of glucocorticoids on neuropathic pain: a review with emphasis on intrathecal methylprednisolone acetate delivery. AB - Methylprednisolone acetate (MPA) has a long history of use in the treatment of sciatic pain and other neuropathic pain syndromes. In several of these syndromes, MPA is administered in the epidural space. On a limited basis, MPA has also been injected intrathecally in patients suffering from postherpetic neuralgia and complex regional pain syndrome. The reports on efficacy of intrathecal administration of MPA in neuropathic pain patients are contradictory, and safety is debated. In this review, we broadly consider mechanisms whereby glucocorticoids exert their action on spinal cascades relevant to the pain arising after nerve injury and inflammation. We then focus on the characteristics of the actions of MPA in pharmacokinetics, efficacy, and safety when administered in the intrathecal space. PMID- 24781578 TI - The perioperative surgical home as a future perioperative practice model. PMID- 24781579 TI - The perioperative surgical home: how anesthesiology can collaboratively achieve and leverage the triple aim in health care. PMID- 24781580 TI - Morton versus Jackson: compare with the soporific sponge and ether therapy. PMID- 24781581 TI - In response. PMID- 24781582 TI - Preoperative evaluation of patients with pacemakers and implanted cardioverter defibrillators. PMID- 24781583 TI - We need to understand our electronics! PMID- 24781584 TI - In response. PMID- 24781585 TI - In response. PMID- 24781586 TI - The Toast++ software suite for forward and inverse modeling in optical tomography. AB - We present the Toast++ open-source software environment for solving the forward and inverse problems in diffuse optical tomography (DOT). The software suite consists of a set of libraries to simulate near-infrared light propagation in highly scattering media with complex boundaries and heterogeneous internal parameter distribution, based on a finite-element solver. Steady-state, time- and frequency-domain data acquisition systems can be modeled. The forward solver is implemented in C++ and supports performance acceleration with parallelization for shared and distributed memory architectures, as well as graphics processing computation. Building on the numerical forward solver, Toast++ contains model based iterative inverse solvers for reconstructing the volume distribution of absorption and scattering parameters from boundary measurements of light transmission. A range of regularization methods are provided, including the possibility of incorporating prior knowledge of internal structure. The user can link to the Toast++ libraries either directly to compile application programs for DOT, or make use of the included MATLAB and PYTHON bindings to generate script based solutions. This approach allows rapid prototyping and provides a rich toolset in both environments for debugging, testing, and visualization. PMID- 24781587 TI - Enhanced spatial resolution in fluorescence molecular tomography using restarted L1-regularized nonlinear conjugate gradient algorithm. AB - Owing to the high degree of scattering of light through tissues, the ill posedness of fluorescence molecular tomography (FMT) inverse problem causes relatively low spatial resolution in the reconstruction results. Unlike L2 regularization, L1 regularization can preserve the details and reduce the noise effectively. Reconstruction is obtained through a restarted L1 regularization based nonlinear conjugate gradient (re-L1-NCG) algorithm, which has been proven to be able to increase the computational speed with low memory consumption. The algorithm consists of inner and outer iterations. In the inner iteration, L1-NCG is used to obtain the L1-regularized results. In the outer iteration, the restarted strategy is used to increase the convergence speed of L1-NCG. To demonstrate the performance of re-L1-NCG in terms of spatial resolution, simulation and physical phantom studies with fluorescent targets located with different edge-to-edge distances were carried out. The reconstruction results show that the re-L1-NCG algorithm has the ability to resolve targets with an edge to-edge distance of 0.1 cm at a depth of 1.5 cm, which is a significant improvement for FMT. PMID- 24781588 TI - Roles of linear and circular polarization properties and effect of wavelength choice on differentiation between ex vivo normal and cancerous gastric samples. AB - Multispectral Mueller matrix imaging was performed over a spectral range from 470 to 632 nm on 4-MUm unstained gastric tissue sections. A complete set of polarization parameters was derived. The combination of linear depolarization and linear retardance yields the highest accuracy in sample classification. When the depolarization of linearly polarized light due to scattering is independent of the orientation angle of the incident linear polarization vector, the derivation of linear polarization properties will require only 3*3 Mueller matrix, which would significantly reduce the complexity of the polarimetry imaging system. When additional parameters are needed to complement the two linear polarization parameters, retardance, circular depolarization, and depolarization can be included in classification in the order of preference. However, these additional parameters would require the measurement of 4*4 Mueller matrix. In addition, it appears that wavelength is not a critical factor in terms of classification accuracy for thin tissue sections in this study. PMID- 24781589 TI - Monitoring the blood coagulation process under various flow conditions with optical coherence tomography. AB - Our previous work demonstrated that an optical coherence tomography (OCT) technique was able to characterize the whole blood coagulation process. The 1/e light penetration depth (d(1/e)) derived from the profiles of reflectance versus depth was developed for detecting the whole blood coagulation process in static state. To consider the effect of blood flow, in the present study, d(1/e) versus time from the coagulating porcine blood circulated in a mock flow loop with various steady laminar flows at mean flow speed in the range from 5 to 25 mm/s. The variation of d(1/e) was used to represent the change of blood properties during coagulation in different hematocrits (HCT) ranging from 25% to 55%, velocities from 5 to 25 mm/s, and tubing sizes from 0.9 to 2 mm. The results showed that there were positive correlations between coagulation time (t(c)) and HCT, velocity, and tubing size, respectively. In addition, the coagulation rate (S(r)) was decreased with the increase of HCT, velocity, and tubing size. This study testified that HCT, flow velocity, and tubing size were substantial factors affecting the backscattering properties during flowing blood coagulation. Furthermore, OCT has the potential to represent the process of flowing blood coagulation with proper parameters. PMID- 24781590 TI - Accurate single-shot quantitative phase imaging of biological specimens with telecentric digital holographic microscopy. AB - The advantages of using a telecentric imaging system in digital holographic microscopy (DHM) to study biological specimens are highlighted. To this end, the performances of nontelecentric DHM and telecentric DHM are evaluated from the quantitative phase imaging (QPI) point of view. The evaluated stability of the microscope allows single-shot QPI in DHM by using telecentric imaging systems. Quantitative phase maps of a section of the head of the drosophila melanogaster fly and of red blood cells are obtained via single-shot DHM with no numerical postprocessing. With these maps we show that the use of telecentric DHM provides larger field of view for a given magnification and permits more accurate QPI measurements with less number of computational operations. PMID- 24781591 TI - Twenty-four-hour ambulatory recording of cerebral hemodynamics, systemic hemodynamics, electrocardiography, and actigraphy during people's daily activities. AB - The feasibility and utility of wearable 24-h multimodality neuromonitoring during daily activities are demonstrated. We have developed a fourth-generation ambulatory near infrared spectroscopy device, namely NINscan 4. NINscan 4 enables recording of brain function (via cerebral hemodynamics), systemic hemodynamics, electrocardiography, and actigraphy simultaneously and continuously for up to 24 h at 250-Hz sampling rate, during (and with minor restriction to) daily activities. We present initial 24-h human subject test results, with example analysis including (1) comparison of cerebral perfusion and oxygenation changes during wakefulness and sleep over a 24-h period and (2) capturing of hemodynamic changes prior, during and after sudden waken up in the night during sleep. These results demonstrate the first ambulatory 24-h cerebral and systemic hemodynamics monitoring, and its unique advantages including long-term data collection and analysis capability, ability to catch unpredictable transient events during activities of daily living, as well as coregistered multimodality analysis capabilities. These results also demonstrate that NINscan 4's motion artifact at 1-g head movement is smaller than physiological hemodynamic fluctuations during motionless sleep. The broader potential of this technology is also discussed. PMID- 24781592 TI - Effects of cavitation bubble interaction with temporally separated fs-laser pulses. AB - We present a time-resolved photographic analysis of the pulse-to-pulse interaction. In particular, we studied the influence of the cavitation bubble induced by a fs-pulse on the optical focusing of the consecutive pulse and its cavitation bubble dynamics in dependence on temporal pulse separation in water. As a first result, by decreasing the temporal separation of laser pulses, there is a diminishment of the laser-induced optical breakdown (LIOB) efficiency in terms of energy conversion, caused by disturbed focusing into persisting gas bubbles at the focal volume. A LIOB at the focal spot is finally suppressed by impinging the expanding or collapsing cavitation bubble of the preceding pulse. These results could be additionally confirmed in porcine gelatin solution with various concentrations. Hence, the interaction between the laser and transparent ophthalmic tissue may be accompanied by a raised central laser energy transmission, which could be observed in case of a temporal pulse overlap. In conclusion, our experimental results are of particular importance for the optimization of the prospective ophthalmic surgical process with future generation fs-lasers. PMID- 24781593 TI - Laser phototherapy triggers the production of reactive oxygen species in oral epithelial cells without inducing DNA damage. AB - Laser phototherapy (LPT) is widely used in clinical practice to accelerate healing. Although the use of LPT has advantages, the molecular mechanisms involved in the process of accelerated healing and the safety concerns associated with LPT are still poorly understood. We investigated the physiological effects of LPT irradiation on the production and accumulation of reactive oxygen species (ROS), genomic instability, and deoxyribose nucleic acid (DNA) damage in human epithelial cells. In contrast to a high energy density (20 J/cm2), laser administered at a low energy density (4 J/cm2) resulted in the accumulation of ROS. Interestingly, 4 J/cm2 of LPT did not induce DNA damage, genomic instability, or nuclear influx of the BRCA1 DNA damage repair protein, a known genome protective molecule that actively participates in DNA repair. Our results suggest that administration of low energy densities of LPT induces the accumulation of safe levels of ROS, which may explain the accelerated healing results observed in patients. These findings indicate that epithelial cells have an endowed molecular circuitry that responds to LPT by physiologically inducing accumulation of ROS, which triggers accelerated healing. Importantly, our results suggest that low energy densities of LPT can serve as a safe therapy to accelerate epithelial healing. PMID- 24781596 TI - Insulin resistance, diabetes, and cardiovascular risk. AB - Obesity and type 2 diabetes mellitus (T2DM) are major drivers of cardiovascular disease (CVD). The link between environmental factors, obesity, and dysglycemia indicates that progression to diabetes with time occurs along a "continuum", not necessarily linear, which involves different cellular mechanisms including alterations of insulin signaling, changes in glucose transport, pancreatic beta cell dysfunction, as well as the deregulation of key genes involved in oxidative stress and inflammation. The present review critically addresses key pathophysiological aspects including (i) hyperglycemia and insulin resistance as predictors of CV outcome, (ii) molecular mechanisms underpinning the progression of diabetic vascular complications despite intensive glycemic control, and (iii) stratification of CV risk, with particular emphasis on emerging biomarkers. Taken together, these important aspects may contribute to the development of promising diagnostic approaches as well as mechanism-based therapeutic strategies to reduce CVD burden in obese and diabetic subjects. PMID- 24781597 TI - Primary prevention of cardiovascular disease with statins in the elderly. AB - Owing to the progressive aging of the population, and the fact that cardiovascular disease (CVD) is the leading cause of death among the elderly, the prevention of CVD in the elderly is becoming increasingly important. Although there is no doubt that statin treatment should be used for reducing CVD risk in the elderly in secondary prevention in the same way as in younger individuals, the evidence that such treatment really prolongs life in elderly subjects in primary prevention is still not so clear. However, it seems that it does reduce CVD morbidity in elderly individuals. Because of limited evidence regarding the benefit of such therapy, particularly in very old subjects (older than 80-85 years), the decision whether to treat or not treat an elderly individual with statins in primary prevention should be based on good clinical judgment and considering the individual subject's situation regarding comorbidities, polypharmacy, and possible adverse effects. PMID- 24781598 TI - Update on primary hypobetalipoproteinemia. AB - "Primary hypobetalipoproteinemia" refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions. PMID- 24781599 TI - Developing national selection processes for entry into postgraduate specialty training: the case of trauma and orthopedics in the United Kingdom. AB - A large body of international research has been done investigating best practice selection across many occupational groups, but there is relatively little research on developing selection methodology for entry to postgraduate training. Hitherto, various selection processes have been used, some of which relied heavily on patronage. Developments in Medical Education, including curriculum design, formal work-based place assessment, alongside the introduction of MMC (Modernizing Medical Careers) paved the way for significant change. Trauma and orthopedics in England is the last surgical specialty to adopt National Selection and did so first in 2013. This paper sets out that journey, the implementation of National selection in 2013, what has been learned, and our goals for the future. PMID- 24781600 TI - Preoperative plasma D-dimer level is an independent prognostic factor in patients with completely resected non-small cell lung cancer. AB - PURPOSE: The plasma D-dimer (D-dimer) level, a marker of hypercoagulation, has been reported to be associated with survival in several types of cancers. This retrospective study was conducted to evaluate the prognostic significance of the preoperative D-dimer level in patients with completely resected non-small cell lung cancer (NSCLC). METHODS: A total of 237 completely resected NSCLC patients were included in this study. In addition to age, sex, the smoking status, etc., the association between the preoperative D-dimer level and survival was explored. RESULTS: The patients were divided into three groups according to the D-dimer level: group A (<= 0.50 MUg/ml, n = 76), group B (0.51-0.86 MUg/ml, n = 79) and group C (>0.86 MUg/ml, n = 82). The 5-year overall survival rate was 89.6 % (95 % confidence interval (CI) 77.7-95.3) for group A, 75.1 % (95 % CI 62.3-83.6) for group B and 60.1 % (95 % CI 46.8-71.1) for group C (P trend <0.001). A multivariate survival analysis showed that the D-dimer level (group B vs. group A HR 4.25, group C vs. group A HR 4.11) was an independent significant prognostic factor, in addition to age, sex, the pathological stage and the serum carcinoembryonic antigen level. CONCLUSIONS: The preoperative D-dimer level is an independent prognostic factor in patients with completely resected NSCLC. PMID- 24781602 TI - Commentary: Posterior tension band wiring and instrumentation for thoracolumbar flexion-distraction injuries. PMID- 24781603 TI - Commentary: Time required for effective action of phenol against giant cell tumour cells. PMID- 24781604 TI - Outcome of locking compression plating for proximal humeral fractures: a prospective study. AB - PURPOSE: To evaluate the outcome of open reduction and internal fixation using locking compression plates for proximal humeral fractures. METHODS: 54 men and 16 women aged 28 to 79 (mean, 54) years underwent open reduction and internal fixation using a locking compression plate for closed 2-part (n=22), 3-part (n=38), and 4-part (n=10) proximal humeral fractures. 10 of the patients also had dislocation of the humeral head; 4 had fractures extending to the shaft. Wound condition, functional outcome, bone union, amount of collapse, and malalignment were assessed. Functional outcome was assessed using the Constant-Murley score. RESULTS; The mean follow-up period was 15 (range, 6-24) months. All fractures achieved union after a mean of 9 (range, 6-12) weeks. The mean Constant-Murley scores for the injured and normal shoulders were 72 and 82, respectively (88% of normal). The final outcome was excellent in 14 patients, good in 28, moderate in 22, and poor in 6. In the latter 6 patients, 2 had screw penetration, 2 had plate impingement, one had a mal-reduced greater tuberosity, and one had adhesive capsulitis. All were preventable. In all, 18 patients had 20 complications: subacromial impingement of the plate (n=6), mal-reduction of the greater tuberosity (n=6), screw penetration (n=2), adhesive capsulitis (n=2), superficial infection (n=2), and haematoma (n=2); 12 of these complications were technique related. CONCLUSION: Locking proximal humeral plates enabled stable fixation in all Neer-type proximal humeral fractures. Most complications were technique related. PMID- 24781605 TI - Polyaxial versus uniaxial volar locking plate for distal radial fractures. AB - PURPOSE: To compare the penetration of the distal screws in relation to the thickness of the distal metaphysis in the polyaxial versus uniaxial volar locking plates. METHODS: Records of 78 patients aged 16 to 79 years who underwent open reduction and internal fixation for distal radial fractures (n=81) were reviewed. All fracture subtypes were included. 20 men and 22 women aged 18 to 79 (mean, 50) years were treated with the uniaxial locking plate, whereas 15 men and 21 women aged 16 to 79 (mean, 51) years were treated with the polyaxial locking plate. The choice of plate was determined by the operating surgeon based on familiarity and perceived advantages of the 2 plates. Penetration of the distal locking screws in relation to the volar-dorsal thickness of the distal radial metaphysis was measured, and the percentage of subchondral bone unsupported by the screws calculated. RESULTS: The mean percentage of unsupported subchondral bone was significantly lower in the polyaxial than uniaxial volar locking plate group (12% vs. 23%, p<0.001). No patient had screw over-penetration. CONCLUSION: The polyaxial volar locking plate system enabled deeper insertion of distal screws into the subchondral bone, and thus providing better buttress for the fracture fragments. PMID- 24781606 TI - Valgus osteotomy and repositioning and fixation with a dynamic hip screw and a 135o single-angled barrel plate for un-united and neglected femoral neck fractures. AB - PURPOSE: To review the outcome of 60 patients who underwent valgus subtrochanteric osteotomy and its repositioning for un-united and neglected femoral neck fractures. METHODS: 60 patients (mean age, 35 years) underwent valgus subtrochanteric osteotomy and repositioning of the osteotomy and fixation with a dynamic hip screw and a 135 degrees single-angled barrel plate for closed un-united femoral neck fractures after failed internal fixation (n=27) or neglected (>3 weeks) fractures (n=33). The most common fracture type was transcervical (n=48), followed by subcapital (n=6) and basal (n=6). All patients had displaced femoral neck fractures (Garden types 3 and 4). According to the Pauwel angle, 45 fractures were type 2 (30o-70o) and 15 were type 3 (>70o). RESULTS: Patients were followed up for a mean of 3.5 (range, 2-7.5) years. The mean Pauwel angle of the fracture was corrected from 65 degrees (range, 50 degrees -89 degrees ) to 26 degrees (range, 25 degrees -28 degrees ). Bone union was achieved in 56 patients after a mean of 3.9 (range, 3-5.5) months. The mean Harris hip score improved from 65 to 87.5. Outcome was excellent in 30 patients, good in 24, and poor in 6. Four of the patients developed avascular necrosis; 2 of whom nonetheless achieved a good outcome. CONCLUSION: Valgus osteotomy and repositioning and fixation with a dynamic hip screw and a 135 degrees single angled barrel plate was effective treatment for un-united and neglected femoral neck fractures. PMID- 24781607 TI - Surgical dislocation of the hip for reduction of acetabular fracture and evaluation of chondral damage. AB - PURPOSE: To assess the outcome of open reduction and internal fixation combined with surgical dislocation of the hip for displaced acetabular fractures. METHODS: 20 men and 2 women aged 20 to 55 (mean, 28) years underwent open reduction and internal fixation combined with surgical dislocation of the hip for displaced acetabular fracture. The most common fracture pattern was bicolumnar (n=12), followed by transverse (n=6) and T-type (n=4). Femoral head chondral lesions were classified as grade 0 (no defect) to grade 4 (osteochondral defect). Fracture fragments were fixed with titanium plates and screws, and the femoral head was redislocated to inspect for intraarticular screws. The association between functional status and acetabular fracture pattern and femoral head chondral lesions was explored. RESULTS: Nine patients had chondral lesions in the femoral head (mostly in the anterosuperior zone), but none in the acetabulum. All femoral heads were viable. Reduction was anatomic in 6 patients and satisfactory in 16. Functional outcome was very good in 6 patients, good in 13, medium in 2, and fair in one. No patient developed avascular necrosis of the femoral head. Four patients had iatrogenic sciatic nerve palsy. One patient developed early degenerative hip arthritis and underwent total hip arthroplasty 14 months later. CONCLUSION: Surgical dislocation of the hip facilitated anatomic reduction and inspection of any chondral lesions. It did not result in avascular necrosis of the femoral head. PMID- 24781608 TI - Periprosthetic fractures after total knee arthroplasty. AB - PURPOSE: To evaluate outcome in 20 patients treated for periprosthetic fractures after total knee arthroplasty (TKA). METHODS: Records of 14 women and 6 men aged 45 to 85 (mean, 67) years who underwent operative (n=18) or conservative (n=2) treatment for periprosthetic fractures of the supracondylar femur (n=15), patella (n=3), and tibia (n=2) following minor falls (n=18) or high-velocity injury (n=2) were reviewed. The mean time from TKA to fracture was 43 (range, 14-98) months. Of the 15 supracondylar femoral fractures, 2 were managed with immobilisation in a long leg cast, 11 with internal fixation using locked compression plating, and 2 with revision arthroplasty. All 3 patellar fractures were managed with tension band wiring. Both tibial fractures were managed with revision arthroplasty. Radiographic and functional outcomes (the Knee Society scores) were assessed. RESULTS: The mean follow-up was 35 (range, 24-48) months. All fractures healed after a mean of 15 (range, 12-38) weeks. One patient had delayed union. Postoperative alignment was satisfactory in all patients except one (with 5o varus). The mean tibiofemoral angle was 4o valgus. The mean range of motion was 98.5o. The mean Knee Society knee score was 85 (range, 75-89) and the functional score was 76 (range, 70-85). No patient had implant failure, loss of reduction, deep infection, deep vein thrombosis, or pulmonary embolism. CONCLUSION: The locked compression plate is effective in managing periprosthetic femoral fractures. Periprosthetic patellar and tibial fractures are uncommon. The latter often warrant revision arthroplasty owing to the loose implant. PMID- 24781609 TI - Negative-pressure wound therapy over surgically closed wounds in open fractures. AB - PURPOSE: To evaluate the outcome of open fracture surgery with negative-pressure wound therapy (NPWT) applied directly over surgical wounds. METHODS: Medical records of 10 men and 4 women aged 6 to 70 (mean, 43.7) years who underwent internal fixation, external fixation, or splint application for open fractures of the lower leg (n=7), foot and ankle (n=5), or knee (n=2), and NPWT were reviewed. The NPWT was applied directly over the surgical wound without a non-adherent contact layer. The foam was changed every 3 days. The standard negative pressure was 125 mm Hg. The NPWT was stopped when the wound discharge became <50 ml per day. The duration of NPWT and the level of negative pressure were recorded, as were wound condition, reasons for NPWT, and outcome. RESULTS: The mean duration of NPWT was 9.1 (range, 3-24) days. Four patients developed maceration of the skin under the foam, whereas 2 patients developed skin blisters under the drape. No necrosis of flap skin or infection occurred, and all the fractures eventually united. CONCLUSIONS: Maceration of the skin was seen in some cases but did not affect the overall outcome. NPWT directly over the skin surface had no deleterious effect on wound and fracture healing. PMID- 24781610 TI - First metatarsophalangeal joint fusion using a Fyxis plate. AB - PURPOSE: To report the outcome of fusion of the first metatarsophalangeal joint (MTPJ) using the Fyxis plate and compression screws. METHODS: Medical records of 12 men and 39 women (54 feet) aged 28 to 74 (mean, 58) years who underwent primary fusion of the first MTPJ using the Fyxis plate and compression screws for hallux rigidus (n=38), severe hallux valgus (n=8), or rheumatoid arthritis (n=8) were reviewed. The outcome measures included the fusion rate, time to fusion, complication rate, hallux valgus angle, dorsiflexion angle, and the American Orthopaedic Foot and Ankle Society (AOFAS) scale. RESULTS: The mean follow-up was 14.8 (range, 12-20) months. The mean time to fusion was 3.2 months. 48 feet achieved complete fusion at 3 months, 5 at 6 months, and one had non-union at 12 months, which was treated with revision surgery. The mean hallux valgus angle improved from 23o to 12o. The mean dorsiflexion angle improved from 22o to 23o. The mean AOFAS scale score improved from 31 to 86. 98% of the feet achieved a score of >72. One patient with non-union had a score of 59. Two feet developed superficial wound infection, which resolved with antibiotic treatment. Two other feet developed numbness over the medial aspect of the great toe, which persisted after one year. CONCLUSION: The outcome of fusion of the first MTPJ using the Fyxis plate and compression screws was good. PMID- 24781611 TI - Scarf osteotomy with or without proximal phalangeal osteotomy for severe hallux valgus deformity. AB - PURPOSE: To report outcome of Scarf osteotomy with or without proximal phalangeal osteotomy for correction of severe hallux valgus deformity. METHODS: Records of 48 women and 4 men aged 28 to 68 (mean, 52) years who underwent 57 Scarf osteotomies with or without proximal phalangeal osteotomy for severe hallux valgus by a single surgeon were reviewed. The patients had a hallux valgus angle (HVA) of up to 55o. An additional proximal phalangeal osteotomy was performed in 11 of the patients whose hallux valgus persisted (HVA >10o). The American Orthopaedic Foot and Ankle Society (AOFAS) hallux score, the HVA and intermetatarsal angle (IMA) on radiographs, and the complication rate were assessed. RESULTS: The mean follow-up period was 26 (range, 24-36) months. The mean AOFAS hallux score improved from 57.4 (range, 49-64) to 91.6 (range, 75 100). The mean HVA improved from 38.1o (range, 28o-52o) to 12.8o (range, 5o-20o). The mean IMA improved from 17.0o (range, 13o-24o) to 6.8o (range, 3o-10o). One patient developed chronic regional pain syndrome. There were no instances of non union, delayed union, or malunion of the osteotomy site. CONCLUSION: Scarf osteotomy with or without proximal phalangeal osteotomy is an effective treatment for correcting severe hallux valgus deformity. PMID- 24781612 TI - Flexible hinge silicone implant with or without titanium grommets for arthroplasty of the first metatarsophalangeal joint. AB - PURPOSE: To review outcomes of 37 patients who underwent arthroplasty of the first metatarsophalangeal joint using flexible hinge silicone implants with or without titanium grommets. METHODS: 36 women and one man (63 feet) underwent arthroplasty of the first metatarsophalangeal joint for rheumatoid arthritis (RA) using Swanson flexible hinge silicone toe implants with or without titanium grommets. 20 women (35 feet) aged 31 to 72 (mean, 52) years with Steinbrocker grade II (n=4), grade III (n=6), and grade IV (n=10) RA of the feet were treated with the implant without grommets, whereas 16 women and one man (28 feet) aged 48 to 73 (mean, 60) years with Steinbrocker grade III (n=4) and grade IV (n=13) RA of the feet were treated with the implant with grommets. Pain levels were self rated. Degenerative changes and the presence of osteophytes or deformity were recorded, as were breakage or deformation of the implants, radiolucencies around the implant, implant loosening, silicone-induced synovitis, and sclerosis around the implant. RESULTS: All patients reported pain relief from severe to mild or moderate. Respectively for the feet with and without grommets, the rates of implant deformation were 25% and 63% (p=0.031), whereas the rates of moderate-to severe radiolucencies (>2 mm) were 4% and 34% (p=0.004). Sclerosis developed around the implant in all feet. CONCLUSION: Titanium grommets appear to protect the implant and improve clinical outcomes. PMID- 24781613 TI - Flexibility of the transverse arch of the forefoot. AB - PURPOSE: To measure the percentage of the transverse arch length (%TAL) in 2 positions using a 3-dimensional motion capture system to determine the flexibility of the transverse arch of the forefoot. METHODS: 19 men and 10 women with no lower extremity injury or deformity were included. The %TAL of the left foot was measured using a digital caliper in the standing position and the lower leg maximum anterior tilting (LMAT) position. The difference in the %TAL between the 2 positions (delta%TAL) was calculated. 10 markers were mounted on skin over each metatarsal head and base of the left foot. Motion was captured using a 3 dimensional motion capture system. Coordinates of each marker were manually digitised. The percentage of the transverse arch height (%TAH) and angle between the first and fifth metatarsals (M1M5) were calculated, and differences in each forefoot parameter in the 2 positions were defined as delta%TAL, delta%TAH, deltaM1M5, and the fore foot flexibility magnitude (FFM) was calculated. Subjects were divided into 3 groups based on their delta%TAL: <25th percentile (hypo flexibility group, n=7), >26th percentile to <74th percentile (control group, n=15), and >75th percentile (hyperflexibility group, n=7). The 3 groups were compared in terms of the delta%TAL. delta%TAH, deltaM1M5, and FFM. RESULTS: The delta%TAL correlated with deltaM1M5 (r=0.61, p<0.001) and FFM (r=0.60, p=0.001). For the deltaM1M5, the hyper-flexibility group differed significantly from other groups (p=0.01). For the FFM, the hyperflexibility group differed significantly from the hypoflexibility group (p=0.02). CONCLUSION: Measurement of the %TAL in both the standing and LMAT positions provides a simple and quantitative method of assessing the flexibility of the transverse arch of the forefoot. PMID- 24781614 TI - Repair of Achilles tendon ruptures with peroneus brevis tendon augmentation. AB - PURPOSE: To report 22 patients who underwent repair of compound Achilles tendon ruptures with peroneus brevis tendon augmentation. METHODS: Records of 6 women and 19 men aged 21 to 42 (mean, 28) years who underwent repair of compound Achilles tendon ruptures with peroneus brevis tendon augmentation were reviewed. All the wounds were transverse/oblique, minimally contaminated, and could be closed primarily. Patients were evaluated at months 3, 9, and 12, using the Foot and Ankle Outcome Score (FAOS) questionnaire. RESULTS: Of the 22 patients, 3 developed superficial skin complications that healed gradually, and 2 developed a superficial discharging sinus and underwent minor debridement. No patient had a re-rupture of the Achilles tendon. At the one-year follow-up, all patients achieved good functional outcome in terms of the FAOS. CONCLUSION: Repair of Achilles tendon ruptures with peroneus brevis tendon augmentation achieved good functional outcome. PMID- 24781615 TI - Calcaneoplasty and reattachment of the Achilles tendon for insertional tendinopathy. AB - PURPOSE: To report the one-year outcome of 44 patients treated with a novel technique of calcaneoplasty and reattachment of the Achilles tendon. METHODS: 15 men and 29 women (mean age, 53 years) with insertional tendinopathy of the Achilles tendon underwent calcaneoplasty, retrocalcaneal bursa excision, debridement and reattachment of the Achilles tendon with suture anchors via a lateral approach. Outcome was measured using the visual analogue score (VAS) for pain, the SF-36 health survey, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scores. Patient expectation and satisfaction were also assessed. RESULTS: Of the 44 patients, 37, 43, and 21 were followed up at 3, 6, and 12 months. The mean VAS for pain and AOFAS ankle-hindfoot score improved significantly up to 6 months. The mean SF-36 score improved significantly up to 6 months for physical functioning, role functioning (physical), and bodily pain. Patient expectation and satisfaction also improved significantly. No patient had postoperative infections or rupture. Three patients had delayed wound healing, which resolved after simple dressings. CONCLUSION: Calcaneoplasty and reattachment of the Achilles tendon via a lateral approach for insertional tendinopathy enables early weight bearing and achieves good outcome and pain relief. PMID- 24781616 TI - Revision anterior cruciate ligament reconstruction using tibial or hamstring tendon allografts. AB - PURPOSE: To report outcomes of revision anterior cruciate ligament (ACL) reconstruction using tibial or hamstring tendon allografts and to compare with another study using non-irradiated fresh-frozen bone-patellar tendon-bone allografts. METHODS: Records of 12 men and 7 women aged 18 to 53 (mean, 33) years who underwent revision ACL reconstructions using tibial tendon (n=17) or hamstring tendon (n=2) allografts were retrospectively reviewed. At the time of primary ACL reconstruction, hamstring autografts (n=8) and bonepatellar tendon bone allografts (n=11) were used. The mean time interval between surgeries was 93 (range, 11-225) months. The causes of failure were traumatic injury (n=7) and technical or biological reasons (n=12). The physical activity level was high in 2 patients, medium in 10, and low in 7. For clinical assessment, the Lysholm test, International Knee Documentation Committee (IKDC) scale, and visual analogue scale (VAS) for pain were used. Patient satisfaction was also assessed. RESULTS: Four of the patients had laxity and were dissatisfied or very dissatisfied with the outcome; the failure rate was 21%. The mean IKDC score was 63% (range, 25 100%), and the mean Lysholm score was 74% (range, 30-100%). Comparing our patients with those in another study using bone-patellar-bone allografts, there was no significant difference in terms of the VAS for pain, IKDC score, and Lysholm score. Comparing our patients with and without chondral and/or meniscal lesions, there was significant difference in terms of the Lysholm score only (86+/-11 vs. 57+/-28, p=0.043). Comparing patients who had used hamstring tendon autografts at the primary ACL reconstruction with those who had used bonepatellar tendon-bone autografts, there was significant difference in terms of the VAS for pain only (4.4+/-3.1 vs. 1.6+/-1.0, p=0.020). CONCLUSION: Revision ACL reconstruction using tibial or hamstring tendon allografts provided acceptable results, similar to those using the bone-patellar tendon-bone allografts. PMID- 24781617 TI - Grafted tendon healing in femoral and tibial tunnels after anterior cruciate ligament reconstruction. AB - PURPOSE: To evaluate tendon-to-bone healing after anterior cruciate ligament (ACL) reconstruction in the fibrous interzone (FIZ) of the femoral and tibial tunnels using magnetic resonance imaging (MRI). METHODS: Five men and 5 women (mean age, 29 years) underwent arthroscopic ACL reconstruction by a single surgeon, using the semitendinosus and gracilis tendon. The tendon-to-bone healing in the FIZ was evaluated using sagittal and coronal MRI at 1, 3, 6, 9, 12, and 24 weeks, with the knee flexed at 60o and the tendon graft straight in both images. The signal intensity of the FIZ was visually assessed by comparing it with anatomic landmarks in the same patient's knee, and classified into 4 grades. It was grade 3 when similar to that of the patellar tendon, grade 2 when similar to that of skeletal muscle, grade 1 when greater than that of muscle but less than that of joint fluid, and grade 0 when similar to that of joint fluid. At 24 weeks, subjective and objective functional outcomes were evaluated using the Lysholm score and the International Knee Documentation Committee score. RESULTS: At 24 weeks, no patient had knee laxity. All patients had an International Knee Documentation Committee score of A, and their mean Lysholm score was 98.5. In the femoral tunnel, the FIZ did not change during the first 9 weeks (in particular the anterior part), but healing occurred rapidly thereafter. In the tibial tunnel, the FIZ healed over time in all locations, and healing was complete in the lateral and posterior parts at 12 weeks, and in all locations at 24 weeks. The mean signal intensity grade was significantly higher in the tibial than femoral FIZ at 3 to 12 weeks (p<0.01). CONCLUSION: After ACL reconstruction, the tendon-to- bone healing in the FIZ of the tibial tunnel was faster than that of the femoral tunnel. PMID- 24781618 TI - Fixation of delayed union or non-union posterior cruciate ligament avulsion fractures. AB - PURPOSE: To report the outcome of fixation for delayed union or non-union posterior cruciate ligament (PCL) avulsion fractures. METHODS: Seven men and 4 women aged 24 to 35 (mean, 28) years underwent lag screw or suture fixation for non-union or delayed union of avulsion fracture of PCL tibial attachment after a mean delay of 8.6 (range, 4-14) months. Patient satisfaction was assessed using a visual analogue scale (VAS). Functional outcome was evaluated using the Lysholm scale. RESULTS: The mean follow-up period was 17 (range, 8-36) months. The mean Lysholm score improved from 82 preoperatively to 92 at the final follow-up (p=0.34), the mean range of knee motion improved from 82o to 87o (p=0.008), and the mean VAS score for patient satisfaction improved from 4.3 to 7.4 (p=0.0004). All patients but one achieved bone union after a mean of 7.5 (range, 7-9) weeks. Functional outcome was excellent for 6 patients, good for 4, and fair for one. Posterior drawer test was positive (grade I laxity) in 3 patients whose outcome was good for 2 and fair for one. The latter had non-union after Ethibond suture repair for a communited fracture. There were no instances of wound complications or implant loosening. CONCLUSION: Fixation with lag screw or suture combined with bone grafting for delayed union or non-union of PCL avulsion fractures achieves acceptable functional outcome. PMID- 24781619 TI - Total knee arthroplasty with an oxidised zirconium femoral component: a 5-year follow-up study. AB - PURPOSE: To report the early results of the Oxinium Genesis II prosthesis with an oxidised zirconium femoral component in 55 patients. METHODS: 71 knees in 21 men and 34 women aged 32 to 75 (mean, 55) years were evaluated; 16 of the patients had bilateral staged total knee replacements with a mean interval of 9 (range, 6 16) months between surgeries. The indications for surgery included osteoarthritis (n=57), rheumatoid arthritis (n=13) and revision from a unicompartmental knee replacement for osteoarthritis (n=1). Postoperatively, patients were evaluated using the Knee Society score (KSS), the modified Oxford Knee Score, and the SF-12 health survey, as were component position, leg and knee alignment, and prosthesis bone interface or fixation on radiographs. RESULTS: The mean follow-up was 62 (range, 51-88) months. The mean KSS, Oxford Knee Score, and SF-12 physical component score improved significantly. Radiolucent lines (<2 mm) were noted in the tibial cement-bone interface in 17 knees (most commonly in zones 4 and 1) and in the femoral cement-bone interface in one knee. The alignment of the knees and positioning of the components were acceptable. There were no revisions for septic or aseptic loosening. CONCLUSION: Early results of the Oxinium Genesis II prosthesis are comparable to the standard total knee prostheses. PMID- 24781620 TI - Patellar clunk syndrome in fixed-bearing posterior-stabilised versus cruciate substituting prostheses. AB - PURPOSE: To compare the outcome of fixed-bearing posterior-stabilised versus cruciate-substituting prostheses in 46 patients who underwent primary bilateral total knee replacement (TKR). METHODS: Records of 35 women and 11 men aged 54 to 78 (mean, 67) years who underwent primary bilateral TKR for osteoarthritis (n=44) and rheumatoid arthritis (n=2) were retrospectively reviewed. A fixed-bearing posterior-stabilised prosthesis (Zimmer NexGen Legacy flex [LPS-Flex]) was used in one knee, and a fixed-bearing cruciate-substituting prosthesis (Depuy Press Fit Condylar Sigma CS [PFC CS]) was used in the contralateral knee. The mean time interval between the 2 operations was 34 (range, 4-60) months. All operations were performed by the same group of surgeons using standardised techniques. The medial parapatellar approach was used, and the patella was resurfaced. Rehabilitation was also standardised. Outcome measures included the pre- and post operative active range of movement and the American Knee Society Score. Postoperative complications were documented. RESULTS: At one year, the mean fixed flexion contracture, maximum flexion, and American Knee Society scores in knees with PFC CS and LPS-Flex prostheses were comparable. Three knees with the PFC CS prosthesis developed the patellar clunk syndrome, compared to none with the LPS Flex prosthesis (p=0.24). The onset of the patellar clunk syndrome was around one year after surgery. Despite this, the axial alignment and rotation of the femoral and tibial components were good. CONCLUSION: Both prostheses produce good clinical outcome. The PFC CS prosthesis is more likely to be associated with the patellar clunk syndrome. PMID- 24781621 TI - Disease activity, knee function, and walking ability in patients with rheumatoid arthritis 10 years after primary total knee arthroplasty. AB - PURPOSE: To evaluate disease activity, knee function, and walking ability of patients with rheumatoid arthritis (RA) over 10 years after total knee arthroplasty (TKA). METHODS: Four men and 26 women (mean age, 59.9 years) underwent 42 TKAs for RA with a mean duration of 151.3 months and were followed up for a mean of 142.3 months. Preoperatively, disease activity was assessed by C reactive protein (CRP) level only, and the range of knee motion was recorded. At the final follow-up, tender joint count, swollen joint count, visual analogue scale of RA symptoms, and the Modified Health Assessment Questionnaire (MHAQ) score were assessed. Disease activity was evaluated using CRP, matrix metalloproteinase-3, and Disease Activity Score. Range of motion and Knee Society knee and function scores were also assessed. RESULTS: The use of methotrexate increased from 4 patients preoperatively to 20 patients at the final follow-up (p<0.001), and the mean dose increased from 3.9 to 6.3 mg/week (p<0.001). Among the 30 patients, the mean CRP level decreased from 2.63 mg/dl preoperatively to 0.61 mg/dl at the final follow-up (p<0.001). Disease activity was controlled. At the final follow-up, disease activity was in remission in 10 patients, low in 11, and moderate in 9. The mean Knee Society knee score was excellent (91.0), but the mean function score was poor (57.0) and diverse. Severe walking disability (function score, <40) was noted in 8 patients (11 TKAs). Knee and function scores did not correlate. CONCLUSION: Walking ability in patients with RA after TKA was generally poor. Poor function was associated with a history of spinal or lower extremity fracture surgery and the MHAQ score. PMID- 24781623 TI - The Dorr type and cortical thickness index of the proximal femur for predicting peri-operative complications during hemiarthroplasty. AB - PURPOSE: To assess the Dorr proximal femoral types and the cortical thickness index for predicting peri-operative complications during hemiarthroplasty. METHODS: Records of 53 male and 147 female elderly who underwent cemented or uncemented monopolar hemiarthroplasty for displaced intracapsular femoral neck fractures were reviewed. Any intra-operative fracture and postoperative dislocation within 30 days was recorded. The cortical thickness index was defined as the ratio of cortical width minus endosteal width to cortical width at a level of 100 mm below the tip of the lesser trochanter. Higher values indicated thicker cortices. The Dorr proximal femur morphology was classified into types A, B, and C. RESULTS: 28 patients were excluded. The proximal femurs of the remaining 172 patients (mean age, 85 years) were categorised as Dorr type A (n=29), type B (n=75), and type C (n=68). The respective mean cortical thickness indices were 1.10, 0.79, and 0.65. Lower cortical thickness indices correlated with worse Dorr types (p<0.05). There were 18 intra-operative fractures; 8 and 10 occurred in Dorr types B and C femurs versus none in Dorr type A femurs (p=0.046). There were 5 postoperative dislocations; 3 and 2 occurred in Dorr types B and C femurs versus none in Dorr type A femurs (p=0.591). The mean cortical thickness index was significantly lower in those with a fracture (n=18) than those without a fracture (n=154) [0.59 vs. 0.81, p=0.0003]. CONCLUSION: Dorr types B and C proximal femurs were at greater risk of intra-operative fracture. PMID- 24781622 TI - Posterior tension band wiring and instrumentation for thoracolumbar flexion distraction injuries. AB - PURPOSE: To evaluate treatment outcome of tension band wiring followed by posterior spinal fusion and instrumentation for thoracolumbar flexiondistraction injury (FDI). METHODS: 36 men and 12 women aged 21 to 56 (mean, 36) years underwent tension band wiring followed by posterior spinal fusion and instrumentation using pedicular screws for FDI of the thoracolumbar spine. The injured vertebral levels were T11 (n=2), T12 (n=12), T11-T12 (n=1), T12-L1 (n=1), L1 (n=28), and L2 (n=4). Anterior vertebral body height and kyphosis were measured before and after surgery. Neurologic status was assessed using the American Spinal Injury Association (ASIA) scale. The Oswestry Disability Index questionnaire and visual analogue scale for pain were also used. RESULTS: The mean follow-up was 38 (range, 26-72) months. At final follow-up, the mean visual analogue scale for pain was 1.7, and the median Oswestry Disability Index was 4% (range, 0-32%). The mean anterior vertebral body height improved from 20.5 to 38.8 mm (p<0.001). The mean kyphosis improved from 20.4o to 1.5o (p<0.001). Four patients had persistent neurologic deficit: ASIA scale C (n=2) and D (n=2); their ASIA scales improved by one grade. All patients returned to their original work at 6 months. There were no intra-operative complications or implant failures. CONCLUSION: Posterior tension band wiring followed by posterior spinal fusion and instrumentation for thoracolumbar FDIs achieved good outcome. PMID- 24781624 TI - Early active motion protocol following triple Kessler repair for flexor tendon injury. AB - PURPOSE: To evaluate outcome of 6-strand triple Kessler repair for flexor tendon injuries, followed by early active motion rehabilitation. METHODS: 25 men and one woman (36 fingers) underwent 6-strand triple Kessler repair for flexor tendon injuries in zones 2 to 5, followed by early active motion rehabilitation. Rehabilitation was started at days 3 to 5. Patients were instructed to passively flex all the fingers with the uninjured hand and to actively retain this position for 10 seconds. Active extension within the confines of the splint was allowed. At the end of week 8, strength training was commenced until a satisfactory range of motion was regained. Outcome measures included total active motion, grip strength, and the Disabilities of the Arm, Shoulder and Hand (DASH) score. Complications such as infection and wound dehiscence were recorded. RESULTS: The mean follow-up was 1.2 (range, 1-2) years. Outcome was excellent in 24 digits, good in 4, and poor in 8. The mean grip strength was 80% (range, 60-100%) of normal in dominant hands and 60% (range, 50-65%) of normal in non-dominant hands. The mean DASH score was 15 (range, 0-52). One patient had wound dehiscence and superficial infection. CONCLUSION: Six-strand triple Kessler repair for flexor tendon injuries, followed by early active motion rehabilitation yields satisfactory results. PMID- 24781625 TI - Enhancing soft-tissue reattachment in proximal humeral endoprosthetic reconstruction. AB - PURPOSE: To report on the use of the Ligament Advanced Reinforcement System (LARS) to enhance joint stability and functional outcome in proximal humeral endoprosthesis reconstruction. METHODS: Two men and 5 women aged 16 to 66 (mean, 28) years underwent wide resection of tumour and endoprosthesis reconstruction of the proximal humerus using the LARS, as the rotator cuff and/or deltoid muscle could be preserved. The preserved muscles were reattached to anatomic positions to regain function. Shoulder range of motion and Musculoskeletal Tumour Society scores were evaluated. RESULTS: The mean follow-up was 26 (range, 14-36) months. All the 7 patients were alive without disease. The mean active abduction was 77o (range, 60 degrees -100 degrees ), and the mean active flexion was 74 degrees (range, 50 degrees -100 degrees ). The mean Musculoskeletal Tumour Society score was 86% (range, 80-93%). One patient had instability of the glenohumeral joint at one year. CONCLUSION: The LARS may enhance soft-tissue reattachment and improve shoulder stability after proximal humeral endoprosthetic reconstruction. PMID- 24781626 TI - Time required for effective action of phenol against giant cell tumour cells. AB - PURPOSE: To evaluate the time required for effective action of phenol against the giant cell tumour (GCT) cells. METHODS: Fresh GCT cells were harvested from 9 patients with primary GCT of the distal femur (n=4), proximal tibia (n=4), and proximal humerus (n=1), with the Campanacci tumour grades 3 (n=6), 2 (n=2), and 1 (n=1). Specimens were immersed in 80 % phenol for one, 3, 6, and 10 minutes, and were assessed by a single pathologist for irreversible cell death and the depth of phenol penetration. RESULTS: Phenol caused consistent GCT cell death in 6 of the 9 specimens after 3 minutes and in all 9 specimens after 6 minutes, compared to none in controls (p<0.0001). The mean depths of phenol penetration were 15 (range, 11-20) and 19 (range, 15-25) cell thickness after 6 and 10 minutes, respectively (p<0.0001). CONCLUSION: GCT cells immersed in 80% phenol for 6 minutes resulted in consistent cell death. PMID- 24781627 TI - Risk factors for recurrence of giant cell tumours of bone. AB - PURPOSE: To determine the risk factors for recurrence of giant cell tumours (GCTs) of bone. METHODS: Medical records of 29 men and 29 women (mean age, 34 years) treated for primary (n=53) or recurrent (n=5) GCTs of bone and followed up for a mean of 40.2 months were reviewed. The tumours were located in the distal femur (n=18), proximal tibia (n=10), proximal femur (n=8), distal radius (n=7), proximal fibula (n=4), distal ulna (n=3), calcaneum (n=3), sacrum (n=2), vertebra (n=1), metatarsal (n=1), and distal humerus (n=1). 26 patients had pathological fractures, 12 had cortical break, and 20 had neither. The Campanacci grades of the tumours were I (n=1), II (n=18), and III (n=33); the grades of the remaining 6 tumours were unknown because radiographs were unavailable. The Enneking stages of the tumours were 1 (n=51), 2 (n=6), and 3 (n=1). Treatment included curettage and cementation (n=29), curettage, cementation, and adjuvant treatment with distilled water or liquid nitrogen for bones without fracture (n=18), wide resection for extensive soft tissue involvement (n=9), and amputation (n=2) for a recurrent GCT of the distal femur and a primary GCT of the calcaneus. Reconstruction included cementation (n=27), bone grafting (n=7), cementation/bone grafting with internal fixation (n=14), reconstruction with endoprosthesis (n=3), and none (n=7). RESULTS: 19 patients had recurrence after a mean of 23.1 months. The overall recurrence-free survival at years 1, 2, and 3 were 86%, 79%, and 72%, respectively. Recurrence did not correlate with patient age (p=0.20), primary or recurrent tumour at presentation (p=0.12), Campanacci grade (p=0.10), Enneking stage (p=0.54), or presence of pathological fracture (p=0.28). Compared to GCTs at other locations, GCTs in the proximal tibia were more likely to recur (27% vs. 60%, p=0.04). CONCLUSION: GCTs of the proximal tibia are more likely to recur than those at other locations. PMID- 24781628 TI - Graft infection following arthroscopic anterior cruciate ligament reconstruction: a report of four cases. AB - Septic arthritis following arthroscopic anterior cruciate ligament reconstruction (ACL) is a rare complication and associated with severe morbidity. Its risk factors include (1) concomitant procedures during the reconstruction, (2) previous knee surgery, (3) allograft usage, (4) peri-operative wound contamination, and (5) presence of intra-articular foreign bodies. We present a series of 3 men and one woman aged 22 to 35 years who developed septic arthritis following ACL reconstruction. The risk factors identified were local infection (n=2), previous ipsilateral knee surgery (n=2), and the use of an allograft (n=1). All patients underwent emergency knee washout and debridement with graft retention within 24 hours, together with a course of intravenous antibiotic therapy. All the patients achieved eradication of their infections (with intact ACL grafts) and satisfactory functional outcome at a mean follow-up of 32 (range, 25-45) months. PMID- 24781629 TI - Hibernoma of the thigh: a report of four cases. AB - Hibernoma is a rare benign adypocyte tumour of brown fat. We report on 4 patients with hibernoma of the thigh. Clinical features and magnetic resonance imaging suggested the tumours were liposarcomas, but biopsy yielded the diagnosis of hibernoma. All 4 patients underwent complete excision of the tumour and had no recurrence. PMID- 24781630 TI - Multifocal epithelioid hemangioendothelioma of the foot and ankle: a case report. AB - We report on a 41-year-old man with multiple epithelioid hemangioendothelioma of the left foot and ankle. The patient was treated with curettage and fixation with 2 separate plates, but later developed local infection. Owing to the potential for malignancy, below-knee amputation was suggested, but the patient declined and was treated symptomatically with close monitoring. The patient underwent removal of the plates, excision of the distal fourth of the fibula, intralesional curettage of all lesions, and fusion of the ankle and subtalar joints with a retrograde intramedullary nail. After 5.5 years, the patient had recovered well and had no evidence of malignancy. The tumour was considered definitively benign. PMID- 24781631 TI - Tuberculosis of the trochanteric bursa: a case report. AB - Tuberculous trochanteric bursitis is rare. We report on a 48-year-old man with a huge gravitational abscess in the thigh secondary to tuberculosis of the trochanteric bursa. PMID- 24781632 TI - Letter to the editor: Proximal femoral locking plate versus dynamic hip screw for unstable intertrochanteric femoral fractures. PMID- 24781633 TI - Letter to the editor: Bipolar hemiarthroplasty for intracapsular femoral neck fractures in elderly patients. PMID- 24781634 TI - Letter to the editor: Outcome after knee arthrodesis for failed septic total knee replacement using a monolateral external fixator. PMID- 24781635 TI - Letter to the editor: Revision total knee arthroplasty for septic versus aseptic failure. PMID- 24781636 TI - Letter to the editor: Web-based information on minimally invasive total knee arthroplasty. PMID- 24781637 TI - Immunomodulation and AD--down but not out. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in the elderly. Interventions that remove existing fibrillar and oligomeric amyloid-beta (Abeta) are believed to be essential for the success of any attempt at stabilization of brain function and mitigation of cognitive decline. Many of these strategies have focused on Abeta vaccination and administration of anti-Abeta antibodies. Both active and passive immunotherapies have been successful in mouse models, but both have had limited effect in clinical trials. Intravenous immunoglobulin (IVIG) has been proposed as a potential treatment for AD following evidence for behavioral benefit in AD models and cognitive benefit in early phase 1 and phase 2 clinical trials. A phase 3 trial IVIG trial failed to meet its primary outcomes. While there was a statistically significant benefit in moderate stage AD patients who carried an APOE epsilon4 allele, this stabilization of cognition was evident only on neuropsychological examination. No benefit on activities of daily living was evident, therefore failing to qualify AD as a new indication for IVIG. Identifying the biologically active component (s) responsible for the neuropsychological benefit in APOE epsilon4-positive AD patients could enable the development of a compound with greater potency that would qualify for FDA (US Food and Drug Administration) registration. PMID- 24781638 TI - Correlates of unstructured antiretroviral treatment interruption in a cohort of HIV-positive individuals in British Columbia. AB - Treatment interruptions (TIs) limit the therapeutic success of combination antiretroviral therapy and are associated with higher morbidity and mortality. HIV-positive individuals dealing with concurrent health issues, access challenges and competing life demands are hypothesized to be more likely to interrupt treatment. Individuals were included if they initiated cART >=1 year prior to interview date and had a CD4 cell count and initial regimen recorded at initiation. Using pharmacy recording, a TI was defined as a patient-initiated gap in treatment >=90 consecutive days during the 12 months preceding or following the study interview. 117 (15.2 %) of 768 participants included in this study had a TI during the study window. 76.0 % of participants were male, 27.5 % were of Aboriginal ancestry and the median age was 46 (interquartile range 40-52). In multivariable logistic regression, TIs were significantly associated with current illicit drug use (adjusted odds ratio [aOR] 1.68, 95 % confidence interval [CI] 1.05-2.68); <95 % adherence in the first year of treatment (aOR 2.68, 95 % CI 1.67-4.12); living with at least one person (aOR 1.95; 95 % CI 1.22-3.14) or living on the street (aOR 5.08, 95 % CI 1.72-14.99) compared to living alone; poor perception of overall health (aOR 1.64 95 % CI 1.05-2.55); being unemployed (aOR: 2.22, 95 % CI 1.16-4.23); and younger age at interview (aOR 0.57, 95 % CI 0.44-0.75, per 10 year increase). Addressing socioeconomic barriers to treatment retention is vital for supporting the continuous engagement of patients in care. PMID- 24781639 TI - HIV prevalence and risk behaviours among foreign migrant women residing in Cape Town, South Africa. AB - HIV prevalence and risk behaviour among foreign migrants in South Africa has not been explored. This paper describes the effectiveness of respondent-driven sampling (RDS) to recruit foreign migrant women residing in Cape Town, reports HIV prevalence, and describes key characteristics among them. We conducted a biological and behavioural surveillance survey using RDS. After written informed consent, participants completed an audio computer assisted self-interview and provided a dried blood sample for HIV analysis. HIV prevalence was estimated to be 7 % (CI 4.9-9.5) among 935 women. HIV sero-positivity was associated with older age (p = 0.001), country of origin (p < 0.000), being unmarried (p < 0.000), having lived in South Africa for 3-5 years (p = 0.023), sexual debut at >=15 years (p = 0.047), and having used a condom at last sex with a main partner (p = 0.007). Few women reported early sexual debut, or multiple sexual partners. RDS was successful in recruiting foreign migrant women. PMID- 24781640 TI - Chromosome biology: controlling CENPA mislocalization. PMID- 24781641 TI - SRF regulation - actin branches out. PMID- 24781642 TI - Some clarification of trigger signs for dental neglect. AB - DATA SOURCES: ASSIA, EBSCO-CINAHL, Cochrane CENTRAL, EMBASE, ERIC, MEDLINE, SCOPUS, OpenGrey, Proquest-Social Services/Sociological Abstracts, Web of Knowledge-Conference Proceedings Citation Index and ISI Science Citation/ Social Science Citation Index. There were no language restrictions and authors were contacted for primary data and additional information when required. STUDY SELECTION: Studies were considered eligible if they were primary studies of children (0 to 18 years) with confirmed oral neglect and with detail of dental, intra- and extra-oral features. Exclusion criteria included; studies of sexual or physical abuse or those where there was oral neglect suspected but no detail was given. All characteristics associated with dental neglect were considered outcomes. DATA EXTRACTION AND SYNTHESIS: Each article was independently reviewed by two reviewers from a panel of 22 trained reviewers with a third reviewer resolving any disagreement. A specifically designed tool for quality assessment was used. RESULTS: Three thousand eight hundred and sixty-three citations and abstracts were scanned, 83 studies were reviewed and nine (with 1595 children aged 0 to 15 years) met the inclusion criteria, including two case control studies. There were not enough data to allow meta-analysis to be carried out.The features most commonly recorded as being characteristics of dental neglect were; failure to seek, or delay in seeking dental treatment, failure to follow advice or complete treatment, and this often co-existed with an adverse impact of dental neglect on the child including pain and swelling. A 'threshold' level of dental caries, that allowed dental neglect to be defined, could not be established from the available literature. CONCLUSIONS: There was limited literature on this topic. The main characteristics of dental neglect highlighted were failure/delay in seeking dental care, with adverse consequences. However, due to a lack of research and additionally, a deficiency in the data on precise clinical features, it was not possible to make the distinction between dental caries and dental neglect. PMID- 24781643 TI - Splicing mutation in MVK is a cause of porokeratosis of Mibelli. AB - Porokeratosis is a chronic skin disorder characterized by the presence of patches with elevated, thick, keratotic borders, with histological cornoid lamella. Classic porokeratosis of Mibelli (PM) frequently appears in childhood with a risk of malignant transformation. Disseminated superficial actinic porokeratosis (DSAP) is the most common subtype of porokeratosis with genetic heterogeneities, and mevalonate kinase gene (MVK) mutations have been identified in minor portion of DSAP families of Chinese origin. To confirm the previous findings about MVK mutations in DSAP patients and test MVK's role(s) in PM development, we performed genomic sequence analysis for 3 DSAP families and 1 PM family of Chinese origin. We identified a splicing mutation of MVK gene, designated as c.1039+1G>A, in the PM family. No MVK mutations were found in three DSAP families. Sequence analysis for complementary DNA templates from PM lesions of all patients revealed a mutation at splice donor site of intron 10, designated as c.1039+1G>A, leading to the splicing defect and termination codon 52 amino acids after exon 10. Although no MVK mutations in DSAP patients were found as reported previously, we identified MVK simultaneously responsible for PM development. PMID- 24781644 TI - Robust and versatile ionic liquid microarrays achieved by microcontact printing. AB - Lab-on-a-chip and miniaturized systems have gained significant popularity motivated by marked differences in material performance at the micro-to-nano scale realm. However, to fully exploit micro-to-nano-scale chemistry, solvent volatility and lack of reproducibility need to be overcome. Here, we combine the non-volatile and versatile nature of ionic liquids with microcontact printing in an attempt to establish a facile protocol for high throughput fabrication of open microreactors and microfluidics. The micropatterned ionic liquid droplets have been demonstrated as electrochemical cells and reactors for microfabrication of metals and charge transfer complexes, substrates for immobilization of proteins and as membrane-free high-performance amperometric gas sensor arrays. The results suggest that miniaturized ionic liquid systems can be used to solve the problems of solvent volatility and slow mass transport in viscous ionic liquids in lab-on a-chip devices, thus providing a versatile platform for a diverse number of applications. PMID- 24781645 TI - Photocatalytic activity of transition-metal-ion-doped coordination polymer (CP): photoresponse region extension and quantum yields enhancement via doping of transition metal ions into the framework of CPs. AB - To improve photocatalytic activity of a coordination polymer (CP) in the visible light region, five different transition metal ions (Fe(3+), Cr(3+), Ru(3+), Co(2+) and Ni(2+)) were introduced into its framework through an ion-exchange process. Among all the resulting transition metal ion doped coordination polymers (TMI/CPs), the one doped with Fe(3+) took on the most excellent photocatalytic activity and the highest quantum yields in the visible light region, decomposing 94% Rhodamine B (RhB) in 8 hours. It can be attributed to the doping of Fe(3+), which reduced the band gap (Eg) of the original CP, facilitating photocatalysis of the obtained polymer. Compared with the coordination polymer with Fe(3+) as a dopant, products doped with other metal ions presented weaker photocatalytic activities in the visible light region, while under the irradiation of ultraviolet light, they showed favorable photocatalytic properties. The results suggest that to dope transition metal ions into the framework of CPs would be an ideal option for enhancing the photocatalytic activity of coordination polymers. PMID- 24781647 TI - Sil: a Streptococcus iniae bacteriocin with dual role as an antimicrobial and an immunomodulator that inhibits innate immune response and promotes S. iniae infection. AB - Streptococcus iniae is a Gram-positive bacterium and a severe pathogen to a wide range of economically important fish species. In addition, S. iniae is also a zoonotic pathogen and can cause serious infections in humans. In this study, we identified from a pathogenic S. iniae strain a putative bacteriocin, Sil, and examined its biological activity. Sil is composed of 101 amino acid residues and shares 35.6% overall sequence identity with the lactococcin 972 of Lactococcus lactis. Immunoblot analysis showed that Sil was secreted by S. iniae into the extracellular milieu. Purified recombinant Sil (rSil) exhibited a dose-dependent inhibitory effect on the growth of Bacillus subtilis but had no impact on the growths of other 16 Gram-positive bacteria and 10 Gram-negative bacteria representing 23 different bacterial species. Treatment of rSil by heating at 50 degrees C abolished the activity of rSil. rSil bound to the surface of B. subtilis but induced no killing of the target cells. Cellular study revealed that rSil interacted with turbot (Scophthalmus maximus) head kidney monocytes and inhibited the innate immune response of the cells, which led to enhanced cellular infection of S. iniae. Antibody blocking of the extracellular Sil produced by S. iniae significantly attenuated the infectivity of S. iniae. Consistent with these in vitro observations, in vivo study showed that administration of turbot with rSil prior to S. iniae infection significantly increased bacterial dissemination and colonization in fish tissues. Taken together, these results indicate that Sil is a novel virulence-associated bacteriostatic and an immunoregulator that promotes S. iniae infection by impairing the immune defense of host fish. PMID- 24781649 TI - Home front: post-deployment mental health and divorces. AB - Since 2003, about 14 % of U.S. Army soldiers have reported symptoms of posttraumatic stress disorder (PTSD) following deployments. In this article, we examine how post-deployment symptoms of PTSD and of other mental health conditions are related to the probability of divorce among married active-duty U.S. Army soldiers. For this purpose, we combine Army administrative individual level longitudinal data on soldiers' deployments, marital history, and sociodemographic characteristics with their self-reported post-deployment health information. Our estimates indicate that time spent in deployment increases the divorce risk among Army enlisted personnel and that PTSD symptoms are associated with further increases in the odds of divorce. Although officers are generally less likely to screen positive for PTSD than enlisted personnel, we find a stronger relationship between PTSD symptoms and divorces among Army officers who are PTSD-symptomatic than among enlisted personnel. We estimate a larger impact of deployments on the divorce risk among female soldiers, but we do not find a differential impact of PTSD symptoms by gender. Also, we find that most of the effect of PTSD symptoms occurs early in the career of soldiers who deploy multiple times. PMID- 24781648 TI - Improvement and optimization of standards for a preclinical animal test model of laser induced choroidal neovascularization. AB - BACKGROUND: As the murine model of laser-induced choroidal neovascularization (CNV) is becoming the most established and commonly utilized model worldwide for studying the pathogenesis of CNV and its response to treatment, specific operating standards are yet to be clarified. The purpose of this study is to compare the lesion size of CNV in mice with different ages, sex, durations of CNV process, and treated positions of laser spots, to make recommendations that may improve and optimize the quality of the model. METHODS AND RESULTS: C57/BL6 mice of different ages were treated with diode laser photocoagulation per eye and perfused with PBS containing fluorescein-labeled dextran at different time of observation. Choroid flat mounts, were then examined by fluorescence microscopy for the measurement of CNV area. Messenger-RNA expression levels of several angiogenic cytokines in eye cups of male and female C57BL/6 mice at 5-8 and 16-20 week-old were analyzed by real-time RT-PCR assay. The results showed significantly more CNV area in eyes of female mice compared to male mice with the expression level of several angiogenic cytokines elevated. 16-20-week-old female mice developed the biggest area of CNV. The mean area of CNV increased significantly at the 14th day after photocoagulation. Laser spots delivered 1PD away from the optic disc induced the biggest area of CNV compared to those 2PD or 3PD away. Interaction of NV was observed in laser spots delivered less than 1PD away from each other. CONCLUSION: The current results suggest that 16-20-week-old female C57BL/6 mice developed the most distinct CNV lesion size with laser spots delivered 1PD away from the optic disc. The best time to observe and analyze is the 14th day after photocoagulation. PMID- 24781650 TI - Do racial disparities in private transfers help explain the racial wealth gap? New evidence from longitudinal data. AB - How do private transfers differ by race and ethnicity, and do such differences explain the racial and ethnic disparity in wealth? Using the Panel Study of Income Dynamics, this study examines private transfers by race and ethnicity in the United States and explores a causal relationship between private transfers and wealth. Panel data and a family-level fixed-effect model are used to control for the endogeneity of private transfers. Private transfers in the form of financial support received and given from extended families and friends, as well as large gifts and inheritances, are examined. We find that African Americans and Hispanics (both immigrant and nonimmigrant) receive less in both types of private transfers than whites. Large gifts and inheritances, but not net financial support received, are related to wealth increases for African American and white families. Overall, we estimate that the African American shortfall in large gifts and inheritances accounts for 12 % of the white-black racial wealth gap. PMID- 24781651 TI - Residential mobility across local areas in the United States and the geographic distribution of the healthy population. AB - Determining whether population dynamics provide competing explanations to place effects for observed geographic patterns of population health is critical for understanding health inequality. We focus on the working-age population-the period of adulthood when health disparities are greatest-and analyze detailed data on residential mobility collected for the first time in the 2000 U.S. census. Residential mobility over a five-year period is frequent and selective, with some variation by race and gender. Even so, we found little evidence that mobility biases cross-sectional snapshots of local population health. Areas undergoing large or rapid population growth or decline may be exceptions. Overall, place of residence is an important health indicator; yet, the frequency of residential mobility raises questions of interpretation from etiological or policy perspectives, complicating simple understandings that residential exposures alone explain the association between place and health. Psychosocial stressors related to contingencies of social identity associated with being black, urban, or poor in the United States may also have adverse health impacts that track with structural location even with movement across residential areas. PMID- 24781652 TI - Evidence for electro-induced membrane defects assessed by lateral mobility measurement of a GPi anchored protein. AB - Electrotransfer is a method by which molecules can be introduced into living cells via plasma membrane electropermeabilization. Here, we show that electropermeabilization affects the lateral mobility of Rae-1, a GPi anchored protein. Our results suggest that 10-20 % of the membrane surface is occupied by defects or pores and that these structures propagate rapidly (<1 min) over the cell surface. Electrotransfer of plasmid DNA (pDNA) also affects the lateral mobility of Rae-1. Furthermore, we clearly show that, once inserted into the plasma membrane, pDNA is completely immobile and excludes Rae-1; this indicates that the pDNA molecules are tightly packed together to form aggregates occupying at least the outer leaflet of the plasma membrane. PMID- 24781653 TI - Incidence of syncope and cardiac arrest in patients with severe aortic stenosis. AB - INTRODUCTION: Syncope and sudden cardiac arrest are known complications of aortic stenosis (AS). OBJECTIVES: The aim of the study was to investigate the incidence of these complications in patients with severe symptomatic AS and to analyze whether basic clinical data and electrocardiographic (ECG) and echocardiographic parameters can be the markers of these complications. PATIENTS AND METHODS: The incidence of syncope and sudden cardiac arrest and its correlations with clinical and diagnostic data (ECG, echocardiography, Holter monitoring) were analyzed in 514 patients (mean age, 60 +/-11 y) with severe symptomatic AS before valve replacement. RESULTS: Syncope was reported in 167 patients (32%), and aborted cardiac arrest in 14 (2.7%; ventricular fibrillation, 13 patients; third-degree atrioventricular block, 1 patient). None of the analyzed parameters was related to syncope. Patients with a history of sudden cardiac arrest had higher New York Heart Association class (P = 0.01), more frequent history of syncope (P = 0.017), higher left ventricular mass index (P = 0.02), lower ejection fraction (P = 0.004), longer QRS duration (P = 0.048), corrected QT (P = 0.002), QT dispersion (P = 0.007), and a higher number of ventricular arrhythmias in 24-hour Holter monitoring (P = 0.002). A multivariate analysis showed correlations between syncope, ejection fraction of less than 45%, and QTd exceeding 60 ms and aborted cardiac arrest. At least 2 of these parameters were observed in 8 of 14 patients (P <0.001): sensitivity, 57%; specificity, 86%; positive predictive value, 10%; and negative predictive value, 98%. CONCLUSIONS: The incidence of sudden cardiac arrest in severe symptomatic AS is low. It is higher in patients with a history of syncope, prolongation of QTd, and reduced ejection fraction. None of the clinical and diagnostic parameters were associated with a history of syncope in patients with AS. PMID- 24781654 TI - When does peer support improve glycemic control in persons with diabetes mellitus? PMID- 24781655 TI - Section for Residents and Fellows-in-Training Leaders: Where Are They Now? AB - The purpose of this study was to examine the experiences of prior governing council (GC) members of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Section for Residents and Fellows-in-Training (SRF) and assess the impact of early Academy involvement. A survey was conducted via email on all prior AAO-HNS SRF GC members. The AAO-HNS SRF has elected 52 GC members since its 2003 inception. Each member served an average of 1.5 year-long terms. The mean time since completion of training is 4.1 years. A subspecialty fellowship was pursued in 86%. Fifty-seven percent practice in academic settings, with 3 members advancing to subspecialty division director within their department. More than half (58%) have served on an AAO-HNS committee, and most are frequent attendees of the annual meeting. All prior members felt involvement in the SRF GC was beneficial, enabling them to gain leadership skills and deeper understanding of the specialty. PMID- 24781656 TI - Poor Survival for American Indians with Head and Neck Squamous Cell Carcinoma. AB - OBJECTIVE: To examine patient characteristics, treatment modalities, and human papillomavirus (HPV) prevalence to identify potential mediators of disparities that may lead to differences in outcomes for American Indians with head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Historical cohort study. SETTING: Community cancer centers. PATIENTS AND METHODS: We reviewed all patients older than 18 years with a new diagnosis of HNSCC in South Dakota from 1999 to 2009. We assessed tissue samples from cases of oropharyngeal cancer for the presence of HPV DNA. RESULTS: In total, 474 white patients were compared with 32 American Indians. American Indians experienced significantly worse survival compared with whites (hazard ratio [HR], 0.59; P = .05), even after controlling for other factors such as age, sex, distance, Charlson comorbidity index, alcohol abuse, smoking, insurance, and disease stage. American Indians had a greater risk of alcohol abuse (68% vs 42%; P = .008), current smoking (67% vs 49%; P = .03), living more than 1 hour from a cancer center (81% vs 30%; P < .001), lacking private insurance (24% vs 68%; P < .001), and late-stage disease presentation (stages III and IV) (74% vs 55%; P = .04). There were no detected differences in age, sex, medical comorbidities, tumor site, tumor grade, HPV status, time to treatment, or type of treatment received. CONCLUSION: American Indians in South Dakota with HNSCC have poorer survival compared with white patients. Once presented to a cancer center, American Indians received nearly identical treatment to white patients. Disparities in outcomes arise primarily due to sociodemographic factors and later stage at presentation. PMID- 24781657 TI - Audiometric Outcome Comparison between Titanium Prosthesis and Molded Autologous Material. AB - OBJECTIVE: To evaluate and compare the audiometric outcomes of ossicular reconstruction with titanium prosthesis and autologous material. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Audiometric results of consecutive patients who performed ossiculoplasty with titanium prosthesis (n = 43) or autologous material (n = 48), from October 2008 to December 2011, were reviewed retrospectively and compared. The association between air-bone gain and age, ossiculoplasty material (autologous or titanium), preoperative diagnosis (chronic otitis media without cholesteatoma, cholesteatoma, or conductive hearing loss with intact tympanic membrane), and type of surgery (tympanoplasty, canal wall-down mastoidectomy, or canal wall-up mastoidectomy) was explored using regression analysis. RESULTS: Preoperative audiometric evaluation did not show differences between titanium and autologous groups in air-bone gap and pure-tone average. A postoperative decrease of 11.0 dB in air-bone gap and 12.4 dB in pure-tone average was observed in titanium ossiculoplasty compared with a reduction of 4.0 dB in air-bone gap and 5.1 dB in pure-tone average when autologous reconstruction was used. Mann-Whitney test revealed superior results in the titanium group compared with autologous reconstruction patients in air-bone gap (P = .02) and pure-tone average (P = .02). However, no statistically significant associations were observed after multivariate linear regression analysis of air-bone gap gain when adjusted for age, ossiculoplasty material, type of surgery, and preoperative diagnosis. One titanium prosthesis extrusion occurred during follow-up (2%). CONCLUSION: Audiometric results achieved by titanium prosthesis are promising, but significant differences compared with autologous ossiculoplasty were not present. PMID- 24781658 TI - Synthesis of novel 1,2,3-triazolyl derivatives of pregnane, androstane and D homoandrostane. Tandem "click" reaction/Cu-catalyzed D-homo rearrangement. AB - Copper-catalyzed 1,3-dipolar cycloaddition has been employed in the reaction of steroidal azides with various terminal alkynes. A number of novel 1,2,3-triazolyl derivatives of pregnane, androstane and D-homoandrostane were obtained in high yield (70-98%). The developed synthetic protocols allowed us to attach the triazolyl moiety to both the side chain and the steroidal backbone directly, despite the steric hindrance exerted by the polycyclic system. The presence of Cu(II) was shown to evoke d-homo rearrangement under mild conditions. A rational choice of the copper precatalyst permitted us to carry out the "click" reaction either along with tandem d-homo rearrangement or in the absence of this process. The tendency of 16-heterosubstituted steroids to undergo D-homo rearrangement under Cu(II) catalysis was studied. PMID- 24781659 TI - Reporter-triggered isothermal exponential amplification strategy in ultrasensitive homogeneous label-free electrochemical nucleic acid biosensing. AB - A simple and novel reporter-triggered isothermal exponential amplification reaction (R-EXPAR) integrated with a miniaturized electrochemical device was developed, which achieved excellent improvement (five orders of magnitude) of sensitivity toward reporter, G-quadruplex. This R-EXPAR strategy has been successfully implemented to construct a homogeneous label-free electrochemical sensor for ultrasensitive DNA detection. PMID- 24781660 TI - Synthesis, spectral characterization, DNA binding studies and antimicrobial activity of Co(II), Ni(II), Zn(II), Fe(III) and VO(IV) complexes with 4 aminoantipyrine Schiff base of ortho-vanillin. AB - A series of transition metal complexes of Co(II), Ni(II), Zn(II), Fe(III) and VO(IV) have been synthesized involving the Schiff base, 2,3-dimethyl-1-phenyl-4 (2-hydroxy-3-methoxy benzylideneamino)-pyrazol-5-one(L), obtained by condensation of 4-aminoantipyrine with 3-methoxy salicylaldehyde. Structural features were obtained from their FT-IR, UV-vis, NMR, ESI Mass, elemental analysis, magnetic moments, molar conductivity and thermal analysis studies. The Schiff base acts as a monovalent bidentate ligand, coordinating through the azomethine nitrogen and phenolic oxygen atom. Based on elemental and spectral studies six coordinated geometry is assigned to Co(II), Ni(II), Fe(III) and VO(IV) complexes and four coordinated geometry is assigned to Zn(II) complex. The interaction of metal complexes with Calf thymus DNA were carried out by UV-VIS titrations, fluorescence spectroscopy and viscosity measurements. The binding constants (K(b)) of the complexes were determined as 5 * 10(5) M(-1) for Co(II) complex, 1.33 * 10(4) M(-1) for Ni(II) complex, 3.33 * 10(5) M(-1) for Zn(II) complex, 1.25 * 10(5) M(-1) for Fe(III) complex and 8 * 10(5) M(-1) for VO(IV) complex. Quenching studies of the complexes indicate that these complexes strongly bind to DNA. Viscosity measurements indicate the binding mode of complexes with CT DNA by intercalation through groove. The ligand and it's metal complexes were screened for their antimicrobial activity against bacteria. The results showed the metal complexes to be biologically active, while the ligand to be inactive. PMID- 24781661 TI - Fluorescent styryl dyes based on novel 4-methoxy-9-methyi-9H-carbazole-3 carbaldehyde--synthesis, photophysical properties and DFT computations. AB - Novel carbazole based styryl derivatives (6a-6c) having styryl group at third position and a methoxy substitution were synthesized by condensing 4-methoxy-9 methyl-9H-carbazole-3-carbaldehyde 3 and different active methylene derivatives (5a-5c). Evaluated photophysical properties of these synthesized novel chromophores, studied the effect of solvent polarity on absorption, emission and quantum yield of these styryl derivatives. DFT and TD-DFT computations are carried out to study structural, molecular, electronic and photophysical parameters of dyes. The ratio of ground state to excited state dipole moment was calculated using Bakhshiev and Kawski-Chamma-Viallet correlations. PMID- 24781662 TI - Catheter-based therapies for deep vein thrombosis. AB - The basic treatment of deep vein thrombosis (DVT) over the past several decades has consisted of anticoagulation only, with inferior vena cava filtration for those who either failed or could not tolerate anticoagulation. Until recently no randomized trials had studied the efficacy of thrombolysis in DVT despite advances in techniques and technologies for endovascular clot removal. This article is a review of the current evidence on catheter-based therapies for patients with DVT. Technical considerations to improve outcome as well as optimal patient selection are discussed. PMID- 24781663 TI - Spectral interferometric microscopy reveals absorption by individual optical nanoantennas from extinction phase. AB - Optical antennas transform light from freely propagating waves into highly localized excitations that interact strongly with matter. Unlike their radio frequency counterparts, optical antennas are nanoscopic and high frequency, making amplitude and phase measurements challenging and leaving some information hidden. Here we report a novel spectral interferometric microscopy technique to expose the amplitude and phase response of individual optical antennas across an octave of the visible to near-infrared spectrum. Although it is a far-field technique, we show that knowledge of the extinction phase allows quantitative estimation of nanoantenna absorption, which is a near-field quantity. To verify our method we characterize gold ring-disk dimers exhibiting Fano interference. Our results reveal that Fano interference only cancels a bright mode's scattering, leaving residual extinction dominated by absorption. Spectral interference microscopy has the potential for real-time and single-shot phase and amplitude investigations of isolated quantum and classical antennas with applications across the physical and life sciences. PMID- 24781664 TI - Psychiatric disorders: A REDD line from stress to depression. PMID- 24781669 TI - Placement of lumbar subarachnoid drain in the sitting position: a technical difficulty. PMID- 24781670 TI - Central cord syndrome: a rare neurological complication following hypotension during general anesthesia in an elderly patient. PMID- 24781674 TI - Determination of the amniotic fluid lecithin/sphingomyelin ratio using a pipette tip column with a cation-exchange resin and mass spectrometry. PMID- 24781671 TI - Formulation development and evaluation of innovative two-polymer (SR-2P) bioadhesive vaginal gel. AB - The main objective of this investigation was to study the feasibility of developing a vaginal bioadhesive microbicide using a SRI's proprietary two polymer gel platform (SR-2P). Several formulations were prepared with different combinations of temperature-sensitive polymer (Pluronic(r) F-127) and mucoadhesive polymer (Noveon(r) AA-1), producing gels of different characteristics. Prototype polymeric gels were evaluated for pH, osmolality, buffering capacity, and viscosity under simulated vaginal semen dilutions, and bioadhesivity using ex vivo mini pig vaginal tissues and texture analyzer. The pH of the polymeric gel formulations ranged from 5.1 to 6.4; the osmolality varied from 13 to 173 mOsm. Absolute viscosity ranged from 513 to 3,780 cPs, and was significantly reduced (1.5- to 3-fold) upon incubation with simulated vaginal and semen fluid mixture. Among the tested gels (indicated in the middle row as a molar ratio of a mixture of Noveon vs. Pluronic), only SR-2P retained gel structure upon dilution with simulated fluids and mild simulated coital stress. The pH of the SR-2P gel was maintained at about 4.6 in simulated vaginal fluid and also showed high peak force of adhesion in mini pig vaginal tissue. Furthermore, SR-2P gel caused no or only minimal irritation in a mouse vaginal irritation model. The results of this preliminary study demonstrated the potential application of SR-2P gel as a vaginal microbicide vehicle for delivery of anti-HIV agents. PMID- 24781675 TI - Age- and gender-specific brain natriuretic peptide (BNP) reference ranges in primary care. AB - BACKGROUND: Chronic heart failure is a common disease with a high morbidity and mortality. In primary care, brain natriuretic peptide (BNP) is used for excluding heart failure. The Dutch and European Society of Cardiology heart failure guidelines apply two BNP cut-off levels without making distinction for gender and age. The aim of our study was to establish BNP reference ranges for use in primary care. METHODS: We investigated BNP values of 9447 eligible subjects in a primary care laboratory. For establishing the reference ranges in various age and gender classes we used the Bhattacharya method. RESULTS: Analysis of variance demonstrated that BNP data were significantly dependent on age and gender (p<0.001 and p=0.002, respectively), with the age effect being the strongest. Further, we found that the reference ranges were significantly higher than the cut-off values used in the heart failure guidelines, particularly in elderly subjects. For example, the proportion of individuals with a BNP value higher than the 29 pmol/L cut-off increased from approximately 5% in the youngest group to no less than about 50% in the oldest subjects. CONCLUSIONS: BNP reference ranges need to be age- and gender-specific. When applying a single cut-off, many healthy subjects, especially the elderly, would be falsely diagnosed as having elevated BNP, and referred for further unnecessary diagnostics. PMID- 24781676 TI - Thalassemia diagnosis in a blood donor from a unique trimorphic red blood cell population observed in the recipient. PMID- 24781677 TI - Thyroid function and thyroid autoimmunity in apparently healthy pregnant and non pregnant Mexican women. AB - BACKGROUND: Thyroid disorders are common in women of reproductive age, and thyroid dysfunction during pregnancy has been associated with adverse outcomes for mother and child. Thyroid function and thyroid function tests (TFTs) can be influenced by a variety of factors, such as ethnicity, the presence of autoimmune thyroid disease (AITD), dietary iodine intake, pregnancy, and methodological differences. However, no large-scale studies have been published which examine TFTs and prevalence of AITD in Mexican pregnant women and women of reproductive age. METHODS: TFTs and thyroid autoantibody testing were performed on 660 pregnant and 104 non-pregnant women from Merida, Yucatan, Mexico. After removal of thyroid autoantibody positive individuals and women with thyroid stimulating hormone (TSH) >4.94 mIU/L, reference intervals were calculated for TFT for non pregnant women and pregnant women by trimester. RESULTS: Anti-thyroidperoxidase antibodies (TPO-Ab) and/or anti-thyroglobulin antibodies (Tg-Ab) were positive in 14.4% and 13.5% of non-pregnant and pregnant women, respectively. TSH values were significantly higher in women who were positive for TPO-Ab and co-positive for TPO-Ab and Tg-Ab. TSH values were also significantly higher in Tg-Ab positive pregnant women. Other TFTs were not significantly different based on antibody status. Using antibody negative women, reference intervals were determined for TFTs in pregnant (gestational age-specific) and non-pregnant women. CONCLUSIONS: Laboratory evidence of AITD is common in this population of Mexican pregnant and non-pregnant women. TFT results and reference intervals are influenced by pregnancy and thyroid autoimmunity. For optimal interpretation of TFT results, gestational age-specific reference intervals established using a local patient population should be used. PMID- 24781678 TI - Top-down, bottom-up, and around the jungle gym: a social exchange and networks approach to engaging afterschool programs in implementing evidence-based practices. AB - This paper uses concepts from social networks and social exchange theories to describe the implementation of evidence-based practices in afterschool programs. The members of the LEGACY Together Afterschool Project team have been involved in conducting collaborative research to migrate a behavioral strategy that has been documented to reduce disruptive behaviors in classroom settings to a new setting that of afterschool programs. We adapted the Paxis Institute's version of the Good Behavior Game to afterschool settings which differ from in-school settings, including more fluid attendance, multiple age groupings, diverse activities that may take place simultaneously, and differences in staff training and experience (Barrish et al. in J Appl Behav Anal 2(2):119-124, 1969; Embry et al. in The Pax Good Behavior Game. Hazelden, Center City, 2003; Hynes et al. in J Child Serv 4(3):4-20, 2009; Kellam et al. in Drug Alcohol Depend 95:S5-S28, 2008; Tingstrom et al. in Behav Modif 30(2):225-253, 2006). This paper presents the experiences of the three adult groups involved in the implementation process who give first person accounts of implementation: (1) university-based scientist-practitioners, (2) community partners who trained and provided technical assistance/coaching, and (3) an afterschool program administrator. We introduce here the AIMS model used to frame the implementation process conceptualized by this town-gown collaborative team. AIMS builds upon previous work in implementation science using four phases in which the three collaborators have overlapping roles: approach/engagement, implementation, monitoring, and sustainability. Within all four phases principles of Social Exchange Theory and Social Network Theory are highlighted. PMID- 24781679 TI - Individualized endovascular treatment of high-grade traumatic vertebral artery injury. AB - BACKGROUND: Traumatic vertebral artery injury (TVAI) is associated with craniocervical trauma that can lead to potentially fatal posterior circulation stroke. It presents a clinical challenge since it is hard to detect and there are no widely accepted guidelines on diagnosis and management. High-grade TVAI is more difficult to treat and no consensus has been reached yet. METHODS: We performed a single-center, long-term, therapeutic study involving 272 patients with craniocervical injury, eleven of which were diagnosed with high-grade TVAI. Individualized endovascular treatments were performed on these patients based upon the hemodynamic and morphological characteristics of the injured vertebral artery. Postoperative angiography was conducted at 2 weeks, 3 months and 6 months, and then annually after intervention. RESULTS: Ten vertebral pseudoaneurysms and one arteriovenous fistula (AVF) were confirmed by postoperative angiography. All the participants' neurological deficit symptoms disappeared or were significantly alleviated gradually, and no new symptoms were found after endovascular treatment. Follow-up angiography of the patients with pseudoaneurysms showed a normally shaped vertebral artery with no stenosis or aneurysms; the angiographic result of the patient with the AVF presented successful embolization in the proximal vertebral artery fistula with no progression or new stenosis. Their modified Rankin Scale (mRS) scores were also satisfactory. CONCLUSIONS: Application of individualized endovascular therapy in high-grade TVAI is safe, technically feasible and clinically effective, but there is no comparison between endovascular management and other management approaches because randomized trials cannot be carried out currently. PMID- 24781680 TI - Transsphenoidal surgery for acromegaly: predicting remission with early postoperative growth hormone assays. AB - BACKGROUND: Early detection of residual disease may benefit management strategies in patients undergoing transsphenoidal surgery for acromegaly. This requires establishing objective thresholds for early postoperative growth hormone (GH) assays, and incorporating these parameters into a scale for outcome prediction. METHOD: We analyzed a database containing the records of 86 patients who had undergone gross total transsphenoidal resection of GH-secreting pituitary adenomas. Early postoperative biochemical testing included a morning fasting basal GH assay on the first postoperative day (POD1) and a second GH assay following suppression with 100 g of oral glucose on the seventh postoperative day (POD7). Remission was defined as a normal IGF-1 with either a GH nadir <0.4 ng/ml following suppression with oral glucose or a basal fasting GH <1 ng/ml on follow up dated >3 months after surgery. Receiver operator characteristic (ROC) curves identified optimal thresholds for all biochemical parameters. Logistic regression analysis assessed the statistical significance of factors associated with cure. A point system was developed, employing regression coefficients obtained from the multivariate statistical model to quantify the impact of each predictor on cure. RESULTS: Remission was achieved in 34.6 % of patients and was associated with smaller, non-invasive tumors with lower preoperative, POD1 and POD7 GH levels. Optimal thresholds obtained from the ROC analysis suggested that lower POD1 and POD7 GH values provided good sensitivity and specificity for cure, despite modest predictive values. The model with the best ability to predict outcome included size, POD1 GH and POD7 GH levels, with a score of >=95 demonstrating high specificity for prediction of remission. CONCLUSION: Early postoperative GH assays are highly sensitivity and specific. The scoring system that we propose provided excellent predictive value and requires further validation in larger cohorts and in different populations. The model may help guide the intensity of follow-up and enable early identification of residual disease. PMID- 24781681 TI - Thromboprophylaxis in haemophilia patients undergoing orthopaedic surgery. AB - The review of literature on thromboprophylaxis in nonhaemophilia patients undergoing orthopaedic surgery and on thromboprophylaxis in people with haemophilia undergoing orthopaedic surgery leads us to the conclusion that we cannot currently recommend thromboprophylaxis extensively in haemophilia patients undergoing orthopaedic surgery. This sharply contrasts with what the literature recommends for nonhaemophilia patients, that is to say mixed pharmacological and mechanical thromboprophylaxis. However, if we detect several risk factors for thromboembolism in a haemophiliac patient who is to undergo orthopaedic surgery, we should carry out the same type of thromboprophylaxis recommended for nonhaemophilia patients. Such risk factors are the following: orthopaedic surgery, increased age, previous thromboembolism, varicose veins, general anaesthesia, malignancy (cancer), factor V (Leiden) mutation, obesity, and the oral contraceptive pill (in women with von Willebrand disease). PMID- 24781683 TI - Management of mineral metabolism in haemodialysis patients: need for new strategies. PMID- 24781684 TI - Don't forget methylmalonic acid quantification in symptomatic exclusively breast fed infants. AB - Vitamin B12 deficiency can lead to serious haematological and neurological signs in infants. The reported clinical cases of vitamin B12 deficiency were found in exclusively breast-fed infants whose asymptomatic mothers were diagnosed later with pernicious anaemia. For the infants, the diagnosis required urinary methylmalonic acid quantification (grossly elevated in these two cases) and treatment rapidly improved the clinical signs. These cases underline the serious consequences of vitamin B12 deficiency in infants and the helpful role of early methylmalonic acid quantification for diagnosis. PMID- 24781682 TI - Technology-supported dietary and lifestyle interventions in healthy pregnant women: a systematic review. AB - Overweight and obesity are associated with increased risk of adverse maternal and fetal outcomes. However, the actuality of delivering effective lifestyle interventions in clinical practice is hampered by a high demand for resources. The use of technology to assist lifestyle interventions needs to be explored as a valid method of reducing strain on resources, and enhancing the effectiveness and population reach of interventions. The aim was to systematically review the literature on the use of technology-supported lifestyle interventions for healthy pregnant women and their impact on maternal outcomes. Online databases and registries were searched in March 2013. Primary outcomes of selected English language studies were fasting maternal glucose, incidence of gestational diabetes mellitus (GDM) and maternal gestational weight gain. Secondary outcomes were intervention uptake and acceptance, and dietary or physical activity modification. Studies whose subjects were diagnosed with GDM prior to intervention were excluded. The minimal number of eligible studies and varying outcomes precluded formal meta-analysis of the data. Initially, 203 articles were identified and screened. Seven articles, including five randomised controlled trials, met inclusion criteria for the current review. Results demonstrate several potential benefits associated with technology-supported interventions in pregnancy, despite minimal search results. Although communication technology holds potential as a safe therapeutic tool for the support of lifestyle interventions in pregnancy, there is a paucity of data on its effectiveness. Further RCTs examining the effectiveness of communication technology are required, particularly among those most likely to benefit from lifestyle interventions, such as overweight and obese pregnant women. PMID- 24781686 TI - Reply to 'management of mineral metabolism in haemodialysis patients: need for new strategies'. PMID- 24781685 TI - The value of Ret-Hb and sTfR in the diagnosis of iron depletion in healthy, young children. AB - OBJECTIVES: Reticulocyte hemoglobin (Ret-Hb) content and soluble transferrin receptor (sTfR) are described as promising biomarkers in the analysis of iron status. However, the value of Ret-Hb and sTfR in the early detection of iron depletion, as frequently observed in children in high-income countries, is unclear. We hypothesized that young children to iron depletion, using the WHO cutoff of ferritin <12 MUg/l, would have lower Ret-Hb and higher sTfR concentrations compared to children with a ferritin ?level 12 MUg/l. SUBJECTS/METHODS: In this cross-sectional study, we analyzed mean concentrations of Ret-Hb and sTfR in 351 healthy children aged 0.5-3 years in a high-income country. The Student's t-test was used to compare Ret-Hb and sTfR concentrations between groups. RESULTS: We showed that concentrations of Ret-Hb and sTfR are similar in children with and without iron depletion. A decrease in Ret-Hb concentration was present only when ferritin concentrations were <8 MUg/l. sTfR concentrations were similar in children with ferritin concentrations <6 MUg/l and ?12 MUg/l. CONCLUSIONS: Our results showed that the discriminative value of Ret Hb and sTfR for the detection of iron depletion is limited. Our findings suggest that ferritin is the most useful biomarker in the screening of iron depletion in healthy children in high-income countries. However, ideally, reference ranges of iron status biomarkers should be based on studies showing that children with concentrations outside reference ranges have poor neurodevelopmental outcomes. PMID- 24781687 TI - Comparison of childhood size and dietary differences at age 4 years between three European countries. AB - BACKGROUND/OBJECTIVES: Obesity in childhood is very common in Europe. It may be linked to diet, and intakes of protein and polyunsaturated fatty acids (PUFA) have been investigated. The study aims to investigate child size and dietary differences at the age of 4 years between three European countries and to assess dietary adequacy. SUBJECTS/METHODS: A total of 161 4-year-old children from Spain, Germany and Hungary, whose mothers participated in a pregnancy micronutrient supplementation trial, were included in this analysis. Child size was assessed by standardised anthropometry and diet calculated from parent completed food frequency questionnaires. Adequacy of the diet was evaluated using US guidelines. RESULTS: The Spanish children had a higher mean body mass index (BMI) (16.4+/-1.5) compared with German (15.7+/-1.0) and Hungarian children (14.9+/-1.4, P<0.01). In Spanish children, dietary intakes were higher in animal protein density, particularly from dairy foods, were little different in total protein density and slightly lower in n-6 PUFA density compared with the intakes in the other groups. Dietary intakes of most children (% contribution to energy) were higher than those recommended for protein, saturated fat and added sugar. CONCLUSIONS: Spanish children had a higher mean BMI compared with German and Hungarian children. Diets taken by Spanish children may be more obesogenic than those taken by German or Hungarian children. In the present study, many children in all three countries were consuming diets that were high in protein, saturated fat and sugar. PMID- 24781688 TI - Impact of body composition on estimated glomerular filtration rate in relatively healthy adults in Taiwan. AB - BACKGROUND/OBJECTIVES: Chronic kidney diseases are associated with changes in cardiometabolic risk (CMR) factors in which body composition parameters have been used as sensitive predictors. This study aimed to explore the associations of anthropometric indicators, body fat (BF), body mass index (BMI) and waist circumference (WC) with estimated glomerular filtration rate (eGFR) in an adult healthy Chinese population. SUBJECTS/METHODS: A cross-sectional study was conducted for the subjects undergoing annual health examinations. The associations of subjects with body composition parameters were analyzed using the cutoff values of BMI, BF and WC in accordance with the criteria for Asian or Taiwanese population by gender. RESULTS: A total of 3473 subjects, aged 30-45 years, who received physical examinations in 2007 were analyzed. The levels of CMR factors were significantly higher in males than in females. eGFR was negatively associated with BMI but positively related to BF. The additional roles of BMI and WC were observed in the subjects who were categorized according to BF. Females with normal weight obese were associated with increased eGFR, whereas a higher eGFR was found in males with low/normal BF and BMI or normal WC. CONCLUSIONS: Our data provided evidence that anthropometric parameters were associated with changes of eGFR in relatively healthy adults. Higher eGFR was observed in females with normal weight obese in whom hyperfiltration may be suspected, and this finding deserves further studies. PMID- 24781689 TI - Infant diet and metabolic outcomes in school-age children. The Generation R Study. AB - BACKGROUND: Breastfeeding duration is associated with the risks of cardio metabolic diseases in adulthood. We examined the associations of infant feeding patterns with metabolic outcomes in children and whether any association was explained by family-based socio-demographic, maternal lifestyle-related or childhood factors. SUBJECTS/METHODS: We performed a population-based prospective cohort study in 3417 children to examine the associations of breastfeeding duration and exclusivity and age at introduction of solid foods with blood levels of lipids, insulin and C-peptide and risk of clustering of cardio-metabolic risk factors at the median age of 6.0 years (90% range 5.7-6.8). RESULTS: We observed that, in the models only adjusted for child's age and sex, ever breastfeeding was not associated with childhood blood levels of lipids but was associated with higher insulin and C-peptide concentrations (P-value<0.05). Breastfeeding duration and exclusivity were not consistently associated with metabolic outcomes. Early introduction of solid foods was associated with higher levels of total cholesterol (P-value<0.05) but not with high-density lipoprotein and low density lipoprotein cholesterol, triglycerides and insulin levels. Shorter breastfeeding duration and exclusive breastfeeding were associated with increased risks of clustering of cardio-metabolic risk factors. After additional adjustment for family, maternal and childhood factors, none of these associations remained significant. CONCLUSIONS: In conclusion, we found no consistent associations of infant feeding patterns with metabolic outcomes at school age, after taking into account family-based socio-demographic, maternal lifestyle-related or childhood factors. Whether infant diet composition influences metabolic outcomes in later life should be further studied. PMID- 24781690 TI - Nutrition education in European medical schools: results of an international survey. AB - Consumers and patients are unsure of whom to trust for nutritional advice. Although medical doctors are seen as experts in nutrition and their advice is regularly followed, data are lacking on the amount of nutrition education in European medical school curricula. In line with US research, we distributed a survey on required and/or optional nutrition contact hours to medical education directors of all accredited medical schools (N=217) in Western European Union countries (N=14). In total, respondents from 32 medical schools (14.7%) from 10 countries indicated that nutrition education, in some form, was required in 68.8% of schools where, on average, 23.68 h of required nutrition education was provided. The results from this small-scale survey are comparable to a 2010 US study; conversely, European educators were satisfied with the amount of nutrition education. We substantiate the increasing concern over the inadequate amounts of nutrition education provided to medical students in Europe. PMID- 24781691 TI - Evaluating the role of Mediterranean diet and eating behaviors on the likelihood of having a non-fatal acute coronary syndrome, under the context of stress perception: a case-control study. AB - BACKGROUND/OBJECTIVES: Mediterranean diet and perceived stress have long been associated with the likelihood of having an acute coronary syndrome (ACS). The aim of this study was to evaluate whether the Mediterranean diet and other eating behaviors mediate and/or moderate the unfavorable impact of perceived stress on the likelihood of having a non-fatal ACS. SUBJECTS/METHODS: This is a case control study with individuals matched by age and sex. A total of 250 consecutive patients (60+/-11 years, 78% men) with a first ACS and 250 population-based, control subjects (60+/-8.6 years, 77.6% men) were enrolled. Perceived stress levels were evaluated with the Perceived Stress Scale (PSS-14; range 0-14), and adherence to the Mediterranean diet was assessed by the MedDietScore (range 0 55). Stress eating, eating heavy meals and eating alone were also evaluated. RESULTS: For each unit increase in the PSS-14, the likelihood of having an ACS increased by 14% (95% confidence interval (CI)=1.10, 1.18). Stratified analysis by Mediterranean diet adherence level revealed a similar association of PSS-14 with ACS likelihood between the low-to-moderate and moderate-to-high adherence groups (that is, odds ratio (OR)=1.15, 95% CI=1.09, 1.21 and OR=1.13, 95% CI=1.07, 1.80, respectively). Stress eating and eating alone were positively associated with the likelihood of having an ACS (OR=1.31, 95% CI=0.97, 1.77 and OR=1.36, 95% CI=1.08, 1.69, respectively). Eating heavy meals was not associated with ACS (OR=1.08, 95% CI=0.82, 1.41); no mediating or moderating effect of these behaviors on perceived stress ACS was observed. CONCLUSIONS: The highly significant impact of perceived stress on ACS likelihood was not mediated or moderated by the level of adherence to the Mediterranean diet or other eating behaviors, underlying the strong effect of this psychological disorder on ACS. PMID- 24781692 TI - The influence of low birth weight body proportionality and postnatal weight gain on anthropometric measures of 8-year-old children: a cohort study in Northeast Brazil. AB - BACKGROUND/OBJECTIVES: Low birth weight (LBW) and rapid postnatal weight gain are associated with future high body adiposity; however, the cumulative effect of LBW and postnatal weight gain remains unclear. The aim of this study was to investigate the influence of body proportionality of LBW infants and postnatal weight gain on body mass index (BMI) and waist circumference (WC) of 8-year-old children. SUBJECTS/METHODS: A nested cross-sectional study was conducted in a cohort of children followed from birth to 6 months and reassessed at 8 years of age. The sample consisted of 167 children born at full term (67 with LBW and 100 with appropriate birth weight). Stunted LBW was defined as length <-2 z-score and wasted LBW as length ? -2 z- score and Ponderal Index <2.5. Rapid growth was defined as weight gain greater than 0.67 s.d. score from birth to 6 months. Multivariate linear regression analysis was used to investigate the net effect of LBW and postnatal weight gain on BMI and WC, controlled for sex, total breastfeeding, socioeconomic status and maternal nutrition. RESULTS: The stunted and wasted LBW contributed significantly to the reduction of BMI and WC, and together explained 10% of the variation of these measurements. Rapid weight gain in the first 6 months of life, shorter total breastfeeding duration, higher socioeconomic status and maternal BMI significantly explained the increase in child BMI and WC. CONCLUSIONS: It was concluded that LBW led to lower body measurements, whereas rapid postnatal weight gain determined higher BMI and WC among school age children. PMID- 24781693 TI - The prisoners' dilemmas: Authorship guidelines and impact factors: between a rock and a hard place. PMID- 24781694 TI - A novel import route for an N-anchor mitochondrial outer membrane protein aided by the TIM23 complex. AB - The membrane topology of Om45 in the yeast mitochondrial outer membrane (OM) is under debate. Here, we confirm that Om45 is anchored to the OM from the intermembrane space (IMS) by its N-terminal hydrophobic segment. We show that import of Om45 requires the presequence receptors, Tom20 and Tom22, and the import channel of Tom40. Unlike any of the known OM proteins, Om45 import requires the TIM23 complex in the inner membrane, a translocator for presequence containing proteins, and the membrane potential (DeltaPsi). Therefore, Om45 is anchored to the OM via the IMS by a novel import pathway involving the TIM23 complex. PMID- 24781695 TI - The presequence pathway is involved in protein sorting to the mitochondrial outer membrane. AB - The mitochondrial outer membrane contains integral alpha-helical and beta-barrel proteins that are imported from the cytosol. The machineries importing beta barrel proteins have been identified, however, different views exist on the import of alpha-helical proteins. It has been reported that the biogenesis of Om45, the most abundant signal-anchored protein, does not depend on proteinaceous components, but involves direct insertion into the outer membrane. We show that import of Om45 occurs via the translocase of the outer membrane and the presequence translocase of the inner membrane. Assembly of Om45 in the outer membrane involves the MIM machinery. Om45 thus follows a new mitochondrial biogenesis pathway that uses elements of the presequence import pathway to direct a protein to the outer membrane. PMID- 24781696 TI - Community care workers, poor referral networks and consumption of personal resources in rural South Africa. AB - Although home-based care (HBC) programs are widely implemented throughout Africa, their success depends on the existence of an enabling environment, including a referral system and supply of essential commodities. The objective of this study was to explore the current state of client referral patterns and practices by community care workers (CCWs), in an evolving environment of one rural South African sub-district. Using a participant triangulation approach, in-depth qualitative interviews were conducted with 17 CCWs, 32 HBC clients and 32 primary caregivers (PCGs). An open-ended interview guide was used for data collection. Participants were selected from comprehensive lists of CCWs and their clients, using a diversified criterion-based sampling method. Three independent researchers coded three sets of data - CCWs, Clients and PCGs, for referral patterns and practices of CCWs. Referrals from clinics and hospitals to HBC occurred infrequently, as only eight (25%) of the 32 clients interviewed were formally referred. Community care workers showed high levels of commitment and personal investment in supporting their clients to use the formal health care system. They went to the extent of using their own personal resources. Seven CCWs used their own money to ensure client access to clinics, and eight gave their own food to ensure treatment adherence. Community care workers are essential in linking clients to clinics and hospitals and to promote the appropriate use of medical services, although this effort frequently necessitated consumption of their own personal resources. Therefore, risk protection strategies are urgently needed so as to ensure sustainability of the current work performed by HBC organizations and the CCW volunteers. PMID- 24781698 TI - Characterization and application of bioflocculant prepared by Rhodococcus erythropolis using sludge and livestock wastewater as cheap culture media. AB - A new bioflocculant was produced by culturing Rhodococcus erythropolis in a cheap medium. When culture pH was 7.0, inoculum size was 2 % (v/v), Na2HPO4 concentration was 0.5 g L(-1), and the ratio of sludge/livestock wastewater was 7:1 (v/v), a maximum flocculating rate of 87.6 % could be achieved. Among 13 different kinds of pretreatments for sludge, the optimal one was the thermal alkaline pretreatment. Different from a bioflocculant produced in a standard medium, this bioflocculant was effective over a wide pH range from 2 to 12 with flocculating rates higher than 98 %. Approximately, 1.6 g L(-1) of crude bioflocculant could be harvested using cold ethanol for extraction. This bioflocculant showed color removal rates up to 80 % when applied to direct and disperse dye solutions, but only 23.0 % for reactive dye solutions. Infrared spectrum showed that the bioflocculant contained functional groups such as -OH, NH2, and -CONH2. Components in the bioflocculant consisted of 91.2 % of polysaccharides, 7.6 % of proteins, and 1.2 % of DNA. When the bioflocculant and copper sulfate (CuSO4) were used together for decolorization in actual dye wastewater, the optimum decolorization conditions were specified by the response surface methodology as pH 11, bioflocculant dosage of 40 mg/L, and CuSO4 80 mg/L, under which a decolorization rate of 93.9 % could be reached. PMID- 24781705 TI - Mucosal lichen planus: an evidence-based treatment update. AB - BACKGROUND: Mucosal lichen planus (MLP) is a chronic mucosal disorder that often poses a therapeutic challenge to dermatologists, dentists, and gynecologists. To relieve patients' pain and discomfort, improve their quality of life, and achieve clinical improvement, various therapeutic approaches can be considered for this disease. Based on the current literature it is difficult to define any particular treatment as the main therapeutic modality. OBJECTIVE: We aimed to systematically review the current literature for the effectiveness of available treatment modalities for MLP. METHODS: All of the randomized controlled trials and systematic reviews of MLP were collected by searching Pubmed, EMBASE, the Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Health Technology Assessment Database, and China National Knowledge Infrastructure. Meta-analysis was performed, if possible. RESULTS: Topical betamethasone valerate, clobetasol 17-propionate, and fluocinonide are effective in the treatment of oral lichen planus (OLP) when compared with placebo. Calcineurin inhibitors and topical retinoids are also beneficial treatment options. LIMITATIONS: The review does not include therapies with a lower level of evidence. CONCLUSION: Topical corticosteroids are the mainstay of therapy for OLP. High-quality evidence is lacking for the treatment of lichen planus. PMID- 24781706 TI - Molecular mapping and validation of a major QTL conferring resistance to a defoliating isolate of verticillium wilt in cotton (Gossypium hirsutum L.). AB - Verticillium wilt (VW) caused by Verticillium dahliae Kleb is one of the most destructive diseases of cotton. Development and use of a VW resistant variety is the most practical and effective way to manage this disease. Identification of highly resistant genes/QTL and the underlining genetic architecture is a prerequisite for developing a VW resistant variety. A major QTL qVW-c6-1 conferring resistance to the defoliating isolate V991 was identified on chromosome 6 in LHB22*JM11 F2?3 population inoculated and grown in a greenhouse. This QTL was further validated in the LHB22*NNG F2?3 population that was evaluated in an artificial disease nursery of V991 for two years and in its subsequent F4 population grown in a field severely infested by V991. The allele conferring resistance within the QTL qVW-c6-1 region originated from parent LHB22 and could explain 23.1-27.1% of phenotypic variation. Another resistance QTL qVW c21-1 originated from the susceptible parent JM11 was mapped on chromosome 21, explaining 14.44% of phenotypic variation. The resistance QTL reported herein provides a useful tool for breeding a cotton variety with enhanced resistance to VW. PMID- 24781707 TI - Noninvasive assessment of liver fibrosis: key messages for clinicians. AB - The management of patients with chronic liver disease (CLD) requires an accurate definition of the staging and grading, as the latter is related to the progression of liver fibrosis. Albeit liver biopsy (LB) is an invasive procedure with possible complications, it is currently the "gold standard" for the assessment of hepatic fibrosis. Over the past decade, several noninvasive approaches have been proposed as surrogates in the evaluation of liver fibrosis. These include serum direct and indirect markers of fibrosis linked, respectively, to fibrogenesis and hepatic function, and instrumental techniques, which measure liver stiffness, a parameter directly correlated with liver fibrosis. Although accuracy of noninvasive methods was initially investigated in chronic hepatitis C, there are now increasing data referred to their application in other CLDs. While in specific settings, there is still need for LB, noninvasive methods have an increasing and crucial role in clinical practice to monitor fibrosis progression in patients with CLD. The aim of this review is to present the current status of knowledge in this new exciting field and to highlight the key messages useful for clinicians. PMID- 24781708 TI - Regiocontrolled palladium-catalyzed and copper-mediated C-H bond functionalization of protected L-histidine. AB - We describe the controlled and regioselective transition-metal-catalyzed C-H bond arylation of protected L-histidine with aryl halides as the coupling partner. Using this approach, a large number of C-2 arylated L-histidines have been synthesized with diverse substitutions bearing electron-donating and electron withdrawing groups, in good to excellent yields. These synthetic amino acids possessing dual hydrophobic-hydrophilic character are important synthons of bioactive peptidomimetics, which are imperative potent inhibitors of Cryptococcus neoformans. PMID- 24781709 TI - Photocatalytic CO2 reduction using a molecular cobalt complex deposited on TiO2 nanoparticles. AB - Hybrid photocatalysts were prepared by depositing a macrocyclic cobalt complex on TiO2 surfaces. Upon UV light irradiation, photoexcited electrons in TiO2 nanoparticles were transferred to the surface cobalt catalyst for CO2 reduction. PMID- 24781710 TI - Designing an effective microbial forensics program for law enforcement and national security purposes. AB - Forensic capabilities that provide lead information, and investigative, intelligence, prosecution and policy decision support can be invaluable for responding to and resolving bioterrorism events. Attributing biological attacks through scientific and other resources and processes is an important goal, for which science can be instrumental. Some even believe that having effective microbial forensics capabilities along with others can even deter adversaries from using biological weapons. For those nations that do not have such or wish to integrate or upgrade capabilities, thoughtful analysis and consideration of certain design principles will increase the likelihood that success will be attained. PMID- 24781711 TI - Structural characterization and biological evaluation of a clioquinol-ruthenium complex with copper-independent antileukaemic activity. AB - In this study, we present the synthesis, biological characterization, and first crystal structure of an organometallic-clioquinol complex. Combining ruthenium with the established apoptotic agent and 8-hydroxyquinoline derivative, clioquinol, resulted in a complex that induces caspase-dependent cell death in leukaemia cells. This activity is copper independent and is improved compared to the parent compound, clioquinol. The study of the mode of action reveals that this clioquinol-ruthenium complex does not intercalate between DNA base pairs. Additionally, this clioquinol-ruthenium complex shows proteasome-independent inhibition of the NFkappaB signalling pathway, with no effects on cell-cycle distribution. These data suggest a mechanism of action that involves a target profile that is different from that for clioquinol alone. PMID- 24781713 TI - Who is at risk for compassion fatigue? An investigation of genetic counselor demographics, anxiety, compassion satisfaction, and burnout. AB - Compassion fatigue is a state of detachment and isolation experienced when healthcare providers repeatedly engage with patients in distress. Compassion fatigue can hinder empathy and cause extreme tension. Prior research suggests 73.8 % of genetic counselors are at moderate to high risk for compassion fatigue and approximately 1 in 4 have considered leaving the field as a result Injeyan et al. (Journal of Genetic Counseling, 20, 526-540, 2011). Empirical data to establish a reliable profile of genetic counselors at risk for compassion fatigue are limited. Thus the purpose of this study was to establish a profile by assessing relationships between state and trait anxiety, burnout, compassion satisfaction, selected demographics and compassion fatigue risk in practicing genetic counselors. Practicing genetic counselors (n = 402) completed an anonymous, online survey containing demographic questions, the State-Trait Anxiety Inventory, and the Professional Quality of Life scale. Multiple regression analysis yielded four significant predictors which increase compassion fatigue risk (accounting for 48 % of the variance): higher levels of trait anxiety, burnout, and compassion satisfaction, and ethnicity other than Caucasian. Additional findings, study limitations, practice implications, and research recommendations are provided. PMID- 24781714 TI - Collaboration of colorado cancer genetic counselors to integrate next generation sequencing panels into clinical practice. AB - The recent introduction of clinically available next generation sequencing (NGS) cancer panels has presented new challenges for genetic counselors. Determining which patients are appropriate for NGS panel testing is complex. Due to the large number of genes included in the NGS panels, thorough and appropriate pre-test counseling and interpretation of NGS results can be a time-consuming and difficult process. Many of the genes associated with increased cancer risk lack published clinical management guidelines and estimates of cancer risk for individuals with deleterious mutations. In order to efficiently and effectively review the clinical utility of NGS panels, Colorado cancer genetic counselors formed a working group to gain a better understanding of the genes included in NGS cancer panels. This publication reports on the approach of this group, the process used to evaluate a selected NGS panel, future directions for this collaboration, and ideas for other genetic counselors to form similar groups to efficiently evaluate new technologies and improve practice. PMID- 24781715 TI - Interdisciplinary education for genetic counselors: developing the concept and assessing the need in australasia. AB - Interdisciplinary teams are increasingly common in healthcare as a means of improving patient care and there is consensus in the literature that a formalized framework of interdisciplinary education for health professionals is an advantageous means of professional development. To our knowledge no such application to genetic counseling has been reported. Prompted by limited direct exposure to the oncology processes discussed during genetic counseling sessions, two genetic counselors completed an interdisciplinary education exercise by observing various oncology settings. As intended we gained a deeper understanding of the: (1) Roles of other health professionals within the oncology interdisciplinary team, (2) Patient experience of cancer screening and treatment, and (3) Clinical processes relevant to cancer genetic counselors' discussions. In addition, further benefits resulted from (4) Insight into how patients and referring providers utilize the FCC within wider oncology care and (5) Strengthening of relationships between the FCC and other oncology-related teams. The observation experience and resulting learnings are described in this paper. To investigate wider application of this novel initiative, a survey of Australasian genetic counselors was conducted, finding that genetic counselors mostly source knowledge about oncology procedures through indirect means and that, overall, anecdotal descriptions from patients were the most common information source (74 %). Over 95 % of respondents expected that interdisciplinary observations would be a beneficial part of their professional development and almost 90 % expected the program to be potentially feasible in their workplace. These findings indicate there is a role for interdisciplinary education to be considered as a formal continual learning tool for genetic counselors. PMID- 24781716 TI - LQTS parents' reflections about genetic risk knowledge and their need to know or not to know their children's carrier status. AB - Long QT syndrome (LQTS) is a contributor to unexplained deaths in infants (SIDS), children, teenagers and young adults. A gene test result may allow for individual tailored treatment, but also pose a burden of knowing one's carrier status, with no treatment recommendation. Genetic risk knowledge in the case of LQTS can promote adjustment and coping, but also fear anxiety, ambivalence and moral dilemmas. This makes it challenging to respect both the right to know and the right not to know. The purpose of this study was to explore LQTS parents' perception of genetic knowledge, and their need to know or not to know about their children's carrier status. Qualitative, semi structured interviews were conducted with thirteen parents of LQTS-children. Results show that parents found it important to know the result of a gene test for LQTS including their children's carrier status. The risk was framed and incorporated into their everyday life and their life perspectives. Pertinent moral dilemmas concerned information disclosure to children and relatives. Parents thought that early and gradual disclosure to children would promote coping. Parents' moral dilemmas were rarely addressed during encounters with healthcare providers. The participants had several suggestions for improvement in that regard. PMID- 24781717 TI - Deletion of 32 base pair in the CCR5 gene may delete the risk for pre-eclampsia. PMID- 24781718 TI - Evaluation of SprayShieldTM Adhesion Barrier in a single center: randomized controlled study in 15 women undergoing reconstructive surgery after laparoscopic myomectomy. AB - OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of SprayShieldTM Adhesion Barrier in preventing and/or reducing postoperative adhesion during gynecological surgery. DESIGN: This was a prospective, controlled, blinded, and randomized study. Patient blinding was performed intraoperatively. Subjects were randomly assigned to the SprayShieldTM or the control group in a 2:1 ratio. SETTING: The study was conducted at the Clinic of Gynaecology and Obstetrics, at the University Hospital for Gynecology in Germany. PATIENTS: Fifteen patients participated in this study; nine patients were assigned to the SprayShieldTM and six patients to the control group. INTERVENTIONS: During first operation (FLL) in the SprayShieldTM group, the agent was applied to all myomectomy suture lines. Patients in the control group did not receive any anti-adhesion treatment, only good surgical practice. A second-look laparoscopy (SLL) was performed 8-12 weeks after myomectomy to evaluate adhesion formation. MAIN OUTCOME MEASURES: Main outcome measures were incidence, severity, and extent of uterine adhesions. RESULTS: No significant differences were found between the two study groups. CONCLUSIONS: SprayShieldTM is easy to use. No serious adverse event related to SprayShieldTM was observed. Efficacy data are inconclusive regarding the performance of SprayShieldTM. Further studies are needed to better understand this performance. PMID- 24781719 TI - Characteristics of medical professional liability claims against internists. PMID- 24781720 TI - Effect of individualized exercise during maintenance haemodialysis on exercise capacity and health-related quality of life in patients with uraemia. AB - OBJECTIVE: To investigate the effect of individualized exercise on exercise capacity and health-related quality of life (HRQoL) in uraemic patients during maintenance haemodialysis (MHD). METHODS: Patients receiving MHD were divided randomly into a test group, who underwent recumbent cycling exercise during dialysis, and a control group, who performed simple stretching exercises. The same dialysis protocol was used for all study participants. At study start and after 12 weeks, exercise capacity was measured using tests of physical ability; HRQoL was measured using the kidney disease quality of life score (KDQOL-SFTM). RESULTS: A total of 65 patients were included in the study: 33 in the control group and 32 in the test group. There were no significant differences in patient characteristics between the two groups at baseline. After 12 weeks, there were significant improvements in exercise capacity and in many of the items of the KDQOL-SFTM in the test group compared with the control group. CONCLUSION: Individualized exercise during MHD significantly improved the exercise capacity and HRQoL for uraemic patients within a short time period, and could therefore be used as a simple, cost-effective therapeutic approach. PMID- 24781722 TI - Thrombotic risk factors in patients undergoing chemotherapy via peripherally inserted central catheter. AB - OBJECTIVE: To evaluate risk factors for venous thrombosis in patients undergoing chemotherapy via peripherally inserted central catheter (PICC). METHODS: Data regarding age, sex, body mass index (BMI), smoking history, diagnosis, medical history, family history of thrombosis, haemoglobin level, and white blood cell (WBC) and platelet counts were prospectively collected from consecutively recruited patients. Patients were evaluated using six thrombotic risk-assessment scales prior to PICC. Assessments of the general venous system and the catheterized vein and limb were made. Deep vein thrombosis (DVT) was diagnosed by colour Doppler ultrasonography. Thrombosis risk factors were identified by logistic regression analysis. RESULTS: Thrombosis occurred in 12/188 patients (6.38%). Age >60 years, BMI >25 kg/m(2) and WBC >11.4 * 10(9)/l were identified as independent risk factors for thrombosis. The incidence of thrombosis was 16.6% (12/72) in patients with one or more risk factors, and 55.5% (five of nine) in those with two or more risk factors. CONCLUSIONS: Age >60 years, BMI >25 kg/m(2) and WBC >1.4 * 10(9)/l are major risk factors for thrombosis in Chinese patients undergoing PICC chemotherapy. PMID- 24781721 TI - The effect of health education in patients with chronic low back pain. AB - OBJECTIVE: To assess the value of health education (active management and postural hygiene) over and above exercise alone, in patients with chronic low back pain. METHODS: Adults (aged 18-30 years) with low back pain of >= 3 months' duration were randomized to undergo a 12-week programme of lumbar strengthening exercise and health education or exercise alone. Pain, disability (Oswestry Disability Index, ODI), static and dynamic muscle endurance, and health-related quality-of-life (short form-36, SF-36) were assessed at baseline and after completion of treatment. RESULTS: At the end of the 12-week intervention period, pain, disability, SF-36 physical component and SF-36 mental component were significantly better in the health education group (n = 25) than in the control group (n = 24). There were no significant between-group differences in static or dynamic endurance. CONCLUSION: Health education provides additional benefits to exercise alone for improving pain, disability and mental and physical health related quality-of-life. PMID- 24781723 TI - Relationship between lysophosphatidic acid and matrix metalloproteinase-9 plasma concentrations and carotid atheromatous plaque stability in patients with cerebral infarction. AB - OBJECTIVE: To investigate the correlation between plasma lysophosphatidic acid (LPA), matrix metalloproteinase (MMP)-9 and carotid atheromatous plaque stability in patients with cerebral infarction. METHOD: Patients with cerebral infarction underwent carotid artery duplex ultrasonography and transcranial Doppler monitoring for detection of microemboli. Patients were stratified by plaque type (no plaque, intima thickening, unstable plaque, stable plaque) and presence or absence of micoremboli. Plasma LPA and MMP-9 were quantified. RESULT: LPA and MMP 9 concentrations were significantly higher and microemboli positivity was significantly more common in patients with unstable plaque (n = 21) than the other three groups (intima thickening, n = 16; stable plaque n = 41; no plaque; n = 12). There was a significant positive correlation between LPA and MMP-9 concentrations. CONCLUSION: Plasma LPA and MMP-9 concentrations may be useful biomarkers in the clinical identification and prediction of unstable plaque, and in guiding treatment. PMID- 24781724 TI - The Modified Mayo Clinic technique: Emphasis on plausible significant reduction of colon cancer. AB - OBJECTIVE: To compare the ability to detect colonic polyps using a modified Mayo Clinic (MMC) barium enema technique with that of the usual gold standard optical colonoscopy (OC). METHODS: Patients considered at an average or increased risk of colorectal cancer were initially screened using the MMC technique. Patients who refused OC, those who had isolated rectal lesions and those with incomplete OC were excluded. Patients with mass lesions in the right colon or left colon were further assessed using OC. RESULTS: A total of 142 consecutive patients were examined using the MMC technique. Of these, 18 patients were found to have mass lesions in the right or left colon and were further evaluated using OC. Sensitivity and specificity of the MMC technique for detecting colonic polyps/cancers of >= 0.3 cm were 87.5% and 80.0%, respectively. Most significantly, for detecting polyps of >= 1.0 cm, the false-negative rate was 0%. CONCLUSIONS: The MMC technique may provide an alternative screening method to OC for the detection of colorectal polyps, particularly in countries where resources are scarce. PMID- 24781725 TI - Influence of levosimendan on organ dysfunction in patients with severely reduced left ventricular function undergoing cardiac surgery. AB - OBJECTIVES: Levosimendan is an inotropic drug with organ-protective properties due to its activation of mitochondrial K(ATP) channels. This prospective, randomized, double-blind, placebo-controlled study investigated whether administration of levosimendan prior to cardiopulmonary bypass could reduce organ dysfunction and influence subsequent secondary endpoints. PATIENTS AND METHODS: Patients with left ventricular ejection fraction <30% scheduled for elective coronary artery bypass surgery (with or without valve surgery) received either levosimendan (12.5 mg, 0.1 ug kg(-1) per min; n = 17) or placebo (n = 16) central venous infusion, immediately after anaesthesia induction, as add-on medication to a goal-orientated treatment algorithm. RESULTS: A total of 33 patients completed the study. There were no statistically significant differences in Sequential Organ Failure Assessment scores, survival, haemodynamic parameters, time to extubation, time in intensive care unit, need for haemodialysis or health-related quality-of-life at 6 months post operation. The levosimendan group compared with the placebo group had significantly lower use of epinephrine (35% versus 81%) and nitroglycerine (6% versus 44%) 24 h postoperation, and significantly less frequent serious adverse events (13% versus 47%). CONCLUSIONS: These preliminary results show that timely perioperative levosimendan treatment is feasible, has a favourable safety profile safe and may help to prevent low cardiac output syndrome. However, organ function was not preserved. Further studies, using larger sample sizes, are required. PMID- 24781726 TI - In vivo models for cancer stem cell research: a practical guide for frequently used animal models and available biomarkers. AB - The identification of a rare population of cancer stem cells whose presence in tumors is believed to determine their growth and metastatic activity, has provided a novel approach for targeted anti-cancer therapy. At the in vivo stage of the development of new therapeutic approaches for killing cancer stem cells, the most significant issues are the appropriate choice of rational animal models that offer the option to select animal species, strains and substrains, essential techniques for the inoculation of tumors, and methods of tumor detection in animals. The identification and validation of various types of cancer stem cell markers, which could serve as potential marker(s) of therapeutic efficacy of applied drugs, is a considerable challenge. The aim of this review is to provide a guide for the in vivo study of novel therapeutics that target cancer stem cells. This review describes frequently used mouse solid tumor models and evaluates their usefulness for cancer stem cell research. The classification of existing compounds that are used in today's experimental anti-cancer stem cell therapy and examples of exploratory first-in-human studies using these compounds for selective elimination of cancer stem cells will also be discussed. Finally, this review will examine the current status of available cancer stem cell markers, and highlight several important cancer stem cell properties that are still not well understood, but could influence the anti-cancer drug development process. PMID- 24781727 TI - A new face of endocannabinoids in pharmacotherapy. Part I: protective role of endocannabinoids in hypertension and myocardial infarction. AB - Cannabinoids are compounds which were first isolated from the Cannabis sativa plant. For thousands of years they have been used for treatment of numerous diseases. Currently, synthetic cannabinoids and endocannabinoids are also known. Cannabinoid receptors, endocannabinoids and the enzymes that catalyze their synthesis and degradation constitute the endocannabinoid system which plays an important role in functioning of the cardiovascular system. The results obtained to date suggest the involvement of endocannabinoids in the pathology of many cardiovascular diseases, including myocardial infarction, hypertension and hypotension associated with hemorrhagic, endotoxic, and cardiogenic shock. Cardioprotective effect and dilation of coronary vessels induced by endocannabinoids deserve special attention. It cannot be excluded now that in the future our better understanding of cannabinoid system will allow to develop new strategies for treatment of cardiovascular diseases. PMID- 24781728 TI - A new face of endocannabinoids in pharmacotherapy. Part II: role of endocannabinoids in inflammation-derived cardiovaascular diseases. AB - Endocannabinoids play an important role in cardiovascular diseases caused by inflammatory disorders. Endocannabinoids are endogenous bioactive lipids that activate cannabinoid receptors and together with enzymes responsible for their synthesis and degradation constitute endocannabinoid system. The results obtained to date suggest the involvement of endocannabinoids in the pathology of many cardiovascular diseases associated with inflammation, such as atherosclerosis, restenosis, chemotherapy-induced myocardial injury, diabetic and hepatic cirrhosis cardiomyopathy. Our better understanding of cannabinoid system may result in the development of new strategies for the treatment of such disorders. PMID- 24781729 TI - Biological properties of human skeletal myoblasts genetically modified to simultaneously overexpress the pro-angiogenic factors vascular endothelial growth factor-A and fibroblast growth factor-4. AB - Myocardial infarction results in cardiomyocyte loss and may eventually lead to cardiac failure. Skeletal myoblast transplantation into the scar area may compensate for this observed cell loss by strengthening the weakened myocardium and inducing myogenesis. Moreover, skeletal myoblasts may serve as potential transgene carriers for the myocardium (i.e., delivering pro-angiogenic factors, which may potentially improve blood perfusion in infarcted heart). We examined the influence of the simultaneous overexpression of two potent pro-angiogenic factors, fibroblast growth factor-4 (FGF-4) and vascular endothelial growth factor (VEGF), on human primary myoblast proliferation, cell cycle, resistance to hypoxic stress conditions and myogenic gene expression, as well as the induction of pro-angiogenic activities. We used a bicistronic plasmid vector encoding two factors introduced via an efficient myoblast electroporation method. The levels of overexpressed proteins were assessed, and their functionality at capillary formation was evaluated. This combined approach led to a high level of non-viral transient overexpression of both pro-angiogenic proteins, which proved to be potent regulators of blood vessel development assayed in capillary formation tests. We demonstrated in in vitro conditions that the transfection of human skeletal myoblasts with both FGF-4 and VEGF did not affect their basic biological properties such as the cell cycle, proliferation or expression of myogenic lineage-specific genes, and the modified cells adapted to oxidative stress conditions. Overall, the results obtained suggest that the applied combined approach with the use of two pro-angiogenic genes overexpressed in skeletal muscle stem cells may be an interesting alternative for the effective therapy of myocardial infarction in animal models and/or prospective clinical trials. PMID- 24781730 TI - Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival. AB - In some tissues, aging impairs angiogenesis and reduces expression of vascular endothelial growth factor A (VEGF), a fundamental regulator of angiogenesis. We previously examined angiogenesis in aging and young gastric mucosa in vivo and in vitro and showed that an imbalance between expressions of VEGF (pro-angiogenic factor) and endostatin (anti-angiogenic protein) results in an aging-related impairment of angiogenesis in rats. However, the human relevance of these findings, and whether these mechanisms apply to endothelial cells derived from other tissues, is not clear. Since P-STAT3 and P-CREB are transcription factors that, in association with HIF-1alpha, can activate VEGF gene expression in some cells (e.g., liver cancer cells, vascular smooth muscle cells), we examined the expression of these two proteins in human dermal microvascular endothelial cells (HMVECs) derived from aging and neonatal individuals. We examined and quantified in vitro angiogenesis, expression of VEGF, P-STAT3, P-CREB and importin-alpha in HMVECs isolated from neonates (neonatal) and a 66 year old subject (aging). We also examined the effects of treatment with exogenous VEGF and endostatin on in vitro angiogenesis in these cells. Endothelial cells isolated from aging individuals had impaired angiogenesis (vs. neonatal endothelial cells) and reduced expression of VEGF mRNA and protein. Aged HMVECs also had reduced importin-alpha expression, and reduced expression and nuclear translocation of P STAT3 and P-CREB. Reduced VEGF gene expression in aged HMVECs strongly correlated with the decreased levels of P-STAT3, P-CREB and importin-alpha in these cells. Our study clearly demonstrates that endothelial cells from aging individuals have impaired angiogenesis and reduced expression of VEGF likely due to impaired nuclear transport of P-STAT3 and P-CREB transcription factors in these cells. PMID- 24781731 TI - Myosin heavy chain composition in the vastus lateralis muscle in relation to oxygen uptake and heart rate during cycling in humans. AB - In this study we examined the relationship between fast myosin heavy chain (MyHC2) content in the vastus lateralis and the rate of oxygen uptake (VO2) and heart rate (HR) increase during an incremental exercise in 38, young, healthy men. Prior to the exercise test, muscle biopsies were taken in order to evaluate the MyHC composition. It was found that during cycling performed below the lactate threshold (LT), a positive relationship between MyHC2 and the intercept of the oxygen uptake and power output (VO2-PO) relationship existed (r=0.49, P=0.002), despite no correlation between MyHC2 and the slope value of the VO2-PO relationship (r= -0.18, P=0.29). During cycling performed above the LT, MyHC2 correlated positively with the magnitude of the nonlinearity in the VO2-PO relationship; i.e. with the accumulated VO2'excess' (r=0.44, P=0.006) and peak VO2'excess' (r=0.44, P=0.006), as well as with the slope of the HR-PO relationship (r=0.49, P=0.002). We have concluded that a greater MyHC2 content in the vastus lateralis is accompanied by a higher oxygen cost of cycling during exercise performed below the LT. This seems to be related to the higher energy cost of the non-cross-bridge activities in the muscles possessing a greater proportion of MyHC2 content. In the case of heavy-intensity exercise, a higher MyHC2 content in the vastus lateralis is accompanied by greater non-linearity in the VO2-PO relationship, as well as a steeper increase in HR in the function of an increase of PO. This relationship can be explained by greater disturbances in metabolic stability in type II muscle fibres during exercise, resulting in a decrease of muscle mechanical efficiency and greater increase of heart rate at a given power output. Therefore, MyHC composition has an impact on the oxygen cost of cycling both below and above the LT. PMID- 24781732 TI - Macroautophagic process was differentially modulated by long-term moderate exercise in rat brain and peripheral tissues. AB - The autophagic process is a lysosomal degradation pathway, which is activated during stress conditions, such as starvation or exercise. Regular exercise has beneficial effects on human health, including neuroprotection. However, the cellular mechanisms underlying these effects are incompletely understood. Endurance and a single bout of exercise induce autophagy not only in brain but also in peripheral tissues. However, little is known whether autophagy could be modulated in brain and peripheral tissues by long-term moderate exercise. Here, we examined the effects on macroautophagy process of long-term moderate treadmill training (36 weeks) in adult rats both in brain (hippocampus and cerebral cortex) and peripheral tissues (skeletal muscle, liver and heart). We assessed mTOR activation and the autophagic proteins Beclin 1, p62, LC3B (LC3B-II/LC3B-I ratio) and the lysosomal protein LAMP1, as well as the ubiquitinated proteins. Our results showed in the cortex of exercised rats an inactivation of mTOR, greater autophagy flux (increased LC3-II/LC3-I ratio and reduced p62) besides increased LAMP1. Related with these effects a reduction in the ubiquitinated proteins was observed. No significant changes in the autophagic pathway were found either in hippocampus or in skeletal and cardiac muscle by exercise. Only in the liver of exercised rats mTOR phosphorylation and p62 levels increased, which could be related with beneficial metabolic effects in this organ induced by exercise. Thus, our findings suggest that long-term moderate exercise induces autophagy specifically in the cortex. PMID- 24781733 TI - 3-Fluoromethcathinone, a structural analog of mephedrone, inhibits growth and induces cell cycle arrest in HT22 mouse hippocampal cells. AB - Recently, the abuse of recreational drugs has become an important problem in many countries. Among these psychoactive substances are synthetic cathinones, a group of compounds derived from the alkaloid cathinone, that have gained widespread popularity. Many cathinones have demonstrated neurotoxic effects. The aim of this study was to examine the effects of 3-fluoromethcathinone, a structural analog of mephedrone, on HT22 mouse hippocampal cells. Cell viability was assessed using the sulforhodamine B assay. Flow cytometry was used to study the cell cycle distribution. We found that 3-fluoromethcathinone inhibits growth of HT22 cells. Our results also revealed that it induces G0/G1-phase cell cycle arrest. To our knowledge, this is the first study to demonstrate the cytotoxic action of 3 fluoromethcathinone. Our findings suggest that abuse of this cathinone derivative may not be without risk. PMID- 24781734 TI - Social isolation-induced epigenetic changes in midbrain of adult mice. AB - Social isolation and loneliness increase the risk of death as much as well established risk factors for mortality such as cigarette smoking and alcohol consumption. The underlying molecular mechanisms are poorly understood. In the present study, 3 months old male C57BL/6 mice were socially isolated by individual housing for another 3 months. At the age of 6 months, epigenetic changes were analyzed in midbrain. Social isolation of male adult mice led to an increased global DNA methylation, which was associated with enhanced activity of DNA methyltransferase. Di- and trimethylation of global histone H3 lysine 4 (H3K4) were increased in midbrain of socially isolated mice, accompanied by enhanced H3K4 histone methyltransferase activity. In addition, social isolation of adult mice led to activation of histone acetyltransferases as well as of histone deacetylases (HDAC) resulting in a net enhancement of histone H3 lysine 9 (H3K9) acetylation. Gene-specific effects were observed for Hdac1, Hdac3 and the serotonin transporter Slc6a4. Social isolation led to an up-regulation of Hdac1 and Hdac3, associated with decreased DNA methylation in the CpG island of the respective genes. On the contrary, the Slc6a4 gene was down-regulated, which was associated with enhanced DNA methylation. Collectively, the results from the present study demonstrate for the first time that social isolation of adult mice leads to a wide range of global epigenetic changes and these effects may have profound impact on gene expression pattern and phenotype of the socially isolated animals. PMID- 24781735 TI - Disrupted brain thyroid hormone homeostasis and altered thyroid hormone-dependent brain gene expression in autism spectrum disorders. AB - The present study examined human postmortem brains for changes consistent with the hypothesis of local brain TH deficiency in autism spectrum disorders (ASD). Brain levels of oxidative stress marker - 3-nitrotyrosine (3-NT), iodothyronine deiodinase type 2(D2) and type 3 (D3), 3',3,5-triiodothyronine (T3) content, mercury content and gene expression levels were analyzed and compared in the several regions of postmortem brains derived from both male and female control and ASD cases, age 4-16 years. We report that some parameters measured, such as D2 are subject to rapid postmortem inactivation, while others that were analyzed showed both brain region- and sex-dependent changes. Levels of 3-NT were overall increased, T3 was decreased in the cortical regions of ASD brains, while mercury levels measured only in the extracortical regions were not different. The expression of several thyroid hormone (TH)-dependent genes was altered in ASD. Data reported here suggest the possibility of brain region-specific disruption of TH homeostasis and gene expression in autism. PMID- 24781736 TI - Effects of xenoestrogens on streptozotocin-induced diabetic mice. AB - In diabetic mellitus, apoptotic or necrotic deaths of pancreatic beta-cells lead to insulin deficiency because plasma insulin is synthesized and released from pancreatic beta-cells and involved with blood glucose homeostasis. Since estrogen receptors have been related with glucose metabolis, estrogen-like chemicals (xenoestrogens) including bisphenol A (BPA) and octylphenol (OP) alter the endocrine system, and cause adverse health consequences such as obesity and diabetes. In the current study, levels of plasma glucose were evaluated after administration of BPA and OP using biochemical analysis, and were investigated in insulin and insulin synthesis-related genes in the pancreas and liver of streptozotocin (STZ)-induced insulin-deficient mice. Although the STZ-induced insulin-deficient groups showed an increase in blood glucose compared with control groups, the induced blood glucose level dropped to that of baseline after administration of xenoestrogens. When insulin level and mRNA expression of insulin transcriptional regulators (Pdx1, Mafa, and Neurod1) in pancreatic beta cells were decreased in STZ-induced insulin-deficient groups, they were significantly restored by administration of xenoestrogens. The latter observation is also related to NF-kappaB activation for anti-apoptosis effects in pancreatic beta-cells. In addition, we observed a complementary convergence in regulation of gluconeogenesis for determination of blood glucose levels. Therefore, the current study may be particularly important for assessment of xenoestrogens under condition of diabetic mellitus or metabolic disorder. PMID- 24781737 TI - Prenatal exposure to hyperoxia modifies the thromboxane prostanoid receptor mediated response to H2O2 in the ductus arteriosus of the chicken embryo. AB - O2 tension plays a critical role in the control of prenatal patency and postnatal closure of the ductus arteriosus (DA). We hypothesized that exposure of chicken embryos to hyperoxia alters the morphology and function of DA. Hyperoxia was induced by incubating fertilized eggs at 60% O2 from day 15 to 19 of the 21-d incubation period. DA reactivity (assessed by wire myography), morphometry and mRNA expression of antioxidant enzymes were studied on day 19. Hyperoxic incubation neither affected embryonic growth nor induced signs of DA constriction or changed the mRNA expression of superoxide dismutase and catalase. The contractions induced by O2 (21%), KCl, 4-aminopyridine, phenylephrine, and endothelin-1 and the relaxations induced by acetylcholine (ACh), sodium nitroprusside, isoproterenol, and hydroxyfasudil were similar in DA from embryos incubated under normoxic or hyperoxic conditions. In contrast, hyperoxic incubation impaired the thromboxane prostanoid (TP) receptor-mediated contractions evoked by U46619, 15-E2t-Isoprostane and high concentrations (>=3 MUM) of ACh. Exogenous hydrogen peroxide (H2O2) evoked endothelium-dependent contraction in the normoxic DA and endothelium-dependent relaxation in the hyperoxic group. The presence of the TP receptor antagonist SQ 29548 unmasked a relaxant response to H2O2 in the normoxic DA and the cyclooxygenase (COX) inhibitor indomethacin blocked H2O2-induced contraction (in the normoxic group) and relaxation (in the hyperoxic group). Altogether our functional data suggest that, in the chicken DA, exogenous H2O2 induces the release of endothelium derived COX metabolite(s) with contractile and relaxant properties. Under normal conditions H2O2-induced contraction prevails and relaxation is unmasked after pharmacological or functional (i.e.hyperoxia) TP receptor impairment. PMID- 24781738 TI - New insight into oseophageal injury and protection in physiologically relevant animal models. AB - Chronic diseases of lifestyle (CDL), the most common chronic group of non infectious and non-transmissible diseases worldwide, which share the similar risk factors of unhealthy lifestyle, have become most recognized as a serious trigger in the genesis of oesophageal injury. Non-erosive oesophageal lesions (NEOL) are found more frequently than erosive or ulcer lesions in patients with reflux oesophagitis (RO) related to CDL. They also have restricted healing options, which often leads to carcinogenesis. Therefore, developing a physiologically relevant animal model of NEOL remains an urgent priority. One of triggers of CDL, postprandial hyperglycemia (PHG), which is characterized by hyperglycemic spikes, and overloading nitro-compounds leading to oxidative stress that may predispose to NEOL. The present study was designed to set up a model of RO related to CDL in rodents to understand mechanisms of oesophageal preulcerogenic injury under such conditions as food-associated long-term PHG, restrained water-immersion stress (WIS), and imbalance of entero-salivary nitrites recirculation (ESNR). Beneficial effects of L-tryptophan (L-Try) have already been described by many activities in kynurenine and melatonin (Mel) synthesis, redox reactions, which play a key role for cytoprotection and proliferation. Nevertheless, the effect of L-Try and Mel on NEOL under PHG is still unknown. An extract of Cucurbita maxim sweet seed (eCMS), which contains a high amount of antioxidants, also appear to play an important role in foregut cytoprotection. Thus, the second aim was to observe the effects of eCSE on oesophageal mucosa (OEM) in modification of ESNR (mESNR). Rats were used with without/with pre-treatment L-Try, Mel during WIS and PHG. In the second series of experiments rats were used with without/with CSE pre-treatment in mESNR; oral and OEM lesions were determined by histology; inflammation of OEM by lectin histochemistry; esophageal NO2(-), cNOS and iNOS via bioassays; interleukin 1beta (IL-1beta), interleukin-8 (IL-8) via ELISA. PHG caused destructive lesions in the OEM accompanied by the up-regulation of iNOS and down regulation of cNOS expressions, excessive NO2(-) while COX significantly aggravated the severity of these lesions; L-Try prevented ulcerogenic response to PHG with potent up-regulation of cNOS but did not affect synthesis NO2(-). Mannose (Man)-containing specific a-DMan glycoconjugates labelled by lectins GNA, PSL, LCA, ConA and fucose (Fuc)-rich Fuc-alpha1 glycoconjugates - PFA, LABA are contributed in OEM integrity. It was shown that the changes of subepithelial and epithelial structures labelled by GNA, PSL, LCA displayed their highest exposure in the surface layer, whereas in the intima of microvasculature and nerve fibres of serosa membrane of the oesophagus by ConA during PHG NEOL. Also, the overexpression of Fuc glycans was present in OEM pre-epithelial and epithelial layers labelled by LABA and in the epithelial-glial-endothelial activity by PFA. Thus, initial changes in endothelial metabolism via iNOS and eNOS can be diagnostic and prognostic markers of NEOL in RO. Our mESNR studies also documented an early increase in pro-inflammatory mediators in the initial stage of oesophageal ulcerogenesis and repair and it can be a model for both proximal and distal oesophageal reflux diseases, as determinate by NEOL in oral mucosa and OEM. These findings suggest that endothelial metabolism is deeply involved in pathogenesis of NEOL. These models may be useful for detecting a new therapeutic strategy NERD, testing anti-ulcer drugs against RO and impaired healing OEM. Our results suggest that L-Try and Mel prevent OEM damage inducted by PHG and oesophagoprotective effect via modulation NO/NOS activity. The anti-inflammatory effect of eCMS could be used to protect oral mucosa and OEM against mESNR. PMID- 24781739 TI - Anti-inflammatory effects of Allium schoenoprasum L. leaves. AB - Allium schoenoprasum has antimicrobial and antifungal properties and is used to relieve pain from sunburn and sore throat. The aim of the present study was to evaluate the anti-inflammatory effects of the extracts from A. schoenoprasum leaves. A 1:1 (w:v) extract was prepared by a modified Squibb repercolation method. The total phenolic content of 68.5+/-2 g gallic acid aquivalent (GAE)/g plant was determined using the Folin-Ciocalteu method. The in vitro antioxidant activity was determined using the 1,1-diphenyl-2-picrylhydrazyl bleaching method (6.72+/-0.44 g/mg DPPH) and the trolox equivalent antioxidant capacity (132.8+/ 23 g trolox eq./g plant) assay. Analysis of the extracts using the hemoglobin ascorbate peroxidase activity inhibition assay or the electron spin resonance did not yield signals above the detection limit. The anti-inflammatory effects of three extract concentrations (25%, 50%, 100%) were evaluated in vivo on a model turpentine oil-induced inflammation in rats. These three extracts were also evaluated in vitro for the ability to inhibit phagocytosis, the accumulation of total nitrites and nitrates in the serum, the total oxidative status, the total antioxidant response and the oxidative stress index. Pure extracts (100% concentration) had the best inhibitory activity on phagocytosis and oxidative stress. In conclusion, these results support the hypothesis that extracts from A. schoenoprasum leaves exert anti-inflammatory activities by inhibiting phagocytosis through the reduction of nitro-oxidative stress. PMID- 24781740 TI - Differential expression of genes involved in the calcium homeostasis in masticatory muscles of MDX mice. AB - Duchenne Muscular Dystrophy (DMD) and its murine model, mdx, are characterized by Ca(2+) induced muscle damage and muscle weakness followed by distorted dentofacial morphology. In both, DMD patients and in mdx mice, could be proven so far that only the extraocular muscles (EOM) are not affected by muscular dystrophy. The EOMs are protected against calcium overload by enhanced expression of genes involved in the Ca(2+) homeostasis. We could recently demonstrate that masticatory muscles of mdx mice are differentially affected by muscle dystrophy. The dystrophic masseter and temporalis shows muscle histology comparable to all other skeletal muscles in this animal model, whereas dystrophic tongue muscles seem to develop a milder phenotype. Due to this fact it is to hypothesize that an altered Ca(2+) homeostasis seems to underlie the mdx masticatory muscle pathology. Aim of this study was to examine the mRNA and protein levels of the sarcoplasmic reticulum Ca(2+) ATPases SERCA1 and SERCA2, the plasma membrane Ca(2+) ATPases Atp2b1 and Atp2b4, the sodium/calcium exchanger NCX1, the ryanodine receptor 1, parvalbumin, sarcolipin, phospholamban and the L-type Ca(2+) channel alpha-1 subunit (Cacna1s) in Musculus masseter, temporalis, and tongue of 100 day old control and mdx mice. In mdx masseter muscle significant increased mRNA levels of NCX1 and Cacna1s were found compared to control mice. In contrast, the mRNA amount of RYR1 was significant reduced in mdx temporalis muscle, whereas ATP2b4 was significant increased. In mdx tongue a down-regulation of the ATP2b1, sarcolipin and parvalbumin mRNA expression was found, whereas the phospholamban mRNA level was significantly increased compared to controls. These data were verified by western blot analyses. Our findings revealed that mdx masticatory muscles showed an unequally altered expression of genes involved in the Ca(2+) homeostasis that can support the differences in masticatory muscles response to dystrophin deficiency. PMID- 24781741 TI - Tropical sprue in 2014: the new face of an old disease. AB - Tropical sprue (TS), once known to be a common cause of malabsorption syndrome (MAS) in India and other tropical countries, is believed to be uncommon currently in spite of contrary evidence. Several recent studies from India showed TS to be the commonest cause of sporadic MAS in Indian adults. TS is diagnosed in patients presenting with suggestive clinical presentation, which cannot be explained by another cause of MAS and investigations revealing malabsorption of two unrelated substances, abnormal small-intestinal mucosal histology, which responds to treatment with antibiotics such as tetracycline and folic acid. There is substantial overlap between TS and postinfectious irritable bowel syndrome. There have been several advances in epidemiology, pathogenesis, and diagnosis of TS, hitherto an enigmatic condition. PMID- 24781742 TI - Polymicrobial infection and bacterium-mediated epigenetic modification of DNA tumor viruses contribute to pathogenesis. AB - ABSTRACT The human body plays host to a wide variety of microbes, commensal and pathogenic. In addition to interacting with their host, different microbes, such as bacteria and viruses, interact with each other, sometimes in ways that exacerbate disease. In particular, gene expression of a number of viruses, including Kaposi's sarcoma-associated herpesvirus (KSHV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV), is known to be regulated by epigenetic modifications induced by bacteria. These viruses establish latent infection in their host cells and can be reactivated by bacterial products. Viral reactivation has been suggested to contribute to periodontal disease and AIDS. In addition, bacterium-virus interactions may play a role in cancers, such as Kaposi's sarcoma, gastric cancer, and head and neck cancer. It is important to consider the effects of coexisting bacterial infections when studying viral diseases in vivo. PMID- 24781743 TI - Alterations in cholesterol metabolism restrict HIV-1 trans infection in nonprogressors. AB - ABSTRACT HIV-1-infected nonprogressors (NP) inhibit disease progression for years without antiretroviral therapy. Defining the mechanisms for this resistance to disease progression could be important in determining strategies for controlling HIV-1 infection. Here we show that two types of professional antigen-presenting cells (APC), i.e., dendritic cells (DC) and B lymphocytes, from NP lacked the ability to mediate HIV-1 trans infection of CD4(+) T cells. In contrast, APC from HIV-1-infected progressors (PR) and HIV-1-seronegative donors (SN) were highly effective in mediating HIV-1 trans infection. Direct cis infection of T cells with HIV-1 was comparably efficient among NP, PR, and SN. Lack of HIV-1 trans infection in NP was linked to lower cholesterol levels and an increase in the levels of the reverse cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) in APC but not in T cells. Moreover, trans infection mediated by APC from NP could be restored by reconstitution of cholesterol and by inhibiting ABCA1 by mRNA interference. Importantly, this appears to be an inherited trait, as it was evident in APC obtained from NP prior to their primary HIV-1 infection. The present study demonstrates a new mechanism wherein enhanced lipid metabolism in APC results in remarkable control of HIV-1 trans infection that directly relates to lack of HIV-1 disease progression. IMPORTANCE HIV-1 can be captured by antigen-presenting cells (APC) such as dendritic cells and transferred to CD4 helper T cells, which results in greatly enhanced viral replication by a mechanism termed trans infection. A small percentage of HIV-1-infected persons are able to control disease progression for many years without antiretroviral therapy. In our study, we linked this lack of disease progression to a profound inability of APC from these individuals to trans infect T cells. This effect was due to altered lipid metabolism in their APC, which appears to be an inherited trait. These results provide a basis for therapeutic interventions to control of HIV-1 infection through modulation of cholesterol metabolism. PMID- 24781744 TI - Integrative conjugative element ICE-betaox confers oxidative stress resistance to Legionella pneumophila in vitro and in macrophages. AB - ABSTRACT Integrative conjugative elements (ICEs) are mobile blocks of DNA that can contribute to bacterial evolution by self-directed transmission of advantageous traits. Here, we analyze the activity of a putative 65-kb ICE harbored by Legionella pneumophila using molecular genetics, conjugation assays, a phenotype microarray screen, and macrophage infections. The element transferred to a naive L. pneumophila strain, integrated site-specifically, and conferred increased resistance to oxacillin, penicillin, hydrogen peroxide, and bleach. Furthermore, the element increased survival of L. pneumophila within restrictive mouse macrophages. In particular, this ICE protects L. pneumophila from phagocyte oxidase activity, since mutation of the macrophage NADPH oxidase eliminated the fitness difference between strains that carried and those that lacked the mobile element. Renamed ICE-betaox (for beta-lactam antibiotics and oxidative stress), this transposable element is predicted to contribute to the emergence of L. pneumophila strains that are more fit in natural and engineered water systems and in macrophages. IMPORTANCE Bacteria evolve rapidly by acquiring new traits via horizontal gene transfer. Integrative conjugative elements (ICEs) are mobile blocks of DNA that encode the machinery necessary to spread among bacterial populations. ICEs transfer antibiotic resistance and other bacterial survival factors as cargo genes carried within the element. Here, we show that Legionella pneumophila, the causative agent of Legionnaires' disease, carries ICE-betaox, which enhances the resistance of this opportunistic pathogen to bleach and beta lactam antibiotics. Moreover, L. pneumophila strains encoding ICE-betaox are more resistant to macrophages that carry phagocyte oxidase. Accordingly, ICE-betaox is predicted to increase the fitness of L. pneumophila in natural and engineered waters and in humans. To our knowledge, this is the first description of an ICE that confers oxidative stress resistance to a nosocomial pathogen. PMID- 24781746 TI - The triphenylethylenes, a novel class of antifungals. AB - ABSTRACT New antifungals are needed, particularly in the developing world, to treat life-threatening fungal infections, such as cryptococcosis. Drug repurposing is one strategy to identify new drug-like compounds, but it is often difficult to identify a mechanism of action. Here we discuss the outstanding effort by Butts et al. to identify calmodulin as an antifungal target of repurposed estrogen receptor antagonists [A. Butts, K. Koselny, Y. Chabrier Rosello, C. P. Semighini, Y. C. S. Brown, et al., mBio 5(1):e00765-13, 2014, doi:10.1128/mBio.00765-13]. The authors show that these compounds bind to and directly inhibit fungal calmodulin and also reduce fungal burden in an animal disease model. These studies thus establish both the key preclinical efficacy and the antifungal mechanism of action, which will allow these compounds to progress toward development of novel antifungal therapies. PMID- 24781745 TI - A Rhodobacter sphaeroides protein mechanistically similar to Escherichia coli DksA regulates photosynthetic growth. AB - ABSTRACT DksA is a global regulatory protein that, together with the alarmone ppGpp, is required for the "stringent response" to nutrient starvation in the gammaproteobacterium Escherichia coli and for more moderate shifts between growth conditions. DksA modulates the expression of hundreds of genes, directly or indirectly. Mutants lacking a DksA homolog exhibit pleiotropic phenotypes in other gammaproteobacteria as well. Here we analyzed the DksA homolog RSP2654 in the more distantly related Rhodobacter sphaeroides, an alphaproteobacterium. RSP2654 is 42% identical and similar in length to E. coli DksA but lacks the Zn finger motif of the E. coli DksA globular domain. Deletion of the RSP2654 gene results in defects in photosynthetic growth, impaired utilization of amino acids, and an increase in fatty acid content. RSP2654 complements the growth and regulatory defects of an E. coli strain lacking the dksA gene and modulates transcription in vitro with E. coli RNA polymerase (RNAP) similarly to E. coli DksA. RSP2654 reduces RNAP-promoter complex stability in vitro with RNAPs from E. coli or R. sphaeroides, alone and synergistically with ppGpp, suggesting that even though it has limited sequence identity to E. coli DksA (DksAEc), it functions in a mechanistically similar manner. We therefore designate the RSP2654 protein DksARsp. Our work suggests that DksARsp has distinct and important physiological roles in alphaproteobacteria and will be useful for understanding structure-function relationships in DksA and the mechanism of synergy between DksA and ppGpp. IMPORTANCE The role of DksA has been analyzed primarily in the gammaproteobacteria, in which it is best understood for its role in control of the synthesis of the translation apparatus and amino acid biosynthesis. Our work suggests that DksA plays distinct and important physiological roles in alphaproteobacteria, including the control of photosynthesis in Rhodobacter sphaeroides. The study of DksARsp, should be useful for understanding structure function relationships in the protein, including those that play a role in the little-understood synergy between DksA and ppGpp. PMID- 24781747 TI - Middle East respiratory syndrome coronavirus quasispecies that include homologues of human isolates revealed through whole-genome analysis and virus cultured from dromedary camels in Saudi Arabia. AB - ABSTRACT Complete Middle East respiratory syndrome coronavirus (MERS-CoV) genome sequences were obtained from nasal swabs of dromedary camels sampled in the Kingdom of Saudi Arabia through direct analysis of nucleic acid extracts or following virus isolation in cell culture. Consensus dromedary MERS-CoV genome sequences were the same with either template source and identical to published human MERS-CoV sequences. However, in contrast to individual human cases, where only clonal genomic sequences are reported, detailed population analyses revealed the presence of more than one genomic variant in individual dromedaries. If humans are truly infected only with clonal virus populations, we must entertain a model for interspecies transmission of MERS-CoV wherein only specific genotypes are capable of passing bottleneck selection. IMPORTANCE In most cases of Middle East respiratory syndrome (MERS), the route for human infection with the causative agent, MERS coronavirus (MERS-CoV), is unknown. Antibodies to and viral nucleic acids of MERS-CoV have been found in dromedaries, suggesting the possibility that they may serve as a reservoir or vector for human infection. However, neither whole viral genomic sequence nor infectious virus has been isolated from dromedaries or other animals in Saudi Arabia. Here, we report recovery of MERS-CoV from nasal swabs of dromedaries, demonstrate that MERS-CoV whole-genome consensus sequences from dromedaries and humans are indistinguishable, and show that dromedaries can be simultaneously infected with more than one MERS-CoV. Together with data indicating widespread dromedary infection in the Kingdom of Saudi Arabia, these findings support the plausibility of a role for dromedaries in human infection. PMID- 24781748 TI - Expression control of nitrile hydratase and amidase genes in Rhodococcus erythropolis and substrate specificities of the enzymes. AB - Bacterial amidases and nitrile hydratases can be used for the synthesis of various intermediates and products in the chemical and pharmaceutical industries and for the bioremediation of toxic pollutants. The aim of this study was to analyze the expression of the amidase and nitrile hydratase genes of Rhodococcus erythropolis and test the stereospecific nitrile hydratase and amidase activities on chiral cyanohydrins. The nucleotide sequences of the gene clusters containing the oxd (aldoxime dehydratase), ami (amidase), nha1, nha2 (subunits of the nitrile hydratase), nhr1, nhr2, nhr3 and nhr4 (putative regulatory proteins) genes of two R. erythropolis strains, A4 and CCM2595, were determined. All genes of both of the clusters are transcribed in the same direction. RT-PCR analysis, primer extension and promoter fusions with the gfp reporter gene showed that the ami, nha1 and nha2 genes of R. erythropolis A4 form an operon transcribed from the Pami promoter and an internal Pnha promoter. The activity of Pami was found to be weakly induced when the cells grew in the presence of acetonitrile, whereas the Pnha promoter was moderately induced by both the acetonitrile or acetamide used instead of the inorganic nitrogen source. However, R. erythropolis A4 cells showed no increase in amidase and nitrile hydratase activities in the presence of acetamide or acetonitrile in the medium. R. erythropolis A4 nitrile hydratase and amidase were found to be effective at hydrolysing cyanohydrins and 2 hydroxyamides, respectively. PMID- 24781749 TI - Regulation of focal adhesion formation by a vinculin-Arp2/3 hybrid complex. AB - Focal adhesions (FAs) are large multi-protein complexes that act as transmembrane links between the extracellular matrix and the actin cytoskeleton. Recently, FAs were extensively characterized, yet the molecular mechanisms underlying their mechanical and signalling functions remain unresolved. To address this question, we isolated protein complexes containing different FA components, from chicken smooth muscle, and characterized their properties. Here we identified 'hybrid complexes' consisting of the actin-nucleating subunits of Arp2/3 and either vinculin or vinculin and alpha-actinin. We further show that suppression of p41 ARC, a central component of native Arp2/3, which is absent from the hybrid complexes, increases the levels of the Arp2/3-nucleating core in FA sites and stimulates FA growth and dynamics. In contrast, overexpression of p41-ARC adversely affects FAs. These results support the view that Arp2/3 can form modular 'hybrid complexes' containing an actin-nucleating 'functional core', and 'anchoring domains' (vinculin/p41-ARC) that regulate its subcellular localization. PMID- 24781750 TI - Recent guidelines for the management of hypertension: what is missing? PMID- 24781751 TI - Inpatient management of acute alcohol withdrawal syndrome. AB - Alcohol withdrawal is a common condition encountered in the hospital setting after abrupt discontinuation of alcohol in an alcohol-dependent individual. Patients may present with mild symptoms of tremulousness and agitation or more severe symptoms including withdrawal seizures and delirium tremens. Management revolves around early identification of at-risk individuals and symptom assessment using a validated tool such as the revised Clinical Institute Withdrawal Assessment for Alcohol score. Benzodiazepines remain the mainstay of treatment and can be administered using a front-loading, fixed-dose, or symptom triggered approach. Long-acting benzodiazepines such as chlordiazepoxide or diazepam are commonly used and may provide a smoother withdrawal than shorter acting benzodiazepines, but there are no data to support superiority of one benzodiazepine over another. Elderly patients or those with significant liver disease may have increased accumulation and decreased clearance of the long acting benzodiazepines, and lorazepam or oxazepam may be preferred in these patients. Patients with symptoms refractory to high doses of benzodiazepines may require addition of a rescue medication such as phenobarbital, propofol or dexmedetomidine. Anticonvulsants (carbamazepine, valproate, gabapentin) may have a role in the management of mild to moderate withdrawal. Other medications such as beta-antagonists or neuroleptics may offer additional benefit in select patients but should not be used a monotherapy. PMID- 24781752 TI - Loss of locus coeruleus noradrenergic neurons alters the inflammatory response to LPS in substantia nigra but does not affect nigral cell loss. AB - In Parkinson's disease (PD), destruction of noradrenergic neurons in the locus coeruleus (LC) may precede damage to nigral cells and subsequently exaggerate dopaminergic cell loss. We examine if destruction of the locus coeruleus with N (2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) alters dopaminergic cell loss in substantia nigra (SN) initiated by lipopolysaccharide (LPS) in the rat through an effect on glial cell activation. In rats, a single intraperitoneal dose of DSP 4 administered 8 days previously, caused a marked loss of tyrosine hydroxylase positive neurons in LC but no change in dopaminergic cell number in SN. Unilateral nigral LPS administration resulted in marked dopaminergic cell death with reactive microgliosis associated with enhanced p47 phox in OX-6 and OX-42 positive microglia. There was proliferation of inducible nitric oxide synthase (iNOS)-positive cells, formation of 3-nitrotyrosine (3-NT) and proliferation of astrocytes that expressed glial cell line-derived neurotrophic factor (GDNF). Following combined DSP-4 treatment and subsequent administration of LPS, unexpectedly, no further loss of tyrosine hydroxylase (TH)-immunoreactivity (-ir) occurred in the SN compared to the effects of LPS alone. However, there was a marked alteration in the morphology of microglial cell and a reduction of 3-NT- and iNOS-ir was evident. Expression of p47 phox was downregulated in microglia but up-regulated in TH-ir neurons. No further change in GFAP-ir was observed compared to that produced by DSP-4 alone or LPS alone, but the expression of GDNF was markedly reduced. This study suggests that in contrast to previous reports, prior LC damage does not influence subsequent nigral dopaminergic cell degeneration induced by LPS. Rather it appears to attenuate the microglial response thought to contribute to disease progression in PD. PMID- 24781753 TI - Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia. AB - Metaphyseal anadysplasia (MANDP) is an uncommon chondrodysplasia characterized by early-onset metaphyseal dysplasia and short stature that improves with age. MANDP is caused by mutations in the matrix metalloproteinase (MMP) 9 and 13 genes. Autosomal dominant (AD) MANDP has been described as more severe, and has been associated with dominant-negative MMP13 mutations that suppress activity of both MMP9 and MMP13; autosomal recessive (AR) MANDP has been described as a milder form associated with AR missense mutations in MMP9 or MMP13. Here we describe the molecular characterization of skeletal dysplasia in two brothers who presented with short stature and mixed epiphyseal and metaphyseal dysplasia. Whole-exome sequencing (WES) identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T) on chromosome 11q22.2 resulting in a premature stop codon p.(R109*) that is predicted to abolish MMP13 activity. This report extends the MANDP phenotype by illustrating that AR nonsense mutations in MMP13 can lead to short stature that persists beyond childhood. PMID- 24781754 TI - Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. AB - In a consanguineous Turkish family diagnosed with autosomal recessive nonsyndromic hearing impairment (arNSHI), a homozygous region of 47.4 Mb was shared by the two affected siblings on chromosome 6p21.1-q15. This region contains 247 genes including the known deafness gene MYO6. No pathogenic variants were found in MYO6, neither with sequence analysis of the coding region and splice sites nor with mRNA analysis. Subsequent candidate gene evaluation revealed CLIC5 as an excellent candidate gene. The orthologous mouse gene is mutated in the jitterbug mutant that exhibits progressive hearing impairment and vestibular dysfunction. Mutation analysis of CLIC5 revealed a homozygous nonsense mutation c.96T>A (p.(Cys32Ter)) that segregated with the hearing loss. Further analysis of CLIC5 in 213 arNSHI patients from mostly Dutch and Spanish origin did not reveal any additional pathogenic variants. CLIC5 mutations are thus not a common cause of arNSHI in these populations. The hearing loss in the present family had an onset in early childhood and progressed from mild to severe or even profound before the second decade. Impaired hearing is accompanied by vestibular areflexia and in one of the patients with mild renal dysfunction. Although we demonstrate that CLIC5 is expressed in many other human tissues, no additional symptoms were observed in these patients. In conclusion, our results show that CLIC5 is a novel arNSHI gene involved in progressive hearing impairment, vestibular and possibly mild renal dysfunction in a family of Turkish origin. PMID- 24781756 TI - Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy. AB - Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5 aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted. PMID- 24781755 TI - Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. AB - The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division. PMID- 24781757 TI - SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. AB - Defects in complex II of the mitochondrial respiratory chain are a rare cause of mitochondrial disorders. Underlying autosomal-recessive genetic defects are found in most of the 'SDHx' genes encoding complex II (SDHA, SDHB, SDHC, and SDHD) and its assembly factors. Interestingly, SDHx genes also function as tumor suppressor genes in hereditary paragangliomas, pheochromocytomas, and gastrointestinal stromal tumors. In these cases, the affected patients are carrier of a heterozygeous SDHx germline mutation. Until now, mutations in SDHx associated with mitochondrial disease have not been reported in association with hereditary tumors and vice versa. Here, we characterize four patients with isolated complex II deficiency caused by mutations in SDHA presenting with multisystem mitochondrial disease including Leigh syndrome (LS) and/or leukodystrophy. Molecular genetic analysis revealed three novel mutations in SDHA. Two mutations (c.64-2A>G and c.1065-3C>A) affect mRNA splicing and result in loss of protein expression. These are the first mutations described affecting SDHA splicing. For the third new mutation, c.565T>G, we show that it severely affects enzyme activity. Its pathogenicity was confirmed by lentiviral complementation experiments on the fibroblasts of patients carrying this mutation. It is of special interest that one of our LS patients harbored the c.91C>T (p.Arg31*) mutation that was previously only reported in association with paragangliomas and pheochromocytomas, tightening the gap between these two rare disorders. As tumor screening is recommended for SDHx mutation carriers, this should also be considered for patients with mitochondrial disorders and their family members. PMID- 24781758 TI - An AP4B1 frameshift mutation in siblings with intellectual disability and spastic tetraplegia further delineates the AP-4 deficiency syndrome. AB - The recently proposed adaptor protein 4 (AP-4) deficiency syndrome comprises a group of congenital neurological disorders characterized by severe intellectual disability (ID), delayed or absent speech, hereditary spastic paraplegia, and growth retardation. AP-4 is a heterotetrameric protein complex with important functions in vesicle trafficking. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been reported in patients with the AP-4 deficiency phenotype. We describe two siblings from a non consanguineous couple who presented with severe ID, absent speech, microcephaly, growth retardation, and progressive spastic tetraplegia. Whole-exome sequencing in the two patients identified the novel homozygous 2-bp deletion c.1160_1161delCA (p.(Thr387Argfs*30)) in AP4B1. Sanger sequencing confirmed the mutation in the siblings and revealed it in the heterozygous state in both parents. The AP4B1-associated phenotype has previously been assigned to spastic paraplegia-47. Identification of a novel AP4B1 alteration in two patients with clinical manifestations highly similar to other individuals with mutations affecting one of the four AP-4 subunits further supports the observation that loss of AP-4 assembly or functionality underlies the common clinical features in these patients and underscores the existence of the clinically recognizable AP-4 deficiency syndrome. PMID- 24781759 TI - Machado-Joseph disease in a Nigerian family: mutational origin and review of the literature. AB - Machado-Joseph disease (MJD) has been described in Africans, but no cases have been reported from Nigeria. Current MJD global distribution results from both the ancestral populations-of-origin and the founder effects of mutations, some as a consequence of the Portuguese sea travels in the 15th to 16th century. Two main ancestral haplotypes have been identified: the Machado lineage, which is more recent, predominant in families of Portuguese extraction, and the Joseph lineage, which is much older and worldwide spread, postulated to have an Asian origin. We report a Nigerian family with MJD from Calabar, once settled by Portuguese slave traders, and assessed its mutational origin. The proband was a 33-year-old man with progressive unsteady gait, weakness of all limbs, dysphagia, dysarthria, urinary frequency and diaphoresis. He had end-of-gaze nystagmus, spastic quadriparesis and atrophic small muscles of the hand. He showed fibrillation potentials on EMG, and nerve conduction studies suggested a central axonopathy without demyelination. This family bears the Joseph haplotype, which has a founder effect in the island of Flores, in the Azores (and their descendants in North-America), but is also the most common in non-Portuguese populations worldwide, with an estimated mutation age of around 7000 years. PMID- 24781760 TI - Further confirmation of the MED13L haploinsufficiency syndrome. AB - MED13L haploinsufficiency syndrome has been described in two patients and is characterized by moderate intellectual disability (ID), conotruncal heart defects, facial abnormalities and hypotonia. Missense mutations in MED13L are linked to transposition of the great arteries and non-syndromal intellectual disability. Here we describe two novel patients with de novo MED13L aberrations. The first patient has a de novo mutation in the splice acceptor site of exon 5 of MED13L. cDNA analysis showed this mutation results in an in-frame deletion, removing 15 amino acids in middle of the conserved MED13L N-terminal domain. The second patient carries a de novo deletion of exons 6-20 of MED13L. Both patients show features of the MED13L haploinsufficiency syndrome, except for the heart defects, thus further confirming the existence of the MED13L haploinsufficiency syndrome. PMID- 24781761 TI - An effective therapy to painful bone metastases: cryoablation combined with zoledronic acid. AB - Approximately half or more of patients diagnosed with late malignant tumors may suffer from metastatic bone pain, effective palliation of pain becomes an important part of comprehensive therapy for malignant tumors. In this study, we examined the efficacy and safety of the combined regimen of cryoablation and zoledronic acid in patients of bone metastatic pain. A total of 84 subjects were randomly divided into three groups, and underwent treatments of cryoablation plus zoledronic acid, cryoablation alone, zoledronic acid alone between June 2009 and March 2012. Patients responses had been assessed for a total of 6 months by using the Brief Pain Inventory (BPI)-Short Form. The results showed that the mean response of worst and average pain significantly dropped at week 2 (all P < 0.05) in group with cryoablation treatment but at week 4 (all P < 0.05) in group with zoledronic acid treatment. While between week 16 and week 24, zoledronic acid treatments showed more durable response to worst and average pain compared to cryoablation (all P < 0.05). Cryoablation plus zoledronic acid regimen showed significant drop in worst and average pain between week 1 and week 4 compared to zoledronic acid alone (all P < 0.05) and more durable effect on bone metastatic pain between week 12 and week 24 than cryoablation alone (all P < 0.05). Additionally, no serious adverse effects and complication were observed by this combination use. In conclusion, cryoablation combined with zoledronic acid was safe and effective regimen and showed its superiority of fast response and durable effect on painful bone metastases. PMID- 24781762 TI - Ectopic lymphoid structures in primary cutaneous melanoma. AB - Ectopic lymphoid structures have been described in several tumor types including metastatic lesions, but not primary tumors, of patients with melanoma. Here we present evidence of B-cell follicles in primary cutaneous melanomas, being present in 39 of 147 cases (27 %). B-cell clusters were associated with T lymphocytes, most of which belonging to CD45RO(+) memory T cells. A network of CD21(+) follicular dendritic cells was demonstrated in 8 of 22 cases studied (36 %). MECA-79(+) HEV-like venules were observed in the neighborhood of the follicles in the majority of cases, however, their presence was not confined to tumors hosting ectopic lymphoid structures. The appearance of B-cell aggregates did not show association with the outcome of the disease, although a trend for their higher prevalence was observed in thicker tumors. Our results show that neogenesis of lymphoid structures does occur in primary melanomas, albeit with lower frequency compared to that reported in metastases. PMID- 24781763 TI - Pertinent to intrapartum nursing. PMID- 24781764 TI - The new hypertensive guidelines for pregnancy: what every nurse should know. PMID- 24781765 TI - What can the transition to extrauterine life teach us about change? PMID- 24781766 TI - Is that your final answer? The deposition process. PMID- 24781767 TI - Internet resources. PMID- 24781768 TI - Supporting labor progress toward physiologic birth. PMID- 24781769 TI - Labor management evidence update: potential to minimize risk of cesarean birth in healthy women. AB - New evidence regarding normal parameters of labor progress for healthy women has the potential to minimize risk of cesarean birth and thereby enhance current and future maternal well-being if clinicians apply the research findings to obstetric practice. The economic and reproductive health consequences of the increasing cesarean birth rate in the United States are considerable; therefore, action on this issue by all stakeholders is necessary. Review and integration of the recent recommendations for labor management from experts convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine are required to make maternity care in the United States as safe as possible. PMID- 24781770 TI - Labor down or bear down: a strategy to translate second-stage labor evidence to perinatal practice. AB - Scientific evidence supports spontaneous physiologic approaches to second-stage labor care; however, most women in US hospitals continue to receive direction from nurses and birth attendants to use prolonged Valsalva bearing-down efforts as soon as the cervix is completely dilated. Delaying maternal bearing-down efforts during second-stage labor until a woman feels an urge to push (laboring down) results in optimal use of maternal energy, has no detrimental maternal effects, and results in improved fetal oxygenation. Although most commonly used with women who are undergoing epidural anesthesia, laboring down is just one component of physiologic second-stage labor care that can be used to achieve optimal maternal and neonatal outcomes for women with or without an epidural. Prior efforts to translate evidence regarding second-stage labor care to practice have not been successful. In this article, the scientific evidence for second stage labor care and previous efforts at clinical translation are reviewed. The Ottawa Hospital Second Stage Protocol is presented as a model with potential to allow translation of evidence to practice. Recommendations to enhance widespread adoption of evidence-based practice are provided, including improved collaboration between nurses and birth attendants. PMID- 24781771 TI - Reliability and validity of an instrument to measure the beliefs of intrapartum nurses. AB - Intrapartum nurses assume a central role in the birth process and make decisions driven by a set of beliefs. Therefore, the purpose of this study was to develop a valid and reliable instrument to measure birth beliefs of intrapartum nurses related to birth practice. A total of 313 intrapartum nurses accessed this online, self-administered instrument over a 3-month period. The Theory of Planned Behavior guided development of the Intrapartum Nurses' Beliefs Related to Birth Practice scale and provided a basis for the connection between beliefs and practice. This article describes the psychometric analysis of the instrument. Findings include a moderate, positive correlation with a similar instrument, a Cronbach alpha of 0.797, and 2 factors identifying belief systems. With further revision, this instrument may provide an accurate measure of the birth beliefs of intrapartum nurses. PMID- 24781772 TI - Consumer information on fetal heart rate monitoring during labor: a content analysis: a content analysis. AB - Electronic fetal monitoring (EFM) is used for the majority of births that occur in the United States. While there are indications for use of EFM for women with high-risk pregnancies, its use in low-risk pregnancies is less evidence-based. In low-risk women, the use of EFM is associated with an increased risk for cesarean birth compared with the use of intermittent auscultation of the fetal heart rate. The purpose of this investigation was to evaluate the existence of evidence-based information on fetal heart rate monitoring in popular consumer-focused maternity books and Web sites. Content analysis of information in consumer-oriented Web sites and books was completed using the NVivo software (QRSinternational, Melbourne, Australia). Themes identified included lack of clear terminology when discussing fetal monitoring, use of broad categories such as low risk and high risk, limited presentation of information about intermittent auscultation, and presentation of EFM as the standard of care, particularly upon admission into the labor unit. More than one-third of the sources did not mention auscultation, and conflicting information about monitoring methods was presented. The availability of accurate, publically accessible information offers consumers the opportunity to translate knowledge into the power to seek evidence-based care practices during their maternity care experience. PMID- 24781773 TI - Not ready for prime time: transitional events in the extremely preterm infant. AB - Successful transition from intrauterine to extrauterine life involves significant physiologic changes. The majority of these changes occur relatively quickly during those first moments following delivery; however, transition for the extremely preterm infant occurs over a longer period of time. Careful assessment and perceptive interventions on the part of neonatal care providers is essential as the extremely preterm infant adjusts to life outside the womb. This article will focus on respiratory, cardiovascular, gastrointestinal, and neurologic transitional events experienced by the extremely premature infant. PMID- 24781774 TI - Transition to postnatal renal function. AB - In-utero the placenta is the primary organ responsible for neonatal homeostasis of fluid and electrolyte balance. With birth, this responsibility now transitions to the neonatal kidney. For successful transition to extrauterine renal physiology to occur maturation of neonatal glomerular filtration must occur, which is dependent on the development of renal blood flow. While these functions are decreased at birth, the term infant's kidneys are still able to manage homeostasis and are sufficient for growth and development. However, stressors can limit the adaptive properties of the neonatal kidney. This is especially important for those infants born before 34 weeks' gestation, when nephrogenesis is not yet complete. Knowledge of the changes in renal physiology is essential in caring for the neonate during transition. This article describes those changes. PMID- 24781775 TI - Defining family. PMID- 24781778 TI - PEG-like nanoprobes: multimodal, pharmacokinetically and optically tunable nanomaterials. AB - "PEG-like Nanoprobes" (PN's) are pharmacokinetically and optically tunable nanomaterials whose disposition in biological systems can be determined by fluorescence or radioactivity. PN's feature a unique design where a single PEG polymer surrounds a short fluorochrome and radiometal bearing peptide, and endows the resulting nanoprobe with pharmacokinetic control (based on molecular weight of the PEG selected) and optical tunability (based on the fluorochrome selected), while the chelate provides a radiolabeling option. PN's were used to image brain capillary angiography (intravital 2-photon microscopy), tumor capillary permeability (intravital fluorescent microscopy), and the tumor enhanced permeability and retention (EPR) effect (111In-PN and SPECT). Clinical applications of PN's include use as long blood half-life fluorochromes for intraoperative angiography, for measurements of capillary permeability in breast cancer lesions, and to image EPR by SPECT, for stratifying patient candidates for long-circulating nanomedicines that may utilize the EPR mechanism. PMID- 24781779 TI - Cross-sectional study of the association between a deepening of the upper eyelid sulcus-like appearance and wide-open eyes. AB - BACKGROUND: Deepening of the upper eyelid sulcus (DUES) is a common complication of prostaglandin F2alpha analog treatment, which causes cosmetic problems. However, identifying this condition using photographs is difficult due to such problems as the camera flash effects, blepharoptosis or wide-open eyes. PURPOSE: We investigated the association between a DUES-like appearance and wide-open eyes regarding the presence of wide-open eyes as a cause for overestimating the incidence of DUES. SUBJECTS AND METHODS: One eye and the forehead in 100 subjects (31 younger subjects, 30 older subjects and 39 patients with blepharoptosis) were evaluated in the present study. Digital photographs of the subjects with natural open and wide-open eyes were taken with a flash. Five signs (a puffy eyelid, the presence/absence of the upper eyelid sulcus (UES), wrinkles on the forehead with natural open eyes and an increase in the number of wrinkles on the forehead and a DUES-like appearance with wide-open eyes) were judged to be negative or positive by three independent observers. Univariate and multivariate logistic regression analyses were performed to determine the independent predictor(s) of a DUES-like appearance with wide-open eyes. RESULTS: Fourteen subjects (four young, three old and seven subjects with blepharoptosis) were judged to have a DUES-like appearance with wide-open eyes (14%). The only predictive factor was the presence of UES in the patients with natural open eyes (odds ratio = 17.244, 95% confidence interval: 3.447-86.270, P<0.001). Among the 12 UES-positive subjects, six (50%) exhibited a DUES-like appearance with wide-open eyes. CONCLUSIONS: The presence of wide-open eyes can thus cause a DUES-like appearance. Blepharoptosis itself is not a predictive factor; however, care should be taken not to overestimate the incidence of DUES, especially in patients with UES with natural open eyes, as a DUES-like appearance can be caused by wide-open eyes, even in treatment-naive patients. TRIAL REGISTRATION: UMIN000010500. PMID- 24781780 TI - High Prevalence of Diabetes and Prediabetes and Their Coexistence with Cardiovascular Risk Factors in a Hispanic Community. AB - This study examined the prevalence and association of diabetes mellitus (DM) and prediabetes with cardiovascular risk factors among Puerto Ricans adults. Data from a household survey of 857 adults aged 21-79 years who underwent interviews, physical exams, and blood draws were analyzed. Prevalence of total DM and prediabetes was estimated using American Diabetes Association diagnostic criteria of fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). Poisson regression models were used to estimate the prevalence ratio for each cardiovascular risk factor under study. Age-standardized prevalence of total DM and prediabetes, detected by FPG and/or HbA1c, was 25.5 and 47.4 %, respectively. Compared with participants with normoglycemia, those with previously diagnosed DM, undiagnosed DM, and prediabetes had more adverse cardiovascular risk factor profiles, characterized by a higher prevalence of general and abdominal obesity, hypertension, low HDL cholesterol, elevated LDL cholesterol, elevated triglycerides, and elevated plasminogen activator inhibitor 1 (p < 0.05). The high prevalence of DM and prediabetes calls for public health actions to plan and implement lifestyle interventions to prevent or delay the onset of DM and cardiovascular disease. PMID- 24781781 TI - The effect of acculturation on obesity among foreign-born Asians residing in the United States. AB - This study examined the relationship between acculturation and obesity in foreign born Asians residing in the United States, using the 2009 California Health Interview Survey secondary data (N = 2,871). Two series of proxies and/or behavioral variables were used to measure level of acculturation: (a) length of US residency (years and percent of life) and (b) English language use and proficiency. It was hypothesized that acculturation measured with both proxies would positively predict obesity among foreign-born Asian adults who live in the United States. Results did not support the relationship between obesity and residency length, and greater English use and proficiency seemed to predict lower obesity. However, additional exploratory analysis was performed for each Asian ethnicity and the results showed that the hypothesized links were partly supported for Filipino subgroup, but the links for Vietnamese subgroup were in the opposite direction of the hypotheses and inconsistent with previous literature. PMID- 24781782 TI - sp3 C-H oxidation by remote H-radical shift with oxygen- and nitrogen-radicals: a recent update. AB - This review updates on recent advances in aliphatic sp(3) C-H bond oxidation by remote H-radical abstraction with oxygen- and nitrogen-radicals classifying by the type of the radical precursors. PMID- 24781784 TI - Involvement of health-care professionals in an adverse event: the role of management in supporting their workforce. AB - INTRODUCTION: After an adverse event, not only patients and family members but also health-care professionals involved in the event become victims. More than 50% of all health-care professionals suffer emotionally and professionally after being involved in an adverse event. Support is needed for these "second victims" to prevent a further negative impact on patient care. OBJECTIVES: The aim of the study was to evaluate the prevalence and content of organizational-level support systems for health-care professionals involved in an adverse event. METHODS: A survey was sent to 109 Belgian hospitals regarding 2 aspects: first, the availability of a protocol for supporting second victims; and, second, the presence of a contact person in the organization to provide support. A total of 59 hospitals participated in the study. Hospitals were asked to submit their protocols for providing support to second victims. A content analysis based on an Institute for Healthcare Improvement's white paper and the Scott Model was performed to evaluate the protocols. RESULTS: Thirty organizations had a systematic plan to support second victims. Twelve percent could not identify a contact person. The chief nursing officer was seen as one of the main contact people when something went wrong. In terms of the quality of the protocols, only a minority followed part of the international resources. CONCLUSIONS: A minority of hospitals are somewhat prepared to provide support for health-care professionals. Management should take a leadership role in establishing support protocols for their health-care professionals in the aftermath of an adverse event. PMID- 24781785 TI - The microfluidic jukebox. AB - Music is a form of art interweaving people of all walks of life. Through subtle changes in frequencies, a succession of musical notes forms a melody which is capable of mesmerizing the minds of people. With the advances in technology, we are now able to generate music electronically without relying solely on physical instruments. Here, we demonstrate a musical interpretation of droplet-based microfluidics as a form of novel electronic musical instruments. Using the interplay of electric field and hydrodynamics in microfluidic devices, well controlled frequency patterns corresponding to musical tracks are generated in real time. This high-speed modulation of droplet frequency (and therefore of droplet sizes) may also provide solutions that reconciles high-throughput droplet production and the control of individual droplet at production which is needed for many biochemical or material synthesis applications. PMID- 24781786 TI - The time-dependent expression of alpha7nAChR during skeletal muscle wound healing in rats. AB - The study on time-dependent expression of alpha7 nicotine acetylcholine receptor (alpha7nAChR) was performed by immunohistochemistry, Western blotting, and real time PCR during skeletal muscle wound healing in rats. Furthermore, co localization of alpha7nAChR with macrophage or myofibroblast marker was detected by double immunofluorescence. A total of 50 Sprague-Dawley male rats were divided into control and contusion groups (3 h, 6 h, 12 h, 1 day, 3 days, 5 days, 7 days, 10 days, and 14 days post-injury). In the uninjured controls, alpha7nAChR positive staining was observed in the sarcolemma and sarcoplasm of normal myofibers. In wounded specimens, a small number of polymorphonuclear cells, a number of macrophages and myofibroblasts showed positive reaction for alpha7nAChR in contused zones. Morphometrically, the average ratios of alpha7nAChR-positive cells were over 50 % from 3 to 10 days after contusion, and exceeded 60 % at 5 and 7 days post-injury. Besides, the positive ratios of alpha7nAChR were <50 % at the other posttraumatic intervals. By Western blotting analysis, the average ratio of alpha7nAChR protein expression maximized at 7 days after injury, which was >2.13. Similarly, the relative quantity of alpha7nAChR mRNA expression peaked at 7 days post-wounding as compared with control by real-time PCR detection, showing a relative quantity of >2.65. In conclusion, the expression of alpha7nAChR is upregulated and temporally distributed in macrophages and myofibroblasts during skeletal muscle wound healing, which might be closely involved in inflammatory response and fibrotic repair after injury. Moreover, alpha7nAChR is promising as a useful marker for wound age determination of skeletal muscle. PMID- 24781787 TI - Application of age estimation methods based on teeth eruption: how easy is Olze method to use? AB - The development of new methods for age estimation has become with time an urgent issue because of the increasing immigration, in order to estimate accurately the age of those subjects who lack valid identity documents. Methods of age estimation are divided in skeletal and dental ones, and among the latter, Olze's method is one of the most recent, since it was introduced in 2010 with the aim to identify the legal age of 18 and 21 years by evaluating the different stages of development of the periodontal ligament of the third molars with closed root apices. The present study aims at verifying the applicability of the method to the daily forensic practice, with special focus on the interobserver repeatability. Olze's method was applied by three different observers (two physicians and one dentist without a specific training in Olze's method) to 61 orthopantomograms from subjects of mixed ethnicity aged between 16 and 51 years. The analysis took into consideration the lower third molars. The results provided by the different observers were then compared in order to verify the interobserver error. Results showed that interobserver error varies between 43 and 57 % for the right lower third molar (M48) and between 23 and 49 % for the left lower third molar (M38). Chi-square test did not show significant differences according to the side of teeth and type of professional figure. The results prove that Olze's method is not easy to apply when used by not adequately trained personnel, because of an intrinsic interobserver error. Since it is however a crucial method in age determination, it should be used only by experienced observers after an intensive and specific training. PMID- 24781790 TI - Coherence and modality of driven interlayer-coupled magnetic vortices. AB - The high-frequency dynamics of mode-coupled magnetic vortices have generated great interest for spintronic technologies, such as spin-torque nano-oscillators. While the spectroscopic characteristics of vortex oscillators have been reported, direct imaging of driven coupled magnetic quasi-particles is essential to the fundamental understanding of the dynamics involved. Here, we present the first direct imaging study of driven interlayer coaxial vortices in the dipolar- and indirect exchange-coupled regimes. Employing in situ high-frequency excitation with Lorentz microscopy, we directly observe the steady-state orbital amplitudes in real space with sub-5 nm spatial resolution. We discuss the unique frequency response of dipolar- and exchange-coupled vortex motion, wherein mode splitting and locking demonstrates large variations in coherent motion, as well as detail the resultant orbital amplitudes. This provides critical insights of the fundamental features of collective vortex-based microwave generators, such as their steady-state amplitudes, tunability and mode-coupled motion. PMID- 24781789 TI - Defining phenotypes in COPD: an aid to personalized healthcare. AB - The diagnosis of chronic obstructive pulmonary disease (COPD) is based on a post bronchodilator fixed forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <70 % ratio and the presence of symptoms such as shortness of breath and productive cough. Despite the simplicity in making a diagnosis of COPD, this morbid condition is very heterogeneous, and at least three different phenotypes can be recognized: the exacerbator, the emphysema-hyperinflation and the overlap COPD-asthma. These subgroups show different clinical and radiological features. It has been speculated that there is an enormous variability in the response to drugs among the COPD phenotypes, and it is expected that subjects with the same phenotype will have a similar response to each specific treatment. We believe that phenotyping COPD patients would be very useful to predict the response to a treatment and the progression of the disease. This personalized approach allows identification of the right treatment for each COPD patient, and at the same time, leads to improvement in the effectiveness of therapies, avoidance of treatments not indicated, and reduction in the onset of adverse effects. The objective of the present review is to report the current knowledge about different COPD phenotypes, focusing on specific treatments for each subgroup. However, at present, COPD phenotypes have not been studied by randomized clinical trials and therefore we hope that well designed studies will focus on this topic. PMID- 24781791 TI - Detection of salmonid alphavirus RNA in Celtic and Irish Sea flatfish. AB - Pancreas disease (PD) caused by the salmonid alphavirus (SAV) has been the most significant cause of mortalities in Irish farmed salmon Salmo salar L. over the past decade. SAV is a single-strand positive-sense RNA virus, originally thought to be unique to salmonids, but has recently been detected using real-time RT-PCR in a number of wild non-salmonid fish. In the present report, 610 wild flatfish (common dab Limanda limanda, plaice Pleuronectes platessa and megrim Lepidorhombus whiffiagonis) were caught from the Irish and Celtic Seas and screened for SAV using real-time RT-PCR and sequencing. In general, a very low prevalence was recorded in common dab and plaice, except for 1 haul in Dublin Bay where 25% of common dab were SAV-positive. SAV sequence analysis supported the fact that real-time RT-PCR detections were specific and further characterised the detected viruses within SAV Subtype I, the predominant subtype found in farmed salmon in Ireland. PMID- 24781792 TI - Genetic positioning of aquabirnavirus isolates from cultured Japanese eel Anguilla japonica in Korea. AB - Aquabirnavirus is an epizootic virus in Japanese eel Anguilla japonica farms in Korea, although its origin is unclear. In the present study, nucleotide sequences of the VP2/NS junction region of 9 Korean aquabirnaviruses from cultured eel in various areas of Korea during 2000-2009 were analyzed to evaluate their genetic relatedness to worldwide isolates. The nucleotide sequences showed more than 94.2% identity among the 9 Korean eel isolates, 71.2% identity among 16 Korean isolates from freshwater and marine fish, and 71.1% identity among 25 worldwide isolates. All 9 isolates in this study were phylogenetically classified into genogroup II, including isolates from Denmark, Spain, Taiwan and Japan, and were discrete from salmonid and marine fish isolates (genogroup I and VII) in Korea. These results suggest that the Korean eel isolates have most likely been introduced from outside the country and not from coastal areas of Korea. PMID- 24781793 TI - White bass Morone chrysops is less susceptible than its hybrid to experimental infection with Flavobacterium columnare. AB - Hybrid striped bass (HSB) and white bass (WB) were evaluated for their susceptibility to Flavobacterium columnare, the causative agent of columnaris disease, in 3 fundamental studies. In the first experiment, we determined whether columnaris disease could be developed by experimental challenge in HSB. This challenge consisted of 3 levels of F. columnare (10, 30, and 60 ml volumes) determined to be 2.25 * 10(7), 6.75 * 10(7), and 1.35 * 10(8) CFU ml(-1), respectively. Each treatment group exhibited significantly different survival rates: 0, 3.3, and 13.3% in the 60, 30, and 10 ml groups, respectively. In Expt 2, using the 30 ml dose, both HSB and WB had a 0% survival rate, with WB taking significantly longer to reach 100% mortality. In Expt 3, using the 10 ml dose, no HSB survived, whereas 33% of WB survived (p < 0.0001). Compared to controls, HSB treated with 10 ml showed extensive gill damage at 24 h, which could have contributed to the higher mortality observed in HSB; in contrast, WB gills showed noticeably less damage. From these series of experiments, it is clear that HSB are more sensitive to F. columnare, having lower survival and more extensive histological damage compared to WB following challenge. PMID- 24781794 TI - Development of a bacterial challenge test for gnotobiotic Nile tilapia Oreochromis niloticus larvae. AB - Gastrointestinal microbiota have an important impact on fish health and disease, stimulating interest in a better understanding of how these gastrointestinal microbial communities are composed and consequently affect host fitness. In this respect, probiotic microorganisms have been extensively used in recent aquaculture production. To study the use of probiotics in the treatment of infectious diseases, the establishment of a method of experimental infection to obtain consistent results for mortality and infection in challenge tests is important. In pathogen-screening tests, 4 candidate pathogenic bacteria strains (Edwardsiella ictaluri gly09, E. ictaluri gly10, E. tarda LMG2793 and Streptococcus agalactiae LMG15977) were individually tested on xenic Nile tilapia larvae. Only Edwardsiella strains delivered via Artemia nauplii, with or without additional pathogen delivery via the culture water, led to increased mortality in fish larvae. A gnotobiotic Nile tilapia larvae model system was developed to provide a research tool to investigate the effects and modes-of-action of probiotics under controlled conditions. A double disinfection procedure using hydrogen peroxide and sodium hypochlorite solution was applied to the fish eggs, which were subsequently incubated in a cocktail of antibiotic and antifungal agents. In the gnotobiotic challenge test, E. ictaluri gly09R was added to the model system via Artemia nauplii and culture water, resulting in a significant mortality of the gnotobiotic fish larvae. The developed gnotobiotic Nile tilapia model can be used as a tool to extend understanding of the mechanisms involved in host-microbe interactions and to evaluate new methods of disease control. PMID- 24781795 TI - Biology of a new xenoma-forming gonadotropic microsporidium in the invasive blotchfin dragonet Callionymus filamentosus. AB - A gonadotropic microsporidian parasite, Obruspora papernae gen. et sp. nov. (Microsporidia: Enterocytozoonidae), is described from Callionymus filamentosus (Teleostei: Callionymidae) in the Mediterranean Sea. The host, a Red Sea invasive species which entered the Mediterranean through the Suez Canal, was first collected in the Levant Basin in 1953, whereas its parasite went unobserved until 2008. Analysis of partial small subunit ribosomal gene sequences (SSU rDNA) placed the new species within the Nucleospora, Desmozoon, and Paranucleospora clade, and as it differs from each of them, it is assigned to a new genus. The development of the parasite is described, and the biological mechanisms underlying this parasite-host system are analyzed. Prevalence of infection approached 80% in female samples throughout most of the year. Males showed no signs of infection, but parasite rDNA was detected in male internal organs. The parasite-induced xenomas progressively occupied and eventually replaced much of the ovary, in some cases producing effective castration. Despite high levels of parasite infection, current trawl fishery statistics indicate that the abundance of Mediterranean populations of the host remains high. The parasite impact on the host population dynamics is unclear. Possible effects of the new microsporidian parasite on the reproductive effort of C. filamentosus and the potential role of another parasite, the ectoparasitic copepod Lernanthropus callionymicola, as an additional host in the life cycle of O. papernae, require further investigation. PMID- 24781796 TI - Cockle Cerastoderma edule fishery collapse in the Ria de Arousa (Galicia, NW Spain) associated with the protistan parasite Marteilia cochillia. AB - The highest shellfishery catch in Galicia (NW Spain) has traditionally been cockle Cerastoderma edule. The shellfish bed located in Lombos do Ulla (Ria de Arousa) used to be among those with the highest cockle production; however, cockle mortality rate increased sharply in this bed in April 2012, reaching 100% in May 2012. Salinity and temperature were discounted as potential causes of the mortality. Marteiliosis, which was first detected in February 2012 and reached 100% prevalence in April 2012, was identified as the most probable cause. Marteiliosis had never been detected in Galician cockles, but extensive surveillance of the Galician coast in May to July 2012 detected marteiliosis in most cockle beds of the Ria de Arousa, whereas it was not found in other rias; 2 mo later, the cockle catch in the Ria de Arousa became negligible. Examination of the aetiological agent of marteiliosis with light and transmission electron microscopy supported its assignation to the genus Marteilia; morphological features showed similarity, but not complete identity, with the recently described species M. cochillia Carrasco et al., 2013. Regarding its molecular characterisation, a consensus sequence of 4433 bp containing a partial sequence of the intergenic spacer region, the complete 18S rRNA gene and a partial sequence of the first internal transcribed spacer region was obtained. The obtained sequences were compared with those available for Marteilia spp. and other Paramyxida. Molecular data support that this parasite corresponds to the species M. cochillia, and a PCR assay was designed for its specific diagnosis. The association of huge cockle mortality with M. cochillia infection urges extreme caution to avoid spreading this disease. PMID- 24781797 TI - Cetacean strandings in Italy: an unusual mortality event along the Tyrrhenian Sea coast in 2013. AB - An unusual mortality event involving cetaceans, mainly striped dolphins Stenella coeruleoalba (Meyen, 1833), occurred along the Tyrrhenian Sea coast of Italy during the first 3 mo of 2013. Based on post-mortem analyses carried out according to body condition on 66 dolphins (54% of stranded animals), several hypotheses to explain the causes of this mortality event were proposed. Although no definitive conclusions can be drawn, dolphin morbillivirus was deemed the most likely cause, although other infectious agents (including Photobacterium damselae damselae and herpesvirus) or environmental factors may also have contributed to this recent mortality event. PMID- 24781798 TI - The activation of Woollins' reagent. Isolation of pyridine stabilised PhPSe2. AB - Woollins' reagent (WR, (PhPSe2)2) plays an essential role in the selenation of organic compounds. Reaction of WR with pyridine gives the P(V) species PhPSe2 stabilised by pyridine coordination which is the first crystallographically characterised mononuclear RPSe2 system stabilised by an external molecule and has potential as a selenation reagent for reactions under mild conditions. PMID- 24781800 TI - Prevention of hemolytic uremic syndrome with daily bowel lavage in patients with Shiga toxin-producing enterohemorrhagic Escherichia coli O104:H4 infection. PMID- 24781801 TI - Suppression of soluble adenylyl cyclase protects smooth muscle cells against oxidative stress-induced apoptosis. AB - Apoptosis of vascular smooth muscle cells (VSMC) significantly contributes to the instability of advanced atherosclerotic plaques. Oxygen radicals are an important cause for VSMC death. However, the precise mechanism of oxidative stress-induced VSMC apoptosis is still poorly understood. Here, we aimed to analyse the role of soluble adenylyl cylclase (sAC). VSMC derived from rat aorta were treated with either H2O2 (300 umol/L) or DMNQ (30 umol/L) for 6 h. Oxidative stress-induced apoptosis was prevented either by treatment with 30 umol/L KH7 (a specific inhibitor of sAC) or by stable sAC-knockdown (shRNA-transfection). A similar effect was found after inhibition of protein kinase A (PKA). Suppression of the sAC/PKA-axis led to a significant increase in phosphorylation of the p38 mitogen activated protein kinase under oxidative stress accompanied by a p38-dependent phosphorylation/inactivation of the pro-apoptotic Bcl-2-family protein Bad. Pharmacological inhibition of p38 reversed these effects of sAC knockdown on apoptosis and Bad phosphorylation, suggesting p38 as a link between sAC and apoptosis. Analysis of the protein phosphatases 1 and 2A activities revealed an activation of phosphatase 1, but not phosphatase 2A, under oxidative stress in a sAC/PKA-dependent manner and its role in controlling the p38 phosphorylation. Inhibition of protein phosphatase 1, but not 2A, prevented the pro-apoptotic effect of oxidative stress. In conclusion, sAC/PKA-signaling plays a key role in the oxidative stress-induced apoptosis of VSMC. The cellular mechanism consists of the sAC-promoted and protein phosphatase 1-mediated suppression of p38 phosphorylation resulting to activation of the mitochondrial pathway of apoptosis. PMID- 24781802 TI - Vespa tropica venom suppresses lipopolysaccharide-mediated secretion of pro inflammatory cyto-chemokines by abrogating nuclear factor-kappa B activation in microglia. AB - OBJECTIVE AND DESIGN: The present study was aimed to evaluate the anti inflammatory potentials of Vespa tropica (VT) venom and its isolated peptides. Effects of whole venom and its two peptides (Vt1512 and Vt1386) on lipopolysaccharide (LPS) challenged BV-2 murine microglial cells was evaluated. MATERIALS: Mouse microglial cell line, BV-2 and crude venom extract as well as purified peptides from VT along with LPS from Salmonella enterica were used for the studies. TREATMENT: BV-2 cells were treated with 500 ng/ml of LPS and different doses of crude wasp venom as well as purified peptides. METHODS: We used immunoblotting, cytokine bead arrays and fluorescence activated cell sorter (FACS) to evaluate the levels of various proteins, cytokines and reactive oxygen species (ROS). RESULTS: Our studies suggest that treatment with whole venom significantly reduces oxidative stress and LPS-stimulated activation of microglia. Also, purified peptides from crude venom exhibited potential anti inflammatory properties. Further, whole venom was found to be targeting Akt and p38 MAPK pathways, leading to suppressed NF-kappaB phosphorylation in LPS challenged BV-2 cells. CONCLUSIONS: VT venom possesses anti-inflammatory properties and can be further explored for their therapeutic potential in treating various inflammatory conditions of the central nervous system (CNS). PMID- 24781803 TI - Divergence with gene flow within the recent chipmunk radiation (Tamias). AB - Increasing data have supported the importance of divergence with gene flow (DGF) in the generation of biological diversity. In such cases, lineage divergence occurs on a shorter timescale than does the completion of reproductive isolation. Although it is critical to explore the mechanisms driving divergence and preventing homogenization by hybridization, it is equally important to document cases of DGF in nature. Here we synthesize data that have accumulated over the last dozen or so years on DGF in the chipmunk (Tamias) radiation with new data that quantify very high rates of mitochondrial DNA (mtDNA) introgression among para- and sympatric species in the T. quadrivittatus group in the central and southern Rocky Mountains. These new data (188 cytochrome b sequences) bring the total number of sequences up to 1871; roughly 16% (298) of the chipmunks we have sequenced exhibit introgressed mtDNA. This includes ongoing introgression between subspecies and between both closely related and distantly related taxa. In addition, we have identified several taxa that are apparently fixed for ancient introgressions and in which there is no evidence of ongoing introgression. A recurrent observation is that these introgressions occur between ecologically and morphologically diverged, sometimes non-sister taxa that engage in well documented niche partitioning. Thus, the chipmunk radiation in western North America represents an excellent mammalian example of speciation in the face of recurrent gene flow among lineages and where biogeography, habitat differentiation and mating systems suggest important roles for both ecological and sexual selection. PMID- 24781804 TI - Segregation of a QTL cluster for home-cage activity using a new mapping method based on regression analysis of congenic mouse strains. AB - Recent genetic studies have shown that genetic loci with significant effects in whole-genome quantitative trait loci (QTL) analyses were lost or weakened in congenic strains. Characterisation of the genetic basis of this attenuated QTL effect is important to our understanding of the genetic mechanisms of complex traits. We previously found that a consomic strain, B6-Chr6C(MSM), which carries chromosome 6 of a wild-derived strain MSM/Ms on the genetic background of C57BL/6J, exhibited lower home-cage activity than C57BL/6J. In the present study, we conducted a composite interval QTL analysis using the F2 mice derived from a cross between C57BL/6J and B6-Chr6C(MSM). We found one QTL peak that spans 17.6 Mbp of chromosome 6. A subconsomic strain that covers the entire QTL region also showed lower home-cage activity at the same level as the consomic strain. We developed 15 congenic strains, each of which carries a shorter MSM/Ms-derived chromosomal segment from the subconsomic strain. Given that the results of home cage activity tests on the congenic strains cannot be explained by a simple single-gene model, we applied regression analysis to segregate the multiple genetic loci. The results revealed three loci (loci 1-3) that have the effect of reducing home-cage activity and one locus (locus 4) that increases activity. We also found that the combination of loci 3 and 4 cancels out the effects of the congenic strains, which indicates the existence of a genetic mechanism related to the loss of QTLs. PMID- 24781806 TI - Population genetic structure of the tree-hole tick Ixodes arboricola (Acari: Ixodidae) at different spatial scales. AB - The endophilic tick Ixodes arboricola infests cavity-nesting birds, and its dispersal strongly depends on the movements of its host. Population genetic structure of I. arboricola was studied with seven polymorphic microsatellite markers. We collected 268 ticks from 76 nest boxes in four woodlots near Antwerp, Belgium. These nest boxes are mainly used by the principal hosts of I. arboricola, the great tit Parus major and the blue tit Cyanistes caeruleus. As these birds typically return to the same cavity for roosting or breeding, ticks within nest boxes were expected to be highly related, and tick populations were expected to be spatially structured among woodlots and among nest boxes within woodlots. In line with the expectations, genetic population structure was found among woodlots and among nest boxes within woodlots. Surprisingly, there was considerable genetic variation among ticks within nest boxes. This could be explained by continuous gene flow from ticks from nearby tree holes, yet this remains to be tested. A pairwise relatedness analysis conducted for all pairs of ticks within nest boxes showed that relatedness among larvae was much higher than among later instars, which suggests that larvae are the most important instar for tick dispersal. Overall, tick populations at the studied spatial scale are not as differentiated as predicted, which may influence the scale at which host-parasite evolution occurs. PMID- 24781805 TI - Revisiting the phylogeography and demography of European badgers (Meles meles) based on broad sampling, multiple markers and simulations. AB - Although the phylogeography of European mammals has been extensively investigated since the 1990s, many studies were limited in terms of sampling distribution, the number of molecular markers used and the analytical techniques employed, frequently leading to incomplete postglacial recolonisation scenarios. The broad scale genetic structure of the European badger (Meles meles) is of interest as it may result from historic restriction to glacial refugia and/or recent anthropogenic impact. However, previous studies were based mostly on samples from western Europe, making it difficult to draw robust conclusions about the location of refugia, patterns of postglacial expansion and recent demography. In the present study, continent-wide sampling and analyses with multiple markers provided evidence for two glacial refugia (Iberia and southeast Europe) that contributed to the genetic variation observed in badgers in Europe today. Approximate Bayesian computation provided support for a colonisation of Scandinavia from both Iberian and southeastern refugia. In the whole of Europe, we observed a decline in genetic diversity with increasing latitude, suggesting that the reduced diversity in the peripheral populations resulted from a postglacial expansion processes. Although MSVAR v.1.3 also provided evidence for recent genetic bottlenecks in some of these peripheral populations, the simulations performed to estimate the method's power to correctly infer the past demography of our empirical populations suggested that the timing and severity of bottlenecks could not be established with certainty. We urge caution against trying to relate demographic declines inferred using MSVAR with particular historic or climatological events. PMID- 24781807 TI - Inferring outcrossing in the homothallic fungus Sclerotinia sclerotiorum using linkage disequilibrium decay. AB - The occurrence and frequency of outcrossing in homothallic fungal species in nature is an unresolved question. Here we report detection of frequent outcrossing in the homothallic fungus Sclerotinia sclerotiorum. In using multilocus linkage disequilibrium (LD) to infer recombination among microsatellite alleles, high mutation rates confound the estimates of recombination. To distinguish high mutation rates from recombination to infer outcrossing, 8 population samples comprising 268 S. sclerotiorum isolates from widely distributed agricultural fields were genotyped for 12 microsatellite markers, resulting in multiple polymorphic markers on three chromosomes. Each isolate was homokaryotic for the 12 loci. Pairwise LD was estimated using three methods: Fisher's exact test, index of association (IA) and Hedrick's D'. For most of the populations, pairwise LD decayed with increasing physical distance between loci in two of the three chromosomes. Therefore, the observed recombination of alleles cannot be simply attributed to mutation alone. Different recombination rates in various DNA regions (recombination hot/cold spots) and different evolutionary histories of the populations could explain the observed differences in rates of LD decay among the chromosomes and among populations. The majority of the isolates exhibited mycelial incompatibility, minimizing the possibility of heterokaryon formation and mitotic recombination. Thus, the observed high intrachromosomal recombination is due to meiotic recombination, suggesting frequent outcrossing in these populations, supporting the view that homothallism favors universal compatibility of gametes instead of traditionally believed haploid selfing in S. sclerotiorum. Frequent outcrossing facilitates emergence and spread of new traits such as fungicide resistance, increasing difficulties in managing Sclerotinia diseases. PMID- 24781808 TI - Accuracy of genomic selection models in a large population of open-pollinated families in white spruce. AB - Genomic selection (GS) is of interest in breeding because of its potential for predicting the genetic value of individuals and increasing genetic gains per unit of time. To date, very few studies have reported empirical results of GS potential in the context of large population sizes and long breeding cycles such as for boreal trees. In this study, we assessed the effectiveness of marker-aided selection in an undomesticated white spruce (Picea glauca (Moench) Voss) population of large effective size using a GS approach. A discovery population of 1694 trees representative of 214 open-pollinated families from 43 natural populations was phenotyped for 12 wood and growth traits and genotyped for 6385 single-nucleotide polymorphisms (SNPs) mined in 2660 gene sequences. GS models were built to predict estimated breeding values using all the available SNPs or SNP subsets of the largest absolute effects, and they were validated using various cross-validation schemes. The accuracy of genomic estimated breeding values (GEBVs) varied from 0.327 to 0.435 when the training and the validation data sets shared half-sibs that were on average 90% of the accuracies achieved through traditionally estimated breeding values. The trend was also the same for validation across sites. As expected, the accuracy of GEBVs obtained after cross validation with individuals of unknown relatedness was lower with about half of the accuracy achieved when half-sibs were present. We showed that with the marker densities used in the current study, predictions with low to moderate accuracy could be obtained within a large undomesticated population of related individuals, potentially resulting in larger gains per unit of time with GS than with the traditional approach. PMID- 24781809 TI - Genetics of decayed sexual traits in a parasitoid wasp with endosymbiont-induced asexuality. AB - Trait decay may occur when selective pressures shift, owing to changes in environment or life style, rendering formerly adaptive traits non-functional or even maladaptive. It remains largely unknown if such decay would stem from multiple mutations with small effects or rather involve few loci with major phenotypic effects. Here, we investigate the decay of female sexual traits, and the genetic causes thereof, in a transition from haplodiploid sexual reproduction to endosymbiont-induced asexual reproduction in the parasitoid wasp Asobara japonica. We take advantage of the fact that asexual females cured of their endosymbionts produce sons instead of daughters, and that these sons can be crossed with sexual females. By combining behavioral experiments with crosses designed to introgress alleles from the asexual into the sexual genome, we found that sexual attractiveness, mating, egg fertilization and plastic adjustment of offspring sex ratio (in response to variation in local mate competition) are decayed in asexual A. japonica females. Furthermore, introgression experiments revealed that the propensity for cured asexual females to produce only sons (because of decayed sexual attractiveness, mating behavior and/or egg fertilization) is likely caused by recessive genetic effects at a single locus. Recessive effects were also found to cause decay of plastic sex-ratio adjustment under variable levels of local mate competition. Our results suggest that few recessive mutations drive decay of female sexual traits, at least in asexual species deriving from haplodiploid sexual ancestors. PMID- 24781811 TI - Charge transfer processes: the role of optimized molecular orbitals. AB - The influence of the molecular orbitals on charge transfer (CT) reactions is analyzed through wave function-based calculations. Characteristic CT processes in the organic radical 2,5-di-tert-butyl-6-oxophenalenoxyl linked with tetrathiafulvalene and the inorganic crystalline material LaMnO3 show that changes in the inner shells must be explicitly taken into account. Such electronic reorganization can lead to a reduction of the CT vertical transition energy up to 66%. A state-specific approach accessible through an adapted CASSCF (complete active space self-consistent field) methodology is capable of reaching good agreement with the experimental spectroscopy of CT processes. A partitioning of the relaxation energy in terms of valence- and inner-shells is offered and sheds light on their relative importance. This work paves the way to the intimate description of redox reactions using quantum chemistry methods. PMID- 24781810 TI - Bradykinesia-akinesia incoordination test: validating an online keyboard test of upper limb function. AB - BACKGROUND: The Bradykinesia Akinesia Incoordination (BRAIN) test is a computer keyboard-tapping task that was developed for use in assessing the effect of symptomatic treatment on motor function in Parkinson's disease (PD). An online version has now been designed for use in a wider clinical context and the research setting. METHODS: Validation of the online BRAIN test was undertaken in 58 patients with Parkinson's disease (PD) and 93 age-matched, non-neurological controls. Kinesia scores (KS30, number of key taps in 30 seconds), akinesia times (AT30, mean dwell time on each key in milliseconds), incoordination scores (IS30, variance of travelling time between key presses) and dysmetria scores (DS30, accuracy of key presses) were compared between groups. These parameters were correlated against total motor scores and sub-scores from the Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: Mean KS30, AT30 and IS30 were significantly different between PD patients and controls (p<=0.0001). Sensitivity for 85% specificity was 50% for KS30, 40% for AT30 and 29% for IS30. KS30, AT30 and IS30 correlated significantly with UPDRS total motor scores (r = -0.53, r = 0.27 and r = 0.28 respectively) and motor UPDRS sub-scores. The reliability of KS30, AT30 and DS30 was good on repeated testing. CONCLUSIONS: The BRAIN test is a reliable, convenient test of upper limb motor function that can be used routinely in the outpatient clinic, at home and in clinical trials. In addition, it can be used as an objective longitudinal measurement of emerging motor dysfunction for the prediction of PD in at-risk cohorts. PMID- 24781812 TI - The experience of an information system for nursing practice: the importance of nursing records in the management of a care plan. AB - Health information systems are becoming common because they are important tools to support decision making and assist nurses in their daily interventions. The Information System for Nursing Practice promotes consistent nursing records, as it is directed to the nursing practice and process. The aims of this study were to identify and describe the most frequent type of nursing actions in the care plan for a patient after acute myocardial infarction, considering the seven-axis model of the International Classification of Nursing Practice and the rate of health education given to patients during hospitalization. A cross-sectional analysis was performed retrospectively by searching the computerized database of the Information System for Nursing Practice. We verified some gaps in information with regard to unidentified records of diagnoses and interventions. During hospitalization, the most used interventions were in the fields of observing (40%) and managing (23%). Interventions associated with management of signs and symptoms were more frequent and were performed in 84.9% of the patients. In the field of informing, health education in relation to diet was performed in 21.7% of the patients; exercise, in 16%; and tobacco, in 11.3%. The use of nursing records and information systems can improve nursing care coordination and care plan management. PMID- 24781813 TI - Developing and testing a computerized decision support system for nurse-to patient assignment: a multimethod study. AB - Nurse-to-patient assignment is a frequently recurring, time-consuming, and complex process owing to the many considerations involved. Creating well balanced, high-quality assignments is crucial to ensuring patient safety, quality of care, and job satisfaction for nurses. A computerized decision support system can assist (charge) nurses in the nurse-to-patient assignment process. In this two-phase multimethod study, a computerized decision support system was developed and evaluated. Three nursing wards in a 1000-bed Dutch university hospital participated. In the first phase of this study, considerations relevant to the assignment process--and their relative importance--were investigated in a literature review, focus group sessions with nurses, and a survey among nurses. Using information from the first phase, the computerized decision support system was developed based on an integer linear program. In the second phase, a before and-after study was conducted to test and evaluate the computerized decision support system both quantitatively (duration of the assignment process) and qualitatively (survey on workload). Thirty-six measurements were performed to test the computerized decision support system. After implementation, a 30% time reduction was achieved in the nurse-to-patient assignments, and nurses (N = 138) experienced a lower workload. Therefore, the implementation of computerized decision support system would increase both the quality and safety of care as well as the nurses' job satisfaction and should be investigated rigorously in the coming years. PMID- 24781814 TI - An improved anonymous authentication scheme for telecare medical information systems. AB - Telecare medical information system (TMIS) constructs an efficient and convenient connection between patients and the medical server. The patients can enjoy medical services through public networks, and hence the protection of patients' privacy is very significant. Very recently, Wu et al. identified Jiang et al.'s authentication scheme had some security drawbacks and proposed an enhanced authentication scheme for TMIS. However, we analyze Wu et al.'s scheme and show that their scheme suffers from server spoofing attack, off-line password guessing attack, impersonation attack. Moreover, Wu et al.'s scheme fails to preserve the claimed patient anonymity and its password change phase is unfriendly and inefficient. Thereby, we present a novel anonymous authentication scheme for telecare medical information systems to eliminate the aforementioned faults. Besides, We demonstrate the completeness of the proposed scheme through the BAN logic. Furthermore, the security of our proposed scheme is proven through Bellare and Rogaways model. Compared with the related existing schemes, our scheme is more secure. PMID- 24781815 TI - Phosphate esters and anhydrides--recent strategies targeting nature's favoured modifications. AB - Esters and anhydrides of phosphoric acid are essential in biology. It is very difficult to identify processes in life that do not involve these modifications and their transformation at some point. Consequently, phosphorylation chemistry is an essential methodology with significant impact on the biological sciences. This perspective gives an overview of some very recent achievements in synthetic phosphorylation chemistry and aims at identifying challenges that lie ahead. PMID- 24781816 TI - Does metastasectomy improve survival in skeletal melanoma? AB - Melanoma metastatic to bone carries a poor prognosis with overall median survival in the 4-6 months range. Others have published data that suggest resection of isolated visceral organ metastases improves survival. We conducted a retrospective analysis of 130 cases of stage IV melanoma with pathologically confirmed bony disease. We used Cox regression survival analysis to compare a group of patients who underwent wide resection of metastases with those who received other surgery or were treated nonoperatively. We also compared the three groups against matched historical stage IV melanoma controls to determine differences between expected and observed 1-year overall survival. Median overall survival for the nonoperative (N=80), intralesional (N=32), and resection (N=18) groups was 4.8, 5.1, and 11.8 months, respectively. Cox regression survival analysis confirmed the overall survival benefit resulting from wide resection (hazard ratio 0.53) after correcting for independent predictors of worse survival, such as pathologic spinal compression fracture (hazard ratio 1.68). The observed 1-year overall survival rate in the resection group was nearly double that of matched historical controls (50.0 vs. 24.8%). We present the largest known series of bony melanoma, along with data which suggest that overall survival may be improved in carefully selected patients where all known macroscopic disease can be resected. LEVEL OF EVIDENCE: level III. PMID- 24781817 TI - Terminal cancer patients' and their primary caregivers' attitudes toward hospice/palliative care and their effects on actual utilization: A prospective cohort study. AB - BACKGROUND: Previous studies on hospice/palliative care indicated that patients' socio-demographic factors, disease status, and availability of health-care resources were associated with hospice/palliative care utilization. However, the impact of family caregivers on hospice/palliative care utilization has not been thoroughly investigated. AIM: To evaluate the association between attitudes toward hospice/palliative care of both patients with terminal cancer (defined as progressive, advanced cancer in which the patient will die within months) and their family caregivers and utilization of inpatient hospice/palliative care facilities. DESIGN: A prospective observational cohort study was performed in 12 hospitals in South Korea. Attitude toward hospice/palliative care was assessed immediately after terminal cancer diagnosis. After the patient's death, caregivers were interviewed whether they utilized hospice/palliative care facilities. PARTICIPANTS: A total of 359 patient-caregiver dyads completed baseline questionnaires. After the patients' death, 257 caregivers were interviewed. RESULTS: At the baseline questionnaire, 137/359 (38.2%) patients and 185/359 (51.5%) of caregivers preferred hospice/palliative care. Preference for hospice/palliative care was associated with awareness of terminal status among both patients (adjusted odds ratio: 1.87, 95% confidence interval: 1.16-3.03) and caregivers (adjusted odds ratio: 2.14, 95% confidence interval: 1.20-3.81). Religion, metastasis, and poor performance status were also independently associated with patient preference for hospice/palliative care. At the post bereavement interview, 104/257 (40.5%) caregivers responded that they utilized hospice/palliative care facilities. Caregiver's preferences for hospice/palliative care were significantly associated with actual utilization (adjusted odds ratio: 2.67, 95% confidence interval: 1.53-4.67). No patient related factors were associated with hospice/palliative care utilization. CONCLUSION: Promoting awareness of prognosis and to improve communication between doctors and families is important for facilitating the use of hospice/palliative care. PMID- 24781818 TI - Accuracy of chemical shift MR imaging in diagnosing indeterminate bone marrow lesions in the pelvis: review of a single institution's experience. AB - OBJECTIVE: To re-assess the accuracy of chemical shift imaging in diagnosing indeterminate bone marrow lesions as benign or malignant. MATERIALS AND METHODS: We retrospectively reviewed our experience with MR imaging of the pelvis to assess the accuracy of chemical shift imaging in distinguishing benign from malignant bone lesions. Two musculoskeletal radiologists retrospectively reviewed all osseous lesions biopsied since 2006, when chemical shift imaging was added to our routine pelvic imaging protocol. Study inclusion criteria required (1) MR imaging of an indeterminate bone marrow lesion about the pelvis and (2) subsequent histologic confirmation. The study group included 50 patients (29 male, 21 female) with an average age of 67 years (range, 41-89 years). MR imaging results were evaluated using biopsy results as the "gold standard." RESULTS: There were 27 malignant and 23 benign lesions. Chemical shift imaging using an opposed-phase signal loss criteria of less than 20 % to indicate a malignant lesion, correctly diagnosed 27/27 malignant lesions and 14/23 benign lesions, yielding a 100 % sensitivity, 61 % specificity, 75 % PPV, 100 % NPV, and 82 % accuracy. The area under the receiver operator characteristic (ROC) curve was 0.88. The inter-rater and intra-rater agreement K values were both 1.0. CONCLUSIONS: Chemical shift imaging is a useful adjunct MR technique to characterize focal and diffuse marrow abnormalities on routine non-contrast pelvic imaging. It is highly sensitive in identifying malignant disease. Despite its lower specificity, the need for biopsy could be eliminated in more than 60 % of patients with benign disease. PMID- 24781819 TI - Perceptions of others' political affiliation are moderated by individual perceivers' own political attitudes. AB - Previous research has shown that perceivers can accurately extract information about perceptually ambiguous group memberships from facial information alone. For example, people demonstrate above-chance accuracy in categorizing political ideology from faces. Further, they ascribe particular personality traits to faces according to political party (e.g., Republicans are dominant and mature, Democrats are likeable and trustworthy). Here, we report three studies that replicated and extended these effects. In Study 1a, we provide evidence that, in addition to showing accuracy in categorization, politically-conservative participants expressed a bias toward categorizing targets as outgroup members. In Study 1b, we replicate this relationship with a larger sample and a stimulus set consisting of faces of professional politicians. In Study 2, we find that trait ascriptions based on target political affiliation are moderated by perceiver political ideology. Specifically, although Democrats are stereotyped as more likeable and trustworthy, conservative participants rated faces that were categorized as Republicans in Study 1a as more likeable and trustworthy than faces categorized as Democrats. Thus, this paper joins a growing literature showing that it is critical to consider perceiver identity in examining perceptions of identities and traits from faces. PMID- 24781821 TI - Nutritional habits and oxidative stress in postmenopausal age. AB - INTRODUCTION: Postmenopausal obesity increases the risk of oxidative stress, but such an association in newly diagnosed dyslipidemia after menopause requires detailed research. OBJECTIVES: The aim of the study was to evaluate the relations between oxidative processes, newly diagnosed dyslipidemia, and nutritional behavior in postmenopausal women who did not receive hypolipidemic treatment. PATIENTS AND METHODS: The nutritional status, dietary habits, and oxidative stress parameters were evaluated in 102 postmenopausal women (51 obese and 51 normal-weight subjects) without lipid disturbances before menopause. RESULTS: In obese subjects, hypercholesterolemia, higher levels of malondialdehyde and advanced oxidation protein products (AOPPs), and a positive correlation between AOPPs and low-density lipoprotein cholesterol (LDL-C) were observed. Plasma superoxide dismutase (SOD) activity positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively with the ratios of total cholesterol to HDL-C and LDL-C to HDL-C in both groups. In obese women, daily food rations were characterized by a higher intake of copper and of energy from fat and saturated fatty acids (SFA), while the intake of carbohydrates and selenium was lower than that in lean women (P <0.05). The multivariable models showed a significant effect of SFA and selenium intake on the variability of serum SOD activity (P = 0.003; R2adj = 17%) and malondialdehyde concentrations (P = 0.00001; R2adj = 45%) in obese women. CONCLUSIONS: The study showed that oxidative stress processes are present at early stages of hypercholesterolemia in obese postmenopausal women and may be caused by a poorly balanced diet. PMID- 24781822 TI - Role of SLC6A6 in promoting the survival and multidrug resistance of colorectal cancer. AB - The treatment of colorectal cancer (CRC) might be improved by the identification of a signalling pathway that could be targeted with novel therapeutics. The results of this study indicate that the taurine transporter SLC6A6 is highly expressed in CRC cells compared with normal colonocytes. SLC6A6 knockdown (KD) attenuated cell survival and was accompanied by enhanced drug sensitivity to 5 fluorouracil (5-FU), doxycycline (DOX) and SN-38. Both the population frequency of the side population (SP) cells and their cancer stem cell (CSC)-like properties (such as tumour initiation, differentiation and chemoresistance) were abrogated by SLC6A6-KD. Conversely, SLC6A6 overexpression increased cell survival and the proportion of SP cells, enhancing multidrug resistance (MDR). Additionally, SLC6A6-siRNA treatment enhanced the cytotoxic effects of all 3 drugs, whereas the efficacy of ABCG2-siRNA treatment was limited to its 2 substrate drugs, DOX and SN-38. This study indicates that SLC6A6 plays an important role in the maintenance of CSC characteristics, thus promoting cell survival signalling and chemoresistance. Therefore, SLC6A6 inhibition may be a promising therapeutic strategy for refractory CRC. PMID- 24781823 TI - Mechanistic data support protecting non-smokers from the lethal effects of second hand smoke. PMID- 24781824 TI - The ruthenium complexes cis-(dichloro)tetramineruthenium(III) chloride and cis tetraammine(oxalato)ruthenium(III) dithionate overcome resistance inducing apoptosis on human lung carcinoma cells (A549). AB - Lung cancer is one of the leading causes of death in the world, and non-small cell lung carcinoma accounts for approximately 75-85 % of all lung cancers. In the present work, we studied the antitumor activity of the compound cis (dichloro)tetramineruthenium(III) chloride {cis-[RuCl2(NH3)4]Cl} against human lung carcinoma tumor cell line A549. The present study aimed to investigate the relationship between the expression of MDR1 and CYP450 genes in human lung carcinoma cell lines A549 treated with cisCarboPt, cisCRu(III) and cisDRu(III). The ruthenium-based coordinated complexes presented low cytotoxic and antiproliferative activities, with high IC50 values, 196 (+/-15.49), 472 (+/ 20.29) and 175 (+/-1.41) for cisCarboPt, cisCRu(III) and cisDRu(III), respectively. The tested compounds induced apoptosis in A549 tumor cells as evidenced by caspase 3 activation, but only at high concentrations. Results also revealed that the amplification of P-gp gene is greater in A549 cells exposed to cisCarboPt and cisCRu(III) than cisDRu(III). Taken together all these results strongly demonstrate that MDR-1 over-expression in A549 cells could be associated to a MDR phenotype of these cells and moreover, it is also contributing to the platinum, and structurally-related compound, resistance in these cells. The identification and characterization of novel mechanisms of drug resistance will enable the development of a new generation of anti-cancer drugs that increase cancer sensitivity and/or represent more effective chemotherapeutic agents. PMID- 24781825 TI - Transport of nickel and cobalt ions into bacterial cells by S components of ECF transporters. AB - Energy-coupling factor (ECF) transporters form a distinct group of ABC-type micronutrient importers in prokaryotes that do not contain extracytoplasmic, soluble substrate-binding proteins. Instead, they consist of a transmembrane substrate-specific S component that interacts with a module composed of a moderately conserved transmembrane (T) component and ABC ATPases. The majority of S components is considered to act as high-affinity binding proteins that strictly depend on their cognate T and ATPase units for transport activity. For a fraction of biotin-specific S units, however, transport activity was demonstrated in their solitary state. Here, we compared the activities of nickel- and cobalt-specific ECF transporters in the presence and absence of their T and ATPase units. Accumulation assays with radioactive metal ions showed that the truncated transporters led to approx. 25% of cell-bound radioactivity compared to the holotransporters. Activity of urease, an intracellular nickel-dependent enzyme, was used as a reporter and clearly indicated that the cell-bound radioactivity correlates with the cytoplasmic metal concentration. The results demonstrate that S units of metal transporters not only bind their substrates on the cell surface but mediate transport across the membrane, a finding of general importance on the way to understand the mechanism of ECF transporters. PMID- 24781826 TI - Dengue: challenges for policy makers and vaccine developers. AB - Because of the increasing incidence, geographic expansion and economic burden of dengue transmission, dengue poses major challenges to policy makers. A vaccine against dengue is urgently needed, but vaccine development has been hampered by the lack of an appropriate animal model, poor understanding of correlates of successful human immunity, the fear of immune enhancement, and viral interference in tetravalent combinations. The most suitable target epitopes for vaccines, as well as the role of nonstructural proteins remain elusive. The chimeric yellow fever bone-based live attenuated dengue vaccine is furthest in development, but initial efficacy results have been disappointing. Lessons learnt from this failure will affect the design of future trials, and increase the urgency to identify the best epitope and immune correlates. Dengue vaccine introduction will not be the only strategy to combat dengue, but needs to be "packaged" with novel vector control approaches, with community-based interventions to reduce the number of breeding sites, and reducing the case fatality rate by improving case management. PMID- 24781827 TI - Non-invasive ventilation for very old patients with limitations to respiratory care in half-open geriatric ward: experience on a consecutive cohort of patients. AB - INTRODUCTION: A leading role for non-invasive ventilation (NIV), as comfort treatment or palliative care, is actually recognized for very old patients suffering from ARF. NIV was frequently used in both ICU and respiratory ICU (RICUs) for very old patients and it is associated with a reduced rate of endotracheal intubations and mortality. This study aims to evaluate the effects of NIV, performed in a setting of half-open geriatric ward with family support, in a cohort of very old patients with ARF and DNI decision. METHODS: A consecutive cohort of 20 very old patients with DNI decision was admitted in our 26-bed geriatric ward during a 6 months' period. DNI decision was obtained in emergency room with an intensive care physician supported by a psychologist. Pressure support ventilation was the first choice of NIV. NIV has been performed by three adequately trained geriatricians, with one of them experienced in ICU, and in close collaboration with intensive care physicians. Arterial blood gases, to assess the response to ventilation, were obtained after 1, 6 and 12 h. NIV settings were modified according to arterial blood gas analyses or respiratory fatigue, if needed. RESULTS: Therefore, 75% of patients were discharged home and 12 out of 20 patients had home respiratory support. PaO2/FiO2 ratio and pH increased while PaCO2 decreased during the 12 h of NIV with statistical significance. At the admission, alive patients had PaCO2 significantly lower than dead patients. After 12 h, alive patients had a better pH than dead patients. Dead patients experienced more complication than survivors. CONCLUSION: Very old DNI patients with ARF could be treated with NIV in half-open geriatric ward with trained physicians and nurses. The presence of family members may improve patients' comfort and reduce anxiety level even at the end of life. Further studies are needed to address the effective role of NIV in very old patients with DNI decisions. PMID- 24781828 TI - Cognitive reserve in a cross-cultural population: the case of Italian emigrants in Montreal. AB - BACKGROUND: Cognitive reserve could be defined as the accumulation of experiences, abilities, knowledge and changes that occur throughout the lifespan. One of the most difficult changes in life is the experience of emigrating to a foreign country. AIMS: The present investigation aimed to compare the cognitive reserve of two paired groups of elderly: Italians living in Italy and Italians who in adult age (around 20 years) emigrated to Montreal. Both groups attended the same years of school, in Italy. METHODS: Cognitive reserve was measured in the two groups by a structured and standardised questionnaire, the cognitive reserve questionnaire. RESULTS: Cognitive reserve showed to be significantly higher in the Italian-Canadian individuals (i.e. Italians who emigrated). CONCLUSIONS: Emigration might act as an environmental factor that enriches people's lifestyle and reflects itself in the amount of their cognitive reserve. PMID- 24781829 TI - Clinical and echocardiographic characteristics of elderly hospitalized patients with high levels of NT-proBNP without clinical diagnosis of heart failure. AB - BACKGROUND: Patients with high NT-proBNP levels but without heart failure (HF) diagnosis have a higher risk of cardiovascular events and mortality; however, there are few data about their characteristic, especially in the elderly. AIMS: To compare the clinical and echocardiographic characteristics of elderly hospitalized patients with and without increased NT-proBNP and with and without a diagnosis of HF. METHODS: We reviewed 209 charts of patients admitted to an acute care ward (mean age 78.9 years, SD 10.2, 62% women). We classified the patients into four groups: no HF with or without increased (>900 pg/mL) NT-proBNP (HF-/BNP , N = 89 and HF-/BNP+, N = 41), and HF with or without increased NT-proBNP (HF+/BNP-, N = 4 and HF+/BNP+, N = 75). The groups were compared with respect to demographic and clinical characteristics, symptoms at admission, comorbidities, echocardiographic parameters, and cardiovascular events at 180 days. RESULTS: Patients in the groups HF+/BNP+ and HF-/BNP+ were older, with higher serum creatinine, blood urea nitrogen, and lower serum hemoglobin compared to patients in the HF-/BNP- group. The prevalence of ischemic heart disease, pulmonary hypertension, and atrial fibrillation progressively decreased across the HF+/BNP+, HF-/BNP+, and HF-/BNP- groups. The prevalence of abnormal echocardiographic findings in the HF-/BNP+ group was intermediate compared to the other two groups for severe aortic or mitralic regurgitation, monophasic transmitralic pattern, biatrial atriomegaly, ejection fraction, akinesia extension, and PAPs. The same pattern was observed for cardiovascular events at follow-up. DISCUSSION: Elderly patients without a diagnosis of HF, but with high NT-proBNP serum concentration have intermediate clinical characteristics compared to the other two groups. CONCLUSION: NT-proBNP may be a useful marker of silent cardiac damage. PMID- 24781830 TI - Comorbidities, polypharmacy, functionality and nutritional status in Turkish community-dwelling female elderly. AB - BACKGROUND AND AIMS: Most elderly persons live in developing countries where current geriatric epidemiological data are scarce. We aimed to study major comorbidities, polypharmacy, functional and nutritional status in a Turkish community-dwelling female elderly clinic population. METHODS: Female geriatrics outpatient clinic patients were assessed cross-sectionally. Patients underwent comprehensive geriatric cassessment, including identification of chronic diseases, drugs, functionality, and nutrition. Comorbidities and drugs were defined by the review of patients' self-reports and current medications. Geriatric depression and cognition were assessed by 30-item geriatric depression scale and Folstein mini-mental-state-examination. Functional status was assessed by the evaluation of activities of daily living (ADL) and instrumental activities of daily living (IADL) scales. Nutritional assessment was performed by mini nutritional-assessment-short form. RESULTS: Five-hundred and fifteen patients were included in this study over an 8-year period. Mean age was 73.4 +/- 6.9 years. Mean number of chronic diseases was 2.8. 61.1 % had >3 chronic diseases. Most common 3 diagnoses were hypertension (75.3 %), depression (45.5 %) and dementia (39.4 %). Mean number of drugs was 4.8. Polypharmacy was noted as 63.2 and 47.6 % by definitions as >4 or >5 chronic drug use, respectively. Subjects with at least one dependency of ADL and IADL were 23.4 and 64.0 %. Prevalence of poor nutrition was 39.1 %. In patients with at least one ADL or IADL dependency, undernutrition (p < 0.001), dementia (p < 0.001), cerebrovascular accident, Parkinson's disease, diabetes were more prevalent (p < 0.05) and were taking higher number of drugs (p < 0.01). CONCLUSIONS: Polypharmacy and functional dependency seem to be prevalent among female elders in our country. Nutritional status was worse than the other reported urban area of Turkey and also than among males of same region but better than among Iranian counterparts. This study illustrates geographical differences in and between the individual countries and supports the continued need for comprehensive geriatric assessment worldwide. PMID- 24781831 TI - Influence of hospitalisation on the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in elderly hypertensive patients. AB - BACKGROUND AND AIMS: The underutilization of beneficial cardiovascular medications such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) in the elderly patients continues to be a matter of concern. The aim of the presented study was to compare the prescription of ACEI and ARB in elderly hypertensive patients at the time of hospital admission and discharge and to identify patient-related factors which determine the prescription of ACEI/ARB. METHODS: The study sample (n = 1111) was selected from 2,157 patients hospitalised at long-term care departments of three municipal hospitals during the period between January 1, 2008 and December 31, 2009 and included hypertensive patients aged >=65 years suffering from myocardial infarction, heart failure, atrial fibrillation, diabetes mellitus or nephropathy. RESULTS: In hypertensive patients with myocardial infarction, diabetes mellitus and nephropathy, a significant increase was found in the use of ACEI/ARB during hospitalisation. However, there was no similar change in the use of such medications during hospitalisation in patients with heart failure and atrial fibrillation. Age >=85 years (OR = 0.59 and OR = 0.50 at hospital admission and discharge, respectively), depression (OR = 0.63 at hospital discharge) and the systolic blood pressure <=115 mmHg (OR = 0.45 at hospital discharge) decreased the probability of ACEI/ARB prescription. On the other hand, increasing the number of evaluated co-morbid conditions increased the patient's likelihood of being an "ACEI/ARB user" (OR = 1.20 at hospital discharge). CONCLUSIONS: Our study has identified a subset of elderly hypertensive patients (with heart failure, atrial fibrillation) in whom the use of ACEI/ARB could be improved. PMID- 24781832 TI - A regression tree for identifying combinations of fall risk factors associated to recurrent falling: a cross-sectional elderly population-based study. AB - BACKGROUND: Regression tree (RT) analyses are particularly adapted to explore the risk of recurrent falling according to various combinations of fall risk factors compared to logistic regression models. The aims of this study were (1) to determine which combinations of fall risk factors were associated with the occurrence of recurrent falls in older community-dwellers, and (2) to compare the efficacy of RT and multiple logistic regression model for the identification of recurrent falls. METHODS: A total of 1,760 community-dwelling volunteers (mean age +/- standard deviation, 71.0 +/- 5.1 years; 49.4 % female) were recruited prospectively in this cross-sectional study. Age, gender, polypharmacy, use of psychoactive drugs, fear of falling (FOF), cognitive disorders and sad mood were recorded. In addition, the history of falls within the past year was recorded using a standardized questionnaire. RESULTS: Among 1,760 participants, 19.7 % (n = 346) were recurrent fallers. The RT identified 14 nodes groups and 8 end nodes with FOF as the first major split. Among participants with FOF, those who had sad mood and polypharmacy formed the end node with the greatest OR for recurrent falls (OR = 6.06 with p < 0.001). Among participants without FOF, those who were male and not sad had the lowest OR for recurrent falls (OR = 0.25 with p < 0.001). The RT correctly classified 1,356 from 1,414 non-recurrent fallers (specificity = 95.6 %), and 65 from 346 recurrent fallers (sensitivity = 18.8 %). The overall classification accuracy was 81.0 %. The multiple logistic regression correctly classified 1,372 from 1,414 non-recurrent fallers (specificity = 97.0 %), and 61 from 346 recurrent fallers (sensitivity = 17.6 %). The overall classification accuracy was 81.4 %. CONCLUSIONS: Our results show that RT may identify specific combinations of risk factors for recurrent falls, the combination most associated with recurrent falls involving FOF, sad mood and polypharmacy. The FOF emerged as the risk factor strongly associated with recurrent falls. In addition, RT and multiple logistic regression were not sensitive enough to identify the majority of recurrent fallers but appeared efficient in detecting individuals not at risk of recurrent falls. PMID- 24781833 TI - Between reduction of glucose fluctuations and increased therapeutic adherence: an example of the benefits of vildagliptin in an elderly diabetic patient. PMID- 24781835 TI - Striatal metabolism and psychomotor speed as predictors of motor onset in Huntington's disease. AB - The clinical diagnosis of Huntington's disease (HD) is based on the motor symptoms, although these can be preceded by cognitive and behavioral changes. Biomarker studies have shown that structural imaging modalities are useful biomarkers of HD onset, while functional imaging measures have been studied less often for this purpose. Our aim was to investigate the combined value of 18 fluorodesoxyglucose (FDG)-PET and cognitive measures as biomarkers of HD onset. Twenty-two premanifest mutation carriers of HD (PMCs) and 11 healthy controls were assessed twice with FDG-PET scan, neurological and neuropsychological assessments over a 2-year interval. Seventeen PMCs had an additional third neurological evaluation, 10 years after baseline. Disease load was defined as the probability of motor onset within 5 years. Metabolism in putamen, caudate and pallidum of PMCs was significantly lower than that of controls, at both assessments. Almost half of the PMCs had converted to manifest HD 10 years later and all converters had low average or abnormal putaminal metabolism at 2 year follow-up. In contrast, all PMCs with normal putaminal metabolism at 2 year follow-up remained premanifest during the following 8 years. Furthermore, glucose metabolism of putamen explained a substantial part of the variance in disease load. A composite score of psychomotor tests contributed significantly to the prediction model as well, while cognitive performance was comparable for PMCs and controls. We conclude that in future clinical trials a combination of psychomotor tests and putaminal glucose metabolism may be used to identify PMCs close to motor onset of HD. PMID- 24781836 TI - Quantitative analysis of upper-limb ataxia in patients with spinocerebellar degeneration. AB - Spinocerebellar degeneration (SCD) is a progressive neurodegenerative disorder in which cerebellar ataxia causes motor disability. There are no widely applicable methods for objective evaluation of ataxia in SCD. An objective system to evaluate ataxia is necessary for use in clinical trials of newly developed medication and rehabilitation. The aim of this study was to develop a simple method to quantify the degree of upper-limb ataxia. Forty-nine patients with SCD participated in this study. Patients were instructed to trace an Archimedean spiral template, and the gap between the template spiral and the drawn spiral (gap area; GA) was measured using Image J software. Ataxia was rated using the Scale for the Assessment and Rating of Ataxia (SARA) and cerebellar volume was evaluated in 37 patients using an axial cross-section of magnetic resonance images that were obtained within 6 months of clinical evaluation. Regression analysis was performed to assess the relation between GA and patient age, disease duration, SARA score, and cerebellar volume. GA was significantly related to total SARA score (r = 0.660, p < 0.001), the posture and gait (r = 0.551, p < 0.001), speech (r = 0.527, p < 0.001), hand movements (r = 0.553, p < 0.001), and heel-shin slide (r = 0.367, p = 0.036) SARA subscores, and cerebellar volume (r = 0.577, p < 0.001) but was not related to patient age (r = 0.176, p = 0.227) or disease duration (r = 0.236, p = 0.103). GA is a simple, useful method to objectively quantify the degree of cerebellar ataxia, especially upper-limb ataxia, and can be widely adopted in various settings, including clinical trials. PMID- 24781837 TI - Clinical phenotype of patients with neuropathy associated with monoclonal gammopathy: a comparative study and a review of the literature. AB - The objective of this study was to investigate if the clinical and electrophysiological phenotype of patients with polyneuropathy associated with IgM monoclonal gammopathy (IgM-PNP) is related to the presence of antibodies against gangliosides or myelin-associated glycoprotein (MAG). We compared clinical and nerve conduction study (NCS) characteristics of 11 IgM-PNP patients with antibodies against asialo-GM1 or gangliosides (GM1, GD1a, GD1b, GM2 or GQ1b) to 11 consecutive IgM-PNP patients with anti-MAG neuropathy and to 9 IgM-PNP patients without antibodies against either MAG or gangliosides. Patients with anti-ganglioside antibodies could not be differentiated from those with anti-MAG antibodies based on clinical characteristics. However, within the group of anti ganglioside antibody positive patients, antibodies against GD1b and GQ1b were associated with a purely sensory neuropathy (p = 0.002), while asymmetric weakness with symmetric sensory loss was associated with anti-asialo-GM1 antibodies. In conclusion, polyneuropathy associated with IgM monoclonal gammopathy and anti-ganglioside antibodies clinically resembles anti-MAG neuropathy. Pure sensory neuropathy and marked asymmetry may suggest the presence of anti-ganglioside rather than anti-MAG antibodies. PMID- 24781838 TI - Intracranial pressure in unresponsive chronic migraine. AB - To assess the prevalence and possible pathogenetic involvement of raised intracranial pressure in patients presenting with unresponsive chronic migraine (CM), we evaluated the intracranial opening pressure (OP) and clinical outcome of a single cerebrospinal fluid withdrawal by lumbar puncture in 44 consecutive patients diagnosed with unresponsive chronic/transformed migraine and evidence of sinus stenosis at magnetic resonance venography. The large majority of patients complained of daily or near-daily headache. Thirty-eight (86.4%) had an OP >200 mmH2O. Lumbar puncture-induced normalization of intracranial pressure resulted in prompt remission of chronic pain in 34/44 patients (77.3%); and an episodic pattern of headache was maintained for 2, 3 and 4 months in 24 (54.6%), 20 (45.4%) and 17 (38.6%) patients, respectively. The medians of overall headache days/month and of disabling headache days/month significantly decreased (p < 0.0001) at each follow-up versus baseline. Despite the absence of papilledema, 31/44 (70.5%) patients fulfilled the ICHD-II criteria for "Headache attributed to Intracranial Hypertension". Our findings indicate that most patients diagnosed with unresponsive CM in specialized headache clinics may present an increased intracranial pressure involved in the progression and refractoriness of pain. Moreover, a single lumbar puncture with cerebrospinal fluid withdrawal results in sustained remission of chronic pain in many cases. Prospective controlled studies are needed before this procedure can be translated into clinical practice. Nonetheless, we suggest that intracranial hypertension without papilledema should be considered in all patients with almost daily migraine pain, with evidence of sinus stenosis, and unresponsive to medical treatment referred to specialized headache clinics. PMID- 24781839 TI - Voxel-based morphometry and intellectual assessment in patients with congenital bilateral perisylvian syndrome. AB - Congenital bilateral perisylvian syndrome (CBPS) presents with heterogeneous clinical manifestations such as pseudobulbar palsy, language disorder, variable cognitive deficits, epilepsy, and perisylvian abnormalities (most frequently polymicrogyria) on imaging studies. We investigated the relationship between seizures and extent of gray matter (GM) and white matter (WM) abnormalities using voxel-based morphometry (VBM) of brain magnetic resonance imaging (MRI) as well the association between seizures, structural abnormalities and cognitive ability. In this cross-sectional study, we evaluated 51 healthy volunteers and 18 patients with CBPS with epilepsy (seizure group, n = 7) and without (non-seizure group, n = 11). We used VBM (SPM8/DARTEL) to investigate areas with excess and atrophy of both gray and white matter, comparing groups of patients with controls. Intellectual ability of patients was assessed by the WISC-III or WAIS-III. Both groups with CBPS and the control group were homogeneous with respect to gender (p = 0.07) and age (p = 0.065). Besides perisylvian polymicrogyria, the seizure group exhibited areas with GM and WM reduction including temporal, frontal, parietal and occipital lobes. In contrast, we identified fewer areas with GM and WM reduction in the non-seizure group. The seizure group presented worse intellectual performance (performance IQ and global IQ) than the non-seizure group. The seizure group presented with a more widespread pattern of cortical and sub-cortical abnormalities, as well as worse cognition. Our results suggest that patients with CBPS and epilepsy appear to have widespread neuronal damage that goes beyond the areas with MRI-visible perisylvian polymicrogyria. PMID- 24781840 TI - Leptomeningeal lymphomatosis from large granular lymphocyte leukaemia. PMID- 24781841 TI - Variable phenotypic expression in families with early-onset Parkinsonism due to PRKN mutations. PMID- 24781843 TI - Controlled synthesis and novel luminescence properties of string SrWO4:Eu3+ nanobeans. AB - One-dimensional SrWO4:Eu(3+) nanostructures were prepared by a hydrothermal method. The structures and morphologies of the nanocrystals were characterized by X-ray diffraction, Raman spectroscopy, transmission electron microscopy, and scanning electron microscopy. The results indicated that the phase compositions, morphologies and sizes and luminescence properties of SrWO4:Eu(3+) are related to the initial reactant content and reaction time, and lower initial reactant content is beneficial for the formation of the string SrWO4:Eu(3+) nanobeans. The photoluminescence properties of SrWO4:Eu(3+) were investigated in detail. In the emission spectra of SrWO4:Eu(3+), the (5)D0->(7)F1 is dominant when the excitation wavelength is 295 nm, while the (5)D0->(7)F2 is dominant when the excitation wavelengths are in the range of 363-537 nm. Obviously, the string SrWO4:Eu(3+) nanobeans have multiple luminescence centers or emitting states. The excitation spectra of SrWO4:Eu(3+) contain several sharp peaks attributed to f-f transitions of Eu(3+) ions and a broad excitation band assigned to the overlap of WO4(3-) absorption and charge transfer transition between Eu(3+) and O(2-). The intensity ratio of the broad excitation band to the sharp excitation peaks changed with the emission wavelength as well as the Eu(3+) content. In addition, Eu(3+) ions occupy higher symmetry sites in SrWO4:Eu(3+) nanocrystals with increasing the particle size of nanocrystals. The effect of Tb(3+) as well as Gd(3+) ions on the photoluminescence of SrWO4:Eu(3+) was also investigated. PMID- 24781842 TI - Longitudinal assessment of von Willebrand factor antigen and von Willebrand factor propeptide in response to alteration of antiplatelet therapy after TIA or ischaemic stroke. AB - The impact of commencing or changing antiplatelet therapy on von Willebrand factor antigen (VWF:Ag) and von Willebrand factor propeptide (VWF:Ag II) levels has not been comprehensively assessed following TIA or ischaemic stroke. In this pilot, longitudinal, observational analytical study, VWF:Ag and VWF:Ag II levels were simultaneously quantified in platelet poor plasma by ELISA in patients within 4 weeks of TIA or ischaemic stroke (baseline), and then 14 days (14d) and >90 days (90d) after altering antiplatelet therapy. Ninety-one patients were recruited. Eighteen were initially assessed on no antiplatelet therapy, and then after 14d (N = 17) and 90d (N = 8) on aspirin monotherapy; 21 patients were assessed on aspirin and after 14d and 90d on clopidogrel; 52 were assessed on aspirin monotherapy, and after 14d and 90d on aspirin and dipyridamole combination therapy. VWF:Ag, VWF:Ag II levels and VWF:Ag/VWF:Ag II ratio were unchanged at 14d and 90d in the overall study population (p >= 0.1). VWF:Ag and VWF:Ag II levels remained stable at 14d and 90d after commencing aspirin (p >= 0.054), and after changing from aspirin to clopidogrel (p >= 0.2). Following the addition of dipyridamole MR to aspirin, there was a significant reduction in VWF:Ag levels at 14d (p = 0.03) and 90d (p = 0.005), but not in VWF:Ag II levels (p >= 0.3). The addition of dipyridamole to aspirin led to a persistent reduction in VWF:Ag but not in VWF:Ag II levels, suggesting that dipyridamole may inhibit release of platelet-derived VWF:Ag following TIA or ischaemic stroke. PMID- 24781844 TI - Carbon enters silica forming a cristobalite-type CO2-SiO2 solid solution. AB - Extreme conditions permit unique materials to be synthesized and can significantly update our view of the periodic table. In the case of group IV elements, carbon was always considered to be distinct with respect to its heavier homologues in forming oxides. Here we report the synthesis of a crystalline CO2 SiO2 solid solution by reacting carbon dioxide and silica in a laser-heated diamond anvil cell (P = 16-22 GPa, T>4,000 K), showing that carbon enters silica. Remarkably, this material is recovered to ambient conditions. X-ray diffraction shows that the crystal adopts a densely packed alpha-cristobalite structure (P4(1)2(1)2) with carbon and silicon in fourfold coordination to oxygen at pressures where silica normally adopts a sixfold coordinated rutile-type stishovite structure. An average formula of C0.6(1)Si0.4(1)O2 is consistent with X-ray diffraction and Raman spectroscopy results. These findings may modify our view on oxide chemistry, which is of great interest for materials science, as well as Earth and planetary sciences. PMID- 24781845 TI - Night blindness due to vitamin A deficiency associated with copper deficiency myelopathy secondary to bowel bypass surgery. AB - We present an interesting case of combined vitamin A and copper deficiency after a history of gastric bypass surgery where symptoms improved after parenteral copper and vitamin A treatment. Gastric bypass surgery as a cause of fat soluble vitamin deficiency is generally under-reported. Copper deficiency has been reported after gastric bypass surgery. Vitamin A deficiency after gastric bypass surgery has also been reported in the literature, but the reported cases again fall below the actual figures. B12 and folate deficiencies can produce a type of myelopathy similar to that produced by copper deficiency, and differentiation on the basis of laboratory tests, neurophysiology and improvement of symptoms after replacement therapy might be the hallmark of diagnosis. Combinations of vitamin deficiencies were previously reported, but no cases of combined vitamin A and copper deficiency could be found in the literature. PMID- 24781846 TI - Portal pyaemia following renal transplantation. PMID- 24781847 TI - Haemoptysis or haematemesis? The not so bleeding obvious. AB - An aortobronchial fistula is a rare but important diagnosis, which if missed is potentially fatal. We describe a case of a man who presented with severe, spontaneous per oral bleeding. The patient believed the bleeding occurred on coughing not vomiting. Despite denying haematemesis, initial investigations were focused on excluding an upper gastrointestinal bleed because of multiple risk factors (previous alcohol dependence, recent gastritis and heavy smoking). Two urgent oesophagogastroduodenoscopys were unremarkable. A plain chest film demonstrated left-sided perihilar shadowing of possible neoplastic origin. Two days later following sudden torrential haemoptysis, an emergency CT angiogram demonstrated a descending aortic aneurysm and associated aorto-bronchial fistula. The case helps reaffirm the old aphorism that "the patient is telling you the diagnosis"--this was indeed haemoptysis not haematemesis. Despite the power of hindsight, it is a reminder that accurate history-taking is essential in selecting the best first-line investigation, particularly in cases of diagnostic uncertainty. PMID- 24781848 TI - Not just another case of low back pain. AB - A 55-year-old woman presented with persistent, progressive low back and neck pain for 5 years that had failed conservative therapy with analgesics and epidural injections. Physical examination revealed range of motion of lumbar and cervical spine were significantly limited in all directions and she had a bluish discolouration of the pinnae bilaterally. She had elevated urinary excretion of homogentisic acid, diagnostic of alkaptonuria. Further investigation with imaging of the spine revealed diffuse advanced degenerative disease of the cervical and lumbar spine consistent with ochronotic arthropathy. PMID- 24781849 TI - Selective synthesis of 4-(sulfonyl)-methyl-1H-pyrazoles and (E)-4,5-dihydro-1H pyrazoles from N-allenic sulfonylhydrazones. AB - Selective synthesis of 4-(sulfonyl)-methyl-1H-pyrazoles and (E)-4,5-dihydro-1H pyrazoles from N-allenic sulfonylhydrazones with sulfonyl group migrations has been developed. A key feature of these reactions is that the migrations of the sulfonyl groups to different positions can be controlled by changing the Lewis acids. PMID- 24781850 TI - Serial expression and activity analysis of LNK-16: a bovine antimicrobial peptide analogue. AB - Indolicidin is a broad-spectrum antimicrobial peptide (AMP) with great therapeutic potential; however, high manufacturing costs associated with industrial-scale chemical synthesis have limited its delivery. Therefore, the use of recombinant DNA technology to produce this peptide is urgently needed. In this study, a new methodology for the large-scale production of a novel bovine AMP was developed. LNK-16 is an analogue of indolicidin that contains a kallikrein protease site at its C-terminus. The amino acid sequence of LNK-16 was synthesized using Escherichia coli-preferred codons. Three copies of the target gene were assembled in series by overlapping PCR and cloned into pET-30a(+) for the expression of His-(LNK-16)(3) in E. coli BL21 (DE3) cells. The expressed fusion protein His-(LNK-16)(3) was purified by Ni(2+)-chelating chromatography and then cleaved by kallikrein to release LNK-16. The recombinant LNK-16 peptide showed antimicrobial activity similar to that of chemically synthesized LNK-16 and indolicidin. Together, these data indicate that the use of serial expression can improve the large-scale production of AMPs for clinical and research applications. PMID- 24781851 TI - Effects of lifestyle intervention improve cardiovascular disease risk factors in community-based menopausal transition and early postmenopausal women in China. AB - OBJECTIVE: The aim of this study was to test the efficacy of a 12-month lifestyle intervention in improving cardiovascular disease risk factors in community-based menopausal transition and early postmenopausal women in China. METHODS: One hundred healthy menopausal transition and early postmenopausal women aged 40 to 60 years were randomly assigned to receive either lifestyle change intervention (n = 53) or usual care (n = 47). Menopause status was defined by the menstrual change criteria of the Stages of Reproductive Aging Workshop + 10 based on prospective menstrual calendars. Women in the intervention group were provided with a colorful booklet that included dietary and physical activity recommendations, were individually interviewed, and completed biophysical cardiovascular risk assessments at the Women's Health Center (Beijing, China). Women were encouraged to follow a healthy eating pattern and to increase their aerobic activity (moderate level, 3 d/wk, 40 min/d). Women in the control group continued their usual eating patterns and activities. Weight, body mass index (BMI), waist circumference-to-hip circumference ratio (WHR), waist circumference (WC), body composition, blood pressure (BP), blood glucose, and serum lipids were assessed at baseline, 3 months, 6 months, and 12 months in both groups. RESULTS: Women in the intervention group were observed to have significant decreases in weight, BMI, WC, WHR, systolic BP, total cholesterol, and low-density lipoprotein cholesterol compared with women in the control group. At 3 months, there were significant decreases in weight (-0.28 vs 0.68 kg, P = 0.002), BMI (-0.06 vs 0.44 kg/m2, P = 0.003), WC (-0.28 vs 1.43 cm, P = 0.001), and WHR (-0.01 vs 0.01, P = 0.045) in the intervention group compared with the control group. At 6 months, there were significant decreases in WC (-0.73 vs 1.02 cm, P = 0.012), WHR (-0.02 vs -0.003, P = 0.020), and systolic BP (-7.52 vs -0.63 mm Hg, P = 0.012) favoring the intervention group over the control group. At 12 months, there were significant decreases in total cholesterol (-0.07 vs 0.03 mmol/L, P = 0.045) and low-density lipoprotein cholesterol (-0.13 vs 0.01 mmol/L, P = 0.022) in the intervention group versus the control group. CONCLUSIONS: Lifestyle intervention may be an effective means for reducing cardiovascular disease risk factors in menopausal transition and early postmenopausal women in China. PMID- 24781852 TI - Hot flashes: is a hot flash just a hot flash? PMID- 24781853 TI - Detection of serum antimullerian hormone in women approaching menopause using sensitive antimullerian hormone enzyme-linked immunosorbent assays. AB - OBJECTIVE: Current antimullerian hormone (AMH) immunoassays are insufficiently sensitive to detect circulating AMH levels in ovulatory women approaching menopause. The aim of this study was to detect serum AMH levels across the menstrual cycle with age, using two new AMH enzyme-linked immunosorbent assay (ELISA) kits with increased sensitivity and differing specificity. METHODS: Serum AMH levels were determined every 2 to 3 days across the interovulatory interval of menstrual cycles among women of early-mid reproductive age (18-35 y; n = 10) and late reproductive age (45-55 y; n = 17). Two highly sensitive AMH ELISAs (designated 24/32 and 24/37) with differing sensitivities were developed and applied to sera using a recombinant human pro-mature AMH preparation as reference. A third AMH ELISA (Gen II AMH ELISA kit; Beckman Coulter, Brea, CA) used was directed on mature-pro regions of AMH. RESULTS: AMH levels in all cycles were detectable with the 24/32 and 24/37 AMH ELISAs. AMH levels across the menstrual cycle were highly correlated (r = 0.98) between the 24/32 and 24/37 AMH ELISAs and the Gen II AMH ELISA (r = 0.94), but with large intracycle variations observed in older women. In late reproductive age, more than 95% of AMH values were detectable with the 24/32 and 24/37 AMH ELISAs, whereas only 36% of AMH values were detectable with the Gen II AMH ELISA. AMH levels were detected in cycles with lower antral follicle count and at a later age using the 24/32 and 24/37 AMH ELISAs compared with the Gen II AMH ELISA. AMH level correlated with antral follicle count in younger women, but not in older women. CONCLUSIONS: The new 24/32 and 24/37 AMH ELISAs have the sensitivity to monitor ovarian follicle profiles in late reproductive age. PMID- 24781854 TI - Endocrine biomarkers and symptom clusters during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study. AB - OBJECTIVE: During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study were likely to belong to one of three symptom severity classes: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); moderate levels of all but hot flashes (moderate severity); and low levels of all (low severity). We tested models of the differential effects of hypothalamic-pituitary-ovarian (HPO) axis, hypothalamic-pituitary-adrenal (HPA) axis, and autonomic nervous system (ANS) biomarkers on the three symptom severity classes. METHODS: The Seattle Midlife Women's Health Study participants recorded symptoms monthly in diaries and provided overnight urine samples several times per year that were analyzed for estrone, follicle-stimulating hormone (FSH), cortisol, testosterone, epinephrine, and norepinephrine. Multilevel latent class analysis with multinomial regression was used to determine the effects of HPO axis, HPA axis, and ANS biomarkers on symptom severity class membership. RESULTS: Having lower estrogen and higher FSH levels was significantly associated with belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine and higher norepinephrine levels increased the likelihood of belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine levels was significantly associated with belonging to the moderate-severity class versus the low-severity class. Cortisol and testosterone were unrelated to symptom severity class membership. CONCLUSIONS: The association of HPO axis biomarkers (estrogen and FSH) with the high-severity hot flash class is anticipated based on prior hot flash research, and the associations of HPA axis biomarkers are as expected based on earlier laboratory studies. The association of lower epinephrine levels with the moderate-severity class suggests that these symptoms may be mediated by the ANS. PMID- 24781855 TI - A theoretical and experimental evaluation of imidazolium-based ionic liquids for atmospheric mercury capture. AB - In this work, the capacity of three different imidazolium-based ionic liquids (ILs) for atmospheric mercury capture has been evaluated. Theoretical calculations using monomer and dimer models of ILs showed that [BMIM]+[SCN]- and [BMIM]+[Cl]- ionic liquids capture gaseous Hg0, while [BMIM]+[PF6]- shows no ability for this purpose. These findings are supported by experimental data obtained using particle induced X-ray emission (PIXE) trace element analysis. Experimental and theoretical infrared data of the ILs were obtained before and after exposure to Hg. In all cases, no displacement of the bands was observed, indicating that the interaction does not significantly affect the force constants of substrate bonds. This suggests that van der Waals forces are the main forces responsible for mercury capture. Since the anion-absorbate is the driving force of the interaction, the largest charge-volume ratio of [Cl]- could explain the higher affinity for mercury sequestration of the [BMIM]+[Cl]- salt. PMID- 24781856 TI - Use of mechanical ventilation by patients with and without dementia, 2001 through 2011. PMID- 24781857 TI - Prevalence of functional gastrointestinal disorders in obese and overweight children. AB - OBJECTIVE: To compare the prevalence of functional gastrointestinal disorders such as functional constipation (FC), functional abdominal pain (FAP), functional abdominal pain syndrome (FAPS) and irritable bowel syndrome (IBS) between a large cohort of healthy obese/overweight children and normal-weight children. METHODS: Healthy children between the ages of 4 and 18 years were eligible for recruitment from the Yale Pediatric Primary Care clinic, Yale Adolescent clinic and a local private practice in Orange, CT, USA. Study subjects or their parents were interviewed using a questionnaire based on the ROME III standardized criteria for diagnosing functional gastrointestinal disorders. Medical records were reviewed to collect information about age, gender, height, weight, body mass index (BMI), ethnicity and chronic medical conditions. Children were classified into obese, overweight and normal-weight based on their BMI for age and gender. Data were analyzed to compare the prevalence of FC, FAP, FAPS and IBS between obese/overweight children and normal-weight children. RESULTS: A total of 450 children (45% males) were recruited. There were 191 (42%) obese/overweight children and 259 (58%) normal-weight children. FAPS (odds ratio (OR) =2.1, 95% confidence interval (CI): 1.21-3.64, P=0.007), FC (OR=1.83, 95% CI: 1.12-2.98, P=0.01), and IBS (OR=2.59, 95% CI: 1.40-4.79, P=0.003) were significantly more prevalent in the obese/overweight children than in the normal-weight children. Of the obese/overweight children, 47% had at least one functional gastrointestinal disorder compared with 27% of the normal-weight children (P?0.001). Only 36% of the children with functional gastrointestinal disorders sought medical attention for their symptoms. CONCLUSIONS: Obese/overweight children have a higher prevalence of functional gastrointestinal disorders than normal-weight children. Almost half of the obese/overweight children had at least one functional gastrointestinal disorder. PMID- 24781858 TI - Mineralocorticoid vs glucocorticoid receptors: solo players or team mates in the control of adipogenesis? PMID- 24781859 TI - Characterization of limes (Citrus aurantifolia) grown in Bhutan and Indonesia using high-throughput sequencing. AB - Lime [Citrus aurantifolia (Cristm.) Swingle] is a Citrus species that is a popular ingredient in many cuisines. Some citrus plants are known to originate in the area ranging from northeastern India to southwestern China. In the current study, we characterized and compared limes grown in Bhutan (n = 5 accessions) and Indonesia (n = 3 accessions). The limes were separated into two groups based on their morphology. Restriction site-associated DNA sequencing (RAD-seq) separated the eight accessions into two clusters. One cluster contained four accessions from Bhutan, whereas the other cluster contained one accession from Bhutan and the three accessions from Indonesia. This genetic classification supported the morphological classification of limes. The analysis suggests that the properties associated with asexual reproduction, and somatic homologous recombination, have contributed to the genetic diversification of limes. PMID- 24781861 TI - Fasting blood glucose--a missing variable for GFR-estimation in type 1 diabetes? AB - OBJECTIVE: Estimation of glomerular filtration rate (eGFR) is one of the current clinical methods for identifying risk for diabetic nephropathy in subjects with type 1 diabetes (T1D). Hyperglycemia is known to influence GFR in T1D and variability in blood glucose at the time of eGFR measurement could introduce bias in eGFR. We hypothesized that simultaneously measured blood glucose would influence eGFR in adults with T1D. METHODS: Longitudinal multivariable mixed models were employed to investigate the relationships between blood glucose and eGFR by CKD-EPI eGFRCYSTATIN C over 6-years in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study. All subjects with T1D and complete data including blood glucose and cystatin C for at least one of the three visits (n = 616, 554, and 521, respectively) were included in the longitudinal analyses. RESULTS: In mixed-models adjusting for sex, HbA1c, ACEi/ARB, protein and sodium intake positive associations were observed between simultaneous blood glucose and eGFRCYSTATIN C (beta+/-SE:0.14+/-0.04 per 10 mg/dL of blood glucose, p<0.0001), and hyperfiltration as a dichotomous outcome (OR: 1.04, 95% CI: 1.01-1.07 per 10 mg/dL of blood glucose, p = 0.02). CONCLUSIONS: In our longitudinal data in subjects with T1D, simultaneous blood glucose has an independent positive effect on eGFRCYSTATIN C. The associations between blood glucose and eGFRCYSTATIN C may bias the accurate detection of early diabetic nephropathy, especially in people with longitudinal variability in blood glucose. PMID- 24781864 TI - miR-145 suppresses thyroid cancer growth and metastasis and targets AKT3. AB - The expression and function of miR-145 in thyroid cancer is unknown. We evaluated the expression and function of miR-145 in thyroid cancer and its potential clinical application as a biomarker. We found that the expression of miR-145 is significantly downregulated in thyroid cancer as compared with normal. Overexpression of miR-145 in thyroid cancer cell lines resulted in: decreased cell proliferation, migration, invasion, VEGF secretion, and E-cadherin expression. miR-145 overexpression also inhibited the PI3K/Akt pathway and directly targeted AKT3. In vivo, miR-145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. miR-145 inhibition in normal primary follicular thyroid cells decreased the expression of thyroid cell differentiation markers. Analysis of indeterminate fine-needle aspiration samples showed miR-145 had a 92% negative predictive value for distinguishing benign from malignant thyroid nodules. Circulating miR-145 levels were significantly higher in patients with thyroid cancer and showed a venous gradient. Serum exosome extractions revealed that miR-145 is secreted. Our findings suggest that miR-145 is a master regulator of thyroid cancer growth, mediates its effect through the PI3K/Akt pathway, is secreted by the thyroid cancer cells, and may serve as an adjunct biomarker for thyroid cancer diagnosis. PMID- 24781862 TI - Beta, but not gamma, band oscillations index visual form-motion integration. AB - Electrophysiological oscillations in different frequency bands co-occur with perceptual, motor and cognitive processes but their function and respective contributions to these processes need further investigations. Here, we recorded MEG signals and seek for percept related modulations of alpha, beta and gamma band activity during a perceptual form/motion integration task. Participants reported their bound or unbound perception of ambiguously moving displays that could either be seen as a whole square-like shape moving along a Lissajou's figure (bound percept) or as pairs of bars oscillating independently along cardinal axes (unbound percept). We found that beta (15-25 Hz), but not gamma (55 85 Hz) oscillations, index perceptual states at the individual and group level. The gamma band activity found in the occipital lobe, although significantly higher during visual stimulation than during base line, is similar in all perceptual states. Similarly, decreased alpha activity during visual stimulation is not different for the different percepts. Trial-by-trial classification of perceptual reports based on beta band oscillations was significant in most observers, further supporting the view that modulation of beta power reliably index perceptual integration of form/motion stimuli, even at the individual level. PMID- 24781866 TI - Hypertrophic cardiomyopathy and left atrial myxoma. PMID- 24781865 TI - Postoperative [125I] seed brachytherapy in the treatment of acinic cell carcinoma of the parotid gland: with associated risk factors. AB - BACKGROUND: This retrospective study was undertaken to analyze data from patients receiving iodine-125 ([(125)I]) seed brachytherapy postoperatively for the treatment of acinic cell carcinoma (ACC) of the parotid gland along with the following risk factors: residual tumor, recurrent tumor, facial nerve invasion, positive resection margins, advanced tumor stage, or tumor spillage. PATIENTS AND METHODS: Twenty-nine patients with ACC (17 females, 12 males; age range, 13-73 years; median age, 37.3 years) were included. Median follow-up was 58.2 months (range, 14-122 months). Patients received [(125)I] seed brachytherapy (median actuarial D90, 177 Gy) 3-41 days (median, 14 days) following surgery. Radioactivity was 18.5-33.3 MBq per seed, and the prescription dose was 80-120 Gy. RESULTS: The 3-, 5-, and 10-year rates of local control were 93.1, 88.7, and 88.7 %, respectively; overall survival was 96.6, 92, and 92 %; disease-free survival was 93.1, 88.4, and 88.4 %; and freedom from distant metastasis was 96.6, 91.2, and 91.2 %. Lymph node metastases were absent in all patients, although two patients died with distant metastases. Facial nerve recovery was quick, and no severe radiotherapy-related complications were noted. Recurrence history, local recurrence, and distant metastasis significantly affected overall survival. CONCLUSION: Postoperative [(125)I] seed brachytherapy is effective in treating ACC and has minor complications. Patients with a history of recurrence showed poor prognosis and were more likely to experience disease recurrence and develop metastases. PMID- 24781868 TI - Few-femtosecond time-resolved measurements of X-ray free-electron lasers. AB - X-ray free-electron lasers, with pulse durations ranging from a few to several hundred femtoseconds, are uniquely suited for studying atomic, molecular, chemical and biological systems. Characterizing the temporal profiles of these femtosecond X-ray pulses that vary from shot to shot is not only challenging but also important for data interpretation. Here we report the time-resolved measurements of X-ray free-electron lasers by using an X-band radiofrequency transverse deflector at the Linac Coherent Light Source. We demonstrate this method to be a simple, non-invasive technique with a large dynamic range for single-shot electron and X-ray temporal characterization. A resolution of less than 1 fs root mean square has been achieved for soft X-ray pulses. The lasing evolution along the undulator has been studied with the electron trapping being observed as the X-ray peak power approaches 100 GW. PMID- 24781869 TI - Coordination chemistry of sterically encumbered pyrrolyl ligands to chromium(II): mono(pyrrolyl)chromium and diazachromocene formation. AB - A series of diazachromocenes with sterically demanding pyrrolyl ligands, 2,5 (Me3C)2C4H2N (1), 2,5-(Me3C)2-3,4-Me2C4N (2) and 2,3,5-(Me3C)3C4HN (3), was prepared and investigated by various spectroscopic techniques, and in some cases by X-ray diffraction and magnetic susceptibility studies. The diazachromocenes exhibit an S = 1 ground state; no indication of a spin-equilibrium was obtained. With the same ligands mono(pyrrolyl)chromium(II) complexes are accessible, [{(kappaN-2,5-(Me3C)2C4H2N)Cr(thf)}2(MU-Cl)2] (1-CrCl(thf)), [(kappaN-2,5-(Me3C)2 3,4-Me2-C4H2N)Cr(Cl)(tmeda)] (2-CrCl(tmeda) and [(eta(5)-2,3,5-(Me3C)3C4HN)Cr(MU Cl)2] (3-CrCl), which show either eta(5)- or eta(1)-(kappaN) coordination depending on the substitution pattern. (1)H NMR spectroscopy serves as a valuable tool to distinguish between these coordination modes. The Cr(II) atoms in the mono(pyrrolyl) complexes adopt a high spin configuration (S = 2) and in dimeric species antiferromagnetic coupling between the spin carriers was observed. However, none of these mono(pyrrolyl)chromium complexes is an effective or selective ethylene oligomerization catalyst on activation with MAO or AlMe3, supporting the importance of a Cr(I)/Cr(III)-based catalytic cycle. PMID- 24781870 TI - 18F-FDG uptake as a prognostic variable in primary differentiated thyroid cancer incidentally detected by PET/CT: a multicentre study. AB - PURPOSE: Our aim was to investigate the association between (18)F fluorodeoxyglucose (FDG) uptake and event-free survival in patients in whom a differentiated thyroid cancer (DTC) was detected by (18)F-FDG positron emission tomography (PET)/CT. METHODS: Among 884 focal (18)F-FDG PET thyroid incidentalomas referred to our 4 Nuclear Medicine Departments, we investigated 54 patients in whom a DTC was confirmed and a clinical follow-up was available. The ratio between maximum standardized uptake value (SUVmax) of DTC and SUVmean of the liver (SUV ratio) was recorded for each scan. All patients underwent total thyroidectomy and (131)I remnant ablation. After a median follow-up of 39 months we assessed the outcome. The association between disease persistence/progression, (18)F-FDG uptake and other risk factors (T, N, M and histological subtype) was evaluated through univariate and multivariate analyses. RESULTS: Of the 54 patients, 39 achieved complete remission. The remaining 15 showed persistence/progression of disease. High (18)F-FDG uptake, i.e. SUV ratio >=3, showed a low positive predictive value (48 %). Low (18)F-FDG uptake (SUV ratio < 3) displayed a high negative predictive value (93 %). The median of SUV ratios in T1-T2 (2.2), in M0 (2.7) and in non-virulent subtypes (2.7) were significantly lower (p < 0.03) than in T3-T4 (5.0), M1 (7.3) and virulent subtypes (6.0). Kaplan-Maier analysis showed a significant association between high (18)F-FDG uptake and disease persistence/progression (p = 0.001). When we adjusted risk estimates by using a multivariate Cox model, only T (p = 0.05) remained independently associated with disease persistence/progression. CONCLUSION: An intense (18)F-FDG uptake of the primary DTC is associated with persistence/progression of disease. However, when all other prognostic factors have been taken into account, (18)F-FDG uptake does not add further prognostic information. PMID- 24781872 TI - Comparison of EANM and SNM guidelines on diuretic renography in children. PMID- 24781871 TI - Correlation between 18F-fluoromisonidazole PET and expression of HIF-1alpha and VEGF in newly diagnosed and recurrent malignant gliomas. AB - PURPOSE: Hypoxia and its consequences at the molecular level promote tumour progression and affect patient prognosis. One of the main early cellular events evoked by hypoxia is induction of hypoxia-inducible factor 1 (HIF-1) and subsequent upregulation of vascular endothelial growth factor (VEGF). In this study we sought to determine whether hypoxia detected by (18)F-fluoromisonidazole (FMISO) PET accurately reflects the expression of HIF-1alpha and VEGF in the tumour and can be used as a biomarker of antiangiogenic treatment and as a prognostic factor in newly diagnosed and recurrent malignant gliomas. METHODS: Enrolled in this study were 32 patients with newly diagnosed glioma and 16 with recurrent glioma of grade III or grade IV. All the patients had undergone FMISO PET preoperatively. The maximum tumour-to-blood FMISO activity ratio (T/Bmax) was used to evaluate the degree of tumour hypoxia and the hypoxic volume (HV) was calculated using a tumour-to-blood FMISO uptake ratio of >=1.2. Immunohistochemical expressions of HIF-1alpha and VEGF were evaluated semiquantitatively using the immunoreactivity score (IRS, scores 0 to 12) and the correlation was examined between IRS of HIF-1alpha or VEGF and FMISO uptake of the tumour (SUVtumour) using navigation-based sampling. Survival was estimated using the Kaplan-Meier method in relation to the T/Bmax and the HV. RESULTS: The T/Bmax and the HV in grade IV gliomas were significantly higher than in grade III gliomas (P < 0.01 and P < 0.01, respectively). Moderate to strong HIF-1alpha and VEGF expression was observed in the majority of malignant gliomas. The IRS of HIF 1alpha and VEGF in the tumour were not significantly different between grade III and grade IV gliomas. The IRS of HIF-1alpha in the tumour did not correlate with the SUVtumour of FMISO in either newly diagnosed or recurrent glioma. There was a significant but weak correlation between the IRS of VEGF and the SUVtumour of FMISO in newly diagnosed glioma, but not in recurrent glioma. The overall survival time in patients with a small HV and a low FMISO T/Bmax was significantly longer than in those with a large HV and a high FMISO T/Bmax (P < 0.01 and P < 0.05, respectively). CONCLUSION: Preoperative FMISO uptake is significantly correlated with the expression of VEGF in the tumour and might be used as a biomarker of antiangiogenic treatment in newly diagnosed malignant gliomas. However, caution is required because the correlation was weak and there was a large overlap of FMISO uptake between glioma with high and low VEGF expression. In addition, hypoxia determined by FMISO PET appears to be a suitable biomarker for predicting a highly malignant tumour and a poor prognosis in patients with malignant glioma. PMID- 24781873 TI - Some opinions on the review process of research papers destined for publication. AB - The current paper discusses the peer review process in journals that publish research papers purveying new science and understandings (scientific journals). Different aspects of peer review including the selection of reviewers, the review process and the decision policy of editor are discussed in details. Here, the pros and cons of different conventional methods of review processes are mentioned. Finally, a suggestion is presented for the review process of scientific papers. PMID- 24781874 TI - Breaking the cyber-security dilemma: aligning security needs and removing vulnerabilities. AB - Current approaches to cyber-security are not working. Rather than producing more security, we seem to be facing less and less. The reason for this is a multi dimensional and multi-faceted security dilemma that extends beyond the state and its interaction with other states. It will be shown how the focus on the state and "its" security crowds out consideration for the security of the individual citizen, with detrimental effects on the security of the whole system. The threat arising from cyberspace to (national) security is presented as possible disruption to a specific way of life, one building on information technologies and critical functions of infrastructures, with relatively little consideration for humans directly. This non-focus on people makes it easier for state actors to militarize cyber-security and (re-)assert their power in cyberspace, thereby overriding the different security needs of human beings in that space. Paradoxically, the use of cyberspace as a tool for national security, both in the dimension of war fighting and the dimension of mass-surveillance, has detrimental effects on the level of cyber-security globally. A solution out of this dilemma is a cyber-security policy that is decidedly anti-vulnerability and at the same time based on strong considerations for privacy and data protection. Such a security would have to be informed by an ethics of the infosphere that is based on the dignity of information related to human beings. PMID- 24781875 TI - Highly efficient exciplex organic light-emitting diodes incorporating a heptazine derivative as an electron acceptor. AB - Highly efficient exciplex systems incorporating a heptazine derivative () as an electron acceptor and 1,3-di(9H-carbazol-9-yl)benzene () as an electron donor are developed. An organic light-emitting diode containing 8 wt% : as an emitting layer exhibits a maximum external quantum efficiency of 11.3%. PMID- 24781876 TI - A facile and convenient sequential homobimetallic catalytic approach towards beta methylstyrenes. A one-pot Stille cross-coupling/isomerization strategy. AB - An efficient one-pot synthetic approach towards beta-methylstyrenes is reported. The transformation, based on sequential homobimetallic catalysis, involves a Stille cross-coupling reaction between aryl halides and allyltributylstannane, followed by an in situ palladium-catalyzed conjugative isomerization. The reaction was optimized, and the best results were obtained with 10 mol% Pd(PPh3)2Cl2, 8.0 equiv. LiCl, and 0.5 equiv. PPh3 in diglyme at 130 degrees C for 12 h. It was demonstrated that the reaction tolerates a wide variety of functional groups. PMID- 24781877 TI - Trends in weight management goals and behaviors among 9th-12th grade students: United States, 1999-2009. AB - To examine trends in weight management goals and behaviors among U.S. high school students during 1999-2009. Data from six biennial cycles (1999-2009) of the national Youth Risk Behavior Survey were analyzed. Cross-sectional, nationally representative samples of 9th-12th grade students (approximately 14,000 students/cycle) completed self-administered questionnaires. Logistic regression models adjusted for grade, race/ethnicity, and obesity were used to test for trends in weight management goals and behaviors among subgroups of students. Combined prevalences and trends differed by sex and by race/ethnicity and weight status within sex. During 1999-2009, the prevalence of female students trying to gain weight decreased (7.6-5.7 %). Among female students trying to lose or stay the same weight, prevalences decreased for eating less (69.6-63.2 %); fasting (23.3-17.6 %); using diet pills/powders/liquids (13.7-7.8 %); and vomiting/laxatives (9.5-6.6 %) for weight control. During 1999-2009, the prevalence of male students trying to lose weight increased (26.1-30.5 %). Among male students trying to lose or stay the same weight, the prevalence of exercising to control weight did not change during 1999-2003 and then increased (74.0-79.1 %) while the prevalence of taking diet pills/powders/liquids for weight control decreased (6.9-5.1 %) during 1999-2009. Weight management goals and behaviors changed during 1999-2009 and differed by subgroup. To combat the use of unhealthy weight control behaviors, efforts may be needed to teach adolescents about recommended weight management strategies and avoiding the risks associated with unhealthy methods. PMID- 24781880 TI - A Predictive Model for the Anticoagulant Bivalirudin Administered to Cardiac Surgical Patients. AB - Bivalirudin is used in patients with heparin-induced thrombocytopenia and is a direct thrombin inhibitor. Since it is a rarely used drug, clinical experience with its dosing is sparse. We develop a model that predicts the effect of bivalirudin, measured by the Partial Thromboplastin Time (PTT), based on its past fusion rates. We learn population-wide model parameters by solving a nonlinear optimization problem that uses a training set of patient data. More interestingly, we devise an adaptive algorithm based on the extended Kalman filter that can adapt model parameters to individual patients. The latter adaptive model emerges as the most promising as it reduces both the mean error and, drastically, the per-patient error variance. The model accuracy we demonstrate on actual patient measurements is sufficient to be useful in guiding optimal therapy. PMID- 24781878 TI - Intimate partner violence, power, and equity among adolescent parents: relation to child outcomes and parenting. AB - Intimate partner violence (IPV) victimization and perpetration and power imbalances in parenting partners may result in poor outcomes for parents and children. Previous work in this area has focused on the maternal experiences, neglecting to examine paternal effects. The present study aimed to elucidate the role of IPV, power, and equity in parenting and child outcomes in an urban sample of adolescent parents. 159 male and 182 female parents in a relationship were recruited through university-affiliated hospitals. Power, equity, and IPV were measured at 6 months post-partum and were used as predictors for parenting and child outcomes 12 months post-partum using general estimating equations. Gender interactions and mediation effects of depression were also assessed. Higher perceived relationship equity was related to better infant temperament (B = 0.052, SE = 0.023, p = 0.02) whereas higher partner power was related to poorer social development (B = -0.201, SE = 0.088, p = 0.02) and fine motor development (B = -0.195, SE = 0.078, p = 0.01). IPV victimization was associated with poor infant temperament (B = -2.925, SE = 1.083, p = 0.007) and lower parenting competence (B = -3.508, SE = 1.142, p = 0.002). Depression mediated the relationship between IPV and parenting and IPV and infant temperament. No gender effects were found. IPV, inequities, and power imbalances were disadvantageous for parenting and child outcomes. Our results suggest that these dynamics may negatively affect both males and females. Interventions to reduce violence in both partners and promote equity in relationships could benefit couples and their children. PMID- 24781879 TI - Sectoral variations of iridocorneal angle width and iris volume in Chinese Singaporeans: a swept-source optical coherence tomography study. AB - PURPOSE: To assess variations in the iridocorneal angle width and iris volume in Chinese subjects using swept-source optical coherence tomography (SS-OCT). METHODS: Consecutive subjects, aged 40-80 years, with no previous ophthalmic problems were recruited from a population-based study of Chinese Singaporeans. All subjects underwent 360 degrees SS-OCT (SS-1000 CASIA, Tomey Corporation, Nagoya, Japan) angle imaging and gonioscopy in one randomly selected eye in the dark. For each eye, 16 frames (11.25 degrees apart) were selected for analysis from 128 cross-sectional images, and measurements of the trabecular iris space area 750 MUm from the scleral spur (TISA750) and iris volume were made for each image. The measurements from four consecutive frames were further averaged as a sector of 45 degrees . Sector-wise angle width and quadrant-wise iris volume were analyzed. RESULTS: Two hundred and twelve subjects (90 with closed-angles) were examined. The majority of the subjects were female (70.7 %) with mean age 61 (+/ 8.9) years. The TISA750 (mm(2)) of superior [0.101 (0.09)], inferior [0.105 (0.09)], superior-nasal [0.111 (0.09)] and superior-temporal [0.117 (0.09)] sectors were smaller compared with other sectors (P < 0.05). The nasal iris volume (mm(3)) was the smallest compared with other quadrants for the entire cohort [nasal 8.18 (1.2) < inferior 9.13 (1.3) < temporal 9.16 (1.2) < superior 9.33 (1.3), P < 0.001], as well as for open- and closed-angle groups. CONCLUSIONS: The irido-corneal angle was narrower in the superior, inferior, superior-nasal and superior-temporal sectors compared with other sectors. Iris volume in the nasal quadrant was the smallest compared with the other quadrants. PMID- 24781881 TI - Coherent destruction of tunneling in chaotic microcavities via three-state anti crossings. AB - Coherent destruction of tunneling (CDT) has been one seminal result of quantum dynamics control. Traditionally, CDT is understood as destructive interference between two intermediate transition paths near the level crossing. CDT near the level anti-crossings, especially the "locking", has not been thoroughly explored so far. Taking chaotic microcavity as an example, here we study the inhibition of the tunneling via the strong couplings of three resonances. While the tunneling rate is only slightly affected by each strong coupling between two modes, the destructive interference between two strong couplings can dramatically improve the inhibition of the tunneling. A "locking" point, where dynamical tunneling is completely suppressed, has even been observed. We believe our finding will shed light on researches on micro- & nano-photonics. PMID- 24781883 TI - Rapid prototyping of multi-scale biomedical microdevices by combining additive manufacturing technologies. AB - The possibility of designing and manufacturing biomedical microdevices with multiple length-scale geometries can help to promote special interactions both with their environment and with surrounding biological systems. These interactions aim to enhance biocompatibility and overall performance by using biomimetic approaches. In this paper, we present a design and manufacturing procedure for obtaining multi-scale biomedical microsystems based on the combination of two additive manufacturing processes: a conventional laser writer to manufacture the overall device structure, and a direct-laser writer based on two-photon polymerization to yield finer details. The process excels for its versatility, accuracy and manufacturing speed and allows for the manufacture of microsystems and implants with overall sizes up to several millimeters and with details down to sub-micrometric structures. As an application example we have focused on manufacturing a biomedical microsystem to analyze the impact of microtextured surfaces on cell motility. This process yielded a relevant increase in precision and manufacturing speed when compared with more conventional rapid prototyping procedures. PMID- 24781882 TI - Microcavity substrates casted from self-assembled microsphere monolayers for spheroid cell culture. AB - Multicellular spheroids are an important 3-dimensional cell culture model that reflects many key aspects of in vivo microenvironments. This paper presents a scalable, self-assembly based approach for fabricating microcavity substrates for multicellular spheroid cell culture. Hydrophobic glass microbeads were self assembled into a tightly packed monolayer through the combined actions of surface tension, gravity, and lateral capillary forces at the water-air interface of a polymer solution. The packed bead monolayer was subsequently embedded in the dried polymer layer. The surface was used as a template for replicating microcavity substrates with perfect spherical shapes. We demonstrated the use of the substrate in monitoring the formation process of tumor spheroids, a proof-of concept scale-up fabrication procedure into standard microplate formats, and its application in testing cancer drug responses in the context of bone marrow stromal cells. The presented technique offers a simple and effective way of forming high-density uniformly-sized spheroids without microfabrication equipment for biological and drug screening applications. PMID- 24781884 TI - Quasi-digital PCR: Enrichment and quantification of rare DNA variants. AB - Rare variant enrichment and quantification was achieved by allele-specific, competitive blocker, digital PCR for aiming to provide a noninvasive method for detecting rare DNA variants from circulating cells. The allele-specific blocking chemistry improves sensitivity and lowers assay cost over previously described digital PCR methods while the instrumentation allowed for rapid thermal cycling for faster turnaround time. Because the digital counting of the amplified variants occurs in the presence of many wild-type templates in each well, the method is called "quasi-digital PCR". A spinning disk was used to separate samples into 1000 wells, followed by rapid-cycle, allele-specific amplification in the presence of a molecular beacon that serves as both a blocker and digital indicator. Monte Carlo simulations gave similar results to Poisson distribution statistics for mean number of template molecules and provided an upper and lower bound at a specified confidence level and accounted for input DNA concentration variation. A 111 bp genomic DNA fragment including the BRAF p.V600E mutation (c.T1799A) was amplified with quasi-digital PCR using cycle times of 23 s. Dilution series confirmed that wild-type amplification was suppressed and that the sensitivity for the mutant allele was <0.01 % (43 mutant alleles amongst 500,000 wild-type alleles). The Monte Carlo method presented here is publically available on the internet and can calculate target concentration given digital data or predict digital data given target concentration. PMID- 24781885 TI - Electromechanical method coupling non-invasive skin impedance probing and in vivo subcutaneous liquid microinjection: controlling the diffusion pattern of nanoparticles within living soft tissues. AB - Transdermal drug delivery is the way to transport drug carriers, such as nanoparticles, across the skin barrier to the dermal and/or subcutaneous layer. In order to control the transdermal drug delivery process, based on the heterogeneous and nonlinear structures of the skin tissues, we developed a novel electromechanical method combining in vivo local skin impedance probing, subcutaneous micro-injection of colloidal nanoparticles, and transcutaneous electrical stimulation. Experiments on the nude mice using in vivo fluorescence imaging exhibited significantly different apparent diffusion patterns of the nanoparticles depending on the skin impedance: Anisotropic and isotropic patterns were observed upon injection into low and high impedance points, respectively. This result implies that the physical complexity in living tissues may cause anisotropic diffusion of drug carriers, and can be used as a parameter for controlling drug delivery process. This method also can be combined with microneedle-based drug release systems, micro-fabricated needle-electrodes, and/or advanced in vivo targeting/imaging technologies using nanoparticles. PMID- 24781886 TI - Cancer-related impairments influence physical activity in uterine cancer survivors. AB - INTRODUCTION: The extent to which physical activity (PA) participation among uterine cancer survivors may be limited by physical and functional impairments (PFI) related to cancer treatment is unknown. We sought to describe PA participation, characterize the prevalence of PFI, and examine the association between PFI status and PA participation within this population. METHODS: We conducted a study using a mailed survey among uterine cancer survivors who received treatment at a university hospital. We asked about PA and PFI using validated self-report questionnaires. PA was calculated using MET-hours per week (MET.h.wk). PFI was defined as having one or more of the following symptoms: lower limb lymphedema, general pain, fatigue, or severe bladder, bowel, or pelvic issues. Ordinal logistic regression was used to quantify the odds ratio (OR) between PA and PFI. RESULTS: The response rate to our survey was 43%. Among the 213 study participants, 40%, 13%, 13%, 12%, and 23% reported participating in <3.0, 3.0-8.9, 9.0-17.9, 18.0-26.9, and >=27.0 MET.h.wk of PA, respectively. Walking is the preferred mode of exercise for physically active uterine cancer survivors. Of the survivors, 53% experience at least one PFI. The most common PFI is lower limb lymphedema (36.2%), followed by general pain (22.5%). The OR of PFI decreased as MET-hours per week of PA increased (OR, 0.51; 95% confidence interval, 0.31-0.84; P = 0.009). CONCLUSIONS: The majority of uterine cancer survivors experience PFI that significantly reduce the likelihood of PA participation. PA recommendations for uterine cancer survivors should take into account treatment-related impairments that can affect PA participation. PMID- 24781887 TI - The prescription or proscription of exercise in colorectal cancer care. AB - PURPOSE: Clinical guidelines recommend that oncologists prescribe exercise to their patients with colorectal cancer (CRC). However, 84% of oncologists do not prescribe exercise, citing concerns of safety and feasibility. Data are inadequate regarding the proportion of CRC survivors that could be safely prescribed with the dose of exercise recommended by the American College of Sports Medicine (ACSM), American Cancer Society (ACS), or National Comprehensive Cancer Network (NCCN) in an unsupervised setting. METHODS: We reviewed published guidelines for exercise prescription among cancer survivors and extracted health factors that may necessitate referral to trained personnel (physical therapist or exercise professional) for an individualized exercise program or supervision of exercise as recommended by the ACSM/ACS/NCCN. We applied these health factors to a cohort of nonmetastatic CRC survivors 6 months after completing curative care. The primary outcome was the proportion of CRC survivors to whom oncologists could prescribe unsupervised exercise at the dose recommended by the ACSM/ACS/NCCN. RESULTS: Among 351 CRC survivors, 6 months after curative care, 21%-42% of patients could be prescribed with the dose of exercise recommended by the ACSM/ACS/NCCN. Estimates varied as a function of the inclusion or exclusion of several prevalent comorbid health conditions including hypertension, diabetes, arthritis, obesity, and hyperlipidemia. CONCLUSIONS: Our data are consistent with the clinical observation that a large proportion of CRC survivors may be unable to participate in unsupervised exercise 6 months after curative care. These data underscore the need for continued research to clarify the safety and feasibility of prescribing exercise to CRC survivors. PMID- 24781888 TI - Deloading tape reduces muscle stress at rest and during contraction. AB - PURPOSE: Taping techniques that aim to protect and reduce stress on an injured tissue during rehabilitation are common in sport. Called deloading tape, the mechanism of action is hypothesized to involve effects ranging from direct mechanical deloading of the underlying soft tissues to psychological effects on confidence. There is no evidence that deloading tape has direct mechanical effects. This study used an elastographic technique (supersonic shear imaging) to test the hypothesis that deloading tape applied to the skin over the rectus femoris would reduce stress within the taped area of this muscle. METHODS: Thirteen healthy volunteers participated in this experiment. Muscle shear elastic modulus was compared between three treatments (no tape, deloading tape, and sham tape) in four conditions: three conditions without muscle contraction at different rectus femoris muscle-tendon unit lengths (moderately stretched, highly stretched, and shortened) and during submaximal isometric leg extension. RESULTS: Although there was no effect of treatment when the muscle was shortened (P = 0.99), the shear elastic modulus was significantly affected by treatment for the three other conditions (all P < 0.002). Muscle shear elastic modulus was significantly less during application of deloading tape than that during both the no tape and sham tape conditions (all P <= 0.001; e.g., vs no tape: moderately stretched, 8.4 +/- 2.7 vs 6.7 +/- 1.7 kPa; highly stretched, 25.2 +/- 8.2 vs 14.4 +/- 4.3 kPa; submaximal contraction, 21.3 +/- 4.8 vs 14.2 +/- 4.3 kPa). CONCLUSIONS: Through the use of elastography, this is the first study to support the hypothesis that deloading tape reduces stress in the underlying muscle region, thereby providing a biomechanical explanation for the effect observed during rehabilitation in clinical practice (reduce pain, restore function, and aid recovery). Further investigations are necessary to confirm these results in injured tissues. PMID- 24781889 TI - Impaired aerobic function in patients with cystic fibrosis during ramp exercise. AB - PURPOSE: This study aimed to document the matching of muscle O2 delivery to O2 use in young patients with cystic fibrosis (CF) from muscle deoxygenation (HHb) dynamics during ramp exercise. METHODS: Ten patients with stable, mild-to moderate CF (12.7 +/- 2.8 yr) and 10 healthy controls (CON, 12.8 +/- 2.8 yr) completed a combined ramp and supramaximal cycling test to determine maximal O2 uptake (VO2max). Changes in gas exchange and ventilation, HR, and m. vastus lateralis HHb (near-infrared spectroscopy) were assessed. Delta[HHb]-work rate and Delta[HHb]-VO2 profiles were normalized and fit using a sigmoid function. RESULTS: Aerobic function was impaired in CF, indicated by very likely reduced fat-free mass-normalized VO2max (mean difference, +/-90% confidence interval: 7.9 mL.kg.min, +/-6.1), very likely lower VO2 gain (-1.44 mL.min.W, +/-1.12), and a likely slower VO2 mean response time (11 s, +/-13). An unclear effect was found upon the absolute and relative work rate (-14 W, +/-44, and -0.7% peak power output, +/-12.0, respectively) and the absolute and percentage (-0.10 L.min, +/ 0.43, and 3.3% VO2max, +/-6.0) VO2 corresponding to 50% Delta[HHb] amplitude, respectively, between groups. However, arterial oxygen saturation (SpO2) was very likely lower in CF (-1%, +/-1) and demonstrated moderate-to-very large relations with parameters of aerobic function. CONCLUSIONS: Young patients with mild-to moderate CF present with impaired aerobic function during ramp incremental cycling exercise. Because the rate of fractional O2 extraction during ramp cycling exercise was not altered by CF, yet SpO2 was lower, the present findings support the notion of centrally mediated oxygen delivery to principally limit the aerobic function of pediatric patients with CF during ramp incremental cycling exercise. PMID- 24781890 TI - Children's physical activity assessed with wrist- and hip-worn accelerometers. AB - BACKGROUND: Recently, triaxial raw acceleration accelerometers have become available from GENEActiv and ActiGraph; both are designed for wrist and hip wear. It is important to determine whether the output from these monitors is comparable with the wealth of data already collected from the hip-worn, epoch-based, uniaxial ActiGraph. PURPOSE: This study aimed to assess the concurrent validity of measures of total activity and time spent at different activity intensities from the GENEActiv relative to the ActiGraph GT3X+. METHODS: Fifty-eight children age 10-12 yr wore two accelerometers at the hip (ActiGraph GT3X+ and GENEActiv) and one at the wrist (GENEActiv) for 7 d. Wear time was matched for all monitors before analysis. RESULTS: Mean daily accelerometer output, time spent sedentary, and time in moderate-to-vigorous physical activity (MVPA) from the hip- or wrist worn GENEActiv were strongly correlated with the corresponding output from the hip-worn ActiGraph (r > 0.83, P < 0.001). However, less time was estimated to be sedentary and more time was estimated to be MVPA using the hip- or wrist-worn GENEActiv (Phillips cut points) than that when using the Evenson vertical axis cut points with the hip-worn ActiGraph. Output from the vertical axis ActiGraph cut points could be predicted with 95% limits of agreement, equating to 23%-28% and 33%-35% of the mean value, by the hip- and wrist-worn GENEActiv, respectively. CONCLUSIONS: The assessment of children's activity level, time spent sedentary, and time in MVPA estimated from the hip- or wrist-worn GENEActiv seems to be comparable with that of the uniaxial ActiGraph. On the basis of the strong linear correlations, ActiGraph output can be predicted from the hip- or wrist-worn GENEActiv for comparative purposes at the group level. However, because of relatively wide limits of agreement, individual-level comparisons are not recommended. PMID- 24781891 TI - Reliability of maximal cardiopulmonary exercise testing in men with prostate cancer. AB - PURPOSE: To accurately assess exercise interventions and to evaluate acute and chronic cardiovascular effects in patients with early-stage cancer, consistently reliable functional outcome measures must be obtained. An incremental cardiopulmonary exercise test (CPET) with gas exchange measurement to assess peak oxygen consumption (VO2peak) provides the gold standard outcome of cardiorespiratory fitness. METHODS: In the context of a randomized controlled trial, 40 patients with prostate cancer (mean age, 59 +/- 7 yr) after radical prostatectomy performed two maximal CPET within 5.6 +/- 5.5 d of each other. Incremental treadmill tests were performed in the morning under identical laboratory conditions. Reliability and within-subject variability from test 1 to test 2 for peak and submaximal variables were assessed by correlation coefficients, intraclass correlations (ICC), Bland-Altman plots, coefficient of variation, and paired t-tests. RESULTS: There was high reliability between CPET for VO2peak (r = 0.92; P < 0.001; ICC, 0.900), ventilatory threshold (r = 0.88; P < 0.001; ICC, 0.927), minute ventilation-carbon dioxide production relation (VE/VCO2) (r = 0.86; P < 0.001; ICC, 0.850), and peak heart rate (r = 0.95; P < 0.001; ICC, 0.944). However, high within-subject variability was observed for all CPET parameters (mean coefficient of variation, 4.7%). Compared with those for test 1, significantly higher mean values were observed for VO2peak (27.0 +/- 5.6 vs 28.1 +/- 5.3 mL.kg.min, P < 0.05), ventilatory threshold (1.91 +/- 0.5 vs 1.97 +/- 0.4 L.min, P < 0.05), and VE/VCO2 (31.3 +/- 5.8 vs 32.8 +/- 3.4, P < 0.05) in test 2. CONCLUSIONS: These findings indicate the presence of significant, and potentially clinically important, variability in CPET procedures in men with clinically localized prostate cancer and have important implications for the application and use of CPET to evaluate the efficacy of interventions to improve aerobic capacity in the oncology setting. PMID- 24781892 TI - Neighborhood environments and objectively measured physical activity in 11 countries. AB - PURPOSE: Environmental changes are potentially effective population-level physical activity (PA) promotion strategies. However, robust multisite evidence to guide international action for developing activity-supportive environments is lacking. We estimated pooled associations of perceived environmental attributes with objectively measured PA outcomes, between-site differences in such associations, and the extent to which perceived environmental attributes explain between-site differences in PA. METHODS: This was a cross-sectional study conducted in 16 cities located in Belgium, Brazil, Colombia, Czech Republic, Denmark, China, Mexico, New Zealand, Spain, United Kingdom, and United States of America. Participants were 6968 adults residing in administrative units stratified by socioeconomic status and transport-related walkability. Predictors were 10 perceived neighborhood environmental attributes. Outcome measures were accelerometry-assessed weekly minutes of moderate-to-vigorous PA (MVPA) and meeting the PA guidelines for cancer/weight gain prevention (420 min.wk of MVPA). RESULTS: Most perceived neighborhood attributes were positively associated with the PA outcomes in the pooled, site-adjusted, single-predictor models. Associations were generalizable across geographical locations. Aesthetics and land use mix-access were significant predictors of both PA outcomes in the fully adjusted models. Environmental attributes accounted for within-site variability in MVPA, corresponding to an SD of 3 min.d or 21 min.wk. Large between-site differences in PA outcomes were observed; 15.9%-16.8% of these differences were explained by perceived environmental attributes. All neighborhood attributes were associated with between-site differences in the total effects of the perceived environment on PA outcomes. CONCLUSIONS: Residents' perceptions of neighborhood attributes that facilitate walking were positively associated with objectively measured MVPA and meeting the guidelines for cancer/weight gain prevention at the within- and between-site levels. Associations were similar across study sites, lending support for international recommendations for designing PA-friendly built environments. PMID- 24781893 TI - A prospective study of sedentary behavior and changes in the body mass index distribution. AB - PURPOSE: We aimed to determine whether baseline sedentary behavior was associated with changes in body mass index (BMI) over 9 yr. METHODS: Participants were enrolled into the National Institutes of Health American Association of Retired Persons (NIH-AARP) Diet and Health study in 1995-1996 (median age, 63 yr), and BMI was reported at baseline and 9 yr later (n = 158,436). Sitting time (<3 (referent), 3-4, 5-6, 7-8, or >=9 h.d), television viewing (none, <1, 1-2, 3-4, 5 6, 7-8, or >=9 h.d), and the covariates (age, sex, race, education, smoking, moderate-to-vigorous physical activity, caloric intake, and sleep duration) were reported at baseline. We used longitudinal quantile regression to model changes at the 10th, 25th, 50th, 75th, and 90th BMI percentiles. RESULTS: More sitting at baseline was associated with additional increases in BMI over time, and the association was stronger at the upper BMI percentiles (e.g., <3 (referent) vs 5-6 h.d of sitting additional increases: 50th percentile = 0.41 kg.m and 95% confidence interval (CI) = 0.34-0.48; 90th percentile = 0.85 kg.m and 95% CI = 0.72-0.98). Similar associations were observed between more television viewing at baseline and additional increases in BMI over time (e.g., no television (referent) vs 3-4 h.d of television: 50th percentile = 1.96 kg.m and 95% CI = 1.77-2.15; 90th percentile = 2.11 kg.m and 95% CI = 1.49-2.73). CONCLUSIONS: Reducing sedentary behavior could help prevent an increase in BMI in adulthood especially at the upper percentiles of the BMI distribution and thereby reduce the prevalence of obesity. PMID- 24781894 TI - Utility of actiwatch sleep monitor to assess waking movement behavior in older women. AB - PURPOSE: Wrist-worn accelerometer devices measure sleep in free-living settings. Few studies, however, have investigated whether these devices can also measure waking movement behavior (e.g., total movement volume, physical activity). The purpose of this study was to investigate the ability of a wrist-worn Actiwatch 2 sleep monitor to rank total movement volume and physical activity levels compared with a waist-worn ActiGraph GT1M accelerometer and self-reported leisure time physical activity, respectively. In addition, we compared temporally matched activity measured via the ActiGraph GT1M and Actiwatch 2 over the study week. METHODS: A subset of women from the Healthy Women Study (n = 145; age, 73.3 +/- 1.7 yr) wore an Actiwatch 2 on their nondominant wrist and an ActiGraph GT1M on their dominant hip for seven consecutive days. Participants recorded their leisure time physical activity in a 7-d diary and completed the past year version of the Modifiable Activity Questionnaire. Analyses were conducted for all wake periods and separately for active periods when both devices were worn. RESULTS: Spearman rank-order correlation coefficients for total movement volume between the Actiwatch 2 and ActiGraph GT1M were significant for wake periods (r = 0.47, P < 0.001) and, to a lesser extent, for active periods (r = 0.26, P < 0.01). However, the Actiwatch 2 did not rank participant's physical activity levels similarly to self-reported leisure time physical activity estimates (kappa <= 0.05, P > 0.05). Multilevel model analyses comparing temporally matched activity measured via the ActiGraph GT1M and Actiwatch 2 suggest that the two devices yielded similar levels of activity during wake periods (B = 0.90; SE, 0.008; P < 0.001) and during active periods (B = 0.81; SE, 0.01; P < 0.001). CONCLUSIONS: A wrist-worn Actiwatch 2 may be useful for ranking total movement volume and for assessing the pattern of activity over a day in older women. However, our data do not support using a wrist-worn Actiwatch 2 device for measuring physical activity. PMID- 24781895 TI - Beetroot juice supplementation does not improve performance of elite 1500-m runners. AB - PURPOSE: Dietary nitrate supplementation with beetroot juice (BR) has received widespread attention as an ergogenic aid. However, recent evidence in well trained cyclists has not consistently reported improved cycling economy or performance. The present study examined the effects of acute and chronic BR supplementation on VO2 during submaximal running and 1500-m time trial (TT) performance of elite distance runners. METHODS: Eight male 1500-m runners (VO2peak, 80 +/- 5 mL.kg.min; 1500-m personal best, 3:56 +/- 9 s) participated in this study. In a randomized, double-blind, crossover design, subjects supplemented with BR or a nitrate-free BR placebo (PL) for 8 d separated by at least 1 wk. On days 1 (acute) and 8 (chronic), subjects ingested 210 mL of BR (19.5-mmol nitrate) or PL and completed a submaximal treadmill run and 1500-m TT on an indoor 200-m track. RESULTS: Plasma nitrate increased from 37 +/- 15 to 615 +/- 151 MUM (acute) and 870 +/- 259 MUM (chronic) after BR supplementation. There were no VO2 differences between conditions at 50%, 65%, and 80% VO2peak (acute PL, 4194 +/- 90 mL.min; chronic PL, 4216 +/- 95 mL.min; acute BR, 4192 +/- 113 mL.min; chronic BR, 4299 +/- 92 mL.min). The 1500-m TT was unaffected by acute or chronic BR supplementation (acute PL, 4:10.4 min:s +/- 2.5 s; chronic PL, 4:11.4 min:s +/- 2.7 s; acute BR, 4:10.7 min:s +/- 1.5 s; chronic BR, 4:10.5 min:s +/- 2.2 s). However, two subjects improved their TT performance after acute (5.8 and 5.0 s) and chronic BR supplementation (7.0 and 0.5 s). CONCLUSIONS: Acute and chronic BR supplementation did not reduce running VO2 or improve 1500-m TT performance of a group of elite distance runners, but two responders to BR were identified. PMID- 24781896 TI - Linear/nonlinear relations of activity and fitness with children's academic achievement. AB - A growing research base suggests that the benefits of physical activity (PA) and aerobic fitness for children extend beyond overall health/well-being to include academic achievement (AA). The majority of research studies on relations of PA and fitness with AA have used linear-only analytic approaches, thereby precluding the possibility that PA and fitness could have a differing effect on AA for those more/less active or fit. OBJECTIVE: This study aimed to evaluate both linear and nonlinear associations of PA and aerobic fitness with children's AA among a sample of 687 second and third grade students from 17 Midwest schools. STUDY DESIGN: Using baseline data (fall 2011) from a larger 3-yr intervention trial, multilevel regression analyses examined the linear and nonlinear associations of AA with PA and with progressive aerobic cardiovascular endurance run (PACER) laps (i.e., aerobic fitness), controlling for relevant covariates. RESULTS: Fitness, but not PA, had a significant quadratic association with both spelling and mathematics achievement. Results indicate that 22-28 laps on the PACER was the point at which the associated increase in achievement per lap plateaued for spelling and mathematics. CONCLUSIONS: Increasing fitness could potentially have the greatest effect on children's AA for those below the 50th fitness percentile on the PACER. PMID- 24781897 TI - Beyond Self-Protection: Self-Affirmation Benefits Hedonic and Eudaimonic Well Being. AB - Limited work has examined how self-affirmation might lead to positive outcomes beyond the maintenance of a favorable self-image. To address this gap in the literature, we conducted two studies in two cultures to establish the benefits of self-affirmation for psychological well-being. In Study 1, South Korean participants who affirmed their values for 2 weeks showed increased eudaimonic well-being (need satisfaction, meaning, and flow) relative to control participants. In Study 2, U.S. participants performed a self-affirmation activity for 4 weeks. Extending Study 1, after 2 weeks, self-affirmation led both to increased eudaimonic well-being and hedonic well-being (affect balance). By 4 weeks, however, these effects were non-linear, and the increases in affect balance were only present for vulnerable participants-those initially low in eudaimonic well-being. In sum, the benefits of self-affirmation appear to extend beyond self-protection to include two types of well-being. PMID- 24781898 TI - Whether Social Schema Violations Help or Hurt Creativity Depends on Need for Structure. AB - Although people and events that disconfirm observers' expectancies can increase their creativity, sometimes such social schema violations increase observers' rigidity of thought and undermine creative cognition. Here we examined whether individual differences in the extent to which people prefer structure and predictability determine whether social schema violations facilitate or hamper creativity. Participants in Study 1 formed impressions of a schema-inconsistent female mechanic (vs. a schema-consistent male mechanic). Following schema inconsistent rather than -consistent information, participants low (high) in need for structure showed better (impeded) creative performance. Participants in Study 2 memorized a series of images in which individuals were placed on a schema inconsistent (vs. consistent) background (e.g., an Eskimo on the desert vs. on a snowy landscape). Following schema-inconsistent imagery, participants low (high) in need for structure increased (decreased) divergent thinking. PMID- 24781899 TI - Discovery of a SAR11 growth requirement for thiamin's pyrimidine precursor and its distribution in the Sargasso Sea. AB - Vitamin traffic, the production of organic growth factors by some microbial community members and their use by other taxa, is being scrutinized as a potential explanation for the variation and highly connected behavior observed in ocean plankton by community network analysis. Thiamin (vitamin B1), a cofactor in many essential biochemical reactions that modify carbon-carbon bonds of organic compounds, is distributed in complex patterns at subpicomolar concentrations in the marine surface layer (0-300 m). Sequenced genomes from organisms belonging to the abundant and ubiquitous SAR11 clade of marine chemoheterotrophic bacteria contain genes coding for a complete thiamin biosynthetic pathway, except for thiC, encoding the 4-amino-5-hydroxymethyl-2-methylpyrimidine (HMP) synthase, which is required for de novo synthesis of thiamin's pyrimidine moiety. Here we demonstrate that the SAR11 isolate 'Candidatus Pelagibacter ubique', strain HTCC1062, is auxotrophic for the thiamin precursor HMP, and cannot use exogenous thiamin for growth. In culture, strain HTCC1062 required 0.7 zeptomoles per cell (ca. 400 HMP molecules per cell). Measurements of dissolved HMP in the Sargasso Sea surface layer showed that HMP ranged from undetectable (detection limit: 2.4 pM) to 35.7 pM, with maximum concentrations coincident with the deep chlorophyll maximum. In culture, some marine cyanobacteria, microalgae and bacteria exuded HMP, and in the Western Sargasso Sea, HMP profiles changed between the morning and evening, suggesting a dynamic biological flux from producers to consumers. PMID- 24781900 TI - Inference of interactions in cyanobacterial-heterotrophic co-cultures via transcriptome sequencing. AB - We used deep sequencing technology to identify transcriptional adaptation of the euryhaline unicellular cyanobacterium Synechococcus sp. PCC 7002 and the marine facultative aerobe Shewanella putrefaciens W3-18-1 to growth in a co-culture and infer the effect of carbon flux distributions on photoautotroph-heterotroph interactions. The overall transcriptome response of both organisms to co cultivation was shaped by their respective physiologies and growth constraints. Carbon limitation resulted in the expansion of metabolic capacities, which was manifested through the transcriptional upregulation of transport and catabolic pathways. Although growth coupling occurred via lactate oxidation or secretion of photosynthetically fixed carbon, there was evidence of specific metabolic interactions between the two organisms. These hypothesized interactions were inferred from the excretion of specific amino acids (for example, alanine and methionine) by the cyanobacterium, which correlated with the downregulation of the corresponding biosynthetic machinery in Shewanella W3-18-1. In addition, the broad and consistent decrease of mRNA levels for many Fe-regulated Synechococcus 7002 genes during co-cultivation may indicate increased Fe availability as well as more facile and energy-efficient mechanisms for Fe acquisition by the cyanobacterium. Furthermore, evidence pointed at potentially novel interactions between oxygenic photoautotrophs and heterotrophs related to the oxidative stress response as transcriptional patterns suggested that Synechococcus 7002 rather than Shewanella W3-18-1 provided scavenging functions for reactive oxygen species under co-culture conditions. This study provides an initial insight into the complexity of photoautotrophic-heterotrophic interactions and brings new perspectives of their role in the robustness and stability of the association. PMID- 24781902 TI - Prophylactic defibrillators in patients with severe chronic kidney disease. PMID- 24781903 TI - Production and consumption of nitrous oxide in nitrate-ammonifying Wolinella succinogenes cells. AB - Global warming is moving more and more into the public consciousness. Besides the commonly mentioned carbon dioxide and methane, nitrous oxide (N2O) is a powerful greenhouse gas in addition to its contribution to depletion of stratospheric ozone. The increasing concern about N2O emission has focused interest on underlying microbial energy-converting processes and organisms harbouring N2O reductase (NosZ), such as denitrifiers and ammonifiers of nitrate and nitrite. Here, the epsilonproteobacterial model organism Wolinella succinogenes is investigated with regard to its capacity to produce and consume N2O during growth by anaerobic nitrate ammonification. This organism synthesizes an unconventional cytochrome c nitrous oxide reductase (cNosZ), which is encoded by the first gene of an atypical nos gene cluster. However, W. succinogenes lacks a nitric oxide (NO)-producing nitrite reductase of the NirS- or NirK-type as well as an NO reductase of the Nor-type. Using a robotized incubation system, the wild-type strain and suitable mutants of W. succinogenes that either produced or lacked cNosZ were analysed as to their production of NO, N2O and N2 in both nitrate sufficient and nitrate-limited growth medium using formate as electron donor. It was found that cells growing in nitrate-sufficient medium produced small amounts of N2O, which derived from nitrite and, most likely, from the presence of NO. Furthermore, cells employing cNosZ were able to reduce N2O to N2. This reaction, which was fully inhibited by acetylene, was also observed after adding N2O to the culture headspace. The results indicate that W. succinogenes cells are competent in N2O and N2 production despite being correctly grouped as respiratory nitrate ammonifiers. N2O production is assumed to result from NO detoxification and nitrosative stress defence, while N2O serves as a terminal electron acceptor in anaerobic respiration. The ecological implications of these findings are discussed. PMID- 24781904 TI - [On rats, bugs, and mosquitoes. "Urban pests" and vectors play an increasingly important role in Germany again]. PMID- 24781901 TI - Reprograming of gut microbiome energy metabolism by the FUT2 Crohn's disease risk polymorphism. AB - Fucosyltransferase 2 (FUT2) is an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. The H antigen is an oligosaccharide moiety that acts as both an attachment site and carbon source for intestinal bacteria. Non-secretors, who are homozygous for the loss-of-function alleles of FUT2 gene (sese), have increased susceptibility to Crohn's disease (CD). To characterize the effect of FUT2 polymorphism on the mucosal ecosystem, we profiled the microbiome, meta-proteome and meta-metabolome of 75 endoscopic lavage samples from the cecum and sigmoid of 39 healthy subjects (12 SeSe, 18 Sese and 9 sese). Imputed metagenomic analysis revealed perturbations of energy metabolism in the microbiome of non-secretor and heterozygote individuals, notably the enrichment of carbohydrate and lipid metabolism, cofactor and vitamin metabolism and glycan biosynthesis and metabolism-related pathways, and the depletion of amino-acid biosynthesis and metabolism. Similar changes were observed in mice bearing the FUT2(-/-) genotype. Metabolomic analysis of human specimens revealed concordant as well as novel changes in the levels of several metabolites. Human metaproteomic analysis indicated that these functional changes were accompanied by sub-clinical levels of inflammation in the local intestinal mucosa. Therefore, the colonic microbiota of non-secretors is altered at both the compositional and functional levels, affecting the host mucosal state and potentially explaining the association of FUT2 genotype and CD susceptibility. PMID- 24781905 TI - [Public health pests. Arthropods and rodents as causative disease agents as well as reservoirs and vectors of pathogens]. AB - Globally, infectious diseases pose the most important cause of death. Among known human pathogenic diseases, approximately 50 % are zoonoses. When considering emerging infectious diseases separately 73 % currently belong to the group of zoonoses. In Central Europe, hard ticks show by far the biggest potential as vectors of agents of human disease. Lyme borreliosis, showing an estimated annual incidence between 60,000 and 214,000 cases is by far the most frequent tick-borne disease in Germany. Continually, formerly unknown disease agents could be discovered in endemic vector species. Additionally, introduction of new arthropod vectors and/or agents of disease occur constantly. Recently, five mosquito species of the genus Aedes have been newly introduced to Europe where they are currently spreading in different regions. Uncommon autochthonous transmission of dengue and chikungunya fever viruses in Southern Europe could be directly linked to these vector species and of these Ae. albopictus and Ae. japonicus are currently reported to occur in Germany. The German Protection against Infection Act only covers the control of public health pests which are either active hematophagous vectors or mechanical transmitters of agents of diseases. Use of officially recommended biocidal products aiming to interrupt transmission cycles of vector-borne diseases, is confined to infested buildings only, including sewage systems in the case of Norway rat control. Outdoor vectors, such as hard ticks and mosquitoes, are currently not taken into consideration. Additionally, adjustments of national public health regulations, detailed arthropod vector and rodent reservoir mapping, including surveillance of vector-borne disease agents, are necessary in order to mitigate future disease risks. PMID- 24781906 TI - [Strategies for sustainable management of commensal rodents. Definitions of control objectives at communal level]. AB - The German Act on the Prevention and Control of Infectious Diseases in Man (Infektionsschutzgesetz, IfSG) provides a legal framework for activities and responsibilities concerning communal rodent control. However, actual governance of communal rodent control is relatively heterogeneous, as federal states (Bundeslander) have different or even no regulations for prevention and management of commensal rodent infestations (e.g. brown rats, roof rats and house mice). Control targets and control requirements are rarely precisely defined and often do not go beyond general measures and objectives. Although relevant regulations provide information about agreed preventive measures against rodents, the concept of sustainability is not expressed as such. A centrally managed database-supported municipal rodent control is a key factor for sustainability because it allows a systematic and analytical approach to identify and reduce rodent populations. The definition of control objectives and their establishment in legal decrees is mandatory for the implementation of a sustainable management strategy of rodent populations at a local level. Systematic recording of rodent infestations through municipal-operated monitoring provides the essential data foundation for a targeted rodent management which is already implemented in some German and European cities and nationwide in Denmark. A sustainable rodent management includes a more targeted rodenticide application which in the long term will lead to an overall reduction of rodenticide use. Thus, the benefits of sustainable rodent management will be a reduction of rodenticide exposure to the environment, prevention of resistance and long-term economical savings. PMID- 24781907 TI - [Monitoring populations of rodent reservoirs of zoonotic diseases. Projects, aims and results]. AB - Rodents can harbor and transmit pathogens that can cause severe disease in humans, companion animals and livestock. Such zoonotic pathogens comprise more than two thirds of the currently known human pathogens. The epidemiology of some zoonotic pathogens, such as hantaviruses, can be linked to the population dynamics of the rodent host. In this case, during an outbreak of the rodent host population many human infections may occur. In other rodent-borne zoonotic diseases such phenomena are not known and in many cases the rodent host specificity of a given pathogen is unclear. The monitoring of relevant rodent populations and of the rodent-borne zoonotic pathogens is essential to (1) understand the distribution and epidemiology of pathogens and (2) develop forecasting tools to predict outbreaks of zoonoses. Presently, there are no systematic long-term monitoring programs in place for zoonoses in Germany. Rodent monitoring activities are largely restricted to the plant protection sector, such as for the common vole (Microtus arvalis) and forest-damaging rodents. However, during the last 10-15 years a number of specific research projects have been initiated and run for a few years and Norway rat (Rattus norvegicus) monitoring has been implemented in Hamburg and Lower Saxony. Based on close cooperation of federal and state authorities and research institutions these efforts could be utilized to gain information about the distribution and importance of rodent borne zoonoses. Nevertheless, for the integration of rodent population dynamics and zoonotic disease patterns and especially for developing predictive models, long-term monitoring is urgently required. To establish a systematic long-term monitoring program, existing networks and cooperation need to be used, additional collaborators (e.g., pest control operators) should be included and synergetic effects of different scientific fields should be utilized. PMID- 24781908 TI - [Rodenticide resistance and consequences]. AB - Resistance to anticoagulant rodenticides, such as warfarin was first described in 1958. Polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene and respective substitutions of amino acids in the VKOR enzyme are the major cause for rodenticide resistance. Resistant Norway rats in Germany are characterized by the Tyr139Cys genotype, which is spread throughout the northwest of the country. Resistant house mice with the VKOR variants Tyr139Cys, Leu128Ser and Arg12Trp/Ala26Ser/Ala48Thr/Arg61Leu (spretus type) are distributed over a number of locations in Germany. Resistance can reduce management attempts with consequences for stored product protection, hygiene and animal health. Anticoagulants of the first generation (warfarin, chlorophacinone, coumatetralyl) as well as bromadiolone and difenacoum are not an option for the control of resistant Norway rats. The same applies for house mice whereby the tolerance to compounds can be different between local incidences. Due to the higher toxicity and tendency to persist, the most potent anticoagulant rodenticides brodifacoum, flocoumafen and difethialone should be applied but only where resistance is known. In other cases less toxic anticoagulants should be preferred for rodent management in order to mitigate environmental risks. Resistance effects of further VKOR polymorphisms and their combinations, the spread of resistant rats and conditions supporting and reducing resistance should be investigated in order to improve resistance management strategies. PMID- 24781909 TI - [The worldwide expansion of bed bugs also constitutes a problem in Germany]. AB - Worldwide, reports of the spread of the bed bugs Cimex lectularius and C. hemipterus (in Australia) are increasing. Irrespective of hygiene conditions, the insects can be especially found in hotels and hostels as well as in other holiday accommodation, health facilities, transport and in the secondhand trade. From these localities the insects spread to private households. A bed bug infestation may well have health consequences and constitutes a heavy burden for those affected. The global spread of bed bugs appears to be multifactorially conditioned and the causes are controversially discussed. The spread could be explained, among other things, by the increase in international travel and trade in used goods. The limited availability of insecticides with long-term effects and the development of resistance to available agents could play a crucial role. In the absence of official data it is impossible to quantify the extent of the spread in Germany but pest controllers and public authorities report increasing numbers of cases and problems in control. As in other countries the latter appear to be caused among other things by the development of drug resistance (particularly pyrethroids). Against this background, prevention and thus the education of the public on the habits and dissemination routes of these insects remain crucial in order to counteract the spread of bed bugs. PMID- 24781910 TI - [Mosquitoes as vectors for exotic pathogens in Germany]. AB - As a result of intensified globalization of international trade and of substantial travel activities, mosquito-borne exotic pathogens are becoming an increasing threat for Europe. In Germany some 50 different mosquito species are known, several of which have vector competence for pathogens. During the last few years a number of zoonotic arboviruses that are pathogenic for humans have been isolated from mosquitoes in Germany including Usutu, Sindbis and Batai viruses. In addition, filarial worms, such as Dirofilaria repens have been repeatedly detected in mosquitoes from the federal state of Brandenburg. Other pathogens, in particular West Nile virus, are expected to emerge sooner or later in Germany as the virus is already circulating in neighboring countries, e.g. France, Austria and the Czech Republic. In upcoming years the risk for arbovirus transmission might increase in Germany due to increased occurrence of new so-called "invasive" mosquito species, such as the Asian bush mosquito Ochlerotatus japonicus or the Asian tiger mosquito Aedes albopictus. These invasive species are characterized by high vector competence for a broad range of pathogens and a preference for human blood meals. For risk assessment, a number of mosquito and pathogen surveillance projects have been initiated in Germany during the last few years; however, mosquito control strategies and plans of action have to be developed and put into place to allow early and efficient action against possible vector-borne epidemics. PMID- 24781911 TI - [Threat of transmission of infectious pathogens by Ixodes ricinus ticks in Germany]. AB - Tick-transmitted diseases are of great importance for the general health of the German population. Several viruses, such as tick-borne encephalitis virus (TBEV), Uukuniemi virus, Tribec virus, Eyach virus or bacteria, such as Borrelia, Rickettsiae, Francisella tularensis, Anaplasma phagocytophilum, Candidatus Neoehrlichia mikurensis (CNM) and Coxiella burnetii were detected in the most prominent tick in Germany, the hard tick Ixodes ricinus. While infections, such as TBE and Lyme disease are well known, other infections are hardly known even among experts. Although there have been a few descriptions of isolated cases in Germany, a systematic investigation regarding the distribution and the pathogenic potential of these pathogens is still lacking. In particular elderly people and people with underlying diseases seem to be mostly affected. The importance of new infectious disease agents, such as Candidatus Neoehrlichia mikurensis but also of long known pathogens, such as Rickettsiae still remains unclear, while some of them could be detected in 20 % of investigated ticks. Whether climate change contributes to the further distribution of these infectious agents remains unclear and requires further investigation. The increasing initiatives to create natural environments and the trend towards spending more time in nature for recreational activities will increase the danger of coming into contact with ticks and the respective infectious agents. Considering these circumstances an increase of diseases caused by these pathogens is to be expected. PMID- 24781912 TI - [The ecology of ticks, tick-borne diseases and biological tick control in Baden Wurttemberg]. AB - Ticks and tick-borne diseases are of great significance for the health of humans and animals. However, the factors influencing their distribution and dynamics are inadequately known. In a project financed by the Baden-Wurttemberg Ministry of the Environment, Climate and Energy Industry, as part of the program BWPLUS, interdisciplinary specialists work together to determine the influence of weather, (micro)climate, habitat, land use, human activities, and the population dynamics of host animals on the distribution and abundance of ticks and the diseases that they transmit in Baden-Wurttemberg. The project comprises four modules: the large-scale distribution of ticks in Baden-Wurttemberg (module 1), detailed studies of host-tick-pathogen interaction in relation to the microclimate (module 2), and the spatial occurrence of important tick-borne pathogens (module 3). The fourth module involves the comprehensive analysis and synthesis of all data in order to determine the relative importance of the factors studied and to develop a risk model. Recently, intensive investigations into tick control have been undertaken using various entomopathogenic fungi and nematodes as well as a parasitoid wasp. Our aim was to determine whether these natural enemies could be used to effectively reduce the number of free-living ticks. PMID- 24781913 TI - [Important vector-borne infectious diseases among humans in Germany. Epidemiological aspects]. AB - Vector-borne infections pathogenic to humans play an important role in Germany. The relevant zoonotic pathogens are either endemic throughout Germany (e.g. Borrelia burgdorferi sensu latu) or only in specific regions, e.g. tick-borne encephalitis (TBE) virus and hantavirus. They cause a substantial burden of disease. Prevention and control largely rely on public advice and the application of personal protective measures (e.g. TBE virus vaccination and protection against vectors). High quality surveillance and targeted epidemiological studies are fundamental for the evaluation of temporal and spatial risks of infection and the effectiveness of preventive measures. Aside from endemic pathogens, vector borne infections acquired abroad, mostly transmitted by mosquitoes, have to be systematically and intensively monitored as well, to assess the risk of infection for German residents traveling abroad and to adequately evaluate the risk of autochthonous transmission. Related issues, such as invasive species of mosquitoes in Germany and climate change, have to be taken into consideration. Such pathogens include West Nile, dengue and chikungunya viruses, as well as malaria parasites (Plasmodium species). The article presents an overview of the epidemiological situation of selected relevant vector-borne infections in Germany. PMID- 24781914 TI - [On the relevance of the official lists for notified products and measures for disinfection, disinfestation and control of vertebrate pests ordered by an authority on the legal basis of S 18 IfSG (German Protection against Infection Act)]. AB - In order to protect human health against communicable diseases, the German Protection against Infection Act (IfSG) requires the use of officially approved products and methods for officially ordered disinfection, disinfestation (control of arthropods) as well as measures for the management of vertebrate pests that spread pathogens. Official approval is granted by registration in lists published by the responsible federal health authorities and only for products and methods that have been tested and found to be sufficiently effective and do not have an unacceptable impact on health and the environment (S 18 IfSG). It is not compulsory for manufacturers to have their products and methods listed in accordance with S 18 IfSG. In particular listing is not a prerequisite for access to the German market. Users are free to choose a product as long as no officially ordered measure, i.e. disinfection, disinfestation or measures against vertebrate pests, according to S 18 IfSG applies. However, it is highly recommended to use approved products included in the abovementioned lists even for routine application, as these registered products and methods have been tested, i.e. the efficacy has been proven by means of specific, recognized and quality assured testing procedures or by expert reports which have been confirmed by independent institutions. PMID- 24781915 TI - [Health risks from pest control products]. AB - According to European biocide legislation, pest control products require assessment and authorization by the responsible national or European authorities. Biocidal products can only be authorized if they have no unacceptable effects on human health. The health risk assessment performed for authorization comprises (a) the derivation of reference values for the active substances and substances of concern contained in the biocidal product and (b) an exposure assessment. These parameters are required for risk characterization. No unacceptable health risks are expected if the determined exposure is less than the relevant reference value. In addition, the toxicological information is used for classification of the biocidal product. The assessment may, where necessary, result in specific conditions for use or other restrictions aimed at minimizing risk. The risk to human health from pest control products is mainly based on the toxicological properties of their active substances. Commonly, the coformulants used in pest control products are of less concern than the active substances (e.g., food ingredients and animal feed products). For example, most rodenticides belong to the group of anticoagulants, which are also effective in humans. Regarding intoxications through insecticides, the group of pyrethroids is of particular importance. Fumigants containing metal phosphides, hydrogen cyanide, or sulfuryl difluoride are particularly toxic. This toxicity is linked to the high acute inhalation toxicity of the gaseous active substances themselves or, in the case of phosphides, of the released gas phosphane. The aim of health risk assessment for the authorization of biocidal products is to ensure their safe application for users and all other persons involved, assuming an adequate and label compliant use. PMID- 24781916 TI - [Cockroaches and co. The role of health pests as allergen source]. AB - In most of the cases health pests are carriers of pathogens or parasites which have a negative impact on human health or affect the health of other mammals. What is lesser known is that they can also act as allergens. Most of the health pests in this sense belong to the arthropods, such as cockroaches (Blattaria), mosquitos (Culiciformia), lice (Pediculus humanus corporis), fleas (Siphonaptera) and ticks (Argasidae). In the group of vertebrates rats (Rattus norvegicus and Rattus rattus), house mice (Mus musculus) and pigeons (Columba livia domestica) are also classified as health pests. Also storage pests which are not carriers of pathogens can induce secondary infestation with hygiene pests or molds and have an underestimated impact on human health. In this article selected examples of health pests and also storage pests as an allergen source are described, taking into account the sensitization prevalence and identified single allergens. PMID- 24781917 TI - Patient-reported outcomes and quality-of-life questionnaires in the assessment of rhinoconjunctivitis in childhood. AB - PURPOSE OF REVIEW: Rhinoconjunctivitis, and especially allergic rhinoconjunctivitis (ARC) are increasing in prevalence, progressively affecting the well being of more and more adults and children. Clinical trials using allergen immunotherapy (AIT), the sole causal treatment of allergies, are being conducted, but discussions on optimal patient-related outcomes (PROs) are still ongoing. RECENT FINDINGS: Almost all publications discussing PROs relate to adults. The authors comment on the importance of broader PROs when assessing the results of AIT trials, as focusing on only nasal symptom improvement and medication reduction does not capture the full benefit of AIT. Such intervention also improves comorbid allergic diseases and general well being. In studies on rhinoconjunctivitis in children, using medical treatment or immunotherapy published between November 2012 - February 2014 nasal symptom (and medication) scores were primary outcomes in 18 of 20 trials. Only two trials applied quality of-life questionnaires. SUMMARY: Clinical trials conducted in children with ARC should be interpreted with caution, as most currently used PROs give a restricted view, by not considering disease manifestations beyond nasal/ocular symptoms. To correctly estimate the full benefit of AIT in pediatric patients with ARC, broader PROs should be investigated, including disease control and quality of health. PMID- 24781919 TI - Pt2Ag acetylide-doped silica nanoparticles: enabling luminescence of Pt2Ag complexes in water and sensors for highly sensitive detection of cyanide anions. AB - Two novel luminescent hetero-trinuclear complexes [Pt2Ag(MU-dpppy)2(C=CC6H4R 4)4](ClO4) (R = H, 1; R = CH3, 2; dpppy = 2,6-bis(diphenylphosphino)pyridine) were synthesized by the self-assembly reaction between [Pt(C[triple bond, length as m-dash]CC6H4R-4)4](2-) and [Ag2(MU-dpppy)3](2+) and characterized by elemental analyses, electrospray ionization mass spectrometry, and (1)H NMR and (31)P{(1)H} NMR spectroscopy and by X-ray crystallography for complex 2. Two Pt2Ag complexes show strong luminescence in the solid state, but exhibit weak emission in CH2Cl2 solution and in acetonitrile-water (1 : 1, v : v) solution at room temperature. To overcome the limitations of low water solubility and weak emission in solutions, a new kind of luminescent Pt2Ag@SiO2 nanoparticles was prepared by incorporating the new Pt2Ag acetylides into monodisperse silica nanoparticles. It is noted that Pt2Ag@SiO2 nanoparticles exhibit strong luminescence in aqueous solution, and cyanide anions tend to decrease their luminescence intensity in NaHCO3-NaOH buffer solution. Based on this, a novel nanosensor for highly sensitive detection of cyanide anions was developed in the range of 0.1-10.0 MUM. PMID- 24781918 TI - Competition in notch signaling with cis enriches cell fate decisions. AB - Notch signaling is involved in cell fate choices during the embryonic development of Metazoa. Commonly, Notch signaling arises from the binding of the Notch receptor to its ligands in adjacent cells driving cell-to-cell communication. Yet, cell-autonomous control of Notch signaling through both ligand-dependent and ligand-independent mechanisms is known to occur as well. Examples include Notch signaling arising in the absence of ligand binding, and cis-inhibition of Notch signaling by titration of the Notch receptor upon binding to its ligands within a single cell. Increasing experimental evidences support that the binding of the Notch receptor with its ligands within a cell (cis-interactions) can also trigger a cell-autonomous Notch signal (cis-signaling), whose potential effects on cell fate decisions and patterning remain poorly understood. To address this question, herein we mathematically and computationally investigate the cell states arising from the combination of cis-signaling with additional Notch signaling sources, which are either cell-autonomous or involve cell-to-cell communication. Our study shows that cis-signaling can switch from driving cis-activation to effectively perform cis-inhibition and identifies under which conditions this switch occurs. This switch relies on the competition between Notch signaling sources, which share the same receptor but differ in their signaling efficiency. We propose that the role of cis-interactions and their signaling on fine-grained patterning and cell fate decisions is dependent on whether they drive cis-inhibition or cis activation, which could be controlled during development. Specifically, cis inhibition and not cis-activation facilitates patterning and enriches it by modulating the ratio of cells in the high-ligand expression state, by enabling additional periodic patterns like stripes and by allowing localized patterning highly sensitive to the precursor state and cell-autonomous bistability. Our study exemplifies the complexity of regulations when multiple signaling sources share the same receptor and provides the tools for their characterization. PMID- 24781920 TI - Fluorescence from bisaryl-substituted maleimide derivatives. AB - A series of bisaryl-substituted fluorescent maleimides was synthesized via the Heck arylation. The compounds showed broad fluorescence emission bands in the visible region, a large Stokes shift in polar solvents and emission quantum yields varying from 0.04 to 0.71, depending on the structure and solvent medium. The difference in dipole moments of ground and excited electronic states of about 12 Debye is ascribed to a substantial charge shift and push-pull character of bisaryl-substituted maleimides. The fluorescence decays of N-benzyl-3,4-bis(4 methoxyphenyl)-1H-pyrrole-2,5-dione (compound 5a) are biexponential with short (1.3-7.6 ns) and long lived (11.5-13.6 ns) components in polar solvents, but in 1,4-dioxane and THF the decays become single exponential. On the other hand, N benzyl-3-(4-methoxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrrole-2,5-dione (compound 5b) exhibited a biexponential decay in DMSO and in DMF with much shorter decay components, and such behavior indicated a charge shift process combined with solvent assisted proton transfer in the excited state. PMID- 24781921 TI - Recombinase-mediated reprogramming and dystrophin gene addition in mdx mouse induced pluripotent stem cells. AB - A cell therapy strategy utilizing genetically-corrected induced pluripotent stem cells (iPSC) may be an attractive approach for genetic disorders such as muscular dystrophies. Methods for genetic engineering of iPSC that emphasize precision and minimize random integration would be beneficial. We demonstrate here an approach in the mdx mouse model of Duchenne muscular dystrophy that focuses on the use of site-specific recombinases to achieve genetic engineering. We employed non-viral, plasmid-mediated methods to reprogram mdx fibroblasts, using phiC31 integrase to insert a single copy of the reprogramming genes at a safe location in the genome. We next used Bxb1 integrase to add the therapeutic full-length dystrophin cDNA to the iPSC in a site-specific manner. Unwanted DNA sequences, including the reprogramming genes, were then precisely deleted with Cre resolvase. Pluripotency of the iPSC was analyzed before and after gene addition, and ability of the genetically corrected iPSC to differentiate into myogenic precursors was evaluated by morphology, immunohistochemistry, qRT-PCR, FACS analysis, and intramuscular engraftment. These data demonstrate a non-viral, reprogramming-plus gene addition genetic engineering strategy utilizing site-specific recombinases that can be applied easily to mouse cells. This work introduces a significant level of precision in the genetic engineering of iPSC that can be built upon in future studies. PMID- 24781922 TI - Independent strong association of HLA-A*02:06 and HLA-B*44:03 with cold medicine related Stevens-Johnson syndrome with severe mucosal involvement. AB - Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucous membranes. Cold medicines including non-steroidal anti-inflammatory drugs (NSAIDs) and multi-ingredient cold medications are reported to be important inciting drugs. We used two sample sets of Japanese patients to investigate the association between HLA genotypes and cold medicine-related SJS/TEN (CM-SJS/TEN), including acetaminophen-related SJS/TEN (AR-SJS/TEN) with severe mucosal involvement such as severe ocular surface complications (SOC). HLA-A*02:06 was strongly associated with CM-SJS/TEN with SOC and AR-SJS/TEN with SOC. HLA-B*44:03 was also detected as an independent risk allele for CM-, including AR-SJS/TEN with SOC. Analyses using data obtained from CM-SJS/TEN patients without SOC and patients with CM-unrelated SJS/TEN with SOC suggested that these two susceptibility alleles are involved in the development of only CM-SJS/TEN with SOC patients. PMID- 24781923 TI - Anatomy of the ilium for bone marrow aspiration: map of sectors and implication for safe trocar placement. AB - PURPOSE: The bony anatomy of the human ilium has been well described from a qualitative perspective; however, there are little quantitative data to help the surgeon to perform bone marrow aspiration from the iliac crest in the thickest part of the ilium. The minimum thickness of the spongiousus bone in an iliac wing (transverse thickness between the two tables) is an important factor in ensuring the safe placement of a trocar between the two tables of the iliac wing. For example, with an 8-gauge (3.26 mm) trocar, one can consider that if the transverse thickness of the spongiousus bone of the iliac wing is <3 mm, it will be difficult to insert the trocar safely between the two tables. METHODS: For this study, we measured spongiousus bone thickness on 48 iliac wings to map the ilium in six sectors, which were defined by drawing lines from equidistant points spaced along the rim of the iliac crest to the centre of the hip. These sectors can be transposed in the same manner to any patient. To evaluate the risks to reach vascular or neurologic structures, 410 trocars were introduced in the different sectors of 20 iliac bones of ten cadavers. RESULTS: A map was constructed indicating the thickness of the spongiousus bone in each sector. The thickness data was used to create a map that identifies the sites where bone marrow can be obtained with a trocar of 3-mm diameter according to the thickness of the spongiousus bone. Sectors 2, 3 and 6 appear to be more favourable for accommodating a 3-mm diameter trocar. Sectors 1, 4 and 5 comprise the areas with the thinnest parts of the iliac crest, with some areas being thinner than the trocar diameter. The sector system reliably predicted safe and unsafe areas for trocar placement. In cadavers, dissection demonstrated nine vascular or neurologic lesions created when trocars were introduced into sectors 1, 5 and 6. CONCLUSION: Using the sector system, trocars can be directed away from neural and vascular structures and towards zones that are likely to contain larger bone marrow stock. PMID- 24781924 TI - CORR Insights((r)): does preoperative psychologic distress influence pain, function, and quality of life after TKA? PMID- 24781925 TI - Reply to the letter to the editor: Bone marrow aspirate concentrate and platelet rich plasma enhanced bone healing in distraction osteogenesis of the tibia. PMID- 24781926 TI - Does use of a powered ankle-foot prosthesis restore whole-body angular momentum during walking at different speeds? AB - BACKGROUND: Whole-body angular momentum (H) influences fall risk, is tightly regulated during walking, and is primarily controlled by muscle force generation. People with transtibial amputations using passive-elastic prostheses typically have greater H compared with nonamputees. QUESTIONS/PURPOSES: (1) Do people with unilateral transtibial amputations using passive-elastic prostheses have greater sagittal and frontal plane H ranges of motion during walking compared with nonamputees and compared with using powered prostheses? (2) Does use of powered ankle-foot prostheses result in equivalent H ranges in all planes of motion compared with nonamputees during walking as a result of normative prosthetic ankle power generation? METHODS: Eight patients with a unilateral transtibial amputation and eight nonamputees walked 0.75, 1.00, 1.25, 1.50, and 1.75 m/s while we measured kinematics and ground reaction forces. We calculated H for participants using their passive-elastic prosthesis and a powered ankle-foot prosthesis and for nonamputees at each speed. RESULTS: Patients using passive elastic prostheses had 32% to 59% greater sagittal H ranges during the affected leg stance phase compared with nonamputees at 1.00 to 1.75 m/s (p < 0.05). Patients using passive-elastic prostheses had 5% and 9% greater sagittal H ranges compared with using powered prostheses at 1.25 and 1.50 m/s, respectively (p < 0.05). Participants using passive-elastic prostheses had 29% and 17% greater frontal H ranges at 0.75 and 1.50 m/s, respectively, compared with nonamputees (p < 0.05). Surprisingly, patients using powered prostheses had 26% to 50% greater sagittal H ranges during the affected leg stance phase compared with nonamputees at 1.00 to 1.75 m/s (p < 0.05). Patients using powered prostheses also had 26% greater frontal H range compared with nonamputees at 0.75 m/s (p < 0.05). CONCLUSIONS: People with a transtibial amputation may more effectively regulate H at two specific walking speeds when using powered compared with passive-elastic prostheses. CLINICAL RELEVANCE: Our results support the hypothesis that an ankle foot prosthesis capable of providing net positive work during the stance phase of walking reduces sagittal plane H; future studies are needed to validate our biomechanical findings with larger numbers of patients and should determine whether powered prostheses can decrease the risk of falls in patients with a transtibial amputation. PMID- 24781927 TI - CORR Insights(r): the Mark Coventry Award: Trabecular metal tibial components were durable and reliable in primary total knee arthroplasty: a randomized clinical trial. PMID- 24781928 TI - Blood lactate and ventilatory thresholds in wheelchair athletes with tetraplegia and paraplegia. AB - PURPOSE: The purpose of this study was to analyse the influence of spinal cord injury level on blood lactate (BLa) and ventilatory thresholds. METHODS: Ten athletes with tetraplegia (TETRA) and nine athletes with paraplegia (PARA) performed a graded wheelchair propulsion treadmill exercise step test to exhaustion. The aerobic and anaerobic BLa thresholds, the ventilatory threshold and the respiratory compensation point (RCP) were determined. RESULTS: The BLa thresholds were determined in 34 of 38 cases, ventilatory thresholds and RCPs in 31 of 38 cases. The anaerobic BLa threshold (76 +/- 7 % [Formula: see text]) and the RCP (77 +/- 8 % [Formula: see text]) did not differ significantly from each other (P = 0.92), with a coefficient of variation of 4.8 +/- 3.4 % between thresholds. All other thresholds differed significantly from each other (P < 0.05). Thresholds expressed as the percentage of peak oxygen uptake did not differ between TETRA and PARA (P > 0.05) despite altered breathing in TETRA, which included a higher ventilatory equivalent for oxygen and a lower tidal volume. CONCLUSION: Measuring BLa leads to a higher threshold determination rate compared with ventilatory data and the anaerobic BLa threshold can be used to predict the RCP. The altered breathing in TETRA does not seem to have a pronounced effect on the ventilatory threshold or the RCP. PMID- 24781929 TI - Orthotopic liver transplantation for liver cirrhosis due to hepatitis C virus in patients with hemophilia A: two benefits of one procedure. PMID- 24781930 TI - Practical access to spiroacetal enol ethers via nucleophilic dearomatization of 2 furylmethylenepalladium halides generated by Pd-catalyzed coupling of furfural tosylhydrazones with aryl halides. AB - Pd-catalyzed cross-coupling of furfural tosylhydrazones with aryl halides produces 2-furylmethylenepalladium halides, which can undergo intramolecular nucleophilic dearomatization to provide spiroacetal enol ethers. This is the first report on the formation of 2-furylmethylenepalladium halides from stable furfural hydrazones instead of from 2-furylmethyl halides, which are not readily accessible or are unstable. PMID- 24781931 TI - The consequences of diminishing industry support on the independent education landscape: an evidence-based analysis of the perceived and realistic impact on professional development and patient care among oncologists. AB - In recent years, commercial funding for continuing medical education (CME) has dropped significantly. Yet, little has been written about how this might affect CME in oncology, a field in which new drugs and advances emerge at a rapid pace. This study examines the role oncologists and oncology fellows say that CME plays in their ongoing professional development and their attitudes about the potential and realistic impact upon both the dissemination of medical information and the impact on patient care if commercial support were removed from CME. The study is based upon a national survey of 368 oncology clinicians (283 oncologists and 85 oncology fellows). Respondents indicated that CME is an important part of their ongoing professional development. The majority of oncologists (90%) and oncology fellows (78%) "agreed" or "strongly agreed" that commercial support may be more necessary for oncology than for other specialties due to the rate at which cancer therapies are introduced. Respondents felt loss of commercial support would impact cost, format, and availability of oncology CME programs. Half of oncologists thought eliminating commercial support for CME would have a negative impact on application of new therapies in oncology. Yet, both oncologists and oncology fellows were reluctant to claim the removal of commercial support would negatively affect the practice of evidence-based medicine, patient outcomes, or patient safety. A possible explanation of this apparent contradiction is found in the social sciences literature. PMID- 24781932 TI - Information needs and disclosure preferences among Jordanian women diagnosed with breast cancer. AB - To determine Jordanian women's attitudes toward disclosure of breast cancer information and their information needs. A descriptive comparative research design was used in this study. A convenience sample of 156 Jordanian women who had a confirmed first time diagnosis of breast cancer within 18 months prior to the study and had treatment at three hospitals in Central and Northern Jordan was recruited for the study. A modified version of the Information Needs Questionnaire (INQ) was used for data collection. The vast majority of patients wanted to know whether the diagnosis was breast cancer (92%) and the stage of the disease (78%). Information about spread of the disease and chances of cure was of highest importance for the majority of the patients (88% and 85% respectively). Younger patients and those with higher education were more likely to express a preference for truthful disclosure of breast cancer diagnosis. The majority of Jordanian women wanted information about breast cancer diagnosis, chances of cure, and treatment side effects. PMID- 24781933 TI - Testing efficacy of teaching food safety and identifying variables that affect learning in a low-literacy population. AB - Nurses at a meeting of the Asociacion de Hemato Oncologia Pediatrica de Centroamerica y El Caribe recognized food safety as one of the main issues affecting patient care. The objective was to increase awareness of food safety issues among caregivers for pediatric cancer patients in Guatemala and El Salvador. A low-literacy booklet about food safety, "Alimentacion del nino con cancer (Feeding the child with cancer)," was developed for caregivers. Tests were developed to assess information acquisition and retention. An educator's guide was developed for consistency of education along with a demographics questionnaire. The efficacy of the booklet was tested with 162 caregivers of patients with newly diagnosed leukemia. Information retention was tested 1 and 3 months after the initial education. The booklet was found to be efficient for food safety education. There was no significant difference between post educational knowledge in either country at 1 month or in Guatemala at 3 months. Pre-educational knowledge was not associated with any demographic variable except for self-reported ability to read in El Salvador. There was no significant association between learning ability and demographic variables in either country. Caregivers from El Salvador had a better ability to learn than caregivers from Guatemala. Education using the booklet greatly improved food safety knowledge, which remained high 1 and 3 months later. Education with the booklet was efficacious for teaching a low-literacy population about food safety. However, it is unknown which part of the education contributed to the significant improvement in knowledge. PMID- 24781934 TI - [Importance of Quick, partial thromboplastin time, and Co]. AB - The Quick test and activated partial thromboplastin time (aPTT) are so-called global assays used to characterize different steps in plasmatic hemostasis. They reflect hemostasis in its classical differentiation into extrinsic and intrinsic pathways. However, they do not cover physiological aspects of cell-based hemostasis. Results are not necessarily congruent with a specific clinical situation and do not replace a complete medical history. Patients suffering from hemophilia A or B, for example, have normal Quick test results. Severe factor XII deficiency reveals an extreme aPTT prolongation without a significant bleeding tendency. In Lupus patients, aPTT is also prolonged with clinically a rather increased thrombotic risk. Fibrinogen as a substrate of coagulation discloses pathological results in both global tests in case of considerable reduction. In case of positive bleeding history and a normal global assay, disorders in platelets, von Willebrand factor and factor XIII must be considered. Reduced Quick test results may be expected in factor VII, II, V, or X deficiency. Disorders of liver synthesis of coagulation factors as well as vitamin K deficiency will be indicated by the Quick test rather than by aPTT. The most frequent hereditary reasons for a prolonged aPTT are hemophilia A and B as well as von Willebrand disease. In case of an acquired bleeding tendency, the diagnostic strategy must include autoantibodies. The sensitivity of the aPTT reagent varies widely. Low-molecular weight heparin and pentasaccharides do not influence the test. Oral direct inhibitors may reveal pathological results in a reagent-dependent manner. PMID- 24781935 TI - Diabetes mellitus leads to accumulation of dendritic cells and nerve fiber damage of the subbasal nerve plexus in the cornea. AB - PURPOSE: To evaluate whether nerve fibers of the subbasal nerve plexus (SNP) and dendritic cells (DCs) are in association with each other leading to neuropathy in the diabetic cornea. METHODS: BALB/c mice were injected with streptozotocin (STZ) for 5 days for induction of diabetes mellitus (DM) or with vehicle solution (control). B6.VLep(ob/ob) (ob/ob) mice served as an obese and glucose-intolerant DM type 2 (DM II) model and lean B6.VLep(ob/+) (ob/+) mice as respective controls. Using in vivo corneal confocal microscopy (CCM), nerve fibers and DCs were quantified over a period of 9 weeks and additionally analyzed by in vitro immunofluorescence whole-mount staining. RESULTS: In STZ-diabetic mice, CCM revealed an increase of DC density (DCD) in contrast to controls, whereas nerve fiber density (NFD) was decreased with duration of DM. In ob/ob mice, DCD was 3 fold higher than in both ob/+ mice and STZ-diabetic mice. Whole-mount staining displayed CD11c(+) and major histocompatibility complex (MHC) class II(+) mature DCs in colocalization with class III beta-tubulin(+) nerve fibers in the cornea. CONCLUSIONS: Hyperglycemia leads to corneal DC infiltration, and obesity aggravates this immune response. The direct contact between DCs and the SNP can be assumed to be a trigger of nerve fiber damage and thus a contributing factor to polyneuropathy in diabetic corneas. PMID- 24781936 TI - Baseline visual field findings in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). AB - PURPOSE: To characterize visual field (VF) loss at the baseline visit and to evaluate VF quality control (QC) procedures in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS: The Visual Field Reading Center (VFRC) evaluated 660 baseline VFs (1320 hemifields) from 165 enrolled patients. Three readers independently classified each superior and inferior hemifield and identified any abnormalities. A subset (20%) of the hemifields was reread to evaluate within- and between-reader agreements. The QC system addressed test parameters, patient data, and shipment errors. RESULTS: The majority (60%) of the baseline hemifields consisted of localized nerve fiber bundle-type VF loss. Approximately one-third (31.5%) of all the classifications consisted of partial arcuate defects combined with an enlarged blind spot, making this the most common type of hemifield classification. Inferior hemifield loss was greater than superior loss for both study and nonstudy eyes. Reader agreements were >90% for both inferior and superior hemifields for two out of three readers. Test-retest reliability agreement for individual readers was 95% for both hemifields. There were few QC errors with only 5.48 error points per 100-point VF. CONCLUSIONS: The most common type of IIHTT baseline hemifield abnormality was a localized nerve fiber bundle-like defect. Localized inferior hemifield loss was more common than superior hemifield loss. Quality control and within- and between-reader agreement were excellent for the IIHTT (ClinicalTrials.gov number, NCT01003639). PMID- 24781937 TI - Comparison of in vivo efficacy of different ocular lubricants in dry eye animal models. AB - PURPOSE: To compare the efficacy of three types of ocular lubricants in protecting corneal epithelial cells in dry eye animal models. METHODS: Ocular lubricants containing 0.1% or 0.3% sodium hyaluronate (SH), carboxymethylcellulose (CMC), or hydroxypropyl methylcellulose (HPMC) were tested. First, ocular lubricant containing 0.002% fluorescein was dropped onto the rabbit corneas. The fluorescein intensity as an index of retention was measured. Second, a rabbit dry eye model was made by holding the eye open with a speculum, and 50 MUL of each ocular lubricant was dropped onto the cornea. After 3 hours, the corneas were stained with 1% methylene blue (MB), and the absorbance of MB was measured. Third, a rat dry eye model was treated with the ocular lubricants for 4 weeks, and the corneal fluorescein staining was scored. Eyes treated with physiological saline were used as controls. Finally, immunohistochemistry was used to analyze occludin, an epithelial barrier protein, in cultured human corneal epithelial cells pretreated with ocular lubricants and desiccated for 20 or 60 minutes. RESULTS: Our results showed that 0.3% SH had a significantly longer retention time than the other lubricants (all P < 0.01). The absorbance of MB was significantly lower in the 0.3% SH group. The corneas of rats exposed to 0.3% SH had significantly lower fluorescein staining scores. A significantly higher number of occludin-positive cells were found after exposure to 0.3% SH than other lubricants. CONCLUSIONS: Ocular lubricant containing 0.3% SH would be preferable to treat patients with dry eye syndrome. PMID- 24781938 TI - Effect of retinopathy of prematurity on scotopic spatial summation. AB - PURPOSE: To evaluate scotopic retinal organization in retinopathy of prematurity (ROP) through a study of spatial summation. METHODS: Thresholds for a range of stimulus diameters (0.4 degrees -10 degrees ) were measured using a two alternative, spatial, forced choice psychophysical procedure. The critical diameter (DCRIT) for complete summation was estimated in subjects with a history of severe ROP (N = 7) and mild ROP (N = 17). Subjects who were born preterm and never had ROP (N = 16) and term-born subjects (N = 7) were also tested. The subjects ranged in age from 9 to 17 (median 13.5) years. RESULTS: Critical diameter for complete spatial summation was significantly larger in ROP subjects than in subjects who never had ROP and in term-born control subjects. Critical diameter varied significantly with severity of ROP. CONCLUSIONS: The larger DCRIT values in ROP are consistent with altered organization of the post receptor retina. This may offer the ROP retina a strategy for achieving noise reduction and good dark-adapted visual sensitivity. PMID- 24781939 TI - Circadian and noncircadian modulation of autophagy in photoreceptors and retinal pigment epithelium. AB - PURPOSE: Autophagy in photoreceptors and the RPE promotes homeostasis and survival. The purpose of this study is to determine the daily pattern of changes in autophagy and factors contributing to its regulation in the outer retina. METHODS: Levels of autophagy markers in the retina and RPE were evaluated over a 24-hour period. To assess the role of phagocytosis in stimulating autophagy in the RPE, cultured RPE-J cells were incubated with isolated photoreceptor outer segments and levels of autophagy markers were measured. Electron microscopy was performed on retina sections and RPE-J cells to assess formation of double membraned vesicles consistent with autophagosomes. RESULTS: In wild-type C57BL/6 mice maintained under normal cycling light conditions, autophagy in photoreceptor cells and the RPE exhibited a bimodal pattern of activation. In photoreceptors, shifts between light and dark evoked a sharp decrease in autophagy that was followed by a time-dependent increase. In photoreceptors, translocation of transducin and arrestin from the outer to inner segment appeared to contribute to the light-dependent upregulation of autophagy. In contrast, the cyclic variations in RPE autophagy were independent of lighting conditions, and are triggered, at least in part, by ingestion of outer segments. CONCLUSIONS: Activation of autophagy in the outer retina exhibits a bimodal pattern that correlates with shifts in transduction proteins within the photoreceptor and by circadian ingestion of outer segments in the RPE. These dynamic shifts suggest a critical role for this pathway in maintaining homeostasis, with further study needed to define the mechanisms underlying the regulation of this phenomenon. PMID- 24781941 TI - Influence of correction of ocular magnification on spectral-domain OCT retinal nerve fiber layer measurement variability and performance. AB - PURPOSE: To analyze the influence of ocular magnification on the peripapillary retinal nerve fiber layer (RNFL) thickness measurement and its performance as acquired with spectral-domain optical coherence tomography (SD-OCT). METHODS: Spectral domain OCT measurements from 108 normal eyes (59 subjects) and 72 glaucoma eyes (58 patients) were exported and custom software was used to correct RNFL measurements for ocular magnification. Retinal nerve fiber layer prediction limits in normal subjects, structure-function relationships, and RNFL performance for detection of glaucoma were compared before and after correction for ocular magnification (Bennett's formula). Association of disc area with cross-sectional RNFL area was explored. RESULTS: The median (interquartile range, [IQR]) visual field mean deviation and scaling factor were 0 (-0.85 to 0.73) dB and 0.96 (0.93 1.00) in normal eyes and -4.0 (-6.0 to -2.2) dB and 0.99 (0.95-1.03) in the glaucoma group (P < 0.001 and P = 0.003, respectively; average correction 3%). Correction for ocular magnification caused a reversal of the negative relationship between the cross-sectional RNFL area and axial length (slope = 0.022 mm(2)/mm, P = 0.015 vs. = 0.22 mm(2)/mm, P = 0.007). However, such correction did not change RNFL prediction limits (except in superior and nasal quadrants), improve global or regional structure-function relationships, or enhance the ability of RNFL measurements to discriminate glaucoma from normal eyes (P > 0.05). The cross-sectional RNFL area was not correlated with optic disc area (P = 0.325). CONCLUSIONS: Correction of RNFL measurements for ocular magnification did not improve prediction limits in normal subjects or enhance the performance of SD-OCT in this group of eyes in which the axial length did not deviate significantly from average values. The cross-sectional area of the RNFL was not related to the optic disc area. PMID- 24781940 TI - Role of angiopoietin-2 in corneal lymphangiogenesis. AB - PURPOSE: Lymphatic research has progressed rapidly in recent years. Lymphatic dysfunction has been found in myriad disorders from cancer metastasis to transplant rejection; however, effective treatment for lymphatic disorders is still limited. This study investigates the role of angiopoietin-2 (Ang-2) in corneal inflammatory lymphangiogenesis (LG) in vivo and in lymphatic endothelial cell (LEC) functions in vitro. METHODS: Standard suture placement model was used to study Ang-2 expression in inflamed cornea, and corneal LG and hemangiogenesis (HG) responses in Ang-2 knockout mice. Moreover, human LEC culture system was used to examine the effect of Ang-2 gene knockdown on LEC functions using small interfering RNAs (siRNAs). The effect of siRNA treatment on corneal LG was also assessed in vivo. RESULTS: Angiopoietin-2 was expressed on lymphatic vessels and macrophages in inflamed cornea. While corneal LG response was abolished in Ang-2 knockout mice, the HG response was also significantly suppressed with disorganized patterning. Moreover, anti-Ang-2 treatment inhibited LEC proliferation and capillary tube formation in vitro and corneal LG in vivo. CONCLUSIONS: Angiopoietin-2 is critically involved in lymphatic processes in vivo and in vitro. Further investigation of the Ang-2 pathway may provide novel insights and therapeutic strategies for lymphatic-related disorders, which occur both inside and outside the eye. PMID- 24781942 TI - Transactivation of EGF receptors in chicken Muller cells by alpha2A-adrenergic receptors stimulated by brimonidine. AB - PURPOSE: Alpha2-adrenergic receptor agonists are used in glaucoma treatment and have been shown to have some neuroprotective effects. We performed this study to test the hypothesis that epidermal growth factor receptors on chicken Muller cells are transactivated by alpha2-adrenergic receptors and we focused on the extracellular signal-activated kinases 1/2 (ERK) pathway. METHODS: Embryonic chicken retina and cultures of primary Muller cells were stimulated by alpha2 adrenergic receptor agonist brimonidine. Immunostaining, quantitative RT-PCR, and Western blot techniques, in combination with Src, epidermal growth factor receptor kinase, and matrix metalloproteinase inhibitors, were used for analysis of the cellular responses. RESULTS: Our results showed that Muller cells express alpha2A-adrenergic receptors in vivo and in vitro and that brimonidine triggered a robust and transient phosphorylation of ERK1/2. This ERK-response was Src kinase dependent, associated with tyrosine phosphorylation of epidermal growth factor receptors (phospho-Y1068, Y1173) and was mediated by matrix metalloproteinase activity on the Muller cells. CONCLUSIONS: Muller cells express the alpha2A-adrenergic receptor, and brimonidine triggers both Src-kinase- and matrix metalloproteinase-mediated autocrine ligand-dependent activation of epidermal growth factor receptors on Muller cells. This response is consistent with transactivation of epidermal growth factor receptors by stimulation of alpha2-adrenergic receptors. PMID- 24781944 TI - Hierarchical cluster analysis of progression patterns in open-angle glaucoma patients with medical treatment. AB - PURPOSE: To classify medically treated open-angle glaucoma (OAG) by the pattern of progression using hierarchical cluster analysis, and to determine OAG progression characteristics by comparing clusters. METHODS: Ninety-five eyes of 95 OAG patients who received medical treatment, and who had undergone visual field (VF) testing at least once per year for 5 or more years. OAG was classified into subgroups using hierarchical cluster analysis based on the following five variables: baseline mean deviation (MD), baseline visual field index (VFI), MD slope, VFI slope, and Glaucoma Progression Analysis (GPA) printout. After that, other parameters were compared between clusters. RESULTS: Two clusters were made after a hierarchical cluster analysis. Cluster 1 showed -4.06 +/- 2.43 dB baseline MD, 92.58% +/- 6.27% baseline VFI, -0.28 +/- 0.38 dB per year MD slope, 0.52% +/- 0.81% per year VFI slope, and all "no progression" cases in GPA printout, whereas cluster 2 showed -8.68 +/- 3.81 baseline MD, 77.54 +/- 12.98 baseline VFI, -0.72 +/- 0.55 MD slope, -2.22 +/- 1.89 VFI slope, and seven "possible" and four "likely" progression cases in GPA printout. There were no significant differences in age, sex, mean IOP, central corneal thickness, and axial length between clusters. However, cluster 2 included more high-tension glaucoma patients and used a greater number of antiglaucoma eye drops significantly compared with cluster 1. CONCLUSIONS: Hierarchical cluster analysis of progression patterns divided OAG into slow and fast progression groups, evidenced by assessing the parameters of glaucomatous progression in VF testing. In the fast progression group, the prevalence of high-tension glaucoma was greater and the number of antiglaucoma medications administered was increased versus the slow progression group. PMID- 24781943 TI - Uveal melanoma cell growth is inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase. AB - PURPOSE: To evaluate the effects and mechanism of aminoimidazole carboxamide ribonucleotide (AICAR), an AMP-dependent kinase (AMPK) activator, on the growth of uveal melanoma cell lines. METHODS: Four different cell lines were treated with AICAR (1-4 mM). Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium (MTT) assay. Cell cycle analysis was conducted by flow cytometry; additionally, expression of cell-cycle control proteins, cell growth transcription factors, and downstream effectors of AMPK were determined by RT-PCR and Western blot. RESULTS: Aminoimidazole carboxamide ribonucleotide inhibited cell growth, induced S-phase arrest, and led to AMPK activation. Aminoimidazole carboxamide ribonucleotide treatment was associated with inhibition of eukaryotic translation initiation factor 4E-BP1 phosphorylation, a marker of mammalian target of rapamycin (mTOR) pathway activity. Aminoimidazole carboxamide ribonucleotide treatment was also associated with downregulation of cyclins A and D, but had minimal effects on the phosphorylation of ribosomal protein S6 or levels of the macroautophagy marker LC3B. The effects of AICAR were abolished by treatment with dipyridamole, an adenosine transporter inhibitor that blocks the entry of AICAR into cells. Treatment with adenosine kinase inhibitor 5 iodotubericidin, which inhibits the conversion of AICAR to its 5'-phosphorylated ribotide 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate (ZMP; the direct activator of AMPK), reversed most of the growth-inhibitory effects, indicating that some of AICAR's antiproliferative effects are mediated at least partially through AMPK activation. CONCLUSIONS: Aminoimidazole carboxamide ribonucleotide inhibited uveal melanoma cell proliferation partially through activation of the AMPK pathway and downregulation of cyclins A1 and D1. PMID- 24781945 TI - Impairment of corneal epithelial wound healing in a TRPV1-deficient mouse. AB - PURPOSE: To examine whether the absence or blockage of an ion channel receptor, transient receptor potential vanilloid subtype 1 (TRPV1), affects the healing of an epithelial injury using an experimental model of an epithelial defect in animal cornea. METHODS: The expression of TRPV1 in the corneal epithelium was examined using immunohistochemistry in mice and rats. The migration of the corneal epithelium was examined in epithelium-debrided rat cornea in organ culture in the presence or absence of a TRPV1 agonist or its antagonist. Epithelial migration and cell proliferation following the debridement were examined in the cornea of a TRPV1-null mouse. Real-time RT-PCR was performed in samples of healing corneas to analyze the expression pattern of epithelial migration-related components (i.e., IL-6, substance P, and TGF-beta1). RESULTS: TRPV1 was detected mainly in the basal layer of mouse or rat corneal epithelium. Adding a TRPV1 receptor agonist to the culture medium enhanced epithelial healing in the rat cornea, and a TRPV1 antagonist retarded it in organ culture. The loss of TRPV1 did not affect the histology of the mouse cornea. In vivo analysis showed the loss of TRPV1-impaired re-epithelialization of the debrided area of the corneal epithelium by the suppression of both cell migration and proliferation. The lack of TRPV1 suppressed the expression of IL-6 and substance P but not of TGF-beta1 in response to epithelial debridement in mice. CONCLUSIONS: TRPV1 signal is required for the upregulation of IL-6 and substance P and the healing of debrided corneal epithelium in mice. PMID- 24781946 TI - Choroidal neovascularization in eyes with choroidal vascular hyperpermeability. AB - PURPOSE: We describe the clinical and genetic characteristics of choroidal neovascularization (CNV) in eyes with choroidal vascular hyperpermeability (CVH). METHODS: This cross-sectional study consisted of 438 consecutive patients who underwent fluorescein and indocyanine green angiography for macular disease. We used the genotypes of 1576 age-related macular degeneration (AMD) cases and 3248 general population controls as reference groups for genetic association analyses. RESULTS: Of 871 eyes (438 patients) examined, CVH was found in 227 eyes (26.1%). Of these 227 eyes, 52 (22.6%) had CNV in the macular area. The proportion of patients with drusen and the choroidal thickness were not different between eyes with and without CNV, after adjusting for age (P = 0.21 and 0.95). Of the 52 eyes with CNV, 51 had type 1 CNV and only one eye had pure type 2 CNV. Of the 51 eyes with type 1 CNV, polypoidal lesions were observed in 17 eyes (33.3%). Genotype distributions of ARMS2 (A69S) and CFH (I62V) in patients with CVH and type 1 CNV significantly differed from those of AMD cases (P = 0.0014 and 0.0098, respectively), but not from general population controls (P = 0.33 and 0.82, statistical power of 88.5% and 72.9%, respectively). CONCLUSIONS: In patients with CVH, type 1 CNV may occur frequently and sometimes accompanies type 2 CNV or polypoidal lesions. In terms of ARMS2 and CFH, genetic background of patients with CVH and type 1 CNV was different from those with AMD, but rather similar to the general Japanese population. PMID- 24781947 TI - Customized, automated stimulus location choice for assessment of visual field defects. AB - PURPOSE: To introduce a perimetric algorithm (gradient-oriented automated natural neighbor approach [GOANNA]) that automatically chooses spatial test locations to improve characterization of visual field (VF) loss without increasing test times. METHODS: Computer simulations were undertaken to assess the performance of GOANNA. GOANNA was run on a 3 degrees grid of 150 locations, and was compared with a zippy estimation by sequential testing (ZEST) thresholding strategy for locations in the 24-2 test pattern, with the remaining 98 locations being interpolated. Simulations were seeded using empirical data from 23 eyes with glaucoma that were measured at all 150 locations. The performance of the procedures was assessed by comparing the output thresholds to the input thresholds (accuracy and precision) and by evaluating the number of presentations required for the procedure to terminate (efficiency). RESULTS: When collated across whole-fields, there was no significant difference in accuracy, precision, or efficiency between GOANNA and ZEST. However, GOANNA targeted presentations on scotoma borders; hence it was more precise and accurate at locations where the sensitivity gradient within the VF was high. CONCLUSIONS: Compared with ZEST, GOANNA was marginally less precise in areas of the VF that had spatially uniform sensitivity, but improved accuracy and precision in regions surrounding scotoma edges. GOANNA provides a principled framework for automatic placement of additional test locations to provide spatially denser testing around the borders of VF loss. PMID- 24781948 TI - Changes in negative and positive EEG shifts during slow cortical potential training in children with attention-deficit/hyperactivity disorder: a preliminary investigation. AB - We examined the effects of self-regulation of slow cortical potentials (SCP) in nine children with attention-deficit/hyperactivity disorder (ADHD) by focusing on the changes in electroencephalographic (EEG) shifts during SCP sessions. In SCP training, individuals learn to increase and decrease their cortical excitabilities (enhancement of negative and positive cortical shifts). To examine the efficiency of SCP training, we conducted an attention task and measured contingent negative variation, which relates to the attention maintenance ability. Moreover, to assess training effects at the behavioral level, the Japanese ADHD rating scale (SNAP-J) was completed by the parents. In SCP training, we analyzed changes in EEG shifts during 16 training sessions by calculating the peak amplitudes of positive and negative shifts. The results of EEG data showed that peak amplitudes increased in sessions 11 and 12 for negative shifts and in sessions 9 and 13 for positive shifts. Moreover, we found an enhancement of contingent negative variation amplitude in the attention task before and after training, suggesting that the ability of these children to maintain attention could be modified by SCP training. However, significant behavioral improvements were not observed on the Japanese ADHD rating scale. It has been proposed that the number of additional training sessions may affect both physiological and behavioral improvements. Our present results, however, suggest the possibility that even low numbers of training sessions, such as 16, can bring about physiological improvement, whereas greater numbers of training sessions may be needed to have an influence on behavioral changes. PMID- 24781949 TI - Downregulation of ABCG2 protein inhibits migration and invasion in U251 glioma stem cells. AB - ABCG2 is a member of the ATP-binding cassette transporter family, which has been detected in a wide variety of human aggressive tumors, including glioma stem cells (GSCs), glioma tissues of higher grades, and implanted glioma xenografts. Previous research has implied that ABCG2 might be associated closely with invasion and spread in tumors. However, the specific roles and mechanisms of ABCG2 in regulating the migration and invasion of GSCs remain unclear. In this study, we aimed to identify the effects and mechanisms of ABCG2 on invasion by GSCs. Our results showed that downregulation of ABCG2 protein significantly inhibited the migration and invasion potentials of U251 GSCs. Further research on the underlying mechanism showed that the effects of ABCG2 downregulation on inhibiting the migration and invasion of U251 GSCs were through significantly decreasing the activity of matrix metalloproteinase-9, but not the expression of matrix metalloproteinase-9 protein. These findings show that ABCG2 plays an important role in regulating the migration and invasion of GSC, and represents a potential novel therapeutic agent to target the progression of GSCs. PMID- 24781950 TI - Systematic review and meta-analysis on iron and cancer risk-response. PMID- 24781951 TI - Systematic review and meta-analysis on iron and cancer risk-letter. PMID- 24781952 TI - Serum vascular adhesion protein-1 level predicts risk of incident cancers in subjects with type II diabetes. AB - BACKGROUND: Serum vascular adhesion protein-1 (VAP-1) predicts cancer-related mortality in diabetic subjects. However, whether serum VAP-1 predicts cancer incidence or cancer progression remains unclear. We conducted a cohort study to investigate whether serum VAP-1 and related clinical variables predict incident cancers in type II diabetic subjects. METHODS: From 1996 to 2003, we enrolled 568 type II diabetic subjects who were free of cancer at baseline. Serum VAP-1 at enrollment was measured by time-resolved immunofluorometric assay. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m(2). The subjects were followed until first occurrence of cancer or until December 31, 2011. RESULTS: During a mean follow-up of 11.3 years, 71 subjects developed incident cancers. The HRs for incident cancers in subjects with highest tertile of serum VAP-1 and in subjects with CKD were 2.95 [95% confidence interval (CI), 1.31-6.63; P = 0.009] and 2.29 (95% CI, 1.18-4.44; P = 0.015), respectively, after multivariate adjustment. There was an interaction between serum VAP-1 and CKD on the risk of incident cancers (P = 0.01 for log-transformed VAP-1 * CKD). The relationship among serum VAP-1, CKD, and incident cancers was similar if death was considered in the competing risk models or if subjects with shorter follow-up period were excluded. CONCLUSIONS: Higher serum VAP-1 and CKD can independently predict future development of cancers in type II diabetic subjects. IMPACT: Physicians should be aware of the early signs of cancer in diabetic individuals with elevated VAP-1 or renal dysfunction. More aggressive treatment strategies might be considered. PMID- 24781953 TI - A comparison of supervised machine learning algorithms and feature vectors for MS lesion segmentation using multimodal structural MRI. AB - Machine learning is a popular method for mining and analyzing large collections of medical data. We focus on a particular problem from medical research, supervised multiple sclerosis (MS) lesion segmentation in structural magnetic resonance imaging (MRI). We examine the extent to which the choice of machine learning or classification algorithm and feature extraction function impacts the performance of lesion segmentation methods. As quantitative measures derived from structural MRI are important clinical tools for research into the pathophysiology and natural history of MS, the development of automated lesion segmentation methods is an active research field. Yet, little is known about what drives performance of these methods. We evaluate the performance of automated MS lesion segmentation methods, which consist of a supervised classification algorithm composed with a feature extraction function. These feature extraction functions act on the observed T1-weighted (T1-w), T2-weighted (T2-w) and fluid-attenuated inversion recovery (FLAIR) MRI voxel intensities. Each MRI study has a manual lesion segmentation that we use to train and validate the supervised classification algorithms. Our main finding is that the differences in predictive performance are due more to differences in the feature vectors, rather than the machine learning or classification algorithms. Features that incorporate information from neighboring voxels in the brain were found to increase performance substantially. For lesion segmentation, we conclude that it is better to use simple, interpretable, and fast algorithms, such as logistic regression, linear discriminant analysis, and quadratic discriminant analysis, and to develop the features to improve performance. PMID- 24781954 TI - Structural elucidation and antimicrobial activity of new phencomycin derivatives isolated from Burkholderia glumae strain 411gr-6. PMID- 24781955 TI - Resistance of Helicobacter pylori to tetracycline, amoxicillin, clarithromycin and metronidazole in Israeli children and adults. AB - The aim of this study was to examine Helicobacter pylori-resistance rate to different antibiotics: tetracycline, amoxicillin, clarithromycin and metronidazole, and to compare eradication rates in adults and children in Israel. The study was based on the hypothesis of high-resistance rates to clarithromycin and metronidazole especially in adults and overall low-resistance rates to tetracycline and amoxicillin. One seventy six biopsies from patients with dyspeptic symptoms were cultured of which 100 were from adults (19-79 years) and 76 from children (7-17 years). All positive cultures were examined by Epsilometer test for MIC determination against tetracycline, amoxicillin, clarithromycin and metronidazole. 48.3% (85 out of 176) were H. pylori positive, of which 44% were from adults and 54% from children. Antibiotic resistance was seen in 31 out of 44 (70.5%) for metronidazole, 1 out of 44 (2.3%) for amoxicillin, 10 out of 44 (22.3%) for clarithromycin and 1 out of 44 (2.3%) for tetracycline among adults. Antibiotic resistance was seen in 10 out of 41 (24.4%) for metronidazole, 5 out of 41 (12.2%) for amoxicillin, 10 out of 41 (24.4%) for clarithromycin and 1 out of 41 (2.4%) for tetracycline among children. High rates of H. pylori resistance to metronidazole and clarithromycin was found especially among adults. Therefore, to increase the success rate of anti-H. pylori treatment, other classes of antibiotics need to be considered. PMID- 24781956 TI - Inuloxins A-D and derivatives as antileishmanial agents: structure-activity relationship study. PMID- 24781958 TI - Role of discoidin domain receptor 2 in wound healing. AB - Until recently, collagen interactions with cells had been ascribed to integrins. The identification of the Discoidin Domain Receptor (DDR) family as collagen receptors represents a new paradigm in the regulation of collagen-cell interactions. How DDR signaling is biochemically linked to specific cell regulatory functions remains largely unknown. Moreover, the characteristic slow and substained phosphorylation of DDRs and the elevated expression of DDR2 in the myofibroblasts of healing wounds suggest a role for DDR2 in physiological and pathological wound healing. In fact, DDR2 signaling regulates cell proliferation and extracellular matrix synthesis, which are key aspects of fibroblast contribution to tissue healing. In this review we summarize evidence in favor of this concept. PMID- 24781959 TI - Posterior cricoarytenoid muscle dynamics in canines and humans. AB - OBJECTIVES/HYPOTHESIS: The posterior cricoarytenoid (PCA) muscle is the sole abductor of the glottis and serves important functions during respiration, phonation, cough, and sniff. The present study examines vocal fold abduction dynamics during PCA muscle activation. STUDY DESIGN: Basic science study using an in vivo canine model and human subjects. METHODS: In four canines and five healthy humans vocal fold abduction time was measured using high-speed video recording. In the canines, PCA muscle activation was achieved using graded stimulation of the PCA nerve branch. The human subjects performed coughing and sniffing tasks. High-speed video and audio signals were concurrently recorded. RESULTS: In the canines, the vocal fold moved posteriorly, laterally, and superiorly during abduction. Average time to reach 10%, 50%, and 90% abduction was 23, 50, and 100 ms with low stimulation; 24, 58, and 129 ms with medium stimulation; and 21, 49, and 117 ms with high-level stimulation, respectively. In the humans, 100% abduction times for coughing and sniffing tasks were 79 and 193 ms, respectively. CONCLUSIONS: The PCA abduction times in canines are within the range in humans. The results also further support the notion that PCA muscles are fully active during cough. PMID- 24781961 TI - Letter to the editor concerning the article "Simple technique for gasless transumbilical single-incisional laparoscopic-assisted appendectomy". PMID- 24781960 TI - Effects of telephone-based peer support in patients with type 2 diabetes mellitus receiving integrated care: a randomized clinical trial. AB - IMPORTANCE: In type 2 diabetes mellitus (T2DM), team management using protocols with regular feedback improves clinical outcomes, although suboptimal self management and psychological distress remain significant challenges. OBJECTIVE: To investigate if frequent contacts through a telephone-based peer support program (Peer Support, Empowerment, and Remote Communication Linked by Information Technology [PEARL]) would improve cardiometabolic risk and health outcomes by enhancing psychological well-being and self-care in patients receiving integrated care implemented through a web-based multicomponent quality improvement program (JADE [Joint Asia Diabetes Evaluation]). DESIGN, SETTING, AND PARTICIPANTS: Between 2009 and 2010, 628 of 2766 Hong Kong Chinese patients with T2DM from 3 publicly funded hospital-based diabetes centers were randomized to the JADE + PEARL (n = 312) or JADE (n = 316) groups, with comprehensive assessment at 0 and 12 months. INTERVENTIONS: Thirty-three motivated patients with well-controlled T2DM received 32 hours of training (four 8-hour workshops) to become peer supporters, with 10 patients assigned to each. Peer supporters called their peers at least 12 times, guided by a checklist. MAIN OUTCOMES AND MEASURES: Changes in hemoglobin A(1c) (HbA(1c)) level (primary), proportions of patients with attained treatment targets (HbA(1c) <7%; blood pressure <130/80 mm Hg; low-density lipoprotein cholesterol <2.6 mmol/L [to convert to milligrams per deciliter, divide by 0.0256]) (secondary), and other health outcomes at month 12. RESULTS: Both groups had similar baseline characteristics (mean [SD] age, 54.7 [9.3] years; 57% men; disease duration, 9.4 [7.7] years; HbA(1c) level, 8.2% [1.6%]; systolic blood pressure, 136 [19] mm Hg; low-density lipoprotein cholesterol level, 2.89 [0.82] mmol/L; 17.4% cardiovascular-renal complications; and 34.9% insulin treated). After a mean (SD) follow-up period of 414 (55) days, 5 patients had died, 144 had at least 1 hospitalization, and 586 had repeated comprehensive assessments. On intention-to-treat analysis, both groups had similar reductions in HbA(1c) (JADE + PEARL, 0.30% [95% CI, 0.12%-0.47%], vs JADE, 0.29% [95% CI, 0.12%-0.47%] [P = .97]) and improvements in treatment targets and psychological-behavioral measures. In the JADE + PEARL group, 90% of patients maintained contacts with their peer supporters, with a median of 20 calls per patient. Most of the discussion items were related to self-management. CONCLUSIONS AND RELEVANCE: In patients with T2DM receiving integrated care, peer support did not improve cardiometabolic risks or psychological well-being. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00950716. PMID- 24781962 TI - Morbidity of central neck dissection: primary surgery vs reoperation. Results of a case-control study. AB - PURPOSE: Complication rate in reoperative central neck node surgery is one of the main arguments to favor prophylactic central neck dissection at first operation in patients with papillary thyroid carcinoma. We evaluated if reoperative central neck dissection implies an increased postoperative morbidity. Secondarily, we aimed also to verify the effectiveness of the surgical resection of reoperative central neck dissection. METHODS: Forty-one patients who underwent reoperative central neck dissection after initial thyroidectomy for papillary thyroid carcinoma between January 2008 and May 2012 were compared to 41 controls who underwent central neck dissection at initial operation. RESULTS: The two groups were well matched for age, sex, and pN stage (P = 0.296, 0.199, and 1.000, respectively). Three patients had distant metastases at presentation. No significant difference was found concerning mean number of removed nodes (P = 0.064). No significant difference was found between the reoperative and the control groups concerning transient hypocalcemia (17 vs 19, respectively) (P = 0.901) and transient recurrent nerve palsy (2 vs 2) (P = 0.608). Follow-up was completed in 69 out of all the included patients (85.2 %). At a mean follow-up of 33 months, two patients (2.9 %) experienced nodal recurrence. CONCLUSIONS: Morbidity of central neck dissection is similar for primary surgery and reoperation. In high-volume centers, reoperative central neck dissection can be safely accomplished when needed, allowing to achieve locoregional control in most of patients. PMID- 24781963 TI - The development and evaluation of mutual support groups in long-term care homes. AB - This article describes the development of a new mutual support group intervention for long-term care homes (LTCH); evaluates the processes, structure, and content of the intervention; and addresses replication and sustainability. Tom Kitwood's model of personhood is used as the basis for developing a weekly discussion group using themes chosen by participants and theme-associated music, readings, and photographs. A mixed-methods qualitative process evaluation design encompasses focus groups, systematic observation of six resident groups, individual resident interviews (N = 65), and staff interviews (N = 7) in three LTCH in British Columbia, Canada. Resident reports and observations indicate positive benefits including a decrease in loneliness, the development of friendships, and increased coping skills, understanding, and support. Participating staff reported numerous benefits and described how the unique group structure fosters active participation of residents with moderate-severe cognitive impairment. This preliminary study suggests that mutual support groups have potential to offset loneliness, helplessness, and depression within LTCH. PMID- 24781964 TI - The impact of numeracy ability and technology skills on older adults' performance of health management tasks using a patient portal. AB - Patient portals, which allow patients to access their health record via the Internet, are becoming increasingly widespread and are expected to be used by diverse consumer populations. In addition to technology skills, numeracy skills are also likely to be critical to performing health management tasks, as much of the data contained in the portal are numeric. This study examined how factors such as Internet experience, numeracy, and education impacted the performance of common tasks using a simulated patient portal among a sample of older adults. In addition, information was gathered on the ability of older adults to estimate their numeracy skills. Results indicated that numeracy and Internet experience had a significant impact on their ability to perform the tasks and that older adults tended to overestimate their numeracy skills. Results from this study can help to identify interventions that may enhance the usability of patient portals for older adults. PMID- 24781965 TI - Psychometric properties of the index of relocation adjustment. AB - More and more American older adults are relocating to retirement communities, and they experience challenges in adjusting to new surroundings that may increase their depression and mortality. An instrument not previously tested in the United States, the Index of Relocation Adjustment (IRA), may help in early identification of poor relocation adjustment. This study examined the psychometric properties of the IRA using secondary data from a convenience sample of 104 older adults who relocated to 6 retirement communities in Northeast Ohio. Cronbach's alpha was .86. The IRA was correlated with measures of positive cognitions (r = .48, p < .01) and relocation controllability (r = -.62, p < .01), suggesting construct validity. Results indicated a single factor reflecting relocation adjustment with loadings for all items ranging from .62 to .83. The IRA is potentially useful as a screening measure for early detection of poor adjustment among relocated older adults. PMID- 24781966 TI - Relationship between nonprescribed therapy use for illness prevention and health promotion and health-related quality of life. AB - OBJECTIVES: This study describes the nonprescribed therapy use (prayer, over-the counter medications [OTC's], home remedies, vitamins, herbs and supplements, and exercise) for health promotion among rural elders. It also delineates the association of such therapy use with physical and mental health-related quality of life (HRQoL). METHOD: The sample (N = 200) consisted of African American and White elders from south-central North Carolina. Participants completed baseline interviews and repeated measures of nonprescribed therapy use over a 6-month follow-up. RESULTS: Prayer had the highest percentage (80.7%) of use for health promotion followed by OTC (54.3%); vitamins only (49.3%); herbs and supplements (40.5%); exercise (31.9%); and home remedies (5.2%). Exercise was significantly associated with better physical HRQoL (p < .05). However, elders who used nonprescribed therapies had poorer mental HRQoL than nonusers, adjusting for potential confounders. CONCLUSION: This analysis suggests that use of some nonprescribed therapies for health promotion is associated with poorer mental HRQoL. PMID- 24781968 TI - Going digital: adoption of electronic health records in assisted living facilities. AB - This pilot study examines the associations between structural characteristics and the adoption and subsequent use of electronic health records (EHR; resident demographics, clinical notes, medication lists, problem lists, discharge summaries, and advance directives) as a process characteristic in assisted living facilities (ALFs). The study is guided conceptually by Donabedian's Structure Process-Outcome (SPO) model. Primary survey data were collected from a randomly selected sample (N = 76) in Florida during 2009-2010. Analysis included descriptive and bivariate statistics. Descriptive results indicated that ALFs most frequently used an EHR to record medication lists. Characteristics, including size, profit status, resident case mix, and staffing, were associated at the bivariate level with the use of one or more functional domains of an EHR. Thus, the use of EHRs in ALFs is correlated with facility characteristics. PMID- 24781967 TI - Risk factors for hospitalization in a national sample of medicare home health care patients. AB - Acute care hospitalization during or immediately following a Medicare home health care (HHC) episode is a major adverse outcome, but little has been published about HHC patient-level risk factors for hospitalization. The authors determined risk factors at HHC admission associated with subsequent acute care hospitalization in a nationally representative Medicare patient sample (N = 374,123). Hospitalization was measured using Medicare claims data; risk factors were measured using Outcome Assessment and Information Set data. Seventeen percent of sample members were hospitalized. Multivariate logistic regression analysis found that the most influential risk factors (all p < .001) were skin wound as primary HHC diagnosis, clinician-judged guarded rehabilitation prognosis, congestive heart failure as primary HHC diagnosis, presence of depressive symptoms, dyspnea severity, and Black, compared to White. HHC initiatives that minimize chronic condition exacerbations and actively treat depressive symptoms might help reduce Medicare patient hospitalizations. Unmeasured reasons for higher hospitalization rates among Black HHC patients deserve further investigation. PMID- 24781969 TI - Fatigue and depressive symptoms in older people. AB - Fatigue is considered an important indicator of aging-related declines in health and functional abilities. Previous studies have indicated strong associations between fatigue and depressive symptoms among younger populations and in patient groups with specific diseases. However, it is not known how different measures of fatigue are associated with depressive symptoms among general older populations. The purpose of this study is to describe the prevalence of depressive symptoms among community-dwelling older adults reporting mobility-related or general feelings fatigue. The study population consisted of 75-year-old community-living individuals (n = 561). Both, mobility-related and general fatigue, were associated in a stepwise relationship with depressive symptoms: a higher level of fatigue was related to higher level of depressive symptoms. Especially major general fatigue was strongly associated with high level of depressive symptoms. It is important for professionals of the field to be aware of the associations between different measures of fatigue and depressive symptoms. PMID- 24781970 TI - Source contributions and spatiotemporal characteristics of PAHs in sediments: Using three-way source apportionment approach. AB - Polycyclic aromatic hydrocarbon (PAHs) were measured in sediments from 29 sites throughout Taihu Lake in China during 2 seasons to investigate spatiotemporal characteristics and source contributions using a 3-way source apportionment approach to positive matrix factorization (PMF3). Seasonal and spatial variations of levels and toxicity suggested higher individual carcinogenic PAH concentrations and toxic equivalent quantity (TEQ) in the flooding season. Three way PAHs dataset (PAH species, spatial variability, and seasonal variability) was analyzed by PMF3, and its results were compared with a widely used 2-way model (PMF2). Consistent results were observed: vehicular emission was the most important contributor (67.08% by PMF2 and 61.83% by PMF3 for the flooding season; 54.21% by PMF2 and 52.94% by PMF3 for dry season), followed by coal combustion and wood combustion in both seasons. The PMF-cluster analysis was employed to investigate spatial variability of source contributions. Findings can introduce the 3-way approach to apportion sources of PAHs and other persistent organic pollutants (POPs) in sediments, offering the advantage of accounting for information on 3-way datasets. PMID- 24781971 TI - Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. AB - Questions remain on how the excess risk of breast cancer associated with menopausal hormone therapy (MHT) evolves after treatment stops. We investigated that issue in the E3N cohort, with 3,678 invasive breast cancers identified between 1992 and 2008 among 78,353 women (881,290 person-years of postmenopausal follow-up). Exposure to MHT was assessed through biennial self-administered questionnaires and classified by type of progestagen component (progesterone or dydrogesterone; other progestagen), duration (short-term <=5 years; long-term >5 years) and time since last use (current, 3 months-5 years, 5-10 years, 10+ years). Hazard ratios (HR) and confidence intervals (CI) were estimated with Cox models. Among short-term users, only those currently using estrogens associated with a progestagen other than progesterone/dydrogesterone had a significantly elevated breast cancer risk (HR 1.70, 95 % CI 1.50-1.91, compared with never users). Long-term use of this type of MHT was associated with a HR of 2.02 (1.81 2.26) when current and of 1.36 (1.13-1.64), 1.34 (1.04-1.73), and 1.52 (0.87 2.63) when stopped <=5, 5-10, and 10+ years earlier, respectively. Our results suggest residual increases in breast cancer risk several years after MHT cessation, which are restricted to long-term treatments. Whether increases persist more than 10 years after cessation deserves continuing investigation. PMID- 24781972 TI - Contributors to nonadherence and nonpersistence with endocrine therapy in breast cancer survivors recruited from an online research registry. AB - Rates of adherence and persistence with endocrine therapy regimens (i.e., tamoxifen, aromatase inhibitors) by breast cancer survivors are suboptimal, with negative implications for prognosis. This study identified potential contributors to nonadherence and nonpersistence. From an online breast cancer research registry (Army of Women) including approximately 51,000 breast cancer survivors, we recruited 1,371 women who currently were taking endocrine therapy and 94 nonpersisters (i.e., diagnosed during the prior 5 years and on endocrine therapy within the prior 12 months, but no longer taking it). Participants completed an online questionnaire assessing demographic/medical characteristics, general and cancer-related psychosocial variables (i.e., depressive symptoms, anxiety, patient-oncologist relationship quality, cancer recurrence worry, general symptoms), and endocrine therapy-specific variables (i.e., endocrine therapy related symptoms, perceived endocrine therapy necessity, long-term therapy use concern, endocrine therapy-related emotions). Two weeks later, current users were re-contacted to complete an endocrine therapy adherence measure. In a final regression model, patient-reported nonadherence among current users was significantly associated with lower financial status, a prior switch in endocrine therapies, a poorer relationship with the oncologist, and lower perceived need for and more negative emotions regarding endocrine therapy (adjusted R (2) = 0.15, P < 0.001). In a final logistic regression model, endocrine therapy nonpersisters were significantly more likely than current users to report depressive symptoms, as well as more negative emotions and lower positive emotions related to endocrine therapy (adjusted R (2) = 0.10, P < 0.001). In addition to demographic/medical variables, several potentially modifiable psychosocial characteristics are likely to contribute to endocrine therapy nonadherence and nonpersistence. PMID- 24781973 TI - The endoplasmic reticulum stress markers GRP78 and CHOP predict disease-free survival and responsiveness to chemotherapy in breast cancer. AB - Glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP) are commonly used as markers of endoplasmic reticulum (ER) stress. As an ER chaperone, GRP78 functions as a potent anti-apoptotic factor and confers drug resistance, whereas CHOP is a key initiating factor of ER stress-related cell death. We aimed at investigating the predictive values of GRP78 and CHOP in breast cancer patients who underwent adjuvant chemotherapy. An immunohistochemistry screen for GRP78 and CHOP was performed using a tissue microarray containing 250 tumors from female patients diagnosed with invasive ductal breast carcinoma at the Fudan University Shanghai Cancer Center. The staining results were scored semi-quantitatively, and a prediction model was constructed to verify the hypothesis. In this retrospective cohort study, CHOP correlated with prolonged disease-free survival (HR = 0.385, 95 % CI 0.215-0.688; P = 0.001), whereas GRP78 showed an opposite association (HR = 4.573; 95 % CI 2.291-9.128; P < 0.001). Moreover, in a GRP78-positive subset, CHOP overexpression correlated with a lower risk of recurrence. In the receiver operating characteristic analysis, the prediction capability of the predictive model combining the above two markers surpassed that of the traditional model (P = 0.0085 for the area under the curve comparison). Within the anthracycline treatment subgroup, the combined GRP78 and CHOP exhibited similar predictive significance. Cumulatively, our findings suggest a tight association between ER stress markers and clinical outcomes for patients with breast cancer. PMID- 24781974 TI - Associations between anthropometric characteristics, physical activity, and breast cancer risk in a Canadian cohort. AB - Obesity, physical inactivity, and sedentary behavior, concomitants of the modern environment, are potentially modifiable breast cancer risk factors. This study investigated the association of anthropometric measurements, physical activity and sedentary behavior, with the risk of incident, invasive breast cancer using a prospective cohort of women enrolled in the Canadian Study of Diet, Lifestyle and Health. Using a case-cohort design, an age-stratified subcohort of 3,320 women was created from 39,532 female participants who returned completed self administered lifestyle and dietary questionnaires at baseline. A total of 1,097 incident breast cancer cases were identified from the entire cohort via linkage to the Canadian Cancer Registry. Cox regression models, modified to account for the case-cohort design, were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between anthropometric characteristics, physical activity, and the risk of breast cancer. Weight gain as an adult was positively associated with risk of post-menopausal breast cancer, with a 6 % increase in risk for every 5 kg gained since age 20 (HR 1.06; 95 % CI 1.01-1.11). Women who exercised more than 30.9 metabolic equivalent task (MET) hours per week had a 21 % decreased risk of breast cancer compared to women who exercised less than 3 MET hours per week (HR 0.79; 95 % CI 0.62-1.00), most evident in pre-menopausal women (HR 0.62; 95 % CI 0.43-0.90). As obesity reaches epidemic proportions and sedentary lifestyles have become more prevalent in modern populations, programs targeting adult weight gain and promoting physical activity may be beneficial with respect to reducing breast cancer morbidity. PMID- 24781975 TI - Chemical bond properties and charge transfer bands of O(2-)-Eu(3+), O(2-)-Mo(6+) and O(2-)-W(6+) in Eu(3+)-doped garnet hosts Ln3M5O12 and ABO4 molybdate and tungstate phosphors. AB - Charge transfer (CT) energy from the ligand to the central ions is an important factor in luminescence properties for rare earth doped inorganic phosphors. The dielectric theory of complex crystals was used to calculate chemical bond properties. Combining the photoluminescence and the dielectric theory of complex crystals, the CT bands of O(2-)-Eu(3+), O(2-)-Mo(6+) and O(2-)-W(6+) for Eu(3+) doped inorganic phosphors have been investigated experimentally and theoretically. Taking Eu(3+)-doped Ln3M5O12 (Ln = Y, Lu and M = Al, Ga), Gd3Ga5O12, MMoO4 (M = Ca, Sr, Ba) and MWO4 (M = Ca, Sr, Ba) as typical phosphors, we investigated the effects of the cation size on the CT bands and chemical bond properties including the bond length (d), the covalency (fc), the bond polarizability (alphab) and the environmental factor (he) of O(2-)-Eu(3+), O(2-) Mo(6+) and O(2-)-W(6+), respectively. For systematic isostructural Ln3M5O12 (Ln = Y, Lu and M = Al, Ga) phosphors, with the increasing M ion radius, the bond length of Ln-O decreases, but fc and alphab increase, which is the main reason that the environmental factor increased. For the isostructural MMoO4:Eu, with the increasing M ion radius, the Mo-O bond length increases, but fc and alphab decrease, and thus he decreases. However, in the compound system MWO4:Eu (M = Ca, Ba) with the increasing M ion radius, the O-W bond length increases, but fc and alphab increase, and thus he increases and the O-W CT energy decreases. Their O(2 )-Eu(3+), O(2-)-Mo(6+) and O(2-)-W(6+) CT bands as well as their full width at half maximum (FWHM) were directly influenced by he. And with the increasing he, CT bands of O-Eu or O-Mo or O-W decrease and their FWHM increases. These results indicate a promising approach for changing the material properties, searching for new Eu(3+) doped molybdate, tungstate or other oxide phosphors and analyzing the experimental result. PMID- 24781976 TI - Chinese brushes: controllable liquid transfer in ratchet conical hairs. AB - The controllable liquid transfer of a Chinese brush is attributable to the unique anisotropic multi-scale structures of the freshly emergent hairs. A large mass of liquid an be dynamically balanced within the brush as a cooperative effect of the Laplace pressure difference, the asymmetrical retention force, and gravity. Inspired by this, a device is developed with parallel hairs that allows for direct writing of micro-lines. PMID- 24781977 TI - Molecularly imprinted supermacroporous cryogels for myoglobin recognition. AB - Myoglobin is a primary iron, and oxygen-binding protein of muscle tissues and levels can be an important diagnostic biomarker for acute myocardial infarction, myocardial necrosis, or other cardiac diseases. The establishment of myoglobin recognition systems is important because of its protein's structural and functional values in physiology, biochemistry, and diagnostic value in some damaged muscle tissue and cardiac diseases. For this purpose, we used molecular imprinting technique for myoglobin recognition from aqueous solutions and human plasma. In the first step, myoglobin-imprinted poly(hydroxyethyl methacrylate) (PHEMA) cryogels (MGb-MIP) were prepared, and optimum myoglobin adsorption conditions were determined. Selectivity experiments have been done with the competitive proteins, and myoglobin adsorption from IgG and albumin-free human plasma was studied. The purity of the desorbed samples was determined with SDS PAGE. The desorption efficiency and reusability of the MGb-MIP cryogels were tested, and it was shown that without any significant loss in the adsorption capacity, MGb-MIP cryogels can be used a number of times for myoglobin recognition and separation. PMID- 24781978 TI - Growth inhibition of thermotolerant yeast, Kluyveromyces marxianus, in hydrolysates from cassava pulp. AB - In this study, we report the inhibition of Kluyveromyces marxianus TISTR5925 growth and ethanol fermentation in the presence of furan derivatives and weak acids (acetic acid and lactic acid) at high temperatures. Cassava pulp, obtained as the waste from starch processing, was collected from 14 starch factories located in several provinces of Thailand. At a high temperature (42 degrees C), the cassava pulp hydrolysate from some starch factories strongly inhibited growth and ethanol production of both K. marxianus (strain TISTR5925) and Saccharomyces cerevisiae (strain K3). HPLC detected high levels of lactic acid and acetic acid in the hydrolysates, suggesting that these weak acids impaired the growth of K. marxianus at high temperature. We isolated Trp-requiring mutants that had reduced tolerance to acetic acid compared to the wild-type. This sensitivity to acetic acid was suppressed by supplementation of the medium with tryptophan. PMID- 24781979 TI - Studies on production and biological potential of prodigiosin by Serratia marcescens. AB - Efficacy of Serratia marcescens for pigment production and biological activity was investigated. Natural substrates like sweet potato, mahua flower extract (Madhuca latifolia L.), and sesam at different concentrations were taken. As a carbon source microorganism favored potato powder was followed by sesam and mannitol, and as nitrogen source casein hydrolysate was followed by yeast and malt extract. The effect of inorganic salts on pigment production was also studied. At final optimized composition of suitable carbon, nitrogen source, and trace materials and at suitable physiological conditions, prodigiosin production was 4.8 g L(-1). The isolated pigment showed antimicrobial activity against different pathogenic bacteria and fungi. Extracted pigment was characterized by spectroscopy, Fourier transform infrared (FTIR), and thin layer chromatography (TLC) which confirm production of biological compound prodigiosin. This study suggests that use of sweet potato powder and casein can be a potential alternative bioresource for commercial production of pigment prodigiosin. PMID- 24781980 TI - Comparative analysis and modeling of superoxide dismutases (SODs) in Brachypodium distachyon L. AB - Superoxide dismutase (SOD, EC 1.15.1.1) is an enzyme catalyzing the dismutation of superoxide radical to hydrogen peroxide and dioxygen. To date, four types of SODs--Cu/ZnSOD, MnSOD, FeSOD, and NiSOD--have been identified. In this study, SOD proteins of Brachypodium distachyon (L.) Beauv. were screened by utilization of bioinformatics approaches. According to our results, Mn/FeSODs and Cu/ZnSODs of B. distachyon were found to be in basic and acidic character, respectively. Domain analyzes of SOD proteins revealed that iron/manganese SOD and copper/zinc SOD were within studied SOD proteins. Based on the seconder structure analyzes, Mn/FeSODs and Cu/ZnSODs of B. distachyon were found as having similar sheets, turns and coils. Although helical structures were noticed in the types of Mn/FeSODs, no the type of Cu/ZnSODs were identified having helical structures. The predicted binding sites of Fe/MnSODs and Cu/ZnSODs were confirmed for having His-His-Asp-His and His-His-His-Asp-Ser residues with different positions, respectively. The 3D structure analyzes of SODs revealed that some structural divergences were observed in patterns of SODs domains. Based on phylogenetic analysis, Mn/FeSODs were found to have similarities whereas Cu/ZnSODs were clustered independently in phylogenetic tree. PMID- 24781981 TI - Comparative analysis of bacterial expression systems for keratinase production. AB - To explore a better expression system for the production of keratinase, the keratinase gene from Bacillus licheniformis BBE11-1 was expressed in Escherichia coli, Bacillus subtilis, and Pichia pastoris. The corresponding recombinant keratinases were named ker E, ker B, and ker P, respectively. All recombinant keratinases had an optimal pH at 10 although the pH stability of ker E and ker P was higher than that of ker E. The optimal temperature and thermostability of ker P were enhanced compared with those of ker E and ker B. The recombinant keratinases were inhibited by Mn2+ but experienced little influence from other metal ions. Furthermore, all recombinant keratinases could retain almost 80 % activity after treatment with 1 M hydrogen peroxide for 5 h. Under optimized conditions in a 3-L fermenter, the maximum keratinase activities obtained from recombinant B. subtilis and P. pastoris were 3,010 and 1,050 U/mL, respectively. This maximum keratinase activity from B. subtilis is the highest activity ever reported for any bacterial strain. These results indicate that B. subtilis is the ideal host for keratinase production, with potential applications in textile processing and feed supplements. PMID- 24781982 TI - First report of a lipopeptide biosurfactant from thermophilic bacterium Aneurinibacillus thermoaerophilus MK01 newly isolated from municipal landfill site. AB - A biosurfactant-producing thermophile was isolated from the Kahrizak landfill of Tehran and identified as a bacterium belonging to the genus Aneurinibacillus. A thermostable lipopeptide-type biosurfactant was purified from the culture medium of this bacterium and showed stability in the temperature range of 20-90 degrees C and pH range of 5-10. The produced biosurfactant could reduce the surface tension of water from 72 to 43 mN/m with a CMC of 1.21 mg/mL. The strain growing at a temperature of 45 degrees C produces a substantial amount of 5 g/L of biosurfactant in the medium supplemented with sunflower oil as the sole carbon source. Response surface methodology was employed to optimize the biosurfactant production using sunflower oil, sodium nitrate, and yeast extract as variables. The optimization resulted in 6.75 g/L biosurfactant production, i.e., 35% improved as compared to the unoptimized condition. Thin-layer chromatography, FTIR spectroscopy, 1H-NMR spectroscopy, and biochemical composition analysis confirmed the lipopeptide structure of the biosurfactant. PMID- 24781984 TI - Long-term changes in nutrients and mussel stocks are related to numbers of breeding eiders Somateria mollissima at a large Baltic colony. AB - BACKGROUND: The Baltic/Wadden Sea eider Somateria mollissima flyway population is decreasing, and this trend is also reflected in the large eider colony at Christianso situated in the Baltic Sea. This colony showed a 15-fold increase from 1925 until the mid-1990's, followed by a rapid decline in recent years, although the causes of this trend remain unknown. Most birds from the colony winter in the Wadden Sea, from which environmental data and information on the size of the main diet, the mussel Mytilus edulis stock exists. We hypothesised that changes in nutrients and water temperature in the Wadden Sea had an effect on the ecosystem affecting the size of mussel stocks, the principal food item for eiders, thereby influencing the number of breeding eider in the Christianso colony. METHODOLOGY/PRINCIPAL FINDING: A positive relationship between the amount of fertilizer used by farmers and the concentration of phosphorus in the Wadden Sea (with a time lag of one year) allowed analysis of the predictions concerning effects of nutrients for the period 1925-2010. There was (1) increasing amounts of fertilizer used in agriculture and this increased the amount of nutrients in the marine environment thereby increasing the mussel stocks in the Wadden Sea. (2) The number of eiders at Christianso increased when the amount of fertilizer increased. Finally (3) the number of eiders in the colony at Christianso increased with the amount of mussel stocks in the Wadden Sea. CONCLUSIONS/SIGNIFICANCE: The trend in the number of eiders at Christianso is representative for the entire flyway population, and since nutrient reduction in the marine environment occurs in most parts of Northwest Europe, we hypothesize that this environmental candidate parameter is involved in the overall regulation of the Baltic/Wadden Sea eider population during recent decades. PMID- 24781983 TI - Nesprin-1 role in DNA damage response. AB - Nuclear envelope (NE) proteins have fundamental roles in maintaining nuclear structure, cell signaling, chromatin organization, and gene regulation, and mutations in genes encoding NE components were identified as primary cause of a number of age associated diseases and cancer. Nesprin-1 belongs to a family of multi-isomeric NE proteins that are characterized by spectrin repeats. We analyzed NE components in various tumor cell lines and found that Nesprin-1 levels were strongly reduced associated with alterations in further NE components. By reducing the amounts of Nesprin-1 by RNAi mediated knockdown, we could reproduce those alterations in mouse and human cell lines. In a search for novel Nesprin-1 binding proteins, we identified MSH2 and MSH6, proteins of the DNA damage response pathway, as interactors and found alterations in the corresponding pathways in cells with lower Nesprin-1 levels. We also noticed increased number of gammaH2AX foci in the absence of exogenous DNA damage as was seen in tumor cells. The levels of phosphorylated kinases Chk1 and 2 were altered in a manner resembling tumor cells and the levels of Ku70 were low and the protein was not recruited to the DNA after hydroxyurea (HU) treatment. Our findings indicate a role for Nesprin-1 in the DNA damage response pathway and propose Nesprin-1 as novel player in tumorigenesis and genome instability. PMID- 24781986 TI - Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice. AB - The adipokine chemerin and its receptor, chemokine-like receptor 1 (Cmklr1), are associated with insulin resistance and nonalcoholic fatty liver disease (NAFLD), which covers a broad spectrum of liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). It is possible that chemerin and/or Cmklr1 exert their effects on these disorders through inflammation, but so far the data have been controversial. To gain further insight into this matter, we studied the effect of whole-body Cmklr1 deficiency on insulin resistance and NAFLD. In view of the primary role of macrophages in hepatic inflammation, we also transplanted bone marrow from Cmklr1 knock-out (Cmklr1-/-) mice and wild type (WT) mice into low-density lipoprotein receptor knock-out (Ldlr-/-) mice, a mouse model for NASH. All mice were fed a high fat, high cholesterol diet containing 21% fat from milk butter and 0.2% cholesterol for 12 weeks. Insulin resistance was assessed by an oral glucose tolerance test, an insulin tolerance test, and by measurement of plasma glucose and insulin levels. Liver pathology was determined by measuring hepatic inflammation, fibrosis, lipid accumulation and the NAFLD activity score (NAS). Whole-body Cmklr1 deficiency did not affect body weight gain or food intake. In addition, we observed no differences between WT and Cmklr1-/- mice for hepatic inflammatory and fibrotic gene expression, immune cell infiltration, lipid accumulation or NAS. In line with this, we detected no differences in insulin resistance. In concordance with whole-body Cmklr1 deficiency, the absence of Cmklr1 in bone marrow-derived cells in Ldlr-/- mice did not affect their insulin resistance or liver pathology. Our results indicate that Cmklr1 is not involved in the pathogenesis of insulin resistance or NAFLD. Thus, we recommend that the associations reported between Cmklr1 and insulin resistance or NAFLD should be interpreted with caution. PMID- 24781988 TI - Relationship between renal injury and the antagonistic roles of angiotensin converting enzyme (ACE) and ACE2. AB - Angiotensin-converting enzyme 2 (ACE2), a newly discovered carboxypeptidase in the renin-angiotensin system (RAS), antagonizes ACE activity and plays an active role during tissue injury. Yet the mechanism of its action is not well known. Using a streptozotocin (STZ)-induced renal injury rat model, we investigated the relationship between renal injury and the antagonism between ACE and ACE2. We assayed the levels of urea nitrogen, urine glucose, creatinine, and protein, Ace2, Ace, angiotensin II type 1 receptor (At1) and Mas receptor mRNA, and renal and plasma angiotensin II (Ang II) in STZ-treated and untreated rats. We also used histology and immunohistochemistry to assess glomerular injury and ACE2 glomerular and cortical expression. The amounts of urea nitrogen, urine glucose, creatinine, and protein were significantly higher in STZ-treated rats than in control rats (P < 0.01). There were significant pathological changes in the kidney upon STZ-treatment. Ace2 and Ace mRNA levels were significantly higher in STZ-treated rats than in control rats (P < 0.05 and P = 0.05, respectively). There was no significant difference in the Mas receptor and At1 mRNA levels in the 2 groups, although At1 levels showed an increase upon STZ-treatment. The Ang II level in the renal cortical tissue and plasma of STZ-treated rats was higher than that of control rats (P < 0.05). The increase in Ace mRNA levels was higher than that of Ace2 mRNA levels, leading to an elevated Ace/Ace2 ratio. Together, these data suggest that the ACE-Ang II-AT1 axis is the dominant axis in severe kidney injury. PMID- 24781989 TI - Association between STAT3 gene polymorphisms and ulcerative colitis susceptibility: a case-control study in the Chinese Han population. AB - Ulcerative colitis (UC) is a chronic inflammation of the large intestine. The aim of this study was to investigate the association of two polymorphisms in STAT3 with the risk of UC development in the Chinese Han population. This is a hospital based case-control study involving 56 UC patients and 274 controls. Genotyping was performed using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. Statistical analyses were conducted using logistic regression and genotype risk score. Overall, there was a significant difference between patients and controls in the genotype distribution of rs2293152 (P = 0.044). The risk for UC associated with the rs2293152-G mutant allele was increased (odds ratio = 2.76; 95% confidence interval = 1.06- 7.24) under the dominant model. However, we failed to find any obvious differences in the rs4796793 genotype or allele distributions between the UC patients and controls, and did not detect any significant association of the rs4796793 polymorphism with UC across different genetic models of inheritance. Our study implies that the STAT3 rs2293152 polymorphism may be associated with the occurrence of UC and might be used as a predictive factor for UC in the Chinese Han population. PMID- 24781990 TI - Diversity of endophytic bacteria in Caragana microphylla grown in the desert grassland of the Ningxia Hui autonomous region of China. AB - The diversity of endophytic bacteria in the sand-fixation plant Caragana microphylla was investigated by amplified rDNA restriction analysis and by sequence and phylogenetic comparisons of the 16S rRNA genes. A total of 24, 19, and 17 operational taxonomic units were identified from 16S rDNA libraries of the plant roots, stems and leaves, respectively. Homology analysis revealed a 92-100% identity of bacterial 16S rDNA sequences compared with those in the GenBank database. The bacteria identified by sequence homology fell into the following groups: alpha-Proteobacteria, beta-Proteobacteria, gamma-Proteobacteria, bacilli, and uncultured bacterium. Sequence analysis demonstrated that the roots were colonized predominantly by Bradyrhizobiaceae, while bacteria from Burkholderiaceae and Sphingomonadaceae were predominant in the stems and leaves, respectively. Additionally, the endophytic bacterial community in leaves was more diverse than those in the roots and stems. Overall, the most abundant bacteria in all three tissues analyzed were from the Sphingomonadaceae and Burkholderiaceae families, although many bacterial populations were found in only a single tissue. These results suggest that the bacterial population of C. microphylla is diverse. PMID- 24781987 TI - Agenesis of the Corpus Callosum Due to Defective Glial Wedge Formation in Lhx2 Mutant Mice. AB - Establishment of the corpus callosum involves coordination between callosal projection neurons and multiple midline structures, including the glial wedge (GW) rostrally and hippocampal commissure caudally. GW defects have been associated with agenesis of the corpus callosum (ACC). Here we show that conditional Lhx2 inactivation in cortical radial glia using Emx1-Cre or Nestin Cre drivers results in ACC. The ACC phenotype was characterized by aberrant ventrally projecting callosal axons rather than Probst bundles, and was 100% penetrant on 2 different mouse strain backgrounds. Lhx2 inactivation in postmitotic cortical neurons using Nex-Cre mice did not result in ACC, suggesting that the mutant phenotype was not autonomous to the callosal projection neurons. Instead, ACC was associated with an absent hippocampal commissure and a markedly reduced to absent GW. Expression studies demonstrated strong Lhx2 expression in the normal GW and in its radial glial progenitors, with absence of Lhx2 resulting in normal Emx1 and Sox2 expression, but premature exit from the cell cycle based on EdU-Ki67 double labeling. These studies define essential roles for Lhx2 in GW, hippocampal commissure, and corpus callosum formation, and suggest that defects in radial GW progenitors can give rise to ACC. PMID- 24781991 TI - Efficient oil palm total RNA extraction with a total RNA extraction kit. AB - Oil palm tissues are rich in polyphenols, polysaccharides and secondary metabolites; these can co-precipitate with RNA, causing problems for downstream applications. We compared two different methods (one conventional and a kit-based method - Easy-Blue(TM) Total RNA Extraction Kit) to isolate total RNA from leaves, roots and shoot apical meristems of tissue culture derived truncated leaf syndrome somaclonal oil palm seedlings. The quality and quantity of total RNA were compared through spectrophotometry and formaldehyde gel electrophoresis. The specificity and applicability of the protocols were evaluated for downstream applications, including cDNA synthesis and RT-PCR analysis. We found that the conventional method gave higher yields of RNA but took longer, and it was contaminated with genomic DNA. This method required extra genomic DNA removal steps that further reduced the RNA yield. The kit-based method, on the other hand, produced good yields as well as well as good quality RNA, within a very short period of time from a small amount of starting material. Moreover, the RNA from the kit-based method was more suitable for synthesizing cDNA and RT-PCR amplification than the conventional method. Therefore, we conclude that the Easy BlueTM Total RNA Extraction Kit method is suitable and superior for isolation of total RNA from oil palm leaf, root and shoot apical meristem. PMID- 24781992 TI - Effect of MPO/H2O2/NO(-) system on nitric oxide-mediated modification of TTR amyloid and serum TTR in FAP ATTR Val30Met patients. AB - Amyloid deposits consist of protein fibrils and amorphous material, and this deposition is related to oxidative stress. Previously, we demonstrated the presence of high-density lipoproteins and/or lipids in amyloid deposits of familial amyloid polyneuropathy patients. In this study, the presence of myeloperoxidase (MPO) in amyloid deposits was demonstrated using immunohistochemical staining. In contrast, normal surrounding tissues were consistently negative for MPO. Nitrotyrosine was present in amyloid deposits after being exposed to the MPO/H2O2/NO(-) system by immunohistochemical staining, and the oxide mediated modification of serum transthyretin (TTR) was observed upon exposure to the MPO/H2O2 system using two-dimensional gel electrophoresis and TTR Western blotting. This observation revealed that the TTR amyloid deposits and serum TTR were oxidized by the MPO/H2O2/NO(-) system. Nitric oxide-mediated modification of TTR may play a role in amyloidogenesis in vivo. PMID- 24781993 TI - Epidemiological analysis of dyslipidemia in adults of three ethnicities in Xinjiang, China. AB - This study investigated the prevalence and distribution of dyslipidemia in adults of Uygur, Kazak, and Han ethnicity in Xinjiang, China. A questionnaire including general data, physical examination (blood pressure, body height, and body weight) and blood lipid [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL C)] was administered to 11,506 adults in Xinjiang, China from 2009 to 2010 using a stratified sampling method. The overall prevalence rates of dyslipidemia in Uygur, Kazak, and Han adults were 42.4, 31.6, and 30.2%, respectively; they were 42.4, 31.8, and 28.2% after age standardization (P < 0.01). After standardization, the overall prevalence rates in Uygur, Kazak, and Han men were 52.6, 35.4, and 33.2%, respectively, which were significantly higher than that in women of the corresponding ethnicities (P < 0.01). In Uygur, Kazak, and Han adults, there were significant differences with respect to the standardized prevalence rates of high TG (9.3, 9.3, and 17.3%), high TC (5.2, 6.9, and 6%), low HDL-C (33.6, 20.8, and 11.1%), and high LDL-C (2.4, 2.9, and 2%) (P < 0.05). The prevalence rates of dyslipidemia in Uygur, Kazak, and Han adults in Xinjiang are higher than the average levels in China, with significant differences in ethnicity, age, and gender. Han adults exhibited the highest prevalence rate of high TG. Meanwhile, Uygur adults had the highest prevalence rate of low HDL-C. Kazak adults had high prevalence rates of high TC, low HDL-C, and high LDL-C. PMID- 24781994 TI - A novel synthetic Cry1Ab gene resists rice insect pests. AB - A few insect control genes of Bacillus thuringiensis have been modified successfully to increase the expression in plants by replacing rare codons, increasing GC content, and avoiding the DNA elements that could cause premature transcription termination, mRNA instability, and potential methylation. However, the modification process was intricate and often confused researchers. In this study, we adopted a simple method to modify Cry1Ab only by individually replacing its amino acid sequence with corresponding rice-preferred codons based on analysis of 92,188 coding DNA sequences. Unexpectedly, all elements of A+T richness, which terminate or destabilize transcription in plants, were avoided in the newly designed mCry1Ab. However, mCry1Ab had 2 notable features: less synonymous codons and high GC content. mCry1Ab only employed 22 of the 61 codons to encode protein and had an enhanced GC content of 65%. The increase in GC content caused abundant potential methylation signals to emerge in mCry1Ab. To test whether mCry1Ab could be expressed in rice, we transferred it into Oryza japonica variety Wanjing97. Insect bioassays revealed that transgenic plants harboring this gene driven by 2 promoters, CaMV35S and OsTSP I, were highly resistant to rice leaffolder (Cnaphalocrocis medinalis). Analysis of R0 to R2 generation plants indicated that the mCry1Ab was inherited stably by the progeny. Our study provided a simple modified method for expressing exogenous genes in rice and confirmed that less synonymous codons and high GC content do not affect transgene expression in rice. PMID- 24781995 TI - Relationship between serum creatinine and obesity in children in Xinjiang, China. AB - This study was designed to analyze the relationship between serum creatinine and body mass index in children in Xinjiang, China. We used a stratified sampling method to select 5222 children aged 6-17 years in 3 areas in Xinjiang and then measured serum creatinine with an enzymatic method. Our analysis showed that the mean serum creatinine of the various age groups differed, and the reference value increased gradually with age. In the groups with subjects older than 10 years, the serum creatinine values had a positive correlation with body mass index (r = 0.016, 10- and 11-year-olds; r = 0.177, 12- and 13-year-olds; r = 0.314, 14- and 15-year-olds; r = 0.380, 16- and 17-year-olds; P < 0.05). In the multivariate regression analysis model, the positive relationship existed even after we removed influencing factors such as blood sugar and cholesterol (beta = 0.041, 10 and 11-year-olds; beta = 0.081, 12- and 13-year-olds; beta = 0.183, 14- and 15 year-olds; beta = 0.171, 16- and 17-year-olds; P < 0.05). Obesity is an independent risk factor associated with increasing serum creatinine levels in children aged more than 10 years. Weight control is important in the protection of renal function. PMID- 24781996 TI - Value of dual-source computed tomography in evaluating left ventricular function in patients with coronary heart disease. AB - We aimed to assess parameters reflecting left ventricular function by dual-source computed tomography (DSCT) with echocardiography (ECG) as control. Fifty-eight patients with coronary heart disease (CHD) were recruited from January to June 2011; 29 CHD patients had type II diabetes. All patients were assessed by cardiac DSCT and ECG examination. DSCT and ECG correlated well for ejection fraction (EF) (r = 0.70), end-systolic volume (ESV) (r = 0.87), stroke volume (SV) (r = 0.83), and end-diastolic volume (EDV) (r = 0.90). The mean ESV and EDV values measured by the two methods in CHD patients with type II diabetes were higher than those in non-diabetic patients, whereas the mean EF was lower. DSCT is an accurate and practical method for assessing left ventricular function. PMID- 24781997 TI - Variability and performance evaluation of introgressed Nigerian dura x Deli dura oil palm progenies. AB - Twelve introgressed oil palm (Elaeis guineensis) progenies of Nigerian dura x Deli dura were evaluated for bunch yield, yield attributes, bunch quality components and vegetative characters at the Malaysian Palm Oil Board Research Station, in Keratong, Pahang, Malaysia. Analysis of variance revealed significant to highly significant genotypic differences, indicating sufficient genetic variability among the progenies for bunch yield and its attributes, vegetative characters and bunch quality components, except fruit to bunch ratio. Fresh fruit bunch yield ranged from 167 kg.palm(-1).year(-1) in PK1330 to 212 kg.palm( 1).year(-1) in PK1351, with a mean yield of 192 kg.palm(-1).year(-1). Among the progeny, PK1313 had the highest oil to bunch ratio (19.36%), due to its high mesocarp to fruit ratio, fruit to bunch ratio and low shell to fruit ratio. Among the progenies, PK1313 produced the highest oil yield of 31.4 kg.palm(-1).year( 1), due to a high mesocarp to fruit ratio (61.2%) and a low shell to fruit ratio (30.7%), coupled with high fruit to bunch ratio (65.6%). PK1330 was found promising for selection, as it had desirable vegetative characters, including smaller petiole cross section (27.15 cm2), short rachis length (4.83 m), short palm height (1.85 m), and the lowest leaf number (164.6), as these vegetative characters are prerequisites for selecting palms for high density planting and high yield per hectare. The genetic variability among the progenies was found to be high, indicating ample scope for further breeding, followed by selection. PMID- 24781998 TI - N-terminal functional region of the invariant chain efficiently targets the binding of a CTL epitope to MHC class I molecules during cross-presentation. AB - Cross-presentation (CP) is important for priming T cell responses to many viral, bacterial, and tumor antigens. Here, we designed two Ii mutants, based on evidence that the invariant chain (Ii, also named CD74) binds newly synthesized MHC class I molecules with the class II-associated invariant chain peptide (CLIP) region of Ii, which occupies the peptide-binding groove. Specifically, we designed (1) Ii-O257, which is a CLIP-substituted Ii chimer, in which OVA257-264 (SIINFEKL) was substituted for CLIP, and (2) Ii-, also named CT257, which is a C terminal truncated form of Ii-O257 that contains the N-terminal flanking region of Ii. We immunized C57BL/6 mice with these recombinant proteins. Real-time PCR detected that mice immunized with either Ii-O257 or Ii-CT257 recombinant proteins exhibited increased IFN-gamma mRNA expression (approximately 11-fold and 13-fold, respectively) and increased IL-2 mRNA expression (approximately 9-fold and 11 fold, respectively), compared to mice immunized with the OVA257-264 peptide. In vivo cytokine analysis showed that recombinant Ii proteins were highly efficient at activating T cells. Confocal microscopy and co-immunoprecipitation showed that the 2 Ii-OVA257-264 chimers are associated intracellularly with H-2K(b) molecules. Thus, Ii-CT257 (amino acids 1-89) binds stably to MHC class I with high affinity, indicating that it is a minimal functional fragment of the Ii immune vector. In conclusion, the N-terminal functional region of the Ii fusion protein containing CTL epitopes might prove to be useful for developing peptide or DNA vaccines that use CP as the main mechanism for CD8(+) T cell stimulation. PMID- 24781999 TI - Survey and analysis of visual acuity of Kazakhs in different lighting environments. AB - The effect of different lighting environments on the vision and refractive error were investigated in 427 Kazakhs (828 eyes) aged from 40 to 60 years old, of which 279 were pastoral (546 eyes) and 148 were urban (282 eyes). Pastoral Kazakhs use natural illumination, whereas city Kazakhs mainly use artificial illumination. Of all cases, 19.1% (54 cases) had a vision of 0.4 to 0.5, 20.9% (59 cases) had 0.6 to 0.8, and 17.7% (50 cases) had above 1.0. However, the visual acuity distribution of the pastoral Kazakhs had a more obvious characteristic, which was mainly concentrated above 0.6. The vision of 25.1% (137) of cases was 0.6 to 0.8, whereas 58.4% (319) of cases had vision above 1.0. There were more cases with vision above 1.0 in the pastoral Kazakhs compared to the city Kazakhs (P < 0.05). The diopter of the city Kazakhs was between 0 D and 4.0 D, whereas that of the pastoral Kazakhs was between +2.0 D and -2.0 D. Diopters between +2.0 D and 0 D or less than 3.0 D differed significantly between the two groups. Daylight lamps were the main illumination photosources of the city Kazakhs. Artificial light illuminated 70.9% (105 cases) of the city Kazakhs for more than 6 h. By contrast, natural light illuminated 75.3% (210 cases) of the pastoral Kazakhs for an outdoor activity time of more than 9 h. These results suggest that poor lighting environment is a very important factor contributing to refractive error. PMID- 24782000 TI - Phylogenetic classification and clinical aspects of a new putative Deltapapillomavirus associated with skin lesions in cattle. AB - Bovine papillomaviruses (BPVs) are recognized as causal agents of benign and malignant tumors in cattle. Thirteen types of BPVs have already been described and classified into 3 distinct genera. Divergences in the nucleotide sequence of the L1 gene are used to identify new viral types through the employment of PCR assays with degenerated primers. In the present study, a method for identifying BPVs based on PCR-RFLP and DNA sequencing allowed the identification of a new putative Deltapapillomavirus, designated JN/3SP (JQ280500.1). The analysis of the L1 gene showed that this strain was most closely related to the BPVs -1, -2, -13 , and OaPV1 (71-73% genetic similarity). In this study, we describe the detection of this new putative Deltapapillomavirus type and verify its phylogenetic position within the genus. PMID- 24782001 TI - Chromosomal distribution of two multigene families and the unusual occurrence of an X1X1X2X2/X1X2Y sex chromosome system in the dolphinfish (Coryphaenidae): an evolutionary perspective. AB - Dolphinfishes (Coryphaenidae) are pelagic predators distributed throughout all tropical and subtropical oceans and are very important for commercial, traditional, and sport fishing. This small family contains the Coryphaena hippurus and Coryphaena equiselis species whose chromosomal aspects remain unknown, despite recent advances in cytogenetic data assimilation for Perciformes. In this study, both species were cytogenetically analyzed using different staining techniques (C-, Ag-, and CMA3 banding) and fluorescence in situ hybridization, to detect 18S rDNA and 5S rDNA. C. hippurus females exhibit 2n = 48 chromosomes, with 2m+4sm+42a (NF = 54). In C. equiselis, where both sexes could be analyzed, females displayed 2n = 48 chromosomes (2m+6sm+40a) and males exhibited 2n = 47 chromosomes (3m+6sm+38a) (NF = 56), indicating the presence of X1X1X2X2/X1X2Y multiple sex chromosomes. Sex-chromosome systems are rare in Perciformes, with this study demonstrating the first occurrence in a marine pelagic species. It remains unknown as to whether this system extends to other populations; however, these data are important with respect to evolutionary, phylogenetic, and speciation issues, as well as for elucidating the genesis of this unique sex system. PMID- 24782002 TI - Genetic diversity and population structure of different varieties of Morada Nova hair sheep from Brazil. AB - The aim of this study was to analyze genetic diversity and population structure among varieties of White (N = 40), Red (N = 32), and Black (N = 31) Morada Nova hair sheep from flocks in the northeastern Brazilian semiarid region. Fifteen nuclear microsatellite markers and two regions of mitochondrial DNA were used. The intra-population analysis demonstrated that the White variety had higher diversity, while the Red variety had the lowest values. The Bayesian analysis to assess the genetic population structure allowed differentiation between White, Red, and Black varieties, and revealed a tendency towards sub-structuring in the White variety flocks from the States of Ceara and Paraiba. The results of analyses of molecular variance showed that the greatest genetic structure was found when comparing flocks rather than varieties (8.59 vs 6.64% of the total variation, P < 0.001). Based on genetic distance, Dtl, both the dendrogram analysis and the principal coordinate analysis showed the formation of two main groups: one composed of White and another of Black and Red individuals. Five and two haplotypes were found for the D-loop region and the ND5 gene, respectively. A haplotype unique to the Red variety was found in the D-loop region and a variety haplotype unique to the Black variety was found in the ND5 gene; however, these frequencies were low and therefore require further validation. These results support the existence of substantial differences between the Red and White varieties and should be used as separate genetic resources and to improve conservation programs. PMID- 24782003 TI - General aspects of fertility and infertility. AB - Fertility rates have been declining in most Western nations over the past several decades, although it is not entirely clear if an increased rate of infertility substantially contributes to this. As compared to other species, the reproductive efficiency of humans is relatively low. Factors related to fertility include age, exposure to sexually transmitted diseases, frequency of intercourse, coital timing, as well as diet and lifestyle habits. Infertility is considered a disease due to its major disruption of major organ systems and life functions. An infertility evaluation is recommended after 12 months or more of regular, unprotected intercourse and may be considered after 6 months for those female patients over the age of 35 or with other known abnormalities. A proper infertility evaluation is a comprehensive examination of possibly identifiable infertility factors of both female and male partners, lending itself to the most appropriate and potentially effective treatment. PMID- 24782004 TI - Genetics of male fertility. AB - Early in embryogenesis, cells that are destined to become germ cells take on a different destiny from other cells in the embryo. The germ cells are not programmed to perform "vital" functions but to perpetuate the species through the transfer of genetic materials to the next generation. To fulfill their destiny, male germ cells undergo meiosis and extensive morphogenesis that transforms the round-shaped cells into freely motile sperm propelled by a beating flagellum to seek out their missing half. Apparently, extra genes and additional regulatory mechanisms are required to achieve all these unique features, and an estimated 11 % of genes are involved in fertility in Drosophila (Hackstein et al., Trends Genet 16(12):565-572, 2000). If comparative numbers of male fertility genes are needed in mammals, extra risks of male fertility problems are associated with disruptive mutations in those genes. Among human male infertility cases, approximately 22 % were classified as "idiopathic," a term used to describe diseases of unknown causes, with idiopathic oligozoospermia being the most common semen abnormality (11.2 %) (Comhaire et al., Int J Androl (Suppl 7):1-53, 1987). "Idiopathic" is a widely used adjective that is used to reflect our lack of understanding of the genetics of male fertility. Fortunately, after more than two decades of phenotypic studies using knockout mice and identifying genes disrupted in spontaneous mutant mice, we have unveiled new and unexpected aspects of crucial gene functions for fertility. Other efforts to categorize genes involved in male fertility in mammals have suggested a total of 1,188 genes (Hermo et al., Microsc Res Tech 73(4):241-494, 2010). Although intracytoplasmic sperm injection (ICSI) can be used to bypass many fertilization obstacles to achieve fertilization with only a few extracted sperm, the widespread use of ICSI without proper knowledge for genetic testing and counseling could still potentially propagate pleiotropic gene mutations associated with male infertility and other genetic diseases (Alukal and Lamb, Urol Clin North Am 35(2):277-288, 2008). In this chapter, we give a brief account of major events during the development of male germ cells and focus on the functions of several crucial genes that have been studied in mutant mouse models and are potential causes of human male infertility. PMID- 24782005 TI - Genetics of female infertility due to anomalies of the ovary and mullerian ducts. AB - Genetic factors are pivotal in reproductive development and subsequent reproductive processes. If disturbed, infertility can occur. In the female, genetic factors affecting the ovary and the uterus are not uncommon causes of infertility. Terminal deletions on the X long arm and X short arm and X chromosomal mosaicism have long been accepted as causes of premature ovarian failure (POF). Responsible genes on the X have not yet elucidated. Attractive candidate genes for POF also exist on autosomes, and in over a dozen genes molecular perturbations are documented in non-syndromic POF. The most common single-gene cause of POF is premutation carriers for FMR1 (fragile X syndrome). As other candidate genes and additional ethnic groups are interrogated, the proportion of POF cases due to single-gene mutation will increase. Among uterine anomalies, incomplete mullerian fusion is most common. Increased recurrence risks for first-degree relatives confirm a role for genetic factors; interrogation of candidate genes is under way. PMID- 24782006 TI - Gene polymorphisms in female reproduction. AB - This chapter presents an overview of the gene polymorphisms underlying the functions of ovarian receptors and their clinical implications in the female fecundity. A selection of genetic studies revealing significant associations between receptor polymorphisms, gene mutations, and some pathological conditions (i.e., female infertility, premature ovarian failure, polycystic ovary syndrome, endometriosis) are reviewed. PMID- 24782007 TI - Understanding the spermatozoon. AB - The former perception of the spermatozoon as a delivery device of the male genome has been expanded to include a new understanding of the cell's complex role in fertilization. Once the spermatozoon reaches the oocyte, it triggers egg activation and orchestrates the stages of pre- and post-fertilization in a preprogrammed pattern while tapping the oocyte's resources in an effort to generate a new life. PMID- 24782008 TI - Derivation of human embryonic stem cells (hESC). AB - Stem cells are characterized by their absolute or relative lack of specialization their ability for self-renewal, as well as their ability to generate differentiated progeny through cellular lineages with one or more branches. The increased availability of embryonic tissue and greatly improved derivation methods have led to a large increase in the number of hESC lines. PMID- 24782009 TI - The endocrinology of the menstrual cycle. AB - The ovulatory menstrual cycle is the result of the integrated action of the hypothalamus, pituitary, ovary, and endometrium. Like a metronome, the hypothalamus sets the beat for the menstrual cycle by the pulsatile release of gonadotropin-releasing hormone (GnRH). GnRH pulses occur every 1-1.5 h in the follicular phase of the cycle and every 2-4 h in the luteal phase of the cycle. Pulsatile GnRH secretion stimulates the pituitary gland to secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH). The pituitary gland translates the tempo set by the hypothalamus into a signal, LH and FSH secretion, that can be understood by the ovarian follicle. The ovarian follicle is composed of three key cells: theca cells, granulosa cells, and the oocyte. In the ovarian follicle, LH stimulates theca cells to produce androstenedione. In granulosa cells from small antral follicles, FSH stimulates the synthesis of aromatase (Cyp19) which catalyzes the conversion of theca-derived androstenedione to estradiol. A critical concentration of estradiol, produced from a large dominant antral follicle, causes positive feedback in the hypothalamus, likely through the kisspeptin system, resulting in an increase in GnRH secretion and an LH surge. The LH surge causes the initiation of the process of ovulation. After ovulation, the follicle is transformed into the corpus luteum, which is stimulated by LH or chorionic gonadotropin (hCG) should pregnancy occur to secrete progesterone. Progesterone prepares the endometrium for implantation of the conceptus. Estradiol stimulates the endometrium to proliferate. Estradiol and progesterone cause the endometrium to become differentiated to a secretory epithelium. During the mid-luteal phase of the cycle, when progesterone production is at its peak, the secretory endometrium is optimally prepared for the implantation of an embryo. A diagrammatic representation of the intricate interactions involved in coordinating the menstrual cycle is provided in Fig. 1. PMID- 24782010 TI - Assisted reproductive techniques. AB - Assisted reproductive technologies (ART) encompass fertility treatments, which involve manipulations of both oocyte and sperm in vitro. This chapter provides a brief overview of ART, including indications for treatment, ovarian reserve testing, selection of controlled ovarian hyperstimulation (COH) protocols, laboratory techniques of ART including in vitro fertilization (IVF), and intracytoplasmic sperm injection (ICSI), embryo transfer techniques, and luteal phase support. This chapter also discusses potential complications of ART, namely ovarian hyperstimulation syndrome (OHSS) and multiple gestations, and the perinatal outcomes of ART. PMID- 24782011 TI - Novel markers of male infertility. AB - Diagnostic tests should detect disease, have prognostic value, and aid in clinical decision making. Nowhere else in laboratory medicine does one have to interpret a subject's results within the dynamic of a couple as in reproductive medicine. Abnormal markers of male reproduction do not necessarily mean sterility, but instead indicate problems with spermatogenesis, sperm maturation, transport through epididymis and ejaculatory duct, or abnormal ejaculatory function. Decades of research suggest that one test will never fit all scenarios and a battery of assays evaluating different aspects of male reproduction will likely have the best prognostic value. There is a strong need for standardization and harmonization of evolving assays to establish their clinical relevance. Next generation genome sequencing and the discovery of small noncoding RNAs in sperm already are changing the field and permit further insight into the biology of male reproduction as well as offer new diagnostic tests. PMID- 24782012 TI - Luteal phase support in ART treatments. AB - In a normal spontaneous menstrual cycle, the luteal phase is characterized by the production and secretion of estradiol (E) and progesterone (P) from the corpus luteum (CL) in an episodic manner. The steroidogenesis of the CL is dependent on continued tonic luteinizing hormone (LH) secretion (Fritz and Speroff, Clinical gynecologic endocrinology and infertility, 8th edn. Wolters Kluwer, Lippincott Williams & Wilkins, Philadelphia, 2011). The dependence of the CL was further supported by the prompt luteolysis that followed the administration of GnRH analogues or withdrawal of GnRH when ovulation has been induced by the administration of pulsatile GnRH (Hutchison and Zeleznik, Endocrinology 115:1780 1786, 1984; Fraser et al., Hum Reprod 12:430-435, 1997). Progesterone concentrations normally rise sharply after ovulation, reaching a peak approximately 8 days after the LH surge. Since the secretion of E and P during the luteal phase is episodic and correlates closely with LH pulses, relatively low mid-luteal progesterone levels can be found in the course of a totally normal luteal phase (Fritz and Speroff, Clinical gynecologic endocrinology and infertility, 8th edn. Wolters Kluwer, Lippincott Williams & Wilkins, Philadelphia, 2011). PMID- 24782013 TI - General principles of cryopreservation. AB - Cryopreservation quickly became a cornerstone technology in assisted reproduction because the banking of gametes, embryos, and gonadal tissues has increased the effectiveness of assisted reproductive technology cycles for infertility treatment as well as fertility preservation for patients at risk of premature sterilization. Cryopreservation protocols, both slow/equilibrium cooling and vitrification methods, have evolved empirically and still depend heavily on operator skill, but further automation promises to improve reproducibility and uniformity of results. PMID- 24782014 TI - In vitro maturation of immature human oocytes for clinical application. AB - Meiotic progression in the oocyte is defined as oocyte maturation from reinitiation of the first meiotic division from the germinal vesicle (GV) stage to the metaphase-II (M-II) stage (Fig. 1), (Cha and Chian, Hum Reprod Update 4:103-120, 1998). Priming with FSH or HCG prior to immature oocyte retrieval improves oocyte maturation and pregnancy rates. The size of follicles may be an important feature for IVM treatment. The combination of natural-cycle IVF with immature oocyte retrieval followed by IVM is an attractive treatment for young women with all types of infertility without recourse to ovarian stimulation with an acceptable pregnancy rate. PMID- 24782015 TI - GnRH antagonist-based protocols for in vitro fertilization. AB - In this chapter we elaborate on the intricacies of employing GnRH antagonists for prevention of the endogenous luteinizing hormone surge during IVF. Several practical aspects of implementing a GnRH antagonist-based stimulation protocol are described; selection of the correct dose, choosing when to start the antagonist, programming of cycle starts, selection of the appropriate gonadotropins, and triggering of final oocyte maturation are elucidated. PMID- 24782016 TI - Ovarian stimulation for IVF: mild approaches. AB - In contrast to current approaches, the aim of mild stimulation is to develop safer and more patient-friendly protocols in which the risks of the treatment as a whole are minimized. Mild stimulation is defined as the method when exogenous gonadotropins are administered at lower doses, and/or for a shorter duration in GnRH antagonist co-treated cycles, or when oral compounds (antiestrogens, aromatase inhibitors) are used for ovarian stimulation for IVF, with the aim of limiting the number of oocytes obtained to fewer than eight. In this chapter we discuss the relevant physiology of follicle development, the development of milder stimulation protocols, the implications of mild stimulation, the current state of affairs, and future developments. PMID- 24782017 TI - IVF stimulation: protocols for poor responders. AB - One of the most vexing challenges in the practice of reproductive medicine is the management of the "poor responder," specifically the patient manifesting an inadequate follicular response to ovarian stimulation. Poor response predicts a reduction in the number of mature oocytes retrieved, with the consequences of fewer embryos available for selection and transfer, reduced pregnancy rates, and a markedly decreased likelihood of residual embryos for cryopreservation. This chapter reviews the definition and prediction of poor response and discusses strategies that have been developed and incorporated into the reproductive endocrinologist's clinical armamentarium in an effort to optimize outcomes for these women. It should be stated at the outset that no single approach is successful for all patients, and that there is currently no firm clinical consensus regarding the relative efficacy of the different stimulation protocols. This arises in part due to inconsistency regarding the definition of what constitutes a poor response and a paucity of well-designed, randomized controlled trials. PMID- 24782018 TI - Oocyte retrieval and quality evaluation. AB - After more than 30 years of harvesting oocytes for in vitro fertilization, collection techniques are well established. Presented here are dependable methods for maintaining environmental stability during such procedures and general descriptions of the materials collected. PMID- 24782019 TI - Sperm retrieval and quality evaluation. AB - Technical refinements in sperm retrieval methods and the application of advanced reproductive technologies (ART) using surgically retrieved sperm have enabled biological paternity in azoospermic men who were considered untreatable 20 years ago. Achievement of optimal reproductive outcomes in these patients benefits greatly from a multistep, interdisciplinary process of sperm acquisition that involves reproductive endocrinologists, urologists, or other specialists in male subfertility, and laboratory personnel with expertise in characterizing and isolating sperm from surgically retrieved specimens. The critical steps in this process are discussed in this chapter. PMID- 24782020 TI - Treatment of male infertility. AB - Major difficulties exist in the accurate and meaningful diagnosis of male reproductive dysfunction, and our understanding of the epidemiology and etiology of male infertility has proven quite complex.The numerous spermatozoa produced in mammals and other species provides some degree of protection against adverse environmental conditions represented by physical and chemical factors that can reduce reproductive function and increase gonadal damage even resulting in testicular cancer or congenital malformations. The wide fluctuations of sperm production in men, both geographical and temporal, may reflect disparate environmental exposures, occurring on differing genetic backgrounds, in varying psychosocial conditions, and leading to the diversified observed outcomes.Sperm analysis is still the cornerstone in diagnosis of male factor infertility, indeed, individually compromised semen paramaters while adequately address therapeutic practices is progressively flanked by additional tests. Administration of drugs, IUI, correction of varicocele, and, to a certain extent, IVF although they may not be capable of restoring fertility itself often result in childbearing. PMID- 24782021 TI - Techniques for slow cryopreservation of embryos. AB - The slow cryopreservation of embryos has been used for nearly three decades as a means of storing surplus conceptuses from single IVF (in vitro fertilization) cycles. Doing so has allowed caregivers to maximize pregnancy rates without wastage of precious biological materials. Very detailed methods are described here using a popular biological freezing unit manufactured by Planer PLC (Middlesex, UK). Culture media preparation and tranfer protocols, including replacement in both natural and stimulated cycles, are included. PMID- 24782022 TI - Cryopreservation of eggs. AB - Oocyte cryopreservation is playing an increasingly important role in the field of human infertility treatment. The ability to store viable oocytes for later use has given many women the option to delay childbearing in order to pursue other ventures in life, without the concern of losing the opportunity to have a family. Furthermore, oocyte cryopreservation is very valuable for diseased patients who have to undergo treatments that may compromise fertility. Also, infertility patients who produce large numbers of oocytes during a retrieval cycle now have the option of storing some eggs prior to fertilization, thereby reducing the number of embryos that have to be managed. Lastly, oocyte cryopreservation enables egg donation programs that are independent of fresh donations, which makes it possible for numerous recipients to benefit from a single donor.Traditionally, slow freezing was the only method available for oocyte cryopreservation. However, recent years have shown that ultrarapid cooling of oocytes results in higher survival and developmental rates. Thus, vitrification is today's preferred method of oocyte cryopreservation and therefore the only technique described.In this chapter, we present two reliable methods of oocyte vitrification that have been in use for several years and that have been experimentally validated. Since no single vitrification method is clearly superior to the rest, other systems are also briefly described to give the reader options when deciding which methods to utilize in their practice. PMID- 24782023 TI - Ovarian tissue cryopreservation and transplantation: a realistic, effective technology for fertility preservation. AB - It is clear that ovarian tissue cryopreservation can serve a very important role in providing fertility preservation. To date, more than 30 live human births have resulted from the transplantation of cryopreserved ovarian tissue, proving the successful implementation of this technique. The ideal conditions for ovarian tissue cryopreservation have yet to be determined, indicating the crucial need for more research in this field. Nonetheless, it is recommended that ovarian tissue cryopreservation be offered as an option to women before undergoing chemotherapy treatment in instances where there is no time to delay for hormonal stimulation and oocyte retrieval. PMID- 24782024 TI - Detection of monogenic disorders and chromosome aberrations by preimplantation genetic diagnosis. AB - This chapter highlights the methodologies of single cell genetic diagnosis along with the strengths and weaknesses of existing techniques. PMID- 24782025 TI - Embryo culture and selection: morphological criteria. AB - In this chapter, we have outlined the various morphological criteria for selection of the best embryo at each important milestone encountered in the progress from the oocyte to the blastocyst. As Gerris et al. stated, a combination of one, two, or even three selection points should lead to a more accurate selection of the best embryo, as no one criterion is better than the other. An embryo that fails to meet the entire set of selection criteria must be avoided as culture cannot correct an impaired embryo. PMID- 24782026 TI - Embryo selection using metabolomics. AB - Faced with an increasing demand to select one embryo to transfer back to patients, a number of techniques are being developed to assist in discriminating differences within the cohort of a patient's embryos. A new and emerging technology which allows us to measure the profile of different metabolites in embryo culture media and formulate a viability score correlated to implantation potential is metabolomics. PMID- 24782027 TI - Embryo transfer. AB - Embryo transfer is a critical step in the overall success of in vitro fertilization (IVF). Despite its apparent simplicity, it is an integral part of the IVF cycle that can be difficult to teach and perform well. In this chapter we describe the procedure of embryo transfer and discuss various modifications that have been evaluated in an effort to improve the probability of embryo implantation including ultrasound guidance, catheter design, transfer technique, as well as enrichment of the embryo transfer media. PMID- 24782028 TI - Safety of intracytoplasmic sperm injection. AB - Early follow-up studies of IVF children showed that the frequency of birth anomalies resembled those arising with natural conception. More detailed analyses confirmed these findings, reinforcing the concept of the preimplantation period as teratologically "safe." The use of intracytoplasmic sperm injection (ICSI) to achieve fertilization introduced another variable.ICSI's safety has often been criticized because the fertilizing spermatozoon neither binds to the zona pellucida nor fuses with oolemma. Bypassing these physiologic steps together with the arbitrary selection of the spermatozoon has been reason for concern. Thus far, ICSI offspring undergoing adolescence and beyond has provided sufficient information to reassure these qualms. In fact, the health of the offspring generated through ICSI, once taken into consideration the gestational order, the age and the genetic makeup of the couples are generally reassuring. PMID- 24782029 TI - Human germ cell differentiation from pluripotent embryonic stem cells and induced pluripotent stem cells. AB - Although 10-15 % of couples are infertile, little is known of the diverse, underlying pathologies in men and women with poor germ cell production; furthermore, for those with few or no high-quality germ cells, there are few options available for treatment. Thus, over the last decade, concerted efforts have been aimed at developing a biological system to probe the fundamentals of human egg and sperm production via pluripotent stem cell cells with the hopes of informing clinical decisions and ultimately providing alternative methods for therapy which may include developing a source of germ cells ultimately for reproductive purposes. PMID- 24782030 TI - Patterns of complementary and alternative medicine (CAM) use in children: a systematic review. AB - Utilization of complementary and alternative medicine (CAM) among children/adolescents is popular. This review summarizes the international findings for prevalence and predictors of CAM use among children/adolescents. We therefore systematically searched four electronic databases (PubMed, Embase, PsycINFO, AMED; last update in 07/2013) and reference lists of existing reviews and all included studies. Publications without language restriction reporting patterns of CAM utilization among children/adolescents without chronic conditions were selected for inclusion. The prevalence rates for overall CAM use, homeopathy, and herbal drug use were extracted with a focus on country and recall period (lifetime, 1 year, current use). As predictors, we extracted socioeconomic factors, child's age, and gender. The database search and citation tracking yielded 58 eligible studies from 19 countries. There was strong variation regarding study quality. Prevalence rates for overall CAM use ranged from 10.9 87.6 % for lifetime use and from 8-48.5 % for current use. The respective percentages for homeopathy (highest in Germany, United Kingdom, and Canada) ranged from 0.8-39 % (lifetime) and from 1-14.3 % (current). Herbal drug use (highest in Germany, Turkey, and Brazil) was reported for 0.8-85.5 % (lifetime) and 2.2-8.9 % (current) of the children/adolescents. Studies provided a relatively uniform picture of the predictors of overall CAM use (higher parental income and education, older children), but only a few studies analyzed predictors for single CAM modalities. CONCLUSION: CAM use is widespread among children/adolescents. Prevalence rates vary widely regarding CAM modality, country, and reported recall period. PMID- 24782031 TI - Prognostic factors in oral and oropharyngeal cancer based on ultrastructural analysis and DNA methylation of the tumor and surgical margin. AB - Oral and oropharyngeal cancers are characterized by relatively low 5- year survival rates due to many factors, including local recurrence. The identification of new molecular markers may serve for the estimation of prognosis and thus augment treatment decisions and affect therapy outcome. The aim of this study was to describe the morphological characteristics and the DNA methylation status of the CDKN2A,CDH1, ATM, FHIT and RAR- genes in the central and peripheral part of the tumor and the surgical margin and evaluate their prognostic significance. 53 patients with oral and oropharyngeal cancer were enrolled to the prospective study, and had been primarily treated surgically. Correlations between morphological data, hypermethylation status and clinicopathological data, as well as prognosis, were assessed. Nuclei polymorphism highly correlated with T stage (p < 0.0001), N stage (p < 0.046), and metastases to the lymph nodes pN (p < 0.004 ). Also, the number of cells in irregular mitosis correlated with T stage (p < 0.004), and highly with pN (p < 0.009). The significance of CDKN2A hypermethylation as a good prognostic factor was also established in the Kaplan Meir test. The ultrastructural analysis showed that none of the examined tumors had homogenous texture and that resection margin specimens clean in HE stained tissue samples frequently contained single tumor cells or few cells in groups surrounded by connective tissue. This indicates the superiority of electron microscopy over standard histopathological analysis. Thus, a combination of such morphological examination with epigenetic parameters described herein could result in the discovery of promising new prognostic markers of the disease. PMID- 24782032 TI - Association of single-nucleotide polymorphisms in ERCC1 and ERCC2 with glioma risk. AB - We conducted a case-control study to assess the role of three single-nucleotide polymorphisms (SNPs) in excision repair cross-complementation group 1 (ERCC1) and two SNPs in excision repair cross-complementation group 2 (ERCC2) on the glioma risk in a Chinese population, and investigate the gene-environmental interaction for the cancer risk. A 1:2 matched case-control study was conducted. Logistic regression analysis revealed that individuals carrying ERCC1 rs2298881 CC genotype were associated with risk of glioma when compared with AA genotype carriers. The significant associations of ERCC1 rs2298881 polymorphism with glioma susceptibility were observed in both the dominant and the recessive models. In a stratification analysis, we found that ERCC1 rs2298881 variants showed an increased association with the risk of glioma in males, ever smokers, and high-grade glioma cases. In conclusion, our study suggests that ERCC1 rs2298881 polymorphism is associated with risk of glioma in codominant, dominant, and recessive models, especially in males, smokers, and high-grade glioma cases. This finding could be useful in revealing the genetic characteristics of glioma and suggests more effective strategies for prevention and treatment. PMID- 24782033 TI - Role of ZIC1 methylation in hepatocellular carcinoma and its clinical significance. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. The zinc finger of the cerebellum (ZIC1) gene is a novel tumor suppressor gene that plays a crucial role in vertebrate development. Altered expression of ZIC1 is observed in various types of human cancers. The aims of the present study were to investigate the methylation status of ZIC1 in HCC and evaluate its clinical implication. The methylation status of ZIC1 was analyzed in 132 pairs of HCC and corresponding noncancerous tissues by methylation-specific polymerase chain reaction (PCR) (MSP). The expression of ZIC1 messenger RNA (mRNA) in HCC tissues was examined by real-time PCR. Methylation frequency of ZIC1 in HCC was significantly higher than that in the corresponding noncancerous tissues (P < 0.001), and it was correlated with tumor size (P = 0.022), histological differentiation (P = 0.033), and tumor stage (P = 0.009). The downregulation of the ZIC1 mRNA expression in HCC was correlated with the ZIC1 methylation (P < 0.001). The patients with methylated ZIC1 had a poorer overall survival than those without methylated ZIC1 (P < 0.001). Taken together, our results suggested that the hypermethylation may lead to promoter silencing of ZIC1 mRNA and associated with poor survival in HCC. Overall, aberrant methylation is an important mechanism for ZIC1 inactivation in HCC, and ZIC1 methylation may be a promising biomarker for the diagnosis and prognosis of HCC. PMID- 24782034 TI - Association of TP53 codon 72 and intron 3 16-bp Ins/Del polymorphisms with cervical cancer risk. AB - Cervical cancer incidence has grown worldwide, with it being a more significant problem in developing countries. Invasive squamous cell cervical cancers are preceded by a long phase of preinvasive disease, known as cervical intraepithelial neoplasia. Cervical cancer can develop when the virus takes advantage of any TP53 gene dysfunction of the host organism. TP53 is responsible for encoding the tumor suppressor p53 phosphoprotein, which helps preserve genome integrity. Currently, many studies have focused on genetic polymorphisms as an important contribution to cancer susceptibility, but few related to cervical intraepithelial neoplasia (CIN). Thus, the present study aimed to see whether patients with suspected CIN had TP53 gene polymorphisms that might have contributed to the development of neoplasia. This study included 133 women who were referred to the Cervical Pathology Clinic of the Maternity School Assis Chateaubriand MEAC for suspected cervical lesions. Polymorphism genotyping was carried out by the PCR-RFLP technique using DNA extracted from patients' blood. The most frequent genotype in both CIN(+) and CIN(-) patients was Arg/Pro TP53 codon 72 and A1A1 for 16-bp Del in intron 3. No risk of cervical cancer was found for the polymorphisms studied. However, a significant association was found when the two polymorphisms were combined: patients with the A1A1/ArgPro genotype were statistically more frequent in the CIN(-) group (p = 0.042), while A2A2 A1A2/ProArg was significantly more frequent in the CIN(+) group. The results of our study suggest that combined analysis of TP53 polymorphisms Arg72Pro and 16-bp Ins/Del may help to monitor the development of CIN in Brazilian women. PMID- 24782035 TI - Antidepressant dose, age, and the risk of deliberate self-harm. AB - IMPORTANCE: A comprehensive meta-analysis of randomized trial data suggests that suicidal behavior is twice as likely when children and young adults are randomized to antidepressants compared with when they are randomized to placebo. Drug-related risk was not elevated for adults older than 24 years. To our knowledge, no study to date has examined whether the risk of suicidal behavior is related to antidepressant dose, and if so, whether risk depends on a patient's age. OBJECTIVE: To assess the risk of deliberate self-harm by antidepressant dose, by age group. DESIGN, SETTING, AND PARTICIPANTS: This was a propensity score-matched cohort study using population-based health care utilization data from 162,625 US residents with depression ages 10 to 64 years who initiated antidepressant therapy with selective serotonin reuptake inhibitors at modal or at higher than modal doses from January 1, 1998, through December 31, 2010. MAIN OUTCOMES AND MEASURES: International Classification of Diseases, Ninth Revision (ICD-9) external cause of injury codes E950.x-E958.x (deliberate self-harm). RESULTS: The rate of deliberate self-harm among children and adults 24 years of age or younger who initiated high-dose therapy was approximately twice as high as among matched patients initiating modal-dose therapy (hazard ratio [HR], 2.2 [95% CI, 1.6-3.0]), corresponding to approximately 1 additional event for every 150 such patients treated with high-dose (instead of modal-dose) therapy. For adults 25 to 64 years of age, the absolute risk of suicidal behavior was far lower and the effective risk difference null (HR, 1.2 [95% CI, 0.8-1.9]). CONCLUSIONS AND RELEVANCE: Children and young adults initiating therapy with antidepressants at high-therapeutic (rather than modal-therapeutic) doses seem to be at heightened risk of deliberate self-harm. Considered in light of recent meta-analyses concluding that the efficacy of antidepressant therapy for youth seems to be modest, and separate evidence that antidepressant dose is generally unrelated to therapeutic efficacy, our findings offer clinicians an additional incentive to avoid initiating pharmacotherapy at high-therapeutic doses and to closely monitor patients starting antidepressants, especially youth, for several months. PMID- 24782036 TI - NOTCH1 signaling promotes chemoresistance via regulating ABCC1 expression in prostate cancer stem cells. AB - Chemotherapy is a strategy for patients with advanced prostate cancer, especially those with castration-resistant prostate cancer. Prostate cancer stem cells (PCSCs) are believed to be the origin of cancer recurrence following therapy intervention, including chemotherapy. The mechanisms underlying the chemoresistance of PCSCs are still poorly understood. In the present study, fluorescence-activated cell sorting was used to isolate PCSCs from LNCaP and PC3 cell lines. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide was used to measure the cell viability. Quantitative real-time PCR and western blotting were utilized to evaluate the mRNA and protein levels. ShRNA was employed to knock down target gene expression. Chromatin immunoprecipitation (ChIP) was performed to explore the detailed mechanism underlying ABCC1 expression. Our results revealed that the sorted PCSCs showed enhanced chemoresistance ability than matched non-PCSCs. Protein level of activated form of NOTCH1(ICN1) was significantly higher in PCSCs. Inhibition of NOTCH1 with shRNA could decrease ABCC1 expression, and improve chemosensitivity in PCSCs. Finally, ChIP-PCR showed ICN1 could directly bind to the promoter region of ABCC1. In conclusion, NOTCH1 signaling could transactivate ABCC1, resulting in higher chemoresistance ability of PCSCs, which might be one of the important mechanisms underlying the chemoresistance of PCSCs. PMID- 24782037 TI - High pre-operative urinary norepinephrine is an independent determinant of peri operative hemodynamic instability in unilateral pheochromocytoma/paraganglioma removal. AB - BACKGROUND: Peri-operative hemodynamic instability (HDI) may increase peri operative morbidity in pheochromocytoma/paraganglioma (PPGL) patients. OBJECTIVE: This study aimed to determine which tumor-related risk factors could lead to peri operative HDI in unilateral or single PPGL removal. METHODS: Before surgery, 66 PPGL patients had at least two sets of 24 h urine collected for fractionated catecholamine analysis. At surgery, an arterial line was inserted to record systolic blood pressure (SBP), diastolic BP, and mean arterial BP (MAP). Peri operative HDI was defined as hypertension (SBP > 160 mmHg) and/or hypotension (SBP < 90 mmHg and/or MAP < 60 mmHg) for >10 consecutive minutes either intra operatively or within the first 12 h after surgery. Urinary fractionated catecholamines and other variables were compared between those with peri operative HDI (group I) and those without (group II). RESULTS: A total of 15 (22.7 %) patients belonged to group I, while 51 patients belonged to group II. One (1.5 %) patient died 9 days after surgery. Relative to group II, group I had significantly higher urinary norepinephrine (NE) (5,488.0 vs. 1,980.0 nmol/L, p < 0.001), urinary normetanephrine (5,130.9 vs. 3,853.4 nmol/L, p = 0.045), maximum SBP at operation (188.2 vs. 167.4 mmHg, p = 0.037), but lower MAP after operation (78.9 vs. 91.8 mmHg, p = 0.026). Urinary NE (OD 1.02, 95 % confidence interval [CI] 1.01-1.03, p = 0.046) was an independent risk factor for peri-operative HDI. The urinary NE level significantly correlated with maximum intra-operative SBP and MAP (r 0.692, p < 0.001; and r 0.669, p < 0.001, respectively) and inversely correlated with maximum post-operative MAP (r -0.305, p = 0.040). CONCLUSIONS: High pre-operative urinary NE was an independent tumor-related factor for peri operative HDI and significantly correlated with sustained intra-operative hypertension and post-operative hypotension. PMID- 24782038 TI - Surgical Management of Rib Fractures: Strategies and Literature Review. AB - BACKGROUND AND AIMS: Rib fractures can cause significant problems in trauma patients, often resulting in pain and difficulty with respiration. To prevent pulmonary complications and decrease the morbidity and mortality rates of patients with rib fractures, currently there is a trend to provide surgical management of patients with flail chest. However, the indications for rib fracture fixation require further specification. MATERIAL AND METHODS: Past and current strategies are described according to a review of the medical literature. A systematic review was performed including current indications for rib fracture fixation. MEDLINE (2000-2013) was searched, as well as Embase (2000-2013) and Cochrane Databases, using the keywords rib, fracture, fixation, plate, repair, and surgery. RESULTS: Three retrospective studies were found that described different techniques for rib fracture fixation. The results demonstrated a reduced number of ventilation days, decreased long-term morbidity and pain, and satisfactory rehabilitation after surgical treatment. In addition to flail chest, age, Injury Severity Score, and the number of rib fractures were important predictive factors for morbidity and mortality. CONCLUSION: Surgical rib fracture fixation might be indicated in a broader range of cases than is currently performed. Prospective randomized trials are needed for further confirmation. PMID- 24782039 TI - Derivatization of antibody Fab fragments: a designer enzyme for native protein modification. AB - Bioconjugates, such as antibody-drug conjugates, have gained recent attention because of their increasing use in therapeutic and diagnostic applications. Commonly used conjugation reactions based upon chemoselective reagents exhibit a number of drawbacks: most of these reactions lack regio- and stereospecificity, thus resulting in loss of protein functionality due to random modifications. Enzymes provide an obvious solution to this problem, but the intrinsic (natural) substrate specificities of existing enzymes pose severe limitations to the kind of modifications that can be introduced. Here we describe the application of the novel trypsin variant trypsiligase for site-specific modification of the C terminus of a Fab antibody fragment via a stable peptide bond. The suitability of this designed biocatalyst was demonstrated by coupling the Her2-specific Fab to artificial functionalities of either therapeutic (PEG) or diagnostic (fluorescein) relevance. In both cases we obtained homogeneously modified Fab products bearing the artificial functionality exclusively at the desired position. PMID- 24782040 TI - Predicting Psychotherapy Dropouts: A Multilevel Approach. AB - The role of therapeutic processes in predicting premature termination of psychotherapy has been a particular focus of recent research. The purpose of this study was to contrast outpatients who completed therapy and those who dropped out with respect to their self-reported in-session experiences of self-esteem, mastery, clarification and the therapeutic alliance. The 296 patients with mixed disorders were treated with an integrative form of cognitive-behavioural therapy without pre-determined time limit (M = 20.2 sessions). Multilevel analyses indicated that patients who did not completetreatment reported, on average, lower levels of self-esteem, mastery and clarification and lower ratings of their therapeutic alliance in treatment in contrast to patients who completed therapy. Patient-reported change in self-esteem experiences over the course of treatment turned out to be the strongest predictor of dropout from psychotherapy or successful completion. When dropout occurred before the average treatment length was reached, patients reported fewer clarifying experiences as early as the first session and their ratings of the therapeutic alliance were characterized by an absence of positive development. Both of these aspects seem to be involved in patients' decisions to leave treatment early. The findings underscore the importance of the therapeutic process in understanding the mechanisms behind treatment dropout. KEY PRACTITIONER MESSAGE: Analyses data from 296 patients at a private outpatient clinic in a routine practice setting (CBT). Completer/dropout definition: presence or absence of measurement battery at post-assessment. Focuses on change in therapy processes by investigating post-session reports. Finds that positive changes in self-esteem experiences is the most robust predictor of dropout, followed by ratings of clarification experiences and the global alliance. In line with recent dropout research, these process indicators might help to detect therapeutic situations that are connected with psychotherapy dropouts. PMID- 24782043 TI - Insertion of alkynes into Pt-X bonds of square planar [PtX2(N^N)] (X = Cl, Br, I) complexes. AB - The reactivity with acetylene of [PtX2(Me2phen)] (X = Cl, Br, I) complexes has been investigated. Whereas the chlorido species [PtCl2(Me2phen)] exhibits negligible reactivity at short reaction times, the bromido and iodido species [PtBr2(Me2phen)] and [PtI2(Me2phen)] lead initially to formation of Pt(II) five coordinate complexes, [PtX2(eta(2)-CH=CH)(Me2phen)], that evolve to four coordinate alkenyl complexes of the type [PtX(eta(1)-E-CH=CHX)(Me2phen)]. The alkenyl complexes, in the presence of excess acetylene, establish an equilibrium with the five-coordinate alkyne-alkenyl species [PtX(eta(1)-E-CH=CHX)(eta(2) CH=CH)(Me2phen)] (X = Br, I). The pi-bonded acetylene can be exchanged with free olefins or C=O, affording the new alkene-alkenyl or carbonyl-alkenyl complexes [PtX(eta(1)-E-CH=CHX)(eta(2)-olefin)(Me2phen)] and [PtX(eta(1)-E CH=CHX)(C=O)(Me2phen)]. The five-coordinate geometry of the alkyne-alkenyl and alkene-alkenyl complexes was assessed from NMR data and is fully consistent with that of a previously determined X-ray structure of [PtBr(eta(1)-E-CH[double bond, length as m-dash]CHBr)(eta(2)-CH2=CH2)(Me2phen)]. PMID- 24782041 TI - Large sex differences in chicken behavior and brain gene expression coincide with few differences in promoter DNA-methylation. AB - While behavioral sex differences have repeatedly been reported across taxa, the underlying epigenetic mechanisms in the brain are mostly lacking. Birds have previously shown to have only limited dosage compensation, leading to high sex bias of Z-chromosome gene expression. In chickens, a male hyper-methylated region (MHM) on the Z-chromosome has been associated with a local type of dosage compensation, but a more detailed characterization of the avian methylome is limiting our interpretations. Here we report an analysis of genome wide sex differences in promoter DNA-methylation and gene expression in the brain of three weeks old chickens, and associated sex differences in behavior of Red Junglefowl (ancestor of domestic chickens). Combining DNA-methylation tiling arrays with gene expression microarrays we show that a specific locus of the MHM region, together with the promoter for the zinc finger RNA binding protein (ZFR) gene on chromosome 1, is strongly associated with sex dimorphism in gene expression. Except for this, we found few differences in promoter DNA-methylation, even though hundreds of genes were robustly differentially expressed across distantly related breeds. Several of the differentially expressed genes are known to affect behavior, and as suggested from their functional annotation, we found that female Red Junglefowl are more explorative and fearful in a range of tests performed throughout their lives. This paper identifies new sites and, with increased resolution, confirms known sites where DNA-methylation seems to affect sexually dimorphic gene expression, but the general lack of this association is noticeable and strengthens the view that birds do not have dosage compensation. PMID- 24782044 TI - Functional Pathways of Social Support for Mental Health in Work and Family Domains Among Chinese Scientific and Technological Professionals. AB - This study investigated the role of social support in the complex pattern of associations among stressors, work-family interferences and depression in the domains of work and family. A questionnaire was administered to a nationwide sample of 11,419 Chinese science and technology professionals. Several structural equation models were specified to determine whether social support functioned as a predictor or a mediator. Using Mplus 5.0, we compared the moderation model, the independence model, the antecedent model and the mediation model. The results revealed that the relationship between work-family interference and social support was domain specific. The independence model fit the data best in the work domain. Both the moderation model and the antecedent model fit the family domain data equally well. The current study was conducted to answer the need for comprehensive investigations of cultural uniqueness in the antecedents of work family interference. The domain specificity, i.e. the multiple channels of the functions of support in the family domain and not in the work domain, ensures that this study is unique and culturally specific. PMID- 24782045 TI - Mechanistic and cytotoxicity studies of group IV beta-diketonate complexes. AB - Group IV metal complexes have previously shown promise as novel anticancer agents. Here, we discuss the mechanistic and cytotoxic nature of a series of group IV beta-diketonate coordination complexes. Clear evidence that the ligands are exchangeable on the metal centre and that the beta-diketonate ligands can act as potential drug delivery vehicles of the group IV metal ions was obtained. When evaluated for the cytotoxicity against human colon adenocarcinoma (HT-29) and human breast adenocarcinoma (MCF-7) cell lines, a general trend of decreasing potency down the group IV metals was observed. The most promising results obtained were for the hafnium complexes, with the tris diphenyl beta-diketonate hafnium complex exhibiting IC50 values of 4.9 +/- 0.9 MUM and 3.2 +/- 0.3 MUM against HT-29 and MCF-7, respectively, which are comparable with the activity of cisplatin against the same cell lines. This tri beta-diketonate hafnium complex is the first to show potent in vitro cytotoxic activity. The results reported show that ligand design has a significant effect on the cytotoxic potential of the complexes, and that these group IV complexes warrant further evaluation as novel metal-containing anticancer agents. PMID- 24782047 TI - Rabbit MSTN gene polymorphisms and genetic effect analysis. AB - We analyzed meat samples of nine pure lines of rabbit and its 37 hybrid combinations by sequencing and single-strand conformation polymorphism techniques to explore genetic polymorphisms of all the three exon regions and part of the 5' regulatory region of the myostatin (MSTN) gene. Thus, we detected a single nucleotide mutation (T->C) on the 476 locus of the 5'-regulatory region, but no mutation sites were detected in the exon areas. The correlation analysis showed that the mutation had some favorable genetic effects, and it resulted in increased liver weight, carcass weight, forelegs weight, back and waist weight, ham weight, and tare weight, whereas it decreased muscle drip loss and cooking loss (P < 0.05). These results suggest that the mutations in the upstream regulatory region of the MSTN gene are beneficial to the rabbit soma development, and the mutations can be used as molecular markers for the selection of the meat quality of rabbits. PMID- 24782046 TI - Interleukin 6 and cognitive dysfunction. AB - The interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in interaction between immune and nervous system. Although IL-6 has neurotrophic properties and beneficial effects in the CNS, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. The source of the increase in peripheral IL-6 remains to be established and varies among different pathologies, but has been found to be associated with cognitive dysfunction in several pathologies. This comprehensive review provides an update summary of the studies performed in humans concerning the role of central and peripheral IL-6 in cognitive dysfunction in dementias and in other systemic diseases accompained by cognitive dysfuction such as cardiovascular, liver disease, Behcet's disease and systemic lupus erythematosus. Further research is needed to correlate specific deficits in IL-6 and its receptors in pathologies characterized by cognitive dysfunction and to understand how systemic IL-6 affects high cerebral function in order to open new directions in pharmacological treatments that modulate IL-6 signalling. PMID- 24782048 TI - Polymorphisms of the vitamin D receptor gene and the risk of inflammatory bowel disease: a meta-analysis. AB - The gene encoding vitamin D receptor (VDR) is recognized as a promising candidate for indicating the development of inflammatory bowel disease (IBD). Four genetic polymorphisms (ApaI, BsmI, FokI, TaqI) in VDR have been widely evaluated to determine their association with IBD, and the results of these evaluations are often inconsistent. Therefore, we conducted a meta-analysis to shed some light on this issue and explored the sources of the heterogeneity between studies. We identified six articles for ApaI (cases/controls: 1902/1468), eight for TaqI (3053/2145), and five each for BsmI (1512/1616) and FokI (2315/1676). Data were analyzed under the random-effects model, and heterogeneity was explored by subgroup analyses. Overall, except for TaqI in allelic comparison [odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.83-0.98], ApaI, BsmI, and FokI polymorphisms showed no significant associations with IBD across different genetic models of inheritance. However, subgroup analyses indicated significance for the association of ApaI with Crohn's disease (CD) risk (AA versus aa: OR = 1.40; 95%CI = 1.05-1.88), for BsmI in East Asians (BB plus Bb versus bb: OR = 1.77, 95%CI = 1.14-2.74), for TaqI in Caucasians (TT plus Tt versus tt: OR = 0.79, 95%CI = 0.63- 1.00), and with ulcerative colitis (UC) risk (T versus t: OR = 0.89, 95%CI = 0.80-0.99). There was a low probability of publication bias for all studied polymorphisms. Pooling previous individual studies on IBD, our findings demonstrated that the ApaI polymorphism may increase the risk of CD, whereas the TaqI polymorphism may decrease the risk of UC, especially in Caucasians. Moreover, this study leaves open the question of divergent genetic profiles across different ethnic groups. PMID- 24782050 TI - Gene polymorphisms associated with susceptibility to coronary artery disease in Han Chinese people. AB - This study investigated 5 single nucleotide polymorphism (SNP) haplotypes in susceptibility genes for coronary artery disease (CAD) and the putative involvement of these SNPs in CAD in the Chi-nese Han population. From March 2008 to June 2009, we selected 119 CAD patients and 115 subjects not related to the CAD of Chinese Han or-igin as controls. The SNP genotypes were performed by multiplex SNaP-shot technology. The HNRPUL1 gene rs11881940T and GATA2 gene rs3803T loci were highly correlated with CAD (P < 0.05). rs10757278G increased the risk of CAD in patients indicated by an odds ratio (OR) = 1.242 [95% confidence interval (CI) = 1.04-1.49]; rs11881940T and rs3803T were protective factors for CAD with ORs = 0.767 (95%CI = 0.61-0.97) and 0.53 (95%CI = 0.40 0.72), respectively. Analysis of the rs10757278, rs11881940 and rs3803 loci showed that haplotypes ATC (OR = 4.26; 95%CI = 2.85-6.40, P < 0.01), GAC (OR = 1.50; 95%CI = 1.25-1.81, P < 0.01) and GAT (OR = 1.53; 95%CI = 1.12-2.09, P < 0.01) were CAD risk factors, whereas GTC was protective (OR = 0.48; 95%CI = 0.32 0.72, P < 0.01). ATC and glucose were positively correlated (OR = 1.91; 95%CI = 1.01-3.61, P < 0.05). GAT was a risk factor for hyper-tension (OR = 2.86; 95%CI = 1.40-5.83, P < 0.01). In conclusion, poly-morphisms and haplotype analysis of susceptibility genes for CAD can improve predicting this disease and will enable early diagnosis of CAD. PMID- 24782049 TI - Different timing and spatial separation of parental chromosomes in intergeneric somatic hybrids between Brassica napus and Orychophragmus violaceus. AB - Experimental and newly formed hybrids and polyploids generated by wide crosses usually show varying degrees of cytological instability. The spatial separation of parental genomes and uniparental chromosome elimination in hybrid cells has been reported in many hybrids from plants and animals. Herein, the behavior of parental genomes in intergeneric somatic hybrids between Brassica napus and Orychophragmus violaceus was analyzed using genomic in situ hybridization (GISH). In mitotic and meiotic cells, the chromosomes from O. violaceus were distinguished from B. napus by their larger size and staining patterns. In interphase nuclei of the hybrid, O. violaceus-labeled chromatin appeared as large heterochromatic blocks that were nonrandomly distributed at prophase, typically distributed toward one side of the nucleus. In pollen mother cells at prophase I of meiosis, O. violaceus chromosomes appeared as one or two deeply stained chromatin blocks that resolved into bivalents at a late stage, after bivalents from B. napus were visible. Thereafter, bivalents of O. violaceus congressed to the equatorial plate and segregated at anaphase I after those from B. napus. The different behavior of O. violaceus chromosomes in the hybrids indicates that they have differential condensation states at interphase and progress later through the cell cycle and meiosis than B. napus chromosomes. This difference in behavior may restrict or prevent the formation of bivalents of mixed genome origin. Differential gene expression of parental alleles including rDNA loci may contribute to their distinct cytological behavior and to the phenotype of hybrids. PMID- 24782051 TI - Effects of destrin pathway mutations on the gene expression profile. AB - This study aimed to explore the interaction and crosstalk between pathways in response to destrin mutations. All the pathways from the MINT database were downloaded, a protein-protein interaction network was then constructed, and the crosstalk between pathways was investigated, in particular, the overlap of 2 significant pathway analysis results. As expected, the results showed that regulation of the actin cytoskeleton was the significant pathway of destrin mutations in mice. Further analysis indicated that 28 significant pathways cross talked with the pathway regulating the actin cytoskeleton. Importantly, 3 pathways, including regulation of actin cytoskeleton pathway, pathways in cancer, and the B cell receptor signaling pathway were linked by inositol phosphate metabolism based on crosstalk analysis of Gene Ontology relationships among pathways. All of these pathways have been demonstrated to participate in cytoskeleton dynamics. These findings might provide valuable insights into cytoskeleton dynamic abnormalities in destrin mutations of corneal diseases. PMID- 24782052 TI - Relationship between the acylation-stimulating protein gene and coronary heart disease in the Xinjiang Uygur and Han populations of China. AB - The association of the single nucleotide polymorphism 301T>C in the coding region of the acylation-stimulating protein (ASP) gene with coronary heart disease (CHD) was investigated in the Uygur (385 CHD patients and 483 control subjects) and Han (390 CHD patients and 439 control subjects) populations of China. The frequency of the CC and CT genotypes was significantly higher in patients with CHD compared to the control group (55.3 vs 46.2%, P = 0.001) in the Uygur population, but in the Han population, the frequency was significantly higher in the control group (51.7 vs 24.4%, P < 0.001). In addition, the C allele was significantly associated with CHD in the Uygur population (C allele: 33.8 vs 26.2%, T allele: 66.2 vs 73.8%; P = 0.004) and in the Han population (C allele: 14.5 vs 30.3%, T allele: 85.5 vs 69.7%; P < 0.001). The CC genotype was independently associated with increased risk of coronary artery disease when adjusted for other cardiovascular risk factors [odds ratio (OR) = 2.189, 95% confidence interval (CI) = 1.251-3.830, P = 0.001] in the Uygur population, but was a protective factor for CHD in the Han population (OR = 0.373, 95%CI = 0.187-0.745, P = 0.005). In conclusion, the 301T>C polymorphism of the ASP gene that influences the serum triglycerides level in the Uygur population, is associated with the development of CHD, and the CC genotype might be a risk factor of CHD. PMID- 24782053 TI - Limitation of high-resolution melting curve analysis for genotyping simple sequence repeats in sheep. AB - Variation in microsatellite or simple sequence repeat (SSR) loci has, until recently, relied heavily on the use of gel-based methods that can be both time consuming and difficult to genotype. Non gel-based systems are therefore important to increase simplicity and improve turn-around time without compromising assay sensitivity and accuracy. In this report, we assessed the latest of the non-gel-based methods, high-resolution melting (HRM) curve analysis. HRM is a technique that monitors exactly the decreasing fluorescence of intercalating dye in the process of dissociation of double-stranded DNA. The measurement immediately follows polymerase chain reaction in a one-step, closed tube method. Four SSR loci of different complexity in sheep, namely MAF209, MCM140, CB226, and SRCRSP5, were assessed using the LightScanners System with LC Greens PLUS DNA binding dye. In order to improve the accuracy of genotyping, we applied internal oligo nucleotide calibrators while performing HRM. DNA polymorphisms were previously identified using capillary electrophoresis analysis (CE). The result showed that CE detected more genotypes than HRM in the same loci regardless of the level of polymorphism at the SSR loci. We demonstrate current limitations of the HRM method for the analysis of SSR loci. PMID- 24782054 TI - Genome-wide analysis of the homeodomain-leucine zipper (HD-ZIP) gene family in peach (Prunus persica). AB - In this study, 33 homeodomain-leucine zipper (HD-ZIP) genes were identified in peach using the HD-ZIP amino acid sequences of Arabidopsis thaliana as a probe. Based on the phylogenetic analysis and the individual gene or protein characteristics, the HD-ZIP gene family in peach can be classified into 4 subfamilies, HD-ZIP I, II, III, and IV, containing 14, 7, 4, and 8 members, respectively. The most closely related peach HD-ZIP members within the same subfamilies shared very similar gene structure in terms of either intron/exon numbers or lengths. Almost all members of the same subfamily shared common motif compositions, thereby implying that the HD-ZIP proteins within the same subfamily may have functional similarity. The 33 peach HD-ZIP genes were distributed across scaffolds 1 to 7. Although the primary structure varied among HD-ZIP family proteins, their tertiary structures were similar. The results from this study will be useful in selecting candidate genes from specific subfamilies for functional analysis. PMID- 24782055 TI - HLA-B35, a common genetic trait, in a familial case of Henoch-Schoenlein purpura and Berger's disease. AB - Nephritis characterized by IgA mesangial depositions has been described both in Henoch-Schoenlein purpura (HSP) and in Berger's disease (BD), but common genetic traits are still uncertain. We report here the case of two brothers, the first affected by HSP with persistent nephritis and the second by BD, accidentally discovered as silent microhematuria 1 year after HSP onset in the first brother. HLA genotyping demonstrated the presence of HLA-B35 in both patients. Our findings reinforce the need to screen for urinary abnormalities in family members of patients affected by HSP nephritis to identify a silent IgA nephropathy. PMID- 24782056 TI - Analysis of differentially expressed genes in malignant biliary strictures. AB - Microarray data were collected from bile duct samples from subjects with malignant biliary strictures by endoscopic retrograde cholangiopancreatography to screen for key genes associated with this disease. A predicted interaction network was constructed for these genes to interpret their functions. The gene expression dataset GSE34166 (10 samples: 6 malignant and 4 benign control samples) was downloaded from the Gene Expression Omnibus database. R package scripts were used to process the data and screen for differentially expressed genes. Genes identified were uploaded to the analysis tool String 8.3 to generate a gene interaction network. A hub gene was identified by calculating the node degree. The interaction network of the hub gene with other genes in the human genome was constructed and screened (score >0.9), and pathway-enrichment analysis was performed to elucidate the hub gene function. In total, 377 differentially expressed genes were identified and a network comprising 209 pairs of interactions was constructed. The most critical hub gene was identified as GSTA1, and a GSTA1-based interaction network was constructed consisting of 25 genes (containing the differentially expressed gene GSTA3). The cytochrome P450 (CYP450)-metabolic pathway displayed the most significant enrichment. Additionally, 4 transcription factors and their binding sites were also identified. In conclusion, we have identified the differentially expressed genes GSTA1 (a hub gene) and GSTA3, which may cause abnormal gene expression and tumorigenesis through CYP450-metabolic pathways. The transcription factors and their binding sites in the promoter of the hub gene provide potential directions for future drug design. PMID- 24782057 TI - Study of white matter at the centrum semiovale level with magnetic resonance spectroscopy and diffusion tensor imaging in cerebral small vessel disease. AB - White matter lesion (WML) in magnetic resonance imaging is commonly observed in patients with cerebral small vessel disease (SVD), but the pathological mechanism of WML in SVD is still unclear. We observed the metabolism and microscopic anatomy of white matter in SVD patients. Twelve subjects clinically diagnosed with SVD and 6 normal control subjects were examined with magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI). The white matter at the centrum semiovale level was selected as the region of interest (ROI). The ROI metabolism parameters, including N-acetyl-l-aspartic acid (NAA), creatine (Cr), and choline (Cho) were measured by MRS. Microscopic parameters such as mean diffusion (MD) and fractional anisotropy (FA) in ROI were obtained by DTI. Compared with the normal control group, bilateral MD values in the SVD group were significantly elevated, whereas bilateral FA values in SVD were decreased, but the difference was not statistically significant. Additionally, NAA/Cho, Cho/Cr, and NAA/Cr showed no significant statistical differences. Our study suggests that the mechanisms of the SVD cognitive impairment are related to damage of the white matter structures rather than to brain metabolism. PMID- 24782058 TI - The significance of post-operative creatinine in predicting prognosis in cardiac surgery patients. AB - The purpose of the study is to investigate the effectiveness of serum creatinine, the most common indicator of acute kidney injury (AKI), in predicting the prognosis of critically ill patients after cardiac surgery. Also, we sought to validate the use of this biomarker in assessing the direct outcome of a clinical setting. We selected 592 patients from our hospital; the relevant information including name, disease, gender, age, EuroSCORE, length of stay (LOS), days of mechanical ventilation, days of noninvasive positive pressure ventilation, days of continuous renal replacement treatment, and mortality was recorded. Creatinine of pre-operative, 24, and 48 h post-operation specimens were analyzed. The difference in serum creatinine levels at various time points was compared using t test. Spearman correlation was used to analyze the correlation of serum creatinine to AKI and hard outcomes. Receiver-operating characteristic curves were generated, and the areas under the curves (AUCs) were compared to validate the adequacy of creatinine in predicting the post-operative AKI. The 48 h post operative and pre-operative serum creatinine were found to be informative in predicting the outcome of patients as indicated by the t test and Spearman correlation analysis. The 48 h creatinine with AUC of 0.811 was indicated to be significantly associated with the hard outcome. However, the 24 h and pre operative creatinine with AUCs of 0.701 and 0.658, respectively, were not adequately related to the outcomes. In conclusion, contrary to the existing belief that creatinine is not an informative parameter for the diagnosis and prognosis of AKI, we found that when measured at 48 h of cardiac surgery, serum creatinine is reflective of the outcome. PMID- 24782059 TI - Finite element analysis of minimal invasive transforaminal lumbar interbody fusion. AB - The purpose of our study is to develop and validate three-dimensional finite element models of transforaminal lumbar interbody fusion, and explore the most appropriate method of fixation and fusion by comparing biomechanical characteristics of different fixation method. We developed four fusion models: bilateral pedicle screws fixation with a single cage insertion model (A), bilateral pedicle screws fixation with two cages insertion model (B), unilateral pedicle screws fixation with a single cage insertion model (C), and unilateral pedicle screws fixation with two cages insertion model (D); the models were subjected to different forces including anterior bending, posterior extension, left bending, right bending, rotation, and axial compressive. The von Mises stress of the fusion segments on the pedicle screw and cages was recorded. Angular variation and stress of pedicle screw and cage were compared. There were differences of Von Mises peak stress among four models, but were within the range of maximum force. The angular variation in A, B, C, and D decreased significantly compared with normal. There was no significant difference of angular variation between A and B, and C and D. Bilateral pedicle screws fixation had more superior biomechanics than unilateral pedicle screws fixation. In conclusion, the lumbar interbody fusion models were established using varying fixation methods, and the results verified that unilateral pedicle screws fixation with a single cage could meet the stability demand in minimal invasive transforaminal interbody fusion. PMID- 24782060 TI - Simultaneous determination of calycosin-7-O-beta-D-glucoside, ononin, calycosin, formononetin, astragaloside IV, and astragaloside II in rat plasma after oral administration of Radix Astragali extraction for their pharmacokinetic studies by ultra-pressure liquid chromatography with tandem mass spectrometry. AB - A sensitive and reliable ultra-pressure liquid chromatography with tandem mass spectrometry (UPLC-MS) was developed and validated for simultaneous quantification of six main bioactive components, i.e., calycosin-7-O-beta-D glucoside, ononin, calycosin, formononetin, astragaloside IV, and astragaloside II in rat plasma after oral administration of the 95 % ethanol extraction from Radix Astragali. Plasma samples were extracted with Waters Oasis(TM) HLB 1 cc (30 mg) Extraction Cartridges (SPE) separated on an UPLCTM BEH C18 column and detected by MS with electro spray ionization interface in positive selective ion monitoring mode. Calibration curves offered linear ranges of two orders of magnitude with r (2) > 0.99. The method had the lower limit quantification of 1.30, 0.73, 1.17, 2.33, 0.63, and 0.83 ng/mL for ononin, calycosin, calycosin-7-O beta-D-glucoside, formononetin, astragaloside IV, and astragaloside II, respectively, with precision less than 10 %. The RSD of intra- and inter-day variations ranged from 1.66 to 6.46 and 3.39 to 6.58 %. This developed method was applied subsequently to pharmacokinetic studies of the six compounds in rats successfully. The proposed method was for the first time to compare the pharmacokinetic difference between calycosin-7-O-beta-D-glucoside and calycosin in rat plasma, so as between ononin and formononetin, and studied to the astragaloside II pharmacokinetics in rat plasma. PMID- 24782061 TI - Establishment of a novel in vitro test setup for electric and magnetic stimulation of human osteoblasts. AB - When large defects occur, bone regeneration can be supported by bone grafting and biophysical stimuli like electric and magnetic stimulation (EMS). Clinically established EMS modes are external coils and surgical implants like an electroinductive screw system, which combines a magnetic and electric field, e.g., for the treatment of avascular bone necrosis or pseudarthrosis. For optimization of this implant system, an in vitro test setup was designed to investigate effects of EMS on human osteoblasts on different 3D scaffolds (based on calcium phosphate and collagen). Prior to the cell experiments, numerical simulations of the setup, as well as experimental validation, via measurements of the electric parameters induced by EMS were conducted. Human osteoblasts (3 * 10(5) cells) were seeded onto the scaffolds and cultivated. After 24 h, screw implants (Stryker ASNIS III s-series) were centered in the scaffolds, and EMS was applied (3 * 45 min per day at 20 Hz) for 3 days. Cell viability and collagen type 1 (Col1) synthesis were determined subsequently. Numerical simulation and validation showed an adequate distribution of the electric field within the scaffolds. Experimental measurements of the electric potential revealed only minimal deviation from the simulation. Cell response to stimulation varied with scaffold material and mode of stimulation. EMS-stimulated cells exhibited a significant decrease of metabolic activity in particular on collagen scaffolds. In contrast, the Col1/metabolic activity ratio was significantly increased on collagen and non-sintered calcium phosphate scaffolds after 3 days. Exclusive magnetic stimulation showed similar but nonsignificant tendencies in metabolic activity and Col1 synthesis. The cell tests demonstrate that the new test setup is a valuable tool for in vitro testing and parameter optimization of the clinically used electroinductive screw system. It combines magnetic and electric stimulation, allowing in vitro investigations of its influence on human osteoblasts. PMID- 24782062 TI - Management of aneurysmal subarachnoid haemorrhage. AB - Aneurysmal subarachnoid haemorrhage (aSAH) occurs as a result of rupture of an intracranial aneurysm and affects a younger population compared with ischaemic stroke or intracerebral haemorrhage. Although it makes up only about 5% of all cerebrovascular events, it accounts for over a quarter of the productive life years lost to stroke. Its surgical and medical treatment represents a multidisciplinary effort. We herein provide an overview of current management options for aSAH. PMID- 24782064 TI - Gravure printing of graphene for large-area flexible electronics. AB - Gravure printing of graphene is demonstrated for the rapid production of conductive patterns on flexible substrates. Development of suitable inks and printing parameters enables the fabrication of patterns with a resolution down to 30 MUm. A mild annealing step yields conductive lines with high reliability and uniformity, providing an efficient method for the integration of graphene into large-area printed and flexible electronics. PMID- 24782063 TI - Early discontinuation and restart of insulin in the treatment of type 2 diabetes mellitus. AB - INTRODUCTION: Although the largest improvement in glycemic control occurs within the first 90 days of insulin therapy, little is known about early persistence on insulin therapy. This research aimed to identify predictors of early discontinuation and of subsequent restart of basal or mixture insulin among patients with type 2 diabetes mellitus (T2DM) and to assess the economic cost associated with such behaviors over a 1-year period. METHODS: Truven's Health Analytics Commercial Claims and Encounters database was utilized for the study. Logistic regressions were used to examine factors associated with early discontinuation of insulin (basal or mixture) and, among patients who discontinued early, the factors associated with restarting. Cost regressions were estimated using generalized linear models with a gamma distribution and logistic link. Kaplan-Meier survival curves were used to examine time to discontinuation and time to restart among those who discontinued. RESULTS: Multivariate analyses revealed that patient characteristics, prior healthcare resource utilization, comorbid diagnoses, and type of initiated insulin were associated with early discontinuation of insulin and of restarting among patients who discontinued early. Acute care (hospitalization and emergency room) costs were 9.6% higher among patients who discontinued early (P < 0.001), although outpatient, drug, and total costs were significantly lower among individuals who discontinued early. Among the early discontinuation subgroup, restarting insulin was associated with higher costs. Specifically: 11.3% higher acute care costs (P < 0.001), 24.0% higher outpatient costs (P < 0.001), 80.2% higher drug costs (P < 0.001), and 30.3% higher total costs (P < 0.001), compared to patients who discontinued early but did not restart insulin therapy in the 1-year post-period. CONCLUSION: Among patients with T2DM who were initiated on insulin therapy, early discontinuation of insulin and its subsequent restart were associated with significantly higher acute care costs, which may signal a more complex and challenging subgroup of patients who tend to be less engaged in outpatient care and may have poorer long term outcomes. PMID- 24782065 TI - The effect of acclimatization and ambient temperature on heat withdrawal threshold in rats. AB - BACKGROUND: Nociception in rats is frequently measured in terms of latency of withdrawal reaction to radiant heat (thermal nociceptive threshold). The aim of this study was to determine how much housing acclimatization and ambient temperature affect the results of thermal pain threshold testing. METHODS: All experiments used adult male Wistar rats. Thermal pain thresholds were tested using the radiant heat withdrawal reaction at three different body sites: forepaws, hind paws and tail. Skin temperature was measured using an Infrared thermometer and ambient temperature was set at 18, 20, 24 or 26 degrees C. RESULTS: The results demonstrate that (1) thermal pain threshold was inversely related to both ambient and skin temperature; (2) housing acclimatization and repeated testing had no effect on nociceptive thresholds at any of the three body sites; (3) a resting, cranio-caudal distribution, of nociceptive sensitivity was observed; (4) hind paws and tail were more sensitive to changes of skin and ambient temperature than forepaws. CONCLUSION: These findings show the importance of recording laboratory conditions in experiments and their influence on results. PMID- 24782066 TI - Involvement of SgvP in carbon-sulfur bond formation during Griseoviridin biosynthesis. AB - Griseoviridin (GV) is an A-type streptogramin antibiotic displaying antimicrobial activity and acting synergistically with viridogrisein (VG). Bioinformatic analyses reveal SgvP as the sole cytochrome P450 enzyme in the GV/VG gene cluster. To explore the role of SgvP in the GV/VG pathway, we inactivated the sgvP gene. The resulting DeltasgvP mutant generated two new products: GV-1 and GV 2, both lacking the C?S bridge. In trans complementation of the sgvP gene into the DeltasgvP mutant strain partially restores GV production. Feeding [1-(13) C] labeled cysteine to the wild-type strain led to enrichment of C-7 in the GV scaffold, thus verifying that the C?S bond in GV is formed through direct coupling of the free ?SH group provided by the side chain of cysteine. The above results highlight the significance of SgvP in C?S bond formation in griseoviridin biosynthesis. PMID- 24782067 TI - Introduction: international research ethics education. AB - NIH's Fogarty International Center has provided grants for the development of training programs in international research ethics for low- and middle-income (LMIC) professionals since 2000. Drawing on 12 years of research ethics training experience, a group of Fogarty grantees, trainees, and other ethics experts sought to map the current capacity and need for research ethics in LMICs, analyze the lessons learned about teaching bioethics, and chart a way forward for research ethics training in a rapidly changing health research landscape. This collection of papers is the result. PMID- 24782068 TI - Research ethics review: identifying public policy and program gaps. AB - We present an analytical framework for use by fellows of the Fogarty International Center-sponsored Advanced Certificate Program in Research Ethics for Central and Eastern Europe to identify gaps in the public policies establishing research ethics review systems that impede them from doing their job of protecting human research subjects. The framework, illustrated by examples from post-Communist countries, employs a logic model based on the public policy and public management literature. This paper is part of a collection of papers analyzing the Fogarty International Center's International Research Ethics Education and Curriculum program. PMID- 24782069 TI - Curricular aspects of the Fogarty bioethics international training programs. AB - The curriculum design, faculty characteristics, and experience of implementing masters' level international research ethics training programs supported by the Fogarty International Center was investigated. Multiple pedagogical approaches were employed to adapt to the learning needs of the trainees. While no generally agreed set of core competencies exists for advanced research ethics training, more than 75% of the curricula examined included international issues in research ethics, responsible conduct of research, human rights, philosophical foundations of research ethics, and research regulation and ethical review process. Common skills taught included critical thinking, research methodology and statistics, writing, and presentation proficiency. Curricula also addressed the cultural, social, and religious context of the trainees related to research ethics. Programs surveyed noted trainee interest in Western concepts of research ethics and the value of the transnational exchange of ideas. Similar faculty expertise profiles existed in all programs. Approximately 40% of faculty were female. Collaboration between faculty from low- and middleincome countries (LMICs) and high-income countries (HICs) occurred in most programs and at least 50% of HIC faculty had previous LMIC experience. This paper is part of a collection of papers analyzing the Fogarty International Research Ethics Education and Curriculum Development program. PMID- 24782070 TI - Research ethics capacity building in Sub-Saharan Africa: a review of NIH Fogarty funded programs 2000-2012. AB - The last fifteen years have witnessed a significant increase in investment in research ethics capacity development throughout the world. We examine nine research ethics training programs that are focused on Sub-Saharan Africa and supported by the US National Institutes of Health. We collected data from grants awards' documents and annual reports supplemented by questionnaires completed by the training program directors. Together, these programs provided long-term training in research ethics to 275 African professionals, strengthened research ethics committees in 19 countries in Sub-Saharan Africa, and created research ethics curricula at many institutions and bioethics centers within Africa. Trainees' leadership resulted in new national systems and policies on research ethics, human tissue storage and export, and methods of monitoring compliance with research ethics guidelines. Training programs adapted to challenges that arose due to varied trainees' background knowledge in ethics, duration of time available for training, spoken and written English language skills, administrative obstacles, and the need to sustain post-training research ethics activities. Our report showcases the development of awareness of research ethics and building/strengthening of basic research ethics infrastructure in Sub-Saharan Africa. Nevertheless, the increasing amount and complexity of health research being conducted in Sub-Saharan Africa suggests the need for continued investment in research ethics capacity development in this region. This paper is part of a collection of papers analyzing the Fogarty International Center's International Research Ethics Education and Curriculum Development program. PMID- 24782071 TI - Evaluating international research ethics capacity development: an empirical approach. AB - The US national institutes of health, Fogarty International Center (NIH-FIC) has, for the past 13 years, been a leading funder of international research ethics education for resource-limited settings. Nearly half of the NIH-FIC funding in this area has gone to training programs that train individuals from sub-Saharan Africa. Identifying the impact of training investments, as well as the potential predictors of post-training success, can support curricular decisionmaking, help establish funding priorities, and recognize the ultimate outcomes of trainees and training programs. Comprehensive evaluation frameworks and targeted evaluation tools for bioethics training programs generally, and for international research ethics programs in particular, are largely absent from published literature. This paper shares an original conceptual framework, data collection tool, and detailed methods for evaluating the inputs, processes, outputs, and outcomes of research ethics training programs serving individuals in resource-limited settings. This paper is part of a collection of papers analyzing the Fogarty International Center's International Research Ethics Education and Curriculum Development program. PMID- 24782072 TI - Perspectives from South and East Asia on clinical and research ethics: a literature review. AB - A review was conducted of English-language peer-reviewed and gray literature on health and ethics written by authors from Bangladesh, China, India, and Pakistan. This was supplemented by the knowledge of co-authors who are involved in bioethics capacity building in these countries. Of the identified literature that focused on the application of Western principles, it largely discussed informed consent and revealed norms in clinical decision-making that include physician paternalism, family involvement in decision-making, and reluctance to provide information that might upset patients. It appears that Western ethical principles may be interpreted and applied in unexpected ways. The literature further indicates that, although there is some consistency with Western ideas, Islamic, Confucian, and Indian religious and philosophical traditions contain concepts not reflected in international guidance. Findings suggest scholars from these countries seek to enter into a bioethics dialogue with the potential to enrich and inform "international" frameworks. PMID- 24782073 TI - Fogarty research ethics training programs in the Asia-Pacific: the merging of cultures. AB - In-depth interviews were undertaken with nine principal investigators and 16 former trainees from eight FIC programs recruiting trainees from the Asia-Pacific to assess the impact of training. Incorporation of new knowledge into teaching, research, and medical practice; advanced training; and ethics committee participation were the most common outcomes identified. When attempting to implement ethics activities posttraining, trainees often had to contend with opposition from more senior staff. Approaches that enhanced the cultural relevance of program content were identified as necessary, including comparing/contrasting non-Western principles and religions with Western bioethics, using region-specific case studies, and integrating clinical and research ethics. Best practices associated with program and trainee success included selecting more senior trainees clustered within Asia-Pacific institutions, offering a variety of degree and nondegree options, and post training mentorship and networking support. This paper is part of a collection of papers analyzing the Fogarty International Center's International Research Ethics Education and Curriculum Development program. PMID- 24782074 TI - Twelve years of Fogarty-funded bioethics training in Latin America and the Caribbean: achievements and challenges. AB - The landscape in research ethics has changed significantly in Latin America and the Caribbean over the past two decades. Research ethics has gone from being a largely foreign concept and unfamiliar practice to an integral and growing feature of regional health research systems. Four bioethics training programs have been funded by the Fogarty International Center (FIC) in this region in the past 12 years. Overall, they have contributed significantly to changing the face of research ethics through the creation of locally relevant training materials and courses (including distance learning), academic publications, workshops, and conferences in Spanish, and strengthening ethics review committees and national systems of governance. This paper outlines their achievements and challenges, and reflects on current regional needs and what the future may hold for research ethics and bioethics training in Latin America and the Caribbean. PMID- 24782075 TI - Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam. AB - Diurnal changes in the activity of drug metabolizing enzymes may contribute to the variability in drug disposition and drug effects. The aim of this study was to quantify the circadian rhythmicity exhibited by hepatic CYP3A. A 10 MUg/kg intravenous bolus dose, followed by a 30-hour 4 MUg/kg/h intravenous infusion of midazolam, used as a probe substrate for hepatic CYP3A activity, was administered to 16 healthy volunteers (8 males and 8 females). Blood samples were drawn hourly for 24 hours after achieving steady state, and plasma concentrations of midazolam and its main metabolite 1-OH midazolam were determined. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. One-compartment pharmacokinetic models best described midazolam and 1-OH midazolam pharmacokinetic disposition. An unequivocal but minor diurnal pattern was identified in the midazolam plasma concentration profiles, which was described using a cosine function with a 24-hours period. The fluctuation in the relative CYP3A activity ranged between 10% above average around 15:00, and 10% below average around 03:00. None of the covariates tested had a significant impact on the parameters estimated. Although a diurnal pattern in hepatic CYP3A activity was identified, its magnitude suggests that it is small and without clinical significance for drug therapy. PMID- 24782076 TI - More can be life threatening. PMID- 24782077 TI - Novel iodinated carboranes: synthesis of the 8-iodo-7,9-dicarba-nido-undecaborate anion and 2-iodo-1,7-dicarba-closo-dodecaborane. AB - Electrophilic iodination of the 7,9-dicarba-nido-undecaborate anion with molecular iodine in the presence of AlCl3 generated a new carborane anion-8-iodo 7,9-dicarba-nido-undecaborate-in excellent yield. The capping of the new anion with HBCl2 yielded a previously unknown neutral iodinated carborane, 2-iodo-1,7 dicarba-closo-dodecaborane. PMID- 24782078 TI - Response of the green alga Oophila sp., a salamander endosymbiont, to a PSII inhibitor under laboratory conditions. AB - In a rare example of autotroph-vertebrate endosymbiosis, eggs of the yellow spotted salamander (Ambystoma maculatum) are colonized by a green alga (Oophila sp.) that significantly enhances salamander development. Previous studies have demonstrated the potential for impacts to the salamander embryo when growth of the algae is impaired by exposure to herbicides. To further investigate this relationship, the authors characterized the response of the symbiotic algae (Oophila sp.) alone to the photosystem II (PSII) inhibitor atrazine under controlled laboratory conditions. After extraction of the alga from A. maculatum eggs and optimization of culturing conditions, 4 toxicity assays (96 h each) were conducted. Recovery of the algal population was also assessed after a further 96 h in untreated media. Average median effective concentration (EC50) values of 123 ug L(-1) (PSII yield), 169 ug L(-1) (optical density), and 299 ug L(-1) (growth rate) were obtained after the 96-h exposure. Full recovery of exposed algal populations after 96 h in untreated media was observed for all endpoints, except for optical density at the greatest concentration tested (300 ug L(-1) ). Our results show that, under laboratory conditions, Oophila sp. is generally less sensitive to atrazine than standard test species. Although conditions of growth in standard toxicity tests are not identical to those in the natural environment, these results provide an understanding of the tolerance of this alga to PSII inhibitors as compared with other species. PMID- 24782079 TI - Trends in prescription of opioids from 2003-2009 in persons with knee osteoarthritis. AB - OBJECTIVE: Osteoarthritis (OA) of the knee is a painful condition affecting ~13% of persons ages >65 years. We sought to examine whether the use of opioids in older persons with OA has increased over the past decade and what patient characteristics may correlate with their use. METHODS: We assembled national cohorts of individuals with knee OA using data from the 2003, 2006, and 2009 waves of the Medicare Current Beneficiary Survey. The survey data contained information on demographics, health status, and prescribed medications linked to Medicare claims. We used multivariate logistic regression to establish whether opioid use changed over time and to identify factors associated with greater opioid use. The outcome was defined as receiving >=1 opioid prescription in the study year. RESULTS: The mean age and sex were similar across years (77 years and 69% women, respectively). There was a significant increase in opioid prescribing between 2003 and 2009, with 31% of patients receiving opioids in 2003, 39% in 2006, and 40% in 2009 (odds ratio [OR] 1.5, 95% confidence interval [95% CI] 1.1 2.0 for 2006 and 2009 compared with 2003). Independent correlates of opioid use across time periods included female sex (OR 1.5, 95% CI 1.2-2.0), functional limitation (OR 2.1, 95% CI 1.6-2.7), poor self-reported health status (OR 1.6, 95% CI 1.2-2.0), chronic obstructive pulmonary disease (OR 1.4, 95% CI 1.0-1.8), and musculoskeletal disease besides OA (OR 1.9, 95% CI 1.2-2.8). CONCLUSION: As the prevalence and incidence of knee OA continues to increase, the public health impact of greater opioid use should be monitored carefully. PMID- 24782080 TI - The structural diversity of benzofuran resorcinarene leads to enhanced fluorescence. AB - An unexpected and previously unknown resorcinarene mono-crown with a fused benzofuran moiety in its macrocyclic core was obtained as a byproduct from a bridging reaction of tetramethoxy resorcinarene with tetraethylene glycol ditosylate. The formation of the fused benzofuran moiety in the resorcinarene macrocycle resulted in a unique rigid and puckered boat conformation, as shown by XRD studies in the solid state. Modification of the macrocycle was also observed to affect the photophysical properties in solution by enhancing the fluorescence brightness compared with a conventional resorcinarene macrocycle. The fluorescent properties enabled unique detection of structural features, that is, the rigid boat conformation with the conjugated benzofuran system and the more flexible crown bridge part, in solution. PMID- 24782081 TI - The Assessment of Allostatic Overload in Patients with Congestive Heart Failure by Clinimetric Criteria. AB - The precipitating role of emotional stress in the development of congestive heart failure (CHF) is a long-standing clinical observation. We employed new clinimetric criteria for the assessment of allostatic overload (AO) in a sample of CHF patients, with regard to its associations with psychological distress and health status. Allostatic overload was assessed by a semi-structured interview based on clinimetric criteria in 70 consecutive outpatients with CHF. One observer-rated scale and two self-rating questionnaires for psychological distress were administered. Cardiac variables were also collected at intake. Twenty-three patients (32.9%) were classified as having AO according to clinimetric criteria. Significant differences were found with regard to gender, with women being more likely to report AO than men (23.5% versus 57.9%). Patients with AO presented significantly higher levels of psychological distress (based on scales administered) compared with those who did not. Among cardiac risk factors, hyperglycaemia was found to be significantly associated with the presence of AO. The use of the clinimetric criteria provides a global index for identifying distress that might adversely influence the course and progression of CHF. It may be of use in clinical practice, leading to therapeutic suggestions such as lifestyle modifications and psychotherapy to help patients deal with their difficulties. PMID- 24782082 TI - Cytotoxic effects of essential oils from three Lippia gracilis Schauer genotypes on HeLa, B16, and MCF-7 cells and normal human fibroblasts. AB - This study aimed to evaluate the chemical composition of the essential oils from three genotypes of Lippia gracilis Schauer (Verbenaceae) and investigate the cytotoxic activities of these oils. Essential oils were extracted from the leaves using a Clevenger-type apparatus, and chemical analysis was performed using a gas chromatograph coupled to a mass spectrometer and flame ionization detector. 3T3, MRC5, B16, HeLa, and MCF-7 cell lines were used to study the in vitro cytotoxicity of the essential oils, and the level of cell death was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test with three replicates. The cytotoxic activity was expressed as the concentration that inhibited 50% of cell growth. The main compound in the essential oil of LGRA-106 was thymol (40.52%), while LGRA-109 and LGRA-201 contained 45.84 and 32.60% carvacrol, respectively, as their major compound. The essential oils of L. gracilis showed cytotoxic activity against both normal and tumor cells at concentrations below 100 MUg/mL; this demonstrated the antitumor potential of these essential oils, which should be further investigated. PMID- 24782083 TI - Effect of atorvastatin on vascular endothelial function in moderately nicotine dependent smokers. AB - We investigated the effect of atorvastatin on vascular endothelial function in moderately nicotine-dependent smokers. One hundred and sixty moderately nicotine dependent smokers were randomly divided into the atorvastatin group (N = 80) and the control group (N = 80). Total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose levels, aspartate aminotransferase, total bilirubin, creatine phosphokinase, and brachial artery flow-mediated vasodilation function (FMD) were measured before and 12 months after atorvastatin treatment. After a 12-month atorvastatin therapy, the TC and LDL-C levels of patients were decreased significantly (P < 0.05) and the FMD of patients were improved significantly (P < 0.05). Compared with the control group, TC and LDL-C of the patients were significantly decreased (P < 0.05) and the FMD of the patients were significantly improved (P < 0.05). Atorvastatin may significantly improve endothelial function in moderately nicotine-dependent smokers. PMID- 24782084 TI - Ginkgo biloba extract postconditioning reduces myocardial ischemia reperfusion injury. AB - We examined the protective effects of Ginkgo biloba extract (EGb761) postconditioning on myocardial ischemia reperfusion injury in rabbits. Four groups of 8 white rabbits were allocated to: pseudo surgery group: the left coronary was lined without blocking for 160 min after thoracotomy; ischemia and reperfusion group (IR): the left anterior descending coronary artery was blocked for 40 min and reperfused for 120 min; ischemic postconditioning group: the left anterior descending artery was ligated for 40 min, reopened for 30 s and ligated for 30 s, repeated three times, and then reperfused for 120 min; EGb761 postconditioning group (E): 100 mg/kg EGb761 was injected into a vein while the left coronary artery was opened for 1 min. The reperfusion took 120 min. Internal carotid arterial blood in each group was collected for cTnI measurement at five times: 20 min before occlusion of the left coronary artery, 20 min after left coronary artery occlusion, 40 min after left coronary artery occlusion, 1 h after myocardial reperfusion, and 2 h after myocardial reperfusion. Superoxide dismutase (SOD), malondialdehyde (MDA) in the centrifuged blood and myocardial infarction area were measured at the end of reperfusion. We found that the serum cTnI concentrations in the E group during reperfusion decreased significantly compared with those in the IR group. The infarction area was significantly lower in the E group than that in the IR group. The SOD activity in the E group was increased compared with that in the IR group; the MDA content decreased significantly in the E group compared with that in the IR group. We conclude that G. biloba extract postconditioning had myocardial protection effects by reducing the generation of oxygen-free radicals and increasing the antioxidant capacity of the myocardial cells. PMID- 24782085 TI - Analysis of sequence diversity through internal transcribed spacers and simple sequence repeats to identify Dendrobium species. AB - The Orchidaceae is one of the largest and most diverse families of flowering plants. The Dendrobium genus has high economic potential as ornamental plants and for medicinal purposes. In addition, the species of this genus are able to produce large crops. However, many Dendrobium varieties are very similar in outward appearance, making it difficult to distinguish one species from another. This study demonstrated that the 12 Dendrobium species used in this study may be divided into 2 groups by internal transcribed spacer (ITS) sequence analysis. Red and yellow flowers may also be used to separate these species into 2 main groups. In particular, the deciduous characteristic is associated with the ITS genetic diversity of the A group. Of 53 designed simple sequence repeat (SSR) primer pairs, 7 pairs were polymorphic for polymerase chain reaction products that were amplified from a specific band. The results of this study demonstrate that these 7 SSR primer pairs may potentially be used to identify Dendrobium species and their progeny in future studies. PMID- 24782086 TI - Genetic diversity of the Chinese traditional herb Blumea balsamifera (Asteraceae) based on AFLP markers. AB - Blumea balsamifera is a commercially important medicinal herb in China and other parts of Asia. It is used to produce borneol. This plant grows in the wild, but resources have diminished greatly in recent years. We examined the genetic diversity of this species to help develop conservation strategies; 35 plants from five provinces were analyzed using AFLPs. Eight AFLP primer combinations generated 1367 fragments, giving a mean of 172 fragments per primer combination. Polymorphism in the germplasm analysis was found for 1360 (99.48%) of the fragments, of which 264 (19.27%) fragments were unique (accession specific) and 423 (25.33%) of the fragments were rare (present in less than 10% of the accessions). The polymorphic fragments were used to group the accessions in a UPGMA phenogram. Most grouping was geographical. In general, accessions coming from Guizhou and Guangxi showed higher diversities as these accessions were scattered in different groups. The genetic distance estimated by Jaccard similarity coefficient index showed low variability among genotypes (coefficient value ranged from 0.60 to 0.95). More attention should be given to the study and conservation of the biodiversity of this economically important genus. PMID- 24782087 TI - Keloid microRNA expression analysis and the influence of miR-199a-5p on the proliferation of keloid fibroblasts. AB - The purpose of this study was to identify microRNAs (miRNAs) involved in keloid formation and determine their influence on the proliferation of keloid fibroblasts (KFs). Eight specimens each of resected keloid tissue and normal skin tissue were collected. miRNAs that are differentially expressed in keloid tissue and normal skin were detected using an miRNA microarray and verified by quantitative real-time polymerase chain reaction (RT-PCR). Seventeen differentially expressed miRNAs, including miR-199a-5p, were identified by microarray hybridization. qRT-PCR analysis confirmed the decrease in miR-199a-5p expression in keloid vs normal tissue that was detected by the microarray analysis. Mimics of differentially expressed miRNAs were then transfected into a KF cell line, and the effect of miRNA overexpression on the proliferation of KFs was assayed using the EdU assay. Compared with mock-transfected cells, KFs transfected with a miR-199a-5p mimic showed significantly lower cell proliferation and an altered cell cycle, with cells having significantly longer S and G2/M phases. The significantly lower expression of miRNA-199a-5p in keloids likely influences the cell cycle of KFs and restrains their proliferation, suggesting that miR-199a-5p probably plays a role in the regulation of KF proliferation. PMID- 24782088 TI - Complete mitochondrial genome sequence of Marmota himalayana (Rodentia: Sciuridae) and phylogenetic analysis within Rodentia. AB - This is the first report of a complete mitochondrial genome sequence from Himalayan marmot (Marmota himalayana, class Marmota). We determined the M. himalayana mitochondrial (mt) genome sequence by using long-PCR methods and a primer-walking sequencing strategy with genus-specific primers. The complete mt genome of M. himalayana was 16,443 bp in length and comprised 13 protein-coding genes, 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and a typical control region (CR). Gene order and orientation were identical to those in mt genomes of most vertebrates. The heavy strand showed an overall A+T content of 63.49%. AT and GC skews for the mt genome of the M. himalayana were 0.012 and 0.300, respectively, indicating a nucleotide bias against T and G. The control region was 997 bp in size and displayed some unusual features, including absence of repeated motifs and two conserved sequence blocks (CSB2 and CSB3), which is consistent with observations from two other rodent species, Sciurus vulgaris and Myoxus glis. Phylogenetic analysis of complete mt DNA sequences without the control region including 30 taxa of Rodentia was performed with Maximum Likelihood (ML) and Bayesian Inference (BI) methods and provided strong support for Sciurognathi polyphyly and Hystricognathi monophyly. This analysis also provided evidence that M. himalayana mt DNA was closely related to that from Sciurus vulgaris (Sciuridae) and was similar to mt DNA from Myoxus glis. PMID- 24782089 TI - A multi-farm assessment of Greek black pig genetic diversity using microsatellite molecular markers. AB - Local breeds are important for the maintenance of genetic diversity and future food security. Nowadays, the worldwide distribution of pigs is dominated by a few breeds, tending towards a severe loss of pig biodiversity. Thus, it is critical to maintain distinct populations of pig breeds. The Greek black pig, a breed raised locally and known for the high quality of its meat for cured products, is the only traditional indigenous pig breed reared in Greece. We investigated the genetic diversity, based on microsatellite analysis, of the Greek black pig and evaluated its genetic uniqueness. One hundred and three pigs from 12 Greek farms were analyzed using 11 microsatellites. The total number of alleles amounted to 135, with a mean number of alleles per locus of 12.27, ranging between 10 and 16 alleles. The observed heterozygosity ranged from 0.363 to 0.825 per locus. The expected heterozygosity ranged from 0.471 to 0.707. The inbreeding coefficient ranged from -0.329 to 0.229. We conclude that the Greek black pig, despite its low population size, has a high degree of genetic variability, which will be useful for breeding programs aimed at maintaining long-term survival of this ancient breed. PMID- 24782090 TI - Isolation and characterization of microsatellites for the yam Dioscorea cayenensis (Dioscoreaceae) and cross-amplification in D. rotundata. AB - Dioscorea cayenensis and Dioscorea rotundata are among the most important yam species for the humid and sub-humid tropics. We isolated nine polymorphic microsatellite markers using a microsatellite-enriched genomic library technique. The nine primer pairs were validated in 22 D. cayenensis accessions, and were tested for transferability in 26 D. rotundata accessions. The number of bands ranged from 2 to 4, with a mean of 3.11. D. cayenensis gave primer polymorphism information content values ranging from 0.37 to 0.62, while for D. rotundata the values ranged from 0.15 to 0.66. The D parameter in D. cayenensis ranged from 0.14 to 0.40, while in D. rotundata it ranged from 0.05 to 0.34. These SSR markers will be useful to characterize genetic diversity in D. cayenensis and D. rotundata accessions. PMID- 24782091 TI - Developmental changes in IGF-I and MyoG gene expression and their association with meat traits in sheep. AB - In the present study, real time-polymerase chain reaction was applied to analyze the expression of IGF-I and MyoG genes in Hu sheep longissimus dorsi at different growth stages and their association with meat traits. Expression of the IGF-I gene in Hu sheep differed significantly between males and females at the two day old (0.01 < P < 0.05), one-month old (0.01 < P < 0.05), and three month-old (P < 0.01) stages. IGF-I gene expression in male longissimus muscles was higher than that of females at all growth stages, except for the three month-old stage. There was no significant difference (P > 0.05) between males and females at any growth stage in expression of the MyoG gene. MyoG gene expression in male longissimus muscles tended to be higher than that of females at all growth stages, except for the six month-old stage. IGF-I gene expression was significantly and positively correlated with live weight (P < 0.01) and carcass weight (0.01< P < 0.05), and was non-significantly positively correlated with net meat weight (P > 0.05). In contrast, MyoG gene expression was non-significantly and positively correlated with live weight, carcass, and net meat weight (P > 0.05). Carcass traits showed highly significant positive correlations (P < 0.01). Furthermore, expressions of IGF-I and MyoG genes showed highly significant positive correlations (P < 0.01). We conclude that the expressions of IGF-I and MyoG genes are significantly and positively correlated with early muscle traits of Hu sheep. PMID- 24782092 TI - Estimates of genetic parameters for total milk yield over multiple ages in Brazilian Murrah buffaloes using different models. AB - The objective of this study was to estimate variance components and genetic parameters for accumulated 305-day milk yield (MY305) over multiple ages, from 24 to 120 months of age, applying random regression (RRM), repeatability (REP) and multi-trait (MT) models. A total of 4472 lactation records from 1882 buffaloes of the Murrah breed were utilized. The contemporary group (herd-year-calving season) and number of milkings (two levels) were considered as fixed effects in all models. For REP and RRM, additive genetic, permanent environmental and residual effects were included as random effects. MT considered the same random effects as did REP and RRM with the exception of permanent environmental effect. Residual variances were modeled by a step function with 1, 4, and 6 classes. The heritabilities estimated with RRM increased with age, ranging from 0.19 to 0.34, and were slightly higher than that obtained with the REP model. For the MT model, heritability estimates ranged from 0.20 (37 months of age) to 0.32 (94 months of age). The genetic correlation estimates for MY305 obtained by RRM (L23.res4) and MT models were very similar, and varied from 0.77 to 0.99 and from 0.77 to 0.99, respectively. The rank correlation between breeding values for MY305 at different ages predicted by REP, MT, and RRM were high. It seems that a linear and quadratic Legendre polynomial to model the additive genetic and animal permanent environmental effects, respectively, may be sufficient to explain more parsimoniously the changes in MY305 genetic variation with age. PMID- 24782093 TI - Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. AB - Although new chemotherapeutic drugs have been applied constantly, their efficacy for non-small cell lung cancer (NSCLC) is still not satisfactory. In recent years, epidemiological investigations have shown that lung cancer may be induced by chronic Chlamydia pneumoniae (Cpn) infection, since stable high titers of Cpn antibodies, especially IgA, are a hallmark of chronic infections. Azithromycin is commonly used for the treatment of Cpn infections; however, there are only few reports regarding the application of azithromycin (A) combined with paclitaxel and cisplatin (TP) for advanced NSCLC. Considering that patients with NSCLC have a higher rate of Cpn infection, we proposed to employ azithromycin for Cpn infection in chemotherapy for advanced NSCLC. The aim of this study was to explore the effects of azithromycin on chemotherapy for NSCLC. A total of 86 patients with stage III-IV NSCLC were randomly divided into TP and ATP groups; the characteristics of patients in the two groups showed no significant differences. The TP group was treated with paclitaxel and cisplatin, and the ATP group was treated with azithromycin combined with TP for at least 4 weeks, followed by evaluation and comparison of efficacy, side effects and patients' quality of life before and after chemotherapy between the two groups. Testing for Cpn infection revealed a significant difference in the case number before and after therapy in the ATP group (P < 0.01) compared with the TP group (P > 0.05), and a statistical difference was observed (P < 0.01) between the ATP and TP groups after treatment. The changes in quality of life of patients after two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only cognitive function after treatment. The changes in symptom scores of patients after the two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only shortness of breath and cough after treatment. Kaplan-Meier estimate was utilized to describe the survival function of patients in the two groups. The median survival time was 12.0 months for the TP group and 13.0 months for the ATP group. One-year survival rates of the TP and ATP groups were 45.0 and 75.0%, respectively, which were significantly different (P < 0.05). Our study of azithromycin+paclitaxe l+cisplatin on stage III-IV NSCLC patients achieved favorable results in terms of side effects and overall survival. PMID- 24782094 TI - Expression of heat shock protein 90 alpha (Hsp90alpha) in primary neonatal rat myocardial cells exposed to various periods of heat stress in vitro. AB - The objective of this study was to investigate the mechanism of heat shock protein 90 alpha (Hsp90alpha) protection against heart damage resulting from heat stress by detecting Hsp90alpha mRNA, Hsp90alpha protein, protein localization, and cell damage in primary myocardial cells of neonatal rats in response to heat stress in vitro. The cells were heat-stressed at 42 degrees C in an incubator with 95% air and 5% CO2 for different periods. Levels of Hsp90alpha, protein localization, enzymes, and cytopathological lesions were detected using Western blot, immunocytochemistry enzymatic assays, and cytopathological techniques. Aspartate aminotransferase, lactate dehydrogenase, and creatine kinase enzyme levels were elevated during heat stress, and acute cellular lesions that were characterized by vacuolar degeneration and necrosis were observed. Hsp90alpha levels decreased between 10 and 60 min of heat stress and increased after 360 and 480 min, while Hsp90alpha mRNA decreased after 360 min. These results indicate that heat stress might induce irreversible damage in certain myocardial cells. The elevated Hsp90alpha level at the end of heat stress and its positive signal in the cytoplasm of myocardial cells after heat stress could be associated with its protective role. Additionally, the consumption of Hsp90alpha exceeded its production in the first period of treatment. PMID- 24782095 TI - Layer-by-layer assembled heteroatom-doped graphene films with ultrahigh volumetric capacitance and rate capability for micro-supercapacitors. AB - Highly uniform, ultrathin, layer-by-layer heteroatom (N, B) co-doped graphene films are fabricated for high-performance on-chip planar micro-supercapacitors with an ultrahigh volumetric capacitance of ~488 F cm(-3) and excellent rate capability due to the synergistic effect of nitrogen and boron co-doping. PMID- 24782096 TI - Variant middle meningeal artery origin from the ophthalmic artery: a case report. AB - We present a rare case of a variant middle meningeal artery (MMA) originating from the ophthalmic artery. During cadaveric dissection of the cranial base of an adult female, it was noted that the foramen spinosum was absent unilaterally. After identifying the MMA, its origin was traced back to the ophthalmic artery within the orbit. Although exceedingly rare, a variant MMA originating from the ophthalmic artery should be kept in mind by surgeons during skull base procedures in order to avoid unwanted complications including potential retrograde thrombosis of the ophthalmic artery with MMA manipulation or coagulation. PMID- 24782097 TI - Spinal protein kinase Mzeta contributes to the maintenance of peripheral inflammation-primed persistent nociceptive sensitization after plantar incision. AB - BACKGROUND: Previous studies suggest that persistent post-surgical pain (PPSP) is correlated with preoperative pain status and amplification of central sensitization. Protein kinase Mzeta (PKMzeta) is an essential substrate of the late long-term potentiation underlying central sensitization, which is one mechanism of pain memory formation. However, the potential contributions of spinal PKMzeta to PPSP, a condition in which preoperative pain is prevalent, are not known. METHODS: Here, a modified 'hyperalgesia priming' model was established to simulate the clinical situation. This model used intraplantar injections of carrageenan (Car) as priming stimuli to elicit persistent nociceptive sensitization after plantar incision in rats. Upon treatment with PKMzeta inhibitor ZIP, Scr-ZIP or protein kinase Cs (PKCs) inhibitor NPC-15437, altered behaviour and spinal PKMzeta/PKCs expression were observed. RESULTS: A long lasting hypersensitivity induced by Car-priming was identified and precipitated by subsequent plantar incision in this 'two-hit' paradigm. Post-treatment with ZIP, but not Scr-ZIP and NPC-15437, after the resolution of Car-priming selectively relieved hypersensitivity. In contrast, pre-priming NPC-15437 treatment only prevented Car-induced initial transient hyperalgesia. Immunoassays showed a significant decrease in spinal PKMzeta expression after plantar incision with post-priming ZIP treatment as compared with Scr-ZIP and NPC-15437, but no notable differences in PKCs expression were observed. CONCLUSIONS: Spinal PKCs solely contribute to the initial induction of persistent pain, whereas PKMzeta plays an essential role in spinal plasticity storage. PKMzeta is responsible for the maintenance of peripheral inflammation-primed PPSP. Therefore, spinal PKMzeta may be a therapeutic target to prevent surgery-induced chronic pain in patients with preoperative pain. PMID- 24782098 TI - An exploratory study of serum creatinine levels in patients with amyotrophic lateral sclerosis. AB - The etiology of amyotrophic lateral sclerosis (ALS) remains unknown, but existing data argue for a role of creatinine in ALS pathophysiology. Our aim is to clarify the correlation between serum creatinine and ALS in Chinese population. A total of 512 sporadic ALS (SALS) patients and 501 age- and gender-matched healthy controls were included. Revised ALS Functional Rating Scale (ALS-FRS-R) was used to assess the motor functional status of SALS patients. Survival analysis was performed using Kaplan-Meier method. Serum creatinine levels were significantly lower in SALS patients than in controls (p < 0.001). Patients with the second, the third and highest quartiles of creatinine levels had a significantly lower presence of ALS compared to those with the lowest quartile (p for trend <0.001). However, decreased presence of ALS was not found in the highest quartiles compared with the lowest quartiles in females. Sporadic ALS patients with different site of onset have similar serum creatinine levels, but underweight patients presented lower levels of serum creatinine. Patients with low serum creatinine levels are more likely to have severe motor impairment and low body mass index (BMI) values. This study demonstrates that SALS patients have lower serum creatinine levels than well-matched controls. Higher levels of serum creatinine are less likely to be associated with the presence of ALS in Chinese populations. Low serum creatinine levels may be related to severe motor impairment in SALS patients, after adjusting the confounding factor-BMI. However, serum creatinine has no deleterious impact on survival in ALS. PMID- 24782099 TI - Systems with competing interlayer interactions and modulations in one direction: finding their structures. AB - Complex structures in polar smectic systems can be studied within framework of discrete phenomenological models. Considered interactions are usually described by nonlinear trigonometric functions that do not allow for a straightforward search for solutions. The review of three methods reported in the literature are presented and their appropriateness, advantages and disadvantages are discussed. Examples are given as an illustration for each method. PMID- 24782100 TI - Identifying medication error chains from critical incident reports: a new analytic approach. AB - Research into the distribution of medication errors usually focuses on isolated stages within the medication use process. Our study aimed to provide a novel process-oriented approach to medication incident analysis focusing on medication error chains. Our study was conducted across a 900-bed teaching hospital in Switzerland. All reported 1,591 medication errors 2009-2012 were categorized using the Medication Error Index NCC MERP and the WHO Classification for Patient Safety Methodology. In order to identify medication error chains, each reported medication incident was allocated to the relevant stage of the hospital medication use process. Only 25.8% of the reported medication errors were detected before they propagated through the medication use process. The majority of medication errors (74.2%) formed an error chain encompassing two or more stages. The most frequent error chain comprised preparation up to and including medication administration (45.2%). "Non-consideration of documentation/prescribing" during the drug preparation was the most frequent contributor for "wrong dose" during the administration of medication. Medication error chains provide important insights for detecting and stopping medication errors before they reach the patient. Existing and new safety barriers need to be extended to interrupt error chains and to improve patient safety. PMID- 24782101 TI - Neuroendocrine pathology of the stomach: the Parma contribution. AB - The current knowledge on gastric neuroendocrine pathology essentially developed in the last four decades. The historical evolution of the concepts and of the relevant clinical implications is described from the perspective of a group actively participating in this research domain. The histamine-producing enterochromaffin-like (ECL) cells have been recognized as the leading cell type involved in the most significant alterations of gastric neuroendocrine cells. The trophic stimulus exerted by circulating gastrin has been demonstrated to have a crucial role on proliferative changes of ECL cells through a sequence of hyperplasia-dysplasia-neoplasia described by Solcia et al. (Digestion 41:185 200,1988). The development of ECL cell tumors in rats treated with toxicological doses of inhibitors of gastric acid secretion prompted appropriate anatomoclinical investigations proving the lack of tumor risk in humans when therapeutic dosages of the drugs are used. Moving from the comprehensive concept of gastric carcinoid, different types of neuroendocrine tumors have been identified in the stomach with substantial variations in prognosis and treatment options. In general, ECL cell tumors developed in hypergastrinemic conditions were found to behave better than those originating outside the setting of hormonal stimulation. Pathological features highly predictive of patient survival have been described. The genetic changes involved in tumor development and progression have revealed substantial overlapping with those of neuroendocrine tumors of other foregut derivatives (i.e., pancreas, duodenum, lung) delineating a family of neuroendocrine tumors genetically distinct from those of the distal parts of the digestive system. PMID- 24782102 TI - Plasmacytoid dendritic cells in cutaneous lesions of patients with chromoblastomycosis, lacaziosis, and paracoccidioidomycosis: a comparative analysis. AB - Plasmacytoid dendritic cells (pDCs) are characterized by expression of CD123 and BDCA-2 (Blood Dendritic Cell Antigen 2) (CD303) molecules, which are important in innate and adaptive immunity. Chromoblastomycosis (CBM), lacaziosis or Jorge Lobo's disease (JLD), and paracoccidioidomycosis (PCM), are noteworthy in Latin America due to the large number of reported cases. The severity of lesions is mainly determined by the host's immune status and in situ responses. The dendritic cells studied in these fungal diseases are of myeloid origin, such as Langerhans cells and dermal dendrocytes; to our knowledge, there are no data for pDCs. Forty-three biopsies from patients with CBM, 42 from those with JLD and 46 diagnosed with PCM, were evaluated by immunohistochemistry. Plasmacytoid cells immunostained with anti-CD123 and anti-CD303 were detected in 16 cases of CBM; in those stained with anti-CD123, 24 specimens were obtained from PCM. We did not detect the presence of pDCs in any specimen using either antibody in JLD. We believe that, albeit a secondary immune response in PCM and CBM, pDCs could act as a secondary source of important cytokines. The BDCA-2 (CD303) is a c-type lectin receptor involved in cell adhesion, capture, and processing of antigens. Through the expression of the c-lectin receptor, there could be an interaction with fungi, similar to other receptors of this type, namely, CD207 in PCM and CD205 and CD209 in other fungal infections. In JLD, the absence of expression of CD123 and CD303 seems to indicate that pDCs are not involved in the immune response. PMID- 24782103 TI - Is biofilm production a predictor of catheter-related candidemia? AB - Catheter-related candidemia (CRC) is typically a biofilm related disease, but it is mostly unknown if the production of biofilm is a feature exclusively shown by Candida spp. isolates causing CRC. We performed an in vitro biofilm assay using Candida isolates obtained from the blood of patients with candidemia. We demonstrated that biofilm production was not a good predictor of catheter-related candidemia. Also, we demonstrated that there was no difference in the mortality of candidemia patients infected by biofilm-forming isolates and those in which the infection is caused by nonbiofilm-forming species. PMID- 24782104 TI - Development and validation of benomyl birdseed agar for the isolation of Cryptococcus neoformans and Cryptococcus gattii from environmental samples. AB - One of the difficulties of isolating Cryptococcus neoformans and Cryptococcus gattii from environmental samples is the abundant overgrowth of other yeast and mold species that occurs on the plates. Here we report the application of benomyl to Guizotia abyssinica seed extract growth medium to improve the isolation of C. neoformans and C. gattii from environmental samples. We validated this medium by recovering C. neoformans and C. gattii from convenience soils and swabs from a region of the United States where these yeasts are endemic. PMID- 24782105 TI - Different risk factors for candidemia occur for Candida species belonging to the C. parapsilosis complex. AB - Previous studies have demonstrated reduced virulence in the species that comprise the Candida parapsilosis complex. We investigated a cohort of 93 patients with candidemia caused by this complex. Most infections were caused by C. parapsilosis (80.6%), followed by C. orthopsilosis (18.3%) and C. metapsilosis (1.1%). Renal failure (P < 0.001) and chronic liver diseases (P = 0.019) were more frequently encountered with infections caused by the C. orthopsilosis group, suggesting an association with patients who had a greater state of immune suppression in comparison with infections caused by C. parapsilosis sensu stricto. PMID- 24782106 TI - Identification of clinical yeasts by Vitek MS system compared with API ID 32 C. AB - We performed a clinical evaluation of the Vitek MS matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) system with the commercial database version 2.0 for rapid identification of medically important yeasts as compared with the conventional phenotypic method API ID 32 C. We tested 161 clinical isolates, nine isolates from culture collections and five reference strains. In case of discrepant results or no identification with one or both methods, molecular identification techniques were employed. Concordance between both methods was observed with 160/175 isolates (91.42%) and misidentifications by both systems occurred only when taxa were not included in the respective databases, i.e., one isolate of Candida etchellsii was identified as C. globosa by Vitek MS and two isolates of C. orthopsilosis were identified as C. parapsilosis by API ID 32 C. Vitek MS could not identify nine strains (5.14%) and API ID 32 C did not identify 13 (7.42%). Vitek MS was more reliable than API ID 32 C and reduced the time required for the identification of clinical isolates to only a few minutes. PMID- 24782107 TI - Immunisation coverage of adults: a vaccination counselling campaign in the pharmacies in Switzerland. AB - OBJECTIVE: To assess vaccination coverage for adults living in Switzerland. METHODS: Through a media campaign, the general population was invited during 1 month to bring their vaccination certificates to the pharmacies to have their immunisation status evaluated with the software viavac(c), and to complete a questionnaire. RESULTS: A total of 496 pharmacies in Switzerland participated in the campaign, of which 284 (57%) submitted valid vaccination information. From a total of 3,634 participants in the campaign, there were 3,291 valid cases (participants born <= 1992) and 1,011 questionnaires completed. Vaccination coverage for the participants was 45.9% and 34.6% for five and six doses of diphtheria, 56.4% and 44.0% for tetanus and 66.3% and 48.0% for polio, respectively. Coverage estimates for one and two doses of measles vaccine were 76.5% and 49.4%, respectively, for the birth cohort 1967-1992 and 4.0% and 0.8%, respectively, for the cohort <= 1966. There was a significant difference in coverage for most vaccinations between the two aforementioned birth cohorts. A plot of the measles vaccine coverage over time shows that the increase in coverage correlated with policy changes in the Swiss Immunisation Schedule. CONCLUSIONS: Despite selection bias and low participation, this study indicates that vaccination coverage for the basic recommended immunisations in the adult population in Switzerland is suboptimal. More efforts using various means and methods are needed to increase immunisation coverage in adolescents before they leave school. An established method to determine vaccination coverage for the general population could provide invaluable insights into the effects of changes in vaccination policies and disease outbreaks. PMID- 24782108 TI - Functional discharge readiness and mobility following total knee arthroplasty for osteoarthritis: a comparison of analgesic techniques. AB - OBJECTIVE: To determine if functional discharge readiness and mobility following total knee arthroplasty (TKA) for osteoarthritis is delayed after femoral nerve block (FNB) with or without patient-controlled analgesia (PCA) opioid compared with PCA opioid alone. METHODS: We analyzed secondary outcomes from a randomized controlled trial with 200 patients undergoing unilateral TKA. Experimental group 1 received single-injection FNB with intravenous PCA opioid, experimental group 2 received continuous FNB, and the control group received PCA opioid alone. FNB was administered using bupivacaine. Patients followed a structured TKA pathway. Discharge readiness outcomes included achievement of 90 degrees knee flexion, independent walking, and stair climbing, and were assessed daily before discharge or day 6, whichever came first. Mobility outcomes included the Timed Up and Go (TUG) test, the 6-Minute Walk Distance (6MWD), and self-reported physical function, and were assessed at weeks 2 and 12. TUG was also assessed on days 3 to 6, postoperation. RESULTS: Both FNB groups (77%) were more likely to achieve 90 degrees knee flexion compared with the control group (59%); odds ratio (OR) 2.3, 95% confidence interval (95% CI) 1.1, 4.8 for single-injection FNB, and OR 2.3, 95% CI 1.1, 4.9 for continuous FNB. There were no significant differences in independent walking and stair-climbing ability before discharge, TUG, 6MWD, or self-reported physical function, between the FNB groups compared with the control group. CONCLUSION: After TKA, FNB (single-injection with PCA opioid or continuous) does not delay achievement of 90 degrees knee flexion or other measures of functional discharge readiness and mobility compared with PCA opioid alone. PMID- 24782109 TI - Successful management of thrombotic thrombocytopenic purpura in a Jehovah's Witness without plasma exchange. AB - Thrombotic thrombocytopenic purpura (TTP) is a hematologic emergency characterized by microangiopathic hemolytic anemia and thrombocytopenia. Plasma exchange is the standard treatment. Treating TTP without plasma exchange is a challenge. Due to religious beliefs, Jehovah's Witnesses do not accept transfusions of blood products. We report a case of successful treatment of TTP in a Jehovah's Witness using plasma exchange with albumin replacement. PMID- 24782110 TI - Oligonucleotides replacing the roles of repetitive sequences pAs1, pSc119.2, pTa 535, pTa71, CCS1, and pAWRC.1 for FISH analysis. AB - Hybrids derived from wheat (Triticum aestivum L.) * rye (Secale cereale L.) have been widely studied because of their important roles in wheat cultivar improvement. Repetitive sequences pAs1, pSc119.2, pTa-535, pTa71, CCS1, and pAWRC.1 are usually used as probes in fluorescence in situ hybridization (FISH) analysis of wheat, rye, and hybrids derived from wheat * rye. Usually, some of these repetitive sequences for FISH analysis were needed to be amplified from a bacterial plasmid, extracted from bacterial cells, and labeled by nick translation. Therefore, the conventional procedure of probe preparation using these repetitive sequences is time-consuming and labor-intensive. In this study, some appropriate oligonucleotide probes have been developed which can replace the roles of repetitive sequences pAs1, pSc119.2, pTa-535, pTa71, CCS1, and pAWRC.1 in FISH analysis of wheat, rye, and hybrids derived from wheat * rye. These oligonucleotides can be synthesized easily and cheaply. Therefore, FISH analysis of wheat and hybrids derived from wheat * rye using these oligonucleotide probes becomes easier and more economical. PMID- 24782111 TI - A reagent-free oxidative cyclization approach to indolizine derivatives from alpha-picoline derivatives and nitroolefins. AB - A reagent-free oxidative cyclization between alpha-picoline derivatives and nitroolefins has been developed. This approach, in which the nitro group acts as an internal oxidant, provides an extremely simple, efficient, and atom-economic way to construct heteroaromatic indolizine derivatives. PMID- 24782113 TI - Excited-state intramolecular proton transfer: photoswitching in salicylidene methylamine derivatives. AB - The effect of chemical substitutions on the photophysical properties of the salicylidene methylamine molecule (SMA) (J. Jankowska, M. F. Rode, J. Sadlej, A. L. Sobolewski, ChemPhysChem, 2012, 13, 4287-4294) is studied with the aid of ab initio electronic structure methods. It is shown that combining pi-electron donating and pi-electron-withdrawing substituents results in an electron-density push-and-pull effect on the energetic landscape of the ground and the lowest excited pipi* and npi* singlet states of the system. The presented search for the most appropriate SMA derivatives with respect to their photoswitching functionality offers an efficient prescreening tool for finding chemical structures before real synthetic realization. PMID- 24782112 TI - Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics. AB - General interest in the biological functions of IFN type I in Mycobacterium tuberculosis (Mtb) infection increased after the recent identification of a distinct IFN gene expression signature in tuberculosis (TB) patients. Here, we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Using this experimental model to mimic primary progressive pulmonary TB, we dissected the immune processes affected by IFN I. IFNAR1 signaling did not affect T-cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung. This process was orchestrated by IFNAR1 expressed on both immune and tissue resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by augmented Mtb replication and in situ death events, along with CXCL5/CXCL1-driven accumulation of neutrophils in alveoli, followed by the discrete compartmentalization of Mtb in lung phagocytes. Early depletion of neutrophils rescued TB-susceptible mice to levels observed in mice lacking IFNAR1. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to fatal immunopathology. These data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB and form a basis for understanding the complex roles of IFN I in chronic inflammation. PMID- 24782114 TI - A balance between activating and repressive histone modifications regulates cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo. AB - The genetic mechanisms that regulate CFTR, the gene responsible for cystic fibrosis, have been widely investigated in cultured cells. However, mechanisms responsible for tissue-specific and time-specific expression are not completely elucidated in vivo. Through the survey of public databases, we found that the promoter of CFTR was associated with bivalent chromatin in human embryonic stem (ES) cells. In this work, we analyzed fetal (at different stages of pregnancy) and adult tissues and showed that, in digestive and lung tissues, which expressed CFTR, H3K4me3 was maintained in the promoter. Histone acetylation was high in the promoter and in two intronic enhancers, especially in fetal tissues. In contrast, in blood cells, which did not express CFTR, the bivalent chromatin was resolved (the promoter was labeled by the silencing mark H3K27me3). Cis-regulatory sequences were associated with lowly acetylated histones. We also provide evidence that the tissue-specific expression of CFTR is not regulated by dynamic changes of DNA methylation in the promoter. Overall, this work shows that a balance between activating and repressive histone modifications in the promoter and intronic enhancers results in the fine regulation of CFTR expression during development, thereby ensuring tissue specificity. PMID- 24782115 TI - Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. AB - BACKGROUND: We investigated the effects of anakinra, an interleukin-1 receptor antagonist, on coronary and left ventricular function in coronary artery disease (CAD) patients with rheumatoid arthritis. METHODS AND RESULTS: In a double-blind crossover trial, 80 patients with rheumatoid arthritis (60 with CAD and 20 without) were randomized to a single injection of anakinra or placebo and after 48 hours to the alternative treatment. At baseline and 3 hours after treatment, we assessed (1) flow-mediated dilation of brachial artery; (2) coronary flow reserve, ejection fraction, systemic arterial compliance, and resistance by echocardiography; (3) left ventricular global longitudinal and circumferential strain, peak twisting, untwisting velocity by speckle tracking; and (4) interleukin-1beta, nitrotyrosine, malondialdehyde, protein carbonyl, and Fas/Fas ligand levels. At baseline, patients with CAD had 3-fold higher interleukin 1beta, protein carbonyl, higher nitrotyrosine, malondialdehyde, and Fas/Fas ligand than non-CAD (P<0.05). After anakinra, there was a greater improvement of flow-mediated dilation (57+/-4% versus 47+/-5%), coronary flow reserve (37+/-4% versus 29+/-2%), arterial compliance (20+/-18% versus 2+/-17%), resistance (-11+/ 19% versus 9+/-21%), longitudinal strain (33+/-5% versus 18+/-2%), circumferential strain (22+/-5% versus 13+/-5%), peak twisting (30+/-5% versus 12+/-5%), untwisting velocity (23+/-5% versus 13+/-5%), ejection fraction (12+/ 5% versus 0.5+/-5%), apoptotic and oxidative markers, and, in particular, of protein carbonyl (35+/-20% versus 14+/-9%) in CAD than in non-CAD patients (P<0.01). No changes in the examined markers were observed after placebo. CONCLUSIONS: Interleukin-1 inhibition causes a greater improvement in endothelial, coronary aortic function in addition to left ventricular myocardial deformation and twisting in rheumatoid arthritis patients with CAD than in those without. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01566201. PMID- 24782116 TI - Influence of renal and hepatic impairment on the pharmacokinetics of anacetrapib. AB - Two open-label, parallel-group studies evaluated the influence of renal and hepatic insufficiency on the pharmacokinetics of a single-dose anacetrapib 100 mg. Eligible participants included adult men and women with moderate hepatic impairment (assessed by Child-Pugh criteria) or severe renal impairment (CrCl <30 mL/min/1.73 m(2)). In both studies, patients were matched (race, age, sex, BMI) with healthy control subjects. Twenty-four subjects were randomized in each study (12 with either moderate hepatic or severe renal impairment and 12 matched healthy controls). In the hepatic insufficiency study, the geometric mean ratio (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% CIs for the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) and the maximum concentration of drug in plasma (C(max)) were 1.16 (0.84, 1.60) and 1.02 (0.71, 1.49), respectively. In the renal insufficiency study, the GMRs (mean value for the group with severe renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC(0-infinity) and Cmax were 1.14 (0.80, 1.63) and 1.31 (0.93, 1.83), respectively. Anacetrapib was generally well tolerated and there was no clinically meaningful effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of anacetrapib. PMID- 24782117 TI - Bendamustine as salvage treatment for patients with relapsed or refractory mantle cell lymphoma patients: a retrospective study of the Spanish experience. AB - Patients with mantle cell lymphoma (MCL) have an adverse outcome after relapse. Bendamustine has demonstrated a good efficacy and toxicity profile in previously reported trials. In this study, we present a retrospective analysis of the Spanish experience in relapsed/refractory MCL treated with bendamustine in combination or alone with the objective of knowing the efficacy and toxicity profile of this treatment in our current clinical practice. Fifty eight patients were registered: 67 % male with median age of 71 years, and 2 is the median number of previous lines. The most frequent bendamustine regimen was bendamustine plus rituximab (83 %). The median number of cycles was 5 (range 1-8). The overall response rate was 84 % with 53 % of complete response/unconfirmed complete response (CR/uCR). Median progression-free survival (PFS) was 16 months (95 % confidence interval (CI) 13.3-18.8), and for patients who achieved CR/uCR, it was 33 months (95 % CI 11.1-54.2). Median overall survival (OS) was 30 months (95 % CI 25.6-34.9). For PFS, only blastoid histology and not achieving CR after bendamustine had a significant negative impact on the univariate and multivariate analyses (p < 0.05). Nevertheless, for OS, only an elevated lactate dehydrogenase (LDH) had negative impact on both, univariate and multivariate analyses (p < 0.05). Only one case of treatment-related mortality in a 79-year-old patient with very bad performance status was reported. In 280 cycles, 12 (4 %) hospitalizations for febrile neutropenia were reported. In our population, bendamustine has been a good salvage treatment with a favorable toxicity profile in a non selected and heavily pretreated population of patients with MCL. PMID- 24782118 TI - Correlation of CD11b and CD56 expression in adult acute myeloid leukemia with cytogenetic risk groups and prognosis. AB - Among other phenotypic markers, CD11b expression has been considered as an unfavorable prognostic factor, both in terms of overall survival (OS), disease free survival (DFS), and attainment and duration of complete remissions (CRs) in adult patients with acute myeloid leukemia (AML). Recently, some groups have restricted its prognostic impact to poor prognostic karyotypic risk groups. The aim of this study was to retrospectively analyze the prevalence of CD11b and of CD56 expression in blast cells of 158 AML patients [excluding those with t(15;17)] stratified according to their cytogenetic risk and to correlate these phenotypic characteristics with OS, DFS, and CR. CD11b was more frequently expressed in intermediate and unfavorable cytogenetic prognostic groups (38.9 and 35.5 %, respectively) than in the favorable group (9.5 %). No differences were observed in CD56 expression according to the cytogenetic risk groups. When OS, DFS, and CR were analyzed according to these two markers, no statistical differences were recorded in any cytogenetic risk group. In conclusion, although CD11b was more frequently expressed in blast cells of patients with intermediate and unfavorable cytogenetic risk groups, this feature did not translate into different clinical outcome. Similarly, CD56 positivity did not have any influence on the prognosis of these patients. PMID- 24782119 TI - Allogeneic stem cell transplantation for mantle cell lymphoma--final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO). AB - This study was conducted in order to evaluate allogeneic stem cell transplantation (alloSCT) as consolidation for patients with mantle cell lymphoma (MCL). Patients with MCL were included into two prospective trials OSHO #060 (refractory/relapsed) and #074 (de novo). Induction was rituximab and chemotherapy. Responding patients proceeded to alloSCT. Minimal residual disease was monitored by quantitative RT-PCR detecting either t(11;14) or clonospecific CDR-III regions. In case of circulating lymphoma cells, immunomodulation (cyclosporine A withdrawal, rituximab, donor lymphocyte infusion) was initiated. Thirty-three of 39 patients underwent alloSCT after myeloablative (n = 7) or toxicity-reduced (n = 26) conditioning. Leukocytes engrafted at day +16 (median, range 0-101) and platelets at day +14 (0-142). Acute graft-versus-host disease stages I-II occurred in 42 % and stages III-IV in 15 %. Five patients have relapsed after SCT. The overall mortality after SCT was 24 % (n = 8). Median follow-up after SCT was 2.8 years (range 0.0-10.9). Five-year progression-free survival was 67 %, and overall survival 73 % after SCT. The results were comparable for primary MCL and refractory/relapsed disease as well as for related vs. unrelated SCT. Younger patients had a significantly better outcome than the elderly. AlloSCT is a feasible and promising consolidation therapy for relapsed and refractory disease and an attractive option for young patients with de novo MCL of high risk. PMID- 24782120 TI - New prognostic model for extranodal natural killer/T cell lymphoma, nasal type. AB - Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive disease with a poor prognosis, requiring risk stratification in affected patients. We designed a new prognostic model specifically for ENKTL to identify high-risk patients who need more aggressive therapy. We retrospectively reviewed 158 patients who were newly diagnosed with ENKTL. The estimated 5-year overall survival rate was 39.4 %. Independent prognostic factors included total protein (TP) <60 g/L, fasting blood glucose (FBG) >100 mg/dL, and Korean Prognostic Index (KPI) score >=2. We constructed a new prognostic model by combining these prognostic factors: group 1 (64 cases (41.0 %)), no adverse factors; group 2 (58 cases (37.2 %)), one adverse factor; and group 3 (34 cases (21.8 %)), two or three adverse factors. The 5-year overall survival (OS) rates of these groups were 66.7, 23.0, and 5.9 %, respectively (p < 0.001). Our new prognostic model had a better prognostic value than did the KPI model alone (p < 0.001). Our proposed prognostic model for ENKTL, including the newly identified prognostic indicators, TP and FBG, demonstrated a balanced distribution of patients into different risk groups with better prognostic discrimination compared with the KPI model alone. PMID- 24782121 TI - Identification of acquired mutations by whole-genome sequencing in GATA-2 deficiency evolving into myelodysplasia and acute leukemia. AB - Heterozygous GATA-2 germline mutations are associated with overlapping clinical manifestations termed GATA-2 deficiency, characterized by immunodeficiency and predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, there is considerable clinical heterogeneity among patients, and the molecular basis for the evolution of immunodeficiency into MDS/AML remains unknown. Thus, we conducted whole-genome sequencing on a patient with a germline GATA-2 heterozygous mutation (c. 988 C > T; p. R330X), who had a history suggestive of immunodeficiency and evolved into MDS/AML. Analysis was conducted with DNA samples from leukocytes for immunodeficiency, bone marrow mononuclear cells for MDS and bone marrow-derived mesenchymal stem cells. Whereas we did not identify a candidate genomic deletion that may contribute to the evolution into MDS, a total of 280 MDS-specific nonsynonymous single nucleotide variants were identified. By narrowing down with the single nucleotide polymorphism database, the functional missense database, and NCBI information, we finally identified three candidate mutations for EZH2, HECW2 and GATA-1, which may contribute to the evolution of the disease. PMID- 24782122 TI - Falsely elevated point-of-care hematocrit and calculated hemoglobin concentration due to extreme leukocytosis. PMID- 24782123 TI - Burkitt-like post-transplant lymphoproliferative disorder (PTLD) presenting with breast mass in a renal transplant recipient: a report of a rare case. PMID- 24782125 TI - Synthetic and computational evaluation of regiodivergent epoxide opening for diol and polyol synthesis. AB - In a combined synthetic and computational study, the factors governing the selectivity of the titanocene(III)-catalyzed regiodivergent epoxide opening (REO) with Kagan's complex via electron transfer leading to derivatives of 1,2-, 1,3-, and 1,4-diols were investigated. In this manner, valuable building blocks for the synthesis of 1,3- and 1,4-diols were identified. The computational study provides crucial structural features and energies of the transition states of ring opening that are important for the design of more selective catalysts. PMID- 24782126 TI - Normative values of skin temperature and thermal sensory thresholds in the pudendal nerve territory. AB - AIMS: The aim of this study was to define normative values of skin temperature and thermal sensory threshold in the pudendal nerve territory. METHODS: Warm and cold detection thresholds (using the method of limits) and skin temperature were measured in a group of 41 presumably healthy female volunteers aged 41 years (range: 23-66 years) at left thenar eminence and in the pudendal nerve territory. Outlying data were discarded and 95% normative values were derived assuming Normal distributions. RESULTS: Room temperature averaged 24.3 +/- 1.1 degrees . Skin temperature and cold detection threshold value were greater anteriorly (clitoris, labia) than posteriorly (para-anal). Para-anal skin temperature and cold detection threshold value were also significantly lower on the right side than on the left side. The warm detection threshold was significantly lower at the clitoris level than at left and right labia. A significant positive effect of skin temperature on cold and warm detection thresholds values was noted especially at thenar and para-anal levels. Age had no effect on skin temperature but warm detection thresholds at clitoris were higher in older subjects. The only qualitative abnormalities observed were after-sensation (4.9%) and habituation (2.8%). Allodynia, dysesthesia, radiation, and dyslocalization were not observed. Two-sided normative values were determined for skin temperature, vertical, and horizontal differences, while one-sided values were derived for cold and warm detection thresholds as well as for their difference. CONCLUSIONS: Normative values for perineal skin temperature and thermal detection thresholds can be used as an alternative non-invasive way to evaluate pudendal neuropathy. PMID- 24782127 TI - iNKT-cell help to B cells: a cooperative job between innate and adaptive immune responses. AB - T-cell help to B lymphocytes is one of the most important events in adaptive immune responses in health and disease. It is generally delivered by cognate CD4(+) T follicular helper (T(FH)) cells via both cell-to-cell contacts and soluble mediators, and it is essential for both the clonal expansion of antibody (Ab)-secreting B cells and memory B-cell formation. CD1d-restricted invariant natural killer T (iNKT) cells are a subset of innate-like T lymphocytes that rapidly respond to stimulation with specific lipid antigens (Ags) that are derived from infectious pathogens or stressed host cells. Activated iNKT cells produce a wide range of cytokines and upregulate costimulatory molecules that can promote activation of dendritic cells (DCs), natural killer (NK) cells, and T cells. A decade ago, we discovered that iNKT cells can help B cells to proliferate and to produce IgG Abs in vitro and in vivo. This adjuvant-like function of Ag-activated iNKT cells provides a flexible set of helper mechanisms that expand the current paradigm of T-cell-B-cell interaction and highlights the potential of iNKT-cell targeting vaccine formulations. PMID- 24782128 TI - Association of beta 2 adrenoceptor gene polymorphisms in Malaysian hypertensive subjects. AB - The sympathetic nervous system plays a major role in blood pressure regulation. Beta 2 (beta2) adrenoceptor gene polymorphisms have been associated with hypertension in different populations with conflicting results. We examined the association of three common polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile, of the beta2 adrenoceptor gene in Malaysian hypertensive subjects. A total of 160 hypertensive and control subjects were recruited. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and anthropometric measurements were obtained from each subject. Biochemical analyses of lipid profiles were conducted with an autoanalyzer. DNA samples were extracted from blood and buccal cells. Genotyping was accomplished with polymerase chain reaction-restriction fragment length polymorphism. SBP, DBP, body mass index, and biochemical factors all differed significantly between case and control subjects (P < 0.05). The genotype frequencies of Arg16Arg, Arg16Gly, and Gly16Gly were 22.5, 70, and 7.5% among cases and 33.1, 63.1, and 3.8% among controls, respectively. The genotype frequencies of Gln27Gln, Gln27Glu, and Glu27Glu among cases were 41.1, 50, and 1.9% compared to 77.5, 20.6, and 1.9% among controls, respectively. In this study, the Gln27Glu polymorphism was significantly associated with Malaysian hypertensive subjects (P < 0.05). Therefore, the Gln27Glu polymorphism of the beta2 adrenoceptor could be a risk factor associated with hypertension among Malaysians. PMID- 24782129 TI - Differential expression and effect of the porcine ANGPTL4 gene on intramuscular fat. AB - In a previous study, we investigated differences in gene expression in backfat between Meishan and Large White pigs and their F1 hybrids, Large White x Meishan, and Meishan x Large White pigs. One potential differentially expressed sequence tag from the mRNA differential display was a homolog of the human angiopoietin like 4 (ANGPTL4) gene, which encodes a protein that is secreted by both liver and white adipose tissues and can inhibit lipoprotein lipase activity and stimulate white adipose tissue lipolysis. Here, ANGPTL4 mRNA was found to be upregulated in the backfat of Large White compared with that in the Meishan pigs and the F1 hybrids, Meishan x Large White and Large White x Meishan, whereas expression was lowest both in the longissimus dorsi and the heart, as shown by the tissue distribution profile. Only one mutation, a G/A transition located in the third intron, was found. The ANGPTL4 G/A polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) showed a significant effect on intramuscular fat (IMF), water moisture of the longissimus dorsi, meat marbling of the longissimus dorsi, and pH of the longissimus dorsi (P < 0.05). This site seemed to be significantly (P < 0.05) additive in its actions on IMF, water moisture, and pH, whereas it showed significant dominance in its action on meat marbling (P < 0.05). This locus can be potentially considered as a marker for IMF improvement. PMID- 24782130 TI - A tiered barcode authentication tool to differentiate medicinal Cassia species in India. AB - DNA barcoding is a desirable tool for medicinal product authentication. DNA barcoding is a method for species identification using short DNA sequences that are conserved within species, but variable between species. Unlike animals, there is no single universal DNA barcode locus for plants. Coding markers, matK and rbcL, and noncoding markers, trnH-psbA (chloroplast) and ITS2 (nuclear), have been reported to be suitable for the DNA barcoding of plants with varying degree of success. Sixty-four accessions from 20 species of the medicinal plant Cassia were collected, and analyzed for these 4 DNA barcoding markers. PCR amplification was 100% successful for all 4 markers, while intra-species divergence was 0 for all 4 Cassia species in which multiple accessions were studied. Assuming 1.0% divergence as the minimum requirement for discriminating 2 species, the 4 markers could only differentiate 15 to 65% of the species studied when used separately. Adding indels to the divergence increased the percentage of species discrimination by trnH-psbA to 90%. In 2-locus barcoding, while matK+rbcL (which is recommended by Consortium for the Barcoding of Life) discriminated 90% of the species, the other combinations of matK+ITS and rbcL+trnH-psbA showed 100% species discrimination. However, matK is plagued with primer issues. The combination of rbcL+trnH-psbA provided the most accurate (100% species ID) and efficient tiered DNA barcoding tool for the authentication of Cassia medicinal products. PMID- 24782131 TI - Different impact of two mutations of a novel compound heterozygous protein C deficiency with late onset thrombosis. AB - We investigated the alteration of coagulation state in a protein C (PC) deficiency pedigree and the impact of the PC gene mutations. The pedigree of a proband with cerebral hemorrhagic infarction had sixteen members with four generations. The plasma levels of PC activity (PC:A), protein S activity (PS:A), factor V:C and factor VIII:C, and routine coagulation tests were measured. Nine exons of the PC gene (PROC) were sequenced. Plasma PC:A and PC antigen (PC:Ag) of the proband were 26 and 18%, respectively, which was significantly lower than normal ranges. Two heterozygous missense mutations of PC in the proband were identified, T>G at site 6128 (exon 7) and G>C at site 8478 (exon 9) resulting in F139V and D255H, respectively. The family members with F139V (N = 4) or D255H (N = 4) had lower levels of PC:A and PC:Ag than members with wild-type PROC (N = 6). D255H mutation caused a more significant decrease in the levels of PC:A, PC:Ag and factor V:C as compared to F139V mutation (P < 0.05). Two independent mutations, F139V and D255H, of PROC reduce PC function. Compound heterozygous condition of the two mutations can cause synergistic PC deficiency, but resulting in later onset of cerebral thrombosis. PMID- 24782132 TI - Screening of the residual normal ovarian tissue adjacent to orthotopic epithelial ovarian carcinomas in nude mice. AB - The objective of this study was to explore the feasibility and methods of screening the residual normal ovarian tissue adjacent to orthotopic ovarian carcinomas in nude mice. Human epithelial ovarian cancer cells (OVCAR3) were subcutaneously implanted for a tumor source and ovarian orthotopic transplantation. The cancer tissue, proximal paraneoplastic tissue, middle paraneoplastic tissue, remote paraneoplastic tissue, and normal ovarian tissue were removed. CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was detected by reverse transcription polymerase chain reaction. We obtained 35 paraneoplastic residual ovarian tissues with normal biopsies from 40 cases of an orthotopic epithelial ovarian carcinoma model (87.5%). CK-7, CA125, p53, survivin, MMP-2, and TIMP-2 expression was lower in proximal paraneoplastic tissue than in cancer tissue (P < 0.05) and higher than in middle and remote paraneoplastic tissue (P < 0.01). There was no statistically significant difference between the expression of these genes in middle and proximal paraneoplastic tissue as well as among residual normal ovarian tissues with different severity (P > 0.05). In ovarian tissues of 20 normal nude mice, the expression of CK- 7, CA125, p53, survivin, MMP-2, and TIMP-2 was negative. Overall, the expression levels of CK-7, CA125, p53, survivin, MMP-2, TIMP-2, and other molecular markers showed a decreasing trend in the non-cancer tissue direction. The expression levels can be used as standards to screen residual normal ovarian tissue. We can obtain relatively safe normal ovarian tissues adjacent to epithelial ovarian cancer. PMID- 24782133 TI - alpha-1,3-N-acetylgalactose aminotransferase gene 539G>C mutation leads to the A2B isoform. AB - In this study, the phenotypic identification and molecular mechanism of one case of an A2B subtype pedigree was investigated. ABO blood groupings were identified by serological methods and sequence amplification was performed by polymerase chain reaction (PCR) using TA cloning and DNA sequencing analysis to identify the pedigree and the ABO gene haploid of the proband. There were both A and B antigens on the proband's red blood cells, and anti-A1 antibodies were found in the serum. Direct sequencing of the 6th and 7th exons of the ABO gene showed the A208/B101 genotype, and haploid determination revealed the A208 and B101 alleles. Compared with the A102 allele sequence, the A208 allele was mutated at the 539 G>C site. Pedigree analysis showed that the ABO blood phenotypes of the proband's father, mother, husband, and daughter were A2, B, AB, and A2B, respectively, and their genotypes were A208/O02, B101/B101, A102/B101, and A208/B101, respectively. The father of the proband had anti-A1 antibodies and the A208 allele of the proband was inherited from her father, which can be passed on to her daughter. The alpha-1, 3-N-acetylgalactose aminotransferase gene 539G>C mutation resulted in A2B phenotype generation, and individual serum contained the anti-A1 antibody. PMID- 24782134 TI - Expression of neurotrophin-4/5 in Streptococcus pneumoniae meningitis. AB - This study aims to investigate the expression of neurotrophin-4/5 (NT-4/5) in the pallium and hippocampus in juvenile rats with intraventricular injection of Streptococcus pneumoniae. We used 40 SPF SD rats (3 weeks old, regardless of gender) in this study. We drew 50 MUL cerebrospinal fluid, and then, we injected 50 MUL normal saline and S. pneumoniae suspension (10(8) CFU/mL) in the brain pool (normal control group and infection group, respectively). After 24 h, the cerebrospinal fluid was collected for bacterial culture and white blood cell count. The immunohistochemical staining was conducted at the day 1, 2, and 5, and the expression of NT-4/5 in rat brain tissue was observed. Compared with the normal control group, NT-4/5 expression in the pallium and hippocampus of rats in the 24-h infection group was significantly increased (both P < 0.05). NT-4/5 expression in the pallium and hippocampus in the 5-day infection group was significantly lower than that in the 24-h infection group (P < 0.05), and they were significantly higher than the normal control group (P < 0.05). After intraventricular injection of S. pneumoniae, the expression of NT-4/5 in the pallium and hippocampus in juvenile rats was increased, especially during early disease course. PMID- 24782135 TI - Genetic variations in the leptin gene associated with growth and carcass traits in Nellore cattle. AB - The aim of the study was to detect polymorphisms in the leptin gene and to determine the association of these polymorphisms with growth and carcass traits in Nellore cattle. The single nucleotide polymorphisms (SNPs) -1457 (AJ571671:g. 1457A>G) and A59V (AF536174.1:g. 321C>T), as well as the microsatellite BM1500 (3.9 kb downstream), were genotyped. The measures of body weight and ultrasound examinations (rib eye area, back, and rump fat thickness) were performed in 3 different periods of animal management. During the first period, the animals were fed with grass and mineralized salt ad libitum. In the second period, they received grass and concentrate, and in the third, only concentrate. After the slaughter of animals, data were collected for classification and typification of carcasses. No significant association was found between the variables assessed and SNP -1457. Conversely, SNP A59V was associated with rump fat thickness and muscle color post-slaughter. BM1500 was associated with rump fat thickness in the first period (pre-slaughter), subcutaneous fat thickness in the second, weight of the animals in the third, and length of the carcass after slaughter. These results suggest that SNP A59V and the microsatellite BM1500 might be useful for marker-assisted selection in Nellore cattle. PMID- 24782136 TI - Short communication: development and characterization of novel transcriptome derived microsatellites for genetic analysis of persimmon. AB - Oriental persimmon (Diospyros kaki Thunb.) (2n = 6x = 90) is a major commercial and deciduous fruit tree that is believed to have originated in China. However, rare transcriptomic and genomic information on persimmon is available. Using Roche 454 sequencing technology, the transcriptome from RNA of the flowers of D. kaki was analyzed. A total of 1,250,893 reads were generated and 83,898 unigenes were assembled. A total of 42,711 SSR loci were identified from 23,494 unigenes and 289 polymerase chain reaction primer pairs were designed. Of these 289 primers, 155 (53.6%) showed robust PCR amplification and 98 revealed polymorphism between 15 persimmon genotypes, indicating a polymorphic rate of 63.23% of the productive primers for characterization and genotyping of the genus Diospyros. Transcriptome sequence data generated from next-generation sequencing technology to identify microsatellite loci appears to be rapid and cost-efficient, particularly for species with no genomic sequence information available. PMID- 24782137 TI - Mini review roles of the bZIP gene family in rice. AB - The basic leucine zipper (bZIP) genes encode transcription factors involved in the regulation of various biological processes. Similar to WRKY, basic helix-loop helix, and several other groups of proteins, the bZIP proteins form a superfamily of transcription factors that mediate plant stress responses. In this review, we present the roles of bZIP proteins in multiple biological processes that include pathogen defense; responses to abiotic stresses; seed development and germination; senescence; and responses to salicylic, jasmonic, and abscisic acids in rice. We also examined the characteristics of the bZIP proteins and their genetic composition. To ascertain the evolutionary changes in and functions of this supergene family, we performed an exhaustive comparison among the 89 rice bZIP genes that were previously described and those more recently listed in the MSU Rice Genome Annotation Project Database using a Hidden Markov Model. We excluded 3 genes from the list, resulting in a total of 86 bZIP genes in japonica rice. PMID- 24782138 TI - Li3PO4-coated LiNi0.5Mn1.5O4: a stable high-voltage cathode material for lithium ion batteries. AB - LiNi0.5Mn1.5O4 is regarded as a promising cathode material to increase the energy density of lithium-ion batteries due to the high discharge voltage (ca. 4.7 V). However, the interface between the LiNi0.5Mn1.5O4 cathode and the electrolyte is a great concern because of the decomposition of the electrolyte on the cathode surface at high operational potentials. To build a stable and functional protecting layer of Li3PO4 on LiNi0.5Mn1.5O4 to avoid direct contact between the active materials and the electrolyte is the emphasis of this study. Li3PO4-coated LiNi0.5Mn1.5O4 is prepared by a solid-state reaction and noncoated LiNi0.5Mn1.5O4 is prepared by the same method as a control. The materials are fully characterized by XRD, FT-IR, and high-resolution TEM. TEM shows that the Li3PO4 layer (<6 nm) is successfully coated on the LiNi0.5Mn1.5O4 primary particles. XRD and FT-IR reveal that the synthesized Li3PO4-coated LiNi0.5Mn1.5O4 has a cubic spinel structure with a space group of Fd3m, whereas noncoated LiNi0.5Mn1.5O4 shows a cubic spinel structure with a space group of P4(3)32. The electrochemical performance of the prepared materials is characterized in half and full cells. Li3PO4-coated LiNi0.5Mn1.5O4 shows dramatically enhanced cycling performance compared with noncoated LiNi0.5Mn1.5O4. PMID- 24782139 TI - Loss of appetite in acutely ill medical inpatients: physiological response or therapeutic target? AB - Loss of appetite and ensuing weight loss is a key feature of severe illnesses. Protein-energy malnutrition (PEM) contributes significantly to the adverse outcome of these conditions. Pharmacological interventions to target appetite stimulation have little efficacy but considerable side effects. Therefore nutritional therapy appears to be the logical step to combat inadequate nutrition. However, clinical trial data demonstrating benefits are sparse and there is no current established standard algorithm for use of nutritional support in malnourished, acutely ill medical inpatients. Recent high-quality evidence from critical care demonstrating harmful effects when parenteral nutritional support is used indiscriminately has led to speculation that loss of appetite in the acute phase of illness is indeed an adaptive, protective response that improves cell recycling (autophagy) and detoxification. Outside critical care, there is an important gap in high quality clinical trial data shedding further light on these important issues. The selection, timing, and doses of nutrition should be evaluated as carefully as with any other therapeutic intervention, with the aim of maximising efficacy and minimising adverse effects and costs. In light of the current controversy, a reappraisal of how nutritional support should be used in acutely ill medical inpatients outside critical care is urgently required. The aim of this review is to discuss current pathophysiological concepts of PEM and to review the current evidence for the efficacy of nutritional support regarding patient outcomes when used in an acutely ill medical patient population outside critical care. PMID- 24782140 TI - Quantum chemical studies on solvents for post-combustion carbon dioxide capture: calculation of pKa and carbamate stability of disubstituted piperazines. AB - Piperazine is a widely studied solvent for post-combustion carbon dioxide capture. To investigate the possibilities of further improving this process, the electronic and steric effects of -CH(3), -CH(2)F, -CH(2)OH, -CH(2)NH(2), -COCH3 , and -CN groups of 2,5-disubstituted piperazines on the pKa and carbamate stability towards hydrolysis are investigated by quantum chemical methods. For the calculations, B3LYP, M11L, and spin-component-scaled MP2 (SCS-MP2) methods are used and coupled with the SMD solvation model. The experimental pK(a) values of piperazine, 2-methylpiperazine, and 2,5-dimethylpiperazine agree well with the calculated values. The present study indicates that substitution of -CH(3), CH(2) NH(2), and -CH(2) OH groups on the 2- and 5-positions of piperazine has a positive impact on the CO(2) absorption capacity by reducing the carbamate stability towards hydrolysis. Furthermore, their higher boiling points, relative to piperazine itself, will lead to a reduction of volatility-related losses. PMID- 24782141 TI - Discovery of syn-/anti-cocaine-N-oxide diastereomers in unwashed postmortem hair via LC-MS-MS. AB - The discovery of two cocaine-N-oxide (CNO) diastereomers, syn- and anti-CNO, is reported for the first time. Prior to this study, only one structural form of CNO was known to exist and has not been analyzed in hair before. CNO is a metabolite of cocaine (COC) and may be considered as an additional biomarker of COC use, along with other known COC metabolites. The analysis of COC in hair for forensic applications is under scrutiny due to the possibility of external contamination. A qualitative liquid chromatography-tandem mass spectrometry method was developed, validated and applied to unwashed postmortem hair samples from drug users. The limit of detection in hair was 8 pg/mg (using 10 mg of unwashed hair) for each CNO diastereomer. The presence of both syn- and anti-forms of CNO was verified in vivo using hair samples collected from known COC-using individuals. Due to the low levels of CNO, it will not always be detectable in COC user hair. In the hair samples analyzed, syn-CNO was detected in more samples than anti-CNO. The stereoselective N-oxidation of COC which favors syn-CNO could have a diagnostic value for COC ingestion determination in hair analysis. PMID- 24782142 TI - Variability in metabolism of imipramine and desipramine using urinary excretion data. AB - Variability in imipramine and desipramine metabolism was evaluated using urinary excretion data from patients with pain. Liquid chromatography-tandem mass spectrometry was used to quantitate concentrations in urine specimens. Interpatient population contained 600 unique imipramine specimens, whereas intrapatient population had 137 patients with two or more specimens. Normal concentration ranges of imipramine, desipramine and the desipramine/imipramine metabolic ratio (MR) were established, and various factors were tested for MR impact. Geometric mean of imipramine urine concentration was 0.46 mg/g of creatinine, and desipramine was 0.67 mg/g of creatinine. Gender, concomitant known CYP2C19 inhibitor use and urine pH did not affect MR. However, proton-pump inhibitor (PPI) users had a significantly lower mean MR than those without a listed PPI. Early age group (18-36 years) had a significantly higher mean MR than middle (37-66 years) and late (67-90 years) age groups. Approximately one-third were positive for one or more of hydrocodone, oxycodone, hydromorphone or oxymorphone. Patients with no opioids reported in the medication list had a significantly lower geometric mean MR than those with prescribed opioids (1.03 vs. 1.54, P = 0.004). Patients with only one prescribed opioid had a lower MR than those with two or more prescribed opioids. Patients with younger age, prescribed opioids and no listed PPI were more likely to have a higher geometric mean urinary desipramine/imipramine MR. PMID- 24782143 TI - A one-step extraction procedure for the screening of cocaine, amphetamines and cannabinoids in postmortem blood samples. AB - A gas chromatography-mass spectrometric (GC-MS) method was developed and validated for the simultaneous detection and quantification in postmortem whole blood samples of cocaine (COC), amphetamines (AMPs) and cannabis; the main drugs involved in cases of impaired driving in Brazil. The analytes were extracted by solid-phase extraction by means of Bond-Elute Certify cartridges, derivatized with N-methyl-N-(trimethylsilyl)trifluoroacetamide at 80 degrees C for 30 min and analyzed by GC-MS. Linearity ranged from 10 to 500 ng/mL, except for ecgonine methyl ester, for which linearity ranged from 10 to 100 ng/mL. Inter- and intra day imprecision ranged from 2.8 to 18.4% and from 1.5 to 14.9%, respectively. Accuracy values lay between 86.9 and 104.4%. The limit of quantitation for all drugs was 10 ng/mL and recoveries were >74% for all analytes, except for cannabinoids, which showed poor recovery (~30%). The developed method was applied to real samples collected from deceased victims due to traffic accidents. These samples were selected according to the results obtained in immunoassay screening on collected urine samples. Five samples were positive for the presence of COC and metabolites, four samples were positive for cannabinoids, six samples were positive for AMPs and two samples were drug negative. Some samples were positive for more than one class of drug. Results obtained from whole blood samples showed good agreement with urine screening. The developed method proved capable of quantifying all three classes of drugs of abuse proposed in this study, through a one-step extraction procedure. PMID- 24782144 TI - Promoting therapeutic equity in pregnancy. PMID- 24782145 TI - Gold-catalyzed cascade reactions of furan-ynes with external nucleophiles consisting of a 1,2-rearrangement: straightforward synthesis of multi-substituted benzo[b]furans. AB - A gold-catalyzed cycloisomerization of silyl-protected 2-(1-alkynyl)-2-alken-1-(2 furanyl)-1-ols with various nucleophiles including water, alcohol, aniline, sulfonamide, and electron-rich arene has been developed. The method provides a highly efficient access to 5,7-disubstituted or 2,5,7-trisubstituted benzo[b]furans with a wide diversity of substituents under mild reaction conditions, which are not easily available by other methods. Remarkably, an interesting rearrangement of the alkyl group from C2 to the C3 position of the furan ring takes place during the cyclization process. The following gold assisted allylic substitution enables an elaboration of benzo[b]furans on its side chain of the C5 position with a wide range of functional groups. PMID- 24782146 TI - Changes in ethnic identity and competence in middle adolescents. AB - PURPOSE: Evidence suggests that the construct of ethnic identity (EI) in adolescents changes over time and is related to factors including social connectedness, social competence, coping, and self-worth. Transitional changes of EI in middle adolescence have not been studied. METHOD: This analysis, part of a longitudinal study of health behaviors, explored how EI changes from the first year of high school to the last, and it examined relationships among EI, social connectedness, indicators of social competence, coping, and self-worth in 602 youth (49% Hispanic, 59% female). RESULTS: EI was significantly related to social connectedness, social competence, coping, and self-worth as adolescents entered and prepared to exit high school. EI increased significantly over time for both genders and for Hispanics more so than for non-Hispanics. DISCUSSION: Findings support and extend the conceptual framework and previous research. Socialization with one's ethnic group is associated with developing competence and self-worth. EI development continues throughout high school. CONCLUSION: Findings extend our understanding of the salience of EI in adolescents in transition throughout high school. IMPLICATIONS: Strengthening EI may contribute to adolescents' feelings of self-worth, skills in coping, and competence within an ethnically diverse society. Nurses might plan interventions to strengthen EI throughout adolescence. PMID- 24782147 TI - A Korean version of the Appraisal of Diabetes Scale (ADS-K): psychometric evaluation with a population of Koreans with type 2 diabetes. AB - The purpose of this study was to evaluate the psychometric properties of the Appraisal of Diabetes Scale (ADS) in Korean patients with Type 2 diabetes. The English-language version of the ADS was translated into Korean using a forward and-backward translation technique. The Korean version of the ADS (ADS-K) was administered to 250 patients who were recruited from two university hospitals. The data were analyzed using principal-component analysis, Cronbach's alpha, analysis of variance, t test, and Pearson's correlation. Six of seven items were meaningfully clustered into a two-factor structure by principal-component analysis, these factors accounting for 63.75% of the total variance. The underlying structure was consistent regardless of either gender or the presence of complications. The Cronbach's alpha of the subscales ranged from .71 to .79, indicating an acceptable internal consistency reliability. As hypothesized, the ADS-K score was moderately correlated with the diabetes-specific quality of life and had satisfactory convergent validity. The known-groups validity of the ADS-K was established using depression groups and HbA1c control status. The ADS-K demonstrated good psychometric properties. In addition, it possessed satisfactory practical properties, such as acceptability and feasibility. Therefore, the ADS-K appears to be suitable for use in both clinical research and clinical practice. PMID- 24782149 TI - [Intensive care: mouth rinse with chlorhexidine or antibiotic prophylaxis? Widespread application of chlorhexidine should be critically scrutinized]. PMID- 24782148 TI - Far-red organic fluorophores contain a fluorescent impurity. AB - Far-red organic fluorophores commonly used in traditional and super-resolution localization microscopy are found to contain a fluorescent impurity with green excitation and near-red emission. This near-red fluorescent impurity can interfere with some multicolor stochastic optical reconstruction microscopy/photoactivated localization microscopy measurements in live cells and produce subtle artifacts in chemically fixed cells. We additionally describe alternatives to avoid artifacts in super-resolution localization microscopy. PMID- 24782150 TI - [Physicians' prescription behavior of potentially inappropriate medications for elderly people: an analysis using the PRISCUS list based on TK routine data]. AB - BACKGROUND: Referring to the German PRISCUS list, the paper analyzes differences in the prescription of potentially inadequate medication (PIM) between older and younger patients. We account for changes in the development over time and for the influence of the publication of the PRISCUS list. METHODS: The retrospective study analyzes pharmaceutical prescriptions based on data from the Techniker Krankenkasse for the years 2008-20012. Age groups are compared regarding PIM prescriptions as share of total prescriptions within therapeutic areas (based on ATC codes). For a comparison of prescribed daily doses between age groups the median of those younger than 65 was indexed to the value 100. RESULTS: The share of older insured with at least one PRISCUS prescription declined from 21,7 % in 2008 to 18,9 % in 2012. Moreover, the total share of PIM prescriptions is steadily higher for elderly persons. Comparing major therapeutic areas shows a heterogeneous picture. An influence of the PRISCUS list on the prescription behavior is not observable. CONCLUSION: The share of PIM prescriptions in the TK sample is slightly declining over time. Unexpectedly, the total share is higher for the elderly than for those below 65. With regard to different therapeutic areas, results are less clear. For future research, our findings emphasize the need to rely on the applied methods. PMID- 24782151 TI - [Muscular sarcocystosis after travel to Malaysia: a case series from Germany]. AB - BACKGROUND: Since 2011, about 100 travellers to the island of Tioman, Malaysia, have been diagnosed worldwide with suspected muscular sarcocystosis, a previously only sporadically observed parasitic disease. Source of infection and therapy remain unclear. Final diagnosis requires microscopic identification of cysts in muscle biopsies. The study objective was a systematic description of characteristic symptoms, laboratory investigations and treatment response. METHODS: Systematic case series. RESULTS: The 26 cases of 5 centers for tropical medicine in Germany showed a characteristic biphasic development: symptoms began in general 2 weeks after mid-holidays (min. 7.5, max. 22 days) with unspecific fever and headaches lasting for almost 1 week. After an asymptomatic period of 2 weeks, severe myalgia (6.5, scale 0-10) and fever developed and lasted for about 6 weeks (min. 7, max. 207 days), accompanied by creatin-phosphokinase(CK) elevation (up to 3.5 times), and eosinophilia (2.9 times). One out of two muscle biopsies revealed a cyst typical for sarcocystosis. In 6 out of 7 patients an increase in Sarcocystis-specific antibody concentration could be demonstrated by ELISA. Treatment with systemic steroids and albendazole, or ivermectin resulted in significant symptomatic improvement in most of the patients. One patient was treated early with cotrimoxazole and subsequently did not develop a second phase of the disease. All patients had stayed in the North-West of the island Tioman. CONCLUSIONS: Muscular sarcocystosis develops in a biphasic pattern with initial fever and later prolonged myalgia, eosinophilia, and CK-elevation. Steroids achieve symptomatic relief in the late phase. Early cotrimoxazole-therapy could possibly prevent parasitic muscle invasion. In fever after travel to Malaysia differential diagnosis should include sarcocystosis. The source of infection appears to be located in North-West of Tioman. Further studies are needed, including addressing early diagnosis and treatment. PMID- 24782152 TI - [Endocrinologic side effects of oncologic treatment with anti-CTLA-4-antibodies]. AB - New immune-modulating treatments like the anti-CTLA-4-antibodies-based therapies are increasingly used in medical oncology. The action of Ipilimumab, a monoclonal anti-CTLA-4-antibody used for the treatment of metastasized melanoma and other solid tumors, is well documented. Blocking the CTLA-4-receptors on lymphocytes leads to T-cell activation and hence reduction of the tumor-mediated immunotolerance. This mechanism constitutes the basis of the antiproliferative effects but is also responsible for a spectrum of specific adverse events (immune related adverse events, IRAE). IRAE of the endocrine system comprise hypophysitis, thyroiditis and adrenalitis. Especially adrenal insufficiency can be fatal when not diagnosed and treated. Symptoms often are unspecific and early diagnosis and targeted treatment are crucial. We present a case report and summarize - based upon the current literature - the diagnosis and treatment of endocrinologic IRAEs. PMID- 24782153 TI - [70-year-old man with treatment-refractory pneumonia]. PMID- 24782154 TI - [Tofacitinib]. AB - Tofacitinib is the first Janus kinase inhibitor which was approved for the therapy of rheumatoid arthritis in the USA. Several phase III studies proved the efficacy of Tofacitinib as monotherapy or in combination with established medication. This article discusses the therapeutic potential of this new pharmacological approach and the current data on efficacy and safety of Tofacitinib therapy with special emphasis on a prospective approval in the EU. PMID- 24782155 TI - [Cheyne-Stokes respiration in patients with chronic heart failure: only a diagnostic marker or also a cardiovascular risk factor?]. AB - Sleep disordered breathing with predominant obstructive or central apnea is an under-recognized but highly prevalent comorbidity in patients with chronic heart failure. As the severity of heart failure increases the prevalence of central sleep apnea (CSA) and Cheyne-Stokes respiration (CSR) is also much more frequent. Cheyne-Stokes respiration is characterized by alternating periods of crescendo and decrescendo respiration followed by central apnea. Present data indicate that CSA-CSR is not only a compensatory response to severe heart failure but also a predictor of worse prognosis. However the results on long-term mortality are not consistent. The prognostic importance of night- and daytime CSR has to be further elucidated. Increased sympathetic nervous activity has been proposed to play a mayor role concerning progression and outcome of chronic heart failure by CSA CSR. PMID- 24782156 TI - [Misconduct in prescription in an elderly patient]. PMID- 24782157 TI - [The US-American Hypertension Guideline 2014: JNC 8]. PMID- 24782158 TI - Sclerostin monoclonal antibody enhanced bone fracture healing in an open osteotomy model in rats. AB - Sclerostin is a negative regulator of bone formation. Sclerostin monoclonal antibody (Scl-Ab) treatment promoted bone healing in various animal models. To further evaluate the healing efficiency of Scl-Ab in osteotomy healing, we investigated the time course effects of systemic administration of Scl-Ab on fracture repair in rat femoral osteotomy model. A total of 120 six-month-old male SD rats were subjected to transverse osteotomy at the right femur mid-shaft. Rats were treated with vehicle or Scl-Ab treatment for 3, 6, or 9 weeks. Fracture healing was evaluated by radiography, micro-CT, micro-CT based angiography, 4 point bending mechanical test and histological assessment. Scl-Ab treatment resulted in significantly higher total mineralized callus volume fraction, BMD and enhanced neovascularization. Histologically, Scl-Ab treatment resulted in a significant reduction in fracture callus cartilage at week 6 and increase in bone volume at week 9, associated with a greater proportion of newly formed bone area at week 6 and 9 by fluorescence microscopy. Mechanical testing showed significantly higher ultimate load in Scl-Ab treatment group at week 6 and 9. This study has demonstrated that Scl-Ab treatment enhanced bone healing in a rat femoral osteotomy model, as reflected in increased bone formation, bone mass and bone strength. PMID- 24782159 TI - IRF4 at the crossroads of effector T-cell fate decision. AB - Interferon regulatory factor 4 (IRF4) is a transcription factor that is expressed in hematopoietic cells and plays pivotal roles in the immune response. Originally described as a lymphocyte-specific nuclear factor, IRF4 promotes differentiation of naive CD4(+) T cells into T helper 2 (Th2), Th9, Th17, or T follicular helper (Tfh) cells and is required for the function of effector regulatory T (eTreg) cells. Moreover, IRF4 is essential for the sustained differentiation of cytotoxic effector CD8(+) T cells, for CD8(+) T-cell memory formation, and for differentiation of naive CD8(+) T cells into IL-9-producing (Tc9) and IL-17 producing (Tc17) CD8(+) T-cell subsets. In this review, we focus on recent findings on the role of IRF4 during the development of CD4(+) and CD8(+) T-cell subsets and the impact of IRF4 on T-cell-mediated immune responses in vivo. PMID- 24782160 TI - JSPS Asian Core Program: 7th & 8th ICCEOCA (Phase II/NICCEOCA-3 & -4), 2nd & 3rd junior ICCEOCA, and partly IUPAC Asian Project. PMID- 24782162 TI - Genotype by environment interaction for post-weaning weight gain, scrotal circumference, and muscling score of composite beef cattle in different regions of Brazil. AB - The objectives of this study were to characterize and define homogenous production environments of composite beef cattle in Brazil in terms of climatic and geographic variables by using multivariate exploratory techniques; to evaluate the presence of genotype by environment interaction (GxE) for post weaning weight gain (PWG), yearling scrotal circumference (SC), and yearling muscling (MUS). Hierarchical and nonhierarchical cluster analysis was used to group farms located in regions with similar environmental variables into clusters. Six clusters of farms were formed. The effect of sire-cluster interaction was tested by single-trait analysis. Genetic parameters were estimated by multi-trait analysis considering the same trait to be different in each cluster. The effect of sire-cluster interaction was significant (P <0.01) for PWG and MUS. Estimates of genetic correlations among clusters ranged from 0.31 to 0.93 for PWG, 0.64 to 0.89 for SC, and 0.18 to 0.80 for MUS. These results indicate the need for a genetic analysis on a regional basis or inclusion of the GxE effect in the statistical model to permit appropriate evaluation of the animals. PMID- 24782163 TI - Expression analysis of differentially expressed miRNAs in male and female chicken embryos. AB - MicroRNAs (miRNAs) are small non-coding RNA molecules that play key roles in the regulation of development processes of many tissues and organs at the post transcriptional level. However, little is known about how they affect chicken gonadal development. We examined the expression of four miRNAs (miR-218, -200b, 196, and -206) in chicken embryonic gonads at embryonic days 3.5-6.5. Their target genes were predicted by miRDB, TargetScan and PicTar algorithms. The expression levels of these four miRNAs differed with sex to varying degrees; miR 200b was expressed at a significantly higher level in female gonads during the entire interval. The whole mount in situ hybridization result showed considerably higher expression of miR-200b in females than in males in E5.5 embryos. The miRNA target scanning results indicated several genes with functions in gonad development and gonad function. We conclude that miR-200b is involved in the regulation of gonad development and sexual differentiation of chicken embryos. PMID- 24782164 TI - Identification of a major quantitative trait locus for ear size induced by space flight in sweet corn. AB - The development of molecular markers has contributed to progress in identifying the gene(s) responsible for favorable variations in maize studies. In this study, quantitative trait locus (QTL) mapping was conducted using simple sequence repeat markers in an F2 sweet corn population from a cross between parental line 1132 and space flight-induced mutant line 751 to identify the loci contributing to an increase in some yield traits. A primary mutated genomic region was located on chromosome 9. In total, 26 QTL were detected for eight yield-related traits and assembled into three clusters on chromosome 9. The largest QTL cluster at bin 9.02/03, primarily contributing to >10% of the phenotypic variation in ear and cob diameters, was likely due to a major QTL. Desired alleles of these QTL were provided by the mutant line 751. The primary action of the major mutant allele was an additive effect. Another mutant locus, which was induced in bin 9.01, increased cob and ear diameters by dominant genetic action. PMID- 24782165 TI - Genetic association of catechol-O-methyltransferase val(158)met polymorphism in Saudi schizophrenia patients. AB - Schizophrenia is a complex neuropsychiatric disorder strongly associated with dopamine dysregulation. Catechol-O-methyl-transferase (COMT) is a candidate gene for schizophrenia that encodes an enzyme involved in the metabolic inactivation of dopamine. The COMT Val(158)Met polymorphism has been associated with schizophrenia and has significant inter- and intra-ethnic variations. We examined a possible association between the COMT Val(158)Met polymorphism and schizophrenia in Saudis, taking into account gender and functional symptoms. Saudi subjects including 172 unrelated schizophrenia patients and 177 matched controls were analyzed for allele and genotype distribution of the COMT Val(158)Met polymorphism. We found significant differences in allele and genotype frequencies between patients and controls. The frequencies of Met(158) allele (A) and genotype Val(158)Met (GA) were significantly higher in patients compared to those in controls. On the other hand, the frequencies of Val(158) allele (G) and genotype Val(158)Val (GG) were significantly higher in controls than those in patients. We found a significant association of the COMT Val(158)Met polymorphism with schizophrenia. Moreover, male patients with the COMT Val(158)Met polymorphism had increased risk for schizophrenia compared to female subjects. However, no association was noticed with the COMT Val(158)Met polymorphism and negative or positive symptoms of schizophrenia. These results provide evidence for a role of the COMT Val(158)Met polymorphism in the etiopathophysiology of schizophrenia in Saudi population. It appears that the association of the COMT Val(158)Met polymorphism with schizophrenia is mediated by gender. PMID- 24782166 TI - Molecular detection of QTL controlling plant height components in a doubled haploid barley population. AB - Yield losses caused by lodging in barley can be partially controlled by reducing plant height. In order to understand dwarfing mechanisms and efficiently use new dwarf germplasms for a breeding program, it is important to identify QTL of plant height components. QTL analysis was performed for seven plant height component traits using a DH population of 122 lines derived from the cross of Huaai 11 x Huadamai 6. Composite interval mapping procedures detected 20 QTL, which were mapped onto chromosomes 2H, 3H, 5H, 6H, and 7H. Eleven QTL were detected in 3 years and four QTL were detected in 2 years. QTL controlling all seven plant height component traits were found near the dwarfing gene btwd1 on chromosome 7H. These QTL accounted for 27.19 to 59.73% of phenotypic variation in seven plant height component traits. Positive transgressive segregation was found for all traits. Some of the QTL identified in this study will be useful for understanding the dwarfing mechanism and for developing new dwarf varieties using marker assisted selection. PMID- 24782167 TI - Role of XRCC1 and ERCC5 polymorphisms on clinical outcomes in advanced non-small cell lung cancer. AB - We aimed to assess the role of polymorphisms of the XRCC1 Arg194Trp, XRCC1 Arg399Gln, ERCC5 His1104Asp, and ERCC5 His46His genes on clinical outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy regimens. A total of 378 NSCLC patients were asked to participate within 1 month after diagnosis between January 2005 and January 2006, and they were followed up until November 2011. Genomic DNA of the four genes was extracted using the Qiagen Blood Kit. Results showed that individuals with XRCC1 399A/A and ERCC5 46T/T genotypes were more likely to show positive responses to chemotherapy, with odds ratio (OR) = 2.27 and 95% confidence interval (CI) = 1.64 6.97, and OR = 1.90, CI = 1.10-3.28, respectively. The XRCC1 399A/A genotype was significantly associated with longer progression-free survival (PFS) and overall survival (OS) rates, and the hazard ratios (HRs) (95%CI) were 0.48 (0.25-0.88) and 0.51 (0.26-0.98), respectively. Similarly, NSCLC patients carrying the ERCC5 46T/T genotype were more likely to show increased PFS and OS, with HRs (95%CI) of 0.47 (0.22-0.82) and 0.52 (0.31-0.96), respectively. In conclusion, our study indicated that XRCC1 Arg399Gln and ERCC5 His46His might significantly influence the response to chemotherapy, and the two genetic polymorphisms are suggested to be routinely detected to determine NSCLC patients that are more likely to benefit from chemotherapy. PMID- 24782168 TI - Clinical features of diabetes mellitus cases complicated by Burkholderia pseudomallei septicemia. AB - The aim of this study was to analyze the clinical characteristics of diabetes mellitus patients with Burkholderia pseudomallei septicemia and evaluate strategies of diagnosis and treatment. The clinical characteristics, diagnosis, treatment, and prognosis of 39 diabetes mellitus patients with B. pseudomallei septicemia were retrospectively analyzed. Farmers, fishermen and workers were found to be high-risk groups. The clinical manifestations of patients were diverse without specific features, but mainly presented manifestations of acute fulminant septicemia, diabetic ketoacidosis, and abscesses in tissues or/and organs. Patients showed high mortality and misdiagnosis rates and were prone to relapses and long treatment duration as there are currently few effective and sensitive antibiotics for the disease. Consequently, the cost of treatment for the disease was high. Early diagnosis, a prolonged course of heavy doses of sensitive intravenous antibiotics, drainage of abscesses, intensive insulin therapy, and supportive treatment are the keys for successful management of the disease. Regular follow-ups combined with long-term blood glucose control can help reduce the disease recurrence. PMID- 24782169 TI - Antioxidant capacity and meat quality of broilers exposed to different ambient humidity and ammonia concentrations. AB - To investigate the effect of humidity and ammonia on the antioxidative capacities and meat qualities of broilers, 192 broilers were divided into 2 groups: high (H, 70 ppm) and low (L, 30 ppm) ammonia concentration. These groups were divided into 30% (Treatment humidity, T) and 60% (Control humidity, C) humidity, giving 4 treatments: C+L, C+H, T+L, and T+H. Blood and muscle antioxidative capacities and meat quality were measured. In the H group, body weight (BW), average daily feed intake (ADFI), average daily weight gain (ADG), blood and muscle antioxidative capacities, and postmortem pectoral muscle a* of broilers were significantly decreased (P < 0.05), and pectoral muscle thiobarbituric acid reactive substance (TBARS) contents and drip losses, postmortem pectoral muscle b* (P < 0.05) and L* (P = 0.054), and pectoral muscle shear forces (P = 0.075) increased. In the T condition, BW, ADFI, pectoral muscle superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and pectoral muscle L* decreased (P = 0.053), and pectoral muscle shear forces and TBARS contents increased (P < 0.05). In the T+H group, BW, ADFI, ADG, blood antioxidative capacities, pectoral muscle SOD and GSH Px activities, and postmortem pectoral muscle a* were significantly lower than those of the C+L group, but postmortem pectoral muscle TBARS contents and pectoral muscle drip losses and shear forces significantly increased (P < 0.05). These results revealed that T+H could significantly reduce growth performance, antioxidative capacities, and meat quality of broilers; T intensified these negative effects. PMID- 24782170 TI - Heliconia phenotypic diversity based on qualitative descriptors. AB - The aim of this study was to characterize Heliconia genotypes phenotypically using 26 qualitative descriptors. The evaluations were conducted in five flowering stems per clump in three replicates of 22 Heliconia genotypes. Data were subjected to multivariate analysis, the Mahalanobis dissimilarity measure was estimated, and the dendrogram was generated using the nearest neighbor method. From the values generated by the dissimilarity matrix and the clusters formed among the Heliconia genotypes studied, the phenotypic characterizations that best differentiated the genotypes were: pseudostem and wax green tone (light or dark green), leaf-wax petiole, the petiole hair, cleft margin at the base of the petiole, midrib underside shade of green, wax midrib underside, color sheet (light or dark green), unequal lamina base, torn limb, inflorescence-wax, position of inflorescence, bract leaf in apex, twisting of the rachis, and type of bloom. These results will be applied in the preparation of a catalog for Heliconia descriptors, in the selection of different genotypes with most promising characteristics for crosses, and for the characterization of new genotypes to be introduced in germplasm collections. PMID- 24782171 TI - Low-frequency ultrasound induces apoptosis of rat aortic smooth muscle cells (A7r5) via the intrinsic apoptotic pathway. AB - Ultrasound, a non-invasive therapy method, is a potential tool for medical applications, but its biological effects on vascular smooth muscle cells (VSMCs) have not been characterized. The aim of this study was to explore the effect and possible apoptotic mechanism of VSMCs that were induced by low-frequency ultrasound (LFU). Cell viability and apoptosis of A7r5 cells were evaluated after treating A7r5 cells with a continuous 45-kHz 1.0-W/cm(2) ultrasound (exposure time of 0, 10, 20, 30, and 35 s) by MTT assay and flow cytometry. At the optimum ultrasound exposure condition (30 s), gene chip analysis was performed, and the apoptotic signaling pathway was confirmed by reverse transcription-polymerase chain reaction and Western blot. As measured by flow cytometry, LFU significantly induced A7r5 cell apoptosis. Comparing the ultrasound group with the control group, the protein expression of caspase-9 and caspase-3 was increased by 50 and 57%, respectively; the caspase-3 mRNA level was increased by 37.5%. These findings indicate that an intrinsic pathway plays a major role in apoptosis that is induced by LFU and that LFU can induce A7r5 cell apoptosis via caspase-9- and caspase-3-dependent pathways. PMID- 24782172 TI - Effects of mycophenolate mofetil on the expression of monocyte chemoattractant protein-1 and fibronectin in high glucose cultured human mesangial cells. AB - The effects of high glucose on the expression of monocyte chemoattractant protein 1 (MCP-1) and the main component of the extracellular matrix, fibronectin (FN), were explored in human mesangial cells (HMCs), along with the intervention effects of mycophenolate mofetil (MMF) on these indicators. Cultured HMCs were divided into five groups: 1) normal control group (5 mM glucose); 2) high glucose group (30 mM glucose); 3) mannitol osmotic pressure control group (5 mM glucose + 25 mM mannitol); 4) high glucose + MMF-10 group (30 mM glucose + 10 MUg/mL MMF); 5) high glucose + MMF-100 group (30 mM glucose + 100 MUg/mL MMF). At 24, 48, and 72 h, reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay methods were used to detect the effects of MMF on MCP-1 mRNA and protein and FN expression in HMCs under high glucose conditions. MCP-1 mRNA and protein expressions and FN secretion significantly increased in HMCs of the high glucose group compared with the normal control group (P < 0.01), with the highest expression observed at 48 h. MMF could reduce the MCP-1 mRNA and protein and FN expression levels (P < 0.01), and the inhibition occurred in a dose- and time-dependent manner (P < 0.05). In conclusion, MMF could inhibit MCP-1 expression and the secretion of FN, indicating that it may delay the progression of glomerulosclerosis and interstitial fibrosis in diabetic nephropathy to ultimately achieve protective effects on the kidney. PMID- 24782173 TI - Case report: familial primary open-angle glaucoma: a case report. AB - Primary open-angle glaucoma (POAG) is a disease that is often inherited, but the rules governing its inheritance are inconclusive. Herein, we report a case of POAG in a Chinese family. A 25-year-old female patient was referred to our department with progressive visual acuity decline in her left eye for the past 3 years. Ophthalmological examination supported our diagnosis of POAG in both eyes. We recorded the case history and clinical data of the proband and her family members and followed standard genetic study procedures. In this family, there were 8 individuals (4 male and 4 female) diagnosed with POAG, 2 of whom died. Genetic analysis revealed that the inheritance pattern of POAG in this family is autosomal dominant. PMID- 24782174 TI - Hand and foot surgery rates in rheumatoid arthritis have declined from 1986 to 2011, but large-joint replacement rates remain unchanged: results from two UK inception cohorts. AB - OBJECTIVE: To assess whether there have been any secular changes in orthopedic interventions in patients with rheumatoid arthritis (RA) since 1986, as examined in 2 early rheumatoid arthritis (RA) inception cohorts with up to 25 years of followup. METHODS: The study examined orthopedic data from the UK Early RA Study (1986-1999, 9 centers; n = 1,465) and the UK Early RA Network (2002-2012, 23 centers; n = 1,236) with linkage to national data sets (Hospital Episode Statistics, National Joint Registry, and Office of National Statistics). Clinical and laboratory measures and hand and foot radiographs were standardized and obtained yearly in both cohorts. The use of disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologic therapies reflected the contemporary conventional practices and guidelines of the time frames examined. Recruitment years were grouped into 6 periods, and interventions were classified into major, intermediate, and minor categories. RESULTS: A total of 1,602 orthopedic surgical procedures were performed in 770 patients (29%) over a maximum of 25 years of followup. The 25-year cumulative incidence rate of major interventions was 21.7% (range 19.4-24.0%), and that of intermediate interventions was 21.5% (range 17.8 25.5%). There was a decline in the 10-year cumulative incidence of intermediate surgeries over time (P < 0.001), but not of major/minor surgery. This decline coincided with a gradual shift from sequential monotherapy to combination DMARD therapies and biologic agents in recent recruitment periods. CONCLUSION: Orthopedic surgery is an important and common outcome in RA. Only the rates of hand/foot surgery showed a consistent decline from 1986 to 2011. Possible explanations include differences in the pathophysiologic processes affecting the joints, variations in the responses to therapy between large-joint and small joint destructive processes, and changes in service provision and thresholds for surgery over time. PMID- 24782175 TI - Periodontitis and Porphyromonas gingivalis in patients with rheumatoid arthritis. AB - OBJECTIVE: To examine the degree to which shared risk factors explain the relationship of periodontitis (PD) to rheumatoid arthritis (RA) and to determine the associations of PD and Porphyromonas gingivalis with pathologic and clinical features of RA. METHODS: Patients with RA (n = 287) and patients with osteoarthritis as disease controls (n = 330) underwent a standardized periodontal examination. The HLA-DRB1 status of all participants was imputed using single nucleotide polymorphisms from the extended major histocompatibility complex. Circulating anti-P gingivalis antibodies were measured using an enzyme-linked immunosorbent assay, and subgingival plaque was assessed for the presence of P gingivalis using polymerase chain reaction (PCR). Associations of PD with RA were examined using multivariable regression. RESULTS: Presence of PD was more common in patients with RA and patients with anti-citrullinated protein antibody (ACPA) positive RA (n = 240; determined using the anti-cyclic citrullinated peptide 2 [anti-CCP-2] test) than in controls (35% and 37%, respectively, versus 26%; P = 0.022 and P = 0.006, respectively). There were no differences between RA patients and controls in the levels of anti-P gingivalis or the frequency of P gingivalis positivity by PCR. The anti-P gingivalis findings showed a weak, but statistically significant, association with the findings for both anti-CCP-2 (r = 0.14, P = 0.022) and rheumatoid factor (RF) (r = 0.19, P = 0.001). Presence of PD was associated with increased swollen joint counts (P = 0.004), greater disease activity according to the 28-joint Disease Activity Score using C-reactive protein level (P = 0.045), and higher total Sharp scores of radiographic damage (P = 0.015), as well as with the presence and levels of anti-CCP-2 (P = 0.011) and RF (P < 0.001). The expression levels of select ACPAs (including antibodies to citrullinated filaggrin) were higher in patients with subgingival P gingivalis and in those with higher levels of anti-P gingivalis antibodies, irrespective of smoking status. Associations of PD with established seropositive RA were independent of all covariates examined, including evidence of P gingivalis infection. CONCLUSION: Both PD and P gingivalis appear to shape the autoreactivity of RA. In addition, these results demonstrate an independent relationship between PD and established seropositive RA. PMID- 24782176 TI - RFC1 80G>A is a genetic determinant of methotrexate efficacy in rheumatoid arthritis: a human genome epidemiologic review and meta-analysis of observational studies. AB - OBJECTIVE: Associations have been reported between candidate genes and the response to methotrexate (MTX) in rheumatoid arthritis (RA) patients, but most of the studies have been small and have yielded conflicting results. This study was undertaken to provide a systematic review of all genetic variant associations with MTX efficacy and toxicity, and to conduct a meta-analysis evaluating the most commonly studied single-nucleotide polymorphism for which prior cumulative analysis has been lacking. METHODS: A systematic review and meta-analysis were performed to identify genetic variant associations with MTX efficacy and toxicity. Studies were identified from the Medline, EMBase, HuGENet Navigator, and Cochrane Library databases through December 2012, and from the 2009-2011 abstracts of the American College of Rheumatology and the European League Against Rheumatism annual meeting proceedings. Additional unpublished genotype data from a Canadian cohort of patients with early RA were also included. RESULTS: Among the 87 identified studies examining genetic associations with MTX efficacy and toxicity, the reduced folate carrier 1 gene (RFC1) variant 80G>A (Arg(27) His, rs1051266) was selected for random-effects meta-analysis. RFC1 80G>A was associated with MTX efficacy in both the recessive model (odds ratio [OR] 1.42, 95% confidence interval [95% CI] 1.04-1.93) and the additive model (OR 1.28, 95% CI 1.10-1.49). Restriction of the sensitivity analyses to studies that involved Caucasian subjects only and that used similar outcome measures (MTX failure versus nonfailure) maintained and improved the associations in both models. No significant association between RFC1 80G>A and MTX toxicity was detected. CONCLUSION: In these analyses of available data from observational studies, RFC1 80G>A was found to be associated with MTX efficacy, but not toxicity, in RA patients. This variant merits further prospective analysis as a potential predictor of MTX efficacy. Variability in the definitions of response in pharmacogenetic studies is a source of data heterogeneity that should be addressed. PMID- 24782178 TI - Antibodies to IgG4 hinge can be found in rheumatoid arthritis patients during all stages of disease and may exacerbate chronic antibody-mediated inflammation. AB - OBJECTIVE: In rheumatoid arthritis (RA), autoantibodies such as anti citrullinated protein antibodies (ACPAs) develop in response to neoepitopes that are formed under conditions of chronic inflammation. These autoantibodies may subsequently be fragmented by inflammation-associated proteases, leading to the formation of F(ab')2 fragments. The hinge of F(ab')2 fragments can serve as a neoepitope, and so-called antihinge antibodies (AHAs) can be found in RA patients, which might modulate the function of (fragmented) autoantibodies. We undertook this study to investigate the presence and specificities of AHAs in different stages of RA and to study their function. METHODS: The presence of AHAs was assessed by radioimmunoassay in healthy controls, blood donors who later developed RA, patients with arthralgia, patients with early RA, and patients with established RA. Specificity of the AHAs was analyzed with inhibition assays, and complement-activating ability was studied with a C4b deposition assay. RESULTS: Antibodies to IgG1 hinge, IgG2 hinge, and IgG4 hinge were detected in patients with established RA, with anti-IgG4 hinge antibodies being most specific (appearing in 1% of healthy controls, 3.8% of blood donors who later developed RA, 13% of arthralgia patients, 19% of early RA patients, and 16% of established RA patients). Anti-IgG4 hinge antibodies were subclass specific and were able to restore C4b deposition by IgG4 F(ab')2 fragments. In patients with arthralgia and patients with early RA, anti-IgG4 hinge antibodies were associated with rheumatoid factors and ACPAs. CONCLUSION: Anti-IgG4 hinge antibodies are present in RA patients and have low sensitivity but high specificity for RA. Since a significant proportion of ACPAs can be of the IgG4 subclass, the formation of anti-IgG4 hinge antibodies may represent one mechanism of ACPA-mediated inflammation. PMID- 24782177 TI - Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans. AB - OBJECTIVE: To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans. METHODS: A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations. RESULTS: Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 * 10(-21) ), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 * 10(-16) ), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 * 10(-15) ). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 * 10(-18) ), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 * 10(-8) ). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis. CONCLUSION: This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants. PMID- 24782179 TI - Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcgamma receptor IIb inhibitory receptor. AB - OBJECTIVE: Engagement of Fcgamma receptor IIb (FcgammaRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. The aim of this study was to characterize B cell immunosuppression mediated by the Fc engineered antibody, XmAb5871, which coengages FcgammaRIIb with the B cell antigen receptor (BCR) complex and that is currently in clinical development for the treatment of rheumatoid arthritis (RA). Because rheumatoid factor (RF) might interfere with the binding of XmAb5871 to FcgammaRIIb, we correlated RF titers with the potency of XmAb5871. METHODS: We analyzed the expression of CD19, FcgammaRIIb, and CD86 on naive and memory B cells from 50 patients with RA and 66 healthy donors, quantified XmAb5871-induced promotion of FcgammaRIIb phosphorylation and suppression of calcium flux in activated B cells, measured CD86 inhibition in whole blood, and correlated RF and anti-citrullinated protein antibody (ACPA) levels with drug potency. We engrafted RA peripheral blood mononuclear cells (PBMCs) into SCID mice, treated them with XmAb5871, and quantified human total IgG, total IgM, and anti-tetanus IgG antibody levels in vivo. RESULTS: B cells from all donors expressed CD19 and FcgammaRIIb, and the expression of FcgammaRIIb was higher on naive, but not memory, B cells from donors with RA compared with healthy donors. BCR-mediated calcium flux was suppressed by XmAb5871 and was associated with FcgammaRIIb phosphorylation. XmAb5871 inhibited CD86 induction, and the levels of RF and ACPAs did not affect efficacy. XmAb5871 suppressed B cell activation regardless of disease severity. In SCID mice engrafted with PBMCs from a patient with RA, XmAb5871 suppressed humoral responses. CONCLUSION: Coengagement of the BCR complex and FcgammaRIIb by XmAb5871 inhibits B cell activation and function. The similar potency in patients with RA and healthy donors and the absence of autoantibody interference suggest that XmAb5871 may represent a new therapeutic strategy to suppress autoreactive B cells in RA. PMID- 24782180 TI - Increased Th17 cell frequency and poor clinical outcome in rheumatoid arthritis are associated with a genetic variant in the IL4R gene, rs1805010. AB - OBJECTIVE: The minor allele of the IL4R gene single-nucleotide polymorphism, rs1805010, confers impaired interleukin-4 (IL-4) signaling and has been associated with an aggressive destructive course of rheumatoid arthritis (RA). IL 4 inhibits the development of Th17 cells, a cell population recently identified as being prominent in RA patients and being associated with cartilage and bone destruction. The purpose of the present study was to investigate whether rs1805010 modulates Th17 cell development and, hence, subsequent clinical outcome in RA. METHODS: A total of 90 patients with early, active RA (mean +/- SD Disease Activity Score in 28 joints 4.6 +/- 1.1) and 39 control subjects (24 healthy subjects and 15 patients with osteoarthritis [OA]) were genotyped. Serum levels of IL-17 and IL-22 as well as frequencies of Th17 cells were analyzed by enzyme linked immunosorbent assay and flow cytometry. Clinical and radiographic data were collected and evaluated at baseline and 1 year after disease onset. RESULTS: Twenty-six percent of the RA patients were homozygous for the major allele of rs1805010, 60% were heterozygous, and 14% were homozygous for the minor allele. The RA patients who were homozygous for the minor allele demonstrated significantly higher clinical activity associated with the presence of erosions after 1 year of followup as compared to the other RA patients. The inhibitory effect of IL-4 on Th17 cell development in these patients was significantly less prominent. Accordingly, the frequencies of Th17 cells and serum levels of IL-17 and IL-22 were significantly increased. CONCLUSION: The data indicate that the rs1805010 minor allele contributes to increased Th17 cell frequency, enhanced clinical activity, and accelerated radiographic progression in RA by rendering CD4 T cells from RA patients insensitive to the attenuating effect of IL-4 on Th17 cell development. PMID- 24782181 TI - Thymic stromal lymphopoietin, a novel proinflammatory mediator in rheumatoid arthritis that potently activates CD1c+ myeloid dendritic cells to attract and stimulate T cells. AB - OBJECTIVE: To determine the levels of thymic stromal lymphopoietin (TSLP) and the numbers of TSLP receptor (TSLPR)-expressing CD1c+ (blood dendritic cell antigen 1 positive) myeloid dendritic cells (MDCs) in the joints as compared with the peripheral blood (PB) of patients with rheumatoid arthritis (RA), as well as to determine the capacity of TSLP to induce MDC-dependent T cell activation. METHODS: TSLP levels were measured in synovial fluid (SF) samples from patients with RA and those with osteoarthritis (OA). MDC numbers in PB and SF samples from RA patients and TSLPR expression on these cells were assessed by fluorescence activated cell sorter analysis. PB and SF MDCs from RA patients were stimulated with TSLP, and cytokine production was measured by multiplex immunoassay. TSLP primed MDCs were cocultured with autologous CD4+ T cells in the absence of additional stimuli, and subsequently, cell proliferation and cytokine production were measured. RESULTS: TSLP levels were significantly increased in SF samples from RA versus OA patients. The numbers of TSLPR-expressing MDCs in the SF of RA patients were significantly increased as compared to those in the PB, and SF MDCs displayed increased levels of TSLPR. TSLP selectively stimulated the production of thymus and activation-regulated chemokine and macrophage inflammatory protein 1alpha by CD1c+ MDCs. TSLP-primed MDCs from PB and SF potently stimulated the proliferation of autologous CD4+ T cells as compared to unstimulated MDCs. Enhanced proliferation was associated with increased production of interferon gamma, interleukin-17 (IL-17), and IL-4. CONCLUSION: These data support an inflammatory mechanism by which increased intraarticular TSLP in RA potently activates TSLPR-expressing CD1c+ MDCs in the joints to secrete chemokines, causing chemotaxis and subsequent activation of CD4+ T cells. In addition to the demonstrated inflammatory potential of TSLP in experimental arthritis, this suggests that TSLP and TSLPR-expressing MDCs could both play a pivotal role in the immunopathology of RA. PMID- 24782182 TI - AT-rich-interactive domain-containing protein 5A functions as a negative regulator of retinoic acid receptor-related orphan nuclear receptor gammat induced Th17 cell differentiation. AB - OBJECTIVE: The proinflammatory cytokines tumor necrosis factor alpha and interleukin-6 (IL-6) and the Th17 cell cytokine IL-17A are implicated in the pathogenesis of rheumatoid arthritis (RA), and the blockade of these cytokines by biologic agents provides clinical benefits for RA patients. We undertook this study to clarify the mechanisms underlying the efficacy of IL-6 blockade in RA and to find a novel target for treatment of RA. METHODS: We examined gene expression profiles of CD4+ T cells by DNA microarray analysis before and after treatment with an anti-IL-6 receptor antibody, tocilizumab (TCZ), in RA patients who exhibited good clinical responses to the treatment. Using murine CD4+ T cells, we then examined the roles of a newly identified molecule whose expression was significantly reduced in CD4+ T cells by TCZ therapy. We also examined the effect of the forced expression of the molecule on retinoic acid receptor-related orphan nuclear receptor gammat (RORgammat)-induced IL-17A production in CD4+ T cells and on RORgammat-induced IL-17A promoter activation. RESULTS: We identified AT-rich-interactive domain- containing protein 5A (ARID-5A) as a new molecule down-regulated by IL-6 blockade in the form of TCZ therapy. IL-6 induced the expression of ARID-5A in CD4+ T cells during Th17 cell differentiation by a STAT 3-dependent mechanism, whereas IL-6-induced ARID-5A expression was not affected by the absence of RORgammat, a lineage-specifying transcription factor of Th17 cells. Furthermore, ARID-5A physically associated with RORgammat through its N terminal region and inhibited RORgammat-induced Th17 cell differentiation. CONCLUSION: ARID-5A is a lineage-specific attenuator of Th17 cell differentiation and may be involved in the pathogenesis of RA. PMID- 24782183 TI - Halofuginone ameliorates autoimmune arthritis in mice by regulating the balance between Th17 and Treg cells and inhibiting osteoclastogenesis. AB - OBJECTIVE: The small molecule halofuginone has been shown to inhibit fibrosis, angiogenesis, and tumor progression. This study was undertaken to evaluate the effects of halofuginone in preventing autoimmune arthritis in mice. METHODS: The effects of halofuginone on joint diseases were assessed by clinical scoring and histologic analysis. Protein expression levels were confirmed by immunohistochemistry, enzyme-linked immunosorbent assay, flow cytometry, and/or Western blotting. The expression levels of messenger RNA (mRNA) for various molecules were determined by real-time polymerase chain reaction (PCR). Proliferation of osteoclast precursors was assessed by bromodeoxyuridine uptake. Osteoclast differentiation and activity were determined by quantifying tartrate resistant acid phosphatase (TRAP)-positive multinucleated cells and area of resorbed bone. RESULTS: Treatment with halofuginone suppressed the development of autoimmune arthritis and reciprocally regulated Th17 cells and FoxP3+ Treg cells. These effects of halofuginone on Th17 differentiation involved increased signaling of ERK and reduction of STAT-3 and NF-ATc1 expression. Furthermore, halofuginone induced the expression of indoleamine 2,3-dioxygenase (IDO) in dendritic cells, leading to reduced production of Th17 cells. In addition, halofuginone prevented the formation and activity of osteoclasts through suppression of transcription factors, such as activator protein 1 and NF-ATc1, and inhibited cell cycle arrest by the committed osteoclast precursors via expression of Ccnd1 encoding cyclin D1. CONCLUSION: Taken together, our results suggest that halofuginone is a promising therapeutic agent for the treatment of Th17 cell-mediated inflammatory diseases and bone diseases. PMID- 24782184 TI - Alternative p38 MAPKs are essential for collagen-induced arthritis. AB - OBJECTIVE: The role of most p38 MAPK isoforms in inflammatory arthritis is not known. This study was undertaken to evaluate p38gamma and p38delta deficiency in the collagen-induced arthritis (CIA) model. METHODS: Wild-type, p38gamma(-/-) , p38delta(-/-) , and p38gamma/delta(-/-) mice were immunized with chicken type II collagen, and disease activity was evaluated by semiquantitative scoring and histologic assessment. Serum cytokine levels and in vitro T cell cytokine responses were quantified by flow cytometry and multiplex analysis, and serum anticollagen antibody levels by enzyme-linked immunosorbent assay. Cytokine and p38 MAPK isoform expression in joints were determined by quantitative polymerase chain reaction. RESULTS: Compound p38gamma and p38delta deficiency markedly reduced arthritis severity compared with that in wild-type mice, whereas lack of either p38gamma or p38delta had an intermediate effect. Joint damage was minimal in arthritic p38gamma/delta(-/-) mice compared with wild-type mice. The p38gamma/delta(-/-) mice had lower levels of pathogenic anticollagen antibodies and interleukin-1beta (IL-1beta) and tumor necrosis factor alpha than controls. In vitro T cell assays showed reduced proliferation, interferon-gamma (IFNgamma) production, and IL-17 production by lymph node cells from p38gamma/delta(-/-) mice. IL-17 and IFNgamma messenger RNA expression in joints was significantly inhibited in p38gamma/delta(-/-) mice. Wild-type chimeric mice with p38gamma/delta(-/-) bone marrow did not show decreased CIA. CONCLUSION: Reduced disease severity in p38gamma/delta(-/-) mice was associated with lower cytokine production and anticollagen antibody responses than in controls, indicating that p38gamma and p38delta are crucial regulators of inflammatory joint destruction in CIA. Our findings indicate that p38gamma and p38delta are potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses. PMID- 24782185 TI - Ankylosing spondylitis, psoriatic arthritis, and risk of malignant lymphoma: a cohort study based on nationwide prospectively recorded data from Sweden. AB - OBJECTIVE: Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relation to therapies, including tumor necrosis factor inhibitor (TNFi), for which lymphoma risks are a concern. METHODS: Through the Swedish National Patient Register we assembled nationwide prevalence cohorts of patients with AS (n = 8,707) and patients with PsA (n = 19,283) for whom data were obtained between 2001 and 2010. Each cohort member was matched to 5 population comparator subjects. Linkage with the nationwide Cancer Register identified all lymphomas recorded from 2001 to 2010. Through the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]), we identified patients exposed to TNFi in the AS cohort (n = 1,908) and the PsA cohort (n = 2,605) before lymphoma diagnosis. Hazard ratios (HRs) for lymphoma were estimated by Cox regression. Crude incidences of lymphoma in TNFi-exposed and TNFi-naive patients were compared. RESULTS: For AS patients, the HR of having lymphoma versus the general population was 0.9 (95% confidence interval [95% CI] 0.5-1.6) (14 lymphomas). For PsA patients, the corresponding HR was 1.2 (95% CI 0.9-1.7) (45 lymphomas). For PsA patients treated with methotrexate and/or sulfasalazine, the HR of having lymphoma was 1.7 (95% CI 1.0-3.1). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and PsA patients, although the numbers of lymphomas were small. CONCLUSION: In contrast to rheumatoid arthritis, the average risks of lymphoma in AS or PsA are not elevated, although increased risks in a subset of PsA patients cannot be excluded. Our findings indicate that TNFi does not affect the risk of lymphoma in AS or in PsA. PMID- 24782186 TI - Fcgamma receptor IIIa single-nucleotide polymorphisms and haplotypes affect human IgG binding and are associated with lupus nephritis in African Americans. AB - OBJECTIVE: To investigate whether the Fcgamma receptor IIIa-66L/R/H (FcgammaRIIIa 66L/R/H) polymorphism influences net effective receptor function and to assess if the FCGR3A combined genotypes formed by FcgammaRIIIa-66L/R/H and FcgammaRIIIa 176F/V, as well as copy number variation (CNV), confer risk of developing systemic lupus erythematosus (SLE) and lupus nephritis. METHODS: FcgammaRIIIa variants, expressed on A20 IIA1.6 cells, were used in flow cytometry-based human IgG-binding assays. Using Pyrosequencing methodology, FCGR3A single-nucleotide polymorphism and CNV genotypes were determined in a cohort of 1,728 SLE patients and 2,404 healthy controls. RESULTS: The FcgammaRIIIa-66L/R/H (rs10127939) polymorphism influenced ligand binding capacity in the presence of the FcgammaRIIIa-176V (rs396991) allele. There was a trend toward an association of the low-binding FcgammaRIIIa-176F allele with lupus nephritis among African Americans (P = 0.0609) but not among European Americans (P > 0.10). Nephritis among African American patients with SLE was associated with FcgammaRIIIa low binding haplotypes containing the 66L/R/H and 176F variants (P = 0.03) and with low-binding genotype combinations (P = 0.002). No association was observed among European American patients with SLE. The distribution of FCGR3A CNV was not significantly different among controls and SLE patients with or without nephritis. CONCLUSION: FcgammaRIIIa-66L/R/H influences ligand binding. The low binding haplotypes formed by 66L/R/H and 176F confer enhanced risk of lupus nephritis in African Americans. FCGR3A CNVs are not associated with SLE or lupus nephritis in either African Americans or European Americans. PMID- 24782187 TI - Brief report: impaired in vivo neovascularization capacity of endothelial progenitor cells in patients with systemic sclerosis. AB - OBJECTIVE: Defective vasculogenesis is thought to play a role in the pathogenesis of systemic sclerosis (SSc). We undertook this study to explore the in vivo functional capacity of CD34+CD133+CD309+ endothelial progenitor cells (EPCs) in SSc patients. METHODS: CD133+ cells and EPCs were enumerated by flow cytometry. Immunomagnetically sorted circulating CD133+ cells from 16 patients with SSc and 12 healthy subjects, as well as murine colon carcinoma CT-26 cells, were transplanted beneath the skin of SCID mice. Tumor volume and blood vessel density were measured 10 days later. Human EPC incorporation into the vascular wall was evaluated using tumor sections double stained for mouse CD31 and human CD31. RESULTS: The number of CD133+ cells and EPCs was significantly decreased in SSc patients as compared to healthy controls (P = 0.001 and P = 0.02, respectively), while the proportion of EPCs in CD133+ cells was similar between the 2 groups. CT 26 cells produced markedly stronger tumor growth and neovessel formation when transplanted with CD133+ cells from healthy subjects than when transplanted with CD133+ cells from SSc patients (P = 0.001 and P = 0.008, respectively). Tumors from mice that received transplants of CT-26 cells and SSc-derived CD133+ cells formed fewer vessels incorporating human EPC-derived mature endothelial cells than did tumors from mice that received transplants of CT-26 cells and CD133+ cells from healthy control subjects (P = 0.0002). CONCLUSION: We established a system that can be used to evaluate the in vivo neovascularization capacity of freshly isolated EPCs. EPCs contribute to vascularization by incorporating into vessel walls and by differentiating into endothelial cells. These EPC functions are impaired in SSc. PMID- 24782188 TI - Long-term outcome of neuro-Behcet's disease. AB - OBJECTIVE: To report the long-term outcome of neurologic involvement in patients with Behcet's disease (BD). METHODS: We performed a retrospective analysis of 115 patients who fulfilled the international criteria for BD (57% male; median age 37 years [interquartile range (IQR) 30-46 years]) and had neuro-BD (NBD) after exclusion of cerebral venous thrombosis. Factors associated with relapse of NBD, inability to perform activities of daily living, and mortality were assessed. RESULTS: Seventy-eight patients (68%) presented with acute NBD and 37 (32%) presented with a progressive course. The HLA-B51 allele was carried by 49% of the patients. Overall, 46 of 115 patients (40%) had severe disability at baseline, represented by a Rankin score of >=3. The 5- and 7-year event-free survival rates were 65% and 53%, respectively. In multivariate analysis, a positive HLA-B51 status was independently associated with the risk of NBD relapse, with an odds ratio (OR) of 3.6 (95% confidence interval [95% CI] 1.5-9.1). After a median followup of 73 months (IQR 59-102 months), 29 patients (25.2%) became dependent (were unable to perform activities of daily living) or died. Factors independently associated with poor outcome were paresis at onset (OR 6.47 [95% CI 1.73-24.23]) and location of inflammatory lesions at the brainstem on magnetic resonance imaging (OR 8.41 [1.03-68.43]). All 115 patients were treated with corticosteroids; 53 (46.1%) also took cyclophosphamide and 40 (34.8%) also took azathioprine. A trend toward longer event-free survival was observed in patients with severe NBD (i.e., with a Rankin score of >=3 at onset) receiving intravenous cyclophosphamide compared with those receiving azathioprine (P = 0.06). CONCLUSION: Our findings indicate that NBD is a severe condition in which patients with the HLA-B51 allele appear to experience a worse prognosis. PMID- 24782190 TI - Diffuse papules and skin tightening. PMID- 24782189 TI - Primary angiitis of the central nervous system: description of the first fifty two adults enrolled in the French cohort of patients with primary vasculitis of the central nervous system. AB - OBJECTIVE: To describe characteristics and outcomes of a multicenter cohort of patients diagnosed as having primary angiitis of the central nervous system (PACNS). METHODS: In 2010, we initiated a cohort study of adults diagnosed as having PACNS <=15 years ago and with followup of >6 months (unless they died earlier of biopsy-proven PACNS). Its first analysis was planned at 2 years. Multidisciplinary investigators verified that appropriate investigations were done and excluded patients with possible alternative diagnoses. We analyzed patient demographics and symptoms, laboratory, radiographic, and histologic findings, and treatments. Studied outcomes included treatment response(s), relapse, death, and disability. RESULTS: We included 52 patients (30 males; median age at diagnosis 43.5 years [range 18-79 years]) in whom PACNS was diagnosed between 1996 and 2012. Nineteen (61%) of 31 patients who had undergone brain biopsy had histologic vasculitis (biopsy-proven PACNS), while the other 12 patients had normal or noncontributive biopsy samples. An additional 21 patients had signs suggestive of PACNS on conventional cerebral angiography. All but 1 patient received corticosteroids, and 44 patients received cyclophosphamide (CYC). After a median followup of 35 months (range 2-148 months) postdiagnosis (1 patient with biopsy-proven PACNS died 2 months after diagnosis), 32 patients responded to treatment with improved modified Rankin scale scores, 4 patients (8%) did not respond, 14 patients (27%) had relapse of their disease at least once, and 3 patients (6%) died (1 patient after a relapse). Relapse was more common in patients with than in those without meningeal gadolinium enhancements on magnetic resonance imaging (MRI) (8 of 10 [80%] versus 6 of 32 [19%]; P = 0.001) and more common in patients with than in those without seizures at diagnosis (8 of 17 [47%] versus 6 of 35 [17%]; P = 0.04). CONCLUSION: In this cohort of patients with PACNS, most patients received corticosteroids and CYC, and mortality was low. Patients with seizures at diagnosis or meningeal enhancements on MRI may be prone to relapse and require a different treatment strategy. PMID- 24782191 TI - The role of transforming growth factor beta signaling in fibroblast-like synoviocytes from patients with oligoarticular juvenile idiopathic arthritis: dysregulation of transforming growth factor beta signaling, including overexpression of bone morphogenetic protein 4, may lead to a chondrocyte phenotype and may contribute to bony hypertrophy. AB - OBJECTIVE: This study was designed to investigate the pathogenic contributions of fibroblast-like synoviocytes (FLS) to juvenile idiopathic arthritis (JIA) by identifying pathways with dysregulated gene expression in FLS from patients with oligoarticular JIA. METHODS: FLS were derived from synovial fluid obtained by arthrocentesis from patients with JIA undergoing intraarticular steroid injections and from orthopedic control patients. Gene expression profiles of the JIA and control FLS were obtained using the Affymetrix platform, with application of Ingenuity Pathway Analysis and Gene Set Enrichment Analysis software to define gene sets in dysregulated pathways and networks of potential pathologic relevance in this disease. Biologically relevant differentially expressed genes were confirmed by RNA and protein analysis. RESULTS: Exploration of global gene expression profiles of the JIA FLS revealed important dysregulated pathways, including the transforming growth factor beta (TGFbeta) signaling, as well as endochondral bone formation, cartilage formation, and beta-catenin networks. Importantly, bone morphogenetic protein 4 (BMP-4) was significantly overexpressed in the JIA FLS. FLS from patients with oligoarticular JIA exhibit a chondrocyte phenotype, as evidenced by expression of type II collagen and aggrecan. CONCLUSION: Dysregulation of the pathways involved in the pathogenesis of oligoarticular JIA were revealed through gene expression profiling. JIA FLS displayed dysregulated TGFbeta signaling and exhibited a hypertrophic chondrocyte phenotype. These characteristics, along with contributions from the beta-catenin network may have implications for endochondral bone formation and local growth disturbances in oligoarticular JIA. Overexpression of BMP-4 in FLS from patients with oligoarticular JIA in particular may play an important role in disease pathogenesis, with a direct effect on functional outcome and with implications for future treatment. PMID- 24782193 TI - Urticaria, fever, and hypofibrinogenemia. PMID- 24782192 TI - Whole blood gene expression profiling predicts therapeutic response at six months in patients with polyarticular juvenile idiopathic arthritis. AB - OBJECTIVE: To determine whether gene expression profiles identified in peripheral whole blood samples could be used to determine therapeutic outcome in a cohort of children with newly diagnosed polyarticular juvenile idiopathic arthritis (JIA). METHODS: Whole blood samples from the Trial of Early Aggressive Therapy (TREAT) in JIA patients were analyzed on Illumina microarrays, and differential gene expression was compared to expression in healthy controls. Microarray results were validated by real-time quantitative polymerase chain reaction in an independent cohort of samples. Pathway analysis software was used to characterize gene expression profiles. Support vector machines were used to develop predictive models for different patient classes. RESULTS: Differential gene expression profiles for rheumatoid factor (RF)-positive and RF-negative patients were remarkably similar. Pathway analysis revealed a broad range of affected pathways, consistent with current mechanistic theories. Modeling showed that the prognosis at 6 months was strongly linked to gene expression at presentation, irrespective of treatment. CONCLUSION: Gene expression is linked to therapeutic outcome, and gene expression in the peripheral blood may be a suitable target for a prognostic test. PMID- 24782194 TI - Extending the floor and the ceiling for assessment of physical function. AB - OBJECTIVE: To improve the assessment of physical function by enhancing precision of physical function assessment as it pertains to subjects at extreme ends of the health continuum (i.e., subjects with extremely poor function ["floor"] or extremely good health ["ceiling"]). METHODS: Under the Patient-Reported Outcomes Measurement Information System (PROMIS) (a National Institutes of Health initiative), we developed new items to assess floor and ceiling physical function in order to supplement the existing item bank. Using item response theory and standard PROMIS methodology, we developed 31 floor items and 31 ceiling items and administered the items during a 12-month prospective, observational study of 737 subjects whose health status was at either extreme. Effect size was calculated and change over time was compared across anchor instruments and across items. Using the observed changes in scores, we back-calculated sample size requirements for the new and comparison measures. RESULTS: We studied 444 subjects who had been diagnosed as having a chronic illness and/or were of old age and 293 generally fit subjects (including athletes in training). Item response theory analyses confirmed that the new floor and ceiling items outperformed reference items (P < 0.001). The estimated post hoc sample size requirements were reduced by a factor of 2-4 for the floor population and a factor of 2 for the ceiling population. CONCLUSION: Extending the range of items by which physical function is measured can substantially improve measurement quality, reduce sample size requirements, and improve research efficiency. The paradigm shift from assessing disability to assessing physical function focuses assessment on the entire spectrum of physical function, signals improvement in the conceptual base of outcome assessment, and may be transformative as medical goals more closely approach societal goals for health. PMID- 24782195 TI - Poor sleep quality is strongly associated with subsequent pain intensity in patients with acute low back pain. AB - OBJECTIVE: Recent research suggests that sleep quality and pain intensity are intimately linked. Although sleep problems are common in patients with low back pain, the effect of sleep quality on the levels of pain intensity is currently unknown. The aim of this study was to investigate the effect of sleep quality on subsequent pain intensity in patients with recent-onset low back pain. METHODS: Data on 1,246 patients with acute low back pain were included in the analysis. Sleep quality was assessed using the sleep quality item of the Pittsburgh Sleep Quality Index, scored on a 0-3-point scale, where 0 = very good sleep quality and 3 = very bad sleep quality. Pain intensity was assessed on a numerical rating scale (range 0-10). A generalized estimating equation (GEE) analysis modeled with an exchangeable correlation structure was used to examine the relationship between sleep quality and pain intensity. The model further controlled for symptoms of depression and prognostic factors for low back pain. RESULTS: The GEE analysis demonstrated a large effect of poor sleep on subsequent pain intensity, such that for every 1-point decrease in sleep quality (based on a 0-3-point scale), pain intensity (based on a 0-10-point scale) increased by 2.08 points (95% confidence interval 1.99-2.16). This effect was independent of depression and common prognostic factors for low back pain. CONCLUSION: Sleep quality is strongly related to subsequent pain intensity in patients with acute low back pain. Future research is needed to determine whether targeting sleep improvement contributes to pain reduction. PMID- 24782196 TI - Brief report: inadequate description and discussion of enrolled patient characteristics and potential inter-study site differences in reports of randomized controlled trials: a systematic survey in six rheumatology journals. AB - OBJECTIVE: Detailed information on patient recruitment and study settings is an important component of reports of randomized controlled trials (RCTs). We had the impression that many RCTs published in rheumatology journals lacked this information. This study was undertaken to systemically survey this matter in 6 leading journals. METHODS: A hand search was conducted for RCTs published in 2011 and 2012 in Arthritis & Rheumatism, Annals of the Rheumatic Diseases, Rheumatology (Oxford), Arthritis Care & Research, The Journal of Rheumatology, and Clinical and Experimental Rheumatology. Using the Consolidated Standards of Reporting Trials (CONSORT) guidelines, 2 observers evaluated the articles for the inclusion of patient eligibility criteria, including method of recruitment; study health care settings; geographic location; and, among multicenter studies, a discussion of possible effects of intercenter differences on outcomes. RESULTS: Among 118 articles, an informative account of the method of recruitment was available in 36 (30.5%). Information about the study health care setting was found in 56 (47.5%). Patient socioeconomic profile was available in 11 (9.3%), patient education level in 10 (8.4%), and patient race in 48 (40.7%). Among 76 multicenter studies, the potential effects of possible intercenter differences on outcome were discussed in 13 (17.1%). There were no important differences between the 3 journals that emphasized the use of CONSORT in their author guidelines and the remaining 3 journals. CONCLUSION: Adequate information on patient recruitment, the trial setting, and a discussion of possible multicenter design effects on outcomes are lacking in the majority of RCT reports in rheumatology. This affects the validity of these reports and calls for closer attention of authors, journals, and reviewers. PMID- 24782197 TI - Relationship between valve calcification and long-term results of percutaneous mitral commissurotomy for rheumatic mitral stenosis. AB - BACKGROUND: Indications of percutaneous mitral commissurotomy (PMC) remain debated in calcific mitral stenosis. We analyzed long-term results of PMC for calcific mitral stenosis and the factors associated with late functional results. METHODS AND RESULTS: We compared the characteristics and outcome of 314 patients undergoing PMC for calcific mitral stenosis with 710 patients with noncalcified valves followed up to 20 years. Calcification was defined by fluoroscopy, and its extent was graded from 1 to 4. Good immediate results (valve area >= 1.5 cm(2) with mitral regurgitation <= 2/4) were obtained in 251 patients (80%) with calcified valves and 661 (93%) with noncalcified valves (P < 0.001). The hazard ratio for good functional results (survival without cardiovascular death, without mitral reintervention, and in New York Heart Association class I or II) was 2.5 (95% confidence interval [2.1-2.9]; P < 0.0001) in patients with calcified valves (12 +/- 3% at 20 years) relative to the noncalcified group (38 +/- 2% at 20 years). In the 251 patients with calcified valves who had good immediate results, 15-year rates of good functional results were 35 +/- 4% for minor (grade 1) calcification, 24 +/- 6% for grade 2, and 10 +/- 6% for severe (grades 3-4) calcification. Factors associated with poor late functional results on multivariable analysis were calcification extent, older age, higher New York Heart Association class, atrial fibrillation, and higher mean gradient after PMC. CONCLUSIONS: Although late results of PMC are less satisfying in calcific mitral stenosis, long-term functional outcome depends on calcification extent, patient characteristics, and immediate results of PMC. These findings support the use of PMC as first-line treatment in selected patients with calcific mitral stenosis. PMID- 24782198 TI - Physiological basis and long-term clinical outcome of discordance between fractional flow reserve and coronary flow velocity reserve in coronary stenoses of intermediate severity. AB - BACKGROUND: Discordance between fractional flow reserve (FFR) and coronary flow velocity reserve (CFVR) may reflect important coronary pathophysiology but usually remains unnoticed in clinical practice. We evaluated the physiological basis and clinical outcome associated with FFR/CFVR discordance. METHODS AND RESULTS: We studied 157 intermediate coronary stenoses in 157 patients, evaluated by FFR and CFVR between April 1997 and September 2006 in which revascularization was deferred. Long-term follow-up was performed to document the occurrence of major adverse cardiac events: cardiac death, myocardial infarction, or target vessel revascularization. Discordance between FFR and CFVR occurred in 31% and 37% of stenoses at the 0.75, and 0.80 FFR cut-off value, respectively, and was characterized by microvascular resistances during basal and hyperemic conditions. Follow-up duration amounted to 11.7 years (Q1-Q3, 9.9-13.3 years). Compared with concordant normal results of FFR and CFVR, a normal FFR with an abnormal CFVR was associated with significantly increased major adverse cardiac events rate throughout 10 years of follow-up, regardless of the FFR cut-off applied. In contrast, an abnormal FFR with a normal CFVR was associated with equivalent clinical outcome compared with concordant normal results: <= 3 years when FFR <0.75 was depicted abnormal and throughout 10 years of follow-up when FFR <= 0.80 was depicted abnormal. CONCLUSIONS: Discordance of CFVR with FFR originates from the involvement of the coronary microvasculature. Importantly, the risk for major adverse cardiac events associated with FFR/CFVR discordance is mainly attributable to stenoses where CFVR is abnormal. This emphasizes the requirement of intracoronary flow assessment in addition to coronary pressure for optimal risk stratification in stable coronary artery disease. PMID- 24782199 TI - Integration of modeling and simulation to support changes to ondansetron dosing following a randomized, double-blind, placebo-, and active-controlled thorough QT study. AB - Prolongation of the QT interval has been observed with ondansetron and other members of the 5-HT3 antagonist class. This is the first thorough QTc study of ondansetron conducted in accordance with ICH E14 guidelines, designed to investigate the effect of single intravenous (IV) doses of ondansetron on cardiac conduction compared to placebo and a positive control, moxifloxacin, in healthy subjects. Statistical analysis of dose-response showed the maximum mean difference in QTcF, compared to placebo and corrected for baseline (ddQTcF), was less than 10 milliseconds (ms) after an 8 mg IV dose and approximately 20 ms after the 32 mg dose, each infused over 15 minutes. The concentration-response (Cp-ddQTcF) model resulted in similar predictions for the 8 and 32 mg and was used to predict the maximum mean ddQTcF (upper 90% CI bound) of 9.2 (11.2) ms for 16 mg IV. As a result, single IV doses of ondansetron greater than 16 mg should no longer be used. Adult cancer patients, under 75 years, may receive up to a maximum initial 15-minute IV dose of 16 mg, prior to chemotherapy, followed by 2 additional IV or IM doses of 8 mg for the management of chemotherapy-induced nausea and vomiting (CINV). PMID- 24782200 TI - Interrelationships between anthropometric variables and overweight in childhood and adolescence. AB - OBJECTIVES: To answer the questions: how does body mass index (BMI) correlate to five overweight related anthropometric variables during different ages in childhood, and which anthropometric variables contribute most to variation in BMI during childhood? METHODS: Data on BMI, height (H), sitting height (SH), waist circumference (WC), waist to height ratio (WHtR), waist to sitting height ratio (WSHtR), subscapular skinfold (SSF), and triceps skinfold (TSF), from 4,576 Norwegian children 4.00-15.99 years of age, were transformed to standard deviation scores (SDS) and studied using correlation and multiple regression analyses. RESULTS: The correlations between BMI SDS and the standardized anthropometric variables were in general strong and positive. For all variables, the correlations were weakest in the youngest age group and highest between 7 and 12 years. WC SDS and WHtR SDS were most strongly correlated with BMI SDS through all ages and in both sexes. A model with seven anthropometric variables adjusted for age and sex explained 81.4% of the variation in BMI SDS. When adjusted for all other variables, WC SDS contributed most to the variation in BMI SDS (b = 0.467, CI [0.372, 0.562]). Age group, but not sex, contributed significantly to variation in BMI SDS. CONCLUSION: The interrelationships between BMI SDS and five standardized overweight related anthropometric variables were dependent on age, being weakest in the youngest age group. Independent of sex and age, WC SDS was in this study superior to other anthropometric variables in contributing to variation in BMI SDS during childhood. PMID- 24782201 TI - Distal arthrogryposis type 5D with novel clinical features and compound heterozygous mutations in ECEL1. PMID- 24782202 TI - The axillary versus internal mammary recipient vessel sites for breast reconstruction with diep flaps: a retrospective study of 256 consecutive cases. AB - The aim of this study is to present our experience on the use of various recipient sites for deep inferior epigastric perforator (DIEP) flap breast reconstruction and compare them by means of objective data. Two hundred fifty six DIEP flap breast reconstructions, performed between March 2004 and May 2011, were retrospectively analyzed. Only unilateral reconstructions were included in the study and divided into three groups depending on the recipient site choice: internal mammary vessels (IMV) (n = 52), thoracodorsal vessels (TDV) (n = 109), and circumflex scapular vessels (CSV) (n = 95). Clinical records of each patient were reviewed to acquire relevant data such as operative time, postoperative complications, and use of a second vein anastomosis. CSV group showed a statistically significant lower operative time (4.92 +/- 0.54 hours) compared to TDV (5.67 +/- 1.01 hours) and IMV groups (6.75 +/- 1.09 hours) (P < 0.001). Second vein anastomosis was performed in 84 cases (88.1%) of CSV, in 85 cases (77.9%) of TDV, and in 18 cases (35.1%) of IMV groups (P < 0.001). No significant differences were observed among groups regarding risk factors and complications (P > 0.05). The axillary vessels seem to be the ideal recipient site because of reduced operative time and increased possibility to perform a second vein anastomosis. Among them, CSV can be safely used due to following advantages: easy dissection, larger vessel caliber, and optimal flap insetting. Moreover, their location does not expose them completely to radiotherapy consequences. PMID- 24782203 TI - Distributed and accumulated reinforcement arrangements: evaluations of efficacy and preference. AB - We assessed the efficacy of, and preference for, accumulated access to reinforcers, which allows uninterrupted engagement with the reinforcers but imposes an inherent delay required to first complete the task. Experiment 1 compared rates of task completion in 4 individuals who had been diagnosed with intellectual disabilities when reinforcement was distributed (i.e., 30-s access to the reinforcer delivered immediately after each response) and accumulated (i.e., 5-min access to the reinforcer after completion of multiple consecutive responses). Accumulated reinforcement produced response rates that equaled or exceeded rates during distributed reinforcement for 3 participants. Experiment 2 used a concurrent-chains schedule to examine preferences for each arrangement. All participants preferred delayed, accumulated access when the reinforcer was an activity. Three participants also preferred accumulated access to edible reinforcers. The collective results suggest that, despite the inherent delay, accumulated reinforcement is just as effective and is often preferred by learners over distributed reinforcement. PMID- 24782205 TI - [Position paper "Chemosensory testing for expert opinion in smell disorders"]. AB - Providing expert opinion in the context of smell disorders is often challenging, not only with regard to general aspects of providing an expert opinion but particularly with regard to chemosensory testing. Currently there is no consensus which chemosensory test should be selected and how they should be executed. This positions paper from Committee on Olfaction and Gustation of the German Society of Otorhinolaryngology, Head and Neck Surgery aims to give concrete recommendations for chemosensory testing for providing expert opinion for smell disorders with regard to the selection and execution of these test. PMID- 24782206 TI - [Traumatic tracheal injury: presentation of a rare case]. PMID- 24782207 TI - [From the expert's office: Is a hearing loss of 100% equivalent to a deafness?]. PMID- 24782208 TI - [Hearing preservation: Better hearing with advanced technology]. AB - Preservation of residual hearing after cochlear implantation allows patients the synergetic use of electric and acoustic stimulation (EAS). The application of specific surgical and therapeutic techniques enables the reduction of inner ear trauma, which leads otherwise to complete hearing loss. Due to simultaneous electric and acoustic stimulation, speech understanding is improved especially in noise. EAS is a well-accepted therapeutic treatment for subjects with profound hearing loss in the higher frequencies and no or mild hearing loss in the low frequencies. Several Manufacturers offer individual soft electrodes specially designed for hearing preservation as well as combined electric-acoustic audio processors. PMID- 24782209 TI - [Operation methods: safe, logical and step by step for frontoethmoidectomy with or without sinusotomy type I, II, III - 2]. PMID- 24782210 TI - The nature of the fourth bond in the ground state of C2: the quadruple bond conundrum. AB - Does, or doesn't C2 break the glass ceiling of triple bonding? This work provides an overview on the bonding conundrum in C2 and on the recent discussions regarding our proposal that it possesses a quadruple bond. As such, we focus herein on the main point of contention, the 4th bond of C2, and discuss the main views. We present new data and an overview of the nature of the 4th bond--its proposed antiferromagnetically coupled nature, its strength, and a derivation of its bond energy from experimentally based thermochemical data. We address the bond-order conundrum of C2 arising from generalized VB (GVB) calculations by comparing it to HC=CH, and showing that the two molecules behave very similarly, and C2 is in no way an exception. We analyse the root cause of the deviation of C2 from the Badger Rule, and demonstrate that the reason for the smaller force constant (FC) of C2 relative to HC=CH has nothing to do with the bond energies, or with the number of bonds in the two molecules. The FC is determined primarily by the bond length, which is set by the balance between the bond length preferences of the sigma- versus pi-bonds in the two molecules. This interplay in the case of C2 clearly shows the fingerprints of the 4th bond. Our discussion resolves the points of contention and shows that the arguments used to dismiss the quadruple bond nature of C2 are not well founded. PMID- 24782211 TI - Development and characterization of single nucleotide polymorphism markers in Camellia sinensis (Theaceae). AB - Tea is the second most popular non-alcoholic beverage in the world. In recent years, several molecular markers have been used in genetic studies of the tea plant. Yet, only a few single nucleotide polymorphisms (SNPs) have been reported. Here, we identified 818 putative SNPs from expressed sequence tag (EST) databases for the tea plant, which produced a frequency of 1 SNP/170 bp. A direct sequencing method was then used to verify 253 putative SNPs in genome DNA of 17 tea varieties. Fifty (20%) candidate and 299 new SNPs were identified. The haplotype polymorphism and nucleotide diversity of these markers ranged from 0 to 0.960 and 0 to 1.797%, respectively. Using these SNPs, the 17 varieties were classified into 2 groups by cluster analysis. The results indicate that Camellia sinensis-derived ESTs provide a valuable resource for SNP discovery. Furthermore, the abundance of SNPs in tea varieties is anticipated to generate the development of associated genetic studies, in addition to enhancing tea plant-breeding programs. PMID- 24782212 TI - Establishment of cytochrome P450 3A4 and glutathione S-transferase A1-transfected human hepatoma cell line and functional analysis. AB - This study aimed to enhance the drug metabolism function of the human hepatoma cell line C3A and to explore the related significance for patients with severe liver disease. The important liver phase I and phase II drug metabolism enzymes, cytochrome P450 3A4 (CYP 3A4) and glutathione S-transferase A1 (GST A1), were constructed into a double expression vector and then transfected into C3A cells. Furthermore, in order to increase the expression of CYP 3A4 and GST A1, they were optimized according to human optimal codons. Another double-expression vector, pBudCE4.1-optimized CYP 3A4-optimized GST A1, was constructed and then transfected into C3A to establish a stable cell line. The drug metabolism function of C3A was evaluated. Sequence determination and analysis results showed that the recombinant plasmid pBudCE4.1-CYP 3A4-GST A1 met the application standard and its transfection was successful. The expression and activity of CYP 3A4 and GST A1 in unoptimized C3A cells were higher than those in blank C3A cells. Unoptimized C3A had a better drug metabolism function. Although some C3A cells transfected with pBudCE4.1-optimized CYP 3A4-optimized GST A1 survived, they grew slowly, and were therefore not applicable in clinical practice. Unoptimized C3A is superior to blank C3A in drug metabolism, and could be applied in the bioartificial liver support system as a new material. PMID- 24782213 TI - Analysis of genetic diversity and trait correlations among Korean landrace rice (Oryza sativa L.). AB - This study analyzed 394 Korean rice landrace accessions, including 93 waxy varieties, for polymorphisms using 29 simple sequence repeat (SSR) markers. In total, 381 alleles served as raw data for estimating the genetic diversity (GD) and population structure. The number of alleles per locus ranged from 3 to 44 (average = 13.14). The expected heterozygosity and polymorphism information content (PIC) ranged from 0.0341 to 0.9358 (mean = 0.5623) and from 0.0783 to 0.9367 (mean = 0.5839), respectively. The mean GDs in waxy, low amylose content, intermediate amylose content, and high amylose content (HAC) varieties were 0.6014, 0.5922, 0.5858, and 0.7232, respectively, whereas the mean PIC values for each SSR locus were 0.5701, 0.5594, 0.5550, and 0.6926, respectively. HAC varieties had the highest GD and PIC. Consistent with clustering by genetic distances, a model-based structural analysis revealed 3 subpopulations. Analysis of molecular variance revealed that the between-population component of genetic variance was 22.35%, and that of the within-population component was 77.65%. Significant correlations were observed between eating quality and protein content (r = -0.262), K(+) (r = -0.655), Mg(2+) (r = -0.680), 1000-GW (r = 0.159), and amylose content (r = -0.134). The overall FST value was 0.2235, indicating moderate differentiation among the groups. Analysis of variance of the 3 genetic groups (mean of 9 phenotypic and 5 physicochemical traits) by the Duncan multiple range test showed significant differences in 10 traits. This preliminary study represents a first step toward more efficient conservation and greater utilization of rice landraces to broaden the genetic bases of commercially grown varieties. PMID- 24782214 TI - Long interspersed nucleotide acid element-1 ORF-1 protein promotes proliferation and invasion of human colorectal cancer LoVo cells through enhancing ETS-1 activity. AB - The human proto-oncogene long interspersed nucleotide acid element-1 (LINE-1) open reading frame-1 protein (ORF-1p) is involved in the progress of several cancers. The transcription factor ETS-1 can mediate the transcription of some downstream genes that play specific roles in the regulation of cancerous cell invasion and metastasis. In this study, the effects of LINE-1 ORF-1p on ETS-1 activity and on the proliferation and invasion of human colorectal cancer LoVo cells were investigated. Results showed that the overexpression of LINE-1 ORF-1p enhanced the transcription of ETS-1 downstream genes and increased their protein levels, and downregulation of the LINE-1 ORF-1p level by small interfering RNA (siRNA) reduced the transcriptional activation of ETS-1. In addition, overexpression of LINE-1 ORF-1p promoted LoVo cell proliferation and anchor independent growth, and a knockdown of the LINE-1 protein level by siRNA reduced the proliferation and anchor-independent growth ability of LoVo cells. In vivo data revealed that LINE-1 ORF-1p overexpression increased LoVo tumor growth in nude mice, whereas the siRNA knockdown of endogenous LINE-1 ORF-1p expression decreased LoVo cell growth in nude mice. Therefore, LINE- 1 ORF-1p could promote LoVo cell proliferation and invasion both in vitro and in vivo, indicating that it might be a useful molecular target for the treatment of human colorectal cancer. PMID- 24782215 TI - Urinary nerve growth factor levels could be a biomarker for overactive bladder symptom: a meta-analysis. AB - To examine whether urinary tract nerve growth factor (uNGF) could be a biomarker for overactive bladder (OAB) symptom, we conducted a comprehensive meta-analysis of 8 case-control studies. In all the studies considered, patients with OAB symptom had a higher uNGF level compared to healthy people. In addition, patients had a significantly lower uNGF level after successful treatment. In the subgroup analysis, we found that patients with OAB-wet symptom had a higher uNGF level than patients with OAB-dry symptom. However, no significant difference was found between patients with OAB symptom and patients with interstitial cystitis/painful bladder syndrome (IC/PBS) symptom in uNGF/Cr levels. In conclusion, uNGF level could be a useful biomarker for the diagnosis of OAB, a possible biomarker for differentiation between OAB subtypes (wet or dry), and a predictive biomarker for a specific treatment, but it cannot be used as the urinary biomarker for the differential diagnosis of IC/PBS and OAB. PMID- 24782216 TI - Serum thyroid hormone reference intervals in the apparently healthy individuals of Zhengzhou area of China. AB - This study aimed to establish reference intervals for serum thyroid hormones [serum thyroid-stimulating hormone (TSH), triiodothyronine (TT3), thyroxine (TT4), free triiodothyronine (FT3), and free thyroxine (FT4)] in apparently healthy individuals living in Zhengzhou. According to the requirement for laboratory support for the diagnosis and monitoring of thyroid diseases in the National Academy of Clinical Biochemistry (NACB) laboratory medicine practice guidelines, a total of 211 apparently healthy individuals were enrolled (94 men, 117 women, 23-77 years old) from Zhengzhou for measurement of serum levels of TSH, TT3, TT4, FT3, and FT4 by using the Siemens ADVIA Centaur XP analyzer. All markers were analyzed across gender- and age-specific groups by using the t-test and ANOVA. The reference intervals of all markers were determined by P2.5-P97.5. We detected gender-associated statistical significances for TT3, TT4, FT3, and FT4 (t=3.299, 2.141, 5.868, 5.358; P<0.05), but not for TSH (t=-1.776, P>0.05). Correlation analysis showed that all markers were negatively correlated with age (P>0.05). The new reference intervals for TT3, TT4, FT3, FT4, and TSH were established: 0.76-1.38 ng/mL, 5.96-11.27 MUg/dL, 3.88-5.59 pM, 11.69-18.84 pM, 0.89-5.93 MUIU/mL, respectively. In conclusion, we added a new database of reference intervals of the serum thyroid hormones for the Chinese adult population. PMID- 24782217 TI - Role of inflammatory parameters in the susceptibility of cerebral thrombosis. AB - We aimed to investigate the association of inflammation-related genes such as IL 10, IL-6 and IL-1B with risk of ischemic stroke. We included 426 cases with ischemic stroke and 426 health controls from Xinxiang, China. Genomic DNA was extracted from the buffy coat layer of collected blood with the TIANamp blood DNA kit. Diabetes, hypertension, obesity, and smoking habits were associated with risk of ischemic stroke. We found that individuals carrying the CC genotype of IL 1B rs1864169 had a higher risk of ischemic stroke when compared with the TT genotype (OR = 1.80, 95%CI = 1.16-2.80). The IL-6 rs1800796 TT genotype was associated with increased risk of ischemic stroke. We found that IL-1B rs1864169 and IL-6 rs1800796 polymorphisms may interact with diabetes, hypertension and obesity. Our study suggests that IL-6 rs1800796 and IL-1B rs1864169 polymorphisms are associated with ischemic stroke risk in the Chinese population. PMID- 24782218 TI - Ethanol oxidation on Pt single-crystal electrodes: surface-structure effects in alkaline medium. AB - Ethanol oxidation in 0.1 M NaOH on single-crystal electrodes has been studied using electrochemical and FTIR techniques. The results show that the activity order is the opposite of that found in acidic solutions. The Pt(111) electrode displays the highest currents and also the highest onset potential of all the electrodes. The onset potential for the oxidation of ethanol is linked to the adsorption of OH on the electrode surface. However, small (or even negligible) amounts of CO(ads) and carbonate are detected by FTIR, which implies that cleavage of the C-C bond is not favored in this medium. The activity of the electrodes diminishes quickly upon cycling. The diminution of the activity is proportional to the measured currents and is linked to the formation and polymerization of acetaldehyde, which adsorbs onto the electrode surface and prevents further oxidation. PMID- 24782219 TI - Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. PMID- 24782220 TI - A high-performance renewable thermosetting resin derived from eugenol. AB - A renewable bisphenol, 4,4'-(butane-1,4-diyl)bis(2-methoxyphenol), was synthesized on a preparative scale by a solvent-free, Ru-catalyzed olefin metathesis coupling reaction of eugenol followed by hydrogenation. After purification, the bisphenol was converted to a new bis(cyanate) ester by standard techniques. The bisphenol and cyanate ester were characterized rigorously by NMR spectroscopy and single-crystal X-ray diffraction studies. After complete cure, the cyanate ester exhibited thermal stability in excess of 350 degrees C and a glass transition temperature (Tg ) of 186 degrees C. As a result of the four carbon chain between the aromatic rings, the thermoset displayed a water uptake of only 1.8% after a four day immersion in 85 degrees C water. The wet Tg of the material (167 degrees C) was only 19 degrees C lower than the dry Tg , and the material showed no significant degradation as a result of the water treatment. These results suggest that this resin is well suited for maritime environments and provide further evidence that full-performance resins can be generated from sustainable feedstocks. PMID- 24782221 TI - The influence of genetic polymorphism of Cyp2c19 isoenzyme on the pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases. AB - An extensive investigation on pharmacokinetics of clopidogrel and its metabolites as well as pharmacodynamics of the drug was performed in patients with cardiovascular disease carrying various alleles coding CYP2C19 isoenzyme. The influence of non-genetic factors on the clopidogrel response was also studied. Plasma concentrations of clopidogrel, its carboxylic metabolite, and diastereoisomers of a thiol metabolite (the inactive H3 and the active H4) following an administration of 75 mg of the drug were determined in three groups of patients divided with respect to their CYP2C19 genotype: ultrametabolizers, extensive metabolizers, and intermediate metabolizers. The mean peak plasma concentration of H4 in intermediate metabolizers was 3.1- and 2.8-fold lower than that of ultrametabolizers (P = 0.055) and extensive metabolizers (P = 0.026), respectively. The mean H4 area under the curve (AUC0-24 h ) for intermediate metabolizers were significantly lower than that for ultrametabolizers (P = 0.046). Intermediate metabolizers exhibited a significantly higher platelet aggregation than ultrametabolizers and extensive metabolizers (P = 0.035). A multivariate analysis showed that the effect of CYP2C19*2 allele on an ADP induced platelet aggregation was better pronounced in the presence of non-genetic risk factors (P = 0.008). We concluded that the CYP2C19*2 genotype is the primary determinant of the antiplatelet response to clopidogrel therapy. PMID- 24782226 TI - Syndactylizing arterialized venous flaps for multiple finger injuries. AB - Multiple soft tissue finger defects in different shapes and locations are usually difficult to manage. Such defects commonly involve tendons and bones. Palmar soft tissue defects may also lead to vascular compromise. In this retrospective report, we report the results of seven patients with multiple soft tissue finger defects that were covered by syndactylizing arterialized venous flaps. Six of the patients suffered hot-pressing machine and crushing injuries, one patient had a rolling belt injury. All patients presented with soft tissue defects on palmar or dorsal sides involving at least two digits. The palmar forearm was donor site for all patients. At least one afferent artery and two efferent veins were selected for the anastomosis. Lengths of afferent and efferent veins were long enough to perform healthy anastomosis outside the injury zone. The afferent vessels were anastamosed to the digital arteries with the largest possible diameter or to the common digital arteries to maximize flow. The efferent veins were anastamosed to dorsal veins. Separations of the digits were performed after three weeks by longitudinal incisions. The mean follow-up period was 12 months. None of our patients suffered a flap loss. Syndactylizing arterialized venous flaps may be used for composite or single tissue reconstruction for multiple finger defects with satisfactory cosmetic and functional outcomes. PMID- 24782222 TI - Subgrouping of patients with rheumatoid arthritis based on pain, fatigue, inflammation, and psychosocial factors. AB - OBJECTIVE: Among patients with rheumatoid arthritis (RA), pain may be attributed to peripheral inflammation or other causes, such as central pain mechanisms. The aim of this study was to use self-report measures and physical examination findings to identify clusters of RA patients who may have different causes of pain as well as different prognoses and treatment options. METHODS: Data from 169 RA patients with pain scores of >0 (on a 10-point numeric rating scale) in the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study were analyzed. The patients completed questionnaires on pain, fatigue, and psychosocial factors. A hierarchical agglomerative clustering procedure with Ward's method was used to obtain subgroups. Multivariate analysis of variance was used to determine the contribution of each variable in a cluster. General linear regression models were used to examine differences in clinical characteristics across subgroups. Discriminant analyses were performed to determine coefficients for linear combinations of variables that assigned cluster membership to individual cases. RESULTS: Three clusters best fit these data. Cluster 1 consisted of 89 individuals with low levels of inflammation, pain, fatigue, and psychosocial distress. Cluster 2 consisted of 57 individuals with minimal inflammation but high levels of pain, fatigue, and psychosocial distress. Cluster 3 consisted of 23 individuals with active inflammatory disease, manifested by high swollen joint counts, high C-reactive protein levels, and high levels of pain and fatigue. CONCLUSION: Although most patients had low levels of inflammation, pain, and fatigue, 47.3% continued to report having moderate to high levels of pain and fatigue. Most of these patients had minimal signs of inflammation but high levels of fatigue, pain catastrophizing, and sleep disturbance, indicative of a chronic widespread pain syndrome. PMID- 24782227 TI - alpha-Glucosidase inhibitory activities of isoflavanones, isoflavones, and pterocarpans from Mucuna pruriens. AB - Three new isoflavanones (1-3) and thirteen known compounds (4-16) were isolated from the roots of Mucuna pruriens. The absolute configurations of isoflavanones 1 3 and parvisoflavanone (4), lespedeol C (5), and uncinanone C (6) were addressed by a circular dichroism technique. Isoflavanones, isoflavones, and pterocarpans of M. pruriens were found to be alpha-glucosidase inhibitors. Medicarpin (7) and parvisoflavone B (9) were potent alpha-glucosidase inhibitors (twofold less active than the standard drug acarbose). The production of bioactive metabolites in M. pruriens seems to be season-dependent. PMID- 24782228 TI - Protein tyrosine phosphatase 1B inhibitory activity of lavandulyl flavonoids from roots of Sophora flavescens. AB - Protein tyrosine phosphatase 1B is a non-transmembrane protein tyrosine phosphatase and major negative regulator in insulin signaling cascades, and much attention has been paid to protein tyrosine phosphatase 1B inhibitors as potential therapies for diabetes. The screening of a natural compound library led to the discovery of five lavandulyl flavonoids, which were isolated from the roots of Sophora flavescens, as novel PTP1B inhibitors: kuraridin (1), norkurarinone (2), kurarinone (3), 2'-methoxykurarinone (4), and kushenol T (5). The three most potent compounds, 1, 2, and 4 (IC50 < 30 uM), were demonstrated to be noncompetitive inhibitors of protein tyrosine phosphatase 1B based on a kinetic analysis, and they exhibited different inhibitory selectivities against four homologous protein tyrosine phosphatases (T cell protein tyrosine phosphatase, vaccinia H1-related phosphatase, and Src homology domain 2 containing protein tyrosine phosphatases 1 and 2). Compounds 1, 2, and 4 also exhibited cellular activity in the insulin signaling pathway by increasing the insulin-stimulated Akt phosphorylation level in human hepatocellular liver carcinoma HepG2 cells, suggesting their potential for new anti-insulin-resistant drug developments. PMID- 24782229 TI - Andrographis paniculata extracts and major constituent diterpenoids inhibit growth of intrahepatic cholangiocarcinoma cells by inducing cell cycle arrest and apoptosis. AB - Andrographis paniculata is an important herbal medicine widely used in several Asian countries for the treatment of various diseases due to its broad range of pharmacological activities. The present study reports that A. paniculata extracts potently inhibit the growth of liver (HepG2 and SK-Hep1) and bile duct (HuCCA-1 and RMCCA-1) cancer cells. A. paniculata extracts with different contents of major diterpenoids, including andrographolide, 14-deoxy-11,12 didehydroandrographolide, neoandrographolide, and 14-deoxyandrographolide, exhibited a different potency of growth inhibition. The ethanolic extract of A. paniculata at the first true leaf stage, which contained a high amount of 14 deoxyandrographolide but a low amount of andrographolide, showed a cytotoxic effect to cancer cells about 4 times higher than the water extract of A. paniculata at the mature leaf stage, which contained a high amount of andrographolide but a low amount of 14-deoxyandrographolide. Andrographolide, not 14-deoxy-11,12-didehydroandrographolide, neoandrographolide, or 14 deoxyandrographolide, possessed potent cytotoxic activity against the growth of liver and bile duct cancer cells. The cytotoxic effect of the water extract of A. paniculata at the mature leaf stage could be explained by the present amount of andrographolide, while the cytotoxic effect of the ethanolic extract of A. paniculata at the first true leaf stage could not. HuCCA-1 cells showed more sensitivity to A. paniculata extracts and andrographolide than RMCCA-1 cells. Furthermore, the ethanolic extract of A. paniculata at the first true leaf stage increased cell cycle arrest at the G0/G1 and G2/M phases, and induced apoptosis in both HuCCA-1 and RMCCA-1 cells. The expressions of cyclin-D1, Bcl-2, and the inactive proenzyme form of caspase-3 were reduced by the ethanolic extract of A. paniculata in the first true leaf stage treatment, while a proapoptotic protein Bax was increased. The cleavage of poly (ADP-ribose) polymerase was also found in the ethanolic extract of A. paniculata in the first true leaf stage treatment. This study suggests that A. paniculata could be a promising herbal plant for the alternative treatment of intrahepatic cholangiocarcinoma. PMID- 24782230 TI - Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. AB - Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed. PMID- 24782231 TI - Correlation between biofilm formation and gelE, esp, and agg genes in Enterococcus spp. clinical isolates. PMID- 24782232 TI - Binding of a ruthenium complex to a thioether ligand embedded in a negatively charged lipid bilayer: a two-step mechanism. AB - The interaction between the ruthenium polypyridyl complex [Ru(terpy)(dcbpy)(H2O)](2+) (terpy = 2,2';6',2"-terpyridine, dcbpy = 6,6' dichloro-2,2'-bipyridine) and phospholipid membranes containing either thioether ligands or cholesterol were investigated using UV-visible spectroscopy, Langmuir Blodgett monolayer surface pressure measurements, and isothermal titration calorimety (ITC). When embedded in a membrane, the thioether ligand coordinated to the dicationic metal complex only when the phospholipids of the membrane were negatively charged, that is, in the presence of attractive electrostatic interaction. In such a case coordination is much faster than in homogeneous conditions. A two-step model for the coordination of the metal complex to the membrane-embedded sulfur ligand is proposed, in which adsorption of the complex to the negative surface of the monolayers or bilayers occurs within minutes, whereas formation of the coordination bond between the surface-bound metal complex and ligand takes hours. Finally, adsorption of the aqua complex to the membrane is driven by entropy. It does not involve insertion of the metal complex into the hydrophobic lipid layer, but rather simple electrostatic adsorption at the water-bilayer interface. PMID- 24782233 TI - Interprofessional practice: magic at the intersection. PMID- 24782234 TI - One size does not fit all: a diagnostic post-occupancy evaluation model for an emergency department. AB - OBJECTIVE: This study presents a detailed account of processes and multiple methodologies used in conducting a diagnostic post-occupancy evaluation (POE) in an urban hospital emergency department. BACKGROUND: Healthcare design POE research findings can lead to improved work environments for healthcare providers and higher levels of staff, patient, and visitor satisfaction. METHODS: This evaluation was conducted in two separate phases over 12 months, with data analysis occurring after each phase. Phase 1 involved 200 hours of observation, physical measurements, and occupancy counts. Phase 2 included surveys (n = 315) of staff, visitors, and patients. In addition, eight distinct staff focus groups (e.g., Nursing, Housekeeping, Physician, etc.) were conducted. RESULTS: To illustrate the process, one healthcare design-related issue, privacy and confidentiality, was assessed in light of the linear design model with a central core. Phase 1 observation results indicated that most confidential conversations were contained within the linear core. However, Phase 2 focus groups revealed that many staff members had concerns regarding the level of privacy and confidentiality due to the core's open design. The use of multiple methods provided greater information and a more comprehensive picture of the emergency department environment and design. CONCLUSIONS: This study presents a comprehensive framework for diagnostic post-occupancy evaluation in healthcare design. The findings indicate that a systematic, multi-methodological approach developed around a conceptual framework can lead to higher quality evaluations. Diagnostic POEs should be grounded in extant literature and customized based on the setting, the client's guiding principles, and the design team's objectives. In diagnostic POEs, one size does not fit all. KEYWORDS: Case study, design process, interdisciplinary, post-occupancy, privacy and confidentiality. PMID- 24782235 TI - The influence of ambient scent and music on patients' anxiety in a waiting room of a plastic surgeon. AB - OBJECTIVE: This study investigates the influence of ambient scent and music, and their combination, on patients' anxiety in a waiting room of a plastic surgeon. BACKGROUND: Waiting for an appointment with a plastic surgeon can increase a patient's anxiety. It is important to make the waiting time before an appointment with the surgeon more pleasant and to reduce the patient's anxiety. Ambient environmental stimuli can influence people's mood, cognition, and behavior. This experimental study was performed to test whether ambient scent and music can help to reduce patients' anxiety. METHODS: Two pre-studies (n = 21) were conducted to measure the subjective pleasantness and arousal of various scents and music styles. Scent and music that scored high on pleasantness and low on arousal were selected for the main study. The field experiment (n = 117) was conducted in the waiting room of a German plastic surgeon. The patients' levels of anxiety were measured in four conditions: (1) without scent and music, (2) with lavender scent; (3) with instrumental music; (4) with both scent and music. RESULTS: When used separately, each of the environmental factors, music and scent, significantly reduced the level of patient's anxiety compared to the control condition. However, the combination of scent and music was not effective in reducing anxiety. CONCLUSIONS: Our results suggest that ambient scent and music can help to reduce patients' anxiety, but they should be used with caution. Adding more ambient elements to environment could raise patients' level of arousal and thus increase their anxiety. KEYWORDS: Healing environments, patient, patient-centered care, quality care, satisfaction. PMID- 24782236 TI - A Hospital's Contemporary Art Collection: Effects on Patient Mood, Stress, Comfort, and Expectations. AB - OBJECTIVE: It is not firmly established whether an art collection of diverse subject matter, media, and imagery in the hospital environment can play a significant role in mitigating the psychological stresses and physical pain associated with a hospital visit, or whether it improves patients' satisfaction with their care. The variety of contemporary art displayed in the institution investigated in this paper served as a case study to assess the qualitative and quantitative effects of such a collection on patient health and experience. We sought to assess whether the diversity in subject matter, imagery, and media would positively affect patient mood, comfort level, stress level, and expectation of visit. BACKGROUND: Previous research concluded that nature art (i.e., representational depictions of nature) has positive effects on patient health outcomes. Studies to date have assessed the effects of individual units of artwork rather than that of an art collection as a whole. METHODS: A survey was sent to 4,376 members of an online Patient Panel, comprised of patients who volunteer to evaluate their experiences at Cleveland Clinic. For this study, Panel members were screened based on whether they had been to the Main Campus in the past 12 months. RESULTS: A majority of respondents noticed the artwork, had improved moods and stress levels due to the artwork, and reported that the art collection positively impacted their overall satisfaction and impression of the hospital. CONCLUSIONS: Our findings demonstrate that this particular collection has a significant effect on the patient experience and on self-reported mood, stress, comfort, and expectations. These results suggest that patients may respond positively to the diversity of the collection, and to other types of art in addition to nature art. KEYWORDS: Art, healing environments, hospital, patient centered care, satisfaction, case study. PMID- 24782238 TI - Research informed design, best practice, and fresh perspectives: can we all get along? PMID- 24782237 TI - A comparative evaluation of Swedish intensive care patient rooms. AB - OBJECTIVE: This study investigates how design strategies in three recent intensive care units in Sweden impact patients, families, and staff. The area of focus is the patient room "module," usually consisting of a pair of patient rooms and a joint location for monitoring and documentation. BACKGROUND: Many countries are expanding their number of intensive care beds and are also in the process of incorporating evidence-based design strategies such as single-bed patient rooms and access to daylight and nature. This situation provides a significant opportunity to review and learn from facilities leading the way in these areas. METHODS: Three intensive care units completed since 2010 were evaluated in relation to a combination of criteria. Methods included plan drawing analysis, staff questionnaires (n = 72), staff interviews (n = 9), and systematic observation (6 hours). RESULTS: In some patient rooms, access to daylight and/or outdoor views was excellent, while in other rooms such access was hindered by frosted glass or adjacent bushes or buildings. Single-bed rooms gave family members improved privacy and greater ability to stay in the patient room. Some patient room modules provided efficient patient observation and staff collaboration, but more noise and reduced patient privacy. Other modules provided a calm patient room environment, but caused some staff to feel isolated and have difficulty in getting assistance. CONCLUSIONS: The evaluation of the three projects reveals variation in whether design strategies successfully achieve their desired outcomes. Varying designs of the patient room module affect users in unique ways and must balance privacy, visibility, quietness, and staff access to assistance. KEYWORDS: Critical care/intensive care, organizational transformation, outcomes, post occupancy, work environment. PMID- 24782239 TI - Exploring the function and use of common spaces in assisted living for older persons. AB - OBJECTIVE: This exploratory study examines the function and use of common spaces in assisted living facilities (ALFs) from the residential and workplace perspectives. BACKGROUND: The impact of the physical environment on human activities in healthcare settings has been emphasized in many studies. Few studies, however, have explored the daily use of common spaces and the impact on the usability of ALFs. METHODS: Four explorative methods-observation, group interviews, individual interviews, and questionnaires-were used to investigate 14 ALFs in Sweden. The study involves residents, staff, relatives, architects, and people responsible for planning and construction of eldercare. This research strategy combines quantitative and qualitative methods to enhance the validity of the results. Method triangulation and data triangulation were used and the data were analyzed using Qualitative Content Analysis (QCA). RESULTS: The results show that residents and staff have different objectives for use and these differences affect usability, although explicit conflicts are rare. The residents, staff, and other stakeholders have different views about the demarcation of home and workplace and the role of common spaces as venues for social interaction. CONCLUSIONS: Both the residential and the workplace perspective must be considered when planning assisted living facilities. Otherwise, inherent conflicts between these perspectives will manifest as a result of the physical design. Common spaces have diverse functions that are reflected in their spatial organization. Therefore, ALFs should be designed so the intended function of a specific space is apparent to all users. KEYWORDS: Built environment, elderly, planning, satisfaction, staff. PMID- 24782240 TI - Environmental Cues: Their Influence within Assisted Living Facilities. AB - OBJECTIVE: This observational study examined the relationship between the number of environmental sensory cues within assisted living facilities (ALFs) and the number of falls by residents, using Lawton's environmental press theory as framework. BACKGROUND: A result of declining physical health is unintentional injury, for example, falling, which is one of the leading causes of death for older adults. Physical limitations increase largely due to age-related physical and sensory decline, which can increase the risk of people falling. Therefore, fall prevention becomes essential (Willis, 2000). METHODS: On-site interviews were scheduled with 140 ALF directors located in the lower peninsula of Michigan. The researchers collected physical environmental data using a sensory cue checklist on a subset of rooms, for example, Lounge/Living Room, Dining Room, Corridor, Public Restroom, and Foyers in ALFs, because of the prevalence of falls within these rooms. RESULTS: Findings showed that fall rates and environmental cues sometimes have a negative correlation. A positive correlation was found between the number of residents living in an ALF and the mean number of cues included in the overall environment. Finally, there were a greater number of environmental cues incorporated when design professionals were involved. CONCLUSIONS: The need to control for facility size and for some room types when relating environmental cues to falls became clear. In addition, design professionals should have a thorough understanding of the nature of the facility and the need to control some factors in facilities, especially when including environmental cues. KEYWORDS: Built environment, elderly, evidence-based design, falls, safety. PMID- 24782241 TI - Evaluating evidence: defining levels and quality using critical appraisal mixed methods tools. PMID- 24782242 TI - Australian Healthcare Design 2000-2015: A critical review of the design and build of infrastructure in Australia. PMID- 24782244 TI - Use of multiple data sources for surveillance of work-related amputations in Massachusetts, comparison with official estimates and implications for national surveillance. AB - BACKGROUND: Accurate surveillance of work-related injuries is needed at national and state levels. We used multiple sources for surveillance of work-related amputations, compared findings with Survey of Occupational Injuries and Illnesses (SOII) estimates, and assessed generalizability to national surveillance. METHODS: Three data sources were used to enumerate work-related amputations in Massachusetts, 2007-2008. SOII eligible amputations were compared with SOII estimates. RESULTS: 787 amputations were enumerated, 52% ascertained through hospital records only, exceeding the SOII estimate (n = 210). The estimated SOII undercount was 48% (95% CI: 36-61%). Additional amputations were reported in SOII as other injuries, accounting for about half the undercount. Proportionately more SOII estimated than multisource cases were in manufacturing and fewer in smaller establishments. CONCLUSION: Multisource surveillance enhanced our ability to document work-related amputations in Massachusetts. While not feasible to implement for work-related conditions nationwide, it is useful in states. Better understanding of potential biases in SOII is needed. PMID- 24782246 TI - What is the role of flap reconstruction in salvage total laryngectomy? PMID- 24782247 TI - Screening nitrogen-rich bases and oxygen-rich acids by theoretical calculations for forming highly stable salts. AB - Nitrogen-rich heterocyclic bases and oxygen-rich acids react to produce energetic salts with potential application in the field of composite explosives and propellants. In this study, 12 salts formed by the reaction of the bases 4-amino 1,2,4-trizole (A), 1-amino-1,2,4-trizole (B), and 5-aminotetrazole (C), upon reaction with the acids HNO3 (I), HN(NO2 )2 (II), HClO4 (III), and HC(NO2 )3 (IV), are studied using DFT calculations at the B97-D/6-311++G** level of theory. For the reactions with the same base, those of HClO4 are the most exothermic and spontaneous, and the most negative Deltar Gm in the formation reaction also corresponds to the highest decomposition temperature of the resulting salt. The ability of anions and cations to form hydrogen bonds decreases in the order NO3 ( ) >N(NO2 )2 (-) >ClO4 (-) >C(NO2 )3 (-) , and C(+) >B(+) >A(+) . In particular, those different cation abilities are mainly due to their different conformations and charge distributions. For the salts with the same anion, the larger total hydrogen-bond energy (EH,tot ) leads to a higher melting point. The order of cations and anions on charge transfer (q), second-order perturbation energy (E2 ), and binding energy (Eb ) are the same to that of EH,tot , so larger q leads to larger E2 , Eb , and EH,tot . All salts have similar frontier orbitals distributions, and their HOMO and LUMO are derived from the anion and the cation, respectively. The molecular orbital shapes are kept as the ions form a salt. To produce energetic salts, 5-aminotetrazole and HClO4 are the preferred base and acid, respectively. PMID- 24782245 TI - Diversity and wiring variability of visual local neurons in the Drosophila medulla M6 stratum. AB - Local neurons in the vertebrate retina are instrumental in transforming visual inputs to extract contrast, motion, and color information and in shaping bipolar to-ganglion cell transmission to the brain. In Drosophila, UV vision is represented by R7 inner photoreceptor neurons that project to the medulla M6 stratum, with relatively little known of this downstream substrate. Here, using R7 terminals as references, we generated a 3D volume model of the M6 stratum, which revealed a retinotopic map for UV representations. Using this volume model as a common 3D framework, we compiled and analyzed the spatial distributions of more than 200 single M6-specific local neurons (M6-LNs). Based on the segregation of putative dendrites and axons, these local neurons were classified into two families, directional and nondirectional. Neurotransmitter immunostaining suggested a signal routing model in which some visual information is relayed by directional M6-LNs from the anterior to the posterior M6 and all visual information is inhibited by a diverse population of nondirectional M6-LNs covering the entire M6 stratum. Our findings suggest that the Drosophila medulla M6 stratum contains diverse LNs that form repeating functional modules similar to those found in the vertebrate inner plexiform layer. PMID- 24782248 TI - Clinical and epidemiological profiles of lower respiratory tract infection in hospitalized children due to human bocavirus in a subtropical area of China. AB - Lower respiratory tract infection is a major cause of morbidity and mortality in children. Human bocavirus (HBoV) is confirmed to have an association with pediatric lower respiratory tract infection. Seasonal and meteorological factors may play a key role in the epidemiology of HBoV. The purpose of this study was to ascertain the frequency, season, and clinical characteristics of hospitalized children with HBoV infection. In addition, an evaluation of the effects of meteorological factors on the incidence of HBoV in a subtropical area in China will be conducted. Children were <14 years in age and hospitalized for lower respiratory tract infection between January 1, 2009 and December 31, 2012 in the Respiratory Disease Department at the Children's Hospital affiliated to Soochow University. Multi-pathogens were detected in nasopharyngeal aspirate samples. The association between HBoV activity and regional meteorological conditions was analyzed. The average incidence of HBoV infection was 6.6% (502/7,626). Of the 502 HBoV positive children, the median age was 13 months (range 1-156 months). The HBoV infection rate was highest among the 7-12 months groups (12.9%, 163/1,267). Seasonal distribution of HBoV was noted during June to November, especially during the summer season (June to August). HBoV activity was associated with temperature and humidity although the lag effect between temperature and HBoV activity observed. HBoV is one of the most common viral pathogens in children with lower respiratory tract infection. HBoV infection occurs throughout the year with a peak during the summer. Temperature and humidity may affect the incidence of HBoV. PMID- 24782249 TI - Contacting is essential for oviposition deterrence of Rhodojaponin-III in Spodoptera litura. AB - In Lepidoptera, choosing the right site for egg laying is particularly important, because the small larvae cannot forage for alternate host plants easily. Some secondary compounds of plants have the ability to deter oviposition behaviors of insects. Rhodojaponin-III, a botanical compound, has been reported to have intense deterring-oviposition activity against many insects, which have important implications for agricultural pest management. This study provided evidence for elucidating the perception mechanism underlying Rhodojaponin-III as oviposition deterrent. In this study, the antennas of moths could not elicit notable electroantennogram responses to Rhodojaponin-III, which suggested the Rhodojaponin-III could not exert effects like those volatile compounds. The results of physiological experiments confirmed the Rhodojaponin-III could produce the oviposition deterrence effect against moths without depending on antennas, while the physical contact was essential for perceiving the compound, which suggested that the sensilla on tarsus and ovipositor could be chemoreceptor for Rhodojaponin-III. Therefore, these sensilla were investigated by scanning electron microscopy to explore their potential functions in detecting Rhodojaponin-III. This study highlighted the contacting mechanism in deterring oviposition behaviors of moths by Rhodojaponin-III and provided new insight for development of contact-based pest management. PMID- 24782250 TI - Interferon-alpha inhibition by intravenous immunoglobulin is independent of modulation of the plasmacytoid dendritic cell population in the circulation: comment on the article by Wiedeman et al. PMID- 24782251 TI - Plasmon-enhanced photocurrent generation from click-chemically modified graphene. AB - The visible-light response of Au nanoparticles (AuNPs) assembled on rGO through different molecular bridges was investigated by transient photocurrent generation. We prepared rGO with two self-assembled monolayers (SAMs), one linear and the other with aromatic triazoles through a click cycloaddition reaction. A fivefold photocurrent enhancement was observed for triazole linkers over the aminopropyltrimethoxysilane (APTMS) linker. Cyclic voltammetry (CV) and impedance measurements also suggest fast electron transfer on account of the low resistance offered by the click-modified rGO surface whereby introduction of triazoles offers the efficient bridge between the donor AuNPs and acceptor rGO. PMID- 24782252 TI - Liver biopsy at the time of bariatric surgery: a benefit for patients and the medical community. PMID- 24782253 TI - New hepatitis C therapies. PMID- 24782254 TI - Targets for antiviral therapy of hepatitis C. AB - Presently, interferon- (IFN-) containing treatment regimens are the standard of care for patients with hepatitis C virus (HCV) infections. Although this therapy eliminates the virus in a substantial proportion of patients, it has numerous side effects and contraindications. Recent approval of telaprevir and boceprevir, targeting the protease residing in nonstructural protein 3 (NS3) of the HCV genome, increased therapy success when given in combination with pegylated IFN and ribavirin, but side effects are more frequent and the management of treatment is complex. This situation will change soon with the introduction of new highly potent direct-acting antivirals. They target, in addition to the NS3 protease, NS5A, which is required for RNA replication and virion assembly and the NS5B RNA dependent RNA polymerase. Moreover, host-cell factors such as cyclophilin A or microRNA-122, essential for HCV replication, have been pursued as therapeutic targets. In this review, the authors briefly summarize the main features of viral and cellular factors involved in HCV replication that are utilized as therapy targets for chronic hepatitis C. PMID- 24782255 TI - New hepatitis C virus (HCV) drugs and the hope for a cure: concepts in anti-HCV drug development. AB - The development of new models and tools has led to the discovery and clinical development of a large number of new anti-hepatitis C virus (HCV) drugs, including direct-acting antivirals and host-targeted agents. Surprisingly, curing HCV infection appears to be easy with these new drugs, provided that a potent drug combination with a high barrier to resistance is used. HCV infection cure rates can be optimized by combining drugs with synergistic antiviral effects, tailoring treatment duration to the patients' needs, and/or using ribavirin. Two HCV drugs have been approved in 2011--telaprevir and boceprevir, both first-wave, first-generation NS3-4A protease inhibitors, two others in 2013/2014--simeprevir, a second-wave, first-generation NS3-4A protease inhibitor, and sofosbuvir, a nucleotide analogue inhibitor of the viral polymerase. Numerous other drugs have reached phase II or III clinical development. From 2015 and onwards, interferon containing regimens will disappear, replaced by interferon-free regimens yielding infection cure rates over 90%. These therapies will raise new issues, including the need for broad-scale screening and access to care. PMID- 24782256 TI - Interferon-combination strategies for the treatment of chronic hepatitis C. AB - Direct acting antiviral agents have revolutionized hepatitis C (HCV) therapy. Many agents that are either currently available or undergoing investigation offer higher rates of sustained virologic response, reduced toxicity and shorter duration of therapy when compared to traditional treatment consisting of pegylated interferon and ribavirin. Although interferon free therapy may be a preferred option, some patients may still require an interferon based regimen to ensure efficacy. In this review, we discuss therapeutic strategies which utilize various combinations of protease inhibitors, NS5A inhibitors, nucleotide polymerase inhibitors and non-nucleoside polymerase inhibitors along with pegylated interferon in the treatment of chronic HCV. PMID- 24782257 TI - Interferon-free strategies with a nucleoside/nucleotide analogue. AB - A key to effective interferon- (IFN-) free therapy for hepatitis C virus (HCV) infection is a direct-acting antiviral (DAA) with a high barrier to resistance that can act as the backbone to any regimen. Ideally, this agent should also be active against all HCV genotypes, be well tolerated and have few drug interactions. Nucleoside/nucleotide analogues (NAs) that inhibit the function of the HCV RNA-dependent-RNA polymerase fit these requirements and thus hold promise as a cornerstone for new IFN-free regimens. To date, the issue with this class of agents has been toxicity. Numerous NAs in early clinical development have led to significant toxicity leading to their abandonment. However, sofosbuvir, a prodrug of a uridine NA, has moved through development with a clean-safety profile leading to its recent approval. When combined with ribavirin (RBV) alone, sofosbuvir is effective against genotype 2 and even genotype 3 if duration is extended. There are currently limited data with this combination in genotype 1; however, when sofosbuvir is combined with other DAAs of different classes, it is highly effective in almost all patients. To date, sofosbuvir has been studied with protease, NS5A, and nonnucleoside HCV polymerase inhibitors, including as part of a fixed-dose combination single tablet with the NS5A inhibitor ledipasvir, with very high rates of SVR with as little as 8 weeks of therapy. Combining two DAAs to sofosbuvir may shorten therapy even further. Because of the poor replicative fitness of the S282T sofosbuvir-resistant variant, resistance to sofosbuvir has not been a significant clinical issue in trials thus far. In addition to sofosbuvir, other NAs are in early-stage development. Provided unanticipated toxicity does not emerge, NAs are likely to play a major role as a backbone for future HCV therapy. The rationale for using this class of agents and the clinical data available to date are reviewed. PMID- 24782258 TI - Interferon-free strategies without a nucleoside/nucleotide analogue. AB - The identification of viral and host factors involved in hepatitis C virus (HCV) replication was a key prerequisite for the discovery and further exploration of antiviral drug targets. As of today, numerous direct-acting antiviral agents (DAAs), as well as host-targeting agents (HTAs), have been developed and entered clinical testing. The goal to omit pegylated interferon due to its unfavorable side-effect profile from novel HCV therapeutic approaches led to an expedited design and competitive conduct of DAA combination trials striving for easily applicable, all-oral HCV treatments. Approval of several interferon-free regimens is awaited in the near future (2014/2015). Results of different DAA combination trials (without nucleos(t)ide polymerase inhibitors) and trials involving HTAs are reviewed herein. PMID- 24782259 TI - Interferon-free regimens in the liver-transplant setting. AB - During 2014 and 2015, different interferon- (IFN-) free regimens will be approved for use in chronic hepatitis C (HCV). The liver-transplantation (LT) setting is the field of hepatology where these regimens will have the highest and fastest impact. Indeed, one study using direct-acting antivirals has already proven the concept that graft HCV infection can be prevented by treating patients awaiting LT. Safety and efficacy of several IFN-free regimens are currently being assessed in patients with hepatitis C recurrence after LT, with good preliminary results. Nevertheless, there are some issues that need to be addressed in the peri-LT setting and are reviewed in this article: (1) efficacy of IFN-free regimens in patients with advanced cirrhosis and portal hypertension, (2) pharmacokinetics of new antivirals in patients with several grades of hepatic or renal impairment, (3) impact of the selection of drug-resistant HCV strains in patients with decompensated cirrhosis or with severe hepatitis C recurrence after LT, and (4) drug-drug interactions. PMID- 24782260 TI - Interferon-containing and interferon-free HCV therapy for HIV-infected patients. AB - In the era of effective treatment for human immunodeficiency virus (HIV) infection, coinfection with hepatitis C virus (HCV) is an important cause of morbidity and mortality. Similar to other observations made in other HCV-infected patient populations, treatment of chronic HCV infection that results in sustained virologic response or eradication of the hepatitis infection has been strongly associated with decreased likelihood of end-stage liver disease and/or hepatocellular carcinoma and improved overall survival in HIV-infected patients. However, the effectiveness of HCV treatment has been limited due to frequent contraindications to interferon-alpha (INFalpha) and prior to the advent of HCV direct acting antivirals, relatively low rates of sustained virologic response. Since 2011, the efficacy of HCV treatment in coinfected patients has improved substantially with the addition of HCV direct-acting antivirals to INFalpha-based regimens. Based on these observations, there is mounting optimism that INFalpha free, oral HCV treatments will further improve efficacy, and more importantly, increase access to treatment for many coinfected patients. PMID- 24782262 TI - Hepatitis C, a global issue: access to care and new therapeutic and preventive approaches in resource-constrained areas. AB - With the advent of all oral direct-acting antiviral drugs with a broad range of genotypic activity and a low incidence of side effects, we are entering an exciting new era in the therapeutics of hepatitis C virus (HCV). However, it is not yet clear who will benefit from these innovations: Will the advantages be limited to HCV patients in industrialized nations or could the whole community of HCV-infected individuals be given access to treatment? As the majority of people infected with HCV live in resource-limited settings it is important to overcome the barriers that restrict access to treatment in these areas. Drug costs, public and professional education, simplified diagnostics, and political imperative all need to be addressed before the majority of HCV-infected individuals can benefit from the new generation of HCV antivirals. PMID- 24782261 TI - Will there be a vaccine to prevent HCV infection? AB - Prevention of hepatitis C virus (HCV) infection by vaccination has been a priority since discovery of the virus and the need has not diminished over the past 25 years. Infection rates are increasing in developed countries because of intravenous drug use. Reducing transmission will be difficult without a vaccine to prevent persistence of primary infections, and also secondary infections that may occur after cure of chronic hepatitis C with increasingly effective direct acting antiviral (DAA) regimens. Vaccine need is also acute in resource poor countries where most new infections occur and DAAs may be unaffordable. Spontaneous resolution of HCV infection confers durable protection, but mechanisms of immunity remain obscure and contested in the context of vaccine design. A vaccine must elicit a CD4+ helper T cell response that does not fail during acute infection. The need for neutralizing antibodies versus cytotoxic CD8+ T cells is unsettled and reflected in the design of two very different vaccines evaluated in humans for safety and immunogenicity. Here we review the status of vaccine development and the scientific and practical challenges that must be met if the burden of liver disease caused by HCV is to be reduced or eliminated. PMID- 24782264 TI - Case report of successful treatment of fibrosing cholestatic hepatitis C with sofosbuvir and ribavirin after liver transplantation. AB - Fibrosing cholestatic hepatitis is an unusual complication of hepatitis C virus (HCV) recurrence after liver transplant. Fibrosing cholestatic hepatitis is marked by aggressive progression of cholestasis and fibrosis, leading to accelerated graft loss and/or death. Sofosbuvir (GS-7977) is an oral nucleotide analogue inhibitor of HCV polymerase activity. It is a second-generation, direct acting, antiviral for the treatment of HCV infection. This case illustrates a patient with recurrent HCV with fibrosing cholestatic hepatitis, who was successfully treated with a combination of sofosbuvir and ribavirin with normalization of liver enzyme activities and resolution of HCV-related symptoms. The favorable side effect profile and the lack of drug-drug interaction with immunosuppressive medications make the combination of sofosbuvir and ribavirin a promising regimen for severe HCV recurrence. PMID- 24782263 TI - Hepatic pathology among patients without known liver disease undergoing bariatric surgery: observations and a perspective from the longitudinal assessment of bariatric surgery (LABS) study. AB - Liver biopsy is not routine during bariatric surgery. Alanine aminotransferase (ALT) is widely used to screen for liver disease. We assessed the relationship between ALT and pathology in biopsies from Longitudinal Assessment of Bariatric Surgery (LABS) patients with normal preoperative ALTs. Biopsies from the LABS-1 and LABS-2 studies were scored using the NASH CRN and Ishak systems. Diagnosis and histology were examined in relation to alanine aminotransferase (ALT) values. Six-hundred ninety-three suitable biopsies were evaluated. Biopsied patients had a median age of 45 years; 78.6% were female and 35.1% diabetic; median body mass index was 46 kg/m(2). Six-hundred thirty-five biopsied patients had preoperative ALTs. Median ALT was 25 IU/L (interquartile range [IQR] 19-36 IU/L); 26.6% had an ALT > 35 IU/L and 29.9% exceeded the more restrictive Prati criteria for normal. Using the Prati criteria, 7.9% of participants with normal ALT had steatohepatitis and 5.3% had >= stage 2 fibrosis. Logistic regression models were used to predict the probabilities of having bridging fibrosis/cirrhosis or a diagnosis of borderline/definite steatohepatitis in the unbiopsied LABS-2 sample. The proportion of biopsied participants with these findings was very similar to the modeled results from the unbiopsied cohorts. We estimated that 86.0% of participants with advanced fibrosis and 88.1% of participants with borderline/definite steatohepatitis were not biopsied and went undiagnosed. As ALT did not reliably exclude significant obesity-related liver disease in bariatric surgery patients, consideration should be given to routine liver biopsy during bariatric surgery and medical follow-up of significant hepatic pathology. PMID- 24782265 TI - In situ thermally cross-linked polyacrylonitrile as binder for high-performance silicon as lithium ion battery anode. AB - Electrode integrity and electric contact between particles and between particle and current collector are critical for electrochemical performance, especially for that of electrode materials with large volume change during cycling and with poor electric conductivity. We report on the in situ thermally cross-linked polyacrylonitrile (PAN) as a binder for silicon-based anodes of lithium-ion batteries. The electrode delivers excellent cycle life and rate capability with a reversible capacity of about 1450 mA h g(-1) even after 100 cycles. The improved electrochemical performance of such silicon electrodes is attributed to heat treatment-induced cross-linking and the formation of conjugated PAN. These findings open new avenues to explore other polymers for both anode and cathode electrodes of rechargeable batteries. PMID- 24782266 TI - Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases. AB - An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and reduced host defence against infection and cancer. Nonclinical strategies to facilitate clinical and market entry in the most efficient timeframe are presented. PMID- 24782268 TI - Patient-initiated research in rheumatic diseases in Sweden--dignity, identity and quality of life in focus when patients set the research agenda. PMID- 24782267 TI - Interferon stimulated exonuclease gene 20 kDa links psychiatric events to distinct hepatitis C virus responses in human immunodeficiency virus positive patients. AB - Hepatitis C Virus (HCV) infection occurs frequently in patients with preexisting mental illness. Treatment for chronic hepatitis C using interferon formulations often increases risk for neuro-psychiatric symptoms. Pegylated-Interferon-alpha (PegIFN-alpha) remains crucial for attaining sustained virologic response (SVR); however, PegIFN-alpha based treatment is associated with psychiatric adverse effects, which require dose reduction and/or interruption. This study's main objective was to identify genes induced by PegIFN-alpha and expressed in the central nervous system and immune system, which could mediate the development of psychiatric toxicity in association with antiviral outcome. Using peripheral blood mononuclear cells from Human Immunodeficiency Virus (HIV)/HCV co-infected donors (N = 28), DNA microarray analysis was performed and 21 differentially regulated genes were identified in patients with psychiatric toxicity versus those without. Using these 21 expression profiles a two-way-ANOVA was performed to select genes based on antiviral outcome and occurrence of neuro-psychiatric adverse events. Microarray analysis demonstrated that Interferon-stimulated exonuclease-gene 20 kDa (ISG20) and Interferon-alpha-inducible-protein 27 (IFI27) were the most regulated genes (P < 0.05) between three groups that were built by combining antiviral outcome and neuro-psychiatric toxicity. Validation by bDNA assay confirmed that ISG20 expression levels were significantly associated with these outcomes (P < 0.035). Baseline levels and induction of ISG20 correlated independently with no occurrence of psychiatric adverse events and non-response to therapy (P < 0.001). Among the 21 genes that were associated with psychiatric adverse events and 20 Interferon-inducible genes (IFIGs) used as controls, only ISG20 expression was able to link PegIFN-alpha related neuro-psychiatric toxicity to distinct HCV-responses in patients co-infected with HIV and HCV in vivo. PMID- 24782269 TI - "I didn't feel like I was a person anymore": realigning full adult personhood after ostomy surgery. AB - Colorectal cancer (CRC) is the third most common cancer in the United States. For some CRC patients, cancer treatment involves creating a permanent or temporary intestinal ostomy. Having an ostomy often results in complex social and physical concerns-including unpredictable and at times publicly noticeable bowel output. In this article, we discuss findings from 30 in-depth interviews with female CRC survivors with ostomies in the western United States. We highlight how having an ostomy disrupts culturally sanctioned practices of continence that mark the attainment of full-adult personhood. We discuss how survivors reclaim a sense of full personhood after ostomy surgery through a process of realignment that entails both learning how to manage ostomy equipment to conceal bowel activity and reappraising their illness and suffering. We suggest that the anthropological categories of personhood and personhood realignment be incorporated into research and interventions aimed at increasing support among cancer survivors living with bodily impairments. PMID- 24782270 TI - Ruthenium complexes of an abnormally bound, anionic N-heterocyclic carbene. AB - The abnormally bound, anionic NHC-borane complex [Ru(IDipp-BF3)(p-cymene)Cl]2 (4; IDipp-BF3=1,3-(2,6-iPr2C6H3)2-2-BF3(C3HN2)-4-yl) was synthesized by transmetalation from Li[(IDipp-BF3)2Ag]. Addition of donors gave species of the form [Ru(IDipp-BF3)(p-cymene)(L)Cl], whereas halide abstraction with Ag(Et2O)[B(C6F5)4] gave C-H activation of the methine position of the IDipp-BF3 ligand. PMID- 24782271 TI - Brain, temperament, and behavior: new approaches to understanding fluency disorders. PMID- 24782272 TI - Temperament and environmental contributions to stuttering severity in children: the role of effortful control. AB - We investigated the contribution of temperament and external environment to the severity of children who stutter. Sixty-nine children who stutter, ages 2;4 to 5;9 (years; months), with a mean age of 3;7, were assessed for temperament, home environment, and significant life events. Temperament was assessed using the Children's Behavior Questionnaire. Home environment and life events were assessed using the Confusion, Hubbub and Order Scale (CHAOS) scale and the Life Events Checklist. Results indicated mother (parent)-reported stuttering severity and clinician-reported stuttering severity to be correlated with child temperament scores in the domain of Effortful Control. When temperament, home environment, and life events were combined, no statistically predictive outcomes were evident in corresponding severity ratings. The current study suggests the temperament domain of Effortful Control in children who stutter is a significant underlying mechanism influencing stuttering severity. Clinical implications are discussed. PMID- 24782273 TI - Exploring the link between stuttering and phonology: a review and implications for treatment. AB - Three lines of research have been pursued in the literature to study the link between phonology and stuttering: (1) effects of phonological complexity on the location (loci) of stutter events; (2) outcomes of standardized test measures in children who do and do not stutter; and (3) studies of phonological encoding in children and adults who stutter. This review synthesizes findings from these three lines of research to address the purported link between phonology and stuttering and its potential implications for stuttering treatment. Results from the loci studies offer some support for the role of phonological complexity in the occurrence of stuttering. Studies of performance in standardized tests of phonology have not identified differences between children who do and do not stutter. Studies of phonological encoding have been equivocal in reporting differences between children and adults who stutter and those who do not stutter. Several cautions are raised in interpreting the findings from the discussed studies, and despite the mixed findings, some implications for treatments are considered. PMID- 24782275 TI - Psychosocial impact of living with a stuttering disorder: knowing is not enough. AB - Stuttering requires a multidimensional perspective given that, in recent years, researchers have shown the impact of the disorder to reach far beyond the surface components with demonstrated psychosocial and anxiety effects for the individual living with a stutter. This article explores the impact a stuttering disorder has on the individual (child, adolescent, and adult) and on their family members (siblings, parents, and partners). These experiences include behavioral and social difficulties, self-awareness, reactions to stuttering, communication difficulties in daily situations, and overall quality of life. The influence of stuttering on the most intimate relationships of the person who stutters is presented. An overview of stuttering across the life span is discussed in terms of stuttering in children and adolescents, and the significant levels of adverse impact as a result of living with a stutter are described. In addition, the impact that the stuttering disorder has on the parents and siblings of children who stutter is also detailed through significant findings pertaining to lack of attachment and trust between the young people and their parents. The responsibilities and demands on parents and siblings in the family context are highlighted. Focus is also placed on the experience of living with a person who stutters from the perspective of their life partner. Perceived quality of life is explored with unexpected differences recounted between the quality of life experienced by the adult who stutters and their partner's perceptions of this disorder. Finally, the potential for a novel Acceptance and Commitment Therapy for individuals who stutter is presented. PMID- 24782274 TI - Temperament, emotion, and childhood stuttering. AB - Reactivity refers to arousal of emotions, motor activity, and attention, and self regulation refers to the ability to moderate those tendencies. In general, temperament is typically thought of as an individual's constitutionally (biologically) based behavioral proclivities. These proclivities often include emotional reactivity and self-regulation. Reactivity refers to arousal of emotions, motor activity, and attention, and self-regulation refers to the ability to moderate those tendencies. The traitlike nature of temperament makes it potentially salient to our understanding of the onset and development of stuttering because temperamental tendencies may result in greater reactivity or difficulty in coping. Emotions, which are more statelike and variable, may influence the variation of stuttering commonly observed both within and between speaking situations. Temperament and emotion may serve as a causal contributor to developmental stuttering, with empirical findings indicating that preschool-aged children who stutter (CWS) exhibit differences in temperament and emotion when compared with children who do not stutter. Given that empirical study of temperament in preschool-aged CWS is nascent, extensive discussion of clinical implications is challenging. With that caution, we present some early possibilities, including matching treatment approaches with the child's temperamental profile and using temperament as a predictor of treatment outcome. PMID- 24782276 TI - Lost in the literature, but not the caseload: working with atypical disfluency from theory to practice. AB - Atypical disfluency is a frustrating but little addressed clinical problem. The purpose of this article and case study was to summarize what is known about atypical fluency profiles and to describe the presenting behaviors and successful treatment of an unusual fluency profile (numerous word-final syllable repetitions) in a school-aged child. To this end, we describe the speech fluency and associated communication characteristics of a young boy diagnosed with Asperger disorder who was between 7;2 and 8;0 when seen for evaluation and treatment. We describe a therapy protocol that was successful in nearly eliminating these atypical disfluencies. The protocol emphasized self-monitoring and was integrated with other goals to improve the child's communication, which had features consistent with mild autism spectrum disorder (ASD). Following an 8 week treatment, the child significantly reduced his percent stuttered syllables of atypical disfluencies (word-final repetition and phrase-final repetition), resulting in significant qualitative improvements to his speech. This case study demonstrates that traditional stuttering modification treatment can be successful in reducing atypical and typical disfluencies in a child with concomitant social language impairment consistent with ASD. The therapy approach reported here may be useful in treatment of other cases having symptoms similar to the child we treated. PMID- 24782277 TI - The effects of preparation conditions for a BaNbO2 N photocatalyst on its physical properties. AB - BaNbO2 N is a semiconductor photocatalyst active for water oxidation under visible-light irradiation up to lambda=740 nm. It is important to understand the nitridation processes of precursor materials to form BaNbO2 N to tune the physical properties and improve the photocatalytic activity. Comprehensive experiments and analyses of temperatures, durations, ammonia flow rates, and barium/niobium ratios in the precursor during the nitridation process reveals that faster ammonia flow rates and higher barium/niobium ratios in the precursors help to suppress reduction of pentavalent niobium ions in the nitridation products and that the use of a precursor prepared by a soft-chemistry route allows the production of BaNbO2 N at lower temperatures in shorter times than the use of physical mixtures of BaCO3 and Nb2 O5 because the niobium species is dispersed among the barium species. BaNbO2 N prepared by the soft-chemistry route exhibits comparatively higher activity than that prepared from physical mixtures of BaCO3 and Nb2 O5 , probably because of lower nitridation temperatures, which suppress excessive dissociation of ammonia, and thereby reduce pentavalent niobium ions, and intimate interaction of niobium and barium sources, which lowers the densities of mid-gap states associated with defects. PMID- 24782278 TI - Reply: To PMID 23840006. PMID- 24782279 TI - Weight-for-length trajectories in the first year of life in children of mothers with eating disorders in a large Norwegian Cohort. AB - OBJECTIVE: To describe weight-for-length (WFL) trajectories in the children (birth-12 months) of mothers with and without eating disorders. METHOD: This study is based on the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. We categorized women (N = 57,185) based on diagnosis prior to and during pregnancy: anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified-purging subtype, binge eating disorder, or no eating disorder. The primary analysis included a shape invariant model fitted with nonlinear mixed effects to compare growth rates across eating disorder subtypes. RESULTS: The children of mothers reporting any eating disorder had a lower WFL growth rate from birth to 12 months than the children of mothers without eating disorders, even after adjusting for relative birth weight and some confounders known to affect growth. DISCUSSION: In this cohort, child WFL was related to maternal eating disorder status before and/or during pregnancy. These differences in growth trajectories warrant further study of long-term health outcomes and, if replicated, tailoring counseling to mothers with eating disorders during pregnancy. PMID- 24782280 TI - IFNL3 (IL28B) and IFNL4 polymorphisms are associated with treatment response in Thai patients infected with HCV genotype 1, but not with genotypes 3 and 6. AB - Recent studies have shown an association between single nucleotide polymorphisms (SNPs) in the interferon lambda-3 (IFNL3 or IL-28B) and IFNL4 genes and treatment response to hepatitis C virus genotype 1 (HCV-1) infection. The importance of these SNPs for HCV genotype 3 (HCV-3), and particularly HCV genotype 6 (HCV-6), remains to be elucidated. We analyzed a cohort of 225 Thai individuals with chronic HCV infection treated with pegylated-interferon and ribavirin, of whom 69 (30.7%), 114 (50.7%) and 42 (18.6%) patients were infected with HCV-1, HCV-3, and HCV-6, respectively. DNA extracted from blood samples was analyzed for the SNPs rs12979860 and ss469415590. The distribution of CC, CT, and TT genotypes of rs12979860 was 189 (84%), 28 (12.4%) and 8 (3.6%), respectively, while the distribution of TT/TT, DeltaG/TT, and DeltaG/DeltaG genotypes of ss469415590 was 192(85.3%), 28(12.5%), and 5(2.2%), respectively. Significantly lower frequencies of the favorable genotypes CC (for rs12979860) and TT/TT (for ss469415590) were found in the HCV-1 group in comparison with the other groups. The favorable genotypes were associated significantly with rapid and sustained virological response in the HCV-1 group. However, they were only associated with rapid virological response in the HCV-3 and HCV-6 groups. Furthermore, both SNPs were associated equally with the treatment outcome in the HCV-1 group. In contrast, the role of these SNPs in predicting treatment response was attenuated in the HCV 3 and HCV-6 groups. Thus, identification of these SNPs may be useful only in patients with refractory HCV-1 infection. PMID- 24782281 TI - Comparison of the biomechanical effects of pertrochanteric fixator and dynamic hip screw on an intertrochanteric femoral fracture using the finite element method. AB - BACKGROUND: This study was conducted to examine and compare the pertrochanteric fixator (PTF) and dynamic hip screw (DHS). METHODS: AnsysWorkbench, a commercial finite element based program, was used to investigate the biomechanical parameters of femoral fractures and implants. The human femoral model was scanned and a femoral intertrochanteric fracture was created. Von Mises stress, von Mises strain, and shear and deformation forces on the upper and lower parts of the fracture line; and the von Mises stress, von Mises strain parameters of the screws and implant bodies during axial loading were calculated and compared. RESULTS: It was determined that the magnitude of displacement forces along the fracture line was lower in PTF. Regarding the von Mises stress and von Mises strain values on the implant bodies, the DHS body had higher levels compared with the PTF body. CONCLUSION: This study demonstrated that PTF is more favorable than DHS for early axial loading and ambulation. PMID- 24782282 TI - Aldosterone antagonists for preventing the progression of chronic kidney disease. AB - BACKGROUND: Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is increasingly used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a review first published in 2009. OBJECTIVES: To evaluate the effect of aldosterone antagonists (both selective (eplerenone) and non-selective (spironolactone)) alone or in combination with ACEi or ARB in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including major cardiovascular events, hospitalisation and all-cause mortality; kidney function (proteinuria, glomerular filtration rate (GFR), serum creatinine, and need for renal replacement therapy; and adverse events (including gynaecomastia and hyperkalaemia). SEARCH METHODS: For this update, we searched the Cochrane Renal Group's Specialised Register to 30 January 2013 using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists alone or in combination with ACEi or ARB (or both) with other anti-hypertensive strategies or placebo. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We tested for heterogeneity in estimated treatment effects using the Cochran Q test and I2 statistic. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes together with their 95% confidence intervals (CI) and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used. MAIN RESULTS: We identified 27 studies (1549 participants) that were eligible for inclusion. These studies provided no data relating to aldosterone antagonists in addition to ACEi or ARB (or both) on patient-level outcomes including major cardiovascular events and mortality and progression to end-stage kidney disease (ESKD) requiring dialysis or transplantation.Compared with ACEi or ARB (or both), non-selective aldosterone antagonists (spironolactone) combined with ACEi or ARB (or both) significantly reduced 24-hour protein excretion (11 studies, 596 participants): SMD -0.61, 95% CI -1.08 to -0.13). There was a significant reduction in both systolic and diastolic blood pressure (BP) at the end of treatment with additional non-selective aldosterone antagonist therapy (systolic BP (10 studies, 556 participants): MD -3.44 mm Hg, 95% CI -5.05 to -1.83) (diastolic BP (9 studies, 520 participants): MD -1.73 mm Hg, 95% CI -2.83 to -0.62).However, we found that aldosterone antagonist treatment had imprecise effects at the end of treatment on GFR (9 studies, 528 participants; MD -2.55 mL/min/1.73 m2, 95% CI 5.67 to 0.51), doubled the risk of hyperkalaemia (11 studies, 632 patients): RR 2.00, 95% CI 1.25 to 3.20; number needed to treat for an additional harmful outcome (NNTH): 7.2, 95% CI 3.4 to infinity) and increased the risk of gynaecomastia compared to ACEi or ARB (or both) (4 studies, 281 patients): RR 5.14, 95% CI 1.14 to 23.23; NNTH: 14.1, 95% CI 8.7 to 37.3).Most studies enrolled few patients (range 12 to 268) and were powered to observe differences in surrogate end points rather than patient-focused outcomes. Nine studies had a cross-over design and the majority of studies did not adequately report study methods to assess methods and study quality. AUTHORS' CONCLUSIONS: Aldosterone antagonists reduced proteinuria and blood pressure in adults who had mild to moderate CKD and were treated with ACEi or ARB (or both), but increase hyperkalaemia and gynaecomastia. Whether adding aldosterone antagonists to ACEi or ARB (or both) reduced the risk of major cardiovascular events or ESKD in this population is unknown. PMID- 24782283 TI - Have we been underestimating the effects of ocean acidification in zooplankton? AB - Understanding how copepods may respond to ocean acidification (OA) is critical for risk assessments of ocean ecology and biogeochemistry. The perception that copepods are insensitive to OA is largely based on experiments with adult females. Their apparent resilience to increased carbon dioxide (pCO2 ) concentrations has supported the view that copepods are 'winners' under OA. Here, we show that this conclusion is not robust, that sensitivity across different life stages is significantly misrepresented by studies solely using adult females. Stage-specific responses to pCO2 (385-6000 MUatm) were studied across different life stages of a calanoid copepod, monitoring for lethal and sublethal responses. Mortality rates varied significantly across the different life stages, with nauplii showing the highest lethal effects; nauplii mortality rates increased threefold when pCO2 concentrations reached 1000 MUatm (year 2100 scenario) with LC50 at 1084 MUatm pCO2 . In comparison, eggs, early copepodite stages, and adult males and females were not affected lethally until pCO2 concentrations >=3000 MUatm. Adverse effects on reproduction were found, with >35% decline in nauplii recruitment at 1000 MUatm pCO2 . This suppression of reproductive scope, coupled with the decreased survival of early stage progeny at this pCO2 concentration, has clear potential to damage population growth dynamics in this species. The disparity in responses seen across the different developmental stages emphasizes the need for a holistic life-cycle approach to make species-level projections to climate change. Significant misrepresentation and error propagation can develop from studies which attempt to project outcomes to future OA conditions solely based on single life history stage exposures. PMID- 24782284 TI - Validation and method development of Tadalafil in bulk and tablet dosage form by RP-HPLC. AB - A novel, precise, rapid and sensitive reverse phase high performance liquid chromatographic method has been developed for the validated estimation of Tadalafil in bulk and tablet dosage form. The separation was achieved on Agilent Eclipse XDB C18 column (150 mm*4.6 mm, 5 u) using a mobile phase that consists of the buffer (potassium dihydrogen orthophosphate) and acetonitrile in the ration of 50:50 V/V, pH 6 was adjusted with orthophosphoric acid. The flow rate was maintained at 1.2 ml/min and the detection wavelength was 285 nm. The method was validated for linearity, specificity, sensitivity as per ICH guidelines. The retention time was found to be 3.181 for Tadalafil. The calibration curve was linear over the concentration range of 10-150 ug/ml. The % RSD was satisfactory which showed the method found to be reliable. The high percentage recovery confirmed the suitability of the method for estimation of Tadalafil in pharmaceutical dosage form. The developed method could be applicable for routine analysis of Tadalafil in bulk and tablet dosage form. PMID- 24782285 TI - A simple HPLC method with fluorescence detection for simultaneous determination of 10-methoxycamptothecin and its metabolite 10-hydroxycamptothecin in rat liver tissue. AB - A simple HPLC method to determine the amount of 10-methoxycamptothecin (MCPT) and its major metabolite 10-hydroxycamptothecin (HCPT) in rat liver tissue was developed in the present study. Camptothecin (CPT) was used as internal standard (IS). A piecewise linear function was used over lower and higher concentrations, respectively. The calibration curves were linear (r (2) >0.99) over concentrations from 2.5 to 20 ng/mL and 20 to 320 ng/mL for both MCPT and HCPT. The method had an accuracy of 92.74% to 112.76%, and the intra- and inter-day precision (RSD%) were 11.85% or less for MCPT and HCPT. The stability data showed no significant degradation occurred under the experimental conditions. This method was successfully applied to the tissue distribution study of MCPT and its metabolite HCPT in liver tissue samples after intravenous administration. PMID- 24782286 TI - Efficacy and Safety of Sufentanil and Pethidine in Spinal Anesthesia for Painless Labor. AB - Saddle spinal is a reliable method for control of pain during labor. This method has rapid onset and causes complete sensory block without significant influence on motor neurons.Our goal was to compare the analgesic efficacy and side effects of pethidine and sufentanil via saddle spinal administration during labor.600 parturients requesting analgesia were randomly divided into 2 groups. First group was composed of 300 patients received 0.4 mg/kg pethidine and the second group was composed of 300 patients received 0.1 MUg/kg sufentanil. Then, analgesia according to Visual Analogue Scale (VAS), itching, nausea, apnea and urinary retention were examined between 2 groups.VAS=3 was noted in both groups. Equal rate of apnea was seen in both groups. Patients received pethidine showed significantly a higher rate of nausea compared with sufentanil group (P<0.0001). Pruritus was significantly higher in patients received sufantanil (P<0.0001).Our findings suggest that saddle spinal by pethidine or sufentanil causes a considerable analgesia for labor. Proper management of the untoward effects of this method may introduce it as a safe and low-cost method for painless labor. PMID- 24782287 TI - Effect of Chronic Administration of Buspirone and Fluoxetine on Inflammatory Cytokines in 6-Hydroxydopamine-lesioned Rats. AB - Neuro-inflammation in Parkinson's disease (PD) is associated with glial cell activation and production of different inflammatory cytokines. In this study we investigated the effect of chronic administration of buspirone and fluoxetine on cerebrospinal fluid (CSF) levels of inflammatory cytokines, TNF-alpha, IL-1beta and IL-6 in 6-hydroxydopamine (6-OHDA)-lesioned rats.6-OHDA (8 MUg/2 MUl/rat) was injected unilaterally into the central region of the substantia nigra pars copmacta (SNc) and after 21 days lesioned rats were treated with buspirone and fluoxetine intraperitonealy (i.p.) for 10 days. CSF samples were collected at tenth day of drugs administration and were analysed by ELISA method to measure TNF-alpha, IL-1beta and IL-6 levels.The results showed that the CSF levels of TNF alpha was increased 3 weeks after 6-OHDA injection while there was a significant decrease in TNF-alpha levels of parkinsonian animals treated with buspirone (1 mg/kg) and fluoxetine (1 mg/kg). IL-1beta and IL-6 both were decreased in parkinsonian rats, while their level was increased in buspirone (1 mg/kg) and fluoxetine (1 mg/kg) treated parkinsonian rats.Our study indicates that chronic administration of buspirone and fluoxetine in 6-OHDA-lesioned rats restores central concentration of inflammatory cytokines to the basal levels. We suggest that serotonergic agents can be used as adjuvant therapy along with commonly used anti-parkinsonian drugs by modulation of cerebral inflammatory cytokines. We suggest that the further clinical investigations may be carried out to prove this hypothesis. PMID- 24782288 TI - Chronopharmacology of analgesic effect and tolerance induced by six narcotic analgesics in mice. AB - Narcotic analgesics, especially morphine, exert significantly different effects depending on the time within one day. The objective of this study was to observe whether the dosing time of 6 narcotic analgesics in mice affected their efficacy, pain tolerance and recovery of tolerance. The chronopharmacology of these 6 narcotics was evaluated using a hot-plate model. Maximum possible effect (MPE) of morphine showed a significant 24 h rhythm, which was higher during the dark phase and lower during the light phase (P<0.05). Conversely, MPEs of fentanyl and bucinnazine groups during the light phase exceeded those during the dark phase (P<0.05). Pain tolerance developed after drug administration at 9:00 am or 9:00 pm for 5 days, of which bucinnazine produced lower tolerance at 9:00 am. After a 2-day washout period, the mice rapidly recovered from tolerance at 3:00 pm for 5 day morphine dosing at 9:00 pm, and for fentanyl dosing at 9:00 am. Not all narcotic analgesics displayed significant circadian variations, and the dosing time-dependent effects also depended on the types of narcotics. Therefore, the time of administration is crucial in clinical pain treatment. Chronotherapy may be more effective to relieve pain while reducing side effects. PMID- 24782289 TI - Alkyl ammonium cation stabilized biocidal polyiodides with adaptable high density and low pressure. AB - The effective application of biocidal species requires building the active moiety into a molecular back bone that can be delivered and decomposed on demand under conditions of low pressure and prolonged high-temperature detonation. The goal is to destroy storage facilities and their contents while utilizing the biocidal products arising from the released energy to destroy any remaining harmful airborne agents. Decomposition of carefully selected iodine-rich compounds can produce large amounts of the very active biocides, hydroiodic acid (HI) and iodine (I2). Polyiodide anions, namely, I3(-), I5(-), which are excellent sources of such biocides, can be stabilized through interactions with large, symmetric cations, such as alkyl ammonium salts. We have designed and synthesized suitable compounds of adaptable high density up to 3.33 g cm(-3) that are low-pressure polyiodides with various alkyl ammonium cations, deliverable iodine contents of which range between 58.0-90.9%. PMID- 24782290 TI - Construction of Hybrid Supercapacitor-Batteries with dual-scale shelled architecture. AB - Pseudocapacitors bridge the gap between supercapacitors and batteries. Controllable microstructures grown on substrates have achieved success with regard to energy storage. However, traditional designs have only focused on the surface of scaffolds, which results in high specific capacitance values for the electroactive material rather than the electrodes. Inspired by slurry-casting, a dual-scale shell-structured NiCo2 O4 on nickel foam was assembled by using a simple and flexible solution-based strategy. First, NiCo2 O4 nanosheets covering the Ni foam skeleton surface loosely (the sample is denoted as 'pasted') is obtained by a solution-grown and 'dip-and-dry' process (in a cobalt-nickel hydroxide solution) followed by annealing. Secondly, the NiCo2 O4 nanosheets are filled in the pores of the Ni scaffold (the obtained material is denoted as 'tailored') through chemical bath deposition process followed by annealing. The capacitance per weight of electroactive materials is not outstanding (1029 F g( 1) at 10 mA cm(-2) ), but is competitive with regard to area (3.23 F cm(-2) at 10 mA cm(-2) ). However, features in the cycling performance imply that the electrode exhibits a hybrid supercapacitor-battery behavior and that thermodynamic hysteresis promotes the 'breaking' and 'fusing' behavior of the material. The overall design highlights a new pathway to step out from surface to space. PMID- 24782292 TI - Investigation of the doping efficiency of poly(styrene sulfonic acid) in poly(3,4 ethylenedioxythiophene)/poly(styrene sulfonic acid) dispersions by capillary electrophoresis. AB - CE can efficiently separate poly(3,4-ethylenedioxythiophene)/poly(styrene sulfonic acid) (PEDOT/PSS) complexes and free PSS in dispersions and can be used to estimate the degree of PSS doping. We investigated the doping efficiency of PSS on PEDOT in dispersions using CE and its effect on the conductivity of the resulting PEDOT/PSS films. Results of this study indicate that dispersions containing 1:2.5-3 EDOT:PSS feed ratio (by weight) exhibiting 72-73% PSS doping generate highly processable and highly conductive films. Conductivity can be optimized by limiting the time of reaction to 12 h. At this point of the reaction, the PEDOT/PSS segments, appearing as broad band in the electropherogram, could still exist in an extended coil conformation favoring charge transport resulting in high conductivity. Above a threshold PEDOT length formed at reaction times longer than 12 h, the PEDOT/PSS complex, appearing as spikes in the electropherogram, most likely have undergone a conformational change to coiled core-shell structure restricting charge transport resulting in low conductivity. The optimal conductivity (5.2 S/cm) of films from dispersions synthesized for 12 h is significantly higher than those from its commercial equivalent Clevios P and other reported values obtained under similar conditions without the addition of codopants. PMID- 24782291 TI - Reversing vascular dysfunction in rheumatoid arthritis: improved augmentation index but not endothelial function with peroxisome proliferator-activated receptor gamma agonist therapy. AB - OBJECTIVE: To examine the hypothesis that improving insulin sensitivity improves vascular function in rheumatoid arthritis (RA). METHODS: We performed a 20-week, single center, randomized, double-blind, placebo-controlled crossover study. Patients with RA (n = 34) with moderate disease activity who were receiving stable disease-modifying antirheumatic drug therapy were randomized to drug sequence, receiving either pioglitazone 45 mg/day or matching placebo for 8 weeks, followed by a 4-week washout period and the alternative treatment for 8 weeks. We measured changes in vascular stiffness (augmentation index and aortic pulse wave velocity [PWV]), endothelial function (reactive hyperemia index), and blood pressure. High-sensitivity C-reactive protein levels and the homeostatic model assessment of insulin resistance were also measured. The treatment effect of pioglitazone on outcomes was analyzed using linear mixed-effects models. RESULTS: Pioglitazone treatment resulted in a change in augmentation index of 4.7% units (95% confidence interval [95% CI] -7.9, -1.5) (P = 0.004) and in diastolic blood pressure of -3.0 mm Hg (95% CI -5.7, -0.2) (P = 0.03), but did not significantly change aortic PWV (P = 0.33) or reactive hyperemia index (P = 0.46). The improvements in augmentation index and diastolic blood pressure were not mediated by the effect of pioglitazone on insulin resistance or inflammation. CONCLUSION: Our findings indicate that pioglitazone improves some indices of vascular function, including augmentation index and diastolic blood pressure, in patients with RA. This is not mediated by improved insulin sensitivity. PMID- 24782293 TI - Initial results of robot-assisted Ivor-Lewis oesophagectomy with intrathoracic hand-sewn anastomosis in the prone position. AB - BACKGROUND: There is scanty experience concerning robot-assisted Ivor-Lewis oesophagectomy, so every new experience is helpful. METHODS: We describe the techniques and short-term results of Ivor-Lewis oesophagectomy using a laparoscopic approach and robot-assisted thoracoscopy, and an observational study of prospective surveillance of the first 14 patients treated for oesophageal cancer. A gastric tube was created laparoscopically. Oesophagectomy was performed through a robot-assisted thoracoscopy followed by hand-sewn intrathoracic anastomosis. RESULTS: There were no conversion cases. Mortality was zero. Six patients had a major complication. There were no cases of respiratory complication or recurrent laryngeal nerve palsy. Three patients had a radiological fistula (21.4%), successfully treated by endoscopic stenting, and one (7.1%) had an anastomosis leak needing reoperation. There were two cases of chylothorax (14.3%). CONCLUSIONS: Our initial results suggest that the reported technique is safe and satisfies the oncological principles. It provides the advantages of minimally invasive surgery by overcoming some limitations of conventional thoracoscopy. PMID- 24782294 TI - What is the best therapeutic strategy in patients with low flow, low-gradient aortic stenosis, and wide QRS? PMID- 24782295 TI - Pharmacologic management of human immunodeficiency virus wasting syndrome. AB - Pharmacologic interventions for human immunodeficiency virus (HIV) wasting have been studied since the 1990s, but the results of these interventions have been difficult to compare because the studies used different HIV wasting definitions and assessed various patient outcomes. Thus, we performed a systematic review of the current literature to identify studies that evaluated pharmacologic management of HIV wasting and to compare and contrast treatment options. Further, we provide a comprehensive review of these treatment options and describe the definition of HIV wasting used in each study, the outcomes assessed, and whether antiretroviral therapy was used during the HIV wasting treatment. Literature searches of the PubMed/Medline (1946-2014) and Google Scholar databases were performed, and a review of the bibliographies of retrieved articles was performed to identify additional references. Only English-language articles pertaining to humans and HIV-infected individuals were evaluated. Thirty-six studies were identified that assessed pharmacologic interventions to treat HIV wasting. Appetite stimulants, such as megestrol acetate, have been shown to increase total body weight (TBW) and body mass index in HIV-infected patients with wasting. Studies evaluating dronabinol showed conflicting data on TBW increases, but the drug may have minimal benefit on body composition compared with other appetite stimulants. Testosterone has been shown to be effective in HIV wasting for those who suffer from hypogonadism. Recombinant human growth hormone has been evaluated for HIV wasting and has shown promising results for TBW and lean body mass increases. Thalidomide has been studied; however, its use is limited due to its toxicities. Although megestrol acetate and dronabinol are approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV wasting, it is important to recognize other comorbidities such as depression or hypogonadism that may contribute to the patient's appetite and weight loss. If a patient is diagnosed with hypogonadism and HIV wasting, testosterone would be a good therapeutic option. Although mirtazapine is not FDA approved for the management of HIV wasting, it has been shown to promote weight gain while treating depression symptoms. Mirtazapine may be a promising pharmacologic option in the management of HIV wasting and depression, but further research is needed. PMID- 24782296 TI - In situ hybridization analysis of invasive breast carcinomas with immunohistochemically negative Her-2 status (a national multicenter study). AB - OBJECTIVE: The aim of this study was to determine the rate of Her-2 gene amplification in breast cancer cases with a previous negative Her-2 result as determined by immunohistochemistry (score 0 or 1). MATERIAL AND METHOD: 552 cases of invasive breast carcinoma were assessed with the contribution of 9 centers. Previous immunohistochemistry score was either 0 or 1+ in all cases. These cases were re-tested by Her-2 silver in situ hybridization in the central laboratory. Her-2 gene amplification was defined as Her-2/CEP 17 ratio of more than 2.2. Cases with a ratio between 1.8 and 2.0 were defined as equivocal and cases with a ratio of less than 1.8 were defined as negative. RESULTS: Re-testing of the 552 cases with silver in situ hybridization showed a total of 22 cases with Her-2 gene amplification, of which 11 (3.2%) were found to be score 0, and 11 were found to be score 1+ (5.3%) by immunohistochemistry previously. Her-2 gene amplification rate of cases (score 0 and 1+) ranged from 0% to 10.48% among the centers. Polysomy was found in 28 (8.1%) of the score 0 cases and 25 (12.1%) among the score 1+ cases. Five (9.4%) of the cases with polysomy were found to be amplified, and 48 (90.6%) were not. CONCLUSION: The results of the study show that a group of cases (3.98%) with a potential to benefit from anti-Her-2 therapy may be missed with the immunohistochemical method. This indicates the importance of quality assurance, especially in central laboratories with many breast cancer cases in daily practice. PMID- 24782297 TI - Caveolin-1 expression in odontogenic cysts and ameloblastomas. AB - OBJECTIVE: The aim of this study is to evaluate the caveolin-1 expression in a group of odontogenic cysts and tumors. MATERIAL AND METHOD: In this cross sectional study, the expression of caveolin-1 was evaluated immunohistochemically in 75 samples including 18 cases of dentigerous cyst, 18 odontogenic keratocysts, 3 orthokeratinized odontogenic cysts, 2 calcifying odontogenic cysts and 34 ameloblastomas (solid and unicystic). RESULTS: Positive immunohistochemical reaction was found in 100% of odontogenic cysts and this was significantly more than both unicystic (65%) and solid (55%) ameloblastomas. CONCLUSION: The present study showed the expression of caveolin-1 in all odontogenic cysts and more than ameloblastomas. The results suggested that absence of caveolin-1 might enhance aggressiveness of odontogenic lesions and could be a useful marker for distinguishing ameloblastomas from other odontogenic lesions. PMID- 24782298 TI - Morphological aspects and distribution of interstitial cells of Cajal in the human upper urinary tract. AB - OBJECTIVE: The mechanism by which the ureter propels urine towards the bladder has a myogenic origin, through peristaltic contractions. This pyeloureteral autorhythmicity is generated by specialized, electrically active cells, the interstitial cells of Cajal, located in the proximal regions of the upper urinary tract. The aim of this study was to describe the exact location and the distribution of interstitial Cajal cells in the human upper urinary tract and to analyze their normal number and morphology. This is a preliminary study, which will allow the study of these cells in different urinary tract pathologies. MATERIAL AND METHOD: Urinary tract fragments were sampled at different levels, from 13 autopsy cases. Cases with clinical evidence of renal disease, and with histological changes in the kidney or in the urinary tract tissue samples, visible in hematoxylin-eosin staining, were excluded. The interstitial Cajal cells were highlighted with anti-CD117 antibody, immunohistochemically. RESULTS: Cajal cells were indirectly highlighted by the presence of a finely granulated cytoplasm indicating immunoreactivity. These cells were spindle-shaped or stellate, with cytoplasmic extensions at one or both poles of the cell and large oval nucleus. We found that interstitial Cajal cells were located at all upper urinary tract levels, with a higher predominance in the calyces and pyelon. Interstitial Cajal cells were observed mostly between the two layers of the muscularis, but also between the muscle bundles. Most often, these cells were parallel to the muscle fibers. CONCLUSION: Our study describes the method of detection of interstitial Cajal cells in normal human urinary tract. These results can be used to analyze the number, morphology and the location of these cells in different congenital pathologies, such as vesicoureteral reflux, pyeloureteral junction obstruction or primary obstructive megaureter. PMID- 24782299 TI - A study on distribution of cancer cases diagnosed in Corum. AB - OBJECTIVE: In order to help obtain accurate knowledge and to contribute to the establishment of data for regional tumor statistics, we aimed to determine the frequency distribution of cancer cases that was diagnosed in Corum province. MATERIAL AND METHOD: In this descriptive study, we retrospectively reviewed the archive records of the pathology departments' of one university hospital and two private hospitals serving in the province of Corum. A total of 138,973 recorded pathology reports were reviewed. Metastatic cancers with a known primary source were excluded. A total of 2184 cases with a diagnosis of cancer were recorded by gender, age, and system/organ and classified to 10 most frequent types of cancer both in general and in terms of gender distribution. RESULTS: The male to female ratio was 1.44 and the mean age was 64.26 years. The cancer is most commonly encountered between 70 and 79 years of age (35.27%) in males whereas the second most common interval was 60 to 69 years of age (23.88%). In females, the cancer is most commonly encountered between 70 and 79 years of age (24.16%) whereas the second most common interval was 60 to 69 years of age (22.60%). The top five cancers were skin (33.60%), prostate (13.87%), stomach (9.07%), urinary bladder (8.61%) and breast (7.88%). CONCLUSION: Distribution of organ/system involvement of cancer cases that were diagnosed in Corum is quite different from the data regarding Turkey in general. Development of cancer registry centers, upgrading to an active registry system and having all cancer data from health institutions unified in a single organization are mandatory to achieve reliable data. PMID- 24782300 TI - Osteosarcoma arising from a haemangioma: case report and review of the literature. AB - To create awareness of the benign lesions from which osteosarcoma may arise. Osteosarcoma is a rare tumour of bone the etiology of which is poorly understood, but it may arise from benign lesions. Malignant transformation in hemangiomas, in the absence of prior radiation, is exceedingly rare and the resulting neoplasm is usually an angiosarcoma. We report the case of a 30-year-old woman where investigation for thigh pain revealed a distal femoral hemangioma. She represented with pain and mass 18 years later, leading to a confirmed diagnosis of osteosarcoma at the same site. Osteosarcomas may arise from a variety of benign lesions. In this article we report the case of a histologically confirmed hemangioma which subsequently underwent malignant change into an osteosarcoma. PMID- 24782301 TI - Rethinking about tubulocystic carcinoma of the kidney after taking into account the existence of tubulocystic chromophobe renal carcinoma. PMID- 24782302 TI - Lymphatic vascularization in primary breast cancer: HER2 overexpressing tumors contain more lymphatics than steroid receptor positive, triple-positive and triple negative breast carcinomas. AB - OBJECTIVE: The aim of this study was to examine the relationship between the immunohistochemical subtypes of invasive breast cancer and lymphatic vascularization. MATERIAL AND METHOD: One hundred and seventy nine cases of randomly selected invasive breast cancer patients, surgically treated between 2004 and 2007, were retrospectively studied. These were classified into steroid receptor positive (steroid receptor positive/ HER2 negative), triple positive (steroid receptor and HER2 positive), triple negative (steroid receptor and HER2 negative) and HER2 overexpressing (steroid receptor negative /HER2 positive) carcinomas. Appropriate immunostaining and in-situ hybridization techniques were applied and results were statistically analyzed. RESULTS: The median intra-tumor lymphatic vascular density and the median intra-tumor relative lymphatic vascular area were found to differ significantly among the studied groups of breast cancer (KW =49.8611; p < 0.0001 and KW =21.5122; p=0.0001 respectively). There was no significant difference in the incidence rate of axillary node involvement among the studied groups of breast cancer (chi < sup > 2 < /sup > =1.66; Df=3; p=0.6460). CONCLUSION: The present study indicates that HER2 overexpressing breast carcinomas have a consistent increase of intra-tumor lymphatic vessel counts as compared to all other subtypes. It is suggested that the newly formed vessels are probably not the only essential factor for lymphogenic spread of HER2 overexpressing breast carcinomas as they are not related to an increased incidence of lymph node metastases compared to the other studied subgroups. PMID- 24782303 TI - Water repellency in hydrophobic nanocapsules--molecular view on dewetting. AB - The hydrophobic effect plays a major role in a variety of important phenomena in chemistry, materials science and biology, for instance in protein folding and protein-ligand interactions. Studies--performed within cavities of the unique metal oxide based porous capsules of the type {(pentagon)12(linker)30}={(W)W5}12{Mo2(ligand)}30 with different acetate/water ligand ratios--have provided unprecedented results revealing segregation/repellency of the encapsulated "water" from the internal hydrophobic ligand walls of the capsules, while the disordered water molecules, interacting strongly with each other via hydrogen bonding, form in all investigated cases the same type of spherical shell. The present results can be (formally) compared--but only regarding the repellency effect--with the amazing "action" of the (super)hydrophobic Lotus (Nelumbo) leaves, which are self-cleaning based on water repellency resulting in the formation of water droplets picking up dirt. The present results were obtained by constructing deliberately suitable hydrophobic interiors within the mentioned capsules. PMID- 24782304 TI - Oral contraceptives for functional ovarian cysts. AB - BACKGROUND: Functional ovarian cysts are a common gynecological problem among women of reproductive age worldwide. When large, persistent, or painful, these cysts may require operations, sometimes resulting in removal of the ovary. Since early oral contraceptives were associated with a reduced incidence of functional ovarian cysts, many clinicians inferred that birth control pills could be used to treat cysts as well. This became a common clinical practice in the early 1970s. OBJECTIVES: This review examined all randomized controlled trials that studied oral contraceptives as therapy for functional ovarian cysts. SEARCH METHODS: In March 2014, we searched the databases of CENTRAL, PubMed, EMBASE, and POPLINE, as well as clinical trials databases (ClinicalTrials.gov and ICTRP). We also examined the reference lists of articles. For the initial review, we wrote to authors of identified trials to seek articles we had missed. SELECTION CRITERIA: We included randomized controlled trials in any language that included oral contraceptives used for treatment and not prevention of functional ovarian cysts. Criteria for diagnosis of cysts were those used by authors of trials. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted data from the articles. One entered the data into RevMan and a second verified accuracy of data entry. For dichotomous outcomes, we computed the Mantel-Haenszel odds ratio with 95% confidence interval (CI). For continuous outcomes, we calculated the mean difference with 95% CI. MAIN RESULTS: We identified eight randomized controlled trials from four countries; the studies included a total of 686 women. Treatment with combined oral contraceptives did not hasten resolution of functional ovarian cysts in any trial. This held true for cysts that occurred spontaneously as well as those that developed after ovulation induction. Most cysts resolved without treatment within a few cycles; persistent cysts tended to be pathological (e.g., endometrioma or para-ovarian cyst) and not physiological. AUTHORS' CONCLUSIONS: Although widely used for treating functional ovarian cysts, combined oral contraceptives appear to be of no benefit. Watchful waiting for two or three cycles is appropriate. Should cysts persist, surgical management is often indicated. PMID- 24782305 TI - VEGF modulates synaptic activity in the developing spinal cord. AB - Although it has been documented that the nervous and the vascular systems share numerous analogies and are closely intermingled during development and pathological processes, interactions between the two systems are still poorly described. In this study, we investigated whether vascular endothelial growth factor (VEGF), which is a key regulator of vascular development, also modulates neuronal developmental processes. We report that VEGF enhances the gamma aminobutyric acid (GABA)/glycinergic but not glutamatergic synaptic activity in embryonic spinal motoneurons (MNs), without affecting MNs excitability. In response to VEGF, the frequency of these synaptic events but not their amplitude was increased. Blocking endogenous VEGF led to an opposite effect by decreasing frequency of synaptic events. We found that this effect occurred specifically at early developmental stages (E13.5 and E15.5) and vanished at the prenatal stage E17.5. Furthermore, VEGF was able to increase vesicular inhibitory amino acid transporter density at the MN membrane. Inhibition of single VEGF receptors did not modify electrophysiological parameters indicating receptor combinations or an alternative pathway. Altogether, our findings identify VEGF as a modulator of the neuronal activity during synapse formation and highlight a new ontogenic role for this angiogenic factor in the nervous system. PMID- 24782306 TI - Desmoglein 2 compensates for desmoglein 3 but does not control cell adhesion via regulation of p38 mitogen-activated protein kinase in keratinocytes. AB - Desmosomal cadherins are transmembrane adhesion molecules that provide cell adhesion by interacting in the intercellular space of adjacent cells. In keratinocytes, several desmoglein (Dsg1-4) and desmocollin (Dsc1-3) isoforms are coexpressed. We have shown previously that Dsg2 is less important for keratinocyte cohesion compared with Dsg3 and that the latter forms a complex with p38 MAPK. In this study, we compared the involvement of Dsg2 and Dsg3 in the p38 MAPK-dependent regulation of keratinocyte cohesion. We show that loss of cell adhesion and keratin filament retraction induced by Dsg3 depletion is ameliorated by specific p38 MAPK inhibition. Furthermore, in contrast to depletion of Dsg2, siRNA-mediated silencing of Dsg3 induced p38 MAPK activation, which is in line with immunoprecipitation experiments demonstrating the interaction of activated p38 MAPK with Dsg3 but not with Dsg2. Cell fractionation into a cytoskeleton unbound and a cytoskeleton-anchored desmosome-containing pool revealed that Dsg3, in contrast to Dsg2, is present in relevant amounts in the unbound pool in which activated p38 MAPK is predominantly detectable. Moreover, because loss of cell adhesion by Dsg3 depletion was partially rescued by p38 MAPK inhibition, we conclude that, besides its function as an adhesion molecule, Dsg3 is strengthening cell cohesion via modulation of p38 MAPK-dependent keratin filament reorganization. Nevertheless, because subsequent targeting of Dsg3 in Dsg2 depleted cells led to drastically enhanced keratinocyte dissociation and Dsg2 was enhanced at the membrane in Dsg3 knockout cells, we conclude that Dsg2 compensates for Dsg3 loss of function. PMID- 24782307 TI - Crystallin-alphaB regulates skeletal muscle homeostasis via modulation of argonaute2 activity. AB - The core functional machinery of the RNAi pathway is the RNA-induced silencing complex (RISC), wherein Argonaute2 (Ago2) is essential for siRNA-directed endonuclease activity and RNAi/microRNA-mediated gene silencing. Crystallin alphaB (CryAB) is a small heat shock protein involved in preventing protein aggregation. We demonstrate that CryAB interacts with the N and C termini of Ago2, not the catalytic site defined by the convergence of the PAZ, MID, and PIWI domains. We further demonstrate significantly reduced Ago2 activity in the absence of CryAB, highlighting a novel role of CryAB in the mammalian RNAi/microRNA pathway. In skeletal muscle of CryAB null mice, we observe a shift in the hypertrophy-atrophy signaling axis toward atrophy under basal conditions. Moreover, loss of CryAB altered the capability of satellite cells to regenerate skeletal muscle. These studies establish that CryAB is necessary for normal Ago2/RISC activity and cellular homeostasis in skeletal muscle. PMID- 24782308 TI - Differential interaction of tomosyn with syntaxin and SNAP25 depends on domains in the WD40 beta-propeller core and determines its inhibitory activity. AB - Neuronal exocytosis depends on efficient formation of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) complexes and is regulated by tomosyn, a SNARE-binding protein. To gain new information about tomosyn's activity, we characterized its mobility and organization on the plasma membrane (PM) in relation to other SNARE proteins and inhibition of exocytosis. By using direct stochastic optical reconstruction microscopy (dSTORM), we found tomosyn to be organized in small clusters adjacent to syntaxin clusters. In addition, we show that tomosyn is present in both syntaxin-tomosyn complexes and syntaxin SNAP25-tomosyn complexes. Tomosyn mutants that lack residues 537-578 or 897-917 from its beta-propeller core diffused faster on the PM and exhibited reduced binding to SNAP25, suggesting that these mutants shift the equilibrium between tomosyn-syntaxin-SNAP25 complexes on the PM to tomosyn-syntaxin complexes. As these deletion mutants impose less inhibition on exocytosis, we suggest that tomosyn inhibition is mediated via tomosyn-syntaxin-SNAP25 complexes and not tomosyn-syntaxin complexes. These findings characterize, for the first time, tomosyn's dynamics at the PM and its relation to its inhibition of exocytosis. PMID- 24782309 TI - The protein synthesis inhibitor blasticidin s enters mammalian cells via leucine rich repeat-containing protein 8D. AB - Leucine-rich repeat-containing 8 (LRRC8) proteins have been identified as putative receptors involved in lymphocyte development and adipocyte differentiation. They remain poorly characterized, and no specific function has been assigned to them. There is no consensus on how this family of proteins might function because homology searches suggest that members of the LRRC8 family act not as plasma membrane receptors, but rather as channels that mediate cell-cell signaling. Here we provide experimental evidence that supports a role for LRRC8s in the transport of small molecules. We show that LRRC8D is a mammalian protein required for the import of the antibiotic blasticidin S. We characterize localization and topology of LRRC8A and LRRC8D and demonstrate that LRRC8D interacts with LRRC8A, LRRC8B, and LRRC8C. Given the suggested involvement in solute transport, our results support a model in which LRRC8s form one or more complexes that may mediate cell-cell communication by transporting small solutes. PMID- 24782310 TI - A bacterial iron exporter for maintenance of iron homeostasis. AB - Nutritional iron acquisition by bacteria is well described, but almost nothing is known about bacterial iron export even though it is likely to be an important homeostatic mechanism. Here, we show that Bradyrhizobium japonicum MbfA (Blr7895) is an inner membrane protein expressed in cells specifically under high iron conditions. MbfA contains an N-terminal ferritin-like domain (FLD) and a C terminal domain homologous to the eukaryotic vacuolar membrane Fe(2+)/Mn(2+) transporter CCC1. An mbfA deletion mutant is severely defective in iron export activity, contains >2-fold more intracellular iron than the parent strain, and displays an aberrant iron-dependent gene expression phenotype. B. japonicum is highly resistant to iron and H2O2 stresses, and MbfA contributes substantially to this as determined by phenotypes of the mbfA mutant strain. The N-terminal FLD was localized to the cytoplasmic side of the inner membrane. Substitution mutations in the putative iron-binding amino acid residues E20A and E107A within the N-terminal FLD abrogate iron export activity and stress response function. Purified soluble FLD oxidizes ferrous iron (Fe(2+)) to incorporate ferric iron (Fe(3+)) in a 2:1 iron:protein ratio, which does not occur in the E20A/E107A mutant. The FLD fragment is a dimer in solution, implying that the MbfA exporter functions as a dimer. MbfA belongs to a protein family found in numerous prokaryotic genera. The findings strongly suggest that iron export plays an important role in bacterial iron homeostasis. PMID- 24782311 TI - Elucidating the role of disulfide bond on amyloid formation and fibril reversibility of somatostatin-14: relevance to its storage and secretion. AB - The storage of protein/peptide hormones within subcellular compartments and subsequent release are crucial for their native function, and hence these processes are intricately regulated in mammalian systems. Several peptide hormones were recently suggested to be stored as amyloids within endocrine secretory granules. This leads to an apparent paradox where storage requires formation of aggregates, and their function requires a supply of non-aggregated peptides on demand. The precise mechanism behind amyloid formation by these hormones and their subsequent release remain an open question. To address this, we examined aggregation and fibril reversibility of a cyclic peptide hormone somatostatin (SST)-14 using various techniques. After proving that SST gets stored as amyloid in vivo, we investigated the role of native structure in modulating its conformational dynamics and self-association by disrupting the disulfide bridge (Cys(3)-Cys(14)) in SST. Using two-dimensional NMR, we resolved the initial structure of somatostatin-14 leading to aggregation and further probed its conformational dynamics in silico. The perturbation in native structure (S-S cleavage) led to a significant increase in conformational flexibility and resulted in rapid amyloid formation. The fibrils formed by disulfide-reduced noncyclic SST possess greater resistance to denaturing conditions with decreased monomer releasing potency. MD simulations reveal marked differences in the intermolecular interactions in SST and noncyclic SST providing plausible explanation for differential aggregation and fibril reversibility observed experimentally in these structural variants. Our findings thus emphasize that subtle changes in the native structure of peptide hormone(s) could alter its conformational dynamics and amyloid formation, which might have significant implications on their reversible storage and secretion. PMID- 24782312 TI - Poly(ADP-ribose) polymerase 1 (PARP1) associates with E3 ubiquitin-protein ligase UHRF1 and modulates UHRF1 biological functions. AB - Poly(ADP-ribose) polymerase 1 (PARP1, also known as ARTD1) is an abundant nuclear enzyme that plays important roles in DNA repair, gene transcription, and differentiation through the modulation of chromatin structure and function. In this work we identify a physical and functional poly(ADP-ribose)-mediated interaction of PARP1 with the E3 ubiquitin ligase UHRF1 (also known as NP95, ICBP90) that influences two UHRF1-regulated cellular processes. On the one hand, we uncovered a cooperative interplay between PARP1 and UHRF1 in the accumulation of the heterochromatin repressive mark H4K20me3. The absence of PARP1 led to reduced accumulation of H4K20me3 onto pericentric heterochromatin that coincided with abnormally enhanced transcription. The loss of H4K20me3 was rescued by the additional depletion of UHRF1. In contrast, although PARP1 also seemed to facilitate the association of UHRF1 with DNMT1, its absence did not impair the loading of DNMT1 onto heterochromatin or the methylation of pericentric regions, possibly owing to a compensating interaction of DNMT1 with PCNA. On the other hand, we showed that PARP1 controls the UHRF1-mediated ubiquitination of DNMT1 to timely regulate its abundance during S and G2 phase. Together, this report identifies PARP1 as a novel modulator of two UHRF1-regulated heterochromatin associated events: the accumulation of H4K20me3 and the clearance of DNMT1. PMID- 24782313 TI - In vitro resistance selections for Plasmodium falciparum dihydroorotate dehydrogenase inhibitors give mutants with multiple point mutations in the drug binding site and altered growth. AB - Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characterizing resistance pathways for antimalarial agents not yet in clinical use will increase our understanding of the potential for resistance. We identified resistance mechanisms of Plasmodium falciparum (Pf) DHODH inhibitors via in vitro resistance selections. We found 11 point mutations in the PfDHODH target. Target gene amplification and unknown mechanisms also contributed to resistance, albeit to a lesser extent. These mutant parasites were often hypersensitive to other PfDHODH inhibitors, which immediately suggested a novel combination therapy approach to preventing resistance. Indeed, a combination of wild-type and mutant-type selective inhibitors led to resistance far less often than either drug alone. The effects of point mutations in PfDHODH were corroborated with purified recombinant wild type and mutant-type PfDHODH proteins, which showed the same trends in drug response as the cognate cell lines. Comparative growth assays demonstrated that two mutant parasites grew less robustly than their wild-type parent, and the purified protein of those mutants showed a decrease in catalytic efficiency, thereby suggesting a reason for the diminished growth rate. Co-crystallography of PfDHODH with three inhibitors suggested that hydrophobic interactions are important for drug binding and selectivity. PMID- 24782314 TI - Induction of p21CIP1 protein and cell cycle arrest after inhibition of Aurora B kinase is attributed to aneuploidy and reactive oxygen species. AB - Cell cycle progression requires a series of highly coordinated events that ultimately lead to faithful segregation of chromosomes. Aurora B is an essential mitotic kinase, which is involved in regulation of microtubule-kinetochore attachments and cytokinesis. Inhibition of Aurora B results in stabilization of p53 and induction of p53-target genes such as p21 to inhibit proliferation. We have previously demonstrated that induction of p21 by p53 after inhibition of Aurora B is dependent on the p38 MAPK, which promotes transcriptional elongation of p21 by RNA Pol II. In this study, we show that a subset of p53-target genes are induced in a p38-dependent manner upon inhibition of Aurora B. We also demonstrate that inhibition of Aurora B results in down-regulation of E2F mediated transcription and that the cell cycle arrest after Aurora B inhibition depends on p53 and pRB tumor suppressor pathways. In addition, we report that activation of p21 after inhibition of Aurora B is correlated with increased chromosome missegregation and aneuploidy but not with binucleation or tetraploidy. We provide evidence that p21 is activated in aneuploid cells by reactive oxygen species (ROS) and p38 MAPK. Finally, we demonstrate that certain drugs that act on aneuploid cells synergize with inhibitors of Aurora B to inhibit colony formation and oncogenic transformation. These findings provide an important link between aneuploidy and the stress pathways activated by Aurora B inhibition and also support the use of Aurora B inhibitors in combination therapy for treatment of cancer. PMID- 24782316 TI - Intrinsic connections within the pedunculopontine tegmental nucleus are critical to the elaboration of post-ictal antinociception. AB - This study investigated the intrinsic connections of a key-structure of the endogenous pain inhibitory system, the pedunculopontine tegmental nucleus (PPTN), in post-ictal antinociceptive process through synaptic inactivation of the PPTN with cobalt chloride. Male Wistar rats (n = 6 or 7 per group), weighing 250-280 g, had the tail-flick baseline recorded and were submitted to a stereotaxic surgery for the introduction of a guide-cannula aiming at the PPTN. After 5 days of postoperative recovery, cobalt chloride (1 mM/0.2 uL) or physiological saline (0.2 uL) were microinjected into the PPTN and after 5 min, the tail-withdrawal latency was measured again at 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, and 120 min after seizures evoked by intraperitoneal injection of pentylenetetrazole (64 mg/kg). The synaptic inactivation of PPTN decreased the post-ictal antinociceptive phenomenon, suggesting the involvement of PPTN intrinsic connections in the modulation of pain, during tonic-clonic seizures. These results showed that the PPTN may be crucially involved in the neural network that organizes the post-ictal analgesia. PMID- 24782315 TI - ChlR protein of Synechococcus sp. PCC 7002 is a transcription activator that uses an oxygen-sensitive [4Fe-4S] cluster to control genes involved in pigment biosynthesis. AB - Synechococcus sp. PCC 7002 and many other cyanobacteria have two genes that encode key enzymes involved in chlorophyll a, biliverdin, and heme biosynthesis: acsFI/acsFII, ho1/ho2, and hemF/hemN. Under atmospheric O2 levels, AcsFI synthesizes 3,8-divinyl protochlorophyllide from Mg-protoporphyrin IX monomethyl ester, Ho1 oxidatively cleaves heme to form biliverdin, and HemF oxidizes coproporphyrinogen III to protoporphyrinogen IX. Under microoxic conditions, another set of genes directs the synthesis of alternative enzymes AcsFII, Ho2, and HemN. In Synechococcus sp. PCC 7002, open reading frame SynPCC7002_A1993 encodes a MarR family transcriptional regulator, which is located immediately upstream from the operon comprising acsFII, ho2, hemN, and desF (the latter encodes a putative fatty acid desaturase). Deletion and complementation analyses showed that this gene, denoted chlR, is a transcriptional activator that is essential for transcription of the acsFII-ho2-hemN-desF operon under microoxic conditions. Global transcriptome analyses showed that ChlR controls the expression of only these four genes. Co-expression of chlR with a yfp reporter gene under the control of the acsFII promoter from Synechocystis sp. PCC 6803 in Escherichia coli demonstrated that no other cyanobacterium-specific components are required for proper functioning of this regulatory circuit. A combination of analytical methods and Mossbauer and EPR spectroscopies showed that reconstituted, recombinant ChlR forms homodimers that harbor one oxygen-sensitive [4Fe-4S] cluster. We conclude that ChlR is a transcriptional activator that uses a [4Fe-4S] cluster to sense O2 levels and thereby control the expression of the acsFII-ho2-hemN-desF operon. PMID- 24782317 TI - Initial experience of robot-assisted thoracoscopic surgery in China. AB - BACKGROUND: The objective of this study was to evaluate the safety and feasibility of robot-assisted thoracoscopic surgery (RATS). METHODS: From May 2009 to May 2013, 48 patients with intrathoracic lesions underwent RATS with the da Vinci(r) Surgical System was reported (11 lobectomies, 37 mediastinal tumour resections). RESULTS: RATS was successfully and safely completed in all 48 patients. Conversion of the operation to open surgery was not needed in any patient. The average operation time was 85.9 min, average blood loss 33 ml, and average hospital stay 3.9 days. No patient required blood transfusion. The only recognized adverse event was the development of a bronchopleural fistula in one patient. CONCLUSIONS: RATS appears feasible and safe in thoracic surgery. More investigation will be needed in order to determine its possible long-term benefits and cost effectiveness. PMID- 24782318 TI - Trend of histone deacetylase inhibitors in cancer therapy: isoform selectivity or multitargeted strategy. AB - Pharmacological inhibition of histone deacetylases (HDACs) has been successfully applied in the treatment of a wide range of disorders, including Parkinson's disease, infection, cardiac diseases, inflammation, and especially cancer. HDAC inhibitors (HDACIs) have been proved to be effective antitumor agents by various stages of investigation. At present, there are two opposite focuses of HDACI design in the cancer therapy, highly selective inhibitor strategy and dual- or multitargeted inhibitors. The former method, which is supposed to elucidate the function of individual HDAC and provide candidate inhibitors with fewer side effects, has been widely accepted by the inhibitor developer. The latter approach, though less practiced, has promising potential for the antitumor therapy based on HDACIs. Effective HDACIs, some of which are in clinic anticancer research, have been developed by both methods. In order to gain insight into HDACI design, the strategies and achievements of the two diverse methods are reviewed. PMID- 24782319 TI - Pilot study for reconstruction of soft tissues: muscle cross-sectional area of the forearm estimated from cortical bone for a Neolithic sample. AB - On a basis of a method for muscle cross-sectional area estimation from cortical bone area that was previously developed (Slizewski et al. Anat Rec 2013; 296:1695 1707), we reconstructed muscle cross-sectional area at 65% of radius length for a sample of Neolithic human remains from the Linear Pottery Culture (ca. 5,700 4,900 years BC). Muscle cross-sectional area estimations for the Neolithic sample were compared to in vivo measurements from a recent human sample. Results demonstrate that the Neolithic individuals had larger muscle cross-sectional area relative to radius length than the contemporary humans and that their forearms were more muscular and robust. We also found significant differences in relative muscle cross-sectional area between Neolithic and recent children that indicate different levels of physical stress and isometric activities. Our results fit into the framework of studies previously published about the sample and the Linear Pottery Culture. Therefore, the new approach was successfully applied to an archaeological sample for the first time here. Results of our pilot study indicate that muscle cross-sectional area estimation could in the future supplement other anthropological methods currently in use for the analysis of postcranial remains. PMID- 24782320 TI - Core-modified rubyrins containing dithienylethene moieties. AB - Two stable core-modified rubyrins bearing one and two dithienylethene (DTE) units (1 and 2) have been synthesized. With one "closed-form" DTE unit, 1 shows aromaticity associated with its conjugated circuit of 26 pi-electrons. In contrast, rubyrin 2 containing one "open-form" DTE unit has nonaromatic properties. PMID- 24782322 TI - Healthcare outcomes assessed with observational study designs compared with those assessed in randomized trials. AB - BACKGROUND: Researchers and organizations often use evidence from randomized controlled trials (RCTs) to determine the efficacy of a treatment or intervention under ideal conditions. Studies of observational designs are often used to measure the effectiveness of an intervention in 'real world' scenarios. Numerous study designs and modifications of existing designs, including both randomized and observational, are used for comparative effectiveness research in an attempt to give an unbiased estimate of whether one treatment is more effective or safer than another for a particular population.A systematic analysis of study design features, risk of bias, parameter interpretation, and effect size for all types of randomized and non-experimental observational studies is needed to identify specific differences in design types and potential biases. This review summarizes the results of methodological reviews that compare the outcomes of observational studies with randomized trials addressing the same question, as well as methodological reviews that compare the outcomes of different types of observational studies. OBJECTIVES: To assess the impact of study design (including RCTs versus observational study designs) on the effect measures estimated.To explore methodological variables that might explain any differences identified.To identify gaps in the existing research comparing study designs. SEARCH METHODS: We searched seven electronic databases, from January 1990 to December 2013.Along with MeSH terms and relevant keywords, we used the sensitivity-specificity balanced version of a validated strategy to identify reviews in PubMed, augmented with one term ("review" in article titles) so that it better targeted narrative reviews. No language restrictions were applied. SELECTION CRITERIA: We examined systematic reviews that were designed as methodological reviews to compare quantitative effect size estimates measuring efficacy or effectiveness of interventions tested in trials with those tested in observational studies. Comparisons included RCTs versus observational studies (including retrospective cohorts, prospective cohorts, case-control designs, and cross-sectional designs). Reviews were not eligible if they compared randomized trials with other studies that had used some form of concurrent allocation. DATA COLLECTION AND ANALYSIS: In general, outcome measures included relative risks or rate ratios (RR), odds ratios (OR), hazard ratios (HR). Using results from observational studies as the reference group, we examined the published estimates to see whether there was a relative larger or smaller effect in the ratio of odds ratios (ROR).Within each identified review, if an estimate comparing results from observational studies with RCTs was not provided, we pooled the estimates for observational studies and RCTs. Then, we estimated the ratio of ratios (risk ratio or odds ratio) for each identified review using observational studies as the reference category. Across all reviews, we synthesized these ratios to get a pooled ROR comparing results from RCTs with results from observational studies. MAIN RESULTS: Our initial search yielded 4406 unique references. Fifteen reviews met our inclusion criteria; 14 of which were included in the quantitative analysis.The included reviews analyzed data from 1583 meta-analyses that covered 228 different medical conditions. The mean number of included studies per paper was 178 (range 19 to 530).Eleven (73%) reviews had low risk of bias for explicit criteria for study selection, nine (60%) were low risk of bias for investigators' agreement for study selection, five (33%) included a complete sample of studies, seven (47%) assessed the risk of bias of their included studies,Seven (47%) reviews controlled for methodological differences between studies,Eight (53%) reviews controlled for heterogeneity among studies, nine (60%) analyzed similar outcome measures, and four (27%) were judged to be at low risk of reporting bias.Our primary quantitative analysis, including 14 reviews, showed that the pooled ROR comparing effects from RCTs with effects from observational studies was 1.08 (95% confidence interval (CI) 0.96 to 1.22). Of 14 reviews included in this analysis, 11 (79%) found no significant difference between observational studies and RCTs. One review suggested observational studies had larger effects of interest, and two reviews suggested observational studies had smaller effects of interest.Similar to the effect across all included reviews, effects from reviews comparing RCTs with cohort studies had a pooled ROR of 1.04 (95% CI 0.89 to 1.21), with substantial heterogeneity (I(2) = 68%). Three reviews compared effects of RCTs and case-control designs (pooled ROR: 1.11 (95% CI 0.91 to 1.35)).No significant difference in point estimates across heterogeneity, pharmacological intervention, or propensity score adjustment subgroups were noted. No reviews had compared RCTs with observational studies that used two of the most common causal inference methods, instrumental variables and marginal structural models. AUTHORS' CONCLUSIONS: Our results across all reviews (pooled ROR 1.08) are very similar to results reported by similarly conducted reviews. As such, we have reached similar conclusions; on average, there is little evidence for significant effect estimate differences between observational studies and RCTs, regardless of specific observational study design, heterogeneity, or inclusion of studies of pharmacological interventions. Factors other than study design per se need to be considered when exploring reasons for a lack of agreement between results of RCTs and observational studies. Our results underscore that it is important for review authors to consider not only study design, but the level of heterogeneity in meta-analyses of RCTs or observational studies. A better understanding of how these factors influence study effects might yield estimates reflective of true effectiveness. PMID- 24782321 TI - Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. AB - Somatic missense mutations can initiate tumorogenesis and, conversely, anti-tumor cytotoxic T cell (CTL) responses. Tumor genome analysis has revealed extreme heterogeneity among tumor missense mutation profiles, but their relevance to tumor immunology and patient outcomes has awaited comprehensive evaluation. Here, for 515 patients from six tumor sites, we used RNA-seq data from The Cancer Genome Atlas to identify mutations that are predicted to be immunogenic in that they yielded mutational epitopes presented by the MHC proteins encoded by each patient's autologous HLA-A alleles. Mutational epitopes were associated with increased patient survival. Moreover, the corresponding tumors had higher CTL content, inferred from CD8A gene expression, and elevated expression of the CTL exhaustion markers PDCD1 and CTLA4. Mutational epitopes were very scarce in tumors without evidence of CTL infiltration. These findings suggest that the abundance of predicted immunogenic mutations may be useful for identifying patients likely to benefit from checkpoint blockade and related immunotherapies. PMID- 24782325 TI - Synthesis of cyclobutenes and allenes by cobalt-catalyzed cross-dimerization of simple alkenes with 1,3-enynes. AB - Cobalt-catalyzed cross-dimerization of simple alkenes with 1,3-enynes is reported. A [2+2] cycloaddition reaction occurred, with alkenes bearing no allylic hydrogen, by reductive elimination of a eta(3)-butadienyl cobaltacycle. On the other hand, aliphatic alkenes underwent 1,4-hydroallylation by means of exo-cyclic beta-H elimination. These reactions can provide cyclobutenes and allenes that were previously difficult to access, from simple substrates in a highly chemo- and regioselective manner. PMID- 24782324 TI - Long-term safety of subcutaneous abatacept in rheumatoid arthritis: integrated analysis of clinical trial data representing more than four years of treatment. AB - OBJECTIVE: To investigate the safety of long-term subcutaneous (SC) abatacept treatment using integrated clinical trial data obtained in patients with rheumatoid arthritis refractory to traditional disease-modifying antirheumatic drugs. METHODS: Data from the double-blind and open-label phases of 5 clinical trials of SC abatacept were pooled. The overall and 6-month incidence rates were calculated as events per 100 patient-years of exposure. RESULTS: This analysis included 1,879 patients with 4,214.6 patient-years of exposure to SC abatacept. The mean +/- SD length of exposure was 27.3 +/- 9.1 months. The reported incidence rate of serious infections was 1.79 (95% confidence interval [95% CI] 1.42-2.24); the most frequent infections were pneumonia (incidence rate 0.36 [95% CI 0.22-0.59]), urinary tract infection (incidence rate 0.14 [95% CI 0.06-0.32]), and gastroenteritis (incidence rate 0.10 [95% CI 0.04-0.25]). Tuberculosis occurred rarely (incidence rate 0.09 [95% CI 0.04-0.25]). The reported incidence rate of malignancies was 1.32 (95% CI 1.01-1.72), and the most common was solid organ malignancy (incidence rate 0.69 [95% CI 0.48-0.99]). The incidence rate of autoimmune events was 1.37 (95% CI 1.06-1.78), and the most frequent events were psoriasis (incidence rate 0.33 [95% CI 0.20-0.56]) and Sjogren's syndrome (incidence rate 0.24 [95% CI 0.13-0.44]). The reported incidence rate of local injection site reactions was 1.72 (95% CI 1.36-2.17); these events occurred primarily during the first 6 months of treatment, and almost all were of mild or moderate intensity. The incidence rates of serious infections, malignancies, autoimmune events, and injection site reactions did not increase over time. CONCLUSION: Long-term treatment with SC abatacept was associated with low incidence rates of serious infections, malignancies, and autoimmune events and was well tolerated, with infrequent injection site reactions. These findings are consistent with those related to treatment with intravenous abatacept. Long-term treatment with SC abatacept did not lead to new safety signals over time. PMID- 24782323 TI - Mechanism of raloxifene-induced upregulation of glutamate transporters in rat primary astrocytes. AB - Raloxifene (RX), a selective estrogen receptor modulator (SERM), exerts neuroprotection in multiple clinical and experimental settings. Astrocytic glutamate transporters GLT-1 (EAAT2) and GLAST (EAAT1) are the main glutamate transporters in the central nervous system, taking up most of excess glutamate from the synaptic cleft to prevent excitotoxic neuronal death. Since drugs targeting astrocytic glutamate transporters to enhance their expression and function represent potential therapeutics for neurodegenerative disorders associated with excitotoxicity, we tested if RX modulates the expression and function of GLT-1 and GLAST in rat primary astrocytes. The results showed that RX significantly increased glutamate uptake and expression of GLT-1 mRNA and protein levels. RX enhanced GLT-1 expression by the activation of multiple signaling pathways including ERK, EGFR, and CREB mediated by estrogen receptors (ERs) ER alpha, ER-beta, and GPR30. At the transcriptional level, NF-kappaB played a critical role in RX-induced GLT-1 expression as RX increased NF-kappaB reporter activity and induced binding of NF-kappaB p65 and p50 to the GLT-1 promoter. RX attenuated the reduction of GLT-1 expression and glutamate uptake induced by manganese (Mn) whose chronic high levels of exposure cause manganism. RX also upregulated GLAST by increasing its promoter activity and protein levels via the NF-kappaB pathway and ERs. Our findings provide new insight into the mechanism of RX-induced enhancement of GLT-1 and GLAST expression, as well as the attenuation of Mn-reduced expression of these transporters. These findings will be highly valuable for developing therapeutics of neurodegenerative diseases associated with impaired astrocytic glutamate transporters. PMID- 24782326 TI - Antifungal catheter lock therapy for the management of a persistent Candida albicans bloodstream infection in an adult receiving hemodialysis. AB - Antifungal catheter lock therapy (AfLT) with liposomal amphotericin B has been used in the treatment of pediatric central line infections caused by Candida species; however, reports describing the use of liposomal amphotericin B lock therapy in the adult hemodialysis patient population are lacking. Management of central line-associated candidemia with systemic therapy alone is often challenging due to the propensity of Candida species to form biofilms on foreign bodies. We describe a 64-year-old woman who was receiving hemodialysis 3 times/week and was hospitalized with persistent fungemia. Despite receiving intravenous micafungin, she had multiple positive blood cultures for Candida albicans, which finally cleared after 7 days. Her double-lumen catheter was considered the most likely nidus of infection. Although catheter removal would have been preferred, this was not possible given her vasculopathy, history of multiple bloodstream infections, and lack of other available sites for vascular access. Catheter exchange was performed, and liposomal amphotericin B AfLT was administered in combination with intravenous micafungin for a total of 6 days. During this time, the patient experienced no discernible adverse effects secondary to AfLT. At discharge, AfLT was discontinued, and intravenous micafungin was changed to oral fluconazole. After 6 months of treatment, the patient remained culture negative and maintained her dialysis access. To our knowledge, this is the first case report of liposomal amphotericin B catheter lock therapy used to manage a persistent C. albicans bloodstream infection in an adult receiving hemodialysis. AfLT is a novel concept for treating catheter associated fungal infections. Liposomal amphotericin B was chosen based on its favorable in vitro activity against Candida species biofilms in catheter lock environments. We identified several barriers to implementing AfLT, and these issues may prohibit the use of AfLT. This case report illustrates the benefits and challenges of managing catheter-associated fungal infections with AfLT. Further study is required to examine the efficacy, safety, and feasibility of this approach. PMID- 24782328 TI - New candidate loci identified by array-CGH in a cohort of 100 children presenting with syndromic obesity. AB - Syndromic obesity is defined by the association of obesity with one or more feature(s) including developmental delay, dysmorphic traits, and/or congenital malformations. Over 25 syndromic forms of obesity have been identified. However, most cases remain of unknown etiology. The aim of this study was to identify new candidate loci associated with syndromic obesity to find new candidate genes and to better understand molecular mechanisms involved in this pathology. We performed oligonucleotide microarray-based comparative genomic hybridization in a cohort of 100 children presenting with syndromic obesity of unknown etiology, after exhaustive clinical, biological, and molecular studies. Chromosomal copy number variations were detected in 42% of the children in our cohort, with 23% of patients with potentially pathogenic copy number variants. Our results support that chromosomal rearrangements are frequently associated with syndromic obesity with a variety of contributory genes having relevance to either obesity or developmental delay. A list of inherited or apparently de novo duplications and deletions including their enclosed genes and not previously linked to syndromic obesity was established. Proteins encoded by several of these genes are involved in lipid metabolism (ACOXL, MSMO1, MVD, and PDZK1) linked with nervous system function (BDH1 and LINGO2), neutral lipid storage (PLIN2), energy homeostasis and metabolic processes (CDH13, CNTNAP2, CPPED1, NDUFA4, PTGS2, and SOCS6). PMID- 24782327 TI - Macrophage migration inhibitory factor inhibits the antiinflammatory effects of glucocorticoids via glucocorticoid-induced leucine zipper. AB - OBJECTIVE: Glucocorticoids remain a mainstay in the treatment of rheumatoid arthritis (RA). Dose-dependent adverse effects highlight the need for therapies that regulate glucocorticoid sensitivity to enable dosage reduction. Macrophage migration inhibitory factor (MIF) is a proinflammatory protein that has been implicated in the pathogenesis of RA; it impairs glucocorticoid sensitivity via MAPK phosphatase 1 (MKP-1) inhibition. The intracellular protein glucocorticoid induced leucine zipper (GILZ) mimics the effects of glucocorticoids in models of RA, but whether it represents a target for the modulation of glucocorticoid sensitivity remains unknown. We undertook this study to investigate whether GILZ is involved in the regulation of glucocorticoid sensitivity by MIF. METHODS: GILZ expression was studied in the presence and absence of MIF, and the role of GILZ in the MIF-dependent regulation of the glucocorticoid sensitivity mediator MKP-1 was studied at the level of expression and function. RESULTS: GILZ expression was significantly inhibited by endogenous MIF, both basally and during responses to glucocorticoid treatment. The effects of MIF on GILZ were dependent on the expression and Akt-induced nuclear translocation of the transcription factor FoxO3A. GILZ was shown to regulate the expression of MKP-1 and consequent MAPK phosphorylation and cytokine release. CONCLUSION: MIF exerts its effects on MKP-1 expression and MAPK activity through inhibitory effects on GILZ. These findings suggest a previously unsuspected interaction between MIF and GILZ and identify GILZ as a potential target for the therapeutic regulation of glucocorticoid sensitivity. PMID- 24782329 TI - European do-it-yourself (DIY) biology: beyond the hope, hype and horror. AB - The encounter of amateur science with synthetic biology has led to the formation of several amateur/do-it-yourself biology (DIYBio) groups worldwide. Although media outlets covered DIYBio events, most seemed only to highlight the hope, hype, and horror of what DIYBio would do in the future. Here, we analyze the European amateur biology movement to find out who they are, what they aim for and how they differ from US groups. We found that all groups are driven by a core leadership of (semi-)professional people who struggle with finding lab space and equipment. Regulations on genetic modification limit what groups can do. Differences between Europe and the US are found in the distinct regulatory environments and the European emphasis on bio-art. We conclude that DIYBio Europe has so far been a responsible and transparent citizen science movement with a solid user base that will continue to grow irrespective of media attention. PMID- 24782331 TI - The homology of the pelvic elements of Zygaspis quadrifrons (Squamata: Amphisbaenia). AB - Limb attenuation with element loss has occurred multiple times among the Squamata (lizards, snakes, and amphisbaenians). Although most of the attention has been focused on the appendicular bones, we found that the pelvic rudiments have been studied less thoroughly and recurring disagreement is common among different authors studying the same species. We studied the osteology of the pelvic region of female and male Zygaspis quadrifrons with high-resolution X-ray computed tomography data. We report an osteological landmark (acetabulum) not previously detected in this taxon, the presence of which has repercussions that call for a reconsideration of the primary homology hypothesis for the identity of these bones in amphisbaenians and other squamates. Finally, we observed that the acetabulum and limb rudiments in amphisbaenians (i.e., the stylopodium when present) are situated medial to the pelvic girdle, contrasting with the large majority of tetrapods where these structures are laterally oriented. PMID- 24782330 TI - Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats. AB - Oxidative stress is known to play a key role in estrogen-induced breast cancer. This study assessed the chemopreventive activity of the naturally occurring gamma tocopherol-rich mixture of tocopherols (gamma-TmT) in early stages of estrogen induced mammary hyperplasia in ACI rats. ACI rats provide an established model of rodent mammary carcinogenesis due to their high sensitivity to estrogen. Female rats were implanted with 9 mg of 17beta-estradiol (E2) in silastic tubings and fed with control or 0.3% gamma-TmT diet for 1, 3, 7, and 14 d. gamma-TmT increased the levels of tocopherols and their metabolites in the serum and mammary glands of the rats. Histological analysis revealed mammary hyperplasia in the E2 treated rats fed with control or gamma-TmT diet. gamma-TmT decreased the levels of E2-induced nitrosative and oxidative stress markers, nitrotyrosine, and 8-oxo-dG, respectively, in the hyperplastic mammary tissues. 8-Isoprostane, a marker of oxidative stress in the serum, was also reduced by gamma-TmT. Noticeably, gamma-TmT stimulated Nrf2-dependent antioxidant response in the mammary glands of E2 treated rats, evident from the induced mRNA levels of Nrf2 and its downstream antioxidant enzymes, superoxide dismutase, catalase, and glutathione peroxidase. Therefore, inhibition of nitrosative/oxidative stress through induction of antioxidant response is the primary effect of gamma-TmT in early stages of E2-induced mammary hyperplasia. Due to its cytoprotective activity, gamma-TmT could be a potential natural agent for the chemoprevention of estrogen-induced breast cancer. PMID- 24782332 TI - Catalytic asymmetric synthesis of 8-oxabicyclooctanes by intermolecular [5+2] pyrylium cycloadditions. AB - Highly enantioselective intermolecular [5+2] cycloadditions of pyrylium ion intermediates with electron-rich alkenes are promoted by a dual catalyst system composed of an achiral thiourea and a chiral primary aminothiourea. The observed enantioselectivity is highly dependent on the substitution pattern of the 5pi component, and the basis for this effect is analyzed using experimental and computational evidence. The resultant 8-oxabicyclo[3.2.1]octane derivatives possess a scaffold common in natural products and medicinally active compounds and are also versatile chiral building blocks for further manipulations. Several stereoselective complexity-generating transformations of the 8-oxabicyclooctane products are presented. PMID- 24782333 TI - Introduction to expert consensus statements for peripheral interventions from the Society for Cardiovascular Angiography and Interventions. PMID- 24782334 TI - Platelet-rich therapies for musculoskeletal soft tissue injuries. AB - BACKGROUND: Platelet-rich therapies are being used increasingly in the treatment of musculoskeletal soft tissue injuries such as ligament, muscle and tendon tears and tendinopathies. These therapies can be used as the principal treatment or as an augmentation procedure (application after surgical repair or reconstruction). Platelet-rich therapies are produced by centrifuging a quantity of the patient's own blood and extracting the active, platelet-rich, fraction. The platelet-rich fraction is applied to the injured tissue; for example, by injection. Platelets have the ability to produce several growth factors, so these therapies should enhance tissue healing. There is a need to assess whether this translates into clinical benefit. OBJECTIVES: To assess the effects (benefits and harms) of platelet-rich therapies for treating musculoskeletal soft tissue injuries. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (25 March 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013 Issue 2), MEDLINE (1946 to March 2013), EMBASE (1980 to 2013 Week 12) and LILACS (1982 to March 2012). We also searched trial registers (to Week 2 2013) and conference abstracts (2005 to March 2012). No language or publication restrictions were applied. SELECTION CRITERIA: We included randomised and quasi randomised controlled trials that compared platelet-rich therapy with either placebo, autologous whole blood, dry needling or no platelet-rich therapy for people with acute or chronic musculoskeletal soft tissue injuries. Primary outcomes were functional status, pain and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed each study's risk of bias. Disagreement was resolved by discussion or by arbitration by a third author. We contacted trial authors for clarification of methods or missing data. Treatment effects were assessed using risk ratios for dichotomous data and mean differences (MD) or standardised mean differences (SMD) for continuous data, together with 95% confidence intervals. Where appropriate, data were pooled using the fixed-effect model for RR and MD, and the random-effects model for SMD. The quality of the evidence for each outcome was assessed using GRADE criteria. MAIN RESULTS: We included data from 19 small single centre trials (17 randomised and two quasi-randomised; 1088 participants) that compared platelet-rich therapy with placebo, autologous whole blood, dry needling or no platelet-rich therapy. These trials covered eight clinical conditions: rotator cuff tears (arthroscopic repair) (six trials); shoulder impingement syndrome surgery (one trial); elbow epicondylitis (three trials); anterior cruciate ligament (ACL) reconstruction (four trials), ACL reconstruction (donor graft site application) (two trials), patellar tendinopathy (one trial), Achilles tendinopathy (one trial) and acute Achilles rupture surgical repair (one trial). We also grouped trials into 'tendinopathies' where platelet-rich therapy (PRT) injections were the main treatment (five trials), and surgical augmentation procedures where PRT was applied during surgery (14 trials). Trial participants were mainly male, except in trials including rotator cuff tears, and elbow and Achilles tendinopathies.Three trials were judged as being at low risk of bias; the other 16 were at high or unclear risk of bias relating to selection, detection, attrition or selective reporting, or combinations of these. The methods of preparing platelet-rich plasma (PRP) varied and lacked standardisation and quantification of the PRP applied to the patient.We were able to pool data for our primary outcomes (function, pain, adverse events) for a maximum of 11 trials and 45% of participants. The evidence for all primary outcomes was judged as being of very low quality.Data assessing function in the short term (up to three months) were pooled from four trials that assessed PRT in three clinical conditions and used four different measures. These showed no significant difference between PRT and control (SMD 0.26; 95% confidence interval (CI) -0.19 to 0.71; P value 0.26; I2 = 51%; 162 participants; positive values favour PRT). Medium-term function data (at six months) were pooled from five trials that assessed PRT in five clinical conditions and used five different measures. These also showed no difference between groups (SMD -0.09, 95% CI -0.56 to 0.39; P value 0.72; I2 = 50%; 151 participants). Long-term function data (at one year) were pooled from 10 trials that assessed PRT in five clinical conditions and used six different measures. These also showed no difference between groups (SMD 0.25, 95% CI -0.07 to 0.57; P value 0.12; I2 = 66%; 484 participants). Although the 95% confidence intervals indicate the possibility of a poorer outcome in the PRT group up to a moderate difference in favour of PRT at short- and long-term follow up, these do not translate into clinically relevant differences.Data pooled from four trials that assessed PRT in three clinical conditions showed a small reduction in short-term pain in favour of PRT on a 10-point scale (MD -0.95, 95% CI -1.41 to -0.48; I2 = 0%; 175 participants). The clinical significance of this result is marginal.Four trials reported adverse events; another seven trials reported an absence of adverse events. There was no difference between treatment groups in the numbers of participants with adverse effects (7/241 versus 5/245; RR 1.31, 95% CI 0.48 to 3.59; I2 = 0%; 486 participants).In terms of individual conditions, we pooled heterogeneous data for long-term function from six trials of PRT application during rotator cuff tear surgery. This showed no statistically or clinically significant differences between the two groups (324 participants).The available evidence is insufficient to indicate whether the effects of PRT will differ importantly in individual clinical conditions. AUTHORS' CONCLUSIONS: Overall, and for the individual clinical conditions, there is currently insufficient evidence to support the use of PRT for treating musculoskeletal soft tissue injuries. Researchers contemplating RCTs should consider the coverage of currently ongoing trials when assessing the need for future RCTs on specific conditions. There is need for standardisation of PRP preparation methods. PMID- 24782335 TI - Fosfomycin for the treatment of resistant gram-negative bacterial infections. Insights from the Society of Infectious Diseases Pharmacists. AB - The antimicrobial agent fosfomycin was discovered in 1969, at a time when bacteria had not yet developed extended-spectrum beta-lactamases or carbapenemases. Decades later, it is not uncommon for gram-negative organisms to be multidrug-resistant and even pan-resistant to available antibiotic regimens, leaving clinicians with few therapeutic alternatives. Because fosfomycin has been shown to retain activity against these virulent pathogens, there is renewed interest in its use as a therapeutic agent. Fosfomycin formulations including fosfomycin disodium and the newer tromethamine salt are less toxic than other alternatives and are attractive options for resistant gram-negative and gram positive infections. Oral fosfomycin tromethamine is approved for urinary tract infections in the United States, and an intravenous formulation is also available outside of the United States for systemic disease. The bactericidal action of fosfomycin occurs at an earlier step in cell wall synthesis than that of beta lactam antibiotics. From an in vitro standpoint, fosfomycin generally has high activity against ESBL- and carbapenemase-producing Enterobacteriaceae; multidrug resistant Pseudomonas aeruginosa susceptibility appears to be more dependent on the local antibiogram. Fosfomycin formulations have a large volume of distribution, penetrate biofilms, and concentrate in the urine. Both oral and intravenous fosfomycin formulations are effective for a wide range of gram negative infections and disease severities; however, clinical studies are limited. Fosfomycin formulations are well-tolerated, and mild gastrointestinal distress is the most common adverse effect. The primary limitations of fosfomycin are the lack of established regimens for complicated infections and the lack of availability of the intravenous formulation in the United States. Further study of this promising agent seems warranted in the current climate of antibiotic resistance. PMID- 24782336 TI - A new 3,5-bisporphyrinylpyridine derivative as a fluorescent ratiometric probe for zinc ions. AB - A new 3,5-disubstituted pyridine with two porphyrin moieties was prepared through an efficient synthetic approach involving 2-formyl-5,10,15,20 tetraphenylporphyrin (1), piperidine, and catalytic amounts of [La(OTf)3]. 3,5 Bis(5,10,15,20-tetraphenylporphyrin-2-ylmethyl)pyridine (2) was fully characterized and its sensing ability towards Zn(2+), Cu(2+), Hg(2+), Cd(2+), and Ag(+) was evaluated in solution by absorption and fluorescence spectroscopy and in gas phase by using matrix-assisted laser desorption/ionization (MALDI)-TOF mass spectrometry. Strong changes in the ground and excited state were detected in the case of the soft metal ions Zn(2+), Cd(2+), Hg(2+), and Cu(2+). A three metal-per-ligand molar ratio was obtained in all cases and a significant ratiometric behavior was observed in the presence of Zn(2+) with the appearance of a new band at 608 nm, which can be assigned to a metal-to-ligand charge transfer. The system was able to quantify 79 ppb of Zn(2+) and the theoretical calculations are in accordance with the stoichiometry observed in solution. The gas-phase sensorial ability of compound 2 towards all metal ions was confirmed by using MALDI-TOF MS and in solid state by using polymeric films of polymethylmethacrylate (PMMA) doped with ligand 2. The results showed that compound 2 can be analytically used to develop new colorimetric molecular devices that are able to discriminate between Hg(2+) and Zn(2+) in solid phase. The crystal structure of Zn(II) complex of 3,5-bisporphyrinylpyridine was unequivocally elucidated by using single-crystal X-ray diffraction studies. PMID- 24782337 TI - Identification of a novel de novo deletion in RAF1 associated with biventricular hypertrophy in Noonan syndrome. AB - Biventricular hypertrophy (BVH) is a disease state characterized by the thickening of the ventricle walls. The differential diagnosis of BVH with other congenital and familial diseases in which increased ventricle wall thickness is a prominent clinical feature is fundamental due to its therapeutic and prognostic value, mainly during infancy. We describe a 2-month-old infant presenting BVH. Using exome sequencing, we identified a novel de novo 3-bp deletion in the RAF1 gene that is located in the binding active site for the 14-3-3 peptide. Based on docking calculations, we demonstrate that this novel mutation impairs protein/target binding, thus constitutively activating Ras signaling, which is a dysregulation associated with Noonan syndrome. Finally, our study underlines the importance of molecular modeling to understand the roles of novel mutations in pathogenesis. PMID- 24782338 TI - Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. AB - OBJECTIVE: Because it has no unique clinical, biologic, or histologic features, reactive hemophagocytic syndrome may be difficult to distinguish from other diseases such as severe sepsis or hematologic malignancies. This study was undertaken to develop and validate a diagnostic score for reactive hemophagocytic syndrome. METHODS: A multicenter retrospective cohort of 312 patients who were judged by experts to have reactive hemophagocytic syndrome (n = 162), were judged by experts to not have reactive hemophagocytic syndrome (n = 104), or in whom the diagnosis of reactive hemophagocytic syndrome was undetermined (n = 46) was used to construct and validate the reactive hemophagocytic syndrome diagnostic score, called the HScore. Ten explanatory variables were evaluated for their association with the diagnosis of hemophagocytic syndrome, and logistic regression was used to calculate the weight of each criterion included in the score. Performance of the score was assessed using developmental and validation data sets. RESULTS: Nine variables (3 clinical [i.e., known underlying immunosuppression, high temperature, organomegaly], 5 biologic [i.e., triglyceride, ferritin, serum glutamic oxaloacetic transaminase, and fibrinogen levels, cytopenia], and 1 cytologic [i.e., hemophagocytosis features on bone marrow aspirate]) were retained in the HScore. The possible number of points assigned to each variable ranged from 0-18 for known underlying immunosuppression to 0-64 for triglyceride level. The median HScore was 230 (interquartile range [IQR] 203-257) for patients with a positive diagnosis of reactive hemophagocytic syndrome and 125 (IQR 91 150) for patients with a negative diagnosis. The probability of having hemophagocytic syndrome ranged from <1% with an HScore of <=90 to >99% with an HScore of >=250. CONCLUSION: The HScore can be used to estimate an individual's risk of having reactive hemophagocytic syndrome. This scoring system is freely available online (http://saintantoine.aphp.fr/score/). PMID- 24782339 TI - Genetic variations in SLC3A2/CD98 gene as prognosis predictors in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the risk of progression. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in the CD98 gene on prognosis of NSCLC patients. We genotyped three potential functional SNPs in CD98 gene using Sequenom iPLEX genotyping system in a cohort of 482 NSCLC patients. Multivariate cox proportional hazards model and Kaplan Meier curve were used for the survival analysis. The variant-containing genotypes of rs1059292 in 5'-flanking region of CD98 gene were significantly associated with an increased risk of death in the multivariate analysis (Hazard ratio [HR], 1.49; 95% confidence interval [95% CI]: 1.04-2.14 in a dominant model). In stratified analysis, the association remained significant in patients with poor differentiation (HR=1.81, 95% CI=1.01-3.25). In addition, rs1059292 also showed a borderline significant association with T stage (OR=1.49; 95% CI: 0.96-2.35) and N stage (OR=1.53; 95% CI: 0.98-2.39). Functional analysis demonstrated that variant genotype of SNP rs1059292 significantly enhanced the transcription activity of CD98 gene promoter. Our data suggest that genetic variation of rs1059292 in CD98 gene may affect clinical outcome of NSCLC in Chinese population. PMID- 24782341 TI - Comparative distribution and arrangement of Herbst corpuscles in the oropharynx of the ostrich (Struthio camelus) and emu (Dromaius novaehollandiae). AB - Herbst corpuscles are widely distributed throughout the oropharynx of the ostrich and emu in contrast to the general situation in birds. Knowledge of the comparative distribution of Herbst corpuscles in the oropharynx of these two commercially important ratite species may assist in a better understanding of their feeding habits. Tissue sections representing all parts of the oropharynx of five ostrich and five emu heads collected after slaughter were prepared for light microscopy, the Herbst corpuscles counted, and the relative percentage of corpuscles calculated for defined anatomical regions. Herbst corpuscles were more widespread in the oropharynx of the emu (where they were additionally found in the tongue and laryngeal mound) than in the ostrich but were absent from the pharyngeal folds in both species. The results further indicated that Herbst corpuscles were strategically located to aid in the handling and transport of food. In this context, the high concentration of Herbst corpuscles in the prominent median palatine and ventral ridges in the ostrich denote these structures as sensory organs, namely the palatal and interramal organs. The presence of these sensory organs, coupled with the higher relative percentage of Herbst corpuscles located on the rostral oropharyngeal floor, indicate that the part of the oropharynx caudal to the mandibular and maxillary rostra forms an important sensory region in the ostrich. Additionally, species-specific concentrations of Herbst corpuscles within the oropharynx were identified which appear to assist in the accurate positioning of the tongue and laryngeal mound for cleaning the choana (internal nares) after swallowing. PMID- 24782342 TI - Right heart catheterization from the arm: back to first principles. PMID- 24782340 TI - Keeping your armour intact: how HIV-1 evades detection by the innate immune system: HIV-1 capsid controls detection of reverse transcription products by the cytosolic DNA sensor cGAS. AB - HIV-1 infects dendritic cells (DCs) without triggering an effective innate antiviral immune response. As a consequence, the induction of adaptive immune responses controlling virus spread is limited. In a recent issue of Immunity, Lahaye and colleagues show that intricate interactions of HIV capsid with the cellular cofactor cyclophilin A (CypA) control infection and innate immune activation in DCs. Manipulation of HIV-1 capsid to increase its affinity for CypA results in reduced virus infectivity and facilitates access of the cytosolic DNA sensor cGAS to reverse transcribed DNA. This in turn induces a strong host response. Here, we discuss these findings in the context of recent developments in innate immunity and consider the implications for disease control and vaccine design. PMID- 24782343 TI - Catalytic enantioselective inverse electron demand hetero-Diels-Alder reaction with allylsilanes. AB - The first diastereo- and enantioselective inverse electron demand hetero-Diels Alder reaction of beta,gamma-unsaturated alpha-ketoesters with allylsilanes is described. Chiral copper(II) catalysts successfully activate the beta,gamma unsaturated alpha-ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes. PMID- 24782344 TI - A new proportion measure of the treatment effect captured by candidate surrogate endpoints. AB - The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut-off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non-captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half-range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints. PMID- 24782345 TI - Synostosis of the sacroiliac joint as a developmental variant, or ankylosis due to sacroiliitis? PMID- 24782346 TI - Conservative management following closed reduction of traumatic anterior dislocation of the shoulder. AB - BACKGROUND: Acute anterior dislocation, which is the most common type of shoulder dislocation, usually results from an injury. Subsequently, the shoulder is less stable and is more susceptible to re-dislocation, especially in active young adults. This is an update of a Cochrane review first published in 2006. OBJECTIVES: To assess the effects (benefits and harms) of conservative interventions after closed reduction of traumatic anterior dislocation of the shoulder. These might include immobilisation, rehabilitative interventions or both. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (September 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 8), MEDLINE (1946 to September 2013), EMBASE (1980 to Week 38, 2013), CINAHL (1982 to September 2013), PEDro (1929 to November 2012), OTseeker (inception to November 2012) and trial registries. We also searched conference proceedings and reference lists of included studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing various conservative interventions versus control (no or sham treatment) or other conservative interventions applied after closed reduction of traumatic anterior dislocation of the shoulder. DATA COLLECTION AND ANALYSIS: All review authors independently selected trials, assessed risk of bias and extracted data. Study authors were contacted for additional information. Results of comparable groups of trials were pooled. MAIN RESULTS: We included three randomised trials and one quasi-randomised trial, which involved 470 participants (371 male) with primary traumatic anterior dislocation of the shoulder reduced by various closed methods. Three studies evaluated mixed populations; in the fourth study, all participants were male and 80% were soldiers. All trials were at some risk of bias but to a differing extent. One was at high risk in all domains of the risk of bias tool, and one was at unclear or high risk in all domains; the other two trials were deemed to have predominantly low risk across all domains. Overall, reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be "very low" for all outcomes, meaning that we are very uncertain about the estimates of effect.The four trials evaluated the same comparison - immobilisation in external rotation versus internal rotation - and each of our three primary outcomes (re-dislocation, patient-reported outcome measures (PROMs) for shoulder instability and resumption of activities) was reported by one or more of the trials, with two-year or longer follow-up. Pooling was possible for "re-dislocation" (three trials) and for aspects of "resumption of sport/activities at pre-injury level" (two trials).There was no evidence to show a difference between the two groups in re-dislocation at two-year or longer follow-up (risk ratio (RR) 1.06 favouring internal rotation, 95% confidence interval (CI) 0.73 to 1.54; P value 0.77; 252 participants; three trials). In a low-risk population, with an illustrative baseline risk of 247 re-dislocations per 1000, these data equate to 15 more (95% CI 67 fewer to 133 more) re dislocations per 1000 after immobilisation in external rotation. In a medium-risk population, with an illustrative baseline risk of 436 re-dislocations per 1000, the data equate to 26 more (95% CI 118 fewer to 235 more) re-dislocations after immobilisation in external rotation.Nor was evidence found to show a difference between the two groups in return to pre-injury levels of activity at two-year or longer follow-up (RR 1.25 favouring external rotation, 95% CI 0.71 to 2.2; P value 0.43; 278 participants; two trials). In a low-risk population, with an illustrative baseline risk of 204 participants per 1000 returning to pre-injury levels of activity, this equates to 41 more (95% CI 59 fewer to 245 more) participants per 1000 resuming activity after immobilisation in external rotation. In a high-risk population, with an illustrative baseline risk of 605 participants per 1000 returning to pre-injury levels of activity, this equates to 161 more (95% CI 76 fewer to 395 more) participants per 1000 resuming activity after immobilisation in external rotation.One trial reported that the difference between the two groups in Western Ontario Shoulder Instability Index scores, analysed using non-parametric statistics, was "not significant (P = 0.32)". Of our secondary outcomes, pooling was possible for "any instability" (two trials) and for important adverse events (three events, two trials). However, adverse event data were collected only in an ad hoc way, and it is unclear whether identification and reporting of such events was comprehensive. No report addressed participant satisfaction or health-related quality of life outcome measures.There was no evidence confirming a difference between the two positions of immobilisation in any of the primary or secondary outcomes; for each outcome, the confidence intervals were wide, covering the possibility of substantial benefit for each intervention. AUTHORS' CONCLUSIONS: Numerous conservative strategies may be adopted after closed reduction of a traumatic anterior dislocation of the shoulder, and many warrant investigation. However, our review reveals that evidence from randomised controlled trials is only available for a single approach: immobilisation in external rotation versus immobilisation in the traditional position of internal rotation. Moreover, this evidence is insufficient to demonstrate whether immobilisation in external rotation confers any benefit over immobilisation in internal rotation.We identified six unpublished trials and two ongoing trials that compare immobilisation in external versus internal rotation. Given this, the main priority for research on this question consists of the publication of completed trials, and the completion and publication of ongoing trials. Meanwhile, increased attention to other interventions is required. Sufficiently powered, good quality, well reported randomised controlled trials with long-term surveillance should be conducted to examine the optimum duration of immobilisation, whether immobilisation is necessary at all (in older age groups particularly), which rehabilitative interventions work best and the acceptability to participants of different care strategies. PMID- 24782347 TI - Controlled synthesis of organic nanophotonic materials with specific structures and compositions. AB - Organic nanomaterials have drawn great interest for their potential applications in high-speed miniaturized photonic integration due to their high photoluminescence quantum efficiency, structural processability, ultrafast photoresponse, and excellent property engineering. Based on the rational design on morphological and componential levels, a series of organic nanomaterials have been controllably synthesized in recent years, and their excitonic/photonic behaviors has been fine-tuned to steer the light flow for specific optical applications. This review presents a comprehensive summary of recent breakthroughs in the controlled synthesis of organic nanomaterials with specific structures and compositions, whose tunable photonic properties would provide a novel platform for multifunctional applications. First, we give a general overview of the tailored construction of novel nanostructures with various photonic properties. Then, we summarize the design and controllable synthesis of composite materials for the modulation of their functionalities. Subsequently, special emphasis is put on the fabrication of complex nanostructures towards wide applications in isolated photonic devices. We conclude with our personal viewpoints on the development directions in the novel design and controllable construction of organic nanomaterials for future applications in highly integrated photonic devices and chips. PMID- 24782348 TI - Microduplication 10q24.31 in a Spanish girl with scoliosis and myopathy: the critical role of LBX. AB - LBX1 plays a cardinal role in neuronal and muscular development in animal models. Its function in humans is unknown; it has been reported as a candidate gene for idiopathic scoliosis. Our goal is to document the first clinical case of a microduplication at 10q24.31 (chr10:102927883-103053612, hg19), affecting exclusively LBX1. The patient, a 12-year-old girl, showed attention problems, dyspraxia, idiopathic congenital scoliosis, and marked hypotrophy of paravertebral muscles. Her paternal aunt had a severe and progressive myopathy with a genetic study that revealed the same duplication. We propose to consider genetic studies, particularly of LBX1, in patients with scoliosis and/or hypotrophy-hypoplasia of paravertebral muscles of unknown etiology. PMID- 24782349 TI - Evaluation of two-fold fully conditional specification multiple imputation for longitudinal electronic health record data. AB - Most implementations of multiple imputation (MI) of missing data are designed for simple rectangular data structures ignoring temporal ordering of data. Therefore, when applying MI to longitudinal data with intermittent patterns of missing data, some alternative strategies must be considered. One approach is to divide data into time blocks and implement MI independently at each block. An alternative approach is to include all time blocks in the same MI model. With increasing numbers of time blocks, this approach is likely to break down because of co linearity and over-fitting. The new two-fold fully conditional specification (FCS) MI algorithm addresses these issues, by only conditioning on measurements, which are local in time. We describe and report the results of a novel simulation study to critically evaluate the two-fold FCS algorithm and its suitability for imputation of longitudinal electronic health records. After generating a full data set, approximately 70% of selected continuous and categorical variables were made missing completely at random in each of ten time blocks. Subsequently, we applied a simple time-to-event model. We compared efficiency of estimated coefficients from a complete records analysis, MI of data in the baseline time block and the two-fold FCS algorithm. The results show that the two-fold FCS algorithm maximises the use of data available, with the gain relative to baseline MI depending on the strength of correlations within and between variables. Using this approach also increases plausibility of the missing at random assumption by using repeated measures over time of variables whose baseline values may be missing. PMID- 24782350 TI - Aspiration thrombectomy in patients undergoing primary angioplasty: totality of data to 2013. AB - OBJECTIVES: We sought to update our meta-analysis on clinical outcomes with aspiration thrombectomy prior to primary percutaneous coronary intervention (PPCI) compared with conventional PPCI alone due to the availability of additional trial data. BACKGROUND: The clinical efficacy of adjunctive aspiration thrombectomy in ST-elevation myocardial infarction (STEMI) patients undergoing PPCI remains controversial. A recent large-scale randomized trial showed no benefit in terms of mortality at 30 days. METHODS: Clinical trials that randomized STEMI patients to aspiration thrombectomy prior to PPCI compared with conventional PPCI alone were included. RESULTS: A total of 11,321 patients from 20 randomized controlled trials were included. The composite major adverse cardiac event (MACE) endpoint was lower in the aspiration thrombectomy arm compared with conventional PPCI alone (risk ratio [RR] = 0.81, 95% CI 0.70-0.94; P = 0.006). Although all-cause mortality was similar between the adjunctive aspiration thrombectomy arm and PPCI arms (RR = 0.83, 95% CI 0.67-1.01; P = 0.06), late mortality (6-12 months) was significantly reduced (RR = 0.64; 95% CI 0.44-0.92; P = 0.016). Reinfarction (RR = 0.64, 95% CI 0.44-0.92; P = 0.017) and stent thrombosis (RR = 0.54; 95% CI 0.32-0.91; P = 0.021) were similarly lower. Differences in target vessel revascularization were of borderline significance (RR = 0.83, 95% CI 0.68-1.01; P = 0.06). CONCLUSIONS: Our meta-analysis including all randomized controlled trials on aspiration thrombectomy to date demonstrates a significant reduction in adverse clinical outcomes including stent thrombosis compared with conventional PCI alone. PMID- 24782351 TI - Evidence of noncentrosymmetry of human tooth hydroxyapatite crystals. AB - Herein, we investigate human single hydroxyapatite crystals (enamel and dentine) by convergent-beam electron diffraction (CBED) and automated electron-diffraction tomography (ADT). The CBED pattern shows the absence of the mirror plane perpendicular to the c axis leading to the P63 space group instead of the P63 /m space group considered for larger-scale crystals, this is confirmed by ADT. This experimental evidence is of prime importance for understanding the morphogenesis and the architectural organization of calcified tissues. PMID- 24782352 TI - Biology of purinergic signalling: its ancient evolutionary roots, its omnipresence and its multiple functional significance. AB - The purinergic signalling system, which utilises ATP, related nucleotides and adenosine as transmitter molecules, appeared very early in evolution: release mechanisms and ATP-degrading enzymes are operative in bacteria, and the first specific receptors are present in single cell eukaryotic protozoa and algae. Further evolution of the purinergic signalling system resulted in the development of multiple classes of purinoceptors, several pathways for release of nucleotides and adenosine, and a system of ectonucleotidases controlling extracellular levels of purinergic transmitters. The purinergic signalling system is expressed in virtually all types of tissues and cells, where it mediates numerous physiological reactions and contributes to pathological responses in a variety of diseases. PMID- 24782353 TI - Stereological investigation of the age-related changes of the myelinated fibers in the hippocampus of male rats. AB - The decline of hippocampus-dependent learning and memory during normal aging is not associated with neuron death and synapse loss. Until now, age-related changes in the myelinated fibers of the hippocampus have not been investigated. Therefore, in this study, the myelinated fibers in the hippocampi of young (6 months), middle-aged (18 months), and old-aged (28 months) male Sprague-Dawley rats were studied with transmission electron microscope and stereological methods, following spatial learning tests in a Morris water maze. The results showed that hippocampus-dependent spatial learning was impaired in old-aged rats but that the total volume, length, and mean diameter of the myelinated fibers in the hippocampus, as well as the hippocampal volume, remained constant during the normal aging process. Our results suggest that the age-related decline in hippocampus-dependent spatial learning is not attributable to myelinated fiber changes in the hippocampus and that other, undetermined factors are responsible. PMID- 24782354 TI - Accessing the single-electron manifold: magnesium-mediated hydrogen release from silanes. AB - Reactions of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) with magnesium hydride species initiate oxidative hydrogen release, which may be elaborated to a catalytic regime within a manifold constructed about sequential TEMPO-mediated redox and Mg-O/Si-H metathesis processes. PMID- 24782355 TI - Intraoperative electrochemotherapy of colorectal liver metastases. AB - BACKGROUND AND OBJECTIVES: Electrochemotherapy is effective in treatment of various cutaneous tumors and could be translated into treatment of deep-seated tumors. With this aim a prospective pilot study was conducted to evaluate feasibility, safety, and efficacy of intraoperative electrochemotherapy in the treatment of colorectal liver metastases. METHODS: Electrochemotherapy with bleomycin was performed during open surgery, by insertion of long needle electrodes into and around the tumor according to the individualized pretreatment plan. RESULTS: A 29 metastases in 16 patients were treated in 16 electrochemotherapy sessions. No immediate (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed. Radiological evaluation of all the treated metastases showed 85% complete responses and 15% partial responses. In a group of seven patients that underwent a second operation at 6-12 weeks after the first one, during which electrochemotherapy was performed, the histology of resected metastases treated by electrochemotherapy showed less viable tissue (P = 0.001) compared to non-treated ones. CONCLUSIONS: Electrochemotherapy of colorectal liver metastases proved to be feasible, safe, and efficient treatment modality, providing its specific place in difficult to treat metastases, located in the vicinity of major hepatic vessels, not amenable to surgery or radiofrequency ablation. PMID- 24782356 TI - New population-based reference values for spinal mobility measures based on the 2009-2010 National Health and Nutrition Examination Survey. AB - OBJECTIVE: To report population-based percentile reference values for selected spinal mobility measures in a nationally representative sample of 5,001 US adults ages 20-69 years who were examined in the 2009-2010 US National Health and Nutrition Examination Survey (NHANES). METHODS: Occiput-to-wall distance (OWD), thoracic expansion (TE), and anterior lumbar flexion (ALF; by modified Schober test) were measured by trained examiners in a standardized manner. TE was measured at the xiphisternal level, while the lower reference point for ALF was a line marked at the level of the superior margin of the lateral iliac crests. We report reference values based on the 95th percentile for the OWD and the 5th percentile for TE and ALF, as well as other summary statistics for these measures, in the study population. RESULTS: An OWD of >0 was present in 3.8% of the participants, while 8.8% of them had out-of-range values for TE based on the commonly used threshold of 2.5 cm. The 95th percentile of the OWD measurement was 0, while the 5th percentile for TE and ALF were 1.9 cm and 2 cm, respectively. The spinal measures were significantly associated with sex, age, ethnicity, height, and body mass index (BMI). Exclusion of individuals with severe obesity (BMI >35 kg/m(2) ) changed the proposed reference values for TE and ALF to 2.2 cm and 1.9 cm, respectively. CONCLUSION: We verified a reference value of 0 for the OWD in the general population. Using the reported population-based percentile values, new reference values for TE and ALF can be derived. PMID- 24782357 TI - Systemic reactions and anaphylaxis with an acute serum tryptase >=14 MUg/L: retrospective characterisation of aetiology, severity and adherence to National Institute of Health and Care Excellence (NICE) guidelines for serial tryptase measurements and specialist referral. AB - AIMS: To characterise patients with systemic reactions and anaphylaxis with an acute serum tryptase of >=14 MUg/L against recently published World Allergy Organisation (WAO) diagnostic criteria. To also perform a clinical audit to assess adherence to National Institute of Health and Care Excellence (NICE) guideline recommendations regarding serial tryptase measurements and specialist referral. METHODS: A systematic retrospective survey (2006-2010) was carried out (n=171; males=86; mean age+/-SD 48+/-20 years) and data were extracted from emergency department and specialist allergy clinic records. RESULTS: 34 patients (20%) had a grade 1 reaction, 61 (36%) grade 2, 46 (27%) grade 3 and 6 patients (4%) grade 4 (24 patients (13%) could not be graded due to lack of adequate clinical details) and 6% developed a biphasic response. Serial tryptase measurements were not available in 117 (69%) of the cohort. 97 (57%) patients were referred for specialist assessment, and 72 (74%) attended. 50% of cases were diagnosed with idiopathic systemic reactions/anaphylaxis and 28%, 14% and 8% triggered by drugs, foods and other allergies including disorders of mast cell overload, respectively. A weak positive correlation was detected between acute serum tryptase and severity. CONCLUSIONS: The correlation between acute serum tryptase and severity of anaphylaxis/systemic reactions is weak. A significant proportion of patients with raised acute serum tryptase had mild reactions which did not meet WAO criteria for anaphylaxis and this may reduce the specificity of the test. The commonest aetiology in this cohort was idiopathic followed by drug and food allergies. NICE guidelines relating to serial tryptase measurements and specialist referral were not followed, and there is an urgent need to raise the awareness among clinicians involved in the management of anaphylaxis. PMID- 24782358 TI - A new class of powerful and informative simultaneous confidence intervals. AB - Step-down tests uniformly improve single-step tests with regard to power and the average number of rejected hypotheses. However, when extended to simultaneous confidence intervals (SCIs), the resulting SCIs often provide no additional information to the sheer hypothesis test. We speak, in this case, of a non informative rejection. Non-informative rejections are particularly problematic in clinical trials with multiple treatments, where an informative rejection is required to obtain useful estimates of the treatment effects. The extension of single-step tests to confidence intervals does not have this deficiency. As a consequence, step-down tests, when extended to SCIs, do not uniformly improve single-step tests with regard to informative rejections. To overcome this deficiency, we suggest the construction of a new class of simultaneous confidence intervals that uniformly improve the Bonferroni and Holm SCIs with regard to informative rejections. This can be achieved using a dual family of weighted Bonferroni tests, with the weights depending continuously on the parameter values. We provide a simple algorithm for these computations and show that the resulting lower confidence bounds have an attractive shrinkage property. The method is extended to union-intersection tests, such as the Dunnett procedure, and is investigated in a comparative simulation study. We further illustrate the utility of the method with an example from a real clinical trial in which two experimental treatments are compared with an active comparator with respect to non-inferiority and superiority. PMID- 24782359 TI - Techniques of monitoring blood glucose during pregnancy for women with pre existing diabetes. AB - BACKGROUND: Self-monitoring of blood glucose is recommended as a key component of the management plan for diabetes therapy during pregnancy. No existing systematic reviews consider the benefits/effectiveness of various techniques of blood glucose monitoring on maternal and infant outcomes among pregnant women with pre existing diabetes. The effectiveness of the various monitoring techniques is unclear. OBJECTIVES: To compare techniques of blood glucose monitoring and their impact on maternal and infant outcomes among pregnant women with pre-existing diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 August 2013), searched reference lists of retrieved studies and contacted trial authors. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing techniques of blood glucose monitoring including self blood glucose monitoring, continuous glucose monitoring (CGM) or clinic monitoring among pregnant women with pre-existing diabetes mellitus (Type 1 or Type 2). Trials investigating timing and frequency of monitoring were also included. Quasi-RCTs and RCTs using a cluster-randomised design were eligible for inclusion but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy. MAIN RESULTS: The search of the Pregnancy and Childbirth Group's Trials Register identified 21 trial reports. Following application of eligibility criteria, nine trials were included in this review. The included trials involved a total of 506 women (436 women with Type 1 diabetes and 70 women with Type 2 diabetes). All trials originated from European countries and the USA. None of the studies included women with gestational diabetes. Five of the nine included studies were at moderate risk of bias and four studies were at low to moderate risk of bias. Primary outcomes were maternal glycaemic control (fasting blood glucose and HbA1c) and infant birthweight or macrosomia.Various methods of glucose monitoring were compared in the trials. The following comparisons were included in the review: (1) self-monitoring versus standard care, (2) self-monitoring versus hospitalisation, (3) pre-prandial versus post-prandial glucose monitoring, (4) automated telemedicine monitoring versus conventional system, (5) CGM versus intermittent monitoring and (6) constant CGM versus intermittent CGM.Neither pooled analyses nor individual trial analyses showed any significant advantages of one monitoring technique over another for primary outcomes (maternal glycaemic control and infant birthweight) and secondary outcomes such as gestational age at birth or preterm birth, frequency of neonatal hypoglycaemia, death of baby including stillbirth, and neonatal intensive care admission. Primary outcome data on macrosomia were reported by one trial but at a different cut-off value than that pre-specified for the review. Secondary outcomes such as shoulder dystocia, major and minor anomalies were not reported by any of the trials. AUTHORS' CONCLUSIONS: This review found no evidence that any glucose monitoring technique is superior to any other technique among pregnant women with pre-existing Type 1 or Type 2 diabetes. The evidence base for the effectiveness of monitoring techniques is weak and additional evidence from large well-designed randomised trials is required to inform choices of glucose monitoring techniques. PMID- 24782360 TI - Comparison of electronic volume and forward scatter principles of cell selection using flow cytometry for the evaluation of acrosome and plasma membrane integrity of bull spermatozoa. AB - The objective of the study was to compare two different flow cytometers to reveal if there are differences between them and to find the most suitable protocol for analysis of spermatozoa. These two flow cytometers; Cell Lab QuantaTM and Coulter Epics XL, have different principles to calculate cell size, electric volume, and forward scatter (FS), respectively. Flow cytometry is a valuable tool to assess various spermatozoa quality traits simultaneously, such as plasma membrane and acrosome integrity. A double- and triple-stain combination was performed to compare evaluation of these two parameters by both flow cytometers and to assess the need of a fluorescent probe to identify the spermatozoa. Propidium iodide was used to assess the proportion of dead spermatozoa, whereas Alexa Fluor((r)) 488 conjugated peanut agglutinin (PNA- Alexa 488) was used to evaluate the percentage of acrosome intact and acrosome-reacted cells or degenerated cells. In the triple stain protocol, MitoTracker((r)) Orange (MO) was included to test the capacity of this probe to discriminate spermatozoa from egg yolk and debris particles present in the semen sample. Cryopreserved semen from 13 Norwegian Red bulls was included in the study and the semen was evaluated immediately after thawing and after 3 hr incubation at 37 degrees C. The results show that there is good agreement between the instruments. Nevertheless, a significant difference was found in percentages of acrosome intact live spermatozoa (% AIL) when including MO as a spermatozoa identification probe, compared to assessment without MO, with the Coulter Epics XL, while no significant difference was found when including the probe with the Cell Lab Quanta. In conclusion, the results show that cell size measurement based on electronic volume used by the Cell Lab Quanta flow cytometer is more accurate than FS used by the Coulter Epics XL flow cytometer in identification of spermatozoa. PMID- 24782362 TI - Single-electron/pericyclic cascade for the synthesis of dienes. AB - The highly efficient and diastereoselective synthesis of E dienes has been accomplished through radical cyclization of bromoallyl hydrazones. This methodology has been further extended to generate these products through a one pot condensation/radical cyclization/cycloreversion cascade from simple aldehyde starting materials in high yields (>75%) and high diastereoselectivities (>95:5). Mechanistic investigations suggest that the cascade reaction proceeds through a cyclic diazene intermediate prior to the cycloreversion. PMID- 24782361 TI - Linking an alpha-tocopherol derivative to cobalt(0) nanomagnets: magnetically responsive antioxidants with superior radical trapping activity and reduced cytotoxicity. AB - Covalent attachment of a phenolic antioxidant analogue of alpha-tocopherol to graphite-coated magnetic cobalt nanoparticles (CoNPs) provided a novel magnetically responsive antioxidant capable of preventing the autoxidation of organic materials and showing a reduced toxicity toward human cells. PMID- 24782363 TI - A validated LC-MS/MS assay for the quantitative determination of curdione in rabbit plasma and its application to a pharmacokinetic study after administration of zedoary turmeric oil and bioavailability of the oil. AB - A selective and sensitive liquid chromatography tandem mass spectrometry method was developed for the first time for the identification and quantification of curdione in rabbit plasma after vaginal drug administration and intravenous administration of zedoary turmeric oil (ZTO) solution (10 mg/kg). The analysis was performed on a triple-quadrupole tandem mass spectrometer with multiple reaction monitoring mode via electrospray ionization source in positive ionization mode. After mixing with internal standard diazepam, plasma samples were extracted with ethyl ether-acetic ether (1:1, v/v). Chromatographic separation was carried out on a C18 column with gradient elution using a mixture of water and acetonitrile (both containing 0.1% formic acid) as mobile phases. Linearity ranged over 1.06-106 and 10.6-530 ng/mL (r >= 0.995) with the lower limit of quantfication 1.06 ng/mL. The intra- and inter-day precision relative standard deviation values were <12% and the accuracy relative error was from 10.6 to -6.1% at all quality control sample levels. The method was applied to a study of the pharmacokinetics of curdione after vaginal drug administration and intravenous administration of ZTO. PMID- 24782364 TI - Radiation reduction in pediatric and adult congenital patients during cardiac catheterization. AB - OBJECTIVES: Our objective was to determine if technical changes combined with radiation safety initiatives reduced the radiation dose delivered to patients during congenital catheterization. BACKGROUND: Use of ionizing radiation is necessary during cardiac catheterization. Minimizing radiation dose, while maintaining clinically useful image quality, is an important safety issue. In our congenital heart center intentional practice changes, including technical changes and provider awareness initiatives, were implemented to decrease radiation dose. METHODS: Data were retrospectively collected for all procedures involving children and adults with congenital heart disease (CHD) undergoing catheterization over 45 months. Cases were divided into three categories including: noninterventional (NI), simple intervention (SI), and complex intervention (CI). The change in dose was modeled as log of cumulative air kerma (Ka,r ). The change in Ka,r was evaluated for each procedural category as well as changes occurring as a function of age and weight. RESULTS: Considering all procedures (n = 1,082), Ka,r decreased by 61%. In the NI group (n = 481), Ka,r decreased by 71%. In the SI group (n = 424), Ka,r decreased by 74%. The Ka,r for the 10-17 year old group (n = 125) and those >=18 years (n = 709) decreased 74 and 67%, respectively. The Ka,r decreased 72 and 66% for those 20-60 kg and >=60 kg, respectively. Groups not showing significant change in Ka,r included CI, age <=9 years, and weight <=20 kg. CONCLUSIONS: Through technical changes and provider awareness initiatives, our institution dramatically reduced the radiation dose in the majority of pediatric and adult CHD patients undergoing cardiac catheterization. PMID- 24782365 TI - [In vitro interaction of deferiprone with cellular membrane transporters of hOCTs and hOAT1]. AB - OBJECTIVE: To develop a LC-MS/MS method for determination of deferiprone in cell lysate and to study the potential interaction between deferiprone and hOCTs or hOAT1 transporters in vitro. METHODS: The determination was performed on an Agilent Eclipse Plus C18 column(3.5 MUm, 2.1 mm*50 mm).The gradient mobile phase was composed of solvent A:0.1% formic acid in water, and B:0.1% formic acid in acetonitrile. The mass spectrometer with an electrospray interface was operated in positive ion mode with multiple reaction monitoring (MRM) scan mode monitored the ion pair of deferiprone at m/z 140->96, or phenacetin at m/z 180->110. The effects of deferiprone on the accumulation of typical substrates of hOCTs and hOAT1 were evaluated by MDCK-hOCTs and MDCK-hOAT1 cells respectively. The accumulation of deferiprone was also investigated in MDCK-hOCTs cells and mock cells with or without typical inhibitors. RESULTS: The standard curve was linear over the range of 5-300 nmol/L. The assay recovery of deferiprone was above 94%, and the intra-day precision (RSD) was less than 2.0%. The accumulation of MPP(+) in MDCK-hOCTs cells with 300 MUmol/L deferiprone were 73.5%, 87.1% and 70.4%, respectively. The uptake of deferiprone in MDCK-hOCTs and mock cells did not show significant difference. Deferiprone of 100 MUmol/L did not significantly affect the accumulation of 6-CF in MDCK-hOAT1 cell. CONCLUSION: The method is sensitivity and suitable for the determination of deferiprone in cell lysate. Deferiprone can significantly inhibit hOCT1 and hOCT3, but has no effects on hOCT2 and hOAT1. hOCTs may not play a major role in the transport of deferiprone. PMID- 24782366 TI - [Simultaneous determination of madecassoside, asiaticoside and their aglycones in Centella asiatica (L.) urban extracts by RP-HPLC]. AB - OBJECTIVE: To establish a HPLC method for simultaneous determination of four major constituents (madecassoside, asiaticoside, madecassic acid and asiatic acid) in Centella asiatica (L.) urban extracts. METHODS: The analysis was performed on an Agilent 1100 HPLC system with a ZORBAX Eclipse XDB-C8 column (4.6 mm*150 mm, 5MUm). The four major constituents were separated with gradient mobile phase that consists of 1mmol/L potassium dihydrogen phosphate and acetonitrile at the detection wavelength of 205 nm. RESULTS: The four major constituents all had good linear response in the determination ranges (R(2)>=0.9998). The average recoveries (n=9) were 97.4%, 93.7%, 97.5% and 99.8% with RSDs of 3.4%, 1.4%, 4.7% and 4.4%, respectively. CONCLUSION: The developed method is sensitive and has good reproducibility, which can be used as a reference for quality control of Centella asiatica (L.) urban extracts. PMID- 24782367 TI - [Quantitative determination of voglibose contents in its tablets with high performance liquid chromatography-mass spectrometry]. AB - OBJECTIVE: To develop a method for determination of voglibose contents in its tablets by high-performance liquid chromatography-mass spectrometry (HPLC-MS). METHODS: The measurements were carried out on an Agilent ZORBAX Eclipse Plus C18 column (2.1*150mm 3.2MUm) with a temperature of 40 degrees Celsius. A mixture of methanol and water (2:3,v/v) was used as a mobile phase at a flow rate of 0.25 ml/min. Voglibose was detected in an electrospray ionization (ESI) mode with MRM. RESULTS: The calibration curves of voglibose showed good linearity in a range of 1.5804-2.6340 MUg/ml (r=0.9990). The average recovery was 100.2% with RSD of 1.37% (n=6) for m/z 268.2/74.2.Linearity was obtained with r=0.9976 and the average recovery was 99.3% with RSD of 1.78% (n=6) for m/z 268.2/92.2. CONCLUSION: HPLC-MS method is accurate,reproducible and can be used for quality control of voglibose tablets. PMID- 24782368 TI - [Determination of R(-)- isomer in repaglinide tablets by capillary electrophoresis]. AB - OBJECTIVE: To develop a capillary electrophoresis system for enantiomeric impurity test of repaglinide. METHODS: An uncoated fused silica capillary (50 MUm*50 cm, with an effective length of 41 cm) was used. The running buffer was composed of 30 mmol/L NaH2PO4 and 5 mg/ml carboxymethyl-beta-cyclodextrin(pH 3.5). RESULTS: Linear range was 2.00-80.00 MUg/ml (correlation coefficient was 0.9993). The average recovery rate was 92.5% to 105.0%. CONCLUSION: The method is simple, accurate and sensitive and it can be used for determination of enantiomeric impurities in repaglinide tablet. PMID- 24782369 TI - [Determination of enantiomeric impurity in levocetirizine tablets by capillary electrophoresis]. AB - OBJECTIVE: To determine enantiomeric impurity in levocetirizine tablets by using capillary electrophoresis. METHODS: The effects of pH and the concentrations of sulfated-Beta-cyclodextrin (S-Beta-CD) and buffer salt on chiral resolution were examined with S-Beta-CD as chiral selector. RESULTS: A good enantioseparation of cetirizine was achieved with 30 mmol/L NaH2PO4 buffer solution (pH 7.0) containing 20 g/L of S-Beta-CD. CONCLUSION: The method developed in the study is sensitive and reliable for determination of enantiomeric impurity in levocetirizine tablets. PMID- 24782370 TI - [Establishment of reverse-phase high-performance liquid chromatography with chiral reagent derivatization for separation of fexofenadine enantiomers]. AB - OBJECTIVE: To establish a precolumn chiral derivatization method for determination of fexofenadine enantiomers, a chiral substrate of OATP1B1, in cellular model. METHODS: R-(+)-phenylethyl isocyanate was selected as chiral derivatization reagent, which was reacted with fexofenadine to form carbamate derivatives. Enantiomers were identified by LC/MS and separated by RP-HPLC. RESULTS: Under the experimental conditions, the fexofenadine enantiomers were separated completely. The standard curve was linear over the concentration range of 25-100 ng/ml (R(2)=0.9992, 0.9989). Accuracy was 101.1% and 98.3%, intra precision was 2.4% and 3.1%, inter-precision was 3.1% and 4.0% for D1 and D2, respectively. CONCLUSION: The method established is sensitive and accurate for determination of fexofenadine enantiomers in cells. PMID- 24782371 TI - [Determination of enantiomeric impurity of timolol maleate in bulk substances and eye drops]. AB - OBJECTIVE: To determine the enantiomeric impurity contents of domestic timolol maleate in bulk drugs and eye drops. METHODS: Enantiomer impurity of timolol was assayed by chiral high performance liquid chromatography. The chromatographic conditions were as follows:chiralcel OD chiral column (4.6 mm *150 mm, 5MUm), detection wavelength:297 nm, mobile phase:hexane-isopropanol-diethylamine (480:20:1), column temperature:25 C, flow rate:1.0 ml/min, sample injection volume:5 MUl. RESULTS: The resolution between R- and S-timolol was more than 4. The enantiomeric impurity contents were less than 0.67% on average in two batches of timolol maleate bulk drugs, and 0.31% on average in three batches of timolol maleate eye drops. CONCLUSION: Enantiomeric impurity contents in each batch of products all meet European Pharmacopoeia criteria, which can be used as references in Chinese Pharmacopoeia criteria. PMID- 24782372 TI - [Enantiomeric separation and impurity determination of valaciclovir hydrochloride]. AB - OBJECTIVE: To determine the contents of L-enantiomer impurity in valaciclovir hydrochloride. METHODS: Valaciclovir enantiomers were separated and determined by using chiral high performance liquid chromatography. Chromatographic conditions were as follows:CROWNPAK((r)) CR(+) chiral column (4 mm*150 mm, 5 MUm), detection wavelength:254 nm, mobile phase:water-methanol-perchloric acid (19:1:0.1), flow rate:0.75 ml/min, sample injection volume:10 MUl. RESULTS: D-valaciclovir was completely separated from L-enantiomer impurity. The contents of L-enantiomer impurity were 0.65%-2.62% on average in 8 batches of valaciclovir hydrochloride. CONCLUSION: Enantiomeric impurity contents in each batch of products were all meet criteria of United States Pharmacopeia, which can be used in criteria of Chinese Pharmacopeia as references. PMID- 24782373 TI - [Expression of human glutathione S-transferase A1, P1 and T1 in Escherichia coli]. AB - OBJECTIVE: To construct the vectors of human glutathione S-transferase A1 (GSTA1), P1 (GSTP1), T1(GSTT1) genes and express in Escherichia coli (E. coli). METHODS: Human GSTA1, GSTP1 and GSTT1 gene whole length cDNAs were amplified by RT-PCR and then subcloned into pET-28a(+) vectors. The proteins were expressed in E. coli BL21(DE3). After purified by Ni2+ affinity chromatography, the enzymatic activities of GSTs were measured with 1-chloro-2,4 -dinitrobenzene (CDNB) as substrate. RESULTS: The correct GSTA1, GSTP1 and GSTT1 genes were cloned. And soluble GSTA1, GSTT1, GSTP1 proteins were expressed in E.coli. After purification, GSTA1, GSTT1 and GSTP1 showed good enzymatic activities, which were 17.55, 0.02, 18.75 MUmol.min-1.mg-1, respectively. CONCLUSION: The expression plasmids for GSTA1, GSTT1 and GSTP1 have been constructed and the recombinant proteins are expressed successfully. PMID- 24782374 TI - [Purification of polyphenols from Sabina vulgaris antoine and its antioxidant properties]. AB - OBJECTIVE: To purify polyphenols from Sabina vulgaris and to investigate its antioxidant properties. METHODS: Polyphenols were purified from Sabina vulgaris Antoine with macroporous resin HPD-700, and the quantity of polyphenols was determined by Folin-Ciocalteu colorimetry. The antioxidant properties of polyphenols were evaluated by total antioxidant capacity (T-AOC) and its activities of scavenging DPPH (1,1 diphenyl-2-picry-hydrazyl) radicals, superoxide anion (O2.-), hydroxyl free radicals (OH.) and ferric reducing antioxidant power (FRAP). RESULTS: After purification, the purity of polyphenols increased from 0.053% to 0.995%.The antioxidant properties study showed that its inhibition rate of scavenging DPPH radicals and FRAP was 151.83 U/ml and 204.59 U/ml. Its scavenging capacity for superoxide anion (O2.-) and hydroxyl free radicals (OH.) was 151.83 U/ml and 204.59 U/ml. The total antioxidant capacity was 72.68 U/ml. CONCLUSION: Polyphenols from Sabina vulgaris Antoine have high antioxidant properties, suggesting that it worth further study of its pharmacological effects. PMID- 24782375 TI - [Highly active antiretroviral therapy on liver function in HIV-positive children with HBV/HCV co-infection]. AB - OBJECTIVE: To assess changes of liver function in HIV-positive children with/without HBV/ HCV co-infection after 1 year of highly active antiretroviral therapy (HARRT). METHODS: Seventy-eight pediatric AIDS patients with HBV/HCV co infection,19 pediatric AIDS patients with HBV co-infection and 44 pediatric AIDS patients without HBV/HCV co-infection who received HAART at least for 1 year were enrolled. HIV-1 viral load was quantitatively detected using a standardized reverse transcriptase-polymerase chain reaction assay, and blood cells were determined by three-color flow cytometry. Anti-HCV antibody and HBsAg was detected using an enzyme-linked immunosorbent technique, and ALT, AST and TBIL were detected by automatic biochemical analyzer. RESULTS: After 1 year-HAART, the viral load was decreased to the lowest limit of detection in 90.34% patients (t=2.61, P<0.01), and CD4+ T cell counts were increased from 170.187+/-132.405/ MUl to 796.014+/-158.491/ MUl (t=3.17, P<0.01). The levels of ALT and AST were elevated (t=2.02, P<0.05), while the ALT and AST levels in patients receiving nevirapine (NVP) based HAART increased from 18.28+/-13.74 U/L and 24.23+/-8.09 U/L to 55.35+/-22.40 U/L and 69.97+/-26.72 U/L, respectively(t=3.80,t=4.11;Ps<0.01). The increment of ALT and AST in NVP based HAART were significantly higher than that in the efavirenz based HAART (ALT:46.28+/-13.35 U/L vs 37.70+/-15.25 U/L and AST:19.53+/-7.23 U/L vs 1.25+/ 0.21 U/L, respectively; t=4.53, t=5.79; Ps<0.01), particularly in patients co infected with HIV/HBV/HCV (ALT:54.32+/-22.85 U/L vs 16.89+/-14.42 U/L and AST:41.71+/-19.26 U/L vs -3.44+/-15.59 U/L, respectively; t=3.42, t=2.98, Ps<0.01). CONCLUSION: HARRT can repress HIV-1 replication effectively, but it also cause the damage of liver function, especially in patients with HBV and/or HCV co-infection. PMID- 24782376 TI - [Screening and detection of patients with macroprolactinemia by application of polyethylene glycol precipitation method]. AB - OBJECTIVE: To establish a polyethylene glycol (PEG6000) precipitation method for screening macroprolactinemia in patients with high serum prolactin (PRL). METHODS: PEG6000 precipitation method was used to remove macroprolactin (MPRL) molecules in serum of PRL-elevated patients. The effect of PEG6000 precipitating serum MPRL was determined by Sephacryl S-100HR chromatography plus chemiluminescent immunoassay and SDS-PAGE plus Western Blot assay. The PEG6000 precipitation plus chemiluminescent immunoassay was applied to screen serum samples of PRL-elevated patients for macroprolactinemia. The clinical manifestations of patients with true-hyperprolactinemia, hyperprolactinemia/macroprolactinemia or true-macroprolactinemia were analyzed and compared. RESULTS: After precipitation with PEG6000, MPRL peak or hybridization signal in the serum samples was markedly decreased, while the big or small prolactin (BPRL or SPRL) levels were not affected. In 1538 PRL-elevated patients, 16.1% (247/1538) were detectable for macroprolactinemia, while the 83.9% (1291/1538) were identified as true-hyperprolactinemia. In 247 samples of macroprolactinemia, 93.5% (231/247) were determined as true-macroprolactinemia, while 6.5% (16/247) were identified as hyperprolactinemia plus macroprolactinemia. In 508 true-hyperprolactinemia patients, menoxenia, menolipsis/menostasia, dysgenesia or hypophysoma were manifested in 438 (86.2%), which were also manifested in 85.7% (6/7) of hyperprolactinemia/macroprolactinemia patients. However, only 11 cases in 71 true macroprolactinemia patients (15.5%) presented above clinical diseases. CONCLUSION: There is a certain proportion of true-macroprolactinemia (pseudo hyperprolactinemia) in serum PRL-elevated patients. The PEG6000 precipitation method established in this study can efficiently distinguish true hyperprolactinemia from pseudo-hyperprolactinemia in patients. PMID- 24782377 TI - [Construction and identification of lentiviral vector containing human ILK-shRNA and mda7 gene]. AB - OBJECTIVE: To construct and identify lentiviral vector containing human ILK-shRNA and mda7 gene. METHODS: Based on the human ILK gene sequences, RNAi target sequences were designed and cloned into the lentiviral vector pSicoR-eGFP by restriction endonuclease HpaI and XhoI double digestion and T4 DNA ligase ligation. Based on the human mda7 gene sequences, PCR primers were designed to clone the full-length mda7, and were cloned into the lentiviral vector pLVX-Puro. After the candidate clones were identified by DNA sequencing, the recombinant plasmid and the three packaging plasmids were co-transfected into the human embryonic kidney 293T cells by lipofectamine 2000 to produce the lentiviral particles. Human prostate cancer PC-3 cells were infected with the constructed lentiviral vector. The ILK and mda7 expression levels in PC-3 cells were quantified by qPCR and Western blot, respectively. The effect of ILK and mda7 on proliferation and migration of PC-3 cells were assessed by MTT method and Transwell assay, respectively. RESULTS: ILK-pSicoR-eGFP and mda7-pLVX-Puro lentiviral vectors were successfully constructed. Strong green fluorescence was observed in the 293T cells under the fluorescent microscope after co-transfection of 293T cells with 4 plasmids of lentiviral vector. The transfection efficiency of the collected virus exceeded 90% in the 293T cells and the PC-3 cells were infected with the lentiviral particles with high efficiency. The A and B lentiviral vector inhibited the expression of ILK at both the mRNA and protein levels in PC-3 cells significantly. The mda7-pLVX-Puro lentiviral vector increased the expression of mda7 in PC-3 cells, and the ability was maintained for one month. Within 96 h, ILK and mad7 significantly inhibited the proliferation and migration of PC-3 cells (Ps<0.05). CONCLUSION: The lentiviral vectors of ILK knockdown and mda7 over-expression have been successfully constructed and identified. The recombinant lentivirus can efficiently infect human prostate cancer PC-3 cells, in which ILK expression is inhibited and mda7 is over-expressed. PMID- 24782378 TI - [Role of Toll-like receptor 2/4-nuclear factor-kappaB signaling pathway in invasion of Mycobacterium tuberculosis to mouse dendritic cells]. AB - OBJECTIVE: To investigate the mechanism of Mycobacterium tuberculosis invasion to mouse dendritic cells (DC). METHODS: Mycobacterium tuberculosis strain H37Rv was co-cultured with mouse DC2.4 cells.The mRNA expression of Toll-like receptor 2/4(TLR2/4) in DC2.4 cells was detected by fluorescent quantitative real-time PCR and the protein expression of nuclear factor kappaB(NF-kappaB) was assessed by Western blotting.The extracellular concentration of tumor necrosis factor alpha(TNF-alpha) was measured by ELISA methods during Mycobacterium Tuberculosis invasion.Indirect immunofluorescent staining and flow cytometry assay were used to detect the expression of CD80 and CD86 on DC2.4 cells before and after invasion. RESULTS: The invasion of Mycobacterium tuberculosis in DC2.4 cells was observed after 2 h of co-incubation.The rates of invasion were (37.9+/ 5.6)%,(51.2+/-7.6)%,(57.2+/-8.9)% and(63.9+/-6.8)% at 6,8,10 and 12 h after co incubation,respectively.The mRNA expression level of TLR2 /4 was significantly increased at 6 h but decreased at 10 h after co-incubation.The expressions of NF kappaB p65 and TNF-alpha were higher in DC2.4 cells after being invaded by 6,8,and 10 h and then gradually decreased.CD80 and CD86 expression were increased on DC2.4 at 6 h after co-incubation. CONCLUSION: Invasion of Mycobacterium tuberculosis strain H37Rv to DC might enhance its antigen-presenting function through activation of TLR2/4-NF-kB signaling pathway. PMID- 24782379 TI - [Value of quality of life evaluation in prognosis of chronic obstructive pulmonary disease]. AB - OBJECTIVE: To evaluate the quality of life in patients with chronic obstructive pulmonary disease (COPD) by COPD Assessment Test (CAT) and Body Mass Index, Airflow Obstruction, Dyspnea, Exercise Capacity Index (BODE). METHODS: One hundred patients with stable COPD admitted in Putuo People's Hospital were recruited in the study. CAT and BODE index were measured for each patient.The deaths and frequency of exacerbations were recorded during 3-year follow-up period,and the correlation between CAT and BODE in evaluating COPD prognosis was analyzed. RESULTS: There were 28, 30, 29 and 13 patients with CAT score of 1, 2, 3 and 4, respectively; while there were 31, 29, 28 and 12 cases with BODE scores of 1, 2, 3 and 4. CAT scores were well correlated with BODE evaluation in terms of overall score and scores of 4 items (r= -0.237, -0.772, 0.789, -0.767, 0.888, respectively, Ps<0.05). COPD exacerbation incidence and mortality increased with the increasing CAT levels. The rank sum test showed that there were no significant differences between CAT and BODE index in the frequency of acute exacerbation(P<0.05); and in the death toll, the difference was not significant(1 group Chi2=0.919, 2 group Chi2=0.001, 3 group Chi2=0.177,4 group Chi2=0.322, Ps>0.05). CONCLUSION: CAT is relevant to BODE in evaluating incidence of exacerbation and mortality for patients with COPD and CAT is more easily to be applied. PMID- 24782380 TI - [Epidemiological investigation of hand-foot-and-mouth disease in children and exposed population in Hangzhou city]. AB - OBJECTIVE: To investigate the epidemic characteristics of hand-foot-and-mouth disease (HFMD) in children and exposed population in Hangzhou city. METHODS: The throat swab or stool samples from children with HFMD admitted in Hangzhou Children's Hospital were collected. The HFMD pathogens were detected by real-time fluorescent quantitative PCR. The distribution of different HFMD pathogens in HFMD patients was subsequently determined. Human enteric virus type-71 (HEV71) in stool samples from subjects, who had close or general contact to 54 severe HFMD children with positive HEV71, was detected, and these contact persons were followed-up for one month. The diversity of predominant pathogens of HFMD in the area during 2011-2013 was investigated. RESULTS: In 641 HFMD children, the male/female ratio was 1.4:1 and 80.3% was 1-3 years old. HEV71 was detected in 24.3% HFMD children (156/641), while coxsackievirus group-A type-16 (CVA16) and other enteroviruses were detected in 4.7% (30/641) and 71.0% (455/641) of the cases, respectively. 75.6% (118/156) of HEV71-infected cases were diagnosed as severe HFMD cases, while those for CVA16-infected and other HFMD viruses-infected were 13.3% (4/30) and 6.2% (28/455) respectively (Chi(2)=43.28, P<0.05). HEV71 was the predominant HFMD pathogens during 2011-2012, while the predominant HFMD pathogens in 2013 were the other HFMD viruses. In the 54 close contact persons or 54 general contact persons, 9 or 10 persons were detectable for HEV71, but no clinical symptoms of HFMD were presented. CONCLUSION: There are no marked changes of epidemic seasons, favorable age and gender ratio of HFMD in Hangzhou area in 2013. The infection of HEV71 tends to cause the severe HFMD but the other enteroviruses have substituted HEV71 as the predominant pathogens of HFMD. PMID- 24782381 TI - [Research progress on biological toxicity of zinc oxide nanoparticle and its mechanism]. AB - Zinc oxide nanoparticle (nano-ZnO) has a size between 1 and 100 nm. Nano-ZnO has some special effects, such as small size effect, surface effect, quantum size effect, which makes it different from the ordinary ZnO, and is widely used in rubber industry, food processing, cosmetics and pharmaceutical fields. It has been reported that nano-ZnO has toxic effects in vitro and in vivo, but the mechanism of toxicity is still unclear. Therefore, it is important to evaluate the safety nano-ZnO by studying its biological toxic effects and related mechanisms. In this paper, we summarize the characterization, ingestion pathway, metabolism, systematic toxicity of nano-ZnO and its mechanisms, which may provide us with new strategy for the toxic research of nano-ZnO. PMID- 24782382 TI - [Advances in genes and molecular markers of pheochromocytoma]. AB - Pheochromocytoma is a tumor derived from chromaffin tissue in the adrenergic system with excessive secretion of catecholamine.Pheochromocytoma occurs at any age of patients,commonly in 40-60 years,and the incidence is slightly higher in women than in men.In recent years,studies have shown that the mutations of von Hippel-Lindau gene (VHL),rearranged during transfection gene (RET),neurofibromatosis type 1 gene (NF-1),succinate dehydrogenase gene (SDH),transmembrane protein 127 gene (TMEM127),myelocytomatosis oncogene associated factor X gene (MAX) are associated with pheochromocytoma.Immunohistochemical studies have revealed that a number of molecular markers,such as telomerase,vascular endothelial growth factor,cyclooxygenase-2,adrenomedullin,plasma chromaffin protein A,signal transducer and activator of transcription-3 are of value in identification of tumor origin,its biological behaviors and differentiation of pheochromocytoma. This article reviews the newest research progresses in molecular biology of pheochromocytoma. PMID- 24782383 TI - [Research advances on the roles of nicotinamide phosphoribosyltransferase in inflammation]. AB - Nicotinamide phosphoribosyltransferase (Nampt) is also called visfatin or pre-B cell colony-enhancing factor. The functions of Nampt have been reported as a cytokine, an adipokine and the rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis. As a pleiotropic multifunctional protein, Nampt is involved in a variety of physiological and pathological conditions including innate immunity, metabolic disorders, and stress; and Nampt also participates in inflammatory disorders such as acute lung injury, atherosclerosis, myocardial infarct, obesity, type 2 diabetes, and rheumatoid arthritis. The studies indicate that Nampt might be a potential target for pharmacological intervention against inflammatory diseases. We review research advances on the roles of Nampt in inflammation. PMID- 24782384 TI - [Design of a satisfaction evaluation indicator system based on patients' experience of medical services]. AB - OBJECTIVE: To construct a satisfaction evaluation indicator system based on patients' experiences of medical services. METHODS: A questionnaire was designed by expert interview and literature review and 400 copies were randomly handed out to inpatients and outpatients from five 3A-public hospitals in Shanghai. The patient's evaluation of importance of various factors in medical services was analyzed and the mean and weight of indicators in terms of recognition, importance and evaluation were determined to establish a satisfaction evaluation indicator system. RESULTS: A total of 396 valid questionnaires were retrieved, with an effective response rate of 99%. By analyzing survey data, the patient satisfaction evaluation indicator system was constructed with 5 primary indicators (hospital environment, medical procedures, attitude, and quality of care and patient rights) and 25 secondary indicators (convenient hospital environment, auxiliary facilities, reasonable arrangement, clearly mark, convenient appointment, simple procedures, short time, the attitude of medical staff, solutions of medical dispute, medical technology, treatment, medical equipment, medical expenses, respect, patient privacy, etc.). CONCLUSION: A patient satisfaction evaluation indicator system has been established based on patients' experience of medical services in the study, which may be applicable to measure patients' satisfaction and to improve medical services in hospitals. PMID- 24782385 TI - [Outcome mapping for decision-making in health system]. AB - Outcome mapping (OM) is a participant-oriented new method for project planning,monitoring and evaluation.It is based on continuous learning and focuses on changes in behavior,relationship and activities of persons,groups and organizations.The use of OM can help to clarify the roles and assignments of the government,managers,health workers,and other relevant personnel,making full use of the limited social resources and improving the efficiency and quality of health services.We introduce the principle and operation steps of OM with case simulation in health resource integration,to show its application in decision making. PMID- 24782386 TI - [Development of expert diagnostic system for common respiratory diseases]. AB - OBJECTIVE: To develop an internet-based expert diagnostic system for common respiratory diseases. METHODS: SaaS system was used to build architecture; pattern of forward reasoning was applied for inference engine design; ASP.NET with C# from the tool pack of Microsoft Visual Studio 2005 was used for website interview medical expert system.The database of the system was constructed with Microsoft SQL Server 2005. RESULTS: The developed expert system contained large data memory and high efficient function of data interview and data analysis for diagnosis of various diseases.The users were able to perform this system to obtain diagnosis for common respiratory diseases via internet. CONCLUSION: The developed expert system may be used for internet-based diagnosis of various respiratory diseases,particularly in telemedicine setting. PMID- 24782387 TI - Prevention of esophagopharyngeal reflux by augmenting the upper esophageal sphincter pressure barrier. AB - OBJECTIVES/HYPOTHESIS: Incompetence of the upper esophageal sphincter (UES) is fundamental to the occurrence of esophagopharyngeal reflux (EPR), and development of supraesophageal manifestations of reflux disease (SERD). However, therapeutic approaches to SERD have not been directed to strengthening of the UES barrier function. Our aims were to demonstrate that EPR events can be experimentally induced in SERD patients and not in healthy controls, and ascertain if these events can be prevented by application of a modest external cricoid pressure. STUDY DESIGN: Individual case control study. METHODS: We studied 14 SERD patients (57 +/- 13 years, 8 females) and 12 healthy controls (26 +/- 3 years, 7 females) by concurrent intraesophageal slow infusion and pharyngoscopic and manometric technique without and with the application of a sustained predetermined cricoid pressure to induce, detect, and prevent EPR, respectively. RESULTS: Slow esophageal infusion (1 mL/s) of 60 mL of HCl resulted in a total of 16 objectively confirmed EPR events in none patients and none in healthy controls. All patients developed subjective sensation of regurgitation. Sustained cricoid pressure resulted in a significant UES pressure augmentation in all participants. During application of sustained cricoid pressure, slow intraesophageal infusion resulted in only one EPR event (P < .01). CONCLUSIONS: Slow esophageal liquid infusion unmasks UES incompetence evidenced as the occurrence of EPR. Application of 20 to 30 mm Hg cricoid pressure significantly increases the UES intraluminal pressure and prevents pharyngeal reflux induced by esophageal slow liquid infusion. These techniques can be useful in diagnosis and management of UES incompetence in patients suffering from supraesophageal manifestations of reflux disease. PMID- 24782388 TI - Comparison of moderate to severe systemic reactions with honeybee and wasp in children. AB - BACKGROUND: The effect of the type of Hymenoptera on the severity of systemic reactions (SRs) is a controversial issue. The aim of the present study was to evaluate demographic, clinical, diagnostic, and therapeutic features of moderate to-severe SRs in children with venom hypersensitivity and to compare the role of the honeybee and wasp stings in these reactions. METHODS: Data on children with moderate-to-severe SRs after a Hymenoptera sting were retrospectively collected for a 17-year period. RESULTS: A total of 55 children with moderate-to-severe SRs (wasp: 44, honeybee: 11) to venom stings were included in the study. In the honeybee group, comorbid allergic rhinitis and any type of atopic disease was more frequent compared to the wasp group (p = 0.009 and p = 0.01, respectively). In 50.9% of the children, family history of SR to the same venom type was higher in the honeybee group (p = 0.02). Dyspnea was more frequent in the wasp, and cyanosis was more frequent in the honeybee compared to each other (p = 0.02 and p < 0.001, respectively). Prick tests results were significantly different between the groups (p = 0.038). There was no difference between honeybee and wasp in moderate-to-severe SR groups in terms of seasonal tendency, age at admission, age at first SR, gender, previous history of SR, sting localization, latency, and affected organ systems (p > 0.05 for each). CONCLUSION: Moderate-to-severe SRs with honeybee and wasp venoms in children may differ in the severity of respiratory symptoms/signs at presentation, in addition to comorbidity of atopic diseases and family history of the SRs. PMID- 24782389 TI - Low-temperature remediation of NO catalyzed by interleaved CuO nanoplates. AB - A copper(II)-oxide-based exhaust catalyst exhibits better activity than Pt- and Rh-nanoparticle catalysts in NO remediation at 175 degrees C. Following theoretical design, the CuO catalyst is rationally prepared; CuO nanoplates bearing a maximized amount of the active {001} facet are arranged in interleaved layers. A field test using a commercial gasoline engine demonstrates the ability of the catalyst to remove NO from the exhaust of small vehicles. PMID- 24782390 TI - A novel idiopathic superficial neocortical degeneration and atrophy in young adult dogs. AB - A diffuse, chronic, superficial neocortical degeneration that resulted in atrophy was detected in five 1 to 2-year-old-dogs. Presenting neurologic signs included ataxia, dysphagia, blindness, and mentation changes. Magnetic resonance imaging on brains from 2 dogs demonstrated severe bilateral cerebrocortical atrophy and enlarged lateral and third ventricles. Grossly, multifocal, bilaterally symmetrical, extensive areas of neocortical brownish discoloration associated with atrophy of gyri and sulcal widening were recorded in the dorsal and lateral cerebral hemispheres in 3 dogs. Microscopically, in all dogs there was subacute to chronic superficial neocortical degeneration affecting all cerebral lobes, ranging from loss of the molecular layer to less frequent larger and deeper cavitations of variable size. Clinical signs probably resulted from a combination of primary neocortical degeneration and secondary degeneration in the corticobulbar and corticospinal tracts. The distribution pattern of gross and histologic cerebrocortical lesions suggests that this is a novel degenerative canine cerebral disease. PMID- 24782391 TI - CELL BIOLOGY SYMPOSIUM: the immune system in pregnancy. PMID- 24782392 TI - Whole-genome association study of fatty acid composition in a diverse range of beef cattle breeds. AB - Fatty acid composition of adipose tissue associated with meat is an important factor for the beef industry because of its implications for human health, processing, meat quality, and palatability. Individual fatty acid composition is a trait under genetic control, so improvement via selective breeding of cattle is possible. The objective of this study was to investigate the genetic architecture of fatty acid composition and identify genes associated with this trait in 3 breed types: Bos indicus (Brahman), Bos taurus (4 breeds), and tropically adapted composites (2 breeds). Using high-density data, regions on chromosomes 1, 9, 14, 16, 19, 23, 26, 29, and X were associated with fat composition and quantity traits. Known candidate genes, such as fatty acid synthase (FASN; chromosome 19) and stearoyl-CoA desaturase (SCD; chromosome 26), were confirmed in our results. Other candidate genes and regions represent novel association results, requiring further validation. PMID- 24782393 TI - Genomic prediction in Japanese Black cattle: application of a single-step approach to beef cattle. AB - The implementation of genomic selection for Japanese Black cattle, known for rich marbling of their meat, is now being explored. Although multiple-step methods are often adopted for dairy cattle, they present shortcomings such as bias and loss of information in addition to operational complexity. These can be avoided using single-step genomic BLUP (ssGBLUP) based on the relationship matrix H, which is constructed from the numerator relationship matrix (A) augmented by the genomic relationship matrix (G). This study assessed the use of ssGBLUP for 3 economically important traits in Japanese Black cattle. Three aspects of ssGBLUP that are important for practical use were examined specifically: the mixing proportions of blending G with A, selection of subsets of genotyped animals used for constructing H, and prediction ability for ungenotyped animals. Different mixing proportions were tested to assess the influence of these proportions on variance component estimation and prediction accuracy. For all traits, the highest or nearly highest accuracy was obtained when the adopted mixing proportion provided heritability closest to that inferred based on A. However, the accuracy did not increase greatly under adjustment of the mixing proportion, thereby suggesting that the influence of the mixing proportion on the accuracy was limited. Genotype data of influential bulls showed a greater contribution to accuracy than that of bulls that were less influential. Genotyping animals with phenotypic records increased the accuracy. It can be prioritized over genotyping bulls that are not influential on the population. These results are expected to present good guides to the future expansion of genotyped populations. Even for animals without genotype data but with genotyped sires, ssGBLUP provided more accurate prediction than BLUP did. For both phenotype and breeding value prediction, ssGBLUP provides more accurate prediction than BLUP, suggesting its usefulness in genomic selection in Japanese Black cattle. PMID- 24782394 TI - Genomewide association study of reproductive efficiency in female cattle. AB - Reproductive efficiency is of economic importance in commercial beef cattle production, as failure to achieve pregnancy reduces the number of calves marketed per cow exposed. Identification of genetic markers with predictive merit for reproductive success would facilitate early selection of sires with daughters having improved reproductive rate without increasing generation intervals. To identify regions of the genome harboring variation affecting reproductive success, we applied a genomewide association study (GWAS) approach based on the >700,000 SNP marker assay, using a procedure based on genotyping multianimal pools of DNA to increase the number of animals that could be genotyped with available resources. Cows from several populations were classified according to reproductive efficiency, and DNA was pooled within population and phenotype prior to genotyping. Populations evaluated included a research population at the U.S. Meat Animal Research Center, 2 large commercial ranch populations, and a number of smaller populations (<100 head) across the United States. We detected 2 SNP with significant genomewide association (P <= 1.49 * 10(-7)), on BTA21 and BTA29, 3 SNP with suggestive associations (P <= 2.91 * 10(-6)) on BTA5, and 1 SNP with suggestive association each on BTA1 and BTA25. In addition to our novel findings, we confirmed previously published associations for SNP on BTA-X and all autosomes except 3 (BTA21, BTA22, and BTA28) encompassing substantial breed diversity including Bos indicus and Bos taurus breeds. The study identified regions of the genome associated with reproductive efficiency, which are being targeted for further analysis to develop robust marker systems, and demonstrated that DNA pooling can be used to substantially reduce the cost of GWAS in cattle. PMID- 24782395 TI - Using multivariate adaptive regression splines to estimate subadult age from diaphyseal dimensions. AB - Subadult age estimation is considered the most accurate parameter estimated in a subadult biological profile, even though the methods are deficient and the samples from which they are based are inappropriate. The current study addresses the problems that plague subadult age estimation and creates age estimation models from diaphyseal dimensions of modern children. The sample included 1,310 males and females between the ages of birth and 12 years. Eighteen diaphyseal length and breadth measurements were obtained from Lodox Statscan radiographic images generated at two institutions in Cape Town, South Africa, between 2007 and 2012. Univariate and multivariate age estimation models were created using multivariate adaptive regression splines. k-fold cross-validated 95% prediction intervals (PIs) were created for each model, and the precision of each model was assessed. The diaphyseal length models generated the narrowest PIs (2 months to 6 years) for all univariate models. The majority of multivariate models had PIs that ranged from 3 months to 5 and 6 years. Mean bias approximated 0 for each model, but most models lost precision after 10 years of age. Univariate diaphyseal length models are recommended for younger children, whereas multivariate models are recommended for older children where the inclusion of more variables minimized the size of the PIs. If diaphyseal lengths are not available, multivariate breadth models are recommended. The present study provides applicable age estimation formulae and explores the advantages and disadvantages of different subadult age estimation models using diaphyseal dimensions. Am J Phys Anthropol 154:376-386, 2014. (c) 2014 Wiley Periodicals, Inc. PMID- 24782396 TI - Asymmetric synthesis of fortucine and reassignment of its absolute configuration. AB - A convergent and enantioselective synthesis of fortucine was achieved from the starting materials tyrosine methyl ester and 3-hydroxy-4-methoxybenzaldehyde. The synthesis is based on two key steps mediated by a hypervalent iodine reagent. This work has enabled us to reassign the absolute configuration of the natural product reported in the literature. PMID- 24782397 TI - A metal-bridged tricyclic aromatic system: synthesis of osmium polycyclic aromatic complexes. AB - Aromaticity is one of the most important concepts in organic chemistry. A variety of metalla-aromatic compounds have been recently prepared and in most of those examples, the metal participates only in a monocyclic ring. In contrast, metal bridged bicyclic aromatic molecules, in which a metal is shared between two aromatic rings, have been less developed. Herein, we report the first metal bridged tricyclic aromatic system, in which the metal center is shared by three aromatic five-membered rings. These metalla-aromatics are formed by reaction between osmapentalyne and arene nucleophiles. Experimental results and theoretical calculations reveal that the three five-membered rings around the osmium center are aromatic. In addition, the broad absorption bands in the UV/Vis absorption spectra of these novel aromatic systems cover almost the entire visible region. This straightforward synthetic strategy may be extended to the synthesis of other metal-bridged polycyclic aromatics. PMID- 24782398 TI - Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution. AB - Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) have karyotypic abnormalities and this low frequency has made using cytogenetic data for the prognostication of CMML patients challenging. Recently, a three-tiered cytogenetic risk stratification system for CMML patients has been proposed by a Spanish study group. Here we assessed the prognostic impact of cytogenetic abnormalities on overall survival (OS) and leukemia-free survival (LFS) in 417 CMML patients from our institution. Overall, the Spanish cytogenetic risk effectively stratified patients into different risk groups, with a median OS of 33 months in the low-, 24 months in intermediate- and 14 months in the high-risk groups. Within the proposed high risk group, however, marked differences in OS were observed. Patients with isolated trisomy 8 showed a median OS of 22 months, similar to the intermediate-risk group (P = 0.132), but significantly better than other patients in the high-risk group (P = 0.018). Furthermore, patients with more than three chromosomal abnormalities showed a significantly shorter OS compared with patients with three abnormalities (8 vs. 15 months, P = 0.004), suggesting possible a separate risk category. If we simply moved trisomy 8 to the intermediate risk category, the modified cytogenetic grouping would provide a better separation of OS and LFS; and its prognostic impact was independent of other risk parameters. Our study results strongly advocate for the incorporation of cytogenetic information in the risk model for CMML. PMID- 24782399 TI - Development of a liquid chromatography-tandem mass spectrometry method for the determination of Grayanotoxins in rat blood and its application to toxicokinetic study. AB - A sensitive and specific high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of Grayanotoxin I (GTX I) and Grayanotoxin III (GTX III) in rat whole blood. Grayanotoxins (GTXs) and clindamycin as internal standard (IS) were extracted from rat blood via solid-phase extraction using PEP solid-phase extraction cartridges. Chromatographic separation of the analytes was achieved on a Kinetex C18 (100 * 2.1 mm, 2.6 um) reversed-phase column using a gradient elution with the mobile phase of 1% acetic acid in water and methanol at a flow rate of 0.2 mL/min. Electrospray ionization mass spectrometry was operated in the positive ion mode with multiple reaction monitoring. The calibration curves obtained were linear over the concentration range of 1-100 ng/mL with a lower limit of quantification of 1 ng/mL for GTXs. The relative standard deviation of intra-day and inter-day precision was below 6.8% and accuracy ranged from 94.8 to 106.6%. The analytes were stable in the stability studies. The validated method was successfully applied to the quantification and toxicokinetic study of GTXs in rats for the first time after oral administration of 11.52 mg/kg mad honey and 0.35 mg/kg GTX III, respectively. PMID- 24782400 TI - A novel technique for transcatheter patent ductus arteriosus closure in extremely preterm infants using commercially available technology. AB - OBJECTIVES: To describe a new technique for transcatheter patent ductus arteriosus (PDA) closure in extremely preterm infants using commercially available technology. BACKGROUND: PDA in premature neonates continues to be a significant clinical problem contributing importantly to both morbidity and mortality. Surgical ligation and medical therapy both have their drawbacks. MATERIAL AND METHODS: Hospital records and catheterization reports of all premature neonates (< 32 weeks gestation) who underwent transcatheter PDA closure between March 2013 and February 2014 were reviewed. Particular attention was paid to procedural details, complications, and short and mid-term outcomes. RESULTS: Six premature infants born at gestational ages ranging between 26 and 31 weeks (median, 26 weeks) underwent attempted transcatheter PDA closure using the Amplatzer Vascular Plug II (AVP II). Median age and weight was 21.5 days (16-80 days) and 1,180 g (870-2,240 g), respectively. Fluoroscopy and echocardiography were used to guide device. Contrast angiography was not used in any patient. Complete closure was achieved in all patients with no major procedural complications. Median fluoroscopy and procedural times were 9.4 (0-19.5) and 51.5 (33-87) min, respectively. All patients were alive at the time of this report. There were no instances of device migration, left pulmonary artery (LPA), or aortic coarctation. CONCLUSIONS: This preliminary study demonstrates that transcatheter PDA closure can be successfully performed in extremely preterm neonates using currently available technology with a high success rate and a low incidence of complications. This report also describes a novel transvenous approach using a combination of echocardiography and judicious use of fluoroscopy to avoid arterial access in this fragile patient population. (c) 2014 Wiley Periodicals, Inc. PMID- 24782401 TI - A new endoscopic staging system for hereditary hemorrhagic telangiectasia. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is predominantly characterized by nasal telangiectases that cause severe epistaxis. Recently, the Epistaxis Severity Score (ESS) was developed and validated as a standardized measurement to evaluate epistaxis treatment efficacy. We propose a new endoscopic staging system to characterize nasal findings in HHT patients and correlate this to the ESS. METHODS: This is a prospective cohort study. A total of 33 individuals with HHT confirmed by Curacao criteria were recruited and evaluated by a single otolaryngologist between August 2010 and February 2013. Endoscopic parameters including patterns and sites of telangiectases and degree of nasal crusting were used to construct an endoscopy score for each subject. Multiple linear regression models were used to correlate this endoscopy score to the ESS. RESULTS: A total of 33 subjects completed the study. The mean +/- standard deviation (SD) age was 50.3 +/- 13.2 years, and 20 (60.6%) were female. In the cohort, mean +/- SD ESS was 4.05 +/- 2.13 (range, 0.50 to 8.22). Most subjects (53.1%) had more than 4 nasal sites involved and (56.2%) had punctate telangiectases; 30.3% had mild crusting and 21.2% had moderate/severe crusting. These endoscopic findings were weighted by their correlation coefficients against epistaxis severity and normalized to create a new endoscopy score. After adjusting for confounding variables, the HHT Endoscopy Score (HES) was strongly associated with the ESS (r = 0.79, p < 0.001). CONCLUSION: The HES correlates highly with patient-reported epistaxis severity and may provide a useful outcome measure in future studies. PMID- 24782402 TI - Isothermal switching and detailed filament evolution in memristive systems. AB - The steady-state solution of filamentary memristive switching may be derived directly from the heat equation, modelling vertical and radial heat flow. This solution is shown to provide a continuous and accurate description of the evolution of the filament radius, composition, heat flow, and temperature during switching, and is shown to apply to a large range of switching materials and experimental time-scales. PMID- 24782403 TI - A morphological intermediate between eosimiiform and simiiform primates from the late middle Eocene of Tunisia: Macroevolutionary and paleobiogeographic implications of early anthropoids. AB - Although advanced anthropoid primates (i.e., Simiiformes) are recorded at the end of the Eocene in North Africa (Proteopithecidae, Parapithecidae, and Oligopithecidae), the origin and emergence of this group has so far remained undocumented. The question as to whether these primates are the result of a monophyletic radiation of endemic anthropoids in Africa, or several Asian clades colonizing Africa, is a current focus of paleoprimatology. In this article, we report the discovery of a new anthropoid from Djebel el Kebar in central Tunisia, dating from the late middle Eocene (Bartonian). This taxon, Amamria tunisiensis, new genus and species, currently known by only one isolated upper molar, is among the most ancient anthropoids to be recorded in Africa thus far. Amamria displays a suite of dental features that are primarily observed in Eosimiiformes (stem Anthropoidea). However, it is not allocated to any known family of that group (i.e., Asian Eosimiidae and Afro-Asian Afrotarsiidae) inasmuch as it develops some dental traits that are unknown among eosimiiforms, but can be found in African simiiform anthropoids such as proteopithecids and oligopithecids. With such a mosaic of dental traits, Amamria appears to be a structural intermediate, and as such it could occupy a key position, close to the root of the African simiiforms. Given its antiquity and its apparent pivotal position, the possibility exists that Amamria could have evolved in Africa from Asian eosimiiform or Asian "proto"-simiiform ancestors, which would have entered Africa sometime during the middle Eocene. Amamria could then represent one of the earliest offshoots of the African simiiform radiation. This view would then be rather in favor of the hypothesis of a monophyletic radiation of endemic simiiform anthropoids in Africa. Finally, these new data suggest that there must have been at least two Asian anthropoid colonizers of Africa: the afrotarsiids and the ancestor of Amamria. PMID- 24782405 TI - Stereocontrol in dinuclear triple lithium-bridged titanium(IV) complexes: solving some stereochemical mysteries. AB - Compounds 1 a-f-H2 form "monomeric" triscatecholate titanium(IV) complexes [Ti(1 a-f)3](2-), which in the presence of Li cations are in equilibrium with the triple lithium-bridged "dimers" [Li3(Ti(1 a-f)3)2](-). The equilibrium strongly depends on the donor ability of the solvent. Usually, in solvents with high donor ability, the stereochemically labile monomer is preferred, whereas in nondonor solvents, the dimer is the major species. In the latter, the stereochemistry at the complex units is "locked". The configuration at the titanium(IV) triscatecholates is influenced by addition of chiral ammonium countercations. In this case, the induced stereochemical information at the monomer is transferred to the dimer. Alternatively, the configuration at the metal complexes can be controlled by enantiomerically pure ester side chains. Due to the different orientation of the ester groups in the monomer or dimer, opposite configurations of the triscatecholates were observed by circular dichroism (CD) spectroscopy for [Ti(1 c-e)3](2-) or [Li3(Ti(1 c-e)3)2](-). A surprising exception was found for the dimer [Li3(Ti(1 f)3)2](-). Herein, the dimer is the dominating species in weak donor (methanol), as well as strong donor (DMSO), solvents. This is due to the bulkiness of the ester substituent destabilizing the monomer. Due to the size of the substituent in [Li3(Ti(1 f)3)2](-) the esters have to adopt an unusual conformation in the dimer resulting in a stereocontrol of the small methyl group. Following this, opposite stereocontrol mechanisms were observed for the central metal-complex units of [Li3(Ti(1 c-e)3)2](-) or [Li3(Ti(1 f)3)2](-). PMID- 24782404 TI - Correlation between Reflux and multichannel intraluminal impedance pH monitoring in untreated volunteers. AB - OBJECTIVES/HYPOTHESIS: Although probable causative agents have been identified (e.g., refluxate components, tobacco smoke), the definitive mechanism for inflammation-related laryngeal mucosal damage remains elusive. Multichannel intraluminal impedance combined with pH monitoring (MII/pH) has emerged as a sensitive tool for diagnosis and characterization of gastroesophageal reflux disease with laryngopharyngeal manifestations. To determine the relationship between laryngeal signs and MII/pH, we examined correlations between Reflux Finding Score (RFS) ratings of videostroboscopic laryngeal examinations and findings from MII/pH. STUDY DESIGN: Correlational study. METHODS: Healthy, untreated volunteers (n = 142) underwent reflux diagnosis using data acquired from MII/pH testing. Eight trained clinicians performed RFS ratings of corresponding laryngeal examinations. Averaged RFS ratings were compared to MII/pH data using Pearson correlation coefficients. The relationship between RFS and MII/pH findings and demographic/clinical information (age, sex, smoking status, reflux) was assessed using general linear modeling. Rater reliability was evaluated. RESULTS: Posterior commissure hypertrophy was negatively correlated with minutes of nonacid refluxate (R = -0.21, P = .0115). General linear modeling revealed that 28% to 40% of the variance in ratings of ventricular obliteration, erythema/hyperemia, vocal fold edema, diffuse laryngeal edema, posterior commissure hypertrophy, and granulation/granuloma could be explained by main and interaction effects of age, sex, smoking status, and reflux. Intra- and inter rater reliability for RFS were poor-fair. CONCLUSIONS: These results support the theory that the RFS is not specific for reflux in healthy, untreated volunteers, suggesting there may be alternate explanations for inflammatory clinical signs commonly ascribed to reflux in this population. PMID- 24782406 TI - Redox chemistry of a hydroxyphenyl-substituted borane. AB - Chemical reduction of a hydroxyphenyl-substituted borane triggers a sequential electron- and intramolecular hydrogen-atom-transfer process to afford a hydridoborate phenoxide dianion. On the other hand, hydrogen-atom abstraction of the borane leads to the isolation of a neutral borylated phenoxyl radical, which can be transformed to the corresponding benzoquinone borataalkene derivative by reduction with cobaltocene. PMID- 24782407 TI - Outcome comparison of African-American and Caucasian patients with severe aortic stenosis subjected to transcatheter aortic valve replacement: a single-center experience. AB - OBJECTIVE: This study aimed to report the outcomes of African Americans (AAs) in the US undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS). BACKGROUND: Compared to Caucasians, AAs are reported to have poorer outcomes from most cardiovascular diseases, including high complication rates after surgical aortic valve replacement. The outcomes of AAs undergoing TAVR are not well established. METHODS: Consecutive patients who underwent TAVR were included in this analysis. Patients' baseline characteristics, procedural data, in-hospital- and long-term outcomes were recorded and a comparison was performed between the AA and Caucasian cohorts. RESULTS: In a cohort of 469 consecutive patients, 51 (10.8%) were AA and 345 (74.5%) were Caucasian. The remaining patients (n = 73; 15.3%) self-reported their race as "unknown" or were from other races. Most baseline characteristics were similar between the two groups except for less men (33.3 vs. 50.1%; P = 0.016), a lower mean left ventricular ejection fraction (48.85 +/- 16.35 vs. 53.24 +/- 13.41%; P = 0.04) and lower rates of atrial fibrillation in AAs (15.7 vs.45.4%; P < 0.001). TAVR procedures in AAs were less frequently performed as part of a clinical trial (60.8 vs. 76.8%; P = 0.014). Most procedural and periprocedural outcome parameters were similar save for a higher rate of hemodynamic instability and postoperative need for intubation in AAs (10.4 vs. 2.5%; P = 0.018 and 29.4 vs. 16.9%; P = 0.03, respectively). This did not translate into a difference in mortality between AAs and Caucasians (30-day mortality 9.8 vs. 9.9%; P = 0.99; 1 year mortality 19.6 vs. 24.3%; P = 0.458, respectively). CONCLUSION: Unlike with other cardiovascular interventions, this study demonstrates that AA patients referred for TAVR shared similar risks and outcomes when compared to a Caucasian population. PMID- 24782408 TI - Development and validation of a UHPLC-qTOF-MS method for quantification of fuziline in rat plasma and its application in a pharmacokinetic study. AB - A specific and sensitive UHPLC-qTOF-MS method was developed and validated for quantification of fuziline in rat plasma after oral administration of three dosages. The analyte was separated on an Acquity UPLC BEH C18 column with a total running time of 3 min using a mobile phase of 0.1% formic acid aqueous solution and methanol (80:20, v/v) at a flow-rate of 0.25 mL/min. The calibration curves for fuziline showed good linearity in the concentrations ranging from 1 to 200 ng/mL with correlation coefficients >0.997. The precision, accuracy, recovery and stability were deemed acceptable. The method was applied to a pharmacokinetics study of fuziline in rats. The mean half-life was 5.93, 6.13 and 5.12 h for 1, 2 and 4 mg/kg oral administration of fuziline, respectively. The peak concentration and area under the concentration-time curve increased linearly with the doses. The sum of these results indicated that, in the range of the doses examined, the pharmacokinetics of fuziline in rat was based on first-order kinetics. PMID- 24782409 TI - Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. AB - OBJECTIVE: Alterations of sphingolipid metabolism are implicated in the pathogenesis of many neurodegenerative disorders. METHODS: We identified a homozygous nonsynonymous mutation in CERS1, the gene encoding ceramide synthase 1, in 4 siblings affected by a progressive disorder with myoclonic epilepsy and dementia. CerS1, a transmembrane protein of the endoplasmic reticulum (ER), catalyzes the biosynthesis of C18-ceramides. RESULTS: We demonstrated that the mutation decreases C18-ceramide levels. In addition, we showed that downregulation of CerS1 in a neuroblastoma cell line triggers ER stress response and induces proapoptotic pathways. INTERPRETATION: This study demonstrates that impairment of ceramide biosynthesis underlies neurodegeneration in humans. PMID- 24782410 TI - Increased expression of TRPC4 channels associated with erectile dysfunction in diabetes. AB - In recent reports, an association between altered TRPC channel function and the development of various diabetic complications has drawn the attention of many investigators. The aim of this study was to investigate the expression of TRPC4 channels of corpus smooth muscle (CSM) cells in diabetes, and to evaluate the association between erectile dysfunction (ED) and altered TRPC4 channel function. The expression of TRPC4 in the penile tissue of human, normal and diabetic rat was investigated using RT-PCR, western blotting and immunohistochemistry (IHC). In vivo gene transfer of dominant negative (DN) TRPC4 into the CSM of rat was conducted. In vivo pelvic nerve stimulation was performed to measure erectile function. Expression of TRPC1, TRPC3, TRPC4 and TRPC6 in human and rat CSM tissues was confirmed by RT-PCR, western blot and IHC. In the diabetic rat, the expression levels of mRNA and protein of the TRPC4, and TRPC6 were significantly increased compared to control rats (p < 0.05). The change in TRPC4 expression in the diabetic rats was higher than those of the other TRPC subunits (p < 0.05). The IHC showed that only TRPC4 expression had a higher intensity in the diabetes compared to normal rats (p < 0.05). Gene transfection with TRPC4(DN) into the diabetic rats restored erectile function to levels similar to that of normal controls. Gene expression of TRPC4(DN) in CSM tissue was confirmed by RT-PCR 2 weeks after transfection. This study demonstrated that TRPC4 channel expression increased in the penile CSM cells of diabetic rats. The down-regulation of TRPC4 with DN form restored erectile function in the diabetic rats. The alteration of TRPC4 channel is one of pathophysiology of ED and could be a target for drug development for ED. PMID- 24782412 TI - State-of-the-art analytical methods for assessing dynamic bonding soft matter materials. AB - Dynamic bonding materials are of high interest in a variety of fields in material science. The reversible nature of certain reaction classes is frequently employed for introducing key material properties such as the capability to self-heal. In addition to the synthetic effort required for designing such materials, their analysis is a highly complex--yet important--endeavor. Herein, we critically review the current state of the art analytical methods and their application in the context of reversible bonding on demand soft matter material characterization for an in-depth performance assessment. The main analytical focus lies on the characterization at the molecular level. PMID- 24782413 TI - The relationship between geographic remoteness and intentions to use a telephone support service among Australian men following radical prostatectomy. AB - OBJECTIVE: The objective is to investigate the influence of characteristics related to place of residence (self-reliance and stoicism) on men's intentions to use a telephone support service following radical prostatectomy. METHODS: A community sample of 447 prostate cancer patients (31% response), recruited via Medicare Australia, completed a survey to assess levels of self-reliance and stoicism, and beliefs about addressing emotional distress through using telephone support services. RESULTS: Results indicated that the model was a partially mediated model. Geographic remoteness was directly related to intention, and indirectly related through stoicism and subjective norms. CONCLUSION: Men from rural and remote areas in Australia might face particular challenges in seeking support following treatment for prostate cancer. These challenges appear to relate to the influence of stoic attitudes and normative expectations, than to issues of access and availability. Addressing stoic attitudes in the clinical setting, through normalising emotional reactions to cancer diagnosis and treatment, and the act of help-seeking for emotional support, may be beneficial. PMID- 24782414 TI - Prokinetic agents and laryngopharyngeal reflux disease: Prokinetic agents and laryngopharyngeal reflux disease: a systematic review. AB - OBJECTIVES: Our objective was to systematically identify and evaluate prospective studies providing evidence for and against the use of prokinetic agents in the treatment of laryngopharyngeal reflux (LPR) disease. DATA SOURCES: Our data sources were PubMed, Embase, BIOSIS, and Web of Science databases. REVIEW METHODS: A systematic literature review was conducted to identify studies prospectively evaluating the effectiveness of prokinetic agents in the treatment of LPR. Data from eligible studies were independently extracted from each study by two authors. The primary outcome of interest was the improvement of LPR symptoms among study participants. Secondary outcomes included resolution of LPR physical signs and the development of side effects from therapy. RESULTS: Among 724 unique articles identified, four studies met inclusion criteria. These four investigations provided mixed evidence about the effectiveness of prokinetic agents in the treatment of LPR. The studies included in the review were deemed to be at high risk of bias. Three of the four investigations demonstrated a statistically significant difference in patient symptoms that favored the use of prokinetics in the management of LPR. The investigations were mixed in their report of improvement in physical examination findings among patients receiving and those not receiving prokinetic medical therapy. No significant adverse effects were described in any of these trials. CONCLUSIONS: Prokinetic agents may be a viable treatment option for LPR. The current body of literature is inadequate to make a recommendation for their use in this disease process. Further research should be conducted to assess the use of prokinetic medications in the management of LPR. PMID- 24782415 TI - The frailty syndrome in the public health agenda. PMID- 24782416 TI - The effect of air pollution on pneumonia-related emergency department visits in a region of extensive sugar cane plantations: a 30-month time-series study. AB - BACKGROUND: In Brazil, many cities are surrounded by sugar cane plantations, and when these plantations are burnt prior to harvesting, millions of people are exposed to the smoke from these fires from May to November every year. METHODS: A daily time-series regression analysis was conducted in a city located in the sugar cane plantation region of Sao Paulo State, Brazil, between 1 February 2005 and 31 July 2007. The percentage increase in the number of pneumonia-related emergency department visits (PEDV) associated with a 10 ug/m(3) increase in the total suspended particles (TSP) concentration was measured, including any effects that were delayed for up to 6 days. RESULTS: A total of 1505 PEDV (a median of two events per day) were analysed. During the burning period, there was an acute effect that began on the day of exposure and remained for 2 days. An increase of 6% (95% CI 2.4 to 9.9) in PEDV was observed for the 2 days following the TSP increase. This pattern and the size of the effect were similar to those observed for the whole period and also during the non-burning period. CONCLUSIONS: Increases in TSP concentrations were found to be associated with increased PEDV in a region affected by air pollution from sugar cane burning. This finding reinforces the need for polices and efforts to ban sugar cane burning prior to harvesting. PMID- 24782417 TI - Retirement and physical activity. PMID- 24782418 TI - You have been QUALIFIED for a smokeless e-cig starter kit. PMID- 24782419 TI - Asymmetric [5+3] formal cycloadditions with cyclic enones through cascade dienamine-dienamine catalysis. AB - A few aminocatalytic modes, such as iminium ions and different dienamines, have provided versatile tools for the functionalization of cyclic enones at various sites. Described here is a previously unreported cascade dienamine/dienamine catalytic pathway for beta-substituted 2-cyclopentenones, and even 2 cyclohexenone. It involves domino alpha'-regioselective Michael addition and a gamma-regioselective Mannich reaction with 3-vinyl-1,2-benzoisothiazole-1,1 dioxides to give fused or bridged architectures, which incorporate a spirocyclic skeleton, in excellent stereocontrol, thus furnishing unusual [5+3] formal cycloaddition reactions. Moreover, preliminary biological assays showed that some of the chiral products exhibited promising activity against some cancer cell lines, thus indicating that such skeletons might serve as leads in drug discovery. PMID- 24782420 TI - Solvent-dependent cation exchange in metal-organic frameworks. AB - We investigated which factors govern the critical steps of cation exchange in metal-organic frameworks by studying the effect of various solvents on the insertion of Ni(2+) into MOF-5 and Co(2+) into MFU-4l. After plotting the extent of cation insertion versus different solvent parameters, trends emerge that offer insight into the exchange processes for both systems. This approach establishes a method for understanding critical aspects of cation exchange in different MOFs and other materials. PMID- 24782421 TI - Autism spectrum disorder secondary to enterovirus encephalitis. AB - Millions of children are infected by enteroviruses each year, usually exhibiting only mild symptoms. Nevertheless, these viruses are also associated with severe and life-threatening infections, such as meningitis and encephalitis. We describe a 32-month-old patient with enteroviral encephalitis confirmed by polymerase chain reaction in cerebrospinal fluid, with unfavorable clinical course with marked developmental regression, autistic features, persistent stereotypes and aphasia. She experienced slow clinical improvement, with mild residual neurologic and developmental deficits at follow-up. Viral central nervous system infections in early childhood have been associated with autism spectrum disorders but the underlying mechanisms are still poorly understood. This case report is significant in presenting a case of developmental regression with autistic features and loss of language improving on follow-up. To our knowledge, this is the first published report of enterovirus encephalitis leading to an autism spectrum disorder. PMID- 24782424 TI - Economic analysis of endovascular interventions for femoropopliteal arterial disease: a systematic review and budget impact model for the United States and Germany. AB - OBJECTIVES: To study the economic impact on payers and providers of the four main endovascular strategies for the treatment of infrainguinal peripheral artery disease. BACKGROUND: Bare metal stents (BMS), drug-eluting stents (DES), and drug coated balloons (DCB) are associated with lower target lesion revascularization (TLR) probabilities than percutaneous transluminal angioplasty (PTA), but the economic impact is unknown. METHODS: In December 2012, PubMed and Embase were systematically searched for studies with TLR as an endpoint. The 24-month probability of TLR for each treatment was weighted by sample size. A decision analytic Markov model was used to assess the budget impact from payers' and facility-providers' perspectives of the four index procedure strategies (BMS, DES, DCB, and PTA). Base cases were developed for U.S. Medicare and the German statutory sickness fund perspectives using current 2013 reimbursement rates. RESULTS: Thirteen studies with 2,406 subjects were included. The reported probability of TLR in the identified studies varied widely, particularly following treatment with PTA or BMS. The pooled 24-month probabilities were 14.3%, 19.3%, 28.1%, and 40.3% for DCB, DES, BMS, and PTA, respectively. The drug eluting strategies had a lower projected budget impact over 24 months compared to BMS and PTA in both the U.S. Medicare (DCB: $10,214; DES: $12,904; uncoated balloons $13,114; BMS $13,802) and German public health care systems (DCB ?3,619; DES ?3,632; BMS ?4,026; PTA ?4,290). CONCLUSIONS: DCB and DES, compared to BMS and PTA, are associated with lower probabilities of target lesion revascularization and cost savings for U.S. and German payers. PMID- 24782425 TI - Fragmentation patterns study of iridoid glycosides in Fructus Gardeniae by HPLC Q/TOF-MS/MS. AB - Iridoid glycosides (IGs), the major constituents in Fructus Gardeniae, have demonstrated various pharmacological activities, but there is no systematic chemical profile of IGs in Fructus Gardeniae in the published literature until now. Therefore, it is imperative that a rapid and sensitive high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-Q/TOF-MS/MS) method is established for comprehensive characterization of IGs in Fructus Gardeniae. Firstly, the fragmentation patterns of six known IGs were investigated and proposed and further concluded the diagnostic fragment ions and characteristic fragmentation pathways. Then, based on the summarized fragmentation patterns and the known compounds in the literatures, the other IGs in Fructus Gardeniae were identified successively. As a result, a total of 20 IGs were identified, of which three pairs of epimers were structurally characterized and differentiated. More importantly, one compound, the isoshanzhiside methyl ester, was tentatively identified as a new compound. The results of this study demonstrate the superiority of HPLC-MS with a high resolution mass spectrometer for the rapid and sensitive structural elucidation of the multiple groups of constituents in Fructus Gardeniae. PMID- 24782426 TI - Distinct roles of age and abdominal visceral fat in reducing androgen receptor dependent negative feedback on LH secretion in healthy men. AB - Testosterone (T) impacts luteinizing hormone (LH) secretion through negative feedback via the androgen receptor (AR) in the hypothalamo-pituitary system. An untested postulate is that increasing body mass index (BMI), abdominal visceral fat (AVF) or total abdominal fat (TAF) with ageing decreases LH secretion by heightening T negative feedback via AR. This hypothesis was tested in a prospective, randomized double-blind cross-over study of 19 healthy men comparing the effects of flutamide, a selective non-steroidal AR antagonist and placebo administration on basal and pulsatile LH secretion as a function of age and obesity measures. To this end, serum levels of 2-hydroxyflutamide (2-OHF), a major active flutamide metabolite, were measured by mass spectrometry, and AVF/TAF quantified by abdominal computerized tomography. Statistical analysis showed that antiandrogen administration elevated 6-h mean LH concentrations to 5.4 +/- 1.3 IU/L compared with 3.3 +/- 1.2 IU/L for placebo (p < 10(-3) ), and total T by 35% (p < 10(-4) ). The LH-T concentration product doubled (p < 10(-8) ). According to deconvolution analysis, flutamide exposure increased total LH secretion (p < 10(-3) ) and pulsatile LH secretion (p = 0.0077), along with LH pulse frequency (p = 0.019). Despite feedback inhibition, the LH-T product declined as a linear function of AVF (p = 0.021) and TAF (p = 0.017). This was explained by the fact that higher BMI was associated with lower 2-OHF concentrations (R = -0.562, p = 0.012). In contrast, age was associated with less pulsatile LH secretion (R = -0.567, p = 0.011) even when LH responses were normalized to antiantrogen levels. In conclusion, increased AVF, TAF and BMI predict decreased LH and flutamide blood levels, whereas older age is marked by impaired stimulation of pulsatile LH secretion even when normalized for antiandrogen levels, suggesting different mechanisms of regulation by adiposity and age. PMID- 24782427 TI - 4,6-Diaryl/heteroarylpyrimidin-2(1H)-ones as a new class of xanthine oxidase inhibitors. AB - A series of 4,6-diaryl/heteroarylpyrimidones was synthesized employing silica supported fluoroboric acid under solvent-free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesized compounds were evaluated for in vitro xanthine oxidase (XO) inhibitory activity for the first time. Structure-activity relationship analyses are also presented. Among the synthesized compounds, VA-5, 9, -10, -12, -22, -23, and -25 were the active inhibitors with IC50 values ranging from 6.45 to 13.46 uM. Compound VA-25 with a pyridinyl ring as ring A and a thiophenyl ring as ring B emerged as the most potent XO inhibitor (IC50 = 6.45 uM) in comparison to allopurinol (IC50 = 12.24 uM). Some of the important interactions of VA-25 with the amino acid residues of the active site of XO were figured out by molecular modeling studies. PMID- 24782428 TI - Assembly of viral hydrogels for three-dimensional conducting nanocomposites. AB - M13 bacteriophages act as versatile scaffolds capable of organizing single-walled carbon nanotubes and fabricating three-dimensional conducting nanocomposites. The morphological, electrical, and electrochemical properties of the nanocomposites are presented, as well as its ability to disperse and utilize single-walled carbon nanotubes effectively. PMID- 24782429 TI - Defining the biomechanical properties of the rabbit trachea. AB - OBJECTIVES/HYPOTHESIS: Surgical advancements rely heavily on validated animal models. The New Zealand White (NZW) rabbit is a widely used model for airway research, including regenerative medicine applications. Currently, the biomechanical properties of the normal rabbit trachea are not known. Our objective was to define these properties to assist in the standardization and understanding of future airway research using this model. STUDY DESIGN: Laboratory-based study. METHODS: Fresh tracheas from four adult NZW rabbits were dissected into 20 segments. To examine the biomechanical properties, segments were subjected to uniaxial tension (n = 9) and compression (n = 11) testing. Yield and maximum load (tension) and force at 50% displacement (compression) were recorded, and differences between segments were examined using analysis of covariance. RESULTS: Normative data for native rabbit trachea show mean maximum load = 6.44 newtons (N), yield load = 5.93 N, and compressive strength = 2.10 N. In addition to establishing the baseline measurements, statistically significant differences in tensile measures based on location along the trachea and diameter were identified. Proximal segments had significantly higher maximum load (P = .0029) and yield load (P = .0062) than distal segments. Association between diameter and both maximum load (P = .0139) and yield load (P = .0082) was observed. CONCLUSIONS: The adult NZW rabbit trachea is intrinsically less able to withstand tensile and compressive forces, compared to other airway models such as sheep or cadaveric human. Establishment of normative values will enable future research into changes in tracheal biomechanical properties during regenerative medicine manipulation and processing. PMID- 24782430 TI - A lab-on-a-chip device for analysis of amlodipine in biological fluids using peroxyoxalate chemiluminescence system. AB - A highly sensitive, rapid and economical method for the determination of amlodipine (AM) in biological fluids was developed using a peroxyoxalate chemiluminescence (CL) system in a lab-on-a-chip device. Peroxyoxalate-CL is an indirect type of CL that allows the detection of native fluorophores or compounds derivatized with fluorescent labels. Here, fluorescamine was reacted with AM, and the derivatization product was used in a bis-(2,4,6-trichlorophenyl)oxalate-CL system. Fluorescamine reacts selectively with aliphatic primary amine at neutral or basic pH. As most of the calcium channel blocker and many cardiovascular drugs do not contain primary amine, the developed method is highly selective. The parameters that influenced the CL signal intensity were studied carefully. These included the chip geometry, pH, concentration of reagents used and flow rates. Moreover, we confirmed our previous observation about the effects of imidazole, which is commonly used in the bis-(2,4,6-trichlorophenyl)oxalate-CL system as a catalyst, and found that the signal was significantly improved when imidazole was absent. Under optimized conditions, a calibration curve was obtained with a linear range (10-100 ug/L). The limit of detection was 3 ug/L, while the limit of quantification was 10 ug/L. Finally the method was applied for the determination of AM in biological fluids successfully. PMID- 24782431 TI - Small-molecule proteomimetic inhibitors of the HIF-1alpha-p300 protein-protein interaction. AB - The therapeutically relevant hypoxia inducible factor HIF-1alpha-p300 protein protein interaction can be orthosterically inhibited with alpha-helix mimetics based on an oligoamide scaffold that recapitulates essential features of the C terminal helix of the HIF-1alpha C-TAD (C-terminal transactivation domain). Preliminary SAR studies demonstrated the important role of side-chain size and hydrophobicity/hydrophilicity in determining potency. These small molecules represent the first biophysically characterised HIF-1alpha-p300 PPI inhibitors and the first examples of small-molecule aromatic oligoamide helix mimetics to be shown to have a selective binding profile. Although the compounds were less potent than HIF-1alpha, the result is still remarkable in that the mimetic reproduces only three residues from the 42-residue HIF-1alpha C-TAD from which it is derived. PMID- 24782432 TI - Errors of Omission: Missed Nursing Care. AB - A series of studies on missed nursing care (i.e., required standard nursing care that is not completed) is summarized. Missed nursing care is substantial and similar levels are found across hospitals. Reasons for missed nursing care are staffing resources, material resources, and communication and these are also similar across hospitals. The higher the staffing levels, the fewer occurrences of missed nursing care. Magnet status and higher levels of teamwork are associated with less missed nursing care, and more missed care leads to a lower level of staff satisfaction. Missed nursing care has been found to be a mediator between staffing levels and patient falls. Patient identified missed nursing care predicts adverse events (i.e., falls, pressure ulcers, new infections etc.). PMID- 24782433 TI - Data validation and other strategies for data entry. AB - Data entry can result in errors that cause analytic problems and delays in disseminating research. Invalid responses can lead to incorrect statistics and statistical conclusions. The purpose of this article is to provide researchers some basic strategies for avoiding out-of-range data entry errors and streamlining data collection. This article identifies some basic strategies using Microsoft(r) Excel, which is an inexpensive method of data entry that can be used when research budgets are constrained. Data files can be structured so that out of-range values cannot be entered. When string variables are entered, researchers may be inconsistent in the way they code responses. Data validation can be accomplished through the use of restricting response options and skipping items can be avoided by using count functions to tabulate the number of valid responses. We also discuss advantages and disadvantages of several methods of data entry, including using web-based data entry and relational databases. PMID- 24782434 TI - Managing opportunities and challenges of co-authorship. AB - Research with the largest impact on practice and science is often conducted by teams with diverse substantive, clinical, and methodological expertise. Team and interdisciplinary research has created authorship groups with varied expertise and expectations. Co-authorship among team members presents many opportunities and challenges. Intentional planning, clear expectations, sensitivity to differing disciplinary perspectives, attention to power differentials, effective communication, timelines, attention to published guidelines, and documentation of progress will contribute to successful co-authorship. Both novice and seasoned authors will find the strategies identified by the Western Journal of Nursing Research Editorial Board useful for building positive co-authorship experiences. PMID- 24782435 TI - Two-dimensional tetrathiafulvalene covalent organic frameworks: towards latticed conductive organic salts. AB - The construction of a new class of covalent TTF lattice by integrating TTF units into two-dimensional covalent organic frameworks (2D COFs) is reported. We explored a general strategy based on the C2 +C2 topological diagram and applied to the synthesis of microporous and mesoporous TTF COFs. Structural resolutions revealed that both COFs consist of layered lattices with periodic TTF columns and tetragonal open nanochannels. The TTF columns offer predesigned pathways for high rate hole transport, predominate the HOMO and LUMO levels of the COFs, and are redox active to form organic salts that exhibit enhanced electric conductivity by several orders of magnitude. On the other hand, the linkers between the TTF units play a vital role in determining the carrier mobility and conductivity through the perturbation of 2D sheet conformation and interlayer distance. These results open a way towards designing a new type of TTF materials with stable and predesignable lattice structures for functional exploration. PMID- 24782436 TI - Enhancement of crop photosynthesis by diffuse light: quantifying the contributing factors. AB - BACKGROUND AND AIMS: Plants use diffuse light more efficiently than direct light. However, experimental comparisons between diffuse and direct light have been obscured by co-occurring differences in environmental conditions (e.g. light intensity). This study aims to analyse the factors that contribute to an increase in crop photosynthesis in diffuse light and to quantify their relative contribution under different levels of diffuseness at similar light intensities. The hypothesis is that the enhancement of crop photosynthesis in diffuse light results not only from the direct effects of more uniform vertical and horizontal light distribution in the crop canopy, but also from crop physiological and morphological acclimation. METHODS: Tomato (Solanum lycopersicum) crops were grown in three greenhouse compartments that were covered by glass with different degrees of light diffuseness (0, 45 and 71 % of the direct light being converted into diffuse light) while maintaining similar light transmission. Measurements of horizontal and vertical photosynthetic photon flux density (PPFD) distribution in the crop, leaf photosynthesis light response curves and leaf area index (LAI) were used to quantify each factor's contribution to an increase in crop photosynthesis in diffuse light. In addition, leaf temperature, photoinhibition, and leaf biochemical and anatomical properties were studied. KEY RESULTS: The highest degree of light diffuseness (71 %) increased the calculated crop photosynthesis by 7.2 %. This effect was mainly attributed to a more uniform horizontal (33 % of the total effect) and vertical PPFD distribution (21 %) in the crop. In addition, plants acclimated to the high level of diffuseness by gaining a higher photosynthetic capacity of leaves in the middle of the crop and a higher LAI, which contributed 23 and 13 %, respectively, to the total increase in crop photosynthesis in diffuse light. Moreover, diffuse light resulted in lower leaf temperatures and less photoinhibition at the top of the canopy when global irradiance was high. CONCLUSIONS: Diffuse light enhanced crop photosynthesis. A more uniform horizontal PPFD distribution played the most important role in this enhancement, and a more uniform vertical PPFD distribution and higher leaf photosynthetic capacity contributed more to the enhancement of crop photosynthesis than did higher values of LAI. PMID- 24782437 TI - Programmed cell death in kiwifruit stigmatic arms and its relationship to the effective pollination period and the progamic phase. AB - BACKGROUND AND AIMS: Kiwifruit is a crop with a highly successful reproductive performance, which is impaired by the short effective pollination period of female flowers. This study investigates whether the degenerative processes observed in both pollinated and non-pollinated flowers after anthesis may be considered to be programmed cell death (PCD). METHODS: Features of PCD in kiwifruit, Actinidia chinensis var. deliciosa, were studied in both non pollinated and pollinated stigmatic arms using transmission electron microscopy, DAPI (4',6-diamidino-2-phenylindole) staining, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) assays, DNA gel electrophoresis and caspase-like activity assays. KEY RESULTS: In the secretory tissues of the stigmatic arms, cell organelles disintegrated sequentially while progressive vacuolization was detected. At the same time, chromatin condensation, nuclear deformation, and DNA fragmentation and degradation were observed. These features were detected in both non-pollinated and pollinated stigmatic arms; they were evident in the stigmas of pollinated flowers by the second day after anthesis but only by 4 d after anthesis in non-pollinated flowers. In addition, in pollinated stigmatic arms, these features were first initiated in the stigma and gradually progressed through the style, consistent with pollen tube growth. This timing of events was also observed in both non-pollinated and pollinated stigmatic arms for caspase-3-like activity. CONCLUSIONS: The data provide evidence to support the hypothesis that PCD processes occurring in the secretory tissue of non-pollinated kiwifruit stigmatic arms could be the origin for the observed short effective pollination period. The results obtained in the secretory tissue of pollinated kiwifruit stigmatic arms upon pollination support the idea that PCD might be accelerated by pollination, pointing to the involvement of PCD during the progamic phase. PMID- 24782438 TI - Psychometric Properties of the Oral Health Impact Profile and New Methodological Approach. AB - OBJECTIVE: Evaluate the validity, reliability, and factorial invariance of the complete Portuguese version of the Oral Health Impact Profile (OHIP) and its short version (OHIP-14). METHODS: A total of 1,162 adults enrolled in the Faculty of Dentistry of Araraquara/UNESP participated in the study; 73.1% were women; and the mean age was 40.7 +/- 16.3 yr. We conducted a confirmatory factor analysis, where chi(2)/df, comparative fit index, goodness of fit index, and root mean square error of approximation were used as indices of goodness of fit. The convergent validity was judged from the average variance extracted and the composite reliability, and the internal consistency was estimated by Cronbach standardized alpha. The stability of the models was evaluated by multigroup analysis in independent samples (test and validation) and between users and nonusers of dental prosthesis. RESULTS: We found best-fitting models for the OHIP 14 and among dental prosthesis users. The convergent validity was below adequate values for the factors "functional limitation" and "physical pain" for the complete version and for the factors "functional limitation" and "psychological discomfort" for the OHIP-14. Values of composite reliability and internal consistency were below adequate in the OHIP-14 for the factors "functional limitation" and "psychological discomfort." We detected strong invariance between test and validation samples of the full version and weak invariance for OHIP-14. The models for users and nonusers of dental prosthesis were not invariant for both versions. CONCLUSION: The reduced version of the OHIP was parsimonious, reliable, and valid to capture the construct "impact of oral health on quality of life," which was more pronounced in prosthesis users. PMID- 24782439 TI - Effects of the oestrogen receptor antagonist Fulvestrant on expression of genes that affect organization of the epididymal epithelium. AB - The role of oestrogens in epididymal function is still unclear. Knockout of the oestrogen receptor ESR1 (Esr1(-/-) ) or treatment with the anti-oestrogen Fulvestrant affect epididymal milieu and sperm motility. We investigated the effect of in vivo treatment of rats with Fulvestrant on: (i) expression of genes that may be important for the architecture and function of the epididymal epithelium: prominins 1 and 2, metalloproteinase 7, claudin 7, beta-catenin and cadherin 13, and (ii) levels of oestradiol and testosterone, and expression of oestrogen and androgen receptors, in the initial segment (IS), caput, corpus and cauda epididymis. Fulvestrant (i) reduced gene expression of prominin 1 (variant 1) in the caput, reduced prominin 1 protein content in the caput epididymis and in the efferent ductules, and increased the localization of prominin 1 in microvilli of the caput and corpus; (ii) reduced gene expression of prominin 2 in the corpus and cauda epididymis; (iii) increased the metalloproteinase 7 content in the apical region of principal cells from IS/caput; (iv) reduced in the corpus epididymis, but increased in the efferent ductules, the cadherin 13 mRNA level; (v) reduced testosterone but increased oestradiol levels in the corpus and cauda; (vi) increased the androgen receptor protein content in all regions of the epididymis, and the oestrogen receptor GPER in the corpus and cauda epididymis. In conclusion, treatment with Fulvestrant induced regional-specific changes in hormonal and steroid receptor content, and affected expression of proteins important for epithelial organization and absorption/secretion. The mechanisms of oestrogen action may differ among epididymal regions, which may contribute to determine region-specific sperm functions. PMID- 24782440 TI - Expression evolution facilitated the convergent neofunctionalization of a sodium channel gene. AB - Ion channels have played a substantial role in the evolution of novel traits across all of the domains of life. A fascinating example of a novel adaptation is the convergent evolution of electric organs in the Mormyroid and Gymnotiform electric fishes. The regulated currents that flow through ion channels directly generate the electrical signals which have evolved in these fish. Here, we investigated how the expression evolution of two sodium channel paralogs (Scn4aa and Scn4ab) influenced their convergent molecular evolution following the teleost specific whole-genome duplication. We developed a reliable assay to accurately measure the expression stoichiometry of these genes and used this technique to analyze relative expression of the duplicate genes in a phylogenetic context. We found that before a major shift in expression from skeletal muscle and neofunctionalization in the muscle-derived electric organ, Scn4aa was first downregulated in the ancestors of both electric lineages. This indicates that underlying the convergent evolution of this gene, there was a greater propensity toward neofunctionalization due to its decreased expression relative to its paralog Scn4ab. We investigated another derived muscle tissue, the sonic organ of Porichthys notatus, and show that, as in the electric fishes, Scn4aa again shows a radical shift in expression away from the ancestral muscle cells into the evolutionarily novel muscle-derived tissue. This study presents evidence that expression downregulation facilitates neofunctionalization after gene duplication, a pattern that may often set the stage for novel trait evolution after gene duplication. PMID- 24782442 TI - Quantitative proteomics reveals differential biological processes in healthy neonatal cord neutrophils and adult neutrophils. AB - Neonatal neutrophils are characterized by the immaturity of bactericidal mechanisms that contributes largely to neonatal mortality. However, underlying molecular mechanism associated with the immaturity remains incompletely understood. In this study, we performed comparative proteomic analysis on neonatal neutrophils derived from human cord blood and adult peripheral neutrophils. A total of 1332 proteins were identified and quantified, and 127 proteins were characterized as differentially expressed between adult and cord neutrophils. The differentially expressed proteins are mapped in KEGG pathways into five clusters and indicated impaired functions of neonatal neutrophils in proteasome, lysosome, phagosome, and leukocyte transendothelial migration. In particular, many proteins associated with NETosis, a critical mechanism for antimicrobial process and auto-clearance, were also found to be downregulated in cord neutrophils. This study represents a first comparative proteome profiling of neonatal and adult neutrophils, and provides a global view of differentially expressed proteome for enhancing our understanding of their various functional difference. PMID- 24782443 TI - The prevalence of voice problems among adults in the United States. AB - OBJECTIVES/HYPOTHESIS: Determine the prevalence of voice problems and types of voice disorders among adults in the United States. STUDY DESIGN: Cross-sectional analysis of a national health survey. METHODS: The 2012 National Health Interview Survey was analyzed, identifying adult cases reporting a voice problem in the preceding 12 months. In addition to demographic data, specific data regarding visits to healthcare professionals for voice problems, diagnoses given, and severity of the voice problem were analyzed. The relationship between voice problems and lost workdays was investigated. RESULTS: An estimated 17.9 +/- 0.5 million adults (mean age, 49.1 years; 62.9% +/- 1.2% female) reported a voice problem (7.6% +/- 0.2%). Overall, 10.0% +/- 0.1% saw a healthcare professional for their voice problem, and 40.3% +/- 1.8% were given a diagnosis. Females were more likely than males to report a voice problem (9.3% +/- 0.3% vs. 5.9% +/- 0.3%, P < .001). Overall, 22% and 11% reported their voice problem to be a moderate or a big/very big problem, respectively. Infectious laryngitis was the most common diagnosis mentioned (685,000 +/- 86,000 cases, 17.8% +/- 2.0%). Gastroesophageal reflux disease was mentioned in 308,000 +/- 54,000 cases (8.0% +/- 1.4%). The mean number of days affected with the voice problem in the past year was 56.2 +/- 2.6 days. Respondents with a voice problem reported 7.4 +/- 0.9 lost workdays in the past year versus 3.4 +/- 0.1 lost workdays for those without (contrast, +4.0 lost workdays; P < .001). CONCLUSIONS: Voice problems affect one in 13 adults annually. A relative minority seek healthcare for their voice problem, even though the self-reported subjective impact of the voice problem is significant. PMID- 24782444 TI - A monolayer polyoxometalate superlattice. PMID- 24782441 TI - Patterns of positive selection in seven ant genomes. AB - The evolution of ants is marked by remarkable adaptations that allowed the development of very complex social systems. To identify how ant-specific adaptations are associated with patterns of molecular evolution, we searched for signs of positive selection on amino-acid changes in proteins. We identified 24 functional categories of genes which were enriched for positively selected genes in the ant lineage. We also reanalyzed genome-wide data sets in bees and flies with the same methodology to check whether positive selection was specific to ants or also present in other insects. Notably, genes implicated in immunity were enriched for positively selected genes in the three lineages, ruling out the hypothesis that the evolution of hygienic behaviors in social insects caused a major relaxation of selective pressure on immune genes. Our scan also indicated that genes implicated in neurogenesis and olfaction started to undergo increased positive selection before the evolution of sociality in Hymenoptera. Finally, the comparison between these three lineages allowed us to pinpoint molecular evolution patterns that were specific to the ant lineage. In particular, there was ant-specific recurrent positive selection on genes with mitochondrial functions, suggesting that mitochondrial activity was improved during the evolution of this lineage. This might have been an important step toward the evolution of extreme lifespan that is a hallmark of ants. PMID- 24782445 TI - Silver-catalyzed formal insertion of arynes into Rf-I bonds. AB - An unprecedented silver-catalyzed formal insertion of arynes into Rf-I (Rf = CF3, C2F5) bonds has been developed. This protocol provides easy access to various ortho-perfluoroalkyl iodoarenes under mild conditions. In this insertion reaction, an ionic atom-transfer reaction of RfI occurs, and a silver-mediated metathesis process is involved in the efficient transfer of the electropositive iodine atom. PMID- 24782446 TI - Association of knee injuries with accelerated knee osteoarthritis progression: data from the Osteoarthritis Initiative. AB - OBJECTIVE: We aimed to evaluate whether a recent knee injury was associated with accelerated knee osteoarthritis (OA) progression. METHODS: In the Osteoarthritis Initiative, we studied participants free of knee OA on their baseline radiographs (Kellgren/Lawrence [K/L] <2). We compared 3 groups as follows: 1) individuals with accelerated progression of knee OA: defined as having at least 1 knee that progressed to end-stage knee OA (K/L grade 3 or 4) within 48 months, 2) common knee OA progression: at least 1 knee increased in radiographic scoring within 48 months (excluding those defined as accelerated knee OA), and 3) no knee OA: no change in K/L grade in either knee. At baseline, participants were asked if their knees had ever been injured, and at each annual visit they were asked about injuries during the prior 12 months. We used multinomial logistic regressions to determine whether a new knee injury was associated with the outcome of accelerated knee OA or common knee OA progression, after adjusting for age, sex, body mass index, static knee malalignment, and systolic blood pressure. RESULTS: A knee injury during the total observation period was associated with accelerated knee OA progression (n = 54; odds ratio [OR] 3.14) but not common knee OA progression (n = 187; OR 1.08). Furthermore, a more recent knee injury (within a year of the outcome) was associated with accelerated (OR 8.46) and common knee OA progression (OR 3.12). CONCLUSION: Recent knee injuries are associated with accelerated knee OA. Most concerning is that certain injuries may be associated with a rapid cascade toward joint failure in less than 1 year. PMID- 24782447 TI - Vestibular suppressants after canalith repositioning in benign paroxysmal positional vertigo. AB - OBJECTIVES/HYPOTHESIS: To investigate the characteristics of residual symptoms and to evaluate the effects of adjuvant vestibular suppressants on residual symptoms after successful canalith repositioning procedures (CRPs). STUDY DESIGN: Individual randomized controlled trial. METHODS: One hundred fifty patients with idiopathic benign paroxysmal positional vertigo who achieved successful CRPs on initial visit participated in this study. Dizziness Handicap Inventory (DHI) questionnaires were completed before CRPs. All study populations were divided into three groups after successful CRPs on the initial visit day: the medication (V) group (treated with a vestibular suppressant [dimenhydrinate 50 mg per day]), the placebo (P) group, and the no medication (N) group. One week after successful CRPs, residual symptoms were checked and repeated DHI questionnaires were completed to compare residual symptoms. RESULTS: Among the 138 patients who did not show positional nystagmus at follow-up, 67 (48.5%) complained of residual symptoms. The presence of residual symptoms was more prevalent in the P and N group compared with the V group (P = .035, P = .017, respectively). The most frequent residual symptom was lightheadedness (n = 42). Moreover, in the V group, lightheadedness was significantly reduced compared with the P group (P = .029). However, in the analysis of DHI, total and subscale scores did not differ across the three groups before or after successful CRP. CONCLUSIONS: Vestibular suppressants significantly reduced residual symptoms compared to both placebo and no medication after CRP. However, there was no significant reduction in DHI score compared with the control group, suggesting that the residual symptoms could not be evaluated by DHI score alone. PMID- 24782448 TI - Comparative interactomes of SIRT6 and SIRT7: Implication of functional links to aging. AB - Sirtuins are NAD(+) -dependent deacetylases that regulate a range of cellular processes. Although diverse functions of sirtuins have been proposed, those functions of SIRT6 and SIRT7 that are mediated by their interacting proteins remain elusive. In the present study, we identified SIRT6- and SIRT7-interacting proteins, and compared their interactomes to investigate functional links. Our interactomes revealed 136 interacting proteins for SIRT6 and 233 for SIRT7 while confirming seven and 111 proteins identified previously for SIRT6 and SIRT7, respectively. Comparison of SIRT6 and SIRT7 interactomes under the same experimental conditions disclosed 111 shared proteins, implying related functional links. The interaction networks of interactomes indicated biological processes associated with DNA repair, chromatin assembly, and aging. Interactions of two highly acetylated proteins, nucleophosmin (NPM1) and nucleolin, with SIRT6 and SIRT7 were confirmed by co-immunoprecipitation. NPM1 was found to be deacetylated by both SIRT6 and SIRT7. In senescent cells, the acetylation level of NPM1 was increased in conjunction with decreased levels of SIRT6 and SIRT7, suggesting that the acetylation of NPM1 could be regulated by SIRT6 and SIRT7 in the aging process. Our comparative interactomic study of SIRT6 and SIRT7 implies important functional links to aging by their associations with interacting proteins. All MS data have been deposited in the ProteomeXchange with identifiers PXD000159 and PXD000850 (http://proteomecentral.proteomexchange.org/dataset/PXD000159, http://proteomecentral.proteomexchange.org/dataset/PXD000850). PMID- 24782449 TI - Galectin-7 is important for normal uterine repair following menstruation. AB - Menstruation involves the shedding of the functional layer of the endometrium in the absence of pregnancy. At sites where tissue shedding is complete, re epithelialization of the tissue is essential for repair and termination of bleeding. The complement of growth factors that mediate post-menstrual endometrial repair are yet to be completely elucidated. Galectins regulate many cell functions important for post-menstrual repair, such as cell adhesion and migration. Galectin-7 has a well characterized role in re-epithelialization and wound healing. We hypothesized that galectin-7 would be important in re epithelialization during post-menstrual repair. We aimed to identify endometrial expression of galectin-7 in women undergoing normal endometrial repair and in women with amenorrhoea who do not experience endometrial breakdown and repair, and to determine whether galectin-7 enhances endometrial re-epithelialization in vitro. Galectin-7 immunolocalized to the endometrial luminal and glandular epithelium during the late secretory and menstrual phases, and to decidualized stroma in regions exhibiting tissue breakdown. Immunostaining intensity was significantly reduced in the endometrium of women with amenorrhoea compared with normally cycling woman. ELISA identified galectin-7 in menstrual fluid at significantly elevated levels compared with matched peripheral plasma. Exogenous galectin-7 (2.5 ug/ml) significantly enhanced endometrial epithelial wound repair in vitro; this was abrogated by inhibition of integrin binding. Galectin-7 elevated epithelial expression of extracellular matrix-related molecules likely involved in repair including beta-catenin, contactin and TGF-beta1. In conclusion, galectin-7 is produced by the premenstrual and menstrual endometrium, where it accumulates in menstrual fluid and likely acts as a paracrine factor to facilitate post-menstrual endometrial re-epithelialization. PMID- 24782450 TI - Protein profiling in the gut of Penaeus monodon gavaged with oral WSSV-vaccines and live white spot syndrome virus. AB - White spot syndrome virus (WSSV) is a pathogen that causes considerable mortality of the farmed shrimp, Penaeus monodon. Candidate 'vaccines', WSSV envelope protein VP28 and formalin-inactivated WSSV, can provide short-lived protection against the virus. In this study, P. monodon was orally intubated with the aforementioned vaccine candidates, and protein expression in the gut of immunised shrimps was profiled. The alterations in protein profiles in shrimps infected orally with live-WSSV were also examined. Seventeen of the identified proteins in the vaccine and WSSV-intubated shrimps varied significantly compared to those in the control shrimps. These proteins, classified under exoskeletal, cytoskeletal, immune-related, intracellular organelle part, intracellular calcium-binding or energy metabolism, are thought to directly or indirectly affect shrimp's immunity. The changes in the expression levels of crustacyanin, serine proteases, myosin light chain, and ER protein 57 observed in orally vaccinated shrimp may probably be linked to immunoprotective responses. On the other hand, altered expression of proteins linked to exoskeleton, calcium regulation and energy metabolism in WSSV-intubated shrimps is likely to symbolise disturbances in calcium homeostasis and energy metabolism. PMID- 24782452 TI - The results of conservative (fertility-sparing) treatment in borderline ovarian tumors vary depending on age and histological type. PMID- 24782451 TI - Suppression of basophil histamine release and other IgE-dependent responses in childhood Schistosoma mansoni/hookworm coinfection. AB - BACKGROUND: The poor correlation between allergen-specific immunoglobulin E (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm. METHODS: Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Nonspecific (anti-IgE), helminth specific, and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post treatment. RESULTS: Nonspecific- and helminth-specific-HR, and associations between helminth-specific IgE and helminth-specific HR increased post-treatment. Hookworm infection appeared to modify the relationship between circulating levels of HDM-IgE and HR: a significant positive association was observed among children without detectable hookworm infection, but no association was observed among infected children. In addition, hookworm infection was associated with a significantly reduced risk of wheeze, and IgG4 to somatic adult hookworm antigen with a reduced risk of HDM-SPT sensitivity. There was no evidence for S. mansoni infection having a similar suppressive effect on HDM-HR or symptoms of allergy. CONCLUSIONS: Basophil responsiveness appears suppressed during chronic helminth infection; at least in hookworm infection, this suppression may protect against allergy. PMID- 24782453 TI - Bone health in cancer patients: ESMO Clinical Practice Guidelines. AB - There are three distinct areas of cancer management that make bone health in cancer patients of increasing clinical importance. First, bone metastases are common in many solid tumours, notably those arising from the breast, prostate and lung, as well as multiple myeloma, and may cause major morbidity including fractures, severe pain, nerve compression and hypercalcaemia. Through optimum multidisciplinary management of patients with bone metastases, including the use of bone-targeted treatments such as potent bisphosphonates or denosumab, it has been possible to transform the course of advanced cancer for many patients resulting in a major reduction in skeletal complications, reduced bone pain and improved quality of life. Secondly, many of the treatments we use to treat cancer patients have effects on reproductive hormones, which are critical for the maintenance of normal bone remodelling. This endocrine disturbance results in accelerated bone loss and an increased risk of osteoporosis and fractures that can have a significant negative impact on the lives of the rapidly expanding number of long-term cancer survivors. Finally, the bone marrow micro-environment is also intimately involved in the metastatic processes required for cancer dissemination, and there are emerging data showing that, at least in some clinical situations, the use of bone-targeted treatments can reduce metastasis to bone and has potential impact on patient survival. PMID- 24782454 TI - High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 24782455 TI - Characterization of lacrimal proline-rich protein 4 (PRR4) in human tear proteome. AB - This study was initiated considering the lack of comprehensive characteristics profile of PRR4 in tears of healthy subjects. Therefore, detailed characterizations of PRR4 from basal tears employing in-gel and in-solution digestions for MS systems are presented herein. First, pooled tear samples (n = 10) were utilized to identify PRR4-rich region/spots in 1DE/2DE gels employing LC MALDI-MS and 1DE-LC-ESI-LTQ-Orbitrap-MS systems. PRR4-rich region and ten spots with vast polymorphisms (Mr : 17-30 kDa, pI: 3.0-6.6) were identified in 1DE and 2DE gels, respectively. In addition, combinations of four types of PTMs, which are methylation, acetylation, oxidation, and pyroglutamate formation, were identified in these ten PRR4 spots. Furthermore, a targeted data-acquisition approach was utilized to identify PRR4 isoforms in individual tear samples (n = 61) by in-solution digestion combined with a LC-ESI-LTQ-Orbitrap-MS system. Importantly, a new PRR4 isoform designated as PRR4-N3 in addition to PRR4 (gi154448886) and pHL E1F1 (gi1050983) was identified. Moreover, different combinations of these three PRR4 isoforms identified in the individual tear samples could be categorized into six distinguished groups. Conclusively, these findings provide fundamental insight into the complex characteristics profile of PRR4 isoforms and their PTMs in tears of healthy individuals. PMID- 24782456 TI - Acute motor and sensory polyganglioradiculoneuritis in a cat: clinical and histopathological findings. AB - Polyneuropathies can have a variety of clinical presentations and tend to be rare in cats. In this report we describe a 6-year-old domestic shorthair cat with an acute and rapidly progressive onset of lower motor neuron and sensory signs affecting the spinal and cranial nerves. Histopathological examination revealed moderate-to-severe multifocal inflammatory infiltrates at the ventral and dorsal nerve roots, and dorsal spinal ganglia at the level of the L4 and cauda equina. The type and severity of inflammation varied between nerve roots, being composed of mainly neutrophils in some and mainly lymphocytes and macrophages in others. Immunohistochemistry showed a combination of neutrophils, macrophages and lymphocytes infiltrating the nerve roots and ganglia. The majority of the lymphocytes were T lymphocytes; only a few B lymphocytes were seen. Neurons within the affected ganglia showed central chromatolysis and necrosis. Wallerian like degeneration and demyelination were observed in the nerve roots. A sensory and motor polyganglioradiculoneuritis was diagnosed. An autoimmune process similar to the acute motor and sensory neuropathy subtype of Guillain-Barre syndrome in humans or an infection by an unidentified agent were considered most likely. PMID- 24782457 TI - Influence of the observer's level of experience on systolic and diastolic arterial blood pressure measurements using Doppler ultrasonography in healthy conscious cats. AB - The objective of this study was to determine the influence of the observer's level of experience on within- and between-day variability, and the percentage of successful systolic (SAP) and diastolic arterial blood pressure (DAP) measurements obtained by Doppler ultrasonography (DU) in awake cats. For this purpose, six healthy conscious cats were used and four observers with different levels of training performed 144 SAP and DAP measurements on 4 days using DU. Measurements were recorded five consecutive times, and mean values were used for statistical analysis. Only the two most skilled observers - a PhD student in cardiology and a Dipl ECVIM-CA (cardiology) - had within- and between-day coefficients of variation (CVs) for SAP ?16% (13-16%). Conversely, the two less experienced observers - a fifth-year student and an assistant - had high between day CVs (61% and 73%). For DAP, only the most experienced observer (Dipl ECVIM CA) succeeded in 100% of the attempts, with within- and between-day CVs of 11% and 4%, respectively. Conversely, DAP could not be measured by the other three observers in 8%, 19% and 56% of attempts (from the highest to the lowest level of experience); therefore, the corresponding CV values could not be calculated. In conclusion, SAP may be assessed using DU in healthy awake cats with good repeatability and reproducibility by a well-trained observer. Measurement of DAP is more difficult than of SAP, and needs a longer training period, which represents one of the limitations of DU in cats. PMID- 24782458 TI - Thymoma associated with exfoliative dermatitis in a cat. AB - A 7-year-old, castrated male, domestic shorthair cat presented with generalized exfoliative dermatitis, lethargy, anorexia and weight loss. Multiple skin scrapings taken at the time did not reveal any abnormalities. Skin histopathological examination was consistent with sebaceous adenitis or exfoliative dermatitis caused by an underlying thymoma (thymoma-associated feline exfoliative dermatitis). Thoracic radiographs revealed a cranial mediastinal mass, which was removed surgically. Histopathological examinations indicated that it was a thymoma. Within 90 days of surgery, the cutaneous signs had resolved, suggesting a causal relationship between the thymoma and the skin disease. Recurrence of thymoma was detected 24 months after surgery. PMID- 24782459 TI - Antiviral treatment of feline immunodeficiency virus-infected cats with (R)-9-(2 phosphonylmethoxypropyl)-2,6-diaminopurine. AB - Feline immunodeficiency virus (FIV), the causative agent of an acquired immunodeficiency syndrome in cats (feline AIDS), is a ubiquitous health threat to the domestic and feral cat population, also triggering disease in wild animals. No registered antiviral compounds are currently available to treat FIV-infected cats. Several human antiviral drugs have been used experimentally in cats, but not without the development of serious adverse effects. Here we report on the treatment of six naturally FIV-infected cats, suffering from moderate to severe disease, with the antiretroviral compound (R)-9-(2-phosphonylmethoxypropyl)-2,6 diaminopurine ([R]-PMPDAP), a close analogue of tenofovir, a widely prescribed anti-HIV drug in human medicine. An improvement in the average Karnofsky score (pretreatment 33.2 +/- 9.4%, post-treatment 65+/-12.3%), some laboratory parameters (ie, serum amyloid A and gammaglobulins) and a decrease of FIV viral load in plasma were noted in most cats. The role of concurrent medication in ameliorating the Karnofsky score, as well as the possible development of haematological side effects, are discussed. Side effects, when noted, appeared mild and reversible upon cessation of treatment. Although strong conclusions cannot be drawn owing to the small number of patients and lack of a placebo treated control group, the activity of (R)-PMPDAP, as observed here, warrants further investigation. PMID- 24782460 TI - Feline double pigtail ureteric stents for management of ureteric obstruction: short- and long-term follow-up of 26 cats. AB - The objective of this study was to determine the outcome of cats with ureteric obstruction managed with double pigtail ureteric stents and to document the incidence of lower urinary tract signs at long-term follow-up. Data were obtained retrospectively from the medical records (2009-2012) of 26 cats that underwent ureteric stent placement. Owners were contacted for follow-up, and a quality of life questionnaire completed. Survival to discharge after stent placement was 85% (22/26). Prevalence of postoperative uroabdomen necessitating further surgery was 15% (4/26). Stents were replaced 4-28 months after the initial surgery in four cats because of migration, fracture, encrustation causing luminal obstruction or sterile cystitis, respectively. Nine cats were alive at follow-up, which was 3-28 months after the original surgery. Nine cats had azotaemic chronic kidney disease and nine had signs related to sterile cystitis; three of these cats were euthanased as a result of the severity of the signs. Preoperative serum creatinine of the survivors (9.4 mg/dl, n = 9) was not significantly different from that of the non-survivors (6.5 mg/dl, n = 13; P = 0.295). Quality of life was assigned a mean score of 8/10. Median survival of cats following discharge was 419 days (range 44-994 days). Signs consistent with sterile cystitis affected 35% of cats. It was concluded that ureteric stent placement in cats was associated with a 15% mortality rate before hospital discharge. Long-term management of ureteric stents is associated with a high rate of lower urinary tract signs. PMID- 24782461 TI - Early pregnancy diagnosis and monitoring in the queen using ultrasonography with a 12.5 MHz probe. AB - Eleven pregnancies in six queens were monitored daily from day 7 to day 28, corresponding to the end of the embryonic period, using ultrasonography with a 12.5 MHz probe. The first mating was considered as the presumed start of gestation, as has been described to be the case in 92.3% of pregnancies. The embryonic vesicles were identified on day 11, while the embryo appeared on day 15 or 16. The stage of pregnancy could be evaluated approximately by measuring the length of the embryonic vesicle or the crown-rump length of the embryo from days 11 and 17, respectively, up until the end of the embryonic phase of gestation. The visualisation of certain organs could also be used to date gestation; for example, the limbs, neural tube and stomach were visible from days 19, 20 and 26, respectively. The 12.5 MHz probe did not enable the diagnosis of gestation to be performed any earlier than with 7.5 and 10 MHz probes. However, there was a significant difference in comparison with a 5 MHz probe. PMID- 24782462 TI - Development of 3-phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide compounds as inhibitors of antiapoptotic Bcl-2 family proteins. AB - Antiapoptotic Bcl-2 family proteins, such as Bcl-xL , Bcl-2, and Mcl-1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radiotherapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure based virtual screening, a lead compound with micromolar binding affinity to Mcl 1 (inhibition constant (Ki )=3 MUM). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl-2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaffold-hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence-polarization binding assay to measure their binding affinities to Bcl-xL , Bcl-2, and Mcl-1. Some of the compounds with a 3-phenylthiophene-2-sulfonamide core moiety showed sub micromolar binding affinities to Mcl-1 (Ki =0.3-0.4 MUM) or Bcl-2 (Ki ~1 MUM). They also showed obvious cytotoxicity on tumor cells (IC50 <10 MUM). Two dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW-E5, YCW-E10, and YCW-E11, indicated that they bind to the BH3-binding groove on Bcl-xL in a similar mode to ABT-737. Several apoptotic assays conducted on HL-60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3-phenylthiophene-2-sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl-1 and Bcl-2. PMID- 24782463 TI - Inflammatory ultrasound features show independent associations with progression of structural damage after over 2 years of follow-up in patients with hand osteoarthritis. AB - OBJECTIVE: To study the development of inflammatory features and it's relation to structural damage over a 2.3-year period in patients with hand osteoarthritis (HOA). METHODS: Synovial thickening, effusion and power Doppler signal (PDS) in distal interphalangeal (DIP), proximal interphalangeal (PIP), 1st carpometacarpal (CMC) metacarpal phalangeal (MCP) and 1st interphalangeal (IP) joints were assessed using ultrasonography in 56 consecutive HOA patients (mean age 61.2 years, 85.7% female) fulfilling American College of Rheumatology (ACR) classification criteria, at baseline and follow-up. Radiographic progression of osteophytes and joint space narrowing (JSN) was scored using the OARSI atlas. With generalised estimating equations (GEE), OR with 95% CIs were calculated for the associations between inflammatory ultrasound features and radiographic progression taking in account patient effect, age, gender, Body Mass Index, baseline osteophytes and JSN scores, and other inflammatory ultrasound features. RESULTS: Of 1680 joints, 8.4%, 8.7%, and 19.8% had synovial thickening, PDS or effusion at baseline, respectively. 7.1% and 5.7% of joints had progression of osteophytes and JSN, respectively. Independent associations were found between synovial thickening, effusion and PDS (grade 2-3 vs 0), and progression of osteophytes (OR (95% CI): 2.6 (1.02 to 6.5), 3.5 (1.7 to 7.4) and 5.7 (1.5 to 21.1)) and of JSN (OR (95% CI): 3.4 (1.3 to 8.4), 3.3 (1.5 to 7.6) and 3.1 (1.01 to 9.2)). Persistent inflammatory features at baseline and follow-up showed stronger associations with radiographic progression than fluctuating inflammatory features in comparison with no inflammatory features. CONCLUSIONS: Inflammatory features, especially when persistently present, are independently associated with radiological progression in HOA after 2.3 years, indicating a role of inflammation in the aetiology of structural damage in HOA. PMID- 24782464 TI - Monoamine oxidase (MAO) inhibitory activity: 3-phenylcoumarins versus 4-hydroxy-3 phenylcoumarins. AB - Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Both isoforms, MAO-A and MAO-B, are known to play critical roles in disease progression, and as such, the identification of novel, potent and selective inhibitors is an important research goal. Here, two series of 3-phenylcoumarin derivatives were synthesized and evaluated against MAO A and MAO-B. Most of the compounds tested acted preferentially on MAO-B, with IC50 values in the micromolar to nanomolar range. Only 6-chloro-4-hydroxy-3-(2' hydroxyphenyl)coumarin exhibited activity against the MAO-A isoform, while still retaining good selectivity for MAO-B. 6-Chloro-3-phenylcoumarins unsubstituted at the 4 position were found to be more active as MAO-B inhibitors than the corresponding 4-hydroxylated coumarins. For 4-unsubstituted coumarins, meta and para positions on the 3-phenyl ring seem to be the most favorable for substitution. Molecular docking simulations were used to explain the observed hMAO-B structure-activity relationships for this type of compound. 6-Chloro-3-(3' methoxyphenyl)coumarin was the most active compound identified (IC50=0.001 MUM) and is several times more potent and selective than the reference compound, R-(-) deprenyl hydrochloride. This compound represents a novel tool for the further investigation of the therapeutic potential of MAO-B inhibitors. PMID- 24782465 TI - Implementation of a nurse-led consultation service for families of the elderly in Switzerland. PMID- 24782466 TI - Assessing the impact of As-Cd-Pb metal mixture on cell transformation by two stage Balb/c 3T3 cell assay. AB - Human beings are exposed to metals as a consequence of various industrial activities, including glass production, agrochemical production, metallurgy and battery manufacture. New data about the possible mechanisms involved in the carcinogenic activity of these metals are constantly being reported. Exposure to complex mixtures of metals is more likely to occur than exposure to a single metal alone. Among these elements, arsenic, cadmium and lead are ubiquitous air and water pollutants that continue to threaten the quality of public health around the world. The aim of the present study was to evaluate the capability of a mixture of 2 uM NaAsO2, 2 uM CdCl2 and 5 uM Pb(C2H3O2)2.3H2O at relevant epidemiological concentrations to induce cell transformation processes. Transforming potential was determined by a murine two-stage Balb/c 3T3 cell assay. Cell viability, reactive oxygen species (ROS), DNA damage, cell cycle analysis, senescence, generation time and metallothionein expression were also evaluated. The results showed that the metal mixture induced morphological cell transformation only when acting as initiator stimuli of the process. A decrease in cell viability was observed at the promotion stage, a time during which ROS increase, especially when a metal mixture was applied as a promoter stimulant. Changes in DNA damage were not observed throughout the assay; however, we observed G1 cell cycle arrest. The metal mixture, acting as a promoter, is capable of inducing senescence, but metals employed as initiators with 12-O tetradecanoylphorbol-13-acetate as a promoter are capable of causing avoidance of senescence and triggering the transformation potential of the cells. PMID- 24782467 TI - A prospective study of acute corneal hydrops by in vivo confocal microscopy in a New Zealand population with keratoconus. AB - BACKGROUND/AIMS: To analyse the clinical and microstructural changes during the course of acute corneal hydrops in keratoconus. METHODS: A prospective study of consecutive patients presenting with acute corneal hydrops over 12 months was performed. Patients were examined with slit-lamp biomicroscopy and in vivo confocal microscopy (IVCM) at 2-weekly intervals until resolution of hydrops. RESULTS: 10 consecutive patients (mean age 23.6+/-7.5 years) were recruited. All were of Maori or Pacific Island Nations origin. All affected eyes exhibited extensive grade 3 acute corneal hydrops. Mean best corrected vision in hydrops eyes was 2/60 at presentation and 6/48 at resolution. Mean time to resolution of hydrops was 9.9+/-4.3 weeks. On IVCM, four corneas exhibited hyper-reflective round cells in the epithelium and stroma. Elongated branching cells with small cell bodies were noted in the anterior stroma in two cases at 6 and 12 weeks, respectively. Three months after presentation, both cases also exhibited unusual stromal cells with large speckled cell bodies and elongated branching cell processes. Both cases subsequently developed corneal neovascularisation. CONCLUSIONS: Corneal neovascularisation occurred in 20% of eyes in this pilot study and prolonged presence of presumed inflammatory cells was observed in these eyes. Further study of this potential association may enable identification of patients at risk of neovascularisation. PMID- 24782468 TI - Fine needle diathermy occlusion of corneal vessels. AB - AIMS: To evaluate the efficacy of fine needle diathermy (FND) occlusion of corneal vessels in relation to defined clinical indications. METHODS: A retrospective, consecutive case series including all patients treated by FND for occlusion of corneal vessels between 2004 and 2012. Indications were lipid keratopathy, preparation for keratoplasty to reduce risk of rejection and treatment of recalcitrant corneal graft rejection associated with stromal vessels. Our outcome measures were occlusion of corneal vessels with reduced corneal vascularisation, reduction in amount of lipid deposition, and reduction of graft rejection episodes. RESULTS: FND effectively reduced lipid deposition associated with the treated vessels in 14 out of 17 eyes (82.3%). When used to reduce corneal vascularisation before keratoplasty and to reduce intraoperative bleeding, the 1-year survival of the high-risk grafts was (84.6%). FND prevented further rejection episodes in 3 out of 4 corneal grafts. Fourteen eyes required retreatment (2-5 times) of which 9 had lipid keratopathy and 5 were in preparation for corneal grafting. CONCLUSIONS: FND is effective in occluding established corneal vessels. Corneal microperforation is a potentially serious adverse event, but other adverse events, such as striae, whitening and intracorneal haemorrhages are reversible. It should be considered for established corneal vessels, and can be combined with antivascular endothelial growth factors. PMID- 24782469 TI - Intraoperative optical coherence tomography using the RESCAN 700: preliminary results from the DISCOVER study. AB - Significant integrative advances are needed for intraoperative optical coherence tomography (iOCT) to achieve widespread use across ophthalmic surgery. A surgeon feedback system that provides microscope integration, heads-up display and foot pedal control of the OCT scan location represents a major interval advance in ophthalmic surgery. In this report, we describe the preliminary findings of the Determination of feasibility of Intraoperative Spectral domain microscope Combined/integrated OCT Visualisation during En face Retinal and ophthalmic surgery (DISCOVER) study, a multisurgeon investigational device study examining the role of microscope integrated iOCT systems with surgeon heads-up display feedback (eg, Carl Zeiss Meditec RESCAN 700, Cole Eye Institute iOCT prototype). During surgical manoeuvres in anterior segment and posterior segment surgery, this technology provides rapid visualisation of the area of interest and provides the surgeon with information regarding instrument-tissue interactions. This system represents a major advance in iterative technology for iOCT and may provide the first widely available platform for surgeons to seamlessly assimilate this technology into the operating room theatre. PMID- 24782470 TI - The impact of intermittent exotropia and surgery for intermittent exotropia on myopic progression among early school-aged children with myopia. AB - AIM: To investigate the relationship between myopic progression and intermittent exotropia, and the impact of surgery for exotropia on myopic progression in early school-aged children (from 7 years to 12 years of age). METHODS: Medical records of early school-aged patients with myopia were reviewed. Patients were divided into three groups; (A) Patients with intermittent exotropia and myopia at presentation and who underwent bilateral lateral rectus muscle recession for exotropia when 7-12 years old; (B) Patients with intermittent exotropia and myopia at presentation and who were merely observed for exotropia; and (C) Patients with myopia and straight ocular alignment. Main outcome measurements were the simple rate of myopic progression per year, the preoperative and postoperative rates of refractive growth with regards to the logarithmic age model in Group A, and the rate of high myopia development at the end of the early school period. RESULTS: The rates of myopic progression were -0.43+/-0.14 dioptre (D) per year in Group A, -0.49+/-0.17 D/year in Group B and -0.42+/-0.24 D/year in Group C. There was no significant difference in the rate of myopic progression among three groups. There was no significant intergroup difference in the preoperative and postoperative rates of refractive growth in Group A. There were no significant intergroup differences in the rates of high myopia development among three groups. CONCLUSIONS: Whether patients with intermittent exotropia underwent surgical correction for intermittent exotropia did not influence the rate of myopic progression. There was no significant difference in the rate of myopic progression between patients with accompanying intermittent exotropia and myopia and those with myopia alone. PMID- 24782471 TI - Polypoidal choroidal vasculopathy in Caucasian patients with presumed age-related macular degeneration. PMID- 24782472 TI - Functional and anatomical outcome of eyes with neovascular age-related macular degeneration treated with intravitreal ranibizumab following an exit strategy regimen. AB - AIMS: To assess the functional and morphological outcome of eyes with neovascular AMD treated with intravitreal ranbizumab following an exit strategy treatment regime. METHODS: The Bern treatment regime for neovascular AMD has a fixed injection schedule, even in the non-active stage of the disease. The regimen has been adapted from the PIER study treatment protocol. Eyes with non-active AMD will receive 4 injections in the first year, and 2 injections in the second year of follow-up before treatment stops. Patients that received ranibizumab for treatment and reached the exit criteria were identified, and charts were reviewed to assess functional and morphological outcome. RESULTS: Only 2.6% of all patients (15 out of 575 patients) reached the exit criteria. Mean change in best corrected ETDRS visual acuity (VA) was 4.5+/-16.9 letters when comparing baseline VA to 4 weeks after the last injection (p=0.32). OCT mean foveal thickness was significantly thinner after last treatment (247.9+/-43.0 um) compared to baseline (332.5+/-83.1 um, p=0.002). The mean total number of ranibizumab injections was 15.6+/-8.0, and the mean total treatment period was 40.9+/-18.3 months. Twenty percent of eyes had geographic atrophy present at baseline versus 46.6% at the end of treatment. CONCLUSIONS: Even with a fixed treatment regime and a defined treatment exit strategy, only a small percentage of patients reach exit criteria. Retinal thickness has been significantly reduced by repeated intravitreal ranibizumab injections, and geographic atrophy became more frequent. PMID- 24782473 TI - Evaluating the safety of air travel for patients with scleral buckles and small volumes of intraocular gas. AB - AIM: To evaluate the effect of scleral buckling on intraocular pressure (IOP) change during atmospheric decompression for eyes with small volumes of intravitreal gas. METHODS: 12 eyes of 12 patients, including 6 with and 6 without scleral buckles, were evaluated in a hypobaric chamber simulating air travel approximately 1 month post pars plana vitrectomy with 15% C3F8 gas fluid exchange. The chamber was decompressed with an ascent rate of 300 feet/min to a peak altitude of 8000 feet. After 15 min of cruising, descent was undertaken at 300 feet/min. IOP was measured at baseline and then every 5 min using slit-lamp mounted Goldmann applanation tonometry. The data were entered onto a spreadsheet and comparative statistics were done. RESULTS: During ascent, IOP steadily rose from an average of 13+/-3 mm Hg to a peak of 26+/-9 mm Hg at 8000 feet. Patients with scleral buckles had significantly lower peak IOPs compared with those without buckles (20+/-5 mm Hg vs 32+/-8 mm Hg, p=0.013, t test) representing lower absolute increases in IOP (7+/-1 mm Hg vs 19+/-7 mm Hg, p=0.001, t test) and lower percentage increases in IOP from baseline (62+/-25% vs 140+/-40%, respectively). CONCLUSIONS: Eyes with small volumes of intravitreal gas demonstrate significant IOP changes during atmospheric decompression in simulated flight. The presence of a scleral buckle significantly limits the magnitude of IOP change, suggesting that such patients can likely tolerate typical air travel without undue risk of dangerous IOP elevation. PMID- 24782474 TI - Retinal nerve fibre layer and macular thickness analysis with Fourier domain optical coherence tomography in subjects with a positive family history for primary open angle glaucoma. AB - AIM: To detect early structural changes of retinal nerve fibre layer (RNFL) and macular ganglion cell complex (GCC) in subjects with a positive family history for primary open angle glaucoma (POAG) using Fourier domain optical coherence tomography (FD-OCT) (RTVue-100). METHODS: This was a cross-sectional observational study. First and second degree relatives of POAG patients, healthy subjects, and subjects with preperimetric glaucoma (PPG) without a family history for glaucoma, were enrolled. All participants underwent complete ophthalmic examination, visual field test and FD-OCT (RTVue-100) imaging. Average RNFL and GCC thicknesses were measured and a pattern analysis was applied to the GCC map. Analysis of variance (ANOVA), least significant difference post-hoc test, and multiple ANOVA were used. RESULTS: The final analysis included 271 eyes divided into several groups: 163 eyes of first and second degree relatives (85 healthy, 40 with ocular hypertension and 38 with PPG); and 108 eyes of subjects without a positive family history (60 healthy and 48 PPG). RNFL and GCC thickness values of these five groups were statistically different (p<0.001). RNFL superior, GCC average, GCC superior, and GCC inferior were found to be significantly thinner and the global loss volume was higher in normal relatives than in healthy subjects without a positive family history of POAG (p=0.04, p=0.001, p=0.005, p=0.004, p=0.009). RNFL and GCC thicknesses obtained by dividing the family members by the degree of consanguinity showed statistically significant thinning in siblings of glaucomatous subjects than in offspring. CONCLUSIONS: Our study shows that the eyes of subjects with a positive family history for POAG have significantly thinner RNFL and GCC than normal eyes and a more accurate follow-up has to be performed. PMID- 24782475 TI - Posterior iris-claw aphakic intraocular lens implantation and Descemet membrane endothelial keratoplasty. AB - PURPOSE: To evaluate clinical outcomes and complications after Descemet membrane endothelial keratoplasty (DMEK) and posterior iris-claw aphakic intraocular lens (IOL) implantation. METHODS: This prospective cohort study comprised seven consecutive eyes (seven patients) without adequate capsular support and bullous keratopathy undergoing posterior iris-claw aphakic IOL implantation and DMEK. Corneal transparency, central corneal thickness, endothelial cell density, visual outcomes and complication rates were measured during the follow-up. RESULTS: The iris-claw IOLs were inserted during an IOL exchange in three eyes, and as a secondary IOL implantation in one aphakic eye during DMEK procedure. Three eyes had IOL exchange prior to secondary DMEK. Mean follow-up was 7 months (range 3-14 months). The final best spectacle-corrected visual acuity improved significantly (0.33+/-0.31 logMAR) compared with the preoperative best spectacle-corrected visual acuity (1.84+/-0.90 logMAR). The mean endothelial cell loss was 24.8% over the follow-up. Complications included graft dislocation in four eyes; which could be easily reattached with a rebubbling procedure. No graft failures, no cases of pupillary block glaucoma and no IOL dislocations were encountered. CONCLUSIONS: DMEK and retropupillar iris-claw IOL implantation provide good visual outcomes with a fast visual recovery and appear to be a feasible method for the management of bullous keratopathy but with higher graft detachment rates. TRIAL REGISTRATION NUMBER: NCT02020044. PMID- 24782476 TI - Incidence of cystoid macular oedema in diabetic patients after phacoemulsification and free radical link to its pathogenesis. AB - PURPOSE: Postoperative onset of cystoid macular oedema (CME) in diabetic patients after cataract surgery is a frequent problem in working-age adults worldwide. Here, we investigate the postoperative development of CME in diabetic patients after undergoing phacoemulsification with other ailing factors associated with CME. METHODS: This prospective study included 65 Type 2 diabetic patients with no diabetic retinopathy (DR), mild to moderate DR, moderate to severe DR and proliferative DR who underwent phacoemulsification surgery. Indirect ophthalmoscopy, fluorescein angiograms and optical coherence tomography were taken for a period of 8 weeks postoperatively to determine visual outcome and development of CME. Serum samples were collected for the measurement of antioxidants and reactive oxygen species (ROS) levels. RESULTS: Our data showed that CME occurred postoperatively in 47% without pre-existing DR and 55% of eyes with pre-existing DR (p<005). Positive association was noticed between morbid conditions, like hypertension (p<0.01) and diabetic nephropathy (p<0.05), and postoperative incidence of CME. The activity of antioxidant enzymes in patients with DR was found to be lower as compared with diabetic (D) patients, but catalase activity was recorded the maximum in these patients. The ROS activity was recorded highest in the serum samples of DR becoming CME positive. CONCLUSIONS: The present results suggest that after phacoemulsification, the chance of development of CME in DR is more as compared to D. Moreover, the development of CME is significantly associated with decrease in antioxidant levels, increased ROS activities, hypertension, diabetic nephropathy, and hyperlipidaemia. PMID- 24782477 TI - Acetabular changes associated with avascularnecrosis of the femoral head in a piglet model. AB - OBJECTIVES: An experimental piglet model induces avascular necrosis (AVN) and deformation of the femoral head but its secondary effects on the developing acetabulum have not been studied. The aim of this study was to assess the development of secondary acetabular deformation following femoral head ischemia. METHODS: Intracapsular circumferential ligation at the base of the femoral neck and sectioning of the ligamentum teres were performed in three week old piglets. MRI was then used for qualitative and quantitative studies of the acetabula in operated and non-operated hips in eight piglets from 48 hours to eight weeks post surgery. Specimen photographs and histological sections of the acetabula were done at the end of the study. RESULTS: The operated-side acetabula were wider, shallower and misshapen, with flattened labral edges. At eight weeks, increased acetabular cartilage thickness characterised the operated sides compared with non operated sides (p < 0.001, ANOVA). The mean acetabular width on the operated side was increased (p = 0.015) while acetabular depth was decreased anteriorly (p = 0.007) and posteriorly (p = 0.44). The cartilage was thicker, with delayed acetabular bone formation, and showed increased vascularisation with fibrosis laterally and focal degenerative changes involving chondrocyte hypocellularity, chondrocyte cloning, peripheral pannus formation and surface fibrillation. CONCLUSIONS: We demonstrate that femoral head AVN in the young growing piglet also induced, and was coupled with, secondary malformation in acetabular shape affecting both articular and adjacent pelvic cartilage structure, and acetabular bone. The femoral head model inducing AVN can also be applied to studies of acetabular maldevelopment, which is less well understood in terms of developing hip malformation. Cite this article: Bone Joint Res 2014;3:130-8. PMID- 24782478 TI - Recording signs of deterioration in acute patients: The documentation of vital signs within electronic health records in patients who suffered in-hospital cardiac arrest. AB - Vital sign documentation is crucial to detecting patient deterioration. Little is known about the documentation of vital signs in electronic health records. This study aimed to examine documentation of vital signs in electronic health records. We examined the vital signs documented in the electronic health records of patients who had suffered an in-hospital cardiac arrest and on whom cardiopulmonary resuscitation was attempted between 2007 and 2011 (n = 228), in a 372-bed district general hospital. We assessed the completeness of vital sign data compared to VitalPACTM Early Warning Score and the location of vital signs within the electronic health records. There was a noticeable lack of completeness of vital signs. Vital signs were fragmented through various sections of the electronic health records. The study identified serious shortfalls in the representation of vital signs in the electronic health records, with consequential threats to patient safety. PMID- 24782479 TI - Use of mobile devices in the emergency department: A scoping review. AB - Electronic health records are increasingly used in regional health authorities, healthcare systems, hospitals, and clinics throughout North America. The emergency department provides care for urgent and critically ill patients. Over the past several years, emergency departments have become more computerized. Tablet computers and Smartphones are increasingly common in daily use. As part of the computerization trend, we have seen the introduction of handheld computers, tablets, and Smartphones into practice as a way of providing health professionals (e.g. physicians, nurses) with access to patient information and decision support in the emergency department. In this article, we present a scoping review and outline the current state of the research using mobile devices in the emergency departments. Our findings suggest that there is very little research evidence that supports the use of these mobile devices, and more research is needed to better understand and optimize the use of mobile devices. Given the prevalence of handheld devices, it is inevitable that more decision support, charting, and other activities will be performed on these devices. These developments have the potential to improve the quality and timeliness of care but should be thoroughly evaluated. PMID- 24782480 TI - The coordination hub: Toward patient-centered and collaborative care processes. AB - The organization and processes of today's health and social care are becoming ever more complex as a consequence of societal trends, including an aging population and an increased reliance on care at home. One aspect of the increased complexity is that a single patient may receive care from several care providers, which easily results in situations with potentially incoherent, uncoordinated, and interfering care processes. In order to describe and analyze such situations, the article introduces the notion of a process conglomeration. This is defined as a set of patient-care processes that all concern the same patient, that are overlapping in time, and that all are sharing the overall goal of improving or maintaining the health and social well-being of the patient. Problems and challenges of process conglomerations are investigated using coordination theory and models for continuous process improvement. In order to address the challenges, a solution is proposed in the form of a Coordination Hub, being an integrated software service that offers a number of information services for coordinating the activities of the processes in a process conglomeration. PMID- 24782481 TI - Effects of electronic emergency-department whiteboards on clinicians' time distribution and mental workload. AB - Whiteboards are a central tool at emergency departments. We investigate how the substitution of electronic for dry-erase whiteboards affects emergency department clinicians' mental workload and distribution of their time. With the electronic whiteboard, physicians and nurses spend more of their time in the work areas where other clinicians are present and whiteboard information is permanently displayed, and less in the patient rooms. Main reasons for these changes appear to be that the electronic whiteboard facilitates better timeouts and handovers. Physicians and nurses are, however, in the patient rooms for longer periods at a time, suggesting a more focused patient contact. The physicians' mental workload has increased during timeouts, whereas the nurses' mental workload has decreased at the start of shifts when they form an overview of the emergency department. Finally, the secretaries, but neither physicians nor nurses, access whiteboard information on computers other than the permanent displays. PMID- 24782482 TI - Jump frequency may contribute to risk of jumper's knee: a study of interindividual and sex differences in a total of 11,943 jumps video recorded during training and matches in young elite volleyball players. AB - BACKGROUND: Male sex, total training volume (number of hours per week) and match exposure (number of sets played per week) are risk factors for jumper's knee among young elite volleyball players. However, it is not known whether jump frequency differs among players on the same squad. OBJECTIVE: To examine interindividual and sex differences in jump frequency during training and matches in young elite volleyball players. DESIGN: Observational study. SETTING: Norwegian elite volleyball boarding school training programme. PARTICIPANTS: Student-athletes (26 boys and 18 girls, 16-18 years). METHODS: Individual jump counts were recorded based on visual analysis of video recordings obtained from 1 week of volleyball training (9 training sessions for boys and 10 for girls, 14.1 h and 17.8 h of training, respectively) and 10 matches (5.9 h for boys (16 sets) and 7.7 h for girls (21 sets). RESULTS: A total of 11,943 jumps were recorded, 4138 during matches and 7805 during training. As training attendance and jump frequency varied substantially between players, the total exposure in training ranged from 50 to 666 jumps/week among boys and from 11 to 251 jumps/week among girls. On average, this corresponded to 35.7 jumps/h for boys and 13.7 jumps/h for girls (Student t test, p=0.002). Total jump exposure during matches ranged between 1 and 339 jumps among boys and between 0 and 379 jumps among girls, corresponding to an average jump frequency of 62.2 jumps/h for boys and 41.9 jumps/h for girls (Student t test, p<0.039). The interindividual differences in jump frequency were substantially greater than any differences observed among player functions. CONCLUSIONS: Jump frequency has substantial interindividual and sex differences during training and matches in young elite volleyball players. Total jump volume may represent a more important risk factor for jumper's knee than total training volume, warranting further research attention. PMID- 24782483 TI - Evolution of accelerometer methods for physical activity research. AB - The technology and application of current accelerometer-based devices in physical activity (PA) research allow the capture and storage or transmission of large volumes of raw acceleration signal data. These rich data not only provide opportunities to improve PA characterisation, but also bring logistical and analytic challenges. We discuss how researchers and developers from multiple disciplines are responding to the analytic challenges and how advances in data storage, transmission and big data computing will minimise logistical challenges. These new approaches also bring the need for several paradigm shifts for PA researchers, including a shift from count-based approaches and regression calibrations for PA energy expenditure (PAEE) estimation to activity characterisation and EE estimation based on features extracted from raw acceleration signals. Furthermore, a collaborative approach towards analytic methods is proposed to facilitate PA research, which requires a shift away from multiple independent calibration studies. Finally, we make the case for a distinction between PA represented by accelerometer-based devices and PA assessed by self-report. PMID- 24782484 TI - Current physical activity guidelines for health are insufficient to mitigate long term weight gain: more data in the fitness versus fatness debate (The HUNT study, Norway). AB - BACKGROUND: To promote and maintain health, all adults are recommended to do moderate-intensity aerobic activity a minimum of 30 min on 5 days, or vigorous intensity activity of 20 min on 3 days, each week. Whether these levels prevent long-term weight gain is uncertain. OBJECTIVE: To assess the relationship between physical activity and long-term weight gain. STUDY DESIGN: An observational prospective cohort study. METHODS: Weight and physical activity were measured in the Nord-Trondelag Health Study in 1984-1986, 1995-1997 and 2006-2008. Participants (n=19 127) were classified based on physical activity into inactive, below recommended level, recommended level or above recommended level. We carried out adjusted mixed model regression analyses with weight as outcome. RESULTS: Men maintaining physical activity above the recommendations for 33 years increased 5.6 kg, while inactive men increased 9.1 kg. For women, corresponding numbers were 3.8 kg in those above recommended physical activity levels, and 9.5 kg in inactive. In adjusted analyses, physical activity above the recommendations was associated with 2.1 kg (95% CI 1.8 to 2.4) less weight gain in men over any 11 year period, compared with inactive. Women exceeding the recommendations gained 1.8 kg (CI 1.5 to 2.2) less than inactive. Compared with inactive, the ORs of gaining meaningful weight of >=2.3 kg were 0.79 (CI 0.69 to 0.91) and 0.70 (CI 0.60 to 0.81) if exceeding the recommendations in men and women, respectively. CONCLUSIONS: Physical activity above the current recommendations for health benefits was associated with significantly lower risk of weight gain. PMID- 24782485 TI - Safety, tolerability, pharmacokinetics and antitumor activity of ganitumab, an investigational fully human monoclonal antibody to insulin-like growth factor type 1 receptor, combined with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer: a phase 1b study. AB - OBJECTIVE: Previous Phase 1 studies have shown the acceptable safety profile of ganitumab-a fully human monoclonal antibody to insulin-like growth factor Type 1 receptor-in patients with advanced solid tumors. However, ganitumab 20 mg/kg in combination with gemcitabine had not been administered to patients with metastatic pancreatic cancer. To evaluate the safety, tolerability, pharmacokinetics and antitumor activity of ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) as first-line therapy in patients with metastatic pancreatic cancer, we conducted a Phase 1b study. METHODS: Eligible patients were adults with previously untreated metastatic adenocarcinoma of the pancreas. Patients received gemcitabine 1000 mg/m(2) on Days 1, 8 and 15 plus ganitumab 20 mg/kg on Days 1 and 15 of each 28-day cycle. Gemcitabine was administered intravenously over 30-60 min. Ganitumab was administered intravenously over 60 min after completing gemcitabine infusion. RESULTS: Six patients were enrolled and received the study treatment. All patients had thrombocytopenia and leukopenia. Other most common adverse events were neutropenia and nausea. One patient had a dose-limiting toxicity defined as Grade 3 neutropenia with fever. Exposure to ganitumab 20 mg/kg was not affected by the administration of gemcitabine. No apparent pharmacokinetic drug-drug interaction was observed. No anti-ganitumab antibodies were detected. Five patients had a measurable tumor region at baseline. Of these, four patients had a best response of stable disease. CONCLUSIONS: Ganitumab 20 mg/kg combined with gemcitabine 1000 mg/m(2) was tolerable and showed an acceptable safety profile in patients with untreated metastatic pancreatic cancer. PMID- 24782486 TI - Bullet 'manicure': does lead prevent hydroxyurea-induced cutaneous toxicity? PMID- 24782487 TI - Five-year relative survival rate of uterus cancer in the USA, Europe and Japan. PMID- 24782488 TI - The Baby-Friendly Initiative in Spain: A Challenging Pathway. AB - The Baby-Friendly Initiative (BFI-Spain) was founded in 1995 by members of key professional associations (pediatricians, midwives, obstetricians, and nurses) and some mother-to-mother support groups. The United Nations International Children's Fund was instrumental in supporting the establishment of BFI-Spain as a not-for-profit organization. In 2007, the need for change was identified. A detailed analysis of BFI-Spain identified its main strengths, weaknesses, opportunities, and threats. A new strategic plan was devised that included the adoption of a staged accreditation system, a new website, expanding the initiative into the community, consolidating working teams to distribute tasks and responsibilities, and trying to involve the national health authorities. This article describes the analysis that was undertaken, the strategies implemented, and some of the outcomes observed 4 years later. The aim of the article is to support BFI teams in other countries who might be facing similar challenges. PMID- 24782489 TI - Phagocytosis of apoptotic or necrotic cells differentially regulates the transcriptional expression of IL-12 family members in dendritic cells. AB - Uptake of apoptotic cells by DCs is considered to contribute to induction and maintenance of immunological tolerance. TolDCs are sought after as cellular therapy in transplantation and autoimmunity and can be generated in vitro using GCs. In this study, we investigated how uptake of dead cells affects the production and expression of different members of the IL-12 family by immature DCs or TolDCs. We show that compared to regular immature DCs, TolDCs display elevated levels of PS-recognizing bridge molecule receptors alphavbeta5 and CD36, and have enhanced phagocytic abilities with accelerated uptake of apoptotic cells. We confirm that apoptotic cell uptake results in diminished production of IL-12p40 and IL-12p70 by DCs. We now show that this also results in increased expression of IL-12p35 and Ebi3. TolDCs completely lack expression of IL-12p40 yet have enhanced levels of Ebi3 and IL-12p35. Uptake by TolDCs of apoptotic or necrotic cells does not affect the expression of Ebi3/IL-12p35 and also does not increase IL-12p40. This is distinct from the culture of immature DCs with necrotic cells, which is sufficient to induce IL-12p40 secretion. Conversely, ingestion of apoptotic cells by DCs leads to increased expression of IL-12p35 and Ebi3 without affecting IL-12p40. In conclusion, we have shown that uptake of apoptotic versus necrotic cells by DCs differentially regulates members of the IL 12 family. Apoptotic cells favor expression of Ebi3 and IL-12p35, and we propose that differential regulation of the IL-12 family is an additional mechanism in determining the immune response to dying cells. PMID- 24782490 TI - B cells promote obesity-associated periodontitis and oral pathogen-associated inflammation. AB - Individuals with T2D and PD suffer significantly from the ability of one disease to intensify the other. Disease-associated inflammation is one mechanism thought to fuel this pathogenic feed-forward loop. Several lines of evidence indicate that proinflammatory B cells promote T2D and PD; thus, B cells are top candidates for a cell type that predisposes PD in T2D. To test directly the role of B cells in T2D-associated PD, we compared outcomes from oral Porphyromonas gingivalis challenge of lean WT or B cell-null mice with outcomes from mice that were obese and insulin-resistant before challenge. Obese WT mice responded to oral P. gingivalis challenge with significant periodontal bone loss, whereas obese B cell null mice were protected completely from PD. By contrast, lean WT and B cell-null mice suffer similar periodontal bone loss in response to oral pathogen. B cells from obese/insulin-resistant hosts also support oral osteoclastogenesis and both oral and systemic production of inflammatory cytokines, including pro osteoclastogenic TNF-alpha and MIP-2, an ortholog of human IL-8. B cells furthermore impact AT inflammation in obese, P. gingivalis-infected hosts. Taken together, these data show that fundamentally different mechanisms regulate PD in lean and obese hosts, with B cells able to promote PD only if the hosts are "primed" by obesity. These results justify more intense analysis of obesity associated changes in B cells that predispose PD in human T2D. PMID- 24782491 TI - The interaction apparatus of Asteridiella callista (Meliolaceae, Ascomycota). AB - We document here for the first time ultrastructural details of the cellular interaction of Asteridiella callista and its host Stachytarpheta mutabilis var. violacea from Costa Rica. A. callista attaches to the host with appressoria, invades the epidermal cell wall and forms an apoplastic complex cisternal net, presumably for nutrient uptake from its host. This unique structure, called an interaction apparatus (Ia), consists of cisternae surrounded by a membrane continuous with the fungal cytoplasmic membrane. Subsequently the apoplastic trunk of the Ia extends into the host epidermal cell wall and contacts the host cytoplasmic membrane. Electron-opaque material, probably of fungal origin appears at the host cytoplasmic membrane. Finally these electron-opaque deposits are encased by host material. Functional and systematical aspects of this interaction scenario are discussed. PMID- 24782492 TI - Intraspecific and intragenomic variability of ITS rDNA sequences reveals taxonomic problems in Ceratocystis fimbriata sensu stricto. AB - Fourteen new species in the Latin American Clade (LAC) of the Ceratocystis fimbriata complex recently were distinguished from C. fimbriata sensu stricto largely based on variation in ITS rDNA sequences. Among the 116 isolates representing the LAC, there were 41 ITS haplotypes. Maximum parsimony (MP) analysis of ITS sequences produced poorly resolved trees. In contrast, analyses of mating-type genes (MAT1-1-2 and MAT1-2-1) resolved a single MP tree with branches of high bootstrap and posterior probability support. Four isolates showed intragenomic variation in ITS sequences. Cloning and sequencing of PCR products from a single haploid strain identified two or more ITS sequences differing at up to 16 base positions and representing two described species. Isolates from introduced populations that appeared to be clonal based on microsatellite markers varied at up to 14 bp in ITS sequence. Strains of seven Brazilian ITS haplotypes and an isolate from Ipomoea batatas (on which the species name C. fimbriata was based) were fully interfertile in sexual crosses. These analyses support three phylogenetic species that differ in pathogenicity: C. platani, C. cacaofunesta and C. colombiana. Five ITS species (C. manginecans, C. mangicola, C. mangivora, C. acaciivora, C. eucalypticola) appear to be ITS haplotypes that have been moved from or within Brazil on nursery stock. The taxonomic status of other species delineated primarily by ITS sequences (C. diversiconidia, C. papillata, C. neglecta, C. ecuadoriana, C. fimbriatomima, C. curvata) needs further study, but they are considered doubtful species. PMID- 24782493 TI - Three new species of arbuscular mycorrhizal fungi discovered at one location in a desert of Oman: Diversispora omaniana, Septoglomus nakheelum and Rhizophagus arabicus. AB - Three new species of arbuscular mycorrhizal (AM) fungi (Glomeromycota) were isolated from soil samples collected from a hyperarid sandy plain of South Arabia. Morphological characteristics of the spores clearly differentiated them from closely related AM species. Molecular analyses were performed on rDNA sequences obtained from single spores including a ~1700 bp region comprising partial SSU, ITS, partial LSU and the ~600 bp ITS region only. The phylogenetic trees based on these regions showed that the three species belong to well described genera but are clearly distinct from known species. Consequently, we describe them here as Diversispora omaniana, Septoglomus nakheelum and Rhizophagus arabicus spp. nov. D. omaniana and R. arabicus were isolated from the native, arid habitat, while S. nakheelum was isolated from a nearby irrigated date palm plantation. The discovery of three new species of AM fungi from this location suggests that a number of additional undescribed AM taxa may be present in such desert ecosystems. Further work to understand the diversity and functional significance of these new AM taxa may offer new opportunities for conservation, re-vegetation, and sustainable agriculture in extremely arid environments. PMID- 24782494 TI - Entomopathogens of Amazonian stick insects and locusts are members of the Beauveria species complex (Cordyceps sensu stricto). AB - In the Amazon the only described species of Cordyceps sensu stricto (Hypocreales, Cordycipitaceae) that parasitize insects of Orthopterida (orders Orthoptera and Phasmida) are Cordyceps locustiphila and C. uleana. However, the type specimens for both taxa have been lost and the concepts of these species are uncertain. To achieve a more comprehensive understanding of the systematics of these species, collections of Cordyceps from the Amazon regions of Colombia, Ecuador and Guyana were subjected to morphological, ecological and molecular phylogenetic studies. Phylogenetic analyses were conducted on partial sequences of SSU, LSU, TEF, RPB1 and RPB2 nuclear loci. Two new species are proposed including C. diapheromeriphila, a parasite of Phasmida, and C. acridophila, a parasite of the superfamily Acridomorpha (Orthoptera), which is broadly distributed across the Amazon. For C. locustiphila a lectotypification and an epitypification are made. Cordyceps locustiphila is host specific with Colpolopha (Acridomorpha: Romaleidae), and its distribution coincides with that of its host. The phylogenetic placement of these three species was resolved with strong support in the Beauveria clade of Cordyceps s. str. (Cordycipitaceae). This relationship and the morphological similarity of their yellow stromata with known teleomorphs of the clade, suggest that the holomorphs of these species may include Beauveria or Beauveria-like anamorphs. The varying host specificity of the beauverioid Cordyceps species suggest the potential importance of identifying the natural host taxon before future consideration of strains for use in biological control of pest locusts. PMID- 24782495 TI - Rhagadolobiopsis, a new genus of Parmulariaceae from Brazil with a description of the ontogeny of its ascomata. AB - During a survey of the mycobiota of selected Brazilian ferns we discovered a new genus of Parmulariaceae causing tar spot-like symptoms on leaves of Thelypteris serrata (Thelypteridaceae). The new genus and species, decribed as Rhagadolobiopsis thelypteridis, differs from morphologically similar species of Rhagadolobium in possessing colorless, aseptate ascospores and a hymenial gel that does not become blue with iodine. In addition this is the first record of a fungus on T. serrata, and the first Parmulariaceae recorded on a member of the Thelypteridaceae. The ontogeny of the ascomata is described and illustrated here for the first time for the Parmulariaceae. PMID- 24782496 TI - Re-evaluation of the morphological variability of Microglossum viride and M. griseoviride sp. nov. AB - Studies in Microglossum viride (Pers.) Gillet revealed that the name was used incorrectly for two similar but different taxa. Analyses of morphological, ecological and molecular (sequences of ITS and LSU region of rRNA gene) characters of type and voucher specimens of M. viride and related taxa resulted in delimitation and description of a new species, Microglossum griseoviride V. Kucera, Lizon & M. Tomsovsky. Lectotypes of Geoglossum viride Pers., and epitype of Geoglossum viride are designated. Species Microglossum minus Velen. and Microglossum lutescens Boud. are confirmed to be conspecific to M. viride. PMID- 24782497 TI - Molecular phylogeny and taxonomy of the genus Veloporphyrellus. AB - Veloporphyrellus is a genus known from North and Central America, southeastern Asia, and Africa. Because species of this genus are phenotypically similar to some taxa in several genera, such as Boletellus, Leccinum, Strobilomyces, Suillus and Tylopilus s.l. belonging to Boletales, its phylogenetic disposition has never been addressed. We analyzed four DNA regions, the nuclear ribosomal LSU and tef 1alpha, and the mitochondrial mtSSU and atp6 genes, to investigate the phylogenetic disposition of Veloporphyrellus. Although the monophyly of the genus and its systematic placement within the Boletaceae was well supported, its relationship to other genera was not resolved. Morphologically Veloporphyrellus is distinguished from other boletoid genera by the combination of the pinkish or grayish pink hymenophore, the membranous veil hanging on the pilea margin, the trichoderm-like pileus covering and the smooth basidiospores. Five species, including two new species and two new combinations, are described and illustrated. A key to the species of Veloporphyrellus also is provided. PMID- 24782498 TI - Cantharellaceae of Guyana II: new species of Craterellus, new South American distribution records for Cantharellus guyanensis and Craterellus excelsus, and a key to the Neotropical taxa. AB - Craterellus olivaceoluteus sp. nov. and Craterellus cinereofimbriatus sp. nov. are described as new to science. These fungi were collected from Guyana in association with ectomycorrhizal host trees in the genera Dicymbe (Fabaceae subfam. Caesalpinioideae) and Pakaraimaea (Dipterocarpaceae). Cantharellus guyanensis Mont., originally described from French Guiana, is redescribed from recent collections from Guyana, with additional range extensions for the species provided based on material examined from French Guiana, Venezuela, and north central, northeastern and southern Brazil, circumscribing nearly the entire Guiana Shield region and beyond. A new distribution record from French Guiana is provided for Craterellus excelsus T.W. Henkel & Aime. Macromorphological, micromorphological and habitat data are provided for the new species and C. guyanensis as well as DNA sequence data from the nuclear ribosomal regions of the internal transcribed spacer (ITS) and 28S large subunit (LSU); additional sequence data is provided for C. guyanensis and C. excelsus specimens collected outside Guyana. The relationships of these taxa within the Cantharellaceae were evaluated with phylogenetic analyses of ITS and LSU sequence data. This work brings the total number of Cantharellaceae species known from Guyana to eight. A key to the Cantharellus and Craterellus species known from the lowland Neotropics and extralimital montane Central and South America is provided. PMID- 24782499 TI - Phylogenetic relationships of Hydnum peroxydatum support the synonymy of Hydnochaete with Hymenochaete (Hymenochaetaceae, Agaricomycetes). AB - A combined dataset of rDNA ITS and LSU sequences was used to infer the phylogenetic relationships of Hydnochaete peroxydata (= Hydnum peroxydatum), the type species of Hydnochaete. The species was retrieved nested within the Hymenochaete s. str. clade; therefore Hydnochaete is regarded as a synonym of Hymenochaete and the new combination Hymenochaete peroxydata is proposed. PMID- 24782500 TI - Acremonium with catenate elongate conidia: phylogeny of Acremonium fusidioides and related species. AB - Acremonium is one of the largest and most complex genera of hyphomycetes. Its taxonomy is not yet resolved and the phylogenetic value of the most distinctive morphological features is unknown. The species of this genus produce conidia in chains or form slimy heads or both. We have studied a set of clinical and environmental Acremonium strains morphologically characterized by producing mostly catenate, elongate, more or less fusiform conidia. Based on phenotypic data and in the analysis of the sequences of the ITS region, the D1/D2 domains of the 28S rRNA gene and a fragment of the beta-tubulin gene, three new species morphologically similar to Acremonium fusidioides and belonging to the family Bionectriaceae (Hypocreales) are described and illustrated; they are Acremonium pilosum, Acremonium parvum and Acremonium citrinum. The first species produces two kinds of conidia: clavate with smooth walls and globose with abundant filiform projections. Acremonium parvum is characterized by slow growth and pyriform or slightly lanceolate conidia with an elongate and truncate base. Acremonium citrinum produces a diffusible yellow pigment and obovoid conidia. PMID- 24782501 TI - Species diversity of Epichloe symbiotic with two grasses from southern Argentinean Patagonia. AB - In this work we performed morphological and molecular phylogenetic analyses (based on sequences of calmodulin M [calM], translation-elongation factor 1-alpha [tefA] and beta-tubulin [tubB] genes) to characterize the diversity of Epichloe endophytes in Bromus setifolius and Phleum alpinum. The phylogenies obtained from the three genes were congruent and allowed differentiation of three lineages of endophytes that also presented morphological differences. One lineage corresponds to the previously described species Epichloe tembladerae, which is present in a wide range of native grasses from Argentina including B. setifolius and P. alpinum. Another genotype isolated only from B. setifolius is a non-hybrid endophyte, a rare condition for the South American Epichloe endophytes. Isolates of this genotype, described herein as a new variety, Epichloe typhina var. aonikenkana, presented waxy colonies at maturity and a low production of conidia. The third lineage, exclusively found in isolates from P. alpinum, is a hybrid between E. typhina and a common ancestor of E. amarillans and E. baconii. Isolates of this lineage produce abundant conidia that are variable in shape and size. Based on its unique phylogenetic position and morphology, we propose the new species, Epichloe cabralii for this lineage. The new combinations Epichloe tembladerae and E. pampeana also are proposed for the previously described Neotyphodium tembladerae and Neotyphodium pampeanum species. PMID- 24782502 TI - A molecular and morphological analysis of the genus Rhizopogon subgenus Villosuli section Villosuli as a preface to ecological monitoring. AB - Rhizopogon (Boletales) represents a model genus for ecological studies of ectomycorrhizal fungi, but the identification of species in subgenus Villosuli section Villosuli has long been challenging due to variation in taxonomically informative morphological characters. Here we re-examine species concepts in this section using data from nuclear ribosomal internal transcribed spacer (ITS) and large subunit (LSU) sequences as well as spore measurements. Our phylogenetic analyses from 34 type and non-type collections of eight species, including the seven currently recognized in this section, found consistent support for only three species-level clades. Each of the clades had a significantly different combination of mean spore widths and Q ratios using digital-assisted measurements, which suggests both molecular and spore-based morphological approaches can be used to identify species in this section. Based on our analysis, we propose that only three species names be applied to future ecological studies: R. hawkerae, R. parksii and R. villosulus. We consider R. subareolatus and R. colossus as taxonomic synonyms of R. hawkerae and R. pseudovillosulus, R. rogersii, R. villescens and R. zelleri as taxonomic synonyms of R. villosulus. PMID- 24782503 TI - Use of the vital stain FUN-1 indicates viability of Phytophthora capsici propagules and can be used to predict maximum zoospore production. AB - The fluorescent vital dye FUN(r)-1 (2-chloro-4-[2,3-dihydro-3-methyl-{benzo-1,3 thiazol-2-yl}-methylidene]-1-phenylquinolinium iodide) was evaluated as a tool to assess Phytophthora capsici sporangia and zoospore metabolic activity and viability. Under aerobic conditions, mycelia, sporangia and zoospores cultured on agar medium and stained with FUN-1 exhibited red fluorescent cylindrical intravacuolar structures (CIVS) that were clearly visible at 100* magnification. Encysted zoospores did not exhibit CIVS after exposure to FUN-1 dye. Over 7 d there was a significant reduction in the percent of sporangia containing CIVS, which corresponded with a significant increase in zoospore formation and release. The decline in the percentage of metabolically active sporangia and increase in the number of zoospores fit both a linear and log regression model. The FUN-1 dye was suitable for distinguishing between live and dead sporangia and effective in monitoring the change in metabolic activity of sporangia over time. It will be useful in determining parameters, including P. capsici culture age, that maximize production of zoospores in vitro. PMID- 24782504 TI - Mutations in TLR/MYD88 pathway identify a subset of young chronic lymphocytic leukemia patients with favorable outcome. AB - Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor kappaB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age <=50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age <=50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome. PMID- 24782506 TI - RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness. AB - Neutrophil responses are central to host protection and inflammation. Neutrophil activation follows a 2-step process in which priming amplifies responses to activating stimuli. Priming is essential for life span extension, chemotaxis, and respiratory burst activity. Here we show that the cytoskeletal organizer RhoA suppresses neutrophil priming via formins. Premature granule exocytosis in Rho deficient neutrophils activated numerous signaling pathways and amplified superoxide generation. Deletion of Rho altered front-to-back coordination by simultaneously increasing uropod elongation, leading edge formation, and random migration. Concomitant negative and positive regulation of beta2 integrin independent and beta2 integrin-dependent migration, respectively, reveal Rho as a key decision point in the neutrophil response to discrete chemotactic agents. Although even restricted influx of Rho-deficient hyperactive neutrophils exacerbated lipopolysaccharide-mediated lung injury, deleting Rho in innate immune cells was highly protective in influenza A virus infection. Hence, Rho is a key regulator of disease progression by maintaining neutrophil quiescence and suppressing hyperresponsiveness. PMID- 24782505 TI - CD28-mediated pro-survival signaling induces chemotherapeutic resistance in multiple myeloma. AB - Chemotherapeutic resistance remains a significant hurdle in the treatment of multiple myeloma (MM) and is significantly mediated by interactions between MM cells and stromal cells of the bone marrow microenvironment. Despite the importance of these interactions, the specific molecules and downstream signaling components involved remain incompletely understood. We have previously shown that the prototypic T-cell costimulatory receptor CD28, which is also expressed on MM cells, is a key mediator of MM survival and apoptotic resistance. Crosslinking CD28 by agonistic antibodies or myeloid dendritic cells (DC; these express the CD28 ligands CD80/CD86) prevents apoptosis caused by chemotherapy or serum withdrawal. We now report that CD28 pro-survival signaling is dependent upon downstream activation of phosphatidyl-inositol 3-kinase/Akt, inactivation of the transcription factor FoxO3a, and decreased expression of the pro-apoptotic molecule Bim. Conversely, blocking the CD28-CD80/CD86 interaction between MM cells and DC in vitro abrogates the DC's ability to protect MM cells against chemotherapy-induced death. Consistent with these observations, in vivo blockade of CD28-CD80/CD86 in the Vk*MYC murine myeloma model sensitizes MM cells to chemotherapy and significantly reduces tumor burden. Taken together, our findings suggest that CD28 is an important mediator of MM survival during stress and can be targeted to overcome chemotherapy resistance. PMID- 24782507 TI - Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. AB - Active cancer is the major predictor of venous thromboembolism (VTE) recurrence, but further stratification of recurrence risk is uncertain. In a population-based cohort study of all Olmsted County, Minnesota, residents with active cancer related incident VTE during the 35-year period from 1966 to 2000 who survived 1 day or longer, we estimated VTE recurrence, bleeding on anticoagulant therapy, and survival and tested cancer and noncancer characteristics and secondary prophylaxis as predictors of VTE recurrence and bleeding, using Cox proportional hazards modeling. Of 477 patients, 139 developed recurrent VTE over the course of 1533 person-years of follow-up. The adjusted 10-year cumulative VTE recurrence rate was 28.6%. The adjusted 90-day cumulative incidence of major bleeding on anticoagulation was 1.9%. Survival was significantly worse for patients with cancer who had recurrent VTE (particularly pulmonary embolism) and with bleeding on anticoagulation. In a multivariable model, brain, lung, and ovarian cancer; myeloproliferative or myelodysplastic disorders; stage IV pancreatic cancer; other stage IV cancer; cancer stage progression; and leg paresis were associated with an increased hazard, and warfarin therapy was associated with a reduced hazard, of recurrent VTE. Recurrence rates were significantly higher for cancer patients with 1 or more vs no predictors of recurrence, suggesting these predictors may be useful for stratifying recurrence risk. PMID- 24782508 TI - TBLR1 fuses to retinoid acid receptor alpha in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia. AB - The majority of acute promyelocytic leukemia (APL) cases are characterized by the PML-RARalpha fusion gene. Although the PML-RARalpha fusion gene can be detected in >98% of APL cases, RARalpha is also found to be fused with other partner genes, which are also related to all-trans retinoic acid (ATRA)-dependent transcriptional activity and cell differentiation. In this study, we identified a novel RARalpha fusion gene, TBLR1-RARalpha (GenBank KF589333), in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q11.2;q21) complex chromosomal rearrangement. To our knowledge, TBLR1-RARalpha is the 10th RARalpha chimeric gene that has been reported up to now. TBLR1-RARalpha contained the B-F domains of RARalpha and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor alpha. As a result, TBLR1-RARalpha exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARalpha. In the presence of pharmacologic doses of ATRA, TBLR1-RARalpha could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARalpha could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RARalpha target genes, and cell differentiation induction in a dose- and time-dependent manner. PMID- 24782509 TI - Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19 T cells and are preserved by IL-7 and IL-15. AB - Adoptive transfer of T lymphocytes expressing a CD19-specific chimeric antigen receptor (CAR.CD19) induces complete tumor regression in patients with lymphoid malignancies. Although in vivo persistence of CAR-T cells correlates with clinical responses, it remains unknown whether specific cell subsets within the CAR-T-cell product correlate with their subsequent in vivo expansion and persistence. We analyzed 14 patients with B-cell malignancies infused with autologous CAR.CD19-redirected T cells expanded ex vivo using IL-2, and found that their in vivo expansion only correlated with the frequency within the infused product of a CD8(+)CD45RA(+)CCR7(+) subset, whose phenotype is closest to "T-memory stem cells." Preclinical models showed that increasing the frequency of CD8(+)CD45RA(+)CCR7(+) CAR-T cells in the infused line by culturing the cells with IL-7 and IL-15 produced greater antitumor activity of CAR-T cells mediated by increased resistance to cell death, following repetitive encounters with the antigen, while preserving their migration to secondary lymphoid organs. This trial was registered at www.clinicaltrials.gov as #NCT00586391 and #NCT00709033. PMID- 24782511 TI - Inactivity, disability, and death are all interlinked. PMID- 24782512 TI - Inducing labour reduces risk of caesarean delivery by 12%, finds analysis. PMID- 24782510 TI - Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function. AB - Pathologic blood clotting is a leading cause of morbidity and mortality in the developed world, underlying deep vein thrombosis, myocardial infarction, and stroke. Genetic predisposition to thrombosis is still poorly understood, and we hypothesize that there are many additional risk alleles and modifying factors remaining to be discovered. Mammalian models have contributed to our understanding of thrombosis, but are low throughput and costly. We have turned to the zebrafish, a tool for high-throughput genetic analysis. Using zinc finger nucleases, we show that disruption of the zebrafish antithrombin III (at3) locus results in spontaneous venous thrombosis in larvae. Although homozygous mutants survive into early adulthood, they eventually succumb to massive intracardiac thrombosis. Characterization of null fish revealed disseminated intravascular coagulation in larvae secondary to unopposed thrombin activity and fibrinogen consumption, which could be rescued by both human and zebrafish at3 complementary DNAs. Mutation of the human AT3-reactive center loop abolished the ability to rescue, but the heparin-binding site was dispensable. These results demonstrate overall conservation of AT3 function in zebrafish, but reveal developmental variances in the ability to tolerate excessive clot formation. The accessibility of early zebrafish development will provide unique methods for dissection of the underlying mechanisms of thrombosis. PMID- 24782513 TI - Exonerated psychiatrist criticises GMC for being ill informed. PMID- 24782514 TI - Relation of physical activity time to incident disability in community dwelling adults with or at risk of knee arthritis: prospective cohort study. AB - OBJECTIVE: To investigate whether objectively measured time spent in light intensity physical activity is related to incident disability and to disability progression. DESIGN: Prospective multisite cohort study from September 2008 to December 2012. SETTING: Baltimore, Maryland; Columbus, Ohio; Pittsburgh, Pennsylvania; and Pawtucket, Rhode Island, USA. PARTICIPANTS: Disability onset cohort of 1680 community dwelling adults aged 49 years or older with knee osteoarthritis or risk factors for knee osteoarthritis; the disability progression cohort included 1814 adults. MAIN OUTCOME MEASURES: Physical activity was measured by accelerometer monitoring. Disability was ascertained from limitations in instrumental and basic activities of daily living at baseline and two years. The primary outcome was incident disability. The secondary outcome was progression of disability defined by a more severe level (no limitations, limitations to instrumental activities only, 1-2 basic activities, or >=3 basic activities) at two years compared with baseline. RESULTS: Greater time spent in light intensity activities had a significant inverse association with incident disability. Less incident disability and less disability progression were each significantly related to increasing quartile categories of daily time spent in light intensity physical activities (hazard ratios for disability onset 1.00, 0.62, 0.47, and 0.58, P for trend=0.007; hazard ratios for progression 1.00, 0.59, 0.50, and 0.53, P for trend=0.003) with control for socioeconomic factors (age, sex, race/ethnicity, education, income) and health factors (comorbidities, depressive symptoms, obesity, smoking, lower extremity pain and function, and knee assessments: osteoarthritis severity, pain, symptoms, prior injury). This finding was independent of time spent in moderate-vigorous activities. CONCLUSION: These prospective data showed an association between greater daily time spent in light intensity physical activities and reduced risk of onset and progression of disability in adults with osteoarthritis of the knee or risk factors for knee osteoarthritis. An increase in daily physical activity time may reduce the risk of disability, even if the intensity of that additional activity is not increased. PMID- 24782515 TI - Dietary fiber intake and mortality among survivors of myocardial infarction: prospective cohort study. AB - OBJECTIVE: To evaluate the associations of dietary fiber after myocardial infarction (MI) and changes in dietary fiber intake from before to after MI with all cause and cardiovascular mortality. DESIGN: Prospective cohort study. SETTING: Two large prospective cohort studies of US women and men with repeated dietary measurements: the Nurses' Health Study and the Health Professionals Follow-Up Study. PARTICIPANTS: 2258 women and 1840 men who were free of cardiovascular disease, stroke, or cancer at enrollment, survived a first MI during follow-up, were free of stroke at the time of initial onset of MI, and provided food frequency questionnaires pre-MI and at least one post-MI. MAIN OUTCOME MEASURES: Associations of dietary fiber post-MI and changes from before to after MI with all cause and cardiovascular mortality using Cox proportional hazards models, adjusting for drug use, medical history, and lifestyle factors. RESULTS: Higher post-MI fiber intake was significantly associated with lower all cause mortality (comparing extreme fifths, pooled hazard ratio 0.75, 95% confidence interval 0.58 to 0.97). Greater intake of cereal fiber was more strongly associated with all cause mortality (pooled hazard ratio 0.73, 0.58 to 0.91) than were other sources of dietary fiber. Increased fiber intake from before to after MI was significantly associated with lower all cause mortality (pooled hazard ratio 0.69, 0.55 to 0.87). CONCLUSIONS: In this prospective study of patients who survived MI, a greater intake of dietary fiber after MI, especially cereal fiber, was inversely associated with all cause mortality. In addition, increasing consumption of fiber from before to after MI was significantly associated with lower all cause and cardiovascular mortality. PMID- 24782517 TI - NEP: web server for epitope prediction based on antibody neutralization of viral strains with diverse sequences. AB - Delineation of the antigenic site, or epitope, recognized by an antibody can provide clues about functional vulnerabilities and resistance mechanisms, and can therefore guide antibody optimization and epitope-based vaccine design. Previously, we developed an algorithm for antibody-epitope prediction based on antibody neutralization of viral strains with diverse sequences and validated the algorithm on a set of broadly neutralizing HIV-1 antibodies. Here we describe the implementation of this algorithm, NEP (Neutralization-based Epitope Prediction), as a web-based server. The users must supply as input: (i) an alignment of antigen sequences of diverse viral strains; (ii) neutralization data for the antibody of interest against the same set of antigen sequences; and (iii) (optional) a structure of the unbound antigen, for enhanced prediction accuracy. The prediction results can be downloaded or viewed interactively on the antigen structure (if supplied) from the web browser using a JSmol applet. Since neutralization experiments are typically performed as one of the first steps in the characterization of an antibody to determine its breadth and potency, the NEP server can be used to predict antibody-epitope information at no additional experimental costs. NEP can be accessed on the internet at http://exon.niaid.nih.gov/nep. PMID- 24782516 TI - A sequence-based approach for prediction of CsrA/RsmA targets in bacteria with experimental validation in Pseudomonas aeruginosa. AB - CsrA/RsmA homologs are an extensive family of ribonucleic acid (RNA)-binding proteins that function as global post-transcriptional regulators controlling important cellular processes such as secondary metabolism, motility, biofilm formation and the production and secretion of virulence factors in diverse bacterial species. While direct messenger RNA binding by CsrA/RsmA has been studied in detail for some genes, it is anticipated that there are numerous additional, as yet undiscovered, direct targets that mediate its global regulation. To assist in the discovery of these targets, we propose a sequence based approach to predict genes directly regulated by these regulators. In this work, we develop a computer code (CSRA_TARGET) implementing this approach, which leads to predictions for several novel targets in Escherichia coli and Pseudomonas aeruginosa. The predicted targets in other bacteria, specifically Salmonella enterica serovar Typhimurium, Pectobacterium carotovorum and Legionella pneumophila, also include global regulators that control virulence in these pathogens, unraveling intricate indirect regulatory roles for CsrA/RsmA. We have experimentally validated four predicted RsmA targets in P. aeruginosa. The sequence-based approach developed in this work can thus lead to several testable predictions for direct targets of CsrA homologs, thereby complementing and accelerating efforts to unravel global regulation by this important family of proteins. PMID- 24782518 TI - Nucleosome eviction and multiple co-factor binding predict estrogen-receptor alpha-associated long-range interactions. AB - Many enhancers regulate their target genes via long-distance interactions. High throughput experiments like ChIA-PET have been developed to map such largely cell type-specific interactions between cis-regulatory elements genome-widely. In this study, we integrated multiple types of data in order to reveal the general hidden patterns embedded in the ChIA-PET data. We found characteristic distance features related to promoter-promoter, enhancer-enhancer and insulator-insulator interactions. Although a protein may have many binding sites along the genome, our hypothesis is that those sites that share certain open chromatin structure can accommodate relatively larger protein complex consisting of specific regulatory and 'bridging' factors, and may be more likely to form robust long range deoxyribonucleic acid (DNA) loops. This hypothesis was validated in the estrogen receptor alpha (ERalpha) ChIA-PET data. An efficient classifier was built to predict ERalpha-associated long-range interactions solely from the related ChIP-seq data, hence linking distal ERalpha-dependent enhancers to their target genes. We further applied the classifier to generate additional novel interactions, which were undetected in the original ChIA-PET paper but were validated by other independent experiments. Our work provides a new insight into the long-range chromatin interactions through deeper and integrative ChIA-PET data analysis and demonstrates DNA looping predictability from ordinary ChIP-seq data. PMID- 24782519 TI - Specificity determinants for the two tRNA substrates of the cyclodipeptide synthase AlbC from Streptomyces noursei. AB - Cyclodipeptide synthases (CDPSs) use two aminoacyl-tRNA substrates in a sequential ping-pong mechanism to form a cyclodipeptide. The crystal structures of three CDPSs have been determined and all show a Rossmann-fold domain similar to the catalytic domain of class-I aminoacyl-tRNA synthetases (aaRSs). Structural features and mutational analyses however suggest that CDPSs and aaRSs interact differently with their tRNA substrates. We used AlbC from Streptomyces noursei that mainly produces cyclo(l-Phe-l-Leu) to investigate the interaction of a CDPS with its substrates. We demonstrate that Phe-tRNA(Phe) is the first substrate accommodated by AlbC. Its binding to AlbC is dependent on basic residues located in the helix alpha4 that form a basic patch at the surface of the protein. AlbC does not use all of the Leu-tRNA(Leu) isoacceptors as a second substrate. We show that the G(1)-C(72) pair of the acceptor stem is essential for the recognition of the second substrate. Substitution of D163 located in the loop alpha6-alpha7 or D205 located in the loop beta6-alpha8 affected Leu-tRNA(Leu) isoacceptors specificity, suggesting the involvement of these residues in the binding of the second substrate. This is the first demonstration that the two substrates of CDPSs are accommodated in different binding sites. PMID- 24782520 TI - A multi-fingerprint browser for the ZINC database. AB - To confirm the activity of an initial small molecule 'hit compound' from an activity screening, one needs to probe the structure-activity relationships by testing close analogs. The multi-fingerprint browser presented here (http://dcb reymond23.unibe.ch:8080/MCSS/) enables one to rapidly identify such close analogs among commercially available compounds in the ZINC database (>13 million molecules). The browser retrieves nearest neighbors of any query molecule in multi-dimensional chemical spaces defined by four different fingerprints, each of which represents relevant structural and pharmacophoric features in a different way: sFP (substructure fingerprint), ECFP4 (extended connectivity fingerprint), MQNs (molecular quantum numbers) and SMIfp (SMILES fingerprint). Distances are calculated using the city-block distance, a similarity measure that performs as well as Tanimoto similarity but is much faster to compute. The list of up to 1000 nearest neighbors of any query molecule is retrieved by the browser and can be then clustered using the K-means clustering algorithm to produce a focused list of analogs with likely similar bioactivity to be considered for experimental evaluation. PMID- 24782521 TI - Enriched domain detector: a program for detection of wide genomic enrichment domains robust against local variations. AB - Nuclear lamins contact the genome at the nuclear periphery through large domains and are involved in chromatin organization. Among broad peak calling algorithms available to date, none are suited for mapping lamin-genome interactions genome wide. We disclose a novel algorithm, enriched domain detector (EDD), for analysis of broad enrichment domains from chromatin immunoprecipitation (ChIP)-seq data. EDD enables discovery of genomic domains interacting with broadly distributed proteins, such as A- and B-type lamins affinity isolated by ChIP. The advantages of EDD over existing broad peak callers are sensitivity to domain width rather than enrichment strength at a particular site, and robustness against local variations. PMID- 24782522 TI - SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. AB - Protein structure homology modelling has become a routine technique to generate 3D models for proteins when experimental structures are not available. Fully automated servers such as SWISS-MODEL with user-friendly web interfaces generate reliable models without the need for complex software packages or downloading large databases. Here, we describe the latest version of the SWISS-MODEL expert system for protein structure modelling. The SWISS-MODEL template library provides annotation of quaternary structure and essential ligands and co-factors to allow for building of complete structural models, including their oligomeric structure. The improved SWISS-MODEL pipeline makes extensive use of model quality estimation for selection of the most suitable templates and provides estimates of the expected accuracy of the resulting models. The accuracy of the models generated by SWISS-MODEL is continuously evaluated by the CAMEO system. The new web site allows users to interactively search for templates, cluster them by sequence similarity, structurally compare alternative templates and select the ones to be used for model building. In cases where multiple alternative template structures are available for a protein of interest, a user-guided template selection step allows building models in different functional states. SWISS-MODEL is available at http://swissmodel.expasy.org/. PMID- 24782523 TI - TSpred: a web server for the rational design of temperature-sensitive mutants. AB - Temperature sensitive (Ts) mutants of proteins provide experimentalists with a powerful and reversible way of conditionally expressing genes. The technique has been widely used in determining the role of gene and gene products in several cellular processes. Traditionally, Ts mutants are generated by random mutagenesis and then selected though laborious large-scale screening. Our web server, TSpred (http://mspc.bii.a-star.edu.sg/TSpred/), now enables users to rationally design Ts mutants for their proteins of interest. TSpred uses hydrophobicity and hydrophobic moment, deduced from primary sequence and residue depth, inferred from 3D structures to predict/identify buried hydrophobic residues. Mutating these residues leads to the creation of Ts mutants. Our method has been experimentally validated in 36 positions in six different proteins. It is an attractive proposition for Ts mutant engineering as it proposes a small number of mutations and with high precision. The accompanying web server is simple and intuitive to use and can handle proteins and protein complexes of different sizes. PMID- 24782524 TI - A family of synthetic riboswitches adopts a kinetic trapping mechanism. AB - Riboswitches are sequences of RNA that control gene expression via RNA-ligand interactions, without the need for accessory proteins. Riboswitches consist of an aptamer that recognizes the ligand and an expression platform that couples ligand binding to a change in gene expression. Using in vitro selection, it is possible to screen large (~ 10(13) members) libraries of RNA sequences to discover new aptamers. However, limitations in bacterial transformation efficiency make screening such large libraries for riboswitch function in intact cells impractical. Here we show that synthetic riboswitches function in an E. coli S30 extract in a manner similar to how they function in intact E. coli cells. We discovered that, although this family of riboswitches regulates the initiation of protein translation, the fate of whether an RNA message is translated is determined during transcription. Thus, ligand binding does not bias a population of rapidly equilibrating RNA structures, but rather, co-transcriptional ligand binding kinetically traps the RNA in a conformation that supports efficient translation. In addition to providing new insights into the mechanisms of action of a family of synthetic riboswitches, our experiments suggest that it may be possible to perform selections for novel synthetic riboswitches in an in vitro system. PMID- 24782525 TI - Auxiliary tRNAs: large-scale analysis of tRNA genes reveals patterns of tRNA repertoire dynamics. AB - Decoding of all codons can be achieved by a subset of tRNAs. In bacteria, certain tRNA species are mandatory, while others are auxiliary and are variably used. It is currently unknown how this variability has evolved and whether it provides an adaptive advantage. Here we shed light on the subset of auxiliary tRNAs, using genomic data from 319 bacteria. By reconstructing the evolution of tRNAs we show that the auxiliary tRNAs are highly dynamic, being frequently gained and lost along the phylogenetic tree, with a clear dominance of loss events for most auxiliary tRNA species. We reveal distinct co-gain and co-loss patterns for subsets of the auxiliary tRNAs, suggesting that they are subjected to the same selection forces. Controlling for phylogenetic dependencies, we find that the usage of these tRNA species is positively correlated with GC content and may derive directly from nucleotide bias or from preference of Watson-Crick codon anticodon interactions. Our results highlight the highly dynamic nature of these tRNAs and their complicated balance with codon usage. PMID- 24782526 TI - A programmable method for massively parallel targeted sequencing. AB - We have developed a targeted resequencing approach referred to as Oligonucleotide Selective Sequencing. In this study, we report a series of significant improvements and novel applications of this method whereby the surface of a sequencing flow cell is modified in situ to capture specific genomic regions of interest from a sample and then sequenced. These improvements include a fully automated targeted sequencing platform through the use of a standard Illumina cBot fluidics station. Targeting optimization increased the yield of total on target sequencing data 2-fold compared to the previous iteration, while simultaneously increasing the percentage of reads that could be mapped to the human genome. The described assays cover up to 1421 genes with a total coverage of 5.5 Megabases (Mb). We demonstrate a 10-fold abundance uniformity of greater than 90% in 1 log distance from the median and a targeting rate of up to 95%. We also sequenced continuous genomic loci up to 1.5 Mb while simultaneously genotyping SNPs and genes. Variants with low minor allele fraction were sensitively detected at levels of 5%. Finally, we determined the exact breakpoint sequence of cancer rearrangements. Overall, this approach has high performance for selective sequencing of genome targets, configuration flexibility and variant calling accuracy. PMID- 24782527 TI - GeneGenie: optimized oligomer design for directed evolution. AB - GeneGenie, a new online tool available at http://www.gene-genie.org, is introduced to support the design and self-assembly of synthetic genes and constructs. GeneGenie allows for the design of oligonucleotide cohorts encoding the gene sequence optimized for expression in any suitable host through an intuitive, easy-to-use web interface. The tool ensures consistent oligomer overlapping melting temperatures, minimizes the likelihood of misannealing, optimizes codon usage for expression in a selected host, allows for specification of forward and reverse cloning sequences (for downstream ligation) and also provides support for mutagenesis or directed evolution studies. Directed evolution studies are enabled through the construction of variant libraries via the optional specification of 'variant codons', containing mixtures of bases, at any position. For example, specifying the variant codon TNT (where N is any nucleotide) will generate an equimolar mixture of the codons TAT, TCT, TGT and TTT at that position, encoding a mixture of the amino acids Tyr, Ser, Cys and Phe. This facility is demonstrated through the use of GeneGenie to develop and synthesize a library of enhanced green fluorescent protein variants. PMID- 24782528 TI - The interaction of MYC with the trithorax protein ASH2L promotes gene transcription by regulating H3K27 modification. AB - The appropriate expression of the roughly 30,000 human genes requires multiple layers of control. The oncoprotein MYC, a transcriptional regulator, contributes to many of the identified control mechanisms, including the regulation of chromatin, RNA polymerases, and RNA processing. Moreover, MYC recruits core histone-modifying enzymes to DNA. We identified an additional transcriptional cofactor complex that interacts with MYC and that is important for gene transcription. We found that the trithorax protein ASH2L and MYC interact directly in vitro and co-localize in cells and on chromatin. ASH2L is a core subunit of KMT2 methyltransferase complexes that target histone H3 lysine 4 (H3K4), a mark associated with open chromatin. Indeed, MYC associates with H3K4 methyltransferase activity, dependent on the presence of ASH2L. MYC does not regulate this methyltransferase activity but stimulates demethylation and subsequently acetylation of H3K27. KMT2 complexes have been reported to associate with histone H3K27-specific demethylases, while CBP/p300, which interact with MYC, acetylate H3K27. Finally WDR5, another core subunit of KMT2 complexes, also binds directly to MYC and in genome-wide analyses MYC and WDR5 are associated with transcribed promoters. Thus, our findings suggest that MYC and ASH2L-KMT2 complexes cooperate in gene transcription by controlling H3K27 modifications and thereby regulate bivalent chromatin. PMID- 24782529 TI - Impact of nuclear Piwi elimination on chromatin state in Drosophila melanogaster ovaries. AB - The Piwi-interacting RNA (piRNA)-interacting Piwi protein is involved in transcriptional silencing of transposable elements in ovaries of Drosophila melanogaster. Here we characterized the genome-wide effect of nuclear Piwi elimination on the presence of the heterochromatic H3K9me3 mark and HP1a, as well as on the transcription-associated mark H3K4me2. Our results demonstrate that a significant increase in the H3K4me2 level upon nuclear Piwi loss is not accompanied by the alterations in H3K9me3 and HP1a levels for several germline expressed transposons, suggesting that in this case Piwi prevents transcription by a mechanism distinct from H3K9 methylation. We found that the targets of Piwi dependent chromatin repression are mainly related to the elements that display a higher level of H3K4me2 modification in the absence of silencing, i.e. most actively transcribed elements. We also show that Piwi-guided silencing does not significantly influence the chromatin state of dual-strand piRNA-producing clusters. In addition, host protein-coding gene expression is essentially not affected due to the nuclear Piwi elimination, but we noted an increase in small nuclear spliceosomal RNAs abundance and propose Piwi involvement in their post transcriptional regulation. Our work reveals new aspects of transposon silencing in Drosophila, indicating that transcription of transposons can underpin their Piwi dependent silencing, while canonical heterochromatin marks are not obligatory for their repression. PMID- 24782530 TI - Molecular determinants of the DprA-RecA interaction for nucleation on ssDNA. AB - Natural transformation is a major mechanism of horizontal gene transfer in bacteria that depends on DNA recombination. RecA is central to the homologous recombination pathway, catalyzing DNA strand invasion and homology search. DprA was shown to be a key binding partner of RecA acting as a specific mediator for its loading on the incoming exogenous ssDNA. Although the 3D structures of both RecA and DprA have been solved, the mechanisms underlying their cross-talk remained elusive. By combining molecular docking simulations and experimental validation, we identified a region on RecA, buried at its self-assembly interface and involving three basic residues that contact an acidic triad of DprA previously shown to be crucial for the interaction. At the core of these patches, (DprA)M238 and (RecA)F230 are involved in the interaction. The other DprA binding regions of RecA could involve the N-terminal alpha-helix and a DNA-binding region. Our data favor a model of DprA acting as a cap of the RecA filament, involving a DprA-RecA interplay at two levels: their own oligomeric states and their respective interaction with DNA. Our model forms the basis for a mechanistic explanation of how DprA can act as a mediator for the loading of RecA on ssDNA. PMID- 24782531 TI - A Sub-Element in PRE enhances nuclear export of intronless mRNAs by recruiting the TREX complex via ZC3H18. AB - Viral RNA elements that facilitate mRNA export are useful tools for identifying cellular RNA export factors. Here we show that hepatitis B virus post transcriptional element (PRE) is one such element, and using PRE several new cellular mRNA export factors were identified. We found that PRE drastically enhances the cytoplasmic accumulation of cDNA transcripts independent of any viral protein. Systematic deletion analysis revealed the existence of a 116 nt functional Sub-Element of PRE (SEP1). The RNP that forms on the SEP1 RNA was affinity purified, in which TREX components as well as several other proteins were identified. TREX components and the SEP1-associating protein ZC3H18 are required for SEP1-mediated mRNA export. Significantly, ZC3H18 directly binds to the SEP1 RNA, interacts with TREX and is required for stable association of TREX with the SEP1-containing mRNA. Requirements for SEP1-mediated mRNA export are similar to those for splicing-dependent mRNA export. Consistent with these similarities, several SEP1-interacting proteins, including ZC3H18, ARS2, Acinus and Brr2, are required for efficient nuclear export of polyA RNAs. Together, our data indicate that SEP1 enhances mRNA export by recruiting TREX via ZC3H18. The new mRNA export factors that we identified might be involved in cap- and splicing dependent TREX recruitment to cellular mRNAs. PMID- 24782532 TI - Synthesis of structurally diverse major groove DNA interstrand crosslinks using three different aldehyde precursors. AB - DNA interstrand crosslinks (ICLs) are extremely cytotoxic lesions that block essential cellular processes, such as replication and transcription. Crosslinking agents are widely used in cancer chemotherapy and form an array of structurally diverse ICLs. Despite the clinical success of these agents, resistance of tumors to crosslinking agents, for example, through repair of these lesions by the cellular machinery remains a problem. We have previously reported the synthesis of site-specific ICLs mimicking those formed by nitrogen mustards to facilitate the studies of cellular responses to ICL formation. Here we extend these efforts and report the synthesis of structurally diverse major groove ICLs that induce severe, little or no distortion in the DNA. Our approach employs the incorporation of aldehyde precursors of different lengths into complementary strands and ICL formation using a double reductive amination with a variety of amines. Our studies provide insight into the structure and reactivity parameters of ICL formation by double reductive amination and yield a set of diverse ICLs that will be invaluable for exploring structure-activity relationships in ICL repair. PMID- 24782533 TI - Association of fibroblast growth factor-23 with arterial stiffness in the Multi Ethnic Study of Atherosclerosis. AB - BACKGROUND: Serum fibroblast growth factor-23 (FGF-23) is associated with cardiovascular disease (CVD), yet the mechanisms remain uncertain. Our objective was to determine whether higher FGF-23 concentrations are associated with arterial stiffness. METHODS: In this cross-sectional study, serum FGF-23 concentrations were measured in 5977 participants without known CVD in the Multi Ethnic Study of Atherosclerosis. The primary outcomes of interest were large (LAE) and small artery elasticity (SAE), pulse pressure and ankle-brachial index (ABI) > 1.30. LAE and SAE were measured by pulse contour analysis of the radial artery. Pulse pressure was measured with an automated sphygmomanometer using the average of two resting blood pressure measurements. ABI was calculated as the ratio of the ankle and brachial systolic blood pressures. RESULTS: Serum FGF-23 concentrations were not significantly associated with LAE [relative difference (RD) per doubling: 0%; 95% confidence interval (CI): -2-1%], SAE (RD per doubling: 0%; 95% CI: -3-2%), pulse pressure (beta per doubling: 0.44; 95% CI: 0.31-1.19), or a high ABI (odds ratio per doubling: 1.14; 95% CI: 0.84-1.55). Findings were similar irrespective of chronic kidney disease status. CONCLUSIONS: Higher serum FGF-23 concentrations are not associated with arterial stiffness, as measured by pulse pressure, LAE, SAE or high ABI, in a community-based population without CVD. PMID- 24782534 TI - Let us give twice-weekly hemodialysis a chance: revisiting the taboo. PMID- 24782535 TI - The forgotten half of scientific thinking. PMID- 24782537 TI - Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli. AB - Two-component systems (TCSs) are highly conserved across bacteria and are used to rapidly sense and respond to changing environmental conditions. The human pathogen Staphylococcus aureus uses the S. aureus exoprotein expression (sae) TCS to sense host signals and activate transcription of virulence factors essential to pathogenesis. Despite its importance, the mechanism by which the histidine kinase SaeS recognizes specific host stimuli is unknown. After mutagenizing the predicted extracellular loop of SaeS, we discovered one methionine residue (M31) was essential for the ability of S. aureus to transcribe sae target genes, including hla, lukAB/lukGH, and hlgA. This single M31A mutation also significantly reduced cytotoxicity in human neutrophils to levels observed in cells following interaction with DeltasaeS. Another important discovery was that mutation of two aromatic anchor residues (W32A and F33A) disrupted the normal basal signaling of SaeS in the absence of inducing signals, yet both mutant kinases had appropriate activation of effector genes following exposure to neutrophils. Although the transcriptional profile of aromatic mutation W32A was consistent with that of WT in response to human alpha-defensin 1, mutant kinase F33A did not properly transcribe the gamma-toxin genes in response to this stimulus. Taken together, our results provide molecular evidence for how SaeS recognizes host signals and triggers activation of select virulence factors to facilitate evasion of innate immunity. These findings have important implications for signal transduction in prokaryotes and eukaryotes due to conservation of aromatic anchor residues across both of these domains and the important role they play in sensor protein structure and function. PMID- 24782538 TI - Phenotypic switching in gene regulatory networks. AB - Noise in gene expression can lead to reversible phenotypic switching. Several experimental studies have shown that the abundance distributions of proteins in a population of isogenic cells may display multiple distinct maxima. Each of these maxima may be associated with a subpopulation of a particular phenotype, the quantification of which is important for understanding cellular decision-making. Here, we devise a methodology which allows us to quantify multimodal gene expression distributions and single-cell power spectra in gene regulatory networks. Extending the commonly used linear noise approximation, we rigorously show that, in the limit of slow promoter dynamics, these distributions can be systematically approximated as a mixture of Gaussian components in a wide class of networks. The resulting closed-form approximation provides a practical tool for studying complex nonlinear gene regulatory networks that have thus far been amenable only to stochastic simulation. We demonstrate the applicability of our approach in a number of genetic networks, uncovering previously unidentified dynamical characteristics associated with phenotypic switching. Specifically, we elucidate how the interplay of transcriptional and translational regulation can be exploited to control the multimodality of gene expression distributions in two promoter networks. We demonstrate how phenotypic switching leads to birhythmical expression in a genetic oscillator, and to hysteresis in phenotypic induction, thus highlighting the ability of regulatory networks to retain memory. PMID- 24782539 TI - GAL3 receptor KO mice exhibit an anxiety-like phenotype. AB - The neuropeptide galanin (GAL) is widely distributed in the central and peripheral nervous systems. It is a modulator of various physiological and pathological processes, and it mediates its effects via three G protein-coupled receptors (GAL1-3 receptors). A role for GAL as a modulator of mood and anxiety was suggested, because GAL and its receptors are highly expressed in limbic brain structures of rodents. In recent years, numerous studies of animal models have suggested an involvement of GAL and GAL1 and GAL2 receptors in anxiety- and depression-related behavior. However, to date, there is sparse literature implicating GAL3 receptors in behavioral functions. Therefore, we studied the behavior of GAL3 receptor-deficient (GAL3-KO) mice to elucidate whether GAL3 receptors are involved in mediating behavior-associated actions of GAL. The GAL3 KO mouse line exhibited normal breeding and physical development. In addition to behavioral tests, phenotypic characterization included analysis of hematology, amino acid profiles, metabolism, and sudomotor function. In contrast to WT littermates, male GAL3-KO mice exhibited an anxiety-like phenotype in the elevated plus maze, open field, and light/dark box tests, and they were less socially affiliated than WT animals to a stranger mouse in a social interaction test. In conclusion, our data suggest involvement of GAL3 receptors in GAL mediated effects on mood, anxiety, and behavior, making it a possible target for alternative treatment strategies for mood disorders. PMID- 24782540 TI - CK2 activates kinesin via induction of a conformational change. AB - Kinesin is the canonical plus-end microtubule motor and has been the focus of intense study since its discovery in 1985. We previously demonstrated a time dependent inactivation of kinesin in vitro that was fully reversible by the addition of purified casein kinase 2 (CK2) and showed that this inactivation/reactivation pathway was relevant in cells. Here we show that kinesin inactivation results from a conformational change that causes the neck linker to be positioned closer to the motor domain. Furthermore, we show that treatment of kinesin with CK2 prevents and reverses this repositioning. Finally, we demonstrate that CK2 treatment facilitates ADP dissociation from the motor, resulting in a nucleotide-free state that promotes microtubule binding. Thus, we propose that kinesin inactivation results from neck-linker repositioning and that CK2-mediated reactivation results from CK2's dual ability to reverse this repositioning and to promote ADP release. PMID- 24782541 TI - How multiplicity determines entropy and the derivation of the maximum entropy principle for complex systems. AB - The maximum entropy principle (MEP) is a method for obtaining the most likely distribution functions of observables from statistical systems by maximizing entropy under constraints. The MEP has found hundreds of applications in ergodic and Markovian systems in statistical mechanics, information theory, and statistics. For several decades there has been an ongoing controversy over whether the notion of the maximum entropy principle can be extended in a meaningful way to nonextensive, nonergodic, and complex statistical systems and processes. In this paper we start by reviewing how Boltzmann-Gibbs-Shannon entropy is related to multiplicities of independent random processes. We then show how the relaxation of independence naturally leads to the most general entropies that are compatible with the first three Shannon-Khinchin axioms, the (c,d)-entropies. We demonstrate that the MEP is a perfectly consistent concept for nonergodic and complex statistical systems if their relative entropy can be factored into a generalized multiplicity and a constraint term. The problem of finding such a factorization reduces to finding an appropriate representation of relative entropy in a linear basis. In a particular example we show that path dependent random processes with memory naturally require specific generalized entropies. The example is to our knowledge the first exact derivation of a generalized entropy from the microscopic properties of a path-dependent random process. PMID- 24782542 TI - Microfluidic single-cell whole-transcriptome sequencing. AB - Single-cell whole-transcriptome analysis is a powerful tool for quantifying gene expression heterogeneity in populations of cells. Many techniques have, thus, been recently developed to perform transcriptome sequencing (RNA-Seq) on individual cells. To probe subtle biological variation between samples with limiting amounts of RNA, more precise and sensitive methods are still required. We adapted a previously developed strategy for single-cell RNA-Seq that has shown promise for superior sensitivity and implemented the chemistry in a microfluidic platform for single-cell whole-transcriptome analysis. In this approach, single cells are captured and lysed in a microfluidic device, where mRNAs with poly(A) tails are reverse-transcribed into cDNA. Double-stranded cDNA is then collected and sequenced using a next generation sequencing platform. We prepared 94 libraries consisting of single mouse embryonic cells and technical replicates of extracted RNA and thoroughly characterized the performance of this technology. Microfluidic implementation increased mRNA detection sensitivity as well as improved measurement precision compared with tube-based protocols. With 0.2 M reads per cell, we were able to reconstruct a majority of the bulk transcriptome with 10 single cells. We also quantified variation between and within different types of mouse embryonic cells and found that enhanced measurement precision, detection sensitivity, and experimental throughput aided the distinction between biological variability and technical noise. With this work, we validated the advantages of an early approach to single-cell RNA-Seq and showed that the benefits of combining microfluidic technology with high-throughput sequencing will be valuable for large-scale efforts in single-cell transcriptome analysis. PMID- 24782544 TI - Moving gating charges through the gating pore in a Kv channel voltage sensor. AB - Voltage sensor domains (VSDs) regulate ion channels and enzymes by transporting electrically charged residues across a hydrophobic VSD constriction called the gating pore or hydrophobic plug. How the gating pore controls the gating charge movement presently remains debated. Here, using saturation mutagenesis and detailed analysis of gating currents from gating pore mutations in the Shaker Kv channel, we identified statistically highly significant correlations between VSD function and physicochemical properties of gating pore residues. A necessary small residue at position S240 in S1 creates a "steric gap" that enables an intracellular access pathway for the transport of the S4 Arg residues. In addition, the stabilization of the depolarized VSD conformation, a hallmark for most Kv channels, requires large side chains at positions F290 in S2 and F244 in S1 acting as "molecular clamps," and a hydrophobic side chain at position I237 in S1 acting as a local intracellular hydrophobic barrier. Finally, both size and hydrophobicity of I287 are important to control the main VSD energy barrier underlying transitions between resting and active states. Taken together, our study emphasizes the contribution of several gating pore residues to catalyze the gating charge transfer. This work paves the way toward understanding physicochemical principles underlying conformational dynamics in voltage sensors. PMID- 24782547 TI - R2-equitability is satisfiable. PMID- 24782546 TI - Quantitative phosphoproteomic analysis reveals system-wide signaling pathways downstream of SDF-1/CXCR4 in breast cancer stem cells. AB - Breast cancer is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.7 million new cases and 522,000 deaths around the world in 2012 alone. Cancer stem cells (CSCs) are essential for tumor reoccurrence and metastasis which is the major source of cancer lethality. G protein-coupled receptor chemokine (C-X-C motif) receptor 4 (CXCR4) is critical for tumor metastasis. However, stromal cell-derived factor 1 (SDF-1)/CXCR4 mediated signaling pathways in breast CSCs are largely unknown. Using isotope reductive dimethylation and large-scale MS-based quantitative phosphoproteome analysis, we examined protein phosphorylation induced by SDF-1/CXCR4 signaling in breast CSCs. We quantified more than 11,000 phosphorylation sites in 2,500 phosphoproteins. Of these phosphosites, 87% were statistically unchanged in abundance in response to SDF-1/CXCR4 stimulation. In contrast, 545 phosphosites in 266 phosphoproteins were significantly increased, whereas 113 phosphosites in 74 phosphoproteins were significantly decreased. SDF-1/CXCR4 increases phosphorylation in 60 cell migration- and invasion-related proteins, of them 43 (>70%) phosphoproteins are unrecognized. In addition, SDF-1/CXCR4 upregulates the phosphorylation of 44 previously uncharacterized kinases, 8 phosphatases, and 1 endogenous phosphatase inhibitor. Using computational approaches, we performed system-based analyses examining SDF-1/CXCR4-mediated phosphoproteome, including construction of kinase-substrate network and feedback regulation loops downstream of SDF-1/CXCR4 signaling in breast CSCs. We identified a previously unidentified SDF-1/CXCR4-PKA-MAP2K2-ERK signaling pathway and demonstrated the feedback regulation on MEK, ERK1/2, delta-catenin, and PPP1Calpha in SDF-1/CXCR4 signaling in breast CSCs. This study gives a system-wide view of phosphorylation events downstream of SDF-1/CXCR4 signaling in breast CSCs, providing a resource for the study of CSC-targeted cancer therapy. PMID- 24782548 TI - Cushing's disease from an ectopic parasellar adenoma. PMID- 24782549 TI - A unidirectional breathing pattern improves breathing efficiency in subjects with severe COPD. AB - BACKGROUND: Unidirectional breathing (UB), nose-in mouth-out (NMB) or vice versa, is thought to create PEEP, stabilize small airways, and increase expiratory flow and exhaled tidal volume (VT) in patients with expiratory obstructive disorders. However, the exact mechanism providing the benefits of UB remains unknown. Our hypothesis was that the benefits of UB are achieved mainly through reduction of upper airway dead space. METHODS: Sixteen stable COPD patients requiring oxygen use at home were enrolled in this prospective study at a tertiary health care center. A nasal mask and a mouthpiece were used, each having a removable one-way valve to direct the breathing pattern. Four experimentally defined patterns of spontaneous breathing, NMB, mouth-in nose-out (MNB), nose-in nose-out (NNB), and mouth-in mouth-out (MMB), were compared. Each breathing pattern lasted 5 min followed by a 5-min rest period. A NICO device continuously monitored respiratory parameters. The functional anatomical dead space volume (VD) and expired VT values were determined. Breathing efficiency (BE) was calculated as alveolar VT divided by expired volume. RESULTS: Functional anatomical VD was higher in bidirectional breathing (BB) (overall: 207.4 +/- 7.9 mL; MMB: 232.5 +/- 72.7 mL; NNB: 182.2 +/- 75 mL) compared to UB (overall: 178.1 +/- 87.2 mL; NMB: 176.9 +/- 91.3 mL; MNB: 179.3 +/- 83.2 mL) (P < .001). BE achieved with UB (overall: 76.2 +/- 6.5%; NMB: 76.8 +/- 6.8%; MNB: 75.6 +/- 6.3%) was higher than that with BB (overall: 66.2 +/- 0.09%; MMB: 64.3 +/- 0.10%; NNB: 68.1 +/- 0.08%) (P < .001). The difference in BE between UB and BB was more pronounced with small VT values (UB: 73.8 +/- 0.08; BB: 49.4 +/- 0.09) than with large VT values (UB: 77.3 +/- 0.06; BB: 63.0 +/- 0.07) (P < .001). CONCLUSIONS: Our data suggest that a reduction in functional anatomic VD may be the underlying mechanism for the benefits associated with UB in COPD patients. (ClinicalTrials.gov registration NCT00784004.). PMID- 24782550 TI - Nintedanib: a novel therapeutic approach for idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with no clear etiology and few therapeutic options. Growth factors that act as mediators in the development of this disease might be important therapeutic targets. Nintedanib is a triple-tyrosine kinase inhibitor and a potent antagonist of growth factors such as platelet-derived growth factor, vascular endothelial growth factor, and basic fibroblast growth factor, and it is currently evaluated in clinical trials as a potential IPF therapy. Treatment with nintedanib may slow decline in lung function, decrease the frequency of exacerbations, and improve quality of life in subjects with IPF. This observation, together with extensive safety and pharmacokinetic data from studies of nintedanib in malignancy, led the way for the clinical development of this drug in IPF. Observations from clinical trials, together with the preclinical data, suggest that nintedanib may become an important therapeutic option for individuals with IPF. High-dose nintedanib improved the quality of life, slowed the progression of lung fibrosis and the decline of lung function, and reduced the rate of exacerbations in individuals with mild and moderate IPF. This is a short review based on the available data (September 2013) on nintedanib. PMID- 24782551 TI - A case of drug-induced interstitial pneumonia potentially related to quetiapine (seroquel) therapy for behavioral and psychological symptoms. AB - Quetiapine is regarded as an effective and safe treatment for delirium. An 82 year-old man presented with a 1-week history of violent behavior and dizziness accompanied by weakness on the left side of his body. He was diagnosed with acute cerebral cortical infarction and delirium associated with alcohol abuse. After quetiapine treatment, he complained of fever and coughed up sputum, whereas his aggressive behavior improved. His symptoms persisted despite empirical antibiotic treatment. All diagnostic tests for infectious causes were negative. High resolution computed tomography revealed bilateral consolidations and ground-glass opacities with predominantly peribronchial and subpleural distributions. The primary differential diagnosis was drug-associated interstitial lung disease, and therefore, we discontinued quetiapine and began methylprednisolone treatment. His symptoms and radiologic findings significantly improved after receiving steroid therapy. We propose that clinicians need to be aware of the possibility that quetiapine is associated with lung injury. PMID- 24782552 TI - Inter-observer agreement of spontaneous breathing trial outcome. AB - BACKGROUND: Spontaneous breathing trials (SBTs) are a very important test in the weaning process. The trial involves evaluation of multiple objective and subjective variables. These characteristics could lead to variability in interpreting outcomes with important clinical implications. We aimed to measure the inter-observer agreement between respiratory therapists when analyzing SBT outcomes. METHODS: In the context of a respiratory therapist-driven weaning protocol, 2 respiratory therapists independently interpreted the subjective variables (use of accessory muscles, agitation, and diaphoresis) and the overall outcome of SBTs (success vs failure) performed in adult subjects mechanically ventilated for any duration. Raw agreements between respiratory therapists and kappa statistics were calculated. RESULTS: One-hundred fifty-one SBTs were interpreted. The overall trial outcome raw agreement was 93.3% (95% CI 88.2-96.3) and kappa 0.63 (95% CI 0.47-0.79). Raw agreement for subjective variables ranged between 92.1% (agitation) and 99.3% (diaphoresis). The group with disagreements in overall trial outcome had higher breathing frequency, breathing-frequency-to tidal-volume ratio, and systolic blood pressure prior to the trial. CONCLUSIONS: Within a respiratory therapist-driven weaning protocol, we found a near 90% inter observer agreement in the interpretation of SBT outcomes. Our findings illustrate the complexity of interpreting fluctuating subjective and objective variables and their integration into one result: SBT success versus failure. Refining the definitions of variables and their limits for failure along with education might reduce this variability. PMID- 24782553 TI - Expiratory and expiratory plus inspiratory muscle training improves respiratory muscle strength in subjects with COPD: systematic review. AB - BACKGROUND: Inspiratory muscle training (IMT) produces beneficial effects in COPD subjects, but the effects of expiratory muscle training (EMT) and EMT plus IMT in ventilatory training are still unclear. The aim of this study was to systematically review the effects of EMT and EMT plus IMT compared to control groups of COPD subjects. METHODS: This study is a systematic review and meta analysis. The search strategy included MEDLINE, Embase, LILACS, PEDro, and Cochrane CENTRAL and also manual search of references in published studies on the subject. Randomized trials comparing EMT and EMT plus IMT versus control groups of subjects with COPD were included. The outcomes analyzed were respiratory muscle strength and functional capacity. Two reviewers independently extracted the data. RESULTS: The search retrieved 609 articles. Five studies were included. We observed that EMT provided higher gain in maximum expiratory pressure (P(E(max)) 21.49 cm H2O, 95% CI 13.39-29.59) and maximum inspiratory pressure (P(I(max)) 7.68 cm H2O, 95% CI 0.90-14.45) compared to control groups. There was no significant difference in the 6-min walk test distance (29.01 m, 95% CI -39.62 to 97.65) and dyspnea (0.15, 95% CI -0.77 to 1.08). In relation to EMT plus IMT, we observed that P(E(max)) (31.98 cm H2O, 95% CI 26.93-37.03) and P(I(max)) (27.98 cm H2O, 95% CI 20.10-35.85) presented higher values compared to control groups. CONCLUSIONS: EMT and EMT plus IMT improve respiratory muscle strength and can be used as part of the treatment during pulmonary rehabilitation of subjects with severe to very severe COPD. PMID- 24782554 TI - Evaluation of adherence to ambulatory liquid oxygen treatment: are commercialized dual-pressure transducers helpful? AB - BACKGROUND: Treatment adherence is widely recognized as a critical problem in long-term oxygen therapy, particularly in ambulatory liquid oxygen (LOX) systems. Adherence-monitoring strategies may be helpful in managing patients. We evaluated subjects' adherence to LOX using VisionOx and compared these results with the subjects' own adherence diaries and self-reported perceptions of use. METHODS: Patients using LOX were recruited for a clinical interview; the number of days/week and the mean time of use according to subjects' perceptions were recorded. A 14-day diary was provided for every subject while VisionOx was attached to the LOX. VisionOx is a small device that uses pressure transducers to detect oxygen flow and the subject's breathing frequency. Information is stored and downloaded using dedicated software. RESULTS: Nineteen subjects were included (57.9% male with a median age of 63 years). When asked about the perception of LOX use, subjects self-reported using the device for a median of 100.0% of days (78.9% reported to have used it every day) for a median time of 180 min/day. According to data from VisionOx and subjects' diaries during the 14-day evaluation period, the median use was 92.8% of days for 210 min/day. No difference was found between the diaries and VisionOx data. Regarding subjects' perceptions of use, the declared use of LOX percent was significantly higher than reported in the diaries (P = .045) and VisionOx monitoring (P = .045) even though both underestimated the median use per day. CONCLUSIONS: Subjects overestimated adherence to LOX therapy (when measuring percent of days of use) compared to adherence diary and objective adherence monitoring. Because no significant difference was found comparing the diaries and VisionOx use, either may be helpful in clinical practice. PMID- 24782555 TI - A survey of extended-interval aminoglycoside dosing practices in United States adult cystic fibrosis programs. AB - INTRODUCTION: The Cystic Fibrosis Foundation recently deemed the use of extended interval dosing (EID) of aminoglycosides acceptable for the treatment of cystic fibrosis (CF) pulmonary exacerbations. However, current practice across United States adult CF programs and affiliate programs is unknown. The objectives of this research are to characterize the practice trends, dosing strategies, therapeutic drug-monitoring practices, and adverse effect monitoring of the EID of aminoglycosides in the treatment of pulmonary exacerbations across United States adult CF programs. METHODS: A 34-question online survey instrument was distributed on behalf of the author by the United States Cystic Fibrosis Foundation to all United States adult CF programs and affiliate programs. RESULTS: Of the 68 participating adult CF programs (44.4% survey response rate), 64 (94.1%) reported using EID of aminoglycosides (as once-daily or twice-daily dosing). More than 95% of programs reported frequently or always using this dosing method. Tobramycin dosed 10 mg/kg/d every 24 h, infused over 30-60 min, was the most commonly cited regimen. Monitoring of aminoglycoside serum concentrations was reported by all programs, with a tobramycin peak of 25-30 mg/L and trough of < 1 mg/L targeted most frequently. Nephrotoxicity was commonly monitored through serum creatinine measurements, while ototoxicity was monitored by audiometry in approximately one-half of programs. CONCLUSIONS: This study indicates that the use of EID of aminoglycosides across United States adult CF programs has increased considerably since the publication of the CF pulmonary exacerbation guidelines and now appears to be the most common method for dosing aminoglycosides in adults with CF. PMID- 24782556 TI - Noninvasive ventilation in severe acute asthma. AB - Noninvasive ventilation (NIV) in severe acute asthma is controversial but may benefit this population by preventing intubation. We report on a 35-year-old male asthma patient who presented to our emergency department via emergency medical services. The patient was responsive, diaphoretic, and breathing at 35 breaths/min on 100% oxygen with bag-mask assistance, with S(pO2) 88%, heart rate 110-120 beats/min, blood pressure 220/110 mm Hg, and temperature 35.8 degrees C. NIV at 12/5 cm H2O and FIO2 0.40 was applied, and albuterol at 40 mg/h was initiated. Admission arterial blood gas revealed a pH of 6.95, P(aCO2) 126 mm Hg, and P(aO2) 316 mm Hg. After 90 min of therapy, P(aCO2) was 63 mm Hg. Improvement continued, and NIV was stopped 4 h following presentation. NIV tolerance was supported with low doses of lorazepam. The patient was transferred to the ICU, moved to general care the next morning, and discharged 3 days later. We attribute our success to close monitoring in a critical care setting and the titration of lorazepam. PMID- 24782557 TI - Reversed halo sign: a systematic review. AB - A reversed halo sign (RHS) is defined as the presence of a focal ring-shaped area of ground-glass opacity within a peripheral rim of consolidation. Although originally described in patients with cryptogenic organizing pneumonia, it has been described with several other noninfectious and infectious diseases, including fungal infections. Thus, it is imperative that a proper diagnosis be established before initiating treatment. In this article, we systematically review the literature (PubMed and Embase) for the associations of the RHS. We have also proposed a diagnostic algorithm for an approach to a patient with an RHS. PMID- 24782558 TI - Immune reconstitution inflammatory syndrome. PMID- 24782559 TI - The analysis of complex mixed-radiation fields using near real-time imaging. AB - A new mixed-field imaging system has been constructed at Lancaster University using the principles of collimation and back projection to passively locate and assess sources of neutron and gamma-ray radiation. The system was set up at the University of Manchester where three radiation sources: (252)Cf, a lead-shielded (241)Am/Be and a (22)Na source were imaged. Real-time discrimination was used to find the respective components of the neutron and gamma-ray fields detected by a single EJ-301 liquid scintillator, allowing separate images of neutron and gamma ray emitters to be formed. (252)Cf and (22)Na were successfully observed and located in the gamma-ray image; however, the (241)Am/Be was not seen owing to surrounding lead shielding. The (252)Cf and (241)Am/Be neutron sources were seen clearly in the neutron image, demonstrating the advantage of this mixed-field technique over a gamma-ray-only image where the (241)Am/Be source would have gone undetected. PMID- 24782560 TI - Full spectrum analysis in environmental monitoring. AB - In environmental radiation monitoring, the time-variable natural gamma radiation background complicates the nuclide identification and analysis of a gamma spectrum. A full spectrum analysis based on the noise adjusted singular value decomposition method for the description of the time-variable background and adjustment calculations is a possible analysis method, which may provide advantages compared with a peak-based analysis, if applied to a time series of gamma spectra. An analysis example is shown and discussed with a measured time series of gamma spectra obtained from a spectroscopic gamma detector with a NaI(Tl) scintillator as it is used in the environmental radiation monitoring. PMID- 24782561 TI - Disrupted modular architecture of cerebellum in schizophrenia: a graph theoretic analysis. AB - Recent studies of schizophrenia have revealed cognitive and memory deficits that are accompanied by disruptions of neuronal connectivity in cortical and subcortical brain regions. More recently, alterations of topological organization of structural networks in schizophrenia are also being identified using graph theoretical analysis. However, the role of the cerebellum in this network structure remains largely unknown. In this study, global network measures obtained from diffusion tensor imaging were computed in the cerebella of 25 patients with schizophrenia and 36 healthy volunteers. While cerebellar global network characteristics were slightly altered in schizophrenia patients compared with healthy controls, the patients showed a retained small-world network organization. The modular architecture, however, was changed mainly in crus II. Furthermore, schizophrenia patients had reduced correlations between modularity and microstructural integrity, as measured by fractional anisotropy (FA) in lobules I-IV and X. Finally, FA alterations were significantly correlated with the Positive and Negative Syndrome Scale symptom scores in schizophrenia patients. Taken together, our data suggest that schizophrenia patients have altered network architecture in the cerebellum with reduced local microstructural connectivity and that cerebellar structural abnormalities are associated symptoms of the disorder. PMID- 24782562 TI - Ventral anterior cingulate connectivity distinguished nonpsychotic bipolar illness from psychotic bipolar disorder and schizophrenia. AB - Bipolar illness is a debilitating neuropsychiatric disorder associated with alterations in the ventral anterior cingulate cortex (vACC), a brain region thought to regulate emotional behavior. Although recent data-driven functional connectivity studies provide evidence consistent with this possibility, the role of vACC in bipolar illness and its pattern of whole brain connectivity remain unknown. Furthermore, no study has established whether vACC exhibits differential whole brain connectivity in bipolar patients with and without co-occurring psychosis and whether this pattern resembles that found in schizophrenia. We conducted a human resting-state functional connectivity investigation focused on the vACC seed in 73 remitted bipolar I disorder patients (33 with psychosis history), 56 demographically matched healthy comparison subjects, and 73 demographically matched patients with chronic schizophrenia. Psychosis history within the bipolar disorder group corresponded with significant between-group connectivity alterations along the dorsal medial prefrontal surface when using the vACC seed. Patients with psychosis history showed reduced connectivity (Cohen's d = -0.69), whereas those without psychosis history showed increased vACC coupling (Cohen's d = 0.8) relative to controls. The vACC connectivity observed in chronic schizophrenia patients was not significantly different from that seen in bipolar patients with psychosis history but was significantly reduced compared with that in bipolar patients without psychosis history. These robust findings reveal complex vACC connectivity alterations in bipolar illness, which suggest differences depending on co-occurrence of lifetime psychosis. The similarities in vACC connectivity patterns in schizophrenia and psychotic bipolar disorder patients may suggest the existence of common mechanisms underlying psychotic symptoms in the two disorders. PMID- 24782563 TI - The sexually transmitted infections and HIV/AIDS Cochrane review groups. PMID- 24782564 TI - Mucus, it is not just a static barrier. AB - The mucus layer is an important component of host defense against microbial infection of the intestinal epithelium. Autophagy is required for secretion of mucus by intestinal goblet cells. However, the upstream pathways that activate autophagy in this context are not yet fully elucidated. A recent study by Wlodarska et al. shows that NLRP6, a member of the Nod-like receptor family of pattern-recognition receptors, and the inflammasome pathway promote autophagy dependent mucus secretion from goblet cells, providing a potential mechanism by which inflammasomes maintain intestinal homeostasis. PMID- 24782565 TI - Screening of odor-receptor pairs in Caenorhabditis elegans reveals different receptors for high and low odor concentrations. AB - Olfactory systems sense and respond to various odorants. Olfactory receptors, which in most organisms are G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors, directly bind volatile or soluble odorants. Compared to the genomes of mammals, the genome of the nematode Caenorhabditis elegans contains more putative olfactory receptor genes, suggesting that in nematodes there may be combinatorial complexity to the receptor-odor relationship. We used RNA interference (RNAi) screening to identify nematode olfactory receptors necessary for the response to specific odorants. This screening identified 194 candidate olfactory receptor genes linked to 11 odorants. Additionally, we identified SRI-14 as being involved in sensing high concentrations of diacetyl. Rescue and neuron-specific RNAi experiments demonstrated that SRI-14 functioned in ASH neurons, specific chemosensory neurons, resulting in avoidance responses. Calcium imaging revealed that ASH neurons responded to high diacetyl concentrations only, whereas another class of chemosensory neurons, AWA neurons, reacted to both low and high concentrations. Loss of SRI-14 function hampered ASH responses to high diacetyl concentrations, whereas loss of ODR-10 function reduced AWA responses to low odorant concentrations. Chemosensory neurons ectopically expressing SRI-14 responded to a high concentration of diacetyl. Thus, nematodes have concentration-dependent odor-sensing mechanisms that are segregated at the olfactory receptor and sensory neuron levels. PMID- 24782566 TI - The DEAH-box RNA helicase DHX15 activates NF-kappaB and MAPK signaling downstream of MAVS during antiviral responses. AB - During infection with an RNA virus, the DExD/H-box RNA helicases RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated gene 5) activate the interferon regulatory factor 3 (IRF3), nuclear factor kappaB (NF kappaB), c-Jun amino-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways through an unknown mechanism involving the adaptor protein MAVS (mitochondrial antiviral signaling). We used a Drosophila misexpression screen to identify DEAH-box polypeptide 15 (DHX15) as an activator of the p38 MAPK pathway. Human DHX15 contributed to the activation of the NF kappaB, JNK, and p38 MAPK pathways, but not the IRF3 pathway, in response to the synthetic double-stranded RNA analog poly(I:C) (polyinosinic-polycytidylic acid), and DHX15 was required for optimal cytokine production in response to poly(I:C) and infection with RNA virus. DHX15 physically interacted with MAVS and mediated the MAVS-dependent activation of the NF-kappaB and MAPK pathways. Furthermore, DHX15 was required for poly(I:C)- and RNA virus-dependent, MAVS-mediated apoptosis. Thus, our findings indicate that, in RIG-I-like receptor signaling, DHX15 specifically stimulates the NF-kappaB and MAPK pathways downstream of MAVS and contributes to MAVS-mediated cytokine production and apoptosis. PMID- 24782568 TI - Immunoglobulin G4-related aortitis mimicking an intramural hematoma. AB - Immunoglobulin G4-related systemic disease is a rare entity with various presenting symptoms. We report the case of a 34-year-old Chinese male who presented with immunoglobulin G4-related aortitis and the unusual symptom of hoarseness of voice. He underwent distal ascending aorta and total aortic arch replacement. PMID- 24782569 TI - Creatine kinase and exercise. PMID- 24782567 TI - Proteome-wide identification of SUMO2 modification sites. AB - Posttranslational modification with small ubiquitin-like modifiers (SUMOs) alters the function of proteins involved in diverse cellular processes. SUMO-specific enzymes conjugate SUMOs to lysine residues in target proteins. Although proteomic studies have identified hundreds of sumoylated substrates, methods to identify the modified lysines on a proteomic scale are lacking. We developed a method that enabled proteome-wide identification of sumoylated lysines that involves the expression of polyhistidine (6His)-tagged SUMO2 with Thr(90) mutated to Lys. Endoproteinase cleavage with Lys-C of 6His-SUMO2(T90K)-modified proteins from human cell lysates produced a diGly remnant on SUMO2(T90K)-conjugated lysines, enabling immunoprecipitation of SUMO2(T90K)-modified peptides and producing a unique mass-to-charge signature. Mass spectrometry analysis of SUMO-enriched peptides revealed more than 1000 sumoylated lysines in 539 proteins, including many functionally related proteins involved in cell cycle, transcription, and DNA repair. Not only can this strategy be used to study the dynamics of sumoylation and other potentially similar posttranslational modifications, but also, these data provide an unprecedented resource for future research on the role of sumoylation in cellular physiology and disease. PMID- 24782570 TI - Reference ranges for atlantodental interval in adults and its variation with age and gender in a large series of subjects on multidetector computed tomography. AB - BACKGROUND: The atlanto-dental interval measurement in the cervical spine in young adults has been reported on multidetector computed tomography (MDCT), but has not been systematically assessed in all ages. PURPOSE: To evaluate the reference ranges for the atlanto-dental interval (ADI) in a large sample of adult patients on MDCT and to analyze the relationships of these measurements with gender and age of the patients as well as inter-observer performance. MATERIAL AND METHODS: First, a consecutive series of 700 Chinese patients aged over 18 years undergoing an upper cervical MDCT scan were divided equally into seven age groups. Second, the mid-sagittal image of the atlanto-dental joint was chosen for measurement and ADI was defined as the distance intercepted from the segment line linking the center of anterior atlas tubercle with that of posterior tubercle. Third, the correlation of ADI with age and gender was analyzed using linear regression analysis. Finally, the inter-observer performance was assessed using Bland and Altman's limits of agreement. RESULTS: The ADI was 1.77 +/- 0.39 mm, 1.61 +/- 0.37 mm, 1.58 +/- 0.36 mm, 1.41 +/- 0.29 mm, 1.31 +/- 0.29 mm, 1.34 +/- 0.28 mm, and 1.06 +/- 0.47 mm in the age groups 18-24 years, 25-29 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, and older than 70 years, respectively. The range of ADI was 0.85-3.12 mm in the age group 18-39 years, 0.71-2.55 mm in the age group 40-59 years, and 0.00-2.37 mm in the age group older than 60 years. There was no difference between gender and ADI (r = 0.00, P = 1.000). ADI decreased linearly with age (r = -0.511, P = 0.000). The inter observer performance was reliable. CONCLUSION: ADI measurements on MDCT linearly decrease with increasing age, and these are not affected by gender in adult patients. Different reference values might be used at different ages when diagnosing atlantoaxial anterior dislocation or subluxation. PMID- 24782571 TI - pASL versus DSC perfusion MRI in lateralizing temporal lobe epilepsy. AB - BACKGROUND: Accurate lateralization of the epileptogenic focus in temporal lobe epilepsy (TLE) is crucial. Pulsed arterial spin labeling (pASL) has the capability of quantifying local relative cerebral blood flow (rCBF) by measuring the inflow of electromagnetically labeled arterial blood into the target area, and can be used in the presurgical workup of refractory TLE. PURPOSE: To evaluate pASL in detecting mesial temporal lobe (mTL) perfusion asymmetry for the lateralization of the epileptogenic focus in patients with refractory TLE and to compare it with dynamic susceptibility contrast enhanced (DSC) magnetic resonance imaging (MRI) technique. MATERIAL AND METHODS: This study was approved by the local ethical committee, and written informed consent was obtained in each patient. Thirty-six patients with medically refractory TLE and 11 healthy volunteer was enrolled in this study. Following brain MRI, pASL and DSC perfusion were performed in all subjects at 3T. rCBF measurements with two different perfusion MRI technique were compared between the patient and healthy volunteers. Lateralization based on perfusion asymmetry index (AI) were also evaluated and compared with clinical lateralization. RESULTS: rCBF ratios measured in healthy volunteers by two different perfusion technique did not show any statistically significant difference. In TLE patients rCBF ratio of the ipsilateral (affected) side was found to be significantly lower than the contralateral (unaffected) side with both technique. The AI in the patient group was 8.86 +/- 3.88 with pASL and 8.39 +/- 4.06 with DSC. Correlation coefficient between clinical laterality and perfusion AI were 0.86 for pASL and 0.83 for DSC. CONCLUSION: pASL can successfully detect interictal asymmetry in patients with TLE and can readily be combined with routine structural assessment for lateralization, providing an alternative to DSC perfusion. PMID- 24782572 TI - Changes in regional brain glucose metabolism measured with F-18-FDG-PET in essential tremor. AB - BACKGROUND: There is growing evidence that essential tremor (ET) is a multiple system disorder. Previous PET studies in ET typically have measured brain oxygen consumption and cerebral blood flow. PURPOSE: To compare ET patients with control subjects to investigate any regional change in cerebral glucose metabolism through statistical parametric mapping (SPM) analysis of F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET). MATERIAL AND METHODS: We studied 17 patients with ET (17 men; mean age, 67.3 +/- 4.8 years) and age-sex matched normal subjects. All subjects underwent FDG-PET imaging, and evaluated severity of tremor symptoms was measured as score on the Fahn-Tolosa-Marin rating scale (FTM). We also evaluated detailed the medical history and neurological examinations in all patients. RESULTS: The mean age of tremor onset was 57.6 +/- 12.9 years and the mean FTM score was 15.1 +/- 4.9. Brain FDG-PET analysis demonstrated hypometabolism in the medial frontal lobe, medial temporal lobe, and the precuneus of parietal lobe. However, there was no significant difference of glucose metabolism in the cerebellum. CONCLUSION: We propose that motor symptom of ET are caused by electrophysiological disturbances within cortical-cerebellar networks, rather than degenerative process of cerebellum, because the metabolism of the cerebellum was normal at rest. Furthermore, the abnormal glucose metabolism in the cerebral regions that do not mainly participate in motor function suggest that these regions may play a role as early markers of non-motor manifestations. PMID- 24782573 TI - Effectiveness of a silicone device for foot MRI in order to obtain homogeneous fat suppression images. AB - BACKGROUND: Incomplete fat suppression induced by magnetic field inhomogeneity is difficult to compensate for with hardware magnetic-field shimming. PURPOSE: To evaluate the effectiveness of a silicone device used to obtain homogeneous fat suppression during 3T magnetic resonance imaging (MRI) scans of the foot. MATERIAL AND METHODS: Thirty-eight healthy volunteers were enrolled and examined twice, before (group A) and after (group B) the application of a silicone device. Fat-saturated, T2-weighted, fast spin-echo images were acquired using the same scanning protocol at both examinations. Signal- and contrast-to-noise ratios (SNR and CNR) were calculated and compared in the four regions of interest (ROIs). ROI 1 and 2 were selected from toe-side bone and soft tissue, while ROI 3 and 4 were selected from proximal bone and soft tissue. Qualitative analysis using a four point scale was performed for three categories. The categories are as follows: the overall image quality, homogeneity of the first phalange and metatarsal bone, respectively. RESULTS: The SNR and CNR in ROI 1 and 2 were significantly higher in group A than in group B (SNR; P < 0.001, CNR; P < 0.001), and there were no significant difference in ROI 3 and 4. The qualitative score of the overall fat suppression in group B was significantly higher than that in group A (P < 0.001). Homogeneity of the first phalange in group B was also significantly higher than that in group A (P < 0.001). On the other hand, the homogeneity of the metatarsal bone was not significantly different in the two groups. CONCLUSION: The use of a silicone device provides homogeneous fat suppression in 3T MRI of the foot and can significantly improve image quality. PMID- 24782574 TI - Dialogue on Ideal End-of-Life Care for Those With Dementia. AB - PURPOSE: To identify both meanings and perceptions of delivery of end-of-life (EoL) care for the person experiencing dementia. DESIGN/METHODS: As part of a larger cross-sectional mixed methods study examining quality of life in dementia, perspectives of EoL care were sought from 136 seniors using open-ended questions administered at interview. RESULTS: Seniors living in various settings identified obligatory requisites of care as time when the finality of death needed to be accepted, comfort was prioritized, family presence was valued, appearance remained important, and solitude or time "to be with God" was stressed. Skilled nursing care, honesty, and engaged family were also necessary. IMPLICATIONS: Understanding EoL preferences of those with dementia is critical for advocacy and service delivery. PMID- 24782575 TI - Diabetes Management in End of Life: A Preliminary Report Stemming From Clinical Experience. AB - The increasing coexistence of cancer and diabetes within the elderly population requires specific palliative care skills on diabetes treatment. We report our experience of diabetes management in a palliative care setting. In our retrospective 3-year activity sample (n = 563), 27.2% of patients have a diagnosis of diabetes mellitus: 80% have cancer whereas 20% have a main diagnosis of other severe chronic diseases. As to the presence/absence of diabetes, no differences emerge in the examined clinical indicators and global survival, with the exception of body mass index and days of hospitalization. At lifetime analysis, Barthel index and palliative prognostic index are the only parameters significantly related to death. Even if diabetes seems not to modify the prognosis, it significantly influences the health care burden and the team engagement. PMID- 24782576 TI - Geometrical Design of a Scalable Overlapping Planar Spiral Coil Array to Generate a Homogeneous Magnetic Field. AB - We present a design methodology for an overlapping hexagonal planar spiral coil (hex-PSC) array, optimized for creation of a homogenous magnetic field for wireless power transmission to randomly moving objects. The modular hex-PSC array has been implemented in the form of three parallel conductive layers, for which an iterative optimization procedure defines the PSC geometries. Since the overlapping hex-PSCs in different layers have different characteristics, the worst case coil-coupling condition should be designed to provide the maximum power transfer efficiency (PTE) in order to minimize the spatial received power fluctuations. In the worst case, the transmitter (Tx) hex-PSC is overlapped by six PSCs and surrounded by six other adjacent PSCs. Using a receiver (Rx) coil, 20 mm in radius, at the coupling distance of 78 mm and maximum lateral misalignment of 49.1 mm (1/?3 of the PSC radius) we can receive power at a PTE of 19.6% from the worst case PSC. Furthermore, we have studied the effects of Rx coil tilting and concluded that the PTE degrades significantly when theta > 60 degrees . Solutions are: 1) activating two adjacent overlapping hex-PSCs simultaneously with out-of-phase excitations to create horizontal magnetic flux and 2) inclusion of a small energy storage element in the Rx module to maintain power in the worst case scenarios. In order to verify the proposed design methodology, we have developed the EnerCage system, which aims to power up biological instruments attached to or implanted in freely behaving small animal subjects' bodies in long-term electrophysiology experiments within large experimental arenas. PMID- 24782579 TI - Understanding undernutrition. PMID- 24782578 TI - Do vitamin A deficiency and undernutrition still matter? PMID- 24782577 TI - Apolipoprotein E gene polymorphism and serum lipid profile in Saudi patients with psoriasis. AB - BACKGROUND/AIM: Apolipoprotein E (APOE) gene variants have been reported to influence psoriasis risk. However, data is limited to a few ethnicities and no similar study has been performed in middle eastern populations. We investigated this association in Saudi psoriasis patients. METHODS: Saudi subjects (294) were genotyped for APOE gene using APOE StripAssay kit. RESULTS: The frequencies of alleles epsilon2, epsilon4, and genotypes epsilon3/epsilon4 and epsilon3/epsilon2 were significantly higher in psoriasis patients compared with those in controls. The frequency of epsilon3 allele and epsilon3/epsilon3 genotype was significantly lower in patients. Other genotypes, epsilon2/epsilon4, epsilon2/epsilon2, and epsilon4/epsilon4, were absent in both groups. The serum cholesterol, triglycerides, and LDL levels were significantly higher in psoriasis patients contrary to HDL level. Patients with APOE epsilon 4 had significantly higher levels of total cholesterol and LDL cholesterol, whereas those with the epsilon2 had higher HDL cholesterol, and triglycerides. CONCLUSION: APOE alleles epsilon2, epsilon4, and genotypes epsilon2/epsilon3 and epsilon4/epsilon3 are associated with psoriasis and can be a risk factor while allele epsilon3 and genotype epsilon3/epsilon3 may be protective for psoriasis in Saudis. Results of lipid profile support that psoriasis is one of the independent risk factors for hyperlipidemia and emphasize the need of screening cardiovascular diseases in psoriatic patients. PMID- 24782580 TI - What is vitamin A and why do we need it? PMID- 24782581 TI - The eye signs of vitamin A deficiency. PMID- 24782582 TI - How to manage children with the eye signs of vitamin A deficiency. PMID- 24782583 TI - Public health programmes for vitamin A deficiency control. PMID- 24782584 TI - Vitamin A supplementation: who, when and how. PMID- 24782586 TI - Keep on operating: how to deal with power cuts. PMID- 24782585 TI - Vitamin A deficiency: what eye health workers can do. PMID- 24782587 TI - How to measure and record blood pressure. PMID- 24782588 TI - Verifying the calibration of a manual one-position keratometer. PMID- 24782589 TI - We have 'a very good chance' of eliminating blinding trachoma by 2020. PMID- 24782590 TI - Test your knowledge and understanding. PMID- 24782591 TI - Diagnose This quiz. PMID- 24782592 TI - Effect of tumor necrosis factor family member LIGHT (TNFSF14) on the activation of basophils and eosinophils interacting with bronchial epithelial cells. AB - Allergic asthma can cause airway structural remodeling, involving the accumulation of extracellular matrix and thickening of smooth muscle. Tumor necrosis factor (TNF) family ligand LIGHT (TNFSF14) is a cytokine that binds herpesvirus entry mediator (HVEM)/TNFRSF14 and lymphotoxin beta receptor (LTbetaR). LIGHT induces asthmatic cytokine IL-13 and fibrogenic cytokine transforming growth factor-beta release from allergic asthma-related eosinophils expressing HVEM and alveolar macrophages expressing LTbetaR, respectively, thereby playing crucial roles in asthmatic airway remodeling. In this study, we investigated the effects of LIGHT on the coculture of human basophils/eosinophils and bronchial epithelial BEAS-2B cells. The expression of adhesion molecules, cytokines/chemokines, and matrix metalloproteinases (MMP) was measured by flow cytometry, multiplex, assay or ELISA. Results showed that LIGHT could significantly promote intercellular adhesion, cell surface expression of intercellular adhesion molecule-1, release of airway remodeling-related IL-6, CXCL8, and MMP-9 from BEAS-2B cells upon interaction with basophils/eosinophils, probably via the intercellular interaction, cell surface receptors HVEM and LTbetaR on BEAS-2B cells, and extracellular signal-regulated kinase, p38 mitogen activated protein kinase, and NF-kappaB signaling pathways. The above results, therefore, enhance our understanding of the immunopathological roles of LIGHT in allergic asthma and shed light on the potential therapeutic targets for airway remodeling. PMID- 24782593 TI - Lancemaside A from Codonopsis lanceolata modulates the inflammatory responses mediated by monocytes and macrophages. AB - In this study, we aimed to examine the cellular and molecular mechanisms of lancemaside A from Codonopsis lanceolata (Campanulaceae) in the inflammatory responses of monocytes (U937 cells) and macrophages (RAW264.7 cells). Lancemaside A significantly suppressed the inflammatory functions of lipopolysaccharide- (LPS ) treated RAW264.7 cells by suppressing the production of nitric oxide (NO), the expression of the NO-producing enzyme inducible NO synthase (iNOS), the upregulation of the costimulatory molecule CD80, and the morphological changes induced by LPS exposure. In addition, lancemaside A diminished the phagocytic activity of RAW264.7 cells and boosted the neutralizing capacity of these cells when treated with the radical generator sodium nitroprusside (SNP). Interestingly, lancemaside A strongly blocked the adhesion activity of RAW264.7 cells to plastic culture plates, inhibited the cell-cell and cell-fibronectin (FN) adhesion of U937 cells that was triggered by treatment with an anti-beta1 integrin (CD29) antibody and immobilized FN, respectively. By evaluating the activation of various intracellular signaling pathways and the levels of related nuclear transcription factors, lancemaside A was found to block the activation of inhibitor of kappaB kinase (IKK) and p65/nuclear factor- (NF-) kappaB. Taken together, our findings strongly suggest that the anti-inflammatory function of lancemaside A is the result of its strong antioxidative and IKK/NF-kappaB inhibitory activities. PMID- 24782595 TI - Association between parathyroid hormone levels and inflammatory markers among US adults. AB - BACKGROUND AND AIMS: High levels of parathyroid hormone (PTH) appear to be associated with an increased mortality. Previous studies concerning the relationship of inflammatory markers with hyperparathyroidism have yielded inconsistent results. This study investigated whether serum PTH concentrations were independently associated with several inflammatory markers among the US adults. MATERIALS AND METHODS: Using data from the National Health and Nutrition Examination Survey, we examined the relation between serum PTH and C-reactive protein (CRP), red cell distribution width (RDW), and platelet-to-lymphocyte ratio (PLR) levels with weighted linear regression. Additionally, we examined the relation with increased modified Glasgow Prognostic Score (mGPS) by using weighted logistic regression. RESULTS: CRP, RDW, and PLR values increased with increasing serum PTH concentration. After extensively adjusting for covariates, CRP and RDW increased linearly and across PTH categories (all P < 0.001), while PLR marginally increased (P = 0.190 and P = 0.095 using PTH as a categorical and continuous variable, resp.). The odds ratio of increased mGPS was 1.11 and 1.31 across PTH categories and with increasing PTH levels continuously. CONCLUSION: These nationally representative data indicate that serum PTH levels are independently associated with several inflammatory markers in the US population. The casual relationship between PTH levels and inflammation remains to be elucidated. PMID- 24782596 TI - Polymorphisms in the tumor necrosis factor receptor genes affect the expression levels of membrane-bound type I and type II receptors. AB - The level of TNF receptors on various cells of immune system and its association with the gene polymorphism were investigated. Determining the levels of membrane bound TNFalpha receptors on peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry using BD QuantiBRITE calibration particles. Soluble TNF alpha receptor (sTNFRs) levels were determined by ELISA and genotyping was determined by PCR-RFLP. Homozygous TT individuals at SNP -609G/T TNFRI (rs4149570) showed lower levels of sTNFRI compared to GG genotype carriers. Homozygous carriers of CC genotype at SNP -1207G/C TNFRI (rs4149569) had lower expression densities of membrane-bound TNFRI on intact CD14(+) monocytes compared to individuals with the GC genotype. The frequency differences in the CD3(+) and CD19(+) cells expressing TNFRII in relation to SNP -1709A/T TNFRII (rs652625) in healthy individuals were also determined. The genotype CC in SNP -3609C/T TNFRII (rs590368) was associated with a lower percentage of CD14(+) cells expressing TNFRII compared to individuals with the CT genotype. Patients with rheumatoid arthritis had no significant changes in the frequencies of genotypes. Reduced frequency was identified for the combination TNFRI -609GT + TNFRII -3609CC only. The polymorphisms in genes represent one of cell type-specific mechanisms affecting the expression levels of membrane-bound TNF alpha receptors and TNF alpha -mediated signaling. PMID- 24782597 TI - Uteroglobin, a possible ligand of the lipoxin receptor inhibits serum amyloid A driven inflammation. AB - Serum amyloid A (SAA) production is increased by inflamed arthritic synovial tissue, where it acts as a cytokine/chemoattractant for inflammatory and immune cells and as an inducer of matrix degrading enzymes. SAA has been shown to bind lipoxin A4 receptor, a member of the formyl-peptide related 2 G-protein coupled receptor family (ALX) and elicit proinflammatory activities in human primary fibroblast-like synoviocytes (FLS). We report on the identification of uteroglobin, a small globular protein with potent anti-inflammatory activities, as a possible ligand of ALX. Uteroglobin-specific association with ALX was demonstrated by an enzyme immunoassay experiment employing a cell line engineered to express the human ALX receptor. Uteroglobin's interaction with ALX resulted in the inhibition of SAA responses, such as attenuation of phospholipase A2 activation and cellular chemotaxis. In FLS, uteroglobin showed an antagonism against SAA-induced interleukin-8 release and decreased cell migration. These novel roles described for uteroglobin via ALX may help elucidate genetic and clinical observations indicating that a polymorphism in the uteroglobin promoter is linked to disease outcome, specifically prediction of bone erosion in patients with rheumatoid arthritis or severity of IgA glomerulonephritis and sarcoidosis. PMID- 24782594 TI - Autoantibodies to posttranslational modifications in rheumatoid arthritis. AB - Autoantibodies have been associated with human pathologies for a long time, particularly with autoimmune diseases (AIDs). Rheumatoid factor (RF) is known since the late 1930s to be associated with rheumatoid arthritis (RA). The discovery of anticitrullinated protein antibodies in the last century has changed this and other posttranslational modifications (PTM) relevant to RA have since been described. Such PTM introduce neoepitopes in proteins that can generate novel autoantibody specificities. The recent recognition of these novel specificities in RA provides a unique opportunity to understand human B-cell development in vivo. In this paper, we will review the three of the main classes of PTMs already associated with RA: citrullination, carbamylation, and oxidation. With the advancement of research methodologies it should be expected that other autoantibodies against PTM proteins could be discovered in patients with autoimmune diseases. Many of such autoantibodies may provide significant biomarker potential. PMID- 24782598 TI - Protective effect of cytosolic phospholipase A2 inhibition against inflammation and degeneration by promoting regulatory T cells in rats with experimental autoimmune encephalomyelitis. AB - Cytosolic phospholipase A2 (cPLA2) is the rate-limiting enzyme that initiates the production of various inflammatory mediators. Previous studies have shown that inhibiting cPLA2 exerts a neuroprotective effect on experimental autoimmune encephalomyelitis (EAE) by ameliorating the severity of the disease and influencing Th1 and Th17 responses. However, it remains unclear whether treatment with a cPLA2 inhibitor will influence the regulatory T cells (Tregs) that play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. In this study, the cPLA2 inhibitor AX059 reduced the onset and progression of EAE in Lewis rats. In addition, this effect was accompanied by activation of Tregs and alterations in the expression of their various cytokines. The study therefore demonstrated that Tregs are involved in the immunomodulatory effect mediated by cPLA2 inhibition. These findings may have clinical application in the treatment of multiple sclerosis. PMID- 24782599 TI - Cytomegalovirus infection impairs immunosuppressive and antimicrobial effector functions of human multipotent mesenchymal stromal cells. AB - Human mesenchymal stromal cells (MSC) possess immunosuppressive and antimicrobial effects that are partly mediated by the tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO). Therefore MSC represent a promising novel cellular immunosuppressant which has the potential to control steroid-refractory acute graft versus host disease (GvHD). In addition, MSC are capable of reducing the risk of infection in patients after haematopoietic stem cell transplantation (HST). Recent data indicate that signals from the microenvironment including those from microbes may modulate MSC effector functions. As Cytomegalovirus (CMV) represents a prominent pathogen in immunocompromised hosts, especially in patients following HST, we investigated the impact of CMV infection on MSC mediated effects on the immune system. We demonstrate that CMV-infected MSC lose their cytokine-induced immunosuppressive capacity and are no longer able to restrict microbial growth. IDO expression is substantially impaired following CMV infection of MSC and this interaction critically depends on intact virus and the number of MSC as well as the viral load. Since overt CMV infection may undermine the clinical efficacy of MSC in the treatment of GvHD in transplant patients, we recommend that patients scheduled for MSC therapy should undergo thorough evaluation for an active CMV infection and receive CMV-directed antiviral therapy prior to the administration of MSC. PMID- 24782600 TI - Increased susceptibility of aging gastric mucosa to injury: the mechanisms and clinical implications. AB - This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury. Experimental and clinical studies indicate that gastric mucosa of aging individuals-"aging gastropathy"-has prominent structural and functional abnormalities vs young gastric mucosa. Some of these abnormalities include a partial atrophy of gastric glands, impaired mucosal defense (reduced bicarbonate and prostaglandin generation, decreased sensory innervation), increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), impaired healing of injury and reduced therapeutic efficacy of ulcer healing drugs. Detailed analysis of the above changes indicates that the following events occur in aging gastric mucosa: reduced mucosal blood flow and impaired oxygen delivery cause hypoxia, which leads to activation of the early growth response-1 (egr-1) transcription factor. Activation of egr-1, in turn, upregulates the dual specificity phosphatase, phosphatase and tensin homologue deleted on chromosome ten (PTEN) resulting in activation of pro-apoptotic caspase 3 and caspase-9 and reduced expression of the anti-apoptosis protein, survivin. The imbalance between pro- and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury. This paradigm has human relevance since increased expression of PTEN and reduced expression of survivin were demonstrated in gastric mucosa of aging individuals. Other potential mechanisms operating in aging gastric mucosa include reduced telomerase activity, increase in replicative cellular senescence, and reduced expression of vascular endothelial growth factor and importin-alpha-a nuclear transport protein essential for transport of transcription factors to nucleus. Aging gastropathy is an important and clinically relevant issue because of: (1) an aging world population due to prolonged life span; (2) older patients have much greater risk of gastroduodenal ulcers and gastrointestinal complications (e.g., NSAIDs-induced gastric injury) than younger patients; and (3) increased susceptibility of aging gastric mucosa to injury can be potentially reduced or reversed pharmacologically. PMID- 24782601 TI - Characteristics of gastric cancer in Asia. AB - Gastric cancer (GC) is the fourth most common cancer in the world with more than 70% of cases occur in the developing world. More than 50% of cases occur in Eastern Asia. GC is the second leading cause of cancer death in both sexes worldwide. In Asia, GC is the third most common cancer after breast and lung and is the second most common cause of cancer death after lung cancer. Although the incidence and mortality rates are slowly declining in many countries of Asia, GC still remains a significant public health problem. The incidence and mortality varies according to the geographic area in Asia. These variations are closely related to the prevalence of GC risk factors; especially Helicobacter pylori (H. pylori) and its molecular virulent characteristics. The gradual and consistent improvements in socioeconomic conditions in Asia have lowered the H. pylori seroprevalence rates leading to a reduction in the GC incidence. However, GC remains a significant public health and an economic burden in Asia. There has been no recent systemic review of GC incidence, mortality, and H. pylori molecular epidemiology in Asia. The aim of this report is to review the GC incidence, mortality, and linkage to H. pylori in Asia. PMID- 24782602 TI - Gastric cancer research in Mexico: a public health priority. AB - This study aimed review studies conducted on Mexican patients diagnosed with gastric cancer and/or diseases associated with its development, in which at least one Mexican institute has participated, and to assess their contributions to the primary and secondary prevention of this disease. A search of the Medline database was conducted using the following keywords: gastric/stomach cancer, Mexico. Studies of the Mexican population were selected in which at least one Mexican Institute had participated and where the findings could support public policy proposals directed towards the primary or secondary prevention of gastric cancer. Of the 148 studies found in the Medline database, 100 were discarded and 48 were reviewed. According to the analysis presented, these studies were classified as: epidemiology of gastric cancer (5/48); risk factors and protectors relating to gastric cancer (9/48); relationship between Helicobacter pylori and pathologies associated with gastric cancer and the development of the disease (16/48); relationship between the Epstein-Barr virus and pathologies associated with gastric cancer and the development of the disease (3/48); molecular markers for the development of diseases associated with gastric cancer and gastric cancer (15/48). Mexico requires a program for the prevention and control of gastric cancer based on national health indicators. This should be produced by a multidisciplinary committee of experts who can propose actions that are relevant in the current national context. The few studies of gastric cancer conducted on the Mexican population in national institutes highlight the poor connection that currently exists between the scientific community and the health sector in terms of resolving this health issue. Public policies for health research should support projects with findings that can be translated into benefits for the population. This review serves to identify national research groups studying gastric cancer in the Mexican population. PMID- 24782603 TI - Role of gene polymorphisms in gastric cancer and its precursor lesions: current knowledge and perspectives in Latin American countries. AB - Latin America shows one of the highest incidence rates of gastric cancer in the world, with variations in mortality rates among nations or even within countries belonging to this region. Gastric cancer is the result of a multifactorial complex process, for which a multistep model of carcinogenesis is currently accepted. Additionally to the infection with Helicobacter pylori, that plays a major role, environmental factors as well as genetic susceptibility factors are significant players at different stages in the gastric cancer process. The differences in population origin, demographic structure, socio-economic development, and the impact of globalization lifestyles experienced in Latin America in the last decades, all together offer opportunities for studying in this context the influence of genetic polymorphisms in the susceptibility to gastric cancer. The aim of this article is to discuss current trends on gastric cancer in Latin American countries and to review the available published information about studies of association of gene polymorphisms involved in gastric cancer susceptibility from this region of the world. A total of 40 genes or genomic regions and 69 genetic variants, 58% representing markers involved in inflammatory response, have been used in a number of studies in which predominates a low number of individuals (cases and controls) included. Polymorphisms of IL-1B (-511 C/T, 14 studies; -31 T/C, 10 studies) and IL-1RN (variable number of tandem repeats, 17 studies) are the most represented ones in the reviewed studies. Other genetic variants recently evaluated in large meta analyses and associated with gastric cancer risk were also analyzed in a few studies [e.g., prostate stem cell antigen (PSCA), CDH1, Survivin]. Further and better analysis centered in gene polymorphisms linked to other covariates, epidemiological studies and the information provided by meta-analyses and genome wide association studies should help to improve our understanding of gastric cancer etiology in order to develop appropriate health programs in Latin America. PMID- 24782604 TI - Adjuvant chemotherapy for gastric cancer: current evidence and future challenges. AB - Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e., limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that disease-free survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment. PMID- 24782605 TI - Role of human epidermal growth factor receptor 2 in gastric cancer: biological and pharmacological aspects. AB - Amplification of the human epidermal growth factor receptor 2 (HER2) gene and overexpression of the HER2 protein is found in 15%-20% of patients with gastric and gastroesophageal junction cancer. The degree of HER2 overexpression and amplification varies with the location of the carcinoma, with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach. Further, HER2 overexpression and amplification also seems to be related to the Lauren histological classification, with higher levels found in the intestinal phenotype compared to the diffuse and mixed types. The prognostic properties of HER2 overexpression and amplification are still under debate, but a large number of studies seem to indicate that HER2 is a negative prognostic factor. The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial, where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive 5 FU/capecitabine and cisplatin, either alone or in combination with trastuzumab. A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy. Patients with a strong overexpression of the HER2 protein (IHC3+) specifically benefited from the treatment, with a median overall survival of 17.9 mo. As a consequence of the positive results of the ToGA trial, patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2. The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab, ado-trastuzumab emtansine, lapatinib, afatinib, and dacomitinib, which are currently undergoing phase II and III clinical testing. Overall, this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy. PMID- 24782606 TI - Targeting receptor tyrosine kinases in gastric cancer. AB - Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies. PMID- 24782607 TI - State-of-the-art preoperative staging of gastric cancer by MDCT and magnetic resonance imaging. AB - Gastric cancer is one of the most common and fatal cancers. The importance of accurate staging for gastric cancer has become more critical due to the recent introduction of less invasive treatment options, such as endoscopic mucosal resection or laparoscopic surgery. The tumor-node-metastasis staging system is the generally accepted staging system for predicting the prognosis of patients with gastric cancer. Multidetector row computed tomography (MDCT) is a widely accepted imaging modality for the preoperative staging of gastric cancer that can simultaneously assess locoregional staging, including the gastric mass, regional lymph nodes, and distant metastasis. The diagnostic performance of MDCT for T- and N-staging has been improved by the technical development of isotropic imaging and 3D reformation. Although magnetic resonance imaging (MRI) was not previously used to evaluate gastric cancer due to the modality's limitations, the development of high-speed sequences has made MRI a feasible tool for the staging of gastric cancer. PMID- 24782608 TI - Ethnic differences in gastric cancer genetic susceptibility: allele flips of interleukin gene. AB - Polymorphisms in promoter regions of inflammatory cytokines have been widely studied, and potentially functional polymorphisms have been discovered. Conflicting results from meta-analyses of interleukin (IL)-1B and IL-10 polymorphisms show differences in gastric cancer susceptibilities between Caucasian and Asian populations. In particular, we note the suggestion of an allele flip in IL-1B and IL-10 gene polymorphisms. In Asian populations, the IL 1B-1464G/-511C/-31T haplotype indicates risk for gastric cancer, while the opposite haplotype, IL-1B-1464C/-511T/-31C is the risk-related allele in Caucasians. Furthermore, while IL-10-1082G/-819C/-592C is associated with gastric cancer in Asians, IL-10-1082A/-819T/-592T is linked to gastric cancer risk in Caucasians. These seemingly contradictory results may be attributed to distinct carcinogenic mechanisms underlying the different gastric cancer subtypes. The allele flip observed in IL-10 and gastric cancer appears to reflect allelic heterogeneity, similar to that observed in IL-1B. In this review, we focus on the allele flip phenomenon observed between different ethnic groups in an effort to resolve certain controversial results from recent studies on interleukin polymorphism. In addition, we re-emphasize the importance of stratifying gastric cancer subtypes based on anatomical site and Lauren classification to prevent false associations arising through dilution of true ones. PMID- 24782609 TI - Endoscopic treatment for early gastric cancer. AB - Gastric cancer remains one of the most common causes of cancer death. However the proportion of early gastric cancer (EGC) at diagnosis is increasing. Endoscopic treatment for EGC is actively performed worldwide in cases meeting specific criteria. Endoscopic mucosal resection can treat EGC with comparable results to surgery for selected cases. Endoscopic submucosal dissection (ESD) increases the en bloc and complete resection rates and reduces the local recurrence rate. ESD has been performed with expanded indication and is expected to be more widely used in the treatment of EGC through the technological advances in the near future. This review will describe the techniques, indications and outcomes of endoscopic treatment for EGC. PMID- 24782610 TI - Diagnosis and evaluation of gastric cancer by positron emission tomography. AB - Gastric cancer is the second leading cause of cancer mortality worldwide. The diagnosis of gastric cancer has been significantly improved with the broad availability of gastrointestinal endoscopy. Effective technologies for accurate staging and quantitative evaluation are still in demand to merit reasonable treatment and better prognosis for the patients presented with advanced disease. Preoperative staging using conventional imaging tools, such as computed tomography (CT) and endoscopic ultrasonography, is inadequate. Positron emission tomography (PET), using (18)F-fluorodeoxyglucose (FDG) as a tracer and integrating CT for anatomic localization, holds a promise to detect unsuspected metastasis and has been extensively used in a variety of malignancies. However, the value of FDG PET/CT in diagnosis and evaluation of gastric cancer is still controversial. This article reviews the current literature in diagnosis, staging, response evaluation, and relapse monitoring of gastric cancer, and discusses the current understanding, improvement, and future prospects in this area. PMID- 24782611 TI - Inflammation-related factors predicting prognosis of gastric cancer. AB - Gastric cancer (GC), which is mainly induced by Helicobacter pylori (H. pylori) infection, is one of the leading causes of cancer-related death in the developing world. Active inflammation initiated by H. pylori infection and maintained by inherent immune disorders promotes carcinogenesis and postoperative recurrence. However, the presence with H. pylori in tumors has been linked to a better prognosis, possibly due to the induction of antitumor immunity. Tumor infiltrations of tumor-associated macrophages, myeloid-derived suppressor cells, neutrophils, Foxp3(+) regulatory T cells are correlated with poor prognosis. Tumor infiltrating CD8(+) cytotoxic T lymphocytes, dendritic cells, and CD45RO T cells are generally associated with good prognosis of GC, although some subsets of these immune cells have inverse prognosis prediction values. High ratios of Foxp3(+)/CD4(+) and Foxp3(+)/CD8(+) in tumors are associated with a poor prognosis; whereas high Th1/Th2 ratio in tumors predicts a good prognosis. High levels of interleukin (IL)-6, IL-10, IL-32, and chemokine C-C motif ligands (CCL)7 and CCL21 in circulation, high expression of CXC chemokine receptor 4, chemokine C-C motif receptor (CCR)3, CCR4, CCR5, CCR7, hypoxia-inducible factor 1alpha, signal transducer activator of transcription-3, cyclooxygenase-2, and orphan nuclear receptor 4A2 in tumors are associated with an unfavorable prognosis. Increased serum levels of matrix metalloproteinases (MMP)-3, MMP-7, and MMP-11 and increased levels of MMP-9, MMP-12, and MMP-21 in tumors are consistently associated with poor survival of GC. Further emphasis should be put on the integration of these biomarkers and validation in large cohorts for personalized prediction of GC postoperative prognosis. PMID- 24782612 TI - Invasive micropapillary carcinoma: a distinct type of adenocarcinomas in the gastrointestinal tract. AB - Invasive micropapillary carcinoma (IMPC) is a rare histological type of tumor, first described in invasive ductal breast cancer, than in malignancies in other organs such as lungs, urinary bladder, ovaries or salivary glands. Recent literature data shows that this histological lesion has also been found in cancers of the gastrointestinal system. The micropapillary components are clusters of neoplastic cells that closely adhere to each other and are located in distinct empty spaces. Moreover, clusters of neoplastic cells do not have a fibrous-vascular core. The IMPC cells show reverse polarity resulting in typical ''inside-out'' structures that determines secretary properties, disturbs adhesion and conditions grade of malignancy in gastrointestinal (GI) tract. Invasive micropapillary carcinoma in this location is associated with metastases to local lymph nodes and lymphovascular invasion. IMPC can be a prognostic factor for patients with cancers of the stomach, pancreas and with colorectal cancer since it is related with disease-free and overall survival. The purpose of this review is to present the characterization of invasive micropapillary carcinoma in colon, rectum, stomach and others site of GI tract, and to determine the immunohistological indentification of IMPC in those localization. PMID- 24782614 TI - Role of pomegranate and citrus fruit juices in colon cancer prevention. AB - Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Recent studies prove that though chemotherapeutic agents are being used for the treatment of colon cancer, they become non-effective when the cancer progresses to an invasive stage. Since consumption of certain dietary agents has been linked with various cancers, fruit juices have been investigated for their consistently protective effect against colon cancer. The unique biochemical composition of fruit juices is responsible for their anticancer properties. In this review, the chemo-preventive effect of fruit juices such as pomegranate and citrus juices against colon cancer are discussed. For this purpose, the bioavailability, in vitro and in vivo effects of these fruit juices on colorectal cancer are highlighted. Moreover, there is a scarcity of studies involving human trials to estimate the preventive nature of these juices against colon cancer. This review will support the need for more preclinical tests with these crude juices and their constituents in different colorectal cancer cell lines and also some epidemiological studies in order to have a better understanding and promote pomegranate and citrus juices as crusaders against colon cancer. PMID- 24782615 TI - Gastric nNOS reduction accompanied by natriuretic peptides signaling pathway upregulation in diabetic mice. AB - AIM: To investigate the relationship between neuronal nitric oxide synthase (nNOS) expression and the natriuretic peptide signaling pathway in the gastric fundus of streptozotocin (STZ)-induced diabetic mice. METHODS: Diabetic mice were induced by injection of STZ solution. Immunofluorescence labeling of HuC/D, nNOS and natriuretic peptide receptor-A, B, C (NPRs) in the gastric fundus (GF) was used to observe nNOS expression and whether NPRs exist on enteric neurons. The expression levels of nNOS and NPRs in the diabetic GF were examined by western blotting. An isometric force transducer recorded the electric field stimulation (EFS)-induced relaxation and contraction in the diabetic GF. An intracellular recording method assessed EFS-induced inhibitory junction potentials (IJP) on the GF. GF smooth muscles acquired from normal mice were incubated with different concentrations of the NPRs agonist C-type natriuretic peptide (CNP) for 24 h, after which their nNOS expressions were detected by western blotting. RESULTS: Eight weeks after injection, 43 diabetic mice were obtained from mouse models injected with STZ. Immunofluorescence indicated that the number of NOS neurons was significantly decreased and that nNOS expression was significantly downregulated in the diabetic GF. The results of physiological and electrophysiological assays showed that the EFS-induced relaxation that mainly caused by NO was significantly reduced, while the contraction was enhanced in the diabetic GF. EFS-induced IJP showed that L-NAME sensitive IJP in the diabetic GF was significantly reduced compared with control mice. However, both NPR-A and NPR B were detected on enteric neurons, and their expression levels were upregulated in the diabetic GF. The nNOS expression level was downregulated dose-dependently in GF smooth muscle tissues exposed to CNP. CONCLUSION: These findings suggested that upregulation of the NPs signaling pathway may be involved in GF neuropathy caused by diabetes by decreasing nNOS expression. PMID- 24782613 TI - Helicobacter pylori infection and diabetes: is it a myth or fact? AB - Helicobacter pylori (H. pylori) is one of the most common human bacterial pathogens, and infection causes a wide array of gastric disorders, including simple gastritis, peptic ulcers and gastric malignancies. Gastrointestinal inflammation caused by H. pylori can influence the absorption of glucose and lipids, which are also abnormal in diabetes mellitus. Type 2 diabetes mellitus (T2DM), formerly known as non-insulin-dependent diabetes mellitus or adult-onset diabetes, is a metabolic disorder that is characterized by high levels of blood glucose resulting from insulin resistance and relative insulin deficiency. It is an emerging pandemic and is rapidly becoming a serious threat to public health. Emerging data now indicate a strong relationship between H. pylori infection and the incidence of T2DM. The mechanisms underlying the pathogenesis of diabetes are complex, involving insulin resistance, chronic inflammation, insulin secretion deficiency as a result of pancreas beta-cell dysfunction, glucotoxicity, and lipotoxicity. H. pylori infection is known to be involved in the pathogenesis of insulin resistance, and the growing awareness of its role in diabetes is important for the early detection of glucose dysregulation and prevention of T2DM in high-risk communities. This review probes the possible relationship between H. pylori and diabetes according to epidemiological surveys and discusses putative mechanisms underlying this correlation. PMID- 24782616 TI - Combined probiotic bacteria promotes intestinal epithelial barrier function in interleukin-10-gene-deficient mice. AB - AIM: To investigate the protective effects of combinations of probiotic (Bifico) on interleukin (IL)-10-gene-deficient (IL-10 KO) mice and Caco-2 cell monolayers. METHODS: IL-10 KO mice were used to assess the benefits of Bifico in vivo. IL-10 KO and control mice received approximately 1.5 * 10(8) cfu/d of Bifico for 4 wk. Colons were then removed and analyzed for epithelial barrier function by Ussing Chamber, while an ELISA was used to evaluate proinflammatory cytokines. The colon epithelial cell line, Caco-2, was used to test the benefit of Bifico in vitro. Enteroinvasive Escherichia coli (EIEC) and the probiotic mixture Bifico, or single probiotic strains, were applied to cultured Caco-2 monolayers. Barrier function was determined by measuring transepithelial electrical resistance and tight junction protein expression. RESULTS: Treatment of IL-10 KO mice with Bifico partially restored body weight, colon length, and epithelial barrier integrity to wild-type levels. In addition, IL-10 KO mice receiving Bifico treatment had reduced mucosal secretion of tumor necrosis factor-alpha and interferon-gamma, and attenuated colonic disease. Moreover, treatment of Caco-2 monolayers with Bifico or single-strain probiotics in vitro inhibited EIEC invasion and reduced the secretion of proinflammatory cytokines. CONCLUSION: Bifico reduced colon inflammation in IL-10 KO mice, and promoted and improved epithelial-barrier function, enhanced resistance to EIEC invasion, and decreased proinflammatory cytokine secretion. PMID- 24782617 TI - Resveratrol inhibits collagen I synthesis by suppressing IGF-1R activation in intestinal fibroblasts. AB - AIM: To investigate whether resveratrol (3,4,5-trihydroxy-trans-stilbene) inhibits collagen I synthesis induced by insulin growth factor-1 (IGF-1) in intestinal fibroblasts, and to explore the possible molecular mechanisms. METHODS: Male Sprague-Dawley rats were randomly divided into two groups: a control group and a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis group. After 21 d of TNBS administration, the degree of inflammation and fibrosis in colon was measured by HE staining and Masson's trichrome staining. Western blotting was used to examine collagen I, IGF-1 and silent information regulator 1 (SIRT1) protein expression in colitis tissues. Western blotting and quantitative real-time polymerase chain reaction were used to characterize collagen I protein and col1a2 mRNA expression in mouse intestinal fibroblasts and CCD-(18)Co cells treated with IGF-1. A MEK inhibitor (U0126) was used to determine whether IGF-1 induced collagen I expression was mediated by extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent mechanism. Effects of resveratrol on collagen I protein level, insulin growth factor-1 receptor (IGF-1R) and ERK1/2 phosphorylation levels were also examined after IGF-1 treatment in fibroblasts. To evaluate whether SIRT1 was necessary for the anti-fibrosis effect of resveratrol, cells were transfected with SIRT1-specific small interfering RNAs, wild-type SIRT1, and deacetylase-inactive mutant SIRT1. RESULTS: Collagen I and IGF-1 expression was increased, and SIRT1 expression was decreased (0.67 +/- 0.04 vs 1.05 +/- 0.07, P < 0.001) in TNBS-induced colitis compared with the control group. In vitro, IGF-1 could induce collagen I expression, mainly through the ERK 1/2 signal pathway. Resveratrol reduced basal and IGF-1-induced collagen I gene and protein expression in intestinal fibroblasts. Overexpression of wild-type SIRT1, not deacetylase-inactive mutant SIRT1, decreased expression of collagen I induced by IGF-1. Moreover, silencing SIRT1 restored collagen I expression in fibroblasts challenged with resveratrol. However, disruption of SIRT1 did not influence the anti-fibrotic effects of resveratrol and IGF-1-induced collagen I expression. Further analysis revealed that resveratrol significantly decreased phosphorylation of IGF-1R and its downstream signaling molecules by inhibiting IGF-1 binding to its receptor. CONCLUSION: Our data suggest that resveratrol effectively inhibits collagen I synthesis in IGF-1-stimulated fibroblasts, partly by inhibiting IGF-1R activation, and SIRT1 is also responsible for the process. PMID- 24782618 TI - Protective effect of glutamine on intestinal injury and bacterial community in rats exposed to hypobaric hypoxia environment. AB - AIM: To investigate the protective effect of glutamine (Gln) on intestinal injury and the bacterial community in rats exposed to hypobaric hypoxia environment. METHODS: Sprague-Dawley rats were divided into control, hypobaric hypoxia (HH), and hypobaric hypoxia + Gln (5.0 g/kg BW.d) (HG) groups. On the first 3 d, all rats were placed in a normal environment. After the third day, the HH and HG groups were transferred into a hypobaric chamber at a simulated elevation of 7000 m for 5 d. The rats in the HG group were given Gln by gavage daily for 8 d. The rats in the control and HH groups were treated with the same volume of saline. The intestinal morphology, serum levels of malondialdehyde (MDA), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and diamino oxidase (DAO) were examined. We also evaluated the expression levels of occludin, toll-like receptor 4 (TLR4), nuclear factor-kappaB p65 (NF-kappaB p65) and myeloid differentiation factor 88 (MyD88), and examined the bacterial community in caecal contents. RESULTS: Hypobaric hypoxia induced the enlargement of the heart, liver, lung and kidney, and caused spleen atrophy. Intestinal villi damage was also observed in the HH group. Supplementation with Gln significantly alleviated hypobaric-induced damage to main organs including the intestine, increased serum SOD (1.14 +/- 0.03 vs 0.88 +/- 0.04, P < 0.05) and MDA (8.35 +/- 1.60, P < 0.01) levels and decreased serum IL-6 (1172.13+/-30.49 vs 1407.05 +/- 34.36, P < 0.05), TNF-alpha (77.46 +/- 0.78 vs 123.70 +/- 3.03, P < 0.001), IFN-gamma (1355.42 +/- 72.80 vs 1830.16 +/- 42.07, P < 0.01) and DAO (629.30 +/- 9.15 vs 524.10 +/- 13.34, P < 0.001) levels. Moreover, Gln significantly increased occludin (0.72 +/- 0.05 vs 0.09 +/- 0.01, P < 0.001), TLR4 (0.15 +/- 0.05 vs 0.30 +/-0.09, P < 0.05), MyD88 (0.32 +/- 0.08 vs 0.71 +/- 0.06, P < 0.01), and NF-kappaB p65 (0.16 +/- 0.04 vs 0.44 +/- 0.03, P < 0.01) expression levels and improved the intestinal bacterial community. CONCLUSION: Gln treatment protects from intestinal injury and regulates the gut flora imbalance in hypoxia environment. These effects may be related to the TLR4/MyD88/NF-kappaB signaling pathway. PMID- 24782619 TI - Role of observation of live cases done by Japanese experts in the acquisition of ESD skills by a western endoscopist. AB - AIM: To evaluate the role of observation of experts performing endoscopic submucosal dissection (ESD) in the acquisition of ESD skills. METHODS: This prospective study is documenting the learning curve of one Western endoscopist. The study consisted of three periods. In the first period (pre-observation), the trainee performed ESDs in animal models in his home institution in the United States. The second period (observation) consisted of visit to Japan and observation of live ESD cases done by experts. The observation of cases occurred over a 5-wk period. During the third period (post-observation), the trainee performed ESD in animal models in a similar fashion as in the first period. Three animal models were used: live 40-50 kg Yorkshire pig, explanted pig stomach model, and explanted pig rectum model. The outcomes from the ESDs done in the animal models before and after observation of live human cases (main study intervention) were compared. Statistical analysis of the data included: Fisher's exact test to compare distributions of a categorical variable, Wilcoxon rank sum test to compare distributions of a continuous variable between the two groups (pre-observation and post-observation), and Kruskal-Wallis test to evaluate the impact of lesion location and type of model (ex-vivo vs live pig) on lesion removal time. RESULTS: The trainee performed 38 ESDs in animal model (29 pre observation/9 post-observation). The removal times post-observation were significantly shorter than those pre-observation (32.7 +/- 15.0 min vs 63.5 +/- 9.8 min, P < 0.001). To minimize the impact of improving physician skill, the 9 lesions post-observation were compared to the last 9 lesions pre-observation and the removal times remained significantly shorter (32.7 +/- 15.0 min vs 61.0 +/- 7.4 min, P = 0.0011). Regression analysis showed that ESD observation significantly reduced removal time when controlling for the sequence of lesion removal (P = 0.025). Furthermore, it was also noted a trend towards decrease in failure to remove lesions and decrease in complications after the period of observation. This study did not find a significant difference in the time needed to remove lesions in different animal models. This finding could have important implications in designing training programs due to the substantial difference in cost between live animal and explanted organ models. The main limitation of this study is that it reflects the experience of a single endoscopist. CONCLUSION: Observation of experts performing ESD over short period of time can significantly contribute to the acquisition of ESD skills. PMID- 24782620 TI - Safety and efficacy of Hansenula-derived PEGylated-interferon alpha-2a and ribavirin combination in chronic hepatitis C Egyptian children. AB - AIM: To investigate the safety and efficacy of a Hansenula-derived PEGylated (polyethylene glycol) interferon (IFN)-alpha-2a (Reiferon Retard) plus ribavirin customized regimen in treatment-naive and previously treated (non-responders and relapsers) Egyptian children with chronic hepatitis C infection. METHODS: Forty six children with chronic hepatitis C virus (HCV) infection were selected from three tertiary pediatric hepatology centers. Clinical and laboratory evaluations were undertaken. Quantitative polymerase chain reaction (PCR) for HCV-RNA was performed before starting treatment, and again at 4, 12, 24, 48, 72 wk during treatment and 6 mo after treatment cessation. All patients were assigned to receive a weekly subcutaneous injection of PEG-IFN-alpha-2a plus daily oral ribavirin for 12 wk. Thirty-four patients were treatment-naive and 12 had a previous treatment trial. Patients were then divided according to PCR results into two groups. Group I included patients who continued treatment on a weekly basis (7-d schedule), while group II included patients who continued treatment on a 5-d schedule. Patients from either group who were PCR-negative at week 48, but had at least one PCR-positive test during therapy, were assigned to have an extended treatment course up to 72 wk. The occurrence of adverse effects was assessed during treatment and follow up. The study was registered at www.ClinicalTrials.gov (NCT02027493). RESULTS: Only 11 out of 46 (23.9%) patients showed a sustained virological response (SVR), two patients were responders at the end of treatment; however, they were lost to follow up at 6 mo post treatment. Breakthrough was seen in 18 (39.1%) patients, one patient (2.17%) showed relapse and 14 (30.4%) were non-responders. Male gender, short duration of infection, low viral load, mild activity, and mild fibrosis were the factors related to a better response. On the other hand, patients with high viral load and absence of fibrosis failed to respond to treatment. Before treatment, liver transaminases were elevated. After commencing treatment, they were normalized in all patients at week 4 and were maintained normal in responders till the end of treatment, while they increased again significantly in non-responders (P = 0.007 and 0.003 at week 24 and 72 respectively). The 5-d schedule did not affect the response rate (1/17 had SVR). Treatment duration (whether 48 wk or extended course to 72 wk) gave similar response rates (9/36 vs 2/8 respectively; P = 0.49). Type of previous treatment (short acting IFN vs PEG-IFN) did not affect the response to retreatment. On the other hand, SVR was significantly higher in previous relapsers than in previous non-responders (P = 0.039). Only mild reversible adverse effects were observed and children tolerated the treatment well. CONCLUSION: Reiferon Retard plus ribavirin combined therapy was safe. Our customized regimen did not influence SVR rates. Further trials on larger numbers of patients are warranted. PMID- 24782621 TI - Localization and vasopressin regulation of the Na+-K+-2Cl- cotransporter in the distal colonic epithelium. AB - AIM: To investigate whether Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) is expressed in the mouse distal colonic epithelia and whether it is regulated by vasopressin in the colon. METHODS: The mRNA expression of NKCC2 in the mouse colonic mucosa was examined by reverse transcription-polymerase chain reaction. NKCC trafficking in the colon stimulated by 1-D-amino(8-D-arginine)-vasopressin (dDAVP) infusion (10 ng/mouse, intraperitoneal injection ) within 15 min, 30 min and 1h was investigated by laser confocal scanning microscopy. Total and membrane NKCC2 expression in the colonic mucosa from control and dDAVP-treated mice was detected by Western blotting. Short circuit current method was performed to determine regulation of NKCC2 by vasopressin in the colon. RESULTS: NKCC2 was predominantly located in the apical region of the surface of the distal colonic epithelia; by comparison, a large amount of NKCC1 was distributed in the basolateral membrane of the lower crypt epithelia of the mouse distal colon. Short-term treatment with dDAVP, a V2-type receptor-specific vasopressin analog, induced NKCC2 re distribution, i.e., NKCC2 traffics to the apical membrane after dDAVP stimulation. In contrast, no obvious NKCC1 membrane translocation was observed. Western blotting results confirmed that membrane NKCC2 had significantly higher abundance in the dDAVP-treated mouse colonic mucosa relative to that in the untreated control, which is consistent with our immunostaining data. Moreover, the short-circuit current method combined with a NKCC2 inhibitor demonstrated that NKCC2 was also activated by serosal vasopressin in isolated distal colonic mucosa. CONCLUSION: Our results provide direct evidence that vasopressin also plays an important role in the colonic epithelia by stimulating NKCC2 trafficking to the apical membrane and inducing NKCC2-mediated ion transport. PMID- 24782622 TI - Controlled attenuation parameter for non-invasive assessment of hepatic steatosis in Chinese patients. AB - AIM: To evaluate the performance of a novel non-invasive controlled attenuation parameter (CAP) to assess liver steatosis. METHODS: This was a multi-center prospective cohort study. Consecutive patients (aged >= 18 years) who had undergone percutaneous liver biopsy and CAP measurement were recruited from three Chinese liver centers. Steatosis was categorized as S0: < 5%; S1: 5%-33%; S2: 34% 66%; or S3: >= 67%, according to the nonalcoholic fatty liver disease (NAFLD) activity score. The FibroScan((r)) 502 equipped with the M probe (Echosens, Paris, France) was used to capture both CAP and liver stiffness measurement values simultaneously. Receiver operating characteristic curves were plotted, and the areas under the curves were calculated to determine the diagnostic efficacy. The accuracy of the CAP values at the optimal thresholds was defined by maximizing the sum of sensitivity and specificity (maximum Youden index). RESULTS: A total of 152 patients were recruited, including 52 (34.2%) patients with NAFLD and 100 (65.8%) with chronic hepatitis B (CHB) virus infection. After adjustment, the steatosis grade (OR = 37.12; 95%CI: 21.63-52.60, P < 0.001) and body mass index (BMI, OR = 6.20; 95%CI: 2.92-9.48, P < 0.001) were found independently associated with CAP by multivariate linear regression analysis. CAP was not influenced by inflammation, fibrosis or aetiology. The median CAP values and interquartile ranges among patients with S0, S1, S2 and S3 steatosis were 211 (181-240) dB/m, 270 (253-305) dB/m, 330 (302-360) dB/m, and 346 (313-363) dB/m, respectively. The cut-offs for the CAP values in all patients with steatosis >= 5%, >= 34% and >= 67% were 253 dB/m, 285 dB/m and 310 dB/m, respectively. The areas under the curves were 0.92, 0.92 and 0.88 for steatosis >= 5%, >= 34% and >= 67%, respectively. No significant differences were found in the CAP values between the NAFLD group and the CHB group in each steatosis grade. CONCLUSION: CAP appears to be a promising tool for the non-invasive detection and quantification of hepatic steatosis, but is limited by BMI. PMID- 24782623 TI - Sonic hedgehog expression in a rat model of chronic pancreatitis. AB - AIM: To analyze the activation of sonic hedgehog (SHh) signaling pathways in a rat model of chronic pancreatitis. METHODS: Forty Wistar rats were randomly divided into 2 groups: experimental group and control group (20 rats in each group). Dibutyltin dichloride was infused into the tail vein of the rats to induce chronic pancreatitis in the experimental group. The same volume of ethanol and glycerol mixture was infused in the control group. The expression of Ptch, Smo and Gli were analyzed using immunohistochemistry, and real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with the control group, significant histological changes in terms of the areas of abnormal architecture, glandular atrophy, fibrosis, pseudo tubular complexes, and edema were observed at week 4 in the experimental group. The expression of Ptch1, Smo and Gli1 in the pancreatic tissue increased significantly in the experimental group. Using RT-PCR, mRNA levels of Ptch, Smo and Gli in the experimental group increased significantly compared with the control group. CONCLUSION: The SHh signaling pathway is aberrantly activated in rats with chronic pancreatitis. The SHh signaling pathway plays an important role in the development of chronic pancreatitis. These results may be helpful in studies focusing on the relationship between chronic pancreatitis and pancreatic cancer. PMID- 24782624 TI - Improved biopsy accuracy in Barrett's esophagus with a transparent cap. AB - AIM: To evaluate the efficacy of endoscopy with a transparent cap on biopsy positioning in Barrett's esophagus (BE). METHODS: One hundred and sixty-eight patients with suspected BE at endoscopy were enrolled in our study from November 2007 to December 2009 and divided into two groups: transparent cap group (n = 60) and control group (n = 108). Endoscopy with or without a transparent cap and subsequent biopsy of suspected lesions were performed by five experienced endoscopists in our hospital. In both groups, two biopsy specimens were taken from each patient, and the columnar epithelium or goblet cells in histological assessment were used as the diagnostic standard for BE. RESULTS: In the transparent cap group, 41 cases were tongue type, while 17 and two cases were identified as island type and circumferential type, respectively. In the control group, 65 tongue-type cases were confirmed, with 38 island-type and five circumferential-type cases. Moreover, there was no significant difference with regard to the composition of endoscopic BE types in the two groups (P > 0.05). In the biopsy specimens, BE was detected in 50 cases in the transparent cap group (83.3%, 50/60), whereas the detection rate in the control group (69.4%, 75/108) was lower compared to that in the transparent cap group (P < 0.05). In addition, goblet cells were recognized in only eight cases (all with columnar epithelium) (8/60, 13.3%) in the transparent cap group, with 11 cases in the control group. CONCLUSION: Transparent cap-fitted endoscopy can guide biopsy positioning in BE without other accompanying complications, thus increasing the detection rate of BE. PMID- 24782625 TI - MT1M and MT1G promoter methylation as biomarkers for hepatocellular carcinoma. AB - AIM: To investigate the potential of promoter methylation of two tumor suppressor genes (TSGs) as biomarkers for hepatocellular carcinoma (HCC). METHODS: A total of 189 subjects were included in this retrospective cohort, which contained 121 HCC patients without any history of curative treatment, 37 patients with chronic hepatitis B (CHB), and 31 normal controls (NCs). DNA samples were extracted from 400 MUL of serum of each subject and then modified using bisulfite treatment. Methylation of the promoters of the TSGs (metallothionein 1M, MT1M; and metallothionein 1G, MT1G) was determined using methylation-specific polymerase chain reaction. The diagnostic value of combined MT1M and MT1G promoter methylation was evaluated using the area under the receiver operating characteristic curves. RESULTS: Our results indicated that the methylation status of serum MT1M (48.8%, 59/121) and MT1G (70.2%, 85/121) promoters in the HCC group was significantly higher than that in the CHB group (MT1M 5.4%, 2/37, P < 0.001; MT1G 16.2%, 6/37, P < 0.001) and NC group (MT1M 6.5%, 2/31, P < 0.001; MT1G 12.9%, 4/27, P < 0.001). Aberrant serum MT1M promoter methylation gave higher specificity to discriminate HCC from CHB (94.6%) and NCs (93.5%), whereas combined methylation of serum MT1M and MT1G promoters showed higher diagnostic sensitivity (90.9%), suggesting that they are potential markers for noninvasive detection of HCC. Furthermore, MT1M promoter methylation was positively correlated with tumor size (rs = 0.321, P < 0.001), and HCC patients with both MT1M and MT1G promoter methylation tended to show a higher incidence of vascular invasion or metastasis (P = 0.018). CONCLUSION: MT1M and MT1G promoter methylation may be used as serum biomarkers for noninvasive detection of HCC. PMID- 24782626 TI - Roles of sphincter of Oddi motility and serum vasoactive intestinal peptide, gastrin and cholecystokinin octapeptide. AB - AIM: To investigate roles of sphincter of Oddi (SO) motility played in pigment gallbladder stone formation in model of guinea pigs. METHODS: Thirty-four adult male Hartley guinea pigs were divided randomly into two groups: the control group and pigment stone group. The pigment stone group was divided into 4 subgroups with 6 guinea pigs each according to time of sacrifice, and were fed a pigment lithogenic diet and sacrificed after 3, 6, 9 and 12 wk. SO manometry and recording of myoelectric activity of the guinea pigs were obtained by multifunctional physiograph at each stage. Serum vasoactive intestinal peptide (VIP), gastrin and cholecystokinin octapeptide (CCK-8) were detected at each stage in the process of pigment gallbladder stone formation by enzyme-linked immunosorbent assay. RESULTS: The incidence of pigment gallstone formation was 0%, 0%, 16.7% and 66.7% in the 3-, 6-, 9- and 12-wk group, respectively. The frequency of myoelectric activity decreased in the 3-wk group. The amplitude of myoelectric activity had a tendency to decrease but not significantly. The frequency of the SO decreased significantly in the 9-wk group. The SO basal pressure and common bile duct pressure increased in the 12-wk group (25.19 +/- 7.77 mmHg vs 40.56 +/- 11.81 mmHg, 22.35 +/- 7.60 mmHg vs 38.51 +/- 11.57 mmHg, P < 0.05). Serum VIP was significantly elevated in the 6- and 12-wk groups and serum CCK-8 was decreased significantly in the 12-wk group. CONCLUSION: Pigment gallstone-causing diet may induce SO dysfunction. The tension of the SO increased. The disturbance in SO motility may play a role in pigment gallstone formation, and changes in serum VIP and CCK-8 may be important causes of SO dysfunction. PMID- 24782627 TI - Association between NOD2/CARD15 gene polymorphisms and Crohn's disease in Chinese Zhuang patients. AB - AIM: To assess the relationship between the P268S, JW1 and N852S polymorphisms and Crohn's disease (CD) susceptibility in Zhuang patients in Guangxi, China. METHODS: Intestinal tissues from 102 Zhuang [48 CD and 54 ulcerative colitis (UC)] and 100 Han (50 CD and 50 UC) unrelated patients with inflammatory bowel disease and 72 Zhuang and 78 Han unrelated healthy individuals were collected in the Guangxi Zhuang Autonomous Region from January 2009 to March 2013. Genomic DNA was extracted using the phenol chloroform method. The P268S, JW1 and N852S polymorphisms were amplified using polymerase chain reaction (PCR), detected by restriction fragment length polymorphism (RFLP), and verified by gene sequencing. RESULTS: Heterozygous mutation of P268S in the NOD2/CARD15 gene was detected in 10 CD cases (six Zhuang and four Han), two Han UC cases, and one Zhuang healthy control, and P268S was strongly associated with the Chinese Zhuang and Han CD populations (P = 0.016 and 0.022, respectively). No homozygous mutant P268S was detected in any of the groups. No significant difference was found in P268S genotype and allele frequencies between UC and control groups (P > 0.05). Patients with CD who carried P268S were likely to be <= 40 years of age (P = 0.040), but were not significantly different with regard to race, lesion site, complications, and other clinical features (P > 0.05). Neither JW1 nor N852S polymorphisms of the NOD2/CARD15 gene were found in any of the subjects (P > 0.05). CONCLUSION: P268S polymorphism may be associated with CD susceptibility in the Zhuang population in the Guangxi Zhuang Autonomous Region, China. In contrast, JW1 and N852S polymorphisms may not be related to CD susceptibility in these patients. PMID- 24782628 TI - Entecavir vs lamivudine therapy for naive patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. AB - AIM: To investigate the short-term and long-term efficacy of entecavir versus lamivudine in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure (ACLF). METHODS: This was a single center, prospective cohort study. Eligible, consecutive hospitalized patients received either entecavir 0.5 mg/d or lamivudine 100 mg/d. All patients were given standard comprehensive internal medicine. The primary endpoint was survival rate at day 60, and secondary endpoints were reduction in hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) levels, and improvement in Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores at day 60 and survival rate at week 52. RESULTS: One hundred and nineteen eligible subjects were recruited from 176 patients with severe acute exacerbation of chronic hepatitis B: 65 were included in the entecavir group and 54 in the lamivudine group (full analysis set). No significant differences were found in patient baseline clinical parameters. At day 60, entecavir did not improve the probability of survival (P = 0.066), despite resulting in faster virological suppression (P < 0.001), higher rates of virological response (P < 0.05) and greater reductions in the CTP and MELD scores (all P < 0.05) than lamivudine. Intriguingly, at week 52, the probability of survival was higher in the entecavir group than in the lamivudine group [42/65 (64.6%) vs 26/54 (48.1%), respectively; P = 0.038]. The pretreatment MELD score (B, 1.357; 95%Cl: 2.138-7.062; P = 0.000) and virological response at day 30 (B, 1.556; 95%Cl: 1.811-12.411; P =0.002), were found to be good predictors for 52-wk survival. CONCLUSION: Entecavir significantly reduced HBV DNA levels, decreased the CTP and MELD scores, and thereby improved the long-term survival rate in patients with spontaneous reactivation of hepatitis B presenting as ACLF. PMID- 24782629 TI - Hepatoprotective effect of Cichorium intybus L., a traditional Uighur medicine, against carbon tetrachloride-induced hepatic fibrosis in rats. AB - AIM: To investigate the hepatoprotective effect of a Cichorium intybus L. extract (CIE) on CCl4-induced hepatic fibrosis in rats. METHODS: Seventy-two male Wistar albino rats were randomly divided into six groups of twelve rats each. The normal control group was allowed free access to food and water. Liver injury was performed in the remaining five groups with an i.p. injection of a 1.0 mL/kg CCl4 and olive oil (2:3 v/v) mixture, twice weekly for 8 weeks. All rats, with the exception of the injury model group, were intragastrically (i.g.,) administered quantum satis (q.s.) dosages [CIE group: 6, 18, and 54 mg/kg, respectively; Fu Fang Bie Jia Ruan Gan Pian (FFBJRGP) group: 780 mg/kg]. The oral administration of different drugs was performed on the day before CCl4 administration and subsequently once per day for 8 wk. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), hydroxyproline (Hyp), and glutathione (GSH), malondialdehyde (MDA) and superoxide dismutase (SOD) in the rat livers were measured. Histopathological changes in the liver were assessed for each group using HE staining and a Masson Trichrome examination. The expression of transforming growth factor-beta1 (TGF beta1) and alpha-smooth muscle actin (alpha-SMA) was examined by immunohistochemical analysis. RESULTS: CIE at oral doses of 6, 18, and 54 g/kg per day showed a significant hepatoprotective effect, especially at a dose of 54 g/kg per day. CIE doses reduced the levels of AST (149.04 +/- 34.44, P < 0.01), ALT (100.72 +/- 27.19, P < 0.01), HA (548.50 +/- 65.09, P < 0.01), LN (28.69 +/- 3.32, P < 0.01) and Hyp (263.33 +/- 75.82, P < 0.01). With regards to hepatoprotective activity, the CIE dose of 54 g/kg per day produced the largest significant effect by increasing GSH (3.11 +/- 0.81), SOD (269.98 +/- 33.77, P < 0.01) and reducing MDA (2.76 +/- 0.51, P < 0.01) levels in the liver. The expressions of TGF-beta1 and alpha-SMA were measured by immunohistology and found to be significantly reduced by CIE in a dose-dependent manner. CONCLUSION: CIE may effectively protect against CCl4-induced hepatic fibrosis in rats; thus, it is a promising anti-fibrotic therapeutic agent. PMID- 24782630 TI - Helicobacter pylori isolates from ethnic minority patients in Guangxi: resistance rates, mechanisms, and genotype. AB - AIM: To investigate the rate of Helicobacter pylori (H. pylori) resistance to clarithromycin among ethnic minority patients in Guangxi, explore the underlying mechanisms, and analyze factors influencing genotype distribution of H. pylori isolates. METHODS: H. pylori strains were isolated, cultured and subjected to drug sensitivity testing. The 23S rRNA gene of H. pylori isolates was amplified by PCR and analyzed by PCR-RFLP and direct sequencing to detect point mutations. REP-PCR was used for genotyping of H. pylori isolates, and NTsys_2 software was used for clustering analysis based on REP-PCR DNA fingerprints. Factors potentially influencing genotype distribution of H. pylori isolates were analyzed. RESULTS: The rate of clarithromycin resistance was 31.3%. A2143G and A2144G mutations were detected in the 23S rRNA gene of all clarithromycin resistant H. pylori isolates. At a genetic distance of 78%, clarithromycin resistant H. pylori isolates could be divided into six groups. Significant clustering was noted among H. pylori isolates from patients with peptic ulcer or gastritis. CONCLUSION: The rate of clarithromycin resistance is relatively high in ethnic minority patients in Guangxi. Main mechanisms of clarithromycin resistance are A2143G and A2144G mutations in the 23S rRNA gene. Clarithromycin resistant H. pylori isolates can be divided into six groups based on REP-PCR DNA fingerprints. Several factors such as disease type may influence the genotype distribution of H. pylori isolates. PMID- 24782631 TI - Intravenous infusion of mesenteric lymph from severe intraperitoneal infection rats causes lung injury in healthy rats. AB - AIM: To investigate whether mesenteric lymph from rats with severe intraperitoneal infection (SII) induces lung injury in healthy rats. METHODS: Twenty adult male specific pathogen-free Wistar rats were divided into two groups. Animals in the SII group received intraperitoneal injection of Escherichia coli (E. coli) at a dose of 0.3 mL/100 g. Control rats underwent the same procedure, but were injected with normal saline rather than E. coli. We ligated and drained the mesenteric lymphatic vessels and collected the mesenteric lymph. Mesenteric lymph collected from SII or control rats was infused intravenously into male healthy rats at a rate of 1 mL/h for 4 h. At the end of the infusion, all rats were sacrificed. Lungs were removed and examined histologically, and wet-to-dry weight (W/D) ratio and myeloperoxidase (MPO) activity were determined. Enzyme-linked immunosorbent assay (ELISA) was performed to determine the levels of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. We performed Western blot to investigate the activation of Toll-like receptor (TLR)-4, and nuclear factor (NF)-kappaB p65. RESULTS: Compared with the control infusion group, there were obvious pathological changes in the SII group. The W/D ratio was significantly increased in the SII compared to control infusion group (5.86 +/- 0.06 vs 5.37 +/- 0.06, P < 0.01). MPO activity significantly increased in the SII infusion rats with a mean level of 0.86 +/- 0.02 U/g compared to 0.18 +/- 0.05 U/g in the control group (P < 0.01). The concentrations of TNF-alpha and IL-6 were significantly increased in the SII infusion group. The concentration of TNF-alpha was significantly increased in the SII infusion rats compared to control infusion rats (2104.46 +/- 245.91 vs 1475.13 +/- 137.82 pg/mL, P < 0.01). The concentration of IL-6 was significantly increased in the SII infusion rats with a mean level of 50.56 +/- 2.85 pg/mL compared to 43.29 +/- 2.02 pg/mL (P < 0.01). The expression levels of TLR-4 (7496.68 +/- 376.43 vs 4589.02 +/- 233.16, P < 0.01) and NF-kappaB (8722.19 +/- 323.96 vs 6498.91 +/- 338.76, P < 0.01) were significantly increased in the SII infusion group compared to the control infusion group. The infusion of SII lymph, but not control lymph, caused lung injury. CONCLUSION: The results indicate that SII lymph is sufficient to induce acute lung injury. PMID- 24782632 TI - Proteomic analysis of liver mitochondria from rats with nonalcoholic steatohepatitis. AB - AIM: To explore mitochondrial dysfunction in nonalcoholic steatohepatitis (NASH) by analyzing the proteome of liver mitochondria from a NASH model. METHODS: The NASH rat model was established by feeding rats a fat-rich diet for 24 wk and was confirmed using hematoxylin and eosin staining of liver tissue and by changes in the levels of serum alanine transaminase, aspartate aminotransferase, triglyceride, total cholesterol and other markers. Liver mitochondria from each group were isolated using differential centrifugation. The mitochondrial samples were lyzed, purified and further analyzed using two-dimensional electrophoresis combined with matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. Bioinformatic analyses of assigned gene ontology and biological pathway was used to study functional enrichments in the abundant proteomic data. RESULTS: Eight up-regulated and sixteen down-regulated proteins were identified that showed greater than 1.5-fold differences between the controls and the NASH group. These dysregulated proteins were predicted to be involved in different metabolic processes including fatty acid beta-oxidation processes, lipid metabolic processes, cell-cycle arrest, cell polarity maintenance, and adenosine triphosphate/sex hormone metabolic processes. Novel proteins that may be involved in NASH pathogenesis including the trifunctional enzyme Hadha, thyroxine, prohibitin, aldehyde dehydrogenase ALDH1L2, UDP glucuronosyltransferase 2B31, and carbamoyl-phosphate synthase were identified using bioinformatics tools. The decreased expression of Hadha in NASH liver was verified by Western blotting, which was used as a complementary technique to confirm the proteomic results. CONCLUSION: This novel report on the liver mitochondrial proteome of a NASH model may provide a reservoir of information on the pathogenesis and treatment of NASH. PMID- 24782633 TI - Point shear wave elastography method for assessing liver stiffness. AB - AIM: To estimate the validity of the point shear-wave elastography method by evaluating its reproducibility and accuracy for assessing liver stiffness. METHODS: This was a single-center, cross-sectional study. Consecutive patients with chronic viral hepatitis scheduled for liver biopsy (LB) (Group 1) and healthy volunteers (Group 2) were studied. In each subject 10 consecutive point shear-wave elastography (PSWE) measurements were performed using the iU22 ultrasound system (Philips Medical Systems, Bothell, WA, United States). Patients in Group 1 underwent PSWE, transient elastography (TE) using FibroScan (Echosens, Paris, France) and ultrasound-assisted LB. For the assessment of PSWE reproducibility two expert raters (rater 1 and rater 2) independently performed the examinations. The performance of PSWE was compared to that of TE using LB as a reference standard. Fibrosis was staged according to the METAVIR scoring system. Receiver operating characteristic curve analyses were performed to calculate the area under the receiver operating characteristic curve (AUC) for F >= 2, F >= 3 and F = 4. The intraobserver and interobserver reproducibility of PSWE were assessed by calculating Lin's concordance correlation coefficient. RESULTS: To assess the performance of PSWE, 134 consecutive patients in Group 1 were studied. The median values of PSWE and TE (in kilopascals) were 4.7 (IQR = 3.8-5.4) and 5.5 (IQR = 4.7-6.5), respectively, in patients at the F0-F1 stage and 3.5 (IQR = 3.2-4.0) and 4.4 (IQR = 3.5-4.9), respectively, in the healthy volunteers in Group 2 (P < 10(-5)). In the univariate analysis, the PSWE and TE values showed a high correlation with the fibrosis stage; low correlations with the degree of necroinflammation, aspartate aminotransferase and gamma-glutamyl transferase (GGT); and a moderate negative correlation with the platelet count. A multiple regression analysis confirmed the correlations of both PSWE and TE with fibrosis stage and GGT but not with any other variables. The following AUC values were found: 0.80 (0.71-0.87) for PSWE and 0.82 (0.73-0.89) for TE (P = 0.42); 0.88 (0.80-0.94) for PSWE and 0.95 (0.88-0.98) for TE (P = 0.06); and 0.95 (0.89 0.99) for PSWE and 0.92 (0.85-0.97) for TE (P = 0.30) for F >= 2, F >= 3 and F = 4, respectively. To assess PSWE reproducibility, 116 subjects were studied, including 47 consecutive patients scheduled for LB (Group 1) and 69 consecutive healthy volunteers (Group 2). The intraobserver agreement ranged from 0.83 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 1 and from 0.84 (95%CI: 0.79-0.88) to 0.96 (95%CI: 0.95-0.97) for rater 2. The interobserver agreement yielded values from 0.83 (95%CI: 0.78-0.88) to 0.93 (95%CI: 0.91-0.95). CONCLUSION: PSWE is a reproducible method for assessing liver stiffness, and it compares with TE. Compared with patients with nonsignificant fibrosis, healthy volunteers showed significantly lower values. PMID- 24782634 TI - Role of 3DCT in laparoscopic total gastrectomy with spleen-preserving splenic lymph node dissection. AB - AIM: To investigate whether computed tomography with 3D imaging (3DCT) can reduce the risks associated with laparoscopic surgery. METHODS: We performed a retrospective case-control study evaluating the efficacy of preoperative 3DCT of the splenic vascular anatomy on surgical outcomes in patients undergoing laparoscopic spleen-preserving splenic hilar lymph node (LN) dissection for upper or middle-third gastric cancer. The clinical records of 312 patients with upper- or middle-third gastric cancer who underwent laparoscopic total gastrectomy with spleen-preserving splenic lymph node dissection in our hospital from January 2010 to June 2013 were collected, and the patients were divided into two groups (group 3DCT vs group NO-3DCT) depending on whether they underwent 3DCT or not. Clinicopathologic characteristics, operative and postoperative measures, the number of retrieved LNs, and complications were compared between these two groups. Patients were further compared regarding operative and postoperative measures, the number of retrieved LNs, and complications when subdivided by body mass index ( >= 23 and < 23 kg/m(2)) and the number of operations performed by their surgeon (<= 40 vs > 40). RESULTS: The mean numbers of retrieved splenic hilar LNs were similar in patients in group 3DCT and group NO-3DCT (2.85 +/- 2.33 vs 2.48 +/- 2.18, P > 0.05). The operation time and blood loss at the splenic hilum were lower in the patients in group 3DCT (P < 0.05 each). The postoperative recovery time and complication rates were similar between the two groups (P > 0.05 each). Subgroup analysis showed that the operation time at the splenic hilum in patients with a BMI >= 23 kg/m(2) was significantly shorter in patients in group 3DCT than in group NO-3DCT (20.27 +/- 5.84 min vs 26.17 +/- 11.01 min, P = 0.003). In patients with a BMI < 23 kg/m(2), the overall operation time (171.8 +/ 26.32 min vs 188.09 +/- 52.63 min, P = 0.028), operation time at the splenic hilum (19.39 +/- 5.46 min vs 23.74 +/- 9.56 min, P = 0.001), and blood loss at the splenic hilum (13.27 +/- 4.96 mL vs 17.98 +/- 8.12 mL, P = 0.000) were significantly lower in patients in group 3DCT than in group NO-3DCT. After 40 operations, the operation time (18.63 +/- 4.40 min vs 23.85 +/- 7.92 min, P = 0.000) and blood loss (13.10 +/- 4.17 mL vs 15.10 +/- 4.42 mL, P = 0.005) at the splenic hilum were significantly lower in patients who underwent 3DCT, but there were no significant between-group differences prior to 40 operations. CONCLUSION: 3DCT is critical for surgical guidance to reduce the risks of splenic LN dissection. This method may be important in safely facilitating laparoscopic spleen-preserving splenic LN dissection. PMID- 24782635 TI - Nasogastric tube as protection for recurrent oesophageal stricture: a case report. AB - This report presents the case of an 8.5-year-old boy with Down syndrome after experiencing extensive caustic injury to the oesophagus and stomach resulting from the accidental ingestion of concentrated sulphuric acid. The patient had undergone 32 unsuccessful endoscopic oesophageal stricture dilatations and stenting procedures performed over a period of 15 mo following the accident. Surgical reconstruction of the oesophagus was not possible due to previous gastric and cardiac surgeries for congenital conditions. Before referring the patient for salivary fistula surgery, the patient received a nasogastric tube with perforations located above the upper margin of the oesophageal stenosis for the passage of saliva and fluid. The tube was well tolerated and improved swallowing; however the backflow of gastric contents caused recurrent infections of the respiratory tract. To overcome these problems, we developed a double lumen, varying diameter, perforated tube for protection of the oesophageal closure. This nasogastric tube was found to be safe and decreased the need for hospitalization and further endoscopic procedures. This newly developed tube can thus be considered as a treatment option for patients with recurrent oesophageal stenosis and contraindications for surgical oesophageal reconstruction. PMID- 24782636 TI - Overlap syndrome consisting of PSC-AIH with concomitant presence of a membranous glomerulonephritis and ulcerative colitis. AB - The association of primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) is known as an overlap syndrome (OS). OS can also be described in the setting of concomitant presence of AIH and PSC. These diseases can in some cases be associated with ulcerative colitis. In this case report we describe, to our knowledge, the first case in the literature of a young Caucasian male suffering from ulcerative colitis and an overlap syndrome consisting of an association between PSC-AIH, with the concomitant presence of a membranous glomerulonephritis. PMID- 24782637 TI - Gastrointestinal stromal tumor of the ampulla of Vater: a case report. AB - Gastrointestinal stromal tumors (GISTs) usually develop in the stomach and small intestine and only rarely occur at the ampulla of Vater, with only 11 cases reported in the literature. We report a case of a GIST of the ampulla of Vater. A 36-year-old, previously healthy man presented with a loss of consciousness lasting a few minutes. A gastroduodenal endoscopy revealed a submucosal tumor with central ulceration at the ampulla of Vater. The enhanced computed tomography scan revealed a smooth-outlined hypervascular solid mass (24 mm * 30 mm) in the second part of the duodenum. Neither lymphadenopathy nor metastasis was observed. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed normal bile and pancreatic ducts. Biopsies were collected from the ulcerative lesion, and the tumor was diagnosed as a GIST. A submucosal tumor with central ulceration may be a characteristic form of GISTs of the ampulla of Vater, and biopsy studies are useful for the diagnosing such tumors. The patient underwent pancreatoduodenectomy, and the operative specimen revealed a 2.2-cm GIST with 1 mitosis per 50 high-power fields. The gold standard for treatment of GISTs is surgical resection without rupture of a capsule. If technically possible, local resection may be considered. However, when the location of the lesion presents challenges, a pancreatoduodenectomy should be performed for GIST of the ampulla of Vater. PMID- 24782638 TI - Solitary Peutz-Jeghers-type appendiceal hamartomatous polyp growing into the terminal ileum. AB - Solitary Peutz-Jeghers type hamartomatous polyp is rare. It is considered to be related to a variant Peutz-Jeghers syndrome (PJS) and may be a separate disease entity. A 50-year-old man was referred to our hospital with a diagnosis of intussusception in the terminal ileum and underwent segmental ileal resection with appendectomy. We identified a 3.5-cm diameter polyp arising from the appendix with ingrowth into the terminal ileum. The polyp was confirmed to be a hamartomatous polyp of Peutz-Jeghers-type, histologically. However, the patient had no characteristic manifestations of PJS such as mucocutaneous pigmentation and family history. There are few reports of appendiceal hamartomatous polyp in PJS patients and solitary appendiceal hamartomatous polyp is even rarer. Also, rather than telescoping, ours is the first reported intussuscepted lesion, to the best of our knowledge. PMID- 24782639 TI - Choledochoduodenal fistula caused by migration of endoclip after laparoscopic cholecystectomy. AB - The wide use of surgical endoclips in laparoscopic surgery has led to a variety of complications. Post-cholecystectomy endoclips migrating into the common bile duct after laparoscopic cholecystectomy is rare. A migrated endoclip can cause obstruction, serve as a nidus for stone formation, and cause cholangitis. While the exact pathogenesis is still unknown, it is probably related to improper clip application, subclinical bile leak, inflammation, and subsequent necrosis, allowing the clips to erode directly into the common bile duct. We present a case of endoclip migrating into the common bile duct and duodenum, resulting in choledochoduodenal fistula after laparoscopic cholecystectomy and a successful reconstruction of the biliary tract by a hepaticojejunostomy with a Roux-en-Y procedure. This case shows that surgical endoclips can penetrate into the intact bile duct wall through serial maceration, and it is believed that careful application of clips may be the only way to prevent their migration after laparoscopic cholecystectomy. PMID- 24782640 TI - ARC syndrome with high GGT cholestasis caused by VPS33B mutations. AB - Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account for most cases of ARC. As low or normal gamma-glutamyl transpeptidase (GGT) activity has been described in all patients with ARC syndrome identified so far, ARC syndrome is a possible diagnosis for low GGT cholestasis. Here we describe a Chinese patient with neonatal cholestasis and a high GGT level in three consecutive tests. She had other typical manifestations of ARC syndrome, including arthrogryposis multiplex congenita, renal involvement and ichthyosis. Genetic study of the VPS33B gene further confirmed the diagnosis by identification of compound heterozygosity of two known disease-causing mutations, c.403+2T > A and c.1509-1510insG. The mechanism of high GGT in this patient is unclear. Nevertheless, this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found. PMID- 24782641 TI - Laparoscopic ligation of proximal splenic artery aneurysm with splenic function preservation. AB - Splenic artery aneurysm is one of the most common visceral aneurysms, and patients with this type of aneurysm often present without symptoms. However, when rupture occurs, it can be a catastrophic event. Although most of these aneurysms can be treated with percutaneous embolization, some located in uncommon parts of the splenic artery may make this approach impossible. We present a patient with an aneurysm in the proximal splenic artery, close to the celiac trunk, which was treated by laparoscopic ligation only, without resection of the aneurysm, and with long-term preservation of splenic function. PMID- 24782642 TI - Senescence affects endothelial cells susceptibility to dengue virus infection. AB - Alteration in the endothelium leading to increased vascular permeability contributes to plasma leakage seen in dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). An earlier study showed that senescent endothelial cells (ECs) altered the ECs permeability. Here we investigated the susceptibility of senescing human umbilical vein endothelial cells (HUVECs) to dengue virus infection and determined if dengue virus infection induces HUVECs senescence. Our results suggest that DENV type-2 (DENV-2) foci forming unit (FFU) and extracellular virus RNA copy number were reduced by at least 35% and 85% in infection of the intermediate young and early senescent HUVECs, respectively, in comparison to infection of young HUVECs. No to low infectivity was recovered from infection of late senescent HUVECs. DENV infection also increases the percentage of HUVECs expressing senescence-associated (SA)-beta-gal, cells arrested at the G2/M phase or 4N DNA content stage and cells with enlarged morphology, indicative of senescing cells. Alteration of HUVECs morphology was recorded using impedance based real-time cell analysis system following DENV-2 infection. These results suggest that senescing HUVECs do not support DENV infection and DENV infection induces HUVECs senescence. The finding highlights the possible role of induction of senescence in DENV infection of the endothelial cells. PMID- 24782643 TI - The use of a whole animal biophotonic model as a screen for the angiogenic potential of estrogenic compounds. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is essential for normal vascular growth and development during wound repair. VEGF is estrogen responsive and capable of regulating its own receptor, vascular endothelial growth factor receptor-2 (VEGFR-2). Several agricultural pesticides (e.g., methoxychlor) have estrogenic potential that can initiate inappropriate physiological responses in estrogenic-sensitive tissues following exposure in vivo. Thus, the current study was designed to determine whether the VEGFR-2-Luciferase (Luc) reporter transgenic mouse is a useful model for evaluating estrogenic tendencies of methoxychlor by monitoring wound healing via VEGFR-2-mediated gene expression using bioluminescence and real-time imaging technology. RESULTS: VEGFR-2-Luc gene activity peaked by d 7 (P<0.001) in all groups but was not different (P>0.05) between control and estrogen/methoxychlor exposed mice. CONCLUSIONS: Changes in VEGFR-2-Luc gene activity associated with the dermal wound healing process were able to be measured via photonic emission. The increase in vasculature recruitment and formation is paralleled by the increase of VEGFR-2-Luc activity with a peak on day 7. However, estrogen/methoxychlor did not significantly alter wound healing mediated VEGFR-2-Luc gene expression patterns compared to controls. This suggests that the VEGFR-2-Luc transgenic mouse wound model tested in this study may not be optimal for use as a screen for the angiogenic potential of estrogenic compounds. PMID- 24782644 TI - Mutational spectrum of the NKX2-5 gene in patients with lone atrial fibrillation. AB - Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans and is responsible for substantial morbidity and mortality worldwide. Emerging evidence indicates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor essential for cardiovascular genesis, were sequenced in 146 unrelated patients with lone AF as well as the available relatives of the mutation carriers. A total of 700 unrelated ethnically matched healthy individuals used as controls were genotyped. The disease-causing potential of the identified NKX2-5 variations was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the mutant NKX2-5 proteins were analyzed using a dual-luciferase reporter assay system. As a result, two heterozygous NKX2-5 mutations, including a previously reported p.E21Q and a novel p.T180A mutation, were identified in two families with AF transmitted in an autosomal dominant pattern. The mutations co-segregated with AF in the families with complete penetrance. The detected substitutions, which altered the amino acids highly conserved evolutionarily across species, were absent in 700 control individuals and were both predicted to be causative. Functional analyses demonstrated that the NKX2-5 mutants were associated with significantly decreased transcriptional activity compared with their wild-type counterpart. The findings expand the spectrum of NKX2-5 mutations linked to AF and provide additional evidence that dysfunctional NKX2-5 may confer vulnerability to AF, suggesting the potential benefit for the early prophylaxis and personalized treatment of AF. PMID- 24782645 TI - Inhibition of MAPKs, Myc/Max, NFkappaB, and hypoxia pathways by Phyllanthus prevents proliferation, metastasis and angiogenesis in human melanoma (MeWo) cancer cell line. AB - BACKGROUND: Melanoma is the most fatal form of skin cancer. Different signalling pathways and proteins will be differentially expressed to pace with the tumour growth. Thus, these signalling molecules and proteins are become potential targets to halt the progression of cancer. The present works were attempted to investigate the underlying molecular mechanisms of anticancer effects of Phyllanthus (P.amarus, P.niruri, P.urinaria and P.watsonii) on skin melanoma, MeWo cells. METHODS: The ten cancer-related pathways reporter array was performed by transfection of plasmid construct of transcription factor-responsive reporter of each pathway in MeWo cells. The affected pathways in MeWo cells after treatment of Phyllanthus extracts were determined using luciferase assay. Western blot, 2D gel electrophoresis and mass spectrometry analysis were performed to identity and confirm the affected proteins and signalling molecules in treated cells. RESULTS: The ten-pathway reporter array revealed five different cancer related signalling pathways were altered by Phyllanthus species in MeWo cells; NFkappaB, Myc/Max, Hypoxia, MAPK/ERK and MAPK/JNK (p<0.05). Western blot revealed that their intracellular signalling molecules including pan-Ras, c-Raf, RSK, phospho-Elk1, c-myc, Akt, HIF-1alpha, Bcl-2, and VEGF were down-regulated with concurrent of up-regulation; Bax, phospho-JNK-1/2 and phospho-GSK3beta, in MeWo cells upon Phyllanthus treatment (p<0.05). Proteomics-based approach was performed and MS/MS results revealed that 52 differential expressed proteins were identified (p<0.05) and involved in tumour growth, metastasis, apoptosis, glycogenesis and glycolysis, angiogenesis, protein synthesis and energy metabolism. CONCLUSION: This study provides insight into the regulation on multiple survival signalling pathways by Phyllanthus in melanoma and might be a therapeutic target for cancer treatment. PMID- 24782646 TI - Tanshinone IIA attenuates bleomycin-induced pulmonary fibrosis via modulating angiotensin-converting enzyme 2/ angiotensin-(1-7) axis in rats. AB - Pulmonary fibrosis (PF) is a common complication in those interstitial lung diseases patients, which will result in poor prognosis and short survival. Traditional therapeutic methods such as glucocorticoid and cytotoxic drugs are insufficient for treating PF and may cause severe side effects. Recent studies showed that traditional Chinese herbal abstraction such as Tanshinone IIA (TIIA) was displayed significant anti-PF effects in animal models. However, the exact mechanisms underlying the protective effects of TIIA were not fully understood. Here we further investigated the protective effects of TIIA and its mechanisms underlying. PF models of rat were induced by bleomycin (BLM); TIIA was administered subsequently. The PF changes were identified by histopathological analyses. The results showed that BLM resulted in severe PF and alveolar inflammation; together with significant elevation of transforming growth factor beta 1 (TGF-beta1). Angiotensin-converting enzyme 2 (ACE-2) together with angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. TIIA treatment notably attenuated BLM induced PF and inflammation, decreased expression of TGF-beta1 and reversed ACE-2 and ANG-(1-7) production in rat lungs. Thus we may draw the conclusion that TIIA may exert protective effects on BLM induced PF in rats, and the ACE-2/ANG-(1-7) axis may ascribe to those protective effects. PMID- 24782647 TI - Late-onset depression in the absence of stroke: associated with silent brain infarctions, microbleeds and lesion locations. AB - BACKGROUND: Late-onset depression (LOD) is a frequent mood disorder among elderly. Previous studies have proved that LOD is associated with cerebral silent lesions especially white matter lesions (WML) and yielded the "vascular depression" hypothesis to explain the pathogenesis of LOD. However, there were relatively few studies about the association between silent brain infarctions (SBIs), microbleeds (MBs) and the prevalence of LOD. In this study we sought to evaluate the presence, accumulation and locations of SBIs and MBs, and explore the possible association between them and LOD. METHODS: 65 patients of LOD diagnosed according to DSM-IV and 270 subjects of control group were enrolled and scanned by MRI to analyze the presence, numbers and locations of SBIs and MBs. Clinical and radiological characteristics were compared between LOD patients and control group. Logistic regression models were constructed to identify the independent risk factors for LOD. RESULTS: LOD patients had higher prevalence and numbers of both SBIs and MBs. SBIs and MBs in the left hemisphere, SBIs in basal ganglia and lobar MBs were all independent risk factors for LOD. CONCLUSION: The presence of both SBIs and MBs were associated with a higher rate LOD. Lesions in some specific locations might be critical for the presence of LOD. PMID- 24782648 TI - King cobra (Ophiophagus hannah) venom L-amino acid oxidase induces apoptosis in PC-3 cells and suppresses PC-3 solid tumor growth in a tumor xenograft mouse model. AB - King cobra (Ophiophagus hannah) venom L-amino acid oxidase (OH-LAAO), a heat stable enzyme, has been shown to exhibit very potent anti-proliferative activity against human breast and lung tumorigenic cells but not in their non-tumorigenic counterparts. We further examine its in vitro and in vivo anti-tumor activity in a human prostate adenocarcinoma (PC-3) model. OH-LAAO demonstrated potent cytotoxicity against PC-3 cells with IC50 of 0.05 ug/mL after 72 h incubation in vitro. It induced apoptosis as evidenced with an increase in caspase-3/7 cleavages and an increase in annexin V-stained cells. To examine its in vivo anti tumor activity, we treated PC-3 tumor xenograft implanted subcutaneously in immunodeficient NU/NU (nude) mice with 1 ug/g OH-LAAO given intraperitoneally (i.p.). After 8 weeks of treatment, OH-LAAO treated PC-3 tumors were markedly inhibited, when compared to the control group (P <0.05). TUNEL staining analysis on the tumor sections showed a significantly increase of apoptotic cells in the LAAO-treated animals. Histological examinations of the vital organs in these two groups showed no significant differences with normal tissues, indicating no obvious tissue damage. The treatment also did not cause any significant changes on the body weight of the mice during the duration of the study. These observations suggest that OH-LAAO cytotoxic effects may be specific to tumor xenografts and less to normal organs. Given its potent anti-tumor activities shown in vitro as well as in vivo, the king cobra venom LAAO can potentially be developed to treat prostate cancer and other solid tumors. PMID- 24782649 TI - Energy and nutritional composition of Tiger milk mushroom (Lignosus tigris Chon S. Tan) sclerotia and the antioxidant activity of its extracts. AB - The Lignosus is a genus of fungi that have useful medicinal properties. In Southeast Asia, three species of Lignosus (locally known collectively as Tiger milk mushrooms) have been reported including L. tigris, L. rhinocerotis, and L. cameronensis. All three have been used as important medicinal mushrooms by the natives of Peninsular Malaysia. In this work, the nutritional composition and antioxidant activities of the wild type and a cultivated strain of L. tigris sclerotial extracts were investigated. The sclerotia are rich in carbohydrates with moderate amount of protein and low fat content. Free radical scavenging activities of L. tigris sclerotial extracts correlate with their phenolic content, which ranges from 6.25 to 45.42 mg GAE/g extract. The FRAP values ranged from 0.002 to 0.041 mmol/min/g extract, while the DPPH(*), ABTS(*+), and superoxide anion (SOA) scavenging activities ranged from 0.18 to 2.53, 0.01 to 0.36, and -4.53 to 10.05 mmol Trolox equivalents/g extract, respectively. L. tigris cultivar shows good prospect to be developed into functional food due to its good nutritional value and potent SOA scavenging activity. PMID- 24782650 TI - The expression of Toll-like receptor 8 and its relationship with VEGF and Bcl-2 in cervical cancer. AB - BACKGROUND: Cervical cancer is one of the most common cancers in women worldwide, often associated with the infection of human papillomavirus (HPV). Toll-like receptor 8 (TLR8), a pattern recognition receptor, is involved in viral nucleic acid sensing. Recently TLR8 has been shown to be expressed in cancer cells, and it has been suggested that it may help cancer cell growth and tumor development. The objective of this study is to investigate the expression of TLR8 expression and its relationship with Bcl-2 and VEGF in cervical cancer cells. METHODOLOGY/PRINCIPAL: The mRNA expression levels of Bcl-2, VEGF and TLR-7,-8,-9 in newly diagnosed cervical cancer patients were detected by quantitative real time PCR (qRT- PCR). Epifluorescence microscope was used to determine the presence of TLR8 protein in Hela cells. The cell cycle and apoptosis were analyzed by flow cytometer, and the cell proliferation was measured by MTT assay. Our data showed the increased mRNA levels of TLR8 in human cervical cancer samples as well as in HeLa cells, a cell line derived from a human cervical cancer. In addition, there was a positive correlation between the expression levels of TLR8 and Bcl-2 and VEGF in cervical cancer patients. When Hela cells were treated with TLR8 agonist CL075, the percentage of cells in G2/M +S was remarkably increased, accompanied by increased COX-2, BCL-2 and VEGF mRNA levels. CONCLUSIONS/SIGNIFICANCE: The mRNA expression level of TLR8 in the patients with cervical cancer and Hela cells were up-regulated, it consistent with the increased expression of VEGF and Bcl-2. The results suggest that TLR8 may be an interesting therapeutic target in cervical cancer. PMID- 24782651 TI - TMPRSS6 rs855791 polymorphism influences the susceptibility to iron deficiency anemia in women at reproductive age. AB - BACKGROUND: Genome-wide-association studies have identified the TMPRSS6 polymorphism rs855791 has the strongest association with red blood cell indices or iron parameters in general population. Whether this genetic variant influences the susceptibility of iron deficiency anemia (IDA) in women with menstruation has not been well studied. METHODS: In this case-control study, we enrolled 67 women with IDA and 107 healthy volunteers, and analyzed their complete blood counts, rs855791 genotypes, and menstrual amounts. Menstrual blood loss was evaluated with a pictorial blood-loss assessment chart. RESULTS: There were significantly fewer rs855791 C homozygotes in the IDA group than in the healthy group (11.9% vs. 25.2%, p = 0.03). The odds ratio (OR) of C homozygotes having IDA versus non CC subjects having IDA was 0.4 (95% CI, 0.17 - 0.95, p = 0.04). When the analysis was confined to study subjects with menorrhagia, this difference became more prominent (9.6% vs. 28.6%, p = 0.01; OR, 0.27, 95% CI, 0.09 - 0.77, p = 0.01). For women with non-CC genotypes, there was an inverse correlation between hemoglobin levels and menstrual loss (p < 0.001); however, this association was not found for those with genotypes CC (p = 0.15). CONCLUSIONS: Our study suggests homozygosity for TMPRSS6 rs855791 C genotype has a protective role against IDA in women at reproductive age, especially in those with menorrhagia. PMID- 24782652 TI - PIK3CA gene amplification and PI3K p110alpha protein expression in breast carcinoma. AB - A family of PI3Ks is the lipid kinases, which enhance intracellular pools of phosphatidyl inositol 3,4,5-tri-phosphate (PIP3) through phosphorylating its precursor. Amplifications and deletions of genes, as well as somatic missense of the PIK3CA gene have been described in many human cancer varieties, including of the brain, colon, liver, lung and stomach. Immunohistochemistry and Real-time quantitative PCR tests were used to determine the PIK3CA gene amplification (gene copy number) and to detect protein expression, respectively. The results obtained were analysed and the ratio of PIK3CA to beta-actin gene copy number was calculated. Positive gene amplification of PIK3CA was appointed as a copy number of >=4. Also, PI3K p110alpha protein expression was scored from 0 to 3+ and the scores of 2+ and 3+ were considered as positive for PI3K p110alpha protein expression. We studied 50 breast carcinoma samples for PI3K p110alpha protein expression and PIK3CA gene copy numbers. In general, 36 out of 50 (72%) breast carcinoma samples showed a significant increase in PIK3CA gene amplification. 12 out of 50 (24%) showed positive staining, and 38 out of 50 (76%) showed negative staining for PI3K p110alpha expression. We have identified no significant relationship between PIK3CA amplification, race (p= 0.630) and histological type (p=0. 731) in breast carcinoma, but correlation of PIK3CA amplification and age showed a significant relationship (p=0. 003) between them. No significant relationship has been identified in correlation of PI3K p110alpha protein expression compared to age (p=0. 284), race (p=0. 546) and histological type (p=0. 285). Amplification of PIK3CA was frequent in breast carcinoma and occurs in stages of breast carcinoma. Our result shows that there is a relationship between gene amplification and age in breast carcinoma. We suggest that PIK3CA is significant in breast tumorigenesis serve as a prevalent mechanism contributes to the oncogenic activation pathway of PIK3CA in breast cancer. PMID- 24782653 TI - HGF/c-Met signaling mediated mesenchymal stem cell-induced liver recovery in intestinal ischemia reperfusion model. AB - PURPOSE: Liver injury triggered by intestinal ischemia-reperfusion (IIR) usually presage multiorgan dysfunction and death in patients. Recent studies suggest mesenchymal stem cells (MSCs) possess a protective potential against organ damage. Since relative evidence is insufficient and the mechanism is not well understood, we investigated the effect of hepatocyte growth factor c-Met signaling (HGF/c-Met) on recruitment of MSCs and subsequent protection against liver injury triggered by IIR in a rat model. METHODS: IIR models were built as rats were subjected to 75 min of superior mesenteric artery occlusion and subsequent 4 h reperfusion. Either of pure MSCs and MSCs pretreated with HGF or SU11274 (c-Met inhibitor) were injected into rat models. Biochemical and pathologic alterations of liver in IIR model were measured to evaluate the therapeutic effect of MSCs and drug treatment. Concurrently, the effect of HGF and SU11274 on c-Met and phosphorylated Met expression in MSCs and MSCs migration were assessed in in vitro experiment. RESULTS: IIR-induced liver injury was manifested by significant increase in serum ALT, AST and HGF levels as well as pathological change. MSCs with highly c-Met expression ameliorated the increase of serum transaminase levels and hepatic histopathological change, while SU11274 weaken these effects. HGF upregulated c-Met and phosphorylated Met expression in MSCs and enhanced its liver protection effect. Transwell assays demonstrated HGF promoted MSCs migration, which was blocked by SU11274. CONCLUSIONS: HGF/c-Met signaling pathway plays an essential role in the homing of MSCs towards injured liver triggered by intestinal ischemia-reperfusion, and then mediates MSC-induced liver repair. PMID- 24782654 TI - Organ donation knowledge and attitudes among health science students in Greece: emerging interprofessional needs. AB - BACKGROUND: The impact of presumed consent on donation rates has been widely debated. In June 2013 Greece adopted a 'soft' presumed consent law for organ and tissue donation, where relatives' approval is sought prior to organ removal. AIMS: To report on the knowledge, attitudes and concerns of undergraduate students, enrolled in three health science disciplines, in regards to organ donation and presumed consent. METHODS: Undergraduate junior and senior health science students [medical (MS), nursing (NS) and medical laboratory students (MLS)] were recruited from higher education settings in Thessaly, Greece. Dichotomous questions, previously used, were adopted to assess knowledge, attitudes and concerns towards organ donation, together with questions regarding the recent presumed consent legislation. RESULTS: Three hundred seventy-one out of 510 students participated in the study (response rate: 72.7%). Only 3.6% of NS, 8.7% of MS and 3.2% of MLS carried a donor card. Although over 78% in all groups knew that it was possible to leave kidneys for transplant after death, only 10% to 39% considered themselves well-informed. NS were more likely to consider opting-out (21.5%), followed by MLS (17.9%) and MS (10.9%). Respondents were more likely to refuse organ removal upon death when expressing one of the following views: a) opposing a system making it lawful to take kidneys from an adult who has just died, unless forbidden while alive [Odds ratio (OR) 95% Confidence Interval (CI): 2.96 (1.48-5.93), p=0.002], b) worrying about their kidneys being removed after death [OR, 95% CI: 3.37 (1.75-6.49), p=<0.001] and c) believing that an intact body was needed after death [OR, 95% CI: 4.23 (2.15 8.31), p<0.001]. CONCLUSION: Health science students, soon to become healthcare professionals, demonstrated limited awareness in regards to the newly reformed organ donation system. Identified knowledge deficits and concerns could have far reaching implications in terms of conveying a clear message and shaping the public's stand. The feasibility and effectiveness of a joint inter-professional curriculum on organ and tissue donation issues across all three health science disciplines, addressing common themes and concerns deserves further study. PMID- 24782655 TI - Serum lactate dehydrogenase levels as a predictive marker of oxaliplatin-induced hypersensitivity reactions in Japanese patients with advanced colorectal cancer. AB - OBJECTIVE: Clinical laboratory test data obtained prior to treatments were previously analyzed from the standpoint of susceptibility to hypersensitivity reactions in patients treated with the platimun anticancer agent, oxaliplatin (L OHP). In the present study, the time course from the first to last cycle of the treatment was additionally analyzed to determine a better predictor of these reactions. METHODS: A total of 20 laboratory test data were obtained from 108 Japanese patients with advanced colorectal cancer who were treated with the L-OHP containing regimens, FOLFOX4 and/or mFOLFOX6. The averages and variation coefficients (CV%) of the data until the last cycle of the treatment were compared between patients with hypersensitivity reactions and those without. RESULTS: The average serum lactate dehydrogenase (LDH) level was lower in patients with grade 1/2 reactions (P=0.016), whereas its CV% value was higher in patients with grade 3/4 reactions (P=0.005) than in those without reactions. An increase in serum LDH levels was observed in some patients with grade 3/4 reactions as the cycle number increased, and thereafter hypersensitivity reactions occurred. This phenomenon was not always observed, but was never detected in patients with grade 1/2 reactions. CONCLUSIONS: Serum LDH levels may be a predictive marker of hypersensitivity reactions in patients treated with L OHP. Further extensive examinations with a larger number of patients are needed to establish a patient management strategy. PMID- 24782656 TI - Transurethral resection syndrome in elderly patients: a retrospective observational study. AB - BACKGROUND: Transurethral resection of the prostate (TURP) involves the risk of transurethral resection (TUR) syndrome owing to hyponatremia. Irrigation fluid type, duration of operation, and weight of resected mass have been evaluated as risk factors for TUR syndrome. The purpose of the present study was to identify risk factors related to TUR syndrome in the elderly. METHODS: After obtaining approval from the Institutional Review Board, data on all elderly males (aged 70 years and older) who underwent TURP under regional anesthesia over a 6-year period at our institution were retrospectively reviewed. TUR syndrome was defined as evidence of a central nervous system disturbance such as nausea, vomiting, restlessness, confusion, or even coma with a circulatory abnormality both intra- and post-operatively. Patients were divided into two groups, positive and negative, for the occurrence of the syndrome. Data such as previous medical history, preoperative and postoperative serum data, weight of resected mass, duration of operation, irrigation fluid drainage technique, anesthetic technique, operative infusion and transfusion volume, and neurological symptoms were collected. Only observational variables with p < 0.05 on univariate analyses were included in the multivariate logistic regression model to ascertain their independent effects on TUR syndrome. RESULTS: Of the 98 patients studied, 23 had TUR syndrome (23.5%, 95% confidence interval [CI] 14.9-32.0%). Multivariate regression analysis revealed that volume of plasma substitute >= 500 ml (odds ratio [OR] 14.7, 95% CI 2.9-74.5), continuous irrigation through a suprapubic cystostomy (OR 4.7, 95% CI 1.3-16.7), and weight of resected mass > 45 g (OR 4.1, 95% CI 1.2-14.7) were associated with significantly increased risks for TUR syndrome (Hosmer-Lemeshow test, p = 0.94, accuracy 84.7%). CONCLUSIONS: These results suggest that the use of a plasma substitute and continuous irrigation through a suprapubic cystostomy must be avoided during TURP procedures in the elderly. PMID- 24782657 TI - 3D-Ultrasonography for evaluation of facial muscles in patients with chronic facial palsy or defective healing: a pilot study. AB - BACKGROUND: While standardized methods are established to examine the pathway from motorcortex to the peripheral nerve in patients with facial palsy, a reliable method to evaluate the facial muscles in patients with long-term palsy for therapy planning is lacking. METHODS: A 3D ultrasonographic (US) acquisition system driven by a motorized linear mover combined with conventional US probe was used to acquire 3D data sets of several facial muscles on both sides of the face in a healthy subject and seven patients with different types of unilateral degenerative facial nerve lesions. RESULTS: The US results were correlated to the duration of palsy and the electromyography results. Consistent 3D US based volumetry through bilateral comparison was feasible for parts of the frontalis muscle, orbicularis oculi muscle, depressor anguli oris muscle, depressor labii inferioris muscle, and mentalis muscle. With the exception of the frontal muscle, the facial muscles volumes were much smaller on the palsy side (minimum: 3% for the depressor labii inferior muscle) than on the healthy side in patients with severe facial nerve lesion. In contrast, the frontal muscles did not show a side difference. In the two patients with defective healing after spontaneous regeneration a decrease in muscle volume was not seen. Synkinesis and hyperkinesis was even more correlated to muscle hypertrophy on the palsy compared with the healthy side. CONCLUSION: 3D ultrasonography seems to be a promising tool for regional and quantitative evaluation of facial muscles in patients with facial palsy receiving a facial reconstructive surgery or conservative treatment. PMID- 24782658 TI - Preparation of Tween 80-Zn/Al-levodopa-layered double hydroxides nanocomposite for drug delivery system. AB - We incorporated anti-Parkinsonian drug, levodopa (dopa), in Zn/Al-LDH by coprecipitation method to form dopa-LDH nanocomposite. Further coating of Tween 80 on the external surfaces of dopa-LDH nanocomposite was achieved through the oxygen of C=O group of Tween-80 with the layer of dopa-LDH nanocomposite. The final product is called Tween-dopa-LDH nanocomposite. The X-ray diffraction indicates that the Tween-dopa-LDH nanocomposite was formed by aggregation structure. From the TGA data, the Tween-80 loading on the surface of LDH and dopa LDH was 8.6 and 7.4%, respectively. The effect of coating process on the dopa release from Tween-dopa-LDH nanocomposite was also studied. The release from Tween-dopa-LDH nanocomposite shows slower release compared to the release of the drug from dopa-LDH nanocomposite as done previously in our study, presumably due to the retarding shielding effect. The cell viability study using PC12 showed improved viability with Tween-80 coating on dopa-LDH nanocomposite as studied by mitochondrial dehydrogenase activity (MTT assay). PMID- 24782659 TI - Modeling and computing of stock index forecasting based on neural network and Markov chain. AB - The stock index reflects the fluctuation of the stock market. For a long time, there have been a lot of researches on the forecast of stock index. However, the traditional method is limited to achieving an ideal precision in the dynamic market due to the influences of many factors such as the economic situation, policy changes, and emergency events. Therefore, the approach based on adaptive modeling and conditional probability transfer causes the new attention of researchers. This paper presents a new forecast method by the combination of improved back-propagation (BP) neural network and Markov chain, as well as its modeling and computing technology. This method includes initial forecasting by improved BP neural network, division of Markov state region, computing of the state transition probability matrix, and the prediction adjustment. Results of the empirical study show that this method can achieve high accuracy in the stock index prediction, and it could provide a good reference for the investment in stock market. PMID- 24782660 TI - Nanoscale strain fields research of boundaries between B2 matrix and G.P. zone in Ni-Ti alloy thin films. AB - Ti-47 at.%Ni alloy films were prepared by magnetron sputtering followed by 460 degrees C for 40 minutes heat-treatment. The strain fields between B2 phase matrix and G.P. zone were mapped by a combination of high-resolution transmission electron microscopy and geometric phase analysis method. It was found that there is a compressive strain region parallel to the longitudinal axis of G.P. zone with 2 nm in width, -2.2% in average strain at the boundaries between B2 phase and G.P. zone. PMID- 24782661 TI - A fast and robust ellipse-detection method based on sorted merging. AB - A fast and robust ellipse-detection method based on sorted merging is proposed in this paper. This method first represents the edge bitmap approximately with a set of line segments and then gradually merges the line segments into elliptical arcs and ellipses. To achieve high accuracy, a sorted merging strategy is proposed: the merging degrees of line segments/elliptical arcs are estimated, and line segments/elliptical arcs are merged in descending order of the merging degrees, which significantly improves the merging accuracy. During the merging process, multiple properties of ellipses are utilized to filter line segment/elliptical arc pairs, making the method very efficient. In addition, an ellipse-fitting method is proposed that restricts the maximum ratio of the semimajor axis and the semiminor axis, further improving the merging accuracy. Experimental results indicate that the proposed method is robust to outliers, noise, and partial occlusion and is fast enough for real-time applications. PMID- 24782662 TI - Dynamic resource allocation in hybrid access femtocell network. AB - Intercell interference is one of the most challenging issues in femtocell deployment under the coverage of existing macrocell. Allocation of resources between femtocell and macrocell is essential to counter the effects of interference in dense femtocell networks. Advances in resource management strategies have improved the control mechanism for interference reduction at lower node density, but most of them are ineffective at higher node density. In this paper, a dynamic resource allocation management algorithm (DRAMA) for spectrum shared hybrid access OFDMA femtocell network is proposed. To reduce the macro-femto-tier interference and to improve the quality of service, the proposed algorithm features a dynamic resource allocation scheme by controlling them both centrally and locally. The proposed scheme focuses on Femtocell Access Point (FAP) owners' satisfaction and allows maximum utilization of available resources based on congestion in the network. A simulation environment is developed to study the quantitative performance of DRAMA in hybrid access-control femtocell network and compare it to closed and open access mechanisms. The performance analysis shows that higher number of random users gets connected to the FAP without compromising FAP owners' satisfaction allowing the macrocell to offload a large number of users in a dense heterogeneous network. PMID- 24782663 TI - An improved proportionate normalized least-mean-square algorithm for broadband multipath channel estimation. AB - To make use of the sparsity property of broadband multipath wireless communication channels, we mathematically propose an l p -norm-constrained proportionate normalized least-mean-square (LP-PNLMS) sparse channel estimation algorithm. A general l p -norm is weighted by the gain matrix and is incorporated into the cost function of the proportionate normalized least-mean-square (PNLMS) algorithm. This integration is equivalent to adding a zero attractor to the iterations, by which the convergence speed and steady-state performance of the inactive taps are significantly improved. Our simulation results demonstrate that the proposed algorithm can effectively improve the estimation performance of the PNLMS-based algorithm for sparse channel estimation applications. PMID- 24782664 TI - Modelling and simulation of fuel cell dynamics for electrical energy usage of Hercules airplanes. AB - Dynamics of proton exchange membrane fuel cells (PEMFC) with hydrogen storage system for generating part of Hercules airplanes electrical energy is presented. Feasibility of using fuel cell (FC) for this airplane is evaluated by means of simulations. Temperature change and dual layer capacity effect are considered in all simulations. Using a three-level 3-phase inverter, FC's output voltage is connected to the essential bus of the airplane. Moreover, it is possible to connect FC's output voltage to airplane DC bus alternatively. PID controller is presented to control flow of hydrogen and oxygen to FC and improve transient and steady state responses of the output voltage to load disturbances. FC's output voltage is regulated via an ultracapacitor. Simulations are carried out via MATLAB/SIMULINK and results show that the load tracking and output voltage regulation are acceptable. The proposed system utilizes an electrolyser to generate hydrogen and a tank for storage. Therefore, there is no need for batteries. Moreover, the generated oxygen could be used in other applications in airplane. PMID- 24782665 TI - Effects of metformin on the cerebral metabolic changes in type 2 diabetic patients. AB - Metformin, a widely used antidiabetic drug, has numerous effects on human metabolism. Based on emerging cellular, animal, and epidemiological studies, we hypothesized that metformin leads to cerebral metabolic changes in diabetic patients. To explore metabolism-influenced foci of brain, we used 2-deoxy-2 [(18)F]fluoro-D-glucose (FDG) positron emission tomography for type 2 diabetic patients taking metformin (MET, n = 18), withdrawing from metformin (wdMET, n = 13), and not taking metformin (noMET, n = 9). Compared with the noMET group, statistical parametric mapping showed that the MET group had clusters with significantly higher metabolism in right temporal, right frontal, and left occipital lobe white matter and lower metabolism in the left parahippocampal gyrus, left fusiform gyrus, and ventromedial prefrontal cortex. In volume of interest (VOI-) based group comparisons, the normalized FDG uptake values of both hypermetabolic and hypometabolic clusters were significantly different between groups. The VOI-based correlation analysis across the MET and wdMET groups showed a significant negative correlation between normalized FDG uptake values of hypermetabolic clusters and metformin withdrawal durations and a positive but nonsignificant correlation in the turn of hypometabolic clusters. Conclusively, metformin affects cerebral metabolism in some white matter and semantic memory related sites in patients with type 2 diabetes. PMID- 24782666 TI - Empirical research on decoupling relationship between energy-related carbon emission and economic growth in Guangdong province based on extended Kaya identity. AB - The decoupling elasticity decomposition quantitative model of energy-related carbon emission in Guangdong is established based on the extended Kaya identity and Tapio decoupling model for the first time, to explore the decoupling relationship and its internal mechanism between energy-related carbon emission and economic growth in Guangdong. Main results are as follows. (1) Total production energy-related carbon emissions in Guangdong increase from 4128 * 104 tC in 1995 to 14396 * 104 tC in 2011. Decoupling elasticity values of energy related carbon emission and economic growth increase from 0.53 in 1996 to 0.85 in 2011, and its decoupling state turns from weak decoupling in 1996-2004 to expansive coupling in 2005-2011. (2) Land economic output and energy intensity are the first inhibiting factor and the first promoting factor to energy-related carbon emission decoupling from economic growth, respectively. The development speeds of land urbanization and population urbanization, especially land urbanization, play decisive roles in the change of total decoupling elasticity values. (3) Guangdong can realize decoupling of energy-related carbon emission from economic growth effectively by adjusting the energy mix and industrial structure, coordinating the development speed of land urbanization and population urbanization effectively, and strengthening the construction of carbon sink. PMID- 24782667 TI - Mean-variance portfolio selection for defined-contribution pension funds with stochastic salary. AB - This paper focuses on a continuous-time dynamic mean-variance portfolio selection problem of defined-contribution pension funds with stochastic salary, whose risk comes from both financial market and nonfinancial market. By constructing a special Riccati equation as a continuous (actually a viscosity) solution to the HJB equation, we obtain an explicit closed form solution for the optimal investment portfolio as well as the efficient frontier. PMID- 24782668 TI - Accelerating content-based image retrieval via GPU-adaptive index structure. AB - A tremendous amount of work has been conducted in content-based image retrieval (CBIR) on designing effective index structure to accelerate the retrieval process. Most of them improve the retrieval efficiency via complex index structures, and few take into account the parallel implementation of them on underlying hardware, making the existing index structures suffer from low-degree of parallelism. In this paper, a novel graphics processing unit (GPU) adaptive index structure, termed as plane semantic ball (PSB), is proposed to simultaneously reduce the work of retrieval process and exploit the parallel acceleration of underlying hardware. In PSB, semantics are embedded into the generation of representative pivots and multiple balls are selected to cover more informative reference features. With PSB, the online retrieval of CBIR is factorized into independent components that are implemented on GPU efficiently. Comparative experiments with GPU-based brute force approach demonstrate that the proposed approach can achieve high speedup with little information loss. Furthermore, PSB is compared with the state-of-the-art approach, random ball cover (RBC), on two standard image datasets, Corel 10 K and GIST 1 M. Experimental results show that our approach achieves higher speedup than RBC on the same accuracy level. PMID- 24782669 TI - Photocatalysis and photoelectrochemical properties of tungsten trioxide nanostructured films. AB - Tungsten trioxide (WO3) possesses a small band gap energy of 2.4-2.8 eV and is responsive to both ultraviolet and visible light irradiation including strong absorption of the solar spectrum and stable physicochemical properties. Thus, controlled growth of one-dimensional (1D) WO3 nanotubular structures with desired length, diameter, and wall thickness has gained significant interest. In the present study, 1D WO3 nanotubes were successfully synthesized via electrochemical anodization of tungsten (W) foil in an electrolyte composed of 1 M of sodium sulphate (Na2SO4) and ammonium fluoride (NH4F). The influence of NH4F content on the formation mechanism of anodic WO3 nanotubular structure was investigated in detail. An optimization of fluoride ions played a critical role in controlling the chemical dissolution reaction in the interface of W/WO3. Based on the results obtained, a minimum of 0.7 wt% of NH4F content was required for completing transformation from W foil to WO3 nanotubular structure with an average diameter of 85 nm and length of 250 nm within 15 min of anodization time. In this case, high aspect ratio of WO3 nanotubular structure is preferred because larger active surface area will be provided for better photocatalytic and photoelectrochemical (PEC) reactions. PMID- 24782670 TI - Hamming distance method with subjective and objective weights for personnel selection. AB - Multicriteria decision making (MCDM) is one of the methods that popularly has been used in solving personnel selection problem. Alternatives, criteria, and weights are some of the fundamental aspects in MCDM that need to be defined clearly in order to achieve a good result. Apart from these aspects, fuzzy data has to take into consideration that it may arise from unobtainable and incomplete information. In this paper, we propose a new approach for personnel selection problem. The proposed approach is based on Hamming distance method with subjective and objective weights (HDMSOW's). In case of vagueness situation, fuzzy set theory is then incorporated onto the HDMSOW's. To determine the objective weight for each attribute, the fuzzy Shannon's entropy is considered. While for the subjective weight, it is aggregated into a comparable scale. A numerical example is presented to illustrate the HDMSOW's. PMID- 24782671 TI - Single-event-upset sensitivity analysis on low-swing drivers. AB - Technology scaling relies on reduced nodal capacitances and lower voltages in order to improve performance and power consumption, resulting in significant increase in layout density, thus making these submicron technologies more susceptible to soft errors. Previous analysis indicates a significant improvement in SEU tolerance of the driver when the bias current is injected into the circuit but results in increase of power dissipation. Subsequently, other alternatives are considered. The impact of transistor sizes and temperature on SEU tolerance is tested. Results indicate no significant changes in Q(crit) when the effective transistor length is increased by 10%, but there is an improvement when high temperature and high bias currents are applied. However, this is due to other process parameters that are temperature dependent, which contribute to the sharp increase in Q(crit). It is found that, with temperature, there is no clear factor that can justify the direct impact of temperature on the SEU tolerance. Thus, in order to improve the SEU tolerance, high bias currents are still considered to be the most effective method in improving the SEU sensitivity. However, good trade off is required for the low-swing driver in order to meet the reliability target with minimal power overhead. PMID- 24782672 TI - A maximal element theorem in FWC-spaces and its applications. AB - A maximal element theorem is proved in finite weakly convex spaces (FWC-spaces, in short) which have no linear, convex, and topological structure. Using the maximal element theorem, we develop new existence theorems of solutions to variational relation problem, generalized equilibrium problem, equilibrium problem with lower and upper bounds, and minimax problem in FWC-spaces. The results represented in this paper unify and extend some known results in the literature. PMID- 24782673 TI - Comment on "Occupational exposure to blood and body fluids in a Department of Oral Sciences: results of a thirteen-year surveillance study". PMID- 24782674 TI - Dynamic properties of the Solow model with bounded technological progress and time-to-build technology. AB - We introduce a time-to-build technology in a Solow model with bounded technological progress. Our analysis shows that the system may be asymptotically stable, or it can produce stability switches and Hopf bifurcations when time delay varies. The direction and the stability criteria of the bifurcating periodic solutions are obtained by the normal form theory and the center manifold theorem. Numerical simulations confirms the theoretical results. PMID- 24782675 TI - Existence and uniqueness theorems for impulsive fractional differential equations with the two-point and integral boundary conditions. AB - We study a boundary value problem for the system of nonlinear impulsive fractional differential equations of order alpha (0 < alpha <= 1) involving the two-point and integral boundary conditions. Some new results on existence and uniqueness of a solution are established by using fixed point theorems. Some illustrative examples are also presented. We extend previous results even in the integer case alpha = 1. PMID- 24782676 TI - Integrated chassis control of active front steering and yaw stability control based on improved inverse nyquist array method. AB - An integrated chassis control (ICC) system with active front steering (AFS) and yaw stability control (YSC) is introduced in this paper. The proposed ICC algorithm uses the improved Inverse Nyquist Array (INA) method based on a 2 degree-of-freedom (DOF) planar vehicle reference model to decouple the plant dynamics under different frequency bands, and the change of velocity and cornering stiffness were considered to calculate the analytical solution in the precompensator design so that the INA based algorithm runs well and fast on the nonlinear vehicle system. The stability of the system is guaranteed by dynamic compensator together with a proposed PI feedback controller. After the response analysis of the system on frequency domain and time domain, simulations under step steering maneuver were carried out using a 2-DOF vehicle model and a 14-DOF vehicle model by Matlab/Simulink. The results show that the system is decoupled and the vehicle handling and stability performance are significantly improved by the proposed method. PMID- 24782677 TI - Research on bounded rationality of fuzzy choice functions. AB - The rationality of a fuzzy choice function is a hot research topic in the study of fuzzy choice functions. In this paper, two common fuzzy sets are studied and analyzed in the framework of the Banerjee choice function. The complete rationality and bounded rationality of fuzzy choice functions are defined based on the two fuzzy sets. An assumption is presented to study the fuzzy choice function, and especially the fuzzy choice function with bounded rationality is studied combined with some rationality conditions. Results show that the fuzzy choice function with bounded rationality also satisfies some important rationality conditions, but not vice versa. The research gives supplements to the investigation in the framework of the Banerjee choice function. PMID- 24782678 TI - A pruning-based disk scheduling algorithm for heterogeneous I/O workloads. AB - In heterogeneous I/O workload environments, disk scheduling algorithms should support different QoS (Quality-of-Service) for each I/O request. For example, the algorithm should meet the deadlines of real-time requests and at the same time provide reasonable response time for best-effort requests. This paper presents a novel disk scheduling algorithm called G-SCAN (Grouping-SCAN) for handling heterogeneous I/O workloads. To find a schedule that satisfies the deadline constraints and seek time minimization simultaneously, G-SCAN maintains a series of candidate schedules and expands the schedules whenever a new request arrives. Maintaining these candidate schedules requires excessive spatial and temporal overhead, but G-SCAN reduces the overhead to a manageable level via pruning the state space using two heuristics. One is grouping that clusters adjacent best effort requests into a single scheduling unit and the other is the branch-and bound strategy that cuts off inefficient or impractical schedules. Experiments with various synthetic and real-world I/O workloads show that G-SCAN outperforms existing disk scheduling algorithms significantly in terms of the average response time, throughput, and QoS-guarantees for heterogeneous I/O workloads. We also show that the overhead of G-SCAN is reasonable for on-line execution. PMID- 24782679 TI - Determination of slope safety factor with analytical solution and searching critical slip surface with genetic-traversal random method. AB - In the current practice, to determine the safety factor of a slope with two dimensional circular potential failure surface, one of the searching methods for the critical slip surface is Genetic Algorithm (GA), while the method to calculate the slope safety factor is Fellenius' slices method. However GA needs to be validated with more numeric tests, while Fellenius' slices method is just an approximate method like finite element method. This paper proposed a new method to determine the minimum slope safety factor which is the determination of slope safety factor with analytical solution and searching critical slip surface with Genetic-Traversal Random Method. The analytical solution is more accurate than Fellenius' slices method. The Genetic-Traversal Random Method uses random pick to utilize mutation. A computer automatic search program is developed for the Genetic-Traversal Random Method. After comparison with other methods like slope/w software, results indicate that the Genetic-Traversal Random Search Method can give very low safety factor which is about half of the other methods. However the obtained minimum safety factor with Genetic-Traversal Random Search Method is very close to the lower bound solutions of slope safety factor given by the Ansys software. PMID- 24782680 TI - An RF energy harvester system using UHF micropower CMOS rectifier based on a diode connected CMOS transistor. AB - This paper presents a new type diode connected MOS transistor to improve CMOS conventional rectifier's performance in RF energy harvester systems for wireless sensor networks in which the circuits are designed in 0.18 MUm TSMC CMOS technology. The proposed diode connected MOS transistor uses a new bulk connection which leads to reduction in the threshold voltage and leakage current; therefore, it contributes to increment of the rectifier's output voltage, output current, and efficiency when it is well important in the conventional CMOS rectifiers. The design technique for the rectifiers is explained and a matching network has been proposed to increase the sensitivity of the proposed rectifier. Five-stage rectifier with a matching network is proposed based on the optimization. The simulation results shows 18.2% improvement in the efficiency of the rectifier circuit and increase in sensitivity of RF energy harvester circuit. All circuits are designed in 0.18 MUm TSMC CMOS technology. PMID- 24782681 TI - The effects of trimetazidine and sildenafil on bilateral cavernosal nerve injury induced oxidative damage and cavernosal fibrosis in rats. AB - AIM: The aim of this study was to compare the effects of sildenafil and trimetazidine on bilateral cavernosal nerve injury-induced oxidative damage and fibrotic changes in cavernosal tissue in rat model. MATERIAL AND METHODS: A total of 32 male Sprague-Dawley rats were randomly divided into 4 groups; each group consist 8 rats (control, BCI, BCI + TMZ, and BCI + sildenafil groups). Tissue superoxide dismutase (SOD), malondialdehyde (MDA), and protein carbonyl (PC) levels were determined biochemically and distribution of cavernosal fibrosis density among groups was performed histopathologically. RESULTS: Tissue SOD levels in BCI group were significantly lower than the control group (P < 0.05). Tissue MDA and PC levels in BCI group were significantly higher than the control group (P < 0.05). TMZ and sildenafil administration significantly increased tissue SOD levels (P < 0.05) and reduced tissue MDA and PC levels (P < 0.05). Histologically, the degree of cavernosal fibrosis and collagen density was higher in BCI group in comparison to control, TMZ-treated, and sildenafil-treated groups. CONCLUSION: BCI caused oxidative damage and increased cavernosal fibrosis in rat penis. TMZ and sildenafil treatment decreased oxidative damage and reduced the degree of fibrosis in penile tissue due to BCI. PMID- 24782682 TI - Simplified formulae for the estimation of offshore wind turbines clutter on marine radars. AB - The potential impact that offshore wind farms may cause on nearby marine radars should be considered before the wind farm is installed. Strong radar echoes from the turbines may degrade radars' detection capability in the area around the wind farm. Although conventional computational methods provide accurate results of scattering by wind turbines, they are not directly implementable in software tools that can be used to conduct the impact studies. This paper proposes a simple model to assess the clutter that wind turbines may generate on marine radars. This method can be easily implemented in the system modeling software tools for the impact analysis of a wind farm in a real scenario. PMID- 24782685 TI - Ensuring safe and effective medication use in pediatric patients. PMID- 24782684 TI - High-intensity interval training and beta-hydroxy-beta-methylbutyric free acid improves aerobic power and metabolic thresholds. AB - BACKGROUND: Previous research combining Calcium beta-hydroxy-beta-methylbutyrate (CaHMB) and running high-intensity interval training (HIIT) have shown positive effects on aerobic performance measures. The purpose of this study was to examine the effect of beta-hydroxy-beta-methylbutyric free acid (HMBFA) and cycle ergometry HIIT on maximal oxygen consumption (VO2peak), ventilatory threshold (VT), respiratory compensation point (RCP) and time to exhaustion (Tmax) in college-aged men and women. METHODS: Thirty-four healthy men and women (Age: 22.7 +/- 3.1 yrs ; VO2peak: 39.3 +/- 5.0 ml . kg(-1) . min(-1)) volunteered to participate in this double-blind, placebo-controlled design study. All participants completed a series of tests prior to and following treatment. A peak oxygen consumption test was performed on a cycle ergometer to assess VO2peak, Tmax, VT, and RCP. Twenty-six participants were randomly assigned into either a placebo (PLA-HIIT) or 3 g per day of HMBFA (BetaTorTM) (HMBFA-HIIT) group. Eight participants served as controls (CTL). Participants in the HIIT groups completed 12 HIIT (80-120% maximal workload) exercise sessions consisting of 5-6 bouts of a 2:1 minute cycling work to rest ratio protocol over a four-week period. Body composition was measured with dual energy x-ray absorptiometry (DEXA). Outcomes were assessed by ANCOVA with posttest means adjusted for pretest differences. RESULTS: The HMBFA-HIIT intervention showed significant (p < 0.05) gains in VO2peak, and VT, versus the CTL and PLA-HIIT group. Both PLA-HIIT and HMBFA-HIIT treatment groups demonstrated significant (p < 0.05) improvement over CTL for Tmax, and RCP with no significant difference between the treatment groups. There were no significant differences observed for any measures of body composition. An independent-samples t-test confirmed that there were no significant differences between the training volumes for the PLA-HIIT and HMBFA-HIIT groups. CONCLUSIONS: Our findings support the use of HIIT in combination with HMBFA to improve aerobic fitness in college age men and women. These data suggest that the addition of HMBFA supplementation may result in greater changes in VO2peak and VT than HIIT alone. STUDY REGISTRATION: The study was registered on ClinicalTrials.gov (ID NCT01941368). PMID- 24782683 TI - Treatment of juvenile idiopathic arthritis: a revolution in care. AB - A generation ago, children with arthritis faced a lifetime of pain and disability. Today, there are a multitude of treatment options, including a variety of biologics targeting key cytokines and other inflammatory mediators. While non-steroidal anti-inflammatory drugs and corticosteroids were once the mainstay of therapy, they are now largely used as bridge or adjunctive therapies. Among the conventional disease-modifying anti-rheumatic drugs, methotrexate remains first-line therapy for most children with juvenile idiopathic arthritis (JIA) due to its long track record of safety and effectiveness in the management of peripheral arthritis. Sulfasalazine and leflunomide may also have a secondary role. The tumor necrosis factor inhibitors (TNFi) have shown tremendous benefit in children with polyarticular JIA and likely in enthesitis-related arthritis and psoriatic JIA as well. There may be additional benefit in combining TNFi with methotrexate. Abatacept and tocilizumab also appear to benefit polyarticular JIA; the role of rituximab remains unclear. For the treatment of systemic JIA, while the TNFi are of less benefit, blockade of interleukin-1 or interleukin-6 is highly effective. Additionally, interleukin-1 blockade appears to be effective treatment of macrophage activation syndrome, one of the most dangerous complications of JIA; specifically, anakinra in combination with cyclosporine and corticosteroids may obviate the need for cytotoxic approaches. In contrast, methotrexate along with the TNFi and abatacept are effective agents for the management of uveitis, another complication of JIA. Overall, the biologics have demonstrated an impressive safety record in children with JIA, although children do need to be monitored for rare but potentially dangerous adverse events, such as tuberculosis and other infections; paradoxical development of additional autoimmune diseases; and possibly an increased risk of malignancy. Finally, there may be a window of opportunity during which children with JIA will demonstrate most optimal responses to aggressive therapy, underscoring the need for rapid diagnosis and initiation of treatment. PMID- 24782686 TI - Survey results: characterization of direct thrombin inhibitor use in pediatric patients. AB - OBJECTIVES: The objective of this multicenter survey is to characterize the use of direct thrombin inhibitors (DTIs) in the pediatric population. The results of this survey may be used to design a prospective multicenter study with the ultimate goal of developing a dosing/titration recommendation for the use of DTIs in the pediatric population. METHODS: This is a multicenter, descriptive study to survey hospitals around the country regarding the use of DTIs (argatroban, bivalirudin, and lepirudin) in the pediatic population. Institutional review board approval was obtained. The survey consisted of 42 questions and was designed utilizing Survey Monkey. The survey was emailed to members of the Pediatric Pharmacy Advocacy Group. Listserv members who responded to the survey within 4 weeks of when the survey was emailed were included in the study. Descriptive statistics were performed utilizing Microsoft Excel 2007. RESULTS: Responses were obtained from 56 institutions from 29 states in the United States. Multiple agents are available on formulary with argatroban being the most common (~80%). The large majority of institutions (41.1%) utilize DTIs 2 to 4 times a year with an additional 33.9% utilizing them less than twice a year. There is no consistent approach to dosing and titration amongst pediatric institutions. CONCLUSIONS: There are a wide variety of methods used by pediatric institutions with regard to dosing and titration of DTIs. Recently published prospective studies and package insert updates should help guide practitioners toward a more consistent approach to dosing of these high-risk medications. PMID- 24782687 TI - Multi-institutional Study of Outcomes After Pediatric Heart Transplantation: Candidate Gene Polymorphism Analysis of ABCC2. AB - OBJECTIVES: Earlier studies have indicated that the pharmacokinetics of mycophenolic acid (MPA) is influenced by polymorphisms of ABCC2, which encodes for the membrane transporter MRP2. The ABCC2 rs717620 A allele has been associated with enterohepatic recirculation of MPA, and our previous work had correlated the discontinuance of MPA with this allele in pediatric heart transplant patients. Therefore, we hypothesized that the ABCC2 rs717620 A allele would be associated with poorer outcomes including rejection with hemodynamic compromise (RHC), graft failure, and death in the pediatric heart transplant (PHTx) population receiving MPA. METHODS: PHTx recipients from 6 institutions in the Pediatric Heart Transplantation Study (PHTS) from the period of 1993-2009, receiving MPA therapy, were genotyped for ABCC2 rs717620. Genotyping was accomplished by direct sequencing. Demographic and outcome data were limited to the data routinely collected as part of the PHTS and included RHC and mortality. RESULTS: Two hundred ninety patients were identified who received MPA at some point post transplantation, of which 200 carried the GG genotype, 81 carried the AG genotype, and 9 carried the AA genotype. Follow-up time after transplantation was 6 years. RHC occurred in 76 patients and 18 patients died. In the 281 patients followed up more than 1 year, late RHC (>1 year post transplantation) occurred in 42 patients. While both RHC and late RHC were associated with the ABCC2 rs717620 GG genotype (hazard ratios: 1.80 and 4.57, respectively, p<0.05) in all patients, this association was not significant in PHTx patients receiving only MPA as the antiproliferative agent from the time of transplant (n=142). CONCLUSIONS: ABCC2 rs717620 polymorphisms varied within racial groups. As a candidate gene assessment, the ABCC2 rs717620 AG and AA genotypes may be associated with improved, rather than poorer, RHC in PHTx patients receiving MPA therapy. ABCC2 rs717620 polymorphisms should be included in any expanded pharmacogenomic analysis of outcomes after pediatric heart transplantation. PMID- 24782688 TI - Chiral stability of an extemporaneously prepared clopidogrel bisulfate oral suspension. AB - OBJECTIVES: The purpose of this study was to evaluate the chiral stability of clopidogrel bisulfate in an extemporaneously compounded oral suspension for a period of 60 days. METHODS: A 5 mg/mL oral suspension of clopidogrel bisulfate was prepared from commercially available Plavix tablets. The clopidogrel suspension was then evenly divided between two light-resistant prescription bottles and stored either under refrigeration (4 degrees C) or at room temperature (25 degrees C). Samples were drawn from the stored suspensions immediately after preparation and on days 7, 14, 28, and 60. Samples were subsequently analyzed at each time point by high-performance liquid chromatography using a reversed-phase column, with chemical stability defined as the retention of at least 90% of the initial intact clopidogrel concentration measured. To determine the chiral stability of the suspension, samples were also analyzed by high-performance liquid chromatography using a chiral column to investigate possible enantiomeric inversion. Chiral stability was defined as the retention of at least 90% of the initial concentration of the suspension as the S enantiomer, the active moiety of Plavix. RESULTS: Regardless of storage conditions, the oral suspension of clopidogrel retained at least 98% of the active S-enantiomer for 60 days after preparation. Compared with the clopidogrel suspension stored in the refrigerator, more chiral inversion was noted in the clopidogrel suspension stored at room temperature. CONCLUSIONS: Our investigation of chiral stability indicates that a 5 mg/mL clopidogrel oral suspension stored under refrigeration and at room temperature maintains chiral stability as the active S-enantiomer. PMID- 24782689 TI - Postoperative complications associated with perioperative sirolimus prior to pediatric cardiac retransplantation. AB - OBJECTIVES: Sirolimus has been used in pediatric cardiac transplantation for the past decade for chronic renal dysfunction, recurrent rejection, and/or coronary allograft vasculopathy. There has been concern regarding the effect of sirolimus on wound healing and other postoperative complications. To date, the pediatric literature on its use is limited and has not specifically addressed its use in the perioperative period following repeat cardiac transplantation. METHODS: We compared the patients in our institution who received sirolimus before repeat cardiac transplantation to those in the same era who did not receive sirolimus. RESULTS: Of the 5 patients in the study group, 5 (100%) developed pleural effusions vs 1 (17%) in the control group (p=0.013). There was no increase in mortality in the sirolimus group, and there were no significant differences in renal dysfunction, serious bacterial infection, rejection, or postoperative length of stay. CONCLUSIONS: In this small data set, there was a statistically significant increase in pleural effusions in patients on sirolimus. Further study is needed to develop an appropriate strategy to avoid postoperative complications in this patient population. PMID- 24782690 TI - Drug utilization, dosing, and costs after implementation of intravenous acetaminophen guidelines for pediatric patients. AB - OBJECTIVES: The objectives of this evaluation of medication use were to characterize the use of intravenous acetaminophen at our institution and to determine if acetaminophen was prescribed at age-appropriate dosages per institutional guidelines, as well as to evaluate compliance with restrictions for use. Total acquisition costs associated with intravenous acetaminophen usage is described as well. METHODS: This retrospective study evaluated the use of acetaminophen in pediatric patients younger than 18 years of age, admitted to a tertiary care hospital, who received at least 1 dose of intravenous acet aminophen between August 1, 2011, and January 31, 2012. RESULTS: A total of 52 doses of intravenous acetaminophen were administered to 31 patients during the 6 month study period. Most patients were admitted to the otorhinolaryngology service (55%), and the majority of doses were administered either in the operating room (46%) or in the intensive care unit (46%). Nineteen doses (37%) of intravenous acetaminophen were administered to patients who did not meet institutional guidelines' eligibility criteria. Three patients received single doses of intravenous acetaminophen that were greater than the dose recommended for their age. One patient during the study period received more than the recommended 24-hour maximum cumulative dose for acetaminophen. Total acquisition cost of intravenous acetaminophen therapy over the 6-month study period was $530.40. CONCLUSIONS: Intravenous acetaminophen was used most frequently among pediatric patients admitted to the otorhinolaryngology service during the perioperative period. Nineteen doses (37%) were administered to patients who did not meet the institutional guidelines' eligibility criteria. Our data support reinforcing the availability of institutional guidelines to promote cost effective use of intravenous acetaminophen while minimizing the prescription of inappropriate doses. PMID- 24782691 TI - Parenteral nutrition-associated liver disease: a retrospective study of ursodeoxycholic Acid use in neonates. AB - OBJECTIVES: To verify the effect of ursodeoxycholic acid (UDCA) on the duration of neonatal parenteral nutrition-associated liver disease. METHODS: Retrospective cohort study of neonates in intensive care between 2004 and 2007 presenting with parenteral nutrition-associated liver disease. RESULTS: Of 118 eligible infants, 64 received UDCA. Cholestasis lasted longer in the UDCA group (79 vs. 50 days, p=0.001). However, treatment was delayed for a median of 24 days after cholestasis onset. Multivariate Cox regression analysis showed no association between UDCA and cholestasis duration. The rate of decline of conjugated bilirubin was greater in treated patients (median 0.084 mg/dL/day vs. 0.60 mg/dL/day; p=0.009) and weight gain was greater (22.8 vs. 17.7 g/kg/day, p=0.010). CONCLUSIONS: UDCA therapy was not associated with the duration of parenteral nutrition-associated liver disease. A delay in treatment initiation might explain this result. UDCA therapy was associated with a faster decline of conjugated bilirubin and greater weight gain. PMID- 24782692 TI - Ethacrynic Acid continuous infusions in critically ill pediatric patients. AB - OBJECTIVES: The purpose of this study was to describe dosage regimens and treatment outcomes in critically ill children receiving ethacrynic acid continuous infusions (CI). METHODS: This retrospective cross-sectional study evaluated patients less than 18 years of age who received ethacrynic acid CI with a duration exceeding 12 hours, from January 1, 2007, through January 31, 2012. The primary objective was to determine the mean/median doses of ethacrynic acid CI. Secondary objectives were to assess surrogate efficacy markers (e.g., urine output [UOP], fluid balance) and the number of patients with electrolyte abnormalities or metabolic alkalosis. Descriptive statistics were used. A series of repeated measures analyses of variance were conducted to assess differences in surrogate efficacy markers and in adverse events that occurred pre-, mid-, and posttherapy. RESULTS: Nine patients were included. The mean +/- SD initial and maximum doses (mg/kg/hr) were 0.13 +/- 0.07 (median 0.1; range, 0.08-0.3) and 0.17 +/- 0.08 (median, 0.16; range 0.09-0.3), respectively. The median UOP (mL/kg/hr) pre-, mid-, and postinfusions (interquartile range [IQR]) were 2.4 (1.8-3.2), 4.2 (3.5-6), and 4 (3.4-5.3), respectively. The median fluid balance (mL; IQR) was 189 (90-526), -258 (-411.7 to 249) and -113.5 (-212.5 to 80.2), respectively. There were statistically significant differences in UOP and fluid balance pre- versus mid-therapy (0.014) and pre- versus posttherapy (p=0.010). No significant differences were noted with magnesium and potassium. Five children (55.6%) developed metabolic alkalosis. CONCLUSIONS: This study provides preliminary evidence for ethacrynic acid CI in children. The median initial dose and maximum dose in this cohort were 0.13 mg/kg/hr and 0.17 mg/kg/hr, respectively. Larger prospective studies are needed to confirm these findings. PMID- 24782693 TI - Hepatotoxicity induced by trimethoprim-sulfamethoxazole in a child with cystic fibrosis. AB - Patients with cystic fibrosis (CF) have chronic and progressive lung infections with various bacterial organisms that require treatment with oral and intravenous antibiotics on a regular basis. Trimethoprim-sulfamethoxazole (TMP-SMX) is one of the medications used to treat acute pulmonary infectious exacerbations in patients with CF. Hepatic toxicity secondary to TMP-SMX was previously described in normal subjects but has not been reported in children with CF. Here we describe a 14-year-old female child with CF who was given oral TMP-SMX for an acute pulmonary infectious exacerbation. She developed a rash, severe constitutional symptoms, and significant elevation of liver enzyme concentrations secondary to immunity-mediated reaction to TMP-SMX. Discontinuation of TMP-SMX and supportive treatment led to resolution of her symptoms and normalization of liver enzyme concentrations. PMID- 24782694 TI - Successful sublingual cobalamin treatment in a child with short-bowel syndrome. AB - Vitamin B12 (B12) is essential for deoxyribonucleic acid synthesis, to maintain normal hematologic and neurologic functions. Studies suggest that cobalamin deficiency in children is more common than previously recognized. Main causes are decreased intake, abnormal absorption, and inborn errors of metabolism. The classic treatment for cobalamin deficiency is intramuscular administration of B12. There are no data concerning the use of alternative routes of cobalamin administration in children. This report shares the experience of sublingual administration of B12 to a patient with short-bowel syndrome and B12 malabsorption. We report the case of successful treatment of cobalamin deficiency by sublingual administration in a 9-year-old patient who had undergone intestinal resection and jejunum-colon, with anastomosis of 32 cm of residual small intestine and absence of distal jejunum and ileocecal junction. We determined a B12 deficiency because low serum cobalamin levels (<200 pg/mL) were shown in 2 consecutive tests (130 pg/mL and 170 pg/mL). The patient presented with neither clinical nor hematological manifestations. He received sublingual cobalamin preparation, 1000-mcg sublingual nuggets per day for 1 month. Normalization of serum cobalamin was obtained (790 pg/mL) after 1 month of treatment. The sublingual route of administration not only improved the quality of life of this patient by avoiding monthly painful injections but also reduced the cost of treatment and the number of hospital visits. PMID- 24782695 TI - Pediatric news. PMID- 24782696 TI - Metalinguistic Ability in Bilingual Children: The Role of Executive Control. AB - Although bilingual children tend to obtain lower scores than their monolingual peers on tests of formal language ability, they exhibit a processing advantage on non-verbal executive control (EC) tasks. This advantage may be attributable to EC practice that bilinguals routinely receive from the constant need to manage attention to two jointly activated languages. Metalinguistic tasks, unlike linguistic tasks, require children to access both their language knowledge (i.e., representations) and recruit EC ability; that is, metalinguistic tasks require children to use attentional processes to operate on linguistic forms. In this article, we review our recent studies examining linguistic and metalinguistic abilities in tasks that differed in the extent to which solutions were based on linguistic knowledge (representations) or control processes, allowing us to examine the relative contribution of each to bilingual language processing. Results indicate that bilinguals' superior EC ability allows them to compensate for weaker linguistic knowledge in metalinguistic tasks where greater recruitment of control processes is required. PMID- 24782697 TI - The impact of frontal and cerebellar lesions on decision making: evidence from the Iowa Gambling Task. AB - Although the frontal lobes have traditionally been considered the neural substrates of executive functioning (EF), recent studies have suggested that other structures, such as the cerebellum, may be associated with these abilities. The role of the cerebellum has only been sparsely investigated in connection with decision making (DM), an important component of EF, and the few results obtained on this front have been inconclusive. The current study sought to investigate the role of the cerebellum in DM by comparing the performance of patients with cerebellar strokes, frontal-damaged patients, and a healthy control group on the Iowa Gambling Task (IGT). A total of nine cerebellar-damaged adults participated in the study, as well as nine individuals with frontal strokes and 18 control individuals. Patients were administered a version of the IGT adapted to the population of Southern Brazil. There was a marginal difference in mean IGT net scores between the two clinical groups, although both displayed impaired performance as compared to the control group. Overall, the DM ability of patients with cerebellar damage proved to be more preserved than that of individuals with frontal lobe strokes, but less preserved than that of the control group. These data suggested that, while the frontal lobes may be the most important brain structures for DM, the cerebellum might also play an active role in this cognitive function. Future studies assessing participants with lesions in different cerebellar regions and hemispheres will prove invaluable for the understanding of the neural structures involved in DM, and make significant contributions to the globalist-localizationist debate in DM neuroscience. PMID- 24782699 TI - Flexible multivariate hemodynamics fMRI data analyses and simulations with PyHRF. AB - As part of fMRI data analysis, the pyhrf package provides a set of tools for addressing the two main issues involved in intra-subject fMRI data analysis: (1) the localization of cerebral regions that elicit evoked activity and (2) the estimation of activation dynamics also known as Hemodynamic Response Function (HRF) recovery. To tackle these two problems, pyhrf implements the Joint Detection-Estimation framework (JDE) which recovers parcel-level HRFs and embeds an adaptive spatio-temporal regularization scheme of activation maps. With respect to the sole detection issue (1), the classical voxelwise GLM procedure is also available through nipy, whereas Finite Impulse Response (FIR) and temporally regularized FIR models are concerned with HRF estimation (2) and are specifically implemented in pyhrf. Several parcellation tools are also integrated such as spatial and functional clustering. Parcellations may be used for spatial averaging prior to FIR/RFIR analysis or to specify the spatial support of the HRF estimates in the JDE approach. These analysis procedures can be applied either to volume-based data sets or to data projected onto the cortical surface. For validation purpose, this package is shipped with artificial and real fMRI data sets, which are used in this paper to compare the outcome of the different available approaches. The artificial fMRI data generator is also described to illustrate how to simulate different activation configurations, HRF shapes or nuisance components. To cope with the high computational needs for inference, pyhrf handles distributing computing by exploiting cluster units as well as multi core machines. Finally, a dedicated viewer is presented, which handles n dimensional images and provides suitable features to explore whole brain hemodynamics (time series, maps, ROI mask overlay). PMID- 24782698 TI - The EEG as an index of neuromodulator balance in memory and mental illness. AB - There is a strong correlation between signature EEG frequency patterns and the relative levels of distinct neuromodulators. These associations become particularly evident during the sleep-wake cycle. The monoamine-acetylcholine balance hypothesis is a theory of neurophysiological markers of the EEG and a detailed description of the findings that support this proposal are presented in this paper. According to this model alpha rhythm reflects the relative predominance of cholinergic muscarinic signals and delta rhythm that of monoaminergic receptor effects. Both high voltage synchronized rhythms are likely mediated by inhibitory Galphai/o-mediated transduction of inhibitory interneurons. Cognitively, alpha and delta EEG measures are proposed to indicate automatic and flexible strategies, respectively. Sleep is associated with marked changes in relative neuromodulator levels corresponding to EEG markers of distinct stages. Sleep studies on memory consolidation present some of the strongest evidence yet for the respective roles of monoaminergic and cholinergic projections in declarative and non-declarative memory processes, a key theoretical premise for understanding the data. Affective dysregulation is reflected in altered EEG patterns during sleep. PMID- 24782700 TI - Interpreting functional diffusion tensor imaging. PMID- 24782701 TI - Dissociable mechanisms of speed-accuracy tradeoff during visual perceptual learning are revealed by a hierarchical drift-diffusion model. AB - Two phenomena are commonly observed in decision-making. First, there is a speed accuracy tradeoff (SAT) such that decisions are slower and more accurate when instructions emphasize accuracy over speed, and vice versa. Second, decision performance improves with practice, as a task is learnt. The SAT and learning effects have been explained under a well-established evidence-accumulation framework for decision-making, which suggests that evidence supporting each choice is accumulated over time, and a decision is committed to when the accumulated evidence reaches a decision boundary. This framework suggests that changing the decision boundary creates the tradeoff between decision speed and accuracy, while increasing the rate of accumulation leads to more accurate and faster decisions after learning. However, recent studies challenged the view that SAT and learning are associated with changes in distinct, single decision parameters. Further, the influence of speed-accuracy instructions over the course of learning remains largely unknown. Here, we used a hierarchical drift-diffusion model to examine the SAT during learning of a coherent motion discrimination task across multiple training sessions, and a transfer test session. The influence of speed-accuracy instructions was robust over training and generalized across untrained stimulus features. Emphasizing decision accuracy rather than speed was associated with increased boundary separation, drift rate and non-decision time at the beginning of training. However, after training, an emphasis on decision accuracy was only associated with increased boundary separation. In addition, faster and more accurate decisions after learning were due to a gradual decrease in boundary separation and an increase in drift rate. The results suggest that speed-accuracy instructions and learning differentially shape decision-making processes at different time scales. PMID- 24782702 TI - Neuroligin-1 knockdown reduces survival of adult-generated newborn hippocampal neurons. AB - Survival of adult-born hippocampal granule cells is modulated by neural activity, and thought to be enhanced by excitatory synaptic signaling. Here, we report that a reduction in the synaptogenic protein neuroligin-1 in adult-born neurons in vivo decreased their survival, but surprisingly, this effect was independent of changes in excitatory synaptic function. Instead, the decreased survival was associated with unexpected changes in dendrite and spine morphology during granule cell maturation, suggesting a link between cell growth and survival. PMID- 24782703 TI - When natural selection should optimize speed-accuracy trade-offs. PMID- 24782704 TI - Orphan nuclear receptor TLX regulates astrogenesis by modulating BMP signaling. AB - Neural stem cells (NSCs) are self-renewing multipotent progenitors that generate both neurons and glia. The precise control of NSC behavior is fundamental to the architecture and function of the central nervous system. We previously demonstrated that the orphan nuclear receptor TLX is required for postnatal NSC activation and neurogenesis in the neurogenic niche. Here, we show that TLX modulates bone morphogenetic protein (BMP)-SMAD signaling to control the timing of postnatal astrogenesis. Genes involved in the BMP signaling pathway, such as Bmp4, Hes1, and Id3, are upregulated in postnatal brains lacking Tlx. Chromatin immunoprecipitation and electrophoretic mobility shift assays reveal that TLX can directly bind the enhancer region of Bmp4. In accordance with elevated BMP signaling, the downstream effectors SMAD1/5/8 are activated by phosphorylation in Tlx mutant mice. Consequently, Tlx mutant brains exhibit an early appearance and increased number of astrocytes with marker expression of glial fibrillary acidic protein (GFAP) and S100B. Taken together, these results suggest that TLX tightly controls postnatal astrogenesis through the modulation of BMP-SMAD signaling pathway activity. PMID- 24782705 TI - The myogenic and neurogenic components of the rhythmic segmentation motor patterns of the intestine. PMID- 24782706 TI - Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain. AB - Early-life experience plays a major role in the stress response throughout life. Neonatal maternal separation (MS) is an animal model of depression with an altered serotonergic response. We hypothesize that this alteration may be caused by differences in 5-HT1A receptor and serotonin transporter (SERT) mRNA expression in brain areas involved in the control of emotions, memory, and fear as well as in regions controlling the central serotonergic tone. To test this, Sprague-Dawley rats were subjected to MS for 3 h daily during postnatal days 2 12. As control, age matched rats were non-separated (NS) from their dams. When animals reached adulthood (11-13 weeks) brain was extracted and mRNA expression of 5-HT1A receptor in amygdala, hippocampus and dorsal raphe nucleus (DRN) and SERT in the DRN was analyzed through in situ hybridisation. Densitometric analysis revealed that MS increased 5-HT1A receptor mRNA expression in the amygdala, and reduced its expression in the DRN, but no changes were observed in the hippocampus in comparison to NS controls. Also, MS reduced SERT mRNA expression in the DRN when compared to NS rats. These results suggest that early life stress induces persistent changes in 5-HT1A receptor and SERT mRNA expression in key brain regions involved in the development of stress-related psychiatric disorders. The reduction in SERT mRNA indicates an alteration that is in line with clinical findings such as polymorphic variants in individuals with higher risk of depression. These data may help to understand how early-life stress contributes to the development of mood disorders in adulthood. PMID- 24782707 TI - The spatiotemporal organization of cerebellar network activity resolved by two photon imaging of multiple single neurons. AB - In order to investigate the spatiotemporal organization of neuronal activity in local microcircuits, techniques allowing the simultaneous recording from multiple single neurons are required. To this end, we implemented an advanced spatial light modulator two-photon microscope (SLM-2PM). A critical issue for cerebellar theory is the organization of granular layer activity in the cerebellum, which has been predicted by single-cell recordings and computational models. With SLM 2PM, calcium signals could be recorded from different network elements in acute cerebellar slices including granule cells (GrCs), Purkinje cells (PCs) and molecular layer interneurons. By combining WCRs with SLM-2PM, the spike/calcium relationship in GrCs and PCs could be extrapolated toward the detection of single spikes. The SLM-2PM technique made it possible to monitor activity of over tens to hundreds neurons simultaneously. GrC activity depended on the number of spikes in the input mossy fiber bursts. PC and molecular layer interneuron activity paralleled that in the underlying GrC population revealing the spread of activity through the cerebellar cortical network. Moreover, circuit activity was increased by the GABA-A receptor blocker, gabazine, and reduced by the AMPA and NMDA receptor blockers, NBQX and APV. The SLM-2PM analysis of spatiotemporal patterns lent experimental support to the time-window and center-surround organizing principles of the granular layer. PMID- 24782708 TI - Simiate is an Actin binding protein involved in filopodia dynamics and arborization of neurons. AB - The Actin cytoskeleton constitutes the functional base for a multitude of cellular processes extending from motility and migration to cell mechanics and morphogenesis. The latter is particularly important to neuronal cells since the accurate functioning of the brain crucially depends on the correct arborization of neurons, a process that requires the formation of several dozens to hundreds of dendritic branches. Recently, a model was proposed where different transcription factors are detailed to distinct facets and phases of dendritogenesis and exert their function by acting on the Actin cytoskeleton, however, the proteins involved as well as the underlying molecular mechanisms are largely unknown. Here, we demonstrate that Simiate, a protein previously indicated to activate transcription, directly associates with both, G- and F Actin and in doing so, affects Actin polymerization and Actin turnover in living cells. Imaging studies illustrate that Simiate particularly influences filopodia dynamics and specifically increases the branching of proximal, but not distal dendrites of developing neurons. The data suggests that Simiate functions as a direct molecular link between transcription regulation on one side, and dendritogenesis on the other, wherein Simiate serves to coordinate the development of proximal and distal dendrites by acting on the Actin cytoskeleton of filopodia and on transcription regulation, hence supporting the novel model. PMID- 24782709 TI - Gephyrin phosphorylation in the functional organization and plasticity of GABAergic synapses. AB - Gephyrin is a multifunctional scaffold protein essential for accumulation of inhibitory glycine and GABAA receptors at post-synaptic sites. The molecular events involved in gephyrin-dependent GABAA receptor clustering are still unclear. Evidence has been recently provided that gephyrin phosphorylation plays a key role in these processes. Gephyrin post-translational modifications have been shown to influence the structural remodeling of GABAergic synapses and synaptic plasticity by acting on post-synaptic scaffolding properties as well as stability. In addition, gephyrin phosphorylation and the subsequent phosphorylation-dependent recruitment of the chaperone molecule Pin1 provide a mechanism for the regulation of GABAergic signaling. Extensively characterized as pivotal enzyme controlling cell proliferation and differentiation, the prolyl isomerase activity of Pin1 has been shown to regulate protein synthesis necessary to sustain the late phase of long-term potentiation at excitatory synapses, which suggests its involvement at synaptic sites. In this review we summarize the current state of knowledge of the signaling pathways responsible for gephyrin post-translational modifications. We will also outline future lines of research that might contribute to a better understanding of molecular mechanisms by which gephyrin regulates synaptic plasticity at GABAergic synapses. PMID- 24782711 TI - High abundance of BDNF within glutamatergic presynapses of cultured hippocampal neurons. AB - In the mammalian brain, the neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key factor for synaptic refinement, plasticity and learning. Although BDNF-induced signaling cascades are well known, the spatial aspects of the synaptic BDNF localization remained unclear. Recent data provide strong evidence for an exclusive presynaptic location and anterograde secretion of endogenous BDNF at synapses of the hippocampal circuit. In contrast, various studies using BDNF overexpression in cultured hippocampal neurons support the idea that postsynaptic elements and other dendritic structures are the preferential sites of BDNF localization and release. In this study we used rigorously tested anti-BDNF antibodies and achieved a dense labeling of endogenous BDNF close to synapses. Confocal microscopy showed natural BDNF close to many, but not all glutamatergic synapses, while neither GABAergic synapses nor postsynaptic structures carried a typical synaptic BDNF label. To visualize the BDNF distribution within the fine structure of synapses, we implemented super resolution fluorescence imaging by direct stochastic optical reconstruction microscopy (dSTORM). Two-color dSTORM images of neurites were acquired with a spatial resolution of ~20 nm. At this resolution, the synaptic scaffold proteins Bassoon and Homer exhibit hallmarks of mature synapses and form juxtaposed bars, separated by a synaptic cleft. BDNF imaging signals form granule-like clusters with a mean size of ~60 nm and are preferentially found within the fine structure of the glutamatergic presynapse. Individual glutamatergic presynapses carried up to 90% of the synaptic BDNF immunoreactivity, and only a minor fraction of BDNF molecules was found close to the postsynaptic bars. Our data proof that hippocampal neurons are able to enrich and store high amounts of BDNF in small granules within the mature glutamatergic presynapse, at a principle site of synaptic plasticity. PMID- 24782710 TI - Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor. AB - Neurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulated and the novel (i.e., non steroid receptor) targets for steroid action for behavior. One endpoint of interest has been lordosis, the mating posture of female rodents. Allopregnanolone is necessary and sufficient for lordosis, and the brain circuitry underlying it, such as actions in the midbrain ventral tegmental area (VTA), has been well-characterized. Published and recent findings supporting a dynamic role of allopregnanolone are included in this review. First, contributions of ovarian and adrenal sources of precursors of allopregnanolone, and the requisite enzymatic actions for de novo production in the central nervous system will be discussed. Second, how allopregnanolone produced in the brain has actions on behavioral processes that are independent of binding to steroid receptors, but instead involve rapid modulatory actions via neurotransmitter targets (e.g., gamma-amino butyric acid-GABA, N-methyl-D-aspartate- NMDA) will be reviewed. Third, a recent focus on characterizing the role of a promiscuous nuclear receptor, pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism and expressed in the VTA, as a target for allopregnanolone and how this relates to both actions and production of allopregnanolone will be addressed. For example, allopregnanolone can bind PXR and knocking down expression of PXR in the midbrain VTA attenuates actions of allopregnanolone via NMDA and/or GABAA for lordosis. Our understanding of allopregnanolone's actions in the VTA for lordosis has been extended to reveal the role of allopregnanolone for broader, clinically-relevant questions, such as neurodevelopmental processes, neuropsychiatric disorders, epilepsy, and aging. PMID- 24782712 TI - Kir3 channel ontogeny - the role of Gbetagamma subunits in channel assembly and trafficking. AB - The role of Gbetagamma subunits in Kir3 channel gating is well characterized. Here, we have studied the role of Gbetagamma dimers during their initial contact with Kir3 channels, prior to their insertion into the plasma membrane. We show that distinct Gbetagamma subunits play an important role in orchestrating and fine-tuning parts of the Kir3 channel life cycle. Gbeta1gamma2, apart from its role in channel opening that it shares with other Gbetagamma subunit combinations, may play a unique role in protecting maturing channels from degradation as they transit to the cell surface. Taken together, our data suggest that Gbeta1gamma2 prolongs the lifetime of the Kir3.1/Kir3.2 heterotetramer, although further studies would be required to shed more light on these early Gbetagamma effects on Kir3 maturation and trafficking. PMID- 24782713 TI - Optimizing neuronal differentiation from induced pluripotent stem cells to model ASD. AB - Autism spectrum disorder (ASD) is an early-onset neurodevelopmental disorder characterized by deficits in social communication, and restricted and repetitive patterns of behavior. Despite its high prevalence, discovery of pathophysiological mechanisms underlying ASD has lagged due to a lack of appropriate model systems. Recent advances in induced pluripotent stem cell (iPSC) technology and neural differentiation techniques allow for detailed functional analyses of neurons generated from living individuals with ASD. Refinement of cortical neuron differentiation methods from iPSCs will enable mechanistic studies of specific neuronal subpopulations that may be preferentially impaired in ASD. In this review, we summarize recent accomplishments in differentiation of cortical neurons from human pluripotent stems cells and efforts to establish in vitro model systems to study ASD using personalized neurons. PMID- 24782715 TI - An investigation of Hebbian phase sequences as assembly graphs. AB - Hebb proposed that synapses between neurons that fire synchronously are strengthened, forming cell assemblies and phase sequences. The former, on a shorter scale, are ensembles of synchronized cells that function transiently as a closed processing system; the latter, on a larger scale, correspond to the sequential activation of cell assemblies able to represent percepts and behaviors. Nowadays, the recording of large neuronal populations allows for the detection of multiple cell assemblies. Within Hebb's theory, the next logical step is the analysis of phase sequences. Here we detected phase sequences as consecutive assembly activation patterns, and then analyzed their graph attributes in relation to behavior. We investigated action potentials recorded from the adult rat hippocampus and neocortex before, during and after novel object exploration (experimental periods). Within assembly graphs, each assembly corresponded to a node, and each edge corresponded to the temporal sequence of consecutive node activations. The sum of all assembly activations was proportional to firing rates, but the activity of individual assemblies was not. Assembly repertoire was stable across experimental periods, suggesting that novel experience does not create new assemblies in the adult rat. Assembly graph attributes, on the other hand, varied significantly across behavioral states and experimental periods, and were separable enough to correctly classify experimental periods (Naive Bayes classifier; maximum AUROCs ranging from 0.55 to 0.99) and behavioral states (waking, slow wave sleep, and rapid eye movement sleep; maximum AUROCs ranging from 0.64 to 0.98). Our findings agree with Hebb's view that assemblies correspond to primitive building blocks of representation, nearly unchanged in the adult, while phase sequences are labile across behavioral states and change after novel experience. The results are compatible with a role for phase sequences in behavior and cognition. PMID- 24782716 TI - A single GABAergic neuron mediates feedback of odor-evoked signals in the mushroom body of larval Drosophila. AB - Inhibition has a central role in defining the selectivity of the responses of higher order neurons to sensory stimuli. However, the circuit mechanisms of regulation of these responses by inhibitory neurons are still unclear. In Drosophila, the mushroom bodies (MBs) are necessary for olfactory memory, and by implication for the selectivity of learned responses to specific odors. To understand the circuitry of inhibition in the calyx (the input dendritic region) of the MBs, and its relationship with MB excitatory activity, we used the simple anatomy of the Drosophila larval olfactory system to identify any inhibitory inputs that could contribute to the selectivity of MB odor responses. We found that a single neuron accounts for all detectable GABA innervation in the calyx of the MBs, and that this neuron has pre-synaptic terminals in the calyx and post synaptic branches in the MB lobes (output axonal area). We call this neuron the larval anterior paired lateral (APL) neuron, because of its similarity to the previously described adult APL neuron. Reconstitution of GFP partners (GRASP) suggests that the larval APL makes extensive contacts with the MB intrinsic neurons, Kenyon Cells (KCs), but few contacts with incoming projection neurons (PNs). Using calcium imaging of neuronal activity in live larvae, we show that the larval APL responds to odors, in a manner that requires output from KCs. Our data suggest that the larval APL is the sole GABAergic neuron that innervates the MB input region and carries inhibitory feedback from the MB output region, consistent with a role in modulating the olfactory selectivity of MB neurons. PMID- 24782717 TI - Striatal dopamine ramping may indicate flexible reinforcement learning with forgetting in the cortico-basal ganglia circuits. AB - It has been suggested that the midbrain dopamine (DA) neurons, receiving inputs from the cortico-basal ganglia (CBG) circuits and the brainstem, compute reward prediction error (RPE), the difference between reward obtained or expected to be obtained and reward that had been expected to be obtained. These reward expectations are suggested to be stored in the CBG synapses and updated according to RPE through synaptic plasticity, which is induced by released DA. These together constitute the "DA=RPE" hypothesis, which describes the mutual interaction between DA and the CBG circuits and serves as the primary working hypothesis in studying reward learning and value-based decision-making. However, recent work has revealed a new type of DA signal that appears not to represent RPE. Specifically, it has been found in a reward-associated maze task that striatal DA concentration primarily shows a gradual increase toward the goal. We explored whether such ramping DA could be explained by extending the "DA=RPE" hypothesis by taking into account biological properties of the CBG circuits. In particular, we examined effects of possible time-dependent decay of DA-dependent plastic changes of synaptic strengths by incorporating decay of learned values into the RPE-based reinforcement learning model and simulating reward learning tasks. We then found that incorporation of such a decay dramatically changes the model's behavior, causing gradual ramping of RPE. Moreover, we further incorporated magnitude-dependence of the rate of decay, which could potentially be in accord with some past observations, and found that near-sigmoidal ramping of RPE, resembling the observed DA ramping, could then occur. Given that synaptic decay can be useful for flexibly reversing and updating the learned reward associations, especially in case the baseline DA is low and encoding of negative RPE by DA is limited, the observed DA ramping would be indicative of the operation of such flexible reward learning. PMID- 24782714 TI - The role of prefrontal catecholamines in attention and working memory. AB - While much progress has been made in identifying the brain regions and neurochemical systems involved in the cognitive processes disrupted in mental illnesses, to date, the level of detail at which neurobiologists can describe the chain of events giving rise to cognitive functions is very rudimentary. Much of the intense interest in understanding cognitive functions is motivated by the hope that it might be possible to understand these complex functions at the level of neurons and neural circuits. Here, we review the current state of the literature regarding how modulations in catecholamine levels within the prefrontal cortex (PFC) alter the neuronal and behavioral correlates of cognitive functions, particularly attention and working memory. PMID- 24782718 TI - A method to investigate radial glia cell behavior using two-photon time-lapse microscopy in an ex vivo model of spinal cord development. AB - The mammalian central nervous system (CNS) develops from multipotent progenitor cells, which proliferate and differentiate into the various cell types of the brain and spinal cord. Despite the wealth of knowledge from progenitor cell culture studies, there is a significant lack of understanding regarding dynamic progenitor cell behavior over the course of development. This is in part due to shortcomings in the techniques available to study these processes in living tissues as they are occurring. In order to investigate cell behavior under physiologically relevant conditions we established an ex vivo model of the developing rat spinal cord. This method allows us to directly observe specific populations of cells ex vivo in real time and over extended developmental periods as they undergo proliferation, migration, and differentiation in the CNS. Previous investigations of progenitor cell behavior have been limited in either spatial or temporal resolution (or both) due to the necessity of preserving tissue viability and avoiding phototoxic effects of fluorescent imaging. The method described here overcomes these obstacles. Using two-photon and confocal microscopy and transfected organotypic spinal cord slice cultures we have undertaken detailed imaging of a unique population of neural progenitors, radial glial cells. This method uniquely enables analysis of large populations as well as individual cells; ultimately resulting in a 4D dataset of progenitor cell behavior for up to 7 days during embryonic development. This approach can be adapted to study a variety of cell populations at different stages of development using appropriate promoter driven fluorescent protein expression. The ability to control the tissue micro-environment makes this ex vivo method a powerful tool to elucidate the underlying molecular mechanisms regulating cell behavior during embryonic development. PMID- 24782719 TI - Greater addition of neurons to the olfactory bulb than to the cerebral cortex of eulipotyphlans but not rodents, afrotherians or primates. AB - The olfactory bulb is an evolutionarily old structure that antedates the appearance of a six-layered mammalian cerebral cortex. As such, the neuronal scaling rules that apply to scaling the mass of the olfactory bulb as a function of its number of neurons might be shared across mammalian groups, as we have found to be the case for the ensemble of non-cortical, non-cerebellar brain structures. Alternatively, the neuronal scaling rules that apply to the olfactory bulb might be distinct in those mammals that rely heavily on olfaction. The group previously referred to as Insectivora includes small mammals, some of which are now placed in Afrotheria, a base group in mammalian radiation, and others in Eulipotyphla, a group derived later, at the base of Laurasiatheria. Here we show that the neuronal scaling rules that apply to building the olfactory bulb differ across eulipotyphlans and other mammals such that eulipotyphlans have more neurons concentrated in an olfactory bulb of similar size than afrotherians, glires and primates. Most strikingly, while the cerebral cortex gains neurons at a faster pace than the olfactory bulb in glires, and afrotherians follow this trend, it is the olfactory bulb that gains neurons at a faster pace than the cerebral cortex in eulipotyphlans, which contradicts the common view that the cerebral cortex is the fastest expanding structure in brain evolution. Our findings emphasize the importance of not using brain structure size as a proxy for numbers of neurons across mammalian orders, and are consistent with the notion that different selective pressures have acted upon the olfactory system of eulipotyphlans, glires and primates, with eulipotyphlans relying more on olfaction for their behavior than glires and primates. Surprisingly, however, the neuronal scaling rules for primates predict that the human olfactory bulb has as many neurons as the larger eulipotyphlan olfactory bulbs, which questions the classification of humans as microsmatic. PMID- 24782721 TI - Effect of biased feedback on motor imagery learning in BCI-teleoperation system. AB - Feedback design is an important issue in motor imagery BCI systems. Regardless, to date it has not been reported how feedback presentation can optimize co adaptation between a human brain and such systems. This paper assesses the effect of realistic visual feedback on users' BCI performance and motor imagery skills. We previously developed a tele-operation system for a pair of humanlike robotic hands and showed that BCI control of such hands along with first-person perspective visual feedback of movements can arouse a sense of embodiment in the operators. In the first stage of this study, we found that the intensity of this ownership illusion was associated with feedback presentation and subjects' performance during BCI motion control. In the second stage, we probed the effect of positive and negative feedback bias on subjects' BCI performance and motor imagery skills. Although the subject specific classifier, which was set up at the beginning of experiment, detected no significant change in the subjects' online performance, evaluation of brain activity patterns revealed that subjects' self regulation of motor imagery features improved due to a positive bias of feedback and a possible occurrence of ownership illusion. Our findings suggest that in general training protocols for BCIs, manipulation of feedback can play an important role in the optimization of subjects' motor imagery skills. PMID- 24782720 TI - Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations. AB - Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e., the multiple-hit hypothesis). However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM) in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal related brain oscillations (mostly in CA1); including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple hit studies of associated neurological disorders. PMID- 24782722 TI - Are videogame training gains specific or general? AB - Many recent studies using healthy adults document enhancements in perception and cognition from playing commercial action videogames (AVGs). Playing action games (e.g., Call of Duty, Medal of Honor) is associated with improved bottom-up lower level information processing skills like visual-perceptual and attentional processes. One proposal states a general improvement in the ability to interpret and gather statistical information to predict future actions which then leads to better performance across different perceptual/attentional tasks. Another proposal claims all the tasks are separately trained in the AVGs because the AVGs and laboratory tasks contain similar demands. We review studies of action and non AVGs to show support for the latter proposal. To explain transfer in AVGs, we argue that the perceptual and attention tasks share common demands with the trained videogames (e.g., multiple object tracking (MOT), rapid attentional switches, and peripheral vision). In non-AVGs, several studies also demonstrate specific, limited transfer. One instance of specific transfer is the specific enhancement to mental rotation after training in games with a spatial emphasis (e.g., Tetris). In contrast, the evidence for transfer is equivocal where the game and task do not share common demands (e.g., executive functioning). Thus, the "common demands" hypothesis of transfer not only characterizes transfer effects in AVGs, but also non-action games. Furthermore, such a theory provides specific predictions, which can help in the selection of games to train human cognition as well as in the design of videogames purposed for human cognitive and perceptual enhancement. Finally this hypothesis is consistent with the cognitive training literature where most post-training gains are for tasks similar to the training rather than general, non-specific improvements. PMID- 24782723 TI - Time for new thinking about sensitive periods. PMID- 24782724 TI - Using virtual reality to augment perception, enhance sensorimotor adaptation, and change our minds. AB - Technological advances that involve human sensorimotor processes can have both intended and unintended effects on the central nervous system (CNS). This mini review focuses on the use of virtual environments (VE) to augment brain functions by enhancing perception, eliciting automatic motor behavior, and inducing sensorimotor adaptation. VE technology is becoming increasingly prevalent in medical rehabilitation, training simulators, gaming, and entertainment. Although these VE applications have often been shown to optimize outcomes, whether it be to speed recovery, reduce training time, or enhance immersion and enjoyment, there are inherent drawbacks to environments that can potentially change sensorimotor calibration. Across numerous VE studies over the years, we have investigated the effects of combining visual and physical motion on perception, motor control, and adaptation. Recent results from our research involving exposure to dynamic passive motion within a visually-depicted VE reveal that short-term exposure to augmented sensorimotor discordance can result in systematic aftereffects that last beyond the exposure period. Whether these adaptations are advantageous or not, remains to be seen. Benefits as well as risks of using VE-driven sensorimotor stimulation to enhance brain processes will be discussed. PMID- 24782725 TI - Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal. AB - Alcohol use disorders are persistent problems with high recidivism rates despite repeated efforts to quit drinking. Neuroadaptations that result from alcohol exposure and that persist during periods of abstinence represent putative molecular determinants of the propensity to relapse. Previously we demonstrated a positive association between phosphodiesterase 10A (PDE10A) gene expression and elevations in relapse-like alcohol self-administration in rats with a history of stress exposure. Because alcohol withdrawal is characterized by heightened anxiety-like behavior, activation of stress-responsive brain regions and an elevated propensity to self-administer alcohol, we hypothesized that Pde10a expression also would be upregulated in reward- and stress-responsive brain regions during periods of acute (8-10 h) and protracted (6 weeks) alcohol withdrawal. During acute withdrawal, elevated Pde10a mRNA expression was found in the medial and basolateral amygdala (BLA), as well as the infralimbic and anterior cingulate subdivisions of the medial prefrontal cortex, relative to alcohol-naive controls. The BLA was the only region with elevated Pde10a mRNA expression during both acute and protracted withdrawal. In contrast to the elevations, Pde10a mRNA levels tended to be reduced during protracted withdrawal in the dorsal striatum, prelimbic prefrontal cortex, and medial amygdala. Together these results implicate heightened PDE10A expression in the BLA as a lasting neuroadaptation associated with alcohol dependence. PMID- 24782726 TI - Does sleep improve memory organization? AB - Sleep can integrate information into existing memory networks, look for common patterns and distil overarching rules, or simply stabilize and strengthen the memory exactly as it was learned. Recent research has shown that sleep facilitates abstraction of gist information as well as integration across multiple memories, insight into hidden solutions, and even the ability to make creative connections between distantly related ideas and concepts. To investigate the effect of sleep on memory organization, 35 normal volunteers were randomly assigned either to the sleep (n = 17) or wake group (n = 18). The sleep subjects performed the Japanese Verbal Learning Test (JVLT), a measure of learning and memory, three times in the evening, and slept. On the following morning (9 h later), they were asked to recall the words on the list. The wake subjects took the same test in the morning, and were asked to recall the words in the same time interval as in the sleep group. The semantic clustering ratio (SCR), divided by the total number of words recalled, was used as an index of memory organization. Our main interest was whether the sleep subjects elicit a greater increase in this measure from the third to the fourth assessments. Time * Group interaction effect on SCR was not significant between the sleep group and wake group as a whole. Meanwhile, the change in the SCR between the third and fourth trials was negatively correlated with duration of nocturnal waking in the sleep group, but not other sleep indices. Based on this observation, further analysis was conducted for subjects in the sleep group who awoke nocturnally for <60 min for comparison with the wake group. A significant Time * Group interaction was noted; these "good-sleepers" showed a significantly greater improvement in the memory index compared with the wake subjects. These results provide the first suggestion that sleep may enhance memory organization, which requires further study. PMID- 24782727 TI - Chronic exposure to a predator or its scent does not inhibit male-male competition in male mice lacking brain serotonin. AB - Although it is well-known that defective signaling of the 5-HT system in the brain and stressful stimuli can cause psychological disorders, their combined effects on male-male aggression and sexual attractiveness remain unknown. Our research aimed at examining such effects using tryptophan hydroxylase 2 (Tph2) knockout male mice vs. a rat- or rat scent-based chronic stress model. Tph2(+/+) and Tph2(-/-) male mice were placed individually into the rat home cage (rat), a cage containing soiled rat bedding (rat scent) or a cage containing fresh bedding (control) for 5 h every other day for 56 consecutive days. In Tph2(+/+) male mice, rat-exposure decreased male-male aggression and sexual attractiveness of urine odor relative to either rat scent-exposure or control; and rat scent exposure decreased aggression rather than sexual attractiveness of urine odor compared with control. However, such dose-dependent and long-lasting behavioral inhibitory effects vanished in Tph2(-/-) male mice. RT-PCR assay further revealed that putative regulatory genes, such as AR, ERalpha and GluR4 in the prefrontal cortex, and TrkB-Tc and 5-HTR1A in the hippocampus, were down-regulated at the mRNA level in either rat- or rat scent-exposed Tph2(+/+) male mice, but partially in the Tph2(-/-) ones. Hence, we suggest that the dose-dependent and long-lasting inhibitory effects of chronic predator exposure on male-male aggression, sexual attractiveness of urine odor, and mRNA expression of central regulatory genes might be mediated through the 5-HT system in the brain of male mice. PMID- 24782728 TI - Repeated exposure to odors induces affective habituation of perception and sniffing. AB - Olfactory perception, and especially hedonic evaluation of odors, is highly flexible, but some mechanisms involved in this flexibility remain to be elucidated. In the present study we aimed at better understanding how repeated exposure to odors can affect their pleasantness. We tested the hypothesis of an affective habituation to the stimuli, namely a decrease of emotional intensity over repetitions. More specifically, we tested whether this effect is subject to inter-individual variability and whether it can also be observed at the olfactomotor level. Twenty-six participants took part in the experiment during which they had to smell two odorants, anise and chocolate, presented 20 times each. On each trial, sniff duration and volume were recorded and paired with ratings of odor pleasantness and intensity. For each smell, we distinguished between "likers" and "dislikers," namely individuals giving positive and negative initial hedonic evaluations. Results showed a significant decrease in pleasantness with time when the odor was initially pleasant ("likers"), while unpleasantness remained stable or slightly decreased when the odor was initially unpleasant ("dislikers"). This deviation toward neutrality was interpreted as affective habituation. This effect was all the more robust as it was observed for both odors and corroborated by sniffing, an objective measurement of odor pleasantness. Affective habituation to odors can be interpreted as an adaptive response to stimuli that prove over time to be devoid of positive or negative outcome on the organism. This study contributes to a better understanding of how olfactory preferences are shaped through exposure, depending on the individual's own initial perception of the odor. PMID- 24782729 TI - Neuropeptide S and BDNF gene expression in the amygdala are influenced by social decision-making under stress. AB - In a newly developed conceptual model of stressful social decision-making, the Stress-Alternatives Model (SAM; used for the 1st time in mice) elicits two types of response: escape or remain submissively. Daily (4d) aggressive social interaction in a neutral arena between a C57BL6/N test mouse and a larger, novel aggressive CD1 mouse, begin after an audible tone (conditioned stimulus; CS). Although escape holes (only large enough for smaller test animals) are available, and the aggressor is unremittingly antagonistic, only half of the mice tested utilize the possibility of escape. During training, for mice that choose to leave the arena and social interaction, latency to escape dramatically decreases over time; this is also true for control C57BL6/N mice which experienced no aggression. Therefore, the open field of the SAM apparatus is intrinsically anxiogenic. It also means that submission to the aggressor is chosen despite this anxiety and the high intensity of the aggressive attacks and defeat. While both groups that received aggression displayed stress responsiveness, corticosterone levels were significantly higher in animals that chose submissive coexistence. Although both escaping and non-escaping groups of animals experienced aggression and defeat, submissive animals also exhibited classic fear conditioning, freezing in response to the CS alone, while escaping animals did not. In the basolateral amygdala (BLA), gene expression of brain-derived neurotrophic factor (BDNF) was diminished, at the same time neuropeptide S (NPS) expression was significantly elevated, but only in submissive animals. This increase in submission-evoked NPS mRNA expression was greatest in the central amygdala (CeA), which coincided with decreased BDNF expression. Reduced expression of BDNF was only found in submissive animals that also exhibit elevated NPS expression, despite elevated corticosterone in all socially interacting animals. The results suggest an interwoven relationship, linked by social context, between amygdalar BDNF, NPS and plasma corticosterone. PMID- 24782730 TI - Spatial reversal learning in chronically sensitized rats and in undrugged sensitized rats with dopamine d2-like receptor agonist quinpirole. AB - Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP) induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive compulsive disorder (OCD). Some of these symptoms persist even after QNP discontinuation. In QNP-sensitization, perseverative behavior has often been implicated. To test the effect of QNP-sensitization on reversal learning and its association with perseveration we selected an aversively motivated hippocampus dependent task, active place avoidance on a Carousel. Performance was measured as the number of entrances into a to-be-avoided sector (errors). We tested separately QNP-sensitized rats in QNP-drugged and QNP-undrugged state in acquisition and reversal tasks on the Carousel. In acquisition learning there were no significant differences between groups and their respective controls. In reversal, QNP-sensitized drugged rats showed a robust but transient increase in number of errors compared to controls. QNP-sensitized rats in an undrugged state were not overtly different from the control animals but displayed an altered learning manifested by more errors at the beginning compensated by quicker learning in the second session compared to control animals. Importantly, performance was not associated with perseveration in neither QNP-sensitized drugged nor QNP-sensitized undrugged animals. The present results show that chronic QNP treatment induces robust reversal learning deficit only when the substance is continuously administered, and suggest that QNP animal model of OCD is also feasible model of cognitive alterations in this disorder. PMID- 24782731 TI - Diminished n1 auditory evoked potentials to oddball stimuli in misophonia patients. AB - Misophonia (hatred of sound) is a newly defined psychiatric condition in which ordinary human sounds, such as breathing and eating, trigger impulsive aggression. In the current study, we investigated if a dysfunction in the brain's early auditory processing system could be present in misophonia. We screened 20 patients with misophonia with the diagnostic criteria for misophonia, and 14 matched healthy controls without misophonia, and investigated any potential deficits in auditory processing of misophonia patients using auditory event related potentials (ERPs) during an oddball task. Subjects watched a neutral silent movie while being presented a regular frequency of beep sounds in which oddball tones of 250 and 4000 Hz were randomly embedded in a stream of repeated 1000 Hz standard tones. We examined the P1, N1, and P2 components locked to the onset of the tones. For misophonia patients, the N1 peak evoked by the oddball tones had smaller mean peak amplitude than the control group. However, no significant differences were found in P1 and P2 components evoked by the oddball tones. There were no significant differences between the misophonia patients and their controls in any of the ERP components to the standard tones. The diminished N1 component to oddball tones in misophonia patients suggests an underlying neurobiological deficit in misophonia patients. This reduction might reflect a basic impairment in auditory processing in misophonia patients. PMID- 24782732 TI - A robust and reliable non-invasive test for stress responsivity in mice. AB - Stress and an altered stress response have been associated with many multifactorial diseases, such as psychiatric disorders or neurodegenerative diseases. As currently mouse mutants for each single gene are generated and phenotyped in a large-scale manner, it seems advisable also to test these mutants for alterations in their stress responses. Here we present the determinants of a robust and reliable non-invasive test for stress-responsivity in mice. Stress is applied through restraining the mice in tubes and recording behavior in the Open Field 20 min after cessation of the stress. Two hours, but not 15 or 50 min of restraint lead to a robust and reproducible increase in distance traveled and number of rearings during the first 5 min in the Open Field in C57BL/6 mice. This behavioral response is blocked by the corticosterone synthesis inhibitor metyrapone, but not by RU486 treatment, indicating that it depends on corticosteroid secretion, but is not mediated via the glucocorticoid receptor type II. We assumed that with a stress duration of 15 min one could detect hyper responsivity, and with a stress duration of 2 h hypo-responsivity in mutant mouse lines. This was validated with two mutant lines known to show opposing effects on corticosterone secretion after stress exposure, corticotropin-releasing hormone (CRH) over-expressing mice and CRH receptor 1 knockout (KO) mice. Both lines showed the expected phenotype, i.e., increased stress responsivity in the CRH over-expressing mouse line (after 15 min restraint stress) and decreased stress responsivity in the CRHR1-KO mouse line (after 2 h of restraint stress). It is possible to repeat the acute stress test several times without the stressed animal adapting to it, and the behavioral response can be robustly evoked at different ages, in both sexes and in different mouse strains. Thus, locomotor and rearing behavior in the Open Field after an acute stress challenge can be used as reliable, non-invasive indicators of stress responsivity and corticosterone secretion in mice. PMID- 24782733 TI - Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits. AB - Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males. PMID- 24782734 TI - Neural decoding of expressive human movement from scalp electroencephalography (EEG). AB - Although efforts to characterize human movement through electroencephalography (EEG) have revealed neural activities unique to limb control that can be used to infer movement kinematics, it is still unknown the extent to which EEG can be used to discern the expressive qualities that influence such movements. In this study we used EEG and inertial sensors to record brain activity and movement of five skilled and certified Laban Movement Analysis (LMA) dancers. Each dancer performed whole body movements of three Action types: movements devoid of expressive qualities ("Neutral"), non-expressive movements while thinking about specific expressive qualities ("Think"), and enacted expressive movements ("Do"). The expressive movement qualities that were used in the "Think" and "Do" actions consisted of a sequence of eight Laban Effort qualities as defined by LMA-a notation system and language for describing, visualizing, interpreting and documenting all varieties of human movement. We used delta band (0.2-4 Hz) EEG as input to a machine learning algorithm that computed locality-preserving Fisher's discriminant analysis (LFDA) for dimensionality reduction followed by Gaussian mixture models (GMMs) to decode the type of Action. We also trained our LFDA-GMM models to classify all the possible combinations of Action Type and Laban Effort quality (giving a total of 17 classes). Classification accuracy rates were 59.4 +/- 0.6% for Action Type and 88.2 +/- 0.7% for Laban Effort quality Type. Ancillary analyses of the potential relations between the EEG and movement kinematics of the dancer's body, indicated that motion-related artifacts did not significantly influence our classification results. In summary, this research demonstrates that EEG has valuable information about the expressive qualities of movement. These results may have applications for advancing the understanding of the neural basis of expressive movements and for the development of neuroprosthetics to restore movements. PMID- 24782735 TI - Neural responses to emotional expression information in high- and low-spatial frequency in autism: evidence for a cortical dysfunction. AB - Despite an overall consensus that Autism Spectrum Disorder (ASD) entails atypical processing of human faces and emotional expressions, the role of neural structures involved in early facial processing remains unresolved. An influential model for the neurotypical brain suggests that face processing in the fusiform gyrus and the amygdala is based on both high-spatial frequency (HSF) information carried by a parvocellular pathway, and low-spatial frequency (LSF) information separately conveyed by a magnocellular pathway. Here, we tested the fusiform gyrus and amygdala sensitivity to emotional face information conveyed by these distinct pathways in ASD individuals (and matched Controls). During functional Magnetical Resonance Imaging (fMRI), participants reported the apparent gender of hybrid face stimuli, made by merging two different faces (one in LSF and the other in HSF), out of which one displayed an emotional expression (fearful or happy) and the other was neutral. Controls exhibited increased fusiform activity to hybrid faces with an emotional expression (relative to hybrids composed only with neutral faces), regardless of whether this was conveyed by LSFs or HSFs in hybrid stimuli. ASD individuals showed intact fusiform response to LSF, but not HSF, expressions. Furthermore, the amygdala (and the ventral occipital cortex) was more sensitive to HSF than LSF expressions in Controls, but exhibited an opposite preference in ASD. Our data suggest spared LSF face processing in ASD, while cortical analysis of HSF expression cues appears affected. These findings converge with recent accounts suggesting that ASD might be characterized by a difficulty in integrating multiple local information and cause global processing troubles unexplained by losses in low spatial frequency inputs. PMID- 24782737 TI - A comparison of geometric- and regression-based mobile gaze-tracking. AB - Video-based gaze-tracking systems are typically restricted in terms of their effective tracking space. This constraint limits the use of eyetrackers in studying mobile human behavior. Here, we compare two possible approaches for estimating the gaze of participants who are free to walk in a large space whilst looking at different regions of a large display. Geometrically, we linearly combined eye-in-head rotations and head-in-world coordinates to derive a gaze vector and its intersection with a planar display, by relying on the use of a head-mounted eyetracker and body-motion tracker. Alternatively, we employed Gaussian process regression to estimate the gaze intersection directly from the input data itself. Our evaluation of both methods indicates that a regression approach can deliver comparable results to a geometric approach. The regression approach is favored, given that it has the potential for further optimization, provides confidence bounds for its gaze estimates and offers greater flexibility in its implementation. Open-source software for the methods reported here is also provided for user implementation. PMID- 24782736 TI - Distinct developmental growth patterns account for the disproportionate expansion of the rostral and caudal isocortex in evolution. AB - In adulthood, the isocortex of several species is characterized by a gradient in neurons per unit of cortical surface area with fewer neurons per unit of cortical surface area in the rostral pole relative to the caudal pole. A gradient in neurogenesis timing predicts differences in neurons across the isocortex: neurons per unit of cortical surface area are fewer rostrally, where neurogenesis duration is short, and higher caudally where neurogenesis duration is longer. How species differences in neurogenesis duration impact cortical progenitor cells across its axis is not known. I estimated progenitor cells per unit of ventricular area across the rostro-caudal axis of the isocortex in cats (Felis catus) and in dogs (Canis familiaris) mostly before layers VI-II neurons are generated. I also estimated the ventricular length across the rostro-caudal axis at various stages of development in both species. These two species were chosen because neurogenesis duration in dogs is extended compared with cats. Caudally, cortical progenitors expand more tangentially and in numbers in dogs compared with cats. Rostrally, the cortical proliferative zone expands more tangentially in dogs compared with cats. However, the tangential expansion in the rostral cortical proliferative zone occurs without a concomitant increase in progenitor cell numbers. The tangential expansion of the ventricular surface in the rostral cortex is mediated by a reduction in cell density. These different developmental growth patterns account for the disproportionate expansion of the rostral (i.e., frontal cortex) and caudal cortex (e.g., primary visual cortex) when neurogenesis duration lengthens in evolution. PMID- 24782738 TI - Movement-based embodied contemplative practices: definitions and paradigms. AB - Over the past decades, cognitive neuroscience has witnessed a shift from predominantly disembodied and computational views of the mind, to more embodied and situated views of the mind. These postulate that mental functions cannot be fully understood without reference to the physical body and the environment in which they are experienced. Within the field of contemplative science, the directing of attention to bodily sensations has so far mainly been studied in the context of seated meditation and mindfulness practices. However, the cultivation of interoceptive, proprioceptive and kinesthetic awareness is also said to lie at the core of many movement-based contemplative practices such as Yoga, Qigong, and Tai Chi. In addition, it likely plays a key role in the efficacy of modern somatic therapeutic techniques such as the Feldenkrais Method and the Alexander Technique. In the current paper we examine how these practices are grounded in the concepts of embodiment, movement and contemplation, as we look at them primarily through the lens of an enactive approach to cognition. Throughout, we point to a series of challenges that arise when Western scientists study practices that are based on a non-dualistic view of mind and body. PMID- 24782739 TI - How do working-memory-related demand, reasoning ability and aversive reinforcement modulate conflict monitoring? AB - Conflict monitoring is a process of stimulus evaluation and a pre-requisite for subsequent recruitment of cognitive control and behavioral adaptations. This study investigated how experimentally manipulated working-memory-related cognitive demand and aversive reinforcement modulate individual differences of conflict monitoring intensity and behavioral adjustments. Individual differences were assessed by means of an anxiety-related trait dimension (trait-BIS) and by means of reasoning abilities-a core determinant of intelligence. Moreover, we investigated the special role of verbal reasoning ability and figural reasoning ability for the modulation of the conflict monitoring intensity. Ninety participants performed a go/nogo task with four conditions each comprising a combination of low vs. high working-memory-related cognitive demand and low vs. high aversive reinforcement. No effect of aversive reinforcement was observed for the N2 amplitude. The fronto-central nogo N2 amplitude was more pronounced for high demand vs. low demand suggesting that cognitive demand served as an aversive costly event. Higher total reasoning abilities were associated with more intense conflict monitoring and shorter response times with increasing aversive reinforcement (defined as verbal error-feedback vs. monetary loss). Individuals with higher trait-BIS scores demonstrated a more intense conflict monitoring even in conditions with low aversive reinforcement and also a more cautious responding (i.e., response times slowing) with increasing aversive reinforcement indicating a focus on negative feedback prevention. The findings provide evidence for the conflict monitoring theory and suggest that working-memory-related demand overrules the impact of aversive reinforcement on conflict monitoring intensity. Reasoning abilities and anxiety-related traits go along with an intensification of conflict monitoring but differences in the flexibility of behavioral adjustment. PMID- 24782740 TI - Proprioception in the cerebellum. PMID- 24782741 TI - ERPLAB: an open-source toolbox for the analysis of event-related potentials. AB - ERPLAB toolbox is a freely available, open-source toolbox for processing and analyzing event-related potential (ERP) data in the MATLAB environment. ERPLAB is closely integrated with EEGLAB, a popular open-source toolbox that provides many EEG preprocessing steps and an excellent user interface design. ERPLAB adds to EEGLAB's EEG processing functions, providing additional tools for filtering, artifact detection, re-referencing, and sorting of events, among others. ERPLAB also provides robust tools for averaging EEG segments together to create averaged ERPs, for creating difference waves and other recombinations of ERP waveforms through algebraic expressions, for filtering and re-referencing the averaged ERPs, for plotting ERP waveforms and scalp maps, and for quantifying several types of amplitudes and latencies. ERPLAB's tools can be accessed either from an easy-to-learn graphical user interface or from MATLAB scripts, and a command history function makes it easy for users with no programming experience to write scripts. Consequently, ERPLAB provides both ease of use and virtually unlimited power and flexibility, making it appropriate for the analysis of both simple and complex ERP experiments. Several forms of documentation are available, including a detailed user's guide, a step-by-step tutorial, a scripting guide, and a set of video-based demonstrations. PMID- 24782742 TI - Creativity-the unconscious foundations of the incubation period. AB - Creativity is one of the most important assets we have to navigate through the fast changing world of the 21st century. Anecdotal accounts of creative individuals suggest that oftentimes, creative discoveries result from a process whereby initial conscious thought is followed by a period during which one refrains from task-related conscious thought. For example, one may spend an embarrassing amount of time thinking about a problem when the solution suddenly pops into consciousness while taking a shower. Not only creative individuals but also traditional theories of creativity have put a lot of emphasis on this incubation stage in creative thinking. The aim of the present article is twofold. First, an overview of the domain of incubation and creativity is provided by reviewing and discussing studies on incubation, mind-wandering, and sleep. Second, the causes of incubation effects are discussed. Previously, little attention has been paid to the causes of incubation effects and most findings do not really speak to whether the effects should be explained by unconscious processes or merely by consequences of a period of distraction. In the latter case, there is no need to assume active unconscious processes. The findings discussed in the current article support the idea that it is not merely the absence of conscious thought that drives incubation effects, but that during an incubation period unconscious processes contribute to creative thinking. Finally, practical implications and directions for future research will be discussed. PMID- 24782743 TI - Association of COMT and COMT-DRD2 interaction with creative potential. AB - Several lines of evidence suggest that genes involved in dopamine (DA) transmission may contribute to creativity. Among these genes, the catechol-O methyltransferase gene (COMT) and the dopamine D2 receptor gene (DRD2) are the most promising candidates. Our previous study has revealed evidence for the involvement of DRD2 in creative potential. The present study extended our previous study by systematically exploring the association of COMT with creative potential as well as the interaction between COMT and DRD2. Twelve single nucleotide polymorphisms (SNPs) covering COMT were genotyped in 543 healthy Chinese college students whose creative potentials were assessed by divergent thinking tests. Single SNP analysis showed that rs174697 was nominally associated with verbal originality, two SNPs (rs737865 and rs5993883) were nominally associated with figural fluency, and two SNPs (rs737865 and rs4680) were nominally associated with figural originality. Haplotype analysis showed that, the TCT and CCT haplotype (rs737865-rs174675-rs5993882) were nominally associated with figural originality, and the TATGCAG and CGCGGGA haplotype (rs4646312-rs6269 rs4633-rs6267-rs4818-rs4680-rs769224) were nominally associated with figural originality and verbal flexibility, respectively. However, none of these nominal findings survived correction for multiple testing. Gene-gene interaction analysis identified one significant four-way interaction of rs174675 (COMT), rs174697 (COMT), rs1076560 (DRD2), and rs4436578 (DRD2) on verbal fluency, one significant four-way interaction of rs174675 (COMT), rs4818 (COMT), rs1076560 (DRD2), and rs4648317 (DRD2) on verbal flexibility, and one significant three-way interaction of rs5993883 (COMT), rs4648319 (DRD2), and rs4648317 (DRD2) on figural flexibility. In conclusion, the present study provides nominal evidence for the involvement of COMT in creative potential and suggests that DA related genes may act in coordination to contribute to creativity. PMID- 24782744 TI - Spaced cognitive training promotes training transfer. AB - Cognitive training studies yield wildly inconsistent results. One dimension on which studies vary is the scheduling of training sessions (Morrison and Chein, 2011). In this study, we systematically address whether or not spacing of practice influences training and transfer. We randomly assigned 115 fifth grade children to an active control group or one of four training groups who received working memory training based on a "running span" task (Zhao et al., 2011). All groups received the same total amount of training: 20 sessions of training with 60 trials for an average of 20 min per session. The training was spread across 2, 5, 10, or 20 days. The active control group received 20-min sessions of math instruction for 20 sessions. Before and after training participants in all five groups performed a single transfer test that assessed fluid intelligence, the Raven's Progressive Matrices Test. Overall, participants in all four training groups improved significantly on the training task (at least partially), as reflected by increased speed. More importantly, the only training group to show significant improvement on the Raven's was the group who had the greatest amount of spacing (20 days group) during training and improvement in this group was significantly higher than that of the control group. PMID- 24782745 TI - Harnessing the neuroplastic potential of the human brain & the future of cognitive rehabilitation. PMID- 24782746 TI - Indestructible plastic: the neuroscience of the new aging brain. AB - In recent years, research on experience-dependent plasticity has provided valuable insight on adaptation to environmental input across the lifespan, and advances in understanding the minute cellular changes underlying the brain's capacity for self-reorganization have opened exciting new possibilities for treating illness and injury. Ongoing work in this line of inquiry has also come to deeply influence another field: cognitive neuroscience of the normal aging. This complex process, once considered inevitable or beyond the reach of treatment, has been transformed into an arena of intense investigation and strategic intervention. However, important questions remain about this characterization of the aging brain, and the assumptions it makes about the social, cultural, and biological space occupied by cognition in the older individual and body. The following paper will provide a critical examination of the move from basic experiments on the neurophysiology of experience-dependent plasticity to the growing market for (and public conception of) cognitive aging as a medicalized space for intervention by neuroscience-backed technologies. Entangled with changing concepts of normality, pathology, and self-preservation, we will argue that this new understanding, led by personalized cognitive training strategies, is approaching a point where interdisciplinary research is crucial to provide a holistic and nuanced understanding of the aging process. This new outlook will allow us to move forward in a space where our knowledge, like our new conception of the brain, is never static. PMID- 24782747 TI - Introduction to the research topic novel insights in rehabilitation of neglect. PMID- 24782748 TI - Artificial neural networks: powerful tools for modeling chaotic behavior in the nervous system. PMID- 24782749 TI - Energy demands of diverse spiking cells from the neocortex, hippocampus, and thalamus. AB - It has long been known that neurons in the brain are not physiologically homogeneous. In response to current stimulus, they can fire several distinct patterns of action potentials that are associated with different physiological classes ranging from regular-spiking cells, fast-spiking cells, intrinsically bursting cells, and low-threshold cells. In this work we show that the high degree of variability in firing characteristics of action potentials among these cells is accompanied with a significant variability in the energy demands required to restore the concentration gradients after an action potential. The values of the metabolic energy were calculated for a wide range of cell temperatures and stimulus intensities following two different approaches. The first one is based on the amount of Na(+) load crossing the membrane during a single action potential, while the second one focuses on the electrochemical energy functions deduced from the dynamics of the computational neuron models. The results show that the thalamocortical relay neuron is the most energy efficient cell consuming between 7 and 18 nJ/cm(2) for each spike generated, while both the regular and fast spiking cells from somatosensory cortex and the intrinsically-bursting cell from a cat visual cortex are the least energy efficient, and can consume up to 100 nJ/cm(2) per spike. The lowest values of these energy demands were achieved at higher temperatures and high external stimuli. PMID- 24782750 TI - Quantized response times are a signature of a neuronal bottleneck in decision. AB - The histograms of response times of optimal YES/NO decisions that are computed from a single sensory Poisson neuron are highly structured. In particular, response times in NO decisions are quantized to a small set of times, while response times in YES decisions have a multimodal structure. Both the times of NO decisions, as well as the modes of the the histogram of YES decisions, are associated to the number of action potentials that were necessary to reach the decision. Their value is a function of the firing rate of the neuron in response to the states of the stimulus. PMID- 24782751 TI - How to evaluate an agent's behavior to infrequent events?-Reliable performance estimation insensitive to class distribution. AB - In everyday life, humans and animals often have to base decisions on infrequent relevant stimuli with respect to frequent irrelevant ones. When research in neuroscience mimics this situation, the effect of this imbalance in stimulus classes on performance evaluation has to be considered. This is most obvious for the often used overall accuracy, because the proportion of correct responses is governed by the more frequent class. This imbalance problem has been widely debated across disciplines and out of the discussed treatments this review focusses on performance estimation. For this, a more universal view is taken: an agent performing a classification task. Commonly used performance measures are characterized when used with imbalanced classes. Metrics like Accuracy, F Measure, Matthews Correlation Coefficient, and Mutual Information are affected by imbalance, while other metrics do not have this drawback, like AUC, d-prime, Balanced Accuracy, Weighted Accuracy and G-Mean. It is pointed out that one is not restricted to this group of metrics, but the sensitivity to the class ratio has to be kept in mind for a proper choice. Selecting an appropriate metric is critical to avoid drawing misled conclusions. PMID- 24782752 TI - Routing in the brain. PMID- 24782753 TI - Machine learning patterns for neuroimaging-genetic studies in the cloud. AB - Brain imaging is a natural intermediate phenotype to understand the link between genetic information and behavior or brain pathologies risk factors. Massive efforts have been made in the last few years to acquire high-dimensional neuroimaging and genetic data on large cohorts of subjects. The statistical analysis of such data is carried out with increasingly sophisticated techniques and represents a great computational challenge. Fortunately, increasing computational power in distributed architectures can be harnessed, if new neuroinformatics infrastructures are designed and training to use these new tools is provided. Combining a MapReduce framework (TomusBLOB) with machine learning algorithms (Scikit-learn library), we design a scalable analysis tool that can deal with non-parametric statistics on high-dimensional data. End-users describe the statistical procedure to perform and can then test the model on their own computers before running the very same code in the cloud at a larger scale. We illustrate the potential of our approach on real data with an experiment showing how the functional signal in subcortical brain regions can be significantly fit with genome-wide genotypes. This experiment demonstrates the scalability and the reliability of our framework in the cloud with a 2 weeks deployment on hundreds of virtual machines. PMID- 24782754 TI - Python-based geometry preparation and simulation visualization toolkits for STEPS. AB - STEPS is a stochastic reaction-diffusion simulation engine that implements a spatial extension of Gillespie's Stochastic Simulation Algorithm (SSA) in complex tetrahedral geometries. An extensive Python-based interface is provided to STEPS so that it can interact with the large number of scientific packages in Python. However, a gap existed between the interfaces of these packages and the STEPS user interface, where supporting toolkits could reduce the amount of scripting required for research projects. This paper introduces two new supporting toolkits that support geometry preparation and visualization for STEPS simulations. PMID- 24782755 TI - How much time has passed? Ask your heart. AB - Internal signals like one's heartbeats are centrally processed via specific pathways and both their neural representations as well as their conscious perception (interoception) provide key information for many cognitive processes. Recent empirical findings propose that neural processes in the insular cortex, which are related to bodily signals, might constitute a neurophysiological mechanism for the encoding of duration. Nevertheless, the exact nature of such a proposed relationship remains unclear. We aimed to address this question by searching for the effects of cardiac rhythm on time perception by the use of a duration reproduction paradigm. Time intervals used were of 0.5, 2, 3, 7, 10, 14, 25, and 40 s length. In a framework of synchronization hypothesis, measures of phase locking between the cardiac cycle and start/stop signals of the reproduction task were calculated to quantify this relationship. The main result is that marginally significant synchronization indices (SIs) between the heart cycle and the time reproduction responses for the time intervals of 2, 3, 10, 14, and 25 s length were obtained, while results were not significant for durations of 0.5, 7, and 40 s length. On the single participant level, several subjects exhibited some synchrony between the heart cycle and the time reproduction responses, most pronounced for the time interval of 25 s (8 out of 23 participants for 20% quantile). Better time reproduction accuracy was not related with larger degree of phase locking, but with greater vagal control of the heart. A higher interoceptive sensitivity (IS) was associated with a higher synchronization index (SI) for the 2 s time interval only. We conclude that information obtained from the cardiac cycle is relevant for the encoding and reproduction of time in the time span of 2-25 s. Sympathovagal tone as well as interoceptive processes mediate the accuracy of time estimation. PMID- 24782756 TI - A new dynamic tactile display for reconfigurable braille: implementation and tests. AB - Different tactile interfaces have been proposed to represent either text (braille) or, in a few cases, tactile large-area screens as replacements for visual displays. None of the implementations so far can be customized to match users' preferences, perceptual differences and skills. Optimal choices in these respects are still debated; we approach a solution by designing a flexible device allowing the user to choose key parameters of tactile transduction. We present here a new dynamic tactile display, a 8 * 8 matrix of plastic pins based on well established and reliable piezoelectric technology to offer high resolution (pin gap 0.7mm) as well as tunable strength of the pins displacement, and refresh rate up to 50s(-1). It can reproduce arbitrary patterns, allowing it to serve the dual purpose of providing, depending on contingent user needs, tactile rendering of non-character information, and reconfigurable braille rendering. Given the relevance of the latter functionality for the expected average user, we considered testing braille encoding by volunteers a benchmark of primary importance. Tests were performed to assess the acceptance and usability with minimal training, and to check whether the offered flexibility was indeed perceived by the subject as an added value compared to conventional braille devices. Different mappings between braille dots and actual tactile pins were implemented to match user needs. Performances of eight experienced braille readers were defined as the fraction of correct identifications of rendered content. Different information contents were tested (median performance on random strings, words, sentences identification was about 75%, 85%, 98%, respectively, with a significant increase, p < 0.01), obtaining statistically significant improvements in performance during the tests (p < 0.05). Experimental results, together with qualitative ratings provided by the subjects, show a good acceptance and the effectiveness of the proposed solution. PMID- 24782757 TI - Bio-inspired hybrid microelectrodes: a hybrid solution to improve long-term performance of chronic intracortical implants. AB - The use of implants that allow chronic electrical stimulation and recording in the brain of human patients is currently limited by a series of events that cause the deterioration over time of both the electrode surface and the surrounding tissue. The main reason of failure is the tissue inflammatory reaction that eventually causes neuronal loss and glial encapsulation, resulting in a progressive increase of the electrode-electrolyte impedance. Here, we describe a new method to create bio-inspired electrodes to mimic the mechanical properties and biological composition of the host tissue. This combination has a great potential to increase the implant lifetime by reducing tissue reaction and improving electrical coupling. Our method implies coating the electrode with reprogrammed neural or glial cells encapsulated within a hydrogel layer. We chose fibrin as a hydrogel and primary hippocampal neurons or astrocytes from rat brain as cellular layer. We demonstrate that fibrin coating is highly biocompatible, forms uniform coatings of controllable thickness, does not alter the electrochemical properties of the microelectrode and allows good quality recordings. Moreover, it reduces the amount of host reactive astrocytes - over time - compared to a bare wire and is fully reabsorbed by the surrounding tissue within 7 days after implantation, avoiding the common problem of hydrogels swelling. Both astrocytes and neurons could be successfully grown onto the electrode surface within the fibrin hydrogel without altering the electrochemical properties of the microelectrode. This bio-hybrid device has therefore a good potential to improve the electrical integration at the neuron-electrode interface and support the long-term success of neural prostheses. PMID- 24782758 TI - Synaptic and nonsynaptic plasticity approximating probabilistic inference. AB - Learning and memory operations in neural circuits are believed to involve molecular cascades of synaptic and nonsynaptic changes that lead to a diverse repertoire of dynamical phenomena at higher levels of processing. Hebbian and homeostatic plasticity, neuromodulation, and intrinsic excitability all conspire to form and maintain memories. But it is still unclear how these seemingly redundant mechanisms could jointly orchestrate learning in a more unified system. To this end, a Hebbian learning rule for spiking neurons inspired by Bayesian statistics is proposed. In this model, synaptic weights and intrinsic currents are adapted on-line upon arrival of single spikes, which initiate a cascade of temporally interacting memory traces that locally estimate probabilities associated with relative neuronal activation levels. Trace dynamics enable synaptic learning to readily demonstrate a spike-timing dependence, stably return to a set-point over long time scales, and remain competitive despite this stability. Beyond unsupervised learning, linking the traces with an external plasticity-modulating signal enables spike-based reinforcement learning. At the postsynaptic neuron, the traces are represented by an activity-dependent ion channel that is shown to regulate the input received by a postsynaptic cell and generate intrinsic graded persistent firing levels. We show how spike-based Hebbian-Bayesian learning can be performed in a simulated inference task using integrate-and-fire (IAF) neurons that are Poisson-firing and background-driven, similar to the preferred regime of cortical neurons. Our results support the view that neurons can represent information in the form of probability distributions, and that probabilistic inference could be a functional by-product of coupled synaptic and nonsynaptic mechanisms operating over several timescales. The model provides a biophysical realization of Bayesian computation by reconciling several observed neural phenomena whose functional effects are only partially understood in concert. PMID- 24782759 TI - Aluminum and its potential contribution to Alzheimer's disease (AD). PMID- 24782760 TI - Blockade of muscarinic receptors impairs the retrieval of well-trained memory. AB - Acetylcholine (ACh) is known to play an important role in memory functions, and its deficit has been proposed to cause the cognitive decline associated with advanced age and Alzheimer's disease (the cholinergic hypothesis). Although many studies have tested the cholinergic hypothesis for recently acquired memory, only a few have investigated the role of ACh in the retrieval process of well-trained cognitive memory, which describes the memory established from repetition and daily routine. To examine this point, we trained rats to perform a two alternative forced-choice visual detection task. Each trial was started by having the rats pull upward a central-lever, which triggered the presentation of a visual stimulus to the right or left side of the display monitor, and then pulling upward a stimulus-relevant choice-lever located on both sides. Rats learned the task within 10 days, and the task training was continued for a month. Task performance was measured with or without systemic administration of a muscarinic ACh receptor (mAChR) antagonist, scopolamine (SCOP), prior to the test. After 30 min of SCOP administration, rats stopped manipulating any lever even though they explored the lever and surrounding environment, suggesting a loss of the task-related associative memory. Three hours later, rats were recovered to complete the trial, but the rats selected the levers irrespective of the visual stimulus, suggesting they remembered a series of lever-manipulations in association with a reward, but not association between the reward and visual stimulation. Furthermore, an m1-AChR, but not nicotinic AChR antagonist caused a similar deficit in the task execution. SCOP neither interfered with locomotor activity nor drinking behavior, while it influenced anxiety. These results suggest that the activation of mAChRs at basal ACh levels is essential for the recall of well-trained cognitive memory. PMID- 24782762 TI - Routine lumbar puncture for the early diagnosis of Alzheimer's disease. Is it safe? PMID- 24782761 TI - Neuropsychological mechanisms of falls in older adults. AB - Falls, a common cause of injury among older adults, have become increasingly prevalent. As the world's population ages, the increase in-and the prevalence of falls among older people makes this a serious and compelling societal and healthcare issue. Physical weakness is a critical predictor in falling. While considerable research has examined this relationship, comprehensive reviews of neuropsychological predictors of falls have been lacking. In this paper, we examine and discuss current studies of the neuropsychological predictors of falls in older adults, as related to sporting and non-sporting contexts. By integrating the existing evidence, we propose that brain aging is an important precursor of the increased risk of falls in older adults. Brain aging disrupts the neural integrity of motor outputs and reduces neuropsychological abilities. Older adults may shift from unconscious movement control to more conscious or attentive motor control. Increased understanding of the causes of falls will afford opportunities to reduce their incidence, reduce consequent injuries, improve overall well-being and quality of life, and possibly to prolong life. PMID- 24782763 TI - Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases beta-amyloid by enhancing expression of presenilin-2. AB - Helicobacter pylori (H. pylori) infection is related with a high risk of Alzheimer's disease (AD), but the intrinsic link between H. pylori infection and AD development is still missing. In the present study, we explored the effect of H. pylori infection on cognitive function and beta-amyloid production in rats. We found that intraperitoneal injection of H. pylori filtrate induced spatial learning and memory deficit in rats with a simultaneous retarded dendritic spine maturation in hippocampus. Injection of H. pylori filtrate significantly increased Abeta42 both in the hippocampus and cortex, together with an increased level of presenilin-2 (PS-2), one key component of gamma-secretase involved in Abeta production. Incubation of H. pylori filtrate with N2a cells which over express amyloid precursor protein (APP) also resulted in increased PS-2 expression and Abeta42 overproduction. Injection of Escherichia coli (E.coli) filtrate, another common intestinal bacterium, had no effect on cognitive function in rats and Abeta production in rats and cells. These data suggest a specific effect of H. pylori on cognition and Abeta production. We conclude that soluble surface fractions of H. pylori may promote Abeta42 formation by enhancing the activity of gamma-secretase, thus induce cognitive impairment through interrupting the synaptic function. PMID- 24782764 TI - An evaluation of alertness training for older adults. AB - We present an evaluation of a self-administered, biofeedback-aided, alertness training programme called the Alertness: Training for Focused Living (ATFL) Programme, which was developed as part of the Technology Research for Independent Living (TRIL) collaboration. We conducted two studies in order to evaluate the programme. A randomized controlled trial was, first of all, conducted with 40 older adults aged between 60 and 83. A series of five single case studies was then conducted to examine the suitability of the programme for use with people with more severe memory difficulties. In the randomized controlled trial, participants were assigned to the ATFL Programme or to a placebo programme. Aspects of participants' memory, attention and executive functioning were assessed via telephone prior to and following completion of the training programmes and at 1, 3, and 6-month follow-up sessions. Significant improvements in sustained attention and verbal fluency were noted in the ATFL group. The series of single case studies illustrated the importance of tailoring a programme to the needs and abilities of the clients in question. The potential benefits of the ATFL programme in terms of periodically boosting alertness and aiding executive functioning are discussed. PMID- 24782765 TI - Site-specific differences in the association between plantar tactile perception and mobility function in older adults. AB - INTRODUCTION: Impaired somatosensation is common in older adults and contributes to age-related loss of mobility function. However, little is known about whether somatosensation at different sites on the plantar surface of the foot are differentially related to mobility function. Such a finding may have important implications for clinical care of older adults and other at-risk populations, such as for optimizing interventions (e.g., footwear for augmenting somatosensory feedback) and for improving the efficiency of clinical assessment. MATERIALS AND METHODS: Tactile perception was evaluated with a 10 g monofilament at four sites on the plantar surface of each foot: great toe (GT), first metatarsal head (MT1), heel (H) and fifth metatarsal head (MT5). Mobility function was assessed with the Berg Balance Scale and walking speed. RESULTS: Sixty-one older adults participated. Tactile perception was significantly positively associated with Berg Balance Score (adjusted r = 0.30 - 0.75; p = 0.03 - < 0.001), with the strongest association found at the site of the MT1. Only at this site was tactile perception found to be significantly associated with usual walking speed (adjusted r = 0.51; p < 0.001) and maximal walking speed (adjusted r = 0.38, p = 0.004). Clinically mild somatosensory impairment at MT1, but not at other sites, was found to yield substantial deficits in both Berg Balance Score and walking speed. DISCUSSION: The present findings indicate that tactile perception at MT1 is more closely linked to mobility function than is tactile perception at GT, MT5 or H. These findings warrant further research to examine whether interventions (e.g., textured insoles) and assessments that preferentially or exclusively focus on the site of MT1 may be more effective for optimizing clinical care. PMID- 24782766 TI - A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. AB - OBJECTIVE: The clinical relationship between brain-derived neurotrophic factor (BDNF) and cognitive function or mild cognitive impairment (MCI) is not well understood. The purpose of this study was to identify the relationship between serum BDNF and cognitive function and MCI, and determine whether serum BDNF level might be a useful biomarker for assessing risk for MCI in older people. MATERIALS AND METHODS: A total of 4463 individuals aged 65 years or older (mean age 72 years) participating in the study. We measured performance in a battery of neuropsychological and cognitive function tests; serum BDNF concentration. RESULTS: Eight hundred twenty-seven participants (18.8%) had MCI. After adjustment for sex, age, education level, diabetes, and current smoking, serum BDNF was associated with poorer performance in the story memory, and digit symbol substitution task scores. Serum BDNF was marginally associated with the presence of MCI (odds ratio, 95% confidence interval: 1.41, 1.00-1.99) when BDNF was 1.5 SD lower than the mean value standardized for sex and age, education level, diabetes, and current smoking. CONCLUSION: Low serum BDNF was associated with lower cognitive test scores and MCI. Future prospective studies should establish the discriminative value of serum BDNF for the risk of MCI. PMID- 24782767 TI - Vitamin d in older adults: the need to specify standard values with respect to cognition. PMID- 24782768 TI - The effect of transdermal scopolamine for the prevention of postoperative nausea and vomiting. AB - Postoperative nausea and vomiting (PONV) is one of the most common and undesirable complaints recorded in as many as 70-80% of high-risk surgical patients. The current prophylactic therapy recommendations for PONV management stated in the Society of Ambulatory Anesthesia (SAMBA) guidelines should start with monotherapy and patients at moderate to high risk, a combination of antiemetic medication should be considered. Consequently, if rescue medication is required, the antiemetic drug chosen should be from a different therapeutic class and administration mode than the drug used for prophylaxis. The guidelines restrict the use of dexamethasone, transdermal scopolamine, aprepitant, and palonosetron as rescue medication 6 h after surgery. In an effort to find a safer and reliable therapy for PONV, new drugs with antiemetic properties and minimal side effects are needed, and scopolamine may be considered an effective alternative. Scopolamine is a belladonna alkaloid, alpha-(hydroxymethyl) benzene acetic acid 9-methyl-3-oxa-9-azatricyclo non-7-yl ester, acting as a non selective muscarinic antagonist and producing both peripheral antimuscarinic and central sedative, antiemetic, and amnestic effects. The empirical formula is C17H21NO4 and its structural formula is a tertiary amine L-(2)-scopolamine (tropic acid ester with scopine; MW = 303.4). Scopolamine became the first drug commercially available as a transdermal therapeutic system used for extended continuous drug delivery during 72 h. Clinical trials with transdermal scopolamine have consistently demonstrated its safety and efficacy in PONV. Thus, scopolamine is a promising candidate for the management of PONV in adults as a first line monotherapy or in combination with other drugs. In addition, transdermal scopolamine might be helpful in preventing postoperative discharge nausea and vomiting owing to its long-lasting clinical effects. PMID- 24782770 TI - Quantification of serotonin O-sulphate by LC-MS method in plasma of healthy volunteers. AB - The objective of this study was to test the hypothesis that serotonin O-sulphate (5-HT-SO4) could be quantified in human plasma using modern liquid chromatography mass spectrometry (LC-MS) method as well as develop and validate that method. First, a suitable LC-MS method for detection of 5-HT-SO4 in human plasma samples was developed and validated. Second, a Pilot phase involving four healthy volunteers was executed, where a basal plasma level of 5-HT-SO4 was measured for all subjects and for one after the intake of 100 mg of a 5-hydroxytryptophan (5 HTP) -containing food supplement used to promote serotonergic stimulation of the central nervous system. The basal level of 0.9-2.8 ng/mL of 5-HT-SO4 was observed. The changes of plasma 5HT-O-SO4 showed 1.2 ng/mL before and 22.6 ng/mL 1 h after stimulation. Finally, nine healthy volunteers were selected for the Study phase, where a basal plasma level of 5-HT-SO4 was measured before and after the intake of 5-HTP. One hour after stimulation, six study subjects showed a decrease in 5-HT-SO4 levels while three subjects showed an increase. The changes of plasma 5HT-O-SO4 from the Study phase showed an average 5-HT-SO4 level of 19.2 ng/mL before and 15.7 ng/mL 1 h after stimulation indicating ability of method to emphasize quantitative changes. This was the first study in which naturally occurring 5-HT-SO4 was detected in the samples of human plasma obtained from healthy volunteers. The method developed herein is specific to the measurement of 5-HT-SO4, sensitive enough to quantify intra-individual changes in the samples of plasma and opens up new possibilities to evaluate pathways of serotonin metabolism by minimally invasive methods. The discovery of novel biomarkers using such approaches is increasingly required to expedite development of mechanism based therapeutics and patient stratification. PMID- 24782771 TI - Perioperative management of neurosurgical patients receiving chronic anticoagulation therapy. PMID- 24782769 TI - Heme in pathophysiology: a matter of scavenging, metabolism and trafficking across cell membranes. AB - Heme (iron-protoporphyrin IX) is an essential co-factor involved in multiple biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, and micro RNA processing. However, excess free-heme is highly toxic due to its ability to promote oxidative stress and lipid peroxidation, thus leading to membrane injury and, ultimately, apoptosis. Thus, heme metabolism needs to be finely regulated. Intracellular heme amount is controlled at multiple levels: synthesis, utilization by hemoproteins, degradation and both intracellular and intercellular trafficking. This review focuses on recent findings highlighting the importance of controlling intracellular heme levels to counteract heme-induced oxidative stress. The contributions of heme scavenging from the extracellular environment, heme synthesis and incorporation into hemoproteins, heme catabolism and heme transport in maintaining adequate intracellular heme content are discussed. Particular attention is put on the recently described mechanisms of heme trafficking through the plasma membrane mediated by specific heme importers and exporters. Finally, the involvement of genes orchestrating heme metabolism in several pathological conditions is illustrated and new therapeutic approaches aimed at controlling heme metabolism are discussed. PMID- 24782772 TI - Neuronal localization of the 5-HT2 receptor family in the amygdaloid complex. AB - The amygdaloid complex (or amygdala), a heterogeneous structure located in the medial portion of the temporal lobe, is composed of deep, superficial, and "remaining" nuclei. This structure is involved in the generation of emotional behavior, in the formation of emotional memories and in the modulation of the consolidation of explicit memories for emotionally arousing events. The serotoninergic fibers originating in the dorsal and medial raphe nuclei are critically involved in amygdalar functions. Serotonin (5-hydroxytryptamine, 5-HT) regulates amygdalar activity through the activation of the 5-HT2 receptor family, which includes three receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. The distribution and the functional activity of the 5-HT2 receptor family has been studied more extensively than that of the 5-HT2A receptor subtypes, especially in the deep nuclei. In these nuclei, the 5-HT2A receptor is expressed on both pyramidal and non-pyramidal neurons, and could play a critical role in the formation of emotional memories. However, the exact role of the 5-HT2A receptor subtypes, as well as that of the 5-HT2B and 5-HT2C receptor subtypes, in the modulation of the amygdalar microcircuits requires additional study. The present review reports data concerning the distribution and the functional roles of the 5 HT2 receptor family in the amygdala. PMID- 24782773 TI - Activation of adenosine receptor A2A increases HSC proliferation and inhibits death and senescence by down-regulation of p53 and Rb. AB - BACKGROUND AND AIMS: During fibrosis hepatic stellate cells (HSC) undergo activation, proliferation, and senescence but the regulation of these important processes is poorly understood. The adenosine A2A receptor (A2A) is known to be present on HSC, and its activation results in liver fibrosis. In this study, we tested if A2A has a role in the regulation of HSC proliferation, apoptosis, senescence, and the relevant molecular mechanism. METHODS: The ability of adenosine to regulate p53 and Rb protein levels, proliferation, apoptosis and senescence was tested in the human HSC cell line LX-2 and rat primary HSC. RESULTS: Adenosine receptor activation down-regulates p53 and Rb protein levels, increases BrdU incorporation and increases cell survival in LX-2 cells and in primary rat HSC. These effects of NECA were reproduced by an adenosine A2A receptor specific agonist (CGS21680) and blocked by a specific antagonist (ZM241385). By day twenty-one of culture primary rat HSC entered senescence and expressed beta-gal which was significantly inhibited by NECA. Furthermore, NECA induced down regulation of p53 and Rb and Rac1, and decreased phosphorylation of p44-42 MAP Kinase in LX-2 cells and primary rat HSC. These effects were reproduced by the cAMP analog 8-Bromo-cAMP, and the adenylyl cyclase activator forskolin, and were blocked by PKA inhibitors. CONCLUSIONS: These results demonstrate that A2A receptor regulates a number of HSC fate decisions and induces greater HSC proliferation, reduces apoptosis and senescence by decreasing p53 and Rb through cAMP-PKA/Rac1/p38 MAPK pathway. This provides a mechanism for adenosine induced HSC regulation and liver fibrosis. PMID- 24782774 TI - N-acetyl-seryl-aspartyl-lysyl-proline: a valuable endogenous anti-fibrotic peptide for combating kidney fibrosis in diabetes. AB - Fibroproliferative diseases are responsible for 45% of deaths in the developed world. Curing organ fibrosis is essential for fibroproliferative diseases. Diabetic nephropathy is a common fibroproliferative disease of the kidney and is associated with multiorgan dysfunction. However, therapy to combat diabetic nephropathy has not yet been established. In this review, we discuss the novel therapeutic possibilities for kidney fibrosis in diabetes focusing on the endogenous anti-fibrotic peptide, N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is the substrate for angiotensin-converting enzyme and exhibits meaningful anti-fibrotic effects in various experimental models of fibrotic disease. PMID- 24782775 TI - Inhibition of visceral nociceptors. PMID- 24782776 TI - Glutathione synthesis is compromised in erythrocytes from individuals with HIV. AB - We demonstrated that the levels of enzymes responsible for the synthesis of glutathione (GSH) such as glutathione synthase (GSS), glutamate-cysteine ligase catalytic subunit (GCLC), and glutathione reductase (GSR) were significantly reduced in the red blood cells (RBCs) isolated from individuals with human immunodeficiency virus (HIV) infection and this reduction correlated with decreased levels of intracellular GSH. GSH content in RBCs can be used as a marker for increased overall oxidative stress and immune dysfunctions caused by HIV infection. Our data supports our hypothesis that compromised levels of GSH in HIV infected individuals' is due to decreased levels of GSH-synthetic enzymes. The role of GSH in combating oxidative stress and improving the functions of immune cells in HIV patients' indicates the benefit of an antioxidant supplement which can reduce the cellular damage and promote the functions of immune cells. PMID- 24782777 TI - Anesthesia and evoked responses in neurosurgery. PMID- 24782778 TI - A practical approach to aid physician interpretation of clinically actionable predictive biomarker results in a multi-platform tumor profiling service. AB - Patients in whom the standard of care has failed or who have uncommon tumors for which no standard of care exists are often treated with drugs selected based on the physician's best guess. The rate of success for this method is generally low. With the advent of fast, affordable tumor profiling technologies, and a growth in the understanding of predictive biomarkers, it is now possible to identify drugs potentially associated with clinical benefit for such patients. We present the Caris approach to evidence-based tumor profiling and two patients with advanced ovarian and prostate cancer in whom standard of care had failed and tumor profiling identified an effective treatment schedule. To establish Caris Molecular Intelligence(TM) (CMI), over 120,000 clinical publications were screened and graded to characterize the predictive value of biomarkers that form the panel of tests. CMI includes multiple technologies to measure changes in proteins, ribonucleic acid, and deoxyribonucleic acid and proprietary software that matches the test results with the published evidence. The CMI results enable physicians to select drugs that are more likely to benefit the patients, avoid drugs that are not likely to work, and find treatment options that otherwise would not be considered. Worldwide, over 60,000 cancer patients have undergone evidence-based tumor profiling with CMI. In the cases reported in this article, CMI identified treatments that would not have been routinely used in the respective clinical setting. The clinical outcomes observed help to illustrate the utility of this approach. PMID- 24782779 TI - Molecular and cell-based therapies for muscle degenerations: a road under construction. AB - Despite the advances achieved in understanding the molecular biology of muscle cells in the past decades, there is still need for effective treatments of muscular degeneration caused by muscular dystrophies and for counteracting the muscle wasting caused by cachexia or sarcopenia. The corticosteroid medications currently in use for dystrophic patients merely help to control the inflammatory state and only slightly delay the progression of the disease. Unfortunately, walkers and wheel chairs are the only options for such patients to maintain independence and walking capabilities until the respiratory muscles become weak and the mechanical ventilation is needed. On the other hand, myostatin inhibition, IL-6 antagonism and synthetic ghrelin administration are examples of promising treatments in cachexia animal models. In both dystrophies and cachectic syndrome the muscular degeneration is extremely relevant and the translational therapeutic attempts to find a possible cure are well defined. In particular, molecular-based therapies are common options to be explored in order to exploit beneficial treatments for cachexia, while gene/cell therapies are mostly used in the attempt to induce a substantial improvement of the dystrophic muscular phenotype. This review focuses on the description of the use of molecular administrations and gene/stem cell therapy to treat muscular degenerations. It reviews previous trials using cell delivery protocols in mice and patients starting with the use of donor myoblasts, outlining the likely causes for their poor results and briefly focusing on satellite cell studies that raise new hope. Then it proceeds to describe recently identified stem/progenitor cells, including pluripotent stem cells and in relationship to their ability to home within a dystrophic muscle and to differentiate into skeletal muscle cells. Different known features of various stem cells are compared in this perspective, and the few available examples of their use in animal models of muscular degeneration are reported. Since non coding RNAs, including microRNAs (miRNAs), are emerging as prominent players in the regulation of stem cell fates we also provides an outline of the role of microRNAs in the control of myogenic commitment. Finally, based on our current knowledge and the rapid advance in stem cell biology, a prediction of clinical translation for cell therapy protocols combined with molecular treatments is discussed. PMID- 24782780 TI - Social interactions affecting caste development through physiological actions in termites. AB - A colony of social insects is not only an aggregation of individuals but also a functional unit. To achieve adaptive social behavior in fluctuating environmental conditions, in addition to coordination of physiological status in each individual, the whole colony is coordinated by interactions among colony members. The study on the regulation of social-insect colonies is termed "social physiology." Termites, a major group of social insects, exhibit many interesting phenomena related to social physiology, such as mechanisms of caste regulation in a colony. In their colonies, there are different types of individuals, i.e., castes, which show distinctive phenotypes specialized in specific colony tasks. Termite castes comprise reproductives, soldiers and workers, and the caste composition can be altered depending on circumstances. For the regulation of caste compositions, interactions among individuals, i.e., social interactions, are thought to be important. In this article, we review previous studies on the adaptive meanings and those on the proximate mechanisms of the caste regulation in termites, and try to understand those comprehensively in terms of social physiology. Firstly, we summarize classical studies on the social interactions. Secondly, previous studies on the pheromone substances that mediate the caste regulatory mechanisms are overviewed. Then, we discuss the roles of a physiological factor, juvenile hormone (JH) in the regulation of caste differentiation. Finally, we introduce the achievements of molecular studies on the animal sociality (i.e., sociogenomics) in terms of social physiology. By comparing the proximate mechanisms of social physiology in termites with those in hymenopterans, we try to get insights into the general principles of social physiology in social animals. PMID- 24782781 TI - Coding space-time stimulus dynamics in auditory brain maps. AB - Sensory maps are often distorted representations of the environment, where ethologically-important ranges are magnified. The implication of a biased representation extends beyond increased acuity for having more neurons dedicated to a certain range. Because neurons are functionally interconnected, non-uniform representations influence the processing of high-order features that rely on comparison across areas of the map. Among these features are time-dependent changes of the auditory scene generated by moving objects. How sensory representation affects high order processing can be approached in the map of auditory space of the owl's midbrain, where locations in the front are over represented. In this map, neurons are selective not only to location but also to location over time. The tuning to space over time leads to direction selectivity, which is also topographically organized. Across the population, neurons tuned to peripheral space are more selective to sounds moving into the front. The distribution of direction selectivity can be explained by spatial and temporal integration on the non-uniform map of space. Thus, the representation of space can induce biased computation of a second-order stimulus feature. This phenomenon is likely observed in other sensory maps and may be relevant for behavior. PMID- 24782783 TI - From microseconds to seconds and minutes-time computation in insect hearing. AB - The computation of time in the auditory system of insects is of relevance at rather different time scales, covering a large range from microseconds to several minutes. At the one end of this range, only a few microseconds of interaural time differences are available for directional hearing, due to the small distance between the ears, usually considered too small to be processed reliably by simple nervous systems. Synapses of interneurons in the afferent auditory pathway are, however, very sensitive to a time difference of only 1-2 ms provided by the latency shift of afferent activity with changing sound direction. At a much larger time scale of several tens of milliseconds to seconds, time processing is important in the context species recognition, but also for those insects where males produce acoustic signals within choruses, and the temporal relationship between song elements strongly deviates from a random distribution. In these situations, some species exhibit a more or less strict phase relationship of song elements, based on phase response properties of their song oscillator. Here we review evidence on how this may influence mate choice decisions. In the same dimension of some tens of milliseconds we find species of katydids with a duetting communication scheme, where one sex only performs phonotaxis to the other sex if the acoustic response falls within a very short time window after its own call. Such time windows show some features unique to insects, and although its neuronal implementation is unknown so far, the similarity with time processing for target range detection in bat echolocation will be discussed. Finally, the time scale being processed must be extended into the range of many minutes, since some acoustic insects produce singing bouts lasting quite long, and female preferences may be based on total signaling time. PMID- 24782782 TI - Vitamin D and gene networks in human osteoblasts. AB - Bone formation is indirectly influenced by 1,25-dihydroxyvitamin D3 (1,25D3) through the stimulation of calcium uptake in the intestine and re-absorption in the kidneys. Direct effects on osteoblasts and bone formation have also been established. The vitamin D receptor (VDR) is expressed in osteoblasts and 1,25D3 modifies gene expression of various osteoblast differentiation and mineralization related genes, such as alkaline phosphatase (ALPL), osteocalcin (BGLAP), and osteopontin (SPP1). 1,25D3 is known to stimulate mineralization of human osteoblasts in vitro, and recently it was shown that 1,25D3 induces mineralization via effects in the period preceding mineralization during the pre mineralization period. For a full understanding of the action of 1,25D3 in osteoblasts it is important to get an integrated network view of the 1,25D3 regulated genes during osteoblast differentiation and mineralization. The current data will be presented and discussed alluding to future studies to fully delineate the 1,25D3 action in osteoblast. Describing and understanding the vitamin D regulatory networks and identifying the dominant players in these networks may help develop novel (personalized) vitamin D-based treatments. The following topics will be discussed in this overview: (1) Bone metabolism and osteoblasts, (2) Vitamin D, bone metabolism and osteoblast function, (3) Vitamin D induced transcriptional networks in the context of osteoblast differentiation and bone formation. PMID- 24782784 TI - Pannexin 1 channels in skeletal muscles. AB - Normal myotubes and adult innervated skeletal myofibers express the glycoprotein pannexin1 (Panx1). Six of them form a "gap junction hemichannel-like" structure that connects the cytoplasm with the extracellular space; here they will be called Panx1 channels. These are poorly selective channels permeable to ions, small metabolic substrate, and signaling molecules. So far little is known about the role of Panx1 channels in muscles but skeletal muscles of Panx1(-/-) mice do not show an evident phenotype. Innervated adult fast and slow skeletal myofibers show Panx1 reactivity in close proximity to dihydropyridine receptors in the sarcolemma of T-tubules. These Panx1 channels are activated by electrical stimulation and extracellular ATP. Panx1 channels play a relevant role in potentiation of muscle contraction because they allow release of ATP and uptake of glucose, two molecules required for this response. In support of this notion, the absence of Panx1 abrogates the potentiation of muscle contraction elicited by repetitive electrical stimulation, which is reversed by exogenously applied ATP. Phosphorylation of Panx1 Thr and Ser residues might be involved in Panx1 channel activation since it is enhanced during potentiation of muscle contraction. Under denervation, Panx1 levels are upregulated and this partially explains the reduction in electrochemical gradient, however its absence does not prevent denervation-induced atrophy but prevents the higher oxidative state. Panx1 also forms functional channels at the cell surface of myotubes and their functional state has been associated with intracellular Ca(2+) signals and regulation of myotube plasticity evoked by electrical stimulation. We proposed that Panx1 channels participate as ATP channels and help to keep a normal oxidative state in skeletal muscles. PMID- 24782786 TI - Breakpoints in ventilation, cerebral and muscle oxygenation, and muscle activity during an incremental cycling exercise. AB - The aim of this study was to locate the breakpoints of cerebral and muscle oxygenation and muscle electrical activity during a ramp exercise in reference to the first and second ventilatory thresholds. Twenty-five cyclists completed a maximal ramp test on an electromagnetically braked cycle-ergometer with a rate of increment of 25 W/min. Expired gazes (breath-by-breath), prefrontal cortex and vastus lateralis (VL) oxygenation [Near-infrared spectroscopy (NIRS)] together with electromyographic (EMG) Root Mean Square (RMS) activity for the VL, rectus femoris (RF), and biceps femoris (BF) muscles were continuously assessed. There was a non-linear increase in both cerebral deoxyhemoglobin (at 56 +/- 13% of the exercise) and oxyhemoglobin (56 +/- 8% of exercise) concomitantly to the first ventilatory threshold (57 +/- 6% of exercise, p > 0.86, Cohen's d < 0.1). Cerebral deoxyhemoglobin further increased (87 +/- 10% of exercise) while oxyhemoglobin reached a plateau/decreased (86 +/- 8% of exercise) after the second ventilatory threshold (81 +/- 6% of exercise, p < 0.05, d > 0.8). We identified one threshold only for muscle parameters with a non-linear decrease in muscle oxyhemoglobin (78 +/- 9% of exercise), attenuation in muscle deoxyhemoglobin (80 +/- 8% of exercise), and increase in EMG activity of VL (89 +/- 5% of exercise), RF (82 +/- 14% of exercise), and BF (85 +/- 9% of exercise). The thresholds in BF and VL EMG activity occurred after the second ventilatory threshold (p < 0.05, d > 0.6). Our results suggest that the metabolic and ventilatory events characterizing this latter cardiopulmonary threshold may affect both cerebral and muscle oxygenation levels, and in turn, muscle recruitment responses. PMID- 24782787 TI - Second hand smoke and COPD: lessons from animal studies. PMID- 24782785 TI - Role of pancreatic stellate cells in chemoresistance in pancreatic cancer. AB - Pancreatic cancer is highly chemoresistant. A major contributing factor is the characteristic extensive stromal or fibrotic reaction, which comprises up to 90% of the tumor volume. Over the last decade there has been intensive research into the role of the pro-fibrogenic pancreatic stellate cells (PSCs) and their interaction with pancreatic cancer cells. As a result of the significant alterations in the tumor microenvironment following activation of PSCs, tumor progression, and chemoresistance is enhanced. This review will discuss how PSCs contribute to chemoresistance in pancreatic cancer. PMID- 24782788 TI - The role of vitamin D in skeletal and cardiac muscle function. AB - Myopathy is a feature of many inflammatory syndromes. Chronic inflammation has been linked to pathophysiological mechanisms which implicate 1,25 dihydroxyvitamin D3 (1,25-(OH)2D3)-mediated signaling pathways with emerging evidence supporting a role for the vitamin D receptor (VDR) in contractile and metabolic function of both skeletal and cardiac muscle. Altered VDR expression in skeletal and cardiac muscle has been reported to result in significant effects on metabolism, calcium signaling and fibrosis in these tissues. Elevated levels of serum inflammatory cytokines, such as IL-6, TNF-alpha and IFNgamma, have been shown to impact myogenic and nuclear receptor signaling pathways in cancer induced cachexia. The dysregulation of nuclear receptors, such as VDR and RXRalpha in muscle cells, has also been postulated to result in myopathy via their effects on muscle structural integrity and metabolism. Future research directions include generating transcriptome-wide information incorporating VDR and its gene targets and using systems biology approaches to identify altered molecular networks in human tissues such as muscle. These approaches will aid in the development of novel therapeutic targeting strategies for inflammation induced myopathies. PMID- 24782789 TI - Stress, Inflammation, and Cellular Vulnerability during Early Stages of Affective Disorders: Biomarker Strategies and Opportunities for Prevention and Intervention. AB - The mood disorder prodrome is conceptualized as a symptomatic, but not yet clinically diagnosable stage of an affective disorder. Although a growing area, more focused research is needed in the pediatric population to better characterize psychopathological symptoms and biological markers that can reliably identify this very early stage in the evolution of mood disorder pathology. Such information will facilitate early prevention and intervention, which has the potential to affect a person's disease course. This review focuses on the prodromal characteristics, risk factors, and neurobiological mechanisms of mood disorders. In particular, we consider the influence of early-life stress, inflammation, and allostatic load in mediating neural mechanisms of neuroprogression. These inherently modifiable factors have known neuroadaptive and neurodegenerative implications, and consequently may provide useful biomarker targets. Identification of these factors early in the course of the disease will accordingly allow for the introduction of early interventions which augment an individual's capacity for psychological resilience through maintenance of synaptic integrity and cellular resilience. A targeted and complementary approach to boosting both psychological and physiological resilience simultaneously during the prodromal stage of mood disorder pathology has the greatest promise for optimizing the neurodevelopmental potential of those individuals at risk of disabling mood disorders. PMID- 24782790 TI - Do manual and voxel-based morphometry measure the same? A proof of concept study. AB - Voxel-based morphometry (VBM) is a commonly used method to study volumetric variations on a whole brain basis. However, it is often criticized for potential confounds, mainly based on imperfect spatial registration. We therefore aimed to evaluate if VBM and "gold standard" manual volumetry are measuring the same effects with respect to subcortical gray matter volumes. Manual regions-of interest were drawn in the hippocampus, amygdala, nucleus accumbens, thalamus, putamen, pallidum, and caudate nucleus bilaterally. Resulting volumes were used for a whole brain VBM correlation analysis with Statistical Parametric Mapping (SPM8). The hippocampus, amygdala, putamen, and caudate nucleus were correctly identified by SPM using the contemporary high-dimensional normalization (DARTEL toolbox). This strongly suggests that VBM and manual volumetry both are indeed measuring the same effects with regard to subcortical brain structures. PMID- 24782791 TI - Recent developments in maximum likelihood estimation of MTMM models for categorical data. AB - Maximum likelihood (ML) estimation of categorical multitrait-multimethod (MTMM) data is challenging because the likelihood involves high-dimensional integrals over the crossed method and trait factors, with no known closed-form solution. The purpose of the study is to introduce three newly developed ML methods that are eligible for estimating MTMM models with categorical responses: Variational maximization-maximization (e.g., Rijmen and Jeon, 2013), alternating imputation posterior (e.g., Cho and Rabe-Hesketh, 2011), and Monte Carlo local likelihood (e.g., Jeon et al., under revision). Each method is briefly described and its applicability for MTMM models with categorical data are discussed. PMID- 24782793 TI - Do cavies talk? The effect of anthropomorphic picture books on children's knowledge about animals. AB - Many books for young children present animals in fantastical and unrealistic ways, such as wearing clothes, talking and engaging in human-like activities. This research examined whether anthropomorphism in children's books affects children's learning and conceptions of animals, by specifically assessing the impact of depictions (a bird wearing clothes and reading a book) and language (bird described as talking and as having human intentions). In Study 1, 3-, 4-, and 5-year-old children saw picture books featuring realistic drawings of a novel animal. Half of the children also heard factual, realistic language, while the other half heard anthropomorphized language. In Study 2, we replicated the first study using anthropomorphic illustrations of real animals. The results show that the language used to describe animals in books has an effect on children's tendency to attribute human-like traits to animals, and that anthropomorphic storybooks affect younger children's learning of novel facts about animals. These results indicate that anthropomorphized animals in books may not only lead to less learning but also influence children's conceptual knowledge of animals. PMID- 24782792 TI - Attending to global versus local stimulus features modulates neural processing of low versus high spatial frequencies: an analysis with event-related brain potentials. AB - Spatial frequency (SF) selection has long been recognized to play a role in global and local processing, though the nature of the relationship between SF processing and global/local perception is debated. Previous studies have shown that attention to relatively lower SFs facilitates global perception, and that attention to relatively higher SFs facilitates local perception. Here we recorded event-related brain potentials (ERPs) to investigate whether processing of low versus high SFs is modulated automatically during global and local perception, and to examine the time course of any such effects. Participants compared bilaterally presented hierarchical letter stimuli and attended to either the global or local levels. Irrelevant SF grating probes flashed at the center of the display 200 ms after the onset of the hierarchical letter stimuli could either be low or high in SF. It was found that ERPs elicited by the SF grating probes differed as a function of attended level (global versus local). ERPs elicited by low SF grating probes were more positive in the interval 196-236 ms during global than local attention, and this difference was greater over the right occipital scalp. In contrast, ERPs elicited by the high SF gratings were more positive in the interval 250-290 ms during local than global attention, and this difference was bilaterally distributed over the occipital scalp. These results indicate that directing attention to global versus local levels of a hierarchical display facilitates automatic perceptual processing of low versus high SFs, respectively, and this facilitation is not limited to the locations occupied by the hierarchical display. The relatively long latency of these attention-related ERP modulations suggests that initial (early) SF processing is not affected by attention to hierarchical level, lending support to theories positing a higher level mechanism to underlie the relationship between SF processing and global versus local perception. PMID- 24782794 TI - Sorting Test, Tower Test, and BRIEF-SR do not predict school performance of healthy adolescents in preuniversity education. AB - Executive functions (EF) such as self-monitoring, planning, and organizing are known to develop through childhood and adolescence. They are of potential importance for learning and school performance. Earlier research into the relation between EF and school performance did not provide clear results possibly because confounding factors such as educational track, boy-girl differences, and parental education were not taken into account. The present study therefore investigated the relation between executive function tests and school performance in a highly controlled sample of 173 healthy adolescents aged 12-18. Only students in the pre-university educational track were used and the performance of boys was compared to that of girls. Results showed that there was no relation between the report marks obtained and the performance on executive function tests, notably the Sorting Test and the Tower Test of the Delis-Kaplan Executive Functions System (D-KEFS). Likewise, no relation was found between the report marks and the scores on the Behavior Rating Inventory of Executive Function-Self Report Version (BRIEF-SR) after these were controlled for grade, sex, and level of parental education. The findings indicate that executive functioning as measured with widely used instruments such as the BRIEF-SR does not predict school performance of adolescents in preuniversity education any better than a student's grade, sex, and level of parental education. PMID- 24782795 TI - Color priming in pop-out search depends on the relative color of the target. AB - In visual search for pop-out targets, search times are shorter when the target and non-target colors from the previous trial are repeated than when they change. This priming effect was originally attributed to a feature weighting mechanism that biases attention toward the target features, and away from the non-target features. However, more recent studies have shown that visual selection is strongly context-dependent: according to a relational account of feature priming, the target color is always encoded relative to the non-target color (e.g., as redder or greener). The present study provides a critical test of this hypothesis, by varying the colors of the search items such that either the relative color or the absolute color of the target always remained constant (or both). The results clearly show that color priming depends on the relative color of a target with respect to the non-targets but not on its absolute color value. Moreover, the observed priming effects did not change over the course of the experiment, suggesting that the visual system encodes colors in a relative manner from the start of the experiment. Taken together, these results strongly support a relational account of feature priming in visual search, and are inconsistent with the dominant feature-based views. PMID- 24782796 TI - Sharing and giving across adolescence: an experimental study examining the development of prosocial behavior. AB - In this study we use economic exchange games to examine the development of prosocial behavior in the form of sharing and giving in social interactions with peers across adolescence. Participants from four age groups (9-, 12-, 15-, and 18 year-olds, total N = 119) played three types of distribution games and the Trust game with four different interaction partners: friends, antagonists, neutral classmates, and anonymous peers. Nine- and 12-year-olds showed similar levels of prosocial behavior to all interaction partners, whereas older adolescents showed increasing differentiation in prosocial behavior depending on the relation with peers, with most prosocial behavior toward friends. The age related increase in non-costly prosocial behavior toward friends was mediated by self-reported perspective-taking skills. Current findings extend existing evidence on the developmental patterns of fairness considerations from childhood into late adolescence. Together, we show that adolescents are increasingly better at incorporating social context into decision-making. Our findings further highlight the role of friendships as a significant social context for the development of prosocial behavior in early adolescence. PMID- 24782797 TI - Human haptic perception is interrupted by explorative stops of milliseconds. AB - INTRODUCTION: The explorative scanning movements of the hands have been compared to those of the eyes. The visual process is known to be composed of alternating phases of saccadic eye movements and fixation pauses. Descriptive results suggest that during the haptic exploration of objects short movement pauses occur as well. The goal of the present study was to detect these "explorative stops" (ES) during one-handed and two-handed haptic explorations of various objects and patterns, and to measure their duration. Additionally, the associations between the following variables were analyzed: (a) between mean exploration time and duration of ES, (b) between certain stimulus features and ES frequency, and (c) the duration of ES during the course of exploration. METHODS: Five different Experiments were used. The first two Experiments were classical recognition tasks of unknown haptic stimuli (A) and of common objects (B). In Experiment C space position information of angle legs had to be perceived and reproduced. For Experiments D and E the PHANToM haptic device was used for the exploration of virtual (D) and real (E) sunken reliefs. RESULTS: In each Experiment we observed explorative stops of different average durations. For Experiment A: 329.50 ms, Experiment B: 67.47 ms, Experiment C: 189.92 ms, Experiment D: 186.17 ms and Experiment E: 140.02 ms. Significant correlations were observed between exploration time and the duration of the ES. Also, ES occurred more frequently, but not exclusively, at defined stimulus features like corners, curves and the endpoints of lines. However, explorative stops do not occur every time a stimulus feature is explored. CONCLUSIONS: We assume that ES are a general aspect of human haptic exploration processes. We have tried to interpret the occurrence and duration of ES with respect to the Hypotheses-Rebuild-Model and the Limited Capacity Control System theory. PMID- 24782798 TI - Can we throw information out of visual working memory and does this leave informational residue in long-term memory? AB - Can we entirely erase a temporary memory representation from mind? This question has been addressed in several recent studies that tested the specific hypothesis that a representation can be erased from visual working memory based on a cue that indicated that the representation was no longer necessary for the task. In addition to behavioral results that are consistent with the idea that we can throw information out of visual working memory, recent neurophysiological recordings support this proposal. However, given the infinite capacity of long term memory, it is unclear whether throwing a representation out of visual working memory really removes its effects on memory entirely. In this paper, we advocate for an approach that examines our ability to erase memory representations from working memory, as well as possible traces that those erased representations leave in long-term memory. PMID- 24782799 TI - Intelligent virtual agents as language trainers facilitate multilingualism. AB - IN THIS PAPER WE INTRODUCE A NEW GENERATION OF LANGUAGE TRAINERS: intelligent virtual agents (IVAs) with human appearance and the capability to teach foreign language vocabulary. We report results from studies that we have conducted with Billie, an IVA employed as a vocabulary trainer, as well as research findings on the acceptance of the agent as a trainer by adults and children. The results show that Billie can train humans as well as a human teacher can and that both adults and children accept the IVA as a trainer. The advantages of IVAs are multiple. First, their teaching methods can be based on neuropsychological research findings concerning memory and learning practice. Second, virtual teachers can provide individualized training. Third, they coach users during training, are always supportive, and motivate learners to train. Fourth, agents will reside in the user's mobile devices and thus be at the user's disposal everywhere and anytime. Agents in apps will make foreign language training accessible to anybody at low cost. This will enable people around the world, including physically, financially, and geographically disadvantaged persons, to learn a foreign language and help to facilitate multilingualism. PMID- 24782800 TI - Age-related differences in neural recruitment during the use of cognitive reappraisal and selective attention as emotion regulation strategies. AB - The present study examined age differences in the timing and neural recruitment within lateral and medial PFC while younger and older adults hedonically regulated their responses to unpleasant film clips. When analyses focused on activity during the emotional peak of the film clip (the most emotionally salient portion of the film), several age differences emerged. When comparing regulation to passive viewing (combined effects of selective attention and reappraisal) younger adults showed greater regulation related activity in lateral PFC (DLPFC, VLPFC, OFC) and medial PFC (ACC) while older adults showed greater activation within a region DLPFC. When assessing distinct effects of the regulation conditions, an ANOVA revealed a significant Age * Regulation Condition interaction within bilateral DLPFC and ACC; older adults but not young adults showed greater recruitment within these regions for reappraisal than selective attention. When examining activity at the onset of the film clip and at its emotional peak, the timing of reappraisal-related activity within VLPFC differed between age groups: younger adults showed greater activity at film onset while older adults showed heightened activity during the peak. Our results suggest that older adults rely more heavily on PFC recruitment when engaging cognitively demanding reappraisal strategies while PFC-mediated regulation might not be as task-specific for younger adults. Older adults' greater reliance on cognitive control processing during emotion regulation may also be reflected in the time needed to implement these strategies. PMID- 24782801 TI - Caregiver influence on looking behavior and brain responses in prelinguistic development. PMID- 24782802 TI - It is premature to regard the ego-depletion effect as "Too Incredible". PMID- 24782803 TI - Olfaction, valuation, and action: reorienting perception. AB - In the philosophy of perception, olfaction is the perennial problem child, presenting a range of difficulties to those seeking to define its proper referents, and its phenomenological content. Here, we argue that many of these difficulties can be resolved by recognizing the object-like representation of odors in the brain, and by postulating that the basic objects of olfaction are best defined by their biological value to the organism, rather than physicochemical dimensions of stimuli. Building on this organism-centered account, we speculate that the phenomenological space of olfaction is organized into a number of coarse affective dimensions that apply categorically. This organization may be especially useful for coupling sensation to decision making and instrumental action in a sensory modality where the stimulus space is especially complex and high dimensional. PMID- 24782804 TI - Electrophysiological evidence of the time course of attentional bias in non patients reporting symptoms of depression with and without co-occurring anxiety. AB - Anxiety is characterized by attentional biases to threat, but findings are inconsistent for depression. To address this inconsistency, the present study systematically assessed the role of co-occurring anxiety in attentional bias in depression. In addition, the role of emotional valence, arousal, and gender was explored. Ninety-two non-patients completed the Penn State Worry Questionnaire (Meyer et al., 1990; Molina and Borkovec, 1994) and portions of the Mood and Anxiety Symptom Questionnaire (Watson et al., 1995a,1995b). Individuals reporting high levels of depression and low levels of anxiety (depression only), high levels of depression and anxiety (combined), or low levels of both (control) completed an emotion-word Stroop task during event-related brain potential recording. Pleasant and unpleasant words were matched on emotional arousal level. An attentional bias was not evident in the depression-only group. Women in the combined group had larger N200 amplitude for pleasant than unpleasant stimuli, and the combined group as a whole had larger right-lateralized P300 amplitude for pleasant than unpleasant stimuli, consistent with an early and later attentional bias that is specific to unpleasant valence in the combined group. Men in the control group had larger N200 amplitude for pleasant than unpleasant stimuli, consistent with an early attentional bias that is specific to pleasant valence. The present study indicates that the nature and time course of attention prompted by emotional valence and not arousal differentiates depression with and without anxiety, with some evidence of gender moderating early effects. Overall, results suggest that co-occurring anxiety is more important than previously acknowledged in demonstrating evidence of attentional biases in depression. PMID- 24782805 TI - Tree shrews (Tupaia belangeri) exhibit novelty preference in the novel location memory task with 24-h retention periods. AB - Novelty preference is pervasive in mammalian species, and describes an inherent tendency to preferentially explore novelty. The novel location memory task studied here assesses the ability of animals to form accurate memories of a spatial configuration, consisting of several identical objects placed within an arena. Tree shrews were first familiarized with a particular object configuration during several sessions, and then an object was displaced during a test session. Tree shrews exhibited enhanced exploration when confronted with this novel configuration. The most reliable indicator associated with novelty preference was an enhancement in directed exploration towards the novel object, although we also observed a non-specific overall increase in exploration in one experiment. During the test session, we also observed an exploration of the location, which had previously been occupied by the displaced object, an effect termed empty quadrant. Our behavioral findings suggest multiple stages of spatial memory formation in tree shrews that are associated with various forms of behavioral responses to novelty. Reduced novelty preference has been linked to major depressive disorder in human patients. Given the established social conflict depression model in tree shrews, we anticipate that the study of the neural circuits of novelty preference and their malfunction during depression may have implications for understanding or treating depression in humans. PMID- 24782806 TI - Making progress in non-human mental time travel. PMID- 24782807 TI - Weight lifting can facilitate appreciative comprehension for museum exhibits. AB - Appreciation of exhibits in a museum can be equated to a virtual experience of lives in the contexts originally surrounding the exhibits. Here we focus on the importance of weight information, and hence tested whether experiencing a weight during museum exhibit appreciation affects the beholders' satisfaction and recognition memory for the exhibits. An experiment was performed at a museum exhibiting skeletal preparations of animals. We used nine preparations and prepared four weight stimuli as weight cues in accordance with the actual weight of four of the preparations: Remaining five preparations was displayed without weight stimuli. In the cued condition, participants were asked to lift up the weight stimuli during their observation of the four exhibits. In the uncued condition, participants observed the exhibits without touching the weight stimuli. After observation of the exhibits, the participants responded to a questionnaire that measured their impressions of the exhibits and the museum, and performed a recognition test on the exhibits. Results showed that memory performance was better and viewing duration was longer with weight lifting instruction than without instruction. A factor analysis on the questionnaires revealed four factors (likeability, contentment, value, and quality). A path analysis showed indirect effects of viewing duration on memory performance and willingness-to-pay (WTP) for the museum appreciation through the impression factors. Our findings provide insight into a new interactive exhibition that enables long appreciation producing positive effects on visitors' impression, memory, and value estimation for exhibits. PMID- 24782808 TI - Random reward priming is task-contingent: the robustness of the 1-trial reward priming effect. AB - Consistent financial reward of particular features influences the allocation of visual attention in many ways. More surprising are 1-trial reward priming effects on attention where reward schedules are random and reward on one trial influences attentional allocation on the next. Those findings are thought to reflect that rewarded features become more salient than unrewarded ones on the subsequent trial. Here we attempt to conceptually replicate this effect, testing its generalizability. In three versions of an analogous paradigm to the additional singleton paradigm involving singleton search for a Gabor patch of odd spatial frequency we found no evidence of reward priming, while we only partially replicate the reward priming in the exact original paradigm tested by Hickey and colleagues. The results cast doubt on the proposal that random reward enhances salience, suggested in the original papers, and highlight the need for a more nuanced account. In many other paradigms reward effects have been found to progress gradually, becoming stronger as they build up, and we argue that for robust reward priming, reward schedules need to be more consistent than in the original 1-trial reward priming paradigm. PMID- 24782810 TI - Olfactory LOVER: behavioral and neural correlates of autobiographical odor memory. AB - Autobiographical memories (AMs) are personally experienced events that may be localized in time and space. In the present work we present an overview targeting memories evoked by the sense of smell. Overall, research indicates that autobiographical odor memory is different than memories evoked by our primary sensory systems; sight, and hearing. Here, observed differences from a behavioral and neuroanatomical perspective are presented. The key features of an olfactory evoked AM may be referred to the LOVER acronym-Limbic, Old, Vivid, Emotional, and Rare. PMID- 24782809 TI - The neural basis of human tool use. AB - In this review, we propose that the neural basis for the spontaneous, diversified human tool use is an area devoted to the execution and observation of tool actions, located in the left anterior supramarginal gyrus (aSMG). The aSMG activation elicited by observing tool use is typical of human subjects, as macaques show no similar activation, even after an extensive training to use tools. The execution of tool actions, as well as their observation, requires the convergence upon aSMG of inputs from different parts of the dorsal and ventral visual streams. Non-semantic features of the target object may be provided by the posterior parietal cortex (PPC) for tool-object interaction, paralleling the well known PPC input to anterior intraparietal (AIP) for hand-object interaction. Semantic information regarding tool identity, and knowledge of the typical manner of handling the tool, could be provided by inferior and middle regions of the temporal lobe. Somatosensory feedback and technical reasoning, as well as motor and intentional constraints also play roles during the planning of tool actions and consequently their signals likewise converge upon aSMG. We further propose that aSMG may have arisen though duplication of monkey AIP and invasion of the duplicate area by afferents from PPC providing distinct signals depending on the kinematics of the manipulative action. This duplication may have occurred when Homo Habilis or Homo Erectus emerged, generating the Oldowan or Acheulean Industrial complexes respectively. Hence tool use may have emerged during hominid evolution between bipedalism and language. We conclude that humans have two parietal systems involved in tool behavior: a biological circuit for grasping objects, including tools, and an artifactual system devoted specifically to tool use. Only the latter allows humans to understand the causal relationship between tool use and obtaining the goal, and is likely to be the basis of all technological developments. PMID- 24782811 TI - Sixty-four or four-and-sixty? The influence of language and working memory on children's number transcoding. AB - Number transcoding (e.g., writing 64 when hearing "sixty-four") is a basic numerical skill; rather faultlessly performed in adults, but difficult for children. In the present study, children speaking Dutch (an inversed number language) and French (a non-inversed number language) wrote Arabic digits to dictation. We also tested their IQ and their phonological, visuospatial, and executive working memory. Although the number of transcoding errors (e.g., hearing 46 but writing 56) was equal in both groups, the number of inversion errors (e.g., hearing 46 but writing 64) was significantly higher in Dutch speaking than in French-speaking children. Regression analyses confirmed that language was the only significant predictor of inversion errors. Working-memory components, in contrast, were the only significant predictors of transcoding errors. Executive resources were important in all children. Less-skilled transcoders also differed from more-skilled transcoders in that they used semantic rather than asemantic transcoding routes. Given the observed relation between number transcoding and mathematics grades, current findings may provide useful information for educational and clinical settings. PMID- 24782812 TI - An ERP study of effects of regularity and consistency in delayed naming and lexicality judgment in a logographic writing system. AB - Phonological access is an important component in theories and models of word reading. However, phonological regularity and consistency effects are not clearly separable in alphabetic writing systems. We investigated these effects in Chinese, where the two variables are operationally distinct. In this orthographic system, regularity is defined as the congruence between the pronunciation of a complex character (or phonogram), and that of its phonetic radical, while phonological consistency indexes the proportion of orthographic neighbors that share the same pronunciation as the phonogram. In the current investigation, regularity and consistency were contrasted in an event-related potential (ERP) study using a lexical decision (LD) task and a delayed naming (DN) task with native Chinese readers. ERP results showed that effects of regularity occurred early after stimulus onset and were long-lasting. Regular characters elicited larger N170, smaller P200, and larger N400 compared to irregular characters. In contrast, significant effects of consistency were only seen at the P200 and consistent characters showed a greater P200 than inconsistent characters. Thus, both the time course and the direction of the effects indicated that regularity and consistency operated under different mechanisms and were distinct constructs. Additionally, both of these phonological effects were only found in the DN task and absent in LD, suggesting that phonological access was non-obligatory for LD. The study demonstrated cross-language variability in how phonological information was accessed from print and how task demands could influence this process. PMID- 24782813 TI - Functional lateralization of lexical stress representation: a systematic review of patient data. AB - According to the functional lateralization hypothesis (FLH) the lateralization of speech prosody depends both on its function (linguistic = left, emotional = right) and on the size of the units it operates on (small = left, large = right). In consequence, according to the FLH, lexical stress should be processed by the left (language-dominant) hemisphere, given its linguistic function and small unit size. We performed an exhaustive search for case studies of patients with acquired dysprosody due to unilateral brain damage. In contrast to previous reviews we only regarded dysprosody at the lexical level (excluding phrasal stress). Moreover, we focused on the representational stage of lexical stress processing, excluding more peripheral perceptual or motor deficits. Applying these criteria, we included nine studies reporting on 11 patients. All of these patients showed representational deficits in word stress processing following a lesion in their language-dominant hemisphere. In 9 out of 11 patients, it was the left hemisphere which was affected. This is a much more consistent pattern as found in previous reviews, in which less rigorous inclusion criteria may have blurred the pattern of results. We conclude that the representation of lexical stress crucially relies on the functioning of the language-dominant (mostly left) hemisphere. PMID- 24782814 TI - Quantum probability theory as a common framework for reasoning and similarity. PMID- 24782815 TI - Enhanced audiovisual integration with aging in speech perception: a heightened McGurk effect in older adults. AB - Two experiments compared young and older adults in order to examine whether aging leads to a larger dependence on visual articulatory movements in auditory-visual speech perception. These experiments examined accuracy and response time in syllable identification for auditory-visual (AV) congruent and incongruent stimuli. There were also auditory-only (AO) and visual-only (VO) presentation modes. Data were analyzed only for participants with normal hearing. It was found that the older adults were more strongly influenced by visual speech than the younger ones for acoustically identical signal-to-noise ratios (SNRs) of auditory speech (Experiment 1). This was also confirmed when the SNRs of auditory speech were calibrated for the equivalent AO accuracy between the two age groups (Experiment 2). There were no aging-related differences in VO lipreading accuracy. Combined with response time data, this enhanced visual influence for the older adults was likely to be associated with an aging-related delay in auditory processing. PMID- 24782816 TI - The case for angioplasty in patients with symptomatic intracranial atherosclerosis. AB - Intracranial atherosclerotic disease (ICAD) is likely the most common cause of stroke worldwide and remains highly morbid even with highly monitored medical therapy. Recent results of the SAMMPRIS trial, which randomized patients to stenting plus aggressive medical management versus aggressive medical management alone have shown that additional treatment of intracranial atherosclerotic lesions with the Wingspan stent is inferior to aggressive medical management alone. In light of these results, there has been renewed interest in angioplasty alone to treat symptomatic ICAD. This article will briefly review the natural history of ICAD and discuss the possible future for endovascular treatment of ICAD with primary intracranial angioplasty in appropriately selected patients. PMID- 24782817 TI - Balloons and stents in the endovascular treatment of cerebral aneurysms: vascular anatomy remodeled. AB - Wide-neck intracranial aneurysms were originally thought to be either untreatable or very challenging to treat by endovascular means because of the risk of coil protrusion into the parent vessel. The introduction of the balloon remodeling technique (BRT) and later stents specifically designed for intracranial use has progressively allowed these lesions to be endovascularly treated. BRT and stent assisted coiling technique (SACT) were first designed to treat sidewall aneurysms but, with gained experience and further technical refinement, bifurcation complex shaped wide-neck aneurysms have been treated by coiling enhanced by BRT and SACT. In this article, we will review and describe the inherent benefits and drawbacks of BRT as well as SACT. PMID- 24782818 TI - Psychological stress as a modulator of functional recovery following spinal cord injury. AB - There is strong evidence indicating that the social environment triggers changes to the psychological stress response and glucocorticoid receptor function. Considerable literature links the subsequent changes in stress resiliency to physical health. Here, converging evidence for the modulatory role of chronic psychological stress in the recovery process following spinal cord injury (SCI) is presented. Despite the considerable advances in SCI research, we are still unable to identify the causes of variability in patients' recovery following injury. We propose that individuals' past and present life experiences (in the form of stress exposure) may significantly modulate patients' outcome post-SCI. We propose a theoretical model to explain the negative impact of chronic psychological stress on physical and psychological recovery. The stress experienced in life prior to SCI and also as a result of the traumatic injury, could compromise glucocorticoid receptor sensitivity and function, and contribute to high levels of inflammation and apoptosis post-SCI, decreasing the tissue remaining at the injury site and undermining recovery of function. Both stress induced glucocorticoid resistance and stress-induced epigenetic changes to the glucocorticoid receptor can modulate the nuclear factor-kappa B regulated inflammatory pathways and the Bcl-2 regulated apoptosis pathways. This model not only contributes to the theoretical understanding of the recovery process following injury, but also provides concrete testable hypotheses for future studies. PMID- 24782819 TI - FMRI and brain activation after sport concussion: a tale of two cases. AB - Sport-related concussions are now recognized as a major public health concern: the number of participants in sport and recreation is growing, possibly playing their games faster, and there is heightened public awareness of injuries to some high-profile athletes. However, many clinicians still rely on subjective symptom reports for the clinical determination of recovery. Relying on subjective symptom reports can be problematic, as it has been shown that some concussed athletes may downplay their symptoms. The use of neuropsychological (NP) testing has enabled clinicians to measure the effects and extent of impairment following concussion more precisely, providing more objective metrics for determining recovery. Nevertheless, there is a remaining concern that brain abnormalities may exist beyond the point at which individuals achieve recovery in self-reported symptoms and cognition measured by NP testing. Our understanding of brain recovery after concussion is important, not only from a neuroscience perspective, but also from the perspective of clinical decision-making for safe return-to-play. A number of advanced neuroimaging tools, including blood oxygen level dependent functional magnetic resonance imaging (fMRI), have independently yielded early information on abnormal brain functioning. In the two cases presented in this article, we report contrasting brain activation patterns and recovery profiles using fMRI. Importantly, fMRI was conducted using adapted versions of the most sensitive computerized NP tests administered in our current clinical practice to determine impairments and recovery after sport-related concussion. One of the cases is consistent with the concept of lagging brain recovery. PMID- 24782820 TI - Blast TBI Models, Neuropathology, and Implications for Seizure Risk. AB - Traumatic brain injury (TBI) due to explosive blast exposure is a leading combat casualty. It is also implicated as a key contributor to war related mental health diseases. A clinically important consequence of all types of TBI is a high risk for development of seizures and epilepsy. Seizures have been reported in patients who have suffered blast injuries in the Global War on Terror but the exact prevalence is unknown. The occurrence of seizures supports the contention that explosive blast leads to both cellular and structural brain pathology. Unfortunately, the exact mechanism by which explosions cause brain injury is unclear, which complicates development of meaningful therapies and mitigation strategies. To help improve understanding, detailed neuropathological analysis is needed. For this, histopathological techniques are extremely valuable and indispensable. In the following we will review the pathological results, including those from immunohistochemical and special staining approaches, from recent preclinical explosive blast studies. PMID- 24782821 TI - Hand functioning in children with cerebral palsy. AB - Brain lesions may disturb hand functioning in children with cerebral palsy (CP), making it difficult or even impossible for them to perform several manual activities. Most conventional treatments for hand dysfunction in CP assume that reducing the hand dysfunctions will improve the capacity to manage activities (i.e., manual ability, MA). The aim of this study was to investigate the directional relationships (direct and indirect pathways) through which hand skills influence MA in children with CP. A total of 136 children with CP (mean age: 10 years; range: 6-16 years; 35 quadriplegics, 24 diplegics, 77 hemiplegics) were assessed. Six hand skills were measured on both hands: touch-pressure detection (Semmes-Weinstein esthesiometer), stereognosis (Manual Form Perception Test), proprioception (passive mobilization of the metacarpophalangeal joints), grip strength (GS) (Jamar dynamometer), gross manual dexterity (GMD) (Box and Block Test), and fine finger dexterity (Purdue Pegboard Test). MA was measured with the ABILHAND-Kids questionnaire. Correlation coefficients were used to determine the linear associations between observed variables. A path analysis of structural equation modeling was applied to test different models of causal relationships among the observed variables. Purely sensory impairments did seem not to play a significant role in the capacity to perform manual activities. According to path analysis, GMD in both hands and stereognosis in the dominant hand were directly related to MA, whereas GS was indirectly related to MA through its relationship with GMD. However, one-third of the variance in MA measures could not be explained by hand skills. It can be concluded that MA is not simply the integration of hand skills in daily activities and should be treated per se, supporting activity-based interventions. PMID- 24782822 TI - Maladaptive plasticity in levodopa-induced dyskinesias and tardive dyskinesias: old and new insights on the effects of dopamine receptor pharmacology. AB - Maladaptive plasticity can be defined as behavioral loss or even development of disease symptoms resulting from aberrant plasticity changes in the human brain. Hyperkinetic movement disorders, in the neurological or psychiatric realms, have been associated with maladaptive neural plasticity that can be expressed by functional changes such as an increase in transmitter release, receptor regulation, and synaptic plasticity or anatomical modifications such as axonal regeneration, sprouting, synaptogenesis, and neurogenesis. Recent evidence from human and animal models provided support to the hypothesis that these phenomena likely depend on altered dopamine turnover induced by long-term drug treatment. However, it is still unclear how and where these altered mechanisms of cortical plasticity may be localized. This study provides an up-to-date overview of these issues together with some reflections on future studies in the field, particularly focusing on two specific disorders (levodopa-induced dyskinesias in Parkinson's disease patients and tardive dyskinesias in schizophrenic patients) where the modern neuroimaging approaches have recently provided new fundamental insights. PMID- 24782823 TI - Magnesium: potential roles in neurovascular disease. AB - OBJECTIVE: Magnesium therapy has been studied extensively in pre-clinical and clinical trials in multiple organ systems. Cerebrovascular diseases may benefit from its neuroprotective properties. This review summarizes current studies of magnesium in a wide range of neurovascular diseases. METHODS: We searched relevant terms in the National Library of Medicine PubMed database and selected research including basic science, translational reports, meta-analyses, and clinical studies. RESULTS: Studies examining magnesium administration in ischemic stroke have failed to show any benefit in clinical outcome. Data on magnesium for intracerebral hemorrhage (ICH) are limited. Preliminary investigations in subarachnoid hemorrhage (SAH) were promising, but definitive studies did not reveal differences in clinical outcome between magnesium and placebo-treated groups. Studies examining magnesium administration in global ischemia following cardiac arrest suggest a trend toward improved clinical outcome. The strongest evidence for clinically relevant neuroprotection following magnesium administration derives from studies of pre-term infants and patients undergoing cardiac bypass and carotid endarterectomy procedures. Magnesium was found to have an excellent safety profile across all investigations. CONCLUSION: Magnesium is easy to administer and possesses a favorable safety profile. Its utility as a neuroprotectant in cardiac surgery, carotid endarterectomy, and pre-term infant hypoxia remain promising. Value as a therapeutic agent in ischemic stroke, ICH, and SAH is unclear and appears to be limited by late administration. Ongoing clinical trials assessing magnesium administration in the first hours following symptom onset may help clarify the role of magnesium therapy in these disease processes. PMID- 24782824 TI - Quantification of dexterity as the dynamical regulation of instabilities: comparisons across gender, age, and disease. AB - Dexterous manipulation depends on using the fingertips to stabilize unstable objects. The Strength-Dexterity paradigm consists of asking subjects to compress a slender and compliant spring prone to buckling. The maximal level of compression [requiring low fingertip forces <300 grams force (gf)] quantifies the neural control capability to dynamically regulate fingertip force vectors and motions for a dynamic manipulation task. We found that finger dexterity is significantly affected by age (p = 0.017) and gender (p = 0.021) in 147 healthy individuals (66F, 81M, 20-88 years). We then measured finger dexterity in 42 hands of patients following treatment for osteoarthritis of the base of the thumb (CMC OA, 33F, 65.8 +/- 9.7 years), and 31 hands from patients being treated for Parkinson's disease (PD, 6F, 10M, 67.68 +/- 8.5 years). Importantly, we found no differences in finger compression force among patients or controls. However, we did find stronger age-related declines in performance in the patients with PD (slope -2.7 gf/year, p = 0.002) than in those with CMC OA (slope -1.4 gf/year, p = 0.015), than in controls (slope -0.86 gf/year). In addition, the temporal variability of forces during spring compression shows clearly different dynamics in the clinical populations compared to the controls (p < 0.001). Lastly, we compared dexterity across extremities. We found stronger age (p = 0.005) and gender (p = 0.002) effects of leg compression force in 188 healthy subjects who compressed a larger spring with the foot of an isolated leg (73F, 115M, 14-92 years). In 81 subjects who performed the tests with all four limbs separately, we found finger and leg compression force to be significantly correlated (females rho = 0.529, p = 0.004; males rho = 0.403, p = 0.003; 28F, 53M, 20-85 years), but surprisingly found no differences between dominant and non-dominant limbs. These results have important clinical implications, and suggest the existence - and compel the investigation - of systemic versus limb-specific mechanisms for dexterity. PMID- 24782825 TI - Endothelial progenitor cells in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a leading cause of visual impairment worldwide. Patients with DR may irreversibly lose sight as a result of the development of diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR); retinal blood vessel dysfunction and degeneration plays an essential role in their pathogenesis. Although new treatments have been recently introduced for DME, including intravitreal vascular endothelial growth factor inhibitors (anti VEGFs) and steroids, a high proportion of patients (~40-50%) do not respond to these therapies. Furthermore, for people with PDR, laser photocoagulation remains a mainstay therapy despite this being an inherently destructive procedure. Endothelial progenitor cells (EPCs) are a low-frequency population of circulating cells known to be recruited to sites of vessel damage and tissue ischemia where they promote vascular healing and re-perfusion. A growing body of evidence suggests that the number and function of EPCs are altered in patients with varying degrees of diabetes duration, metabolic control, and in the presence or absence of DR. Although there are no clear-cut outcomes from these clinical studies, there is mounting evidence that some EPC sub-types may be involved in the pathogenesis of DR and may also serve as biomarkers for disease progression and stratification. Moreover, some EPC sub-types have considerable potential as therapeutic modalities for DME and PDR in the context of cell therapy. This study presents basic clinical concepts of DR and combines this with a general insight on EPCs and their relation to future directions in understanding and treating this important diabetic complication. PMID- 24782826 TI - Exploring a new therapy for diabetic polyneuropathy - the application of stem cell transplantation. AB - Diabetic polyneuropathy (DPN) is the most common complication that emerges early in diabetic patients. Intervention with strict blood glucose control or treatment with aldose reductase inhibitor is reported to be effective in early stages of DPN. Curative treatment for overt or symptomatic DPN, however, has not been established, thus requiring much effort to explore a new therapy. Recent preclinical studies on the use of gene or cell therapy have provided promising results in the treatment of DPN. Of particular interest, induced pluripotent stem cells are introduced. In these studies, restoration of DPN was proposed to be attributed to either neurotrophic factors released from transplanted stem cells or differentiation of stem cells to substitute the damaged peripheral nerve. There are still several problems, however, that remain to be overcome, such as perturbed function, fragility, or limited survival of transplanted cells in diabetes milieu and risk for malignant transformation of transplanted cells. Questions, which cell is the most appropriate as the source for cell therapy, or which site is the best for transplantation to obtain the most effective results, remain to be answered. In this communication, we overview the current status of preclinical studies on the cell therapy for DPN and discuss the future prospect. PMID- 24782828 TI - The regulated secretory pathway in neuroendocrine cells. PMID- 24782827 TI - Alternative polyadenylation of tumor suppressor genes in small intestinal neuroendocrine tumors. AB - The tumorigenesis of small intestinal neuroendocrine tumors (SI-NETs) is poorly understood. Recent studies have associated alternative polyadenylation (APA) with proliferation, cell transformation, and cancer. Polyadenylation is the process in which the pre-messenger RNA is cleaved at a polyA site and a polyA tail is added. Genes with two or more polyA sites can undergo APA. This produces two or more distinct mRNA isoforms with different 3' untranslated regions. Additionally, APA can also produce mRNAs containing different 3'-terminal coding regions. Therefore, APA alters both the repertoire and the expression level of proteins. Here, we used high-throughput sequencing data to map polyA sites and characterize polyadenylation genome-wide in three SI-NETs and a reference sample. In the tumors, 16 genes showed significant changes of APA pattern, which lead to either the 3' truncation of mRNA coding regions or 3' untranslated regions. Among these, 11 genes had been previously associated with cancer, with 4 genes being known tumor suppressors: DCC, PDZD2, MAGI1, and DACT2. We validated the APA in three out of three cases with quantitative real-time-PCR. Our findings suggest that changes of APA pattern in these 16 genes could be involved in the tumorigenesis of SI-NETs. Furthermore, they also point to APA as a new target for both diagnostic and treatment of SI-NETs. The identified genes with APA specific to the SI-NETs could be further tested as diagnostic markers and drug targets for disease prevention and treatment. PMID- 24782829 TI - Mice deficient in cryptochrome 1 (cry1 (-/-)) exhibit resistance to obesity induced by a high-fat diet. AB - Disruption of circadian clock enhances the risk of metabolic syndrome, obesity, and type 2 diabetes. Circadian clocks rely on a highly regulated network of transcriptional and translational loops that drive clock-controlled gene expression. Among these transcribed clock genes are cryptochrome (CRY) family members, which comprise Cry1 and Cry2. While the metabolic effects of deletion of several core components of the clock gene machinery have been well characterized, those of selective inactivation of Cry1 or Cry2 genes have not been described. In this study, we demonstrate that ablation of Cry1, but not Cry2, prevents high-fat diet (HFD)-induced obesity in mice. Despite similar caloric intake, Cry1 (-/-) mice on HFD gained markedly less weight (-18%) at the end of the 16-week experiment and displayed reduced fat accumulation compared to wild-type (WT) littermates (-61%), suggesting increased energy expenditure. Analysis of serum lipid and glucose profiles showed no difference between Cry1 (-/-) and WT mice. Both Cry1 (-/-) and Cry2 (-/-) mice are indistinguishable from WT controls in body weight, fat and protein contents, and food consumption when they are allowed unlimited access to a standard rodent diet. We conclude that although CRY signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, Cry1 may play a role in readjusting energy balance under changing nutritional circumstances. These studies reinforce the important role of circadian clock genes in energy homeostasis and suggest that Cry1 is a plausible target for anti-obesity therapy. PMID- 24782830 TI - The impact of genetics and hormonal contraceptives on the steroid profile in female athletes. AB - The steroid module of the Athlete Biological Passport, the newest innovation in doping testing, is currently being finalized for implementation. Several factors, other than doping, can affect the longitudinal steroid profile. In this study, we investigated the effect of hormonal contraceptives (HC) as well as the effect of three polymorphisms on female steroid profiles in relation to doping controls. The study population consisted of 79 female elite athletes between the ages of 18 and 45. HC were used by 32% of the subjects. A full urinary steroid profile was obtained using World Anti-Doping Agency accredited methods. In addition all subjects were genotyped for copy number variation of UGT2B17 and SNPs in UGT2B7 and CYP17. Subjects using HC excreted 40% less epitestosterone as compared to non users (p = 0.005) but showed no difference in testosterone excretion. When removing individuals homozygous for the deletion in UGT2B17, the testosterone to epitestosterone (T/E) ratio was 29% higher in the HC group (p = 0.016). In agreement with previous findings in men, copy number variation of UGT2B17 had significant effect on female urinary testosterone excretion and therefore also the T/E ratio. Subjects homozygous for the T allele of CYP17 showed a lower urinary epitestosterone concentration than the other CYP17 genotypes. It is of great importance that the athlete's steroidal passport can compensate for all possible normal variability in steroid profiles from women. Therefore, considering the large impact of HC on female steroid profiles, we suggest that the use of HC should be a mandatory question on the doping control form. PMID- 24782831 TI - Mechanisms of prenatal programing: identifying and distinguishing the impact of steroid hormones. AB - Developmental programing is gaining considerable leverage as a conceptual framework for understanding individual variability in human behavioral and somatic health. The current mini-review examines some of the key conceptual and methodological challenges for developmental programing research focused on fetal sex steroid exposure and physical, behavioral, physiological, and health outcomes. Specifically, we consider the bases for focusing on sex steroids, methods for assessing prenatal steroid hormone exposure, confounding factors, and the most relevant postnatal outcomes. We conclude with a brief consideration, based on current knowledge, of the applications of the existing findings for further research and practice. PMID- 24782832 TI - Endocannabinoids are Involved in Male Vertebrate Reproduction: Regulatory Mechanisms at Central and Gonadal Level. AB - Endocannabinoids (eCBs) are natural lipids regulating a large array of physiological functions and behaviors in vertebrates. The eCB system is highly conserved in evolution and comprises several specific receptors (type-1 and type 2 cannabinoid receptors), their endogenous ligands (e.g., anandamide and 2 arachidonoylglycerol), and a number of biosynthetic and degradative enzymes. In the last few years, eCBs have been described as critical signals in the control of male and female reproduction at multiple levels: centrally, by targeting hypothalamic gonadotropin-releasing-hormone-secreting neurons and pituitary, and locally, with direct effects on the gonads. These functions are supported by the extensive localization of cannabinoid receptors and eCB metabolic enzymes at different levels of the hypothalamic-pituitary-gonadal axis in mammals, as well as bonyfish and amphibians. In vivo and in vitro studies indicate that eCBs centrally regulate gonadal functions by modulating the gonadotropin-releasing hormone-gonadotropin-steroid network through direct and indirect mechanisms. Several proofs of local eCB regulation have been found in the testis and male genital tracts, since eCBs control Sertoli and Leydig cells activity, germ cell progression, as well as the acquisition of sperm functions. A comparative approach usually is a key step in the study of physiological events leading to the building of a general model. Thus, in this review, we summarize the action of eCBs at different levels of the male reproductive axis, with special emphasis, where appropriate, on data from non-mammalian vertebrates. PMID- 24782833 TI - Thyroid regeneration: how stem cells play a role? AB - Many tissues if not all are thought to contain stem cells that are responsible for regeneration and repair of the tissue after injury. Dysregulation of tissue regeneration may result in various pathological conditions, among which cancer is the most extensively studied. Notably, the so-called cancer stem cells or tumor initiating cells, have been studied in order to understand the mechanisms of carcinogenesis and/or metastasis. However, the nature of cancer stem cells, let alone normal stem/progenitor cells, particularly those of the thyroid remains elusive. There remains a gap in knowledge between adult thyroid stem/progenitor cells and cancer stem cells of the thyroid, and if and/or how they are related to each other. Understanding of the mechanism for thyroid regeneration and mode of participation of normal adult thyroid stem/progenitor cells in this process will hopefully yield a more complete understanding of the nature of thyroid cancer stem cells, and/or help understand the pathogenesis of other thyroid diseases. This review summarizes the current understanding of adult thyroid stem/progenitor cells, with particular emphasis on how they contribute to thyroid regeneration. PMID- 24782834 TI - New insights into an X-traordinary viral protein. AB - Vpx is a protein encoded by members of the HIV-2/SIVsmm and SIVrcm/SIVmnd-2 lineages of primate lentiviruses, and is packaged into viral particles. Vpx plays a critical role during the early steps of the viral life cycle and has been shown to counteract SAMHD1, a restriction factor in myeloid and resting T cells. However, it is becoming evident that Vpx is a multifunctional protein in that SAMHD1 antagonism is likely not its sole role. This review summarizes the current knowledge on this X-traordinary protein. PMID- 24782836 TI - Population and genomic analysis of the genus Halorubrum. AB - The Halobacteria are known to engage in frequent gene transfer and homologous recombination. For stably diverged lineages to persist some checks on the rate of between lineage recombination must exist. We surveyed a group of isolates from the Aran-Bidgol endorheic lake in Iran and sequenced a selection of them. Multilocus Sequence Analysis (MLSA) and Average Nucleotide Identity (ANI) revealed multiple clusters (phylogroups) of organisms present in the lake. Patterns of intein and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) presence/absence and their sequence similarity, GC usage along with the ANI and the identities of the genes used in the MLSA revealed that two of these clusters share an exchange bias toward others in their phylogroup while showing reduced rates of exchange with other organisms in the environment. However, a third cluster, composed in part of named species from other areas of central Asia, displayed many indications of variability in exchange partners, from within the lake as well as outside the lake. We conclude that barriers to gene exchange exist between the two purely Aran-Bidgol phylogroups, and that the third cluster with members from other regions is not a single population and likely reflects an amalgamation of several populations. PMID- 24782835 TI - Cell division in Corynebacterineae. AB - Bacterial cells must coordinate a number of events during the cell cycle. Spatio temporal regulation of bacterial cytokinesis is indispensable for the production of viable, genetically identical offspring. In many rod-shaped bacteria, precise midcell assembly of the division machinery relies on inhibitory systems such as Min and Noc. In rod-shaped Actinobacteria, for example Corynebacterium glutamicum and Mycobacterium tuberculosis, the divisome assembles in the proximity of the midcell region, however more spatial flexibility is observed compared to Escherichia coli and Bacillus subtilis. Actinobacteria represent a group of bacteria that spatially regulate cytokinesis in the absence of recognizable Min and Noc homologs. The key cell division steps in E. coli and B. subtilis have been subject to intensive study and are well-understood. In comparison, only a minimal set of positive and negative regulators of cytokinesis are known in Actinobacteria. Nonetheless, the timing of cytokinesis and the placement of the division septum is coordinated with growth as well as initiation of chromosome replication and segregation. We summarize here the current knowledge on cytokinesis and division site selection in the Actinobacteria suborder Corynebacterineae. PMID- 24782837 TI - Comparison of transcriptional profiles of Clostridium thermocellum grown on cellobiose and pretreated yellow poplar using RNA-Seq. AB - The anaerobic, thermophilic bacterium, Clostridium thermocellum, secretes multi protein enzyme complexes, termed cellulosomes, which synergistically interact with the microbial cell surface and efficiently disassemble plant cell wall biomass. C. thermocellum has also been considered a potential consolidated bioprocessing (CBP) organism due to its ability to produce the biofuel products, hydrogen, and ethanol. We found that C. thermocellum fermentation of pretreated yellow poplar (PYP) produced 30 and 39% of ethanol and hydrogen product concentrations, respectively, compared to fermentation of cellobiose. RNA-seq was used to analyze the transcriptional profiles of these cells. The PYP-grown cells taken for analysis at the late stationary phase showed 1211 genes up-regulated and 314 down-regulated by more than two-fold compared to the cellobiose-grown cells. These affected genes cover a broad spectrum of specific functional categories. The transcriptional analysis was further validated by sub-proteomics data taken from the literature; as well as by quantitative reverse transcription PCR (qRT-PCR) analyses of selected genes. Specifically, 47 cellulosomal protein encoding genes, genes for 4 pairs of SigI-RsgI for polysaccharide sensing, 7 cellodextrin ABC transporter genes, and a set of NAD(P)H hydogenase and alcohol dehydrogenase genes were up-regulated for cells growing on PYP compared to cellobiose. These genes could be potential candidates for future studies aimed at gaining insight into the regulatory mechanism of this organism as well as for improvement of C. thermocellum in its role as a CBP organism. PMID- 24782838 TI - Evidence from phylogenetic and genome fingerprinting analyses suggests rapidly changing variation in Halorubrum and Haloarcula populations. AB - Halobacteria require high NaCl concentrations for growth and are the dominant inhabitants of hypersaline environments above 15% NaCl. They are well-documented to be highly recombinogenic, both in frequency and in the range of exchange partners. In this study, we examine the genetic and genomic variation of cultured, naturally co-occurring environmental populations of Halobacteria. Sequence data from multiple loci (~2500 bp) identified many closely and more distantly related strains belonging to the genera Halorubrum and Haloarcula. Genome fingerprinting using a random priming PCR amplification method to analyze these isolates revealed diverse banding patterns across each of the genera and surprisingly even for isolates that are identical at the nucleotide level for five protein coding sequenced loci. This variance in genome structure even between identical multilocus sequence analysis (MLSA) haplotypes indicates that accumulation of genomic variation is rapid: faster than the rate of third codon substitutions. PMID- 24782839 TI - Effect of the soil type on the microbiome in the rhizosphere of field-grown lettuce. AB - The complex and enormous diversity of microorganisms associated with plant roots is important for plant health and growth and is shaped by numerous factors. This study aimed to unravel the effects of the soil type on bacterial communities in the rhizosphere of field-grown lettuce. We used an experimental plot system with three different soil types that were stored at the same site for 10 years under the same agricultural management to reveal differences directly linked to the soil type and not influenced by other factors such as climate or cropping history. Bulk soil and rhizosphere samples were collected 3 and 7 weeks after planting. The analysis of 16S rRNA gene fragments amplified from total community DNA by denaturing gradient gel electrophoresis and pyrosequencing revealed soil type dependent differences in the bacterial community structure of the bulk soils and the corresponding rhizospheres. The rhizosphere effect differed depending on the soil type and the plant growth developmental stage. Despite the soil type dependent differences in the bacterial community composition several genera such as Sphingomonas, Rhizobium, Pseudomonas, and Variovorax were significantly increased in the rhizosphere of lettuce grown in all three soils. The number of rhizosphere responders was highest 3 weeks after planting. Interestingly, in the soil with the highest numbers of responders the highest shoot dry weights were observed. Heatmap analysis revealed that many dominant operational taxonomic units were shared among rhizosphere samples of lettuce grown in diluvial sand, alluvial loam, and loess loam and that only a subset was increased in relative abundance in the rhizosphere compared to the corresponding bulk soil. The findings of the study provide insights into the effect of soil types on the rhizosphere microbiome of lettuce. PMID- 24782840 TI - New edge of antibiotic development: antimicrobial peptides and corresponding resistance. PMID- 24782841 TI - A survey of deepwater horizon (DWH) oil-degrading bacteria from the Eastern oyster biome and its surrounding environment. AB - The deepwater horizon (DWH) accident led to the release of an estimated 794,936,474 L of crude oil into the northern Gulf of Mexico over an 85 day period in 2010, resulting in the contamination of the Gulf of Mexico waters, sediments, permeable beach sands, coastal wetlands, and marine life. This study examines the potential response of the Eastern oyster's microbiome to hydrocarbon contamination and compares it with the bacterial community responses observed from the overlaying water column (WC) and the oyster bed sediments. For this purpose, microcosms seeded with DWH crude oil were established and inoculated separately with oyster tissue (OT), mantle fluid (MF), overlaying WC, and sediments (S) collected from Apalachicola Bay, FL, USA. Shifts in the microbial community structure in the amended microcosms was monitored over a 3-month period using automated ribosomal intergenic spacer region analysis, which showed that the microbiome of the OT and MF were more similar to the sediment communities than those present in the overlaying WC. This pattern remained largely consistent, regardless of the concentration of crude oil or the enrichment period. Additionally, 72 oil-degrading bacteria were isolated from the microcosms containing OT, MF, WC, and S and identified using 16S ribosomal RNA gene sequencing and compared by principal component analysis, which clearly showed that the WC isolates were different to those identified from the sediment. Conversely, the OT and MF isolates clustered together; a strong indication that the oyster microbiome is uniquely structured relative to its surrounding environment. When selected isolates from the OT, MF, WC, and S were assessed for their oil-degrading potential, we found that the DWH oil was biodegraded between 12 and 42%, under the existing conditions. PMID- 24782843 TI - The safety of biocleaning technologies for cultural heritage. PMID- 24782842 TI - Microbial ecology and biogeochemistry of continental Antarctic soils. AB - The Antarctica Dry Valleys are regarded as the coldest hyperarid desert system on Earth. While a wide variety of environmental stressors including very low minimum temperatures, frequent freeze-thaw cycles and low water availability impose severe limitations to life, suitable niches for abundant microbial colonization exist. Antarctic desert soils contain much higher levels of microbial diversity than previously thought. Edaphic niches, including cryptic and refuge habitats, microbial mats and permafrost soils all harbor microbial communities which drive key biogeochemical cycling processes. For example, lithobionts (hypoliths and endoliths) possess a genetic capacity for nitrogen and carbon cycling, polymer degradation, and other system processes. Nitrogen fixation rates of hypoliths, as assessed through acetylene reduction assays, suggest that these communities are a significant input source for nitrogen into these oligotrophic soils. Here we review aspects of microbial diversity in Antarctic soils with an emphasis on functionality and capacity. We assess current knowledge regarding adaptations to Antarctic soil environments and highlight the current threats to Antarctic desert soil communities. PMID- 24782844 TI - The fail-safe system to rescue the stalled ribosomes in Escherichia coli. AB - Translation terminates at stop codon. Without stop codon, ribosome cannot terminate translation properly and reaches and stalls at the 3'-end of the mRNA lacking stop codon. Bacterial tmRNA-mediated trans-translation releases such stalled ribosome and targets the protein product to degradation by adding specific "degradation tag." Recently two alternative ribosome rescue factors, ArfA (YhdL) and ArfB (YaeJ), have been found in Escherichia coli. These three ribosome rescue systems are different each other in terms of molecular mechanism of ribosome rescue and their activity, but they are mutually related and co operate to maintain the translation system in shape. This suggests the biological significance of ribosome rescue. PMID- 24782845 TI - Metal resistance or tolerance? Acidophiles confront high metal loads via both abiotic and biotic mechanisms. AB - All metals are toxic at high concentrations and consequently their intracellular concentrations must be regulated. Extremely acidophilic microorganisms have an optimum growth of pH <3 and proliferate in natural and anthropogenic low pH environments. Some acidophiles are involved in the catalysis of sulfide mineral dissolution, resulting in high concentrations of metals in solution. Acidophiles are often described as highly metal resistant via mechanisms such as multiple and/or more efficient active resistance systems than are present in neutrophiles. However, this is not the case for all acidophiles and we contend that their growth in high metal concentrations is partially due to an intrinsic tolerance as a consequence of the environment in which they live. In this perspective, we highlight metal tolerance via complexation of free metals by sulfate ions and passive tolerance to metal influx via an internal positive cytoplasmic transmembrane potential. These tolerance mechanisms have been largely ignored in past studies of acidophile growth in the presence of metals and should be taken into account. PMID- 24782846 TI - Aflatoxins and safe storage. AB - The paper examines both field experience and research on the prevention of the exponential growth of aflatoxins during multi-month post-harvest storage in hot, humid countries. The approach described is the application of modern safe storage methods using flexible, Ultra HermeticTM structures that create an unbreatheable atmosphere through insect and microorganism respiration alone, without use of chemicals, fumigants, or pumps. Laboratory and field data are cited and specific examples are given describing the uses of Ultra Hermetic storage to prevent the growth of aflatoxins with their significant public health consequences. Also discussed is the presently limited quantitative information on the relative occurrence of excessive levels of aflatoxin (>20 ppb) before vs. after multi month storage of such crops as maize, rice, and peanuts when under high humidity, high temperature conditions and, consequently, the need for further research to determine the frequency at which excessive aflatoxin levels are reached in the field vs. after months of post-harvest storage. The significant work being done to reduce aflatoxin levels in the field is mentioned, as well as its probable implications on post-harvest storage. Also described is why, with some crops such as peanuts, using Ultra Hermetic storage may require injection of carbon dioxide, or use of an oxygen absorber as an accelerant. The case of peanuts is discussed and experimental data is described. PMID- 24782847 TI - Phages of Listeria offer novel tools for diagnostics and biocontrol. AB - Historically, bacteriophages infecting their hosts have perhaps been best known and even notorious for being a nuisance in dairy-fermentation processes. However, with the rapid progress in molecular microbiology and microbial ecology, a new dawn has risen for phages. This review will provide an overview on possible uses and applications of Listeria phages, including phage-typing, reporter phage for bacterial diagnostics, and use of phage as biocontrol agents for food safety. The use of phage-encoded enzymes such as endolysins for the detection and as antimicrobial agent will also be addressed. Desirable properties of candidate phages for biocontrol will be discussed. While emphasizing the enormous future potential for applications, we will also consider some of the intrinsic limitations dictated by both phage and bacterial ecology. PMID- 24782848 TI - Kinetic parameters for nutrient enhanced crude oil biodegradation in intertidal marine sediments. AB - Availability of inorganic nutrients, particularly nitrogen and phosphorous, is often a primary control on crude oil hydrocarbon degradation in marine systems. Many studies have empirically determined optimum levels of inorganic N and P for stimulation of hydrocarbon degradation. Nevertheless, there is a paucity of information on fundamental kinetic parameters for nutrient enhanced crude oil biodegradation that can be used to model the fate of crude oil in bioremediation programmes that use inorganic nutrient addition to stimulate oil biodegradation. Here we report fundamental kinetic parameters (Ks and qmax) for nitrate- and phosphate-stimulated crude oil biodegradation under nutrient limited conditions and with respect to crude oil, under conditions where N and P are not limiting. In the marine sediments studied, crude oil degradation was limited by both N and P availability. In sediments treated with 12.5 mg/g of oil but with no addition of N and P, hydrocarbon degradation rates, assessed on the basis of CO2 production, were 1.10 +/- 0.03 MUmol CO2/g wet sediment/day which were comparable to rates of CO2 production in sediments to which no oil was added (1.05 +/- 0.27 MUmol CO2/g wet sediment/day). When inorganic nitrogen was added alone maximum rates of CO2 production measured were 4.25 +/- 0.91 MUmol CO2/g wet sediment/day. However, when the same levels of inorganic nitrogen were added in the presence of 0.5% P w/w of oil (1.6 MUmol P/g wet sediment) maximum rates of measured CO2 production increased more than four-fold to 18.40 +/- 1.04 MUmol CO2/g wet sediment/day. Ks and qmax estimates for inorganic N (in the form of sodium nitrate) when P was not limiting were 1.99 +/- 0.86 MUmol/g wet sediment and 16.16 +/- 1.28 MUmol CO2/g wet sediment/day respectively. The corresponding values for P were 63 +/- 95 nmol/g wet sediment and 12.05 +/- 1.31 MUmol CO2/g wet sediment/day. The qmax values with respect to N and P were not significantly different (P < 0.05). When N and P were not limiting Ks and qmax for crude oil were 4.52 +/- 1.51 mg oil/g wet sediment and 16.89 +/- 1.25 MUmol CO2/g wet sediment/day. At concentrations of inorganic N above 45 MUmol/g wet sediment inhibition of CO2 production from hydrocarbon degradation was evident. Analysis of bacterial 16S rRNA genes indicated that Alcanivorax spp. were selected in these marine sediments with increasing inorganic nutrient concentration, whereas Cycloclasticus spp. were more prevalent at lower inorganic nutrient concentrations. These data suggest that simple empirical estimates of the proportion of nutrients added relative to crude oil concentrations may not be sufficient to guarantee successful crude oil bioremediation in oxic beach sediments. The data we present also help define the maximum rates and hence timescales required for bioremediation of beach sediments. PMID- 24782849 TI - Biodegradation of MC252 oil in oil:sand aggregates in a coastal headland beach environment. AB - Unique oil:sand aggregates, termed surface residue balls (SRBs), were formed on coastal headland beaches along the northern Gulf of Mexico as emulsified MC252 crude oil mixed with sand following the Deepwater Horizon spill event. The objective of this study is to assess the biodegradation potential of crude oil components in these aggregates using multiple lines of evidence on a heavily impacted coastal headland beach in Louisiana, USA. SRBs were sampled over a 19 month period on the supratidal beach environment with reasonable control over and knowledge of the residence time of the aggregates on the beach surface. Polycyclic aromatic hydrocarbons (PAHs) and alkane concentration ratios were measured including PAH/C30-hopane, C2/C3 phenanthrenes, C2/C3 dibenzothiophenes and alkane/C30-hopane and demonstrated that biodegradation was occurring in SRBs in the supratidal. These biodegradation reactions occurred over time frames relevant to the coastal processes moving SRBs off the beach. In contrast, submerged oil mat samples from the intertidal did not demonstrate chemical changes consistent with biodegradation. Review and analysis of additional biogeochemical parameters suggested the existence of a moisture and nutrient limited biodegradation regime on the supratidal beach environment. At this location, SRBs possess moisture contents <2% and molar C:N ratios from 131-323, well outside of optimal values for biodegradation in the literature. Despite these limitations, biodegradation of PAHs and alkanes proceeded at relevant rates (2-8 year(-1)) due in part to the presence of degrading populations, i.e., Mycobacterium sp., adapted to these conditions. For submerged oil mat samples in the intertidal, an oxygen and salinity-impacted regime is proposed that severely limits biodegradation of alkanes and PAHs in this environment. These results support the hypothesis that SRBs deposited at different locations on the beach have different biogeochemical characteristics (e.g., moisture, salinity, terminal electron acceptors, nutrient, and oil composition) due, in part, to their location on the landscape. PMID- 24782850 TI - Effective bioremediation strategy for rapid in situ cleanup of anoxic marine sediments in mesocosm oil spill simulation. AB - The purpose of present study was the simulation of an oil spill accompanied by burial of significant amount of petroleum hydrocarbons (PHs) in coastal sediments. Approximately 1000 kg of sediments collected in Messina harbor were spiked with Bunker C furnace fuel oil (6500 ppm). The rapid consumption of oxygen by aerobic heterotrophs created highly reduced conditions in the sediments with subsequent recession of biodegradation rates. As follows, after 3 months of ageing, the anaerobic sediments did not exhibit any significant levels of biodegradation and more than 80% of added Bunker C fuel oil remained buried. Anaerobic microbial community exhibited a strong enrichment in sulfate-reducing PHs-degrading and PHs-associated Deltaproteobacteria. As an effective bioremediation strategy to clean up these contaminated sediments, we applied a Modular Slurry System (MSS) allowing the containment of sediments and their physical-chemical treatment, e.g., aeration. Aeration for 3 months has increased the removal of main PHs contaminants up to 98%. As revealed by CARD-FISH, qPCR, and 16S rRNA gene clone library analyses, addition of Bunker C fuel oil initially affected the activity of autochthonous aerobic obligate marine hydrocarbonoclastic bacteria (OMHCB), and after 1 month more than the third of microbial population was represented by Alcanivorax-, Cycloclasticus-, and Marinobacter-related organisms. In the end of the experiment, the microbial community composition has returned to a status typically observed in pristine marine ecosystems with no detectable OMHCB present. Eco-toxicological bioassay revealed that the toxicity of sediments after treatment was substantially decreased. Thus, our studies demonstrated that petroleum-contaminated anaerobic marine sediments could efficiently be cleaned through an in situ oxygenation which stimulates their self-cleaning potential due to reawakening of allochtonous aerobic OMHCB. PMID- 24782852 TI - Cooperation, communication, and co-evolution: grand challenges in microbial symbiosis research. PMID- 24782851 TI - Counteraction of the multifunctional restriction factor tetherin. AB - The interferon-inducible restriction factor tetherin (also known as CD317, BST-2 or HM1.24) has emerged as a key component of the antiviral immune response. Initially, tetherin was shown to restrict replication of various enveloped viruses by inhibiting the release of budding virions from infected cells. More recently, it has become clear that tetherin also acts as a pattern recognition receptor inducing NF-kappaB-dependent proinflammatory gene expression in virus infected cells. Whereas the ability to restrict virion release is highly conserved among mammalian tetherin orthologs and thus probably an ancient function of this protein, innate sensing seems to be an evolutionarily recent activity. The potent and broad antiviral activity of tetherin is reflected by the fact that many viruses evolved means to counteract this restriction factor. A continuous arms race with viruses has apparently driven the evolution of different isoforms of tetherin with different functional properties. Interestingly, tetherin has also been implicated in cellular processes that are unrelated to immunity, such as the organization of the apical actin network and membrane microdomains or stabilization of the Golgi apparatus. In this review, I summarize our current knowledge of the different functions of tetherin and describe the molecular strategies that viruses have evolved to antagonize or evade this multifunctional host restriction factor. PMID- 24782853 TI - Protective role of salt in catalysis and maintaining structure of halophilic proteins against denaturation. AB - Search for new industrial enzymes having novel properties continues to be a desirable pursuit in enzyme research. The halophilic organisms inhabiting under saline/ hypersaline conditions are considered as promising source of useful enzymes. Their enzymes are structurally adapted to perform efficient catalysis under saline environment wherein n0n-halophilic enzymes often lose their structure and activity. Haloenzymes have been documented to be polyextremophilic and withstand high temperature, pH, organic solvents, and chaotropic agents. However, this stability is modulated by salt. Although vast amount of information have been generated on salt mediated protection and structure function relationship in halophilic proteins, their clear understanding and correct perspective still remain incoherent. Furthermore, understanding their protein architecture may give better clue for engineering stable enzymes which can withstand harsh industrial conditions. The article encompasses the current level of understanding about haloadaptations and analyzes structural basis of their enzyme stability against classical denaturants. PMID- 24782854 TI - Glutamine synthetase 2 is not essential for biosynthesis of compatible solutes in Halobacillus halophilus. AB - Halobacillus halophilus, a moderately halophilic bacterium isolated from salt marshes, produces various compatible solutes to cope with osmotic stress. Glutamate and glutamine are dominant compatible solutes at mild salinities. Glutamine synthetase activity in cell suspensions of Halobacillus halophilus wild type was shown to be salt dependent and chloride modulated. A possible candidate to catalyze glutamine synthesis is glutamine synthetase A2, whose transcription is stimulated by chloride. To address the role of GlnA2 in the biosynthesis of the osmolytes glutamate and glutamine, a deletion mutant (DeltaglnA2) was generated and characterized in detail. We compared the pool of compatible solutes and performed transcriptional analyses of the principal genes controlling the solute production in the wild type strain and the deletion mutant. These measurements did not confirm the hypothesized role of GlnA2 in the osmolyte production. Most likely the presence of another, yet to be identified enzyme has the main contribution in the measured activity in crude extracts and probably determines the total chloride-modulated profile. The role of GlnA2 remains to be elucidated. PMID- 24782855 TI - Extracellular enzyme production and cheating in Pseudomonas fluorescens depend on diffusion rates. AB - Bacteria produce extracellular enzymes to obtain resources from complex chemical substrates, but this strategy is vulnerable to cheating by cells that take up reaction products without paying the cost of enzyme production. We hypothesized that cheating would suppress enzyme production in co-cultures of cheater and producer bacteria, particularly under well-mixed conditions. To test this hypothesis, we monitored protease expression and frequencies of Pseudomonas fluorescens producer and cheater genotypes over time in mixed liquid cultures and on agar plates. In mixed culture inoculated with equal frequencies of cheaters and producers, enzyme concentration declined to zero after 20 days, consistent with our hypothesis. We observed a similar decline in cultures inoculated with producers only, suggesting that cheater mutants arose de novo and swept the population. DNA sequencing showed that genetic changes most likely occurred outside the protease operon. In one experimental replicate, the population regained the ability to produce protease, likely due to further genetic changes or population dynamics. Under spatially structured conditions on agar plates, cheaters did not sweep the population. Instead, we observed a significant increase in the variation of enzyme activity levels expressed by clones isolated from the population. Together these results suggest that restricted diffusion favors a diversity of enzyme production strategies. In contrast, well-mixed conditions favor population sweeps by cheater strains, consistent with theoretical predictions. Cheater and producer strategies likely coexist in natural environments with the frequency of cheating increasing with diffusion rate. PMID- 24782856 TI - Biochemical aspects of bacterial strategies for handling the incomplete translation processes. AB - During protein synthesis in cells, translating ribosomes may encounter abnormal situations that lead to retention of immature peptidyl-tRNA on the ribosome due to failure of suitable termination processes. Bacterial cells handle such situations by employing three systems that rescue the stalled translation machinery. The transfer messenger RNA/small protein B (tmRNA/SmpB) system, also called the trans-translation system, rescues stalled ribosomes by initiating template switching from the incomplete mRNA to the short open reading frame of tmRNA, leading to the production of a protein containing a C-terminal tag that renders it susceptible to proteolysis. The ArfA/RF2 and ArfB systems rescue stalled ribosomes directly by hydrolyzing the immature peptidyl-tRNA remaining on the ribosome. Here, the biochemical aspects of these systems, as clarified by recent studies, are reviewed. PMID- 24782857 TI - Triactome: neuro-immune-adipose interactions. Implication in vascular biology. AB - Understanding how the precise interactions of nerves, immune cells, and adipose tissue account for cardiovascular and metabolic biology is a central aim of biomedical research at present. A long standing paradigm holds that the vascular wall is composed of three concentric tissue coats (tunicae): intima, media, and adventitia. However, large- and medium-sized arteries, where usually atherosclerotic lesions develop, are consistently surrounded by periadventitial adipose tissue (PAAT), we recently designated tunica adiposa (in brief, adiposa like intima, media, and adventitia). Today, atherosclerosis is considered an immune-mediated inflammatory disease featured by endothelial dysfunction/intimal thickening, medial atrophy, and adventitial lesions associated with adipose dysfunction, whereas hypertension is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell hypertrophy/hyperplasia. PAAT expansion is associated with increased infiltration of immune cells, both adipocytes and immunocytes secreting pro-inflammatory and anti-inflammatory (metabotrophic) signaling proteins collectively dubbed adipokines. However, the role of vascular nerves and their interactions with immune cells and paracrine adipose tissue is not yet evaluated in such an integrated way. The present review attempts to briefly highlight the findings in basic and translational sciences in this area focusing on neuro-immune-adipose interactions, herein referred to as triactome. Triactome-targeted pharmacology may provide a novel therapeutic approach in cardiovascular disease. PMID- 24782858 TI - Understanding the biology of antigen cross-presentation for the design of vaccines against cancer. AB - Antigen cross-presentation, the process in which exogenous antigens are presented on MHC class I molecules, is crucial for the generation of effector CD8(+) T cell responses. Although multiple cell types are being described to be able to cross present antigens, in vivo this task is mainly carried out by certain subsets of dendritic cells (DCs). Aspects such as the internalization route, the pathway of endocytic trafficking, and the simultaneous activation through pattern recognition receptors have a determining influence in how antigens are handled for cross-presentation by DCs. In this review, we will summarize new insights in factors that affect antigen cross-presentation of human DC subsets, and we will discuss the possibilities to exploit antigen cross-presentation for immunotherapy against cancer. PMID- 24782859 TI - Mouse models to study dengue virus immunology and pathogenesis. AB - The development of a compelling murine model of dengue virus (DENV) infection has been challenging, because DENV clinical isolates do not readily replicate or cause pathology in immunocompetent mice. However, research using immunocompromised mice and/or mouse-adapted viruses allows investigation of questions that may be impossible to address in human studies. In this review, we discuss the potential strengths and limitations of existing mouse models of dengue disease. Human studies are descriptive by nature; moreover, the strain, time, and sequence of infection are often unknown. In contrast, in mice, the conditions of infection are well defined and a large number of experimental parameters can be varied at will. Therefore, mouse models offer an opportunity to experimentally test hypotheses that are based on epidemiological observations. In particular, gain-of-function or loss-of-function models can be established to assess how different components of the immune system (either alone or in combination) contribute to protection or pathogenesis during secondary infections or after vaccination. In addition, mouse models have been used for pre-clinical testing of anti-viral drugs or for vaccine development studies. Conclusions based on mouse experiments must be extrapolated to DENV-infection in humans with caution due to the inherent limitations of animal models. However, research in mouse models is a useful complement to in vitro and epidemiological data, and may delineate new areas that deserve attention during future human studies. PMID- 24782861 TI - Evolving strategies for cancer and autoimmunity: back to the future. AB - Although current thinking has focused on genetic variation between individuals and environmental influences as underpinning susceptibility to both autoimmunity and cancer, an alternative view is that human susceptibility to these diseases is a consequence of the way the immune system evolved. It is important to remember that the immunological genes that we inherit and the systems that they control were shaped by the drive for reproductive success rather than for individual survival. It is our view that human susceptibility to autoimmunity and cancer is the evolutionarily acceptable side effect of the immune adaptations that evolved in early placental mammals to accommodate a fundamental change in reproductive strategy. Studies of immune function in mammals show that high affinity antibodies and CD4 memory, along with its regulation, co-evolved with placentation. By dissection of the immunologically active genes and proteins that evolved to regulate this step change in the mammalian immune system, clues have emerged that may reveal ways of de-tuning both effector and regulatory arms of the immune system to abrogate autoimmune responses whilst preserving protection against infection. Paradoxically, it appears that such a detuned and deregulated immune system is much better equipped to mount anti-tumor immune responses against cancers. PMID- 24782860 TI - Towards a liquid self: how time, geography, and life experiences reshape the biological identity. AB - The conceptualization of immunological self is amongst the most important theories of modern biology, representing a sort of theoretical guideline for experimental immunologists, in order to understand how host constituents are ignored by the immune system (IS). A consistent advancement in this field has been represented by the danger/damage theory and its subsequent refinements, which at present represents the most comprehensive conceptualization of immunological self. Here, we present the new hypothesis of "liquid self," which integrates and extends the danger/damage theory. The main novelty of the liquid self hypothesis lies in the full integration of the immune response mechanisms into the host body's ecosystems, i.e., in adding the temporal, as well as the geographical/evolutionary and environmental, dimensions, which we suggested to call "immunological biography." Our hypothesis takes into account the important biological changes occurring with time (age) in the IS (including immunosenescence and inflammaging), as well as changes in the organismal context related to nutrition, lifestyle, and geography (populations). We argue that such temporal and geographical dimensions impinge upon, and continuously reshape, the antigenicity of physical entities (molecules, cells, bacteria, viruses), making them switching between "self" and "non-self" states in a dynamical, "liquid" fashion. Particular attention is devoted to oral tolerance and gut microbiota, as well as to a new potential source of unexpected self epitopes produced by proteasome splicing. Finally, our framework allows the set up of a variety of testable predictions, the most straightforward suggesting that the immune responses to defined molecules representing potentials antigens will be quantitatively and qualitatively quite different according to the immuno biographical background of the host. PMID- 24782862 TI - The Interplay between Chromatin and Transcription Factor Networks during B Cell Development: Who Pulls the Trigger First? AB - All mature blood cells derive from hematopoietic stem cells through gradual restriction of their cell fate potential and acquisition of specialized functions. Lineage specification and cell commitment require the establishment of specific transcriptional programs involving the activation of lineage-specific genes and the repression of lineage-inappropriate genes. This process requires the concerted action of transcription factors (TFs) and epigenetic modifying enzymes. Within the hematopoietic system, B lymphopoiesis is one of the most studied differentiation programs. Loss of function studies allowed the identification of many TFs and epigenetic modifiers required for B cell development. The usage of systematic analytical techniques such as transcriptome determination, genome-wide mapping of TF binding and epigenetic modifications, and mass spectrometry analyses, allowed to gain a systemic description of the intricate networks that guide B cell development. However, the precise mechanisms governing the interaction between TFs and chromatin are still unclear. Generally, chromatin structure can be remodeled by some TFs but in turn can also regulate (i.e., prevent or promote) the binding of other TFs. This conundrum leads to the crucial questions of who is on first, when, and how. We review here the current knowledge about TF networks and epigenetic regulation during hematopoiesis, with an emphasis on B cell development, and discuss in particular the current models about the interplay between chromatin and TFs. PMID- 24782863 TI - Organizing MHC Class II Presentation. AB - Major histocompatibility complex (MHC) class II molecules are ligands for CD4(+) T cells and are critical for initiating the adaptive immune response. This review is focused on what is currently known about MHC class II organization at the plasma membrane of antigen presenting cells and how this affects antigen presentation to T cells. The organization and diffusion of class II molecules have been measured by a variety of biochemical and microscopic techniques. Membrane lipids and other proteins have been implicated in MHC class II organization and function. However, when compared with the organization of MHC class I or TCR complexes, much less is known about MHC class II. Since clustering of T cell receptors occurs during activation, the organization of MHC molecules prior to recognition and during synapse formation may be critical for antigen presentation. PMID- 24782864 TI - Cross-Talks between Natural Killer Cells and Distinct Subsets of Dendritic Cells. AB - In recent years, the essential role of bi-directional cross-talk between natural killer (NK) and dendritic cells (DC) during immune responses has been clearly elucidated. In particular, this cross-talk results in the development of an efficient innate response, through DC-mediated NK cell activation, and a potent adaptive immune response, through NK-mediate DC editing and maturation. Recently, some novel human DC subsets have been identified: migratory DCs in afferent lymph and draining lymph nodes; CLEC9A(+)/BDCA3(+) (CD141) DCs in interstitial dermis, liver, lung; inflammatory DCs in several inflammatory fluids. At the same time, it has been shown that also human NK cells are present in these compartments. Here, we will review the most recent findings on NK/DC cross-talk and we will discuss the necessity of acquiring more complete knowledge about these interactions in view of the new information available on both DC and NK cell subsets. PMID- 24782865 TI - Plasma exosomes as markers of therapeutic response in patients with acute myeloid leukemia. AB - PURPOSE: Exosomes isolated from the plasma of newly diagnosed acute myeloid leukemia (AML) patients have elevated protein and transforming growth factor-beta 1 (TGF-beta1) contents and inhibit natural killer (NK) cell cytotoxicity (Haematologica 96, p. 1302, 2011). A potential role of exosomes in predicting responses to chemotherapy (CT) was evaluated in AML patients undergoing treatment. EXPERIMENTAL DESIGN: Plasma was obtained from AML patients at diagnosis (n = 16); post-induction CT (n = 9); during consolidation CT (n = 10); in long-term remission (Lt-CR, n = 5); and from healthy volunteers (n = 7). Exosomes were isolated by size-exclusion chromatography and ultracentrifugation. The exosomal protein, soluble TGFbeta-1 levels (ELISA), and the TGF-beta1 profiles (western blots) were compared among patients' cohorts. The results were correlated with the patients' cytogenetic profile, percentage of leukemic blast, and outcome. RESULTS: At diagnosis, protein and TGF-beta1 levels were higher (p < 0.009 and p < 0.004) in AML than control exosomes. These values decreased after induction CT (p < 0.05 and p < 0.004), increased during consolidation CT (p < 0.02 and p < 0.005), and normalized in Lt-CR. While TGF-beta1 and protein levels tracked one another, TGF-beta1 pro-peptide, latency-associated peptide (LAP), or mature TGF-beta1 differentially decorated exosomes isolated before, during, and after CT. Only TGF-beta1 pro-peptide was seen in exosomes of controls or Lt-CR patients. During consolidation CT, exosomes carried TGF-beta1 pro-peptide, LAP, and low levels of mature TGF-beta1. NK cell co-incubation with AML exosomes carrying all three TGF-beta1 forms induced down-regulation of NKG2D expression. CONCLUSION: Changes in exosomal protein and/or TGF-beta1 content may reflect responses to CT. The exosomal profile may suggest the presence of residual disease in patients considered to have achieved complete remission. PMID- 24782866 TI - Cancer: A Tale of Aberrant PRR Response. PMID- 24782867 TI - Breaking immunological tolerance in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a fairly heterogeneous autoimmune disease of unknown etiology that mainly affects women in the childbearing age. SLE is a prototype type III hypersensitivity reaction in which immune complex depositions cause inflammation and tissue damage in multiple organs. Two distinct cell death pathways, apoptosis and NETosis, gained a great deal of interest among scientists, since both processes seem to be deregulated in SLE. There is growing evidence that histone modifications induced by these cell death pathways exert a central role in the induction of autoimmunity. In the current review, we discuss how abnormalities in apoptosis, NETosis, and histone modifications may lead to a break of immunological tolerance in SLE. PMID- 24782869 TI - An Interaction Library for the FcepsilonRI Signaling Network. AB - Antigen receptors play a central role in adaptive immune responses. Although the molecular networks associated with these receptors have been extensively studied, we currently lack a systems-level understanding of how combinations of non covalent interactions and post-translational modifications are regulated during signaling to impact cellular decision-making. To fill this knowledge gap, it will be necessary to formalize and piece together information about individual molecular mechanisms to form large-scale computational models of signaling networks. To this end, we have developed an interaction library for signaling by the high-affinity IgE receptor, FcepsilonRI. The library consists of executable rules for protein-protein and protein-lipid interactions. This library extends earlier models for FcepsilonRI signaling and introduces new interactions that have not previously been considered in a model. Thus, this interaction library is a toolkit with which existing models can be expanded and from which new models can be built. As an example, we present models of branching pathways from the adaptor protein Lat, which influence production of the phospholipid PIP3 at the plasma membrane and the soluble second messenger IP3. We find that inclusion of a positive feedback loop gives rise to a bistable switch, which may ensure robust responses to stimulation above a threshold level. In addition, the library is visualized to facilitate understanding of network circuitry and identification of network motifs. PMID- 24782868 TI - Paradigm Shift in Dendritic Cell-Based Immunotherapy: From in vitro Generated Monocyte-Derived DCs to Naturally Circulating DC Subsets. AB - Dendritic cell (DC)-based immunotherapy employs the patients' immune system to fight neoplastic lesions spread over the entire body. This makes it an important therapy option for patients suffering from metastatic melanoma, which is often resistant to chemotherapy. However, conventional cellular vaccination approaches, based on monocyte-derived DCs (moDCs), only achieved modest response rates despite continued optimization of various vaccination parameters. In addition, the generation of moDCs requires extensive ex vivo culturing conceivably hampering the immunogenicity of the vaccine. Recent studies, thus, focused on vaccines that make use of primary DCs. Though rare in the blood, these naturally circulating DCs can be readily isolated and activated thereby circumventing lengthy ex vivo culture periods. The first clinical trials not only showed increased survival rates but also the induction of diversified anti-cancer immune responses. Upcoming treatment paradigms aim to include several primary DC subsets in a single vaccine as pre-clinical studies identified synergistic effects between various antigen-presenting cells. PMID- 24782870 TI - Stimulation of monocytes by placental microparticles involves toll-like receptors and nuclear factor kappa-light-chain-enhancer of activated B cells. AB - Human pregnancy is accompanied by a mild systemic inflammatory response, which includes the activation of monocytes circulating in maternal blood. This response is exaggerated in preeclampsia, a placental-dependent disorder specific to human pregnancies. We and others showed that placental syncytiotrophoblast membrane microparticles (STBM) generated in vitro from normal placentas stimulated peripheral blood monocytes, which suggest a contribution of STBM to the systemic maternal inflammation. Here, we analyzed the inflammatory potential of STBM prepared from preeclamptic placentas on primary monocytes and investigated the mode of action in vitro. STBM generated in vitro by placental villous explants of normal or preeclamptic placentas were co-incubated with human peripheral blood monocytes. In some cases, inhibitors of specific cellular functions or signaling pathways were used. The analysis of the monocytic response was performed by flow cytometry, enzyme-linked immunoassays, real-time PCR, and fluorescence microscopy. STBM derived from preeclamptic placentas up-regulated the cell surface expression of CD54, and stimulated the secretion of the pro-inflammatory interleukin (IL)-6 and IL-8 in a similar, dose-dependent manner as did STBM prepared from normal placentas. STBM bound to the cell surface of monocytes, but phagocytosis was not necessary for activation. STBM-induced cytokine secretion was impaired in the presence of inhibitors of toll-like receptor (TLR) signaling or when nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) activation was blocked. Our results suggest that the inflammatory reaction in monocytes may be initiated by the interaction of STBM with TLRs, which in turn signal through NF-kappaB to mediate the transcription of genes coding for pro-inflammatory factors. PMID- 24782871 TI - How Do CD4(+) T Cells Detect and Eliminate Tumor Cells That Either Lack or Express MHC Class II Molecules? AB - CD4(+) T cells contribute to tumor eradication, even in the absence of CD8(+) T cells. Cytotoxic CD4(+) T cells can directly kill MHC class II positive tumor cells. More surprisingly, CD4(+) T cells can indirectly eliminate tumor cells that lack MHC class II expression. Here, we review the mechanisms of direct and indirect CD4(+) T cell-mediated elimination of tumor cells. An emphasis is put on T cell receptor (TCR) transgenic models, where anti-tumor responses of naive CD4(+) T cells of defined specificity can be tracked. Some generalizations can tentatively be made. For both MHCII(POS) and MHCII(NEG) tumors, presentation of tumor-specific antigen by host antigen-presenting cells (APCs) appears to be required for CD4(+) T cell priming. This has been extensively studied in a myeloma model (MOPC315), where host APCs in tumor-draining lymph nodes are primed with secreted tumor antigen. Upon antigen recognition, naive CD4(+) T cells differentiate into Th1 cells and migrate to the tumor. At the tumor site, the mechanisms for elimination of MHCII(POS) and MHCII(NEG) tumor cells differ. In a TCR-transgenic B16 melanoma model, MHCII(POS) melanoma cells are directly killed by cytotoxic CD4(+) T cells in a perforin/granzyme B-dependent manner. By contrast, MHCII(NEG) myeloma cells are killed by IFN-gamma stimulated M1-like macrophages. In summary, while the priming phase of CD4(+) T cells appears similar for MHCII(POS) and MHCII(NEG) tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed. PMID- 24782872 TI - Reticulate leaves and stunted roots are independent phenotypes pointing at opposite roles of the phosphoenolpyruvate/phosphate translocator defective in cue1 in the plastids of both organs. AB - Phosphoenolpyruvate (PEP) serves not only as a high energy carbon compound in glycolysis, but it acts also as precursor for plastidial anabolic sequences like the shikimate pathway, which produces aromatic amino acids (AAA) and subsequently secondary plant products. After conversion to pyruvate, PEP can also enter de novo fatty acid biosynthesis, the synthesis of branched-chain amino acids, and the non-mevalonate way of isoprenoid production. As PEP cannot be generated by glycolysis in chloroplasts and a variety of non-green plastids, it has to be imported from the cytosol by a phosphate translocator (PT) specific for PEP (PPT). A loss of function of PPT1 in Arabidopsis thaliana results in the chlorophyll a/b binding protein underexpressed1 (cue1) mutant, which is characterized by reticulate leaves and stunted roots. Here we dissect the shoot- and root phenotypes, and also address the question whether or not long distance signaling by metabolites is involved in the perturbed mesophyll development of cue1. Reverse grafting experiments showed that the shoot- and root phenotypes develop independently from each other, ruling out long distance metabolite signaling. The leaf phenotype could be transiently modified even in mature leaves, e.g. by an inducible PPT1RNAi approach or by feeding AAA, the cytokinin trans-zeatin (tZ), or the putative signaling molecule dehydrodiconiferyl alcohol glucoside (DCG). Hormones, such as auxins, abscisic acid, gibberellic acid, ethylene, methyl jasmonate, and salicylic acid did not rescue the cue1 leaf phenotype. The low cell density1 (lcd1) mutant shares the reticulate leaf-, but not the stunted root phenotype with cue1. It could neither be rescued by AAA nor by tZ. In contrast, tZ and AAA further inhibited root growth both in cue1 and wild-type plants. Based on our results, we propose a model that PPT1 acts as a net importer of PEP into chloroplast, but as an overflow valve and hence exporter in root plastids. PMID- 24782873 TI - Bacterial quorum sensing compounds are important modulators of microbe-plant interactions. PMID- 24782874 TI - Regulation of cell fate determination by single-repeat R3 MYB transcription factors in Arabidopsis. AB - MYB transcription factors regulate multiple aspects of plant growth and development. Among the large family of MYB transcription factors, single-repeat R3 MYBs are characterized by their short sequence (<120 amino acids) consisting largely of the single MYB DNA-binding repeat. In the model plant Arabidopsis, R3 MYBs mediate lateral inhibition during epidermal patterning and are best characterized for their regulatory roles in trichome and root hair development. R3 MYBs act as negative regulators for trichome formation but as positive regulators for root hair development. In this article, we provide a comprehensive review on the role of R3 MYBs in the regulation of cell type specification in the model plant Arabidopsis. PMID- 24782875 TI - Involvement of autophagy in the direct ER to vacuole protein trafficking route in plants. AB - Trafficking of proteins from the endoplasmic reticulum (ER) to the vacuole is a fundamental process in plants, being involved both in vacuole biogenesis as well as with plant growth and response to environmental stresses. Although the canonical transport of cellular components from the ER to the vacuole includes the Golgi apparatus as an intermediate compartment, there are multiple lines of evidence that support the existence of a direct ER-to-vacuole, Golgi-independent, trafficking route in plants that uses the autophagy machinery. Plant autophagy was initially described by electron microscopy, visualizing cellular structures that are morphologically reminiscent of autophagosomes. In some of these reports these structures were shown to transport vacuole residing proteins, particularly seed storage proteins, directly from the ER to the vacuole. More recently, following the discovery of the proteins of the core autophagy machinery, molecular tools were implemented in deciphering the involvement of autophagy in this special trafficking route. Here we review the relatively older and more recent scientific observations, supporting the involvement of autophagy in the special cellular trafficking pathways of plants. PMID- 24782876 TI - A unifying modeling of plant shoot gravitropism with an explicit account of the effects of growth. AB - Gravitropism, the slow reorientation of plant growth in response to gravity, is a major determinant of the form and posture of land plants. Recently a universal model of shoot gravitropism, the AC model, was presented, in which the dynamics of the tropic movement is only determined by the conflicting controls of (1) graviception that tends to curve the plants toward the vertical, and (2) proprioception that tends to keep the stem straight. This model was found to be valid for many species and over two orders of magnitude of organ size. However, the motor of the movement, the elongation, was purposely neglected in the AC model. If growth effects are to be taken into account, it is necessary to consider the material derivative, i.e., the rate of change of curvature bound to expanding and convected organ elements. Here we show that it is possible to rewrite the material equation of curvature in a compact simplified form that directly expresses the curvature variation as a function of the median elongation and of the distribution of the differential growth. By using this extended model, called the ACE model, growth is found to have two main destabilizing effects on the tropic movement: (1) passive orientation drift, which occurs when a curved element elongates without differential growth, and (2) fixed curvature, when an element leaves the elongation zone and is no longer able to actively change its curvature. By comparing the AC and ACE models to experiments, these two effects are found to be negligible. Our results show that the simplified AC mode can be used to analyze gravitropism and posture control in actively elongating plant organs without significant information loss. PMID- 24782877 TI - Analysis of apical hook formation in Alaska pea with a 3-D clinostat and agravitropic mutant ageotropum. AB - The formation of the apical hook in dicotyledonous seedlings is believed to be effected by gravity in the dark. However, this notion is mostly based on experiments with the hook formed on the hypocotyl, and no detailed studies are available with the developmental manners of the hook, particularly of the epicotyl hook. The present study aims at clarifying the dynamics of hook formation including the possible involvement of gravity. Time-course studies with normal Alaska pea (Pisum sativum L., cv. Alaska) and an agravitropic pea mutant, ageotropum, under the 1-g conditions and on a 3-D clinostat revealed that (1) the apical hook of the epicotyl forms by the development of the arc-shaped plumule of the embryo existing in the non-germinated seed. The process of formation consists of two stages: development and partial opening, which are controlled by some intrinsic property of the plumule, but not gravity. Approximately when the epicotyl emerges from the seed coat, the hook is established in both pea varieties. In Alaska the established hook is sustained or enhanced by gravity, resulting in a delay of hook opening compared with on a clinostat, which might give an incorrect idea that gravity causes hook formation. (2) During the hook development and opening processes the original plumular arc holds its orientation unchanged to be an established hook, which, therefore, is at the same side of the epicotyl axis as the cotyledons. This is true for both Alaska and ageotropum under 1-g conditions as well as on the clinostat, supporting finding (1). (3) Application of auxin polar transport inhibitors, hydroxyfluorenecarboxylic acid, naphthylphthalamic acid, and triiodobenzoic acid, suppressed the curvature of hook by equal extents in Alaska as well as ageotropum, suggesting that the hook development involves auxin polar transport probably asymmetrically distributed across the plumular axis by some intrinsic property of the plumule not directly related with gravity action. PMID- 24782878 TI - Degradation of plant peroxisomes by autophagy. AB - Peroxisomes play a critical role in many metabolic pathways during the plant life cycle. It has been proposed that the transition between different types of peroxisomes involves the degradation of obsolete peroxisomal enzymes via proteolytic activities in the peroxisome matrix, the cytosol, or the vacuole. Forward and reverse genetic studies recently provided evidence for autophagic degradation of peroxisomes in the vacuole of Arabidopsis seedlings. Here, we briefly review a model of pexophagy, or selective autophagy of peroxisomes, in plant cells. PMID- 24782879 TI - Mitochondrial Band-7 family proteins: scaffolds for respiratory chain assembly? AB - The band-7 protein family comprises a diverse set of membrane-bound proteins characterized by the presence of a conserved domain. The exact function of this band-7 domain remains elusive, but examples from animal and bacterial stomatin type proteins demonstrate binding to lipids and the ability to assemble into membrane-bound oligomers that form putative scaffolds. Some members, such as prohibitins (PHB) and human stomatin-like protein 2 (HsSLP2), localize to the mitochondrial inner membrane where they function in cristae formation and hyperfusion. In Arabidopsis, the band-7 protein family has diversified and includes plant-specific members. Mitochondrial-localized members include prohibitins (AtPHBs) and two stomatin-like proteins (AtSLP1 and -2). Studies into PHB function in plants have demonstrated an involvement in root meristem proliferation and putative scaffold formation for mAAA proteases, but it remains unknown how these roles are achieved at the molecular level. In this minireview we summarize the current status of band-7 protein functions in Arabidopsis, and speculate how the mitochondrial members might recruit specific lipids to form microdomains that could shape the organization and functioning of the respiratory chain. PMID- 24782881 TI - beta-catenin in plants and animals: common players but different pathways. PMID- 24782880 TI - Competence and regulatory interactions during regeneration in plants. AB - The ability to regenerate is widely exploited by multitudes of organisms ranging from unicellular bacteria to multicellular plants for their propagation and repair. But the levels of competence for regeneration vary from species to species. While variety of living cells of a plant display regeneration ability, only a few set of cells maintain their stemness in mammals. This highly pliable nature of plant cells in-terms of regeneration can be attributed to their high developmental plasticity. De novo organ initiation can be relatively easily achieved in plants by proper hormonal regulations. Elevated levels of plant hormone auxin induces the formation of proliferating mass of pluripotent cells called callus, which predominantly express lateral root meristem markers and hence is having an identity similar to lateral root primordia. Organ formation can be induced from the callus by modulating the ratio of hormones. An alternative for de novo organogenesis is by the forced expression of plant specific transcription factors. The mechanisms by which plant cells attain competence for regeneration on hormonal treatment or forced expression remain largely elusive. Recent studies have provided some insight into how the epigenetic modifications in plants affect this competence. In this review we discuss the present understanding of regenerative biology in plants and scrutinize the future prospectives of this topic. While discussing about the regeneration in the sporophyte of angiosperms which is well studied, here we outline the regenerative biology of the gametophytic phase and discuss about various strategies of regeneration that have evolved in the domain of life so that a common consensus on the entire process of regeneration can be made. PMID- 24782882 TI - Impact of 1-methylcyclopropene and controlled atmosphere storage on polyamine and 4-aminobutyrate levels in "Empire" apple fruit. AB - 1-Methylcyclopropene (1-MCP) delays ethylene-meditated ripening of apple (Malus domestica Borkh.) fruit during controlled atmosphere (CA) storage. Here, we tested the hypothesis that 1-MCP and CA storage enhances the levels of polyamines (PAs) and 4-aminobutyrate (GABA) in apple fruit. A 46-week experiment was conducted with "Empire" apple using a split-plot design with four treatment replicates and 3 degrees C, 2.5 kPa O2, and 0.03 or 2.5 kPa CO2 with or without 1 MUL L(-1) 1-MCP. Total PA levels were not elevated by the 1-MCP treatment. Examination of the individual PAs revealed that: (i) total putrescine levels tended to be lower with 1-MCP regardless of the CO2 level, and while this was mostly at the expense of free putrescine, large transient increases in soluble conjugated putrescine were also evident; (ii) total spermidine levels tended to be lower with 1-MCP, particularly at 2.5 kPa CO2, and this was mostly at the expense of soluble conjugated spermidine; (iii) total spermine levels at 2.5 kPa CO2 tended to be lower with 1-MCP, and this was mostly at the expense of both soluble and insoluble conjugated spermine; and (iv) total spermidine and spermine levels at 0.03 kPa were relatively unaffected, compared to 2.5 kPa CO2, but transient increases in free spermidine and spermine were evident. These findings might be due to changes in the conversion of putrescine into higher PAs and the interconversion of free and conjugated forms in apple fruit, rather than altered S-adenosylmethionine availability. Regardless of 1-MCP and CO2 treatments, the availability of glutamate showed a transient peak initially, probably due to protein degradation, and this was followed by a steady decline over the remainder of the storage period which coincided with linear accumulation of GABA. This pattern has been attributed to the stimulation of glutamate decarboxylase activity and inhibition of GABA catabolism, rather than a contribution of PAs to GABA production. PMID- 24782883 TI - Evolution and significance of the Lon gene family in Arabidopsis organelle biogenesis and energy metabolism. AB - Lon is the first identified ATP-dependent protease highly conserved across all kingdoms. Model plant species Arabidopsis thaliana has a small Lon gene family of four members. Although these genes share common structural features, they have distinct properties in terms of gene expression profile, subcellular targeting and substrate recognition motifs. This supports the notion that their functions under different environmental conditions are not necessarily redundant. This article intends to unravel the biological role of Lon proteases in energy metabolism and plant growth through an evolutionary perspective. Given that plants are sessile organisms exposed to diverse environmental conditions and plant organelles are semi-autonomous, it is tempting to suggest that Lon genes in Arabidopsis are paralogs. Adaptive evolution through repetitive gene duplication events of a single archaic gene led to Lon genes with complementing sets of subfunctions providing to the organism rapid adaptability for canonical development under different environmental conditions. Lon1 function is adequately characterized being involved in mitochondrial biogenesis, modulating carbon metabolism, oxidative phosphorylation and energy supply, all prerequisites for seed germination and seedling establishment. Lon is not a stand-alone proteolytic machine in plant organelles. Lon in association with other nuclear-encoded ATP dependent proteases builds up an elegant nevertheless, tight interconnected circuit. This circuitry channels properly and accurately, proteostasis and protein quality control among the distinct subcellular compartments namely mitochondria, chloroplasts, and peroxisomes. PMID- 24782884 TI - The FLC-like gene BvFL1 is not a major regulator of vernalization response in biennial beets. AB - Many plant species in temperate climate regions require vernalization over winter to initiate flowering. Flowering Locus C (FLC) and FLC-like genes are key regulators of vernalization requirement and growth habit in winter-annual and perennial Brassicaceae. In the biennial crop species Beta vulgaris ssp. vulgaris in the evolutionarily distant Caryophyllales clade of core eudicots growth habit and bolting time are controlled by the vernalization and photoperiod response gene BTC1 and the downstream BvFT1-BvFT2 module. B. vulgaris also contains a vernalization-responsive FLC homolog (BvFL1). Here, to further elucidate the regulation of vernalization response and growth habit in beet, we functionally characterized BvFL1 by RNAi and over-expression in transgenic plants. BvFL1 RNAi neither eliminated the requirement for vernalization of biennial beets nor had a major effect on bolting time after vernalization. Over-expression of BvFL1 resulted in a moderate late-bolting phenotype, with bolting after vernalization being delayed by approximately 1 week. By contrast, RNAi-induced down-regulation of the BvFT1-BvFT2 module led to a strong delay in bolting after vernalization by several weeks. The data demonstrate for the first time that an FLC homolog does not play a major role in the control of vernalization response in a dicot species outside the Brassicaceae. PMID- 24782886 TI - The genetics of indirect ecological effects-plant parasites and aphid herbivores. AB - When parasitic plants and aphid herbivores share a host, both direct and indirect ecological effects (IEEs) can influence evolutionary processes. We used a hemiparasitic plant (Rhinanthus minor), a grass host (Hordeum vulgare) and a cereal aphid (Sitobion avenae) to investigate the genetics of IEEs between the aphid and the parasitic plant, and looked to see how these might affect or be influenced by the genetic diversity of the host plants. Survival of R. minor depended on the parasite's population of origin, the genotypes of the aphids sharing the host and the genetic diversity in the host plant community. Hence the indirect effects of the aphids on the parasitic plants depended on the genetic environment of the system. Here, we show that genetic variation can be important in determining the outcome of IEEs. Therefore, IEEs have the potential to influence evolutionary processes and the continuity of species interactions over time. PMID- 24782885 TI - Fine tuning of trehalose biosynthesis and hydrolysis as novel tools for the generation of abiotic stress tolerant plants. AB - The impact of abiotic stress on plant growth and development has been and still is a major research topic. An important pathway that has been linked to abiotic stress tolerance is the trehalose biosynthetic pathway. Recent findings showed that trehalose metabolism is also important for normal plant growth and development. The intermediate compound - trehalose-6-phosphate (T6P) - is now confirmed to act as a sensor for available sucrose, hereby directly influencing the type of response to the changing environmental conditions. This is possible because T6P and/or trehalose or their biosynthetic enzymes are part of complex interaction networks with other crucial hormone and sugar-induced signaling pathways, which may function at different developmental stages. Because of its effect on plant growth and development, modification of trehalose biosynthesis, either at the level of T6P synthesis, T6P hydrolysis, or trehalose hydrolysis, has been utilized to try to improve crop yield and biomass. It was shown that alteration of the amounts of either T6P and/or trehalose did result in increased stress tolerance, but also resulted in many unexpected phenotypic alterations. A main challenge is to characterize the part of the signaling pathway resulting in improved stress tolerance, without affecting the pathways resulting in the unwanted phenotypes. One such specific pathway where modification of trehalose metabolism improved stress tolerance, without any side effects, was recently obtained by overexpression of trehalase, which results in a more sensitive reaction of the stomatal guard cells and closing of the stomata under drought stress conditions. We have used the data that have been obtained from different studies to generate the optimal plant that can be constructed based on modifications of trehalose metabolism. PMID- 24782887 TI - Pharmacogenomics in oncology care. AB - Cancer pharmacogenomics have contributed a number of important discoveries to current cancer treatment, changing the paradigm of treatment decisions. Both somatic and germline mutations are utilized to better understand the underlying biology of cancer growth and treatment response. The level of evidence required to fully translate pharmacogenomic discoveries into the clinic has relied heavily on randomized control trials. In this review, the use of observational studies, as well as, the use of adaptive trials and next generation sequencing to develop the required level of evidence for clinical implementation are discussed. PMID- 24782888 TI - Paired-like homeodomain 2: a novel therapeutic target for atrial fibrillation? PMID- 24782889 TI - Impact of artifact removal on ChIP quality metrics in ChIP-seq and ChIP-exo data. AB - With the advent of ChIP-seq multiplexing technologies and the subsequent increase in ChIP-seq throughput, the development of working standards for the quality assessment of ChIP-seq studies has received significant attention. The ENCODE consortium's large scale analysis of transcription factor binding and epigenetic marks as well as concordant work on ChIP-seq by other laboratories has established a new generation of ChIP-seq quality control measures. The use of these metrics alongside common processing steps has however not been evaluated. In this study, we investigate the effects of blacklisting and removal of duplicated reads on established metrics of ChIP-seq quality and show that the interpretation of these metrics is highly dependent on the ChIP-seq preprocessing steps applied. Further to this we perform the first investigation of the use of these metrics for ChIP-exo data and make recommendations for the adaptation of the NSC statistic to allow for the assessment of ChIP-exo efficiency. PMID- 24782890 TI - Connecting functional and statistical definitions of genotype by genotype interactions in coevolutionary studies. AB - Predicting how species interactions evolve requires that we understand the mechanistic basis of coevolution, and thus the functional genotype-by-genotype interactions (G * G) that drive reciprocal natural selection. Theory on host parasite coevolution provides testable hypotheses for empiricists, but depends upon models of functional G * G that remain loosely tethered to the molecular details of any particular system. In practice, reciprocal cross-infection studies are often used to partition the variation in infection or fitness in a population that is attributable to G * G (statistical G * G). Here we use simulations to demonstrate that within-population statistical G * G likely tells us little about the existence of coevolution, its strength, or the genetic basis of functional G * G. Combined with studies of multiple populations or points in time, mapping and molecular techniques can bridge the gap between natural variation and mechanistic models of coevolution, while model-based statistics can formally confront coevolutionary models with cross-infection data. Together these approaches provide a robust framework for inferring the infection genetics underlying statistical G * G, helping unravel the genetic basis of coevolution. PMID- 24782892 TI - Why network approach can promote a new way of thinking in biology. AB - This work deals with the particular nature of network-based approach in biology. We will comment about the shift from the consideration of the molecular layer as the definitive place where causative process start to the elucidation of the among elements (at any level of biological organization they are located) interaction network as the main goal of scientific explanation. This shift comes from the intrinsic nature of networks where the properties of a specific node are determined by its position in the entire network (top-down explanation) while the global network characteristics emerge from the nodes wiring pattern (bottom-up explanation). This promotes a "middle-out" paradigm formally identical to the time honored chemical thought holding big promises in the study of biological regulation. PMID- 24782893 TI - PPARs and Metabolic Syndrome. PMID- 24782891 TI - Chromatin regulators, phenotypic robustness, and autism risk. AB - Though extensively characterized clinically, the causes of autism spectrum disorder (ASD) remain a mystery. ASD is known to have a strong genetic basis, but it is genetically very heterogeneous. Recent studies have estimated that de novo disruptive mutations in hundreds of genes may contribute to ASD. However, it is unclear how it is possible for mutations in so many different genes to contribute to ASD. Recent findings suggest that many of the mutations disrupt genes involved in transcription regulation that are expressed prenatally in the developing brain. De novo disruptive mutations are also more frequent in girls with ASD, despite the fact that ASD is more prevalent in boys. In this paper, we hypothesize that loss of robustness may contribute to ASD. Loss of phenotypic robustness may be caused by mutations that disrupt capacitors that operate in the developing brain. This may lead to the release of cryptic genetic variation that contributes to ASD. Reduced robustness is consistent with the observed variability in expressivity and incomplete penetrance. It is also consistent with the hypothesis that the development of the female brain is more robust, and it may explain the higher rate and severity of disruptive de novo mutations in girls with ASD. PMID- 24782895 TI - Hydatid disease located in the cerebellomedullary cistern. AB - Hydatid disease is an endemic zoonotic disease in many areas of the world. Liver, followed by lung, is the most commonly affected organ and involvement of other organs is rare. When brain is involved, lesions are typically supratentorial, and infratentorial localisation is even rarer. We present a 45-year-old woman with hydatid disease located in premedullary location compressing the brain stem, an exceedingly rare location for cerebral echinococcosis. Relevant literature regarding typical properties of cerebral disease was reviewed. PMID- 24782894 TI - The Prediction of ADL and IADL Disability Using Six Physical Indicators of Frailty: A Longitudinal Study in the Netherlands. AB - Frailty is a predictor of disability. A proper understanding of the contribution of individual indicators of frailty in the prediction of disability is a requisite for preventive interventions. The aim of this study was to determine the predictive power of the individual physical frailty indicators: gait speed, physical activity, hand grip strength, Body Mass Index (BMI), fatigue, and balance, for ADL and IADL disability. The sample consisted of 505 community dwelling persons (>=75 years, response rate 35.1%). Respondents first participated between November 2007 and June 2008, and a subset of all respondents participated again one year later (N = 264, 52.3% response rate). ADL and IADL disability were assessed by the Groningen Activity Restriction Scale. BMI was assessed by self-report, and the other physical frailty indicators were assessed with the TUG test (gait speed), the LAPAQ (physical activity), a hand grip strength test, the SFQ (fatigue), and the Four-test balance scale. All six physical frailty indicators were associated with ADL and IADL disability. After controlling for previous disability, sociodemographic characteristics, self perceived lifestyle, and chronic diseases, only gait speed was predictive of both ADL and IADL disability, whereas there was a small effect of fatigue on IADL disability. Hence, these physical frailty indicators should be included in frailty assessment when predicting future disability. PMID- 24782896 TI - A confusing coincidence: neonatal hypoglycemic seizures and hyperekplexia. AB - Hyperekplexia is a rare, nonepileptic, genetic, or sporadic neurologic disorder characterized by startle responses to acoustic, optic, or tactile stimuli. Genetic defects in glycine receptors as well as encephalitis, tumors, inflammation, and disgenesis are among the etiologic causes of the disease. The main problem in hyperekplexia is the incomplete development of inhibitory mechanisms or exaggerated stimulation of excitatory mediators. Hyperekplexia is often confused with epileptic seizures. Here we present a case with hypoglycemic convulsions coexisting with hyperekplexia, causing diagnostic difficulty. PMID- 24782897 TI - Acute ascending muscle weakness secondary to medication-induced hyperkalemia. AB - Secondary hyperkalemic paralysis is an uncommon but potentially life-threatening consequence of drug-induced disease. We report a case of a 53-year-old female with history of chronic kidney disease presenting to the emergency department with a one-day history of upper and lower extremity weakness and paresthesias. Serum potassium concentration on admission was greater than 8 mEq/L, and serum creatinine was elevated above baseline. Electrocardiogram showed first-degree atrioventricular block with peaked T waves. The patient reported compliance with daily lisinopril 10 mg, spironolactone 25 mg, and 40 mEq twice daily of potassium chloride. Symptoms and electrocardiogram returned to baseline within 24 hours of presentation and serum potassium returned to 4.2 mEq/L at approximately 36 hours without the need for dialysis. This case emphasizes the importance of including such a condition in the differential diagnosis of patients with ascending paralysis and the importance of close monitoring of patients placed on potassium elevating agents. PMID- 24782898 TI - Fluorodeoxyglucose positron emission tomography/computed tomography imaging of a patient with squamous cell carcinoma of prostate. AB - Primary squamous cell carcinoma is an uncommon tumor of the prostate gland. We report a 77-year-old male patient with urinary frequency and constipation. Fine needle biopsy from prostate was suspicious of squamous cell carcinoma of the prostate. Whole body positron emission tomography/computed tomography scan revealed high fluorodeoxyglucose uptake in prostate gland. Transurethral resection confirmed the diagnosis. In contrast to prostatic adenocarcinoma, high fluorodeoxyglucose accumulation was observed in the primary tumor of the prostate gland. PMID- 24782899 TI - PFAAs in fish and other seafood products from Icelandic waters. AB - Perfluorinatedalkyl acids (PFAAs) are of growing concern due to possible health effects on humans. Exposure assessments indicate that fish consumption is one of the major sources of perfluorooctane sulfonate (PFOS) exposure to humans, one of the major PFASs, whereas concerns of overestimation of this exposure source have been raised. Therefore, PFAAs concentrations in fish from the North Atlantic (Icelandic fishing grounds) in the flesh of different fish species were investigated along with more detailed analyses of tissue concentrations in cod (Gadus morhua) and lumpfish (Cyclopterus lumpus). Further, fish feed was investigated as a possible source of PFAAs in aquaculture by examining fish meal as feed ingredient. No PFAAs were detected in the edible part of all fish samples, except for PFOS in pollock (Pollachius virens, 0,05 ng/g wet weight). PFOS was the only PFAA detected in the fish meal samples with the exception of PFOSA in blue whiting (Micromesistius poutassou) meal (0,45 ng/g dry weight (d.w.)), where the PFOS concentration was 1,3-13 ng/g d.w. in the capelin (Mallotus villosus) and mackerel (Scomber scombrus) meal samples. The conclusions of the study are that fish commonly consumed from the Icelandic fishing grounds are unlikely to be an important source of PFAAs exposure. PMID- 24782900 TI - Residential relocation by older adults in response to incident cardiovascular health events: a case-crossover analysis. AB - OBJECTIVE: We use a case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new home address. METHODS: We conducted an ambidirectional case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new address using data from the Cardiovascular Health Study (CHS), a community based prospective cohort study of 5,888 older adults from four U.S. sites beginning in 1989. Relocation was assessed twice a year during follow-up. Event occurrences were classified as present or absent for the period preceding the first reported move, as compared with an equal length of time immediately prior to and following this period. RESULTS: Older adults (65+) that experience incident cardiovascular disease had an increased probability of reporting a change of residence during the following year (OR 1.6, 95% confidence interval (CI) = 1.2-2.1). Clinical conditions associated with relocation included stroke (OR: 2.0, 95% CI: 1.2-3.3), angina (OR: 1.6, 95% CI: 1.0-2.6), and congestive heart failure (OR: 1.5, 95% CI: 1.0-2.1). CONCLUSIONS: Major incident cardiovascular disease may increase the probability of residential relocation in older adults. Case-crossover analyses represent an opportunity to investigate triggering events, but finer temporal resolution would be crucial for future research on residential relocations. PMID- 24782901 TI - Non-steroidal anti-inflammatory drug hypersensitivity: association with elevated basal serum tryptase? AB - BACKGROUND: It is hypothesized that because of higher mast cell numbers and mediator release, mastocytosis predisposes patients for systemic immediate-type hypersensitivity reactions to certain drugs including non-steroidal anti inflammatory drugs (NSAID). OBJECTIVE: To clarify whether patients with NSAID hypersensitivity show increased basal serum tryptase levels as sign for underlying mast cell disease. METHODS: As part of our allergy work-up, basal serum tryptase levels were determined in all patients with a diagnosis of NSAID hypersensitivity and the severity of the reaction was graded. Patients with confirmed IgE-mediated hymenoptera venom allergy served as a comparison group. RESULTS: Out of 284 patients with NSAID hypersensitivity, 26 were identified with basal serum tryptase > 10.0 ng/mL (9.2%). In contrast, significantly (P = .004) more hymenoptera venom allergic patients had elevated tryptase > 10.0 ng/mL (83 out of 484; 17.1%). Basal tryptase > 20.0 ng/mL was indicative for severe anaphylaxis only in venom allergic subjects (29 patients; 4x grade 2 and 25x grade 3 anaphylaxis), but not in NSAID hypersensitive patients (6 patients; 4x grade 1, 2x grade 2). CONCLUSIONS: In contrast to hymenoptera venom allergy, NSAID hypersensitivity do not seem to be associated with elevated basal serum tryptase levels and levels > 20 ng/mL were not related to increased severity of the clinical reaction. This suggests that mastocytosis patients may be treated with NSAID without special precautions. PMID- 24782902 TI - First report of 3-oxothiolase deficiency in iran. AB - INTRODUCTION: Mitochondrial acetoacetyl-CoA thiolase (3-oxothiolase) deficiency is a rare metabolic disorder involving ketone body metabolism characterized by acute attacks of vomiting, acidosis, ketosis, and lethargy along with some laboratory criteria including excessive excretion of 2-methyl-3-hydroxybutyric acid in urine. CASE PRESENTATION: This is a case report of 3-oxothiolase deficiency in a young Iranian boy with presentation of intractable vomiting and severe metabolic acidosis following a common cold in six months of age with abundant urinary 2-methyl-3- hydroxybutyric acid. DISCUSSION: This is the first Iranian 3-oxothiolase deficiency case report as searched in the literature. Because of the high rate of consanguineous marriages in Iran, physicians should consider the 3-oxothiolase deficiency in the differential diagnosis of any patient with intractable vomiting and severe metabolic acidosis. PMID- 24782903 TI - Surgical management of an atypical presentation of a thyroid storm. AB - INTRODUCTION: Thyroid storm is a rare complication of Graves' disease that can carry a poor prognosis. In order to prevent major complications, thyroid storm must be quickly identified in patients and treatment must be promptly implemented. Medical treatment is usually initiated with antithyroid medications, such as propylthiouracil (PTU), methimazole, and beta-blockers. However, some patients may experience adverse reactions to these medications and alternate treatment options must be explored. CASE PRESENTATION: We report a case of a 30 year-old female initiated on PTU after diagnosis with Graves' disease that later presented an acute thyroid storm. DISCUSSION: Therapy was changed to methimazole, yet the patient subsequently developed angioedema and dyspnea. Medical management was discontinued and emergent thyroidectomy was performed without complication. PMID- 24782904 TI - Neuroprotective effect of a formula, moschus combined with borneolum synthcticum, from traditional chinese medicine on ischemia stroke in rats. AB - Moschus compatible with borneolum synthcticum is a well-known herb pair in Traditional Chinese Medicine and the present study aims to assess the neuroprotective effect of a formula composed of this herb pair on ischemia stroke in rats. The middle cerebral artery occlusion model of focal cerebral ischemia in rat was performed by using intraluminal suture method. The behavioral scores, infarct volume, and neuron ultrastructure of model and formula-treated rats were investigated after the 2 h of ischemia and 24 h of reperfusion. Meanwhile the expression levels of caspase-3, caspase-9, Bcl-2, and Bax were measured by western blot analysis. The formula treatment showed obvious neuroprotective effect according to significant decrease of the neurological scores (P < 0.01) and the infarct volumes (P < 0.05) when compared to the MCAO group. We also observed that this formula had antiapoptosis activity on neuron cell under electron microscope. Furthermore, our result supported the idea that pro- and postadministration of this formula had an antiapoptosis effect by decreasing remarkably the expression of caspase-3 and caspase-9 (P < 0.05) as well as increasing significantly the ratio of Bcl-2 to Bax (P < 0.01). All evidences demonstrated the neuroprotective effect of this formula on ischemia stroke due to decrease of brain infract volume and modulation of the expression of apoptosis related proteins. PMID- 24782905 TI - Assessment of total phenolic and flavonoid content, antioxidant properties, and yield of aeroponically and conventionally grown leafy vegetables and fruit crops: a comparative study. AB - A comparison of the product yield, total phenolics, total flavonoids, and antioxidant properties was done in different leafy vegetables/herbs (basil, chard, parsley, and red kale) and fruit crops (bell pepper, cherry tomatoes, cucumber, and squash) grown in aeroponic growing systems (AG) and in the field (FG). An average increase of about 19%, 8%, 65%, 21%, 53%, 35%, 7%, and 50% in the yield was recorded for basil, chard, red kale, parsley, bell pepper, cherry tomatoes, cucumber, and squash, respectively, when grown in aeroponic systems, compared to that grown in the soil. Antioxidant properties of AG and FG crops were evaluated using 2,2-diphenyl-1-picrylhydrazyl (DDPH) and cellular antioxidant (CAA) assays. In general, the study shows that the plants grown in the aeroponic system had a higher yield and comparable phenolics, flavonoids, and antioxidant properties as compared to those grown in the soil. PMID- 24782906 TI - The anxiolytic effects of valtrate in rats involves changes of corticosterone levels. AB - Valtrate is a principle compound isolated from Valeriana jatamansi Jones, which is a Traditional Chinese Medicine used to treat various mood disorders. The aim of the present study was to investigate the anxiolytic effects of valtrate in rats. The animals were orally administered valtrate (5, 10, and 20 g/kg daily) for 10 days and exposed to open field test (OFT) and elevated plus-maze (EPM). Then the corticosterone levels in the rat serum were measured by enzyme-linked immunosorbent assay (ELISA). The valtrate (10 mg/kg, p.o.) exhibited the anxiolytic effect in rats by increasing the time and entry percentage into the open arms in the EPM and the number of central entries in the OFT. Valtrate (10 mg/kg, p.o.) significantly reduced the corticosterone level in the rat serum. Taken together, these results suggest that the valtrate has anxiolytic activity in behavioral models that might be mediated via the function of hypothalamus pituitary-adrenal axis. PMID- 24782907 TI - Can tongue acupuncture enhance body acupuncture? First results from heart rate variability and clinical scores in patients with depression. AB - Tongue acupuncture (TA) is a method which is not used in western medicine and even in China it is applied very rarely in clinical practice. This study aimed at investigating whether additional TA can improve the efficacy of body acupuncture (BA) in patients with depression. Twenty patients with a mean age of +/- SD of 42.9 +/- 11.2 years were randomly divided into two groups (n = 10 patients each), one group receiving BA (Zusanli, Sanyinjiao, Neiguan, Shenting, Yintang, and Baihui) and the other receiving BA and TA (Liver, Heart, and Brain). The quantitative and qualitative outcome measures were heart rate (HR), heart rate variability (HRV), and different clinical scores. We found that in both groups all scores and HR improved significantly, whereas HRV increased partly significantly. It seems that TA can enhance acute and treatment effects of BA in patients with depression. The investigation of de qi sensation in TA needs further attention. PMID- 24782908 TI - GBE50 Attenuates Inflammatory Response by Inhibiting the p38 MAPK and NF- kappa B Pathways in LPS-Stimulated Microglial Cells. AB - Overactivated microglia contribute to a variety of pathological conditions in the central nervous system. The major goal of the present study is to evaluate the potential suppressing effects of a new type of Ginko biloba extract, GBE50, on activated microglia which causes proinflammatory responses and to explore the underlying molecular mechanisms. Murine BV2 microglia cells, with or without pretreatmentof GBE50 at various concentrations, were activated by incubation with lipopolysaccharide (LPS). A series of biochemical and microscopic assays were performed to measure cell viability, cell morphology, release of tumor necrosis factor- alpha (TNF- alpha ) and interleukin-1 beta (IL-1 beta ), and signal transduction via the p38 MAPK and nuclear factor-kappa B (NF- kappa B) p65 pathways. We found that GBE50 pretreatment suppressed LPS-induced morphological changes in BV2 cells. Moreover, GBE50 treatment significantly reduced the release of proinflammatory cytokines, TNF- alpha and IL-1 beta , and inhibited the associated signal transduction through the p38 MAPK and NF- kappa B p65 pathways. These results demonstrated the anti-inflammatory effect of GBE50 on LPS-activated BV2 microglia cells, and indicated that GBE50 reduced the LPS-induced proinflammatory TNF- alpha and IL-1 beta release by inhibiting signal transduction through the NF- kappa B p65 and p38 MAPK pathways. Our findings reveal, at least in part, the molecular basis underlying the anti-inflammatory effects of GBE50. PMID- 24782909 TI - Synergistic Effect between Cryptotanshinone and Antibiotics against Clinic Methicillin and Vancomycin-Resistant Staphylococcus aureus. AB - Cryptotanshinone (CT), a major tanshinone of medicinal plant Salvia miltiorrhiza Bunge, demonstrated strong antibacterial activity against clinic isolated methicillin and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) in this experiment. The CT was determined against clinic isolated MRSA 1-16 with MIC and MBC values ranging from 4 to 32 and 8 to 128 MU g/mL; for MSSA 1-2 from 16 to 32 MU g/mL and 64 to 128 MU g/mL; for VRSA 1-2 from 2 to 4 MU g/mL and 4 to 16 MU g/mL, respectively. The range of MIC50 and MIC90 of CT was 0.5-8 MU g/mL and 4-64 MU g/mL, respectively. The combination effects of CT with antibiotics were synergistic (FIC index <0.5) against most of tested clinic isolated MRSA, MSSA, and VRSA except additive, MRSA 4 and 16 in oxacillin, MRSA 6, 12, and 15 in ampicillin, and MRSA 6, 11, and 15 in vancomycin (FIC index < 0.75-1.0). Furthermore, a time-kill study showed that the growth of the tested bacteria was completely attenuated after 2-6 h of treatment with the 1/2 MIC of CT, regardless of whether it was administered alone or with ampicillin, oxacillin, or vancomycin. The results suggest that CT could be employed as a natural antibacterial agent against multidrug-resistant pathogens infection. PMID- 24782910 TI - The effect of resveratrol on surgery-induced epidural fibrosis in laminectomy rats. AB - Epidural fibrosis (EF) is a common complication for the patients who underwent laminectomy. Recently, EF is thought to cause recurrent postoperative pain after laminectomy. Resveratrol has been shown to exert its anti-inflammatory, antifibrotic, and antiproliferative multifaceted properties. The object of this study was to investigate the effects of resveratrol on the prevention of postlaminectomy EF formation in laminectomy rats. A controlled double-blinded study was performed on 60 healthy adult Sprague-Dawley rats that underwent lumbar laminectomy at the L1-L2 levels. They were divided randomly into 3 groups (1, 2, and 3) of 20 rats each-group 1: resveratrol treatment group; group 2: resveratrol dilution saline treatment group; group 3: sham group (rats underwent laminectomy without treatment). All rats were killed 4 weeks after operation. The Rydell score, hydroxyproline content, vimentin cells density, fibroblasts density, and inflammatory factors expressional levels all suggested better results in resveratrol group than the other two groups. Resveratrol is able to inhibit fibroblasts proliferation, and TGF- beta 1 and IL-6 expressions and prevent epidural fibrosis in postlaminectomy rat. PMID- 24782911 TI - Fitting C2 continuous parametric surfaces to frontiers delimiting physiologic structures. AB - We present a technique to fit C(2) continuous parametric surfaces to scattered geometric data points forming frontiers delimiting physiologic structures in segmented images. Such mathematical representation is interesting because it facilitates a large number of operations in modeling. While the fitting of C(2) continuous parametric curves to scattered geometric data points is quite trivial, the fitting of C(2) continuous parametric surfaces is not. The difficulty comes from the fact that each scattered data point should be assigned a unique parametric coordinate, and the fit is quite sensitive to their distribution on the parametric plane. We present a new approach where a polygonal (quadrilateral or triangular) surface is extracted from the segmented image. This surface is subsequently projected onto a parametric plane in a manner to ensure a one-to-one mapping. The resulting polygonal mesh is then regularized for area and edge length. Finally, from this point, surface fitting is relatively trivial. The novelty of our approach lies in the regularization of the polygonal mesh. Process performance is assessed with the reconstruction of a geometric model of mouse heart ventricles from a computerized tomography scan. Our results show an excellent reproduction of the geometric data with surfaces that are C(2) continuous. PMID- 24782912 TI - SOSORT 2012 consensus paper: reducing x-ray exposure in pediatric patients with scoliosis. AB - This 2012 Consensus paper reviews the literature on side effects of x-ray exposure in the pediatric population as it relates to scoliosis evaluation and treatment. Alternative methods of spinal assessment and imaging are reviewed, and strategies for reducing the number of radiographs are developed. Using the Delphi technique, SOSORT members developed consensus statements that describe how often radiographs should be taken in each of the pediatric and adolescent sub populations. PMID- 24782913 TI - Relationship between HPV and the biomarkers annexin A1 and p53 in oropharyngeal cancer. AB - BACKGROUND: Human papillomavirus (HPV) is often present in oropharyngeal cancers. Head and neck tumors have been examined for other molecular markers including p53 and annexin A1 (ANXA1). Here, we investigated the prevalence of HPV and its relationship with p53 and ANXA1 in patients with oropharyngeal cancer. METHODS: We have analyzed tumor and adjacent mucosa from 22 patients with squamous cell carcinoma of the oropharynx in addition to samples of the oropharyngeal epithelium in subjects without cancer. We evaluated the presence of the HPV (subtypes 16/18 and 31/33) by chromogenic in situ hybridization. Additionally, we used immunofluorescence to examine the expression of p16, p53, ANXA1 and the phosphorylation of the ANXA1 residues Ser27 (ANXA1-SER) and Tyr21 (ANXA1-TYR). RESULTS: We have detected the presence of HPV genome in 59% of the 22 tumors. Of those, 92% were also positive for p16 immunostaining. Furthermore, we demonstrated a reduction in the expression of p53 in HPV + compared to HPV- tumors. Also, a reduction was observed in the expression of ANXA1 in tumors compared to epithelium from the margins and from controls. We also noted a reduction in ANXA1-TYR in tumors. However, the expression of both ANXA1 and ANXA1 SER were elevated in the margins of the HPV + versus HPV- tumors. CONCLUSIONS: Our results confirm a high prevalence of HPV in oropharyngeal cancer and a reduction in p53 expression in HPV + tumors. We observed a hypoexpression of ANXA1 and ANXA1-TYR in oropharyngeal cancer. The increase in ANXA1-SER in the margins of HPV + tumors suggests that the epithelium in these cases had been activated by an infectious agent. Those findings indicate that ANXA1 and its phosphorylated forms can play important roles in the response to HPV infection and the carcinogenesis of the oropharynx. PMID- 24782914 TI - Repeatability of a multi-segment foot model with a 15-marker set in healthy adults. AB - BACKGROUND: Several 3D multi-segment foot models (MFMs) have been introduced for the in vivo analysis of dynamic foot kinematics. However, reproducibility of a model should be checked and ascertained before clinical utilization of a MFM. The purpose of this study was to determine the reliability of recently introduced MFM with a 15-marker set by assessing the participant's stride-to-stride (intra session) and visit-to-revisit (inter-session) repeatability. METHODS: Twenty healthy adults with a mean age of 28.9 years (10 males and 10 females) were tested. Three representative strides from five separate trials were used for analysis from each session. Kinematic data of foot segmental motion was collected and tracked using the Foot3D Multi-Segment Software (Motion Analysis Co., Santa Rosa. CA). A retest was performed in the same manner at an interval of 4 weeks. Coefficients of multiple correlation (CMC) and intra-class correlation coefficient (ICC) were calculated in order to assess the intra-session and inter session repeatability. RESULTS: Inter-segment foot angles from healthy adults from a MFM with 15-marker set showed a narrow range of variability during the gait cycle. The mean intra-session ICC was 0.981 (+/-0.010), which was interpreted as excellent. The mean intra-session CMC was 0.948 (+/-0.027), which was interpreted as very good repeatability. The mean inter-session ICC was 0.886 (+/-0.047) and the mean inter-session CMC was 0.801 (+/-0.077), which were interpreted as excellent and good repeatability, respectively. CONCLUSION: We demonstrated a MFM with a 15-marker set had high intra-session and inter-session repeatability, especially in sagittal plane motion. We thought this MFM would be applicable to evaluation of the segmental foot motion during gait. PMID- 24782915 TI - Helicobacter pylori antibody patterns in Germany: a cross-sectional population study. AB - BACKGROUND: Helicobacter pylori infection that is usually acquired in childhood and lasts for lifetime is mostly asymptomatic but associated with severe gastrointestinal disease including cancer. During chronic infection, the gastric mucosa is histologically changing. This forces H. pylori to permanent adaptation in its gastric habitat by expression of different proteins which might be reflected in distinctive antibody patterns. METHODS: To characterize dynamics of the immune response to H. pylori we analysed 1797 sera of a cross-sectional study representative for the German population (age range 1-82 years) with multiplex serology, a fluorescent bead-based antibody binding assay that allows simultaneous and quantitative detection of antibodies. Fifteen recombinant, affinity-purified H. pylori proteins (UreA, GroEL, Catalase, NapA, CagA, CagM, Cagdelta, HP0231, VacA, HpaA, Cad, HyuA, Omp, HcpC and HP0305) were used as antigens. RESULTS: H. pylori seroprevalence (positivity for at least three antigens) was 48% and increased with age from 12% in children <15 years to 69% in females and 90% in males >65 years. Prevalences were highest (>83%) for Omp, VacA and GroEL. For 11 proteins, seroprevalence was higher in males than females (P < 0.05) from age 55 onwards. For all antigens, the median prevalence increase per age decade was stronger in males (8.4%, range 3.8-12.9%) than females (6.1%, range 3.4-10.8%). However, among seropositives the median number of antigens recognized increased from children <15 years to individuals >65 years stronger in females (P = 0.02). Antibody reactivities to GroEL, HyuA, CagM, Catalase, NapA and UreA also increased stronger in females (average 1.7-fold/decade, SD 0.5) than in males (1.5-fold/decade, SD 0.4). CONCLUSION: H. pylori antibody response accumulates qualitatively and quantitatively with age. This may reflect a lifelong stimulation of the immune response by chronically active infection. PMID- 24782916 TI - Statins use is associated with poorer glycaemic control in a cohort of hypertensive patients with diabetes and without diabetes. AB - BACKGROUND: The US Federal and Drug Administration (FDA) recently revised statin drug labels to include the information that increases in fasting serum glucose and glycated haemoglobin levels have been reported with the use of statins. Yet in a survey, 87% of the doctors stated that they had never or infrequently observed increases in glucose or HbA1c levels in patients on statin. In this study we would like to determine the association between the use of statins and glycaemic control in a retrospective cohort of patients with hypertension. METHODS: A retrospective review of 1060 medical records of patients with hypertension at a primary care clinic was conducted. These records were selected using systematic random sampling (1:4). Data on patient socio-demographic factors; clinical profile; investigation results and prescribed medications were collected. Independent t-test was used for continuous variables while Pearson's chi2 test was used for categorical variables. Logistic regression was done to adjust for confounders. RESULTS: 810 (76.4%) patients with hypertension were on statins, out of which 792 (97.8%) were taking simvastatin 10 mg or 20 mg daily. Analysis of the whole group regardless of diabetes status showed that the statin user group had higher HbA1c and fasting blood glucose values. The difference in HbA1c levels remained significant (adjusted OR = 1.290, p = 0.044, 95% CI 1.006, 1.654) after adjustment for diabetes, diabetic medication and fasting blood glucose. In the study population who had diabetes, statin users again had significantly higher HbA1c level compared to statin non-users. This difference remained significant (adjusted OR 1.208, p = 0.037, 95% CI 1.012, 1.441) after adjustment for age and diabetic medications. CONCLUSIONS: Statins use is associated with increased HbA1c levels among hypertensive patients and hypertensive patients with diabetes. Clinicians managing hypertensive patients on statins should consider monitoring the HbA1c level and ensure that those with diabetes have their hyperglycaemia kept under control. PMID- 24782917 TI - New insights into the management of rhythm and conduction disorders after acute myocardial infarction. AB - PATIENT: Male, 53 FINAL DIAGNOSIS: Myocardial infarction Symptoms: Chest pain * tachycardia MEDICATION: - Clinical Procedure: - Specialty: Cardiology. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: Comorbidities, including obesity and sleep-breathing disorders, can adversely influence outcomes in acute myocardial infarction (AMI), and should be considered in diagnosis and treatment administration. CASE REPORT: The case demonstrates the difficulties of treating a middle-aged Caucasian patient with multiple comorbidities that could be overcome by a personalized approach and evaluation of concomitant sleep-breathing disorders (by polysomnography study). Diagnosis and treatment of sleep apnea by positive airway pressure (PAP therapy) played a pivotal role in heart rate and rhythm control. CONCLUSIONS: In this case, effective PAP therapy enabled titration of antiarrhythmic drugs (to maximal doses) to achieve heart rate control and to eliminate severe ventricular tachyarrhythmias and contributed to the better recovery in a post-AMI patient with left ventricular systolic dysfunction. PMID- 24782918 TI - MHC-DRB1/DQB1 Gene Polymorphism and Its Association with Resistance/Susceptibility to Cystic Echinococcosis in Chinese Merino Sheep. AB - The aim of this study was to analyze the relationship between polymorphism of the MHC-DRB1/DQB1 gene and its resistance to Cystic Echinococcosis (C.E), as well as to screen out the molecular genetic marker of antiechinococcosis in Chinese Merino sheep. The MHCII-DRB1/DQB1 exon 2 was amplified by polymerase chain reaction (PCR) from DNA samples of healthy and hydatidosis sheep. PCR products were characterized by restriction fragment length polymorphism (RFLP) technique. Five restriction enzymes (Mval, HaeIII, SacI, SacII, and Hin1I) were employed to cut DRB1, while seven restriction enzymes (MroxI, ScaI, SacII, NciI, TaqI, Mval, and HaeIII) were employed to cut DQB1.Results showed that frequencies of patterns Mvalbb (P < 0.01), SacIab in DRB1 exon 2 (P < 0.05), and TaqIaa, HaeIIInn (P < 0.01) in DQB1 exon 2 were significantly higher in the healthy group compared with the C.E individuals, which implied that there was a strong association between these genotypes and hydatidosis resistance or susceptibility. Chi-square test showed that individuals with the genic haplotype DRB1-SacIab/DRB1-Mvalbb/DQB1 TaqIaa/DQB1-HaeIIInn (P < 0.01) were relatively resistant to C.E, while individuals with the genic haplotypes DRB1-Mvalbc/DQB1-Mvalyy/DQB1-TaqIab/DQB1 HaeIIImn (P < 0.01) and DRB1-Mvalbb/DQB1-Mvalcc/DQB1-TaqIab/DQB1-HaeIIImn (P < 0.01) were more susceptible to C.E. In addition, to confirm these results, a fielding experiment was performed with Chinese Merino sheep which were artificially infected with E.g. The result was in accordance with the results of the first study. In conclusion, MHC-DRB1/DQB1 exon 2 plays an important role as resistant to C.E in Chinese Merino sheep. In addition, the molecular genetic marker of antiechinococcosis (DRB1-SacIab/DRB1-Mvalbb/DQB1-TaqIaa/DQB1-HaeIIInn) was screened out in Chinese Merino sheep. PMID- 24782919 TI - Disturbance of inorganic phosphate metabolism in diabetes mellitus: its relevance to the pathogenesis of diabetic retinopathy. AB - Early in the progression of diabetes, a paradoxical metabolic imbalance in inorganic phosphate (Pi) occurs that may lead to reduced high energy phosphate and tissue hypoxia. These changes take place in the cells and tissues in which the entry of glucose is not controlled by insulin, particularly in poorly regulated diabetes patients in whom long-term vascular complications are more likely. Various conditions are involved in this disturbance in Pi. First, the homeostatic function of the kidneys is suboptimal in diabetes, because elevated blood glucose concentrations depolarize the brush border membrane for Pi reabsorption and lead to lack of intracellular phosphate and hyperphosphaturia. Second, during hyperglycemic-hyperinsulinemic intervals, high amounts of glucose enter muscle and fat tissues, which are insulin sensitive. Intracellular glucose is metabolized by phosphorylation, which leads to a reduction in plasma Pi, and subsequent deleterious effects on glucose metabolism in insulin insensitive tissues. Hypophosphatemia is closely related to a decrease in adenosine triphosphate (ATP) in the aging process and in uremia. Any interruption of optimal ATP production might lead to cell injury and possible cell death, and evidence will be provided herein that such cell death does occur in diabetic retinopathy. Based on this information, the mechanism of capillary microaneurysms formation in diabetic retinopathy and the pathogenesis of diabetic retinopathy must be reevaluated. PMID- 24782920 TI - Systemic lupus erythematosus 2014. PMID- 24782921 TI - The contribution of applied social sciences to obesity stigma-related public health approaches. AB - Obesity is viewed as a major public health concern, and obesity stigma is pervasive. Such marginalization renders obese persons a "special population." Weight bias arises in part due to popular sources' attribution of obesity causation to individual lifestyle factors. This may not accurately reflect the experiences of obese individuals or their perspectives on health and quality of life. A powerful role may exist for applied social scientists, such as anthropologists or sociologists, in exploring the lived and embodied experiences of this largely discredited population. This novel research may aid in public health intervention planning. Through these studies, applied social scientists could help develop a nonstigmatizing, salutogenic approach to public health that accurately reflects the health priorities of all individuals. Such an approach would call upon applied social science's strengths in investigating the mundane, problematizing the "taken for granted" and developing emic (insiders') understandings of marginalized populations. PMID- 24782922 TI - Development of automatic visceral fat volume calculation software for CT volume data. AB - OBJECTIVE: To develop automatic visceral fat volume calculation software for computed tomography (CT) volume data and to evaluate its feasibility. METHODS: A total of 24 sets of whole-body CT volume data and anthropometric measurements were obtained, with three sets for each of four BMI categories (under 20, 20 to 25, 25 to 30, and over 30) in both sexes. True visceral fat volumes were defined on the basis of manual segmentation of the whole-body CT volume data by an experienced radiologist. Software to automatically calculate visceral fat volumes was developed using a region segmentation technique based on morphological analysis with CT value threshold. Automatically calculated visceral fat volumes were evaluated in terms of the correlation coefficient with the true volumes and the error relative to the true volume. RESULTS: Automatic visceral fat volume calculation results of all 24 data sets were obtained successfully and the average calculation time was 252.7 seconds/case. The correlation coefficients between the true visceral fat volume and the automatically calculated visceral fat volume were over 0.999. CONCLUSIONS: The newly developed software is feasible for calculating visceral fat volumes in a reasonable time and was proved to have high accuracy. PMID- 24782923 TI - The cut-off values of anthropometric indices for identifying subjects at risk for metabolic syndrome in Iranian elderly men. AB - AIM: This study aimed to investigate which anthropometric indices could be a better predictor of metabolic syndrome (MetS) and the cut-off points for these surrogates to appropriately differentiate MetS in the Iranian elderly. METHOD: The present cross-sectional study was conducted on a sample of Isfahan Healthy Heart Program (IHHP). MetS was defined according to Third Adult Treatment Panel (ATPIII). In total, 206 elderly subjects with MetS criteria were selected. Anthropometric indices were measured and plotted using receiver operating characteristic (ROC) curves. RESULTS: WC followed by WHtR yielded the highest area under the curve (AUC) (0.683; 95% CI 0.606-0.761 and 0.680; 95% CI 0.602 0.758, resp.) for MetS. WC at a cut of 94.5 cm resulted in the highest Youden index with sensitivity 64% and 68% specificity to predict the presence of >=2 metabolic risk factors. BMI had the lowest sensitivity and specificity for MetS and MetS components. WC has the best ability to detect MetS which followed by WHtR and BMI had a lower discriminating value comparatively. CONCLUSION: WC is the best predictor for predicting the presence of >=2 metabolic risk factors among Iranian elderly population and the best value of WC is 94.5 cm. This cut off values of WC should be advocated and used in Iranian men until larger cross sectional studies show different results. PMID- 24782924 TI - Organizing safe transitions from intensive care. AB - Background. Organizing and performing patient transfers in the continuum of care is part of the work of nurses and other staff of a multiprofessional healthcare team. An understanding of discharge practices is needed in order to ultimate patients' transfers from high technological intensive care units (ICU) to general wards. Aim. To describe, as experienced by intensive care and general ward staff, what strategies could be used when organizing patient's care before, during, and after transfer from intensive care. Method. Interviews of 15 participants were conducted, audio-taped, transcribed verbatim, and analyzed using qualitative content analysis. Results. The results showed that the categories secure, encourage, and collaborate are strategies used in the three phases of the ICU transitional care process. The main category; a safe, interactive rehabilitation process, illustrated how all strategies were characterized by an intention to create and maintain safety during the process. A three-way interaction was described: between staff and patient/families, between team members and involved units, and between patient/family and environment. Discussion/Conclusions. The findings highlight that ICU transitional care implies critical care rehabilitation. Discharge procedures need to be safe and structured and involve collaboration, encouraging support, optimal timing, early mobilization, and a multidiscipline approach. PMID- 24782925 TI - Minor physical anomalies in adults with autism spectrum disorder and healthy controls. AB - Minor Physical Anomalies (MPAs) are subtle abnormalities of the head, face, and limbs, without significant cosmetic or functional impact to the individual. They are assumed to represent external markers of developmental deviations during foetal life. MPAs have been suggested to indicate severity in mental illness and constitute external markers for atypical brain development. Higher frequencies of MPAs can be found in children with autism. The aims of the present study were to examine the prevalence and patterns of MPAs in adults with autism spectrum disorder (ASD) and to investigate whether MPAs are associated with symptom severity and overall functioning. Fifty adults with ASD and intelligence within the normal range and 53 healthy controls were examined with the Waldrop scale, an instrument for assessing MPAs. Face and feet were photographed enabling blinded assessment. Significant differences between the ASD and the control group were found on the MPA total scores, and also in the craniofacial region scores. Moreover, the shape of the ears was associated with autistic traits, in the ASD group. High MPA total scores were associated with poorer functioning. The findings suggest a link between MPAs, autistic traits, and level of functioning. Assessment of MPAs may assist in the diagnostic procedure of psychiatric disorders. PMID- 24782926 TI - Primer Based Approach for PCR Amplification of High GC Content Gene: Mycobacterium Gene as a Model. AB - The genome of Mycobacterium is rich in GC content and poses problem in amplification of some genes, especially those rich in the GC content in terminal regions, by standard/routine PCR procedures. Attempts have been made to amplify three GC rich genes of Mycobacterium sp. (Rv0519c and Rv0774c from M. tuberculosis and ML0314c from M. leprae). Out of these three genes, Rv0774c gene was amplified with normal primers under standard PCR conditions, while no amplification was observed in case of Rv0519c and ML0314c genes. In the present investigation a modified primer based approach was successfully used for amplification of GC rich sequence of Rv0519c through codon optimization without changing the native amino acid sequence. The strategy was successfully confirmed by redesigning the standard primers with similar modifications followed by amplification of ML0314c gene. PMID- 24782927 TI - Skin cancer knowledge, attitudes, and behaviors in collegiate athletes. AB - Outdoor athletes represent an important group at risk for skin cancer because they are routinely exposed to high levels of ultraviolet radiation. The purpose of this study was to assess current skin cancer knowledge, attitudes, and behaviors among collegiate athletes. A modified version of the Melanoma Risk Behavior Survey was completed by 343 athletes attending a Southern University in the USA, generating an 87% response rate. Survey results demonstrated that the majority of the athletes do not limit their sun exposure and reported low levels of sun protective behaviors. In addition, athletes lacked knowledge about skin cancer and sun protection. Eighty-three percent of the athletes stated that tanning beds improve one's overall health. Race was significantly associated with skin cancer knowledge, whereas, gender was found to be significantly associated with knowledge, attitudes, and behaviors towards skin cancer. Additionally, there was a significant relationship between knowledge and behavior, but not between attitude and behavior. This study highlights the need to educate athletes about the hazards of tanning to minimize UV exposure and promote sun protection habits. Moreover, athletes should be educated on the dangers of indoor tanning facilities and encouraged to avoid these facilities. PMID- 24782928 TI - An unusual case of cirrhosis. AB - 49-year-old white female with remote h/o sarcoidosis was referred to GI when her liver was noted to be nodular. Physical examination revealed normal vital signs and no icterus, spider nevi, clubbing, ascites, hepatosplenomegaly, or ankle edema. LFTs, hepatitis serologies, ANA, AMA, ASMA, Ferritin, Ceruloplasmin, and alpha 1-AT, level were unremarkable. Liver biopsy showed cirrhosis. She developed worsening of baseline SOB and was hospitalized. She was eventually diagnosed with constrictive pericarditis. A diagnosis of cardiac cirrhosis was made. PMID- 24782929 TI - Syncope as the presenting feature of splenic rupture after colonoscopy. AB - Splenic rupture is a rare, catastrophic complication of colonoscopy and an exceptional cause of syncope. This injury is believed to be from direct trauma or tension on the splenocolic ligament with subsequent capsule avulsion or else from direct instrument-induced splenic injury. Diagnosis requires a high index of suspicion that may be absent because presentation can be subtle, nonspecific, and delayed anywhere from hours to days and therefore not easily attributed to a recent endoscopy. We describe a case of syncope as the initial manifestation of splenic rupture after colonoscopy. Our patient's pain was delayed; his discomfort was mild and not localized to the left upper quadrant. Clinicians should consider syncope, lightheadedness, and drop in hemoglobin in absence of rectal bleeding following a colonoscopy as possible warning signs of imminent or emergent splenic injury. PMID- 24782930 TI - Unique presentation of giant metastatic microcystic serous adenocarcinoma of the pancreas. AB - Tumors of the pancreas that contain substantial cystic components include mainly mucinous cystic neoplasm, intraductal papillary mucinous neoplasm, solid pseudopapillary tumor, and cystadenomas (which encompass microcystic, macrocystic/oligocystic, and rare solid serous adenomas). Microcystic adenoma of the pancreas is a tumor that is benign in nature. Malignant transformation in the tumor with metastases is rare and only about 26 cases have been reported so far. Here we present a giant microcystic adenoma of the pancreas, possibly the largest ever malignant type in this group ever reported in the literature with extensive metastases to the liver and causing extensive compression and encasement on surrounding structures. PMID- 24782931 TI - Pancytopenia in a 70-year-old african-american male: an unusual presentation of a rare disease. AB - Hairy cell leukemia is a rare lymphoid neoplasm arising from mature B lymphocytes. Clinically, the disease presents with splenomegaly and abdominal discomfort, frequent infections, fatigue and bleeding because of related cytopenias. Bone marrow biopsy is essential for diagnosis. Below we describe a case of a 70-year-old African-American male who presented to our hematology clinic complaining of fatigue. Clinical exam and computed tomography imaging did not reveal splenic enlargement. Blood work-up revealed pancytopenia and bone marrow was diagnostic for hairy cell leukemia.The patient was started on cladribine, with gradual improvement of his symptoms and blood count abnormalities. Therefore, it is essential to keep hairy cell leukemia in the differential of pancytopenia even in the absence of a splenomegaly. PMID- 24782932 TI - Lenalidomide and Dexamethasone for a Patient of POEMS Syndrome Presenting with Massive Ascites. AB - POEMS syndrome is a multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. POEMS syndrome is a rare cause of refractory ascites. We report the case of a patient with POEMS syndrome presenting with massive ascites who was treated with very-low dose lenalidomide and dexamethasone. A 57-year-old Japanese man was admitted to our hospital with pleural effusion, massive ascites, and leg edema. The diagnosis of POEMS syndrome was made based on the combination of the following findings: peripheral neuropathy, organomegaly, endocrinopathy, serum monoclonal protein elevation, skin changes, plasma VEGF elevation, and evidence of extravascular volume overload. Renal dysfunction induced by biopsy-proven renal involvement of POEMS syndrome was observed. Massive ascites of the patient dramatically diminished with long-time treatment of very-low-dose lenalidomide and dexamethasone. Lenalidomide seems to be a very promising therapy for POEMS syndrome presenting with extravascular volume overload such as edema, pleural effusion, and ascites. Very-low-dose lenalidomide might be effective especially for the patients with POEMS-related nephropathy. PMID- 24782933 TI - Mixed fungal infection (Aspergillus, mucor, and Candida) of severe hand injury. AB - Severe hand injuries are almost always heavily contaminated and hence wound infections in those patients are frequent. Fungal wound infections are rare in immunocompetent patients. A case of mixed fungal infection (Aspergillus, Mucor, and Candida) was documented in a young male patient, with a severe hand injury caused by a corn picker. The diagnosis of fungal infection was confirmed microbiologically and histopathologically. The treatment was conducted with repeated surgical necrectomy and administration of antifungal drugs according to the antimycogram. After ten weeks the patient was successfully cured. The aggressive nature of Mucor and Aspergillus skin infection was described. A high degree of suspicion and a multidisciplinary approach are necessary for an early diagnosis and the initiation of the adequate treatment. Early detection, surgical intervention, and appropriate antifungal therapy are essential in the treatment of this rare infection that could potentially lead to loss of limbs or even death. PMID- 24782934 TI - Prenatal Diagnosis of Cantrell's Pentalogy Associated with Agenesis of Left Limb in a Twin Pregnancy. AB - Pentalogy of Cantrell is a rare malformation described in the literature. We report a case of pentalogy of Cantrell associated with left limb deficiency in a twin pregnancy. The fetus with multiple anomalies revealed kyphosis, ectopia cordis, and a large defect with protruding liver and bowel loops at 12 weeks and 3 days of gestational age on ultrasound scan. The other fetus was ultrasonographically normal. We diagnosed a case of pentalogy of Cantrell in a twin pregnancy after exclusion of limb body wall complex, body stalk anomaly, and amniotic band syndrome and after delivery of the fetuses. Macroscopic examinations were ectopia cordis, extrusion of the abdominal organs without membranes surrounding, and agenesis of the left limb. PMID- 24782935 TI - An unusual cervical tumor as presentation of a non-hodgkin lymphoma. AB - Rare cervical cancers are responsible for a minority of cases encountered by a clinician. However, behavioral patterns, management, and prognosis of certain rare cervical cancers differ from either squamous carcinomas or adenocarcinomas. Here we present a case of a locally advanced cervical tumor as a presentation of an extranodal cervical non-Hodgkin lymphoma (NHL), with a review of the current literature. PMID- 24782936 TI - A second trimester caesarean scar pregnancy. AB - Caesarean scar pregnancy, where conceptus is implanted on previous scar, is a rare entity. We present one such case of scar pregnancy presenting to us in the second trimester and was managed with methotrexate and uterine artery embolization, followed by hysterotomy. Uterus could be conserved and hysterectomy could be avoided. PMID- 24782937 TI - Grisel's Syndrome: A Rare Complication following Adenotonsillectomy. AB - Grisel's syndrome is a nontraumatic atlantoaxial subluxation which is usually secondary of an infection or an inflammation at the head and neck region. It can be observed after surgery of head and neck region. Etiopathogenesis has not been clearly described yet, but increased looseness of paraspinal ligament is thought to be responsible. Patients typically present with painful torticollis. Diagnosis of Grisel's syndrome is largely based on suspicion of the patient who has recently underwent surgery or history of infection in head and neck region. Physical examination and imaging techniques assist in diagnosis. Therefore, clinicians should be aware of acute nontraumatic torticollis after recently applied the head and neck surgery or undergone upper respiratory tract infection. In this paper, a case of an eight-year-old male patient who had Grisel's syndrome after adenotonsillectomy is discussed with review of the literature. PMID- 24782938 TI - Intestinal type of lung adenocarcinoma in younger adults. AB - Intestinal type of lung adenocarcinoma (ILADC) was initially described by Tsao and Fraser in 1991. Morphology and immunophenotype of ILADC are the same as in colorectal adenocarcinoma. Rectocolonoscopy must be performed to exclude colorectal origin of adenocarcinoma. Colorectal adenocarcinoma claimed to be genetically similar to an ILADC. Patients. We describe 24- and 26-year-old patients of both genders who went under surgery because of a lung tumor mass detected on CT scan. ILADC was diagnosed on resected lung specimens. According to positivity of Cytokeratin20, CDX-2, and Villin, respectively, and negativity of Cytokeratin7, TTF-1, Napsin-A, SurfactantB, MUC-1, and MUC-2, respectively, ILADC was diagnosed. KRAS mutation was detected in tumor tissue of the male patient. Conclusion. Rectocolonoscopy is the only relevant method for distinguishing the intestinal type of lung adenocarcinoma from metastatic colorectal carcinoma because immunohistochemistry and detection of mutation status are frequently the same in both types of adenocarcinoma. More investigations are needed for further understanding of ILADC in purpose of personalized lung carcinoma therapy particularly introducing detection of mutation status, especially in younger patients. PMID- 24782939 TI - The adventitia resection in treatment of liver hydatid cyst: a case report of a 15-year-old boy. AB - Human hydatid disease is a significant health problem in endemic regions caused by the larval form of Echinococcus granulosus. In this paper, we report a case of liver hydatid cyst. The patient, a 15-year-old boy, presented with a history of intermittent upper abdominal pain of a few-month duration was referred to our hospital for investigation. Computed tomographic scan and laboratory test suggested a hydatid cyst in the right lobe of liver. The adventitia resection of hydatid cyst was smoothly performed as there was a less bloody virtual space between adventitia and outer membrane. Our diagnosis was made using an imaging approach and was confirmed during surgery. We proposed the adventitia resection of hydatid cyst could be safe and easy to perform with low risk of bleeding and bile leakage. PMID- 24782940 TI - Breeding services and the factors influencing their use on smallholder dairy farms in central Uganda. AB - Dairy cattle breeding is an important technology in the enhancement and promotion of dairy production in Uganda. The introduction of germplasm through AI is crucial to enhance the production potential of the local breeds. A study was conducted in six districts of Uganda in the central region using a questionnaire survey involving 450 randomly selected households to profile the dairy breeding services in use and investigate the factors that affect the success of dairy breeding focusing on AI. Adoption of the AI service was highly (P < 0.05) dependent on ava ilability of extension services, record keeping practice (P < 0.05), and availability of milk markets (P < 0.05). On the other hand AI adoption was independent of formal education, age of farmer, labor availability, and feed/water availability (P > 0.05). Use or nonuse of AI did not significantly (P > 0.05) influence the sex of the calf born. While preference for AI was marked, very few farmers actually used it. This implies that focus should be put on improved AI service delivery alongside improved extension services. PMID- 24782942 TI - Extraction and Chromatographic Determination of Shikimic Acid in Chinese Conifer Needles with 1-Benzyl-3-methylimidazolium Bromide Ionic Liquid Aqueous Solutions. AB - An ionic liquids-based ultrasound-assisted extraction (ILUAE) method was successfully developed for extracting shikimic acid from conifer needles. Eleven 1-alkyl-3-methylimidazolium ionic liquids with different cations and anions were investigated and 1-benzyl-3-methylimidazolium bromide solution was selected as the solvent. The conditions for ILUAE, including the ionic liquid concentration, ultrasound power, ultrasound time, and liquid-solid ratio, were optimized. The proposed method had good recovery (99.37%-100.11%) and reproducibility (RSD, n = 6; 3.6%). ILUAE was an efficient, rapid, and simple sample preparation technique that showed high reproducibility. Based on the results, a number of plant species, namely, Picea koraiensis, Picea meyeri, Pinus elliottii, and Pinus banksiana, were identified as among the best resources of shikimic acid. PMID- 24782941 TI - Environmental attributes to respiratory diseases of small ruminants. AB - Respiratory diseases are the major disease crisis in small ruminants. A number of pathogenic microorganisms have been implicated in the development of respiratory disease but the importance of environmental factors in the initiation and progress of disease can never be overemphasized. They irritate the respiratory tree producing stress in the microenvironment causing a decline in the immune status of the small ruminants and thereby assisting bacterial, viral, and parasitic infections to break down the tissue defense barriers. Environmental pollutants cause acute or chronic reactions as they deposit on the alveolar surface which are characterized by inflammation or fibrosis and the formation of transitory or persistent tissue manifestation. Some of the effects of exposures may be immediate, whereas others may not be evident for many decades. Although the disease development can be portrayed as three sets of two-way communications (pathogen-environment, host-environment, and host-pathogen), the interactions are highly variable. Moreover, the environmental scenario is never static; new compounds are introduced daily making a precise evaluation of the disease burden almost impossible. The present review presents a detailed overview of these interactions and the ultimate effect on the respiratory health of sheep and goat. PMID- 24782943 TI - Determination of lactones in wines by headspace solid-phase microextraction and gas chromatography coupled with mass spectrometry. AB - Application of headspace solid-phase microextraction (HS-SPME) coupled with high resolution gas chromatographic (HRGC) analysis was studied for determining lactones in wines. Six different SPME fibers were tested, and the influence of different factors such as temperature and time of desorption, ionic strength, time of extraction, content of sugar, ethanol, tannins and anthocyanins, and pH and influence of SO2 were studied. The proposed HS-SPME-GC method is an appropriate technique for the quantitative analysis of gamma-butyrolactone, gamma hexalactone, trans-whiskey lactone, gamma-octalactone, cis-whiskey lactone, gamma nonalactone, gamma-decalactone, delta-decalactone, and gamma-undecalactone in wines. Method reproducibility and repeatability ranged between 0.6 and 5.2% for all compounds. Detection limit for gamma-butyrolactone was 0.17 mg/L and a few MUg/L for the rest of the compounds. The optimized method has been applied to several wine samples. PMID- 24782944 TI - What is temporal fine structure and why is it important? AB - Complex sound like speech can be characterized as the sum of number of amplitude modulated signals representing the outputs of an array of narrow frequency bands. Temporal information at the output of each band can be separated into temporal fine structure (TFS), the rapid oscillations close to the center frequency and temporal envelope (ENV), slower amplitude modulations superimposed on the TFS. TFS information can be carried in the pattern of phase locking to the stimulus waveform, while ENV by the changes in firing rate over time. The relative importance of temporal ENV and TFS information in understanding speech has been studied using various sound-processing techniques. A number of studies demonstrated that ENV cues are associated with speech recognition in quiet, while TFS cues are possibly linked to melody/pitch perception and listening to speech in a competing background. However, there are evidences that recovered ENV from TFS as well as TFS itself may be partially responsible for speech recognition. Current technologies used in cochlear implants (CI) are not efficient in delivering the TFS cues, and new attempts have been made to deliver TFS information into sound-processing strategy in CI. We herein discuss the current updated findings of TFS with a literature review. PMID- 24782945 TI - Clinical reasons for returning hearing aids. AB - BACKGROUND AND OBJECTIVES: Increases in older aged populations and exposure to complicated noise environments have increased the number of hearing-impaired patients, creating greater demands for hearing aids. We have assessed the reasons that individuals rejected wearing and returned properly prescribed hearing aids, as well as differences in individual factors between younger and elderly adults. SUBJECTS AND METHODS: Of 1138 patients for whom hearing aids were prescribed at Kyung Hee University Medical Center Hearing Aid Clinic, 81 (6.14%) returned their hearing aids, including 36 patients aged <65 years and 45 aged >=65 years. Patient-related, hearing-related, and hearing aid-related factors were assessed by retrospective chart analysis and phone survey and compared in the two groups. RESULTS: The primary symptoms reported by the 81 patients who returned their hearing aids were hearing disturbance, ringing, and fullness in the ear, in that order and in both groups. The rate of hearing aid return was similar in elderly females and males (p=0.288). The spondee recognition threshold was significantly higher in younger than in elderly adults (63.3+/-14.0 dB vs. 55.6+/-14.74 dB, p=0.019), but the hearing aid return rate was highest in patients with moderate hearing loss in both groups. In evaluating the reasons for return of hearing aids, we found that ineffectiveness of the device was the most frequent reason, accounting for 32.0% of returns, the highest percentage in both groups, with the most frequent patient problem caused by management difficulty in elderly and financial difficulty in younger adults. CONCLUSIONS: The reasons for hearing aid return were different in two groups. Financial considerations were cited more by younger adults, while difficulties in managing hearing aids were cited more frequently by elderly adults. Patients in both groups, however, reported that the most frequent reasons for return were inadequate hearing improvement and inconvenience wearing the hearing aid due to noise amplification. PMID- 24782946 TI - Conductive and Mixed Hearing Losses: A Comparison between Summer and Autumn. AB - BACKGROUND AND OBJECTIVES: Conductive hearing loss is common among children and adults. This study aims at comparing the results of conductive hearing loss in summer and autumn. SUBJECTS AND METHODS: Puretone audiometry and tympanometry tests were done for all patients who referred to the Iranian-based audiology center of Imam Khomeini Hospital in Ahvaz. Data on the patients with conductive or mixed hearing loss were analyzed. The impacts of season, age, and etiology of the disease were analyzed on the patients who visited the audiology clinic due to the conductive hearing loss in summer and autumn. RESULTS: One hundred and fifty nine patients in summer and 123 patients in autumn had conductive or mixed hearing loss. Their age ranged from four to 82 years, with the average age of 35. The percentage of the patients, with acute otitis media and chronic otitis media (COM), who visited this clinic, was significantly higher than those with middle ear problems. COM and mastoid surgeries rate was higher in summer than autumn among adults. CONCLUSIONS: There is no relationship between season and middle ear diseases between children and juveniles, but COM and mastoid problems are more common in summer among adults visiting this clinic. Most of the patients had mild conductive hearing loss and bilateral middle ear impairments. PMID- 24782947 TI - Adequacy of the Simplified Version of the Tinnitus Handicap Inventory (THI-S) to Measure Tinnitus Handicap and Relevant Distress. AB - BACKGROUND AND OBJECTIVES: The Tinnitus Handicap Inventory (THI) often requires patients to devote their time to complete the questionnaire than they expect. Given that it limits the effectiveness of THI in a busy clinical practice that desires a quick and easy assessment of tinnitus handicap, this study evaluated clinical usefulness of a Simplified version of Tinnitus Handicap Inventory (THI S) in measuring the severity of tinnitus handicap as well as predicting the psychological distress associated with tinnitus. SUBJECTS AND METHODS: A total of 129 outpatients suffering from tinnitus (61 with normal hearing and 68 with hearing loss) participated in this study. The responses of THI-S (10 items) and THI (25 items) were evaluated to quantify the subjective handicap of tinnitus. The self-perceived level of stress, anxiety, and depression of all participants was measured with a series of self-report questionnaires such as Korean version of Brief Encounter Psychosocial Instrument (BEPSI), State Trait Anxiety Inventory (STAI), and Beck Depression Inventory (BDI), respectively. All the questionnaire responses were analyzed using non-parametric analyses to examine the convergence, comparability, internal consistency reliability and validity of THI-S. RESULTS: The severity of tinnitus handicap and the relevant psychological distress greatly varied across individuals. The THI-S responses were comparable to original THI responses, regardless of hearing status of patients. The internal consistency of THI-S responses was found to be good for total score (Cronbach's alpha=0.83 0.91), with moderately high consistency for the emotional, functional, and catastrophic subscales. Significant (p<0.01) correlations of the THI-S with the THI (rs =0.95) as well as with the BEPSI, STAI, BDI questionnaires (rs =0.40 0.45) suggest that the THI-S questionnaire appeared to be useful to provide objective data of subjective tinnitus handicap as well as predict psychological distress. Three factors were extracted through factor analysis, which explained 73% of the total variance. CONCLUSIONS: Despite reducing the length of 25 items of THI to 10 items, the THI-S can be used as s a simple but reliable and valid tool for evaluating severity of tinnitus handicap as well as detecting its negative impact on psychological functioning. PMID- 24782948 TI - Speech perception in older listeners with normal hearing:conditions of time alteration, selective word stress, and length of sentences. AB - BACKGROUND AND OBJECTIVES: Deficits of the aging auditory system negatively affect older listeners in terms of speech communication, resulting in limitations to their social lives. To improve their perceptual skills, the goal of this study was to investigate the effects of time alteration, selective word stress, and varying sentence lengths on the speech perception of older listeners. SUBJECTS AND METHODS: Seventeen older people with normal hearing were tested for seven conditions of different time-altered sentences (i.e., +/-60%, +/-40%, +/-20%, 0%), two conditions of selective word stress (i.e., no-stress and stress), and three different lengths of sentences (i.e., short, medium, and long) at the most comfortable level for individuals in quiet circumstances. RESULTS: As time compression increased, sentence perception scores decreased statistically. Compared to a natural (or no stress) condition, the selectively stressed words significantly improved the perceptual scores of these older listeners. Long sentences yielded the worst scores under all time-altered conditions. Interestingly, there was a noticeable positive effect for the selective word stress at the 20% time compression. CONCLUSIONS: This pattern of results suggests that a combination of time compression and selective word stress is more effective for understanding speech in older listeners than using the time expanded condition only. PMID- 24782949 TI - Unusual presentation of a metastatic tumor to the temporal bone: severe otalgia and facial paralysis. AB - Metastatic temporal bone tumors are rare diseases and they are usually clinically asymptomatic, so it is difficult to diagnose them. Breasts are the most common sites of temporal bone metastasis. Tumors of lung, kidney, gastrointestinal tract, prostate gland, larynx and thyroid gland are the other sites. The pathogenesis of the temporal bone is most commonly related to the hematogenous route. We present the case of a 78-year-old man with facial paralysis combined with severe otalgia. This patient was initially diagnosed with Bell's palsy. However, based on the radiologic findings, the patient was diagnosed with lung cancer with temporal bone metastasis. PMID- 24782950 TI - Osteoma of the promontory mimicking a congenital cholesteatoma. AB - Osteoma of the temporal bone most commonly occurs in the external ear. Osteomas in the middle ear are not common, and only 25 relevant cases (18 papers) have been reported in the English literature. With only 5 cases reported to date, osteoma of the promontory in the middle ear is rare. This study reports a case of asymptomatic osteoma of the promontory in the middle ear mimicking a congenital cholesteatoma in a 4-year-old girl. PMID- 24782951 TI - A Case of Post-Traumatic Meniere's Disease. AB - There are only a few reports of post-traumatic Meniere's disease and there is few literature that contains detailed data associated with the disease. We report a case of post-traumatic Meniere's disease. He suffered from tinnitus, fluctuating sensorineural hearing loss, and recurrent vertigo. Symptomatic medical treatment was not helpful and neither was soft tissue plugging around the oval and round windows during exploratory tympanotomy. Three months after soft tissue plugging, endolymphatic sac decompression surgery was performed. The patient's symptoms improved markedly thereafter. The clinical significance of post-traumatic Meniere's disease is described and we present a brief review of the literature. PMID- 24782952 TI - Recent Perspectives on APP, Secretases, Endosomal Pathways and How they Influence Alzheimer's Related Pathological Changes in Down Syndrome. AB - Down syndrome is one of the most common genetic conditions occurring in one in 700 live births. The trisomy of chromosome 21 causes over-expression of APP which in turn is indicated in the increased production of Abeta associated with AD. This makes DS the most common presenile form of AD exceeding PS1 and PS2 FAD. Since a majority of DS individuals develop dementia, it is important to examine whether DS and sporadic AD share common features, for example, to anticipate shared treatments in the future. Here we explore commonalities and differences for secretases and endosomal pathways in DS and AD. PMID- 24782953 TI - Use of antiretroviral therapy in households and risk of HIV acquisition in rural KwaZulu-Natal, South Africa, 2004-12: a prospective cohort study. AB - BACKGROUND: Studies of HIV-serodiscordant couples in stable sexual relationships have provided convincing evidence that antiretroviral therapy can prevent the transmission of HIV. We aimed to quantify the preventive effect of a public sector HIV treatment and care programme based in a community with poor knowledge and disclosure of HIV status, frequent migration, late marriage, and multiple partnerships. Specifically, we assessed whether an individual's hazard of HIV acquisition was associated with antiretroviral therapy coverage among household members of the opposite sex. METHODS: In this prospective cohort study, we linked patients' records from a public-sector HIV treatment programme in rural KwaZulu Natal, South Africa, with population-based HIV surveillance data collected between 2004 and 2012. We used information about coresidence to construct estimates of HIV prevalence and antiretroviral therapy coverage for each household. We then regressed the time to HIV seroconversion for 14,505 individuals, who were HIV-uninfected at baseline and individually followed up over time regarding their HIV status, on opposite-sex household antiretroviral therapy coverage, controlling for household HIV prevalence and a range of other potential confounders. FINDINGS: 2037 individual HIV seroconversions were recorded during 54,845 person-years of follow-up. For each increase of ten percentage points in opposite-sex household antiretroviral therapy coverage, the HIV acquisition hazard was reduced by 6% (95% CI 2-9), after controlling for other factors. This effect size translates into large reductions in HIV acquisition hazards when household antiretroviral therapy coverage is substantially increased. For example, an increase of 50 percentage points in household antiretroviral therapy coverage (eg, from 20% to 70%) reduced the hazard of HIV acquisition by 26% (95% CI 9-39). INTERPRETATION: Our findings provide further evidence that antiretroviral therapy significantly reduces the risk of onward transmission of HIV in a real-world setting in sub-Saharan Africa. Awareness that antiretroviral therapy can prevent transmission to coresident sexual partners could be a powerful motivator for HIV testing and antiretroviral treatment uptake, retention, and adherence. FUNDING: Wellcome Trust and National Institute of Child Health and Human Development (US National Institutes of Health). PMID- 24782954 TI - Burden of disease in adults admitted to hospital in a rural region of coastal Kenya: an analysis of data from linked clinical and demographic surveillance systems. AB - BACKGROUND: Estimates of the burden of disease in adults in sub-Saharan Africa largely rely on models of sparse data. We aimed to measure the burden of disease in adults living in a rural area of coastal Kenya with use of linked clinical and demographic surveillance data. METHODS: We used data from 18,712 adults admitted to Kilifi District Hospital (Kilifi, Kenya) between Jan 1, 2007, and Dec 31, 2012, linked to 790,635 person-years of observation within the Kilifi Health and Demographic Surveillance System, to establish the rates and major causes of admission to hospital. These data were also used to model disease-specific disability-adjusted life-years lost in the population. We used geographical mapping software to calculate admission rates stratified by distance from the hospital. FINDINGS: The main causes of admission to hospital in women living within 5 km of the hospital were infectious and parasitic diseases (303 per 100,000 person-years of observation), pregnancy-related disorders (239 per 100,000 person-years of observation), and circulatory illnesses (105 per 100,000 person-years of observation). Leading causes of hospital admission in men living within 5 km of the hospital were infectious and parasitic diseases (169 per 100,000 person-years of observation), injuries (135 per 100,000 person-years of observation), and digestive system disorders (112 per 100,000 person-years of observation). HIV-related diseases were the leading cause of disability-adjusted life-years lost (2050 per 100,000 person-years of observation), followed by non communicable diseases (741 per 100,000 person-years of observation). For every 5 km increase in distance from the hospital, all-cause admission rates decreased by 11% (95% CI 7-14) in men and 20% (17-23) in women. The magnitude of this decline was highest for endocrine disorders in women (35%; 95% CI 22-46) and neoplasms in men (30%; 9-45). INTERPRETATION: Adults in rural Kenya face a combined burden of infectious diseases, pregnancy-related disorders, cardiovascular illnesses, and injuries. Disease burden estimates based on hospital data are affected by distance from the hospital, and the amount of underestimation of disease burden differs by both disease and sex. FUNDING: The Wellcome Trust, GAVI Alliance. PMID- 24782955 TI - Current status of oncothermia therapy for lung cancer. AB - Lung cancer is one of the most common malignant tumors, and it has the highest death rate. Oncothermia is a feasible and successful treatment for lung cancer. Results show a remarkable survival benefit for patients, with a good quality of life. The treatment has no, or in some cases mild, side-effects and could decrease the adverse effects of the complementary treatment. Applying oncothermia together with other treatment methods could increase the effects and result in better performance. A comparison of studies demonstrates a good correspondence in the data, which strengthens the reliability of the studies, and clearly shows the feasibility of the application of oncothermia to treating all kinds of pulmonary malignancies including non-small-cell and small-cell primary tumors, and all of the metastatic diseases of the pulmonary system. PMID- 24782956 TI - Surgery for partial anomalous pulmonary venous connections: modification of the warden procedure with a right atrial appendage flap. AB - BACKGROUND: Surgical repair of a partial anomalous pulmonary venous connection (PAPVC) to the superior vena cava (SVC) may be complicated by sinus node dysfunction or SVC obstruction. We modified the Warden procedure by using a right atrial auricular flap to decrease the occurrence of these complications. METHODS: Between February 2005 and July 2012, 10 consecutive patients underwent a modified Warden procedure to correct PAPVC. The median patient age was 5.7 years. Eight patients (80%) had an atrial septal defect. To surgically correct the PAPVC, we made a U-shaped incision on the right atrial appendage and sutured the flap to the posterior wall of the SVC. The anterior wall was reconstructed with various patch materials. RESULTS: No early or late deaths occurred, nor did any patient require early or late reoperation for SVC or pulmonary venous obstruction. No new arrhythmias appeared during follow-up, which was complete in all patients (mean, 29.5 months). CONCLUSION: Our modification of the Warden procedure seems to be effective and safe. This technique may lower the risk of SVC obstruction, pulmonary venous obstruction, and sinus dysfunction. PMID- 24782957 TI - Percutaneous extracorporeal membrane oxygenation for graft dysfunction after heart transplantation. AB - BACKGROUND: We evaluated the safety and efficacy of percutaneous extracorporeal membrane oxygenation (ECMO) in patients with primary graft dysfunction after heart transplantation. METHODS: Of 65 patients (44 males and 21 females) who underwent heart transplantation from January 2006 to December 2012, 13 patients (group I) needed peripheral ECMO support due to difficulty in weaning from cardiopulmonary bypass (CPB) and 52 patients (group II) were weaned from CPB without mechanical support. The mean age of the patients at the time of operation was 54.4+/-13.6 years. There were no differences in the preoperative characteristics of the two groups. Multivariable analysis was performed to identify the risk factors for ECMO therapy. RESULTS: All group I patients were successfully weaned from ECMO after 53+/-9 hours of circulatory support. Early mortality occurred in four patients (1 [7.7%] in group I and 3 [5.8%] in group II, p>0.999). There were no differences in the postoperative complications between the two groups, with the exception of reoperation for bleeding. A greater number of group I patients underwent reoperation for bleeding (5 [38.5%] in group I vs. 6 [11.5%] in group II, p=0.035). In multivariable analysis, preoperative mechanical support (ECMO and intra-aortic balloon pump) and longer CPB time were the risk factors of ECMO therapy for graft dysfunction (odds ratio, 6.377; 95% confidence interval, 1.519 to 26.77; p=0.011 and odds ratio, 1.010; 95% confidence interval, 1.001 to 1.019; p=0.033). CONCLUSION: Percutaneous ECMO support could be a viable option for rescuing patients when graft dysfunction refractory to medical management develops after heart transplantation. PMID- 24782958 TI - Hybrid coronary revascularization using limited incisional full sternotomy coronary artery bypass surgery in multivessel disease: early results. AB - BACKGROUND: There are several modalities of coronary artery revascularization for multivessel coronary artery disease. Hybrid coronary revascularization (HCR) with minimally invasive direct coronary artery bypass grafting was introduced for high risk patients, and recently, many centers have been using it. Limited incisional full sternotomy coronary artery bypass (LIFCAB) involves left internal thoracic artery (LITA)-to-left anterior descending coronary artery (LAD) anastomosis through a sternotomy with a minimal skin incision; it could be considered another technique for minimally invasive LITA-to-LAD anastomosis. Our center has performed HCR using LIFCAB, and in this paper, we report our short-term results, obtained in the past 3 years. METHODS: The medical records of 38 patients from May 2010 to June 2013 were analyzed retrospectively. The observation period after HCR was 1 to 37 months (average, 18.3+/-10.3 months). The patency of revascularization was confirmed with postoperative coronary angio-computerized tomography or coronary angiography. RESULTS: There were 3 superficial wound complications, but no mortalities. All the LITA-to-LAD anastomoses were patent in the immediate postoperative and follow-up studies, but stenosis was detected in 3 cases of percutaneous coronary intervention. CONCLUSION: HCR using LIFCAB is safe and yields satisfactory results from the viewpoint of revascularization for multivessel disease. PMID- 24782959 TI - Elastofibroma dorsi: clinicopathological analysis of 76 cases. AB - BACKGROUND: We aimed to investigate the epidemiological, clinical, paraclinical, and treatment aspects of elastofibroma dorsi through a retrospective study of 76 patients who underwent surgery between January 2008 and December 2012 in our department. METHODS: Our study is retrospective between January 2008 and December 2012. We admitted 79 patients with a subscapular mass, and only 76 patients had ED. The others (n=2) had high associated risk of anesthesia and were managed by a medical treatment and one patient had a subscapular sclerotic hemangioma. RESULTS: The average age of the patients was 49 years (range, 38 to 70 years), with a female predominance (54 females and 22 males). Subscapular location was constant. The right, left, and bilateral form was noted in 41, 15 and 20 cases, respectively. The diagnosis was clinical in 60 cases. Ultrasound and computerized tomography scans confirmed the diagnosis of an ill-defined mass in a subscapular location in all cases. Surgical treatment consisted of complete resection of the mass. The clinical diameter of the mass remained significantly lower than that of the surgical specimen (7 cm versus 12 cm) because the major hidden part of the mass in the subscapular area was inaccessible to palpation. Complications were noted in 9 cases (11.8%), seroma in 8 cases (10.5%), infection of wound site in 4 cases (5%), and parietal textilome in one case (1%). No case of recurrence was noted. CONCLUSION: Surgery of elastofibroma is unique because of the subscapular location of the parietal tumor, whose histological fibrous nature makes it very adherent to the chest wall. PMID- 24782960 TI - Incidents and complications of permanent venous central access systems: a series of 1,460 cases. AB - BACKGROUND: Implanted venous access devices or permanent central venous access systems (PCVASs) are routinely used in oncologic patients. Complications can occur during the implantation or use of such devices. We describe such complications of the PCVAS and their management. METHODS: Our retrospective study included 1,460 cases in which PCVAS was implanted in the 11 years between January 2002 and January 2013, including 810 women and 650 men with an average age of 45.2 years. We used polyurethane or silicone catheters. The site of insertion and the surgical or percutaneous procedure were selected on the basis of clinical data and disease information. The subclavian and cephalic veins were our most common sites of insertion. RESULTS: About 1,100 cases (75%) underwent surgery by training surgeons and 360 patients by expert surgeons. Perioperative incidents occurred in 33% and 12% of these patients, respectively. Incidents (28%) included technical difficulties (n=64), a subcutaneous hematoma (n=37), pneumothoraces (n=15), and an intrapleural catheter (n=1). Complications in the short and medium term were present in 14.2% of the cases. Distortion and rupture of the catheter (n=5) were noted in the costoclavicular area (pinch-off syndrome). There were 5 cases of catheter migration into the jugular vein (n=1), superior vena cava (n=1), and heart cavities (n=3). No patient died of PCVAS insertion or complication. CONCLUSION: PCVAS complications should be diagnosed early and treated with probable removal of this material for preventing any life threatening outcome associated with complicated PVCAS. PMID- 24782961 TI - Is There a Role for a Needle Thoracoscopic Pleural Biopsy under Local Anesthesia for Pleural Effusions? AB - BACKGROUND: A closed pleural biopsy is commonly performed for diagnosing patients exhibiting pleural effusion if prior thoracentesis is not diagnostic. However, the diagnostic yield of such biopsies is unsatisfactory. Instead, a thoracoscopic pleural biopsy is more useful and less painful. METHODS: We compared the diagnostic yield of needle thoracoscopic pleural biopsy performed under local anesthesia with that of closed pleural biopsy. Sixty-seven patients with pleural effusion were randomized into groups A and B. Group A patients were subjected to closed pleural biopsies, and group B patients were subjected to pleural biopsies performed using needle thoracoscopy under local anesthesia. RESULTS: The diagnostic yields and complication rates of the two groups were compared. The diagnostic yield was 55.6% in group A and 93.5% in group B (p<0.05). Procedure related complications developed in seven group A patients but not in any group B patients. Of the seven complications, five were pneumothorax and two were vasovagal syncope. CONCLUSION: Needle thoracoscopic pleural biopsy under local anesthesia is a simple and safe procedure that has a high diagnostic yield. This procedure is recommended as a useful diagnostic modality if prior thoracentesis is non-diagnostic. PMID- 24782962 TI - Arch reconstruction with autologous pulmonary artery patch in interrupted aortic arch. AB - Various surgical techniques have been developed for the repair of an interrupted aortic arch. However, tension and Gothic arch formation at the anastomotic site have remained major problems for these techniques: Excessive tension causes arch stenosis and left main bronchus compression, and Gothic arch configuration is related to cardiovascular complications. To resolve these problems, we adopted a modified surgical technique of distal aortic arch augmentation using an autologous main pulmonary artery patch. The descending aorta was then anastomosed to the augmented aortic arch in an end-to-side manner. Here, we report two cases of interrupted aortic arch that were repaired using this technique. PMID- 24782963 TI - Normothermic cardiac surgery with warm blood cardioplegia in patient with cold agglutinins. AB - Cold agglutinins are predominately immunoglobulin M autoantibodies that react at cold temperatures with surface antigens on the red blood cell. This can lead to hemagglutination at low temperatures, followed by complement fixation and subsequent hemolysis on rewarming. Development of hemagglutination or hemolysis in patients with cold agglutinins is a risk of cardiac surgery under hypothermia. In addition, there is the potential for intracoronary hemagglutination with inadequate distribution of cardioplegic solutions, thrombosis, embolism, ischemia, or infarction. We report a patient with incidentally detected cold agglutinin who underwent normothermic cardiac surgery with warm blood cardioplegia. PMID- 24782964 TI - Multiple embolic aortic valve endocarditis with small patent ductus arteriosus in adult. AB - A 50-year-old female was admitted to Pusan National University Hospital with complaints of fatigue and sweating. Echocardiography showed a small patent ductus arteriosus (PDA) and highly mobile vegetations on the aortic valve. Emergency operation was performed due to the high risk of embolization and severe aortic regurgitation. When the pulmonary artery opened, we found unexpected fresh vegetation. The tissue of the PDA was fragile and infected. We successfully removed the infected tissue, closed the PDA with a patch, and replaced the aortic valve with a mechanical prosthesis. PMID- 24782965 TI - Schwannoma of the heart. AB - We present a case of a 55-year-old woman who complained of chest pain at rest. A mass was detected adjacent to her left atrium. The mass was completely excised, and a pathologic examination revealed it to be a schwannoma. Schwannomas are tumors that originate in the nerve sheath and are rarely detected in the heart. Here, we describe a rare case of primary schwannoma of the left atrium. PMID- 24782966 TI - Cardiac parasitic infection in trichinellosis associated with right ventricle outflow tract obstruction. AB - Here, we present a rare case of cardiac parasitic infection found in an adult female patient who had the symptoms of dyspnea upon exertion. She was diagnosed with a double-chambered right ventricle due to infundibular hypertrophy confirmed by transthoracic echocardiography and cardiac computed tomography. We performed surgery of infundibulectomy around the pulmonary valve. In the end, histopathological findings of the resected infundibular muscle demonstrated trichinellosis, a type of roundworm infection. PMID- 24782967 TI - Cardiac hemangioma: a case report. AB - Hemangioma of the heart, presenting as a primary cardiac tumor is extremely rare; it accounts for approximately 2% of all primary resected heart tumors. In our patient, the tumor was located in the orifice of the right lower pulmonary vein. Few cases of cardiac hemangiomas have been reported to arise from the left atrial (LA) wall. Left atrial hemangiomas, especially those attached to the LA wall, may be erroneously diagnosed as myxomas. Cardiac hemangioma is a rare disease; furthermore, a tumor arising from the LA wall and misconceived as a myxoma is extremely rare. We removed a mass misdiagnosed as a myxoma; it was pathologically confirmed to be a cardiac capillary hemangioma. Therefore, we report a rare case of a cardiac hemangioma misconceived as a myxoma; the tumor was removed successfully. PMID- 24782968 TI - An unusual form of coronary artery fistula: a small aneurysm of vieussens' arterial ring communicating with the pulmonary artery. AB - Vieussens' arterial ring (VAR) is the connection between the conus branch of the right coronary artery and the proximal right ventricular branch of the left anterior descending coronary artery. VARs are found in 48% of the population; however, pathologic VAR is rare. We experienced a case of pathologic VAR that involved a fistula connecting to the main pulmonary artery. PMID- 24782969 TI - Primary Purulent Pericarditis with Cardiac Tamponade due to Oropharyngeal Polymicrobial Infection: A Case Report and Literature Review. AB - Cardiac tamponade due to purulent pericarditis with a characteristic greenish fluid is rare in this antibiotic era. It is highly fatal despite early diagnosis and advanced treatment. Gram-positive cocci are the leading cause of purulent pericarditis, which usually results from a direct or hematogenous spread of organisms to the pericardium from the primary foci of infection. We describe an index case of rapidly developing pericardial tamponade caused by oropharyngeal polymicrobial infection in the absence of a primary source of infection in a 62 year-old man, who was successfully managed with emergency large-volume pericardiocentesis followed by pericardiectomy. PMID- 24782970 TI - Incidentally detected cardiac cyst hydatid after blunt thoracic trauma. AB - Cardiac involvement in hydatid disease is more seldom than the involvement of the liver and the lungs. Cardiac cyst hydatid disease is diagnosed incidentally or by means of symptoms such as dyspnea and angina pectoris. Here, we present the case of a 45-year-old male patient who underwent open heart surgery for a randomly detected cardiac cyst hydatid during investigations carried out in a healthcare institution after accidentally falling from height. On the other hand, this patient did not have any complaints associated with hydatid disease before this event. PMID- 24782971 TI - Hybrid technique to correct cerebral malperfusion following repair of a type a aortic dissection. AB - A 49-year-old man with drowsy mentality was diagnosed with acute type A aortic dissection; he underwent an emergency operation. When selective antegrade cerebral perfusion was initiated, the right regional cerebral oxygen saturation (rSO2) decreased as compared to the left one. Adequate blood flow was perfused through the branch of the artificial graft, after distal anastomosis, but the right rSO2 did not recover. Angiography revealed another intimal tear on the right common carotid artery. A stent was then inserted. The right rSO2 promptly increased to the same level as that of the left one. The patient was discharged without any neurologic complications. PMID- 24782972 TI - Surgical experience of persistent type 2 endoleaks with aneurysmal sac enlargement after endovascular aneurysm repair. AB - Herein, we present a case of a successful treatment of persistent type 2 endoleaks associated with aneurysmal sac enlargement after endovascular aneurysm repair in an elderly patient. We confirmed the diagnosis by abdominal computed tomography and selective angiography revealing an 11.0-cm aneurysm sac with type 2 endoleaks. An attempt for the endovascular embolization of collateral arteries was unsuccessful due to anatomic variations and their multiple complex communications. Instead, transperitoneal sacotomy and direct suturing on the feeding target vessels was successfully performed without any endograft damage. In conclusion, sacotomy appears to be a feasible therapeutic substitute where endovascular or other techniques have a high risk of failure and lead to unsuccessful results. PMID- 24782973 TI - Saccular aneurysm of the external jugular vein: a case report. AB - Saccular aneurysm of the external jugular vein presenting as a neck mass is very rare. We report the surgical treatment of an external jugular venous aneurysm in a 48-year-old female patient due to the cosmetic problem of neck engorgement, concomitant with thyroidectomy for cancer. PMID- 24782974 TI - Endovascular Revascularization for the Obstruction after Patch Angioplasty in Buerger's Disease. AB - Surgical revascularization for patients with Buerger's disease is possible only in a few cases, due to the diffuse segmental involvement and the lack of distal runoff vessels available for bypass surgery. We encountered a case of resting pain in the right foot, coldness with dysesthesia, and cyanosis on the right 1st toe. The patient was treated with an endovascular intervention after vein patch angioplasty failed due to an inflammatory reaction of Buerger's disease. We suggest that an endovascular procedure can be an effective treatment, even in addition to more conservative and surgical management, in patients with Buerger's disease and critical limb ischemia. PMID- 24782975 TI - Massive Hemoptysis Caused by Atypical Behcet's Disease. AB - Pulmonary and/or bronchial aneurysm with systemic thrombophlebitis can be seen in the case of both Behcet's disease and Hughes-Stovin syndrome. These two diseases may be indistinguishable since the clinical, radiological, and histopathological findings are similar in both cases. In particular, from the perspective of pulmonary involvement, hemoptysis is the leading cause of death in both conditions and is followed by aneurysmal rupture. Here, we report a case in which surgical resection was performed for a patient presenting recurrent hemoptysis as an atypical presentation of Behcet's disease. PMID- 24782976 TI - Massive rhabdomyolysis following cardiopulmonary bypass. AB - Here, we report a case of massive rhabdomyolysis following an uncomplicated repair of a ventricular septal defect in a five-month-old baby. Postoperatively, the patient was hemodynamically stable but metabolic acidosis continued, accompanied by fever and delayed mental recovery. The next day, he became comatose and never regained consciousness thereafter. The computed tomography of the brain revealed a diffuse brain injury. The patient followed a downhill course and eventually died on postoperative day 33. An unusually high level of creatine phosphokinase was noticed, peaking (21,880 IU/L) on postoperative day 2, suggesting severe rhabdomyolysis. The relevant literature was reviewed, and the possibility of malignant hyperthermia obscured by cardiopulmonary bypass and hypothermia was addressed. PMID- 24782977 TI - Single incision thoracoscopic left lower lobe superior segmentectomy for non small cell lung cancer. AB - Lobectomy with mediastinal node dissection has been standard treatment for non small cell lung cancer (NSCLC). Nowadays, video-assisted thoracoscopic surgery (VATS) is gaining acceptance as an alternative treatment option, given the quality-of-life benefits that it confers. For the VATS procedure, most surgeons create two or three ports with a utility incision of 3 to 5 cm. However, with acquired skill and instrumentation advances, single-incision thoracoscopic surgery has emerged over time. Here, we report the case of an 86-year-old female with NSCLC treated by single-incision segmentectomy. PMID- 24782978 TI - Bilateral video-assisted thoracoscopic surgery resection for multiple mediastinal myelolipoma: report of a case. AB - Myelolipoma in the mediastinum is an extremely rare entity. In this report, we present the case of a 79-year-old asymptomatic man who had three bilateral paravertebral mediastinal tumors. The three tumors were resected simultaneously using bilateral three-port video-assisted thoracoscopic surgery (VATS). There has been no evidence of recurrence within four years after the operation. Multiple bilateral mediastinal myelolipomas are extremely rare. There are no reports in the English literature of multiple bilateral thoracic myelolipomas that were resected simultaneously using bilateral VATS. We also present characteristic features of myelolipomas, which are helpful for diagnosis. PMID- 24782979 TI - Primary bronchial granular cell tumor in an adult male. AB - We report a rare case of granular cell tumor arising in the left lower lobe (LLL) bronchus with secondary obstructive change in a 60-year-old male. The patient was found to have a nodule in the LLL on a computed tomography scan, three months prior to his presentation to the Asan Medical Center. Bronchoscopic biopsies revealed a granular cell tumor. After undergoing LLL lobectomy with bronchoplasty, the patient has not experienced any tumor recurrence. PMID- 24782980 TI - Mediastinal paraganglioma: complete resection using video-assisted thoracoscopic surgery. AB - Mediastinal paragangliomas are very rare neuroendocrine tumors. Complete resection is the standard treatment of a paraganglioma because of the tumor's potential malignancy and poor response to chemo- or radiotherapy. However, the highly vascular nature of the tumor and its characteristic anatomic location make complete resection difficult. We report a case of an anterior mediastinal paraganglioma, which was incidentally found on a chest computed tomography scan for chronic cough work-up of a 55-year-old woman. Complete resection was accomplished using video-assisted thoracoscopic surgery, and the patient recovered without any complications. PMID- 24782981 TI - Targeting PI3K/Akt/mTOR Signaling in Cancer. AB - The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are two pathways crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions (e.g., cancer). Indeed, they are so interconnected that, in a certain sense, they could be regarded as a single, unique pathway. In this paper, after a general overview of the biological significance and the main components of these pathways, we address the present status of the development of specific PI3K, Akt, and mTOR inhibitors, from already registered medicines to novel compounds that are just leaving the laboratory bench. PMID- 24782984 TI - Effect of treatment modality on the hypothalamic-pituitary function of patients treated with radiation therapy for pituitary adenomas: hypothalamic dose and endocrine outcomes. AB - BACKGROUND: Both fractionated external beam radiotherapy and single fraction radiosurgery for pituitary adenomas are associated with the risk of hypothalamic pituitary (HP) axis dysfunction. OBJECTIVE: To analyze the effect of treatment modality (Linac, TomoTherapy, or gamma knife) on hypothalamic dose and correlate these with HP-axis deficits after radiotherapy. METHODS: Radiation plans of patients treated post-operatively for pituitary adenomas using Linac-based 3D conformal radiotherapy (CRT) (n = 11), TomoTherapy-based intensity modulated radiation therapy (IMRT) (n = 10), or gamma knife stereotactic radiosurgery (n = 12) were retrospectively reviewed. Dose to the hypothalamus was analyzed and post radiotherapy hormone function including growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, and gonadotropins (follicle stimulating hormone/luteinizing hormone) were assessed. RESULTS: Post-radiation, 13 of 27 (48%) patients eligible for analysis developed at least one new hormone deficit, of which 8 of 11 (72%) occurred in the Linac group, 4 of 8 (50%) occurred in the TomoTherapy group, and 1 of 8 (12.5%) occurred in the gamma knife group. Compared with fractionated techniques, gamma knife showed improved hypothalamic sparing for DMax Hypo and V12Gy. For fractionated modalities, TomoTherapy showed improved dosimetric characteristics over Linac-based treatment with hypothalamic DMean (44.8 vs. 26.8 Gy p = 0.02), DMax (49.8 vs. 39.1 Gy p = 0.04), and V12Gy (100 vs. 76% p = 0.004). CONCLUSION: Maximal dosimetric avoidance of the hypothalamus was achieved using gamma knife-based radiosurgery followed by TomoTherapy-based IMRT, and Linac-based 3D conformal radiation therapy, respectively. PMID- 24782983 TI - Molecular epigenetics in the management of ovarian cancer: are we investigating a rational clinical promise? AB - Epigenetics is essentially a phenotypical change in gene expression without any alteration of the DNA sequence; the emergence of epigenetics in cancer research and mainstream oncology is fueling new hope. However, it is not yet known whether this knowledge will translate to improved clinical management of ovarian cancer. In this malignancy, women are still undergoing chemotherapy similar to what was approved in 1978, which to this day represents one of the biggest breakthroughs for treating ovarian cancer. Although liquid tumors are benefiting from epigenetically related therapies, solid tumors like ovarian cancer are not (yet?). Herein, we will review the science of molecular epigenetics, especially DNA methylation, histone modifications and microRNA, but also include transcription factors since they, too, are important in ovarian cancer. Pre clinical and clinical research on the role of epigenetic modifications is also summarized. Unfortunately, ovarian cancer remains an idiopathic disease, for the most part, and there are many areas of patient management, which could benefit from improved technology. This review will also highlight the evidence suggesting that epigenetics may have pre-clinical utility in pharmacology and clinical applications for prognosis and diagnosis. Finally, drugs currently in clinical trials (i.e., histone deacetylase inhibitors) are discussed along with the promise for epigenetics in the exploitation of chemoresistance. Whether epigenetics will ultimately be the answer to better management in ovarian cancer is currently unknown; but we hope so in the future. PMID- 24782982 TI - The impact of the immune system on tumor: angiogenesis and vascular remodeling. AB - Angiogenesis, the formation of new blood vessels, as well as inflammation with massive infiltration of leukocytes are hallmarks of various tumor entities. Various epidemiological, clinical, and experimental studies have not only demonstrated a link between chronic inflammation and cancer onset but also shown that immune cells from the bone marrow such as tumor-infiltrating macrophages significantly influence tumor progression. Tumor angiogenesis is critical for tumor development as tumors have to establish a blood supply in order to progress. Although tumor cells were first believed to fuel tumor angiogenesis, numerous studies have shown that the tumor microenvironment and infiltrating immune cell subsets are important for regulating the process of tumor angiogenesis. These infiltrates involve the adaptive immune system including several types of lymphocytes as well as cells of the innate immunity such as macrophages, neutrophils, eosinophils, mast cells, dendritic cells, and natural killer cells. Besides their known immune function, these cells are now recognized for their crucial role in regulating the formation and the remodeling of blood vessels in the tumor. In this review, we will discuss for each cell type the mechanisms that regulate the vascular phenotype and its impact on tumor growth and metastasis. PMID- 24782986 TI - Targeted Disruption of the JAK2/STAT3 Pathway in Combination with Systemic Administration of Paclitaxel Inhibits the Priming of Ovarian Cancer Stem Cells Leading to a Reduced Tumor Burden. AB - Chemotherapy resistance associated with recurrent disease is the major cause of poor survival of ovarian cancer patients. We have recently demonstrated activation of the JAK2/STAT3 pathway and the enhancement of a cancer stem cell (CSC)-like phenotype in ovarian cancer cells treated in vitro with chemotherapeutic agents. To elucidate further these mechanisms in vivo, we used a two-tiered paclitaxel treatment approach in nude mice inoculated with ovarian cancer cells. In the first approach, we demonstrate that a single intraperitoneal administration of paclitaxel in mice 7 days after subcutaneous transplantation of the HEY ovarian cancer cell line resulted in a significant increase in the expression of CA125, Oct4, and CD117 in mice xenografts compared to control mice xenografts which did not receive paclitaxel. In the second approach, mice were administered once weekly with paclitaxel and/or a daily dose of the JAK2-specific inhibitor, CYT387, over 4 weeks. Mice receiving paclitaxel only demonstrated a significant decrease in tumor volume compared to control mice. At the molecular level, mouse tumors remaining after paclitaxel administration showed a significant increase in the expression of Oct4 and CD117 coinciding with a significant activation of the JAK2/STAT3 pathway compared to control tumors. The addition of CYT387 with paclitaxel resulted in the suppression of JAK2/STAT3 activation and abrogation of Oct4 and CD117 expression in mouse xenografts. This coincided with significantly smaller tumors in mice administered CYT387 in addition to paclitaxel, compared to the control group and the group of mice receiving paclitaxel only. These data suggest that the systemic administration of paclitaxel enhances Oct4- and CD117-associated CSC-like marker expression in surviving cancer cells in vivo, which can be suppressed by the addition of the JAK2-specific inhibitor CYT387, leading to a significantly smaller tumor burden. These novel findings have the potential for the development of CSC-targeted therapy to improve the treatment outcomes of ovarian cancer patients. PMID- 24782985 TI - Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity. AB - Oncolytic viruses (OVs) are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD), including immunogenic apoptosis, necrosis/necroptosis, pyroptosis, and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high-mobility group box 1, uric acid, and other damage-associated molecular patterns as well as pathogen-associated molecular patterns as danger signals, along with tumor-associated antigens, to activate dendritic cells and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis, or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells toward certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity, and thus the overall therapeutic efficacy. PMID- 24782987 TI - Metronomics as maintenance treatment in oncology: time for chemo-switch. PMID- 24782990 TI - A new kid on the block: the European thyroid journal. PMID- 24782989 TI - Transcriptional Activity of Heparan Sulfate Biosynthetic Machinery is Specifically Impaired in Benign Prostate Hyperplasia and Prostate Cancer. AB - Heparan sulfates (HSs) are key components of mammalian cells surface and extracellular matrix. Structure and composition of HS, generated by HS biosynthetic system through non-template-driven process, are significantly altered in cancer tissues. The aim of this study was to investigate the involvement of HS-metabolic machinery in prostate carcinogenesis. Transcriptional patterns of HS-metabolic enzymes (EXT1, EXT2, NDST1, NDST2, GLCE, 3OST1/HS3ST1, SULF1, SULF2, HPSE) were determined in normal, benign, and cancer human prostate tissues and cell lines (PNT2, LNCaP, PC3, DU145). Stability of the HS-metabolic system patterns under the pressure of external or internal stimuli was studied. Overall impairment of transcriptional activity of HS-metabolic machinery was detected in benign prostate hyperplasia, while both significant decrease in the transcriptional activity and changes in the expression patterns of HS metabolism involved genes were observed in prostate tumors. Prostate cancer cell lines possessed specific transcriptional patterns of HS metabolism-involved genes; however, expression activity of the system was similar to that of normal prostate PNT2 cells. HS-metabolic system was able to dynamically react to different external or internal stimuli in a cell type-dependent manner. LNCaP cells were sensitive to the external stimuli (5-aza-deoxycytidin or Trichostatin A treatments; co-cultivation with human fibroblasts), whereas PC3 cells almost did not respond to the treatments. Ectopic GLCE over-expression resulted in transcriptional activation of HS-biosynthetic machinery in both cell lines, suggesting an existence of a self-regulating mechanism for the coordinated transcription of HS metabolism-involved genes. Taken together, these findings demonstrate impairment of HS-metabolic system in prostate tumors in vivo but not in prostate cancer cells in vitro, and suggest that as a potential microenvironmental biomarker for prostate cancer diagnostics and treatment. PMID- 24782988 TI - Oncolytic virus-mediated reversal of impaired tumor antigen presentation. AB - Anti-tumor immunity can eliminate existing cancer cells and also maintain a constant surveillance against possible relapse. Such an antigen-specific adaptive response begins when tumor-specific T cells become activated. T-cell activation requires two signals on antigen presenting cells (APCs): antigen presentation through major histocombatibility complex (MHC) molecules and co-stimulation. In the absence of one or both these signals, T cells remain inactivated or can even become tolerized. Cancer cells and their associated microenvironment strategically hinder the processing and presentation of tumor antigens and consequently prevent the development of anti-tumor immunity. Many studies, however, demonstrate that interventions that over-turn tumor-associated immune evasion mechanisms can establish anti-tumor immune responses of therapeutic potential. One such intervention is oncolytic virus (OV)-based anti-cancer therapy. Here, we discuss how OV-induced immunological events override tumor associated antigen presentation impairment and promote appropriate T cell-APC interaction. Detailed understanding of this phenomenon is pivotal for devising the strategies that will enhance the efficacy of OV-based anti-cancer therapy by complementing its inherent oncolytic activities with desired anti-tumor immune responses. PMID- 24782991 TI - 2012 European thyroid association guidelines for metastatic medullary thyroid cancer urge restrained use of novel kinase inhibitors. PMID- 24782992 TI - 2012 European thyroid association guidelines for metastatic medullary thyroid cancer. AB - Distant metastases are the main cause of death in patients with medullary thyroid cancer (MTC). These 21 recommendations focus on MTC patients with distant metastases and a detailed follow-up protocol of patients with biochemical or imaging evidence of disease, selection criteria for treatment, and treatment modalities, including local and systemic treatments based on the results of recent trials. Asymptomatic patients with low tumor burden and stable disease may benefit from local treatment modalities and can be followed up at regular intervals of time. Imaging is usually performed every 6-12 months, or at longer intervals of time depending on the doubling times of serum calcitonin and carcinoembryonic antigen levels. Patients with symptoms, large tumor burden and progression on imaging should receive systemic treatment. Indeed, major progress has recently been achieved with novel targeted therapies using kinase inhibitors directed against RET and VEGFR, but further research is needed to improve the outcome of these patients. PMID- 24782993 TI - Thyroid Cancer: Role of RET and Beyond. AB - Specific thyroid cancer histotypes, such as papillary and medullary thyroid carcinoma, display genetic rearrangements or point mutations of the RET gene, resulting in its oncogenic conversion. The molecular mechanisms mediating RET rearrangement with other genes and the role of partner genes in tumorigenesis have been described. In addition, the RET protein has become a molecular target for medullary thyroid carcinoma treatment. PMID- 24782994 TI - Pre-conception counselling in graves' disease. AB - Risks to mother, fetus and neonate from untreated Graves' hyperthyroidism during gestation are compelling reasons for recommending pre-conception counselling. Pre conception counselling should include discussion as to the optimum treatment of Graves' hyperthyroidism in women wishing to become pregnant. Thyrotropin receptor antibodies remain elevated following radioiodine therapy, so medical or surgical treatment may be preferred to avoid fetal or neonatal hyperthyroidism. A TSH level <2.5 mIU/l must be achieved in women receiving LT4 before conception. The patient should be reassured that both she and the fetus can be maintained in a euthyroid state and that neonatal hyperthyroidism can be readily managed with a good outcome. The risks of antithyroid drug therapy during gestation should be fully discussed with emphasis on the very low risk (although real) of liver disease with propylthiouracil treatment and embryopathy with methimazole or carbimazole therapy. While propylthiouracil is the preferred drug for the first trimester, if it is not available other thionamides may be given. Breast-feeding while on antithyroid drugs is not contraindicated provided the dose of drug is low. The patient should also be advised of the importance of thyroid monitoring in the post-partum period. PMID- 24782995 TI - Breastfeeding and antithyroid drugs: a view from within. AB - The aim of this communication is to provide information regarding the use of antithyroid drugs (ATD) during lactation. Three ATD are used today: propylthiouracil (PTU), methimazole (MMI) and carbimazole (CMZ). The latter is a prodrug which is bioactivated to MMI. PTU is transferred in small amounts (0.025%) into milk. These amounts were considered nonsignificant for inducing adverse effects for the suckling infant. The amount of MMI excreted in milk is equal to MMI levels in serum. Due to its lower concentrations in milk, PTU was used for decades as the treatment of choice during breastfeeding. Recent studies have demonstrated that physical development, intelligence scores and thyroid status of children whose mothers had received MMI while breastfeeding were similar to those of healthy children. These new data offered clinicians an alternative drug approach. Several hepatic dysfunction studies have been published so far. Clinical manifestations varied from mild to severe hepatic failure, liver transplantation or death. Most PTU cases were more severe, idiosyncratic and not dose related. We recommend that PTU should not be prescribed for thyrotoxicosis during lactation. MMI should be used instead, in doses up to 30 mg/day, while PTU should be used in special cases for a restricted time period. PMID- 24782996 TI - A Case of Propylthiouracil-Induced Hepatitis during Pregnancy. AB - A 32-year-old with no pre-existing liver disease was diagnosed with Graves' disease at week 4 of pregnancy. Thyroid-stimulating hormone was undetectable with elevated free thyroxine levels and positive thyroid receptor antibodies. She was started on a reducing regime of propylthiouracil (PTU). At week 20 in pregnancy, she became jaundiced. Initial bloods revealed: bilirubin 91 MUmol/l, alanine aminotransferase 1,796 IU/l, alkaline phosphatase 200 IU/l, international normalized ratio 1.2, and albumin 33 g/l. A presumptive diagnosis of PTU-induced hepatitis was made. PTU was immediately discontinued and best supportive care instigated. Serum markers for autoimmune and viral hepatitis were negative, abdomen ultrasound, ferritin and caeruloplasmin were normal. Although her alanine aminotransferase began to fall, her bilirubin continued to rise, peaking at 378. Two weeks after PTU cessation she became thyrotoxic and was started on a reducing regime of carbimazole. Her thyroid function stabilized and liver function tests continued to improve with carbimazole stopped at week 32. Growth scans remained normal with delivery of a healthy baby at 38 weeks. This report highlights that good outcomes can be achieved in PTU-induced hepatitis in pregnancy. Patients on PTU should be warned of the potential risk of hepatic failure and advised to seek medical advice immediately if they develop jaundice. PMID- 24782997 TI - Management of subclinical hypothyroidism: the thyroidologists' view. AB - Subclinical hypothyroidism is a common finding when serum thyrotropin and thyroid hormones are measured, but the benefits of treating such patients with levothyroxine remain unproven. During the 14th International Thyroid Congress, a debate and discussion relating to three different clinical case scenarios of subclinical hypothyroidism was held. The audience consisted predominantly of members of the European Thyroid Association. Participants (n = 380) voted using an electronic system to express their opinion about the treatment of the 3 cases. For a 53-year-old woman with fatigue and difficulty losing weight, who has a serum TSH of 6.8 mU/l, 49% would treat with levothyroxine. Whereas, for an 84 year-old woman with a serum TSH of 6.8 mU/l, only 8% of participants would treat with levothyroxine. In contrast, for a 39-year-old woman who is trying to become pregnant, with a serum TSH of 4.5 mU/l and strongly positive thyroid peroxidase antibodies, 95% of respondents would treat with levothyroxine. This article details the clinical case scenarios and the results of the thyroidologists' opinions on treatment. It forms a snapshot of the range of accepted clinical practice in this common condition. PMID- 24782998 TI - European thyroid association guidelines on L-t4 + L-t3 combination for hypothyroidism: a weary step in the right direction. PMID- 24782999 TI - 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. AB - BACKGROUND: Data suggest symptoms of hypothyroidism persist in 5-10% of levothyroxine (L-T4)-treated hypothyroid patients with normal serum thyrotrophin (TSH). The use of L-T4 + liothyronine (L-T3) combination therapy in such patients is controversial. The ETA nominated a task force to review the topic and formulate guidelines in this area. METHODS: Task force members developed a list of relevant topics. Recommendations on each topic are based on a systematic literature search, discussions within the task force, and comments from the European Thyroid Association (ETA) membership at large. RESULTS: SUGGESTED EXPLANATIONS FOR PERSISTING SYMPTOMS INCLUDE: awareness of a chronic disease, presence of associated autoimmune diseases, thyroid autoimmunity per se, and inadequacy of L-T4 treatment to restore physiological thyroxine (T4) and triiodothyronine (T3) concentrations in serum and tissues. There is insufficient evidence that L-T4 + L-T3 combination therapy is better than L-T4 monotherapy, and it is recommended that L-T4 monotherapy remains the standard treatment of hypothyroidism. L-T4 + L-T3 combination therapy might be considered as an experimental approach in compliant L-T4-treated hypothyroid patients who have persistent complaints despite serum TSH values within the reference range, provided they have previously received support to deal with the chronic nature of their disease, and associated autoimmune diseases have been excluded. Treatment should only be instituted by accredited internists/endocrinologists, and discontinued if no improvement is experienced after 3 months. It is suggested to start combination therapy in an L-T4/L-T3 dose ratio between 13:1 and 20:1 by weight (L-T4 once daily, and the daily L-T3 dose in two doses). Currently available combined preparations all have an L-T4/L-T3 dose ratio of less than 13:1, and are not recommended. Close monitoring is indicated, aiming not only to normalize serum TSH and free T4 but also normal serum free T4/free T3 ratios. Suggestions are made for further research. CONCLUSION: L-T4 + L-T3 combination therapy should be considered solely as an experimental treatment modality. The present guidelines are offered to enhance its safety and to counter its indiscriminate use. PMID- 24783000 TI - Understanding the hypothalamus-pituitary-thyroid axis in mct8 deficiency. AB - Thyroid hormone (TH) metabolism and action via binding to nuclear receptors are intracellular events that require the passage of TH across the plasma membrane. This process is mediated by specific TH transporters of which the monocarboxylate transporter 8 (Mct8) has received major attention. Mct8 is highly expressed in different tissues such as liver, kidney, thyroid, pituitary and brain. In humans, inactivating mutations of the MCT8 gene (SLC16A2) are associated with severe forms of psychomotor retardation and abnormal TH serum levels (Allan-Herndon Dudley syndrome). Surprisingly, Mct8 knockout (ko) mice do not exhibit overt neurological symptoms but fully replicate the unusual serum TH profile with highly increased serum T3 in the presence of low serum T4. In order to evaluate the underlying mechanisms for these abnormalities, TH transport and metabolism have been intensively studied in different tissues of Mct8 ko mice. Here, we summarize the observed changes within the hypothalamus-pituitary-thyroid axis that result in altered TH production and secretion. Although analysis of Mct8 ko mice has greatly expanded our knowledge, many open questions still remain to be addressed in order to define the tissue- and cell-specific role of this important TH transporter. PMID- 24783001 TI - Oxidative stress in graves' disease. AB - Increased reactive oxygen species (ROS) generation and the consequent oxidative damage are involved in the development of several diseases, including autoimmune diseases. Graves' disease is an autoimmune disorder characterized by hyperthyroidism and, less frequently, orbitopathy. Hyperthyroidism is characterized by increased oxidative stress. Untreated hyperthyroidism is associated with an increase of several parameters of oxidative stress and in most studies (but not all) by an increase of antioxidant defense enzymes. Restoration of euthyroidism with antithyroid drug is associated with a reversal of the biochemical abnormalities associated with oxidative stress. Animal and human studies suggest that increased ROS may directly contribute to some clinical manifestation of the disease, including orbitopathy. Antioxidants administered alone improve some clinical signs and symptoms of hyperthyroidism and, when associated with antithyroid drugs, induce a more rapid control of clinical manifestations and a faster achievement of euthyroidism. A large randomized clinical trial has shown that antioxidant supplementation (selenium) may also be beneficial for mild Graves' orbitopathy. PMID- 24783003 TI - Alcohol consumption as a risk factor for autoimmune thyroid disease: a prospective study. AB - BACKGROUND: Alcohol consumption has been identified as a protective factor for some autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus. OBJECTIVE: We hypothesized that alcohol consumption would reduce the risk of developing autoimmune thyroid disease (AITD). STUDY DESIGN: Two nested case-control studies in the prospective Amsterdam AITD cohort. Follow-up was 5 years, with annual assessments. In study A, we compared alcohol consumption between cases (subjects who during follow-up remained euthyroid but developed thyroid peroxidase antibodies (TPO-Ab), called event) and controls (subjects who remained euthyroid and TPO-Ab-negative). In study B, we compared alcohol consumption between cases (subjects who during follow-up developed overt hypothyroidism, called event) and controls (subjects who did not develop overt hypothyroidism). For each case, 2 controls were selected, matched for age, duration of follow-up and smoking behavior at baseline and at the time of event. RESULTS: In study A, alcohol consumption did not differ between cases and controls at any time point. In study B, the number of subjects consuming >10 units of alcohol per week was not different between cases and controls at study entrance (8.3 vs. 14.5%, NS), but lower at 1 year before (5.3 vs. 19.7%, p = 0.041) and at the time of event (6.7 vs. 23.7%, p = 0.044); respective odds ratios are 0.54 (0.14-2.06), 0.23 (0.05-1.04) and 0.23 (0.05-1.06). CONCLUSION: Alcohol consumption is not associated with de novo development of TPO-Ab, but is lower in subjects who developed overt hypothyroidism. The data suggest alcohol consumption may protect against overt autoimmune hypothyroidism. PMID- 24783002 TI - Thyroid hormone replacement therapy: three 'simple' questions, complex answers. AB - Current guidelines recommend that hypothyroid patients should be treated with levothyroxine, which in the vast majority of the cases leads to resolution of the symptoms and normalization of serum free T4 (FT4), T3 and TSH levels. However, a small group of hypothyroid patients remain symptomatic for neurocognitive dysfunction despite normal serum FT4 and TSH, which could be explained by localized brain hypothyroidism. More than half of the T3 in the brain is produced locally via the action of the type II deiodinase (D2) and variability/defects in this pathway could explain the residual symptoms. If this rationale is correct, adding liothyronine to the replacement therapy could prove beneficial. However, with a few exceptions, several clinical trials failed to identify any beneficial effects of combined therapy. More recently, the results of a large clinical trial revealed a better neurocognitive outcome with combined therapy only in hypothyroid patients carrying a polymorphism in the DIO2 gene. This obviously needs to be confirmed by other groups but it is tempting to speculate that combined levothyroxine and liothyronine has a place in the treatment of hypothyroidism, for some. PMID- 24783004 TI - Is Recombinant Human TSH a Trigger for Graves' Orbitopathy? AB - The pathogenesis of Graves' orbitopathy (GO) remains unknown. The hypothesis of a causal relationship between autoimmunity against the TSH receptor (TSHR) and GO is supported by clinical studies. Radioiodine treatment is associated with worsening or new onset of GO, possibly via antigen shedding or by inducing hypothyroidism. The coexistence of thyroid cancer with Graves' disease (GD) and GO is rare. Here we report 3 cases of reactivation of GO in patients who underwent treatment with recombinant human TSH (rhTSH) and radioiodine ablation. In each case, a thyroidectomy was performed to treat the GD, and an incidental thyroid cancer was discovered. In all 3 cases, reactivation of GO was observed 3 6 weeks after administration of rhTSH, despite maintaining euthyroidism, which was unaccompanied by a rise in serum TSHR antibodies after radioiodine and despite steroids in 1 of the 3 patients. These observations suggest that binding of either TSH or TSHR antibodies to the TSHR, independently of thyroid status, may be causally related to deterioration of GO. Clinicians should be aware of a possible association between rhTSH administration and reactivation of GO, which should be taken into account before prescribing rhTSH in patients with GO. Prophylactic steroids may need to be considered for patients at high risk of exacerbation of GO. PMID- 24783005 TI - High prevalence of papillary thyroid microcarcinoma in danish patients: a prospective study of 854 consecutive patients with a cold thyroid nodule undergoing fine-needle aspiration. AB - We aimed to investigate the diagnostic accuracy of ultrasound (US)-guided fine needle aspirates (FNAs) obtained from 854 consecutive Danish patients with a scintigraphically cold thyroid nodule in a borderline iodine-deficient area. Clinical, sonographic, and pathological findings in patients with a cold thyroid nodule undergoing US-guided FNA were prospectively registered. 408 patients underwent thyroid surgery, resulting in 50 cancers and in addition 37 patients had an incidental finding of papillary thyroid microcarcinomas. Based on the diagnostic FNA, we found sensitivity and specificity for malignancy of 73.9 and 99.2%, respectively. The positive and negative predictive values of a diagnostic FNA for malignancy were 89.5 and 97.7%. We identified 6 false-negative and 2 false-positive diagnoses. Solid versus cystic feature of the nodule, as well as >2 high-risk US features, were predictive for malignancy. Cancer incidence was 13% among females and 9% among males. The accuracy of a diagnostic set-up based on clinical examination, scintigraphy, US, and US-guided FNA was determined with a 48% rate of histopathological validation in the cohort. The overall thyroid cancer incidence has increased worldwide, but our results suggest that the most frequent occurring cancer is an incidental papillary thyroid microcarcinoma of which the clinical significance has yet to be established. PMID- 24783006 TI - Assessment of SPAG9 Transcript in Fine Needle Aspirates of Thyroid Nodules. AB - OBJECTIVES: Sperm-associated antigen 9 (SPAG9) has been suggested as a possible biomarker in several malignancies including thyroid cancer. We investigated the expression of SPAG9 mRNA in fine needle aspiration (FNA) material from papillary thyroid carcinoma (PTC) and benign thyroid nodules. STUDY DESIGN: SPAG9 expression was assessed in 36 FNA samples corresponding to 16 PTC and 20 benign nodules using the original method detecting the SPAG9 transcript containing intron 21 (NCBI X91879). The presence of the BRAF V600E point mutation was also analyzed by pyrosequencing. RESULTS: Six of 16 (38%) PTC samples were positive for X91879 SPAG9 transcript compared to 8 of 20 (40%) benign samples (p = 0.88). Out of 12 BRAF-positive PTC, 3 (25%) also expressed the SPAG9 transcript compared to 3 out of 4 BRAF-negative PTC (75%; p = 0.12). CONCLUSIONS: The X91879 SPAG9 transcript originally described does not appear to be overexpressed in FNA material from PTC or to be clinically relevant in the diagnosis of thyroid nodules. PMID- 24783007 TI - Greater Efficacy of Total Thyroidectomy versus Radioiodine Therapy on Hyperthyroidism and Thyroid-Stimulating Immunoglobulin Levels in Patients with Graves' Disease Previously Treated with Antithyroid Drugs. AB - AIMS: We compared the effects of total thyroidectomy (TTx) and radioiodine (RAI) administration on the course of thyroid hormones and thyroid-stimulating immunoglobulins (TSI) in patients with Graves' disease. METHODS: We retrospectively studied 80 patients initially treated with antithyroid drugs and requiring either RAI (8.3 +/- 1.7 mCi of (131)I; n = 40) or TTx (n = 40) as second-line therapy. RESULTS: The TTx and RAI groups were not different, except for larger goiter, higher FT3 and more frequent Graves' orbitopathy at diagnosis in the surgery group (p < 0.05). A persistent remission of hyperthyroidism was observed in 97% of operated patients versus 73% of the RAI patients at 3 years (p < 0.01). TTx was followed by a rapid and steady decrease in TSI during the first 9 months, while a surge of antibodies was observed during the first 6 months after RAI, followed by a slow decrease over the next 18 months. At the last visit, high TSI levels were still observed in 18 and 60% of patients in the surgery and RAI groups, respectively (p < 0.001). CONCLUSIONS: TTx is more efficient than RAI to induce a rapid and permanent correction of hyperthyroidism and TSI decrease in patients previously treated with antithyroid drugs. PMID- 24783008 TI - Polyneuropathy after radioactive iodine treatment of hyperthyroidism and beneficial effect of combined t4/t3 therapy of hypothyroidism. PMID- 24783009 TI - Thoughts about the 'Antenatal Thyroid Screening and Childhood Cognitive Function' Study. PMID- 24783010 TI - Reply. PMID- 24783011 TI - Use of t4, t4 + t3, and t3 in the dutch population in the period 2005-2011. PMID- 24783012 TI - Database(d) Guidelines: A Small World. PMID- 24783013 TI - 2012 European thyroid association guidelines for the management of familial and persistent sporadic non-autoimmune hyperthyroidism caused by thyroid-stimulating hormone receptor germline mutations. AB - All cases of familial thyrotoxicosis with absence of evidence of autoimmunity and all children with persistent isolated neonatal hyperthyroidism should be evaluated for familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) or persistent sporadic non-autoimmune hyperthyroidism (PSNAH). First, all index patients should be analysed for the presence/absence of a thyroid-stimulating hormone (TSH) receptor (TSHR) germline mutation, and if they display a TSHR germline mutation, all other family members including asymptomatic and euthyroid family members should also be analysed. A functional characterization of all new TSHR mutations is necessary. Appropriate ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences, especially in children. Therefore, in children the diagnosis of FNAH or PSNAH needs to be established as early as possible in the presence of the clinical hallmarks of the disease. PMID- 24783014 TI - Thyroid consequences of the fukushima nuclear reactor accident. AB - BACKGROUND: A special report, 'The Fukushima Accident', was delivered at the 35th Annual Meeting of the European Thyroid Association in Krakow on September 11, 2011, and this study is the follow-up of the special report. OBJECTIVES: To present a preliminary review of potential thyroid consequences of the 2011 Fukushima nuclear reactor accident. METHODS: Numerous new data have been presented in Japanese, and most of them are available on the website from each research institute and/or from each municipality. The review was made using these data from the website. RESULTS: When individual radiation doses were expressed as values in more than 99% of residents, radiation doses by behavior survey in evacuation and deliberate evacuation areas were less than 10 mSv in the first 4 months, and internal radiation doses measured by whole body counters were less than 1 mSv/year. Individual thyroid radiation doses were less than 50 mSv (intervention levels) even in evacuation areas. As for health consequences, no one died and no one suffered from acute effects. The thyroid ultrasound examination is in progress and following examination of almost 40,000 children, 35% of them have nodules and/or cysts but no cancers. CONCLUSIONS: Countermeasures against radiation must consider current individual measured values, although every effort must be taken to reconstruct radiation doses as precisely as possible. At present, the difference of thyroid radiation dose between Chernobyl and Fukushima appears to be due to the strict control of milk started within a week after the accident in Fukushima. Since the iodine-131 plume moved around in wide areas and for a long time, the method of thyroid protection must be reconsidered. PMID- 24783015 TI - Thyroid function and obesity. AB - Important interaction exists between thyroid function, weight control, and obesity. Several mechanisms seem to be involved, and in studies of groups of people the pattern of thyroid function tests depends on the balance of obesity and underlying thyroid disease in the cohort studied. Obese people with a normal thyroid gland tend to have activation of the hypothalamic-pituitary-thyroid axis with higher serum TSH and thyroid hormones in serum. On the other hand, small differences in thyroid function are associated with up to 5 kg difference in body weight. The weight loss after therapy of overt hypothyroidism is caused by excretion of water bound in tissues (myxoedema). Many patients treated for hyperthyroidism experience a gain of more weight than they lost during the active phase of the disease. The mechanism for this excessive weight gain has not been fully elucidated. New studies on the relation between L-T3 therapy and weight control are discussed. The interaction between weight control and therapy of thyroid disease is important to many patients and it should be studied in more detail. PMID- 24783016 TI - The vitamin d receptor in thyroid development and function. AB - BACKGROUND AND OBJECTIVE: Vitamin D is known to modulate thyroid neoplastic and autoimmune disease. We investigated the role of the vitamin D receptor (VDR) in normal thyroid development and function (thyrocytes and C cells). METHODS: The thyroid phenotype of VDR knockout mice was studied in comparison to wild-type controls. The mice were fed a normal diet or a calcium-rich diet to circumvent effects induced by hypocalcemia. RESULTS: Thyroid morphology was unaltered in VDR knockout mice. Also, expression of different parameters of thyrocyte function was comparable (immunohistochemistry). C cell physiology was, however, affected in the absence of the VDR, resulting in increased thyroidal calcitonin expression (immunohistochemistry), paralleled by increased serum calcitonin levels, but only in normocalcemic mice. To study a possible effect of vitamin D status on basal calcitonin levels in humans, serum calcitonin concentrations were compared between vitamin D-deficient and -sufficient patients (serum 25-OH vitamin D3 <=10 and >=40 ng/ml, respectively), but no difference was observed. CONCLUSIONS: In mice, the VDR is redundant for normal thyrocyte function, but not for C cell function, where it mediates the negative control of calcitonin by 1,25 dihydroxyvitamin D3. In patients, vitamin D status does not affect basal serum calcitonin levels. A study in healthy individuals is needed to confirm these findings. PMID- 24783017 TI - Side effects of anti-thyroid drugs and their impact on the choice of treatment for thyrotoxicosis in pregnancy. AB - INTRODUCTION: Hyperthyroidism in pregnancy is a serious condition and its management is complex. Whilst carbimazole/methimazole (CBZ/MMI) and propylthiouracil (PTU) have similar efficacies in controlling hyperthyroidism, their risk of side effects such as major congenital abnormalities and hepatotoxicity are different. METHODS: Various combinations of the terms 'anti thyroid drugs', 'thionamide', 'carbimazole', 'methimazole', 'propylthiouracil', 'pregnancy', 'side effects', 'agranulocytosis', 'birth defects', 'congenital malformations', 'embryopathy', 'aplasia cutis', 'hepatotoxicity', 'hepatic failure', 'maternal' and 'fetus' were used to search MEDLINE and the Cochrane library. The references of retrieved papers were also reviewed. RESULTS: There is increasing evidence for a CBZ/MMI embryopathy, whilst data remain lacking for major congenital abnormalities with PTU. In contrast, PTU is associated with increased risk of severe liver injury. Management strategies to reduce these risks by using PTU in the first trimester and CBZ/MMI in the later trimesters remain untested. CONCLUSION: More evidence is still needed in defining the relative risks between CBZ/MMI and PTU of major congenital abnormalities and severe liver injury in pregnancy. Studies are also needed to establish the suitability of recent management suggestions in switching from PTU to CBZ/MMI after the first trimester. Major adverse outcomes secondary to CBZ/MMI and PTU are rare, and inadequately treated hyperthyroidism poses a far greater risk. PMID- 24783018 TI - Is Thyroid Autoimmunity per se a Determinant of Quality of Life in Patients with Autoimmune Hypothyroidism? AB - PURPOSE: To evaluate the relationship between thyroid variables and health related quality of life (QoL) in patients with autoimmune hypothyroidism, using the thyroid-specific QoL questionnaire ThyPRO. METHODS: In a cross-sectional study, responses to the ThyPRO from 199 outpatients with autoimmune hypothyroidism were analyzed in relation to thyroid volume, thyroid function and markers of thyroid autoimmunity. Based on a classical QoL framework, we hypothesized that physiological dysfunction caused specific physical and psychological symptoms, which affected functioning and well-being, and consequently participation in life and QoL. These hypotheses were tested through multiple regression and multivariate path analysis models. RESULTS: None of the thyroid function tests were associated with QoL scores. However, in the pairwise regression, the thyroid peroxidase antibody (TPOAb) level was associated with several QoL outcomes: Goitre Symptoms (p = 0.024), Depressivity (p = 0.004), Anxiety (p = 0.004), Emotional Susceptibility (p = 0.005) and Impaired Social Life (p = 0.047). In the multivariate model, the TPOAb level was related to Goitre Symptoms (r = 0.17, p = 0.019), Depressivity (r = 0.24, p = 0.001), and Anxiety (r = 0.23, p = 0.002), but no longer to Emotional Susceptibility or Impaired Social Life, indicating that the effect on these were mediated through an effect on the symptom scales (i.e. Goitre Symptoms, Depressivity and Anxiety). CONCLUSION: Health-related QoL, evaluated with state-of-the-art QoL methodology, was related to TPOAb level but not to thyroid function. This raises the hypothesis that autoimmunity, independent of thyroid function, impacts on QoL in patients with autoimmune hypothyroidism, especially in terms of psychological symptoms. Longitudinal studies, in initially untreated patients, are needed to test this hypothesis. PMID- 24783019 TI - Large discrepancy in the results of sensitive measurements of thyroglobulin antibodies in the follow-up on thyroid cancer: a diagnostic dilemma. AB - During follow-up on patients treated for differentiated thyroid cancer, thyroglobulin (Tg) antibodies can interfere with the Tg assay, making the use of Tg less reliable as a tumor marker. PURPOSE: To compare Tg and Tg autoantibodies (Tg-Ab) methods used in Denmark, regarding the number of patient samples being accepted for evaluating the result of a serum thyroglobulin (s-Tg) measurement. DESIGN: 95 consecutive blood samples drawn from patients in 2006 in one center were selected according to the following criteria: s-Tg <1MUg/l and accepted BRAHMS Tg+ recovery test using 50 ng of Tg. Samples were retested with: (1) DPC IMMULITE 2000 Tg and Tg-Ab, (2) BRAHMS Tg and Tg-Ab on Kryptor, (3) BRAHMS Tg+ and Dynotest anti-Tg, (4) DELFIA hTg and recovery test using 25 ng of Tg, and (5) BRAHMS Tg+ with recovery test using 1 and 50 ng of Tg. RESULTS: The number of patient samples that was not accepted for Tg evaluation varied from 2 to 26% when the reference values suggested by the manufacturers of the assay were used. When using the detection limit to the cutoff seen in epidemiological studies the number increased to 40%. CONCLUSION: We found large discrepancies in acceptance of patient samples for s-Tg evaluation, thus illustrating a diagnostic dilemma. PMID- 24783020 TI - Single lobe disease in cases of advanced endemic goiter: a new phenotype. AB - OBJECTIVES: To report a new phenotype of advanced endemic goiter that affects only one lobe of the thyroid gland. PATIENTS AND METHODS: This study included 60 patients from the west of Sudan with long-standing unilateral simple endemic goiter that required obectomy, with emphasis on the gross appearance, measurements and cytological features of the contralateral lobe. RESULTS: Out of 60 patients with unilateral goiter, 50 (83%) were found to have the disease on the ipsilateral lobe only (monolobar goiter). The contralateral lobe in these 50 patients showed no nodularity, and its volume was within the normal limits. All patients with monolobar disease had total lobectomy on the affected side, and postoperatively they continued to have normal blood levels of T3, T4 and TSH. CONCLUSION: We report a new phenotype of advanced endemic goiter that affects only one lobe of the thyroid gland, and in the presence of a structurally and functionally normal contralateral lobe. PMID- 24783021 TI - A case of asymptomatic riedel thyroiditis with follicular adenoma in a patient with a multinodular goiter: an unusual association. AB - BACKGROUND: Riedel's thyroiditis (RT) is a rare inflammatory disease that results in fibrosis of the thyroid gland and invasion to the surrounding structures of the neck. Follicular adenoma (FA) of the thyroid is the most common benign neoplasm of the gland. PATIENT FINDINGS: A 42-year-old woman was referred to the outpatient clinic due to a multinodular goiter and thyroiditis. The patient was euthyroid and thyroid function tests were within normal limits. Thyroid antibodies (thyroid peroxidase antibody and thyroglobulin antibody) were high. Thyroid ultrasonography showed multiple iso-hypoechoic nodules and thyroiditis. Fine-needle aspiration cytology was performed, and it was consistent with 'suspicious for a follicular neoplasm' according to the Bethesda system. Due to the clinical findings, which included weight loss and sweating, and the cytological results indicative of a follicular neoplasm, the patient underwent a total thyroidectomy. The histopathological diagnosis was RT associated with FA. The patient was started on thyroid hormone (thyroxine) replacement therapy after surgery and was evaluated for additional fibrosis related to RT. CONCLUSIONS: To our knowledge, this is the first case of RT associated with FA in an asymptomatic patient with a multinodular goiter and high thyroid antibodies reported in the literature. PMID- 24783022 TI - Functional TSH Receptors, Malignant Melanomas and Subclinical Hypothyroidism. PMID- 24783023 TI - The leipzig thyrotropin receptor mutation database: update 2012. PMID- 24783024 TI - Radioactive iodine activities for postsurgical thyroid ablation: the lower the better. PMID- 24783025 TI - 2012 European thyroid association guidelines for genetic testing and its clinical consequences in medullary thyroid cancer. AB - Twenty-five percent of medullary thyroid cancers (MTC) are familial and inherited as an autosomal dominant trait. Three different phenotypes can be distinguished: multiple endocrine neoplasia (MEN) types 2A and 2B, in which the MTC is associated with other endocrine neoplasias, and familial MTC (FMTC), which occurs in isolation. The discovery that germline RET oncogene activating mutations are associated with 95-98% of MEN 2/FMTC syndromes and the availability of genotyping to identify mutations in affected patients and their relatives has revolutionized the diagnostic and therapeutic strategies available for the management of these patients. All patients with MTC, both those with a positive familial history and those apparently sporadic, should be submitted to RET genetic screening. Once an RET mutation has been confirmed in an index patient, first-degree relatives should be screened rapidly to identify the 50% who inherited the mutation and are therefore at risk for development of MTC. Relatives in whom no RET mutation is identified can be reassured and discharged from further follow-up, whereas RET positive subjects (i.e. gene carriers) must be investigated and a therapeutic strategy initiated. These guideline recommendations are derived from the most recent studies identifying phenotype-genotype correlations following the discovery of causative RET gene mutations in MEN 2 eighteen years ago. Three major points will be discussed: (a) identification of patients and relatives who should have genetic screening for RET mutations, (b) management of asymptomatic gene carriers, and (c) ethics. PMID- 24783026 TI - The immunopathogenesis of chronic autoimmune thyroiditis one century after hashimoto. AB - Hakaru Hashimoto described 4 patients with a hitherto unknown cause for goitre, struma lymphomatosa, a century ago. He was careful to distinguish this from Riedel thyroiditis but it has become clear that fibrosis and atrophy of the thyroid are indeed components of Hashimoto thyroiditis, and in rare cases IgG4 related sclerosing disease may be an outcome. Although the cause of the lymphocytic infiltration was unknown to Hashimoto, we now know through the pioneering studies of N.R. Rose and E. Witebsky [J Immunol 1956;76:417-427] that this condition is the archetype for autoimmune destruction as a disease mechanism. In the last two decades in particular, there has been huge interest in unravelling the genetic basis for this and related autoimmune disorders. The list of polymorphisms associated with autoimmune thyroid disease grows each year, and in the case of vitiligo, which is frequently found in association with thyroid autoimmunity, we know that 27 separate susceptibility loci account for less than 20% of the heritability of this condition. Environmental and existential factors may turn out to be just as complex in number and in interactions. We can thus imagine a 'Swiss cheese' model for the causation of autoimmune thyroid disease, in which the effects of cumulative weaknesses line up - like the holes in slices of cheese - to allow the catastrophic event of autoimmune destruction to occur. PMID- 24783027 TI - Genotype and phenotype predictors of relapse of graves' disease after antithyroid drug withdrawal. AB - BACKGROUND: For patients with Graves' disease (GD), the primary goal of antithyroid drug therapy is to temporarily restore the patient to the euthyroid state and wait for a subsequent remission of the disease. This study sought to identify the predictive markers for the relapse of disease. METHODS: To do this, we studied 262 GD patients with long enough follow-up after drug withdrawal to determine treatment outcome. The patients were divided into three groups by time of relapse: early relapse group (n = 91) had an early relapse within 9 months, late relapse group (n = 65) had a relapse between 10 and 36 months, and long-term remission group (n = 106) were either still in remission after at least 3 years or relapsed after 3 years of drug withdrawal. We assessed the treatment outcome of 23 SNPs of costimulatory genes, phenotype and smoking habits. We used permutation to obtain p values for each SNP as an adjustment for multiple testing. Cox proportional hazards models was performed to assess the strength of association between the treatment outcome and clinical and laboratory variables. RESULTS: FOUR SNPS WERE SIGNIFICANTLY ASSOCIATED WITH DISEASE RELAPSE: rs231775 (OR 1.96, 95% CI 1.18-3.26) at CTLA-4 and rs745307 (OR 7.97, 95% CI 1.01-62.7), rs11569309 (OR 8.09, 95% CI 1.03-63.7), and rs3765457 (OR 2.60, 95% CI 1.08-6.28) at CD40. Combining risk alleles at CTLA-4 and CD40 improved the predictability of relapse. Using 3 years as the cutoff point for multivariate analysis, we found several independent predictors of disease relapse: number of risk alleles (HR 1.30, 95% CI 1.09-1.56), a large goiter size at the end of the treatment (HR 1.30, 95% CI 1.05-1.61), persistent TSH-binding inhibitory Ig (HR 1.64, 95% CI 1.15-2.35), and smoking habit (HR 1.60, 95% CI 1.05-2.42). CONCLUSION: Genetic polymorphism of costimulatory genes, smoking status, persistent goiter, and TSH binding inhibitory Ig predict disease relapse. PMID- 24783028 TI - Atypical Presentation of Riedel's Thyroiditis: Multifocal Nodular Fibrosis and Resolution with Levothyroxine. AB - BACKGROUND: Riedel's thyroiditis is characterised by chronic inflammatory invasive fibrosclerosis of the thyroid gland, surrounding structures, and extrathyroidal fibrosis. We present a case of Riedel's thyroiditis associated with nodular fibrosis of the lungs and liver. CASE: A 40-year-old woman presented with a 3-month history of neck swelling, difficulty swallowing and breathlessness on exertion. Core biopsy of the goitre revealed dense fibrous tissue with mixed chronic inflammatory cells. A staging computed tomography scan revealed a large thyroid mass encasing the oesophagus and compressing the trachea, multiple bilateral pulmonary nodules with no evidence of lymphadenopathy, and multiple suspicious nodular lesions in the liver. A thorascopic biopsy of a lung lesion in its entirety revealed a hyalinising lung lesion with no evidence of malignancy. Following the introduction of levothyroxine replacement, symptomatic improvement occurred in parallel with improvements in imaging. CONCLUSION: To our knowledge, this is the first description of Riedel's thyroiditis presenting with nodular extrathyroidal fibrosis, and which showed resolution following institution of levothyroxine. PMID- 24783029 TI - Relative impact of iodine supplementation and maternal smoking on cord blood thyroglobulin in pregnant women with normal thyroid function. AB - OBJECTIVE: To assess the impact on cord blood (CB) thyroglobulin (Tg) of early iodine supplementation during pregnancy. METHODS: A total of 111 healthy pregnant women with normal thyroid function were included in a prospective randomized study and divided into two groups with (150 MUg/day) or without iodine supplementation started during the first trimester. Maternal smoking was assessed qualitatively by self-reported statements and quantitatively by cotininuria. Exhaustive thyroid tests were performed at delivery in the mother and in CB. RESULTS: Third-trimester ioduria documented compliance with iodine supplementation (160 vs. 76 MUg/l in controls). CB Tg was not different between the iodine and control groups (median 77 vs. 79.5 ng/ml, respectively) and did not correlate with maternal ioduria. CB Tg was higher in newborns from smoking mothers (114 vs. 64.7 ng/ml) and correlated with self-reported smoking status more than with maternal cotininuria. Nonsmokers had no difference in CB Tg whether they took iodine supplementation or not, as opposed to smokers, who tended to benefit from supplementation. CONCLUSIONS: Iodine supplementation does not significantly impact CB Tg in healthy nonsmoker pregnant women selected for normal thyroid function, as opposed to maternal smoking. CB Tg appears to be a marker of in utero tobacco exposure. In areas of mild iodine deficiency, iodine supplementation could especially benefit the fetuses of smokers. PMID- 24783030 TI - An unusual presenting symptom of graves' disease: myalgia. AB - A 50-year-old female patient presented with severe myalgia involving her proximal muscles for 3-4 weeks. She also reported mild thyrotoxic symptoms over the same time period. Examination revealed mild thyrotoxicosis, a moderate diffuse goiter and no eye signs. The clinical picture was dominated by muscle pain and tenderness involving mainly her proximal arms and legs, her calves and her fingers, requiring opiate analgesia. Muscle power and tendon reflexes were normal. Laboratory evaluation revealed undetectable serum thyroid stimulating hormone (TSH) with raised FT4, FT3 and positive TSH receptor antibodies. Treatment with carbimazole was started. Additional laboratory investigations were negative (inflammatory markers, creatine kinase and antibodies to antinuclear antibodies, gastric parietal cell, smooth muscle, mitochondrial, dsDNA, centromere, extractable nuclear antigen (ENA) ribonucleoprotein, ENA Sm, ENA Ro, ENA Anti-La, ENA Scl70, ENA Jo-1, anti-CCP and rheumatoid factor). Further assessment in the rheumatology clinic confirmed there was no small joint tenderness or loss of range of movement of her limbs, but widespread and profound muscle tenderness of the common extensors of the forearms, biceps, trapezius, calves and thighs. She was treated symptomatically with analgesic medication and continued on carbimazole. A month later she was euthyroid and her myalgia had resolved. Hyperthyroidism has a profound effect on skeletal muscle and often leads to myopathy. Severe myalgia in association with Graves' disease is rare and resolves with the restoration of euthyroidism. PMID- 24783031 TI - What's in the Image? Pituitary Metastasis from Papillary Carcinoma of the Thyroid: A Case Report and a Comprehensive Review of the Literature. AB - A 67-year-old female patient presented with visual field impairment and hyperprolactinemia. Imaging revealed a sellar and suprasellar mass and during the evaluation of the sellar lesion, papillary thyroid carcinoma (PTC) was diagnosed by fine-needle aspiration biopsy in a long-standing euthyroid multinodular goiter. The patient did not have a previous history of PTC. Total thyroidectomy confirmed the diagnosis of PTC. Due to progressive visual loss, she underwent transcranial surgery for decompression of the optic chiasm. Pituitary metastasis from PTC was confirmed, histologically and immunohistochemically. In literature, overall 13 cases, including ours, with PTC metastasis to the sellar region have been reported. Most were women, with a median age of 56 years. Two thirds of patients were previously diagnosed with PTC. The presence of other distant metastases was confirmed in less than half of the patients. Only 2 and our patient had immunohistochemical confirmation of PTC metastasis to the sellar region. The presenting signs and symptoms included: visual field defects, ophthalmoplegia, and anterior pituitary hormone deficiencies. In conclusion, this is a rare case of metastatic PTC to the sellar region unequivocally confirmed by immunohistochemistry in whom the disease first presented with a sellar and suprasellar mass. PMID- 24783032 TI - The European thyroid journal enters its second year of publication in excellent shape. PMID- 24783033 TI - Thyroid hormone actions in cartilage and bone. AB - Thyroid hormones exert widespread and complex actions in almost all tissues during development, throughout childhood and in adults. The skeleton is an important T3-target tissue that exemplifies these processes, and yet understanding of the specific cellular and molecular mechanisms of T3 action in bone and cartilage remains incomplete. Here, the skeleton is considered as a T3 target tissue. The actions of thyroid hormones during skeletal development and in chondrocytes and growth plate cartilage during post-natal linear growth are outlined. The physiological importance of these actions are discussed in relation to patients with autosomal dominant mutations in genes encoding the thyroid hormone receptors TRalpha1 and TRbeta, and in mice harbouring deletions or mutations of the orthologous genes. The role of thyroid hormones and the control of T3 action in bone turnover and maintenance are also outlined, and T3 action in bone-forming osteoblasts and bone-resorbing osteoclasts discussed. The physiological and functional consequences of T3 action in bone are considered in relation to mutant mouse models and to effects on bone mineral density and fracture susceptibility in humans. Finally, new studies identifying a putative role for thyroid hormone metabolism in articular cartilage maintenance and the pathogenesis of osteoarthritis are considered. The pharmacological context of these new findings is discussed, emphasising the importance of this emerging field of study in thyroid hormone pathophysiology. PMID- 24783034 TI - Differential involvement of orbital fat and extraocular muscles in graves' ophthalmopathy. AB - Graves' ophthalmopathy (GO) is characterized by swelling of orbital fat and extraocular muscles, but little attention has been given to differential involvement of fat and muscles. Advancements in imaging allow rather accurate measurements of orbital bony cavity volume (OV), fat volume (FV) and muscle volume (MV), and are the topics of this review. Ratios of FV/OV and MV/OV neutralize gender differences. In adult Caucasian controls, mean values +/- SD of FV/OV are 0.56 +/- 0.11 and of MV/OV are 0.15 +/- 0.02. FV increases substantially and MV decreases slightly with advancing age, requiring age specific reference ranges. In 95 consecutive untreated Caucasian GO patients, both FV and MV were within normal limits in 25%, increased FV but normal MV was present in 5%, normal FV but increased MV was detected in 61%, and both increased FV and MV was evident in 9%. Increased FV was associated with more proptosis and longer GO duration. Increased MV was associated with older age, more severe GO (more proptosis and diplopia, worse eye muscle ductions), higher TBII and current smoking. At the cellular and molecular level differential involvement of fat and muscles might be related to differences between fibroblast phenotypes and cytokine profiles in each compartment, to different orbital T cell subsets during the course of the disease and to peroxisome proliferator activator receptor-gamma polymorphisms and modulation of 11beta-hydroxysteroid dehydrogenase-1. Enlarged muscles are apparently a rather early phenomenon in GO, whereas increases in fat mass occur relatively late. Why a minor subset of GO patients presents with an increase of only fat remains poorly understood. PMID- 24783035 TI - Metformin and thyroid: an update. AB - BACKGROUND: Metformin is one of the most widely prescribed antidiabetic medications with a favorable safety profile. In the last decade, several studies have reported a TSH-lowering effect of metformin in patients with diabetes mellitus. OBJECTIVE: To review literature data on the role of metformin use on thyroid function tests and the course of thyroid cancer. METHODS: WE PERFORMED A SEARCH IN THE PUBMED DATABASE USING THE TERMS: 'metformin', 'thyroid', 'TSH', 'diabetes', 'polycystic ovarian syndrome (PCOS)' and 'thyroid cancer'. RESULTS: The majority of available evidence suggests that metformin therapy results in a modest reduction of TSH levels in diabetic and/or PCOS patients with thyroid disorder, while thyroid hormone levels remain unaltered. It appears that this effect is independent of thyroid autoimmunity and thyroxine treatment. However, metformin use in subjects with an intact thyroid axis is not associated with a significant change of TSH levels. Concerning thyroid cancer, there is experimental evidence showing antimitogenic properties of metformin in differentiated and medullary thyroid cancer cells. On the other hand, there is also data supporting that metformin administration inhibits iodine uptake by thyroid cells and thus may limit the effectiveness of radioactive iodine treatment. CONCLUSIONS: Most studies suggest a TSH suppressive action of metformin in subjects with overt or subclinical thyroid dysfunction, while this is not apparent in euthyroid individuals. It appears that metformin has antimitogenic properties against various thyroid cancer types; however, experimental evidence of reduced efficacy of radioactive iodine treatment following metformin administration may limit its use in the management of differentiated thyroid cancer. PMID- 24783036 TI - Histological diagnosis of thyroid disease using ultrasound-guided core biopsies. AB - BACKGROUND: Thyroid core biopsies obtained with ultrasound (US)-guided needles are an alternative to conventional fine-needle aspiration and, according to various authors, have greater sensitivity and specificity. The technique is inexpensive, rapid and reliable with a low rate of complications, similar to conventional fine-needle aspiration procedures. OBJECTIVES: This paper critically reviews the methodology for obtaining samples and processing them in the pathology laboratory. METHODS: Accumulated experience with 1,065 cases of US guided core biopsy of the thyroid gland in a 15-year period. RESULTS: US-guided core biopsy is a useful, inexpensive and safe method in the histological diagnosis of thyroid gland pathology. Thyroid samples obtained this way are not a substitute for fine-needle aspiration cytology. Indeed, some authors assert that the best results are obtained by combining the two approaches, the methods being complementary. CONCLUSIONS: To take best advantage of the findings from these techniques, pathologists must know which types of diagnoses can be made and the fundamentals of how and, lastly, what cannot be diagnosed and the reasons why. Best results are obtained with a multidisciplinary approach in a hospital committee composed of endocrinologists, surgeons, radiologists and pathologists, who analyse and provide a background on each case. PMID- 24783037 TI - Standardized Ultrasound Report for Thyroid Nodules: The Endocrinologist's Viewpoint. AB - BACKGROUND: Ultrasonography (US) plays a crucial role in the diagnostic management of thyroid nodules, but its widespread use in clinical practice might generate heterogeneity in ultrasound reports. OBJECTIVES: The aims of the study were to propose (a) a standardized lexicon for description of thyroid nodules in order to reduce US reports of interobserver variability and (b) a US classification system of suspicion for thyroid nodules in order to promote a uniform management of thyroid nodules. METHODS: RELEVANT PUBLISHED ARTICLES WERE IDENTIFIED BY SEARCHING MEDLINE AT PUBMED COMBINING THE FOLLOWING SEARCH TERMS: ultrasonography, thyroid, nodule, malignancy, carcinoma, and classification system. Results were supplemented with our data and experience. RESULTS: A STANDARDIZED US REPORT SHOULD ALWAYS DOCUMENT POSITION, EXTRACAPSULAR RELATIONSHIPS, NUMBER, AND THE FOLLOWING CHARACTERISTICS OF EACH THYROID LESION: shape, internal content, echogenicity, echotexture, presence of calcifications, margins, vascularity, and size. Combining the previous US features, each thyroid nodule can be tentatively classified as: malignant, suspicious for malignancy, borderline, probably benign, and benign. CONCLUSIONS: We propose a standardized US report and a tentative US classification system that may become helpful for endocrinologists dealing with thyroid nodules in their clinical practice. The proposed classification does not allow to bypass the required cytological confirmation, but may become useful in identifying the lesions with a lower risk of neoplasm. PMID- 24783038 TI - Stimulated calcitonin cut-offs by different tests. AB - Medullary thyroid cancer can be highly aggressive, especially if the diagnosis is done in advanced stages. Early diagnosis is based on RET genetic testing, for familial forms, and on the routine measurement of calcitonin (Ct). Nevertheless, since false-positive results can be obtained with the basal measurement of Ct, a provocative test to evaluate stimulated Ct is often needed. Pentagastrin which has been widely used to stimulate basal Ct, especially in European countries, is now hardly available. Thus, the stimulation with calcium (Ca), used in the 1970s 1980s and then abandoned for around 30 years, has recently elicited more interest. In the past 3 years, studies in patients and normal controls have demonstrated that the stimulation with Ca (2.3-2.5 mg/kg of elemental Ca, corresponding to 25 mg/kg of Ca gluconate) is highly potent and accurate. Novel gender-related cut-offs have been proposed for the Ca test, though the analysis of additional large series is predicted to modify these preliminary data. Finally, Ca seems to be the test of choice to stimulate Ct for the diagnosis and follow-up of medullary thyroid cancer, also because it is widely available, has a low cost and it is associated with a low number and intensity of side effects. In the present review the different methods to stimulate Ct and the cut-offs for the identification of the hyperplastic/neoplastic transformation of the C cells will be reported and discussed. PMID- 24783039 TI - Ki-67 labeling index is a predictor of postoperative persistent disease and cancer growth and a prognostic indicator in papillary thyroid carcinoma. AB - BACKGROUND: We previously reported that the Ki-67 labeling index (LI) in primary tumors and the thyroglobulin (Tg)-doubling time (DT) were potent prognostic indicators in patients with papillary thyroid carcinoma (PTC). OBJECTIVES: To elucidate the relationship between these two factors. METHODS: A total of 390 patients with PTC who underwent total thyroidectomy between 1998 and 2004 and in whom the Tg-DT was calculated were enrolled. We determined the Ki-67 LI in primary tumors and compared these values with the patients' clinicopathological factors, postoperative Tg status, Tg-DT, and prognosis. Tg status was categorized by postoperative serum Tg values: biochemically persistent disease (BPD), equivocal state, and biochemical remission. RESULTS: The Ki-67 LI was <=5% in 312 patients (80%), 5%-10% in 48 patients (12%), and >10% in 30 patients (8%). Ki-67 LI was significantly associated with BPD (p < 0.0001). The proportion of BPD patients increased with the higher Ki-67 LI category: 24, 67, and 87%, respectively. The Ki-67 LI had a significant inverse correlation with the Tg-DT (Spearman's rho = -0.5267, p < 0.0001). Of the 378 patients without distant metastasis at surgery, 68 patients had recurrence, and 6 of the 390 patients died of PTC during the follow-up (mean 88 months). On multivariate analyses, the Ki-67 LI remained an independent predictor of disease-free survival and disease specific survival when Tg-DT and Tg status were excluded from the analyses. CONCLUSIONS: Evaluation of the Ki-67 LI in primary tumors may allow the prediction of the postoperative Tg status, Tg-DT and prognosis of patients with PTC. Published by S. Karger AG, Basel. PMID- 24783040 TI - Amiodarone-induced destructive thyroiditis associated with coronary artery vasospasm and recurrent ventricular fibrillation. AB - A 55-year-old male on long-term amiodarone therapy presented with ischaemic chest pain and recurrent unwitnessed syncope. Interrogation of his internal cardiac defibrillator, which had been inserted 4 years earlier, revealed two episodes of ventricular fibrillation, the timing of which corresponded to his syncopal events. Severe spontaneous coronary artery vasospasm was observed on coronary angiogram. Thyroid function testing revealed severe hyperthyroidism with a diagnosis of type 2 amiodarone-induced thyrotoxicosis (AIT) subsequently made. Treatment with prednisolone therapy was commenced and thyroid function rapidly normalized. Prednisolone was weaned without recurrence of hyperthyroidism and on last review, 6 months after initial presentation, he remains free from further chest pain and arrhythmias. Our patient's presentation is a very rare case of AIT associated coronary artery spasm and documented ischaemic ventricular fibrillation with fortunate survival. PMID- 24783041 TI - Sporadic cretinism: a dangerous misnomer. PMID- 24783042 TI - Oxidative Stress, Nuclear Factor-kappaB Pathway and Current Smoking in Graves' Ophthalmopathy. PMID- 24783043 TI - Robot-assisted transaxillary thyroid surgery: as safe as conventional-access thyroid surgery? PMID- 24783044 TI - 2013 European thyroid association guidelines for the diagnosis and treatment of thyrotropin-secreting pituitary tumors. AB - Hyperthyroidism is mainly due to autoimmune thyroid disorders or toxic goiter, and very rarely to the presence of thyrotropin (TSH)-secreting pituitary adenomas (TSHomas). These tumors are characterized by high levels of circulating free thyroid hormones (FT4 and FT3) in the presence of nonsuppressed serum TSH concentrations. Failure to correctly diagnose TSHomas may result in inappropriate thyroid ablation, which results in a significant increase of pituitary tumor mass. The diagnosis is mainly achieved by measuring TSH after T3 suppression and TRH stimulation tests. These dynamic tests, together with pituitary imaging and genetic testing are useful in distinguishing TSHomas from the syndromes of resistance to thyroid hormone action. The treatment of choice is surgery. In cases of surgical failure, somatostatin analogs have been found to be effective in normalizing TSH secretion in more than 90% of patients. PMID- 24783045 TI - Thyroid hormones and the metabolic syndrome. AB - BACKGROUND: Clustering of various metabolic parameters including abdominal obesity, hyperglycaemia, low high-density lipoprotein cholesterol, elevated triglycerides and hypertension have been used worldwide as metabolic syndrome to predict cardiometabolic risk. Thyroid dysfunction impacts on various levels of these components. OBJECTIVES: The purpose of the present review is to summarize available data on thyroid hormone-dependent action on components of the metabolic syndrome. METHODS: A PubMed search for any combination of hyperthyroidism, thyrotoxicosis or hypothyroidism and metabolic syndrome, blood pressure, hypertension, hyperlipidaemia, cholesterol, high-density lipoprotein cholesterol, glucose, diabetes mellitus, body weight or visceral fat was performed. We included papers and reviews published between 2000 and today but accepted also frequently cited papers before 2000. RESULTS: There is convincing evidence for a major impact of thyroid function on all components of the metabolic syndrome, reflecting profound alterations of energy homeostasis at many levels. CONCLUSION: Even though the interactions shown in animal models and man are complex, it is evident that insulin sensitivity is highest and adverse thyroid effects on the metabolic system are lowest in euthyroid conditions. PMID- 24783046 TI - Robotic surgery for thyroid disease. AB - Robotic surgery is an innovation in thyroid surgery that may compensate for the drawbacks of conventional endoscopic surgery. A surgical robot provides strong advantages, including three-dimensional imaging, motion scaling, tremor elimination, and additional degrees of freedom. We review here recent adaptations, experience and applications of robotics in thyroid surgery. Robotic thyroid surgeries include thyroid lobectomy, total thyroidectomy, central compartment neck dissection, and radical neck dissection for benign and malignant thyroid diseases. Most of the current literature consists of case series of robotic thyroidectomies. Recent retrospective and prospective analyses have evaluated the safety and oncologic efficacy of robotic surgery for thyroid cancer. Although robotic thyroid surgery is often associated with longer operation times than conventional open surgery, robotic techniques have shown similar or superior levels of surgical completeness and safety compared with conventional open or endoscopic surgery. Compared to open thyroidectomy, robotic thyroidectomy has been associated with several quality-of-life benefits, including excellent cosmetic results, reduced neck pain and sensory changes, and decreased voice and swallowing discomfort after surgery. For surgeons, robotic surgery has improved ergonomics and has a shorter learning curve than open or endoscopic surgery. The advantages of robotic thyroid surgery over conventional surgery suggest that robotic thyroidectomy with or without neck dissection may become the preferred surgical option for thyroid diseases. Robotic thyroid surgery will likely continue to develop as more endocrine and head-and-neck surgeons are trained and more patients seek this newly developed surgical option. PMID- 24783047 TI - Indications for the gasless transaxillary robotic approach to thyroid surgery: experience of forty-seven procedures at the american hospital of paris. AB - BACKGROUND: Thyroid surgery is in a state of evolution from traditional open approaches to novel robotic techniques. The gasless transaxillary approach to thyroid surgery is effective in the management of thyroid cancer, and complications after robotic thyroidectomy are no higher than experienced after open or endoscopic techniques. The transaxillary robotic approach also avoids an anterior neck scar. This paper presents what the authors believe to be the largest cohort of patients reported in Europe undergoing gasless transaxillary robotic thyroid surgery, with the aim of defining the indications for this procedure. METHODS: Forty-six patients underwent robotic thyroid surgery via the transaxillary approach and were enrolled in this study between March 2010 and September 2012. All patients were operated on by one surgeon at one clinical center. Reviewed data included patient characteristics, pathological characteristics, extent of surgery and postoperative complications. The mean follow-up time was 7.29 months. RESULTS: Forty-six patients underwent 47 procedures, the average age of the patients was 43 years and the male to female ratio was 1:22. Undertaken were 30 lobectomies, 3 subtotal thyroidectomies, 13 total thyroidectomies and 1 totalization. One case was converted to an open procedure. The ratio of malignant to benign disease was 1:6.67 (6:40 cases) and analysis of the surgical specimens showed 6 follicular lesions, 24 follicular adenomas, 3 colloid lesions, 1 case of thyroiditis/lymphatic lesion, 3 adenomatoid lesions, 3 oncocytic adenomas, 3 papillary cancers and 3 microcapillary cancers. The overall average size of an individual specimen removed was 45.40 +/- 28.95 cm(3) (range 5-160, n = 47) and the average largest diameter of the lesion removed was 3.72 +/- 0.95 cm (range 1.4-6.0, n = 47). Postoperatively, there were 5 recurrent laryngeal nerve injuries (4 transient), 2 transient brachial plexopathies, 1 case of postoperative dysphagia and 1 of collection of blood at the site of surgery. There were no cases of disease recurrence at follow-up. CONCLUSIONS: The gasless robotic transaxillary approach to thyroid surgery has been predicted to become a standard technique. It has been shown to be efficacious in the management of thyroid cancer with lateral neck metastases; however, more data relating to oncological safety in long-term follow up is required. This intervention is also appropriate for benign thyroid disease including Graves' disease. To achieve consistently successful results, careful patient selection is fundamental in terms of patient characteristics and the anatomical aspects of the lesion. This is especially important with a geographical expansion to include North America and Europe. The excellent cosmetic results of this procedure make it ideal for patients who have esthetic concerns regarding particular difficulties with healing; however, in common with all new surgical procedures, further evidence must be sought to confirm its indications over time. PMID- 24783048 TI - Transaxillary robotic thyroid surgery: a preliminary European experience. AB - BACKGROUND: Robot-assisted endoscopic transaxillary thyroidectomy is an emerging surgical technique that needs to be evaluated in European patients. We evaluate the feasibility and preliminary results of our experience of this technique in a cohort of patients from within a single European university hospital (Nimes, France). METHODS: We performed a retrospective review of the first 23 patients, treated consecutively between September 2010 and June 2012. RESULTS: Nine patients underwent total thyroidectomy and 14 patients lobectomies. All procedures were completed successfully with a mean total operative time of 134 min. We observed a single case of internal jugular vein injury during the console time. No instances of persistent complications were observed; however, minor postoperative events occurred in 5 patients. Pathological diagnoses included benign follicular adenoma in 18 patients, benign adenoma with lymphoid thyroiditis in 1 patient, and benign adenoma with Graves' disease in 4 patients. CONCLUSIONS: Robotic thyroid surgery is feasible in European patients and can be safely performed on selected patients. This technique has infrequent minor complications and provides a high level of satisfaction. PMID- 24783049 TI - Improvement of Cerebral Hypoperfusion with Levothyroxine Therapy in Hashimoto's Encephalopathy Demonstrated by (99m)Tc-HMPAO-SPECT. AB - BACKGROUND: Hashimoto's encephalopathy (HE) is a rare immune-mediated encephalopathy associated with autoimmune Hashimoto's thyroiditis. OBJECTIVES AND METHODS: We report on a patient with HE and significant clinical improvement correlating with an increase in cerebral blood flow demonstrated by hexamethylpropyleneamine oxime (HMPAO) single-photon emission computed tomography (SPECT). HMPAO-SPECT was performed with 740 MBq of technetium-99m-HMPAO. To demonstrate the improvement in regional cerebral blood flow, individual regions of interest were drawn around visually diminished HMPAO uptake, the lesion to reference region ratio was calculated and transverse section images and semi quantitative measurements were performed. RESULTS: We show a 5-year follow-up with significant clinical improvement, a 10-fold reduction in autoantibodies to thyroid peroxidase and an approximately 20% improvement in cerebral blood flow with HMPAO-SPECT. CONCLUSION: Adequate levothyroxine treatment achieving and maintaining euthyroidism should be considered as therapy to lower autoantibodies and improve clinical outcome in patients with Hashimoto's thyroiditis and encephalopathy. PMID- 24783050 TI - Use of color Doppler ultrasonography to measure thyroid blood flow and differentiate graves' disease from painless thyroiditis. AB - BACKGROUNDS: Color Doppler ultrasonography (CDU) has not yet been established as a method to investigate the pathogenesis of thyrotoxicosis. OBJECTIVES: Our first objective was to determine whether the measurement of peak systolic blood-flow velocity in the superior thyroid artery (STV) and thyroid tissue blood flow (TBF) using CDU could differentiate Graves' disease (GD) from painless thyroiditis (PT). The second objective was to examine the factors mediating increased blood flow to the thyroid gland in GD. METHODS: Recruited patients had untreated GD or PT and visited the Department of Internal Medicine (I), Osaka Medical College, between April 1, 2006 and May 31, 2010. Age, gender, blood pressure, pulse rate, thyroid-stimulating hormone, free thyroxine, tri-iodothyronine, TSH receptor antibody and thyroid volume were evaluated in patients. In addition, bilateral measurements of STV, TBF and peak systolic velocity in the common carotid artery (CCV) were also performed. TBF was quantified by calculating the ratio of blood flow pixels to total pixels in the region of interest using sagittal section images of the thyroid gland. Receiver-operating characteristic curve analysis was performed to determine the ability of STV and TBF measurements to differentiate GD from PT. RESULTS: For the average of STV measured on both sides, the area under the receiver-operating characteristic curve (AUC) was 0.956. For the average of TBF measured on both sides, the AUC was 0.920. At an average STV cut off value of 43 cm/s, the sensitivity to discriminate GD from PT was 0.87 and the specificity was 1.00. At an average TBF cut-off value of 3.8%, the sensitivity was 0.71 and the specificity was 1.00. In the GD group, neither blood pressure nor pulse rate correlated with the average STV or TBF. Moreover, there was no correlation between STV and CCV or between TBF and CCV on either side. However, STV was correlated with TBF (right side: R = 0.47; left side: R = 0.52). CONCLUSIONS: The results demonstrate that STV and TBF are useful for differentiating GD from PT. Furthermore, the increased STV and TBF found in GD are not related to hyperthyroidism-induced increases in systolic blood pressure, pulse rate or CCV. PMID- 24783051 TI - Smoothed Urinary Iodine Percentiles for the US Population and Pregnant Women: National Health and Nutrition Examination Survey, 2001-2010. AB - BACKGROUND: Iodine intake is essential for normal growth, development and metabolism throughout life, especially for women during gestation and lactation. The present study applies a novel statistical approach, providing smoothed urinary iodine (UI) percentile curves for the total US population as well as the categories of sex, race/ethnicity, women of childbearing age and pregnant women who were participants in the National Health and Nutrition Examination Survey (NHANES) 2001-2010. To our knowledge, this is the first application of this technique to NHANES nutritional biomarker data. METHODS: We used UI and urinary creatinine that were measured in participants aged 6 and older in the NHANES survey periods 2001-2002, 2003-2004, 2005-2006, 2007-2008 and 2009-2010. A nonparametric double-kernel method was applied to smooth percentile curves for UI and creatinine-corrected results. RESULTS: The UI population estimates showed a U shaped distribution by age for the total US population. Overall, females had lower UI concentrations and median values compared to males (median UI for females, 141.8 ug/l; median UI for males, 176.1 ug/l; p < 0.0001). Non-Hispanic blacks had the lowest median UI concentrations compared to other racial/ethnic groups (p < 0.0001). Among women of childbearing age (15-44 years), UI concentrations mostly declined with increasing age. Pregnant women aged 35 years and older tended to have higher UI concentrations than younger pregnant women at similar percentiles. CONCLUSIONS: The smoothed reference distribution of UI concentrations provides an improved and visual display of the entire distribution of values for the US population and specific demographic categories. PMID- 24783052 TI - Low Birth Weight in Children Born to Mothers with Hyperthyroidism and High Birth Weight in Hypothyroidism, whereas Preterm Birth Is Common in Both Conditions: A Danish National Hospital Register Study. AB - OBJECTIVES: Maternal hyper- and hypothyroidism have been associated with increased risk of adverse pregnancy outcomes, but studies have led to inconsistent results. We aimed to identify children born to mothers with a hospital-recorded diagnosis of thyroid dysfunction in Denmark and to study the association with gestational age at delivery and birth weight of the child. STUDY DESIGN: Population-based cohort study using Danish nationwide registers. All singleton live births in Denmark between January 1, 1978 and December 31, 2006 were identified and stratified by maternal diagnosis of hyper- or hypothyroidism registered in the Danish National Hospital Register before January 1, 2007. RESULTS: Maternal first-time diagnosis of thyroid dysfunction before, during or after pregnancy was registered in 32,809 (2.0%) of the singleton live births (n = 1,638,338). Maternal diagnosis of hyperthyroidism (adjusted OR 1.22, 95% CI 1.15 1.30) and hypothyroidism (adjusted OR 1.17, 95% CI 1.08-1.27) were associated with increased risk of preterm birth. Moreover, birth weight in children born to mothers with a diagnosis of hyperthyroidism was lower (adjusted difference -51 g, 95% CI -58 to -43 g) and higher in relation to maternal hypothyroidism (adjusted difference 20 g, 95% CI 10-30 g). Hyperthyroidism was associated with small-for gestational-age (adjusted OR 1.15, 95% CI 1.10-1.20) and hypothyroidism with large-for-gestational-age children (adjusted OR 1.24, 95% CI 1.17-1.31). CONCLUSIONS: Based on Danish nationwide registers, both maternal hyper- and hypothyroidism were associated with increased risk of preterm birth. Actual birth weight of the child and birth weight for gestational age were low if the mother had a diagnosis of hyperthyroidism and high if the diagnosis was hypothyroidism. PMID- 24783053 TI - 2013 ETA Guideline: Management of Subclinical Hypothyroidism. AB - Subclinical hypothyroidism (SCH) should be considered in two categories according to the elevation in serum thyroid-stimulating hormone (TSH) level: mildly increased TSH levels (4.0-10.0 mU/l) and more severely increased TSH value (>10 mU/l). An initially raised serum TSH, with FT4 within reference range, should be investigated with a repeat measurement of both serum TSH and FT4, along with thyroid peroxidase antibodies, preferably after a 2- to 3-month interval. Even in the absence of symptoms, replacement therapy with L-thyroxine is recommended for younger patients (<65-70 years) with serum TSH >10 mU/l. In younger SCH patients (serum TSH <10 mU/l) with symptoms suggestive of hypothyroidism, a trial of L thyroxine replacement therapy should be considered. For such patients who have been started on L-thyroxine for symptoms attributed to SCH, response to treatment should be reviewed 3 or 4 months after a serum TSH within reference range is reached. If there is no improvement in symptoms, L-thyroxine therapy should generally be stopped. Age-specific local reference ranges for serum TSH should be considered in order to establish a diagnosis of SCH in older people. The oldest old subjects (>80-85 years) with elevated serum TSH <=10 mU/l should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. If the decision is to treat SCH, then oral L-thyroxine, administered daily, is the treatment of choice. The serum TSH should be re-checked 2 months after starting L thyroxine therapy, and dosage adjustments made accordingly. The aim for most adults should be to reach a stable serum TSH in the lower half of the reference range (0.4-2.5 mU/l). Once patients with SCH are commenced on L-thyroxine treatment, then serum TSH should be monitored at least annually thereafter. PMID- 24783055 TI - Regulation of iodide uptake in placental primary cultures. AB - BACKGROUND: Maintenance of adequate iodide supply to the developing fetus is dependent not only on maternal dietary iodine intake but also on placental iodide transport. The objective of this study was to examine the effects of different pregnancy-associated hormones on the uptake of radioiodide by the placenta and to determine if iodide transporter expression is affected by hormone incubation. METHODS: Primary cultures of placental trophoblast cells were established from placentas obtained at term from pre-labor caesarean sections. They were pre incubated with 17beta-estradiol, prolactin, oxytocin, human chorionic gonadotropin (hCG) and progesterone either singly or in combination over 12 h with (125)I uptake being measured after 6 h. RNA was isolated from placental trophoblasts and real-time RT-PCR performed using sodium iodide symporter (NIS) and pendrin (PDS) probes. RESULTS: Significant dose response increments in (125)I uptake by trophoblast cells (p < 0.01) were observed following incubation with hCG (60% increase), oxytocin (45% increase) and prolactin (32% increase). Although progesterone (50-200 ng/ml) and 17beta-estradiol (1,000-15,000 pg/ml) alone produced no significant differences in uptake, they facilitated increased uptake when combined with prolactin or oxytocin, with a combination of all four hormones producing the greatest increase (82%). Increased (125)I uptake was accompanied by corresponding increments in NIS mRNA (ratio 1.52) compared to untreated control cells. No significantly increased expression levels of PDS were observed. CONCLUSIONS: Pregnancy-associated hormones, particularly oxytocin and hCG, have a role in promoting placental iodide uptake which may protect the fetus against iodine deficiency. PMID- 24783054 TI - New model systems to illuminate thyroid organogenesis. Part I: an update on the zebrafish toolbox. AB - Thyroid dysgenesis (TD) resulting from defects during embryonic thyroid development represents a major cause of congenital hypothyroidism. The pathogenetic mechanisms of TD in human newborns, however, are still poorly understood and disease-causing genetic variants have been identified in only a small percentage of TD cases. This limited understanding of the pathogenesis of TD is partly due to a lack of knowledge on how intrinsic factors and extrinsic signalling cues orchestrate the differentiation of thyroid follicular cells and the morphogenesis of thyroid tissue. Recently, embryonic stem cells and zebrafish embryos emerged as novel model systems that allow for innovative experimental approaches in order to decipher cellular and molecular mechanisms of thyroid development and to unravel pathogenic mechanisms of TD. Zebrafish embryos offer several salient properties for studies on thyroid organogenesis including rapid and external development, optical transparency, ease of breeding, relative short generation time and amenability for genome editing. In this review, we will highlight recent advances in the zebrafish toolkit to visualize cellular dynamics of organ development and discuss specific prospects of the zebrafish model for studies on vertebrate thyroid development and human congenital thyroid diseases. PMID- 24783056 TI - Se- and s-based thiouracil and methimazole analogues exert different inhibitory mechanisms on type 1 and type 2 deiodinases. AB - The thioamide anti-thyroid drugs methimazole (MMI) and propylthiouracil (PTU) play a pivotal role in the treatment of hyperthyroidism. MMI exerts its effect via inhibiting one of the key enzymes involved in synthesis of thyroid hormones (TH), thyroid peroxidase (TPO). PTU is both an inhibitor of TPO and type 1 deiodinase (D1), which catalyzes TH deiodination at both aromatic rings. In contrast, no selective inhibitors are known for type 2 deiodinase (D2) or type 3 deiodinase, which deiodinate TH at the phenolic or tyrosyl ring, respectively. We aimed to identify specific inhibitors for D1 or D2. New Se- and S-based PTU and MMI-like compounds have been generated. The D1 and D2 inhibiting capacity of several compounds was tested in vitro. Our data show that compounds based on a PTU and MMI backbone can differentially influence the reaction kinetics of deiodinases. For inhibition of D1, the addition of a phenyl group to the PTU backbone increases potency by at least 10-fold over PTU. For inhibition of D2, the addition of an aromatic ring structure to MMI and its Se isomer increases inhibitory potency by an order of magnitude. Furthermore, S-methylation of the MMI changes its reaction kinetics from non-competitive to uncompetitive with respect to the cofactor dithiothreitol. These results open perspectives for further investigations on identifying specific inhibitors of the deiodinase isoenzymes, potentially based on the addition of aromatic ring structures or alkyl groups to PTU and MMI. PMID- 24783058 TI - Papillary thyroid carcinoma with honeycomb-like multiple small cysts: characteristic features on ultrasonography. AB - BACKGROUND: Thyroid nodules with cystic content or mixed sponge-like aspect on ultrasonography and a concordant cytology are strongly predictive of benignity. OBJECTIVES: We present 8 patients with honeycomb-like papillary thyroid carcinoma with multiple small cysts on ultrasonography. METHODS: The patients were 6 women and 2 men aged between 30 and 57 years. The tumors of these patients showed honeycomb-like multiple small cysts that were aggregated in some area of the thyroid gland on ultrasonography. Histopathological examination indicated a well differentiated type of papillary thyroid carcinoma with multiple small cysts and a small solid lesion. The cysts were lined with papillary carcinoma cells, and normal thyroid tissue lay between the cysts. RESULTS: There is a peculiar type of papillary thyroid carcinoma that histopathologically shows honeycomb-like multiple small cysts in the thyroid gland. Ultrasonography can be used to identify characteristic features of honeycomb-like multiple small cysts in the thyroid gland in such patients. CONCLUSIONS: One should be aware of this peculiar type of papillary thyroid carcinoma with honeycomb-like multiple small cysts on ultrasonography, although thyroid nodules with cystic lesions are generally regarded as benign in clinical management. PMID- 24783057 TI - Graves' orbitopathy: imperfect treatments for a rare disease. AB - Graves' orbitopathy (GO) is the most frequent and invalidating extrathyroidal expression of Graves' disease. Its incidence and prevalence are, however, low. About three quarters of Graves' patients have no GO at diagnosis, and moderate-to severe and severe forms represent no more that 5-6% of cases. Progression to severe forms occurs rarely, but it may be caused by risk factors, the most important being smoking and poor control of thyroid dysfunction. Lot of progress has been recently achieved in the understanding of GO pathogenesis, while the disease remains a therapeutic challenge and dilemma. Common treatments for moderate-to-severe and active forms of GO (glucocorticoids and orbital radiotherapy) frequently provide incomplete responses and may be followed by relapse or progression of GO. After the disease has been inactivated by medical treatment, many patients need rehabilitative surgery for residual manifestations (orbital decompression for exophthalmos, squint surgery for extraocular muscle dysfunction, eyelid surgery for eyelid malposition). Novel pharmacological treatments are on the horizon and might target pathogenetic mechanisms of the disease better than glucocorticoids. Clinical evidence concerning their efficacy and safety is presently lacking. PMID- 24783059 TI - Use of Pre-Ablation Radioiodine-131 Scan to Assess the Impact of Surgical Volume and Specialisation following Thyroidectomy for Differentiated Thyroid Carcinoma. AB - BACKGROUND: We evaluated the relationship between thyroid remnant size following thyroidectomy for differentiated thyroid carcinoma and surgical volume and specialisation by assessing pre-ablation radioiodine-131 ((131)I) thyroid bed uptake (TBU) scanning as a surrogate for residual thyroid tissue. METHODS: We analysed data of 651 patients in our thyroid cancer database. Patients' data were included if the following criteria were met: (1) diagnosis of differentiated thyroid carcinoma, (2) total or near-total thyroidectomy, (3) pre-ablation (131)I scan prior to radioiodine ablation (RAI), (4) no distant metastasis, and (5) >3,000 MBq ablative dose of (131)I. (131)I diagnostic whole-body scans and measurement of thyroglobulin levels were carried out 3-9 months after RAI. 305 patients were included in the final analysis. RESULTS: Four endocrine, 19 otolaryngology and 25 general surgeons performed thyroidectomies with median pre ablation (131)I TBU values of 1.0, 1.8 and 2.9%, respectively (p = 0.0031). There was a statistically significant relationship between number of thyroidectomies performed and median pre-ablation (131)I TBU values up to the optimal number of 11 operations beyond which there was no further significant difference between surgeons. There were differences in remnant size between endocrine and general surgeons (p = 0.001), otolaryngology and general surgeons (p = 0.023) but not between endocrine and otolaryngology surgeons (p = 0.167). CONCLUSION: Using the pre-ablation (131)I uptake scan as a surrogate for thyroid remnant quantification following thyroidectomy demonstrates the relationship between the surgical volume and size of thyroid remnant. The study also demonstrated beneficial effects of specialisation with specialist surgeons achieving the smallest thyroid remnant. PMID- 24783060 TI - Host immune responses after hypoxic reactivation of IFN-gamma induced persistent Chlamydia trachomatis infection. AB - Genital tract infections with Chlamydia trachomatis (C. trachomatis) are the most frequent sexually transmitted disease worldwide. Severe clinical sequelae such as pelvic inflammatory disease (PID), tubal occlusion, and tubal infertility are linked to inflammatory processes of chronically infected tissues. The oxygen concentrations in the female urogenital tract are physiologically low and further diminished (0.5-5% O2, hypoxia) during an ongoing inflammation. However, little is known about the effect of a low oxygen environment on genital C. trachomatis infections. In this study, we investigated the host immune responses during reactivation of IFN-gamma induced persistent C. trachomatis infection under hypoxia. For this purpose, the activation of the MAP-kinases p44/42 and p38 as well as the induction of the pro-inflammatory cytokines IL-1beta, IL-6, IL-8, and MCP-1 were analyzed. Upon hypoxic reactivation of IFN-gamma induced persistent C. trachomatis infection, the phosphorylation of the p44/42 but not of the p38 MAP kinase was significantly diminished compared to IFN-gamma induced chlamydial persistence under normoxic condition. In addition, significantly reduced IL-6 and IL-8 mRNA expression levels were observed for reactivated Chlamydiae under hypoxia compared to a persistent chlamydial infection under normoxia. Our findings indicate that hypoxia not only reactivates IFN-gamma induced persistent C. trachomatis infections resulting in increased bacterial growth and progeny but also dampens inflammatory host immune signaling responses that are normally observed in a normoxic environment. PMID- 24783061 TI - Commonly prescribed beta-lactam antibiotics induce C. trachomatis persistence/stress in culture at physiologically relevant concentrations. AB - Chlamydia trachomatis, the most common bacterial sexually transmitted disease agent worldwide, enters a viable, non-dividing and non-infectious state (historically termed persistence and more recently referred to as the chlamydial stress response) when exposed to penicillin G in culture. Notably, penicillin G exposed chlamydiae can reenter the normal developmental cycle upon drug removal and are resistant to azithromycin-mediated killing. Because penicillin G is less frequently prescribed than other beta-lactams, the clinical relevance of penicillin G-induced chlamydial persistence/stress has been questioned. The goal of this study was to determine whether more commonly used penicillins also induce C. trachomatis serovar E persistence/stress. All penicillins tested, as well as clavulanic acid, induced formation of aberrant, enlarged reticulate bodies (RB) (called aberrant bodies or AB) characteristic of persistent/stressed chlamydiae. Exposure to the penicillins and clavulanic acid also reduced chlamydial infectivity by >95%. None of the drugs tested significantly reduced chlamydial unprocessed 16S rRNA or genomic DNA accumulation, indicating that the organisms were viable, though non-infectious. Finally, recovery assays demonstrated that chlamydiae rendered essentially non-infectious by exposure to ampicillin, amoxicillin, carbenicillin, piperacillin, penicillin V, and clavulanic acid recovered infectivity after antibiotic removal. These data definitively demonstrate that several commonly used penicillins induce C. trachomatis persistence/stress at clinically relevant concentrations. PMID- 24783063 TI - Surgical importance of arterial segments of human kidneys: an angiography and corrosion cast study. AB - OBJECTIVE: Variations in the arterial supply of human kidney have been observed frequently, either in routine dissections or surgical practice. The main objective of the present study was to describe the arterial segmental pattern of human kidneys and its variation by angiography and corrosion cast techniques. MATERIALS AND METHODS: Forty kidneys were washed and a plastic cannula was inserted into renal artery and the omnipaque dye was injected into it and X-ray was taken. The corrosion casts were prepared by injecting coloured acetate butyrate (CAB) granules solution. RESULTS: Five vascular segments of kidney were seen based on the branching pattern of the renal artery by angiography and corrosion cast techniques. The renal artery was divided into anterior and posterior branches. The anterior branch further divided into four branches viz. apical segmental artery (ASA), Upper segmental artery (USA), middle segmental artery (MSA), lower segmental artery (LSA) while the posterior branch continue as posterior segmental artery. The origins of segmental arteries were variable. In 60% cases apical segmental artery (ASA) had common origin with upper segmental artery (USA) while in 40% cases it took origin directly from the main renal artery. Similarly the variations in the origin of the other branches of anterior division of renal artery were observed. The posterior segmental artery (PSA) however was single and comparatively small and supplied the posterior surface of the kidney. CONCLUSION: The knowledge of the vascular pattern of the kidney is thus important for the purpose of angiography and surgical procedures especially for nephrectomy and kidney transplantation. PMID- 24783062 TI - Virulent Type A Francisella tularensis actively suppresses cytokine responses in human monocytes. AB - BACKGROUND: Human monocyte inflammatory responses differ between virulent and attenuated Francisella infection. RESULTS: A mixed infection model showed that the virulent F. tularensis Schu S4 can attenuate inflammatory cytokine responses to the less virulent F. novicida in human monocytes. CONCLUSION: F. tularensis dampens inflammatory response by an active process. SIGNIFICANCE: This suppression may contribute to enhanced pathogenicity of F. tularensis. Francisella tularensis is a Gram-negative facultative bacterium that can cause the disease tularemia, even upon exposure to low numbers of bacteria. One critical characteristic of Francisella is its ability to dampen or subvert the host immune response. Previous work has shown that monocytes infected with highly virulent F. tularensis subsp. tularensis strain Schu S4 responded with a general pattern of quantitatively reduced pro-inflammatory signaling pathway genes and cytokine production in comparison to those infected with the less virulent related F. novicida. However, it has been unclear whether the virulent Schu S4 was merely evading or actively suppressing monocyte responses. By using mixed infection assays with F. tularensis and F. novicida, we show that F. tularensis actively suppresses monocyte pro-inflammatory responses. Additional experiments show that this suppression occurs in a dose-dependent manner and is dependent upon the viability of F. tularensis. Importantly, F. tularensis was able to suppress pro-inflammatory responses to earlier infections with F. novicida. These results lend support that F. tularensis actively dampens human monocyte responses and this likely contributes to its enhanced pathogenicity. PMID- 24783064 TI - Effect of Aging on the Quantitative Number of Brunner's Glands. AB - BACKGROUND: Age related changes in the number of Brunner's Glands (BG) in four anatomical parts of human duodenum were studied. The few studies done on this topic were conducted mainly in men. Studies involving a much larger age group, from foetuses to elderly individuals up to 85years of age including both sexes were not done earlier and were evaluated. AIM: To find out whether the number of (BG) differs with increasing age in the four anatomical parts of duodenum. MATERIALS AND METHODS: This study was carried out on the basis of 74 specimens taken from still-born foetuses. The patients were divided into four groups as <1 25 years, 26-50 years, 51-75 years and 76-85 years. Duodenal biopsies without gastrointestinal disorders were included in the study group. Sections were prepared and stained with haematoxylin-eosin. Ten microscopic fields of vision (FOV) were examined under high power on every representative slide from each duodenal portion and average was calculated. The (BGs) were analyzed quantitatively. The final result was expressed as the number of glands per high power field. The average number of (BG) in field of vision per high power field for each of the age groups was tabulated for subsequent statistical study. The documented data was calculated by the SPSS, version 16.0 software. RESULT: The decrease in (BG) is significant (p-value < 0.001) in the superior (first) and ascending (fourth) part of duodenum in all the age groups. CONCLUSION: It suggests that the number of glands can differ according to variations in age in duodenum. PMID- 24783065 TI - Morphometric study of suprascapular notch in Indian dry scapulae with specific reference to the incidence of completely ossified superior transverse scapular ligament. AB - BACKGROUND: The suprascapular notch, a depression on the lateral part of the superior border of the scapula, medial to the coracoid process, is bridged by the superior transverse scapular ligament, which is sometimes ossified and the foramen which is thus completed, transmits the suprascapular nerve to the supraspinatus fossa. Variations in the morphology of suprascapular notch have been identified as one of the causes of suprascapular nerve entrapment. Rengachary et al. classified this notch into six types, based on its shape. AIM OF STUDY: To study morphological variations of suprascapular notch in Indian dry scapulae and to analyze the incidence of completely ossified superior transverse scapular ligament with other ethnic populations which have been cited earlier. MATERIALS AND METHODS: A total of 400 human dry scapulae which were obtained from the Department of Anatomy of selected eight medical colleges were analyzed. The type of suprascapular notch was noted and it was recorded as per the description given by Rengachary et al. The results of the present study were compared with the results of previous authors in different populations. RESULTS: In our study, out of 400 scapulae, 40 (10%), were identified to have completely ossified superior transverse scapular ligaments. The frequencies of various types of suprascapular notches were: Type I -20%, Type II -10%, Type III -52%, Type IV 4%, Type V -4%, Type VI -10%. CONCLUSION: Since the suprascapular nerve entrapment syndrome might be caused by complete ossification of superior transverse scapular ligament with formation of suprascapular foramen and other morphometric variations of suprascapular notch, the knowledge on such variations is essential for clinicians, for making a proper diagnosis and for planning the most suitable surgical intervention. PMID- 24783066 TI - Assessment of RV Function in Patients of (COPD). AB - INTRODUCTION: Chronic Obstructive Pulmonary Disease (COPD) has considerable effects on cardiac functions primarily affecting the pulmonary vasculature and then right ventricle along with left ventricle. One of the important causes of increased morbidity and mortality associated with COPD is cor pulmonale. Echocardiography provides a rapid, non-invasive method to evaluate cardiac changes. Our aim was to evaluate RVfunction in COPD as per guidelines of American Society of Echocardiography with an aim to find a simpler way of predicting cardiac morbidity. MATERIALS AND METHODS: A cross sectional observational study was conducted on 17 COPD patients attending Respiratory Medicine outdoor of R. G. KAR Medical College, Kolkata, India, through history taking, clinical examination, PFT (PFT) and Echocardiography. Statistical analysis was done by using Statistical Package for the Social Sciences (SPSS) version-17. RESULTS: Fractional area change of RV (FAC-%) was positively correlated with Forced Expiratory Volume in One Second (FEV1) (r = 0.4879), FEV1/ Forced Vital Capacity (FVC) ratio (r = 0.5048) and Peak Expiratory Flow Rate (PEFR) (r = 0.5361). There was strong negative correlation of Systolic Pulmonary Artery Pressure (SPAP) with FEV1/FVC ratio (r = -0.5553) and PEFR (r = - 0.4604). Right Index of Myocardial Performance (RIMP) of right ventricle was negatively correlated with FEV1/FVC ratio (r = - 0.598), PEFR (r = - 0.619), Forced Expiratory Flow (FEF) 25-75 (r = 0.515). Tricuspid annular plane systolic excursion (TAPSE) did not show any association with PFT parameters though it showed strong positive correlation with RV wall thickness. CONCLUSION: This study substantiates that FAC% and RIMP can be vital prognostic factors for RV function apart from SPAP, TAPSE to define RV dysfunction and predict morbidity in COPD. PMID- 24783067 TI - Significance of ferritin in recurrent oral ulceration. AB - BACKGROUND: Ferritin is the storage form of iron. Hence, the sensitive test which can be used for diagnosing iron deficiency anaemia is estimation of ferritin in serum. One of the causative factors of oral ulceration is nutritional deficiency, which includes iron also. AIM: To study the meaningful association between recurrent oral ulcer and ferritin. MATERIALS AND METHODS: Fifty oral ulcer cases which were diagnosed clinically in the ENT Department of Sree Balaji Medical College and Hospital and Twenty Five controls were included in this study. Serum ferritin was estimated by doing a particle enhanced turbidimetric immunoassay for both cases and controls. RESULTS: 66% of cases had decreased ferritin values and 34% had normal values, which was significant. CONCLUSION: From this study, it can be concluded that it is mandatory to screen oral ulcer patients for iron deficiency anaemia by estimating serum ferritin and it is also advisable for the patients to have iron supplementation on regular basis, along with diet rich in iron in addition to vitamins. PMID- 24783068 TI - Effect of Ramadan Fasting on Body Weight, (BP) and Biochemical Parameters in Middle Aged Hypertensive Subjects: An Observational Trial. AB - INTRODUCTION: Ramadan fasting is a religious obligation which is practised by Muslim population all over the world. However, there is scarcity of scientific literature regarding its effects on health determinants in cardiovascular disturbances like hypertension. OBJECTS: The present study was done to assess the (BP), body weight and serum cholesterol changes over the period of Ramadan fasting in patients with hypertension. Materails And Methods:This prospective observational trial was done on 15 hypertensive subjects who were in the age group of 35 to 65 years, who were determined to complete Ramadan fast. All subjects were on antihypertensive therapy. Outcome measures of (BP), body weight and serum cholesterol were assessed in all the subjects before and after Ramadan month. RESULTS: Mean age of subjects was 44.6 +/- 5.62 years. Systolic BP decreased from 148 +/- 19.6 to 132.5 +/- 17.9 mm of Hg. The decrease of 15.5 units (95% CI: 7.5 to 24.4) was statistically significant (p = 0.0009). Diastolic BP decreased from 90.4 +/- 7.8 to 81.1 +/- 6.3 mm of Hg. The decrease of 9.3 units (95% CI: 5.7 to 13) was statistically significant (p < 0.0001). There was statistically significant decrease in body weight from 66.6 +/- 13 to 65.2 +/- 12.7 kg (p < 0.0001). There was no significant difference in serum cholesterol from 187.3 +/- 28.9 to 192.7 +/- 31.3 mg% (p = 0.37). CONCLUSION: Hypertensive patients with continuation of their medicines showed a decrease in blood pressure and reduction in body weight at the end of Ramadan fasting duration. However there was no change found in serum cholesterol levels. PMID- 24783069 TI - Hepatitis B Virus (HBV) Infection in Liver Disease Patients in Mumbai, India with Special Reference to Hepatitis B Surface Antigen (HBsAg) Mutant Detection. AB - OBJECTIVES: To determine the prevalence of Hepatitis B Surface antigen (HBsAg) in patients attending the Hepatology Out Patient Department (OPD) of a tertiary care hospital and to compare the routinely used HBsAg detection kit with the mutant detection kit to find out the presence of mutants in a given setting. MATERIALS AND METHODS: A cross-sectional study was carried out in adult patients with liver disease attending the Hepatology OPD, of a tertiary care hospital in Mumbai, India. Age, gender and clinical history of the patient were recorded. Blood specimen was tested for HBsAg (Microscreen(TM) ELISA, Span diagnostics, India) and HBsAg mutants (Hepanostika HBsAg Ultra(TM) ELISA, Biomerieux, France). The samples with discordant results between these two ELISAs were confirmed by Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Polymerase Chain Reaction (PCR) (Cobas Taqman(TM), Roche Molecular Systems, USA). RESULTS: Seven hundred and eighteen patients were enrolled in the study. The mean age of patients in the study group was 41 years (range 17 to 69 years). Four hundred and ninety seven (69.22%) were males and remaining were females. The prevalence of HBsAg was found to be 17.4%. The positivity amongst the male population was 18.1% which was higher than the female population (15.8%). Of the 718 samples tested, 120 were positive for HBsAg by Microscreen(TM) ELISA and 132 were positive by Hepanostika HBsAg ultra(TM). Of the 12 discordant samples, HBV DNA was detected in five samples indicating 0.7% prevalence of mutants. CONCLUSION: Hepatitis B is prevalent in liver disease patients. The mutant detecting assay is recommended in set-ups where missing HBsAg in patients would have tremendous impact on the outcome such as in blood donors, organ or tissue donors and antenatal screening of mothers. It is also helpful in chronic liver disease patients where the routine HBsAg detection test is negative and the other causes of chronic liver disease have been ruled out. However, it is not recommended for use in routine diagnostic set-ups where high false positivity would lead to over-diagnosis of the condition. PMID- 24783070 TI - Prevalence of Invasive Aspergillosis Among (PTB) Patients in Kanchipuram, India. AB - BACKGROUND: Tuberculosis (TB) remains a major health problem worldwide. (PTB) is commonly associated with secondary aspergilloma. Repeated exposure of Aspergillus spores can aggravate the bronchial pathology and can manifest as asthmatic episodes. AIM AND OBJECTIVE: Pulmonary invasive aspergillosis is difficult to evaluate. Culture based diagnosis is time consuming. Hence (PCR) was done to evaluate the invasive fungal aspergillosis in (PTB) patients. MATERIALS AND METHODS: Eighty sputum samples collected from TB patients were processed as per standard protocol. Species level identification was done using PCR. RESULTS: Among 80 patients, 26 isolates were obtained, only 8 were Aspergillus species. All Aspergillus were taken up for PCR evaluation. CONCLUSION: Fungal infection should be suspected in all sputum positive patients. PCR is an effective tool to diagnose invasive aspergillosis. PMID- 24783071 TI - Anticonvulsant effect of hydroalcoholic seed extract of croton tiglium in rats and mice. AB - AIMS AND OBJECTIVES: The study was aimed to evaluate the anticonvulsant effect of hydro-alcoholic seed extract of croton tiglium in rats and mice. MATERIALS AND METHODS: Forty -eight each of rats and mice of either sex were randomised into four groups and subjected to seizures induced by electroconvulsiometer and pentylenetetrazole. The hydroalcoholic seed extract of croton tiglium (250 and 500mg/kg) was studied for its anticonvulsant effect using sodium valproate (200mg/kg) as standard and distilled water as control. The parameters observed were time for onset of HLE (Hind Limb Extension) and duration of HLE in electrically induced seizures, and time for onset of convulsions and duration of convulsions in chemically induced seizures. Mortality of the animals over 24 hours was observed in both the models. For testing statistical significance between various groups unpaired student t-test was used. OBSERVATIONS AND RESULTS: In electrically induced seizures croton tiglium produced dose dependant prolongation of time for onset of HLE and a reduction in duration of HLE and in chemically induced convulsions, it prolonged time for onset of convulsions and reduced the duration of convulsions indicating its anticonvulsant effect in both models. However, anticonvulsant effect was less compared to sodium valproate. There was a higher percentage of mortality in croton tiglium group in chemically induced convulsions when compared to sodium valproate. CONCLUSION: Croton tiglium has dose dependant anticonvulsant effect in electrically induced seizures, while in pentylenetetrazole induced-seizures the protection is very minimal. PMID- 24783072 TI - Alternate Day versus Once Daily Atorvastatin for Primary Prevention of (CHD) in Naive Patients of Dyslipidemia. AB - INTRODUCTION: Statins (or HMG-CoA reductase inhibitors) have become drug of choice for raised Low-Density Lipoprotein Cholesterol (LDL-C) in treating. Of these, Atorvastatin, because of its prolonged 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibition has been considered for alternate day therapy in primary prevention of (CHD). OBJECTIVES: To compare the efficacy and safety of daily versus alternate day 10 mg Atorvastatin on reduction of lipid levels in patients of dyslipidemia and to evaluate the number of patients reaching the target Low-Density Lipoprotein (LDL) goals in these groups. METHODOLOGY: In this comparative, randomized, parallel group, non-blinded study, 100 naive dyslipidemic patients in low to moderate risk group as per NCEP ATP (III) Guidelines were divided in two groups. Group A (n=50) received Atorvastatin 10 mg every alternate day for three months and Group B (n=50) received Atorvastatin 10 mg daily for three months. Apart from general examination and baseline investigations, lipid profile was also done. Efficacy was assessed by the percentage reduction in LDL and attainment of LDL goals as per NCEP ATP III Guidelines at the end of the study. Safety of the medication was assessed. RESULTS: Atorvastatin 10 mg daily produced a significant reduction in Total Cholesterol (TC), LDL, Very Low Density Lipoprotein (VLDL) as compared to Atorvastatin 10 mg alternate day. The increase in the HDL level was also greater with a daily dose as compared to alternate day (but not statistically significant). In Low risk category 86.12 % patients (n=31) on daily dose reached their LDL-C goal vis-a-vis 66.67% (n=18) of patients on alternate day therapy. In the moderate risk category 100 % of daily Atorvastatin patients (n=10) achieved their LDL-C goal versus 33.33% patients (n=4) on alternate day therapy. Adverse events with alternate day therapy (n=4) were less as compared with daily treatment (n=10). CONCLUSION: Atorvastatin 10 mg daily was found to be safe and efficacious in patients with dyslipidemia compared to an alternate day therapy. PMID- 24783073 TI - Pharmacovigilance Knowledge among Patients at a Teaching Hospital in Lalitpur District, Nepal. AB - BACKGROUND: Consumer's knowledge and perception towards adverse drug reactions (ADR) can play an important role in ensuring a healthy lifestyle and proper use of medicines. AIMS: This study aimed to assess the knowledge and perception towards pharma covigilance in general and consumer pharmacovigilance in particular among out patients in a teaching hospital of Nepal. SETTINGS AND DESIGN: A descriptive cross-sectional study using qualitative and quantitative methods was carried out from 1(st) May to 3 June 2013. METHODS: Every fifth patient visiting the outpatient pharmacy was interviewed using a semi-structured questionnaire. Gender, age, educational qualification, profession and ethnicity were noted. Twenty-three patients were interviewed. RESULTS: There were 10 males and 13 females. The age of the respondents ranged from 11 to 50 years with a mean age of 27.8 (SD = 5.61) years. Seven (30.43%) respondents were students studying in different levels. Thirteen (56.52%) participants were from the Newar community. Majority of the patients (86.95%) knew ADRs may be caused by the medicines they consume and 18 (78.26%) were of the opinion that ADRs should be reported to doctors and other health care professionals including pharmacists. CONCLUSION: Knowledge and perception were low in certain areas. There is a need for educational interventions for improving the awareness of patients and general public for ensuring medicine safety and promoting rational use of medicines. PMID- 24783074 TI - Antidepressant activity of brahmi in albino mice. AB - CONTEXT: In traditional system of medicine brahmi has been used to enhance memory. Recently it has been reported to have action in psychiatric disorders. With these backgrounds the work has been undertaken to study antidepressant activity of brahmi in albino mice. AIM: To evaluate antidepressant activity of brahmi in experimental models. MATERIALS AND METHODS: The antidepressant activity was studied in albino mice using forced swimming test (FST), tail suspension test (TST) and shock induced depression (SID). Imipramine (10mg/kg), fluoxetine (30mg/kg) were used as standard drugs and brahmi (10, 20, 30mg/kg) was used as test drug. RESULTS: Brahmi exhibited significant decrease in duration of immobility in FST and reduced the shock induced decrease in activity in SID models. It didn't show any activity in the TST model. CONCLUSION: Brahmi has shown antidepressant activity in FST and SID. PMID- 24783075 TI - Role of s-100 immunostaining in demonstration of nerve changes and quantification of dendritic cells in leprosy. AB - BACKGROUND: A definitive diagnosis of leprosy is based on a demonstration of either acid-fast bacilli or nerve elements within the granulomas. On routine hematoxylin and eosin stains, the nerve fibers are not easily identifiable. In this study, S-100 immunostain is used to highlight the nerve elements and to demonstrate and compare the nerve changes in spectrum of leprosy including reactions. AIM: To demonstrate the nerve changes in spectrum of leprosy using S 100 immunostaining so as to categorize them for the purpose of early diagnosis and treatment. We also want to demonstrate and quantify the dendritic cells in lepromatous spectrum of leprosy using S-100 immunostain. MATERIALS AND METHODS: Twenty consecutive skin biopsy specimens from patients with histopathological diagnosis of leprosy in the year 2012 were studied. Of these 20 cases, 13 were Borderline Tuberculoid, 1 was of indeterminate leprosy, 1 Borderline Lepromatous, 2 cases of Lepromatous Lep-rosy , 1 case of Type 1 reac-tion and 2 cases of Type 2 reaction. Stains used were Hematoxylin and Eosin stain for the histopathological diagnosis, Fites stain for Bacillary index and S-100 immunoperoxidase staining for nerve changes. 5 cases of granulomatous dermatosis of skin other than leprosy (5 cases of lupus vulgaris) were included as controls. RESULTS: On Hematoxylin and Eosin staining, the nerve fibers showed vertical orientation in relation to epidermis in Borderline Tuberculoid leprosy. In addition , the nerve fibers showed rounded contour in Tuberculoid leprosy. The entire spectrum of leprosy showed evidence of nerve damage in S-100 immunostaining which was categorized in 4 patterns 1. Absent, 2. Fragmented, 3. Discontinuous and 4. Intact. The majority of Borderline Tuberculoid leprosy cases showed absent pattern of nerve damage. Dendritic cells were also positive for S 100 immunostaining with granular positivity in Borderline Tuberculoid Leprosy cases and membranous positivity in Lepromatous spectrum. CONCLUSION: Nerve damage is seen across the entire spectrum of leprosy and the early identification of this nerve damage using S-100 immunostaining, helps to differentiate between Lepromatous and Tuberculoid leprosy, especially in the borderline and indeterminate forms. PMID- 24783076 TI - Correlation of cytohistlogical expression and serum level of ca125 in ovarian neoplasm. AB - Context or Background: CA125 is a biomarker that has potential utility across the spectrum: risk assessment, early detection, diagnosis, prognosis, monitoring and therapy. AIMS AND OBJECTIVES: This study was conducted to establish the validity and reliability of correlation of CA125 serum level with immunochemistry expression in imprint cytology and tissues for diagnostic purpose. MATERIALS AND METHODS: A prospective study was done on 50 cases of clinically and radiologically diagnosed ovarian tumor. Imprint smears were made intraoperatively from fresh samples and stained with M.G.G. stain for air dried smears and Papanicoloau stain for alcohol fixed smears. Stained smear was assessed and compared with subsequent histopathology report. Preoperative blood samples were obtained from all patients and sent for the assay of serum CA125 levels. Analysis of CA125 immunochemistry expression in imprint cytology and tissue was done and correlated with preoperative serum blood CA125 levels. RESULTS: Significant positive correlation was found between elevated serum CA125 levels and cytohistological expression of CA125. Overall sensitivity was 100%, specificity was 86%, positive predictive value was 74% and negative predictive value 100%. Diagnostic accuracy was 90% with high statistical significance (p<0.001). CONCLUSION: We considered 35 U/mL as the cut-off value when evaluating serum CA125 ovarian cancer. Patients with high serum levels show good cytohistological expression. PMID- 24783077 TI - Spectrum of cytology of neck lesions: comparative study from two centers. AB - BACKGROUND: The objective of this descriptive study was to observe the frequency of various pathological conditions detected in FNAC of patients presenting with neck swellings coming from two different regions of southern India. MATERIALS AND METHODS: This study included 100 consecutive patients from each region (Region 1: Wyanad, Region 2: Salem) presenting to the department of Pathology with swelling in the neck region as the chief complaint. All age groups were included. All patients underwent FNAC and results were recorded. Frequency of various pathologies was determined. RESULTS: Thyroid lesions were predominant in both the regions with colloid goiter being the commonest lesion followed by lymphadenitis. Metastasis was more common compared to primary malignancies in Salem due to the elderly population under study. CONCLUSION: Non-neoplastic lesions were commonly encountered in our study which is in accordance with findings in similar studies conducted in other developing countries. FNAC should be the primary investigation of choice as it is inexpensive, safe and has a high degree of diagnostic accuracy. PMID- 24783078 TI - Follicular variant of papillary thyroid carcinoma: cytological indicators of diagnostic value. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) is an important investigation in preoperative diagnosis of thyroid lesions. Follicular variant of papillary carcinoma thyroid (FVPTC) is a well defined entity in histopathology, but its diagnosis in FNAC is usually missed and is challenging compared to classic papillary thyroid carcinoma. AIMS: The purpose of this study is to retrospectively analyze cytological features in histologically confirmed cases of FVPTC, compare them with literature and document the features that could increase the sensitivity of FNAC diagnosis. MATERIALS AND METHODS: Cytological smears from 22 histologically confirmed cases of FVPTC were evaluated for microscopic pattern and nuclear features by two independent pathologists and results compared with previous studies. Statistical analysis was done based on bivariate Pearson's correlation coefficient. RESULTS: Among 22 cases 21 were female and one male with age range 21 - 50 years. All patients had a solitary nodule except one with multicentric presentation. Preoperative cytological diagnosis were, classic papillary thyroid carcinoma (PTC); 7, FVPTC; 3, suspicious for PTC; 4, follicular neoplasm; 5 and adenomatous goiter;3. Diagnosis upon cytological review were, FVPTC; 11, classic PTC; 7 , suspicious for PTC; 2, follicular adenoma;1 and adenomatous goiter; 1. CONCLUSION: We conclude that cellular smears with features as observed in our case like microfollicular pattern, syncytial clusters, fine powdery chromatin, anisonucleosis and nucleomegaly should alert the pathologist to look carefully for other more specific features like nuclear grooves and nuclear pseudoinclusions. This approach will help in avoiding misdiagnosis of FVPTC and would aid in choosing the right treatment modality. PMID- 24783079 TI - Correlation among lip print pattern, finger print pattern and abo blood group. AB - AIM: To study correlation between lip print pattern, finger print pattern and ABO blood group. MATERIALS AND METHODS: The study group consisted of 27 males and 27 females who were aged between 20-40 years. Lip prints, finger prints and ABO and Rh blood groups of each individual were recorded. Lip prints were classified, based on Suzuki's and Tsuchihashi's classification and finger prints were classified, based on Michael's and Kucken's classification. The results were statistically analyzed by using Chi-square test. RESULTS: Complete vertical lip print, loop finger print pattern, O+ blood group were predominant among individual groups. O+ blood group-type I lip print combination, loop finger print pattern-type IV lip print pattern combination, O+ blood group-loop finger print pattern combination and both B+ blood group-loop finger print pattern- type IV lip print pattern combination and O+ blood group-loop finger print pattern-type I lip print pattern were predominant. CONCLUSION: Though lip prints, finger prints and blood groups had their own specificities, correlation of the three parameters did not show any significance. PMID- 24783080 TI - Comprehensive Evaluation of Drug De-addiction Centres (DDCs) in Punjab (Northern India). AB - BACKGROUND: Drug addiction is on the rise in Punjab,India. There are 15 DDCs which are supported by the Indian Red Cross Society. There is alleged mushrooming of private Drug De-addiction Centres (DDCs) in the smaller towns, villages and cities of Punjab. OBJECTIVE: This study aimed to evaluate DDCs in Punjab. MATERIALS AND METHODS: A total of 10 DDCs were included in the study and scheduled visits were made to collect data by using a pre-tested questionnaire. RESULTS: The duration of treatment was 1 month at the Red Cross DDCs and it was approximately 6 months at private DDCs. The staff at the private DDCs were inadequate. The major drugs which were abused by patients were Propoxyphene, Alcohol, Bhukki and Cannabis. Patients were usually referred to the DDCs either by family members (35.3%) or social workers (29.8%). About 72.5% of patients were married, 36.3% had passed 10th standard and 54.4% were employed. A majority dropped out of the DDCs due to personal reasons and lack of family support. On comparison, more patients were found to be treated at Red Cross centres (75.3%) than at private centres (65.8%). All DDCs had conducted regular sessions of individual, group and family counseling for patients. Red Cross DDCs ensured that ex-clients received follow-ups and home visits. More patients were satisfied with the services which were provided by the Red Cross DDCs. On the contrary, more patients at the private DDCs complained about harassment fromstaff personnel (p>0.05). CONCLUSION: It is recommended that all DDCs should be checked regularly, and that the private centres should be provided with additional support from the government, to help run them more efficiently. PMID- 24783081 TI - Status of biomedical waste management in nursing homes of delhi, India. AB - INTRODUCTION: Improper management of biomedical waste (BMW) poses a risk for health and environment. Healthcare workers have an important responsibility to properly segregate and train the staff in its disposal. OBJECTIVE: To study the awareness, attitude and practices of health care workers in biomedical waste management and to observe the appropriateness of the same in the private nursing homes in Delhi, India. MATERIALS AND METHODS: A cross-sectional study was conducted among private nursing homes in Delhi. In both south and east zones, 116 nursing homes were selected by random sampling method. Data was collected using a validated questionnaire of WHO. Data was analysed using SPSS software (version 16). Chi-square or fisher tests were used and accepted statistically significant if p-value was less than 0.05. RESULTS: 41.7% of the workers in south zone and 25% in east zone had no knowledge about BMW generation (chi2=24.26, p=0.001). 57 (95%) workers in south zone and 55 (98.2%) in east zone agreed strongly that BMW management is helpful in reducing spread diseases in the community (chi2=1.22, p=0.5). On observation, it was found that 13 (21.7%) nursing homes in south zone and 15 (26.8%) in east zone did not have black bags. Practice of biomedical waste management in nursing homes in both the zones of Delhi was poor. CONCLUSION: The study concluded that the awareness regarding biomedical waste management was not satisfactory among health care workers in private sector. There is a need of strict implementation of guidelines of BMW management. PMID- 24783082 TI - Study in Southern India Among Hypertensive Patients Using ECG To Screen Left Ventricular Hypertrophy - Can We Do It in Rural Health Centres? AB - BACKGROUND: Electrocardiogram (ECG) is a cost effective tool to evaluate left ventricular hypertrophy (LVH). However, its reliability is often questionable when compared to the gold standard - echocardiography.The validation of ECG as a tool to diagnose LVH would benefit centres that lack access to echocardiography. AIM: (1) To assess the efficacy of ECG criteria to screen for left ventricular hypertrophy in comparison to echocardiography. (2) To determine whether ECG can be used as a screening tool for LVH in rural primary health centres. MATERIALS AND METHODS: Fifty hypertensive patients admitted to a tertiary level hospital fulfilling the inclusion and the exclusion criteria, were evaluated for LVH using ECG and echocardiography. Romhilt-Estes and Sokolow-Lyon criteria were applied to all subjects and their efficiency in detecting LVH was measured using Kappa statistics in comparison to echocardiography. RESULTS: Among the 50 patients, 23 had LVH by echocardiography. In comparison to echocardiography, Romhilt-Estes and Sokolow-Lyon criteria were specific for LVH (96.3%, 88.9% respectively), but were poorly sensitive (43.5%, 43.5%). Combining both the criteria, raised the sensitivity to 60.9% and specificity to 85.2%. Kappa statistical analysis showed moderate to fair agreement of the Romhilt-Estes criteria with echocardiography. Both criteria had high positive predictive values (90.9%, 76.9%). CONCLUSION: Both Romhilt-Estes and Sokolow-Lyon ECG criteria are poor screening tools due to low sensitivity. But during routine screening of hypertensive patients with ECG alone, if any patient is positive by Romhilt-Estes criteria or both criteria, it would certainly warrant echocardiographic evaluation. As echocardiography cannot be recommended to screen every patient with hypertension in developing countries, initial evaluation using ECG can certainly help in selecting those who require echocardiography. PMID- 24783083 TI - Relation between Neonatal Icter and Gilbert Syndrome in Gloucose-6-Phosphate Dehydrogenase Deficient Subjects. AB - BACKGROUND AND AIM: The pathogenesis of neonatal hyperbilirubinemia hasn't been completely defined in Gloucose-6-Phosphate Dehydrogenase (G6PD) deficient newborns. The aim of this study was to detect the relationship between Gilbert's syndrome and hyperbilirubinemia in Gloucose-6-Phosphate Dehydrogenase (G6PD) deficient neonates. MATERIALS AND METHODS: This case-control study was conducted in Amirkola pediatrics teaching hospital, Babol, Iran. A total number of one hundred four infants were included in the study (51 infants with neonatal jaundice and Gloucose-6-Phosphate Dehydrogenase (G6PD) deficiency admitted to phototherapy or transfusion were selected as the case group and 53 infants with Gloucose-6-Phosphate Dehydrogenase (G6PD) deficiency admitted for other reasons than jaundice were selected as the control group). Exclusion criteria were ABO or Rh incompatibility or other reasons that made Coombs test positive, sepsis, hepatosplenomegaly, metabolic diseases, medical treatment and phototherapy. The promoter and coding regions of Uridine diphosphate Glucuronosyl Transferase 1A1 (UGT1A1) of genomic DNA were amplified by polymerase chain reaction (PCR) isolated from leukocytes. We used chi-square test and t-test to compare cases and controls. RESULTS: Distribution of Gilbert genome was not significantly different between the two groups; among cases, 33.3% were homozygote, 35.3% heterozygote, and 31.4% normal. Among controls, 22.6% were homozygote, 34% heterozygote, and 43.4% normal (p-value=xxx). Hyperbilirubinemia family history didn't differ significantly between these two groups. CONCLUSIONS: We showed that in Gloucose-6 Phosphate Dehydrogenase (G6PD) deficient neonates, there was no significant association between Gilbert's syndrome (promoter polymorphism) and hyperbilirubinemia. PMID- 24783084 TI - Epidemiological trends of trauma in tertiary care centre in dakshina kannada district of karnataka, India. AB - AIMS AND OBJECTIVES: To study the pattern and burden of trauma cases which presented to a tertiary care centre in an upcoming Dakshina Kannada District of Karnataka, India. METHODS: This was an epidemiological study. Data was collected by purposive sampling technique. Study period lasted from Jan 2013 to Aug 2013. Collected data was analyzed. RESULTS: The annual incidence of trauma at our centre was 15.96% (1140 cases). Most of the injuries were reported in 21-30 years age group. The male to female ratio was approximately 2.3:1. Limb injury (66.92%) constituted the commonest form of injury. Among the various injuries, fall was the commonest cause of injury (60.78%), followed by RTA (16.75%) and assault (11.6%). A majority of the cases were admitted during night time (61.24%). CONCLUSION: There has been an alarming increase in the number of trauma cases in the past decade. The target age group being the most productive one; it affects the economy directly . There is a need of urgent protective measures which are required for the benefit of the community. PMID- 24783085 TI - Impact of injectable progestogen contraception in early puerperium on lactation and infant health. AB - INTRODUCTION: Unmet need for family planning approaches 40% or higher and many women are at risk of unintended pregnancy. Progesterone contraception after birth is frequently recommended, but concern remain of inhibition of lactation or effects on infant health. In present study we aimed to evaluate impact of short term use of injectable depot medroxy progesterone acetate (DMPA) if given in early post partum period on infant health and breast feeding performance. MATERIAL AND METHODS: A prospective case control study was conducted and 250 women immediately after delivery were recruited in the study. 150 women who were recruited as study group received Inj. DMPA 150 mg intra muscularly after initiation of lactation before discharge from hospital (Day 2-Day 10 of their delivery). 100 post partum women, not using hormonal contraception were taken as controls. All the subjects were followed to complete a full 6 months follow up. Duration and frequency of lactation, gain in weight, gain in height and any illness spells in the infant were noted at 6 weeks, 3 months and 6 months follow up. In the study group 100 subjects completed 6 months follow-up. The statistical analysis was carried out by using SPSS software version 7. The statistical technique used was z score(significance shown by z score> 1.96) and repeated measure analysis (two way Anova technique). RESULTS: Hundred percent of primigravidas in the study group and 95% in the control group were satisfied with their lactation amount. The average gain in height was comparable in both study and control group {4.36+/-0.56 vs 4.33+/-0.54 (z score 0.38) at 6 weeks, 12.44+/ 0.73 vs 12.40+/-0.71 (z score 0.39) at 3 months 17.30+/-0.91 vs 17.28+/-0.83 (z score 0.16) at 6 months}. Similarly average gain in weight was also not significantly different in two groups {0.89+/-0.11 vs 0.93+/-0.10 (z score 0.71) at 6 weeks, 1.77+/-0.17 vs 1.78+/-0.16 (z score 1.07) at 3 months and 3.53+/-0.30 vs 3.46+/-0.33 (z score 1.19) at 6 months}. The results were comparable with other studies. CONCLUSION: Injectable DMPA use as a contraceptive in the immediate post partum period was found to be a safe and effective alternate method with no deleterious effect on mother's milk and infant's growth. PMID- 24783086 TI - The impact of labour epidural analgesia on the childbirth expectation and experience at a tertiary care center in southern India. AB - BACKGROUND: Labour epidural analgesia is increasingly used as a means of pain relief for women during labour and delivery. The significant pain during labour and delivery can be terrifying for mothers-to-be and the prospect of relief from pain can help reduce fear of childbirth to an extent. However, it is not necessary that reduced fear of childbirth may lead to an increased satisfaction with the childbirth experience. AIM: To determine the influence of labour epidural analgesia (LEA) on the experience of childbirth in pregnant women at a tertiary care center in southern India Materials and Methods: A pre-post interventional non-randomized study design at a tertiary care perinatal institute that used the Wijma Delivery Expectation and Experience questionnaires to determine baseline expectations of labour and childbirth and the actual experience in pregnant women. Labour analgesia was provided on maternal request or demand. Total and domain scores were compared between the two groups using non parametric tests and a generalized linear repeated measures model after adjusting for factors that were found significant in the bivariate model. RESULTS: The study included 235 pregnant women who opted for LEA and 219 pregnant women who opted against LEA. Overall, 37 (15.74%) of woman with LEA and 30 (13.70%) of women without LEA had a worse than expected experience of childbirth. Significant pain relief (p<0.001) was provided with LEA, however, the post-delivery scores did not differ significantly between the two groups (F=0.90, p=0.34) in a generalized linear repeated measures model. CONCLUSION: Maternal satisfaction with the process of childbirth is a complex dynamic that is not limited to the significant relief from pain provided by LEA. PMID- 24783087 TI - Airway management in maxillofacial trauma: do we really need tracheostomy/submental intubation. AB - BACKGROUND: There are various techniques available for airway management in patients with maxillofacial trauma. Patients with panfacial injuries may need surgical airway access like submental intubation or tracheostomy, which have their associated problems. We have been managing these types of cases by a novel technique, i.e, intraoperative change of nasotracheal to orotracheal intubation. AIM: To review our experience about various techniques for the airway management in patient with maxillofacial trauma. To analyse the possibility of using nasotracheal intubation and intraoperative change of nasotracheal to orotracheal intubation in panfacial fractures. MATERIALS AND METHODS: In a tertiary care centre four hundred eighty seven patients of maxillofacial injuries, operated over a period of 2 years were reviewed in relation to age, sex, mode of injury, type of facial fractures, methods of airway management and their associated complications. RESULTS: Young patients with male predominance is the most common affected population. Panfacial fracture is the most common type of injury (39.83%) among facial fractures. Airway was managed with intraoperative change of nasotracheal to orotracheal intubation in 33.05% of the patients whereas submental intubation or tracheostomy was done in 8.62% of the patients. CONCLUSION: Nasal route for endotracheal intubation is not a contraindication in the presence of nasal fractures, base of skull fractures and CSF leak. By changing the nasotracheal intubation to orotracheal intubation intraoperatively in cases panfacial fractures, most of the tracheostomies and submental intubations can be avoided. PMID- 24783088 TI - i-gelTM in Ambulatory Surgery: A Comparison with LMA-ProSealTM in Paralyzed Anaesthetized Patients. AB - INTRODUCTION: Supraglottic devices have mostly eliminated the need of hemodynamically stressful routine endotracheal intubation for ambulatory surgeries. We aimed to compare hemodynamics- like blood pressure (BP) and heart rate (HR) alterations caused by stress response due to i-gelTM and LMA-ProSealTM usage in Day care surgeries. Secondary outcomes included ease of insertion, time and number of attempts for the placement of devices. MATERIALS AND METHODS: From April 2008 to July 2009, Sixty adult ASA I-II patients of either sex, aged 20-30, were randomly allocated into two groups (Group i-gel (n=30) receiving i-gel and Group PLMA (n=30) receiving LMA-ProSeal for airway maintenance) undergoing day care surgical procedures under general anaesthesia (GA).The ease of insertion and time taken for placement of device, postoperative complications were assessed. Haemodynamic parameters (HR, BP) were noted. It was a prospective, double blinded, and randomized controlled study. Parametric data were analyzed with the unpaired t-test and non-parametric data were analyzed with the Chi-square test. Unless otherwise stated, data are presented as mean (+ SD). p <0.05 was considered statistically significant. RESULTS: Demographically both the groups were similar. i-gel was more easily inserted than LMA-ProSeal (90% vs. 83.33% respectively). i-gel insertion time was shorter than PLMA (14.9 vs. 20.0 sec respectively) and was statistically significant. Hemodynamics (HR, BP) were less altered in i-gel than PLMA and the results were statistically significant (p <0.05). CONCLUSION: i-Gel; a relatively newer and cheap supraglottic device; insertion is easier and quicker as well as hemodynamically less stressful when compared with LMA-ProSeal in a day care setting. PMID- 24783089 TI - Design of customizable automated low cost eye testing system. AB - BACKGROUND AND OBJECTIVES: In many underdeveloped and third world countries, eye care is often neglected due to illiteracy. Particularly people in rural areas suffer with eye problems due to mal nutrition. The government is spending lot of money and efforts in screening the people at periodic intervals. One of the challenges faced by the doctors is screening the school children. MATERIALS AND METHODS: The standard Snellen letter chart based diagnostic system does not work always. There are instances where the first few students who undergo this diagnostic system, memorize the letter sequence of the Snellen letter chart and convey the same to other fellow students. Hence other students simply read out the Snellen letter sequence from their memory, not by looking at the Snellen letter chart. Thus there is a need of randomizing the sequence of letters being displayed on the Snellen letter chart for every student to be diagnosed for eye testing. CONCLUSION: In the present paper we are proposing a customizable, software based, cost effective solution which involves a standard personal computer (PC) fitted with a camera, headphone and speaker system. The envisaged system can be administered even by the trained persons. The proposed system is also suitable for remote diagnosis of patients, particularly in the field of telemedicine. PMID- 24783090 TI - Genetic Risk of Azoospermia Factor (AZF) Microdeletions in Idiopathic Cases of Azoospermia and Oligozoospermia in Central Indian Population. AB - BACKGROUND: Genetic factors cause about 15% of male infertility. Azoospermia factors (AZFa, AZFb, and AZFc) present on Yq are most important for spermatogenesis. We have made an attempt to evaluate the frequencies of microdeletions of AZFa, AZFb, AZFc in idiopathic cases of azoospermia and oligozoospermia from central Indian population. MATERIALS AND METHODS: We have analyzed a total of 156 subjects (95 oligozoospermia and 61 azoospermia) & 50 control subjects. DNA samples were analyzed for microdeletions of Y chromosome by PCR-screening of 18 sequences-tagged-site (STS) markers from different region of the AZF on Yq and SRY on Yp. RESULTS: Out of 156 cases analyzed, 13 (8.33%) subjects (8 azoospermia and 5 oligozoospermia) showed partial deletion of AZF regions, of which deletion in AZFc region was the most common (84.6%) followed by AZFb (15.4%) and AZFa (15.4%). The sites and sizes of deletions varied among patients. Histological study of the testicular tissue of the available subjects, who showed microdeletions of Y chromosome, showed spermatogenic arrest at different stages. The frequency of Y chromosome microdeletion in our subjects was 8.33%. CONCLUSION: Some Indian studies reported low frequencies of microdeletions than that of our result. We suggest that the frequency of deletions may be affected by the involvement of different genetic factors, ethnic population and different geographical regions. PCR based Y chromosome screening for microdeletions will be useful and great help to infertility clinics for genetic counselling and assisted reproduction. PMID- 24783091 TI - Correlation between Sex Chromatin and Female Breast Tumour in Paraffin Sections, Buccal Smears and Peripheral Blood Films. AB - INTRODUCTION: Sex chromatin is a plano-convex to triangular DNA mass measuring approximately 1MUm in size and lying adjacent to the inner side of nuclear membrane in the somatic cells of the females. There is consistent loss in the sex chromatin percentage in the carcinoma cases in comparison to benign lesions and normal individuals. AIM: To know the correlation between the sex chromatin status in female breast tumors on paraffin sections, buccal smears and peripheral blood films. MATERIALS AND METHODS: The study was conducted on the paraffin sections prepared from carcinoma breast patients from their lumpectomy and mastectomy specimens. Buccal smears and a peripheral blood films were also prepared from each patient. DISCUSSION: The control group had shown a mean sex chromatin of 54.6+/-6.73% which was found to be similar to the mean sex chromatin percentage in the fibroadenoma breast cases i.e. 54.91+/-6.06%. However, the mean sex chromatin in the carcinoma breast cases was markedly reduced i.e. 8.22+/-6.03%. Maximum no. of fibroadenoma cases (67%) were in the younger age group i.e. 15 to 25 year, while maximum number of carcinoma breast cases (42%) occurred in the 4(th) and 5(th) decade. CONCLUSION: There is a loss of sex chromatin in cases of carcinoma breast and is associated with poor histological markers. A statistically significant correlation was also found between sex chromatin status and microscopic grading in carcinoma breast. The tumors with higher microscopic grade had lower sex chromatin as compared to those with lower microscopic grading. PMID- 24783092 TI - Piriformis fossa - an anatomical and orthopedics consideration. AB - INTRODUCTION: Piriformis fossa is an important anatomical landmark having significant clinical value in orthopedic surgery; but its location and anatomical relationship with surrounding structures are not clearly defined. Hence it is necessary to clearly describe it in respect to anatomical and orthopedic aspect. MATERIALS AND METHODS: Fifty Cadaveric dry femoral bones and Dissection of the four hip specimens were used to study the Piriformis fossa in respect to location and its relationship with surrounding structures. Clinical importance of piriformis fossa was determined in reference to antegrade femoral nail insertion. OBSERVATIONS: Piriformis muscle and so called piriformis fossa are unrelated entities. Piriformis fossa is anatomical site of insertion of obturator externus. In dry cadaveric femora; fossa was not always located in the direction of femoral shaft. It was located in the direction of femoral shaft in 24% cases only. In 68% cases femoral canal was aligned lateral and in 8% cases, it lies medial to the fossa. CONCLUSION: Piriformis fossa should be named as Trorchanteric fossa or Obturator fossa for better anatomical description. So called Piriformis fossa does not found to be universally corresponding to femoral shaft hence selection of entry site should be based on variable proximal femur and area on femur which corresponds to femoral shaft. PMID- 24783093 TI - Effectiveness of progressive resistance strength training versus traditional balance exercise in improving balance among the elderly - a randomised controlled trial. AB - INTRODUCTION: Falls are important health issues among the elderly people. Most falls in elderly result from abnormal balance control mechanisms. Balance and muscle force generation are directly related, and are associated with age related muscular changes. Studies addressing fall prevention have focused on various group and individualised strength training. However, evidence on strengthening of key muscles necessary for maintaining balance and postural control is lacking. OBJECTIVES: To evaluate the effectiveness of individualised progressive resistance strength training (PRT) programme in improving balance for forward limits of stability in elderly with balance impairment, compared to traditional balance exercise (TBE), and combination of both (COMBI). MATERIALS AND METHODS: This randomised controlled trial included three groups; 18 subjects in each aged >= 65 years, from the elderly care centres of Mangalore city in Southern India (between June 2008 and December 2012). Block randomisation technique was used and allocation concealment was done using sequentially arranged sealed opaque envelopes. The TBE group received 8 component traditional balance exercise; 4 times a week for 6 months. The PRT group received resistance training for the key muscles of lower extremities, using DeLormes and Watkins protocol. The COMBI group received PRT and TBE alternately (2 days of PRT and 2 days of TBE per week). Functional reach test (FRT) was used for measurement of forward limits of stability. The data was analyzed using Statistical Package for Social Sciences (SPSS) version 15. RESULTS: For functional reach, PRT group had steady progression from baseline to 6 months (p<0.001). The TBE and COMBI groups showed considerable initial improvement; beyond 3 months, moderate improvement was seen. The changes in scores of FRT were significantly better for PRT than TBE. CONCLUSION: Individualised PRT intervention targeting the key muscles of lower limbs is more effective than TBE in improving forward limits of stability among non-frail elderly aged >=65 years. PMID- 24783094 TI - Diagnostic Accuracy of MRCP as Compared to Ultrasound/CT in Patients with Obstructive Jaundice. AB - BACKGROUND: The expanding spectrum of therapeutic options for patients with surgical jaundice makes it necessary for the radiologist to precisely assess the etiology, location, level and extent of disease. AIM: To compare the diagnostic accuracy of Magnetic Resonance Cholangiopancreatography (MRCP) with Ultrasound and Computed Tomography (CT) in evaluation of patients with obstructive jaundice taking direct cholangiographies (ERCP and PTC), hystologic tests and anatomo pathological findings after surgical intervention as gold standard. SETTINGS AND DESIGN: This prospective study included 50 patients who were referred to the radiology department with clinical features of biliary obstructive disease. MATERIALS AND METHODS: Initial ultrasonography (USG) evaluation was followed by Computed tomography (CT) and Magnetic Resonance Cholangiopancreatography (MRCP);however in cases of benign pathologies where USG findings were unequivocal Computed tomography (CT )was not done to avoid unnecessary radiation exposure. The results were read by radiologists blinded to other imaging findings. The characteristic Endoscopic Retrograde Cholangiopancreatography (ERCP) features/ histopathological diagnosis / surgical findings (as applicable) were considered as final. RESULTS: Diagnostic accuracy of MRCP (98%) in the diagnosis of benign and malignant diseases was relatively high (98% and 98%) as compared to CT (82.86% and 91.43% in benign and malignant respectively) and USG (88% and 88%). In the diagnosis of benign diseases MRCP was 100% sensitive compared to ultrasound (80.77%), which was more sensitive than CT scan (54.55%).In the diagnosis of malignant diseases, MRCP was more sensitive (95.83%) as compared to CT scan (91.67%), which was more sensitive than ultrasonography (79.17%). CONCLUSION: Ultrasound as a screening modality is useful to confirm or exclude biliary dilatation and to choose patients for MRCP examination. MRCP is an important non invasive imaging investigation in the pre operative evaluation of patients with obstructive jaundice. PMID- 24783095 TI - Study on total antioxidant status in relation to oxidative stress in type 2 diabetes mellitus. AB - BACKGROUND: Diabetes Mellitus is a condition of increased oxidative stress and requiries antioxidants. The sum of endogenous and food derived antioxidants represents the total antioxidant activity of the system. The cooperation among different antioxidants provides greater protection against damage caused by reactive oxygen species or reactive nitrogen species, than any single compound alone. Thus the overall antioxidant capacity may provide more relevant biological information compared to that obtained by the measurement of individual components, as it considers the cumulative effect of all antioxidants present in plasma and body fluids and hence the study. MATERIALS AND METHODS: The study population included healthy volunteers from staff of Sree Balaji Medical College & Hospital (SBMC&H) and Type 2 Diabetic patients attending SBMC&H, Chennai, India. Malondialdehyde levels and total antioxidant status of the case and controls was assessed. RESULTS: A significant decrease in the total antioxidant status among Diabetic patients and significant increase in their malondialdehyde levels in comparison to healthy controls was observed. CONCLUSION: Type 2 Diabetes Mellitus is a condition in which there is increased oxidative stress as evident by increased Malondialdehyde levels and the condition calls for utilization of antioxidants to combat the oxidants thereby resulting in decreased total antioxidants status. PMID- 24783096 TI - Circumaortic left renal vein-a rare case report. AB - During routine dissection which was carried out for the medical students, a circumaortic left renal vein draining into inferior vena cava was observed. There were 2 renal veins through which the left kidney drained into the inferior vena cava, of which the larger one ran ventral to aorta and the other smaller one ran posterior to aorta and received lumbar veins before opening into inferior vena cava. This is a relatively rare condition which can result in left renal hypertension (LRVH) syndrome which is otherwise called as anterior and posterior nutcracker syndromes. This venous anomaly results from the errors of embryological development. It is of clinical significance, mainly during retroperitoneal surgeries and intra caval interventions. It is also important in conditions which warrant extensive venous dissections, venous reconstructions as in transplantations and invasion of veins by cancerous tissue, resulting in life threatening haemorrhage. PMID- 24783097 TI - Microfilaria in human subcutaneous dirofilariasis: a case report. AB - Human subcutaneous dirofilariasis, a rare zoonosis is being increasingly reported from various parts of the world. Most of the reported cases have lesions in and around the eye. The adult female dirofilariae release microfilaria into the definitive host's blood. Various mosquitoes that serve as intermediate hosts such as Culex, Aedes and Anopheles take up the microfilariae (mf-L1) while feeding on an infected host. Microfilariae develop in the mosquitoes. The transmission to dogs or other hosts including humans occurs through mosquito bite during subsequent blood meal. Humans may be infected as aberrant (accidental) hosts, mainly by D. repens and D. immitis. D. repens usually resides subcutaneously, while D. immitis frequently ends up in the human lung. In human infections usually just one larva develops, which does not reach sexual maturity. In India, almost all reported cases of dirofilariasis in humans have involvement of face in the form of ocular dirofilariasis with a few reports on subcutaneous dirofilariasis. We report a case of human subcutaneous dirofilariasis, from western India, involving leg and showing microfilaria in tissue indicating presence of gravid female dirofilaria (sexual maturity). To the best of our knowledge, it is among rare cases of subcutaneous dirofilariasis wherein microfilariae have developed in human host. PMID- 24783098 TI - Solitary Necrotic Nodule of Liver (SNNL): A Report of Two Cases. AB - SNNL is a rare, benign lesion which may arise from trauma, a sclerosing haemangioma or it may represent a burned out phase of various conditions like parasitic infections, or chronic infections like tuberculosis. Histopathology provides the definite diagnosis, which thus helps clinicians in allaying unnecessary anxiety of the patient and in planning proper management.We are reporting two cases here, which had solitary necrotic nodules of liver (SNNL), with emphasis on the aetiology and morphology of the lesions. SNNL was incidentally detected during cholecystectomy done in both young female patients. The lesion was solitary in one case and it was multiple in the other. The suspected aetiology in one of the cases was parasitic, whereas it was tuberculosis in the other. The clinical features in both cases were suggestive of neoplasms. PMID- 24783099 TI - Adrenocortical carcinoma presenting as a rupture and extensive retroperitoneal haemorrhage. AB - Adrenocortical carcinoma (ACC) is an extremely rare tumour. We are reporting a 45 year-male patient who had a history of sudden severe worsening epigastric pain and fullness in abdomen, with giddiness. The radiological investigations showed a large right suprarenal mass with extensive destruction and retroperitoneal haemorrhage, with extra capsular, periportal and liver metastases. Exploratory laparotomy was done for excisions of mass and surrounding tissue. On histopathological examination, diagnosis was given as Adreno Cortical Carcinoma with capsular, vascular, and soft tissue nodular involvement. PMID- 24783100 TI - Benign Hepatic Mesenchymal Hamartoma (HMH) - A Case Report. AB - A one-year-old male child presented with progressive enlargement of abdomen and loss of appetite which he had suffered from, since 4 months. Physical examination showed a palpable mass in right hypochondrium. Ultrasonography and MRI showed a solid mass arising from right lobe of liver. The resected mass was well encapsulated, yellowish white in colour and it measured 20 x 18 x 17cm. Cut surface showed a Nutmeg like appearance. Histology showed a well-defined, fibrous capsule with numerous ducts which were lined by flat to low cuboidal epithelium and which were surrounded by concentric layers of fibrous tissue which showed myxoid changes at places. Intervening area showed normal appearing hepatocytes with clear cell changes, dilated congested sinusoids, along with extramedullary haematopoiesis. Based on distinctive morphological features, a histological diagnosis of Benign Hepatic Mesenchymal Hamartoma of liver was made. IHC was not done, as no specific marker has been described for making a differential diagnosis. Benign Hepatic Mesenchymal Hamrtoma (HMH) of liver is an extremely rare tumour of childhood and therefore, the case was considered worth documentation. PMID- 24783101 TI - Nasal discharge cytology an important diagnostic method for allergic fungal sinusitis: report of three cases. AB - Allergic fungal sinusitis (AFS) is a distinct clinicopathological entity. It occurs in immunocompetent individuals with history of atopy, increased IgE levels and peripheral eosinophilia and causes noninvasive pansinusitis. It is histologically characterised by the presence of 'allergic mucin' with clusters of eosinophils, charcot - Leyden crystals and scattered fungal hyphae. AFS is an immunological reaction to fungal deposits. As AFS is noninvasive, fungal hyphae can be demonstrated in nasal secretions on cytology. Etiological agent of AFS is Aspergillus or pigmented dematiaceous family. Special stains are helpful for identification. We came across three cases of age group ranging from 26 to 60 year of recurrent rhinitis with nasal discharge. The nasal secretions were collected by nasal swabs onto the glass slide and stained with Giemsa and silver stains. Smears revealed fungal hyphae amidst inflammatory cells with occasional Charcot-Leyden crystals. Nasal secretion cytology plays an important role in diagnosis and can be used for preoperative as well as intraoperative diagnosis of AFS and can be used as an additional diagnostic tool. PMID- 24783102 TI - Sclerosing peritonitis occurring in association with juvenile granulosa cell tumour - a cause of concern. AB - Sclerosing Peritonitis (SP) is characterized by fibrous thickening and adhesions of the peritoneum and it is encountered frequently in association with peritoneal dialysis, practolol and anticonvulsant therapy. Rarely does it present as a gynaecological complication, most commonly in conjunction with luteinized thecoma of ovary. Very rarely has sclerosing peritonitis been reported to occur with ovarian cystic teratoma and a luteinized variant of adult granulosa cell tumour, among which only one case has been reported in the English literature. An 18-year female presented with a history of lower abdominal pain, of one month's duration. At surgery, an ovarian mass was noted, along with adhesion of bowel loops which were enclosed within a diffusely thickened peritoneal membrane, forming a cocoon. Adhesions were seen in bilateral paracolic gutter and infracolic omentum, which were suggestive of metastatic deposits. Histopathology of ovarian lesion was interpreted as a juvenile granulosa cell tumour. The peritoneal process revealed sclerosing peritonitis. We emphasize this rare association of sclerosing peritonitis with juvenile granulosa cell tumour and that the peritoneal process of sclerosing peritonitis in a juvenile granulosa cell tumour should not lead to over staging of an ovarian tumour. PMID- 24783103 TI - Sclerosing Lobular Hyperplasia- Correlation between Cytomorphological and Histological Findings. AB - Sclerosing lobular hyperplasia of the mammary gland is an uncommmon benign lesion which is mainly seen in adolescents and young women. The breast lobules are enlarged due to ductal and acinar proliferations but they have normal architecture. There is extensive fibrosis of the intralobular stroma, and to a lesser degree, of the interlobular parenchyma. Patients generally complain of a palpable, painless/slightly tender and well-defined lump in breast. Fine-needle aspiration cytology of sclerosing lobular hyperplasia is non diagnostic with features similar to fibroadneoma except for the absence of stromal fragments. In order to reach a definitive diagnosis, a histopathologic evaluation is needed. However, a distinction between the two benign entities is of no clinical significance.We are describing a case of sclerosing lobular hyperplasia that occurred in the left breast of a 26-year-old lady. PMID- 24783104 TI - Sertoli-leydig cell tumor of ovary- a diagnostic dilemma. AB - Sertoli Leydig Cell Tumours (SLCTs) are rare, unilateral, sex cord stromal tumours of ovary, which constitute less than 1% of all the ovarian neoplasms. These tumours can be functionally diverse and they may have heterologous elements. We aim to report a case of a 25-year- old woman who presented with suprapubic pain of 5 days duration, a unilateral adnexal mass, hypertestosteronism without virilization. Intraoperative frozen section of the unilateral salpingo-oophorectomy specimen was suggestive of granulosa cell tumour. Histopathological examination, supplemented with alpha-inhibin immunohistochemistry, was diagnostic of Meyer's type II SLCT. Clinical presentation, pathology and the diagnostic pitfalls in the present case have been presented with a brief review of literature. PMID- 24783105 TI - Dermatofibrosarcoma protuberans - a recurrent lesion with unusual presentation in the parotid region. AB - Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous malignant neoplasm consisting of relatively monomorphous mononuclear spindle cells that show diffuse CD34+ positivity. Management of this lesion poses problem because of its infiltrative margins and high propensity for local recurrence and rare distant metastasis. It is said that clear margins with minimal removal of normal tissues can be achieved by Mohs' micrographic surgery, which is particularly important in head and neck locations where the presence of vital anatomical structures and aesthetic considerations hinders a wide surgical excision. A case of DFSP, at a very uncommon site of parotid region, which recurred within 9 months after initial surgical treatment, is being reported. PMID- 24783106 TI - Perforated GIST in Jejunum - A Rare Cause of Abdominal Cocoon. AB - Gastrointestinal stromal tumours [GISTs] are rare but they commonly arise in stomach, and small or large intestines. They are usually accompanied with gastrointestinal bleeding. We are reporting a case of GIST which occurred in a 52 year-old male,who presented with acute abdomen. On laparotomy, the entire segment of jejunum was found to be partially encased in fibrocollagenous tissue, which formed a cocoon. Moreover, the intestine showed diffuse thickening with multiple tumour masses, which is an uncommon gross finding in GIST. This case report highlights variable clinical and morphological manifestations of GIST. Awareness on its rare clinical manifestations, including abdominal cocoon, may help in making an early diagnosis and providing timely appropriate treatment. PMID- 24783107 TI - Extraskeletal chondroma of the foot-a case report. AB - Extraskeletal Chondroma (ESC) is uncommon which occurs predominantly in hands and feet. It has a variable histology, with two thirds of the ESCs showing mature hyaline cartilage which is arranged in distinct lobules with fibrosis, or ossification, or myxoid areas and few showing immature patterns, with chondroblasts mimicking extraskeletal myxoid chondrosarcomas (ESMCSs). ESCs can recur but they never metastasize, whereas ESMCSs can metastasize, which require aggressive treatment. We are reporting a case of ESC which was located in the distal phalanx of right foot great toe in a 58-year-old male patient. The histopathology in our case showed features of ESC, with some foci showing myxoid stroma and few chondroblasts with atypical pleomorphic nuclei mimicking ESMCS. Hence, the case had to be carefully evaluated to exclude ESMCS and to make the diagnosis of ESC. The treatment was limited to simple excision of the tumour and extensive surgery and post operative radiotherapy were avoided. PMID- 24783108 TI - A case of massive broad ligament leiomyoma imitating an ovarian tumour. AB - Leiomyomas are the most common benign tumours of female reproductive system which occur in women of child- bearing ages. Large fibroids are known to arise from uterus, but rarely from broad ligament. An unusual clinical presentation of a massive, broad ligament fibroid which measured 25 cm x 22 cm x 21 cm, and imitated an ovarian tumour because of its myxoid and cystic degenerations, has been described. PMID- 24783109 TI - Papillary poroid hidradenoma: a distinct histopathological entity a rare case report. AB - Papillary poroid hidradenoma is a very rare entity which belongs to poroid neoplasms, which represents 10% of sudoriferous tumours. It can be easily misdiagnosed as a malignant neoplasm. A 34-years-old male presented with an asymptomatic mass over the right chest wall, below the nipple, of 18 months duration. Clinical examination revealed tense cystic swelling which revealed hypoechoic and solid components on imaging. Clinically, a malignancy was suspected and a surgical excision was done. Histology and immunoreactivity to pan cytokeratin, epithelial membrane antigen and carcino- embryonic antigen confirmed the diagnosis. We are reporting this case because of the rarity of its presentation. PMID- 24783110 TI - Struma ovarii with elevated ca-125 levels and ascites mimicking advanced ca ovary. AB - Struma ovarii is uncommon tumor of ovary which can mimic as advanced carcinoma of ovary. Thyroid tissue is relatively frequent constituent of mature ovarian teratoma. Case of struma ovarii masquerading as cancer of ovary in a female aged 63 yrs showing complex large unilateral multilocular adnexal mass with elevated CA 125 (more than 1721 IU/L) and massive ascites mislead treating surgeons for long time. Clinicians were virtually clueless about preoperative diagnosis. Combination of ascites has been seen in one third cases but association with raised CA 125 is rare(only 8-10 cases so far). This case developed hypothyroidism one week after surgery. PMID- 24783111 TI - Chondrosarcoma arising in an enchondroma of the metacarpal bone - a case report. AB - Chondrosarcoma is a rare malignant tumour of proliferating cartilaginous tissue. It may arise as a primary lesion, or occur secondarily at the site of a previous benign lesion such as enchondroma . Primary chondrosarcomas are rare in the hand with a frequency of less than 0.5% to 3.2% of all chondrosarcomas, and are seen involving the phalanges, trapezium and trapezoid. Malignant transformation of a benign solitary enchondroma to secondary chondrosarcoma, especially in the hand, is extremely rare. We report a case, where the patient had developed a painful swelling in the 5th metacarpal bone of the right hand, 15 years back, which was diagnosed as enchondroma. Subsequently the patient presented with a 3-year history of increase in the size of the swelling at the same site, which on radiological and histopathological examination revealed malignant transformation into chondrosarcoma. We also discuss the differential diagnosis of chondrosarcoma. Keeping in mind the possibility of local recurrence and metastasis of chondrosarcoma, a ray amputation of the 4th and 5th digits of the right hand along with the mass was performed retaining the normal functioning of the hand. PMID- 24783112 TI - Angiolymphoid hyperplasia with eosinophilia of root of nose: a rare phenomenon. AB - Angiolymphoid Hyperplasia with eosinophilia (ALHE), also known as epithelioid haemangioma, is an atypical vascular tumour which occurs with a predilection for the head and neck region. It is characterized by the presence of solitary or multiple lesions with varying clinical appearances, from intradermal papules to subcutaneous nodules. PMID- 24783113 TI - Calcified vocal cord nodule - a unique case report. AB - Vocal cord nodules are benign neoplastic lesions which occur due to submucosal oedema and haemorrhage, leading to fibrosis and hyalinization. Calcification in vocal cord nodules has not been reported so far in literature. It is thought to be a laryngeal counterpart of idiopathic calcinosis cutis. Here, we are reporting a case of a 38-year-old male patient who presented with a change in voice, which had a duration of one month. Laryngoscopic examination revealed a globular, yellowish white, sessile mass which arose from anterior commissure region of right vocal cord. Micro laryngeal excision was done. Histopathological examination was suggestive of a calcified nodule in vocal cord. PMID- 24783114 TI - Grade-III Paraplegia in Spinal Tuberculosis: Follow up of A Case Report and Review of Literature. AB - This is a case report of spinal tuberculosis which could not be diagnosed in the early stages. Individuals who work in hospital settings and suffer from psychological stress need to be aware of the various hospital acquired infections and consequences of late diagnoses. A CT scan is indicated to rule out the spinal involvement, at the beginning of a severe backache, which does not respond to painkillers, rest, and if X-ray is normal. It is of immense help and much of the problems like paraplegia and morbidity which are associated with this kind of extra - pulmonary tuberculosis, could be avoided. Once paraplegia sets in, the response to treatment as well as the recovery are slow. The cost of CT Scan or MRI (Magnetic Resonance Imaging), no doubt, is very high, which ranges from Rs.4,500/- to Rs.5,000/- for an average Indian, but which goes a long way in reducing the debilitating conditions, excruciating pain and confinement to bed which occur during the spinal tuberculosis. Prolonged follow-up is essential in cases of Pott's disease, as it was in the presented case. A strict treatment schedule of 18 months, combined with good nutritional support and bed rest, with spinal braces, is adequate for recovery from immobility and paraplegia caused by an advanced stage of spinal infection. This case therefore, supports an approach of nonoperative treatment over surgery, where the patient had progressive paralysis. PMID- 24783115 TI - Cerebral stroke after valvular surgery in young patients: case studies. AB - Intracranial haemorrhage (ICH) is a dreaded complication caused by oral anticoagulants (OAC) after valvular heart surgeries. Anticoagulant use in conventional doses increases the risk of ICH 7-10 fold. Intracerebral haematomas constitute 70% of the anticoagulant-related intracranial haemorrhages, with mortalities approaching 60%. Predisposing factors for anticoagulant-related ICH in Indian patients are unique as compared to those seen in their western counterparts. In anticoagulated patients, ICH evolves rapidly within hours; hence, emergency reversal of anticoagulation is crucial. We are reporting four cases of cerebral strokes which followed valvular surgeries in our institution, who were admitted during August 2012 to July 2013. There is an increasing need to educate the patients and update the physicians regarding the various issues which are involved in anticoagulation management. PMID- 24783116 TI - Single therapeutic catheterization for treatment of late diagnosed native coarctation of aorta using a covered stent. AB - Here in we are reporting a 35-year-old pregnant, hypertensive woman with a strict descending aorta coarctation. She had two missing pregnancies which were complicated with hypertension, but which were not diagnosed for any pathologies before. We diagnosed coarctation of aorta, but however postponed her treatment after delivery of baby, because hypertension was under control with medical treatment and she had no complication. She had an uneventful delivery. MRI angiography revealed coarctation of aorta and it was successfully treated by using an endovascular covered stent during a single cardiac catheterization. Endovascular covered stent implantation is an easy, safe and effective method for treating coarctation of aorta in adults. PMID- 24783117 TI - Haemophagocytic lymphohistiocytosis with lung cavity and lytic bone lesion in a 45 day infant. AB - Haemophagocytic lymphohistiocytosis (HLH) is a potentially fatal, hyper inflammatory condition which is caused by a highly stimulated but ineffective immune response. We are presenting here, a case of HLH which occurred in a 45 day infant. Presence of lung cavity and a lytic bone lesion in the skull, as was seen in this case, have not been reported in HLH in the literature. This raises a possibility of a simultaneous occurrence of HLH and Langerhans cell histiocytosis. In a child who presents with septicaemia but does not respond to treatment, the possibility of HLH needs to be considered. PMID- 24783118 TI - Cryptogenic gelastic epilepsy: a pediatric case vignette. AB - Gelastic seizures, characterized by epileptic laughter, are rare and the majority is associated with hypothalamic hamartomas. We report a case with cryptogenic Gelastic seizure (without hypothalamic hamartoma), as the MRI was normal and, EEG and clinical data suggested a focal origin of the seizures. PMID- 24783119 TI - Cow's Milk Protein Allergy Mimicking Acrodermatitis Enteropathica. AB - Cow's milk protein allergy is an adverse immune reaction to one or more of the constituent proteins of milk obtained from any animal, most commonly alpha s 1 casein cow's milk. In many cases, the allergy is genetic in origin. The infants may experience symptoms within minutes after feeding (rapid onset) or commonly after 7-10 days of consuming the cow's milk (slower onset). Many children with cow's milk protein allergy develop symptoms in at least two of the following organ systems: gastrointestinal, skin and respiratory tract. Acrodermatitis Enteropathica (primary or secondary zinc deficiency) can also produce lesions in the skin and also gastro intestinal symptoms which can mimic milk protein allergy and differentiating between these two may be difficult. We are reporting a case of cow's milk protein allergy in an infant, which was initially diagnosed as Acrodermatitis Enteropathica and treated with zinc. The lesions did not subside completely even after achieving adequate zinc levels, but on stopping the cow's milk all the symptoms and signs disappeared completely and there was no recurrence on long term follow up. PMID- 24783120 TI - Persistent mullerian duct syndrome with transverse testicular ectopia: rare entity. AB - We are reporting on a 35-year-old male from low socio-economic strata, who presented with a left-sided inguinal hernia. Intraoperatively, a uterus and two fallopian tubes were found in the hernial sac which was adjacent to the two gonads, which received their blood supply partly, along with Mullerian duct remnants (Persitent Mullerian duct Syndrome with Transverse testicular ectopia). The gonads were testes by histological examination, with features of degeneration and fibrosis. Complete excision of the mass was done and mesh hernioplasty was done.The diagnosis of persistent Mullerian duct syndrome with Transverse testicular ectopia was confirmed. Persistent Mullerian duct Syndrome is a rare entity and itis association with Transverse testicular ectopia is even more rare. PMID- 24783121 TI - Spontaneous cholecystocolic fistula: case report. AB - Cholecystocolic fistula is a rare billiary-enteric fistula with variable clinical presentation. Despite modern diagnostic tool a high degree of suspicion is required to diagnose it preoperatively. These fistulae are treated by open as well as laparoscopic surgery, with no difference in intraoperative and postoperative complications. We are describing a 50-year-old female patient with the diagnosis of chronic cholecystitis with cholelithiasis, which was investigated with routine lab investigations, and abdominal ultrasonography but none of these gave us any clue to the presence of fistula, were discovered incidentally during an open surgery and were appropriately treated. PMID- 24783122 TI - Be Careful with an IV Line. AB - Obtaining an intravenous (IV) access is a simple procedure which can be done in almost any hospital setting. One of the most dreaded complications of this procedure is an inadvertent intra-arterial cannulation. This can result in an accidental injection of medications intra-arterially, which can potentially lead to life altering consequences. In the hope that these types of events can be prevented, we are presenting a case of a 57-year-old male who underwent bougie dilatation for an oesophageal stricture and was accidentally given medication for pain management intra-arterially through an improperly placed IV line, which resulted in ischaemia, gangrene and subsequent loss of the hand. Those who try to obtain an IV access should always be on the lookout for possible clues that can prevent an inadvertent IA injection, especially if cannulation is in an area where an artery is in close proximity to a vein; these clues include but are not limited to the following: a bright-red flash of blood in the cannula, pulsatile movement of blood in the IV line, and intense pain or burning at the site of injection. These signs, as well as educating the patient on early symptoms of ischaemia, may allow early action to be taken, to prevent irreparable damage. We always have to be careful when we insert an I.V line. PMID- 24783123 TI - A rare case of small bowel obstruction due to primary trichobezoar. AB - A trichobezoar is a mass of culminated hair within the gastrointestinal tract. Stomach is the common site of occurrence. Intestinal obstruction due to primary trichobezoar is extremely rare. Only few cases have been reported so far. We also present a case of 13-year-old girl having primary ileal trichobezoar causing intestinal obstruction. PMID- 24783124 TI - Anaesthetic implications and management of a giant ovarian cyst. AB - With improvement in health care, improved access to hospitals and better imaging modalities, huge abdominal tumours are rarely seen in modern day surgical practice. They present many challenges to anaesthesiologists. Difficult intubations, life threatening cardiovascular and pulmonary complications, are commonly encountered. Management of such cases is associated with significant mortality and morbidity. The consequences of surgery are mainly attributable to the size of the mass rather than to its distinctive pathology. We hereby report a very rare case of a giant ovarian cyst weighing 57kg, which was successfully managed by a careful pre-operative evaluation, maintenance of intraoperative haemodynamic and fluid management. PMID- 24783125 TI - Anaesthetic management of a patient with dilated cardiomyopathy for fracture femur surgery-a case report. AB - Dilated cardiomyopathy (DCM) is defined as impairment of the ventricular function of the myocardium. The management of a patient with dilated cardiomyopathy, who undergoes a non-cardiac surgery, is always a challenge for an anaesthesiologist, as this situation is associated with a high mortality rate. We are reporting the successful anaesthetic management of a patient with severe dilated cardiomyopathy for fractured femur surgical repair under graded epidural anaesthesia. PMID- 24783126 TI - Solitary sessile osteochondroma of scapula, a rare case report. AB - Osteochondromas are the most common benign tumours of bone. These are most commonly seen on the metaphysis of a long bone, but they can arise from any bone which is preformed from cartilage. To best of our knowledge, very few cases of osteochondroma scapula have been reported in literature. We hereby report a very rare case of osteochondroma which arose from scapula in a four year old boy, which was treated by excisional biopsy. PMID- 24783127 TI - Alkaptonuric arthropathy with periprosthetic fracture:a case report. AB - Alkaptonuria or Ochronosis is an autosomal recessive congenital metabolic error due to absence of enzyme homogentisic acid oxidase. Recently, we had an opportunity to diagnose this condition in one of our patients. An old aged man developed a pathological fracture of femur after a trivial fall at home. He was diagnosed to have intracapsular fracture neck of femur. Intraoperatively we noticed blackish discoloration of femoral head which lead us to investigate the case for alkaptonuria. Hemiarthroplasty was done with Austin moore prosthesis. Patient had cutaneous pigmentation and gross arthritic changes at multiple joints including spine. After one and half year patient developed a periprosthetic fracture of the femur for which open reduction and internal fixation was done. A periprosthetic fracture in ochronotic patient has never been reported till date which makes it a rarer entity. This article presents the clinico-radiologic manifestations of the case with surgical management and a follow up of two years. PMID- 24783128 TI - Utility of diagnostic ultrasound in evaluating fracture healing. AB - With increase in population, modes of transportation and a fast pace of life, an individual's chances of accident and thereby chances of getting fractured have increased significantly. Fracture has thus become a significant factor contributing to morbidity and mortality. To resume a normal life, after one suffers from a fracture is also an ordeal. The transition appears smooth if the fracture healing goes on in a smooth manner as is expected through its routine stages of reactive phase, reparative phase and remodeling phase. But if in this chain something goes wrong or some factors are not optimum upto the mark, then the process becomes unsuccessful and the repair is either partial or directionless. It is therefore very vital to confirm whether or not the callus which bridges the fractured fragments is healthy or not. Here in lies the role of imaging as it can show the status of callus without disturbing it. What complicates the picture is that a callus might not be well demonstratable unless it mineralizes or calcifies. An imaging modality like ultrasound therefore stands out as it can show the state of callus in its different stages. This article aims at demonstrating how ultrasound- a non invasive diagnostic imaging modality can give precise information about the progress of fracture healing and thereby aid in management of fractures, so that an individual can return back to normal productive lifestyle. This preliminary study highlights the spectrum of fracture healing as seen on ultrasound. PMID- 24783129 TI - Effect of various physical stress models on serum cortisol level in wistar rats. AB - BACKGROUND: Stress indicates the response or reaction of an organism to the environmental circumstances and their outcomes. Acute stress is well known to trigger several hormonal alterations in animals. An increase in glucocorticoid concentration can represent intensity of discomfort or distress experienced by an animal. The study was undertaken to evaluate the effects of various physical stress models on serum cortisol level in Wistar male rats. METHODOLOGY: In this study six Wistar male rats weighing 150-200 gm were randomly selected. Animals were exposed to 'forced swim test' and 'restraint test'. Their serum cortisol level was measured by ELISA test using alpha prime ELISA system before and after the tests respectively. RESULTS: RESULTS were analyzed by students paired t-test. Serum cortisol level was significantly higher after forced swim test as well as after restraint test. When both the physical activities were compared, serum cortisol level was increased more after restraint stress than after forced swim test however, the difference was not significant statistically. INTERPRETATION AND CONCLUSION: The rise in serum cortisol level was observed in both the physical activity models . Rise in serum cortisol level was significantly higher after restraint test than exposing them to forced swim test. This indicates that restraining the rats produced more stress than making them forcefully swim. PMID- 24783130 TI - Rare cause of recurrent stroke: bilateral cervical internal carotid artery aneurysm. PMID- 24783131 TI - Precaval Right Renal Arteries with Circum-aortic Left Renal Vein. PMID- 24783132 TI - An Early Sign of Wilson's Disease: Dysarthria. PMID- 24783133 TI - Hospital based serosurveillance study of dengue infection. PMID- 24783134 TI - A position for administration of difficult spinal anesthesia. PMID- 24783135 TI - Radiomorphometric indices of the mandible - an indicator of osteoporosis. AB - INTRODUCTION: Osteoporosis is a regressive change which occurs in the bone and it is seldom diagnosed before the occurrence of fractures. Hence, determination of mandibular bone density is of paramount importance for the detection of this silent disease. AIMS AND OBJECTIVES: The purpose of this study was to evaluate the influences of gender and age on the radiomorphometric indices and to assess the differences in the various indices, if any, between digital and analog radiographs. MATERIALS AND METHODS: Two hundred and fifty six panoramic radiographs (128 digital and 128 analog) were obtained and they were grouped into 8 age groups which were between 21 to 60 years with 5 year intervals between them, with equal sex distributions. The mandibular cortical index (MCI), mental index (MI) and panoramic mandibular index (PMI) were analyzed. RESULTS: C2 and C3 categories of MCI increased as age advanced in females. MI showed a significant difference in genders and MI Values decreased from younger to older females. PMI (p<0.05) was significant for both the genders. CONCLUSION: This study showed that MCI, MI and PMI indices were useful for identifying patients with low skeletal bone mineral densities (BMD) or osteoporosis and that digital panoramic radiographs were better than analog radiographs for measuring the indices. PMID- 24783136 TI - A changing trend in eruption age and pattern of first deciduous tooth: correlation to feeding pattern. AB - BACKGROUND: Feeding mode during infancy and its effect on deciduous tooth appearance in oral cavity in two generations and among genders. AIM AND OBJECTIVE: Study aimed to compare and correlate times and patterns of deciduous tooth eruption in breastfeeding (OBF), partial breastfeeding (PBF) and spoon feeding (SF) infants and initiation of semisolid food feeding (SSF) in infants. It also aimed to address the variations in the time of eruption of first deciduous tooth and its pattern in two generations who had more than a decade of difference in ages. MATERIALS AND METHODS: An open-ended questionnaire study was conducted on mothers of 265 patients from two groups, generation 1 (G1)- adults who were aged 20-35 years and second group, generation 2 (G2) - children who were below 5 years of age . RESULTS: A statistical significance was observed with respect to age, gender, generations, and frequency of breastfeeding, partial breastfeeding and time of initiation of semisolid food. CONCLUSION: There is a delayed eruption of teeth in present generation. For girls, it occurs at age of 7.88 months and for boys, it occurs at the age of 8.08 months. PMID- 24783137 TI - Assessment of lingual frenulum lengths in skeletal malocclusion. AB - BACKGROUND: The orofacial musculature plays a pivotal role in maintaining a balance in positioning of the teeth and any imbalance which occurs in this , results in malocclusion. Lingual frenum is a soft tissue structure which tethers the ventral surface of the tongue to the floor of the mouth. OBJECTIVE: This study was performed to analyze the lingual frenal lengths in skeletal class I, class II and Class III malocclusion and to correlate relationship between both. MATERIALS AND METHODS: This study comprised of 30 subjects, with 10 in each group and an impression was made with the maximum mouth opening position and the tip of tongue touching the incisive papilla. The length of the lingual frenum was then measured from the casts. The maximum mouth opening position was also determined by measuring the interincisal distance with the maximum mouth opening position. Statistical analysis was done to analyze the relationship between both. RESULTS: The lingual frenum was found to be longest in class III malocclusion, with a statistical significant value of p<0.01. The class II and class I malocclusion did not show much difference. The maximum mouth opening position was also increased in class III malocclusion, followed by class II and class I malocclusion, in a descending order. CONCLUSION: The lingual frenum exerts erratic forces and a long lingual frenum pushes the mandibular anteriors forwards, resulting in malocclusion. Hence, a relationship between the lingual frenum and malocclusion is essential, so that the erratic forces can be eliminated and excellent results can be achieved, following the correction of malocclusion. PMID- 24783138 TI - Drug abuse in paediatric dentistry: a cross-sectional study. AB - Compared to adult medicine, drug use in children is not extensively researched. OBJECTIVE: The objective of present study is to find out drug prescribing pattern in the Department of Pedodontics and Preventive Dentistry and Orthodontics in teaching hospitals in Rajasthan, India. METHODS: A prospective study was conducted in June 2011. A total of 619 prescriptions were collected randomly. Prescribing pattern was analyzed using WHO basic drug indicator. RESULTS: The average number of drugs and antimicrobial agent prescribed per prescription were 2.24 and 0.81 respectively. Antimicrobial agent contained 81.74% of all prescriptions. Most common groups of drugs prescribed by pedodontist were NSAIDS & Antipyretics (37.7%), Antimicrobial (36.4%) and Vitamins (12.3%). Prophylactic use of antimicrobial agents was 5.5 +/- 0.5 days. Fixed dose combination (45.6%) frequently used by brand name. twelve percent generic drugs were used. Most of the drugs were from Essential Drug List especially a only one drug was prescribed. CONCLUSION: There is a need of mass awareness amongst dentists about good prescribing habit. Every institution must have Drugs and Therapeutic Committees. The five steps of WHO Program on Rational Use of Drugs (RUD) should be followed for rational prescribing of drugs. PMID- 24783139 TI - In-vitro Evaluation of Fracture Strength Recovery of Reattached Anterior Fractured Tooth Fragment Using Different Re-Attachment Techniques. AB - BACKGROUND: Traumatic injuries caused to anterior teeth are most common. Emergency management of fractured fragments is necessary, for preserving their vitalities and for retaining aesthetics in an economical way. Various methods are available for restoring fractured, uncomplicated teeth, such as reattachment of fractured fragments, composite restoration. But only limited data is available on evaluation of the strength of reattached fractured fragments. Hence, the present study was designed. OBJECTIVES: The objective of this study was to evaluate the fracture strength recovery of re-attached anterior fractured tooth fragment by using different re-attachment techniques. METHODOLOGY: Forty human upper central incisions were used in this study. The roots of the teeth were confined in a special device (holder) and adapted in a Universal Testing Machine. Load was applied to each tooth in bucco-lingual direction, by using a small stainless steel ball. The force which was required to fracture the tooth was recorded. Both the fragment and remaining fractured tooth was restored by using four reattachment techniques - simple reattachment, external chamfer, over contour and internal dentinal groove. Specimens were loaded in same pre-determined area which was used in procedure to obtain fragments. The force required to detach each fragment was recorded and it was correlated with the fracture strength of an intact tooth and that which was obtained after doing restorative procedures for all groups i.e. fracture strength recovery. RESULTS: Technique I (simple reattachment) and Technique 2 (external chamfer) showed fracture strength recoveries of 44.3% and 60.6% respectively. However, these values were lower than those which were obtained by usingTechnique 3 (Over contour) -86.8% and Technique 4 (internal dentinal groove) -89.5%. CONCLUSION: Over contour and internal dentinal groove reattachment is a preferred technique as compared to the other reattachment techniques which were tested. PMID- 24783140 TI - Toothpaste Utilization Profiles among Preschool Children. AB - BACKGROUND: Oral healthcare for pre-school children is given due priority, as their oral health will determine the oral health status of future generations. Generally, the type, frequency and quantity of toothpaste used by children are based purely on parental preferences. METHODOLOGY: A descriptive, cross-sectional study was conducted among mothers of preschool children by using a questionnaire. RESULTS: Sixty two percent (n=154) mothers started brushing their children's teeth more than one year after eruption of their teeth. A majority of the mothers used adult toothpaste to brush their children's teeth and supervised their children while brushing. Fiftytwo percent mothers were aware about presence of fluoride in tooth paste but its clinical significance. Half the mothers applied full length of tooth paste to their children's brushes and most mothers made their children brush their teeth twice daily. CONCLUSION: Based on the findings of this study, it appears that there is still much lack of awareness on the proper guidelines on the selection and usage of toothpastes in children. Dental professionals should use this knowledge to help and motivate parents to properly supervise and assist their children's brushing, with the goal of reducing the potential risk of fluorosis. PMID- 24783141 TI - Intra-osseous jaw lesions in paediatric patients: a retrospective study. AB - OBJECTIVE: This study was undertaken to comprehensively analyze the distribution of intra-osseous paediatric jaw lesions (0-16 years) and to correlate the same with the data which has been published in the literature. STUDY DESIGN: A total of 171 hard tissue paediatric pathologies obtained from the archives of Department of Oral Pathology, Maulana Azad Institute of Dental Sciences, India were retrospectively reviewed over a period of 6 years. All the cases were analyzed for gender, site, radiographic findings, histopathological diagnosis, treatment modality and recurrence rate. RESULTS: The present study revealed 54/171 odontogenic cysts, 45/171 odontogenic tumours, 33/171 bone pathologies, 2 malignant tumours, 1 connective tissue pathology and 36/171 miscellaneous category cases. The highlights of this analysis showed a relatively higher incidence of odontogenic tumours (26.3%) as compared to those seen in other studies which have been published in literature. KCOT and ameloblastoma (solid and unicystic) were the most frequently diagnosed tumours. Also, one case of dentigerous cyst which was converted into calcifying ghost cell odontogenic tumour was a unique feature which was noted in the current study. CONCLUSION: In the current study, a preponderance of odontogenic pathosis was seen in the paediatric age group which was studied. PMID- 24783142 TI - Comparative Evaluation of the Effects of Light Intensities and Curing Cycles of QTH, and LED Lights on Microleakage of Class V Composite Restorations. AB - BACKGROUND: The purpose of this study was to evaluate the effects of light intensity and curing cycles of QTH and LED lights on the microleakage of Class V composite restorations. MATERIALS AND METHODS: Eighty freshly extracted human maxillary premolars were used for this study. Standardized Class V cavities were prepared and they were restored with microhybrid resin composite. According to the curing protocol, the teeth were then divided into 4 groups (n=20): QTH curing (standard and soft start modes), and LED (standard and soft start modes) irradiations. Microleakage was evaluated by immersion of the samples in 50% silver nitrate solution. The samples were then sectioned, evaluated under a stereomicroscope, and scored for microleakage. RESULTS: The results of the present in-vitro study showed mean dye leakage scores of 1.9, 1.2, 1.45 and 0.90 for Group I (QTH-Standard mode), Group II (QTH-Soft Start mode), Group III (LED Standard mode) and Group IV (LED-Soft Start mode) respectively. CONCLUSION: It was thus concluded that the soft start polymerization showed a highly significant difference as compared to the standard curing modes of QTH and LED lights, respectively. PMID- 24783143 TI - Importance of Different Modalities of Treatment For the Management of Keratocystic Odontogenic Tumour with Five year follow-up. AB - BACKGROUND: The keratocystic odontogenic tumors is a benign but one of most aggressive developmental cyst with many distinguishing clinical and histologic features and high recurrence rate. In the given study, authors have studied and presented their experience of managing Keratocystic odontogenic tumour. The aim of the study was to define an appropriate treatment protocol for the management of KCOT. MATERIALS AND METHODS: Total 8 patients, whose histopathological reports confirmed Gorlin - Goltz syndrome and KCOT, with age between 10 - 50 years, were selected from cases being treated at Sree Balaji Dental College, Chennai, India. Enucleation and resection were the surgical techniques employed. Modality of treatment was based on parameters like age , size, aggressiveness and extent of the lesion. All the patients were operated under general anaesthesia. Cases were studied, reviewed and followed up for five years between 2007-2012. RESULTS: The study included 8 cases in which three cases were opted for resection and five cases for enucleation followed by application of Carnoy's solution. CONCLUSION: Treatment modality should be decided on age, extent, aggressiveness and nature of the tumour. PMID- 24783144 TI - Diagnostic efficacy of saliva for dengue - a reality in near future? A piloting initiative. AB - BACKGROUND: Dengue, a mosquito-transmitted viral infection presents variable symptoms, including death. Due to their increasing incidences, early detection and improved diagnoses of severe cases are of prime importance. Currently, viral antigens and antibodies are detected by traditional serological tests. However, the introduction of oral fluid as an alternative, has led to many researches. Hence, this prompted us to carry out a pilot study to evaluate the diagnostic efficacy of saliva in detecting dengue antibody by using Enzyme Linked Immunosorbent Assay (ELISA). AIM AND OBJECTIVES: To evaluate the presence of Dengue antibody in saliva and its sensitivity and specificity through ELISA. METHODOLOGY AND RESULTS: Twenty seropositive patients and twenty seronegative patients of Dengue were considered individually. Saliva samples collected from these patients were subjected to ELISA test for detection of Dengue antibody. A sensitivity of 100% and a specificity of 100% were obtained for making a diagnosis of Dengue infection. CONCLUSION: Many studies have been conducted by utilizing saliva as a diagnostic tool, especially in western population. Its advantages over venipuncture are many, especially as it is less invasive, safe, less expensive and as it allows large numbers of samples to be collected easily for screening and epidemiological purposes. In a developing tropical country like India, such a diagnostic tool has to be encouraged. Further research necessitates the implementation of saliva as a diagnostic tool. PMID- 24783145 TI - Odontometric sexual dimorphism: a sibling correlation. AB - AIMS AND BACKGROUND: Teeth form an excellent material for anthropological, genetic, odontologic and forensic investigations. The aim of this study was to establish the genetic control of sexual dimorphism in tooth size amongst siblings of Goan children in age range of 14-22 years. MATERIALS AND METHODS: Twenty-two sibling pairs were selected (22 males and 22 females) to assess genetic control of sexual dimorphism in tooth size. Alginate impressions were obtained for maxillary and mandibular arches and study models were prepared. Measurements were done using Zoom Digimatic Vernier Calipers with a resolution of 0.01 mm. STATISTICAL ANALYSIS: Correlation between mesiodistal and buccolingual tooth sizes amongst siblings was calculated using Pearson's correlation coefficient. RESULTS: A statistically significant association was found between Mesiodistal Widths of Permanent Maxillary Right and Left Second Molars and between Maxillary Right and Left First Premolars amongst sibling pairs. A statistically significant association was also found between Buccolingual Widths of Mandibular Right and Left First Premolars amongst sibling pairs. This statistically significant correlation found amongst siblings establishes a genetic control over sexual dimorphism in these teeth. CONCLUSION: The genetic basis of sexual dimorphism in human dentition was ascertained as a significant correlation was found between mesio-distal and bucco-lingual widths of premolars between sibling pairs. PMID- 24783146 TI - The evaluation of effect of developer age in the detection of approximal caries using three speed dental x-ray films: an in-vitro study. AB - BACKGROUND AND OBJECTIVES: Ever since the first radiograph was taken in 1895, radiographs have become an essential part of dental practice. Since radiation exposure for the patients is a major concern, it is important for us to reduce the radiation exposure to the patient and surrounding environment, without compromising the quality of image. Since improper film processing is one of the major causes of poor image quality, it is very important to test dental films under a variety of processing conditions. So this study was conducted to compare the diagnostic accuracy between Kodak Ultraspeed, Ektaspeed and Agfa Dentus M2 Comfort films for the detection of approximal caries in fresh as well as in aged processing solution. METHODS: Hundred extracted unrestored maxillary and mandibular teeth were aligned in a group of five teeth in each plaster model. Total of 20 plaster models were constructed and only 3 teeth in the middle were utilized for the study. The final sample consisted of 60 teeth in the study. The exposure time for Ultraspeed film was standardized at 0.5 seconds and for Ektaspeed and Agfa Dentus M2 films, the exposure time was 0.32 seconds. For each radiograph two blocks were used simulating bitewing radiograph. All 20 plaster blocks were exposed using three film types at standardized exposure timings with 30 radiographs each week. The procedure was repeated every week until 6 weeks. Radiographs were evaluated by an observer and assessed by following four point scale 0- sound tooth, 1- lesion in enamel, 2- lesion in amelodentinal junction, 3 dentinal lesion. Only distal surfaces were assessed. Thereafter all the teeth were subjected for histological study and actual depth of the lesion was recorded which acted as gold standard and this reading was subtracted in observer readings after radiographic examination. All data collected were analyzed statistically using ANOVA, paired and unpaired t-tests. RESULTS: Ektaspeed and Agfa films required less exposure compared to Ultraspeed film. With respect to film, all films had equal diagnostic accuracy upto three weeks. From fourth week Ultraspeed and Agfa films were considerably better than E speed film. E speed film was inferior in the depleted solution compared to other two solutions. With respect to lesion detection Agfa film was inferior to other two films. CONCLUSION: All three films had equal diagnostic accuracy in fresh solution. Considering the significant reduction in patient radiation with Ektaspeed film, this should be the film of choice whenever possible. As far as the diagnosis of approximal caries is concerned processing solutions should not be used longer than 3 weeks. PMID- 24783147 TI - Study comparing the effectiveness of chlorhexidine, calcium hydroxide and linezolid based medicaments against enterococcus faecalis. AB - PURPOSE: This study evaluated the efficacy of 2% chlorhexidine (CX), calcium hydroxide (CH), Vitapex(r) (VP), linezolid (LZ), a combination of LZ with CH (LC) against Enterococcus faecalis (EF). STUDY DESIGN: EF strains were mixed with peptone water and the turbidity was adjusted to the McFarland's turbidity standard tube No: 0.5. The inoculum obtained was used to make lawn cultures on the agar plates. A total of 30 agar plates were prepared, such that each plate had five wells containing the five medicaments. The plates were incubated and evaluated for zones of inhibition after intervals of 24 hours and 72 hours. The results were statistically evaluated by paired t-test, ANOVA and Post-hoc analysis using Tukey's HSD. RESULTS: The difference between values of the zones of inhibition around various medicaments after 24 hours and 72 hours was found to be statistically significant. A comparison between the five groups after 24 hours or 72 hours showed that each group differed significantly from the rest of the groups. CONCLUSIONS: LC had the greatest effectiveness against EF, followed by LZ, CX, VP and CH. PMID- 24783148 TI - Comparative Evaluation of Marginal Adaptation of Biodentine(TM) and Other Commonly Used Root End Filling Materials-An Invitro Study. AB - AIM: The purpose of this investigation was to evaluate the marginal adaptation of three root-end filling materials Glass ionomer cement, Mineral trioxide aggregate and Biodentine(TM). METHODOLOGY: Thirty human single-rooted teeth were resected 3 mm from the apex. Root-end cavities were then prepared using an ultrasonic tip and filled with one of the following materials Glass ionomer cement (GIC), Mineral trioxide aggregate (MTA) and a bioactive cement Biodentine(TM). The apical portions of the roots were then sectioned to obtain three 1 mm thick transversal sections. Confocal laser scanning microscopy (CLSM) was used to determine area of gaps and adaptation of the root-end filling materials with the dentin. The Post hoc test, a multiple comparison test was used for statistical data analysis. RESULTS: Statistical analysis showed lowest marginal gaps (11143.42+/-967.753m2) and good marginal adaptation with Biodentine(TM) followed by MTA (22300.97+/-3068.883m(2)) and highest marginal gaps with GIC (33388.17+/ 12155.903m(2)) which were statistically significant (p<0.0001). CONCLUSION: A new root end filling material Biodentine(TM) showed better marginal adaptation than commonly used root end filling materials. PMID- 24783149 TI - Physico-chemical and bacterial evaluation of packaged drinking water marketed in delhi - potential public health implications. AB - INTRODUCTION: Quality of drinking water is a powerful environmental determinant of health. The main objective of introduction of bottled water in the society was its better safety, taste and convenience over tap water. The present study was conducted to assess physicochemical and bacterial qualities of bottled water and sachet water which were available in various markets of Delhi. MATERIALS AND METHODS: Sixteen water bottles and four water sachets were selected through stratified random sampling from various public places in Delhi and their analysis was done at National Test House, Ghaziabad. RESULTS were then compared with national (IS10500, IS14543) and international (WHO, FDA, USEPA) standards. RESULTS: Bottled water showed better quality than sachet water. The mean value of copper (0.0746mg/l) in bottles exceeded the standard values of IS10500 and IS14543(0.05), while the mean value of lead (0.008mg/l) exceeded the FDA standard value (0.005). When the results of sachets were compared with those of standards, the mean values of selenium (0.1195mg/l) and lead (0.862mg/l) were found to exceed values of both Indian and International standards. For the biological parameter i.e. coliform count, the mean value for bottles was 0 (nil), whereas the mean value for sachets was 16.75, which showed the unhealthy nature of sachets. CONCLUSION: The parameters which were tested in the present study showed excess of various chemical and bacterial parameters in drinking water, which could pose serious threats to consumers. Thus, these results suggest a more stringent standardization of bottled water market with special attention to quality, identity and licensing by concerned authorities, to safeguard health of consumers. PMID- 24783150 TI - A Comparative Evaluation of the Effect of Resin based Sealers on Retention of Crown Cemented with Three Types of Cement - An In Vitro Study. AB - AIM: In an effort to control postoperative sensitivity, dentin sealers are being applied following crown preparations, with little knowledge of how crown retention might be affected. A previous study demonstrated no adverse effect when using a gluteraldehyde-based sealer, and existing studies have shown conflicting results for resin-based products. This study determined the retention of the casting cemented with three types of cement, with and without use of resin sealers and it determined the mode of failure. MATERIALS AND METHODS: Extracted human molars (n=60) were prepared with a flat occlusal, 20-degree taper, and 4-mm axial length. The axial surface area of each preparation was determined and specimens were distributed equally among groups (n=10). A single-bottle adhesive system (one step single bottle adhesive system) was used to seal dentin, following tooth preparation. Sealers were not used on the control specimens. The test castings were prepared by using Ni-Cr alloy for each specimen and they were cemented with a seating force of 20 Kg by using either Zinc Phosphate (Harvard Cement), Glass Ionomer (GC luting and lining cement,GC America Inc.) and modified resin cement (RelyXTMLuting2). Specimens were thermocycled for one month and were then removed along the path of insertion by using a Universal Testing Machine at 0.5 mm/min. A single-factor ANOVA was used with a p value of .05. The nature of failure was recorded and the data was analyzed by using Chi-square test. RESULTS: Mean dislodgement stress for Zinc phosphate (Group A) was 24.55+/-1.0 KgF and that for zinc phosphate with sealer (Group D) was 14.65+/-0.8 KgF. For glass ionomer (Group B) without sealer, the mean value was 32.0+/-1.0 KgF and mean value for glass ionomer with sealer (Group E) was 37.90+/-1.0 KgF. The mean value for modified resin cement (Group C) was 44.3+/-1.0KgF and that for modified resins with sealer (Group F) was 57.2+/-1.2 KgF. The tooth failed before casting dislodgement in 8 to 10 specimens cemented with modified-resin cement. CONCLUSION: Resin sealer decreased casting retentive stress by 46% when it was used with Zinc phosphate. However, sealer use resulted in 60% increased retention when it was used with Glass ionomer cement. The modified-resin cement produced the highest mean dislodgement stress, which nearly always exceeded the strength of the tooth. PMID- 24783151 TI - Ehlers danlos syndrome - a case report. AB - Ehlers Danlos syndrome (EDS) is a hereditary collagen disorder which primarily manifests in the skin and joints. Clinically, it is characterized by hyperelasticity of skin and joint hypermobility. This article has described a rare condition seen in a 10-year-old boy who was diagnosed with EDS, based on the clinical, radiographic and histological findings. PMID- 24783152 TI - Prosthetic management of a masticatory muscle disorder with customized occlusal splint. AB - Occlusal splints of various types and designs are used in the diagnosis and treatment of different masticatory muscle and TMJ disorders. These appliances or devices provide a relatively simple, reversible and non-invasive form of treatment management. Treating such a disorder is really challenging for both dental and medical specialists and often it is difficult to diagnose as the presenting symptoms can be variable. The present article thus describes a case report on fabrication of simplified customized occlusal splint emphasizing the importance of medico-dental team approach for successful management with occlusal splint therapy. PMID- 24783153 TI - Endodontic Management of a Mandibular Central Incisor with Type IV Canal Pattern: A Case Report. AB - The success of endodontic treatment requires the knowledge of tooth morphology and its variations. Mandibular incisor's anatomy presents a challenge when an endodontic access is made, because of its small size and high prevalence of two canals. We are describing a Weine's Type IV root canal configuration that was detected in a mandibular central incisor, which was demonstrated by a radiographic examination. This article also focuses on the successful endodontic treatment of a mandibular central incisor with a single canal at the pulp chamber, which divided into two distinct and separate canals (buccolingual) at the middle third of the root. PMID- 24783154 TI - Intra-oral schwannoma- a case report. AB - Neurilemmoma (Schwannoma) is a benign tumour of neuroectodermal origin. It usually occurs as a asymptomatic, solitary, smooth-surfaced and slow growing lesion, emerging at any age, with as such, no gender prelidiction. Occurring as a common tumour in the head and neck region, its intraoral presentation is very rare. Here, we are reporting a rare case of intraoral schwannoma of the posterior palate which occurred in a 34-year-old female patient who had chief complaint of a painless, slow growing swelling on posterior palate. PMID- 24783155 TI - Adenoid cystic carcinoma of the buccal mucosa: a case report with review of literature. AB - Minor salivary gland neoplasms of the buccal mucosa are relatively uncommon. Adenoid cystic carcinoma (ACC), a well-defined entity, occurs most of the times in the parotid, submandibular glands and palate, as far as the intraoral site is concerned. Adenoid cystic carcinoma tends to have an indolent, extended clinical course with wide local infiltration and late distant metastases. We are presenting a case of an adenoid cystic carcinoma of the buccal mucosa in a 48 year-old female patient. PMID- 24783156 TI - Prosthognathic rehabilitation of a patient with underlying skeletal discrepancy- a case report. AB - Vertical and anterioposterior maxillary excesses can be treated with a combination of orthopaedic functional appliances, orthodontics and surgery. Treatment varies according to the age, patient reports for treatment. In patients who are treated with either of the above mentioned treatment modalities, if they require prosthetic replacement on a later date, especially of anterior teeth, prosthetic treatment alone does not give an aesthetic outcome. A partially edentulous, elderly patient with underlying skeletal discrepancy (Class II Skeletal deformity) in relation to 12,11,21,22 was treated with a combination of orthognathic surgery and prosthetic rehabilltation. An orthognathic surgery (leforte I osteotomy) was performed to manage vertical maxillary excess, class II skeletal pattern of maxilla and increased lower third facial height. Dental compensations in the mandibular arch were decompensated surgically with lower subapical osteotomy. Prosthetic restorations of missing anterior teeth were done later, such that facial and dental aesthetics. The records showed that the results were stable 12 months after prosthognathic (prosthodontic and orthognathic) treatment. A team approach enabled the female patient in her fifth decade of life, to receive better function, aesthetics and increased quality of life. Doing prosthetic restorations in patients with underlying skeletal discrepancies may become a challenge , which should be achieved without compromising on final outcome, with a calculated risk benefit ratio. PMID- 24783157 TI - Primary Extranodal Lymphomas of Lip - A Rare Manifestation in Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is a chronic autoimmune disorder which is characterized by lymphocyte-mediated destruction of exocrine glands, which produces the classical symptoms of dry eyes and dry mouth, which is referred to as primary SS or the Sicca complex. When it is associated with another autoimmune disease such as rheumatoid arthritis or lupus erythematosus, the condition is termed as secondary SS. One of the known major complications in patients with Sjogren's syndrome is the occurrence of Non-Hodgkin's lymphoma of B cell type. It is not uncommon for malignant lymphomas to occur in head and neck region at nodal and sometimes, extranodal sites. However, only rarely may they involve the oral cavity primarily. This case report describes a rare occurrence of isolated extranodal lymphomas in the upper and lower lips of a patient, which clinically resembled a mucocele, and eventually was diagnosed as lymphoma which was associated with Sjogren's syndrome, thereby stressing the importance which was played by an oral diagnostician. PMID- 24783158 TI - Herbal toothpowder induced erythema multiforme. AB - Herbal toothpowders are available in market in a wide varieties, which consist of various ingredients. In rural areas of the developing countries, they are still used for cleansing teeth. Erythema multiforme (EM) is an acute mucocutaneous disorder that is believed to be a sequel of a cytotoxic immunologic attack on keratinocytes which express non-self-antigens. A 31-year-old male who used herbal toothpowder for oral-hygiene maintenance presented with ulcers in mouth, encrustation on lips and target lesions on both hands, suggesting Erythema multiforme. An oral biopsy confirmed the diagnosis. To the best of our knowledge, there is no report of an association of herbal extracts and EM in the English literature. With this report, we present a rare new triggering factor of Erythema mutiforme, thus adding it to the endless list of aetiologies. PMID- 24783159 TI - Pericoronal occurrence of cemento-ossifying fibroma: an unexemplified and unusual case report with review of literature. AB - The Cemento-ossifying fibroma (COF) is an odontogenic neoplasm that is predominantly considered as a fibro osseous lesion of the jaw bone. The histogenetic origin of COF was thought to be derived from the periodontal cells, which have the ability to form fibrous, cementum and osseous tissue. Due to the periodontal cellular origin, the lesion often occurs in the radicular portion of the bicuspid and molar tooth region of the lower jaw. We present a case of Cemento-ossifying fibroma in a 43-year-old female in the pericoronal aspect of an impacted third molar mimicking an odontogenic lesion. The occurrence of COF in pericoronal region is an unusual site. This article also discusses about the various hamartomatous lesions occurring in the pericoronal region of the teeth. PMID- 24783160 TI - Endodontic Retreatment of a Mandibular Second Molar with four Separate Roots: A Case Report. AB - Aberrations in the root canal anatomy are a commonly occurring phenomenon. Although the mandibular second molar is commonly a bi-rooted tooth with an uncomplicated endodontic anatomy, variations have to be considered every time endodontic therapy is performed. This case report describes the non-surgical endodontic retreatment performed on a mandibular second molar with four seperate roots and canals. ProTaper Universal rotary nickel-titanium instruments (Dentsply Maillefer, Ballaigues, Switzerland) for treatment and retreatment were used to remove the old gutta percha and to clean and shape all root canals, followed by the complete obturation of root canal system. Post-operative CBCT scan was taken to confirm the quality of the performed treatment. PMID- 24783161 TI - Management of velopharyngeal defects: a review. AB - Success in Maxillofacial Prosthetics depends on full cognizance of the principles that underlie facial harmony, anchorage and retention, weight bearing and leverage, durability, tissue compatibility and tolerance. The maxillofacial prosthodontist normally provides appliances to restore aesthetics and function to the patients who cannot be restored to normal appearances or functions by means of plastic reconstructions. The velopharynx is a dynamic anatomic structure which is essential for normal breathing, eating, and speaking. The soft palate acts as a separator between oral and nasal cavities. Impairment of velopharyngeal function can be caused by insufficiency or incompetency. This article describes in brief about velopharyngeal defects and their management. PMID- 24783162 TI - Aviation dentistry. AB - With the rapid expansion of the airline industry in all sectors, dentists should pay special attention to crews and frequent flyers, due to change of pressure in flight, that cause different types of oro-facial pain. Aviation dentistry deals with evaluation, principles of prevention, treatment of diseases, disorders or conditions which are related to oral cavity and maxillofacial area or adjacent and associated structures and their impact on people who travel or on aircrew members and flight restrictions. Dentists should prevent the creation of in flight hazards when they treat aircrew members and frequent flyers. PMID- 24783163 TI - Taxonomy of salivary gland neoplasm. AB - Classification of neoplasms of any organ should be predicted on the patterns of differentiation that reflect the organization and cell types of the parental tissue. The ability to classify a neoplasm instills confidence in its predicted biologic behavior and the selection of treatment. There has not been a single universally used classification system for salivary gland tumor. Histogenetic and morphogenetic concepts and the developing information on various molecular parameters will have significant influence on the classification of salivary glands tumors. In this article we would highlight the histogenetic and morphogenetic concepts in salivary gland neoplasms and elaborate on the taxonomic system of classification of salivary gland neoplasms. PMID- 24783164 TI - Haptics - touchfeedback technology widening the horizon of medicine. AB - Haptics, or touchsense haptic technology is a major breakthrough in medical and dental interventions. Haptic perception is the process of recognizing objects through touch. Haptic sensations are created by actuators or motors which generate vibrations to the users and are controlled by embedded software which is integrated into the device. It takes the advantage of a combination of somatosensory pattern of skin and proprioception of hand position. Anatomical and diagnostic knowledge, when it is combined with this touch sense technology, has revolutionized medical education. This amalgamation of the worlds of diagnosis and surgical intervention adds precise robotic touch to the skill of the surgeon. A systematic literature review was done by using MEDLINE, GOOGLE SEARCH AND PubMed. The aim of this article was to introduce the fundamentals of haptic technology, its current applications in medical training and robotic surgeries, limitations of haptics and future aspects of haptics in medicine. PMID- 24783165 TI - Dental implant fractures - aetiology, treatment and case report. AB - PURPOSE: This study aimed to investigate the etiology, clinical manifestations, and treatment options of dental implants fractures through a literature review and to relate a clinical report. METHODS: A literature review was performed using the Medline database and this paper describes a case demonstrating the management of implant fracture. Twenty two articles were selected in the present literature review. RESULTS: Nowadays the use of dental implants to rehabilitate completely and partially edentulous patients became the best treatment option; however, this treatment is suitable to failure. The fracture of implant body is a possible complication. The fracture of implant body is a late complication and is related to the failure in implant design or material, non-passive fitting of the prosthetic crown and overloading. Clinically, prosthesis instability and spontaneous bleeding are observed. Three options of treatment have been indicated: complete removal of implant fragment, maintenance of implant fragment, and surface preparation of the fragment with insertion of a new abutment. CONCLUSION: The literature indicates the complete removal of the fragment as the best treatment option. PMID- 24783166 TI - Evaluation of teaching by students of a professional institution. PMID- 24783167 TI - Alcohol saliva strip test. AB - Alcohol is a factor in many categories of injury. Alcohol intoxication is frequently associated with injuries from falls, fires, drowning, overdoses, physical and sexual abusements, occupational accidents, traffic accidents and domestic violence. In many instances, for forensic purpose, it may be necessary to establish whether the patients have consumed alcohol that would have been the reason for the injury/accidents. Combining rapidity and reliability, alcohol saliva strip test (AST) has been put forward for the detection of alcohol in saliva for blood alcohol concentration (BAC). PMID- 24783168 TI - Renal failure prevalence in poisoned patients. AB - BACKGROUND: Renal failure is an important adverse effect of drug poisoning. Determining the prevalence and etiology of this serious side effect could help us find appropriate strategies for the prevention of renal failure in most affected patients. OBJECTIVES: The present study is aimed to identify drugs that induce renal failure and also to find the prevalence of renal failure in patients referred to emergency departments with the chief complaint of drug poisoning, in order to plan better therapeutic strategies to minimize the mortality associated with drug poisoning induced renal failure. PATIENTS AND METHODS: This cross sectional study surveyed 1500 poisoned patients referred to the Emergency Department of Baharloo Hospital in Tehran during 2010. Demographic data including age and gender as well as clinical data including type of medication, duration of hospital stay, and presence of renal failure were recorded. Mann-Whitney U test and chi-squared statistics were used to analyze the results. RESULTS: A total number of 435 patients were poisoned with several drugs, 118 patients were intoxicated with sedative-hypnotic drugs, 279 patients were exposed to opium, and 478 patients were administered to other drugs. The method of intoxication included oral 84.3%, injective 9%, inhalation 4.3% and finally a combination of methods 2.3%. Laboratory results revealed that 134 cases had renal failure and 242 had rhabdomyolysis. The incidence of rhabdomyolysis and renal failure increased significantly with age, and also with time of admission to the hospital. Renal failure was reported in 25.1% of patients exposed to opium, vs. 18.2% of patients poisoned with aluminum phosphide, 16.7% of those with organophosphate, 8% with multiple drugs, 6.7% with alcohol, heavy metals and acids, and 1.7% with sedative hypnotics. CONCLUSIONS: Based on the findings of this study, there is a high probability of renal failure for patients poisoned with drugs such as opium, aluminum phosphide, and multiple drugs as well as the patients with delayed admission to the hospital, and it is necessary to seek appropriate treatment to prevent this significant side effect. PMID- 24783169 TI - Lethal Pneumocystis jiroveci pneumonia 24 Years After Kidney Transplantation. AB - INTRODUCTION: Pneumocystis jiroveci is an opportunistic infectious fungus in immunosuppressed patients, particularly in ones with acquired immunodeficiency syndrome (AIDS). The use of immunosuppressive drugs especially corticosteroids predisposes the transplanted patients to a variety of infectious diseases including Pneumocystis infection. In many developed countries, the incidence of Pneumocystis jiroveci pneumonia (PJP) is dwindling in transplant patients receiving appropriate prophylaxis. In this study, definitive diagnosis of Pneumocystis infection in a patient receiving kidney transplant was presented. CASE PRESENTATION: The patient was a 45-year-old man with a history of kidney transplantation 24 years ago, admitted to a specialized hospital in Tehran because of fever and respiratory distress. Upon admission, the patient showed symptoms of unconsciousness and shortness of breath. Paraclinical tests and complementary examinations such as microscopic observation and molecular analysis confirmed the definitive diagnosis of Pneumocystis infection. Specific treatment with trimethoprim/sulfamethoxazole was carried out alongside other therapeutic measures; but unfortunately the patient did not respond to the specific treatment and died in the course of a progressive disease. DISCUSSION: The disease progress in these patients can still be fast and deadly. Applying rapid molecular diagnostic techniques to start appropriate and timely treatment is essential. Utilization of such diagnostic methods is recommended in our country. PMID- 24783170 TI - Three distinct urethral fistulae 35 years after pelvic radiation. AB - INTRODUCTION: While the development of fistulae is a well-known complication of radiotherapy, such fistulae can often be challenging to manage. CASE PRESENTATION: We describe the case of a 37 year old male who developed in succession a urethrocutaneous fistula to the thigh, a rectourethral fistula and a peritoneo-urethral fistula 35 years after radiotherapy for pediatric pelvic rhabdomyosarcoma. These complications were managed successfully after multiple surgical procedures. DISCUSSION: We subsequently discuss the different approaches currently employed for the management of radiation induced urinary fistulas and describe the rationale behind our approach towards their surgical management. PMID- 24783171 TI - On demand urethral dilatation versus intermittent urethral dilatation: results and complications in women with urethral stricture. AB - BACKGROUND: The treatment of urethral stricture in female patients is through dilatation of the urethra by tubes of increasing diameter. There are two main methods: intermittent dilatation and on demand dilatation. OBJECTIVES: The main aim of this study was to compare the results of these two methods, and to determine the best one. PATIENTS AND METHODS: In this clinical trial study, we reviewed the documents of women diagnosed with urethral stricture, who came to the Baqiyatallah Clinic from 2007 and 2012. According to the method of dilatation, the patients were divided into two groups: intermittent dilatation and on demand dilatation. Patients' data were then collected and analyzed. RESULTS: Eighty-six patients were enrolled in the study. The mean age of the participants was 48.13 years (between 44 and 79 years). The mean urinary residual and maximum urinary flow speed changes, before and after on demand dilatation, were higher than in the intermittent method. CONCLUSIONS: For treating urethral stricture, on demand urethral dilatation is more effective than intermittent dilatation. PMID- 24783172 TI - Serum cystatin C as a marker of renal function in critically ill patients with normal serum creatinine. AB - BACKGROUND: Serum creatinine as a classic marker of renal function has several limitations in the detection of renal dysfunction. OBJECTIVES: This study assessed the validity of serum cystatin C as a marker of renal function in critically ill patients with normal serum creatinine. PATIENTS AND METHODS: Eighty adult patients referred to intensive care units with serum creatinine levels < 1.5 mg/dL and without hemodynamic instability were chosen and their serum creatinine and cystatin C levels were measured. A 24-hour urine sample was collected to calculate creatinine clearance (Ccr). Renal dysfunction was defined as Ccr < 80 mL/min/1.73 m(2). RESULTS: There were significant correlations between measured Ccr and 1/serum creatinine (R = 0.51, P < 0.001) and 1/serum cystatin C (R = 0.25, P = 0.028). The difference between false negative rates of serum creatinine (93.33%) and cystatin C (80%) in the detection of renal dysfunction was significant (P = 0.032). Receiver operating characteristic curve analysis illustrated that area under the curve of serum creatinine and cystatin C for detecting renal dysfunction were 0.711 and 0.607, respectively; however, this difference was not significant (P = 0.222). CONCLUSIONS: Our data demonstrated that serum cystatin C is not superior to serum creatinine in the early detection of renal dysfunction in critically ill patients. PMID- 24783173 TI - Lower Urinary Tract Urological Abnormalities and Urodynamic Findings of Physiological Urinary Incontinence Versus Non-mono Symptomatic Nocturnal Enuresis in Children. AB - BACKGROUND: Although 98% of children attain daytime bladder control by three years of age, urinary incontinence is regarded physiological up to the fifth year of life. OBJECTIVES: This study aimed to assess whether lower urinary tract urological abnormalities and abnormal urodynamic findings are infrequent in children with physiological urinary incontinence in contrast to those with non monosymptomatic nocturnal enuresis (NMNE). PATIENTS AND METHODS: During a three year period (2007-2009), 66 neurologically normal children including 51 children (34 girls, 17 boys) older than five years of age with NMNE and intermittent daytime incontinence, and 15 children with physiological urinary incontinence (eight girls and seven boys) aged four to five years of age without any known urological abnormalities were enrolled in the study. Patients with neurologic deficits or known urological anomalies were excluded from the study. Kidney bladder ultrasonography, voiding cystourethrography (VCUG), and urodynamic studies were performed to evaluate the anatomy of urinary tract and bladder function. RESULTS: Urinary tract infection was found in 23 (34.8%) children, 17 (33.3%) and 6 (40%) patients with NMNE and physiological urinary incontinence, respectively. Out of 48 patients who underwent VCUG, vesicoureteral reflux (VUR) was found in seven and eight children younger and older than five years of age, respectively. Abnormal urodynamic findings were reported in 5 (62.5%) of eight children younger than five-year-old, and 14 (63.6%) of 22 patients older than 5 year-old. CONCLUSIONS: VUR might be more frequent in children with physiological urinary incontinence than the normal population, and might be as common as NMNE with intermittent daytime incontinence. PMID- 24783174 TI - Perception about transplant of rural and urban patients with chronic kidney disease; a qualitative study. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem with increasing incidence and prevalence and associated expenses. OBJECTIVES: To explore different perceptions of rural and urban patients with chronic kidney disease (CKD) about kidney transplant. PATIENTS AND METHODS: We conducted four focus groups, each including 5 or 6 patients with stage 5 CKD or end stage renal disease living in a rural or urban area. Open-ended questions probed patient familiarity with kidney transplant, perceptions of benefits of kidney transplant, perceived barriers to kidney transplant, and views about living donation. All the sessions were recorded and professionally transcribed. Responses were pooled, de identified, and analyzed using qualitative thematic content analysis. RESULTS: Urban patients were more likely to receive supplementary information and being strongly encouraged by their nephrologists to seek transplant. All participants acknowledged "independence" as the main advantage of transplantation. Increased freedom to travel and improved life expectancy were mentioned only among the urban groups. The main themes in all groups regarding perceived barriers to transplant were the tedious pre-transplant testing and workup expenses. Among rural groups, there was a perception that distance from transplant centers impedes transplant evaluation. Religious reasons favoring and opposing transplant were mentioned by participants in a rural group. Some members contended that since illness is God's will, we should not change it. Others in the same group argued that "God is not ready for us to give up". Praise and gratitude for the living donor were expressed in all groups, but concerns about donor's outcome were discussed only within the rural groups. In discussing preference about known or anonymous donors, members of an urban group mentioned favoring an anonymous donor, citing unease with a sense of life-long indebtedness. CONCLUSIONS: Observed differences in perceptions among rural and urban patients about aspects of transplant may contribute to geographic disparities in transplant. The findings could be helpful to guide future individualized, culturally sensitive educational interventions about transplant for patients with CKD. PMID- 24783175 TI - The prognosis and treatment of primary thyroid cancer occurred in breast cancer patients: comparison with ordinary thyroid cancer. AB - PURPOSE: Due to the increased prevalence of thyroid cancer, it has been frequently detected in breast cancer patients recently. The aim of this study was to evaluate the clinicopathologic characteristics of thyroid cancer in breast cancer patients with respect to prognosis and treatment. METHODS: From August 1998 to September 2012, 101 breast cancer patients were diagnosed with thyroid cancer (BT group). One hundred ninety-three female patients with a thyroid malignancy that underwent thyroidectomy in 2008 were recruited as controls (oT group). The clinicopathologic results of these two groups were compared. RESULTS: Patients were older (51.40 vs. 47.16, P < 0.001), mean tumor size was smaller (0.96 cm vs. 1.43 cm, P < 0.001), and extrathyroidal extension was less common in the BT group. In both groups, papillary thyroid carcinoma was the most common type of thyroid malignancy. T and N classifications of thyroid cancer were less severe in the BT group, but group TNM stages were similar. Endoscopic thyroid surgery was performed in 12.9% of patients in the BT group and in 6.7% of patients in the oT group. Postoperative radioactive iodine ablation was performed less often in the BT group (P < 0.001). Group recurrence rates were not significantly different. CONCLUSION: Thyroid cancer in breast cancer patients was diagnosed at earlier status than ordinary thyroid cancer. However, the prognosis of thyroid cancer in breast cancer patients was not superior to that in patients with thyroid cancer alone. Radioactive iodine ablation was performed less often and endoscopic surgery could be performed in breast cancer patients. PMID- 24783176 TI - Single incision laparoscopic cholecystectomy using Konyang Standard Method. AB - PURPOSE: Single incision laparoscopic cholecystectomy (SILC) is a minimally invasive surgery that is growing rapidly among surgical procedures. However, there is no standard method for SILC. Therefore, we evaluated the adequacy and feasibility of SILC using Konyang Standard Method. METHODS: We retrospectively reviewed our series of 307 SILCs performed between April 2010 and August 2012. Initially we excluded the patients who were more than 70 years old, had cardiologic or pulmonologic problems and complications of acute cholecystitis. After 50 cases, we did not apply the exclusion criteria. We performed SILC by Konyang Standard Method using three-trocar single port (hand-made) and long articulated instruments. RESULTS: Three hundred and seven patients underwent SILC. Male were 131 patients and female were 176 patients. Mean age was 51.6 +/- 13.7 years old and mean body mass index was 24.8 +/- 3.6 kg/m(2). Ninety-three patients had histories of previous abdominal operation. Patient's pathologies included: chronic cholecystitis (247 cases), acute cholecystitis (30 cases), gall bladder (GB) polyps (24 cases), and GB empyema (6 cases). Mean operating time was 53.1 +/- 25.4 minutes and mean hospital stay was 2.9 +/- 3.4 days. There were four cases of 3-4 ports conversion due to cystic artery bleeding. Complications occurred in 5 cases including wound infection (2 cases), bile duct injury (1 case), duodenal perforation (1 case), and umbilical hernia (1 case). CONCLUSION: SILC using Konyang Standard Method is safe and feasible. Therefore, our standard procedure can be applied to almost all benign GB disease. PMID- 24783177 TI - Outcomes of living donor liver transplantation using elderly donors. AB - PURPOSE: Living donor liver transplantation (LDLT) using elderly donors is increasing in frequency in response to organ shortage. However, elderly donor graft has been reported to negatively affect graft patency and patient survival. METHODS: We retrospectively reviewed the medical records of 604 patients who underwent LDLT at Seoul St. Mary's Hospital, The Catholic University of Korea between May 1999 and September 2012. Elderly donors were defined as those >=55 years of age. Here, we evaluate the survival differences and causes of death of recipients of elderly donor grafts. RESULTS: THE OVERALL MORTALITY RATE OF THE RECIPIENTS WAS SIGNIFICANTLY HIGHER IN THE ELDERLY DONOR GROUP (GROUP A) THAN IN THE YOUNGER DONOR GROUP (GROUP B: 46.2% vs. 18.1%, P = 0.004). The survival length of group A was significantly shorter than that of group B (31.2 +/- 31.3 and 51.4 +/- 40.8 months, P = 0.014). The significantly common causes of death in group A were biliary (41.7%) and arterial complication (16.7%), and it was higher than those in group B (P = 0.000 and P = 0.043, respectively). CONCLUSION: LDLT using elderly donors could induce more serious complications and higher mortality rates than those at using younger donors. As such, careful donor selection is needed, especially with regard to assessing the condition of potential elderly donor livers. Furthermore, a large-volume and multicenter study of complications and outcomes of LDLT using elderly donor liver is required. PMID- 24783178 TI - A multicenter experience with generic mycophenolate mofetil conversion in stable liver transplant recipients. AB - PURPOSE: Generic substitution of brand-name medications can lead to significant cost savings and is an accepted medical practice. This study evaluated clinical and safety outcomes among liver transplant recipients whose mycophenolate mofetil (MMF) was converted from the brand-name formulation (Cellcept) to a generic formulation (My-rept). METHODS: Clinical data from multiple centers were prospectively collected for determination of complications, safety, and quality of life after in 154 clinically stable, adult liver transplant recipients whose MMF was converted to a generic formulation between April 2010 and September 2012. This protocol was approved by Institutional Review Boards of all involved sites. RESULTS: In eight patients (5.19%), nine instances of drug-related complications occurred after medication conversion. Half of these complications were gastrointestinal disorders (n = 4), and most (7 of 9) were mild. No significant differences were noted in mean pre- and postconversion gastrointestinal symptoms via a rating system (8.9 vs. 10.4) or gastrointestinal quality-of-life index scores (125.6 vs. 123.1). More than 90% of patients reported a status of "about the same" when questioned about the brand-name and generic formulation using the Patient Overall Treatment Effect and Investigator Overall Treatment Effect measures. The incidence of serious adverse events was 5.8%. Acute rejection occurred in two patients, with no graft loss or death. CONCLUSION: Clinical experience as well as research data showed that generic MMF was comparable in efficacy to the brand-name drug. Given the lack of adverse events and the safety findings, conversion from brand-name MMF to generic MMF should be encouraged. PMID- 24783179 TI - Laparoscopic resection for 125 gastroduodenal submucosal tumors. AB - PURPOSE: The present study aims to elucidate the treatment strategies of laparoscopic resection for gastroduodenal submucosal tumors (SMTs). METHODS: Data of 125 gastroduodenal STMs were collected retrospectively resected from August, 2004 to February, 2013. Surgical outcomes according to tumor locations, pathologic results and survival data for gastrointestinal stromal tumors (GISTs) were collected and analyzed. RESULTS: There were 55 male and 70 female patients with mean age 57.9 +/- 12.7 years old. Mean tumor size of gastric SMTs was 2.7 +/ 1.64 cm (range, 0.4-8.5 cm). GIST was the most common (n = 70, 56%). Regarding the tumor location, all the fundic lesions were GISTs and leiomyoma was occurred 58.8% of cardiac lesions. Ectopic pancreas and schwannomas were mostly located at body portion, 73% and 80%, respectively. SMTs located at duodenal bulb comprise 4 GISTs and 3 carcinoids. Surgical results comparing between lesions located at cardia, near-pylorus and else had no difference in operation time, hospital stay and complications. In terms of outcome of GIST, all patients underwent curative resection except one case of peritoneal sarcomatosis. There was one recurrence in a high risk group following resection. The cumulative 5-year disease free survival rate was 93.5% in all GISTs. There were two postoperative complications, one gastric outlet obstruction and one leakage following wedge resection. CONCLUSION: Laparoscopic wedge resection is a safe and feasible procedure for the small to medium sized gastroduodenal SMTs even their locations are near cardia or pylorus. PMID- 24783180 TI - The nutritional risk is a independent factor for postoperative morbidity in surgery for colorectal cancer. AB - PURPOSE: The authors evaluate the prevalence of malnutrition and its effect on the postoperative morbidity of patients after surgery for colorectal cancer. METHODS: Three hundred fifty-two patients were enrolled prospectively. Nutritional risk screening 2002 (NRS 2002) score was calculated through interview with patient on admission. Clinical characteristics, tumor status and surgical procedure were recorded. RESULTS: The prevalence of patients at nutritional risk was 28.1 per cent according to the NRS 2002. The rate of postoperative complication was 27%. There was a significant difference in postoperative complication rates between patients at nutritional risk and those not at risk (37.4% vs. 22.9%, P = 0.006). Nutritional risk was identified as an independent predictor of postoperative complications (odds ratio, 3.05; P = 0.045). Nutritional risk increased the rate of anastomotic leakage (P = 0.027) and wound infection (P = 0.01). CONCLUSION: NRS may be a prognostic factor for postoperative complication after surgery for colorectal cancer. A large scaled prospective study is needed to confirm whether supplementing nutritional deficits reduces postoperative complication rates. PMID- 24783181 TI - The availability of computed tomography for pulmonary staging in colorectal cancer. AB - PURPOSE: Chest computed tomography is performed frequently for the preoperative pulmonary staging in colorectal cancers (CRCs) regardless of the result of chest x-ray (CXR) due to its high sensitivities and specificities. The advancement of CT technology detects more indeterminate lung lesions that may require further investigations, referrals and follow-up. The aim of this study was to suggest a guideline for performing chest CT for preoperative pulmonary staging in colorectal cancer. METHODS: We performed a retrospective analysis of the records of patients who had chest CT preformed without the evidence of metastasis on CXR for preoperative pulmonary staging. RESULTS: Of 21 patients with metastatic nodules on chest CT, 23.8% showed pulmonary metastasis on positron emission tomography, 47.6% showed extrapulmonary metastasis on preoperative evaluation and 61.9% showed elevated serum carcinoembryonic antigen level above 10 ng/mL. These results showed significant value compared to patients without metastatic nodules. But, in analyzing patients with or without indeterminate nodules in the three contents listed above, there was no significance. CONCLUSION: In the patients with CRC who show normal CXR and exhibit positivity in PET, preoperative extrapulmonary metastasis and elevated serum CEA level above 10 ng/mL preoperatively, chest CT would be helpful in preoperative staging. PMID- 24783182 TI - Left paraduodenal hernia combined with acute cholecystitis. AB - Paraduodenal hernia is a rare congenital malformation. Management consists of reduction of the herniated intestine and repair of the defect. A 74-year-old woman presented to the Emergency Department with persistent right upper quadrant pain that began 3 hours ago. Physical examination revealed tenderness at right upper quadrant of abdomen. Computed tomography revealed multiple gallstones with gallbladder wall thickening, marked dilatation of stomach and duodenum and a sac like mass of small bowel loops to left of ligament of Treitz suggesting acute cholecystitis and left paraduodenal hernia. Laparoscopic exploration of abdomen was performed and cholecystectomy, bowel reduction, and closure of defect with intracorporeal interrupted suturing were performed. For left paraduodenal hernia without bowel necrosis, laparoscopic reduction of incarcerated bowel and closure of hernial orifice are technically feasible and may be the surgical method of choice because of its minimal invasiveness and aesthetic advantage. PMID- 24783183 TI - Bowel perforation associated sunitinib therapy for recurred gastric gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Several recent findings that there are activating mutations in the KIT and PDGFRA (platelet-derived growth factor receptor-alpha) genes of GISTs provide the rationale for using targeted therapies such as imatinib or sunitinib. Sunitinib, an oral multitargeted receptor tyrosine kinase inhibitor that inhibits kinases such as KIT, PDGFR (platelet-derived growth factor recepter), and VEGFR (vascular endothelial growth factor receptor), was recently approved for the treatment of imatinib-refractory GIST. Sunitinib is generally well tolerated and has an acceptable toxicity profile; an adverse event such as bowel perforation is rare. We present a patient with imatinib-refractory GIST who was successfully treated using sunitinib, but developed bowel perforation. The mechanism involved in bowel perforation associated with sunitinib is unknown. However, we presume that in our patient, the dramatic reduction in disseminated peritoneal metastases and bowel invasion of recurrent GIST during sunitinib treatment might have resulted in the bowel perforation. PMID- 24783184 TI - Laparoscopy in the surgical management of the non-palpable testis. AB - INTRODUCTION: To demonstrate that laparoscopic intervention should be considered as the initial surgical approach in the management of the non-palpable testis (NPT). METHODS: From 2007 to 2011, 100 testicular units underwent same surgeon laparoscopic management for NPT. Diagnostic laparoscopy was performed in all NPT and intra-abdominal testes (IAT) were managed by laparoscopic orchiopexy if low, laparoscopic Fowler-Stephens technique if high, and laparoscopic orchiectomy if atrophic. Percutaneous access to the abdomen was performed in most cases and laparoscopic management was performed with three 5 mm ports. We compared patient's age, race, pre/post-operative exam, pre-operative work up, and IAT location upon laparoscopic intervention with surgical outcome. Fisher's exact test for two independent proportions was used for statistical analysis and reported our results. RESULTS: One hundred testicular units underwent diagnostic laparoscopy for NPT. All patients were from Puerto Rican descent. 55.0% were found to be intra-abdominal and were subdivided into groups according to surgical intervention. Mean post-operative follow-up was 24 months. Patients 24 months of age or younger undergoing diagnostic laparoscopy for NPT had a statistically significant probability of resulting in successful laparoscopic orchiopexy as opposed to laparoscopic orchiectomy due to an atrophied IAT (n = 55 testicular units, p < 0.05). No laparoscopic related complications were reported. CONCLUSION: Our findings support the use of an initial laparoscopic approach in the NPT as the majority of these patients will have IAT, avoiding unnecessary inguinal and scrotal explorations. We also recommend that patients with IAT should undergo laparoscopic orchiopexy prior to 2 years of age to increase probability of successful management. Further studies focusing in patients with NPT are needed in the future to confirm our findings. PMID- 24783185 TI - Inflammatory injury to the neonatal brain - what can we do? AB - Perinatal brain damage is one of the leading causes of life long disability. This damage could be hypoxic-ischemic, inflammatory, or both. This mini-review discusses different interventions aiming at minimizing inflammatory processes in the neonatal brain, both before and after insult. Current options of anti inflammatory measures for neonates remain quite limited. We describe current anti inflammatory intervention strategies such as avoiding perinatal infection and inflammation, and reducing exposure to inflammatory processes. We describe the known effects of anti-inflammatory drugs such as steroids, antibiotics, and indomethacin, and the possible anti-inflammatory role of other substances such as IL-1 receptor antagonists, erythropoietin, caffeine, estradiol, insulin-like growth factor, and melatonin as well as endogenous protectors, and genetic regulation of inflammation. If successful, these may decrease mortality and long term morbidity among term and pre-term infants. PMID- 24783186 TI - Body composition and pulmonary function in cystic fibrosis. AB - BACKGROUND: Lower body mass index (BMI) is associated with worse pulmonary function in cystic fibrosis (CF). HYPOTHESIS: lean body mass (LBM) is more strongly associated with pulmonary function than BMI is. METHODS: Anthropometrics, body composition by dual x-ray absorptiometry, and pulmonary function were determined in pancreatic insufficient CF (PI-CF) youth. Sex and age adjusted Z-scores (BMI-Z, LBMI-Z, FMI-Z) were generated for CF and controls. (1) Associations of BMI-Z with LBMI-Z and FMI-Z and (2) age-adjusted associations of BMI-Z, LBMI-Z, and FMI-Z with FEV1%-predicted were tested. RESULTS: Two hundred eight PI-CF subjects had lower BMI-Z, LBMI-Z, and FMI-Z compared to 390 controls. BMI-Z was associated with lower LBMI-Z (p < 0.0001) in PI-CF. In females, LBMI-Z and BMI-Z were positively associated with FEV1%-predicted; this relationship did not persist for FMI-Z after adjustment for LBMI-Z. In males, only LBMI-Z and BMI Z were associated with FEV1%-predicted. CONCLUSION: In PI-CF youth, deficits in LBM were apparent. At lower BMI percentiles, BMI may not accurately depict LBM in PI-CF. In under-nourished PI-CF youth, this preservation of FM in preference to LBM is relevant since LBMI-Z, but not FMI-Z, is positively associated with FEV1% predicted. Lean body mass index is more strongly associated with lung function compared to BMI, especially in the under-nourished child and adolescent with PI CF. PMID- 24783187 TI - A single-item self-rated health measure correlates with objective health status in the elderly: a survey in suburban beijing. AB - INTRODUCTION: The measurement of health status of the elderly remains one important topic. Self-rated health status (SRH) is considered to be a simple indicator to measure the health status of the old population. But some researchers still take a skeptical view about its reliability. This study aims to investigate the association between SRH indicator and health status of the elderly and discuss its subsequent public health implications. METHODS: In a total 1096 people who were 60 years of age or older from 1784 households from a suburban area of Beijing were interviewed using multistage stratified cluster sampling. SRH was measured by a single question "please choose one point in this 0-100 scale, which can best represent your health today." The disease status and physical functional status were also obtained. A multiple linear regression was conducted to test the associate between SRH and individual's disease/functional status. RESULTS: The average of SRH scores of the elderly was 72.49 +/- 15.64 (on a 1-100 scale). The SRH scores declined not only with the severity of self reported mental/disease status, but also with the decrease of physical functional status. Multiple linear regression showed that after adjustment for other variables, 2-week sickness, chronic diseases, hospitalization, and ability of self-care (washing and dressing) were able to explain 35% of the variation in SRH among the elderly. Among them, disease status and self-care ability were the most powerful predictor of SRH. After adjusting other variables, physical functional status could explain only 5% of the variation in SRH. CONCLUSION: Self-rated health reflects the disease/functional health status of the elderly. It is an easy-to-implement variable and it can reduce both recall bias and investigator bias, thus being widely used in health surveys. It is a cost-effective means of measuring the health status. However, the comparability of SRH in different populations should be studied in future. PMID- 24783188 TI - Prevention and treatment of traumatic brain injury due to rapid-onset natural disasters. AB - The prevention and treatment of traumatic brain injury (TBI) attributable to rapid-onset natural disasters is a major challenge confronting disaster preparedness planners and emergency medical personnel responding to those incidents. The kinetic energy released by rapid-onset natural disasters such as earthquakes, hurricanes or typhoons, and tornadoes can cause mild, moderate, or severe TBIs. As a result, neurotrauma is a major risk factor for mortality and morbidity outcomes within the spatial domain impacted by a rapid-onset natural disaster. This review article elucidates major challenges associated with immediate emergency medical response, long-term care, and prevention of post event increases in pediatric TBIs because of child abuse when rapid-onset natural disasters occur. PMID- 24783189 TI - The "Arab World" is Not a Useful Concept When Addressing Challenges to Public Health, Public Health Education, and Research in the Middle East. PMID- 24783190 TI - Health promotion and disease prevention strategies in older adults with intellectual and developmental disabilities. AB - The rapid growth in the number of individuals living with intellectual and developmental disabilities (IDD) along with their increased longevity present challenges to those concerned about health and well-being of this unique population. While much is known about health promotion and disease prevention in the general geriatric population, far less is known about those in older adults with IDD. Effective and efficient health promotion and disease prevention strategies need to be developed and implemented for improving the health and quality of life of older adults living with IDD. This is considered to be challenging given the continued shrinkage in the overall health care and welfare system services due to the cut in the governmental budget in some of the western countries. The ideal health promotion and disease prevention strategies for older adults with IDD should be tailored to the individuals' health risks, address primary and secondary disease prevention, and prevent avoidable impairments that cause premature institutionalization. Domains of intervention should include cognitive, mental and physical health, accommodations, workplace considerations, assistive technology, recreational activities, and nutrition. PMID- 24783191 TI - A gaussian mixture model approach for estimating and comparing the shapes of distributions of neuroimaging data: diffusion-measured aging effects in brain white matter. AB - Neuroimaging signal intensity measures underlying physiology at each voxel unit. The brain-wide distribution of signal intensities may be used to assess gross brain abnormality. To compare distributions of brain image data between groups, t tests are widely applied. This approach, however, only compares group means and fails to consider the shapes of the distributions. We propose a simple approach for estimating both subject- and group-level density functions based on the framework of Gaussian mixture modeling, with mixture probabilities that are testable between groups. We demonstrate this approach by application to the analysis of fractional anisotropy image data for assessment of aging effects in white matter. PMID- 24783192 TI - Continued vigilance - development of an online evaluation tool for assessing preparedness of medical facilities for biological events. AB - OBJECTIVE: Effective response to biological events necessitates ongoing evaluation of preparedness. This study was a bilateral German-Israeli collaboration aimed at developing an evaluation tool for assessing preparedness of medical facilities for biological events. METHODS: Measurable parameters were identified through a literature review for inclusion in the evaluation tool and disseminated to 228 content experts in two modified Delphi cycles. Focus groups were conducted to identify psychosocial needs of the medical teams. Table-top and functional exercises were implemented to review applicability of the tool. RESULTS: One hundred seventeen experts from Germany and Israel participated in the modified Delphi. Out of 188 parameters that were identified, 183 achieved a consensus of >75% of the content experts. Following comments recommended in the Delphi cycles, and feedback from focus groups and hospital exercises, the final tool consisted of 172 parameters. Median level of importance of each parameter was calculated based on ranking recommended in the Delphi process. Computerized web-based software was developed to calculate scores of preparedness for biological events. CONCLUSION: Ongoing evaluation means, such as the tool developed in the study, can facilitate the need for a valid and reliable mechanism that may be widely adopted and implemented as quality assurance measures. The tool is based on measurable parameters and indicators that can effectively present strengths and weaknesses in managing a response to a public health threat, and accordingly, steps can be implemented to improve readiness. Adoption of such a tool is an important component of assuring public health and effective emergency management. PMID- 24783193 TI - Evaluation of 12-lipoxygenase (12-LOX) and plasminogen activator inhibitor 1 (PAI 1) as prognostic markers in prostate cancer. AB - In carcinoma of prostate, a causative role of platelet 12-lipoxygenase (12-LOX) and plasminogen activator inhibitor 1 (PAI-1) for tumor progression has been firmly established in tumor and/or adjacent tissue. Our goal was to investigate if 12-LOX and/or PAI-1 in patient's plasma could be used to predict outcome of the disease. The study comprised 149 patients (age 70+/-9) divided into two groups: a study group with carcinoma confirmed by positive biopsy of prostate (n=116) and a reference group (n=33) with benign prostatic hyperplasia (BPH). The following parameters were determined by the laboratory test in plasma or platelet rich plasma: protein level of 12-LOX, PAI-1, thromboglobulin (TGB), prostate specific antigen (PSA), C-reactive protein (CRP), hemoglobin (HGB, and hematocrit (HCT), as well as red (RBC) and white blood cells (WBC), number of platelets (PLT), international normalized ratio of blood clotting (INR), and activated partial thromboplastin time (APTT). The only difference of significance was noticed in the concentration of 12-LOX in platelet rich plasma, which was lower in cancer than in BPH group. Standardization to TGB and platelet count increases the sensitivity of the test that might be used as a biomarker to assess risk for prostate cancer in periodically monitored patients. PMID- 24783194 TI - Alleviation of plasma homocysteine level by phytoestrogen alpha-zearalanol might be related to the reduction of cystathionine beta-synthase nitration. AB - Hyperhomocysteinemia is strongly associated with cardiovascular diseases. Previous studies have shown that phytoestrogen alpha-zearalanol can protect cardiovascular system from hyperhomocysteinemia and ameliorate the level of plasma total homocysteine; however, the underlying mechanisms remain to be clarified. The aim of this research is to investigate the possible molecular mechanisms involved in ameliorating the level of plasma homocysteine by alpha zearalanol. By the successfully established diet-induced hyperhomocysteinemia rat models, we found that, after alpha-zearalanol treatment, the activity of cystathionine beta-synthase, the key enzyme in homocysteine metabolism, was significantly elevated and level of nitrative stress in liver was significantly reduced. In correlation with this, results also showed a decreased nitration level of cystathionine beta-synthase in liver. Together data implied that alleviation of plasma homocysteine level by phytoestrogen alpha-zearalanol might be related to the reduction of cystathionine beta-synthase nitration. PMID- 24783195 TI - HIV prevention services and testing utilization behaviors among men who have sex with men at elevated risk for HIV in Chongqing, China. AB - OBJECTIVE: To investigate barriers and correlates of the use of HIV prevention services and HIV testing behaviors among men who have sex with men in Chongqing. METHODS: Three consecutive cross-sectional surveys provided demographic, sexual behavior, HIV/syphilis infection, HIV prevention service, and testing behavior data. RESULTS: Of 1239 participants, 15.4% were infected with HIV, incidence was 12.3 per 100 persons/year (95% CI: 9.2-15.3), 38% of the participants reported ever having unprotected insertive anal sex, 40% ever received free condom/lubricants in the past year, and 27.7% ever obtained free sexually transmitted infection examination/treatment in the past year. Multivariable logistic regression revealed that lower levels of HIV/AIDS related stigmatizing/discriminatory attitudes, full-time jobs, and sex debut with men at a younger age were independently associated with use of free condom/lubricants. Large social networks, higher incomes, and sexual debut with men at a younger age were associated with use of any HIV prevention and HIV testing services. Lower levels of stigmatizing/discriminatory attitudes were also associated with HIV testing. Fearing needles and being unaware of the venues for testing were top barriers for testing service utilization. CONCLUSION: It is imperative to address HIV/AIDS related stigmatizing/discriminatory attitudes and other barriers while delivering intervention and testing services. PMID- 24783196 TI - Male and couple fertility impairment due to HPV-DNA sperm infection: update on molecular mechanism and clinical impact--systematic review. AB - Recent evidences identify Human Papillomavirus (HPV) sperm infection as a possible cause of male and couple infertility. It acts through different mechanisms at various steps of human conception and early gestational development. We performed a systematic review to assess the role of HPV semen infection on male and couple infertility. Analysis of available and eligible data does not permit us to fund clear evidences about clinical impact of HPV infection on fertility, although sperm parameters impairment is the most widely recognized effect. Regarding biomolecular implications, the available data are often conflicting. More studies are required to define the role of HPV sperm infection in clinical practice. The great majority of evidences are obtained by in vitro studies and this fact represents a limitation for the clinical management of HPVDNA sperm infection. Understanding the biological significance of HPV-DNA semen infection could permit us to explain most of the idiopathic male and couple infertility, leading to a better management of infertile men and a better timing for sperm banking storage before ART cycles. PMID- 24783197 TI - Cerebral vasospasm in patients over 80 years treated by coil embolization for ruptured cerebral aneurysms. AB - OBJECT: The effect on clinical outcomes of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage (SAH) in patients over 80 years who underwent coil embolization was evaluated. METHODS: Forty-four cases were reviewed and divided into two groups according to patient age: Group A, 79 years or younger, and Group B, 80 or older. Patient characteristics, prevalence of symptomatic vasospasm, modified Rankin Scale (mRS) scores at discharge and frequency of symptomatic vasospasm in patients with mRS scores of 3-6 were analyzed. RESULTS: Thirty-two (73%) of the 44 cases were categorized as Group A and 12 (27%) as Group B. Group B had a significantly higher prevalence of symptomatic vasospasm compared to Group A (P=0.0040). mRS scores at discharge were significantly higher in Group B than in Group A (P=0.0494). Among cases with mRS scores of 3-6, there was a significantly higher frequency of symptomatic vasospasm in Group B than in Group A (P=0.0223). CONCLUSIONS: In our cohort of aneurysmal SAH patients treated by coil embolization, patients over 80 years of age were more likely to suffer symptomatic vasospasm, which significantly correlated with worse clinical outcomes, than those 79 years and under. PMID- 24783198 TI - Change of muscle architecture following body weight support treadmill training for persons after subacute stroke: evidence from ultrasonography. AB - Although the body weight support treadmill training (BWSTT) in rehabilitation therapy has been appreciated for a long time, the biomechanical effects of this training on muscular system remain unclear. Ultrasonography has been suggested to be a feasible method to measure muscle morphological changes after neurological diseases such as stroke, which may help to enhance the understanding of the mechanism underlying the impaired motor function. This study investigated the muscle architectural changes of tibialis anterior and medial gastrocnemius in patients after subacute stroke by ultrasound. As expected, we found the effect of BWSTT on the muscular system. Specifically, the results showed larger pennation angle and muscle thickness of tibialis anterior and longer fascicle length of medial gastrocnemius after the training. The findings of this study suggest that the early rehabilitation training of BWSTT in subacute stage of stroke provides positive changes of the muscle architecture, leading to the potential improvement of the force generation of the muscle. This may not only help us understand changes of subacute stroke in muscular system but also have clinical implications in the evaluation of rehabilitation training after neurological insults. PMID- 24783200 TI - New advances of preimplantation and prenatal genetic screening and noninvasive testing as a potential predictor of health status of babies. AB - The current morphologically based selection of human embryos for transfer cannot detect chromosome aneuploidies. So far, only biopsy techniques have been able to screen for chromosomal aneuploidies in the in vitro fertilization (IVF) embryos. Preimplantation genetic diagnosis (PGD) or screening (PGS) involves the biopsy of oocyte polar bodies or embryonic cells and has become a routine clinical procedure in many IVF clinics worldwide, including recent development of comprehensive chromosome screening of all 23 pairs of chromosomes by microarrays for aneuploidy screening. The routine preimplantation and prenatal genetic diagnosis (PND) require testing in an aggressive manner. These procedures may be invasive to the growing embryo and fetus and potentially could compromise the clinical outcome. Therefore the aim of this review is to summarize not only the new knowledge on preimplantation and prenatal genetic diagnosis in humans, but also on the development of potential noninvasive embryo and fetal testing that might play an important role in the future. PMID- 24783199 TI - Complete workplace indoor smoking ban and smoking behavior among male workers and female nonsmoking workers' husbands: a pseudo cohort study of Japanese public workers. AB - A pseudo cohort study using national cross-sections (2001, 2004, 2007, and 2010) was conducted to examine differences in smoking prevalence under different smoking ban policies such as a complete workplace indoor smoking ban (early or recent implementation) and a partial smoking ban among male public workers and husbands of female nonsmoking public workers. The effectiveness of smoking bans was estimated by difference-in-differences (DID) with age group stratification. The results varied considerably by age and implementation period. Although DID estimates (positive value of DID estimate represents smoking cessation percentage) for both smoking bans on total male smoking were not significant, the over-40 age group indicated a significant DID estimate of 5.0 (95% CI: 0.2, 9.8) for the recent smoking ban. For female workers' husbands' smoking, the over-40 age group indicated positive, but not significant, DID estimates for the early and recent smoking bans of 7.2 (-4.7, 19.2) and 8.4 (-2.0, 18.7), respectively. A complete indoor workplace smoking ban, particularly one recently implemented among public office workers aged over 40, may reduce male workers' smoking and female workers' husbands' smoking compared with a partial smoking ban, but the conclusion remains tentative because of methodological weaknesses in the study. PMID- 24783201 TI - Acute ethanol-induced changes in edema and metabolite concentrations in rat brain. AB - The aim of this study is to describe the acute effects of EtOH on brain edema and cerebral metabolites, using diffusion weight imaging (DWI) and proton magnetic resonance spectroscopy ((1)H-MRS) at a 7.0T MR and to define changes in apparent diffusion coefficient (ADC) values and the concentration of metabolites in the rat brain after acute EtOH intoxication. ADC values in each ROI decreased significantly at 1 h and 3 h after ethanol administration. ADC values in frontal lobe were decreased significantly compared with other regions at 3 h. For EtOH/Cr+PCr and cerebral metabolites (Cho, Tau, and Glu) differing over time, no significant differences for Ins, NAA, and Cr were observed in frontal lobes. Regression analysis revealed a significant association between TSEtOH/Cr+PCr and TSCho, TSTau, TSGlu, and TSADC. The changes of ADC values in different brain regions reflect the process of the cytotoxic edema in vivo. The characterization of frontal lobes metabolites changes and the correlations between TSEtOH/Cr+PCr and TSCho, TSTau, and TSGlu provide a better understanding for the biological mechanisms in neurotoxic effects of EtOH on the brain. In addition, the correlations between TSEtOH/Cr+PCr and TSADC will help us to understand development of the ethanol-induced brain cytotoxic edema. PMID- 24783203 TI - Gastroprotective effect of ethanolic extract of Curcuma xanthorrhiza leaf against ethanol-induced gastric mucosal lesions in Sprague-Dawley rats. AB - Herbal medicines appeared promising in prevention of many diseases. This study was conducted to investigate the gastroprotective effect of Curcuma xanthorrhiza leaf in the rats induced gastric ulcer by ethanol. Normal and ulcer control received carboxymethycellulose (5 mL/kg) orally, positive control was administered with 20 mg/kg omeprazole (reference drug) and 2 groups were received 250 mg/kg and 500 mg/kg of the leaf extract, respectively. To induce of gastric ulcers formation, ethanol (5 mL/kg) was given orally to all groups except normal control. Gross ulcer areas, histology, and amount of prostaglandin E2, superoxide dismutase and malondialdehyde were assessed to determine the potentiality of extract in prevention against gastric ulcers. Oral administration of extract showed significant gastric protection effect as the ulcer areas was remarkably decreased. Histology observation showed less edema and leucocytes infiltration as compared with the ulcer control which exhibited severe gastric mucosa injury. Furthermore, the leaf extract elevated the mucus weight, level of prostaglandin E2 and superoxide dismutase. The extract also reduced malondialdehyde amount significantly. Results showed leaf extract of Curcuma xanthorrhiza can enhanced the gastric protection and sustained the integrity of gastric mucosa structure. Acute toxicity test did not showed any sign of toxicity (2 g/kg and 5 g/kg). PMID- 24783202 TI - Effect of antioxidants supplementation on aging and longevity. AB - If aging is due to or contributed by free radical reactions, as postulated by the free radical theory of aging, lifespan of organisms should be extended by administration of exogenous antioxidants. This paper reviews data on model organisms concerning the effects of exogenous antioxidants (antioxidant vitamins, lipoic acid, coenzyme Q, melatonin, resveratrol, curcumin, other polyphenols, and synthetic antioxidants including antioxidant nanoparticles) on the lifespan of model organisms. Mechanisms of effects of antioxidants, often due to indirect antioxidant action or to action not related to the antioxidant properties of the compounds administered, are discussed. The legitimacy of antioxidant supplementation in human is considered. PMID- 24783204 TI - RNA sequencing reveals upregulation of RUNX1-RUNX1T1 gene signatures in clear cell renal cell carcinoma. AB - In the past few years, therapies targeted at the von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC). However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq) was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA). We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC. PMID- 24783205 TI - Bacteriostatic antimicrobial combination: antagonistic interaction between epsilon-viniferin and vancomycin against methicillin-resistant Staphylococcus aureus. AB - Stilbenoids have been considered as an alternative phytotherapeutic treatment against methicillin-resistant Staphylococcus aureus (MRSA) infection. The combined effect of epsilon-viniferin and johorenol A with the standard antibiotics, vancomycin and linezolid, was assessed against MRSA ATCC 33591 and HUKM clinical isolate. The minimum inhibitory concentration (MIC) value of the individual tested compounds and the fractional inhibitory concentration index (FICI) value of the combined agents were, respectively, determined using microbroth dilution test and microdilution checkerboard (MDC) method. Only synergistic outcome from checkerboard test will be substantiated for its rate of bacterial killing using time-kill assay. The MIC value of epsilon -viniferin against ATCC 33591 and johorenol A against both strains was 0.05 mg/mL whereas HUKM strain was susceptible to 0.1 mg/mL of epsilon-viniferin. MDC study showed that only combination between epsilon-viniferin and vancomycin was synergistic against ATCC 33591 (FICI 0.25) and HUKM (FICI 0.19). All the other combinations (epsilon-viniferin-linezolid, johorenol A-vancomycin, and johorenol A-linezolid) were either indifferent or additive against both strains. However, despite the FICI value showing synergistic effect for epsilon-viniferin-vancomycin, TKA analysis displayed antagonistic interaction with bacteriostatic action against both strains. As conclusion, epsilon-viniferin can be considered as a bacteriostatic stilbenoid as it antagonized the bactericidal activity of vancomycin. These findings therefore disputed previous report that epsilon viniferin acted in synergism with vancomycin but revealed that it targets similar site in close proximity to vancomycin's action, possibly at the bacterial membrane protein. Hence, this combination has a huge potential to be further studied and developed as an alternative treatment in combating MRSA in future. PMID- 24783207 TI - Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. AB - Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures. PMID- 24783208 TI - Reoxygenation of asphyxiated newborn piglets: administration of 100% oxygen causes significantly higher apoptosis in cortical neurons, as compared to 21%. AB - OBJECTIVE: Evaluation of neuronal changes in an animal experimental model of normocapnic hypoxia- reoxygenation. MATERIALS AND METHODS: Fifty male piglets were the study subjects; normocapnic hypoxia was induced in 40 piglets and ten were sham-operated (controls). When bradycardia and/or severe hypotension occurred, reoxygenation was initiated. Animals were allocated in 4 groups according to the oxygen concentration, they were resuscitated with 18%, 21%, 40%, and 100% O2. Persisting asystole despite 10 minutes of cardiopulmonary resuscitation and return of spontaneous circulation were the endpoints of the experiment. Surviving animals were euthanized and brain cortex samples were collected, hematoxylin and eosin-stained, and examined for apoptotic bodies observing 10 consecutive high power fields. RESULTS: Histological examination of the control group did not show any pathological change. On the contrary, apoptosis of neurons was found in 87.5% of treated animals. When specimens were examined according to the oxygen concentration used for resuscitation, we found marked intergroup variability; a higher percentage of apoptotic neurons was observed in piglets of group 4 (100% oxygen) compared to the others (P=0.001). CONCLUSIONS: This preliminary data shows that normocapnic hypoxia and reoxygenation in Landrace/Large White piglets resulted in significant histological changes in the brain cortex. The degree of pathological changes in cortical neurons was significantly associated with the oxygen concentration used for reoxygenation, with a higher percentage of apoptotic neurons being observed in piglets reoxygenated with 100% compared to 18% O2 and to 21% O2. PMID- 24783206 TI - Optimal management of the critically ill: anaesthesia, monitoring, data capture, and point-of-care technological practices in ovine models of critical care. AB - Animal models of critical illness are vital in biomedical research. They provide possibilities for the investigation of pathophysiological processes that may not otherwise be possible in humans. In order to be clinically applicable, the model should simulate the critical care situation realistically, including anaesthesia, monitoring, sampling, utilising appropriate personnel skill mix, and therapeutic interventions. There are limited data documenting the constitution of ideal technologically advanced large animal critical care practices and all the processes of the animal model. In this paper, we describe the procedure of animal preparation, anaesthesia induction and maintenance, physiologic monitoring, data capture, point-of-care technology, and animal aftercare that has been successfully used to study several novel ovine models of critical illness. The relevant investigations are on respiratory failure due to smoke inhalation, transfusion related acute lung injury, endotoxin-induced proteogenomic alterations, haemorrhagic shock, septic shock, brain death, cerebral microcirculation, and artificial heart studies. We have demonstrated the functionality of monitoring practices during anaesthesia required to provide a platform for undertaking systematic investigations in complex ovine models of critical illness. PMID- 24783209 TI - Inflammatory reaction as determinant of foreign body reaction is an early and susceptible event after mesh implantation. AB - PURPOSE: To investigate and relate the ultrashort-term and long-term courses of determinants for foreign body reaction as biocompatibility predictors for meshes in an animal model. MATERIALS AND METHODS: Three different meshes (TVT, UltraPro, and PVDF) were implanted in sheep. Native and plasma coated meshes were placed bilaterally: (a) interaperitoneally, (b) as fascia onlay, and (c) as muscle onlay (fascia sublay). At 5 min, 20 min, 60 min, and 120 min meshes were explanted and histochemically investigated for inflammatory infiltrate, macrophage infiltration, vessel formation, myofibroblast invasion, and connective tissue accumulation. The results were related to long-term values over 24 months. RESULTS: Macrophage invasion reached highest extents with up to 60% in short-term and decreased within 24 months to about 30%. Inflammatory infiltrate increased within the first 2 hours, the reached levels and the different extents and ranking among the investigated meshes remained stable during long-term follow up. For myofibroblasts, connective tissue, and CD31+ cells, no activity was detected during the first 120 min. CONCLUSION: The local inflammatory reaction is an early and susceptible event after mesh implantation. It cannot be influenced by prior plasma coating and does not depend on the localisation of implantation. PMID- 24783210 TI - A novel electronic nose as adaptable device to judge microbiological quality and safety in foodstuff. AB - This paper presents different applications, in various foodstuffs, by a novel electronic nose (EN) based on a mixed metal oxide sensors array composed of thin films as well as nanowires. The electronic nose used for this work has been done, starting from the commercial model EOS835 produced by SACMI Scarl. The SENSOR Lab (CNR-INO, Brescia) has produced both typologies of sensors, classical MOX and the new technologies with nanowire. The aim of this work was to test and to illustrate the broad spectrum of potential uses of the EN technique in food quality control and microbial contamination diagnosis. The EN technique was coupled with classical microbiological and chemical techniques, like gas chromatography with mass spectroscopy (GC-MS) with SPME technique. Three different scenarios are presented: (a) detection of indigenous mould in green coffee beans, (b) selection of microbiological spoilage of Lactic Acid Bacteria (LAB), and (c) monitoring of potable water. In each case, the novel EN was able to identify the spoiled product by means of the alterations in the pattern of volatile organic compounds (VOCs), reconstructed by principal component analysis (PCA) of the sensor responses. The achieved results strongly encourage the use of EN in industrial laboratories. Finally, recent trends and future directions are illustrated. PMID- 24783211 TI - Trend analysis of visceral leishmaniasis at Addis Zemen health center, Northwest Ethiopia. AB - BACKGROUND: Visceral leishmaniasis (VL) is a systemic disease caused by the Leishmania donovani complex. It is one of the fatal diseases if left untreated. In Ethiopia, there are many VL endemic foci. The aim of this study was to determine the trends of VL in the study area. METHODOLOGY: A retrospective study was conducted at Addis Zemen health center from September 2005 to August 2011. Data were collected from laboratory registration book and entered and analyzed by using SPSS version 20 software and P value of <=0.05 was considered statistically significant. RESULT: A total of 7161 VL suspected cases were reported in the study area. The overall prevalence of VL was 2801 (39.1%). Of the 2801 VL positive cases, the highest annual prevalence, 988 (46.8%), was reported in 2005 but the trend gradually decreases. Majority of the VL confirmed cases were in the age groups of 5-14 years and males were more affected. CONCLUSION: The prevalence of VL in the study area was high in early 2005 but, gradually, the trend has been decreased and it becomes one of VL endemic foci in Ethiopia. PMID- 24783212 TI - Norfloxacin--toxicity for Zebrafish (Danio rerio) focused on oxidative stress parameters. AB - The aim of the study was to investigate the effects of subchronic exposure of zebrafish (Danio rerio) to a fluoroquinolone norfloxacin, using selected oxidative stress parameters as a target. Toxicity tests were performed on zebrafish according to the OECD Guidelines number 203 and number 215. In the Subchronic Toxicity Test, a significant (P < 0.01) increase in the activity of glutathione peroxidase, glutathione S-transferase, and catalase was found. In the test, norfloxacin did not affect lipid peroxidation and catalytic activity of glutathione reductase. From the results, we can conclude that norfloxacin has a negative impact on specific biochemical processes connected with the production of reactive oxygen species in fish tested. PMID- 24783213 TI - Effect of different rhBMP-2 and TG-VEGF ratios on the formation of heterotopic bone and neovessels. AB - Bioengineered bone substitutes might represent alternatives to autologous bone grafts in medically compromised patients due to reduced operation time and comorbidity. Due to the lack of an inherent vascular system their dimension is limited to the size of critical bone size defect. To overcome this shortcoming, the experiment tried to create heterotopic bone around vessels. In vivo, a two component fibrin and thrombin gel containing recombinant bone morphogenic protein (rhBMP-2) and transglutamate vascular endothelial growth factor (TG-VEGF) in different ratios, respectively, was injected into a dimensionally stable membrane tube, wrapped around the femoral vessel bundle in twelve New Zealand white rabbits. Sacrifice occurred eight weeks postoperatively. Microcomputed tomography of the specimens showed significantly increased bone volume in the rhBMP-2 to TG VEGF ratio of 10 to 1 group. Histology showed new bone formation in close proximity to the vessel bundle. Immunohistochemistry detected increased angiogenesis within the newly formed bone in the rhBMP-2 to TG-VEGF ratios of 3 to 1 and 5 to 1. Heterotopic bone was engineered in vivo around vessels using different rhBMP-2 and TG-VEGF ratios in a fibrin matrix injected into a dimensionally stable membrane tube which prevented direct contact with skeletal muscles. PMID- 24783214 TI - Significance of Lewis phenotyping using saliva and gastric tissue: comparison with the Lewis phenotype inferred from Lewis and secretor genotypes. AB - Lewis phenotypes using various types of specimen were compared with the Lewis phenotype predicted from Lewis and Secretor genotypes. This is the first logical step in explaining the association between the Lewis expression and Helicobacter pylori. We performed a study of the followings on 209 patients who underwent routine gastroscopy: erythrocyte and saliva Lewis phenotyping, gastric Lewis phenotyping by the tissue array, and the Lewis and Secretor genes genotyping. The results of phenotyping were as follows [Le(a-b-), Le(a+b-), Le(a-b+), and Le(a+b+), respectively, in order]: erythrocyte (12.4%, 25.8%, 61.2%, and 0.5%); saliva (2.4%, 27.3%, 70.3%, and 0.0%); gastric mucosa (8.1%, 6.7%, 45.5%, and 39.7%). The frequency of Le, le (59/508) , le (59/1067) , and le (59) alleles was 74.6%, 21.3%, 3.1%, and 1.0%, respectively, among 418 alleles. The saliva Lewis phenotype was completely consistent with the Lewis phenotype inferred from Lewis and Secretor genotypes, but that of gastric mucosa could not be predicted from genotypes. Lewis phenotyping using erythrocytes is only adequate for transfusion needs. Saliva testing for the Lewis phenotype is a more reliable method for determining the peripheral Lewis phenotype of an individual and the gastric Lewis phenotype must be used for the study on the association between Helicobacter pylori and the Lewis phenotype. PMID- 24783215 TI - Recombinant keratinocyte growth factor 1 in tobacco potentially promotes wound healing in diabetic rats. AB - Keratinocyte growth factor 1 (KGF1) is a growth factor that promotes epidermal cell proliferation, migration, differentiation, and wound repair. It is expressed at low levels in a form of inclusion body in E. coli. In order to increase its expression and activity, we produced tobacco plants expressing KGF1 via Agrobacterium-mediated transformation using a potato virus X (PVX)-based vector (pgR107). The vector contained the sequence encoding the KGF1 gene fused with a green florescence protein. The recombinant plasmid was introduced into leaf cells of Nicotiana benthamiana (a wild Australian tobacco) via Agrobacterium-mediated agroinfiltration. As determined by fluorescence and Western blot of leaf extracts, the KGF1 gene was correctly translated into the tobacco plants. The recombinant KGF1 was purified from plant tissues by heparin affinity chromatography, and cell proliferation in NIH/3T3 cells was stimulated by the purified KGF1. The purified KGF1 was also applied to the wounds of type-II diabetic rats. KGF1 had accumulated to levels as high as 530 MU g/g fresh weight in the leaves of agroinfected plants. We show that plant-derived KGF1 can promote the proliferation of NIH/3T3 cells and have significant effects on the type-II diabetic rat. The present findings indicated that KGF1 from tobacco maintains its biological activity, implying prospective industrial production in a plant bioreactor. PMID- 24783216 TI - The dynamic trends of HIV prevalence, risks, and prevention among men who have sex with men in Chongqing, China. AB - OBJECTIVE: This study was to characterize the continuously changing trends of HIV prevalence, risks, sexual behaviors, and testing behaviors among men who have sex with men (MSM) in Chongqing, China. METHODS: Five consecutive cross-sectional surveys were conducted among MSM in 2006, 2008, 2010, 2012, and 2013. Testing for HIV and syphilis was performed, and HIV risks, sexual behavior, prevention, and HIV testing behavior were collected using the same questionnaire. RESULTS: HIV prevalence increased from 13.0% to 19.7% from 2006 to 2013 (P = 0.004), with an increase of 1.0% per year. Syphilis prevalence peaked in 2008 with a positive rate of 11.6% and then experienced a sharp drop to 2.8% in 2012 and 2.9% in 2013. Percentage of those who ever received HIV testing in the last year increased from 17.0% to 43.3% (P < 0.001); condom use at the last anal intercourse and reported consistent condom use in the last 6 months increased from 51.8% to 71.0% (P < 0.001) and from 24.7% to 47.9% (P < 0.001), respectively. CONCLUSIONS: HIV continued to spread among MSM in Chongqing even when a decline in prevalence of syphilis and increase in awareness rate, condom use, and HIV testing seeking behaviors seemed to occur. PMID- 24783217 TI - Can ki-67 play a role in prediction of breast cancer patients' response to neoadjuvant chemotherapy? AB - BACKGROUND: Currently the choice of breast cancer therapy is based on prognostic factors. The proliferation marker Ki-67 is used increasingly to determine the method of therapy. The current study analyses the predictive value of Ki-67 in foreseeing breast cancer patients' responses to neoadjuvant chemotherapy. METHODS: This study includes patients with invasive breast cancer treated between 2008 and 2013. The clinical response was assessed by correlating Ki-67 to histological examination, mammography, and ultrasonography findings. RESULTS: The average Ki-67 value in our patients collectively (n = 77) is 34.9 +/- 24.6%. The average Ki-67 value is the highest with 37.4 +/- 24.0% in patients with a pCR. The Ki-67 values do not differ significantly among the 3 groups: pCR versus partial pathological response versus stable disease/progress (P = 0.896). However, Ki-67 values of patients with luminal, Her2 enriched, and basal-like cancers differed significantly from each other. Furthermore, within the group of luminal tumors Ki-67 values of patients with versus without pCR also differed significantly. CONCLUSION: Our data shows that the Ki-67 value predicts the response to neoadjuvant chemotherapy as a function of the molecular subtype, reflecting the daily routine concerning Ki-67 and its impressing potential and limitation as a predictive marker for neoadjuvant chemotherapy response. PMID- 24783218 TI - Ankylosing spondylitis and rheumatoid arthritis: serum levels of TNF-alpha and Its soluble receptors during the course of therapy with etanercept and infliximab. AB - The effects of the TNF- alpha blockers infliximab or etanercept on the levels of TNF- alpha , TNF-receptor 1 (TNF-R1), and TNF-receptor 2 (TNF-R2), as well as the levels of the inflammation markers CRP and IL-6, were measured in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) patients receiving treatment with either compound. We found that RA patients tend to have higher levels of TNF- alpha than both healthy individuals and AS patients prior to treatment (P < 0.05). We measured greatly increased levels of TNF- alpha in both the AS and RA etanercept patient groups during the course of treatment, while in the infliximab treated patients, the amount of TNF- alpha measured remained unchanged. Elevated TNF- alpha in the etanercept treated patients does not appear to be a significant risk factor for the spontaneous development of further autoimmune diseases in our study group. Increased levels of TNF-R1 were determined in both AS (P < 0.05) and RA (P < 0.001) patients when compared to healthy controls. In AS patients, the levels of TNF-R1 dropped significantly when treated with either infliximab (P < 0.01) or etanercept (P < 0.001). In contrast, the levels of this receptor remained unchanged in RA patients treated with either compound. PMID- 24783219 TI - From structure to catalysis: recent developments in the biotechnological applications of lipases. AB - Microbial lipases are highly appreciated as biocatalysts due to their peculiar characteristics such as the ability to utilize a wide range of substrates, high activity and stability in organic solvents, and regio- and/or enantioselectivity. These enzymes are currently being applied in a variety of biotechnological processes, including detergent preparation, cosmetics and paper production, food processing, biodiesel and biopolymer synthesis, and the biocatalytic resolution of pharmaceutical derivatives, esters, and amino acids. However, in certain segments of industry, the use of lipases is still limited by their high cost. Thus, there is a great interest in obtaining low-cost, highly active, and stable lipases that can be applied in several different industrial branches. Currently, the design of specific enzymes for each type of process has been used as an important tool to address the limitations of natural enzymes. Nowadays, it is possible to "order" a "customized" enzyme that has ideal properties for the development of the desired bioprocess. This review aims to compile recent advances in the biotechnological application of lipases focusing on various methods of enzyme improvement, such as protein engineering (directed evolution and rational design), as well as the use of structural data for rational modification of lipases in order to create higher active and selective biocatalysts. PMID- 24783220 TI - N-acetyl-seryl-aspartyl-lysyl-proline inhibits diabetes-associated kidney fibrosis and endothelial-mesenchymal transition. AB - Endothelial-to-mesenchymal transition (EndMT) emerges as an important source of fibroblasts. MicroRNA let-7 exhibits anti-EndMT effects and fibroblast growth factor (FGF) receptor has been shown to be an important in microRNA let-7 expression. The endogenous antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl proline (AcSDKP) is a substrate of angiotensin-converting enzyme (ACE). Here, we found that AcSDKP inhibited the EndMT and exhibited fibrotic effects that were associated with FGF receptor-mediated anti-fibrotic program. Conventional ACE inhibitor plus AcSDKP ameliorated kidney fibrosis and inhibited EndMT compared to therapy with the ACE inhibitor alone in diabetic CD-1 mice. The endogenous AcSDKP levels were suppressed in diabetic animals. Cytokines induced cultured endothelial cells into EndMT; coincubation with AcSDKP inhibited EndMT. Expression of microRNA let-7 family was suppressed in the diabetic kidney; antifibrotic and anti-EndMT effects of AcSDKP were associated with the restoration of microRNA let-7 levels. AcSDKP restored diabetes- or cytokines suppressed FGF receptor expression/phosphorylation into normal levels both in vivo and in vitro. These results suggest that AcSDKP is an endogenous antifibrotic molecule that has the potential to cure diabetic kidney fibrosis via an inhibition of the EndMT associated with the restoration of FGF receptor and microRNA let-7. PMID- 24783221 TI - Safety and efficacy of tree pollen specific immunotherapy on the ultrarush administration schedule method using purethal trees. AB - BACKGROUND: Specific immunotherapy (SIT) with an ultrarush administration schedule with Purethal for tree pollen allergens has been evaluated to assess its efficacy and safety. METHODS: The study group consisted of 22 patients with symptoms of allergic rhinitis and confirmed allergy to tree pollens. Patients were randomized and given an administration schedule of either ultrarush therapy or conventional preseasonal SIT. Treatment was performed during three consecutive years. RESULTS: After three years of treatment, a similar reduction in nasal symptoms was observed; according to the visual analog scale, there was a decrease from 3.991 +/- 0.804 points to 1.634 +/- 0.540 in the ultrarush group and from 3.845 +/- 0.265 to 1.501 +/- 0.418 in the group desensitized using the conventional method (P > 0.05). There was also a comparable reduction in the use of relief drugs during pollen season and an increase in the serum concentration of IgG4 to tree pollens. No significant differences in the safety profile were observed. CONCLUSION: An administration schedule of ultrarush SIT with Purethal Trees is a safe treatment in preliminary observations. This therapy is comparable with conventional administration of SIT in the field of efficacy and safety. PMID- 24783222 TI - Colorectal cancer: prevention and management of metastatic disease. AB - This paper compared the similarities and differences of the two most common types of colorectal cancer metastases. The treatment of liver metastases by surgery combined with systemic chemotherapy was explained. The different natural history of liver metastases as compared to peritoneal metastases and the possibility for prevention of peritoneal metastases were emphasized. Perioperative cancer chemotherapy or second-look surgery must be considered as individualized treatments of selected patients who have small volume peritoneal metastases or who are known to be at risk for subsequent disease progression on peritoneal surfaces. However, the fact that peritoneal metastases, when diagnosed in the follow-up of colorectal cancer patients, can be cured with a combination of cytoreductive surgery and hyperthermic perioperative chemotherapy cannot be ignored. Careful follow-up and timely intervention in colorectal cancer patients with progressive disease are a necessary part of the management strategies recommended by the multidisciplinary team. After a critical evaluation of the data currently available, these strategies for prevention and management of colorectal metastases are presented as the author's recommendations for a high standard of care. As more information becomes available, modifications may be necessary. PMID- 24783223 TI - Age and SPARC change the extracellular matrix composition of the left ventricle. AB - Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, has been implicated in procollagen processing and deposition. The aim of this study was to investigate age- and SPARC-dependent changes in protein composition of the cardiac extracellular matrix (ECM). We studied 6 groups of mice (n = 4/group): young (4-5 months old), middle-aged (11 12 m.o.), and old (18-29 m.o.) C57BL/6J wild type (WT) and SPARC null. The left ventricle (LV) was decellularized to enrich for ECM proteins. Protein extracts were separated by SDS-PAGE, digested in-gel, and analyzed by HPLC-ESI-MS/MS. Relative quantification was performed by spectral counting, and changes in specific proteins were validated by immunoblotting. We identified 321 proteins, of which 44 proteins were extracellular proteins. Of these proteins, collagen III levels were lower in the old null mice compared to WT, suggestive of a role for SPARC in collagen deposition. Additionally, fibrillin showed a significant increase in the null middle-aged group, suggestive of increased microfibril deposition in the absence of SPARC. Collagen VI increased with age in both genotypes (>3-fold), while collagen IV showed increased age-associated levels only in the WT animals (4-fold, P < 0.05). These changes may explain the previously reported age-associated increases in LV stiffness. In summary, our data suggest SPARC is a possible therapeutic target for aging induced LV dysfunction. PMID- 24783224 TI - Inflammation induced by perfluorocarbon liquid: intra- and postoperative use. AB - Perfluorocarbon liquids (PFCLs) are useful and safe surgical tools in vitreoretinal surgery. The use of PFCL as a tamponade has been controversial due to the corneal toxicity, retinal infiltration, and inflammatory reaction in experimental studies. Several authors have studied in humans the anatomical and functional outcome and adverse effects of perfluorocarbon liquids used as short-, medium-, and long-term tamponade. PFCLs develop dispersion a few days after injection and droplets may move into the anterior chamber and cause corneal endothelial damage. When PFCLs are used as postoperative tamponades for more than one week, a foreign-body inflammatory reaction is observed in up to 30% of cases but such a reaction does not induce PVR, and it resolves after removal of PFCLs. Although most clinical studies have found no signs of retinal toxicity such as progressive visual acuity deterioration or macular anatomical changes, few performed ERG or retinal histological analysis. PMID- 24783226 TI - Flow cytometric microsphere-based immunoassay as a novel non-radiometric method for the detection of glutamic acid decarboxylase autoantibodies in type 1 diabetes mellitus. AB - The first measurable sign of arising autoimmunity in type 1 diabetes mellitus is the detection of autoantibodies against beta-cell antigens, such as glutamic acid decarboxylase (GAD65). GAD65 autoantibodies (GADA) are usually measured by the Radioligand Binding Assay (RBA). The aim of this work was to develop protocols of flow cytometric microsphere-based immunoassays (FloCMIA) which involved glutamic acid decarboxylase fused to thioredoxin (TrxGAD65) adsorbed on polystyrene microspheres. Detection of bound GADA was accomplished by the use of anti-human IgG-Alexa Fluor 488 (protocol A), anti-human IgG-biotin and streptavidin dichlorotriazinyl aminofluorescein (DTAF) (protocol B) or TrxGAD65-biotin and streptavidin-DTAF (protocol C). Serum samples obtained from 46 patients assayed for routine autoantibodies at Servicios Tecnologicos de Alto Nivel (STAN-CONICET) were analyzed by RBA, ELISA and three alternative FloCMIA designs. Protocol C exhibited the highest specificity (97.8%) and sensitivity (97.4%) and a wide dynamic range (1.00-134.40 SDs). Samples obtained from 40 new-onset diabetic patients were also analyzed to further evaluate the performance of protocol C. The latter protocol showed a sensitivity of 58.6% and a prevalence of 47.5%. Two patients resulted positive only by FloCMIA protocol C and its SDs were higher than those of RBA and ELISA, showing a significantly wide dynamic range. In conclusion, FloCMIA proved to be highly sensitive and specific, requiring a low sample volume; it is environmentally adequate, innovative and represents a cost effective alternative to traditional GADA determination by RBA and/or ELISA, making it applicable to most medium-complexity laboratories. PMID- 24783227 TI - Brain benefit seen in being bilingual. PMID- 24783228 TI - New method predicts individualized progression of Alzheimer's disease. PMID- 24783229 TI - Study to examine older adults' resilience after superstorm Sandy. PMID- 24783230 TI - Medications and falls: addressing the risk through pharmacist-led quality initiatives. AB - Falls in older adults are common in the long-term care setting and are associated with functional decline, isolation, and depression. Increased attention is being given by Centers for Medicare and Medicaid services to have nursing homes implement quality assurance programs with the aim to reduce at least monthly medication reviews and monitors for therapeutic effectiveness as well as adverse consequences pharmacist-led team interventions to reduce fall risk in residents at a continuing care retirement community. One intervention is a fall risk evaluation form that notifies the assisted living care team of modifiable risk factors for residents who fall frequently. Examples include discontinuing psychotropic medications that effect gait or alter mental status. In conjunction with the nursing home care team, the pharmacist also created two other programs tha aim to (a) improve bone health by identifying residents who have low vitamin D levels, and evaluating their need for calcium and vitamin D supplementation, and (b) educate the nursing staff of specific medication side effects that increase fall risk. PMID- 24783231 TI - BRCA-negative women from BRCA-positive families may still be at increased risk of developing breast cancer. PMID- 24783225 TI - Musculoskeletal disorders in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by airway obstruction and inflammation but also accompanied by several extrapulmonary consequences, such as skeletal muscle weakness and osteoporosis. Skeletal muscle weakness is of major concern, since it leads to poor functional capacity, impaired health status, increased healthcare utilization, and even mortality, independently of lung function. Osteoporosis leads to fractures and is associated with increased mortality, functional decline, loss of quality of life, and need for institutionalization. Therefore, the presence of the combination of these comorbidities will have a negative impact on daily life in patients with COPD. In this review, we will focus on these two comorbidities, their prevalence in COPD, combined risk factors, and pathogenesis. We will try to prove the clustering of these comorbidities and discuss possible preventive or therapeutic strategies. PMID- 24783232 TI - Acquired resistance mechanisms further characterized in melanoma. PMID- 24783233 TI - Previously unknown side effect of crizotinib emerges. PMID- 24783234 TI - Biomarkers of oxidative stress and cataract. Novel drug delivery therapeutic strategies targeting telomere reduction and the expression of telomerase activity in the lens epithelial cells with N-acetylcarnosine lubricant eye drops: anti cataract which helps to prevent and treat cataracts in the eyes of dogs and other animals. AB - Cataracts in small animals are shown to be at least partially caused by oxidative damage to lens epithelial cells (LECs) and the internal lens; biomarkers of oxidative stress in the lens are considered as general biomarkers for life expectancy in the canine and other animals. Telomeres lengths and expressed telomerase activity in canine LECs may serve as important monitors of oxidative damage in normal LECs with documented higher levels of telomerase activity in cataractous LECs during cells' lifespan. Loss of functional telomere length below a critical threshold in LECs of canines during the effect of UV and chronic oxidative stress or metabolic failure, can activate programs leading to LEC senescence or death. Telomerase is induced in LECs of canines at critical stages of cataractogenesis initiation and exposure to oxidative stress through the involvement of catalytically active prooxidant transition metal (iron) ions. This work documents that transition metal ions (such as, ferrous ions- catalytic oxidants) might induce premature senescence in LECs of canines, telomere shortening with increased telomerase activity as adaptive response to UV light, oxidative and metabolic stresses. The therapeutic treatment with 1% N acetylcarnosine (NAC) prodrug delivery is beneficial for prevention and dissolution of ripe cataracts in canines. This biological activity is based on the findings of ferroxidase activity pertinent to the dipeptide carnosine released ophthalmically from NAC prodrug of L-carnosine, stabilizing properties of carnosine on biological membranes based on the ability of the imidazole containing dipeptides to interact with lipid peroxidation products and reactive oxygen species (ROS), to prevent membrane damage and delute the associated with membrane fragements protein aggregates. The advent of therapeutic treatment of cataracts in canines with N-acetylcarnosine lubricant eye drops through targeting the prevention of loss of functional telomere length below a critical threshold and "flirting" with an indirect effect with telomerase expression in LECs of canines during the effects of UV, chronic oxidative stress increases the successful rate of cataract management challenges in home veterinary care. PMID- 24783235 TI - Assessment of hupu gum for its carrier property in the design and evaluation of solid mixtures of poorly water soluble drug - rofecoxib. AB - There are no reports about the pharmaceutical applications of hupu gum (HG). Hence the present study was undertaken to test its suitability in the dissolution enhancement of poorly water soluble drug. Rofecoxib (RFB) was taken as model drug. For comparison solid mixtures were prepared with carriers such as poly vinyl pyrrolidone (PVP), sodium starch glycollate (SSG) and guar gum (GG). Physical mixing (PM), co-grinding (CG), kneading (KT) and solvent evaporation (SE) techniques were used to prepare the solid mixtures, using all the carriers in different carrier and drug ratios. The solid mixtures were characterized by powder X-ray diffraction (XRD) and Fourier-transformed infrared spectroscopy (FTIR). There was a significant improvement in the dissolution rate of solid mixtures of HG, when compared with the solid mixtures of other carriers. There was an increase in dissolution rate with increase in concentration of HG upto 1:1 ratio of carrier and drug. No drug-carrier interaction was found by FTIR studies. XRD studies indicated reduction in crystallinity of the drug with increase in HG concentration. Hence HG could be a useful carrier for the dissolution enhancement of poorly water soluble drugs. PMID- 24783236 TI - Formulation and characterizations of delayed release multi particulates system of indomethacin: optimization by response surface methodology. AB - Indomethacin is a widely used non-steroidal anti-inflammatory drug (NSAID) and extensively employed for treatment of arthritis. Delayed action (at the morning or night) is needed for arthritic patients. To improve the patient compliance, in this study we aimed to delay the drug release by designing multi-particulates system in the form of microspheres, which would efficiently release the drug into the colon and replace the conventional therapy. The aim of the present work was to elucidate the effect of formulation variables e.g., amount of eudragit polymer (X1), surfactant concentration (X2) and agitation speed (X3) on in-vitro release profiles (Y1-Y3), drug entrapment efficiency (Y4) and particle size (Y5) of multi particulates system of indomethacin. Experiments were designed according to a three levels face centered central composite design. Microspheres were formulated with the combination of ethyl cellulose (EC) and Eudragit RS 100/Eudragit S100; by using a novel quasi emulsion solvent diffusion technique. Developed formulations were characterized and evaluated on the basis of FTIR, thermal, particle size, SEM, XRD analysis and drug release kinetics studies. The formulation variables were optimized by response surface methodology (RSM). It was found that in-vitro release (Y1-Y3) was decreased significantly (p<0.05) with increase in amount of eudragit polymer but increased significantly (p<0.05) with increase in surfactant concentration and stirring speed. It was observed that the drug release data of the selected formulation was similar to the predicted release pattern. FTIR study indicated that no prominent chemical interaction or changes took place between the drug and excipients of prepared formulations. DSC and XRD studies indicated that drug was present in the amorphous state and may have been homogenously dispersed into the polymers matrix. Therefore this approach suggested that the combination of EC and Eudragit S100 microspheres may be useful in a better way, for the delivery of maximum amount of indomethacin in intact form to the colon. PMID- 24783237 TI - Helping the aging population. PMID- 24783238 TI - Fully automatic lesion segmentation in breast MRI using mean-shift and graph-cuts on a region adjacency graph. AB - PURPOSE: To present and evaluate a fully automatic method for segmentation (i.e., detection and delineation) of suspicious tissue in breast MRI. MATERIALS AND METHODS: The method, based on mean-shift clustering and graph-cuts on a region adjacency graph, was developed and its parameters tuned using multimodal (T1, T2, DCE-MRI) clinical breast MRI data from 35 subjects (training data). It was then tested using two data sets. Test set 1 comprises data for 85 subjects (93 lesions) acquired using the same protocol and scanner system used to acquire the training data. Test set 2 comprises data for eight subjects (nine lesions) acquired using a similar protocol but a different vendor's scanner system. Each lesion was manually delineated in three-dimensions by an experienced breast radiographer to establish segmentation ground truth. The regions of interest identified by the method were compared with the ground truth and the detection and delineation accuracies quantitatively evaluated. RESULTS: One hundred percent of the lesions were detected with a mean of 4.5 +/- 1.2 false positives per subject. This false-positive rate is nearly 50% better than previously reported for a fully automatic breast lesion detection system. The median Dice coefficient for Test set 1 was 0.76 (interquartile range, 0.17), and 0.75 (interquartile range, 0.16) for Test set 2. CONCLUSION: The results demonstrate the efficacy and accuracy of the proposed method as well as its potential for direct application across different MRI systems. It is (to the authors' knowledge) the first fully automatic method for breast lesion detection and delineation in breast MRI. PMID- 24783239 TI - Sclerosed hemangioma of the liver: concordance of MRI features with histologic characteristics. AB - PURPOSE: To correlate the MRI features of sclerosed hemangiomas with histologic appearance. MATERIALS AND METHODS: A medical record search identified patients with sclerosed hemangioma who underwent MRI and biopsy/resection from January 2000 to March 2012 for this retrospective institutional review board approved study. Two radiologists independently performed image analysis. A pathologist evaluated lesion histologic characteristics. RESULTS: Twelve patients (median age 65; range 41-78 years) were included; 7/12 patients had typical hemangiomas which were also analyzed. Sclerosed hemangiomas were less often moderately T2 hyperintense (5/11 45%; compared with 7/7, 100%; P = 0.0377) and demonstrated moderate arterial phase enhancement less frequently (4/12, 33% compared with 7/7, 100%; P = 0.0128) than typical hemangiomas. Markedly sclerosed hemangiomas (N = 7) exhibited the least "typical" findings, including mild T2 hyperintensity (5/7; 71%), absent arterial phase enhancement (4/7; 57%), mild portal venous phase enhancement (6/7; 86%), and absent centripetal fill-in (6/7; 86%). Arterial phase hyperenhancement occurred more often in mild/moderately sclerosed hemangiomas (3/5; 60%) compared with markedly sclerosed hemangiomas (1/7; 14%). CONCLUSION: Sclerosed hemangiomas exhibit MRI features that appear to correspond with the degree of sclerosis. These features coupled with the presence of other typical hemangiomas may aid in prospectively diagnosing sclerosed hemangioma. PMID- 24783240 TI - Dorsal column. From the archives. PMID- 24783241 TI - Noninvasive visualization of the basilar artery wall and branch ostia with high resolution three-dimensional black-blood sequence at 3 tesla. AB - PURPOSE: To evaluate the usefulness of three-dimensional (3D) MR black-blood sequence flow-dephasing-prepared fast spoiled gradient recalled echo (FDP-FSPGR) in screening the basilar artery (BA) wall and the ostia of the adjacent branch arteries. MATERIALS AND METHODS: Twenty-one patients with BA stenosis >50% on digital subtraction angiography (DSA) were imaged. Three-dimensional FDP-FSPGR images were acquired using a flow-dephasing-prepared segmented technique, including two spin echoes to overcome the inhomogeneity of the radiofrequency field. Precontrast and postcontrast 3D FDP-FSPGR sequences were performed. RESULTS: The wall of the BA could be visualized in 20 patients with good contrast, and 82 ostia of the adjacent branch arteries were identified on 3D FDP FSPGR images. Compared with DSA, the accuracy of it was 0.94 (95% confidence interval [CI], 0.89 to 0.99) for reader 1 and 0.92 (95% CI, 0.86 to 0.98) for reader 2, with strong agreement between the two readers (kappa = 0.82). BA plaque enhancement was noted in 16 of the 20 patients after contrast administration. CONCLUSION: The 3D FDP-FSPGR can be used for high-spatial-resolution demonstration and large coverage of the BA wall and the ostia of the adjacent branch arteries. This sequence will make it possible to evaluate therapeutic effects in clinical studies. PMID- 24783242 TI - MRI of the petromastoid canal in children. AB - PURPOSE: To characterize the MRI features of the petromastoid canal in children with sensorineural hearing loss (SNHL) and in normal infants. MATERIALS AND METHODS: High resolution MRI examinations of 564 children who were evaluated for SNHL and brain MRI examinations of 112 infants who had normal studies were studied independently by two reviewers. RESULTS: In SNHL group, visibility of the PMC decreased for right and left PMC (P < 0.001). The width of the right PMC significantly decreased as age increased (P < 0.0001). There was no relation between abnormalities of membranous labyrinth and cochlear nerve and PMC visibility in children with SNHL (p > 0.05). In the normal group, the PMC visibility decreased with increasing age (right P = 0.0001, left P = 0.001). In the normal group also, as age increased, the PMC width decreased for both PMCs (right, P = 0.0006; left, P = 0.03). CONCLUSION: The PMC is more frequently visualized in young children. Its visibility and width are not associated with abnormalities of membranous labyrinth and cochlear nerves. PMID- 24783244 TI - Education and imaging. Hepatobiliary and pancreatic: calcified perihepatic and capsular metastases. PMID- 24783243 TI - Measuring venous blood oxygenation in fetal brain using susceptibility-weighted imaging. AB - PURPOSE: To evaluate fetal cerebral venous blood oxygenation, Yv, using principles of MR susceptometry. MATERIALS AND METHODS: A cohort of 19 pregnant subjects, with a mean gestational age of 31.6 +/- 4.7 weeks were imaged using a modified susceptibility-weighted imaging (SWI) sequence. Data quality was first assessed for feasibility of oxygen saturation measurement, and data from five subjects (mean +/- std gestational age of 33.7 +/- 3.6 weeks) were then chosen for further quantitative analysis. SWI phase in the superior sagittal sinus was used to evaluate oxygen saturation using the principles of MR susceptometry. Systematic error in the measured Y(v) values was studied through simulations. RESULTS: Simulations showed that the systematic error in Yv depended upon the assumed angle of the vessel, theta, relative to the main magnetic field and the error in that vessel angle deltatheta. For the typical vessel angle of theta = 30 degrees encountered in the fetal data analyzed, a deltatheta as large as +/-20 degrees led to an absolute error, deltaYv, of less than 11%. The measured mean oxygen saturation across the five fetuses was 66% +/- 9.4%. This average cerebral venous blood oxygenation value is in close agreement with values in the published literature. CONCLUSION: We have reported the first in vivo measurement of human fetal cerebral venous oxygen saturation using MRI. PMID- 24783245 TI - Interview with Linda Burnes Bolton, DrPH, RN, FAAN: American Organization of Nurse Executives, http://www.aone.org. PMID- 24783246 TI - Issues associated with the emergence of coeliac disease in the Asia-Pacific region: a working party report of the World Gastroenterology Organization and the Asian Pacific Association of Gastroenterology. AB - BACKGROUND AND AIM: Once thought to be uncommon in Asia, coeliac disease (CD) is now being increasingly recognized in Asia-Pacific region. In many Asian nations, CD is still considered to be either nonexistent or very rare. In recognition of such heterogeneity of knowledge and awareness, the World Gastroenterology Organization and the Asian Pacific Association of Gastroenterology commissioned a working party to address the key issues in emergence of CD in Asia. METHODS: A working group consisting of members from Asia-Pacific region, Europe, North America, and South America reviewed relevant existing literature with focus on those issues specific to Asia-Pacific region both in terms of what exists and what needs to be done. RESULTS: The working group identified the gaps in epidemiology, diagnosis, and management of CD in Asian-Pacific region and recommended the following: to establish prevalence of CD across region, increase in awareness about CD among physicians and patients, and recognition of atypical manifestations of CD. The challenges such as variability in performance of serological tests, lack of population-specific cut-offs values for a positive test, need for expert dietitians for proper counseling and supervision of patients, need for gluten-free infrastructure in food supply and creation of patient advocacy organizations were also emphasized. CONCLUSIONS: Although absolute number of patients with CD at present is not very large, this number is expected to increase over the next few years or decades. It is thus appropriate that medical community across the Asia-Pacific region define extent of problem and get prepared to handle impending epidemic of CD. PMID- 24783248 TI - Impact of rapid on-site evaluation on the adequacy of endoscopic-ultrasound guided fine-needle aspiration of solid pancreatic lesions: a systematic review and meta-analysis. AB - BACKGROUND: Rapid on-site evaluation (ROSE) has the potential to improve adequacy rates for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of solid pancreatic lesions, but its impact is context-dependent. No studies exist that summarize the relationship between ROSE, number of needle passes, and resulting adequacy rates. AIMS: To analyze data from previous studies to establish if ROSE is associated with improved adequacy rates; to evaluate the relationship between ROSE, number of needle passes, and the resulting adequacy rates of EUS-FNA for solid pancreatic lesions. METHODS: Systematic review and meta-analysis of studies reporting the adequacy rates for EUS-FNA of solid pancreatic lesions. RESULTS: The search produced 3822 original studies, of which 70 studies met our inclusion criteria. The overall average adequacy rate was 96.2% (95% confidence interval: 95.5, 96.9). ROSE was associated with a statistically significant improvement of up to 3.5% in adequacy rates. There was heterogeneity in adequacy rates across all subgroups. No association between the assessor type and adequacy rates was found. Studies with ROSE have high per-case adequacy and a relatively high number of needle passes in contrast to non-ROSE studies. ROSE is an effect modifier of the relationship between number of needle passes and adequacy. CONCLUSIONS: ROSE is associated with up to 3.5% improvement in adequacy rates for EUS-FNA of solid pancreatic lesions. ROSE assessor type has no impact on adequacy rates. ROSE is an effect modifier on the relationship between needle passes and per-case adequacy for EUS-FNA of solid pancreatic lesions. PMID- 24783247 TI - Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress. AB - Idiosyncratic drug-induced liver injury (DILI) is a significant adverse effect of antitubercular therapy with isoniazid (INH). Although the drug has been used for many decades, the underlying mode of action (both patient-specific and drug specific mechanisms) leading to DILI are poorly understood. Among the patient specific determinants of susceptibility to INH-associated DILI, the importance of HLA genetic variants has been increasingly recognized, whereas the role of polymorphisms of drug-metabolizing enzymes (NAT2 and CYP2E1) has become less important and remains controversial. However, these polymorphisms are merely correlative, and other molecular determinants of susceptibility have remained largely unknown. Regarding the drug-specific mechanisms underlying INH-induced liver injury, novel concepts have been emerging. Among these are covalent protein adduct formation via novel reactive intermediates, leading to hapten formation and a potential immune response, and interference with endogenous metabolism. Furthermore, INH and/or INH metabolites (e.g. hydrazine) can cause mitochondrial injury, which can lead to mitochondrial oxidant stress and impairment of energy homeostasis. Recent studies have revealed that underlying impairment of complex I function can trigger massive hepatocellular injury induced by otherwise nontoxic concentrations of INH superimposed on these mitochondrial deficiencies. This review discusses these emerging new paradigms of INH-induced DILI and highlights recent insights into the mechanisms, as well as points to the existing large gaps in our understanding of the pathogenesis. PMID- 24783249 TI - Combining TNFSF15 and ASCA IgA can be used as a predictor for the stenosis/perforating phenotype of Crohn's disease. AB - BACKGROUND AND AIM: Focusing on TNFSF15 instead of NOD2, we set out to evaluate whether combining serologic and genetic markers could distinguish between Crohn's disease (CD) and ulcerative colitis (UC), and whether they could be used to stratify the disease behavior of Taiwanese CD patients. METHODS: Clinical information, serum isolation, and DNA were collected after obtaining informed consent. The serological markers were analyzed by ELISA kits and the genetic analysis for TNFSF15 single-nucleotide polymorphisms (SNPs) by Sequenom. Statistic analyses were conducted by SAS 9.2 (Cary, NC, USA). RESULTS: This study included 108 patients (55 CD, 53 UC) and 60 healthy controls. An initial low positive rate and low sensitivity for the serological markers led us to reset the cut-off values. This reset cut-off for ASCA IgA yielded a sensitivity of 0.291 and specificity of 0.925 for differentiating CD from UC patients. The reset cut off value for p-ANCA (anti-MPO) had a sensitivity of 0.461 and a specificity of 0.817 for differentiating inflammatory bowel disease patients from healthy controls. Among the TNFSF15 SNPs, rs4263839 associated with CD in Taiwan (P = 0.005), haplotype analysis did not increase the association. Combining the genetic marker TNFSF15 (rs4263839) and serological marker ASCA IgA increased the area under the curve from 0.61 to 0.70 for predicting stenosis/perforating phenotype, compared to ASCA IgA alone. CONCLUSIONS: Serological markers need to be tested and tailored to different countries/ethnicities. Combining the genetic marker TNFSF15 with ASCA IgA increased the power of predicting stenosis/perforating phenotype in CD patients with TNFSF15 but not with a NOD2 genetic background. PMID- 24783250 TI - Reply to letter to the editor. PMID- 24783251 TI - Pre-S mutations of hepatitis B virus affect genome replication and expression of surface antigens. AB - BACKGROUNDS AND AIMS: In chronic hepatitis B virus (HBV) infection, quantitative HBV surface antigen (qHBsAg) is useful for monitoring viral replication and treatment responses. We aimed to determine whether pre-S mutations have any effect on circulating qHBsAg. METHODS: Plasmids expressing 1-8 amino acid deletion in pre-S1 ("pre-S1Delta1-8") and 3-25 amino acid deletion in pre-S2 ("pre-S2Delta3-25") were constructed. At 72 h posttransfection into Huh7 cells, qHBsAg were measured using electrochemiluminescence immunoassay analyzer. To mimic milieus of quasispecies, we co-transfected either pre-S1Delta1-8 or pre S2Delta3-25 with wild type (WT). RESULTS: Pre-S mutations affected transcription and replication ability of HBV because of altered overlapping polymerase. Compared with WT, extracellular qHBsAg in pre-S1Delta1-8 and pre-S2Delta3-25 were on average 3.87-fold higher and 0.92-fold lower, respectively, whereas intracellular qHBsAg in pre-S1Delta1-8 and pre-S2Delta3-25 were 0.57-fold lower and 1.60-fold higher, respectively. Immunofluorescence staining of cellular HBsAg showed that pre-S1Delta1-8 had less staining and that pre-S2Delta3-25 had denser staining. As ratios of either pre-S1Delta1-8 or pre-S2Delta3-25:WT increased from 0:10 to 10:0 gradually, relative extracellular qHBsAg increased from 1.0 to 3.85 in pre-S1Delta1-8 co-transfection, whereas those decreased from 1.0 to 0.88 in pre-S2Delta3-25 co-transfection. CONCLUSION: Pre-S mutations exhibit different phenotypes of genome replication and HBsAg expression according to their locations. Thus, qHBsAg level for diagnosis and prognostification in chronic HBV infection should be used more cautiously, considering emergences of pre-S deletion mutants. PMID- 24783252 TI - Clinical factors associated with accuracy of EUS-FNA for pancreatic or peripancreatic solid mass without on-site cytopathologists. AB - BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUSFNA) is a safe and effective technique for tissue diagnosis in patients with pancreatic or peripancreatic solid masses. However, the procedure is difficult to accomplish without an on-site cytopathologist. The aims of this study were to examine the outcomes of EUS-FNA for pancreatic or peripancreatic solid masses without an on-site cytopathologist and to determine the factors associated with diagnostic accuracy. METHODS: From December 2005 to November 2011, 230 patients with pancreatic or peripancreatic solid masses had 240 EUS-FNAs performed without an on-site cytopathologist. The medical records of the 230 patients from a single tertiary center were retrospectively reviewed. RESULTS: Among the 230 patients who underwent EUS-FNA, 201 patients (88%) had malignancy, which included 171 adenocarcinomas (74%). Assuming that the cytopathological malignancy was positive or suspicious for malignant cells with cytology, the accuracy without an on-site cytopathologist was 67.9%. However, the accuracy increased from 40.0% for the first 30 cases (from 2006 to 2008) to 83.3% for the last 30 cases (in 2011) and was constantly over 80.0% starting from the sixth octile onwards for every 30 cases (in 2011). From the analysis of factors associated with the accuracy of the diagnosis using logistic regression analysis, the number of needle passes and the experience of endosonographer were statistically associated with the diagnostic accuracy. CONCLUSIONS: In the case of performing EUS-FNA for pancreatic or peripancreatic solid masses without an on-site cytopathologist, the experience of the endosonographer, and the number of needle passes were associated with the diagnostic accuracy. PMID- 24783253 TI - Reply: To PMID 22411755. PMID- 24783254 TI - Tight glucose control in critically ill children--a systematic review and meta analysis. AB - BACKGROUND: It is unclear if tight glucose control (TGC) with intensive insulin therapy (IIT) can improve outcomes in critically ill children admitted to the intensive care unit (ICU). The objective of this systematic review and meta analysis is to describe the benefits and risks of TGC with IIT in critically ill children and explore differences between published studies. METHODS: Prospective randomized controlled trials (RCTs) of TGC with IIT in critically ill children admitted to the ICU were identified through a search of MEDLINE, PubMed, EMBASE, Scopus, ISI Web of Science and Cochrane Database of Systematic Reviews as well as detailed citation review of relevant primary and review articles. RCTs of TGC with IIT in critically ill adults and preterm neonates were excluded. Data on study design and setting, sample size, incidence of hypoglycemia, incidence of acquired infection, and 30-day mortality were abstracted. Meta-analytic techniques were used for analysis of outcomes including 30-day mortality, acquired infection, and incidence of hypoglycemia. RESULTS: We identified four RCTs of TGC with IIT in critically ill children that included 3288 subjects. Overall, TGC with IIT did not result in a decrease in 30-day mortality [odds ratio (OR): 0.79; 95% confidence interval (CI): 0.55-1.15, p = 0.22]. TGC with IIT was associated with decrease in acquired infection (OR: 0.76; 95% CI: 0.59 0.99, p = 0.04). TGC with IIT was also associated with significant increase in hypoglycemia (OR: 6.14; 95% CI: 2.74-13.78, p < 0.001). CONCLUSIONS: TGC with IIT does not result in decrease in 30-day mortality, but appears to reduce acquired infection in critically ill children. However, TGC with IIT is associated with higher incidence of hypoglycemia. Large multi-center studies of TGC with IIT using continuous glucose monitoring in critically ill children are needed to determine if this strategy can definitively improve clinical outcomes in this population without increasing hypoglycemia. PMID- 24783255 TI - [Outpatient treatment of anorexia nervosa]. PMID- 24783256 TI - Anemia and thrombocytopenia: diagnosis from the blood smear. PMID- 24783257 TI - A man with anemia and a change in personality. PMID- 24783258 TI - Frequency, pattern, and extent of skin diseases in relation to CD4+ cell count among adults with human immunodeficiency virus infection or acquired immunodeficiency syndrome in Osogbo, southwestern Nigeria. AB - BACKGROUND: Skin diseases characterize all stages of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) and contribute significantly to associated morbidity and mortality. OBJECTIVES: The aim of this study was to document the prevalences, patterns, and extents (severity) of skin diseases and their relationships with immunologic status in HIV/AIDS patients. METHODS: A total of 140 HIV/AIDS patients in different stages of HIV infection and 140 controls were recruited. Skin diseases were documented and CD4+ cell counts determined in all subjects. Severity was assessed according to the body surface area affected (using the Wallace rule of nines and the rule of palm) for lesions that tended to be widespread. The number of digits involved was counted for lesions involving the nails. Intensity of pain was graded for specific conditions such as herpes zoster. Chi-squared statistics and Pearson correlations were determined. RESULTS: Mean+/-standard deviation age was 35.04+/-8.83 years in the patient group and 32.21+/-8.30 years in the control group. The prevalences and patterns of skin diseases in HIV/AIDS patients were similar to those reported in previous studies. Most commonly found dermatoses were oral candidiasis (n=28, 20.0%), pruritic papular eruption (n=27, 19.3%), xeroderma (n=23, 16.4%), dermatophytosis (n=22, 15.7%), and fluffy hair (n=19, 13.6%). The presence of specific skin lesions represented a better correlate with immunosuppression than cutaneous extents. However, the extents of viral warts and multiple blue-black nails correlated significantly with CD4+ cell count. The presence of a lighter hair color phenotype signifies a lower CD4+ cell count than a softer hair phenotype. CONCLUSIONS: The presence of specific skin lesions correlates more strongly with a low CD4+ cell count than does the extent of their distribution, except in cases of viral warts. The presence of and higher numbers of nails affected with blue-black nail hyperpigmentation suggest severe immunosuppression. PMID- 24783259 TI - Pityriasis rubra pilaris: clinicopathological study of 32 cases from Lebanon. AB - BACKGROUND: Pityriasis rubra pilaris (PRP) is an uncommon papulosquamous disorder of unknown etiology. Studies on this condition from our region are lacking. METHODS: To describe the clinical and histopathological findings as well as response to treatment of all patients diagnosed with PRP at the American University of Beirut Medical Center between 1995 and 2010 and compare our findings with those published in the literature. RESULTS: Pityriasis rubra pilaris was diagnosed in 32 patients (16 males, 16 females). Age of onset ranged between 2.5 and 70 years. The majority of patients (n=15) were classified as type I (47%) followed by type III (n=9, 28%) and type IV (n=6, 19%). Based on treatment responses, retinoids appear to be very effective in our population as all patients treated with isotretinoin or acitretin had excellent response. In addition to checkerboard alternating orthokeratosis/parakeratosis, which was observed in 31 cases, interesting features, including the presence of follicular plugging in all 21 cases in which follicles were available for examination, eosinophils in 12 cases, and focal acantholysis in three cases were observed. CONCLUSIONS: Features of patients with PRP in our study are generally comparable to those published in the literature, with minor differences. Microscopically follicular plugging, in addition to checkerboard alternating orthokeratosis/parakeratosis, may serve as clues to PRP diagnosis. The presence of eosinophils and focal acantholysis, observed in a few cases, should not exclude PRP diagnosis. PMID- 24783260 TI - Multiple hobnail hemangiomas. PMID- 24783261 TI - Eye, magnetism and magnets. PMID- 24783262 TI - Measurement and control of bioprocesses.Preface. PMID- 24783263 TI - Message from the editor-in-chief. IEEE Transactions on Visualization and Computer Graphics. PMID- 24783264 TI - Message from the paper chairs and guest editors. IEEE Transactions on Visualization and Computer Graphics. PMID- 24783265 TI - Enantioselective syntheses and chiral technologies. Preface. PMID- 24783266 TI - Serum human epidermal growth factor receptor 2 levels as a real-time marker for tumor burden in breast cancer patients. AB - BACKGROUND AND OBJECTIVES: Human epidermal growth factor receptor 2 (HER2) status, an important factor in the treatment of breast cancer patients, is usually determined using primary tumor tissue samples; however, the HER2 status of metastatic lesions may differ from that of the primary tumor, but biopsies cannot be performed in all cases. Here, we investigated whether serum HER2 levels can serve as an alternative to assessments of HER2 expression in cancer tissues. METHODS: Between April 2008 and July 2009, serum HER2 levels were evaluated in 295 patients with newly diagnosed breast cancer, 1,068 patients under follow-up care without recurrence after curative surgery, and 82 patients with disease recurrence. RESULTS: Among 303 patients with histologically confirmed HER2 positive tumors, the rates of serum HER2 elevation were 9.2% in preoperative patients, 0.9% in patients under follow-up care without recurrence, and 44.0% in patients with recurrent disease; for patients with HER2-negative primary tumors, the corresponding values were 0.8%, 2.6%, and 15.8%, respectively. CONCLUSION: Our results suggest that serum HER2 could be a useful real-time marker for tumor burden and recurrence in patients with HER2-positive disease. PMID- 24783267 TI - Evaluating the significance of expression of CEA mRNA and levels of CEA and its related proteins in colorectal cancer patients. AB - OBJECTIVE: To explore the clinical significance of expression of CEA mRNA and serum CEA and the related proteins in colorectal cancer (CRC). METHODS: Blood samples were collected from 370 CRC patients and 350 controls. CEA mRNA was determined by RT-PCR and levels of CEA, CA19-9, CA242, and CA724 were examined with chemiluminescence. RESULTS: The positive rate of jointly detecting serum CEA, CA19-9, CA242, and CA724 was significantly higher than CEA mRNA expressions (P < 0.01), both positive rates were significantly correlated with TNM stage, lymph node, and visceral metastasis. The positive rate of jointly detecting in patients with poorly differentiated tumor was significantly higher than that in patients with highly differentiated tumor (P < 0.01). By contrast, CEA mRNA expression was not related with histopathologic grading. Postoperative follow-up found that all patients with high levels of CEA mRNA and serum CEA and the related proteins had liver, lung, pelvis, or other distant metastases. CONCLUSIONS: These results suggest that high expressions of CEA mRNA and high levels of serum CEA and the related proteins are associated with the incidence and advanced of CRC. In addition, joint detection of serum CEA and the related proteins is more sensitivity than examination of serum CEA mRNA. PMID- 24783268 TI - Prognostic factors for medium- and long-term survival of esophageal cancer patients in the Netherlands. AB - BACKGROUND AND OBJECTIVES: Medium- and long-term survival is low in esophageal cancer (EC) patients, which is thought to be due to tumor characteristics. Our aim was to determine both tumor- and non-tumor-related characteristics affecting survival in these patients. METHODS: Patients with primary EC between 1990 and 2008 in the southern part of the Netherlands were identified. Multivariable logistic regression was used to identify determinants of survival. RESULTS: In total, 703 patients with EC were included for the 1-year, 551 for the 3-year and 436 for the 5-year survival analysis. Poor 1-year survival was independently associated with chemoradiation (compared to surgery), positive lymph nodes (N1 stage) and 1 or >=2 comorbidities. Adenocarcinoma (EAC) compared to squamous cell carcinoma was significantly associated with a better 1-year survival. Poor 3- and 5-year survival was associated with N1-stage and chemoradiation. Positive prognostic factors for 3- and 5-year survival were neoadjuvant therapy and female gender. CONCLUSION: Both tumor-related (negative lymph nodes and EAC histology) and non-tumor-related factors (surgery, neoadjuvant therapy, and female gender) are associated with a better survival of EC. Although it is not clear how histology and gender affect EC survival, knowledge of these factors may be relevant for clinical decision making. PMID- 24783269 TI - A comprehensive resequence-analysis of 250 kb region of 8q24.21 in men of African ancestry. AB - BACKGROUND: Genome-wide association studies (GWAS) have identified that a ~1 M region centromeric to the MYC oncogene on chromosome 8q24.21 harbors at least five independent loci associated with prostate cancer risk and additional loci associated with cancers of breast, colon, bladder, and chronic lymphocytic leukemia (CLL). Because GWAS identify genetic markers that may be indirectly associated with disease, fine-mapping based on sequence analysis provides important insights into patterns of linkage disequilibrium (LD) and is critical in defining the optimal variants to nominate for biological follow-up. METHODS: To catalog variation in individuals of African ancestry, we resequenced a region (250 kb; chr8:128,050, 768-128, 300,801, hg19) containing several prostate cancer susceptibility loci as well as a locus associated with CLL. Our samples included 78 individuals from Ghana and 47 of African-Americans from Johns Hopkins University. RESULTS: After quality control metrics were applied to next generation sequence data, 1,838 SNPs were identified. Of these, 285 were novel and not yet reported in any public database. Using genotypes derived from sequencing, we refined the LD and recombination hotspots within the region and determined a set of tag SNPs to be used in future fine-mapping studies. Based on LD, we annotated putative risk loci and their surrogates using ENCODE data, which should help guide laboratory studies. CONCLUSIONS: In comparison to the 1000 Genome Project data, we have identified additional variants that could be important in establishing priorities for future functional work designed to explain the biological basis of associations between SNPs and both prostate cancer and CLL. PMID- 24783313 TI - Quality improvement methodologies increase autologous blood product administration. AB - Whole blood from the heart-lung (bypass) machine may be processed through a cell salvaging device (i.e., cell saver [CS]) and subsequently administered to the patient during cardiac surgery. It was determined at our institution that CS volume was being discarded. A multidisciplinary team consisting of anesthesiologists, perfusionists, intensive care physicians, quality improvement (QI) professionals, and bedside nurses met to determine the challenges surrounding autologous blood delivery in its entirety. A review of cardiac surgery patients' charts (n = 21) was conducted for analysis of CS waste. After identification of practices that were leading to CS waste, interventions were designed and implemented. Fishbone diagram, key driver diagram, Plan-Do-Study-Act (PDSA) cycles, and data collection forms were used throughout this QI process to track and guide progress regarding CS waste. Of patients under 6 kg (n = 5), 80% had wasted CS blood before interventions, whereas those patients larger than 36 kg (n = 8) had 25% wasted CS before interventions. Seventy-five percent of patients under 6 kg who had wasted CS blood received packed red blood cell transfusions in the cardiothoracic intensive care unit within 24 hours of their operation. After data collection and didactic education sessions (PDSA Cycle I), CS blood volume waste was reduced to 5% in all patients. Identification and analysis of the root cause followed by implementation of education, training, and management of change (PDSA Cycle II) resulted in successful use of 100% of all CS blood volume. PMID- 24783314 TI - State affairs. AVMA helps behind the scenes in state governmental relations. PMID- 24783315 TI - FDA's Dunham delves into drug issues. PMID- 24783316 TI - More virus strains found in pigs. PMID- 24783317 TI - Erratum for "Evolving Health Care Systems and Approaches to Maintenance of Certification" from the Journal of Continuing Education in the Health Professions, Volume 33, Supplement 1, pages S1-S4. PMID- 24783318 TI - The AVMA responds. PMID- 24783319 TI - Jejunal varices causing recurrent obscure gastrointestinal hemorrhage. PMID- 24783320 TI - Appropriate administration timing and clinical indications of thiopurine in Crohn's disease. PMID- 24783321 TI - Introduction to the special section on falls prevention. PMID- 24783322 TI - The case for moderate gun control. AB - In addressing the shape of appropriate gun policy, this essay assumes for the sake of discussion that there is a legal and moral right to private gun ownership. My thesis is that, against the background of this right, the most defensible policy approach in the United States would feature moderate gun control. The first section summarizes the American gun control status quo and characterizes what I call "moderate gun control." The next section states and rebuts six leading arguments against this general approach to gun policy. The section that follows presents a positive case for moderate gun control that emphasizes safety in the home and society as well as rights whose enforcement entails some limits or qualifications on the right to bear arms. A final section shows how the recommended gun regulations address legitimate purposes, rather than imposing arbitrary restrictions on gun rights, and offers concluding reflections. PMID- 24783323 TI - Beneficence, justice, and health care. AB - This paper argues that societal duties of health promotion are underwritten (at least in large part) by a principle of beneficence. Further, this principle generates duties of justice that correlate with rights, not merely "imperfect" duties of charity or generosity. To support this argument, I draw on a useful distinction from bioethics and on a somewhat neglected approach to social obligation from political philosophy. The distinction is that between general and specific beneficence; and the approach from political philosophy has at times been called equality of concern. After clarifying the distinction and setting out the basis of the equality of concern view, I argue that the result is a justice based principle of "specific" beneficence that should be reflected in a society's health policy. I then draw on this account to criticize, refine, and extend some prominent health care policy proposals from the bioethics literature. PMID- 24783324 TI - Resolving the conflict: clarifying 'vulnerability' in health care ethics. AB - Vulnerability has been extensively discussed in medical research, but less so in health care. Thus, who the vulnerable in this domain are still remains an open question. One difficulty in their identification is due to the general criticism that vulnerability is not a property of only some, but rather of everyone. By presenting a philosophical analysis of the conditions of vulnerability ascription, we show that these seemingly irreconcilable understandings of vulnerability are not contradictory. Rather, they are interdependent: they refer to the same concept with different likelihoods of manifestation. We argue that the general vulnerability of living beings relies on their having certain types of interests. In health care, those individuals are particularly vulnerable who are more likely to have these interests unjustly considered. They should be afforded special protection in order to receive what is due to everyone, but which they are likely to fail to receive. PMID- 24783325 TI - Chauncey Leake and the development of bioethics in America. AB - Chauncey D. Leake (1896-1978) occupies a unique place in the history of American bioethics. A pharmacologist, he was largely an autodidact in both history and philosophy, and believed that ethics should ideally be taught to medical students by those with philosophical training. After pioneering work on medical ethics during the 1920s, he helped to lay the groundwork for important centers for bioethics and medical humanities at two institutions where he worked, the University of California-San Francisco and the University of Texas Medical Branch Galveston. Understanding Leake's role in American bioethics requires navigating a number of paradoxes--why he was described respectfully in his time but largely forgotten today; how in the 1920s he could write forward-looking pieces that anticipated many of the themes taken up by bioethics a half-century later, yet played largely a reactionary role when the new bioethics actually arrived; and why he advocated turning to philosophy and philosophers for a proper understanding of ethics, yet appeared often to misunderstand philosophical ethics. PMID- 24783326 TI - Completing the permit to work explained. AB - Two articles that featured in HEJ's April and November 2013 issues focused, respectively, on the roles and responsibilities of those operating and managing medical gas pipeline systems, and on the MGPS Permit to Work System. In this third article in a four-part 'series' by the same author, experienced medical gas systems trainer, Geoff Dillow, who also has extensive expertise in project management, developing medical gas Operational Policies, and assessing medical gas system compliance, and co-authored HTM 02-01, explains how to raise and complete The MGPS Permit to Work. PMID- 24783327 TI - Joint 'vision' for a sustainable future. AB - A vision showing how key organisations in the health and care system will join forces to address sustainability challenges, potentially saving millions of pounds' is how NHS England and Public Health England describe the new Sustainability Strategy for the NHS, Public Health and Social Care System for 2014-2020. The Strategy, and five accompanying 'modules' focused on priority areas for action, were officially unveiled to an audience of over 300 people drawn from across the healthcare, public health, local authority, private, and not-for-profit sectors, at Westminster Central Hall in London. HEJ editor, Jonathan Baillie reports. PMID- 24783328 TI - Design-led choice is a growing feature. AB - Alongside key elements such as lighting, interior decor, artwork, and good air quality, the quality of furniture in a healthcare setting plays a key role in creating a comfortable, fit-for-purpose, and therapeutic environment for patients, and a good staff working environment. Specifiers of healthcare furniture must, however, balance the need for comfort, aesthetics, and an appropriate 'style', with practical factors such as ease-of-cleaning, durability, robustness, load-bearing capacity, and, where patients are at risk of self-harm, an anti-ligature design. HEJ asked Alan Towns, managing director of Knightsbridge Furniture, for his views on some of the key aspects of furniture selection and specification for healthcare facilities. PMID- 24783329 TI - Improving facilities, transforming attitudes. AB - Providing an effective healing environment for patients facing a wide range of mental health issues, while balancing their needs with security, safety, and affordability considerations, will be key area of focus at this year's Design in Mental Health (DIMH) conference and exhibition, taking place from 13-14 May at the National Motorcycle Museum in Bickenhill near Solihull. As HEJ editor, Jonathan Baillie, reports, conference speakers will include the director of estates and new business at the Priory Group; the chief executive of mental health charity, Mind; architects and designers with substantial mental healthcare experience; top academics, and service-users--all with their own perspective on the 2014 conference theme, 'Improving facilities, transforming attitudes'. PMID- 24783330 TI - Specifying to meet multiple demands. AB - Choosing flooring for healthcare takes careful consideration. New legislation in healthcare places greater responsibility on those throughout the supply chain to ensure the safety of staff, visitors, and patients - now, and in the future. This undoubtedly impacts on flooring choices, but there is also the need for the most stringent hygiene, an aesthetically pleasing healing environment, maintenance and cleaning considerations, environmental impact, and some very specific requirements for dementia and elderly care to consider. Martyn West, Altro's specification manager, examines these key issues. PMID- 24783332 TI - [Difficult decision: dismissed in the trial period]. PMID- 24783331 TI - Freeing up valuable time and resources. AB - Danish manufacturer, V Guldmann, says ceiling-mounted patient hoists can 'improve working environments for nurses and care staff, and, if considered correctly, provide long-term cost savings and free up resources to provide such personnel with more time to care'. Chris McConnell, the company's area sales manager, UK, examines some of the key benefits of such equipment to both patients and staff, considers the technical elements of the many different solutions available, and discusses some of the installation issues. PMID- 24783333 TI - [Nursing director explains why he dismisses increasingly more students still in the trial period. "We observe the development of narcissism" (interview by Christian Heinemeyer)]. PMID- 24783334 TI - [Geriatric nursing congress begins the end of March in Hannover. Pflegezeitschrift reveals the agenda of this large specialty meeting. A mix of established knowledge and innovations]. PMID- 24783335 TI - [Certification of fitness and health apps - a critical acknowledgment. Available for free, commercial or research oriented]. PMID- 24783338 TI - [Rooms for patients with dementia. Creating an comprehensible environment]. PMID- 24783339 TI - [Individually adapted activities for patients with dementia in inpatient geriatric nursing. Interests, preferences and wishes]. PMID- 24783340 TI - [Expert tells what is involved in nursing care of the aging skin. Not too dry, not too greasy]. PMID- 24783341 TI - [The life and health status of homeless persons - results of a Munster survey. Many have chronic psychiatric and physical disorders]. PMID- 24783342 TI - [Nursing expert explains the alpha and omega of geriatric rehabilitation. Including the living environment]. PMID- 24783343 TI - [Malnutrition in the hospital. Identifying risk patients]. PMID- 24783344 TI - [Satisfaction with the quality of care in nursing homes--the nurses' perspective]. AB - BACKGROUND: In Germany, the number of residents in Nursing Homes (NH) has increased in recent years, residents become older, increasingly multimorbid and suffer more from dementia. In parallel demands concerning the quality of care in NH have increased. The vivid poltical and public debate about quality of care, however, widely disregards the perception of nurses. The aim of this study is to investigate the nurses' satisfaction with the quality of care in their NH and potential psychological consequences. METHODS: Secondary questionnaire data from 1489 nurses in 88 NH of the German 3Q-study (www.3q-studie.de) were used from the 2011 investigation. Questions regarding satisfaction enquire satsifaction in five nursing work domains. Descriptive analyses as well Chi2-tests were performed. RESULTS: The majority of nurses were satisfied in the subdomain "overall quality of care" and "physical care" (80% each). 67% were satisfied with "the quality of care for residents with dementia" and 64% with "end-of-life care". Only 56% of the nurses were satisfied with "mental care". If nurses were unsatisfied with the quality of care, this was mostly perceived as a psychological stressor. Subgroup analysis showed a pattern for four of the five domains: dissatisfied nurses were older, better qualified, worked more than 25 hours per week and worked in larger NH. No such pattern was found for "quality of care for residents with dementia". CONCLUSIONS: Nurses' satisfaction with the quality of care has shown to be a relevant work factor and potential stressor deserving more scientific and clinical attention. For NH it could constitute a core indicator for internal quality management as well as for human resource management. Research in work, health and economy in NH should also consider this factor. PMID- 24783345 TI - [Self perception and coping strategies of patients with dementia]. PMID- 24783346 TI - [Motivational interviewing. A creative concept]. PMID- 24783347 TI - [In focus: overtime. Court supports employee rights]. PMID- 24783348 TI - [Prurigo in the elderly. When the skin itches and burns]. PMID- 24783349 TI - The first volume of the Advances in Clinical Chemistry series for 2014 is presented. PMID- 24783350 TI - Vitamin D binding protein: a multifunctional protein of clinical importance. AB - Since the discovery of group-specific component and its polymorphism by Hirschfeld in 1959, research has put spotlight on this multifunctional transport protein (vitamin D binding protein, DBP). Besides the transport of vitamin D metabolites, DBP is a plasma glycoprotein with many important functions, including sequestration of actin, modulation of immune and inflammatory responses, binding of fatty acids, and control of bone development. A considerable DBP polymorphism has been described with a specific allele distribution in different geographic area. Multiple studies have shed light on the interesting relationship between polymorphisms of the DBP gene and the susceptibility to diseases. In this review, we give an overview of the multifunctional character of DBP and describe the clinical importance of DBP and its polymorphisms. Finally, we discuss the possibilities to use DBP as a novel therapeutic agent. PMID- 24783351 TI - Free testosterone: clinical utility and important analytical aspects of measurement. AB - Testosterone, the most abundant androgen in men, is a steroid hormone that is synthesized predominantly by the testes. In women, minor amounts are synthesized in the ovaries. Androgen precursors are also produced and secreted from the adrenal glands in both sexes, where they undergo peripheral conversion to testosterone. Circulating concentrations are approximately 15-25 times higher in adult men compared to women. Maintenance of these levels is necessary for development and maintenance of secondary sexual characteristics, libido, growth, prevention of osteoporosis, and most importantly in men, spermatogenesis. Most testosterone circulates tightly bound to sex hormone-binding globulin (SHBG) or weakly bound to albumin. A minor amount circulates as free testosterone, and it is believed that this is the metabolically active fraction. Measurement of free testosterone is important in the diagnosis of many diseases, most importantly disorders of androgen deficiency in men (i.e., hypogonadism) and androgen excess in women (i.e., polycystic ovary syndrome and hirsutism). Many methodologies are available for free testosterone measurement including the reference methods (equilibrium dialysis and ultrafiltration), analog immunoassay, and calculated free testosterone based on measurement of total testosterone, SHBG, and albumin. Moreover, measurement of bioavailable testosterone, a combination of albumin bound and free testosterone, also has clinical utility and can be measured by selective protein precipitation or calculation. In this review, the advantages and limitations of each of these methods will be discussed in the context of clinical utility and implementation into a routine hospital laboratory. Furthermore, up and coming methodologies for free testosterone measurement, including liquid chromatography-tandem mass spectrometry, will also be discussed. PMID- 24783352 TI - Urine retinol-binding protein 4: a functional biomarker of the proximal renal tubule. AB - Measurement of retinol-binding protein 4 in urine (uRBP4) is arguably the most sensitive biomarker for loss of function of the human proximal renal tubule. Megalin- and cubilin-receptor-mediated endocytosis normally absorbs > 99% of the approximately 1.5 g/24 h of protein filtered by the renal glomerulus. When this fails there is "tubular proteinuria," comprising uRBP4, albumin, and many other proteins and peptides. This tubular proteinuria is a consistent feature of the renal Fanconi syndrome (FS) and measurement of uRBP4 appears to be an excellent screening test for FS. FS occurs in rare inherited renal diseases including cystinosis, Dent disease, Lowe syndrome, and autosomal dominant FS. Acquired FS occurs in paraproteinemias, tubulointerstitial renal disease, oncogenic osteomalacia, Chinese herbs nephropathy, and Balkan endemic nephropathy. Though poorly understood, FS may be associated with HIV disease and antiretroviral treatment; cadmium poisoning may cause FS. In addition to FS, uRBP4 measurement has a different role: the early detection of acute kidney injury. Urine RBP4 comprises several isoforms, including intact plasma RBP4, MW 21.07 kDa, and C terminal truncated forms, des-L- and des-LL-RBP4, also probably plasma derived. In FS, uRBP4 levels are about 104-fold above the upper limit of normal and small increments are frequently seen in carriers of some inherited forms of FS and in acquired disease. The very high levels in disease, frequent assay nonlinearity, lack of defined calibrants, and multiple uRBP4 isoforms make accurate assay challenging; top-down mass spectrometry has brought advances. Assays for uRBP4 with defined molecular targets allowing good interlaboratory comparisons are needed. PMID- 24783353 TI - Proteomics for breast cancer urine biomarkers. AB - Although the survival of breast cancer (BC) patients has increased over the last two decades due to improved screening programs and postoperative adjuvant systemic therapies, many patients die from metastatic relapse. Current biomarkers used in the clinic are not useful for the early detection of BC, or monitoring its progression, and have limited value in predicting response to treatment. The development of proteomic techniques has sparked new searches for novel protein markers for many diseases including BC. Proteomic techniques allow for a high throughput analysis of samples with the visualization and quantification of thousands of potential protein and peptide markers. Human urine is one of the most interesting and useful biofluids for routine testing and provides an excellent resource for the discovery of novel biomarkers, with the advantage over tissue biopsy samples due to the ease and less invasive nature of collection. In this review, we summarize the results from studies where urine was used as a source for BC biomarker research and discuss urine sample preparation, its advantage, challenges, and limitation. We focus on the gel-based proteomic approaches as well as the recent development of quantitative techniques in BC urine biomarker detection. Finally, the future use of modern proteomic techniques in BC biomarker identification will be discussed. PMID- 24783354 TI - Pregnancy-associated plasma protein A (PAPP-A) and preeclampsia. AB - Pregnancy-associated plasma protein A (PAPP-A) is a key regulator of insulin-like growth factor bioavailability essential for normal fetal development. In maternal blood, this protein increases with gestational age and then rapidly decreases after delivery. It is routinely used for Down syndrome screening in the first trimester of pregnancy, and its decrease compared to a normal pregnancy indicates an increased risk for both chromosomal anomalies and adverse pregnancy outcomes. It belongs to a group of biomarkers that predict later preeclampsia development, primarily early onset preeclampsia; however, it should be combined with a Doppler ultrasonography of the uterine artery (pulsatile index) and other biochemical and maternal factors to achieve a higher detection rate with an acceptable false positivity rate. Some studies have demonstrated an even more pronounced decrease of PAPP-A in the early second trimester of pregnancy in women who subsequently develop preeclampsia compared with women who do not develop preeclampsia. Conversely, during the last trimester of pregnancy, its concentration increases even more in patients with preeclampsia than in patients without. It is also detectable at very low levels in nonpregnant individuals, and a higher concentration indicates an adverse effect in patients with acute coronary syndromes or stable atherosclerotic disease and in patients with end-stage renal disease who are being treated with hemodialysis. PMID- 24783355 TI - Pediatric hypoglycemia. AB - Hypoglycemia in the pediatric population is a common finding important to recognize and manage to prevent brain injury. Recent advances in molecular genetics have provided new insight into its biochemical and physiologic basis and have led to more appropriate and specific treatment. Although a major cause of brain injury in pediatrics, the ability to predict the long-term outcome in these patients remains difficult. Identification of these at-risk individuals is important. The physiologic adaptations associated with transition from fetal to neonatal life are now better understood thus allowing for improved surveillance and management. Despite these advances, analytical limitations of point-of-care testing instruments at low glucose concentration continue to persist, This review aims to address these questions and provide an overview of pediatric hypoglycemia and the molecular pathways involved. PMID- 24783356 TI - Paraoxonases and chemokine (C-C motif) ligand-2 in noncommunicable diseases. AB - Oxidative stress and inflammation underpin most diseases; their mechanisms are inextricably linked. Chronic inflammation is associated with oxidation, anti inflammatory cascades are linked to decreased oxidation, increased oxidative stress triggers inflammation, and redox balance inhibits the inflammatory cellular response. Whether or not oxidative stress and inflammation represent the cause or consequence of cellular pathology, they contribute significantly to the pathogenesis of noncommunicable diseases (NCD). The incidence of obesity and other related metabolic disturbances are increasing, as are age-related diseases due to a progressively aging population. Relationships between oxidative stress, inflammatory signaling, and metabolism are, in the broad sense of energy transformation, being increasingly recognized as part of the problem in NCD. In this chapter, we summarize the pathologic consequences of an imbalance between circulating and cellular paraoxonases, the system for scavenging excessive reactive oxygen species and circulating chemokines. They act as inducers of migration and infiltration of immune cells in target tissues as well as in the pathogenesis of disease that perturbs normal metabolic function. This disruption involves pathways controlling lipid and glucose homeostasis as well as metabolically driven chronic inflammatory states that encompass several response pathways. Dysfunction in the endoplasmic reticulum and/or mitochondria represents an important feature of chronic disease linked to oxidation and inflammation seen as self-reinforcing in NCD. Therefore, correct management requires a thorough understanding of these relationships and precise interpretation of laboratory test results. PMID- 24783357 TI - Episodes of care--year 1. PMID- 24783358 TI - Great expectations. PMID- 24783359 TI - A look back at the 2013-14 flu season in Arkansas. PMID- 24783360 TI - Unusual presentation of Wegener's granulomatosis as a gastric ulcer. PMID- 24783361 TI - Top tips to maximize reimbursements: avoid denials with accurate medical record notes. PMID- 24783362 TI - Non melanoma skin cancer review. AB - The diagnosis of skin cancer is often distressing for the individual patient even though 20% of the population may develop a skin cancer during their life. As with most conditions, an ounce of prevention is worth a pound of cure. Employing sun smart behaviors in childhood that last into adulthood is a good place to start. Regularly scheduled full body skin exams by a health care provider in addition to monthly self skin check exams allow for early detection. PMID- 24783363 TI - Splenomegaly in adult sickle cell disease patients. PMID- 24783364 TI - When everything is changing, change can become unmanageable. PMID- 24783365 TI - Interview with Mama P. Borgstrom, FACHE, President and Chief Executive Officer, Yale New Haven Health System, and Chief Executive Officer, Yale-New Haven Hospital, Connecticut. PMID- 24783366 TI - Specialties: missing in our healthcare reform strategies? PMID- 24783367 TI - Costs and benefits of transforming primary care practices: a qualitative study of North Carolina's Improving Performance in Practice. AB - Primary care organizations must transform care delivery to realize the Institute for Healthcare Improvement's Triple Aim of better healthcare, better health, and lower healthcare costs. However, few studies have considered the financial implications for primary care practices engaged in transformation. In this qualitative, comparative case study, we examine the practice-level personnel and nonpersonnel costs and the benefits involved in transformational change among 12 primary care practices participating in North Carolina's Improving Performance in Practice (IPIP) program. We found average annual opportunity costs of $21,550 ($6,659 per full-time equivalent provider) for maintaining core IPIP activities (e.g., data management, form development and maintenance, meeting attendance). This average represents the cost of a 50% full-time equivalent registered nurse or licensed practical nurse. Practices were able to limit transformation costs by scheduling meetings during relatively slow patient care periods and by leveraging resources such as the assistance of IPIP practice coaches. Still, the costs of practice transformation were not trivial and would have been much higher in the absence of these efforts. Benefits of transformation included opportunities for enhanced revenue through reimbursement incentives and practice growth, improved efficiency and care quality, and maintenance of certification. Given the potentially high costs for some practices, policy makers may need to consider reimbursement and other strategies to help primary care practices manage the costs of practice redesign. PMID- 24783368 TI - Practitioner application. PMID- 24783369 TI - Governing board, C-suite, and clinical management perceptions of quality and safety structures, processes, and priorities in U.S. hospitals. AB - To achieve quality improvement in hospitals requires greater attention to systems thinking than is typical at this time, including a shared understanding across different levels of the hospital of the current state of quality improvement efforts. A self-administered survey assessed the perceptions of board members, C suite executives, and clinical managers regarding quality activities and structures. This instrument, the Hospital Leadership and Quality Assessment Tool (HLQAT), includes 13 domains in six conceptual areas that we believe are major organizational drivers of quality and safety: (1) commitment of senior leaders, (2) a vision of exemplary quality, (3) a supportive culture, (4) accountable leadership, (5) appropriate organizational structures, and (6) adaptive capability. HLQAT survey results from a convenience sample of more than 300 hospitals were linked to performance on the Centers for Medicare & Medicaid Services (CMS) Core Measures. The results show significantly different perceptions between the groups. Higher HLQAT scores for each respondent group were associated with better hospital performance on the CMS Core Measures. There is no magic bullet--no one domain dominates. Leaders in higher-performing hospitals appear to be more effective at conveying their vision of quality care and creating a culture that supports an expectation that staff and leadership will work across traditional boundaries to improve quality. PMID- 24783370 TI - Practitioner application. PMID- 24783371 TI - Use of electronic health record documentation by healthcare workers in an acute care hospital system. AB - Acute care clinicians spend significant time documenting patient care information in electronic health records (EHRs). The documentation is required for many reasons, the most important being to ensure continuity of care. This study examined what information is used by clinicians, how this information is used for patient care, and the amount of time clinicians perceive they review and document information in the EHR. A survey administered at a large, multisite healthcare system was used to gather this information. Findings show that diagnostic results and physician documents are viewed more often than documentation by nurses and ancillary caregivers. Most clinicians use the information in the EHR to understand the patient's overall condition, make clinical decisions, and communicate with other caregivers. The majority of respondents reported they spend 1 to 2 hours per day reviewing information and 2 to 4 hours documenting in the EHR. Bedside nurses spend 4 hours per day documenting, with much of this time spent completing detailed forms seldom viewed by others. Various flow sheets and forms within the EHR are rarely viewed. Organizations should provide ongoing education and awareness training for hospital clinical staff on available forms and best practices for effective and efficient documentation. New forms and input fields should be added sparingly and in collaboration with informatics staff and clinical team members to determine the most useful information when developing documentation systems. PMID- 24783372 TI - Practitioner application. PMID- 24783373 TI - Why hospital improvement efforts fail: a view from the front line. AB - In the 21st century, healthcare executives are facing changes of unprecedented magnitude in virtually every area, affecting their ability to compete. That hindrance brings with it a greater need for rapid and effective organizational change and improvement. Yet changes in the U.S. healthcare delivery system have historically been criticized as slow and less than effective in responding to the changes necessary for rapid performance improvement. To that end, the purpose of this applied research study was to help healthcare executives better understand the barriers to effective organizational change and improvement from the perspective of frontline leaders. Focus groups were conducted with 167 frontline leaders from four community hospitals to explore why hospital change efforts fail. Participants representing 11 different functional areas, including all facets of hospital operations, were asked to identify the primary causes of failure of a recent change initiative at their hospital. A content analysis of the focus group data identified 10 primary barriers to successful hospital change, some of which are ineffective implementation planning and overly aggressive timelines, failure to create project buy-in and ownership, ineffective leadership and lack of trust in upper management, unrealistic improvement plans, and communication breakdowns. Leadership lessons and recommendations based on the research findings are provided. PMID- 24783374 TI - Practitioner application. PMID- 24783375 TI - Centralized IRB models for emergency care research. PMID- 24783376 TI - Evidence-based research ethics and determinations of "engagement in research". PMID- 24783377 TI - Research with dementia patients in the nursing home setting: a protocol for informed consent and assent. PMID- 24783378 TI - Perioperative services overhaul proves effort is worth the time. PMID- 24783379 TI - Conference takes OR leaders and business managers to the next level. PMID- 24783380 TI - Keynoter Tim Porter-O'Grady sees new roles for perioperative nurses. PMID- 24783381 TI - Restructuring and revamping workflow help a small hospital make big strides. PMID- 24783382 TI - Formula for successful cost control includes hard data plus surgeon champion. PMID- 24783383 TI - Firm policies and the right procedures tip the cost-benefit balance toward flip rooms. PMID- 24783384 TI - Learning from leaning: case cart readiness improves after barriers are removed. PMID- 24783385 TI - Multiple OR multidisciplinary team huddles promote ownership of process improvements. PMID- 24783386 TI - Competency matrix modeled on ski trail difficulty validates staff skills at Vail center. PMID- 24783387 TI - Global burden of kidney diseases. PMID- 24783388 TI - Correlation between severity of chronic kidney disease and thyroid dysfunction. AB - Kidneys play a significant role in thyroid hormone metabolism by conversion of thyroxine (T4) to triiodothyronine (T3) and abnormal thyroid function tests are frequently observed in patients of chronic kidney disease. The aim of present study was to analyse the thyroid function in patients of chronic kidney disease and its correlation with severity of kidney disease. Fifty patients of chronic kidney disease were included. All patients were on conservative management and were divided into 3 groups. Those with creatinine clearance < 7.5 ml/minute were placed in group A (n = 21), with creatinine clearance 7.5 - 15 ml/minute in group B (n = 21) and with creatinine clearance > 15 ml/minute in group C (n = 8). Thyroid profile was studied in all patients. The results were compared to age and sex matched healthy controls. Thirty-five patients (70%) of chronic kidney disease were found to be having abnormal thyroid functions. The mean values of serum total T3, free T3, total T4, free T4 were significantly reduced and that of thyroid stimulating hormone (TSH) were significantly higher in cases as compared to controls and these abnormities in thyroid function test increased as the creatinine clearance decreased (from group C to group A). It is concluded that thyroid dysfunction occurs in patients with chronic kidney disease. Mean values of TT3, FT3, TT4, FT4 reduced and that of TSH increased as severity of renal failure increased. PMID- 24783389 TI - Current state of renal transplantation in India. PMID- 24783390 TI - HLA match, mismatch and crossmatch: what clinicians should know? PMID- 24783391 TI - Peritoneal dialysis. PMID- 24783392 TI - Online haemodiafiltration, a new form of dialysis. PMID- 24783393 TI - Renal manifestations of rheumatological disorders. PMID- 24783394 TI - Complicated urinary tract infections. PMID- 24783395 TI - Contrast induced nephropathy: our experience. AB - Even in the light of newer and less nephrotoxic contrast media solutions, their increased use during standard and new radiological procedures has resulted in the growing incidence of contrast-induced nephropathy, an iatrogenic disorder caused by exposure to contrast media. This retrospective study was conducted among the patients admitted in North Bengal Medical College from January 2007 to December 2010 with significant rise in serum creatinine level within 48 to 72 hours of systemic administration of contrast media. The study sample constituted 14 patients with mean age being 45.2 years. Among them, 10 patients (71.4%) required haemodialysis. One patient (7.1%) expired after receiving three sessions of haemodialysis. Three patients (21.4%) became dependent on haemodialysis. Once developed, contrast induced nephropathy is associated with high morbidity, long hospital-stay and patient becomes dependent on haemodialysis. Till now, no available current treatment can reverse or ameliorate the condition once it develops. Some precautionary measures taken in the high risk patients before administration of contrast medium is essential to reduce the incidence. PMID- 24783396 TI - Desogestrel mini pill: is this safe in lactating mother? AB - To find out the safety, effectiveness and tolerability of using desogestrel (75 microg/day), a progesterone only pill on lactating mother, a prospective clinical study was undertaken among 200 lactating women during the period from 1st January 2010 to 13th June 2011 at Gice Clinic, Kalyani, Nadia, West Bengal. The same number of cases were taken as placebo for comparison. Desogestrel was started after six weeks of delivery for six months. Patients were reviewed at 8th, 12th, 16th, 24th weeks and one year. The very interesting results were found from the follow-up study that desogestrel (75 microg/day) did not alter the amount and composition of breast milk, pregnancy was not reported as compared to placebo. The drug had good tolerability, less side-effects and did not affect the growth and development of breastfed babies. Due to the safety, good efficacy, tolerability and less side-effects it is concluded that desogestrel (75 microg/day) was well accepted in majority of women (97.5%) and provided good contraceptive efficacy during the lactating period. This treatment does not have any effect on the growth and development of breastfed baby. PMID- 24783397 TI - Acute kidney injury in hereditary renal hypouricaemia --a case report and review of literature. AB - A young male patient was admitted to our hospital with history of dysuria, recurrent vomiting, severe muscle pain and weakness which was induced by a session of rigorous exercise for the first time in the local gymnasium. He was subsequently diagnosed with exercise-induced acute kidney injury and rhabdomyolysis and managed accordingly. Later on during follow-up he was found to have extreme hypouricaemia (serum uric acid 0.2 mg/dl) and was subsequently diagnosed with renal hypouricaemia. Biochemical investigations on other family members of the patient revealed hereditary renal hypouricaemia in the family. PMID- 24783398 TI - Spontaneous rupture of renal allograft: an uncommon complication with an uncommon cause. AB - Renal allograft rupture is defined as a renal laceration, which involves two or more surfaces of the graft and extends beyond renal capsule with or without involvement of the collecting system. Acute and hyperacute rejections are the causes in most of the cases. Non-rejection aetiologies of graft rupture include acute tubular necrosis, renal vein thrombosis, ureteric obstruction, polyarteritis nodosa, ischaemia, hypertension and biopsy. Early detection of these causes is of prime importance for graft salvage. Here we report an uncommon case of spontaneous renal allograft rupture due to intrarenal ischaemia leading to infarction and hypertensive crisis. PMID- 24783399 TI - Complete transection of common bile duct after blunt trauma abdomen--a case report. AB - Isolated injury to the extrahepatic biliary system after blunt trauma is rare, Complete transection of the common bile duct is also a rare entity. Here a case of a 45-year-old male admitted with the history of blunt trauma abdomen with features of peritonitis and jaundice, found to have complete transection of common bile duct and there was no other visceral injury is reported. Cases of isolated complete transection of common bile duct in blunt trauma abdomen are rarely reported in the literature. PMID- 24783400 TI - Mediastinal granulocytic sarcoma: poor risk AML? AB - Granulocytic sarcoma (GS), a rare extramedullary manifestation of acute myeloid leukaemia (AML) has been frequently reported in the skin, orbits, gingiva, maxilla and lymph nodes. GS in the mediastinum is often mistaken as lymphoblastic lymphoma or mediastinal germ cell tumour. We presented here three cases of AML with normal cytogenetics who presented with mediastinal masses with superior vena caval (SVC) syndrome. All the three cases summarised in this write-up, received standard AML therapy but had, poor outcome. PMID- 24783401 TI - Standardizing revenue cycle operations across multiple clinics. PMID- 24783402 TI - How to prepare patient financial services for reform. PMID- 24783403 TI - Three potential ways EFTs could affect cash flow. PMID- 24783404 TI - Getting ready for ICD-10 diagnosis codes. PMID- 24783405 TI - Querying KEGG pathways in logic. AB - Understanding the interaction patterns among biological entities in a pathway can potentially reveal the role of the entities in biological systems. Although considerable effort has been contributed to this direction, querying biological pathways remained relatively unexplored. Querying is principally different in which we retrieve pathways satisfying a given property in terms of its topology, or constituents. One such property is subnetwork matching using various constituent parameters. In this paper, we introduce a logic based framework for querying biological pathways using a novel and generic subgraph isomorphism computation technique. We develop a graphical interface called IsoKEGG to facilitate flexible querying of KEGG pathways based on isomorphic pathway topologies as well as matching any combination of node names, types, and edges. It allows editing KGML represented query pathways and returns all isomorphic patterns in KEGG pathways satisfying a given query condition for further analysis. PMID- 24783406 TI - A novel figure panel classification and extraction method for document image understanding. AB - With the availability of full-text documents in many online databases, the paradigm of biomedical literature mining and document understanding has shifted to analysis of both text and figures to derive implicit messages that are unforeseen with text mining only. To enable automatic, massive processing, a key step is to extract and parse figures embedded in papers. In this paper, we present a novel model-driven, hierarchical method to classify and extract panels from figures in scientific papers. Our method consists of two integrated components: figure (or panel) classification and panel segmentation. Figure classification evaluates each panel and decides the existence of photographs and drawings. Mixtures of photographs and non-photographs are divided into subfigures. The splitting process repeats until no further panel collage can be identified. Detection of highlighted views is addressed with Hough space analysis. Using reconstruction from Hough peaks, enclosed panels are retrieved and saved into separate files. Experiments were conducted with a total of 360 figures extracted from two sets of papers that are retrieved with difference sets of keywords. Experimental results demonstrated that our method successfully segmented figures and extracted photographs and non-photographs with high accuracy and robustness. In addition, our method was able to identify zoom-in views that are superimposed on the original photographs. The efficiency of our method allows online implementation. PMID- 24783407 TI - Identifying significant associations of orthologous simple sequence repeats with gene ontologies. AB - Simple Sequence Repeats (SSRs), also known as microsatellites, regulate gene functions. SSR mutations in a disease gene may cause various genetic disorders. To identify putative functional SSRs, a web-based system, Gene Ontology SSR Hierarchy (GOSH), was developed to facilitate discovery of significant associations between SSRs and Gene Ontology (GO) terms. Using the GO hierarchy term structure, GOSH assists users with selecting functional or biological gene subsets. Significant SSR patterns are retrieved and identified via comprehensive overrepresentation analysis within a target gene subset and by comparing results with orthologous genes. Pattern relationships between different biological subsets or supersets can be observed by using the GO hierarchy structure directly. GOSH also supports GO searching through identified significant SSR patterns and all GO terms possessing such patterns are listed for consultation. GOSH is the first comprehensive and efficient online mining tool for discovering significant orthologous SSR patterns in GO terms and is available at http://gosh.cs.ntou.edu.tw/. PMID- 24783408 TI - Effective peak alignment for mass spectrometry data analysis using two-phase clustering approach. AB - In recent years, mass spectrometry data analysis has become an important protein identification technique. The mass spectrometry technologies emerge as useful tools for biomarker discovery through studying protein profiles in various biological specimens. In mining mass spectrometry datasets, peak alignment is a critical issue among the preprocessing steps that affect the quality of analysis results. However, the existing peak alignment methods are sensitive to noise peaks across various mass spectrometry samples. In this paper, we proposed a novel algorithm named Two-Phase Clustering for peak Alignment (TPC-Align) to align mass spectrometry peaks across samples in the pre-processing phase. The TPC Align algorithm sequentially considers the distribution of intensity values and the locations of mass-to-charge ratio values of peaks between samples. Moreover, TPC-Align algorithm can also report a list of significantly differential peaks between samples, which serve as the candidate biomarkers for further biological study. The proposed peak alignment method was compared to the current peak alignment approach based on one-dimension hierarchical clustering through experimental evaluations and the results show that TPC-Align outperforms the traditional method on the real dataset. PMID- 24783409 TI - Identification of glioma cancer-alerted gene markers based on a diagnostic outcome correlation analysis preferential approach. AB - Identifying glioma cancer-alerted genetic markers through analysis of microarray data allows us to detect tumours at the genome-wide level. To this end, we propose to identify glioma gene markers based primarily on their correlation with the glioma diagnostic outcomes, rather than merely on the classification quality or differential expression levels, as it is not the classification or expression level per se that is crucial, but the selection of biologically relevant biomarkers is the most important issue. With the help of singular value decomposition, microarray data are decomposed and the eigenvectors corresponding to the biological effect of diagnostic outcomes are identified. Genes that play important roles in determining this biological effect are thus detected. Therefore, genes are essentially identified in terms of their strength of association with diagnostic outcomes. Monte Carlo simulations are then used to fine tune the selected gene set in terms of classification accuracy. Experiments show that the proposed method achieves better classification accuracies and is data sets independent. Graph-based statistical analysis showed that the selected genes have close relationships with glioma diagnostic outcomes. Further biological database and literature study confirms that the identified genes are biologically relevant. PMID- 24783410 TI - Comparing ensemble learning methods based on decision tree classifiers for protein fold recognition. AB - In this paper, some methods for ensemble learning of protein fold recognition based on a decision tree (DT) are compared and contrasted against each other over three datasets taken from the literature. According to previously reported studies, the features of the datasets are divided into some groups. Then, for each of these groups, three ensemble classifiers, namely, random forest, rotation forest and AdaBoost.M1 are employed. Also, some fusion methods are introduced for combining the ensemble classifiers obtained in the previous step. After this step, three classifiers are produced based on the combination of classifiers of types random forest, rotation forest and AdaBoost.M1. Finally, the three different classifiers achieved are combined to make an overall classifier. Experimental results show that the overall classifier obtained by the genetic algorithm (GA) weighting fusion method, is the best one in comparison to previously applied methods in terms of classification accuracy. PMID- 24783411 TI - Enhanced classification for high-throughput data with an optimal projection and hybrid classifier. AB - High-throughput screening technologies recently developed allow scientists to conduct millions of biological and medical tests simultaneously and rapidly. A major bottleneck for the analysis is to reduce the inherent high dimensionality for subsequent analysis. Principal Component Analysis (PCA) is a popular tool for dimensionality reduction by selecting typically a few Principal Components (PCs) ranked by their variances, eigenvalues. Since this selection approach is not always effective in reducing dimensionality, we consider a different ranking criterion, the canonical variate criterion. To further enhance the classification performance, we propose an integrated classification framework to combine the criterion and two hybrid classification methods and compare with several popular classification methods using leave-one-out cross-validation. For illustration, three real high-throughput data sets are considered and analysed to illustrate the methods. PMID- 24783412 TI - Alternative method for direct measurement of tibial slope. AB - BACKGROUND/AIM: The tibial slope is one of the most frequently cited anatomical causes of anterior cruciate ligament trauma. The aim of this study was to determine the possibility of direct measuring of the tibial slope of the knee without prior soft tissue dissection in cadavers. METHODS: Measurement was performed on the two groups of samples: osteological and cadaveric. The osteological group consisted of 102 matured tibiae and measurement was performed: indirectly by sagittal photographing of the tibia, and directly by a set of parallel bars. The cadaveric group consisted of 50 cadaveric knees and measurement was performed directly by a set of parallel bars. The difference and correlation between indirect and the direct measurements were observed, which included also measuring of the difference and correlation of the tibial slope on the medial and lateral condyles. RESULTS: A statistically significant difference between the direct and indirect method of measuring (p < 0.01) of 1 degree was found for the tibial slope on the medial condyle, which is of no practical importance. Direct measurement of the osteological and cadaveric groups of samples did not show a statistically significant difference regarding the values of the tibial slope on the lateral condyle (p > 0.05). However, the slope on the medial condyle, as well as indirect measurement showed a statistically significant difference (p < 0.01). CONCLUSION: By the use of a set of parallel bars it is possible to measure the tibial slope directly without removal of the soft tissue. The results of indirect, photographic measurement did not statistically differ from the results of direct measurement of the tibial slope. PMID- 24783413 TI - Heidelberg Retina Tomography II parameters in evaluating high- and normal pressure glaucoma progression. AB - BACKGROUND/AIM: Heidelberg retina tomography II (HRT II) haves been employed to quantitatively assess the topography of optic discs in eyes with high-pressure glaucoma (HPG) and normal-pressure glaucoma (NPG), in order to determine which of global and segmental optic disc parameters will prove to be most suitable for monitoring the progression of these two conditions. METHODS: The results of 73 eyes of 73 patients with HPG and NPG were analyzed in relation to age, refractive error, quality of HRT images and stereometric parameters. RESULTS: A statistically significant difference (p < 0.05) between the global baseline and follow-up results was found in: rim volume, maximum cup depth and cup shape measure (in the HPG group), and C/D ratio, cup volume, rim volume and cup shape measure (in the NPG group). The baseline and follow-up results of the retinal nerve fiber layer in the temporal and inferotemporal sectors show a significant difference in both groups. CONCLUSION: Several HRT stereometric parameters are useful for monitoring the progression of changes of the optic disc and local retina in eyes with HPG and NPG. Both segmental and global scanning is of importance in glaucoma progression analysis. PMID- 24783414 TI - When do the symptoms of autonomic nervous system malfunction appear in patients with Parkinson's disease? AB - BACKGROUND/AIM: Dysautonomia appears in almost all patients with Parkinson's disease (PD) in a certain stage of their condition. The aim of our study was to detect the development and type of autonomic disorders, find out the factors affecting their manifestation by analyzing the potential association with demographic variables related to clinical presentation, as well as the symptoms of the disease in a PD patient cohort. METHODS: The patients with PD treated at the Clinic of Neurology in Belgrade during a 2-year period, divided into 3 groups were studied: 25 de novo patients, 25 patients already treated and had no long term levodopa therapy-related complications and 22 patients treated with levodopa who manifested levodopa-induced motor complications. Simultaneously, 35 healthy control subjects, matched by age and sex, were also analyzed. RESULTS: Autonomic nervous system malfunction was defined by Ewing diagnostic criteria. The tests, indicators of sympathetic and parasympathetic nervous systems, were significantly different in the PD patients as compared with the controls, suggesting the failure of both systems. However, it was shown, in the selected groups of patients, that the malfunction of both systems was present in two treated groups of PD patients, while de novo group manifested only sympathetic dysfunction. For this reason, the complete autonomic neuropathy was diagnosed only in the treated PD patients, while de novo patients were defined as those with the isolated sympathetic dysfunction. The patients with the complete autonomic neuropathy differed from the subjects without such neuropathy in higher cumulative and motor unified Parkinson's disease rating score (UPDRS) (p < 0.01), activities of daily living scores (p < 0.05), Schwab-England scale (p < 0.001) and Hoehn-Yahr scale. There was no difference between the patients in other clinical-demographic characteristics (sex, age at the time of diagnosis, actual age, duration of disease, involved side of the body, pain and freezing), but mini mental status (MMS) score and Hamilton depression and anxiety rating scale were significantly lower (p < 0.05). CONCLUSION: Our results confirm a high prevalence of autonomic nervous system disturbances among PD patients from the near onset of disease, with a predominant sympathetic nervous system involvement. The patients who developed complete autonomic neuropathy (both sympathetic and parasympathetic) were individuals with considerable level of functional failure, more severe clinical presentation and the existing anxiety and depression. PMID- 24783415 TI - Natural autoantibodies in healthy neonatals recognizing a peptide derived from the second conserved region of HIV-1 gp120. AB - BACKGROUND/AIM: High sera reactivity with a peptide derived from human immunodeficiency virus HIV-1 envelope protein gpl20, NTM1, correlate with non progressive HIV-1 infection and also may have protective role in breast and prostate cancer. We also detected a low NTM1 reactive antibodies titer in healthy HIV negative sera and showed that antibody levels can be significantly increased with vigorous physical activity. However, the immune system seems to be unresponsive or tolerant to this peptide, implicating that the NTM1 sequence encompasses or overlaps a certain innate immune epitope. The aim of this study was to present evidences that NTM1 - binding antibodies - are components of innate immune humoral response, by confirming their presence in sera of newborn babies. For this purpose we collected a set of 225 innate antigen sequences reported in the literature and screened it for candidate antigens with the highest sequence and spectral similarity to NTM1 derived from HIV-1 gp120. METHODS: Sera from 18 newborns were tested using ELISA, with peptide NTM1. Sequences from innate antigen database were aligned by an EMBOSS Water bioinformatics tool. RESULTS: We identified NTM1 reactive antibodies in sera of HIV negative newborn babies. Further, in order to identify which of already known innate antigens are the most similar to NTM1 peptide we screened innate immune antigen sequence database collected from the literature. This screening revealed that the most similar sequence are ribonucleoproteins RO60, in addition to previously identified N-terminus of vasoactive intestinal peptide. CONCLUSION: The results of this study confirm the hypothesis that NTM1 recognizing antibodies are a part of humoral innate immune response. Further, computational similarity screening revealed a vasoactive intestinal peptide and RO60 as the most similar sequences and the strongest candidate antigens. In the light of the presented results, it is appealing that testing blood reactivity at birth, with specific innate antigens, particularly a vasoactive intestinal peptide, can reveal the potential to develop or boost protective immune response in breast and prostate cancer and HIV infection later in life. PMID- 24783416 TI - Apolipoprotein E gene polymorphisms as risk factors for carotid atherosclerosis. AB - BACKGROUND/AIM: Atherosclerosis is still the leading cause of death in Western world. Development of atherosclerotic plaque involves accumulation of inflammatory cells, lipids, smooth muscle cells and extracellular matrix proteins in the intima of the vascular wall. Apolipoprotein E participates in the transport of exogenous cholesterol, endogenously synthesized lipids and triglycerides in the organism. Apolipoprotein E gene has been identified as one of the candidate genes for atherosclerosis. Previous studies in different populations have clearly implicated apolipoprotein E genetic variation (E polymorphisms) as a major modulator of low density lipoprotein cholesterol levels. Data considering apolipoprotein E polymorphisms in relation to carotid atherosclerosis gave results that are not in full compliance. The aim of present study was to investigate the apolipoprotein E polymorphisms in association with carotid plaque presence, apolipoprotein E and lipid serum levels in patients with carotid atherosclerosis from Serbia. METHODS: The study group enrolled 495 participants: 285 controls and 210 consecutive patients with carotid atherosclerosis who underwent carotid endarterectomy. Genotyping of apolipoprotein E polymorphisms were done using polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: Patients had significantly decreased frequency of the epsilon2 allele compared to controls. Patients who carry at least one epsilon2 allele had a significantly higher level of serum apolipoprotein E and significantly lower low density lipoprotein cholesterol levels compared to those who do not carry this allele. CONCLUSION: Our results suggest protective effect of apolipoprotein E epsilon2 allele on susceptibility for carotid plaque presence as well as low density lipoprotein cholesterol lowering effect in Serbian patients with carotid atherosclerosis. Further research of multiple gene and environmental factors that contribute to the appearance and the progression of atherosclerosis should be continued with respect to different populations. PMID- 24783417 TI - Chromosomal instability in patients with Fanconi anemia from Serbia. AB - BACKGROUND/AIM: Fanconi anemia (FA) is a rare hereditary disease in a heterogeneous group of syndromes, so-called chromosome breakage disorders. Specific hypersensitivity of its cells to chemical agents, such as diepoxybutane (DEB), was used as a part of screening among patients with clinical suspicion of FA. The aim of this study was to determine chromosomal instability in patients with FA symptoms in Serbia. METHODS: A total of 70 patients with phenotypic symptoms of FA, diagnosed at the Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic, Belgrade and University Children's Hospital, Belgrade from February 2004 to September 2011, were included in this study. Cytogenetic instability analysis was performed on untreated and DEB-treated 72 h-cultures of peripheral blood. RESULTS: Ten patients in the group of 70 suspected of FA, showed increased DEB induced chromosome breakage and were classified into the FA group. The range of DEB induced aberrant cells percentages in the FA group was from 32% to 82%. DEB sensitivity of 58 tested patients were bellow FA values (range: 0-6%) (non-FA group), with no overlapping. The remaining two patients showed borderline sensitivity (borderline FA group - FA*), comparing to the healthy controls. CONCLUSION: This study revealed 10 patients with FA on the basis of cytogenetic analysis of DEB induced chromosome aberrations. Our results are in consistency with those from the literature. Early and precise diagnosis of FA is very important in further treatment of these patients, considering its cancer prone and lethal effects. PMID- 24783418 TI - Development and initial validation of a scale to measure attitudes and beliefs of pharmacists toward their work with patients. AB - BACKGROUND/AIM: Studies on physicians and other health care professionals indicate that attitudes towards and beliefs in their work with patients, can affect the quality of health care, and patients' behaviour and compliance, thus an instrument is needed to survey pharmacists as healthcare providers. The aim of this study was to describe the development and psychometric validation of a survey instrument to assess attitudes and beliefs of pharmacists toward their work with patients (Pharmacists' Attitudes and Beliefs Scale, PABS). The aim of this research was to determine the reliability, validity and factor structure of a newly constructed instrument - PABS. METHODS: The statements from the cognitive, affective, and behavioral areas were identified by literature review and selected to cover the behavior of pharmacists in providing pharmaceutical care at community settings. The initial 5-point Likert type scale of 30 items was constructed and after initial validation its revised form developed. The reliability, construct validity and factor structure of the scale were established. RESULTS: The reliability of the scale was determined by the method of internal consistency, on a convenient sample of 123 community pharmacists. The Cronbach's alpha coefficient was 0.67. Factor analysis of principal components was performed and 7 factors with latent roots greater than 1 were extracted, explaining 64.92% of total variance, a single 30.84%, 8.20%, 6.55%, 5.63%00, 5.01%, 4.68% and 4.01%. Based on the results of factor analysis in the development of the scale, some items in the scale were excluded (totally 7), so that the revised form of the PABS contained a total of 23 items. CONCLUSION: The initial PABS scale did not meet theoretical statistical criteria for reliability (Cronbach's alpha coefficient was < 0.7), but the findings indicated its potentially acceptable construct validity. The results support its use as a research tool to assess the behavior of pharmacists in daily practice, and provide its use as an indicator of quality in delivering pharmaceutical care. PMID- 24783419 TI - The impact of anabolic androgenic steroids abuse and type of training on left ventricular remodeling and function in competitive athletes. AB - BACKGROUND/AIM: Long-term intensive training is associated with distinctive cardiac adaptations which are known as athlete's heart. The aim of this study was to determine whether the use of anabolic androgenic steroids (AAS) could affect echocardiographic parameters of left ventricular (LV) morphology and function in elite strength and endurance athletes. METHODS: A total of 20 elite strength athletes (10 AAS users and 10 non-users) were compared to 12 steroid-free endurance athletes. All the subjects underwent comprehensive standard echocardiography and tissue Doppler imaging. RESULTS: After being indexed for body surface area, both left atrium (LA) and LV end-diastolic diameter (LVEDD) were significantly higher in the endurance than strength athletes, regardless of AAS use (p < 0.05, for both). A significant correlation was found between LA diameter and LVEDD in the steroid-free endurance athletes, showing that 75% of LA size variability depends on variability of LVEDD (p < 0.001). No significant differences in ejection fraction and cardiac output were observed among the groups, although mildly reduced LV ejection fraction was seen only in the AAS users. The AAS-using strength athletes had higher A-peak velocity when compared to steroid-free athletes, regardless of training type (p < 0.05 for both). Both AAS-using and AAS-free strength athletes had lower e' peak velocity and higher E/e' ratio than endurance athletes (p < 0.05, for all). CONCLUSIONS: There is no evidence that LV ejection fraction in elite athletes is altered by either type of training or AAS misuse. Long-term endurance training is associated with preferable effects on LV diastolic function compared to strength training, particularly when the latter is combined with AAS abuse. PMID- 24783420 TI - Difficulties in proving medical errors - where do we stand? PMID- 24783421 TI - Congenital thrombocytopenia with nephritis - The first case of MYH9 related disorder in Serbia. AB - INTRODUCTION: The group of autosomal dominant disorders - Epstein syndrome, Sebastian syndrome, Fechthner syndrome and May-Hegglin anomaly - are characterised by thrombocytopenia with giant platelets, inclusion bodies in granulocytes and variable levels of deafness, disturbances of vision and renal function impairment. A common genetic background of these disorders are mutations in MYH9 gene, coding for the nonmuscle myosin heavy chain IIA. Differential diagnosis is important for the adequate treatment strategy. The aim of this case report was to present a patient with MYH9 disorder in Serbia. CASE REPORT: A 16 year-old boy was referred to our hospital with the diagnosis of resistant immune thrombocytopenia for splenectomy. Thrombocytopenia was incidentally discovered at the age of five. The treatment with corticosteroids on several occasions was unsuccessful. Although the platelet count was below 10 x 10(9)/L, there were no bleeding symptoms. Besides thrombocytopenia with giant platelets, on admission the patient also suffered sensorineuronal hearing loss and proteinuria. The diagnosis was confirmed with immunofluorescence and genetic analyses. CONCLUSION: Early recognition of MYH9-related diseases is essential to avoid unnecessary and potentially harmful treatments for misdiagnosed immune thrombocytopenia, and also for timely and proper therapy in attempt to delay end-stage renal failure and improve quality of life. PMID- 24783422 TI - Isolated hepatic sarcoidosis. AB - INTRODUCTION: Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Although hepatic granulomas occur in 50-65% of patients with systemic sarcoidosis, isolated liver sarcoidosis is rare. Clinical presentation varies from asymptomatic to manifest. The diagnosis is based on a characteristic histopathological finding of liver biopsy. CASE REPORT: We reported a 69-year old man was admitted due to abdominal swelling and abdominal pain. Laboratory studies detected: cholestasis, pancytopenia and elevaton of angiotensin-converting enzyme. Abdominal imaging techniques showed liver cirrhosis, splenomegaly and ascites. The diagnosis of the hepatic sarcoidosis was confirmed by histopathological examination of liver biopsy. The patient was treated with corticosteroids. After 18 months the patient was without any subjective symptoms, and with biochemical and clinical improvement. CONCLUSION: Isolated hepatic sarcoidosis should be considered in the differential diagnosis of asymptomatic or simptomatic patients with hepatosplenomegaly and changes in liver functional tests. Only the timely diagnosis and proper treatment can lead to subjective and objective improvement of patients. PMID- 24783423 TI - Aggravation of symptomatic occipital epilepsy of childhood by carbamazepine. AB - INTRODUCTION: Carbamazepine can lead to aggravation of epileptic seizures in generalized epilepsies (primary or secondary) with clinical manifestations of absence (typical or atypical) and/or myoclonic seizures. However, some focal epilepsies can be also aggravated by the introduction of carbamazepine. CASE REPORT: We presented a 10-year-old boy born after a complicated and prolonged delivery completed by vacuum extraction, of early psychomotor development within normal limits. At the age of 8 years he had the first epileptic seizure of simple occipital type with generalization and urination. Brain magnetic resonance imaging (MRI) showed focal cortical reductions in the left parietal and occipital regions. Interictal EEG recorded slowed basic activities above the posterior regions of the left hemisphere, with intermittent occurrence of occipital sharp waves and bioccipital sharp and slow-wave complexes. Initially, treatment with valproate was administered; however, the addition of carbamazepine into therapy induced aggravation of seizures and EEG findings, changed behavior and poor performance at school. By withdrawal of carbamazepine the condition improved both clinically and in EEG findings. CONCLUSION: Childhood occipital epilepsy lesions show deterioration due to carbamazepine, which if administered induces aggravation of seizures, behavior changes, cognition with occurrence of long-term bilateral discharges, and posterior sharp and slow-wave high amplitude complexes recorded by EEG. PMID- 24783424 TI - Bilateral giant angiomyolipomas revealed after massive retroperitoneal hemorrhage - A case report. AB - INTRODUCTION: Angiomyolipomas (AML) are benign neoplasms composed of fat, smooth muscle and thick-walled blood vessels in varying proportions. These tumors have a significant female predominance. CASE REPORT: We reported a 61-year-old man with spontaneous rupture of AML. Computerized tomography revealed a change in morphology of both kidneys. Multiple lesions of fat density with dilated blood vessels were found in the left kidney. The right retroperitoneum was obliterated with a giant heterogeneous mass originating from the right kidney with a massive hemorrhage, active extravasations, compression of inferior the vena cava and intraperitoneal collections. After radical nephrectomy, histological examination revealed that the tumor was composed of relative proportions of fat, smooth muscle and blood vessels. We incidentally found small renal adenoma. CONCLUSION: The true nature of AML is unclear, but they are usually classified as hamartomas. Angiomyolipomas are generally benign lesions, although the epithelioid angiomyolipoma, a subtype that occurs in about 3% of cases, can behavior aggressively. PMID- 24783425 TI - Invalidity and deformity in the art of Weimar Republic. PMID- 24783426 TI - Chekhov speaks to us. PMID- 24783427 TI - [Expression profile of genes associated with the histaminergic system estimated by oligonucleotide microarray analysis HG-U133A in women with endometrial adenocarcinoma]. AB - INTRODUCTION: Influence of histamine on tumor development remains obscure. The exact mechanism of this action is not known. Different data indicate high concentrations of histamine in tumor tissues, such as malignant melanoma, breast cancer, colon carcinoma, lymphomas and leukemia. To the best of our knowledge, the literature offers no reports about the role of histamine and of differences between expression patterns of histamine-related genes in endometrial cancer AIM: The aim of the study was a comparative analysis of the gene expression profile involved with histaminergic system in endometrioid endometrial cancer in relation to histologically normal endometrium, and identification of differentiation genes whose transcriptional activity significantly differs in pathomorphological grades G1,G2, G3 of endometrial cancer as compared to the control group. MATERIAL AND METHODS: Total RNA was extracted from 24 endometrial probes using TRIzol reagent (Invitrogen). The expression profile of 119 transcripts associated with histaminergic system was assessed using oligonucleotide microarrays of HG-U 133A (Affymetrix). After normalization of the results with RMA Express software, differentiation genes were mined by the use of one-way analysis ANOVA and U Mann Whitney test carried out in Gene Spring 11.5 software. RESULTS: Among 119 transcripts, 14 expressed more than 1.5-fold change and were significant at p<0.05 in endometrioid endometrial cancer in relation to the normal endometrium. Further analysis led to the identification of differentially expressed genes in grades G1, G2 and G3 of endometrial adenocarcinoma as compared to the control group, which were specific for each of the studied groups in grade G1 (CPA3), in grade G2 (HNMT LYN, DPT ITPKB, RASA4, APR RAB1 1FIP1, YWHAZ, VAMP8, RAB25) and in grade G3 (HRH3). CONCLUSIONS: Our results confirmed the role of the histaminergic system in the pathogenesis of endometrial adenocarcinoma. The observed differences in the expression of those genes, depending on the grade of adenocarcinoma, may indicate an important role of the isolated differentiation genes in endometrial tumorigenesis. PMID- 24783428 TI - The importance of 8993C>T (Thr399Ile) TLR4 polymorphism in etiology of osteoporosis in postmenopausal women. AB - INTRODUCTION: Toll-like receptors (TLR) may play a key role in initiating cellular signaling pathways by increasing the levels of inflammatory cytokines which, cooperating with osteoclasts, influence bone turnover Numerous research articles focused on the genetic background of this condition, among others on polymorphic variants in TLR genes. The aim of the study was to examine the role of 20877G>A (Arg753GIn) in TLR2 gene and 8993C>T (Thr399lle) in TLR4 gene in the etiopathogenesis of postmenopausal osteoporosis in Polish women. MATERIAL AND METHODS: This study included 180 postmenopausal women (t-score < or = -2.5), 153 postmenopausal women with osteopenia (t-score between -2.5 and -1), and 91 postmenopausal healthy women with correct t-score (t-score >-1). The 20877G>A TLR2 and 8993C>T TLR4 polymorphisms were determined by PCR/RFLP analysis. RESULTS: The analysis did not reveal statistically significant differences in the distribution of genetic variants of 20877G>A TLR2 polymorphism between the investigated groups of women. The most interesting results were connected with 8993C>T TLR4 polymorphism. Comparison of the group with osteoporosis and controls revealed overrepresentation of heterozygous 8993CT genotype (13.3 vs. 5.5%, OR=2.65, p=0.03). Also, mutated 8993T allele was overrepresented in the group with osteoporosis (6.7 vs. 2.7%, OR=2.52, p=0.04). Higher frequency of heterozygous 8993CT genotype (13.3 vs. 4.6%, OR=3.21, p=0.004) and mutated 8993T allele (6.7 vs. 2.3%, OR=3.05, p=0. 005) was noted in osteoporotic women as compared to the group with osteopenia. Higher frequency of heterozygous 8993CT genotype (13.3% vs. 5.3%, OR=2.73, p=0.003) and mutated 8993T allele (6.7 vs. 2.7%, OR=2.67, p=0.004) was observed in the group with osteoporosis as compared to women with osteopenia and with correct t-score. CONCLUSIONS: Results of our study suggest an important role of mutated 8993T allele of 8993C>T TLR4 polymorphisms in the etiology of postmenopausal osteoporosis. Nevertheless, this observation requires further investigation with larger sample size comprised of Polish women. PMID- 24783429 TI - [Comparative analysis of interuterine therapy of unilateral and bilateral fetal obstructive uropathy]. AB - OBJECTIVE: The goal of the work was a comparative analysis of intrauterine therapy among pregnant women with diagnosed fetal uropathy and unilateral hydronephrosis. METHODS: The study was conducted on a group of 98 pregnant women hospitalized at the Department of Gynecology Fertility and Fetal Therapy Polish Mother's Memorial Hospital between 2006-2012. The study group included 77 cases of fetal obstructive uropathy (79%) and 21 cases of unilateral hydronephrosis (21%). Both groups have been analyzed in terms of prognosis. Follow-up has been conducted and results have been statistically analyzed. RESULTS: In 11% of cases of obstructive uropathy therapy early complications were observed. The remaining 89% of the patients delivered at a later date, of which 54% after 34 weeks of pregnancy The average weight of a newborn was 2645g and Apgar score - 7.45. 73% of newborns were discharged home in good condition, with preserved diuresis. CONCLUSIONS: 1. The use of intrauterine therapy has a positive effect on fetal condition and newborn postnatal state. 2. Unilateral hydronephrosis group was characterized by a significantly longer duration of pregnancy higher birth weight, Apgar score, and greater survival of newborns. 3. In the group of obstructive uropathy survival improvement was achieved and dieresis was preserved Intrauterine interventions were associated with a low risk of complications. PMID- 24783430 TI - [Clinical study of perinatal hysterectomy between 2000-2011 in the clinic of obstetrics, gynecological diseases and oncological gynecology in Bydgoszcz]. AB - INTRODUCTION: Perinatal hysterectomy (PH) is usually a life-saving procedure, which is performed after all conservative treatment options fail. The PH frequency rate ranges from 0.04 to 0.23%. The most frequent indications for this procedure include: abnormal placental implantation, placenta previa, uterine rupture and uterine atony OBJECTIVE: Clinical study of perinatal hysterectomy cases taking into consideration the frequency indications, complications and risk factors related to this procedure. MATERIALS AND METHODS: The study included 16 women who underwent perinatal hysterectomy at the Department and Clinic of Obstetrics and Gynecological Diseases between 2000-2011. The following data were collected from medical records: course of pregnancy labor and puerperium. The profile of the study group was conducted in terms of: maternal age, parity gestation length, history of caesarean sections and gynecological operations. The following factors were studied: the termination of pregnancy, indications for caesarean section, hysterectomy-related complications and indications, neonatal birth weight and Apgar score. The statistical analysis was performed using Statistica 9.1 by StatSoft. Data are expressed as the arithmetic mean and standard deviation (SD). RESULTS: Sixteen perinatal hysterectomy procedures were performed, accounting for 0.066% of the overall number of labors. Average maternal age and pregnancy length were 31.6 years [SD+/-6.3] and 36.1 weeks of gestation [SD+/-3.4], respectively PH was more frequently performed among multiparous women (81.25%) and after caesarean sections (87.5%). Fetal asphyxia was the most frequent indication for caesarean section (35.7%). Fourteen percent of all indications accounted for the lack of consent from a pregnant woman to make an attempt at spontaneous vaginal delivery after previous c-section. Fifty percent of the women from the study group had a previous caesarean section, whereas 25% had more than one prior c-section. Between 2009-2011, as compared to previous years, the highest percentage of hysterectomies (80%) was reported in pregnant women after a previous caesarean section. The most frequent indication for hysterectomy included abnormal placental implantation (43.75%) diagnosed more often in patients with a history of caesarean section (57%). Among PH complications, a hemorrhagic shock was reported in 37.4% and bladder injury in 18.7% of the women. Every patient required a transfusion of erythrocyte concentrate, 4.7 units [SD+/-3.5] on average. Twenty-five percent of the neonates were born in poor condition with an Apgar score of 1-3. In case of all women, the therapy required cooperation of different specialists including obstetricians, anesthesiologists, urologists, surgeons and general practitioners. CONCLUSIONS: 1. Current and previous caesarean section constitutes a risk factor for perinatal hysterectomy 2. Placental pathology is the most frequent indication for perinatal hysterectomy 3. The growing number of caesarean sections should encourage obstetricians to conduct a more careful analysis of indications. PMID- 24783432 TI - Prognostic value of elastography in predicting premature delivery. AB - OBJECTIVES: The aim of the study was to assess changes in the consistency of the uterine cervix and correlate the obtained results with the risk of premature delivery and time from examination to delivery MATERIAL AND METHODS: Elastographic images of the cervix in a group of 44 patients, admitted to the hospital due to uterine contractions before 37 weeks of gestation, were recorded and analyzed. Elastograms were assessed with the use of Elastography Index (El), a five-step (0-4) color scale, which visualizes tissue hardness by encoding numerical values in specific colors (0-violet/the hardest tissue; 4-red/the softest tissue). Correlation between El for different parts of the uterine cervix was evaluated and analyzed in relation to preterm delivery and time from examination to delivery. RESULTS: Twenty-one patients delivered before term and 23 at term. A strong correlation for El of the internal os and time from examination to delivery (Pearson test, p<0.001), and risk of preterm birth (Mann Whitney-Wilcoxon test, p<0.001), was noted. We also found a strong correlation between cervical canal length and risk of preterm delivery (Anova test, p=0.001), and time from examination to delivery (Pearson test, p=0.006). CONCLUSIONS: Elastography may offer a chance for an objective assessment of elasticity of the uterine cervix and may become an alternative to vaginal examination and Bishop score. Proper selection of patients with high or low risk of preterm delivery may facilitate good management decisions and, consequently decrease the percentage of immature deliveries, unnecessary medical procedures, and hospitalization. PMID- 24783431 TI - Mean platelet volume, neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in severe preeclampsia. AB - OBJECTIVES: The aim of the study was to compare the changes in the values of leukocytes, neutrophils, lymphocytes, mean platelet volume (MPV), and systemic inflammatory response (SIR) markers (neutrophil-lymphocyte ratio/ platelet lymphocyte ratio) in patients with severe preeclampsia (PE) of healthy pregnant and non-pregnant women. MATERIAL AND METHODS: Hematological parameters including MPV and SIR markers [neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR)] were compered between the between three groups comprising of women with severe PE, healthy pregnant women and healthy non-pregnant women. RESULTS: MPV and PLR did not show statistically significant differences between the three groups (p=0.081, p=0.098). NLR showed a statistically significant difference between the three groups (p=0.000). NLR values of patients with severe PE were statistically significantly higher than healthy non-pregnant women (p=0.000). No statistically significant difference was found between patients with severe PE and healthy pregnant women (p=0.721). The cut-off value of the leukocyte number for severe PE was 7.6 x 10(3)/ml, with 76.7% sensitivity and 60.6% specificity. The cut-off value of neutrophil number was 6.4 x 10(3)/ml for the group with severe PE, with 76.7% sensitivity and 69% specificity. CONCLUSIONS: Our results showed that MPV level did not differ among patients with severe PE, healthy pregnant women and non-pregnant women. NLR cannot be used to identify patients with severe PE. PLR measured before termination of pregnancy is not an effective marker for severe PE, either. PMID- 24783433 TI - [Non-invasive prenatal diagnosis of the most common aneuploidies with cell-free fetal DNA in maternal serum--preliminary results]. AB - OBJECTIVES: The aim of the study was to present initial results of non-invasive prenatal diagnosis of common aneuploidies of chromosomes 21, 18 and 13 based on cell-free fetal DNA in maternal serum in high-risk patients, and to compare the results with routine karyotyping. MATERIAL AND METHODS: Before the invasive procedure, 10 ml of peripheral blood from 10 patients was collected to isolate cell-free fetal DNA and to perform a non-invasive fetal trisomy test (NIFTY provided by Beijing Genomics Institute, BGI, Shenzen, China). RESULTS: Three out of 10 samples showed an abnormal karyotype in traditional karyotyping. There were 9 conclusive NIFTY results. NIFTY detected 1 out of 2 trisomies 18. The quantity of cell-free fetal DNA in maternal plasma in the second probe with trisomy 18 was unsatisfactory fora conclusive NIFTY result. In 1 case traditional karyotyping revealed mosaicism impossible to detect with NIFTY PMID- 24783434 TI - [The new era in the pharmacological treatment of overactive bladder (OAB): mirabegron--a new selective beta3agonist]. AB - Overactive bladder is defined by ICS as urgency frequency and nocturia, with or without urgency urinary incontinence in the absence of urinary tract infection, or other obvious causative pathology Lower urinary tract symptoms (LUTS) are highly prevalent, especially in aging populations. Epidemiological studies reported LUTS in 62% of men and 67% of women, rising to 81% and 79%, respectively in adults over 60 years old. However the actual burden of LUTS remains relatively unrecognized. LUTS, mainly due to considerable distress including almost all aspects of social functioning, impact on sleep and mental health, may significantly affect quality of life. Management of LUTS including OAB has undergone dramatic changes since 1972, when the first antimuscarinic drug oxybutynin, was introduced into clinical practice. In the last two decades, six new antimuscarinic drugs entered OAB field and this was accompanied by introduction of botulinum toxin into clinical practice in patients resistant to or not compliant with antimuscarinics. Nowadays, it is recognized that OAB is progressive, age-related and non sex-specific condition with most patients experiencing a combination of storage, voiding and post-micturition symptoms. In 2013, the next step was taken, with new therapeutic options for OAB, enabling an even more patient-tailored approach. This was possible for both, male and female OAB sufferers with new class of oral 3 adrenoreceptor agonist (mirabegron). This drug, by stimulation of 3-adrenoceptors, couples via Gs proteins to adenylyl cyclase, what results in an increase of intracellular cAMP levels and a subsequent activation of cAMP-dependent protein kinase A, which then phosphorylates myosin light chain kinase responsible for inhibition of calcium calmodulin dependent interaction of myosin with actin. Moreover the cAMP increase also leads to the reduction of cytoplasmic Ca2+ concentration by removal of calcium ions from cytoplasm. These both actions result in a significant increase in the storage bladder capacity and by this interval between micturitions is prolonged. Mirabegron was evaluated in three 12-week, double blind, randomized, placebo controlled, parallel-group, multicenter clinical trials in OAB patients with symptoms of urge urinary incontinence, urgency and frequency - study 046, 047 and 074. It should be pointed out that efficacy of mirabegron was maintained through the entire 12-month period in phase Ill long-term study Discoveries on the physiology of the normal bladder and on the pathophysiology underlying OAB have led to the development of new treatment options for OAB. Pharmacological management of OAB should be tailored to patient's characteristics. New and recent options of pharmacological treatment have undoubtedly expanded treatment possibilities, what should allow physicians to select the optimal treatment for each patient. PMID- 24783435 TI - [Is diabetes mellitus worth treating?]. AB - The aim of the paper was to present data that enable us to determine whether treatment of hyperglycemia diagnosed during pregnancy in the era of a steadily growing number of women with gestational diabetes mellitus (GDM) and an ongoing debate about new criteria and diagnostic strategies, is a valid option. GDM is the main metabolic disorder developing during pregnancy complicating around 6% of all pregnancies. Mistreatment of hyperglycemia during pregnancy may cause several fetal complications, especially neonatal overgrowth (macrosomia or LGA). The risk of macrosomia is directly related to maternal hyperglycemia (twice as high as in the control group with glucose levels exceeding 130 mg/dl). Apart from maternal hyperglycemia and fetal hyperinsulinemia, insulin-like growth factors and selected adipocytokines produced by adipose tissue and placenta are among the factors contributing to the development of diabetic fetopathy, whose risk increases by 2-fold with glucose levels exceeding 130 mg/dl. The role of hyperglycemia as a factor inducing several perinatal complications was confirmed by the HAPO study but it is not the sole reason of adverse effects. Also, maternal obesity weight gain during pregnancy and maternal hyperlipidemia seem to be involved in the pathogenesis of feto-maternal complications. Changes in fetal growth, disturbances in the perinatal period, there just some of the negative consequences of maternal GDM. Disturbance of carbohydrate metabolism during pregnancy causes long-lasting consequences for both, the mother and the child, including increased risk of overt diabetes, metabolic syndrome and cardiovascular complications. Children born to GDM mothers are at a significant risk of psycho motoric disability and a higher risk of schizophrenia. ACHOIS and MFMU studies have confirmed that even mild hyperglycemia, detected and treated in a timely manner significantly improves maternal and fetal outcome. Various meta-analyses have revealed a positive effect of GDM treatment. To the best of our knowledge, no clinical study has revealed negative effects of such treatment, with the exception of an increased number of perinatal visits. PMID- 24783436 TI - [Severe hemolytic disease of the newborn as a result of late and undiagnosed alloimmunization--case report]. AB - We report a case of a hemolytic disease in a newborn from the first pregnancy due to anti-D antibodies. The maternal blood group was A Rhesus negative. She had an antibody screening test twice during the pregnancy (in the second trimester) and it was negative. The pregnancy was uneventful, without any invasive procedures and bleeding. The infant was born at 39 weeks of gestation in good overall condition. After the delivery the blood group of the neonate was indicated - A Rhesus positive, BOC positive. Anti-D antibodies were detected in maternal blood. Neonatal blood tests revealed severe anemia (hemoglobin level: 6.0g/dl, hematocrit: 22.2%, erythrocytes: 2.01T/L). During the first day of neonatal life, the newborn received two transfusions of red blood cells. Bilirubin level and rate of rise were not recommendation enough for exchange transfusion. The newborn was treated with continuous phototherapy since the delivery The perinatal period was complicated with intrauterine infection and respiratory failure. Hematopoietic vitamins and iron supplementation was initiated in the second week of neonatal life due to persistent anemia. The child remained under medical care of a hematologic clinic and received human recombinant erythropoietin treatment. PMID- 24783437 TI - [Chorioangioma--a case study]. AB - Chorioangioma (chorionic angioma) is the most common non-malignant placental tumor Taking into account its morphological structure, it can have significant influence on fetal condition and pregnancy depending on its size. In the presented case a substantial placental tumor was diagnosed and complications typical for chorioangioma, such as fetal hemodynamic disorders, polyhydramnios, gestational diabetes and premature labor were observed. The applied treatment led to normalization of the fetal and maternal condition and to prolongation of the pregnancy PMID- 24783438 TI - [Safety and eligibility for hormonal and intrauterine contraceptions--Polish Gynecological Society Recommendation]. PMID- 24783439 TI - [Mental health care systems and provisions in the immediate and acute phase of the Great East Japan Earthquake: situational and support activities in Miyagi Prefecture]. AB - The Great East Japan Earthquake on March 11, 2011, which measured 9.0 on the Richter scale, was followed by a huge tsunami that caused catastrophic damage to the area extending from the Tohoku to Kanto regions. It was also accompanied by the meltdown of the Fukushima Daiichi Nuclear Power Station. Mental health service provisions were hit equally hard by the disaster, with a wide range of support and relief activities being implemented. This article reviews damage that was inflicted and support activities that were carried out in the mental health field in Miyagi Prefecture in the immediate aftermath and acute phase of the disaster, and also examines future challenges. Almost all mental health institutions in Miyagi Prefecture were affected by the disaster, and experienced difficulties such as feeding inpatients and securing necessary medication. Mental health institutions in the coastal area, in particular, were severely hit. Three hospitals-were seriously damaged by the tsunami, which forced them to make arrangements for the transfer of 300 inpatients. In the aftermath of the earthquake, it became difficult to access medical institutions, and confusion ensued regarding the provision of mental health services. Many municipalities in Miyagi Prefecture were seriously affected by the disaster, and information gathering was crippled due to the disruption of communication and transport networks. Consequently, the administrative function regarding mental health service provisions was significantly impaired. Through official, private, and academic channels, volunteers in the field of mental health were sent to the affected areas in the immediate aftermath of the disaster. It was very difficult to coordinate these volunteers because of the confusion in gathering-information and in the chain of command for support activities. The number of support teams working in the affected areas peaked one to two months after the earthquake, but it became clear that continuous and long-term support in mental health service provisions by external support teams was necessary in some remote areas. Measures were taken to care for the elderly and children, to tackle alcohol-related problems, and provide support for volunteers, but many challenges remain. When a disaster hits, measures appropriate to the nature and size of the disaster become necessary, and the need arises to construct a model to facilitate such responses. It is now necessary to integrate mental health measures with a municipality's plan for medical care in a disaster, along with develop a permanent system to provide support for mental health care at the time of a disaster. PMID- 24783440 TI - [Mental health care management after the 2011 tsunami disaster in Higashi Matsushima, Japan]. AB - The Department of Neuropsychiatry of Tokyo University continues to support mental health care in Higashi-Matsushima City, Miyagi, Japan. We participate in mental care from the acute to the chronic phase. We also provide mental care for children. In this paper, we summarize our activities during the two years since the disaster. We also state our views on management in disaster care. PMID- 24783441 TI - [After the Great East Japan Earthquake : suicide prevention and a gatekeeper program]. AB - When considering approaches to mental health in areas affected by the 2011 Great East Japan Earthquake, as well as the resulting tsunami and Fukushima nuclear power plant accident, it is not sufficient to focus interventions solely on individuals experiencing mental health issues. The situation demands a comprehensive approach that includes programs that target improvements to mental health literacy among residents in areas affected by the disaster, the rebuilding of relationships between residents themselves, collaboration with recovery and support activities, and mental health support for people participating in recovery and support efforts. From a medium- to long-term perspective, suicide prevention is an important issue. Comprehensive suicide prevention efforts are being promoted in areas of Iwate Prefecture affected by the disaster. In suicide prevention programs, it is crucial to foster the development of human resources in the local community. In order to expand community supports, it is necessary to provide education on ways of supporting those affected by a disaster to local medical personnel, people staffing inquiry and consultation offices, and people in fields related to mental health. Suicide prevention and disaster relief efforts are both approaches that target people in difficulty, and they share commonalities in principles, systems, and approaches to human resource development. "Mental health first aid" is a program developed in Australia that defines methods of early intervention by non-professionals who encounter someone experiencing a mental health problem. The mental health first aid-based gatekeeper training program of the Japanese government's Cabinet Office, which the author's research team helped to develop, allows participants to obtain the knowledge and skills required of gatekeepers. In 2012, a module for disaster affected areas was developed and added to the program, with additional content that provides program participants with the skills to respond in crisis situations encountered during advice/counseling work in evacuation centers and temporary housing facilities. In addition, since 2011 the Cabinet Office has offered a facilitator training program that was developed based on the gatekeeper training program. Program text materials may be downloaded from the Web site of the Cabinet Office, and it is hoped that they will be used in the education of those involved in caring for people affected by a disaster. PMID- 24783442 TI - [Activity to prevent mental diseases after the Great East Japan Earthquake]. AB - Following the Great East Japan Earthquake, we have been supporting psychiatric hospitals and mental health and welfare centers in Miyagi Prefecture. In October 2011, with a grant from Miyagi Prefecture, the Department of Preventive Psychiatry was established in Tohoku University Graduate School of Medicine. The institute aims to promote the prevention of and early intervention for mental diseases. As its members, we carry out our duties in collaboration with the Miyagi Disaster Mental Health Care Center. We refer to our activities as the Great East Japan Earthquake Mental Health Support and Research (GEMS) project. The GEMS project includes both practices and research in the affected areas in Miyagi Prefecture. The focus is on supporting those who provide services for survivors long-term, such as municipal employees, nurses, fire fighters, and staff of the social welfare council. We investigated how much the disaster impaired the functioning of psychiatric hospitals and clinics in Miyagi Prefecture. We also conduct mental health surveys in public organizations. Based on the results, we arrange workshops, consultation, or counseling. Moreover, we promote improvement of the mental health skills of mental health professionals, which are essential for mid and long-term support after the disaster. One of them is "Skills for Psychological Recovery". As members of the support organization in the region, we keep working toward the recovery and development of mental health systems in Miyagi Prefecture. PMID- 24783443 TI - [My work giving university-funded lectures launched after Great East Japan Earthquake]. AB - On March 11, 2011, a mega earthquake shook the eastern part of Japan, recording a magnitude of 9.0. I have written about my work experience at the university hospital-funded lectures, set up to provide support in the disaster areas. When the lecture was launched, the university did not give official approval to it. For me, it was almost like I had just landed a job at a hospital in a rural area. Now, there are a number of funded lectures mainly in and around disaster-hit areas. I expect that these lectures will narrow down their objectives so that people involved in them will be able to end their tenure happily. PMID- 24783444 TI - [Report from Minamisoma City: diversity and complexity of psychological distress in local residents after a nuclear power plant accident]. AB - Natural disasters can severely impact local communities. When a disaster is limited in type or scope, the loss and distress felt by individual residents can be sympathetically visualized and shared, and this can help bring the community together. In 2011, however, Japan experienced the Great East Japan Earthquake and accompanying tsunami, and the scale of this disaster was compounded by the Fukushima nuclear power plant accident. As a result of this complex disaster, residents experienced very different problems, particularly in Fukushima Prefecture. In this paper, we describe the situation in Minamisoma City, which is located to the north of the Fukushima Daiichi nuclear power plant. After the accident, the city was divided into three zones. The southern part of the city, which is within 20 km of the plant, was designated as a restricted area; the middle section, located between 20 and 30 km of the plant, was initially designated as an evacuation readiness area; and the northern part of the city received no evacuation-related designation. In April 2012, ordinary residents were finally allowed to visit the restricted area, but utilities and municipal services in the area had not yet been restored, and residents were still prohibited from staying overnight even in August 2013. The overall situation was further complicated by the existence of conflicting opinions regarding exposure to low dose ionizing radiation and compensation for subsequent distress. Things became so complex that residents of the same city sometimes struggled to imagine their neighbors' feelings and state of mind. After the disaster, aging of the city accelerated dramatically. The proportion of elders (those aged 65 or older) in the population stood at 25.9% in March 2011, but this had increased to 32.9% by March 2013. Elders tend to have strong emotional ties to their hometowns, while younger generations are more likely to move away and start over. As some young people have left the area or stopped working, the city is suffering from a lack of workers. A number of residents are in a state of being overworked. While children and mothers face more difficulties after the disaster, they are less able to find support in the city. As of the end of March 2013, 406 deaths in Minamisoma were officially attributed to disaster-related distress. The psychological burdens placed on residents of this city are too heavy to be ignored. Robust efforts and interventions are urgently needed in order to improve mental hygiene in the area. PMID- 24783445 TI - [Mental health in evacuees from the 3.11 complex disaster in Japan]. AB - Two years after the "3.11" complex disaster--the Great East Japan Earthquake, the resulting tsunami, and the Fukushima nuclear power plant accident--that occurred on March 11, 2011, approximately 150,000 people were still living as evacuees, with approximately 50,000 evacuees living outside Fukushima Prefecture. In a survey conducted by the Asahi Shimbun newspaper in February 2012, the top three sources of anxiety among evacuees were radiation contamination (mentioned by 56% of respondents), income (48%), and school attendance of children (21%). In June 2012, results from the Mental Health Survey, which was conducted as part of the Fukushima Health Management Survey, indicated that 14.8% of adult evacuees had K6 scores equal to or greater than the standard cut-off of 13, a much higher proportion than the 3% found in previous studies. In the same survey, 21.5% of child evacuees had SDQ scores equal to or greater than the standard cut-off of 16, whereas previous studies suggest a typical ratio of around 9.5%. It is natural for people to experience anxiety when facing radiation exposure, even at low levels. Here the important thing is to be "accurately" afraid: people should pay attention to scientific facts, and avoid danger appropriately, but not be unduly frightened. However, some people remain anxious even when objective radiation levels are low enough to not result in harm. A number of parents with young children decided to relocate outside of Fukushima Prefecture. In consideration of the desires of these parents to have areas where their children could play without being concerned about radiation, some municipalities constructed spacious indoor play facilities where parents have increased opportunities to communicate with each other, which actually leads to effective risk communication. Compared to the trajectory of mental health recovery after the 1995 Hanshin-Awaji Earthquake, recovery after the present disaster is delayed, particularly in Fukushima. In Fukushima, many disturbing events, such as the issue of water contaminated by radiation, have distressed evacuees, resulting in their delayed recovery in terms of mental health. PMID- 24783446 TI - [Mental health support for disaster relief personnel]. AB - The Tohoku-Pacific Ocean Earthquake, which occurred on March 11, 2011, caused serious damage and resulted in numerous fatalities and almost 20,000 missing persons. Furthermore, a major accident accompanied by exudation of radioactive material occurred in the Fukushima Daiichi Nuclear Power Plant. A statement regarding the victims' mental health was issued by the Japanese Society of Psychiatry and Neurology on May 21, 2011, which established the Department of Disaster Psychiatry for the provision and assurance of long-term mental care support for the victims. The Department of Disaster Psychiatry was consequently reformed in April 2012, focusing on the following objectives: to verify the validity of current mental support methods; to ensure disaster psychiatry and medical care in Japan; and to promote human resource development that can respond to future large-scale disasters. Mental health support for disaster victims is of highest priority. However, the mental health of relief personnel, who act as front liners during disasters (i. e., police officers, fire fighters, Self Defense Forces, and health care workers), has often been neglected. Therefore, countermeasures for the problems faced by relief personnel are indispensable for a more effective reconstruction. Volunteers are also important members of the disaster relief team and they have witnessed the actual tragedy, and some have experienced burnout. Thus, they require sufficient mental health support, as do relief personnel. We thought that the mental health of disaster relief personnel is an important issue; thus, we report their mental health needs, the systematic correspondence to disaster stress, and our works for relief assistance. As first responders, relief personnel even without prior disaster education proceed to the area of disaster and may get injured. We therefore suggest that prior to the occurrence of any disaster, networking, education, and disaster awareness should be advocated among relief personnel and volunteers to safeguard their mental health. However, programs on these subjects remain insufficient. We extend our utmost respect and appreciation to the disaster relief workforce for doing their best to save lives. We hope that this aids in the reconstruction process of such affected areas. PMID- 24783447 TI - [Perspectives on researches in disaster psychiatry]. AB - After experiencing the catastrophic Great East Japan Earthquake and Tsunami disaster in 2011, Tohoku University founded the International Research Institute of Disaster Science (IRIDeS) in April, 2012. IRIDeS, comprising 7 divisions and 36 laboratories with broad areas of specialization, from the humanities to natural sciences, aims to become a global center for the study of disasters and disaster mitigation, learning from and building upon past lessons in disaster management from Japan and around the world. In IRIDeS, the Department of Disaster Psychiatry is in charge of dealing with issues related to disaster psychiatry, including the psychosocial impact of disasters. Now, at more than 2 and a half years after the catastrophic disaster, the psychological impact actually seems to be getting stronger and wider, whereas the memory of the disaster seems to be waning in other areas of the country. In such a situation, where a number of problems need to be resolved, what can/should we do as psychiatrists? On the other hand, other natural disasters, such as storms and floods, have kept hitting Japan, and catastrophes seem to strike somewhere in the world every year. In addition, we need to prepare for the possibility of a Nankai Trough Quake and an earthquake directly hitting the Tokyo area, which may occur sometime in the future. Considering the situation, we need to establish an education system for disaster psychiatry, and proceed with research to collect useful information to prepare for coming disasters. The aim of our department is to integrate multi faceted basic and clinical research approaches to investigate the following topics: 1) to identify social, psychological, and biological factors involved in the pathophysiology of and recovery from disaster-related mental health problems; 2) to develop systems for disaster prevention, disaster response, and recovery, considering disaster-related psychiatric and psychological issues; 3) to develop useful tools for the prevention, screening, diagnosis, and treatment of disaster related disorders; 4) to archive information regarding disaster psychiatry; and 5) to corporate with other countries regarding disaster-related psychiatric issues. As knowledge regarding the above issues will be accumulated, and awareness of disaster-related psychiatric issues will be shared among mental health professionals and society, disaster psychiatry will be advanced. PMID- 24783448 TI - [Organic and psychogenic causes of psychopathology: co-construction between the brain and culture]. AB - Rather than attempting to reduce findings to fit a particular standard of explanation, understanding into mental diseases should abandon the dichotomy between organic and psychogenic causes and instead investigate what can be explained at each level from genes, materials, cells and circuits across the spheres of psychology, society and culture, and focus on how findings can be clinically applied. Using this "pluralistic" approach, the author attempts herein to deepen understanding of mental disorders as diseases of mentality. The author depicts the process and significance of mental disorders and introduces the concept of "cultural affordance" while touching on a pathogenic framework comprising both organic and psychogenic causes, namely "culture" and "the brain". This approach has been little considered to date during psychopathological research when attempting to understand disease state and implement clinical application. PMID- 24783449 TI - [Gamma band neural synchronization deficits for auditory steady state responses in bipolar disorder patients]. AB - INTRODUCTION: Bipolar disorder is a chronic illness and included functional impairment, disability or lost work productivity, increased health care costs, and high risk of suicide. Recently some reports showed cognitive dysfunction in bipolar disorder. In neurophysiologically, steady state response (SSR) is one of index of the neural circuitry, and might be contributed to cognitive integration. Though previously there were some reports about low gamma oscillations in bipolar disorder, there was no report about high gamma oscillations in bipolar disorder as far as we know. In the current study, we examined high and low gamma SSR in bipolar disorder. METHODS: 14 bipolar disorder patients and 25 healthy controls participated. Auditory steady state response (ASSR) was recorded by presenting 20 Hz, 30 Hz, 40 Hz and 80 Hz click trains using a whole-head 306-channel magnetoencephalography. We calculated ASSR power and phase locking factor (PLF). The mean ASSR power and PLF were submitted a repeated measures analysis of variance. RESULTS: Bipolar disorder patients showed significantly reduced mean ASSR power and PLF bilaterally, specific to the 30, 40, and 80 Hz frequencies. CONCLUSIONS: Bipolar disorder patients are characterized by deficits in gamma band oscillations, which may be associated with gamma-amino butyric acid (GABA) inhibitory interneuronal activity dysfunction. PMID- 24783450 TI - [A clinical study of auditory ossicular malformations in 44 ears]. AB - Generally reporting, among the various forms of conductive hearing loss, auditory ossicular malformation clinically treated by surgery had good hearing improvement. We conducted a retrospective review of 40 patients (44 ears) with auditory ossicular malformations who were treated in our hospitals between April 2004 and March 2011. We analyzed the following preoperative features, surgical methods, and results of surgery. An otomicroscopic examination, auditory ossicules reflection, tympanometory, and temporal bone high-resolution computed tomography were undertaken in all patients. We also investigated whether these preoperative examinations would enable surgeons to make a preoperative diagnosis. There were 13 males (14 ears) and 27 females (30 ears), with an average age of 19.0 years. Classification of the pathologic condition based on surgical findings showed separation of the incus-stapes joint in 24 ears, fixation of the malleus or incus in 6 ears, fixation of the stapes footplate in 7 ears, and multifocal ossicular malformations in 7 ears. Ossicular reconstruction was performed by the modified type III method in 27 ears (including IIIc in 21 ears, IIIi-M in 1 ears, IIIi-I in 5 ears) and by the modified type IV method in 7 ears (including IVc in 5 ears, and IVi-I in 2 ears), stapes surgery in 11 ears (include total stapedectomy in 9 ears and partial stapedectomy in 2 ears) and exploratory tympanotomy in 1 ear. Postoperative hearing evaluations based on the criteria classified by the Japan Otology Society in 2010 were obtained for all cases. The procedure was deemed successful when the postoperative hearing level met at least one of these three bench marks; (1) Air-bone gap less than 15dB, (2) Recovered hearing more than 15dB, and (3) Improved or preserved hearing less than 30dB. Hearing was evaluated at 1 year after surgery. The success rates of hearing improvement was 92.3%. The success rates of postoperative hearing improvement were satisfactory. Surgeons should treat auditory ossicular malformations actively. PMID- 24783451 TI - [A study of 9 cases of cervical tuberculous lymphadenitis with the diagnosis of cervical tuberculous lymphadenitis]. AB - The incidence of tuberculosis patients is high in Japan compared with the other developed countries. The ratio of extrapulmonary tuberculosis patients, for example cervical tuberculous lymphadenitis, tends to increase. In otolaryngology, the number of tuberculosis patients (especially those with cervical tuberculous lymphadenitis) is high and followed by pleuritis patients in extrapulmonary tuberculosis. Although otolaryngologists often diagnose extrapulmonary tuberculosis, it is difficult for them to diagnose appropriately because of various clinical features. Thus, we examined and presented the clinical history of 9 cases of tuberculosis patients in our Otolaryngology department and added a review of the related literature. We diagnosed 9 patients as having cervical tuberculous lymphadenitis from April 2002 to December 2012. They were 30 to 90 years old (mean 57.9 years old), and the male/female ratio was 3 : 6. Five cases were diagnosed as the abscess types and 4 were the swelling types based on the imaging analysis of cervical tuberculous lymphadenitis. Four cases showed multiple lymphadenopathy and 5 showed a solitary involvement. Five sputum and 7 gastric fluid cultures were all negative, whereas 4 QuantiFERON tests were all positive. Fine-needle aspiration cytology was performed in 8 patients, and epithelioid cells were seen in 4 cases. Because tuberculosis presents various clinical features, if we obtained the atypical findings from those patients, it is important in the first instance to suspect tuberculosis. Based on the viewpoint for preventing the spread of infection, we should perform cellular analysis using ultrasound-guided fine needle aspiration after sufficient assessment of the spreading risk by sputum, gastric fluid culture and TB-PCR and QuantiFERON tests, and if a diagnosis remains difficult, the lymph node open biopsy need to be considered. PMID- 24783452 TI - [A clinical study of acute epiglottitis in adults]. AB - Acute epiglottitis may trigger death because of serious airway obstruction. It is necessary to perform emergency and accurate airway intervention. In this retrospective study we present 216 cases of acute epiglottitis in adults. Airway management was done in 39 cases (18.1%), but most cases were treated conservatively. The mean patient age was 53 years and the male-to-female ratio was 1.9 to 1.0. The most frequent symptoms were sore throat (88%). The mean duration from symptom onset to consultation to our hospital was 1.9 days in the airway management group and 2.9 days in the conservatively treated group, which was statistically significant (p<0.05). Focusing on epiglottal swelling seen under the flexible laryngoscope, the percentage of airway management was 52.6% for swelling of the unilateral false vocal cords and 12.9% for swelling of the aryepiglottic fold. A statistically significant difference was also seen in complaints of respiratory difficulties (p<0.01), the rise of WBC (p<0.01), the rise of CRP (p<0.01), and diabetes mellitus (p<0.01). PMID- 24783453 TI - [A clinical investigation of pediatric patients with sleep-disordered breathing who suffered perioperative respiratory complications of adenotonsillectomy]. AB - The aim of this study was to investigate the clinical background and identify the risk factors for perioperative respiratory complication in pediatric patients with sleep-disordered breathing (SDB) who underwent adenotonsillectomy (AT). Of the 186 pediatric subjects (male: 131, female: 55) undergoing AT as the first surgical treatment for SDB, 14 patients (male: 9, female: 5) fulfilled the following criteria: 1) disturbed ventilation, 2) cyanosis with an oxygen saturation of less than 90% on pulse oximetry during the perioperative period and 3) the subsequent need for medical intervention, including immediate intubation, continuous positive airway pressure (CPAP) or airway insertion. Among these 14 patients, nine were less than 3 years of age. In addition, 5 and 3 patients had hypotonia due to cerebral paralysis and metabolic disturbances, respectively. Seven had a short stature with an SD of worse than - 1.5. A statistical analysis showed that cases with either an age of less than 3 years, hypotonia or a short stature had a high risk for suffering from respiratory complications, and suggested that low body weight and a high value for preoperative apnea-hypopnea index were additional risk factors. However, a chart review exhibited that, of the 14 cases with respiratory complications, the 8 cases whose age was under 3 years had either of hypotonia or a short stature. In thirteen of the 14 cases, respiratory complications were associated with the process of general anesthesia, and ten patients exhibited pharyngeal collapse. After surgery, 7 and 3 patients required intensive care in the ICU and the pediatric recovery unit, respectively. Based on these results, it is suggested that pediatric SDB cases under 3 years of age and either with hypotonia or a short stature have a high risk for respiratory complications associated with AT, and therefore AT for such patients should only be performed in medical facilities with an ICU or an equivalent department. PMID- 24783454 TI - [A case of intracranial abscess caused by peri-odontogenic infection]. AB - The authors report a case in which a 42-year-old woman developed an intracranial abscess in the temporal lobe as a result of a peri-odontogenic infection. A subdural abscess also developed in the middle cranial fossa, expanding directly from the base of the skull through the foramen ovale and the foramen spinosum. An operation involving a left-front temporal incision extending to the tragus was performed. Debridement and brain aspiration with drainage were carried out after the craniotomy via the same skin incision without operative complications. The patient left hospital 36 days after the operation without sequelae. PMID- 24783455 TI - [Evaluation of HIV-infected patients suspected as having HIV-associated neurocognitive disorders]. AB - BACKGROUND: HIV-associated neurocognitive disorders (HAND) have emerged as a problem among HIV-infected individuals in the era of antiretroviral therapy. However, there are insufficient data on HAND regarding its prevalence and clinical features in Japan. METHODS: A test battery composed of eight neuropsycological tests proposed by the Ministry of Health, Labour and Welfare (MHLW test battery) was applied to assess 30 subjects at Tokyo Metropolitan Komagome Hospital. Among them, 5 subjects were excluded due to central nervous system complications. The background of each patient along with the results of head magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis and neuropsychological tests were compared to each HAND category. In addition, the clinical utility of a combination of neuropsychological tests as an abbreviated test battery of HAND was evaluated. RESULTS: A total of 19 (76%) subjects were diagnosed as having a HAND. Among them, HIV-associated dementia, mild neurocognitive disorders and asymptomatic neurocognitive disorders were diagnosed in 7, 8, and 4 subjects, respectively. Neither the patient's background nor the results of the head MRI and CSF analysis showed relevance to disease severity. The conventional International HIV Dementia Scale with the Digit Symbol Substitute Test was capable of detecting 94.7% cases of HAND. CONCLUSIONS: Most HIV-infected subjects clinically suspected as having neurocognitive disorders were diagnosed as having a HAND. Neuropsychological tests of the MHLW test battery were in some part useful to diagnose HAND. However, more precise neuropsychological tests are warranted to screen and diagnose HAND, based on the current criteria. PMID- 24783456 TI - [An outbreak of Streptococcus pneumoniae serotype 11A pneumonia at a nursing home, Tokyo, 2009]. AB - This is a report of an outbreak of Pneumococcal pneumonia among nursing home residents in Tokyo, 2009. A total of 15 cases were identified, and their sputum culture grew Streptococcus pneumoniae, all of which were confirmed as serotype 11A and ST116. This outbreak ended through the implementation of strict contact precautions, education regarding the standard precautions among the staff, administration of prophylactic antibiotics to other asymptomatic residents, and vaccination. The fact that many cases were unvaccinated in this outbreak implies the importance of vaccination against S. pneumoniae among nursing home residents. PMID- 24783457 TI - [The first case report of Ross River virus disease in a Japanese patient who returned from Australia]. AB - A 31-year-old Japanese female had stayed in Australia from January to May 2013. She presented with a sudden onset of left ankle and right knee arthralgia in March but neither fever nor rash was present. As her arthralgia persisted, she visited our hospital upon her return to Japan in May. When she came to our hospital, she complained of left ankle and right knee pain, but no arthritis findings. Laboratory findings were also within normal ranges. Ross River virus (RRV) antibody levels were examined as she was suspected of having contracted the disease in Australia. RRV IgG antibody and IgM antibody were positive, and the patient was confirmed as a case of acute RRV disease. RRV disease is endemic in Australia, but there are no prior reports of the disease in Japan. This is the first case of RRV disease confirmed in Japan. Typical symptoms of RRV disease include arthralgia, fever, and rash. Our patient had only arthralgia. With the increase in the number of travelers and length of stay in RRV endemic regions, health care providers need to consider the disease in their differential diagnosis, among returning travelers with arthralgia, fever, rash and a travel history to RRV-endemic regions. PMID- 24783458 TI - [Two cases of Mycoplasma pneumoniae bronchopneumonia diagnosed with LAMP (loop mediated isothermal amplification) as a rapid assay]. AB - Mycoplasma pneumoniae is one of the common pathogens of the community-acquired pneumonia in adults and children. Macrolide antibiotics are considered to be the first-choice drug for M. pneumoniae infections. However, macrolide-resistant M. pneumoniae was first detected from Japanese pediatric patients in 2000,and it has been increasing over the past decade. On the other hand, the Immunocard Mycoplasma IgM test is widely used as a rapid and easy diagnostic method for M. pneumoniae pneumonia, but false-positive or false-negative cases have been reported in adults. Therefore new methods have been developed recently. Using the LAMP assay, the results are available rapidly and accurately. We report herein on two cases of M. pneumoniae bronchopneumonia in which the LAMP assay was useful in the diagnosis and treatment. PMID- 24783459 TI - [Murine typhus in a Japanese traveler returning from Indonesia: a case report]. AB - We report herein on a 20-year-old Japanese man who was referred to our hospital for fever and diarrhea after returning from Indonesia. On admission, his blood test was essentially normal, besides a slight elevation in inflammatory markers. After excluding malaria and dengue fever, empiric use of ceftriaxone was initiated for suspected enteric fever, which was unsuccessful. However, drastic clinical improvement was observed after initiation of minocycline. The polymerase chain reaction test for Rickettsia typhi was positive from serum samples on admission, confirming the diagnosis of murine typhus. Although rarely seen in Japan, clinicians should be aware of this disease when examining patients with fever coming back from murine typhus endemic areas. PMID- 24783460 TI - [A case of primary intestinal tuberculosis in which small intestine perforation developed]. AB - We report herein on a case of the primary intestinal tuberculosis in which small intestine perforation developed. A 60-year-old man with congestive heart failure developed fever and sudden onset of abdominal pain while he was in the hospital. Computed tomography of the abdomen showed a large amount of free-air and the thickening of a part of the ileum. Perforation of the gastrointestinal tract was diagnosed, The patient underwent emergency exploratory laparotomy and a partial resection of the ileum was performed. The presence of nodules in the ileum suggested possible tuberculosis of the intestine. Pathologically caseating epithelioid granulomas were noted and the diagnosis of tuberculosis of the ileum was made although microbiologically tuberculous bacilli were not documented. The patient was successfully treated with antituberculosis chemotherapy. Although intestinal tuberculosis is a rare cause of intestinal perforation, it is important to include intestinal tuberculosis as one of the cases. PMID- 24783461 TI - Increased cardiovascular risk in patients with rheumatoid arthritis: an overview. AB - Patients with established rheumatoid arthritis (RA) have a higher cardiovascular morbidity and mortality in comparison with the general population. It is considered to be an independent risk factor for cardiovascular disease. The purpose of this article is to describe the mechanisms responsible for accelerated atherogenesis in RA patients and to give an overview of the effects of different RA therapies (methotrexate, TNF antagonists and other biologicals). PMID- 24783462 TI - When does low normal blood pressure become too low? The J-curve phenomenon. AB - The J-shaped relationship between blood pressure lowering and cardiovascular morbidity and mortality has been the topic of debates in the last three decades, especially because it has been shown that this relationship is not the same in different populations of hypertensive patients. This phenomenon is very important from a clinical point of view because it determines blood pressure cut-off values in patients with different comorbidities (diabetes, coronary artery disease, kidney disease, previous stroke). There is still no consensus about the J-shaped relationship. However, the number of studies supporting the existence of the inverse relationship between blood pressure reduction, especially diastolic pressure lowering, and cardiovascular morbidity and mortality, is increasing each year. The aim of this review is to summarize current knowledge about the J curve in a different population of hypertensive patients. PMID- 24783463 TI - Is recent cannabis use associated with acute coronary syndromes? An illustrative case series. AB - Cannabis is a frequently used recreational drug that potentially imposes serious health problems. We report three cases where recent and/or chronic use of marijuana led to severe cardiac dysfunction. All three patients collapsed at home and required cardiopulmonary resuscitation (CPR) with initial restoration of spontaneous circulation (ROSC). The mechanism of the cardiovascular collapse was different in each case. The first case presented with asystole and was found to have diffuse coronary vasospasm on coronary angiography in the hours after acute cannabis abuse. In the second case, an acute anterior infarction with occlusion of both the right coronary artery (RCA) and the left anterior descendens (LAD) was observed in a young patient without known cardiovascular risks but with chronic cannabis abuse. The third case presented at home with ventricular fibrillation presumably caused by an acute coronary syndrome due to left anterior descending (LAD) artery occlusion. The hetero-anamnesis of the family reported that all three patients had recently used cannabis. Toxicological screening also showed no other substance abuse than cannabis. Using these three cases, we would like to illustrate that the widespread use of cannabis is not as innocent as is believed. Cannabis use can lead to severe cardiovascular problems and sudden death, not only in people at increased cardiovascular risk, but also in young people without any medical history or risk factors. PMID- 24783464 TI - Study of coronary artery perforation during percutaneous coronary intervention in the Cangzhou Chinese population. AB - OBJECTIVE: Coronary artery perforation (CAP) is a rare, serious complication of percutaneous coronary intervention (PCI). Many studies have addressed the incidence, risk factors, and management of CAP in different countries except China. The aim of this study is to determine the risk factors and types of treatment for coronary perforation occurring in patients undergoing PCI and living in the Cangzhou Chinese population. METHODS AND RESULTS: A retrospective cohort of 12,113 patients who underwent PCI was used: 64 patients with CAP and 192 case-control patients were evaluated. Clinical data and findings from coronary arteriography and PCI were analysed. Logistic regression was used to evaluate candidate risk factors for CAP. The treatments were also evaluated. The incidence of CAP in patients undergoing PCI was 0.53%, and the mortality was 7.8% (5/64). Risk factors included female gender, hypertension, non-ST-elevation acute coronary syndrome (NSTE-ACS), right coronary artery (RCA) lesion, calcified lesion, and chronic total occlusion (CTO) (all P < 0.05, all OR > 1). CTO had the highest risk (OR = 5.077, P < 0.001). Patients with class I CAP underwent conservative treatment. Patients with class II CAP underwent conservative treatment or low-pressure balloon dilatation (61.1% and 22.2%, respectively). Patients with class III CAP underwent low-pressure balloon dilatation, coated stent implantation, and emergency surgery (40.9%, 27.3%, and 22.7%, respectively). CONCLUSIONS: CAP risk factors in Cangzhou Chinese patients undergoing PCI included CTO, NSTE-ACS, hypertension, calcified and RCA lesions, and female gender. Different treatment methods should be used according to the different classes of CAP. PMID- 24783465 TI - Implementation of transmural disease management in patients admitted with advanced heart failure. AB - OBJECTIVE: The objective of this study was to assess the feasibility and impact on readmissions of transmural disease management across the borders of the cardiology department in patients with advanced heart failure (HF). METHODS AND RESULTS: Consecutive patients, readmitted within one year for advanced HF by a dedicated specialist (n = 55), were followed for 22 +/- 10 months after implementation of a hospitalwide transmural disease management strategy. Participants received a tag in their electronic medical record, triggering a HF caregiver contact, with subsequent guideline-recommended, protocol-driven care on each cardiac or non-cardiac hospitalization as well as outpatient evaluation. Upon transition to outpatient follow-up, patients were instructed to call the HF caregiver with any question at low threshold. Readmission rates were prospectively collected. Despite receiving adequate treatment with neurohumoral blockers, patients (71 +/- 11 years; ejection fraction 35 +/- 13%) had spent 4% (27%) of the year preceding study inclusion in hospital, with 73% admitted once, 20% twice, and 7% more than twice for acute decompensated HF (ADHF). During the study, patients were exposed to 6 +/- 4 dedicated HF caregiver contacts. Participation in remote device monitoring increased from 31% to 92%, with 1 (0-3) additional phone contacts per patient-year of follow-up in this subgroup (n = 24). All-cause mortality and readmission rates for ADHF were 10% and 25% after one year, and 19% and 39% after 2 years, respectively. Follow-up time spent in hospital decreased significantly to 2% (16%) (P value = 0.047). CONCLUSIONS: Follow-up of advanced HF patients through transmural disease management is feasible and associated with favourable clinical outcome. PMID- 24783466 TI - Single ventricle function and exercise tolerance in adult patients after Fontan operation. AB - BACKGROUND: Patients who have undergone a Fontan operation (FO) may suffer from both systolic and diastolic single ventricle (SV) dysfunction. AIM: The aim of the study was to quantify non-invasively the systolic and diastolic single ventricle function in adult FO patients and to assess its effect on exercise tolerance. METHODS: We investigated 21 patients (12F; 9M) after FO with morphological left ventricle with a mean age of 26 +/- 6 years, and 17 age matched, healthy people (control group). Pulse-wave Doppler signals from the mitral inflow, aortic flow and tissue Doppler imaging of the mitral annulus were obtained. A cardiopulmonary exercise test (CPET) was performed. RESULTS: The Fontan patients, as compared to the controls, had a lower value of SV ejection fraction (SVEF), E velocity, E/A ratio, aortic valve velocity time integral, exercise time, SatO2, VO(2peak) and significantly higher E/E' ratio, VE/VCO(2peak) and VE/VO(2peak'). We found negative correlations between E/E' and exercise time and VO(2peak). Positive correlations were found between E/E' and VE/VCO(2peak) and age at surgery. S' velocity correlated positively with SVEF, VO(2peak) and negatively with E/E' ratio. Patients after FO with E/E' ratio > or = 12 had a significantly lower oxygen uptake when compared to those with E/E' ratio < 12. CONCLUSION: Adult patients after Fontan operations are characterized by both systolic and diastolic dysfunction of the single ventricle, associated with severe exercise intolerance reflected by shorter duration of exercise with decreased oxygen uptake and increased ventilatory response. E/E' ratio assessed by Tissue Doppler echocardiography can be a powerful predictor of oxygen uptake and ventilatory response. PMID- 24783467 TI - Mean platelet volume levels predict pulmonary artery hypertension in patients with atrial septal defect. AB - INTRODUCTION: Some reports have shown increased platelet aggregation and activation in patients with pulmonary artery hypertension (PAH). Mean platelet volume (MPV) is a simple and easy method of assessing platelet function. We aimed to investigate the mean platelet volume levels in patients with atrial septal defect (ASD) and the association between MPV levels and pulmonary artery hypertension. METHOD: One hundred and forty consecutive patients (42 males and mean age 35 +/- 9 y) and forty healthy controls (15 males and mean age 35 +/- 4 y) were enrolled in the study between December 2008 and February 2011. RESULTS: The ASD group demonstrated a significantly higher right ventricular size and pulmonary artery pressure than the control group (42 +/- 4 mm vs. 36 +/- 3 mm and 43 +/- 12 mmHg vs. 32 +/- 11 mmHg; P < 0.001 and P < 0.001, respectively). MPV levels were higher in the ASD group than the control group (9.3 +/- 1.2 fl vs. 8.6 +/- 0.8 fl, P < 0.001). There was a significant, positive correlation between MPV and systolic pulmonary artery pressure (PAP) (r = 0.542 and P < 0.001) in the ASD group. MPV was also significantly correlated with right ventricular size but not ASD diameter in the ASD group (r = 0.441, P < 0.001 and r = 0.126, P = 0.268, respectively). In receiver operating characteristics curve analysis, the cut-off value of MPV levels was > 8.7 fl and had 82% sensitivity and 63% specificity in predicting pulmonary artery hypertension. CONCLUSION: In the present study, we found that MPV levels, an indicator of platelet activation, were significantly higher in patients with ASD and correlated with systolic pulmonary artery pressure and right ventricular diameter. PMID- 24783468 TI - Non-invasive cardiac output assessment in critically ill paediatric patients. AB - OBJECTIVE: Recently, non-invasive methods for cardiac output (CO) assessment have been developed including the ultrasonic cardiac output monitor (USCOM). This technique uses the same concept as Doppler echocardiography but differs in two aspects including continuous wave (CW) Doppler and estimated outflow tract diameter (OTD) used in USCOM compared to pulsed wave Doppler and directed measurement of OTD used in echocardiography. We sought to assess the agreement between CO assessment by USCOM and echocardiography in critically ill paediatric patients. METHODS: Paired measurements of CO in critically ill paediatric patients were simultaneously and independently obtained by USCOM and echocardiography. Agreement between OTD, velocity time integral (VTI), CO, and cardiac index (CI) were assessed by percentage error and Bland-Altman analysis. RESULTS: Thirty-four children (aged 7.86 +/- 5.78years, 44.1% male) had a mean OTD (1.47 +/- 0.38, 1.41 +/- 0.40), VTI (19.13 +/- 6.06, 23.53 +/- 7.31 cm), CO (3.88 +/- 2.19,4.41 +/- 2.83 l/min) and CI (4.23 +/- 1.19,4.77 +/- 1.43 l/min/m2) by echocardiography and USCOM, respectively. Bias +/- precision and percentage of error of OTD, VTI, CO, and CI were -0.07 +/- 0.20 cm, 27.80%; -4.40 +/- 3.84 cm, 31.99%; -0.53 +/- 1.23 l/min, 54.66%; and 0.54 +/- 1.03 l/min/m2, 42.32%, respectively. The bias +/- precision and percentage error were more important in patients with septic shock (n = 16). CONCLUSION: USCOM was an unreliable tool for absolute value measurement of CO and CI due to the errors of VTI by CW Doppler. PMID- 24783469 TI - Impact of continuous positive airway pressure therapy on left atrial function in patients with obstructive sleep apnoea: assessment by conventional and two dimensional speckle-tracking echocardiography. AB - OBJECTIVE: The objective of this study was to evaluate left atrial (LA) function in patients with obstructive sleep apnoea (OSA) receiving continuous positive airway pressure therapy (CPAP), incorporating two-dimensional speckle-tracking echocardiography (2D-STE). METHODS: Forty-five control and 117 OSA patients were enrolled in the study. They were categorized into mild, moderate and severe OSA groups according to the apnoea-hypopnoea index (AHI). All patients underwent conventional and 2D-STE. Forty-three patients with AHI greater than 20 were enrolled to receive CPAP therapy for 24 weeks. They underwent echocardiography examination at baseline, after 12 weeks and 24 weeks of CPAP therapy. RESULTS: Severe OSA patients have higher total emptying volume index (EVI) and lower total emptying fraction (EFr) (P < 0.05). LA contractile strain and strain rate values of severe OSA were greater than in the other groups (P < 0.05). Left ventricular filling pressure (E/E') increased with severity of OSA (P < 0.05). The AHI correlated positively with LA-maximal, -pre-contraction, -minimum volume index, contractile strain and strain rate and E/E' (P < 0.05). AHI correlated negatively with LA reservoir strain and strain rate, conduit strain and strain rate (P < 0.05). In the compliant CPAP group: (i) reduction in the E/E' ratio (P < 0.05); (ii) reduction in the LA volume indexes (P < 0.05); (iii) reduction in the LA total EVI, -active EVI and -active EFr (P < 0.05); (iv) increase in the LA passive emptying volume and -passive emptying fraction (P < 0.05); (v) increase in the LA reservoir strain, -conduit strain and strain rate (P < 0.05) were observed. CONCLUSION: LA volumetric and deformation abnormalities in OSA patients can be reversed as early as 12 weeks into CPAP therapy, with progressive improvement in LA anatomical remodelling over 24 weeks as assessed by conventional and 2D-STE. PMID- 24783470 TI - Aberrant right coronary artery arising from the left sinus of Valsalva with an interarterial course. AB - An anomalous origin of the right coronary artery from the left sinus of Valsalva with an interarterial course is a rather rare congenital anomaly. Treatment strategies are determined by the risk of sudden cardiac death and the presence of cardiac ischaemia. We present two cases of middle-aged patients who were diagnosed with an interarterial course of a right coronary artery originating from the opposite sinus of Valsalva. As no cardiac ischaemia could be documented these patients were treated medically with excellent long-term follow-up. PMID- 24783471 TI - Multiple cerebral infarction as the initial manifestation of left atrial myxoma: a case report and literature review. AB - Left atrial myxoma is a rare cause of cardioembolic stroke in adults and when stroke occurs, it is mainly due to arterial embolism in cerebral vessels. Cerebral infarction is the first clinical manifestation in one-third of cases. We report a 24-year-old female patient with left atrial myxoma, and no other conventional vascular risk factors such as hypertension, diabetes or hyperlipidaemia. The patient presented with multiple infarctions as the first clinical manifestation and was diagnosed with a left atrial myxoma. The literature on similar cases was also reviewed. PMID- 24783472 TI - Treatment of pre-existing cardiomyopathy during pregnancy. AB - Heart failure is an established predictor of primary cardiac events during pregnancy. Adequate heart failure treatment in pregnant women is hampered by important foetotoxicity of several conventional drugs. Hydralazine with or without long-acting nitrates has been proposed as an alternative for ACE inhibitors or angiotensin receptor blockers. There are no published data, however, on the use of hydralazine to treat heart failure during pregnancy. We describe the course and outcome of pregnancy in two patients with heart failure. A 31-year-old woman with dilated cardiomyopathy was not treated with hydralazine during pregnancy and developed worsening heart failure. A 36-year-old woman with ischaemic cardiomyopathy was treated with hydralazine early during pregnancy and remained stable throughout and after pregnancy. We assume that early initiation of hydralazine as an alternative for ACE inhibitors or angiotensin receptor blockers during pregnancy in patients with cardiomyopathy could prevent further left ventricular dilatation and worsening heart failure. PMID- 24783473 TI - Heparin-induced thrombocytopenia after ICD-lead flushing. AB - Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening prothrombotic complication following heparin administration. We describe a patient, known with idiopathic dilating cardiomyopathy, presenting nine days after a biventricular ICD implantation with dyspnoea and thrombocytopenia. Thirteen days after administration of a single heparin flush during ICD implantation, the patient developed venous thrombosis in two extremities and pulmonary embolism caused by HIT. HIT is the development of thrombocytopenia, caused by IgG antibodies against complexes of platelet factor 4 and heparin, leading to platelet aggregation. HIT may be accompanied by thrombosis in 20-50% of patients and untreated mortality rates are high. Once HIT is suspected, heparin should be replaced by an alternative anti-factor Xa or anti-factor II therapy. Regardless of the low incidence of HIT, because of the widespread use of heparin and the potentially life-threatening course of HIT, all physicians should be aware of it. PMID- 24783474 TI - Radiation therapy for Hodgkin lymphoma. AB - The long-term cardiac complications of radio(chemo)therapy for Hodgkin lymphoma include coronary artery disease, cardiac arrhythmias, valvular disease, pericardial disease, cardiomyopathy and heart failure. The extent of myocardial damage after radiotherapy is dependent on the dose, the volume and the technique of chest irradiation. Also, patient-specific factors, such as the age of the patient at the time of treatment and the presence of classical cardiac risk factors are supposed to be important. The relative risk of cardiovascular events is estimated to be 2 to 7 times higher than the general population. The patient's clinical picture can vary from asymptomatic to an acute presentation of end-stage coronary artery or valvular disease. PMID- 24783475 TI - Renal infarctions caused by dissections of surnumerary renal arteries. AB - Renal infarction is an uncommon and underdiagnosed cause of acute flank pain. We describe a 48-year-old male patient, previously diagnosed with a bicuspid aortic valve, who presented with multiple renal infarctions, secondary to multiple dissections of the aberrant renal vascular anatomy. PMID- 24783476 TI - Chagas disease: don't forget it in Latin American patients with heart block! AB - Chagas disease is caused by the parasite Trypanosoma cruzi, and mostly affects poor rural populations of central and south America. It is mainly acquired by bugs (triatoma) but also by ingestion of the parasite (fresh fruit juices) or by foetal-maternal blood passing. Despite an important decrease in transmission during the last decades in several countries, millions of patients are still chronically infected and most of them are asymptomatic. In 2012-2013, two cases were admitted in our cardiac intensive care unit (ICU) with heart block due to Chagas cardiomyopathy. Diagnosis was established by echocardiography and positive serological results for Trypanosoma cruzi. This report underlines that in cases of heart failure and conduction abnormalities of unclear aetiology, Chagas disease should be taken into consideration, even in patients originating from non endemic countries. PMID- 24783477 TI - Self-limiting left ventricular wall rupture following myocardial infarction: a case report and literature review. AB - We report the case of a 62-year-old woman presenting with symptoms and findings of myocardial infarction and a left ventricular free wall rupture. Coronary angiography revealed a critical stenosis in the middle right coronary artery. A contrast left ventriculogram revealed extravasation of contrast through the inferolateral wall of the left ventricle. Left ventricular free wall rupture is a rare complication of acute myocardial infarction, occurring in approximately 2% of cases. It is often fatal because of the development of haemopericardium and tamponade. Some patients, like the one described in this case, may present with small leaks that might close spontaneously by epicardial fibrin deposits, thus self-limiting, without requiring surgical intervention. This patient received only intense medical treatment. Indeed, blood clots at the endocardial and the epicardial site of the rupture have often been identified, suggesting protection for further rupture. PMID- 24783478 TI - Pneumopericardium: an uncommon complication of atrial lead perforation following pacemaker implantation. AB - Cardiac perforation is an infrequent but potentially life-threatening complication of pacemaker implantation. We report a case of right atrial lead perforation complicated by pneumopericardium shortly after pacemaker lead insertion. Transthoracic echocardiography revealed no evidence of pericardial effusion and pacemaker lead displacement, but a thoracic computed tomography scan illustrated the lead course and confirmed the diagnosis. This case suggests that computed tomography is a sensitive modality to confirm the diagnosis at the early stage of this complication. PMID- 24783479 TI - Three-dimensional echocardiography of a subtotal mitral valve ring dehiscence. PMID- 24783480 TI - Eclipse of the heart: the echocardiographic finding of endomyocardial calcification. PMID- 24783481 TI - Dual-chamber pacemaker implantation through a persistent left superior vena cava with remaining connection to the right superior vena cava. PMID- 24783483 TI - A call to occupationology. PMID- 24783482 TI - Almanac 2013: cardiac arrhythmias and pacing--an editorial overview of selected research that has driven recent advances in clinical cardiology. AB - Important advances have been made in the past few years in the fields of clinical cardiac electrophysiology and pacing. Researchers and clinicians have a greater understanding of the pathophysiological mechanisms underlying atrial fibrillation (AF), which has transpired into improved methods of detection, risk stratification, and treatments. The introduction of novel oral anticoagulants has provided clinicians with alternative options in managing patients with AF at moderate to high thromboembolic risk and further data has been emerging on the use of catheter ablation for the treatment of symptomatic AF. Another area of intense research in the field of cardiac arrhythmias and pacing is in the use of cardiac resynchronisation therapy (CRT) for the treatment of patients with heart failure. Following the publication of major landmark randomised controlled trials reporting that CRT confers a survival advantage in patients with severe heart failure and improves symptoms, many subsequent studies have been performed to further refine the selection of patients for CRT and determine the clinical characteristics associated with a favourable response. The field of sudden cardiac death and implantable cardioverter defibrillators also continues to be actively researched, with important new epidemiological and clinical data emerging on improved methods for patient selection, risk stratification, and management.This review covers the major recent advances in these areas related to cardiac arrhythmias and pacing. PMID- 24783484 TI - Spirituality in bedlam: exploring patient conversations on acute psychiatric units. AB - BACKGROUND: Spirituality is a complex yet vital aspect of care on acute psychiatric units. Occupational therapists play a role in engaging their clients regarding spirituality as a resource for recovery. PURPOSE: This manuscript reports on Part I of a research study that explored the experience of spiritual conversations for patients (Part I) and mental health professionals (Part 2) on acute psychiatric units. METHOD: Community-based participatory research framed the project philosophically and relationally, and interpretive description defined the data collection, data analysis, and dissemination methods. FINDINGS: Seven inpatients on acute psychiatric units participated in interviews or focus groups. Authentic spiritual conversation that was not associated with mental illness symptoms proved difficult to initiate on inpatient psychiatric units. Participants desired direct questioning and the provision of optional spiritual resources. IMPLICATIONS: Therapists can make a range of spirituality educational resources available for clients. They can also advocate for clients' spiritual needs in the acute context. PMID- 24783485 TI - Spirituality in bedlam: exploring professional conversations on acute psychiatric units. AB - BACKGROUND: The inclusion of spiritual conversations in occupational therapy is congruent with the Canadian Model of Occupational Performance and Engagement, which identifies spirituality as the core of every human being. Research indicates that spirituality can be a resource for mental health recovery. PURPOSE: This manuscript reports on Part 2 of a research study that explored the experience of spiritual conversations for patients (Part I) and mental health professionals (Part 2) on acute psychiatric units. METHOD: Eight acute-based mental health professionals (MHPs)/participants, representing a variety of disciplines, participated in a focus group or individual interview. Community based participatory research, appreciative inquiry, and interpretive description provided methodological and analytic guidance. FINDINGS: MHP/participants described challenges in setting boundaries related to spirituality conversations and discerning spiritual experience from psychosis. MHPs/participants emphasized the importance in providing an empathetic presence while also engaging in spiritual networking. IMPLICATIONS: Therapists can incorporate spiritual conversations with patients in acute psychiatric settings by taking specific actions to enhance their openness and engaging in spiritual networking. PMID- 24783486 TI - Optimizing participation of children with autism spectrum disorder experiencing sensory challenges: a clinical reasoning framework. AB - BACKGROUND: Remedial sensory interventions currently lack supportive evidence and can be challenging to implement for families and clinicians. It may be timely to shift the focus to optimizing participation of children with autism spectrum disorders (ASD) through accommodation and self-regulation of their sensory differences. PURPOSE: A framework to guide practitioners in selecting strategies is proposed based on clinical reasoning considerations, including (a) research evidence, (b) client- and family-centredness, (c) practice contexts, (d) occupation-centredness, and (e) risks. KEY ISSUES: Information-sharing with families and coaching constitute the basis for intervention. Specific strategies are identified where sensory aversions or seeking behaviours, challenges with modulation of arousal, or sensory-related behaviours interfere with participation. Self-regulatory strategies are advocated. The application of universal design principles to shared environments is also recommended. IMPLICATIONS: The implications of this framework for future research, education, and practice are discussed. The clinical utility of the framework now needs to be tested. PMID- 24783487 TI - Belonging, occupation, and human well-being: an exploration. AB - BACKGROUND: Researchers identify the importance of belonging to human well-being and provide evidence-based support for occupation as a medium for expressing and achieving a sense of belonging and connectedness. PURPOSE: The purpose of this article is to highlight the imperative for occupational therapy theory and practice to address occupations concerned with belonging needs. KEY ISSUES: Dominant occupational therapy models emphasise doing self-care, productive, and leisure occupations, thereby ignoring occupations undertaken to contribute to the well-being of others, occupations that foster connections to nature and ancestors, collaborative occupations, and those valued for their social context and potential to strengthen social roles. IMPLICATIONS: Belonging, connectedness, and interdependence are positively correlated with human well-being, are prioritized by the majority of the world's people, and inform the meanings attributed to and derived from the occupations of culturally diverse people. If occupational therapy is to address meaningful occupations, attention should be paid to occupations concerned with belonging, connecting, and contributing to others. PMID- 24783488 TI - The emerging role of occupational therapy in primary care. AB - BACKGROUND: Few studies have examined the role of occupational therapy working in a primary care setting. PURPOSE: The objective of the study was to describe the emerging role of occupational therapy in Family Health Teams, a model of interprofessional primary care. METHOD: A multiple case study design was used to provide in-depth description of the occupational therapy role. Data collection included interviews, document analyses, and questionnaires. Each case was first analyzed individually, followed by cross-case analyses to determine common themes. FINDINGS: The role of occupational therapy in Family Health Teams epitomizes that of a generalist, whose overarching focus is on function. Occupational therapists are working across the life span with a wide range of client populations. Older adults and individuals with complex chronic conditions are two prominent areas of occupational therapy focus. IMPLICATIONS: Understanding the impact of health conditions on daily function and enabling participation in activities are unique and important contributions of occupational therapy. PMID- 24783489 TI - Routines of families with adolescents with autistic disorders: a comparison study. AB - BACKGROUND: Research has consistently shown that families with children with autism spectrum disorders (ASD) have difficulty engaging in family routines, yet little is known about families with adolescents with ASD. PURPOSE: The purpose of this study is to compare the routines of families with adolescents with ASD (FASD) and families with typically developing adolescents. METHOD: Twenty families in each group were compared using the Family Routines Inventory and supplemental questions. Data were analyzed using a Mann-Whitney U and content analysis. FINDINGS: No significant difference between groups was found; however, there was a trending toward significance in the subscale of mealtime routines in both endorsement and adherence. Analysis of open-ended questions revealed differences in how routines were carried out. IMPLICATIONS: Occupational therapists should consider assessing and addressing routines of importance to FASD to increase family health and well-being. Further research is needed to better understand the routines of FASD. PMID- 24783490 TI - The "Prince of Medicine": Yuhanna ibn Masawayh and the foundations of the western pharmaceutical tradition. AB - This essay examines three medieval pharmaceutical treatises purportedly authored by Yuhanna ibn Masawayh (anglicized to John Mesue) and traces their immense influence on the development of pharmacy in early modem Europe and the Hispanic world. Despite the importance of these works throughout the early modern period, Mesue is relatively unknown in the history of pharmacy and medicine, and his exact identity remains unclear. This essay argues that "Mesue" was most likely a pseudonym used by an unknown author of the Latin West and that the three works were crafted to meet the demands of the developing "medical marketplace" of late thirteenth-century Europe, where the manuscripts first appeared. At the same time, however, as the Arabic reference of the pseudonym suggests, these treatises were clearly products of the medieval Islamic world, including many innovations that would provide the basis for the theory and practice of pharmacy for centuries and arguably formed part of the artisanal epistemological influence on the Scientific Revolution. PMID- 24783491 TI - Scientific equity: experiments in laboratory education in Ghana. AB - During the 1960s the Ministry of Education in Ghana created a network of school laboratories to increase scientific literacy among young citizens. The ministry stocked these "Science Centres" with imported beakers, Bunsen burners, and books. Education officials and university scientists worked with teachers to create lesson plans on water, air, plants, and other topics. The government hoped that scientifically minded schoolchildren would be better prepared to staff the industries of the future. The adoption of laboratory norms represented a desire for scientific equity, rather than a condition of cultural mimicry. Interviews with ministry officials and science educators, alongside letters and reports, indicate how students and teachers appropriated the laboratories in the small West African nation. Their experiences in mobilizing resources from across Ghana and around the world provide a metaphor for ongoing efforts to establish access to scientific goods in Africa. PMID- 24783492 TI - Social science as a "weapon of the weak": Max Weinreich, the Yiddish Scientific Institute, and the study of culture, personality, and prejudice. AB - This essay examines Max Weinreich's efforts to turn "culture and personality studies" into social and psychological weapons that could be used to combat the effects of prejudice. It focuses on language choice, audience, and purpose in the production of such knowledge by and for a Yiddish-speaking Eastern European population. During the 1930s, Weinreich led the Yiddish Scientific Institute, a research organization headquartered in Poland but affiliated with neither a state nor a university. He was profoundly influenced by a year spent at Yale and a trip through the American South visiting segregated African-American universities. In his 1935 study Der veg tsu undzer yugnt [The Way to Our Youth], Weinreich blended European, Soviet, American, and African-American research traditions to examine the effects of prejudice on child and adolescent development; he also considered the ways members of "despised minorities" could use such science. In 1940 he fled to New York and in 1946 published Hitler's Professors, the first book analyzing the uses of the human sciences to advance Nazi state-sponsored antisemitism. In examining Weinreich's Yiddish and English writings, this essay explores the broader relationship of social science not only to state power but also to statelessness and powerlessness. PMID- 24783493 TI - Focus: global currents in national histories of science: the "global turn" and the history of science in Latin America. AB - The "global turn" in the history of science offers new ways to think about how to do national and regional histories of science, in this case the history of science in Latin America. For example, it questions structuralist and diffusionist models of the spread of science and shows the often active role that people in Latin America (and the rest of the Global South) played in the construction of "universal" scientific knowledge. It suggests that even national or regional histories of science must be situated in a global context; all too often, such histories have treated global processes as a distant backdrop. At the same time, historians need to pay constant attention to the role of power in the construction of scientific knowledge. Finally, this essay highlights a methodological tool for writing globally inflected histories of science: the method of "following". PMID- 24783494 TI - Between the national and the universal: natural history networks in Latin America in the nineteenth and twentieth centuries. AB - This essay examines contemporary Latin American historical writing about natural history from the nineteenth through the twentieth centuries. Natural history is a "network science," woven out of connections and communications between diverse people and centers of scholarship, all against a backdrop of complex political and economic changes. Latin American naturalists navigated a tension between promoting national science and participating in "universal" science. These tensions between the national and the universal have also been reflected in historical writing on Latin America. Since the 1980s, narratives that recognize Latin Americans' active role have become more notable within the renewal of the history of Latin American science. However, the nationalist slant of these approaches has kept Latin American historiography on the margins. The networked nature of natural history and Latin America's active role in it afford an opportunity to end the historiographic isolation of Latin America and situate it within world history. PMID- 24783495 TI - Islands of knowledge: science and agriculture in the history of Latin America and the Caribbean. AB - This essay explores the participation of Latin America and the Caribbean in the construction and circulation of tropical agricultural science during the nineteenth century and the first half of the twentieth century. It uses the term "islands of knowledge" to underscore the idea that each producing region across the global tropics, including Latin America and the Caribbean, was instrumental in the creation, adoption, and application of scientific procedures. At the same time, it emphasizes the value of interchange and interconnection between these regions, as well as the many and heterogeneous local areas, for analyzing what it calls "global archipelago agricultural scientific knowledge." This focus challenges the traditional center/periphery hierarchy and opens it to a wider vision of science and practice in agriculture. This essay shows how writing in related areas of research--specifically, commodity histories, biological exchange studies, and knowledge exchange studies--introduces approaches and case studies that are useful for the history of tropical agricultural science. In particular, this work provides analytical frameworks for developing studies of exchanges across the Global South. PMID- 24783496 TI - Globalizing the history of disease, medicine, and public health in Latin America. AB - The history of Latin America, the history of disease, medicine, and public health, and global history are deeply intertwined, but the intersection of these three fields has not yet attracted sustained attention from historians. Recent developments in the historiography of disease, medicine, and public health in Latin America suggest, however, that a distinctive, global approach to the topic is beginning to emerge. This essay identifies the distinguishing characteristic of this approach as an attentiveness to transfers of contagions, cures, and medical knowledge from Latin America to the rest of the world and then summarizes a few episodes that demonstrate its promise. While national as well as colonial and neocolonial histories of Latin America have made important contributions to our understanding, works taking the global approach have the potential to contribute more directly to the decentering of the global history of disease, medicine, and public health. PMID- 24783497 TI - Beyond prejudice and pride: The human sciences in nineteenth- and twentieth century Latin America. AB - Grappling with problematics of status and hierarchy, recent literature on the history of the human sciences in Latin America has gone through three overlapping phases. First, the scholarship has reflected a dialogue between Latin American scientists and their European colleagues, characterized by the "center/periphery" model of scientific diffusion. Next, scholars drew on postcolonial theory to undermine the power of the "center" and to recover the role of local agents, including both elites and subalterns. In the wake of numerous studies embracing both models, the way has been cleared to look at multiple dimensions simultaneously. Histories of the human sciences in the complex multicultural societies of Latin America provide an unusually direct path to integration. Moreover, this dynamic and multilayered approach has the potential to address ambivalences about authority and power that have characterized previous analyses of the production and application of knowledge about the human condition. PMID- 24783499 TI - [Lead compound optimization strategy (2)--structure optimization strategy for reducing toxicity risks in drug design]. AB - Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug. PMID- 24783500 TI - [Progress in methodology of establishing physiologically based pharmacokinetic models]. AB - Physiologically based pharmacokinetic model (PBPK), a mechanistic mathematic model, which can simulate the absorption, distribution, metabolism and excretion of drugs, is being more widely used in pharmaceutical research and development areas. This article reviews primarily the recent advances in the procedure of establishing a PBPK model, including specifying of the PBPK model structure, specification of the tissue model, writing of equations, set of model parameters, simulation and evaluation. Application significance, major challenges and future developments of PBPK model in pharmaceutical areas are also discussed. PMID- 24783501 TI - [Recent development of natural and reconstituted lipoprotein based nano drug delivery vehicles]. AB - Lipoproteins are biological lipids carriers. The natural and reconstituted lipoprotein based drug delivery systems have been extensively developed in recent years. This article reviews the development of natural and reconstituted low density lipoprotein and high-density lipoprotein based vehicles in the antitumor area. PMID- 24783502 TI - [Recent advances in the study of mechanism of APOBEC3G against virus]. AB - APOBEC3 is a class of cytidine deaminase, which is considered as a new member of the innate immune system, and APOBEC3G belongs to this family. The research about APOBEC3G is a new direction of innate immune defense mechanism against virus. APOBEC3G has the restrictive activity on many viral replications, which deaminates dC to dU in the viral genome and then induces extensive hypermutation. APOBEC3G can also interrupt viral replication at several phases such as reverse transcription, replication, nucleocapsid and so on by non-deamination mechanisms. However, virus can encode viral proteins to counteract the restriction activity of APOBEC3G. Elucidation of the antagonistic interaction between APOBEC3G and the virus will be contributed to development of new antiviral drugs in the future. PMID- 24783503 TI - [Application of synthetic biology to sustainable utilization of Chinese materia medica resources]. AB - Bioactive natural products are the material bases of Chinese materia medica resources. With successful applications of synthetic biology strategies to the researches and productions of taxol, artemisinin and tanshinone, etc, the potential ability of synthetic biology in the sustainable utilization of Chinese materia medica resources has been attracted by many researchers. This paper reviews the development of synthetic biology, the opportunities of sustainable utilization of Chinese materia medica resources, and the progress of synthetic biology applied to the researches of bioactive natural products. Furthermore, this paper also analyzes how to apply synthetic biology to sustainable utilization of Chinese materia medica resources and what the crucial factors are. Production of bioactive natural products with synthetic biology strategies will become a significant approach for the sustainable utilization of Chinese materia medica resources. PMID- 24783504 TI - [Anti-tumor effects of a novel cyclophosphamide derivate 9b in vivo and in vitro]. AB - This study is to investigate the anti-tumor activities of a novel cyclophosphamide derivate 4, 6-diphenyl cyclophosphamide (9b) in vivo and in vitro, and its possible mechanism of action. The inhibitory effects of 9b on human hepatoma cell line HepG2, human breast carcinoma cell line MCF-7 and human myeloid leukemia cell line K562 were measured by MTT assay in vitro. Cell cycle distribution and apoptotic rate were evaluated by flow cytometry. To evaluate the anti-tumor effect of 9b in vivo, mouse model bearing inoculated H22 tumor was established. The results indicated that 9b could inhibit the proliferation of HepG2, MCF-7 and K562 cells in a dose and time dependent manner. The ICo50 values of 9b were 32.34 micromol.L-1 to HepG2 cells, 87.07 micromol.L-1 to MCF-7 cells and 149.10 micromol.L-1 to K562 cells after incubation for 48 h. The results of flow cytometry indicated that after being treated for 48 h with different concentrations of 9b, the ratios of HepG2, MCF-7 cells at the Go/G1 phase and K562 cells at the G0/Gl phase and G2/M phase increased significantly compared with control group, and the apoptotic rate increased with the increase of the concentration of 9b. 9b could significantly reduce tumor weight of H22 solid tumor mouse model in vivo. To summarize, 9b showed significantly anti-tumor activity in vivo and in vitro, of which the mechanism might be associated with the change of cell cycle distribution and induction of tumor cell apoptosis. PMID- 24783505 TI - Expression of recombinant human acetylcholinesterase and its application in screening its inhibitors. AB - This study is designed to obtain recombinant human acetylcholinesterase (rhAChE) and apply it in screening acetylcholinesterase inhibitors. The rhAChE was overexpressed in HEK293 cells transfected by plasmid of pCMV-AChE with the cationic liposome and rhAChE was found to be secreted into cell culture medium. AChE activity was assayed according to modified Ellman method to obtain kinetic parameters. IC so50 values for donepezil compounds of rhAChE were calculated to determine their activities of inhibition. The results showed that Km value was 151.9 micromol.L-1 donepezil inhibited rhAChE in a mixed competitive noncompetitive way (Ki= 16.03 nmol.L-1, Ki = 18.36 nmol.L-1) and that most new compounds tested exhibited high activities of inhibition on rhAChE. The study suggests that rhAChE is available to be applied in screening AChE inhibitors in vitro. PMID- 24783506 TI - [Effects of paeoniflorin on cerebral blood flow and the balance of PGI2/TXA2 of rats with focal cerebral ischemia-reperfusion injury]. AB - This study is to investigate the effects of paeoniflorin on cerebral blood flow and the balance of PGI2/TXA2 of rats with focal cerebral ischemia-reperfusion injury. A total of 72 SD rats (3) were randomly divided into 6 groups: sham operation group, cerebral ischemia-reperfusion model group (I/R gourp), low (10 mg.kg-1), middle (20 mg.kg-1) and high (40 mg.kg-1) doses of paeoniflorin groups and nimrnodipine group. Focal cerebral ischemia in rats was made by inserting a monofilament suture into internal carotid artery for 90 min and then reperfused for 24 h. The effects of paeoniflorin on neurological deficit scores and the infarction volume of brain were detected. Relative regional cerebral blood flow (rCBF) was continuously monitored over ischemic hemispheres by laser-Doppler flowmetry (LDF). The expression of COX-2 in hippocampal CAl region was estimated by immunohistochemistry and the contents of prostacyclin I2 (PGI2), thromboxane A2 (TXA2), and ratio of PGIJ2/TXA2 in serum were measured by ELISA kits. Paeoniflorin significantly ameliorated neurological scores, reduced the infarction volume, and increased regional cerebral blood flow relative to the I/R group. In addition, paeoniflorin could inhibit COX-2 expression and the release of TXA2 and prevent the downregulation of PGI2 induced by I/R injury. The neuroprotective effects of paeoniflorin against focal cerebral ischemia reperfusion rats might be attributed to improve the supply of injured hemisphere blood flow and adjust the balance between PGI2/TXA2. PMID- 24783507 TI - [A novel dipeptidyl peptidase IV inhibitors developed through scaffold hopping and drug splicing strategy]. AB - Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules. PMID- 24783508 TI - A new steroid with long cross-conjugation structure from the marine-derived fungus Aspergillus aculeatus. AB - A new steroid with a long cross-conjugation structure, 15a-hydroxy-(22E, 24R) ergosta-3, 5, 8 (14), 22-tetraen-7-one (1), was isolated from the marine-derived fungus Aspergillus aculeatus. Its structure was established by the extensive spectroscopic analyses, and its cytotoxicities against P388, HL-60, and PC-3 cell lines were measured in vitro. PMID- 24783509 TI - [Simultaneous determination of repaglinide and pravastatin sodium in rat plasma by LC-ms/MS and its application on pharmacokinetic interactions study]. AB - The study aims to establish a method for simultaneous determination of repaglinide and pravastatin sodium in rat plasma by LC-MS/MS and to study its pharmacokinetic interactions. Eighteen male SD rats were divided into repaglinide group, pravastatin sodium group and co-administration group. Blood samples were collected at different times after oral administration. Repaglinide and pravastatin sodium in rat plasma were separated by Agilent HC-C18 with the mobile phase consisting of methanol-0.1% formic acid (80 : 20). Detection and quantification were performed by using ESI-MS. The detector was operated in selected Reaction-monitoring mode at m/z 453.3-->230.1 for repaglinide, m/z 447.2 ->327.4 for pravastatin sodium and m/z 285.1-->192.9 for diazepam as the internal standard. The calibration curve obtained was linear (R2>0.99) over the concentration range of 9.77-10,000 ng.mL-1 for repaglinide and 4.88-625 ng.mL-1 for pravastatin sodium. Compared with the single administration group, Cmax and AUC0-6h of repaglinide increased significantly (P<0.05) and tmax of pravastatin sodium prolonged (P<0.05) in co-administration group. The method is found to be simple, sensitive and accurate for determining the concentration of repaglinide and pravastatin sodium in rat plasma. There exists pharmacokinetic interactions in the co-administration of repaglinide and pravastatin sodium. PMID- 24783510 TI - [High performance preparation and structural confirmation of lignans from Schisandrae chinensis fructus by using HSCCC combined with ESI-MSn method]. AB - High-speed counter-current chromatography (HSCCC) was used to high performance separate and prepare lignans from Schisandrae chinensis fructus. The solvent system is composed of n-hexane-ethyl acetate-methanol-water (9 : 1 : 5 : 5) and n hexane-ethyl acetate-methanol-water (9 : 1 : 9 : 5), speed is at 900 r.min-1, and flow rate is at 2.0 mL.min-1. Five fractions from Schisandrae chinensis fructus extract were separated and prepared with one HSCCC process. They were identified as schisandrin, gomisin J, schisandrol B, schisantherin A and deoxyschizandrin by electrospray ionization-multiple tandem mass spectrometry (ESI-MSn), respectively. Their contents were obtained in 98.74%, 94.32%, 99.53%, 94.23% and 98.68% by ultra high performance liquid chromatography (UPLC), separately. The rapid and simple method can be applied for the preparation of lignans from Schisandrae chinensis fructus. PMID- 24783511 TI - [LC-MS/MS assay of methylphenidate: stability and pharmacokinetics in human]. AB - The study aims to solve the instability problem of methylphenidate (MPH) in plasma, and establish a LC-MS/MS method for simultaneous determining of MPH in human plasma. The stabilities of MPH in different media were studied, and the degradation characteristics of MPH in these media were also investigated by HPLC and LC-MS/MS. To a 200 microL aliquot of freshly collected plasma sample, 10 microL 2% formic acid was added immediately to prevent the hydrolysis of MPH in human plasma samples. Chromatographic separation was performed on a Sapphire C18 column using the mobile phase of methanol - 5 mmol.L-1 ammonium acetate buffer solution containing 0.1% formic acid (46 : 54). MPH was quantified by tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring. The detection used the transitions of protonated molecules at m/z 234.2-->84.1 for MPH and m/z 260.3-->183.1 for propranolol (IS), separately. The intra- and inter-assay precisions were all below 5.0%. The accuracies were all in standard ranges. The linear calibration curve was obtained in the concentration range of 0.035-40 ng.mL-1. The methods fulfilled the demand. The method was used to determine the concentration of MPH in human plasma after a single dose of 36 mg MPH tablet to 6 healthy Chinese volunteers. The method is suitable for the precisely determination of MPH and for pharmacokinetic study of MPH in human plasma. PMID- 24783512 TI - [NMR-based analysis of water soluble extracts of different Astragali Radix]. AB - Water soluble extract (WSE) is an important index for the quality evaluation of Astragali Radix (AR). In this study, the WSE of the wild AR from Shanxi province (SX) and the cultivated AR from Gansu Province (GS) were compared. The WSEs of two types of AR were determined according to the appendix of Chinese pharmacopoeia. Then the WSEs were subjected to NMR analysis, and the obtained data were analyzed using HCA, PCA, OPLS-DA, microarray analysis, and Spearman rank analysis. In addition, the Pearson correlation of differential metabolites were also calculated. The results showed that the WSE content of GS-AR (37.80%) was higher than that of SX-AR (32.13%). The main constituent of WSE was sucrose, and other 18 compounds, including amino acids, organic acids, were also detected. Multivariate analysis revealed that SX-AR contained more choline, succinic acid, citric acid, glutamate, taurine and aspartate, while GS samples contained more sucrose, arginine and fumaric acid. In addition, the Pearson correlations between different metabolites of the two types of AR also showed apparent differences. The results suggested that the WSE of two types of AR differs not only in the content, but also in the chemical compositions. Thus, the cultivation way is important to the quality of AR. This study supplied a new method for the comparison of extract of herbal drugs. PMID- 24783513 TI - [Simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma by LC-HESI/MS/MS method]. AB - The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL 1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers. PMID- 24783514 TI - Cross-validation of the osmotic pressure based on Pitzer model with air humidity osmometry at high concentration of ammonium sulfate solutions. AB - The osmotic pressure of ammonium sulfate solutions has been measured by the well established freezing point osmometry in dilute solutions and we recently reported air humidity osmometry in a much wider range of concentration. Air humidity osmometry cross-validated the theoretical calculations of osmotic pressure based on the Pitzer model at high concentrations by two one-sided test (TOST) of equivalence with multiple testing corrections, where no other experimental method could serve as a reference for comparison. Although more strict equivalence criteria were established between the measurements of freezing point osmometry and the calculations based on the Pitzer model at low concentration, air humidity osmometry is the only currently available osmometry applicable to high concentration, serves as an economic addition to standard osmometry. PMID- 24783515 TI - [Co-delivery of paclitaxel and cyclosporine by a novel liposome-silica hybrid nano-carrier for anti-tumor therapy via oral route]. AB - In this study, we developed a novel liposome-silica hybrid nano-carrier for tumor combination therapy via oral route, using paclitaxel and cyclosporine as a model drug pair. Optimization of the preparation of the drug-loading formulation and characterization of its physicochemical parameters and drug release profile were performed in vitro. Then in vivo pharmacodynamics and pharmacokinetics studies were performed. The results showed that the obtained formulation has a small particle size (mean diameter of 100.2 +/- 15.2 nm), a homogeneous distribution [the polydispersity index was (0.251 +/- 0.018)] and high encapsulation efficiency (90.15 +/- 2.47) % and (80.64 +/- 3.52) % for paclitaxel and cyclosporine respectively with a mild and easy preparation process. A sequential drug release trend of cyclosporine prior to palictaxel was observed. The liposome silica hybrid nano-carrier showed good biocompatibility in vivo and co-delivery of cyclosporine and paclitaxel significantly enhanced the oral absorption of paclitaxel with improved anti-tumor efficacy, suggesting a promising approach for multi-drug therapy against tumor and other serious diseases via oral route. PMID- 24783516 TI - [Extraction of total RNA and cloning of sgDHAR gene from Siraitia grosvenorii]. AB - Total RNA was isolated from Siraitia grosvenorii fruit by the method of modified Trizol, according to S. grosvenorii fruit characteristics of rich phenols, polysaccharide, oil and proteins. The OD260/280, OD260/230, RNA integrity (RIN) and yield of the total RNA with this method were 2.01, 2.02, 9.50 and 260 mirog.g 1, respectively. The open reading frame (ORF) of dehydroascorbate reductase (DHAR), named as SgDHAR, was cloned by rapid amplification of cDNA ends (RACE) and RT-PCR method from S. grosvenorii. The GenBank accession number for this gene is KC907731. The SgDHAR gene contains a full-length cDNA of 1,252 bp including ORF of 819 bp and encodes a predicted protein of 272 amino acids. The molecular mass is 30.217 7 kD and the isoelectric point is 8.76. Homology comparison showed that it shared 87% nucleotide sequence homology with Cucumis sativus. Expression patterns using qRT-PCR analysis showed that SgDHAR was mainly expressed in fruit and stem, followed by flower, and was lowest in root, while the expression level was 6.83 times in triploid. T than that in diploid. Therefore, SgDHAR gene may be involved in abortion of triploid seedless S. grosvenorii. PMID- 24783517 TI - [Cloning and expression analysis of pathogenesis-related protein 1 gene of Panax notoginseng]. AB - By reverse transcription-polymerase chain reaction (RT-PCR), an open reading frame of pathogenesis-related protein 1 (PR1) was isolated from Panax notoginseng and named as PnPR1. Molecular and bioinformatic analyses of PnPR1 revealed that an open reading frame of 501 bp was predicted to encode a 166-amino acid protein with a deduced molecular mass of 18.1 kD. Homology analysis showed that the deduced amino acid sequence of PR1 protein of Panax notoginseng had a high similarity with other higher plants had the same conservative structure domain of cysteine-rich secretory protein (CAP). The recombinant expressed plasmid pET28a(+)-PnPR1 was expressed in Escherichia coli BL21. The expression conditions were optimized by induction at different times, different temperatures, different IPTG concentrations and different giving times. The optimum expression condition was 0.4 mmol.L-1 IPTG at 28 degrees C for 20 h. The successful expression of PnPR1 provides some basis for protein purification and preparation of the monoclonal antibody. PMID- 24783518 TI - [Apoptosis of MDA-MB-231 cells induced by berberine alpha-hydroxy beta decanoylethyl sulfonate]. AB - To investigate the cell proliferation inhibition and apoptosis induced by berberine a-hydroxy f-decanoylethyl sulfonate (HB) on MDA-MB-231 cells in vitro, and the inhibitory effect of HB on the expression of poly adenosine diphosphate RNA polymerase (PARP), MTT assay was used to detect the viability of MDA-MB-231 cells and cell cycle was examined by flow cytometry. The results showed that HB could significantly inhibit the proliferation of MDA-MB-231 cells, and mildly arrested cell cycle progression at S phase. The IC50S for 24, 48 and 72 h treatment were 4.65, 1.46 and 0.75 mg.L-1 (7.55, 2.37 and 1.22 micromol.L-1), respectively. Annexin V-FITC/PI double staining assay showed that HB increased apoptotic ratio of MDA-MB-231 cells. Western blotting analysis showed the expressions of procaspase-3, procaspase-9 and PARP were decreased after HB treatment, while their fragment increased. The results suggest that HB can inhibit the growth and induce apoptosis of MDA-MB-231 cells, which may be associated with inhibition of the expression of procaspase-3, procaspase-9 and PARP. PMID- 24783519 TI - [In vitro effect of total flavones of Fructus Chorspondiatis on expression of collagen type I and type III mRNA and protein of cultured rat cardiac fibroblasts]. AB - This study aims to investigate the effect of total flavones of Fructus Chorspondiatis (TFFC) on the mRNA and protein expression of collagen type I and III of rat cardiac fibroblasts (CFs) induced by angiotensin II (Ang II), and explore its anti-myocardial fibrosis molecular mechanism. Neonatal rat CFs were prepared from Sprague-Dawley rats (1-3 d after birth). The expression of collagen type I and III mRNA and protein were measured by RT-PCR and Western blotting, respectively. The study showed that stimulation of neonatal rat CFs with 100 nmol.L-1 of Ang II for 72 h resulted in a significant increase of the expression of collagen type I and III mRNA and protein. The changes on the expression level were blocked by TFFC. The results demonstrated that TFFC can inhibit myocardial fibrosis induced by Ang II in rats, which is probably associated with the collagen type I and III mRNA and protein levels up-regulated by Ang II, and TFFC was shown to decrease the expression levels of collagen type I and III mRNA and protein. PMID- 24783520 TI - [Relationship between artesunate influence on the process of TGF-beta1 induced alveolar epithelial cells transform into mesenchymal cells and on idiopathic pulmonary fibrosis]. AB - This study is to investigate the effect of artesunate on transforming growth factor-beta1 (TGF-beta1) induced epithelial-mesenchymal transition (EMT) and its possible mechanism. After the in vitro cultured RLE-6TN cells were treated with TGF-beta1 then artesunate intervened on it, after 24 h, expression of the markers of mesenchymal cell was assayed using Western blotting and real-time PCR analysis. Western blotting was also used to detect the effect of TGF-beta1 on the Smad3 and Smad7 expressions of RLE-6TN cells. Morphological alterations were examined by phase-contrast microscope, and ultrastructure changes by electron microscope. Incubation of RLE-6TN cells with TGF-beta1 resulted in the up regulation of the expression of the mesenchymal cell markers, after artesunate intervened on it, resulted in the down-regulation of the expression. Meanwhile, incubation with artesunate intervened on RLE-6TN cells could lead to the apparent down-regulation of the expression of Smad3 and up-regulation of Samd7 and the transition of RLE-6TN cells to mesenchymal-like by TGF-beta1 induction, after artesunate intervened on it, RLE-6TN cells to epithelial-like. TGF-beta1 induced epithelial-mesenchymal transition process; artesunate can inhibit TGF-beta1 induced epithelial-mesenchymal transition process, the possible mechanism is up regulation of the expression of Smad7 and down-regulation of the expression of Smad3, meanwhile inhibits phosphorylation of Smad3. PMID- 24783521 TI - [Research on night visibility estimation method based on image features of dual light sources]. AB - Haze, rain and snow bring a lot of inconvenience in our daily life, especially produce serious potential safety hazard for night transport. In the present paper the authors propose the vision-based dual light sources visibility method to estimate night visibility. This method is significantly advantaged with wide range, high precision and low cost, and has a good robustness in many kinds of weather conditions. Firstly, the authors give the basic visibility estimation model under the atmosphere multiple scattering theory. Secondly, the authors propose the dual light sources method to remove the luminance fluctuations of light sources and the atmosphere light effect, and formulize the algorithm to accurately gain information of light sources from the dual light sources image. At last, the authors design the dual light sources system and conduct a long time experiments under various atmosphere conditions. The experiments show that, with the baseline of 35 m, the visibility range is up to 15 000 m, and relative error is below 20%. This method and system can satisfy the demand of meteorological department and transport agency. PMID- 24783522 TI - Research on testing the nonlinear optical performance of nonlinear optical materials based on the effect of second-harmonic generation. AB - In the present paper the authors report a research on testing the nonlinear optical performance of optical materials in visible and infrared band. Based on the second order nonlinear optic principle and the photoelectric signal detection technology, the authors have proposed a new testing scheme in which a infrared OPO laser and a method for separating the beams arising from frequency matching and the light produced by other optical effects were used. The OPO laser is adopted as light source to avoid the error of measurement caused by absorption because the double frequency signal of the material is in the transmittance band Our research work includes testing system composition, operational principle and experimental method. The experimental results of KTP, KDP, AGS tested by this method were presented. In the experiment several new infrared non-linear materials were found. This method possesses the merits of good stability and reliability, high sensitivity, simple operation and good reproducibility, which can effectively make qualitative and semi-quantitative test for optical material's nonlinear optical properties from visible to infrared. This work provides an important test -method for the research on second order nonlinear optical materials in visible, infrared and ultraviolet bands. PMID- 24783523 TI - [Study on influence of source spectra on retro-reflection coefficient]. AB - Based on emission spectra of light sources and reflectivity curve of retroreflective materials, relative relations and changing trend of retroreflection coefficient of materials in different light sources was researched through data fitting. The tests were carried on the standard A light source test system. One kind of test results are emission spectra of halogen light source, xenon light source and white LED with different color temperature. And another kind of results are reflectivity curve of retroreflective materials with five different colors such as red, yellow, white, green and blue. Then the correction factors of retroreflection coefficient in different light sources were obtained by test results and data fitting. It shows that the change inlight source spectra has no effect on retroreflection coefficient of white material, which has continuous reflectivity curve in the range of visible light, but has some effect on retroreflection coefficient of the other color materials. Compared with halogen light source, white LED and xenon light source can increase retroreflection coefficient of red and yellow materials, and the increase in the color temperature of light source will decrease retroreflection coefficient of red and yellow materials by the maximum of 47.7% and 4.9%. Conversely, retroreflection coefficient of green and blue materials will increase by the maximum of 16.5% and 28.9%. PMID- 24783524 TI - [Spectroscopic characteristics of DC excited atmospheric pressure glow discharges generated in a needle-plate electrode device and a needle-water electrode one]. AB - Glow discharge characteristics in two discharge devices, i.e. in a needle-plate electrode geometry and a needle-water electrode one were compared by using spectroscopic method. Results show that the different emission regions were found in both discharges generated by the two devices. From the cathode to the anode, there are a cathode glow region, cathode dark glow, a positive column, and an anode glow region. The anode dark region can be clearly discerned in the glow discharge in the needle-plate electrode device, while it almost cannot be found in the needle-water electrode discharge. Comparing the current-voltage characteristics of the two glow discharges, it was found that the voltage across the electrodes decreases with increasing the discharge current in both discharge devices, while the voltage in the needle-water glow discharge is higher than that of the needle-plate one at the same current value. The current-voltage curves have a negative slope and their current densities lie in the range from 10-5 to 10-4 A? cm-2, which indicates that a normal glow discharge mechanism was involved in the two discharges. Comparing the optical spectra scanning from 300nm to 800nm and emitted from the whole normal glow discharge in the two electrode devices, similar spectral lines from the two discharges can be found on the optical emission spectrum, including the second positive system of nitrogen molecules (337.1nm) and the first negative system of nitrogen molecular ions (391.4nm). However, the intensity ratio of spectral lines is different. The intensity ratio (391.4nm to 337.1nm) and vibrational temperature were investigated at different locations. It was found that the intensity ratio of the needle-water electrode discharge is larger than that of the needle-plate electrode discharge at the same location. Furthermore, the vibrational temperature in the needle-water electrode discharge is higher than that of the needle-plate one at the same location. PMID- 24783525 TI - [Investigation of spectroscopy of ZnCuInS/ZnSe/ZnS quantum dots]. AB - ZnCuInS/ZnSe/ZnS quantum dots were non-toxic and heavy-metal free semiconductor nanocrystals. In the present paper, ZnCuInS/ZnSe/ZnS core/shell/shell quantum dots were prepared with the particle size of 3.3, 2.7 and 2.3 nm. The photoluminescence of ZnCuInS/ZnSe/ZnS quantum dots with different size were measured, and the wavelength of peak was blue-shifted with decreasing the diameter. The wavelength of absorption peaks and photoluminescence peaks were 510 nm, 611 nm (3.3 nm), 483 nm, 583 nm (2.7 nm) and 447 nm and 545 nm(2.3 nm). The obvious size-dependence of ZnCuInS/ZnSe/ZnS quantum dots was shown. The Stokes shifts of ZnCuInS/ZnSe/ZnS quantum dots were 398 meV (3.3 nm), 436 meV (2.7 nm) and 498 meV (2.3 nm). Such large Stokes shifts indicate that the emission should be ascribed to the defect-related recombination. The temperature-dependent photoluminescence of ZnCuInS/ZnSe/ZnS quantum dots with the particle size of 3.3 nm were measured. The wavelength of peaks was red-shifted with increasing temperature and the intensity of photoluminescence spectra was decreased with increasing temperature. Therefore, the emission was concluded to be the transition from the conduction band to defect state. PMID- 24783526 TI - [Preparation of Tb3+, Yb3+ doped Y2O3 luminescent powders and near-infrared quantum cutting research]. AB - Y2O3:Tb3+ and Y2O3:Tb3+, Yb3+ samples were prepared by co-precipitation method. The morphology, microstructure and fluorescence spectra at room temperature of samples were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and fluorescence spectrometer, The optimal process conditions of Y2O3:Tb3+ under different doping concentrations, annealing temperature, and pH value of the solution were obtained: Tb3+ concentration is 1.5%, annealing temperature is 1400 degrees C, an alkaline solution environment, and samples under 300 nm light excitation have the largest green light emission at 543 nm. The corresponding relation of Tb3+ ion level structure and transition properties and experimental spectra were analyzed in detail, and we explained the influence mechanism of process conditions and the fluorescence quenching process mainly effects luminous intensity of samples. The energy transfer from sensitizing ions Tb3+ to active ion Yb3+ was confirmed, it made the sample have considerable emitting light in the near-infrared region; the authors described the process of cooperation conversion luminescence between the two ions from the level transition angle, and also analyzed the system of fluorescence quenching process. Test results showed that the near infrared quantum cutting can effectively improve the luminous efficiency of doped ions, and will have broad application prospects in the silicon solar cells and other fields. PMID- 24783527 TI - [White organic light-emitting diodes applied for lighting technology]. AB - Lighting accounts for approximately 22 percent of the electricity consumed in buildings in the United States, with 40 percent of that amount consumed by inefficient incandescent lamps. This has generated increased interest in the use of white electroluminescent organic light-emitting devices (WOLEDS) as the next generation solid-state lighting source, owing to their potential for significantly improved efficiency over incandescent sources, combined with low cost, high-throughput manufacturability. The research and application of the devices have witnessed great progress. WOLEDS have incomparable advantages for its special characteristics. This progress report sketched the principle of WOLEDS and provided some common structures, and further investigation of the mechanism of different structures was made. Meanwhile, the key technologies of WOLEDS were summarized. Finally, the latest research progress of WOLEDS was reviewed. PMID- 24783528 TI - [Effect of critical process parameters on luminescence properties of Eu2+/Dy3+ co doped high silica luminescence glass]. AB - In the present work, Eu2+/Dy3+ co-doped high silica glasses with different process parameters were prepared and the effect of critical process parameters including phase separation temperature, solution concentration and sintering temperature on the luminescence properties of Eu2+/Dy3+ co-doped high silica glasses was investigated by means of measuring pore surface parameters of porous glasses, emission spectra, infrared absorption spectra and densities of high silica glasses. Pore structure parameters of porous glass samples and emission spectra of corresponding high silica glass samples with different phase separation temperatures show that the phase separation temperature has indirect effect on luminescence properties of high silica glass by influencing specific surface area value of corresponding porous glass. Specific surface area of porous glass changes when phase separation temperature changes. High silica glass achieves maximum emission intensity when the maximum specific surface area of porous glass is obtained. Luminescence intensity of high silica glass increases when specific surface area of porous glass increases. Emission spectra of high silica glass samples with different solution concentrations show that the emission intensities of Eu2+ and Dy3+ in high silica glass are enhanced with the increase in the Dy3+ concentration in solution; when the Dy3+ concentration is beyond 0.1 mol x L(-1), the emission intensities of Eu2+ and Dy3+ in high silica glass are both decreased due to the occurring of concentration quench of Dy3+ in the glass. Emission spectra and infrared absorption spectra of high silica glass samples with different sintering temperatures show that the emission intensity of high silica glass is increased with the increase in the sintering temperature because the content of residual hydroxyl groups -OH in the glass is decreased; when the sintering temperature is beyond 1000 degrees C, the high silica glass exhibits crystalline and the luminescence intensity decreases. PMID- 24783529 TI - [The optical characteristics of hollow cathode discharge striations in nitrogen]. AB - The characteristics of striations in cylindrical hollow cathode discharge were investigated experimentally. The spectra of striations were measured at a pressure of 20 Pa in a discharge of 1.3 mA, in which the main spectra are the emission spectrum lines of the N2 first positive band (B3pi(g)-->A3pi(u)) and second positive band system (C3pi(u)-->B3pi(g)). The spatial characteristics of vibrational temperature of N2 were calculated based on the theory of double molecular spectrum. It is shown that the emission intensity exhibits a periodic structure with an unequal magnitude, and the spectral intensity of bright striation is higher than that of dark striations. The vibrational temperature of bright striation is of the value of 3500-4400K, moreover the vibrational temperature in the bright regions decreases from the cathode to the anode. In addition, the characteristics of striations at 1.0 mA and 1.5 mA were obtained, and the influence of discharge current on the striations was investigated. It is shown that the vibrational temperature and the distance between two striations increase. Finally the reduced electric field was calculated, which is about 44 approximately 49 m(-1) x Pa(-1), moreover it decreases with the increase in discharge current. The results are very useful for understanding the mechanism of discharge striations and for improving the stability of hollow cathode discharge. PMID- 24783530 TI - [Synthesis and fluorescence properties of SrZn(WO4)2:Tb3+, Ce3+ phosphors]. AB - SrZn(1-x) (WO4)2:xTb3+, yCe3+ green fluorescent phosphors for near ultraviolet excitation were prepared using chemical co-precipitation. The phases of different doping ratio samples were characterized by the X-ray diffraction (XRD). The emission spectrum and excitation spectrum of samples were characterized by fluorescence spectroscopy (PL). The luminescence properties of the rare-earth Tb3+ ion doped and Ce3+ and Tb3+ ion codoped samples were discussed. XRD analysis shows that the main diffraction peaks of samples were consistent with the standard card (JCPDS 08-0490 and the JCPDS 15-0774) of the diffraction peak data. This showed that the doping rare earth ions did not change matrix lattice structure. The excitation spectrum showed that the excitation spectrum peaks at 223 nm which is assigned to the 7F-7D absorption transitions of Tb3+. The emission spectrum excited by 223 nm exhibits sharp lines peaking at 543 nm which was assigned to the 5D4-7F5 transitions of the Tb3+ ions. With Tb3+ and Ce3+ co doping, the spectrum didn't change much. The intensity of fluorescence reached the strongest when the concentration of Tb3+:Ce3+ arrived at 0.06:0.02 which may means that there was energy transfer between the ions of Ce3+ and Tb3+. PMID- 24783531 TI - IR spectrum simulation of molecular structure model of Shendong coal vitrinite by using quantum chemistry method. AB - The structure of coal needs to be understood from a molecular point of view for clean, effective and high value-added utilization of coal. In the literature, molecular structure model of Shendong coal vitrinite (SV) was established by the authors on the basis of experimental results of ultimate analysis and 13C NMR, and the calculated 13C NMR spectrum of SV model was consistent with the experimental spectrum. In order to further verify the accuracy of SV structure model established by the authors, the infrared spectrum of SV structure model was calculated using quantum chemistry semi-empirical VAMP in this thesis. The results showed that the peak shape of calculated IR spectrum of SV structure model was similar to the experiment's, but the wave number of calculated IR spectrum was obviously higher than that of experimental spectrum. According to the calculated results for model compounds by using the same method, calculated vibrational frequency was higher than that of experiment for the same functional groups. Hence, the calculated IR spectrum should be corrected. After correction the calculated IR spectrum of SV structure model matched well with the experimental spectrum. In other words, the SV structure model can truly reflect the structure characteristics of SV. PMID- 24783532 TI - [Studies on corrosion property of the anodic coating on the Mg alloy by micro FTIR mapping]. AB - Micro-FTIR mapping technology was used to monitor the amount and distribution of Mg(OH)2 on the anodic coating of magnesium alloy which was immersed in the 7.3 Wt% Na2SO4 solution for different time. In the solution, part of the MgO on the surface of the Mg alloy could gradually transform into Mg(OH)2 which could be detached from the Mg alloy surface and dis- solved into the solution. With immersion time of 2 h in 7.3 Wt% Na2SO4 solution 2h, FTIR mapping results showed that FTIR absorption signal of Mg(OH)2 was strongest and Mg(OH)2 was most on the surface of the anodic coating. After 4 hours, the content of Mg(OH)2 began to decrease, and the Mg alloy was etched gradually. The FTIR mapping results of another component Al2O3 with immersion time were almost similar to those of Mg(OH)2. The impedance of the oxide film was also analyzed using electrochemical impedance spectroscopy. It showed that the impedance changed with the immersion time and conformed to the corrosion law of the oxide coating. This research has a good guidance and application value for characterization of the anodic coating on magnesium alloy. PMID- 24783533 TI - [Analysis of infrared spectra of 60 kinds of plant extract of traditional Chinese medicine and study on the identification and evaluation of characteristics of the regional markers associated with cold and heat nature]. AB - By using the Fourier transform infrared spectroscopy and linear discriminant analysis (LDA), logistic discriminant analysis (Logistic-DA), principal component analysis-linear discriminant analysis (PCA-LDA), partial least-squares discriminant analysis (PLS-DA), random forest (RF), support vector machine (SVM), infrared spectra of 60 kinds of plant extract of Chinese traditional medicine were analyzed and the identification and evaluation of characteristics of the regional markers associated with cold and heat nature were studied. Results indicated that LDA and SVM are suitable for the recognition model of water extract infrared spectral data, LDA is suitable for the identification model of anhydrous ethanol extract infrared spectral data, SVM is suitable for the identification model of chloroform extract infrared spectral data, while petroleum ether extract group recognition effect is not ideal. According to the suitable characteristic parameters identification model, data were analyzed by infrared spectroscopy, and parameters and resistance characteristics of the traditional Chinese drug composition can be obtained. Regional characteristics of these two parameters can be used to identify drug ingredients, and can also be used to indicate different degrees of resistance characteristics of traditional Chinese medicine. Component parameter is model identification coefficient corresponding to the position of spectrum and infrared, with a value greater than zero it is cold nature marker, while with a value less than zero it is heat nature marker; model identification score is a parameter reflecting the degree of cold and heat nature, the greater the score (positive), the more it is cold, while the smaller the score, the more it is hot. a parameter reflecting the degree of cold and heat,the greater the score (positive) is cold more strong, the score is small (negative) heat stronger. PMID- 24783534 TI - [Identification of transmission fluid based on NIR spectroscopy by combining sparse representation method with manifold learning]. AB - An identification method based on sparse representation (SR) combined with autoencoder network (AN) manifold learning was proposed for discriminating the varieties of transmission fluid by using near infrared (NIR) spectroscopy technology. NIR transmittance spectra from 600 to 1 800 nm were collected from 300 transmission fluid samples of five varieties (each variety consists of 60 samples). For each variety, 30 samples were randomly selected as training set (totally 150 samples), and the rest 30 ones as testing set (totally 150 samples). Autoencoder network manifold learning was applied to obtain the characteristic information in the 600-1800 nm spectra and the number of characteristics was reduced to 10. Principal component analysis (PCA) was applied to extract several relevant variables to represent the useful information of spectral variables. All of the training samples made up a data dictionary of the sparse representation (SR). Then the transmission fluid variety identification problem was reduced to the problem as how to represent the testing samples from the data dictionary (training samples data). The identification result thus could be achieved by solving the L-1 norm-based optimization problem. We compared the effectiveness of the proposed method with that of linear discriminant analysis (LDA), least squares support vector machine (LS-SVM) and sparse representation (SR) using the relevant variables selected by principal component analysis (PCA) and AN. Experimental results demonstrated that the overall identification accuracy of the proposed method for the five transmission fluid varieties was 97.33% by AN-SR, which was significantly higher than that of LDA or LS-SVM. Therefore, the proposed method can provide a new effective method for identification of transmission fluid variety. PMID- 24783535 TI - [New method of near infrared spectra analysis for the content of acid soluble lignin of Acacia]. AB - The near infrared spectra analysis model of the content of the acid soluble lignin and the model of the content of the Klason lignin were built by the iterative method separately at first. The results show that the prediction effect of the content of the Klason lignin is obviously better than that of the acid soluble lignin. Different from usual methods of building near infrared spectra analysis model, the approximate linear relation between the contents of the acid soluble lignin and the contents of the Klason lignin was used. Combined with the near infrared spectroscopy data of multi-wavelength, twenty sub models of prediction of the content of the acid soluble lignin were built with the help of the Klason lignin content whose prediction effect is better than that of the acid soluble lignin. By calculating the weighted mean value of the prediction values of these sub models, the new prediction value of the content of the acid soluble lignin of each acacia specimen was obtained at last. The prediction error of the new model is obviously less than that of the model built by the iterative method. It is possible that the method of modeling in the paper can be used to some chemical component contents when the predictions of them by usual methods are not very effective, and the effects of the near infrared spectra analysis of them will be improved. PMID- 24783536 TI - [Quantitative analysis of contents in compound fertilizer and application research using near infrared reflectance spectroscopy]. AB - In the present study, a new approach to fast determining the content of urea, biuret and moisture in compound fertilizer composed of urea, ammonium dihydrogenphosphate and potassium chloride was proposed by using near infrared diffuse reflectance spectroscopy. After preprocessing the original spectrum, partial least squares (PLS) models of urea, biuret and moisture were built with the R2 values of 0.9861, 0.9770 and 0.9713 respectively, the root mean square errors of cross validation were 2.59, 0.38, 0.132 respectively. And the prediction correlation factors were 0.9733, 0.9215 and 0.9679 respectively. The authors detected six kinds of compound fertilizer in market for the model verification, the correlation factors were 0.9237, 0.9786 and 0.9874 respectively. The data implied that the new method can be used for situ quality control in the production process of compound fertilizer. PMID- 24783537 TI - [Adsorption behaviors of protonation modified chitosan and the analysis of spectra]. AB - In order to improve adsorbing performance and stability of chitosan in acid simultaneously, cross-linking was employed after the protection of amino groups for improving its stability, then the protection of amino groups was removed and protonated to obtain high adsorption performance. With formaldehyde as amino group protective agent and glutaraldehyde as cross-linking reagent, cross-linked chitosan (CCTS) was prepared by reversed phase suspension method in this paper, then it was protonated to make protonation modified chitosan adsorbent (P-CCTS). The adsorption performance of sulfate ion onto P-CCTS was firstly studied and investigated by static adsorption test. Elemental analysis by energy dispersive spectrometer of X-rays (EDS) and identifying of functional groups by Fourier transform infrared spectroscopy (FTIR) were used to analyze the preparation and adsorption of the adsorbent, and the reaction mechanism of cross-linking and adsorption was investigated. The results show that the adsorption performance of P-CCTS towards sulfate ion is 10 times higher than that of unmodified chitosan, and formaldehyde and glutaraldehyde mainly react with amino (-NH2) and part of hydroxy (C6-OH) of chitosn. A salt of chitosan protonated amino chlorine was formed through the process of the protonation of amino, the adsorption of sulfate ion mainly occurs on the protonated amino on which ion exchange happened between chlorine ion and sulfate ion. PMID- 24783538 TI - [Rapid identification of Dendrobium plants based on near infrared diffuse reflection spectroscopy]. AB - Near infrared diffuse reflection spectra of 15 species' 171 samples of Dendrobium combined with chemometrics statistical analysis were used to build prediction model, in order to discriminate different species of Dendrobium quickly and nondestructively. Hotelling T2 was applied to stability analysis of spectrum of 5 random drawing samples, and the results showed that the samples spectrum possessed good stability. Orthogonal test L24 (2 x 4 x 3 x 8) was designed to optimize optical path type, spectral band, derivative and smooth. The result of orthogonal test was analyzed by principal component analysis, which revealed that when 6500-4000 cm(-1) spectral band was applied, and with multiplicative scatter correction, second derivative, Norris smooth, and the number of principal components 7, the spectrum distinguishing accuracy was 100%. With the optimized condition of orthogonal test as the input value of partial least squares discriminant analysis and random drawing 123 samples as calibration set to establish the prediction model, and the rest 48 samples as prediction set were use to assess the property of the prediction model, the results indicated that the accumulating contribution rate of the first 3 principal components of the model was 99.36%, the identification of the standard deviation was +/- 0.1, and the correct recognition rate of the model was 97.92%. The results were satisfied. The method provided a new way for the rapid identification of different species of Dendrobium, and also supplied a reference for the authentication of medicinal plants. PMID- 24783539 TI - [Research on Raman spectra of chalcopyrite under 0-1400 MPa and ambient temperature]. AB - The variation characters of the A1 mode Raman spectra of chalcopyrite under 0.1 1400 MPa and ambient temperature were researched using diamond anvil cell. The results show that the shape and intensity of the Raman peak remains constant under experimental conditions, indicating that the chemical bounds of Cu-S and Fe S remain unchanged. The authors have also noticed that the position of the Raman peak shifts to higher frequency with increasing pressure, which could be described as: nu(290) = 0.031 2p + 290.60 (0.1< or =p<58.8 MPa) and nu(290) = 0.00572p+292.10 (58.8 < or =p<1400 MPa). The rate of the Raman peak shifting with increasing pressure changed abruptly at about 58.8 MPa, the d(nu)/dp is 31.2 and 5.72 cm(-1) x GPa(-1) below and above 58.8 MPa respectively, which perhaps indicate that some structural changes occurred in the chalcopyrite. PMID- 24783540 TI - Spectroscopic investigation of the influence of calcium ion on the structures of casein micelles. AB - The effects of calcium ion on the structural properties of casein micelles in the course of heat treatment were synthetically examined by non-structure-invasive spectrometry. The hydrophobicity, reflected by extrinsic fluorescence (ANS fluorescence), was positively correlated with the concentration of the calcium ion, within the range of 0 to 12 mmol x L(-1). Meanwhile, the turbidity and stability of casein micelles also increased with the growth of calcium concentrations. However, opposite results were observed for hydrodynamic diameter and polydispersity index. Compared with the calcium ion, the calcium-chelator (citrate) has an opposite effect on the structural characteristics of casein micelles. Within the calcium concentrations range of 0 to 12 mmol x L(-1), the hydrophobicity, stability and turbidity were negatively correlated with the concentration of the calcium ion, nevertheless, opposite results were observed for hydrodynamic diameter and polydispersity index. All the results indicate that the calcium ion could be used to modify the structures of casein micelles during heat heatment. PMID- 24783541 TI - [Reserach on Raman spectra of organic ingredients on colored pearls]. AB - Based on the visible spectra and Raman spectra test of a variety of colored pearls samples to study the relationship between the organic component and the pearl's color was studied. The study results show that both the freshwater and seawater pearls exhibit strong characteristic peaks in 1121-1132 and 1506-1524 cm(-1) range, which is respectively attributed to the C-C and C=C stretching vibration; the peak intensity in 1117-1132, 1502-1524 and 2000-3500 cm(-1) range increases as the color deepens, which is closely related to the pearl's color; The peak in the 1475-1575 cm(-1) range is divided into 8-10 secondary peaks of purple freshwater pearl and deep orange seawater pearl. The number of C=C double bonds is N=9 approximately 27 and N=7 approximately 27 respectively after calculation. Polyene compound of different varieties and content could be the reason for the pearls' color. PMID- 24783542 TI - [A new peak detection algorithm of Raman spectra]. AB - The authors proposed a new Raman peak recognition method named bi-scale correlation algorithm. The algorithm uses the combination of the correlation coefficient and the local signal-to-noise ratio under two scales to achieve Raman peak identification. We compared the performance of the proposed algorithm with that of the traditional continuous wavelet transform method through MATLAB, and then tested the algorithm with real Raman spectra. The results show that the average time for identifying a Raman spectrum is 0.51 s with the algorithm, while it is 0.71 s with the continuous wavelet transform. When the signal-to-noise ratio of Raman peak is greater than or equal to 6 (modern Raman spectrometers feature an excellent signal-to-noise ratio), the recognition accuracy with the algorithm is higher than 99%, while it is less than 84% with the continuous wavelet transform method. The mean and the standard deviations of the peak position identification error of the algorithm are both less than that of the continuous wavelet transform method. Simulation analysis and experimental verification prove that the new algorithm possesses the following advantages: no needs of human intervention, no needs of de-noising and background removal operation, higher recognition speed and higher recognition accuracy. The proposed algorithm is operable in Raman peak identification. PMID- 24783543 TI - [Low-temperature-dependent characteristics of Raman scattering in N-type 4H-SiC]. AB - In the present paper, Raman scattering techniques for N-type 4H-SiC single crystal material were performed at the temperatures ranging from 30 to 300 K. These measurements revealed that the Raman phonon modes have a redshift and the linewidth gradually broadens with temperature increasing. Based on the experimental results, the reason for the redshift and broadening is discussed. With the temperature increasing, the lattice thermal vibration restoring force decreases with the lattice thermal vibration increasing, and the interaction between the atom and unit cell is weakened, resulting in the redshift of the acoustic phonon modes and optical phonon modes. The mean number of phonons increase with the temperature increasing, which leads to an increase in scattering probability, in result of decreasing the phonon lifetime. The linewidth and phonon lifetime is inversely proportional, so the linewidth gradually broadens with temperature increasing. Phonon mode intensity with increasing temperature showed different laws that the intensity of E2 (LA), E2 (TA), E1 (TA) and A1 (LA) phonon mode monotonously increases as the temperature increases, while the intensity of E2 (TO), E1 (TO) and A1 (LO) phonon mode decreases after 138 K. The reason is that the high-energy phonons split into multiple lower energy phonons. PMID- 24783544 TI - [Quantitative analysis of two food colors using excitation-emission matrix spectra coupled with parallel factor algorithm]. AB - In the present paper, British Edinburgh FLS920P Steady State and Time-Resolved Fluorescence Spectrometer was applied to measure three dimensional fluorescence spectra of 12 pigment solution samples and the parallel factor algorithm was combined with the excitation-emission matrix to find a way to detect the food colors. In the experiment, making use of CORCONDIA determination method to confirm that the number of the components is 3 in mixed solution, and then by using parallel factor analysis (PARAFAC) algorithms, get the average recoveries of carminum and Allura red were 99.3% +/- 5.0% and 102.2% +/- 5.6%, and the root mean square errors of prediction (RMSEP) were 0.054 and 0.205, respectively. The results show that the method can be applied to determine carminum and Allura red in the mixed solution simultaneously even in the presence of interfering amaranth, which was simple and convenient, rapid, etc, and provides references for synthetic food pigments detection. PMID- 24783546 TI - [Density functional theory investigations of the spectroscopic characteristics and luminescent mechanisms of dipterex and dichlorvos]. AB - By using G09 program package, the ground-state structures, infrared spectra, NMR spectra, UV-Vis spectra as well as the excited structures and fluorescence/phosphorescence spectra of dipterex and dichlorvos were investigated systematically, and luminescence principles were analyzed with the molecular orbitals to provide the theoretical foundation for the detection of trace dipterex and dichlorvos. Our theoretical model revealed that the IR spectra of dipterex and dichlorvos bear strong absorptions at about 1107 cm(-1), which belong to the P-O stretch modes, but dipterex has strong absorption peaks involving the O-H bond; for UV-Vis spectra, dichlorvos has a strong absorption peak at 182.03 nm, but dipterex has a weak one at 192.42 nm, which are assigned to pipi* and sigmapi* transitions, respectively; the emission spectra of dichlorvos are very weak, and has double fluorescence/phosphorescence characteristics, which may be attributed to the resonance structures of dichlorvos; the fluorescence of dipterex has a unique broad peak at 1849.22 nm, corresponding to the LUMO-->HOMO transition of S1 state. PMID- 24783545 TI - [Assessment of inner filter effect corrections in fluorimetry of the interaction between polyphenols and proteins]. AB - Using persimmon tannin fraction (PT40), epicatechin-3-gallate-(4beta-->8, 2beta- >O-->7)-epicatechin-3-gallate (A-type ECG dimer) and epigallocatechin-3-gallate (EGCG) as representatives of polyphenols and Chinese cobra snake venom phospholipase A2 (PLA2) as a model protein, different mathematical equations were compared to correct the inner filter effects produced by the fluorescence quenching of those polyphenols to PLA2 based on the gradient, linearity and intercept of Stern-Volmer regression equation. The results revealed that correction by the equation developed by Gauthier et al made a significant reduction in gradients. Besides, the linearity was clearly improved and the intercepts were closer to 1 after correction in all cases. The binding constant of PT40 and PLA2 declined by 60% and the inferred interaction forces were more convinced after correction by the above equation. Therefore, the equation developed by Gauthier et al was the most appropriate equation for correcting the inner filter effects when studying the interaction of polyphenols and protein using fluorescence quenching method. PMID- 24783547 TI - [DFT/TDDFT study on the structure and absorption spectra of free base, N-/neo confused porphyrin]. AB - Porphyrin is an important class of photochemical materials, which has been widely used in various fields. Computational investigations into the ground state structures and orbital energy levels of free base porphyrin (FBP), neo-confused porphyrin (NECP) and N-confused porphyrin (NCP) were performed with density functional theory(DFT). Absorption spectra were calculated at TD-B3LYP/6-31+G(d). Degeneracy of HOMO and HOMO-1 is lost, which would account for the shoulder peaks about the most intense transitions of FBP and NECP. Following FBP, NECP and NCP order, the orbital energy level (OEL) of LUMO decreases while the OEL of HOMO increases, which lead to the red shift of adsorption spectra. The energy difference between LUMO and LUMO+1 is almost the same as the difference between HOMO and HOMO-1, which would account for the only most intense transition of NCP. Solvent effect on ground state structures and absorption spectra was also investigated. The data shows that the character peak of Soret band and Q band changes in different solvent (benzene, chloroform, acetonitrile and water). So we further focus on discussing the N atom position and solvent effects on the energy level and Soret/Q bands of FBP, NCP and NECP, as well as clarifying its variation regularity and mechanism. PMID- 24783548 TI - A novel spectral fingerprint analysis to discriminate dry red wines. AB - A novel spectral fingerprint to discriminate different dry red wines was built using data visualization method. Twelve red wines with different vintages, cultivars and ageing methods from Changli and Shacheng were sampled. Nine fractions of each wine were collected with a reversed-phase C18 column, and then they were lyophilized. The residue of each fraction was resolved with synthetic wine of the same volume with the fraction sample. The transmittance spectra of wines and their fractions were recorded from 190 to 1100 nm. And the spectral data were visualized to show their visual differences directly. Mono-phenols in wine and fractions were analyzed by HPLC-DAD at wavelengths in the range where located the obvious differences of the spectral fingerprints. The results showed that the spectral differences of wine samples lied in the range of 190 to 600 nm. There were obvious differences in visual maps among wines with different vintages, mainly around 520 nm. The visualization differences among wines with distinct geographical origins lay in the F8 maps, and the differences from the aging methods almost cover the whole wavelength range visualized. However, wines from different grape cultivars had the similar visual characteristics. HPLC-DAD identified the possible monophenol groups for the spectral differences at 280, 313, 365 and 520 nm. It was concluded that the visualization of spectral data from 190 to 600 nm could be used to build red wine spectral fingerprint to distinguish dry red wines with different vintages, origins, and ageing methods. PMID- 24783549 TI - [Quantum chemical study of ultraviolet and visible spectra of four amino cobalt phthalocyanin]. AB - Four amino cobalt phthalocyanine is well known as a promising photosensitizer. In order to enrich and complete the theoretical system of structural properties and reactivity, four amino cobalt phthalocyanine was synthesized and its ultraviolet visible spectrum was obtained by experimental research. Then the experimental spectrum was compared with that obtained from theoretical calculation by quantum chemistry. The experimental results show that there are two obvious absorption peaks at 324.98 and 709.94 nm respectively in the ultraviolet-visible spectrum of four amino cobalt phthalocyanine. The density functional B3LYP/3-21G* method was used in simulating ultraviolet-visible absorption spectra of four amino cobalt phthalocyanine. The calculation results show that there should be two absorption peaks at 321.41 and 709.92 nm respectively. The simulation results agree well with the experimental values, which demonstrates that the density functional theory is valid and reliable in the theoretical research on four amino cobalt phthalocyanine. The contribution rate of various electron transitions in every absorption peak was determined by quantum computation. The contribution rate of various electron transition in every absorption peak was determined by quantum computation. The absorption peak at 326.22 nm is mainly resulted from electronic transition from 152 to 163 LUMO orbit, the absorption peak at 314.42 nm is due to electronic transition from 149 to 164 LUMO+1 orbit, the absorption peak at 747.57 nm is mainly caused by electronic transition from 162 to 163 LUMO orbit, and the absorption peak at 676. 01 nm is mainly caused by electronic transition from 162 to 164 LUMO+1 orbit. These data provide great theoretical complement to experimental study. The quantum chemical study for four amino cobalt phthalocyanine ultraviolet-visible spectrum has very important theoretical significance for experimental research in the future. PMID- 24783550 TI - [Study on the polarized reflectance characteristics of single greenhouse tomato nutrient deficiency leaves]. AB - In order to improve accuracy of quantitative analysis model for the greenhouse tomato nitrogen, phosphorus and potassium nutrient stress, and explore the advantages of polarization non-destructive detection in single-leaf plants scale, polarized reflectance characteristics of greenhouse nutrient deficiency tomato leaves in different growing seasons and different deficiency extents were both examined via means of polarized reflectance spectroscopy system, which was self developed by the research group. The main factors with effects on the polarized reflectance characteristics of tomato leaves were discussed, such as incident zenith angle, azimuth angle, detection zenith angle, light source polarizer degree, and detector polarizer degree. Experiments were carried out to verify the optimum level of above five parameters by means of range analysis of orthogonal experiments, through that way we can know the best angle combination of five parameters. Based on the above analysis, the angle combination and sorting of detecting tomato nutrients deficiency leaves via means of polarization spectroscopy system were obtained as follows: incident zenith angle 60 degrees, light source polarizer degree 0 degrees, detection zenith angle 45 degrees, detector polarizer degree 45 degrees and azimuth angle 180 degrees. At the same time, both the spectra of nitrogen, phosphorus and potassium deficiency leaves in different growth stages and different deficiency extent leaves were compared with each other. Results show that there is a positive correlation between the greenhouse nutrient deficiency tomato leaves growth cycle and tomato leaves polarized reflectance spectra. Nutrient excess or nutrient deficiency can both lead to polarized reflectance decline and polarized reflectance decline extent of greenhouse tomato leaves is more obvious during the fruiting and harvest period. This paper has a certain theoretical and practical significance in the research on nutrition rapid detection on the plant single leaf scale by means of polarized reflectance spectrum. PMID- 24783551 TI - [A novel pol SAR image classification method with subsequent category adjustment by terrain scattering characteristic]. AB - The present paper,on the basis of analyzing the terrain scattering characteristics, proposed a novel supervised classification method combined with complex Wishart classifier ideology. This method used coherent matrix which almost contains all the polarization information to make subsequent adjustments for the supervised classification result to achieve higher accuracy division categories. For the first beginning, supervised classification was carried out on the Cloude & Pottier polarimetric characteristics combination to get the initial classification result. Then, in order to achieve the purpose to correct the mistakes resulting from just using the spatial distribution of feature vectors in supervised classification, we did some analysis as follow. The accuracy analysis of the classification results and the analysis of study area feature scattering similarity play an important role in our study to help us make the determination that the pixels need to be adjusted. Furthermore, taking the mean value of each category coherence matrix as the initial cluster centers of subsequent iterations, and using Kernel Fuzzy C-Means algorithm to adjust the fixed pixel set categories by subsequent category iterative correction, the fine and high accuracy classification results were obtained, combined with complex Wishart distribution of coherence matrix. The domestic X-band full polarization SAR data of Lingshui area in Hainan province was applied in this classification experiment. The experiment results demonstrate that the proposed method can obtain a favorable classification accuracy polarization SAR image classification results, and better meet the scattering characteristics of the surface objects compared to the original method. PMID- 24783552 TI - [A fluoride-sensor for kink structure in DNA condensation process]. AB - Bloomfield has pointed out that the kink structure occurs for sharp bending during DNA condensation process, until now, which has not been proved by experiments. Using UV Spectrophotometer, the effects of fluoride and chlorine on the polyamine-DNA condensation system can be detected. Fluoride and chlorine both belong to the halogen family, but their effects on spermine-DNA condensation system are totally different. Fluoride ions make blue-shift and hyperchromicity appear in the spermine-DNA condensation system, but chlorine ions only make insignificant hyperchromicity happen in this system. Both fluoride ions and chlorine ions only make insignificant hyperchromicity happen in spermidine-DNA condensation system. Based on the distinguished character of fluoride, a fluoride sensor for "kink" structure in DNA condensation was developed and the second kind of "kink" structure only appear in the spermine-DNA condensation system. PMID- 24783553 TI - [Characteristics and antioxidant activity of bovine serum albumin and quercetin interaction in different solvent systems]. AB - Modes and influencing factors of bovine serum albumin (BSA) and quercetin (QUE) interaction will help us understand the interaction mechanisms and functional changes of bioactive small molecules and biomacromolecules. The fluorescence spectroscopy, UV-Vis spectroscopy, synchronous fluorescence spectroscopy, DPPH and ABTS radical scavenging assays were used to investigate the characteristics and antioxidant activity of BSA and QUE interaction in three solvent systems (deionized water, dH2O; dimethyl sulfoxide, DMSO and ethanol, EtOH). The results revealed that QUE had a great ability to quench BSA's fluorescence in both static and dynamic modes, and that hydrophobic interaction played a dominant role in BSA and QUE interaction in three solvent systems. The binding constant values and binding site numbers between BSA and QUE were in the order of dH2O>DMSO>EtOH. The binding distances were in the order of EtOH>DMSO>dH2O. On the basis of the binding distance, the binding forces were in the order of dH2O>DMSO>EtOH. The synchronous fluorescence spectra demonstrated that QUE interacted with both tyrosine and tryptophan residues of BSA in three solvent systems. Moreover, the DPPH radical scavenging rates of both QUE and BSA-QUE were 30%. While, the ABTS radical scavenging rate of QUE was significantly decreased from 80% to 70% when bound to BSA. No significant difference in antioxidant activity between QUE and BSA-QUE was observed in three solvent systems. PMID- 24783554 TI - [Responses of vegetation changes to climatic variations in Panxi area based on the MODIS multispectral data]. AB - It is an important research area to quantitatively studying the relationship between global climatic change and vegetation change based on the remote sensing technology. Panxi area is the ecological barrier of the upper reaches of the Yangtze River, and it is essential for the stability of the ecological environment of Sichuan as well as that of the whole China. The present article analyzes the vegetation change in 2001-2008 and the relationship between vegetation change and climatic variations of Panxi area, based on MODIS multispectral data and meteorological data. The results indicate that NDVI is positively correlated with temperature and precipitation. The precipitation is the major factor that affects the change of vegetation in the Panxi region and the trend of NDVI is similar with autumn precipitation; while at the same time the influence of climate has a one-month-time-lag. PMID- 24783555 TI - [Atomic layer deposited aluminum oxide on SnO2 particles and its impact on dye sensitized solar cells performance]. AB - An ultra-thin deposition of alumina covered the SnO2 photoelectrode surface by atomic layer deposition for dye sensitized cell. Trimethyl aluminum (TMA) and water were used as precursor. The influence of alumina on dye-sensitized cells photoelectric conversion efficiency was discussed. The results showed that atomic layer deposition rate per cycle was about 0.12 nm by use of elliptic polarization apparatus (SE). The SnO2 crystal structure and surface morphology were not changed by deposited alumina as observed by X-ray diffraction (XRD) and field emission scanning electron microscopy (FESEM). The dye adsorption capacity increased with the deposition alumina cycles as found by ultraviolet-visible spectra (UV-Vis). Finally, the mechanism of the effect of deposited alumina using atomic layer deposition was discussed. PMID- 24783556 TI - [Research on living tree volume forecast based on PSO embedding SVM]. AB - In order to establish volume model,living trees have to be fallen and be divided into many sections, which is a kind of destructive experiment. So hundreds of thousands of trees have been fallen down each year in China. To solve this problem, a new method called living tree volume accurate measurement without falling tree was proposed in the present paper. In the method, new measuring methods and calculation ways are used by using photoelectric theodolite and auxiliary artificial measurement. The diameter at breast height and diameter at ground was measured manually, and diameters at other heights were obtained by photoelectric theodolite. Tree volume and height of each tree was calculated by a special software that was programmed by the authors. Zhonglin aspens No. 107 were selected as experiment object, and 400 data records were obtained. Based on these data, a nonlinear intelligent living tree volume prediction model with Particle Swarm Optimization algorithm based on support vector machines (PSO-SVM) was established. Three hundred data records including tree height and diameter at breast height were randomly selected form a total of 400 data records as input data, tree volume as output data, using PSO-SVM tool box of Matlab7.11, thus a tree volume model was obtained. One hundred data records were used to test the volume model. The results show that the complex correlation coefficient (R2) between predicted and measured values is 0. 91, which is 2% higher than the value calculated by classic Spurr binary volume model, and the mean absolute error rates were reduced by 0.44%. Compared with Spurr binary volume model, PSO-SVM model has self-learning and self-adaption ability,moreover, with the characteristics of high prediction accuracy, fast learning speed,and a small sample size requirement, PSO-SVM model with well prospect is worth popularization and application. PMID- 24783557 TI - [Rapid determination of total phosphorus by ultrasonic assisted sample digestion spectrum analysis]. AB - Aiming at the technological shortage of national standard method for the determination of total phosphorus, a rapid determination method of total phosphorus based on ultrasonic assisted sample digestion-spectrum analysis was put forward, and the on-line analysis experiment system was designed. Relying on the experiment system, the experimental method and technology was studied. In view of the actual environmental water samples, contrast test experiment with the national standard method for determination method of total phosphorus was carried on. The experimental results showed that the digestion rate of ultrasonic assisted sample digestion using fenton reagents could reach 97%-100% in 13.5 minutes, and the determination method could complete one copy of sample analysis within 16 minutes. This determination method can solve national standard method's technical problems. All of this research work provides the important experimental basis and technical support for the development of the rapid on-line monitoring instrument for determination of total phosphorus. PMID- 24783558 TI - [Monte Carlo simulation based on diffuse hyperspectrum collection with detection fiber]. AB - The present paper brings the parameters of the detection fiber into Monte Carlo model, and we studied the influence of fiber optic parameters and the distance of fiber from the detector on the detected optic signal,. The simulation results show that signals are obviously different when the NA (numerical aperture) and diameter of the fiber are different respectively. With the increase in NA and diameter of the fiber, the diffuse reflectance and diffuse transmission increase gradually. However, the distance from the sample surface, to some extent, brings little influence when we control it within 1 mm. By further study of the simulation result, we found that the collection efficient of the fiber is the same in different spatial positions. And the collection efficient of strong scattering material is a constant, in spite of absorption coefficient and scattering coefficient. We can normalize the diffuse signals collected by fibers with different angular aperture beta by the collection efficient. Meanwhile, this paper provided the fitting curve of the collection efficient in a certain range. For fibers with different diameters, we can get a good consistence by area normalization. Therefore, the research on the effects of the difference of the detection fiber on diffuse hyper-spectrum has great significance for practical measurement. And the detection results can be transplanted by collection efficient and area normalization when we change the actual detecting fiber. PMID- 24783559 TI - [Study on the modeling of earth-atmosphere coupling over rugged scenes for hyperspectral remote sensing]. AB - Adjacency effects may introduce errors in the quantitative applications of hyperspectral remote sensing, of which the significant item is the earth atmosphere coupling radiance. However, the surrounding relief and shadow induce strong changes in hyperspectral images acquired from rugged terrain, which is not accurate to describe the spectral characteristics. Furthermore, the radiative coupling process between the earth and the atmosphere is more complex over the rugged scenes. In order to meet the requirements of real-time processing in data simulation, an equivalent reflectance of background was developed by taking into account the topography and the geometry between surroundings and targets based on the radiative transfer process. The contributions of the coupling to the signal at sensor level were then evaluated. This approach was integrated to the sensor level radiance simulation model and then validated through simulating a set of actual radiance data. The results show that the visual effect of simulated images is consistent with that of observed images. It was also shown that the spectral similarity is improved over rugged scenes. In addition, the model precision is maintained at the same level over flat scenes. PMID- 24783560 TI - [Effective endmembers based bilinear unmixing model]. AB - An effective endmembers based bilinear unmixing algorithm is prompted in the present paper together with an end-member subset selection algorithm as well. Firstly, the endmembers are ranked according to their distance to the mixed pixel, involving the Euclidean distance and spectral angle. And then, an effective subset of the endmembers is abstracted considering both the ranking result and the change of error. The algorithm reduces the influence of endmembers which are not component of the mixed pixel, decrease the number of endmembers involved in unmixing and improve the accuracy of abundance. The test results for simulation image prove that the algorithm would provide a lower reconstructing error. And the analysis results of actual airborne hyperspectral oil spill image further illustrate its effectiveness. PMID- 24783561 TI - [Inversion of organic matter content of the north fluvo-aquic soil based on hyperspectral and multi-spectra]. AB - The present study aims to assess the feasibility of multi-spectral data in monitoring soil organic matter content. The data source comes from hyperspectral measured under laboratory condition, and simulated multi-spectral data from the hyperspectral. According to the reflectance response functions of Landsat TM and HJ-CCD (the Environment and Disaster Reduction Small Satellites, HJ), the hyperspectra were resampled for the corresponding bands of multi-spectral sensors. The correlation between hyperspectral, simulated reflectance spectra and organic matter content was calculated, and used to extract the sensitive bands of the organic matter in the north fluvo-aquic soil. The partial least square regression (PLSR) method was used to establish experiential models to estimate soil organic matter content. Both root mean squared error (RMSE) and coefficient of the determination (R2) were introduced to test the precision and stability of the modes. Results demonstrate that compared with the hyperspectral data, the best model established by simulated multi-spectral data gives a good result for organic matter content, with R2=0.586, and RMSE=0.280. Therefore, using multi spectral data to predict tide soil organic matter content is feasible. PMID- 24783562 TI - [Inversion of LAI by considering the hotspot effect for different geometrical wheat]. AB - Aimed to deal with the limitation of canopy geometry to crop LAI inversion accuracy a new LAI inversion method for different geometrical winter wheat was proposed based on hotspot indices with field-measured experimental data. The present paper analyzed bidirectional reflectance characteristics of erective and loose varieties at red (680 nm) and NIR wavelengths (800 nm and 860 nm) and developed modified normalized difference between hotspot and dark-spot (MNDHD) and hotspot and dark-spot ratio index (HDRI) using hotspot and dark-spot index (HDS) and normalized difference between hotspot and dark-spot (NDHD) for reference. Combined indices were proposed in the form of the product between HDS, NDHD, MNDHD, HDRI and three ordinary vegetation indices NDVI, SR and EVI to inverse LAI for erective and loose wheat. The analysis results showed that LAI inversion accuracy of erective wheat Jing411 were 0.9431 and 0.9092 retrieved from the combined indices between NDVI and MNDHD and HDRI at 860 nm which were better than that of HDS and NDHD, the LAI inversion accuracy of loose wheat Zhongyou9507 were 0.9648 and 0.8956 retrieved from the combined indices between SR and HDRI and MNDHD at 800 nm which were also higher than that of HDS and NDHD. It was finally concluded that the combined indices between hotspot-signature indices and ordinary vegetation indices were feasible enough to inverse LAI for different crop geometrical wheat and multiangle remote sensing data was much more advantageous than perpendicular observation data to extract crop structural parameters. PMID- 24783563 TI - [Development of prediction models for determining N content in citrus leaves based on hyperspectral imaging technology]. AB - The present study presents prediction models for determining the N content in citrus leaves by using hyperspectral imaging technology combined with several chemometrics methods. The steps followed in this study are: hyperspectral image scanning, extracting average spectra curves, pretreatment of raw spectra data, extracting characteristic wavelengths with successive projection algorithm and developing prediction models for determining N content in citrus leaves. The authors obtained three optimal pretreatment methods through comparing eleven different pretreatment methods including Savitzky-Golay (SG) smoothing, standard normal variate (SNV), multiplicative scatter correction (MSC), first derivative (1-Der) and so on. These selected pretreatment methods are SG smoothing, detrending and SG smoothing-detrending. Based on these three pretreatment methods, the authros first extracted the characteristic wavelengths respectively with successive projection algorithm, and then used the spectral reflectance of the extracted characteristic wavelengths as input variables of partial least squares regression (PLS), multiple linear regression (MLR) and back propagation neural network (BPNN) modeling. Hence, the authors developed three prediction models with each pretreatment method, and obtained nine models in total. Among all the nine prediction models, the two models based on the methods of SG smoothing-detrending-SPA-BPNN (R(p): 0.8513, RMSEP: 0.1881) and detrending SPABPNN (R(p): 0.8609, RMSEP: 0.1595) were found to have achieved the best prediction results. The final results show that using hyperspectra data to determine N content in citrus leaves is feasible. This would provide a theoretical basis for real-time and accurate monitoring of N content in citrus leaves as well as rational N fertilizer application during the plant's growth. PMID- 24783564 TI - [Quantitative analysis of vanadium and titanium in steel samples using LIBS]. AB - The concentrations of vanadium and titanium elements in the steel samples were quantitatively analyzed by Laser-induced breakdown spectroscopy technique in the present paper. The lines of V (VI: 440.85 nm) and Ti (Ti I: 334.19 nm) were chosen as the quantitative analysis spectral lines, while spectral line of Fe (Fe I: 438.35 nm) was chosen as the internal calibration line due to it being the matrix element. Then the calibration curves of V and Ti elements were established with basic calibration method and internal calibration method respectively to quantitatively analyze the concentrations of vanadium and titanium elements in steel. The experimental results showed that the fitting correlation coefficient (R2) of vanadium and titanium elements are 0.9875 and 0.9909 when using basic calibration method, and their maximum relative errors of measurement are 11.09% and 4% respectively; while the fitting correlation coefficient (R2) of vanadium and titanium elements reachs 0.9952 and 0.9921 respectively when using internal calibration method, at the same time, the relative errors of measurement for vanadium and titanium elements were decreased to be lower than 4%. The results of this study demonstrated that the concentration measurement of vanadium and titanium elements in the steel was more suitable with internal calibration method in laser-induced breakdown spectroscopy. PMID- 24783565 TI - [Study of laser energy in multi-element detection of pulverized coal flow with laser-induced breakdown spectroscopy]. AB - The logical range of laser power density and optimum laser power density were explored for multi-element analysis of pulverized coal flow with laser-induced breakdown spectroscopy in the present paper. The range of laser energy was chosen from 20 to 160 mJ in the experiment. Pulverized coal less than 200 microm in diameter of particles fell freely through feeder outlet and the rate of flow was controlled by screw feeder. Emissions were collected with pulse laser at 1 064 nm focusing on pulverized coal flow and plasma was generated. The intensity and cause of fluctuation of emission spectra at various laser energy levels were studied. A suitable range of laser power density is from 14.4 to 34.4 GW x cm( 2), and the optimum laser power density is 19.5 GW x cm(-2) for the determination of pulverized coal flow with LIBS. PMID- 24783566 TI - [Determination and uncertainty evaluation of microelements in flaxseed by using ICP-MS under two modes]. AB - Copper, iron, zinc and manganese in flaxseed were determined by inductively coupled plasma mass spectrometry (ICP-MS). After digestion by microwave-assisted, Cu, Fe, Zn and Mn were analyzed by using Standard and KED modes. In the present study, testing effectiveness of the two modes was compared. On this base, valid determination mode was selected for each of the elements and uncertainty evaluations of the four microelements were explored. According to JJF1059-1999 (Evaluation and Expression of Uncertainty in Measurement), the main influence factors were analyzed one by one. Each of the uncertainties was calculated separately. It was showed that the results of Cu, Fe, Zn and Mn in flaxseed determined by ICP-MS method were satisfactory. At the same time, the results obtained in this work were considered to be valuable as a reference for the evaluation of uncertainty in measurement of Fe, Cu, Zn and Mn with ICP-MS. PMID- 24783567 TI - [Analysis of mineral elements of sunflower (Helianthus annuus L.) grown on saline land in Hetao Irrigation District by ICP-AES]. AB - The absorption and accumulation of ten mineral elements in four kinds of organs (root, steam, leaf and flower disc) in Helianthus annuus L. plants cultured in Hetao Irrigation District under different level of salinity stress were determined by ICP-AES with wet digestion (HNO3 + HClO4). The results showed that: (1) The contents of Fe, Mn, Zn, Ca, and Na were highest in roots, so was K in stems, B and Mg in leaves and P in flower discs, while no significant difference was detected in the content of Cu among these organs; (2) The cumulants of Ca, Mg, P, Cu, B and Zn were highest in flower discs, so were Na, Fe and Mn in roots and K in stems; (3) In sunflower plants, the proportion of mineral element cumulant for K : Ca : Mg : P : Na was 16.71 : 5.23 : 3.86 : 1.23 : 1.00, and for Zn : Fe : B : Mn: Cu was 56.28 : 27.75 : 1.93 : 1.17 : 1.00, respectively; (4) The effect of salinity stress on absorption of mineral elements differed according to the kind of organ and element, root was the most sensitive to soil salt content, followed by stem and leaf, and the effect on flower disc seemed complex. PMID- 24783568 TI - [Determination of trace selenium in plants by hydride generation atomic fluorescence spectrometry with program temperature-controlled graphite digestion]. AB - Discussed several methods of pretreatment for the determination of selenium were discussed, and a program temperature-controlled graphite digestion method was developed to digest 5 kinds of representative standard plant samples of citrus leaves, tea, cabbage leaves, shrubs and rice. The effect of the pretreatment method of digestion solution, digestion temperature and digestion time on the extraction of selenium was investigated in detail. The instrumental working parameters were optimized. For the reaction conditions of hydride generation atomic fluorescence spectrometry (HG-AFS), the effect of the concentration of KBH4 and HCl on the determination of selenium was emphasized. Not only the effect of the concentration of carrier flow HCl was considered, but also the effect of the concentration of sample HCl on the determination of selenium was studied. The best method for determination of trace selenium in plant samples by atomic fluorescence spectrometry with program temperature-controlled graphite digestion was established. Results indicated that the recovery of the method of selenium was 87.1% - 106.2%, the detection limit was 0.018 microg x L(-1) and the relative standard deviation (RSD) was less than 6.0%. In the range of 0-10 microg x L(-1) (low standard) and 0-100 microg x L(-1) (high standard) fluorescence was linearly related to the concentration of selenium, the coefficient of r was 0.9999 and r was 0.9997. Therefore, this method has wide linear range, high sensitivity, low detection limit and good stability, which was very suitable for the determination of trace selenium of plant. And the method was of easy and safe operation, strong practicability, low cost, and low toxicity of chemicals used, so it can be used as a routine analysis method in general laboratory. PMID- 24783569 TI - Sensitive determination of hemoglobin in human blood and serum by flow injection coupled with chemiluminescence detection. AB - A sensitive method to detect hemoglobin (Hb) by flow injection (FI) coupled with chemiluminescence (CL) detection was described, which based on Hb strong enhancing effect on weak luminol-hydrazine CL system in alkaline medium. Parameters affecting the CL detection conditions and FI-CL system were optimized. The effects of possible coexisting substances in human blood and serum of detection Hb were evaluated. Under the optimum conditions, the net CL intensity versus Hb concentration was linear in the range of 5.0 x 10(-9) - 6.0 x 10(-5) g x mL(-1) with the detection limit of 5.8 x 10(-10) g x mL(-1) (9.0 x 10(-12) mol x L(-1)). The relative standard deviations (RSDs) for 8 replicate determinations of 5.0 x 10(-7) and 3.0 x 10(-6) g x mL(-1) Hb were 1.6% and 1.5%, respectively. In addition, the recoveries of Hb in human blood and serum were carried out and varied from 83.0% to 101.0%. The proposed method has been successfully applied for the determination of Hb in healthy human blood and serum. The possible mechanism of Hb enhancing the weak CL emission of luminol-hydrazine system in NaOH solution was discussed by fluorescence spectrophotometer and UV-Vis spectrophotometer. PMID- 24783570 TI - [Research on optimization of mathematical model of flow injection-hydride generation-atomic fluorescence spectrometry]. AB - Flow injection-hydride generation-atomic fluorescence spectrometry was a widely used method in the industries of health, environmental, geological and metallurgical fields for the merit of high sensitivity, wide measurement range and fast analytical speed. However, optimization of this method was too difficult as there exist so many parameters affecting the sensitivity and broadening. Generally, the optimal conditions were sought through several experiments. The present paper proposed a mathematical model between the parameters and sensitivity/broadening coefficients using the law of conservation of mass according to the characteristics of hydride chemical reaction and the composition of the system, which was proved to be accurate as comparing the theoretical simulation and experimental results through the test of arsanilic acid standard solution. Finally, this paper has put a relation map between the parameters and sensitivity/broadening coefficients, and summarized that GLS volume, carrier solution flow rate and sample loop volume were the most factors affecting sensitivity and broadening coefficients. Optimizing these three factors with this relation map, the relative sensitivity was advanced by 2.9 times and relative broadening was reduced by 0.76 times. This model can provide a theoretical guidance for the optimization of the experimental conditions. PMID- 24783571 TI - [Research on spectral characteristic of miniature X-ray tube and determination of beryllium window thickness]. AB - Applying Monte Carlo method, the present paper simulates the emitted X-ray spectrum of miniature X-ray tube with thirteen thickness of beryllium window in the range from 50 to 500 microm. By analyzing the characteristic of the spectrums, the reasonable choice of thickness of beryllium window relies on the application and for the beryllium window it is not the thinner the better. Taking in-situ EDXRF as an example, though the emission X-ray intensity is higher as the thickness of the beryllium window becomes thinner, the proportion of useless low energy X-ray (<5 keV) intensity to all energy X-ray intensity also is higher (>20%). The accuracy of in-situ EDXRF will be reduced when the high-throughput low-energy X-ray enters the detector. Therefore, this paper puts forward several parameters as judgment index for beryllium window thickness, which is described as follows: 1)The intensity ratios of the K-series X-ray to middle-energy (5-25 keV) bremsstrahlung and middle-high-energy (5-50 keV) bremsstrahlung (F1 and F3); 2)The intensity ratios of useless low-energy X-ray (<5 keV) to middle-energy (5 25 keV) X-ray and middle-high-energy (5-50 keV) X-ray (F2 and F4), it can reflect the relative intensity of useless low-energy X-ray. The simulation results demonstrate that with the increase in the beryllium window thickness, the value of F1 (F3) improves slowly, and the value of F2 (F4) decreases rapidly. In addition to the judgment index discussed above, and considering the X-ray shielded by beryllium window, the beryllium window of miniature X-ray tube can be determined. Based on simulation analysis, the thickness of around 250 microm is appropriate to miniature X-ray tube applied in the in-situ EDXRF. Comparing the emitted spectrum with 50 microm-thick beryllium window, 71.66% of low-energy X rays are shielded, only 21.31% of X-rays with energy from 5 to 50 keV is shielded, the intensity ratio of low-energy X-ray to total energy X-ray is less than 10%, and the intensity proportion of K-series X-ray to middle-high energy X ray maintains a high level. In other words, when the mobile X-ray source with 250 microm beryllium window is used in the in-situ EDXRF, proportion of effective signal is higher, and effect of energy resolution of the detection is least; Moreover, the relative intensity of the excitation spectral scattering background, which is obtained by detection for specimen excitation analysis, will remain at low level, thus to ensure the precision of the result of element analysis. For the beryllium window in the application of radiation therapy, the thicker the better. At this time, low-energy X-ray flux maintains a high level, and it can ensure that radiation dose is concentrated on treatment tissue. PMID- 24783572 TI - [Nondestructive analysis of the silicate artifacts excavated from Baofeng and Xinzheng, Henan Province]. AB - Nondestructive analysis plays an important role in the studies of ancient artifacts. The present paper reports the chemical compositions and micro-area phases of 21 silicate artifacts samples analyzed by portable X-ray fluorescence spectrometer and laser Raman spectrometer. Based on the chemical compositions, these samples can be divided into PbO-BaO-SiO2, K2O-SiO2 glass systems, faience and PbO-BaO glassy faience which were discussed respectively, and preliminary investigation of colorants in different parts of some samples was also involved. By laser Raman spectroscopy, Chinese blue (BaCuSi4O10), Chinese purple (BaCuSi2O6) and Chinese dark blue (BaCu2Si2O7) were identified invasively in the blue pigment of some eye beads and circle beads, and then a variety of mineral phase including quartz, calcite, lead carbonate, burnt umber and terre verte were also analyzed successfully in the same way. According to the archaeological research results, the provenances of these samples were discussed briefly. PbO BaO-SiO2 glass, K2O-SiO2 ear pendant and PbO-BaO glassy faience were made in China while the faience was suspected to be from the west. Those results illustrated the communications of culture and technologies among different regions of ancient China, and between ancient China and the western regions. The combination of portable X-ray fluorescence spectrometer and laser Raman spectrometer can provide chemical and phase information of relics, and has great advantages in scientific analysis of ancient artifacts, which supports future studies of archaeology. PMID- 24783573 TI - [Automatic classification method of star spectra data based on manifold-based discriminant anaysis and Support Vector Machine]. AB - Although Support Vector Machine (SVM) is widely used in astronomy, it only takes the margin between classes into consideration while neglects the data distribution in each class, which seriously limits the classification efficiency. In view of this, a novel automatic classification method of star spectra data based on manifold-based discriminant analysis (MDA) and SVM is proposed in this paper. Two important concepts in MDA, manifold-based within-class scatter (MWCS) and manifold-based between-class scatter (MBCS), are introduced in the proposed method, the separating hyperplane found by which ensures MWCS is minimized and MBCS is maximized. Based on the above analysis, the corresponding optimal problem can be established, and then MDA transforms the original optimization problem to the QP dual form and we can obtain the support vectors and decision function. The classes of test samples are decided by the decision function. The advantage of the proposed method is that it not only focuses on the information between classes and distribution characteristics, but also preserves the manifold structure of each class. Experiments on SDSS star spectra datasets verify the effectiveness of the proposed method. PMID- 24783574 TI - [Stellar spectral outliers detection based on Isomap]. AB - How to find the spectra misclassified by traditional methods is the key problem that has been widely studied by the experts of astronomical data processing. We found that Isomap algorithm performs well for this problem. By comparing the performance of Isomap with that of principal component analysis (PCA), we found that (1) Isomap can project the spectra with similar features together and project the spectra with different features far away, while PCA may project the spectra with different features into nearby regions; (2) the outliers given by Isomap can be easily determined, and most of the outliers are binary stars with high scientific values; while the outliers given by PCA are difficult to determine and most of outliers are not binary stars. Thus, Isomap is more efficient than PCA in finding the outliers. Since the spectral data used in experiment are the spectra from the ninth data release of Sloan Digital Sky Survey (SDSS DR9), Isomap can find the spectra misclassified by SDSS pipeline efficiently and improve the classification accuracy obviously. Furthermore, since most of the spectra misclassified by SDSS pipeline are binary stars, Isomap can improve the efficiency of finding the binary stars with high scientific values. Though the experiment results show that Isomap is more sensitive to the noise than PCA, this disadvantage will not affect the application of Isomap in spectral classification since most of the spectra with low signal-to-noise ratios are the spectra whose spectral type can't be determined manually. PMID- 24783575 TI - [Influence of collimation system on static Fourier transform spectrometer]. AB - Collimation system provides collimated light for the static Fourier-transform spectroscopy (SFTS). Its quality is crucial to the signal to noise ratio (SNR) of SFTS. In the present paper, the physical model of SFTS was established based on the Fresnel diffraction theory by means of numerical software. The influence of collimation system on the SFTS was discussed in detail focusing on the aberrations of collimation lens and the quality of extended source. The results of simulation show that the influences of different kinds of aberrations on SNR take on obvious regularity, and in particular, the influences of off-axis aberrations on SNR are closely related to the location of off-axis point source. Finally the extended source's maximum radius allowed was obtained by simulation, which equals to 0.65 mm. The discussion results will be used for the design of collimation system. PMID- 24783576 TI - [Integration design and diffraction characteristics analysis of prism-grating prism]. AB - Prism-grating-prism (PGP) module is the important dispersing component in the hyper spectral imager. In order to effectively predict the distribution of diffraction efficiency of the whole PGP component and its diffraction characteristics before fabrication, a method of the PGP integration design is proposed. From the point of view of the volume phase holographic grating (VPHG) design, combined with the restrictive correlation between the various parameters of prisms and grating, we compiled the analysis software for calculating the whole PGP's diffraction efficiency. Furthermore, the effects of the structure parameters of prisms and grating on the PGP's diffraction characteristics were researched in detail. In particular we discussed the Bragg wavelength shift behaviour of the grating and a broadband PGP spectral component with high diffraction efficiency was designed for the imaging spectrometers. The result of simulation indicated that the spectral bandwidth of the PGP becomes narrower with the dispersion coefficient of prism 1 material decreasing; Bragg wavelength shift characteristics broaden the bandwidth of VPHG both spectrally and angularly, higher angular selectivity is desirable for selection requirements of the prism 1 material, and it can be easily tuned to achieve spectral bandwidth suitable for imaging PGP spectrograph; the vertex angle of prism 1, the film thickness and relative permittivity modulation of the grating have a significant impact on the distribution of PGP's diffraction efficiency, so precision control is necessary when fabrication. The diffraction efficiency of the whole PGP component designed by this method is no less than 50% in the wavelength range from 400 to 1000 nm, the specific design parameters have been given in this paper that have a certain reference value for PGP fabrication. PMID- 24783577 TI - The myth of the compassionate execution. PMID- 24783579 TI - Our inflated universe. PMID- 24783578 TI - Eureka once, eureka twice. PMID- 24783580 TI - The little volcanoes that could. PMID- 24783582 TI - The physics of long, loose tresses. PMID- 24783581 TI - Ancient footprint. PMID- 24783583 TI - Kepler's afterlife. PMID- 24783584 TI - A pontoon of pupae. PMID- 24783585 TI - "Millions of people are suffering". PMID- 24783586 TI - Pot ingredient for epilepsy. PMID- 24783587 TI - Are e-cigarettes safe? PMID- 24783588 TI - Fear the worst. PMID- 24783589 TI - Supersymmetry and the crisis in physics. PMID- 24783590 TI - Cancer's off switch. PMID- 24783591 TI - Paleontology fossil GPS. PMID- 24783592 TI - Is anybody in there? PMID- 24783593 TI - Shape-shifting things to come. PMID- 24783595 TI - The oracle. PMID- 24783594 TI - The great coral grief. PMID- 24783596 TI - The genesis of justice. PMID- 24783597 TI - [Why don't we feel astronomically]. PMID- 24783598 TI - [Anesthetic management of six patients with surgically repaired tetralogy of Fallot undergoing the second intra-cardiac surgery]. AB - In Japan, more than 9,000 patients with congenital heart disease reach adulthood every year with improved medical treatment, and perioperative encounter with patients requiring the second intra-cardiac operation in adulthood is more often. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, and long-term prognosis is good. Therefore, we have more chances to care the postoperarive adult patients with TOF. This is a retrospective study in 6 patients with TOF who underwent the second intra-cardiac operation in adulthood from 2008 to 2012. Among the six patients, six had pulmonary valve replacement; four had tricuspid valve replacements or valvuloplastys; four had ventricular septal defect closures; two had right ventricular outflow tract obstruction releases; one had aortic valve replacement; and three had cryoablations. Right ventricular end-diastolic volume was 194.1 +/- 83.5 ml x m(-2) (mean +/- SD), and right ventricular ejection fraction was 38.2 +/- 4.8%. The factors which influence the anesthetic management were as follows: right cardiac failure by abnormality of the pulmonary valve; residual disease and deuteropathy of two or more combination; the risks associated with the second open chest surgery such as long operative time and severe bleeding. Perioperative management of an adult with congenital heart disease requires full understanding of its pathophysiology such as congenital heart disease, adult-specific complications, and the second open chest surgery. PMID- 24783599 TI - [Evaluation of anesthetic management and renal function in open and endovascular repair of abdominal aortic aneurysm]. AB - BACKGROUND: Since 2007, the number of patients receiving endovascular aneurysm repairs (EVARs) is increasing in Japan. Although EVAR is less invasive and has a lower short-term mortality, it has no long-term advantages and may lead to deterioration of renal function. METHODS: We retrospectively evaluated anesthetic management and renal function in patients undergoing EVAR and open repair (OR) between July 2010 and June 2011. RESULTS: Sixty-three patients (EVAR 33, OR 30) were studied. The average age of patients was significantly older in the EVAR group, and the duration of surgery and anesthesia were longer in the OR group. Despite lower blood loss in the EVAR group compared with the OR group, a massive hemorrhage (1,563 g) occurred in the EVAR group. The renal function of the EVAR group did not deteriorate within 1 year after surgery. However, the rate of acute kidney injuries (AKI) was higher in patients with renal dysfunction before operation than in patients with normal renal function. CONCLUSIONS: Although EVAR is less invasive than OR, anesthesiologists should pay attention to pre-operative comorbidity and massive hemorrhage during the operation. To avoid postoperative renal dysfunction, it is important to protect the kidney during surgery. PMID- 24783600 TI - [GlideScope Cobalt: assessment of performance in 50 children]. AB - BACKGROUND: GlideScope Cobalt video laryngoscope is a new type of GlideScope series. A reusable camera baton is inserted into a disposable plastic curved blade. The blade has 5 choices of size and can be used from infants to adults. The aim of the current study was to evaluate the efficacy of GlideScope Cobalt in children. METHODS: Endotracheal intubation was performed in 50 surgical children undergoing general anesthesia. The length of time in intubation, percentage of glottic opening (POGO) score and optimizing procedures were recorded. RESULTS: 100% POGO score was obtained in 42 cases. Successful endotracheal intubation was performed in 47 cases and 37 patients were intubated within 1 minute. It took over 1 minute to intubate in 13 cases, because of the difficulty of tracheal tube maneuver. Particular children, mostly aged 6-8, had difficulty in matching the size of the blade because of the large difference between the sizes of blade 2 and that of blade 3. CONCLUSIONS: GlideScope Cobalt is a useful tool in chidlren's airway management but it necessitates getting used to the tracheal tube maneuver and lacks the suitable blade size for 6-8 years old children. PMID- 24783601 TI - [Evaluation of postoperative pain intensity related to post-thoracotomy pain syndrome occurring after video-assisted thoracic surgery lobectomy for lung cancer]. AB - BACKGROUND: We conducted a retrospective study to evaluate the relationship between post-thoracotomy pain syndrome (PTPS) and early postoperative analgesia with multimodal analgesia administered via a combination of patient-controlled epidural analgesia (PCEA) and nonsteroidal anti-inflammatory drugs (NSAIDs) in patients who had undergone video-assisted lobectomy for lung cancer. METHODS: A total of 73 adult patients were divided into 2 groups: group A included 12 patients (16.4%) with PTPS, and group B included 61 patients without PTPS. All patients received postoperative multimodal analgesia via a combination of NSAIDs and PCEA with a mixture of 2 microg x ml(-1) fentanyl and 1.5 mg x ml(-1) ropivacaine. For statistical analyses, unpaired t-test, Mann-Whitney test and chi square test were used and considered P significant if lower than 0.05. RESULTS: Pain intensity was measured on a 100-mm non-graduated visual analogue scale (VAS), and it was significantly greater in group A (8 mm) than that in group B (2 mm). There was no significant difference between groups in pain intensity during movement, with a VAS score of 33 mm in group A and 35 mm in group B. The number of PCEA bolus injections given to patients was significantly higher in group A (3 times) than in group B (2 times). The duration of PCEA was also significantly longer in group A (4 days) than in group B (3 days). There was no significant difference in the rate of NSAIDs usage between the 2 groups CONCLUSIONS: This study demonstrated a significant difference in early postoperative pain intensity between patients with PTPS and those without. We conclude that there is a possibility of intervention in the early postoperative period in patients who underwent thoracic surgery. PMID- 24783602 TI - [Effect of concentration on counting numbers on pain induced by injection of propofol]. AB - BACKGROUND: One of the concerns in the use of propofol is the pain on injection of the drug. Many attempts were made to prevent such pain, none of which has been reasonably successful. We hypothesized that the pain is attenuated when the patient is directed to concentrate on counting numbers while propofol is injected. METHODS: Ninety-one patients undergoing elective surgery under general anesthesia were enrolled. They were randomly assigned to counting or non-counting group. Patients in counting group were instructed to verbally count numbers backwards starting 100 when propofol was injected, while patients in non-counting group were injected propofol without any instructions. The size of the i.v. cannula, the temperature of the drug, and speed by which the drug was injected were controlled. No premedication was given. We interviewed the patients after the surgery and scored the pain on propofol injection, the pain on the placement of the iv cannula, and the anxiety level on entering the operating room. RESULTS: There was no significant difference in the incidence of pain on injection of propofol (34% and 33% in the counting and the non-counting group, respectively). A multiple logistic-regression analysis revealed that the significant factors to cause pain on the injection of propofol were age and the degree of pain on inserting intravenous line. CONCLUSIONS: Intensive counting did not reduce the incidence of pain on injection of propofol. Age and the degree of pain on inserting intravenous cannula can be a useful predictor for an intolerable pain on injection of propofol. PMID- 24783603 TI - [Evaluation of factors associated with postoperative sore throat]. AB - BACKGROUND: Postoperative sore throat should be recognized seriously as an avoidable complication because of high incidence and dissatisfaction with anesthesia. The aim of the study was to identify the risk factors of postoperative sore throats in patients undergoing general anesthesia. METHODS: We retrospectively studied 1,733 patients (above 18 years of age) who had undergone general anesthesia from January to December 2010 and who had visited Department of Anesthesia, postoperative anesthesia clinic. RESULTS: Age, ASA classification, position, airway device, methods of postoperative pain management and site of surgery were significantly identified as the associated factors for postoperative sore throat using univariate analysis. Under 65 year of age (odds ratio 2.3), operation of head and neck and pharynx (odds ratio 1.6), spine surgeries (odds ratio 0.33), laryngeal mask (odds ratio 0.47), and postoperative intravenous patient-controlled analgesia (IV-PCA, odds ratio 0.4) were significantly identified as the factors with multivariate studies. CONCLUSIONS: Six associated factors for postoperative sore throat were identified in this study. PMID- 24783604 TI - [Successful double-lumen tube insertion using Pentax-AWS Airwayscope with an infant-sized intlock in a rheumatoid arthritis patient with restricted mouth opening and head tilting]. AB - Successful tracheal intubation with a double-lumen tube was achieved using Pentax AWS Airwayscope (AWS) with an infant-size Intlock in a patient with restricted mouth opening and head tilting. A 78-year-old woman with rheumatoid arthritis was scheduled for extended thymectomy under general anesthesia, with anticipated difficult airway. Sufficient mask ventilation with the jaw-thrust maneuver was achieved. The laryngoscopic view was defined as grade III (Cormack & Lehane's classification)with Macintosh laryngoscope. The AWS with an infant-size Intlock facilitated visualization of the glottis, leading to a successful placement of a 32-Fr double-lumen tube under the guidance of the AWS image. Double-lumen tube insertion assisted by the AWS with an infant-size Intlock may be useful for difficult airway management in patients with restricted mouth opening and head tilting. PMID- 24783605 TI - [Successful nasotracheal intubation with the Pentax-AWS Airwayscope and gum elastic bougie in a patient with recurrent tongue cancer]. AB - We report our experience of successful nasotracheal intubation with a spiral tube, by using the Pentax-AWS Airwayscope (AWS) with a gum-elastic bougie (GEB) in a patient with invasive recurrent tongue cancer. The patient was a 55-year-old man who had undergone partial resection of the tongue and cervical lymphadenectomy, and was scheduled for extended resection of the tongue and larynx under general anesthesia. Sufficient mask ventilation with the head-tilt and chin-lift maneuver was achieved. We first inserted AWS gently and visualized the glottis. Next, we inserted the 15 Fr GEB through his nasal aperture and placed it in the trachea under the guidance of the AWS monitor. This allowed us to place the spiral tube uneventfully through the GEB. No evidence of bleeding or damage of the tumor was found. Nasotracheal intubation with the GEB under the guidance of the AWS monitor may be useful in cases such as those involving tongue cancer in which oral space is either narrowed or restricted. PMID- 24783606 TI - [Intubation using the Pentax-AWS Airwayscope with an infant-size Intlock in a patient with increased intracranial pressure due to acute hydrocephalus]. AB - We report our experience with the Pentax-AWS Airwayscope with an infant-size Intlock (AWS-I) in a patient with increased intracranial pressure due to acute hydrocephalus. A 12-month-old female infant with increased intracranial pressure due to acute hydrocephalus was scheduled to undergo emergent ventriculoperitoneal shunting under general anesthesia. She had a clonic convulsion and was sedated with midazolam. As her head was enlarged, head-tilting was difficult. Tracheal intubation while preventing an intracranial pressure increase was needed. After induction of general anesthesia with thiamylal and fentanyl the AWS-I was inserted to obtain a laryngoscopic view without excessive force. Under AWS observation, tracheal intubation was uneventful, and no vital sign change was observed. PMID- 24783607 TI - [Case of drug-induced angioedema (DIAE) on induction of anesthesia with difficult ventilation due to oropharyngeal edema]. AB - A 69-year-old man with a past history of hypertension on angiotensin II receptor blocker (ARB) for three months presented for radical prostatectomy. Immediately after induction of anesthesia with fentanyl and propofol, mask ventilation became difficult, although no significant hemodynamic changes occurred. Fiberoptic examination revealed severe oropharyngeal edema, but, the trachea was successfully intubated. Afterward, the operation proceeded without complications. He stayed in the ICU for 4 days until the trachea was extubated successfully. He was diagnosed with DIAE because of his history of dyspnea with exclusion of other possible pathophysiological conditions. PMID- 24783608 TI - [Severe asthmatic crisis during general anesthesia in a patient with IgG4 related disease]. AB - We experienced severe asthmatic crisis during general anesthesia in a 45-year-old man with IgG4-related disease, COPD and athma undergoing removal of submandibular gland. The ventilatiory failure was caused by the stimulation of the operation, sputum, and neostigmine. His serum IgG4 level was extremely high. IgG4 related disease is a recently emerging entity characterized by a diffuse or mass forming inflammatory reaction rich in IgG4-positive plasma cells associated with fibrosclerosis and obliterative phlebitis. It is associated with an elevated serum level of IgG4 and an allergic disease. We must be careful in perioperative management of the patients with IgG4-related disease because general anesthesia can induce asthmatic crisis. PMID- 24783609 TI - [Effect of fibrinogen concentrate on coagulopathy patient with left ventricular assist system in surgical repair of thoracic abdominal aortic aneurysm (TAAA): a case report]. AB - We describe a case in which fibrinogen concentrate was useful to improve anticoagulation after aortic graft replacement. A 44-year-old man with left ventricular assist system (LVAS) underwent thoracic abdominal aortic aneurysm (TAAA) graft replacement. LVAS requires anticoagulant therapy for thromboprophylaxis. Therefore, we supposed that it would be difficult to stop bleeding in TAAA graft replacement surgery. For this reason, we planned to administer fibrinogen concentrate during the surgery. When the patient was weaned from cardiopulmonary bypass, blood fibrinogen value decreased to 58.0 mg x dl( 1). At this time, we administered fibrinogen concentrate 6 g with other blood preparations. After the administration of fibrinogen concentrate, calculated blood fibrinogen level increased immediately to 120.0 mg x dl(-1). Three hours after administration of fibrinogen concentrate, TAAA graft replacement operation was finished. Ten days after the surgery, he was discharged from the ICU. Fibrinogen concentrate might be useful in difficult hemostasis reducing consumption of blood preparations. PMID- 24783610 TI - [Case of papillary fibroelastoma which caused cardiopulmonary arrest leading to emergent extirpation surgery]. AB - A 73-year-old woman with cardiac tumor arising from aortic valve was scheduled for extirpation surgery. She has a symptom of chest discomfort during her walk. Contrasted CT scan around the aortic valve demonstrated a 1 cm-size tumor close to the left coronary inlet. Coronary blood flow was preserved. On the day of admission she became unconscious during preoperative interview with the surgeon. Cardiopulmonary resuscitation was immediately initiated and she regained her consciousness. Emergency operation was scheduled and started about two hours after the event of syncope. Cardiac tumor attached to the left cusp of the aortic valve was found and later identified as papillary fibroelastoma by pathological diagnosis. She was discharged on the 13th day from admission without neurological deficit. Occlusion of the left coronary artery inlet was strongly suspected from preoperative event of her syncope. Cardiac tumor around aortic value may cause significant derangement of circulation, and we should closely monitor the patient's status and prompt operation was indicated especially when tumor is impeding coronary artery inlet. PMID- 24783611 TI - [Dexmedetomidine is useful for sedation during laryngoplasty with voice monitoring]. AB - BACKGROUND: Laryngoplasty is an operation for voice reconstruction performed for recurrent laryngeal nerve palsy, and this operation needs intraoperative speech monitoring. Previously, all procedures were performed under local anesthesia. Therefore, patients were suffering, and otolaryngologists had difficulty because of patients' coughs and laryngeal movements. We used dexmedetomidine (DEX) with local anesthesia for laryngoplasty. METHODS: We retrospectively examined 6 patients who had undergone laryngoplasty from January 2008 to October 2010. Patients received local anesthesia for pain control and DEX for sedation. Anesthesiologists achieved adequate sedation level (Ramsay's score 3-4) with DEX. RESULTS: Sedation was induced with 6 microg x kg(-1). hr(-1) of DEX for 10 minutes. All patients were maintained at 0.2-1.2 microg x kg(-1) x hr(-1). A local anesthetic(8.6 +/- 2.3 ml of 1% lidocaine 1 : 100,000 epinephrine) was used. During the initial loading of DEX, the patients' vital signs were stable. DEX suppressed coughs and laryngeal movements and did not cause respiratory depression. They were able to respond to the otolaryngologists' demand for a voice test. CONCLUSIONS: Dexmedetomidine was useful for sedation during laryngoplasty with voice monitoring. PMID- 24783612 TI - [Case report of re-expansion pulmonary edema in a patient with anorexia nervosa after removal of a huge ovarian tumor]. AB - We described a case of 19-year-old female who developed re-expansion pulmonary edema (RPE) after removal of a huge ovarian tumor. Altered lung volume after the surgery was observed by chest X-ray. Preoperatively, the lung was highly compressed by the tumor. Patient was intubated under general anesthesia and was ventilated by pressure controlled mode with only 5 cmH2O of positive end expiratory pressure (PEEP). P/F ratio was changed from 163 to 444 after removal of the tumor. At the end of the surgery, P/F ratio decreased to 263 with yellow frothy sputum in the endotracheal tube and we diagnosed re-expansion pulmonary edema based on appearing yellow frothy sputum and chest X-ray. No recruitment procedure was carried out through the course except positive pressure ventilation with 5 cmH2O of PEEP in the intensive care unit after surgery. Twelve hours after the surgery, we could not confirm the recovery of lung volume on chest X-ray; however the patient was extubated because of P/F ratio increasing to 507. After 8 days of the surgery, the chest X-ray showed recovery of the lung volume to almost normal size. In this case, the compressed lung needed almost 1 week to recover the lung volume. This change in chest X-ray might indicate inadequate recovery of lung volume by recruitment maneuver and this should be avoided in order not to allow development of unfavorable clinical course of RPE. PMID- 24783613 TI - [Anesthetic management for removal of a giant ovarian tumor using FloTrac x Vigileo monitoring system]. AB - We successfully managed anesthesia in a patient with a giant ovarian tumor weighting 22 kg, using FloTrac x Vigileo monitoring system. A 43-year-old woman (67.2 kg, 154.5 cm and abdominal girth 111.3 cm) was admitted for removal of a giant ovarian tumor. Arterial blood pressure (ABP), heart rate, percutaneous arterial oxygen saturation, cardiac index (CI) and stroke volume variation (SVV) were monitored. General anesthesia was induced, with the patient in the supine position, using 50 mg propofol, 0.25 microgram x kg(-1) x min(-1) remifentanil. 30 mg rocuronium bromide and inhalation of 100% oxygen, and maintained with sevoflurane 1.5% and remifentanil administration between 0.1-0.3 microgram x kg( 1) x min(-1). Following 6 l fluid drainage from the ovarian tumor, ABP and CI decreased, but SVV remained within normal ranges. Therefore, we only decreased the drainage speed without increasing fluid administration rate. When the tumor was lifted up, both CI and SVV increased, but the increase of SVV was 10%, still within normal ranges. Therefore, we did not increase fluid administration rate to avoid excessive hydration. After tracheal extubation, respiratory and hemodynamic states were stable, and the patient had no postoperative complication. We conclude that FloTrac x Vigileo System is useful for monitoring cardiac performance parameters, and helps anesthesiologists adjust drainage speed of the content and infusion rate to maintain the stability of circulatory state, in removal of a giant cyst. PMID- 24783614 TI - [Investigation of the amount of blood loss in patients with ruptured and unruptured ectopic pregnancies: a 3-year comparative study]. AB - BACKGROUND: Anesthesiologists should carefully monitor clinical symptoms and hemodynamics of ectopic pregnant patients. METHODS: We retrospectively investigated the backgrounds, vital signs, and amount of blood loss during surgery of ectopic pregnant patients who visited our hospital between July 2009 and June 2012. RESULTS: Ultrasonic examinations revealed a ruptured ectopic pregnancy (REP) in 17 patients and unruptured ectopic pregnancy (UEP) in 19 patients. All operations were uneventful. One UEP patient became hemodynamically unstable immediately after arriving at the operating room because of a sudden rupture. The differences in patients' ages, heights, weights, gestational ages, and human chorionic gonadotropin levels were not statistically significant between the REP and UEP groups. Clinical symptoms (abdominal pain or atypical genital bleeding) were observed in 14 of 17 REP patients and in 5 of 19 UEP patients (relative risk 3.1, odds ratio 13.1). The amount of blood loss was 79 g in the UEP patients, 356 g in the 14 hemodynamically stable REP patients, and 1,762 g in the 3 hemodaynamically unstable REP patients. The clinical symptoms were related to the existence of ruptures. CONCLUSIONS: It is important to monitor clinical symptoms in addition to hemodynamics for sudden hemodynamic changes in ectopic pregnancy. PMID- 24783615 TI - [Prominent elevation of liver enzymes after Fontan operation]. AB - It is known that acute liver dysfunction is one of the complications after Fontan operation. We tend to overlook it because their laboratory abnormalities are typically mild and hepatic dysfunction is an uncommon complication in children after cardiac surgery. However, this complication is likely to be an important indicator of poor prognosis. We report a patient who showed a prominent elevation of liver enzymes after Fontan operation. A year and 5 month old boy was scheduled for Fontan operation due to hypoplastic left heart syndrome. We used arterial pressure, central venous pressure and rSO2 probes (INVOS 5100, Somanetics Corp., USA) attaching on his head, abdomen and leg for circulatory management. The operation was performed with the heart beating. The blood removal tubes were inserted to the superior vena cava and inferior vena cava and the blood sending tube was inserted to the innominate artery when Norwood stage 1 was performed. After making an extracardiac conduit and a fenestration, we tried to take off the oxygenator with dopamine 5 microg x kg(-1) x min(-1), dobutamine 3 microg x kg( 1) x min(-1), isosorbide 2.5 microg x kg(-1) x min(-1). The central venous pressure was increased to 22-25 mmHg and systematic arterial pressure was unstable around 50 mmHg. We suggested the surgeons to expand the fenestration because the low flow through it was found on TEE examination, and introduced 15 ppm of nitric monoxide (NO) to decrease pulmonary vascular resistance and to control the central venous pressure at the same time. rSO2 was decreased to 50 temporarily when the oxygenator was taken off, however it was returned to 70 just after expanding the fenestration. On the first postoperative day, the patient showed marked elevations in GOT 17,305 U x l(-1), GPT 8,110 U x l(-1), gradually peaking out to GOT 105 U x l(-1), GPT 1,348 U x l(-1) by the seventh postoperative day. Hepatic dysfunction is related mainly to hemodynamic disturbances and is also related to the abdominal rSO2 and the high central venous pressure. PMID- 24783616 TI - [Anesthetic management for surgery of giant coronary aneurysms complicated with Churg-Strauss syndrome]. AB - Few cases of Churg-Strauss syndrome (CSS) complicated by giant coronary aneurysms (CAs)have been reported thus far. We report a case of CSS in a 60-year-old man who underwent surgery for giant CAs, and was managed with anesthetics. The patient developed acute myocardial infarction, and was diagnosed with giant CAs in the right coronary artery (RCA, 11 cm) and circumflex artery (3 cm). The CA in RCA was communicating with the right ventricle. He had a history of pericardiectomy for pericarditis caused by the CSS and developed thrombocytopenia due to consumptive coagulopathy within the CAs. An operation, including ligation and excision of the CAs, and coronary artery bypass grafting was performed under general anesthesia and cardiopulmonary bypass. There was massive hemorrhage followed by hemodynamic instability while detaching the tight pericardial adhesion and fragile surface of the CAs. Massive transfusion was required along with inotropes administration and intraaortic balloon support. In this case, determination of the appropriate surgical timing was difficult because symptoms of the CSS became worse followed by rapid enlargement of the CAs, myocardial infarction, and thrombocytopenia. Steroids were administered for treating CSS, and the blood transfusion was sufficient. However, it was difficult to control the hemorrhage and maintain hemodynamic stability. PMID- 24783617 TI - [Perioperative management of a patient with primary adrenal insufficiency who underwent general anesthesia twice]. AB - Perioperative corticosteroid supplementation is generally applied in patients with primary adrenal insufficiency or treated with long-term corticosteroid. Currently, appropriate dose and timing of corticosteroid were revised. A 77-year old woman with primary adrenal insufficiency underwent transurethral resection of bladder tumor (operation 1) and mastectomy (operation 2). In both operations, we supplied stress dose of hydrocortisone on the operative day (100 mg x day(-1) of hydrocortisone for operation 1 or 300 mg x day(-1) of hydrocortisone for operation 2) and decreased gradually in one day (operation 1) or in three days (operation 2), respectively. No remarkable symptoms of adrenal deficiency and side effects of corticosteroid during perioperative period were observed. According to current recommendation, the dose of corticosteroid we used could be smaller. Perioperative management of adrenal insufficiency is still controversial, and further investigation is necessary. PMID- 24783618 TI - [Anesthetic management of a patient with 8 trisomy mosaic combined with cerebral palsy]. AB - We administered general anesthesia for a patient with 8 trisomy mosaic and cerebral palsy. Constitutional 8 trisomy mosaic has been associated with syndromic dysmorphology, corneal opacities, leukemia and trophoblastic disease. In Japan only 4 reports of general anesthesia related with 8 trisomy were found. This patient was a 24-year-old woman (140 cm, 35 kg), with mental retardation, poor body development and severe scoliosis. Since she suffered from repeated serious asthma and pneumonia since childhood, tracheotomy was performed at the age of 9. Epileptic seizures were also seen and antiepileptics were prescribed. This time, general anesthesia was scheduled for the extraction of a maxillary cyst. Anesthesia was induced slowly with sevoflurane from the tracheotomy, followed by rocuronium 25 mg i.v., and maintained with sevoflurane 1.5-2 % and remifentanil 0.05-0.2 microg x kg(-1) x min(-1) Throughout the operation, BIS score fluctuated between 40-60, and stable anesthesia was maintained. We reversed the rocuronium with sugammadex 140 mg promptly. The 8 trisomy mosaic patient is known to have various complications related to circulation and respiration. Careful management is necessary in anesthesia for an 8 trisomy patient. PMID- 24783619 TI - [Clinical application of the tidal flow-volume curve--a computer simulation]. AB - BACKGROUND: Since the tidal flow-volume (V-V) curve obtained during mechanical ventilation is difficult to interpret, there have been few reports on how to interpret it. METHODS: The tidal V-V curve during mechanical ventilation was analyzed using a computer simulation. Ventilatory modes, the time constant of a patient's respiratory system (TC), spontaneous breathing during mechanical ventilation, airway obstructions, and circuit leakage were simulated. RESULTS: The inspiratory shape depended on ventilatory modes and was affected by TC only in pressure-regulated breathing. The expiratory shape was not dependent on ventilatory modes and was influenced by TC. Spontaneous breathing synchronized with the mandatory ventilatory phase increased the flow rate. Characteristic double expiratory flow pattern was observed in spontaneous expiration during the inspiratory phase of the ventilator. A dip in the expiratory tidal V-V curve was observed with a peripheral airway obstruction model. A central airway obstruction attenuated the slope of the expiratory phase. In circuit leakage, the tidal V-V curve did not return to the origin at the end of the expiration. CONCLUSIONS: New findings on the tidal V-V curve were observed and this systematic analysis will be helpful in clinical respiratory care. PMID- 24783620 TI - [Video-laryngoscope (McGRATH MAC): a clinical assessment of its performance in consecutive 100 patients]. AB - BACKGROUND: The McGRATH MAC Video laryngoscope (Covidien Japan) is a relatively new device for tracheal intubation, which provides an excellent glottis view. We here report the clinical experience of the McGRATH in 100 patients who received general anesthesia. METHODS: Tracheal intubation with the McGRATH was performed in 100 patients requiring oro/naso tracheal intubation. The view of glottic opening was scored according to the classification of Cormack-Lehane. The time required to intubate and the number of intubation attempts were recorded. RESULTS: Cormack-Lehane classification 1 or 2 was obtained in 99 of 100 patients, respectively, and successful intubation was achieved in all patients. The mean +/ SD time to successful intubation was 40 +/- 19 seconds. CONCLUSIONS: The McGRATH was easily handled not only by experienced anesthetists but also by novice personnel. The McGRATH seems to be a useful device in routine and difficult airway management. PMID- 24783621 TI - [Role of the i-gel in emergency airway management]. AB - The i-gel is a relatively new supraglottic airway, which has been shown to be useful during general anesthesia, and it may have a potential role during cardiopulmonary resuscitation. In a manikin study, we have found that, compared with laryngeal mask airways, the i-gel was significantly easier and faster to insert, due mainly to no-necessity of cuff inflation. One possible difficulty in using the i-gel during cardiopulmonary resuscitation is that the device cannot be fixed with the Thomas Tube Holder (Laerdal Medical Japan KK, Tokyo, Japan). A specially tailored device for cardiopulmonary resuscitation, recently has become available. The pack includes the i-gel O2 (which has a side port for oxygen delivery), a suction catheter, a sachet containing lubrication jelly, and a fixation strap. We describe the role of the i-gel during emergency airway management. PMID- 24783622 TI - [Efficacy and safety of remifentanil-based regimen for postoperative pain management in abdominal surgery patients: a double-blind study with low-dose remifentanil infusion of 0.02 microg x kg(-1) x min(-1)]. AB - BACKGROUND: Remifentanil is a powerful analgesic with fast onset and ultra-short duration of action. Its context-sensitive half-time is consistently short even after a prolonged infusion. Remifentanil is effective for providing better postoperative analgesia, but this method is not generally accepted in Japan. The present study was conducted to document efficacy and safety of low-dose remifentanil infusion in postoperative patients. METHODS: Forty patients undergoing abdominal surgery were studied prospectively. They were randomly assigned to either remifentanil (0.02 microg x kg(-1) x min(-1)) or placebo group. Postoperatively all patients received continuous epidural anesthesia with lidocaine and IV patient-controlled analgesia with fentanyl. Flurbiprofen was administered only when no pain relief was achieved. Visual analogue scale (VAS), requirement of fentanyl and flurbiprofen, and the incidence of remifentanil related adverse effects (respiratory depression, nausea, vomiting, pruritus) were examined at 3 hourly intervals for 12 hours. RESULTS: There are no statistical differences between two groups in pain scores. No adverse events including respiratory depression occurred throughout the study in both groups. CONCLUSIONS: Remifentanil infusion at 0.02 microg x kg(-1) x min(-1) can safely be used without any serious adverse events, while it may not be enough for postoperative analgesia. The best dosage of this drug for postoperative analgesia remains to be elucidated. PMID- 24783623 TI - Abstracts of the 6th Triennial Congress of the Italian Society of Pathologic Anatomy and Cytopathology, 26-30 October, 2013, Rome, Italy. PMID- 24783624 TI - Periodontal Abstracts. PMID- 24783625 TI - Proceedings of the 6th International Conference on relaxin and related peptides, October 8-12, 2013, Florence, Italy. PMID- 24783627 TI - Abstracts of the Annual Meeting of the Royal Belgian Society for Ear, Nose and Throat, Head and Neck Surgery, April 5, 2014, Brussels, Belgium. PMID- 24783626 TI - Bibliography of the history of science and its cultural influences. PMID- 24783628 TI - Chronic kidney disease in cats. PMID- 24783630 TI - Abstracts of the Aerospace Medical Association (AsMA) 85th Annual Scientific Meeting, May 5-10, 2014, San Diego, California. PMID- 24783629 TI - The authors respond. PMID- 24783631 TI - On the need for year-round heartworm prevention. PMID- 24783632 TI - Adopting dogs from a warzone. PMID- 24783633 TI - FDA veterinary feed directive plan creates professional conflicts of interest. PMID- 24783635 TI - Texas Dental Association directory of members, 2013-2014. PMID- 24783634 TI - Diagnostic testing as a moneymaker. PMID- 24783636 TI - The orthopedic stepchild. PMID- 24783637 TI - Preprosthetic interceptive orthodontics for missing lateral incisors in late mixed dentition. AB - BACKGROUND: Different treatment alternatives are possible in the preprosthetic orthodontic management of missing of lateral incisors. We describe an efficient approach in a 12.11-year-old girl with incisors agenesis. CASE REPORT: Treatment started with repositioning of the permanent canines in site 2 and the deciduous canines in site 3. After growth completion the deciduous canines will be extracted and replaced by dental implants. Permanent canines will then undergo reshaping in order to look like lateral incisors. The molar and cuspid relationships were finalised in Class I, with correct overjet and overbite. The mandibular and maxillary arch forms were acceptable without crowding and rotations. Opening the space offers different solutions for maintaining the alveolar bone for a future implant, with the advantage of a molar Class I relationship and a wider arch. It would also be possible to achieve distalisation of the permanent canine, following the Kokich's principle of alveolar development. CONCLUSION: The described treatment is a valid alternative in the management of missing lateral incisors. This solution can avoid an additional orthodontic treatment in adulthood and allow easy management of the retention phase prior to final rehabilitation with single tooth implants PMID- 24783638 TI - [Endoscopic sclerosis with pneumatic distension for pyriform sinus fistula treatment]. AB - Classic treatment for pyriform sinus fistula (PSF) has been surgical excision; however, less invasive therapeutic alternatives whose aim is the obliteration of the sinus have been described subsequently. The authors present a technical modification of endoscopic sclerosis with diathermy (ESD): continuous infusion of air flow through the flexible endoscope was used to distend the pyriform sinus and facilitate recognition of the fistula opening. The sinus obliteration was performed with a wire guide and diathermy. In the last 15 years, 9 patients were diagnosed of suffering from PSF in our institution. Initial treatment was antibiotics therapy associated in some cases to cervical abscess drainage. Fistulectomy was performed in 4 cases and ESD in 4. The ninth patient received both treatments, performing electrocauterization after a surgical recurrence. Three of the patients who underwent surgery relapsed; none treated by ESD did, or had any complications. In our experience, endoscopic sclerosis with pneumatic distension is a simple technique, reproducible, not invasive and very effective; hence we consider it might become a first line therapy for PSF. PMID- 24783639 TI - [Achalasia in children and adolescents, a therapeutic challenge]. AB - INTRODUCTION: Treatment of achalasia in children is in permanent discussion. It is a rare disorder without cure, which makes its management challenging. METHODS: Retrospective review of patients under 18 years old treated for achalasia in our Hospital between 2000 and 2012, by either pneumatic dilatation (PD) or Heller myotomy (HM). RESULTS: Thirteen children were treated during this time. Mean age was 12 years (4-18), interval time between the onset of symptoms and diagnosis was 15 months (2-48) and mean follow-up was 66,8 months (4-144). Dysphagia and vomits were the main symptoms (61%). A single PD was performed in 5 patients; four were the oldest children of the series (16-18). Three girls remain asymptomatic and 2 boys suffer from moderate dysphagia. Six patients required multiple PD and, after a mean of 3 dilatations, HM was needed in all of them. The last 2 children of the series received surgery as the first treatment. In total, eight patients underwent HM and fundoplication, with 6 laparoscopic procedures. Two boys suffer from low-moderate dysphagia, but additional treatments have not been required. The mean of total hospital stay was 12,7 days (2-45) for PD and 9 days (3-30) for HM. Two patients were reoperated because of oesophagic perforation, one after PD and one after open HM. CONCLUSION: Although PD and HM could be complementary, laparoscopic Heller myotomy should be considered the first therapeutic option, specially in young boys. PMID- 24783640 TI - [Hyaluronic acid scrotoplasty: minimally-invasive procedure to enhance the volume of scrotum until puberty]. AB - PURPOSE: There is a controversy concerning infant testicular prosthesis. The problem is that this may necessitate further surgery to insert a larger prosthesis when the child gets older. An alternative strategy is to delay the placement of the definitive prosthesis until the child reaches adolescence. However, the underdeveloped scrotum may fail to accommodate the desired sized testicular prosthesis. We present scrotoplasty using hyaluronic acid gel injection as a minimally-invasive alternative to enhance the volume of scrotum until puberty. MATERIAL AND METHODS: A prospective report of 35 boys younger than seven years old with monorchia underwent injection of hyaluronic acid for scrotal filling. Mean follow-up of 24 months (range 12-48 months). RESULTS: The only complication was early resorption in 2 patients at 8 and 10 months after implantation, respectively. In long-term followup 100 per cent of the families rated the cosmetic appearance as good and 95 per cent were content with the decision regarding placement of a testicular implant irrespective of whether they had been retreated. CONCLUSIONS: It shows that hyaluronic acid gel scrotal injection can provide satisfactory improvement in enhance the volume of scrotum. It is associated with high family and patient satisfaction, and provides a long lasting result. This technique makes placement of prosthetic testis a very simple procedure that can be performed at the time of diagnostic exploration or orchiectomy, increasing scrotal space until post pubertal definitive prosthesis. PMID- 24783641 TI - [Study of bacteriology and resistances in pediatric appendicitis]. AB - There is controversy about the convenience of performing a bacteriological peritoneal culture in pediatric appendicitis. We performed a sero-epidemiological survey of the bacteria found in peritoneal swabs from pediatric appendicitis operated in our hospital. METHODS: Ambispective study. Retrospective revision of the bacteriological results from peritoneal swabs performed in pediatric appendicitis from january 2009 to december 2010 (2 years) and prospective study of peritoneal swabs collected between january 2011 and december 2011 (one year). RESULTS: We found 728 pediatric patients (mean age 7.1, range: 2-11 years). Among these, 108 were < 5 years. Cultures were performed in 328 (45.1%). A positive result was found in 155 swabs, (47.3%). Positive cultures were more frequent in patients < 5 years (69.2% vs 40.4%, p < 0.001). The most frequent pathogens were E. coli: 122 specimens, Streptococcus spp (50 swabs), P. aeruginosa: (45) and B.fragilis: (35) Younger age was strongly associated with P. aeruginosa: (30.8% vs 8.4%, p < 0.001. OR: 4.8. IC 95%: 2.3-9.8). So was the detection of E. coli (50% vs 33.2% p = 0.01). 21.3% (26 swabs) of E. coli were resistant to amoxicillin-clavulanic acid. There were 15 (12.3%) multiresistant (ESBL) E. coli. Among the Streptococcus, 32% (16 out of 50) were resistant to clindamicin, and so were 28.6% of the B. fragilis (10 out of 35). DISCUSSION: . The most frequent pathogens were E. coli, Streptococcus spp and P. aeruginosa. P. aeruginosa is five times more frequent in patients < 5 years. Resistance of E. coli to amoxiclavulanate was high: 21.3% of the specimens. We found that 12.3% of the E. coli produced ESBL. PMID- 24783642 TI - [Keloid scars of the external ear: a non solved problem]. AB - The external ear is a location with high risk of keloid scar formation. Its incidence is growing since general use of piercings and performance of plastic surgery of the external ear. The external ear keloid can be a devasting process for adolescent population which is worried about their appearance. Our aim is to attract attention about the risk of keloid scars of the external ear, reviewing our experience. After dismissing radiotherapy, corticoid infiltration and surgical removal are the most used options, with a high recurrence risk. We have reviewed traumatic, surgical and piercing wounds of the external ear, with a subsequent keloid formation treated in our outpatient clinic, collecting data about wound etiology, treatment and results. During the last 10 years we have found 11 keloid scars, 2 of them improved with topical corticosteroid. Treatment has been surgical in 9 cases, 4 of them with skin graft: 5 recovered and 4 recurred; 2 of them were reoperated. 2 of them were treated with intralesional corticosteroid solely, one recovered and the other one had improved. Treatment management of keloid scars is complex and there isn't a procedure with superior results than the others. Risk of complication must be explained within adolescent population. PMID- 24783643 TI - [Ovarian torsion. long-term follow-up of the black-bluish ovary after laparoscopic detorsion]. AB - INTRODUCTION: Ovarian torsion presents low incidence in children and unspecific clinical presentation, therefore the diagnostic delay is rather common. Traditionally, necrotic appearance has been synonymous of oophorectomy, however the current trend defends ovary preservation. We present our experience in conservative management of ovarian torsion. METHODS: A retrospective review was made of patients between May 2010 and May 2013. Seven girls were operated by laparoscopy because of ultrasound and clinical suspicion of ovarian torsion. The diagnosis was confirmed in six patients, finding an enlarged, friable and black bluish ovary. Detorsion and adnexal sparing were performed in all cases, despite the gross appearance. RESULTS: The mean age was 8.5 years (3-12), the time interval between the onset of symptoms to surgery was 6.5 days (1-15) and postoperative stay was 2.6 days (2-3). In 4 cases the damaged ovary was right, and the average size was 5.8 cm. Tumor markers were normal. During the first 6 months the follow-up ultrasound showed good results. However, the long-term outcome evidenced one involved ovary atrophied and two oophorectomies due to recurrent adnexal torsion and ovarian mass consistent with teratoma. CONCLUSIONS: Laparoscopic conservative management with untwisting the ovary, allows that macroscopically nonviable ovaries could be recovered. However, an exhaustive and long-term follow-up is required to confirm the outcome. PMID- 24783644 TI - [Analysis of prognostic factors in biliary atresia]. AB - OBJECTIVE: Biliary atresia presents a worldwide incidence about 1 of every 9000 12000 live newborns. Our goal was to analyze the prognostic variables of our patients with biliary atresia. MATERIAL AND METHODS: Retrospective study, based on the review of all patients who underwent surgery at our centre by the Kasai technique from March 1983 to January 2012. A total of 52 variables were analyzed such as: clinical history, symptoms, diagnostic tests, use of corticosteroids, complications and evolution. RESULTS: From 35 patients operated by Kasai Technical we included 29, being 58.82% male; grouped according to the age of surgery: Group A (< 60 days) 14/29; Group B (60-90) 14/29 and Group C (> 90) 1/29. We observed that atresia type II was more common in the Group A and III in group B and C. There was a predominance of hepatic fibrosis in patients from Group A and C, and cirrhosis in B. The mean hospital stay was 24.66; 28.50 and 50.00 days for Group A, B and C respectively. Since 2004 it is established a treatment with corticosteroids in the postoperative period; complications noted in 40% of the treated and in 70% of the untreated. In 10 years, 44.82% are asymptomatic and transplanted 37.9%. CONCLUSIONS: In this study both the diagnosis and early Kasai technique improve prognosis. Treatment with corticoids could benefit short-term results. PMID- 24783645 TI - [Surgical treatment of giant congenital melanocytic nevi: a change of aim]. AB - OBJECTIVE: To review the surgical experience in Giant Congenital Melanocytic Nevi (GCMN). MATERIAL AND METHODS: Review of GCMN cases consulting at the Department of Pediatric Surgery since 1994. Data registered were: year and age at 1st consultation, type of treatment, number of surgical procedures and complications, histology, central nervous system MRI and follow-up. RESULTS: Eleven patients with GCMN > 10% of body surface consulted at ages ranging from newborn to 8 years. All of them had multiple surgical procedures (2-19), from nevus removal to only biopsies. Eight patients had tissue expansion, completed in 3 of them with skin grafts on dermal substitute. Six patients had complications: 4 expander extrusions, 5 infections, 3 flap necrosis and 1 dehiscence. In 6 children a total or subtotal resection of the nevus was achieved; in 2 the treatment was interrupted, remaining 20% and 50% of the initial nevus; three patients had not had nevus treatment. None of the patients presented cutaneous melanoma; one died from intracranial melanoma; another one has leptomeningeal melanosis. The first 4 patients underwent an average of 16 surgical procedures each, the last 7 patients only 5. CONCLUSIONS: The aim of GCNM management has changed: GCNM treatment is now surgically conservative. Complete excision is now not the aim when technically unfeasible in few procedures; multiple surgical procedures with poor cosmetical results are not acceptable. The gravity is determined by CNS involvement. PMID- 24783646 TI - [Poland's syndrome and free autologous fat grafts]. AB - OBJECTIVE: To evaluate the final reconstructive results in 6 cases of female Poland syndrome treated in a first stage with an anatomical high cohesive breast implants and in a second stage with free autologous fat grafts. METHODS: Six females were submitted to bilateral breast reconstruction. The reconstruction was done using anatomical breast implants as first step and after 11 to 18 months the free autologous fat grafting using the Coleman technique as well as treating the contralateral breast to achieve a better symmetry and volume. Photographies taken pre and postoperatively and the Foucras Classification were used to determine volume. Four months after the last surgery the patients answered a satisfaction questionnaire. RESULTS: In all 6 patients there was an improvement of the thoracic contour a year after the last surgery in terms of volume, projection and width of the breast. CONCLUSIONS: The use of free autologous fat grafts improves the results in cases of Poland's syndrome previously treated with breast implants making possible to correct the anterior axillary fold, projection and symmetry with a versatile method, with a low morbidity rate, allowing for a personalized treatment. PMID- 24783647 TI - [Ureteral triplication]. AB - INTRODUCTION: Ureteral triplication is considered a rare anomaly and its association with ectopic ureterocele, is unusual. CLINICAL CASE: We report a male with a history of recurrent urinary tract infections, who showed left vesicoureteral reflux associated with apparent ureteral duplication in multiple test performed, and only during the vesicostomy was discovered a third ureter ending in a ectopic ureterocele corresponding with the upper pole ectopic kidney. CONCLUSIONS: Being a very unusual and complex pathology, and despite all the tests made, it is very difficult to make an accurate presurgical diagnosis, therefore the diagnosis sometimes is only performed during the surgical treatment, which must be individualized according to fthe unctional stage of each renal portion and the termination of each ureter. PMID- 24783648 TI - Pure partial trisomy 4q syndrome in a child with der(9)ins(9;4)(q34.3;q26q35.2)mat. AB - Pure partial trisomy 4q syndrome in a child with der(9)ins(9;4)(q34.3;q26q35.2)mat: Partial trisomy 4q is a rare chromosomal abnormality and mostly results from unbalanced inheritance of balanced parental chromosomal translocations. Here, we present a 5-year-old boy with partial trisomy 4q who exhibited distinctive features of 'pure' partial trisomy 4q syndrome including moderate mental and growth retardation, microcephaly, peculiar face appearance, tooth anomaly, cleft palate, language handicap, preaxial polydactyly, and urogenital anomaly. Karyotype analysis of the child revealed der(9)ins(9;4)(q34.3;q26q35.2) inherited from mother carrying ins(9;4)(q34.3;q26q35.2) resulting in trisomy of the 4q26qter segment. Whole chromosome painting, locus specific, and subtelomeric FISH analysis in mother proved that q26qter of the chromosome 4 segment was directly inserted into the telomeric sequence in chromosome 9, and depending on nature of the rearrangement in mother, karyotype of the child was determined to be pure partial 4q trisomy. This is the first report of this kind of rearrangement causing pure partial trisomy 4q with accompanying white matter change demonstrated by MRI and bilateral preaxial polydactyly of both hands. PMID- 24783649 TI - Treacher Collins syndrome with multiple congenital heart defects after paroxetine exposure: case report. AB - Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development with an incidence of I in 40,000 to in 70,000 live births. It is characterized by abnormalities of the pinnae which are frequently associated with atresia of the external auditory canals and anomalies of the middle ear ossicles. Rarely congenital heart defects can be present. Prenatal paroxetine exposure may enhance the risks of major malformation, particularly cardiac defects. This article reports a newborn, whose mother used paroxetine during pregnancy, presenting with multiple congenital heart defects associated to typical physical characteristics of Treacher Collins syndrome. PMID- 24783650 TI - Tricho-rhino-phalangeal syndrome type 1 as an outcome of in vitro fertilization? AB - Trichorhinophalangeal syndrome type I [OMIM #190350] is an autosomal dominant disorder. Common features are: Slowly growing sparse hair, laterally thin eyebrows, bulbous tip of the nose, long philtrum, thin upper lip, protruding ears. Common skeletal anomalies include shortening of phalanges and metacarpals causing mild to severe brachydactyly, cone shaped epiphyses, hip dysplasia and short stature. Recently many reports have been published on the use of assisted reproductive technology (ART) and the increased risk of congenital major malformations or syndromes. We present a 6 years old Turkish Trichorhinophalangeal syndrome (TRPS) case of a twin pair after in vitro fertilization (IVF). TRPS with IVF pregnancy has not been reported previously. This new case reported herein will contribute to a better understanding whether ART pregnancy increases congenital malformations. PMID- 24783651 TI - Ectrodactyly and tetralogy of Fallot in a fetus with del(6)(q21q23). AB - We report a fetus with del(6)(q21q23) who had tetralogy of Fallot and ectrodactyly of the right hand. Analysis of the literature showed that both these defects were reported in several patients with similar deletions. The minimal segment responsible for ectrodactyly may be limited to 7.35 Mb (106.650.000 114.600.000). However 1) significant number of patients with this deletion but without ectrodactyly or other defects of extremities, and 2) wide range of unusual birth defects in some persons with deletions of the critical segment allow to propose involvement of regulatory element(s) necessary for the occurrence of ectrodactyly in patients with del 6q21. PMID- 24783652 TI - Fryns syndrome with vertebral defects: a novel association in a Mexican infant. AB - We report a Mexican mestizo 2 months old male with Fryns syndrome and vertebral defects. The patient's phenotype included typical craniofacial dysmorphism, short neck, agenesis of the corpus callosum, congenital left diaphragmatic hernia, complex heart disease, C1 to C6 vertebral agenesis with increased interpedicular space, thoracic rotoscoliosis, broad medial ends of the clavicles, brachytelephalangy of hands and feet with fingers axially deviated, and nail hypoplasia. Renal and chromosomal evaluations were normal. Since this is the first description of cervical vertebrae agenesis and thoracic rotoscoliosis in Fryns syndrome, we propose that these clinical and radiological features should be incorporated to the Fryns syndrome phenotype and specifically looked for in other children. PMID- 24783653 TI - Partial monosomy 8q and partial trisomy 9q due to the maternal translocation t(8;9(q24.3;q34.1): a case report. AB - Partial trisomy 9q34-qter and partial monosomy 8q24.3-qter are very rare chromosomal abnormalities. Characteristic features of partial trisomy 9q34-qter are hypotonia, developmental delay, mild intellectual disability, dolichocephaly, distinct facial phenotype, long and thin fingers, and cardiac anomalies. Unlike the partial trisomy 9q34-qter, partial monosomy 8q24.3-qter has no distinct phenotype. Here we report a four years old female patient with partial trisomy 9q34-qter and partial monosomy 8q24.3-qter due to the maternal translocation t(8;9)(q24.3;q34. I). She has developmental delay, brachycephaly, facial dysmorphism, hand and foot anomalies, bilateral hearing loss, cardiac defect and abnormal brain MRI findings. To the best of our knowledge, this is the first report of the combination of partial trisomy 9q and partial monosomy 8q. PMID- 24783654 TI - Branchio-oculo-facial syndrome in a newborn caused by a novel TFAP2A mutation. AB - We present an 18-day old boy with bilateral cervical cutaneous defect in the retroauricular region, low-set and posteriorly rotated ears, bilateral microphtalmia and bilateral pseudocleft of the upper lip. Histopathological evaluation of cervical cutaneous defect showed ulceration on the surface and ectopic thymus tissue in the deep dermis with cortex, medulla and Hassal's corpuscles. Clinical findings led to the diagnosis of Branchio-oculo-facial syndrome, characterized by branchial defects (erythematous cutaneous defects in cervical region), ocular anomalies (microphthalmia, anophthalmia, lacrimal duct obstruction, coloboma, cataract, ptosis) and facial defects (cleft lip and/or palate, pseudocleft or abnormal philtrum). DNA sequencing showed a novel heterozygous mutation, c.731T>C (p.L244P), in TFAP2A gene confirming the diagnosis of this rare autosomal dominant developmental disorder with variable clinical findings. PMID- 24783655 TI - A new case of holoprosencephaly-polydactyly syndrome with alobar holoprosencephaly, preaxial polydactyly and congenital glaucoma. AB - We report a case of a female baby born at 34 weeks of gestation. Birth weight was 1760 g (10th-25th centile), length 41cm (10th-25th centile) and head circumference 27cm (< 10th centile). Clinical examination revealed microcephaly, hypotelorism, micrognathia, a flat rudimentary nose, high palate, thick dysplastic low-set ears, a short neck, preaxial polydactyly of the right hand, and overriding toes. Investigations showed bilateral congenital glaucoma, alobar holoprosencephaly, severe ventriculomegaly and absence midline structures of the brain, a large atrial septal defect. The karyotype was 46,XX. The case was also diagnosed as having holoprosencephaly-polydactyly syndrome (pseudotrisomy 13) because she had alobar holoprosencephaly, preaxial polydactyly, facial dysmorfism (hypotelorism, micrognathia, a flat rudimentary nose, high palate, thick dysplastic low-set ears) and normal karyotype. PMID- 24783656 TI - Parental factors in prenatal decision making and the impact of prenatal genetic counseling: a study on Turkish families. AB - OBJECTIVE: This study explored the social factors affecting prenatal decision making, the impact of genetic counseling on prenatal decision making, and how genetic counseling is perceived by Turkish women. METHOD: A standardized questionnaire was given to 231 patients, before and after genetic counseling, at Hacettepe University Ihsan Dogramaci Children's Hospital in 2007-2008. RESULTS: The level of education was an important factor both in prenatal decision making and in the patients' perception of genetic counseling. Decisions of pregnancy termination differed by geographic region of referral and history of healthy children but the differences were not statistically significant. The decisions were not influenced by poor obstetric history, number and sex of previous children, and disability of previous children. CONCLUSION: The level of education and the geographic region of referral in Turkey had an effect on the prenatal decisions and on the amount of prenatal genetic counseling received by the individuals. PMID- 24783657 TI - Terminal deletion 6q syndrome with 11q partial trisomy mosaicism due to maternal balanced translocation. PMID- 24783659 TI - A case of de novo mosaic 18q21.3 deletion with a mild phenotype. PMID- 24783660 TI - Joubert syndrome overlapping with Dandy-Walker malformation. PMID- 24783661 TI - Omphalocele, radial ray defect and diaphragmatic hernia: another case of Gershoni Baruch syndrome? PMID- 24783662 TI - A newborn case of intestinal infarction with homozygous MTHFR C677T and heterozygous of factor V Leiden G1691A, PAL-1 4G/5G mutations. PMID- 24783663 TI - Healthcare system performance improvement: a comparison of key policies in seven high-income countries. AB - PURPOSE: Evidence suggests that healthcare system performance may be improved with policy emphasis on primary care, quality improvement, and information technology. The authors therefore sought to investigate the extent to which policy makers in seven countries are emphasizing these areas. DESIGN/METHODOLOGY/APPROACH: Policies in these three areas in seven high-income countries were compared. A comparative descriptive approach was taken in which each of the country-specialist authors supplied information on key policies and developments pertaining to primary care, quality improvement and information technology, supplemented with routine data. FINDINGS: Each of the seven countries faces similar challenges with healthcare system performance, yet differs in emphasis on the three key policy areas; efforts in each are, at best, patchy. The authors conclude that there is substantial scope for policy makers to further emphasize primary care, quality improvement and information technology if aiming for high-performing healthcare systems. ORIGINALITY/VALUE: This is the first study to investigate policy-makers' commitment to key areas known to improve health system performance. The comparative method illustrates the different emphases that countries have placed on primary care, quality improvement and information technology development. PMID- 24783664 TI - A meta-ethnography of organisational culture in primary care medical practice. AB - PURPOSE: Over the past decade, there has been growing international interest in shaping local organisational cultures in primary healthcare. However, the contextual relevance of extant culture assessment instruments to the primary care context has been questioned. The aim of this paper is to derive a new contextually appropriate understanding of the key dimensions of primary care medical practice organisational culture and their inter-relationship through a synthesis of published qualitative research. DESIGN/METHODOLOGY/APPROACH: A systematic search of six electronic databases followed by a synthesis using techniques of meta-ethnography involving translation and re-interpretation. FINDINGS: A total of 16 papers were included in the meta-ethnography from the UK, the USA, Canada, Australia and New Zealand that fell into two related groups: those focused on practice organisational characteristics and narratives of practice individuality; and those focused on sub-practice variation across professional, managerial and administrative lines. It was found that primary care organisational culture was characterised by four key dimensions, i.e. responsiveness, team hierarchy, care philosophy and communication. These dimensions are multi-level and inter-professional in nature, spanning both practice and sub-practice levels. RESEARCH LIMITATIONS/IMPLICATIONS: The research contributes to organisational culture theory development. The four new cultural dimensions provide a synthesized conceptual framework for researchers to evaluate and understand primary care cultural and sub-cultural levels. PRACTICAL IMPLICATIONS: The synthesised cultural dimensions present a framework for practitioners to understand and change organisational culture in primary care teams. ORIGINALITY/VALUE: The research uses an innovative research methodology to synthesise the existing qualitative research and is one of the first to develop systematically a qualitative conceptual framing of primary care organisational culture. PMID- 24783665 TI - The rules of engagement: physician engagement strategies in intergroup contexts. AB - PURPOSE: Recognition of the importance and difficulty of engaging physicians in organisational change has sparked an explosion of literature. The social identity approach, by considering engagement in terms of underlying group identifications and intergroup dynamics, may provide a framework for choosing among the plethora of proposed engagement techniques. This paper seeks to address this issue. DESIGN/METHODOLOGY/APPROACH: The authors examined how four disparate organisations engaged physicians in change. Qualitative methods included interviews (109 managers and physicians), observation, and document review. FINDINGS: Beyond a universal focus on relationship-building, sites differed radically in their preferred strategies. Each emphasised or downplayed professional and/or organisational identity as befit the existing level of inter group closeness between physicians and managers: an independent practice association sought to enhance members' identity as independent physicians; a hospital, engaging community physicians suspicious of integration, stressed collaboration among separate, equal partners; a developing integrated-delivery system promoted alignment among diverse groups by balancing "systemness" with subgroup uniqueness; a medical group established a strong common identity among employed physicians, but practised pragmatic co-operation with its affiliates. RESEARCH LIMITATIONS/IMPLICATIONS: The authors cannot confirm the accuracy of managers perceptions of the inter-group context or the efficacy of particular strategies. Nonetheless, the findings suggested the fruitfulness of social identity thinking in approaching physician engagement. PRACTICAL IMPLICATIONS: Attention to inter-group dynamics may help organisations engage physicians more effectively. ORIGINALITY/VALUE: This study illuminates and explains variation in the way different organisations engage physicians, and offers a theoretical basis for selecting engagement strategies. PMID- 24783666 TI - Learning the lessons from banding appeals: evidence based guidance for running junior doctor rotas. AB - PURPOSE: Designing and running robust junior doctor rotas is a challenging task and much previous advice has been based on consensus or anecdote. This paper aims to discern the most frequently occurring problems with trainee working patterns and produce evidence-based guidance for implementing and running contract compliant rotas. DESIGN/METHODOLOGY/APPROACH: A total of 35 secondary care trusts in North West England were invited to supply information on pay banding appeals requested under the New Deal junior doctor contract. Of these, 15 (43 per cent) participated with data from 35 appeals between 2004 and 2012. A thematic analysis was undertaken to discern the commonly occurring causes of contractual breaches. FINDINGS: A total of 83 per cent (n = 29/35) of appeals were based on data showing the rota to be non-compliant with the contract (band 3), with the remainder being compliant with the contract but not in keeping with the pay banding currently assigned. Inability to take adequate natural breaks was the most frequently cited cause of rota non-compliance. Where underlying reasons were given for breaches of hours/rest limits they clustered around 20 themes, the top four being poor or absent dialogue between HR and doctors, excessive workload, inappropriately timed ward rounds, and inadequate or non-existent bleep policies. ORIGINALITY/VALUE: This is the first analysis of banding appeals under the UK junior doctor contract. The findings show that problems with rotas cluster around specific themes. The authors provide recommendations to target these so as to avoid financially detrimental contract breaches and trainee dissatisfaction. PMID- 24783667 TI - How healthcare organisations can act as institutional entrepreneurs in a context of change. AB - PURPOSE: The aim of this paper is to illustrate and discuss how healthcare organisations can act as institutional entrepreneurs in a context of change. DESIGN/METHODOLOGY/APPROACH: The authors conducted an in-depth longitudinal case study (2005-2008) of a healthcare organisation in the province of Quebec, Canada. Data collection consisted of real-time observations of senior managers (n = 87), interviews (n = 24) with decision-makers and secondary data analysis of documents. FINDINGS: The paper reports on the extent to which entrepreneurial healthcare organisations can be a driving force in the creation of a new practice. The authors analyse the development of a diabetes reference centre by a healthcare organisation acting as an institutional entrepreneur that illustrates the conceptualisation of an innovation and the mobilisation of resources to implement it and to influence other actors in the field. The authors discuss the case in reference to three stages of change: emergence, implementation and diffusion. The results illustrate the different strategies used by managers to advance their proposed projects. RESEARCH LIMITATIONS/IMPLICATIONS: This study helps to better understand the dynamics of mandated change in a mature field such as healthcare and the roles played by organisations in this process. By adopting a proactive strategy, a healthcare organisation can play an active role and strongly influence the evolution of its field. ORIGINALITY/VALUE: This paper is one of only a few to analyse strategies used by healthcare organisations in the context of mandated change. PMID- 24783669 TI - Guidance for research-practice partnerships (R-PPs) and collaborative research. AB - PURPOSE: The purpose of this paper is to provide evidence based guidance to researchers and practice personnel about forming and carrying out effective research partnerships. DESIGN/METHODOLOGY/APPROACH: A review of the literature, interviews and discussions with colleagues in both research and practice roles, and a review of the authors' personal experiences as researchers in partnership research. FINDINGS: Partnership research is, in some respects, a distinct "approach" to research, but there are many different versions. An analysis of research publications and of their research experience led the authors to develop a framework for planning and assessing the partnership research process, which includes defining expected outcomes for the partners, their roles, and steps in the research process. PRACTICAL IMPLICATIONS: This review and analysis provides guidance that may reduce commonly-reported misunderstandings and help to plan more successful partnerships and projects. It also identifies future research which is needed to define more precisely the questions and purposes for which partnership research is most appropriate, and methods and designs for specific types of partnership research. ORIGINALITY/VALUE: As more research moves towards increased participation of practitioners and patients in the research process, more precise and differentiated understanding of the different partnership approaches is required, and when each is most suitable. This article describes research approaches that have the potential to reduce "the research-practice gap". It gives evidence- and experience-based guidance for choosing and establishing a partnership research process, so as to improve partnership relationship-building and more actionable research. PMID- 24783668 TI - Implementing change in physiotherapy: professions, contexts and interventions. AB - PURPOSE: The purpose of this paper is to report findings from qualitative interviews with physiotherapists to demonstrate why even minor changes to clinical work resulting from the introduction of new interventions, are often difficult to implement. The paper seeks to illustrate how some of the obstacles to implementing change were managed by physiotherapists. DESIGN/METHODOLOGY/APPROACH: A total of 32 qualitative interviews with participating physiotherapists were conducted, 12 interviews prior to the introduction of the new system, and 20 afterwards. The interviews were coded and analysed thematically. FINDINGS: The findings reveal a number of perceived limitations of current management of low back pain and identify key themes around convergence with the new approach, such as willingness by physiotherapists to adopt the new approach, the perception of benefits to adopting the new approach, as well as some difficulty in adjusting to it. The authors refer to the positive and negative elements as "soft" and "hard" disruption. The adoption of the new approach is explored with reference to the "situated" dimensions of physiotherapy practice and normalisation process theory. RESEARCH LIMITATIONS/IMPLICATIONS: The study raises the need to conduct future observational research to support the interview findings. ORIGINALITY/VALUE: The study describes the "situated" components of physiotherapy work, which have received limited research attention. The value of the study lies less in its ability to explain specifically why physiotherapists adopted or rejected the new system, but in describing the conditions and consequences of change that might be translated to other professions, contexts and interventions. PMID- 24783670 TI - The roots of multilevel selection: concepts of biological individuality in the early twentieth century. AB - As multilevel selection theory has gained greater acceptance over the past quarter-century, scientists and scholars have shown an increased interest in the theory's historical antecedents. Despite this interest, however, the early twentieth century remains largely unexplored. It is generally assumed that biologists thought "naively" about evolutionary dynamics during this era, and that their attempts to explain biological phenomena often lacked sophistication. Now that several recent works have called attention to the complex relationship between biological individuality and the levels of selection, we believe it will prove instructive to revisit these early-twentieth-century biologists and reassess their criteria for biological individuality. Doing so reveals that they constructed a multilevel explanation of evolution that anticipated modern interpretations in several important ways. Though it is certainly true that most of these early biologists failed to recognize natural selection's pervasive agency, it is no less true that one of them, termite expert Alfred Emerson, artfully united the multilevel theory of "emergent evolution" with natural selection in a way that differs but little from the theory of multilevel selection that many scientists and scholars now promote. After reviewing the historical record, we place these early-twentieth-century biologists in their proper historical context, and we compare their interpretation of evolution with modern interpretations. PMID- 24783671 TI - Autonomous mathematical models: constructing theories of metabolic control. AB - This paper considers how the relationship between mathematical models and theories in biology may change over time, on the basis of a historical analysis of the development of a mathematical model of metabolism, metabolic control analysis, and its relationship to theories of metabolic control. I argue that one can distinguish two ways of characterising the relationship between models and theories, depending on the stage of model and/or theory development that one is considering: partial independence and autonomy. Partial independence describes a model's relationship with existing theory, thus referring to relationships that have already been established between model and theory during model construction. By contrast, autonomy is a feature of relationships which may become established between model and theory in the future, and is expressed by a model's open ended role in constructing emerging theory. These characteristics have often been conflated by existing philosophical accounts, partly because they can only be identified and analysed when adopting a historical perspective on scientific research. Adopting a clear distinction between partial independence and autonomy improves philosophical insight into the changing relationship between models and theories. PMID- 24783672 TI - Tracing organizing principles: learning from the history of systems biology. AB - With the emergence of systems biology, the identification of organizing principles is being highlighted as a key research aim. Researchers attempt to "reverse engineer" the functional organization of biological systems using methodologies from mathematics, engineering and computer science while taking advantage of data produced by new experimental techniques. While systems biology is a relatively new approach, the quest for general principles of biological organization dates back to systems theoretic approaches in early and mid twentieth century. The aim of this paper is to draw on this historical background in order to increase the understanding of the motivation behind the search for general principles and to clarify different epistemic aims within systems biology. We pinpoint key aspects of earlier approaches that also underlie the current practice. These are i) the focus on relational and system-level properties, ii) the inherent critique of reductionism and fragmentation of knowledge resulting from overspecialization, and iii) the insight that the ideal of formulating abstract organizing principles is complementary to, rather than conflicting with, the aim of formulating detailed explanations of biological mechanisms. We argue that looking back not only helps us understand the current practice but also points to possible future directions for systems biology. PMID- 24783673 TI - Bridging the lab-field divide? The "eco" in ecological genomics. AB - The emerging field of ecological genomics promises to bring about a marriage between ecological and laboratory-based, genomic investigations. In this paper, I will reflect on this promise by exploring how ecology and genomics are integrated in the two approaches that currently dominate this field: the organism-centred approach, focusing on individual (model) organisms, and the metagenomic approach, concentrating on (the metagenome of) entire microbial communities composed of a variety of species. I will show that both approaches have already taken some important steps in bridging the gap between genomics and ecology. Since the introduction of next-generation sequencing methodology in 2007, the organism centred approach does not need to stick to classical model organisms like Arabidopsis anymore. Instead, it is now able to apply genomic tools to ecologically interesting species (e.g. amphibians, reptiles, birds) as well. The metagenomic approach has been able to give ecology a more prominent place in its investigations, in another way. Contrary to classical microbiology (the field from which it originates), it does not study microbial communities under controlled laboratory settings, but under nature's own conditions. However, in the marriage between genomics and ecology, genomics still appears to be the dominant partner, especially in the case of the organism-centred approach that continues to study the new ecological models in artificial lab environments. Moreover, the organism-centred and metagenomic approaches employ a gene-centred perspective in understanding critical ecological interactions, thus strengthening a reductionist rather than a holistic (systems-oriented) approach. PMID- 24783674 TI - When do models provide genuine understanding, and why does it matter? AB - In spite of a number of remarkable advances over the last few decades, the question of how scientific models provide explanations remains rather controversial. In the case of biology, this question is quite pressing, since according to many specialists we do not find genuine universal explanatory laws in biology, and yet, biologists constantly use models as explanatory devices. It is probably not possible to reduce all of the ways in which models explain to one unifying pattern. If there is a common trait in all of these different ways it is perhaps that they achieve a better understanding of phenomena. It is argued in this paper that the notion of "understanding" is not irremediably subjective. Various contextual but objectively justifiable criteria are suggested in order to establish when a feeling of understanding corresponds to a genuine understanding. PMID- 24783675 TI - Direct stool EHEC testing. PMID- 24783677 TI - The last word on the LEAN laboratory? PMID- 24783678 TI - Current and novel biomarkers for diagnosis and monitoring of sepsis. PMID- 24783679 TI - Sepsis: use of clinical criteria as well as novel diagnostic tests aim to improve patient outcomes. PMID- 24783680 TI - Sepsis and antibiotic stewardship: the importance of rapid ID, rapid AST and right drug-bug match. PMID- 24783681 TI - The biology of HPV infections: understanding the progression to cervical cancer. PMID- 24783682 TI - Cardiotoxicity associated with trastuzumab and chemotherapy used for HER2 positive cancers. PMID- 24783684 TI - Technology of a high-performance blood bank refrigerator. PMID- 24783683 TI - Superior service, impressive innovation: lab of the year 2014. PMID- 24783685 TI - Barrett's esophagus and the need for improved diagnostic and prognostic testing. PMID- 24783686 TI - The changing landscape of diagnostic testing for diarrheal disease. PMID- 24783687 TI - STR typing: method and applications. PMID- 24783688 TI - Hepatitis C testing today. PMID- 24783690 TI - Field trip success. PMID- 24783691 TI - Starting insulin. PMID- 24783692 TI - Meet the Manns. PMID- 24783693 TI - Health head to toe. PMID- 24783694 TI - Checkup reminders. PMID- 24783695 TI - Golden girl. PMID- 24783696 TI - Cut to the chase. PMID- 24783697 TI - Breakfast boost. PMID- 24783699 TI - Food. PMID- 24783698 TI - 45 carb-counting tips. PMID- 24783700 TI - Regaining nerve. PMID- 24783701 TI - Looking forward. The American College of Surgeons' Transition to Practice Program. PMID- 24783702 TI - Dual eligible beneficiaries: roles for surgeons under health care reform. PMID- 24783703 TI - Trauma and emergency care under the Affordable Care Act. PMID- 24783704 TI - Is your office helping you prevent wrong site surgery? PMID- 24783705 TI - The aging surgeon: when is it time to leave active practice? PMID- 24783706 TI - The Measure Applications Partnership. PMID- 24783707 TI - Rural surgery is a global issue: the perspective of an Argentine surgeon. PMID- 24783708 TI - RAS-ACS International Exchange Scholarship Program provides unique opportunity for global collaboration. PMID- 24783709 TI - Community-based physicians and hospitals need to participate in clinical trials. PMID- 24783710 TI - ACS returns books to the Illinois College Medical Library: a look at their history. PMID- 24783711 TI - Physicians invited to play a larger role in standards process. PMID- 24783712 TI - NTDB data points: top 10 list. PMID- 24783713 TI - Hartford Consensus in action: law enforcement gets equipment, training to control bleeding. PMID- 24783714 TI - Surgeons, anesthesiologists develop resource standards for optimal pediatric care. PMID- 24783715 TI - Advocacy is not a bad word. PMID- 24783716 TI - Radiological features of horizontal gaze palsy with progressive scoliosis. An 'Aunt Minnie' diagnosis? AB - Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder characterized by congenital absence of normal horizontal eye movements and progressive scoliosis through childhood and adolescence. The characteristic radiological features in HGPPS are butterfly configuration of the medulla, split pons sign, selective volume loss of dorsomedial brainstem, relatively spared cerebellum, relatively prominent inferior olivary nucleus and absent posterior prominence of the facial colliculi and gracilis and cuneate nuclei. These radiological features are reflective of ROBO3 gene mutation required for hindbrain axon midline crossing. Awareness of this diagnosis is important as the radiological features are characteristic enough to be considered as a rare 'Aunt Minnie' and a radiologist may be the first one to raise the possibility of this diagnosis as in this case. PMID- 24783717 TI - Why we should care about global health. PMID- 24783718 TI - An opportunity for improvement: adolescent administration of the human papillomavirus vaccine. AB - Despite having access to a safe, effective, licensed vaccine against Human Papillomavirus, many adolescents fail to complete the three-dose series falling far short of our Healthy People 2020 goal of 80 percent. There are a number of theories about why patients and health care professionals may choose to skip this vaccine series: Infrequent adolescent visits compared with the infant/toddler preventive care schedule, parental fear over appearing permissive to sexual activity, cost of the vaccine series, and being uninformed about the vaccination. Given the high prevalence of infection, low rate of adverse events associated with vaccination, and significant morbidity and mortality associated with disease, physicians should be strongly recommending this vaccine series. This article reviews the typical barriers and provides suggestions for national and Delaware-specific resources for health care professionals and patients. PMID- 24783719 TI - Medical Society of Delaware Contemporary Veteran Project. PMID- 24783720 TI - "My professor said to submit my paper" (we hope they also told you this). PMID- 24783721 TI - Development of leadership behaviors in undergraduate nursing students: a service learning approach. AB - AIM: The purpose of this study was to determine leadership behaviors developed by nursing students and peers before and after a service-learning experience. BACKGROUND: Nurses have been called to fill growing needs in the health care setting, rendering care to vulnerable and diverse populations in a wide range of organizations. Leadership behaviors are therefore essential. METHOD: Baccalaureate students (N = 65) completed the Student Leadership Practices Inventory-Self at the beginning and end of the semester. The students also rated peers using the Leadership Practices Inventory-Observer and answered six questions about service-learning. RESULTS: Repeated measures of analysis of variance for pre- and posttests revealed that leadership behaviors improved (p < .0001). A significant correlation was found (p = .02) between the overall posttest scores for both instruments. CONCLUSION Integrating service-learning into a leadership course is an effective approach to the development of leadership behaviors. PMID- 24783722 TI - Cultural competency among nurses with undergraduate and graduate degrees: implications for nursing education. AB - AIM: To compare the level of cultural awareness, knowledge, skills, and comfort of nurses with undergraduate and graduate degrees when encountering patients from diverse populations. BACKGROUND: Cultural competency is a core curriculum standard in undergraduate and graduate nursing programs. Assessing cultural awareness, knowledge, skills, and comfort among nurses can help identify areas to strengthen in nursing curricula. METHOD: A prospective, cross-sectional, descriptive study design was used. Two thousand surveys were sent to nurses in a southeastern state; 365 nurses participated. RESULTS: Undergraduate-degree nurses scored lower than graduate-degree nurses on cultural knowledge. Scores on cultural awareness, skills, and comfort with patient encounters did not vary between groups. Both groups of nurses reported little cultural diversity training in the workplace or in professional continuing education. CONCLUSION: The findings of this study indicate areas of need for undergraduate and graduate nursing education. PMID- 24783723 TI - "It all depends": how minority nursing students experience belonging during clinical experiences. AB - AIM: The purpose of this study was to identify factors that influence minority nursing students' sense of belonging during clinical experiences. BACKGROUND: Minority nursing students encounter multiple barriers within their clinical education experiences and have a higher attrition rate than Caucasian women. METHOD: A mixed-method approach using a survey and individual qualitative interviews was used to generate data for this study. RESULTS: Minority students' sense of belonging is dependent on their interactions with registered nurses with whom they work, clinical nursing instructors, and student peers. Positive experiences enhance students' sense of belonging, while negative experiences may severely impact their belongingness. CONCLUSION: Every interaction that minority students have with clinical nursing instructors, registered nurses, and their student peers has the potential to impact belongingness. Engaging in reflection, developing mission statements that appreciate and value diversity, and using transformative learning strategies enhance minority students' sense of belonging. PMID- 24783724 TI - Effects of a retention intervention program for associate degree nursing students. AB - AIM: To evaluate the effects of a retention intervention program on nursing students' persistence in obtaining an associate's degree. BACKGROUND: An associate degree nursing program at a large community college used a three-year grant from the US Department of Labor to create a program to improve retention of nursing students. METHOD: Seven retention interventions (stipends, learning communities, comprehensive orientation, individualized academic planning, counseling, peer tutoring, and community nurse mentoring) were provided to participants. Correlational analyses were conducted between demographic variables and degree completion and between individual intervention program participation and degree completion. RESULTS: The program produced a statistically significant improvement in retention, but no specific intervention or mixture of interventions was significantly correlated with retention. CONCLUSION: Retention programs must be comprehensive, integrated efforts in order to increase the degree completion rate. PMID- 24783725 TI - Nursing and medical student attitudes about communication and collaboration before and after an interprofessional education experience. AB - AIM: The purpose of this study was to examine attitudes about interprofessional communication and collaboration as well as the effect of an interprofessional educational intervention on health care students. BACKGROUND: Interprofessional education requires an understanding of student attitudes about interprofessional communication and collaboration, as well as whether those attitudes are affected by participation in such educational initiatives. METHOD: Medical and nursing students were placed in health care teams. Attitudes about communication and collaboration were measured at the beginning and end of the project using the Jefferson scale of Attitudes Toward Physician-Nurse Collaboration and the Baggs Collaboration and Satisfaction About Care Decisions tool. RESULTS: Significant differences were seen between the medical and nursing groups as well as across time. CONCLUSION: Compared with nursing students, medical students began their student careers with less positive attitudes toward interprofessional communication and collaboration. In spite of the three-semester health care team program, these differences persisted. PMID- 24783726 TI - From learning to teach to teaching effectiveness: nurse educators describe their experiences. AB - AIM: The aim of the study was to understand the lived experience of nurse educators and the characteristics, traits, practices, and experiences that influenced their development and competence. BACKGROUND: The nurse and nurse faculty shortage has resulted in a continuous demand for new nurse educators. Clinical experts recruited as faculty face numerous challenges in the move to academia. METHOD: A purposive sample of nurse educators with five or more years of full-time teaching experience, peer-nominated as effective teachers, was recruited for this phenomenological study. RESULTS: Eight overarching themes were identified, including factors that supported new faculty entering academia and the process of learning to teach in higher education. Characteristics of effective teachers are explored, with implications for both new and experienced faculty. CONCLUSION: Suggestions for attracting more nurses to academia and supporting retention of current faculty are provided. PMID- 24783727 TI - E-books: nurse faculty use and concerns. AB - AIM: The purpose of this study was to identify nurse educators' stage of concern regarding e-books and examine relationships between stage of concern and demographic variables. BACKGROUND: The use of e-books is growing, and nursing faculty must be prepared to use this evolving technology. METHOD: A descriptive design was used with a convenience sample of 50 nurse educators attending a professional conference. Data were collected using a demographic questionnaire and the Stages of Concern (SoC) questionnaire. RESULTS: Sixty-four percent of participants' first high stage was Stage 0 (awareness); 22 percent had a first high stage of Stage 1 (informational). Using ordinal regression, no statistical significance was noted with the highest Stage of Concern and age (p = .431) or experience as a nurse educator (p = .893). CONCLUSION: Findings indicate low usage, faculty concerns, and the need for ongoing education regarding e-books. PMID- 24783728 TI - Experiences of first-year nursing students during an education redesign: findings from the Oregon Consortium for Nursing Education. AB - AIM: The aim of this article is to summarize first-year students' (n = 908) experience during a nursing education redesign. BACKGROUND: Oregon Consortium for Nursing Education (OCNE) began its redesign of nursing education in 2000, long before the current national calls for nursing education reform. As OCNE moved from planning to implementation, a comprehensive evaluation of the students, the program, and curriculum ensued. METHOD: Data were collected from first-year nursing students each spring from 2007-2010 using a standardized survey instrument that included demographic, attitudinal, and opinion-based survey items. RESULTS: Results indicated fellow students, course lectures and interaction, and faculty and courses were rated areas of satisfaction. CONCLUSION: Areas needing improvement included advising and facilities, administration, quality of instruction and curriculum, and overall program effectiveness. Mean scaled and open-ended responses from each area are reported. PMID- 24783729 TI - Raising students' clinical alarm awareness: evaluating a learning activity. PMID- 24783730 TI - High-fidelity simulation in nursing education: a change in clinical practice. PMID- 24783731 TI - A model for orientation and mentoring of online adjunct faculty in nursing. PMID- 24783732 TI - The Connected Age and the 2014 Horizon Report. PMID- 24783733 TI - [Obesity: the forgotten disease that scares]. PMID- 24783734 TI - [Role of the psychiatrist in the management of obesity]. AB - The management of obese patients is complex and often generates a sense of powerlessness on the part of caregivers. Psychopathologies associated with obesity are omnipresent and require greater attention from the somaticians to better assist their patients in this chronic disease and to guide their care. Despite the often legitimate reluctance of patients, it remains fundamental to question the symptom, weight, beyond any prejudice. Obesity, with or without bypass project, requires support in the long term by a multidisciplinary team with an holistic approach in order to avoid creating a new failure as is the case with the methods of food restrictions perpetuate eating disorders. PMID- 24783735 TI - [Rehabilitation: a case for obese patients?]. AB - In the word obesity, a clinical concept of chronic systemic disease pairs up with pejorative individual or social representations. Being obese is also facing situations of disability, organ failure, uncertainty of the fate and stigmatization. A care concept inspired by rehabilitation and therapeutic patient education could offer a new way and other purposes to the treatment of obesity. Restoring functions, learning how to adapt and change their environment, obese people may live better today, out of their isolation and develop partners in their projects of life and health. Rehabilitation of an obese patient is much more than weight loss! PMID- 24783736 TI - [Prevalence of early and late dumping after gastric bypass]. AB - Gastric bypass surgery is an effective treatment of obesity, bringing a significant weight loss and a major improvement of carbohydrate profile. However, in some patients, a deregulation in carbohydrate metabolism between insulin secretion and sensitivity is observed, whereupon early and late dumping happen. Their prevalence isn't well studied, although it seems that 10 to 20% of patients are affected. We've studied a cohort of 70 patients who undergone gastric bypass surgery at the CHUV. 18 (25.7%) patients have a positive anamnesis for early dumping and 10 (14.3%) for late dumping, being it superior as what is described in the literature. PMID- 24783737 TI - [The role of patient education in bariatric surgery]. AB - Therapeutic patient education (TPE) has demonstrated its efficacy in treating numerous chronic conditions, including obesity. Currently, TPE has broadened its field of activity to the preparation of obese patients undergoing bariatric surgery. A preparative program allows informing patients about the surgery, the necessity of the follow-up and the risk of weight regain. It also aims to allow the patient to understand the behaviors which initially brought about its obesity and to help modify these behaviors in order to avoid weight regain after the surgery. A follow-up post surgery by trained health care providers is also recommended. Current literature suggests that patients are satisfied with such educational programs, and that they help them to lose weight before surgery. The efficacy on post surgery weight loss and compliance is yet to be proved. PMID- 24783738 TI - [Long-term implication of bariatric surgery: beyond deficiencies]. AB - Bariatric surgery frequently leads to several nutritional deficiencies that are well reported in the literature. However, numerous other aspects of the patients' life are concerned by bariatric interventions, so that the follow-up of these patients after bariatric surgery does not only encompass a mere correction of the well-known nutritional deficiencies. Only a thorough knowledge of all possible consequences of bariatric interventions permits an adequate follow-up of these patients. Overtly addressing all these issues with the patients before performing a bariatric intervention is the best way for them to be prepared for the intervention itself and to understand the need of a life-long follow-up thereafter. PMID- 24783739 TI - [Understanding obesity in Africa: the effect of [economic] development and [mental] concepts]. AB - Obesity is becoming more and more common in Africa. It is the direct consequence of the socio-economic development that the continent is going through and the changes in lifestyle that it entails: greater consumption of calorically dense foods accompanied by a more sedentary lifestyle. Furthermore, there are various representations and beliefs that promote voluntary weight gain. Studies have shown that obesity is not only a criterion of beauty but also often perceived as a sign of wealth and even good health. To remedy this problem, the authorities in collaboration with health care professionals must develop populational strategies that take into account the different representations and beliefs in order for them to be effective. PMID- 24783740 TI - [MOOCs (Massive Open Online Courses): the end of conventional medical schools?]. PMID- 24783741 TI - [No return to the era before the antibiotics -- the future and the old medicine]. PMID- 24783742 TI - [A hunting story]. PMID- 24783743 TI - [Golden Holocaust, or the incestuous marriage of sugar and tobacco]. PMID- 24783744 TI - [Alcohol and baclofen: France will finally experiment on a large scale]. PMID- 24783745 TI - [The doctor learning from the patient]. PMID- 24783746 TI - Ellen R. Grass Lecture: extraordinary EEG. AB - The electroencephalogram (EEG) is a unique measure of the electrical function of the brain. Cerebral sources of EEG potentials expressed by the human brain have been recorded on the surface of the scalp for almost 100 years. With the advances in digital technology, present day EEG has evolved to include specialized techniques that offer new capabilities never realized before. Refined intracranial recording techniques and multi-channel systems now permit access to regions of the brain that have previously been off limits to conventional EEG recording. Extraordinary biorhythms beyond 1 to 35 Hz that have been typically used in routine EEG are now exploring extreme bandwidths that may disclose epileptogenic regions and their yield causative networks involved in generating seizures. These spectral frequencies ranging from infraslow activity to high frequency oscillations have far reaching implications for people with uncontrolled seizures. Micro-EEG recordings are now shedding light on electrophysiological recordings of single columns of neuronal activity in clinical research expanding our understanding of epilepsy to the cellular level. Beyond the routine application of EEG analyzed for clinical use, special EEG techniques now provide a window to reveal detailed information about the seizure onset zone in patients with epilepsy, as well as advance our understanding of the functional processes of the brain itself. These breakthroughs will allow EEG based treatment alternatives. PMID- 24783747 TI - Late-onset epilepsy with status myoclonicus: a diagnostic and management dilemma. AB - Status myoclonicus (myoclonic status epilepticus) has been described in generalized epilepsy syndromes, neurodegenerative disease, infectious or inflammatory neurologic disease, toxic-metabolic states, and following anoxic brain injury. It is extremely uncommon in elderly people. Hence, status myoclonicus can be a challenge to diagnose and manage especially if it is cryptogenic epilepsy (unknown cause). We describe the case of a 77-year-old female who had new-onset uncontrolled seizures despite three antiepileptic drugs. Following concern about nonepileptic events, she was eventually diagnosed by epilepsy monitoring to have status myoclonicus. Her seizures were then controlled with appropriate antiepileptic drug changes. PMID- 24783748 TI - Anesthesia considerations for monitoring TCMEPs in adults diagnosed with poliomyelitis as children: a case report. AB - The use of transcranial motor evoked potentials (TCMEPs) to detect and hopefully prevent injury to the brain, spinal cord, and peripheral nerves intraoperatively has increased greatly in recent years. It is well established that in addition to certain anesthetic agents, patient factors such as advanced age, obesity, diabetes, hypertension, and a collection of neurological and neuromuscular diseases and disorders can greatly reduce or completely eliminate the ability to monitor TCMEPs effectively. One such disease, poliomyelitis (polio), is a highly contagious viral disease that has been mostly forgotten since its near eradication through vaccination. Over the past three decades there has been increasing recognition of late onset neurological deterioration in individuals who were afflicted by, and apparently recovered from, paralytic poliomyelitis much earlier in life. This condition is known as post-poliomyelitis syndrome (PPS). Patients that appear to have fully recovered from polio, and those with PPS, may require special anesthetic considerations to facilitate effective TCMEP monitoring. CASE REPORT: We report the rapid loss of only lower extremity TCMEPs bilaterally during a C6-C7, C7-T1 ACDF in a 67-year-old female to treat left sided C7-C8 radiculopathy and C6-T1 foraminal stenosis. The general anesthetic maintenance regimen of 0.3 MAC sevoflurane and 100 microg/kg/min propofol was paused, and a wake-up test was initiated. Full upper and lower extremity motor function was observed. A thorough review of the patient's medical history revealed the potential risk factor of full recovery from poliomyelitis as a child. The sevoflurane was removed from the anesthetic regimen, and the lower extremity TCMEPs returned and were present for the remainder of the surgery. PMID- 24783749 TI - Auto-antibodies and seizures: clinical and EEG findings. AB - Epilepsy is a common disorder that may be caused by wide ranging etiologies. Historically a significant number of people with epilepsy have idiopathic epilepsy without a definitive etiology. More recently, auto-antibodies have been discovered to be associated with numerous conditions affecting the nervous system, including epilepsy. With this increased understanding of the potential for immune-based etiologies for epilepsy it is important to recognize the associated EEG patterns in such cases. This report presents the EEG findings in epilepsy patients with one or more auto-antibodies. PMID- 24783750 TI - Application and use of prime electrodes and eye leads. AB - Often the standard International 10-20 System of electrode placement doesn't provide enough information regarding abnormal EEG activity. The application and use of prime electrodes can help to localize abnormal activity and also establish polarity of activity past the end of the chain of a bipolar montage. The proper application and use of eye leads can help to determine if EEG activity is abnormal or a non-cephalic artifact. This article will outline application and use of prime electrodes and eye leads. PMID- 24783751 TI - Indiana University Health staffing model for neurotelemetry and epilepsy monitoring unit patient populations: Part 1. AB - This is part one of a two part series of articles describing the staffing model utilized for neurotelemetry and epilepsy unit monitoring. After peer review, many administrative and technical questions were left unanswered which will be addressed in the second article. Indiana University Health Neuroscience is a facility that provides all levels of care for adult and pediatric patients regarding their specific neurological needs. The facility currently has 24/7 monitoring at Methodist Hospital and Riley Hospital for Children, consisting of adult and pediatric patients for neurotelemetry and epilepsy unit monitoring. Each unit must have staffing models as well as specific protocols in order to adequately monitor each patient's EEG and maintain safety. Specific recommendations, protocols, and requirements have been drafted by administration to maintain a safe patient to neurodiagnostic technologist ratio of 4:1. PMID- 24783752 TI - Technical tips: event testing in the epilepsy monitoring unit. AB - Event testing plays an important role in the determination of event type. This is true for epileptic and/or nonepileptic events. Any individuals who spend a significant amount of time in a patient's room can contribute to this important part of an admission to the epilepsy monitoring unit (EMU). What follows is an explanation outlining the purpose of event testing and some suggestions on how to do it effectively. The nurses and support staff on the floor are usually the "first ones there." Properly trained, they can do the event testing, thereby providing valuable information. PMID- 24783753 TI - Majority of mental health social workers and charity managers believe the mental health of communities is declining. PMID- 24783754 TI - Cuts to early intervention in psychosis services could create a lost generation of young people, warns professor Max Birchwood. PMID- 24783755 TI - Getting involved. PMID- 24783756 TI - Mind the gap. PMID- 24783757 TI - Making progress. PMID- 24783758 TI - Tom Messere gives an update on changes to when migration from old to new welfare and sickness benefits is occurring. PMID- 24783759 TI - The personalisation agenda's focus on individual rather than collective services risks people becoming isolated and lacking in peer support, says Alison Faulkner. PMID- 24783760 TI - While the menta health crisis care Concordat looks like a step in the right direction, there is scepticism over whether it will deliver if there isn't the funding to back it up. PMID- 24783762 TI - Viewpoint. Evidencing the value of activity-based occupational therapy. PMID- 24783761 TI - Mental health, resilience and partnership commissioning. Your guide to today's mental health issues. PMID- 24783763 TI - Viewpoint. The IAPT programme is providing results. PMID- 24783764 TI - Perspectives. Set up a social care charity? PMID- 24783765 TI - Preventing the tragedy of railway suicides. PMID- 24783766 TI - Mutual benefits. Partnership between a housing association and university. PMID- 24783767 TI - On the record. Looking at ordinary people's tales of living with their mental illness. PMID- 24783768 TI - Quality of life in end stage renal disease: a concept analysis. AB - AIM: This concept analysis examines quality of life (QOL) in the context of end stage renal disease (ESRD). BACKGROUND: Quality of life is a multidimensional concept historically used by governmental bodies to measure society's satisfaction of economic and social outcomes. However, health care researchers have demonstrated that the concept of QOL relates to a deeper meaning of an individual's experience of life and health. DESIGN: Walker and Avant's (2010) framework of concept analysis was chosen to provide conceptual clarity for nephrology nurses and allied health care professionals. DATA SOURCES: The CINHAL, EBSCO, ERIC, Medline, PsycINFO, and PubMed databases were searched for the period of 1998-2013 for literature published in English and French with a focus of peer reviewed journals from disciplines of health sciences and psychology. RESULTS: Consequent to this concept analysis, QOL has been defined by three defining attributes, such as the ability to engage in vigorous activities, the ability to perform activities of daily living (ADL), and the ability to engage in family, social, and occupational roles. CONCLUSION: These findings enable a clear and functional definition of the concept of QOL in the context of ESRD, therefore facilitating the ability of nephrology nurses and allied health care professionals to assess clients' needs and improve their health care outcomes through their lived experience. PMID- 24783769 TI - Dosing chemotherapy agents in hemodialysis--a focus on multiple myeloma. PMID- 24783770 TI - Satellite hemodialysis services for patients with end stage renal disease. AB - More than 40,000 Canadians are living with end stage renal disease and approximately 22,400 of those are currently being treated with hemodialysis (The Kidney Foundation of Canada, 2013). Long distance travel to access hemodialysis services can be a serious burden for patients, and travelling more than 60 minutes can mean a 20% greater risk for death, as compared with those who travel 15 minutes or less (Moist et al., 2008). Satellite hemodialysis units are seen as one solution to this problem. This study assessed the impact of services provided by one satellite hemodialysis unit on patients' satisfaction, access to care and quality of life using a qualitative interview research design. Seven patients were interviewed and three themes emerged including the burden of long distance travel before satellite services (safety, time and cost), satisfaction with satellite services (pleasant environment and continuity of care), and improved quality of life. This study showed that a satellite hemodialysis unit improved access to services and enhanced the quality of life of those patients who participated in the study. PMID- 24783771 TI - Addressing quality of life and end-of-life decisions with patients. PMID- 24783772 TI - Treatment of petroleum hydrocarbon polluted environment through bioremediation: a review. AB - Bioremediation play key role in the treatment of petroleum hydrocarbon contaminated environment. Exposure of petroleum hydrocarbon into the environment occurs either due to human activities or accidentally and cause environmental pollution. Petroleum hydrocarbon cause many toxic compounds which are potent immunotoxicants and carcinogenic to human being. Remedial methods for the treatment of petroleum contaminated environment include various physiochemical and biological methods. Due to the negative consequences caused by the physiochemical methods, the bioremediation technology is widely adapted and considered as one of the best technology for the treatment of petroleum contaminated environment. Bioremediation utilizes the natural ability of microorganism to degrade the hazardous compound into simpler and non hazardous form. This paper provides a review on the role of bioremediation in the treatment of petroleum contaminated environment, discuss various hazardous effects of petroleum hydrocarbon, various factors influencing biodegradation, role of various enzymes in biodegradation and genetic engineering in bioremediation. PMID- 24783773 TI - The hematopoietic growth factor "erythropoietin" enhances the therapeutic effect of mesenchymal stem cells in Alzheimer's disease. AB - Alzheimer's disease is a neurodegenerative disorder clinically characterized by cognitive dysfunction and by deposition of amyloid plaques, neurofibrillary tangles in the brain. The study investigated the therapeutic effect of combined mesenchymal stem cells and erythropoietin on Alzheimer's disease. Five groups of mice were used: control group, Alzheimer's disease was induced in four groups by a single intraperitoneal injection of 0.8 mg kg(-1) lipopolysaccharide and divided as follows: Alzheimer's disease group, mesenchymal stem cells treated group by injecting mesenchymal stem cells into the tail vein (2 x 10(6) cells), erythropoietin treated group (40 microg kg(-1) b.wt.) injected intraperitoneally 3 times/week for 5 weeks and mesenchymal stem cells and erythropoietin treated group. Locomotor activity and memory were tested using open field and Y-maze. Histological, histochemical, immunohistochemical studies, morphometric measurements were examined in brain sections of all groups. Choline transferase activity, brain derived neurotrophic factor expression and mitochondrial swellings were assessed in cerebral specimens. Lipopolysaccharide decreased locomotor activity, memory, choline transferase activity and brain derived neurotrophic factor. It increased mitochondrial swelling, apoptotic index and amyloid deposition. Combined mesenchymal stem cells and erythropoietin markedly improved all these parameters. This study proved the effective role of mesenchymal stem cells in relieving Alzheimer's disease symptoms and manifestations; it highlighted the important role of erythropoietin in the treatment of Alzheimer's disease. PMID- 24783774 TI - Pancreatic effect of andrographolide isolated from Andrographis paniculata (Burm. f.) Nees. AB - Andrographis paniculata (Burm. f.) Nees is a plant that originates from India and grows widely to Southeast which used for several purposes mainly as treatment of diabetes mellitus so the aim of this study was evaluate andrographolide for its pancreatic effect in neonatal streptozotocin (STZ)-induced diabetic rats, a model of type 2 diabetic rats. Diabetic condition was induced with an intraperitoneal injection of 90 mg kg(-1) streptozotocin in two-day-old rats. After three months, the neonatal STZ-induced diabetic rats were treated with andrographolide or andrographolide-enriched extract of A. paniculata (AEEAP) for 8 consecutive days. Pancreatic effect was evaluated by estimating mainly the preprandial and postprandial blood glucose levels and other parameters such as morphology of pancreatic islet, beta cells density and morphology and immunohistochemically pancreatic insulin. Andrographolide significantly (p < 0.05) decreased the levels of blood glucose and improved diabetic rat islet and beta cells. However, AEEAP exhibited moderate hypoglycaemic effects on the blood glucose levels. Moderate changes in beta cells were observed after AEEAP treatment. They could restore decreasing of pancreatic insulin contents. Based on these results andrographolide and AEEAP exhibited pancreatic actions in neonatal STZ-induced diabetic rats. The activity of andrographolide was more effective than this of AEEAP. PMID- 24783775 TI - Ectomycorrhizal diversity associated with Cedrus deodara and Pinus wallichiana in the Kashmir Himalaya, India. AB - The present study was undertaken to document the ectomycorrhizal diversity associated with the Cedrus deodara and Pinus wallichiana in the Kashmir Himalaya, India. The extensive field surveys carried out in the Kashmir Himalaya at five study sites resulted in the collection and identification of 76 potential ectomycorrhizal fungal species associated with the Cedrus deodara and Pinus wallichiana. Maximum 32 number of species were found associated with Pinus wallichiana, 19 with Cedrus deodara and 25 species were found growing in association with both the conifers. The present study reveals that Cedrus deodara and Pinus wallichiana in the Kashmir Himalaya, India harbour diverse ectomycorrhizal fungal species. PMID- 24783776 TI - Evaluation of phenolic content and antioxidant potency in various parts of Cassia auriculata L.: a traditionally valued plant. AB - Presence of polyphenolic content in various part of the plant exhibit wide pharmacological activities including antioxidant activity. The present study was designed to evaluate the phenolic contents (total phenols, flavonoid and tannins) and antioxidant properties of ethanolic extracts of flower, leaf, pod, bark and root obtained from Cassia auriculata. Ethanolic extracts of various parts of C. auriculata obtained by sonication extraction techniques are studied for their phenolic contents and DPPH (2,2-diphenyl-1-picrylhydrazine) radical scavenging assay as well as total antioxidant assays using UV visible spectrophotometer. Among the various parts of the plant studied, bark showed significant content of phenolics, flavonoids and tannins followed by the root, leaf, flower and pod. Even bark extract exhibited highest antioxidant capacity in DPPH assay followed by root, leaf, flower and pod with a value of 766.7, 679.3, 644.9, 572.5 and 474.7 mg vitamin C equivalent antioxidant capacity (mg VCEAC)/sample, respectively. In addition, mg VCEAC values obtained from the total antioxidant assay was in the increasing order of bark > root > leaf > flower > pod. Moreover, a strong correlation was also found between phenolic contents and antioxidant values indicating their influence in the found antioxidant activity, hence the bark extract can be employed as an ideal candidate for herbal based pharmaceutical product. Results of the present study also emphasize variation in the chemical composition as well as biological activity ensuring the importance of proper selection of particular part of the plant to evaluate their therapeutic potency. PMID- 24783777 TI - Activity of Kaempferia pandurata (Roxb.) rhizome ethanol extract against MRSA, MRCNS, MSSA, Bacillus subtilis and Salmonella typhi. AB - Temu kunci (Kaempferia pandurata (Roxb.)) has a number of benefits and one of these is antibacterial. The rhizome is said to have antibacterial activity against Streptococcus mutans, Lactocillus sp. and Candida albicans. The aim of the study is to test the antibacterial activity of Kaempferia pandurata (Roxb.) rhizome ethanol extract on methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative Staphylococci (MRCNS), methicillin sensitive Staphylococcus aureus (MSSA), Bacillus subtilis and Salmonella typhi. Antimicrobial activity of the extract was assayed by the microdilution method using Mueller Hinton Broth with sterilized 96 round-bottomed microwells to determine the Minimum Inhibitory Concentration (MIC) as well as to determine the time-kill activity. The MIC of the extract was 16 ppm for both Bacillus subtilis and MRSA; 8 ppm for both MSSA and Salmonella typhi and 4 ppm for MRCNS. Ethanol extract of Kaempferia pandurata (Roxb.) showed antibacterial activity against all the tested bacteria and was the most potent against MRCNS, with MIC 4 ppm. The killing profile test of the extract displayed bactericidal activity at 8-16 ppm against MRSA, MSSA, Bacillus subtilis and Salmonella typhi and bacteriostatic activity at 4 ppm towards MRCNS. PMID- 24783778 TI - Assessment of genetic diversity and relationships among Egyptian mango (Mangifera indica L.) cultivers grown in Suez Canal and Sinai region using RAPD markers. AB - DNA-based RAPD (Random Amplification of Polymorphic DNA) markers have been used extensively to study genetic diversity and relationships in a number of fruit crops. In this study, 10 (7 commercial mango cultivars and 3 accessions) mango genotypes traditionally grown in Suez Canal and Sinai region of Egypt, were selected to assess genetic diversity and relatedness. Total genomic DNA was extracted and subjected to RAPD analysis using 30 arbitrary 10-mer primers. Of these, eleven primers were selected which gave 92 clear and bright fragments. A total of 72 polymorphic RAPD bands were detected out of 92 bands, generating 78% polymorphisms. The mean PIC values scores for all loci were of 0.85. This reflects a high level of discriminatory power of a marker and most of these primers produced unique band pattern for each cultivar. A dendrogram based on Nei's Genetic distance co-efficient implied a moderate degree of genetic diversity among the cultivars used for experimentation, with some differences. The hybrid which had derived from cultivar as female parent was placed together. In the cluster, the cultivars and accessions formed separate groups according to bearing habit and type of embryo and the members in each group were very closely linked. Cluster analysis clearly showed two main groups, the first consisting of indigenous to the Delta of Egypt cultivars and the second consisting of indigenous to the Suez Canal and Sinai region. From the analysis of results, it appears the majority of mango cultivars originated from a local mango genepool and were domesticated later. The results indicated the potential of RAPD markers for the identification and management of mango germplasm for breeding purposes. PMID- 24783779 TI - Heavy metals concentration relationship with Perna viridis physical properties in Mengkabong Lagoon, Sabah, Malaysia. AB - Perna viridis (P. viridis) has been identified as a good biological indicator in identifying environmental pollution, especially when there are various types of Heavy Metals Accumulations (HMA) inside its tissue. Based on the potential of P. viridis to accumulate heavy metals and the data on its physical properties, this study proffers to determine the relationships between both properties. The similarities of the physical properties are used to mathematical model their relationships, which included the size (length, width, height) and weight (wet and dry) of P. viridis, whilst the heavy metals are focused on concentrations of Pb, Cu, Cr, Cd and Zn. The concentrations of metal elements are detected by using Flame Atomic Adsorption Spectrometry. Results show that the mean concentration of Pb, Cu, Cr, Cd, Zn, length, width, height, wet weight and dry weight are: 1.12 +/ 1.00, 2.36 +/- 1.65, 2.12 +/- 2.74, 0.44 +/- 0.41 and 16.52 +/- 10.64 mg kg(-1) (dry weight), 105.08 +/- 14.35, 41.64 +/- 4.64, 28.75 +/- 3.92 mm, 14.56 +/- 3.30 and 2.37 +/- 0.86 g, respectively. It is also found out that the relationships between the Heavy Metals Concentrations (HMA) and the physical properties can be represented using Multiple Linear Regressions (MLR) models, relating that the HMA of Zinc has affected significantly the physical growth properties of P. viridis. PMID- 24783780 TI - Restriction analyze of starch synthesis genes in Amaranth mutant lines. AB - The increase interest and study of underutilized and neglected crops is actual for the last years. In the study, the restriction polymorphisms of GBSSI and SSSI gene in gamma-irradiated mutant lines of amaranth was performed. To evaluate polymorphisms of restriction sites endonucleases AciI, BsaJI, FatI EcoRI, BamHI, PstI, HpaII and PciI were used. GBSSI gene responsible to amylose synthesis was digested with HpaII and PciI restriction endonucleases. Two PciI restriction sites and three HpaII restriction sites were evaluated and any changes in restriction sites were recorded. Profile changes of the SSSI gene in mutant lines C 15/1 and C 236/1 were recorded after the restriction digest by BsaJI. Restriction cleavage polymorphism was recorded after the restriction digest of segment 5250-6854 bp with restriction endonuclease FatI, too. PMID- 24783781 TI - Poultry farm hygiene: microbiological quality assessment of drinking water used in layer chickens managed under the battery cage and deep litter systems at three poultry farms in southwestern Nigeria. AB - Water troughs from deep litter and caged chicken water troughs (drinkers) fixed to each of the different 3-tier cages containing layer chickens in Farms A, B and C were subjected to a 7-day study which involved the monitoring of poultry farm hygiene. Drinkers were washed before filling with water on Day 1. For Days 3, 5 and 7 water was served without prior washing. The occurrence and characterization of the bacteria isolates were investigated and data obtained were analyzed and compared. For the bacterial count on Day 1, for layer chickens on cage system, no significant differences (p > 0.05) among the farms and between the farms tier interactions. On Day 3, no significant difference (p > 0.05) among the parameters. On Day 5, there was significant difference (p<0.05) among the farms and on Day 7, there was high significant difference (p < 0.01) among the farms. On Days 5 and 7, there were no significant differences (p>0.05) among the tiers nor between the interactions of the farms and tiers. The bacterial count in water troughs of layer chickens in deep litter system, on Day 1, had no significant differences (p > 0.05) between the farms, water troughs and their interactions. On Day 3, no significant difference (p > 0.05) among the parameters. On Days 5 and 7, there were significant difference (p<0.05) and a high significant difference (p < 0.01) between the farms respectively. On Days 5 and 7, no significant differences between the water troughs and between the interaction of the farms and the water troughs. Farm A isolates contained Staphylococcus aureus, Proteus vulgaris, Streptococcus faecalis, Escherichia coli, Staphylococcus epidermis, Klebsiella sp., Salmonella sp., Bacillus subtilis, Lactobacillus salivarius and Corynebacterium sp. Farm B had Staphylococcus aureus, S. epidermis, Bacillus subtilis, Corynebacterium sp., Escherichia coli, Streptococcus faecalis and Klebsiella sp. while for Farm C, apart from the prevalent bacteria isolates obtained in Farms A and B, additional 2 bacterial isolates, Lactobacillus salivarius and Pseudomonas aeuriginosa were found. In conclusion, water troughs when cleaned on daily basis carry minimum bacterial load. Those left for 3, 5 and 7 days uncleaned had progressively high bacterial loads, suggesting that the flock of birds and the consumers of the eggs and meat from the chickens are at risk of bacterial infection unless strict farm hygiene is ensured through regular monitoring. PMID- 24783782 TI - Bioinformatical evaluation of desiccation-responsive rd29A gene in Arabidopsis thaliana. AB - In Arabidopsis thaliana expression of two Desiccation-Responsive rd29 genes are intensity induced under drought, salinity and temperature (heat and cold) conditions. These two genes called, rd29A and rd29B are located in 8-9 Kb of Arabidopsis genome. Also, transgenic plants containing these genes have more tolerant toward environmental stresses. Since rd29A has an important role in various non-biological stresses, in this study genetic and promoter analysis of this gene was performed, rd29A nucleotide sequence was obtained from NCBI gene bank, for bioinformatic analysis used the Map viewer, Plant care and Genevestigator software. In Arabidopsis rd29A has 8048 nucleotides and encode a linear mRNA with 2133bp. It located at AT5G52310 locus on chromosome 5 between nucleotides 21241898 and 21242457 and contains 4 exons and 3 introns. Promoter region analysis to determine the gene regulatory elements performed with using 1500 bp of the 5 'UTR sequence and the results indicated that the existence of diverse regulatory elements such as ABRE, DRE, Box I, C-repeat/DRE and TCA element which represent involvement of this gene in different physiological pathways in plants. In addition the TATA-Box was identified as Core promoter in 30 position. Also, the pattern of gene expression was examined by Microarrays data and it was found that the expression levels were variable in different developmental stages, so that the lowest and highest expressions were in germination and mature stages. It seems that using of this gene promoter in expression cassettes can raise tolerance of transgenic plants to environmental stresses. PMID- 24783783 TI - Efficiency of local Indonesia honey bees (Apis cerana L.) and stingless bee (Trigona iridipennis) on tomato (Lycopersicon esculentum Mill.) pollination. AB - Tomato (Lycopersicon esculentum Mill.) is considered as one of major agricultural commodity of Indonesia farming. However, monthly production is unstable due to lack of pollination services. Common pollinator agent of tomatoes is bumblebees which is unsuitable for tropical climate of Indonesia and the possibility of alteration of local wild plant interaction with their pollinator. Indonesia is rich with wild bees and some of the species already domesticated for years with prospect as pollinating agent for tomatoes. This research aimed to assess the efficiency of local honey bee (Apis cerana L.) and stingless bee (Trigona iridipennis), as pollinator of tomato. During this research, total visitation rate and total numbers of pollinated flowers by honey bee and stingless bee were compared between them with bagged flowers as control. Total fruit production, average weight and size also measured in order to correlated pollination efficiency with quantity and quality of fruit produced. Result of this research showed that A. cerana has slightly higher rate of visitation (p>0.05) and significantly shorter handling time (p < 0.05) than T. iridipennis due to their larger colony demand and low reward provide by tomato flowers. However, honey bee pollinated tomato flowers more efficient pollinator than stingless bee (80.3 and 70.2% efficiency, respectively; p < 0.05) even though the average weight and size of tomatoes were similar (p>0.05). Based on the results, it is concluded that the use of Apis cerana and Trigona spp., for pollinating tomatoes in tropical climates could be an alternative to the use of non-native Apis mellifera and bumblebees (Bombus spp.). However, more researches are needed to evaluate the cost/benefit on large-scale farming and greenhouse pollination using both bees against other bee species and pollination methods. PMID- 24783784 TI - Interrelationship and path coefficient analysis of yield components in F4 progenies of tef (Eragrostis tef). AB - This experiment was conducted at Debre Zeit and Akaki during 2004-2005 cropping season on F2-derived F4 bulk families of three crosses, viz, DZ-01-974 x DZ-01 2786, DZ-01-974 x DZ-Cr-37 and Alba x Kaye Murri. To estimate the correlations and path coefficients between yield and yield components, 63 F4 families were taken randomly from each of the three crosses. The 189 F4 families, five parents and two checks were space planted following in 14 x 14 simple lattice design. Study of associations among traits indicated that yield was positively associated with shoot biomass, harvest index, lodging index and panicle kernel weight at phenotypic level at Debre Zeit. At Akaki, yield had significant positive correlation with shoot biomass, harvest index, plant height, panicle length and panicle weight. At genotypic level, grain yield per plot exhibited positive association with harvest index, shoot biomass, lodging index and panicle kernel weight at Debre Zeit. By contrast, days to heading, days to maturity, plant height and panicle length showed negative association with yield. At Akaki, kernel yield per plot was positively correlated at genotypic level with all the traits considered where lodging index had the highest correlation followed by shoot biomass, panicle kernel weight and harvest index. Path coefficient analysis at both phenotypic and genotypic levels for both the locations suggested those shoot biomass and harvest indexes are the two important yield determining traits. These two traits might be useful in indirect selection for yield improvement in the material generated from the three crosses under consideration. PMID- 24783785 TI - Influence of nutrient composition and plant growth regulators on callus induction and plant regeneration in glutinous rice (Oryza sativa L.). AB - The potential for callus induction and regeneration depends on nutrient composition and plant growth regulators. The aim of the present study was to investigate the effect of nutrient composition and plant growth regulators on callus induction and plant regeneration in the glutinous rice cultivar Khunvang. The effect of 2,4-D concentrations (1, 2, 3, 4 and 5 mg L(-1)) on callus induction and growth were investigated. The results revealed that the highest percentage of callus induction (97%) was observed in MS medium supplemented with 5 mg L(-1) 2,4-D under 16 h Photoperiod. The effects of casein hydrolysate concentrations of casein hydrolysate (0, 300, 500, 700 and 900 mg L(-1)) and proline (0, 300, 500, 700 and 900 mg L(-1)) on callus induction and growth of Khunvang were also observed. The results indicated that the increasing casein hydrolysate and proline concentrations did not show a significant effect on callus growth. However, proline concentration of 900 mg L(-1) yielded 85.67% of callus growth. PMID- 24783786 TI - Prevalence of O157:H7 and non-O157 E. coli in Iranian domestic sheep. AB - The aim of the present study was the isolation of both E. coli O157 and non-O157 in sheep. Verotoxins (VT) 1, 2 and eae genes were tested for this propose. Sheep faces are an important source of Shiga toxin-producing Escherichia coli (STEC). Escherichia coli O157:H7 is a highly virulent food-borne pathogen and threat to public health. Rectal swab samples from sheep were collected during 2009-2010. Conventional plating and Polymerase Chain Reaction (PCR) were carried out according to virulence factors (Stx1, Stx2 and eaeA).There significant differences between prevalence of STEC and session were observed. It was at highest in spring and late summer. Six (3.92%) sheep carcasses were contaminated by E. coli O157:H7.Only six samples were positive by PCR specific for the VT2 gene and produced verocytotoxin VT2, whereas all isolates were negative for the presence of VT1 and eae virulence genes considered. Geographical variations and season may be influenced in the prevalence rate. The composition of the gastrointestinal flora may be changed by different diet and, therefore O157 STEC rate in sheep and lamb was different. Iranian sheep indicated as a natural host of E. coli O157 strains therefore, may be potentially pathogenic for humans. This is the first report of E. coli O157 detection from sheep in Iran. PMID- 24783787 TI - Occurrence of extended spectrum beta-lactamases producing alpha hemolytic Escherichia coli in neonatal diarrhea. AB - E. coli, often highly pathogenic in neonatal and immuno-compromised patients, are usually supposed susceptible to a variety of chemotherapeutic agents, however with the time and also due to the extensive use of chemotherapeutic agents irrespective of their susceptibility, have evolved drug resistant strains. Moreover, the production of extended spectrum beta-lactamases producing enteric pathogens is a serious issue. In this context the present study was conducted to find out occurrence of extended spectrum Beta-lactamases producing alpha hemolytic Escherichia coli in neonates, of less than one month of age, suffering from diarrhea. Fecal samples were collected from various private hospitals in Mathura and Agra districts of Uttar Pradesh, India. With the help of hospital nursing staffs sterilized stool samples were collected and processed for isolation of E. coli. The double disk diffusion method was applied to assess the ESBL production. E. coli organisms were isolated from 39 kids out of 120 samples. The assessment of isolates revealed alpha hemolytic nature of 23 isolates on 5% sheep blood agar. As usual when drug sensitivity was performed that revealed their multi drug resistance pattern which on further examination with double disk method showed 17 of them to be extended spectrum beta-lactamases producing E. coli. The presence of enterohemorrhagic extended spectrum beta-lactamases producing Escherichia coli in kids is a matter of concern and public health importance as it may be due to the transmission from hospital itself during the birth time or post birth admission period. PMID- 24783788 TI - Anti-nutritional factors in the roots of a local cultivar of Moringa oleifera (Lam). AB - The evergreen plant, Moringa oleifera (Lam) has been known to have both medicinal and nutritional properties, thus its wide use in traditional medicine in Africa and Asia. The roots, in particular, have been reported to possess antibiotic, anti-tumour and anti-oxidative activities. This study therefore seeks to determine the levels of the anti-nutritional factors and other proximate analyses in the roots of a local cultivar of Moringa oleifera which might be responsible for such activities. The concentrations of oxalates and phytates in the roots were determined using the methods of Munro and Bassir and Griffith and Thomas, respectively. The methods of Association of Analytical Chemists (AOAC) were used to estimate the amount of tannins, saponins and cyanogenic glycosides while the Technicon sequential Multi-sample amino acid analyzer (TSM) was used determine the amino acid concentration in the roots. Tannins (45 mg 100 g(-1)) and oxalates (17.08 mg 100 g(-1)) were present in the roots at higher levels while saponins (4.20mg 100 g(-1)), cyanogenic glycosides (2.72 mg 100 g(-1)) and phytates (0.07 mg 100 g(-1)) occurred at much lower levels. The roots contained (Mean +/- Standard Error of mean) %crude lipid (6.33 +/- 1.64), %crude proteins (5.02 +/- 1.52), %carbohydrates (76.75), %ash (4.97 +/- 0.53) and %moisture (6.93 +/- 0.58). The roots lacked the water-soluble vitamins pyridoxine, riboflavin and thiamine but contained ascorbic acid (48.13 mg 100 g(-1)) and niacin (5.83 mg 100 g(-1)). This study has shown that Moringa oleifera roots are rich in anti nutritional factors and that is why they are widely used in traditional medicine in Africa, Asia and Americas for its medicinal importance. PMID- 24783789 TI - Thyroid stimulating hormone assay as the first line biochemical parameter to determine thyroid gland abnormalities. AB - Increased cellular catabolic activities observed in hyperthyroid state had been established. This is consequent to excessive hormones secreted by the thyroid gland during this condition. A total of 60 subjects comprising of 45 females mean age 43.02 +/- 1.90 (range 22-70 years) and 15 males mean age 50.40 +/- 3.59 (range 25-68) and 60 controls comprising of 45 females mean age 41.18 +/- 1.68 (range 22-68 years) and 15 males mean age 40.53 +/- 2.88 (range 25-65) were recruited for the study. The plasma level of T4, T3 and TSH were determined in both the experiment group and the controls. A significant increase (p < 0.05) in plasma T4, T3 and a significant decrease (p < 0.05) in plasma TSH were observed in the experiment group in comparison to the controls. Also, an inverse relationship was noted to exist between the plasma T4 and T3; and TSH in primary hyperthyroid state. PMID- 24783790 TI - Enhanced root and shoot growth of wheat (Triticum aestivum L.) by Trichoderma harzianum from Turkey. AB - It is well known that Trichoderma species can be used as biocontrol and plant growth promote agent. In this study, Trichoderma harzianum isolates were evaluated for their growth promotion effects on wheat in greenhouse experiments. Two isolates of T. harzianum were used. The experimental design was a randomized complete block with three replications. Seeds were inoculated with conidial suspensions of each isolate. Wheat plants grown in steriled soil in pots. T. harzianum T8 and T15 isolates increased wheat length, root dry weight and shoot dry weight according to untreated control. Turkish isolates T8 and T15 did not produce damage in seeds nor in plants. PMID- 24783791 TI - Study on antioxidant potential of Murraya koenigii leaves in Wistar rats. AB - The antioxidant activity of Murraya koenigii (L.) Spreng (Family: Rutaceae), leaves was investigated in male wistar rats. Potassium dichromate was used to induce oxidative stress. The traditional medical literature describes its potential role as a source of many vitamins, flavonoids, phenols and domestic remedy for many human disorders. The whole plant is considered to be tonic, antidiarrhoeal, febrifuge, blood purifier and as stomachic. In the present study animals were divided into four groups Group I (Control), Group II (Potassium dichromate), Group III (Murraya koenigii + Potassium dichromate) and Group IV (Murraya koenigii). in vivo antioxidant activity of Murraya koenigii inhibited the toxicity of potassium dichromate. The GSH content in liver (1.79 +/- 0.019) and kidney (1.967 +/- 0.013) of Group IV rats significantly (p < 0.05) increased whereas, hepatic malondialdehyde content in liver (2.44 +/- 0.29) and kidney (2.34 +/- 0.057) was significantly (p < 0.05) reduced as compare to control. However, Chromate significantly (p < 0.05) decreased the reduced glutathione (GSH) content and increases hepatic malondialdehyde (MDA) content in both liver and kidney as compared to control. Further post treatment with Murraya koenigii (Group III) significantly (p<0.05) increase the GSH content in liver (1.54 +/- 0.013) and kidney (1.27 +/- 0.011) as compared to Group II whereas, hepatic malondialdehyde content in liver (4.24 +/- 0.71) and kidney (3.86 +/- 0.038) was significantly (p<0.05) reduced as compare to Group II(Potassium dichromate) These results clearly indicate that Murraya koenigii leaves have significant potential as a natural antioxidant agents. PMID- 24783792 TI - Plasmid curing analysis of antibiotic resistance in beta-lactamase producing Staphylococci from wounds and burns patients. AB - Hospitals worldwide are facing unprecedented crisis due to increasingly rapid emergence and dissemination of antimicrobial resistant staphylococci in wounds and burns and its environs via plasmid mediation. This study was conducted to evaluate the plasmid-mediated or chromosomal-mediated resistance in staphylococci. One hundred clinical swabs from wounds and burns patients were demonstrated for presence of staphylococci using mannitol salt agar. Various biochemical, DNase and beta-lactamase test was carried out and the plasmid curing assay was demonstrated using 0.1 mg mL(-1) acridine orange on antibiotic resistant isolates. The results revealed S. aureus (47) and coagulase negative staphylococci (CoNS) (6). beta-lactamase producing species of S. aureus were 14 and CoNS was 1. Most isolates showed high resistance pattern to gentamicin, ciprofloxacin, norfloxacin, rifampicin, chloramphenicol, ampiclox and others. The antibiotic resistance isolates were highly indicative ofplasmid-borne and few are chromosomal-borne after the plasmid curing analysis. The plasmid-mediated resistance observed among various antibiotics poses difficulty in treatment for clinicians. This high plasmid-mediated resistance among the isolates and from other studies calls for an urgent surveillance and epidemiological studies to infection control. PMID- 24783793 TI - Dietary effects of spaghetti waste as maize replacement in the diet of juvenile African catfish, Clarias gariepinus. AB - A 56-day experiment was conducted with Clarias gariepinus juvenile to evaluate the effects of replacing maize with Spaghetti Waste (SW). Four isonitrogenous experimental diets were formulated by substituting maize with spaghetti waste at different graded levels of 50, 75 and 100%, respectively with a control (100% maize). The experiment was run in triplicate and fish distributed into 21 plastic tanks. The fish were fed to satiation twice daily and water changed every two days to maintain good water quality. The weight of the fish was determined weekly by bulk weighing. The highest mean weight gain (106.40 +/- 4.59 g) and specific growth rate (2.96 +/- 0.07) were recorded in fish fed 100% SW, though no significant difference (p > 0.05) was recorded between the control and other test diets. There was significant increase (p < 0.05) in the feed intake with increased inclusion of the test ingredient. All the analysed blood parameters recorded significant difference (p < 0.05) except in the white blood cell. The proximate composition of carcass recorded significant difference (p < 0.05) for crude protein, while the ether extract and the dry matter were not significantly different (p > 0.05). The highest crude protein (59.33 +/- 0.50) was however recorded in 75% SW inclusion. This study showed that maize can totally be replaced with spaghetti waste without any adverse effect on the growth and health status of C. gariepinus. PMID- 24783794 TI - Changes in the activity of ascorbate peroxidase under anaerobiosis in cocoyam (Colocasia esculenta). AB - This study was conducted to determine the activity of ascorbate peroxidase in the cormels of cocoyam (Colocasia esculenta var. antiquorum) immediately after harvest and in storage under anaerobiosis for one and three weeks, respectively. During stress condition in plants, hydrogen peroxide is released and mechanisms to detoxify it must be maintained. The cocoyam tubers that were neither damaged nor affected by disease were harvested from a local farm in Ugbogui, Ovia North Local Government Area in Edo State, Nigeria. The selected cocoyam tubers were peeled manually, washed with ice cold water and cut into pieces. The root tissues (50 g) were homogenised with 100 mL of ice cold 0.05 M phosphate buffer. The extract obtained was clarified by centrifugation for 15 min at 8000 g at 4 degrees C. Ascorbate-peroxidising activity was assayed using the initial rate of decrease in ascorbate concentration as measured by its absorbance at 290 nm using Milton Roy Spectron 21D. Results showed the weight of the cormels decreased all through during storage. Immediately after harvest the activity of ascorbate peroxidase was 15.49 unit mL(-1) with a significant increase (p < 0.05) after one week to 73.05 U mL(-1). Thereafter there was a significant decrease in activity of the enzyme after three weeks of storage to 33.33 U mL(-1). This increase in activity of ascorbate peroxidase after three weeks of storage may be related to increase in response to various biotic stresses. Therefore, manipulation of the capacity of cocoyam to tolerate anaerobiosis is a function of its ability to modulate the antioxidant enzymes' armory in case of need. PMID- 24783795 TI - Automatic alkaloid removal system. AB - This alkaloid automated removal machine was developed at Instrumentation Laboratory, Universiti Sultan Zainal Abidin Malaysia that purposely for removing the alkaloid toxicity from Dioscorea hispida (DH) tuber. It is a poisonous plant where scientific study has shown that its tubers contain toxic alkaloid constituents, dioscorine. The tubers can only be consumed after it poisonous is removed. In this experiment, the tubers are needed to blend as powder form before inserting into machine basket. The user is need to push the START button on machine controller for switching the water pump ON by then creating turbulence wave of water in machine tank. The water will stop automatically by triggering the outlet solenoid valve. The powders of tubers are washed for 10 minutes while 1 liter of contaminated water due toxin mixture is flowing out. At this time, the controller will automatically triggered inlet solenoid valve and the new water will flow in machine tank until achieve the desire level that which determined by ultra sonic sensor. This process will repeated for 7 h and the positive result is achieved and shows it significant according to the several parameters of biological character ofpH, temperature, dissolve oxygen, turbidity, conductivity and fish survival rate or time. From that parameter, it also shows the positive result which is near or same with control water and assuming was made that the toxin is fully removed when the pH of DH powder is near with control water. For control water, the pH is about 5.3 while water from this experiment process is 6.0 and before run the machine the pH of contaminated water is about 3.8 which are too acid. This automated machine can save time for removing toxicity from DH compared with a traditional method while less observation of the user. PMID- 24783796 TI - Promotion and computation of inhibitory effect on tyrosinase activity of herbal cream by incorporating indigenous medicinal plants. AB - Herbal cream imparts a chief role in regulating melanin production of skin. The phytoconstituents present in herbal cream impact biological functions of skin and contribute nutrients required for the healthy skin. In the present study, it was envisaged to prepare three batches of herbal cream (HC1, HC2 and HC3) containing ethanol extracts of Emblica officinalis (fruits), Daucus carota (root), Mangifera indica (leaves), Mentha arvensis (leaves), Terminalia arjuna (bark) and Cucumis sativus (fruits) and investigated the prepared cream for inhibitory effect on tyrosinase activity. The herbal cream was formulated by incorporating different ratio of extracts, by using cream base. Each formulation HC1, HC2 and HC3 were segregated into three different formulations (HC1.1, HC1.2, HC1.3, HC2.1, HC2.2, HC2.3, HC3.1, HC3.2 and HC3.3) by incorporating increasing ratio of extract in formulation. The HC3.2 cream produces highest tyrosinase inhibitory effect 65.23 +/- 0.07%, while the HC2.1 exhibited minimum tyrosinase inhibitory effect 26.19 +/- 0.08% compared to other prepared cream. Comparison of the inhibitory activity of the formulations demonstrated that the rank order was HC3.2 > HC3.3 > HC1.2 > HC1.3 > HC3.1 > HC1.1 > HC2.3 > HC2.2 > HC2.1. It has been observed from the result that the formulations of antityrosinase activity were not concentrate dependent. This finding suggests that decrease in antityrosinase activity of HC1 and HC3 might be considering that the incompatibility of the higher extract content with the base of cream. The HC3 produce the maximum inhibitory effects on tyrosinase activity might be due to higher level of polyphenol and flavonoids present in extracts. PMID- 24783797 TI - Loop-mediated isothermal amplification of DNA (LAMP): a new diagnostic tool lights the world of diagnosis of animal and human pathogens: a review. AB - Diagnosis is an important part in case of animal husbandry as treatment of a disease depends on it. Advancement in molecular biology has generated various sophisticated tools like Polymerase Chain Reaction (PCR), its versions along with pen-side diagnostic techniques. Every diagnostic test however has both advantages and disadvantages; PCR is not an exception to this statement. To ease the odds faced by PCR several non-PCR techniques which can amplify DNA at a constant temperature has become the need of hour, thus generating a variety of isothermal amplification techniques including Nucleic Acid Sequence-Based Amplification (NASBA) along with Self-Sustained Sequence Replication (3SR) and Strand Displacement Amplification (SDA) and Loop mediated isothermal amplification (LAMP) test. LAMP stands out to be a good and effective diagnostic test for empowering in developing countries as it does not require sophisticated equipments and skilled personnel and proves to be cost-effective. Performance of LAMP mainly relies on crafting of six primers (including 2 loop primers) ultimately accelerating the reaction. LAMP amplifies DNA in the process pyrophosphates are formed causing turbidity that facilitates visualisation in a more effective way than PCR. The Bst and Bsm polymerase are the required enzymes for LAMP that does not possess 5'-3' exonuclease activity. Results can be visualized by adding DNA binding dye, SYBR green. LAMP is more stable than PCR and real-time PCR. Non-involvement of template DNA preparation and ability to generate 10(9) copies of DNA are added benefits that make it more effective than NASBA or 3SR and SDA. Thus, it fetches researcher's interest in developing various versions of LAMP viz., its combination with lateral flow assay or micro LAMP and more recently lyophilized and electric (e) LAMP. Availability of ready to use LAMP kits has helped diagnosis of almost all pathogens. LAMP associated technologies however needs to be developed as a part of LAMP platform rather than developing them as separate entities. This review deals with all these salient features of this newly developed tool that has enlightened the world of diagnosis. PMID- 24783798 TI - Dermatological consequences of photosensitization with an approach to treat them naturally. AB - Photosensitization is a process in which the skin reacts to exposure to ultraviolet radiations. There are various associated dermatological consequences like photoxicity and photoallergic reactions which make the disease more complicated. There are various drugs which together with solar radiations worsen the situation of photosensitivity and hence termed as photosensitizers. The developments on the use of phytoconstituents from the herbal extract is the ardent need for fighting against the deleterious photosensitization reactions. This review attempts to highlight the problems of photosensitivity its pathological manifestation with the approach to treat them naturally with the help of skin rejuvenating herbs. PMID- 24783799 TI - Isolation, culture optimization and physico-chemical characterization of laccase enzyme from Pleurotus fossulatus. AB - Pleurotus fossulatus (Cooke) Sace is member of oyster mushroom can produced extracellular laccase (benzenediol: oxygen oxidoreductase; EC 1.10.3.2) in submerged fermentation. To analyze the optimum production for laccase P. fossulatus was cultured both in stationary and shaking condition in different media. Partial purification of laccase was done after 0-80% ammonium sulphate precipitation, followed by DEAE (Diethylaminoethyl) Sephadex (A-50) anion exchange chromatography. Potato-sucrose peptone (PSP) medium and Potato-dextrose (PD) medium showed highest laccase production in shaking and stationary conditions, respectively. Though the time required for optimum laccase production in stationary condition was much more than the shaking condition but the amount of laccase was about 2.75t greater in former condition. The laccase produced in stationary condition was more stable than the enzyme produced in shaking condition. The partially purified enzyme showed highest affinity towards o dianisidine than guaiacol and ABTS (2,2'-Azino-bis (3-ethylbenzothiazoline-6 sulfonic acid) as evidenced by their K(m). The physico-chemical properties of the laccase suggested the significance of this enzyme in industrial applications. PMID- 24783800 TI - Population structure and genetic diversity of a medicinal plant species Retama raetam in southern Tunisia. AB - Retama raetam is a stem-assimilating, C3, evergreen, medicinal plant species, desert legume common to arid ecosystems around the Mediterranean basin. This study addresses the genetic diversity and relationship among and within three populations collected from different habitats in southern Tunisia by Random Amplified Polymorphic DNA (RAPD). Estimates of the percentage of polymorphic bands, Shannon's diversity information index and Nei's gene diversity index were determined. Results showed that population from the Island Djerba has the lowest Nei's gene diversity; this also was for Shannon diversity index. An analysis of molecular variance indicated that the majority of variation existed within populations (68%) and that there was significant differentiation among populations (phiPT = 0.316, p < 0.001). Genetic distance (phiPT based values) between pairwise populations ranged from 0.098 to 0.505 and the differentiation between pair-wise populations was significant when individual pairs of populations were compared. Based on the coefficient of gene differentiation (Gst), gene flow (Nm) was estimated and was found to vary from 0.490 to 4.609 between pair-wise populations and 1.42 among populations. The results of UPGMA cluster analysis and PCoA analysis indicated that most variation occurred within populations and that genetic differentiation had happened between populations. These findings are important for a better understanding of the adaptive strategy of R. raetam in southern Tunisia and will be useful for conservation managers to work out an effective strategy to protect this important species. PMID- 24783801 TI - Culture of Borrelia persica and its flagellar antigen in vitro. AB - Borrelia persica is a strain seen only in the Middle East and responsible for relapsing fever. These spirochetes are notable for multiphasic antigenic variation of polymorphic outer membrane lipoproteins, a phenomenon responsible for immune evasion. Diagnosis of the disease is a problem and requires a fixed antigen like the flagellar antigen. In vitro culture of B. persica was carried out for the first time and flagellar antigen was purified from culture. 10% SDS was added to the mixture to dissolve the cell wall and then the solution was sheared in an Omni mixer. Electron microscopy confirmed the purity of a 42 KDa periplasmic antigen as revealed by SDS-PAGE. Indirect haemagglutination kits were designed using the pure flagella and tested for cross reactivity with another relapsing fever spirochaete Borrelia microtii positive serum. The kit showed 98% sensitivity and 95% specificity. PMID- 24783802 TI - Microbiological assessment of well water at different durations of storage. AB - Water is the most universally used single necessity of life. To attain a safe water quality to various communities, an understanding of water microbiology and chemistry is therefore imperative. In this study, well water at different storage durations of 0, 2, 4, 6 and 8 weeks were assessed for bacteriological quality using standard microbiological techniques. Black barrel-shaped plastic containers (300 liter capacity) were used for different storage durations. Water samples at the different storage durations were collected from each corresponding containers. Sterile swabs were used to sample the sides and bottom of the storage containers to determine the prevalence of specific bacteria present in the samples. The results obtained showed that 0 week storage had the highest (100.00 CFU mL(-1)) coliform counts while the lowest (28 CFU mL(-1)) was obtained for 8 weeks of storage. Escherichia coli were not found in 4, 6 and 8 weeks old water. 0 and 2 weeks old water contained E. coli and the mean values were 1.80 x 10(4) +/- 0.03 and 1.43 x 10(4) +/- 0.01 CFU mL(-1), respectively (p < 0.05). Salmonella organisms were found in the 0 week old water but absent in the 2, 4, 6 and 8 weeks old water. Shigella count (62.33 x 10(2) +/- 45.30 CFU mL(-1)) was highest in 4 week old water while the lowest (11.0 x 10(3) +/- 1.00 CFU mL(-1)) was found in 6 week old water (p < 0.05). Zero week old water had the lowest significant (p < 0.05) value of 0.35 x 10(4) +/- 0.05 CFU mL(-1) for mesophilic bacteria and the highest value of 50.00 x 10(4) +/- 10.0 CFU mL(-1) was recorded in the 8 weeks old water. Sides and bottom samples were contaminated with coliforms, E. coli, Salmonella and Shigella organisms. It was concluded that the variously stored well water samples were contaminated with bacteria and the values obtained were above the recommended standards by the World Health Organization (WHO). PMID- 24783803 TI - Screening of multiple metal and antibiotic resistant isolates and their plant growth promoting activity. AB - Heavy metal contamination has accelerated due to the rapid industrialization world wide. Accumulation of metals in excess can modify the structure of essential protein or can replace an essential element. Bradyrhizobium strains showed tolerance to cadmium, chromium, nickel, lead, zinc and copper. All the isolates showed maximum tolerance towards lead and zinc which was followed by nickel and chromium. These strains also showed tolerance towards most of the antibiotics. Bradyrhizobium strains were also tested for their Plant Growth Promoting (PGP) substances, all isolates produced good amount of indole acetic acid and were positive for ammonia but only three strains were positive for HCN and siderophore (RM1, RM2 and RM8), the rest isolates showed negative result. Based on the above intrinsic abilities of Bradyrhizobium species, these strains can be used for the growth promotion, as well for the detoxification of the heavy metals in metal polluted soils. PMID- 24783804 TI - Evaluation of biomass of some invasive weed species as substrate for oyster mushroom (Pleurotus spp.) cultivation. AB - This study assessed the bioconversion of Agriculture wastes like invasive weeds species (Lantana camara, Prosopis juliflora, Parthenium hysterophorus) as a substrate for oyster mushroom (Pleurotus species) cultivation together with wheat straw as a control. The experiment was laid out in factorial combination of substrates and three edible oyster mushroom species in a Completely Randomized Design (CRD) with three replications. Pleurotus ostreatus gave significantly (p < 0.01) total yield of 840 g kg(-1) on P. hysterophorus, Significantly (p < 0.01) biological efficiency (83.87%) and production rate of 3.13 was recorded for P. ostreatus grown on P. hysterophorus. The highest total ash content (13.90%) was recorded for P. florida grown on L. camara. while the lowest (6.92%) was for P. sajor-caju grown on the P. juliflora. Crude protein ranged from 40.51-41.48% for P. florida grown on P. hysterophorus and L. camara. Lowest crude protein content (30.11%) was recorded for P. ostreatus grown on wheat straw. The crude fiber content (12.73%) of P. sajor-caju grown on wheat straw was the highest. The lowest crude fiber (5.19%) was recorded for P. ostreatus on P. juliflora. Total yield had a positive and significant correlation with biological efficiency and production. Utilization of the plant biomass for mushroom cultivation could contribute to alleviating ecological impact of invasive weed species while offering practical option to mitigating hunger and malnutrition in areas where the invasive weeds became dominant. PMID- 24783805 TI - Whey powder: a potential anti-diarrheal agent through its biofilm formation. AB - Whey, the natural product resulting from coagulation of milk is reported to have diverse pharmaceutical credentials. In the present investigation the anti diarrhoeal activity of the whey powder was investigated. The Whey powder which was prepared using rennet powder and lactic acid, was studied against Magnesium sulphate-induced Diarrhea in Swiss Albino mice. Castor oil-induced enteropooling studies and in vitro biofilm-forming potentials of the whey powder were also carried out, as this is believed to contribute to the anti-diarrhoeal activities of the preparation. Anti-diarrhoeal activity was more pronounced in mice which received 250 mg kg b.wt. of whey powder when compared to those which received 500 mg kg(-1) b.wt. The percentage inhibition of total number of feces in the 250 mg kg(-1) b.wt. drug-treated group was 56.14%,whereas the animals which received 500 mg kg(-1) b.wt. of whey powder showed 37.18% inhibition. The loperamide treated animal group showed 63.81% inhibition. In castor oil induced enteropooling, the percentage inhibition of intestinal content in the 250 mg kg(-1) b.wt. drug treated group was 61.42% against atropine-treated animal group that showed 26.24% inhibition. The whey powder also exhibited strong biofilm forming capacity with increase in concentration. The anti-diarrhoeal activity of whey preparation established herein is believed to be owing to certain active principles present in it or due to biofilm-forming capacity, which inhibits the attachment of mediators of diarrhoea to mucosal walls of the GI tract or due to interaction of diarrhoea inducing chemicals with whey peptides, which needs further investigation. PMID- 24783806 TI - Family physician program in Iran, patients satisfaction in a multicenter study. AB - Patient satisfaction is an integral component of service quality and obtaining feedback from patients about quality of primary healthcare is a powerful way to develop more patient-centered approaches to healthcare delivery. The aim of this study was to measure patients' satisfaction with family physician program in central provinces of Iran in the fall of 2010. A cross sectional survey was conducted at 60 medical centers with family physician services at central provinces of Iran. Patient satisfaction was measured by a standardized questionnaire with eight domains: personnel manner, time consumption, guidance and training, cost of services, service adequacy, capability and skills of personnel, adequacy of equipment and amenities. Student t test, Analysis of Variance (AVOVA) and Kruskal-Wallis test were used in data analysis. Overall, 76.03% of the respondents were satisfied with the whole performance of family physician program, 76.41% of the respondents were satisfied with the family physicians. The strongest domains of client satisfaction were the manner of staffs and adequacy of equipments. It was shown that high patient satisfaction with the family physician was the most powerful predictor of patients' satisfaction with the program. A considerable proportion of patients are unsatisfied with guidance and training and adequacy of program services. Iranian policymakers can develop better programs based on comments from service recipients and promoting the project and some program processes. PMID- 24783807 TI - Morphological observation and length-weight relationship of critically endangered riverine catfish Rita rita (Hamilton). AB - The experiment was conducted to investigate the morphological status of the critically endangered riverine catfish Rita rita using morphometric and meristic traits. About 158 species of Rita were collected from the old Brahmaputra river in Mymensingh district and were studied in the laboratory of the Fisheries Biology and Genetics Department, Bangladesh Agricultural University. Measurement of length and weight of Rita were recorded by using measuring scale and electric balance respectively. Significant curvilinear relationship existed between total length and other morphometric characters and between head length and other characters of the head. Relationships between total length and various body measurements of the fish were highly significant (p < 0.01) except the relationship between total length and pelvic fin length of male fish (p < 0.05). In case of meristic characters-dorsal fin rays, pelvic fin rays, pectoral fin rays, anal fin rays, caudal fin rays, number of vertebrae and branchiostegal rays were found to be more or less similar except slight differences. The values of condition factors (k) in the total length body-weight relationships for female and male were found to be 0.41 and 0.38, respectively. The mean values of relative condition factors (kn) were 1.0 and 1.005 for female and male, respectively. PMID- 24783808 TI - The effect of ginger extract on glycoproteins of Raji cells. AB - Protein glycosylation is associated with the development and progression of specific diseases, including cancers. The ginger rhizome is known to have anti cancer and anti-fungal properties. This investigation was carried out to study the effect of ginger on glycoproteins of Raji cells. A 10% yield of ginger extract was mixed with 0.01% DMSO and added to 6 x 10(4) Raji cells at different concentrations for 24, 48 and 72 h at 37 degrees C. Their half maximal inhibitory concentration (IC50) was determined and analyzed statistically using Graphpad prism software. Cell extracts were prepared and their glycoproteins purified using lectin-affinity chromatography (Q proteome total glycoprotein and O glycoprotein kits) and SDS PAGE was carried out. IC50 of ginger extract on Raji cells was 20 microg mL(-1) at 72 h with < 0.01 significance. Silver staining of purified glycoprotiens in Raji cells indicated the presence of O-glycans and N glycans. N-linked mannose and N-linked sialic acids were detected with the total glycoprotein kit. O-linked galactose and O-linked sialic acids were identified with the O-glycoprotein. Ginger reduced the expression of O-linked sialic acid and also N-linked mannose on Raji cells but had no effect on other glycoproteins. Sialic acid is now well known as a cancer marker and investigations are on to use it as a drug-target in cancerous tissues. PMID- 24783809 TI - Decolourization of synthetic textile dyes using the edible mushroom fungi Pleurotus. AB - The ability of three Pleurotus species (P. florida LCJ 65, P. ostreatus LCJ 183 and P. sajorcaju LCJ 184) was compared for the decolourization of bromophenol blue, brilliant green and methylred using by solid and liquid medium. All three Pleurotus species were effective in decolourizing the dyes on potato dextrose agar plate. During quantitative decolourization experiments, the absorption spectrum of the dye solution showed a steady decrease in decolourization with the increase in the days of incubation. The decolourization efficiency varied for species to species and it was found that P. sajorcaju LCJ 184 effectively decolourized the selected dyes by 85-98%. In present study, different factors (dye concentration, inoculums size, pH, static and shaking culture conditions) influencing the ability of Pleurotus species to decolourize three different dyes is documented and the result proposes P. florida LCJ 65 and P. sajorcaju LCJ 184 as potential strains for decolourization ofbromophenol blue, brilliant green and methylred dye. PMID- 24783810 TI - Epinephrine promotes development potential of vitrified mouse oocytes. AB - Cryopreserved oocytes show low developmental ability. To understand the mechanism underlying their development impairment, study was designed to determine the effect of epinephrine on the in vitro developmental competence of vitrified mouse oocytes. Mature oocytes were vitrified using Open Pulled Straw (OPS) method. The vitrified oocytes were warmed and introduced into M2 medium which contains epinephrine at different concentrations (10(-2), 10(-4), 10(-6), 10(-8) mol L(-1) in an incubator for 1 h. Then the survival rate of the oocytes was evaluated and the subsequent development of oocytes was assessed through in vitro Fertilization (IVF). Furthermore, the levels of intracellular ROS, GSH and the concentration of ATP were determined among 10(-4) mol L(-1) epinephrine-treated group, vitrification group and fresh group. Results showed that vitrified oocytes treated with 10(-4)) mol L(-1) epinephrine had significant higher rates of cleavage (66.4 vs.45.2%) and blastocyst (47.2 vs. 34.7%) than no epinephrine treated group, as well as more blastocyst cells (54.5 vs. 36.8) and lower ratio of apoptotic cells (5.9 vs. 21.5%; p < 0.05). Further experiment found that 10( 4) mol L(-1) epinephrine treatment could significantly reduce intracellular ROS level and enhance cytoplasmic ATP concentration (p < 0.05), but there was no different in GSH level compared to vitrification group. In conclusion, epinephrine could promote vitrified oocytes cryosurvival and their subsequent development ability, which maybe related with the changes of intracellular ROS level and ATP content. PMID- 24783811 TI - Maternal-neonatal outcome in pregnancies with non-obstetric laparotomy during pregnancy. AB - In this study maternal and neonatal outcome evaluated in each trimester of pregnancies with non obstetric laparotomies. In this descriptive-analytic study, 100 pregnant women operated during pregnancy were evaluated. Based on available data a questionnaire comprising general information, kind of surgery as well as the maternal-neonatal outcome was fulfilled. These outcomes were compared in the different gestational ages. In this study, 28 (28%), 48 (48%) and 24 (24%) patients had been operated in the first, second and third trimester, respectively. The patients of these three groups were matched for general characters. Sixty one patients had appendectomy, 30 adnexal mass or torsion, 6% cholecystectomy, 3% abdominal mass. Maternal complications were recorded in 6, 3 and 9% patient in 3rd, 2nd and 1st trimester of pregnancy, respectively. Abortion in first trimester was 8.2%. Low apgar in fifth minute and asphyxia were higher in third trimester. Appendectomy was the most common surgery in the pregnancy. Maternal and fetal complications were higher in third and first trimester. Besides obstetric and pediatric consultation before surgery are necessary for optimal safety of the woman and the fetus. PMID- 24783812 TI - Ant-cuckoo colony optimization for feature selection in digital mammogram. AB - Digital mammogram is the only effective screening method to detect the breast cancer. Gray Level Co-occurrence Matrix (GLCM) textural features are extracted from the mammogram. All the features are not essential to detect the mammogram. Therefore identifying the relevant feature is the aim of this work. Feature selection improves the classification rate and accuracy of any classifier. In this study, a new hybrid metaheuristic named Ant-Cuckoo Colony Optimization a hybrid of Ant Colony Optimization (ACO) and Cuckoo Search (CS) is proposed for feature selection in Digital Mammogram. ACO is a good metaheuristic optimization technique but the drawback of this algorithm is that the ant will walk through the path where the pheromone density is high which makes the whole process slow hence CS is employed to carry out the local search of ACO. Support Vector Machine (SVM) classifier with Radial Basis Kernal Function (RBF) is done along with the ACO to classify the normal mammogram from the abnormal mammogram. Experiments are conducted in miniMIAS database. The performance of the new hybrid algorithm is compared with the ACO and PSO algorithm. The results show that the hybrid Ant Cuckoo Colony Optimization algorithm is more accurate than the other techniques. PMID- 24783813 TI - Evaluation of chemical, botanical and cultural managements of termites control. AB - The study was conducted at Bojdi Dirmaji District, Wollega Zone (Western Ethiopia) using Randomized Complete Block Design with three replications. Eight different treatments of chemical, botanical and cultural control methods independently and in combinations were evaluated to identify the most effective method which is environmentally sustainable and economically feasible in controlling the termite problems. The data were collected over 12 weeks and analysis of variance showed significant difference among the treatments for all parameters. Maesa lanceolata 100 g alone showed lower percent damage between 2-8 weeks (33.3%), later on after 9-12 weeks it become non significant and the destructed mound was recovered. Mound treated with Diazinon 60% EC at the rate of 25 and 20 mL alone and Diazinon 60% EC combination with queen removal at rate of 15 and 10 mL showed significant control overall the treatment. From the results of the study the lower rate of Diazinon 60% EC (10 mL per mound) and queen removal could be better option to manage the termite problem and could be more sustainable and integrated manner in the study area. PMID- 24783814 TI - Activity and stability of uricase from Lactobacillus plantarum immobilizated on natural zeolite for uric acid biosensor. AB - Determination of uric acid concentration in human urine and blood is needed to diagnose several diseases, especially the occurrence of kidney disease in gout patients. Therefore, it is needed to develop a simple and inexpensive method for uric acid detection. The purpose of the research was to observe the use of Indonesian microbe that was immobilized on natural zeolite as a source of uricase for uric acid biosensor. Selection of mediators and determination of optimum condition measurement, the stability and kinetic properties of L. plantarum uricase were performed using carbon paste electrode. Cyclic voltammetry was employed to investigate the catalytic behavior of the biosensor. The result indicated that the best mediator for measurement of L. plantarum uricase activity was Qo (2,3-dimethoxy-5-methyl-1,4 benzoquinone). Optimum conditions for immobilization of L. plantarum uricase on zeolite were obtained at pH 7.6, with temperature of 28 degrees C, using uric acid concentration of 0.015 mM and zeolite mass at 135 mg K(M) and V(Max) of L. plantarum uricase obtained from Lineweaver-burk equation for the immobilization uricase on zeolite were 8.6728 x 10(-4) mM and 6.3052 mM, respectively. K(M) value of L. plantarum uricase directly immobilized onto the electrode surface was smaller than K(M) value of L. plantarum uricase immobilized on zeolite. The smaller K(M) value shows the higher affinity toward the substrate. The Electrode when kept at 10 degrees C was stable until 6 days, however the immobilized electrode on zeolite was stable until 18 days. Therefore, Indonesian L. plantarum could be used as a uric acid biosensor. PMID- 24783815 TI - Biochemical and haematologic effects of intake of Macrotermes nigeriensis fortified functional diet. AB - Twenty-four male albino rats, 4 weeks old were randomly distributed into 4 groups (A-D) and fed growers' mash as the control diet and 25, 50 and 75% oven-dried, ground Macrotermes nigeriensis fortified diets respectively for a total period of 28 days. The effects of the diets on hepatic, renal and haematologic function indices of albino rats were studied. The animals fed the fortified diets had non significantly (p > 0.05) lesser body weight gains than the control animals. The fortified diets elicited dose-dependent increases in the levels of blood total protein, albumin, packed cell volume, hemoglobin and red blood cell counts as well as on the calculated red cell indices. The fortified diets did not significantly (p > 0.05) alter the activities of plasma alanine and aspartate aminotransferases as well as the concentrations of total bilirubin, urea and creatinine. The results indicate that the fortified diets do not have detrimental hepatic, renal or haematologic effects but rather may be recommended for fortification of human and animal food, especially in weaning diets of growing children and nursing mothers to combat food insecurity and malnutrition. PMID- 24783816 TI - Physico-chemical analysis of drinking groundwater of around Tehran by seasonal variation. AB - This study was a cross-sectional descriptive study and done in four seasons during April 2011 to March 2012.The objective of the present study was to examine Physico-chemical properties of groundwater around Tehran. The results are also compared with the guideline values of Iranian legislation. A total of 160 drinking water samples were collected from different drinking groundwater around the Tehran. Total Dissolved Solids (TDS), conductivity and pH, were measured by using standard methods and the concentration of ions Cl-, F-, NO3-, NO2-, Br-, SO4(2-), PO4(3-), Ca2+, K+, Na+ and NH4+ in groundwater was performed using Ion chromatography (Metrohm Company, USA) with standard method. This study showed that most of the parameters in groundwater were below the Iranian permissible limit except total dissolved solids (N = 2), conductivity (N = 2), nitrate as NO3 (N = 22), chloride (N = 3), sulphate (N = 2), fluoride (N = 3) and ammonia (N = 8). There were significant differences (p < 0.05) between physico-chemical parameters such as pH, nitrite (NO2-), sodium, potassium, sulphate, ammonia, bromide and phosphate in different seasons. These results are important, not only for the many people who drink groundwater but also for the health supervisory agencies such as Ministry of Health and Institute of Standards and Industrial of Iran (ISIRI) to have more effective control on groundwater. PMID- 24783817 TI - Effect of morphine and lacosamide on levels of dopamine and 5-HIAA in brain regions of rats with induced hypoglycemia. AB - The study aimed to determine the effect of morphine and lacosamide on levels of dopamine and 5-HIAA in a hypoglycemic model. Female Wistar rats (n = 30), mean weight of 180 g were treated as follow: Group 1 (control) received 0.9% NaCl, Group II; morphine (10 mg kg(-1)), Group III; lacosamide (10 mg kg(-1)), Group IV; insulin (10 U.I. per rat), Group V; morphine (10 mg kg(-1))+insulin, Group VI; lacosamide (10 mg kg(-1))+ insulin. All administrations were made intraperitoneally every 24 h, for 5 days. Animals were sacrificed after the last dose to measure the levels of glucose in blood; dopamine and 5-HIAA in cortex, hemispheres and cerebellum/medulla oblongata regions. Levels of glucose decreased significantly in animals treated with morphine, lacosamide and all groups that received insulin alone or combined with respect to control group. Levels of Dopamine diminished significantly in cortex and increased significantly in hemispheres of animals that received morphine. In cortex, 5-HIAA increase significantly in the groups treated with morphine, morphine+insulin and lacosamide+insulin, however a significant decrease of the same substance was witnessed in cerebellum and medulla oblongata of animals that received morphine or lacosamide plus insulin. GSH increased significantly in cortex and cerebellum/medulla oblongata of animals treated with morphine and lacosamide alone or combined with insulin. Lipid peroxidation decreased significantly in cortex and cerebellum/medulla oblongata of groups that received lacosamide alone or combined with insulin. These results indicate that hypoglycemia induced changes in cellular regulation while morphine and lacosamide are accompanied by biochemical responses. PMID- 24783818 TI - Effect of exercise on serum adiponectin and lipoprotein levels in male rat. AB - The effect of exercise and recovery period on adiponectin level is not still cleared. The aim of this study was to evaluate the effect of different intensities of running on serum adiponectin and lipoproteins levels in male rats. In this experimental study, one hundred and sixty rats aged 2 months years old (250 +/- 5 g) were randomly assigned into four groups including the control and the 3 groups running at the speeds of 18, 24 and 30 m min(-1) for 30 min. Serum adiponectin, Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL) levels were evaluated in four stages: Before running, immediately, 30 min and 5 h after the running finished. In different stages, 10 rats of each group were anesthetized and blood were collected from abdominal aorta. Serum adiponectin concentrations increased immediately after running in the rats ran with the speeds of 18, 24 and 30 m min(-1) in 30 min (p < 0.05). Thirty minute after running, serum adiponectin concentrations did not change only in the rats ran with the speed of 18 m min(-1) (p = 0.46). Five hours after running, serum adiponectin concentrations approximately reached into the before running levels in the rats ran with the speeds of 18, 24 and 30 m min(-1) (p < 0.05). There was no significant difference in serum LDL and HDL concentrations between and within rat groups (p > 0.05). Serum adiponectin concentrations rose when the running intensities in one exercise session increased in male rats. During recovery period, serum adiponectin concentrations decreased with the same pattern in different exercise intensities. PMID- 24783819 TI - Oral health and integrated care--the generational challenge. PMID- 24783820 TI - Address by the President of the Royal Australasian College of Dental Surgeons Werner H Bischof, BDSc, MDSc, FRACDS, MRACDS (perio), FPFA, FICD at the Opening Ceremony. PMID- 24783821 TI - Periodontal diseases: basic concepts, association with systemic health, and contemporary studies of pathobiology. PMID- 24783822 TI - "MI" caries management--an overview. AB - Minimum intervention dentistry, with its non-operative prevention and control of disease, underpins the basis of a patient-centred, team-based approach to managing dental caries in patients, who must take an active responsibility in maintaining their personal oral health. In patients where cavities are present causing pain, poor aesthetics and/or functional problems, restorations will need to be placed. Minimally invasive caries excavation strategies can be deployed depending on the patient's caries risk, lesion-pulp proximity and vitality, the extent of remaining supra-gingival tooth structure and clinical factors (e.g., moisture control, access) present in each case treated. Excavation instruments, including burs/handpieces, hand excavators, chemo-mechanical agents and/or air abrasives which limit caries removal selectively to the more superficial caries infected dentine and partial removal of caries-affected dentine when required, help create smaller cavities with healthy enamel/dentine margins. Using adhesive restorative materials, the operator can, if handling with care, optimize the histological substrate coupled with the applied chemistry of the material so helping to form a durable peripheral seal and bond to aid retention of the restoration as well as arresting the carious process within the remaining tooth structure. Achieving a smooth tooth-restoration interface clinically to aid the co-operative, motivated patient in biofilm removal, is an essential pre-requisite to prevent further secondary caries. PMID- 24783824 TI - The mutilated dentition--orthodontic considerations. PMID- 24783823 TI - The mutilated dentition--management of the debilitated dentition. AB - An interdisciplinary treatment plan is often required to allow restoration of function and aesthetics in the "mutilated dentition". Loss of teeth is associated with social and psycological impacts for the patient, however most often aesthetic requirements and financial constraints predominate in the treatment decision making. Historically, unfavourable occlusal contacts have been viewed as predisposing factors in the development of temporo-mandibular joint dysfunction (TMD). This linkage has now been refuted by many authors and it is understood that occlusion may be a co-factor only in TMD. In determining the "ideal occlusion" to restore the mutilated dentition consideration must be given to an occlusion that is physiologic for the patient, and the simplest scheme to construct from a clinical and technical view point. In successfully restoring function of the teeth an aesthetic outcome can be achieved. The planning and treatment for three patients is reviewed to highlight interdisciplinary patient care from a prosthodontics perspective. PMID- 24783825 TI - Caries management: is the "seal the deal"? AB - A barrier to providing sealants has been the concern about inadvertently sealing over caries, but today the management of dental caries has evolved from the domain of techniques based on complete removal of carious tissue prior to tooth restoration or sealant, to include a range of techniques where some, or even all caries is sealed in beneath restorations, sealants or infiltrants. There is a significant, and growing, evidence base supporting these techniques as caries management strategies for children and adolescents. These techniques are not new but build on earlier concepts and research. These concepts offer a real way forward and departure from invasive restorative treatments. Some issues, however, are not completely resolved, and future solutions may herald a new era of restorative dentistry, perhaps with the concept of filling with no drilling since the "seal is the deal". These techniques and issues will be considered in the New Zealand context. PMID- 24783826 TI - Molar incisor hypomineralization. AB - Molar Incisor Hypomineralization (MIH) is a common condition in New Zealand children and children around the world and can result in a significant defect in first permanent molars. This condition inevitably leads to a large amount of dental treatment for young children and may even result in the removal of their first permanent molars. This lecture will outline the understanding of the physical properties of these teeth and provide an evidence based review of the treatment options for affected teeth. PMID- 24783827 TI - Advances in gastroenterology--opportunities and challenges for the dental practitioner. AB - As the oral cavity marks the beginning of the gastrointestinal tract (GIT), it is not surprising that it frequently mirrors disease that occurs lower in the GIT. Increasingly, clinical signs in the oral cavity are recognized as future predictors and prognostic indicators of GIT and, indeed, other systemic disease. This paper discusses recent advances in the overlap area of Oral Medicine and Gastroenterology and the significant role of the dental practitioner in the management of these patients. PMID- 24783828 TI - Diagnosis and management of potentially malignant oral disorders. AB - The optimum management strategy for potentially malignant disorders remains a constant challenge as our present knowledge is still short of being conclusive. In spite of its shortcomings as an accurate predictive marker, the assessment of the severity of epithelial dysplasia continues to be useful in risk assessment. It is important to use a combination of epidemiological, clinical and histopathological input when deciding on the most appropriate management for an individual patient. Advanced research exploring molecular markers for diagnosis and risk predictions appear to be promising. However, these tests have not evolved to a stage that they could be used for routine diagnostics at the clinical setting. PMID- 24783829 TI - The multidisciplinary management of obstructive sleep apnoea. PMID- 24783830 TI - Obstructive sleep apnoea: investigations, diagnostic techniques and predicting surgical success. AB - Obstructive sleep apnoea (OSA) is diagnosed using a sleep study or Polysomnogram. The paper discusses the role of imaging and other examination techniques to assess the nature of OSA and what treatment you can offer a patient. When should a patient be offered a mandibular advancement splint? What type should be used? How do we know it is working? Surgical treatment of OSA is a controversial area. This paper provides an understanding of which patients may benefit from surgery and when is an appropriate time to refer. An overview of the three main types of surgery and their outcomes are discussed. Less experienced practitioners will feel better able to talk to patients about OSA and for those with a special interest in OSA there is new material to stimulate further discussion. PMID- 24783831 TI - The changing complexity of geriatric health care and the implications for oral health care for the individual and community. AB - Geriatric healthcare has already changed. We are living longer and we are enduring those additional years with more severe chronic disease and a greater number of chronic diseases. Current mechanisms to improve oral health care for individuals and the community are considered in this paper. We are still yet to measure the effectiveness of these changes. Even more complex is the confusion and conjecture about what we should be measuring and whether what we measure actually has an impact on the quality of life. PMID- 24783832 TI - Management of the medically compromised elderly. PMID- 24783833 TI - Informed consent, dementia and oral health care provision. AB - Managing patients with dementia requires a practitioner to exercise diverse skills. Communicating with the patient (as their dementia allows), relatives, caregivers and medical personnel are essential elements in the care process. Diagnosis of oral health problems may not be straightforward, clinical examination and treatment planning may be hampered by poor cooperation from the person with dementia. Practitioners must view any treatment from the patient's perspective and balance this with the requirements for sound clinical care. The consent process must be approached in a manner that fulfils the ethical responsibilities that acknowledge patient rights. This can be difficult when managing a patient with dementia. This paper will explore issues surrounding the consent process and the provision of oral health care to people suffering from dementia. It is hoped that readers will be stimulated to review their practice; especially related to informed consent, whether they routinely manage patients with dementia or not. Such practice evaluation should consider the wants and needs of patients and families on a broader than clinical basis and thus enhance the care that is brought to this group of interesting and often challenging patients. PMID- 24783834 TI - Workforce education--the co-ordination of oral health care for the elderly--the role of the dental profession. AB - It is a well-understood fact that the world's population is ageing. Concomitant with that is an increase in the chronicity of disease including dental disease. The challenges faced by the dental profession in managing patients as they age are becoming increasingly important. What do we know and understand about diseases and their impact on dental health in the elderly? What role do salivary dysfunction and biofilms play and how are these integrated with general and oral health? Are we really prepared to manage the impact of these factors and what is the profession doing to better equip itself for the inevitable change to dental practice that is likely to ensue? Dental education in Special Needs Dentistry and in particular geriatric care expands beyond the realms of the University setting. There is potential to expand knowledge in dental care amongst the elderly through continuing professional development that is now mandatory across Australia and New Zealand. Training should not be limited to University curricula. It should extend to include medical and allied health staff, staff in aged care facilities and all those involved in policy and decision making for the elderly. The aim of this paper is to address where education in geriatric oral health is currently placed and the role to be played by all key stakeholders from University to Community arenas. PMID- 24783835 TI - Periodontal treatment and systemic conditions. AB - It has been reported that patients with periodontal disease have a greater prevalence of systemic disease than the general population. Furthermore, we are faced with an ageing population that is retaining its teeth for longer, and tends to present for periodontal management with a variety of systemic conditions. There is ample evidence to show that periodontal treatment results in a systemic response, which includes bacteraemia and systemic inflammatory cytokine release. Certain systemic conditions present unique challenges in the treatment of periodontal disease. These conditions include cardiovascular disease, diabetes mellitus and cancer. The various treatment modalities for these systemic diseases can impact on periodontal treatment, and conversely periodontal treatment can influence systemic conditions and their management. Close collaboration with the treating physician and timely provision of periodontal treatment are important considerations of managing the systemically compromised patient. PMID- 24783836 TI - The role of the dentist in the management of systemic conditions. AB - The rates of lifestyle-related diseases are increasing. Worldwide there is an obesity epidemic, one of the consequences of which is an overwhelming increase in type 2 diabetes, not only in adults, but also in children and adolescents. Many cases are currently undiagnosed resulting in serious complications and placing individuals at increased risk for cardiovascular disease. As many diseases share common risk factors, the current emphasis is on primary prevention and risk assessment by all health care providers to enable detection and early intervention. Lifestyle factors that impact on oral health can also have an impact on general health, and lifestyle behaviours that promote better oral health can decrease the risk for chronic disease. In this context, changing oral health behaviour to promote better oral health may directly impact on improving general health for all age groups. Risk assessment for systemic diseases in the dental setting is explored to provide dental professionals with a framework for promoting better overall health for their patients. PMID- 24783837 TI - Non-prescription medications: considerations for the dental practitioner. AB - The widespread availability of non-prescription medications has a significant potential impact on dental practice. Dentists are trained to provide scientifically-based advice on the appropriate use of medications, but it is not uncommon for patients to take matters into their own hands, especially if it is felt that the treatment provided is not solving a specific problem, or is insufficient. Well-meaning but often ill-informed family and friends frequently have an opinion as to what should be done. Not only may the suggested treatment not be effective, it may also be harmful. Over-the-counter medications can easily be obtained, and there is nothing to stop individuals exceeding recommended doses, and if this occurs, there could be adverse medical sequelae. Patient compliance in taking prescription medications is known to be problematic, and when combined with the ready availability of complementary medications, probiotics and illicit drugs, the risk of self-harm can be seen to be a distinct possibility. To compound the position, sometimes there seems to be, in a practical sense, little regulation on the advertising and marketing of non prescription medications, which can leave consumers not only confused but potentially vulnerable. While complementary medicines may not have a significant role in dental practice in 2012, that may not always be the case as research continues, and reference is made to some aspects of ongoing work. Non prescription medications are discussed, and some effects on oral health are considered. PMID- 24783838 TI - Adverse drug reactions: oral and dental manifestations and complications. AB - Adverse, that is unintended untoward effects of medications, are increasing in incidence and their severity, given the aging of the Australian and New Zealand population and associated drug use. Not only are the number of agents that our patients are using increasing, including the increased use of "alternate" or "complimentary" medications, but also their complexity, with the advent of potent, targeted, biological agents. The result is an increasing number of our patients will be at greater risk of adverse effects from their medications. These adverse effects include the impeding of the safe delivery of dental treatment and the adverse oral and dental manifestations and complications related to the use of medications. PMID- 24783839 TI - Attrition and erosion: assessment and diagnosis. AB - The management of patients with extensively worn and badly broken down dentitions presents a difficult challenge in dental practice and restorative treatments are often complex, time consuming and costly to implement, so careful case selection and treatment planning is essential. Ultimately the success of any restorative intervention is very dependent on the stability of the oral environment and the status of the remaining tooth structure. Prior to the commencement of any restorative treatment an understanding of the importance of the disease process, the risk factors in the mouth, and the intrinsic and extrinsic factors which affect the oral balance is critical. While there is a growing range of materials and techniques available for cost effective and conservative management of these cases, failure to take a systematic approach to assessment and stabilization may result in early restorative failure, rapid recurrence of the problems and a repeat restoration cycle. Therefore successful management of these patients must include an appropriate mix of preventive and restorative strategies. PMID- 24783840 TI - Attrition and erosion: restorative planning and performance. AB - The number of patients presenting with severe attrition and associated erosion is increasing in frequency. Treatment of this patient group is very challenging as it is simply not just a case of replacing lost tooth tissue, but also trying to identify and then eliminate the aetiological factors responsible for the loss of tooth structure. In most cases restorative treatment involves extensive rehabilitation of the dentition to restore the aesthetics and function and also to prevent further tooth loss. Such treatment often involves a multidisciplinary approach to eliminate and/or reduce causative factors prior to definitive restoration of teeth. Treatment needs to focus on quick intervention when the problem has been identified and diagnosed. Restorative treatment involves careful if not complex planning culminating in the establishment of a well defined and ongoing maintenance plan. Long-term success of treatment is centred on the maintenance phase. Current restorative options include the use of extensive resin composite build-ups. This is often the best initial starting point as it allows for adjustments, as well as being a reversible and more conservative procedure. The use of indirect restorations is likely to provide a longer lasting outcome after initial stabilization, whether it is metal- or ceramic-based or a combination. PMID- 24783841 TI - Endodontic assessment: pulps, pain and prognosis. PMID- 24783842 TI - Persistent endodontic infection--re-treatment or surgery? AB - Management of a tooth with persistent periradicular disease primarily involves management of persistent intraradicular infection. Conventional endodontic re treatment is the main modality that will manage this condition although endodontic surgery with or without retreatment is a viable option in cases. Case selection involves an appreciation of the disease aetiology and expected outcomes and consideration of patient, tooth and clinician factors. Both conventional endodontic re-treatment and surgery have high long-term success and survival rates and it has been shown that an endodontically treated tooth with persistent periradicular pathology that can be managed by conventional endodontic re treatment or surgery and restoration has comparable, and potentially more beneficial, outcomes to treatment options involving tooth loss and rehabilitation, such as an implant supported crown. As such endodontic retreatment should be the prime treatment modality unless a tooth has reached a stage where these techniques cannot manage ongoing disease and/or structural integrity. PMID- 24783843 TI - Timing of implant placement: planning and procedures for predictable clinical and aesthetic outcomes. AB - The placement of dental implants is dependent on a number of factors relating to both the patient and the site in which implant placement is contemplated. Additionally, there has been a general trend towards immediacy in implant therapy. This paper considers case selection and clinical decision-making and treatment guidelines in cases where immediate implant placement is contemplated. Treatment alternatives, including site preservation, early and delayed implant placement are also discussed. PMID- 24783844 TI - Implant complications: risk evaluation, diagnosis, management and outcomes. AB - Dental implants and their restorations have become an accepted and predictable modality of treatment. The literature reflects excellent long-term survival rates. However, survival of an implant does not necessarily translate to success, and in between these two outcomes lies the world of implant complications. Complications associated with dental implants occur with both the restorative and surgical components, with the restorative component complications being more frequent and to some extent, more easily managed. Surgical complications are difficult to manage, and can be the result of many aspects of the implant surgery. Potential complications can arise from poor planning, poor case selection, and poor execution. Complications can also occur where no technical or surgical errors are apparent, but where biology and the fundamental flaw of the trans-mucosal design of dental implant prostheses, adversely affects the outcome. This presentation outlines the nature of potential complications and looks at practical and pragmatic methods, first to try to prevent complications, through improved case selection and execution; secondly, it discusses the most effective methods to prevent complications in implants already installed, by adequate maintenance programmes. Lastly, it deals with those cases which require clinical management of the complications. This presentation provides the clinician with a greater understanding of the difficulties in managing implants that are not progressing as we, the clinicians, and the patients, had originally expected. PMID- 24783845 TI - The impacted canine--an orthodontic perspective. AB - The impacted canine is relatively common in incidence and can often lead to difficult treatment planning decisions. Cone Beam Computed Tomography (CBCT) imaging has improved diagnosis and treatment planning of impacted canines. In particular, this technology has allowed the clinician to accurately locate and visualize these teeth better than ever before, as well as greater appreciate the degree of damage to neighbouring teeth such as lateral incisors. Improved diagnosis and treatment planning with CBCT has therefore resulted in improved treatment outcomes. The objective of this presentation will be to cover the incidence, complications and management of impacted canines from an orthodontic perspective. Impacted canines are commonly cited as occurring in 1% of the population. Complications of impacted canines include root resorption and devitalization of the adjacent lateral incisor, ankylosis, cyst formation and prolonged retention of the deciduous canine. Interceptive management of impacted canines may include the removal of the deciduous canine. Managementof impacted canines also include either their removal or orthodontic movement into their correct position. PMID- 24783846 TI - The application of skeletal anchorage in the correction of anterior open bite and skeletal Class III malocclusion: a paradigm shift. AB - In recent years orthodontic treatment has been revolutionized by the introduction of skeletal anchorage or temporary anchorage devices (TADs). Many malocclusions, which have been previously only treatable through orthognathic surgery, such as skeletal open-bites, can now be managed non-surgically with less biological cost to the patient. Furthermore the recent application of TADs in the treatment of growing skeletal Class III patients is not only minimizing the need for obtrusive appliances, such as head gear and face masks, but it is also proving to deliver better and superior results to conventional growth modification protocols with more patient acceptance and less need for compliance. This overview covers the applications of TADs in the treatment of skeletal open bites and skeletal Class III malocclusions with reference to current evidence and clinical case presentations. PMID- 24783847 TI - Resin infiltration-taking the first steps to filling the holes in cheese molars. AB - Molar incisor hypomineralization (MIH) involves enamel hypomineralization of systemic origin affecting one or more first permanent molars (FPM) and is often associated with other teeth, particularly the incisors. A challenging condition for both the clinician and the patient, MIH affected teeth are often subjected to repeated treatments and frequently the decision to extract one or more FPM is made. At present, there are no clinical reports of available restorative materials that are able to provide consistently adequate restorations on hypomineralized teeth. The concept of resin infiltration, which involves occluding incipient enamel carious lesions with low viscosity resins to arrest or slow the development of caries has the potential to be applied to hypomineralized enamel. Successful penetration of resin infiltrant into MIH affected enamel may aid in improving its micromechanical properties. PMID- 24783848 TI - [Funding for division of microbiology by National Natural Science Foundation of China in 2013]. AB - We provide an overview of proposals applied and projects funded by the division of microbiology, department of life sciences, National Natural Science Foundation of China in 2013,. The traits and problems in different sub-disciplines were also analyzed, which provides reference for Chinese researchers to apply funding in microbiology next year. PMID- 24783849 TI - [Improvements of shikimic acid production in Escherichia coli with ideal metabolic modification in biosynthetic pathway--a review]. AB - Shikimic acid (SA) is an important intermediate in the synthesis of aromatic amino acids and has emerged as a key chiral starting material for the synthesis of antiviral drug oseltamivir phosphate (Tamiflu). Microbial production of SA has a variety of advantages, and E. coli is commonly applied in large-scale fermentation and industrial production. Metabolic engineering is one of the main technical methods to construct the industrialized high-yield shikimic acid producing strains. Phosphoenolpyruvate: carbohydrate phosphotransferase system (PTS) is the major active transport system involved in the glucose internalization and phosphorylation in E. coli in which it affects the use ratio of PEP in cell. Modification and transformation of the PTS system could regulate the flow of intracellular metabolism and reduce the waste of PEP caused by the PTS system, in the same time, a more ideal shikimic acid producing strain can be constructed combined with the specific modifications of metabolic pathways. It was reported that in the 10 L system, shikimic acid yield reached up to 0.36 mol/mol, with concentration up to 84 g/L. This paper takes a brief overview of the metabolic engineering in the shikimic acid pathway and the transformation of the glucose transporter system, summarizes some latest researches and developments in recent years. PMID- 24783850 TI - [Virulence-associated gene detection and ERIC-PCR typing of Campylobacter jejuni strains isolated from foods in four Southern Chinese provinces]. AB - OBJECTIVE: To know food contamination and genetic diversity of Campylobacter jejuni in four provinces of South China, and to provide data for C. jejuni associated foodborne disease prevention and control. METHODS: According to the national standard and the most probable number (MPN) method, we detected the contamination of C. jejuni from 558 food samples including vegetables, meat product, cooked food, seafood, frozen food, dairy product and edible fungi during 2011 and 2012. The isolates were used to detect 12 virulence-associated genes with PCR methods and construct ERIC-PCR fingerprints. RESULTS: Fourteen positive samples were determined from 558 samples, and all positive samples come from meat product samples. The average value of MPN of positive samples was 8.77 MPN/g. Virulence-associated gene analysis reveals that more than 50% of the C. jejuni isolates had at least 9 virulence genes. Interestingly, virB11 gene was not found and the genes of pldA and wlaN were 14.30% in all isolates. Total of 15 C. jejuni isolates could be divided into 10 genotypes belonging to 3 clusters by ERIC-PCR fingerprints. CONCLUSION: Meat product was the main source of C. jejuni food contamination in four provinces of South China. More control measures must be taken to avoid C. jejuni contamination. PMID- 24783851 TI - [Effect of pps and aroGfbr overexpression on L-tryptophan production in Corynebacterium pekinense]. AB - OBJECTIVE: In order to redirect carbon flows into aromatic amino acids biosynthesis pathway and further improve the production of L-tryptophan in Corynebacterium pekinense PD-67, two schemes were implemented. First, the supply of phosphoenolpyruvate (PEP), one of precursors of L-tryptophan biosynthesis, was increased. Second, the feedback inhibition of 3-deoxy-D-arabino-heptulosonate-7 phosphate synthase (DS), a key enzyme in the aromatic amino acids biosynthesis, was relieved and the activity of DS was increased. METHODS: The phosphoenolpyruvate synthase gene (pps) was cloned from C. pekinense PD-67 chromosome by PCR and inserted into expression vector to construct a recombinant plasmid pXPPS; the aroG gene encoding DS isozymes was cloned from Escherichia coli chromosome by PCR and the mutation of Leu175Asp was introduced by site directed mutagenesis using sequence-overlap extension PCR. The mutated gene named as aroGfbr was cloned to expression vector to construct a recombinant plasmid pXA; and the recombinant plasmid pXAPS co-expressing pps and aroGfbr was constructed. The three recombinant plasmids were transformed into PD-67 to generate the engineering strains PD-67/pXPS, PD-67/pXA and PD-67/pXAPS, respectively. The fermentation characteristics of the three engineering strains were investigated. RESULTS: The expression of pps and aroGfbr was confirmed by enzyme activity assays. The deregulation of feedback inhibition of AroGfbr was confirmed by determining DS activity in the presence of three aromatic amino acids. The overexpression of pps and aroGfbr resulted in an increase of L tryptophan biosynthesis by 12.1% and 26.8%, respectively, while the co-expression of two genes increased the production of L-tryptophan by 35.9% in the engineering strain PD-67/pXAPS. CONCLUSION: Both of the overexpressions of the pps gene and aroGfbr gene can increase L-tryptophan biosynthesis, while the production was further improved by the co-expression of the two genes. PMID- 24783852 TI - [Identification of spore germination and virulence related biomarkers from Beauveria bassiana using an LC-MS-based metabolomic technique]. AB - OBJECTIVE: To identify biomarkers associated with germination and virulence of Beauveria bassiana. METHODS: Spore germination rate and virulence of seven B. bassiana isolates against Euproctis pseudoconspersa were determined, and an LC-MS based metabolomic analysis was applied to identify the biomarkers from mycelia and conidial extracts associated with spore germination and virulence. RESULTS: The metabolites of carnitine, hercynine, acetylcarnitine, alpha, alpha-trehalose; Octa-Me, arg-arg-gln, phosphatidylethanolamine (PE(18:2/0:0)), phosphotidylcholine (PC(18:3/0:0)) and PC(18:2/0:0)) were higher in the mycelia of highly virulent isolates than those less virulent strains. Conidia of isolates with a high germination rate were characterized by containing higher levels of 2, 3-dimethylmaleate, acetylcarnitine, propionyl-carnitine and PC(18:2/0:0). Histamine, 2,5-pyrrolidinedicarboxylic acid; Diamide, carnitine, acetylcarnitine, propionyl-carnitine, butyrylcarnitine, PE(18:2/0:0), PC(16:1/0:0) and PC(18: 3/0:0) were higher in the conidia of highly virulent isolates. Furthermore, relative content comparison of insecticidal cyclopeptides, such as beauverolides, beauvericins and bassianolide in mycelia showed that the content of a single peptide was not highly related to fungal virulence. However, the contents of 9 peptides were found higher in the highly virulent isolate Bb1898, suggesting that they might exert synergetic effects against insect hosts. CONCLUSION: The common biomarkers related to fungal virulence and germination are acyl carnitine and phospholipid which may play roles in maintaining appressorium turgor pressure and providing energy for penetrating the host cuticle. PMID- 24783853 TI - [Engineering of a D-xylose metabolic pathway in eutropha W50]. AB - OBJECTIVE: This study aimed to broaden the substrate spectrum of Ralstonia eutropha W50 to use D-xylose, which can produce poly-beta-hydroxybutyrates (PHB) at a high level. METHODS: The D-xylose transporter gene xylE from Escherichia coli K-12 W3110 was cloned by PCR technique and integrated into the R. eutropha W50 chromosome. The recombinant strain W50-E was obtained. The D-xylose catabolic genes xylAB from E. coli K-12 W3110 and the promotor of PHA synthase gene phaC1 from R. eutropha H16 were cloned into pBBR1MCS to construct a recombinant plasmid. The plasmid was transformed into R. eutropha W50 and W50-E to generate the recombinant strains W50-AB and W50-EAB respectively. The characteristics of D xylose utilization by W50-AB and W50-EAB were investigated. RESULTS: The expression of xylA and xylB genes in R. eutropha W50 was confirmed by enzyme assay. The recombinant strain W50-AB could grow on 0.1 mol/L D-xylose with the maximum specific growth rate of 0.025 h(-1), but no growth and D-xylose consumption were observed when cultivated on 0.01 mol/L D-xylose. The recombinant strain W50-EAB exhibited a faster growth than W50-AB on 0.1 mol/L D-xylose, with the maximum specific growth rate of 0.035 h(-1). Furthermore, it exhibited a slow but defined growth and D-xylose consumption on 0.01 mol/L D-xylose. The PHB content assay showed that both recombinant strains accumulated a small amount of PHB, with a proportion of 15.07 +/- 1.01% and 15.07 +/- 1.64% on the basis of dry cell weight respectively, by using D-xylose (0.1 mol/L) as substrate. And their final D-xylose-PHB conversion rates were 0.0920 g x g(-1) and 0.0838 g x g(-1) respectively, which were much lower than their glucose-PHB conversion rates( > 0.22 g x g(-1)). However, the recombinant strains W50-AB and W50-EAB exhibited better fermentation performance and more PHB accumulation when using glucose(0.01 mol/L) and D-xylose (0.09 mol/L) mixed sugars as fermentative substrate. CONCLUSION: The recombinant strain W50-AB can metabolize D-xylose by the expression of xylAB genes, and the further expression of xylE gene is able to improve its D-xylose consumption rate. Meanwhile, the two recombinant strains can accumulate a small amount of PHB by using D-xylose as the sole carbon source. PMID- 24783854 TI - [Gene diversity of the bacterial 48 family glycoside hydrolase (GH48) in rumen environment]. AB - OBJECTIVE: The gene diversity of the bacterial 48 family glycoside hydrolase (GH48) in rumen environment was studied and new gene resources for efficient cellulose degradation were provided. METHODS: A pair of gh48 degenerate primers was designed through sequences alignment of the gh48 gene sequences from ruminal Ruminococcus. The total DNA and RNA were extracted from two rumen samples and cDNA was synthetized through reverse transcription from total RNA. Four gh48 gene clone libraries were constructed and analyzed. RESULTS: In total 455 gh48 gene sequences were obtained from the 4clone libraries. Sequence similarity among the 455 gene sequences varies between 58.65% and 100%. They fell into 66 species with the sequence similarity > or = 89%, and divided into 5 different clusters. OTU65 in cluster C represents an abundant gh48 gene which in both DNA and cDNA clones libraries, accounting for 36.4% and 19.5% respectively. Our study reveals rich gene diversity of the 48 family glycoside hydrolase and provided new gene resources for cellulose degradation. PMID- 24783855 TI - [Biological conversion of stevioside to steviol by Aspergillus aculeatus and the purification of rebaudioside A]. AB - OBJECTIVE: The purpose of this research was to apply Aspergillus aculeatus solid fermentation extracts to convert stevioside and rebaudioside C, followed by identifying and purifying the new conversion product. METHODS: The product was identified by high performance liquid chromatography, chromatography-mass spectrometry and Infrared spectrum. The new product and rebaudioside A exited in the supernatant were purified by alcohol and macroporous resin. RESULTS: The Aspergillus aculeatus enzyme extracts could convert the stevioside and rebaudioside C to the new product within 10 hours. The conversion rate was 98.0% in 24 hours. The conversion product existed in deposit was identified as steviol. The purity and recovery percent of steviol were 95.2% and 84.0% respectively. Because stevioside could occur to deposit, the rebaudioside A existed in supernatant was purified easily. We used the resin chromatography to purify RA and the recovery could reach 80.5%. CONCLUSION: Aspergillus aculeatus enzyme extracts could convert stevioside efficiently and specifically, and we could obtain rebaudioside A and steviol at the same time. PMID- 24783856 TI - [Contamination of typical human enteric viruses in economic shellfish along the Chinese coast]. AB - OBJECTIVE: The objective of this study is to understand the contamination of human enteric viruses in economic shellfish along the Chinese coast, an important issue of ensuring the seafood safety. METHODS: We established the specific, sensitive and high-throughput gene chip technology, to investigate the contamination of economic shellfish by enteric viruses across a large geographical region of China. RESULTS: The percentage of positive samples for each virus was as follows: Hepatitis A Virus 4.3%, norovirus 14.8%, rotavirus 6.2%, astrovirus 5.6%, and adenovirus 9.9%. In these five viruses, norovirus was contaminated in the first place. The results detected by gene chip were highly consistent with that of polymerase chain reaction (PCR). The economic shellfishes in shellfish-growing areas along the coastal cities were all contaminated with enteric viruses at different levels. However, there was no significant correlation between any two cities. In the selected 6 economic shellfishes, oyster had the highest positive rate of enteric viruses, followed by blood clam. CONCLUSION: The contamination of shellfish with human enteric viruses was common across the main coastal cities of China, indicating a potential public health threat from seafood. PMID- 24783857 TI - [Virulence-related genes of Vibrio alginolyticus and its virulence in mice]. AB - OBJECTIVE: We determinated the virulence factors of Vibrio alginolyticus strains isolated from the environment by multiplex PCRs and animal experiments, in order to compare the differences between the highly virulent strain and attenuated virulent strain, and to explore the virulent mechanism of V. alginolyticus in mammals. METHODS: The virulence-related genes of V. alginolyticus were investigated by multiplex PCRs. Hemolysin and pathogenic proteins were detected using Kanagawa phenomenon tests and enzyme activity tests. In vivo pathogenetic tests of V. alginolyticus were done through orogastric and intraperitoneal Kunming mouse. RESULTS: Amylase and lecithinase activities were observed in 100% of the strains, whereas lipase and gelatinase activities were found in only 70% and urease activity was not detected. In Kanagawa phenomenon tests 60% of the strains gave positive results. The related virulence genes such as toxR, Collagenase, tlh, FlaA, ompW, AspA and fur were distributed among 10 strains of V. alginolyticus collected, with the exception of toxS, trh, tdh and UreR. Among those 10 strains, VA009 has shown a strong pathogenesis to the mouse, which caused fluid accumulation and led the mortality rate as high as 80% within 7 days by intraperitoneal infection. CONCLUSION: This study indicates that there is a great difference in pathogenicity among V. alginolyticus strains to mouse. The cell toxicity of V. alginolyticus made more contribution than extracellular secretion, while the extracellular secretion of V. parahaemolyticus played a major role in its toxicity. The virulence gene profiles were consistent between the highly virulent and attenuated virulent strains, indicating that V. alginolyticus might have a different virulence system and different pathogenic mechanism compared with V. parahaemolyticus. PMID- 24783858 TI - [Construction of expression vectors for alkaliphilic Bacillus sp. N16-5]. AB - OBJECTIVE: To construct an expression vector for alkaliphilic Bacillus sp. N16-5. METHODS: Bacillus subtilis expression vector pHCMC04 was used as a backbone. Its xylose-inducible promoter cassette was replaced by the constitutive promoters P43 (from B. subtilis) and P(EF) (from Bacillus sp. N165), separately, resulting in two expression vectors pABN165P43 and pABN165P(EF). Green fluorescent protein gene gfp was linked to the two vectors as a reporter gene. Fluorescence microscope and multifunctional fluorescent reader were used to test the expression efficiency of the system. RESULTS: Green fluorescence was visualized in Bacillus sp. N16-5 with pABN165P(EF)-gfp or pABN165P43-gfp. Quantitative data analysis revealed that fluorescence was first detected around the 7th hour. The fluorescence intensity increased rapidly from the 7th hour to the 12th hour and reached the maximum at about the 12th hour. CONCLUSION: Two expression vectors for Bacillus sp. N16-5 have been constructed, allowing expression of exogenous protein in alkaliphilic Bacillus sp. N165. PMID- 24783859 TI - [A simple error-prone PCR method through dATP reduction]. AB - The error-prone PCR is one of the main methods for in vitro gene mutagenesis, usually through adding Mn2+ increasing Mg2+ and dCTP/dTTP concentration. OBJECTIVE AND METHODS: In this study, both the antifungal protein gene Ace-AMP1 from Allium cepa and the Bt toxin gene cry1A(c) from Bacillus thuringiensis were subjected to PCR mutagenesis through reducing the dATP concentration, but without adding Mn2+ or adjusting other PCR components. RESULTS: The result showed that the rates of base mutation and sequence variation were increased along with the decrease of dATP concentrations. When dTTP/dCTP/dGTP: dATP equaled 20:1-40:1, the rate of base mutation was between 1.4% and 1.8%, and the rate of sequence variation was between 77.8% and 100%. DISCUSSION AND CONCLUSION: This method is simple and practical, and enables the process optimization of several mutagenic factors in conventional error-prone PCR. Moreover, as the resulting base mutations were mainly A x T-->G x C transition, the present method provides a new way to improve the GC content of gene by in vitro mutagenesis. The mutagenesis method of simply reducing single dNTP concentration could improve AT or GC content of the target gene, it is an expansion of error-prone PCR. PMID- 24783861 TI - [2013 annual review of capillary electrophoresis technology]. AB - This paper reviews the capillary electrophoresis (CE) in 2013. Six international and two national conferences are included and the important reports are introduced briefly. Literatures searched from ISI Web of Science ranged in 2013. 1 . 1 - 2013. 12 . 7 are classified and introduced based on the biology and medicine applications as well as the use of detectors and the important analytical chemical journals. PMID- 24783860 TI - [Discovery of the target genes inhibited by formic acid in Candida shehatae]. AB - OBJECTIVE: At transcriptional level, the inhibitory effects of formic acid was investigated on Candida shehatae, a model yeast strain capable of fermenting xylose to ethanol. Thereby, the target genes were regulated by formic acid and the transcript profiles were discovered. METHODS: On the basis of the transcriptome data of C. shehatae metabolizing glucose and xylose, the genes responsible for ethanol fermentation were chosen as candidates by the combined method of yeast metabolic pathway analysis and manual gene BLAST search. These candidates were then quantitatively detected by RQ-PCR technique to find the regulating genes under gradient doses of formic acid. RESULTS: By quantitative analysis of 42 candidate genes, we finally identified 10 and 5 genes as markedly down-regulated and up-regulated targets by formic acid, respectively. CONCLUSION: With regard to gene transcripts regulated by formic acid in C. shehatae, the markedly down-regulated genes ranking declines as follows: xylitol dehydrogenase (XYL2), acetyl-CoA synthetase (ACS), ribose-5-phosphate isomerase (RKI), transaldolase (TAL), phosphogluconate dehydrogenase (GND1), transketolase (TKL), glucose-6-phosphate dehydrogenase (ZWF1), xylose reductase (XYL1), pyruvate dehydrogenase (PDH) and pyruvate decarboxylase (PDC); and a declining rank for up regulated gens as follows: fructose-bisphosphate aldolase (ALD), glucokinase (GLK), malate dehydrogenase (MDH), 6-phosphofructokinase (PFK) and alcohol dehydrogenase (ADH). PMID- 24783862 TI - [Advances in isolation and enrichment of circulating tumor cells in microfluidic chips]. AB - The research of circulating tumor cells (CTCs) has drawn increasing attention in recent years, because its potential value in the early diagnosis of cancers, management of clinical treatment, development of personalized medicine, and exploring the mechanism of metastasis. However, the difficulty in using CTCs lies in their extremely low concentrations. Recently, microfluidic devices have shown the potential to efficiently isolate and detect rare CTCs in cancer patients. A variety of on-chip blood analysis has been demonstrated by several groups. The advantages of microfluidics include low cost, short reaction times, high throughput, and ease of use. Recently, a variety of microfluidic devices have been developed to CTCs isolation and enrichment which can realize high capture efficiency, high purity and high throughput. In this article, we review some of the recent works in microfluidic CTCs isolation and enrichment devices and discuss in what field should be done next based on our researches. PMID- 24783863 TI - [Simultaneous determination of 20 illegally added anti-diabetic chemical components in hypoglycemic and weight-reducing health foods by ultra-high performance liquid chromatography-tandem mass spectrometry]. AB - A rapid method for the simultaneous screening and detection of 20 illegally added anti-diabetic chemical components in hypoglycemic and weight-reducing health foods was developed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). After extracted by methanol, the sample was separated on a Poroshell 120 EC C18 column (100 mm x 2.1 mm, 2.7 microm) with the gradient elution of 5 mmol/L ammonium acetate and acetonitrile as mobile phases. The electrospray ionization (ESI) source in positive or negative ion mode was used for multiple reaction monitoring (MRM) mode. The 20 illegally added chemical components showed good linear relationships with the correlation coefficients more than 0.99. The recoveries were in the range of 75.9% - 114.0%, and the relative standard deviations (RSDs) were all not more than 11.3%. The limits of detection (LODs) were all in the range of 0.3 - 1.5 microg/L. This method is rapid, simple, sensitive, accurate and of good specificity for cracking down illegally added anti-diabetic chemical components. PMID- 24783864 TI - [Determination of thiourea dioxide in lotus seed paste fillings by solid phase extraction-liquid chromatography-tandem mass spectrometry]. AB - A method of solid phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) was developed to determine thiourea dioxide which was illegally added into lotus seed paste fillings. An amount of 0.05% (v/v) acetic acid was used to extract thiourea dioxide from fillings, and the BOND ELUT PLEXA column (60 mg/3 mL) was used as the SPE column to clean-up the extraction. Then, an Agilent HILIC column (100 mm x 2.1 mm, 3.5 microm) was applied to separate target compounds by using the mobile phases of 0.01 mol/L ammonium acetate (pH 3.5) and acetonitrile. Qualitative and quantitative analyses were operated by the multiple reaction monitoring (MRM) mode. The calibration curve showed a good linearity for the target compound in the detection range of 10 - 1 000 microg/L. The limit of detection (LOD) and limit of quantitation (LOQ) of this method were 8.0 microg/kg and 30.0 microg/kg, respectively. The recoveries were in the ranges of 75.3% - 80.7% with the RSDs of no more than 4.83%. This proposed method was rapid, highly specific and suitable for the confirmation and quantitative determination of thiourea dioxide in lotus seed paste fillings. PMID- 24783865 TI - [High throughput analysis of cerebroside molecular species from sea cucumber Parastichopus californicus by liquid chromatography-quadrupole-time-of-flight mass spectrometry]. AB - Cerebrosides from sea cucumber Parastichopus californicus were identified by using liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-Q-TOF MS/ MS). The samples were extracted with chloroform-methanol (2: 1, v/v) solution and purified by a SPE cartridge. In positive ion mode electrospray ionization (ESI), the precursor ion scan mass spectra and product ion scan mass spectra were obtained through the automatic MS/MS mode. Cerebroside molecules were selected according to the neutral loss fragments of 180 Da, and then were identified according to long-chain base (LCB) fragments and fatty acid (FA) fragments. One hundred and twenty-three cerebroside molecular species were identified. There are 18 species of LCB, and the relative content ratio of phytosphingosines and sphingosines is 1: 2. The carbon numbers of fatty acids are mainly 18 - 25, of which 24 carbon fatty acids are predominant. The relative content ratio of saturated fatty acids and monounsaturated fatty acid is about 1: 3, and the presence of 2-hydroxy fatty acids is about 58.62%. LC-Q-TOF MS/MS method is sensitive, accurate and simple. At the same time, this study provided a theoretical basis for structure-activity relationship studies and functional food development of Parastichopus californicus as well. PMID- 24783867 TI - [Determination of phenolic compounds in fresh tobacco leaves by high performance liquid chromatography-ultraviolet/mass spectrometry]. AB - Twenty-five phenolic compounds in tobacco were analyzed using high performance liquid chromatography-ultraviolet/mass spectrometry (HPLC-UV/MS), including absolute quantification of 11 main phenols by HPLC-UV and relative quantification of other 14 phenols by SHPLC-MS. The validation results of this method were satisfactory. Eleven phenol standards showed good linearity with correlation coefficients (r2) of 0.999 3 - 0.999 9 over the mass concentration range from 0.90 mg/L to 99.00 mg/L (the range of chlorogenic acid and rutin was from 0.95 mg/L to 380.00 mg/L). The recoveries of the 11 phenol standards were 91.0% - 112.4% with the RSDs of 0.33% - 8.11% at the three spiked levels of 22.5 - 24.8, 45.0 - 49.5 and 67.5 - 74.3 mg/L. The reproducibility of the method was good with the RSDs of 1.48% - 13.40%. In addition, the intra-day and inter-day precisions were also satisfactory with the RSDs of 0.35% - 15.54%. Mature fresh tobacco leaves from Yunnan, Henan and Guizhou Provinces, China were analyzed using this method. The results showed that the total amount of main phenols was Guizhou > Yunnan > Henan and there was significant difference between Guizhou and Henan. The amount of rutin was Yunnan > Guizhou > Henan, and there were significant differences among them each other. The method is reproducible with a simple pretreatment covering a wide range of phenols, and can be applied in batch analysis of tobacco leaves. PMID- 24783866 TI - [Determination of carcinogenic aromatic amines derived from azo colorants in plastic components of electrical and electronic products by high performance liquid chromatography-mass spectrometry]. AB - A study for the simultaneous determination of 21 primary aromatic amines derived from the reduction of the azo colorants in plastic components of electrical and electronic products was conducted. Organic solvents were used to dissolve or swell the plastics to release the azo dyes existing in the plastic components. The azo colorants were reduced to aromatic amines under strong reducing condition of dithionite. Aromatic amines were extracted with methyl tert-butyl ether. Methanol-water (1: 1, v/v) was used to concentrate the extract to constant-volume for HPLC-MS analysis. The analytes were separated on a ZORBAX Eclipse XDB C18 column using the gradient elution with acetonitrile and 0.1% (v/v) formic acid aqueous solution at a flow rate of 0.6 mL/min. The analyte confirmation was performed using retention time and characteristic ions in selected ion monitoring (SIM) mode. The correlation coefficients (r) of all the standard curves were more than 0.998, and the limits of quantification of the analytes were 0.5 mg/kg. The recoveries were 60.1% - 129.5% for the 21 aromatic amines with the RSDs not more than 14.0% except for a few compounds. The results showed that the banned azo colorants in the plastic products can be analyzed qualitatively and quantitatively through reductive conversion into aromatic amines. In addition, this method has high accuracy and good precision. PMID- 24783868 TI - [Determination of triterpenoic acid isomers in Eriobotryae folium using high performance liquid chromatography on C30 column]. AB - A rapid and easy assay method for four triterpenoic acid isomers in Eriobotryae folium was established. The sample was extracted with methanol, then separated on a C30 column (250 mm x 4.6 mm, 5 microm) at 20 degrees C using acetonitrile-water (95 : 5, v/v) as the mobile phase at a flow rate of 1.0 mL/min. The target compounds were simultaneously detected at 210 nm, and the injection volume was 10 microL. The validation was carried out and the resolution (R > or = 2.2), the precision (RSD < or = 1.1%), the linearity (r > or = 0.999 2), the repeatability (RSD < or = 4.4%), and the recovery (range from 95.4% to 101.7%, RSD < or = 4.8%) were acceptable. The method is reliable for the quantification of the four triterpenoic acid isomers by HPLC on C30 column. PMID- 24783869 TI - [Determination of seven additives in polymer products by ultra performance supercritical fluid chromatography]. AB - A method for rapid determination of seven commonly used additives in polymer products by ultra performance supercritical fluid chromatography (UPSFC) photodiode array detector (PDA) was developed. In this experiment, the detection wavelength was set at 220 nm. After the important parameters of UPSFC, such as the diluting solvent, mobile phase additive, column temperature, automatic back pressure regulator (ABPR) and flow rate were investigated, the optimized conditions were acquired as follows: n-hexane/isopropanol (1/1, v/v) was chosen as the diluting solvent, the mixture of methanol/acetonitrile (1/1, v/v) as the mobile phase additive, 2 mL/min as the flow rate, 50 degrees C as the column temperature, 12.41 - 13.79 MPa as the ABPR. Under these conditions, seven additives were separated in 5 min, and full baseline separation was achieved. The real sample was pretreated by microwave-assisted extraction (MAE) and analyzed by UPSFC-PDA. The seven additives can be detected with the recoveries of 69.9% - 118.9%, and the relative standard deviations (RSDs, n = 9) were less than 10%. This method is simple, fast with good selectivity and suitable for the analysis of the additives in polymer products. PMID- 24783870 TI - [Rapid screening and quantitative analysis of 144 pesticide residues in traditional Chinese medicinal herbs by gas chromatography-tandem mass spectrometry]. AB - An analytical method for the simultaneous determination of 144 pesticide residues in traditional Chinese medicinal herbs was established based on optimized QuEChERS with gas chromatography-tandem mass spectrometry (GC-MS/MS). The influences of different extraction solvents, different buffer systems and different purifying agents on the recoveries of the pesticides were investigated. The pesticide residues in the samples were extracted with acetonitrile, then cleaned-up by mixed sorbents and analyzed by GC-MS/MS in multi-reaction monitoring (MRM) mode. The external standard method was applied to quantify the pesticides. The linear range of the method was from 20 to 2 000 microg/kg with the correlation coefficients (r2) of more than 0. 983. The recoveries of the pesticides at the spiked levels of 20, 50 and 200 microg/kg ranged from 74.3% to 111.8% with the relative standard deviations lower than 15%, except for acephate, amitraz and aldrin. The method was successfully used for the analysis of target pesticides in testing samples, and had a good consistency in results with the existed standard one. This multi-residue analytical method allows for a rapid, efficient, sensitive and reliable screening and quantitative analysis of the target pesticides in traditional Chinese medicinal herbs. PMID- 24783872 TI - [Determination of 39 polychlorinated biphenyls in indoor dust using ultrasonic extraction and gas chromatography-tandem mass spectrometry]. AB - A method for the determination of 39 polychlorinated biphenyls (PCBs) in indoor dust was developed. A vacuum cleaner was used for gathering the house dust. N Hexane-dichloromethane (1: 1, v/v) was added and the extraction was performed in an ultrasonic bath. The supernatant was concentrated and then 0.1 mL n-hexane dichloromethane (1: 1, v/v) was added. Gas chromatography-tandem mass spectrometry (GC-MS/MS) in selected-reaction monitoring (SRM) mode has been investigated for the determination of the 39 PCBs congeners in indoor dust. The 39 PCBs had highly efficient separation within 30 min and showed good linearity in the range of 0.1 - 100 microg/L with the correlation coefficients of 0.991 0 - 0.999 9. The spiked recoveries were 57.2% - 120.3%. The intra-day relative standard deviations (RSDs) were between 0.3% and 24.7%, while the inter-day RSDs were between 0.6% and 29.9%. This method has good linearity, high sensitivity, high accuracy and precision. Also, it is simple, rapid and low solvent consumption. The low chemical background interference allowed it to be used in more complex matrices. PMID- 24783871 TI - [Simultaneous determination of nine preservatives in fruits using gas chromatography-mass spectrometry]. AB - A gas chromatography-mass spectrometry (GC-MS) method was established for the simultaneous determination of nine typical preservatives (pyrimethanil, chlorothalonil, chlorpyrifos, triadimefon, thiabendazole, imazalil, myclobutanil, iprodione, prochloraz) in fruits. The fruit samples were subjected to ultrasonic extraction with hexane/ethyl acetate (1/1, v/v), and followed by purification using diatomite column chromatography with hexane/ethyl acetate (1/3, v/v) eluant. Qualitative and quantitative analysis of the nine preservatives were performed on the GC-MS at full-scan (SCAN) and selected ion monitoring (SIM) modes, in which triphenylphosphate was used as the internal standard. The detection limits obtained for the nine preservatives were ranged from 0.10 microg/kg to 2.16 microg/kg. The average recoveries were in the range of 75.3% to 128% at the spiked levels of 50, 100 and 200 microg/kg with the relative standard deviations (RSDs) of 1.57% to 11.6% (n = 5). The results showed that the developed method is sensitive and accurate for the determination of the nine preservatives in fruits. PMID- 24783873 TI - [Determination of migration of 15 N-nitrosamines and N-nitrosatable substances from children's latex articles by gas chromatography-tandem mass spectrometry using solid phase extraction]. AB - A method based on gas chromatography-tandem mass spectrometry (GC-MS/MS) using solid phase extraction (SPE) has been developed for the determination of 15 N nitrosamines from children's latex articles. Artificial saliva was used as the migration solution to extract N-nitrosamines in children' s latex articles. And then a polar modified polystyrene-divinylbenzene copolymer (Chromabond Easy) was used for the selective SPE of the analytes in the migration solution. The analytes were then separated on an HP-5MS UI GC column and determined by MS/MS in multiple reaction monitoring mode for qualitative and quantitative analysis. Good linearity ranged from 5 microg/L to 2 000 microg/L was observed for all the compounds (R2 > 0.998) and the limits of quantification for the 15 N-nitrosamines were 0.625 - 12.50 microg/kg (S/N = 10), which were lower than the limits required by the EU 2009/48/EC Directive. The average recoveries of the target analytes at low, medium, and high spiked levels were in the ranges of 53.8% - 116.2%, 52.7% - 105.1% and 49.5% - 102.9%, respectively. The average within-day and between-day RSDs were from 1.3% to 14.0% (n = 6) and from 1.6% to 7.6% (n = 4), respectively. The proposed method was used to monitor N-nitrosamines in baby nipples and balloons, and N-nitrosamines were found in some samples. The total contents of the 15 N-nitrosamines in the analyzed nipples and balloons samples ranged from 0.049 9 mg/kg to 41.2 mg/kg. And the total contents of the N nitrosatable substances in the analyzed samples ranged from 0.026 4 mg/kg to 12.5 mg/kg. PMID- 24783874 TI - [Determination of N-nitrosamines in rubber products by solid phase extraction purification and ultra high performance liquid chromatography-tandem mass spectrometry]. AB - A method using C18 solid phase extraction (SPE) for purification and ultra high performance liquid chromatography (UHPLC) coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) for detection was developed to simultaneously determine 13 N-nitrosamines in rubber products. The analytes were extracted with methanol (60 degrees C, 30 min) with the aid of ultrasonic technique and then purified by a C18 SPE cartridge. The analytes were separated on a C18 chromatographic column and qualitatively and quantitatively detected by a mass spectrometer with positive ESI at multiple reaction monitoring (MRM) mode. The operating parameters for UHPLC separation and ESI-MS/MS detection were also optimized. Under optimum operating conditions, the relative standard deviations (RSDs, n = 7) were less than 10% at spiked level of 50 microg/kg for all analytes except N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) which were spiked at 500 microg/kg. The recoveries spiked in real from 70.7% to 117.0%. The limits of detection (LODs, 10 times of standard deviation) were in the range of 0.5 - 500 microg/kg. The method has been successfully applied to the simultaneous determination of the 13 N-nitrosamines in rubber products. PMID- 24783875 TI - [Analysis of the preservative chlorphenesin in cosmetics by high performance liquid chromatography]. AB - An analytical method was developed for the determination of the preservative of chlorphenesin in cosmetics by high performance liquid chromatography (HPLC). A C18 column (250 mm x 4.6 mm, 5 microm) and a photodiode array detector were used. The mobile phase was methanol-water (55:45, v/v) with a flow rate of 1.0 mL/min. The detection wavelength was set at 280 nm and the column temperature was 25 degrees C. The limit of detection was 3 ng. A good linear relationship was obtained between the peak area and the mass concentration of chlorphenesin in the range of 1 - 500 mg/L and the correlation coefficient was 1.000 0. The recoveries of chlorphenesin at different spiked levels were 99.0% - 103% with the relative standard deviations (RSD) < or = 1.2%. Interference test and sample test were also applied meanwhile and validation experiments were performed by three laboratories. The method is simple, sensitive, accurate, stable and suitable for the determination of chlorphenesin in cosmetics. PMID- 24783876 TI - [Process analysis for levulinic acid generated in waste wood liquefaction by non development thin-layer chromatography based on oblique projection]. AB - A rapid and quantitative method is presented for multi-component process analysis, based on multi-wavelength thin-layer chromatography (TLC) scanning but without the routine development. The samples from the waste wood liquefaction process are applied on silica plates, and just the last sample of spot need to be developed for getting separated spectra. These spectra are divided into two parts of production (levulinic acid) and background, respectively, to build an oblique projection operator. The other process samples do not need to be developed repeatedly, and are scanned to collect hybrid spectra immediately. The pure production spectrum can be separated from the process spectrum by the oblique projection algorithms to realize the production quantification. It was showed that the relative errors between the determination results by this method and those by high performance liquid chromatography (HPLC) were less than 3.27%, and so the consistency is perfect. PMID- 24783877 TI - A consensus of opinion. PMID- 24783878 TI - Management of the single discoloured tooth. Part 1: Aetiology, prevention and minimally invasive restorative options. AB - The single discoloured tooth is commonly encountered in general practice. This is the first of two articles covering the broad range of management options for the single discoloured tooth. This first part outlines the common causes of discoloration and possible methods of prevention. Minimally invasive techniques are covered. Clinical procedures are outlined and clinical cases used to demonstrate outcomes that can be achieved. CLINICAL RELEVANCE: The single discoloured tooth is a commonly encountered clinical problem in general dental practice. A wide variety of management options exist and any one in particular may be most appropriate given the clinical scenario. It is therefore essential that general dental practitioners are familiar with the range of options that exist, as well as their indications, and consider adopting minimally invasive techniques in the first instance before moving to more invasive therapies. PMID- 24783879 TI - A guide to skin cancer of the face for the dental team. AB - The incidence of skin cancer in the United Kingdom is increasing and is associated with an ageing population and increasing lifetime exposure to sunlight. The three most common types of skin cancer are basal cell carcinoma, squamous cell carcinoma and malignant melanoma, all three of which may present on the skin of the face. The dental team are, therefore, well-placed to recognize suspicious lesions and arrange for further advice or assessment. This paper outlines the epidemiology, important clinical features and principles of modern management of facial skin cancers to aid dental practitioners in the recognition of suspicious lesions. In addition, some of these treatments have side-effects which have the potential to affect a patient's oral health or its management and these aspects are also discussed. CLINICAL RELEVANCE: The dental surgeon is ideally placed to recognize malignant or potentially malignant lesions on patients'faces and to advise on seeking further advice or refer for assessment, as appropriate. Dental practitioners will increasingly encounter patients who have undergone surgical or non-surgical management of facial skin cancer and should understand the potential oro-facial side-effects of such treatment. PMID- 24783880 TI - The state-of-the-art of ART sealants. AB - Sealing caries-prone pits and fissure systems is an effective caries-preventive measure. There are basically two types of sealant materials: glass-ionomer and resin-based materials. Low- and medium-viscosity glass-ionomers were initially used and showed a low level of retention. With the advent of the ART approach in the mid-nineties, high-viscosity glass-ionomers were introduced as sealant material and the retention rate of ART sealants increased substantially. As the effectiveness of a sealant is measured by its capacity to prevent (dentine) carious lesion development, sealant retention is considered a surrogate endpoint. The ART sealant protocol is described. Systematic reviews and meta-analysis covering low- medium- and high-viscosity glass-ionomer (ART) sealants have concluded that there is no evidence that either glass-ionomer or resin-based sealants prevent dentine carious lesions better. The annual dentine carious lesion development in teeth with high-viscosity glass-ionomer ART sealants over the first three years is 1%. These ART sealants have a high capacity of preventing carious lesion development. Because no electricity and running water is required, ART sealants can be placed both inside and outside the dental surgery. CLINICAL RELEVANCE: High-viscosity glass-ionomer ART sealants can be used alongside resin-based sealants.41:119-124 PMID- 24783881 TI - Quality assurance tests for digital radiography in general dental practice. AB - Quality assurance (QA) is essential in dental radiography. Digital radiography is becoming more common in dentistry, so it is important that appropriate QA tests are carried out on the digital equipment, including the viewing monitor. The aim of this article is to outline the tests that can be carried out in dental practice. CLINICAL RELEVANCE: Quality assurance for digital equipment is important to ensure consistently high quality images are produced. PMID- 24783882 TI - Implant-supported mandibular denture: planning to delivery--a case report. AB - Restoring the edentulous mandible with a removable prosthesis can be a challenging prospect for both the dentist and patient during and after treatment. Poor retention and support are the major problems reported with a mandibular complete denture and these can be significantly improved with the use of implants and retentive attachments. Utilizing implants requires careful planning from both the surgical and restorative aspects to ensure that the intended treatment aim and outcome is achieved. CLINICAL RELEVANCE: This case highlights the importance of both restorative and surgical considerations when planning the rehabilitation of the mandible with dental implants. PMID- 24783883 TI - Diabetes mellitus: considerations for the dental practitioner. AB - The prevalence of diabetes is increasing significantly and, therefore, dental practitioners are having to manage diabetic patients on a more regular basis. Alongside the systemic effects on the various tissues and organs of the body, diabetes can adversely affect oral health and all clinicians should be aware of the issues that may arise. CLINICAL RELEVANCE: Dental practitioners are almost guaranteed to encounter both diagnosed and undiagnosed diabetic patients. It is therefore important that they are aware of the oral signs and symptoms of disease and the reciprocal relationship between oral health and glycaemic control, so that diabetic patients are managed accordingly. PMID- 24783884 TI - What makes a good dentist? A pilot study. AB - This study investigates the attributes of a 'good dentist' with respect to the opinions of dental patients, dental students and qualified dentists and determines whether the dental profession and its patients are in agreement with the standards published by the General Dental Council (GDC) in 2005. A questionnaire was circulated amongst the above groups at the University Of Birmingham, School of Dentistry. Each participant was asked to rank 14 attributes for a dentist in order of their importance. The results indicated that generally there was no consensus between individual participants. There was, however, significant overlap between the top six attributes chosen by dental care professionals and the GDC standards. Patients tended to rank other non-GDC mentioned attributes more frequently. Attributes which were considered important by all were 'putting patient interests first and acting to protect them, respecting a patient's dignity and choices and having good technical ability'. CLINICAL RELEVANCE: It is important to gain an insight into patient attitudes and to be knowledgeable of the GDC professional standards, in order to improve overall conduct and performance as a dental practitioner. PMID- 24783885 TI - Aspects of dento/medico-legal report writing. AB - This paper offers some guidance on aspects of dento/medico-legal report writing, citing anonymized examples from the author's caseload for clarification of the points made, and also serves to illustrate that sometimes not everything is as straightforward as it may initially appear. It provides reference to the current Civil Procedure Rules in England and Wales and its relevance in report writing. CLINICAL RELEVANCE: To provide guidance on aspects of dento/medico-legal report writing. PMID- 24783886 TI - The management of risk. Part 1: Why complaints happen and how to prevent them. AB - There is increasing concern amongst dentists, and dental care professionals (DCPs), about the risks associated with complaints from patients and the possibility of escalation to legal action or referral to the General Dental Council (GDC). This is the first of a series of four articles considering the management of risk. It will describe why complaints happen, how to identify problems at an early stage and strategies for preventing complaints occurring. CLINICAL RELEVANCE: The prevention of complaints will reduce stress and anxiety for all members of the dental team. PMID- 24783887 TI - An update on optical coherence tomography in dentistry. AB - An update and overview of the use of optical coherence tomography (OCT) in dentistry is described. Specific aspects discussed include the evolution of the technology and the basic process of light beam interference used to obtain OCT images. In addition, aspects of the optical properties of dentine and enamel and the range of current diagnostic applications of OCT in dentistry are reviewed. CLINICAL RELEVANCE: The technique of optical coherence tomography is considered to be significant since the technology involved allows imaging using light to around 2-3 mm in teeth and can, for example, allow the extent and progression of carious lesions to be determined. PMID- 24783888 TI - Oral medicine: 15. Radiolucencies and radio-opacities. B. odontogenic diseases and cysts. PMID- 24783889 TI - Technique tips--dynamic working length determination. PMID- 24783890 TI - Operating theatre quality and prevention of surgical site infections. AB - Surgical site infections (SSI) account for 14% to 17% of all hospital-acquired infections and 38% of nosocomial infections in surgical patients. SSI remain a substantial cause of morbidity and death, possibly because of the larger numbers of elderly surgical patients or those with a variety of chronic and immunocompromising conditions, and emergence of antibiotic-resistant microorganisms. Factors causing surgical site infection are multifarious. Several studies have identified the main patient-related (endogenous risk factors) and procedure-related (external risk factors) factors that influence the risk of SSI. The rate of surgical wound infections is strongly influenced by operating theatre quality, too. A safe and salubrious operating theatre is an environment in which all sources of pollution and any micro-environmental alterations are kept strictly under control. This can be achieved only through careful planning, maintenance and periodic checks, as well as proper ongoing training for staff Many international scientific societies have produced guidelines regarding the environmental features of operating theatres (positive pressure, exchanges of filtered air per hour, air-conditioning systems with HEPA filters, etc.) and issued recommendations on healthcare-associated infection, including SSI, concerning surveillance methods, intervention to actively prevent SSI and approaches to monitoring the implementation of such strategies. Therefore, the prevention of SSI requires a multidisciplinary approach and the commitment of all concerned, including that of those who are responsible for the design, layout and functioning of operating theatres. PMID- 24783892 TI - Health workers sensitization: effects on perceived quality of immunization services among mothers of under five children in Ilorin, North Central Nigeria. AB - Clients' satisfaction with services received is an important dimension of evaluation that is examined only rarely in developing countries. Health care professionals have always acknowledged that satisfying the consumers at some level is essential to providing services of high quality. This is a quasi experimental study. The study group included 150 mothers bringing their children for immunization at Alanamu Health Centre, Ilorin. The control group included 150 mothers bringing their children for immunization at Okelele Health Centre. Total population of mothers bringing their children for vaccines against tuberculosis/poliomyelitis/hepatitis B (BCG/ OPV/HBV) and against diphterite pertussis-tetanus (DPT)/OPV/ HBV were recruited sequentially until sample size was attained. Mean waiting time at pre-intervention was 82.7 +/- 32.5 and 90.4 +/ 41.7 minutes for the study and control groups respectively. Post intervention, there was a significant decrease (p < 0.05) in the estimated waiting time in the study group (mean = 48.0 +/- 24.4 minutes) while there was no observed difference in the control p > 0.05 (mean = 88.4 +/- 40.6 minutes). Perceived adequacy of information on services being provided by the health facility was low (58%) in the study group while it was relatively higher in the control group (80%) but there was a significant increase in proportion of those that felt information was adequate only in the study group (p < 0.05) at post intervention. Waiting time in health facilities by clients should be reduced as this may give clients a positive perception of the service they have come to access. Information dissemination to clients should be encouraged among health workers as this would affect clients' knowledge and also quality of health care delivery. PMID- 24783891 TI - Biphosphonates-associated osteonecrosis of the jaw: the role of gene-environment interaction. AB - Biphosphonate (BPN) are widely used in clinics to treat metastatic cancer and osteoporosis thus representing a problem not only for patients but also for workers involved in their preparation and administration. A similar exposure occurred years ago in match-making workers undergoing bone alterations similar to those consequent to BPN exposure. Osteonecrosis of the jaw (ONJ) is a main adverse effect related to BPN administration, which is performed in millions of patients worldwide for osteoporosis and cancer therapy, thus representing an emerging problem in public health. In susceptible patients, BPN induce severe, progressive, and irreversible degeneration of facial bones, resulting in avascular ONJ often triggered by dental surgery. BPN induced ONJ occurs in subjects depending on lifestyle factors of both environmental and endogenous origins. Exogenous risk factors include cigarette smoke, alcohol consumption, bacterial infections, and cyclosporine therapy. Endogenous risk factors include systemic diseases such as diabetes or hypertension and adverse polymorphisms of genes involved in metabolism (CYPs, MTHFR), thrombosis (Factor V, Prothrombin), and detoxification (MDR). Available molecular findings provide evidence that ONJ is related to risk-factors associated with environmental mutagenesis and gene environment interactions. This issues may be useful to identify susceptible subjects by molecular analyses in order to prevent ONJ occurrence. PMID- 24783893 TI - Personal hygiene among primary school children living in a slum of Kolkata, India. AB - INTRODUCTION AND OBJECTIVES: For children, maintenance of personal hygiene helps to improve the quality of life and longevity. This is of particular importance in a slum community with compromised living situation. This study was undertaken to find out the knowledge and practice of personal hygiene among the primary school children living in a slum area, to identify any misconception among them regarding the maintenance of personal hygiene, to find out their morbidity pattern, and also to elicit the relationship between practice of personal hygiene among the children and the literacy status of their mother. METHODS: A cross sectional observational study was conducted among 104 primary school children of a primary school situated in the slum area of Chetla, Kolkata, India with the help of a predesigned, pre-tested and structured questionnaire. Data were analyzed statistically by simple proportions and tests of significance. RESULTS: It was found that the female students were more knowledgeable than the male students regarding the maintenance of personal hygiene. There was a wide gap between practice and knowledge of personal hygiene among the primary school children living in the slum area. Even, misconceptions do exist on certain indicators of personal hygiene among the students. Statistically significant association was observed between practices of personal hygiene among the primary school children and the literacy status of their mother. DISCUSSION AND CONCLUSIONS: Future of a society depends considerably on the health of its children. The parents and the school teachers, as constructive shapers of children's health behaviors, should play a responsible role in early education of children on personal hygiene. PMID- 24783894 TI - Frequency and profile of induced abortions: hospital based study in tertiary hospitals in Egypt. AB - OBJECTIVES: To determine the frequency and profile of induced abortions among hospitalized cases of abortions in three tertiary hospitals in Egypt. METHODS: A total of 517 consecutive cases of abortions with complete records were enrolled from three tertiary hospitals in Egypt: two hospitals in Cairo and one hospital in Alexandria. A data extraction sheet was designed to extract the required information from the records. It included: File No., Age, marital status, occupation, parity, number of children, previous abortion, history of contraception, trial of induction for this abortion and management of abortion in the hospital. The World Health Organization (WHO) criteria of categorizing the abortion as possible, probable or certainly induced abortion was used for classification of abortion cases. RESULTS: The proportion of classified induced abortions (certainly, probably and possibly induced abortions) was 30.6% in the total sample, being higher in Alexandria hospital (60.9%) compared to 14 and 19% in the other two hospitals respectively. Using the multiple logistic regression, the following factors were found independently related to induced abortions: Alexandria hospital (as proxy for residence), age > or = 30 years and having more than 2 children. CONCLUSION: The current study revealed that about one third of hospitalized cases of abortion can be suspected of being induced. Induced abortion may be linked to elder age, higher number of children in the family and probably have geographical variation in Egypt. PMID- 24783895 TI - Testicular-self examination among Nigerian adolescent secondary school boys: knowledge, attitudes and practices. AB - BACKGROUND: Testicular-self examination (TSE) is a cheap and easy-to-perform procedure for early detection of testicular cancer but data on this subject is lacking in Nigeria, particularly among male adolescents. OBJECTIVE: To assess the knowledge, attitudes and practices of testicular-self examination among secondary school boys. METHODS: Knowledge, attitudes and practices in relation to TSE were assessed, using anonymous structured self-administered questionnaires in a sample of 540 secondary school boys aged between 15 and 20 years. RESULTS: Nearly all (98.7%) the male students had never heard of TSE and had hardly practiced TSE. Of the 7 students who admitted examining their testicles, none did so at the recommended level (10 or more times per year) and did not follow the standard procedure for TSE. Nearly half (47.2%) of the participants had a positive intention to start performing TSE regularly after hearing of TSE (through the questionnaire and subsequent teaching on the subject). CONCLUSIONS: The level of knowledge, practice and the rating of the importance of TSE are all very low among adolescent secondary school boys in Benin City, suggesting that these students are unaware of the value of this personal health surveillance tool. The students demonstrated a positive intention to start performing TSE regularly after hearing of TSE (through the questionnaire and subsequent teaching on the subject). PMID- 24783896 TI - Sequence based typing of Legionella pneumophila sg 1 isolated in nosocomial acquired infections in Apulia, Southern Italy. AB - OBJECTIVE: The present report aims to molecularly characterize seven clinical L. pneumophila (L. pn.) sg 1 isolated from nosocomial acquired infections in Apulia region, using the European Working Group on Legionella Infections (EWGLI), sequence-based typing (SBT) and amplified fragment length polymorphism (AFLP) protocols and to compare the identified sequence types (STs) with those available in the EWGLI database. METHODS: In the period, January 2000-December 2012, 151 is cases (136 of community and 15 of nosocomial origin) of Legionnaires' disease were notified to the Regional Center for Epidemiology. With regard to nosocomial cases, 8 were confirmed by the isolation of Legionella spp. from respiratory secretions. These clinical isolates were characterized by amplified fragment length polymorphism (AFLP) and sequence-based typing (SBT), using the EWGLI standardized protocol. RESULTS: The clinical isolates belong to ST42, ST23 and ST1. The AFLP confirms the SBT results. Comparing the STs herein detected with those already in the EWGLI SBT database, the 3 STs are frequent in other European countries. CONCLUSIONS: The molecular analysis demonstrates that the 3 STs are the most frequent in Italy and in Europe, supporting the hypothesis that some specific L. pn. sg 1 clones have gained widespread dissemination probably due to a common ecological niche. Further researches are required to investigate the potential changing incidence of STs and the fitness of emerging strains or clonal groups in environmental strains. PMID- 24783897 TI - Urinary tract infection among intellectual disability individuals "etiology and antibiotic resistance patterns" in rehabilitation centers of Mazandaran province, Northern Iran. AB - OBJECTIVE. Urinary tract infections (UTIs) are amongst the most common infections and account for large proportion of antibacterial drug consumption. The aim of this study was to determine the rate and the etiologic agents of UTIs in inhabitants of rehabilitation centers of Mazandaran province in northern Iran and to evaluate the antimicrobial susceptibility patterns of the uropathogens isolated. METHODS: Clean catch midstream urine sample was collected from each of 314 participants (163 males, 151 females) residing in 12 rehabilitation centers of Ramsar, Nowshahr, Chalous, Amol, Sari and Behshahr. Urine specimens were cultured and bacterial isolates were identified by conventional methods. All urines fulfilling the criteria for the presence of significant bacteriuria (> or = 10(4) cfu/ml urine) were defined as positive. Antibiotic susceptibility testing was performed by Kirby-Bauer disc diffusion method. RESULTS: The rate of urinary tract infection was 30.9% with the highest rate in pediatrics (p < 0.0001).The prevalence of UTIs were shown to be higher in females than in males with the rate of 46.3% in young aged females (20-29 years), 60% in middle aged group (40-49 years) and 50% in elderly (> 50 years). Bacteria most frequently isolated from urine specimens was Escherichia coli (39.2%) with the highest rate of infection in females age group < 10 years (p < 0.001). Among the antibiotics tested against the isolated organisms for susceptibility test, ceftriaxone and gentamicin maintain good activity against the majority of gram negative bacteria that cause UTIs recovered from individuals with intellectual disability. Vancomycin was effective against Staphylococcus aureus. CONCLUSIONS: This survey shows that the prevalence of UTIs among inhabitants of institutions for mentally retarded persons in Mazandaran province of Iran is much higher than normal population. PMID- 24783898 TI - Anti-rods and rings autoantibodies can occur in the hepatitis c-naive population. AB - INTRODUCTION: The anti-Rods and Rings autoantibody recently described in clinical populations is thought to occur in the setting of hepatitis C treatment, specifically in the context of cytidine triphosphate (CTP) and guanosine triphosphate (GTP) synthetic pathway inhibitors, and is important in its potential impact on response to therapy. This study asks the question: what is the epidemiology of anti-RR autoantibody in the general, non-clinical population? MATERIALS AND METHODS: This is a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES). Immunofluorescence assay for anti-Rods and Rings autoantibody were performed by NHANES labs and the results made publically available. Sample weights were used to calculate the prevalence and distribution of the autoantibody across demographics. A medication profile of the autoantibody positive population was also constructed RESULTS: The study sample consisted of 4738 persons over the age of 12 years. Anti-Rods and Rings autoantibodies were found in 39 persons representing 1.3 million persons in the United States population. 38 of 39 persons with anti-Rods and Rings autoantibody had no prior history of hepatitis C virus infection. A majority of these persons were found to have poly-pharmacy. DISCUSSION: This is the first study to show that anti-RR can occur in the general population without evidence of hepatits C virus infection, and that the majority of persons with anti-RR in the population have no evidence of prior hepatitis C infection. This indicates that there may be another undetermined etiology for anti-rods and rings autoantibodies besides the currently accepted exposure etiology of hepatitis C virus infection and treatment found in clinical studies. PMID- 24783899 TI - Suspension of mandatory vaccination and public health preserving: Rovigo local health unit experience after appliance of Veneto regional law 7/2007. AB - The burden of infectious diseases preventable by vaccination decreased considerably over last decades in all countries provided with effective immunization schedules. Implementation of these programs with new vaccines has started discussion on duality between mandatory and recommended vaccinations. Regional autonomy has allowed the Veneto Region, with introduction of Law 7/2007, to experience suspension of all mandatory childhood vaccinations, replaced by an active and free offer of all vaccines recognized as safe and effective. Coverage's trends and acceptance of invitation are carefully monitored to avoid loss of compliance and reduction of immunized children. The evaluation, performed on population of Rovigo ULSS18 for 2002-2008 birth cohorts (2008 is the first concerned by the change), revealed no fall for previously mandatory vaccinations, but rather a slight increase. Percentage of non-vaccinated children was negligible. The leading cause of non-vaccination to polio was inability to deliver the letter of invitation due to wrong address. An informed dissent was expressed only by a minority (0.9% in 2008 birth cohort). Compliance to immunization offer was elevated both for previously compulsory and recommended vaccinations. Experience of Rovigo ULSS 18 showed that, in a context of already high levels of coverage for recommended vaccinations with optimal organization of immunization services, coverage rates for ex-mandatory vaccines remain unchanged. Further research and reports are required to carefully assess the effect on coverage rates in next birth cohorts, but available data are encouraging. Similar legislative measures can be successfully adopted by other Regions with starting conditions comparable to Veneto Region. PMID- 24783900 TI - Attitude and knowledge of Iranian female nurses about human papilomavirus infection and cervical cancer: a cross sectional survey. AB - BACKGROUND AND AIM: Human Papilomavirus (HPV) is one of the most widespread sexually transmitted diseases is highly related to cervical cancer in women. Cervical cancer's crude incidence rate in Iran is 6-8 per 100,000. The HPV vaccine provides a chance to considerably decrease the transmission of most types of HPV. The aim of this study was to evaluate awareness and knowledge of HPV infection and vaccines and to assess the attitude and approach toward these vaccines among female nurses at Shahid Sadoughi University of Medical Sciences, Yazd, Iran. MATERIALS AND METHODS: This cross-sectional, descriptive study was performed among 380 female nurses. Data were collected using a questionnaire was consisted in demographic variables and questions on knowledge of participants about HPV infection, HPV vaccine and cervical cancer and also questions on attitude of ourses towards HPV vaccination. The validity and internal consistency of questionnaire was confirmed during experts consents and pilot testing (alpha = 0.79). Data analysis was performed using SPSS15 using chi2-test or Fisher's exact test. RESULTS: Three hundred and eighty questionnaires were distributed and 357 female nurses completed and returned their questionnaires: Only one hundred and thirty-one of the nurses (36.7%) knew about HPV infection and how it can cause abnormal pap Smear results. about 147 (41.2%) of the nurses stated they would want to be vaccinated. About 146 (40.9%) of respondents supported vaccination of preadolescent girls. CONCLUSION: The results of this study confirm the lack of knowledge about HPV vaccine and its relation to cervical cancer and also the ways of this cancer prevention. Our study shows an urgent need to design similar studies in other regions of Iran and draw a broad estimation on knowledge of different target groups to make a national program to increase the knowledge of women on this matter and help to decrease the rate of cervical cancer in Iranian population. PMID- 24783901 TI - Review of the Journal Medical Archives in 2013. PMID- 24783903 TI - Comparison of Alvarado score evaluation and clinical judgment in acute appendicitis. AB - BACKGROUND: Acute appendicitis is the most common surgical emergency in children, but its diagnosis is sometimes difficult. The aim of this study is to evaluate retrospectively the Alvarado score in relation to the surgical management based on clinical judgment. METHODS: Medical files of 232 children who underwent appendectomy at Makassed General Hospital from January 1997 till December 2006 were reviewed. Demographic characteristics, symptoms and signs, laboratory results and imaging findings for all children were recorded. RESULTS: The positive predictive value of our clinical judgment was 86.4% and the negative appendectomy rate was 13.6% based on the pathology results. The reliability of Alvarado score in our population found a PPV of 80.7% and a negative appendectomy rate of 11.3%. A multivariate analysis revealed that anorexia, neutrophils left shift and rebound tenderness are significantly correlated with a correct diagnosis of appendicitis (p = 0.012, 0.023 and 0.046 respectively). CONCLUSION: Although, Alvarado score provides measurably useful diagnostic information in evaluating children with suspected appendicitis, we found that good clinical judgment remain the main stay of correct diagnosis of appendicitis. PMID- 24783902 TI - Response of smooth bronchial musculature in bronchoconstrictor substances in newborn with lung atelectasis at the respiratory distress syndrome (RDS). AB - OBJECTIVE: Role of the atelectasis (hypoxia) in the respiratory system of the live and exited newborn (250 up to 3000 g. of body weight), which has died due to different causes was studied in this work. METHODS: Response of tracheal rings to dopamine, serotonine and ethanol in the different molar concentrations (dopamine: 0.05 mg/ml, 0.5 mg/ml, 5 mg/ml; serotonine (5-HT): 10(-4), 10(-3), 10(-2), 10(-1) mol/dm3; ethanol: 0.2 ml, 0.5 ml, 1.0 ml; 96%) was followed up. Study of the smooth tracheal musculature tone (STM) was elaborated in 16 tracheal preparations taken following the newborn death due to different causes. RESULTS: Based on functional researches of tracheal isolated preparations, it was ascertained as follows: atelectasis (cases born with lung hypoxia) has changed the response of STM to dopamine, serotonine and ethanol in a significant manner (p < 0.01) in comparison to cases of controlling group, which has died due to lung inflammatory processes (e.g. pneumonia, bronchopneumonia, cerebral hemorrhage), which have also caused significant response (p < 0.05). CONCLUSION: Results suggest that exited cases from lung atelectasis and cases of controlling group reacts to above mentioned substances by causing significant constrictor action of tracheobronchial system. PMID- 24783904 TI - The changes of arterial blood gases in COPD during four-year period. AB - INTRODUCTION: COPD (Chronic Obstructive Pulmonary Disease) is characterized by airflow limitation that is not fully reversible and that can lead to respiratory failure. OBJECTIVE: To show the changes of arterial blood gases in COPD during the 4-year evolution of illness. MATERIAL AND METHODS: The research was done on patients suffering from COPD treated at the Clinic "Podhrastovi" during 2006 and 2007 year. The tested parameters were examined from the date of receiving patient with COPD to hospital treatment in 2006 and 2007 and then followed prospectively until 2010 or 2011 year (the follow-up period was 4 years). There were total 199 treated patients who were chosen at random and regularly attended the control examinations. The study was conducted on adult patients of both sexes, different age group. In each patient the duration of illness was recorded so is sex, age, data of smoking habits, information about the regularity of taking bronchodilator therapy during remissions of disease, about the treatment of disease exacerbations, results of blood gases analysis as follows: pH value, PaO2 (partial pressure of oxygen in arterial blood), PaCO2 (partial pressure of carbon dioxide in arterial blood). All these parameters were measured at the beginning and at the end of each hospital treatment. We took in elaboration data obtained in the beginning of the first hospitalization and at the end of the last hospitalization or at the last control in outpatient department when patient was in stable state. Patients were divided into three groups according to the number of exacerbations per year. RESULTS: There is the statistically significant decrease of PaO2 (p < 0.01) and pH, (p < 0.05) and an increase of PaCO2 (p < 0.01) during follow-up period. But in patients regularly treated in phases of remission and exacerbations of illness the course of illness is slower. The decrease of pH and PaO2 and increase of PaCO2 is statistically significantly smaller in those received regular treatment in phases of remissions (P values are respectively: < 0.05, < 0.01 and < 0.01) and exacerbations of illness (p values are respectively: < 0.01, < 0.01 and < 0.05). CONCLUSION: COPD is characterized with airflow limitation which is progressive in the course of illness, and by the changes in arterial blood gases that can lead to respiratory failure, but that course may be made slower using appropriate treatment during remission and exacerbations of diseases. PMID- 24783905 TI - Metabolic syndrome in Mexican women survivors of breast cancer: a pilot study at a general hospital. AB - INTRODUCTION: According to developed countries' studies, in breast cancer survivors there is a high prevalence of metabolic syndrome; however, in Mexico data is lacking about this issue. GOAL: To explore if metabolic syndrome occurs in Mexican women survivors of breast cancer. MATERIAL AND METHODS: At a second level general hospital, women with breast cancer with a surviving > 2 years were studied. The analysis involved their demographic and anthropometric features, blood pressure measurement, time of surviving, besides fasting blood levels of lipids and glucose. RESULTS: The sample consisted of 100 women; 42% were obese (body mass index > or = 30 kg/m2). The sample's mean age was 60 years with a mean surviving time of 6.5 years. Their mean glucose level was 122 mg/dL and triglycerides 202 mg/dL. There were 33% with blood pressure > or = 130/85mm Hg or diagnosis of hypertension. Fifty-seven percent had glucose > 99 mg/dL or diagnosis of diabetes mellitus, and 58% had triglycerides > 149 mg/dL. Metabolic syndrome occurred in 57% of obese women. CONCLUSION: Our results suggest that metabolic syndrome occurs in more than 50% of obese Mexican women survivors of breast cancer. PMID- 24783907 TI - Variations in diameters of vertebro-basilar tree in patients with or with no aneurysm. AB - INTRODUCTION: The morphological anatomy of the posterior circulation is very complex and variable. Aims of this research were to document the morphological anatomy of the posterior circulation along with variations in the Bosnian population, in patients with or without aneurysm. Measurements of the outer diameters of the vertebral artery, basilar artery and posterior cerebral artery were taken. The second aim was to determine the possible relationship between diameters of the area with subsequent aneurysm formation. MATERIAL AND METHODS: The study involved 60 consecutive patients, adults of both sexes, treated in the UKC Tuzla. The patients were divided into two groups. One group consisted of the patients without aneurysm of basilar artery, and the other group of patients with aneurysm. All the 60 patients were treated by means of MRI angiography. RESULTS: The mean diameter of the vertebral artery was 2.43 mm; 3.61 mm on the right and 2.83 mm; 3.94 mm on the left. The diameter of the basilar artery varied from 3.8 mm; 3.43 mm. The diameter of the posterior cerebral arteries 2.5 mm; 2.52 mm on the right and 2.46 mm; 2.62 mm on the left. CONCLUSIONS: We have documented the various morphometry variations as well as the differences of the anatomy in this area in Bosnian population as compared to the medicine literature. PMID- 24783906 TI - Anthropometric and biochemical characteristics of patients with nonalcoholic fatty liver diagnosed by non-invasive diagnostic methods. AB - INTRODUCTION: Non-alcoholic (NAFLD) encompasses a spectrum of disease states, from steatosis (fatty liver) to non-alcoholic steatohepatitis (also called NASH steatosis with inflammatory changes) followed by progression to fibrosis and cirrhosis and hepatocellular carcinoma Excess liver fat is believed to be a manifestation of the metabolic syndrome and not surprisingly NASH is associated with obesity, insulin resistance, dyslipidemia and type 2 diabetes in humans. AIM OF THE STUDY: Is to establish anthropometric and biochemical specificities in patients with non-alcoholic steatohepatitis diagnosed with non-invasive diagnostic methods. MATERIAL AND METHODS: Study enrolled 170 participants, 130 with NASH steatosis. The non-alcoholic group (control), consisted of 40 normal weight patients without metabolic syndrome. Alcohol intake was estimated with established protocol. Routine biochemistry analysis were performed by standard laboratory procedures; serum levels of serum levels of fasting cholesterol and triglycerides, fasting glucose and insulin, insulin resistance estimated by HOMA index (Homeostasis model assessment), biochemistry tests and a liver ultrasound examination. RESULTS: In study participants group, patients were more obese comparing with controls p < 0.01, waist line extent also was of greater statistical significance in the non-alcoholic group fatty liver (p < 0, 01). Comparing biochemical parameter values, significant statistical deference has been noted in glaucosis and insulin levels, total cholesterol and gama-glutamil transferase levels, between groups (p < 0.01). Fasting glucose and insulin levels, HOMA-IR were significantly greater in study cohort group patients, as was significantly positive correlation between BMI and waist line extent. CONCLUSION: Patients with non-alcoholic fatty liver are excessively obese, have greater waist line extent, consequently insulin resistance and impaired glucose metabolism, insulin resistance, dyslipidemia, risk factors known to be associated with the development of cardiovascular disease. PMID- 24783908 TI - Complications and functional recovery in treatment of femoral shaft fractures with unreamed intramedullary nailing. AB - INTRODUCTION: Fracture of the femoral shaft is a common fracture encountered in orthopedic practice. In the 1939, Kuntscher introduced the concept of intramedullary nailing for stabilization of long bone fractures. Intramedullary nailing has revolutionized the treatment of fractures. MATERIAL AND METHODS: The study included 37 male patients and 13 female patients, averaged 39 +/- 20.5 years (range, 16 to 76 years). RESULTS AND DISCUSSION: There were 31 left femurs and 21 right femurs fractured. 46 fractures were the result of blunt trauma. Low energy trauma was the cause of fractures in six patients, of which five in elderly females. 49 fractures were closed. Healing time given in weeks was 19.36 +/- 6.1. The overall healing rate was 93.6%. There were three (6.25%) major complications nonunion. There were one (2%) delayed union, one (2%) rotational malunion and no infection. The shortening of 1 cm were in two patients. Antercurvatum of 10 degrees was found in one patient. There was no statistically significant reduction of a motion in the hip and knee (p < 0.05). There was statistically significant in the thigh (knee extensors) muscle weakness (p < 0.001). CONCLUSION: : Intramedullary nailing is the treatment of choice for femoral shaft fractures. PMID- 24783909 TI - Gastric cancer staging: EUS and CT. AB - INTRODUCTION: Gastric cancer is the fourth most common cancer and the second leading cause of death from cancer. Only complete resection of all gross disease with negative microscopic margins (R0 resection) provides a long-term survival benefit, and the overall 5-year relative survival rate is approximately 20%. To improve survival and quality of life, new therapeutic approaches have been introduced. MATERIAL AND METHODS: A total of 277 patients (171 men, 106 women) were included in this analysis. The results from the preoperative EUS and MDCT were compared to the postoperative pathological findings. A radial scanning ultrasonic endoscope was used. In patients with early gastric cancer, especially in cases confined to mucosa, endoscopic resection is performed to avoid unnecessary surgical procedures. To achieve R0 resection for locally-advanced gastric cancer, neoadjuvant treatments have been investigated. RESULTS AND DISCUSSION: Laparoscopic surgery has been shown to improve quality of life for both early and locally advanced gastric cancer. Endoscopic ultrasonography (EUS), which is considered to be the most precise method for locoregional staging, was commonly used for differentiating mucosal lesions from submucosal lesions. By contrast, computed tomography (CT) was used to detect the presence of distant metastasis. The difference in accuracy between the < or = 20-mm group and other groups was statistically significant for both EUS and MDCT (P = 0.026 and P = 0.044, respectively). CONCLUSION: However, recent technological advances with the helical and multi-detector scanners have provided better CT performance. PMID- 24783910 TI - Screening for depression patients in family medicine. AB - GOAL: The aims are to establish the prevalence of newfound, unidentified cases of depressive disorder by screening with the Becks Depression scale; To establish a comparative relationship with self-identified cases of depression in the patients in the family medicine; To assess the significance of the BDI in screening practice of family medicine. PATIENTS AND METHODS: A prospective study was conducted anonymously by Beck's Depression scale (Beck Depression Questionnaire org.-BDI) and specially created short questionnaire. The study included 250 randomly selected patients (20-60 years), users of services in family medicine in "Dom Zdravlja" Zenica, and the final number of respondents with included in the study was 126 (51 male, 75 female; response or response rate 50.4%). Exclusion factor was previously diagnosed and treated mental disorder. Participation was voluntary and respondents acknowledge the validity of completing the questionnaire. BDI consists of 21 items. Answers to questions about symptoms were ranked according to the Likert type scale responses from 0-4 (from irrelevant to very much). Respondents expressed themselves on personal perception of depression, whether are or not depressed. RESULTS: Depression was observed in 48% of patients compared to 31% in self estimate depression analyzed the questionnaires. The negative trend in the misrecognition of depression is -17% (48:31). Depression was significantly more frequent in unemployed compared to employed respondents (p = 0.001). The leading symptom in both sexes is the perception of lost hope (59% of cases). CONCLUSION: All respondents in family medicine care in Zenica showed a high percentage of newly detected (17%) patients with previously unrecognized depression. BDI is a really simple and effective screening tool for the detection and identification of persons with symptoms of depression. PMID- 24783911 TI - Re-laparotomy after cesarean section: risk, indications and management options. AB - AIM: To identify risks, indications and outcomes for relaparotomy after cesarean delivery. METHODS: A prospective case-controlled study conducted at Mansoura University Hospital, Egypt from 2009 to 2012. Each case was matched randomly to 2 cases that had delivered by cesarean section during the same period and did not undergo repeated surgical intervention. Information's on indications were obtained to gather information's on risks factors. RESULTS: relaparotomy complicated 1.04% (n = 26) of the total number of the cesarean section (CS) (n = 2500). The principal indications for relaparotomy were internal bleeding (Intra abdominal bleeding in 41.7% (n = 10); rectus sheath hematoma in 29.2% (n = 7) and uncontrolled postpartum hemorrhage (PPH) in 29.2% (n = 7) of cases, followed by infections in 7.7% (n = 2) of cases. Resulting in 11.5% (n = 3) maternal death. Predictors for relaparotomy after cesarean delivery from univariate logistic model, placenta previa (OR = 6.898, 95% CI = 1.867- 25.4, P = .004), fetal weight greater than 4 kg (OR = 6.409, 95% CI = 1.444-28.44, .015). Previous cesarean section and parity were not a risk for re-laparotomy. CONCLUSION: In this study, the incidence of relaparotomy after cesarean delivery was very high (1.04%). Associated with high maternal mortality (11.5%). The main predictors were placenta previa and fetal macrosomia. PMID- 24783912 TI - Correlation of age and severity of clinical manifestation assessed by UPDRS in patients with idiopathic Parkinson's disease. AB - AIM: In older people with Parkinson's disease the symptoms are more expressed. BACKGROUND: Essential change in Parkinson's disease is the impaired neurotransmission in basal ganglia. Idiopathic Parkinson's disease (IPD) is the most frequent type of Parkinsonism, being present in about 70% of the patients with Parkinsonism. MATERIAL AND METHODS: This study has been prospective, clinically one, which has been lasting for whole 2 years. This study comprised a total of 32 subjects with clinically verified diagnosis for idiopathic Parkinson's disease, 18 men and 14 women (with mean age of 52,7 years). Control group consisted of 31 randomly selected, literally healthy persons, at similar age, with similar gender representation without clinical and anamnestic data for Parkinsonism and similar clinical entities. This study was made at the University Clinic of Neurology in Skopje, Medical Faculty, University "St. Cyril and Methodius'. The persons investigated had idiopathic Parkinson's disease (IPD), in whom IPD was verified by means of: detailed anamnesis, detailed clinical neurologic examination, strictly keeping to Brain Bank Criteria, and by means of neurophysiologic investigations, neuroimaging investigations and neuropsychologic investigations. Minimal symptoms of IPD after UPDRS were present in 34.4% of the examinees, there were 40.6% with slight signs, while equal number of the examinees 4 (12.5%) had pronounce and very expressed symptoms of Parkinson's disease after UPDRS. CONCLUSION: Parkinson's disease is with more expressed signs and symptoms and with slight symptoms in older patients with this diagnosis. PMID- 24783913 TI - Post stroke depression. AB - INTRODUCTION: Comorbidity of depression and stroke significantly reduces the quality of life of patients after the stroke. Squeal after stroke also determines the quality of life and have impact on the occurrence of depression after the stroke. In our study we investigated the occurrence of depression in patients after different types and subtypes of stroke measured by the Hamilton scale compared to the level of disability measured by NIHSS scale. GOAL: The goal was to make a comparative analysis of depression after stroke, according to gender and age, side of the lesion and the severity of neurological deficit. MATERIAL AND METHODS: Material for our work are 210 patients with stroke treated at the Neurology Clinic, Clinical Center of Sarajevo University in 2012, 105 male and 105 female. The mean age of the patients was 67.12 +/- 9.5 years. Ischemic stroke was present in 65% cases. There was no statistically significant difference between ischemic and hemorrhagic stroke among genders. In case of hemorrhagic M 56.7%, F-43.3%; ischemic M-48.3%, F-51.7% (chi-square = 6.563, p = 0.082). Depression was more prevalent among younger patients (52-60 years) with 39.2% then in the group of older patients (61-70 years) with 32% of depressed. In relation to gender there was significantly more patients with depression among women compared to men (63.8:27.2%, chi-square = 14.38, p = 0.00019). Depression was more frequent in patients with stroke in the left hemisphere medial localization (63%). NIHSS scale average was 16.07 with the minimum of 11 and maximum of 22, F = 52.56, p = 0.001. CONCLUSIONS: We can conclude that depression after stroke is more frequent in younger patients, female patients, patients with localized stroke in the medial left hemisphere and with higher disability score. PMID- 24783914 TI - Treatment of rheumatoid arthritis with biologic DMARDS (Rituximab and Etanercept). AB - GOAL: To determine efficacy and safety of treatment with Rituximab and Etanercept plus Methotrexate in patients with active Rheumatoid Arthritis (RA), who had an inadequate response to nonbiologic DMARDS therapies and to explore the pharmacogenetics and pharmacodynamics of Rituximab and Etanercept in our populations. Study was done at Rheumatology Clinic of University Clinical Centre in Prishtina during 2009-2011 years. METHODS: We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the study of long-term efficacy of Rituximab and Etanercept. Patients with active Rheumatoid Arthritis and an inadequate response to 1 or more non biologic DMARDS were randomized to receive intravenous Rituximab (1 course consisting of 2 infusions of 1.000 mg each -one group, and Etanercept 25 mg twice weekly -second group, but both groups with background MTX. The primary efficacy end point was a response on the ACR 20%, improvement criteria at 24 weeks, Secondary end points were responses on the ACR 50 and ACR 70, improvement criteria, the DAS 28, and EULAR response criteria at 24 weeks. RESULTS: During our investigations we treated 20 patients, 15 females and 5 males, in the treated group with RTX and 13 patients 8 females and 5 males in the treated group with ETN. Patients of group 1 and group 2 were of ages 37-69 years old and 19-69 years old (average 47-44) Most of the patients belong in 2nd and 3rd functional stage according to Steinbrocker. All ACR response parameters were significantly improved in RTX treated patients who also had clinically meaningful improvement in fatigue, disability and quality of life. Patients showed a trend less progression in radiographic end points. Most adverse events occurred with the first RTX infusion and were mild to moderate severity. CONCLUSION: At 24 weeks, a single course of RTX and ETN provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more nonbiologic DMARDS. PMID- 24783915 TI - External dacryocystorhinostomy with and without suturing the posterior mucosal flaps. AB - PURPOSE: To evaluate the outcome of the external dacryocystorhinostomy with and without suturing the posterior mucosal flaps. METHODS: This study included 106 patients with lacrimal drainage system disorders who underwent the external dacryocystorhinostomy. Fifty four patients (Group A) underwent external dacryocystorhinostomy with suturing anterior and posterior flaps of the lacrimal sac and nasal mucosa, and the results obtained were compared with those of another series of 52 patients (Group B) where dacryocystorhinostomy was performed with suturing only the anterior flaps, whereas posterior mucosal flaps were excised. RESULTS: The success rate was evaluated by lacrimal patency to irrigation and relief of epiphora. Patency achieved in groups A and B was 94.4% and 96.2%, respectively. There was no statistically significant difference in success rate between the groups. CONCLUSION: Our study suggests that external dacryocystorhinostomy with suturing anterior and posterior flaps have no advantage over dacryocystorhinostomy with suturing only anterior flaps. Anastomosis by suturing only anterior flaps and excision of the posterior flaps is easier to perform and may improve the success rate of external dacryocystorhinostomy. PMID- 24783916 TI - Patient monitoring in mobile health: opportunities and challenges. AB - BACKGROUND: In most countries chronic diseases lead to high health care costs and reduced productivity of people in society. The best way to reduce costs of health sector and increase the empowerment of people is prevention of chronic diseases and appropriate health activities management through monitoring of patients. To enjoy the full benefits of E-health, making use of methods and modern technologies is very important. METHODS: This literature review articles were searched with keywords like Patient monitoring, Mobile Health, and Chronic Disease in Science Direct, Google Scholar and Pub Med databases without regard to the year of publications. RESULTS: Applying remote medical diagnosis and monitoring system based on mobile health systems can help significantly to reduce health care costs, correct performance management particularly in chronic disease management. Also some challenges are in patient monitoring in general and specific aspects like threats to confidentiality and privacy, technology acceptance in general and lack of system interoperability with electronic health records and other IT tools, decrease in face to face communication between doctor and patient, sudden interruptions of telecommunication networks, and device and sensor type in specific aspect. CONCLUSIONS: It is obvious identifying the opportunities and challenges of mobile technology and reducing barriers, strengthening the positive points will have a significant role in the appropriate planning and promoting the achievements of the health care systems based on mobile and helps to design a roadmap for improvement of mobile health. PMID- 24783917 TI - The role of medical staff in providing patients rights. AB - Among the priority basic human rights, without a doubt, are the right to life and health-social protection. The process of implementation of human rights in the everyday life of an ordinary citizen in the post-war recovery of Bosnia and Herzegovina faces huge objective and subjective difficulties. Citizens need to be affordable adequate healthcare facilities that will be open to all on equal terms. The term hospital activity implies a set of measures, activities and procedures that are undertaken for the purpose of treatment, diagnosis and medical rehabilitation of patients in the respective health institutions. Principles of hospital care should include: Comprehensiveness (Hospital care is available to all citizens equally); Continuity (Provided is continuous medical care to all users); Availability (Provided approximately equal protection of rights for all citizens). Education of health professionals: The usual threats to patient safety include medical errors, infections occurred in the hospital, unnecessary exposure to high doses of radiation and the use of the wrong drug. Everyday continuing education in the profession of a doctor is lifelong. PMID- 24783918 TI - An unexpected cause of hemoptysis: endobronchial lipomatous hamartoma. AB - Hamartomas are the most common benign tumors of the lung. Endobnronchial hamartomas are even rarer and infrequently causes hemoptysis. We report a case of endobronchial hamartoma that was originating from a segment bronchus and invisible in chest X-ray. A 63-year-old man was admitted to hospital with hemoptysis. A CT scan revealed endobronchial mass obstructing anterior bronchus of the right lower lob of the right lung. It wasn't radiographically presented. Flexible bronchoscopy detected a polypoid mass (1.5 x 1.0 cm) that arising from the posterior wall of the anterior segment of right lower lob. Histopathologic examination revealed lipoumatous hamartoma. It was resected with an electro surgical snare. Cryotherapy was applied to residual lesion on surface of the bronchus. The patient was successfully recovered. In conclusion, lipoumatous hamartoma may presented as rare cause of hemoptysis. Endoscopic treatment is safe and currently modality used for select cases. PMID- 24783919 TI - Chylopericardium after mitral valve repair for rheumatic valve disease treated with surgery. AB - Chylopericardium is a rare disorder that may be primary (idiopathic) or secondary to injury of the thoracic duct or thymus gland. Pediatric cardiac operations are more commonly related to this complication because thymus gland is very active in this population and atrophies in the adult patients. We present a case of chylopericardium after mitral valve repair for rheumatic disease, due to thymus gland tributaries injury. PMID- 24783920 TI - Treatment of endometrial cancer in patient with malignant obesity. AB - Our 60-year-old patient menarche in 13-year, two delivery, last menstruation in 53-year, without uterine bleeding or any kind of symptomatology. The gynecological transvaginal ultrasound examination showed hyperplasio endometrii (20 mm). After curettage, pathological examination was diagnostic polypus carcinomatoides. The patient with HTA and obesity was admitted to and operated on at the Gynecological Department due to endometrial carcinoma (FIGO stage IA1). Because of her giant obesity, BMI - 71.50 kg/m2, weight 219 kg and height 175 cm, surgery by the abdominal approach was very difficult to perform, so vaginal hysterectomy was carried out. The procedure was completed within 127 minutes without any intraoperative complications. Blood loss was less than 100 ml. The patient was discharged on postoperative day 7. The patient was followed up for 6 months after surgery. No complications or recurrence were reported during the 6 month follow up. PMID- 24783921 TI - Qingkailing injection for the treatment of acute stroke: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate systematically the clinical efficacy and safety of Qingkailing (QKL) injection in the treatment of acute stroke. METHODS: Searches for randomized controlled trials into acute stroke treated with QKL injection were performed in the China National Knowledge Infrastructure Database, China Science and Technology Journal Database, Wan fang Database, Chinese Biomedical Literature Database, PubMed and Cochrane Library, from January 1979 to March 2013. Two reviewers independently retrieved the RCTs and extracted the information. The Cochrane risk of bias method was used to assess the quality of the included studies, and a Meta-analysis was conducted with Review Manager 5.2 software. RESULTS: A total of 13 studies with 1110 participants were included. The quality of the studies was generally low. The Meta-analysis indicated that the combined use of QKL and Western Medicine was significantly superior to control group therapy in terms of the total effective rate. The relative risk (RR) in the acute cerebral hemorrhage (ACH) sub-group was 1.17 [95% confidence interval (CI) (1.08, 1.26), P = 0.0001]. In the acute cerebral infarction (ACI) sub-group, RR was 1.27 [95% CI (1.14, 1.42), P < 0.0001], and in the ACH and ACI mixed sub-group, RR was 1.34 [95% CI (1.20, 1.50), P < 0.00001]. Additionally, QKL promoted the absorption of hematoma [mean difference (MD) = - 3.73, 95% CL (- 4.48, - 2.98), P < 0.000 01], decreased neurological damage in ACI [MD = - 5.60, 95% CI (- 8.50, - 2.70), P = 0.0002] and ACH [MD = - 4.08, 95% CI (- 8.00, - 0.16), P = 0.04], promoted the recovery of awareness [RR = 1.56, 95% CI (1.09, 2.21), P = 0.01] and reduced the whole blood viscosity coefficient [MD = - 0.75, 95% CI (- 1.47, - 0.03), P = 0.04]. There were no adverse drug reactions reported in the included studies. CONCLUSION: Based on this systematic review, QKL combined with conventional therapy was effective compared with control treatment. However, because the articles used in the study were not of high quality, further studies should be conducted into the efficacy and safety of QKL in treating acute stroke. PMID- 24783922 TI - Effect of banxiaxiexin tang on treatment of functional dyspepsia: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy of Banxiaxiexin Tang compared with Western Medicine in the treatment of functional dyspepsia (FD) through Meta-analysis. METHODS: Literature was searched in the following databases: MEDLINE, Excerpta Medica Database, Chinese Medical Current Contents, China Science and Technology Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. Randomized controlled trials evaluating the efficacy of Banxiaxiexin Tang for the treatment of FD were selected according to certain standards including clear general situation of patients, specific diagnostic criteria, definite clinical outcomes, etc. Articles were evaluated with quality assessment standards in the Cochrane Handbook for Systematic Reviews of Interventions. Meta-analysis was conducted with RevMan 5.0.23 software. RESULTS: Ten articles with a total of 972 patients were included. The comparison of efficacy between Banxiaxiexin Tang and Western Medicine showed a combined effect size [OR = 2.75, 95% CI (1.86-4.07)] and combined effect of value of Z = 5.07 (P < 0.000 01), suggesting a significant difference between the groups. CONCLUSION: Banxiaxiexin Tang was more effective than Western Medicine in treating FD. PMID- 24783923 TI - Clinical efficacy and safety of traditional Chinese medicine combined with Western Medicine in patients with diabetic acute ischemic stroke. AB - OBJECTIVE: To observe the clinical efficacy and safety of Traditional Chinese Medicine (TCM) combined with Western Medicine (WM) in patients with diabetic acute ischemic stroke. METHODS: Ninety patients with diabetic acute ischemic stroke were randomly divided into a treatment group and a control group. The 45 patients in the treatment group were given standardized treatment with TCM combined with WM. They received corresponding oral Chinese decoctions three times daily, according to their TCM syndromes, along with basic western medical treatment. The 45 patients in the control group were given non-standardized treatment with TCM combined with WM. They received an oral Chinese decoction for promotion of blood circulation to inhibit hemostasis, regardless of their TCM syndromes, along with basic western medical treatment. The treatments lasted for 4 weeks. Scores were evaluated on the National Institutes of Health Stroke Scale (NIHSS) score, activity of daily life (ADL) scores, and TCM symptoms before treatment and 2 and 4 weeks after treatment. RESULTS: Analysis of variance for repeated measurements showed that there were significant differences in NIHSS and ADL score before and after treatment in both groups (P < 0.05). There were also significant differences between the scores at 2 and 4 weeks after treatment. There were significant differences in TCM syndrome scores before and after treatment in both groups (P < 0.05). There were also significant differences between the scores at 2 and 4 weeks after treatment. The X2 test showed no statistically significant difference in the incidence of adverse reactions between the two groups (P > 0.05). CONCLUSION: Standardized treatment was superior to non-standardized treatment for clinical efficacy of TCM combined with WM in patients with diabetic acute ischemic stroke, and the superiority was more obvious in improving neural dysfunction, ADL score, and TCM symptoms. The adverse reactions were similar in the two treatment groups. PMID- 24783924 TI - Effect of externally applied jidesheng anti-venom on skin and soft-tissue necrosis after Chinese cobra bite: a retrospective study. AB - OBJECTIVE: To evaluate the effects of Jidesheng anti-venom used externally for skin and soft-tissue necrosis from Chinese cobra bite. METHODS: A retrospective review was performed according to the clinical data recorded from January 2002 to December 2012. A total of 126 patients (116 females and 10 males) with skin and soft-tissue necrosis due to Chinese cobra bite were divided into two groups. The control group was treated externally with 40% glyceride magnesium sulfate (n = 52), and the treatment group was given Jidesheng anti-venom externally (n = 74). The data collected included maximum local necrotic area of skin and soft tissues, de-tumescence time, healing time, and skin-grafting rate. RESULTS: There were no significant differences in gender, age, and disease condition between the control and treatment groups (P > 0.05). No statistically significant difference was found in de-tumescence time between the two groups (P > 0.05). The maximum local necrotic area of skin and soft tissues was (19.9 +/- 7.3) cm2 in the treatment group, while it was (23.3 +/- 6.4) cm2 in the control group. The healing time of the treatment group was shorter than that of the control group [(32.1 +/- 3.7) vs (34.4 +/- 4.5) days)]. The skin-grafting rate in the treatment group was lower than that of the control group (10.81% vs 25.00%). There were statistically significant differences in maximum local necrotic area of skin and soft tissues, healing time, and skin-grafting rate between the control and treatment groups (all P < 0.05). CONCLUSION: External application of Jidesheng anti-venom may help to promote wound healing and reduce the skin-grafting rate in cases of skin and soft-tissue necrosis due to Chinese cobra bite. PMID- 24783925 TI - Effects of jianpi herbal suppository on hemorheology and CD62p in patients with ulcerative colitis. AB - OBJECTIVE: To compare the effects of a Chinese herbal suppository (Jianpi suppository) and Western Medicine (mesalazine) on hemorheology and CD62p in patients with ulcerative colitis (UC). METHODS: In a randomized trial, 120 mild to moderate UC patients were randomly divided into two equal groups. The Jianpi suppository group used Chinese herbal suppository rectally, while the mesalazine group was treated with mesalazine tablets orally. Two 15-day courses of treatment were carried out in both groups. Changes in the hemorheology and CD62p indices in patients were observed. RESULTS: The hemorheology and CD62p indices in the Jianpi suppository group decreased significantly more than those of the mesalazine group. CONCLUSION: Jianpi suppository is effective in improving the hypercoagulability of UC patients, and therefore may be worth using in clinical practice. PMID- 24783926 TI - Effects of five-element music therapy on elderly people with seasonal affective disorder in a Chinese nursing home. AB - OBJECTIVE: To explore the effects of five-element music therapy on elderly patients with seasonal affective disorder in a Chinese nursing home. METHODS: The patients (n = 50) were recruited from a Shijingshan district nursing home in Beijing, China. They were randomly assigned to two groups, a treatment group and a control group, with 25 participants in each group. The patients received music therapy for 1-2 h each week over an 8-week period. The music therapy involved four phases: introduction, activities, listening to the Chinese five-element music, and a concluding phase. The participants in the control group did not listen to the five-element music. This study consisted of two parts: (a) a qualitative study that used focus groups to understand the feelings of the patients with seasonal affective disorder; (b) a quantitative study that involved administration of the self-rating depression scale (SDS) and Hamilton depression scale (HAMD) before and after treatment. RESULTS: (a) Qualitative analysis results: strength derived from the five-element group music therapy and emotional adjustment. The five-element group music therapy can reduce patients' psychological distress and let them feel inner peace and enhance their life satisfaction. (b) No significant difference in SDS and HAMD scores was found between the two groups (P > 0.05) prior to treatment. After treatment, the mean SDS score of the control group was 49.9 +/- 18.8, while the treatment group's score was 40.2 +/- 18.1. The HAMD score of the control group was 11.2 +/-3.1, and the treatment group's score was 8.8 +/- 4.9. Following 8 weeks of music therapy, the SDS and HAMD scores of the treatment group were significantly lower than those for the control group (P < 0.05). CONCLUSION: Five-element music therapy alleviated the symptoms of seasonal affective disorder in the elderly patients. PMID- 24783927 TI - Correlation between tongue manifestations and glucose, total cholesterol, and high-density lipoprotein cholesterol in patients with acute cerebral infarction. AB - OBJECTIVE: To analyze the association between tongue manifestations and the levels of glucose (GLU), total cholesterol (TCH), and high-density lipoprotein cholesterol (HDL-C) in subjects with acute cerebral infarction. METHODS: Hospitalized patients with first unilateral cerebral infarction in the Neurological Department of Xuanwu Hospital were included and the correlation between tongue fur color, fur nature, and the levels of GLU, TCH, HDL-C were analyzed. RESULTS: HDL level in the thin fur group was higher than that in the thick fur group (P = 0.02). The difference in the levels of GLU, TCH, and HDL-C among the groups was significant (P < 0.05), classified in terms of slippery, moist, and dry fur. Further comparison between the groups by Student-Newman-Keuls test showed that GLU level in the dry fur group was the highest. Moreover, the TCH level in the slippery fur group was higher than the other two groups. CONCLUSION: A correlation between tongue manifestations and GLU, TCH, HDL-C was identified in the patients with acute cerebral infarction. PMID- 24783928 TI - An magnetic resonance-based plasma metabonomic investigation on abnormal Savda in different complicated diseases. AB - OBJECTIVE: To provide potential evidence for the existence of abnormal Savda, we assessed host metabonomic responses and dynamic changes occurring in various diseases using 1H nuclear magnetic resonance (NMR)-based metabonomics. METHODS: Plasma samples taken from patients with complicated diseases with abnormal Savda (n = 140, including 35 cases each of diabetes, asthma, breast cancer, and cervical carcinoma) and from healthy controls (n = 35) were analyzed by 1H NMR (600 MHz), and the spectral profiles were analyzed by multivariate analysis using orthogonal projection to latent structure with discriminant analysis. RESULTS: Supervised modeling of the data provided very good discrimination between patients and healthy controls. Compared with the healthy controls, the patient groups with different disease conditions displayed similar metabolic changes, characterized by lower creatine, creatinine, lactate, and amino acid levels (including isoleucine, leucine, valine, alanine, and 1-methylhistidine) and higher lipid levels (very low-density lipoproteins and unsaturated lipids). Additionally, cancer patients (breast and cervical) showed decreased myo inositol, a-glucose, and beta-glucose, and increased pyruvate and carnitine in plasma. CONCLUSION: The data indicate that decreased oxidative defense, liver function abnormalities, amino acid deficiencies, and energy metabolism disorders are common characteristics of complicated diseases, which may be related to the formation of abnormal Savda. PMID- 24783929 TI - Inhibitive effect on apoptosis in splenic lymphocytes of mice pretreated with lingzhi (Ganoderma lucidum) spores. AB - OBJECTIVE: To investigate how the pretreatment of mice with Ganoderma spores affected the apoptosis of their splenic lymphocytes induced by dexamethasone after 19 days treatment. METHODS: Sixty Kunming mice were randomly divided into six groups: blank control groupdrenched with normal saline; a drug control group drenched with 150 mg/mL Ganoderma spores; a model group treated with saline; a low dose group with 50 mg/mL Ganoderma spores; a moderate dose group with 100 mg/mL Ganoderma spores; and a high dose group with 150 mg/mL Ganoderma spores. The effect of Ganoderma spores on apoptosis in spleen lymphocytes was analyzed. All groups were treated for 19 days. On day 20, the model group and the 3 treatment groups were intraperitoneally injected dexamethasone to induce apoptosis. Splenic index and apoptosis indes were employed to measure cell apoptosis. RESULTS: The results showed that Ganoderma spores reduced the splenic index to different degrees in each group and the best effect was seen in the high dose group (P < 0.05).Terminal dexynucleotidyl transferase (TdT)-mediated 2' Deoxyuridine 5'-Triphosphate nick end labeling staining revealed that the apoptotic index in all groups administered Ganoderma spores differed significantly from the model group, and a dose-response was observed. Flow cytometric analysis indicated that spleen lymphocyte apoptosis in the model group was extensive. Each dose of Ganoderma spores inhibited dexamethasone-induced apoptosis in spleen lymphocytes, and a dose-response was observed as well. The highest dose of Ganoderma spores decreased Malondialdehyde content in serum induced by dexamethasone (P < 0.05). CONCLUSION: The findings imply that the pretreatment of the mice with Ganoderma spores could reduce the apoptosis rate induced by dexamethasone in their splenic lymphocytes. PMID- 24783930 TI - Chaiqinchengqi decoction regulates necrosis-apoptosis via regulating the release of mitochondrial cytochrome c and caspase-3 in rats with acute necrotizing pancreatitis. AB - OBJECTIVE: To explore the effect and the mechanism of Chaiqinchengqi decoction (CQCQD) on the apoptosis-necrosis switch of pancreatic acinar cells in acute necrotizing pancreatitis (ANP) in rats. METHODS: Sixty Sprague-Dawley rats were randomized into the control group, the ANP group and the CQCQD group. The acute pancreatitis (AP) model was induced by intraperitoneal injections of 4 g/kg 8% L Arginine (PH 7.0) twice with a 1 h interval. Rats in the CQCQD group were intragastrically administered CQCQD (20 mL/kg every 2 h, 3 times, then 20 mL/kg every 6 h, 3 times). Rats were killed at the 6 and 24 h after the induction of AP. The pancreatic tissues were collected for pathology and to isolate pancreatic acinar cells and mitochondria. RESULTS: CQCQD significantly ameliorated the severity of ANP by reducing the pancreatic histopathology score, indicated by lactate dehydrogenase levels at the 6 and 24 h. The CQCQD group promoted the apoptosis of pancreatic acinar cells by raising the apoptosis index compared with the ANP group and the control group. Mitochondrial cytochrome c at the 6 and 24 h in the ANP group were lower than that in the control group or the CQCQD group (0.67 +/- 0.13 vs 1.54 +/- 0.03 vs 0.81 +/- 0.09; 0.71 +/- 0.08 vs 1.55 +/- 0.09 vs 0.89 +/- 0.16, P < 0.01). The cytochrome c levels in the cytoplasm at the 6 and 2 h in the CQCQD group were higher than in the control group (1.36 +/- 0.15 vs 0.67 +/- 0.04, 1.46 +/- 0.08 vs 0.59 +/- 0.09, P < 0.01), or the ANP group (0.96 +/- 0.13, P > 0.05; 0.97 +/- 0.09, P < 0.05). CQCQD increased caspase-3 activity over the ANP group at the 6 h. CONCLUSION: CQCQD can induce apoptosis and relieve the necrosis of pancreatic acinar cells via promoting the release of mitochondrial cytochrome c and increasing pancreatic caspase-3 activity in ANP rats. PMID- 24783931 TI - Sedative and hypnotic effect of freeze-dried paeoniflorin and sini san freeze dried powder in pentobarbital sodium-induced mice. AB - OBJECTIVE: To investigate the sedative and hypnotic activity of paeoniflorin and freeze-dried Sini San powder on mice and provide a reliable method for determining the pharmacodynamic material basis of Sini San. METHODS: Male adult mice weighing 20-22 g were used in this study. Three experiments were carried out. Synergism with pentobarbital was used as an index for hypnotic effect. Loss of the righting reflex was used to determine the start of sleep. Sleep latency and sleeping time were recorded in each experiment. RESULTS: The coefficient of variation of the suprathreshold dose (55 mg/kg) was significantly lower than that of the threshold dose. The sleep latency of mice was significantly decreased, and the sleeping time of mice was significantly prolonged. The effects of paeoniflorin and Sini San on prolonging the sleeping time of mice induced by pentobarbital sodium were significantly stronger than those in the control group. CONCLUSION: Paeoniflorin produces significant sedative and hypnotic effects, and there is an obvious dose-effect relationship. PMID- 24783932 TI - Effect of qilongtoutong granule on calcitonin gene-related peptide, beta endorphin, serotonin, dopamine, and noradrenalin in migraine model rats and mice. AB - OBJECTIVE: To study the effect of Qilongtoutong granule (QLTT) on plasma calcitonin gene-related peptide (CGRP), beta-endorphin (beta-EP), 5-HT, dopamine (DA), noradrenalin (NE), and blood viscosity in migraine model rats and mice. METHODS: Both the acute blood stasis model group and nitroglycerin-induced migraine model group included 60 Sprague-Dawley rats. The reserpine-reduced model group had 60 Kunming mice. Rats from each test were grouped into normal control group, model group, Zhengtian pill (ZTP) group, and high, moderate, or low-dose QLTT groups. In the acute blood stasis model test, after gavage for 7 days, rats were given 0.8 mL/kg adrenaline hydrochloride subcutaneously twice, and kept in ice water for 5 min. After fasting for 12 h, rats were anesthetized and blood samples were collected for detection of blood viscosity. In the nitroglycerin induced migraine group, after gavage for 7 days, rats were intraperitoneally injected nitroglycerin (10 mg/kg), and 4 h later, blood samples were collected from postcava for measuring the plasma CGRP and beta-EP levels. In the reserpine reduced model test, except the normal control group, mice were administered reserpine (0.25 mg/ kg, i.h.) for 9 days. Mice received intragastric administration from the third day to the ninth day. One hour after the last gavage, blood and brain tissue samples were obtained. Then, blood clotting time and the contents of neurotransmitters were determined. RESULTS: QLTT- (3.6, 1.8, and 0.9 g/kg) and ZTP-treated rats had lower blood viscosity than that in model rats under different shear rates (P < 0.01). QLTT- (3.6, 1.8 g/kg) and ZTP treated rats had significantly lower plasma CGRP levels and higher plasma beta-EP levels than those in model rats (P < 0.01). QLTT treatment at dose of 0.9 g/kg had lower plasma CGRP levels as well (P < 0.05). QLTT- (5.2, 2.6 g/kg) and ZTP treated mice had longer blood clotting time than that in model mice (P < 0.01). QLTT- (2.6 g/kg) and ZTP-treated mice had higher plasma serotonin (5-HT) levels than those in model mice (P < 0.05). CONCLUSION: QLTT-treated animals had lower plasma CGRP level, higher plasma beta-EP, 5-HT, higher brain tissue 5-HT, NE, DA levels, and lower blood viscosity than those in the migraine model animals. PMID- 24783933 TI - Effect of acupotomy on nitric oxide synthase and beta-endorphin in third lumbar vertebrae transverse process syndrome model rats. AB - OBJECTIVE: To explore the long-term effects and pain relief mechanism of acupotomy by observing changes in nitric oxide synthase (NOS) and beta-endorphin (beta-EP) in the hypothalamus, spinal cord, and peripheral blood of rats with third lumbar vertebrae (L3) transverse process syndrome. METHODS: Twenty-eight SD rats were randomly assigned to normal, model, electroacupuncture (EA), and acupotomy group. The last three groups were put through an operation to emulate L3 transverse process syndrome. Fourteen days after the simulation operation, EA and acupotomy treatments were applied to the respective groups. Fifty-six days after the simulation operation, biochemistry tests and enzyme-linked immunosorbent assay were used to measure NOS and beta-EP in the hypothalamus, spinal cord, and peripheral blood. RESULTS: Rats with the simulation operation showed significantly higher levels of NOS and beta-EP in the hypothalamus, spinal cord, and peripheral blood than those in the normal group. The EA and acupotomy groups had significantly lower levels of NOS and beta-EP than those in the model group. There was no statistical difference between the EA and acupotomy groups. CONCLUSION: EA and acupotomy treatments significantly lowered NOS and beta-EP levels in the hypothalamus, spinal cord, and peripheral blood and alleviated L3 transverse process syndrome. PMID- 24783934 TI - Autotetraploidy induced in nianmaohuangqin (Radix Scutellariae Viscidulae) with colchicine in vitro. AB - OBJECTIVE: To establish and optimize the propagation of Nianmaohuangqin (Radix Scutellariae Viscidulae) and induce and characterize polyploidy of Nianmaohuangqin (Radix Scutellariae Viscidulae). METHODS: Buds from germinating seed-derived explants were induced by tissue culture. With an orthogonal test, different concentrations of 6-benzyl-aminopurine (BAP), indole-3-acetic acid (IAA) and kinetin (KT) were used to determine the optimal concentrations for the propagation of Nianmaohuangqin (Radix Scutellariae Viscidulae). The different concentrations of IAA and rooting powder (ABT) were used to induce rooting. A 0.3% w/v colchicine solution was used to induce polyploidy and the induced buds was identified by root-tip chromosome determination and stomatal apparatus observation. RESULTS: A large number of buds could be induced directly from epicotyl and hypocotyl explants on Murashige and Skoog (MS) (Murashige and Skoog 1962) medium supplemented with 1.1-1.3 mg/L BAP and 0.2 mg/L IAA. Root induction and development could be observed within 20 days of inoculation on 1/2 MS medium supplemented with 0.2 mg/L IAA and 0.1 mg/L ABT. Furthermore, 27 lines of autotetraploid individuals were obtained with a plantlet chromosome number of 2n = 4x = 36. CONCLUSION: Autotetraploid lines could be obtained through induction with colchicine in vitro, proving that this method might be used for plant selection and breeding. PMID- 24783935 TI - Effects of drying process of yuanzhi (Radix Palygalae) on its bioactive ingredients. AB - OBJECTIVE: To study the effects of the drying processing in terms operational parameters on the bioactive constituents of six Yuanzhi (Radix Palygalae) samples across China. METHODS: Six Yuanzhi (Radix Palygalae) samples were investigated using thermogravimetry analysis. The heating courses were set in two ways: the temperature-programmed process from room temperature to 150 degrees C, and the constant-temperature course at 50 degrees C, 70 degrees C and 90 degrees C. RESULTS: The peak temperature of six Yuanzhi (Radix Palygalae) samples ranged from 78 degrees C to 88 degrees C. The mass loss rate of Yuanzhi (Radix Palygalae) alcohol-soluble extract was significantly increased when heated at 90 degrees C. Four types of bioactive ingredients were detected in volatile oils of Yuanzhi (Radix Palygalae) sample from Shanxi province by Gas Chromatography-mass spectrometry analysis. Fourier Transform Infrared Spectroscopy results showed that the drying temperature exerted a great influence on types and amount of ingredients of Yuanzhi (Radix Palygalae). The kinetic study showed that the constant-temperature drying process of Yuanzhi Radix Palygalae) samples could be well described by the Page Model, especially for the drying process at 50 degrees C, in which R2 and SD values were more than 0.98 and less than 0.04, respectively. The drying constant k of three Yuanzhi (Radix Palygalae) samples from Shanxi, Gansu and Shaanxi provinces in China was corresponding to the Arrhenius equation, and their activation energies were 28.07, 25.38 and 21.48 kJ/mol, respectively. CONCLUSION: The drying process of Yuanzhi (Radix Palygalae) was very important for bioactive ingredients improvement in Yuanzhi (Radix Palygalae). Temperature was a thermodynamic property significantly affecting the process. PMID- 24783936 TI - Effect of polypeptide 2B1 on condition of dampness pattern in rats in terms of traditional Chinese medicine. AB - OBJECTIVE: This study investigated how polypeptide 2B1 is involved in regulating and governing dampness in rat models with dampness pattern defined in terms of Traditional Chinese Medicine. METHODS: We randomly divided 48 SPF 10-week-old male Sprague-Dawley (SD) rats into a normal group, normal + Aristolochic acid I (AA-I) for 5 min group, normal + AA-I for 60 min group, dampness pattern group (DS-Group), dampness pattern + AA-I for 5 min group, and dampness pattern + AA-I for 60 min group. Groups were then treated accordingly. We took out the lung, stomach, liver, spleen, kidney, large intestine, and small intestine tissues to detect gene and protein expression of organic anion transporter polypeptide 2B1 (OATP2B1). RESULTS: Gene expression of OATP2B1 in spleen, kidney, and small intestine of rats with dampness pattern was lower than that in normal rats (P < 0.05). The gene expressions of OATP2B1 in liver, stomach, large intestine, and small intestine were lower than that in control rats at different time points after being stimulated by AA-I (P < 0.05). CONCLUSION: There is coordination among multiple viscera in handling the condition of dampness, and the mechanism underlying the action may rely on regulating the expression of OATP2B1. PMID- 24783937 TI - Effect of cold-dryness on pulmonary and immunologic function in chronic obstructive pulmonary disease model rats. AB - OBJECTIVE: To study the effects of cold-dryness on pulmonary and immunologic function of peripheral T-lymphocytes in chronic obstructive pulmonary disease (COPD) model rats, and to provide references for the prevention and treatment of cold-dryness COPD in the Xinjiang region. METHODS: The COPD model was established with an elastase drip into the trachea combined with smoking. The cold-dryness COPD model was developed by stressing with a cold-dry environment. Success of the model was determined by observation of pathologic lung sections. Rats were sacrificed by exsanguination from the femoral artery and changes of peripheral blood CD4+, CD8+, and CD4+/CD8+ were detected by flow cytometry. Data were analyzed with SAS 11.5 statistical software. RESULTS: On the ninetieth day after ending the experiment, Peak expiratory flow in the cold-dryness COPD group was lower than that in the COPD and normal control groups (P < 0.01). The time of inspiration in the cold-dryness COPD group was higher than that in the COPD and normal groups (P < 0.05). Time of expiration (Te) in the cold-dryness COPD group was higher than that in the COPD and normal groups (P < 0.01). 50% tidal volume expiratory flow (EF50) in the cold-dryness COPD group was lower than that in the COPD and normal groups (P < 0.01), and EF50 in the COPD group was lower than that in the normal group (P < 0.05). CD4+ content of peripheral blood in the cold dryness COPD group was lower than that in the COPD and the normal groups (P < 0.05). CD8+ content in the cold-dryness COPD and COPD groups was higher than that in the normal control group (P < 0.01), and CD8+ content in the cold-dryness COPD group was higher than that in the COPD group (P < 0.01). CD4+/CD8+ in the cold dryness COPD group and the COPD group was lower than that in the normal control group (P < 0.01), and CD4+/CD8+ in the cold-dryness COPD group was lower than that in the COPD group (P < 0.05). CONCLUSION: In the cold-dryness COPD model, CD8+ increased and CD4+/CD8+ decreased. Moreover, cold-dryness may aggravate this state. The effects of cold-dryness on pulmonary function mainly manifested as prolongation of Te and decrease of EF50, which could be one of causes of cold dryness environment in the northwest of China leading to COPD with region characteristics. PMID- 24783938 TI - Effects of radix ginseng on microbial infections: a narrative review. AB - OBJECTIVE: To summarized the antimicrobial-like effects of Radix Ginseng, which provide important information to the relevant researchers and clinicians, and will benefit the clinical treatment of infectious diseases. METHODS: PubMed and Google were used to search for and collect scientific publications related to Radix Ginseng and microbial infections. The authors read, classified, and discussed the associated scientific results or evidences, and summarized the corresponding results. RESULTS: In this review, recent studies on the beneficial effects of Radix Ginseng extracts on microbial and biofilm infections were reviewed. The importance and significance of Radix Ginseng's beneficial effects are discussed. Evidence for the favorable effects of Radix Ginseng extracts on viral, bacterial, fungal, and parasitic infections and the possible underlying mechanisms are summarized. CONCLUSION: Radix Ginseng might be a promising supplemental remedy for the prevention and treatment of infectious diseases. PMID- 24783939 TI - Insulin sources and types: a review of insulin in terms of its mode on diabetes mellitus. AB - Insulin is involved in regulation of glucose utilization in the body. Inability of the body to synthesize insulin of human cells resistance to insulin leads to a condition called Diabetes mellitus which is characterized by chronic hyperglycaemia. There are two types of diabetes; type 1 and type 2. Exogenous supply of insulin is needed consistently for type 1 diabetes treatment and type 2 diabetes also needs to be cured by the exogenous supply of insulin in advance stages of the disease. These sources have been proved very useful to meet the needs of the patients. However, these insulin types are expensive for the large population of patients in the developing countries. Furthermore, the incidence of diabetes is advancing at an alarming rate. Hence production systems with even higher capabilities of production are desired. Therefore, currently plants are being investigated as alternative production systems. Based on the mode of action of insulin various formulations of insulin have been developed that have different onset of action, peak effect and duration of action according to the needs of the patients. PMID- 24783940 TI - Evaluation indexes for symptom changes in Chinese medicine. AB - OBJECTIVE: To screen and summarize evaluation indexes for symptom changes in Chinese medicine (CM). METHODS: A case database was established based on information from subsequent patient visits from the case records of famous doctors since 1866. Symptom change descriptions in the database were regarded as research materials. The evaluation indexes of the symptom changes were screened and summarized. RESULTS: In total, 243 evaluation indexes for 256 symptoms were summarized. Among them, common symptoms were frequency, quantity, degree, mobility, color, and correlation with fatigue. CONCLUSION: There are many aspects to evaluating the changes in a symptom. Some symptoms occur with other simultaneous symptoms. The alleviation or aggravation of simultaneous symptoms could reflect the corresponding changes in a symptom. The changes of inducing factors are important to judging changes in symptoms. PMID- 24783941 TI - Effect of milk thistle, Silybium marianum, extract on toxicity, development, nutrition, and enzyme activities of the small white butterfly, Pieris rapae. AB - The methanolic extract of milk thistle, Silybium marianum L. (Asterales: Asteraceae), was investigated for its effects on the mortality, growth, feeding indices, enzymatic activity, and levels of non-enzymatic molecules of the small white butterfly, Pieris rapae L. (Lepidoptera: Pieridae), a pest of cruciferous plants. Feeding indices including approximate digestibility (AD), efficiency of conversion of digested food (ECD), efficiency of conversion of ingested food (ECI), relative growth rate (RGR), and relative consumption rate (RCR) were measured. These indices were variously affected: the RGR, RCR, and AD decreased, but the ECD and ECI increased. The LC50 and LC25 values were estimated as 2.94% and 1.20%, respectively. At the lowest concentration of S. marianum extract (0.625%), the feeding deterrence index was 40.48%. The duration of the pupal stage and the rate of larval growth decreased. These changes may be due to alterations in metabolic activity, such as the increase in alkaline phosphatase activity, which is likely involved in detoxification. Additionally, the activities of alanine aminotransferase and aspartate aminotransferase, which are key components of amino acid catabolism, decreased. The amount of glucose (an energy source) and uric acid (the excreted end product) increased, while total protein (another energy source) and cholesterol decreased. These results indicate that this plant possesses potential secondary metabolites that may be useful for the future study of the control of insect pests. PMID- 24783942 TI - Enhancement of photovoltaic response in multilayer MoS2 induced by plasma doping. AB - Layered transition-metal dichalcogenides hold promise for making ultrathin-film photovoltaic devices with a combination of excellent photovoltaic performance, superior flexibility, long lifetime, and low manufacturing cost. Engineering the proper band structures of such layered materials is essential to realize such potential. Here, we present a plasma-assisted doping approach for significantly improving the photovoltaic response in multilayer MoS2. In this work, we fabricated and characterized photovoltaic devices with a vertically stacked indium tin oxide electrode/multilayer MoS2/metal electrode structure. Utilizing a plasma-induced p-doping approach, we are able to form p-n junctions in MoS2 layers that facilitate the collection of photogenerated carriers, enhance the photovoltages, and decrease reverse dark currents. Using plasma-assisted doping processes, we have demonstrated MoS2-based photovoltaic devices exhibiting very high short-circuit photocurrent density values up to 20.9 mA/cm(2) and reasonably good power-conversion efficiencies up to 2.8% under AM1.5G illumination, as well as high external quantum efficiencies. We believe that this work provides important scientific insights for leveraging the optoelectronic properties of emerging atomically layered two-dimensional materials for photovoltaic and other optoelectronic applications. PMID- 24783943 TI - Tachyarrhythmias and catheter ablation in adult congenital heart disease. AB - Advances in surgical technique have had an immense impact on longevity and quality of life in patients with congenital heart disease. However, an inevitable consequence of these surgical successes is the creation of a unique patient population whose anatomy, surgical history and haemodynamics result in the development of a challenging and complex arrhythmia substrate. Furthermore, this patient group remains susceptible to the arrhythmias seen in the general adult population. It is through a thorough appreciation of the cardiac structural defect, the surgical corrective approach, and haemodynamic impact that the most effective arrhythmia care can be delivered. Catheter ablation techniques offer a highly effective management option but require a meticulous attention to the real time integration of anatomical and electrophysiological information to identify and eliminate the culprit arrhythmia substrate. This review describes the current approach to the interventional management of patients with tachyarrhythmias in the context of congenital heart disease. PMID- 24783944 TI - Comparison of viral burden and disease progression in Chinese-origin rhesus macaques infected with common experimentally applied chimeric virus: SHIV 1157ipd3N4, SHIV-162P3, or SHIV-KB9. AB - BACKGROUND: Little is known about the comparative susceptibility and differential pathogenic characteristics of Chinese-origin rhesus macaques upon infection with the chimeric SHIVs most commonly applied in experimental research. METHODS: In vivo infectivity, viral replication, and disease progression related to SHIV 1157ipd3N4, SHIV-162P3, and SHIV-KB9 infections were assessed after intravenous inoculation of Chinese-origin rhesus macaques (n = 10 each). RESULTS: SHIV-KB9 infected monkeys had higher plasma viral loads than those infected with SHIV 1157ipd3N4 or SHIV-162P3 (P < 0.05). The SHIV-KB9 group had a member that progressed rapidly to simian acquired immunodeficiency syndrome and was moribund at 155 days post-inoculation. SHIV-KB9 and SHIV-162P3 showed reverse trends in the effects on levels of memory T-cell subpopulations. CONCLUSIONS: This study provides foundational data for future efficacy testing of candidate vaccine and antiviral therapy using a Chinese-origin rhesus macaque system. PMID- 24783946 TI - The bioefficacy of microemulsified natural pigments in egg yolk pigmentation. AB - 1. This study was designed to test the hypothesis that microemulsified carotenoid products show improved bioavailability over corresponding regular preparations, leading to greater yolk pigmentation at lower dosages. 2. The first trial was conducted using a maize-soya bean basal diet supplemented with either 0.25, 0.5, 0.75, 1.0 and 1.25 g/kg of microemulsified Red or non-microemulsified Red. The second trial involved feeding microemulsified Yellow or non-microemulsified Yellow using a similar dosage range. The layers were divided into 4 replicates of 8 layers each (32 layers per treatment). The 8 cages of layers were fed from a single feed trough. Feed and water were provided ad libitum throughout the trial. Each week, the eggs were collected. The whole liquid egg colour was determined by means of a commercially available yolk colour fan. Where required, HPLC-(high performance liquid chromatography) based analysis of trans-capsanthin or trans lutein equivalents using the Association of Analytical Communities method was carried out. Data were statistically analysed by one-way ANOVA method using Statgraphics. 3. Results showed that the colour and carotenoid content of the egg yolk increased with increasing amount of carotenoids in the diet. The colour of egg yolks from layers fed similar concentrations of microemulsified versus the regular preparation was significantly different. At the commercial recommended dose of one g/kg regular Yellow or Red product, the microemulsified pigmenter is able to provide the equivalent yolk colour at a 20-30% lower dose. 4. In conclusion, the trial results supported the hypothesis that a desired yolk colour score is achievable at a significantly lower inclusion rate when carotenoid molecules are emulsified using the microemulsion nanotechnology. PMID- 24783945 TI - Direct imaging of band profile in single layer MoS2 on graphite: quasiparticle energy gap, metallic edge states, and edge band bending. AB - Using scanning tunneling microscopy and spectroscopy, we probe the electronic structures of single layer MoS2 on graphite. The apparent quasiparticle energy gap of single layer MoS2 is measured to be 2.15 +/- 0.06 eV at 77 K, albeit a higher second conduction band threshold at 0.2 eV above the apparent conduction band minimum is also observed. Combining it with photoluminescence studies, we deduce an exciton binding energy of 0.22 +/- 0.1 eV (or 0.42 eV if the second threshold is use), a value that is lower than current theoretical predictions. Consistent with theoretical predictions, we directly observe metallic edge states of single layer MoS2. In the bulk region of MoS2, the Fermi level is located at 1.8 eV above the valence band maximum, possibly due to the formation of a graphite/MoS2 heterojunction. At the edge, however, we observe an upward band bending of 0.6 eV within a short depletion length of about 5 nm, analogous to the phenomena of Fermi level pinning of a 3D semiconductor by metallic surface states. PMID- 24783947 TI - Generation of geometrically ordered lipid-based liquid-crystalline nanoparticles using biologically relevant enzymatic processing. AB - High-symmetry lipid nanoparticles with internal bicontinuous cubic phase structure (cubosomes) are prepared from a simple emulsion containing a mixture of a nondigestible lipid (phytantriol) and a digestible short-chained triglyceride using enzymatic lipolysis of the incorporated short-chained triglyceride. The lipolytic products partition away from the nondigestible lipid, resulting in crystallization of the cubic-phase internal structure. Time-resolved small-angle X-ray scattering revealed the kinetics of the disorder-to-order transition, with cryo-transmission electron microscopy showing an absence of liposomes. The new approach offers a new "sideways" method for the generation of lipid-based nanostructured materials that avoids the problems of top-down and bottom-up approaches. PMID- 24783949 TI - Oxidation debris in graphene oxide is responsible for its inherent electroactivity. AB - Graphene oxide is known to exhibit many interesting properties, ranging from inherent fluorescence to inherent electrochemistry, just to name a few. Recent research has found that graphene oxide is a composite material consisting of the so-called "oxidation debris" and unoxidized graphene fragments. Surprisingly, the oxidation debris, which contains small and highly oxidized aromatic fragments adsorbed on graphene surfaces, is responsible for the excellent solubility and inherent fluorescence of graphene oxide. Here, we examine the origin of the inherent electroactivity of graphene oxide and demonstrate that such phenomenon is attributed to the presence of oxidation debris. We separate oxidation debris from the less oxidized graphene backbone in "as-prepared" graphene oxide nanoplatelets using ultrasonication. We found that the extension of ultrasonication time corresponded to a larger amount of oxidation debris released from the graphene oxide nanoplatelets' surfaces and subsequently caused detrimental effects to the inherent electroactivity of the graphene material. Since graphene oxide is often the material of choice for energy storage devices, such as batteries and supercapacitors, a thorough understanding on the origin of such inherent electrochemical properties of graphene oxide is of very high importance. PMID- 24783948 TI - Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human alpha galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense alpha-galactosidase A (alpha-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin arylthioureas (DGJ-ArTs), capable of stabilizing alpha-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N'H thiourea proton and the catalytic aspartic acid acid D231 of alpha-Gal A, as confirmed by a 2.55 A resolution cocrystal structure. Selected candidates enhanced alpha-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD. PMID- 24783950 TI - Foraging in subterranean termites (Isoptera: Rhinotermitidae): how do Heterotermes tenuis and Coptotermes gestroi behave when they locate equivalent food resources? AB - A previous research suggests that when subterranean termites locate equivalent food they consume the initial food resource. However, little is known about the movement of foragers among these food sources. For this reason, this study analyzed the feeding behavior of Heterotermes tenuis and Coptotermes gestroi in the presence of equivalent foods. The experimental arenas were composed of a release chamber connected to food chambers. The consumption of each wood block and percentage of the foraging individuals recruited for the food chambers were observed in relation to the total survival rate. The results showed that in the multiple-choice tests, wood block consumptions and the recruitment of individuals did not differ between replicates of each termite species. However, in different tests of tenacity, the chambers with the first food presented higher feeding rates by both H. tenuis and C. gestroi and resulted in a higher recruitment of workers and soldiers. In these conditions, it may be concluded that foragers of either species do not concentrate their efforts on the consumption of only one food resource when they are able to reach multiple cellulosic sources simultaneously. Additionally, the data concerning tenacity tests suggest that there is a chronologic priority of consumption in relation to the discovery of available food sources. Knowledge about the foraging biology of subterranean termites is important for future studies of their feeding behavior, and it is indispensable for improving control strategies. PMID- 24783951 TI - A fluvial mercury budget for Lake Ontario. AB - Watershed mercury (Hg) flux was calculated for ten inflowing rivers and the outlet for Lake Ontario using empirical measurements from two independent field sampling programs. Total Hg (THg) flux for nine study watersheds that directly drain into the lake ranged from 0.2 kg/yr to 13 kg/yr, with the dominant fluvial THg load from the Niagara River at 154 kg/yr. THg loss at the outlet (St. Lawrence River) was 68 kg/yr and has declined approximately 40% over the past decade. Fluvial Hg inputs largely (62%) occur in the dissolved fraction and are similar to estimates of atmospheric Hg inputs. Fluvial mass balances suggest strong in-lake retention of particulate Hg inputs (99%), compared to dissolved total Hg (45%) and methyl Hg (22%) fractions. Wetland land cover is a good predictor of methyl Hg yield for Lake Ontario watersheds. Sediment deposition studies, coupled atmospheric and fluvial Hg fluxes, and a comparison of this work with previous measurements indicate that Lake Ontario is a net sink of Hg inputs and not at steady state likely because of recent decreases in point source inputs and atmospheric Hg deposition. PMID- 24783952 TI - The Red journal at 25 years. Looking back and looking ahead. PMID- 24783953 TI - The Red journal at 25. A perspective from the founding editors. PMID- 24783954 TI - Primary prevention of chronic lung disease: a role for basic science. PMID- 24783955 TI - NO turning back. PMID- 24783956 TI - Noblesse oblige: NRF2 functions in the airways. AB - The transcription factor, nuclear factor (NF), erythroid-derived 2-related factor 2 (NRF2), was discovered nearly 2 decades ago. Since then, over 4,000 papers have been published on NRF2 function in diverse biological systems, and it has been found to be a critical regulator of antioxidant and defense genes with antioxidant response elements in their promoters. NRF2 is particularly important in protecting cells and tissues under highly oxidative microenvironments, including the airways that interface with the external environment and are exposed to pollutants and other oxidant stressors. Using mice with targeted deletion of Nrf2, a protective role for this transcription factor has been determined in many model diseases, including acute lung injury, emphysema, allergy and asthma, pulmonary fibrosis, and respiratory syncytial virus disease. Recent studies have also found that murine Nrf2 is important in lung development and protection against neonatal lung injury. Moreover, functional polymorphisms in human NRF2 have been known to associate with disease severity, indicating a potentially important protective function. However, there is also a "dark side" to NRF2 function, as it has been found to enhance advanced stages of carcinogenesis in the lung and some other tissues. NRF2 inducers such as phytochemical isothyocyanates and synthetic triterpenoids, have been discovered and used in model systems of oxidant-induced lung diseases, and data suggest a potential for clinical interventions. Future investigations of NRF2 should yield further insight into its contribution to normal and pathophysiological conditions in the airways, and alternative treatment strategies to protect against oxidative respiratory disease. PMID- 24783957 TI - Alveolar epithelium: beyond the barrier. AB - I am deeply honored to have been awarded an American Thoracic Society Recognition Award for Scientific Accomplishment for 2014. Over the last 20 years, it has become clear that the alveolar epithelium, my area of research focus, is not simply a gas exchange surface and barrier to leakage of fluid and protein into the alveoli, but is an active participant in the pathogenesis of a number of lung diseases, including pulmonary fibrosis. Recognition by this Award stimulates a review of the awardee's contributions to the field, as summarized in this perspective. PMID- 24783960 TI - Kinetic analysis of the formation and decay of a non-heme ferric hydroperoxide species susceptible to O-O bond homolysis. AB - The formation of a ferric hydroperoxide species from [Fe(bbpc)(MeCN)2](2+) (bbpc = N,N'-dibenzyl-N,N'-bis(2-pyridylmethyl)-1,2-cyclohexanediamine) and its subsequent decomposition were analyzed kinetically. The rate of decay is not strongly influenced by the presence of either water or substrate, suggesting that the ferric hydroperoxide degrades through O-O bond homolysis and is not the relevant metal-based oxidant in the observed catalysis of C-H activation. The rate law corresponding to the complex's formation from O2 is consistent with the intermediacy of a mononuclear ferric superoxo species. PMID- 24783958 TI - Rhinovirus-induced macrophage cytokine expression does not require endocytosis or replication. AB - Rhinovirus (RV) is responsible for the majority of virus-induced asthma exacerbations. We showed previously that RV infection of ovalbumin-sensitized and -challenged BALB/c mice induces production of type 2 cytokines from M2-polarized macrophages. In the present study, we sought to determine the mechanism of RV induced cytokine expression. We infected bone marrow-derived macrophages (BMMs) from BALB/c mice with RV serotype 1B, a minor group virus that infects mouse cells. Selected cultures were pretreated with IL-4, a type 2 cytokine increased in allergic asthma. RV infection of untreated cells increased messenger RNA and protein expression of the M1 cytokines TNF-alpha, CXCL1, and IL-6 but failed to induce expression of the M2 cytokines CCL22 and CCL24. Cells pretreated with IL-4 showed decreased expression of M1 cytokines but increased expression of Ym-1, Arg 1 (M2 markers), CCL22, and CCL24. Infection with ultraviolet (UV)-irradiated, replication-deficient RV elicited similar cytokine responses, suggesting that the outcome is replication independent. Consistent with this, viral RNA copy number did not increase in RV-treated BMMs or bronchoalveolar macrophages. RV-induced cytokine expression was not affected when cells were pretreated with cytochalasin D, suggesting that viral endocytosis is not required for the response. Finally, RV-induced cytokine expression and viral attachment were abolished in BMMs from myeloid differentiation factor 88 and Toll-like receptor (TLR)2 KO mice, suggesting a specific requirement of TLR2. We conclude that RV elicits a proinflammatory cytokine response in BMMs through a cell-surface-mediated, TLR2 dependent mechanism that does not require viral endocytosis or replication. PMID- 24783961 TI - Energy balance for kids with play: design and implementation of a multi-component school-based obesity prevention program. AB - BACKGROUND: Improving nutrition and physical activity behaviors associated with childhood obesity are significant national public health goals. Energy Balance for Kids with Play (EB4K with Play), developed through a partnership between the Academy of Nutrition and Dietetics Foundation and Playworks, is a multi-component school-based intervention designed to address youth's nutrition and physical activity behaviors. This article describes the EB4K with Play intervention and evaluation study and presents the baseline data. METHODS: The evaluation is a 2 year cluster-randomized design targeting third- to fifth-grade students enrolled in a low-income, urban school district in northern California. Six schools were recruited to participate. Four were randomized to the intervention group and two into a control group. Baseline student-level data pertaining to nutrition, physical activity, fitness, and BMI were collected in the fall of 2011. The EB4K with Play program, which includes direct-to-student nutrition and physical activity interventions, a school wellness component, and parent/community partner outreach components, began immediately after baseline data collection. RESULTS: An ethnically diverse sample of students (n=844) was recruited to participate in the study. Baseline data showed a higher percent of eligibility for free and reduced-price school lunch and higher rates of obesity/overweight than the California state averages. Fitness levels and levels of moderate-to-vigorous physical activity were comparable to state averages. CONCLUSIONS: End-point data will be collected after 2 years of the intervention. The findings from this study should help guide future efforts to design effective intervention programs to support the prevention of pediatric obesity. PMID- 24783962 TI - Blue light irradiation affects anthocyanin content and enzyme activities involved in postharvest strawberry fruit. AB - Blue light irradiation was applied to postharvest strawberry fruit to explore its influence on anthocyanin content and anthocyanin biosynthetic enzyme activities. Strawberry fruit was irradiated with blue light at 40 MUmol m(-2) s(-1) for 12 days at 5 degrees C. The results indicated that blue light treatment improved total anthocyanin content in strawberry fruit during storage. Meanwhile, the treatment increased the activities of glucose-6-phosphate, shikimate dehydrogenase, tyrosine ammonia-lyase, phenylalanine ammonia-lyase, cinnamate-4 hydroxylase, 4-coumarate/coenzyme A ligase, dihydroflavonol-4-reductase, chalcone synthase, flavanone-3-beta-hydroxylase, anthocyanin synthase, and UDP-glycose flavonoid-3-O-glycosyltranferase, which suggested that the enhancement of anthocyanin concentration by blue light might result from the activation of its related enzymes. Blue light might be proposed as a supplemental light source in the storage of strawberry fruit to improve its anthocyanin content. PMID- 24783963 TI - Copper-promoted reductive coupling of aryl iodides with 1,1,1-trifluoro-2 iodoethane. AB - An efficient Cu-promoted reductive coupling of aryl iodides with 1,1,1-trifluoro 2-iodoethane has been developed. This reaction could occur in good yields under milder conditions as compared with previous studies. The reaction tolerated nitro, formyl, ester, ether, carbonyl, sulfonyl, and even azo groups. PMID- 24783964 TI - Synthesis of carbohydrate methyl phosphoramidates. AB - A two-step route for introducing methyl phosphoramidate moieties onto carbohydrates is reported. The approach uses methyl pivolyl H-phosphonate as the phosphorylating reagent to produce an isolable carbohydrate H-phosphonate intermediate that is then oxidized by a Todd-Atherton reaction. The stability of the product methyl phosphoramidates was subsequently evaluated using various deprotection strategies. PMID- 24783965 TI - MAS-1 adjuvant immunotherapy generates robust Th2 type and regulatory immune responses providing long-term protection from diabetes in late-stage pre-diabetic NOD mice. AB - MAS-1, a nanoparticular, emulsion-based adjuvant, was evaluated for its ability to promote Th2 and regulatory immune responses and prevent type 1 diabetes progression when given alone or as antigen-specific immunotherapy (ASI) using insulin B chain (IBC; MER3101) and its analog B:9-23(19Ala) (MER3102). MAS-1 formulations were administered to NOD mice at age 9 and 13 weeks and followed through 52 weeks. MER3101 and MER3102 provided long-term protection with 60% and 73% of mice remaining diabetes-free at week 35, and 60% and 47% at week 52. MAS-1 adjuvant emulsion by itself also provided protection with 60% and 40% of mice diabetes-free at 35 and 52 weeks, respectively. Higher levels of interleukin (IL) 10 and IL-2 positive T cells were detected among splenocytes by week 15 in MER3101 and MER3102 immunized mice, whereas MAS-1 alone induced higher levels of IL-10-positive T cells. Diabetes-free 52-week-old mice expressed significant levels of antigen-specific IL-10-positive type 1 regulatory T cells and FoxP3 positive T cells when stimulated ex vivo with IBC. Antibodies targeting IBC and B:9-23(19Ala) induced by MER3101 and MER3102 were overwhelmingly Th2 type IgG1 and IgG2b isotypes. Splenocyte cultures from 52 week diabetes-free, MER3101 treated mice secreted significantly increased levels of IL-4 and IL-5 Th2 cytokines. Based on these pre-clinical results and its clinical safety profile, MAS-1 has the requisite qualities to be considered for use in prophylactic or early stage disease settings to augment ASI to prevent disease progression in type 1 diabetes. PMID- 24783966 TI - Ophthalmic diagnostic tests in captive red-footed tortoises (Chelonoidis carbonaria) in Salvador, northeast Brazil. AB - PURPOSE: The aim of this study was to establish normal ophthalmic parameters for select diagnostic tests in red-footed tortoises (Chelonoides carbonaria). A total of 52 animals, approximately 20-30 years old, were studied. METHOD: Ophthalmic diagnostic tests included culturing of the normal conjunctival bacterial flora in summer and winter, evaluation of tear production using Schirmer tear test (STT) and endodontic absorbent paper point tear test in two different environmental temperatures (EAPPTT-1 at 32 degrees C and EAPPTT-2 at 18 degrees C), cytology of conjunctival cells, B-mode ultrasonography, measurement of palpebral fissure length (PFL), and applanation tonometry (in two different positions). RESULTS: In both seasons, Gram-positive bacteria were predominant. Median (+/- IQR/2) STT was 12.0 +/- 3.5 mm/min, EAPPTT-1 was 15.9 +/- 0.7 mm/15 s, and EAPPTT-2 was 15.4 +/- 0.4 mm/min (OD) and 17.8 +/- 1.0 mm/min (OS). Anterior chamber depth was 1.0 +/- 0.1 mm, lens axial length was 2.3 +/- 0.1 mm, vitreous chamber depth was 4.3 +/- 0.2 mm, and axial globe length was 7.7 +/- 0.3 mm. PFL was 11.7 +/- 1.7 mm. Intraocular pressure was 11.5 +/- 2.8 mmHg for males and 14.0 +/- 3.5 mmHg for females (dorsoventral position) and 18.0 +/- 3.2 mmHg for males and 24.1 +/- 3.0 mmHg for females (ventrodorsal position with inclination of 45 degrees ). The ophthalmic parameters reported here can aid in the diagnosis of eye diseases in red-footed tortoises (Chelonoides carbonaria). PMID- 24783967 TI - Diagnostic value of screening tests in subgroups of women with recurrent pregnancy loss. AB - OBJECTIVE: To evaluate the diagnostic value of screening laboratory tests in women who had recurrent pregnancy loss (RPL). METHODS: A total of 252 women with RPL managed in our tertiary referral research and education hospital were included in the study. Risk factors recorded involved age, gravidity, parity, number of prior live births, number of pregnancy losses, and thrombophlia tests. The cases were divided into three different groups and each group was analyzed separately. RESULTS: There was no statistically significant difference between the first and second groups in terms of clinical and laboratory parameters (p > 0.05). In the third group, there was a statistically significant difference among cases in terms of parity, gravidity, number of pregnancy losses, serum AT III levels, APCR, and age of the women. According to the logistic regression model, odds ratios (95% CI) were 6.116 (3.797-9.852), 5.665 (2.657-12.079), 4.763 (3.099 7.321), 4.729 (3.080-7.260), 2.820 (1.836-4.333), and 1.911 (1.232-2.965), respectively. CONCLUSIONS: We do not recommend the screening of all women with RPL, but in women with high parity and those who had prior live birth pregnancies, increased AT III, and APCR may be diagnostic markers for subsequent pregnancy loss. PMID- 24783969 TI - Return to competitive football after major knee surgery: more questions than answers? AB - Despite significant advances in the diagnostics and treatment of knee injuries over the last decade, several challenges related to the subject "return to sport" remain largely unknown. For example, how should "return to sport" be defined precisely? What is the optimal timing and progression to enable a return to sport? Which criteria should be used during this process? What type of training is indicated? Which measurements can support the decision-making process? How do we optimally prepare athletes for competition without risking re-injury? This paper critically addresses these questions, and proposes a return to play model to prepare football players to compete after major knee surgery (anterior cruciate ligament reconstruction, cartilage repair). The goal is to re-integrate the player gradually into the game, taking into account his individual characteristics. Several evidence-based and empirical criteria are needed to plan and monitor the efficient return to competitive football. Injury-prevention education should be part of this process to maximise the chance of a durable career and decrease the risk of re-injury. However, because of the paucity of research on "return to sport", further research is more than warranted. PMID- 24783968 TI - One step ATRP initiator immobilization on surfaces leading to gradient-grafted polymer brushes. AB - A method is described that allows potentially any surface to be functionalized covalently with atom transfer radical polymerization (ATRP) initiators derived from ethyl-2-bromoisobutyrl bromide in a single step. In addition, the initiator surface density was variable and tunable such that the thickness of polymer chain grafted from the surface varied greatly on the surfaces providing examples, across the surface of a substrate, of increased chain stretching due to the entropic nature of crowded polymer chains leading toward polymer brushes. An initiator gradient of increasing surface density was deposited by plasma copolymerization of an ATRP initiator (ethyl 2-bromoisobutyrate) and a non-ATRP reactive diluent molecule (ethanol). The deposited plasma polymer retained its chemical ability to surface-initiate polymerization reactions as exemplified by N,N'-dimethyl acrylamide and poly(ethylene glycol) methyl ether methacrylate polymerizations, illustrating linear and bottle-brush-like chains, respectively. A large variation in graft thickness was observed from the low to high chain density side suggesting that chains were forced to stretch away from the surface interface--a consequence of entropic effects resulting from increased surface crowding. The tert-butyl bromide group of ethyl 2-bromoisobutyrate is a commonly used initiator in ATRP, so a method for covalent linkage to any substrate in a single step desirably simplifies the multistep surface activation procedures currently used. PMID- 24783970 TI - Comparison of magnetic resonance spectroscopy and positron emission tomography in detection of tumor recurrence in posttreatment of glioma: A diagnostic meta analysis. AB - It is important to distinguish between tumor recurrence and treatment effects in posttreatment patients with high-grade gliomas. Several imaging modalities have been reported in differentiating between tumor recurrence and treatment effects. However, there were no consistent conclusions between different studies. We performed a meta-analysis of 23 studies that compared the diagnostic values of fluorine-18-fluorodeoxyglucose ((18)F-FDG) and (11)C-methionine ((11)C-MET) PET (positron emission tomography) or PET/CT (computed tomography) and magnetic resonance spectroscopy (MRS) in predicting tumor recurrence of gliomas. The pooled estimated sensitivity, specificity, positive likelihood ratios, negative likelihood ratios and summary receiver operating characteristic curves of (18)F FDG and (11)C-MET PET or PET/CT and MRS in detecting tumor recurrence were calculated. In conclusion, MRS is highly sensitive in the detection of tumor recurrence in glioma.(18)F-FDG PET or PET/CT is highly specific in recurrence diagnosis. (11)C-MET does not have noticeable advantage over (18)F-FDG. The current evidence shows no statistical difference between MRS and PET on the accuracy. PMID- 24783971 TI - Genome-wide identification, evolution, and expression analysis of RNA-binding glycine-rich protein family in maize. AB - The RNA-binding glycine-rich protein (RB-GRP) family is characterized by the presence of a glycine-rich domain arranged in (Gly)n-X repeats and an RNA recognition motif (RRM). RB-GRPs participate in varied physiological and biochemical processes especially in the stress response of plants. In this study, a total of 23 RB-GRPs distributed on 10 chromosomes were identified in maize (Zea mays L.), and they were divided into four subgroups according to their conserved domain architecture. Five pairs of paralogs were identified, while none of them was located on the same chromosomal region, suggesting that segmental duplication is predominant in the duplication events of the RB-GRPs in maize. Comparative analysis of RB-GRPs in maize, Arabidopsis (Arabidopsis thaliana L.), rice (Oryza sativa L.), and wheat (Triticum aestivum) revealed that two exclusive subgroups were only identified in maize. Expression of eight ZmRB-GRPs was significantly regulated by at least two kinds of stresses. In addition, cis-elements predicted in the promoter regions of the ZmRB-GRPs also indicated that these ZmRB-GRPs would be involved in stress response of maize. The preliminary genome-wide analysis of the RB-GRPs in maize would provide useful information for further study on the function of the ZmRB-GRPs. PMID- 24783972 TI - Atypical lung metastasis. PMID- 24783973 TI - An examination of the misuse of prescription stimulants among college students using the theory of planned behavior. AB - The misuse of prescription stimulants (MPS) is an emergent adverse health behavior among undergraduate college students. However, current research on MPS is largely atheoretical. The purpose of this study was to validate a survey to assess MPS-related theory of planned behavior (TPB) constructs (i.e. attitudes, subjective norms, and perceived behavioral control) and determine the relationship between these constructs, MPS-related risk factors (e.g. gender and class status), and current MPS (i.e. past 30 days use) among college students. Participants (N = 978, 67.8% female and 82.9% Caucasian) at a large public university in the southeastern USA completed a survey assessing MPS and MPS related TPB constructs during fall 2010. To examine the relationship between MPS related TPB constructs and current MPS, we conducted (1) confirmatory factor analyses to validate that our survey items assessed MPS-related TPB constructs and (2) a series of regression analyses to examine associations between MPS related TPB constructs, potential MPS-related risk factors, and MPS in this sample. Our factor analyses indicated that the survey items assessed MPS-related TPB constructs and our multivariate logistic regression analysis indicated that perceived behavioral control was significantly associated with current MPS. In addition, analyses found that having a prescription stimulant was a protective factor against MPS when the model included MPS-related TPB variables. PMID- 24783974 TI - Advance directives from the point of view of primary care physicians in Spain. PMID- 24783975 TI - Efficient reduction of CO2 to CO with high current density using in situ or ex situ prepared Bi-based materials. AB - The development of inexpensive electrocatalysts that can promote the reduction of CO2 to CO with high selectivity, efficiency, and large current densities is an important step on the path to renewable production of liquid carbon-based fuels. While precious metals such as gold and silver have historically been the most active cathode materials for CO2 reduction, the price of these materials precludes their use on the scale required for fuel production. Bismuth, by comparison, is an affordable and environmentally benign metal that shows promise for CO2 conversion applications. In this work, we show that a bismuth-carbon monoxide evolving catalyst (Bi-CMEC) can be formed under either aqueous or nonaqueous conditions using versatile electrodeposition methods. In situ formation of this thin-film catalyst on an inexpensive carbon electrode using an organic soluble Bi(3+) precursor streamlines preparation of this material and generates a robust catalyst for CO2 reduction. In the presence of appropriate imidazolium based ionic liquid promoters, the Bi-CMEC platform can selectively catalyze conversion of CO2 to CO without the need for a costly supporting electrolyte. This inexpensive system can catalyze evolution of CO with current densities as high as jCO = 25-30 mA/cm(2) and attendant energy efficiencies of PhiCO ~ 80% for the cathodic half reaction. These metrics highlight the efficiency of Bi-CMEC, since only noble metals have been previously shown to promote this fuel forming half reaction with such high energy efficiency. Moreover, the rate of CO production by Bi-CMEC ranges from approximately 0.1-0.5 mmol.cm(-2).h(-1) at an applied overpotential of eta ~ 250 mV for a cathode with surface area equal to 1.0 cm(2). This CO evolution activity is much higher than that afforded by other non-noble metal cathode materials and distinguishes Bi CMEC as a superior and inexpensive platform for electrochemical conversion of CO2 to fuel. PMID- 24783976 TI - Comparing life experiences in active addiction and recovery between veterans and non-veterans: a national study. AB - The costs of addiction are well documented, but the potential benefits of recovery are less well known. Similarly, substance use issues among both active duty military personnel and veterans are well known but their recovery experiences remain underinvestigated. Furthermore, little is known about whether and how addiction and recovery experiences differ between veterans and non veterans. This knowledge can help refine treatment and recovery support services. Capitalizing on a national study of individuals in recovery (N = 3,208), we compare addiction and recovery experiences among veterans (n = 481) and non veterans. Veterans' addiction phase was 4 years longer than non-veterans and they experienced significantly more financial and legal problems. Dramatic improvements in functioning were observed across the board in recovery with subgroup differences leveling off. We discuss possible strategies to address the specific areas where veterans are most impaired in addiction and note study limitations including the cross-sectional design. PMID- 24783977 TI - The structural role of manganese ions in soil active silicate-phosphate glasses. AB - Silicate-phosphate glasses of SiO2P2O5K2OMgOCaO system containing manganese ions were synthesized by the melt-quenching technique and were investigated to obtain information about the influence of Mn-cations on the glass structure and their chemical activity. Structural properties were studied using X-ray method, FTIR and Raman spectroscopies. The chemical activity of analyzed glasses in the 2 wt.% citric acid solution was measured by chemical analysis (ICP-AES, EDS) and SEM observations. It has been found that increasing amount of MnO2 in the structure of investigated glasses causes their gradual depolymerization. This process is more apparent in the case of the silico-oxygen subnetwork than phospho-oxygen one. This is related to increasing amounts of SiO4 tetrahedra containing two nonbridging oxygen atoms in silico-oxygen subnetwork. It has been also found that the presence of "weaker" chemical bonds of SiOMn type in comparison to SiOCa and SiOMg bonds is responsible for the increase in solubility of the analyzed silicate-phosphate glasses in conditions simulating natural soil environment. PMID- 24783978 TI - Luminescent property of a novel green emitting phosphor Sr3Bi(PO4)3:Tb(3+). AB - A novel green phosphor Sr3Bi(PO4)3:Tb(3+) is synthesized by a high temperature solid-state method at 1250 degrees C in air, and its luminescent property is investigated. The powder X-ray diffraction patterns of Sr3Bi(PO4)3:Tb(3+) indicate a similarity crystalline phases to Sr3Bi(PO4)3. Sr3Bi(PO4)3:Tb(3+) shows green emission under the 376 nm radiation excitation, and the prominent luminescence in green (543 nm) due to the (5)D4-(7)F5 transition of Tb(3+). For the 543 nm emission, the excitation spectrum has several excitation bands, and the strongest excitation peak locates at 376 nm. The emission intensities of Sr3Bi(PO4)3:Tb(3+) can be influenced by the Tb(3+) doping concentration, and can be achieved the maximum at 0.1 mol Tb(3+). Moreover, the concentration quenching effect of Tb(3+) in Sr3Bi(PO4)3 can be observed. The CIE color coordinate of Sr3Bi(PO4)3:0.1Tb(3+) is (0.299, 0.542). PMID- 24783979 TI - Allosteric transition induced by Mg2+ ion in a transactivator monitored by SERS. AB - We demonstrate the utility of the surface-enhanced Raman spectroscopy (SERS) to monitor conformational transitions in protein upon ligand binding. The changes in protein's secondary and tertiary structures were monitored using amide and aliphatic/aromatic side chain vibrations. Changes in these bands are suggestive of the stabilization of the secondary and tertiary structure of transcription activator protein C in the presence of Mg(2+) ion, whereas the spectral fingerprint remained unaltered in the case of a mutant protein, defective in Mg(2+) binding. The importance of the acidic residues in Mg(2+) binding, which triggers an overall allosteric transition in the protein, is visualized in the molecular model. The present study thus opens up avenues toward the application of SERS as a potential tool for gaining structural insights into the changes occurring during conformational transitions in proteins. PMID- 24783984 TI - Aspirin and age-related macular degeneration: positives versus negatives. AB - The anti-inflammatory, analgesic, antipyretic and antithrombotic activities of aspirin confer its wide therapeutic application. The three former activities require higher doses of aspirin, whereas the latter can be achieved through a lower, thus safer dose of the drug. Low-dose, long-term aspirin is used as an antithrombotic therapy to prevent cardiovascular disease. Such therapy is used by millions of people worldwide, including those suffering from age-related macular degeneration (AMD); thus, questions have arisen as to whether such treatment has any impact on the development and course of AMD. This editorial addresses the important issue of possible beneficial and adverse effects of long-term, low-dose aspirin treatment of AMD patients. Special emphasis is given to the ability of aspirin to acetylate cyclooxygenases (especially COX-2) and thus to initiate a biochemical pathway leading to the generation of anti-inflammatory pro-resolving mediators synthesized from both omega-3 and omega-6 long-chain polyunsaturated fatty acids. Such mediators (e.g., resolvins, lipoxins) may be of therapeutic value in retarding the development of dry form AMD. PMID- 24783985 TI - Nature of electrogenerated intermediates in nitro-substituted nor-beta lapachones: the structure of radical species during successive electron transfer in multiredox centers. AB - Electrochemical, spectroelectrochemical, and theoretical studies of the reduction reactions in nor-beta-lapachone derivatives including a nitro redox center showed that reduction of the compounds involves the formation of several radical intermediates, including a biradical dianion resultant from the separate reduction of the quinone and nitro groups in the molecules. Theoretical descriptions of the corresponding Fukui functions f(alphaalpha)+ and f(betabeta)+(r) and LUMO densities considering finite differences and frozen core approximations for describing the changes in electron and spin densities of the system allowed us to confirm these results. A description of the potential relationship with the obtained results and biological activity selectivity indexes suggests that both the formation of stable biradical dianion species and the stability of the semiquinone intermediates during further reduction are determining factors in the description of their biological activity. PMID- 24783986 TI - Facial transplantation: the first 9 years. AB - Since the first facial transplantation in 2005, 28 have been done worldwide with encouraging immunological, functional, psychological, and aesthetic outcomes. Unlike solid organ transplantation, which is potentially life-saving, facial transplantation is life-changing. This difference has generated ethical concerns about the exposure of otherwise young and healthy individuals to the sequelae of lifelong, high-dose, multidrug immunosuppression. Nevertheless, advances in immunomodulatory and immunosuppressive protocols, microsurgical techniques, and computer-aided surgical planning have enabled broader clinical application of this procedure to patients. Although episodes of acute skin rejection continue to pose a serious threat to face transplant recipients, all cases have been controlled with conventional immunosuppressive regimens, and no cases of chronic rejection have been reported. PMID- 24783980 TI - Extracellular RNA mediates and marks cancer progression. AB - Different types of RNAs identified thus far represent a diverse group of macromolecules that are involved in the regulation of different biological processes. RNA is generally thought to be localized primarily in the nucleus and cytoplasm; however, some types of RNA have been detected in the extracellular milieu. These extracellular RNA (exRNA) molecules are protected from degradation and it is now widely accepted that extracellular vesicles and ribonucleoprotein particles serve as transport vehicles for exRNA among cells. The functional consequence of this transfer of genetic information probably encompasses a broad range of normal developmental and physiologic processes in many organisms. This review will focus on the role of exRNA communication in cancer. We will focus on different types of RNA species identified and characterized within tumor-derived extracellular vesicles. Further, we will describe the role of exRNAs in cancer progression, as well as their potential for use as diagnostic biomarkers and therapeutic tools for monitoring and treating cancer, respectively. PMID- 24783987 TI - Initial therapy for HIV: can less be more? PMID- 24783989 TI - Do whole-body vibrations affect spatial hearing? AB - To assist the human operator, modern auditory interfaces increasingly rely on sound spatialisation to display auditory information and warning signals. However, we often operate in environments that apply vibrations to the whole body, e.g. when driving a vehicle. Here, we report three experiments investigating the effect of sinusoidal vibrations along the vertical axis on spatial hearing. The first was a free-field, narrow-band noise localisation experiment with 5- Hz vibration at 0.88 ms(-2). The other experiments used headphone-based sound lateralisation tasks. Experiment 2 investigated the effect of vibration frequency (4 vs. 8 Hz) at two different magnitudes (0.83 vs. 1.65 ms(-2)) on a left-right discrimination one-interval forced-choice task. Experiment 3 assessed the effect on a two-interval forced-choice location discrimination task with respect to the central and two peripheral reference locations. In spite of the broad range of methods, none of the experiments show a reliable effect of whole-body vibrations on localisation performance. PRACTITIONER SUMMARY: We report three experiments that used both free-field localisation and headphone lateralisation tasks to assess their sensitivity to whole-body vibrations at low frequencies. None of the experiments show a reliable effect of either frequency or magnitude of whole-body vibrations on localisation performance. PMID- 24783988 TI - Dual therapy with lopinavir and ritonavir plus lamivudine versus triple therapy with lopinavir and ritonavir plus two nucleoside reverse transcriptase inhibitors in antiretroviral-therapy-naive adults with HIV-1 infection: 48 week results of the randomised, open label, non-inferiority GARDEL trial. AB - BACKGROUND: Daily oral triple therapy is effective at halting HIV disease progression, but can have toxic effects and is costly. We investigated whether dual therapy with lopinavir and ritonavir plus lamivudine is non-inferior to standard triple therapy. METHODS: The GARDEL study (Global AntiRetroviral Design Encompassing Lopinavir/r and Lamivudine vs LPV/r based standard therapy) is a 48 week, phase 3, randomised, controlled, open-label, non-inferiority trial in antiretroviral-therapy-naive adults (age >=18 years) with documented HIV-1 RNA viral load of at least 1000 copies per mL. The study was done at 19 centres in six countries. Patients were randomly assigned (1:1) to dual therapy or triple therapy by sealed envelopes, in blocks of four, stratified by baseline viral load (<100,000 vs >=100,000 copies per mL). Dual therapy consisted of lopinavir 400 mg and ritonavir 100 mg plus lamivudine 150 mg, both twice daily. Triple therapy consisted of lopinavir 400 mg and ritonavir 100 mg twice daily and lamivudine or emtricitabine plus another nucleoside reverse transcriptase inhibitor (NRTI) in fixed-dose combination. Efficacy was analysed in all participants who received at least one dose of study drug. The primary endpoint was virological response rate, defined as the proportion of patients with HIV RNA less than 50 copies per mL at 48 weeks. Dual therapy was classed as non-inferior to triple therapy if the lower bound of the 95% CI for the difference between groups was no lower than -12%. Patients and investigators were unmasked to treatment allocation. This study is registered with ClinicalTrials.gov, number NCT01237444. FINDINGS: Between Dec 10, 2010, and May 15, 2012, 217 patients were randomly assigned to the dual-therapy group and 209 to the triple-therapy group. 198 patients in the dual-therapy group and 175 in the triple-therapy group completed 48 weeks of treatment. At week 48, 189 patients (88.3%) in the dual-therapy group and 169 (83.7%) in the triple therapy group had viral response (difference 4.6%, 95% CI -2.2 to 11.8; p=0.171). Patients with baseline viral load of at least 100,000 copies per mL showed similar results (87.2% vs 77.9%, respectively; difference 9.3%, 95% CI -2.8 to 21.5; p=0.145). Toxicity-related or tolerability-related discontinuations were more common in the triple-therapy group (n=10 [4.9%]) than in the dual-therapy group (n=1 [0.4%]; difference 4.5%, 95% CI -8.1 to -0.9; p=0.011). 65 adverse events in the dual-therapy group and 88 in the triple-therapy group were possibly or probably drug related (p=0.007). Two serious adverse events occurred, both in the dual-therapy arm, one of which (a case of gastritis) was reported as possibly or probably related to drug treatment. INTERPRETATION: Dual therapy with lopinavir and ritonavir plus lamivudine regimen warrants further clinical research and consideration as a potential therapeutic option for antiretroviral therapy-naive patients. FUNDING: Fundacion Huesped and AbbVie. PMID- 24783990 TI - Influence of extraction solvent on antioxidant capacity value of oleaster measured by ORAC method. AB - Oxygen radical absorbance capacity (ORAC) is a widely used hydrogen atom transfer based method which measures the antioxidant capacity of natural products. ORAC values of oleaster (Elaeagnus angustifolia L.), which was extracted with ethanol/acetone (7:3, v/v), ethanol/water (1:1, v/v) and methanol/water (1:1, v/v) in order to evaluate the effects of solvent type on antioxidant capacity, were examined. In general, results revealed that ethanol/water extracts exhibited better antioxidant capacity values. Furthermore, results obtained by using ORAC eosin y (ORAC-EY), one of the widely used derivative of fluorescein (FL), as a fluorescent probe were compared with those obtained by using ORAC-FL. According to the results, ORAC-EY values were found to be compatible with ORAC-FL values. PMID- 24783991 TI - The relationships among physician and hospital volume, processes, and outcomes of care for acute myocardial infarction. AB - BACKGROUND: A volume-outcome relationship has been found for acute myocardial infarction (AMI); however, the mechanisms underlying the relationship remain unclear. In particular, it is not known whether processes of care are mediators of the volume-outcome relationship, that is, whether the mechanisms underlying the relationship are through processes of care. OBJECTIVE: We used nationwide population-based data to examine the mediating effects of processes of care on the relationships of physician and hospital volume with AMI mortality. METHODS: We analyzed all 6838 ST-elevation myocardial infarction (STEMI) patients admitted in 2008, treated by 740 physicians in 142 hospitals through Taiwan's National Health Insurance Research Database. Multilevel meditational models were performed after adjustment for patient, physician, and hospital characteristics to test the relationships among physician and hospital volume, processes of care, and 30-day STEMI mortality. RESULTS: Physicians with higher volume had higher use of percutaneous coronary intervention and aspirin, and lower mortality in the following year, and the processes of care were mediators of the relationship between physician volume and mortality. Low-volume hospitals had higher mortality in the following year than medium-volume hospitals. In stratified analyses the relationships only existed in nonlarge hospitals. CONCLUSIONS: Physicians with high volume perform better on certain processes of care than those with medium and low volume, and have better outcomes for patients with AMI. The processes of care could partly explain the relationship between physician volume and AMI mortality. However, the relationships existed in nonlarge hospitals but not in large hospitals. PMID- 24783992 TI - Elective, major noncardiac surgery on the weekend: a population-based cohort study of 30-day mortality. AB - IMPORTANCE: Previous research has demonstrated that patients undergoing elective surgery on the weekend had an adjusted risk of 30-day mortality that was significantly higher than that of patients operated upon during the week. The generalizability of this association and effect size is unknown. OBJECTIVES: The aim of this study was to investigate the generalizability of the association between elective weekend surgery and increased 30-day postoperative mortality. RESEARCH DESIGN: A retrospective, propensity score-matched cohort analysis of linked population-based health administrative data was carried out. SUBJECTS: Individuals undergoing elective, intermediate, intermediate-risk to high-risk all describe the noncardiac surgery exposure at all acute care hospitals in Ontario, Canada, between 2002 and 2012 were included. EXPOSURE: Elective surgery was performed on the weekends. MEASURES: All-cause mortality was measured within 30 days of the operation. RESULTS: A total of 333,344 patients were studied, of whom 2826 died within 30 days of surgery (overall crude mortality rate 8.5 deaths per 1000). Weekend elective surgery was performed on 2520 patients, of whom 2518 were successfully propensity score matched to weekday surgical patients. Undergoing elective surgery on the weekend was associated with a 1.96 times higher odds of 30-day mortality than weekday surgery (95% confidence interval, 1.36-2.84) in a propensity-matched analysis. This significant increase in the odds of postoperative mortality was confirmed using a multivariable logistic regression analysis (odds ratio 1.51; 95% confidence interval, 1.19-1.92). CONCLUSIONS: Similar to previous studies in distinct health care systems, patients in Ontario undergoing elective surgery on the weekend experienced an increased risk of 30 day postoperative mortality. Mechanisms underlying this effect require further study. PMID- 24783993 TI - Will health care reform reduce disparities in insurance coverage?: Evidence from the dependent coverage mandate. AB - OBJECTIVES: We used data from the Medical Expenditure Panel Survey to assess the impact of the Affordable Care Act's dependent coverage mandate on disparities in health insurance coverage rates and evaluated whether non-Hispanic blacks and Hispanics gained coverage at the same rates as non-Hispanic whites. METHODS: To estimate changes in insurance rates, we employed a difference-in-difference regression approach comparing 7962 young adults aged 19-25 to 9321 adults aged 27 34. Separate regressions were estimated for non-Hispanic blacks, Hispanics, and non-Hispanic whites to understand whether the mandate had differential effects by race/ethnicity. Separate regressions by income level and race/ethnicity were also estimated. RESULTS: Insurance rates increased by 9.3 percentage points among non Hispanic whites, 7.2 percentage points among Hispanics, and 9.4 percentage points among non-Hispanic blacks. These changes were not significantly different from each other. Among individuals with income of <133% of the Federal Poverty Level, non-Hispanic whites experienced significantly larger gains, whereas at higher income levels, non-Hispanic blacks experienced significantly larger gains than other racial/ethnic groups. CONCLUSIONS: The dependent coverage mandate of the Affordable Care Act increased insurance rates among all racial and ethnic groups but did not change overall disparities. Disparities may have widened among low income populations which highlights the importance of Medicaid expansions in reducing disparities. Among higher-income populations, disparities between non Hispanic blacks and non-Hispanic whites were reduced. PMID- 24783994 TI - Reliability of surgical outcomes for predicting future hospital performance. AB - BACKGROUND: Because of small sample sizes and low event rates, risk-adjusted surgical outcomes often do not meet reliability benchmarks for distinguishing hospital performance. Nonetheless, it is unclear whether these measures may still be useful for predicting future hospital surgical performance. METHODS: We used national Medicare data to analyze patients undergoing colectomy from 2007 to 2010 (n=462,959 patients). We first quantified 2007-2008 outcome reliability (ability to differentiate quality differences) and ranked hospitals based on their 2007 2008 risk-adjusted outcome rates. To assess the ability of adjusted outcomes to predict true performance, we evaluated future (2009-2010) outcomes across quintiles of past performance. We then systematically sampled 2007-2008 cases to evaluate performance prediction when hospitals' past performance was measured with progressively lower reliability levels. RESULTS: Outcomes in 2007-2008 were good predictors of outcomes in the next 2 years (2009-2010), but predictive strength depended upon reliability. With progressive sampling of 2007-2008 caseloads, outcome reliability and predictive strength decreased. With 100% sampling of 2007-2008 caseloads, the worst versus best hospital quintile based on past performance had 1.52 [95% confidence interval (CI), 1.44-1.60] times the odds of mortality and 1.50 (95% CI, 1.44-1.56) times the odds of complications in 2009-2010. With 10% sampling, outcome reliability was well below commonly accepted benchmarks, but the worst quintile of hospitals in 2007-2008 still had 1.12 (95% CI, 1.06-1.19) times the odds of mortality and 1.16 (95% CI, 1.11-1.21) times the odds of complications in 2009-2010 compared with the best quintile of hospitals. CONCLUSIONS: Even at very low reliability levels, risk-adjusted outcome measures may distinguish best and worst hospitals' surgical performance. This study suggests that commonly accepted reliability thresholds may be too high, especially in the context of selective referral. PMID- 24783995 TI - RR interval variability during galvanic vestibular stimulation correlates with arterial pressure upon head-up tilt. AB - RR interval variability (RRIV) in the supine position without and with galvanic vestibular stimulation (GVS (off) and GVS (on), respectively), changes in mean arterial pressure (MAP) at the onset of 60 degrees head-up tilt (HUT) during GVS (off), and their relationship were analyzed in 25 healthy young subjects. MAP decreased by less than 5mmHg or increased upon HUT in 12 subjects (UP), but MAP decreased by more than 5mmHg in 13 subjects (DOWN). Applying sinusoidal GVS of 2mA at a random frequency of 0.2 to 10.0Hz did not change the RR intervals or MAP. However, the high frequency component (HF) of RRIV increased in both UP and DOWN subjects. The increase in DOWN subjects was larger than that in UP subjects. The ratio of the low frequency component to HF (L/H) increased in UP subjects during GVS (on), but did not reach a significant level in DOWN subjects. The changes in the HF were significantly correlated with changes in MAP at the onset of HUT; i.e., the subjects with larger increases in the HF during GVS (on) showed larger decreases in MAP. Thus, GVS or vestibular input during HUT possibly activates the vagal nerves, and the dominance of excitation in sympathetic or vagal nerves during vestibular stimulation is important for controlling MAP at the onset of HUT. PMID- 24783996 TI - Coping, psychopathology, and quality of life in cancer patients under palliative care. AB - OBJECTIVE: To assess hopelessness, anxiety, depression, and quality of life in cancer patients undergoing palliative treatment by comparing their scores at the onset of treatment and one month later and by assessing possible correlations with coping strategies. METHOD: Participants included 85 patients of both genders (56.5% female) diagnosed with advanced cancer who did not have curative therapeutic options who were assessed with self-applied instruments (the Beck Hopelessness Scale, the European Organization for the Research and Treatment of Cancer Quality of Life Core Questionnaire-Cancer 30, the Hospital Anxiety and Depression Scale, and the Coping Strategies Inventory by Folkman and Lazarus) at two timepoints: first before their appointment with doctors and other professionals in their first visit to the palliative care outpatient clinic (PCOC) and then as soon as patients arrived at the PCOC for their first medical follow-up visit (approximately 30 days after the first appointment). RESULTS: The scores for hopelessness, anxiety, and depression remained stable (p = 0.24). The results were the same for the quality-of-life (QoL) variables, except for the fatigue and pain scores, which decreased (p = 0.01), and social impairment, which increased (p = 0.03). Analysis of the correlations between the coping mechanisms used after the onset of palliative treatment showed that confronting coping, seeking social support, and positive reappraisal were inversely correlated with hopelessness. Seeking social support, planful problem solving, and positive reappraisal were inversely correlated with indicators of depression. In contrast, use of the escape-avoidance strategy and reduced use of the planful problem solving strategy were associated with increased anxiety. SIGNIFICANCE OF RESULTS: The employment of problem-focused coping strategies exerted a positive impact on the end-of-life process and, above all, protected patients from the negative experiences associated with psychiatric symptoms, thus enabling them to look for alternative solutions for experiencing the end-of-life process in a more well adjusted manner. PMID- 24783997 TI - Eye darkening as a reliable, easy and inexpensive indicator of stress in fish. AB - We expand the use of eye darkening (ED) to indicate non-social stress in the fish Nile tilapia Oreochromis niloticus (L.). ED is easily estimated, not requiring any sophisticated equipment, and is non-invasive, facilitating the collection of several measures of stress over time. In the current study, we showed the following: (i) high- and low-ED occur spontaneously, indicating different fish reactions to adjustments to a novel environment; (ii) fish confinement or air exposure clearly increases ED (air exposure is a stronger stressor than confinement), and the time to restore basal values indicates the severity of the impact of the stressor on the fish (this response is not affected by period of the day, e.g., morning or afternoon); and (iii) in adults, females were more responsive (slower recovery) to 2-min air exposure than to 30-min confinement. PMID- 24783998 TI - Hemodynamic-directed cardiopulmonary resuscitation during in-hospital cardiac arrest. AB - Cardiopulmonary resuscitation (CPR) guidelines assume that cardiac arrest victims can be treated with a uniform chest compression (CC) depth and a standardized interval administration of vasopressor drugs. This non-personalized approach does not incorporate a patient's individualized response into ongoing resuscitative efforts. In previously reported porcine models of hypoxic and normoxic ventricular fibrillation (VF), a hemodynamic-directed resuscitation improved short-term survival compared to current practice guidelines. Skilled in-hospital rescuers should be trained to tailor resuscitation efforts to the individual patient's physiology. Such a strategy would be a major paradigm shift in the treatment of in-hospital cardiac arrest victims. PMID- 24783999 TI - Alcohol consumption has a protective effect against hematological malignancies: a population-based study in Sweden including 420,489 individuals with alcohol use disorders. AB - BACKGROUND: It has been suggested that alcohol consumption is associated with increased risk of a few solid cancers, although studies that examined the association with hematological malignancies have shown inconsistent results. In this study, we examined the risk of hematological malignancies among individuals who had alcohol use disorders (AUDs) in Sweden. METHODS: Individuals with AUDs were identified from the nationwide Swedish Hospital Discharge Register and Outpatient Register, the Crime Register, and the Prescription Drug Register, and they were linked to the Swedish Cancer Registry to calculate standardized incidence ratios (SIRs) of hematological malignancies, using those Swedes without AUDs as a reference. In addition, we used a quasi-experimental sibling design to investigate the odds ratios among sibling pairs who were discordant with AUDs. RESULTS: A total of 420,489 individuals were identified with AUDs. After more than 15 million person-years of follow-up, a total of 1755 individuals developed hematological malignancies demonstrating a low risk, i.e., SIR = 0.60 (95% confidence interval = 0.57-0.63). People with AUDs had low risks for developing specific types of malignancies. The lowest risk (0.51) was for leukemia, followed by myeloma (0.52), non-Hodgkin lymphoma (0.65), and Hodgkin disease (0.71). The risk was lower among AUDs identified at an older age. The low risks of hematological malignancies were also noted using sibling analysis. CONCLUSIONS: Our data suggest that alcohol consumption has a protective effect against hematological malignancies. However, further studies are needed to identity the underlying mechanisms of the protective effect of alcohol consumption against hematological malignancies. PMID- 24784000 TI - Optical tomography of MMP activity allows a sensitive noninvasive characterization of the invasiveness and angiogenesis of SCC xenografts. AB - For improved tumor staging and therapy control, imaging biomarkers are of great interest allowing a noninvasive characterization of invasiveness. In squamous epithelial skin and cervix lesions, transition to invasive stages is associated with enhanced matrix metalloproteinase (MMP) activity, increased angiogenesis, and worsened prognosis. Thus, we investigated MMP activity as imaging biomarker of invasiveness and the potential of optical tomography in characterizing the angiogenic and invasive behavior of skin squamous cell carcinoma (SCC) xenografts. MMP activity was measured in vivo in HaCaT-ras A-5RT3 tumors at different angiogenic and invasive stages (onset of angiogenesis, intermediate and highly angiogenic, invasive stage) and after 1 week of sunitinib treatment by fluorescence molecular tomography-microcomputed tomography imaging using an activatable probe. Treatment response was additionally assessed morphologically by optical coherence tomography (OCT). In vivo MMP activity significantly differed between the groups, revealing highest levels in the highly angiogenic, invasive tumors that were confirmed by immunohistochemistry. At the onset of angiogenesis with lowest MMP activity, fibroblasts were detected in the MMP positive areas, whereas macrophages were absent. Accumulation of both cell types occurred in both invasive groups, again to a significantly higher degree at the most invasive and angiogenic stage. Sunitinib treatment significantly reduced the MMP activity and accumulation of fibroblasts and macrophages and blocked tumor invasion that was additionally visualized by OCT. Human cervical SCCs also showed high MMP activity and a similar stromal composition as the HaCaT xenografts, whereas normal tissue was negative. This study strongly suggests MMP activity as imaging biomarker and demonstrates the high sensitivity of optical tomography in determining tumor invasiveness that can morphologically be supported by OCT. PMID- 24784001 TI - KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple negative breast cancer. AB - Despite evidence that kinesin family member 14 (KIF14) can serve as a prognostic biomarker in various solid tumors, how it contributes to tumorigenesis remains unclear. We observed that experimental decrease in KIF14 expression increases docetaxel chemosensitivity in estrogen receptor-negative/progesterone receptor negative/human epidermal growth factor receptor 2-negative, "triple-negative" breast cancers (TNBC). To investigate the oncogenic role of KIF14, we used noncancerous human mammary epithelial cells and ectopically expressed KIF14 and found increased proliferative capacity, increased anchorage-independent grown in vitro, and increased resistance to docetaxel but not to doxorubicin, carboplatin, or gemcitabine. Seventeen benign breast biopsies of BRCA1 or BRCA2 mutation carriers showed increased KIF14 mRNA expression by fluorescence in situ hybridization compared to controls with no known mutations in BRCA1 or BRCA2, suggesting increased KIF14 expression as a biomarker of high-risk breast tissue. Evaluation of 34 cases of locally advanced TNBC showed that KIF14 expression significantly correlates with chemotherapy-resistant breast cancer. KIF14 knockdown also correlates with decreased AKT phosphorylation and activity. Live cell imaging confirmed an insulin-induced temporal colocalization of KIF14 and AKT at the plasma membrane, suggesting a potential role of KIF14 in promoting activation of AKT. An experimental small-molecule inhibitor of KIF14 was then used to evaluate the potential anticancer benefits of downregulating KIF14 activity. Inhibition of KIF14 shows a chemosensitizing effect and correlates with decreasing activation of AKT. Together, these findings show an early and critical role for KIF14 in the tumorigenic potential of TNBC, and therapeutic targeting of KIF14 is feasible and effective for TNBC. PMID- 24784002 TI - Current applications of miniaturized chromatographic and electrophoretic techniques in drug analysis. AB - In the last decade, miniaturized separation techniques have become greatly popular in pharmaceutical analysis. Miniaturized separation methods are increasingly utilized in all processes of drug discovery as well as quality control of pharmaceutical preparation. The great advantages presented by the analytical miniaturized techniques, including high separation efficiency and resolution, rapid analysis and minimal consumption of reagents and samples, make them an attractive alternative to the conventional chromatographic methods for drug analysis. The purpose of this review is to give a general overview of the applicability of capillary electrophoresis (CE), capillary electrochromatography (CEC) and micro/capillary/nano-liquid chromatography (micro-LC/CLC/nano-LC) for the analysis of pharmaceutical formulations, active pharmaceutical ingredients (API), drug impurity testing, chiral drug separation, determination of drugs and metabolites in biological fluids. The results concerning the use of CEC, micro LC, CLC, and nano-LC in the period 2009-2013, while for CE, those from 2012 up to the review draft are here summarized and some specific examples are discussed. PMID- 24784003 TI - Hepatic venous outflow obstruction after transplantation: outcomes for treatment with self-expanding stents. AB - OBJECTIVES: To evaluate the safety and patency of self-expanding stents to treat hepatic venous outflow obstruction after orthotopic liver transplantation. To evaluate differences in the response between patients with early obstruction and patients with late obstruction. MATERIAL AND METHODS: This is a retrospective analysis of 16 patients with hepatic venous outflow obstruction after liver transplantation treated with stents (1996-2011). Follow-up included venography/manometry, ultrasonography, CT, and laboratory tests. We did a descriptive statistical analysis of the survival of patients and stents, technical and clinical success of the procedure, recurrence of obstruction, and complications of the procedure. We also did an inferential statistical analysis of the differences between patients with early and late obstruction. RESULTS: The mean follow-up period was 3.34 years (21-5,331 days). The technical success rate was 93.7%, and the clinical success rate was 81.2%. The rate of complications was 25%. The survival rates were 87.5% for patients and 92.5% for stents. The rate of recurrence was 12.5%. The rate of primary patency was 0.96 (95% CI 0.91-1) at 3 months, 0.96 (95% CI 0.91-1) at 6 months, 0.87 (95% CI 0.73-1) at 12 months, and 0.87 (95% CI 0.73-1) at 60 months. There were no significant differences between patients with early and late obstruction, although there was a trend toward higher rates of primary patency in patients with early obstruction (P=.091). CONCLUSIONS: Treating hepatic venous outflow obstruction after orthotopic transplantation with self-expanding stents is effective, durable, and effective. There are no significant differences between patients with early obstruction and those with late obstruction. PMID- 24784004 TI - Late spontaneous nonanastomotic transgraft hemorrhage from biological material impregnated fabric vascular graft may be due to autologous tissue detachment: a clinical hypothesis. AB - Spontaneous nonanastomotic transgraft hemorrhage occurring several years after grafting may be a new late complication of biological material-impregnated fabric vascular grafts (BMIFVs). Autologous connective tissue detachment may be caused by high porosity of the fabric graft and high blood pressure. Bleeding around the fiber is the first sign of development. Fabric grafts with optimal porosity and biocompatibility should be used for manufacturing BMIFVs. PMID- 24784005 TI - Disclosing a dementia diagnosis: what do patients and family consider important? AB - BACKGROUND: The literature available on the format of the feedback session following assessment of memory impairment is minimal. This study explored how this information should be presented from the perspective of patients and their families. METHODS: Thirty-two semi-structured interviews were conducted with memory clinic patients and their carer at the clinic visit that followed the feedback session, to ask: what they recalled, what they found helpful, and what they thought was the best way to disclose a diagnosis of dementia. A second interview was conducted with 14 patient/carer dyads at their next appointment. RESULTS: Recall of information from the feedback session was variable. Most respondents (76% of patients; 66% of carers) thought that a direct approach was best when informing the patient of a dementia diagnosis, and that both written information and compassion demonstrated by the doctor were helpful. Opinions on whether all the information should be given at once or in stages were divided. CONCLUSIONS: The current format of the feedback session needs revision to improve recall. Patients and their families want a direct approach to be used by a supportive and professional doctor with an opportunity to ask questions. They want the support of a family member or friend when they are told of their diagnosis and they would like a written summary to refer to afterwards. PMID- 24784006 TI - Item-location binding in working memory: is it hippocampus-dependent? AB - A general consensus is emerging that the hippocampus has an important and active role in the creation of new long-term memory representations of associations or bindings between elements. However, it is less clear whether this contribution can be extended to the creation of temporary bound representations in working memory, involving the retention of small numbers of items over short delays. We examined this by administering a series of recognition and recall tests of working memory for colour-location binding and object-location binding to a patient with highly selective hippocampal damage (Jon), and groups of control participants. Jon achieved high levels of accuracy in all working memory tests of recognition and recall binding across retention intervals of up to 10s. In contrast, Jon performed at chance on an unexpected delayed test of the same object-location binding information. These findings indicate a clear dissociation between working memory and long-term memory, with no evidence for a critical hippocampal contribution to item-location binding in working memory. PMID- 24784007 TI - Accelerated long-term forgetting in children with temporal lobe epilepsy. AB - Adults with temporal lobe epilepsy (TLE) have been found to have accelerated long term forgetting, but this phenomenon has not yet been investigated in children. Although deficits in recall of materials after short (20- to 30-minute) delays have been shown to slowly emerge from childhood to adolescence in patients with TLE, it is unknown whether such a trend will also be found in recall of materials after long delays. This study examined the presence of accelerated long-term forgetting in children with TLE and how it relates to chronological age. Twenty three children with TLE and 58 healthy controls of similar age, sex distribution and socioeconomic status completed a battery of neuropsychological tests, including standardised tests of story recall and design location, as well as two experimental tests requiring the learning of words and design locations to a criterion, both of which assessed recall after short (30-min) and long (7-day) delays. Word recall at the 7-day delay (relative to the 30-min recall) was significantly poorer in the TLE group, compared to the control group. The TLE group also exhibited worse 30-min recall performance on a standardised test of story recall. Individual patient analyses revealed dissociation between performance on the experimental and standardised verbal memory tests; children who were impaired on the experimental test (7-day delay) were not impaired on the standardised test (30-min delay). Compared to controls, patients with a left hemisphere seizure focus recalled fewer words at short and long delays while patients with an abnormal hippocampus recalled fewer words at the long delay. No between-group differences were found with respect to the design location task. Age negatively correlated with the recall of words after short- and long-term delays within the TLE group, where older age was associated with worse memory. This association was not present in the control group. To our knowledge, this is the first study to show evidence of accelerated long-term forgetting in children with TLE, which could not be explained by poor performance on standardised memory tests. Additionally, these results suggest that the developmental trajectory of long-term memory in children with TLE is similar to that of short-term memory: deficits emerge gradually, therefore older children are more likely to present with long-term memory deficits. PMID- 24784008 TI - Strategy selection in Alzheimer patients: a study in arithmetic. AB - OBJECTIVE: We compared Alzheimer's disease (AD) patients' and elderly controls' abilities to select the best strategy on each item and determined whether AD patients tended to repeat the same strategy across consecutive items more often than controls. METHOD: A total of 60 participants (30 healthy older adults, HOA; 30 AD patients) were asked to select the best rounding strategy to estimate products of multiplication problems (e.g., estimating 42 * 76 by rounding operands down or up, like doing 40 * 70 = 2800 or 50 * 80 = 3200). We identified strategies used on each problem and measured solution latencies and percentage errors with each strategy as a function of problem characteristics. RESULTS: Older adults and AD patients were able to use both available strategies. However, AD patients were less able to select the best strategy than HOA, especially on problems for which selecting the best strategy was most difficult. Moreover, AD patients significantly repeated the preceding strategies across successive problems more often than HOA. CONCLUSIONS: Our findings have important implications for further our understanding of dementia-related differences in strategic aspects of cognitive performance. PMID- 24784009 TI - Perforator infarction immediately distal to the stenosis of parental artery: is it hemodynamic? AB - Perforator infarction accompanying intracranial atherosclerosis is usually explained by the obstruction of perforator by atheroma of the parent artery. However, the improvement of neurologic symptom after stenting is hardly explained by the concept. Here, we report a case of perforator infarction caused by the unique hemodynamic condition of the poststenotic area without any plaque at the origin of perforator, which was confirmed by high-resolution magnetic resonance image. Poststenotic area with eddying flow separating the region from the main flow may hemodynamically contribute to the perforator infarction and neurologic symptom. PMID- 24784010 TI - Persistent leukocytosis-is this a persistent problem for patients with acute ischemic stroke? AB - BACKGROUND: In the setting of acute ischemic stroke (AIS), leukocytosis has been shown to be an indicator of inflammatory response. Although leukocytosis on admission has been shown to correlate with initial stroke severity in AIS patients, no work has been done to assess if there are differences in transient or persistent leukocytosis in patients without infection. The objective of this study is to determine the clinical significance of persistent versus transient leukocytosis during the early phase of AIS. METHODS: Patients who presented with AIS to our center within 48 hours of symptom onset between July 2008 and June 2010 were retrospectively identified by chart review. Patients were included if they had leukocytosis on admission (defined as white blood cell count >11,000/MUL based on laboratory reference range values). A logistic regression model was used to evaluate persistent leukocytosis (leukocytosis 48 hours after admission) as a predictor of several outcome measures, including good functional outcome (discharge modified Rankin Scale score of 0-2). Marginal effects were used to estimate the probability of poor functional outcome. RESULTS: Of the 438 patients screened, 49 had leukocytosis on admission and of those 24 (49%) had persistent leukocytosis. NIHSS score correlated significantly with persistence of leukocytosis (r = .306; P = .0044). More people with transient leukocytosis (leukocytosis lasting <48 hours) had a good functional outcome (44% versus 16%; P = .006). After adjusting for baseline NIHSS score, persistent leukocytosis was not a significant independent predictor of good functional outcome, but showed an association (OR, 2.5; 95% CI, .562-10.7; P = .2322). Persistent leukocytosis after adjusting for age and NIHSS score at admission is associated with a poor functional outcome, but it is not statistically significant (OR, 2.43; 95% CI, .59-9.87; P = .2151). After controlling for age and NIHSS score on admission, for patients with persistent leukocytosis, the probability of having poor functional outcome at discharge was increased by 16 percentage points. CONCLUSIONS: Persistent leukocytosis is associated with higher baseline NIHSS scores. Persistent leukocytosis is tightly linked with baseline stroke severity and is associated with poor patient outcomes. Our study found that patients with persistent leukocytosis are more likely to present with severe strokes and maintain a high NIHSS score at 24 hours after admission, unlike patients without leukocytosis or patients with transient leukocytosis. Furthermore, it appears that persistent leukocytosis outside the setting of an infection negatively impacts the short-term functional outcome of AIS patients. Identifying patients with persistent leukocytosis could help to prognosticate and target patients that may benefit from future anti-inflammatory interventions. PMID- 24784011 TI - Prevalence and clinical correlation of left ventricular systolic dysfunction in african americans with ischemic stroke. AB - BACKGROUND: The goal of the present study was to determine the prevalence of left ventricular systolic dysfunction (LVSD) and associated clinical correlates in African Americans (AA) diagnosed with ischemic stroke (IS). METHODS: Retrospective chart analysis was done on all diagnosed AA IS patients between January 2010 and March 2012. Patients with atrial fibrillation were excluded. A total of 147 patients were included in the study. Transthoracic 2-dimensional echocardiography was used to assess left ventricular systolic function, and study groups were categorized as normal, mild, moderate, and severely abnormal, based on the ejection fraction (EF). Available imaging studies were analyzed for data collection. Logistic regression and Pearson chi-square tests were performed. RESULTS: Normal EF was present in 114 of 147 patients (78%). Mild abnormality was present in 9 of 147 (6%), moderate in 8 of 147 (5%), and severe in 16 of 147 (11%) patients. In patients with mildly reduced EF, smoking was the most common (RF). In patients with moderately and severely reduced EFs, hypertension was the most common RF. History of smoking was commonly found in systolic dysfunction group compared with normal group (P = .001). Logistic regression analysis revealed that smoking and advanced age were the significant predictors for LVSD. Large-vessel IS were more common in systolic dysfunction group than normal EF group (P = .017). CONCLUSIONS: Prevalence of LVSD in AA with IS was 22% in our study. Smoking was a significant modifiable RF associated with systolic dysfunction. A history of smoking and higher age could predict the occurrence of LVSD. There were more large-vessel IS in patients with LVSD. PMID- 24784012 TI - Factors predicting high estimated 10-year stroke risk: thai epidemiologic stroke study. AB - BACKGROUND: The purpose of the study was to determine the factors predicting high estimated 10-year stroke risk based on a risk score, and among the risk factors comprising the risk score, which factors had a greater impact on the estimated risk. METHODS: Thai Epidemiologic Stroke study was a community-based cohort study, which recruited participants from the general population from 5 regions of Thailand. Cross-sectional baseline data of 16,611 participants aged 45-69 years who had no history of stroke were included in this analysis. Multiple logistic regression analysis was used to identify the predictors of high estimated 10-year stroke risk based on the risk score of the Japan Public Health Center Study, which estimated the projected 10-year risk of incident stroke. RESULTS: Educational level, low personal income, occupation, geographic area, alcohol consumption, and hypercholesterolemia were significantly associated with high estimated 10-year stroke risk. Among these factors, unemployed/house work class had the highest odds ratio (OR, 3.75; 95% confidence interval [CI], 2.47-5.69) followed by illiterate class (OR, 2.30; 95% CI, 1.44-3.66). Among risk factors comprising the risk score, the greatest impact as a stroke risk factor corresponded to age, followed by male sex, diabetes mellitus, systolic blood pressure, and current smoking. CONCLUSIONS: Socioeconomic status, in particular, unemployed/house work and illiterate class, might be good proxy to identify the individuals at higher risk of stroke. The most powerful risk factors were older age, male sex, diabetes mellitus, systolic blood pressure, and current smoking. PMID- 24784013 TI - The severities of white matter lesions possibly influence the recurrences of several stroke types. AB - BACKGROUND: White matter lesions (WML) have been reported to be a surrogate marker of stroke occurrences. To investigate the recurrent stroke types associated with WML, we prospectively observed recurrences in stroke patients. METHODS: We prospectively analyzed the types of stroke recurrence in 807 patients (351 women, 69.8 +/- 12.0 years old) consecutively admitted to our hospital with strokes from April 2004 to October 2009. WML were graded using Fazekas grades. Recurrence-free rate curves were generated by the Kaplan-Meier method using the log-rank test. RESULTS: The follow-up period was 31.6 +/- 22.2 (range .5-71) months. During this period, 111 strokes recurred. The incidence of all stroke recurrences in 223 patients with grades 2 and 3 was 6.0% per year, which was significantly higher than that seen in 287 patients with grade 0 (2.1% per year, P = .006) and 297 patients with grade 1 (4.3% per year, P < .0001). The incidences of intracerebral hemorrhages (ICHs), lacunar infarctions, and atherothrombotic infarctions in patients with grades 2 and 3 were 1.2, 1.4, and 2.4% per year, respectively, which were higher than those seen in patients with grade 0 (.3%, P = .004; .2%, P = .002; and .9% per year, P = .010) but not similar to those in patients with grade 1 (.9%, P = .180; .9%, P = .161; and 1.4% per year, P = .249). There was no significant difference among grades 0, 1, 2, and 3 in incidence of stroke recurrences presenting as cardioembolic infarctions. CONCLUSIONS: The presence of high-grade WML elevated the rate of stroke recurrences presenting as ICHs, lacunar infarctions, and atherothrombotic infarctions but not as cardioembolic infarctions. PMID- 24784014 TI - A case of anterior cerebral artery dissection caused by scuba diving. AB - A 51-year-old man was admitted with right hemiparesis during scuba diving, without headache. Brain magnetic resonance (MR) imaging depicted high-intensity areas in the left superior frontal and cingulate gyri on diffusion-weighted imaging. Dissection of the anterior cerebral artery (ACA) was detected using axial MR angiography and 3-dimensional MR cisternography. Dissection of the ACA during and after scuba diving has not been reported before. Dissection of the arteries should be included in the differential diagnosis when neurologic symptoms occur both during and after scuba diving, even if the patient does not experience headache. Furthermore, the combination of MR cisternography and MR angiography is useful to detect ACA dissection. PMID- 24784015 TI - Predicting 30-day case fatality of primary inoperable intracerebral hemorrhage based on findings at the emergency department. AB - BACKGROUND: Early survival of patients with intracerebral hemorrhage (ICH) depends on several factors, including the location and size of the hematoma and the level of consciousness on admission. The aim of our study was to estimate the case fatality of primary inoperable ICH 30 days after the event in our hospital and to identify clinical and laboratory characteristics, recordable at the Emergency Department (ED), which could predict death at 30 days. METHODS: Clinical and laboratory data on all patients with primary ICH admitted to our hospital were retrospectively collected. RESULTS: Between January 2011 and June 2013 191 patients with primary ICH were admitted to our hospital. The 30-day case fatality rate was estimated to be 31.9%, as 61 patients died within 30 days after the ICH. Five variables were independently associated with 30-day case fatality: each decreased point at the Glasgow Coma Scale (GCS) is associated with a 1.3 fold increase in the odds of death at 30 days; infratentorial location and intraventricular extension are associated with a 5.5-fold and a 4.7-fold increase in the odds of death at 30 days, respectively; each centimeter of the maximum diameter of the hematoma and each point increase of the international normalized ratio (INR) are associated with a 1.9-fold and a 3.5-fold increase in the odds of death at 30 days, respectively. CONCLUSIONS: GCS score on admission, infratentorial location of the hematoma, intraventricular extension of the hematoma, INR on admission, and maximum diameter of the hematoma are the 5 variables that are independently associated with 30-day case fatality of primary inoperable ICH. EDICH is introduced as a new grading scale, which includes laboratory and clinical findings at the ED and has predicting value of the 30-day case fatality. PMID- 24784016 TI - In Vitro and In Vivo evaluation of a magnetic resonance imaging-guided focused ultrasound system for dissolving clots in combination with thrombolytic drugs. AB - BACKGROUND: The potential of a magnetic resonance imaging (MRI)-guided focused ultrasound (MRgFUS) system combined with thrombolytic drugs to dissolve clots is investigated using in vitro and in vivo models. METHODS: Two spherically focused transducers of 5 cm diameter focusing at 10 cm and operating at either .5 or 1 MHz were used. Doppler ultrasound was used to measure the blood flow during the in vivo experiments. RESULTS: The effect of ultrasound intensity, transducer beam area, and frequency on the dissolved volume was investigated. The goal was to maintain a temperature increase of less than 1 degrees C (called safe temperature) at the clot during the application of pulsed ultrasound and at the same time achieve efficient thrombolysis. CONCLUSIONS: The MRgFUS technique was proven successful in dissolving clots in vitro and in vivo. It was found that the volume of dissolved clot increases with acoustic intensity and beam size and decreases with frequency. With this system, it was possible to push ultrasound through a plastic phantom skull using a .5 MHz transducer. The beam of ultrasound through the phantom skull was monitored using the MRI technique of fast spoiled gradient. Finally, the thrombus in the in vivo model (ear artery) was successfully destroyed with the therapeutic protocols investigated in the in vitro models. This study shows that FUS using a single element MR-compatible transducer has the potential to treat clots in synergy with thrombolytic drugs. More advanced MRgFUS systems, such as phased arrays, will have a greater impact in sonothrombolysis. PMID- 24784017 TI - Alleviating poverty or reinforcing inequality? Interpreting micro-finance in practice, with illustrations from rural China. AB - Academic and political discussions about micro-finance have been found lacking in predictive power, because they are based on orthodox economic theory, which does not properly comprehend the social components of credit. I take a better approach, utilizing credit theory--specifically, Ingham's explication of how the nature of money as credit leads to social inequality. I also expound the perspective that morality is not separate from considerations borrowers make in micro-finance programmes on the micro level. I draw upon illustrations from my fieldwork in rural China, where a group-lending micro-finance programme was administered as part of a larger government-initiated effort across the country. PMID- 24784018 TI - Low-dose arsenic: in search of a risk threshold. PMID- 24784019 TI - Antioxidant properties of isolated compounds from banana rhizome. AB - In this study, we attempted to explore banana rhizome (BR) as a source of natural bioactive compounds. Dried BR powder was subjected to sequential extraction using solvents with increasing polarity and studied for antioxidant activities. Chloroform and acetone extracts were selected for isolation and identification of bioactive compounds because of their high antioxidant properties. Antioxidant activity guided fractionation of these extracts yielded 3 compounds. The spectroscopy studies revealed the identity of isolated compounds as 4 epicyclomusalenone, cycloeucalenol acetate and chlorogenic acid. Polyphenolic compound chlorogenic acid and triterpenoid compounds, 4-cyclomusalenone and cycloeucalenol acetate displayed multifunctional antioxidant activity. PRACTICAL APPLICATION: The isolated compounds namely 4-epicyclomusalenone, cycloeucalenol acetate and chlorogenic acid have demonstrated their antioxidant properties in different in vitro assay models. The present study indicated that the vast quantity of banana rhizome which was incinerated could be a potential source of natural antioxidant compounds. This can also be used in the food, nutraceutical and pharmaceutical industries. PMID- 24784020 TI - The time trend temperature-mortality as a factor of uncertainty analysis of impacts of future heat waves. PMID- 24784021 TI - TXT@WORK: pediatric hospitalists and text messaging. AB - BACKGROUND: Many studies assess provider-patient communication through text messaging; however, minimal research has addressed communication among physicians. The purpose of this study was to evaluate the use of text messaging by pediatric hospitalists. MATERIALS AND METHODS: A brief, anonymous, electronic survey was distributed through the American Academy of Pediatrics Section on Hospital Medicine Listserv in February 2012. Survey questions assessed work related text messaging. RESULTS: Of the 106 pediatric hospitalist respondents, 97 met inclusion criteria. Most were female (73%) and had been in practice <10 years (67%). Ninety-one percent of responders used a smartphone. More than half sent (60%) and received (61%) work-related text messages, some (12%) more than 10 times per shift. More than half (53%) received work-related text messages when not at work. When asked to identify all potential work recipients, most often sent work-related text messages to other pediatric hospitalists (64%), fellows or resident physicians (37%), and subspecialists/consulting physicians (28%). When asked their preferred mode for brief communication, respondents' preferences varied. Many (46%) respondents worried privacy laws can be violated by sending/receiving text messages, and some (30%) reported having received protected health information (PHI) through text messages. However, only 11% reported their institution offered encryption software for text messaging. CONCLUSIONS: Physicians were using text messaging as a means of brief, work related communication. Concerns arose regarding transfer of PHI using unsecure systems and work-life balance. Future research should examine accuracy and effectiveness of text message communication in the hospital, as well as patient privacy issues. PMID- 24784022 TI - Lattice Boltzmann simulation of shale gas transport in organic nano-pores. AB - Permeability is a key parameter for investigating the flow ability of sedimentary rocks. The conventional model for calculating permeability is derived from Darcy's law, which is valid only for continuum flow in porous rocks. We discussed the feasibility of simulating methane transport characteristics in the organic nano-pores of shale through the Lattice Boltzmann method (LBM). As a first attempt, the effects of high Knudsen number and the associated slip flow are considered, whereas the effect of adsorption in the capillary tube is left for future work. Simulation results show that at small Knudsen number, LBM results agree well with Poiseuille's law, and flow rate (flow capacity) is proportional to the square of the pore scale. At higher Knudsen numbers, the relaxation time needs to be corrected. In addition, velocity increases as the slip effect causes non negligible velocities on the pore wall, thereby enhancing the flow rate inside the pore, i.e., the permeability. Therefore, the LBM simulation of gas flow characteristics in organic nano-pores provides an effective way of evaluating the permeability of gas-bearing shale. PMID- 24784023 TI - Effects of eight-month treatment with ONO-5334, a cathepsin K inhibitor, on bone metabolism, strength and microstructure in ovariectomized cynomolgus monkeys. AB - This study examined the effect of ONO-5334, a cathepsin K inhibitor, on bone turnover, mineral density (BMD), mechanical strength and microstructure in ovariectomized (OVX) cynomolgus monkeys. Vehicle, ONO-5334 (3, 10 or 30 mg/kg) or alendronate (0.5 mg/kg) was orally administered for eight months to sham- and OVX operated monkeys. ONO-5334 dose-dependently suppressed OVX-induced increase in bone turnover markers (urinary C-terminal cross-linking telopeptide of type I collagen (CTX) and serum osteocalcin). At the dose of 30 mg/kg, ONO-5334 maintained urinary CTX at nearly zero level and kept serum osteocalcin around the level of the sham animals. Marker levels in the alendronate-treated animals were similar to those in the sham animals throughout the study. ONO-5334 dose dependently reversed the effect of OVX on vertebral BMD as measured by dual energy X-ray absorptiometry (DXA) with improvement of bone mechanical strength. Both ONO-5334 and alendronate suppressed OVX-induced changes in vertebral microstructure and turnover state. In the femoral neck, peripheral quantitative computed tomography (pQCT) analysis showed that ONO-5334 increased total and cortical BMD. In particular, ONO-5334 significantly increased cortical BMD with improvement of bone mechanical strength. In microstructural analysis, alendronate suppressed OVX-induced increase in femoral mid-shaft osteonal bone formation rate (BFR) to a level below that recorded in the sham group, whereas ONO-5334 at 30 mg/kg did not suppress periosteal, osteonal and endocortical BFR. This finding supports the significant effect of ONO-5334 on cortical BMD and mechanical strength in the femoral neck. The results of this study suggest that ONO-5334 has good therapeutic potential for the treatment of osteoporosis. PMID- 24784024 TI - Transplant patient classification and tacrolimus assays: more evidence of the need for assay standardization. AB - BACKGROUND: A global tacrolimus proficiency study recently showed clinically significant variability between laboratories, the inability of a common calibrator to harmonize methods, and differences in patient classification depending on the test method. The authors evaluated (1) the effect of a change in methodology on patient classification based on tacrolimus blood concentration and (2) the ability of 2 methods to position the concentration in a given specimen within the correct range. METHODS: A total of 839 consecutive samples were analyzed at The Rogosin Institute and New York Presbyterian Hospital for routine tacrolimus monitoring over 30 days. Concordance analysis between the methods was performed covering dosage target ranges of 8-10, 6-8, 4-6 ng/mL currently used at our center. Six Sigma Metrics were applied to statistically evaluate the discordance rate. RESULTS: Deming regression comparing liquid chromatography tandem mass spectrometry and immunoassay yielded y = 0.927x - 0.24; 95% confidence interval, 0.903-0.951; R = 0.875; n = 839. There were 310 pairs (37%) discordant by 1, 21 (2.5%) discordant by 2, and 4 (0.5%) discordant by 3 therapeutic ranges. Surprisingly, 40% of patient samples were discordant when therapeutic ranges were 2 ng/mL wide. This discordant rate is equivalent to 1.7 Sigma and falls far below the minimum acceptable threshold of 3 Sigma. CONCLUSIONS: Both methods are capable of measuring tacrolimus in the clinically relevant range between 1 and 10 ng/mL, yet 40% of the samples were discordant with an unacceptable Sigma level. Standardization of tacrolimus assays will mitigate this issue. PMID- 24784025 TI - Limited sampling strategies to predict the area under the concentration-time curve for rifampicin. AB - BACKGROUND: Rifampicin (RMP) is the most effective first-line antituberculosis drug. One of the most critical aspects of using it in fixed-drug combination formulations is to ensure it reaches therapeutic levels in blood. The determination of the area under the concentration-time curve (AUC) and appropriate dose adjustment of this drug may contribute to optimization of therapy. Even when the maximal concentration (Cmax) of RMP also predicts its sterilizing effect, the time to reach it (Tmax) takes 40 minutes to 6 hours. The aim of this study was to develop a limited sampling strategy (LSS) for therapeutic drug monitoring assistance for RMP. METHODS: Full concentration-time curves were obtained from 58 patients with tuberculosis (TB) after the oral administration of RMP in fixed-drug combination formulation. A validated high performance liquid chromatographic method was used. Pharmacokinetic parameters were estimated with a noncompartmental model. Generalized linear models were obtained by forward steps, and bootstrapping was performed to develop LSS to predict AUC curve from time 0 to the last measured at 24 hours postdose (AUC0 24). The predictive performance of the proposed models was assessed using RMP profiles from 25 other TB patients by comparing predicted and observed AUC0-24. RESULTS: The mean AUC0-24 in the current study was 91.46 +/- 36.7 mg.h.L, and the most convenient sampling time points to predict it were 2, 4 and 12 hours postdose (slope [m] = 0.955 +/- 0.06; r = 0.92). The mean prediction error was 0.355%, and the root mean square error was 5.6% in the validation group. Alternate LSSs are proposed with 2 of these sampling time points, which also provide good predictions when the 3 most convenient are not feasible. CONCLUSIONS: The AUC0-24 for RMP in TB patients can be predicted with acceptable precision through a 2- or 3-point sampling strategy, despite wide interindividual variability. These LSSs could be applied in clinical practice to optimize anti-TB therapy based on therapeutic drug monitoring. PMID- 24784027 TI - MicroRNAs in human skin ageing. AB - The skin protects humans from the surrounding environment. Tissues undergo continuous renewal throughout an individual's lifetime; however, there is a decline in the regenerative potential of tissue with age. The accumulation of senescent cells over time probably reduces tissue regenerative capacity and contributes to the physiological ageing of the tissue itself. The mechanisms that govern ageing remain unclear and are under intense investigation, and insight could be gained by studying the mechanisms involved in cellular senescence. In vitro, keratinocytes and dermal fibroblasts undergo senescence in response to multiple cellular stresses, including the overproduction of reactive oxygen species and the shortening of telomeres, or simply by reaching the end of their replicative potential (i.e., reaching replicative senescence). Recent findings demonstrate that microRNAs play key roles in regulating the balance between a cell's proliferative capacity and replicative senescence. Here, we will focus on the molecular mechanisms regulated by senescence-associated microRNAs and their validated targets in both keratinocytes and dermal fibroblasts. PMID- 24784026 TI - Host genetics and immune control of HIV-1 infection: fine mapping for the extended human MHC region in an African cohort. AB - Multiple major histocompatibility complex (MHC) loci encoding human leukocyte antigens (HLA) have allelic variants unequivocally associated with differential immune control of HIV-1 infection. Fine mapping based on single nucleotide polymorphisms (SNPs) in the extended MHC (xMHC) region is expected to reveal causal or novel factors and to justify a search for functional mechanisms. We have tested the utility of a custom fine-mapping platform (the ImmunoChip) for 172 HIV-1 seroconverters (SCs) and 449 seroprevalent individuals (SPs) from Lusaka, Zambia, with a focus on more than 6400 informative xMHC SNPs. When conditioned on HLA and nongenetic factors previously associated with HIV-1 viral load (VL) in the study cohort, penalized approaches (HyperLasso models) identified an intergenic SNP (rs3094626 between RPP21 and HLA-E) and an intronic SNP (rs3134931 in NOTCH4) as novel correlates of early set-point VL in SCs. The minor allele of rs2857114 (downstream from HLA-DOB) was an unfavorable factor in SPs. Joint models based on demographic features, HLA alleles and the newly identified SNP variants could explain 29% and 15% of VL variance in SCs and SPs, respectively. These findings and bioinformatics strongly suggest that both classic and nonclassic MHC genes deserve further investigation, especially in Africans with relatively short haplotype blocks. PMID- 24784028 TI - Cryptic habitats and cryptic diversity: unexpected patterns of connectivity and phylogeographical breaks in a Mediterranean endemic marine cave mysid. AB - The marine cave-dwelling mysid Hemimysis margalefi is distributed over the whole Mediterranean Sea, which contrasts with the poor dispersal capabilities of this brooding species. In addition, underwater marine caves are a highly fragmented habitat which further promotes strong genetic structuring, therefore providing highly informative data on the levels of marine population connectivity across biogeographical regions. This study investigates how habitat and geography have shaped the connectivity network of this poor disperser over the entire Mediterranean Sea through the use of several mitochondrial and nuclear markers. Five deeply divergent lineages were observed among H. margalefi populations resulting from deep phylogeographical breaks, some dating back to the Oligo Miocene. Whether looking at the intralineage or interlineage levels, H. margalefi populations present a high genetic diversity and population structuring. This study suggests that the five distinct lineages observed in H. margalefi actually correspond to as many separate cryptic taxa. The nominal species, H. margalefi sensu stricto, corresponds to the westernmost lineage here surveyed from the Alboran Sea to southeastern Italy. Typical genetic breaks such as the Almeria Oran Front or the Siculo-Tunisian Strait do not appear to be influential on the studied loci in H. margalefi sensu stricto. Instead, population structuring appears more complex and subtle than usually found for model species with a pelagic dispersal phase. The remaining four cryptic taxa are all found in the eastern basin, but incomplete lineage sorting is suspected and speciation might still be in process. Present-day population structure of the different H. margalefi cryptic species appears to result from past vicariance events started in the Oligo-Miocene and maintained by present-day coastal topography, water circulation and habitat fragmentation. PMID- 24784030 TI - A moving-barber-pole illusion. AB - In the barber-pole illusion (BPI), a diagonally moving grating is perceived as moving vertically because of the shape of the vertically oriented window through which it is viewed-a strong shape-motion interaction. We introduce a novel stimulus-the moving barber pole-in which a diagonal, drifting sinusoidal carrier is windowed by a raised, vertical, drifting sinusoidal modulator that moves independently of the carrier. In foveal vision, the moving-barber-pole stimulus can be perceived as several active barber poles drifting horizontally but also as other complex dynamic patterns. In peripheral vision, pure vertical motion (the moving-barber-pole illusion [MBPI]) is perceived for a wide range of conditions. In foveal vision, the MBPI is observed, but only when the higher-order modulator motion is masked. Theories to explain the BPI make indiscriminable predictions in a standard barber-pole display. But, in moving-barber-pole stimuli, the motion directions of features (e.g., end stops) of the first-order carrier and of the higher-order modulator are all different from the MBPI. High temporal frequency stimuli viewed peripherally greatly reduce the effectiveness of higher-order motion mechanisms and, ideally, isolate a single mechanism responsible for the MBPI. A three-stage motion-path integration mechanism that (a) computes local motion energies, (b) integrates them for a limited time period along various spatial paths, and (c) selects the path with the greatest motion energy, quantitatively accounts for these high-frequency data. The MBPI model also accounts for the perceived motion-direction in peripherally viewed moving-barber pole stimuli that do and do not exhibit the MBPI over the entire range of modulator (0-10 Hz) and carrier (2.5-10 Hz) temporal frequencies tested. PMID- 24784029 TI - The histone H2A deubiquitinase Usp16 regulates embryonic stem cell gene expression and lineage commitment. AB - Polycomb Repressive Complex 1 and histone H2A ubiquitination (ubH2A) contribute to embryonic stem cell (ESC) pluripotency by repressing lineage-specific gene expression. However, whether active deubiquitination co-regulates ubH2A levels in ESCs and during differentiation is not known. Here we report that Usp16, a histone H2A deubiquitinase, regulates H2A deubiquitination and gene expression in ESCs, and importantly, is required for ESC differentiation. Usp16 knockout is embryonic lethal in mice, but does not affect ESC viability or identity. Usp16 binds to the promoter regions of a large number of genes in ESCs, and Usp16 binding is inversely correlated with ubH2A levels, and positively correlates with gene expression levels. Intriguingly, Usp16(-/-) ESCs fail to differentiate due to ubH2A-mediated repression of lineage-specific genes. Finally, Usp16, but not a catalytically inactive mutant, rescues the differentiation defects of Usp16(-/-) ESCs. Therefore, this study identifies Usp16 and H2A deubiquitination as critical regulators of ESC gene expression and differentiation. PMID- 24784032 TI - The influence of Au film thickness and annealing conditions on the VLS-assisted growth of ZnO nanostructures. AB - High temperature evaporation methods, such as the vapor-liquid-solid mechanism, have been exploited for the controlled growth of ZnO nanostructures on various substrates. While Au is the most frequently used catalyst for growing ZnO nanowires, its morphological features on the substrate, which determine the size and shape of the nanostructures grown, have not yet been methodically explored. In the current work, we investigated the details of the thermal dewetting of Au films into nanoparticles on Si substrates. Au films of various thicknesses ranging from 2 to 15 nm were annealed under slow and fast rates at various temperatures and the morphological details of the nanoparticles formed were investigated. The dependence of the mean particle size on the nominal film thickness is in fair agreement with theoretical predictions. The vapor-liquid solid method was employed to investigate the role of the Au nanoparticles on the growth details of ZnO nanowires. The efficient and high throughput growth of ZnO nanowires, for a given growth time, is realized in cases of thin Au films, i.e. when the thickness is lower than 10 nm. Based on these experimental findings, a two-step mechanism is proposed to account for the growth of ZnO nanorods ending in ultrathin (~30 nm), micron-long tips. PMID- 24784031 TI - Self-management interventions for chronic disease: a systematic scoping review. AB - OBJECTIVE: To investigate the contributions of physiotherapy and occupational therapy to self-management interventions and the theoretical models used to support these interventions in chronic disease. DATA SOURCES: We conducted two literature searches to identify studies that evaluated self-management interventions involving physiotherapists and occupational therapists in MEDLINE, the Cochrane Library, CINAHL, EMBASE, AMED (Allied and Complementary Medicine), SPORTdiscus, and REHABDATA databases. STUDY SELECTION: Four investigator pairs screened article title and abstract, then full text with inclusion criteria. Selected articles (n = 57) included adults who received a chronic disease self management intervention, developed or delivered by a physiotherapist and/or an occupational therapist compared with a control group. DATA EXTRACTION: Four pairs of investigators performed independent reviews of each article and data extraction included: (a) participant characteristics, (b) the self-management intervention, (c) the comparison intervention, (d) outcome measures, construct measured and results. DATA SYNTHESIS: A total of 47 articles reported the involvement of physiotherapy in self-management compared with 10 occupational therapy articles. The type of chronic condition produced different yields: arthritis n = 21 articles; chronic obstructive pulmonary disease and chronic pain n = 9 articles each. The theoretical frameworks most frequently cited were social cognitive theory and self-efficacy theory. Physical activity was the predominant focus of the self-management interventions. Physiotherapy programmes included disease-specific education, fatigue, posture, and pain management, while occupational therapists concentrated on joint protection, fatigue, and stress management. CONCLUSIONS: Physiotherapists and occupational therapists make moderate contributions to self-management interventions. Most of these interventions are disease-specific and are most frequently based on the principles of behaviour change theories. PMID- 24784033 TI - Antimicrobial resistance is now widespread, warns WHO. PMID- 24784034 TI - Mesoscopic modeling of cancer photothermal therapy using single-walled carbon nanotubes and near infrared radiation: insights through an off-lattice Monte Carlo approach. AB - Single-walled carbon nanotubes (SWNTs) are promising heating agents in cancer photothermal therapy when under near infrared radiation, yet few efforts have been focused on the quantitative understanding of the photothermal energy conversion in biological systems. In this article, a mesoscopic study that takes into account SWNT morphologies (diameter and aspect ratio) and dispersions (orientation and concentration), as well as thermal boundary resistance, is performed by means of an off-lattice Monte Carlo simulation. Results indicate that SWNTs with orientation perpendicular to the laser, smaller diameter and better dispersion have higher heating efficiency in cancer photothermal therapy. Thermal boundary resistances greatly inhibit thermal energy transfer away from SWNTs, thereby affecting their heating efficiency. Through appropriate interfacial modification around SWNTs, compared to the surrounding healthy tissue, a higher temperature of the cancer cell can be achieved, resulting in more effective cancer photothermal therapy. These findings promise to bridge the gap between macroscopic and microscopic computational studies of cancer photothermal therapy. PMID- 24784035 TI - Congestion prediction modeling for quality of service improvement in wireless sensor networks. AB - Information technology (IT) is pushing ahead with drastic reforms of modern life for improvement of human welfare. Objects constitute "Information Networks" through smart, self-regulated information gathering that also recognizes and controls current information states in Wireless Sensor Networks (WSNs). Information observed from sensor networks in real-time is used to increase quality of life (QoL) in various industries and daily life. One of the key challenges of the WSNs is how to achieve lossless data transmission. Although nowadays sensor nodes have enhanced capacities, it is hard to assure lossless and reliable end-to-end data transmission in WSNs due to the unstable wireless links and low hard ware resources to satisfy high quality of service (QoS) requirements. We propose a node and path traffic prediction model to predict and minimize the congestion. This solution includes prediction of packet generation due to network congestion from both periodic and event data generation. Simulation using NS-2 and Matlab is used to demonstrate the effectiveness of the proposed solution. PMID- 24784036 TI - Humidity sensors principle, mechanism, and fabrication technologies: a comprehensive review. AB - Humidity measurement is one of the most significant issues in various areas of applications such as instrumentation, automated systems, agriculture, climatology and GIS. Numerous sorts of humidity sensors fabricated and developed for industrial and laboratory applications are reviewed and presented in this article. The survey frequently concentrates on the RH sensors based upon their organic and inorganic functional materials, e.g., porous ceramics (semiconductors), polymers, ceramic/polymer and electrolytes, as well as conduction mechanism and fabrication technologies. A significant aim of this review is to provide a distinct categorization pursuant to state of the art humidity sensor types, principles of work, sensing substances, transduction mechanisms, and production technologies. Furthermore, performance characteristics of the different humidity sensors such as electrical and statistical data will be detailed and gives an added value to the report. By comparison of overall prospects of the sensors it was revealed that there are still drawbacks as to efficiency of sensing elements and conduction values. The flexibility offered by thick film and thin film processes either in the preparation of materials or in the choice of shape and size of the sensor structure provides advantages over other technologies. These ceramic sensors show faster response than other types. PMID- 24784037 TI - Serum uric acid concentration is linked to wearing-off fluctuation in Japanese Parkinson's disease patients. AB - BACKGROUND: Serum uric acid (UA) concentration is linked to the risk of progression of Parkinson's disease (PD). OBJECTIVES: The aim of this study was to examine the association between serum UA concentration and the occurrence of wearing-off fluctuation (WOF) in Japanese PD patients. METHODS: A total of 123 Japanese patients with PD were enrolled in this study. We collected data on demographics, clinical features, medications, and laboratory findings including serum UA concentration, and examined the presence of WOF. The association between serum UA concentration and WOF was assessed using multivariate logistic regression analysis. RESULTS: After adjusting for possible confounders, it was found that the odds ratio (OR) for WOF decreased with increasing quartile of UA (highest quartile vs. lowest quartile, adjusted OR 0.218, 95% confidence interval [CI] 0.053-0.891). This association was significant only in male PD patients, regardless of the use of sex-specific quartiles of UA. Additionally, disease duration (OR 7.80, 95% CI 2.62-23.17) and daily levodopa dosage (OR 4.06, 95% CI 1.45-11.38) were associated with the occurrence of WOF. CONCLUSIONS: Our results showed that serum UA concentration was associated with the occurrence of WOF. Serum UA concentration may be a predictive factor for WOF. PMID- 24784038 TI - 500 MHz spaced Yb:fiber laser frequency comb without amplifiers. AB - An optical frequency comb based on Yb:ring fiber laser was demonstrated. This is the first time, to our knowledge, f(ceo) has been generated directly from the oscillator without further amplifications above 500 MHz repetition rate. The signal-to-noise ratio of the offset frequency was above 40 dB at 300 kHz resolution bandwidth, which supports easy stabilization. The offset frequency was stabilized for more than 6 h in an open air environment without temperature control. The stabilized repetition rate has an in-loop tracking stability of 4.46*10(-13)/tau(1/2). PMID- 24784039 TI - Beam wavefront dynamical compensation by aberrations of the gain medium in laser amplifiers for beam quality improvement. AB - A method is presented to dynamically improve the beam quality in laser amplifiers by spherical aberration compensation. By imaging the field with a negative spherical aberration into a laser amplifier, the wavefront aberration of an input beam could be compensated by that of the gain medium in the amplifier with positive spherical aberration. Both power amplification and beam quality improvement can be achieved simultaneously. No additional optical components are introduced. Experiments are conducted for a beam from an oscillator with 28 W output power. The M2 factor of the beam was improved from 4.2 to 1.6 after amplification. The power was also amplified to 54.7 W. It is a cost-effective and passive way for wavefront compensation, as compared to deformable mirrors and phase corrector plates. PMID- 24784040 TI - Radiation-hard erbium optical fiber and fiber amplifier for both low- and high dose space missions. AB - We present a new structure for erbium-doped optical fibers [hole-assisted carbon coated, (HACC)] that, combined with an appropriate choice of codopants in the core, strongly enhances their radiation tolerance. We built an erbium-doped fiber amplifier based on this HACC fiber and characterize its degradation under gamma ray doses up to 315 krad (SiO2) in the ON mode. The 31 dB amplifier is practically radiation insensitive, with a gain change of merely -2.2*10(-3) dB/krad. These performances authorize the use of HACC doped fibers and amplifiers for various applications in environments associated with today's missions (of doses up to 50 krad) and even for future space missions associated with higher dose constraints. PMID- 24784041 TI - Eavesdropping time and frequency: phase noise cancellation along a time-varying path, such as an optical fiber. AB - Single-mode optical fiber is a highly efficient connecting medium used not only for optical telecommunications but also for the dissemination of ultrastable frequencies or timing signals. Ma et al. [Opt. Lett.19, 1777 (1994)] described a measurement and control system to deliver the same optical frequency at two places, namely the two ends of a fiber, by eliminating the "fiber-induced phase noise modulation, which corrupts high-precision frequency-based applications." I present a simple detection and control scheme to deliver the same optical frequency at many places anywhere along a transmission path, or in its vicinity, with a relative instability of 1 part in 10(19). The same idea applies to radio frequency and timing signals. This considerably simplifies future efforts to make precise timing or frequency signals available to many users, as required in some large-scale science experiments. PMID- 24784042 TI - Generation of a controllable optical cage by focusing a Laguerre-Gaussian correlated Schell-model beam. AB - We analyze the intensity of a Laguerre-Gaussian correlated Schell-model (LGCSM) beam focused by a thin lens near the focal region, and it is found that a controllable optical cage can be formed through varying the initial spatial coherence width. Furthermore, we carry out experimental measurement of the intensity of a focused LGCSM beam, and we observe that the optical cage is indeed formed in experiment. Our results will be useful for trapping particles or atoms. PMID- 24784043 TI - On-chip synthesis of circularly polarized emission of light with integrated photonic circuits. AB - The helicity of circularly polarized (CP) light plays an important role in the light-matter interaction in magnetic and quantum material systems. Exploiting CP light in integrated photonic circuits could lead to on-chip integration of novel optical helicity-dependent devices for applications ranging from spintronics to quantum optics. In this Letter, we demonstrate a silicon photonic circuit coupled with a 2D grating emitter operating at a telecom wavelength to synthesize vertically emitting, CP light from a quasi-TE waveguide mode. Handedness of the emitted circular polarized light can be thermally controlled with an integrated microheater. The compact device footprint enables a small beam diameter, which is desirable for large-scale integration. PMID- 24784044 TI - Fractal signatures in the aperiodic Fibonacci grating. AB - The Fibonacci grating (FbG) is an archetypal example of aperiodicity and self similarity. While aperiodicity distinguishes it from a fractal, self-similarity identifies it with a fractal. Our paper investigates the outcome of these complementary features on the FbG diffraction profile (FbGDP). We find that the FbGDP has unique characteristics (e.g., no reduction in intensity with increasing generations), in addition to fractal signatures (e.g., a non-integer fractal dimension). These make the Fibonacci architecture potentially useful in image forming devices and other emerging technologies. PMID- 24784045 TI - Hanbury Brown-Twiss effect with partially coherent electromagnetic beams. AB - We derive expressions that allow us to examine the influence of different source parameters on the correlation of intensity fluctuations (the Hanbury Brown-Twiss effect) at two points in the same cross section of a random electromagnetic beam. It is found that these higher-order correlations behave quite differently than the lower-order amplitude-phase correlations that are described by the spectral degree of coherence. PMID- 24784046 TI - Simultaneous optical absorption and viscoelasticity imaging based on photoacoustic lock-in measurement. AB - We propose a dual-parameter detection method to realize the simultaneous optical absorption and viscoelasticity imaging based on photoacoustic lock-in measurement. Both optical absorption and viscoelasticity properties can be obtained simultaneously by analyzing the amplitude and phase of photoacoustic signals. This method is experimentally verified by imaging of gelatin phantoms with different absorption coefficients and viscoelastic coefficients. Furthermore, pilot experiments were performed on an in vivo murine EMT6 tumor from the back of a BALB/c mouse. Results demonstrate that the method can be used to measure the optical absorption and viscoelasticity of different biological tissues. PMID- 24784047 TI - Automatic method for focusing biological specimens in digital lensless holographic microscopy. AB - A self-focusing method applicable to digital lensless holographic microscopy is presented. The method searches for the global minimum of the area enclosing a given amount of energy in a region surrounding the object of interest. The proposed modified enclosed energy method has been tested on self-focusing experimental holograms of a paramecium specimen and a section of the head of a drosophila melanogaster fly. The presented self-focusing technique also has been contrasted with some of the already reported methods to seek the best focus image. PMID- 24784048 TI - Ice thickness measurements by Raman scattering. AB - A compact Raman LIDAR system with a spectrograph was used for express ice thickness measurements. The difference between the Raman spectra of ice and liquid water is employed to locate the ice-water interface while elastic scattering was used for air--ice surface detection. This approach yields an error of only 2 mm for an 80 mm thick ice sample, indicating that it is a promising express noncontact thickness measurements technique in field experiments. PMID- 24784049 TI - Integrated 10 Gb/s multilevel multiband passive optical network and 500 Mb/s indoor visible light communication system based on Nyquist single carrier frequency domain equalization modulation. AB - We propose and experimentally demonstrate a novel integrated passive optical network (PON) and indoor visible light communication (VLC) system based on Nyquist single carrier frequency domain equalization (N-SC-FDE) modulation with direct detection. In this system, a directly modulated laser and a commercially available red light emitting diode are served as the transmitters of the PON and VLC, respectively. To enable high spectral efficiency, high-speed transmission, and flexible multiple access with simplified optical network unit-side digital signal processing, multilevel, multiband quadrature amplitude modulations 128/64/16 are implemented here. VLC N-SC-FDE signals are successfully delivered a further 30 cm indoor distance after transmitting over a span of 40 km single mode fiber (SMF) together with 3 sub-band PON signals. As a proof of concept, a 10 Gb/s PON and 500 Mb/s VLC integrated system for three wired users and one wireless user is successfully achieved, which shows the promising potential and feasibility of this proposal to extend multiple services from metropolitan to suburban areas. PMID- 24784050 TI - Locally pressed photonic crystal fiber interferometer for multiparameter sensing. AB - A mode interferometer consisting of a short section of photonic crystal fiber (PCF) fusion spliced to a standard single-mode optical fiber with localized perturbations is proposed for multiparameter sensing. In this sensing configuration, the parameter being sensed changes the visibility (an absolute parameter) of the interference pattern and also causes a shift (a relative parameter) to the interference pattern. To achieve this dual effect, a portion of the PCF is squeezed on localized regions with a serrated mechanical piece. In this manner, we introduce attenuation losses and effective refractive index changes to the interfering modes, hence, visibility changes and a shift to the interference pattern. Our device is suitable for monitoring diverse physical parameters, such as weight, lateral force, pressure, load, etc., with the advantage that compensation to temperature or power fluctuations is not required. Moreover, the sensor sensitivity can be adjusted in a simple manner. PMID- 24784051 TI - Two-pulse structured illumination imaging. AB - Structured illumination (SI), which is an imaging technique that is employed in a variety of fields, permits unique possibilities to suppress unwanted signal contributions that carry misguiding information such as out-of-focus light or multiply scattered light. So far SI has been applied mostly for averaged imaging or for imaging of slowly occurring events because it requires three acquisitions (subimages) to construct the final SI image. This prerequisite puts technological constraints on SI that make "instantaneous" imaging of fast transient processes (occurring on submicrosecond time scales) very challenging and expensive. Operating SI with fewer subimages generates errors in the form of residual lines that stretch across the image. Here, a new approach that circumvents this limiting factor is presented and experimentally demonstrated. By judiciously choosing the intensity modulation, it is possible to extract an SI image from two subimages only. This development will allow standard double-pulsed lasers and interline transfer CCD or scientific CMOS cameras to be used to acquire temporally frozen SI images of rapidly occurring processes as well as to boost the frame-rate of current SI video systems; a technical advancement that will benefit both macro- and microscopic imaging applications. PMID- 24784052 TI - Sub-20 fs MUJ-energy pulses tunable down to the near-UV from a 1 MHz Yb-fiber laser system. AB - Optical parametric amplifiers render widely tunable ultrashort pulses, but for full spectral coverage, complex mixing schemes are needed. In particular, the blue and near-UV part of the spectrum is not directly reached with the 800 nm pump from Ti:sapphire systems or the 1030 nm pump of Yb-based lasers. We combine third harmonic pumping at 343 nm with seeding by a second harmonic (SH) pumped continuum to tune a noncollinear optical parametric amplifier down to 395 nm. Together with a SH pumped branch, the full range from 395 to 970 nm is covered with 20 fs pulse length or less. Pulse energies up to the MUJ-level with an average power of up to 200 mW at 200 kHz and 480 mW at 1 MHz are achieved. With additional frequency doubling, the full range down to 210 nm is reached without gap. Two-photon absorption in the amplifier crystal is discussed as the critical issue in UV-pumped systems. PMID- 24784053 TI - Quantification of the atmospheric scintillation for laser illumination in active imaging. AB - Most of the analytical scintillation models used by experts to simulate the illumination performances of active imaging systems are based on the use of monochromatic, punctual, and coherent sources. These analytical models seem pessimistic regarding lightpipe-based illumination techniques. Outdoor trials have been made with 1.57 MUm laser illuminators with and without lightpipe to record illumination maps and associated refractive index structure parameter C(n)2 with a propagation distance of 1 km. Analysis shows a reduction of the scintillation by a factor of 2.5 comparing analytical models and laser illumination with lightpipe. PMID- 24784054 TI - Megawatt-scale average-power ultrashort pulses in an enhancement cavity. AB - We investigate power scaling of ultrashort-pulse enhancement cavities. We propose a model for the sensitivity of a cavity design to thermal deformations of the mirrors due to the high circulating powers. Using this model and optimized cavity mirrors, we demonstrate 400 kW of average power with 250 fs pulses and 670 kW with 10 ps pulses at a central wavelength of 1040 nm and a repetition rate of 250 MHz. These results represent an average power improvement of one order of magnitude compared to state-of-the-art systems with similar pulse durations and will thus benefit numerous applications such as the further scaling of tabletop sources of hard x rays (via Thomson scattering of relativistic electrons) and of soft x rays (via high harmonic generation). PMID- 24784056 TI - Impact of dispersive and saturable gain/loss on bistability of nonlinear parity time Bragg gratings. AB - We report on the impact of realistic gain and loss models on the bistable operation of nonlinear parity-time (PT) Bragg gratings. In our model we include both dispersive and saturable gain and show that levels of gain/loss saturation can have a significant impact on the bistable operation of a nonlinear PT Bragg grating based on GaAs material. The hysteresis of the nonlinear PT Bragg grating is analyzed for different levels of gain and loss and different saturation levels. We show that high saturation levels can improve the nonlinear operation by reducing the intensity at which the bistability occurs. However, when the saturation intensity is low, saturation inhibits the PT characteristics of the grating. PMID- 24784055 TI - Laser-induced cavitation in nanoemulsion with gold nanospheres for blood clot disruption: in vitro results. AB - Optically activated cavitation in a nanoemulsion contrast agent is proposed for therapeutic applications. With a 56 degrees C boiling point perfluorohexane core and highly absorptive gold nanospheres at the oil-water interface, cavitation nuclei in the core can be efficiently induced with a laser fluence below medical safety limits (70 mJ/cm2 at 1064 nm). This agent is also sensitive to ultrasound (US) exposure and can induce inertial cavitation at a pressure within the medical diagnostic range. Images from a high-speed camera demonstrate bubble formation in these nanoemulsions. The potential of using this contrast agent for blood clot disruption is demonstrated in an in vitro study. The possibility of simultaneous laser and US excitation to reduce the cavitation threshold for therapeutic applications is also discussed. PMID- 24784057 TI - Optics of water cloud droplets mixed with black-carbon aerosols. AB - We use the recently extended superposition T-matrix method to calculate scattering and absorption properties of micrometer-sized water droplets contaminated by black carbon. Our numerically exact results reveal that, depending on the mode of soot-water mixing, the soot specific absorption can vary by a factor exceeding 6.5. The specific absorption is maximized when the soot material is quasi-uniformly distributed throughout the droplet interior in the form of numerous small monomers. The range of mixing scenarios captured by our computations implies a wide range of remote sensing and radiation budget implications of the presence of black carbon in liquid-water clouds. We show that the popular Maxwell-Garnett effective-medium approximation can be used to calculate the optical cross sections, single-scattering albedo, and asymmetry parameter for the quasi-uniform mixing scenario, but is likely to fail in application to other mixing scenarios and in computations of the elements of the scattering matrix. PMID- 24784058 TI - Heterodyne architecture for tunable laser chirped dispersion spectroscopy using optical processing. AB - Dispersion-based spectroscopic techniques present many desirable features when compared with classical absorption spectroscopy implementations, such as the normalization-free operation and the extended dynamic range. In this Letter, we present a new sensor design based on direct optical processing for heterodyne conversion in tunable laser chirped dispersion spectroscopy that allows sensor implementations using low-speed photodetectors and low-cost FM demodulators. The performance of the new setup has been validated using as a target the ro vibrational transition of methane at approximately 1650.96 nm. PMID- 24784059 TI - Optical eigenmode imaging with a sparse constraint. AB - Optical eigenmode imaging (OEI) is an interesting nonlocal imaging method but has the drawback that the completeness of eigenmodes used in OEI is hard guarantee. This may lead to significant blurring of the reconstructed images. Here we show that in OEI with a sparse constraint, the correlation between the original target and the recovered image can be extremely close to 1 by retrieving lost information, and the compressibility is enhanced. In addition, high-quality images can be received for a wide range of both object and system parameters. PMID- 24784060 TI - CMOS self-powered monolithic light-direction sensor with digitalized output. AB - We present a novel self-powered chip to detect the direction of incident light. This chip directly provides digitized output without the need of any off-chip power supply or optical or mechanical components. The chip was implemented in a standard 0.5 MUm CMOS process. A microscale metal baffle was created by stacking all metal layers, contacts, and vias available in the process to produce on-chip shadowing. N-well/p+ photodiode arrays are located on both sides of the baffle to sense light. The photocurrent generated by a photodiode depends on the size of the photodiode and the shadowing. The shadowed area depends on the incident angle of the light. A current mirror circuit is used to compare the currents generated by the photodiodes on the opposite sides of the baffle and, consequently, provide a digital signal to indicate the incident light angle. Compared with the ideal linear digital light-angle detector with the same resolution, the presented sensor achieved the maximum error of only 2 deg over 110 deg test range. PMID- 24784061 TI - Toward multi-Gbps indoor optical wireless multicasting system employing passive diffractive optics. AB - This Letter presents the evaluation and demonstration of an optical free-space (FS) multicasting system for multi-Gigabits-per-second (multi-Gbps) indoor transmission. These simultaneous line-of-sight links are formed by infrared beams and are beam-steered using a passive diffraction grating. The experiment has resulted in error-free links (bit error rate <10(-9) at 2.5 Gbps on-off keying) and is scalable to support higher data rates. This system is proposed for short range optical wireless communication and can be seamlessly integrated in in building fiber networks. PMID- 24784062 TI - High signal-to-noise ratio, single-frequency 2 MUm Brillouin fiber laser. AB - A high optical signal-to-noise ratio (OSNR) single-frequency 2 MUm Brillouin fiber laser (BFL) with watt-level output and high transfer efficiency is demonstrated for the first time to the best of our knowledge. The Brillouin pump is constructed with a two-stage thulium-doped fiber amplifier (TDFA) seeded by a 2 MUm laser diode, providing 4.02 W average power with 1 MHz linewidth. Using an optimized length of 14 m for the Brillouin ring cavity, the BFL works stably in single-mode region with 8 kHz linewidth because of the linewidth narrowing effect. The transfer efficiency is 51% with 1.08 W output power and 62 dB OSNR for 3.22 W pump power. PMID- 24784063 TI - Terahertz inverse synthetic aperture radar imaging using self-mixing interferometry with a quantum cascade laser. AB - We propose a terahertz (THz)-frequency synthetic aperture radar imaging technique based on self-mixing (SM) interferometry, using a quantum cascade laser. A signal processing method is employed which extracts and exploits the radar-related information contained in the SM signals, enabling the creation of THz images with improved spatial resolution. We demonstrate this by imaging a standard resolution test target, achieving resolution beyond the diffraction limit. PMID- 24784064 TI - Heterojunction of ZnO nanoparticle/PMMA and its ultraviolet electroluminescence. AB - A ZnO nanoparticle layer was synthesized by the sol-gel method on ITO glass. Devices with a ZnO nanoparticle layer/polymethylmethacrylate (PMMA) heterojunction structure were then fabricated and the room temperature electroluminescence (EL) spectra were studied. Under DC bias, ultraviolet (UV) EL at 390 nm from the ZnO band edge emission was observed, and defect-related emission of ZnO at 600 and 760 nm were also detected. The EL mechanisms are discussed in terms of the carrier tunneling process. PMID- 24784065 TI - Nearly perfect resonant absorption of TE-polarized light at metal surfaces coated with arrayed dielectric stripes. AB - A quasi-transverse electric (TE) surface wave mode exists at a metal surface coated with an ultrathin high-index dielectric layer. As the coating is in dielectric stripe arrays, nearly perfect absorption of TE-polarized incidence light is observed in simulations, due to resonances of the quasi-surface waves at each segment of the dielectric-coated metal surfaces. In analysis, the Fabry Perot-like nature of the resonances is clarified, and effects of symmetry on different behaviors of the odd- and even-order resonance modes are discussed. While the absorption peak is tunable, perfect absorption appears near cut-off wavelength of the surface mode. PMID- 24784066 TI - Improved linearity in down-converted analog photonic link by polarization manipulation. AB - A method to improve the linearity of the down-converted analog photonic link is proposed and experimentally demonstrated, consisting of two phase modulators, a polarizer, and an optical filter. Down-conversion of a 10-GHz microwave signal to 100-MHz intermediate frequency is successfully achieved. By carefully optimizing the angles between the transverse-electric and transverse-magnetic modes, the third-order inter-modulation distortion (IMD3) is suppressed. The linearization method leads to a suppression of the IMD3 by more than 14 and 13 dB improvement of spurious-free dynamic range. PMID- 24784067 TI - Polarization spectroscopy of a velocity-selected molecular sample. AB - This Letter demonstrates polarization spectroscopy of a velocity selected and vibrationally excited molecular sample. Specifically, the anisotropy induced by a circularly polarized IR pump beam tuned to the R(14.5)(1/2)v=1<-v=0 transition of nitric oxide is observed using an IR probe resonant with the R(15.5)(1/2)v=2<-v=1 hot band transition. Using two detectors in combination with the rapidly swept probe allows both the absorptive and dispersive components of the excited state polarization to be observed for the first time. The data are well described by simulations based upon a three-level density matrix model. PMID- 24784068 TI - High-efficiency diode-pumped actively Q-switched ceramic Nd:YAG/BaWO4 Raman laser operating at 1666 nm. AB - A diode-pumped actively Q-switched Raman laser employing BaWO4 as the Raman active medium and a ceramic Nd:YAG laser operating at 1444 nm as the pump source is demonstrated. The first-Stokes-Raman generation at 1666 nm is achieved. With a pump power of 20.3 W and pulse repetition frequency rate of 5 kHz, a maximum output power of 1.21 W is obtained, which is the highest output power for a 1.6 MUm Raman laser. The corresponding optical-to-optical conversion efficiency is 6%; the pulse energy and peak power are 242 MUJ and 8.96 kW, respectively. PMID- 24784069 TI - Generating the orbital angular momentum of radio frequency signals using optical true-time-delay unit based on optical spectrum processor. AB - A system for generating radio frequency signals with orbital angular momentum (OAM) is proposed and certificated for the first time, which employs an array of multiple optical-true-time-delay elements and circular antennas array (CAAs). A constructive Fourier series theory about CAAs collectively forming an OAM radio beam is demonstrated. An optical spectrum processor offers the four lines high resolution time delay by adding a series of linear optical phase shifts. The OAM radio beam with topological charge L=1 is produced and measured successfully. PMID- 24784071 TI - Intense sub-two-cycle infrared pulse generation via phase-mismatched cascaded nonlinear interaction in DAST crystal. AB - Octave-spanning, 12.5 fs, (1.9 cycle) pulses with 115 MUJ energy in the short wavelength mid-infrared spectral range (1-2.5 MUm) have been generated via phase mismatched cascaded nonlinear frequency conversion using organic DAST (4-N, N dimethylamino-4'-N'-methylstilbazolium tosylate) crystal. Such ultrafast cascading effect is ensured by the interaction of a pump pulse with the exceptionally large effective nonlinearity of the DAST crystal and experiencing nonresonant, strongly phase-mismatched, Kerr-like negative nonlinearity. PMID- 24784070 TI - Single-shot spatially modulated Stokes polarimeter based on a GRIN lens. AB - A new polarimeter for the simultaneous measurement of all Stokes parameters in a single shot is presented. It consists of only a gradient index (GRIN) lens, a polarizer, an imaging lens, and a CCD, without mechanical movements, electrical signal modulation, or the division of amplitude components. This design takes advantage of the continuous spatial distributions of birefringence value and the fast axis direction of a GRIN lens and derives the state of polarization (SOP) of the incident beam from the characteristic patterns on the CCD images. Tests show that this polarimeter is very accurate even with low-resolution images. It is versatile and adapts to light sources of different wavelengths. It is also very stable, robust, low cost, and simple to use. PMID- 24784072 TI - Light focusing and two-dimensional imaging through scattering media using the photoacoustic transmission matrix with an ultrasound array. AB - We implement the photoacoustic transmission matrix approach on a two-dimensional photoacoustic imaging system, using a 15 MHz linear ultrasound array. Using a black leaf skeleton as a complex absorbing structure, we demonstrate that the photoacoustic transmission matrix approach allows to reveal structural features that are invisible in conventional photoacoustic images, as well as to selectively control light focusing on absorbing targets, leading to a local enhancement of the photoacoustic signal. PMID- 24784073 TI - Thermal effects on sudden changes and freezing of correlations between remote atoms in a cavity quantum electrodynamics network. AB - We investigate thermal effects on sudden changes and freezing of the quantum and classical correlations of remote qubits in a cavity quantum electrodynamics (CQED) network with losses. We find that the detrimental effect of thermal reservoirs on the freezing of correlations can be compensated via an efficient coupling of the fiber connecting the two cavities of the system. Furthermore, for certain initial conditions, we find a double sudden transition in the dynamics of Bures geometrical quantum discord. The second transition tends to disappear at a critical temperature, hence freezing the discord. Finally, we discuss the feasibility of the experimental realization of the present proposal. PMID- 24784074 TI - All-optical frequency upconversion for radio-over-fiber applications based on cross-gain modulation and cross-polarization modulation in a semiconductor optical amplifier. AB - We propose a novel all-optical frequency upconversion technique for radio-over fiber (RoF) systems based on cross-gain modulation (XGM) and cross-polarization modulation (XPolM) in a semiconductor optical amplifier (SOA). A local oscillator signal is carried onto a continuous wave probe beam with orthogonally polarized single-sideband (SSB) modulation using a polarization modulator and a tunable optical filter. The intermediate frequency signal carried by a pump beam is only intensity modulated onto the sideband of the probe beam while the carrier of the probe beam is unmodulated thanks to the joint use of the XGM and XPolM effects in the SOA. This SSB upconversion scheme is inherently free from the chromatic dispersion-induced power fading after transmission over single-mode fiber. The proposed scheme is theoretically analyzed and experimentally verified. PMID- 24784075 TI - Dependence of lasing threshold on Q factor in a deformed microcavity laser. AB - The relationship between lasing threshold and quality (Q) factor is investigated. When a deformed microcavity laser composed of a circular arc and an isosceles trapezoid is excited by current injection, various modes lase in ten emission directions. The lasing modes are classified into four groups, and the lasing threshold of each mode group is obtained according to emission spectra. The Q factor of each mode group is obtained from the resonance by comparing the far field patterns of resonances with those of mode groups. Through the study, we find that the lasing threshold strongly depends on the Q factor. PMID- 24784076 TI - Scaling the mode instability threshold with multicore fibers. AB - Mode instabilities (MIs) have quickly become the most limiting effect for the average power scaling of nearly diffraction-limited beams from state-of-the-art fiber laser systems. In this work it is shown that, by using an advanced multicore photonic crystal fiber design, the threshold power of MIs can be increased linearly with the number of cores. An average output power of 536 W, corresponding to 4 times the threshold power of a single core, is demonstrated. PMID- 24784077 TI - Multioctave midinfrared supercontinuum generation in suspended-core chalcogenide fibers. AB - An As2S3 fiber-based supercontinuum source that covers 3500 nm, extending from near visible to the midinfrared, is successfully reported by using a 200-fs pulsed pump with nJ-level energy at 2.5 MUm. The main features of our fiber-based source are two-fold. On the one hand, a low-loss As2S3 microstructured optical fiber has been fabricated, with typical attenuation below 2 dB/m in the 1-4 MUm wavelength range. On the other hand, a 20-mm-long microstructured fiber sample is sufficient to enable a spectral broadening, spreading from 0.6 to 4.1 MUm in a 40 dB dynamic range. PMID- 24784078 TI - Multiheterodyne spectroscopy with optical frequency combs generated from a continuous-wave laser. AB - Dual-drive Mach-Zehnder modulators were utilized to produce power-leveled optical frequency combs (OFCs) from a continuous-wave laser. The resulting OFCs contained up to 50 unique frequency components and spanned more than 200 GHz. Simple changes to the modulation frequency allowed for agile control of the comb spacing. These OFCs were then utilized for broadband, multiheterodyne measurements of CO2 using both a multipass cell and an optical cavity. This technique allows for robust measurements of trace gas species and alleviates much of the cost and complexity associated with the use of femtosecond OFCs produced with mode-locked pulsed lasers. PMID- 24784079 TI - Red emission of additional Pr3+ and adjusting effect of additional Mg2+ in Ca3Sc2Si3O12:Ce3+, Mn2+ phosphor. AB - In this Letter, we report the addition of Pr3+ and Mg2+ in CSS:Ce3+, Mn2+ phosphor for improving the performances of white light-emitting diodes (LEDs). The additional trivalent Pr3+ will occupy the Ca2+ site in this host like the situation of Ce3+, its concentration can be enhanced by the addition of Mg2+ in Sc3+ site due to the substitution of Mg2+ for Sc3+ can compensate the charge mismatch between Pr3+ and Ca2+. Based on the efficient Ce3+->Pr3+ and Mn2+->Pr3+ energy transfers (ETs) and the compensation effect of Mg2+, the additional Pr3+ in our present phosphors exhibits an intense red-emission around 610 nm, which is significant for enhancing the color rendering property. In addition, we also find that the additional Mg2+ in Sc3+ site can markedly adjust the photoluminescence (PL) spectrum shape of our phosphor by controlling the distribution of Mn2+ at Ca2+ and Sc3+ sites. A new tunable full-color emission is obtained via the ETs (Ce3+->Mn2+, Ce3+->Pr3+ and Mn2+->Pr3+) and the adjusting effect of Mg2+ in our present phosphors. Finally, a white LED with higher color rendering index of 90, lower correlated color temperature of 4980 K, and chromaticity coordinates of (0.34, 0.31) was obtained by combining the single CSS:0.08Ce3+, 0.01Pr3+, 0.3Mn2+, 0.2Mg2+ phosphor with a blue-emitting InGaN LED chip. PMID- 24784080 TI - Diffraction-limited, 10-W, 5-ns, 100-kHz, all-fiber laser at 1.55 MUm. AB - This Letter reports on an all-fiber-integrated master-oscillator, power amplifier system at 1.55 MUm producing 5-ns, 100-MUJ pulses. These pulses are generated at a 100 kHz repetition rate, corresponding to 10 W of average power. The seed source is a low-power, current-modulated, single-frequency, distributed feedback semiconductor laser. System output is obtained from a standard single-mode fiber (Corning SMF-28). Consequently, the beam is truly diffraction limited, which was independently proven by M2 measurements. Further increase of peak power is limited by onset of significant spectral broadening due to nonlinear effects, primarily four-wave mixing. Numerical simulations based on six-level rate equations with full position- and time-dependence were developed to model propagation of pulses through the amplifier chain. This capability allows minimization of the amplified spontaneous emission, which can be directly measured using a fast acousto-optic modulator to gate the pulses. PMID- 24784081 TI - Thermally controlled coupling of a rolled-up microtube integrated with a waveguide on a silicon electronic-photonic integrated circuit. AB - We report on the first experimental demonstration of the thermal control of coupling strength between a rolled-up microtube and a waveguide on a silicon electronic-photonic integrated circuit. The microtubes are fabricated by selectively releasing a coherently strained GaAs/InGaAs heterostructure bilayer. The fabricated microtubes are then integrated with silicon waveguides using an abruptly tapered fiber probe. By tuning the gap between the microtube and the waveguide using localized heaters, the microtube-waveguide evanescent coupling is effectively controlled. With heating, the extinction ratio of a microtube whispering-gallery mode changes over an 18 dB range, while the resonant wavelength remains approximately unchanged. Utilizing this dynamic thermal tuning effect, we realize coupling modulation of the microtube integrated with the silicon waveguide at 2 kHz with a heater voltage swing of 0-6 V. PMID- 24784082 TI - Virtual source of a Pearcey beam. AB - A virtual source that yields a family of a Pearcey wave is demonstrated. A closed form expression is derived for the Pearcey wave that simplifies to the paraxial Pearcey beam (PB) in the appropriate limit. From the perturbative series representation of a complex-source-point spherical wave, an infinite series nonparaxial correction expression for a PB is obtained. The infinite series expression of a PB can give accuracy up to any order of the diffraction angle. By applying the integral representation of the Pearcey wave, the first three terms in the nonparaxial correction series to the paraxial PB are provided. PMID- 24784083 TI - Sapphire-based graphene saturable absorber for long-time working femtosecond lasers. AB - We report a long-time working femtosecond laser using metal-free sapphire-based graphene as a saturable absorber (SA). The sapphire-based graphene yielded excellent nonlinear saturable absorption properties and was demonstrated to be suitable as an SA for an ultrafast solid-state laser. Stable mode-locked pulses of 325 fs were obtained at a central wavelength of 1032 nm with a repetition rate of 66.3 MHz. At pump power of 8.23 W the average output power was 1.78 W and the highest pulse energy reached 26.8 nJ with a peak power of 72.6 kW. Our work opens up a facile route for making reliable graphene SA in the mode-locking technique and also displays an exciting prospect in making low-cost and ultrafast lasers. PMID- 24784084 TI - Large efficiency at telecom wavelength for optical quantum memories. AB - We implement the ROSE protocol in an erbium-doped solid, compatible with the telecom range. The ROSE scheme is an adaptation of the standard two-pulse photon echo to make it suitable for a quantum memory. We observe a retrieval efficiency of 40% for a weak laser pulse in the forward direction by using specific orientations of the light polarizations, magnetic field, and crystal axes. PMID- 24784085 TI - Sum frequency generation vibrational spectroscopic studies on buried heterogeneous biointerfaces. AB - A sum frequency generation (SFG) vibrational micro-spectroscopy system was developed to examine buried heterogeneous biointerfaces. A compact optical microscope was constructed with total-internal reflection (TIR) SFG geometry to monitor the tightly focused SFG laser spots on interfaces, providing the capability of selectively probing different regions on heterogeneous biointerfaces. The TIR configuration ensures and enhances the SFG signal generated only from the sample/substrate interfacial area. As an example for possible applications in biointerfaces studies, the system was used to probe and compare buried interfacial structures of different biological samples attached to underwater surfaces. We studied the interface of a single mouse oocyte on a silica prism to demonstrate the feasibility of tracing and studying a single live cell and substrate interface using SFG. We also examined the interface between a marine mussel adhesive plaque and a CaF2 substrate, showing the removal of interface-bonded water molecules. This work also paves the way for future integration of other microscopic techniques such as TIR-fluorescence microscopy or nonlinear optical imaging with SFG spectroscopy for multimodal surface or interface studies. PMID- 24784086 TI - Optical metasurfaces for beam scanning in space. AB - The concept of a layered metasurface constructed from loop nanoantennas for beam scanning in space is explored. Each layer of the metasurface can be envisioned as a shunt impedance sheet designable by modifying the loop configuration cell by cell. The single and concentric loop nanoantennas made of silver provide capacitive and inductive impedances, respectively, with negligible loss at 1.5 MUm, managing full control of the beam phase and amplitude. A telecom metasurface for beam scanning in 3D space is presented. The complex structure is modeled with an in-house-developed finite-difference time-domain method considering interactions among elements, in contrast to many designs in which isolated elements are simulated by assuming local periodicity. PMID- 24784087 TI - Transfer and conversion of images based on EIT in atom vapor. AB - Transfer and conversion of images between different wavelengths or polarization has significant applications in optical communication and quantum information processing. We demonstrated the transfer of images based on electromagnetically induced transparency (EIT) in a rubidium vapor cell. In experiments, a 2D image generated by a spatial light modulator is used as a coupling field, and a plane wave served as a signal field. We found that the image carried by coupling field could be transferred to that carried by signal field, and the spatial patterns of transferred image are much better than that of the initial image. It also could be much smaller than that determined by the diffraction limit of the optical system. We also studied the subdiffraction propagation for the transferred image. Our results may have applications in quantum interference lithography and coherent Raman spectroscopy. PMID- 24784088 TI - Generalized image principle for cylindrical waves. AB - In this Letter, we analyze the reflection of cylindrical waves (CWs) at planar interfaces. We consider the reflected CW proposed in the literature as a spectral integral. We present a Laurent series expansion of the Fresnel coefficient convergent on the whole real axis and we use it to solve analytically the reflected-wave integral. We found a solution that involves both Bessel functions and Anger-Weber functions, i.e., solutions of both the homogeneous and inhomogeneous Bessel differential equations. We compare the analytical solution with the numerical results obtained with a quadrature formula presented in the literature. Moreover, we present a physical interpretation that connects our solution to the image principle. PMID- 24784089 TI - Difference of two Gaussian Schell-model cross-spectral densities. AB - We present a number of results relating to the difference of two Gaussian Schell model cross-spectral densities (CSDs). They allow us to specify conditions under which such a difference represents itself in a valid CSD. In particular, a sufficient condition is derived for the non-negative definiteness of the resulting CSD, for any admissible choice of the involved parameters, while a necessary and sufficient condition is obtained for the case of CSDs endowed with the property of being shape-invariant upon propagation. PMID- 24784090 TI - Adjustable pulse compression scheme for generation of few-cycle pulses in the midinfrared. AB - A novel adjustable adiabatic soliton compression scheme is presented, enabling a coherent pulse source with pedestal-free, few-cycle pulses in the infrared or midinfrared regime. This scheme relies on interaction of a dispersive wave and a soliton copropagating at nearly identical group velocities in a fiber with enhanced infrared transmission. The compression is achieved directly in one stage, without the necessity of an external compensation scheme. Numerical simulations are employed to demonstrate this scheme for silica and fluoride fibers, indicating ultimate limitations as well as the possibility of compression down to the single-cycle regime. Such output pulses appear to be ideally suited as seed sources for parametric amplification schemes in the midinfrared. PMID- 24784091 TI - Fiber-laser-pumped, dual-wavelength, picosecond optical parametric oscillator. AB - We report a simple, compact, picosecond, dual-wavelength optical parametric oscillator (DW-OPO) at 160 MHz, based on two MgO:PPLN crystals sharing the same cavity and synchronously pumped by an Yb-fiber laser at 1064 nm. The two signal and idler wavelength pairs are independently tunable in the near- and mid infrared across 1550-1615 nm and 3118-3393 nm, respectively, and can be arbitrarily tuned, even to degeneracy and beyond, without coherent coupling, irrespective of operating wavelength. The DW-OPO provides two signal and idler pulse trains and delivers as much as 1.5 W of average signal power at a degenerate wavelength of 1550 nm from each arm, at a total (signal plus idler) power extraction efficiency of as much as 44%. The two output signal pulse trains have durations of ~18 ps and ~15.2 ps, with Gaussian spatial quality, and exhibit passive power stability, better than 3.6% rms over >5 h. We also demonstrate the possibility of tailoring the pulse trains from the DW-OPO by controlling the delay between the pump pulses at the input to the two MgO:PPLN crystals. PMID- 24784092 TI - Surface modes in "photonic cholesteric liquid crystal-phase plate-metal" structure. AB - The light transmission spectrum has been calculated for a "cholesteric liquid crystal-phase plate-metal" structure. It is shown that the system can have an isolated waveguide surface mode with characteristics efficiently controllable by external fields acting on the cholesteric. The degree of localization of surface modes and the transmission coefficients have been found to differ considerably for the light of different polarizations. PMID- 24784093 TI - Laser cooling of Yb3+-doped LuLiF4 crystal. AB - In order to meet the demands for applications of optical refrigerators in the fields of spaceflight, aviation, space science, and detection, a 2 wt. % Yb3+ doped LuLiF4 crystal, as a new laser cooling material, was prepared and demonstrated by using a 178 mW diode laser centered at 1015 nm and a resonant extra-cavity scheme with an enhancement factor of 12.8. Cooling efficiency of 1.27% and a temperature drop of 14.3 K/W are obtained with 79% of the incident laser power being absorbed. Based on our results, a sample with background absorption of alpha=4.2*10(-4) cm(-1) can be potentially cooled down to ~145 K. Our investigation shows that Yb3+-doped LuLiF4 crystal is potentially a promising candidate for solid-state refrigeration. PMID- 24784095 TI - Random fiber Bragg grating Raman fiber laser. AB - We demonstrate for the first time to our knowledge a Raman random fiber laser (RRFL) based on a long random fiber Bragg grating (RFBG-RRFL). Unlike other recently demonstrated random fiber lasers that rely on incoherent Rayleigh scattering feedback, the present scheme uses randomly distributed phase shifts inside a fiber-meter long Bragg grating as a random coherent feedback mechanism. The laser is pumped at 1480 nm and emits a CW signal at 1576 nm. The emission spectrum is dependent on pump intensity and is shown to exhibit single and multi mode characteristics. The RRFL shows a relatively low threshold (2.2 W) and a ~430 kHz FWHM linewidth. PMID- 24784094 TI - Angular spectrum detection instrument for label-free photonic crystal sensors. AB - An angular spectrum analysis system was demonstrated to monitor the optical resonant mode of a photonic crystal (PC) sensor comprised of a one-dimensional grating structure. Exposed to solutions with different refractive indices or adsorbed with biomaterials, the PC sensor exhibited changes of the optical resonant modes. The developed detection system utilized a focused laser beam to detect shifts of the resonant angle, and thereby allowed a kinetic analysis of chemical absorption. Such a detection apparatus offers an adjustable angular resolution and a tunable detection range for a wide variety of refractometric sensing applications. A limit of detection of 6.57*10(-5) refractive index unit has been observed. The instrument also offers an imaging capability of rapidly characterizing low-contrast samples deposited on the PC surface with a spatial resolution of 10 MUm. PMID- 24784096 TI - Holographic tracking of living cells by three-dimensional reconstructed complex wavefronts alignment. AB - We propose here a new three-dimensional (3D) holographic tracking method capable to track, simultaneously and in a single step, all the spatial coordinates of micro-objects. The approach is based on the enhanced correlation coefficient (ECC) maximization method but applied, for the first time to the best of our knowledge, directly on the holographic reconstructed complex wave fields. The key novelty of the proposed strategy is its ability to calculate simultaneously the 3D coordinates of cells, without decoupling the contribution of amplitude and phase. The proposed strategy is tested on living cells (i.e., NIH 3T3 mouse fibroblast) flowing into a microfluidic channel and compared with classical holographic tracking approach. Theoretical description and experimental validation of the proposed strategy are reported. PMID- 24784097 TI - High-sensitivity dispersive Mach-Zehnder interferometer based on a dissimilar doping dual-core fiber for sensing applications. AB - A dual-core fiber in which one of the cores is doped with germanium and the other with phosphorus is used as an in-line Mach-Zehnder dispersive interferometer. By ensuring an equal length but with different dispersion dependencies in the interferometer arms (the two cores), high-sensitivity strain and temperature sensing are achieved. Opposite sensitivities for high and low wavelength peaks were also demonstrated when strain and temperature was applied. To our knowledge this is the first time that such behavior is demonstrated using this type of in line interferometer based on a dual-core fiber. A sensitivity of (0.102+/-0.002) nm/MUepsilon, between 0 and 800 MUepsilon and (-4.2+/-0.2) nm/ degrees C between 47 degrees C and 62 degrees C is demonstrated. PMID- 24784098 TI - Experimental observation of particle cones formed by optical trapping. AB - We report on observation of particle cones formed by optical trapping of absorbing particles in air using two sets of simple geometric optical schemes. Further, the trapped particles on a cone in both schemes are size-sorted with large particles or particle ensembles close to the cone vertex. This new experimental observation shows an excellent example of 3D particle trapping between the two extreme cases, photon radiation trapping of nonabsorbing particles and photophoretic trapping of strongly absorbing particles; and the observation may challenge theoretical calculations of the trapping forces applied in this case. PMID- 24784099 TI - Vibrationally excited NO tagging by NO(A2?+) fluorescence and quenching for simultaneous velocimetry and thermometry in gaseous flows. AB - We present measurements demonstrating simultaneous determination of velocity and temperature using a variant of the Vibrationally Excited Nitric Oxide Monitoring (VENOM) technique that does not employ NO2. The variant is based on tagging by electronic excitation of NO in the A2?(1/2)+ (v'=0)<-X2Pi1/2(v''=0) band and subsequent formation of vibrationally excited NO(X2Pi) by spontaneous emission and collisional quenching. Sequential planar laser-induced fluorescence imaging of the nascent NO(X2Pi, v''=1) was used to obtain spatially resolved average streamwise velocity and rotational/translational temperature. The temperature determination using this approach extends the applicability of the VENOM technique to low-density, high-speed flows, where slow thermalization of the tagged molecules represents a limiting factor. PMID- 24784100 TI - Divided-pulse lasers. AB - We demonstrate the use of coherent division and recombination of the pulse within an ultrafast laser cavity to manage the nonlinear phase accumulation and scale the output pulse energy. We implement the divided-pulse technique in an ytterbium doped fiber laser and achieve 16 times scaling of the pulse energy, to generate 6 nJ and 1.4 ps solitons in single-mode fiber. Potential extensions of this concept are discussed. PMID- 24784102 TI - Tunable two-color hard x-ray multilayer Bragg mirrors. AB - A tunable two-color multilayer Bragg coating capable of simultaneously reflecting the fundamental and the third harmonic of an x-ray free-electron laser at the same angle and with high reflectance R>0.70 is presented. The novel coating will enable two-color x-ray pump/x-ray probe experiments. This mirror consists of a Si substrate that is coated with two different types of multilayer systems, Mo/B4C layers with a periodicity of d=3. nm directly on the substrate and Ni/B4C layers with a periodicity of d=11.85 nm on top. Fundamental radiation with photon energies between 3 and 9 keV is reflected by a Ni/B4C multilayer system while the third harmonic (9 keV2.0 for all pairs of compounds. The drug product was subjected to International Conference on Harmonization (ICH)-prescribed hydrolytic, oxidative, photolytic and thermal stress conditions. The method is validated as per the ICH guidelines with respect to specificity, linearity, limit of detection, limit of quantification, accuracy, precision, robustness and ruggedness. PMID- 24784117 TI - Enhanced passive bat rabies surveillance in indigenous bat species from Germany- a retrospective study. AB - In Germany, rabies in bats is a notifiable zoonotic disease, which is caused by European bat lyssaviruses type 1 and 2 (EBLV-1 and 2), and the recently discovered new lyssavirus species Bokeloh bat lyssavirus (BBLV). As the understanding of bat rabies in insectivorous bat species is limited, in addition to routine bat rabies diagnosis, an enhanced passive surveillance study, i.e. the retrospective investigation of dead bats that had not been tested for rabies, was initiated in 1998 to study the distribution, abundance and epidemiology of lyssavirus infections in bats from Germany. A total number of 5478 individuals representing 21 bat species within two families were included in this study. The Noctule bat (Nyctalus noctula) and the Common pipistrelle (Pipistrellus pipistrellus) represented the most specimens submitted. Of all investigated bats, 1.17% tested positive for lyssaviruses using the fluorescent antibody test (FAT). The vast majority of positive cases was identified as EBLV-1, predominately associated with the Serotine bat (Eptesicus serotinus). However, rabies cases in other species, i.e. Nathusius' pipistrelle bat (Pipistrellus nathusii), P. pipistrellus and Brown long-eared bat (Plecotus auritus) were also characterized as EBLV-1. In contrast, EBLV-2 was isolated from three Daubenton's bats (Myotis daubentonii). These three cases contribute significantly to the understanding of EBLV-2 infections in Germany as only one case had been reported prior to this study. This enhanced passive surveillance indicated that besides known reservoir species, further bat species are affected by lyssavirus infections. Given the increasing diversity of lyssaviruses and bats as reservoir host species worldwide, lyssavirus positive specimens, i.e. both bat and virus need to be confirmed by molecular techniques. PMID- 24784118 TI - Coverage, timeliness, and determinants of immunization completion in Pakistan: evidence from the Demographic and Health Survey (2006-07). AB - BACKGROUND: Immunization coverage data and determinants for completion are not well described for Pakistan. This study determines immunization coverage rates and timeliness based on the 2006-07 Pakistan Demographic and Health Survey (DHS) and identifies determinants for completion of immunizations. METHODS: DHS data from 9177 randomly selected households from across Pakistan were analyzed to assess immunization coverage and timeliness for children aged 0-5 years, and to investigate determinants of immunization completion through logistic regressions. RESULTS: The proportion of children immunized for a third dose of the oral poliovirus vaccine (OPV3) was 80.3%, and combination diphtheria, tetanus, and pertussis vaccines (DTP3) was 55.9%. Measles coverage was 62.5%. Late immunizations were most likely to occur for third doses of the OPV (65.5%) and DTP series (65.5%). Early doses were most likely to be administered for measles (21.9%). The proportion of children not immunized for any vaccine was 6.2%. Receiving a dose of maternal tetanus was a major determinant for immunization completion for OPV3 (OR 1.35, 95% CI: 1.14-1.60), DTP3 (OR 2.54, 95% CI: 2.13 3.02), and measles (OR 2.78, 95% CI: 2.27-3.40). Other independent variables associated with improved immunization completion included higher household wealth and maternal education. CONCLUSION: Poor routine immunization coverage and timeliness were identified through the DHS in Pakistan. Encouraging maternal tetanus uptake among women of child-bearing age and greater integration of immunization services with antenatal care may help improve childhood immunization completion. PMID- 24784120 TI - AAFP recommends universal screening for HIV infection beginning at age 18 years of age. PMID- 24784121 TI - Diagnosis and management of pancreatic cancer. AB - Pancreatic cancer remains the fourth leading cause of cancer-related deaths in the United States. Risk factors include family history, smoking, chronic pancreatitis, obesity, diabetes mellitus, heavy alcohol use, and possible dietary factors. Because more than two-thirds of adenocarcinomas occur in the head of the pancreas, abdominal pain, jaundice, pruritus, dark urine, and acholic stools may be presenting symptoms. In symptomatic patients, the serum tumor marker cancer antigen 19-9 can be used to confirm the diagnosis and to predict prognosis and recurrence after resection. Pancreas protocol computed tomography is considered standard for the diagnosis and staging of pancreatic cancer. Although surgical resection is the only potentially curative treatment for pancreatic ductal adenocarcinomas, less than 20% of surgical candidates survive five years. The decision on resectability requires multidisciplinary consultation. Pancreatic resections should be performed at institutions that complete at least 15 of the surgeries annually. Postoperatively, use of gemcitabine or fluorouracil/leucovorin as adjuvant chemotherapy improves overall survival by several months. However, more than 80% of patients present with disease that is not surgically resectable. For patients with locally advanced or metastatic disease, chemoradiotherapy with gemcitabine or irinotecan provides clinical benefit and modest survival improvement. Palliation should address pain control, biliary and gastric outlet obstruction, malnutrition, thromboembolic disease, and depression. PMID- 24784122 TI - Care of the homeless: an overview. AB - Homelessness affects men, women, and children of all races and ethnicities. On any given night, more than 610,000 persons in the United States are homeless; a little more than one-third of these are families. Homeless persons are more likely to become ill, have greater hospitalization rates, and are more likely to die at a younger age than the general population. The average life span for a homeless person is between 42 and 52 years. Homeless children are much sicker and have more academic and behavioral problems. Insufficient personal income and the lack of affordable housing are the major reasons for homelessness. Complex, advanced medical problems and psychiatric illnesses, exacerbated by drug and alcohol abuse, in combination with the economic and social issues (such as the lack of housing and proper transportation) make this subset of the population a unique challenge for the health care system, local communities, and the government. An integrated, multidisciplinary health care team with an outreach focus, along with involvement of local and state agencies, seems best suited to address the components needed to ensure quality of care, to help make these patients self-sufficient, and to help them succeed. Family physicians are well suited to manage the needs of the homeless patient, provide continuity of care, and lead these multidisciplinary teams. PMID- 24784123 TI - Chronic daily headache: diagnosis and management. AB - Chronic daily headache is defined as the presence of a headache on 15 days or more per month for at least three months. The most common types of chronic daily headache are chronic migraines and chronic tension-type headaches. If a red flag for a secondary cause of headache is present, magnetic resonance imaging of the head should be performed. All patients should be asked about medication overuse, which can increase the frequency of headaches. Patients who overuse medications for abortive therapy for headache should be encouraged to stop the medications entirely and consider prophylactic treatment. Several prophylactic treatments for chronic daily headache can reduce headache frequency and severity, as well as improve overall quality of life. Nonpharmacologic treatments include relaxation techniques, cognitive behavior therapy, acupuncture, osteopathic manipulation, and cervical exercises. Pharmacologic therapies include amitriptyline, gabapentin, onabotulinumtoxinA, propranolol, tizanidine, topiramate, and valproate. PMID- 24784124 TI - Evaluation of elbow pain in adults. AB - The elbow is a complex joint designed to withstand a wide range of dynamic exertional forces. The location and quality of elbow pain can generally localize the injury to one of the four anatomic regions: anterior, medial, lateral, or posterior. The history should include questions about the onset of pain, what the patient was doing when the pain started, and the type and frequency of athletic and occupational activities. Lateral and medial epicondylitis are two of the more common diagnoses and often occur as a result of occupational activities. Patients have pain and tenderness over the affected tendinous insertion that are accentuated with specific movements. If lateral and medial epicondylitis treatments are unsuccessful, ulnar neuropathy and radial tunnel syndrome should be considered. Ulnar collateral ligament injuries occur in athletes participating in sports that involve overhead throwing. Biceps tendinopathy is a relatively common source of pain in the anterior elbow; history often includes repeated elbow flexion with forearm supination and pronation. Olecranon bursitis is a common cause of posterior elbow pain and swelling. It can be septic or aseptic, and is diagnosed based on history, physical examination, and bursal fluid analysis if necessary. Plain radiography is the initial choice for the evaluation of acute injuries and is best for showing bony injuries, soft tissue swelling, and joint effusions. Magnetic resonance imaging is the preferred imaging modality for chronic elbow pain. Musculoskeletal ultrasonography allows for an inexpensive dynamic evaluation of commonly injured structures. PMID- 24784125 TI - A swollen thumb. PMID- 24784126 TI - Screening for HIV. PMID- 24784127 TI - Apixaban (eliquis) for stroke prevention in atrial fibrillation. PMID- 24784128 TI - AAP releases guideline on diagnosis and management of acute bacterial sinusitis in children one to 18 years of age. PMID- 24784129 TI - Apolipoproteins for cardiovascular risk assessment. PMID- 24784131 TI - Help for chronic daily headache. PMID- 24784130 TI - Screening for HIV: recommendation statement. PMID- 24784132 TI - Pancreatic cancer. PMID- 24784134 TI - PHYTOCHROME AND FLOWERING TIME1/MEDIATOR25 Regulates Lateral Root Formation via Auxin Signaling in Arabidopsis. AB - Root system architecture is a major determinant of water and nutrient acquisition as well as stress tolerance in plants. The Mediator complex is a conserved multiprotein complex that acts as a universal adaptor between transcription factors and the RNA polymerase II. In this article, we characterize possible roles of the MEDIATOR8 (MED8) and MED25 subunits of the plant Mediator complex in the regulation of root system architecture in Arabidopsis (Arabidopsis thaliana). We found that loss-of-function mutations in PHYTOCHROME AND FLOWERING TIME1 (PFT1)/MED25 increase primary and lateral root growth as well as lateral and adventitious root formation. In contrast, PFT1/MED25 overexpression reduces these responses, suggesting that PFT1/MED25 is an important element of meristematic cell proliferation and cell size control in both lateral and primary roots. PFT1/MED25 negatively regulates auxin transport and response gene expression in most parts of the plant, as evidenced by increased and decreased expression of the auxin-related reporters PIN-FORMED1 (PIN1)::PIN1::GFP (for green fluorescent protein), DR5:GFP, DR5:uidA, and BA3:uidA in pft1-2 mutants and in 35S:PFT1 seedlings, respectively. No alterations in endogenous auxin levels could be found in pft1-2 mutants or in 35S:PFT1-overexpressing seedlings. However, detailed analyses of DR5:GFP and DR5:uidA activity in wild-type, pft1-2, and 35S:PFT1 seedlings in response to indole-3-acetic acid, naphthaleneacetic acid, and the polar auxin transport inhibitor 1-N-naphthylphthalamic acid indicated that PFT1/MED25 principally regulates auxin transport and response. These results provide compelling evidence for a new role for PFT1/MED25 as an important transcriptional regulator of root system architecture through auxin-related mechanisms in Arabidopsis. PMID- 24784133 TI - Natural compounds as next-generation herbicides. AB - Herbicides with new modes of action (MOAs) are badly needed due to the rapidly evolving resistance to commercial herbicides, but a new MOA has not been introduced in over 20 years. The greatest pest management challenge for organic agriculture is the lack of effective natural product herbicides. The structural diversity and evolved biological activity of natural phytotoxins offer opportunities for the development of both directly used natural compounds and synthetic herbicides with new target sites based on the structures of natural phytotoxins. Natural phytotoxins are also a source for the discovery of new herbicide target sites that can serve as the focus of traditional herbicide discovery efforts. There are many examples of strong natural phytotoxins with MOAs other than those used by commercial herbicides, which indicates that there are molecular targets of herbicides that can be added to the current repertoire of commercial herbicide MOAs. PMID- 24784136 TI - Novel population genetics in ciliates due to life cycle and nuclear dimorphism. AB - Our understanding of population genetics comes primarily from studies of organisms with canonical life cycles and nuclear organization, either haploid or diploid, sexual, or asexual. Although this template yields satisfactory results for the study of animals and plants, the wide variety of genomic organizations and life cycles of unicellular eukaryotes can make these organisms behave differently in response to mutation, selection, and drift than predicted by traditional population genetic models. In this study, we show how each of these unique features of ciliates affects their evolutionary parameters in mutation selection, selection-drift, and mutation-selection-drift situations. In general, ciliates are less efficient in eliminating deleterious mutations-these mutations linger longer and at higher frequencies in ciliate populations than in sexual populations--and more efficient in selecting beneficial mutations. Approaching this problem via analytical techniques and simulation allows us to make specific predictions about the nature of ciliate evolution, and we discuss the implications of these results with respect to the high levels of polymorphism and high rate of protein evolution reported for ciliates. PMID- 24784135 TI - Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy. AB - Many eukaryotic cell-surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). There are at least 26 genes involved in biosynthesis and remodeling of GPI anchors. Hypomorphic coding mutations in seven of these genes have been reported to cause decreased expression of GPI anchored proteins (GPI-APs) on the cell surface and to cause autosomal-recessive forms of intellectual disability (ARID). We performed homozygosity mapping and exome sequencing in a family with encephalopathy and non-specific ARID and identified a homozygous 3 bp deletion (p.Leu197del) in the GPI remodeling gene PGAP1. PGAP1 was not described in association with a human phenotype before. PGAP1 is a deacylase that removes an acyl-chain from the inositol of GPI anchors in the endoplasmic reticulum immediately after attachment of GPI to proteins. In silico prediction and molecular modeling strongly suggested a pathogenic effect of the identified deletion. The expression levels of GPI-APs on B lymphoblastoid cells derived from an affected person were normal. However, when those cells were incubated with phosphatidylinositol-specific phospholipase C (PI-PLC), GPI-APs were cleaved and released from B lymphoblastoid cells from healthy individuals whereas GPI-APs on the cells from the affected person were totally resistant. Transfection with wild type PGAP1 cDNA restored the PI-PLC sensitivity. These results indicate that GPI-APs were expressed with abnormal GPI structure due to a null mutation in the remodeling gene PGAP1. Our results add PGAP1 to the growing list of GPI abnormalities and indicate that not only the cell surface expression levels of GPI-APs but also the fine structure of GPI-anchors is important for the normal neurological development. PMID- 24784137 TI - Reducing pervasive false-positive identical-by-descent segments detected by large scale pedigree analysis. AB - Analysis of genomic segments shared identical-by-descent (IBD) between individuals is fundamental to many genetic applications, from demographic inference to estimating the heritability of diseases, but IBD detection accuracy in nonsimulated data is largely unknown. In principle, it can be evaluated using known pedigrees, as IBD segments are by definition inherited without recombination down a family tree. We extracted 25,432 genotyped European individuals containing 2,952 father-mother-child trios from the 23andMe, Inc. data set. We then used GERMLINE, a widely used IBD detection method, to detect IBD segments within this cohort. Exploiting known familial relationships, we identified a false-positive rate over 67% for 2-4 centiMorgan (cM) segments, in sharp contrast with accuracies reported in simulated data at these sizes. Nearly all false positives arose from the allowance of haplotype switch errors when detecting IBD, a necessity for retrieving long (>6 cM) segments in the presence of imperfect phasing. We introduce HaploScore, a novel, computationally efficient metric that scores IBD segments proportional to the number of switch errors they contain. Applying HaploScore filtering to the IBD data at a precision of 0.8 produced a 13-fold increase in recall when compared with length-based filtering. We replicate the false IBD findings and demonstrate the generalizability of HaploScore to alternative data sources using an independent cohort of 555 European individuals from the 1000 Genomes project. HaploScore can improve the accuracy of segments reported by any IBD detection method, provided that estimates of the genotyping error rate and switch error rate are available. PMID- 24784138 TI - Intestine-specific deletion of acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 protects mice from diet-induced obesity and glucose intolerance. AB - The absorption of dietary fat involves the re-esterification of digested triacylglycerol in the enterocytes, a process catalyzed by acyl CoA:monoacylglycerol acyltransferase (MGAT) 2. Mice without a functional gene encoding MGAT2 (Mogat2(-/-)) are protected from diet-induced obesity. Surprisingly, these mice absorb normal amounts of dietary fat but increase their energy expenditure. MGAT2 is expressed in tissues besides intestine, including adipose tissue in both mice and humans. To test the hypothesis that intestinal MGAT2 regulates systemic energy balance, we generated and characterized mice deficient in MGAT2 specifically in the small intestine (Mogat2(IKO)). We found that, like Mogat2(-/-) mice, Mogat2(IKO) mice also showed a delay in fat absorption, a decrease in food intake, and a propensity to use fatty acids as fuel when first exposed to a high fat diet. Mogat2(IKO) mice increased energy expenditure although to a lesser degree than Mogat2(-/-) mice and were protected against diet-induced weight gain and associated comorbidities, including hepatic steatosis, hypercholesterolemia, and glucose intolerance. These findings illustrate that intestinal lipid metabolism plays a crucial role in the regulation of systemic energy balance and may be a feasible intervention target. In addition, they suggest that MGAT activity in extraintestinal tissues may also modulate energy metabolism. PMID- 24784140 TI - Jewish mortality reconsidered. AB - It is known that mortality of Jews is different from the mortality of the populations that surround them. However, the existence of commonalities in mortality of different Jewish communities across the world has not received scholarly attention. This paper aims to identify common features of the evolution of Jewish mortality among Jews living in Israel and the Diaspora. In the paper the mortality of Jews in Israel is systematically compared with the mortality of the populations of developed countries, and the findings from the earlier studies of mortality of Jews in selected Diaspora communities are re-examined. The outcome is a re-formulation and extension of the notion of the 'Jewish pattern of mortality'. The account of this pattern is based on the consistently low level of behaviourally induced mortality, the migration history of Jewish populations and the enduring influence of early-life conditions on mortality at older ages. PMID- 24784139 TI - 4-methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid (C75), an inhibitor of fatty-acid synthase, suppresses the mitochondrial fatty acid synthesis pathway and impairs mitochondrial function. AB - 4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid (C75) is a synthetic fatty-acid synthase (FASN) inhibitor with potential therapeutic effects in several cancer models. Human mitochondrial beta-ketoacyl-acyl carrier protein synthase (HsmtKAS) is a key enzyme in the newly discovered mitochondrial fatty acid synthesis pathway that can produce the substrate for lipoic acid (LA) synthesis. HsmtKAS shares conserved catalytic domains with FASN, which are responsible for binding to C75. In our study, we explored the possible effect of C75 on HsmtKAS and mitochondrial function. C75 treatment decreased LA content, impaired mitochondrial function, increased reactive oxygen species content, and reduced cell viability. HsmtKAS but not FASN knockdown had an effect that was similar to C75 treatment. In addition, an LA supplement efficiently inhibited C75 induced mitochondrial dysfunction and oxidative stress. Overexpression of HsmtKAS showed cellular protection against low dose C75 addition, whereas there was no protective effect upon high dose C75 addition. In summary, the mitochondrial fatty acid synthesis pathway has a vital role in mitochondrial function. Besides FASN, C75 might also inhibit HsmtKAS, thereby reducing LA production, impairing mitochondrial function, and potentially having toxic effects. LA supplements sufficiently ameliorated the toxicity of C75, showing that a combination of C75 and LA may be a reliable cancer treatment. PMID- 24784141 TI - Communicating bodily changes: physicians' ways of enabling patient understanding in gastrointestinal cancer consultations. AB - OBJECTIVE: To explore how physicians communicatively enable patients' understanding of bodily changes in gastrointestinal cancer care consultations. METHOD: Two datasets were used. The first consisted of transcribed video-recorded palliative care consultations with three oncologists and six patients diagnosed with advanced gastrointestinal cancer, in the context of outpatient palliative care. The second dataset was audio-recorded transcriptions from diagnostic consultations with six surgeons and seven patients diagnosed with colorectal cancer, in the context of cancer surgery. An inductively driven and iterative analysis of interaction was performed, guided by Wetherell et al. (2001). RESULTS: Two overarching communicative strategies were identified: (1) "visualizing strategies," with the dimensions: visible strategies (visualizing with what you actually or potentially can see), sensory strategies (visualizing with what is possible to feel), and imaginative strategies; and (2) "contrasting strategies," with the dimensions: contrasting subjective experiences and contrasting between the patient and other people. SIGNIFICANCE OF RESULTS: The visualizing and contrasting communicative strategies form parts of physicians' tacit and experience-based knowledge. The strategies employed by physicians reveal clear potentials to enable patients' understanding and sense making of bodily changes. However, these strategies need to be explicated and problematized as parts of both consultation practice and basic medical education. By means of increased awareness, physicians can more easily identify turning points in patients' levels of understanding, thereby enriching ordinary medical consultations with reflected pedagogical strategies and skills in how to dialogue in a person-centered manner. PMID- 24784142 TI - Spectrum of mast cell activation disorders. AB - Mast cell (MC) activation disorders present with multiple symptoms including flushing, pruritus, hypotension, gastrointestinal complaints, irritability, headaches, concentration/memory loss and neuropsychiatric issues. These disorders are classified as: cutaneous and systemic mastocytosis with a c-kit mutation and clonal MC activation disorder, allergies, urticarias and inflammatory disorders and mast cell activation syndrome (MCAS), idiopathic urticaria and angioedema. MCs are activated by IgE, but also by cytokines, environmental, food, infectious, drug and stress triggers, leading to secretion of multiple mediators. The symptom profile and comorbidities associated with these disorders, such as chronic fatigue syndrome and fibromyalgia, are confusing. We propose the use of the term 'spectrum' and highlight the main symptoms, useful diagnostic tests and treatment approaches. PMID- 24784143 TI - Bottle and sippy cup use is associated with diet and energy intake in toddlers. AB - The second year of life incorporates a continued shift from a liquid- to solid based diet. Little is known about the prevalence and dietary impact of bottle and sippy cup use. This paper describes associations between percent of energy consumed via drinking containers (bottles and sippy cups combined) and dietary outcomes, between 1 and 2 years of age. This observational study recruited n = 299 low-income, nutrition programme clients from the Bronx, NY, whose 12 month olds consumed >= 2 non-water bottles per day. The main exposure variable was percent of energy intake via drinking containers (PEDC), dichotomized at the median into low-percent-energy-from-drinking-containers (LOW-C) and high-percent energy-from-drinking-containers (HIGH-C) groups, assessed quarterly, for 1 year. We report 24-hour dietary recall nutrient and food serving data by LOW-C vs. HIGH C. We employed linear mixed models to study associations between PEDC and nutrient intake. PEDC decreased from 52% to 33% between 1 and 2 years of age in both groups. The LOW-C group had higher intake of energy, dietary fibre, iron and sodium, grains, protein-rich foods and sweets. Conversely, LOW-C group had lower intake of Vitamin D and calcium vs. the HIGH-C group. PEDC was inversely associated with total energy intake in a model controlling for baseline age, baseline-weight-for-length and gender (beta = -5.8, P = 0.029, 95% confidence interval (-10.96, -0.6). Lower bottle and sippy cup use had significant, albeit mixed association with diet quality in the second year of life, and was associated with higher energy intake. Evidence-based guidelines are needed to determine the appropriate use of those feeding methods. PMID- 24784144 TI - Long-term care benefits may reduce end-of-life medical care costs. AB - Abstract This study explores whether personal care services for functionally dependent or cognitively impaired individuals paid for by a long-term care (LTC) insurance policy can reduce health care utilization and costs at the end of life. This retrospective study uses propensity score matching methodology, hierarchical multiple regression, and Poisson regression to compare 830 decedents who utilized benefits from a voluntary LTC insurance plan ("claimants") to 6860 decedents who never purchased coverage but were similar to claimants on 17 variables, including age, sex, frailty, burden of illness markers, and propensity to have needed LTC services. Claimants using LTC benefits experienced significantly lower health care costs at end of life, including 14% lower total medical costs, 13% lower pharmacy costs, 35% lower inpatient admission costs, and 16% lower outpatient visit costs. They also experienced 8% fewer inpatient admissions and 10% fewer inpatient days. The presence of dementia at the end of life moderated these effects. This study suggests that use of insurance-based LTC services measurably reduces health care expenditures at the end of life. (Population Health Management 2014;17:332-339). PMID- 24784145 TI - The polygenic profile of Russian football players. AB - Research concerned with predictors of talent in football has highlighted a number of potentially important and partially inherited measures such as body size, anaerobic power, aerobic capacity, agility, psychological profile, game intelligence and susceptibility to injuries. Genotyping for performance associated DNA polymorphisms at an early age could be useful in predicting later success in football. The aim of the study was to investigate individually and in combination the association of common gene polymorphisms with football player's status. A total of 246 Russian football players and 872 controls were genotyped for 8 gene polymorphisms, which were previously reported to be associated with athlete status. Four alleles (ACE D, ACTN3 Arg577, PPARA rs4253778 C and UCP2 55Val) were first identified, showing discrete associations with football player's status. Next, we determined the total genotype score (TGS, from the accumulated combination of the 4 polymorphisms, with a maximum value of 100 for the theoretically optimal polygenic score) in athletes and controls. The mean TGS was significantly higher in football players (52.0 (17.6) vs. 41.3 (15.5); P < 0.0001) than in controls. These data suggest that the likelihood of becoming a football player depends on the carriage of a high number of "favourable" gene variants. PMID- 24784146 TI - Impairments in local heat loss in type 1 diabetes during exercise in the heat. AB - Studies show that vasomotor and sudomotor activities are compromised in individuals with Type 1 diabetes mellitus (T1DM), which could lead to impaired skin blood flow (SkBF) and sweating during heat stress. However, recent work suggests the impairments may only be evidenced beyond a certain level of heat stress. PURPOSE: We examined T1DM-related differences in heat loss responses of SkBF and sweating during exercise performed at progressive increases in the requirement for heat loss. METHODS: Sixteen adults (10 males and six females) with (T1DM, n = 8) and without T1DM (control, n = 8) matched for age, sex, body surface area, and fitness cycled at fixed rates of metabolic heat production of 200, 250, and 300 W.m in the heat (35 degrees C and 20% relative humidity). Each rate was performed sequentially for 30 min. Local sweat rate (LSR, ventilated capsule), sweat gland activation (modified iodine paper technique), and sweat gland output were measured on the forearm, upper back, and chest, whereas SkBF (laser Doppler) was measured on the forearm and upper back. RESULTS: Despite a similar requirement for heat loss, LSR was lower in T1DM on the forearm and chest relative to that in the control. Reductions were measured in the second (forearm: 0.68 +/- 0.14 vs 0.85 +/- 0.11 mg.min.cm, P = 0.004; chest: 0.58 +/- 0.08 vs 0.82 +/- 0.12 mg.min.cm, P = 0.046) and third exercise bouts (forearm: 0.75 +/- 0.11 vs 0.98 +/- 0.12 mg.min.cm, P = 0.005; chest: 0.66 +/- 0.1 vs 1.02 +/- 0.16 mg.min.cm, P = 0.032). Differences in forearm LSR were the result of a reduction in sweat gland output, whereas the decrease in chest LSR was due to lower sweat gland activation. SkBF did not differ between groups. CONCLUSIONS: We show that T1DM is associated with impairments in heat dissipation during exercise in the heat, as evidenced by attenuated LSR. However, these differences are only shown beyond a certain requirement for heat loss. PMID- 24784147 TI - Sexual and fertility adverse effects associated with chemotherapy treatment in women. AB - INTRODUCTION: Earlier diagnosis and novel chemotherapy strategies have resulted in a considerable improvement in cancer survival, but the quality of that survival is influenced by late effects of chemotherapy. Premature ovarian failure is a common consequence of chemotherapy in reproductive-aged women, and, as a result, fertility issues and sexual dysfunction occur frequently in women who have undergone chemotherapy. AREAS COVERED: This article reviews what is known about the effects of chemotherapy on fertility and sexuality. We also discuss risk factors for premature ovarian failure, fertility preservation options in patients willing to have a child after treatment, and sexual changes associated with estrogen withdrawal and psychological factors. EXPERT OPINION: Chemotherapy induced ovarian failure in young women is associated with poorer quality of life, decreased sexual functioning, psychosocial distress related to fertility concerns, and infertility. Fertility preservation options should be considered in women at risk of premature ovarian failure caused by chemotherapy. Sexual dysfunction associated with estrogen withdrawal and psychological stress is common in cancer survivors. Women who suffer from sexual dysfunction may benefit from brief counseling and targeted intervention. PMID- 24784148 TI - FREQUENT RESIDENTIAL RELOCATIONS CUMULATIVELY ACCELERATE MENARCHEAL TIMING IN A SAMPLE OF ENGLISH ADOLESCENT GIRLS. AB - Childhood adversity has been associated with accelerated menarcheal and reproductive timing in females. The relationship between family- and neighbourhood-level measures of childhood adversity, menarcheal timing and intended reproductive timing was investigated in a sample of 354 English adolescent girls. The data were collected from March to June 2012. In total 90 of the participants had reached menarche. Frequent residential relocations increased the likelihood of reaching menarche (HR 1.11; 95%CI 1.02-1.22). Girls who had moved house one to four times or five or more times, were respectively, more than twice (HR 2.14; 95%CI 1.23-3.73) and more than three times (HR 3.20; 95%CI 1.44 7.10) as likely to have reached menarche than girls who had never moved house. Frequent residential relocations were associated with stepfather co-residence, increased number of half/stepsiblings and reduced feelings of family support. Menarche was also accelerated by the presence of half/stepsisters. There was no relationship between menarcheal timing and intended reproductive timing. Frequent residential relocations may indicate instability in a young person's life, which is often outside of their control. Extending childhood adversity measures to include residential relocations could be important in better understanding the role early life events play in accelerating menarche. PMID- 24784149 TI - Bistable dynamics underlying excitability of ion homeostasis in neuron models. AB - When neurons fire action potentials, dissipation of free energy is usually not directly considered, because the change in free energy is often negligible compared to the immense reservoir stored in neural transmembrane ion gradients and the long-term energy requirements are met through chemical energy, i.e., metabolism. However, these gradients can temporarily nearly vanish in neurological diseases, such as migraine and stroke, and in traumatic brain injury from concussions to severe injuries. We study biophysical neuron models based on the Hodgkin-Huxley (HH) formalism extended to include time-dependent ion concentrations inside and outside the cell and metabolic energy-driven pumps. We reveal the basic mechanism of a state of free energy-starvation (FES) with bifurcation analyses showing that ion dynamics is for a large range of pump rates bistable without contact to an ion bath. This is interpreted as a threshold reduction of a new fundamental mechanism of ionic excitability that causes a long lasting but transient FES as observed in pathological states. We can in particular conclude that a coupling of extracellular ion concentrations to a large glial-vascular bath can take a role as an inhibitory mechanism crucial in ion homeostasis, while the Na+/K+ pumps alone are insufficient to recover from FES. Our results provide the missing link between the HH formalism and activator inhibitor models that have been successfully used for modeling migraine phenotypes, and therefore will allow us to validate the hypothesis that migraine symptoms are explained by disturbed function in ion channel subunits, Na+/K+ pumps, and other proteins that regulate ion homeostasis. PMID- 24784151 TI - Positive emotion can protect against source memory impairment. AB - Despite widespread belief that memory is enhanced by emotion, evidence also suggests that emotion can impair memory. Here we test predictions inspired by object-based binding theory, which states that memory enhancement or impairment depends on the nature of the information to be retrieved. We investigated emotional memory in the context of source retrieval, using images of scenes that were negative, neutral or positive in valence. At study each scene was paired with a colour and during retrieval participants reported the source colour for recognised scenes. Critically, we isolated effects of valence by equating stimulus arousal across conditions. In Experiment 1 colour borders surrounded scenes at study: memory impairment was found for both negative and positive scenes. Experiment 2 used colours superimposed over scenes at study: valence affected source retrieval, with memory impairment for negative scenes only. These findings challenge current theories of emotional memory by showing that emotion can impair memory for both intrinsic and extrinsic source information, even when arousal is equated between emotional and neutral stimuli, and by dissociating the effects of positive and negative emotion on episodic memory retrieval. PMID- 24784152 TI - Discovery and confirmation of ligand binding specificities of the Schistosoma japonicum polarity protein Scribble. AB - BACKGROUND: Schistosomiasis is a chronic debilitating parasitic disease that afflicts more than 200 million individuals worldwide. Long-term administration of chemotherapy with the single available drug, praziquantel, has led to growing concerns about drug resistance. The PSD-95/Dlg/ZO-1 (PDZ) domain is an important module found in many scaffolding proteins, which has been recognized as promising targets for the development of novel drugs. However, the parasite-derived PDZ domains and their associated functions are still largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: The gene encoding the Schistosoma japonicum Scribble protein (SjScrib) was identified by homologous search with the S. mansoni Scrib sequence. By screening an arbitrary peptide library in yeast two hybrid (Y2H) assays, we identified and confirmed the ligand binding specificity for each of the four PDZ domains of SjScrib. Both SjScrib-PDZ1 and SjScrib-PDZ3 recognize type I C-terminal PDZ-domain binding motifs (PBMs), which can be deduced as consensus sequences of -[Phi][x][E][TS][x][ILF] and [x][RKx][ETS][T][WPhi][ILV], respectively. SjScrib-PDZ2 prefers stringent type II C-terminal PBMs, which significantly differs from that of its human ortholog. SjScrib-PDZ4 binds to typical II C-terminal PBMs with a consensus sequence [x][FW][x][LI][x][LIV], in which the aromatic residue Phe is predominantly selected at position -4. The irregular and unconventional internal ligand binding specificities for the PDZ domains of SjScrib were confirmed by point mutations of the key amino acids within the ligand binding motifs. We also compared the differences in ligand specificities between SjScrib-PDZs and hScrib-PDZs, and explored the structural basis for the ligand binding properties of SjScrib-PDZs. CONCLUSIONS/SIGNIFICANCE: In this study, we characterized and confirmed the ligand binding specificities of all four PDZ domains of SjScrib for the first time. We denoted the differential ligand binding specificities between SjScrib PDZs and hScrib-PDZs as well as the structural basis for these properties. This work may provide a fundamental basis for the rational design of novel anti schistosomal drugs. PMID- 24784153 TI - Time to get healthy: associations of time perspective with perceived health status and health behaviors. AB - The present study examined the associations of time perspective (TP) with health behaviors including smoking, exercise, and body mass index (BMI), and perceptions of health status after controlling for sociodemographic factors. Participants (N = 413) completed a web-based questionnaire that included a short version of the Zimbardo Time Perspective Inventory, and reported their weight, height, smoking, and exercise frequency. Future TP was associated with more physical exercise, whereas past-negative and present-fatalistic dimensions were associated with higher BMI. Smoking was not associated with any of the TP dimensions. Additionally, all of the dimensions of TP were found to be associated with conceptually relevant perceptions of health status. Research on TP predominantly focuses on the future and the present orientation, but the findings of the present study suggest that all dimensions of TP should be used in health-related research. Also, issues regarding the role of the present-hedonistic dimension are discussed and directions for future research are proposed. PMID- 24784154 TI - Genetic interactions involving five or more genes contribute to a complex trait in yeast. AB - Recent research suggests that genetic interactions involving more than two loci may influence a number of complex traits. How these 'higher-order' interactions arise at the genetic and molecular levels remains an open question. To provide insights into this problem, we dissected a colony morphology phenotype that segregates in a yeast cross and results from synthetic higher-order interactions. Using backcrossing and selective sequencing of progeny, we found five loci that collectively produce the trait. We fine-mapped these loci to 22 genes in total and identified a single gene at each locus that caused loss of the phenotype when deleted. Complementation tests or allele replacements provided support for functional variation in these genes, and revealed that pre-existing genetic variants and a spontaneous mutation interact to cause the trait. The causal genes have diverse functions in endocytosis (END3), oxidative stress response (TRR1), RAS-cAMP signalling (IRA2), and transcriptional regulation of multicellular growth (FLO8 and MSS11), and for the most part have not previously been shown to exhibit functional relationships. Further efforts uncovered two additional loci that together can complement the non-causal allele of END3, suggesting that multiple genotypes in the cross can specify the same phenotype. Our work sheds light on the complex genetic and molecular architecture of higher-order interactions, and raises questions about the broader contribution of such interactions to heritable trait variation. PMID- 24784155 TI - Wearing a crotch strap on a correctly fitted lifejacket improves lifejacket performance. AB - Wearing a lifejacket when immersed in water should support the wearer, maintaining their airway clear of the water. It is proposed that a retention system would improve airway protection by improving retention of the lifejacket around the torso. Study one (n = 10) quantified the performance of lifejackets immediately following a step into water from height when a lifejacket was worn with a crotch strap (two different tightness) and without a crotch strap. Airway freeboard was improved when wearing a crotch strap (P < 0.05) compared with no crotch strap. Study two used a manikin to examine the performance of lifejackets with and without a crotch strap during 3-h exposures to waves. During exposure to waves, the time taken to aspirate the lethal dose of seawater for drowning was doubled when wearing a crotch strap compared with the no-crotch-strap conditions (P < 0.001). Therefore, wearing a crotch strap (functioning retention system) on a correctly fitted lifejacket improves airway protection following accidental immersion and prolonged wave exposure. PMID- 24784156 TI - Direct-to-patient disclosure of results of mismatch repair screening for Lynch syndrome via electronic personal health record: a feasibility study. AB - PURPOSE: The adoption of universal mismatch repair screening of colorectal and endometrial cancers has the potential to improve detection of Lynch syndrome, as well as to improve health outcomes among cancer patients and their family members. Electronic patient health records represent an innovative, resource efficient route of delivering results directly to patients that could be enhanced by multimedia interventions to improve critical downstream outcomes. The current study examines the feasibility and acceptability of this approach. METHODS: Patients hospitalized for resection of colorectal or endometrial cancer were recruited to receive their mismatch repair result via institutional electronic patient health record. Baseline and follow-up assessments were conducted. RESULTS: In all, 74% (49/66) of eligible patients consented, and 81% (29/36) of participants who had a result posted to their electronic patient health record completed follow-up, surpassing feasibility thresholds, with 14% (5/36) receiving an abnormal result. Ratings of the study approach surpassed the acceptability threshold--97% had a mean score of >= 4 on a 7-point scale--and were high, regardless of whether the results were normal or abnormal. Ineligibility was more common among non-white patients (P = 0.009) and patients >= 65 of age (P = 0.035) due to either low Internet use or access to the Internet. CONCLUSION: Electronic patient health record-based result disclosure for mismatch repair screening is feasible to study and is acceptable to patients, but minority and elderly patients may experience greater barriers to participation.Genet Med 16 11, 854 861. PMID- 24784158 TI - Judith G. Hall: a genetic journey. PMID- 24784159 TI - Michael Kaback: people and places. PMID- 24784157 TI - The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. AB - PURPOSE: Using exome sequence data from 159 families participating in the National Institutes of Health Undiagnosed Diseases Program, we evaluated the number and inheritance mode of reportable incidental sequence variants. METHODS: Following the American College of Medical Genetics and Genomics recommendations for reporting of incidental findings from next-generation sequencing, we extracted variants in 56 genes from the exome sequence data of 543 subjects and determined the reportable incidental findings for each participant. We also defined variant status as inherited or de novo for those with available parental sequence data. RESULTS: We identified 14 independent reportable variants in 159 (8.8%) families. For nine families with parental sequence data in our cohort, a parent transmitted the variant to one or more children (nine minor children and four adult children). The remaining five variants occurred in adults for whom parental sequences were unavailable. CONCLUSION: Our results are consistent with the expectation that a small percentage of exomes will result in identification of an incidental finding under the American College of Medical Genetics and Genomics recommendations. Additionally, our analysis of family sequence data highlights that genome and exome sequencing of families has unavoidable implications for immediate family members and therefore requires appropriate counseling for the family. PMID- 24784161 TI - Tunable threshold voltage of an n-type Si nanowire ferroelectric-gate field effect transistor for high-performance nonvolatile memory applications. AB - We successfully fabricated ferroelectric-gate field effect transistor (FEFET) based nonvolatile memory devices using an n-type Si nanowire coated with omega shaped-gate organic ferroelectric poly(vinylidene fluoride-trifluoroethylene) via a low-temperature fabrication process. Our FEFET memory devices with controllable threshold voltage via adjustment of the doping concentration exhibit excellent memory characteristics with ultra-low ON state power dissipation (<=3 nW), a large modulation in channel conductance between the ON and OFF states exceeding 10(5), a long retention time of over 3 * 10(4) s and a high endurance of over 10(5) programming cycles whilst maintaining an I ON/I OFF ratio higher than 10(3). This result may be promising for next-generation nonvolatile memory on flexible substrate applications. PMID- 24784162 TI - Macroscopic and histological variations in the cellular tapetum in dogs. AB - We aimed to document macroscopic variations in the cellular tapetum in the dog, to provide a histologic description of the macroscopic results and to evaluate the correlation between the macroscopic appearance and aging. Fifty three dogs including 5 beagles, 1 Chihuahua and 47 mixed breeds of each gender were used. For a macroscopic study, the fresh tapetal fundi were photographed using digital camera. For a histological study, the glutaraldehyde-formalin fixed eyes were embedded in nitrocellulose and stained with hematoxylin-eosin or thionine. The normal tapetum was triangular with the rounded angles and the smooth contour. The atypical tapetum was smaller and more variable in shape, contour and color than the normal one. In severe cases, the fundus was devoid of the tapetum. The atypical tapetum tended to increase in frequency with aging. Retinal pigment epithelial cells on the normal tapetum were unpigmented. In the eye with the atypical tapetum, regardless of tapetal size and shape, unpigmented retinal pigment epithelial cells showed a similar distribution to that on the normal tapetum, even in a dog without a tapetum. Although there is a congenitally hypoplastic tapetum, the atypical tapetum tends to increase in incidence and severity with aging. PMID- 24784163 TI - The relationship between obesity and prescription of smoking cessation medications. AB - The objective of this study was to examine the differences in prescription of smoking cessation medications among smokers with different body mass index (BMI) classifications. A retrospective cross-sectional study was conducted using National Ambulatory Medical Care Survey data (2006-2010). Self-reported current smokers aged 18 years and older were included in the study. The outcome of interest was receiving a prescription for a Food and Drug Administration-approved smoking cessation medication. Multivariate logistic regression was performed to assess the association between the outcome variable and the main independent variable (BMI classification), controlling for other covariates. The results showed that overweight, obese, and severely obese smokers were less likely to be prescribed a smoking cessation medication as compared to normal weight smokers. Although 5.11% of normal weight smokers were prescribed a smoking cessation medication, only 3.70% of overweight smokers, 3.41% of obese smokers, and 2.50% of severely obese smokers were prescribed a smoking cessation medication. In addition, older smokers, whites, smokers visiting primary care providers, smokers receiving tobacco counseling, and nondiabetic smokers were more likely to be prescribed a smoking cessation medication. Lower prescription of smoking cessation medications among overweight, obese, and severely obese smokers might be driven by patients' health concerns and behavioral factors or providers' treatment preferences or biases. The disparity in smoking cessation medication prescription among smokers with different BMI classifications raises quality of care and health care concerns for overweight, obese, and severely obese smokers. PMID- 24784164 TI - Malaria no more: nothing but nets. PMID- 24784165 TI - Synthesis, crystal structure, and high-temperature phase transition of the novel plumbide Na2MgPb. AB - A hitherto unknown sodium magnesium plumbide, Na2MgPb, was synthesized by heating the constituent elements. Na2MgPb crystallizes in a hexagonal unit cell with the Li2CuAs-type structure (P63/mmc, Z = 2, a = 5.110(2) A, c = 10.171(4) A at 293 K). The compound furthermore displays polymorphism: high-temperature powder XRD measurements revealed that hexagonal Na2MgPb (dubbed the "alpha" phase) transforms to another hexagonal phase (beta) which is existent at 493-553 K, and the beta phase changes to a cubic structure (gamma) at 533-633 K further. The molar volume of gamma-Na2MgPb is approximately 9% and 13% smaller than the molar volumes of the alpha phase and the beta phase, respectively (at 543 K). The electrical resistivity of Na2MgPb is 0.39 mOmega at 300 K; it rises with increasing temperature from 300 to 491 K, and then drops at 491 and 523 K. These abrupt changes in resistivity may be attributed to the alpha -> beta and beta -> gamma phase transitions, respectively. To gain further insight into the structure of cubic gamma-Na2MgPb, putative models with regular Heusler-type (Cu2MnAl-type) and inverse Heusler-type (Li2AgSb-type) arrangements were probed using first principles computations based on density functional theory (DFT). These computations indicate that, for the cubic gamma phase, an inverse Heusler-type structure is distinctly more stable than the alternative regular Heusler type (at 0 K); beyond that, ab initio thermochemistry was successfully used to verify the stability ordering (alpha-Na2MgPb being favorable at low temperature, gamma Na2MgPb at high temperature), albeit the theoretically predicted transition temperature of 900 K which is higher than observed in experiment. PMID- 24784166 TI - College men's depression-related help-seeking: a gender analysis. AB - BACKGROUND: Men's health help-seeking behaviours vary considerably depending on the context. The current empirical literature on the influence of masculinity on college men's attitudes towards mental health-related help-seeking is largely limited to investigations involving psychology students. AIM: To describe the connections between masculinities and college men's depression-related help seeking. METHODS: Qualitative interviews with 21 college men who were diagnosed or self-identified as depressed. Constant comparison was used to inductively derive gendered understandings about participants' depression-related help seeking. RESULTS: Three themes were identified: (1) denying weakness; (2) limiting self-disclosure and mustering autonomy; and (3) redefining strength. CONCLUSION: The findings demonstrate connections between masculinities and help seeking that can assist health care providers to understand the practices of college men who experience depression. PMID- 24784167 TI - Hypertension detection, management, control and associated factors among residents accessing community health services in Beijing. AB - The aim of this study was to analyse high blood pressure detection, management, control and associated factors among residents accessing community health services (CHSs) in Beijing. We screened for HBP in 9524 individuals aged 50 years or older who accessed care in four Beijing CHSs. Among the 9397 residents with questionnaire responses that qualified them for inclusion in the study, 5029 patients with HBP were identified, 1510 (i.e., 30% of the HBP patient group) of whom were newly identified cases. The rate of hypertension detection was 53.5%. Among the 5029 HBP patients, the rates of awareness, treatment and control of hypertension were 70.0%, 62.1% and 29.6%, respectively. In general, the rate of hypertension control was higher when the rates of hypertension awareness and treatment were higher in subgroups stratified by different sociodemographic and risk factors, except for the overweight and obesity subgroups. In conclusion, suboptimal HBP awareness, treatment, and control are still major problems confronting CHSs in Beijing. Control of hypertension in the population may be improved by increasing awareness and improving the treatment of hypertension in CHSs. PMID- 24784168 TI - In vitro metabolic formation of perfluoroalkyl sulfonamides from copolymer surfactants of pre- and post-2002 scotchgard fabric protector products. AB - Currently there is a scientific debate on whether fluorinated polymers (or copolymers) are a source, as a result of their degradation and subsequent formation, of perfluorinated carboxylic acids (PFCAs) and perfluorinated alkanesulfonates (PFSAs). The present study investigated whether commercially available fluorinated surfactants, such as Scotchgard fabric protector (3M Company), can be metabolically degraded, using a model microsomal in vitro assay (Wistar-Han rats liver microsomes), and with concomitant formation of PFCAs, PFASs, and/or their precursors. The results showed that the main in vitro metabolite from the pre-2002 product was perfluorooctane sulfonamide (FOSA), and coincident with the detection of the major fabric protector components, which contains the N-ethyl-perfluorooctanesulfonyl chemical moiety (C8F17SO2N(C2H5)-); the main in vitro metabolite of the post-2002 product was perfluorobutane sulfonamide (FBSA), which was coincident with the detection of the major fabric protector components, and contains the N-methyl-perfluorobutanesulfonyl chemical moiety (C4F9SO2N(CH3)-). FOSA or FBSA metabolite concentrations increased over the 0-60 min microsomal incubation period. However, concentrations of their small molecule precursors such as alkylated FOSAs or FBSAs were not detectable (10(6). Films with an aspect ratio of 10(5) can bear loads up to 10(6) times the mass of the film itself. The presence of the adsorbed layer can be observed using X-ray photoelectron spectroscopy, and this layer is persistent through multiple uses. In the system studied, elimination of sacrificial materials leads to an enhancement in the failure strength of the free-standing thin film. The robustness, persistence, and the self-optimizing nature distinguish this method from various fabrication methods utilizing sacrificial materials and make it a potentially scalable process for the fabrication of ultrathin free-standing or transferrable films for filtration, MEMS, or tissue engineering applications. PMID- 24784174 TI - Asynchronous virtual visits for the follow-up of chronic conditions. AB - BACKGROUND: Both primary care and specialty care in many areas face access constraints. Tools to evaluate and engage patients with chronic disease, without having them present to the clinic, are needed. Asynchronous virtual care has been explored as one of the ways to deliver care more efficiently, yet this has not been integrated into a busy practice environment. This pilot study aims to assess the utility of a Web platform that allows patients with chronic disease to be evaluated for follow-up care, thereby avoiding an office visit. MATERIALS AND METHODS: Patients with 10 common chronic conditions were recruited into the study at a busy primary care clinic. Instead of booking an in-office follow-up visit, they were directed online to complete a questionnaire pertaining to their condition 7-28 days after their office visit. Their physician would review their responses and make treatment decisions, informing the patient online. Patient and physician satisfaction was measured using a validated Likert scale after each visit. RESULTS: Patients were satisfied with the Web site and process as a way to receive their follow-up care. Clinicians were satisfied in making clinical decisions with the information received via the Web site. The clinician time spent for the overall encounter was significantly shorter than for an in-person follow-up visit. CONCLUSIONS: Clinicians and patients are interested in tools that improve patient health, are convenient, and save time for both parties. Targeting patients with chronic illness and leveraging available technology to deliver the care are very satisfactory to both clinicians and patients. Asynchronous virtual visits for patients with chronic medical conditions are an effective way to evaluate and manage patients, while providing physicians significant time savings. These visits have the potential to reduce in-office follow-up visits across primary care, potentially improving access and reducing costs. PMID- 24784175 TI - Effects of zinc-methionine on growth performance, intestinal flora and immune function in pigeon squabs. AB - 1. Different concentrations of zinc-methionine (Zn-Met) were given to pigeon squabs, and the resulting effects on growth, immune functions and intestinal microflora were investigated from hatching to 28 d of age. A total of 180 artificially hatched pigeon squabs were randomly allotted to each of three treatments with three replicates of 20 squabs. The three treatments given were either one ml (2 mg/ml) Zn-Met, one ml (10 mg/ml) Zn-Met or one ml 0.9% NaCl solution. 2. The results showed that Zn-Met improved the growth performance of squabs. The average daily and average weekly weight gain was significantly greater in squabs treated with Zn-Met than in the control group. 3. The group given 2 and 10 mg supplemental Zn-Met had heavier thymus, spleen and bursa of Fabricius than the control group at d 28. 4. Maternal antibody titres against Newcastle disease haemagglutination inhibition and alpha-naphthyl acetate esterase were significantly higher in squabs treated with supplemental 2 and 10 mg Zn-Met compared to the control group at d 14 and d 28. 5. Additionally, the squabs given supplemental 2 mg Zn-Met exhibited significantly higher Bacillaceae, Lactobacillus, Enterococcus and Bifidobacterium populations at d 14 and d 28, but lower Escherichia coli populations at d 28 compared to the control group. On the contrary, Lactobacillus, Enterococcus and Bifidobacterium populations were significantly decreased with 10 mg Zn-Met at d 28. 6. This study indicates that supplementation with Zn-Met has a positive effect on growth performance, immune function and regulation of intestinal flora in pigeons. An inclusion level of 2 mg seems to be better than 10 mg Zn-Met per day per bird. PMID- 24784176 TI - Shared burden: public health impact of nine environmental pollutants in Europe. PMID- 24784177 TI - Role of prokaryotic type I and III pantothenate kinases in the coenzyme A biosynthetic pathway of Bacillus subtilis. AB - Pantothenate kinases (CoaAs) catalyze the phosphorylation of pantothenate in the first step of the coenzyme A (CoA) biosynthetic pathway. These bacterial enzymes have been categorized into 3 types, the prokaryotic type I, II, and III CoaAs. Bacteria typically carry a single CoaA gene on their genome, but Bacillus subtilis possesses 2 proteins homologous to type I and III CoaAs, known as BsCoaA and BsCoaX, respectively. Both recombinant proteins exhibited the expected kinase activity and the characteristic properties of type I and III CoaAs, i.e., regulation by CoASH and acyl-CoAs in BsCoaA and the requirement of a monovalent cation in BsCoaX. Both gene disruptants appeared to grow in a manner similar to the wild-type strain. With the BsCoaX disruptant, the BsCoaA had the ability to completely fill the intracellular CoA pool, whereas the BsCoaA disruptant did not. These findings clearly indicate that these 2 CoaAs are employed together in the CoA biosynthetic pathway in B. subtilis and that the contribution of the type I CoaA (BsCoaA) to the formation of the intracellular CoA pool is larger than that of the type III CoaA (BsCoaX). PMID- 24784178 TI - False positives. PMID- 24784179 TI - No magic fix for carbon. PMID- 24784180 TI - Agency for change. PMID- 24784181 TI - The moral problem with commercial seal hunting. PMID- 24784193 TI - Doubts over heart stem-cell therapy. PMID- 24784194 TI - US biodefence facilities ramp up. PMID- 24784195 TI - Basic science finds corporate refuge. PMID- 24784197 TI - Two plants to put 'clean coal' to test. PMID- 24784198 TI - Infectious diseases: Smallpox watch. PMID- 24784199 TI - Agriculture: Engage farmers in research. PMID- 24784200 TI - Policy: Regulate embryos made for research. PMID- 24784204 TI - Politics: Scottish separation could harm science. PMID- 24784206 TI - Conservation: Former Iron Curtain safeguards wildlife. PMID- 24784207 TI - Publishing: Rise in retractions is a signal of integrity. PMID- 24784208 TI - Open access: Practical costs of data sharing. PMID- 24784209 TI - History: Two brains and a forgotten theory. PMID- 24784210 TI - Applied physics: Bright electron twisters. PMID- 24784211 TI - Neuroscience: Feedback throttled down for smooth moves. PMID- 24784212 TI - Geophysics: Making the Earth move. PMID- 24784213 TI - Astronomy: A new spin on exoplanets. PMID- 24784215 TI - Presynaptic inhibition of spinal sensory feedback ensures smooth movement. AB - The precision of skilled movement depends on sensory feedback and its refinement by local inhibitory microcircuits. One specialized set of spinal GABAergic interneurons forms axo-axonic contacts with the central terminals of sensory afferents, exerting presynaptic inhibitory control over sensory-motor transmission. The inability to achieve selective access to the GABAergic neurons responsible for this unorthodox inhibitory mechanism has left unresolved the contribution of presynaptic inhibition to motor behaviour. We used Gad2 as a genetic entry point to manipulate the interneurons that contact sensory terminals, and show that activation of these interneurons in mice elicits the defining physiological characteristics of presynaptic inhibition. Selective genetic ablation of Gad2-expressing interneurons severely perturbs goal-directed reaching movements, uncovering a pronounced and stereotypic forelimb motor oscillation, the core features of which are captured by modelling the consequences of sensory feedback at high gain. Our findings define the neural substrate of a genetically hardwired gain control system crucial for the smooth execution of movement. PMID- 24784216 TI - Fast spin of the young extrasolar planet beta Pictoris b. AB - The spin of a planet arises from the accretion of angular momentum during its formation, but the details of this process are still unclear. In the Solar System, the equatorial rotation velocities and, consequently, spin angular momenta of most of the planets increase with planetary mass; the exceptions to this trend are Mercury and Venus, which, since formation, have significantly spun down because of tidal interactions. Here we report near-infrared spectroscopic observations, at a resolving power of 100,000, of the young extrasolar gas giant planet beta Pictoris b (refs 7, 8). The absorption signal from carbon monoxide in the planet's thermal spectrum is found to be blueshifted with respect to that from the parent star by approximately 15 kilometres per second, consistent with a circular orbit. The combined line profile exhibits a rotational broadening of about 25 kilometres per second, meaning that beta Pictoris b spins significantly faster than any planet in the Solar System, in line with the extrapolation of the known trend in spin velocity with planet mass. PMID- 24784217 TI - Molecular photons interfaced with alkali atoms. AB - Future quantum communication will rely on the integration of single-photon sources, quantum memories and systems with strong single-photon nonlinearities. Two key parameters are crucial for the single-photon source: a high photon flux with a very small bandwidth, and a spectral match to other components of the system. Atoms or ions may act as single-photon sources--owing to their narrowband emission and their intrinsic spectral match to other atomic systems--and can serve as quantum nonlinear elements. Unfortunately, their emission rates are still limited, even for highly efficient cavity designs. Single solid-state emitters such as single organic dye molecules are significantly brighter and allow for narrowband photons; they have shown potential in a variety of quantum optical experiments but have yet to be interfaced with other components such as stationary memory qubits. Here we describe the optical interaction between Fourier-limited photons from a single organic molecule and atomic alkali vapours, which can constitute an efficient quantum memory. Single-photon emission rates reach up to several hundred thousand counts per second and show a high spectral brightness of 30,000 detectable photons per second per megahertz of bandwidth. The molecular emission is robust and we demonstrate perfect tuning to the spectral transitions of the sodium D line and efficient filtering, even for emitters at ambient conditions. In addition, we achieve storage of molecular photons originating from a single dibenzanthanthrene molecule in atomic sodium vapour. Given the large set of molecular emission lines matching to atomic transitions, our results enable the combination of almost ideal single-photon sources with various atomic vapours, such that experiments with giant single photon nonlinearities, mediated, for example, by Rydberg atoms, become feasible. PMID- 24784218 TI - North Atlantic forcing of tropical Indian Ocean climate. AB - The response of the tropical climate in the Indian Ocean realm to abrupt climate change events in the North Atlantic Ocean is contentious. Repositioning of the intertropical convergence zone is thought to have been responsible for changes in tropical hydroclimate during North Atlantic cold spells, but the dearth of high resolution records outside the monsoon realm in the Indian Ocean precludes a full understanding of this remote relationship and its underlying mechanisms. Here we show that slowdowns of the Atlantic meridional overturning circulation during Heinrich stadials and the Younger Dryas stadial affected the tropical Indian Ocean hydroclimate through changes to the Hadley circulation including a southward shift in the rising branch (the intertropical convergence zone) and an overall weakening over the southern Indian Ocean. Our results are based on new, high-resolution sea surface temperature and seawater oxygen isotope records of well-dated sedimentary archives from the tropical eastern Indian Ocean for the past 45,000 years, combined with climate model simulations of Atlantic circulation slowdown under Marine Isotope Stages 2 and 3 boundary conditions. Similar conditions in the east and west of the basin rule out a zonal dipole structure as the dominant forcing of the tropical Indian Ocean hydroclimate of millennial-scale events. Results from our simulations and proxy data suggest dry conditions in the northern Indian Ocean realm and wet and warm conditions in the southern realm during North Atlantic cold spells. PMID- 24784219 TI - Electrical conductivity during incipient melting in the oceanic low-velocity zone. AB - The low-viscosity layer in the upper mantle, the asthenosphere, is a requirement for plate tectonics. The seismic low velocities and the high electrical conductivities of the asthenosphere are attributed either to subsolidus, water related defects in olivine minerals or to a few volume per cent of partial melt, but these two interpretations have two shortcomings. First, the amount of water stored in olivine is not expected to be higher than 50 parts per million owing to partitioning with other mantle phases (including pargasite amphibole at moderate temperatures) and partial melting at high temperatures. Second, elevated melt volume fractions are impeded by the temperatures prevailing in the asthenosphere, which are too low, and by the melt mobility, which is high and can lead to gravitational segregation. Here we determine the electrical conductivity of carbon-dioxide-rich and water-rich melts, typically produced at the onset of mantle melting. Electrical conductivity increases modestly with moderate amounts of water and carbon dioxide, but it increases drastically once the carbon dioxide content exceeds six weight per cent in the melt. Incipient melts, long-expected to prevail in the asthenosphere, can therefore produce high electrical conductivities there. Taking into account variable degrees of depletion of the mantle in water and carbon dioxide, and their effect on the petrology of incipient melting, we calculated conductivity profiles across the asthenosphere for various tectonic plate ages. Several electrical discontinuities are predicted and match geophysical observations in a consistent petrological and geochemical framework. In moderately aged plates (more than five million years old), incipient melts probably trigger both the seismic low velocities and the high electrical conductivities in the upper part of the asthenosphere, whereas in young plates, where seamount volcanism occurs, a higher degree of melting is expected. PMID- 24784222 TI - Synthesis and biological evaluation of antimetastatic agents predicated upon dihydromotuporamine C and its carbocyclic derivatives. AB - The motuporamines isolated from the sea sponge Xestospongia exigua are of biological interest because of their unique antimigration and antiangiogenic properties. Key bioactive features were found to be a saturated 15-membered heterocycle and a norspermidine motif. This paper describes new analogues that modulate the cytotoxicity of this compound class and have enhanced antimigration properties. By movement of the polyamine chain outside the ring, new carbocycles were discovered that doubled the antimigration potency and reduced compound toxicity by 133-fold. Mice injected with metastatic human L3.6pl pancreatic cancer cells demonstrated significant reduction in liver metastases when treated with N(1)-(3-aminopropyl)-N(3)-(cyclopentadecylmethyl)propane-1,3-diamine compared with dihydromotuporamine C. Significant changes in specific ceramide populations (N16:0 and N22:1) were noted in L3.6pl cells treated with dihydromotuporamine C but not for the cyclopentadecylmethylnorspermidine derivative, which had lower toxicity. Both compounds gave increased levels of specific low molecular weight sphingomyelins, suggesting that they may act upon sphingomyelin processing enzymes. PMID- 24784220 TI - Agonist-bound structure of the human P2Y12 receptor. AB - The P2Y12 receptor (P2Y12R), one of eight members of the P2YR family expressed in humans, is one of the most prominent clinical drug targets for inhibition of platelet aggregation. Although mutagenesis and modelling studies of the P2Y12R provided useful insights into ligand binding, the agonist and antagonist recognition and function at the P2Y12R remain poorly understood at the molecular level. Here we report the structures of the human P2Y12R in complex with the full agonist 2-methylthio-adenosine-5'-diphosphate (2MeSADP, a close analogue of endogenous agonist ADP) at 2.5 A resolution, and the corresponding ATP derivative 2-methylthio-adenosine-5'-triphosphate (2MeSATP) at 3.1 A resolution. These structures, together with the structure of the P2Y12R with antagonist ethyl 6-(4 ((benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283), reveal striking conformational changes between nucleotide and non-nucleotide ligand complexes in the extracellular regions. Further analysis of these changes provides insight into a distinct ligand binding landscape in the delta-group of class A G-protein-coupled receptors (GPCRs). Agonist and non-nucleotide antagonist adopt different orientations in the P2Y12R, with only partially overlapped binding pockets. The agonist-bound P2Y12R structure answers long standing questions surrounding P2Y12R-agonist recognition, and reveals interactions with several residues that had not been reported to be involved in agonist binding. As a first example, to our knowledge, of a GPCR in which agonist access to the binding pocket requires large-scale rearrangements in the highly malleable extracellular region, the structural and docking studies will therefore provide invaluable insight into the pharmacology and mechanisms of action of agonists and different classes of antagonists for the P2Y12R and potentially for other closely related P2YRs. PMID- 24784223 TI - Amyloid fibril nucleation: effect of amino acid hydrophobicity. AB - We consider the nucleation of amyloid fibrils when the process occurs by direct polymerization of fully extended peptides (i.e., beta-strands) into fibrils composed of successively layered beta-sheets with alternating weak and strong hydrophobic surfaces. We extend our recently developed nucleation model (Kashchiev, D.; Cabriolu, R.; Auer, S. J. Am. Chem. Soc. 2013, 135, 1531-1539) to derive general expressions for the work to form such fibrils, the fibril solubility, the nucleation work, the equilibrium concentration of nuclei, and the fibril nucleation rate as explicit functions of the supersaturation of the protein solution. Analysis of these expressions illustrates the effect of increased asymmetry between the weak and strong hydrophobic beta-sheet surfaces on the thermodynamics and kinetics of the polymerization process. In particular, the application of our theoretical framework to a simple model peptide system shows that lowering the hydrophobicity of one beta-sheet surface can hamper protein fibrillation because the threshold concentration below which the fibril nucleation is practically arrested, and above which the process occurs vigorously -because then each monomer in the solution acts as a fibril nucleus--is shifted to higher concentrations. This effect is entirely due to the effect of asymmetry of the two hydrophobic beta-sheet surfaces on the fibril solubility. In addition, with increasing asymmetry, the nucleation rate of one fibril polymorph becomes increasingly dominant, illustrating that there is a morphological selection between the two possible polymorphs. PMID- 24784224 TI - 'Triply cursed': racism, homophobia and HIV-related stigma are barriers to regular HIV testing, treatment adherence and disclosure among young Black gay men. AB - In the USA, young Black gay men are disproportionately impacted upon by HIV. In this qualitative study consisting of in-depth interviews with 31 young Black gay men and nine service providers, where we used thematic analysis to guide our interpretations, we found that HIV-related stigma and homophobia, within the larger societal context of racism, were related to sexual risk behaviour, reluctance to obtain HIV testing or care, lower adherence to treatment medication, and non-disclosure of a positive HIV status to sexual partners. Participants experienced homophobia and HIV-related stigma from churches and families within the Black community and from friends within the Black gay community, which otherwise provide support in the face of racism. Vulnerability to HIV was related to strategies that young Black gay men enacted to avoid being stigmatised or as a way of coping with alienation and rejection. PMID- 24784225 TI - Age-based mating success in the codling moth, Cydia pomonella, and the obliquebanded leafroller, Choristoneura rosaceana. AB - In this study, the passage of spermatophores was examined between 1-day-old males mated in no-choice situations with females 0, 2, 4, or 6 days old and the converse for both the codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae), and the obliquebanded leafroller, Choristoneura rosaceana (Harris). For C. pomonella, female age had no effect on the passage of spermatophores from males, and only 6-day-old female C. rosaceana had reduced spermatophore number. The ages of moths at the time of mating had a greater effect on males, with C. pomonella males older than 2 days showing significant reductions in the ability to successfully pass a spermatophore to 1-day-old females. For C. rosaceana, 2- and 6-day-old males were significantly less likely to pass a spermatophore, but reduced transfer from 4-day-old males did not reach statistical significance. Wind-tunnel assays were used to evaluate the ability of 1- or 4-day-old males to fly upwind and successfully contact a young calling female. Four-day-old males were more likely to initiate flight upwind, but were less efficient at finding and contacting the females than younger males. This study suggests that evaluation of multiple components of the mating process are required to understand the effect of age at the time of mating on population dynamics of these moths. PMID- 24784226 TI - Laparoscopic extended right hepatectomy, portal lymphadenectomy, and hepaticojejunostomy for hilar cholangiocarcinoma. AB - BACKGROUND: Laparoscopic-assisted extended hepatectomy and laparoscopic hepaticojejunostomy reconstruction can be performed for hilar cholangiocarcinoma by combining our existing protocols for laparoscopic anatomic hepatectomy and laparoscopic hand-sewn bilio-enteric anastomosis. SUBJECTS AND METHODS: Our first patient was a 42-year-old man with cholangitis and jaundice from tumor obstructing the hepatic duct bifurcation who underwent a right extended hepatectomy for hilar cholangiocarcinoma (Bismuth IIIa), radical portal lymphadenectomy, and Roux-en-Y hepaticojejunostomy using laparoscopic techniques. A four-trocar, one 6-cm wound protector laparoscopic technique was used. Inflow and outflow exclusion was achieved first, followed by liver transection. Radical portal lymphadenectomy was performed. A Roux-en-Y hepaticojejunostomy was constructed laparoscopically. We have performed three other cases using the same technique: two requiring right extended hepatectomy and one requiring left extended hepatectomy. RESULTS: No intraoperative complications occurred during the 4.0-hour procedure. Tumor margins were clear. The patient was given oral diet on Day 1 and discharged on Day 3 after surgery. No blood transfusions were necessary. A cholangiogram performed 10 days after surgery demonstrated patent hepaticojejunostomy, and magnetic resonance imaging performed during week 3 demonstrated the normal caliber of the intrahepatic biliary system. At 6 months, the patient was completely without symptoms and exhibited normal liver function tests. CONCLUSIONS: Laparoscopic-assisted right extended hepatectomy for hilar cholangiocarcinoma with laparoscopically hand-sewn hepaticojejunostomy in select patients can be achieved with good outcomes. PMID- 24784227 TI - UV-induced selective oxidation of Met5 to Met-sulfoxide leads to the formation of neurotoxic fibril-incompetent alpha-synuclein oligomers. AB - Oxidative stress and the formation of cytotoxic aggregates of the presynaptic protein alpha-synuclein (AS) are two important events associated with the pathogenesis of Parkinson's disease (PD) and several other neurodegenerative diseases. In this context, extensive efforts have been made to elucidate the molecular basis of the cytotoxic synergy between oxidative stress and AS aggregation. In this study, we demonstrate that the exposure of AS to oxidative stress induced by UV radiation (ASUV) blocks the protein fibrillation, leading to the formation of highly toxic fibril-incompetent oligomers. In addition, ASUV exhibited stronger anti-fibrillogenic properties than H2O2-treated AS, inhibiting the fibrillation of unmodified AS at notably low concentrations. Mass spectrometry indicated that Met5 oxidation to Met-sulfoxide was the only modification promoted by UV exposure, which is reinforced by NMR data indicating that Met5 is the only residue whose amide resonance completely disappeared from the (1)H-(15)N HSQC spectrum after UV exposure. This result is supported by previous data that indicate that C-terminal Met residues (Met116 and Met127) and N-terminal Met1 are less susceptible to oxidation than Met5 because of the residual structure of the disordered AS monomer. Overall, our findings suggest that specific oxidation of Met5 might be sufficient to promote the formation of highly neurotoxic oligomers of AS. PMID- 24784228 TI - New potassium-sodium niobate ceramics with a giant d33. AB - For potassium-sodium niobate, poor piezoelectric properties always perplex most researchers, and then it becomes important to attain a giant piezoelectricity. Here we reported a giant piezoelectric constant in (1 x)(K0.48Na0.52)(Nb0.95Sb0.05)O3-xBi0.5Ag0.5ZrO3 lead-free ceramics. The rhombohedral-tetragonal phase boundary was shown in the ceramics with 0.0470% of total population in the lowest rotational level at 300 K and over 99% at 77 K. In principle, the multiple Q-branch lines could be pumped with just two broad-band (~Deltanu = 0.4-3 cm(-1)) infrared lasers. PMID- 24784278 TI - Theoretical calculations and vibrational potential energy surface of 4 silaspiro(3,3)heptane. AB - Theoretical computations have been carried out on 4-silaspiro(3,3)heptane (SSH) in order to calculate its molecular structure and conformational energies. The molecule has two puckered four-membered rings with dihedral angles of 34.2 degrees and a tilt angle of 9.4 degrees between the two rings. Energy calculations were carried out for different conformations of SSH. These results allowed the generation of a two-dimensional ring-puckering potential energy surface (PES) of the form V = a(x1 (4) + x2 (4)) - b(x1 (2) + x2 (2)) + cx1 (2)x2 (2), where x1 and x2 are the ring-puckering coordinates for the two rings. The presence of sufficiently high potential energy barriers prevents the molecule from undergoing pseudorotation. The quantum states, wave functions, and predicted spectra resulting from the PESs were calculated. PMID- 24784279 TI - The PtAl(-) and PtAl2(-) anions: theoretical and photoelectron spectroscopic characterization. AB - We report a joint photoelectron spectroscopic and theoretical study of the PtAl( ) and PtAl2(-) anions. The ground state structures and electronic configurations of these species were identified to be Cinfinityv, (1)Sigma(+) for PtAl(-), and C2v, (2)B1 for PtAl2(-). Structured anion photoelectron spectra of these clusters were recorded and interpreted using ab initio calculations. Good agreement between theory and experiment was found. All experimental features were successfully assigned to one-electron transitions from the ground state of the anions to the ground or excited states of the corresponding neutral species. PMID- 24784280 TI - Photoelectron spectroscopy of boron aluminum hydride cluster anions. AB - Boron aluminum hydride clusters are studied through a synergetic combination of anion photoelectron spectroscopy and density functional theory based calculations. Boron aluminum hydride cluster anions, BxAlyHz(-), were generated in a pulsed arc cluster ionization source and identified by time-of-flight mass spectrometry. After mass selection, their photoelectron spectra were measured by a magnetic bottle-type electron energy analyzer. The resultant photoelectron spectra as well as calculations on a selected series of stoichiometries reveal significant geometrical changes upon substitution of aluminum atoms by boron atoms. PMID- 24784281 TI - Onset of simple liquid behaviour in modified water models. AB - The transition to simple liquid behaviour is studied in a set of modified hybrid water models where the potential energy contribution of the Lennard-Jones dispersion-repulsion contribution is progressively enhanced relative to the electrostatic contribution. Characteristics of simple liquid behaviour that indicate the extent to which a given system can be mapped onto an inverse power law fluid are examined, including configurational energy-virial correlations, functional form of temperature dependence of the excess entropy along isochores, and thermodynamic and excess entropy scaling of diffusivities. As the Lennard Jones contribution to the potential energy function increases, the strength of the configurational energy-virial correlations increases. The Rosenfeld-Tarazona temperature dependence of the excess entropy is found to hold for the range of state points studied here for all the hybrid models, regardless of the degree of correlating character. Thermodynamic scaling is found to hold for weakly polar fluids with a moderate degree of energy-virial correlations. Rosenfeld-scaling of transport properties is found not to be necessarily linked with the strength of energy-virial correlations but may hold for systems with poor thermodynamic scaling if diffusivities and excess entropies show correlated departures from the isomorph-invariant behaviour characteristic of approximate inverse power law fluids. The state-point dependence of the configurational energy-virial correlation coefficient and the implications for thermodynamic and excess entropy scalings are considered. PMID- 24784282 TI - Intermittent dynamics and logarithmic domain growth during the spinodal decomposition of a glass-forming liquid. AB - We use large-scale molecular dynamics simulations of a simple glass-forming system to investigate how its liquid-gas phase separation kinetics depends on temperature. A shallow quench leads to a fully demixed liquid-gas system whereas a deep quench makes the dense phase undergo a glass transition and become an amorphous solid. This glass has a gel-like bicontinuous structure that evolves very slowly with time and becomes fully arrested in the limit where thermal fluctuations become negligible. We show that the phase separation kinetics changes qualitatively with temperature, the microscopic dynamics evolving from a surface tension-driven diffusive motion at high temperature to a strongly intermittent, heterogeneous, and thermally activated dynamics at low temperature, with a logarithmically slow growth of the typical domain size. These results elucidate the microscopic mechanisms underlying a specific class of viscoelastic phase separation. PMID- 24784283 TI - Correlation between thermodynamic anomalies and pathways of ice nucleation in supercooled water. AB - The well-known classical nucleation theory (CNT) for the free energy barrier towards formation of a nucleus of critical size of the new stable phase within the parent metastable phase fails to take into account the influence of other metastable phases having density/order intermediate between the parent metastable phase and the final stable phase. This lacuna can be more serious than capillary approximation or spherical shape assumption made in CNT. This issue is particularly significant in ice nucleation because liquid water shows rich phase diagram consisting of two (high and low density) liquid phases in supercooled state. The explanations of thermodynamic and dynamic anomalies of supercooled water often invoke the possible influence of a liquid-liquid transition between two metastable liquid phases. To investigate both the role of thermodynamic anomalies and presence of distinct metastable liquid phases in supercooled water on ice nucleation, we employ density functional theoretical approach to find nucleation free energy barrier in different regions of phase diagram. The theory makes a number of striking predictions, such as a dramatic lowering of nucleation barrier due to presence of a metastable intermediate phase and crossover in the dependence of free energy barrier on temperature near liquid-liquid critical point. These predictions can be tested by computer simulations as well as by controlled experiments. PMID- 24784284 TI - Inelastic incoherent neutron scattering study of the molecular properties of pure hydrogen peroxide and its water mixtures of different concentration. AB - We have investigated the spectra of shock-frozen H2O2-H2O mixtures across the full composition range 99.1%-0.0% H2O2. In contrast to literature reports, we find that intermediate compositions (30%-70% H2O2) freeze to a solid solution rather than phase separating, which only occurs on annealing to just below the melting point. We have fully characterised the dihydrate H2O2.2H2O (48.6% H2O2) for the first time and shown that its spectrum can account for the features previously observed on the surface of a Au/TiO2 catalyst. PMID- 24784285 TI - Catalytic activity of methanol in all-vapor subsecond clathrate-hydrate formation. AB - Methanol's property as a catalyst in the formation of gas clathrate hydrates has been recognized for several years and was recently employed in a broad ranging study [K. Shin, K. A. Udachin, I. L. Moudrakovski, D. M. Leek, S. Alavi, C. I. Ratcliffe, and J. A. Ripmeester, Proc. Natl. Acad. Sci. U.S.A. 110, 8437 (2013)]. A new measure of that activity is offered here from comparative rates of formation of methanol (MeOH) clathrate hydrates within our all-vapor aerosol methodology for which tetrahydrofuran (THF) and other small ethers have set a standard for catalytic action. We have previously described numerous examples of the complete conversion of warm all-vapor mixtures to aerosols of gas clathrate hydrates on a sub-second time scale, generally with the catalyst confined primarily to the large cage of either structure-I (s-I) or structure-II (s-II) hydrates. THF has proven to be the most versatile catalyst for the complete subsecond conversion of water to s-II hydrate nanocrystals that follows pulsing of appropriate warm vapor mixtures into a cold chamber held in the 140-220 K range. Here, the comparative ability of MeOH to catalyze the formation of s-I hydrates in the presence of a small-cage help-gas, CO2 or acetylene, is examined. The surprising result is that, in the presence of either help gas, CH-formation rates appear largely unchanged by a complete replacement of THF by MeOH in the vapor mixtures for a chamber temperature of 170 K. However, as that temperature is increased, the dependence of effective catalysis by MeOH on the partial pressure of help gases also increases. Nevertheless, added MeOH is shown to markedly accelerate the s-II THF-CO2 CH formation rate at 220 K. PMID- 24784286 TI - Two-component order parameter for quantifying clathrate hydrate nucleation and growth. AB - Methane clathrate hydrate nucleation and growth is investigated via analysis of molecular dynamics simulations using a new order parameter. This order parameter (OP), named the Mutually Coordinated Guest (MCG) OP, quantifies the appearance and connectivity of molecular clusters composed of guests separated by water clusters. It is the first two-component OP used for quantifying hydrate nucleation and growth. The algorithm for calculating the MCG OP is described in detail. Its physical motivation and advantages compared to existing methods are discussed. PMID- 24784287 TI - Channel flow of a tensorial shear-thinning Maxwell model: Lattice Boltzmann simulations. AB - We discuss pressure-driven channel flow for a model of shear-thinning glass forming fluids, employing a modified lattice-Boltzmann (LB) simulation scheme. The model is motivated by a recent microscopic approach to the nonlinear rheology of colloidal suspensions and captures a nonvanishing dynamical yield stress and the appearance of normal-stress differences and a flow-induced pressure contribution. The standard LB algorithm is extended to deal with tensorial, nonlinear constitutive equations of this class. The new LB scheme is tested in 2D pressure-driven channel flow and reproduces the analytical steady-state solution. The transient dynamics after startup and removal of the pressure gradient reproduce a finite stopping time for the cessation flow of yield-stress fluids in agreement with previous analytical estimates. PMID- 24784288 TI - Thermal equation of state of solid naphthalene to 13 GPa and 773 K: in situ X-ray diffraction study and first principles calculations. AB - In a wide range of P-T conditions, such fundamental characteristics as compressibility and thermoelastic properties remain unknown for most classes of organic compounds. Here we attempt to clarify this issue by the example of naphthalene as a model representative of polycyclic aromatic hydrocarbons (PAHs). The elastic behavior of solid naphthalene was studied by in situ synchrotron powder X-ray diffraction up to 13 GPa and 773 K and first principles computations to 20 GPa and 773 K. Fitting of the P-V experimental data to Vinet equation of state yielded T 0 = 8.4(3) GPa and T' = 7.2 (3) at V0 = 361 A(3), whereas the thermal expansion coefficient was found to be extremely low at P > 3 GPa (about 10(-5) K(-1)), in agreement with theoretical estimation. Such a diminishing of thermal effects with the pressure increase clearly demonstrates a specific feature of the high-pressure behavior of molecular crystals like PAHs, associated with a low energy of intermolecular interactions. PMID- 24784289 TI - The Raman spectrum of CaCO3 polymorphs calcite and aragonite: a combined experimental and computational study. AB - Powder and single crystal Raman spectra of the two most common phases of calcium carbonate are calculated with ab initio techniques (using a "hybrid" functional and a Gaussian-type basis set) and measured both at 80 K and room temperature. Frequencies of the Raman modes are in very good agreement between calculations and experiments: the mean absolute deviation at 80 K is 4 and 8 cm(-1) for calcite and aragonite, respectively. As regards intensities, the agreement is in general good, although the computed values overestimate the measured ones in many cases. The combined analysis permits to identify almost all the fundamental experimental Raman peaks of the two compounds, with the exception of either modes with zero computed intensity or modes overlapping with more intense peaks. Additional peaks have been identified in both calcite and aragonite, which have been assigned to (18)O satellite modes or overtones. The agreement between the computed and measured spectra is quite satisfactory; in particular, simulation permits to clearly distinguish between calcite and aragonite in the case of powder spectra, and among different polarization directions of each compound in the case of single crystal spectra. PMID- 24784290 TI - Quadrupole terms in the Maxwell equations: Debye-Huckel theory in quadrupolarizable solvent and self-salting-out of electrolytes. AB - If the molecules of a given solvent possess significant quadrupolar moment, the macroscopic Maxwell equations must involve the contribution of the density of the quadrupolar moment to the electric displacement field. This modifies the Poisson Boltzmann equation and all consequences from it. In this work, the structure of the diffuse atmosphere around an ion dissolved in quadrupolarizable medium is analyzed by solving the quadrupolar variant of the Coulomb-Ampere's law of electrostatics. The results are compared to the classical Debye-Huckel theory. The quadrupolar version of the Debye-Huckel potential of a point charge is finite even in r = 0. The ion-quadrupole interaction yields a significant expansion of the diffuse atmosphere of the ion and, thus, it decreases the Debye-Huckel energy. In addition, since the dielectric permittivity of the electrolyte solutions depends strongly on concentration, the Born energy of the dissolved ions alters with concentration, which has a considerable contribution to the activity coefficient gamma+/- known as the self-salting-out effect. The quadrupolarizability of the medium damps strongly the self-salting-out of the electrolyte, and thus it affects additionally gamma+/-. Comparison with experimental data for gamma+/- for various electrolytes allows for the estimation of the quadrupolar length of water: LQ ~ 2 A, in good agreement with previous assessments. The effect of quadrupolarizability is especially important in non aqueous solutions. Data for the activity of NaBr in methanol is used to determine the quadrupolarizability of methanol with good accuracy. PMID- 24784291 TI - Ab initio calculation of the electronic absorption spectrum of liquid water. AB - The electronic absorption spectrum of liquid water was investigated by coupling a one-body energy decomposition scheme to configurations generated by classical and Born-Oppenheimer Molecular Dynamics (BOMD). A Frenkel exciton Hamiltonian formalism was adopted and the excitation energies in the liquid phase were calculated with the equation of motion coupled cluster with single and double excitations method. Molecular dynamics configurations were generated by different approaches. Classical MD were carried out with the TIP4P-Ew and AMOEBA force fields. The BLYP and BLYP-D3 exchange-correlation functionals were used in BOMD. Theoretical and experimental results for the electronic absorption spectrum of liquid water are in good agreement. Emphasis is placed on the relationship between the structure of liquid water predicted by the different models and the electronic absorption spectrum. The theoretical gas to liquid phase blue-shift of the peak positions of the electronic absorption spectrum is in good agreement with experiment. The overall shift is determined by a competition between the O-H stretching of the water monomer in liquid water that leads to a red-shift and polarization effects that induce a blue-shift. The results illustrate the importance of coupling many-body energy decomposition schemes to molecular dynamics configurations to carry out ab initio calculations of the electronic properties in liquid phase. PMID- 24784292 TI - Probing the interplay between electrostatic and dispersion interactions in the solvation of nonpolar nonaromatic solute molecules in ionic liquids: an OKE spectroscopic study of CS2/[C(n)C(1)im][NTf(2)] mixtures (n = 1-4). AB - The intermolecular dynamics of dilute solutions of CS2 in 1-alkyl-3 methylimidazolium bis[(trifluoromethane)sulfonyl]amide ([CnC1im][NTf2] for n = 1 4) were studied at 295 K using femtosecond optical Kerr effect (OKE) spectroscopy. The OKE spectra of the CS2/ionic liquid (IL) mixtures were analyzed using an additivity model to obtain the CS2 contribution to the OKE spectrum from which information about the intermolecular modes of CS2 in these mixtures was gleaned. The intermolecular spectrum of CS2 in these mixtures is lower in frequency and narrower than that of neat CS2, as found previously for CS2 in [C5C1im][NTf2]. Moreover, a dependence of the spectra on alkyl chain length is observed that is attributed to the interplay between electrostatic and dispersion interactions. The surprising result in this study is the solubility of CS2 in [C1C1im][NTf2], which involves the interaction of a nonpolar nonaromatic molecular solute and only the charged groups of the IL. We propose that the solubility of CS2 in [C1C1im][NTf2] is determined by three favorable factors - (1) large polarizability of the solute molecule; (2) small size of the solute molecule; and (3) low cohesive energy in the high-charge density regions of the IL. PMID- 24784293 TI - Surface forces: surface roughness in theory and experiment. AB - A method of incorporating surface roughness into theoretical calculations of surface forces is presented. The model contains two chief elements. First, surface roughness is represented as a probability distribution of surface heights around an average surface height. A roughness-averaged force is determined by taking an average of the classic flat-surface force, weighing all possible separation distances against the probability distributions of surface heights. Second the model adds a repulsive contact force due to the elastic contact of asperities. We derive a simple analytic expression for the contact force. The general impact of roughness is to amplify the long range behaviour of noncontact (DLVO) forces. The impact of the elastic contact force is to provide a repulsive wall which is felt at a separation between surfaces that scales with the root mean-square (RMS) roughness of the surfaces. The model therefore provides a means of distinguishing between "true zero," where the separation between the average centres of each surface is zero, and "apparent zero," defined by the onset of the repulsive contact wall. A normal distribution may be assumed for the surface probability distribution, characterised by the RMS roughness measured by atomic force microscopy (AFM). Alternatively the probability distribution may be defined by the histogram of heights measured by AFM. Both methods of treating surface roughness are compared against the classic smooth surface calculation and experimental AFM measurement. PMID- 24784294 TI - Mechanism of oil detachment from hybrid hydrophobic and hydrophilic surface in aqueous solution. AB - In this paper, the detachment mechanism of alkane molecules from one hybrid hydrophobic and hydrophilic solid surface was studied by molecular dynamics simulation. First, some alkyl chains were linked through C-O bonds with silica surface to get one half-hydrophobic one, and the other half-hydrophilic area was still same as silica surface, thus one modified hybrid hydrophobic and hydrophilic silica surface was constructed. Second, some alkane molecules were adsorbed on the hybrid surface to get one whole hydrophobic oil layer, and the detachment mechanism of alkane molecules on the surface was discussed in aqueous solution using molecular dynamics. The simulated results showed that the key to the detachment of alkane molecules is the formation of water channel in oil layer between water phase and solid surface. In the detachment process, water molecules can penetrate oil layer to the silica surface through the strong H-bonding interaction among water molecules in water channel, and soon these molecules can form a gel layer along the silica surface by fast diffusion under the H-bonding interaction and electrostatic interaction between water molecules and silica surface. At last, the half-hydrophilic area on hybrid surface becomes hydrophilic again after the oil layer's detachment, and alkane molecules aggregate on the modified surface linked the alkyl chains. For the hybrid surface, some of alkane molecules insert into the interstice among the alkyl chains, and thus the oil drop cannot be dispatched thoroughly from the surface linked alkyl chains in aqueous solution. Our results showed that the detachment mechanism of oil from hybrid surface is different, compared with the whole pure hydrophilic surface. PMID- 24784295 TI - Negative differential resistance devices by using N-doped graphene nanoribbons. AB - Recently, extensive efforts have been devoted to the investigations of negative differential resistance (NDR) behavior in graphene. Here, by performing fully self-consistent density functional theory calculations combined with non equilibrium Green's function technique, we investigate the transport properties of three molecules from conjugated molecule, one-dimension alkane chain, and single molecule magnet, which are sandwiched between two N-doped zigzag and armchair graphene nanoribbons (GNRs). We observe robust NDR effect in all examined molecular junctions including benzene, alkane, and planar four coordinated Fe complex. Through the analyses of the calculated electronic structures and the bias-dependent transmission coefficients, we find that the narrow density of states of N-doped GNRs and the bias-dependent effective coupling between the discrete frontier molecular orbitals and the subbands of N doped GNRs are responsible for the observed NDR phenomenon. These theoretical findings imply that N-doped GNRs hold great potential for building NDR devices based on various molecules. PMID- 24784296 TI - Phase stability limit of c-BN under hydrostatic and non-hydrostatic pressure conditions. AB - Phase stability limit of cubic boron nitride (c-BN) has been investigated by the crystal structure search technique. It indicated that this limit is ~1000 GPa at hydrostatic pressure condition. Above this pressure, c-BN turns into a metastable phase with respect to rocksalt type boron nitride (rs-BN). However, rs-BN cannot be retained at 0 GPa owing to its instability at pressure below 250 GPa. For non hydrostatic pressure conditions, the phase stability limit of c-BN is substantially lower than that under hydrostatic pressure conditions and it is also dramatically different for other pressure mode. PMID- 24784297 TI - Do Ag(n) (up to n = 8) clusters retain their identity on graphite? Insights from first-principles calculations including dispersion interactions. AB - Adsorption of pre-formed Agn clusters for n = 1 - 8 on a graphite substrate is studied within the density functional theory employing the vdW-DF2 functional to treat dispersion interactions. Top sites above surface layer carbon atoms turn out to be most favorable for a Ag adatom, in agreement with experimental observations. The same feature is observed for clusters of almost all sizes which have the lowest energies when the Ag atoms are positioned over top sites. Most gas phase isomers retain their structures over the substrate, though a couple of them undergo significant distortions. Energetics of the adsorption can be understood in terms of a competition between energy cost of disturbing Ag-Ag bonds in the cluster and energy gain from Ag-C interactions at the surface. Ag3 turns out to be an exceptional candidate in this regard that undergoes significant structural distortion and has only two of the Ag atoms close to surface C atoms in its lowest energy structure. PMID- 24784298 TI - Pressure-induced ferroelastic phase transition in SnO2 from density functional theory. AB - High-pressure ferroelastic transition of rutile- to CaCl2-type SnO2 is investigated within density functional theory and Landau free energy theory. The calculated Landau energy map around the ground state is successfully used to clarify the softening mechanism of B1g mode (order parameter Q) and the coupling mechanism between the soft B1g mode and the soft transverse acoustic (TA) mode (strain E). It is found that the Sn-O-Sn bending induced soft B1g mode effectively slows the excess energy increase caused by bond stretching, while the coupling between the soft B1g mode and the soft TA mode further decreases the energy since the lattice distortion strain E minimizes the SnO6 octahedral distortion. Q induced Landau Gibbs free energy is interpreted as the sum of the bond stretching energy, bending energy, and octahedral distortion energy, while that induced by E is interpreted as the lattice distortion energy. PMID- 24784299 TI - A model for the latent heat of melting in free standing metal nanoparticles. AB - Nanoparticles of many metals are known to exhibit scale dependent latent heats of melting. Analytical models for this phenomenon have so far failed to completely capture the observed phenomena. Here we present a thermodynamic analysis for the melting of metal nanoparticles in terms of their internal energy and a scale dependent surface tension proposed by Tolman. The resulting model predicts the scale dependence of the latent heat of melting and is confirmed using published data for tin and aluminum. PMID- 24784300 TI - Periodic ordering of clusters and stripes in a two-dimensional lattice model. II. Results of Monte Carlo simulation. AB - The triangular lattice model with nearest-neighbor attraction and third-neighbor repulsion, introduced by Pekalski, Ciach, and Almarza [J. Chem. Phys. 140, 114701 (2014)] is studied by Monte Carlo simulation. Introduction of appropriate order parameters allowed us to construct a phase diagram, where different phases with patterns made of clusters, bubbles or stripes are thermodynamically stable. We observe, in particular, two distinct lamellar phases-the less ordered one with global orientational order and the more ordered one with both orientational and translational order. Our results concern spontaneous pattern formation on solid surfaces, fluid interfaces or membranes that is driven by competing interactions between adsorbing particles or molecules. PMID- 24784301 TI - The different roles of Pu-oxide overlayers in the hydrogenation of Pu-metal: an ab initio molecular dynamics study based on van der Waals density functional (vdW DF)+U. AB - Based on the non-local van der Waals density functional (vdW-DF)+U scheme, we carry out the ab initio molecular dynamics (AIMD) study of the interaction dynamics for H2 impingement against the stoichiometric PuO2(111), the reduced PuO2(111), and the stoichiometric alpha-Pu2O3(111) surfaces. The hydrogen molecular physisorption states, which cannot be captured by pure DFT+U method, are obtained by employing the vdW-DF+U scheme. We show that except for the weak physisorption, PuO 2(111) surfaces are so difficult of access that almost all of the H2 molecules will bounce back to the vacuum when their initial kinetic energies are not sufficient. Although the dissociative adsorption of H2 on PuO2(111) surfaces is found to be very exothermic, the collision-induced dissociation barriers of H2 are calculated to be as high as 3.2 eV and 2.0 eV for stoichiometric and reduced PuO2 surfaces, respectively. Unlike PuO2, our AIMD study directly reveals that the hydrogen molecules can penetrate into alpha Pu2O3(111) surface and diffuse easily due to the 25% native O vacancies located along the ?111? diagonals of alpha-Pu2O3 matrix. By examining the temperature effect and the internal vibrational excitations of H2, we provide a detailed insight into the interaction dynamics of H2 in alpha-Pu2O3. The optimum pathways for hydrogen penetration and diffusion, the corresponding energy barriers (1.0 eV and 0.53 eV, respectively) and rate constants are systematically calculated. Overall, our study fairly reveals the different interaction mechanisms between H2 and Pu-oxide surfaces, which have strong implications to the interpretation of experimental observations. PMID- 24784302 TI - Near-edge X-ray absorption fine-structure spectroscopy of naphthalene diimide thiophene co-polymers. AB - Near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy is an important tool for probing the structure of conjugated polymer films used in organic electronic devices. High-performance conjugated polymers are often donor-acceptor co-polymers which feature a repeat unit with multiple functional groups. To facilitate better application of NEXAFS spectroscopy to the study of such materials, improved understanding of the observed NEXAFS spectral features is required. In order to examine how the NEXAFS spectrum of a donor-acceptor co polymer relates to the properties of the sub-units, a series of naphthalene diimide-thiophene-based co-polymers have been studied where the nature and length of the donor co-monomer has been systematically varied. The spectra of these materials are compared with that of a thiophene homopolymer and naphthalene diimide monomer enabling peak assignment and the influence of inter-unit electronic coupling to be assessed. We find that while it is possible to attribute peaks within the pi* manifold as arising primarily due to the naphthalene diimide or thiophene sub-units, very similar dichroism of these peaks is observed indicating that it may not be possible to separately probe the molecular orientation of the separate sub-units with carbon K-edge NEXAFS spectroscopy. PMID- 24784303 TI - Predicting for thermodynamic instabilities in water/oil/surfactant microemulsions: a mesoscopic modelling approach. AB - The thermodynamics and structural properties of flexible and rigid nonionic water/oil/surfactant microemulsions have been investigated using a two level-cut Gaussian random field method based on the Helfrich formalism. Ternary stability diagrams and scattering spectra have been calculated for different surfactant rigidities and spontaneous curvatures. A more important contribution of the Gaussian elastic constants compared to the bending one is observed on the ternary stability diagrams. Furthermore, influence of the spontaneous curvature of the surfactant points out a displacement of the instability domains which corresponds to the difference between the spontaneous and effective curvatures. We enlighten that a continuous transition from a connected water in oil droplets to a frustrated locally lamellar (oil in water in oil droplets) microstructure is found to occur when increasing the temperature for an oil-rich microemulsion. This continuous transition translated in a shift in the scattering functions, points out that the phase inversion phenomenon occurs by a coalescence of the water droplets. PMID- 24784304 TI - Homogeneous states in driven granular mixtures: Enskog kinetic theory versus molecular dynamics simulations. AB - The homogeneous state of a binary mixture of smooth inelastic hard disks or spheres is analyzed. The mixture is driven by a thermostat composed by two terms: a stochastic force and a drag force proportional to the particle velocity. The combined action of both forces attempts to model the interaction of the mixture with a bath or surrounding fluid. The problem is studied by means of two independent and complementary routes. First, the Enskog kinetic equation with a Fokker-Planck term describing interactions of particles with thermostat is derived. Then, a scaling solution to the Enskog kinetic equation is proposed where the dependence of the scaled distributions phii of each species on the granular temperature occurs not only through the dimensionless velocity c = v/v0 (v0 being the thermal velocity) but also through the dimensionless driving force parameters. Approximate forms for phii are constructed by considering the leading order in a Sonine polynomial expansion. The ratio of kinetic temperatures T1/T2 and the fourth-degree velocity moments lambda1 and lambda2 (which measure non Gaussian properties of phi1 and phi2, respectively) are explicitly determined as a function of the mass ratio, size ratio, composition, density, and coefficients of restitution. Second, to assess the reliability of the theoretical results, molecular dynamics simulations of a binary granular mixture of spheres are performed for two values of the coefficient of restitution (alpha = 0.9 and 0.8) and three different solid volume fractions (phi = 0.00785, 0.1, and 0.2). Comparison between kinetic theory and computer simulations for the temperature ratio shows excellent agreement, even for moderate densities and strong dissipation. In the case of the cumulants lambda1 and lambda2, good agreement is found for the lower densities although significant discrepancies between theory and simulation are observed with increasing density. PMID- 24784305 TI - Hydrodynamic radius approximation for spherical particles suspended in a viscous fluid: influence of particle internal structure and boundary. AB - Systems of spherical particles moving in Stokes flow are studied for different particle internal structures and boundaries, including the Navier-slip model. It is shown that their hydrodynamic interactions are well described by treating them as solid spheres of smaller hydrodynamic radii, which can be determined from measured single-particle diffusion or intrinsic viscosity coefficients. Effective dynamics of suspensions made of such particles is quite accurately described by mobility coefficients of the solid particles with the hydrodynamic radii, averaged with the unchanged direct interactions between the particles. PMID- 24784306 TI - Diradicals acting through diamagnetic phenylene vinylene bridges: Raman spectroscopy as a probe to characterize spin delocalization. AB - We present a complete Raman spectroscopic study in two structurally well-defined diradical species of different lengths incorporating oligo p-phenylene vinylene bridges between two polychlorinated triphenylmethyl radical units, a disposition that allows sizeable conjugation between the two radicals through and with the bridge. The spectroscopic data are interpreted and supported by quantum chemical calculations. We focus the attention on the Raman frequency changes, interpretable in terms of: (i) bridge length (conjugation length); (ii) bridge conformational structure; and (iii) electronic coupling between the terminal radical units with the bridge and through the bridge, which could delineate through-bond spin polarization, or spin delocalization. These items are addressed by using the "oligomer approach" in conjunction with pressure and temperature dependent Raman spectroscopic data. In summary, we have attempted to translate the well-known strategy to study the electron (charge) structure of pi-conjugated molecules by Raman spectroscopy to the case of electron (spin) interactions via the spin delocalization mechanism. PMID- 24784307 TI - Lattice-Boltzmann simulations of the electrophoretic stretching of polyelectrolytes: the importance of hydrodynamic interactions. AB - In this article we examine the electrophoretic stretching of polyelectrolytes between parallel uncharged plates using molecular dynamics simulations. We compare simulations where the fluid is modeled implicitly using a Langevin thermostat, which ignore hydrodynamic interactions, to simulations with an explicit lattice-Boltzmann fluid that take hydrodynamic interactions into account. The difference between simulations with and without hydrodynamic interactions is larger for longer polyelectrolytes, as one would expect. Furthermore, we present simulation results which show that the effects of hydrodynamic interactions are reduced as the distance between the confining plates is diminished. The main result of our study is that hydrodynamic interactions play a larger role in systems with a shorter Debye length, in contrast to conventional wisdom. PMID- 24784308 TI - Mixtures composed of liquid crystals and carbon nanotubes. AB - The phenomenological model to describe the liquid crystal-carbon nanotubes mixture presented in a previous paper [P. van der Schoot, V. Popa-Nita, and S. Kralj, J. Phys. Chem. B 112, 4512 (2008)] has been extended to include the isotropic carbon nanotubes-nematic thermotropic liquid crystal interaction. It is assumed that the carbon nanotubes in the isotropic phase act as an external random field on liquid crystal component. The influence of the randomly orientational disorder on the phase diagram of the mixture and orientational order parameters profiles of both components is theoretically analyzed for different values of temperature, volume fraction of carbon nanotubes, nematic carbon nanotubes-nematic liquid crystal coupling strength and the random field strength. PMID- 24784309 TI - Electrostatic interaction between colloidal particles trapped at an electrolyte interface. AB - The electrostatic interaction between colloidal particles trapped at the interface between two immiscible electrolyte solutions is studied in the limit of small inter-particle distances. Within an appropriate model analytic expressions for the electrostatic potential as well as for the surface and line interaction energies are obtained. They demonstrate that the widely used superposition approximation, which is commonly applied to large distances between the colloidal particles, fails qualitatively at small distances, and is quantitatively unreliable even at large distances. Our results contribute to an improved description of the interaction between colloidal particles trapped at fluid interfaces. PMID- 24784310 TI - Hydration of non-polar anti-parallel beta-sheets. AB - In this work we focus on anti-parallel beta-sheets to study hydration of side chains and polar groups of the backbone using all-atom molecular dynamics simulations. We show that: (i) water distribution around the backbone does not depend significantly on amino acid sequence, (ii) more water molecules are found around oxygen than nitrogen atoms of the backbone, and (iii) water molecules around nitrogen are highly localized in the planed formed by peptide backbones. To study hydration around side chains we note that anti-parallel beta-sheets exhibit two types of cross-strand pairing: Hydrogen-Bond (HB) and Non-Hydrogen Bond (NHB) pairing. We show that distributions of water around alanine, leucine, and valine side chains are very different at HB compared to NHB faces. For alanine pairs, the space between side chains has a higher concentration of water if residues are located in the NHB face of the beta-sheet as opposed to the HB face. For leucine residues, the HB face is found to be dry while the space between side chains at the NHB face alternates between being occupied and non occupied by water. Surprisingly, for valine residues the NHB face is dry, whereas the HB face is occupied by water. We postulate that these differences in water distribution are related to context dependent propensities observed for beta sheets. PMID- 24784311 TI - Comment on "Effective field parameters in iron Mossbauer spectroscopy" [J. Chem. Phys. 47, 961 (1967)]. PMID- 24784315 TI - Mechanism of the action of SMTP-7, a novel small-molecule modulator of plasminogen activation. AB - SMTP-7 is a small molecule that promotes the proteolytic activation of plasminogen by relaxing its conformation. SMTP-7 has excellent therapeutic activities against thrombotic stroke in several rodent models. The objective of this study was to elucidate detailed mechanism of the action of SMTP-7 in vitro. We report here that the action of SMTP-7 requires a cofactor with a long-chain alkyl or alkenyl group, and that the fifth kringle domain (kringle 5) of plasminogen is involved in the SMTP-7 action. In this study, we found that the SMTP-7 action to enhance plasminogen activation depended on the presence of a certain type of surfactant, and we screened biologically relevant molecules for their cofactor activity for the SMTP action. As a result, phospholipids, sphingolipids, and oleic acid were found to be active in assisting the SMTP-7 action. On the contrary, stearic acid and bile acids were inactive. Thus, a certain structural element, not only the surface-activating potential, is required for a compound to act as a cofactor for the SMTP-7 action. The plasminogen molecule consists of a PAN domain, five kringle domains, and a serine protease domain. The cofactor-dependent effects of SMTP-7 was observed with plasminogen species including kringle 5 such as intact plasminogen (Glu plasminogen), des-PAN plasminogen (Lys-plasminogen), and des-[PAN - (kringles 1 4)] plasminogen (mini-plasminogen). However, SMTP-7 effect was not observed with the smallest plasminogen species des-[PAN - (kringles 1-4) and a half of kringle 5)] plasminogen (micro-plasminogen). Thus, kringle 5 is crucial for the action of SMTP-7. PMID- 24784316 TI - The influence of coagulopathy on outcome after traumatic subdural hematoma: a retrospective single-center analysis of 319 patients. AB - The aim of this study was to identify the effects of coagulopathy on the outcome of patients with traumatic subdural hematoma (SDH). Based on a retrospective study, the records of all patients admitted between 2001 and 2007 to a large emergency hospital with acute SDH resulting from traumatic brain injury (TBI) were analyzed. An initial Glasgow coma score (GCS), clinical state, and Glasgow outcome score (GOS) were recorded for all patients. All computer assisted tomography and MRI scans obtained from patients were saved on an electronic storage device and were reviewed by a neurosurgeon and a neuroradiologist. The coagulation parameters were analyzed for all patients. Coagulopathy was defined as international normalized ratio more than 1.2 or partial thromboplastin time more than 37 s. One hundred and five women and 214 men aged between 1 and 100 years (mean 59 years) were included in the study. Patients with coagulopathy had a significantly worse outcome. Almost twice as many patients died in the coagulopathy group (mean GOS 3.10 +/- 1.46) than in the group without coagulopathy (mean GOS 2.16 +/- 1.45), (P < 0.001). In-hospital mortality is twice as frequent in patients with coagulopathy with traumatic SDH compared with noncoagulopathic patients, even if the initial severity of the TBI does not differ. PMID- 24784317 TI - Analysis of chosen polymorphisms in FoxP3 gene in children and adolescents with autoimmune thyroid diseases. AB - INTRODUCTION: Forkhead box P3 (Foxp3) is an important regulatory factor for the development and function of T regulatory (Treg) cells. Moreover, it has been established that deficiency of the Foxp3 gene in Treg cells suppresses their regulatory function leading to the development of autoimmune diseases especially autoimmune thyroid diseases. The aim of our study was to estimate the association of three polymorphism of FOXP3 gene with the predisposition to Graves' disease (GD) and Hashimoto's thyroiditis (HT) in children and adolescents. MATERIALS AND METHODS: The study was performed in the group consisting of 145 patients with GD (mean age, 16.5 +/- 2 years), 87 patients with HT (mean age, 15.2 +/- 2.2 years) sequentially recruited from the endocrinology outpatient clinic and 161 healthy volunteers (mean age, 16.3 +/- 3 years). DNA was extracted from the peripheral blood leukocytes using a classical salting-out method. The three single nucleotide polymorphisms (SNPs) rs3761549 (-2383C/T), rs3761548 (-3279G/T) and rs3761547 (-3499T/C) in the FOXP3 gene were genotyped by TaqMan SNP genotyping assay using the real-time PCR method. The levels of thyroid hormones, TSH and anti-thyroid autoantibody were determined using chemiluminescence method. RESULTS: In our study, rs3761549G/A genotype was more frequent in female patients with GD in comparison to healthy female (15% vs. 7%, p = 0.033) with OR = 2.15 and 95% confidence interval for OR: 1.07-4.63. We have also observed rs3761547T/C to be more frequent in females with GD in comparison to control females, and this difference was close to statistically important (13% vs. 7%, p = 0.066) with OR = 1.99 and 95% confidence interval for OR: 0.96-4.48. There were no significant differences in males in analyzed SNPs and in females with rs3761548 SNP. CONCLUSION: In conclusion, these results may suggest that rs3761549G/A polymorphism in Foxp3 gene could contribute to GD development in females. PMID- 24784318 TI - Optimal aggregation of FcepsilonRI with a structurally defined trivalent ligand overrides negative regulation driven by phosphatases. AB - To investigate why responses of mast cells to antigen-induced IgE receptor (FcepsilonRI) aggregation depend nonlinearly on antigen dose, we characterized a new artificial ligand, DF3, through complementary modeling and experimentation. This ligand is a stable trimer of peptides derived from bacteriophage T4 fibritin, each conjugated to a hapten (DNP). We found low and high doses of DF3 at which degranulation of mast cells sensitized with DNP-specific IgE is minimal, but ligand-induced receptor aggregation is comparable to aggregation at an intermediate dose, optimal for degranulation. This finding makes DF3 an ideal reagent for studying the balance of negative and positive signaling in the FcepsilonRI pathway. We find that the lipid phosphatase SHIP and the protein tyrosine phosphatase SHP-1 negatively regulate mast cell degranulation over all doses considered. In contrast, SHP-2 promotes degranulation. With high DF3 doses, relatively rapid recruitment of SHIP to the plasma membrane may explain the reduced degranulation response. Our results demonstrate that optimal secretory responses of mast cells depend on the formation of receptor aggregates that promote sufficient positive signaling by Syk to override phosphatase-mediated negative regulatory signals. PMID- 24784319 TI - Controlling the catalytic aerobic oxidation of phenols. AB - The oxidation of phenols is the subject of extensive investigation, but there are few catalytic aerobic examples that are chemo- and regioselective. Here we describe conditions for the ortho-oxygenation or oxidative coupling of phenols under copper (Cu)-catalyzed aerobic conditions that give rise to ortho-quinones, biphenols or benzoxepines. We demonstrate that each product class can be accessed selectively by the appropriate choice of Cu(I) salt, amine ligand, desiccant and reaction temperature. In addition, we evaluate the effects of substituents on the phenol and demonstrate their influence on selectivity between ortho-oxygenation and oxidative coupling pathways. These results create an important precedent of catalyst control in the catalytic aerobic oxidation of phenols and set the stage for future development of catalytic systems and mechanistic investigations. PMID- 24784320 TI - Calculated globulin (CG) as a screening test for antibody deficiency. AB - Calculated globulin (total protein - albumin) is usually tested as part of a liver function test profile in both primary and secondary care and determines the serum globulin concentration, of which immunoglobulins are a major component. The main use hitherto of calculated globulin is to detect paraproteins when the level is high. This study investigated the potential to use low levels of calculated globulin to detect antibody deficiency. Serum samples with calculated globulin cut-off < 18 g/l based on results of a pilot study were collected from nine hospitals in Wales over a 12-month period. Anonymized request information was obtained and the samples tested for immunoglobulin levels, serum electrophoresis and, if appropriate, immunofixation. A method comparison for albumin measurement using bromocresol green and bromocresol purple was undertaken. Eighty-nine per cent (737 of 826) samples had an immunoglobulin (Ig)G level of < 6 g/l using the bromocresol green methodology with a cut-off of < 18 g/l, and 56% (459) had an IgG of < 4 g/l. Patients with both secondary and primary antibody deficiency were discovered and serum electrophoresis and immunofixation showed that 1.2% (10) had previously undetected small paraproteins associated with immune-paresis. Using bromocresol purple, 74% of samples had an IgG of < 6 g/l using a cut-off of < 23 g/l. Screening using calculated globulin with defined cut-off values detects both primary and secondary antibody deficiency and new paraproteins associated with immune-paresis. It is cheap, widely available and under-utilized. Antibody deficient patients have been discovered using information from calculated globulin values, shortening diagnostic delay and time to treatment with immunoglobulin replacement therapy. PMID- 24784321 TI - Antroquinonol D, isolated from Antrodia camphorata, with DNA demethylation and anticancer potential. AB - DNA methyltransferase 1 (DNMT1) catalyzes DNA methylation and is overexpressed in various human diseases, including cancer. A rational approach to preventing tumorigenesis involves the use of pharmacologic inhibitors of DNA methylation; these inhibitors should reactivate tumor suppressor genes (TSGs) in tumor cells and restore tumor suppressor pathways. Antroquinonol D (3-demethoxyl antroquinonol), a new DNMT1 inhibitor, was isolated from Antrodia camphorata and identified using nuclear magnetic resonance. Antroquinonol D inhibited the growth of MCF7, T47D, and MDA-MB-231 breast cancer cells without harming normal MCF10A and IMR-90 cells. The SRB assay showed that the 50% growth inhibition (GI50) in MCF7, T47D, and MDA-MB-231 breast cancer cells following treatment with antroquinonol D was 8.01, 3.57, and 25.08 MUM, respectively. d-Antroquinonol also inhibited the migratory ability of MDA-MB-231 breast cancer cells in wound healing and Transwell assays. In addition, antroquinonol D inhibited DNMT1 activity, as assessed by the DNMT1 methyltransferase activity assay. As the cofactor SAM level increased, the inhibitory effects of d-antroquinonol on DNMT1 gradually decreased. An enzyme activity assay and molecular modeling revealed that antroquinonol D is bound to the catalytic domain of DNMT1 and competes for the same binding pocket in the DNMT1 enzyme as the cofactor SAM, but does not compete for the binding pocket in the DNMT3B enzyme. An Illumina Methylation 450 K array-based assay and real-time PCR assay revealed that antroquinonol D decreased the methylation status and reactivated the expression of multiple TSGs in MDA-MB-231 breast cancer cells. In conclusion, we showed that antroquinonol D induces DNA demethylation and the recovery of multiple tumor suppressor genes, while inhibiting breast cancer growth and migration potential. PMID- 24784322 TI - Modulation of Alloimmune Responses by Interleukin-10 Prevents Rejection of Implanted Allogeneic Smooth Muscle Cells and Restores Postinfarction Ventricular Function. AB - Interleukin-10 (IL-10) gene transduction into allogeneic smooth muscle cells (SMCs) was evaluated to improve the long-term benefits of allogeneic cell transplantation into infarcted myocardium. Allogeneic cells, including SMCs, have been demonstrated to restore cardiac function and repair the infarcted myocardium, but late rejection of the transplanted cells by the host immune system may reverse the benefits of cell therapy. In a rat myocardial infarction model, three groups of rats were injected with either unmodified autologous, unmodified allogeneic, or allogeneic + IL-10 SMCs into the infarct region. Three weeks later, most of the allogeneic cells were rejected, whereas autologous cells were engrafted in the myocardium. IL-10 gene transduction of the allogeneic SMCs significantly improved the cell survival. To understand the mechanism of this improved survival, we evaluated the host immune responses against the SMCs. Allogeneic SMCs expressing IL-10 decreased leukocyte-mediated cytotoxicity in coculture, decreased the number of cytotoxic CD8(+) T-cells, and increased the number of CD4(+)CD25(+) regulatory T-cells in vitro and in vivo. Furthermore, IL 10 prevented the production of antidonor antibodies by the recipients against the allogeneic SMCs. Transplantation of unmodified autologous SMCs, but not unmodified allogeneic SMCs, significantly improved fractional shortening and left ventricular dimensions compared to the media-injected control group. However, IL 10 gene-enhanced allogeneic SMCs improved ventricular function, increased wall thickness, and decreased scar length in association with their enhanced survival. We conclude that IL-10 gene-enhanced cell therapy with allogeneic SMCs prevents detrimental alloimmune responses in the recipient, thereby increasing the survival of transplanted allogeneic SMCs and more effectively restoring cardiac function. PMID- 24784323 TI - Draft genome sequences of two Bacillus thuringiensis strains and characterization of a putative 41.9-kDa insecticidal toxin. AB - In this work, we report the genome sequencing of two Bacillus thuringiensis strains using Illumina next-generation sequencing technology (NGS). Strain Hu4-2, toxic to many lepidopteran pest species and to some mosquitoes, encoded genes for two insecticidal crystal (Cry) proteins, cry1Ia and cry9Ea, and a vegetative insecticidal protein (Vip) gene, vip3Ca2. Strain Leapi01 contained genes coding for seven Cry proteins (cry1Aa, cry1Ca, cry1Da, cry2Ab, cry9Ea and two cry1Ia gene variants) and a vip3 gene (vip3Aa10). A putative novel insecticidal protein gene 1143 bp long was found in both strains, whose sequences exhibited 100% nucleotide identity. The predicted protein showed 57 and 100% pairwise identity to protein sequence 72 from a patented Bt strain (US8318900) and to a putative 41.9-kDa insecticidal toxin from Bacillus cereus, respectively. The 41.9-kDa protein, containing a C-terminal 6* HisTag fusion, was expressed in Escherichia coli and tested for the first time against four lepidopteran species (Mamestra brassicae, Ostrinia nubilalis, Spodoptera frugiperda and S. littoralis) and the green-peach aphid Myzus persicae at doses as high as 4.8 ug/cm2 and 1.5 mg/mL, respectively. At these protein concentrations, the recombinant 41.9-kDa protein caused no mortality or symptoms of impaired growth against any of the insects tested, suggesting that these species are outside the protein's target range or that the protein may not, in fact, be toxic. While the use of the polymerase chain reaction has allowed a significant increase in the number of Bt insecticidal genes characterized to date, novel NGS technologies promise a much faster, cheaper and efficient screening of Bt pesticidal proteins. PMID- 24784324 TI - Uremic toxins and lipases in haemodialysis: a process of repeated metabolic starvation. AB - Severe kidney disease results in retention of uremic toxins that inhibit key enzymes for lipid breakdown such as lipoprotein lipase (LPL) and hepatic lipase (HL). For patients in haemodialysis (HD) and peritoneal dialysis (PD) the LPL activity is only about half of that of age and gender matched controls. Angiopoietin, like protein 3 and 4, accumulate in the uremic patients. These factors, therefore, can be considered as uremic toxins. In animal experiments it has been shown that these factors inhibit the LPL activity. To avoid clotting of the dialysis circuit during HD, anticoagulation such as heparin or low molecular weight heparin are added to the patient. Such administration will cause a prompt release of the LPL and HL from its binding sites at the endothelial surface. The liver rapidly degrades the release plasma compound of LPL and HL. This results in a lack of enzyme to degrade triglycerides during the later part of the HD and for another 3-4 h. PD patients have a similar baseline level of lipases but are not exposed to the negative effect of anticoagulation. PMID- 24784325 TI - Association between maternal depressive symptoms in the early post-natal period and responsiveness in feeding at child age 2 years. AB - Maternal depression is a known risk factor for poor outcomes for children. Pathways to these poor outcomes relate to reduced maternal responsiveness or sensitivity to the child. Impaired responsiveness potentially impacts the feeding relationship and thus may be a risk factor for inappropriate feeding practices. The aim of this study was to examine the longitudinal relationships between self reported maternal post-natal depressive symptoms at child age 4 months and feeding practices at child age 2 years in a community sample. Participants were Australian first-time mothers allocated to the control group of the NOURISH randomized controlled trial when infants were 4 months old. Complete data from 211 mothers (of 346 allocated) followed up when their children were 2 years of age (51% girls) were available for analysis. The relationship between Edinburgh Postnatal Depression Scale (EPDS) score (child age 4 months) and child feeding practices (child age 2 years) was tested using hierarchical linear regression analysis adjusted for maternal and child characteristics. Higher EPDS score was associated with less responsive feeding practices at child age 2 years: greater pressure [beta = 0.18, 95% confidence interval (CI): 0.04-0.32, P = 0.01], restriction (beta = 0.14, 95% CI: 0.001-0.28, P = 0.05), instrumental (beta = 0.14, 95% CI: 0.005-0.27, P = 0.04) and emotional (beta = 0.15, 95% CI: 0.01 0.29, P = 0.03) feeding practices (DeltaR(2) values: 0.02-0.03, P < 0.05). This study provides evidence for the proposed link between maternal post-natal depressive symptoms and lower responsiveness in child feeding. These findings suggest that the provision of support to mothers experiencing some levels of depressive symptomatology in the early post-natal period may improve responsiveness in the child feeding relationship. PMID- 24784326 TI - Two new bicyclic sesquiterpenes from the stems of Kadsura heteroclita. AB - Two new bicyclic sesquiterpenes, namely 6alpha,9alpha-dihydroxycadinan-4-en-3-one (1) and guai-3-en-10alpha-ol (2), together with one known sesquiterpene were isolated from the stems of Kadsura heteroclita, which is a Tujia ethnomedicine called 'Xue Tong'. Their structures were elucidated by using spectroscopic analyses and by comparing the NMR data with those reported previously. PMID- 24784329 TI - Acupuncture for the treatment of Bell palsy. PMID- 24784327 TI - The time trend temperature-mortality as a factor of uncertainty analysis of impacts of future heat waves: Wu et al. respond. PMID- 24784331 TI - Transitions of care: optimizing the handoff from hospital-based teams to primary care physicians. PMID- 24784332 TI - Gabapentin for the prophylaxis of episodic migraine in adults. PMID- 24784333 TI - Progestin-only contraceptives: effects on weight. PMID- 24784334 TI - Unintentional weight loss in older adults. AB - Unintentional weight loss in persons older than 65 years is associated with increased morbidity and mortality. The most common etiologies are malignancy, nonmalignant gastrointestinal disease, and psychiatric conditions. Overall, nonmalignant diseases are more common causes of unintentional weight loss in this population than malignancy. Medication use and polypharmacy can interfere with taste or cause nausea and should not be overlooked. Social factors may contribute to unintentional weight loss. A readily identifiable cause is not found in 16% to 28% of cases. Recommended tests include a complete blood count, basic metabolic panel, liver function tests, thyroid function tests, C-reactive protein levels, erythrocyte sedimentation rate, glucose measurement, lactate dehydrogenase measurement, and urinalysis. Chest radiography and fecal occult blood testing should be performed. Abdominal ultrasonography may also be considered. When baseline evaluation is unremarkable, a three- to six-month observation period is justified. Treatment focuses on the underlying cause. Nutritional supplements and flavor enhancers, and dietary modification that takes into account patient preferences and chewing or swallowing disabilities may be considered. Appetite stimulants may increase weight but have serious adverse effects and no evidence of decreased mortality. PMID- 24784335 TI - Evaluation of scrotal masses. AB - Scrotal masses are caused by a variety of disorders, ranging from benign conditions to those requiring emergent surgical intervention. Painful scrotal masses require urgent evaluation. Characteristics that suggest testicular torsion include rapid symptom onset, nausea and vomiting, high position of the testicle, and abnormal cremasteric reflex. Doppler ultrasonography or surgical exploration is required to confirm the diagnosis. Surgical repair must occur within six hours of symptom onset to reliably salvage the testicle. Epididymitis/orchitis have a slower onset and are associated with a C-reactive protein level greater than 24 mg per L (228.6 nmol per L) and increased blood flow on ultrasonography. Acute onset of pain with near normal physical examination and ultrasound findings is consistent with torsion of the testicular appendage. Testicular malignancies cause pain in 15% of cases. If ultrasonography shows an intratesticular mass, timely urology referral is indicated. Inguinal hernias are palpated separate to the testicle and can cause pain. Emergent surgery is indicated for a strangulated hernia. Hydrocele, varicocele, and scrotal skin lesions may be managed in nonurgent settings. A biopsy should be performed to rule out cancer in patients with scrotal skin lesions that are erosive, vascular, hyperkeratotic, or nonhealing, or that change color or have irregular borders. PMID- 24784336 TI - Leukemia: an overview for primary care. AB - Leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow. The four broad subtypes most likely to be encountered by primary care physicians are acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous. Acute lymphoblastic leukemia occurs more often in children, whereas the other subtypes are more common in adults. Risk factors include a genetic predisposition as well as environmental factors, such as exposure to ionizing radiation. Symptoms are nonspecific and include fever, fatigue, weight loss, bone pain, bruising, or bleeding. A complete blood count usually reveals leukocytosis and other abnormally elevated or depressed cell lines. Patients with suspected leukemia should be referred promptly to a hematologist-oncologist. The diagnosis is confirmed by further examination of the bone marrow or peripheral blood. Treatment may include chemotherapy, radiation, monoclonal antibodies, or hematopoietic stem cell transplantation. Complications of treatment include tumor lysis syndrome and serious infections from immunosuppression. Leukemia survivors should be monitored closely for secondary malignancies, cardiac complications, and endocrine disturbances such as metabolic syndrome, hypothyroidism, and hypogonadism. Five-year survival rates are highest in younger patients and in patients with chronic myelogenous leukemia or chronic lymphocytic leukemia. PMID- 24784337 TI - 20-year history of diarrhea with intermittent constipation. PMID- 24784338 TI - Acute migraine treatment in emergency settings. PMID- 24784339 TI - The hospice referral. PMID- 24784343 TI - What you should know about scrotal masses. PMID- 24784342 TI - The changing landscape of primary care HPSAs and the influence on practice location. PMID- 24784344 TI - Leukemia: the basics. PMID- 24784345 TI - Unintentional weight loss in older adults. PMID- 24784346 TI - Wilms' tumor gene 1 immunotherapy in pelvic gynecological malignancies. AB - Pelvic gynecological malignancies account for 6% of all cancers. In the relapsed state, classical treatments are limited. There is an urgent need for new and personalized treatment. Wilms' tumor gene 1 (WT1) is the most important tumor associated antigen. Although highly present in gynecological tumors, active immunotherapy against it is still underexplored. This review gives an insight into the importance of WT1 in pelvic gynecological malignancies and the first taken steps into the world of WT1 immunotherapy. PMID- 24784347 TI - Biosynthesis of stable iron oxide nanoparticles in aqueous extracts of Hordeum vulgare and Rumex acetosa plants. AB - We report the synthesis and characterization of amorphous iron oxide nanoparticles from iron salts in aqueous extracts of monocotyledonous (Hordeum vulgare) and dicotyledonous (Rumex acetosa) plants. The nanoparticles were characterized by TEM, absorbance spectroscopy, SAED, EELS, XPS, and DLS methods and were shown to contain mainly iron oxide and iron oxohydroxide. H. vulgare extracts produced amorphous iron oxide nanoparticles with diameters of up to 30 nm. These iron nanoparticles are intrinsically unstable and prone to aggregation; however, we rendered them stable in the long term by addition of 40 mM citrate buffer pH 3.0. In contrast, amorphous iron oxide nanoparticles (diameters of 10 40 nm) produced using R. acetosa extracts are highly stable. The total protein content and antioxidant capacity are similar for both extracts, but pH values differ (H. vulgare pH 5.8 vs R. acetosa pH 3.7). We suggest that the presence of organic acids (such oxalic or citric acids) plays an important role in the stabilization of iron nanoparticles, and that plants containing such constituents may be more efficacious for the green synthesis of iron nanoparticles. PMID- 24784348 TI - Density functional theory study of Rh(n)S(0,+/-) and Rh(n+1)(0,+/-) (n = 1-9). AB - A basin-hopping search strategy has been used to determine likely candidates for low-energy Rh(n)S(0,+/-) (n = 1-9) cluster structures. Cluster structures were optimized at the density functional level of theory using the PBE and PBE0 functionals. Ionization energies, electron detachment energies, HOMO-LUMO gap energies, UV-visible spectra, low-lying fragmentation channels and energies, cluster structures, spin multiplicities, and vibrational spectra are predicted for Rh(n)S(0,+/-) and Rh(n+1)(0,+/-) (n = 1-9). Donation from valence sulfur atomic p orbitals to valence rhodium atomic d orbitals and back-donation to valence sulfur atomic d orbitals leads to electron density delocalization and metal-like behavior for rhodium sulfide clusters. PMID- 24784349 TI - Lead, cadmium and chromium in raw and boiled portions of Norway lobster. AB - Lead, cadmium and chromium levels were determined in different raw and boiled portions of Norway lobster caught in the central Adriatic Sea (Italy). In raw specimens, the lowest concentrations were always detected in the white meat. Lead and cadmium content in the edible portion never exceeded the maximum levels set by European legislation. The highest cadmium and chromium values (0.47 +/- 0.04 and 0.62 +/- 0.13 mg/kg wet weight, respectively) were detected in the brown meat, while the highest lead concentrations were found in the exoskeleton (0.21 +/- 0.01 mg/kg wet weight). Also, the boiled samples showed the lowest metal levels in the white meat, even if a significant increase (p < 0.01) was found for lead and cadmium compared to the corresponding raw portions. Among metals, chromium showed the highest concentrations in both raw and boiled portions, but up to now, the European legislation did not envisage any limits in seafood. PMID- 24784351 TI - Viability of the Lactobacillus rhamnosus HN001 probiotic strain in Swiss- and Dutch-type cheese and cheese-like products. AB - The objective of this study was to determine the viability of the probiotic Lactobacillus rhamnosus HN001 in Swiss-type and Dutch-type cheese and cheese-like products (milk fat is substituted by stearin fraction of palm fat) during manufacture, ripening, and storage. The use of the probiotic L. rhamnosus HN001 in Dutch-type cheese and cheese-like products significantly (P = 0.1) changed their chemical composition (protein and fat content) and an insignificant increase (approximately 1.6% in cheese-like products and approximately 0.3% in cheese) in yield. L. rhamnosus HN001 did not affect the rate of changes in the pH of ripened cheese and cheese-like products. A minor increase in probiotic counts was observed in initial stages of production and were partially removed with whey. Ripened cheese and cheese-like products were characterized by high survival rates of probiotic bacteria which exceeded 8 log CFU/g after ripening. An insignificant reduction in the number of viable probiotic cells was noted during storage of Swiss-type and Dutch-type cheese, whereas a significant increase in probiotic cell counts was observed in cheese-like products during storage. PMID- 24784352 TI - Electron induced surface reactions of organometallic metal(hfac)2 precursors and deposit purification. AB - The elementary processes associated with electron beam-induced deposition (EBID) and post-deposition treatment of structures created from three metal(II)(hfac)2 organometallic precursors (metal = Pt, Pd, Cu; hfac = CF3C(O)CHC(O)CF3) have been studied using surface analytical techniques. Electron induced reactions of adsorbed metal(II)(hfac)2 molecules proceeds in two stages. For comparatively low electron doses (doses <1 * 10(17) e(-)/cm(2)) decomposition of the parent molecules leads to loss of carbon and oxygen, principally through the formation of carbon monoxide. Fluorine and hydrogen atoms are also lost by electron stimulated C-F and C-H bond cleavage, respectively. Collectively, these processes are responsible for the loss of a significant fraction (>= 50%) of the oxygen and fluorine atoms, although most (>80%) of the carbon atoms remain. As a result of these various transformations the reduced metal atoms become encased in an organic matrix that is stabilized toward further electron stimulated carbon or oxygen loss, although fluorine and hydrogen can still desorb in the second stage of the reaction under the influence of sustained electron irradiation as a result of C-F and C-H bond cleavage, respectively. This reaction sequence explains why EBID structures created from metal(II)(hfac)2 precursors in electron microscopes contain reduced metal atoms embedded within an oxygen-containing carbonaceous matrix. Except for the formation of copper fluoride from Cu(II)(hfac)2, because of secondary reactions between partially reduced copper atoms and fluoride ions, the chemical composition of EBID films and behavior of metal(II)(hfac)2 precursors was independent of the transition metal's chemical identity. Annealing studies of EBID structures created from Pt(II)(hfac)2 suggest that the metallic character of deposited Pt atoms could be increased by using post deposition annealing or elevated substrate temperatures (>25 degrees C) during deposition. By exposing EBID structures created from Cu(II)(hfac)2 to atomic oxygen followed by atomic hydrogen, organic contaminants could be abated without annealing. PMID- 24784353 TI - Ordered arrays of embedded Ga nanoparticles on patterned silicon substrates. AB - We fabricate site-controlled, ordered arrays of embedded Ga nanoparticles on Si, using a combination of substrate patterning and molecular-beam epitaxial growth. The fabrication process consists of two steps. Ga droplets are initially nucleated in an ordered array of inverted pyramidal pits, and then partially crystallized by exposure to an As flux, which promotes the formation of a GaAs shell that seals the Ga nanoparticle within two semiconductor layers. The nanoparticle formation process has been investigated through a combination of extensive chemical and structural characterization and theoretical kinetic Monte Carlo simulations. PMID- 24784356 TI - Letter from the editor. PMID- 24784355 TI - Reliability of trachoma clinical grading--assessing grading of marginal cases. AB - BACKGROUND: Clinical examination of trachoma is used to justify intervention in trachoma-endemic regions. Currently, field graders are certified by determining their concordance with experienced graders using the kappa statistic. Unfortunately, trachoma grading can be highly variable and there are cases where even expert graders disagree (borderline/marginal cases). Prior work has shown that inclusion of borderline cases tends to reduce apparent agreement, as measured by kappa. Here, we confirm those results and assess performance of trainees on these borderline cases by calculating their reliability error, a measure derived from the decomposition of the Brier score. METHODS AND FINDINGS: We trained 18 field graders using 200 conjunctival photographs from a community randomized trial in Niger and assessed inter-grader agreement using kappa as well as reliability error. Three experienced graders scored each case for the presence or absence of trachomatous inflammation-follicular (TF) and trachomatous inflammation-intense (TI). A consensus grade for each case was defined as the one given by a majority of experienced graders. We classified cases into a unanimous subset if all 3 experienced graders gave the same grade. For both TF and TI grades, the mean kappa for trainees was higher on the unanimous subset; inclusion of borderline cases reduced apparent agreement by 15.7% for TF and 12.4% for TI. When we assessed the breakdown of the reliability error, we found that our trainees tended to over-call TF grades and under-call TI grades, especially in borderline cases. CONCLUSIONS: The kappa statistic is widely used for certifying trachoma field graders. Exclusion of borderline cases, which even experienced graders disagree on, increases apparent agreement with the kappa statistic. Graders may agree less when exposed to the full spectrum of disease. Reliability error allows for the assessment of these borderline cases and can be used to refine an individual trainee's grading. PMID- 24784354 TI - A computational model for the analysis of lipoprotein distributions in the mouse: translating FPLC profiles to lipoprotein metabolism. AB - Disturbances of lipoprotein metabolism are recognized as indicators of cardiometabolic disease risk. Lipoprotein size and composition, measured in a lipoprotein profile, are considered to be disease risk markers. However, the measured profile is a collective result of complex metabolic interactions, which complicates the identification of changes in metabolism. In this study we aim to develop a method which quantitatively relates murine lipoprotein size, composition and concentration to the molecular mechanisms underlying lipoprotein metabolism. We introduce a computational framework which incorporates a novel kinetic model of murine lipoprotein metabolism. The model is applied to compute a distribution of plasma lipoproteins, which is then related to experimental lipoprotein profiles through the generation of an in silico lipoprotein profile. The model was first applied to profiles obtained from wild-type C57Bl/6J mice. The results provided insight into the interplay of lipoprotein production, remodelling and catabolism. Moreover, the concentration and metabolism of unmeasured lipoprotein components could be determined. The model was validated through the prediction of lipoprotein profiles of several transgenic mouse models commonly used in cardiovascular research. Finally, the framework was employed for longitudinal analysis of the profiles of C57Bl/6J mice following a pharmaceutical intervention with a liver X receptor (LXR) agonist. The multifaceted regulatory response to the administration of the compound is incompletely understood. The results explain the characteristic changes of the observed lipoprotein profile in terms of the underlying metabolic perturbation and resultant modifications of lipid fluxes in the body. The Murine Lipoprotein Profiler (MuLiP) presented here is thus a valuable tool to assess the metabolic origin of altered murine lipoprotein profiles and can be applied in preclinical research performed in mice for analysis of lipid fluxes and lipoprotein composition. PMID- 24784357 TI - Return to play after acute infectious disease in football players. AB - Acute infectious diseases are common in athletes and can impair their ability to train and to compete. Furthermore, continuing exercise during infectious diseases may lead to prolongation or aggravation of illness with severe acute or chronic organ manifestations. Therefore, even simple infectious diseases require a sufficient period of convalescence and recovery, during which exercise may be not allowed. Nowadays, especially in professional football with high pressures on players, staff and clubs due to broad public interests as well as financial constraints, the return-to-play decision is of utmost significance. Based on previous suggestions and our own experience within amateur and professional athletes and football players, this article aims to give a short overview on return-to-play decisions after common acute infectious diseases in football players. PMID- 24784358 TI - Vertically stacked quantum dot pairs fabricated by nanohole filling. AB - Strain-free, vertically coupled GaAs quantum dots (QDs) with an ultra-low density below 1 * 10(7) cm(-2) are fabricated by filling of self-assembled nanoholes with a GaAs/AlGaAs/GaAs layer sequence. The sizes of the two QDs, forming a QD pair (QDP), as well as the AlGaAs tunnel-barrier between the dots are tuned independently. We present atomic force microscopy studies of the QDP formation steps. We have performed photoluminescence studies of single QDPs with varied dot size and tunnel-barrier thickness. The data indicate non-resonant tunnelling between the dots. Furthermore, we apply the quantum confined Stark effect to tune the photoluminescence energy by up to 25 meV. PMID- 24784360 TI - Tacrolimus trough level at discharge predicts acute rejection in moderately sensitized renal transplant recipients. AB - BACKGROUND: Goal tacrolimus concentrations for the prevention of rejection in sensitized renal transplant recipients are not well established. METHODS: We evaluated the association between discharge tacrolimus trough concentration and the incidence of biopsy-proven acute rejection (BPAR) in 216 moderately sensitized renal transplant recipients (negative flow crossmatch and positive donor-specific antibodies) treated with tacrolimus. RESULTS: At transplant, the mean+/-standard deviation (SD) peak panel-reactive antibody was 60+/-33 and median donor-specific antibody level was a mean fluorescence intensity of 710 (interquartile range, 328-1202). The mean+/-SD tacrolimus trough concentration at discharge (median postoperative day, 5; interquartile range, 4-7) was 7.6+/-3.7 ng/dL. Patients were divided into two groups based on a discharge tacrolimus trough concentration of 8 ng/mL. Baseline characteristics were similar between groups. Thirty-four (28.6%) of the 119 patients with a tacrolimus trough concentration less than 8 ng/mL and 19 (19.6%) of 97 patients with concentrations of 8 ng/mL or greater experienced BPAR during a median follow-up of 14+/-4.7 months (P=0.04). Adjusting for age, race, donor status, and peak panel-reactive antibody, a discharge tacrolimus trough concentration less than 8 ng/mL was significantly associated with a higher risk of BPAR (hazard ratio, 1.84; 95% confidence interval, 1.04-3.25; P=0.04). Serum creatinine, cytomegalovirus, BK viremia, or BK nephropathy at 1 year did not differ between groups. CONCLUSIONS: In a patient population predisposed to BPAR, discharge tacrolimus trough concentration less than 8 ng/mL was associated with a nearly two times greater risk of BPAR. PMID- 24784361 TI - Combining words in the brain: the processing of compound words. Introduction to the special issue. PMID- 24784359 TI - GluA2 mRNA distribution and regulation by miR-124 in hippocampal neurons. AB - AMPA-type glutamate receptors mediate fast, excitatory neurotransmission in the brain, and their concentrations at synapses are important determinants of synaptic strength. We investigated the post-transcriptional regulation of GluA2, the calcium-impermeable AMPA receptor subunit, by examining the subcellular distribution of its mRNA and evaluating its translational regulation by microRNA in cultured mouse hippocampal neurons. Using computational approaches, we identified a conserved microRNA-124 (miR-124) binding site in the 3'UTR of GluA2 and demonstrated that miR-124 regulated the translation of GluA2 mRNA reporters in a sequence-specific manner in luciferase assays. While we hypothesized that this regulation might occur in dendrites, our biochemical and fluorescent in situ hybridization (FISH) data indicate that GluA2 mRNA does not localize to dendrites or synapses of mouse hippocampal neurons. In contrast, we detected significant concentrations of miR-124 in dendrites. Overexpression of miR-124 in dissociated neurons results in a 30% knockdown of GluA2 protein, as measured by immunoblot and quantitative immunocytochemistry, without producing any changes in GluA2 mRNA concentrations. While total GluA2 concentrations are reduced, we did not detect any changes in the concentration of synaptic GluA2. We conclude from these results that miR-124 interacts with GluA2 mRNA in the cell body to downregulate translation. Our data support a model in which GluA2 is translated in the cell body and subsequently transported to neuronal dendrites and synapses, and suggest that synaptic GluA2 concentrations are modified primarily by regulated protein trafficking rather than by regulated local translation. PMID- 24784362 TI - Word structure and decomposition effects in reading. AB - Theories on the processing of compound words differ on the role attributed to access to individual constituents. These theories are mostly based on empirical evidence obtained in experimental settings that could induce artificial effects normally not occurring in natural processing. In this study we investigated the processing of compounds as compared to noncompound complex words in Italian through a reading task with eye movement recording. We included both head-initial and head-final compounds, in order to test whether the position of the head may influence the reading process. After ruling out the effects of length and frequency, we observed that pseudocompounds (i.e., words with a segment homograph to a real word in the leftmost part) elicited longer total reading times than all other types of complex words, including compounds. Furthermore, head-final compounds elicited longer total reading times than head-initial compounds. The results suggest that a word structure resembling a compound may induce longer processing, presumably related to unexpected morphological structures. The results also converge with previous evidence that in some cases there is a higher processing costs for head-final as opposed to head-initial compounds, possibly indexing a reanalysis of the stimulus in order to correctly assign the constituent properties. However, a deeper analysis restricted to compounds revealed a more complex scenario where several variables interact with headedness (namely, first and second constituent frequency, compound frequency, and compound length), and future studies are needed to discriminate among possible interpretations. Overall, our findings suggest that longer reading times are related to solving incongruities due to noncanonical structures, rather than to morphologically complexity per se. PMID- 24784364 TI - Point/Counterpoint. Practicing and aspiring medical physicists can safely disregard university rankings at no peril to them. PMID- 24784365 TI - Vision 20/20: the role of Raman spectroscopy in early stage cancer detection and feasibility for application in radiation therapy response assessment. AB - Raman spectroscopy is an optical technique capable of identifying chemical constituents of a sample by their unique set of molecular vibrations. Research on the applicability of Raman spectroscopy in the differentiation of cancerous versus normal tissues has been ongoing for many years, and has yielded successful results in the context of prostate, breast, brain, skin, and head and neck cancers as well as pediatric tumors. Recently, much effort has been invested on developing noninvasive "Raman" probes to provide real-time diagnosis of potentially cancerous tumors. In this regard, it is feasible that the Raman technique might one day be used to provide rapid, minimally invasive real-time diagnosis of tumors in patients. Raman spectroscopy is relatively new to the field of radiation therapy. Recent work involving cell lines has shown that the Raman technique is able to identify proteins and other markers affected by radiation therapy. Although this work is preliminary, one could ask whether or not the Raman technique might be used to identify molecular markers that predict radiation response. This paper provides a brief review of Raman spectroscopic investigations in cancer detection, benefits and limitations of this method, advances in instrument development, and also preliminary studies related to the application of this technology in radiation therapy response assessment. PMID- 24784367 TI - Fast dose kernel interpolation using Fourier transform with application to permanent prostate brachytherapy dosimetry. AB - PURPOSE: Boyer and Mok proposed a fast calculation method employing the Fourier transform (FT), for which calculation time is independent of the number of seeds but seed placement is restricted to calculation grid points. Here an interpolation method is described enabling unrestricted seed placement while preserving the computational efficiency of the original method. METHODS: The Iodine-125 seed dose kernel was sampled and selected values were modified to optimize interpolation accuracy for clinically relevant doses. For each seed, the kernel was shifted to the nearest grid point via convolution with a unit impulse, implemented in the Fourier domain. The remaining fractional shift was performed using a piecewise third-order Lagrange filter. RESULTS: Implementation of the interpolation method greatly improved FT-based dose calculation accuracy. The dose distribution was accurate to within 2% beyond 3 mm from each seed. Isodose contours were indistinguishable from explicit TG-43 calculation. Dose-volume metric errors were negligible. Computation time for the FT interpolation method was essentially the same as Boyer's method. CONCLUSIONS: A FT interpolation method for permanent prostate brachytherapy TG-43 dose calculation was developed which expands upon Boyer's original method and enables unrestricted seed placement. The proposed method substantially improves the clinically relevant dose accuracy with negligible additional computation cost, preserving the efficiency of the original method. PMID- 24784366 TI - Vision 20/20: perspectives on automated image segmentation for radiotherapy. AB - Due to rapid advances in radiation therapy (RT), especially image guidance and treatment adaptation, a fast and accurate segmentation of medical images is a very important part of the treatment. Manual delineation of target volumes and organs at risk is still the standard routine for most clinics, even though it is time consuming and prone to intra- and interobserver variations. Automated segmentation methods seek to reduce delineation workload and unify the organ boundary definition. In this paper, the authors review the current autosegmentation methods particularly relevant for applications in RT. The authors outline the methods' strengths and limitations and propose strategies that could lead to wider acceptance of autosegmentation in routine clinical practice. The authors conclude that currently, autosegmentation technology in RT planning is an efficient tool for the clinicians to provide them with a good starting point for review and adjustment. Modern hardware platforms including GPUs allow most of the autosegmentation tasks to be done in a range of a few minutes. In the nearest future, improvements in CT-based autosegmentation tools will be achieved through standardization of imaging and contouring protocols. In the longer term, the authors expect a wider use of multimodality approaches and better understanding of correlation of imaging with biology and pathology. PMID- 24784368 TI - Out-of-field organ doses and associated radiogenic risks from para-aortic radiotherapy for testicular seminoma. AB - PURPOSE: The aims of this study were to (a) calculate the radiation dose to out of-field organs from radiotherapy for stage I testicular seminoma and (b) estimate the associated radiogenic risks. METHODS: Monte Carlo methodology was employed to model radiation therapy with typical anteroposterior and posteroanterior para-aortic fields on an anthropomorphic phantom simulating an average adult. The radiation dose received by all main and remaining organs that defined by the ICRP publication 103 and excluded from the treatment volume was calculated. The effect of field dimensions on each organ dose was determined. Additional therapy simulations were generated by introducing shielding blocks to protect the kidneys from primary radiation. The gonadal dose was employed to assess the risk of heritable effects for irradiated male patients of reproductive potential. The lifetime attributable risks (LAR) of radiotherapy-induced cancer were estimated using gender- and organ-specific risk coefficients for patient ages of 20, 30, 40, and 50 years old. The risk values were compared with the respective nominal risks. RESULTS: Para-aortic irradiation to 20 Gy resulted in out-of-field organ doses of 5.0-538.6 mGy. Blocked field treatment led to a dose change up to 28%. The mean organ dose variation by increasing or decreasing the applied field dimensions was 18.7% +/- 3.9% and 20.8% +/- 4.5%, respectively. The out-of-field photon doses increased the lifetime intrinsic risk of developing thyroid, lung, bladder, prostate, and esophageal cancer by (0.1-1.4)%, (0.4 1.1)%, (2.5-5.4)%, (0.2-0.4)%, and (6.4-9.2)%, respectively, depending upon the patient age at exposure and the field size employed. A low risk for heritable effects of less than 0.029% was found compared with the natural incidence of these defects. CONCLUSIONS: Testicular cancer survivors are subjected to an increased risk for the induction of bladder and esophageal cancer following para aortic radiotherapy. The probability for the appearance of any other malignant disease to out-of-field organs was slightly elevated in respect to the nominal cancer incidence rates. PMID- 24784369 TI - Interstitial rotating shield brachytherapy for prostate cancer. AB - PURPOSE: To present a novel needle, catheter, and radiation source system for interstitial rotating shield brachytherapy (I-RSBT) of the prostate. I-RSBT is a promising technique for reducing urethra, rectum, and bladder dose relative to conventional interstitial high-dose-rate brachytherapy (HDR-BT). METHODS: A wire mounted 62 GBq(153)Gd source is proposed with an encapsulated diameter of 0.59 mm, active diameter of 0.44 mm, and active length of 10 mm. A concept model I RSBT needle/catheter pair was constructed using concentric 50 and 75 MUm thick nickel-titanium alloy (nitinol) tubes. The needle is 16-gauge (1.651 mm) in outer diameter and the catheter contains a 535 MUm thick platinum shield. I-RSBT and conventional HDR-BT treatment plans for a prostate cancer patient were generated based on Monte Carlo dose calculations. In order to minimize urethral dose, urethral dose gradient volumes within 0-5 mm of the urethra surface were allowed to receive doses less than the prescribed dose of 100%. RESULTS: The platinum shield reduced the dose rate on the shielded side of the source at 1 cm off-axis to 6.4% of the dose rate on the unshielded side. For the case considered, for the same minimum dose to the hottest 98% of the clinical target volume (D(98%)), I RSBT reduced urethral D(0.1cc) below that of conventional HDR-BT by 29%, 33%, 38%, and 44% for urethral dose gradient volumes within 0, 1, 3, and 5 mm of the urethra surface, respectively. Percentages are expressed relative to the prescription dose of 100%. For the case considered, for the same urethral dose gradient volumes, rectum D(1cc) was reduced by 7%, 6%, 6%, and 6%, respectively, and bladder D(1cc) was reduced by 4%, 5%, 5%, and 6%, respectively. Treatment time to deliver 20 Gy with I-RSBT was 154 min with ten 62 GBq (153)Gd sources. CONCLUSIONS: For the case considered, the proposed(153)Gd-based I-RSBT system has the potential to lower the urethral dose relative to HDR-BT by 29%-44% if the clinician allows a urethral dose gradient volume of 0-5 mm around the urethra to receive a dose below the prescription. A multisource approach is necessary in order to deliver the proposed (153)Gd-based I-RSBT technique in reasonable treatment times. PMID- 24784370 TI - Characterization of a two-dimensional liquid-filled ion chamber detector array used for verification of the treatments in radiotherapy. AB - PURPOSE: The purpose of the study is to investigate the characteristics of a two dimensional (2D) liquid-filled ion chamber detector array, which is used for the verification of radiotherapy treatment plans that use small field sizes of up to 10 * 10 cm. METHODS: The device used in this study was Octavius 1000 SRS model (PTW, Freiburg, Germany). Its 2D array of detectors consists of 977 liquid-filled ion chambers arranged over an area of 11 * 11 cm. The size of the detectors is 2.3 * 2.3 * 0.5 mm (volume of 0.003 cm(3)) and their spacing in the inner area of 5.5 * 5.5 cm is 2.5 mm center-to-center, whereas in the outer area it is 5 mm center-to-center. The detector reproducibility, dose linearity, and sensitivity to positional changes of the collimator were tested. Also, the output factors of field sizes ranging from 0.5 * 0.5 to 10 * 10 cm(2) both for open and wedged fields have been measured and compared against those measured by a pin-point ionization chamber, liquid filled microchamber, SRS diode, and EDR2 film. RESULTS: Its short-term reproducibility was within 0.2% and its medium and long term reproducibility was within 0.5% (verified with air ionization chamber absolute dose measurements), which is an excellent result taking into account the daily fluctuation of the linear accelerator and the errors in the device setup reproducibility. The dose linearity and dose rate dependence were measured in the range of 0.5-85 Gy and 0.5-10 Gy min(-1), respectively, and were verified with air ionization chamber absolute dose measurements was within 3%. The measurements of the sensitivity showed that the 2D Array could detect millimetric collimator positional changes. The measured output factors showed an agreement of better than 0.3% with the pinpoint chamber and microliquid filled chamber for the field sizes between 3 * 3 and 10 * 10 cm(2). For field sizes down to 1 * 1 cm(2), the agreement with SRS diode and microliquid filled chamber is better than 2%. The measurements of open and wedge-modulated field profiles were compared to the film and ionization chamber in water measurements. CONCLUSIONS: The Octavius Detector 1000 SRS is an accurate, precise, and reliable detector, very useful for the daily performance of the patient specific quality assurance of radiotherapy treatment plans. PMID- 24784372 TI - Increasing dose gradient and uniformity in small fields using modulation: theory and prototypes for cone-based stereotactic radiosurgery. AB - PURPOSE: To investigate the theoretical limits to the tradeoff between dose gradient and uniformity when modulation is used in the context of cone based SRS, and to design a prototype collimation device that allows for steeper dose gradients and/or higher target uniformity as compared to a standard circular collimator. METHODS: An inverse planning optimization is performed in the context of idealized phantom geometry to determine the ideal fluence pattern that best approximates a "rect function" dose distribution. Ideal fluence patterns were approximated in a prototype device and radiochromic film dosimetry was utilized to compare the prototype device to a standard circular collimator. RESULTS: For choices of prescription isodose lines above approximately 50%, utilizing modulation allows for an improved tradeoff between dose gradient index and dose heterogeneity index. Compensators placed within the circular collimator can achieve the necessary modulation. CONCLUSIONS: Using modulation with features on a submillimeter distance scale, it is possible to increase the dose gradient and/or uniformity in small fields. PMID- 24784371 TI - Predicting oropharyngeal tumor volume throughout the course of radiation therapy from pretreatment computed tomography data using general linear models. AB - PURPOSE: The purpose of this work was to develop and evaluate the accuracy of several predictive models of variation in tumor volume throughout the course of radiation therapy. METHODS: Nineteen patients with oropharyngeal cancers were imaged daily with CT-on-rails for image-guided alignment per an institutional protocol. The daily volumes of 35 tumors in these 19 patients were determined and used to generate (1) a linear model in which tumor volume changed at a constant rate, (2) a general linear model that utilized the power fit relationship between the daily and initial tumor volumes, and (3) a functional general linear model that identified and exploited the primary modes of variation between time series describing the changing tumor volumes. Primary and nodal tumor volumes were examined separately. The accuracy of these models in predicting daily tumor volumes were compared with those of static and linear reference models using leave-one-out cross-validation. RESULTS: In predicting the daily volume of primary tumors, the general linear model and the functional general linear model were more accurate than the static reference model by 9.9% (range: -11.6%-23.8%) and 14.6% (range: -7.3%-27.5%), respectively, and were more accurate than the linear reference model by 14.2% (range: -6.8%-40.3%) and 13.1% (range: -1.5% 52.5%), respectively. In predicting the daily volume of nodal tumors, only the 14.4% (range: -11.1%-20.5%) improvement in accuracy of the functional general linear model compared to the static reference model was statistically significant. CONCLUSIONS: A general linear model and a functional general linear model trained on data from a small population of patients can predict the primary tumor volume throughout the course of radiation therapy with greater accuracy than standard reference models. These more accurate models may increase the prognostic value of information about the tumor garnered from pretreatment computed tomography images and facilitate improved treatment management. PMID- 24784373 TI - Monte Carlo simulation of TrueBeam flattening-filter-free beams using varian phase-space files: comparison with experimental data. AB - PURPOSE: Phase-space files for Monte Carlo simulation of the Varian TrueBeam beams have been made available by Varian. The aim of this study is to evaluate the accuracy of the distributed phase-space files for flattening filter free (FFF) beams, against experimental measurements from ten TrueBeam Linacs. METHODS: The phase-space files have been used as input in PRIMO, a recently released Monte Carlo program based on the PENELOPE code. Simulations of 6 and 10 MV FFF were computed in a virtual water phantom for field sizes 3 * 3, 6 * 6, and 10 * 10 cm(2) using 1 * 1 * 1 mm(3) voxels and for 20 * 20 and 40 * 40 cm(2) with 2 * 2 * 2 mm(3) voxels. The particles contained in the initial phase-space files were transported downstream to a plane just above the phantom surface, where a subsequent phase-space file was tallied. Particles were transported downstream this second phase-space file to the water phantom. Experimental data consisted of depth doses and profiles at five different depths acquired at SSD = 100 cm (seven datasets) and SSD = 90 cm (three datasets). Simulations and experimental data were compared in terms of dose difference. Gamma analysis was also performed using 1%, 1 mm and 2%, 2 mm criteria of dose-difference and distance-to agreement, respectively. Additionally, the parameters characterizing the dose profiles of unflattened beams were evaluated for both measurements and simulations. RESULTS: Analysis of depth dose curves showed that dose differences increased with increasing field size and depth; this effect might be partly motivated due to an underestimation of the primary beam energy used to compute the phase-space files. Average dose differences reached 1% for the largest field size. Lateral profiles presented dose differences well within 1% for fields up to 20 * 20 cm(2), while the discrepancy increased toward 2% in the 40 * 40 cm(2) cases. Gamma analysis resulted in an agreement of 100% when a 2%, 2 mm criterion was used, with the only exception of the 40 * 40 cm(2) field (~95% agreement). With the more stringent criteria of 1%, 1 mm, the agreement reduced to almost 95% for field sizes up to 10 * 10 cm(2), worse for larger fields. Unflatness and slope FFF-specific parameters are in line with the possible energy underestimation of the simulated results relative to experimental data. CONCLUSIONS: The agreement between Monte Carlo simulations and experimental data proved that the evaluated Varian phase-space files for FFF beams from TrueBeam can be used as radiation sources for accurate Monte Carlo dose estimation, especially for field sizes up to 10 * 10 cm(2), that is the range of field sizes mostly used in combination to the FFF, high dose rate beams. PMID- 24784374 TI - Electron contamination modeling and reduction in a 1 T open bore inline MRI-linac system. AB - PURPOSE: A potential side effect of inline MRI-linac systems is electron contamination focusing causing a high skin dose. In this work, the authors reexamine this prediction for an open bore 1 T MRI system being constructed for the Australian MRI-Linac Program. The efficiency of an electron contamination deflector (ECD) in purging electron contamination from the linac head is modeled, as well as the impact of a helium gas region between the deflector and phantom surface for lowering the amount of air-generated contamination. METHODS: Magnetic modeling of the 1 T MRI was used to generate 3D magnetic field maps both with and without the presence of an ECD located immediately below the MLC's. Forty-seven different ECD designs were modeled and for each the magnetic field map was imported into Geant4 Monte Carlo simulations including the linac head, ECD, and a 30 * 30 * 30 cm(3) water phantom located at isocenter. For the first generation system, the x-ray source to isocenter distance (SID) will be 160 cm, resulting in an 81.2 cm long air gap from the base of the ECD to the phantom surface. The first 71.2 cm was modeled as air or helium gas, with the latter encased between two windows of 50 MUm thick high density polyethlyene. 2D skin doses (at 70 MUm depth) were calculated across the phantom surface at 1 * 1 mm(2) resolution for 6 MV beams of field size of 5 * 5, 10 * 10, and 20 * 20 cm(2). RESULTS: The skin dose was predicted to be of similar magnitude as the generic systems modeled in previous work, 230% to 1400% of D(max) for 5 * 5 to 20 * 20 cm(2), respectively. Inclusion of the ECD introduced a nonuniformity to the MRI imaging field that ranged from ~20 to ~140 ppm while the net force acting on the ECD ranged from ~151 N to ~1773 N. Various ECD designs were 100% efficient at purging the electron contamination into the ECD magnet banks; however, a small percentage were scattered back into the beam and continued to the phantom surface. Replacing a large portion of the extended air-column between the ECD and phantom surface with helium gas is a key element as it significantly minimized the air-generated contamination. When using an optimal ECD and helium gas region, the 70 MUm skin dose is predicted to increase moderately inside a small hot spot over that of the case with no magnetic field present for the jaw defined square beams examined here. These increases include from 12% to 40% of [Formula: see text] for 5 * 5 cm(2), 18% to 55% of D(max) for 10 * 10 cm(2), and from 23% to 65% of D(max) for 20 * 20 cm(2). CONCLUSIONS: Coupling an efficient ECD and helium gas region below the MLCs in the 160 cm isocenter MRI-linac system is predicted to ameliorate the impact electron contamination focusing has on skin dose increases. An ECD is practical as its impact on the MRI imaging distortion is correctable, and the mechanical forces acting on it manageable from an engineering point of view. PMID- 24784375 TI - Helical tomotherapy with dynamic running-start-stop delivery compared to conventional tomotherapy delivery. AB - PURPOSE: Despite superior target dose uniformity, helical tomotherapy((r)) (HT) may involve a trade-off between longitudinal dose conformity and beam-on time (BOT), due to the limitation of only three available jaw sizes with the conventional HT (1.0, 2.5, and 5.0 cm). The recently introduced dynamic running start-stop (RSS) delivery allows smaller jaw opening at the superior and inferior ends of the target when a sharp penumbra is needed. This study compared the dosimetric performance of RSS delivery with the fixed jaw HT delivery. METHODS: Twenty patient cases were selected and deidentified prior to treatment planning, including 16 common clinical cases (brain, head and neck (HN), lung, and prostate) and four special cases of whole brain with hippocampus avoidance (WBHA) that require a high degree of dose modulation. HT plans were generated for common clinical cases using the fixed 2.5 cm jaw width (HT2.5) and WBHA cases using 1.0 cm (HT1.0). The jaw widths for RSS were preset with a larger size (RSS5.0 vs HT2.5 and RSS2.5 vs HT1.0). Both delivery techniques were planned based on identical contours, prescriptions, and planning objectives. Dose indices for targets and critical organs were compared using dose-volume histograms, BOT, and monitor units. RESULTS: The average BOT was reduced from 4.8 min with HT2.5 to 2.5 min with RSS5.0. Target dose homogeneity with RSS5.0 was shown comparable to HT2.5 for common clinical sites. Superior normal tissue sparing was observed in RSS5.0 for optic nerves and optic chiasm in brain and HN cases. RSS5.0 demonstrated improved dose sparing for cord and esophagus in lung cases, as well as penile bulb in prostate cases. The mean body dose was comparable for both techniques. For the WBHA cases, the target homogeneity was significantly degraded in RSS2.5 without distinct dose sparing for hippocampus, compared to HT1.0. CONCLUSIONS: Compared to the fixed jaw HT delivery, RSS combined with a larger jaw width provides faster treatment delivery and improved cranial-caudal target dose conformity. The target coverage achieved by RSS with a large jaw width is comparable to the fixed jaw HT delivery for common cancer sites, but may deteriorate for cases where complex geometry is present in the middle part of the target. PMID- 24784376 TI - Investigation of a pulsed current annealing method in reusing MOSFET dosimeters for in vivo IMRT dosimetry. AB - PURPOSE: To explore the feasibility of pulsed current annealing in reusing metal oxide semiconductor field-effect transistor (MOSFET) dosimeters for in vivo intensity modulated radiation therapy (IMRT) dosimetry. METHODS: Several MOSFETs were irradiated at d(max) using a 6 MV x-ray beam with 5 V on the gate and annealed with zero bias at room temperature. The percentage recovery of threshold voltage shift during multiple irradiation-annealing cycles was evaluated. Key dosimetry characteristics of the annealed MOSFET such as the dosimeter's sensitivity, reproducibility, dose linearity, and linearity of response within the dynamic range were investigated. The initial results of using the annealed MOSFETs for IMRT dosimetry practice were also presented. RESULTS: More than 95% of threshold voltage shift can be recovered after 24-pulse current continuous annealing in 16 min. The mean sensitivity degradation was found to be 1.28%, ranging from 1.17% to 1.52%, during multiple annealing procedures. Other important characteristics of the annealed MOSFET remained nearly consistent before and after annealing. Our results showed there was no statistically significant difference between the annealed MOSFETs and their control samples in absolute dose measurements for IMRT QA (p = 0.99). The MOSFET measurements agreed with the ion chamber results on an average of 0.16% +/- 0.64%. CONCLUSIONS: Pulsed current annealing provides a practical option for reusing MOSFETs to extend their operational lifetime. The current annealing circuit can be integrated into the reader, making the annealing procedure fully automatic. PMID- 24784377 TI - MRI-based treatment planning with pseudo CT generated through atlas registration. AB - PURPOSE: To evaluate the feasibility and accuracy of magnetic resonance imaging (MRI)-based treatment planning using pseudo CTs generated through atlas registration. METHODS: A pseudo CT, providing electron density information for dose calculation, was generated by deforming atlas CT images previously acquired on other patients. The authors tested 4 schemes of synthesizing a pseudo CT from single or multiple deformed atlas images: use of a single arbitrarily selected atlas, arithmetic mean process using 6 atlases, and pattern recognition with Gaussian process (PRGP) using 6 or 12 atlases. The required deformation for atlas CT images was derived from a nonlinear registration of conjugated atlas MR images to that of the patient of interest. The contrasts of atlas MR images were adjusted by histogram matching to reduce the effect of different sets of acquisition parameters. For comparison, the authors also tested a simple scheme assigning the Hounsfield unit of water to the entire patient volume. All pseudo CT generating schemes were applied to 14 patients with common pediatric brain tumors. The image similarity of real patient-specific CT and pseudo CTs constructed by different schemes was compared. Differences in computation times were also calculated. The real CT in the treatment planning system was replaced with the pseudo CT, and the dose distribution was recalculated to determine the difference. RESULTS: The atlas approach generally performed better than assigning a bulk CT number to the entire patient volume. Comparing atlas-based schemes, those using multiple atlases outperformed the single atlas scheme. For multiple atlas schemes, the pseudo CTs were similar to the real CTs (correlation coefficient, 0.787-0.819). The calculated dose distribution was in close agreement with the original dose. Nearly the entire patient volume (98.3%-98.7%) satisfied the criteria of chi-evaluation (<2% maximum dose and 2 mm range). The dose to 95% of the volume and the percentage of volume receiving at least 95% of the prescription dose in the planning target volume differed from the original values by less than 2% of the prescription dose (root-mean-square, RMS < 1%). The PRGP scheme did not perform better than the arithmetic mean process with the same number of atlases. Increasing the number of atlases from 6 to 12 often resulted in improvements, but statistical significance was not always found. CONCLUSIONS: MRI-based treatment planning with pseudo CTs generated through atlas registration is feasible for pediatric brain tumor patients. The doses calculated from pseudo CTs agreed well with those from real CTs, showing dosimetric accuracy within 2% for the PTV when multiple atlases were used. The arithmetic mean process may be a reasonable choice over PRGP for the synthesis scheme considering performance and computational costs. PMID- 24784378 TI - HDRMC, an accelerated Monte Carlo dose calculator for high dose rate brachytherapy with CT-compatible applicators. AB - PURPOSE: To present a new accelerated Monte Carlo code for CT-based dose calculations in high dose rate (HDR) brachytherapy. The new code (HDRMC) accounts for both tissue and nontissue heterogeneities (applicator and contrast medium). METHODS: HDRMC uses a fast ray-tracing technique and detailed physics algorithms to transport photons through a 3D mesh of voxels representing the patient anatomy with applicator and contrast medium included. A precalculated phase space file for the(192)Ir source is used as source term. HDRM is calibrated to calculated absolute dose for real plans. A postprocessing technique is used to include the exact density and composition of nontissue heterogeneities in the 3D phantom. Dwell positions and angular orientations of the source are reconstructed using data from the treatment planning system (TPS). Structure contours are also imported from the TPS to recalculate dose-volume histograms. RESULTS: HDRMC was first benchmarked against the MCNP5 code for a single source in homogenous water and for a loaded gynecologic applicator in water. The accuracy of the voxel-based applicator model used in HDRMC was also verified by comparing 3D dose distributions and dose-volume parameters obtained using 1-mm(3) versus 2-mm(3) phantom resolutions. HDRMC can calculate the 3D dose distribution for a typical HDR cervix case with 2-mm resolution in 5 min on a single CPU. Examples of heterogeneity effects for two clinical cases (cervix and esophagus) were demonstrated using HDRMC. The neglect of tissue heterogeneity for the esophageal case leads to the overestimate of CTV D90, CTV D100, and spinal cord maximum dose by 3.2%, 3.9%, and 3.6%, respectively. CONCLUSIONS: A fast Monte Carlo code for CT-based dose calculations which does not require a prebuilt applicator model is developed for those HDR brachytherapy treatments that use CT-compatible applicators. Tissue and nontissue heterogeneities should be taken into account in modern HDR brachytherapy planning. PMID- 24784379 TI - Beam geometry selection using sequential beam addition. AB - PURPOSE: The selection of optimal beam geometry has been of interest since the inception of conformal radiotherapy. The authors report on sequential beam addition, a simple beam geometry selection method, for intensity modulated radiation therapy. METHODS: The sequential beam addition algorithm (SBA) requires definition of an objective function (score) and a set of candidate beam geometries (pool). In the first iteration, the optimal score is determined for each beam in the pool and the beam with the best score selected. In the next iteration, the optimal score is calculated for each beam remaining in the pool combined with the beam selected in the first iteration, and the best scoring beam is selected. The process is repeated until the desired number of beams is reached. The authors selected three treatment sites, breast, lung, and brain, and determined beam arrangements for up to 11 beams from a pool comprised of 25 equiangular transverse beams. For the brain, arrangements were additionally selected from a pool of 22 noncoplanar beams. Scores were determined for geometries comprised equiangular transverse beams (EQA), as well as two tangential beams for the breast case. RESULTS: In all cases, SBA resulted in scores superior to EQA. The breast case had the strongest dependence on beam geometry, for which only the 7-beam EQA geometry had a score better than the two tangential beams, whereas all SBA geometries with more than two beams were superior. In the lung case, EQA and SBA scores monotonically improved with increasing number of beams; however, SBA required fewer beams to achieve scores equivalent to EQA. For the brain case, SBA with a coplanar pool was equivalent to EQA, while the noncoplanar pool resulted in slightly better scores; however, the dose-volume histograms demonstrated that the differences were not clinically significant. CONCLUSIONS: For situations in which beam geometry has a significant effect on the objective function, SBA can identify arrangements equivalent to equiangular geometries but using fewer beams. Furthermore, SBA provides the value of the objective function as the number of beams is increased, allowing the planner to select the minimal beam number that achieves the clinical goals. The method is simple to implement and could readily be incorporated into an existing optimization system. PMID- 24784380 TI - Evaluation of dual energy quantitative CT for determining the spatial distributions of red marrow and bone for dosimetry in internal emitter radiation therapy. AB - PURPOSE: To evaluate a three-equation three-unknown dual-energy quantitative CT (DEQCT) technique for determining region specific variations in bone spongiosa composition for improved red marrow dose estimation in radionuclide therapy. METHODS: The DEQCT method was applied to 80/140 kVp images of patient-simulating lumbar sectional body phantoms of three sizes (small, medium, and large). External calibration rods of bone, red marrow, and fat-simulating materials were placed beneath the body phantoms. Similar internal calibration inserts were placed at vertebral locations within the body phantoms. Six test inserts of known volume fractions of bone, fat, and red marrow were also scanned. External-to internal calibration correction factors were derived. The effects of body phantom size, radiation dose, spongiosa region segmentation granularity [single (~17 * 17 mm) region of interest (ROI), 2 * 2, and 3 * 3 segmentation of that single ROI], and calibration method on the accuracy of the calculated volume fractions of red marrow (cellularity) and trabecular bone were evaluated. RESULTS: For standard low dose DEQCT x-ray technique factors and the internal calibration method, the RMS errors of the estimated volume fractions of red marrow of the test inserts were 1.2-1.3 times greater in the medium body than in the small body phantom and 1.3-1.5 times greater in the large body than in the small body phantom. RMS errors of the calculated volume fractions of red marrow within 2 * 2 segmented subregions of the ROIs were 1.6-1.9 times greater than for no segmentation, and RMS errors for 3 * 3 segmented subregions were 2.3-2.7 times greater than those for no segmentation. Increasing the dose by a factor of 2 reduced the RMS errors of all constituent volume fractions by an average factor of 1.40 +/- 0.29 for all segmentation schemes and body phantom sizes; increasing the dose by a factor of 4 reduced those RMS errors by an average factor of 1.71 +/- 0.25. Results for external calibrations exhibited much larger RMS errors than size matched internal calibration. Use of an average body size external-to-internal calibration correction factor reduced the errors to closer to those for internal calibration. RMS errors of less than 30% or about 0.01 for the bone and 0.1 for the red marrow volume fractions would likely be satisfactory for human studies. Such accuracies were achieved for 3 * 3 segmentation of 5 mm slice images for: (a) internal calibration with 4 times dose for all size body phantoms, (b) internal calibration with 2 times dose for the small and medium size body phantoms, and (c) corrected external calibration with 4 times dose and all size body phantoms. CONCLUSIONS: Phantom studies are promising and demonstrate the potential to use dual energy quantitative CT to estimate the spatial distributions of red marrow and bone within the vertebral spongiosa. PMID- 24784381 TI - Provision of the DDSM mammography metadata in an accessible format. AB - PURPOSE: The Digital Database for Screening Mammography (DDSM) is the largest publicly available resource for mammographic image analysis research and has been used extensively in the past for computer assisted diagnosis (CADx) studies. However, the database has not been searchable for a specific kind of lesion, which rendered the case selection process in past studies often times arbitrary. Therefore, the authors want to provide the complete metadata of the DDSM in an accessible format. METHODS: The authors semiautomatically transformed the data available athttp://marathon.csee.usf.edu/Mammography/Database.html into table format. The 1769 cases (914 from cancer volumes, 855 from benign volumes) comprise 1220 mass lesions (578 benign, 642 malignant) and 859 calcifications (433 benign, 426 malignant). Additionally, 694 normal cases were processed to allow for matching according to age and breast density. RESULTS: The authors provide the entire DDSM metadata (for benign, malignant, and normal cases) as tab delimited text files[see supplementary material at http://dx.doi.org/10.1118/1.4870379E-MPHYA6-41-006405 for DDSM metadata]. CONCLUSIONS: The data provided make the case selection for future studies using the DDSM reproducible. Furthermore, it may serve as a validation dataset for CADx approaches using the BI-RADS lexicon. PMID- 24784382 TI - Free software for performing physical analysis of systems for digital radiography and mammography. AB - PURPOSE: In this paper, the authors present a free software for assisting users in achieving the physical characterization of x-ray digital systems and image quality checks. METHODS: The program was developed as a plugin of a well-known public-domain suite ImageJ. The software can assist users in calculating various physical parameters such as the response curve (also termed signal transfer property), modulation transfer function (MTF), noise power spectra (NPS), and detective quantum efficiency (DQE). It also includes the computation of some image quality checks: defective pixel analysis, uniformity, dark analysis, and lag. RESULTS: The software was made available in 2009 and has been used during the last couple of years by many users who gave us valuable feedback for improving its usability. It was tested for achieving the physical characterization of several clinical systems for digital radiography and mammography. Various published papers made use of the outcomes of the plugin. CONCLUSIONS: This software is potentially beneficial to a variety of users: physicists working in hospitals, staff working in radiological departments, such as medical physicists, physicians, engineers. The plugin, together with a brief user manual, are freely available and can be found online (www.medphys.it/downloads.htm). With our plugin users can estimate all three most important parameters used for physical characterization (MTF, NPS, and also DQE). The plugin can run on any operating system equipped with ImageJ suite. The authors validated the software by comparing MTF and NPS curves on a common set of images with those obtained with other dedicated programs, achieving a very good agreement. PMID- 24784383 TI - Analysis of perceived similarity between pairs of microcalcification clusters in mammograms. AB - PURPOSE: Content-based image retrieval aims to assist radiologists by presenting example images with known pathology that are visually similar to the case being evaluated. In this work, the authors investigate several fundamental issues underlying the similarity ratings between pairs of microcalcification (MC) lesions on mammograms as judged by radiologists: the degree of variability in the similarity ratings, the impact of this variability on agreement between readers in retrieval of similar lesions, and the factors contributing to the readers' similarity ratings. METHODS: The authors conduct a reader study on a set of 1000 image pairs of MC lesions, in which a group of experienced breast radiologists rated the degree of similarity between each image pair. The image pairs are selected, from among possible pairings of 222 cases (110 malignant, 112 benign), based on quantitative image attributes (features) and the results of a preliminary reader study. Next, the authors apply analysis of variance (ANOVA) to quantify the level of variability in the readers' similarity ratings, and study how the variability in individual reader ratings affects consistency between readers. The authors also measure the extent to which readers agree on images which are most similar to a given query, for which the Dice coefficient is used. To investigate how the similarity ratings potentially relate to the attributes underlying the cases, the authors study the fraction of perceptually similar images that also share the same benign or malignant pathology as the query image; moreover, the authors apply multidimensional scaling (MDS) to embed the cases according to their mutual perceptual similarity in a two-dimensional plot, which allows the authors to examine the manner in which similar lesions relate to one another in terms of benign or malignant pathology and clustered MCs. RESULTS: The ANOVA results show that the coefficient of determination in the reader similarity ratings is 0.59. The variability level in the similarity ratings is proved to be a limiting factor, leading to only moderate correlation between the readers in their readings. The Dice coefficient, measuring agreement between readers in retrieval of similar images, can vary from 0.45 to 0.64 with different levels of similarity for individual readers, but is higher for average ratings from a group of readers (from 0.59 to 0.78). More importantly, the fraction of retrieved cases that match the benign or malignant pathology of the query image was found to increase with the degree of similarity among the retrieved images, reaching average value as high as 0.69 for the radiologists (p-value <10(-4) compared to random guessing). Moreover, MDS embedding of all the cases shows that cases having the same pathology tend to cluster together, and that neighboring cases in the plot tend to be similar in their clustered MCs. CONCLUSIONS: While individual readers exhibit substantial variability in their similarity ratings, similarity ratings averaged from a group of readers can achieve a high level of intergroup consistency and agreement in retrieval of similar images. More importantly, perceptually similar cases are also likely to be similar in their underlying benign or malignant pathology and image features of clustered MCs, which could be of diagnostic value in computer-aided diagnosis for lesions with clustered MCs. PMID- 24784384 TI - Assessment of contrast enhanced respiration managed cone-beam CT for image guided radiotherapy of intrahepatic tumors. AB - PURPOSE: Contrast enhancement and respiration management are widely used during image acquisition for radiotherapy treatment planning of liver tumors along with respiration management at the treatment unit. However, neither respiration management nor intravenous contrast is commonly used during cone-beam CT (CBCT) image acquisition for alignment prior to radiotherapy. In this study, the authors investigate the potential gains of injecting an iodinated contrast agent in combination with respiration management during CBCT acquisition for liver tumor radiotherapy. METHODS: Five rabbits with implanted liver tumors were subjected to CBCT with and without motion management and contrast injection. The acquired CBCT images were registered to the planning CT to determine alignment accuracy and dosimetric impact. The authors developed a simulation tool for simulating contrast-enhanced CBCT images from dynamic contrast enhanced CT imaging (DCE-CT) to determine optimal contrast injection protocols. The tool was validated against contrast-enhanced CBCT of the rabbit subjects and was used for five human patients diagnosed with hepatocellular carcinoma. RESULTS: In the rabbit experiment, when neither motion management nor contrast was used, tumor centroid misalignment between planning image and CBCT was 9.2 mm. This was reduced to 2.8 mm when both techniques were employed. Tumors were not visualized in clinical CBCT images of human subjects. Simulated contrast-enhanced CBCT was found to improve tumor contrast in all subjects. Different patients were found to require different contrast injections to maximize tumor contrast. CONCLUSIONS: Based on the authors' animal study, respiration managed contrast enhanced CBCT improves IGRT significantly. Contrast enhanced CBCT benefits from patient specific tracer kinetics determined from DCE-CT. PMID- 24784385 TI - Noise-weighted spatial domain FBP algorithm. AB - PURPOSE: The purpose of this paper is to implement a noise-weighted filtered backprojection (FBP) algorithm in the form of "convolution" backprojection, but this "convolution" has a spatially variant integration kernel. METHODS: Noise weighted FBP algorithms have been developed in recent years, with filtering being performed in the Fourier domain. The noise weighting makes the ramp filter in the FBP algorithm shift-varying. It is not efficient to implement shift-varying filtration in the Fourier domain. It is known that Fourier-domain multiplication is equivalent to spatial-domain convolution. An expansion method is suggested in this paper to obtain a closed-form integration kernel. RESULTS: The noise weighted FBP algorithm can now be implemented in the spatial domain efficiently. The total computation cost is less than that of the Fourier domain implementation. CONCLUSIONS: Computer simulations are used to show the three-term expansion method to approximate the filter kernel. A clinical study is used to verify the feasibility of the proposed algorithm. PMID- 24784386 TI - Evaluation of clinical full field digital mammography with the task specific system-model-based Fourier Hotelling observer (SMFHO) SNR. AB - PURPOSE: The purpose of this work is to evaluate the performance of the image acquisition chain of clinical full field digital mammography (FFDM) systems by quantifying their image quality, and how well the desired information is captured by the images. METHODS: The authors present a practical methodology to evaluate FFDM using the task specific system-model-based Fourier Hotelling observer (SMFHO) signal to noise ratio (SNR), which evaluates the signal and noise transfer characteristics of FFDM systems in the presence of a uniform polymethyl methacrylate phantom that models the attenuation of a 6 cm thick 20/80 breast (20% glandular/80% adipose). The authors model the system performance using the generalized modulation transfer function, which accounts for scatter blur and focal spot unsharpness, and the generalized noise power spectrum, both estimated with the phantom placed in the field of view. Using the system model, the authors were able to estimate system detectability for a series of simulated disk signals with various diameters and thicknesses, quantified by a SMFHO SNR map. Contrast detail (CD) curves were generated from the SNR map and adjusted using an estimate of the human observer efficiency, without performing time-consuming human reader studies. Using the SMFHO method the authors compared two FFDM systems, the GE Senographe DS and Hologic Selenia FFDM systems, which use indirect and direct detectors, respectively. RESULTS: Even though the two FFDM systems have different resolutions, noise properties, detector technologies, and antiscatter grids, the authors found no significant difference between them in terms of detectability for a given signal detection task. The authors also compared the performance between the two image acquisition modes (fine view and standard) of the GE Senographe DS system, and concluded that there is no significant difference when evaluated by the SMFHO. The estimated human observer efficiency was 30 +/- 5% when compared to the SMFHO. The results showed good agreement when compared to other model observers as well as previously published human observer data. CONCLUSIONS: This method generates CD curves from the SMFHO SNR that can be used as figures of merit for evaluating the image acquisition performance of clinical FFDM systems. It provides a way of creating an empirical model of the FFDM system that accounts for patient scatter, focal spot unsharpness, and detector blur. With the use of simulated signals, this method can predict system performance for a signal known exactly/background known exactly detection task with a limited number of images, therefore, it can be readily applied in a clinical environment. PMID- 24784387 TI - Assessment of dedicated low-dose cardiac micro-CT reconstruction algorithms using the left ventricular volume of small rodents as a performance measure. AB - PURPOSE: Phase-correlated microcomputed tomography (micro-CT) imaging plays an important role in the assessment of mouse models of cardiovascular diseases and the determination of functional parameters as the left ventricular volume. As the current gold standard, the phase-correlated Feldkamp reconstruction (PCF), shows poor performance in case of low dose scans, more sophisticated reconstruction algorithms have been proposed to enable low-dose imaging. In this study, the authors focus on the McKinnon-Bates (MKB) algorithm, the low dose phase correlated (LDPC) reconstruction, and the high-dimensional total variation minimization reconstruction (HDTV) and investigate their potential to accurately determine the left ventricular volume at different dose levels from 50 to 500 mGy. The results were verified in phantom studies of a five-dimensional (5D) mathematical mouse phantom. METHODS: Micro-CT data of eight mice, each administered with an x-ray dose of 500 mGy, were acquired, retrospectively gated for cardiac and respiratory motion and reconstructed using PCF, MKB, LDPC, and HDTV. Dose levels down to 50 mGy were simulated by using only a fraction of the projections. Contrast-to-noise ratio (CNR) was evaluated as a measure of image quality. Left ventricular volume was determined using different segmentation algorithms (Otsu, level sets, region growing). Forward projections of the 5D mouse phantom were performed to simulate a micro-CT scan. The simulated data were processed the same way as the real mouse data sets. RESULTS: Compared to the conventional PCF reconstruction, the MKB, LDPC, and HDTV algorithm yield images of increased quality in terms of CNR. While the MKB reconstruction only provides small improvements, a significant increase of the CNR is observed in LDPC and HDTV reconstructions. The phantom studies demonstrate that left ventricular volumes can be determined accurately at 500 mGy. For lower dose levels which were simulated for real mouse data sets, the HDTV algorithm shows the best performance. At 50 mGy, the deviation from the reference obtained at 500 mGy were less than 4%. Also the LDPC algorithm provides reasonable results with deviation less than 10% at 50 mGy while PCF and MKB reconstruction show larger deviations even at higher dose levels. CONCLUSIONS: LDPC and HDTV increase CNR and allow for quantitative evaluations even at dose levels as low as 50 mGy. The left ventricular volumes exemplarily illustrate that cardiac parameters can be accurately estimated at lowest dose levels if sophisticated algorithms are used. This allows to reduce dose by a factor of 10 compared to today's gold standard and opens new options for longitudinal studies of the heart. PMID- 24784388 TI - Combined iterative reconstruction and image-domain decomposition for dual energy CT using total-variation regularization. AB - PURPOSE: Dual-energy CT (DECT) is being increasingly used for its capability of material decomposition and energy-selective imaging. A generic problem of DECT, however, is that the decomposition process is unstable in the sense that the relative magnitude of decomposed signals is reduced due to signal cancellation while the image noise is accumulating from the two CT images of independent scans. Direct image decomposition, therefore, leads to severe degradation of signal-to-noise ratio on the resultant images. Existing noise suppression techniques are typically implemented in DECT with the procedures of reconstruction and decomposition performed independently, which do not explore the statistical properties of decomposed images during the reconstruction for noise reduction. In this work, the authors propose an iterative approach that combines the reconstruction and the signal decomposition procedures to minimize the DECT image noise without noticeable loss of resolution. METHODS: The proposed algorithm is formulated as an optimization problem, which balances the data fidelity and total variation of decomposed images in one framework, and the decomposition step is carried out iteratively together with reconstruction. The noise in the CT images from the proposed algorithm becomes well correlated even though the noise of the raw projections is independent on the two CT scans. Due to this feature, the proposed algorithm avoids noise accumulation during the decomposition process. The authors evaluate the method performance on noise suppression and spatial resolution using phantom studies and compare the algorithm with conventional denoising approaches as well as combined iterative reconstruction methods with different forms of regularization. RESULTS: On the Catphan(c)600 phantom, the proposed method outperforms the existing denoising methods on preserving spatial resolution at the same level of noise suppression, i.e., a reduction of noise standard deviation by one order of magnitude. This improvement is mainly attributed to the high noise correlation in the CT images reconstructed by the proposed algorithm. Iterative reconstruction using different regularization, including quadratic orq-generalized Gaussian Markov random field regularization, achieves similar noise suppression from high noise correlation. However, the proposed TV regularization obtains a better edge preserving performance. Studies of electron density measurement also show that our method reduces the average estimation error from 9.5% to 7.1%. On the anthropomorphic head phantom, the proposed method suppresses the noise standard deviation of the decomposed images by a factor of ~14 without blurring the fine structures in the sinus area. CONCLUSIONS: The authors propose a practical method for DECT imaging reconstruction, which combines the image reconstruction and material decomposition into one optimization framework. Compared to the existing approaches, our method achieves a superior performance on DECT imaging with respect to decomposition accuracy, noise reduction, and spatial resolution. PMID- 24784389 TI - Automatic segmentation of head and neck CT images for radiotherapy treatment planning using multiple atlases, statistical appearance models, and geodesic active contours. AB - PURPOSE: Accurate delineation of organs at risk (OARs) is a precondition for intensity modulated radiation therapy. However, manual delineation of OARs is time consuming and prone to high interobserver variability. Because of image artifacts and low image contrast between different structures, however, the number of available approaches for autosegmentation of structures in the head neck area is still rather low. In this project, a new approach for automated segmentation of head-neck CT images that combine the robustness of multiatlas based segmentation with the flexibility of geodesic active contours and the prior knowledge provided by statistical appearance models is presented. METHODS: The presented approach is using an atlas-based segmentation approach in combination with label fusion in order to initialize a segmentation pipeline that is based on using statistical appearance models and geodesic active contours. An anatomically correct approximation of the segmentation result provided by atlas-based segmentation acts as a starting point for an iterative refinement of this approximation. The final segmentation result is based on using model to image registration and geodesic active contours, which are mutually influencing each other. RESULTS: 18 CT images in combination with manually segmented labels of parotid glands and brainstem were used in a leave-one-out cross validation scheme in order to evaluate the presented approach. For this purpose, 50 different statistical appearance models have been created and used for segmentation. Dice coefficient (DC), mean absolute distance and max. Hausdorff distance between the autosegmentation results and expert segmentations were calculated. An average Dice coefficient of DC = 0.81 (right parotid gland), DC = 0.84 (left parotid gland), and DC = 0.86 (brainstem) could be achieved. CONCLUSIONS: The presented framework provides accurate segmentation results for three important structures in the head neck area. Compared to a segmentation approach based on using multiple atlases in combination with label fusion, the proposed hybrid approach provided more accurate results within a clinically acceptable amount of time. PMID- 24784390 TI - Absolute x-ray dosimetry on a synchrotron medical beam line with a graphite calorimeter. AB - PURPOSE: The absolute dose rate of the Imaging and Medical Beamline (IMBL) on the Australian Synchrotron was measured with a graphite calorimeter. The calorimetry results were compared to measurements from the existing free-air chamber, to provide a robust determination of the absolute dose in the synchrotron beam and provide confidence in the first implementation of a graphite calorimeter on a synchrotron medical beam line. METHODS: The graphite calorimeter has a core which rises in temperature when irradiated by the beam. A collimated x-ray beam from the synchrotron with well-defined edges was used to partially irradiate the core. Two filtration sets were used, one corresponding to an average beam energy of about 80 keV, with dose rate about 50 Gy/s, and the second filtration set corresponding to average beam energy of 90 keV, with dose rate about 20 Gy/s. The temperature rise from this beam was measured by a calibrated thermistor embedded in the core which was then converted to absorbed dose to graphite by multiplying the rise in temperature by the specific heat capacity for graphite and the ratio of cross-sectional areas of the core and beam. Conversion of the measured absorbed dose to graphite to absorbed dose to water was achieved using Monte Carlo calculations with the EGSnrc code. The air kerma measurements from the free air chamber were converted to absorbed dose to water using the AAPM TG-61 protocol. RESULTS: Absolute measurements of the IMBL dose rate were made using the graphite calorimeter and compared to measurements with the free-air chamber. The measurements were at three different depths in graphite and two different filtrations. The calorimetry measurements at depths in graphite show agreement within 1% with free-air chamber measurements, when converted to absorbed dose to water. The calorimetry at the surface and free-air chamber results show agreement of order 3% when converted to absorbed dose to water. The combined standard uncertainty is 3.9%. CONCLUSIONS: The good agreement of the graphite calorimeter and free-air chamber results indicates that both devices are performing as expected. Further investigations at higher dose rates than 50 Gy/s are planned. At higher dose rates, recombination effects for the free-air chamber are much higher and expected to lead to much larger uncertainties. Since the graphite calorimeter does not have problems associated with dose rate, it is an appropriate primary standard detector for the synchrotron IMBL x rays and is the more accurate dosimeter for the higher dose rates expected in radiotherapy applications. PMID- 24784391 TI - Adaptive error detection for HDR/PDR brachytherapy: guidance for decision making during real-time in vivo point dosimetry. AB - PURPOSE: This study presents an adaptive error detection algorithm (AEDA) for real-time in vivo point dosimetry during high dose rate (HDR) or pulsed dose rate (PDR) brachytherapy (BT) where the error identification, in contrast to existing approaches, does not depend on an a priori reconstruction of the dosimeter position. Instead, the treatment is judged based on dose rate comparisons between measurements and calculations of the most viable dosimeter position provided by the AEDA in a data driven approach. As a result, the AEDA compensates for false error cases related to systematic effects of the dosimeter position reconstruction. Given its nearly exclusive dependence on stable dosimeter positioning, the AEDA allows for a substantially simplified and time efficient real-time in vivo BT dosimetry implementation. METHODS: In the event of a measured potential treatment error, the AEDA proposes the most viable dosimeter position out of alternatives to the original reconstruction by means of a data driven matching procedure between dose rate distributions. If measured dose rates do not differ significantly from the most viable alternative, the initial error indication may be attributed to a mispositioned or misreconstructed dosimeter (false error). However, if the error declaration persists, no viable dosimeter position can be found to explain the error, hence the discrepancy is more likely to originate from a misplaced or misreconstructed source applicator or from erroneously connected source guide tubes (true error). RESULTS: The AEDA applied on two in vivo dosimetry implementations for pulsed dose rate BT demonstrated that the AEDA correctly described effects responsible for initial error indications. The AEDA was able to correctly identify the major part of all permutations of simulated guide tube swap errors and simulated shifts of individual needles from the original reconstruction. Unidentified errors corresponded to scenarios where the dosimeter position was sufficiently symmetric with respect to error and no-error source position constellations. The AEDA was able to correctly identify all false errors represented by mispositioned dosimeters contrary to an error detection algorithm relying on the original reconstruction. CONCLUSIONS: The study demonstrates that the AEDA error identification during HDR/PDR BT relies on a stable dosimeter position rather than on an accurate dosimeter reconstruction, and the AEDA's capacity to distinguish between true and false error scenarios. The study further shows that the AEDA can offer guidance in decision making in the event of potential errors detected with real-time in vivo point dosimetry. PMID- 24784392 TI - Beam characteristics of energy-matched flattening filter free beams. AB - PURPOSE: Flattening filter free (FFF) linear accelerators can increase treatment efficiency and plan quality. There are multiple methods of defining a FFF beam. The Elekta control system supports tuning of the delivered FFF beam energy to enable matching of the percentage depth-dose (PDD) of the flattened beam at 10 cm depth. This is compared to FFF beams where the linac control parameters are identical to those for the flattened beam. All beams were delivered on an Elekta Synergy accelerator with an Agility multi-leaf collimator installed and compared to the standard, flattened beam. The aim of this study is to compare "matched" FFF beams to both "unmatched" FFF beams and flattened beams to determine the benefits of matching beams. METHODS: For the three modes of operation 6 MV flattened, 6 MV matched FFF, 6 MV unmatched FFF, 10 MV flattened, 10 MV matched FFF, and 10 MV unmatched FFF beam profiles were obtained using a plotting tank and were measured in steps of 0.1 mm in the penumbral region. Beam penumbra was defined as the distance between the 80% and 20% of the normalized dose when the inflection points of the unflattened and flattened profiles were normalized with the central axis dose of the flattened field set as 100%. PDD data was obtained at field sizes ranging from 3 cm * 3 cm to 40 cm * 40 cm. Radiation protection measurements were additionally performed to determine the head leakage and environmental monitoring through the maze and primary barriers. RESULTS: No significant change is made to the beam penumbra for FFF beams with and without PDD matching, the maximum change in penumbra for a 10 cm * 10 cm field was within the experimental error of the study. The changes in the profile shape with increasing field size are most significant for the matched FFF beam, and both FFF beams showed less profile shape variation with increasing depth when compared to flattened beams, due to consistency in beam energy spectra across the radiation field. The PDDs of the FFF beams showed less variation with field size, the d(max) value was deeper for the matched FFF beam than the FFF beam and deeper than the flattened beam for field sizes greater than 5 cm * 5 cm. The head leakage when using the machine in FFF mode is less than half that for a flattened beam, but comparable for both FFF modes. The radiation protection dose-rate measurements show an increase of instantaneous dose-rates when operating the machines in FFF mode but that increase is less than the ratio of MU/min produced by the machine. CONCLUSIONS: The matching of a FFF beam to a flattened beam at a depth of 10 cm in water by increasing the FFF beam energy does not reduce any of the reported benefits of FFF beams. Conversely, there are a number of potential benefits resulting from matching the FFF beam; the depth of maximum dose is deeper, the out of field dose is potentially reduced, and the beam quality and penetration more closely resembles the flattened beams currently used in clinical practice, making dose distributions in water more alike. Highlighted in this work is the fact that some conventional specifications and methods for measurement of beam parameters such as penumbra are not relevant and further work is required to address this situation with respect to "matched" FFF beams and to determine methods of measurement that are not reliant on an associated flattened beam. PMID- 24784393 TI - Development and characterization of a three-dimensional radiochromic film stack dosimeter for megavoltage photon beam dosimetry. AB - PURPOSE: Three-dimensional (3D) dosimeters are particularly useful for verifying the commissioning of treatment planning and delivery systems, especially with the ever-increasing implementation of complex and conformal radiotherapy techniques such as volumetric modulated arc therapy. However, currently available 3D dosimeters require extensive experience to prepare and analyze, and are subject to large measurement uncertainties. This work aims to provide a more readily implementable 3D dosimeter with the development and characterization of a radiochromic film stack dosimeter for megavoltage photon beam dosimetry. METHODS: A film stack dosimeter was developed using Gafchromic((r)) EBT2 films. The dosimeter consists of 22 films separated by 1 mm-thick spacers. A Virtual WaterTM phantom was created that maintains the radial film alignment within a maximum uncertainty of 0.3 mm. The film stack dosimeter was characterized using simulations and measurements of 6 MV fields. The absorbed-dose energy dependence and orientation dependence of the film stack dosimeter were investigated using Monte Carlo simulations. The water equivalence of the dosimeter was determined by comparing percentage-depth-dose (PDD) profiles measured with the film stack dosimeter and simulated using Monte Carlo methods. Film stack dosimeter measurements were verified with thermoluminescent dosimeter (TLD) microcube measurements. The film stack dosimeter was also used to verify the delivery of an intensity-modulated radiation therapy (IMRT) procedure. RESULTS: The absorbed dose energy response of EBT2 film differs less than 1.5% between the calibration and film stack dosimeter geometries for a 6 MV spectrum. Over a series of beam angles ranging from normal incidence to parallel incidence, the overall variation in the response of the film stack dosimeter is within a range of 2.5%. Relative to the response to a normally incident beam, the film stack dosimeter exhibits a 1% under-response when the beam axis is parallel to the film planes. Measured and simulated PDD profiles agree within a root-mean-square difference of 1.3%. In field film stack dosimeter and TLD measurements agree within 5%, and measurements in the field penumbra agree within 0.5 mm. Film stack dosimeter and TLD measurements have expanded (k = 2) overall measurement uncertainties of 6.2% and 5.8%, respectively. Film stack dosimeter measurements of an IMRT dose distribution have 98% agreement with the treatment planning system dose calculation, using gamma criteria of 3% and 2 mm. CONCLUSIONS: The film stack dosimeter is capable of high-resolution, low-uncertainty 3D dose measurements, and can be readily incorporated into an existing film dosimetry program. PMID- 24784394 TI - The effects of magnetic field distortion on the accuracy of passive device localization frames in MR imaging. AB - PURPOSE: The interventional magnetic resonance (MR) imaging environment presents many challenges for the accurate localization of interventional devices. In particular, geometric distortion of the static magnetic field may be both appreciable and unpredictable. This paper aims to quantify the sensitivity of localization error of various passive device localization frames to static magnetic field distortion in MR. METHODS: Three localization frames were considered based on having distinctly different methods of encoding position and orientation in MR images. For each frame, the effects of static field distortion were modeled, allowing rotational and translational errors to be computed as functions of the level of distortion, which was modeled using a first order approximation. Validation of the model was performed by imaging the localization frames in a 3T clinical MR scanner, and simulating the effects of static field distortion by varying the scanner's center frequency and gradient shim values. RESULTS: Plots of the rotational and translational components of error in localization frame position and orientation estimates are provided for ranges of uniform static field distortions of 1-100 MUT and static field distortion gradients of 0.01-1 mT/m in all three directions. The theoretical estimates are in good agreement with the results obtained by imaging. CONCLUSIONS: The error in position and orientation estimation of passive localization frames in MR can be sensitive to static magnetic field distortions. The level of sensitivity, the type of error (i.e., rotational or translational), and the direction of error are dependent on the frame's design and the method used to image it. If 2D gradient echo imaging is employed, frames with position and orientation estimate sensitivity to slice-select error (such as the z-frame) should be avoided, since this source of error is not easily correctable. Accurate frame position and orientation estimates that are insensitive to static field distortion can be achieved using 2D gradient echo imaging if: (a) the method of determining position and orientation only uses in-plane measurements of marker positions, (b) the in-plane marker positions in images are not sensitive to slice-select error, and (c) methods of correcting in-plane error in the frequency-encoded direction are employed. PMID- 24784395 TI - Longitudinal, intermodality registration of quantitative breast PET and MRI data acquired before and during neoadjuvant chemotherapy: preliminary results. AB - PURPOSE: The authors propose a method whereby serially acquired DCE-MRI, DW-MRI, and FDG-PET breast data sets can be spatially and temporally coregistered to enable the comparison of changes in parameter maps at the voxel level. METHODS: First, the authors aligned the PET and MR images at each time point rigidly and nonrigidly. To register the MR images longitudinally, the authors extended a nonrigid registration algorithm by including a tumor volume-preserving constraint in the cost function. After the PET images were aligned to the MR images at each time point, the authors then used the transformation obtained from the longitudinal registration of the MRI volumes to register the PET images longitudinally. The authors tested this approach on ten breast cancer patients by calculating a modified Dice similarity of tumor size between the PET and MR images as well as the bending energy and changes in the tumor volume after the application of the registration algorithm. RESULTS: The median of the modified Dice in the registered PET and DCE-MRI data was 0.92. For the longitudinal registration, the median tumor volume change was -0.03% for the constrained algorithm, compared to -32.16% for the unconstrained registration algorithms (p = 8 * 10(-6)). The medians of the bending energy were 0.0092 and 0.0001 for the unconstrained and constrained algorithms, respectively (p = 2.84 * 10(-7)). CONCLUSIONS: The results indicate that the proposed method can accurately spatially align DCE-MRI, DW-MRI, and FDG-PET breast images acquired at different time points during therapy while preventing the tumor from being substantially distorted or compressed. PMID- 24784396 TI - Semiautomatic segmentation and follow-up of multicomponent low-grade tumors in longitudinal brain MRI studies. AB - PURPOSE: Tracking the progression of low grade tumors (LGTs) is a challenging task, due to their slow growth rate and associated complex internal tumor components, such as heterogeneous enhancement, hemorrhage, and cysts. In this paper, the authors show a semiautomatic method to reliably track the volume of LGTs and the evolution of their internal components in longitudinal MRI scans. METHODS: The authors' method utilizes a spatiotemporal evolution modeling of the tumor and its internal components. Tumor components gray level parameters are estimated from the follow-up scan itself, obviating temporal normalization of gray levels. The tumor delineation procedure effectively incorporates internal classification of the baseline scan in the time-series as prior data to segment and classify a series of follow-up scans. The authors applied their method to 40 MRI scans of ten patients, acquired at two different institutions. Two types of LGTs were included: Optic pathway gliomas and thalamic astrocytomas. For each scan, a "gold standard" was obtained manually by experienced radiologists. The method is evaluated versus the gold standard with three measures: gross total volume error, total surface distance, and reliability of tracking tumor components evolution. RESULTS: Compared to the gold standard the authors' method exhibits a mean Dice similarity volumetric measure of 86.58% and a mean surface distance error of 0.25 mm. In terms of its reliability in tracking the evolution of the internal components, the method exhibits strong positive correlation with the gold standard. CONCLUSIONS: The authors' method provides accurate and repeatable delineation of the tumor and its internal components, which is essential for therapy assessment of LGTs. Reliable tracking of internal tumor components over time is novel and potentially will be useful to streamline and improve follow-up of brain tumors, with indolent growth and behavior. PMID- 24784397 TI - Evaluation of template matching for tumor motion management with cine-MR images in lung cancer patients. AB - PURPOSE: Accurate determination of tumor position is crucial for successful application of motion compensated radiotherapy in lung cancer patients. This study tested the performance of an automated template matching algorithm in tracking the tumor position on cine-MR images by examining the tracking error and further comparing the tracking error to the interoperator variability of three human reviewers. METHODS: Cine-MR images of 12 lung cancer patients were analyzed. Tumor positions were determined both automatically with template matching and manually by a radiation oncologist and two additional reviewers trained by the radiation oncologist. Performance of the automated template matching was compared against the ground truth established by the radiation oncologist. Additionally, the tracking error of template matching, defined as the difference in the tumor positions determined with template matching and the ground truth, was investigated and compared to the interoperator variability for all patients in the anterior-posterior (AP) and superior-inferior (SI) directions, respectively. RESULTS: The median tracking error for ten out of the 12 patients studied in both the AP and SI directions was less than 1 pixel (= 1.95 mm). Furthermore, the median tracking error for seven patients in the AP direction and nine patients in the SI direction was less than half a pixel (= 0.975 mm). The median tracking error was positively correlated with the tumor motion magnitude in both the AP (R = 0.55, p = 0.06) and SI (R = 0.67, p = 0.02) directions. Also, a strong correlation was observed between tracking error and interoperator variability (y = 0.26 + 1.25x, R = 0.84, p < 0.001) with the latter larger. CONCLUSIONS: Results from this study indicate that the performance of template matching is comparable with or better than that of manual tumor localization. This study serves as preliminary investigations towards developing online motion tracking techniques for hybrid MRI-Linac systems. Accuracy of template matching makes it a suitable candidate to replace the labor intensive manual tumor localization for obtaining the ground truth when testing other motion management techniques. PMID- 24784398 TI - Three dosimetry models of lipoma arborescens treated by 90Y synovectomy. AB - PURPOSE: Lipoma arborescens (LA) is a benign intra-articular lipomatous proliferation of the synovial membrane. This extremely rare condition has previously been treated by intra-articular (90)Y radiosynoviorthesis but dosimetry literature on this form of radionuclide therapy is nonexistent. The authors detail methodology for successful treatment of LA and provide for the first time estimates of radiation dosimetry. The authors also analyze the biodistribution of the radiopharmaceutical over the course of the patient's treatment through sequential imaging. METHODS: A patient with bilateral LA underwent intracavity injection of (90)Y citrate colloid to the right and left knee joint spaces (181 and 198 MBq, respectively). SPECT/CT datasets were acquired over 9 days to quantify the biodistribution and kinetics of the radiopharmaceutical. Radiation dosimetry was performed using the MIRD schema (through OLINDA software), a custom voxel-based method, and a direct Monte Carlo calculation (OEDIPE). RESULTS: Follow-up MRI showed marked reduction in LA size in both knees. Mean absorbed doses to the LA were 21.2 +/- 0.8 and 42.9 +/- 2.3 Gy using OLINDA, 8.1 +/- 0.3 and 16.7 +/- 0.5 Gy using voxel based methodology, and 8.2 +/- 0.3 and 15.7 +/- 0.5 Gy for OEDIPE in the right and left LA, respectively. Distribution of the radiopharmaceutical within the joint space alters over the imaging period, with less than 1% of the remaining activity having moved posteriorly in the knee cavity. No uptake was detected outside of the joint space after assessment with whole-body scintigraphy. CONCLUSIONS: An activity of approximately 185 MBq successfully relieved clinical symptoms of LA. There was good correlation between direct Monte Carlo and voxel based techniques, but OLINDA was shown to overestimate the absorbed dose to the tumor. Accurate dosimetry may help select an activity more tailored to the specific size and location of the LA. PMID- 24784399 TI - Correction for FDG PET dose extravasations: Monte Carlo validation and quantitative evaluation of patient studies. AB - PURPOSE: Current procedure guidelines for whole body [18F]fluoro-2-deoxy-D glucose (FDG)-positron emission tomography (PET) state that studies with visible dose extravasations should be rejected for quantification protocols. Our work is focused on the development and validation of methods for estimating extravasated doses in order to correct standard uptake value (SUV) values for this effect in clinical routine. METHODS: One thousand three hundred sixty-seven consecutive whole body FDG-PET studies were visually inspected looking for extravasation cases. Two methods for estimating the extravasated dose were proposed and validated in different scenarios using Monte Carlo simulations. All visible extravasations were retrospectively evaluated using a manual ROI based method. In addition, the 50 patients with higher extravasated doses were also evaluated using a threshold-based method. RESULTS: Simulation studies showed that the proposed methods for estimating extravasated doses allow us to compensate the impact of extravasations on SUV values with an error below 5%. The quantitative evaluation of patient studies revealed that paravenous injection is a relatively frequent effect (18%) with a small fraction of patients presenting considerable extravasations ranging from 1% to a maximum of 22% of the injected dose. A criterion based on the extravasated volume and maximum concentration was established in order to identify this fraction of patients that might be corrected for paravenous injection effect. CONCLUSIONS: The authors propose the use of a manual ROI based method for estimating the effectively administered FDG dose and then correct SUV quantification in those patients fulfilling the proposed criterion. PMID- 24784400 TI - Isotope specific resolution recovery image reconstruction in high resolution PET imaging. AB - PURPOSE: Measuring and incorporating a scanner-specific point spread function (PSF) within image reconstruction has been shown to improve spatial resolution in PET. However, due to the short half-life of clinically used isotopes, other long lived isotopes not used in clinical practice are used to perform the PSF measurements. As such, non-optimal PSF models that do not correspond to those needed for the data to be reconstructed are used within resolution modeling (RM) image reconstruction, usually underestimating the true PSF owing to the difference in positron range. In high resolution brain and preclinical imaging, this effect is of particular importance since the PSFs become more positron range limited and isotope-specific PSFs can help maximize the performance benefit from using resolution recovery image reconstruction algorithms. METHODS: In this work, the authors used a printing technique to simultaneously measure multiple point sources on the High Resolution Research Tomograph (HRRT), and the authors demonstrated the feasibility of deriving isotope-dependent system matrices from fluorine-18 and carbon-11 point sources. Furthermore, the authors evaluated the impact of incorporating them within RM image reconstruction, using carbon-11 phantom and clinical datasets on the HRRT. RESULTS: The results obtained using these two isotopes illustrate that even small differences in positron range can result in different PSF maps, leading to further improvements in contrast recovery when used in image reconstruction. The difference is more pronounced in the centre of the field-of-view where the full width at half maximum (FWHM) from the positron range has a larger contribution to the overall FWHM compared to the edge where the parallax error dominates the overall FWHM. CONCLUSIONS: Based on the proposed methodology, measured isotope-specific and spatially variant PSFs can be reliably derived and used for improved spatial resolution and variance performance in resolution recovery image reconstruction. The benefits are expected to be more substantial for more energetic positron emitting isotopes such as Oxygen-15 and Rubidium-82. PMID- 24784401 TI - Exploring potential mechanisms responsible for observed changes of ultrasonic backscattered energy with temperature variations. AB - PURPOSE: Previous studies have provided the observation that the ultrasonic backscattered energy from a tissue region will change due to a change of temperature. The mechanism responsible for the changes in backscattered energy (CBE) with temperature has been hypothesized to be from the changes in scattering properties of local aqueous and lipid scatterers. An alternative mechanism is hypothesized here to be capable of producing similar CBE curves, i.e., changes in speckle resulting from changes in summation of scattered wavelets. METHODS: Both simulations and experiments were conducted with a 5.5 MHz, 128-element linear array and synthetic and physical phantoms containing randomly spaced scatterers. The speckle pattern resulting from summation of scattered wavelets was changed in simulations and experiments by directly increasing the background sound speed from 1520 to 1540 m/s, and changing the temperature from 37 degrees C to 48 degrees C, respectively. Shifts in the backscattered signal were compensated using 2D cross-correlation techniques. RESULTS: Excellent agreement between simulations and experiments was observed, with each pixel in the CBE images on average undergoing either a monotonic increase (up to 3.2 dB) or a monotonic decrease (down to -1.9 dB) with increasing sound speed or temperature. Similar CBE curves were also produced by shifting the image plane in the elevational and axial directions even after correcting for apparent motion. CONCLUSIONS: CBE curves were produced by changing the sound speed or temperature in tissue mimicking phantoms or by shifting the image plane in the elevational and axial directions and the production of these CBE curves did not require the presence of lipid and aqueous scatterers. PMID- 24784402 TI - Temporally diffeomorphic cardiac motion estimation from three-dimensional echocardiography by minimization of intensity consistency error. AB - PURPOSE: Quantitative analysis of cardiac motion is important for evaluation of heart function. Three dimensional (3D) echocardiography is among the most frequently used imaging modalities for motion estimation because it is convenient, real-time, low-cost, and nonionizing. However, motion estimation from 3D echocardiographic sequences is still a challenging problem due to low image quality and image corruption by noise and artifacts. METHODS: The authors have developed a temporally diffeomorphic motion estimation approach in which the velocity field instead of the displacement field was optimized. The optimal velocity field optimizes a novel similarity function, which we call the intensity consistency error, defined as multiple consecutive frames evolving to each time point. The optimization problem is solved by using the steepest descent method. RESULTS: Experiments with simulated datasets, images of anex vivo rabbit phantom, images of in vivo open-chest pig hearts, and healthy human images were used to validate the authors' method. Simulated and real cardiac sequences tests showed that results in the authors' method are more accurate than other competing temporal diffeomorphic methods. Tests with sonomicrometry showed that the tracked crystal positions have good agreement with ground truth and the authors' method has higher accuracy than the temporal diffeomorphic free-form deformation (TDFFD) method. Validation with an open-access human cardiac dataset showed that the authors' method has smaller feature tracking errors than both TDFFD and frame-to frame methods. CONCLUSIONS: The authors proposed a diffeomorphic motion estimation method with temporal smoothness by constraining the velocity field to have maximum local intensity consistency within multiple consecutive frames. The estimated motion using the authors' method has good temporal consistency and is more accurate than other temporally diffeomorphic motion estimation methods. PMID- 24784403 TI - Temperature elevation by HIFU in ex vivo porcine muscle: MRI measurement and simulation study. AB - PURPOSE: High-intensity focused ultrasound is a rapidly developing medical technology with a large number of potential clinical applications. Computational model can play a pivotal role in the planning and optimization of the treatment based on the patient's image. Nonlinear propagation effects can significantly affect the temperature elevation and should be taken into account. In order to investigate the importance of nonlinear propagation effects, nonlinear Westervelt equation was solved. Weak nonlinear propagation effects were studied. The purpose of this study was to investigate the correlation between the predicted and measured temperature elevations and lesion in a porcine muscle. METHODS: The investigated single-element transducer has a focal length of 12 cm, an aperture of 8 cm, and frequency of 1.08 MHz. Porcine muscle was heated for 30 s by focused ultrasound transducer with an acoustic power in the range of 24-56 W. The theoretical model consists of nonlinear Westervelt equation with relaxation effects being taken into account and Pennes bioheat equation. RESULTS: Excellent agreement between the measured and simulated temperature rises was found. For peak temperatures above 85-90 degrees C "preboiling" or cavitation activity appears and lesion distortion starts, causing small discrepancy between the measured and simulated temperature rises. From the measurements and simulations, it was shown that distortion of the lesion was caused by the "preboiling" activity. CONCLUSIONS: The present study demonstrated that for peak temperatures below 85-90 degrees C numerical simulation results are in excellent agreement with the experimental data in three dimensions. Both temperature rise and lesion size can be well predicted. Due to nonlinear effect the temperature in the focal region can be increased compared with the linear case. The current magnetic resonance imaging (MRI) resolution is not sufficient. Due to the inevitable averaging the measured temperature can be 10-30 degrees C lower than the peak temperature. Computational fluid dynamics can provide additional important information that is lost using a state of the art MRI device. PMID- 24784404 TI - Joint intensity-and-point based registration of free-hand B-mode ultrasound and MRI of the carotid artery. AB - PURPOSE: To introduce a semiautomatic algorithm to perform the registration of free-hand B-Mode ultrasound (US) and magnetic resonance imaging (MRI) of the carotid artery. METHODS: The authors' approach combines geometrical features and intensity information. The only user interaction consists of placing three seed points in US and MRI. First, the lumen centerlines are used as landmarks for point based registration. Subsequently, in a joint optimization the distance between centerlines and the dissimilarity of the image intensities is minimized. Evaluation is performed in left and right carotids from six healthy volunteers and five patients with atherosclerosis. For the validation, the authors measure the Dice similarity coefficient (DSC) and the mean surface distance (MSD) between carotid lumen segmentations in US and MRI after registration. The effect of several design parameters on the registration accuracy is investigated by an exhaustive search on a training set of five volunteers and three patients. The optimum configuration is validated on the remaining images of one volunteer and two patients. RESULTS: On the training set, the authors achieve an average DSC of 0.74 and a MSD of 0.66 mm on volunteer data. For the patient data, the authors obtain a DSC of 0.77 and a MSD of 0.69 mm. In the independent set composed of patient and volunteer data, the DSC is 0.69 and the MSD is 0.87 mm. The experiments with different design parameters show that nonrigid registration outperforms rigid registration, and that the combination of intensity and point information is superior to approaches that use intensity or points only. CONCLUSIONS: The proposed method achieves an accurate registration of US and MRI, and may thus enable multimodal analysis of the carotid plaque. PMID- 24784405 TI - Real-time tumor ablation simulation based on the dynamic mode decomposition method. AB - PURPOSE: The dynamic mode decomposition (DMD) method is used to provide a reliable forecasting of tumor ablation treatment simulation in real time, which is quite needed in medical practice. To achieve this, an extended Pennes bioheat model must be employed, taking into account both the water evaporation phenomenon and the tissue damage during tumor ablation. METHODS: A meshless point collocation solver is used for the numerical solution of the governing equations. The results obtained are used by the DMD method for forecasting the numerical solution faster than the meshless solver. The procedure is first validated against analytical and numerical predictions for simple problems. The DMD method is then applied to three-dimensional simulations that involve modeling of tumor ablation and account for metabolic heat generation, blood perfusion, and heat ablation using realistic values for the various parameters. RESULTS: The present method offers very fast numerical solution to bioheat transfer, which is of clinical significance in medical practice. It also sidesteps the mathematical treatment of boundaries between tumor and healthy tissue, which is usually a tedious procedure with some inevitable degree of approximation. The DMD method provides excellent predictions of the temperature profile in tumors and in the healthy parts of the tissue, for linear and nonlinear thermal properties of the tissue. CONCLUSIONS: The low computational cost renders the use of DMD suitable for in situ real time tumor ablation simulations without sacrificing accuracy. In such a way, the tumor ablation treatment planning is feasible using just a personal computer thanks to the simplicity of the numerical procedure used. The geometrical data can be provided directly by medical image modalities used in everyday practice. PMID- 24784406 TI - Electrical circuit modeling and analysis of microwave acoustic interaction with biological tissues. AB - PURPOSE: Numerical study of microwave imaging and microwave-induced thermoacoustic imaging utilizes finite difference time domain (FDTD) analysis for simulation of microwave and acoustic interaction with biological tissues, which is time consuming due to complex grid-segmentation and numerous calculations, not straightforward due to no analytical solution and physical explanation, and incompatible with hardware development requiring circuit simulator such as SPICE. In this paper, instead of conventional FDTD numerical simulation, an equivalent electrical circuit model is proposed to model the microwave acoustic interaction with biological tissues for fast simulation and quantitative analysis in both one and two dimensions (2D). METHODS: The equivalent circuit of ideal point-like tissue for microwave-acoustic interaction is proposed including transmission line, voltage-controlled current source, envelop detector, and resistor-inductor capacitor (RLC) network, to model the microwave scattering, thermal expansion, and acoustic generation. Based on which, two-port network of the point-like tissue is built and characterized using pseudo S-parameters and transducer gain. Two dimensional circuit network including acoustic scatterer and acoustic channel is also constructed to model the 2D spatial information and acoustic scattering effect in heterogeneous medium. RESULTS: Both FDTD simulation, circuit simulation, and experimental measurement are performed to compare the results in terms of time domain, frequency domain, and pseudo S-parameters characterization. 2D circuit network simulation is also performed under different scenarios including different sizes of tumors and the effect of acoustic scatterer. CONCLUSIONS: The proposed circuit model of microwave acoustic interaction with biological tissue could give good agreement with FDTD simulated and experimental measured results. The pseudo S-parameters and characteristic gain could globally evaluate the performance of tumor detection. The 2D circuit network enables the potential to combine the quasi-numerical simulation and circuit simulation in a uniform simulator for codesign and simulation of a microwave acoustic imaging system, bridging bioeffect study and hardware development seamlessly. PMID- 24784407 TI - WAXS fat subtraction model to estimate differential linear scattering coefficients of fatless breast tissue: phantom materials evaluation. AB - PURPOSE: Develop a method to subtract fat tissue contributions to wide-angle x ray scatter (WAXS) signals of breast biopsies in order to estimate the differential linear scattering coefficients MU(s) of fatless tissue. Cancerous and fibroglandular tissue can then be compared independent of fat content. In this work phantom materials with known compositions were used to test the efficacy of the WAXS subtraction model. METHODS: Each sample 5 mm in diameter and 5 mm thick was interrogated by a 50 kV 2.7 mm diameter beam for 3 min. A 25 mm(2) by 1 mm thick CdTe detector allowed measurements of a portion of the theta = 6 degrees scattered field. A scatter technique provided means to estimate the incident spectrum N(0)(E) needed in the calculations of MU(s)[x(E, theta)] where x is the momentum transfer argument. Values of [Formula: see text] for composite phantoms consisting of three plastic layers were estimated and compared to the values obtained via the sum [Formula: see text], where nu(i) is the fractional volume of the ith plastic component. Water, polystyrene, and a volume mixture of 0.6 water + 0.4 polystyrene labelled as fibphan were chosen to mimic cancer, fat, and fibroglandular tissue, respectively. A WAXS subtraction model was used to remove the polystyrene signal from tissue composite phantoms so that the MU(s) of water and fibphan could be estimated. Although the composite samples were layered, simulations were performed to test the models under nonlayered conditions. RESULTS: The well known MU(s) signal of water was reproduced effectively between 0.5 < x < 1.6 nm(-1). The [Formula: see text] obtained for the heterogeneous samples agreed with [Formula: see text]. Polystyrene signals were subtracted successfully from composite phantoms. The simulations validated the usefulness of the WAXS models for nonlayered biopsies. CONCLUSIONS: The methodology to measure MU(s) of homogeneous samples was quantitatively accurate. Simple WAXS models predicted the probabilities for specific x-ray scattering to occur from heterogeneous biopsies. The fat subtraction model can allow MU(s) signals of breast cancer and fibroglandular tissue to be compared without the effects of fat provided there is an independent measurement of the fat volume fraction nu(f). Future work will consist of devising a quantitative x-ray digital imaging method to estimate nu(f) in ex vivo breast samples. PMID- 24784408 TI - Photoacoustic detection and optical spectroscopy of high-intensity focused ultrasound-induced thermal lesions in biologic tissue. AB - PURPOSE: The aims of this study are: (a) to investigate the capability of photoacoustic (PA) method in detecting high-intensity focused ultrasound (HIFU) treatments in muscle tissues in vitro; and (b) to determine the optical properties of HIFU-treated and native tissues in order to assist in the interpretation of the observed contrast in PA detection of HIFU treatments. METHODS: A single-element, spherically concaved HIFU transducer with a centre frequency of 1 MHz was utilized to create thermal lesions in chicken breast tissues in vitro. To investigate the detectability of HIFU treatments photoacoustically, PA detection was performed at 720 and 845 nm on seven HIFU treated tissue samples. Within each tissue sample, PA signals were acquired from 22 locations equally divided between two regions of interest within two volumes in tissue - a HIFU-treated volume and an untreated volume. Optical spectroscopy was then carried out on 10 HIFU-treated chicken breast specimens in the wavelength range of 500-900 nm, in 1-nm increments, using a spectrophotometer with an integrating sphere attachment. The authors' optical spectroscopy raw data (total transmittance and diffuse reflectance) were used to obtain the optical absorption and reduced scattering coefficients of HIFU-induced thermal lesions and native tissues by employing the inverse adding-doubling method. The aforementioned interaction coefficients were subsequently used to calculate the effective attenuation coefficient and light penetration depth of HIFU-treated and native tissues in the wavelength range of 500-900 nm. RESULTS: HIFU-treated tissues produced greater PA signals than native tissues at 720 and 845 nm. At 720 nm, the averaged ratio of the peak-to-peak PA signal amplitude of HIFU-treated tissue to that of native tissue was 3.68 +/- 0.25 (mean +/- standard error of the mean). At 845 nm, the averaged ratio of the peak-to-peak PA signal amplitude of HIFU-treated tissue to that of native tissue was 3.75 +/- 0.26 (mean +/- standard error of the mean). The authors' spectroscopic investigation has shown that HIFU treated tissues have a greater optical absorption and reduced scattering coefficients than native tissues in the wavelength range of 500-900 nm. In fact, at 720 and 845 nm, the ratio of the optical absorption coefficient of HIFU treated tissues to that of native tissues was 1.13 and 1.17, respectively; on the other hand, the ratio of the reduced scattering coefficient of HIFU-treated tissues to that of native tissues was 13.22 and 14.67 at 720 and 845 nm, respectively. Consequently, HIFU-treated tissues have a higher effective attenuation coefficient and a lower light penetration depth than native tissues in the wavelength range 500-900 nm. CONCLUSIONS: Using a PA approach, HIFU treated tissues interrogated at 720 and 845 nm optical wavelengths can be differentiated from untreated tissues. Based on the authors' spectroscopic investigation, the authors conclude that the observed PA contrast between HIFU induced thermal lesions and untreated tissue is due, in part, to the increase in the optical absorption coefficient, the reduced scattering coefficient and, therefore, the deposited laser energy fluence in HIFU-treated tissues. PMID- 24784409 TI - Phase-based x-ray scattering--a possible method to detect cancer cells in a very early stage. AB - PURPOSE: This theoretical work contains a detailed investigation of the potential and sensitivity of phase-based x-ray scattering for cancer detection in biopsies if cancer is in a very early stage of development. METHODS: Cancer cells in their early stage of development differ from healthy ones mainly due to their faster growing cell nuclei and the enlargement of their densities. This growth is accompanied by an altered nucleus-plasma relation for the benefit of the cell nuclei, that changes the physical properties especially the index of refraction of the cell and the one of the cell nuclei. Interaction of radiation with matter is known to be highly sensitive to small changes of the index of refraction of matter; therefore a detection of such changes of volume and density of cell nuclei by means of high angular resolved phase-based scattering of x rays might provide a technique to distinguish malignant cells from healthy ones if the cell cell nucleus system is considered as a coherent phase shifting object. Then one can observe from a thin biopsy which represents a monolayer of cells (no multiple scattering) that phase-based x-ray scattering curves from healthy cells differ from those of cancer cells in their early stage of development. RESULTS: Detailed calculations of x-ray scattering patterns from healthy and cancer cell nuclei yield graphs and numbers with which one can distinguish healthy cells from cancer ones, taking into account that both kinds of cells occur in a tissue within a range of size and density. One important result is the role and the influence of the (lateral) coherence width of the radiation on the scattering curves and the sensitivity of phase-based scattering for cancer detection. A major result is that a larger coherence width yields a larger sensitivity for cancer detection. Further import results are calculated limits for critical sizes and densities of cell nuclei in order to attribute the investigated tissue to be healthy or diseased. CONCLUSIONS: With this proposed method it should be in principle possible to detect cancer cells in apparently healthy tissues in biopsies and/or in samples of the far border region of abscised or excised tissues. Thus this method could support established methods in diagnostics of cancer-suspicious samples. PMID- 24784410 TI - Comment on "Future radiotherapy practice will be based on evidence from retrospective interrogation of linked clinical data sources rather than prospective randomized controlled clinical trials" [Med. Phys. 41(3) 030601 (3pp.) (2014)]. PMID- 24784411 TI - Response to "Comment on 'Future radiotherapy practice will be based on evidence from retrospective interrogation of linked clinical data sources rather than prospective randomized controlled clinical trials'" [Med. Phys. 41(3) 030601 (3pp.) (2014)]. PMID- 24784412 TI - Response to "Comment on 'Future radiotherapy practice will be based on evidence from retrospective interrogation of linked clinical data sources rather than prospective randomized controlled clinical trials'" [Med. Phys. 41(3), 030601 (3pp.) (2014)]. PMID- 24784413 TI - Clues to autistic behaviors: exploring the role of endocrine disruptors. PMID- 24784414 TI - Serum proteomics of hepatitis C virus infection reveals retinol-binding protein 4 as a novel regulator. AB - Persistent infection of hepatitis C virus (HCV) can lead to liver cirrhosis and hepatocellular carcinoma, which are currently diagnosed by invasive liver biopsy. Approximately 15-20 % of cases of chronic liver diseases in India are caused by HCV infection. In North India, genotype 3 is predominant, whereas genotype 1 is predominant in southern parts of India. The aim of this study was to identify differentially regulated serum proteins in HCV-infected Indian patients (genotypes 1 and 3) using a two-dimensional electrophoresis approach. We identified eight differentially expressed proteins by MS. Expression levels of one of the highly upregulated proteins, retinol-binding protein 4 (RBP4), was validated by ELISA and Western blotting in two independent cohorts. We also confirmed our observation in the JFH1 infectious cell culture system. Interestingly, the HCV core protein enhanced RBP4 levels and partial knockdown of RBP4 had a positive impact on HCV replication, suggesting a possible role for this cellular protein in regulating HCV infection. Analysis of RBP4-interacting partners using a bioinformatic approach revealed novel insights into the possible involvement of RBP4 in HCV-induced pathogenesis. Taken together, this study provided information on the proteome profile of the HCV-infected Indian population, and revealed a link between HCV infection, RBP4 and insulin resistance. PMID- 24784415 TI - The PI3K pathway acting on alternative HIV-1 pre-mRNA splicing. AB - HIV-1 mediates pro-survival signals and prevents apoptosis via the phosphatidylinositol-3-kinase (PI3K) pathway. This pathway, however, also affects phosphorylation of serine-arginine (SR) proteins, a family of splicing regulatory factors balancing splice site selection. We now show that pharmacologic inhibition of PI3K signalling alters the HIV-1 splicing pattern of both minigene- and provirus-derived mRNAs. This indicates that HIV-1 might also promote PI3K signalling to balance processing of its transcripts by regulating phosphorylation of splicing regulatory proteins. PMID- 24784417 TI - Effect of nilotinib on airway remodeling in a murine model of chronic asthma. AB - ABSTRACT Objective: The tyrosine kinase inhibitor nilotinib has potent inhibitory activity against the stem cell growth factor receptor c-Kit and platelet-derived growth factor receptor (PDGFR). The present study aimed to determine whether nilotinib suppresses airway remodeling and whether its effect is associated with the c-Kit and PDGFR pathways. We also aimed to compare the effect of nilotinib and imatinib on remodeling. METHODS: We developed a mouse model of airway remodeling, which includes smooth muscle thickening, in which ovalbumin (OVA) sensitized mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated with nilotinib or imatinib during the OVA challenge. RESULTS: Compared with control mice, the mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, airway hyperresponsiveness (AHR), and exhibited features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of nilotinib significantly inhibited eosinophilic inflammation, AHR, and remodeling in mice chronically exposed to OVA. Nilotinib showed a trend of more potent effect than imatinib on attenuating remodeling in hydroxyproline assay and smooth muscle staining. Nilotinib treatment significantly reduced the expression of phosphorylated (p)-c-Kit, p-PDGFRbeta, and p-extracellular signal-regulated kinase 1/2. The expression levels of the genes encoding c-Kit and PDGFRbeta were also reduced by nilotinib treatment. Treatment with nilotinib did not affect significantly the level of OVA-specific IgE and IgG1 in serum. In vitro, nilotinib significantly inhibited cell proliferation of fibroblast. CONCLUSIONS: These results suggest that nilotinib administration can prevent airway inflammation, AHR, and airway remodeling associated with chronic allergen challenge. PMID- 24784416 TI - Poliomyelitis in transgenic mice expressing CD155 under the control of the Tage4 promoter after oral and parenteral poliovirus inoculation. AB - An important step in poliovirus (PV) infection by the oral route in humans is replication of the virus in lymphatic tissues of the gastrointestinal (GI) tract, thought to be mainly in the Peyer's patches of the small intestine. No immunocompetent transgenic (tg) mice that express human PV receptor (CD155) under the control of different promoters can be infected orally. The mouse orthologue of human CD155 is Tage4, a protein expressed at the surface of enterocytes and in the Peyer's patches. We describe here the generation of a tg mouse model in which the Tage4 promoter was used to drive expression of the human PV receptor-coding region (Tage4-CD155tg mice). In this model, CD155 expression was observed by immunostaining in different regions in the Peyer's patches but not in their germinal centres. Although a similar pattern of staining was observed between 3- and 6-week-old Tage4-CD155tg mice, poliomyelitis was only seen in the younger mice after PV infection by the oral route. When compared with TgPVR21 mice that expressed CD155 driven by its human promoter, 3-week-old Tage4-CD155tg mice were more susceptible to gut infection and paralysis following feeding with PV. Also, Tage4-CD155tg mice exhibited higher susceptibility to poliomyelitis after parenteral inoculation of PV. Remarkably, the LD50 after intracerebral inoculation of PV was similar in both CD155 tg mouse strains. The CD155 tg mouse model reported here, although moderately susceptible to oral infection, may be suitable to study mechanisms of PV replication in the gastrointestinal tract and to dissect important aspects of PV neuroinvasiveness. PMID- 24784418 TI - Pollutant emissions and energy efficiency of Chinese gasifier cooking stoves and implications for future intervention studies. AB - Household air pollution from solid fuel combustion is the leading environmental health risk factor globally. In China, almost half of all homes use solid fuel to meet their household energy demands. Gasifier cookstoves offer a potentially affordable, efficient, and low-polluting alternative to current solid fuel combustion technology, but pollutant emissions and energy efficiency performance of this class of stoves are poorly characterized. In this study, four Chinese gasifier cookstoves were evaluated for their pollutant emissions and efficiency using the internationally recognized water boiling test (WBT), version 4.1.2. WBT performance indicators included PM2.5, CO, and CO2 emissions and overall thermal efficiency. Laboratory investigation also included evaluation of pollutant emissions (PM2.5 and CO) under stove operating conditions designed to simulate common Chinese cooking practices. High power average overall thermal efficiencies ranged from 22 to 33%. High power average PM2.5 emissions ranged from 120 to 430 mg/MJ of useful energy, and CO emissions ranged from 1 to 30 g/MJ of useful energy. Compared with several widely disseminated "improved" cookstoves selected from the literature, on average, the four Chinese gasifier cookstoves had lower PM2.5 emissions and higher CO emissions. The recent International Organization for Standardization (ISO) International Workshop Agreement on tiered cookstove ranking was developed to help classify stove performance and identify the best performing stoves. The results from this study highlight potential ways to further improve this approach. Medium power stove operation emitted nearly twice as much PM2.5 as was emitted during high power stove operation, and the lighting phase of a cooking event contributed 45% and 34% of total PM2.5 emissions (combined lighting and cooking). Future approaches to laboratory-based testing of advanced cookstoves could improve to include greater differentiation between different modes of stove operation, beyond those evaluated with the WBT. PMID- 24784419 TI - Are you willing to risk it? The relationship between risk, regret, and vaccination intent. AB - Medically unsupported concerns pertaining to the safety and necessity of childhood vaccines may have contributed to a proportion of American parents opting against measles, mumps, and rubella vaccinations. Given this, the present investigation sought to explore the influence of perceived severity, perceived likelihood, and anticipated regret on surrogate vaccination decision-making among parents of young children. An online survey was distributed to 110 parents with unvaccinated children between 0 and 23 months of age. Significant correlations were found among focal study constructs. Anticipated regret was found to fully mediate the link between risk perceptions and vaccination intentions. The practical and theoretical implications of these findings were discussed. PMID- 24784420 TI - Effect of a genomic classifier test on clinical practice decisions for patients with high-risk prostate cancer after surgery. AB - OBJECTIVES: To evaluate the impact of a genomic classifier (GC) test for predicting metastasis risk after radical prostatectomy (RP) on urologists' decision-making about adjuvant treatment of patients with high-risk prostate cancer. SUBJECTS AND METHODS: Patient case history was extracted from the medical records of each of the 145 patients with pT3 disease or positive surgical margins (PSMs) after RP treated by six high-volume urologists, from five community practices. GC results were available for 122 (84%) of these patients. US board certified urologists (n = 107) were invited to provide adjuvant treatment recommendations for 10 cases randomly drawn from the pool of patient case histories. For each case, the study participants were asked to make an adjuvant therapy recommendation without (clinical variables only) and with knowledge of the GC test results. Recommendations were made without knowledge of other participants' responses and the presentation of case histories was randomised to minimise recall bias. RESULTS: A total of 110 patient case histories were available for review by the study participants. The median patient age was 62 years, 71% of patients had pT3 disease and 63% had PSMs. The median (range) 5 year predicted probability of metastasis by the GC test for the cohort was 3.9 (1 33)% and the GC test classified 72% of patients as having low risk for metastasis. A total of 51 urologists consented to the study and provided 530 adjuvant treatment recommendations without, and 530 with knowledge of the GC test results. Study participants performed a mean of 130 RPs/year and 55% were from community-based practices. Without GC test result knowledge, observation was recommended for 57% (n = 303), adjuvant radiation therapy (ART) for 36% (n = 193) and other treatments for 7% (n = 34) of patients. Overall, 31% (95% CI: 27-35%) of treatment recommendations changed with knowledge of the GC test results. Of the ART recommendations without GC test result knowledge, 40% (n = 77) changed to observation (95% CI: 33-47%) with this knowledge. Of patients recommended for observation, 13% (n = 38 [95% CI: 9-17%]) were changed to ART with knowledge of the GC test result. Patients with low risk disease according to the GC test were recommended for observation 81% of the time (n = 276), while of those with high risk, 65% were recommended for treatment (n = 118; P < 0.001). Treatment intensity was strongly correlated with the GC-predicted probability of metastasis (P < 0.001) and the GC test was the dominant risk factor driving decisions in multivariable analysis (odds ratio 8.6, 95% CI: 5.3-14.3%; P < 0.001). CONCLUSIONS: Knowledge of GC test results had a direct effect on treatment strategies after surgery. Recommendations for observation increased by 20% for patients assessed by the GC test to be at low risk of metastasis, whereas recommendations for treatment increased by 16% for patients at high risk of metastasis. These results suggest that the implementation of genomic testing in clinical practice may lead to significant changes in adjuvant therapy decision making for high-risk prostate cancer. PMID- 24784421 TI - Antibiotics. PMID- 24784422 TI - Drug discovery: Leaving no stone unturned. PMID- 24784423 TI - Perspective: Synthetic biology revives antibiotics. PMID- 24784424 TI - Diagnostics: Detection drives defence. PMID- 24784425 TI - Public health: The politics of antibiotics. PMID- 24784426 TI - Antibiotic resistance: An infectious arms race. PMID- 24784427 TI - Drug development: Time for teamwork. PMID- 24784428 TI - Microbiology: Resistance fighters. PMID- 24784429 TI - Perspective: The age of the phage. PMID- 24784430 TI - Circumscribed choroidal hemangioma associated with choroidal neovascularization in a HIV-infected case: photodynamic therapy and intravitreous ranibizumab. AB - Circumscribed choroidal hemangioma (CCH) is rarely associated with choroidal neovascularization (CNV), especially in HIV-infected patients. And the therapy is still controversial. In this study, we discussed the mechanism, clinical feature and treatment of such lesions, based on multi-modality imaging evidences. Photodynamic therapy (PDT) might aggravate CNV as a side effect, and we concluded that intravitreal ranibizumab could be suggested as an effective therapy. PMID- 24784431 TI - Photodynamic therapy of ovarian cancer peritoneal metastasis with hexaminolevulinate: a toxicity study. AB - CONTEXT: While photodynamic therapy (PDT) is a promising treatment for peritoneal carcinomatosis, its use is often limited because of the toxicity of photosensitizers. In this study, safety of PDT with hexaminoevulinate (HAL), a second generation photosensitizer, is assessed. METHODS: PDT of the peritoneal cavity was performed in a rat model of peritoneal carcinomatosis. Rats were treated according to different protocols: with full or half HAL dose, after intraperitoneal or oral administration of HAL, 4 or 8h after its injection, using red or green light, after protection of the liver or cooling of the abdominal wall. Toxicity was assessed by blood tests quantifying hematocrit, liver and muscular enzymes and by pathological examination of abdominal and intrathoracic organs after treatment. The results were analyzed in the light of quantification of fluorescence and protoporphyrin IX (PPIX) content of the same organs. RESULTS: PDT with HAL induced rhabdomyolysis, intestinal necrosis and liver function test anomalies, leading to death in 2 out of 34 rats. The liver and the intestine contained high levels of PPIX (3-5 times more than tumor nodules). CONCLUSION: HAL PDT lacked specificity. However, the strategy associating diagnosis, treatment and evaluation of the results in one single procedure was effective and should be tested with other photosensitizers. PMID- 24784433 TI - Water immersion in the treatment of exertional hyperthermia: physical determinants. AB - PURPOSE: We examined the effect of differences in body surface area-to-lean body mass ratio (AD/LBM) on core temperature cooling rates during cold water immersion (CWI, 2 degrees C) and temperate water immersion (TWI, 26 degrees C) after exercise-induced hyperthermia. METHODS: Twenty male participants were divided into two groups: high (315.6 +/- 7.9 cm.kg, n = 10) and low (275.6 +/- 8.6 cm.kg, n = 10) AD/LBM. On two separate occasions, participants ran on a treadmill in the heat (40.0 degrees C, 20% relative humidity) wearing an impermeable rain suit until rectal temperature reached 40.0 degrees C. After exercise, participants were immersed up to the nipples (arms remained out of the water) in either a CWI (2 degrees C) or a TWI (26 degrees C) circulated water bath until rectal temperature returned to 37.5 degrees C. RESULTS: Overall rectal cooling rates were significantly different between experimental groups (high vs low AD/LBM, P = 0.005) and between immersion conditions (CWI vs TWI, P < 0.001). Individuals with a high AD/LBM had an approximately 1.7-fold greater overall rectal cooling rate relative to those with low AD/LBM during both CWI (high: 0.27 degrees C.min +/- 0.10 degrees C.min vs low: 0.16 degrees C.min +/- 0.10 degrees C.min) and TWI (high: 0.10 degrees C.min +/- 0.05 degrees C.min vs low: 0.06 degrees C.min +/- 0.02 degrees C.min). Further, the overall rectal cooling rates during CWI were approximately 2.7-fold greater than during TWI for both the high (CWI: 0.27 degrees C.min +/- 0.10 degrees C.min vs TWI: 0.10 degrees C.min +/- 0.05 degrees C.min) and the low (CWI: 0.16 degrees C.min +/- 0.10 degrees C.min vs TWI: 0.06 degrees C.min +/- 0.02 degrees C.min) AD/LBM groups. CONCLUSION: We show that individuals with a low AD/LBM have a reduced rectal cooling rate and take longer to cool than those with a high AD/LBM during both CWI and TWI. However, CWI provides the most effective cooling treatment irrespective of physical differences. PMID- 24784432 TI - Diverse outcomes of Photodynamic Antimicrobial Chemotherapy on five Enterococcus faecalis strains. AB - OBJECTIVES: In the present study, the effectiveness of Photodynamic Antimicrobial Chemotherapy (PACT) was evaluated on planktonic cells and biofilms of five Enterococcus faecalis clinical isolates. METHODS: Planktonic cells and biofilms of E. faecalis E2, E3, ER3/2s, OS16 and AA-OR34 were grown in SDMY medium plus 0.4% glucose. Approximately 5.0*10(7)CFU planktonic cells and 24h biofilms were subjected to PACT using the combination of Light Emitting Diodes (LEDs, Biotable((r))) and Photogem((r)). The metabolic activity of bacterial cells was evaluated by a resazurin assay. Biomass values of the biofilms were determined by a crystal violet assay. RESULTS: Compared to the water-treated control group, gradual increases of light energy led to greater reduction of metabolic activity of planktonic cells and biofilms of E. faecalis when the combination of LEDs and Photogem((r)) was applied. Photogem((r)) alone significantly reduced the metabolic activity of planktonic cells, whereas LEDs or Photogem((r)) alone did not result in biofilm viability changes. PACT yielded similar antimicrobial outcomes on planktonic cells of all tested E. faecalis strains, whereas biofilms of E. faecalis E3, ER3/2s and OS16 were more resistant to PACT than biofilms of E. faecalis E2 and AA-OR34. CONCLUSIONS: The efficacy of PACT on E. faecalis biofilms was strain dependent. PACT demonstrated its potential as an adjuvant antimicrobial treatment by killing of E. faecalis planktonic and biofilm cells. PMID- 24784434 TI - Emerging and reemerging epidemic-prone diseases among settling nomadic pastoralists in Uganda. AB - Epidemic-prone diseases have traditionally been uncommon among nomadic pastoralists as mobility allows already dispersed populations to migrate away from epidemic threats. In the Karamoja region of Uganda, nomadic pastoralists are transitioning to an increasingly settled lifestyle due to cattle raiding and associated civil insecurity. In attempts to reduce conflict in the region, the Ugandan government has instituted disarmament campaigns and encouraged sedentism in place of mobility. In Karamoja, this transition to sedentism has contributed to the emergence and reemergence of epidemic-prone diseases such as cholera, hepatitis E, yellow fever, and meningococcal meningitis. The incidence of these diseases remains difficult to measure and several challenges exist to their control. Challenges to communicable disease surveillance and control among settling nomadic pastoralists are related to nomadic mobility, remote geography, vaccination and immunity, and poor sanitation and safe water access. In addition to improving gaps in infrastructure, attracting well-trained government health workers to Karamoja and similar areas with longstanding human resource limitations is critical to address the challenges to epidemic-prone disease surveillance and control among settling nomadic pastoralists. In conjunction with government health workers, community health teams provide a sustainable method by which public health programs can be improved in the austere environments inhabited by mobile and settling pastoralists. PMID- 24784435 TI - More of a good thing or less of a bad thing: gene copy number variation in polyploid cells of the placenta. PMID- 24784436 TI - Aggregation behavior of polyisoprene-pluronic graft copolymers in selective solvents. AB - Novel amphiphilic graft copolymers composed of a polyisoprene (PIP) backbone with Pluronic side chains, polyisoprene-g-Pluronic, have been synthesized using a "graft onto" technique. Small-angle neutron scattering (SANS) has been used to characterize the conformation of the P123 and P103 Pluronic graft copolymers in selective solvents such as ethanol and hexane and in a nonselective solvent, tetrahydrofuran (THF). The results indicated that, in a selective solvent for the side chain Pluronics (e.g., ethanol), "crew-cut" micelles were formed with a large core of radius ~ 120 A; data were fitted with a core-shell model. In a good solvent for the backbone (e.g., hexane), "flowerlike" micelles were formed with a small inner radius of ~64 A. In the nonselective solvent, a swollen polymer coil was found, which was described using the Guinier-Debye model. As THF/ethanol and THF/hexane can be prepared in any ratio, it was possible to vary the solvent composition gradually in order to study the transition from swollen coil to micelle. When going from 100% THF to 100% ethanol, the transition to micellar behavior was observed at a ratio of 20:80 (v/v %) THF/ethanol for both grafted copolymers and 40:60 (v/v %) THF/hexane for grafted P123 copolymers. PMID- 24784438 TI - CTX-M-type extended-spectrum beta-lactamase-producing Klebsiella pneumoniae isolated from cases of bovine mastitis in Japan. AB - Three Klebsiella pneumoniae isolates producing extended-spectrum beta-lactamase (ESBL) were obtained from three dairy cows with clinical mastitis in two farms in western Japan. Two of the 3 isolates from cows in different farms were able to transfer plasmids carrying the blaCTX-M-2 gene to Escherichia coli recipient. Pulsed-field gel electrophoresis (PFGE) patterns of the 2 isolates were different from each other, although restricted-fragment patterns of the two conjugative plasmids were similar to each other. Additionally, PCR-based replicon typing revealed that both the plasmids belonged to type Inc.T. These results suggest that ESBL-encoding genes can be distributed in bacteria on dairy farms through the plasmids. PMID- 24784437 TI - Opening the door to innovation. AB - Open innovation is the new buzz, with initiatives popping up left and right. Here, we give a personal perspective on a very successful, knowledge-driven innovation initiated in an academia- industry alliance, which culminated in technology platforms that enable the generation of therapeutic antibodies with novel properties. To start, we provide a general background on open innovation in the drug development field. PMID- 24784439 TI - Phylogenetic analysis of astrovirus and kobuvirus in Korean dogs. AB - Astroviruses and kobuviruses are frequently found in mammalian feces, including that of humans. The present study examined fecal samples from 91 Korean dogs suffering from diarrhea. Canine astroviruses (CAstVs) and canine kobuviruses (CKoVs) were identified in 2 (2.1%) and 46 (50.6%) dogs, respectively. Nucleotide sequence analysis coupled with phylogenetic analysis using the neighbor-joining method showed that CAstVs clustered into four genetically diverse groups. Two Korean CAstVs belonged to group 2 alongside strains isolated in Italy and France. Twelve of the Korean CKoVs belonged to a single clade, along with strain UK003 identified in the UK and six CKoVs identified in the USA. Thus, the results suggest that the Korean strain of CAstV is closely related to strains isolated in Europe. Surely, CKoV in South Korea could identify the circulation among dogs population. PMID- 24784440 TI - Repression of hepatic cytochrome P450 2D expression in mice during Babesia microti infection. AB - To examine the effect of Babesia infection on the level of the drug-metabolizing enzyme hepatic cytochrome P450 (CYP) 2D, we intraperitoneally inoculated Babesia microti into male ICR mice. CYP2D protein and CYP2D9 mRNA were significantly decreased at 12 days after infection with B. microti. The activity of bunitrolol 4-hydroxylase, which is catalyzed by CYP2D, was also significantly decreased. The mRNA levels of transcriptional regulators of CYP2D9, hepatocyte nuclear factor 4alpha and signal transducer and activator of transcription 5b, were markedly suppressed. These results suggest that Babesia infection represses CYP2D expression in the mouse liver. The decline in CYP2D-dependent drug metabolism might be involved in the incidence of adverse drug reactions in patients with babesiosis. PMID- 24784441 TI - Neonatal exposure to 17alpha-ethinyl estradiol affects kisspeptin expression and LH-surge level in female rats. AB - Contamination of estrogenic compounds disrupts endocrinological and neurological reproductive systems in animals. Neonatal exposure to 17alpha-ethinyl estradiol (EE) induced an abnormal estrous cycle at postnatal day (PND) 180, but not at PND90. We found that serum level of luteinizing hormone (LH) at the latter half of proestrus in EE-treated rats was lower than in the controls at PND90 when there was no significant difference on estrous cyclicity. Additionally, kiss1 mRNA levels in the anteroventral periventricular nucleus-preoptic area (AVPV/POA) were lower in EE-treated rats than in the controls. The expression of GnRH precursor (GNRH1) mRNA in the AVPV/POA and that of LH beta subunit (LHb) mRNA in the pituitary were similar in the control- and EE-treated groups. Our results indicated that neonatal exposure to EE leads to reduced expression of kiss1 mRNA in AVPV/POA and LH-surge, which is likely related to the delayed reproductive dysfunction seen in adult female rats. PMID- 24784442 TI - Abundance and distribution of Tursiops truncatus in the Western Mediterranean Sea: an assessment towards the Marine Strategy Framework Directive requirements. AB - The Mediterranean Sea common bottlenose dolphin population has been assessed as Vulnerable according to the IUCN Red List Criteria. The species is also included in several International Agreements, European Union Regulations and Directives. Amongst them, a strict protection and identification of special conservation areas are requested by the EU Habitats Directive. Despite direct takes, by-catch, chemical and acoustic pollution, and prey depletion, general habitat degradation and fragmentation have been indicated as detrimental for the species, the degree to which these threats pose population risk is still largely unknown. At present it is thus not possible to depict the actual status of the population and to assess prospective trends. To address this gap in the current knowledge, line transect distance sampling aerial surveys were conducted in a wide portion of the Western Mediterranean Sea between the summer of 2010 and winter 2011. A total of 165 parallel transects equally spaced at 15 km were designed providing homogeneous coverage probability. Overall, 21,090 km were flown on effort and 16 bottlenose dolphin sightings were recorded and used for the analysis. The surface abundance and density estimates resulted in 1676 animals (CV = 38.25; 95% CI = 804-3492) with a density of 0.005 (CV = 38.25%). These results represent the first ever estimates for the common bottlenose dolphin over a wide portion of the Western Mediterranean Sea Subregion, with the potential to be useful baseline data to inform conservation. Specifically, they could be used as indicators under the Marine Strategy Framework Directive requirements, in conjunction with other study methods. PMID- 24784443 TI - Triclosan exacerbates the presence of 14C-bisphenol A in tissues of female and male mice. AB - Current human generations are commonly exposed to both triclosan (TCS), an antimicrobial agent, and bisphenol A (BPA), the monomer of polycarbonate plastics and epoxies. Both are readily absorbed into circulation and found distributed among diverse tissues. Potential interactions between TCS and BPA are largely unstudied. We investigated whether TCS exposure affects the distribution of ingested (14)C-BPA in select tissues. CF-1 mice were each subcutaneously injected with TCS then orally administered 50 MUg/kg (14)C-BPA. Females received 0, 0.2, 0.6, 1, 2, or 18 mg TCS (equivalent respectively to 0, 6.3, 16.9, 30.1, 60.5, and 558.9 mg/kg). Males received 0, 0.2, 2, or 18 mg TCS (equivalent respectively to 0, 5.3, 53.4, and 415.0mg/kg). Levels of radioactivity were measured through liquid scintillation counting in blood serum and brain, reproductive, and other tissues. Significantly elevated levels of radioactivity were observed following combined TCS and (14)C-BPA administration, with minimally effective TCS doses being tissue-dependent (Females: lungs, 0.6 mg; uterus, 1mg; heart, muscle, ovaries, and serum, 18 mg. Males: serum, 0.2mg; epididymides, 2mg). Subsequently, we found that 2 or 6 mg TCS increased radioactivity in the ovaries and serum of females orally given only 5 MUg/kg (14)C-BPA. These data indicate that TCS can interact with BPA in vivo, magnifying its presence in certain tissues and serum. The data are consistent with evidence that TCS utilizes enzymes that are critical for metabolism and excretion of BPA. Further research should investigate the mechanisms through which these two chemicals interact at environmentally-relevant doses. PMID- 24784445 TI - Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleus. AB - Serotonergic neurons of the dorsal raphe nucleus, with their extensive innervation of limbic and higher brain regions and interactions with the endocrine system have important modulatory or regulatory effects on many cognitive, emotional and physiological processes. They have been strongly implicated in responses to stress and in the occurrence of major depressive disorder and other psychiatric disorders. In order to quantify some of these effects, detailed mathematical models of the activity of such cells are required which describe their complex neurochemistry and neurophysiology. We consider here a single-compartment model of these neurons which is capable of describing many of the known features of spike generation, particularly the slow rhythmic pacemaking activity often observed in these cells in a variety of species. Included in the model are 11 kinds of ion channels: a fast sodium current INa, a delayed rectifier potassium current IKDR, a transient potassium current IA, a slow non-inactivating potassium current IM, a low-threshold calcium current IT, two high threshold calcium currents IL and IN, small and large conductance potassium currents ISK and IBK, a hyperpolarization-activated cation current IH and a leak current ILeak. In Sections 3-8, each current type is considered in detail and parameters estimated from voltage clamp data where possible. Three kinds of model are considered for the BK current and two for the leak current. Intracellular calcium ion concentration Cai is an additional component and calcium dynamics along with buffering and pumping is discussed in Section 9. The remainder of the article contains descriptions of computed solutions which reveal both spontaneous and driven spiking with several parameter sets. Attention is focused on the properties usually associated with these neurons, particularly long duration of action potential, steep upslope on the leading edge of spikes, pacemaker-like spiking, long-lasting afterhyperpolarization and the ramp-like return to threshold after a spike. In some cases the membrane potential trajectories display doublets or have humps or notches as have been reported in some experimental studies. The computed time courses of IA and IT during the interspike interval support the generally held view of a competition between them in influencing the frequency of spiking. Spontaneous activity was facilitated by the presence of IH which has been found in these neurons by some investigators. For reasonable sets of parameters spike frequencies between about 0.6Hz and 1.2Hz are obtained, but frequencies as high as 6Hz could be obtained with special parameter choices. Topics investigated and compared with experiment include shoulders, notches, anodal break phenomena, the effects of noradrenergic input, frequency versus current curves, depolarization block, effects of cell size and the effects of IM. The inhibitory effects of activating 5-HT1A autoreceptors are also investigated. There is a considerable discussion of in vitro versus in vivo firing behavior, with focus on the roles of noradrenergic input, corticotropin releasing factor and orexinergic inputs. Location of cells within the nucleus is probably a major factor, along with the state of the animal. PMID- 24784447 TI - rAAV9 combined with renal vein injection is optimal for kidney-targeted gene delivery: conclusion of a comparative study. AB - Effective gene therapy strategies for the treatment of kidney disorders remain elusive. We report an optimized kidney-targeted gene delivery strategy using recombinant adeno-associated virus (rAAV) administered via retrograde renal vein injection in mice. Renal vein injection of rAAV consistently resulted in superior kidney transduction compared with tail vein injection using as little as half the tail vein dose. We compared rAAV5, 6, 8 and 9, containing either green fluorescent protein (GFP) or luciferase reporter genes driven by the Cytomegalovirus promoter. We demonstrated that although rAAV6 and 8 injected via renal vein transduced the kidney, transgene expression was mainly restricted to the medulla. Transgene expression was systematically low after rAAV5 injection, attributed to T-cell immune response, which could be overcome by transient immunosuppression. However, rAAV9 was the only serotype that permitted high transduction efficiency of both the cortex and medulla. Moreover, both the glomeruli and tubules were targeted, with a higher efficiency within the glomeruli. To improve the specificity of kidney-targeted gene delivery with rAAV9, we used the parathyroid hormone receptor 'kidney-specific' promoter. We obtained a more efficient transgene expression within the kidney, and a significant reduction in other tissues. Our work represents the first comprehensive and clinically relevant study for kidney gene delivery. PMID- 24784448 TI - Overexpression of Ad5 precursor terminal protein accelerates recombinant adenovirus packaging and amplification in HEK-293 packaging cells. AB - Recombinant adenoviruses are one of the most common vehicles for efficient in vitro and in vivo gene deliveries. Here, we investigate whether exogenous precursor terminal protein (pTP) expression in 293 cells improves the efficiency of adenovirus packaging and amplification. We used a piggyBac transposon-based vector and engineered a stable 293 line that expresses high level of Ad5 pTP, designated as 293pTP. Using the AdBMP6-GLuc that expresses green fluorescent protein (GFP), BMP6 and Gaussia luciferase, we found that the infectivity of AdBMP6-GLuc viral samples packaged in 293pTP cells was titrated up to 19.3 times higher than that packaged in parental 293 cells. AdBMP6-GLuc viral samples packaged in 293pTP cells exhibited significantly higher transduction efficiency in 143B and immortalized mouse embryonic fibroblast (iMEF) cells, as assessed by fluorescence-activated cell sorting analysis of GFP-positive cells, the luciferase activity assay and BMP6-induced osteogenic marker alkaline phosphatase activities in iMEFs. When adenovirus amplification efficiency was analyzed, we found that 293pTP cells infected with AdBMP6-GLuc yielded up to 12.6 times higher titer than that in parental 293 cells, especially at lower multiplicities of infection. These results strongly suggest that exogenous pTP expression may accelerate the packaging and amplification of recombinant adenoviruses. Thus, the engineered 293pTP cells should be a superior packaging line for efficient adenovirus production. PMID- 24784449 TI - Endospanin 1 silencing in the hypothalamic arcuate nucleus contributes to sustained weight loss of high fat diet obese mice. AB - Leptin targets specific receptors (OB-R) expressed in the hypothalamus to regulate energy balance. Leptin decreases food intake in normal weight individuals, but this effect is blunted in obese subjects who are characterized by a state of leptin resistance. The prevention of leptin resistance is one of the major goals of obesity research. Recently, we identified endospanin 1 as a negative regulator of OB-R, which by interacting with OB-R retains the receptor inside the cell. We show here that in obese mice endospanin 1 is upregulated in the hypothalamic arcuate nucleus (ARC), the major brain structure involved in body weight regulation, suggesting that endospanin 1 is implicated in obesity development and/or the installation of leptin resistance. In contrast, silencing of endospanin 1 with lentiviral vectors in the ARC of obese mice fully restores leptin responsiveness when combined with a switch to ad libitum fed chow diet. The recovery of central leptin sensitivity is accompanied by sustained body weight loss and amelioration of blood lipid parameters and steatosis. Collectively, our results define endospanin 1 as a novel therapeutic target against obesity. PMID- 24784450 TI - Synthesis of methoxy-substituted picenes: substitution position effect on their electronic and single-crystal structures. AB - A series of picenes having methoxy groups was synthesized through Pd-catalyzed Suzuki-Miyaura couplings or Wittig reaction/intramolecular cyclization sequences, and their physicochemical properties and single-crystal structures were evaluated. The substitution position effects between the outer 1,12-, 2,11-, and 4,9-position and the inner 3,10-position are quite different; the former showed the same electronic structure as that of picene, but the latter results in a HOMO geometry different from those of picene and other methoxy picenes. In addition, crystal structures of four types of methoxy-substituted picenes 4a-c,e strongly depend on their substitution position and number of methoxy groups, which dramatically changes the structures from the fully anisotropic 1D pi-stacked structure to a unique 3D herringbone structure due to steric hindrance of methoxy groups. The calculations of transfer integrals based on their single-crystal structures reveal that the methoxy picenes have intermolecular overlaps less effective than that of the parent nonsubstituted picene. These results are attributed not only to the packing structure but also to electronic structures such as the HOMO distribution. The preliminary OFET of the representative 4c,e showed hole mobilities significantly lower than that of picene due to their less effective intermolecular overlaps, as predicted by the calculated transfer integrals. PMID- 24784451 TI - Prediction of preschool functional abilities after early complex cardiac surgery. AB - BACKGROUND: It is important to identify early predictors of functional limitations in children after congenital heart surgery to optimise their independence as they prepare for school. The purpose of this study is to determine potentially modifiable predictor variables of functional abilities in pre-school children who underwent complex cardiac surgery at 6 weeks of age or earlier. METHODS: This prospective inception cohort study comprised a sample of 165 survivors (63% boys) who had complex cardiac surgery (75% biventricular repairs) at Stollery Children's Hospital, Edmonton, Alberta. We excluded children with chromosomal abnormalities. When children were 4-5 years of age, the parents completed the Adaptive Behavioral Assessment System II. Regression analysis was used to assess the association between multiple risk factors and each of the four continuous composite scores. RESULTS: The mean scores for the practical domain and general adaptive composite score of the Adaptive Behavioural Assessment System were lower than the conceptual and social domains, with 13.3% of the children having a delay in the practical domain. There was a significant association between the general adaptive (p=0.003; 0.012), conceptual (p=0.0004; 0.042), social (p=0.0007; 0.028), and the practical (p=0.046; 0.003) domain composite scores with the mother's education and preoperative plasma lactate, respectively. CONCLUSION: Maternal education may be a marker for the social context of children, and warrants societal attention to improve functional outcomes. Preoperative lactate as a potentially modifiable variable may warrant increased attention to early diagnosis and aggressive resuscitation of young infants with congenital heart disease. PMID- 24784452 TI - Intensified nitrogen and phosphorus removal in a novel electrolysis-integrated tidal flow constructed wetland system. AB - A novel electrolysis-integrated tidal flow constructed wetland (CW) system was developed in this study. The dynamics of intensified nitrogen and phosphorus removal and that of hydrogen sulphide control were evaluated. Ammonium removal of up to 80% was achieved with an inflow concentration of 60 mg/L in wetland systems with and without electrolysis integration. Effluent nitrate concentration decreased from 2 mg/L to less than 0.5 mg/L with the decrease in current intensity from 1.5 mA/cm(2) to 0.57 mA/cm(2) in the electrolysis-integrated wetland system, thus indicating that the current intensity of electrolysis plays an important role in nitrogen transformations. Phosphorus removal was significantly enhanced, exceeding 95% in the electrolysis-integrated CW system because of the in-situ formation of a ferric iron coagulant through the electro dissolution of a sacrificial iron anode. Moreover, the electrolyzed wetland system effectively inhibits sulphide accumulation as a result of a sulphide precipitation coupled with ferrous-iron electro-dissolution and/or an inhibition of bacterial sulphate reduction under increased aerobic conditions. PMID- 24784453 TI - Effect of sulfate on the transformation of corrosion scale composition and bacterial community in cast iron water distribution pipes. AB - The chemical stability of iron corrosion scales and the microbial community of biofilm in drinking water distribution system (DWDS) can have great impact on the iron corrosion and corrosion product release, which may result in "red water" issues, particularly under the situation of source water switch. In this work, experimental pipe loops were set up to investigate the effect of sulfate on the dynamical transformation characteristics of iron corrosion products and bacterial community in old cast iron distribution pipes. All the test pipes were excavated from existing DWDS with different source water supply histories, and the test water sulfate concentration was in the range of 50-350 mg/L. Pyrosequencing of 16S rRNA was used for bacterial community analysis. The results showed that iron release increased markedly and even "red water" occurred for pipes with groundwater supply history when feed water sulfate elevated abruptly. However, the iron release of pipes with only surface water supply history changed slightly without noticeable color even the feed water sulfate increased multiply. The thick-layered corrosion scales (or densely distributed tubercles) on pipes with surface water supply history possessed much higher stability due to the larger proportion of stable constituents (mainly Fe3O4) in their top shell layer; instead, the rather thin and uniform non-layered corrosion scales on pipes with groundwater supply history contained relatively higher proportion of less stable iron oxides (e.g. beta-FeOOH, FeCO3 and green rust). The less stable corrosion scales tended to be more stable with sulfate increase, which was evidenced by the gradually decreased iron release and the increased stable iron oxides. Bacterial community analysis indicated that when switching to high sulfate water, iron reducing bacteria (IRB) maintained dominant for pipes with stable corrosion scales, while significant increase of sulfur oxidizing bacteria (SOB), sulfate reducing bacteria (SRB) and iron oxidizing bacteria (IOB) was observed for pipes with less stable corrosion scales. PMID- 24784454 TI - Optimization of operation conditions for the startup of aerobic granular sludge reactors biologically removing carbon, nitrogen, and phosphorous. AB - The transformation of conventional flocculent sludge to aerobic granular sludge (AGS) biologically removing carbon, nitrogen and phosphorus (COD, N, P) is still a main challenge in startup of AGS sequencing batch reactors (AGS-SBRs). On the one hand a rapid granulation is desired, on the other hand good biological nutrient removal capacities have to be maintained. So far, several operation parameters have been studied separately, which makes it difficult to compare their impacts. We investigated seven operation parameters in parallel by applying a Plackett-Burman experimental design approach with the aim to propose an optimized startup strategy. Five out of the seven tested parameters had a significant impact on the startup duration. The conditions identified to allow a rapid startup of AGS-SBRs with good nutrient removal performances were (i) alternation of high and low dissolved oxygen phases during aeration, (ii) a settling strategy avoiding too high biomass washout during the first weeks of reactor operation, (iii) adaptation of the contaminant load in the early stage of the startup in order to ensure that all soluble COD was consumed before the beginning of the aeration phase, (iv) a temperature of 20 degrees C, and (v) a neutral pH. Under such conditions, it took less than 30 days to produce granular sludge with high removal performances for COD, N, and P. A control run using this optimized startup strategy produced again AGS with good nutrient removal performances within four weeks and the system was stable during the additional operation period of more than 50 days. PMID- 24784455 TI - Index models to evaluate the potential metal pollution contribution from washoff of road-deposited sediment. AB - The proper evaluation of pollutant strength and loads associated with road deposited sediment (RDS) is crucial for controlling diffuse pollution in urban areas. A new index model, which combines source and transport factors and is called the RDS index, was developed using RDS characteristics (e.g., the amount, grain size, mobility, and metal concentrations) and used in a case study in the Beijing region. The observed and weighted RDS characteristics along an urban rural gradient, which included central urban (UCA), urban village (UVA), central suburban county (CSA), rural town (RTA), and rural village (RVA) areas, were used to calculate the RDS index for the pollutant load (RDSindex,load) and the pollutant strength (RDSindex,strength). Our results demonstrated that the RDSindex,load and RDSindex,strength values both changed significantly along the urban-rural gradient. RDSindex,strength increased along the urban-rural gradient and the RDSindex,load value along the main roads decreased in the order RVA > UCA > CSA > RTA. The method offers a new way of assessing metal pollution in RDS and provides an important scientific basis for controlling pollution caused by RDS washoff. PMID- 24784456 TI - Critical evaluation of spectroscopic indices for organic matter source tracing via end member mixing analysis based on two contrasting sources. AB - Despite the wide use of absorption and fluorescence spectroscopy for tracking the sources of dissolved organic matter (DOM), there are limited studies on evaluating their source discrimination capabilities at variable solution chemistry (pH, NaCl, Ca(2+), and DOM concentration). For this study, we compared the applicability of several well-known spectroscopic indices via end member mixing analysis based on two contrasting DOM sources (Suwannee River fulvic acid and an algal DOM). The absorption coefficients and the intensities of fluorescent components from parallel factor analysis (PARAFAC) showed linear relationships with increasing algal carbon fraction in the mixture of the two DOMs. In contrast, although they still behaved conservatively, spectral ratio indices such as spectral slopes, ratios of PARAFAC components, humification index, and fluorescence index changed in nonlinear patterns with the mixing ratios. The indices based on PARAFAC results exhibited strong discrimination capabilities, as indicated by high susceptibility to the changes in DOM sources relative to the analytical precision. While variable NaCl concentrations had limited effects, most fluorescence indices were considerably affected by other solution chemistry such as pH, Ca(2+), and DOM level. Our study demonstrated that the applicability of the source discrimination indices should be critically examined especially in the environments with notable changes in the solution chemistry. The solution chemistry effects could be minimized by adjusting samples to a constant condition prior to the measurements or otherwise the effects should be fully taken into account in interpreting the field observations. PMID- 24784457 TI - Hydrothermal synthesis of K2CO3-promoted hydrotalcite from hydroxide-form precursors for novel high-temperature CO2 sorbent. AB - In many materials for CO2 sorption, hydrotalcite is attracting substantial attention as a high temperature (200-500 degrees C) CO2 sorbent because of its fast sorption/desorption kinetics and easy regenerability. However, the CO2 sorption capacity of conventional hydrotalcite is relatively low for large-scale commercial use. To enhance CO2-sorption capacity, hydrotalcite is conventionally impregnated with alkali metals such as K2CO3. Although K2CO3-impregnated hydrotalcite has high CO2-sorption capacity, the preparation method takes long time and is inconvenient because hydrotalcite synthesis step and alkali metal impregnation step are separated. In this study, K2CO3-promoted hydrotalcite was newly synthesized from hydroxide-form percursors by a simple and eco-friendly method without a solvent-consuming washing step. Analysis based on X-ray diffraction indicated that the prepared samples had structures of well-defined hydrotalcite crystalline and un-reacted Mg(OH)2 precursor. Moreover, K2CO3 was successfully incorporated in hydrotalcite during the synthesis step. The prepared K2CO3-promoted hydrotalcite showed high CO2-sorption capacity and had potential for use as a high-temperature CO2 sorbent. PMID- 24784458 TI - Static magnetic field inhibits adenosine deaminase activity in cancerous and noncancerous human gastric tissues. AB - AIM: Investigation of possible effects of static magnetic field (SMF) on adenosine deaminase (ADA) activity in cancerous and noncancerous human gastric and colon tissues to obtain information about possible action mechanism of SMF. MATERIALS AND METHODS: Cancerous and noncancerous human gastric and colon tissues removed from patients by surgical operations were used in the studies. SMF was created by using two static magnets. Before and after treatment with SMF, ADA activities in the tissue samples were measured. RESULTS: The ADA activity was found to be lowered in gastric tissues treated with the SMF. However, no change was observed in the ADA activity of colon tissues. CONCLUSIONS: Our results suggest that SMF inhibits the ADA enzyme in gastric tissues significantly. It is supposed that, in addition to other proposed mechanisms, accumulated adenosine due to the inhibition of the ADA enzyme might also play a part in the anticancer activity of SMF. PMID- 24784459 TI - A growth mechanism for free-standing vertical graphene. AB - We propose a detailed mechanism for the growth of vertical graphene by plasma enhanced vapor deposition. Different steps during growth including nucleation, growth, and completion of the free-standing two-dimensional structures are characterized and analyzed by transmission electron microscopy. The nucleation of vertical graphene growth is either from the buffer layer or from the surface of carbon onions. A continuum model based on the surface diffusion and moving boundary (mass flow) is developed to describe the intermediate states of the steps and the edges of graphene. The experimentally observed convergence tendency of the steps near the top edge can be explained by this model. We also observed the closure of the top edges that can possibly stop the growth. This two dimensional vertical growth follows a self-nucleated, step-flow mode, explained for the first time. PMID- 24784460 TI - Systolic flow displacement correlates with future ascending aortic growth in patients with bicuspid aortic valves undergoing magnetic resonance surveillance. AB - OBJECTIVES: Altered systolic blood flow in the ascending aorta has been correlated with increased aortic growth in patients with bicuspid aortic valves (BAVs). We used conventional, 2-dimensional (2D) phase contrast magnetic resonance imaging (PC-MRI) to assess the relationship between altered flow and future growth in patients with BAV. MATERIALS AND METHODS: Aortic MRI data were reviewed for 17 adult patients with BAV with right-left leaflet fusion undergoing surveillance imaging who had 2D PC-MRI through their ascending aortas on an initial study, follow-up studies more than 1 year later, and an initial maximum aortic diameter of less than 4.5 cm. Diameters were measured at standard levels by 2 blinded reviewers. Normalized systolic flow displacement was calculated at peak systole from the PC-MRI data, and correlation with the interval aortic growth was performed, with adjustment for clinical/demographic factors. RESULTS: The average follow-up interval was 2.9 +/- 1.3 years. Systolic flow displacement at the initial study strongly correlated with ascending aortic growth rate (r = 0.71, P < 0.005) with moderate, non-significant correlation between initial diameter and growth (r = 0.45, P = 0.214). Aortic growth was 4 times faster in patients with initial flow displacement of 0.2 or greater (n = 9) compared with those (n = 8) with initial flow displacement less than 0.2 (0.8 +/- 0.4 vs 0.2 +/ 0.3 mm/y; P = 0.002). CONCLUSIONS: Systolic flow displacement calculated from conventional 2D PC-MRI in the ascending aorta correlates with future aortic growth in patients undergoing routine surveillance imaging for BAV. With a cutoff valve of 0.2, flow displacement may be used to identify a subset of patients likely to have elevated growth rates and may better risk-stratify patients with BAV for aortic disease progression than vessel diameter alone. PMID- 24784461 TI - The development of a shock-tube based characterization technique for air-coupled ultrasonic probes. AB - The present paper proposes a new characterization technique for air-coupled ultrasound probes. The technique is based on a shock tube to generate a controlled pressure wave to calibrate transducers within their operating frequency range. The aim is to generate a high frequency pressure wave (at least up to 200 kHz) with the low energy levels typical of commonly used air-coupled ultrasound probes. A dedicated shock-tube has been designed and tested to assess calibration performances. The sensor transfer function has been measured by using a pressure transducer as reference. PMID- 24784462 TI - Ultrasonic wave propagation in concentrated slurries--the modelling problem. AB - The suspended particle size distribution in slurries can, in principle, be estimated from measured ultrasonic wave attenuation across a frequency band in the 10s of MHz range. The procedure requires a computational model of wave propagation which incorporates scattering phenomena. These models fail at high particle concentrations due to hydrodynamic effects which they do not incorporate. This work seeks an effective viscosity and density for the medium surrounding the particles, which would enable the scattering model predictions to match experimental data for high solids loading. It is found that the required viscosity model has unphysical characteristics leading to the conclusion that a simple effective medium modification to the ECAH/LB is not possible. The paper confirms the successful results which can be obtained using core-shell scattering models, for smaller particles than had previously been studied, and outlines modifications to these which would permit rapid computation of sufficient stability to support fast particle sizing procedures. PMID- 24784463 TI - CONTEXT MATTERS: FOSTERING, ORPHANHOOD AND SCHOOLING IN SUB-SAHARAN AFRICA. AB - A growing body of research suggests that orphanhood and fostering might be (independently) associated with educational disadvantage in sub-Saharan Africa. However, literature on the impacts of orphanhood and fostering on school enrolment, attendance and progress produces equivocal, and often conflicting, results. This paper reports on quantitative and qualitative data from sixteen field-sites in Ghana and Malawi, highlighting the importance of historical and social context in shaping schooling outcomes for fostered and orphaned children. In Malawi, which has been particularly badly affected by AIDS, orphans were less likely to be enrolled in and attending school than other children. By contrast, in Ghana, with its long tradition of 'kinship fostering', orphans were not significantly educationally disadvantaged; instead, non-orphaned, purposively fostered children had lower school enrolment and attendance than their peers. Understanding the context of orphanhood and fostering in relation to schooling is crucial in achieving 'Education for All'. PMID- 24784464 TI - Nutritional intake of elite football referees. AB - There is a paucity of dietary data in football referees. In this study, 23 elite main and assistant referees (34.4 +/- 5.6 years) completed a 7-day dietary record during the competitive season. No nutritional intake differences were observed between main and assistant referees. Referees' mean daily energy intake (DEI) was 2819 +/- 279 kcal. The intake of proteins (1.7 +/- 0.2 g . kg(-1)), carbohydrates (4.1 +/- 0.8 g . kg(-1)) and fats (1.4 +/- 0.2 g . kg(-1)) represented, respectively, 18.4 +/- 1.5%, 44.4 +/- 4.4% and 34.6 +/- 4.1% of the DEI. Carbohydrate intakes before, during and after exercise were 66 +/- 42, 7 +/- 15 and 120 +/- 62 g. Daily carbohydrate, fibre, polyunsaturated fat and water intakes were below recommendations, while fat, saturated fat, cholesterol and sodium intakes were above recommended values. The prevalence of inadequate intake was high for vitamin E (96%), folate (74%), vitamin A (61%), vitamin C (39%), magnesium (26%) and calcium (22%). Carbohydrate intake before, during and after exercise were far from achieving the minimum recommended values. Most referees demonstrated a negligent behaviour of hydration during exercise. Referees would benefit from dietary education in order to optimise performance and health. PMID- 24784465 TI - Information conservation principle determines electrophilicity, nucleophilicity, and regioselectivity. AB - Electrophilic and nucleophilic reactions are important chemical transformations involving charge acceptance and donation, so chemical intuition suggests that atomic charges should be a reliable descriptor to determine electrophilicity, nucleophilicity, and regioselectivity. Nevertheless, no such theoretical framework has been established as of yet. Herein, we report that the Hirshfeld charge can be used for such purposes. We justify this usage by showing that it results from the Information Conservation Principle. This principle not only decides where electrophilic and nucleophilic attacks will preferably occur but also dictates the amount of the Hirshfeld charge distribution, which, as we will show here, remarkably strongly correlates with experimental scales of both electrophilicity and nucleophilicity. PMID- 24784466 TI - A novel practical trocar placement technique for extraperitoneal laparoscopic and robotic-assisted laparoscopic radical prostatectomy in patients with lower midline abdominal incisions. AB - OBJECTIVE: To describe a novel practical technique for trocar placement in extraperitoneal laparoscopic radical prostatectomy (eLRP) and robotic-assisted laparoscopic radical prostatectomy (eRALP) in patients who had lower midline abdominal incisions. SUBJECTS AND METHODS: Between March 1999 and November 2013, 3080 LRPs were performed in our department. In total, 1745 eLRPs and 416 eRALPs were enrolled in the study. Group 1 consisted of 57 cases (45 eLRPs and 12 eRALPs) with median lower incision scars after previous abdominal surgery. Group 2 consisted of the same numbers of patients without previous surgeries after matched-pair analyses was performed according to body mass index, age, and operation style. Demographic, perioperative, and postoperative data were recorded. Additionally, we described our novel practical trocar replacement technique for extraperitoneal approach. Statistical analyses were performed. RESULTS: Mean age was 65.6+/-6.2 years. Mean follow-up was 102.9+/-24.5 months. There were 12 eRALPs and 45 eLRPs in each group. Demographic, perioperative, and postoperative data were similar in the two groups except for trocar placement time. The trocar placement time was longer in Group 1 than in Group 2 (P<.001). In all patients with previous abdominal surgery with lower abdominal incision scars, we were able to establish trocar placement and correct access to the extraperitoneal space. Moreover, we had no conversions or complications in any patient. CONCLUSIONS: Our technique seems safe and practical for trocar placements for eLRP and eRALP in patients with lower abdominal incision scars. PMID- 24784467 TI - Barriers to obtaining employment for people with severe mental illness experiencing homelessness. AB - BACKGROUND: The rate of unemployment among homeless people is estimated to exceed 80%. A high prevalence of mental illness partially explains this figure, but few studies about the relationship between employment and homelessness have focused on homeless people with mental illness. AIM: The present study explores the self reported barriers to employment in a sample of individuals with mental illness when they were homeless. METHODS: A sample of 27 individuals with mental illness and recent experiences of homelessness, who had expressed an interest in working, participated in semi-structured qualitative interviews. Inductive analysis was used to identify barriers to employment. FINDINGS: The prominent barriers include: (1) current substance abuse, (2) having a criminal record, (3) work impeding shelter practices, and (4) difficulties obtaining adequate psychiatric care. CONCLUSION: Individuals who have been homeless and have a mental illness report facing specific barriers associated with mental illness, homelessness, or the interaction between the two. Additional research should explore how supported housing and employment interventions can be tailored to effectively serve this group. PMID- 24784468 TI - Nobiletin, a flavone from Citrus depressa, induces gene expression and increases the protein level and activity of neprilysin in SK-N-SH cells. AB - Neprilysin (NEP) is one of the candidate amyloid beta protein (Abeta) degrading enzymes affecting brain Abeta clearance. This enzyme declines in the brain with age, which leads to the increased Abeta deposition in Alzheimer's disease (AD). Pharmacological activation of NEP during the aging process, therefore, represents a potential strategy to prevent the development of AD. To examine the influence of nobiletin on neprilysin activity, we measured cellular NEP activity in SK-N-SH cells. Moreover, NEP expression was examined by using reverse transcription - polymerase chain reaction and Western blotting. Measurement of cellular NEP activity showed that nobiletin stimulated this in a dose- and time-dependent manner in SK-N-SH cells. Moreover, nobiletin increased the expression of NEP mRNA, and then the levels of NEP protein, also in a dose- and time-dependent manner. Our findings showed that nobiletin promoted NEP gene and protein expression, resulting in enhancement of cellular NEP activity in SK-N-SH cells. This compound could be a novel Abeta-degrading compound for use in the development of disease-modifying drugs to prevent and (or) cure AD. PMID- 24784469 TI - Endurance exercise attenuates cardiotoxicity induced by androgen deprivation and doxorubicin. AB - Doxorubicin (DOX) is associated with cardiac dysfunction and irreversible testicular damage. Androgen deprivation therapy (ADT) is administered prior to DOX treatment to preserve testicular function. However, ADT may exacerbate DOX induced cardiac dysfunction. Exercise is cardioprotective, but the effects of exercise on cardiac function during combined ADT and DOX treatment are currently unknown. In this study, male Sprague-Dawley rats were randomly assigned to experimental groups: control (CON), ADT, DOX, or ADT+DOX. Animals received ADT or control implants on days 1 and 29 of the 56-day protocol. Animals remained sedentary (SED) or engaged in treadmill endurance exercise (TM) beginning on day 1. On day 15, the animals received DOX at 1 mg.(kg body mass)(-1).d(-1) by intraperitoneal injection for 10 consecutive days, or an equivalent volume of saline. On day 57, cardiac function was assessed in vivo and ex vivo. Animals treated with DOX alone, or with combined ADT+DOX, showed significant (P < 0.05) reductions in left ventricular developed pressure (-21% and -27%), maximal rate of pressure development (-29% and -32%), and maximal rate of pressure decline (25% and 31%), respectively when compared with the sedentary control animals. Endurance exercise training attenuated (P > 0.05) cardiac dysfunction associated with combined ADT+DOX treatment, indicating that exercise during simultaneous ADT+DOX treatment is cardioprotective. PMID- 24784470 TI - Vitronectin [correction of Vitronetcin] promotes cell growth and inhibits apoptotic stimuli in a human hepatoma cell line via the activation of caspases. AB - This study sought to understand the effects of vitronectin (VTN) on the growth of SMMC-7721 hepatoma cells. In addition, this study examined how VTN inhibits the induction of apoptosis in SMMC-7721 cells by 3,3'-diindolylmethane (DIM), a metabolite of natural phytochemicals, and preliminarily investigated the signaling molecules involved in this process. A cell proliferation reagent was used to observe the effects of VTN on cell proliferation rates. Laser scanning confocal microscopy was performed to observe the effects of VTN on the morphology of tubulin, a component of the cytoskeleton. Flow cytometry and Western blotting assays were used to observe the inhibitory effects of VTN on DIM-induced apoptosis in SMMC-7721 cells and changes in the expression levels of the signaling molecules involved in this process. VTN promoted tumor cell growth in a concentration-dependent manner and inhibited apoptosis caused by the effects of apoptosis-inducing agents. Under in vitro experimental conditions, VTN contributed to the growth of SMMC-7721 hepatoma cells and protected them from the effects of an apoptosis-inducing agent. These findings suggest that during hepatocellular carcinogenesis, VTN may promote tumor cell growth and inhibit chemically induced apoptosis. PMID- 24784471 TI - Sequoyitol ameliorates diabetic nephropathy in diabetic rats induced with a high fat diet and a low dose of streptozotocin. AB - Sequoyitol decreases blood glucose, improves glucose intolerance, and enhances insulin signaling in ob/ob mice. The aim of this study was to investigate the effects of sequoyitol on diabetic nephropathy in rats with type 2 diabetes mellitus and the mechanism of action. Diabetic rats, induced with a high-fat diet and a low dose of streptozotocin, and were administered sequoyitol (12.5, 25.0, and 50.0 mg.(kg body mass)(-1).d(-1)) for 6 weeks. The levels of fasting blood glucose (FBG), serum insulin, blood urea nitrogen (BUN), and serum creatinine (SCr) were measured. The expression levels of p22(phox), p47(phox), NF-kappaB, and TGF-beta1 were measured using immunohistochemisty, real-time PCR, and (or) Western blot. The total antioxidative capacity (T-AOC), as well as the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) were also determined. The results showed that sequoyitol significantly decreased FBG, BUN, and SCr levels, and increased the insulin levels in diabetic rats. The level of T-AOC was significantly increased, while ROS and MDA levels and the expression of p22(phox), p47(phox), NF-kappaB, and TGF-beta1 were decreased with sequoyitol treatment both in vivo and in vitro. These results suggested that sequoyitol ameliorates the progression of diabetic nephropathy in rats, as induced by a high fat diet and a low dose of streptozotocin, through its glucose-lowering effects, antioxidant activity, and regulation of TGF-beta1 expression. PMID- 24784472 TI - Tadalafil enhances the neuroprotective effects of ischemic postconditioning in mice, probably in a nitric oxide associated manner. AB - This study investigates the modulatory effect of tadalafil, a selective phosphodiesterase (PDE-5) inhibitor, on the neuroprotective effects of ischemic postconditioning (iPoCo) in mice. Bilateral carotid artery occlusion (BCAO) for 12 min followed by reperfusion for 24 h was employed to produce ischemia and reperfusion induced cerebral injury. Cerebral infarct size was measured using TTC staining. Memory was assessed using the Morris water maze test. Degree of motor incoordination was evaluated using inclined beam-walking, rota-rod, and lateral push tests. Brain nitrite/nitrate, acetylcholinesterase activity, TBARS, and glutathione levels were also estimated. BCAO followed by reperfusion produced a significant increase in cerebral infarct size, brain nitrite/nitrate and TBARS levels, and acetylcholinesterase activity along with a reduction in glutathione. Marked impairment of memory and motor coordination was also noted. iPoCo consisting of 3 episodes of 10 s carotid artery occlusion and reperfusion instituted immediately after BCAO significantly decreased infarct size, memory impairment, motor incoordination, and altered biochemistry. Pretreatment with tadalafil mimicked the neuroprotective effects of iPoCo. The tadalafil-induced neuroprotective effects were significantly attenuated by l-NAME, a nonselective NOS inhibitor. We concluded that tadalafil mimics the neuroprotective effects of iPoCo, probably through a nitric oxide dependent pathway, and PDE-5 could be a target of interest with respect to the neuroprotective mechanism of iPoCo. PMID- 24784474 TI - Is open-access publishing the wave of the future in science? PMID- 24784475 TI - In memoriam of Dr. Heinz Rupp: associate editor of the Canadian Journal of Physiology and Pharmacology. PMID- 24784476 TI - MicroRNAs and the immune response to respiratory virus infections. AB - MicroRNAs (miRNAs) are small ssRNA molecules, which are involved in gene expression regulation at the post-transcriptional level. Their biological functions include modulation of both innate and adaptive immune response. miRNAs participate in the maintenance of the airway epithelial barrier and are also implicated in the modulation of antiviral defense in epithelial cells. The immune response to respiratory viruses such as rhinovirus, influenza virus and respiratory syncytial virus is associated with an altered expression of distinct miRNAs, and the changes in the miRNA expression profile in epithelial cells may contribute to the pathogenesis of both acute and chronic airway disease. Understanding the role of these small molecules in the antiviral immune response and identification of miRNAs target genes may help to clarify the mechanisms of virus-host interaction, and in the future may lead to development of new antiviral treatments. PMID- 24784477 TI - Modeling the current density generated by transcutaneous spinal direct current stimulation (tsDCS). AB - OBJECTIVE: Non-invasive transcutaneous spinal direct current stimulation (tsDCS) induces changes in spinal cord function in humans. Nonetheless, the current density (J) spatial distributions generated by tsDCS are unknown. This work aimed to estimate the J distributions in the spinal cord during tsDCS. METHODS: Computational electromagnetics techniques were applied to realistic human models, based on high-resolution MRI of healthy volunteers (a 26-years-old female adult model "Ella"; a 14years-old male adolescent model "Louis"; an 11years old female adolescent model "Billie"). Three electrode montages were modeled. In all cases, the anode was always over the spinal process of the tenth thoracic vertebra and the cathode was placed: (A) above the right arm; (B) over the umbilicus; (C) over Cz. The injected current was 3mA. The electrodes were conductors within rectangular sponges. RESULTS: Despite inter-individual differences, the J tends to be primarily directed longitudinally along the spinal cord and cauda equina with the region of higher amplitude influenced by the reference electrode position; on transversal sections, the J amplitude distributions were quite uniform. CONCLUSIONS: Our modeling approach reveals that the J generated by tsDCS reaches the spinal cord, with a current spread also to the muscle on the back and the spinal nerve. SIGNIFICANCE: This study is a first step in better understanding the mechanisms underlying tsDCS. PMID- 24784478 TI - Mechanochemical synthesis of Li2MnO3 shell/LiMO2 (M = Ni, Co, Mn) core-structured nanocomposites for lithium-ion batteries. AB - Core/shell-like nanostructured xLi2MnO3.(1-x)LiMO2 (M = Ni, Co, Mn) composite cathode materials are successfully synthesized through a simple solid-state reaction using a mechanochemical ball-milling process. The LiMO2 core is designed to have a high-content of Ni, which increases the specific capacity. The detrimental surface effects arising from the high Ni-content are countered by the Li2MnO3 shell, which stabilizes the nanoparticles. The electrochemical performances and thermal stabilities of the synthesized nanocomposites are compared with those of bare LiMO2. In particular, the results of time-resolved X ray diffraction (TR-XRD) analyses of xLi2MnO3.(1-x)LiMO2 nanocomposites as well as their differential scanning calorimetry (DSC) profiles demonstrate that the Li2MnO3 shell is effective in stabilizing the LiMO2 core at high temperatures, making the nanocomposites highly suitable from a safety viewpoint. PMID- 24784479 TI - The communication experiences of patients with palliative care needs: A systematic review and meta-synthesis of qualitative findings. AB - OBJECTIVE: Optimal communication is essential in ensuring that the palliative care needs of patients are met. This continues to be an area of concern for healthcare providers. The goal of our present review was to gain a deeper understanding of the communication experiences of patients with palliative care needs that have been identified within the qualitative literature. METHOD: A systematic search for qualitative research papers was undertaken in February of 2012. Five databases (ASSIA, CINAHL, MEDLINE, PsychArticles, and PsychINFO) were searched using the search terms ["palliative care" OR "terminal care" OR "end of life care"] AND ["experience" OR "perspective" OR "qualitative" OR "interview"] AND ["patients" OR "clients" OR "service-user"]. Meta-synthesis was conducted on the data within the found papers. RESULTS: A line-of-argument synthesis of 15 studies yielded four overarching themes: talking-facilitating and inhibiting factors; the importance of humanitarian qualities within communication encounters; perceptions of autonomy within communication experiences; and individual differences in preferences for honesty within interactions. SIGNIFICANCE OF RESULTS: Our findings are discussed in relation to existing literature and offer a deeper insight into the communication experiences of this clinical population. A number of clinical implications are offered for the healthcare professionals who are providing support to patients with palliative care needs. PMID- 24784481 TI - Summary health statistics for U.S. children: National Health Interview Survey, 2012. AB - OBJECTIVES: This report presents both age-adjusted and unadjusted statistics from the 2012 National Health Interview Survey (NHIS) on selected health measures for children under age 18 years, classified by sex, age, race, Hispanic origin, family structure, parent's education, family income, poverty status, health insurance coverage, place of residence, region, and current health status. Topics included are asthma, allergies, learning disability, attention deficit hyperactivity disorder (ADHD), prescription medication use for at least 3 months, respondent-assessed health status, school days missed due to illness or injury, usual place of health care, time since last contact with a health care professional, selected measures of health care access, emergency room (ER) visits, dental care, and special education or early intervention services. DATA SOURCE: NHIS is a multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention's National Center for Health Statistics and is representative of the civilian noninstitutionalized population of the United States. This report analyzes data from two of the main components of NHIS: the Family Core, in which data are collected for all family members by interviewing an adult family respondent, and the Sample Child Core, in which additional health information is collected about a randomly selected child (the sample child) from an adult familiar with the child's health. SELECTED HIGHLIGHTS: In 2012, most U.S. children under age 18 years had excellent or very good health (83%). However, 7% of children had no health insurance coverage, and 4% of children had no usual place of health care. Six percent of children had unmet dental need because their families could not afford dental care. Twelve percent of children had one ER visit and 6% had two or more visits. Ten percent of children aged 3-17 years had ADHD. PMID- 24784480 TI - Anti-atherogenic peptide Ep1.B derived from apolipoprotein E induces tolerogenic plasmacytoid dendritic cells. AB - Tolerogenic dendritic cells (DCs) play a critical role in the induction of regulatory T cells (Tregs ), which in turn suppress effector T cell responses. We have previously shown the induction of DCs from human and mouse monocytic cell lines, mouse splenocytes and human peripheral blood monocytes by a novel apolipoprotein E (ApoE)-derived self-peptide termed Ep1.B. We also showed that this C-terminal region 239-252 peptide of ApoE has strong anti-atherogenic activity and reduces neointimal hyperplasia after vascular surgery in rats and wild-type as well as ApoE-deficient mice. In this study, we explored the phenotype of DC subset induced by Ep1.B from monocytic cell lines and from the bone marrow-derived cells. We found Ep1.B treatment induced cells that showed characteristics of plasmacytoid dendritic cells (pDC). We explored in-vitro and in-vivo effects of Ep1.B-induced DCs on antigen-specific T cell responses. Upon in-vivo injection of these cells with antigen, the subsequent ex-vivo antigen specific proliferation of lymph node cells and splenocytes from recipient mice was greatly reduced. Our results suggest that Ep1.B-induced pDCs promote the generation of Treg cells, and these cells contribute to the induction of peripheral tolerance in adaptive immunity and potentially contribute its anti atherogenic activity. PMID- 24784482 TI - Rediscovering a key interface in dye-sensitized solar cells: guanidinium and iodine competition for binding sites at the dye/electrolyte surface. AB - We propose a new mechanism by which the common electrolyte additive guanidinium thiocyanate (GdmSCN) improves efficiency in dye-sensitized solar cells (DSSCs). We demonstrate that binding of Gdm(+) to TiO2 is weak and does not passivate recombination sites on the TiO2 surface as has been previously claimed. Instead, we show that Gdm(+) binds strongly to the N719 and D131 dyes and probably to many similar compounds. The binding of Gdm(+) competes with iodine binding to the same molecule, reducing the surface concentration of dye-I2 complexes. This in turn reduces the electron/iodine recombination rate constant, which increases the collection efficiency and thus the photocurrent. We further observe that GdmNO3 can increase efficiency more than the current Gdm(+) source, GdmSCN, at least in some DSSCs. Overall, the results point to an improved paradigm for DSSC operation and development. The TiO2/electrolyte surface has long been held to be the key interface in DSSCs. We now assert that the dye layer/electrolyte interaction is at least, and probably more, important. PMID- 24784483 TI - Elastic modulus and fracture strength evaluation on the nanoscale by scanning force microscope experiments. AB - This work first reviews the capability of scanning force microscopy (SFM) to perform experiments with forces in a wide range, from low non-contact forces to high contact forces which induce mechanical deformations in the substrate. In analogy to fracture strength evaluation, as established in materials science, SFM is used to exert forces on pillars with nanometer dimensions while the cantilever deformations are monitored quantitatively. Hence, it is possible to bend the pillars until the threshold for triggering fracture is reached, and to determine the mechanical properties at the different stages of this process. Using this novel approach, in combination with 'state of the art' nanofabrication to produce nanopillar arrays on silicon and silicon dioxide substrates, a number of experiments are performed. Furthermore, quantitative measurements of the fracture strength of Si and of the SiO2/Si interface and E-modulus are presented. To analyze the experimental data obtained in the different experimental procedures and modes, finite element method calculations were used. The methods introduced herein provide a versatile toolbox for addressing a wide range of scientific problems and for applications in materials science and technology. PMID- 24784484 TI - Chemical constituents from the roots of Leea thorelii Gagnep. AB - Phytochemical investigation of the roots of Leea thorelii led to the isolation of nine compounds. Their structures were determined from spectroscopic data as bergenin (1), 11-O-acetyl bergenin (2), 11-O-(4'-O-methylgalloyl) bergenin (3), 3,5-dihydroxy-4-methoxybenzoic acid (4), ( - )-epicatechin (5), 4"-O-methyl-( - ) epicatechin gallate (6), ( - )-epicatechin gallate (7), microminutinin (8) and stigmasterol. Compounds 1-8 are reported for the first time from this plant, and this is also the first report of the presence of 1, 3, 4, 6 and 8 in the Vitaceae family. PMID- 24784485 TI - Organic electronic materials: recent advances in the DFT description of the ground and excited states using tuned range-separated hybrid functionals. AB - CONSPECTUS: Density functional theory (DFT) and its time-dependent extension (TD DFT) are powerful tools enabling the theoretical prediction of the ground- and excited-state properties of organic electronic materials with reasonable accuracy at affordable computational costs. Due to their excellent accuracy-to-numerical costs ratio, semilocal and global hybrid functionals such as B3LYP have become the workhorse for geometry optimizations and the prediction of vibrational spectra in modern theoretical organic chemistry. Despite the overwhelming success of these out-of-the-box functionals for such applications, the computational treatment of electronic and structural properties that are of particular interest in organic electronic materials sometimes reveals severe and qualitative failures of such functionals. Important examples include the overestimation of conjugation, torsional barriers, and electronic coupling as well as the underestimation of bond-length alternations or excited-state energies in low-band gap polymers. In this Account, we highlight how these failures can be traced back to the delocalization error inherent to semilocal and global hybrid functionals, which leads to the spurious delocalization of electron densities and an overestimation of conjugation. The delocalization error for systems and functionals of interest can be quantified by allowing for fractional occupation of the highest occupied molecular orbital. It can be minimized by using long range corrected hybrid functionals and a nonempirical tuning procedure for the range-separation parameter. We then review the benefits and drawbacks of using tuned long-range corrected hybrid functionals for the description of the ground and excited states of pi-conjugated systems. In particular, we show that this approach provides for robust and efficient means of characterizing the electronic couplings in organic mixed-valence systems, for the calculation of accurate torsional barriers at the polymer limit, and for the reliable prediction of the optical absorption spectrum of low-band-gap polymers. We also explain why the use of standard, out-of-the-box range-separation parameters is not recommended for the DFT and/or TD-DFT description of the ground and excited states of extended, pi-conjugated systems. Finally, we highlight a severe drawback of tuned range separated hybrid functionals by discussing the example of the calculation of bond length alternation in polyacetylene, which leads us to point out the challenges for future developments in this field. PMID- 24784486 TI - Objective measures of executive functioning are highly discrepant with parent report in fetal alcohol spectrum disorders. AB - The purpose of the current study was to evaluate the relationship between parent report and objective measures of executive function in children diagnosed with Fetal Alcohol Spectrum Disorder (FASD). The participants were a clinical sample of 551 children who completed 597 evaluations, including initial and re evaluations. Participants were 6-16 years old, with a mean age of 10. Pearson correlations were used to determine the relationship between performance-based measures and parent-report measures of executive functioning. Relationships among the same types of measures, that is, performance based or parent report, were also evaluated. The data largely demonstrate low nonsignificant correlations between performance-based measures and parental report of executive function. Parent-report measures were internally consistent as were objective measures. It is possible that a third variable, for example, parental frustration, significantly influences parent reports. It is also likely that objective measures, which are administered in a controlled environment, do not fully capture children's day-to-day functioning. That is, a child may have the executive function abilities (i.e., good performance on objective measures) but may be unable to deploy the appropriate skills in their daily lives, as evidenced by parental report. Children with FASD who have executive function abilities but not implementation skills likely require different interventions than children who lack abilities and skills. PMID- 24784487 TI - Introduction to dynamic treatment strategies and sequential multiple assignment randomization. AB - BACKGROUND: In June 2013, a 1-day workshop on Dynamic Treatment Strategies (DTSs) and Sequential Multiple Assignment Randomized Trials (SMARTs) was held at the University of Pennsylvania in Philadelphia, Pennsylvania. These two linked topics have generated a great deal of interest as researchers have recognized the importance of comparing entire strategies for managing chronic disease. A number of articles emerged from that workshop. PURPOSE: The purpose of this survey of the DTS/SMART methodology (which is taken from the introductory talk in the workshop) is to provide the reader the collected articles presented in this volume with sufficient background to appreciate the more detailed discussions in the articles. METHODS: The way that the DTS arises naturally in clinical practice is described, along with its connection to the well-known difficulties of interpreting the analysis by intention-to-treat. The SMART methodology for comparing DTS is described, and the basics of estimation and inference presented. RESULTS: The DTS/SMART methodology can be a flexible and practical way to optimize ongoing clinical decision making, providing evidence (based on randomization) for comparative effectiveness. LIMITATIONS: The DTS/SMART methodology is not a solution for unstandardized study protocols. CONCLUSIONS: The DTS/SMART methodology has growing relevance to comparative effectiveness research and the needs of the learning healthcare system. PMID- 24784488 TI - Transcriptional reprogramming and phenotypical changes associated with growth of Xanthomonas campestris pv. campestris in cabbage xylem sap. AB - Xylem sap (XS) is the first environment that xylem phytopathogens meet in planta during the early infection steps. Xanthomonas campestris pv. campestris (Xcc), the causative agent of Brassicaceae black rot, colonizes the plant xylem vessels to ensure its multiplication and dissemination. Besides suppression of plant immunity, Xcc has to adapt its metabolism to exploit plant-derived nutrients present in XS. To study Xcc behaviour in the early infection steps, we used cabbage XS to analyse bacterial growth. Mineral and organic composition of XS were determined. Significant growth of Xcc in XS was allowed by the rapid catabolism of amino acids, sugars and organic acids, and it was accompanied by the formation of biofilm-like structures. Transcriptome analysis of Xcc cultivated in XS using cDNA microarrays revealed a XS-specific transcriptional reprogramming compared to minimal or rich media. More specifically, up-regulation of genes encoding transporters such as TonB-dependent transporters (TBDTs), that could be associated with nutrient acquisition and detoxification, was observed. In agreement with the aggregation phenotype, expression of genes important for twitching motility and adhesion was up-regulated in XS. Taken together, our data show specific responses of Xcc to colonization of cabbage XS that could be important for the pathogenesis process and establish XS as a model medium to study mechanisms important for the early infection events. PMID- 24784489 TI - Bringing technology to the bedside: using smartphones to improve interprofessional communication. AB - The purpose of this project was to evaluate the impact of using Smartphones at the bedside on the quality of interprofessional communication and measure the response time between nurses and physicians compared with the usual paging device. Smartphones were provided to nurses and physicians on a 26-bed medical unit during a 2-month study period. Data were collected using Nurse-Physician Communication Questionnaires and Time and Motion data collection tools. Baseline data gathered from a convenience sample of general medicine nurses (n=61) and physicians (n=44) indicated that both nurses and physicians were dissatisfied with the current one-way paging devices and were frequently interrupted during patient care (P=.000). Postimplementation data suggested that the use of Smartphones significantly reduced patient interruptions (P=.021), allowed nurses to stay with patients (P=.002), and reduced wait times for a returned call (P=.001). Nurse travel time to answer a telephone call and time spent on hold by nurses and physicians also decreased by 100% from a range of 8 to 79 minutes down to 0 minutes. Staff reported improvement in quality of communication, and significant workflow efficiency was noted. Further research on the impact on patient safety and satisfaction is needed and other nursing units should consider implementing Smartphones within their medical centers. PMID- 24784490 TI - How to enhance nursing students' intention to use information technology: the first step before integrating it in nursing curriculum. AB - Today, in the 21st century, information technology has an important and critical role in the healthcare delivery system. Nursing educators already know and understand that they should integrate nursing informatics into the nursing curriculum to prepare future nurses for the new world of information technology. However, as of now, the core program of nursing studies in Israel does not put an emphasis on the skills required to properly use nursing informatics. The present research is the first step toward achieving this target by recognizing the importance of the human factor. The main goal is to examine the correlation between nursing students' attitudes and a number of variables: self-efficacy, threat, challenge, and innovativeness. This quantitative study used a convenience sample of nursing students in a bachelor's degree program at a large academic center in central Israel. Results show significant positive correlations between nursing students' attitudes to computer use and self-efficacy, a sense of challenge in using a computer, a sense of threat in using a computer, and previous experience with computers. The insights of these results will benefit nursing educators by helping them find creative ways to expose the students to the world of information technology and to improve the quality of future nurses. PMID- 24784491 TI - Altered significance of D'Amico risk classification in patients with prostate cancer linked to a familial breast cancer (kConFab) cohort. AB - OBJECTIVE: To ascertain whether D'Amico risk classification is an accurate discriminator of prostate cancer mortality risk in BRCA2 pathogenic mutation carriers and non-carriers from a familial breast cancer cohort. PATIENTS AND METHODS: From family cancer pedigrees of patients evaluated through a familial breast cancer cohort all related men with a diagnosis of prostate cancer were identified. Genotyping of each patient or of the dominant familial BRCA2 mutation was undertaken in each instance. Prostate cancers were analysed by BRCA2 carrier vs non-carrier status for their clinical progression and survival according to their D'Amico risk groups. RESULTS: For patients who were BRCA2-mutation positive, there was no significant difference in cancer-specific survival (CSS) between those patients who were graded as having D'Amico high- or intermediate risk disease. For patients who were BRCA2-mutation negative, but were identified via a family cancer pedigree, there was no statistically significant difference in CSS between D'Amico high- and intermediate-risk prostate cancers. Patients with D'Amico high-risk disease who were BRCA2-mutation carriers had substantially increased disease-specific mortality compared with high-risk non-carriers (hazard ratio 2.94, P = 0.004). CONCLUSION: D'Amico risk classification has limitations in predicting variations in prostate cancer-specific mortality for this group of patients. PMID- 24784492 TI - Isolation, characterization, and insecticidal activity of an endophyte of drunken horse grass, Achnatherum inebrians. AB - Abstract Endophytic microorganisms reside within plant tissues and have often been found to promote plant growth. In this study, endophytic microorganisms were isolated from the roots, stems, leaves, and seeds of healthy drunken horse grass, Achnatherum inebrians (Hance) Keng (Poales: Poaceae), through the use of a grinding separation method and identified by a dual approach of morphological and physiological observation and 16S rRNA gene-based (for bacteria) and internal transcribed sequence-based (for fungi) molecular identification. The endophytes were then inoculated into liquid media for fermentation, and their crude extracts were employed for insecticidal activity tests using slide disc immersion and nebulization methods. A total of 89 bacteria species, which were classified into eight genera, Bacillus, Pseudomonas, Actinomyces, Corynebacterium, Acinetobacter, Sphingomonas, Paenibacillus, and Phyllobacterium, and two fungi, Claviceps and Chaetomium, were isolated. Of these species, isolates Streptomyces albus (Rossi Doria) Waksman and Henrici (Actinomycetales: Streptomycetaceae) (GA) and Claviceps purpurea (Fr.) Tul. (Hypocreales: Clavicipitaceae) (PF-2) were shown to produce mortality rates of more than 90% in the cotton aphid, Aphis gossypii Glover (Hemiptera: Aphididae), after first and second screenings. The isolates PF 2 and GA associated with A. inebrians had significant insecticidal activities towards A. gossypii Glover (Hemiptera: Aphididae) and may provide a new biological resource for exploring a new microbial insecticide. PMID- 24784493 TI - Stabilizing radical cation and dication of a tetrathiafulvalene derivative by a weakly coordinating anion. AB - After the chemical oxidation of the neutral tetrakis(methylthio)tetrathiafulvalene (TMT-TTF, 1) by specific oxidation agents with weakly coordinating anion, [Al(ORF)4](-) [ORF = OC(CF3)3], the radical cation TMT-TTF(*+) (1(*+)) and dication TMT-TTF(2+) (1(2+)) were successfully stabilized and isolated. All the compounds are well-soluble in some solvents and have been systematically investigated by absorption spectra, (1)H NMR, electron paramagnetic resonance (EPR) measurements. Their crystal structures and electronic properties have been studied in conjunction with theoretical calculation. The synthetic approach for chemical oxidation by specific salts of weakly coordinating anions is useful for stable radical cations of tetrathiafulvalene (TTF) and its derivatives in both solution and solid state, which will extend the further research, including structure-property relations on stable radicals for TTF derivatives and new functional materials based on them. PMID- 24784494 TI - A Russian tragedy. PMID- 24784495 TI - Acute neurorehabilitation: does a neurosensory and coordinated interdisciplinary programme reduce tracheostomy weaning time and weaning failure? AB - BACKGROUND/PURPOSE: A new coordinated interdisciplinary unit was created in the acute section of the department of clinical neurosciences, the Acute NeuroRehabilitation (NRA) unit. The objective was to evaluate the impact of the unit and its neurosensory programme on the management of tracheostomy patients in terms of reduction in the average time taken for weaning, weaning success rate and therapeutic efficiency. METHODS: This 49-month retrospective study compares 2 groups of tracheostomy patients before (n = 34) and after (n = 46) NRA intervention. The outcome measures evaluate the benefits of the NRA unit intervention (time to decannulation, weaning and complication rates) and the benefits of the coordination (time to registration in a rehabilitation centre and rate of non-compliance with standards of care). RESULTS: Weaning failure rate was reduced from 27.3% to 9.1%, no complications or recannulations were observed in the post-intervention group after weaning and time to decannulation following admission to our unit decreased from 19.13 to 12.75 days. The rate of non compliance with patient standards of care was significantly reduced from 45% to 30% (Mann-Whitney p = 0.003). DISCUSSION/CONCLUSIONS: This interdisciplinary weaning programme helped to reduce weaning time and weaning failure, without increased complications, in the sample studied. Coordination improved the efficiency of the interdisciplinary team in the multiplicity and complexity of the different treatments. PMID- 24784496 TI - Point-of-care-testing of standing posture with Wii balance board and Microsoft Kinect during transcranial direct current stimulation: a feasibility study. AB - BACKGROUND: Non-invasive brain stimulation (NIBS) is a promising tool for facilitating motor function. NIBS therapy in conjunction with training using postural feedback may facilitate physical rehabilitation following posture disorders (e.g., Pusher Syndrome). OBJECTIVES: The objectives of this study were, 1) to develop a low-cost point-of-care-testing (POCT) system for standing posture, 2) to investigate the effects of anodal tDCS on functional reach tasks using the POCT system. METHODS: Ten community-dwelling elderly (age >50 years) subjects evaluated the POCT system for standing posture during functional reach tasks where their balance score on Berg Balance Scale was compared with that from Center-of-Mass (CoM) - Center-of-Pressure (CoP) posturography. Then, in a single blind, sham-controlled study, five healthy right-leg dominant subjects (age: 26.4 +/- 5.3 yrs) were evaluated using the POCT system under two conditions - with anodal tDCS of primary motor representations of right tibialis anterior muscle and with sham tDCS. RESULTS: The maximum CoP-CoM lean-angle was found to be well correlated with the BBS score in the elderly subjects The anodal tDCS strongly (p = 0.0000) affected the maximum CoP excursions but not the return reaction time in healthy. CONCLUSION: It was concluded that the CoM-CoP lean-line could be used for posture feedback and monitoring during tDCS therapy in conjunction with balance training exercises. PMID- 24784497 TI - Structured flexibility and context-sensitive behavioral support for the chronically cranky. AB - BACKGROUND: A significant number of individuals with brain injury demonstrate behavioral challenges that negatively affect their ability to live successfully in community settings. While there are a number of treatment approaches that have demonstrable effects in well controlled clinical settings, it is very difficult to implement these approaches in natural settings. OBJECTIVES: The goal of this study was to report the results of an investigation of the effects of a multicomponent behavioral intervention on the challenging behavior of an adolescent and young adult with growing behavioral concerns after acquired brain injury (TBI). METHODS: The participants were an 16 year old adolescent male and a 24 year old female, with escalating behavior problems after severe TBI. Multiple baseline designs were used to document the effects of an intervention package that integrated cognitive and executive function intervention to address severe challenging behaviors in natural settings. The following dependent variables were used to establish the effectiveness of the interventions: frequency and intensity of aggressive behaviors and participation in scheduled activities. The intervention included integrated components of positive behavior supports, cognitive supports and specific executive function scripts. RESULTS: These single subject experiments demonstrated the effectiveness of a multicomponent intervention on the reduction of the frequency of problem behaviors and the increase of pro-social behaviors. CONCLUSION: These two successful interventions extended the findings of previously published data for the successful treatment of behavioral challenges using a flexible support-oriented intervention that combines behavioral, cognitive, and executive function components. PMID- 24784498 TI - Substance use trends among younger vs. older homeless parolees. AB - This cross-sectional study of 540 homeless ex-offenders exiting prisons and jails assessed sociodemographic, childhood, and drug-related differences. Older ex offenders from prison were more likely to have been married, come from a two parent family, and used crack, whereas younger ex-offenders from prison were more likely to have used methamphetamine. Older ex-offenders from jail were more likely to be African American, have children, and report a history of crack and injection drug use, whereas younger ex-offenders from jail were more likely to have engaged in binge drinking and be in a gang. Our findings showcase the need to understand unique correlates of younger and older incarcerated populations. PMID- 24784499 TI - Effects and mechanism of dehydroepiandrosterone on epithelial-mesenchymal transition in bronchial epithelial cells. AB - BACKGROUND: Chronic persistent asthma is characterized by airway remodeling, in which epithelial-mesenchymal transition (EMT) may play a significant role. Dehydroepiandrosterone (DHEA), a steroid hormone and testosterone analog, is considered as an important immunomodulating hormone. However, its role in EMT remains unclear. We sought to investigate whether transforming growth factor beta1 (TGF-beta1) stimulates human bronchial epithelial cells (16HBE-14o) to undergo EMT, and whether this transition can be abrogated by DHEA. METHODS: The 16HBE-14o cells were stimulated with 5 ng/ml TGF-beta1 for 3 days to induce EMT, with or without DHEA pretreatment, and assayed for epithelial or mesenchymal markers using Western Blot. The involvement of phosphoinositide 3-kinase (PI3K) mediated signaling pathway was also evaluated, the epithelial cells were also incubated with pharmacological approaches (agonists and antagonists of Akt, LY294002 or IGF-1) or flutamide, the antagonist of androgen receptor. Results were analyzed using nonparametric statistical tests. RESULTS: Our data demonstrate that treatment of 16HBE-14o cells with TGF-beta1 for 3 days induced EMT as reflected by conversion to the spindle-like morphology, loss of E cadherin, and acquisition of a-smooth muscle actin (a-SMA). Pretreatment of 16HBE 14o cells with DHEA preserved the epithelial-like morphology, restored the expression of E-cadherin, and abolished the activation of a-SMA, and this effect is a PI3K-dependent mechanism. CONCLUSION: Our results indicate that TGF-beta1 induces EMT in a PI3K-dependent manner in 16HBE-14o cells. DHEA inhibits the bronchial epithelial to mesenchymal transition via the inhibition of PI3K/Akt dependent signal pathway stimulated by TGF-beta1. Therefore, DHEA may be a useful therapy for asthma. PMID- 24784500 TI - 1H-2H cross-relaxation study in a partially deuterated nematic liquid crystal. AB - A detailed study of the cross-relaxation effects between the 1H and 2H spins systems is presented in the nematic phase of a 5-cyanobiphenyl (5CB) liquid crystal, partially deuterated at alpha position (5CB-alphad2). The proton spin lattice relaxation time was measured at a frequency range from 5 kHz to 100 MHz at a temperature 5 K below the nematic-isotropic phase transition. In the low frequency domain, the spin-lattice relaxation rate (T1-1) dispersion clearly differs from that of the fully protonated 5CB homologue. At two distinct frequencies, T1-1 presents two distinct local maxima and for low frequencies T1-1 presents a stronger frequency dependence when compared with what is observed for 5CB. The T1-1 dispersion obtained for 5CB-alphad2 for frequencies above 60 kHz was interpreted in terms of the relaxation mechanisms usually accepted to interpret the spin-lattice relaxation in nematic phases in general and 5CB in particular. For lower frequencies it was necessary to consider cross-relaxation contributions between the proton and deuterium reservoirs. A detailed model interpretation of the deuterium quadrupolar dips with respect to the proton-spin relaxation is presented. The analysis of the quadrupolar relaxation independently confirms that the order director fluctuations is the dominant mechanism of proton relaxation in the low frequency domain. PMID- 24784501 TI - Antioxidative, hemocompatible, fluorescent carbon nanodots from an "end-of-pipe" agricultural waste: exploring its new horizon in the food-packaging domain. AB - The attention of researchers is burgeoning toward oilseed press-cake valorization for its high protein content. Protein removal from oil-cakes generates large quantities of fibrous residue (oil-and-protein spent meal) as a byproduct, which currently has very limited practical utility. In the wake of increasing awareness in waste recycling, a simple environmentally benign hydrothermal carbonization process to convert this "end-of-pipe" waste (spent meal) into antioxidative, hemocompatible, fluorescent carbonaceous nanoparticles (FCDs) has been described. In the present investigation, an interesting application of FCDs in fabricating low-cost rapeseed protein-based fluorescent film, with improved antioxidant potential (17.5-19.3-fold) and thermal stability has been demonstrated. The nanocomposite film could also be used as forgery-proof packaging due to its photoluminescence property. For assessing the feasibility of antioxidative FCDs in real food systems, a comparative investigation was further undertaken to examine the effect of such nanocarbon-loaded composite film on the oxidative shelf life of rapeseed oil. Oil samples packed in nanocomposite film sachets showed significant delay in oxidative rancidity compared to those packed in pristine protein-film sachet (free fatty acids, peroxide value, and thiobarbituric acid-reactive substances reduced up to 1.4-, 2-, and 1.2-fold, respectively). The work presents a new concept of biobased fluorescent packaging and avenues for harnessing this potent waste. PMID- 24784502 TI - Asphaltene aggregation and impact of alkylphenols. AB - The main objective of this study was to provide novel insights into the mechanism of asphaltene aggregation in toluene/heptane (Heptol) solutions and the effect of alkylphenols on asphaltene dispersion through the integration of advanced experimental and modeling methods. High-resolution transmission electron microscope (HRTEM) images revealed that the onset of asphaltene flocculation occurs near a toluene/heptane volume ratio of 70:30 and that flocculates are well below 1 MUm in size. To assess the impact of alkylphenols on asphaltene aggregation, octylphenol (OP) and dodecylphenol (DP) were evaluated by impedance analysis based on their ability to delay the precipitation onset and to reduce the size of nonflocculated asphaltene aggregates in 80:20 toluene/heptane solutions. Although a longer dispersant chain length did not affect the precipitation onset, it reduced the size of the aggregates. Molecular dynamics simulations were then performed to understand the mechanism of interaction between a model asphaltene and OP in heptane. OP molecules saturated the H bonding sites of asphaltenes and prevented them from interacting laterally between themselves. This explained why OP favored the formation of flocculates with filamentary rather than globular structures, which were clearly observed by HRTEM. Although OP proved to be an effective dispersant, its effectiveness was hindered by its self-association and the fact that it interacted at the periphery of asphaltenes, leaving their aromatic cores uncovered. PMID- 24784503 TI - Processing of configural and componential information in face-selective cortical areas. AB - We investigated how face-selective cortical areas process configural and componential face information and how race of faces may influence these processes. Participants saw blurred (preserving configural information), scrambled (preserving componential information), and whole faces during fMRI scan, and performed a post-scan face recognition task using blurred or scrambled faces. The fusiform face area (FFA) showed stronger activation to blurred than to scrambled faces, and equivalent responses to blurred and whole faces. The occipital face area (OFA) showed stronger activation to whole than to blurred faces, which elicited similar responses to scrambled faces. Therefore, the FFA may be more tuned to process configural than componential information, whereas the OFA similarly participates in perception of both. Differences in recognizing own- and other-race blurred faces were correlated with differences in FFA activation to those faces, suggesting that configural processing within the FFA may underlie the other-race effect in face recognition. PMID- 24784504 TI - Just doing it. PMID- 24784505 TI - Pushing the envelope? Immediately loaded, removable, unsplinted implant overdenture. PMID- 24784506 TI - Creating predictable success with invisible Class IVs. PMID- 24784508 TI - Well-intentioned or misguided? PMID- 24784507 TI - Co-administration of oral contraceptives and antibiotics used in dentistry. PMID- 24784509 TI - Bonded anterior orthodontic retainers. PMID- 24784510 TI - The effect of sodium hypochlorite and ginger extract on microorganisms and endotoxins in endodontic treatment of infected root canals. AB - This in vitro study sought to evaluate the biomechanical preparation action on microorganisms and endotoxins by using sodium hypochlorite (NaOCl) and an intracanal medication containing Zingiber officinale, with or without calcium hydroxide. Single-rooted teeth were contaminated, and root canal instrumentation (using 2.5% NaOCl) was performed. Samples were divided into 4 groups, according to the intracanal medication employed. The root canal content was gathered 28 days after contamination (baseline), immediately after biomechanical preparation, 7 days after biomechanical preparation, 14 days after intracanal medication, and 7 days after intracanal medication was removed. The results (submitted to Kruskal Wallis and Dunn tests) showed that the NaOCl eliminated 100% of root canal microorganisms and reduced 88.8% of endotoxins immediately after biomechanical preparation, and 83.2% at 7 days after biomechanical preparation. PMID- 24784511 TI - Concurrent intentional replantation of maxillary molars using a novel root-end filling. AB - This article describes the successful concurrent intentional replantation (IR) of 2 maxillary molars. A 28-year-old woman complained of repeated swelling and pain in the left maxilla when chewing. Teeth No. 14 and 15 were sensitive to percussion and palpation. Radiographs revealed a large periapical radiolucent lesion and inadequate root canal fillings in both teeth. The patient refused nonsurgical retreatment, periradicular surgery, or implant replacement as treatment options, so IR was chosen. After the extraction of tooth No. 14, root end resection and root-end preparation of the 3 roots were completed. All root end cavities were filled with calcium enriched mixture cement and the tooth was replanted. The same procedure was done for tooth No. 15. The patient was recalled 1, 7, and 14 days post-treatment for clinical evaluations. Follow-up visits at 6, 10, 15, and 24 months postsurgery revealed that both teeth were functional with no signs or symptoms of inflammation or resorption. The periapical lesion was healed at 24 months. PMID- 24784512 TI - Role of mouthguards in reducing mild traumatic brain injury/concussion incidence in high school football athletes. AB - There is continued speculation on the value of mouthguards (MGs) in preventing mild traumatic brain injury (MTBI)/concussion injuries. The purpose of this randomized prospective study was to compare the impact of pressure-laminated (LM), custom-made, properly fitted MGs to over-the-counter (OTC) MGs on the MTBI/concussion incidence in high school football athletes over a season of play. Four hundred twelve players from 6 high school football teams were included in the study. Twenty-four MTBI/concussion injuries (5.8%) were recorded. When examining the MTBI/concussion injury rate by MG type, there was a significant difference (P = 0.0423) with incidence rates of 3.6% and 8.3% in the LM MG and OTC MG groups, respectively. PMID- 24784513 TI - Proposal for clinical classification of multifactorial noncarious cervical lesions. AB - Noncarious cervical lesions often present with overlapping symptoms and have a multifactorial etiology. The dimensions of the lesion axially (depth) and occlusogingivally (width), along with the orientation of the walls of the lesion to each other (angle), are the 3 factors that can be quantified to classify the lesion and assess its progress over time. This article analyzes these factors and proposes a simple classification system based upon the clinical appearance of the lesion in order to derive simple, therapeutic, treatment-based classifications. PMID- 24784514 TI - Distinguishing and diagnosing contemporary and conventional features of dental erosion. AB - The vast number and variety of erosion lesions encountered today require reconsideration of the traditional definition. Dental erosion associated with modern dietary habits can exhibit unique features that symbolize a departure from the decades-old conventional image known as tooth surface loss. The extent and diversity of contemporary erosion lesions often cause conflicting diagnoses. Specific examples of these features are presented in this article. The etiologies, genesis, course of development, and characteristics of these erosion lesions are discussed. Contemporary and conventional erosion lesions are distinguished from similar defects, such as mechanically induced wear, carious lesions, and dental fluorosis, which affect the human dentition. PMID- 24784515 TI - Unusual occurrence of missing central incisor: a case report. AB - An unerupted maxillary central incisor is an uncommon finding in general dental practice. A thorough patient history and radiological examinations can reveal surprising findings. This article presents a case involving a dilacerated and impacted maxillary central incisor, examines its probable etiology, and discusses the condition in terms of pertinent literature. PMID- 24784516 TI - Microtensile bond strength of etch-and-rinse and self-etch adhesives to artificially created carious dentin. AB - This article evaluates a pH-cycling model for simulation of caries-affected and caries-infected dentin (CAD and CID, respectively) surfaces, by comparing the bond strength of an etch-and-rinse and a self-etch adhesive system. For both adhesives, bonding to sound dentin (SD) showed that the microtensile bond strength (MUTBS) values of SD, CAD, and CID were SD > CAD > CID (P < 0.05). Knoop microhardness number mean values followed the same trend. Adhesive systems were not able to totally penetrate into CAD and CID, forming more irregular resin dentin interdiffusion zones and atypical resin tags than SD. The tested in vitro pH-cycling caries model allowed the evaluation of specific dentin substrate alterations in response to MUTBS. The type of dentin and its histological structure played an important role in etch-and-rinse and self-etch bonding, as lower MUTBS values were attained in CAD and CID. PMID- 24784517 TI - Which is a stronger indicator of dental caries: oral hygiene, food, or beverage? A clinical study. AB - Dental caries is a multifactorial disease with various risk factors. Oral hygiene and dietary factors--specifically, the consumption of snacks and beverages with added sugars--have been shown to be risk indicators for this disease. It is critical for dental professionals to understand the relative roles of each of these food categories in the dental caries process. This article presents a cross sectional study of 76 people living in a Southern Illinois fluoridated community. The amount of sugar-sweetened beverages, snack food consumption, plaque index, and age showed statistically significant relationships with the outcome variable- dental caries (P < 0.05). The results indicated that dietary factors and oral hygiene both contribute equally to dental caries in young adults living in a fluoridated community. Sugar-sweetened beverage consumption was a much stronger indicator of dental caries than snack food consumption in our study population. PMID- 24784518 TI - Changing the gingival color discrepancy induced by pigmented root using subepithelial connective tissue graft: a case report. AB - Metallic alloys can suffer corrosion, and metallic posts and cores used for restorative procedures may develop a blue-gray pigmentation in root dentin, which in turn changes the color of gingival tissues. Removing posts and cores may lead to root fracture, and bleaching agents have a limited effect on staining from alloy corrosion. Surgical techniques for correcting undesirable esthetic deficiencies have been investigated in the literature. This article describes the case of a patient with gingival discoloration caused by root pigmentation in the maxillary area. A subepithelial connective graft harvested from the palate was used to treat the gingival color discrepancy. PMID- 24784519 TI - Total rehabilitation of maxilla using a tooth-to-implant restoration: case report. AB - Dental implants in partially edentulous patients are a predictable therapeutic option. However, using tooth-to-implant restorations to rehabilitate partially edentulous patients involves highly complex biomechanical aspects. This type of prosthesis utilizes different kinds of support that react distinctly to the functional forces developed in the oral cavity. In some cases, a tooth-to-implant restoration is a treatment option for difficulties related to reduced bone volume, inadequate interdental space, or an implant's failure to osseointegrate. This case report describes the rehabilitation of a patient whose partially edentulous maxilla was treated with a tooth-to-implant restoration. In this case, telescopic crowns were used to better match the tooth-implant union. No biomechanical or functional problems were found 8 years post-treatment, indicating that the combination of implant and tooth support is a possible treatment option with an improved long-term prognosis. PMID- 24784520 TI - Erythematous nodule of lower lip. Mucous extravasation phenomenon. PMID- 24784521 TI - CAD/CAM-fabricated telescopic prostheses on periodontally compromised abutments of a patient undergoing intravenous bisphosphonate treatment for osteoporosis: a case report. AB - Preserving periodontally compromised abutments in patients who are actively undergoing oral and intravenous bisphosphonate treatment for osteoporosis provides an alternative to tooth extraction and dental implants, both of which put patients at risk for bisphosphonate-related osteonecrosis of the jaw. This case report describes how a CAD/CAM-fabricated cobalt-chromium telescopic prosthesis was placed on periodontally compromised abutments of a 74-year-old woman actively undergoing oral and intravenous bisphosphonate treatment for osteoporosis. PMID- 24784522 TI - Diagnosis and management of cemental tear: a case report. AB - A 32-year-old man complained of swelling after an extraction in the vicinity of the left maxillary premolars. The occlusal surface of the first premolar showed no caries while the second premolar was covered with a crown. Radiographic examination revealed a thin radiolucent defect subgingivally below the cementodentinal junction on the distal aspect. During a review of medical history, the patient presented an extracted fragment that was sent for histopathological examination. A root canal was performed and the defect was closed with mineral trioxide aggregate followed by glass ionomer cement. Histopathology revealed the fragment to be a cemental tear, a condition associated typically with old age, trauma, and traumatic occlusion. Dentists should be aware of this rare entity as a differential diagnosis in cases involving noncarious odontogenic pain. PMID- 24784523 TI - Talon cusps occurring concurrently with dens invaginatus on a permanent maxillary lateral incisor: a case report and literature review. AB - A talon cusp is a prominent accessory horn-like structure that projects from the cingulum or cementoenamel junction of the maxillary or mandibular teeth. It can occur in primary and permanent dentition and can lead to occlusal interference, irritation of the tongue, pulpal necrosis, caries, and periodontal problems. Talon cusp has been reported to affect both sexes, and may be unilateral or bilateral. Talon cusps occur most often on the palatal surface of permanent maxillary incisors. A comprehensive literature review revealed only 6 reported cases of facial talon cusps. A talon cusp occurring simultaneously with dens invaginatus in a tooth is extremely rare; to date, only 9 case reports have been published. This article presents a unique case of concurrent dens invaginatus and palatal and facial talon cusps in the right maxillary central incisor of a 12 year-old girl. PMID- 24784524 TI - Palatogingival groove mimicking as a mutilated root fracture in a maxillary lateral incisor: a case report. AB - This article presents a case of a palatogingival groove (PPG) in tooth No. 12 that was misdiagnosed as a mutilated root fracture. A PPG is a developmental anomaly that predisposes a tooth to a severe periodontal defect. The initial diagnosis of mutilated root fracture on tooth No. 12 was made solely from radiographs that showed a vertical and horizontal radiolucent line with a radiolucent halo-shaped bone resorption in relation to the root apex. Transillumination, bite test, surgical visualization of the site, and the use of high-end diagnostic modalitieswere not considered prior to the final diagnosis. PPG was confirmed only after the tooth was extracted and observed under a dental operating microscope. PMID- 24784525 TI - An overlay partial denture to restore worn mandibular anterior teeth. AB - Restoring worn anterior mandibular teeth is a challenge, especially when teeth are small, esthetics are a concern, the long-term prognosis is questionable, and/or patient finances are an issue. This article describes an alternate treatment for a patient with a collapsed bite, missing posterior mandibular teeth, an ill-fitting complete maxillary denture with poor esthetics, and irregular, worn mandibular anterior teeth. PMID- 24784526 TI - Effect of surface treatment of brackets and mechanical cycling on adhesion to enamel. AB - This in vitro study sought to evaluate how surface conditioning from bracket and mechanical cycling aging affected the bond strength between metallic brackets and bovine enamel, and to determine the adhesive remnant index. Eighty bovine incisors were embedded in acrylic resin using polyvinyl chloride rings and divided into 4 groups based on surface treatment (n = 20). Group 1 (control) received no surface treatment, Group 2 specimens were sandblasted with aluminum oxide particles, Group 3 specimens were sandblasted with silicon oxide and treated with a tribochemichemical silica coupling agent, and Group 4 specimens were primed with a multidomain protein-based agent. Half of the specimens were submitted to shear bond testing, while the others were subjected to mechanical cycling. ANOVA showed that mechanical cycling did not have a significant influence on bond strength (P = 0.9244), while surface conditioning of the brackets did (P = 0.0001). Tukey's test results were similar for mechanical cycling, and indicated that only Group 3 significantly improved the resin bond to the brackets; however, this group also demonstrated the highest percentage of enamel failure. PMID- 24784527 TI - Nanopatterned PMMA-Yb:Er/Tm:Lu2O3 composites with visible upconversion emissions. AB - Nanopillars, nanotubes and nanofibers of transparent polymethyl methacrylate (PMMA) polymer with Yb:Ln:Lu2O3 (Ln = Er or Tm) nanoparticles (NPs) (~30-35 nm average size) have been prepared by infiltration of anodized aluminum oxide hexagonally nanopatterned templates. The outer diameter of these nanostructures is in the 330-400 nm range, with lengths up to 50 MUm and a period distance of 430 nm. These nanostructures show visible upconversion (UC) emissions under excitation with 978 nm light. The steady state temperature of the polymer nanostructures is optically evidenced by the Er(3+) UC emission and optically controlled around the PMMA glass transition temperature by the excitation light, introducing a new method for NP storage in a solid and potential optically induced particle release. Full color emission is shown in tridoped (Yb:Er:Tm) samples. PMID- 24784528 TI - Genus Kadsura, a good source with considerable characteristic chemical constituents and potential bioactivities. AB - In China, the plants of genus Kadsura had been used as the folk medicines for a long time and showed good effect of activating blood and dissolving stasis, promoting qi circulation to relieve pain, dispelling wind and eliminating dampness. The bioactivities of genus Kadsura were attributed to the existence of its characteristic chemical constituents. This review systematically summarized the traditional efficacy and medicinal application of genus Kadsura in China, chemical constituents and bioactivities of the plants of genus Kadsura. And, lignans and triterpenoids were the main bioactive constituents, which exhibited good anti-HIV, anti-tumor, anti-hepatitis, anti-oxidant, anti-platelet aggregation activities and neuroprotective effect etc. Moreover, some structure activity relationships mining would greatly enrich the opportunity of finding new and promising lead compounds and promote the reasonable development and utilization of the plants of genus Kadsura. PMID- 24784529 TI - High- and low-throughput scoring of fat mass and body fat distribution in C. elegans. AB - Fat accumulation is a complex phenotype affected by factors such as neuroendocrine signaling, feeding, activity, and reproductive output. Accordingly, the most informative screens for genes and compounds affecting fat accumulation would be those carried out in whole living animals. Caenorhabditis elegans is a well-established and effective model organism, especially for biological processes that involve organ systems and multicellular interactions, such as metabolism. Every cell in the transparent body of C. elegans is visible under a light microscope. Consequently, an accessible and reliable method to visualize worm lipid-droplet fat depots would make C. elegans the only metazoan in which genes affecting not only fat mass but also body fat distribution could be assessed at a genome-wide scale. Here we present a radical improvement in oil red O worm staining together with high-throughput image-based phenotyping. The three-step sample preparation method is robust, formaldehyde-free, and inexpensive, and requires only 15min of hands-on time to process a 96-well plate. Together with our free and user-friendly automated image analysis package, this method enables C. elegans sample preparation and phenotype scoring at a scale that is compatible with genome-wide screens. Thus we present a feasible approach to small-scale phenotyping and large-scale screening for genetic and/or chemical perturbations that lead to alterations in fat quantity and distribution in whole animals. PMID- 24784532 TI - Assessment of dietary exposure in the French population to 13 selected food colours, preservatives, antioxidants, stabilizers, emulsifiers and sweeteners. AB - The results of French intake estimates for 13 food additives prioritized by the methods proposed in the 2001 Report from the European Commission on Dietary Food Additive Intake in the European Union are reported. These 13 additives were selected using the first and second tiers of the three-tier approach. The first tier was based on theoretical food consumption data and the maximum permitted level of additives. The second tier used real individual food consumption data and the maximum permitted level of additives for the substances which exceeded the acceptable daily intakes (ADI) in the first tier. In the third tier reported in this study, intake estimates were calculated for the 13 additives (colours, preservatives, antioxidants, stabilizers, emulsifiers and sweeteners) according to two modelling assumptions corresponding to two different food habit scenarios (assumption 1: consumers consume foods that may or may not contain food additives, and assumption 2: consumers always consume foods that contain additives) when possible. In this approach, real individual food consumption data and the occurrence/use-level of food additives reported by the food industry were used. Overall, the results of the intake estimates are reassuring for the majority of additives studied since the risk of exceeding the ADI was low, except for nitrites, sulfites and annatto, whose ADIs were exceeded by either children or adult consumers or by both populations under one and/or two modelling assumptions. Under the first assumption, the ADI is exceeded for high consumers among adults for nitrites and sulfites (155 and 118.4%, respectively) and among children for nitrites (275%). Under the second assumption, the average nitrites dietary exposure in children exceeds the ADI (146.7%). For high consumers, adults exceed the nitrite and sulfite ADIs (223 and 156.4%, respectively) and children exceed the nitrite, annatto and sulfite ADIs (416.7, 124.6 and 130.6%, respectively). PMID- 24784530 TI - Eye development. AB - The eye has been one of the most intensively studied organs in Drosophila. The wealth of knowledge about its development, as well as the reagents that have been developed, and the fact that the eye is dispensable for survival, also make the eye suitable for genetic interaction studies and genetic screens. This article provides a brief overview of the methods developed to image and probe eye development at multiple developmental stages, including live imaging, immunostaining of fixed tissues, in situ hybridizations, and scanning electron microscopy and color photography of adult eyes. Also summarized are genetic approaches that can be performed in the eye, including mosaic analysis and conditional mutation, gene misexpression and knockdown, and forward genetic and modifier screens. PMID- 24784533 TI - Mercury, cadmium and lead levels in samples of the main traded fish and shellfish species in Galicia, Spain. AB - The presence of mercury, cadmium and lead has been studied in raw and processed fish and shellfish of the main traded species in Galicia (Spain) from at least 40 commercial outlets between January 2002 and October 2003. The results show that, according to European legislation, the products on the market are generally "safe", although the high levels of mercury in swordfish and shark are notable, with 22% of samples (n = 37) over the limit. We also indicate the relatively important contribution to mercury ingestion of widely consumed species, such as tuna, with 25% of samples (n = 378) over 0.25 mg kg-1. Cadmium was over the limit (1.0 mg kg-1) in 15% of the tested cephalopods (n = 79) and 29% of Chlamys sp. bivalves (n = 17). PMID- 24784534 TI - Monitoring programme on cadmium, lead and mercury in fish and seafood from Valencia, Spain: levels and estimated weekly intake. AB - The study was carried out to determine the current levels of mercury, cadmium, and lead in fish and seafood from the market of Comunitat Valenciana, Spain. Levels of total mercury ranged from 0.02 to 3.15 mg kg-1 w.w. (average = 0.073 mg kg-1 w.w.). Cadmium concentrations ranged from 0.003 to 0.66 mg kg-1 w.w. (average = 0.27 mg kg-1 w.w.) for seafood, and between 0.003 and 0.71 mg kg-1 w.w. (average = 0.01 mg kg-1 w.w.) for marine fish. Concerning lead, concentrations from 0.02 to 0.36 mg kg-1 w.w (average = 0.04 mg kg-1 w.w.) were found in fish, and from 0.02 to 1.02 mg kg-1 w.w. in seafood (average = 0.147 mg kg-1 w.w.). The levels found were, in general, lower than maximum levels proposed by European legislation. The estimated weekly intake of mercury, cadmium and lead through fish and seafood consumption was found to be about 43%, 10% and 3% of the established provisional tolerable weekly intake, respectively. PMID- 24784535 TI - Pesticide and non-dioxin-like polychlorinated biphenyls (NDL-PCBs) residues in foodstuffs from Ismailia city, Egypt. AB - Samples of vegetables and cereals from Egypt were screened for 113 pesticides, of which 68 were quantified, using gas chromatography-mass spectrometry (GC/MS) with limits of detection (LODs) ranging from 0.02 to 1.9 ug kg-1. In addition, the residues of 17 non-dioxin-like polychlorinated biphenyls (NDL-PCBs) were measured in samples of animal origin (meat, dairy products and seafood) using high resolution gas chromatography (HRGC)/high-resolution mass spectroscopy (HRMS). None of the cereal samples and 72.7% of the vegetables contained any detectable levels of the pesticides. Detectable residues, not exceeding the current European Union maximum residue limits (MRLs) were found in 27.3% of vegetables. The estimated daily intake for detected pesticides was well below their corresponding acceptable daily intake (ADI), with exposure ranges between 0.002% of the ADI for profenofos and 0.2% of the ADI for lambda-cyhalothrin. The sum concentration of 17 PCBs congeners varied between 2.5 and 322 ng g-1 fat, corresponding to 1.7-216 ng g-1 fat for the seven indicator PCBs. The highest values were measured in seafood, the lowest in dairy products. Hexa-CB 153, 138 and hepta-CB180 were the congeners with the highest contribution. PCBs congener profiles found in most of the samples were consistent with the expected profile for Aroclor 1260 and 1262. PCBs' contamination levels reported in this paper were many times lower than in developed countries, except for chicken samples. Also, the dietary intake of seven indicator PCBs due to the consumption of food of animal origin (4.84 ng kg 1 body weight day-1) from Ismailia city, Egypt, is several times lower than the intake in European Union countries. PMID- 24784536 TI - Occurrence of mycotoxins in maize, grass and wheat silage for dairy cattle in the Netherlands. AB - The occurrence of mycotoxins in 140 maize silages, 120 grass silages and 30 wheat silages produced in the Netherlands between 2002 and 2004 was determined using a liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS) multi-method. Deoxynivalenol (DON) was detected above the limit of quantification (LOQ) of 250 MUg kg-1 in 72% of maize and 10% of wheat silages. Average DON concentrations were 854 and 621 MUg kg-1, respectively, and maximum concentrations 3142 and 1165 MUg kg-1, respectively. Zearalenone was detected above the LOQ of 25 MUg kg-1 in 49% of maize and 6% of grass silages. Average zearalenone concentrations were 174 and 93 MUg kg-1, respectively, and maximum concentrations 943 and 308 MUg kg-1, respectively. The incidences and average concentrations of DON and zearalenone in maize silage were highest in 2004. The incidence of other mycotoxins was low: fumonisin B1 and 15-acetyl-DON were detected in 1.4 and 5% of maize silages, respectively, and roquefortin C in 0.8% of grass silages. None of the silages contained aflatoxins, ochratoxin A, T2 toxin, HT2-toxin, sterigmatocystin, diacetoxyscirpenol, fusarenon-X, ergotamine, penicillinic acid, or mycophenolic acid. This study demonstrates that maize silage is an important source of DON and zearalenone in the diet of dairy cattle. Since the carryover of these mycotoxins into milk is negligible, their occurrence in feed is not considered to be of significant concern with respect to the safety of dairy products for consumers. Potential implications for animal health are discussed. PMID- 24784537 TI - Survey on ochratoxin A in Indian green coffee destined for export. AB - Ochratoxin A (OTA) is a toxic metabolite, produced by Aspergillus spp. and Penicillium verrucosum, that is nephrotoxic and possibly carcinogenic to humans. The aim of this study was to evaluate OTA contamination in batches of green coffee destined for export. Analysis of 80 green coffee samples indicated that, although a high incidence (74%) of OTA contamination (0.2-13.5 ng g-1) was recorded, the overall mean OTA level (2.17 +/- 2.45 ng g-1) was low. The highest recorded OTA concentration was 13.5 ng g-1 in a robusta cherry sample and only five samples had OTA above 5 ng g-1 level. The mean OTA level was higher in cherry (range: 1.63 +/- 0.97-4.8 +/- 3.90) than parchment (0.56 +/- 0.35-1.10 +/- 0.28), indicating a correlation between processing method and OTA contamination. PMID- 24784538 TI - Dietary intake estimations of polybrominated diphenyl ethers (PBDEs) based on a total diet study in Osaka, Japan. AB - This study presents the results of a total diet study performed for estimating the dietary intake of polybrominated diphenyl ethers (PBDEs) in Osaka, Japan. The concentrations of 36 PBDEs were measured in samples from 14 food groups (Groups I XIV). PBDEs were detected only in Groups IV (oils and fats), V (legumes and their products), X (fish, shellfish, and their products), and XI (meat and eggs) at concentrations of 1.8, 0.03, 0.48, and 0.01 ng g-1, respectively. For an average person, the lower bound dietary intakes of penta- and deca-formulations were estimated to be 46 and 21 ng day-1, respectively. A high proportion of the decabrominated congener (DeBDE-209) was observed in Group IV. To confirm the presence of DeBDE-209 in vegetable oils, an additional analysis was performed using 18 vegetable oil samples. Of these, seven contained ng g-1 levels of DeBDE 209. PMID- 24784539 TI - Levels of polychlorinated biphenyls in fish and shellfish from the Adriatic Sea. AB - Levels of 18 polychlorinated biphenyl (PCB) congeners were determined by gas chromatography-mass spectrometry (GC-MS) in some marine species, living both in the coastal area and in deeper seawater. In some species analysis was performed separately in edible parts (fillets) and in viscera. The existence and degree of bioaccumulation was assessed studying individual species of very different size, with the smaller being younger. Furthermore, with a multivariate statistical analysis, a correlation between PCB congeners and the feeding habits and habitat of the fish was demonstrated. The results show that fat from edible parts (fish fillets) had total PCB levels in the range 22.6-601.9 ug kg-1 (with 601.9 ug kg-1 in anchovies), while fat from viscera showed much higher concentrations (407.3 916.6 ug kg-1). Bioaccumulation was confirmed, comparing PCB levels between younger and older individual hake, squid, and horned octopus. The total PCB concentration ratio (older/younger individuals) ranges from 2.11 (squid = 292.1/137.8 ug kg-1) to 3.46 (hake = 546.0/158.0 ug kg-1). PMID- 24784540 TI - Levels of benzo[a]pyrene and benzo[a]anthracene in smoked "Provola" cheese from Calabria (Italy). AB - Levels of benzo[a]pyrene (BaP) and benzo[a]anthracene (BaA) in "Provola" cheese samples from Calabria, smoked naturally and using commercial smoke-flavouring, have been determined. A comparative study of BaP and BaA concentrations was carried out on rind, exterior zone, core and slice of these samples. Quantitative determination of BaP and BaA was ascertained by HPLC using fluorescence detection. Levels of BaP and BaA were found in all smoked "Provola" cheese samples, but higher in cheese smoked with natural methods (0.46-1.13 ug kg-1 for BaP and 1.38-9.29 ug kg-1 for BaA) compared to samples smoked using commercial flavouring (0.085-0.32 ug kg-1 for BaP and 1.20-2.98 ug kg-1 for BaA). The smoking process contributes to polycyclic aromatic hydrocarbons contamination; however, for improved food safety, the use of commercial buffered smoke is preferable to traditional smoking procedures. PMID- 24784541 TI - Introducing a new monitoring manual for home fortification and strengthening capacity to monitor nutrition interventions. AB - Lack of monitoring capacity is a key barrier for nutrition interventions and limits programme management, decision making and programme effectiveness in many low-income and middle-income countries. A 2011 global assessment reported lack of monitoring capacity was the top barrier for home fortification interventions, such as micronutrient powders or lipid-based nutrient supplements. A Manual for Developing and Implementing Monitoring Systems for Home Fortification Interventions was recently disseminated. It is comprehensive and describes monitoring concepts and frameworks and includes monitoring tools and worksheets. The monitoring manual describes the steps of developing and implementing a monitoring system for home fortification interventions, including identifying and engaging stakeholders; developing a programme description including logic model and logical framework; refining the purpose of the monitoring system, identifying users and their monitoring needs; describing the design of the monitoring system; developing indicators; describing the core components of a comprehensive monitoring plan; and considering factors related to stage of programme development, sustainability and scale up. A fictional home fortification example is used throughout the monitoring manual to illustrate these steps. The monitoring manual is a useful tool to support the development and implementation of home fortification intervention monitoring systems. In the context of systematic capacity gaps to design, implement and monitor nutrition interventions in many low-income and middle-income countries, the dissemination of new tools, such as monitoring manuals may have limited impact without additional attention to strengthening other individual, organisational and systems levels capacities. PMID- 24784542 TI - In situ one-step synthesis of hierarchical nitrogen-doped porous carbon for high performance supercapacitors. AB - A hierarchically structured nitrogen-doped porous carbon is prepared from a nitrogen-containing isoreticular metal-organic framework (IRMOF-3) using a self sacrificial templating method. IRMOF-3 itself provides the carbon and nitrogen content as well as the porous structure. For high carbonization temperatures (950 degrees C), the carbonized MOF required no further purification steps, thus eliminating the need for solvents or acid. Nitrogen content and surface area are easily controlled by the carbonization temperature. The nitrogen content decreases from 7 to 3.3 at % as carbonization temperature increases from 600 to 950 degrees C. There is a distinct trade-off between nitrogen content, porosity, and defects in the carbon structure. Carbonized IRMOFs are evaluated as supercapacitor electrodes. For a carbonization temperature of 950 degrees C, the nitrogen-doped porous carbon has an exceptionally high capacitance of 239 F g( 1). In comparison, an analogous nitrogen-free carbon bears a low capacitance of 24 F g(-1), demonstrating the importance of nitrogen dopants in the charge storage process. The route is scalable in that multi-gram quantities of nitrogen doped porous carbons are easily produced. PMID- 24784543 TI - Response to: Bouwman, H. et al. Hallogenated pollutants in terrestrial and aquatic bird eggs: converging patterns of pollutant profiles, and impacts and risks from higher levels Environ. Res. (2013) http://dx.doi.org/10.1016/j.envres.2013.06.003. AB - Bouwman and coauthors present data and analyses of DDT and other halogenated pollutants in environmental samples and based on their data and analyses thereof, argue against the use of DDT for malaria control. Regrettably, the analyses, presentations, and interpretations of data presented by Bouwman and coauthors are biased and erroneous. PMID- 24784544 TI - Demographic processes drive increases in wildlife disease following population reduction. AB - Population reduction is often used as a control strategy when managing infectious diseases in wildlife populations in order to reduce host density below a critical threshold. However, population reduction can disrupt existing social and demographic structures leading to changes in observed host behaviour that may result in enhanced disease transmission. Such effects have been observed in several disease systems, notably badgers and bovine tuberculosis. Here we characterise the fundamental properties of disease systems for which such effects undermine the disease control benefits of population reduction. By quantifying the size of response to population reduction in terms of enhanced transmission within a generic non-spatial model, the properties of disease systems in which such effects reduce or even reverse the disease control benefits of population reduction are identified. If population reduction is not sufficiently severe, then enhanced transmission can lead to the counter intuitive perturbation effect, whereby disease levels increase or persist where they would otherwise die out. Perturbation effects are largest for systems with low levels of disease, e.g. low levels of endemicity or emerging disease. Analysis of a stochastic spatial meta population model of demography and disease dynamics leads to qualitatively similar conclusions. Moreover, enhanced transmission itself is found to arise as an emergent property of density dependent dispersal in such systems. This spatial analysis also shows that, below some threshold, population reduction can rapidly increase the area affected by disease, potentially expanding risks to sympatric species. Our results suggest that the impact of population reduction on social and demographic structures is likely to undermine disease control in many systems, and in severe cases leads to the perturbation effect. Social and demographic mechanisms that enhance transmission following population reduction should therefore be routinely considered when designing control programmes. PMID- 24784546 TI - Sexual and reproductive health education in Iranian schools. PMID- 24784545 TI - A randomized controlled trial of students for nutrition and eXercise: a community based participatory research study. AB - PURPOSE: To conduct a randomized controlled trial of Students for Nutrition and eXercise, a 5-week middle school-based obesity-prevention intervention combining school-wide environmental changes, multimedia, encouragement to eat healthy school cafeteria foods, and peer-led education. METHODS: We randomly selected schools (five intervention, five waitlist control) from the Los Angeles Unified School District. School records were obtained for number of fruits and vegetables served, students served lunch, and snacks sold per attending student, representing an average of 1,515 students (SD = 323) per intervention school and 1,524 students (SD = 266) per control school. A total of 2,997 seventh-graders (75% of seventh-graders across schools) completed pre- and postintervention surveys assessing psychosocial variables. Consistent with community-based participatory research principles, the school district was an equal partner, and a community advisory board provided critical input. RESULTS: Relative to control schools, intervention schools showed significant increases in the proportion of students served fruit and lunch and a significant decrease in the proportion of students buying snacks at school. Specifically, the intervention was associated with relative increases of 15.3% more fruits served (p = .006), 10.4% more lunches served (p < .001), and 11.9% fewer snacks sold (p < .001) than would have been expected in its absence. Pre-to-post intervention, intervention school students reported more positive attitudes about cafeteria food (p = .02) and tap water (p = .03), greater obesity-prevention knowledge (p = .006), increased intentions to drink water from the tap (p = .04) or a refillable bottle (p = .02), and greater tap water consumption (p = .04) compared with control school students. CONCLUSIONS: Multilevel school-based interventions may promote healthy adolescent dietary behaviors. PMID- 24784547 TI - Synthesis and characterization of novel Wells-Dawson-type mono vanadium(V) substituted tungsto-polyoxometalate isomers: 1- and 4-[S2VW17O62](5-). AB - Two vanadium(V)-substituted tungsto-polyoxometalate isomers, 1- and 4 [S2VW17O62](5-), were prepared as their tetra-alkyl ammonium salts from a W(VI) H2SO4-V(V) reaction mixture in aqueous CH3CN solution. X-ray crystallographic structural analysis revealed that both isomers have a Wells-Dawson-type structure with a higher occupancy of vanadium at polar sites and belt sites for 1- and 4 [S2VW17O62](5-), respectively. The isomers were also characterized by elemental analysis, infrared, Raman, UV-vis, and (51)V NMR spectroscopies as well as voltammetry, and the data obtained were compared with that derived from [S2W18O62](4-). Significantly, the reversible potentials for the vanadium(V/IV) couple for both 1- and 4-[S2VW17O62](5-) in CH3CN (0.1 M n-Bu4NPF6) are considerably more positive than the tungstate reduction process exhibited by the [S2W18O62](4-) framework, implying that the presence of vanadium should be useful in catalytic reactions. The one-electron-reduced [S2V(IV)W17O62](6-) forms of both isomers were prepared in solution by controlled potential bulk electrolysis and characterized by voltammetry and EPR spectroscopy. PMID- 24784548 TI - New confidence: optimizing benchmark dose modeling to improve risk assessment. PMID- 24784551 TI - Endovascular treatment for stroke: when does the window for good outcome close? PMID- 24784549 TI - Prefrontal cortical GABA transmission modulates discrimination and latent inhibition of conditioned fear: relevance for schizophrenia. AB - Inhibitory gamma-aminobutyric acid (GABA) transmission within the prefrontal cortex (PFC) regulates numerous functions, and perturbations in GABAergic transmission within this region have been proposed to contribute to some of the cognitive and behavioral abnormalities associated with disorders such as schizophrenia. These abnormalities include deficits in emotional regulation and aberrant attributions of affective salience. Yet, how PFC GABA regulates these types of emotional processes are unclear. To address this issue, we investigated the contribution of PFC GABA transmission to different aspects of Pavlovian emotional learning in rats using translational discriminative fear conditioning and latent inhibition (LI) assays. Reducing prelimbic PFC GABAA transmission via infusions of the antagonist bicuculline before the acquisition or expression of fear conditioning eliminated the ability to discriminate between an aversive conditioned stimulus (CS+) paired with footshock vs a neutral CS-, resembling similar deficits observed in schizophrenic patients. In a separate experiment, blockade of PFC GABAA receptors before CS preexposure (PE) and conditioning did not affect subsequent expression of LI, but did enhance fear in rats that were not preexposed to the CS. In contrast, PFC GABA-blockade before a fear expression test disrupted the recall of learned irrelevance and abolished LI. These data suggest that normal PFC GABA transmission is critical for regulating and mitigating multiple aspects of aversive learning, including discrimination between fear vs safety signals and recall of information about the irrelevance of stimuli. Furthermore, they suggest that similar deficits in emotional regulation observed in schizophrenia may be driven in part by deficient PFC GABA activity. PMID- 24784550 TI - Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial. AB - BACKGROUND: The IMS III trial did not show a clinical benefit of endovascular treatment compared with intravenous alteplase (recombinant tissue plasminogen activator) alone for moderate or severe ischaemic strokes. Late reperfusion of tissue that was no longer salvageable could be one explanation, as suggested by previous exploratory studies that showed an association between time to reperfusion and good clinical outcome. We sought to validate this association in a preplanned analysis of data from the IMS III trial. METHODS: We used data for patients with complete proximal arterial occlusions in the anterior circulation who received endovascular treatment and achieved angiographic reperfusion (score on Thrombolysis in Cerebral Infarction scale of grade 2-3) during the endovascular procedure (within 7 h of symptom onset). We used logistic regression to model good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 3 months) as a function of the time to reperfusion. We prespecified variables to be considered for adjustment, including age, baseline National Institutes of Health Stroke Scale score, sex, and baseline blood glucose concentration. FINDINGS: Of 240 patients who were otherwise eligible for inclusion in our analysis, 182 (76%) achieved angiographic reperfusion. Mean time from symptom onset to reperfusion (ie, procedure end) was 325 min (SD 52). Increased time to reperfusion was associated with a decreased likelihood of good clinical outcome (unadjusted relative risk for every 30-min delay 0.85 [95% CI 0.77-0.94]; adjusted relative risk 0.88 [0.80-0.98]). INTERPRETATION: Delays in time to angiographic reperfusion lead to a decreased likelihood of good clinical outcome in patients after moderate to severe stroke. Rapid reperfusion could be crucial for the success of future acute endovascular trials. FUNDING: US National Institutes of Health and National Institute of Neurological Disorders and Stroke. PMID- 24784553 TI - State of the art in gluten-free research. AB - Celiac disease (CD) is widespread and is often under diagnosed. It can affect a variety of genetically susceptible people from the young to the old. Presently, the only treatment for celiac patients is lifelong avoidance of any food, drink, sauce, or dressing containing gluten. Scientists and technologists continue in their quest to improve the quality of gluten-free products. Their main goal is to create a product of a similar standard to the gluten-containing products, currently on the market. However, the quality of these products still tends to be poor. Bread products have a low volume, pale crust, crumbly texture, bland flavor and a high rate of staling. Other gluten-free products contain minimal nutrition and substandard product characteristics, for example, pasta having an inferior texture, sauces which separate more easily. The main focus of this review is to discuss the most recent advances in gluten-free research which have arisen between the years 2011 and 2013. In particular, the manuscript focuses on ingredients and processing methods which have been documented to develop or improve the processing characteristics and nutritional properties of gluten-free products. PMID- 24784552 TI - Dysregulation of multiple inflammatory molecules in lymph node and ileum of macaques during RT-SHIV infection with or without antiretroviral therapy. AB - BACKGROUND: Pathogenic infection with human immunodeficiency virus type 1 (HIV-1) or simian immunodeficiency virus (SIV) is characterized by a loss of CD4+ T cells and chronic lymphocyte activation even during suppressive antiretroviral therapy (ART). METHODS: Using NanoString, expression of >100 molecules associated with inflammation or immune activation was evaluated in mesenteric lymph nodes and ileum of macaques infected with a pathogenic SIV/HIV virus, RT-SHIV, during viremia or during suppressive ART and compared to uninfected controls. RESULTS: Of the 105 RNA species quantified in the tissues, expression of 33 genes was altered significantly in one or both tissues during viremia but returned to normal levels during ART. However, 29 additional genes were altered in expression levels in the tissues of both viremic and ART-suppressed macaques. CONCLUSIONS: Identification of the mechanisms of chronic inflammation in specific cells and in different tissues may help determine whether early ART initiation or novel therapies can prevent it. PMID- 24784554 TI - The present future. PMID- 24784555 TI - Protecting children from smoking in the home: an ethics of care perspective. AB - Community nurses are uniquely placed to help protect child health by facilitating the creation of smoke-free homes. However, there are a number of perceived barriers that may concern community nurses in their role of supporting parents in the creation of smoke-free homes, particularly those faced by disadvantaged parents. Arguments against intervening within the private domain of the home focus on concerns about protecting parents' autonomy to smoke within their own home and the potential for stigmatising parents who smoke, particularly mothers. Drawing on an ethics of care perspective, the authors propose an alternative perspective to the intervention in private settings. An ethics of care perspective may help to justify and encourage parents and community nurses to work in partnership to create a healthy environment for children and decrease the likelihood of children becoming smokers in the future. PMID- 24784556 TI - Using a complex audit tool to measure workload, staffing and quality in district nursing. AB - This major community, workload, staffing and quality study is thought to be the most comprehensive community staffing project in England. It involved over 400 staff from 46 teams in 6 localities and is unique because it ties community staffing activity to workload and quality. Scotland was used to benchmark since the same evidence-based Safer Nursing Care Tool methodology developed by the second-named author was used (apart from quality) and took into account population and geographical similarities. The data collection method tested quality standards, acuity, dependency and nursing interventions by looking at caseloads, staff activity and service quality and funded, actual, temporary and recommended staffing. Key findings showed that 4 out of 6 localities had a heavy workload index that stretched staffing numbers and time spent with patients. The acuity and dependency of patients leaned heavily towards the most dependent and acute categories requiring more face-to-face care. Some areas across the localities had high levels of temporary staff, which affected quality and increased cost. Skill and competency shortages meant that a small number of staff had to travel significantly across the county to deliver complex care to some patients. PMID- 24784557 TI - Food safety and older people: the Kitchen Life study. AB - Foodborne illness (FBI) is a major public health problem in the UK. Recent increases in cases of listeriosis in older people have focused attention on consumer food-related practices. Previous studies highlight poor relationships between what people know, what they say they do and what they actually do in the kitchen. The aim of the Kitchen Life study was to examine what actually happens in the domestic kitchen to assess whether and how this has the potential to influence food safety in the home. Drawing on a qualitative ethnographic approach, methods included a kitchen tour, photography, observation, video observation, informal interviews and diary methods. Ten households with older people (aged 60+) were recruited across the UK. It was found that trust in the food supply, use of food-labelling (including use-by dates), sensory logics (such as the feel or smell of food) and food waste were factors with the potential to influence risk of foodborne illness. Practices shifted with changing circumstances, including increased frailty, bereavement, living alone, receiving help with care and acquiring new knowledge, meaning that the risk of and vulnerability to foodborne illness is not straightforward. PMID- 24784558 TI - Addressing older people's mental health needs in the community setting. AB - It is estimated that more than one third of older people may experience problems with their mental health. While, in some of these cases, people will be able to self-manage with little or no support, individuals who are socially isolated or physically unwell may experience significant mental distress. Community nurses are ideally placed to identify mental health problems in patients who are housebound, and to make appropriate referrals. Yet many nurses report apprehension regarding a perceived lack of knowledge and skills in which to undertake an initial assessment. This article outlines the most common mental illnesses experienced by older people living in the community and provides guidance for community nurses on conducting an initial assessment to ensure that patients' holistic needs are met. PMID- 24784559 TI - District nurses' crucial role in identifying unlawful deprivation of liberty. AB - A recent judgement by the UK Supreme Court has widened the criteria for the type of care and treatment that amounts to a deprivation of liberty in hospitals and care homes. Very many more vulnerable residents in care homes should now benefit from the protection of the Mental Capacity Act 2005 deprivation of liberty safeguards. This protection will only happen if care-home staff, who are the gatekeepers of the system, recognise which of their residents are deprived of their liberty. District nurses have a crucial role to play in promoting the use of the deprivation of liberty safeguards. They are ideally placed to help identify care that amounts to a deprivation of liberty in the care homes that they visit. This article discusses how district nurses must inform their practice by making reference to the UK Supreme Court judgement on the use of the deprivation of liberty safeguards and the actions that district nurses must take if they suspect a care home is depriving a resident of their liberty without authorisation. PMID- 24784560 TI - World War I remembered with reference to district nurses. AB - World War I is remembered for the appalling loss of life, but it also heralded major social and political change which included wider opportunities for women and, later, universal suffrage. World War I also formed the context for the emergence of the 1919 Nurses' Registration Act. District nurses (Queen's Nurses) undertook a range of roles during the war, including roles overseas as members of the military nursing services. Like nurses, they had their work supplemented by Voluntary Aid Detachments. This article discusses the war from the perspective of the district nursing profession. PMID- 24784561 TI - End-of-life care after the Liverpool Care Pathway. AB - This article presents a review of key issues around caring for people in the last hours and days of life. The aim is that community nurses will be able to support patients and families, and to provide and explain decisions and interventions to promote comfort and dignity based on current evidence. PMID- 24784562 TI - Supporting patients in coping with cancer. PMID- 24784563 TI - The revalidation debate. PMID- 24784564 TI - Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin. AB - Indoleamine 2,3-dioxygenase-1 (IDO) is an immunosuppressive molecule expressed by most human tumors. IDO levels correlate with poor prognosis in cancer patients and IDO inhibitors are under investigation to enhance endogenous anticancer immunosurveillance. Little is known of immune-independent functions of IDO relevant to cancer therapy. We show, for the first time, that IDO mediates human tumor cell resistance to a PARP inhibitor (olaparib), gamma radiation, cisplatin, and combined treatment with olaparib and radiation, in the absence of immune cells. Antisense-mediated reduction of IDO, alone and (in a synthetic lethal approach) in combination with antisense to the DNA repair protein BRCA2 sensitizes human lung cancer cells to olaparib and cisplatin. Antisense reduction of IDO decreased NAD+ in human tumor cells. NAD+ is essential for PARP activity and these data suggest that IDO mediates treatment resistance independent of immunity and at least partially due to a previously unrecognized role for IDO in DNA repair. Furthermore, IDO levels correlated with accumulation of tumor cells in G1 and depletion of cells in G2/M of the cell cycle, suggesting that IDO effects on cell cycle may also modulate sensitivity to radiation and chemotherapeutic agents. IDO is a potentially valuable therapeutic target in cancer treatment, independent of immune function and in combination with other therapies. PMID- 24784566 TI - "I'm happy to be able to help:" why women donate milk to a peer via Internet based milk sharing networks. AB - The process by which women came to donate milk via online milk sharing networks was explored via a questionnaire administered to 97 peer milk donors. Seventy-one respondents stated that they were motivated to donate milk because they wanted to help someone. Many described milk donation as an empathic response to women with insufficient milk. Seventy-four respondents donated milk that they had previously expressed but did not need. Their desire to ensure that their milk was not wasted contributed to their decision to donate. Fifty-one respondents expressed milk specifically for donation, including 20 donors who initially donated previously expressed surplus milk but then expressed milk specifically for recipient peers. The motivations of peer-to-peer donors are the same as those reported for women donating to a milk bank. Respondents who donated previously expressed milk had originally expressed so they had milk when separated from their baby, to manage an overabundant milk supply, because their baby was unwilling or unable to breastfeed, in case of emergency, and to maintain milk supply. This study is the first to clearly identify that some women express milk because they believe this is required for milk supply maintenance. Peer milk donors appeared satisfied with their experience of donating milk. The importance of altruistic motivation should be considered in discussions of the desirability of financial compensation for milk donation. Further research is needed on why women express their milk and whether such expression is beneficial to them. PMID- 24784567 TI - GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. AB - Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe dose-limiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4 oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4 amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was >150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting. PMID- 24784568 TI - Pharmacology of a central nervous system delivered 2'-O-methoxyethyl-modified survival of motor neuron splicing oligonucleotide in mice and nonhuman primates. AB - Spinal muscular atrophy (SMA) is a debilitating neuromuscular disease caused by the loss of survival of motor neuron (SMN) protein. Previously, we demonstrated that ISIS 396443, an antisense oligonucleotide (ASO) targeted to the SMN2 pre mRNA, is a potent inducer of SMN2 exon 7 inclusion and SMN protein expression, and improves function and survival of mild and severe SMA mouse models. Here, we demonstrate that ISIS 396443 is the most potent ASO in central nervous system (CNS) tissues of adult mice, compared with several other chemically modified ASOs. We evaluated methods of ISIS 396443 delivery to the CNS and characterized its pharmacokinetics and pharmacodynamics in rodents and nonhuman primates (NHPs). Intracerebroventricular bolus injection is a more efficient method of delivering ISIS 396443 to the CNS of rodents, compared with i.c.v. infusion. For both methods of delivery, the duration of ISIS 396443-mediated SMN2 splicing correction is long lasting, with maximal effects still observed 6 months after treatment discontinuation. Administration of ISIS 396443 to the CNS of NHPs by a single intrathecal bolus injection results in widespread distribution throughout the spinal cord. Based upon these preclinical studies, we have advanced ISIS 396443 into clinical development. PMID- 24784569 TI - Molecular phylogeny of hantaviruses harbored by insectivorous bats in Cote d'Ivoire and Vietnam. AB - The recent discovery of genetically distinct hantaviruses in multiple species of shrews and moles prompted a further exploration of their host diversification by analyzing frozen, ethanol-fixed and RNAlater(r)-preserved archival tissues and fecal samples from 533 bats (representing seven families, 28 genera and 53 species in the order Chiroptera), captured in Asia, Africa and the Americas in 1981-2012, using RT-PCR. Hantavirus RNA was detected in Pomona roundleaf bats (Hipposideros pomona) (family Hipposideridae), captured in Vietnam in 1997 and 1999, and in banana pipistrelles (Neoromicia nanus) (family Vespertilionidae), captured in Cote d'Ivoire in 2011. Phylogenetic analysis, based on the full length S- and partial M- and L-segment sequences using maximum likelihood and Bayesian methods, demonstrated that the newfound hantaviruses formed highly divergent lineages, comprising other recently recognized bat-borne hantaviruses in Sierra Leone and China. The detection of bat-associated hantaviruses opens a new era in hantavirology and provides insights into their evolutionary origins. PMID- 24784570 TI - Vampire bat rabies: ecology, epidemiology and control. AB - Extensive surveillance in bat populations in response to recent emerging diseases has revealed that this group of mammals acts as a reservoir for a large range of viruses. However, the oldest known association between a zoonotic virus and a bat is that between rabies virus and the vampire bat. Vampire bats are only found in Latin America and their unique method of obtaining nutrition, blood-feeding or haematophagy, has only evolved in the New World. The adaptations that enable blood-feeding also make the vampire bat highly effective at transmitting rabies virus. Whether the virus was present in pre-Columbian America or was introduced is much disputed, however, the introduction of Old World livestock and associated landscape modification, which continues to the present day, has enabled vampire bat populations to increase. This in turn has provided the conditions for rabies re-emergence to threaten both livestock and human populations as vampire bats target large mammals. This review considers the ecology of the vampire bat that make it such an efficient vector for rabies, the current status of vampire transmitted rabies and the future prospects for spread by this virus and its control. PMID- 24784573 TI - Being in a process of transition to psychosis, as narrated by adults with psychotic illnesses acutely admitted to hospital. AB - To assist in improving early interventions for psychosis, this study explored how adult people narrated their experience of becoming psychotic, and how contact with mental health personnel was established. Narrative interviews were conducted with 12 participants with psychotic illnesses recruited from acute psychiatric wards. The interviews were content analysed. Participants described being in a process of transition to psychosis as follows: experiencing changes as well-known signs of psychosis, experiencing sudden unexpected changes as signs of psychosis and experiencing unidentified changes as signs of illness. Our results show that participants and their close others who knew the signs of psychosis established a dialogue with mental health personnel and were better equipped to prevent and mitigate the psychosis. Our results demonstrate that participants who did not perceive the signs of psychosis and did not have other people to advocate for them were at risk for delayed treatment, poor communication and coercive interventions. Furthermore, participants who did not know the signs of psychosis perceived these changes as deterioration in their health and awareness of illness. We suggest that participants' experiential knowledge of transitioning to psychosis and an awareness of illness can be used to improve the communication during interventions for psychosis. PMID- 24784574 TI - Minister defends government spending on vCJD research. PMID- 24784572 TI - Universal influenza vaccines, a dream to be realized soon. AB - Due to frequent viral antigenic change, current influenza vaccines need to be re formulated annually to match the circulating strains for battling seasonal influenza epidemics. These vaccines are also ineffective in preventing occasional outbreaks of new influenza pandemic viruses. All these challenges call for the development of universal influenza vaccines capable of conferring broad cross protection against multiple subtypes of influenza A viruses. Facilitated by the advancement in modern molecular biology, delicate antigen design becomes one of the most effective factors for fulfilling such goals. Conserved epitopes residing in virus surface proteins including influenza matrix protein 2 and the stalk domain of the hemagglutinin draw general interest for improved antigen design. The present review summarizes the recent progress in such endeavors and also covers the encouraging progress in integrated antigen/adjuvant delivery and controlled release technology that facilitate the development of an affordable universal influenza vaccine. PMID- 24784575 TI - Micromechanics and poroelasticity of hydrated cellulose networks. AB - The micromechanics of cellulose hydrogels have been investigated using a new rheological experimental approach, combined with simulation using a poroelastic constitutive model. A series of mechanical compression steps at different strain rates were performed as a function of cellulose hydrogel thickness, combined with small amplitude oscillatory shear after each step to monitor the viscoelasticity of the sample. During compression, bacterial cellulose hydrogels behaved as anisotropic materials with near zero Poisson's ratio. The micromechanics of the hydrogels altered with each compression as water was squeezed out of the structure, and microstructural changes were strain rate-dependent, with increased densification of the cellulose network and increased cellulose fiber aggregation observed for slower compressive strain rates. A transversely isotropic poroelastic model was used to explain the observed micromechanical behavior, showing that the mechanical properties of cellulose networks in aqueous environments are mainly controlled by the rate of water movement within the structure. PMID- 24784571 TI - Hantavirus reservoirs: current status with an emphasis on data from Brazil. AB - Since the recognition of hantavirus as the agent responsible for haemorrhagic fever in Eurasia in the 1970s and, 20 years later, the descovery of hantavirus pulmonary syndrome in the Americas, the genus Hantavirus has been continually described throughout the World in a variety of wild animals. The diversity of wild animals infected with hantaviruses has only recently come into focus as a result of expanded wildlife studies. The known reservoirs are more than 80, belonging to 51 species of rodents, 7 bats (order Chiroptera) and 20 shrews and moles (order Soricomorpha). More than 80 genetically related viruses have been classified within Hantavirus genus; 25 recognized as human pathogens responsible for a large spectrum of diseases in the Old and New World. In Brazil, where the diversity of mammals and especially rodents is considered one of the largest in the world, 9 hantavirus genotypes have been identified in 12 rodent species belonging to the genus Akodon, Calomys, Holochilus, Oligoryzomys, Oxymycterus, Necromys and Rattus. Considering the increasing number of animals that have been implicated as reservoirs of different hantaviruses, the understanding of this diversity is important for evaluating the risk of distinct hantavirus species as human pathogens. PMID- 24784577 TI - Integrin-linked kinase regulates tubular aquaporin-2 content and intracellular location: a link between the extracellular matrix and water reabsorption. AB - One of the clinical alterations observed in chronic renal disease (CRD) is the impaired urine concentration, known as diabetes insipidus (DI). Tubulointerstitial fibrosis of the kidney is also a pathological finding observed in CRD and involves composition of extracellular matrix (ECM). However, an association between these two events has not been elucidated. In this study, we showed that the extracellular-to-intracellular scaffold protein integrin-linked kinase (ILK) regulates expression of tubular water channel aquaporin-2 (AQP2) and its apical membrane presence in the renal tubule. Basally, polyuria and decreased urine osmolality were present in ILK conditional-knockdown (cKD-ILK) adult mice compared with nondepleted ILK littermates. No changes were observed in arginine vasopressin (AVP) blood levels, renal receptor (V2R), or AQP3 expression. However, tubular AQP2 was decreased in expression and apical membrane presence in cKD-ILK mice, where the canonical V2R/cAMP axis activation is still functional, but independent of the absence of ILK. Thus, cKD-ILK constitutes a nephrogenic diabetes insipidus (NDI) model. AQP2 and ILK colocalize in cultured inner medullary collecting duct (mIMCD3) cells. Specific ILK siRNAs and collagen I (Col) decrease ILK and AQP2 levels and AQP2 presence on the membrane of tubular mIMCD3 cells, which impairs the capacity of the cells to transport water under hypotonic stress. The present work points to ILK as a therapeutic target in NDI. PMID- 24784579 TI - Cellular contractility and extracellular matrix stiffness regulate matrix metalloproteinase activity in pancreatic cancer cells. AB - The pathogenesis of cancer is often driven by local invasion and metastasis. Recently, mechanical properties of the tumor microenvironment have been identified as potent regulators of invasion and metastasis, while matrix metalloproteinases (MMPs) are classically known as significant enhancers of cancer cell migration and invasion. Here we have been able to sensitively measure MMP activity changes in response to specific extracellular matrix (ECM) environments and cell contractility states. Cells of a pancreatic cancer cell line, Panc-1, up-regulate MMP activities between 3- and 10-fold with increased cell contractility. Conversely, they down-regulate MMP activities when contractility is blocked to levels seen with pan-MMP activity inhibitors. Similar, albeit attenuated, responses are seen in other pancreatic cancer cell lines, BxPC-3 and AsPC-1. In addition, MMP activity was modulated by substrate stiffness, collagen gel concentration, and the degree of collagen cross-linking, when cells were plated on collagen gels ranging from 0.5 to 5 mg/ml that span the physiological range of substrate stiffness (50-2000 Pa). Panc-1 cells showed enhanced MMP activity on stiffer substrates, whereas BxPC-3 and AsPC-1 cells showed diminished MMP activity. In addition, eliminating heparan sulfate proteoglycans using heparinase completely abrogated the mechanical induction of MMP activity. These results demonstrate the first functional link between MMP activity, contractility, and ECM stiffness and provide an explanation as to why stiffer environments result in enhanced cell migration and invasion. PMID- 24784578 TI - Rapid actin-cytoskeleton-dependent recruitment of plasma membrane-derived dysferlin at wounds is critical for muscle membrane repair. AB - Deficits in membrane repair may contribute to disease progression in dysferlin deficient muscular dystrophy. Dysferlin, a type-II transmembrane phospholipid binding protein, is hypothesized to regulate fusion of repair vesicles with the sarcolemma to facilitate membrane repair, but the dysferlin-containing compartments involved in membrane repair and the mechanism by which these compartments contribute to resealing are unclear. A dysferlin-pHluorin [dysf-pH sensitive green fluorescent protein (pHGFP)] muscle-specific transgenic mouse was developed to examine the dynamic behavior and subcellular localization of dysferlin during membrane repair in adult skeletal muscle fibers. Live-cell confocal microscopy of uninjured adult dysf-pHGFP muscle fibers revealed that dysferlin is highly enriched in the sarcolemma and transverse tubules. Laser wounding induced rapid recruitment of ~30 MUm of local dysferlin-containing sarcolemma, leading to formation of stable dysferlin accumulations surrounding lesions, endocytosis of dysferlin, and formation of large cytoplasmic vesicles from distal regions of the fiber. Disruption of the actin cytoskeleton decreased recruitment of sarcolemma-derived dysferlin to lesions in dysf-pHGFP fibers without affecting endocytosis and impaired membrane resealing in wild-type fibers, similar to findings in dysferlin deficiency (a 2-fold increase in FM1-43 uptake). Our data support a new mechanism whereby recruitment of sarcolemma derived dysferlin creates an active zone of high lipid-binding activity at wounds to interact with repair vesicles and facilitate membrane resealing in skeletal muscle. PMID- 24784580 TI - The cost of self-imposed regulatory burden in animal research. AB - U.S. federal regulations and standards governing the care and use of research animals enacted in the mid- to late 1980s, while having positive effects on the welfare and quality of the animals, have resulted in dramatic increases in overall research costs. In addition to the expenses of housing and caring for animals according to the standards, establishing the requisite internal compliance bureaucracies has markedly driven up costs, in both institutional monetary expenditures and lost research effort. However, many institutions are increasing these costs even further through additional self-imposed regulatory burden, typically characterized by overly complex compliance organizations and unnecessary policies and procedures. We discuss the sources of this self-imposed burden and recommend strategies for avoiding it while preserving an appropriate focus on animal well-being and research success. PMID- 24784581 TI - Determining effects of non-synonymous SNPs on protein-protein interactions using supervised and semi-supervised learning. AB - Single nucleotide polymorphisms (SNPs) are among the most common types of genetic variation in complex genetic disorders. A growing number of studies link the functional role of SNPs with the networks and pathways mediated by the disease associated genes. For example, many non-synonymous missense SNPs (nsSNPs) have been found near or inside the protein-protein interaction (PPI) interfaces. Determining whether such nsSNP will disrupt or preserve a PPI is a challenging task to address, both experimentally and computationally. Here, we present this task as three related classification problems, and develop a new computational method, called the SNP-IN tool (non-synonymous SNP INteraction effect predictor). Our method predicts the effects of nsSNPs on PPIs, given the interaction's structure. It leverages supervised and semi-supervised feature-based classifiers, including our new Random Forest self-learning protocol. The classifiers are trained based on a dataset of comprehensive mutagenesis studies for 151 PPI complexes, with experimentally determined binding affinities of the mutant and wild-type interactions. Three classification problems were considered: (1) a 2 class problem (strengthening/weakening PPI mutations), (2) another 2-class problem (mutations that disrupt/preserve a PPI), and (3) a 3-class classification (detrimental/neutral/beneficial mutation effects). In total, 11 different supervised and semi-supervised classifiers were trained and assessed resulting in a promising performance, with the weighted f-measure ranging from 0.87 for Problem 1 to 0.70 for the most challenging Problem 3. By integrating prediction results of the 2-class classifiers into the 3-class classifier, we further improved its performance for Problem 3. To demonstrate the utility of SNP-IN tool, it was applied to study the nsSNP-induced rewiring of two disease-centered networks. The accurate and balanced performance of SNP-IN tool makes it readily available to study the rewiring of large-scale protein-protein interaction networks, and can be useful for functional annotation of disease-associated SNPs. SNIP-IN tool is freely accessible as a web-server at http://korkinlab.org/snpintool/. PMID- 24784583 TI - iPSCs, aging and age-related diseases. AB - Human histocompatibility antigens are quite heterogeneous and promote the rejection of transplanted tissue. Recent advances in stem cell research that enable the use of a patient's own stem cells for transplantation are very important because rejection could be avoided. In particular, Yamanaka's group in Japan gave new hope to patients with incurable diseases when they developed induced murine pluripotent stem cells (iPSCs) in 2006 and human iPSCs in 2007. Whereas embryonic stem cells (ESCs) are derived from the inner cell mass and are supported in culture by LIF, iPSCs are derived from fetal or adult somatic cells. Through the application of iPSC technology, adult somatic cells can develop a pluripotent state. One advantage of using iPSCs instead of ESCs in regenerative medicine is that (theoretically) immune rejection could be avoided, although there is some debate about immune rejection of a patient's own iPSCs. Many diseases occur in elderly patients. In order to use regenerative medicine with the elderly, it is important to demonstrate that iPSCs can indeed be generated from older patients. Recent findings have shown that iPSCs can be established from aged mice and aged humans. These iPSCs can differentiate to cells from all three germ layers. However, it is not known whether iPSCs from aged mice or humans show early senescence. Before clinical use of iPSCs, issues related to copy number variation, tumorigenicity and immunogenicity must be resolved. It is particularly important that researchers have succeeded in generating iPSCs that have differentiated to somatic cells related to specific diseases of the elderly, including atherosclerosis, diabetes, Alzheimer's disease and Parkinson's disease. These efforts will facilitate the use of personalized stem cell transplantation therapy for currently incurable diseases. PMID- 24784582 TI - Ubiquitin is phosphorylated by PINK1 to activate parkin. AB - PINK1 (PTEN induced putative kinase 1) and PARKIN (also known as PARK2) have been identified as the causal genes responsible for hereditary recessive early-onset Parkinsonism. PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates. PINK1 acts as an upstream factor for parkin and is essential both for the activation of latent E3 parkin activity and for recruiting parkin onto depolarized mitochondria. Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed, and PINK1-dependent phosphorylation of parkin has been reported. However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation, and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure. Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (also known as UBE2L3) and ubiquitin (UBCH7~ubiquitin) in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. PMID- 24784584 TI - Effects of inferior olive lesion on fear-conditioned bradycardia. AB - The inferior olive (IO) sends excitatory inputs to the cerebellar cortex and cerebellar nuclei through the climbing fibers. In eyeblink conditioning, a model of motor learning, the inactivation of or a lesion in the IO impairs the acquisition or expression of conditioned eyeblink responses. Additionally, climbing fibers originating from the IO are believed to transmit the unconditioned stimulus to the cerebellum in eyeblink conditioning. Studies using fear-conditioned bradycardia showed that the cerebellum is associated with adaptive control of heart rate. However, the role of inputs from the IO to the cerebellum in fear-conditioned bradycardia has not yet been investigated. To examine this possible role, we tested fear-conditioned bradycardia in mice by selective disruption of the IO using 3-acetylpyridine. In a rotarod test, mice with an IO lesion were unable to remain on the rod. The number of neurons of IO nuclei in these mice was decreased to ~40% compared with control mice. Mice with an IO lesion did not show changes in the mean heart rate or in heart rate responses to a conditioned stimulus, or in their responses to a painful stimulus in a tail-flick test. However, they did show impairment of the acquisition/expression of conditioned bradycardia and attenuation of heart rate responses to a pain stimulus used as an unconditioned stimulus. These results indicate that the IO inputs to the cerebellum play a key role in the acquisition/expression of conditioned bradycardia. PMID- 24784585 TI - Acute blockage of voltage-gated K+ currents by 17beta-estradiol in mouse neuroblastoma N2A cells. AB - In this study, whole-cell recording was carried out to explore the effects of 17beta-estradiol on voltage-gated K+ (Kv) currents in N2A cells. The acute exposure to 17beta-estradiol, in a concentration-dependent manner, significantly inhibited the peak and steady-state currents through Kv channels, showing IC50 values of 3.6 and 3.8 MUM, respectively. The reduction in both the amplitude and the decay rate of Kv currents, with an increase in depolarization, suggested that it was a voltage-dependent block. The activation and inactivation experiments were conducted to determine the exact causes of the inhibitory effects. The half maximum activation potential (V1/2) was +8.1 mV in control and remained stable after exposure to 10 MUM 17beta-estradiol. For steady-state inactivation, the half-maximum inactivation potential (V1/2) was -45.0 mV and shifted right to 39.7 mV without a statistical difference, and the time constants of recovery from inactivation were not altered by 17beta-estradiol, suggesting that the depression was not correlated with the inactivation gate. PMID- 24784587 TI - Laboratory-based micro-X-ray fluorescence setup using a von Hamos crystal spectrometer and a focused beam X-ray tube. AB - The high-resolution von Hamos bent crystal spectrometer of the University of Fribourg was upgraded with a focused X-ray beam source with the aim of performing micro-sized X-ray fluorescence (XRF) measurements in the laboratory. The focused X-ray beam source integrates a collimating optics mounted on a low-power micro spot X-ray tube and a focusing polycapillary half-lens placed in front of the sample. The performances of the setup were probed in terms of spatial and energy resolution. In particular, the fluorescence intensity and energy resolution of the von Hamos spectrometer equipped with the novel micro-focused X-ray source and a standard high-power water-cooled X-ray tube were compared. The XRF analysis capability of the new setup was assessed by measuring the dopant distribution within the core of Er-doped SiO2 optical fibers. PMID- 24784586 TI - Functional polymorphisms in toll-like receptor 4 are associated with worse outcome in acute ischemic stroke patients. AB - Toll-like receptor-4 (TLR4) is important in neuroinflammation. Single nucleotide polymorphisms (SNPs) in TLR4, including 1063 A/G [Asp299Gly] and 1363 C/T [Thr399Ile], are associated with altered immune responses but their effect on acute ischemic stroke (AIS) outcome is unknown. We collected demographic, clinical, laboratory, radiologic, and genotype data on 113 AIS patients and performed multivariate analyses to assess associations between TLR4 SNP haplotype and either neurological outcome, infection, or inflammatory markers. In adjusted analyses, TLR4 SNPs were associated with worse outcome as well as increases in circulating leukocytes, C-reactive protein, and interleukin-1 receptor antagonist. In AIS, variations in TLR4 may influence neurological outcome (for video abstract, please see Supplemental digital content 1 file, http://links.lww.com/WNR/A274). PMID- 24784588 TI - Atom chip apparatus for experiments with ultracold rubidium and potassium gases. AB - We present a dual chamber atom chip apparatus for generating ultracold (87)Rb and (39)K atomic gases. The apparatus produces quasi-pure Bose-Einstein condensates of 10(4) (87)Rb atoms in an atom chip trap that features a dimple and good optical access. We have also demonstrated production of ultracold (39)K and subsequent loading into the chip trap. We describe the details of the dual chamber vacuum system, the cooling lasers, the magnetic trap, the multicoil magnetic transport system, the atom chip, and two optical dipole traps. Due in part to the use of light-induced atom desorption, the laser cooling chamber features a sufficiently good vacuum to also support optical dipole trap-based experiments. The apparatus is well suited for studies of atom-surface forces, quantum pumping and transport experiments, atom interferometry, novel chip-based traps, and studies of one-dimensional many-body systems. PMID- 24784589 TI - Freestanding sample holder for ultrafast optical spectroscopy at low temperatures. AB - Ultrafast optical spectroscopy techniques are often employed to gain information about samples that are liquid at room temperature and frozen at cryogenic temperatures. However, the measurements suffer from the presence of unwanted, non resonant signals originating in the sample cell walls. Most of these artifacts can be avoided in the measurements performed at room temperature by using liquid jet systems, i.e., by removing the sample cell. However, these systems cannot be used in low temperature measurements, when the sample is frozen. Herein we describe a freestanding sample holder that allows low temperature ultrafast spectroscopy measurements free of artifacts caused by the sample cell. PMID- 24784590 TI - Calibration of a gated flat field spectrometer as a function of x-ray intensity. AB - We present an experimental determination of the response of a gated flat-field spectrometer at the Shenguang-II laser facility. X-rays were emitted from a target that was heated by laser beams and then were divided into different intensities with a step aluminum filter and collected by a spectrometer. The transmission of the filter was calibrated using the Beijing Synchrotron Radiation Facility. The response characteristics of the spectrometer were determined by comparing the counts recorded by the spectrometer with the relative intensities of the x-rays transmitted through the step aluminum filter. The response characteristics were used to correct the transmission from two shots of an opacity experiment using the same samples. The transmissions from the two shots are consistent with corrections, but discrepant without corrections. PMID- 24784591 TI - Direct inversion methods for spectral amplitude modulation of femtosecond pulses. AB - In the present work, we applied an amplitude-spatial light modulator to shape the spectral amplitude of femtosecond pulses in a single step, without an iterative algorithm, by using an inversion method defined as the generalized retardance function. Additionally, we also present a single step method to shape the intensity profile defined as the influence matrix. Numerical and experimental results are presented for both methods. PMID- 24784592 TI - An ultra-high vacuum electrochemical flow cell for in situ/operando soft X-ray spectroscopy study. AB - An in situ flow electrochemical cell has been designed and fabricated to allow better seal under UHV chamber thus to achieve a good signal to noise ratio in fluorescence yield detection of X-ray absorption spectra for spectroelectrochemical study. The cell also stabilizes the thin silicon nitride membrane window in an effective manner so that the liquid cell remains intact during X-ray absorption experiments. With the improved design of the liquid cell, electrochemical experiments such as cyclic voltammetry have been performed for 10 cycles with a good stability of sample window. Also an operando electrochemical experiment during photoelectrochemistry has been performed on n-type hematite electrode deposited on silicon nitride window. The experiment allows us to observe the formation of two extra electronic transitions before pre edge of O K edge spectra. PMID- 24784593 TI - Analysis of higher harmonic contamination with a modified approach using a grating analyser. AB - Soft x-ray spectra of the toroidal grating monochromator (TGM) at the reflectivity beamline of Indus-1 synchrotron source are analyzed for higher harmonic contribution. A diffraction grating of central line spacing 1200 l/mm is used to disperse the monochromatic beam received from TGM to quantify the harmonic contents in the 50-360 A wavelength range. In order to calculate the harmonic contamination, conventionally the intensity of higher order peak is divided by first order peak intensity of the desired wavelength. This approach is found to give wrong estimate as first order peak itself is overlapped by higher order peaks. In the present study, a modified approach has been proposed to calculate harmonic contamination where the intensity contributions of overlapping orders have been removed from the first order diffraction peak of the desired wavelength. It is found that the order contamination in the TGM spectra is less than 15% in the wavelength range of 90-180 A. The total harmonic contribution increases from 6%-60% in the wavelength range of 150-260 A. The critical wavelength of Indus-1 is 61 A hence the harmonic contamination below 90 A is significantly low. The results obtained with modified approach match well with those obtained by quantitative analysis of multilayer reflectivity data. The obtained higher harmonics data are used to fit the transmission of aluminum edge filter in the 120-360 A wavelength range. PMID- 24784594 TI - Design and performance of AERHA, a high acceptance high resolution soft x-ray spectrometer. AB - A soft x-ray spectrometer based on the use of an elliptical focusing mirror and a plane varied line spacing grating is described. It achieves both high resolution and high overall efficiency while remaining relatively compact. The instrument is dedicated to resonant inelastic x-ray scattering studies. We set out how this optical arrangement was judged best able to guarantee performance for the 50 - 1000 eV range within achievable fabrication targets. The AERHA (adjustable energy resolution high acceptance) spectrometer operates with an effective angular acceptance between 100 and 250 MUsr (energy dependent) and a resolving power well in excess of 5000 according to the Rayleigh criterion. The high angular acceptance is obtained by means of a collecting pre-mirror. Three scattering geometries are available to enable momentum dependent measurements with 135 degrees , 90 degrees , and 50 degrees scattering angles. The instrument operates on the Synchrotron SOLEIL SEXTANTS beamline which serves as a high photon flux 2 * 200 MUm(2) focal spot source with full polarization control. PMID- 24784595 TI - Optical fiber Sagnac interferometer for sensing scalar directional refraction: application to magnetochiral birefringence. AB - We present a setup dedicated to the measurement of the small scalar directional anisotropies associated to the magnetochiral interaction. The apparatus, based on a polarization-independent fiber Sagnac interferometer, is optimized to be insensitive to circular anisotropies and to residual absorption. It can thus characterize samples of biological interests, for which the two enantiomers are not available and/or which present poor transmission. The signal-to-noise ratio is shown to be limited only by the source intensity noise, leading to a detection limit of Deltaphi = 500 nrad Hz(-1/2). It yields a limit on the magnetochiral index nMC < 4 * 10(-13) T(-1) at 1.55 MUm for the organic molecules tested. PMID- 24784596 TI - Open-loop correction for an eddy current dominated beam-switching magnet. AB - A beam-switching magnet and the pulsed power supply it requires have been developed for the Japan Proton Accelerator Research Complex. To switch bunched proton beams, the dipole magnetic field must reach its maximum value within 40 ms. In addition, the field flatness should be less than 5 * 10(-4) to guide each bunched beam to the designed orbit. From a magnetic field measurement by using a long search coil, it was found that an eddy current in the thick endplates and laminated core disturbs the rise of the magnetic field. The eddy current also deteriorates the field flatness over the required flat-top period. The measured field flatness was 5 * 10(-3). By using a double-exponential equation to approximate the measured magnetic field, a compensation pattern for the eddy current was calculated. The integrated magnetic field was measured while using the newly developed open-loop compensation system. A field flatness of less than 5 * 10(-4), which is an acceptable value, was achieved. PMID- 24784597 TI - Empirical assessment of the detection efficiency of CR-39 at high proton fluence and a compact, proton detector for high-fluence applications. AB - CR-39 solid-state nuclear track detectors are widely used in physics and in many inertial confinement fusion (ICF) experiments, and under ideal conditions these detectors have 100% detection efficiency for ~0.5-8 MeV protons. When the fluence of incident particles becomes too high, overlap of particle tracks leads to under counting at typical processing conditions (5 h etch in 6N NaOH at 80 degrees C). Short etch times required to avoid overlap can cause under-counting as well, as tracks are not fully developed. Experiments have determined the minimum etch times for 100% detection of 1.7-4.3-MeV protons and established that for 2.4-MeV protons, relevant for detection of DD protons, the maximum fluence that can be detected using normal processing techniques is ?3 * 10(6) cm(-2). A CR-39-based proton detector has been developed to mitigate issues related to high particle fluences on ICF facilities. Using a pinhole and scattering foil several mm in front of the CR-39, proton fluences at the CR-39 are reduced by more than a factor of ~50, increasing the operating yield upper limit by a comparable amount. PMID- 24784598 TI - University of Lodz an electron spectrometer--a new conversion-electron spectrometer for "in-beam" measurements. AB - The designed and constructed at the University of Lodz an electron spectrometer is devoted to "in-beam" measurements. The apparatus is characterized by high efficiency up to 9%, good energy resolution (FWHM = 5 keV at 482 keV) and, what is very important good suppression of delta electrons, positrons, and photons emitted by the targets. This achievement was obtained using a combination of magnetic field in two different layouts: perpendicular and parallel to the axis of the spectrometer being orthogonal to the beamline. The conversion-electron spectrometer coupled to the EAGLE array was successfully tested in an "in-beam" measurement. PMID- 24784599 TI - Design, development, and acceleration trials of radio-frequency quadrupole. AB - A deuteron radio frequency quadrupole (RFQ) accelerator has been designed, fabricated, and tested at BARC, which will be used for neutron generation. The RFQ operates at a frequency of 350 MHz and needs an inter-vane voltage of 44 kV to accelerate the deuteron beam to 400 keV within a length of 1.03 m. The error analysis shows that the offset of two opposite vanes in the same direction by 100 MUm leads to a change in resonant frequency by 1.3 MHz and a significant change of fields in the quadrants (~+/-40% with respect to average field). From the 3D analysis, we have observed that the unwanted dipole mode frequencies are very near to the quadrupole mode frequency which will make structure sensitive to the perturbations. In order to move the dipole modes away from the quadrupole modes, we have used the dipole stabilizer rods. The 5 wire transmission line theory was used to study the perturbative analysis of the RFQ and based on this a computer program has been written to tune the cavity to get required field distribution. Based on these studies, a 1.03 m long RFQ made of OFE copper has been fabricated and tested. Even though the RFQ was designed for deuteron (D(+)) beam, we tested it by accelerating both the proton (H(+)) and D(+) beams. The RFQ was operated in pulsed mode and accelerated both H(+) and D(+) beams to designed values of 200 and 400 keV, respectively. The measured parameters are in good agreement with the designed values validating our simulations and fabrication processes. In this paper, simulations, RF measurements, and beam commissioning results are presented. PMID- 24784600 TI - Improved spectral data unfolding for radiochromic film imaging spectroscopy of laser-accelerated proton beams. AB - An improved method to unfold the space-resolved proton energy distribution function of laser-accelerated proton beams using a layered, radiochromic film (RCF) detector stack has been developed. The method takes into account the reduced RCF response near the Bragg peak due to a high linear energy transfer (LET). This LET dependence of the active RCF layer has been measured, and published data have been re-interpreted to find a nonlinear saturation scaling of the RCF response with stopping power. Accounting for the LET effect increased the integrated particle yield by 25% after data unfolding. An iterative, analytical, space-resolved deconvolution of the RCF response functions from the measured dose was developed that does not rely on fitting. After the particle number unfold, three-dimensional interpolation is performed to determine the spatial proton beam distribution for proton energies in-between the RCF data points. Here, image morphing has been implemented as a novel interpolation method that takes into account the energy-dependent, changing beam topology. PMID- 24784601 TI - A compact fast ionization gauge for in situ measurement of high-density neutral flow dynamics. AB - A compact ionization gauge has been developed to carry out in situ measurements of high density (10(20)-10(22) m(-3)) neutral gas flow dynamics with high temporal and spatial resolution. Key design aspects are discussed including gauge sensitivity and time response scaling with decreased probe dimensions, high pressure operation, improved driver circuit bandwidth, and techniques for constructing a miniaturized probe head. Gas adsorption was discovered to significantly alter emission current and gauge sensitivity over timescales of several seconds. This effect must be taken into consideration when making time resolved, high-density measurements. Over short timescales gauge response was predicted by scaling the sensitivity of a nominal Bayard-Alpert gauge to account for variations in probe dimensions and species-dependent ionization cross section. Time-resolved neutral density profiles have been acquired in the Magnetized Shock Experiment at Los Alamos National Laboratory, providing data on the initial conditions of the ionization, plasmoid formation, and translation processes. It is shown that the desired density profiles can be achieved using a dynamic gas fill and that density can be scaled independently of the spatial profile. PMID- 24784602 TI - Analytical compensation of axisymmetric equilibrium fluxes picked up by locked mode detectors in tokamaks. AB - In the detection of locked modes using saddle loops, the problem of how to remove the axisymmetric equilibrium flux picked up by the loops has still to be solved. The problem becomes more difficult when there are conductive structures located near the saddle loops. In this paper, we present an analytical model based on lumped eddy current circuits and use it to interpret the measured equilibrium flux and the corresponding eddy current fluxes. Using this model, precise compensation for fluxes induced by the horizontal field coils and the toroidal field coils, with relative errors of less than 1%, has been realized for the saddle loops in the Joint Texas Experimental Tokamak. This paper also presents a new method to compensate for the detection of equilibrium flux by the locked mode detector. PMID- 24784603 TI - Second generation fusion neutron time-of-flight spectrometer at optimized rate for fully digital data acquisition. AB - The progress on high-rate event recording of data is taken as starting point to revisit the design of fusion neutron spectrometers based on the TOF (time-of flight) technique. The study performed was aimed at how such instruments for optimized rate (TOFOR) can be further developed to enhance the plasma diagnostic capabilities based on measurement of the 2.5 MeV dd neutron emission from D plasmas, especially the weak spectral components that depend on discrimination of extraneous events. This paper describes a design (TOFOR II) adapted for use with digital wave form recording of all detector pulses providing information on both amplitude (pulse height) and timing. The results of simulations are presented and the performance enhancement is assessed in comparison to the present. PMID- 24784604 TI - Monochromatic short pulse laser produced ion beam using a compact passive magnetic device. AB - High-intensity laser accelerated protons and ions are emerging sources with complementary characteristics to those of conventional sources, namely high charge, high current, and short bunch duration, and therefore can be useful for dedicated applications. However, these beams exhibit a broadband energy spectrum when, for some experiments, monoenergetic beams are required. We present here an adaptation of conventional chicane devices in a compact form (10 cm * 20 cm) which enables selection of a specific energy interval from the broadband spectrum. This is achieved by employing magnetic fields to bend the trajectory of the laser produced proton beam through two slits in order to select the minimum and maximum beam energy. The device enables a production of a high current, short duration source with a reproducible output spectrum from short pulse laser produced charged particle beams. PMID- 24784605 TI - Inversion of infrared imaging bolometer based on one-dimensional and three dimensional modeling in HL-2A. AB - Linear regularization has been applied to the HL-2A infrared imaging bolometer to reconstruct local plasma emission with one-dimensional (1D) and three-dimensional (3D) modeling under the assumption of toroidal symmetry. In the 3D modeling, a new method to calculate the detector point response function is introduced. This method can be adapted to an arbitrarily shaped pinhole. With the full 3D treatment of the detector geometry, up to 50% of the mean-squared error is reduced compared with the 1D modeling. This is attributed to the effects of finite detector size being taken into account in the 3D modeling. Meanwhile, the number of the bolometer pixels has been optimized to 20 * 20 by making a trade off between the number of bolometer pixels and the sensitivity of the system. The plasma radiated power density distributions have been calculated as a demonstration using 1D modeling and 3D modeling, respectively. PMID- 24784606 TI - Single crystal diamond detector measurements of deuterium-deuterium and deuterium tritium neutrons in Joint European Torus fusion plasmas. AB - First simultaneous measurements of deuterium-deuterium (DD) and deuterium-tritium neutrons from deuterium plasmas using a Single crystal Diamond Detector are presented in this paper. The measurements were performed at JET with a dedicated electronic chain that combined high count rate capabilities and high energy resolution. The deposited energy spectrum from DD neutrons was successfully reproduced by means of Monte Carlo calculations of the detector response function and simulations of neutron emission from the plasma, including background contributions. The reported results are of relevance for the development of compact neutron detectors with spectroscopy capabilities for installation in camera systems of present and future high power fusion experiments. PMID- 24784607 TI - Fusion-neutron-yield, activation measurements at the Z accelerator: design, analysis, and sensitivity. AB - We present a general methodology to determine the diagnostic sensitivity that is directly applicable to neutron-activation diagnostics fielded on a wide variety of neutron-producing experiments, which include inertial-confinement fusion (ICF), dense plasma focus, and ion beam-driven concepts. This approach includes a combination of several effects: (1) non-isotropic neutron emission; (2) the 1/r(2) decrease in neutron fluence in the activation material; (3) the spatially distributed neutron scattering, attenuation, and energy losses due to the fielding environment and activation material itself; and (4) temporally varying neutron emission. As an example, we describe the copper-activation diagnostic used to measure secondary deuterium-tritium fusion-neutron yields on ICF experiments conducted on the pulsed-power Z Accelerator at Sandia National Laboratories. Using this methodology along with results from absolute calibrations and Monte Carlo simulations, we find that for the diagnostic configuration on Z, the diagnostic sensitivity is 0.037% +/- 17% counts/neutron per cm(2) and is ~ 40% less sensitive than it would be in an ideal geometry due to neutron attenuation, scattering, and energy-loss effects. PMID- 24784608 TI - A new method for determining the plasma electron density using optical frequency comb interferometer. AB - A new method of plasma electron density measurement using interferometric phases (fractional fringes) of an optical frequency comb interferometer is proposed. Using the characteristics of the optical frequency comb laser, high density measurement can be achieved without fringe counting errors. Simulations show that the short wavelength and wide wavelength range of the laser source and low noise in interferometric phases measurements are effective to reduce ambiguity of measured density. PMID- 24784609 TI - A spatially resolved retarding field energy analyzer design suitable for uniformity analysis across the surface of a semiconductor wafer. AB - A novel retarding field energy analyzer design capable of measuring the spatial uniformity of the ion energy and ion flux across the surface of a semiconductor wafer is presented. The design consists of 13 individual, compact-sized, analyzers, all of which are multiplexed and controlled by a single acquisition unit. The analyzers were tested to have less than 2% variability from unit to unit due to tight manufacturing tolerances. The main sensor assembly consists of a 300 mm disk to mimic a semiconductor wafer and the plasma sampling orifices of each sensor are flush with disk surface. This device is placed directly on top of the rf biased electrode, at the wafer location, in an industrial capacitively coupled plasma reactor without the need for any modification to the electrode structure. The ion energy distribution, average ion energy, and average ion flux were measured at the 13 locations over the surface of the powered electrode to determine the degree of spatial nonuniformity. The ion energy and ion flux are shown to vary by approximately 20% and 5%, respectively, across the surface of the electrode for the range of conditions investigated in this study. PMID- 24784610 TI - Wide-frequency range, dynamic matching network and power system for the "Shoelace" radio frequency antenna on the Alcator C-Mod tokamak. AB - A wide-frequency range (50-300 kHz) power system has been implemented for use with a new RF antenna - the "Shoelace" antenna - built to drive coherent plasma fluctuations in the edge of the Alcator C-Mod tokamak. A custom, dynamically tunable matching network allows two commercial 1 kW, 50-Omega RF amplifiers to drive the low-impedance, inductive load presented by the antenna. This is accomplished by a discretely variable L-match network, with 81 independently selected steps available for each of the series and parallel legs of the matching configuration. A compact programmable logic device provides a control system that measures the frequency with better than 1 kHz accuracy and transitions to the correct tuning state in less than 1 ms. At least 85% of source power is dissipated in the antenna across the operational frequency range, with a minimum frequency slew rate of 1 MHz/s; the best performance is achieved in the narrower band from 80 to 150 kHz which is of interest in typical experiments. The RF frequency can be run with open-loop control, following a pre-programmed analog waveform, or phase-locked to track a plasma fluctuation diagnostic signal in real time with programmable phase delay; the amplitude control is always open-loop. The control waveforms and phase delay are programmed remotely. These tools have enabled first-of-a-kind measurements of the tokamak edge plasma system response in the frequency range and at the wave number at which coherent fluctuations regulate heat and particle transport through the plasma boundary. PMID- 24784611 TI - Space-resolved extreme ultraviolet spectroscopy free of high-energy neutral particle noise in wavelength range of 10-130 A on the large helical device. AB - A flat-field space-resolved extreme ultraviolet (EUV) spectrometer system working in wavelength range of 10-130 A has been constructed in the Large Helical Device (LHD) for profile measurements of bremsstrahlung continuum and line emissions of heavy impurities in the central column of plasmas, which are aimed at studies on Zeff and impurity transport, respectively. Until now, a large amount of spike noise caused by neutral particles with high energies (<=180 keV) originating in neutral beam injection has been observed in EUV spectroscopy on LHD. The new system has been developed with an aim to delete such a spike noise from the signal by installing a thin filter which can block the high-energy neutral particles entering the EUV spectrometer. Three filters of 11 MUm thick beryllium (Be), 3.3 MUm thick polypropylene (PP), and 0.5 MUm thick polyethylene terephthalate (PET: polyester) have been examined to eliminate the spike noise. Although the 11 MUm Be and 3.3 MUm PP filters can fully delete the spike noise in wavelength range of lambda <= 20 A, the signal intensity is also reduced. The 0.5 MUm PET filter, on the other hand, can maintain sufficient signal intensity for the measurement and the spike noise remained in the signal is acceptable. As a result, the bremsstrahlung profile is successfully measured without noise at 20 A even in low-density discharges, e.g., 2.9 * 10(13) cm(-3), when the 0.5 MUm PET filter is used. The iron n = 3-2 Lalpha transition array consisting of FeXVII to FeXXIV is also excellently observed with their radial profiles in wavelength range of 10-18 A. Each transition in the Lalpha array can be accurately identified with its radial profile. As a typical example of the method a spectral line at 17.62 A is identified as FeXVIII transition. Results on absolute intensity calibration of the spectrometer system, pulse height and noise count analyses of the spike noise between holographic and ruled gratings and wavelength response of the used filters are also presented with performance of the present spectrometer system. PMID- 24784612 TI - Novel multipole Wien filter as three-dimensional spin manipulator. AB - Spin polarized electron beam is often used in material characterizations which relates to magnetism as well as in the high energy particle physics. The manipulation of the spin polarization toward the arbitrary direction is indispensable in such studies. In the present work, a novel multipole Wien filter is proposed as the three-dimensional spin manipulator, and a prototype 8-pole Wien filter is developed. It is applied to spin polarized low energy electron microscopy, and the variation of the magnetic contrast with managing the spin polarization is evaluated. It is confirmed that the novel multipole Wien filter can manipulate the spin polarization three-dimensionally. PMID- 24784613 TI - Facility for low-temperature spin-polarized-scanning tunneling microscopy studies of magnetic/spintronic materials prepared in situ by nitride molecular beam epitaxy. AB - Based on the interest in, as well as exciting outlook for, nitride semiconductor based structures with regard to electronic, optoelectronic, and spintronic applications, it is compelling to investigate these systems using the powerful technique of spin-polarized scanning tunneling microscopy (STM), a technique capable of achieving magnetic resolution down to the atomic scale. However, the delicate surfaces of these materials are easily corrupted by in-air transfers, making it unfeasible to study them in stand-alone ultra-high vacuum STM facilities. Therefore, we have carried out the development of a hybrid system including a nitrogen plasma assisted molecular beam epitaxy/pulsed laser epitaxy facility for sample growth combined with a low-temperature, spin-polarized scanning tunneling microscope system. The custom-designed molecular beam epitaxy growth system supports up to eight sources, including up to seven effusion cells plus a radio frequency nitrogen plasma source, for epitaxially growing a variety of materials, such as nitride semiconductors, magnetic materials, and their hetero-structures, and also incorporating in situ reflection high energy electron diffraction. The growth system also enables integration of pulsed laser epitaxy. The STM unit has a modular design, consisting of an upper body and a lower body. The upper body contains the coarse approach mechanism and the scanner unit, while the lower body accepts molecular beam epitaxy grown samples using compression springs and sample skis. The design of the system employs two stages of vibration isolation as well as a layer of acoustic noise isolation in order to reduce noise during STM measurements. This isolation allows the system to effectively acquire STM data in a typical lab space, which during its construction had no special and highly costly elements included, (such as isolated slabs) which would lower the environmental noise. The design further enables tip exchange and tip coating without breaking vacuum, and convenient visual access to the sample and tip inside a superconducting magnet cryostat. A sample/tip handling system is optimized for both the molecular beam epitaxy growth system and the scanning tunneling microscope system. The sample/tip handing system enables in situ STM studies on epitaxially grown samples, and tip exchange in the superconducting magnet cryostat. The hybrid molecular beam epitaxy and low temperature scanning tunneling microscopy system is capable of growing semiconductor-based hetero structures with controlled accuracy down to a single atomic-layer and imaging them down to atomic resolution. PMID- 24784614 TI - Bi-harmonic cantilever design for improved measurement sensitivity in tapping mode atomic force microscopy. AB - This paper presents a method and cantilever design for improving the mechanical measurement sensitivity in the atomic force microscopy (AFM) tapping mode. The method uses two harmonics in the drive signal to generate a bi-harmonic tapping trajectory. Mathematical analysis demonstrates that the wide-valley bi-harmonic tapping trajectory is as much as 70% more sensitive to changes in the sample topography than the standard single-harmonic trajectory typically used. Although standard AFM cantilevers can be driven in the bi-harmonic tapping trajectory, they require large forcing at the second harmonic. A design is presented for a bi harmonic cantilever that has a second resonant mode at twice its first resonant mode, thereby capable of generating bi-harmonic trajectories with small forcing signals. Bi-harmonic cantilevers are fabricated by milling a small cantilever on the interior of a standard cantilever probe using a focused ion beam. Bi-harmonic drive signals are derived for standard cantilevers and bi-harmonic cantilevers. Experimental results demonstrate better than 30% improvement in measurement sensitivity using the bi-harmonic cantilever. Images obtained through bi-harmonic tapping exhibit improved sharpness and surface tracking, especially at high scan speeds and low force fields. PMID- 24784615 TI - A tunable line optical tweezers instrument with nanometer spatial resolution. AB - We describe a simple scanning-line optical tweezers instrument for measuring pair interactions between micrometer-sized colloidal particles. Our instrument combines a resonant scanning mirror and an acousto-optic modulator. The resonant scanning mirror creates a time-averaged line trap whose effective one-dimensional intensity profile, and corresponding trapping potential energy landscape can be programmed using the acousto-optic modulator. We demonstrate control over the confining potential by designing and measuring a family of one-dimensional harmonic traps. By adjusting the spring constant, we balance scattering-induced repulsive forces between a pair of trapped particles, creating a flat potential near contact that facilitates interaction measurements. We also develop a simple method for extracting the out-of-plane motion of trapped particles from their relative brightness, allowing us to resolve their relative separation to roughly 1 nm. PMID- 24784616 TI - Combining low-energy electron microscopy and scanning probe microscopy techniques for surface science: development of a novel sample-holder. AB - We introduce an experimental facility dedicated to surface science that combines Low-Energy Electron Microscopy/Photo-Electron Emission Microscopy (LEEM/PEEM) and variable-temperature Scanning Probe Microscopy techniques. A technical challenge has been to design a sample-holder that allows to exploit the complementary specifications of both microscopes and to preserve their optimal functionality. Experimental demonstration is reported by characterizing under ultrahigh vacuum with both techniques: Au(111) surface reconstruction and a two-layer thick graphene on 6H-SiC(0001). A set of macros to analyze LEEM/PEEM data extends the capabilities of the setup. PMID- 24784617 TI - A 30 mK, 13.5 T scanning tunneling microscope with two independent tips. AB - We describe the design, construction, and performance of an ultra-low temperature, high-field scanning tunneling microscope (STM) with two independent tips. The STM is mounted on a dilution refrigerator and operates at a base temperature of 30 mK with magnetic fields of up to 13.5 T. We focus on the design of the two-tip STM head, as well as the sample transfer mechanism, which allows in situ transfer from an ultra high vacuum preparation chamber while the STM is at 1.5 K. Other design details such as the vibration isolation and rf-filtered wiring are also described. Their effectiveness is demonstrated via spectral current noise characteristics and the root mean square roughness of atomic resolution images. The high-field capability is shown by the magnetic field dependence of the superconducting gap of CuxBi2Se3. Finally, we present images and spectroscopy taken with superconducting Nb tips with the refrigerator at 35 mK that indicate that the effective temperature of our tips/sample is approximately 184 mK, corresponding to an energy resolution of 16 MUeV. PMID- 24784618 TI - Frequency-modulated atomic force microscopy operation by imaging at the frequency shift minimum: the dip-df mode. AB - In frequency modulated non-contact atomic force microscopy, the change of the cantilever frequency (Deltaf) is used as the input signal for the topography feedback loop. Around the Deltaf(z) minimum, however, stable feedback operation is challenging using a standard proportional-integral-derivative (PID) feedback design due to the change of sign in the slope. When operated under liquid conditions, it is furthermore difficult to address the attractive interaction regime due to its often moderate peakedness. Additionally, the Deltaf signal level changes severely with time in this environment due to drift of the cantilever frequency f0 and, thus, requires constant adjustment. Here, we present an approach overcoming these obstacles by using the derivative of Deltaf with respect to z as the input signal for the topography feedback loop. Rather than regulating the absolute value to a preset setpoint, the slope of the Deltaf with respect to z is regulated to zero. This new measurement mode not only makes the minimum of the Deltaf(z) curve directly accessible, but it also benefits from greatly increased operation stability due to its immunity against f0 drift. We present isosurfaces of the Deltaf minimum acquired on the calcite CaCO3(1014) surface in liquid environment, demonstrating the capability of our method to image in the attractive tip-sample interaction regime. PMID- 24784619 TI - Compact cold stage for micro-computerized tomography imaging of chilled or frozen samples. AB - High resolution X-ray microCT (computerized tomography) can be used to image a variety of objects, including temperature-sensitive materials. In cases where the sample must be chilled or frozen to maintain sample integrity, either the microCT machine itself must be placed in a refrigerated chamber, or a relatively expensive commercial cold stage must be purchased. We describe here the design and construction of a low-cost custom cold stage suitable for use in a microCT imaging system. Our device uses a boron nitride sample holder, two-stage Peltier cooler, fan-cooled heat sink, and electronic controller to maintain sample temperatures as low as -25 degrees C +/- 0.2 degrees C for the duration of a tomography acquisition. The design does not require modification to the microCT machine, and is easily installed and removed. Our custom cold stage represents a cost-effective solution for refrigerating CT samples for imaging, and is especially useful for shared equipment or machines unsuitable for cold room use. PMID- 24784620 TI - Use of intermediate focus for grazing incidence small and wide angle x-ray scattering experiments at the beamline P03 of PETRA III, DESY. AB - We describe the new experimental possibilities of the micro- and nanofocus X-ray scattering beamline P03 of the synchrotron source PETRA III at DESY, Hamburg (Germany), which arise from experiments with smaller beam sizes in the micrometer range. This beamline has been upgraded recently to perform new kinds of experiments. The use of an intermediate focus allows for reducing the beam size of microfocused hard X-rays while preserving a large working distance between the focusing elements and the focus position. For the first time, this well-known methodology has been employed to grazing incidence small- and wide-angle X-ray scattering (GISAXS/GIWAXS). As examples, we highlight the applications to in situ studies using microfluidic devices in GISAXS geometry as well as the investigation of the crystallinity of thin films in GIWAXS geometry. PMID- 24784621 TI - Organic ferroelectric evaporator with substrate cooling and in situ transport capabilities. AB - We report on the design, operation, and performance of a thermal evaporation chamber capable of evaporating organic thin films. Organic thin films are employed in a diverse range of devices and can provide insight into fundamental physical phenomena. However, growing organic thin films is often challenging and requires very specific deposition parameters. The chamber presented here is capable of cooling sample substrates to temperatures below 130 K and allows for the detachment of the sample from the cooling stage and in situ transport. This permits the use of multiple deposition techniques in separate, but connected, deposition chambers without breaking vacuum and therefore provides clean, well characterized interfaces between the organic thin film and any adjoining layers. We also demonstrate a successful thin film deposition of an organic material with a demanding set of deposition parameters, showcasing the success of this design. PMID- 24784622 TI - Moissanite anvil cell design for Giga-Pascal nuclear magnetic resonance. AB - A new design of a non-magnetic high-pressure anvil cell for nuclear magnetic resonance (NMR) experiments at Giga-Pascal pressures is presented, which uses a micro-coil inside the pressurized region for high-sensitivity NMR. The comparably small cell has a length of 22 mm and a diameter of 18 mm, so it can be used with most NMR magnets. The performance of the cell is demonstrated with external-force vs. internal-pressure experiments, and the cell is shown to perform well at pressures up to 23.5 GPa using 800 MUm 6H-SiC large cone Boehler-type anvils. (1)H, (23)Na, (27)Al, (69)Ga, and (71)Ga NMR test measurements are presented, which show a resolution of better than 4.5 ppm, and an almost maximum possible signal-to-noise ratio. PMID- 24784623 TI - High-pressure cell for neutron diffraction with in situ pressure control at cryogenic temperatures. AB - Pressure generation at cryogenic temperatures presents a problem for a wide array of experimental techniques, particularly neutron studies due to the volume of sample required. We present a novel, compact pressure cell with a large sample volume in which load is generated by a bellow. Using a supply of helium gas up to a pressure of 350 bar, a load of up to 78 kN is generated with leak-free operation. In addition, special fiber ports added to the cryogenic center stick allow for in situ pressure determination using the ruby pressure standard. Mechanical stability was assessed using finite element analysis and the dimensions of the cell have been optimized for use with standard cryogenic equipment. Load testing and on-line experiments using NaCl and BiNiO3 have been done at the WISH instrument of the ISIS pulsed neutron source to verify performance. PMID- 24784624 TI - A robust and well shielded thermal conductivity device for low temperature measurements. AB - We present a compact mechanically robust thermal conductivity measurement apparatus for measurements at low temperatures (<1 K) and high magnetic fields on small high-purity single crystal samples. A high-conductivity copper box is used to enclose the sample and all the components. The box provides protection for the thermometers, heater, and most importantly the sample increasing the portability of the mount. In addition to physical protection, the copper box is also effective at shielding radio frequency electromagnetic interference and thermal radiation, which is essential for low temperature measurements. A printed circuit board in conjunction with a braided ribbon cable is used to organize the delicate wiring and provide mechanical robustness. PMID- 24784625 TI - Multifunctional probes for high-throughput measurement of Seebeck coefficient and electrical conductivity at room temperature. AB - An apparatus capable of rapid measurement of the Seebeck coefficient and electrical resistivity at room temperature is reported. The novel aspect of this apparatus is the use of 4 multifunctional probes that comprise a junction of two conductors at the tip and serve as both thermocouples and electrical contacts. In addition, one of the probes has a built-in heater that can establish a temperature gradient in the sample for the Seebeck measurement. The technique does not require special sample geometries or preparation of contacts and is suitable for bulk and thin film materials. Together with automated sample stage and data acquisition, the equipment is able to measure both the Seebeck coefficient and electrical resistivity in less than 20 s with good accuracy. Less than 5% and 4% relative errors were found for the measurement of the Seebeck coefficient and electrical resistivity, respectively. This makes the apparatus especially useful for high throughput evaluation of thermoelectric materials. PMID- 24784626 TI - Effects, determination, and correction of count rate nonlinearity in multi channel analog electron detectors. AB - Detector counting rate nonlinearity, though a known problem, is commonly ignored in the analysis of angle resolved photoemission spectroscopy where modern multichannel electron detection schemes using analog intensity scales are used. We focus on a nearly ubiquitous "inverse saturation" nonlinearity that makes the spectra falsely sharp and beautiful. These artificially enhanced spectra limit accurate quantitative analysis of the data, leading to mistaken spectral weights, Fermi energies, and peak widths. We present a method to rapidly detect and correct for this nonlinearity. This algorithm could be applicable for a wide range of nonlinear systems, beyond photoemission spectroscopy. PMID- 24784627 TI - Laser-driven flyer plates for shock compression science: launch and target impact probed by photon Doppler velocimetry. AB - We investigated the launch and target impact of laser-driven Al flyer plates using photon Doppler velocimetry (PDV). We studied different flyer designs launched by laser pulses of different energies, pulse durations and beam diameters, that produced km s(-1) impacts with transparent target materials. Laser-launching Al flyers 25-100 MUm thick cemented to glass substrates is usually thought to involve laser vaporization of a portion of the flyer, which creates many difficulties associated with loss of integrity and heating of the flyer material. However, in the system used here, the launch mechanism was surprising and unexpected: it involved optical damage at the glass/cement/flyer interface, with very little laser light reaching the flyer itself. In fact the flyers launched in this manner behaved almost identically to multilayer flyers that were optically shielded from the laser pulses and insulated from heat generated by the pulses. Launching flyers with nanosecond laser pulses creates undesirable reverberating shocks in the flyer. In some cases, with 10 ns launch pulses, the thickest flyers were observed to lose integrity. But with stretched 20 ns pulses, we showed that the reverberations damped out prior to impact with targets, and that the flyers maintained their integrity during flight. Flyer impacts with salt, glass, fused silica, and acrylic polymer were studied by PDV, and the durations of fully supported shocks in those media were determined, and could be varied from 5 to 23 ns. PMID- 24784628 TI - Pump-probe surface photovoltage spectroscopy measurements on semiconductor epitaxial layers. AB - Pump-probe Surface Photovoltage Spectroscopy (SPS) measurements are performed on semiconductor epitaxial layers. Here, an additional sub-bandgap cw pump laser beam is used in a conventional chopped light geometry SPS setup under the pump probe configuration. The main role of pump laser beam is to saturate the sub bandgap localized states whose contribution otherwise swamp the information related to the bandgap of material. It also affects the magnitude of Dember voltage in case of semi-insulating (SI) semiconductor substrates. Pump-probe SPS technique enables an accurate determination of the bandgap of semiconductor epitaxial layers even under the strong influence of localized sub-bandgap states. The pump beam is found to be very effective in suppressing the effect of surface/interface and bulk trap states. The overall magnitude of SPV signal is decided by the dependence of charge separation mechanisms on the intensity of the pump beam. On the contrary, an above bandgap cw pump laser can be used to distinguish the signatures of sub-bandgap states by suppressing the band edge related feature. Usefulness of the pump-probe SPS technique is established by unambiguously determining the bandgap of p-GaAs epitaxial layers grown on SI-GaAs substrates, SI-InP wafers, and p-GaN epilayers grown on Sapphire substrates. PMID- 24784629 TI - The development and deployment of a ground-based, laser-induced fluorescence instrument for the in situ detection of iodine monoxide radicals. AB - High abundances of iodine monoxide (IO) are known to exist and to participate in local photochemistry of the marine boundary layer. Of particular interest are the roles IO plays in the formation of new particles in coastal marine environments and in depletion episodes of ozone and mercury in the Arctic polar spring. This paper describes a ground-based instrument that measures IO at mixing ratios less than one part in 10(12). The IO radical is measured by detecting laser-induced fluorescence at wavelengths longer that 500 nm. Tunable visible light is used to pump the A(2)Pi3/2 (v(') = 2) <- X(2)Pi3/2 (v(") = 0) transition of IO near 445 nm. The laser light is produced by a solid-state, Nd:YAG-pumped Ti:Sapphire laser at 5 kHz repetition rate. The laser-induced fluorescence instrument performs reliably with very high signal-to-noise ratios (>10) achieved in short integration times (<1 min). The observations from a validation deployment to the Shoals Marine Lab on Appledore Island, ME are presented and are broadly consistent with in situ observations from European Coastal Sites. Mixing ratios ranged from the instrumental detection limit (<1 pptv) to 10 pptv. These data represent the first in situ point measurements of IO in North America. PMID- 24784630 TI - Automated high-pressure titration system with in situ infrared spectroscopic detection. AB - A fully automated titration system with infrared detection was developed for investigating interfacial chemistry at high pressures. The apparatus consists of a high-pressure fluid generation and delivery system coupled to a high-pressure cell with infrared optics. A manifold of electronically actuated valves is used to direct pressurized fluids into the cell. Precise reagent additions to the pressurized cell are made with calibrated tubing loops that are filled with reagent and placed in-line with the cell and a syringe pump. The cell's infrared optics facilitate both transmission and attenuated total reflection (ATR) measurements to monitor bulk-fluid composition and solid-surface phenomena such as adsorption, desorption, complexation, dissolution, and precipitation. Switching between the two measurement modes is accomplished with moveable mirrors that direct the light path of a Fourier transform infrared spectrometer into the cell along transmission or ATR light paths. The versatility of the high-pressure IR titration system was demonstrated with three case studies. First, we titrated water into supercritical CO2 (scCO2) to generate an infrared calibration curve and determine the solubility of water in CO2 at 50 degrees C and 90 bar. Next, we characterized the partitioning of water between a montmorillonite clay and scCO2 at 50 degrees C and 90 bar. Transmission-mode spectra were used to quantify changes in the clay's sorbed water concentration as a function of scCO2 hydration, and ATR measurements provided insights into competitive residency of water and CO2 on the clay surface and in the interlayer. Finally, we demonstrated how time-dependent studies can be conducted with the system by monitoring the carbonation reaction of forsterite (Mg2SiO4) in water-bearing scCO2 at 50 degrees C and 90 bar. Immediately after water dissolved in the scCO2, a thin film of adsorbed water formed on the mineral surface, and the film thickness increased with time as the forsterite began to dissolve. However, after approximately 2.5 h, the trend reversed, and a carbonate precipitate began to form on the forsterite surface, exposing dramatic chemical changes in the thin-water film. Collectively, these applications illustrate how the high-pressure IR titration system can provide molecular-level information about the interactions between variably wet scCO2 and minerals relevant to underground storage of CO2 (geologic carbon sequestration). The apparatus could also be utilized to study high pressure interfacial chemistry in other areas such as catalysis, polymerization, food processing, and oil and gas recovery. PMID- 24784631 TI - Measuring the Newtonian constant of gravitation with a differential free-fall gradiometer: a feasibility study. AB - An original setup is presented to measure the Newtonian Constant of Gravitation G. It is based on the same principle as used in ballistic absolute gravimeters. The differential acceleration of three simultaneously freely falling test masses is measured in order to determine G. In this paper, a description of the experimental setup is presented. A detailed uncertainty budget estimates the relative uncertainty to be of the order of 5.3 * 10(-4), however with some improvements a relative uncertainty in G of one part in 10(4) could be feasible. PMID- 24784632 TI - Precision high-value resistance scaling with a two-terminal cryogenic current comparator. AB - We describe a cryogenic two-terminal high-resistance bridge and its application in precision resistance scaling from the quantized Hall resistance (QHR) at RH = RK/2 = 12 906.4035 Omega to decade resistance standards with values between 1 MOmega and 1 GOmega. The design minimizes lead resistance errors with multiterminal connections to the QHR device. A single variable voltage source and resistive ratio windings are utilized to achieve excellent dynamic stability, which is not readily obtained in low-current measurements with conventional cryogenic current comparators (CCCs). Prototypes of this bridge have been verified by a successful international comparison of high-resistance scaling using two-terminal CCCs in the national metrology institutes of Argentina, Mexico, and the United States. PMID- 24784633 TI - A very low noise, high accuracy, programmable voltage source for low frequency noise measurements. AB - In this paper an approach for designing a programmable, very low noise, high accuracy voltage source for biasing devices under test in low frequency noise measurements is proposed. The core of the system is a supercapacitor based two pole low pass filter used for filtering out the noise produced by a standard DA converter down to 100 mHz with an attenuation in excess of 40 dB. The high leakage current of the supercapacitors, however, introduces large DC errors that need to be compensated in order to obtain high accuracy as well as very low output noise. To this end, a proper circuit topology has been developed that allows to considerably reduce the effect of the supercapacitor leakage current on the DC response of the system while maintaining a very low level of output noise. With a proper design an output noise as low as the equivalent input voltage noise of the OP27 operational amplifier, used as the output buffer of the system, can be obtained with DC accuracies better that 0.05% up to the maximum output of 8 V. The expected performances of the proposed voltage source have been confirmed both by means of SPICE simulations and by means of measurements on actual prototypes. Turn on and stabilization times for the system are of the order of a few hundred seconds. These times are fully compatible with noise measurements down to 100 mHz, since measurement times of the order of several tens of minutes are required in any case in order to reduce the statistical error in the measured spectra down to an acceptable level. PMID- 24784634 TI - Influence of different illumination profiles on the on-state resistances of silicon carbide photoconductive semiconductor switches. AB - Characteristics of a silicon-carbide (SiC) photoconductive switch under different illumination profiles are presented. We triggered a V-doped semi-insulated 6H-SiC switch with lateral geometry using a laser beam of 532-nm wavelength. Photoconductivity tests for different spot profiles and locations show that such switches achieve a minimum on-state resistance when the switching gap is illuminated. The differences between on-state resistances are small for various partial illuminations of the switching gap. Semiconductor modeling is used to simulate the electric field and current profiles for different partial illuminations. The simulation results show poor on-state switch performance when partially illuminated. Based on these results, a more revealing circuit model for the switch matches well with experimental results for partial illuminations. PMID- 24784635 TI - Pulsed magnetic field measurement system based on colossal magnetoresistance-B scalar sensors for railgun investigation. AB - A high pulsed magnetic field measurement system based on the use of CMR-B-scalar sensors was developed for the investigations of the electrodynamic processes in electromagnetic launchers. The system consists of four independent modules (channels) which are controlled by a personal computer. Each channel is equipped with a CMR-B-scalar sensor connected to the measurement device-B-scalar meter. The system is able to measure the magnitude of pulsed magnetic fields from 0.3 T to 20 T in the range from DC up to 20 kHz independently of the magnetic field direction. The measurement equipment circuit is electrically separated from the ground and shielded against low and high frequency electromagnetic noise. The B scalar meters can be operated in the presence of ambient pulsed magnetic fields with amplitudes up to 0.2 T and frequencies higher than 1 kHz. The recorded signals can be transmitted to a personal computer in a distance of 25 m by means of a fiber optic link. The system was tested using the electromagnetic railgun RAFIRA installed at the French-German Research Institute of Saint-Louis, France. PMID- 24784636 TI - LabVIEW-based control software for para-hydrogen induced polarization instrumentation. AB - The elucidation of cell metabolic mechanisms is the modern underpinning of the diagnosis, treatment, and in some cases the prevention of disease. Para-Hydrogen induced polarization (PHIP) enhances magnetic resonance imaging (MRI) signals over 10,000 fold, allowing for the MRI of cell metabolic mechanisms. This signal enhancement is the result of hyperpolarizing endogenous substances used as contrast agents during imaging. PHIP instrumentation hyperpolarizes Carbon-13 ((13)C) based substances using a process requiring control of a number of factors: chemical reaction timing, gas flow, monitoring of a static magnetic field (Bo), radio frequency (RF) irradiation timing, reaction temperature, and gas pressures. Current PHIP instruments manually control the hyperpolarization process resulting in the lack of the precise control of factors listed above, resulting in non-reproducible results. We discuss the design and implementation of a LabVIEW based computer program that automatically and precisely controls the delivery and manipulation of gases and samples, monitoring gas pressures, environmental temperature, and RF sample irradiation. We show that the automated control over the hyperpolarization process results in the hyperpolarization of hydroxyethylpropionate. The implementation of this software provides the fast prototyping of PHIP instrumentation for the evaluation of a myriad of (13)C based endogenous contrast agents used in molecular imaging. PMID- 24784637 TI - Design and development of ultra-wideband 3 dB hybrid coupler for Ion cyclotron resonance frequency heating in tokamak. AB - Design and development of a high power ultra-wideband, 3 dB tandem hybrid coupler is presented and its application in ICRF heating of the tokamak is discussed. In order to achieve the desired frequency band of 38-112 MHz and 200 kW power handling capability, the 3 dB hybrid coupler is developed using two 3-element 8.34 +/- 0.2 dB coupled lines sections in tandem. In multi-element coupled lines, junctions are employed for the joining of coupled elements that produce the undesirable reactance called junction discontinuity effect. The effect becomes prominent in the high power multi-element coupled lines for high frequency (HF) and very high frequency(VHF) applications because of larger structural dimensions. Junction discontinuity effect significantly deteriorates coupling and output performance from the theoretical predictions. For the analysis of junction discontinuity effect and its compensation, a theoretical approach has been developed and generalized for n-element coupled lines section. The theory has been applied in the development of the 3 dB hybrid coupler. The fabricated hybrid coupler has been experimentally characterized using vector network analyzer and obtained results are found in good agreement with developed theory. PMID- 24784638 TI - A cryogenic infrared calibration target. AB - A compact cryogenic calibration target is presented that has a peak diffuse reflectance, R ? 0.003, from 800 to 4800 cm(-1) (12 - 2 MUm). Upon expanding the spectral range under consideration to 400-10,000 cm(-1) (25 - 1 MUm) the observed performance gracefully degrades to R ? 0.02 at the band edges. In the implementation described, a high-thermal-conductivity metallic substrate is textured with a pyramidal tiling and subsequently coated with a thin lossy dielectric coating that enables high absorption and thermal uniformity across the target. The resulting target assembly is lightweight, has a low-geometric profile, and has survived repeated thermal cycling from room temperature to ~4 K. Basic design considerations, governing equations, and test data for realizing the structure described are provided. The optical properties of selected absorptive materials-Acktar Fractal Black, Aeroglaze Z306, and Stycast 2850 FT epoxy loaded with stainless steel powder-are characterized and presented. PMID- 24784639 TI - A center frequency adjustable narrow band filter for the detection of weak single frequency signal. AB - We describe and implement a center frequency adjustable narrow band filter based on the crystal filter for the detection of weak single frequency signal. It is formed by a multiplier, a direct digital frequency synthesizer, a multi-stage crystal bandpass filter, and a micro control unit which is used to set the center frequency of the filter. A theoretical study is proposed and experimentally validated. The test results show that the 3 db and 20 db bandwidths are 0.84 Hz and 2.73 Hz, respectively, and the filter system can effectively detect the signal with amplitude below 1 MUV and a frequency which ranges from 10 Hz to the frequency that is mainly limited by the components applied. PMID- 24784640 TI - Inner surface flash-over of insulator of low-inductance high-voltage self breakdown gas switch and its application. AB - In this paper, the inner surface flash-over of high-voltage self-breakdown switch, which is used as a main switch of pulse modulator, is analyzed in theory by employing the method of distributed element equivalent circuit. Moreover, the field distortion of the switch is simulated by using software. The results of theoretical analysis and simulation by software show that the inner surface flash over usually starts at the junction points among the stainless steel, insulator, and insulation gas in the switch. A switch with improved structure is designed and fabricated according to the theoretical analysis and simulation results. Several methods to avoid inner surface flash-over are used to improve the structure of switch. In experiment, the inductance of the switch is no more than 100 nH, the working voltage of the switch is about 600 kV, and the output voltage and current of the accelerator is about 500 kV and 50 kA, respectively. And the zero-to-peak rise time of output voltage at matched load is less than 30 ns due to the small inductance of switch. The original switch was broken-down after dozens of experiments, and the improved switch has been worked more than 200 times stably. PMID- 24784641 TI - Geometric moment extraction equipment for image processing applications. AB - An equipment for calculating 2nd, 3rd, and higher order geometric moments by using accumulators, adders, subtractors, and multiplier blocks has been presented. The performance analysis of the proposed equipment with the existing systems in terms of speed and power dissipation has been carried out and has been shown that the computational time to calculate the geometric moments is reduced to half and the power dissipation is reduced by a factor of about 3 at a clock frequency of 10 MHz. The hardware has been implemented in BSIM4.3.0 50 nm technology operating at 1 V and its functionality has been verified using P-Spice simulator. PMID- 24784642 TI - Temperature measurements using multicolor pyrometry in thermal radiation heating environments. AB - Temperature measurements are important for thermal-structural experiments in the thermal radiation heating environments such as used for thermal-structural stress analyses. This paper describes the use of multicolor pyrometry for the measurements of diffuse surfaces in thermal radiation environments that eliminates the effects of background radiation reflections and unknown emissivities based on a least-squares algorithm. The near-infrared multicolor pyrometer had a spectral range of 1100-2400 nm, spectrum resolution of 6 nm, maximum sampling frequency of 2 kHz, working distance of 0.6 m to infinity, temperature range of 700-1700 K. The pyrometer wavelength response, nonlinear intensity response, and spectral response were all calibrated. The temperature of a graphite sample irradiated by quartz lamps was then measured during heating and cooling using the least-squares algorithm based on the calibrated irradiation data. The experiments show that higher temperatures and longer wavelengths are more suitable for the thermal measurements in the quartz lamp radiation heating system. This analysis provides a valuable method for temperature measurements of diffuse surfaces in thermal radiation environments. PMID- 24784643 TI - Fiber-optic thermometry using thermal radiation from Tm end doped SiO2 fiber sensor. AB - Fiber-optic thermometry based on temperature dependence of thermal radiation from Tm(3+) ions was studied using Tm end doped SiO2 fiber sensor. Visible light radiation peaks due to f-f transition of Tm(3+) ion were clearly observed at lambda = 690 and 790 nm from Tm end doped SiO2 fibers sensor at the temperature above 600 degrees C. Thermal radiation peaks are assigned with f-f transition of Tm(3+) ion, (1)D2-(3)H6, and (1)G4-(3)H6. Peak intensity of thermal radiation from Tm(3+) ion increases with temperature. Intensity ratio of thermal radiation peaks at lambda = 690 nm against that at lambda = 790 nm, I790/690, is suitable for the temperature measurement above 750 degrees C. Two-dimensional temperature distribution in a flame is successfully evaluated by Tm end doped SiO2 fiber sensor. PMID- 24784644 TI - Pulse transient hot strip technique adapted for slab sample geometry to study anisotropic thermal transport properties of MUm-thin crystalline films. AB - A new method based on the adaptation of the Pulse Transient Hot Strip technique to slab sample geometry has been developed for studying thermal conductivity and thermal diffusivity of anisotropic thin film materials (<50 MUm) with thermal conductivity in the 0.01-100 W/mK range, deposited on thin substrates (i.e., wafers). Strength of this technique is that it provides a well-controlled thermal probing depth, making it possible to probe a predetermined depth of the sample layer and thereby avoiding the influence from material(s) deeper down in the sample. To verify the technique a series of measurements were conducted on a y cut single crystal quartz wafer. A Hot Strip sensor (32-MUm wide, 3.2-mm long) was deposited along two orthogonal crystallographic (x- and z-) directions and two independent pulse transients were recorded. Thereafter, the data was fitted to our theoretical model, and the anisotropic thermal transport properties were determined. Using a thermal probing depth of only 30 MUm, we obtained a thermal conductivity along the perpendicular (parallel) direction to the z-, i.e., optic axis of 6.48 (11.4) W/mK, and a thermal diffusivity of 3.62 (6.52) mm(2)/s. This yields a volumetric specific heat of 1.79 MJ/mK. These values agree well with tabulated data on bulk crystalline quartz supporting the accuracy of the technique, and the obtained standard deviation of less than 2.7% demonstrates the precision of this new measurement technique. PMID- 24784645 TI - High-precision instrument for measuring the surface tension, viscosity and surface viscoelasticity of liquids using ripplon surface laser-light scattering with tunable wavelength selection. AB - Here we describe our new high-precision instrument that simultaneously measures the surface tension, viscosity, and surface viscoelasticity of liquids. The instrument works on the ripplon surface-laser light scattering principle and operates with an automatically tunable selection of ripplon wavelength from 4 to 1500 MUm, which corresponds to the frequency range of observing surface phenomena from approximately 400 Hz to 3 MHz in the case of water. The heterodyne technique instrument uses a reference laser beam which intersects at an arbitrarily adjustable angle with a vertically directed probing beam. For the determination of the wavelength of selected ripplons we substituted with the interference fringe spacing, measured using a high-resolution beam profiler. To extract reliable surface tension and viscosity data from the experimentally obtained spectrum shape for a selected wavelength of ripplon, we developed an algorithm to calculate the exact solution of the dispersion equation. The uncertainties of surface tension and viscosity measurement were confirmed through the measurement of seven pure Newtonian liquids at 25 degrees C measured with the selected wavelength of ripplon from 40 MUm to 467 MUm. To verify the genuine capability of the tunable wavelength selection of ripplon, we measured the surface elasticity of soluble surface molecular layers spread on pentanoic acid solutions. PMID- 24784646 TI - Double threshold ultrasonic distance measurement technique and its application. AB - The double threshold method realized by hardware circuits and high performance timing chip TDC-GP21 was successfully adapted to solve the key problem of ultrasonic distance measurement, the accurate time-of-flight (TOF) measurement of ultrasonic wave. Compared with other techniques of TOF measurement, the double threshold method presented in this work can suppress noise in the received signal, and achieve a time resolution of around 22 ps and real-time. This method is easy to realize and pertains the advantage of low cost. To compensate temperature and pressure deviations, a temperature measurement module of 10 mK in precision as well as a pressure measurement module of 0.01% in accuracy was developed. The system designed in this work can be exactly used as a two paths ultrasonic gas flowmeter without any adjustment of the hardware circuit. The double threshold method was further corroborated using experiment results of both the ultrasonic distance measurement and ultrasonic gas flow measurement. In distance measurement, the maximum absolute deviation and the maximum relative error are 0.69 mm and 0.28%, respectively, for a target distance range of 100-600 mm. In flow measurement, the maximum absolute deviation and the worst repeatability are 1.16% and 0.65% for a flow in the range of 50-700 m(3)/h. PMID- 24784647 TI - Experimental study on detection of electrostatic discharges generated by polymer granules inside a metal silo. AB - To detect electrostatic discharges generated by polymer granules within a metal silo, we developed a novel and simple electrostatic discharge detector that utilizes a photosensor. The novel detector consists of a photosensor module in a metal cylinder, an optical band-pass filter, a quartz glass, a power supply, an amplifier for the photosensor module, and a digital oscilloscope. In this study, we conducted experiments at a real pneumatic powder transport facility that includes a metal silo to evaluate the novel detector using polypropylene granules. To determine the performance of the novel detector, we observed the electrostatic discharge within the metal silo using a conventional image intensifier system. The results obtained from the experiments show that the novel detector worked well in this study. The signals obtained with the novel detector were identical to the electrostatic discharges obtained with the conventional image intensifier system. The greatest advantage of this novel detector is that it is effective even when placed under external lights. In addition, the influence of various optical band-pass filters on the performance of the novel detector was discussed. Our study confirmed that an optical band-pass filter with a center wavelength of lambda 330 nm (lambda1/2: 315-345 nm) was the best performer among the optical band-pass filters used in this study. PMID- 24784648 TI - Selective nano-patterning of graphene using a heated atomic force microscope tip. AB - In this study, we introduce a selective thermochemical nano-patterning method of graphene on insulating substrates. A tiny heater formed at the end of an atomic force microscope (AFM) cantilever is optimized by a finite element method. The cantilever device is fabricated using conventional micromachining processes. After preliminary tests of the cantilever device, nano-patterning experiments are conducted with various conducting and insulating samples. The results indicate that faster scanning speed and higher contact force are desirable to reduce the sizes of nano-patterns. With the experimental condition of 1 MUm/s and 24 mW, the heated AFM tip generates a graphene oxide layer of 3.6 nm height and 363 nm width, on a 300 nm thick SiO2 layer, with a tip contact force of 100 nN. PMID- 24784649 TI - Range-based control of dual-stage nanopositioning systems. AB - A novel dual-stage nanopositioner control framework is presented that considers range constraints. Dual-stage nanopositioners are becoming increasingly popular in applications such as scanning probe microscopy due to their unique ability to achieve long-range and high-speed operation. The proposed control approach addresses the issue that some precision positioning trajectories are not achievable through existing control schemes. Specifically, short-range, low-speed inputs are typically diverted to the long-range actuator, which coincidentally has lower positioning resolution. This approach then limits the dual-stage nanopositioner's ability to achieve the required positioning resolution that is needed in applications where range and frequency are not inversely correlated (which is a typical, but not always the correct assumption for dual stage systems). The proposed range-based control approach is proposed to overcome the limitations of existing control methods. Experimental results show that the proposed control strategy is effective. PMID- 24784650 TI - Repulsively driven frequency-increased-generators for durable energy harvesting from ultra-low frequency vibration. AB - An electromagnetic kinetic energy harvester has been developed, which can convert ultra-low-frequency motion and vibration energy into electrical power. This harvester employs a two-stage vibratory structure to collect low-frequency kinetic energy and effectively transfer it into electric power by using a pair of high-frequency resonant generators. Non-contact magnetic repulsive force is herein utilized for the 1st-stage sliding vibrator to drive the 2nd-stage resonators into frequency-up-conversion resonance. The non-contact actuation is helpful for durable and long-life working of the device. The prototyped device is fabricated and the design is well confirmed by experimental test. The harvester can be well operated at the frequency as low as 0.25 Hz. Under driving acceleration of 1 g at 0.5 Hz, the miniaturized harvester can generate a peak power of 4.42 mW and an average power of 158 MUW. PMID- 24784651 TI - Implementation and analysis of an innovative digital charge amplifier for hysteresis reduction in piezoelectric stack actuators. AB - Smart actuators are the key components in a variety of nanopositioning applications, such as scanning probe microscopes and atomic force microscopes. Piezoelectric actuators are the most common smart actuators due to their high resolution, low power consumption, and wide operating frequency but they suffer hysteresis which affects linearity. In this paper, an innovative digital charge amplifier is presented to reduce hysteresis in piezoelectric stack actuators. Compared to traditional analog charge drives, experimental results show that the piezoelectric stack actuator driven by the digital charge amplifier has less hysteresis. It is also shown that the voltage drop of the digital charge amplifier is significantly less than the voltage drop of conventional analog charge amplifiers. PMID- 24784652 TI - Miniaturized high-precision piezo driven two axes stepper goniometer. AB - A miniaturized inertial stepper goniometer with two orthogonal axes (theta and phi axes) has been realized using four shear piezo based actuators arranged in a tetrahedral configuration tangent with a polished sapphire spherical rotor. The measured sensitivity is about 11.5 microdegree (MU degrees ) per Volt. The smallest angular step size, achieved with a minimal peak-to-peak voltage Upp of 200 V is about 0.6 millidegree (m degrees ). The crosstalk between both axes is below 10%. Our specific design is used to accurately position a glass fiber, but the concept can be utilized for many different applications as well. PMID- 24784653 TI - Three-dimensional surface figure measurement of high-accuracy spherical mirror with nanoprofiler using normal vector tracing method. AB - Processing technology using an extreme ultraviolet light source, e.g., next generation lithography, requires next-generation high-accuracy mirrors. As it will be difficult to attain the degree of precision required by next-generation high-accuracy mirrors such as aspherical mirrors through conventional processing methods, rapid progress in nanomeasurement technologies will be needed to produce such mirrors. Because the measuring methods used for the surface figure measurement of next-generation mirrors will require high precision, we have developed a novel nanoprofiler that can measure the figures of high-accuracy mirrors without the use of a reference surface. Because the accuracy of the proposed method is not limited by the accuracy of a reference surface, the measurement of free-form mirrors is expected to be realized. By using an algorithm to process normal vectors and their coordinate values at the measurement point obtained by a nanoprofiler, our measurement method can reconstruct three-dimensional shapes. First, we measured the surface of a concave spherical mirror with a 1000-mm radius of curvature using the proposed method, and the measurement repeatability is evaluated as 0.6 nm. Sub-nanometer repeatability is realized, and an increase in the repeatability would be expected by improving the dynamic stiffness of the nanoprofiler. The uncertainty of the measurement using the present apparatus is estimated to be approximately 10 nm by numerical simulation. Further, the uncertainty of a Fizeau interferometer is also approximately 10 nm. The results obtained using the proposed method are compared with those obtained using a Fizeau interferometer. The resulting profiles are consistent within the range of each uncertainty over the middle portions of the mirror. PMID- 24784654 TI - A seamless acquisition digital storage oscilloscope with three-dimensional waveform display. AB - In traditional digital storage oscilloscope (DSO), sampled data need to be processed after each acquisition. During data processing, the acquisition is stopped and oscilloscope is blind to the input signal. Thus, this duration is called dead time. With the rapid development of modern electronic systems, the effect of infrequent events becomes significant. To capture these occasional events in shorter time, dead time in traditional DSO that causes the loss of measured signal needs to be reduced or even eliminated. In this paper, a seamless acquisition oscilloscope without dead time is proposed. In this oscilloscope, three-dimensional waveform mapping (TWM) technique, which converts sampled data to displayed waveform, is proposed. With this technique, not only the process speed is improved, but also the probability information of waveform is displayed with different brightness. Thus, a three-dimensional waveform is shown to the user. To reduce processing time further, parallel TWM which processes several sampled points simultaneously, and dual-port random access memory based pipelining technique which can process one sampling point in one clock period are proposed. Furthermore, two DDR3 (Double-Data-Rate Three Synchronous Dynamic Random Access Memory) are used for storing sampled data alternately, thus the acquisition can continue during data processing. Therefore, the dead time of DSO is eliminated. In addition, a double-pulse test method is adopted to test the waveform capturing rate (WCR) of the oscilloscope and a combined pulse test method is employed to evaluate the oscilloscope's capture ability comprehensively. The experiment results show that the WCR of the designed oscilloscope is 6,250,000 wfms/s (waveforms per second), the highest value in all existing oscilloscopes. The testing results also prove that there is no dead time in our oscilloscope, thus realizing the seamless acquisition. PMID- 24784655 TI - An automated thermophoretic soot sampling device for laboratory-scale high pressure flames. AB - Studying soot particle morphology in high-pressure flames via thermophoretic sampling critically depends on sampling precision, speed, and reproducibility. This is mainly limited by the challenges of applying pneumatically driven devices for burner chamber pressures higher than the pneumatic pressure. We present a pneumatically driven device for high-pressure applications up to 90 bars. The novelty is to separate the pneumatic driver section from the high-pressure environment in the burner chamber. The device was tested by sampling soot from a laminar high-pressure flame at 20 bars. PMID- 24784656 TI - Design of voice coil motor dynamic focusing unit for a laser scanner. AB - Laser scanning systems have been used for material processing tasks such as welding, cutting, marking, and drilling. However, applications have been limited by the small range of motion and slow speed of the focusing unit, which carries the focusing optics. To overcome these limitations, a dynamic focusing system with a long travel range and high speed is needed. In this study, a dynamic focusing unit for a laser scanning system with a voice coil motor (VCM) mechanism is proposed to enable fast speed and a wide focusing range. The VCM has finer precision and higher speed than conventional step motors and a longer travel range than earlier lead zirconium titanate actuators. The system has a hollow configuration to provide a laser beam path. This also makes it compact and transmission-free and gives it low inertia. The VCM's magnetics are modeled using a permeance model. Its design parameters are determined by optimization using the Broyden-Fletcher-Goldfarb-Shanno method and a sequential quadratic programming algorithm. After the VCM is designed, the dynamic focusing unit is fabricated and assembled. The permeance model is verified by a magnetic finite element method simulation tool, Maxwell 2D and 3D, and by measurement data from a gauss meter. The performance is verified experimentally. The results show a resolution of 0.2 MUm and travel range of 16 mm. These are better than those of conventional focusing systems; therefore, this focusing unit can be applied to laser scanning systems for good machining capability. PMID- 24784657 TI - Algorithm to optimize transient hot-wire thermal property measurement. AB - The transient hot-wire method has been widely used to measure the thermal conductivity of fluids. The ideal working equation is based on the solution of the transient heat conduction equation for an infinite linear heat source assuming no natural convection or thermal end effects. In practice, the assumptions inherent in the model are only valid for a portion of the measurement time. In this study, an algorithm was developed to automatically select the proper data range from a transient hot-wire experiment. Numerical simulations of the experiment were used in order to validate the algorithm. The experimental results show that the developed algorithm can be used to improve the accuracy of thermal conductivity measurements. PMID- 24784658 TI - Design and test of a flat-top magnetic field system driven by capacitor banks. AB - An innovative method for generating a flat-top pulsed magnetic field by means of capacitor banks is developed at the Wuhan National High Magnetic Field Center (WHMFC). The system consists of two capacitor banks as they are normally used to generate a pulsed field. The two discharge circuits (the magnet circuit and the auxiliary circuit) are coupled by a pulse transformer such that the electromotive force (EMF) induced via the transformer in the magnet circuit containing the magnet coil is opposed to the EMF of the capacitor bank. At a certain point before the current pulse in the coil reaches its peak, the auxiliary circuit is triggered. With optimized parameters for charging voltage and trigger delay, the current in the magnet circuit can be approximately kept constant to obtain a flat top. A prototype was developed at the WHMFC; the magnet circuit was energized by seven 1 MJ (3.2 mF/25 kV) capacitor modules and the auxiliary circuit by four 1 MJ modules. Fields up to 41 T with 6 ms flat-top have been obtained with a conventional user magnet used at the WHMFC. PMID- 24784659 TI - High-accuracy direct ZT and intrinsic properties measurement of thermoelectric couple devices. AB - Advances in thermoelectric materials in recent years have led to significant improvements in thermoelectric device performance and thus, give rise to many new potential applications. In order to optimize a thermoelectric device for specific applications and to accurately predict its performance ideally the material's figure of merit ZT as well as the individual intrinsic properties (Seebeck coefficient, electrical resistivity, and thermal conductivity) should be known with high accuracy. For that matter, we developed two experimental methods in which the first directly obtains the ZT and the second directly measures the individual intrinsic leg properties of the same p/n-type thermoelectric couple device. This has the advantage that all material properties are measured in the same sample direction after the thermoelectric legs have been mounted in the final device. Therefore, possible effects from crystal anisotropy and from the device fabrication process are accounted for. The Seebeck coefficients, electrical resistivities, and thermal conductivities are measured with differential methods to minimize measurement uncertainties to below 3%. The thermoelectric couple ZT is directly measured with a differential Harman method which is in excellent agreement with the calculated ZT from the individual leg properties. The errors in both the directly measured and calculated thermoelectric couple ZT are below 5% which is significantly lower than typical uncertainties using commercial methods. Thus, the developed technique is ideal for characterizing assembled couple devices and individual thermoelectric materials and enables accurate device optimization and performance predictions. We demonstrate the methods by measuring a p/n-type thermoelectric couple device assembled from commercial bulk thermoelectric Bi2Te3 elements in the temperature range of 30 degrees C-150 degrees C and discuss the performance of the couple thermoelectric generator in terms of its efficiency and materials' self compatibility. PMID- 24784660 TI - Impact of parasitic thermal effects on thermoelectric property measurements by Harman method. AB - Harman method is a rapid and simple technique to measure thermoelectric properties. However, its validity has been often questioned due to the over simplified assumptions that this method relies on. Here, we quantitatively investigate the influence of the previously ignored parasitic thermal effects on the Harman method and develop a method to determine an intrinsic ZT. We expand the original Harman relation with three extra terms: heat losses via both the lead wires and radiation, and Joule heating within the sample. Based on the expanded Harman relation, we use differential measurement of the sample geometry to measure the intrinsic ZT. To separately evaluate the parasitic terms, the measured ZTs with systematically varied sample geometries and the lead wire types are fitted to the expanded relation. A huge discrepancy (~28%) of the measured ZTs depending on the measurement configuration is observed. We are able to separately evaluate those parasitic terms. This work will help to evaluate the intrinsic thermoelectric property with Harman method by eliminating ambiguities coming from extrinsic effects. PMID- 24784661 TI - Enhanced reaction rates in NDP analysis with neutron scattering. AB - Neutron depth profiling (NDP) makes accessible quantitative information on a few isotopic concentration profiles ranging from the surface into the sample a few micrometers. Because the candidate analytes for NDP are few, there is little interference encountered. Furthermore, neutrons have no charge so mixed chemical states in the sample are of no direct concern. There are a few nuclides that exhibit large probabilities for neutron scattering. The effect of neutron scattering on NDP measurements has not previously been evaluated as a basis for either enhancing the reaction rates or as a source of measurement error. Hydrogen is a common element exhibiting large neutron scattering probability found in or around sample volumes being analyzed by NDP. A systematic study was conducted to determine the degree of signal change when neutron scattering occurs during analysis. The relative signal perturbation was evaluated for materials of varied neutron scattering probability, concentration, total mass, and geometry. Signal enhancements up to 50% are observed when the hydrogen density is high and in close proximity to the region of analysis with neutron beams of sub thermal energies. Greater signal enhancements for the same neutron number density are reported for thermal neutron beams. Even adhesive tape used to position the sample produces a measureable signal enhancement. Because of the shallow volume, negligible distortion of the NDP measured profile shape is encountered from neutron scattering. PMID- 24784662 TI - Measurement method for roll angular displacement with a high resolution by using diffraction gratings and a heterodyne interferometer. AB - The roll angle measurement is difficult to be achieved directly using a typical commercial interferometer due to its low sensitivity in axial direction, where the axial direction is orthogonal to the plane of the roll angular displacement. A roll angle measurement method combined diffraction gratings with a laser heterodyne interferometer is discussed in this paper. The diffraction grating placed in the plane of a roll angular displacement and the interferometer arranged in the plane's orthogonal direction, constitute the measurement pattern for the roll angle with high resolution. The roll angular displacement, considered as the linear, can be tested precisely when the corresponding angle is very small. Using the proposed method, the angle roll measurement obtains the high resolution of 0.002". Experiment has proved its feasibility and practicability. PMID- 24784663 TI - Thermal desorption mass spectrometer for mass metrology. AB - This article presents a device for the study of physisorbed elements on polished surfaces (diameter ?56 mm) of the kind used in mass metrology. The technique is based on mass spectrometry of molecules desorbed after heating under vacuum of the analyzed surface. We describe a first application of the device to study current and future mass standards in order to understand how their surface reactivity depends on storage conditions, cleaning processes, and polishing methods. Surface contamination analysis by thermal desorption mass spectrometry to examine the effect of cleaning on pure iridium is given as an example. PMID- 24784664 TI - Free-flight measurement technique in the free-piston high-enthalpy shock tunnel. AB - A novel multi-component force-measurement technique has been developed and implemented at the impulse facility JAXA-HIEST, in which the test model is completely unrestrained during the test and thus experiences free-flight conditions for a period on the order of milliseconds. Advantages over conventional free-flight techniques include the complete absence of aerodynamic interference from a model support system and less variation in model position and attitude during the test itself. A miniature on-board data recorder, which was a key technology for this technique, was also developed in order to acquire and store the measured data. The technique was demonstrated in a HIEST wind-tunnel test campaign in which three-component aerodynamic force measurement was performed on a blunted cone of length 316 mm, total mass 19.75 kg, and moment of inertia 0.152 kgm(2). During the test campaign, axial force, normal forces, and pitching moment coefficients were obtained at angles of attack from 14 degrees to 32 degrees under two conditions: H0 = 4 MJ/kg, P0 = 14 MPa; and H0 = 16 MJ/kg, P0 = 16 MPa. For the first, low-enthalpy condition, the test flow was considered a perfect gas; measurements were thus directly compared with those obtained in a conventional blow-down wind tunnel (JAXA-HWT2) to evaluate the accuracy of the technique. The second test condition was a high-enthalpy condition in which 85% of the oxygen molecules were expected to be dissociated; high-temperature real-gas effects were therefore evaluated by comparison with results obtained in perfect-gas conditions. The precision of the present measurements was evaluated through an uncertainty analysis, which showed the aerodynamic coefficients in the HIEST low enthalpy test agreeing well with those of JAXA-HWT2. The pitching-moment coefficient, however, showed significant differences between low- and high-enthalpy tests. These differences are thought to result from high-temperature real-gas effects. PMID- 24784665 TI - A comparison of four direct geometry time-of-flight spectrometers at the Spallation Neutron Source. AB - The Spallation Neutron Source at Oak Ridge National Laboratory now hosts four direct geometry time-of-flight chopper spectrometers. These instruments cover a range of wave-vector and energy transfer space with varying degrees of neutron flux and resolution. The regions of reciprocal and energy space available to measure at these instruments are not exclusive and overlap significantly. We present a direct comparison of the capabilities of this instrumentation, conducted by data mining the instrument usage histories, and specific scanning regimes. In addition, one of the common science missions for these instruments is the study of magnetic excitations in condensed matter systems. We have measured the powder averaged spin wave spectra in one particular sample using each of these instruments, and use these data in our comparisons. PMID- 24784666 TI - Fast, multi-channel real-time processing of signals with microsecond latency using graphics processing units. AB - Fast, digital signal processing (DSP) has many applications. Typical hardware options for performing DSP are field-programmable gate arrays (FPGAs), application-specific integrated DSP chips, or general purpose personal computer systems. This paper presents a novel DSP platform that has been developed for feedback control on the HBT-EP tokamak device. The system runs all signal processing exclusively on a Graphics Processing Unit (GPU) to achieve real-time performance with latencies below 8 MUs. Signals are transferred into and out of the GPU using PCI Express peer-to-peer direct-memory-access transfers without involvement of the central processing unit or host memory. Tests were performed on the feedback control system of the HBT-EP tokamak using forty 16-bit floating point inputs and outputs each and a sampling rate of up to 250 kHz. Signals were digitized by a D-TACQ ACQ196 module, processing done on an NVIDIA GTX 580 GPU programmed in CUDA, and analog output was generated by D-TACQ AO32CPCI modules. PMID- 24784667 TI - A field-programmable-gate-array based time digitizer for the time-of-flight mass spectrometry. AB - The time-of-flight (TOF) mass spectrometry is one of the most widely used techniques to get information about the composition and structure of compounds. The time digitizer, based on time-to-digital conversion, is one of the important parts in modern TOF mass spectrometry, which is often implemented with analog circuitry or application-specific-integrated-circuit (ASIC) devices. However, it is difficult to achieve a high density with the analog approach. Furthermore, ASIC requires a long design cycle and the function cannot be easily revised for different applications. In this work, we present a highly flexible, accurate, yet low-costing design of time digitizer which is based on a field-programmable-gate array (FPGA) and time interpolation method. Test results indicate that the bin size of this time digitizer is 390 ps with an average standard deviation (about 150 ps). The differential nonlinearity is in the range of -0.10 to +0.05 LSB (least significant bit), and the measurement time range is larger than 107 s. Compared with other techniques, it reduces the system complexity while providing a good flexibility. In addition, this technique can also accommodate one or more STOP pulse measurements for each START pulse reference, enabling measurement of multiple times-of-flight with a common start trigger. Besides, a time stamp is recorded for each input pulse, rendering this time digitizer versatile in other applications. Moreover, because of the programmable characteristic of a FPGA, more functions can be integrated in the time digitizer, such as a trigger function, data transfer interface; the parameters such as the number of the channels. The measurement range can also be modified according to different requirements. PMID- 24784668 TI - Measurement of coherence length and incoherent source size of hard x-ray undulator beamline at Pohang Light Source-II. AB - We measured the spatial coherence length and incoherent source size of a hard x ray undulator beamline at Pohang Light Source-II, the stored electron energy of which has been increased from 2.5 GeV to 3 GeV. The coherence length was determined by single-slit measurement of the visibility of the Fresnel diffraction pattern. The correlated incoherent source size was cross-checked for three different optics: the single slit, beryllium parabolic compound refractive lenses, and the Fresnel zone plate. We concluded that the undulator beamline has an effective incoherent source size (FWHM) of 540 MUm (horizontal) * 50 MUm (vertical). PMID- 24784669 TI - Sustainable energy at the 100 W level for scientific sites on the Antarctic Plateau: lessons learned from the Polar Experiment Network for Geospace Upper atmosphere Investigations-Automatic Geophysical Observatory project. AB - The need to provide power to unmanned instrumentation over the course of an entire year on the Antarctic plateau presents a large number of engineering and logistical challenges. Designs formulated in ideal laboratory environments often fail in the Antarctic due to the harsh operating conditions, and field experience is necessary to achieve year-round operation in the 100 W power range. In this paper we present our current power design for the Automatic Geophysical Observatories; a design based on over two decades of experience on the ice and allows for relatively continuous operation at the aforementioned power level. We also discuss our various implementation methods, both failures and successes, in an effort assist other unmanned deployments on the ice. PMID- 24784671 TI - A new dual-plate slipometer for measuring slip between molten polymers and extrusion die materials. AB - In this work, we study the slip behaviors common to plastics die extrusion metals or platings using a new instrument called a dual-plate slipometer. By dual-plate, we mean that whereas the stationary plate incorporates a local shear stress transducer, the moving plate does not. The stationary plate and transducer are made of one stainless steel, but the moving plate is made from, or plated with, different extrusion die materials under study. This new instrument allows slip velocity to be measured without having to build a new shear stress transducer from each extrusion metal or plating under study. We explore the effect of extrusion die composition and die metal surface morphology on the slip properties of polyolefins using a sliding plate rheometer. In this work, we studied the slip behaviors of polyolefins on four common plastics die extrusion metals or platings, without having to build a new shear stress transducer from each. Specifically, our new method replaces the moving plate; with each of the four die metals or platings under study without changing the stainless steel material of the shear stress transducer and its stationary plate. Our experiments include high-density polyethylene, low-density polyethylene, and polypropylene (PP) on four different die metals or platings. We use steady simple shear to obtain shear stress versus nominal shear rate for different gaps, from which we can then deduce the slip velocity using the Mooney analysis. We then fit four slip models to our experimental measurements, and we find the Hatzikiriakos hyperbolic sine model to be accurate, even for the measured inflections in the slip velocity as a function of shear stress curves. Our analysis includes detailed characterization of the die metal plating surfaces, including measurements of the composition of the sliding plates by energy dispersive spectroscopy, surface energy by contact angle goniometry, and surface roughness by both white light interference and stylus profilometries. We use our slip measurements to evaluate the Allal-Vergnes equation for the critical shear stress for slip [A. Allal and B. Vergnes, "Effect of die surface on the onset of stick-slip transition in the flow of molten linear polymers," J. Non-Newtonian Fluid Mech. 167-168, 46-49 (2012)]. We conclude our analysis by dedimensionalizing slip, and we then use these dimensionless groups to analyze slip. This paper provides a set of reference data for extrusion die designers for polyolefins. PMID- 24784670 TI - ADL ORVIS: an air-delay-leg, line-imaging optically recording velocity interferometer system. AB - An interferometry system that enables acquisition of spatially resolved velocity time profiles with very high velocity sensitivity has been designed and applied to two diverse, instructive experimental problems: (1) measurement of low amplitude reverberations in laser-driven flyer plates and (2) measurement of ramp wave profiles in symmetric impact studies of fused silica. The delay leg in this version of a line-imaging optically recording velocity interferometer system (ORVIS) consists of a long air path that includes relay optics to transmit the optical signal through the interferometer cavity. Target image quality from the delay path at the image recombination plane is preserved by means of a compact and flexible optical design utilizing two parabolic reflectors (serving as the relay optics) in a folded path. With an instrument tuned to a velocity per fringe constant of 22.4 m s(-1) fringe(-1), differences of 1-2 m s(-1) across the probe line segment can be readily distinguished. Measurements that capture small spatial variations in flyer velocity are presented and briefly discussed. In the fused silica impact experiments, the ramp-wave profile observed by this air-delay instrument compares favorably to the profile recorded simultaneously by a conventional line-imaging ORVIS. PMID- 24784672 TI - An experimental technique of split Hopkinson pressure bar using fiber micro displacement interferometer system for any reflector. AB - A novel non-contact measurement technique had been developed for the mechanical properties of materials in Split Hopkinson Pressure Bars (SHPB). Instead of the traditional strain gages mounted on the surfaces of bars, two shutters were mounted on the end of bars to directly measure interfacial velocity using Fiber Micro-Displacement Interferometer System for Any Reflector. Using the new technique, the integrated stress-strain responses could be determined. The experimental technique was validated by SHPB test simulation. The technique had been used to investigate the dynamic response of a brittle explosive material. The results showed that the new experimental technique could be applied to the dynamic behavior in SHPB test. PMID- 24784673 TI - Ultraviolet digital image correlation (UV-DIC) for high temperature applications. AB - A method is presented for extending two-dimensional digital image correlation (DIC) to a higher range of temperatures by using ultraviolet (UV) lights and UV optics to minimize the light emitted by specimens at those temperatures. The method, which we refer to as UV-DIC, is compared against DIC using unfiltered white light and DIC using filtered blue light which in the past have been used for high temperature applications. It is shown that at low temperatures for which sample glowing is not an issue all three methods produce the same results. At higher temperatures in our experiments, the unfiltered white light method showed significant glowing between 500 and 600 degrees C and the blue light between 800 and 900 degrees C, while the UV-DIC remained minimally affected until the material began nearing its melting point (about 1260 degrees C). The three methods were then used to obtain the coefficient of thermal expansion as a function of temperature for the nickel superalloy Hastelloy-X. All three methods give similar coefficients at temperatures below which glowing becomes significant, with the values also being comparable to the manufacturers specifications. Similar results were also seen in uniaxial tension tests. PMID- 24784674 TI - Development of an electrochemical micromachining instrument for the confined etching techniques. AB - This study proposes an electrochemical micromachining instrument for two confined etching techniques, namely, confined etchant layer technique (CELT) and electrochemical wet stamping (E-WETS). The proposed instrument consists of a granite bridge base, a Z-axis coarse/fine dual stage, and a force sensor. The Z axis coarse/fine dual stage controls the vertical movement of the substrate with nanometer accuracy. The force sensor measures the contact force between the mold and the substrate. A contact detection method based on a digital lock-in amplifier is developed to make the mold-substrate contact within a five-nanometer range in CELT, and a force feedback controller is implemented to keep the contact force in E-WETS at a constant value with a noise of less than 0.2 mN. With the use of the confined etching techniques, a microlens array and a curvilinear ridge microstructure are successfully fabricated with high accuracy, thus demonstrating the promising performance of the proposed micromachining instrument. PMID- 24784675 TI - Isothermal method for hydrate studies using a transparent variable volume cell. AB - The measurements of hydrate dissociation points are generally achieved using the well-established isochoric method. This method implies determination of the total pressure of the system under study, as a function of temperature. It is quite time consuming, especially at higher pressures. Working at higher pressures requires equilibrium cells with thicker walls, which compromises on fast heat exchange. The use of a variable volume cell is therefore quite attractive as it allows for the measurements of hydrate dissociation pressure under isothermal conditions. This paper describes a transparent variable volume cell used for efficient and rapid measurements via the isothermal procedure. PMID- 24784676 TI - An optically modulated zero-field atomic magnetometer with suppressed spin exchange broadening. AB - We demonstrate an optically pumped (87)Rb magnetometer in a microfabricated vapor cell based on a zero-field dispersive resonance generated by optical modulation of the (87)Rb ground state energy levels. The magnetometer is operated in the spin-exchange relaxation-free regime where high magnetic field sensitivities can be achieved. This device can be useful in applications requiring array-based magnetometers where radio frequency magnetic fields can induce cross-talk among adjacent sensors or affect the source of the magnetic field being measured. PMID- 24784677 TI - Nonlinear characterization of a single-axis acoustic levitator. AB - The nonlinear behavior of a 20.3 kHz single-axis acoustic levitator formed by a Langevin transducer with a concave radiating surface and a concave reflector is experimentally investigated. In this study, a laser Doppler vibrometer is applied to measure the nonlinear sound field in the air gap between the transducer and the reflector. Additionally, an electronic balance is used in the measurement of the acoustic radiation force on the reflector as a function of the distance between the transducer and the reflector. The experimental results show some effects that cannot be described by the linear acoustic theory, such as the jump phenomenon, harmonic generation, and the hysteresis effect. The influence of these nonlinear effects on the acoustic levitation of small particles is discussed. PMID- 24784678 TI - Four-probe measurements with a three-probe scanning tunneling microscope. AB - We present an ultrahigh vacuum (UHV) three-probe scanning tunneling microscope in which each probe is capable of atomic resolution. A UHV JEOL scanning electron microscope aids in the placement of the probes on the sample. The machine also has a field ion microscope to clean, atomically image, and shape the probe tips. The machine uses bare conductive samples and tips with a homebuilt set of pliers for heating and loading. Automated feedback controlled tip-surface contacts allow for electrical stability and reproducibility while also greatly reducing tip and surface damage due to contact formation. The ability to register inter-tip position by imaging of a single surface feature by multiple tips is demonstrated. Four-probe material characterization is achieved by deploying two tips as fixed current probes and the third tip as a movable voltage probe. PMID- 24784679 TI - Note: large area deposition of Rh single and Rh/W/Cu multilayer thin films on stainless steel substrate by pulsed laser deposition technique. AB - Mirror like thin films of single layer Rh and multilayer Rh/W/Cu are deposited on highly polished 50 mm diameter stainless steel substrate by Pulsed Laser Deposition (PLD) technique for first mirror application in fusion reactors. For this, the conventional PLD technique has been modified by incorporating substrate rastering stage for large area deposition via PLD. Process optimization to achieve uniformity of deposition as estimated from fringe visibility and thickness is also discussed. PMID- 24784680 TI - Note: a Piezo Tip/Tilt Platform: structure, kinematics, and experiments. AB - A Piezo Tip/Tilt Platform (PT(2)P) is presented with its structure, kinematics, and preliminary experiments. Two essential models of the presented PT(2)P, an equivalent hinge of the flexure hinge and a simplified model of the transmission mechanism, are discussed with the analysis on the structure of the PT(2)P. Based on these models, the inverse kinematics of the PT(2)P is derived. Two experiments are conducted on a prototype of the PT(2)P. The kinematic model is verified with experimental results, which also indicate that the resolution and the repeatability of the PT(2)P is, respectively, better than 0.50 MUrad and 0.25 MUrad. PMID- 24784681 TI - Note: laser beam scanning using a ferroelectric liquid crystal spatial light modulator. AB - In this work we describe laser beam scanning using a ferroelectric liquid crystal spatial light modulator. Commercially available ferroelectric liquid crystal spatial light modulators are capable of displaying 85 colored images in 1 s using a time dithering technique. Each colored image, in fact, comprises 24 single bit (black and white) images displayed sequentially. We have used each single bit image to write a binary phase hologram. For a collimated laser beam incident on the hologram, one of the diffracted beams can be made to travel along a user defined direction. We have constructed a beam scanner employing the above arrangement and demonstrated its use to scan a single laser beam in a laser scanning optical sectioning microscope setup. PMID- 24784682 TI - Note: efficient generation of optical sidebands at GHz with a high-power tapered amplifier. AB - Two methods using a laser-diode tapered amplifier to produce high-power, high efficiency optical frequency sidebands over a wide tunable frequency range are studied and compared. For a total output of 500 mW at 811 nm, 20% of the power can be placed in each of the first-order sidebands. Functionality and characterization are presented within the sideband frequency region of 0.8-2.3 GHz, and it is shown that both methods can be applied beyond this frequency range. These methods provide a versatile and effective tool for atomic physics experiments. PMID- 24784683 TI - Note: deep ultraviolet Raman spectrograph with the laser excitation line down to 177.3 nm and its application. AB - Deep UV Raman spectrograph with the laser excitation line down to 177.3 nm was developed in this laboratory. An ellipsoidal mirror and a dispersed-subtractive triple monochromator were used to collect and disperse Raman light, respectively. The triple monochromator was arranged in a triangular configuration with only six mirrors used. 177.3 nm laser excited Raman spectrum with cut-off wavenumber down to 200 cm(-1) and spectral resolution of 8.0 cm(-1) can be obtained under the condition of high purity N2 purging. With the C-C sigma bond in Teflon selectively excited by the 177.3 nm laser, resonance Raman spectrum of Teflon with good quality was recorded on the home-built instrument and the sigma sigma(*) transition of C-C bond was studied. The result demonstrates that deep UV Raman spectrograph is powerful for studying the systems with electronic transition located in the deep UV region. PMID- 24784684 TI - Note: application of UF-4 emulsion films to detect low-energy ions from plasmas produced by laser ablation. AB - Detection of low-energy ions via Thomson parabola mass analyzer in the absence of any additional electrical systems is examined. Numerous low-energy ions were recorded on UF-4 solid state emulsion films. Kinetic energies between 1 and 4 keV of ions generated by YAG laser focused on Al and Ti targets were obtained using Thomson parabola measurements. Characteristics of ion tracks on the UF-4 detector are discussed in terms of pressure ranges of vacuum chamber. Moreover, differences in charges of ions between this study and previous spectroscopic measurements are discussed. PMID- 24784685 TI - Note: nonlinear susceptibility from high DC field torque magnetometry. AB - Torque magnetometry is a convenient technique to measure the magnetic properties of anisotropic materials. Advances in micromachining have made torque magnetometers precise and reliable even in adverse conditions such as very high magnetic fields and very low temperatures. In most applications with such magnetometers the measured torque signals are used to arrive at the linear magnetic susceptibility. In this short note we extend torque magnetometry to measure nonlinear susceptibilities and illustrate our methods with representative data on the heavy fermion compound UPt3. PMID- 24784686 TI - Note: neutron bang time diagnostic system on Shenguang-III prototype. AB - A neutron bang time (NBT) diagnostic system has been implemented on Shenguang-III prototype. The bang time diagnostic system is based on a sensitive fusion neutron detector, which consists of a plastic scintillator and a micro-channel plate photomultiplier tube (PMT). An optical fiber bundle is used to couple the scintillator and the PMT. The bang time system is able to measure bang time above a neutron yield of 10(7). Bang times and start time of laser were related by probing x-ray pulses produced by 200 ps laser irradiating golden targets. Timing accuracy of the NBT is better than 60 ps. PMID- 24784687 TI - Note: application of a pixel-array area detector to simultaneous single crystal X ray diffraction and X-ray absorption spectroscopy measurements. AB - X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS) are two main x ray techniques in synchrotron radiation facilities. In this Note, we present an experimental setup capable of performing simultaneous XRD and XAS measurements by the application of a pixel-array area detector. For XRD, the momentum transfer in specular diffraction was measured by scanning the X-ray energy with fixed incoming and outgoing x-ray angles. By selecting a small fixed region of the detector to collect the XRD signal, the rest of the area was available for collecting the x-ray fluorescence for XAS measurements. The simultaneous measurement of XRD and X-ray absorption near edge structure for Pr0.67Sr0.33MnO3 film was demonstrated as a proof of principle for future time-resolved pump-probe measurements. A static sample makes it easy to maintain an accurate overlap of the X-ray spot and laser pump beam. PMID- 24784688 TI - Note: a novel vacuum ultraviolet light source assembly with aluminum-coated electrodes for enhancing the ionization efficiency of photoionization mass spectrometry. AB - A novel vacuum ultraviolet (VUV) light source assembly (VUVLSA) for enhancing the ionization efficiency of photoionization mass spectrometer has been described. The VUVLSA composes of a Krypton lamp and a pair of disk electrodes with circular center cavities. The two interior surfaces that face the photoionization region were aluminum-coated. VUV light can be reflected back and forth in the photoionization region between the electrodes, thus the photoionization efficiency can be greatly enhanced. The performances of two different shaped electrodes, the coated double flat electrodes (DFE), and double conical electrodes, were studied. We showed that the signal amplification of coated DFE is around 4 times higher than that of uncoated electrodes without VUV light reflection. The relationship between the pressure of ionization chamber and mass signal enhancement has also been studied. PMID- 24784689 TI - Note: switching crosstalk on and off in Kelvin Probe Force Microscopy. AB - In Kelvin Probe Force Microscopy (KPFM) electronic crosstalk can occur between the excitation signal and probe deflection signal. Here, we demonstrate how a small modification to our commercial instrument enables us to literally switch the crosstalk on and off. We study in detail the effect of crosstalk on open-loop KPFM and compare with closed-loop KPFM. We measure the pure crosstalk signal and verify that we can correct for it in the data-processing required for open-loop KPFM. We also demonstrate that open-loop KPFM results are independent of the frequency and amplitude of the excitation signal, provided that the influence of crosstalk has been eliminated. PMID- 24784690 TI - Note: computational estimation of sparkgap inductance in nitrogen medium. AB - In this Note, attempt has been made to analytically derive the inductance of a sparkgap arc channel using fundamental circuit theory, heat transfer theory, and gas plasma equations. Simulation of a picosecond phenomenon of arc channel formation is attempted using coupled codes. Arc channel is assumed to be cylindrical and modeled as finite number of small coaxial cylinders filled with gas plasma. Conductivity of each gas plasma cylinder is found by its temperature. Current distribution in the cylinders is calculated using circuit theory and change in the current distribution with time is simulated. Over all inductance of the arc channel is computed for the current density distribution. Simulation is done for fast sub-nanosecond rising pulse. Experiments are conducted to measure the arc channel inductance and validate the same with the value found using computation. PMID- 24784691 TI - Note: a novel method to measure the deformation of diamond anvils under high pressure. AB - A novel and simple method based on optical-fiber frequency domain interferometer to measure the deformation of diamond anvils under high pressure is presented. The working principle and application examples are given in this paper. The deformation of diamond anvils is obtained up to 37.7 GPa, our results verify that the deformation has an obvious difference between uploading and downloading at a given pressure, the maximum difference is up to 4.5 MUm at 18.8 GPa, and the cupping effect is observed directly. PMID- 24784692 TI - Note: error elimination for ellipsometry by laser feedback instrument. AB - Ellipsometry has in recent decades been used in measuring optical phase retardation. Known for its high resolution but uncertain accuracy, we analyze the systematic error involved with this technique and give error values regarding phase retardation measurements. We developed a laser-feedback assembly to measure phase retardation to a higher resolution and accuracy compared with that from ellipsometry. We eliminated the systematic error associated with ellipsometry using results obtained with this assembly and improved measurement accuracies for ellipsometry to about 0.2 degrees . Such high-precision ellipsometry would greatly improve the manufacturing of wave plates. PMID- 24784698 TI - Inhaled budesonide and oral dexamethasone prevent acute mountain sickness. AB - BACKGROUND: This double-blind, randomized controlled trial aimed to investigate inhaled budesonide and oral dexamethasone compared with placebo for their prophylactic efficacy against acute mountain sickness after acute high-altitude exposure. METHODS: There were 138 healthy young male lowland residents recruited and randomly assigned to receive inhaled budesonide (200 MUg, twice a day [bid]), oral dexamethasone (4 mg, bid), or placebo (46 in each group). They traveled to 3900 m altitude from 400 m by car. Medication started 1 day before high-altitude exposure and continued until the third day of exposure. Primary outcome measure was the incidence of acute mountain sickness after exposure. RESULTS: One hundred twenty-four subjects completed the study (42, 39, and 43 in the budesonide, dexamethasone, and placebo groups, respectively). Demographic characteristics were comparable among the 3 groups. After high-altitude exposure, significantly fewer participants in the budesonide (23.81%) and dexamethasone (30.77%) groups developed acute mountain sickness compared with participants receiving placebo (60.46%) (P = .0006 and P = .0071, respectively). Both the budesonide and dexamethasone groups had lower heart rate and higher pulse oxygen saturation (SpO2) than the placebo group at altitude. Only the budesonide group demonstrated less deterioration in forced vital capacity and sleep quality than the placebo group. Four subjects in the dexamethasone group reported adverse reactions. CONCLUSIONS: Both inhaled budesonide (200 MUg, bid) and oral dexamethasone (4 mg, bid) were effective for the prevention of acute mountain sickness, especially its severe form, compared with placebo. Budesonide caused fewer adverse reactions than dexamethasone. PMID- 24784699 TI - Quantifying human sensitivity to spatio-temporal information in dynamic faces. AB - A great deal of perceptual and social information is conveyed by facial motion. Here, we investigated observers' sensitivity to the complex spatio-temporal information in facial expressions and what cues they use to judge the similarity of these movements. We motion-captured four facial expressions and decomposed them into time courses of semantically meaningful local facial actions (e.g., eyebrow raise). We then generated approximations of the time courses which differed in the amount of information about the natural facial motion they contained, and used these and the original time courses to animate an avatar head. Observers chose which of two animations based on approximations was more similar to the animation based on the original time course. We found that observers preferred animations containing more information about the natural facial motion dynamics. To explain observers' similarity judgments, we developed and used several measures of objective stimulus similarity. The time course of facial actions (e.g., onset and peak of eyebrow raise) explained observers' behavioral choices better than image-based measures (e.g., optic flow). Our results thus revealed observers' sensitivity to changes of natural facial dynamics. Importantly, our method allows a quantitative explanation of the perceived similarity of dynamic facial expressions, which suggests that sparse but meaningful spatio-temporal cues are used to process facial motion. PMID- 24784700 TI - Salient stimulus attracts focus of peri-saccadic mislocalization. AB - Visual localization during saccadic eye movements is prone to error. Flashes shortly before and after the onset of saccades are usually perceived to shift towards the saccade target, creating a "compression" pattern. Typically, the saccade landing point coincides with a salient saccade target. We investigated whether the mislocalization focus follows the actual saccade landing point or a salient stimulus. Subjects made saccades to either a target or a memorized location without target. In some conditions, another salient marker was presented between the initial fixation and the saccade landing point. The experiments were conducted on both black and picture backgrounds. The results show that: (a) when a saccade target or a marker (spatially separated from the saccade landing point) was present, the compression pattern of mislocalization was significantly stronger than in conditions without them, for both black and picture background conditions, and (b) the mislocalization focus tended towards the salient stimulus regardless of whether it was the saccade target or the marker. Our results suggest that a salient stimulus presented in the scene may have an attracting effect and therefore contribute to the non-uniformity of saccadic mislocalization of a probing flash. PMID- 24784701 TI - Neglected leptospirosis in raccoons (Procyon lotor) in Indiana, USA. AB - BACKGROUND: Leptospirosis is a globally important zoonotic disease occurring clinically and subclinically in humans and animals. OBJECTIVES: To determine whether raccoons in Indiana carried leptospires in their kidneys. ANIMALS AND METHODS: Thirty-four raccoons were live-trapped from two forest patches in central Indiana. Following euthanasia, a portion of kidney (2 cm(2)) from each raccoon was homogenized and used for leptospiral culture. Leptospiral cultures were subjected to DNA extraction and various polymerase chain reaction (PCR) procedures reported previously. Serum sample from each raccoon was collected and antibody titers to leptospiral serovars were determined by microscopic agglutination test (MAT). RESULTS: All leptospiral cultures were positive for Leptospira by various PCR procedures. The PCR with the primers targeting the conservative region of LipL32 gene was the most sensitive PCR in the detection of pathogenic leptospires. The variable LipL32 PCR amplicons were sequenced and compared to the reference strains available in GenBank. Twelve kidney cultures had Leptospira interrogans, eight had Leptospira kirschneri and two had Leptospira borgpetersenii. They were predominantly Grippotyphosa serogroup. Antileptospire antibodies were detected in 16 out of 34 raccoons (47.1%) by MAT. There were titers >= 1:80 in 16 raccoons (47.1%) and titers >= 1:400 in 3 raccoons (8.8%). The highest leptospiral serovar-specific seroreactivity among 34 raccoons was L. interrogans Bratislava (38.2%) and L. interrogans Grippotyphosa (32.4%). CONCLUSIONS: Raccoons in Indiana carry leptospiral organisms in kidneys and the leptospires are predominantly L. interrogans species and of the Grippotyphosa serogroup. CLINICAL IMPORTANCE: The raccoons serve as reservoir hosts that exposure sources to wildlife, livestock, pets and humans. PMID- 24784702 TI - Goshajinkigan, a traditional Japanese medicine, prevents oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels in rat. AB - The acute peripheral neuropathy induced by oxaliplatin treatment occurs very frequently and is aggravated by exposure to cold. Goshajinkigan (GJG), a traditional Japanese (kampo) medicine, was recently shown to be effective against oxaliplatin-induced acute neuropathy. However, because the effects of GJG and its mechanism in relation to those of its ingredients and its mechanism are not well understood, we examined the effects of GJG on acute neuropathy. Further, we investigated whether GJG affects the functions and gene expressions of transient receptor potential (TRP) channels using a rat model of oxaliplatin-induced neuropathy. Administration of oxaliplatin increased withdrawal responses from cold stimulation, and GJG or calcium gluconate/magnesium sulfate significantly inhibited the oxaliplatin-induced cold hypersensitivity. Application of menthol, a TRPA1/TRPM8 agonist, or allyl isothiocyanate (AITC), a selective TRPA1 agonist, to the hind paw of oxaliplatin-treated rats enhanced the nocifensive behaviors evoked by each agonist, whereas oxaliplatin had no significant effect on nocifensive behaviors evoked by capsaicin, a TRPV1 agonist. GJG treatment reduced menthol- or AITC-evoked withdrawal responses potentiated by oxaliplatin. Furthermore, GJG suppressed the increase of TRPA1 and TRPM8 mRNA expression induced by oxaliplatin in dorsal root ganglia. These findings suggest that GJG prevented oxaliplatin-induced acute peripheral neuropathy by suppressing functional alteration of TRP channels, especially TRPA1 and TRPM8. PMID- 24784703 TI - Antievaporative mechanism of wax esters: implications for the function of tear fluid. AB - The tear film lipid layer (TFLL) is considered to act as an evaporation barrier and to maintain the tear film intact between blinks. In vitro methods have, however, failed to reproduce this evaporation-retarding effect. Wax esters (WEs) are a major component of the TFLL. Close to their bulk melting temperature, WEs have been found to retard the evaporation of water, but the nature of this mechanism has remained unclear. We studied the interfacial organization of WE films by measuring their isochors and isotherms and evaporation-retarding effect, and we imaged these films by Brewster angle microscopy (BAM). Behenyl palmitoleate (BP) was used as a representative WE because it resembles the WEs found in meibum. At low temperatures, BP forms solid monolayer crystals in which the molecules are organized in a bulk-like extended conformation. Within approximately 3 degrees C below the bulk melting temperature, these solid monolayer domains coexist with a fluid monolayer film. At temperatures above the bulk melting temperature, BP forms a completely fluid monolayer in which the molecules are in a hairpin conformation. A fluid hairpin monolayer of BP does not significantly retard evaporation, whereas a solid monolayer decreases evaporation by >50%. The results provide a molecular-level rationale for the evaporation retarding properties of WEs close to their melting temperature. PMID- 24784704 TI - Blood microRNA profile associates with the levels of serum lipids and metabolites associated with glucose metabolism and insulin resistance and pinpoints pathways underlying metabolic syndrome: the cardiovascular risk in Young Finns Study. AB - Since metabolic syndrome (MetS) is a collection of cardiovascular risk factors involving multiple signaling systems, we related the metabolic abnormalities associated with MetS with circulating microRNA profiles to pinpoint the affected signaling pathways. The blood microRNA profile, genome wide gene expression and serum NMR metabolomics were analyzed from 71 participants of the Young Finns Study. We found nine microRNAs that associated significantly with metabolites connected to MetS. MicroRNA-144-5p concentration correlated with glucose levels, hsa-1207-5p with glycosylated hemoglobin and hsa-miR-484 with metabolites related to insulin resistance. Hsa-miR-625-3p correlated with cholesterol levels, hsa-miR 1237-3p and hsa-miR-331-3p expression with certain fatty acids levels and hsa-miR 129-1-3p, -129-2-3p, and -1288-3p with glycerol levels. The down-regulated targets of miR-1207-5p and -129-2-3p were enriched in PI3K and MAPK pathways and 8 out of the 12 enriched pathways were down-regulated in individuals with MetS. In conclusion microRNAs associated with several aspects of MetS, possibly regulating glucose and lipid metabolism. PMID- 24784705 TI - Expression and regulation of stromal cell-derived factor-1 (SDF1) and chemokine CXC motif receptor 4 (CXCR4) in equine and bovine preovulatory follicles. AB - The interaction between stromal cell-derived factor-1 (SDF1) and chemokine CXC motif receptor 4 (CXCR4) has been implicated in leukocyte attraction, tissue remodeling and angiogenesis. The objective of the present study was to characterize the expression and regulation of SDF1 and CXCR4 in equine follicles during the ovulatory process. Equine preovulatory follicles were isolated during estrus 0-39h after hCG treatment. Follicle wall preparations (theca interna with attached granulosa cells) and isolated preparations of granulosa cells and theca interna were obtained, and total RNA extracts were analyzed by RT-PCR/Southern blot. Results showed that levels of CXCR4 transcripts were induced by hCG in follicles at 36 h post-hCG (P<0.05 vs 0 h), with the induction observed in both granulosa and theca cells. Immunoblotting and immunohistochemical analyses confirmed an increase in CXCR4 protein in follicles after hCG treatment. In contrast, levels of SDF1 transcripts were very low in granulosa cells but high in theca interna cells throughout most of the ovulatory period. Studies in vivo performed with bovine preovulatory follicles collected 0-24h post-hCG revealed a marked and significant up-regulation of CXCR4 transcripts after hCG (P<0.05), as observed in equine follicles. A similar pattern of CXCR4 mRNA up-regulation was observed in cultures of bovine granulosa cells treated with forskolin (P<0.05). This forskolin-dependent induction of CXCR4 mRNA was suppressed by co-treatment with inhibitors of PKA, ERK1/2 and EGFR, and by the progesterone receptor antagonist RU486 (P<0.05), underscoring the contribution of multiple signaling pathways. In complementary studies, treatment of bovine granulosa cells with EGF or the hypoxia mimetic cobalt chloride significantly increased CXCR4 transcript levels, whereas co-treatment with forskolin and a CXCR4 antagonist repressed the expression of several ovulation-related genes. Collectively, this study describes for the first time the gonadotropin-dependent up-regulation of CXCR4 transcript in ovarian follicles of large monoovulatory species, provides some insights into the regulation of CXCR4 gene expression in granulosa cells, and identifies a potential link between follicular SDF1/CXCR4 activation and the regulation of ovulation-related genes. PMID- 24784706 TI - Cardioprotective effects of thyroid hormones in a rat model of myocardial infarction are associated with oxidative stress reduction. AB - Reactive oxygen species (ROS) are involved with progression from infarction to heart failure. Studies show that thyroid hormones (TH) present cardioprotective effects. This study aims to evaluate whether TH effects after infarction are associated to redox balance modulation. Male Wistar rats were divided into four groups: Sham-operated (SHAM), infarcted (AMI), sham-operated+TH (SHAMT), and infarcted+TH (AMIT). During 26 days, animals received T3 (2 MUg/100g/day) and T4 (8 MUg/100g/day) by gavage. Echocardiographic parameters were assessed and heart tissue was collected to biochemical analysis. AMIT rats presented absence of lung congestion, less cardiac dilatation, and normalization in myocardial performance index, compared with AMI. AMI rats presented an increase in hydrogen peroxide levels and in lipid peroxidation and a decrease in GSH/GSSG. TH prevented these alterations in AMIT. In conclusion, TH seem to reduce the levels of ROS, preventing oxidative stress, and improving cardiac function in infarcted rats. PMID- 24784707 TI - Resolvin D1 reduces ER stress-induced apoptosis and triglyceride accumulation through JNK pathway in HepG2 cells. AB - Research has indicated that stress on the endoplasmic reticulum (ER) of a cell affects the pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD). Resolvins, a novel family derived from omega-3 polyunsaturated fatty acids, have anti-inflammatory and insulin sensitizing properties, and it has been suggested that they play a role in the amelioration of obesity-related metabolic dysfunctions. This study showed that pretreatment with resolvin D1 (RvD1) attenuated ER stress-induced apoptosis and also decreased caspase 3 activity in HepG2 cells. Furthermore, RvD1 significantly decreased tunicamycin-induced triglycerides accumulation as well as SREBP-1 expression. However, tunicamycin-induced ER stress markers were not significantly affected by RvD1 treatment. Moreover, RvD1 treatment did not affect the tunicamycin-induced expression of chaperones that assist protein folding in the ER. These results suggest that RvD1-conferred cellular protection may occur downstream of the ER stress. This was supported by the finding that RvD1 significantly inhibited tunicamycin-induced c-Jun N-terminal kinase (JNK) expression, although P38 and ERK1/2 phosphorylation were not affected. In addition, anisomycin, a JNK activator, increased caspase 3 activity and apoptosis as well as triglycerides accumulation and SREBP1 expression, and RvD1 treatment reversed these changes. In conclusion, RvD1 attenuated ER stress-induced hepatic steatosis and apoptosis via the JNK-mediated pathway. This study may provide insight into a novel underlying mechanism and a strategy for treating NAFLD. PMID- 24784708 TI - Risk factors for the development of stress urinary incontinence during pregnancy in primigravidae: a review of the literature. AB - The most common type of urinary incontinence (UI) in pregnant women is stress urinary incontinence (SUI). The number of pregnant women with SUI was variable, the prevalence ranged from 18.6% to 75% and increased with gestational age. It can affect the quality of life (QoL) of approximately 54.3% of all pregnant women in four domains including physical activity, travel, social relationships and emotional health. Pregnancy is one of the main risk factors for the development of SUI in young women. Physiological changes during pregnancy, such as increasing pressure of the growing uterus and fetal weight on the pelvic floor muscle (PFM) throughout pregnancy, together with pregnancy-related hormonal changes such as increased progesterone, decreased relaxin, and decreased collagen levels, may lead to reduced strength and supportive and sphincteric function of the PFM. Pregnancy may associate with the reduction of the PFM strength which can develop the SUI. However, the exact causes of pregnancy-related SUI remain unclear. Multiple factors have been found to be associated with the development of SUI during pregnancy. In genetic risk factors, aging is an important role in SUI development. The other risk factors such as obesity, smoking, constipation, pre pregnancy SUI, gestational diabetes mellitus (GDM), and pelvic floor muscle exercise (PFME) that utilized preventive strategies can reduce SUI in pregnant women. The purpose of this review is to identify the risk factors for the development of SUI in pregnant women. These understanding can be useful for health professions to inform and counsel the pregnant women to prevent and reduce the risk factors that contribute to the development of SUI during pregnancy and postpartum period. PMID- 24784709 TI - Clinical and sonographic risk factors and complications of shoulder dystocia - a case-control study with parity and gestational age matched controls. AB - OBJECTIVES: To examine the clinical risk factors and complications of shoulder dystocia today and to evaluate ultrasound methods predicting it. STUDY DESIGN: Retrospective, matched case-control study at a University Hospital with 5000 annual deliveries. The study population consisted of 152 deliveries complicated by shoulder dystocia over a period of 8.5 years (January 2004-June 2012) and 152 controls matched for gestational age and parity. The data was collected from the medical records of mothers and children and analyzed by conditional logistic regression. Incidences and odds ratios were calculated for risk factors and complications. Antenatal ultrasound data was analyzed when available by conditional logistic regression to test for significant differences between study groups. RESULTS: Birthweight (OR 12.1 for >=4000 g; 95% CI 4.18-35.0) and vacuum extraction (OR 3.98; 95% CI 1.25-12.7) remained the most significant clinical risk factors. Only a trend of an association of pregestational or gestational diabetes was noticed (OR 1.87; 95% CI 0.997-3.495, probability of type II error 51%). Of the complications of shoulder dystocia the incidence of brachial plexus palsies was high (40%). Antenatal ultrasound method based on the difference between abdominal and biparietal diameters had a significant difference between cases and controls. CONCLUSIONS: The impact of diabetes as a risk factor has diminished, which may reflect improved screening and treatment. Antenatal ultrasound methods are showing some promise, but the predictive value of ultrasound alone is probably low. PMID- 24784710 TI - Differential expression of AP-1 proteins in human myometrium after spontaneous term labour onset. AB - OBJECTIVES: The aims of this study were (i) to determine the localisation of activator protein (AP)-1 family members (cFos, FosB, cJun, JunB and JunD) in human myometrium; and (ii) to determine the effect of human term labour on the expression of AP-1 family of transcription factors in myometrium. STUDY DESIGN: This localised the AP-1 family members cFos, FosB, cJun, JunB and JunD in human myometrium was performed by immunohistochemistry. The effect of term labour on the expression of these family members at the mRNA and protein level was assessed by qRT-PCR and Western blotting, respectively. The effect of pro-inflammatory stimuli on AP-1 transcriptional activity was assessed using a luciferase assay in primary human myometrial cells. RESULTS: Immunohistochemical expression of cFos, FosB, cJun, JunB and JunD were all present in human myometrial tissue and displayed cytoplasmic staining. FosB and JunD also displayed nuclear staining. Term labour was associated with an increase in cFos and JunB mRNA and protein expression. On the other hand, JunD mRNA and protein expression was decreased with labour. FosB mRNA was increased with labour, but there was no change at the protein level. There was no change in cJun mRNA or protein expression. AP-1 transcriptional activity was increased in human myometrial cells by the pro inflammatory cytokine TNF-alpha. There was, however, no effect of the bacterial products lipopolysaccharide (LPS; TLR4 ligand), iE-DAP (NOD1 ligand), MDP (NOD2 ligand), FSL-1 (TLR2 ligand) or flagellin (TLR5 ligand) on AP-1 transcriptional activity. CONCLUSION: This study shows that human labour is associated with changes in AP-1 family members. Further studies are required to determine the exact role of the AP-1 family members in myometrium. PMID- 24784711 TI - Common determinants of breech presentation at birth in singletons: a population based study. AB - OBJECTIVE: To estimate common determinants of breech presentation at parturition. STUDY DESIGN: A population-based cohort study (between 1/1/2001 and 31/12/2010) was conducted among all women who delivered a singleton baby in breech presentation from 22 completed weeks of gestation. A binary logistic regression was used to determine independent feto-maternal characteristics of breech presentation at birth, adjusted odds ratios and 95% confidence intervals. Variables were: gestational age, birth weight, maternal age, parity and gender of the baby, presence or absence of a history of cesarean section, gestational diabetes, gestational hypertension, pregnancy after assisted reproduction technology and congenital malformations. RESULTS: From a population of 611,021 women; 28,059 were delivered in breech presentation (4.59%). Independent determinants of breech presentation at delivery were: gestational age and birth weight (the lower, the higher the incidence of breech at birth), parity (the frequency of breech decreased with increasing parity) and maternal age (the older the mother, the higher the odds for breech presentation). Women who had a scarred uterus, due to a previous cesarean section, women who gave birth to a female offspring and women whose baby showed a congenital malformation, were more prone to be delivered in breech presentation. CONCLUSION: Low gestational age and birth weight, advanced maternal age, a scarred uterus, a female baby and a baby with a congenital malformation increased the odds for singleton breech presentation at parturition. The latter gradually decreased with increasing parity. PMID- 24784712 TI - Pelvic floor symptoms and severity of pelvic organ prolapse in women seeking care for pelvic floor problems. AB - OBJECTIVE: The aim of the study was to estimate whether POP severity is related to lower urinary tract symptoms (LUTS) and symptoms of sexual difficulties, when evaluated with validated questionnaires. STUDY DESIGN: Multicentric cross sectional study of 521 women seeking care for PFD in 35 specialized urogynecological clinics. Patients answered the EPIQ to detect symptoms of PFD. The severity of urinary incontinence and the OAB symptoms were measured by ICIQ UI SF and BSAQ. POP anatomic severity was measured by the anatomic stage of each compartment, determined in pelvic examination in accordance with the IUGA-ICS terminology. A maximum POP stage (M-POP-S) was assigned to each patient: Group A, patients with no POP (stage 0-I); group B, M-POP-S stage II; and group C, M-POP-S stage III-IV. RESULTS: Pelvic examination demonstrated anatomic POP in 224 patients (stage from II to IV). 288 women (56.25%) were classified in group A (no prolapse); 102 (19.92%) group B (stage II); and 122 (28.83%) group C (stage III IV). Several associations were found between studied variables and M-POP-S (age<55 years, menopause, number of vaginal deliveries, symptom of vaginal bulge, feeling of a bulge makes it difficult to have sexual relations, symptoms of stress urinary incontinence, nocturia and voiding difficulties), but the only variables independently associated were age, symptom of vaginal bulge and difficulty in having sexual relations due to feeling of a bulge. CONCLUSIONS: In patients seeking care for PFD, LUTS are not independently associated to the prolapse stage. PMID- 24784713 TI - Early onset preeclampsia in subsequent pregnancies correlates with early onset preeclampsia in first pregnancy. AB - OBJECTIVE: Preeclampsia is a major complication of pregnancy and its occurrence in a first pregnancy is a major risk factor for recurrence in subsequent pregnancies. Whether the time of onset or the severity of preeclampsia in a first pregnancy is associated with the incidence of recurrent preeclampsia is not clear. We performed a retrospective study to analyse the incidence of recurrent preeclampsia and associations of the time of onset and the severity of preeclampsia between first preeclampsia and recurrent preeclampsia. STUDY DESIGN: Ninety-two women with previous preeclampsia who had a second pregnancy in a 4 year period were included. Data on the first and second pregnancies were obtained and included maternal age, maternal height and weight, gestation week at onset of preeclampsia and at delivery, blood pressure, proteinuria, interval between pregnancies and birth weights. RESULTS: Fifty-five women with previous preeclampsia developed recurrent preeclampsia (59.8%). The difference in the incidence of recurrent early and late onset preeclampsia was not significant different (65.3% versus 53.4%, p>0.05). The difference in the incidence of mild or severe disease in those who experienced recurrent preeclampsia was also not significant (59.6% versus 60%, p>0.05). The severity of preeclampsia in second pregnancy was not associated with the severity of preeclampsia in first pregnancy. However 93.7% women with previous early onset preeclampsia developed early onset preeclampsia in second pregnancy and 56.5% women with previous late onset preeclampsia developed early onset preeclampsia in second pregnancy. In addition, 76.2% women with previous mild preeclampsia developed severe preeclampsia in second pregnancy. The baby weight in recurrent preeclampsia was significantly decreased compared to that in first pregnancy with preeclampsia. CONCLUSION: Our data demonstrate that there was no association between the incidence of recurrent preeclampsia and the time of onset or severity of preeclampsia in first pregnancy. But our data here may suggest that women with early onset preeclampsia in first pregnancy are more likely to experience early onset preeclampsia in second pregnancy. The severity of recurrent preeclampsia is increased regardless the severity in first pregnancy. PMID- 24784714 TI - First-trimester maternal serum C-reactive protein as a predictor of third trimester impaired glucose tolerance. AB - OBJECTIVE: We evaluated whether first-trimester high-sensitivity C-reactive protein (hsCRP), a suggested marker of pregnancy-associated hyperglycemia, predicts third-trimester impaired glucose tolerance (IGT) in a secondary analysis of a prospective cohort of nondiabetic singletons enrolled at <26 weeks gestation. STUDY DESIGN: We measured the association between hsCRP collected at <14 weeks among women classified as IGT (gestational diabetes screening results, 135 to <200 mg/dL) and those among normoglycemic women. Multivariable modeling estimated the association between log hsCRP and IGT, adjusted for maternal body mass index (BMI). RESULTS: Among 300 women, 13% (39 of 300) had IGT. The hsCRP was positively associated with glucose (P = .005). Compared with normoglycemic women, women with IGT had higher log hsCRP (0.87 +/- 0.66 vs 0.67 +/- 0.60, P = .04), but the association was not significant in adjusted models (adjusted odds ratio 1.20, 95% confidence interval 0.65-2.21). The hsCRP did not predict third trimester IGT in this analysis when BMI is considered. CONCLUSION: Early identification of women at risk of IGT remains a priority, but the contribution of maternal BMI appears greater than hsCRP. PMID- 24784715 TI - Immunolocalization of growth, inhibitory, and proliferative factors involved in initial ovarian folliculogenesis from adult common squirrel monkey (Saimiri collinsi). AB - We performed an immunohistochemical (IHC) study to determine the follicular expression of growth differentiation factor 9 (GDF-9), anti-Mullerian hormone (AMH), Kit Ligand (KL), and c-Kit in squirrel monkey ovary. Ovarian tissue fragments from 4 squirrel monkeys were collected by laparotomy and processed for classical histology and IHC. Additionally, follicle development was assessed by Ki67 immunostaining to evaluate proliferative status of granulosa cells. A total of 4025 follicles were examined (1475 for classical histology and 2550 for immunohistochemistry). More than 80% of the evaluated follicles were morphologically normal. The GDF-9 protein was detectable in oocyte cytoplasm from primordial (100%), primary (99.1%), and secondary (100%) follicles. The AMH was not expressed in primordial follicles but just in few primary follicles (13.8%). On the other hand, it was highly expressed in granulosa cells from secondary follicles (67.9%). c-Kit, KL receptor, was found in the oolemma of primordial (100%), primary (100%), and secondary (100%) follicles. The KL expression was observed in oocytes and granulosa cells from primordial (94.9%), primary (91.6%) and secondary follicles (100%). Ki67 immunostaining was observed in granulosa cells from primary (5.7%) and secondary (54.8%) follicles but not in primordial follicles. In conclusion, we described the localization of GDF-9, KL, c-Kit, and Ki67 proteins and confirmed the presence of AMH protein in preantral follicles from squirrel monkey. Our results offer contribution for understanding of folliculogenesis in neotropical nonhuman primates. Moreover, these markers can be used to assess follicular viability and functionality after cryopreservation, transplantation, or in vitro culture of ovarian tissue. PMID- 24784716 TI - Telomerase expression abrogates rapamycin-induced irreversible growth arrest of uterine fibroid smooth muscle cells. AB - Uterine fibroids are the most common solid tumors found in women of reproductive age. It has been reported that deregulation of the mammalian target of rapamycin (mTOR) pathway plays an important role in the etiology of leiomyoma. Here, we investigated the effect of rapamycin, an inhibitor of mTORC1, on the growth of primary fibroid smooth muscle cells (fSMCs) and human telomerase reverse transcriptase (hTERT)-transduced and immortalized fSMCs. With the primary fSMCs, a 24-hour treatment with rapamycin was sufficient to trigger a growth arrest that was not reversible upon drug removal. By contrast, the growth inhibitory effect of rapamycin on the hTERT-transduced fSMCs was readily reversible, as these cells resumed proliferation upon the withdrawal of the drug. These results suggest that rapamycin-induced irreversible growth arrest of fSMCs is dependent on the senescence barrier that is abrogated by the ectopic expression of telomerase. PMID- 24784717 TI - Altered genome-wide methylation in endometriosis. AB - Endometriosis has been associated with aberrant methylation in the eutopic endometrium. Using a genome-wide methylation array, we identified differentially methylated genes in the endometrium from women with or without endometriosis. One hundred and twenty genes were significantly altered by >1.5-fold. In all, 59 genes were significantly hypermethylated and 61 genes were significantly hypomethylated. Changes in gene expression associated with the altered methylation status were validated using quantitative real-time polymerase chain reaction. A limited number of candidate genes are selectively methylated in the endometrium of women with endometriosis. Several genes not previously associated with endometriosis are aberrantly methylated and expressed. These include O-6 methylguanine-DNA methyltransferase, dual specificity phosphatase 22, cell division cycle associated 2, inhibitor of DNA binding 2, retinoblastoma binding protein 7, bone morphogenetic protein receptor, type 1B, tumor necrosis factor receptor 1B, zinc finger protein receptor 681, immunoglobulin superfamily, member 21, and tumor protein 73. Aberrant DNA methylation and gene expression of these genes may contribute to abnormal regulation of endometrial cell proliferation and function in women. PMID- 24784718 TI - Immunohistochemical detection of promyelocytic leukemia zinc finger and histone 1.5 in uterine leiomyosarcoma and leiomyoma. AB - OBJECTIVES: The accurate distinction of leiomyoma from leiomyosarcoma is essential for patient management. However, the distinction can be difficult to make, particularly in tissue biopsy samples. Immunohistochemistry has been established as a useful technique to aid in the diagnosis of malignancies. The advantages of immunohistochemical studies are their ease of use and interpretation. This study is the first to evaluate the utility of the promyelocytic leukemia zinc finger (PLZF) protein and the histone 1.5 (H1.5) protein as potential diagnostic immunohistochemical markers for distinguishing leiomyosarcoma from leiomyoma. METHODS: Tissue samples from 21 leiomyosarcomas and 26 leiomyomas were studied. The student t-test and the Fisher exact test were used to calculate the differences in staining between the 2 groups. RESULTS: Statistically significant differences were found in the staining indices of anti PLZF and anti-H1.5 when comparing benign and malignant tumors (P < .0001 and P < .0001, respectively). The mean H1.5 staining score in leiomyosarcomas was 158.3, compared to 28.3 in leiomyomas. The mean PLZF score in leiomyosarcomas was 1.5 in contrast to 71.5 in leiomyomas. For H1.5 at a score >=60, the sensitivity and specificity were 90.5% and 84.6%, respectively. For PLZF, a score <=15 had a test sensitivity and specificity of 100% and 80.8%, respectively. This suggests that staining for H1.5 or PLZF can serve as a good screening test. Additionally, combining the 2 immunostains results in a sensitivity and specificity of 90.5% and 97.5%, respectively, in differentiating between leiomyoma and leiomyosarcoma. CONCLUSIONS: We describe immunostaining for PLZF and H1.5 in benign and malignant uterine smooth muscle tumors. Statistically significant differences in staining patterns were found, suggesting utility in distinguishing leiomyosarcomas from leiomyomas. PMID- 24784719 TI - Effect of a low-dose contraceptive patch on efficacy, bleeding pattern, and safety: a 1-year, multicenter, open-label, uncontrolled study. AB - This Phase III, uncontrolled, open-label, multicenter study was conducted to investigate the contraceptive efficacy, bleeding pattern, and cycle control of a novel once-a-week contraceptive patch, delivering low-dose ethinyl estradiol (EE) and gestodene (GSD) at the same systemic exposure seen after oral administration of a combined oral contraceptive containing 0.02 mg EE/0.06 mg GSD. Participants were women aged 18 to 35 years, all of whom received the EE/GSD patch for 13 cycles each of 21 treatment days (one patch per week for 3 weeks) followed by a 7 day, patch-free interval. The primary efficacy variable was the occurrence of unintended pregnancies during the study period as assessed by life table analysis and the Pearl Index. Secondary efficacy variables were days with bleeding during four 90-day reference periods and during 1 treatment year, bleeding pattern, and cycle control. The Kaplan-Meier probability of contraceptive protection after 364 treatment days was 98.8% and the adjusted Pearl Index was 0.81. The percentage of participants with intracyclic bleeding/spotting decreased over time, from 11.4% to 6.8% in cycles 1 and 12, respectively. Almost all participants (range: 90.8% 97.6%) experienced withdrawal bleeding across the study period. Compliance was very high (mean: 97.9%; median: 100%). The most frequent adverse events were headache (9.5%) and application site reaction (8.5%); no clinically significant safety concerns were observed. Results suggest the EE/GSD patch is highly effective in preventing pregnancy. Menstrual bleeding pattern was favorable and within the ranges expected of a healthy female population. The patch was well tolerated and treatment compliance was high. PMID- 24784720 TI - Assess bleeding risk with HAS-BLED and assess stroke risk with CHA2DS2-VASc in patients with atrial fibrillation. PMID- 24784721 TI - Long-term blockade of the renin-angiotensin system: an adequate evaluation is still needed. PMID- 24784722 TI - The complexity of role balance: support for the Model of Juggling Occupations. AB - OBJECTIVE: This pilot study aimed to establish the appropriateness of the Model of Juggling Occupations in exploring the complex experience of role balance amongst working women with family responsibilities living in Perth, Australia. METHODS: In meeting this aim, an evaluation was conducted of a case study design, where data were collected through a questionnaire, time diary, and interview. RESULTS: Overall role balance varied over time and across participants. Positive indicators of role balance occurred frequently in the questionnaires and time diaries, despite the interviews revealing a predominance of negative evaluations of role balance. Between-role balance was achieved through compatible role overlap, buffering, and renewal. An exploration of within-role balance factors demonstrated that occupational participation, values, interests, personal causation, and habits were related to role balance. CONCLUSIONS: This pilot study concluded that the Model of Juggling Occupations is an appropriate conceptual framework to explore the complex and dynamic experience of role balance amongst working women with family responsibilities. It was also confirmed that the case study design, including the questionnaire, time diary, and interview methods, is suitable for researching role balance from this perspective. PMID- 24784723 TI - Young persons with visual impairment: challenges of participation. AB - OBJECTIVE: To describe the challenges to activity and participation faced by young people with visual impairment within the framework of the International Classification of Functioning (ICF). METHODS: 14 young persons (aged 16-22 years) with visual impairment and their parents (n = 22) participated in the study. The Canadian Occupational Performance Measure (COPM) was used to describe challenges of participation as perceived by the young persons themselves. Individual interviews with the young persons and their parents were used to investigate in more depth the challenges the young persons face with regard to participation. RESULTS: Young persons with visual impairment face challenges to participation most frequently with regard to mobility, domestic life, interpersonal interaction and relationships, major life areas, and leisure activities. The environment in which they live has a central role as a barrier or facilitator of participation. CONCLUSIONS: The challenges related to activities and participation that young persons with visual impairment face are diverse. It is important that these challenges are assessed individually and with the help of subjective measures. Serving as a broad framework for classifying the data, the ICF proved to be a useful tool, but used strictly at category level it may limit the coding of data and narrow interpretation. PMID- 24784724 TI - Men's and women's perspectives on using a powered mobility device: benefits and societal challenges. AB - OBJECTIVE: To describe how men and women experience their use of powered wheelchairs (PW) and powered scooters (PS) in everyday occupations, in the home and in society at large. METHODS: A qualitative research approach with focus group methodology was used. Four focus groups were created, with men and women as well as PW and PS users in different groups. Applying a descriptive approach, data were analysed according to the principles described by Krueger. FINDINGS: Three categories emerged and revealed that even though use of PW and PS increased independence and enabled everyday occupations, participants struggled to be independent powered mobility device (PMD) users. They experienced many accessibility problems in dwellings and in society, described similarly by users of PW and PS. Men and women experienced their use of (PMD) differently, especially in relation to the service delivery process. CONCLUSIONS: The study contributes with new knowledge on accessibility for PW and PS users and related service delivery processes, stating that gender differences regarding provision and training must be taken into account. Occupational therapists can contribute to an enhanced understanding of PMD users' challenges in person-environment occupation transactions in the home and society, and thereby promote occupational justice for PMD users. PMID- 24784725 TI - Evaluation of housing adaptation interventions: integrating the economic perspective into occupational therapy practice. AB - OBJECTIVE: The home environment is a key determinant of health, quality of life, and well-being. Given its relevance for such aspects, the scarcity of evaluations of housing adaptation (HA) interventions aimed at removing environmental barriers and accessibility problems in the homes of people with disabilities is surprising. This article aims to contribute to the development of strategies for economic evaluations of HA interventions, by stimulating the dissemination and application of the concepts of effectiveness, cost, and cost-effectiveness as used within health economics. METHODS: The focus is limited to three overarching questions for the evaluation of HA interventions. Considering X and Y as two hypothetical interventions for the same individual case, the article asks: (i) Will X be more effective than Y?; (ii) Will X cost more than Y?, and (iii) Will X be more cost-effective than Y? Vignette-like descriptions of fictional cases are used to exemplify the economic concepts explained in the article. RESULTS AND CONCLUSION: In the conclusion, the need is stressed for new experimental data regarding both costs and outcomes of HA interventions, in order to realize sound evaluations with the potential to inform policy and professionals in this field. Given the heterogeneity among national contexts, systematic approaches applied in a coherent manner could strengthen cross-national research and collaborations. PMID- 24784726 TI - Uhl's anomaly: a difficult prenatal diagnosis. AB - Uhl's anomaly is an evolutive disease leading to terminal right ventricular failure. The most difficult differential diagnosis at presentation is the Ebstein disease. We describe the evolution of a foetus with Uhl's anomaly from 21 to 30 weeks of gestation, with progressive reduction in the right ventricular anterior myocardium suggestive of apoptosis, leading to foetal demise. PMID- 24784727 TI - Strength from weakness: conformational divergence between solid and solution states of substituted cyclitols facilitated by CH...O hydrogen bonding. AB - We have investigated the conformational preferences of a series of cyclitol derivatives, namely mono- and diesters of 1,2:5,6-di-O-isopropylidene-myo inositol and 1,2:5,6-di-O-cyclohexylidene-myo-inositol, in both solid and solution states. The solid-state conformations were determined by single-crystal X-ray analysis. The solution-state conformations were determined by using NMR. The experimental (3)J(HH) values were applied in the Haasnoot-Altona equation to calculate the dihedral angle (phi) between the respective vicinal protons. By fixing the dihedral angle between different sets of vicinal protons, the molecules were energy-minimized by MM2 method to visualize their conformation in solution. As the solvent polarities can influence the conformational preference, we have determined the conformations of these molecules in various solvents of different polarities such as benzene-d6, chloroform-d, acetonitrile-d3, acetone d6, methanol-d4, and DMSO-d6. All of the compounds adopted boat conformations in solution irrespective of the solvents, acyl groups, or alkylidene protecting groups. This conformation places H6 and O3 of the cyclitol ring in proximity, such that an intramolecular CH...O hydrogen bond between them stabilizes this otherwise unstable conformation. However, in the solid state, several intermolecular CH...O hydrogen bonds force these molecules to adopt the chair conformation. This study uncovers the role of weak noncovalent interactions in influencing the molecular conformations differentially in different states. PMID- 24784728 TI - The relationships between XPC binding to conformationally diverse DNA adducts and their excision by the human NER system: is there a correlation? AB - The first eukaryotic NER factor that recognizes NER substrates is the heterodimeric XPC-RAD23B protein. The currently accepted hypothesis is that this protein recognizes the distortions/destabilization caused by DNA lesions rather than the lesions themselves. The resulting XPC-RAD23B-DNA complexes serve as scaffolds for the recruitment of subsequent NER factors that lead to the excision of the oligonucleotide sequences containing the lesions. Based on several well known examples of DNA lesions like the UV radiation-induced CPD and 6-4 photodimers, as well as cisplatin-derived intrastrand cross-linked lesions, it is generally believed that the differences in excision activities in human cell extracts is correlated with the binding affinities of XPC-RAD23B to these DNA lesions. However, using electrophoretic mobility shift assays, we have found that XPC-RAD23B binding affinities of certain bulky lesions derived from metabolically activated polycyclic aromatic hydrocarbon compounds such as benzo[a]pyrene and dibenzo[a,l]pyrene, are not directly, or necessarily correlated with NER excision activities observed in cell-free extracts. These findings point to features of XPC-RAD23B-bulky DNA adduct complexes that may involve the formation of NER productive or unproductive forms of binding that depend on the structural and stereochemical properties of the DNA adducts studied. The pronounced differences in NER cleavage efficiencies observed in cell-free extracts may be due to differences in the successful recruitment of subsequent NER factors by the XPC RAD23B-DNA adduct complexes, and/or in the verification step. These phenomena appear to depend on the structural and conformational properties of the class of bulky DNA adducts studied. PMID- 24784731 TI - Palladium(0)-catalyzed methylenecyclopropanation of norbornenes with vinyl bromides. AB - Highly strained methylenecyclopropane derivatives have been achieved via a novel and efficient Pd(0)-catalyzed domino reaction. The formal [2 + 1] cycloaddition reaction of vinyl bromides to norbornenes involves a Heck-type coupling and a C(sp(2))-H bond activation. PMID- 24784729 TI - A novel C2H2 transcription factor that regulates gliA expression interdependently with GliZ in Aspergillus fumigatus. AB - Secondary metabolites are produced by numerous organisms and can either be beneficial, benign, or harmful to humans. Genes involved in the synthesis and transport of these secondary metabolites are frequently found in gene clusters, which are often coordinately regulated, being almost exclusively dependent on transcription factors that are located within the clusters themselves. Gliotoxin, which is produced by a variety of Aspergillus species, Trichoderma species, and Penicillium species, exhibits immunosuppressive properties and has therefore been the subject of research for many laboratories. There have been a few proteins shown to regulate the gliotoxin cluster, most notably GliZ, a Zn2Cys6 binuclear finger transcription factor that lies within the cluster, and LaeA, a putative methyltransferase that globally regulates secondary metabolism clusters within numerous fungal species. Using a high-copy inducer screen in A. fumigatus, our lab has identified a novel C2H2 transcription factor, which plays an important role in regulating the gliotoxin biosynthetic cluster. This transcription factor, named GipA, induces gliotoxin production when present in extra copies. Furthermore, loss of gipA reduces gliotoxin production significantly. Through protein binding microarray and mutagenesis, we have identified a DNA binding site recognized by GipA that is in extremely close proximity to a potential GliZ DNA binding site in the 5' untranslated region of gliA, which encodes an efflux pump within the gliotoxin cluster. Not surprisingly, GliZ and GipA appear to work in an interdependent fashion to positively control gliA expression. PMID- 24784732 TI - Rich soil carbon and nitrogen but low atmospheric greenhouse gas fluxes from North Sulawesi mangrove swamps in Indonesia. AB - The soil to atmosphere fluxes of greenhouse gases N2O, CH4 and CO2 and their relationships with soil characteristics were investigated in three tropical oceanic mangrove swamps (Teremaal, Likupang and Kema) in North Sulawesi, Indonesia. Mangrove soils in North Sulawesi were rich in organic carbon and nitrogen, but the greenhouse gas fluxes were low in these mangroves. The fluxes ranged -6.05-13.14 MUmol m(-2)h(-1), -0.35-0.61 MUmol m(-2)h(-1) and -1.34-3.88 mmol m(-2)h(-1) for N2O, CH4 and CO2, respectively. The differences in both N2O and CH4 fluxes among different mangrove swamps and among tidal positions in each mangrove swamp were insignificant. CO2 flux was influenced only by mangrove swamps and the value was higher in Kema mangrove. None of the measured soil parameters could explain the variation of CH4 fluxes among the sampling plots. N2O flux was negatively related to porewater salinity, while CO2 flux was negatively correlated with water content and organic carbon. This study suggested that the low gas emissions due to slow metabolisms would lead to the accumulations of organic matters in North Sulawesi mangrove swamps. PMID- 24784733 TI - Zinc stable isotope fractionation upon accelerated oxidative weathering of sulfidic mine waste. AB - Accelerated oxidative weathering in a reaction cell (ASTM D 5744 standard protocol) was performed over a 33 week period on well characterized, sulfidic mine waste from the Kidd Creek Cu-Zn volcanogenic massive sulfide deposit, Canada. The cell leachate was monitored for physicochemical parameters, ion concentrations and stable isotope ratios of zinc. Filtered zinc concentrations (<0.45 MUm) in the leachate ranged between 4.5 mg L(-1) and 1.9 g L(-1) potentially controlled by pH, mineral solubility kinetics and (de)sorption processes. The zinc stable isotope ratios varied mass-dependently within +0.1 and +0.520/00 relative to IRMM 3702, and were strongly dependent on the pH (rpH d66Zn=0.65, p<0.005, n=31). At a pH below 5, zinc mobilization was governed by sphalerite oxidation and hydroxide dissolution-pointing to the isotope signature of sphalerite (+0.1 to +0.160/00). Desorption processes resulted in enrichment of (66)Zn in the leachate reaching a maximum offset of +0.320/00 compared to the proposed sphalerite isotope signature. Over a period characterized by pH=6.1 +/- 0.6, isotope ratios were significantly more enriched in (66)Zn with an offset of ~ 0.230/00 compared to sphalerite, suggesting that zinc release may have been derived from a second zinc source, such as carbonate minerals, which compose 8 wt.% of the tailings. This preliminary study confirms the benefit of applying zinc isotopes alongside standard monitoring parameters to track principal zinc sources and weathering processes in complex multi-phase matrices. PMID- 24784734 TI - The determination of polycyclic aromatic hydrocarbons in the urine of non-smoking Polish pregnant women. AB - The aim of this study was to characterize the PAH exposure level among the non smoking Polish pregnant women and to identify the minimal set of PAH metabolites that specifically reflect environmental PAH exposure. The study population consisted of 210 non-smoking pregnant women. The urine sample was used for analysis of the following PAH metabolites: 1-, 2-, 3-, 4-, 9-hydroxyphenanthrene (1-, 2-, 3-, 4-, 9-OH-PHE), 1-hydroxypyrene (1-OH-PYR), 1,6+1,8-dihydroxypyrene (DI-OH-PYR), phenanthrene trans-1,2-dihydrodiol (PHE-1,2-diol) and phenanthrene trans-9,10-dihydrodiol (PHE-9,10-diol). The analysis of all the biomarkers was performed by gas chromatography-mass spectrometry after their derivatization. The mean PAH metabolite concentrations were in the range of 0.15 (+/- 0.2) MUg/g creatinine for 9-OH-PHE to 5.9 (+/- 10.6) MUg/g creatinine for PHE-9,10-diol. Women living in the city center had higher concentrations of 1-OH-PHE (beta=0.6; p=0.04), 3-OH-PHE (beta=0.8; p=0.02), 9-OH-PHE (beta=0.9; p=0.02), and DI-OH-PYR (beta=1.0; p=0.006) than those living outside the city center. The usage of coal for residential heating was a significant predictor of all PAH metabolites except for 9-OH-PHE (p=0.1) and PHE-9,10-diol (p=0.08). With the increasing cotinine levels we observed a significant increase in the concentrations of the following PAH metabolites: 3-OH-PHE (beta=0.2; p=0.007), 4-OH-PHE (beta=0.3; p=0.002), PHE 1,2-diol (beta=0.3; p<0.001), 1-OH-PYR (beta=0.2; p=0.01). High-density housing, usage of coal for residential heating, cotinine level in saliva, season of urine collection and distance from the place of residence to the main road explained 26% of the variance of 3-OH-PHE and 21% of the variance of 1-OH-PHE. 2-OH-PHE, 3 OH-PHE, 9-OH-PHE and PHE-9,10-diol are sufficient to predict environmental PAH exposure. The urinary PAH biomarker levels found in this study indicate that non smoking Polish pregnant women suffer from a higher PAH exposure than those in other western countries. This higher PAH exposure level probably poses a significant health risk for the newborns and young children and will require further attention in the future. PMID- 24784735 TI - A multi-taxon approach reveals the effect of management intensity on biodiversity in Alpine larch grasslands. AB - In the Alps, larch grasslands form one of the most pleasing aspects of the landscape. However, their effectiveness in contributing to biodiversity conservation may depend on the intensity of their management. We used a multi taxon approach to evaluate the effects of the intensification of management practices and those of abandonment on the biodiversity of the main autotrophic organisms hosted in this habitat, including vascular plants, bryophytes, and lichens. The study was carried out in the eastern part of South Tyrol, in the Italian Alps, where the diversity patterns of these three organismal groups were compared among intensively managed, extensively managed, and abandoned stands. The management intensity was found to strongly influence the biodiversity of the organisms, with a general pattern indicating the best conditions in extensively managed stands. Both abandonment and management intensification were detrimental to biodiversity through different mechanisms that led to species loss or to major shifts in species composition. However, the most negative effects were related to management intensification, mainly due to the high nitrogen supply, providing evidence for the increasing impact of eutrophication on Alpine environments. PMID- 24784736 TI - Genotoxicity of perfluorinated chemicals (PFCs) to the green mussel (Perna viridis). AB - Concerns regarding perfluorinated chemicals (PFCs) have grown significantly in recent years. However, regulations and guidelines regarding the emission and treatment of PFCs are still missing in most parts of the world, mostly due to the lack of PFC toxicity data. In the current study, the genotoxic effects of four common PFCs, named perfluorooctanesulfonate (PFOS), perfluoroocanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) were investigated on marine mussels. The effects of exposure time and concentration on the toxic behavior of the compounds were also examined. Genotoxicity of PFCs was assessed in biomarker assays, showing that exposure to the target compounds could damage the organism's genetic material to varying extents, including DNA strand breaks and fragmentation, chromosomal breaks and apoptosis. The adverse effects increased with both exposure concentration and time and were related with the organism burden of PFCs. The integrated biomarker response analysis demonstrated that PFOS exhibited a higher genotoxicity than the other tested compounds. The EC50 values and confidence intervals based on integrative genotoxicity were 33 (29-37), 594 (341-1036), 195 (144-265) and 78 (73-84) MUg/L for PFOS, PFOA, PFNA and PFDA respectively, classifying PFOS as a highly genotoxic compound. Although primary DNA damage was shown to be recoverable after exposure ceased, permanent genetic damage caused by elevated PFC concentrations was not restored. This is the first ecotoxicity study of PFCs that focuses on the genotoxic effects of the compounds, clearly indicating the genotoxicity of the tested PFCs and demonstrating that functional groups have a major impact on the compounds' genotoxic behavior. PMID- 24784737 TI - Hydrogen and oxygen isotopic composition of karst waters with and without acid mine drainage: impacts at a SW China coalfield. AB - Karst water resources, which are critical for the support of human societies and ecological systems in many regions worldwide, are extremely sensitive to mining activities. Identification and quantification of stable isotope (delta(2)HH2O anddelta(18)OH2O) composition for all sources is essential if we are to fully understand the dynamics of these unique systems and propose successful remediation strategies. For these purposes, a stable isotope study was undertaken in two similar watersheds, one impacted by acid mine drainage, and the other not. It was found that the majority of delta(2)HH2O and delta(18)OH2O values of acid mine drainage (AMD), AMD-impacted and Main channel mix waters plotted above the local meteoric water line (LMWL), while the non-AMD-impacted water was below the LMWL. The AMD and AMD-impacted water had a similar composition ofdelta(18)OH2O and heavierdelta(2)HH2O than that of the other waters as a result of pyrite oxidation and Fe hydrolysis. The non-AMD-impacted and spring waters were the background waters in the study area. The composition ofdelta(2)HH2O and delta(18)OH2O for the former was influenced by the re-evaporation and water-rock interaction, and that for the latter was controlled by re-condensation. Along the water flow, the Main channel mix water is recharged by AMD-impacted, non-AMD impacted and spring waters. The composition ofdelta(2)HH2O anddelta(18)OH2O for the Main channel mix water was coincident with the characteristics of water mixing, supported by three-component mixing modeling of upstream spring, non-AMD impacted and AMD-impacted waters. The composition of delta(2)HH2O and delta(18)OH2O for the Main channel mix water was mainly affected by the AMD impacted water. These results help elucidate the impact of AMD on delta(2)HH2O and delta(18)OH2O compositions for karst waters and demonstrate the utility for impact assessments and remediation planning in these unique systems. PMID- 24784738 TI - A probabilistic model of gastroenteritis risks associated with consumption of street food salads in Kumasi, Ghana: evaluation of methods to estimate pathogen dose from water, produce or food quality. AB - With a rapidly growing urban population in Kumasi, Ghana, the consumption of street food is increasing. Raw salads, which often accompany street food dishes, are typically composed of perishable vegetables that are grown in close proximity to the city using poor quality water for irrigation. This study assessed the risk of gastroenteritis illness (caused by rotavirus, norovirus and Ascaris lumbricoides) associated with the consumption of street food salads using Quantitative Microbial Risk Assessment (QMRA). Three different risk assessment models were constructed, based on availability of microbial concentrations: 1) Water - starting from irrigation water quality, 2) Produce - starting from the quality of produce at market, and 3) Street - using microbial quality of street food salad. In the absence of viral concentrations, published ratios between faecal coliforms and viruses were used to estimate the quality of water, produce and salad, and annual disease burdens were determined. Rotavirus dominated the estimates of annual disease burden (~10(-3)Disability Adjusted Life Years per person per year (DALYs pppy)), although norovirus also exceeded the 10(-4)DALY threshold for both Produce and Street models. The Water model ignored other on farm and post-harvest sources of contamination and consistently produced lower estimates of risk; it likely underestimates disease burden and therefore is not recommended. Required log reductions of up to 5.3 (95th percentile) for rotavirus were estimated for the Street model, demonstrating that significant interventions are required to protect the health and safety of street food consumers in Kumasi. Estimates of virus concentrations were a significant source of model uncertainty and more data on pathogen concentrations is needed to refine QMRA estimates of disease burden. PMID- 24784739 TI - The impact of the Fukushima nuclear accident on marine biota: retrospective assessment of the first year and perspectives. AB - An international study under the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) was performed to assess radiological impact of the nuclear accident at the Fukushima-Daiichi Nuclear Power Station (FDNPS) on the marine environment. This work constitutes the first international assessment of this type, drawing upon methodologies that incorporate the most up-to-date radioecological models and knowledge. To quantify the radiological impact on marine wildlife, a suite of state-of-the-art approaches to assess exposures to Fukushima derived radionuclides of marine biota, including predictive dynamic transfer modelling, was applied to a comprehensive dataset consisting of over 500 sediment, 6000 seawater and 5000 biota data points representative of the geographically relevant area during the first year after the accident. The dataset covers the period from May 2011 to August 2012. The method used to evaluate the ecological impact consists of comparing dose (rates) to which living species of interest are exposed during a defined period to critical effects values arising from the literature. The assessed doses follow a highly variable pattern and generally do not seem to indicate the potential for effects. A possible exception of a transient nature is the relatively contaminated area in the vicinity of the discharge point, where effects on sensitive endpoints in individual plants and animals might have occurred in the weeks directly following the accident. However, impacts on population integrity would have been unlikely due to the short duration and the limited space area of the initially high exposures. Our understanding of the biological impact of radiation on chronically exposed plants and animals continues to evolve, and still needs to be improved through future studies in the FDNPS marine environment. PMID- 24784740 TI - Assessment and forecast of Beijing and Shanghai's urban ecosystem health. AB - In this paper, we first analyze the 5 most cited papers with the title containing "Urban ecosystem health" in Chinese academic journals, and 5 newer papers retrieved from the CSSCI (Chinese Social Sciences Citation Index). The results show that the number of indicators to be used together in more than three papers is 28, and then we select 27 of them to assess Beijing and Shanghai's urban ecosystem health from 2000 to 2011. Secondly, when we standardize the original data, the worst value adjustment coefficient is introduced innovatively. Thirdly, using the entropy method, the weights of concrete indicators of Beijing and Shanghai in the different adjustment coefficients are calculated respectively. Fourthly, based on the fuzzy matter-element method, using the Hamming approach degree, the two cities' ecosystem health index and the contribution value to overall health index from each component are calculated. Lastly, using gray prediction model, the evolutionary time response sequence function of Beijing and Shanghai's urban ecosystem health index is identified, and thus both cities' urban ecosystem health is predicted. PMID- 24784741 TI - Review and analysis of global agricultural N2O emissions relevant to the UK. AB - As part of a UK government funded research project to update the UK N2O inventory methodology, a systematic review of published nitrous oxide (N2O) emission factors was carried out of non-UK research, for future comparison and synthesis with the UK measurement based evidence base. The aim of the study is to assess how the UK IPCC default emission factor for N2O emissions derived from synthetic or organic fertiliser inputs (EF1) compares to international values reported in published literature. The availability of data for comparing and/or refining the UK IPCC default value and the possibility of analysing sufficient auxiliary data to propose a Tier 2 EF1 reporting strategy is evaluated. The review demonstrated a lack of consistency in reporting error bounds for fertiliser-derived EFs and N2O flux data with 8% and 44% of publications reporting EF and N2O flux error bounds respectively. There was also poor description of environmental (climate and soil) and experimental design auxiliary data. This is likely to be due to differences in study objectives, however potential improvements to soil parameter reporting are proposed. The review demonstrates that emission factors for agricultural-derived N2O emissions ranged -0.34% to 37% showing high variation compared to the UK Tier 1 IPCC EF1 default values of 1.25% (IPCC 1996) and 1% (IPPC 2006). However, the majority (83%) of EFs reported for UK-relevant soils fell within the UK IPCC EF1 uncertainty range of 0.03% to 3%. Residual maximum likelihood (REML) analysis of the data collated in the review showed that the type and rate of fertiliser N applied and soil type were significant factors influencing EFs reported. Country of emission, the length of the measurement period, the number of splits, the crop type, pH and SOC did not have a significant impact on N2O emissions. A subset of publications where sufficient data was reported for meta-analysis to be conducted was identified. Meta-analysis of effect sizes of 41 treatments demonstrated that the application of fertiliser has a significant effect on N2O emissions in comparison to control plots and that emission factors were significantly different to zero. However no significant relationships between the quantity of fertiliser applied and the effect size of the amount of N2O emitted from fertilised plots compared to control plots were found. Annual addition of fertiliser of 35 to 557 kg N/ha gave a mean increase in emissions of 2.02 +/- 0.28 g N2O/ha/day compared to control treatments (p<0.01). Emission factors were significantly different from zero, with a mean emission factor estimated directly from the meta analysis of 0.17 +/- 0.02%. This is lower than the IPCC 2006 Tier 1 EF1 value of 1% but falling within the uncertainty bound for the IPCC 2006 Tier 1 EF1 (0.03% to 3%). As only a small number of papers were viable for meta analysis to be conducted due to lack of reporting of the key controlling factors, the estimates of EF in this paper cannot include the true variability under conditions similar to the UK. Review-derived EFs of 0.34% to 37% and mean EF from meta-analysis of 0.17 +/- 0.02% highlight variability in reporting EFs depending on the method applied and sample size. A protocol of systematic reporting of N2O emissions and key auxiliary parameters in publications across disciplines is proposed. If adopted this would strengthen the community to inform IPCC Tier 2 reporting development and reduce the uncertainty surrounding reported UK N2O emissions. PMID- 24784742 TI - PAHs (polycyclic aromatic hydrocarbons), nitro-PAHs, and hopane and sterane biomarkers in sediments of southern Lake Michigan, USA. AB - PAHs in the Great Lakes basin are of concern due to their toxicity and persistence in bottom sediments. Their nitro derivatives, nitro-PAHs (NPAHs), which can have stronger carcinogenic and mutagenic activity than parent PAHs, may follow similar transport routes and also are accumulated in sediments. Limited information exists regarding the current distribution, trends and loadings of these compounds, especially NPAHs, in Lake Michigan sediments. This study characterizes PAHs, NPAHs, and biomarkers steranes and hopanes in surface sediments collected at 24 offshore sites in southern Lake Michigan. The SigmaPAH14 (sum of 14 compounds) ranged from 213 to 1,291 ng/g dry weight (dw) across the sites, levels that are 2 to 10 times lower than those reported 20 to 30 years earlier. Compared to consensus-based sediment quality guidelines, PAH concentrations suggest very low risk to benthic organisms. The SigmaNPAH5 concentration ranged from 2.9 to 18.6 ng/g dw, and included carcinogenic compounds 1-nitropyrene and 6-nitrochrysene. SigmaSterane6 and SigmaHopane5 concentrations ranged from 6.2 to 36 and 98 to 355 ng/g dw, respectively. Based on these concentrations, Lake Michigan is approximately receiving 11, 0.16, 0.25 and 3.6 metrictons per year (t/yr) of SigmaPAH14, SigmaNPAH5, SigmaSterane6 and SigmaHopane5, respectively. Maps of OC-adjusted concentrations display that concentrations decline with increasing off-shore distance. The major sources of PAHs and NPAHs are pyrogenic in nature, based on diagnostic ratios. Using chemical mass balance models, sources were apportioned to emissions from diesel engines (56 +/- 18%), coal power plants (27 +/- 14%), coal-tar pavement sealants (16 +/- 11%), and coke ovens (7 +/- 12%). The biomarkers identify a combination of petrogenic and biogenic sources, with the southern end of the lake more impacted by petroleum. This first report of NPAH levels in sediments of Lake Michigan reveals several carcinogenic compounds at modest concentrations, and a need for further work to assess potential risks to aquatic organisms. PMID- 24784743 TI - Structure, inter-annual recurrence, and global-scale connectivity of airborne microbial communities. AB - Dust coming from the large deserts on Earth, such as the Sahara, can travel long distances and be dispersed over thousands of square kilometers. Remote dust deposition rates are increasing as a consequence of global change and may represent a mechanism for intercontinental microbial dispersal. Remote oligotrophic alpine lakes are particularly sensitive to dust inputs and can serve as sentinels of airborne microbial transport and the ecological consequences of accelerated intercontinental microbial migration. In this study, we applied high throughput sequencing techniques (16S rRNA amplicon pyrosequencing) to characterize the microbial communities of atmospheric deposition collected in the Central Pyrenees (NE Spain) along three years. Additionally, bacteria from soils in Mauritania and from the air-water interface of high altitude Pyrenean lakes were also examined. Communities in aerosol deposition varied in time with a strong seasonal component of interannual similarity. Communities from the same season tended to resemble more each other than those from different seasons. Samples from disparate dates, in turn, slightly tended to have more dissimilar microbial assemblages (i.e., temporal distance decay), overall suggesting that atmospheric deposition may influence sink habitats in a temporally predictable manner. The three habitats examined (soil, deposition, and air-water interface) harbored distinct microbial communities, although airborne samples collected in the Pyrenees during Saharan dust outbreaks were closer to Mauritian soil samples than those collected during no Saharan dust episodes. The three habitats shared c.a. 1.4% of the total number of microbial sequences in the dataset. Such successful immigrants were spread in different bacterial classes. Overall, this study suggests that local and regional features may generate global trends in the dynamics and distribution of airborne microbial assemblages, and that the diversity of viable cells in the high atmosphere is likely higher than previously expected. PMID- 24784744 TI - PM2.5., EC and OC in atmospheric outflow from the Indo-Gangetic Plain: temporal variability and aerosol organic carbon-to-organic mass conversion factor. AB - Temporal variability (November'09-March'10) in the mass concentrations of PM2.5, mineral dust, organic carbon and elemental carbon (OC and EC), water-soluble organic carbon (WSOC) and inorganic species (WSIS) has been studied in the atmospheric outflow to the Bay of Bengal from a sampling site [Kharagpur: 22.02 degrees N, 87.11 degrees E] in the Indo-Gangetic Plain (IGP). Based on diagnostic ratios of carbonaceous species [OC/EC ~ 7.0 +/- 2.2, WSOC/OC ~ 0.52 +/- 0.16, and K(+)/EC~0.48+/-0.17], we document dominant impact from biomass burning emissions (wood-fuel and post-harvest agricultural-waste burning) in the IGP-outflow. Relatively high concentration of sulphate (SO4(2-) ~ 6.9-25.3 MUg m(-3); SO4(2 )/SigmaWSIS=45-77%) and characteristic ratios of nss-SO4(2-)/EC (3.9 +/- 2.1) and nss-SO4(2-)/OC (0.61 +/- 0.46) provide information on absorption/scattering properties of aerosols. Based on quantitative assessment of individual components of PM2.5, we document aerosol organic carbon-to-organic mass (OC to OM) conversion factor centring at 1.5 +/- 0.2 (range: 1.3-2.7) in the atmospheric outflow from IGP. The aerosol composition over the Bay of Bengal shows striking similarity with the diagnostic ratios documented for the IGP-outflow. Relatively high conversion factor for assessing the mass of organic aerosols over the Bay of Bengal (1.1-3.7) provides evidence for their oxidation during long-range atmospheric transport. PMID- 24784745 TI - Atmospheric particulate deposition in temperate deciduous forest ecosystems: interactions with the canopy and nutrient inputs in two beech stands of Northeastern France. AB - As wood harvests are expected to increase to satisfy the need for bio-energy in Europe, quantifying atmospheric nutrient inputs in forest ecosystems is essential for forest management. Current atmospheric measurements only take into account the <0.45 MUm fraction and dry deposition is generally modeled. The aims of this study were to quantify atmospheric particulate deposition (APD), the >0.45 MUm fraction of atmospheric deposition, below the canopy, to study the influence of the canopy on APD, and to determine the influence of APD below canopy to nutrient input-output budgets with a focus on base cations calcium, magnesium and potassium, and phosphorus. APD was sampled every four weeks by passive collectors. We divided APD into an organic and a mineral fraction, respectively POM and MDD. MDD was divided into a soluble and a hardly soluble fraction in hydrogen peroxide, referred to as S-MDD and H-MDD, respectively. In order to better understand the influence of the canopy on APD, we studied APD in three pathways below the canopy (litterfall, stemflow and throughfall), and in open field. Our results indicated that APD in throughfall (123 +/- 64 kg ha(-1)year( 1)) was significantly higher and synchronic with that in open field (33 +/-9 kg ha(-1)year(-1)) in the two study sites. This concerned both POM and MDD, suggesting a large interception of APD by foliar surfaces, which is rapidly washed off by rain within four weeks. Throughfall H-MDD was the main pathway with an average of 16 +/- 2 kg ha(-1)year(-1). Stemflow and litterfall were neglected. In one study site, canopy intercepted about 8 kg ha(-1)year(-1) of S-MDD. Although base cations and phosphorus inputs by APD are lower than those of <0.45 MUm deposition, they contributed from 5 to 32% to atmospheric deposition and improved the nutrient budget in one of the study sites. PMID- 24784746 TI - Detection of pharmaceuticals and other personal care products in groundwater beneath and adjacent to onsite wastewater treatment systems in a coastal plain shallow aquifer. AB - Onsite wastewater treatment systems (OWTS) are the predominant disposal method for human waste in areas without municipal sewage treatment alternatives. Relatively few studies have addressed the release of pharmaceuticals and personal care products (PPCPs) from OWTS to groundwater. PPCP fate and transport from OWTS are important, particularly where these systems are adjacent to sensitive aquatic ecosystems such as coastal areas or wetlands. The objectives of this study were to identify PPCPs in residential wastewater and groundwater beneath OWTS and to characterize the environmental conditions affecting the OWTS discharge of PPCPs to nearby streams. The study sites are in coastal plain aquifers, which may be considered vulnerable "end-members" for subsurface PPCP transport. The PPCPs most commonly detected in the OWTS, at concentrations ranging from 0.12 MUg L(-1) to 12.04 MUg L(-1) in the groundwater, included: caffeine, ibuprofen, DEET, and homosalate. Their presence was related to particulate and dissolved organic carbon abundance. PMID- 24784747 TI - Bioaccumulation of microcystins (MCs) in four fish species from Lake Taihu, China: assessment of risks to humans. AB - Microcystins (MCs) are the toxic products of harmful algal blooms and they accumulate in fish. The accumulation of MCs in fish living in different trophic levels from different parts of Lake Taihu was determined. This information was then used to evaluate the risks posed by the MCs in fish to human health. The concentrations of three MCs, MC-LR, MC-YR and MC-RR, were quantified in the following four fish species: silver carp (Hypophthalmichthys molitrix), bighead carp (Aristichthys nobilis), crucian carp (Carassius auratus) and common carp (Cyprinus carpio), using high performance liquid chromatography interfaced with tandem (triple quadrupole) mass spectrometry. The mean concentrations of MCs in the muscle, the kidney, the intestinal wall and the heart were significantly different among the four fishes except in the liver. C. carpio contained the highest mean concentration of MCs in the muscle (31.7 +/- 12.1 ng/g, dry mass (dm)), whereas C. auratus had the highest mean concentrations of MCs in the liver (45.4 +/- 44.5 ng/g, dm), kidney (114 +/- 51.1 ng/g, dm), intestinal wall (2.04 * 10(3)+/- 4.43 * 10(3)ng/g, dm) and heart (59.5 +/- 26.7 ng/g, dm). The mean concentration of MCs in the intestinal walls of the fish species was significantly higher than in other organs (p<0.01). The fish from Meiliang Bay had significantly higher concentrations of MCs than those from the centre, west or south banks of the lake (p<0.01). The body lengths and masses of the fish were negatively correlated with the concentrations of MCs in the kidney (p<0.05) and heart (p<0.01). The average daily intake (ADI) of MCs in the muscle of all fishes exceeded the provisional tolerable daily intake (TDI) set by World Health Organization. The estimated daily intakes of MCs in 55.6% of the muscle samples exceeded the TDI. The MCs in the tissues of the fish from Lake Taihu pose potential risks to the health of humans who consume these four fish species. PMID- 24784748 TI - Metal concentration in water, sediment and four fish species from Lake Titicaca reveals a large-scale environmental concern. AB - Although intensive mining activity and urban sewage discharge are major sources of metal inputs to Lake Titicaca, the risk posed by metal pollution to wildlife and human populations has been poorly studied. In this study we compared the concentrations of Cu, Zn, Cd, Hg, Pb, Co, and Fe in water, sediment, and two tissues (liver and muscle) of four fish species (Odontesthes bonariensis, Orestias luteus, Orestias agassii, and Trichomycterus rivulatus) across important fishery areas in Lake Titicaca. The concentration of Pb in water at the discharge sites of the main rivers and of most elements, with the exception of Co and Fe, in all fish collected in this study exceeded the safety thresholds established by international legislation. The highest metal concentrations were observed in benthopelagic species, and liver tissue was identified as the main depository for all metals with the exception of mercury. The metal bioaccumulation pattern in fish was weakly related to the metal concentrations in the environment with the exception of Hg at the most polluted location, partly explained by the different metabolic role of essential and non-essential elements and the influence of other factors such as species' ecology and individual traits in the bioaccumulation of most metals. As metal pollution extended across the study area and high metal concentrations were detected in all four fish species, we urge the authorities to enforce legislation for water and fish consumption and to evaluate the effects of metal pollution on fish health. PMID- 24784749 TI - Characterization of the Gacka River basin karst aquifer (Croatia): hydrochemistry, stable isotopes and tritium-based mean residence times. AB - The Gacka River basin aquifer is a highly-developed karst system, located in the Croatian Dinarides. It is mostly composed of permeable Jurassic and Cretaceous carbonate rocks, and clastic sedimentary rocks of Paleogene age. Gacka River provides high quality water for the town of Otocac and several villages; together with the neighboring Lika River, the water is used for the Hydroelectric Power Plant at Senj on the coast. About 10 perennial and over 20 seasonal springs are located at 450 to 460 ma.s.l. (above sea level). Three major springs (Pecina, Majerovo and Tonkovica) provide 57% of the mean annual river flow. Similarities between the average groundwater temperatures as well as between the average specific electrical conductivity values (9.0 degrees C-328 MUS/cm, 9.6 degrees C 350 MUS/cm and 8.9 degrees C-312 MUS/cm) of the springs imply that they are fed from aquifers with similar mean residence times (MRTs). The mean delta(18)O contents of Majerovo, Tonkovica, and Pecina are around -10.10/00, -9.20/00 and 8.90/00, respectively, revealing differences in the mean recharge area elevations. Compared to the temporal amplitude of the(18)O signal of precipitation, the (18)O signal variations of the springs are substantially attenuated because the recharges occurring at different times are well mixed within the aquifers. This indicates MRTs of more than just a few years. The average tritium contents of Pecina, Majerovo and Tonkovica are 5.48 TU, 6.13 TU and 6.17 TU, respectively. Serially connected exponential-plug type unsteady lumped-parameter models run on an annual time scale resulted in rather satisfactory matches between the observed and calculated tritium contents for all studied springs. The models revealed similar MRTs (and corresponding reservoir volumes) for Pecina, Tonkovica and Majerovo of 12 years (470 Mm(3)), 12 years (1,190 Mm(3)), and 12.2 years (1,210 Mm(3)), respectively. Plug flow conditions dominate in about 90% of the total aquifer volumes. PMID- 24784750 TI - Incorrect installation and use of materials as the cause of a severe air pollution incident in a school building. AB - The proofing treatment of the floor slabs with a solvent based material and successive treatment with epoxy resin resulted in significant air contamination in a primary school. The contamination caused illnesses in many occupants of school. The GC/MS investigations of the air showed the presence of indane and other aromatic solvents, which was unusual as they are not correlated to outdoor pollution and derived from inner layers of the new flooring. The total concentration of these chemicals in air was in the order of several mg/m(3). PMID- 24784751 TI - Heavy metal leaching and environmental risk from the use of compost-like output as an energy crop growth substrate. AB - Conversion of productive agricultural land towards growth of energy crops has become increasingly controversial. Closed landfill sites represent significant areas of brownfield land, which have potential for the establishment of energy crops. Increasingly composts are now being produced from the degradable fraction of mixed municipal solid waste (MSW) and are commonly referred to as Compost-Like Output (CLO). However, leaching of heavy metal and other elements due to the use of CLO as soil amendment has the potential to pose a risk to the wider environment as a diffuse pollution source if not managed correctly. Salix viminalis and Eucalyptus nitens were grown at 5 different CLO application rates (equivalent to 250, 1000, 3000, 6000, 1,0000 kg N/Ha) with weekly leachate analysis to assess the solubility of heavy metals and the potential release into the environment. The change in plant total dry mass suggested 3,000 kgN/Ha as the optimum application rate for both species. Weekly leachate analysis identified excess soluble ions within the first 4 weeks, with heavy metals concentrations exceeding water quality limits at the higher application rates (>3,000 kg N/Ha). Heavy metal uptake and accumulation within each species was also investigated; S. viminalis accumulated greater levels of heavy metals than E. nitens with a general trend of metal accumulation in root>stem>leaf material. Heavy metal leaching from soils amended with CLO has the potential to occur at neutral and slightly alkaline pH levels as a result of the high buffering capacity of CLO. The use of CLO at application rates of greater than 250 kg N/Ha may be limited to sites with leachate collection and containment systems, not solely for the heavy metal leaching but also excess nitrogen leaching. Alternatively lower application rates are required but will also limit biomass production. PMID- 24784752 TI - Contrasting microbial functional genes in two distinct saline-alkali and slightly acidic oil-contaminated sites. AB - To compare the functional gene structure and diversity of microbial communities in saline-alkali and slightly acidic oil-contaminated sites, 40 soil samples were collected from two typical oil exploration sites in North and South China and analyzed with a comprehensive functional gene array (GeoChip 3.0). The overall microbial pattern was significantly different between the two sites, and a more divergent pattern was observed in slightly acidic soils. Response ratio was calculated to compare the microbial functional genes involved in organic contaminant degradation and carbon, nitrogen, phosphorus, and sulfur cycling. The results indicated a significantly low abundance of most genes involved in organic contaminant degradation and in the cycling of nitrogen and phosphorus in saline alkali soils. By contrast, most carbon degradation genes and all carbon fixation genes had similar abundance at both sites. Based on the relationship between the environmental variables and microbial functional structure, pH was the major factor influencing the microbial distribution pattern in the two sites. This study demonstrated that microbial functional diversity and heterogeneity in oil contaminated environments can vary significantly in relation to local environmental conditions. The limitation of nitrogen and phosphorus and the low degradation capacity of organic contaminant should be carefully considered, particularly in most oil-exploration sites with saline-alkali soils. PMID- 24784753 TI - Influence of hen breeding type on PCDD/F, PCB & PBDE levels in eggs. AB - The aim of this study was to assess levels of PCDD/Fs, PCBs and PBDEs in free range eggs and in farm eggs available on the Polish retail market. Congener profiles that might be used to identify different sources of contamination have also been assessed. Generally higher mean values of PCDD/F, PCB and PBDEs found in free range eggs than in farm eggs reflect occurrence of highly contaminated samples. However, medians were similar in both groups; PCDD/F medians were even higher in farm eggs. High concentrations (accompanied by changed congener profile) indicate contamination sources other than environmental background. Congener profiles and absolute concentration values found in majority of the tested samples from both groups were typical for environmental background of the studied persistent organic pollutants. Due to their small market share free range eggs do not seem to pose any essential threat to human health. PMID- 24784754 TI - Application of constructed wetlands for wastewater treatment in developing countries--a review of recent developments (2000-2013). AB - Inadequate access to clean water and sanitation has become one of the most pervasive problems afflicting people throughout the developing world. Replication of centralized water-, energy- and cost-intensive technologies has proved ineffective in resolving the complex water-related problems resulting from rapid urbanization in the developing countries. Instead constructed wetlands (CWs) have emerged and become a viable option for wastewater treatment, and are currently being recognized as attractive alternatives to conventional wastewater treatment methods. The primary objective of this review is to present a comprehensive overview of the diverse range of practice, applications and researches of CW systems for removing various contaminants from wastewater in developing countries, placing them in the overall context of the need for low-cost and sustainable wastewater treatment systems. Emphasis of this review is placed on the treatment performance of various types of CWs including: (i) free water surface flow CW; (ii) subsurface flow CW; (iii) hybrid systems; and, (iv) floating treatment wetland. The impacts of different wetland design and pertinent operational variables (e.g., hydraulic loading rate, vegetation species, physical configurations, and seasonal variation) on contaminant removal in CW systems are also summarized and highlighted. Finally, the cost and land requirements for CW systems are critically evaluated. PMID- 24784755 TI - Prolonged use of nimotuzumab in children with central nervous system tumors: safety and feasibility. AB - Primary brain tumors constitute the most frequent solid tumor of childhood. High expression of the epidermal growth factor receptor (EGFR) protein has been associated with tumor progression and enhanced tumorigenicity in adult and children gliomas. Nimotuzumab is a humanized antibody that targets the EGFR and has proven efficacy in adult and children gliomas. To provide a new therapeutic option for patients with active, poor prognosis central nervous system (CNS) tumors and to evaluate the feasibility and safety of long-term nimotuzumab therapy in children with diverse CNS tumors, an expanded access program was launched at the Juan Manuel Marquez hospital. Patients were required to be 18 or younger and have one CNS tumor: low-grade glioma (LGG) or high-grade glioma (HGG), brainstem glioma (BSG), ependymoma or primitive neuroectodermal tumor (PNET), and a Lansky or Karnofsky performance status >=40. Treatment consisted of weekly nimotuzumab administered at 150 mg/m(2) for 12 weeks, continuing every 14 days in the absence of severe condition worsening or unacceptable toxicity. Nimotuzumab was administered alone or in combination with radiotherapy, chemotherapy, or both, depending on the tumor type, stage, and previous treatment. Eighty-eight patients, 39 with BSG, 25 with HGG, 9 with progressive LGG, 9 with anaplastic ependymomas, and 6 with other tumor types, including PNET, neuroblastoma, meduloblastoma, and thalamic tumors, were treated with the antibody. The mean number of nimotuzumab doses was 36, from 1 to 108. The most frequent adverse events were mild to moderate skin rash, mucositis, vomiting, seizures, hypothermia, hyperthermia, and paleness. One patient had a grade 3 mucositis, while the other had a grade 3 bleeding on surgery. Sixteen children stopped treatment after at least 2 years with stable disease, partial or complete response. All children were able to maintain the best response achieved on treatment after a 3-year interruption. In summary, this study shows the feasibility of very prolonged administration of nimotuzumab together with the lack of rebound effect after treatment cessation. PMID- 24784756 TI - Feasibility of eyes open alpha power training for mental enhancement in elite gymnasts. AB - This study focuses on a novel, easy to use and instruction-less method for mental training in athletes. Previous findings suggest that particular mental capacities are needed for achieving peak performance; including attentional control, focus, relaxation and positive affect. Electroencephalography (EEG) alpha brain activity has been associated with neural inhibition during processes of selective attention, for improving efficiency in information processing. Here we hypothesised that eyes open alpha power training by music teaches athletes to (1) learn to self-regulate their brain activity, and (2) learn to increase their baseline alpha power, herewith improving mental capacities such as focusing the allocation of attention. The study was double-blind and placebo-controlled. Twelve elite gymnasts were either given eyes open alpha power training or random beta power training (controls). Results indicate small improvements in sleep quality, mental and physical shape. In our first attempt at getting a grip on mental capacities in athletes, we think this novel training method can be promising. Because gymnastics is one of the most mentally demanding sports, we value even small benefits for the athlete and consider them indicative for future research. PMID- 24784757 TI - A UDP-Glucose:Monoterpenol Glucosyltransferase Adds to the Chemical Diversity of the Grapevine Metabolome. AB - Terpenoids represent one of the major classes of natural products and serve different biological functions. In grape (Vitis vinifera), a large fraction of these compounds is present as nonvolatile terpene glycosides. We have extracted putative glycosyltransferase (GT) sequences from the grape genome database that show similarity to Arabidopsis (Arabidopsis thaliana) GTs whose encoded proteins glucosylate a diversity of terpenes. Spatial and temporal expression levels of the potential VvGT genes were determined in five different grapevine varieties. Heterologous expression and biochemical assays of candidate genes led to the identification of a UDP-glucose:monoterpenol beta-d-glucosyltransferase (VvGT7). The VvGT7 gene was expressed in various tissues in accordance with monoterpenyl glucoside accumulation in grape cultivars. Twelve allelic VvGT7 genes were isolated from five cultivars, and their encoded proteins were biochemically analyzed. They varied in substrate preference and catalytic activity. Three amino acids, which corresponded to none of the determinants previously identified for other plant GTs, were found to be important for enzymatic catalysis. Site specific mutagenesis along with the analysis of allelic proteins also revealed amino acids that impact catalytic activity and substrate tolerance. These results demonstrate that VvGT7 may contribute to the production of geranyl and neryl glucoside during grape ripening. PMID- 24784758 TI - Hemoglobin Control of Cell Survival/Death Decision Regulates in Vitro Plant Embryogenesis. AB - Programmed cell death (PCD) in multicellular organisms is a vital process in growth, development, and stress responses that contributes to the formation of tissues and organs. Although numerous studies have defined the molecular participants in apoptotic and PCD cascades, successful identification of early master regulators that target specific cells to live or die is limited. Using Zea mays somatic embryogenesis as a model system, we report that the expressions of two plant hemoglobin (Hb) genes (ZmHb1 and ZmHb2) regulate the cell survival/death decision that influences somatic embryogenesis through their cell specific localization patterns. Suppression of either of the two ZmHbs is sufficient to induce PCD through a pathway initiated by elevated NO and Zn2+ levels and mediated by production of reactive oxygen species. The effect of the death program on the fate of the developing embryos is dependent on the localization patterns of the two ZmHbs. During somatic embryogenesis, ZmHb2 transcripts are restricted to a few cells anchoring the embryos to the subtending embryogenic tissue, whereas ZmHb1 transcripts extend to several embryonic domains. Suppression of ZmHb2 induces PCD in the anchoring cells, allowing the embryos to develop further, whereas suppression of ZmHb1 results in massive PCD, leading to abortion. We conclude that regulation of the expression of these ZmHbs has the capability to determine the developmental fate of the embryogenic tissue during somatic embryogenesis through their effect on PCD. This unique regulation might have implications for development and differentiation in other species. PMID- 24784759 TI - Global Regulation of Embryonic Patterning in Arabidopsis by MicroRNAs. AB - The development of the embryo in Arabidopsis (Arabidopsis thaliana) involves a carefully controlled set of cell divisions and cell fate decisions that lead to a mature embryo containing shoot and root meristems and all basic tissue types. Over the last 20 years, a number of transcriptional regulators of embryonic patterning have been described, but little is known about the role of posttranscriptional regulators such as microRNAs (miRNAs). Previous work has centered on the study of null or very weak alleles of miRNA biosynthetic genes, but these mutants either arrest early in embryogenesis or have wild-type-looking embryos. Here, we significantly extend those analyses by characterizing embryos mutant for a strong hypomorphic allele of DICER-LIKE1 (dcl1-15). Our data demonstrate that miRNAs are required for the patterning of most regions of the embryo, with the exception of the protoderm. In mutant embryos with the most severe morphological defects, the majority of tissue identities are lost. Different levels of miRNAs appear to be required to specify cell fates in various regions of the embryo. The suspensor needs the lowest levels, followed by the root apical meristem and hypocotyl, cotyledons, and shoot apical meristem. Furthermore, we show that erecta acts as a suppressor of dcl1-15, a novel role for this signaling pathway in embryos. Our results also indicate that the regulation of the messenger RNA levels of miRNA targets involves not just the action of miRNAs but has a significant transcriptional component as well. PMID- 24784760 TI - Overexpression of a Calcium-Dependent Protein Kinase Confers Salt and Drought Tolerance in Rice by Preventing Membrane Lipid Peroxidation. AB - The OsCPK4 gene is a member of the complex gene family of calcium-dependent protein kinases in rice (Oryza sativa). Here, we report that OsCPK4 expression is induced by high salinity, drought, and the phytohormone abscisic acid. Moreover, a plasma membrane localization of OsCPK4 was observed by transient expression assays of green fluorescent protein-tagged OsCPK4 in onion (Allium cepa) epidermal cells. Overexpression of OsCPK4 in rice plants significantly enhances tolerance to salt and drought stress. Knockdown rice plants, however, are severely impaired in growth and development. Compared with control plants, OsCPK4 overexpressor plants exhibit stronger water-holding capability and reduced levels of membrane lipid peroxidation and electrolyte leakage under drought or salt stress conditions. Also, salt-treated OsCPK4 seedlings accumulate less Na+ in their roots. We carried out microarray analysis of transgenic rice overexpressing OsCPK4 and found that overexpression of OsCPK4 has a low impact on the rice transcriptome. Moreover, no genes were found to be commonly regulated by OsCPK4 in roots and leaves of rice plants. A significant number of genes involved in lipid metabolism and protection against oxidative stress appear to be up regulated by OsCPK4 in roots of overexpressor plants. Meanwhile, OsCPK4 overexpression has no effect on the expression of well-characterized abiotic stress-associated transcriptional regulatory networks (i.e. ORYZA SATIVA DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN1 and ORYZA SATIVA No Apical Meristem, Arabidopsis Transcription Activation Factor1-2, Cup-Shaped Cotyledon6 genes) and LATE EMBRYOGENESIS ABUNDANT genes in their roots. Taken together, our data show that OsCPK4 functions as a positive regulator of the salt and drought stress responses in rice via the protection of cellular membranes from stress induced oxidative damage. PMID- 24784761 TI - Prevalence of vitamin D inadequacy in European women aged over 80 years. AB - Inadequate vitamin D status is associated with secondary hyperparathyroidism and increased bone turnover and bone loss, which in turn increases fracture risk. The objective of this study is to assess the prevalence of inadequate vitamin D status in European women aged over 80 years. Assessments of serum 25 hydroxyvitamin D levels (25(OH)D) were performed on 8532 European women with osteoporosis or osteopenia of which 1984 were aged over 80 years. European countries included in the study were: France, Belgium, Denmark, Italy, Poland, Hungary, United Kingdom, Spain and Germany. Two cut-offs of 25(OH)D inadequacy were fixed: <75 nmol/L (30 ng/ml) and <50 nmol/L (20 ng/ml). Mean (SD) age of the patients was 83.4 (2.9) years, body mass index was 25.0 (4.0) kg/m(2) and level of 25(OH)D was 53.3 (26.7) nmol/L (21.4 [10.7] ng/ml). There was a highly significant difference of 25(OH)D level across European countries (p<0.0001). In these women aged over 80 years, the prevalence of 25(OH)D inadequacy was 80.9% and 44.5% when considering cut-offs of 75 and 50 nmol/L, respectively. In the 397 (20.0%) patients taking supplemental vitamin D with or without supplemental calcium, the mean serum 25(OH)D level was significantly higher than in the other patients (65.2 (29.2) nmol/L vs. 50.3 (25.2) nmol/L; P<0.001). This study indicates a high prevalence of vitamin D (25(OH)D) inadequacy in old European women. The prevalence could be even higher in some particular countries. PMID- 24784762 TI - Summary health statistics for the U.S. population: National Health Interview Survey, 2012. AB - OBJECTIVES: This report presents both age-adjusted and unadjusted health statistics from the 2012 National Health Interview Survey (NHIS) for the civilian noninstitutionalized population of the United States. Estimates are disaggregated by sex, age, race, Hispanic origin, education, family income, poverty status, health insurance coverage (where appropriate), place of residence, and region of residence. The topics covered are respondent-assessed health status, limitations in activities, injury and poisoning episodes, health care access and utilization, and health insurance coverage. DATA SOURCE: NHIS is a household, multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention's National Center for Health Statistics. In 2012, household interviews were completed for 108,131 persons living in 42,366 households. SELECTED HIGHLIGHTS: Nearly 7 in 10 persons were in excellent or very good health in 2012. About 40 million persons (12%) were limited in their usual activities due to one or more chronic health conditions. About 5 million persons (2%) required the help of another person with activities of daily living, and about 10 million persons (4%) required the help of another person with instrumental activities of daily living. Among persons under age 65, about 45 million (17%) did not have any health insurance coverage. The most common reason for lacking health insurance was cost, followed by a change in employment. PMID- 24784763 TI - HIV protective efficacy and correlates of tenofovir blood concentrations in a clinical trial of PrEP for HIV prevention. AB - BACKGROUND: Antiretroviral pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy for which adherence is a known determinant of efficacy. Blood concentrations of PrEP medications are one objective marker of adherence. METHODS: In a placebo-controlled PrEP efficacy trial of tenofovir disoproxil fumarate (TDF) and TDF with emtricitabine (FTC/TDF) among 4747 African women and men with an HIV-infected partner, we measured plasma tenofovir concentrations from participants in the active PrEP arms: 29 HIV seroconverters (cases) and 196 randomly selected controls who remained uninfected. RESULTS: Among controls, 71% of visits had tenofovir concentrations >40 ng/mL, consistent with steady-state daily dosing, compared with 21% of cases at the visit HIV was first detected. Pill count data indicated that 96% of controls and 66% of cases had >80% adherence for these same visits. The estimated protective effect of PrEP against HIV, based on concentrations >40 ng/mL, was 88% (95% confidence interval: 60 to 96, P < 0.001) for individuals receiving TDF and 91% (95% confidence interval: 47 to 98, P = 0.008) for individuals receiving FTC/TDF. Controls had consistent patterns of PrEP concentrations during follow-up; among the 81% with concentrations >40 ng/mL at month 1, 75% maintained this concentration at month 12. Only 5 of 29 seroconverters seemed to be consistently adherent to PrEP. Tenofovir concentrations >40 ng/mL were associated with older age and shorter time on study; concentrations <=40 ng/mL occurred more commonly when participants reported no sex with their HIV-infected partner. CONCLUSIONS: Plasma concentrations of tenofovir consistent with daily dosing were highly predictive of protection from HIV acquisition. Most of those who took PrEP seemed to have high and consistent adherence. PMID- 24784764 TI - Regulatory T cells in HIV-infected immunological nonresponders are increased in blood but depleted in lymphoid tissue and predict immunological reconstitution. AB - BACKGROUND: HIV-infected immunological nonresponders fail to immune reconstitute despite optimal treatment. We hypothesized that regulatory T cells (Tregs) are involved in immunological reconstitution. Tregs and Treg subpopulations were measured in blood and Foxp3 cells in lymphoid tissue, and the impact of Tregs on immunological reconstitution was determined. METHODS: HIV-infected individuals on combination antiretroviral therapy for a minimum of 2 years were included. The study population included 14 immunological nonresponders (INR; CD4 T-cell count <200 cells/MUL), 33 intermediate responders (CD4 T-cell count 200-500 cells/MUL), 30 responders (CD4 T-cell count >500 cells/MUL), and 34 healthy controls. Tregs, Treg subpopulations, and intracellular staining for interleukin 10 in peripheral blood were measured using flow cytometry. Foxp3 cells in lymphoid tissue were evaluated using immunolabeling. The CD4 T-cell count was determined at inclusion and after 1 year of follow-up. RESULTS: INR displayed high percentage of Tregs and activated Tregs in peripheral blood accompanied by a high percentage of Tregs expressing interleukin 10, whereas numbers of Foxp3 cells in lymphoid tissue were low. In contrast, responders resembled healthy controls. Finally, in INR, high level of Tregs in blood and Foxp3 cells in lymphoid tissue were associated with higher level of immunological reconstitution after 1 year of follow-up. CONCLUSIONS: In conclusion, altered distribution of Tregs was found in INR. Interestingly, high level of Tregs predicted higher level of immunological reconstitution suggesting a role for Tregs in immunological reconstitution. PMID- 24784765 TI - Emerging technologies in point-of-care molecular diagnostics for resource-limited settings. AB - Emerging molecular technologies to diagnose infectious diseases at the point at which care is delivered have the potential to save many lives in developing countries where access to laboratories is poor. Molecular tests are needed to improve the specificity of syndromic management, monitor progress towards disease elimination and screen for asymptomatic infections with the goal of interrupting disease transmission and preventing long-term sequelae. In simplifying laboratory based molecular assays for use at point-of-care, there are inevitable compromises between cost, ease of use and test performance. Despite significant technological advances, many challenges remain for the development of molecular diagnostics for resource-limited settings. There needs to be more advocacy for these technologies to be applied to infectious diseases, increased efforts to lower the barriers to market entry through streamlined and harmonized regulatory approaches, faster policy development for adoption of new technologies and novel financing mechanisms to enable countries to scale up implementation. PMID- 24784766 TI - Light controlled reversible inversion of nanophosphor-stabilized Pickering emulsions for biphasic enantioselective biocatalysis. AB - In this work, by utilizing photochromic spiropyrans conjugated upconversion nanophosphors, we have successfully prepared NIR/visible light tuned interfacially active nanoparticles for the formulation of Pickering emulsions with reversible inversion properties. By loading a model enantioselective biocatalytic active bacteria Alcaligenes faecalis ATCC 8750 in the aqueous phase, we demonstrated for the first time that the multifunctional Pickering emulsion not only highly enhanced its catalytic performance but also relieved the substrate inhibition effect. In addition, product recovery, and biocatalysts and colloid emulsifiers recycling could be easily realized based on the inversion ability of the Pickering emulsion. Most importantly, the utilization of NIR/visible light to perform the reversible inversion without any chemical auxiliaries or temperature variation showed little damage toward the biocatalysts, which was highlighted by the high catalytic efficiency and high enantioselectivity even after 10 cycles. The NIR/visible light controlled Pickering emulsion showed promising potential as a powerful technique for biocatalysis in biphasic systems. PMID- 24784767 TI - Functional materials from self-assembled bis-urea macrocycles. AB - CONSPECTUS: This Account highlights the work from our laboratories on bis-urea macrocycles constructed from two C-shaped spacers and two urea groups. These simple molecular units assembled with high fidelity into columnar structures guided by the three-centered urea hydrogen bonding motif and aryl stacking interactions. Individual columns are aligned and closely packed together to afford functional and homogeneous microporous crystals. This approach allows for precise and rational control over the dimensions of the columnar structure simply by changing the small molecular unit. When the macrocyclic unit lacks a cavity, columnar assembly gives strong pillars. Strong pillars with external functional groups such as basic lone pairs can expand like clays to accept guests between the pillars. Macrocycles that contain sizable interior cavities assemble into porous molecular crystals with aligned, well-defined columnar pores that are accessible to gases and guests. Herein, we examine the optimal design of the macrocyclic unit that leads to columnar assembly in high fidelity and probe the feasibility of incorporating a second functional group within the macrocycles. The porous molecular crystals prepared through the self-assembly of bis-urea macrocycles display surface areas similar to zeolites but lower than MOFs. Their simple one-dimensional channels are well-suited for studying binding, investigating transport, diffusion and exchange, and monitoring the effects of encapsulation on reaction mechanism and product distribution. Guests that complement the size, shape, and polarity of the channels can be absorbed into these porous crystals with repeatable stoichiometry to form solid host-guest complexes. Heating or extraction with an organic solvent enables desorption or removal of the guest and subsequent recovery of the solid host. Further, these porous crystals can be used as containers for the selective [2 + 2] cycloadditions of small enones such as 2-cyclohexenone or 3-methyl cyclopentenone, while larger hosts bind and facilitate the photodimerization of coumarin. When the host framework incorporates benzophenone, a triplet sensitizer, UV-irradiation in the presence of oxygen efficiently generates singlet oxygen. Complexes of this host were employed to influence the selectivity of photooxidations of 2-methyl-2-butene and cumene with singlet oxygen. Small systematic changes in the channel and bound reactants should enable systematic evaluation of the effects of channel dimensions, guest dimensions, and channel guest interactions on the processes of absorption, diffusion, and reaction of guests within these nanochannels. Such studies could help in the development of new materials for separations, gas storage, and catalysis. PMID- 24784768 TI - Crossbreeding: implications for dairy cow fertility and survival. AB - In pasture-based seasonal calving systems, failure to become pregnant during the breeding season results in important economic losses as maximum profit is attained by minimising costs and increasing the proportion of grass in the diet of the lactating dairy cow. In the United States, dairy producers primarily strive to maximise production potential but are becoming increasingly aware of the economic consequences of sub-optimal cow fertility and survival. For this reason, interest in crossbreeding is emerging. The objective of this paper is to review the fertility and survival outcomes reported from recent research studies and data analyses in Ireland, New Zealand and the United States. Research conducted in Ireland during the early 2000s concluded that of three 'alternative' dairy breeds the Norwegian Red was most suited to seasonal grass-based production. A key finding was favourable fertility and survival. A follow-up study confirmed a fertility advantage with Norwegian Red*Holstein-Friesian compared with Holstein-Friesian: proportion pregnant to first service; +0.08 and in-calf after 6 weeks breeding; +0.11. Another study found higher fertility with Jersey crossbreds: pregnant to first service; +0.21, and in-calf after 6 weeks breeding; +0.19. Studies conducted in Northern Ireland also found superior fertility performance with Jersey crossbred cows offered low and moderate concentrate diets. In New Zealand, crossbred dairy cattle (primarily Jersey*Friesian) are achieving similar rates of genetic gain for farm profit as the purebred populations, but creating additional gain derived from economic heterosis. In the United States, analysis of commercial data from California showed higher first-service conception rates for Scandinavian Red*Holstein (+6 percentage units) and Montbeliarde*Holstein (+10 percentage units) compared with Holstein (23%). They also exhibited fewer days open and greater survival. At Penn State University, Brown Swiss*Holstein cows had 17 fewer days open than Holstein cows during first lactation, and numerically fewer in second (12 days) and third lactation (6 days). At the University of Minnesota, crossbred cows had 21 percentage units higher first-service conception rates, 41 fewer days open and 12 percentage units higher in-calf rates compared with pure Holstein cows. They also had greater survival to second (+13 percentage units), third (+24 percentage units), fourth (+25 percentage units) and fifth (+17 percentage units) lactation. The literature clearly illustrates favourable animal performance benefits from crossbreeding, using a range of modern breeds, and within the context of both grass-based and high-input confinement production environments. Economic analyses generally indicate profitable performance owing to lower replacement cost and higher herd productivity. PMID- 24784769 TI - Benzosulfonamides in wastewater: method development, occurrence and removal efficiencies. AB - Benzosulfonamides (BeSAs) are a family of compounds with a broad application as industrial chemicals: plasticizers, intermediates for pesticides and drugs or used in the production of artificial sweeteners, among others. BeSAs constitute a class of organic compounds of emerging environmental concern. However, analytical methodologies for their determination in the environment are scarce as well as there is a lack of environmental occurrence data for these substances. An analytical methodology based on pseudo-SRM liquid chromatography-tandem mass spectrometry (LC-(ESI-)MS/MS) was developed and optimized for the determination of three BeSAs (benzenesulfonamide (BSA), o-toluenesulfonamide (o-TSA) and p toluenesulfonamide (p-TSA)) in wastewater. The solid phase extraction protocol was also carefully optimized. The method provided recoveries in the range 83-118% (three different fortification levels). Good precision (<10.2% (intra-day) and <13.6% (inter-day)) and limits of detection achieved (11-89 ng L(-1)) allow a reliable quantification of these compounds in both effluent and influent wastewaters. The presence of BeSAs has been evaluated during seven consecutive days in influent and effluent samples from the wastewater treatment plant of Athens, Greece. o-TSA and p-TSA were detected in 100% of the samples, while BSA was detected in all the influents and in 43% of the effluents. All three compounds were determined in relevant concentrations (up to 1.4 MUg L(-1) in the case of p-TSA), constituting the first evidence of the presence of these compounds in Greece, and contributing to the scarce occurrence data. Removal efficiencies of BeSAs during wastewater treatment was also assessed and discussed. In this regard, different behaviors were observed: while BSA and p-TSA were removed in different rates, o-TSA was formed during wastewater treatment. A daily load of 0.48 kg of o-TSA and 0.47 kg of p-TSA was discarded in the receiving Saronikos Gulf. PMID- 24784770 TI - BFR international symposia: now expanded to also include phosphorus-based and other flame retardants. PMID- 24784771 TI - Evaluation of aeration energy saving in two modified activated sludge processes. AB - A variety of modified activated sludge processes are widely used in wastewater treatment plants (WWTPs) for removing organics and nutrients (N and P). Since energy consumption in aeration basin accounts for the major part of the overall energy usage in WWTPs, efforts have been made to find ways to reduce aeration energy. In this study, two modified activated sludge processes in a pilot scale designed for nutrient removal were evaluated for the extent of energy saving: (1) ABA(2) process - adjusting air on/off period (i.e., with a temporal change); and (2) MB-A(2)O process - changing volume ratio of aerobic tank to anoxic tank (i.e., with a spatial change). For the 1st process, the air on/off period was fixed at 60min/45min with aerobic fraction being 0.57, while for the 2nd process, the aerobic/anoxic volume ratio was reduced from 0.58 to 0.42. The results demonstrate that the effluent COD, TN, NH4(+) and TP concentrations are acceptable while reduced aeration time/volume certainly saves significant energy consumption. To the best of our knowledge, this is 1st attempt to reduce the aeration period or aeration volume to save the aeration energy in these two modified activated sludge processes. The implication of these observations is further discussed. PMID- 24784772 TI - Nanostructure and charge transfer in Bi2S3-TiO2 heterostructures. AB - Interfacial nanostructures in Bi2S3-TiO2 nanorod-nanoparticle heterostructures with a change of coupling mode have been engineered. The samples were characterized by x-ray diffraction, scanning electron microscopy, transmission electron microscopy, and ultraviolet-visual light absorption spectroscopy. By means of in situ growth of TiO2 nanoparticles on the surfaces of Bi2S3 nanorods in one pot, heterostructures with high-quality interfaces were obtained in which the {105} facet of anatase TiO2 selectively coupled with the {010} facet of orthorhombic Bi2S3 nanorods without any crystal defects, showing the epitaxial relationship of Bi2S3 {011} // TiO2 {101}. By means of a two-step method, TiO2 nanoparticles also could be grown on the {310} facet of the pre-prepared Bi2S3 nanorods to form heterostructures but with interfacial defects. Charge transfer in the interface-different heterostructures was evaluated by photodegradation of methyl orange under visible-light irradiation. The defect-free interfaces favored electron-hole separation and transfer, resulting in improved photocatalytic activity. The current structural characterization and interface engineering should be expanded to other heterostructures when studying the relationship between synthesis, interfacial structure, and photocatalytic or photovoltaic applications. PMID- 24784773 TI - Allergic rhinitis and its impact on asthma classification correlations. AB - OBJECTIVE: Allergic rhinitis is inflammation of the nasal mucosa following exposure to allergens. A few studies have investigated how the Allergic Rhinitis and its Impact on Asthma classification correlates with symptom severity and skin prick test results in allergic rhinitis patients. Our objective was to evaluate such a correlation. MATERIALS AND METHODS: The study population consisted of 268 patients who had allergic symptoms and were diagnosed with allergic rhinitis. RESULTS: Analysis of the Allergic Rhinitis and its Impact on Asthma classification with regard to symptom severity revealed that there were statistically significant differences between the groups for nasal symptoms, wheezing, eye itching/watering and eye redness. Symptom frequency and severity increased gradually towards the moderate to severe persistent allergic group. There was a statistically significant difference between the groups for grass pollen and house dust mite allergy. CONCLUSION: The Allergic Rhinitis and its Impact on Asthma classification, which takes symptoms and quality of life into consideration in addition to allergen exposure, is a useful classification system for allergic rhinitis. PMID- 24784774 TI - Atmospheric reaction of Cl + methacrolein: a theoretical study on the mechanism, and pressure- and temperature-dependent rate constants. AB - Methacrolein is a major degradation product of isoprene, the reaction of methacrolein with Cl atoms may play some roles in the degradation of isoprene where these species are relatively abundant. However, the energetics and kinetics of this reaction, which govern the reaction branching, are still not well understood so far. In the present study, two-dimensional potential energy surfaces were constructed to analyze the minimum energy path of the barrierless addition process between Cl and the C?C double bond of methacrolein, which reveals that the terminal addition intermediate is directly formed from the addition reaction. The terminal addition intermediate can further yield different products among which the reaction paths abstracting the aldehyde hydrogen atom and the methyl hydrogen atom are dominant reaction exits. The minimum reaction path for the direct aldehydic hydrogen atom abstraction is also obtained. The reaction kinetics was calculated by the variational transition state theory in conjunction with the master equation method. From the theoretical model we predicted that the overall rate constant of the Cl + methacrolein reaction at 297 K and atmospheric pressure is koverall = 2.3* 10(-10) cm(3) molecule(-1) s(-1), and the branching ratio of the aldehydic hydrogen abstraction is about 12%. The reaction is pressure dependent at P < 10 Torr with the high pressure limit at about 100 Torr. The calculated results could well account for the experimental observations. PMID- 24784775 TI - The effects of neoadjuvant chemoradiotherapy on physical fitness and morbidity in rectal cancer surgery patients. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) followed by surgery for resectable locally advanced rectal cancer improves outcome compared with surgery alone. Our primary hypothesis was that NACRT impairs objectively-measured physical fitness. We also wished to explore the relationship between fitness and postoperative outcome. METHOD: In an observational study, we prospectively studied 27 consecutive patients, of whom 25 undertook cardiopulmonary exercise testing (CPET) 2 weeks before and 7 weeks after standardized NACRT, then underwent surgery. In-hospital post-operative morbidity and mortality were recorded. Patients were followed up to 1 year for mortality. Data was analysed blind to clinical details. Receiver-operating characteristic (ROC) analysis defined the predictive value of CPET for in-hospital morbidity at day 5. RESULTS: Oxygen uptake ( [Formula: see text] in ml kg(-1) min(-1)) at estimated lactate threshold (theta^L) and at peak exercise ( [Formula: see text] at peak in ml kg( 1) min(-1)) both significantly decreased post-NACRT: [Formula: see text] at theta^L 12.1 (pre-NACRT) vs. 10.6 (post-NACRT), p < 0.001 (95%CI -1.7, -1.2); [Formula: see text] at peak 18.1 vs. 16.7, p < 0.001 (95%CI -3.1, -1.0). Optimal [Formula: see text] at theta^L and peak pre-NACRT for predicting postoperative morbidity were 12.0 and 18.1 ( [Formula: see text] at theta^L - AUC = 0.71, 77% sensitive and 75% specific; [Formula: see text] at peak - AUC = 0.75, 78% sensitive and 76% specific). Optimal [Formula: see text] at theta^L and peak post NACRT for predicting postoperative morbidity were 10.7 and 16.7 ( [Formula: see text] at theta^L - AUC = 0.72, 77% sensitive and 83% specific; [Formula: see text] at peak - AUC = 0.80, 85% sensitive and 83% specific). CONCLUSION: NACRT before major rectal cancer surgery significantly decreased physical fitness as assessed by CPET. TRIALS REGISTRY NUMBER: NCT01334593. PMID- 24784777 TI - RECOMB/ISCB systems biology, regulatory genomics, and DREAM 2013 special issue. PMID- 24784776 TI - VEGF-A clinical significance in gastric cancers: immunohistochemical analysis of a wide Italian cohort. AB - PURPOSE: The clinical significance of VEGF-A expression in gastric cancer (GC) has been reported with contradicting results. We analyzed the expression and clinical significance of VEGF-A in a wide Italian cohort of GC specimens. METHODS: VEGF-A expression was tested by immunohistochemistry in 507 patients with GC of all clinical stages. The impact of VEGF-A on overall survival (OS) was evaluated in conjunction with clinical and pathological parameters. RESULTS: In the Italian cohort we studied VEGF-A was not an independent prognostic factor neither at the univariate nor at multivariate analysis. CONCLUSIONS: Although frequently expressed, in our study VEGF-A was not able to discriminate between groups of patients with different risk. PMID- 24784778 TI - Polarization singularities and orbital angular momentum sidebands from rotational symmetry broken by the Pockels effect. AB - The law of angular momentum conservation is naturally linked to the rotational symmetry of the involved system. Here we demonstrate theoretically how to break the rotational symmetry of a uniaxial crystal via the electro-optic Pockels effect. By numerical method based on asymptotic expansion, we discover the 3D structure of polarization singularities in terms of C lines and L surfaces embedded in the emerging light. We visualize the controllable dynamics evolution of polarization singularities when undergoing the Pockels effect, which behaves just like the binary fission of a prokaryotic cell, i.e., the splitting of C points and fission of L lines are animated in analogy with the cleavage of nucleus and division of cytoplasm. We reveal the connection of polarization singularity dynamics with the accompanying generation of orbital angular momentum sidebands. It is unexpected that although the total angular momentum of light is not conserved, the total topological index of C points is conserved. PMID- 24784779 TI - Public stigma towards patients with schizophrenia of ethnic Malay: a comparison between the general public and patients' relatives. AB - BACKGROUND: The stigma attached to mental disorders has been recognized as a major concern in healthcare services across societies. AIMS: To compare the stigmatizing attitude towards patients with schizophrenia between the general public, relatives of patient with schizophrenia and relatives of patient with neurotic illnesses. METHOD: The study sample of 600 subjects of Malay families was equally divided into three groups. The sample was selected using convenience sampling. Each subject completed a seven-item Social Distance Scale (SDS) and a six-item stereotypical beliefs (SB) scale of people with schizophrenia. Appropriate statistical analysis was then conducted to compare the differences in SDS and SB scores between the groups. RESULTS: The scores of both SD and SB were consistent with each other, which reflected that far social distance and more negative attitudes were strongly adopted by the general public. There were significant differences in the total and most of the individual item scores of the SDS and the SB between the general public and the two relatives groups. However, the difference in the SDS scores between the relatives of patient with schizophrenia and neurotic illnesses was not significant. Among the socio demographic factors, educational status had a stronger influenced on stigma than age and sex. CONCLUSIONS: The stigma towards patients with schizophrenia among the Malay community was strong. Individuals who had been exposed to patient with schizophrenia or neurotic illnesses tended to have better perceptions towards schizophrenia than the general public. The contact that promotes familiarity with mental illness, which may diminish prejudicial attitudes, attributed to the improvement. PMID- 24784780 TI - Primers for overlooked nirK, qnorB, and nosZ genes of thermophilic Gram-positive denitrifiers. AB - Although efforts have been made the past few years, knowledge on genomic and phenotypic diversity and occurrence of the denitrification ability in Gram positive bacteria are still fragmentary. Many environmental monitoring approaches have used nir, nor, and nos genes as marker genes for detection of denitrification or denitrifying bacteria. However, primers used in these methods often fail to detect the genes in specific bacterial taxa, such as Gram-positive denitrifiers. In this study, novel primer sets specifically targeting nirK, qnorB, and nosZ genes of the Firmicute genus Geobacillus were developed by genomic mining and tested in parallel with commonly used primers on a set of phylogenetically closely related denitrifying geobacilli. Novel nirK and qnorB sequences were recovered from all strains tested, whereas nosZ was detected in part of the strain set, which was in agreement with observed phenotypes. Interspecies and modest intraspecies variations in amplified fragment length polymorphism (AFLP) patterns were observed, verifying presence of genomic variation within the strain set. Our study shows that closely related Gram positive denitrifiers may differ in denitrification phenotype and genotype. But foremost, novel primers targeting very divergent nirK, qnorB, and nosZ gene sequences of Gram-positive denitrifiers, are now available for cultivation independent environmental surveys. PMID- 24784781 TI - Suture choice matters in rabbit model of laparoscopic, preperitoneal, inguinal hernia repair. AB - PURPOSE: We evaluated the effect of different suture materials in a laparoscopic preperitoneal ligation of the patent processus vaginalis in a rabbit survival model. MATERIALS AND METHODS: New Zealand White rabbits underwent laparoscopic assisted preperitoneal ligation of the patent processus vaginalis. The processus vaginalis was closed with silk (n=10), polyglactin 910 (Vicryl((r)); Ethicon, a Johnson & Johnson Company, Somerville, NJ) (n=10), or polypropylene (Prolene((r)); Ethicon) (n=10). At necropsy, the suture was removed, and repair integrity was evaluated. RESULTS: All rabbits survived to necropsy without complications. No suture material was identified during necropsy of the Vicryl group. Eight (80%) of the Vicryl closures failed, with six (60%) failing at initial inspection. Following removal of suture material, nine (90%) of the Prolene closures failed, and only one (10%) of the silk closures failed (P=.009). CONCLUSIONS: The silk suture resulted in an improved closure rate. Ligation with silk suture probably incited an increased inflammatory response that likely created a scar while persisting long enough for the scar to become established. In contrast, the Vicryl sutures probably failed because the sutures dissolved before a scar was able to fully develop. Finally, the Prolene closures were suture dependent as evidenced by failure when the suture was removed. Nonabsorbable braided suture may improve closure of pediatric indirect inguinal hernias during laparoscopic-assisted preperitoneal ligation. PMID- 24784782 TI - Acutissimanide, a new lignan with antioxidant activity isolated from the bark of Quercus acutissima Carruth. AB - Acutissimanide (1), a new lignin, together with 11 known polyphenols (2-12) were isolated from the bark of the deciduous oak tree, Quercus acutissima Carruth. The structure of compound 1 was determined using multidimensional (1)H and (13)C NMR and mass spectroscopy. The antioxidant properties of compounds 1-12 were investigated using a 1,1-diphenyl-2-picryhydrazyl radical-scavenging assay with compounds 6-11 displaying significant antioxidant activity (EC50 values of 5.2 23.7 MUM). Our findings suggest the extracts of Q. acutissima Carruth are a potential source of natural antioxidant additives for use in the food and other allied industries. PMID- 24784783 TI - The "doc fix" - another missed opportunity. PMID- 24784784 TI - Collagen gels for delivery of bioactive peptide derived from BMP-9. PMID- 24784785 TI - Reconsider treatment agreements and drug testing. PMID- 24784786 TI - Mutations in POT1 predispose to familial cutaneous malignant melanoma. PMID- 24784787 TI - Microsubthalamotomy improves sleep in patients affected by advanced Parkinson's disease. AB - BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves sleep in patients affected by Parkinson's disease (PD). Since microsubthalamotomy (mSTN) shows positive effects on motor symptoms, it could improve sleep in PD patients. Our goals were: to assess the effects of mSTN on sleep in patients affected by advanced PD; and to look for a correlation between sleep and motor features after the neurosurgical procedure. METHODS: Fifteen patients who underwent bilateral STN-DBS were enrolled. Subjective sleep evaluation was assessed using the Parkinson's Disease Sleep Scale (PDSS). Data on sleep schedule and presence of restless legs syndrome (RLS) were obtained. Objective sleep features were investigated by polysomnography (PSG). To evaluate the mSTN effect, we compared motor state and sleep features before and after the neurosurgical procedure, before the programmable pulse generator was switched on. RESULTS: mSTN had beneficial effects on motor state and sleep features. After the surgery, the mean total PDSS score increased from 84.0+/-25.2 to 115.2+/-16.6 (P<0.001). PD patients reported longer total sleep time duration, decreased daytime sleepiness, and improvement in RLS symptoms. PSG data showed an increase in total sleep time and sleep efficiency with a decrease in wakefulness after sleep onset and arousal index. No correlation between motor improvements and sleep features modifications was observed after mSTN. CONCLUSIONS: mSTN improves sleep quality and ameliorates several sleep complaints, as well as motor symptoms, in advanced PD patients who have undergone STN-DBS. PMID- 24784788 TI - Obstructive sleep apnea research: challenges and new horizons. PMID- 24784789 TI - Increased cerebrospinal fluid levels of nerve cell biomarkers in narcolepsy with cataplexy. AB - BACKGROUND: The association between narcolepsy with cataplexy and the hypocretinergic system in the central nervous system is strong since up to 75-90% of all patients have cerebrospinal fluid (CSF) hypocretin-1 deficiency. The predominant occurrence of HLADQB1*0602 tissue type in narcolepsy patients and recent results from genome-wide association studies suggest an underlying immunological mechanism. The present study was initiated to clarify whether measurement of nerve cell biomarkers in CSF could give additional knowledge of the pathophysiological mechanisms causing narcolepsy with cataplexy. METHODS: Two patient groups with narcolepsy, comprising 18 patients with low CSF hypocretin-1 concentrations and typical cataplexy, and 18 patients with normal CSF hypocretin 1 levels and mild cataplexy-like symptoms, were compared to 17 controls. We measured the nerve cell biomarkers beta-amyloid (Abeta42), total tau protein (T tau), phosphorylated tau (P-tau) and neuron-specific enolase (NSE) in CSF. RESULTS: The concentrations of all biomarkers were significantly elevated in both patient groups compared to the controls. The concentration of beta-amyloid was significantly higher in the patient group with normal CSF hypocretin-1 concentration than in those with low concentrations, whereas the other biomarkers showed no difference between the patient groups. CONCLUSION: The findings of elevated levels of CSF biomarkers independent of CSF hypocretin-1 reduction may reflect alterations in cell metabolism. The results suggest a more extensive affection of the sleep regulating cellular network, affecting other neuronal sites important in the regulation of sleep, in addition to the hypocretin producing neurons. PMID- 24784790 TI - Monthly activity of Phlebotominae sand flies in Sistan-Baluchistan Province, Southeast Iran. AB - The monthly activity of sand flies, which are vectors of leishmaniasis, was studied from May to October 1997 in three regions (plains, mountainous, coastal) of the Sistan-Bluchistan Province using sticky paper traps. In each village, three houses were selected. 30 sticky traps were installed indoors (bedroom, guestroom, toilet, bathroom) and 30 were installed outdoors (rodent burrows, wall cracks). In total, 8,558 and 1,596 sand fly specimens were collected and identified from outdoors and indoors, respectively. Ten species of Phlebotomus and eight species of Sergentomyia were collected outdoors, and nine species of Phlebotomus and 10 species of Sergentomyia were collected indoors. Phlebotomus papatasi (Scopoli) (Diptera: Psychodidae) was the predominant species found indoors in the plains region (58.4% of insects caught in the region) and was active during the whole study period. The P. papatasi peaks of activity were in early May and early October. Sergentomyia clydei (Sinton) was found to be the most abundant species outdoors in the plains region and comprised 64.7% of the total insects caught in the region. Sergentomyia clydei and S. tiberiadis (Alder, Theodor, and Lourie) were the predominant indoor and outdoor, respectively, species from the mountainous region, making up 19.8% and 35%, respectively, of all the insects caught in the region. Phlebotomus sergenti Parrot is a proven vector of urban cutaneous leishmaniasis, and P. alexandri (Sinton) is a probable vector of Kala-Azar, and both were collected during this study. Phlebotomus papatasi was the most predominant species collected indoors in the coastal region (50.8%), its peak activity was in May. Sergentomyia sintoni Pringle was the most predominant species collected outdoors in the coastal region (36.4%), and its peak activity was in October. Awareness of the peak activity times of sand flies can be useful in developing strategies to control the flies. PMID- 24784791 TI - Electrochemical immunosensors for effective evaluation of amyloid-beta modulators on oligomeric and fibrillar aggregation processes. AB - A novel electrochemical immunosensor fabricated from gold compact disc electrodes was designed for rapid evaluation of aggregation processes that lead to the formation of oligomeric and fibrillar states of amyloid-beta(1-42) (Abeta(1-42)) during Alzheimer's disease. Conformation-specific antibodies were immobilized on the surface of the gold electrode using a 3,3'-dithiobis (sulfosuccinimidyl) propionate (DTSSP) linker. Surface binding events were analyzed by electrochemical impedance spectroscopy (EIS) in which the formation of an antigen antibody complex was quantified as a function of charge transfer resistance using a [Fe(CN)6](3-/4-) redox probe. The effectiveness of novel sym-triazine-derived aggregation modulators (TAE-1, TAE-2) to reduce the population of toxic oligomers was evaluated. Abeta fibril formation was validated by thioflavin T (ThT) fluorescence, whereas oligomer formation was investigated by MALDI. Antigen detection by EIS was further supported by immuno dot blot assays for oligomeric and fibrillar components. Docking simulations of the aggregation modulators TAE-1 and TAE-2 with Abeta(1-42) fibrils performed using Autodock Vina suggest a mechanism for the improved aggregation inhibition observed for TAE-2. The results demonstrate the utility and convenience of impedance immunosensing as an analytical tool for rapid and comprehensive evaluation of effective Abeta aggregation modulating agents. PMID- 24784793 TI - The role of the uplift of the Qinghai-Tibetan Plateau for the evolution of Tibetan biotas. AB - Biodiversity is unevenly distributed on Earth and hotspots of biodiversity are often associated with areas that have undergone orogenic activity during recent geological history (i.e. tens of millions of years). Understanding the underlying processes that have driven the accumulation of species in some areas and not in others may help guide prioritization in conservation and may facilitate forecasts on ecosystem services under future climate conditions. Consequently, the study of the origin and evolution of biodiversity in mountain systems has motivated growing scientific interest. Despite an increasing number of studies, the origin and evolution of diversity hotspots associated with the Qinghai-Tibetan Plateau (QTP) remains poorly understood. We review literature related to the diversification of organisms linked to the uplift of the QTP. To promote hypothesis-based research, we provide a geological and palaeoclimatic scenario for the region of the QTP and argue that further studies would benefit from providing a complete set of complementary analyses (molecular dating, biogeographic, and diversification rates analyses) to test for a link between organismic diversification and past geological and climatic changes in this region. In general, we found that the contribution of biological interchange between the QTP and other hotspots of biodiversity has not been sufficiently studied to date. Finally, we suggest that the biological consequences of the uplift of the QTP would be best understood using a meta-analysis approach, encompassing studies on a variety of organisms (plants and animals) from diverse habitats (forests, meadows, rivers), and thermal belts (montane, subalpine, alpine, nival). Since the species diversity in the QTP region is better documented for some organismic groups than for others, we suggest that baseline taxonomic work should be promoted. PMID- 24784792 TI - Improvement of bone regeneration capability of ceramic scaffolds by accelerated release of their calcium ions. AB - To regenerate the bone tissue, the fabrication of scaffolds for better tissue regeneration has attracted a great deal of attention. In fact, growth factors are already used in clinical practice and are being investigated for enhancing the capacity for bone tissue regeneration. However, despite their strong osteoinductive activity, these growth factors have several limitations: safety issues, high treatment costs, and the potential for ectopic bone formation. The aim of this study was therefore to develop ceramic scaffolds that could promote the capacity for bone regeneration without growth factors. Three-dimensional ceramic scaffolds were successfully fabricated from hydroxyapatite (HA) and tricalcium phosphate (TCP) using projection-based microstereolithography, which is an additive manufacturing technology. The effects of calcium ions released from ceramic scaffolds on osteogenic differentiation and bone regeneration were evaluated in vitro and in vivo. The osteogenesis-related gene expression and area of new bone formation in the HA/TCP scaffolds was higher than those in the HA scaffolds. Moreover, regenerated bone tissue in HA/TCP scaffolds were more matured than that in HA scaffolds. Through this study, we were able to enhance the bone regeneration capacity of scaffolds not by growth factors but by calcium ions released from the scaffolds. Ceramic scaffolds developed in this study might be useful for enhancing the capacity for regeneration in complex bone defects. PMID- 24784794 TI - Variables affecting the emergence of untaught equivalence relations in children with and without autism. AB - OBJECTIVE: This study examined the formation of equivalence classes among children with ASD and typically developing children. DESIGN: A single-subject AB and BA design was used. METHODS: Two of the six equivalence relations were taught. Participants were then tested to determine whether the remaining four equivalence relations were acquired without teaching. Half of the children were taught naming responses first, then selecting responses. Half were taught in the reverse order. RESULTS: Five out of 10 participants with ASD demonstrated the emergence of all four untaught relations. The remaining five participants showed variability. Nine of the 10 typically developing children demonstrated emergence of all untaught relations. Variation in teaching conditions had no significant effect on outcomes. CONCLUSIONS: Many children with ASD are capable of generalising to untaught equivalence relations. The results fail to support the claim that acquisition of naming responses is a pre-requisite for the emergence of untaught equivalence relations. PMID- 24784795 TI - Lattice parameters and stability of the spinel compounds in relation to the ionic radii and electronegativities of constituting chemical elements. AB - A thorough consideration of the relation between the lattice parameters of 185 binary and ternary spinel compounds, on one side, and ionic radii and electronegativities of the constituting ions, on the other side, allowed for establishing a simple empirical model and finding its linear equation, which links together the above-mentioned quantities. The derived equation gives good agreement between the experimental and modeled values of the lattice parameters in the considered group of spinels, with an average relative error of about 1% only. The proposed model was improved further by separate consideration of several groups of spinels, depending on the nature of the anion (oxygen, sulfur, selenium/tellurium, nitrogen). The developed approach can be efficiently used for prediction of lattice constants for new isostructural materials. In particular, the lattice constants of new hypothetic spinels ZnRE2O4, CdRE2S4, CdRE2Se4 (RE = rare earth elements) are predicted in the present Article. In addition, the upper and lower limits for the variation of the ionic radii, electronegativities, and their certain combinations were established, which can be considered as stability criteria for the spinel compounds. The findings of the present Article offer a systematic overview of the structural properties of spinels and can serve as helpful guides for synthesis of new spinel compounds. PMID- 24784796 TI - Supramolecular colloidosomes based on tri(dodecyltrimethylammonium) phosphotungstate: a bottom-up approach. AB - Hybrid tri(dodecyldimethylammonium) phosphotungstate ([C12]3[PW12O40]) amphiphilic nanoparticles self-assemble in situ at the water/toluene interface to form stable water-in-oil (W/O) Pickering emulsions (droplet size ~ 20 MUm). These emulsions are used as a template for the preparation of colloidosomes (phi ~ 5 MUm), which are produced solely through the self-assembly properties of the [C12]3[PW12O40] nanoparticles into a "fused" phase on the water-drop surface in contact with toluene. The structure of the emulsions has been determined using optical and cross-polarized light microscopy, while the colloidosomes have been characterized by scanning electron microscopy (SEM). The structure as well as the aggregation behavior of these nanoparticles has been investigated. Small- and wide-angle X-ray scattering (SWAXS) and transmission electron microscopy (TEM) experiments have revealed a lamellar organization of the inorganic polyoxometalate anions because of the van der Waals interactions between the alkyl chains of the organic cations. According to the solvent, the internal molecular arrangement inside the nanoparticles can be modified: in water, the nanoparticles tend to aggregate in a lamellar structure, whereas in toluene, the nanoparticles are "fused" or coagulated. PMID- 24784797 TI - Pica during pregnancy among Mexican-born women: a formative study. AB - Although pica, the craving and purposive consumption of non-food substances, is common among many populations, especially during pregnancy, the health consequences are not well understood. Further, very little is known about pica among Mexican populations in the United States and Mexico. Therefore, we conducted formative research to understand pica in this understudied population. Our objectives were to identify the frequency and types of pica behaviours, to understand perceived aetiologies and consequences of pica and to ascertain if the behaviour was common enough to warrant a larger study. We held nine focus group discussions (three in the Salinas Valley, California; six in Xoxocotla, Morelos, Mexico) with 76 Mexican-born women who were currently pregnant or had delivered within the past 2 years. Earth, adobe, bean stones and ice were the most commonly reported pica substances. Twenty-eight of the 76 participants (37%) reported ever engaging in pica; 22 participants (29%) reported doing so during pregnancy. The proportion of women reporting pica in the United States and Mexico was 43% and 34%, respectively. Women attributed pica to the overwhelming organoleptic appeal of pica substances (especially smell and texture) and to micronutrient deficiencies. Perceived consequences of unfulfilled pica cravings were birthmarks or fetal loss; fulfilled pica cravings were also thought to be generally harmful to the mother or child, with several women specifying toxic lead, pesticides or 'worms'. In sum, pica among Mexican women is common enough to warrant a larger epidemiologic study of its sociodemographic correlates and physiological consequences. PMID- 24784798 TI - User-generated online health content: a survey of Internet users in the United Kingdom. AB - BACKGROUND: The production of health information has begun to shift from commercial organizations to health care users themselves. People increasingly go online to share their own health and illness experiences and to access information others have posted, but this behavior has not been investigated at a population level in the United Kingdom. OBJECTIVE: This study aims to explore access and production of user-generated health content among UK Internet users and to investigate relationships between frequency of use and other variables. METHODS: We undertook an online survey of 1000 UK Internet users. Descriptive and multivariate statistical analyses were used to interpret the data. RESULTS: Nearly one-quarter of respondents (23.7%, 237/1000) reported accessing and sharing user-generated health content online, whereas more than 20% (22.2%, 222/1000) were unaware that it was possible to do this. Respondents could be divided into 3 groups based on frequency of use: rare users (78.7%, 612/778) who accessed and shared content less than weekly, users (13.9%, 108/778) who did so weekly, and superusers (7.5%, 58/778) who did so on a daily basis. Superusers were more likely to be male (P<.001) and to be employed (P<.001), but there were no differences between the groups with respect to educational level (P=.99) or health status (P=.63). They were more likely to use the Internet for varied purposes such as banking and shopping (P<.001). CONCLUSIONS: Although this study found reasonably widespread access of user-generated online health content, only a minority of respondents reported doing so frequently. As this type of content proliferates, superusers are likely to shape the health information that others access. Further research should assess the effect of user-generated online content on health outcomes and use of health services by Internet users. PMID- 24784799 TI - TMEM16A protein attenuates lipopolysaccharide-mediated inflammatory response of human lung epithelial cell line A549. AB - OBJECTIVE: To observe the expression of endogenous TMEM16A in rat alveolar type II epithelial cells (AT-II) and A549, and study the effect of TMEM16A on lipopolysaccharide (LPS)-induced proinflammatory cytokine secretion. METHODS: Rat AT-II cells were isolated and TMEM16A protein expression in rat AT-II cells was measured by Western blot. TMEM16A mRNA and protein expressions in A549 were measured by real-time quantitative polymerase chain reaction (PCR) and Western blot, respectively. TMEM16A gene was transfected into A549 using Lipofectamine 2000. Transfected cells were selected in the presence of G418 to create a stable TMEM16A overexpression A549 cell line. The expression of TMEM16A in A549 was knocked down by lentiviral vector-mediated RNA interference. TNF-alpha and IL-8 levels were determined by enzyme-linked immunosorbent assay (ELISA). A dual luciferase reporter assay system was used to measure the transcriptional activity of NF-kappaB. RESULTS: (1) Endogenous TMEM16A was expressed in rat AT-II and A549. (2) TMEM16A expression in A549 significantly increased at 24 hours and 36 hours, and then decreased at 48 hours after LPS treatment. (3) TMEM16A mRNA and protein expressions were increased in the stable TMEM16A overexpression A549 cell line. (4) TMEM16A overexpression decreased the LPS-induced TNF-alpha and IL-8 secretions. (5) TMEM16A mRNA and protein expressions were knocked down in TMEM16A siRNA lentivirus transfected A549. (6) TMEM16A knockdown increased the LPS induced TNF-alpha and IL-8 secretions. (7) TMEM16A overexpression inhibited LPS induced NF-kappaB activation. CONCLUSIONS: TMEM16A is expressed in AT-II. TMEM16A in A549 inhibits LPS-induced NF-kappaB activation and decreases proinflammatory cytokines release, protecting A549 from acute LPS-mediated damage. PMID- 24784800 TI - Multi-atlas segmentation of the whole hippocampus and subfields using multiple automatically generated templates. AB - INTRODUCTION: Advances in image segmentation of magnetic resonance images (MRI) have demonstrated that multi-atlas approaches improve segmentation over regular atlas-based approaches. These approaches often rely on a large number of manually segmented atlases (e.g. 30-80) that take significant time and expertise to produce. We present an algorithm, MAGeT-Brain (Multiple Automatically Generated Templates), for the automatic segmentation of the hippocampus that minimises the number of atlases needed whilst still achieving similar agreement to multi-atlas approaches. Thus, our method acts as a reliable multi-atlas approach when using special or hard-to-define atlases that are laborious to construct. METHOD: MAGeT Brain works by propagating atlas segmentations to a template library, formed from a subset of target images, via transformations estimated by nonlinear image registration. The resulting segmentations are then propagated to each target image and fused using a label fusion method. We conduct two separate Monte Carlo cross-validation experiments comparing MAGeT-Brain and basic multi-atlas whole hippocampal segmentation using differing atlas and template library sizes, and registration and label fusion methods. The first experiment is a 10-fold validation (per parameter setting) over 60 subjects taken from the Alzheimer's Disease Neuroimaging Database (ADNI), and the second is a five-fold validation over 81 subjects having had a first episode of psychosis. In both cases, automated segmentations are compared with manual segmentations following the Pruessner-protocol. Using the best settings found from these experiments, we segment 246 images of the ADNI1:Complete 1Yr 1.5 T dataset and compare these with segmentations from existing automated and semi-automated methods: FSL FIRST, FreeSurfer, MAPER, and SNT. Finally, we conduct a leave-one-out cross-validation of hippocampal subfield segmentation in standard 3T T1-weighted images, using five high-resolution manually segmented atlases (Winterburn et al., 2013). RESULTS: In the ADNI cross-validation, using 9 atlases MAGeT-Brain achieves a mean Dice's Similarity Coefficient (DSC) score of 0.869 with respect to manual whole hippocampus segmentations, and also exhibits significantly lower variability in DSC scores than multi-atlas segmentation. In the younger, psychosis dataset, MAGeT-Brain achieves a mean DSC score of 0.892 and produces volumes which agree with manual segmentation volumes better than those produced by the FreeSurfer and FSL FIRST methods (mean difference in volume: 80 mm(3), 1600 mm(3), and 800 mm(3), respectively). Similarly, in the ADNI1:Complete 1Yr 1.5 T dataset, MAGeT-Brain produces hippocampal segmentations well correlated (r>0.85) with SNT semi-automated reference volumes within disease categories, and shows a conservative bias and a mean difference in volume of 250 mm(3) across the entire dataset, compared with FreeSurfer and FSL FIRST which both overestimate volume differences by 2600 mm(3) and 2800 mm(3) on average, respectively. Finally, MAGeT-Brain segments the CA1, CA4/DG and subiculum subfields on standard 3T T1-weighted resolution images with DSC overlap scores of 0.56, 0.65, and 0.58, respectively, relative to manual segmentations. CONCLUSION: We demonstrate that MAGeT-Brain produces consistent whole hippocampal segmentations using only 9 atlases, or fewer, with various hippocampal definitions, disease populations, and image acquisition types. Additionally, we show that MAGeT-Brain identifies hippocampal subfields in standard 3T T1-weighted images with overlap scores comparable to competing methods. PMID- 24784801 TI - A novel single-labeled fluorescent oligonucleotide probe for silver(I) ion detection in water, drugs, and food. AB - Due to the high toxicity of silver(I) ions, a method for the rapid, sensitive, and selective detection for silver(I) ions in water, pharmaceutical products, and food is of great importance. Herein, a novel single-labeled fluorescent oligonucleotide (OND) probe based on cytosine-Ag(I)-cytosine coordination and the inherent fluorescence quenching ability of the G-quadruplex is designed to detect silver(I) ions. The formation of a hairpin structure in the OND-Ag(I) complex brings the hexachloro fluorescein (HEX) labeled at the 5'-end of the OND probe close to the G-quadruplex located at the 3'-end of the OND probe, leading to a fluorescence quenching due to photoinduced electron transfer between HEX and the G-quadruplex. Through this method, silver(I) ions can be detected quantitatively, the linear response range is from 1 to 100 nmol/L with a detection limit of 50 pmol/L, and no obvious interference occurs with other metal ions with a 10-fold concentration. This assay is simple, sensitive, and selective, and it can be used to detect silver(I) ions in actual water, drug, and food samples. PMID- 24784802 TI - Solution-grown 3D Cu2O networks for efficient solar water splitting. AB - We report a facile and large-scale solution fabrication of cuprous oxide (Cu2O) nanowires/nanorods and 3D porous Cu2O networks and their application as photocathodes for efficient solar water splitting. The growth mechanism and structural characterization of 3D porous Cu2O networks are studied in detail. The photocathodic performance of Cu2O electrodes prepared under different growth conditions is investigated in a pH-neutral medium. The porous Cu2O network photocathodes exhibit large photocurrent, high spectral photoresponse, and incident photon-to-current efficiency compared with Cu2O nanowire/nanorod photoelectrodes. The photoelectrochemical stability of the 3D Cu2O network is significantly improved by applying multi-layer metal oxide protection. PMID- 24784803 TI - Survey of acrylamide levels in Chinese foods. AB - A survey of levels of acrylamide (AA) in 349 food products obtained from the Chinese market was conducted. AA was determined by an liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The limit of detection (LOD) and the limit of quantification (LOQ) of the method in four different matrices ranged from 0.8 to 10 ug kg(-1) and from 4.0 to 25 ug kg(-1), respectively. The results from this survey indicated that AA was present in all samples except drinking water and tea. AA contents in different samples varied greatly according to the raw materials and processing conditions. The highest level of AA was found in potato products, with an average level of 1467 ug kg(-1). Preliminary estimates of AA exposure and risk assessment of AA from foods in the Chinese population were performed using a combination of data obtained in the present survey and 2002 dietary consumption survey carried out in 2002 for the Chinese population. The average dietary exposure of AA was estimated to be 0.38 ug kg(-1) body weight day(-1), which is relatively low compared with the result reported by the Food and Agricultural Organization/World Health Organization (FAO/WHO). Furthermore, the margin of exposure for neurotoxicity, reproductive toxicity, and carcinogenicity of AA was calculated to be 1318, 5250, and 787, respectively. PMID- 24784804 TI - Dietary exposure to chloropropanols of secondary school students in Hong Kong. AB - This paper reports levels of 3-monochloropropan-1,2-diol (3-MCPD) and 1,3 dichloro-2-propanol (1,3-DCP) in a wide range of food items and estimates their dietary exposure for secondary school students in Hong Kong. Dietary exposure to chloropropanols was estimated using local food consumption data obtained from secondary school students in 2000 and the concentrations of 3-MCPD and 1,3-DCP in food samples taken from the local market. The dietary exposure to 3-MCPD for an average secondary school student consumer was estimated to be 0.063-0.150 ug kg( 1) body weight (bw) day(-1), whilst that for the high consumer was 0.152-0.300 ug kg(-1) bw day(-1). Both estimates fell below the provisional maximum tolerable daily intake of 2 ug kg(-1) bw established by the Joint Expert Committee on Food Additives (JECFA) and amounted to less than 20% of this safety reference value. The dietary exposure to 1,3-DCP for an average secondary school student consumer was estimated to be 0.003-0.019 ug kg(-1) bw day(-1), whilst that for the high consumer was 0.009-0.040 ug kg(-1) bw day(-1). The resulting margins of exposures were of low concern for human health. It could be concluded that both the average and high secondary school student consumers were unlikely to experience major toxicological effects of 3-MCPD and 1,3-DCP. PMID- 24784805 TI - Toxic (Pb, Cd, Hg) and essential (Fe, Cu, Zn, Mn) metal content of liver tissue of some domestic and bush animals in Ghana. AB - Accumulation of toxic metals in liver, a rich natural source of essential elements, can present health risks to regular consumers of liver. A total of 35 fresh liver samples of cow, sheep, goat, pig, grass-cutter (Thryonomys swinderianus), giant rat (Cricetomys gambianus), red deer (Cervus elaphus), chicken and antelope (Antilocapra americana) were obtained from three different markets in Accra and Kumasi, Ghana. Samples were analyzed using atomic absorption spectrometry and an automatic mercury analyzer. Levels of iron in the grass cutter and pig of 500.5-645.4 mg kg(-1) were the highest in the animal livers examined. Mn concentrations were highest in grass-cutter and rat liver, ranging 16.5-30.2 mg kg(-1). The safe Cu and Zn permissible limits of 20 and 50 mg kg(-1) were exceeded in 70 and 75% of the liver samples, respectively. Generally, for each animal group studied, at least 50% of the sample livers exceeded the Cd permissible limit of 0.5 mg kg(-1). The levels of Pb, which ranged 1.3-13.8 mg kg(-1), exceeded the proposed European Commission (EC) limit of 0.5 mg kg(-1). Care must be taken by regular consumers of the iron-rich animal livers of grass cutter, pig and rat because they also had the highest levels of Pb (in grass cutter and pig) and Cd (in grass-cutter, rat and pig). The liver samples analyzed for Hg had values far below the permissible limit of 0.5 mg kg(-1). PMID- 24784806 TI - Mercury and methylmercury levels in the main traded fish species in Hong Kong. AB - Levels of total mercury (tHg) and mono-methylmercury (MeHg) were measured in 280 different fish, including fresh/frozen raw whole fish of 89 different species and canned tuna fish of three different species, that are traded mainly in Hong Kong, China. These samples were purchased from different commercial outlets between April and August 2007. All samples of raw whole fish were identified at species level by the Agriculture, Fisheries and Conservation Department. The range for tHg and MeHg of all samples were 3-1370 and 3-1010 ug kg(-1), respectively, with medians of 63 and 48 ug kg(-1), respectively. The results show that, according to Hong Kong legislation, the products on the market are generally 'safe'. A total of 277 samples (99?) contained tHg and MeHg below the legal limit of 500 ug kg( 1). The remaining three samples of alfonsino (species: Beryx splendens) were found to contain tHg and MeHg at levels higher than 500 ug kg(-1) (tHg: 609-1370 ug kg(-1); MeHg: 509-1010 ug kg(-1)). The ratios of MeHg to tHg in the different fish species ranged from 0.46 to 0.99. PMID- 24784807 TI - Trace elemental composition of curry by inductively coupled plasma optical emission spectrometry (ICP-OES). AB - A methodology based on inductively coupled plasma optical emission spectrometry (ICP-OES) after microwave-assisted acid digestion was developed to determine the content of traces elements in curry samples from the Spanish market. The methodology was validated in terms of accuracy by the analysis of citrus and tomato leaf reference materials achieving comparable results with the certified values. The trace metal content of curry samples was compared with data available from previously published reports concerning Indian samples, especially in terms of heavy metal composition, in order to guarantee the quality of the commercially available spices in the European countries. Values found for the analysis of arsenic, lead and cadmium were significantly lower than the maximum limit allowed by European Union statutory limits for heavy metals and lower than those obtained for Indian curry leaves reported by Indian research teams by using neutron activation and gamma-ray analysis. PMID- 24784808 TI - Survey of the histamine content in fish samples randomly selected from the Greek retail market. AB - The histamine content of fish sold in the Greek retail market was surveyed and the performance of high-performance liquid chromatography (HPLC) and enzyme linked immunoabsorbant assay (ELISA) methods for the determination of histamine were compared. A total of 125 samples of fresh and canned tuna, fresh and canned sardines, deep frozen swordfish, smoked and deep frozen mackerel, anchovies, salted and smoked herring were analysed by HPLC (55 samples), ELISA (106 samples) and both methods (36 samples). Histamine levels as determined by HPLC, ranged from 2.7 mg kg(-1) to 220 mg kg(-1). The highest histamine concentrations obtained by HPLC were found in herring and anchovy samples. Eight out of the 55 samples (14.5%) analysed by HPLC, exceeded the US Food and Drug Administration (USFDA) limit (50 mg kg(-1)), while 16 out of the 106 samples (15%) analysed by ELISA exceeded the limit. The results show that for histamine concentrations below 50 mg kg(-1), there is good agreement between the ELISA and HPLC but above 50 mg kg(-1) big differences were found. PMID- 24784809 TI - Co-occurrence of deoxynivalenol and zearalenone in crops marketed in Portugal. AB - A total of 307-samples of plant crops (both home-grown and imported) marketed in Portugal, including maize and maize-based products (132), wheat and wheat-based products (82), barley (25), soybean (53), sunflower (8) and alfalfa (7), were analyzed for the co-occurrence of the Fusarium toxins, zearalenone (ZEA) and deoxynivalenol (DON). Analysis for ZEA and DON was carried out by HPLC, with fluorescence and UV detection, respectively. Of the 307 samples, ZEA and DON co occurred in 46 samples (co-occurrence of 15?); 84 samples were DON-positive and 171 were ZEA-positive. The mean ZEA and DON concentrations were 0.17 and 0.07 mg kg(-1), respectively. The highest levels found in the samples were 0.93 mg kg(-1) for ZEA and 17.9 mg kg(-1) for DON. One DON-positive and 13 ZEA-positive samples had contamination levels above the EU maximum legal limit. PMID- 24784810 TI - Occurrence of patulin and its dietary intake through pear, peach, and apricot juices in Italy. AB - Pear, peach, apricot, and mixed juices (125 samples) were purchased in Italian supermarkets and organic food shops and analysed for patulin content. An overall incidence of 34.4% was observed in the fruit juices, with a mean contamination level of 3.6 ug kg(-1). No one sample exceeded 50 ug kg(-1), the maximum permitted limit according to European legislation. However, 19 positive samples contained more than 10 ug kg(-1) of patulin, which is the maximum level permitted for baby food. The incidence of patulin contamination was significantly higher in pear juices (64.1%) than in apricot, peach, or mixed juices. Statistical analysis (p = 0.002; Kruskal-Wallis test) showed a significantly higher level of patulin in pear (5.1 ug kg(-1)) and mixed juices (4.9 ug kg(-1)) than in the other juices. A slightly higher incidence of positive samples was found in conventional juices (35.7%) compared with the organic ones (29.6%). The magnitude between the mean contamination levels was similar in conventional (3.6 ug kg(-1)) and organic (3.3 ug kg(-1)) juices (p = 0.474; Mann-Whitney U-test). Samples were further divided based on the fruit content in fruit juices, fruit nectars, and fruit drinks. In fruit nectars the incidence of positive samples (37.8%) was slightly higher than in fruit drinks (27.2%), but the mean patulin contamination was higher in fruit drinks (5.2 ug kg(-1)) than in fruit nectars (3.4 ug kg(-1)). However, the magnitude between the two means was not statistically different (p = 0.734; Mann-Whitney U-test). Italian juices had a higher incidence of patulin (35.3%), with a lower mean content (3.5 ug kg(-1)), compared with the incidence (22.2%) and level (4.1 ug kg(-1)) foreign juices commercially available in Italy. The magnitude of the means between Italian and foreign juices was not statistically different, according to the Mann-Whitney U-test (p = 0.616). The estimated intake of patulin ranged from 0.1 to 1.5 ng kg(-1) body weight for the whole population and from 0.3 to 5.1 ng kg(-1) body weight for the consumers only. The highest patulin intake was estimated for consumers of pear juices, followed by consumers of mixed juices. The daily intake of patulin derived from the consumption of pear juice suggests that also pear juices, though a minor patulin source, could be monitored for their patulin content in order to control the mycotoxin contamination, especially in countries, such as Italy, where pear nectars are preferred as fruit drinks. PMID- 24784811 TI - Patulin in apple juices: Incidence and likely intake in an Indian population. AB - Fifty samples of apple juices were investigated for patulin levels using HPLC with UV detection. It was found that 38 (76? samples contained no detectable patulin (LOD = 7.5 ug l(-1)), but some samples had high patulin levels (845 ug l( 1)) compared to other branded mixed juices (21-70 ug l(-1)) and apple juices procured from local vendors (191 ug l(-1)). The survey provides evidence of a need to educate the apple-juice industry in the use of good quality apples for juice production. In addition, the levels of patulin found showed a saturation of the provisional maximum tolerable daily intake (PMTDI) based on intake figures in terms of an average and 90th percentile of 27-60% and 107-190%, respectively, in different age groups. This monitoring study may help in formulating guidelines for patulin levels, which are not yet implemented by Prevention of Food Adulteration (PFA) Act of India. PMID- 24784812 TI - Aflatoxins and cyclopiazonic acid in feed and milk from dairy farms in Sao Paulo, Brazil. AB - The occurrence of aflatoxins (AF) B1, B2, G1, G2 and cyclopiazonic acid (CPA) in feeds, and AFM1 and CPA in milk was determined in dairy farms located in the northeastern region of Sao Paulo state, Brazil, between October 2005 and February 2006. AF and CPA determinations were performed by HPLC. AFB1 was found in 42% of feed at levels of 1.0-26.4 ug kg(-1) (mean: 7.1 +/- 7.2 ug kg(-1)). The concentrations of AFM1 in raw milk varied between 0.010 and 0.645 ug l(-1) (mean: 0.104 +/- 0.138 ug l(-1)). Only one sample was above the tolerance limit adopted in Brazil (0.50 ug l(-1)) for AFM1 in milk. Regarding CPA in feed, six (12%) samples showed concentrations of 12.5-153.3 ug kg(-1) (mean: 57.6 +/- 48.7 ug kg( 1)). CPA was detected in only three milk samples (6%) at levels of 6.4, 8.8 and 9.1 ug l(-1). Concentrations of aflatoxins and CPA in feed and milk were relatively low, although the high frequency of both mycotoxins indicates the necessity to continuously monitor dairy farms to prevent contamination of feed ingredients. PMID- 24784813 TI - Analysis of environmental chemical residues in products of emerging aquaculture industry in Uganda as case study for Sub-Saharan Africa. AB - A study was conducted to analyse market-regulated heavy metals (lead, mercury and cadmium), organochlorine pesticides and total polychlorinated biphenyls (PCBs) in samples of 38 farmed fish comprising Nile tilapia (Oreochromis niloticus) (20 samples) and African catfish (Clarias gariepinus) (18 samples) from ten selected fish farms in Uganda. The goal of this case study was to understand the safety of aquaculture products from Sub-Saharan Africa. Lead was detected in all the 38 samples (maximum = 1.08 mg kg(-1) (dry weight)), mercury in 31 out of 38 samples (maximum = 0.35 mg kg(-1) (dry weight)), and cadmium in two samples (maximum = 0.03 mg kg(-1) (dry weight)). Total levels of PCBs were below the limit of detection of 0.02 mg kg(-1) (wet weight) in all the samples. Traces of 4,4' dichloro-diphenyldichloroethylene (DDE) were detected in ten out of 38 samples (maximum = 0.01 mg kg(-1) (wet weight)) making it the most prevalent organochlorine pesticide. Other pesticides detected were: 4,4'-dichloro-diphenyl trichloroethane (DDT) and endosulfan sulphate, which were found in one fish sample (both 0.002 mg kg(-1) (wet weight)). There was no statistically significant difference between the levels of lead and mercury in catfish and tilapia (t-test at p = 0.05). More catfish samples (eight) contained DDE as compared with tilapia (two). Cadmium, DDT and endosufan sulphate were only detected in catfish implying that catfish is more prone to contamination than tilapia. The levels of contaminants were below the US Food and Drug Administration (USFDA) action levels and European Union maximum residue limits (MRLs), indicating that such fish have the potential for export to these markets. PMID- 24784814 TI - Survey of bisphenol A in bottled water products in Canada. AB - A method based on isotope dilution headspace solid-phase microextraction and gas chromatography/mass spectrometry was used to assess levels of bisphenol A (BPA) in 56 samples of bottled water products sold in Canada. Levels of BPA in samples of all 51 non-polycarbonate (PC) bottled water products were lower than the method detection limit (0.50 ug l(-1)). Levels of BPA in most bottled water products in PC carboys were low, ranging from <0.50 to 1.4 ug l(-1) with an average of 0.75 ug l(-1). However, BPA was detected at levels of 8.8 and 6.5 ug l(-1) in two bottles of the bottled water products in PC carboys from the same product analysed over a 5-week period, likely due to accidental or careless exposure of the products to heat (e.g. under the sun) during storage and/or transportation for extended periods of time. PMID- 24784815 TI - Vapor pressures and heats of sublimation of crystalline beta-cellobiose from classical molecular dynamics simulations with quantum mechanical corrections. AB - In this paper, we report the calculation of the enthalpy of sublimation, Delta(sub)H, as a function of temperature of crystalline beta-cellobiose from molecular dynamics (MD) simulations, using two popular carbohydrate force fields. Together with the entropy difference between the solid and the vapor, DeltaS, evaluated at atmospheric pressure, Delta(sub)H gives the vapor pressure of cellobiose over the solid phase as a function of T. It is found that when quantum mechanical corrections to the enthalpy calculated from the distribution of normal modes is applied both force fields give Delta(sub)H close to experiments. The entropy change, DeltaS, which is calculated within a harmonic approximation becomes too small, leading to vapor pressures that are too low. These findings are relevant to MD simulations of crystalline carbohydrates in general, e.g., native cellulose. PMID- 24784816 TI - Tin dioxide@carbon core-shell nanoarchitectures anchored on wrinkled graphene for ultrafast and stable lithium storage. AB - The SnO2@C@GS composites as a new type of 3D nanoarchitecture have been successfully synthesized by a facile hydrothermal process followed by a sintering strategy. Such a 3D nanoarchitecture is made up of SnO2@C core-shell nanospheres and nanochains anchored on wrinkled graphene sheets (GSs). Transmission electron microscopy shows that these core-shell nanoparticles consist of 3-9 nm diameter secondary SnO2 nanoparticles embedded in about 50 nm diameter primary carbon nanospheres. Large quantities of core-shell nanoparticles are uniformly attached to the surface of wrinkled graphene nanosheets, with a portion of them further connected into nanochains. This new 3D nanoarchitecture consists of two different kinds of carbon-buffering matrixes, i.e., the carbon layer produced by glucose carbonization and the added GS template, leading to enhanced lithium storage properties. The lithium-cycling properties of the SnO2@C@GS composite have been evaluated by galvanostatic discharge-charge cycling and electrochemical impedance spectroscopy. Results show that the SnO2@C@GS composite has discharge capacities of 883.5, 845.7, and 830.5 mA h g(-1) in the 20th, 50th and 100th cycles, respectively, at a current density of 200 mA g(-1) and delivers a desirable discharge capacity of 645.2 mA h g(-1) at a rate of 1680 mA g(-1). This new 3D nanoarchitecture exhibits a high capability and excellent cycling and rate performance, holding great potential as a high-rate and stable anode material for lithium storage. PMID- 24784818 TI - Climate change mitigation: assessing strategies that offer potential human health benefits. PMID- 24784817 TI - Rotator cuff crepitus: could Codman really feel a cuff tear? AB - BACKGROUND: The objective of this study was to assess the accuracy of palpating crepitus to diagnose rotator cuff tears. METHODS: Seventy consecutive consenting patients who presented with shoulder pain and no previous imaging or surgery on the affected shoulder were prospectively enrolled during a 10-month period. A standardized patient history and examination, including the crepitus test, were recorded in addition to obtaining standard radiographs. Additional imaging after initial evaluation was performed with magnetic resonance imaging and interpreted by a musculoskeletal radiologist blinded to the examination findings. Statistical analysis was used to determine sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the crepitus test in the clinical diagnosis of a rotator cuff tear. RESULTS: Sixty-three patients had histories, examinations, and imaging studies available for analysis. The crepitus test had a sensitivity of 67%, specificity of 80%, PPV of 91%, and NPV of 43% for all types of rotator cuff tears. The sensitivity and specificity for full thickness or high-grade partial tears was 82% and 73%, respectively; the PPV and NPV were 77% and 79%. Increasing age improved accuracy as the presence of crepitus in patients older than 55 years had a sensitivity of 76%, specificity of 100%, PPV of 100%, and NPV of 38%. CONCLUSION: The crepitus test has a favorable sensitivity, specificity, PPV, and NPV to assess the integrity of the rotator cuff and may be a useful examination in the clinical diagnosis of a rotator cuff tear. PMID- 24784819 TI - Deep brain optical measurements of cell type-specific neural activity in behaving mice. AB - Recent advances in genetically encoded fluorescent sensors enable the monitoring of cellular events from genetically defined groups of neurons in vivo. In this protocol, we describe how to use a time-correlated single-photon counting (TCSPC) based fiber optics system to measure the intensity, emission spectra and lifetime of fluorescent biosensors expressed in deep brain structures in freely moving mice. When combined with Cre-dependent selective expression of genetically encoded Ca(2+) indicators (GECIs), this system can be used to measure the average neural activity from a specific population of cells in mice performing complex behavioral tasks. As an example, we used viral expression of GCaMPs in striatal projection neurons (SPNs) and recorded the fluorescence changes associated with calcium spikes from mice performing a lever-pressing operant task. The whole procedure, consisting of virus injection, behavior training and optical recording, takes 3-4 weeks to complete. With minor adaptations, this protocol can also be applied to recording cellular events from other cell types in deep brain regions, such as dopaminergic neurons in the ventral tegmental area. The simultaneously recorded fluorescence signals and behavior events can be used to explore the relationship between the neural activity of specific brain circuits and behavior. PMID- 24784821 TI - Synthesis of a highly Zn(2+)-selective cyanine-based probe and its use for tracing endogenous zinc ions in cells and organisms. AB - The zinc ion has a key role in a variety of physiological and pathological processes. As a consequence, the development of sensitive and reliable methods to monitor the presence of zinc ions in cells and organisms is of great importance to biological research and biomedical applications. This protocol describes detailed procedures for the five-stage synthesis of a zinc ion-selective, cyanine based fluorescent probe, CTMPA, from 2,6-bis(hydroxymethyl)pyridine. In addition, we describe its applications in the detection of Zn(2+) released during apoptosis in cells and endogenous Zn(2+) in living zebrafish. Notably, the use of CTMPA enabled our research group to monitor for the first time the presence of zinc ions in neuromasts of zebrafish via fluorescence. The approximate time frame for the synthesis of CTMPA is 4-5 d, and for its use in bioimaging is 8-10 h for cells and 2 h for zebrafish. PMID- 24784820 TI - 3D mouse embryonic stem cell culture for generating inner ear organoids. AB - This protocol describes a culture system in which inner-ear sensory tissue is produced from mouse embryonic stem (ES) cells under chemically defined conditions. This model is amenable to basic and translational investigations into inner ear biology and regeneration. In this protocol, mouse ES cells are aggregated in 96-well plates in medium containing extracellular matrix proteins to promote epithelialization. During the first 14 d, a series of precisely timed protein and small-molecule treatments sequentially induce epithelia that represent the mouse embryonic non-neural ectoderm, preplacodal ectoderm and otic vesicle epithelia. Ultimately, these tissues develop into cysts with a pseudostratified epithelium containing inner ear hair cells and supporting cells after 16-20 d. Concurrently, sensory-like neurons generate synapse-like structures with the derived hair cells. We have designated the stem cell-derived epithelia harboring hair cells, supporting cells and sensory-like neurons as inner ear organoids. This method provides a reproducible and scalable means to generate inner ear sensory tissue in vitro. PMID- 24784822 TI - Acute Achilles tendon rupture: Mini-incision repair with double-Tsuge loop suture vs. open repair with modified Kessler suture. AB - BACKGROUND AND PURPOSE: Achilles tendon rupture is a common injury of the foot and ankle. However, the optimal treatment strategy for Achilles tendon rupture is still not established. This study was conducted to compare the efficacy and complications of mini-incision repair with double-Tsuge loop sutures and open repair with modified Kessler sutures. METHODS: We evaluated data from 60 patients with acute closed Achilles tendon ruptures who underwent mini-incision repair with double-Tsuge loop sutures (n = 30) or open repair with modified Kessler sutures (n = 30) from 2006 to 2010 in an ongoing prospective study conducted by us and have finished at least 18-month follow-up or finished the study. The AOFAS Ankle-Hindfoot score, ATRS, maximal ankle range of motion and the time to achieve 20 continuous single heel raises after operation were recorded to compare the efficacy. The complications were also evaluated. RESULTS: During a mean follow-up of 25 months after surgery, the time to achieve 20 continuous single heel raises after operation of patients in Group Mini was significantly shorter than patients in Group Open. Moreover, the mini-incision with double-Tsuge repair was associated with a significantly shorter operating time, smaller incision length, and lower rate of complications. CONCLUSION: The mini-incision with double-Tsuge suture method in our study was shown to provide earlier strength recovery, as well as shorter operation time, less complications and improved cosmetic appearance. PMID- 24784823 TI - The forgotten foot - An assessment of foot and ankle radiograph pathology in final year medical students. AB - INTRODUCTION: It has been shown that doctors in Emergency Departments (EDs) have inconsistent knowledge of musculoskeletal anatomy. This is most likely due to a deficiency in focused musculoskeletal modules at undergraduate level in medical school. The aims of this study were to evaluate the knowledge of final year medical students on foot anatomy and common foot and ankle pathology as seen on radiographs. METHODS: Final year medical students were asked to complete our short examination on a handout. The handout was anonymous and non-mandatory. There were four images. The first image is the anatomical section and the remaining images are the pathological section. RESULTS: All 235 students responded. 57% were females. For the identification of the normal bones of the foot as shown on an X-ray, the average score for the group was 2.69 (out of a maximum of 6) {SD 1.67}7. Only 8.3% achieved a 6/6 or 100% grade i.e. recognising all six bones correctly. A further 8.3% achieved 5/6 (83%). 8.3% failed to correctly identify any bone seen on the X-ray, a corresponding score of 0. DISCUSSION: This quick test showed normal anatomy of the foot and common pathology. One would expect final year medical students to be familiar with, especially two weeks before their finals in surgery. The curriculum should address the paucity of time spent in educating students in foot and ankle pathology. PMID- 24784824 TI - A study to investigate changes in the microbiology and antibiotic sensitivity of head and neck space infections. AB - BACKGROUND AND OBJECTIVES: Due to a growing concern regarding antibiotic resistance, we aim to investigate if there has been a change in the microbiology and antibiotic sensitivity of head and neck space infections over the last 30-40 years. PATIENTS AND METHOD: A retrospective study was undertaken of 100 patients admitted for inpatient management of head and neck infections. A literature search of the data from the last 30-40 years was performed for comparative purposes. RESULTS: There were 57 male and 43 female patients (average age 37 years). The most common infections were of odontogenic (67) and skin (14) origin. The submandibular (69%) and buccal (60%) spaces were more commonly involved. Sixty-six cases had multiple space involvement. Seventy-eight cases had swabs taken for microbiology culture and sensitivity, with 67 (85.9%) having microorganisms isolated. Fifty (74.6%) of these were aerobic infections and 17 (25.4%) anaerobic. Bacteria were isolated in 64 (95.5%) cultures. 70.1% of the bacteria were gram positive. Gram-positive cocci were isolated in 65.4% of cultures. The most common bacteria isolated were streptococcus. 73.4% of the bacteria were sensitive to amoxicillin and 81.3% sensitive to both amoxicillin and metronidazole. 15.6% were resistant to penicillin, which were Staphylococcus aureus from skin infections. CONCLUSION: Comparing our results with a review of the literature shows no significant change in the microbiology and antibiotic sensitivity of odontogenic head and neck infections over the last 30-40 years. Amoxicillin is still shown to be an effective empirical drug for odontogenic head and neck infections. PMID- 24784825 TI - Determination of tert-butylhydroquinone in vegetable oils using surface-enhanced Raman spectroscopy. AB - Monitoring the level of tert-butylhydroquinone (TBHQ), a permissible antioxidant additive in edible vegetable oils in many countries, is important to ensure that oils and products that contain them comply with the relevant import regulations. Surface-enhanced Raman spectroscopy (SERS) technology coupled with chemometric methods including partial least squares (PLS) and support vector machine (SVM) regression was applied to determine levels of TBHQ in spiked corn oils (0 to 500 mg/kg, n = 40) and commercial vegetable oils (0 to 99.7 mg/kg, n = 25). The lowest detectable concentration was 5 mg/L for TBHQ in standard solutions and 10 mg/kg of TBHQ in vegetable oils from various plant sources. The TBHQ levels predicted by the PLS or SVM model had a high correlation with actual TBHQ levels in commercial oil samples (SVM: R(2) = 0.972, ratio of performance to deviation [RPD] = 5.55, root mean square error [RMSE] = 5.73 mg/kg; PLS: R(2) = 0.976, RPD = 6.43, RMSE = 4.94 mg/kg), indicating great potential of SERS methods for detection and quantification of TBHQ in oils from a variety of sources. PRACTICAL APPLICATION: This study provides an alternative approach for analysis of trace amounts of chemicals in complex food matrices with surface-enhanced Raman spectroscopy. PMID- 24784826 TI - Early hyperglycemia detected by continuous glucose monitoring in children at risk for type 1 diabetes. AB - OBJECTIVE: We explore continuous glucose monitoring (CGM) as a new approach to defining early hyperglycemia and diagnosing type 1 diabetes in children with positive islet autoantibodies (Ab+). RESEARCH DESIGN AND METHODS: Fourteen Ab+ children, free of signs or symptoms of diabetes, and nine antibody-negative (Ab-) subjects, followed by the Diabetes Autoimmunity Study in the Young, were asked to wear a Dexcom SEVEN CGM. RESULTS: The Ab+ subjects showed more hyperglycemia, with 18% time spent above 140 mg/dL, compared with 9% in Ab- subjects (P = 0.04). Their average maximum daytime glucose value was higher, and they had increased glycemic variability. The mean HbA1c in the Ab+ subjects was 5.5% (37 mmol/mol). Among Ab+ subjects, >=18-20% CGM time spent above 140 mg/dL seems to predict progression to diabetes. CONCLUSIONS: CGM can detect early hyperglycemia in Ab+ children who are at high risk for progression to diabetes. Proposed CGM predictors of progression to diabetes require further validation. PMID- 24784827 TI - Effect of early multifactorial therapy compared with routine care on microvascular outcomes at 5 years in people with screen-detected diabetes: a randomized controlled trial: the ADDITION-Europe Study. AB - OBJECTIVE: To determine the benefit of multifactorial treatment on microvascular complications among people with type 2 diabetes detected by screening. RESEARCH DESIGN AND METHODS: This study was a multicenter cluster randomized controlled trial in primary care with randomization at the practice level. In four centers in Denmark; Cambridge, U.K.; the Netherlands; and Leicester, U.K., 343 general practices participated in the trial. Eligible for follow-up were 2,861 of the 3,057 people with diabetes detected by screening included in the original trial. Biomedical data on nephropathy were collected in 2,710 (94.7%) participants, retinal photos in 2,190 (76.6%), and questionnaire data on peripheral neuropathy in 2,312 (80.9%). The prespecified microvascular end points were analyzed by intention to treat. Results from the four centers were pooled using fixed-effects meta-analysis. RESULTS: Five years after diagnosis, any kind of albuminuria was present in 22.7% of participants in the intensive treatment (IT) group and in 24.4% in the routine care (RC) group (odds ratio 0.87 [95% CI 0.72-1.07]). Retinopathy was present in 10.2% of the IT group and 12.1% of the RC group (0.84 [0.64-1.10]), and severe retinopathy was present in one patient in the IT group and seven in the RC group. Neuropathy was present in 4.9% and 5.9% (0.95 [0.68 1.34]), respectively. Estimated glomerular filtration rate increased between baseline and follow-up in both groups (4.31 and 6.44 mL/min, respectively). CONCLUSIONS: Compared with RC, an intervention to promote target-driven, intensive management of patients with type 2 diabetes detected by screening was not associated with significant reductions in the frequency of microvascular events at 5 years. PMID- 24784830 TI - Evaluating structured care for diabetes: can calibration on margins help to avoid overestimation of the benefits? An illustration from French diabetes provider networks using data from the ENTRED Survey. AB - OBJECTIVE: While there is growing evidence on the effectiveness of structured care for diabetic patients in trial settings, standard population level evaluations may misestimate intervention benefits due to patient selection. In order to account for potential biases in measuring intervention benefits, we tested the impact of calibration on margins as a novel adjustment method in an evaluation context compared with simple poststratification. RESEARCH DESIGN AND METHODS: We compared the results of a before-after evaluation on HbA1c levels after 1 year of enrollment in a French diabetes provider network (DPN) using an unadjusted sample and samples adjusted by simple poststratification to results obtained after adjustment via calibration on margins to the general diabetic population's characteristics using a national cross-sectional sample of diabetic patients. RESULTS: Both with and without adjustment, patients in the DPN had significantly lower HbA1c levels after 1 year of enrollment. However, the reductions in HbA1c levels among the adjusted samples were 22-183% lower than those measured in the unadjusted sample, regardless of the poststratification method and characteristics used. Compared with simple poststratification, estimations using calibration on margins exhibited higher performance. CONCLUSIONS: Evaluations of diabetes management interventions based on uncontrolled before-after experiments may overestimate the actual benefit for patients. This can be corrected by using poststratification approaches when data on the ultimate target population for the intervention are available. In order to more accurately estimate the effect an intervention would have if extended to the target population, calibration on margins seems to be preferable over simple poststratification in terms of performance and usability. PMID- 24784828 TI - Adipose and muscle tissue profile of CD36 transcripts in obese subjects highlights the role of CD36 in fatty acid homeostasis and insulin resistance. AB - OBJECTIVE: Fatty acid (FA) metabolism is tightly regulated across several tissues and impacts insulin sensitivity. CD36 facilitates cellular FA uptake, and CD36 genetic variants associate with lipid abnormalities and susceptibility to metabolic syndrome. The objective of this study was to gain insight regarding the in vivo metabolic influence of muscle and adipose tissue CD36. For this, we determined the relationships between CD36 alternative transcripts, which can reflect tissue-specific CD36 regulation, and measures of FA metabolism and insulin resistance. RESEARCH DESIGN AND METHODS: The relative abundance of alternative CD36 transcripts in adipose tissue and skeletal muscle from 53 nondiabetic obese subjects was measured and related to insulin sensitivity and FA metabolism assessed by hyperinsulinemic-euglycemic clamps and isotopic tracers for glucose and FA. RESULTS: Transcript 1C, one of two major transcripts in adipose tissue, that is restricted to adipocytes predicted systemic and tissue (adipose, liver, and muscle) insulin sensitivity, suggesting adipocyte CD36 protects against insulin resistance. Transcripts 1B and 1A, the major transcripts in skeletal muscle, correlated with FA disposal rate and triglyceride clearance, supporting importance of muscle CD36 in clearance of circulating FA. Additionally, the common CD36 single nucleotide polymorphism rs1761667 selectively influenced CD36 transcripts and exacerbated insulin resistance of glucose disposal by muscle. CONCLUSIONS: Alternative CD36 transcripts differentially influence tissue CD36 and consequently FA homeostasis and insulin sensitivity. Adipocyte CD36 appears to be metabolically protective, and its selective upregulation might have therapeutic potential in insulin resistance. PMID- 24784829 TI - Depressive symptoms, antidepressant use, and the incidence of diabetes in the Black Women's Health Study. AB - OBJECTIVE: To assess the relationship of depressive symptoms and use of antidepressants with incident type 2 diabetes in prospective data from a large cohort of U.S. African American women. RESEARCH DESIGN AND METHODS: The Black Women's Health Study (BWHS) is an ongoing prospective cohort study. We followed 35,898 women from 1999 through 2011 who were without a diagnosis of diabetes and who had completed the Center for Epidemiologic Studies Depression Scale (CES-D) in 1999. CES-D scores were categorized as <16, 16-22, 23-32, and >=33, which reflected increasingly more depressive symptoms. We estimated incidence rate ratios (IRRs) and 95% CIs for incident diabetes using Cox proportional hazards models. The basic multivariable model included age, time period, family history of diabetes, and education. In further models, we controlled for lifestyle factors and BMI. We also assessed the association of antidepressant use with incident diabetes. RESULTS: Over 12 years of follow-up, there were 3,372 incident diabetes cases. Relative to CES-D score <16, IRRs (95% CI) of diabetes for CES-D scores 16-22, 23-32, and >=33 were 1.23 (1.12-1.35), 1.26 (1.12-1.41), and 1.45 (1.24-1.69), respectively, in the basic multivariate model. Multiple adjustment for lifestyle factors and BMI attenuated the IRRs to 1.11 (1.01-1.22), 1.08 (0.96 1.22), and 1.22 (1.04-1.43). The adjusted IRR for antidepressant use was 1.26 (1.11-1.43). Results were similar among obese women. CONCLUSIONS: Both depressive symptoms and antidepressant use are associated with incident diabetes among African American women. These associations are mediated in part, but not entirely, through lifestyle factors and BMI. PMID- 24784831 TI - Psychological distress and incidence of type 2 diabetes in high-risk and low-risk populations: the Whitehall II Cohort Study. AB - OBJECTIVE: We examined whether psychological distress predicts incident type 2 diabetes and if the association differs between populations at higher or lower risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a prospective cohort of 5,932 diabetes-free adults (4,189 men and 1,743 women, mean age 54.6 years) with three 5-year data cycles (1991-2009): a total of 13,207 person observations. Participants were classified into four groups according to their prediabetes status and Framingham Offspring Type 2 Diabetes Risk Score: normoglycemia with a risk score of 0-9, normoglycemia with a risk score of 10-19, prediabetes with a risk score of 10-19, and prediabetes with a risk score of >19. Psychological distress was assessed by the General Health Questionnaire. Incident type 2 diabetes was ascertained by 2-h oral glucose tolerance test, doctor diagnosis, or use of antihyperglycemic medication at the 5-year follow-up for each data cycle. Adjustments were made for age, sex, ethnicity, socioeconomic status, antidepressant use, smoking, and physical activity. RESULTS: Among participants with normoglycemia and among those with prediabetes combined with a low risk score, psychological distress did not predict type 2 diabetes. Diabetes incidence in these groups varied between 1.6 and 15.6%. Among participants with prediabetes and a high risk score, 40.9% of those with psychological distress compared with 28.5% of those without distress developed diabetes during the follow-up. The corresponding adjusted odds ratio for psychological distress was 2.07 (95% CI 1.19-3.62). CONCLUSIONS: These data suggest that psychological distress is associated with an accelerated progression to manifest diabetes in a subpopulation with advanced prediabetes. PMID- 24784832 TI - A low-glycemic index meal and bedtime snack prevents postprandial hyperglycemia and associated rises in inflammatory markers, providing protection from early but not late nocturnal hypoglycemia following evening exercise in type 1 diabetes. AB - OBJECTIVE: To examine the influence of the glycemic index (GI) of foods consumed after evening exercise on postprandial glycemia, metabolic and inflammatory markers, and nocturnal glycemic control in type 1 diabetes. RESEARCH DESIGN AND METHODS: On two evenings (~1700 h), 10 male patients (27 +/- 5 years of age, HbA1c 6.7 +/- 0.7% [49.9 +/- 8.1 mmol/mol]) were administered a 25% rapid-acting insulin dose with a carbohydrate bolus 60 min before 45 min of treadmill running. At 60 min postexercise, patients were administered a 50% rapid-acting insulin dose with one of two isoenergetic meals (1.0 g carbohdyrate/kg body mass [BM]) matched for macronutrient content but of either low GI (LGI) or high GI (HGI). At 180 min postmeal, the LGI group ingested an LGI snack and the HGI group an HGI snack (0.4 g carbohdyrate/kg BM) before returning home (~2300 h). Interval samples were analyzed for blood glucose and lactate; plasma glucagon, epinephrine, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha); and serum insulin, cortisol, nonesterified fatty acid, and beta-hydroxybutyrate concentrations. Interstitial glucose was recorded for 20 h postlaboratory attendance through continuous glucose monitoring. RESULTS: Following the postexercise meal, an HGI snack induced hyperglycemia in all patients (mean +/- SD glucose 13.5 +/- 3.3 mmol/L) and marked increases in TNF-alpha and IL-6, whereas relative euglycemia was maintained with an LGI snack (7.7 +/- 2.5 mmol/L, P < 0.001) without inflammatory cytokine elevation. Both meal types protected all patients from early hypoglycemia. Overnight glycemia was comparable, with a similar incidence of nocturnal hypoglycemia (n = 5 for both HGI and LGI). CONCLUSIONS: Consuming LGI food with a reduced rapid-acting insulin dose following evening exercise prevents postprandial hyperglycemia and inflammation and provides hypoglycemia protection for ~8 h postexercise; however, the risk of late nocturnal hypoglycemia remains. PMID- 24784833 TI - KrF excimer laser precision machining of hard and brittle ceramic biomaterials. AB - KrF excimer laser precision machining of porous hard-brittle ceramic biomaterials was studied to find a suitable way of machining the materials into various desired shapes and sizes without distorting their intrinsic structure and porosity. Calcium phosphate glass ceramics (CPGs) and hydroxyapatite (HA) were chosen for the study. It was found that KrF excimer laser can cut both CPGs and HA with high efficiency and precision. The ablation rates of CPGs and HA are respectively 0.081 um/(pulse J cm(-2)) and 0.048 um/(pulse J cm(-2)), while their threshold fluences are individually 0.72 and 1.5 J cm(-2). The cutting quality (smoothness of the cut surface) is a function of laser repetition rate and cutting speed. The higher the repetition rate and lower the cutting speed, the better the cutting quality. A comparison between the cross sections of CPGs and HA cut using the excimer laser and using a conventional diamond cutting blade indicates that those cut by the excimer laser could retain their intrinsic porosity and geometry without distortion. In contrast, those cut by conventional machining had distorted geometry and most of their surface porosities were lost. Therefore, when cutting hard-brittle ceramic biomaterials to prepare scaffold and implant or when sectioning them for porosity evaluation, it is better to choose KrF excimer laser machining. PMID- 24784835 TI - Knowledge and perception of breastfeeding practices in Hispanic mothers in association with their preferred language for communication. AB - Economically disadvantaged minority mothers with limited proficiency in English show suboptimal breastfeeding rates. In the present survey, the knowledge and perception of Hispanic mothers regarding their breastfeeding practices were analyzed in association with their language preference for communication. Among the mostly Hispanic-origin Special Supplemental Nutrition Program for Women, Infants, and Children-eligible mothers surveyed at our pediatric clinic, 109 were Spanish-respondent Hispanics (Group 1), 31 were English-respondent Hispanics (Group 2), and 56 were U.S.-born non-Hispanics (Group 3). Overall, 70-90% of mothers reported understanding the beneficial effect of breastmilk, thought breastfeeding was good to do, and had discussed breastfeeding with their obstetricians and pediatricians. Groups 1 and 2 mothers were more likely to have predecided to breastfeed their infant, to feel comfortable about breastfeeding at the doctor's office, and to have discussed with their mothers about how they had been fed. However, they were less likely to be able to identify who to approach for breastfeeding advice. A higher proportion of the Group 1 mothers admitted to inadequate breastfeeding knowledge, unfamiliarity with "latch on," and inability to identify who had educated them about breastfeeding. We conclude that in economically disadvantaged Hispanic mothers, a preference for communication in Spanish is associated with limited breastfeeding knowledge and lack of breastfeeding-related educational networks. Language preference should be addressed while providing breastfeeding education and support for Hispanic mothers to help improve their understanding and breastfeeding networks. PMID- 24784837 TI - Realizing nursing: a multimodal biopsychopharmacosocial approach to psychiatric nursing. AB - The biological and psychosocial components of health, illness and treatment are well recognized. In addition, pharmacological interventions interact with both these components regarding health and illness; all components are potentially modifiable. A better understanding of these interactions on the course of illness, especially at the interface between illness and treatment, is needed to guide effective clinical and psychiatric nursing interventions. To this end, a multimodal biopsychopharmacosocial approach to assessment, formulation, care planning and implementation by psychiatric nurses is proposed. It is argued that a biopsychopharmacosocial approach, including a multimodal functional element, provides a person-centred, responsive and responsible basis for a comprehensive approach to practice. The use of this approach will improve intervention outcomes and contribute to the ongoing development of psychiatric nursing practice. It is suggested that, in part, this will be achieved through innovative teaching methods delivered by 'expert nurses' and clinical academics. PMID- 24784836 TI - Dopamine preferentially inhibits NMDA receptor-mediated EPSCs by acting on presynaptic D1 receptors in nucleus accumbens during postnatal development. AB - Nucleus accumbens (nAcb), a major site of action of drugs of abuse and dopamine (DA) signalling in MSNs (medium spiny neurons), is critically involved in mediating behavioural responses of drug addiction. Most studies have evaluated the effects of DA on MSN firing properties but thus far, the effects of DA on a cellular circuit involving glutamatergic afferents to the nAcb have remained rather elusive. In this study we attempted to characterize the effects of dopamine (DA) on evoked glutamatergic excitatory postsynaptic currents (EPSCs) in nAcb medium spiny (MS) neurons in 1 to 21 day-old rat pups. The EPSCs evoked by local nAcb stimuli displayed both AMPA/KA and NMDA receptor-mediated components. The addition of DA to the superfusing medium produced a marked decrease of both components of the EPSCs that did not change during the postnatal period studied. Pharmacologically isolated AMPA/KA receptor-mediated response was inhibited on average by 40% whereas the isolated NMDA receptor-mediated EPSC was decreased by 90%. The effect of DA on evoked EPSCs were mimicked by the D1-like receptor agonist SKF 38393 and antagonized by the D1-like receptor antagonist SCH 23390 whereas D2-like receptor agonist or antagonist respectively failed to mimic or to block the action of DA. DA did not change the membrane input conductance of MS neurons or the characteristics of EPSCs produced by the local administration of glutamate in the presence of tetrodotoxin. In contrast, DA altered the paired pulse ratio of evoked EPSCs. The present results show that the activation D1-like dopaminergic receptors modulate glutamatergic neurotransmission by preferentially inhibiting NMDA receptor-mediated EPSC through presynaptic mechanisms. PMID- 24784838 TI - Prognostic factors for kidney allograft survival in the Eurotransplant Senior Program. AB - BACKGROUND: The shortage of organ donors has led to the introduction of the Eurotransplant Senior Program (ESP) to optimize the allocation of kidneys from elderly donors by age-matching. In the face of a rapidly aging population, identification of prognostic factors for kidney allograft survival within the ESP population will be of enormous significance. MATERIAL AND METHODS: Donor and recipient data from 89 patients transplanted under the ESP protocol between 1999 and 2007 were retrospectively analyzed. Data were correlated with initial graft function, graft survival, acute rejection episodes, serum creatinine levels, glomerular filtration rates, and patient survival using univariate and multivariate analysis. Maximum follow-up was 5 years. RESULTS: Cold ischemia time (CIT) >16 hours, body mass index (BMI) >=25 kg/m(2), and kidney re transplantation were significant risk factors for delayed graft function (DGF). Odds ratio for primary non-function was significantly increased with prolonged CIT, BMI >=25 kg/m(2), and duration of renal replacement therapy >69 months. CIT >15 h, DGF, and kidney re-transplantation were associated with poor graft survival (P<0.05). CONCLUSIONS: Risk reduction (e.g., aiming at CIT <15 h) and close surveillance of patients at risk appear to be crucial for allograft survival in the ESP. PMID- 24784839 TI - FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism. AB - Activating mutations and/or overexpression of FGFR3 are common in bladder cancer, making FGFR3 an attractive therapeutic target in this disease. In addition, FGFR3 gene rearrangements have recently been described that define a unique subset of bladder tumors. Here, a selective HSP90 inhibitor, ganetespib, induced loss of FGFR3-TACC3 fusion protein expression and depletion of multiple oncogenic signaling proteins in RT112 bladder cells, resulting in potent cytotoxicity comparable with the pan-FGFR tyrosine kinase inhibitor BGJ398. However, in contrast to BGJ398, ganetespib exerted pleiotropic effects on additional mitogenic and survival pathways and could overcome the FGFR inhibitor-resistant phenotype of FGFR3 mutant-expressing 97-7 and MHG-U3 cells. Combinatorial benefit was observed when ganetespib was used with BGJ398 both in vitro and in vivo. Interestingly, two additional FGFR3 fusion-positive lines (RT4 and SW480) retained sensitivity to HSP90 inhibitor treatment by the ansamycins 17-AAG and 17 DMAG yet displayed intrinsic resistance to ganetespib or AUY922, both second generation resorcinol-based compounds. Both cell lines, compared with RT112, expressed considerably higher levels of endogenous UGT1A enzyme; this phenotype resulted in a rapid glucuronidation-dependent metabolism and subsequent efflux of ganetespib from SW780 cells, thus providing a mechanism to account for the lack of bioactivity. IMPLICATIONS: Pharmacologic blockade of the molecular chaperone HSP90 represents a promising approach for treating bladder tumors driven by oncogenic gene rearrangements of FGFR3. Furthermore, UDP-glucuronosyltransferase enzyme expression may serve as a predictive factor for clinical response to resorcinol-based HSP90 inhibitors. PMID- 24784840 TI - Cooperativity of E-cadherin and Smad4 loss to promote diffuse-type gastric adenocarcinoma and metastasis. AB - Loss of E-cadherin (CDH1), Smad4, and p53 has been shown to play an integral role in gastric, intestinal, and breast cancer formation. Compound conditional knockout mice for Smad4, p53, and E-cadherin were generated to define and compare the roles of these genes in gastric, intestinal, and breast cancer development by crossing with Pdx-1-Cre, Villin-Cre, and MMTV-Cre transgenic mice. Interestingly, gastric adenocarcinoma was significantly more frequent in Pdx-1 Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) mice than in Pdx-1 Cre;Smad4(F/F);Trp53(F/F);Cdh1(+/+) mice, demonstrating that Cdh1 heterozygosity accelerates the development and progression of gastric adenocarcinoma, in combination with loss of Smad4 and p53. Pdx-1-Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) mice developed gastric adenocarcinomas without E-cadherin expression. However, intestinal and mammary adenocarcinomas with the same genetic background retained E-cadherin expression and were phenotypically similar to mice with both wild-type Cdh1 alleles. Lung metastases were identified in Pdx-1 Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) mice, but not in the other genotypes. Nuclear beta-catenin accumulation was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the inhibition of beta-catenin signaling by E-cadherin or Smad4 downregulates signaling pathways involved in metastases in Pdx-1 Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) mice. Knockdown of beta-catenin significantly inhibited the migratory activity of Pdx-1 Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) cell lines. Thus, loss of E-cadherin and Smad4 cooperates with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human gastric adenocarcinoma. IMPLICATIONS: This study demonstrates that inhibition of beta catenin is a converging node for the antimetastatic signaling pathways driven by E-cadherin and Smad4 in Pdx-1-Cre;Smad4(F/F);Trp53(F/F);Cdh1(F) (/+) mice, providing novel insights into mechanisms for gastric cancer metastasis. PMID- 24784841 TI - Differential expression of stress and immune response pathway transcripts and miRNAs in normal human endothelial cells subjected to fractionated or single-dose radiation. AB - Although modern radiotherapy technologies can precisely deliver higher doses of radiation to tumors, thus, reducing overall radiation exposure to normal tissues, moderate dose, and normal tissue toxicity still remains a significant limitation. The present study profiled the global effects on transcript and miR expression in human coronary artery endothelial cells using single-dose irradiation (SD, 10 Gy) or multifractionated irradiation (MF, 2 Gy * 5) regimens. Longitudinal time points were collected after an SD or final dose of MF irradiation for analysis using Agilent Human Gene Expression and miRNA microarray platforms. Compared with SD, the exposure to MF resulted in robust transcript and miR expression changes in terms of the number and magnitude. For data analysis, statistically significant mRNAs (2-fold) and miRs (1.5-fold) were processed by Ingenuity Pathway Analysis to uncover miRs associated with target transcripts from several cellular pathways after irradiation. Interestingly, MF radiation induced a cohort of mRNAs and miRs that coordinate the induction of immune response pathway under tight regulation. In addition, mRNAs and miRs associated with DNA replication, recombination and repair, apoptosis, cardiovascular events, and angiogenesis were revealed. IMPLICATIONS: Radiation-induced alterations in stress and immune response genes in endothelial cells contribute to changes in normal tissue and tumor microenvironment, and affect the outcome of radiotherapy. PMID- 24784842 TI - Automated registration of optical coherence tomography and dermoscopy in the assessment of sub-clinical spread in basal cell carcinoma. AB - Optical coherence tomography (OCT) has been shown to be of clinical value in imaging basal cell carcinoma (BCC). A novel dual OCT-video imaging system, providing automated registration of OCT and dermoscopy, has been developed to assess the potential of OCT in measuring the degree of sub-clinical spread of BCC. Seventeen patients selected for Mohs micrographic surgery (MMS) for BCC were recruited to the study. The extent of BCC infiltration beyond a segment of the clinically assessed pre-surgical border was evaluated using OCT. Sufficiently accurate (<0.5 mm) registration of OCT and dermoscopy images was achieved in 9 patients. The location of the OCT-assessed BCC border was also compared with that of the final surgical defect. Infiltration of BCC across the clinical border ranged from 0 mm to >2.5 mm. In addition, the OCT border lay between 0.5 mm and 2.0 mm inside the final MMS defect in those cases where this could be assessed. In one case, where the final MMS defect was over 17 mm from the clinical border, OCT showed >2.5 mm infiltration across the clinical border at the FOV limit. These results provide evidence that OCT allows more accurate assessment of sub clinical spread of BCC than clinical observation alone. Such a capability may have clinical value in reducing the number of surgical stages in MMS for BCC. There may also be a role for OCT in aiding the selection of patients most suitable for MMS. PMID- 24784843 TI - Toward unimolecular micelles with tunable dimensions using hyperbranched dendritic-linear polymers. AB - A library of amphiphilic, hyperbranched dendritic-linear polymers (HBDLPs) are successfully synthesized, and evaluated as potential unimolecular micelles. Hyperbranched macroinitiators (HBMI), extended with poly(ethylene glycol) methacrylate (P(OEGMA)), are afforded via a combination of self-condensing vinyl (co)polymerization (SCV(C)P) and atom transfer radical polymerization (ATRP), providing a versatile two-step synthetic route. The HBDLP architecture and chain lengths are varied, and the effect on the nanoparticle (NP) stability and properties are evaluated. The HBDLPs form predominantly stable and spherical NPs, and the NP dimensions could be tailored by the HBDLP characteristics. The NPs formed are of high molecular weight, and their stability varies with the properties of the corresponding HBDLP. Too small dendritic segment, or too low degree of PEGylation, results to some extent in NP aggregation, while higher molecular weight HBDLPs, with a high amount of hydrophilic segments, appears to form discrete unimolecular micelles. The versatility of the platform is further demonstrated by the convenience of forming a HBDLP with a more complex, linear copolymer extension instead of P(OEGMA). PMID- 24784844 TI - Force decay evaluation of thermoplastic and thermoset elastomeric chains: A mechanical design comparison. AB - OBJECTIVES: To compare the following over a period of 8 weeks: (1) force decay between thermoplastic (TP) and thermoset (TS) elastomeric chains; (2) force decay between light (200-g) and heavy (350-g) initial forces; and (3) force decay between direct chains and chain loops (stretched from one pin around the second pin and back to the first pin). MATERIALS AND METHODS: TP and TS chains were obtained from American OrthodonticsTM (AOTP, AOTS) and ORMCOTM (OrTP, OrTS). Each of the four chain groups was subdivided into four subgroups with 10 specimens per subgroup: (1) direct chains light force, (2) direct chains heavy force, (3) chain loops light force, and (4) chain loops heavy force. The experiment was performed in artificial saliva (pH of 6.75) at 37 degrees C. RESULTS: A significant difference was found between TP and TS chains, with an average mean difference of around 20% more force decay found in the TP chains (P < .001, alpha = .05). There was no significant difference between direct chains and chain loops except in OrTP, in which direct chains showed more force decay. There was also no significant difference in force decay identified when using light vs heavy forces. CONCLUSIONS: TS chains decayed less than TP chains, and chain loop retraction was beneficial only when using OrTP chains. Contrary to the interchangeable use of TP and TS chains in the published literature and in clinical practice, this study demonstrates that they perform differently under stress and that a clear distinction should be made between the two. PMID- 24784845 TI - Hounsfield Units: a new indicator showing maxillary resistance in rapid maxillary expansion cases? AB - OBJECTIVE: To determine if density measurements of several maxillary regions in Hounsfield Units (HU) and outcomes of rapid maxillary expansion (RME) are correlated. Is correlation powerful enough to give us direct information about maxillary resistance to RME? MATERIALS AND METHODS: Twenty-two computed tomographic (CT) scans (14 years) are used in this archive study. Two CT records were collected, one before RME (T1) and one after 3 months of retention period (T2). Maxillary measurements were made using dental and skeletal landmarks in first molar and first premolar slides to measure the effects of RME. Density of midpalatal suture (MPSD) and segments of maxillary bone is measured in HU at T1. Correlation analysis was conducted between density measurements and maxillary variables. Regression analysis was then performed for variables that showed positive correlation. RESULTS: There was no correlation between density and skeletal measurements. Intermolar angle (ImA) in molar slice showed statistically significant correlation with density measurements. The ImA variable showed the highest correlation with MPSD in frontal section (r = 0.669, P < .01). CONCLUSIONS: There is correlation of 32.1-43.3% between density measurements and ImA increase. Our density measurements explain a certain percentage of ImA increase, but density is not the only and definitive indicator of changes after RME. PMID- 24784846 TI - A career in public health: the chance to save lives by the millions. PMID- 24784847 TI - Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat. AB - We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6alpha ethyl-3alpha,7alpha-dihydroxy-5beta-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6alpha-ethyl-23(S)-methyl-3alpha,7alpha,12alpha trihydroxy-5beta-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6alpha-ethyl-3alpha,7alpha-dihydroxy-24-nor-5beta cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7alpha-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7 dehydroxylation. The hepatic metabolism and biliary secretion were different: 6alpha-ethyl-3alpha,7alpha-dihydroxy-5beta-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6alpha-Ethyl-23(S) methyl-3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6alpha-ethyl-3alpha,7alpha-dihydroxy-24-nor-5beta-cholan-23-sulfate was secreted in bile unmodified and as 3-glucuronide. Therefore, minor structural modifications profoundly influence the metabolism and biodistribution in the target organs where these analogs exert therapeutic effects by interacting with FXR and/or TGR5 receptors. PMID- 24784848 TI - An update on data reporting standards. PMID- 24784856 TI - Hypertension in 2014: making sense of the guidelines. AB - Hypertension, if not appropriately treated, can lead to stroke, kidney failure, myocardial infarction, and death. Substantial evidence from multiple randomized clinical trials demonstrates the benefit of antihypertensive therapy. Healthcare providers seek scientific evidence by which to base treatments. The purpose of this article is to discuss current hypertension guidelines. PMID- 24784857 TI - Prescribing opioids in primary care: avoiding perils and pitfalls. AB - Millions of Americans have chronic pain for which chronic opioid therapy may be warranted. In light of recent abuse of these medications, clinicians must exercise caution and develop uniform approaches to prescribing. It is possible to assess for opioid risk and safely prescribe opioids. PMID- 24784858 TI - A probabilistic method for the estimation of residual risk in donated blood. AB - The residual risk (RR) of transfusion-transmitted infections, including the human immunodeficiency virus and hepatitis B and C viruses, is typically estimated by the incidence[Formula: see text]window period model, which relies on the following restrictive assumptions: Each screening test, with probability 1, (1) detects an infected unit outside of the test's window period; (2) fails to detect an infected unit within the window period; and (3) correctly identifies an infection-free unit. These assumptions need not hold in practice due to random or systemic errors and individual variations in the window period. We develop a probability model that accurately estimates the RR by relaxing these assumptions, and quantify their impact using a published cost-effectiveness study and also within an optimization model. These assumptions lead to inaccurate estimates in cost-effectiveness studies and to sub-optimal solutions in the optimization model. The testing solution generated by the optimization model translates into fewer expected infections without an increase in the testing cost. PMID- 24784859 TI - Global Burden of Disease Study 2010: a real advance in global descriptive epidemiology: prospective for developing countries. PMID- 24784860 TI - Evaluating causes of death and morbidity in Iran, global burden of diseases, injuries, and risk factors study 2010. AB - BACKGROUND: we aimed to recap and highlight the major results of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 by mortality and morbidity to clarify the current health priorities and challenges in Iran. METHODS: We estimated Iran's mortality and burden of 289 diseases with 67 risk factors and 1160 sequelae, which were used to clinically present each disease and its disability or cause of death. We produced several measures to report health loss and status: all-cause mortality, cause-specific mortality, years of life lost due to death (YLL), healthy years of life lost due to disability (YLD), disability-adjusted life years (DALYs), life expectancy, and healthy life expectancy, for three time periods: 1990, 2005, and 2010. RESULTS: We found out that life expectancy at birth was 71.6 years in men and 77.8 years in women. Almost 350 thousand deaths occurred in both sexes and all age groups in 2010. In both males and females and all age groups, ischemic heart disease was the main cause of death, claiming about 90 thousand lives. The main contributors to DALYs were: ischemic heart disease (9.1%), low back pain (9.0%), road injuries (7.3%), and unipolar depressive disorders (6.3%). The main causes of death under 5 years of age included: congenital anomalies (22.4%), preterm birth complications (18.3%), and other neonatal disorders (13.5%). The main causes of death among 15 49 year olds in both sexes included: injuries (23.6%) and ischemic heart disease (12.7%) The highest rates of YLDs were observed among 70+ year olds for both sexes (27,365 per 100,000), mainly due to low back pain, osteoarthritis, diabetes, falls, and major depressive disorder. The main risk factors to which deaths were attributable among children under 5 years included: suboptimal breast feeding, ambient PM pollution, tobacco smoking, and underweight. The most important risk factors among 15 to 49 year olds were: dietary risks, high blood pressure, high body mass index, physical inactivity, smoking, and ambient PM pollution. The pattern was similar among 50+ year olds. CONCLUSION: Although non communicable diseases had the greatest burden in 2010, the challenge of communicable and maternal diseases for health system is not over yet. Diet and physiological risk factors appear to be the most important targets for public health policy in Iran. Moreover, Iranians would greatly benefit from effective strategies to prevent injury and musculoskeletal disorders and expand mental care. Persistent improvement is possible by strengthening the health information system to monitor the population health and evaluate current programs. PMID- 24784861 TI - Health transition in Iran toward chronic diseases based on results of Global Burden of Disease 2010. AB - BACKGROUND: Drawing on the results of the country-level Global Burden of Diseases, Injuries, and Risk Factors 2010 Study, we attempted to investigate the drivers of change in the healthcare system in terms of mortality and morbidity due to diseases, injuries, and risk factors for the two decades from 1990 to 2010. METHODS: We decomposed trends in mortality, cause of death, years of life lost due to disability, disability-adjusted life years (DALYs), life expectancy, health-adjusted life expectancy, and risk factors into the contribution of total increase in population size, aging of the population, and changes in age-specific and sex-specific rates. RESULTS: We observed a decrease in age-specific mortality rate for both sexes, with a higher rate for women. The ranking of causes of death and their corresponding number of years of life lost remained unchanged between 1990 and 2010. However, the percentages of change indicate patterns of reduction for most causes, such as ischemic and hemorrhagic stroke, hypertensive heart disease, stomach cancer, lower respiratory infections, and congenital anomalies. The number of years lost due to disability caused by diabetes and drug use disorders has significantly increased in the last two decades. Major causes of DALYs, such as injuries, interpersonal violence, and suicide, showed increasing trends, while rates of communicable diseases, neonatal disorders, and nutritional deficiencies have declined significantly. Life expectancy and health-adjusted life expectancy increased for both sexes by approximately 7 years, with the highest rate of increase pertaining to females over the age 30. CONCLUSIONS: Time trend information presented in this paper can be used to evaluate problems and policies specific to medical conditions or risk factors. Despite recent improvements, implementing policies to reduce the number of deaths and years of life lost due to road traffic injury remains the highest priority for Iranian policymakers. Immediate action by Iranian researchers is required to match Iran's decreasing mortality rate due to liver and stomach cancers to a rate comparable to the global level. Prevention and treatment plans for mental disorders, such as major depressive disorder, anxiety disorder, and particularly drug use disorders, should be considered in reforms of the health, education, and judiciary systems in Iran. PMID- 24784862 TI - Population health and burden of disease profile of Iran among 20 countries in the region: from Afghanistan to Qatar and Lebanon. AB - BACKGROUND: Population health and disease profiles are diverse across Iran's neighboring countries. Borrowing the results of the country-level Global Burden of Diseases, Injuries, and Risk Factors 2010 Study (GBD 2010), we aim to compare Iran with 19 countries in terms of an important set of population health and disease metrics. These countries include those neighboring Iran and a few other countries from the Middle East and North Africa (MENA) region. METHODS: We show the pattern of health transition across the comparator countries from 1990 through 2010. We use classic GBD metrics measured for the year 2010 to indicate the rank of Iran among these nations. The metrics include disability-adjusted life years (DALYs), years of life lost as a result of premature death (YLLs), years of life lost due to disability (YLDs), health-adjusted life expectancy (HALE), and age-standardized death rate (ASD). RESULTS: Considerable and uniform transition from communicable, maternal, neonatal, and nutritional (CMMN) conditions to non-communicable diseases (NCDs) was seen between 1990 and 2010. On average, ischemic heart disease, lower respiratory infections, and road injuries were the three principal causes of YLLs, while low back pain and major depressive disorders were the top causes of YLDs in these countries. Iran ranked 13th in HALE and 12th in ASD. The function of Iran's health care, measured by DALYs, was somewhat in the middle of the HALE spectrum for the comparator countries. This intermediate position becomes rather highlighted when Afghanistan, as outlier, is taken out of the comparison. CONCLUSION: Effective policies to reduce NCDs need to be formulated and implemented through an integrated health care system. Our comparison shows that Iran can learn from the experience of a number of these countries to devise and execute the required strategies. PMID- 24784863 TI - Serum lipids and lipoproteins in patients with psoriasis. AB - BACKGROUND: Psoriasis is a common chronic and recurrent inflammatory skin disorder characterized by hyperproliferation of keratinocytes and infiltration of T cells, monocytes/macrophages and neutrophils into dermal and epidermal layers of the skin. The prevalence of cardiovascular disorders in these patients is remarkably higher compared to normal individuals, which seems to be associated with the hyperlipidemia. This study was designed and conducted to investigate the serum lipid profile in psoriatic patients and its association with the severity of disease. MATHERIALS AND METHODS: This case-control study was performed on 50 plaque-type psoriasis patients and 50 healthy individuals as control, matched for age and sex. Blood samples were collected after 14 h fasting. Serum triglyceride, cholesterol and lipoproteins were assayed using the standard kit (made by Pars Azmon Co. Iran). RESULTS: Certain parameters, including serum triglyceride, cholesterol, low density lipoprotein (LDL), and very low density lipoprotein (VLDL), were significantly higher in the case group compared to the controls (P < 0.001), while high density lipoprotein (HDL) was significantly lower in the former (P < 0.001). In addition, there was a significant relationship between severity of psoriasis and serum lipid profile. CONCLUSION: The results have revealed the higher plasma level of lipids in psoriatic patients. This may elevate the risk of atherosclerosis, particularly cardiovascular disorders. Therefore, from the epidemiological point of view, screening psoriatic patients, particularly those with severe psoriasis, is recommended. PMID- 24784864 TI - Thyroid disorders and the prevalence of antithyroid antibodies in Shiraz population. AB - BACKGROUND AND OBJECTIVES: Thyroid dysfunction is a common health problem affecting millions of patients worldwide. Autoimmune thyroid disorders are among the most common autoimmune disorders. In this population-based study, we assessed the prevalence of abnormal thyroid function, antithyroid antibodies and the probable relationship between them in Shiraz, southern Iran. METHODS: Serum thyrotropin (TSH) was determined in 981 subjects (66.8% female and 33.2% male; mean age: 39.1 +/- 14.3 years), who were selected with stratified random sampling. Because of the preponderance of females over males, we performed the statistical analyses using sex-weighted data (50% for each sex). Also, antithyroid peroxidase antibodies (TPOAb), and antithyroglobulin antibodies (TgAb) were measured in two random subgroups of 376 and 537 patients respectively). Thyromegaly detected on physical examination. RESULTS: In this cross-sectional study, 8.1% of participants had elevated serum TSH level and 3.4% had low serum TSH level. A statistically significant relationship was found between gender and thyromegaly and TSH values. Positive TPOAb and positive TgAb were detected in 17% and 5.1% of participants respectively. In addition, a significant relationship was observed between elevated TSH levels and positive results for both antibodies. Detectable levels of thyroid antibodies correlated with female sex, while no correlation was observed between detectable levels of thyroid antibodies and thyromegaly. CONCLUSION: Thyroid disorders, especially elevated TSH level, are common. It seems that autoimmune mechanisms are strongly involved in the etiology of hypothyroidism in this area. PMID- 24784865 TI - Lithium increases radiosensitivity by abrogating DNA repair in breast cancer spheroid culture. AB - BACKGROUND: Lithium chloride (LiCl), a drug for bipolar disorder, has antiproliferative and apoptotic effects on certain breast cancer cell lines. This study was conducted to determine the effect of LiCl on radiosensitivity in a human breast cancer cell line in monolayer culture and the more realistic tumor model, multicellular tumor spheroid. METHODS: Monolayer and spheroid cells were treated with LiCl (20 mM) for 24 hours. The clonogenic assay was used to indicate changes in survival after x-ray radiation. The percentage of apoptotic cells was determined by acridine orange/ethidium bromide double staining. The amounts of DNA damage and repair after exposure to ionizing radiation were assessed by comet assay. Mre11 mRNA level was determined by RT-PCR. GSK-3beta and beta-catenin protein levels were measured by Western blotting. RESULTS: Treatment with LiCl decreased surviving fraction at 2, 3 and 6 Gy doses of x-ray (P < 0.01). The sensitizer enhancement ratio was higher in spheroids than monolayer culture. LiCl also decreased DNA repair (P < 0.05) and Mre11 mRNA level (P < 0.01) in T47D cells. These decreases were more prominent in spheroids than monolayer culture. CONCLUSION: Treatment of T47D cells with LiCl sensitized this breast cancer cell line to ionizing radiation in monolayer and especially in the tumor-like spheroid culture. This radiosensitization was attributed, in part, to decline in DNA repair. Decrease in Mre11 mRNA level upon LiCl treatment was suggested to be an important cause for the decreased DNA repair in T47D monolayer and spheroid cells. PMID- 24784866 TI - Reliability and validity of Persian version of perceived stress scale (PSS-10) in adults with asthma. AB - BACKGROUND: Asthma is a major public health problem in the world, and recent findings suggest that stress influences asthma and asthma morbidity. The 10-item Perceived Stress Scale (PSS-10) is one of the most frequently used instruments to measure psychological stress. This study was conducted to evaluate the psychometric properties of the Persian versions of the PSS-10 in adults with asthma. METHODS: In this descriptive cross-sectional study as a methodological research, 106 asthmatic patients referring to several clinics in Sanandaj (western Iran) were selected through convenience sampling. The PSS-10 and the 21 item Depression anxiety and stress scale (DASS-21) were administrated to all patients. Cronbach's alpha was used to evaluate reliability of PSS-10, and confirmatory factor analysis (CFA) and convergent validity were used to evaluate its validity. RESULTS: The results of confirmatory factor analysis indicated that a two-factor structure of PSS-10 provided a good fit to data. The Cronbach's alpha coefficients for negative factor, positive factor and total score (PSS-10) were 0.86, 0.83, and 0.90, respectively. The PSS-10 was positively correlated with the DASS-21 and its subscales, indicating an acceptable convergent validity. Female asthmatic patients scored higher on PSS-10 in comparison with male asthmatic patients. CONCLUSION: The Persian version of PSS-10 is a valid and reliable instrument to measure perceived stress in adults with asthma. PMID- 24784867 TI - Silibinin induces apoptosis and inhibits proliferation of estrogen receptor (ER) negative breast carcinoma cells through suppression of nuclear factor kappa B activation. AB - BACKGROUND: Silibinin is a traditionally well-known drug for its hepatoprotective efficacy against various types of liver afflictions. In addition, it has recently been considered broadly as a potential chemopreventive agent against many types of cancers. The current study was designed to evaluate the restrictive effects of pharmacological doses of silibinin on SKBR3, an ErbB2-overexpressed and ER negative human breast carcinoma cell line. METHODS: Effect of silibinin on metabolic activity and proliferation of human breast carcinoma (SKBR3) cell line were evaluated by MTT and BrdU assays respectively. Furthermore, the proapoptotic effect of silibinin was investigated using flow cytometry. The NF-kappaB phosphorylation assay was also used to assess the effect of silibinin on NF kappaB activation. The alkalizing effect of silibinin on SKBR3 cell line was evaluated by measuring pH of media of the silibinin-treated cells compared to control. RESULTS: Our results indicate that silibinin inhibited metabolic activity and cell proliferation of SKBR3 cells in a dose-dependent manner. Moreover, silibinin significantly induced apoptosis in SKBR3 cells. On the other hand, silibinin significantly inhibited activation of NF-kappaB which is known to be highly active in this cell line. Alkalizing effect of silibinin was also observed. CONCLUSION: The results obtained here indicate that silibinin may be an efficacious therapeutic agent against ER-negative breast carcinomas with high inhibitory effect on NF-kappaB. PMID- 24784868 TI - Validating modified PHEEM questionnaire for measuring educational environment in academic emergency departments. AB - BACKGROUND: The quality of the educational environment is a key determinant in postgraduate training programs. In order to evaluate and understand this environment a valid and reliable instrument is required. The PHEEM (Postgraduate Hospital Educational Environment Measure) questionnaire is one of the most widely used tools for evaluating the perception of hospital-based residents. The aim of this study was to examine the psychometric quality of the PHEEM in the context of emergency medicine program. METHODS: This study evaluated the reliability, construct validity and applicability of the Persian version of the PHEEM questionnaire using a sample of emergency medicine residents from 3 emergency medicine residency programs in Iran. Eighty-nine residents were asked to complete the questionnaire and indicate their agreement with each of the 37 statements using a 5-point Likert scale(strongly disagree: 0 to strongly agree: 4). Cronbach's alpha coefficient was calculated to determine internal consistency. Confirmatory and explanatory factor analyses were performed to assess the construct validity of the original 3 subscales of the questionnaire. RESULTS: The mean score for the total questionnaire was 2.24 (SD: 0.06). The Cronbach's alpha value was found to be 0.86. Factor analysis did not confirm the original three subscales of the PHEEM questionnaire. CONCLUSION: The Persian version of PHEEM proved a reliable and practical tool for assessing clinical educational environment in emergency medicine departments. PMID- 24784869 TI - Multiple endocrine neoplasia type 2A in an Iranian family: clinical and genetic studies. AB - Multiple endocrine neoplasia (MEN) type 2A, a dominant inherited syndrome caused by germline activating mutations in the RET protooncogene, is characterized by association of medullary thyroid carcinoma, pheochromocytoma and primary hyperparathyroidism. There is limited data on this disease in the Middle East region. In this paper, we present clinical and genetic studies of an Iranian patient and her family members. The patient was a 49-year old Iranian woman who presented with hypertension due to bilateral pheochromocytoma. She had history of a medullary carcinoma of thyroid which had been operated 28 years ago. Analysis of the RET gene in the family revealed a C634R mutation in codon 11 and 3 polymorphisms, G691S, S836S and S904S in codons 11, 14 and 15, respectively, that might have been important in modifying the clinical picture. Due to paucity of information on MEN type 2 in the area, this study can be helpful in portraying the clinical and cytogenetic characteristics of the disease in the region. PMID- 24784870 TI - Leiomyosarcoma of the inferior vena cava. AB - The purpose of this article is to present the CT features in five cases of pathologically verified Inferior vena cava (IVC) leiomyosarcoma. In this retrospective analysis, we reviewed CT features in 5 cases of clinicopathologically confirmed IVC leiomyosarcoma with respect to its location (infra renal, trans renal, supra renal), its extent (with or without involvement of renal vein, hepatic IVC with or without involvement of hepatic vein, right atrial & extra caval extension) and pattern of enhancement. CT guided biopsy was performed in four patients while the last patient underwent successful resection of the tumor. Three male and two female patients (aged 45 to 72 years) were included in the study. Heterogeneously enhancing retroperitoneal mass involving IVC is the most common imaging feature. The intra and extra luminal extension was demonstrated excellently in all patients. IVC leiomyosarcoma is a rare neoplasm often presenting very late with non-specific symptoms. Cross sectional imaging establishes the exact location and extension and plays a vital role in determining the resectibility and planning the management. PMID- 24784871 TI - Successful treatment of Chronic Myelogenic Leukemia (CML) with imatinib after renal transplantation. AB - Chronic Myelogenic Leukemia (CML) is a rare malignant disorder after solid organ transplantation, especially in renal transplant recipients. Imatinib Mesylate is currently approved as first line treatment of CML. Most reports on CML are from kidney recipients who received azathioprine in combination with cyclosporine and prednisolone as immunosuppressive therapy. We report a case with CML who was treated with Mycophenolate Mofetil. PMID- 24784872 TI - Reduction in mean deviation values in automated perimetry in eyes with multifocal compared to monofocal intraocular lens implants. AB - PURPOSE: To evaluate differences in mean deviation values in automated perimetry in healthy eyes with multifocal compared to monofocal intraocular lens (IOL) implants. DESIGN: Prospective, age-matched, comparative analysis. METHODS: SETTING: Single-center, tertiary referral academic practice. PATIENT POPULATION: A total of 37 healthy eyes in 37 patients with bilateral multifocal (n=22) or monofocal (n=15) IOL implants were studied. INTERVENTION/OBSERVATION PROCEDURE: Humphrey Visual Field 10-2 testing was performed on all patients. MAIN OUTCOME MEASURES: Mean deviation (MD) and pattern standard deviation (PSD) numerical values were evaluated and compared between groups. RESULTS: The average MD was 2.84 dB (SD 2.32) for the multifocal IOL group and -0.97 dB (SD 1.58) for the monofocal IOL group (P=.006). There was no significant difference in PSD between the 2 groups (P=.99). Eyes that had the visual field 10-2 testing>=6 months from time of IOL placement showed no improvement in MD when compared to eyes that were tested within 6 months from IOL placement. CONCLUSION: Multifocal IOL implants cause significant nonspecific reduction in MD values on Humphrey Visual Field 10 2 testing that does not improve with time or neuroadaptation. Multifocal IOL implants may be inadvisable in patients where central visual field reduction may not be tolerated, such as macular degeneration, retinal pigment epithelium changes, and glaucoma. PMID- 24784873 TI - Optical quality of the cornea after Descemet membrane endothelial keratoplasty. AB - PURPOSE: To evaluate corneal higher-order aberrations (HOAs) and backscattered light before and after Descemet membrane endothelial keratoplasty (DMEK) and their correlation with visual outcome. DESIGN: Retrospective study. METHODS: In a total of 118 consecutive eyes of 118 patients who underwent uneventful DMEK for Fuchs endothelial dystrophy at a tertiary referral center, best spectacle corrected visual acuity (BSCVA), corneal HOAs, and backscattered light were evaluated preoperatively and at 6 months postoperatively. Outcome data were compared to an age-matched control group with uncomplicated eyes (n = 27). RESULTS: Compared to the control group, Fuchs endothelial dystrophy eyes, before as well as 6 months after DMEK, showed higher values of anterior and posterior HOAs and backscattered light (P < .033). Postoperative anterior HOAs and backscattered light (0-2 mm) were associated with lower 6-month BSCVA (positively related with logMAR BSCVA) (P <= .020). Anterior corneal HOAs did not change from preoperative to 6 months after DMEK (P = .649), while total posterior HOAs (RMS third to sixth Zernike order) and haze decreased (P < .001). CONCLUSIONS: Anterior and posterior corneal HOAs, as well as backscattered light from the cornea, were elevated in eyes suffering from Fuchs endothelial dystrophy and remained higher throughout 6 months after DMEK. If present, anterior surface irregularities and anterior corneal haze may be the most important limiting factors in visual rehabilitation after DMEK. PMID- 24784874 TI - Post-operative radiotherapy in patients with early stage cervical cancer. AB - OBJECTIVE: The aim of this study is to investigate the impact of treatment policy changes in cervical cancer patients treated with adjuvant (chemo) radiotherapy. METHODS: Between 1970 and 2007, 292 patients received adjuvant radiotherapy after a radical hysterectomy with pelvic lymphadenectomy for early stage cervical carcinoma. All patients received pelvic radiotherapy (40 Gy-46 Gy in 1.8 Gy-2 Gy/fraction). Vaginal vault brachytherapy boost (10-14 Gy) was increasingly used for patients with high-risk factors, and since 1993 systematically applied in patients with at least 2 of the 3 risk factors: adenocarcinoma, nodal involvement and parametrial invasion. Cisplatin-based chemotherapy was introduced in this group of patients from 2000. RESULTS: The 5-year cumulative risk of local recurrence (CRLR) was 13% (95%CI 9%-17%), resulting in an overall 5-year survival (OS) of 78% (95%CI 83%-73%). Since 1970, the OR for the 5-year locoregional recurrence risk (LRR) decreased from 2.5 to 1.15 (linear-OR=-0.02/year). The OR for the 5-year mortality risk reduced from 2.2 in 1970 to 1.0 in 2007 (linear-OR= 0.03/year). The largest risk reductions were observed before 1990 with a minor rise after 2002. The risk of severe late toxicity reduced from 1.8% to 1.5% (linear-OR=-0.03/year). The addition of concomitant adjuvant chemotherapy since 2000 may have benefited a subgroup of patients with squamous cell carcinoma, but not the patients with adenocarcinoma, and after introduction of chemotherapy the risk of severe late toxicity tripled from 2% to 7%. CONCLUSION: Since 1970, tumour recurrence risk and mortality have decreased, as radiation dose increased. The potential benefit of concomitant adjuvant chemotherapy could not be demonstrated in this nonrandomized study. PMID- 24784875 TI - Paving the way towards a successful and fulfilling career in computational biology. PMID- 24784876 TI - Altered gene expression in an embolic stroke model after thrombolysis with tissue plasminogen activator and Stachybotrys microspora triprenyl phenol-7. AB - The present study compares gene expression and infarct area in a mouse model of embolic stroke after thrombolysis with t-PA and SMTP-7. Embolic occlusion was induced by transfer of acetic acid-induced embolus into the brain. t-PA or SMTP-7 was administered 3 h after embolization. Changes in gene expression were evaluated using microarray and RT-PCR analysis. To determine the involvement of reactive oxygen species in the response to t-PA, the free radical scavenger edaravone was infused immediately before t-PA administration. The expressions of 459 genes involved in the inflammatory response, cell-to-cell signaling, cell movement, and inflammatory disease were altered by embolic occlusion. Twenty-two of those genes were upregulated after t-PA but not SMTP-7 administration. Differences between the t-PA- and SMTP-7-treated groups in the expression of genes including the proinflammatory genes Il6, Stat3, S100a8, and Mmp9 were confirmed with RT-PCR. Edaravone ameliorated the overexpression of these genes. Our data demonstrate differences in gene expression following treatment with SMTP 7 or t-PA that likely explain the difference in therapeutic time windows of the two drugs. ROS are involved in the overexpression of proinflammatory genes. The wide therapeutic time window may be achieved through an anti-oxidative effect and inhibition of proinflammatory gene overexpression. PMID- 24784877 TI - Creating controlled thickness gradients in polymer thin films via flowcoating. AB - Flowcoating is a popular technique for generating thin (5-200 nm), substrate supported polymer films. In this process, a reservoir of coating fluid is held between the horizontal substrate and a nearly horizontal blade above the substrate; a film of fluid is drawn out of the reservoir by moving the substrate. Accelerating the substrate produces a film with a thickness gradient, particularly useful for high-throughput measurements where film thickness is an important parameter. The present work compares experimental film thickness profiles with a model based on a Landau-Levich treatment to identify the experimental parameters which govern film thickness. The key parameters are the capillary number and the radius of curvature of the reservoir's static meniscus, which is set by the blade angle, gap height, solution reservoir volume, and contact angles of the fluid with the blade and substrate. The results show excellent quantitative agreement with the first-principles model; the model thus provides a design approach which allows a user to produce polymer thin films of virtually any desired thickness profile. PMID- 24784878 TI - When and why health care personnel respond to a disaster: the state of the science. AB - OBJECTIVE: Emergency response relies on the assumption that essential health care services will continue to operate and be available to provide quality patient care during and after a patient surge. The observed successes and failures of health care systems during recent mass-casualty events and the concern that these assumptions are not evidence based prompted this review. METHOD: The aims of this systematic review were to explore the factors associated with the intention of health care personnel (HCP) to respond to uncommon events, such as a natural disaster or pandemic, determine the state of the science, and bolster evidence based measures that have been shown to facilitate staff response. RESULTS: Authors of the 70 studies (five mixed-methods, 49 quantitative, 16 qualitative) that met inclusion criteria reported a variety of variables that influenced the intent of HCP to respond. Current evidence suggests that four primary factors emerged as either facilitating or hindering the willingness of HCP to respond to an event: (1) the nature of the event; (2) competing obligations; (3) the work environment and climate; and (4) the relationship between knowledge and perceptions of efficacy. CONCLUSIONS: Findings of this study could influence and strengthen policy making by emergency response planners, staffing coordinators, health educators, and health system administrators. PMID- 24784879 TI - Helmet therapy in infants with positional skull deformation: randomised controlled trial. AB - OBJECTIVE: To determine the effectiveness of helmet therapy for positional skull deformation compared with the natural course of the condition in infants aged 5-6 months. DESIGN: Pragmatic, single blinded, randomised controlled trial (HEADS, HElmet therapy Assessment in Deformed Skulls) nested in a prospective cohort study. SETTING: 29 paediatric physiotherapy practices; helmet therapy was administered at four specialised centres. PARTICIPANTS: 84 infants aged 5 to 6 months with moderate to severe skull deformation, who were born after 36 weeks of gestation and had no muscular torticollis, craniosynostosis, or dysmorphic features. Participants were randomly assigned to helmet therapy (n=42) or to natural course of the condition (n=42) according to a randomisation plan with blocks of eight. INTERVENTIONS: Six months of helmet therapy compared with the natural course of skull deformation. In both trial arms parents were asked to avoid any (additional) treatment for the skull deformation. MAIN OUTCOME MEASURES: The primary outcome was change in skull shape from baseline to 24 months of age assessed using plagiocephalometry (anthropometric measurement instrument). Change scores for plagiocephaly (oblique diameter difference index) and brachycephaly (cranioproportional index) were each included in an analysis of covariance, using baseline values as the covariate. Secondary outcomes were ear deviation, facial asymmetry, occipital lift, and motor development in the infant, quality of life (infant and parent measures), and parental satisfaction and anxiety. Baseline measurements were performed in infants aged between 5 and 6 months, with follow-up measurements at 8, 12, and 24 months. Primary outcome assessment at 24 months was blinded. RESULTS: The change score for both plagiocephaly and brachycephaly was equal between the helmet therapy and natural course groups, with a mean difference of -0.2 (95% confidence interval -1.6 to 1.2, P=0.80) and 0.2 (-1.7 to 2.2, P=0.81), respectively. Full recovery was achieved in 10 of 39 (26%) participants in the helmet therapy group and 9 of 40 (23%) participants in the natural course group (odds ratio 1.2, 95% confidence interval 0.4 to 3.3, P=0.74). All parents reported one or more side effects. CONCLUSIONS: Based on the equal effectiveness of helmet therapy and skull deformation following its natural course, high prevalence of side effects, and high costs associated with helmet therapy, we discourage the use of a helmet as a standard treatment for healthy infants with moderate to severe skull deformation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18473161. PMID- 24784880 TI - Helmet therapy for positional plagiocephaly and brachycephaly. PMID- 24784883 TI - Development of performance objectives for Listeria monocytogenes contaminated salmon (Salmo salar) intended used as sushi and sashimi based on analyses of naturally contaminated samples. AB - Raw salmon is commonly used in sushi and sashimi, indicating that fresh salmon may be considered as a ready-to-eat product. Listeria monocytogenes is occasionally present in fresh salmon, but studies of prevalence and growth of the bacterium in this matrix have been few. In the present study, salmon from a company where L. monocytogenes is present in low levels has been investigated in order to develop performance objectives for L. monocytogenes in fresh salmon intended for use in ready-to-eat products as sushi and sashimi. According to the European Food Law, the maximum level of L. monocytogenes on the last day of shelf life is 100 cfu/g. The variations between and within eight batches have been determined, and the results were used to estimate limit values for L. monocytogenes in salmon and develop a tentative sampling plan for the processing day. Various time-temperature scenarios for storage until the fish is consumed as sushi, sashimi or native fillets have been taken into account. The results indicate that limit values in the range from 0.5 to 10 cfu/g are sufficient to ensure that the regulatory limit of <100 cfu/g of L. monocytogenes on the last day of shelf life is not exceeded, provided that the recommended time-temperature conditions are respected. For instance, if the fish is intended for processing into sushi within one week of storage at 4 degrees C after filleting, no samples should have higher levels of L. monocytogenes than 2 cfu/g at the day of filleting. PMID- 24784881 TI - Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling. AB - The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development. PMID- 24784884 TI - Bilateral blepharoconjunctivitis as the presenting sign of disseminated herpes simplex 1 infection in a preterm neonate. PMID- 24784885 TI - Return to play following muscle injuries in professional footballers. AB - This prospective cohort study described return-to-play (RTP) data for different types of muscle injuries in male elite-level football players in Europe. Eighty nine European professional teams were followed between 2001 and 2013. Team medical staff recorded individual player exposure and time-loss injuries. A total of 17,371 injuries occurred, including 5603 (32%) muscle injuries. From 2007, we received results from 386 magnetic resonance imaging (MRI) examinations, and radiological grading was performed. A negative MRI was associated with shorter recovery time (6 +/- 7 days). Lay-off days were correlated with MRI grading of thigh muscle injuries (P < 0.001). Among hamstring injuries, 83% occurred to the biceps femoris, 12% affected the semimembranosus and 5% the semitendinosus. Recurrence rate was higher among biceps femoris injuries (18%) compared with semitendinosus and semimembranosus injuries (2% together). Groin muscle injuries caused shorter median absence (9 days) than hamstring (13 days; P < 0.001), quadriceps (12 days; P < 0.001) and calf muscle (13 days; P < 0.001) injuries. Overall, we found that MRI was valuable for prognosticating RTP, with radiological grading associated with lay-off times after injury. Re-injuries were common in biceps femoris injuries but rare in semitendinosus and semimembranosus injuries. PMID- 24784886 TI - Silencing of PKCeta induces cycle arrest of EBV(+) B lymphoma cells by upregulating expression of p38-MAPK/TAp73/GADD45alpha and increases susceptibility to chemotherapeutic agents. AB - PKCeta is involved in proliferation, differentiation, and drug resistance. However, PKCeta function in EBV(+) B lymphoma remains poorly understood. Gene silencing of PKCeta through siRNA knockdown inhibited cellular proliferation, induced cell cycle arrest in G0/G1 and G2/M phases, and sensitized cells to chemotherapeutic drugs. Upon PKCeta knockdown, expression levels of p21, GADD45alpha, and TAp73 were all increased, whereas expression levels of CDK2, CDK4, CDK6, cyclin E, cyclin B1, and cdc2 were all downregulated. PKCeta silencing also activated p38-MAPK, which in turn contributed to the expression of cell cycle arrest-related molecules. These results suggest that siRNA-mediated silencing of PKCeta can be a potent tool to complement existing chemotherapy regimens for treating EBV(+) B lymphoma. PMID- 24784888 TI - Diastereoselective construction of trans-fused octalone framework via ruthenium porphyrin-catalyzed cycloaddition. AB - Lewis acid catalyzed cycloaddition of cyclohexenone and butadiene affords trans fused octalone with high regio- and diastereoselectivity. The use of the ruthenium porphyrin complex as the Lewis acid catalyst is key to the reaction. The cycloaddition proceeds in toluene with 1 mol % of the ruthenium catalyst at 25 degrees C. PMID- 24784887 TI - Estrogen metabolism and breast cancer. AB - There is currently accumulating evidence that endogenous estrogens play a critical role in the development of breast cancer. Estrogens and their metabolites have been studied in both pre- and postmenopausal women with more consistent results shown in the latter population, in part because of large hormonal variations during the menstrual cycle and far fewer studies having been performed in premenopausal women. In this review we describe in detail estrogen metabolism and associated genetic variations, and provide a critical review of the current literature regarding the role of estrogens and their metabolites in breast cancer risk. PMID- 24784889 TI - Measurement of endothelial dysfunction via peripheral arterial tonometry predicts vasculogenic erectile dysfunction. AB - Endothelial cell dysfunction is associated with cardiovascular disease and vasculogenic erectile dysfunction (ED). Measured via peripheral artery tonometry (PAT), endothelial dysfunction in the penis is an independent predictor of future cardiovascular events. The aim of the study was to determine whether measurement of endothelial dysfunction differentiates men with vasculogenic ED identified by duplex ultrasound from those without. A total of 142 men were retrospectively assessed using patient history, penile duplex ultrasonography (US) and PAT (EndoPAT 2000). ED was self-reported and identified on history. Vasculogenic ED was identified in men who exhibited a peak systolic velocity (PSV) of ? 25 cm s( 1) at 15 min following vasodilator injection. The reactive hyperemia index (RHI), a measurement of endothelial dysfunction in medium/small arteries, and the augmentation index (AI), a measurement of arterial stiffness, were recorded via PAT. Penile duplex US was used to categorize men into those with ED (n = 111) and those without ED (n = 31). The cohort with ED had a PSV of 21 +/- 1 cm s(-1) (left cavernous artery) and 22 +/- 1 cm s(-1) (right cavernous artery). The control group without ED had values of 39 +/- 2 cm s(-1) (left) and 39 +/- 2 cm s(-1) (right). Given the potential for altered endothelial function in diabetes mellitus, we confirmed that hemoglobin A1c, urinary microalbumin and vibration pulse threshold were not different in men with vasculogenic ED and those without. RHI in patients with ED (1.85 +/- 0.06) was significantly decreased compared to controls (2.15 +/- 0.2) (P<0.05). The AI was unchanged when examined in isolation, and when standardized to heart rate. Measurement of endothelial function with EndoPAT differentiates men with vasculogenic ED from those without. RHI could be used as a non-invasive surrogate in the assessment of vasculogenic ED and to identify those patients with higher cardiovascular risk. PMID- 24784890 TI - Preoperative erectile function is the only predictor of the use of a high number of phosphodiesterase type-5 inhibitors after bilateral nerve-sparing radical prostatectomy. AB - It is well known that the administration of phosphodiesterase type-5 inhibitors (PDE5-Is) may improve erectile function (EF) recovery after bilateral nerve sparing radical prostatectomy (BNSRP). The aim of our study was to identify predictors of the use of a high number of PDE5-Is (one or more per week) after surgery among 184 patients taking proerectile medications on demand. At a mean follow-up of 22.7 months, 116 patients (63%) recovered EF. Overall, EF recovery rates at 1- and 2- year follow-up were 47.3% and 65.4%, respectively. Overall, 43 (23.4%) patients used one or more PDE5-Is per week. Preoperative EF was the only predictor of the use of one or more PDE5-Is per week after BNSRP. This held true even after adjusting our analyses for age at surgery, body mass index and EF at 1 month after surgery. Particularly, patients fully potent before surgery had roughly 2.1-fold higher probability of using one or more pills per week compared with their counterparts with some degree of preoperative erectile dysfunction (ED; odds ratio: 2.16; 95% confidence interval: 1.03-4.37). In conclusion, preoperative EF represents the only determinant of the use of a higher number of PDE5-Is after surgery. Patients with better preoperative EF might represent individuals more motivated to achieve satisfactory sexual function after surgery. These observations should provide physicians with better preoperative patient counseling and management of postoperative ED. PMID- 24784891 TI - A comprehensive, prospective study of penile dimensions in Chinese men of multiple ethnicities. AB - This study aimed to establish a reference range of penile length and circumference of adult males in China, and to compare the penile dimensions of different ethnical backgrounds. To do this, penile length and circumference measurements were obtained from 5196 healthy males attending the Urology Counseling Clinic. The mean value of penile dimensions was a flaccid length of 6.5 +/- 0.7 cm, a stretched length of 12.9 +/- 1.2 cm and a flaccid circumference of 8.0 +/- 0.8 cm. In the subgroup of 311 males, the mean erectile length was 12.9 +/- 1.3 cm and the mean erectile circumference was 10.5 +/- 0.9 cm, the mean flaccid and erectile glans lengths were 2.7 +/- 0.3 and 3.4 +/- 0.4 cm, respectively, and the mean flaccid and erectile glans diameters were 2.6 +/- 0.2 and 3.4 +/- 0.4 cm, respectively. We found that flaccid penile length and circumference varied among different ethnicities. This study established a reference range for penile dimensions, which will help when counseling patients worried about their penile size or seeking penis enlargement surgery. We also found that penile dimensions are different in different ethnicities, but further investigations are needed to validate this. PMID- 24784892 TI - Dracaena arborea extracts delay the pro-ejaculatory effect of dopamine and oxytocin in spinal male rats. AB - Dracaena arborea is a medicinal plant with ethnopharmacological aphrodisiac reputation. In the present study, the effect of an intravenous administration of aqueous and ethanolic extracts from the dried roots of this plant on the ejaculatory pattern of spinal cord-transected and urethane-anaesthetized rats was investigated. In addition, the effects of these extracts were also determined on dopamine and oxytocin-induced ejaculation. Systemic administration of aqueous and ethanolic extracts (5, 20, 60, 100 mg kg(-1)) of D. arborea did not activate fictive ejaculation, whereas dopamine (0.1 MUM kg(-1)) and oxytocin (0.5 UI kg( 1)) provoked ejaculation evidenced by the rhythmic contractions of the bulbospongiosus muscles accompanied with penile erection and sometimes with expulsion of the seminal plugs. Pretreatment of spinal rats with D. arborea extracts dose-dependently blocked the pro-ejaculatory activity of dopamine and oxytocin. In conclusion, the present study shows that the bioactive substances present in the extracts of D. arborea inhibit the activity of the bulbospongiosus muscles through the blockade of dopaminergic and oxytocinergic receptors in rats. PMID- 24784893 TI - Effects of bupropion on the ejaculatory response of male rats. AB - Chronic antidepressant treatment is associated with sexual side effects, particularly affecting the ejaculatory response. Bupropion (BP), an antidepressant inhibiting dopamine/noradrenaline reuptake, seems to have a low impact upon male sexual function. Ejaculation is regulated both at the brain and spinal cord by the spinal generator for ejaculation (SGE). We investigated the effects of chronic BP treatment on ejaculatory behavior and on SGE functioning. Sexually experienced male rats were intraperitoneally (i.p.) injected with BP (7.5 or 15 mg kg(-1)) during 14 days and tested for sexual behavior on days 1, 7 and 14 of treatment; these same males were used to evaluate the functioning of the SGE by recording the genital motor pattern for ejaculation (GMPE). Acute and chronic BP administration did not importantly modify copulatory behavior of male rats. Chronic treatment with the low dose of BP produced deficits in the functioning of the SGE that were restored by activation of the SGE through afferent stimulation. Conversely, chronic treatment with the high-dose of BP disrupted the functioning of the SGE, as the deficits were not compensated by activating the SGE through sensory stimulation. It is concluded that chronic BP at high doses alters the functioning of the SGE. PMID- 24784895 TI - On the stability of AuFe alloy nanoparticles. AB - AuFe nanoparticles with mean diameters d p = 13.2 nm have been prepared by inert gas condensation. Conventional and high-resolution transmission electron microscopy and energy-dispersive x-ray spectroscopy investigations show that the particles are mostly icosahedra. Scanning transmission electron microscopy-energy dispersive x-ray spectroscopy and scanning transmission electron microscopy electron energy-loss spectroscopy show that the as-grown particles exhibit a core shell structure. The shell is mainly composed of an amorphous FeO layer. Although Fe and Au are immiscible in the bulk, the particle cores are found to be homogeneously mixed at the atomic level with a local composition of around Au84Fe16 (at.%). AuFe nanoparticles exhibit a complex magnetic structure in which the core behaves as a spin glass with a freezing temperature of 35 K, whereas the amorphous FeO shell behaves as a ferro-ferrimagnetic system. On annealing above 300 degrees C, the AuFe icosahedra phases separate into their elemental constituents. Hence the as-grown AuFe icosahedra are metastable, thereby implying that the bulk phase diagram also applies for nanoscopic materials. PMID- 24784894 TI - Psychosocial outcomes after initial treatment of erectile dysfunction with tadalafil once daily, tadalafil on demand or sildenafil citrate on demand: results from a randomized, open-label study. AB - Initiation of ED treatment with a particular PDE5I may influence treatment adherence and other outcomes. In this multicenter, open-label study, men with ED, naive to PDE5I, were randomized to tadalafil 5 mg once-a-day (OaD; N=257), 10 mg on demand (PRN; N = 252) or sildenafil-citrate (sildenafil) 50 mg PRN (N = 261) for 8 weeks (dose adjustments allowed), followed by 16 weeks of pragmatic treatment (switching between PDE5I allowed). Primary outcomes (treatment adherence) were reported previously. Here, we report effects on: Psychological and Interpersonal Relationship Scales, Self-Esteem and Relationship (SEAR) questionnaire, ED Inventory of Treatment Satisfaction (EDITS), International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) and Global Assessment Questions (GAQ). Mixed-model for repeated measures and analysis of covariance were used to analyze changes from baseline; GAQ-responses were evaluated by logistic regression. Analyses were adjusted for treatment, country, ED-severity, baseline and baseline-by-treatment interaction. Patients randomized to tadalafil OaD or PRN reported greater improvement (least-square mean (s.e.) change) in Sexual Self-Confidence (OaD +0.90 (0.048), PRN +0.93 (0.050), vs +0.73 (0.049); P=0.006 and P=0.001) and Spontaneity (OaD +0.11 (0.035), PRN +0.13 (0.035), vs +0.02 (0.035); P = 0.044 and P = 0.010) compared with sildenafil. Improvements in GAQ and SEP responses, IIEF-EF, orgasmic function, sexual desire, overall satisfaction domains, SEAR and EDITS scores did not differ significantly between treatment groups. PMID- 24784896 TI - Prenatal diagnosis for CF using High Resolution Melting Analysis and simultaneous haplotype analysis through QF-PCR. AB - BACKGROUND: High Resolution Melting (HRM) Analysis is a validated, robust, low cost, high throughput CF screening method. Here, we report the development and retrospective evaluation of the diagnostic value of a novel multiplex HRM, genotyping and haplotyping method for CF prenatal diagnosis (generic HRM/haplotyping). METHODS: 80 study samples from 20 carrier couples referred for PND (whole blood in EDTA and CVS or amniotic fluid) were genotyped retrospectively using the suggested protocol. RESULTS: All DNA samples (variable sources, extraction methods and unknown concentrations) were successfully amplified by the 1st and 2nd round PCR. The Se, Sp, NPV and PPV for the generic HRM/haplotyping method are calculated at 100%. CONCLUSIONS: This generic protocol for PND using HRM, facilitates the simultaneous analysis of DNA samples from various sources in a fast, robust and efficient way. It can be easily adapted and applied for any genetic condition. PMID- 24784897 TI - Emission tuning of fluorescent kinase inhibitors: conjugation length and substituent effects. AB - Fluorescent N-phenyl-4-aminoquinazoline probes targeting the ATP-binding pocket of the ERBB family of receptor tyrosine kinases are reported. Extension of the aromatic quinazoline core with fluorophore "arms" through substitution at the 6- position of the quinazoline core with phenyl, styryl, and phenylbutadienyl moieties was predicted by means of TD-DFT calculations to produce probes with tunable photoexcitation energies and excited states possessing charge-transfer character. Optical spectroscopy identified several synthesized probes that are nonemissive in aqueous solutions and exhibit emission enhancements in solvents of low polarity, suggesting good performance as turn-on fluorophores. Ligand-induced ERBB2 phosphorylation assays demonstrate that despite chemical modification to the quinazoline core these probes still function as ERBB2 inhibitors in MCF7 cells. Two probes were found to exhibit ERBB2-induced fluorescence, demonstrating the utility of these probes as turn-on, fluoroescent kinase inhibitors. PMID- 24784898 TI - Use of fluorescence quenching method to measure sorption constants of phenolic xenoestrogens onto humic fractions from sediment. AB - Humic substance (HS) in sediment can affect hydrophobic organic compound distribution, transportation, bioavailability, and toxicity. This study investigated the HS (BKHS) extracted from sediment and separated it into low molecular humic (LMHS, <1kDa) and high molecular humic substances (HMHS, 1kDa 0.45MUm). Nonylphenol (NP), octylphenol (OP), and bisphenol A (BPA) have a significant sorption capacity for HMHS and BKHS solutions. They are xenoestrogenic endocrine-disrupting compounds that are widely produced and discharged to the environment. The log KHS values of the BKHS and HMHS solutions were between 4.74-5.09Lkg-C(-1) and 4.57-5.09Lkg-C(-1), respectively. However, the three compounds were not sorbed by the LMHS solution. The average values of SUVA254 for HMHS and LMHS were 4.29 and 1.31Lm(-1)mg-C(-1) and the average values of A250-400 for HMHS and LMHS were 18.1 and 4.51nmcm(-1), respectively. The HMHS peak position in the fluorescence excitation/emission matrix at longer wavelengths corresponded to the peak position of LMHS, which indicates that the HMHS had a higher degree of humification than the LMHS. The results suggested that the KHS value's dominant factor was the degree of HS humification. PMID- 24784899 TI - Understanding the influence of codon translation rates on cotranslational protein folding. AB - Protein domains can fold into stable tertiary structures while they are synthesized by the ribosome in a process known as cotranslational folding. If a protein does not fold cotranslationally, however, it has the opportunity to do so post-translationally, that is, after the nascent chain has been fully synthesized and released from the ribosome. The rate at which a ribosome adds an amino acid encoded by a particular codon to the elongating nascent chain can vary significantly and is called the codon translation rate. Recent experiments have illustrated the profound impact that codon translation rates can have on the cotranslational folding process and the acquisition of function by nascent proteins. Synonymous codon mutations in an mRNA molecule change the chemical identity of a codon and its translation rate without changing the sequence of the synthesized protein. This change in codon translation rate can, however, cause a nascent protein to malfunction as a result of cotranslational misfolding. In some situations, such dysfunction can have profound implications; for example, it can alter the substrate specificity of an ABC transporter protein, resulting in patients who are nonresponsive to chemotherapy treatment. Thus, codon translation rates are crucial in coordinating protein folding in a cellular environment and can affect downstream cellular processes that depend on the proper functioning of newly synthesized proteins. As the importance of codon translation rates makes clear, a necessary aspect of fully understanding cotranslational folding lies in considering the kinetics of the process in addition to its thermodynamics. In this Account, we examine the contributions that have been made to elucidating the mechanisms of cotranslational folding by using the theoretical and computational tools of chemical kinetics, molecular simulations, and systems biology. These efforts have extended our ability to understand, model, and predict the influence of codon translation rates on cotranslational protein folding and misfolding. The application of such approaches to this important problem is creating a framework for making quantitative predictions of the impact of synonymous codon substitutions on cotranslational folding that has led to a novel hypothesis regarding the role of fast-translating codons in coordinating cotranslational folding. In addition, it is providing new insights into proteome-wide cotranslational folding behavior and making it possible to identify potential molecular mechanisms by which molecular chaperones can influence such behavior during protein synthesis. As we discuss in this Account, bringing together these theoretical developments with experimental approaches is increasingly helping answer fundamental questions about the nature of nascent protein folding on the ribosome. PMID- 24784900 TI - Insight into the mechanism of carbonyl hydrosilylation catalyzed by Brookhart's cationic iridium(III) pincer complex. AB - New experimental findings suggest partial revision of the currently accepted mechanism of the carbonyl hydrosilylation catalyzed by the iridium(III) pincer complex introduced by Brookhart. Employing silicon-stereogenic silanes as a stereochemical probe results in racemization rather than inversion of the configuration at the silicon atom. The degree of the racemization is, however, affected by the silane/carbonyl compound ratio, and inversion is seen with excess silane. Independently preparing the silylcarboxonium ion intermediate and testing its reactivity then helped to rationalize that effect. The stereochemical analysis together with these control experiments, rigorous multinuclear NMR analysis, and quantum-chemical calculations clearly prove that another silane molecule participates in the hydride transfer. The activating role of the silane is unexpected but, in fact, vital for the catalytic cycle to close. PMID- 24784901 TI - Rhodobacter capsulatus DprA is essential for RecA-mediated gene transfer agent (RcGTA) recipient capability regulated by quorum-sensing and the CtrA response regulator. AB - Gene transfer agents (GTAs) are genetic exchange elements that resemble small DNA bacteriophages that transfer random pieces of the producing cell's genome to recipient cells. The best-studied GTA is that of Rhodobacter capsulatus, termed RcGTA. We discovered that the putative response regulator CtrA, which is essential for RcGTA production, is required for RcGTA-mediated gene acquisition, and confirmed that a RecA homologue is required. It was also discovered that a DprA (DNA-protecting protein A) homologue is essential for RcGTA-mediated gene acquisition, and that dprA expression is induced by gtaI-dependent quorum-sensing and non-phosphorylated CtrA. Modelling of the R. capsulatus DprA structure indicated the presence of a C-terminal region that resembles a dsDNA-binding protein domain. Purified His-tagged R. capsulatus DprA protein bound to both single-stranded (ss)DNA and double-stranded (ds)DNA, but with a greater affinity for ssDNA. Additionally, DprA protected dsDNA from endonuclease digestion, and increased the rate of nucleation of Escherichia coli RecA onto ssDNA. Single-cell expression analyses revealed that dprA is expressed in the majority of cells throughout a population. Overall, the results suggest that incorporation of RcGTA DNA into the recipient cell genome proceeds through a homologous recombination pathway resembling DNA recombination in natural transformation. PMID- 24784902 TI - Strategies for the economic evaluation of end-of-life care: making a case for the capability approach. AB - Economic evaluation of end of life care is increasingly expected from both research funders and those making decisions about the use of health and social care resources. There are, however, difficulties in applying the currently established evaluative methods to end of life. These are partly associated with the sensitivity of the topic and the feasibility of data collection but also, more fundamentally, a lack of agreement about the terms in which such care should be evaluated. This paper examines different theoretical perspectives from which economic evaluation of end of life care could be conducted, and argues for the application of a capability approach focusing on the opportunity for a good death. It then examines challenges with taking forward such an approach, including defining, measuring and valuing appropriate outcomes. It concludes that such an approach is viable, and explores how it might be taken forward to assist with resource allocation decisions. PMID- 24784903 TI - Nutritional care of the obese adult burn patient: a U.K. Survey and literature review. AB - Obesity is an emerging healthcare problem and affects an increasing number of burn patients worldwide. An email survey questionnaire was constructed and distributed among the 16 U.K. burn services providing adult inpatient facilities to investigate nutritional practices in obese thermally injured patients. Responses received from all dieticians invited to participate in the study were analyzed, and a relevant literature review of key aspects of nutritional care is presented. The majority of services believe that obese patients warrant a different nutritional approach with specific emphasis to avoid overfeeding. The most common algebraic formulae used to calculate calorific requirements include the Schofield, Henry, and modified Penn State equations. Indirect calorimetry despite being considered the "criterion standard" tool to calculate energy requirements is not currently used by any of the U.K. burn services. Gastric/enteral nutrition is initiated within 24 hours of admission in the services surveyed, and a variety of different practices were noted in terms of fasting protocols before procedures requiring general anesthesia/sedation. Hypocaloric regimens for obese patients are not supported by the majority of U.K. facilities, given the limited evidence base supporting their use. The results of this survey outline the wide diversity of dietetic practices adopted in the care of obese burn patients and reveal the need for further study to determine optimal nutritional strategies. PMID- 24784904 TI - Exposure to an iridium-192 source in an industrial safety worker. AB - Radiation burn injuries account for 0.2% of burn injury admissions. Treatment of radiation burns remains challenging because of unpredictable inflammatory changes and soft tissue necrosis. Conventional treatment consists of multistaged surgical procedures. Here, we present a case of an Iridium-192 exposure treated nonoperatively. A 23-year-old man presented with a 7-day-old, less than 1% TBSA radiation burn to his right hand. He initially sought treatment at an outside hospital and plastic surgeon's office postinjury days 2 and 3. He later presented to our facility because of worsening pain, edema, and discoloration. He was admitted and hospitalized for 15 days. Narcotics were initiated and wound care consisted of daily antibiotic ointment and petroleum gauze dressings. We continued dexamethasone and pentoxyfilline for 1 week. He underwent nineteen 90 minute treatments of hyperbaric oxygen therapy during an 8-week period. He had complete wound healing 1 month postdischarge. This case report provides background on radiation burn injuries and applicability of nonoperative management in treating radiation burn injuries. Furthermore, it encourages the development of individualized treatment plans, consideration of the use of hyperbaric oxygen therapy, referral to a burn center, and consulting radiation experts for guidance. PMID- 24784905 TI - Management and sequelae of a 41-year-old jehovah's witness with severe anhydrous ammonia inhalation injury. AB - Anhydrous ammonia is a commonly used chemicals that are found in fertilizer, refrigeration, and in other occupational environments. Lung damage because of inhalation of ammonia can be devastating, producing debilitating lung disease and can ultimately lead to death. This is the case of a 41-year-old male, previously healthy, Jehovah's Witness, who was working at a poultry plant facility when an explosion occurred exposing him to toxic levels of anhydrous ammonia. Our patient developed end-stage lung disease after sustaining a severe ammonia inhalation injury. Despite aggressive pulmonary rehabilitation, the patient continued to deteriorate, and his only option for a chance at improved quality of life was a double-lung transplant. To our knowledge, this is the first report of a bloodless lung transplantation for inhalational lung injury in the literature. Further study is needed to better understand the effects of ammonia on lung physiology in order to better manage and treat patients who develop acute and chronic lung complications after exposure. PMID- 24784906 TI - Association of the neighborhood retail food environment with sodium and potassium intake among US adults. AB - INTRODUCTION: High sodium intake and low potassium intake, which can contribute to hypertension and risk of cardiovascular disease, may be related to the availability of healthful food in neighborhood stores. Despite evidence linking food environment with diet quality, this relationship has not been evaluated in the United States. The modified retail food environment index (mRFEI) provides a composite measure of the retail food environment and represents the percentage of healthful-food vendors within a 0.5 mile buffer of a census tract. METHODS: We analyzed data from 8,779 participants in the National Health and Nutrition Examination Survey, 2005-2008. By using linear regression, we assessed the relationship between mRFEI and sodium intake, potassium intake, and the sodium potassium ratio. Models were stratified by region (South and non-South) and included participant and neighborhood characteristics. RESULTS: In the non-South region, higher mRFEI scores (indicating a more healthful food environment) were not associated with sodium intake, were positively associated with potassium intake (P [trend] = .005), and were negatively associated with the sodium potassium ratio (P [trend] = .02); these associations diminished when neighborhood characteristics were included, but remained close to statistical significance for potassium intake (P [trend] = .05) and sodium-potassium ratio (P [trend] = .07). In the South, mRFEI scores were not associated with sodium intake, were negatively associated with potassium intake (P [trend] = < .001), and were positively associated with sodium-potassium ratio (P [trend] = .01). These associations also diminished after controlling for neighborhood characteristics for both potassium intake (P [trend] = .03) and sodium-potassium ratio (P [trend] = .40). CONCLUSION: We found no association between mRFEI and sodium intake. The association between mRFEI and potassium intake and the sodium potassium ratio varied by region. National strategies to reduce sodium in the food supply may be most effective to reduce sodium intake. Strategies aimed at the local level should consider regional context and neighborhood characteristics. PMID- 24784907 TI - Impact of individual and worksite environmental factors on water and sugar sweetened beverage consumption among overweight employees. AB - INTRODUCTION: The worksite environment may influence employees' dietary behaviors. Consumption of water and sugar-sweetened beverages (SSBs) affect weight management; however, little research has evaluated the influence of worksite factors on beverage consumption. Our purpose was to determine whether individual and worksite factors are associated with water and SSB intake among overweight and obese employees. METHODS: Data were collected as part of baseline assessments for a worksite-based, weight-management intervention trial. Height and weight of participants (N = 1,482; 74% female; mean age = 47 y [standard deviation (SD) = 11 y]; mean weight = 208 lbs [SD = 46 lbs]) were assessed, and participants completed a validated beverage intake questionnaire. Environmental characteristics of worksites (N = 28) were audited. A qualitative comparative analysis (QCA) was used to identify worksite conditions that may support healthier beverage intake patterns. RESULTS: Most participants were white (75% of sample) with at least some college education or a college degree (approximately 82% of sample). Mean water and SSB intake were 27 fl oz (SD = 18 fl oz) and 17 fl oz (SD = 18 fl oz), respectively; SSB intake (191 kcal [SD = 218 kcal]) exceeded the recommended discretionary energy intake. Statistical models did not identify any significant predictors of water intake. Female sex and increasing level of education and household income were associated with lower SSB intake; baseline body weight and greater number of worksite water coolers and vending machines were associated with higher SSB intake. The QCA identified worksite type (ie, not manual labor) as a condition necessary for healthier beverage consumption; a worksite break policy of 2 or more per day may lead to unhealthy beverage consumption. Lower SSB consumption was noted among older participants, female participants, and among participants with higher education and income levels. CONCLUSION: Workplace factors influence beverage consumption among overweight employees. Limiting vending machine availability and implementing policies that promote weight management may improve employee health. PMID- 24784908 TI - Developing theoretically based and culturally appropriate interventions to promote hepatitis B testing in 4 Asian American populations, 2006-2011. AB - INTRODUCTION: Hepatitis B infection is 5 to 12 times more common among Asian Americans than in the general US population and is the leading cause of liver disease and liver cancer among Asians. The purpose of this article is to describe the step-by-step approach that we followed in community-based participatory research projects in 4 Asian American groups, conducted from 2006 through 2011 in California and Washington state to develop theoretically based and culturally appropriate interventions to promote hepatitis B testing. We provide examples to illustrate how intervention messages addressing identical theoretical constructs of the Health Behavior Framework were modified to be culturally appropriate for each community. METHODS: Intervention approaches included mass media in the Vietnamese community, small-group educational sessions at churches in the Korean community, and home visits by lay health workers in the Hmong and Cambodian communities. RESULTS: Use of the Health Behavior Framework allowed a systematic approach to intervention development across populations, resulting in 4 different culturally appropriate interventions that addressed the same set of theoretical constructs. CONCLUSIONS: The development of theory-based health promotion interventions for different populations will advance our understanding of which constructs are critical to modify specific health behaviors. PMID- 24784909 TI - Prompts to disrupt sitting time and increase physical activity at work, 2011 2012. AB - INTRODUCTION: The objective of this study was to assess change in sitting and physical activity behavior in response to a workplace intervention to disrupt prolonged sitting time. METHODS: Sixty office workers were randomized to either a Stand group (n = 29), which received hourly prompts (computer-based and wrist worn) to stand up, or a Step group (n = 31), which received the same hourly prompts and an additional prompt to walk 100 steps or more upon standing. An ActivPAL monitor was used to assess sitting and physical activity behavior on the same 3 consecutive workdays during baseline and intervention periods. Mixed effect models with random intercepts and random slopes for time were performed to assess change between groups and across time. RESULTS: Both groups significantly reduced duration of average sitting bouts (Stand group, by 16%; Step group, by 19%) and the number of sitting bouts of 60 minutes or more (Step group, by 36%; Stand group, by 54%). The Stand group significantly reduced total sitting time (by 6.6%), duration of the longest sitting bout (by 29%), and number of sitting bouts of 30 minutes or more (by 13%) and increased the number of sit-to-stand transitions (by 15%) and standing time (by 23%). Stepping time significantly increased in the Stand (by 14%) and Step (by 29%) groups, but only the Step group significantly increased (by 35%) the number of steps per workday. Differences in changes from baseline to intervention between groups were not significant for any outcome. CONCLUSION: Interventions that focus on disrupting sitting time only in the workplace may result in less sitting. When sitting time disruptions are paired with a physical activity prompt, people may be more likely to increase their workday physical activity, but the effect on sitting time may be attenuated. PMID- 24784910 TI - The effect of the Missouri WISEWOMAN program on control of hypertension, hypercholesterolemia, and elevated blood glucose among low-income women. AB - INTRODUCTION: The Well-Integrated Screening and Evaluation for Women Across the Nation (WISEWOMAN) public health program is designed to reduce the risk of heart disease and stroke among low-income, underinsured or uninsured women through clinical screenings, risk factor assessment, and lifestyle interventions. We assessed the effect of the Missouri WISEWOMAN program on the control of high blood pressure, total cholesterol, and blood glucose levels. METHODS: We calculated the proportion of participants (N = 1,130) with abnormal blood pressure, total cholesterol, or blood glucose levels at an initial screening visit who gained control at a follow-up visit 11 to 18 months later during a 7 year period from June 30, 2005, to June 29, 2012. We used logistic regression to identify sociodemographic characteristics and other factors associated with achieving control. RESULTS: Many WISEWOMAN participants gained control of their blood pressure (41.2%), total cholesterol (24.7%), or blood glucose levels (50.0%). After controlling for sociodemographic factors, smoking status, weight status, medication use, and number of lifestyle interventions, nondiabetic women with stage II hypertension (adjusted odds ratio [AOR] = 0.36, 95% confidence interval [CI] = 0.21-0.60) and diabetic women with stage I (AOR = 0.54, 95% CI = 0.32-0.92) and stage II (AOR = 0.23, 95% CI = 0.07-0.77) hypertension were less likely to achieve control of their blood pressure than nondiabetic women with stage I hypertension. Women aged 45 to 64, women with less than a high school education, women who were obese in the initial visit, women who gained 7% or more of their weight, and women who did not participate in any lifestyle intervention sessions were significantly less likely to achieve total cholesterol control than their counterparts. CONCLUSION: The Missouri WISEWOMAN program helps many participants achieve control of blood pressure, total cholesterol, and blood glucose levels; the lifestyle intervention is likely to help participants control total cholesterol. More efforts are needed for women with diabetes and stage II hypertension to achieve blood pressure control. PMID- 24784911 TI - Relationships between abnormal MMP2 expression and prognosis in gastric cancer: a meta-analysis of cohort studies. AB - We carried out this current meta-analysis of relevant cohort studies in an attempt to investigate the relationships between abnormal matrix metalloproteinases-2 (MMP2) expression and gastric cancer (GC) prognosis. A range of electronic databases were searched for relevant articles without any language restrictions: Web of Science (1945-2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966-2013), EMBASE (1980-2013), CINAHL (1982-2013), and the Chinese Biomedical Database (CBM) (1982-2013). Meta-analysis was conducted using the STATA 12.0 software. Crude hazard ratios (HRs), with 95% confidence intervals (95% CIs), were calculated. Ten clinical cohort studies with a total of 1669 GC patients were included in this meta-analysis. The results of our meta-analysis suggested that MMP2-positive patients display a shorter overall survival (OS) than MMP2-negative patients (HR=1.31, 95% CI=0.98-1.63, p<0.001). Subgroup analysis based on ethnicity revealed that abnormal MMP2 expression was associated with significantly worse OS in patients with GC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis indicated that abnormal MMP2 expression may be strongly correlated with poor prognosis in patients with GC. Thus, MMP2 expression may serve as an independent prognostic factor for GC. PMID- 24784912 TI - Growth of optically active chiral inorganic films through DNA self-assembly and silica mineralisation. AB - The circularly polarized reflection of nature is due to their distinct azimuthally twisted or helical character in the nanostructure of the surface films. Although many chiral inorganic powders have been successfully synthesised, the artificial synthesis of chiral inorganic films is rare. Herein, we reported a facile synthetic route for the growth of monolayered chiral film on the quaternary ammonium-modified silicon substrate. The films grew on the substrate surface because of the strong electrostatic interaction between positively charged quaternary ammonium groups and negatively charged phosphate groups of DNA, with subsequent growth to right-handed, vertically aligned, impeller-like helical architectures with left-handed two-dimensional square p4mm-structured DNA chiral packing. The DNA-silica composite films exhibited strong optical activity at 295 nm and in the range of 400-800 nm, corresponding to DNA chiral packing (absorption) and to the helical blade in the impeller (scattering), respectively. Upon removal of DNA templates, the pure inorganic impeller-like helical morphology was maintained; consequently, the scattering-based optical response was blue-shifted approximately 200 nm as a result of a decrease in the effective average refractive index. The hierarchical structures were reflected from the surfaces by cross-polarised light, which confirmed that the films were strongly birefringent, with long-range anisotropy. PMID- 24784913 TI - Psychopathy and self-injurious thoughts and behaviour: application of latent class analysis. AB - BACKGROUND: Although early conceptualisations posited an inverse relationship between psychopathy and self-injury, little research has tested this. AIMS: To examine the self-injurious thoughts and behaviours associated with psychopathy. METHODS: Data from the MacArthur Violence Risk Assessment Project (N = 871) were used to examine homogenous subtypes of participants based on their responses to six self-injury items. A binary logistic regression model was used to interpret the nature of the latent classes by estimating the associations with the four psychopathy factors, mixed anxiety-depression, violence victimisation, and gender. RESULTS: A 2-class solution provided the best fit to the data. Most participants (86.2%) were assigned to the baseline ("low self-injury risk") group. "The high-risk self-injury group" was characterised by a higher probability of endorsing all self-injury items, particularly "thoughts of hurting self" and "attempts to hurt self". The four psychopathy factors showed differential associations with self-injury group membership. Participant's scorings, higher on the affective component and lower on interpersonal component of psychopathy, were significantly more likely to be assigned to the high risk group. Significant associations were also found between mixed anxiety/depression and gender, and "high-risk self-injury group" membership. CONCLUSIONS: These findings have important implications for the identification of individuals at risk of self-injury. PMID- 24784914 TI - Acute stent thrombosis of a bioresorbable vascular scaffold implanted for ST segment elevation myocardial infarction. PMID- 24784915 TI - Improvement and problems in appropriate use of cardiac CT: 2003, 2007 and 2011 use of CT-based on ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac CT. PMID- 24784916 TI - [Anthrax meningoencephalitis: a case following a cutaneous lesion in Morocco]. AB - Anthrax meningoencephalitis is very rare especially following skin location. We report a case of meningoencephalitis secondary to skin lesion. The diagnosis is based on clinical presentation and confirmed by microbiological tests. Its evolution remains fatal despite aggressive resuscitation. PMID- 24784917 TI - [Physicochemical stability study of injectable solutions of cisatracurium besilate in clinical conditions]. AB - OBJECTIVES: To assess the stability of cisatracurium besilate solution stored at 5 degrees C and 25 degrees C. MATERIALS AND METHODS: Cisatracurium solutions at 2, 5 and 0.1mg/mL in 0.9 % sodium chloride or 5 % glucose were exposed to 5 degrees C and 25 degrees C under 60 % relative humidity for seven days. The physicochemical stability was assessed at 24, 48hours and seven days with dosage of the active substance, detection of degradation products and a possible racemization, measuring pH, osmolality and turbidity, assessment of coloration, visible particles and invisible particles count. RESULTS: Cisatracurium besilate present good stability for 24hours at 5 degrees C and 25 degrees C for concentrations between 0.1 and 5mg/mL. Beyond 24hours, the solutions at 2 and 5mg/mL remained stable for seven days at 5 degrees C. At 25 degrees C, potentially toxic degradation products appear in solutions of 0.1mg/mL between 24 and 48hours. No racemization was detected, the drug remains in its active form cis. CONCLUSION: Cisatracurium solutions at 2 and 5mg/mL may be stored at 5 degrees C or 25 degrees C for seven days. It's advisable to keep the solutions in a dilution of 0.1mg/mL in 0.9 % sodium chloride or 5 % glucose in the refrigerator. No diluted solution should be stored at room temperature beyond 24hours. PMID- 24784918 TI - Emergence delirium in children: an update. AB - PURPOSE OF REVIEW: Emergence delirium in children is still considered as a mysterious complication occurring after pediatric anesthesia. Although the pharmacology of fast-acting volatile agent is highly suspected in the genesis of this complication, no strong evidence has been published to support this hypothesis. This review summarizes the recent findings concerning this complication. RECENT FINDINGS: Emergence delirium occurs typically in preschool children, with a high intensity of anxiety, after sevoflurane or desflurane anesthesia. In addition, although pain has been suspected in the genesis of this complication, emergence delirium has also been described after nonpainful procedure (imaging). Prevention of this complication relies on preventing preoperative anxiety (using premedication and psychological approaches), providing a sufficient analgesia (either systemically or by regional analgesia) and administering intraoperative sedative agents such as ketamine, clonidine, dexmedetomidine, gabapentine, midazolam, magnesium, hydroxyzine, midazolam and dexamethasone. Treatment of emergence delirium should be pharmacological when facing intense agitation with self-injury risks. This could be achieved using propofol, opioid agents or dexmedetomidine. As a result of the delayed discharge from a postoperative care unit associated with these agents, dexmedetomidine should be favored because of its analgesic and postoperative nausea and vomiting preventive effects. As emergence delirium shares many risk factors with long lasting cognitive complications such as postoperative maladaptative behavioral changes, letting parents know about these complications is requested. SUMMARY: Emergence delirium in children is a frequent but preventable complication. Strategies for prevention and therapy include particularly pain management and medication with alpha-2 agonists. PMID- 24784919 TI - Developing a conceptual model of possible benefits of condensed tannins for ruminant production. AB - Enteric methane (CH4) emissions from ruminants have compelled a wide range of research initiatives to identify environmental abatement opportunities. However, although such mitigations can theoretically be attained with feed additives and feeding strategies, the limited empirical evidence on plant extracts used as feed additives does not support extensive or long-term reductions. Nevertheless, their strategic use (i.e. alone or combined in a simultaneous or consecutive use) may provide not only acceptable CH4 abatement levels, but also relevant effects on animal physiology and productivity. Condensed tannins (CT) represent a range of polyphenolic compounds of flavan-3-ol units present in some forage species that can also be added to prepared diets. Methods to determine CT, or their conjugated metabolites, are not simple. Although there are limitations and uncertainties about the methods to be applied, CT are thought to reduce CH4 production (1) indirectly by binding to the dietary fibre and/or reducing the rumen digestion and digestibility of the fibre and (2) directly by inhibiting the growth of rumen methanogens. On the basis of their role in livestock nutrition, CT influence the digestion of protein in the rumen because of their affinity for proteins (e.g. oxidative coupling and H bonding at neutral pH) that causes the CT-protein complex to be insoluble in the rumen; and dissociate in the abomasum at pH 2.5 to 3.0 for proteolysis and absorption in the small intestine. CT may also reduce gastro-intestinal parasite burdens and improve reproductive performance, foetal development, immune system response, hormone serum concentrations, wool production and lactation. The objectives of this paper are to discuss some of the beneficial and detrimental effects of CT on ruminant production systems and to develop a conceptual model to illustrate these metabolic relationships in terms of systemic physiology using earlier investigations with the CT-containing legume Lotus corniculatus. Our conceptual model indicated four complex and long-lasting relationships (digestive, toxicological, physiological and morphological) that can alter the normal biology of the animal. These relationships are interdependent, integrative, and sometimes, complementary to each other. This conceptual model can be used to develop mechanistic models to improve the understanding of the interaction between CT and the ruminants as well as to guide research initiatives of the impact of polyphenol-rich foods on human health. PMID- 24784920 TI - Validation of a histopathologic classification scheme for antineutrophil cytoplasmic antibody-associated glomerulonephritis. AB - Antineutrophil cytoplasmic antibody-associated small-vessel vasculitides cause multiple organ system disease including rapidly progressive glomerulonephritis. Recently, Berden et al (J Am Soc Nephrol. 2010;21:1628-1636) proposed a new histopathologic classification scheme separating renal biopsies into 4 classes: focal, crescentic, mixed, and sclerotic. We validated the prognostic implications of this classification scheme in a retrospective cohort study of 67 individuals with antineutrophil cytoplasmic antibody glomerulonephritis who underwent kidney biopsy in Calgary, Alberta, between 2005 and 2010. Their biopsies were rescored according to the classification scheme of Berden et al. Additional tubulointerstitial parameters were also scored. Clinical information including demographics and creatinine values at presentation and 1-year follow-up was retrieved. The mean age was 60 years. Forty-one percent were female. Biopsies were classified as follows: 35% crescentic, 32% mixed, 21% focal, and 11% sclerotic. Ten patients (14%) died within 1 year. Among surviving patients, the overall mean (95% confidence interval) change in estimated glomerular filtration rate (eGFR) at 1 year was 11 (7-15) mL/min per 1.73 m(2), and this change significantly differed (P = .02) between the classes: 19 (11-27) mL/min per 1.73 m(2) with crescentic histology, 11 (1-21) mL/min per 1.73 m(2) with focal, 8 (3 13) mL/min per 1.73 m(2) with mixed, and -4 (-7 to -1) mL/min per 1.73 m(2) with sclerotic. Tubulointerstitial pathology parameters did not predict outcomes. Patients with crescentic class biopsies showed significantly more improvement in eGFR at 1 year compared with the mixed (P = .04) and sclerotic (P = .005) classes. The focal class was associated with the highest eGFR values at presentation and 1 year. These findings validate the prognostic utility of the Berden classification scheme and suggest that it may be generalizable. PMID- 24784921 TI - Prognostic value of microRNA-223/epithelial cell transforming sequence 2 signaling in patients with osteosarcoma. AB - MicroRNA-223 (miR-223) has been demonstrated to be implicated in cell proliferation and cell cycle progression of osteosarcoma cell lines by regulating its target gene epithelial cell transforming sequence 2 (ECT2). However, the clinical significance of the deregulation of the miR-223/Ect2 axis in human osteosarcoma has not been fully elucidated. To address this problem, we firstly showed that the expression levels of miR-223 and Ect2 messenger RNA were, respectively, down-regulated and up-regulated in osteosarcoma tissues compared with those in noncancerous bone tissues significantly (both P < .001), according to the results of quantitative real-time reverse transcription-polymerase chain reaction. Notably, miR-223 down-regulation was negatively correlated with Ect2 messenger RNA up-regulation in osteosarcoma tissues (r = -0.68, P = .01). Then, the combined low miR-223 expression and high Ect2 expression (miR-223-low/Ect2 high) was significantly associated with high tumor grade (P = .01), poor response to chemotherapy (P = .01), positive metastasis (P < .001), and recurrence (P < .001) of osteosarcomas. Moreover, patients with miR-223-low/Ect2-high expression had the shortest overall survival (P < .001) and disease-free survival (P < .001) compared with patients in the other 3 groups (miR-223-low/Ect2-low, miR-223 high/Ect2-high, and miR-223-high/Ect2-low). Furthermore, the multivariate analysis identified miR-223/Ect2 expression and the status of metastasis as independent prognostic factors for overall survival and disease-free survival. In conclusion, our data offer convincing evidence that the deregulation of miR-223 and its target gene ECT2 may be associated with the aggressive tumor progression of human osteosarcoma. Of note, the combined miR-223 down-regulation and Ect2 up regulation may be a possible marker of poor prognosis in this malignancy. PMID- 24784922 TI - Sarcomatoid features, necrosis, and grade are prognostic factors in metastatic clear cell renal cell carcinoma with vascular endothelial growth factor-targeted therapy. AB - Various clinical and laboratory parameters are used to determine the prognosis of patients with renal cell carcinoma (RCC), but the prognostic significance of histologic features has not been fully examined in patients with metastatic clear cell RCC receiving vascular endothelial growth factor (VEGF)/tyrosine kinase inhibitor (TKI; VEGF-TKI)-targeted therapy. To define prognostic clinicopathological factors, 83 such patients were retrospectively analyzed. Of these patients, 38 (45.8%) showed response to VEGF-TKI, whereas 45 (54.2%) were nonresponsive. Response to VEGF-TKI was associated with less than 10% sarcomatoid features and less than 10% tumor necrosis. Multivariate analysis showed that tumor necrosis was independently prognostic of VEGF-TKI response. During a median follow-up of 18 months (range, 1-62 months), 54 patients (65.1%) showed disease progression and 44 (53.0%) died. Shorter progression-free survival and overall survival (OS) were associated with a period less than 1 year from initial diagnosis to VEGF-TKI initiation, high Fuhrman grade, at least 10% sarcomatoid features, and at least 10% tumor necrosis. In addition, thrombocytosis was associated with shorter OS. Multivariate analysis showed that sarcomatoid features was independently prognostic of progression-free survival, whereas time from initial diagnosis to VEGF-TKI initiation and sarcomatoid features were independent prognostic factors of OS. In summary, sarcomatoid features, tumor necrosis, and tumor grade are histologic prognostic factors and should be considered in determining whether to initiate targeted treatment in patients with metastatic clear cell RCC. PMID- 24784923 TI - A newly discovered Anaerococcus strain responsible for axillary odor and a new axillary odor inhibitor, pentagalloyl glucose. AB - Skin surface bacteria contribute to body odor, especially axillary odor. We aimed to investigate anaerobic bacteria that had not been previously studied for axillary odor formation. A new anaerobic Anaerococcus sp. A20, that releases 3 hydroxy-3-metyl-hexanoic acid (HMHA, main component of axillary odor) from its glutamyl conjugate, was discovered from axillary isolates. This strain showed strong resistance to the antimicrobial agents, triclosan and 4-isopropyl-3 methylphenol; therefore, we screened plant extracts that inhibit the A20 strain. We discovered that pentagalloyl glucose (PGG) extracted from the Chinese Gall plant exhibited both antibacterial and inhibitory activities against HMHA release by the A20 strain. As the excellent antibacterial activity and inhibitory effect of PGG against HMHA release were seen in vitro, we conducted an open study to evaluate the deodorant effects of PGG on axillary odor. The sensory tests on odor strength showed that application of the PGG solution could reduce axillary odors in vivo. Although there was a small change in axillary microbiota, the microbial count of A20 significantly reduced. These results strongly indicate PGG as a new innovative deodorant material that only affects odor-releasing bacteria in the axillary microbiota. PMID- 24784924 TI - The effect of radiofrequency radiation generated by a Global System for Mobile Communications source on cochlear development in a rat model. AB - OBJECTIVE: This study aimed to determine the effect of radiofrequency radiation generated by 900 and 1800 MHz Global System for Mobile Communications sources on cochlear development in the rat model. METHODS: Eight pregnant albino Wistar rats were divided into three groups: control, 900 MHz and 1800 MHz. The latter two groups of pregnant rats were exposed to radiofrequency radiation for 1 hour per day starting on the 12th day of pregnancy until delivery. The rats in the control, 900 MHz and 1800 MHz groups gave birth to 24, 31 and 26 newborn rats respectively. Newborn rats in the 900 MHz and 1800 MHz groups were exposed to radiofrequency radiation for 1 hour per day for 21 days after delivery. Hearing evaluations of newborn rats were carried out using distortion product otoacoustic emissions testing. Eight newborn rats were randomly selected from each group for electron microscopic evaluation. RESULTS: Distortion product otoacoustic emission tests revealed no significant difference among the groups, but electron microscopic evaluation revealed significant differences among the groups with regard to the number of normal, apoptotic and necrotic cells. CONCLUSION: The findings indicated cellular structural damage in the cochlea caused by radiofrequency radiation exposure during cochlear development in the rat model. PMID- 24784925 TI - Influence of weight and structure on biological behavior of polypropylene mesh prostheses placed at the esophageal hiatus. AB - BACKGROUND: Experimental knowledge about mesh behavior at the esophageal hiatus is rare, but such information is essential in order to find a safe and effective method of mesh reinforcement. This study aimed to investigate the influence of mesh structure on the biological behavior of polypropylene prostheses placed at the hiatus. MATERIALS AND METHODS: Twenty-four pigs in three groups of eight underwent implantation of heavyweight small-porous (HW-SP), heavyweight large porous (HW-LP), or lightweight large-porous (LW-LP) circular polypropylene mesh at the hiatus. Eight weeks later, the meshes were explanted. Macroscopic analysis was performed evaluating mesh deformation, adhesions, and position relative to the hiatal margin. Histological analysis comprised evaluation of foreign body reaction and tissue integration by mononuclear cell count and immunostaining of Ki-67, collagen type I, and collagen type III. RESULTS: No mesh-related complications occurred. Mesh shrinkage was observed within all groups and was the lowest for HW-LP, higher for HW-SP, and highest for LW-LP (13.8% versus 19.5% versus 25.5%; P<.001). The adhesion score was highest for HW-SP, lower for HW-LP, and lowest for LW-LP (11.0 versus 8.0 versus 6.0; P<.001). The collagen type I/III ratio was higher for HW-SP compared with HW-LP and LW-LP (3.1 versus 2.2 versus 1.8; P=.014). CONCLUSIONS: Heavyweight polypropylene meshes may be advantageous for application at the hiatus. They provide a solid fixation of the esophagogastric junction by adhesions, which may contribute to a reduction of hernia recurrence. In heavyweight meshes, the large-porous structure is associated with superior form stability, and small-porous meshes are superior with regard to solidity of tissue integration, which may prevent mesh migration. PMID- 24784926 TI - Some useful odds and ends from the n-electron valence state perturbation theory. AB - The n-electron valence state perturbation theory makes use of zero-order wave functions whose energies are endowed with a direct physical interest, describing various processes occurring in the active space (removal/addition of one or two electrons, electronic excitations). It is shown that the zero-order energies related to the process of removal of an electron from the active space provide a reasonable and cheap approximation to the vertical ionization potentials. The zero-order energies referring to the process of an electronic excitation within the active space can also provide a first approximation to electronic transition energies, provided that a careful choice of the active molecular orbitals is performed. Test calculations have been carried out on the molecules N2 and H2CO. PMID- 24784927 TI - Controversial and future role of thrombolysis and endovascular therapies in submassive pulmonary embolism. PMID- 24784928 TI - [Analysis of clinical, echocardiographic, microbiological and cytopathological characteristics of pericardial effusions in a tertiary hospital care]. AB - OBJECTIVE: To determine the prevalence, etiology, clinical, echocardiographic, microbiological and cytopathological characteristics of patients with pericardial effusion. METHODS: Observational, retrospective, cross-sectional analytical study. We reviewed medical records of patients undergoing pericardiocentesis for a 5 years period. We used descriptive statistics, measures of central tendency and dispersion for analysis. RESULTS: The prevalence of pericardial effusion was 1.1%. Predominant in women (60.4%) and there was a mean age of 49 years. The main causes were neoplastic 32.1%, idiopathic 27.4% and rheumatological 10.4%. A percentage of 27.1 had cardiac tamponade whereas dyspnea and muffled heart sounds were the most common clinical data. The right atrial and ventricular collapse occurred in 84.9 and 75.5%, respectively. The pericardial fluid cytology yielded better in neoplastic causes a sensitivity of 54%, specificity 95%, positive predictive value 85% and negative predictive value 81%. CONCLUSIONS: The prevalence of pericardial effusion in a tertiary care hospital was 1.1%, the main cause was neoplastic. In the evaluation of moderate or severe pericardial effusion we found that right atrial and ventricular collapses were the most common echocardiographic findings. The cytopathological study had a high specificity for the diagnosis of neoplasia. PMID- 24784929 TI - Allelopathic activity and chemical constituents of walnut (Juglans regia) leaf litter in walnut-winter vegetable agroforestry system. AB - Walnut agroforestry systems have many ecological and economic benefits when intercropped with cool-season species. However, decomposing leaf litter is one of the main sources of allelochemicals in such systems. In this study, lettuce (Lactuca sativa var. angustata) was grown in the soil incorporated with walnut leaf litter to assess its allelopathic activity. Lettuce growth and physiological processes were inhibited by walnut leaf litter, especially during early growth stage (1-2 euphylla period) or with large amount of litter addition. The plants treated by small amount of leaf litter recovered their growth afterwards, while the inhibition for 180 g leaf litter persisted until harvest. Twenty-eight compounds were identified in the leaf litter, and several of them were reported to be phytotoxic, which may be responsible for the stress induced by walnut leaf litter. Thus, for highest economic value of vegetables such as lettuce, excessive incorporation of leaf litter should be discouraged. PMID- 24784930 TI - Localized pemphigus foliaceus with unilateral facial involvement. AB - Pemphigus foliaceus is a superficial vesiculobullous disease that typically presents with widespread lesions. Localized presentations are less frequent, and they typically occur in middle-aged patients, following exposure to topical medications, and later on, become more disseminated. We present a case of a 19 year-old female with a localized presentation of pemphigus foliaceus unrelated to previous topical medications, that was a diagnostic and therapeutically challenging case. We also discuss the literature on localized cases, differences in presentations and responses to various treatment modalities. PMID- 24784931 TI - Allergic contact dermatitis due to acrylates in acrylic gel nails: a report of 3 cases. PMID- 24784932 TI - Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation. AB - The conserved oligomeric Golgi (COG) complex is involved in intra-Golgi retrograde trafficking, and mutations in six of its eight subunits have been reported in congenital disorders of glycosylation (CDG). Here we report a patient showing severe acquired microcephaly, psychomotor retardation, seizures, liver dysfunction, hypocupremia, and hypoceruloplasminemia. Analysis of his serum glycoproteins revealed defects in both sialylation and galactosylation of glycan termini. Trio-based whole-exome sequencing identified two heterozygous mutations in COG2: a de novo frameshift mutation [c.701dup (p.Tyr234*)] and a missense mutation [c.1900T > G (p.Trp634Gly)]. Sequencing of cloned reverse-transcription polymerase chain reaction (RT-PCR) products revealed that both mutations were located on separate alleles, as expected, and that the mutant transcript harboring the frameshift mutation underwent degradation. The c.1900T > G (p.Trp634Gly) mutation is located in a domain highly conserved among vertebrates and was absent from both the public database and our control exomes. Protein expression of COG2, along with COG3 and COG4, was decreased in fibroblasts from the patient. Our data strongly suggest that these compound heterozygous mutations in COG2 are causative of CDG. PMID- 24784933 TI - Redox control of thermopower and figure of merit in phase-coherent molecular wires. AB - We demonstrate how redox control of intra-molecular quantum interference in phase coherent molecular wires can be used to enhance the thermopower (Seebeck coefficient) S and thermoelectric figure of merit ZT of single molecules attached to nanogap electrodes. Using first principles theory, we study the thermoelectric properties of a family of nine molecules, which consist of dithiol-terminated oligo (phenylene-ethynylenes) (OPEs) containing various central units. Uniquely, one molecule of this family possesses a conjugated acene-based central backbone attached via triple bonds to terminal sulfur atoms bound to gold electrodes and incorporates a fully conjugated hydroquinonecentral unit. We demonstrate that both S and the electronic contribution Z el T to the figure of merit ZT can be dramatically enhanced by oxidizing the hydroquinone to yield a second molecule, which possesses a cross-conjugated anthraquinone central unit. This enhancement originates from the conversion of the pi-conjugation in the former to cross conjugation in the latter, which promotes the appearance of a sharp anti resonance at the Fermi energy. Comparison with thermoelectric properties of the remaining seven conjugated molecules demonstrates that such large values of S and Z el T are unprecedented. We also evaluate the phonon contribution to the thermal conductance, which allows us to compute the full figure of merit ZT = Z el T/(1 + kappa p/kappa el), where kappa p is the phonon contribution to the thermal conductance and kappa el is the electronic contribution. For unstructured gold electrodes, kappa p/kappa el ?? 1 and therefore strategies to reduce kappa p are needed to realize the highest possible figure of merit. PMID- 24784934 TI - MALDI-TOF identification of the human Gut microbiome in people with and without diarrhea in Senegal. AB - BACKGROUND: In Africa, there are several problems with the specific identification of bacteria. Recently, MALDI-TOF mass spectrometry has become a powerful tool for the routine microbial identification in many clinical laboratories. METHODOLOGY/PRINCIPAL FINDINGS: This study was conducted using feces from 347 individuals (162 with diarrhea and 185 without diarrhea) sampled in health centers in Dakar, Senegal. Feces were transported from Dakar to Marseille, France, where they were cultured using different culture conditions. The isolated colonies were identified using MALDI-TOF. If a colony was unidentified, 16S rRNA sequencing was performed. Overall, 2,753 isolates were tested, allowing for the identification of 189 bacteria from 5 phyla, including 2 previously unknown species, 11 species not previously reported in the human gut, 10 species not previously reported in humans, and 3 fungi. 2,718 bacterial isolates (98.8%) out of 2,750 yielded an accurate identification using mass spectrometry, as did the 3 Candida albicans isolates. Thirty-two bacterial isolates not identified by MALDI-TOF (1.2%) were identified by sequencing, allowing for the identification of 2 new species. The number of bacterial species per fecal sample was significantly higher among patients without diarrhea (8.6+/ 3) than in those with diarrhea (7.3+/-3.4; P = 0.0003). A modification of the gut microbiota was observed between the two groups. In individuals with diarrhea, major commensal bacterial species such as E. coli were significantly decreased (85% versus 64%), as were several Enterococcus spp. (E. faecium and E. casseliflavus) and anaerobes, such as Bacteroides spp. (B. uniformis and B. vulgatus) and Clostridium spp. (C. bifermentans, C. orbiscindens, C. perfringens, and C. symbosium). Conversely, several Bacillus spp. (B. licheniformis, B. mojavensis, and B. pumilus) were significantly more frequent among patients with diarrhea. CONCLUSIONS/SIGNIFICANCE: MALDI-TOF is a potentially powerful tool for routine bacterial identification in Africa, allowing for a quick identification of bacterial species. PMID- 24784935 TI - Interleukin-1beta -511T>C genetic variant contributes to recurrent pregnancy loss risk and peripheral natural killer cell proportion. AB - OBJECTIVE: To identify whether interleukin gene polymorphisms are risk factors for idiopathic recurrent pregnancy loss (RPL) in Korean women. DESIGN: Case control study. SETTING: Hospital-based study. PATIENT(S): A cohort of 385 idiopathic RPL patients and 232 controls with Korean ethnicity. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotyping was assessed with a polymerase chain reaction-restriction fragment length polymorphism assay. We examined polymorphisms in three interleukin (IL) genes: IL-1beta, IL-4, and IL-10. RESULT(S): The IL-1beta -511T>C polymorphism was associated with RPL (-511TT vs. 511CC: adjusted odds ratio 1.826; 95% confidence interval 1.130-2.953). Allelic gene-gene interaction analysis revealed that the T/B2/G (IL-1beta/IL-4/IL-10) allele combination was only detected in the RPL group (adjusted odds ratio 20.046; 95% confidence interval 1.188-338.204). The proportion of peripheral natural killer cells was higher in patients with the IL-1beta -511C allele compared with the -511T allele. CONCLUSION(S): According to these results, IL 1beta -511T>C may be a predisposing factor to RPL susceptibility. However, the mechanism underlying the function of IL-1beta -511T>C in RPL remains to be determined, and further studies are needed to improve understanding of the roles of IL-1beta -511T>C, using a larger and more heterogeneous cohort. PMID- 24784936 TI - Ethics of uterus transplantation with live donors. PMID- 24784937 TI - Prospective observational cohort studies for studying rare diseases: the European PedNet Haemophilia Registry. AB - Haemophilia is a rare disease. To improve knowledge, prospective studies of large numbers of subjects are needed. To establish a large well-documented birth cohort of patients with haemophilia enabling studies on early presentation, side effects and outcome of treatment. Twenty-one haemophilia treatment centres have been collecting data on all children with haemophilia with FVIII/IX levels up to 25% born from 2000 onwards. Another eight centres collected data on severe haemophilia A only. At baseline, details on delivery and diagnosis, gene mutation, family history of haemophilia and inhibitors are collected. For the first 75 exposure days, date, reason, dose and product are recorded for each infusion. Clinically relevant inhibitors are defined as follows: at least two positive inhibitor titres and a FVIII/IX recovery <66% of expected. For inhibitor patients, results of all inhibitor- and recovery tests are collected. For continued treatment, data on bleeding, surgery, prophylaxis and clotting factor consumption are collected annually. Data are downloaded for analysis annually. In May 2013, a total of 1094 patients were included: 701 with severe, 146 with moderate and 247 with mild haemophilia. Gene defect data were available for 87.6% of patients with severe haemophilia A. The first analysis, performed in May 2011, lead to two landmark publications. The outcome of this large collaborative research confirms its value for the improvement of haemophilia care. High-quality prospective observational cohorts form an ideal source to study natural history and treatment in rare diseases such as haemophilia. PMID- 24784939 TI - The emotional well-being of young people having a parent with younger onset dementia. AB - Younger onset dementia (YOD) not only affects the person with the diagnosis but the whole family, which often includes young people. A limited body of research on this group of young people indicates that they experience varying degrees of emotional trauma. We explored the lived experiences of young people having a parent with YOD from the perspective of the social model of disability. Data were available from semi-structured interviews with 12 young people who had a parent with YOD looking at their lived experiences between 8 and 24 years. Thematic analysis identified four main themes: the emotional toll of caring, keeping the family together, grief and loss and psychological distress The social model of disability theory provides a helpful framework for these families who experience significant emotional distress, demonstrating that the disability is often socially constructed by a society, which marginalizes and excludes them. A 'whole family' approach is proposed, where the needs of young people and their parents are respected and responded to age appropriately. PMID- 24784938 TI - Measuring hope among families impacted by cognitive impairment. AB - The current exploratory investigation aims to establish the reliability and validity of a hope measure, the Herth Hope Index, among families impacted by early cognitive impairment (N = 96). Exploratory factor analysis was used to examine the dimensionality of the measure. Bivariate analyses were used to examine construct validity. The sample had moderately high hope scores. A two factor structure emerged from the factor analysis, explaining 51.44% of the variance. Both factors exhibited strong internal consistency (Cronbach's alphas ranged from .83 to .86). Satisfaction with social support was positively associated with hope, supporting convergent validity. Neurocognitive status, illness insight, and depression were not associated with hope, indicating discriminant validity. Families impacted by cognitive impairment may maintain hope in the face of a potentially progressive illness, regardless of cognitive status. The Herth Hope Index can be utilized as a reliable and valid measure of hope by practitioners providing support to families impacted by cognitive impairment. PMID- 24784940 TI - Measuring cultural justifications for caregiving in African American and White caregivers. AB - OBJECTIVES: This report will elucidate the psychometric properties of the Cultural Justifications for Caregiving Scale (CJCS) and evaluate the differences in cultural values and demographic variables among a group of African American and White caregivers. The CJCS measures the cultural reasons for and expectations about providing care to an older relative. METHODS: CJCS data were collected from 202 adults caring for an older relative with memory loss. The factor structure of the CJCS was analyzed for reliability and its correlation with other measures pertaining to the caregiving experience. RESULTS: Exploratory factor analyses suggested two underlying factors relating to Duty and Reciprocity with high levels of reliability. The two factors showed different correlational patterns with other measures associated with the caregiving experience (CG demographics and well-being). DISCUSSION: Findings provide further evidence that the CJCS is a reliable measure for use with African American and White caregivers. Moreover, cultural motivations to provide care may differ for ethnically diverse CGs based on religious backgrounds and beliefs about family expectations surrounding the care of loved ones. The application of the CJCS is also discussed. PMID- 24784942 TI - Introduction. PMID- 24784941 TI - Tracing the successful incorporation of assistive technology into everyday life for younger people with dementia and family carers. AB - Research shows that people with late-onset dementia and their relatives can benefit from using assistive technology (AT). Few researchers have investigated the use and utility of AT in everyday life for younger people with dementia (YPD) and their family carers. The aim of this study is to explore what characterised the implementation process when the AT was experienced as beneficial to the YPD and the family carer in their daily life. The qualitative longitudinal study followed 12 younger people (i.e. those under 65 years of age), who had recently been diagnosed with dementia and 14 of their family carers. In-depth interviews and observations during the process were conducted at the beginning, and were repeated every 3rd month for up to 12 months. The data were analysed, and the participants' experiences further discussed on the basis of embodied, social- and everyday life-situated approaches, in order to provide a deeper understanding of the interactive processes involved in the trajectory. Five elements in the process were identified as important for the experience of usefulness and successful incorporation of AT. The AT had to: (1) be valuable by addressing practical, emotional, and relational challenges; (2) fit well into, or be a better solution for, habitual practice and established strategies; (3) generate positive emotions, and become a reliable and trustworthy tool; (4) be user friendly, adaptable, and manageable; and (5) interest and engage the family carer. The study demonstrated the importance of understanding the use and utility of AT on the basis of embodied and social participation in daily life. The family carers played a significant role in whether or not, and in which ways, AT was absorbed into the everyday life practice of YPD. PMID- 24784943 TI - Some like indians endure. PMID- 24784944 TI - Mati-ism and Black Lesbianism. AB - Abstract There are different ways in which black women in the Diaspora have given expression to their erotic fascination with other women. In this article two idealtypical expressions of black female homosexuality and the outlines of their underlying cosmologies are sketched: mati-ism and black lesbianism. Mati (or matisma) is the Sranan Tongo word for women who have sexual relations with other women, but who typically also will have had or still have relationships with men, simultaneously. More often than not they will also have children. While both types can only be understood via a constructionist view of homosexuality, the institution of mati-ism will be shown to have retained more Afrocentric, working class elements, while black lesbianism has more middle class, Eurocentric features. PMID- 24784945 TI - "Coming out" in the age of social constructionism. AB - Abstract This article examines sexual identity formation among 346 lesbian identified and 60 bisexual-identified women. On average, bisexuals come out at later ages and exhibit less "stable" identity histories. However, variations in identity history among lesbians and bisexuals overshadow the differences between them and demonstrate that coming out is not a linear, goal-oriented, developmental process. Sexual identity formation must be reconceptualized as a process of describing one's social location within a changing social context. Changes in sexual identity are, therefore, expected of mature individuals as they maintain an accurate description of their position vis-a-vis other individuals, groups, and institutions. PMID- 24784946 TI - A study of lesbian lifestyles in the homosexual micro-culture and the heterosexual macro-culture. AB - Abstract Ninety-one lesbians were surveyed in an effort to determine how homosexual women function within the heterosexual macro-culture and the homosexual micro-culture. Those sampled tended to be young, white, urban, and well-educated professionals. By exploring four major categories (demographics, lesbian lifestyles/homosexual culture, social relationships, and participation in the heterosexual culture) it was found that respondents felt isolated from the heterosexual macro-culture and turn to the homosexual micro-culture for friends, emotional support, and social interaction. It was also discovered that while lesbians do feel isolated from the majority of society, they function productively in a dual role within their general environment. PMID- 24784947 TI - Sappho was a right-on adolescent. AB - Abstract Beginning with the interaction between the coming-out process and adolescent development, this paper explores the young lesbian experience. The words and perceptions of over 20 young lesbians are used to depict the experience from their own points of view. PMID- 24784948 TI - Growing older female. AB - Abstract An analysis of the age-related content of "Personals" ads placed by heterosexual and homosexual women was undertaken to test hypotheses derived from theoretical notions about differences and similarities between lesbian and nonlesbian aging. No support was found for a hypothesized overrepresentation of older advertisers of either sexual orientation. Contrary to popular notions, lesbians were not found to be seeking young partners. However, age differences between groups did indicate support for "accelerated aging" among heterosexual women. Possible advantages of lesbian over non-lesbian women in their experience of aging are presented. PMID- 24784949 TI - Lesbianism in female and coed correctional institutions. AB - Abstract Questionnaire responses from 13- to 17-year-old girls in four all-female and three coed institutions were used to determine rates and causes of institutional homosexuality. Rates were as high in coed as in single-sexed institutions. The overall rates of homosexuality for all seven institutions were 14% for "going with or being married" to another girl, 10% for passionately kissing, 10% for writing love letters, and 7% for having sex, beyond hugging and kissing, with another girl. The data suggest that previous homosexuality, often experienced in other correctional programs, explains much of the variance in institutional homosexuality. PMID- 24784950 TI - Lesbian women of color. PMID- 24784951 TI - Statins decrease thrombin generation in patients with hypercholesterolemia. AB - OBJECTIVE: Statins are cholesterol-lowering agents with antithrombotic effect possibly unrelated to their lipid-lowering properties. Traditional global coagulation tests failed, however, to reveal clinically relevant change after treatment. We therefore sought to investigate whether statins were able to modify thrombin generation in hypercholesterolemia. METHODS: Fifty-one patients who needed treatment with statins were enrolled in this study. Thrombin generation, assessed as endogenous thrombin potential (the amount of thrombin generated after triggering coagulation with small amount of tissue factor) was measured at pre- and two months post-treatment with statins. RESULTS: The median (inter-quartile range) level of total cholesterol that was 325 mg/dL (278-405) decreased significantly [211 mg/dL (197-247)] at post-treatment (p<0.001); the median level of HDL cholesterol that was 49 mg/dL (43-56) increased significantly [55 mg/dL (47-66)] at post-treatment (p<0.001). The median endogenous thrombin potential (inter-quartile range) before treatment was 2372 nM.min (2008-2617) and decreased to 2,048 nM.min (1764-2375) (p<0.001) after treatment. CONCLUSION: The results support the hypothesis of a direct link between statins and coagulation through their capacity to lower thrombin generation in patients with hypercholesterolemia. PRACTICE IMPLICATIONS: The antithrombotic properties of statins could be mediated (at least in part) by their endogenous thrombin potential lowering effect. This interesting hypothesis warrants evaluation by clinical trials. PMID- 24784952 TI - Is it time to change the neurofibromatosis 1 diagnostic criteria? AB - Neurofibromatosis 1 is a complex inherited neurocutaneous disease that is often difficult to diagnose early because of its age-dependent presentation. The diagnosis is also extremely difficult to communicate to patients and their parents because of the disease's clinical variability, unpredictable evolution, and uncertain prognosis. Since 1988, the year of publication of the last Consensus Conference statement concerning the diagnosis of neurofibromatosis 1, our understanding of the disease has naturally increased and, in addition to the availability of increasingly precise molecular analyses, some new clinical signs have been reported such as anaemic nevi, unidentified bright objects, choroidal hamartomas, and a typical neuropsychological phenotype. We critically review the current diagnostic criteria, and suggest the addition of new signs on the basis of published findings and our own clinical experience. This proposal aims to improve diagnostic power in paediatric age, securing a better and more reliable healthcare transition toward adult age. We finally recommend a new Consensus Conference in order to revise the diagnostic criteria, possibly differentiated by age of presentation. PMID- 24784953 TI - Spatial and temporal distribution of non-biting midge larvae assemblages in streams in a mountainous region in southern Brazil. AB - The spatial and temporal structure of non-biting midge (Diptera: Chironomidae) larvae assemblages and some environmental factors that affect their distribution were analyzed in a montane river and its tributaries in a temperate climate region of southernmost Brazil. In total, 69 taxa were recorded after four seasonal samplings (winter, spring, summer, and autumn). The dominant taxa were Rheotanytarsus sp. 1, Rheotanytarsus sp. 2, Cricotopus sp. 2, and Polypedilum (Polypedilum) sp., although dominance varied among the four sampling sites. The variations in dominance, abundance, and richness among the different sites were affected by environmental characteristics, such as the presence of marginal vegetation and a heterogeneous substratum, and also by human activities. Strictly environmental factors, such as altitude, and factors related to annual weather patterns, such as mean temperature and precipitation, influenced the spatial and temporal distribution of certain taxa and the structure of faunal assemblages. The influence of the riparian vegetation and riverbed heterogeneity on the composition, richness, and abundance of the chironomid larvae assemblages indicates that human activities, such as deforestation and the construction of dams, constitute a serious threat to the conservation of these insects and to the fauna that depends on them for food. PMID- 24784954 TI - Molecular imaging and therapy of merkel cell carcinoma. AB - Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review the current modalities and their impact on MCC in this brief review article. PMID- 24784955 TI - Multinuclear cobalt(II)-containing heteropolytungstates: structure, magnetism, and electrochemistry. AB - Interaction of the trilacunary Keggin polyanions [A-alpha-XW9O34](10-) (X = Si(IV), Ge(IV)) with Co(II) and phosphate ions in aqueous, basic media and under mild heating leads to the formation of the tetrameric, Co16-containing heteropolytungstates [{Co4(OH)3PO4}4(A-alpha-XW9O34)4](32-) (X = Si(IV), Ge(IV)). Both polyanions were characterized in the solid state by single-crystal X-ray diffraction, IR spectroscopy, and thermogravimetric and elemental analyses. Furthermore, the electrochemical and magnetic properties of these isostructural polyanions were investigated. PMID- 24784956 TI - Magnetically aligned nanodomains: application in high-performance ion conductive membranes. AB - Polyelectrolyte-coated magnetic nanoparticles were prepared by decorating the surface of superparamagnetic iron oxide nanoparticles (SPIONs) with crosslinked chitosan oligopolysaccharide (CS). These positively charged particles (CS-SPIONs) were then added to a negatively charged polymer (Nafion), and cast into membranes under an applied magnetic field. TEM and SAXS measurements confirmed this process created aligned, cylindrical nanodomains in the membranes. This was also indirectly confirmed by proton conductivity values. The strong electrostatic interaction between chitosan and Nafion prevented oxygen permeability and water evaporation at elevated temperatures through the proton conductive channels. The resultant proton exchange membranes showed lower conduction dependency to relative humidity, which is highly desirable for hydrogen fuel cells. The fuel cell performance tests were performed on the designed polyelectrolyte membrane by hydrogen-oxygen single cells at elevated temperature (120 degrees C) and low relative humidity. PMID- 24784957 TI - In memoriam: Prof. Wojciech A. Rowinski, MD (1935--------2014). PMID- 24784958 TI - Predictors of early readmission among patients 40 to 64 years of age hospitalized for chronic obstructive pulmonary disease. AB - RATIONALE: Various causes can contribute to the high rates of readmission among patients hospitalized with chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine the frequency and predictors of early readmission among patients aged 40-64 years, hospitalized with COPD. METHODS: In a retrospective cohort study, using a large national commercial insurance database, we obtained the clinical information within 12 months of the index hospitalization and 30 days after discharge. MEASUREMENTS AND MAIN RESULTS: Primary outcome was early readmission, defined as hospitalization within 30 days of discharge. We categorized predictor variables as patient, provider, and system factors, and compared these variables between patients readmitted and those not readmitted. Logistic regression was used for multivariable analysis. Of 8,263 patients who met the inclusion criteria, 741 (8.9%) had early readmission. Multivariable analysis showed patient factors (male, history of heart failure, lung cancer, osteoporosis, and depression), provider factors (no prior prescription of statin within 12 mo of the index hospitalization and no prescription of short-acting bronchodilator, oral steroid and antibiotic on discharge), and system factors (length of stay, <2 or >5 d and lack of follow-up visit after discharge) were associated with early readmission among patients hospitalized with COPD. The C statistic of the model including patient characteristics was 0.677 (95% confidence interval, 0.656-0.697), which was improved to 0.717 (95% confidence interval, 0.702-0.732) after addition of provider- and system-based factors. CONCLUSIONS: One of 11 patients hospitalized with COPD is readmitted within 30 days of discharge. Provider and system factors are important modifiable risk factors of early readmission. PMID- 24784960 TI - Estimate of mercury and methyl mercury intake associated with fish consumption from Sagua la Grande River, Cuba. AB - This paper provides an estimate of the weekly intake of total mercury (THg) and methyl mercury (MeHg) from consumption of fish from the Sagua la Grande River, Villa Clara, Cuba, by determining the THg levels in different fish species. The levels varied between 0.143 and 0.484 MU g g(-1) on a fresh weight basis. None of the analysed fish was found to have levels above the national and international regulatory levels, although THg levels over 0.2 MU g g(-1), the threshold concentration established by the World Health Organization (WHO) for the consumption by vulnerable population groups, were found in 75% of samples. The MeHg level was found to be 84% of the THg content. A Food Frequency Survey was given to 127 townspeople to estimate river fish consumption. The weekly intake of MeHg was found to be greater than the value established by the provisional tolerable weekly intake (PTWI) in 50% of children, in 80% of pregnant women, and in 75% of women in childbearing age. These weekly intakes can represent an important risk to the population's health, especially for vulnerable groups. PMID- 24784961 TI - Dietary exposure of Hong Kong secondary school students to total mercury and methylmercury from fish intake. AB - Fish is the main source of dietary exposure to methylmercury (MeHg), which is a public health concern owing to its potential neurotoxicity. To evaluate the public health risk, this study estimated the total mercury (tHg) and MeHg exposure from fish intake in Hong Kong secondary school students. Median tHg and MeHg concentrations of 280 samples purchased from different commercial outlets (covering 89 species of whole fish and three types of canned tuna), together with the local food consumption data of secondary school students obtained by semi quantitative food frequency questionnaire in 2000, were used to estimate dietary exposure from fish intake for the average and high consumer (95th percentile exposure). For tHg, the median concentration was 63 ug kg(-1) (range 3-1370 ug kg(-1)) and estimated exposures ranged 0.5-0.6 ug kg(-1) body weight (bw) week( 1) for an average consumer and 1.6-1.9 ug kg(-1) bw week(-1) for a high consumer. For MeHg, median concentration was 48 ug kg(-1) (range 3-1010 ug kg(-1)) and estimated dietary exposures were 0.4-0.5 ug kg(-1) bw week(-1) for an average consumer and 1.2-1.4 ug kg(-1) bw week(-1) for a high consumer. These values are below the respective provisional tolerable weekly intake (PTWI) established by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA). The health risk is greater for high consumers since MeHg exposures may approach or exceed the PTWI when other dietary sources are taken into account. PMID- 24784962 TI - Occurrence of dioxins (PCDDs, PCDFs) and polychlorinated biphenyls (PCBs) in wild, farmed and processed fish, and shellfish. AB - Forty-eight composite samples of the most commonly consumed fish and shellfish species were prepared from up to 60 individual subsamples of each species and analysed for chlorinated dioxins (PCDD/Fs) and polychlorinated biphenyls (PCBs). These included 24 species of fresh wild fish, seven of farmed fish, seven of fresh shellfish, and ten processed fish and shellfish products. The ISO 17025 accredited analytical methodology used is consistent with the requirements given in European Commission Directive 2002/69/EC. Concentrations ranged from 0.03 ng kg(-1) PCDD/F plus PCB World Health Organization-toxic equivalent quantity (WHO TEQ) for a sample of surimi, to approximately 6 ng kg(-1) for wild pilchards/sardines. The corresponding range for the SigmaICES-6 PCBs was 0.04 MU g kg(-1) to approximately 47 MU g kg(-1). None of the samples showed concentrations above the European Union maximum permitted limits. Averaged PCDD/F and PCB concentrations for the two groups of farmed and wild fish show that there is little difference between the two categories, although individual species may show variations depending on factors such as the sampling location. PMID- 24784963 TI - Pesticide residues in conventionally grown and organic New Zealand produce. AB - A study was carried out to determine the prevalence and concentrations of pesticide residues in conventionally grown and organic produce (bananas, broccoli, grapes, lettuce, potatoes, tomatoes, wine). Sampling was stratified, with organic produce being over-sampled, when available. All food samples were analysed, as received, by a multi-residue pesticide residue screen. Residues were found in 130 of 307 conventionally grown food samples (42%) and in nine of 41 organic food samples (22%), including six of eleven (55%) organic tomato samples. Only four organic samples (9.8%) contained multiple residues, while 24% of conventionally grown food samples contained multiple residues. Nine conventionally grown food samples (2.6%) contained pesticide residues that exceeded the maximum residue limit (MRL). Where direct comparisons were possible between conventionally grown and organic produce, the mean concentration of residues was usually lower in the organic produce, but was generally higher than would be expected from spray drift or other adventitious sources. While the presence of these residues does not represent a significant risk to human health, their presence is inconsistent with consumer expectations for organic produce. PMID- 24784964 TI - Pesticide residue monitoring in Korean agricultural products, 2003-05. AB - Between 2003 and 2005, a total of 11,716 samples were collected and analysed to determine the level of pesticides residues. Multi-residue methods (MRMs) capable of simultaneously determining 250 pesticides were used. Of the 11,716 samples, 89.1% had no detectable residues and 1.7% had violative residues. The detection rates by commodity group were 11.4, 8.6, 0.3, and 0.02% for vegetables, fruit, grain, mushrooms, and the others, respectively. Agricultural products with pesticide residues were pepper, Perilla frutescens, leafy lettuce and spinach in decreasing order. Of the 250 pesticides that were monitored, 70 pesticides were actually found. Procymidone, endosulfan, chlorfenapyr, metalaxyl, and diethofencarb were frequently detected. Of the samples, parsley, Petasites hybridus, Aster scaber and leek had high violative rates of 23.1, 12.6, 8.2, and 7.9%, respectively. From violative samples, procymidone, endosulfan, metalaxyl, diazinon and chlorpyrifos were frequently detected. The violation rates were 1.71, 1.68, and 1.76% in 2003, 2004 and 2005, respectively, and the detection rates were 8.5, 12.0, and 13.3% in 2003, 2004, and 2005, respectively. PMID- 24784965 TI - Cadmium content in fresh and canned squid (Loligo opalescens) from the Pacific coastal waters of California (USA). AB - Cadmium (Cd) levels were determined in 70 samples of mantle tissue and 70 whole individual squid (Loligo opalescens; commercially known as California squid). Samples were collected from the coastal zones of California (USA) during the period 2007/2008. To further investigate consumer exposure to processed fishery products, cadmium concentration was also determined in 200 canned samples of squid. Cd concentrations in raw mantle were low, between 0.01 and 0.29 mg kg(-1) and below the tolerance limit of current regulations (1 mg kg(-1)). Respective concentrations in whole individuals were significantly higher, ranging from 0.51 to 1.18 mg kg(-1), attributed to the presence of the visceral portion in whole squid samples. Cd concentrations varied in relation to age and sex of squid, indicating that several physiological factors may influence accumulation. Furthermore, canning of squid substantially enhanced Cd levels. Cd concentration ranged 0.17-0.67 mg kg(-1) in canned mantle tissue and 0.86-2.07 mg kg(-1) in canned whole squid samples, due to both concentration after canning and movement of the metal between different tissues. Several biological compounds, including metallothioneins, nucleic acids and enzymes, may affect Cd concentrations in commercial fishery products. PMID- 24784966 TI - Trimethylamine oxide, dimethylamine, trimethylamine and formaldehyde levels in main traded fish species in Hong Kong. AB - Levels of trimethylamine oxide (TMAO), dimethylamine (DMA), trimethylamine (TMA) and formaldehyde (FA) were studied in 266 different fishes, including fresh/frozen raw whole fishes of 89 different species that traded in Hong Kong, China. Determination of TMAO can confirm the source of DMA and FA if present in the sample. These samples were purchased from different commercial outlets between April and August 2007. All samples of raw whole fish were identified for their species by the Agriculture, Fisheries and Conservation Department. The content of TMAO was determined by high-performance liquid chromatography (HPLC) coupled with a chemiluminescent nitrogen detector. The possible decomposition products of TMAO, DMA and TMA were analysed by headspace solid-phase micro extraction gas chromatography-mass spectrometry (HS-SPME-GC-MS), while FA was conducted by steam distillation then quantified by a HPLC. The range for TMAO of all samples was <5-3800 mg kg(-1) with median of 970 mg kg(-1), while the endogenous enzymatic cleavage products DMA, TMA and FA were in the range of <2 320, <1-190 and <1-160 mg kg(-1), respectively. These cleavage products were mainly found in three fish species, Harpadon nehereus, Saurida elongata and Saurida tumbil, that belong to the family Synodontidae (Lizardfishes) and subfamily Harpadontinae. Besides, freshwater fish species, namely, Micropterus salmoides, Oreochromis niloticus niloticus and Siniperca chuatsi, were found to contain TMAO in the range of 510-760, 85-720 and 400-640 mg kg(-1), respectively. PMID- 24784967 TI - Residues of antibacterial drugs in honey from the Italian market. AB - Antibacterial drugs are used worldwide for the control of American and, less often, European foulbrood. Their administration is mostly uncontrolled and applied without approved protocols and instructions for use as well as precautionary recommendations. Consequently, this practice is responsible for the contamination of beehive products and contributes to the problem of food safety. According to this situation, 4672 analyses were carried out on 5303 honeys collected from 2001 to 2007. These samples were investigated for antibacterial residues of tetracyclines, sulphonamides, streptomycin, chloramphenicol and tylosin. Honeys were classified according to their origin: imported honey and honey from the Italian market. In the last group (only for samples collected from 2001 to 2004), another type of honey was distinguished: that of local honey. A total of 6.3% of all samples were positive for the antibacterial drugs analysed; in particular, 6.8% of imported honeys and 6.1% of honeys on the Italian market. Only 1.7% of local honey had antibacterial residues. These results are indicative of a rather frequent presence of antibacterial drug residues in both Italian and imported honeys. Furthermore, the data showed that among the active substances analysed, sulphonamides are the most used antibacterial substance followed by tetracyclines, streptomycin, tylosin, and chloramphenicol. Finally, a continuous monitoring programme is needed, accompanied by an education programme to beekeepers on proper hive management. PMID- 24784959 TI - Estimation of linkage disequilibrium and interspecific gene flow in Ficedula flycatchers by a newly developed 50k single-nucleotide polymorphism array. AB - With the access to draft genome sequence assemblies and whole-genome resequencing data from population samples, molecular ecology studies will be able to take truly genome-wide approaches. This now applies to an avian model system in ecological and evolutionary research: Old World flycatchers of the genus Ficedula, for which we recently obtained a 1.1 Gb collared flycatcher genome assembly and identified 13 million single-nucleotide polymorphism (SNP)s in population resequencing of this species and its sister species, pied flycatcher. Here, we developed a custom 50K Illumina iSelect flycatcher SNP array with markers covering 30 autosomes and the Z chromosome. Using a number of selection criteria for inclusion in the array, both genotyping success rate and polymorphism information content (mean marker heterozygosity = 0.41) were high. We used the array to assess linkage disequilibrium (LD) and hybridization in flycatchers. Linkage disequilibrium declined quickly to the background level at an average distance of 17 kb, but the extent of LD varied markedly within the genome and was more than 10-fold higher in 'genomic islands' of differentiation than in the rest of the genome. Genetic ancestry analysis identified 33 F1 hybrids but no later-generation hybrids from sympatric populations of collared flycatchers and pied flycatchers, contradicting earlier reports of backcrosses identified from much fewer number of markers. With an estimated divergence time as recently as <1 Ma, this suggests strong selection against F1 hybrids and unusually rapid evolution of reproductive incompatibility in an avian system. PMID- 24784968 TI - Survey of patulin occurrence in apple juice and apple products in Catalonia, Spain, and an estimate of dietary intake. AB - This study was conducted to assess patulin exposure in the Catalonian population. Patulin levels were determined in 161 apple juice samples, 77 solid apple-based food samples and 146 apple-based baby food samples obtained from six hypermarkets and supermarkets from twelve main cities of Catalonia, Spain. Patulin was analysed by a well-established validated method involving ethyl acetate extraction and direct analysis by high-performance liquid chromatography (HPLC) with ultraviolet light detection. Mean patulin levels for positive samples in apple juice, solid apple-based food and apple-based baby food were 8.05, 13.54 and 7.12 ug kg(-1), respectively. No samples exceeded the maximum permitted levels established by European Union regulation. Dietary intake was separately assessed for babies, infants and adults through a Food Frequency Questionnaire developed from 1056 individuals from Catalonia. Babies were the main group exposed to patulin, however no risk was detected at these levels of contamination. Adults and infants consumers were far from risk levels. Another approach to determine estimated exposure was conducted through Monte Carlo simulation that distinguishes variability in exposures from uncertainty of distributional parameter estimates. PMID- 24784969 TI - Surveillance of dioxins and polychlorinated biphenyls (PCBs) in food commercialized in Barcelona, Spain. AB - This study explored the potential use of seven congeners of polychlorinated biphenyls (PCBs-7) as indicator compounds for the presence of dioxins and PCBs in food samples, as part of the routine surveillance programme of a public health agency. Samples of 24 foodstuffs with high fat content were collected (ten fresh fish, six dairy products, five meat and three eggs). Duplicate analyses were performed. A research laboratory tested samples for seven polychlorinated dibenzo p-dioxin (PCDDs), ten dibenzofurans (PCDFs) and twelve dioxin-like PCBs, with limits of detection in the range of ng kg(-1) (ppt). The public health services official control laboratory tested samples for PCBs-7, with a limit of quantification of 5 ug kg(-1) (ppb). The research laboratory detected the presence of dioxins and dioxin-like PCBs in all samples; fish samples had the highest levels (0.04-10.3 pg WHO-TEQ g(-1)). The public health service official control laboratory detected PCBs-7 only in five samples, which were all fish. Comparing the results in the two laboratories there seems to be an association between the detection of PCB-7 and the presence of higher levels of PCDD/Fs and dioxin-like PCBs. The use of PCB-7 as an indicator compound may be a practical surveillance strategy for those foodstuffs with higher concentrations of dioxin like congeners. PMID- 24784971 TI - Ergot alkaloids in some rye-based UK cereal products. AB - UK rye-based cereal products were analysed for six major ergot alkaloids using an in-house-validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method that distinguished -ine and -inine epimers (isomers). Ergot alkaloids were detected in 25 of 28 samples subject to quantification limits of 1-3 ug kg(-1), including all of eleven rye crispbreads that had up to 340 ug kg(-1). Continental style rye breads contained up to 121 ug kg(-1). Loaf breads, bread-mix flours, and crackers contained only low levels of alkaloids. Ergotamine, ergocristine, and ergosine were the predominant ergot alkaloids in terms of level and frequency of occurrence. There were no apparent differences in the ergot levels between the organic and non-organic products, although the numbers tested were low. Most rye breads had a ratio of -ines to -inines of about 1.5, and rye crispbreads had lower and more variable -ine to -inine ratios. PMID- 24784970 TI - Cadmium accumulation in pak choi (Brassica chinensis L.) and estimated dietary intake in the suburb of Hangzhou city, China. AB - The total content of cadmium and its distribution between leaves and roots were investigated for pak choi (Brassica chinensis L.), which was grown in a contaminated area of Hangzhou city, China. Results showed that cadmium concentrations in 90% of samples exceeded the Chinese tolerance limit for food. Although roots of pak choi had a higher concentration of cadmium than leaves, leaf tissue (the edible part) accumulated over 80% (on average) of the whole plant cadmium burden due to the greater biomass in leaf tissue. Since pak choi is the staple vegetable in the study area and of great relevance to human health, the dietary intake of cadmium and calculated risk indexes to local residents through the food chain were determined. PMID- 24784972 TI - Polybrominated diphenylethers (PBDEs) and brominated dioxins (PBDD/Fs) in Irish food of animal origin. AB - Brominated dioxins (PBDD/Fs) and 17 polybrominated diphenylether (PBDE) congeners including BDE-209 were analysed in 100 composite samples of commonly consumed foods of animal origin, prepared from ten to 40 individual subsamples of each type. These included 30 samples of milk from farms; eggs from chickens; fat from cows, pigs, sheep, and poultry; and liver from cows, pigs, sheep, horses, and poultry. The ISO 17025-accredited analytical methodology used, follows similar guidelines as given for chlorinated dioxins and polychlorinated biphenyls (PCBs) in European Commission Directive 2002/69/EC. Apart from some samples of milk, PBDD/Fs and PBDEs were detected in all food types. Concentrations ranged from 0.31 ug kg(-1) Sigma17 PBDEs for a sample of milk to 37.5 ug kg(-1) Sigma17 PBDEs for a sample of liver. The corresponding range for the PBDD/F toxicity (computed using analogous PCDD/F toxic equivalency factors (TEFs)) was 0.09 ng TEQ kg(-1) to approximately 3.5 ng TEQ kg(-1). The detection of these compounds, in particular PBDD/Fs, is consistent with the increased use and disposal of brominated organic compounds. PMID- 24784973 TI - Tiotropium effects on airway inflammatory events in the cat as an animal model for acute cigarette smoke-induced lung inflammation. AB - BACKGROUND: Chronic obstructive pulmonary disease is an inflammatory lung disease mainly caused by tobacco smoke inhalation. METHODS: Fifteen healthy adult male cats were categorized into 3 groups: (1) control group, (2) exposed to cigarette smoke (CS), and (3) exposed to CS treated with tiotropium. RESULTS: Increases in clinical signs and airway responsiveness in CS cats were found compared to control animals. The airway hyperresponsiveness and clinical signs were significantly attenuated by treatment with tiotropium. The CS-induced pulmonary release of interleukin-6, interleukin-8, monocyte chemotactic protein-1, and tumor necrosis factor alpha was reduced in the tiotropium group. Exposure to CS significantly increased total inflammatory cells number in bronchoalveolar lavage fluid, which was significantly attenuated by treatment with tiotropium. The number of macrophages, eosinophils and neutrophils and lymphocytes was increased after exposure to CS. Tiotropium significantly reduced the number of all these cells. Perivascular, peribronchiolar infiltration of inflammatory cells and Reid index increased in the CS group. Treatment with tiotropium significantly reduced these parameters to control level. Enhanced lipid peroxidation with concomitant reduction of antioxidants status was observed in the CS group. Tiotropium significantly reduced the serum, lung lavage, lung, and tracheal tissue lipid peroxides to near control levels. Tiotropium also decreased lung and tracheal protein leakage, and prevented the reduction of total antioxidant status in serum, lung lavage, lung and tracheal tissue of the CS group. CONCLUSION: Cigarette smoke increases airway responsiveness and inflammation in a cat model of CS induced lung inflammation. It can effectively be reduced by treatment with tiotropium. PMID- 24784974 TI - Phylogeny of the Centaurea group (Centaurea, Compositae) - geography is a better predictor than morphology. AB - The Centaurea group is part of the Circum-Mediterranean Clade (CMC) of genus Centaurea subgenus Centaurea, a mainly Mediterranean plant group with more than 200 described species. The group is traditionally split on morphological basis into three sections: Centaurea, Phalolepis and Willkommia. This division, however, is doubtful, especially in light of molecular approaches. In this study we try to resolve this phylogenetic problem and to consolidate the circumscription and delimitation of the entire group against other closely related groups. We analyzed nuclear (internal transcribed spacer of the ribosomal genes) and chloroplast (rpl32-trnL intergenic spacer) DNA regions for most of the described species of the Centaurea group using phylogenetic and network approaches, and we checked the data for recombination. Phylogeny was used to reconstruct the evolution of the lacerate-membranaceous bract appendages using parsimony. The magnitude of incomplete lineage sorting was tested estimating the effective population sizes. Molecular dating was performed using a Bayesian approach, and the ancestral area reconstruction was conducted using the Dispersal Extinction-Cladogenesis method. Monophyly of the Centaurea group is confirmed if a few species are removed. Our results do not support the traditional sectional division. There is a high incongruence between the two markers and between genetic data and morphology. However, there is a clear relation between geography and the structure of the molecular data. Diversification in the Centaurea group mainly took place during the Pliocene and Pleistocene. The ancestral area infered for the Circum-Mediterranean Clade of Centaurea is the Eastern Mediterranean, whereas for the Centaurea group it is most likely NW-Africa. The large incongruencies, which hamper phylogenetic reconstruction, are probably the result of introgression, even though the presence of incomplete lineage sorting as an additional factor cannot be ruled out. Convergent evolution of morphological traits may have led to incongruence between morphology-based, traditional systematics and molecular results. Our results also cast major doubts about current species delimitation. PMID- 24784975 TI - Toward an understanding of mechanisms involved in non-polyphenol oxidase (Non PPO) darkening in yellow alkaline noodles (YAN). AB - Asian noodles prepared from bread wheat flour darken over time due to a combination of polyphenol oxidase (PPO) activity and non-PPO effects. Although the enzymatic mechanism associated with the PPO reaction is well established, the non-PPO component consists of both physical (e.g., changes in surface properties) and chemical reactions. Variations in pH and solvents were used to gain a quantitative estimate of the contribution of physical and chemical components to non-PPO darkening in yellow alkaline noodles (YAN). In a set of five common high PPO Australian wheat cultivars it was estimated that on average non-PPO darkening accounted for 69% of total darkening, with approximately two-thirds of this due to physical darkening and one-third had a chemical origin. Data from the chemical portion of non-PPO darkening is consistent with the presence of a PPO-like enzyme that oxidizes tyrosine, has a pH maximum of 8.1, and is inhibited by 50% methanol or ethanol but in the noodle is insensitive to PPO inhibitors such as tropolone. Therefore, with low-PPO and PPO-free wheat varieties becoming available, it may be possible to further reduce darkening in YAN by breeding for wheat varieties with low or zero levels of this PPO-like enzyme. PMID- 24784976 TI - Preventative lipid-based nutrient supplements (LNS) and young child feeding practices: findings from qualitative research in Haiti. AB - To prevent undernutrition in an urban slum in Haiti, a lipid-based nutrient supplement (LNS) was introduced through a randomised control trial. Food supplementation for young child nutrition has a long history in Haiti, but there is little empirical information regarding the effects of supplementation on young child feeding practices. One of the concerns raised by supplementation is that it may disrupt other positive feeding practices such as breastfeeding and use of other complementary foods, with negative consequences for child nutrition. We conducted 29 in-depth interviews with mother-baby pairs from the three comparison groups: control, 3-month LNS supplementation and 6-month LNS supplementation. Findings from those in the LNS groups indicated high acceptance and satisfaction with LNS and perceptions that it positively affects child health and development. LNS was integrated into and enhanced ongoing complementary feeding practices. The effects of LNS use on duration and perceived quantity of breastfeeding were variable, but generally, breastfeeding was maintained during and after the intervention. Interviews generated insights into beliefs regarding infant and young child feeding practices such as introduction and use of complementary foods, and breastfeeding duration, exclusivity and cessation. Implications for the use of LNS in public health nutrition programmes are discussed. PMID- 24784977 TI - Fibrin sealant to prevent subdural electrode migration during intracranial electroencephalographic monitoring in a patient with a large arachnoid cyst. AB - Ensuring a stable position of intracranial electrode grids with good proximity to the cortical surface can be a technical challenge in patients with complex anomalous cerebral anatomy. This report illustrates the use of fibrin sealant to secure subdural electrodes to concave cortical surfaces during intracranial electroencephalographic monitoring for localization-related medically intractable epilepsy in a patient with a large arachnoid cyst. PMID- 24784978 TI - Thoracolumbar spinal vascular malformation as a rare cause of isolated intraventricular hemorrhage. AB - Spinal vascular malformations are rare vascular lesions that most frequently present with back pain, radiculopathy, and/or myelopathy. Neurological decline is typically secondary to progressive radiculopathy, myelopathy, venous thrombosis, and stroke. Few case reports have described thoracolumbar spinal vascular malformations that present with both subarachnoid and intraventricular hemorrhage. This is the first reported case of a thoracolumbar spinal vascular malformation presenting with isolated intraventricular hemorrhage on initial imaging followed by acute and fatal rehemorrhage. PMID- 24784979 TI - Reducing perinatal complications and preterm delivery for patients undergoing in utero closure of fetal myelomeningocele: further modifications to the multidisciplinary surgical technique. AB - OBJECT.: As more pediatric neurosurgeons become involved with fetal myelomeningocele closure efforts, examining refined techniques in the overall surgical approach that could maximize beneficial outcomes becomes critical. The authors compared outcomes for patients who had undergone a modified technique with those for patients who had undergone fetal repair as part of the earlier Management of Myelomeningocele Study (MOMS). METHODS: Demographic and outcomes data were collected for a series of 43 delivered patients who had undergone in utero myelomeningocele closure at the Fetal Center at Vanderbilt from March 2011 through January 2013 (the study cohort) and were compared with data for 78 patients who had undergone fetal repair as part of MOMS (the MOMS cohort). For the study cohort, no uterine trocar was used, and uterine entry, manipulation, and closure were modified to minimize separation of the amniotic membrane. Weekly ultrasound reports were obtained from primary maternal-fetal medicine providers and reviewed. A test for normality revealed that distribution for the study cohort was normal; therefore, parametric statistics were used for comparisons. RESULTS: The incidence of premature rupture of membranes (22% vs 46%, p = 0.011) and chorioamnion separation (0% vs 26%, p < 0.001) were lower for the study cohort than for the MOMS cohort. Incidence of oligohydramnios did not differ between the cohorts. The mean (+/- SD) gestational age of 34.4 (+/- 6.6) weeks for the study cohort was similar to that for the MOMS cohort (34.1 +/- 3.1 weeks). However, the proportion of infants born at term (37 weeks or greater) was significantly higher for the study cohort (16 of 41; 39%) than for the MOMS cohort (16 of 78; 21%) (p = 0.030). Compared with 10 (13%) of 78 patients in the MOMS cohort, only 2 (4%) of 41 infants in the study cohort were delivered earlier than 30 weeks of gestation (p = 0.084, approaching significance). For the study cohort, 2 fetal deaths were attributed to the intervention, and both were believed to be associated with placental disruption; one of these mothers had previously unidentified thrombophilia. Mortality rates did not statistically differ between the cohorts. CONCLUSIONS: These early results suggest that careful attention to uterine entry, manipulation, and closure by the surgical team can result in a decreased rate of premature rupture of membranes and chorioamnion separation and can reduce early preterm delivery. Although these results are promising, their confirmation will require further study of a larger series of patients. PMID- 24784980 TI - Fixation with C-2 laminar screws in occipitocervical or C1-2 constructs in children 5 years of age or younger: a series of 18 patients. AB - OBJECT.: There are rare indications for upper cervical spine fusion in young children. Compared with nonrigid constructs, rigid instrumentation with screw fixation increases the fusion rate and reduces the need for halo fixation. Instrumentation may be technically challenging in younger children. A number of screw placement techniques have been described. Use of C-2 translaminar screws has been shown to be anatomically feasible, even in the youngest of children. However, there are few data detailing the clinical outcome. In this study, the authors describe the clinical and radiographic follow-up of 18 children 5 years of age or younger who had at least one C-2 translaminar screw as part of an occipitocervical or C1-2 fusion construct. METHODS: A retrospective review of all children treated with instrumented occipitocervical or C1-2 fusion between July 1, 2007, and June 30, 2013, at Riley Children's Hospital and Texas Children's Hospital was performed. All children 5 years of age or younger with incorporation of at least one C-2 translaminar screw were identified. RESULTS: Eighteen children were studied (7 boys and 11 girls). The mean age at surgery was 38.1 months (range 10-68 months). Indications for surgery included traumatic instability (6), os odontoideum (3), destructive processes (2), and congenital instability (7). A total of 24 C-2 translaminar screws were placed; 23 (95.8%) of 24 were satisfactorily placed (completely contained within the cortical walls). There was one medial cortex breach without neurological impingement. There were no complications with screw placement. Three patients required wound revisions. Two patients died as a result of their original condition (trauma, malignant tumor). The mean follow-up duration for the surviving patients was 17.5 months (range 3-60 months). Eleven (91.7%) of the 12 patients followed for 6 months or longer showed radiographic stability or completed fusion. CONCLUSIONS: Use of C-2 translaminar screws provides an effective anchor for internal fixation of the upper cervical spine. In this study of children 5 years of age or younger, the authors found a high rate of radiographic fusion with a low rate of complications. PMID- 24784982 TI - Using online social media for recruitment of human immunodeficiency virus positive participants: a cross-sectional survey. AB - BACKGROUND: There are many challenges in recruiting and engaging participants when conducting research, especially with HIV-positive individuals. Some of these challenges include geographical barriers, insufficient time and financial resources, and perceived HIV-related stigma. OBJECTIVE: This paper describes the methodology of a recruitment approach that capitalized on existing online social media venues and other Internet resources in an attempt to overcome some of these barriers to research recruitment and retention. METHODS: From May through August 2013, a campaign approach using a combination of online social media, non financial incentives, and Web-based survey software was implemented to advertise, recruit, and retain participants, and collect data for a survey study with a limited budget. RESULTS: Approximately US $5,000 was spent with a research staff designated at 20% of full-time effort, yielding 2034 survey clicks, 1404 of which met the inclusion criteria and initiated the survey, for an average cost of US $3.56 per survey initiation. A total of 1221 individuals completed the survey, yielding 86.97% retention. CONCLUSIONS: These data indicate that online recruitment is a feasible and efficient tool that can be further enhanced by sophisticated online data collection software and the addition of non-financial incentives. PMID- 24784984 TI - Enhancing the gene-environment interaction framework through a quasi-experimental research design: evidence from differential responses to September 11. AB - This article uses a gene-environment interaction framework to examine the differential responses to an objective external stressor based on genetic variation in the production of depressive symptoms. This article advances the literature by utilizing a quasi-experimental environmental exposure design, as well as a regression discontinuity design, to control for seasonal trends, which limit the potential for gene-environment correlation and allow stronger causal claims. Replications are attempted for two prominent genes (5-HTT and MAOA), and three additional genes are explored (DRD2, DRD4, and DAT1). This article provides evidence of a main effect of 9/11 on reports of feelings of sadness and fails to replicate a common finding of interaction using 5-HTT but does show support for interaction with MAOA in men. It also provides new evidence that variation in the DRD4 gene modifies an individual's response to the exposure, with individuals with no 7-repeats found to have a muted response. PMID- 24784985 TI - Social network ties and inflammation in U.S. adults with cancer. AB - The growing evidence linking social connectedness and chronic diseases such as cancer calls for a better understanding of the underlying biophysiological mechanisms. This study assessed the associations between social network ties and multiple measures of inflammation in a nationally representative sample of adults with a history of cancer (N = 1,075) from the National Health and Nutrition Examination Survey III (1988-94). Individuals with lower social network index (SNI) scores showed significantly greater inflammation marked by C-reactive protein and fibrinogen, adjusting for age and sex. Compared to fully socially integrated individuals (SNI = 4), those who were more socially isolated or had a SNI score of 3 or less exhibited increasingly elevated inflammation burdens. Specifically, the age- and sex-adjusted odds ratios (95%CI) for SNIs of 3, 2, and 0-1 were 1.49 (1.08, 2.06), 1.69 (1.21, 2.36), and 2.35 (1.62, 3.40), respectively (p < .001). Adjusting for other covariates attenuated these associations. The SNI gradients in the risks of inflammation were particularly salient for the lower socioeconomic status groups and remained significant after adjusting for other social, health behavioral, and illness factors. This study provided initial insights into the immunological pathways by which social connections are related to morbidity and mortality outcomes of cancer in particular and aging-related diseases in general. PMID- 24784986 TI - Validation of blood-based assays using dried blood spots for use in large population studies. AB - Assessment of health in large population studies has increasingly incorporated measures of blood-based biomarkers based on the use of dried blood spots (DBS). The validity of DBS assessments made by labs used by large studies is addressed by comparing assay values from DBS collected using conditions similar to those used in the field with values from whole blood samples. The DBS approach generates values that are strongly related to whole blood levels of HbA1c, cystatin C, and C-reactive protein. Assessing lipid levels reliably with DBS appears to be a greater challenge. However, even when DBS values and values from venous blood are highly correlated, they are often on a different scale, and using conventional cutoffs may be misleading. PMID- 24784987 TI - Understanding the complexity of ambivalence toward pregnancy: does it predict inconsistent use of contraception? AB - Ambivalence towards future pregnancy is common and may increase the risk of unprotected sex and unintended pregnancy. We propose that ambivalent attitudes toward pregnancy consist of subtypes that are differentially associated with contraceptive use. Using data from a nationally representative survey of unmarried young adults (N = 1,147), we constructed four categories of ambivalence based on attitudes toward a hypothetical pregnancy. Multivariate analyses examined characteristics of ambivalence and the association between ambivalence and contraceptive use. Approximately one third of sexually active unmarried young adults are ambivalent about pregnancy. Having positive ambivalence (important to avoid a pregnancy but would be happy if it occurred) is associated with age, gender, education, and Hispanic origin. Although ambivalence toward pregnancy is associated with lower contraceptive use, this is true only among women with negative ambivalence (not important to avoid a pregnancy but would be unhappy if a pregnancy occurred). Attitudes toward pregnancy are multifaceted, and a more nuanced understanding of women's attitudes toward pregnancy can help target prevention programs and related policies for women at risk of unintended pregnancy. PMID- 24784988 TI - The changing timing of births in Iran: an explanation of the rise and fall in fertility after the 1979 Islamic Revolution. AB - Studies exploring the course of period fertility in Iran after the 1979 Islamic Revolution have not examined systematically the role played by changes in the timing of births. Using retrospective data from the 2000 Iran Demographic and Health Survey and frailty hazard models, this study finds that the rise in fertility in the early 1980s was due to faster transitions to the first birth among all social groups of women and to the fourth birth largely among illiterate and less educated women. In contrast, the rapid fertility decline after 1985 is attributed to slower transition to successive births, especially to the second, third, and fourth births. These findings point to the importance of education and contraceptive use (measured by length of previous birth interval) as key determinants of birth timing in Iran. Interaction between age at marriage and education positively influenced the timing of births, with stronger effects among highly educated women, suggesting that the onset of rapid fertility decline was likely driven by these highly educated women. Another interaction between the gender of prior children and education shows that birth timing, even among highly educated women, appears to have been influenced by son preference in Iran. PMID- 24784989 TI - Contribution of immigration to adolescent fertility in Spain considering the reproductive pattern in the country of origin. AB - Adolescent fertility displays a trend that does not follow-and even runs contrary to-the general temporal fertility pattern. Multiple factors determine this trend, including socioeconomic conditions and cultural patterns at both immigrants' place of origin of and their destination. This article analyzes adolescent fertility in Spain with regard to country of maternal origin using records of deliveries (1980-2008) and information from countries with high immigration rates to Spain. After 1980, deliveries to adolescents diminished; after 1996, only Spanish-born adolescents continued this downward trend, but not immigrants. The factors responsible for these differences are diverse and related to the characteristics of the immigrants themselves, in addition to the situation of immigrants in the Spanish context. PMID- 24784990 TI - Height convergence and internal migration in mid-twentieth-century Italy. AB - Height convergence across Italian regions during the second half of the twentieth century is a widely recognized fact. However, it has been suggested that this process was partly affected by the massive migratory flow of people from southern to northern Italy in the 1950s and 1960s, which greatly slowed the height growth rate in the receiving regions, since immigrants were on average shorter than the receiving northern population. The main aims of this study were to estimate the speed of height convergence of Italian military conscripts in the second half of the twentieth century, and to estimate the contribution of internal migration from the south to the north of Italy to height convergence. We hypothesized that migrants from southern Italy reduced height levels among northerners relative to what they would have been without considering migration. We used cohort data on Italian conscripts born in 1951 and 1980. Results indicate that internal migration may explain from 24 to 32.7 percent of height convergence, meaning that ignoring migration flows yields an overestimation of the height changes for conscripts living in the south of Italy. PMID- 24784991 TI - Contrasting role of antimony and bismuth dopants on the thermoelectric performance of lead selenide. AB - Increasing the conversion efficiency of thermoelectric materials is a key scientific driver behind a worldwide effort to enable heat to electricity power generation at competitive cost. Here we report an increased performance for antimony-doped lead selenide with a thermoelectric figure of merit of ~1.5 at 800 K. This is in sharp contrast to bismuth doped lead selenide, which reaches a figure of merit of <1. Substituting antimony or bismuth for lead achieves maximum power factors between ~23-27 MUW cm(-1) K(-2) at temperatures above 400 K. The addition of small amounts (~0.25 mol%) of antimony generates extensive nanoscale precipitates, whereas comparable amounts of bismuth results in very few or no precipitates. The antimony-rich precipitates are endotaxial in lead selenide, and appear remarkably effective in reducing the lattice thermal conductivity. The corresponding bismuth-containing samples exhibit smaller reduction in lattice thermal conductivity. PMID- 24784992 TI - Predictive value of bacterial analysis of laparotomy wounds. AB - BACKGROUND: Despite improvements in antibiotic prophylaxis, surgical site infections represent the most common postoperative complication with important clinical consequences for patients. AIM: The hypothesis that a bacterial analysis of the surgical wound in the operating room could predict the likelihood of developing a clinical infection, and might allow a tailored and preemptive approach, aimed to reduce the consequences of an infection, seems appealing. We would like to present a prospective study on the predictive value of the bacterial analysis of laparotomy wounds. MATERIAL OF STUDY: Seventy eight prospective patients undergoing surgery were included in the study. To evaluate the risk factors associated with increased rate of wound infection, we performed a bacterial analysis of the wound. RESULTS: 48 patients out of 78 (61%) had positive cultures. 23 patients out of 32 patients (72%) who didn't receive antibiotic prophylaxis were positive to the wound culture whereas 25 patients out of 46 patients (54%) grew positive cultures in the group of patients that received antibiotic prophylaxis. None of the 30 patients with negative cultures developed clinical infection. Only 6 patients out of 48 patients who had positive cultures (12.5%) developed wound infection. Clinical infection occurred in 5 patients who had gram-negative contamination of the wound. No clinical infection occurred in patients who had gram-positive contamination. CONCLUSION: Wound cultures and their positivity are predictive tools to identify the patients that are at risk to develop wound infection. The positive predictive value of the bacterial analysis of the wound was 12.5%. KEY WORDS: Abdominal surgery, Bacterial analysis, Wound infection. PMID- 24784994 TI - sigma-Bond activation of small molecules and reactions catalyzed by transition metal complexes: theoretical understanding of electronic processes. AB - sigma-Bond activations of R1-R2 and R1-X1 (R1, R2 = H, alkyl, aromatics, etc.; X1 = electronegative group) by transition-metal complexes are classified into two main categories: sigma-bond activation by a metal (M) center and that by a metal ligand bond. The former is classified into two subcategories: concerted oxidative addition to M and stepwise oxidative addition via nucleophilic attack of M. The latter is also classified into two subcategories: heterolytic activaton by M-X2 (X2 = anion ligand) and oxidative addition to M-L (L = neutral ligand). In the concerted oxidative addition, charge transfer (CT) occurs from the M d orbital to the sigma* antibonding orbital of R1-R2, the clear evidence of which is presented here. The concerted oxidative additions of Ph-CN, Me-CN, and Ph-Cl to a nickel(0) complex are discussed as examples. The stepwise oxidative addition occurs through nucleophilic attack of M to R1-X1 to form an ion-pair intermediate. In the nucleophilic attack, CT occurs from the M dsigma to either the sigma* orbital or empty ppi orbital of R1-X1. Solvation plays a crucial role in stabilizing the transition state and ion-pair intermediate. The oxidative addition reactions of Ph-I, CH3-Br, and Br2B(OSiH3) to platinum(0), platinum(II), and palladium(0) complexes are discussed. In the heterolytic activation of R1-R2 by an M-X2 bond, R1 and R2 are bound with M and X2, respectively, indicating that R1 becomes anion like and R2 becomes cation-like. CT mainly occurs from the X2 ligand to the sigma* antibonding orbital of R1-R2 and also from R1 to the M empty d orbital. In the oxidative addition to an M-L moiety, R1 is bound with M, R2 is bound with L, and thus-formed L-R2 is bound with M. The oxidative addition reaction of the Si-H bond of silane to Cp2Zr(C2H4) and that of the H-H bond of H2 to Ni[MesB(o Ph2PC6H4)2] are discussed as examples. The importance of the sigma-bond activation in such catalytic reactions as nickel(0)-catalyzed phenylcyanation of alkyne, nickel(0)-catalyzed carboxylation of phenyl chloride, ruthenium(II) catalyzed hydrogenation of carbon dioxide, and the Hiyama cross-coupling reaction is discussed based on theoretical studies. PMID- 24784993 TI - Ethyl-3,4-dihydroxybenzoate with a dual function of induction of osteogenic differentiation and inhibition of osteoclast differentiation for bone tissue engineering. AB - The current approach in biomaterial design of bone implants is to induce in situ regeneration of bone tissue, thus improving integration of the implants and reducing their failure. Therefore, ethyl-3,4-dihydroxybenzoate (EDHB), which stimulates differentiation of osteoblasts and the resultant bone formation, should be studied. In this study, the osteoinductive ability of EDHB in preosteoblasts and human mesenchymal stem cells was examined. EDHB for future use in bone tissue engineering was evaluated by examination of early markers of differentiation (such as alkaline phosphatase [ALP] activity and collagen type I expression) and late markers of osteoblast differentiation (bone nodule formation). As bone remodeling and implant osteointegration depend not only on osteoblast response but also on interaction of the biomaterial with bone resorbing osteoclasts, differentiation of osteoclasts in response to the compounds was also observed. For in vivo study, alginate gel comprised of EDHB and cells was transplanted into the back subcutis of mice. Our results show that EDHB might have beneficial effects through regulation of both osteoblast and osteoclast differentiation. Therefore, we suggest that EDHB could be a strong candidate for dual regulation to increase osteoblast differentiation and decrease osteoclast differentiation. PMID- 24784995 TI - Simultaneous determination of 15 phenolic constituents of Chinese black rice wine by HPLC-MS/MS with SPE. AB - This study established a new method for quantitative and qualitative determination of certain components in black rice wine, a traditional Chinese brewed wine. Specifically, we combined solid-phase extraction and high performance liquid chromatography (HPLC) with triple quadrupole mass spectrometry (MS/MS) to determine 8 phenolic acids, 3 flavonols, and 4 anthocyanins in black rice wine. First, we clean samples with OASIS HLB cartridges and optimized extraction parameters. Next, we performed separation on a SHIM-PACK XR-ODS column (I.D. 3.0 mm * 75 mm, 2.2 MUm particle size) with a gradient elution of 50% aqueous acetonitrile (V/V) and water, both containing 0.2% formic acid. We used multiple-reaction monitoring scanning for quantification, with switching electrospray ion source polarity between positive and negative modes in a single chromatographic run. We detected 15 phenolic compounds properly within 38 min under optimized conditions. Limits of detection ranged from 0.008 to 0.030 mg/L, and average recoveries ranged from 60.8 to 103.1% with relative standard deviation <=8.6%. We validated the method and found it to be sensitive and reliable for quantifying phenolic compounds in rice wine matrices. PRACTICAL APPLICATION: This study developed a new, reliable HPLC-MS/MS method for simultaneous determination of 15 bioactive components in black rice wine. This method was validated and found to be sensitive and reliable for quantifying phenolic compounds in rice wine. PMID- 24784996 TI - Best face forward: crystal-face competition at the ice-water interface. AB - The ice-water interface plays an important role in determining the outcome of both biological and environmental processes. Under ambient pressure, the most stable form of ice is hexagonal ice (Ih). Experimentally probing the surface free energy between each of the major faces of Ih ice and the liquid is both experimentally and theoretically challenging. The basis for the challenge is the near-equality of the surface free energy for the major faces along with the tendency of water to supercool. As a result, morphology from crystallization initiated below 0 degrees C is kinetically controlled. The reported work circumvents supercooling consequences by providing a polycrystalline seed, followed by isothermal, equilibrium growth. Natural selection among seeded faces results in a single crystal. A record of the growth front is preserved in the frozen boule. Crystal orientation at the front is revealed by examining the boule cross section with two techniques: (1) viewing between crossed polarizers to locate the optical axis and (2) etching to distinguish the primary-prism face from the secondary-prism face. Results suggest that the most stable ice-water interface at 0 degrees C is the secondary-prism face, followed by the primary prism face. The basal face that imparts the characteristic hexagonal shape to snowflakes is a distant third. The results contrast with those from freezing the vapor where the basal and primary-prism faces have comparable free energy followed by the secondary-prism face. PMID- 24784997 TI - Assessment of CO2 adsorption capacity on activated carbons by a combination of batch and dynamic tests. AB - In this work, batch and dynamic adsorption tests are coupled for an accurate evaluation of CO2 adsorption performance of three different activated carbons (AC) obtained from olive stones by chemical activation followed by physical activation with CO2 at varying times (i.e., 20, 40, and 60 h). Kinetic and thermodynamic CO2 adsorption tests from simulated flue gas at different temperatures and CO2 pressures are carried out under both batch (a manometric equipment operating with pure CO2) and dynamic (a lab-scale fixed-bed column operating with a CO2/N2 mixture) conditions. The textural characterization of the AC samples shows a direct dependence of both micropore and ultramicropore volume on the activation time; hence, AC60 has the higher contribution. The adsorption tests conducted at 273 and 293 K showed that when CO2 pressure is lower than 0.3 bar, the lower the activation time, the higher CO2 adsorption capacity; a ranking of omega(eq)(AC20) > omega(eq)(AC40) > omega(eq)(AC60) can be exactly defined when T = 293 K. This result is likely ascribed to the narrower pore size distribution of the AC20 sample, whose smaller pores are more effective for CO2 capture at higher temperature and lower CO2 pressure, the latter representing operating conditions of major interest for decarbonation of flue gas effluent. Moreover, the experimental results obtained from dynamic tests confirm the results derived from the batch tests in terms of CO2 adsorption capacity. It is important to highlight the fact that the adsorption of N2 on the synthesized AC samples can be considered to be negligible. Finally, the importance of proper analysis for data characterization and adsorption experimental results is highlighted for the correct assessment of the CO2 removal performance of activated carbons at different CO2 pressures and operating temperatures. PMID- 24784998 TI - In vivo performance of combinations of autograft, demineralized bone matrix, and tricalcium phosphate in a rabbit femoral defect model. AB - Large bone defects may be treated with autologous or allogeneic bone preparations. Each treatment has advantages and disadvantages; therefore, a clinically viable option for treating large (e.g., gap) bone defects may be a combination of the two. In the present study, bone repair was determined with combinations of autografts, allografts, and synthetic bone grafts using an established rabbit femoral defect model. Bilateral unicortical femoral defects were surgically prepared and treated with combinatorial bone grafts according to one of seven treatment groups. Recipient sites were retrieved at six weeks. Cellular/tissue responses and new bone formation were assessed by histology and histomorphometry. Histological analysis images indicated neither evidence of inflammatory, immune responses, tissue necrosis, nor osteolysis. Data suggested co-integration of implanted agents with host and newly formed bone. Finally, the histomorphometric data suggested that the tricalcium phosphate-based synthetic bone graft substitute allowed new bone formation that was similar to the allograft (i.e., demineralized bone matrix, DBM). PMID- 24784999 TI - Anxiety- and depressive-like traits in Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats. AB - Anxiety, depression, and alcohol use disorders often go together. The aim of the present study was to evaluate anxiety- and depressive-like traits in selectively bred Warsaw alcohol high-preferring (WHP) and Warsaw alcohol low-preferring (WLP) rats. Alcohol-naive WHP rats were more active in the open field test as compared to alcohol-naive WLP rats. WHP rats made more central entries and spent more time in the central sector of the open field, i.e. presented less "neophobia", as compared to WLP subjects. The latter difference remained significant after controlling for the difference in locomotor activity as the anti-thigmotaxis ratio was also higher in WHP subjects. WHPs presented less freezing (i.e. less conditioned fear) than WLPs in the fear conditioning test. The difference in conditioned fear could not be explained by different pain sensitivity as the lines did not differ in pain threshold assessed in the flinch-jump test. WHPs were slightly less immobile in the Porsolt forced swim test as compared to WLPs. In conclusion, the present results suggest that alcohol high-preferring WHP rats show less anxiety- and depressive-like behavior than their low-preferring WLP counterparts. PMID- 24785000 TI - Ontogeny and adolescent alcohol exposure in Wistar rats: open field conflict, light/dark box and forced swim test. AB - Epidemiological studies have demonstrated that heavy drinking and alcohol abuse and dependence peak during the transition between late adolescence and early adulthood. Studies in animal models have demonstrated that alcohol exposure during adolescence can cause a modification in some aspects of behavioral development, causing the "adolescent phenotype" to be retained into adulthood. However, the "adolescent phenotype" has not been studied for a number of behavioral tests. The objective of the present study was to investigate the ontogeny of behaviors over adolescence/young adulthood in the light/dark box, open field conflict and forced swim test in male Wistar rats. These data were compared to previously published data from rats that received intermittent alcohol vapor exposure during adolescence (AIE) to test whether they retained the "adolescent phenotype" in these behavioral tests. Three age groups of rats were tested (post-natal day (PD) 34-42; PD55-63; PD69-77). In the light/dark box test, younger rats escaped the light box faster than older adults, whereas AIE rats returned to the light box faster and exhibited more rears in the light than controls. In the open field conflict test, both younger and AIE rats had shorter times to first enter the center, spent more time in the center of the field, were closer to the food, and consumed more food than controls. In the forced swim test no clear developmental pattern emerged. The results of the light/dark box and the forced swim test do not support the hypothesis that adolescent ethanol vapor exposure can "lock-in" all adolescent phenotypes. However, data from the open field conflict test suggest that the adolescent and the AIE rats both engaged in more "disinhibited" and food motivated behaviors. These data suggest that, in some behavioral tests, AIE may result in a similar form of behavioral disinhibition to what is seen in adolescence. PMID- 24785001 TI - Multidentate block-copolymer-stabilized ultrasmall superparamagnetic iron oxide nanoparticles with enhanced colloidal stability for magnetic resonance imaging. AB - Ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) with diameters <5 nm hold great promise as T1-positive contrast agents for in vivo magnetic resonance imaging. However, control of the surface chemistry of USPIOs to ensure individual colloidal USPIOs with a ligand monolayer and to impart biocompatibility and enhanced colloidal stability is essential for successful clinical applications. Herein, an effective and versatile strategy enabling the development of aqueous colloidal USPIOs stabilized with well-defined multidentate block copolymers (MDBCs) is reported. The multifunctional MDBCs are designed to consist of an anchoring block possessing pendant carboxylates as multidentate anchoring groups strongly bound to USPIO surfaces and a hydrophilic block having pendant hydrophilic oligo(ethylene oxide) chains to confer water dispersibility and biocompatibility. The surface of USPIOs is saturated with multiple anchoring groups of MDBCs, thus exhibiting excellent long-term colloidal stability as well as enhanced colloidal stability at biologically relevant electrolyte, pH, and temperature conditions. Furthermore, relaxometric properties as well as in vitro and in vivo MR imaging results demonstrate that the MDBC-stabilized USPIO colloids hold great potential as an effective T1 contrast agent. PMID- 24785002 TI - Stress-induced cortisol secretion impairs detection performance in x-ray baggage screening for hidden weapons by screening novices. AB - Aviation security strongly depends on screeners' performance in the detection of threat objects in x-ray images of passenger bags. We examined for the first time the effects of stress and stress-induced cortisol increases on detection performance of hidden weapons in an x-ray baggage screening task. We randomly assigned 48 participants either to a stress or a nonstress group. The stress group was exposed to a standardized psychosocial stress test (TSST). Before and after stress/nonstress, participants had to detect threat objects in a computer based object recognition test (X-ray ORT). We repeatedly measured salivary cortisol and X-ray ORT performance before and after stress/nonstress. Cortisol increases in reaction to psychosocial stress induction but not to nonstress independently impaired x-ray detection performance. Our results suggest that stress-induced cortisol increases at peak reactivity impair x-ray screening performance. PMID- 24785003 TI - Bag free in the Bay State. AB - BACKGROUND: The deleterious effect of formula company-sponsored discharge bags on breastfeeding is well established. As of July 2012, all 49 maternity facilities in Massachusetts had banned these bags, making it the second "bag-free" state in the United States. Obstacles to changing this long-standing practice were numerous, including concerns regarding the cost of a substitute gift. This study was designed to describe what practices maternity facilities in Massachusetts have adopted in place of giving out a formula company-sponsored discharge bag. MATERIALS AND METHODS: Maternity facilities in Massachusetts were surveyed regarding discharge gift practices. Information was collected regarding gifts given and cost. RESULTS: The response rate was 100%. Fifty-nine percent of the facilities replaced the formula company-sponsored bag with their own gift bag carrying the hospital's logo. Bags were either given empty or contained educational materials and/or a gift such as a T-shirt, hat, or baby book. Fourteen percent of the facilities gave a gift that did not include a bag. Twenty seven percent of facilities gave no gift. Cost of the gifts ranged from $1 to $35, with a mean cost of $10.67. The hospital budget was used to partially or fully fund 58% of gifts; 22% were covered in part by donations. CONCLUSIONS: Although most maternity facilities surveyed replaced the formula company sponsored discharge bag with a different gift, one-quarter gave no replacement. These data indicate that discontinuing discharge gifts can be a readily accepted, cost-neutral step toward evidence-based breastfeeding best practice. PMID- 24785004 TI - Abeta dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies. AB - Dimers of Abeta (amyloid beta-protein) are believed to play an important role in Alzheimer's disease. In the absence of sufficient brain-derived dimers, we studied one of the only possible dimers that could be produced in vivo, [Abeta](DiY) (dityrosine cross-linked Abeta). For comparison, we used the Abeta monomer and a design dimer cross-linked by replacement of Ser26 with cystine [AbetaS26C]2. We showed that similar to monomers, unaggregated dimers lack appreciable structure and fail to alter long-term potentiation. Importantly, dimers exhibit subtly different structural propensities from monomers and each other, and can self-associate to form larger assemblies. Although [Abeta](DiY) and [AbetaS26C]2 have distinct aggregation pathways, they both populate bioactive soluble assemblies for longer durations than Abeta monomers. Our results indicate that the link between Abeta dimers and Alzheimer's disease results from the ability of dimers to further assemble and form synaptotoxic assemblies that persist for long periods of time. PMID- 24785006 TI - Facile generation of cell microarrays using vacuum degassing and coverslip sweeping. AB - A simple method to generate cell microarrays with high-percentage well occupancy and well-defined cell confinement is presented. This method uses a synergistic combination of vacuum degassing and coverslip sweeping. The vacuum degassing step dislodges air bubbles from the microwells, which in turn enables the cells to enter the microwells, while the physical sweeping step using a glass coverslip removes the excess cells outside the microwells. This low-cost preparation method provides a simple solution to generating cell microarrays that can be performed in basic research laboratories and point-of-care settings for routine cell-based screening assays. PMID- 24785005 TI - NbIT--a new information theory-based analysis of allosteric mechanisms reveals residues that underlie function in the leucine transporter LeuT. AB - Complex networks of interacting residues and microdomains in the structures of biomolecular systems underlie the reliable propagation of information from an input signal, such as the concentration of a ligand, to sites that generate the appropriate output signal, such as enzymatic activity. This information transduction often carries the signal across relatively large distances at the molecular scale in a form of allostery that is essential for the physiological functions performed by biomolecules. While allosteric behaviors have been documented from experiments and computation, the mechanism of this form of allostery proved difficult to identify at the molecular level. Here, we introduce a novel analysis framework, called N-body Information Theory (NbIT) analysis, which is based on information theory and uses measures of configurational entropy in a biomolecular system to identify microdomains and individual residues that act as (i)-channels for long-distance information sharing between functional sites, and (ii)-coordinators that organize dynamics within functional sites. Application of the new method to molecular dynamics (MD) trajectories of the occluded state of the bacterial leucine transporter LeuT identifies a channel of allosteric coupling between the functionally important intracellular gate and the substrate binding sites known to modulate it. NbIT analysis is shown also to differentiate residues involved primarily in stabilizing the functional sites, from those that contribute to allosteric couplings between sites. NbIT analysis of MD data thus reveals rigorous mechanistic elements of allostery underlying the dynamics of biomolecular systems. PMID- 24785007 TI - A lipid-based method for the preparation of a piezoelectric DNA biosensor. AB - A piezoelectric DNA biosensor was prepared by immobilizing DNA probes on a quartz crystal microbalance (QCM) using a lipid-based method. A QCM electrode was coated with a hybrid bilayer membrane composed of an octadecanethiol monolayer and a lipid monolayer containing biotinylated lipids to establish biotin groups on the electrode surface. A DNA biosensor was prepared by sequentially immobilizing avidin and the biotinylated probe. The DNA biosensor was stable throughout repeated surface regeneration and showed higher sensitivity than that prepared by the conventional chemical method using diimide. We also optimized the surface regeneration conditions and flow rate for flow injection analysis. PMID- 24785008 TI - Higher predictive value of tumour and node [18F]-FDG PET metabolic volume and TLG in advanced lung cancer under chemotherapy. AB - INTRODUCTION: The prognostic value of standardized uptake values (SUVs) at initiation of and during chemotherapy remains controversial in lung cancer patients. However, metabolic volume (MV) and total lesion glycolysis (TLG) have shown promise in lung cancer stratification before treatment. Our aim was to define the prognostic value of MV and TLG in a homogenous group of advanced-stage lung cancer patients treated with bevacizumab and paclitaxel. MATERIALS AND METHODS: Fifty (18)F-fluorodeoxyglucose PET-computed tomography examinations were studied. SUV, MV and TLG were measured for each detectable lesion (classified as primary tumour, node or distant metastasis). MV values were added to compute tumour MV (MVt), nodal MV (MVn), metastatic MV (MVm) and whole-body MV (MVwb). TLGt, TLGn, TLGm and TLGwb were computed using the same method. Maximal SUVt, SUVn, SUVm and SUVwb were measured. Patients were stratified according to each parameter. Overall survival was compared between parameter-stratified groups using the log rank test. RESULTS: At initiation of bevacizumab and paclitaxel therapy (n=12), only TLGwb and TLGn had strong prognostic value with hazard ratios (HRs) of 11.8 and 5.6, respectively (P<0.03). During treatment with bevacizumab and paclitaxel (n=38), SUVwb (HR: 4.9), MVwb (HR: 4.9), TLGwb (HR: 8.9), SUVt (HR: 15.1), MVt (HR: 15.6) and TLGt (HR: 15.6) had significant prognostic value (P<0.05). Metastasis measurements showed no significant prognostic value. CONCLUSION: MV and TLG are powerful prognostic factors in advanced-stage lung adenocarcinoma being treated with chemotherapy. Focusing on the intrathoracic primary tumour increases the prognostic value of PET in these patients. PMID- 24785009 TI - A meta-analysis comparing SPECT with PET for the assessment of myocardial viability in patients with coronary artery disease. AB - OBJECTIVE: The aim of this meta-analysis was to examine the diagnostic accuracy of single-photon emission computed tomography (SPECT) for the assessment of myocardial viability in patients with coronary artery disease as compared with PET. MATERIALS AND METHODS: The literature was searched using the following keywords: single-photon emission computed tomography, positron emission tomography, perfusion, viability, myocardial infarction. Studies involving patients with coronary artery disease, left ventricular dysfunction, or a history of myocardial infarction and that compared SPECT and PET for the assessment of myocardial viability were included in the analysis. RESULTS: Eight studies including 310 patients were included in the meta-analysis. The total number of myocardial segments analyzed was 3580. The sensitivity and specificity of SPECT for the eight studies ranged from 59 to 95% and from 79 to 100%, respectively. The pooled sensitivity of SPECT was 82% [95% confidence interval (CI): 81-84%]. The pooled specificity of SPECT was 88% (95% CI: 86-90%). For all studies, the pooled diagnostic odds ratio was 62.60 (95% CI: 19.29-203.15) and the area under the receiver-operating characteristic curve was 0.945, indicating that SPECT could accurately assess myocardial viability. CONCLUSION: The meta-analysis indicated that SPECT can accurately assess myocardial viability, as compared with PET, and supports the use of SPECT for the assessment of myocardial viability in patients with coronary artery disease. PMID- 24785010 TI - Risk factors for N2 metastasis in patients with non-small-cell lung cancer: multivariate analyses of 18F-FDG PET/CT data. AB - OBJECTIVES: N staging is a key factor when considering the choice of treatment for non-small-lung cancer. It is possible that there is a correlation between N2 metastasis and some risk factors. The objective of the present study was to evaluate associations between several risk factors and N(2) metastasis using univariate and multivariate analyses, which may assist clinicians in therapeutic planning. MATERIALS AND METHODS: The enrolled patients were divided into two groups on the basis of histopathological results after surgery: those with pN(2) disease (N(2) group) and those without (N(2) group). Sex, age, location, size, maximum standardized uptake value (SUV(max)) on fluorine-18 fluorodeoxyglucose PET, histopathological type, and tumor cell grade were compared between N(2) and N(2) groups. Correlations between each significant factor and groups were analyzed using univariate analyses. Independent risk factors were finally identified with multivariate analyses. RESULTS: A total of 258 patients met the inclusion criteria. Univariate analyses showed significant correlation between size, SUV(max), tumor cell grade, and N(2) status (P<0.05). Multivariate logistic regression showed that both SUV(max) and tumor cell grade were independent risk factors and had predictive value for N(2) disease (P<0.05). There were no N(2) node metastases when tumor SUV(max) was up to 2.5 and the tumor cell grade was low. However, the likelihood of metastasis increased to 0.29 and 0.28 when tumor SUV(max) was greater than 7.5 and when the tumor cell grade was high. CONCLUSION: SUV(max) and tumor cell grade are independent risk factors for N(2) metastasis. PMID- 24785011 TI - Expression of miR-100 and RBSP3 in FTC-133 cells after exposure to 131I. AB - BACKGROUND: Sodium iodide ((131)I) therapy for the management of differentiated thyroid cancer is based on the deposition of certain doses of ionizing radiation, which can modulate microRNA (miRNA, miR) expression. Recent studies have suggested that miR-100 is significantly differentially expressed between benign and malignant thyroid tissue samples and modulates retinoblastoma 1 serine phosphates from human chromosome 3 (RBSP3), which is involved in the regulation of cell growth and differentiation. Therefore, the authors tested the hypothesis that a potential mechanism of (131)I treatment affects miR-100, which in turn regulates RBSP3 to modulate cell proliferation in thyroid cancer in vitro. MATERIALS AND METHODS: A follicular thyroid carcinoma cell line (FTC-133) was treated with (131)I or transfected with an oligonucleotide (miR-100 mimics, inhibitor, or negative control). Real-time quantitative PCR was used to confirm the expression levels of the miR-100 and RBSP3 mRNAs. Western blot analysis was performed to detect the levels of the RBSP3 protein. The cell cycle was analyzed on a cytofluorimeter by fluorescence-activated cell sorting analysis. RESULTS: RBSP3 protein expression was detected in FTC-133 cells. (131)I treatment inhibited the expression of miR-100 in FTC cells, as assessed by real-time quantitative PCR analysis, whereas it upregulated the RBSP3 mRNA and protein. Overexpression and knockdown experiments indicated that miR-100 repressed the expression of the RBSP3 mRNA by blocking its translation. Overexpression of miR 100 led to the downregulation of the RBSP3 protein and promoted the transition of FTC cells from the G1 to the S phase, as assessed using FACS analysis. CONCLUSION: (131)I treatment inhibited the expression of miR-100, which modulated RBSP3 in FTC cells. The new mechanism of suppression of the proliferation of FTC cells by I described here might occur through the downregulation of miR-100. PMID- 24785012 TI - Does catastrophizing of bodily sensations maintain health-related anxiety? A 14 day daily diary study with longitudinal follow-up. AB - BACKGROUND: Health anxiety is common, impairing, and costly. The role of catastrophizing of bodily sensations (i.e. rumination about, overconcern with, and intolerance of bodily sensations) in maintaining health-related anxiety (i.e. anxiety about perceived health problems) is important, but understudied, in the health anxiety literature. AIMS: The present study investigates the role of catastrophizing of bodily sensations as a maintenance factor for health-related anxiety over time. METHOD: Undergraduates (n = 226 women; n = 226 men) completed a baseline assessment, 14-day daily diary study, and 14-day longitudinal follow up. RESULTS: Path analysis indicated catastrophizing of bodily sensations maintains health-related anxiety from one month to the next in both men and women. CONCLUSIONS: The present study bridges an important gap between theory and evidence. Results support cognitive behavioral theories and extend cross sectional research asserting catastrophizing of bodily sensations maintains health-related anxiety over time. A cyclical, self-perpetuating pattern was observed in the present study wherein catastrophizing of bodily sensations and health-related anxiety contribute to one another over time. Results also suggest targeting catastrophizing of bodily sensations may reduce health-related anxiety. PMID- 24785013 TI - Periodic thermodynamics of isolated quantum systems. AB - The nature of the behavior of an isolated many-body quantum system periodically driven in time has been an open question since the beginning of quantum mechanics. After an initial transient period, such a system is known to synchronize with the driving; in contrast to the nondriven case, no fundamental principle has been proposed for constructing the resulting nonequilibrium state. Here, we analytically show that, for a class of integrable systems, the relevant ensemble is constructed by maximizing an appropriately defined entropy subject to constraints, which we explicitly identify. This result constitutes a generalization of the concepts of equilibrium statistical mechanics to a class of far-from-equilibrium systems, up to now mainly accessible using ad hoc methods. PMID- 24785014 TI - Exact nonadiabatic holonomic transformations of spin-orbit qubits. AB - An exact analytical solution is derived for the wave function of an electron in a one-dimensional moving quantum dot in a nanowire, in the presence of time dependent spin-orbit coupling. For cyclic evolutions we show that the spin of the electron is rotated by an angle proportional to the area of a closed loop in the parameter space of the time-dependent quantum dot position and the amplitude of a fictitious classical oscillator driven by time-dependent spin-orbit coupling. By appropriate choice of parameters, we show that the spin may be rotated by an arbitrary angle on the Bloch sphere. Exact expressions for dynamical and geometrical phases are also derived. PMID- 24785015 TI - Extracting entanglement from identical particles. AB - Identical particles and entanglement are both fundamental components of quantum mechanics. However, when identical particles are condensed in a single spatial mode, the standard notions of entanglement, based on clearly identifiable subsystems, break down. This has led many to conclude that such systems have limited value for quantum information tasks, compared to distinguishable particle systems. To the contrary, we show that any entanglement formally appearing amongst the identical particles, including entanglement due purely to symmetrization, can be extracted into an entangled state of independent modes, which can then be applied to any task. In fact, the entanglement of the mode system is in one-to-one correspondence with the entanglement between the inaccessible identical particles. This settles the long-standing debate about the resource capabilities of such states, in particular spin-squeezed states of Bose Einstein condensates, while also revealing a new perspective on how and when entanglement is generated in passive optical networks. Our results thus reveal new fundamental connections between entanglement, squeezing, and indistinguishability. PMID- 24785016 TI - Phase transitions in Brownian pumps. AB - We study stochastic particle transport between two reservoirs along a channel, where the particles are pumped against a bias by a traveling wave potential. It is shown that phase transitions of period-averaged densities or currents occur inside the channel when exclusion interactions between the particles are taken into account. These transitions reflect those known for the asymmetric simple exclusion process. We argue that their occurrence is a generic feature of Brownian motors operating in open systems. PMID- 24785017 TI - Quantum optomechanical heat engine. AB - We investigate theoretically a quantum optomechanical realization of a heat engine. In a generic optomechanical arrangement the optomechanical coupling between the cavity field and the oscillating end mirror results in polariton normal mode excitations whose character depends on the pump detuning and the coupling strength. By varying that detuning it is possible to transform their character from phononlike to photonlike, so that they are predominantly coupled to the thermal reservoir of phonons or photons, respectively. We exploit the fact that the effective temperatures of these two reservoirs are different to produce an Otto cycle along one of the polariton branches. We discuss the basic properties of the system in two different regimes: in the optical domain it is possible to extract work from the thermal energy of a mechanical resonator at finite temperature, while in the microwave range one can in principle exploit the cycle to extract work from the blackbody radiation background coupled to an ultracold atomic ensemble. PMID- 24785018 TI - Nonergodic subdiffusion from Brownian motion in an inhomogeneous medium. AB - Nonergodicity observed in single-particle tracking experiments is usually modeled by transient trapping rather than spatial disorder. We introduce models of a particle diffusing in a medium consisting of regions with random sizes and random diffusivities. The particle is never trapped but rather performs continuous Brownian motion with the local diffusion constant. Under simple assumptions on the distribution of the sizes and diffusivities, we find that the mean squared displacement displays subdiffusion due to nonergodicity for both annealed and quenched disorder. The model is formulated as a walk continuous in both time and space, similar to the Levy walk. PMID- 24785019 TI - Increasing sensing resolution with error correction. AB - The signal to noise ratio of quantum sensing protocols scales with the square root of the coherence time. Thus, increasing this time is a key goal in the field. By utilizing quantum error correction, we present a novel way of prolonging such coherence times beyond the fundamental limits of current techniques. We develop an implementable sensing protocol that incorporates error correction, and discuss the characteristics of these protocols in different noise and measurement scenarios. We examine the use of entangled versue untangled states, and error correction's reach of the Heisenberg limit. The effects of error correction on coherence times are calculated and we show that measurement precision can be enhanced for both one-directional and general noise. PMID- 24785020 TI - Quantum error correction for metrology. AB - We propose and analyze a new approach based on quantum error correction (QEC) to improve quantum metrology in the presence of noise. We identify the conditions under which QEC allows one to improve the signal-to-noise ratio in quantum limited measurements, and we demonstrate that it enables, in certain situations, Heisenberg-limited sensitivity. We discuss specific applications to nanoscale sensing using nitrogen-vacancy centers in diamond in which QEC can significantly improve the measurement sensitivity and bandwidth under realistic experimental conditions. PMID- 24785021 TI - Instability windows and evolution of rapidly rotating neutron stars. AB - We consider an instability of rapidly rotating neutron stars in low-mass x-ray binaries (LMXBs) with respect to excitation of r modes (which are analogous to Earth's Rossby waves controlled by the Coriolis force). We argue that finite temperature effects in the superfluid core of a neutron star lead to a resonance coupling and enhanced damping (and hence stability) of oscillation modes at certain stellar temperatures. Using a simple phenomenological model we demonstrate that neutron stars with high spin frequency may spend a substantial amount of time at these "resonance" temperatures. This finding allows us to explain puzzling observations of hot rapidly rotating neutron stars in LMXBs and to predict a new class of hot, nonaccreting, rapidly rotating neutron stars, some of which may have already been observed and tentatively identified as quiescent LMXB candidates. We also impose a new theoretical limit on the neutron star spin frequency, which can explain the cutoff spin frequency ~730 Hz, following from the statistical analysis of accreting millisecond x-ray pulsars. In addition to explaining the observations, our model provides a new tool to constrain superdense matter properties by comparing measured and theoretically predicted resonance temperatures. PMID- 24785022 TI - Electromagnetic particle-in-cell simulations of the solar wind interaction with lunar magnetic anomalies. AB - We present the first three-dimensional fully kinetic and electromagnetic simulations of the solar wind interaction with lunar crustal magnetic anomalies (LMAs). Using the implicit particle-in-cell code iPic3D, we confirm that LMAs may indeed be strong enough to stand off the solar wind from directly impacting the lunar surface forming a mini-magnetosphere, as suggested by spacecraft observations and theory. In contrast to earlier magnetohydrodynamics and hybrid simulations, the fully kinetic nature of iPic3D allows us to investigate the space charge effects and in particular the electron dynamics dominating the near surface lunar plasma environment. We describe for the first time the interaction of a dipole model centered just below the lunar surface under plasma conditions such that only the electron population is magnetized. The fully kinetic treatment identifies electromagnetic modes that alter the magnetic field at scales determined by the electron physics. Driven by strong pressure anisotropies, the mini-magnetosphere is unstable over time, leading to only temporal shielding of the surface underneath. Future human exploration as well as lunar science in general therefore hinges on a better understanding of LMAs. PMID- 24785024 TI - Method to calibrate the absolute energy scale of air showers with ultrahigh energy photons. AB - Calibrating the absolute energy scale of air showers initiated by ultrahigh energy (UHE) cosmic rays is an important experimental issue. Currently, the corresponding systematic uncertainty amounts to 14%-21% using the fluorescence technique. Here, we describe a new, independent method which can be applied if ultrahigh energy photons are observed. While such photon-initiated showers have not yet been identified, the capabilities of present and future cosmic-ray detectors may allow their discovery. The method makes use of the geomagnetic conversion of UHE photons (preshower effect), which significantly affects the subsequent longitudinal shower development. The conversion probability depends on photon energy and can be calculated accurately by QED. The comparison of the observed fraction of converted photon events to the expected one allows the determination of the absolute energy scale of the observed photon air showers and, thus, an energy calibration of the air shower experiment. We provide details of the method and estimate the accuracy that can be reached as a function of the number of observed photon showers. Already a very small number of UHE photons may help to test and fix the absolute energy scale. PMID- 24785025 TI - Gravity resonance spectroscopy constrains dark energy and dark matter scenarios. AB - We report on precision resonance spectroscopy measurements of quantum states of ultracold neutrons confined above the surface of a horizontal mirror by the gravity potential of Earth. Resonant transitions between several of the lowest quantum states are observed for the first time. These measurements demonstrate that Newton's inverse square law of gravity is understood at micron distances on an energy scale of 10-14 eV. At this level of precision, we are able to provide constraints on any possible gravitylike interaction. In particular, a dark energy chameleon field is excluded for values of the coupling constant beta>5.8*108 at 95% confidence level (C.L.), and an attractive (repulsive) dark matter axionlike spin-mass coupling is excluded for the coupling strength gsgp>3.7*10-16 (5.3*10 16) at a Yukawa length of lambda=20 MUm (95% C.L.). PMID- 24785026 TI - Astrophysical constraints on Planck scale dissipative phenomena. AB - The emergence of a classical spacetime from any quantum gravity model is still a subtle and only partially understood issue. If indeed spacetime is arising as some sort of large scale condensate of more fundamental objects, then it is natural to expect that matter, being a collective excitation of the spacetime constituents, will present modified kinematics at sufficiently high energies. We consider here the phenomenology of the dissipative effects necessarily arising in such a picture. Adopting dissipative hydrodynamics as a general framework for the description of the energy exchange between collective excitations and the spacetime fundamental degrees of freedom, we discuss how rates of energy loss for elementary particles can be derived from dispersion relations and used to provide strong constraints on the base of current astrophysical observations of high energy particles. PMID- 24785027 TI - Entanglement monotonicity and the stability of gauge theories in three spacetime dimensions. AB - We employ the recent results on the generalization of the central charge theorem to three spacetime dimensions to derive nonperturbative results for several strongly interacting quantum field theories, including quantum electrodynamics (QED-3), and the theory corresponding to certain quantum phase transitions in condensed matter systems. In particular, by demanding that the universal constant part of the entanglement entropy decreases along the renormalization group flow (F theorem), we find sufficient conditions for the stability of QED-3 against chiral symmetry breaking and confinement. Using similar ideas, we derive strong constraints on the nature of quantum critical points in condensed matter systems with topological order. PMID- 24785028 TI - Holographic turbulence. AB - We construct turbulent black holes in asymptotically AdS4 spacetime by numerically solving Einstein's equations. Using the AdS/CFT correspondence we find that both the dual holographic fluid and bulk geometry display signatures of an inverse cascade with the bulk geometry being well approximated by the fluid gravity gradient expansion. We argue that statistically steady-state black holes dual to d dimensional turbulent flows have horizons whose area growth has a fractal-like structure with fractal dimension D=d+4/3. PMID- 24785029 TI - Leptonic decay of the Upsilon(1S) meson at third order in QCD. AB - We present the complete next-to-next-to-next-to-leading order short-distance and bound-state QCD correction to the leptonic decay rate Gamma(Upsilon(1S)->l+l-) of the lowest-lying spin-1 bottomonium state. The perturbative QCD prediction is compared to the measurement Gamma(Upsilon(1S)->e+e-)=1.340(18) keV. PMID- 24785023 TI - Inferred cosmic-ray spectrum from Fermi large area telescope gamma-ray observations of Earth's limb. AB - Recent accurate measurements of cosmic-ray (CR) species by ATIC-2, CREAM, and PAMELA reveal an unexpected hardening in the proton and He spectra above a few hundred GeV, a gradual softening of the spectra just below a few hundred GeV, and a harder spectrum of He compared to that of protons. These newly discovered features may offer a clue to the origin of high-energy CRs. We use the Fermi Large Area Telescope observations of the gamma-ray emission from Earth's limb for an indirect measurement of the local spectrum of CR protons in the energy range ~90 GeV-6 TeV (derived from a photon energy range 15 GeV-1 TeV). Our analysis shows that single power law and broken power law spectra fit the data equally well and yield a proton spectrum with index 2.68+/-0.04 and 2.61+/-0.08 above ~200 GeV, respectively. PMID- 24785030 TI - Energy reconstruction in the long-baseline neutrino experiment. AB - The Long-Baseline Neutrino Experiment aims at measuring fundamental physical parameters to high precision and exploring physics beyond the standard model. Nuclear targets introduce complications towards that aim. We investigate the uncertainties in the energy reconstruction, based on quasielastic scattering relations, due to nuclear effects. The reconstructed event distributions as a function of energy tend to be smeared out and shifted by several 100 MeV in their oscillatory structure if standard event selection is used. We show that a more restrictive experimental event selection offers the possibility to reach the accuracy needed for a determination of the mass ordering and the CP-violating phase. Quasielastic-based energy reconstruction could thus be a viable alternative to the calorimetric reconstruction also at higher energies. PMID- 24785032 TI - Evidence for tetrahedral symmetry in (16)O. AB - We derive the rotation-vibration spectrum of a 4alpha configuration with tetrahedral symmetry Td and show evidence for the occurrence of this symmetry in the low-lying spectrum of (16)O. All vibrational states with A, E, and F symmetry appear to have been observed as well as the rotational bands with LP=0+, 3-, 4+, 6+ on the A states and part of the rotational bands built on the E, F states. We derive analytic expressions for the form factors and B(EL) values of the ground state rotational band and show that the measured values support the tetrahedral symmetry of this band. PMID- 24785033 TI - Direct measurement of the (23)Na(alpha,p)(26)Mg reaction cross section at energies relevant for the production of galactic (26)Al. AB - The 1809-keV gamma ray from the decay of (26)Al(g) is an important target for gamma-ray astronomy. In the convective C/Ne burning shell of massive presupernova stars, the (23)Na(alpha,p)(26)Mg reaction directly influences the production of (26)Al. We have performed a direct measurement of the (23)Na(alpha,p)(26)Mg reaction cross section at the appropriate astrophysically important energies. The stellar rate calculated in the present work is larger than the recommended rate by nearly a factor of 40 and could strongly affect the production of (26)Al in massive stars. PMID- 24785034 TI - Measurement of the survival probabilities for hot fusion reactions. AB - We have studied the fission-neutron emission competition in highly excited (274)Hs (Z=108) (where the fission barrier is due to shell effects) formed by a hot fusion reaction. Matching cross bombardments ((26)Mg+(248)Cm and (25)Mg+(248)Cm) were used to identify the properties of first chance fission of (274)Hs. A Harding-Farley analysis of the fission neutrons emitted in the (25)Mg,26+(248)Cm was performed to identify the prescission and postscission components of the neutron multiplicities in each system. (Gamman/Gammat) for the first chance fission of (274)Hs (E*=63 MeV) is 0.89+/-0.13; i.e., ~90% of the highly excited nuclei survive. The high value of that survival probability is due to dissipative effects during deexcitation. A proper description of the survival probabilities of excited superheavy nuclei formed in hot fusion reactions requires consideration of both dynamic and static (shell-related) effects. PMID- 24785035 TI - Attosecond pulse shaping around a Cooper minimum. AB - High harmonic generation (HHG) is used to measure the spectral phase of the recombination dipole matrix element (RDM) in argon over a broad frequency range that includes the 3p Cooper minimum (CM). The measured RDM phase agrees well with predictions based on the scattering phases and amplitudes of the interfering s- and d-channel contributions to the complementary photoionization process. The reconstructed attosecond bursts that underlie the HHG process show that the derivative of the RDM spectral phase, the group delay, does not have a straightforward interpretation as an emission time, in contrast to the usual attochirp group delay. Instead, the rapid RDM phase variation caused by the CM reshapes the attosecond bursts. PMID- 24785036 TI - Spatial coherence properties of organic molecules coupled to plasmonic surface lattice resonances in the weak and strong coupling regimes. AB - We study spatial coherence properties of a system composed of periodic silver nanoparticle arrays covered with a fluorescent organic molecule (DiD) film. The evolution of spatial coherence of this composite structure from the weak to the strong coupling regime is investigated by systematically varying the coupling strength between the localized DiD excitons and the collective, delocalized modes of the nanoparticle array known as surface lattice resonances. A gradual evolution of coherence from the weak to the strong coupling regime is observed, with the strong coupling features clearly visible in interference fringes. A high degree of spatial coherence is demonstrated in the strong coupling regime, even when the mode is very excitonlike (80%), in contrast to the purely localized nature of molecular excitons. We show that coherence appears in proportion to the weight of the plasmonic component of the mode throughout the weak-to-strong coupling crossover, providing evidence for the hybrid nature of the normal modes. PMID- 24785037 TI - Charge exchange and energy loss of slow highly charged ions in 1 nm thick carbon nanomembranes. AB - Experimental charge exchange and energy loss data for the transmission of slow highly charged Xe ions through ultrathin polymeric carbon membranes are presented. Surprisingly, two distinct exit charge state distributions accompanied by charge exchange dependent energy losses are observed. The energy loss for ions exhibiting large charge loss shows a quadratic dependency on the incident charge state indicating that equilibrium stopping force values do not apply in this case. Additional angle resolved transmission measurements point on a significant contribution of elastic energy loss. The observations show that regimes of different impact parameters can be separated and thus a particle's energy deposition in an ultrathin solid target may not be described in terms of an averaged energy loss per unit length. PMID- 24785038 TI - Mimicking Faraday rotation to sort the orbital angular momentum of light. AB - The efficient separation of the orbital angular momentum (OAM) is essential to both the classical and quantum applications with twisted photons. Here we devise and demonstrate experimentally an efficient method of mimicking the Faraday rotation to sort the OAM based on the OAM-to-polarization coupling effect induced by a modified Mach-Zehnder interferometer. Our device is capable of sorting the OAM of positive and negative numbers, as well as their mixtures. Furthermore, we report the first experimental demonstration to sort optical vortices of noninteger charges. The possibility of working at the photon-count level is also shown using an electron-multiplying CCD camera. Our scheme holds promise for quantum information applications with single-photon entanglement and for high capacity communication systems with polarization and OAM multiplexing. PMID- 24785039 TI - Two-dimensional phononic-photonic band gap optomechanical crystal cavity. AB - We present the fabrication and characterization of an artificial crystal structure formed from a thin film of silicon that has a full phononic band gap for microwave X-band phonons and a two-dimensional pseudo-band gap for near infrared photons. An engineered defect in the crystal structure is used to localize optical and mechanical resonances in the band gap of the planar crystal. Two-tone optical spectroscopy is used to characterize the cavity system, showing a large coupling (g0/2pi~220 kHz) between the fundamental optical cavity resonance at omegao/2pi=195 THz and colocalized mechanical resonances at frequency omegam/2pi~9.3 GHz. PMID- 24785040 TI - Metaweaves: sector-way nonreciprocal metasurfaces. AB - Confluent with the single dimension of time, breach of time-reversal symmetry is usually perceived as a one-dimensional concept. In its ultimate realization-the one-way guiding device-it allows optical propagation in one direction, say +z, and forbids it in the opposite direction -z. Hence, in studies of time-reversal asymmetry the mapping t?-t is naturally associated with z?-z. However, strongly nonreciprocal or one-way nanoscale threads can be used to weave metasurfaces thus adding dimensions to this concept. In this new family of surfaces the aforementioned association cannot be made. An example of appropriate threads is the planar one-way particle chains based on the two-type rotation principle. The resulting surfaces-the metaweaves-possess generalized nonreciprocity such as "sector-way" propagation, and offer new possibilities for controlling light in thin surfaces. We study several metaweave designs and their asymmetries in the wave-vector space. PMID- 24785041 TI - Chimera death: symmetry breaking in dynamical networks. AB - For a network of generic oscillators with nonlocal topology and symmetry-breaking coupling we establish novel partially coherent inhomogeneous spatial patterns, which combine the features of chimera states (coexisting incongruous coherent and incoherent domains) and oscillation death (oscillation suppression), which we call "chimera death". We show that due to the interplay of nonlocality and breaking of rotational symmetry by the coupling, two distinct scenarios from oscillatory behavior to a stationary state regime are possible: a transition from an amplitude chimera to chimera death via in-phase synchronized oscillations and a direct abrupt transition for larger coupling strength. PMID- 24785042 TI - Experimental demonstration of an inertial collimation mechanism in nested outflows. AB - Interaction between a central outflow and a surrounding wind is common in astrophysical sources powered by accretion. Understanding how the interaction might help to collimate the inner central outflow is of interest for assessing astrophysical jet formation paradigms. In this context, we studied the interaction between two nested supersonic plasma flows generated by focusing a long-pulse high-energy laser beam onto a solid target. A nested geometry was created by shaping the energy distribution at the focal spot with a dedicated phase plate. Optical and x-ray diagnostics were used to study the interacting flows. Experimental results and numerical hydrodynamic simulations indeed show the formation of strongly collimated jets. Our work experimentally confirms the "shock-focused inertial confinement" mechanism proposed in previous theoretical astrophysics investigations. PMID- 24785043 TI - Formation of phase space holes and clumps. AB - It is shown that the formation of phase space holes and clumps in kinetically driven, dissipative systems is not restricted to the near threshold regime, as previously reported and widely believed. Specifically, we observe hole-clump generation from the edges of an unmodulated phase space plateau, created via excitation, phase mixing and subsequent dissipative decay of a linearly unstable bulk plasma mode in the electrostatic bump-on-tail model. This has now allowed us to elucidate the underlying physics of the hole-clump formation process for the first time. Holes and clumps develop from negative energy waves that arise due to the sharp gradients at the interface between the plateau and the nearly unperturbed, ambient distribution and destabilize in the presence of dissipation in the bulk plasma. We confirm this picture by demonstrating that the formation of such nonlinear structures in general does not rely on a "seed" wave, only on the ability of the system to generate a plateau. In addition, we observe repetitive cycles of plateau generation and erosion, the latter due to hole-clump formation and detachment, which appear to be insensitive to initial conditions and can persist for a long time. We present an intuitive discussion of why this continual regeneration occurs. PMID- 24785044 TI - Equation of state measurements of warm dense carbon using laser-driven shock and release technique. AB - We present a new approach to equation of state experiments that utilizes a laser driven shock and release technique combined with spatially resolved x-ray Thomson scattering, radiography, velocity interferometry, and optical pyrometry to obtain independent measurements of pressure, density, and temperature for carbon at warm dense matter conditions. The uniqueness of this approach relies on using a laser to create very high initial pressures to enable a very deep release when the shock moves into a low-density pressure standard. This results in material at near normal solid density and temperatures around 10 eV. The spatially resolved Thomson scattering measurements facilitate a temperature determination of the released material by isolating the scattering signal from a specific region in the target. Our results are consistent with quantum molecular dynamics calculations for carbon at these conditions and are compared to several equation of state models. PMID- 24785045 TI - Phonon-mediated Casimir interaction between mobile impurities in one-dimensional quantum liquids. AB - Virtual phonons of a quantum liquid scatter off impurities and mediate a long range interaction, analogous to the Casimir effect. In one dimension the effect is universal and the induced interaction decays as 1/r3, much slower than the van der Waals interaction ~1/r6, where r is the impurity separation. The sign of the effect is characterized by the product of impurity-phonon scattering amplitudes, which take a universal form and have been seen to vanish for several integrable impurity models. Thus, if the impurity parameters can be independently tuned to lie on opposite sides of such integrable points, one can observe an attractive interaction turned into a repulsive one. PMID- 24785046 TI - Mass and chirality inversion of a Dirac cone pair in Stuckelberg interferometry. AB - We show that a Stuckelberg interferometer made of two massive Dirac cones can reveal information on band eigenstates such as the chirality and mass sign of the cones. For a given spectrum with two gapped cones, we propose several low-energy Hamiltonians differing by their eigenstates properties. The corresponding interband transition probability is affected by such differences in its interference fringes being shifted by a new phase of geometrical origin. This phase can be a useful bulk probe for topological band structures realized with artificial crystals. PMID- 24785031 TI - Measurement of the W boson production charge asymmetry in pp->W+X->enu+X events at ?s=1.96 TeV. AB - We present a measurement of the W boson production charge asymmetry in pp->W+X >enu+X events at a center of mass energy of 1.96 TeV, using 9.7 fb-1 of integrated luminosity collected with the D0 detector at the Fermilab Tevatron Collider. The neutrino longitudinal momentum is determined by using a neutrino weighting method, and the asymmetry is measured as a function of the W boson rapidity. The measurement extends over wider electron pseudorapidity region than previous results and is the most precise to date, allowing for precise determination of proton parton distribution functions in global fits. PMID- 24785047 TI - Ideal shear strength of a quantum crystal. AB - Using path-integral Monte Carlo simulations, we compute the ideal shear strength (ISS) on the basal plane of hcp (4)He. The failure mode upon reaching the ISS limit is characterized by the homogeneous nucleation of a stacking fault and it is found to be anisotropic, consistent with Schmid's law of resolved shear stress. Comparing the ISS of hcp (4)He to a large set of classical crystals shows that it closely fits the approximately universal modified Frenkel model of ideal strength. In addition to giving quantitative stress levels for the homogeneous nucleation of extended defects in hcp (4)He, our findings lend support to assumptions in the literature that inherently classical models remain useful for the description of mechanical behavior in quantum crystals. PMID- 24785048 TI - Detecting multiparticle entanglement of Dicke states. AB - Recent experiments demonstrate the production of many thousands of neutral atoms entangled in their spin degrees of freedom. We present a criterion for estimating the amount of entanglement based on a measurement of the global spin. It outperforms previous criteria and applies to a wider class of entangled states, including Dicke states. Experimentally, we produce a Dicke-like state using spin dynamics in a Bose-Einstein condensate. Our criterion proves that it contains at least genuine 28-particle entanglement. We infer a generalized squeezing parameter of -11.4(5) dB. PMID- 24785049 TI - Bulk metallic glasses deform via slip avalanches. AB - For the first time in metallic glasses, we extract both the exponents and scaling functions that describe the nature, statistics, and dynamics of slip events during slow deformation, according to a simple mean field model. We model the slips as avalanches of rearrangements of atoms in coupled shear transformation zones (STZs). Using high temporal resolution measurements, we find the predicted, different statistics and dynamics for small and large slips thereby excluding self-organized criticality. The agreement between model and data across numerous independent measures provides evidence for slip avalanches of STZs as the elementary mechanism of inhomogeneous deformation in metallic glasses. PMID- 24785050 TI - Charge transfer doping of silicon. AB - We demonstrate a novel doping mechanism of silicon, namely n-type transfer doping by adsorbed organic cobaltocene (CoCp2*) molecules. The amount of transferred charge as a function of coverage is monitored by following the ensuing band bending via surface sensitive core-level photoelectron spectroscopy. The concomitant loss of electrons in the CoCp2* adlayer is quantified by the relative intensities of chemically shifted Co2p components in core-level photoelectron spectroscopy which correspond to charged and neutral molecules. Using a previously developed model for transfer doping, the evolution in relative intensities of the two components as a function of coverage has been reproduced successfully. A single, molecule-specific parameter, the negative donor energy of -(0.50+/-0.15) eV suffices to describe the self-limiting doping process with a maximum areal density of transferred electrons of 2*1013 cm-2 in agreement with the measured downward band bending. The advantage of this doping mechanism over conventional doping for nanostructures is addressed. PMID- 24785051 TI - Influence of contact aging on nanoparticle friction kinetics. AB - One of the oldest concepts in tribology is stick-slip dynamics, where a disruptive sequence of stick and slip phases determine the overall resistance in sliding friction. While the mechanical energy dissipates in the sudden slip phase, the stick phase has been shown to be characterized by contact strengthening mechanisms, also termed contact aging. We present experiments of sliding nanoparticles, where friction is measured as a function of sliding velocity and interface temperature. The resulting complex interdependence is in good agreement with Monte Carlo simulations, in which the energy barrier for contact breaking increases logarithmically with time, at a rate governed by thermal activation. PMID- 24785052 TI - Self-assembly at a nonequilibrium critical point. AB - We use analytic theory and computer simulation to study patterns formed during the growth of two-component assemblies in two and three dimensions. We show that these patterns undergo a nonequilibrium phase transition, at a particular growth rate, between mixed and demixed arrangements of component types. This finding suggests that principles of nonequilibrium statistical mechanics can be used to predict the outcome of multicomponent self-assembly, and suggests an experimental route to the self-assembly of multicomponent structures of a qualitatively defined nature. PMID- 24785053 TI - Mechanism of hollow nanoparticle formation due to shape fluctuations. AB - Shape fluctuations in nanoparticles strongly influence their stability. Here, we introduce a quantitative model of such shape fluctuations and apply this model to the important case of Pt-shell/transition metal-core nanoparticles. By using a Gibbs distribution for the initial shapes, we find that there is typically enough thermal energy at room temperature to excite random shape fluctuations in core shell nanoparticles, whose amplitudes are sufficiently high that the cores of such particles are transiently exposed to the surrounding environment. If this environment is acidic and dissolves away the core, then a hollow shell containing a pinhole is formed; however, this pinhole quickly closes, leaving a hollow nanoparticle. These results favorably compare to experiment, much more so than competing models based on the room-temperature Kirkendall effect. PMID- 24785054 TI - Microtransition cascades to percolation. AB - We report the discovery of a discrete hierarchy of microtransitions occurring in models of continuous and discontinuous percolation. The precursory microtransitions allow us to target almost deterministically the location of the transition point to global connectivity. This extends to the class of intrinsically stochastic processes the possibility to use warning signals anticipating phase transitions in complex systems. PMID- 24785055 TI - Stiffness from disorder in triangular-lattice Ising thin films. AB - We study the triangular lattice Ising model with a finite number of vertically stacked layers and demonstrate a low temperature reentrance of two Berezinskii Kosterlitz-Thouless transitions, which results in an extended disordered regime down to T=0. Numerical results are complemented with the derivation of an effective low-temperature dimer theory. Contrary to order by disorder, we present a new scenario for fluctuation-induced ordering in frustrated spin systems. While short-range spin-spin correlations are enhanced by fluctuations, quasi-long-range ordering is precluded at low enough temperatures by proliferation of topological defects. PMID- 24785056 TI - Role of physisorption states in molecular scattering: a semilocal density functional theory study on O2/Ag(111). AB - We simulate the scattering of O2 from Ag(111) with classical dynamics simulations performed on a six-dimensional potential energy surface calculated within semilocal density-functional theory. The enigmatic experimental trends that originally required the conjecture of two types of repulsive walls, arising from a physisorption and chemisorption part of the interaction potential, are fully reproduced. Given the inadequate description of the physisorption properties in semilocal density-functional theory, our work casts severe doubts on the prevalent notion to use molecular scattering data as indirect evidence for the existence of such states. PMID- 24785057 TI - Oxygen vacancies versus fluorine at CeO2(111): a case of mistaken identity? AB - We propose a resolution to the puzzle presented by the surface defects observed with STM at the (111) surface facet of CeO 2 single crystals. In the seminal paper of Esch et al. [Science 309, 752 (2005)] they were identified with oxygen vacancies, but the observed behavior of these defects is inconsistent with the results of density functional theory (DFT) studies of oxygen vacancies in the literature. We resolve these inconsistencies via DFT calculations of the properties of both oxygen vacancies and fluorine impurities at CeO2(111), the latter having recently been shown to exist in high concentrations in single crystals from a widely used commercial source of such samples. We find that the simulated filled-state STM images of surface-layer oxygen vacancies and fluorine impurities are essentially identical, which would render problematic their experimental distinction by such images alone. However, we find that our theoretical results for the most stable location, mobility, and tendency to cluster, of fluorine impurities are consistent with experimental observations, in contrast to those for oxygen vacancies. Based on these results, we propose that the surface defects observed in STM experiments on CeO2 single crystals reported heretofore were not oxygen vacancies, but fluorine impurities. Since the similarity of the simulated STM images of the two defects is due primarily to the relative energies of the 2p states of oxygen and fluorine ions, this confusion might also occur for other oxides which have been either doped or contaminated with fluorine. PMID- 24785058 TI - Grain-boundary-enhanced carrier collection in CdTe solar cells. AB - When CdTe solar cells are doped with Cl, the grain boundaries no longer act as recombination centers but actively contribute to carrier collection efficiency. The physical origin of this remarkable effect has been determined through a combination of aberration-corrected scanning transmission electron microscopy, electron energy loss spectroscopy, and first-principles theory. Cl substitutes for a large proportion of the Te atoms within a few unit cells of the grain boundaries. Density functional calculations reveal the mechanism, and further indicate the grain boundaries are inverted to n type, establishing local p-n junctions which assist electron-hole pair separation. The mechanism is electrostatic, and hence independent of the geometry of the boundary, thereby explaining the universally high collection efficiency of Cl-doped CdTe solar cells. PMID- 24785059 TI - Lifshitz transition and chemical instabilities in Ba(1-x)K(x)Fe2As2 superconductors. AB - For solid-solution Ba1-xKxFe2As2 Fermi surface evolution is mapped via Bloch spectral functions calculated using density functional theory implemented in Korringa-Kohn-Rostoker multiple scattering theory with the coherent-potential approximation. Spectral functions reveal electronic dispersion, topology, orbital character, and broadening (electron-lifetime effects) due to chemical disorder. Dissolution of electron cylinders occurs near x~0.9 with a nonuniform, topological (Lifshitz) transition, reducing the interband interactions; yet the dispersion maintains its dxz or dyz character. Formation energies indicate alloying at x=0.35, as observed, and a tendency for segregation on the K-rich (x>0.6) side, explaining the difficulty of controlling sample quality and the conflicting results between characterized electronic structures. Our results reveal Fermi surface transitions in alloyed samples that influence s+/- to nodal superconductivity and suggest the origin for deviations of common trends in Fe based superconductors, such as Bud'ko-Ni-Canfield scaling. PMID- 24785060 TI - Real-space visualization of remnant Mott gap and magnon excitations. AB - We demonstrate the ability to visualize real-space dynamics of charge gap and magnon excitations in the Mott phase of the single-band Hubbard model and the remnants of these excitations with hole or electron doping. At short times, the character of magnetic and charge excitations is maintained even for large doping away from the Mott and antiferromagnetic phases. Doping influences both the real space patterns and long timescales of these excitations with a clear carrier asymmetry attributable to particle-hole symmetry breaking in the underlying model. Further, a rapidly oscillating charge-density-wave-like pattern weakens, but persists as a visible demonstration of a subleading instability at half filling which remains upon doping. The results offer an approach to analyzing the behavior of systems where momentum space is either inaccessible or poorly defined. PMID- 24785061 TI - Competing orders in the 2D half-filled SU(2N) Hubbard model through the pinning field quantum Monte Carlo simulations. AB - We nonperturbatively investigate the ground state magnetic properties of the 2D half-filled SU(2N) Hubbard model in the square lattice by using the projector determinant quantum Monte Carlo simulations combined with the method of local pinning fields. Long-range Neel orders are found for both the SU(4) and SU(6) cases at small and intermediate values of U. In both cases, the long-range Neel moments exhibit nonmonotonic behavior with respect to U, which first grow and then drop as U increases. This result is fundamentally different from the SU(2) case in which the Neel moments increase monotonically and saturate. In the SU(6) case, a transition to the columnar dimer phase is found in the strong interaction regime. PMID- 24785062 TI - Controllable Rashba spin-orbit interaction in artificially engineered superlattices involving the heavy-fermion superconductor CeCoIn5. AB - By using a molecular beam epitaxy technique, we fabricate a new type of superconducting superlattices with controlled atomic layer thicknesses of alternating blocks between the heavy-fermion superconductor CeCoIn5, which exhibits a strong Pauli pair-breaking effect, and nonmagnetic metal YbCoIn5. The introduction of the thickness modulation of YbCoIn5 block layers breaks the inversion symmetry centered at the superconducting block of CeCoIn5. This configuration leads to dramatic changes in the temperature and angular dependence of the upper critical field, which can be understood by considering the effect of the Rashba spin-orbit interaction arising from the inversion symmetry breaking and the associated weakening of the Pauli pair-breaking effect. Since the degree of thickness modulation is a design feature of this type of superlattices, the Rashba interaction and the nature of pair breaking are largely tunable in these modulated superlattices with strong spin-orbit coupling. PMID- 24785063 TI - Optical spin noise of a single hole spin localized in an (InGa)As quantum dot. AB - We advance spin noise spectroscopy to the ultimate limit of single spin detection. This technique enables the measurement of the spin dynamic of a single heavy hole localized in a flat (InGa)As quantum dot. Magnetic field and light intensity dependent studies reveal even at low magnetic fields a strong magnetic field dependence of the longitudinal heavy hole spin relaxation time with an extremely long T1 of >=180 MUs at 31 mT and 5 K. The wavelength dependence of the spin noise power discloses for finite light intensities an inhomogeneous single quantum dot spin noise spectrum which is explained by charge fluctuations in the direct neighborhood of the quantum dot. The charge fluctuations are corroborated by the distinct intensity dependence of the effective spin relaxation rate. PMID- 24785064 TI - Floquet fractional Chern insulators. AB - We show theoretically that periodically driven systems with short range Hubbard interactions offer a feasible platform to experimentally realize fractional Chern insulator states. We exemplify the procedure for both the driven honeycomb and the square lattice, where we derive the effective steady state band structure of the driven system by using the Floquet theory and subsequently study the interacting system with exact numerical diagonalization. The fractional Chern insulator state equivalent to the 1/3 Laughlin state appears at 7/12 total filling (1/6 filling of the upper band). The state also features spontaneous ferromagnetism and is thus an example of the spontaneous breaking of a continuous symmetry along with a topological phase transition. We discuss light-driven graphene and shaken optical lattices as possible experimental systems that can realize such a state. PMID- 24785065 TI - Stripe domains and first-order phase transition in the vortex matter of anisotropic high-temperature superconductors. AB - We report the direct imaging of a novel modulated flux striped domain phase in a nearly twin-free YBCO crystal. These domains arise from instabilities in the vortex structure within a narrow region of tilted magnetic fields at small angles from the in-plane direction. By comparing the experimental and theoretically derived vortex phase diagrams we infer that the stripe domains emerge from a first-order phase transition of the vortex structure. The size of domains containing vortices of certain orientations is controlled by the balance between the vortex stray field energy and the positive energy of the domain boundaries. Our results confirm the existence of the kinked vortex chain phase in an anisotropic high temperature superconductor and reveal a sharp transition in the state of this phase resulting in regular vortex domains. PMID- 24785066 TI - Melting of charge stripes in vibrationally driven La(1.875)Ba(0.125)CuO4: assessing the respective roles of electronic and lattice order in frustrated superconductors. AB - We report femtosecond resonant soft x-ray diffraction measurements of the dynamics of the charge order and of the crystal lattice in nonsuperconducting, stripe-ordered La1.875Ba0.125CuO4. Excitation of the in-plane Cu-O stretching phonon with a midinfrared pulse has been previously shown to induce a transient superconducting state in the closely related compound La1.675Eu0.2Sr0.125CuO4. In La1.875Ba0.125CuO4, we find that the charge stripe order melts promptly on a subpicosecond time scale. Surprisingly, the low temperature tetragonal (LTT) distortion is only weakly reduced, reacting on significantly longer time scales that do not correlate with light-induced superconductivity. This experiment suggests that charge modulations alone, and not the LTT distortion, prevent superconductivity in equilibrium. PMID- 24785067 TI - Vector chiral phases in the frustrated 2D XY model and quantum spin chains. AB - The phase diagram of the frustrated 2D classical and 1D quantum XY models is calculated analytically. Four transitions are found: the vortex unbinding transitions triggered by strong fluctuations occur above and below the chiral transition temperature. Vortex interaction is short range on small and logarithmic on large scales. The chiral transition, though belonging to the Ising universality class by symmetry, has different critical exponents due to nonlocal interaction. In a narrow region close to the Lifshitz point a reentrant phase transition between paramagnetic and quasiferromagnetic phase appears. Applications to antiferromagnetic quantum spin chains and multiferroics are discussed. PMID- 24785068 TI - Abrupt transition from ferromagnetic to antiferromagnetic of interfacial exchange in perpendicularly magnetized L1(0)-MnGa/FeCo tuned by Fermi level position. AB - An abrupt transition of the interfacial exchange coupling from ferromagnetic to antiferromagnetic was observed in the interface of perpendicularly magnetized L10 MnGa/Fe1-xCox epitaxial bilayers when x was around 25%. By considering the special band structure of the MnGa alloy, we present a model explaining this transition by the spin-polarization reversal of Fe1-xCox alloys due to the rise of the Fermi level as the Co content increases. The effect of interfacial exchange coupling on the coercive force (Hc) and the spin-dependent tunneling effect in perpendicular magnetic tunnel junctions (pMTJs) based on the coupled composite were also studied. Changes from the normal spin valve to inverted magnetoresistance loops corresponding to the coupling transition were observed in pMTJs with MnGa/Fe1-xCox as an electrode. PMID- 24785069 TI - Atomistic model of fluorescence intermittency of colloidal quantum dots. AB - Optoelectronic applications of colloidal quantum dots demand a high emission efficiency, stability in time, and narrow spectral bandwidth. Electronic trap states interfere with the above properties but understanding of their origin remains lacking, inhibiting the development of robust passivation techniques. Here we show that surface vacancies improve the fluorescence yield compared to vacancy-free surfaces, while dynamic vacancy aggregation can temporarily turn fluorescence off. We find that infilling with foreign cations can stabilize the vacancies, inhibiting intermittency and improving quantum yield, providing an explanation of recent experimental observations. PMID- 24785070 TI - Effectiveness of thin films in lieu of hyperbolic metamaterials in the near field. AB - We show that the near-field functionality of hyperbolic metamaterials (HMM), typically proposed for increasing the photonic local density of states (LDOS), can be achieved with thin metal films. Although HMMs have an infinite density of internally propagating plane-wave states, the external coupling to nearby emitters is severely restricted. We show analytically that properly designed thin films, of thicknesses comparable to the metal size of a hyperbolic metamaterial, yield an LDOS as high as (if not higher than) that of HMMs. We illustrate these ideas by performing exact numerical computations of the LDOS of multilayer HMMs, along with their application to the problem of maximizing near-field heat transfer, to show that single-layer thin films are suitable replacements in both cases. PMID- 24785071 TI - Emergence of ferroelectricity at a metal-semiconductor transition in a 1T monolayer of MoS2. AB - Using a combination of Landau theoretical analysis and first-principles calculations, we establish a spontaneous symmetry breaking of the metallic state of the 1T monolayer of MoS2 that opens up a band gap and leads to an unexpected yet robust ferroelectricity with ordering of electric dipoles perpendicular to its plane. Central to the properties of this thinnest known ferroelectric is a strong coupling of conducting states with valley phonons that induce an effective electric field. The current in a semiconducting 1T-MoS2 channel can, thus, be controlled independently by changing its ferroelectric dipolar structure with a gate field, opening up a possibility of a class of nanoscale dipolectronic devices. Our analysis applies equally well to MoSe2, WS2, and WSe2, giving tunability in design of such devices based on two-dimensional chalcogenides. PMID- 24785072 TI - Low cation coordination in oxide melts. AB - The complete set of partial pair distribution functions for a rare earth oxide liquid are measured by combining aerodynamic levitation, neutron and x-ray diffraction on Y2O3, and Ho2O3 melts at 2870 K. The average Y-O (or Ho-O) coordination of these isomorphic melts is measured to be 5.5(2), which is significantly less than the octahedral coordination of crystalline Y2O3 (or Ho2O3). Investigation of La2O3, ZrO2, and Al2O3 melts by x-ray diffraction and molecular dynamics simulations also show lower-than-crystal cation-oxygen coordination. These measurements suggest a general trend towards lower coordination compared to their crystalline counterparts. It is found that the coordination drop is larger for lower field strength, larger radius cations and is negligible for high field strength (network forming) cations, such as SiO2. These findings have broad implications for predicting the local structure and related physical properties of metal-oxide melts and oxide glasses. PMID- 24785073 TI - Limit of metastability for liquid and vapor phases of water. AB - We report the limits of superheating of water and supercooling of vapor from Monte Carlo simulations using microscopic models with configurational enthalpy as the order parameter. The superheating limit is well reproduced. The vapor is predicted to undergo spinodal decomposition at a temperature of Tspvap=46+/-10 degrees C (0 degrees C?Tspvap?100 degrees C) under 1 atm. The water-water network begins to form at the supercooling limit of the vapor. Three-dimensional water-water and cavity-cavity unbroken networks are interwoven at critically superheated liquid water; if either network breaks, the metastable state changes to liquid or vapor. PMID- 24785074 TI - Anomalous melting scenario of the two-dimensional core-softened system. AB - We present a computer simulation study of the phase behavior of two-dimensional (2D) classical particles repelling each other through an isotropic core-softened potential. As in the analogous three-dimensional (3D) case, a reentrant-melting transition occurs upon compression for not too high pressures, along with a spectrum of waterlike anomalies in the fluid phase. However, in two dimensions in the low density part of the phase diagram melting is a continuous two-stage transition, with an intermediate hexatic phase. All available evidence supports the Kosterlitz-Thouless-Halperin-Nelson-Young scenario for this melting transition. On the other hand, at the high density part of the phase diagram one first-order transition takes place. PMID- 24785075 TI - Transport powered by bacterial turbulence. AB - We demonstrate that collective turbulentlike motion in a bacterial bath can power and steer the directed transport of mesoscopic carriers through the suspension. In our experiments and simulations, a microwedgelike "bulldozer" draws energy from a bacterial bath of varied density. We obtain that an optimal transport speed is achieved in the turbulent state of the bacterial suspension. This apparent rectification of random motion of bacteria is caused by polar ordered bacteria inside the cusp region of the carrier, which is shielded from the outside turbulent fluctuations. PMID- 24785076 TI - de Gennes narrowing describes the relative motion of protein domains. AB - The relative motion of structural domains is essential for the biological function of many proteins. Here, by analyzing neutron scattering data and performing molecular dynamics simulations, we find that interdomain motion in several proteins obeys the principle of de Gennes narrowing, in which the wave vector dependence of the interdomain diffusion coefficient is inversely proportional to the interdomain structure factor. Thus, the rate of interdomain motion is inversely proportional to the probability distribution of the spatial configurations of domains. PMID- 24785077 TI - Single-molecule force spectroscopy of rapidly fluctuating, marginally stable structures in the intrinsically disordered protein alpha-synuclein. AB - Intrinsically disordered proteins form transient, fluctuating structures that are difficult to observe directly. We used optical tweezers to apply force to single alpha-synuclein molecules and measure their extension, characterizing the resulting conformational transitions. Force-extension curves revealed rapid fluctuations at low force, arising from the folding of two different classes of structure that were only marginally stable. The energy landscape for these transitions was characterized via the force-dependent kinetics derived from correlation analysis of the extension trajectories. The barriers were small, only a few kBT, but the diffusion was slow, revealing a landscape that is flat but rough. PMID- 24785078 TI - Is the voter model a model for voters? AB - The voter model has been studied extensively as a paradigmatic opinion dynamics model. However, its ability to model real opinion dynamics has not been addressed. We introduce a noisy voter model (accounting for social influence) with recurrent mobility of agents (as a proxy for social context), where the spatial and population diversity are taken as inputs to the model. We show that the dynamics can be described as a noisy diffusive process that contains the proper anisotropic coupling topology given by population and mobility heterogeneity. The model captures statistical features of U.S. presidential elections as the stationary vote-share fluctuations across counties and the long range spatial correlations that decay logarithmically with the distance. Furthermore, it recovers the behavior of these properties when the geographical space is coarse grained at different scales-from the county level through congressional districts, and up to states. Finally, we analyze the role of the mobility range and the randomness in decision making, which are consistent with the empirical observations. PMID- 24785079 TI - Comment on "Aharonov-Casher and scalar Aharonov-Bohm topological effects". PMID- 24785080 TI - Retraction: Alfvenic propagation: a key to nonlocal effects in magnetized plasmas [Phys. Rev. Lett. 112, 095003 (2014)]. PMID- 24785081 TI - Role of protein kinase A signaling pathway in cyclosporine nephrotoxicity. AB - Cyclosporine is an important immunosuppressive agent; however, nephrotoxicity is one of the main adverse effects. The purpose of this study was to evaluate the effect of inhibiting the protein kinase A (PKA) signaling pathway in nephrotoxicity caused by cyclosporine from the assessment of cell viability, pro inflammatory cytokines, and nitric oxide (NO) production in LLC-PK1 and MDCK cell lines. Cyclosporine proved to be cytotoxic for both cell lines, as assessed by the mitochondrial enzyme activity assay (MTT), caused DNA fragmentation, determined by flow cytometry using the propidium iodide dye, and activated the PKA pathway (western blot assay). In MDCK cells, the inhibition of the PKA signaling pathway (H89 inhibitor) caused a significant reduction in DNA fragmentation. In both cell lines, the production of IL-6 proved to be a dependent PKA pathway, while TNF-alpha was not influenced by the inhibition of the PKA pathway. The NO production was increased when cells were pre-incubated with H89 followed by cyclosporine, and this production was dependent on the PKA pathway in LLC-PK1 and MDCK cells lines. Therefore, considering the present study's results, it can be concluded that the inhibition of PKA signaling pathway can aid in reducing the degree of nephrotoxicity caused by cyclosporine. PMID- 24785082 TI - An in vivo EGF receptor localization screen in C. elegans Identifies the Ezrin homolog ERM-1 as a temporal regulator of signaling. AB - The subcellular localization of the epidermal growth factor receptor (EGFR) in polarized epithelial cells profoundly affects the activity of the intracellular signaling pathways activated after EGF ligand binding. Therefore, changes in EGFR localization and signaling are implicated in various human diseases, including different types of cancer. We have performed the first in vivo EGFR localization screen in an animal model by observing the expression of the EGFR ortholog LET-23 in the vulval epithelium of live C. elegans larvae. After systematically testing all genes known to produce an aberrant vulval phenotype, we have identified 81 genes regulating various aspects of EGFR localization and expression. In particular, we have found that ERM-1, the sole C. elegans Ezrin/Radixin/Moesin homolog, regulates EGFR localization and signaling in the vulval cells. ERM-1 interacts with the EGFR at the basolateral plasma membrane in a complex distinct from the previously identified LIN-2/LIN-7/LIN-10 receptor localization complex. We propose that ERM-1 binds to and sequesters basolateral LET-23 EGFR in an actin rich inactive membrane compartment to restrict receptor mobility and signaling. In this manner, ERM-1 prevents the immediate activation of the entire pool of LET 23 EGFR and permits the generation of a long-lasting inductive signal. The regulation of receptor localization thus serves to fine-tune the temporal activation of intracellular signaling pathways. PMID- 24785083 TI - Solvent-controlled spin-coating method for large-scale area deposition of two dimensional silica nanosphere assembled layers. AB - In this article, we show that introducing a N,N-dimethyl-formamide (DMF) solvent for silica nanosphere (SNS) monolayer spin-coating can offer a low-cost and simple spin-coating approach for SNS monolayer deposition even on large-area silicon surfaces. From our method, more than 95% monolayer coverage for a 2 in round Si surface was achieved, which is one of the highest reported coverage by a spin-coating method. We prove that DMF offers highly enhanced wettability and slow solvent evaporation rate compared to a conventional solvent, water, in addition to excellent SNS dispersibility in solution preventing SNS cluster deposition on the surface and consequently produces a close-packed SNS monolayer with good uniformity over the surface. In addition, the benefits of DMF are retained as the deposition area increases indicating its high tolerance to spin coating area. Better than 90% SNS monolayer coverage on a 4 in Si substrate was achieved with the DMF spin-coating method. Moreover, DMF has the advantage that SNS spin-coating can be done under common ambient laboratory conditions with 100% pure DMF unlike previous approaches which require humidity and temperature controls or additional surfactant additions to the solution. PMID- 24785085 TI - Kelch-like ECT2-interacting protein KLEIP regulates late-stage pulmonary maturation via Hif-2alpha in mice. AB - Respiratory distress syndrome (RDS) caused by preterm delivery is a major clinical problem with limited mechanistic insight. Late-stage embryonic lung development is driven by hypoxia and the hypoxia-inducible transcription factors Hif-1alpha and Hif-2alpha, which act as important regulators for lung development. Expression of the BTB-and kelch-domain-containing (BTB-kelch) protein KLEIP (Kelch-like ECT2-interacting protein; also named Klhl20) is controlled by two hypoxia response elements, and KLEIP regulates stabilization and transcriptional activation of Hif-2alpha. Based on the available data, we hypothesized an essential role for KLEIP in murine lung development and function. Therefore, we have performed a functional, histological, mechanistic and interventional study in embryonic and neonatal KLEIP(-/-) mice. Here, we show that about half of the KLEIP(-/-) neonates die due to respiratory failure that is caused by insufficient aeration, reduced septal thinning, reduced glycogenolysis, type II pneumocyte immaturity and reduced surfactant production. Expression analyses in embryonic day (E) 18.5 lungs identified KLEIP in lung capillaries, and showed strongly reduced mRNA and protein levels for Hif-2alpha and VEGF; such reduced levels are associated with embryonic endothelial cell apoptosis and lung bleedings. Betamethasone injection in pregnant females prevented respiratory failure in KLEIP(-/-) neonates, normalized lung maturation, vascularization, aeration and function, and increased neonatal Hif-2alpha expression. Thus, the experimental study shows that respiratory failure in KLEIP(-/-) neonates is determined by insufficient angiocrine Hif-2alpha-VEGF signaling and that betamethasone activates this newly identified signaling cascade in late-stage embryonic lung development. PMID- 24785086 TI - A pinch of salt is all it takes: chemistry at the frozen water surface. AB - Chemical interactions at the air-ice interface are of great importance to local atmospheric chemistry but also to the concentrations of pollutants deposited onto natural snow and ice. However, the study of such processes has been hampered by the lack of general, surface-specific probes. Even seemingly basic chemical properties, such as the local concentration of chemical compounds, or the pH at the interface, have required the application of assumptions about solute distributions in frozen media. The measurements that have been reported have tended for the most part to focus on entire ice or snow samples, rather than strictly the frozen interface with the atmosphere. We have used glancing-angle laser spectroscopy to interrogate the air-ice interface; this has yielded several insights into the chemical interactions there. The linear fluorescence and Raman spectra thus measured have the advantage of easy interpretability; careful experimentation can limit their probe depth to that which is relevant to atmospheric heterogeneous processes. We have used these techniques to show that the environment at the interface between air and freshwater ice surfaces is distinct from that at the interface between air and liquid water. Acids such as HCl that adsorb to ice surfaces from the gas phase result in significantly different pH responses than those at liquid water surfaces. Further, the solvation of aromatic species is suppressed at freshwater ice surfaces compared with that at liquid water surfaces, leading to extensive self-association of aromatics at ice surfaces. Photolysis kinetics of these species are much faster than at liquid water surfaces; this can sometimes (but not always) be explained by red shifts in the absorption spectra of self-associated aromatics increasing the extent to which solar radiation is absorbed. The environment presented by frozen saltwater surfaces, in contrast, appears to be reasonably well-described by liquid water. The extent of hydrogen bonding and the solvation of adsorbed species are similar at liquid water surfaces and at frozen saltwater surfaces. Adsorbed acids and bases evoke similar pH responses at frozen saltwater ice surfaces and liquid water surfaces, and photochemical kinetics of at least some aromatic compounds at frozen saltwater ice surfaces are well-described by kinetics in liquid water. These differences are not observed in experiments that interrogate the entire ice sample (i.e., that do not distinguish between processes occurring in liquid regions within bulk ice and those at the air-ice interface). Our work has shown that in general, the chemistry occurring at salty frozen interfaces is well described as being cold aqueous chemistry, whereas that seen at the pure ice interface is not. These findings have significant implications for heterogeneous atmospheric processes in ice-covered environments. PMID- 24785087 TI - Tandem Michael addition-ring transformation reactions of 3-hydroxyoxindoles/3 aminooxindoles with olefinic azlactones: direct access to structurally diverse spirocyclic oxindoles. AB - An efficient method for the direct construction of two classes of spirocyclic oxindoles by the reactions of 3-hydroxyoxindoles/3-aminooxindoles and (Z) olefinic azlactones through a tandem Michael addition-ring transformation process has been developed. With DBU as the catalyst, a range of spiro butyrolactoneoxindoles and spiro-butyrolactamoxindoles, containing an oxygen or a nitrogen heteroatom, respectively, in the spiro stereocenter, were smoothly obtained with good to excellent diastereoselectivities in high yields. PMID- 24785088 TI - Thymine vanadyl(II) compound as a diabetic drug model: chemical spectroscopic and antimicrobial assessments. AB - The aim of this study was to synthesize a novel bifunctionalized thymine vanadyl(II) compound. The solid vanadyl(II) compound has been characterized by elemental analyses (CHN), Raman laser, infrared spectra, molar conductivity, electronic spectra, thermogravimetric analyses (TGA), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD) studies. Electronic and magnetic measurements have confirmed that the speculated geometry of vanadyl(II) compound is square pyramidal geometry. The microbial test was performed for the vanadyl complex against some kinds of bacteria and fungi. The results suggested that [VO(Thy)2] adduct has an anti-diabetic profile. PMID- 24785090 TI - Raman spectra of oriented and non-oriented Cu hydroxy-phosphate minerals: libethenite, cornetite, pseudomalachite, reichenbachite and ludjibaite. AB - Oriented cornetite [Cu3PO4(OH)3], libethenite [Cu2PO4(OH)] and pseudomalachite [Cu5(PO4)2(OH)4] and non-oriented reichenbachite [Cu5(PO4)2(OH)4] and ludjibaite [Cu5(PO4)2(OH)4] minerals from Lubietova and Spania Dolina dump fields, Banska Bystrica, Slovakia were examined by polarized Raman spectroscopy. The examined minerals display the characteristic vibrational modes of PO4 and OH groups and further lattice modes. The PO4 stretching and bending vibrations of the investigated minerals occur between 1150 and 900 cm(-1) and between 700 and 350 cm(-1), respectively. On the other hand, the hydroxyl group stretching and bending modes appear above 3350 cm(-1) and between 900 and 700 cm(-1), respectively. The lattice vibrations occur below 350 cm(-1). The different bond distances of the PO4 groups readily explain the shift of the bands to higher or lower wavenumbers among the studied Cu hydroxy-phosphate minerals. PMID- 24785089 TI - Quantum chemical vibrational study, molecular property, FTIR, FT-Raman spectra, NBO, HOMO-LUMO energies and thermodynamic properties of 1-methyl-2-phenyl benzimidazole. AB - The solid phase FT-IR and FT-Raman spectra of 1-methyl-2-phenyl benzimidazole (MPBZ) have been recorded in the condensed state. In this work, experimental and theoretical study on the molecular structure, quantum chemical calculations of energies and vibrational wavenumbers of MPBZ is presented. The vibrational frequencies of the title compound were obtained theoretically by DFT/B3LYP calculations employing the standard 6-311+G(d,p) and 6-311++G(d,p) basis set for optimized geometry and were compared with Fourier transform infrared spectrum (FTIR) in the region of 4000-400 cm(-1) and with Fourier transform Raman spectrum in the region of 4000-100 cm(-1). Complete vibrational assignments, analysis and correlation of the fundamental modes for the title compound were carried out. The vibrational harmonic frequencies were scaled using scale factor, yielding a good agreement between the experimentally recorded and the theoretically calculated values. The study is extended to calculate the HOMO-LUMO energy gap, NBO, mapped molecular electrostatic potential (MEP) surfaces, polarizability, Mulliken charges and thermodynamic properties of the title compound. PMID- 24785091 TI - Computational studies of the first order kinetic reactions for mononuclear copper(II) complexes having a hard-soft NS donor ligand. AB - The chelation behaviour of 4-((E)-2-(1-(thiophen-2-yl)ethylidene)hydrazinyl)-1-(4 methoxyphenyl)-1H-pyrrole-3-carbonitrile (HL) towards Cu(II) ions has been investigated. These Cu(II) complexes are characterized by elemental analyses, molar-solid conductance, ESR, FTIR and electronic spectral studies. Also, the kinetic and thermodynamic parameters (Ea, A, DeltaH, DeltaS, DeltaG) for all thermal decomposition steps have been evaluated using Coats-Redfern and Horowitz Metzger methods. Furthermore, antimicrobial activity of the ligand and its complexes were studied against Gram-negative bacteria: Escherichia coli, Gram positive Bacillus cereus, Bacillus subtilis and pathogenic fungi Pseudomonas aeruginosa by using minimum inhibitory concentrations (MICs) method. PMID- 24785092 TI - Raman and IR studies and DFT calculations of the vibrational spectra of 2,4 Dithiouracil and its cation and anion. AB - Raman and FTIR spectra of solid 2,4-Dithiouracil (DTU) at room temperature have been recorded. DFT calculations were carried out to compute the optimized molecular geometries, GAPT charges and fundamental vibrational frequencies along with their corresponding IR intensities, Raman activities and depolarization ratios of the Raman bands for the neutral DTU molecule and its cation (DTU+) and anion (DTU-) using the Gaussian-03 software. Addition of one electron leads to increase in the atomic charges on the sites N1 and N3 and decrease in the atomic charges on the sites S8 and S10. Due to ionization of DTU molecule, the charge at the site C6 decreases in the cationic and anionic radicals of DTU as compared to its neutral species. As a result of anionic radicalization, the C5C6 bond length increases and loses its double bond character while the C4C5 bond length decreases. In the case of the DTU+ ion the IR and Raman band corresponding to the out-of-phase coupled NH stretching mode is strongest amongst the three species. The anionic DTU radical is found to be the most stable. The two NH out-of-plane bending modes are found to originate due to out-of-phase and in-phase coupling of the two NH bonds in the anion and cation contrary to the case of the neutral DTU molecule in which the out-of-plane bending motions of the two NH bonds are not coupled. PMID- 24785093 TI - Experimental and computational study on 2,2'-[(1E,2E)-hydrazine-1,2 diylidenedi(1E)eth-1-yl-1-ylidene]diphenol and its Ni(II), Pt(II), Pd(II) complexes. AB - 2,2'-[(1E,2E)-hydrazine-1,2-diylidenedi(1E)eth-1-yl-1-ylidene]diphenol and its dimeric, binuclear Ni(II), Pd(II) and Pt(II) metal complexes were synthesized. Hydrazine derivative and its complexes were characterized by elemental analyses, LC-MS, IR, electronic spectra, (1)H and (13)C NMR spectra, conductivity and magnetic measurements. 1H and 13C shielding tensors for crystal structure were calculated with GIAO/DFT/B3LYP/6-311++G(d,p) methods in CDCl3. The vibrational band assignments were performed at B3LYP/6-311++G(d,p) theory level combined with scaled quantum mechanics force field (SQMFF) methodology. The antibacterial activities of synthesized compounds were studied against some Gram-positive and Gram-negative bacteria by using the microdilution and disk diffusion method. As the antibacterial activity results evidently show, the compound possessed a broad spectrum of activity against the tested bacteria. PMID- 24785094 TI - A solvatochromic study of N-[4-(9-acridinylamino)-3 methoxyphenyl]methanesulfonamide hydrochloride: an experimental and theoretical approach. AB - The effects of a solvent on the position of the long-wavelength electronic absorption band of N-[4-(9-acridinylamino)-3-methoxyphenyl]methanesulfonamide hydrochloride [m-AMSA.HCl], an antitumor drug, were investigated. To assess the nature of molecular interactions of protonated m-AMSA (1) with various organic solvents the solvatochromic shifts of absorption maxima (nu?A) with (i) traditionally used bulk solvent polarity functions (Deltaf and F(epsilon, n)) and (ii) empirical scales of solvent polarity (Z, chiB and ETN) were analyzed. Additionally, in order to investigate the influence of non-specific and specific solute-solvent interactions on absorption band shifts in protic solvents the multicomponent linear regression with two Kamlet-Taft's solvatochromic parameters (pi* and alpha) was used. The nu?A in solvents were also obtained using theoretical calculations with the AM1-SM5.4 method and compared with experimental values. Finally, all the results show that in aprotic solvents there are general dipolarity/polarizability effects, while in protic solvents specific interactions connected with the formation of hydrogen bonds are additionally observed. PMID- 24785095 TI - OPG and PgR show similar cohort specific effects as prognostic factors in ER positive breast cancer. AB - The RANK/RANKL/OPG pathway is well known for bone destruction in skeletal metastases but has also been implicated in osteoclast-independent roles in tumorigenesis and de novo metastasis. Experimental data suggest contribution of progesterone to tumorigenesis may be mediated by RANKL. Importantly, modulation of this pathway became possible through the availability of denosumab, an artificial counterpart of OPG, but significant gaps remain in the translation of preclinical findings on the pathway. We analyzed gene expression of RANK, RANKL and OPG from 40 Affymetrix datasets encompassing 4467 primary breast cancers and focused on ER positive disease. We did not observe a significant prognostic value of RANK and RANKL mRNA expression. In contrast, OPG was associated with a better prognosis among 1941 ER positive cancers (HR 0.64, 95% CI 0.53-0.77; P < 0.0001) using a cutoff from its highly bimodal expression. We detected considerable heterogeneity regarding the prognostic value of OPG between different datasets. This heterogeneity could neither be attributed to technical reasons nor to differences in standard clinical parameters or treatments of the cohorts. Interestingly, the prognostic value of the progesterone receptor and of OPG showed similar cohort specific effects. Still both factors were no surrogates for each other but contributed independent prognostic value in multivariate analyses. Thus, both OPG and PgR are independently associated with good prognosis in ER positive breast cancer. However both markers share common cohort specific differences in contrast to proliferation markers as Ki67 which may be based on the underlying biology. PMID- 24785096 TI - Breast cancer prognosis predicted by nuclear receptor-coregulator networks. AB - Although molecular signatures based on transcript expression in breast cancer samples have provided new insights into breast cancer classification and prognosis, there are acknowledged limitations in current signatures. To provide rational, pathway-based signatures of disrupted physiology in cancer tissues that may be relevant to prognosis, this study has directly quantitated changed gene expression, between normal breast and cancer tissue, as a basis for signature development. The nuclear receptor (NR) family of transcription factors, and their coregulators, are fundamental regulators of every aspect of metazoan life, and were rigorously quantified in normal breast tissues and ERalpha positive and ERalpha negative breast cancers. Coregulator expression was highly correlated with that of selected NR in normal breast, particularly from postmenopausal women. These associations were markedly decreased in breast cancer, and the expression of the majority of coregulators was down-regulated in cancer tissues compared with normal. While in cancer the loss of NR-coregulator associations observed in normal breast was common, a small number of NR (Rev-ERBbeta, GR, NOR1, LRH-1 and PGR) acquired new associations with coregulators in cancer tissues. Elevated expression of these NR in cancers was associated with poorer outcome in large clinical cohorts, as well as suggesting the activation of ERalpha -related, but ERalpha-independent, pathways in ERalpha negative cancers. In addition, the combined expression of small numbers of NR and coregulators in breast cancer was identified as a signature predicting outcome in ERalpha negative breast cancer patients, not linked to proliferation and with predictive power superior to existing signatures containing many more genes. These findings highlight the power of predictive signatures derived from the quantitative determination of altered gene expression between normal breast and breast cancers. Taken together, the findings of this study identify networks of NR coregulator associations active in normal breast but disrupted in breast cancer, and moreover provide evidence that signatures based on NR networks disrupted in cancer can provide important prognostic information in breast cancer patients. PMID- 24785097 TI - RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC). AB - Ral (Ras like) leads an important proto-oncogenic signaling pathway down-stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non-malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl-geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR-Knockout) also revealed an elevated level of RalA-GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention. PMID- 24785098 TI - Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia. AB - Skeletal muscle is the most abundant body tissue accounting for many physiological functions. However, muscle mass and functions are not routinely assessed. Sarcopenia is defined as skeletal muscle loss and dysfunction in aging and chronic diseases. Inactivity, inflammation, age-related factors, anorexia and unbalanced nutrition affect changes in skeletal muscle. Mechanisms are difficult to distinguish in individual subjects due to the multifactorial character of the condition. Sarcopenia includes both muscle loss and dysfunction which induce contractile impairment and metabolic and endocrine abnormalities, affecting whole body metabolism and immune/inflammatory response. There are different metabolic trajectories for muscle loss versus fat changes in aging and chronic diseases. Appetite regulation and physical activity affect energy balance and changes in body fat mass. Appetite regulation by inflammatory mediators is poorly understood. In some patients, inflammation induces anorexia and fat loss in combination with sarcopenia. In others, appetite is maintained, despite activation of systemic inflammation, leading to sarcopenia with normal or increased BMI. Inactivity contributes to sarcopenia and increased fat tissue in aging and diseases. At the end of the metabolic trajectories, cachexia and sarcopenic obesity are paradigms of the two patient categories. Pre-cachexia and cachexia are observed in patients with cancer, chronic heart failure or liver cirrhosis. Sarcopenic obesity and sarcopenia with normal/increased BMI are observed in rheumatoid arthritis, breast cancer patients with adjuvant chemotherapy and in most of patients with COPD or chronic kidney disease. In these conditions, sarcopenia is a powerful prognostic factor for morbidity and mortality, independent of BMI. PMID- 24785099 TI - Multifocal Necrotizing Chorioretinitis Following Phacoemulsification Surgery. AB - INTRODUCTION: Toxoplasma chorioretinitis is a leading cause of infectious posterior uveitis worldwide. METHODS: We report an atypical presentation of Toxoplasma chorioretinitis presenting after uneventful cataract surgery in an 81 year-old male, with known hypernephroma and rheumatoid arthritis, treated with prednisolone and methotrexate. RESULTS: He was treated for acute retinal necrosis and cytomegalovirus retinitis before Toxoplasma chorioretinitis was confirmed by vitreous biopsy 11 months after presentation. He developed a secondary rhegmatogenous retinal detachment, treated successfully with pars plana vitrectomy, silicone oil and endolaser. Visual acuity at discharge was 6/12 following silicone oil removal. DISCUSSION: Necrotising chorioretinitis in immunosuppressed or elderly patients may present with an atypical phenotype. Clinical diagnosis in this context remains challenging. We discuss the clinical reasoning behind investigation and management of this patient group in whom viral and Toxoplasma retinitis may be clinically indistinguishable. The significance of vitreous PCR results in clinical decision making in the context of infectious posterior uveitis is discussed. PMID- 24785100 TI - Immunohistochemical analysis of tau phosphorylation and astroglial activation with enhanced leptin receptor expression in diet-induced obesity mouse hippocampus. AB - Accumulating evidence indicates that obesity is an independent risk factor for developing Alzheimer disease (AD). Recent studies have shown that diet-induced obesity (DIO) enhances AD-related pathologies in transgenic mouse models of the disease. DIO increases amyloid beta (Abeta) deposition in amyloidogenic transgenic mice and enhances tau phosphorylation in tau transgenic mice. However, it remains unclear whether DIO also enhances AD-related pathological processes in wild-type (WT) mice. In this study, we examined the effects of DIO on Abeta and tau pathology in WT mice using immunohistochemistry. In addition, we evaluated the protective effect of voluntary exercise on the DIO-induced pathological changes. DIO caused tau phosphorylation and astroglial activation in the hippocampus in WT mice. Interestingly, these changes were associated with enhanced astrocytic leptin receptor (LepR) expression and mild microgliosis, but not Abeta accumulation. Although phosphorylated tau staining was only observed in the hippocampus, astrogliosis and microgliosis were present in both the amygdala and hippocampus. However, no apparent neuronal loss was observed. Voluntary exercise prevented these DIO-induced pathological changes. Our results demonstrate for the first time that DIO causes tau phosphorylation and that astrocytic LepR might be involved in the pathological process in WT mouse hippocampus. Our findings also suggest that physical exercise is a promising strategy for the prevention of AD in patients with obesity. PMID- 24785101 TI - Phosphorylated alpha-synuclein-immunoreactive retinal neuronal elements in Parkinson's disease subjects. AB - Visual symptoms are relatively common in Parkinson's disease (PD) and optical coherence tomography has indicated possible retinal thinning. Accumulation of aggregated alpha-synuclein is thought to be a central pathogenic event in the PD brain but there have not as yet been reports of retinal synucleinopathy. Retinal wholemounts were prepared from subjects with a primary clinicopathological diagnosis of PD (N=9), dementia with Lewy bodies (DLB; N=3), Alzheimer's disease (N=3), progressive supranuclear palsy (N=2) as well as elderly normal control subjects (N=4). These were immunohistochemically stained with an antibody against alpha-synuclein phosphorylated at serine 129, which is a specific molecular marker of synucleinopathy. Phosphorylated alpha-synuclein-immunoreactive (p-syn IR) nerve fibers were present in 7/9 PD subjects and in 1/3 DLB subjects; these were sparsely distributed and superficially located near or at the inner retinal surface. The fibers were either long and straight or branching, often with multiple en-passant varicosities along their length. The straight fibers most often had an orientation that was radial with respect to the optic disk. Together, these features are suggestive of either retinopetal/centrifugal fibers or of ganglion cell axons. In one PD subject there were sparse p-syn IR neuronal cell bodies with dendritic morphology suggestive of G19 retinal ganglion cells or intrinsically photosensitive ganglion cells. There were no stained nerve fibers or other specific staining in any of the non-PD or non-DLB subjects. It is possible that at least some of the observed visual function impairments in PD subjects might be due to alpha-synucleinopathy. PMID- 24785102 TI - Effects of pregnancy on obesity-induced inflammation in a mouse model of fetal programming. AB - OBJECTIVE: Maternal obesity is associated with increased risk of metabolic dysfunction in the offspring. It is not clear whether it is the metabolic changes or chronic low-grade inflammation in the obese state that causes this metabolic programming. We therefore investigated whether low-grade inflammation was present in obese dams compared with controls dams at gestation day 18 (GD18). METHODS: Female mice were fed either a standard chow diet or a highly palatable obesogenic diet for 6 weeks before conception. Mice were either kileed before mating (n=12 in each group) or on GD18 (n=8 in each group). Blood and tissues were collected for analysis. RESULTS: The obesogenic diet increased body weight and decreased insulin sensitivity before conception, while there was no difference between the groups at GD18. Local inflammation was assayed by macrophage count in adipose tissue (AT) and liver. Macrophage count in the AT was increased significantly by the obesogenic diet, and the hepatic count also showed a tendency to increased macrophage infiltration before gestation. This was further supported by a decreased population of monocytes in the blood of the obese animals, which suggested that monocytes are being recruited from the blood to the liver and AT in the obese animals. Gestation reversed macrophage infiltration, such that obese dams showed a lower AT macrophage count at the end of gestation compared with pre pregnancy obese mice, and there were no longer a tendency toward increased hepatic macrophage count. Placental macrophage count was also similar in the two groups. CONCLUSION: At GD18, obese dams were found to have similar macrophage infiltration in placenta, AT and liver as lean dams, despite an incipient infiltration before gestation. Thus, the obesity-induced inflammation was reversed during gestation. PMID- 24785104 TI - Reply to Armani et al. Can cortisol stimulate adipogenesis without the glucocorticoid receptor? PMID- 24785103 TI - Relatively low endogenous fatty acid mobilization and uptake helps preserve insulin sensitivity in obese women. AB - BACKGROUND: Although obesity is commonly linked with metabolic disease risk, some obese adults do not develop metabolic abnormalities, such as insulin resistance. OBJECTIVES: The primary aim of this study was to determine whether alterations in fatty acid mobilization and uptake underlie differences in insulin sensitivity (Si) among a seemingly homogeneous cohort of obese women. METHODS: Insulin sensitivity (frequently sampled intravenous glucose tolerance test), basal fatty acid rate of disappearance from plasma (Rd), resting whole-body fat oxidation, intramyocellular triacylglycerol (IMTG) concentration and markers of skeletal muscle inflammation were measured in 21 obese women. Participants were divided into tertiles based on their S(i). The subset of participants with the lowest S(i) (LOW-S(i); S(i) ? 2.1 (mU/l)(-1) min(-1); n = 7) was compared with the subset of participants with the highest S(i), who exhibited relatively normal insulin sensitivity (NORM-S(i); S(i) ? 3.4 (mU/l)(-1) min(-1); n = 8). RESULTS: Despite nearly identical physical characteristics in LOW-S(i) vs NORM-S(i) (body mass index: 34 +/- 2 vs 34 +/- 1 kg m(-2); %body fat: 48 +/- 1 vs 47 +/- 1%; waist circumference: 104 +/- 2 vs 104 +/- 2 cm; VO2 max: 2.2 +/- 0.2 vs 2.3 +/- 0.1 l min(-1)), fatty acid Rd was nearly 30% lower in NORM (P=0.02). Importantly, the greater rate of fatty acid uptake in LOW-S(i) vs NORM-S(i) did not translate to higher rate of fat oxidation (3.5 +/- 0.2 vs 3.7 +/- 0.2 MUmol kg(-1) min(-1)) or to a measureable difference in IMTG content (68.3 +/- 12.7 vs 63.7 +/- 6.7 MUmol g(-1) dry weight). In conjunction with the lower fatty acid Rd in NORM-S(i) vs LOW-S(i), activation of inflammatory pathways known to impair insulin action in skeletal muscle was also lower (lower phosphorylated c-jun N-terminal kinase (JNK) and higher inhibitor of kappaB (IkappaB-alpha) abundance). In contrast, LOW S(i) and NORM-S(i) exhibited no differences in plasma markers of inflammation (TNFalpha, IL-6 (interleukin-6), MCP-1). CONCLUSION: These findings suggest that obese women who maintain a relatively low rate of endogenous fatty acid uptake may be somewhat 'protected' against the development of insulin resistance potentially by less activation of inflammatory pathways within skeletal muscle. PMID- 24785105 TI - Foot-and-mouth disease: technical and political challenges to eradication. AB - Foot-and-mouth disease (FMD) is a highly-contagious livestock disease with global socioeconomic ramifications. The disease negatively impacts both individual farmers through reduced herd viability and nations through trade restrictions of animals and animal derivatives. Vaccines for FMD prevention have existed for over 70 years, yet the disease remains enzootic in a large percentage of the globe. FMD persistence is due in part to technical limitations of historic and current vaccine technologies. There also exist many socioeconomic and political barriers to global FMD eradication. Here we highlight the barriers to eradication and discuss potential avenues toward FMD eradication. PMID- 24785106 TI - Label-free aptasensor based on ultrathin-linker-mediated hot-spot assembly to induce strong directional fluorescence. AB - We have demonstrated the proof-of-concept of a label-free biosensor based on emission induced by an extreme hot-spot plasmonic assembly. In this work, an ultrathin linking layer composed of cationic polymers and aptamers was fabricated to mediate the assembly of a silver nanoparticles (AgNPs)-dyes-gold film with a strongly coupled architecture through sensing a target protein. Generation of directional surface plasmon coupled emission (SPCE) was thus stimulated as a means of reporting biorecognition. Both the biomolecules and the nanoparticles were totally free of labeling, thereby ensuring the activity of biomolecules and allowing the use of freshly prepared metallic nanoparticles with large dimensions. This sensor smartly prevents the plasmonic assembly in the absence of targets, thus maintaining no signal through quenching fluorophores loaded onto a gold film. In the presence of targets, the ultrathin layer is activated to link NPs-film junctions. The small gap of the junction (no greater than 2 nm) and the large diameter of the nanoparticles (~100 nm) ensure that ultrastrong coupling is achieved to generate intense SPCE. A >500-fold enhancement of the signal was observed in the biosensing. This strategy provides a simple, reliable, and effective way to apply plasmonic nanostructures in the development of biosensing. PMID- 24785107 TI - Importance of proapoptotic protein PUMA in cell radioresistance. AB - Protein p53 plays an essential role in the induction of apoptosis by ionizing radiation in haemopoietic cells, the damage of which is the main reason for the development of bone marrow post-irradiation syndrome. p53 activation leads to an increase in the Bcl-2 family pro-apoptotic protein PUMA level. PUMA inhibits all the five anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-XL, Bcl-W and A1) and directly triggers apoptosis mediated by pro-apoptotic proteins Bax/Bak. In proliferating cells, knockout of p53 inhibits apoptosis on the one hand, but on the other disables the cellular division arrest moderated by p21Cip1/Waf1. The radioprotective effect of p53 inhibitor pifithrin was obvious at radiation doses causing the bone marrow syndrome. Knockout of PUMA also exerts its radioprotective effect through blocking the apoptosis induction, but the arrest of cells in the cell cycle through p21 induction is not abolished. PUMA -/- mice are radioresistant in terms of the development of post-irradiation syndrome after all radiation doses. Small molecules are being searched for that could prevent binding of PUMA with Bcl-2 family anti-apoptotic proteins. This would result in apoptosis inhibition and radioprotective or mitigating effects of these inhibitors. PMID- 24785108 TI - Wnt5a influences viability, migration, adhesion, colony formation, E- and N cadherin expression of human ovarian cancer cell line SKOV-3. AB - Epithelial ovarian cancer (EOC) cells express Wnt5a, but its role in ovarian cancer progression is poorly defined. The aims of the present study were two fold: 1) to determine the Wnt5a role in viability, apoptosis, migration, colony formation and adhesion of human serous epithelial ovarian cancer cell line SKOV 3, and 2) to assess the relationship of Wnt5a with E- and N-cadherin in high- and low-grade human serous ovarian cancer specimens. Wnt5a over-expression led to 29% increased serum-independent cell viability (P < 0.05) and 35% decreased caspase-3 activity (P < 0.01) compared to SKOV-3 cells. There was 96% (P < 0.001) increased cell motility in Wnt5a-transfected SKOV-3 (SKOV-3/Wnt5a) cells compared to SKOV 3, which was abrogated in the presence of JNK inhibitor. In addition, there was about 42% increased cell adhesion to Matrigel compared to SKOV-3 cells (P < 0.001). Colony-forming assay showed a 4.4-fold increased colony formation in SKOV 3/Wnt5a cells compared to SKOV-3 cells (P < 0.001). E- and N-cadherin levels were reduced by 49 % and 67 % in SKOV-3/Wnt5a cells compared to mock cells, respectively. Wnt5a and E-cadherin immunoexpression was significantly (P < 0.001) different in low-grade serous ovarian cancer (LGSC) and high-grade serous ovarian cancer (HGSC). In HGSC specimens, strong immunoexpression of Wnt5a was detected compared to LGSC. However, E-cadherin showed moderate immunostaining (84 %) in HGSC, whereas 100 % of LGSC specimens showed strong immunoexpression. In both groups no N-cadherin immunoexpression was detected. Moreover, Wnt5a showed a positive relationship with E-cadherin in the LGSC group (r = 0.661, P = 0.027). These results may support important roles for Wnt5a in EOC progression. PMID- 24785109 TI - Expression levels of elastin and related genes in human varicose veins. AB - Among the suspected reasons for varicose vein formation are changes in the quantity and content of the elastin protein; however, comprehensive investigations about elastin assembly in varicose vein formation are yet lacking. In this study, we aimed to determine the changes in mRNA levels of elastin and some of its functionally related proteins, fibulin 5, LOXL-1, MMP-2 and MMP-9 in varicose vein formation. We analysed the mRNA levels of elastin, fibulin-5, LOXL1, MMP2 and MMP9 in samples of 35 healthy and 35 varicose great saphenous vein tissues. mRNA levels of these genes were determined by using real-time PCR and normalized with HPRT1. When we compared the patient and control groups, elastin mRNA levels were significantly higher in the patient group than in the control group (P = 0.047), although there were no significant differences in fibulin 5, LOXL1, MMP2 and MMP9 mRNA levels between the patient and control groups. We showed that up-regulation of MMP2 mRNA expression was significantly correlated with hyperlipidaemia (P = 0.029). The up-regulation of elastin expression may play an important role in the pathogenesis of primary varicose veins. Additionally, the up-regulation of MMP2 expression was strongly correlated with hyperlipidaemia in varicose veins. PMID- 24785110 TI - Gene expression of subunits of the IL-12 family cytokines in moDCs derived in vitro from the cord blood of children of healthy and allergic mothers. AB - The incidence of allergic diseases is steadily increasing an urgent need to clarify the immunologic processes which occur early in life and signal an increased risk of possible future allergy development. The ratio and maturation state of DCs together with the cytokine environment are important in directing and modulating immune responses. The maturation state (presence of CD83) of cord blood monocyte-derived dendritic cells (moDCs) of 52 children of healthy mothers and 58 children of allergic mothers was estimated by flow cytometry. The capacity of moDCs to express genes for subunits of IL-12 family cytokines was monitored using real-time PCR and protein secretion in cell culture supernatants by ELISA. The percentage of CD83+ moDCs was significantly higher in the allergic group after LPS stimulation (43.11 +/- 4.41) in comparison to the healthy group (24.85 +/- 3.37). Significantly higher gene expression of subunits of IL-12 family members was observed in moDCs of children of allergic mothers, in comparison with children of healthy mothers. The differences were evident mainly after LPS stimulation of moDCs (healthy group: p19: 3.05 +/- 1.24; p28: 14.8 +/- 6.8; p35: 1.8 +/- 0.6; p40: 8.0 +/- 3.5; EBI3: 3.0 +/- 1.2; allergic group: p19: 6.1 +/- 2.7; p28: 61.4 +/- 22.2; p35: 14.9 +/- 6.5; p40: 36.4 +/- 18.8; EBI3: 11.3 +/- 3.2), with the exception of p28, whose expression was significantly higher in the allergic group even without stimulation (healthy group: 0.28 +/- 0.12, allergic group: 0.87 +/- 0.62). No significant difference between the healthy and allergic groups was found at the protein level. The observation of both increased presence of cell surface activation marker on moDCs and higher IL-12 family gene expression in LPS-stimulated moDCs of children of allergic mothers indicates a higher reactivity of these cells. PMID- 24785111 TI - MTHFR and HFE, but not preproghrelin and LBP, polymorphisms as risk factors for all-cause end-stage renal disease development. AB - End-stage renal disease (ESRD) is a serious health problem worldwide. The high prevalence of cardiovascular diseases and chronic inflammation remains a major cause of morbidity and mortality in haemodialysed patients. Beside some external factors, genetic predisposition both to renal failure and poor prognosis has been assumed. We have collected a total of 1,014 haemodialysed patients and 2,559 unrelated healthy Caucasians. Single-nucleotide polymorphisms (SNPs) in genes for preproghrelin (GHRL), lipopolysaccharide-binding protein (LBP), HFE and MTHFR were genotyped. In the group of patients, significantly more carriers presented the MTHFR T667T (P = 0.002) and HFE Asp63Asp (P = 0.001) and Cys282Cys (P = 0.01) genotypes. The frequencies of individual SNPs within GHRL and LBP genes did not differ between the patients and controls. The trends in genotype frequencies did not differ between the subgroups of patients with different time on haemodialysis. Common variants in MTHFR and HFE could be a risk factor for all cause ESRD development, but are not predictors for the survival on haemodialysis. PMID- 24785112 TI - Effects of depsidones from Hypogymnia physodes on HeLa cell viability and growth. AB - The anti-proliferative activitiy of Hypogymnia physodes methanol extracts (ME) and its main constituents, physodalic acid (P1), physodic acid (P2), and 3 hydroxy physodic acid (P3), was tested on human cancer HeLa cell lines. Three lichen depsidones, P1, P2 and P3, were isolated from H. physodes ME using column chromatography and their structures were determined by UV, ESI TOF MS, 1H and 13C NMR. The content of P1, P2 and P3 in ME was determined using reversed-phase highperformance liquid chromatography with photodiode array detection. P1-3 represented even 70 % of the studied extract. The HeLa cells were incubated during 24 and 72 h in the presence of ME and depsidones P1, P2 and P3, at concentrations of 10-1000 MUg/ml. Compounds P2 and P3 showed higher activity than compound P1. Half maximal inhibitory concentrations (IC50, MUg/ml) of P1, P2, P3 and ME for 24-h incubation were 964, 171, 97 and 254 MUg/ml, respectively, while for 72-h incubation they were 283, 66, 63 and 68 MUg/ml. As far as we know, this is the first report on the effect of H. physodes ME and their depsidones on HeLa cells. PMID- 24785113 TI - Atomistic modeling of mechanical properties of polycrystalline graphene. AB - We performed molecular dynamics (MD) simulations to investigate the mechanical properties of polycrystalline graphene. By constructing molecular models of ultra fine-grained graphene structures, we studied the effect of different grain sizes of 1-10 nm on the mechanical response of graphene. We found that the elastic modulus and tensile strength of polycrystalline graphene decrease with decreasing grain size. The calculated mechanical proprieties for pristine and polycrystalline graphene sheets are found to be in agreement with experimental results in the literature. Our MD results suggest that the ultra-fine-grained graphene structures can show ultrahigh tensile strength and elastic modulus values that are very close to those of pristine graphene sheets. PMID- 24785114 TI - Hematopoietic stem cell transplantation in older persons: respecting the heterogeneity of age. AB - Demographic trends establish that older adults are the fastest growing segment of population, with over 19% of the population expected to be aged >65 years by 2030. As the risk for hematologic malignancies increases with age, it is imperative that our field continues to strive to individualize and manage risk and benefit in an aging population. While hematologic diseases are more common in the elderly, only a small minority of patients with hematological malignancy aged >65 years receive allogeneic hematopoietic cell transplantation, relative to the burden of disease in this population. In this editorial we explore some of the obstacles to transplantation, the rationale to consider the procedure in the older adult and ways that the stem cell consultative process can be individualized. Finally, we outline key areas where additional research is needed. PMID- 24785115 TI - Genetic diagnosis of familial hypercholesterolaemia by targeted next-generation sequencing. AB - OBJECTIVES: The aim of this study was to combine clinical criteria and next generation sequencing (pyrosequencing) to establish a diagnosis of familial hypercholesterolaemia (FH). DESIGN, SETTING AND SUBJECTS: A total of 77 subjects with a Dutch Lipid Clinic Network score of >= 3 (possible, probable or definite FH clinical diagnosis) were recruited from the Lipid Clinic at Sahlgrenska Hospital, Gothenburg, Sweden. Next-generation sequencing was performed in all subjects using SEQPRO LIPO RS, a kit that detects mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLR adapter protein 1 (LDLRAP1) genes; copy number variations in the LDLR gene were also examined. RESULTS: A total of 26 mutations were detected in 50 subjects (65% success rate). Amongst these, 23 mutations were in the LDLR gene, two in the APOB gene and one in the PCSK9 gene. Four mutations with unknown pathogenicity were detected in LDLR. Of these, three mutations (Gly505Asp, Ile585Thr and Gln660Arg) have been previously reported in subjects with FH, but their pathogenicity has not been proved. The fourth, a mutation in LDLR affecting a splicing site (exon 6-intron 6) has not previously been reported; it was found to segregate with high cholesterol levels in the family of the proband. CONCLUSIONS: Using a combination of clinical criteria and targeted next-generation sequencing, we have achieved FH diagnosis with a high success rate. Furthermore, we identified a new splicing-site mutation in the LDLR gene. PMID- 24785117 TI - How we do it: the absorbable gelatin sponge cube, an effective and economical approach to packing in ear surgery. AB - INTRODUCTION: There is currently a lack of robust evidence on the best form of packing for otological surgery. We describe the use of the absorbable gelatin sponge, a packing material that does not require removal and has the benefit of being considerably cheaper compared to other common forms of ear packing. METHODS: A comparison was made of the financial cost of several forms of packing for common otological procedures. In addition, a retrospective audit of complications was undertaken of all patients in whom the absorbable gelatin sponge was used over the past three years. RESULTS: The absorbable gelatin sponge was shown to be cheaper to purchase per unit and also more economical to use. It has been the exclusive form of packing used in 519 procedures over the past three years at the William Harvey Hospital in Ashford (UK), with very few complications noted at the follow-up review. CONCLUSION: We strongly advocate using the absorbable gelatin sponge, a packing material that is kinder to the patient, has similar efficacy to other forms of packing and is also much cheaper to use compared to other common forms of packing. PMID- 24785118 TI - Scheduling for anesthesia at geographic locations remote from the operating room. AB - PURPOSE OF REVIEW: Providing general anesthesia at locations away from the operating room, called remote locations, poses many medical and scheduling challenges. This review discusses how to schedule procedures at remote locations to maximize anesthesia productivity (see Video, Supplemental Digital Content 1). RECENT FINDINGS: Anesthesia labour productivity can be maximized by assigning one or more 8-h or 10-h periods of allocated time every 2 weeks dedicated specifically to each remote specialty that has enough cases to fill those periods. Remote specialties can then schedule their cases themselves into their own allocated time. Periods of allocated time (called open, unblocked or first come first served time) can be used by remote locations that do not have their own allocated time. Unless cases are scheduled sequentially into allocated time, there will be substantial extra underutilized time (time during which procedures are not being performed and personnel sit idle even though staffing has been planned) and a concomitant reduction in percent productivity. Allocated time should be calculated on the basis of usage. SUMMARY: Remote locations with sufficient hours of cases should be allocated time reserved especially for them in which to schedule their cases, with a maximum waiting time of 2 weeks, to achieve an average wait of 1 week. PMID- 24785119 TI - Anesthesia for bronchoscopy. AB - PURPOSE OF REVIEW: To discuss the recent advances in sedation and anesthesia for the practice of both flexible and rigid bronchoscopy, which are increasingly performed outside of the operating room by interventional pulmonologists and thoracic surgeons. RECENT FINDINGS: Studies have recently documented the advantages of pharmacological sedatives and anesthetics for use in bronchoscopy. In particular, we review the increasing body of literature highlighting the advantages and benefits of propofol anesthesia for both flexible and rigid bronchoscopy. SUMMARY: As our practice expands, relocation of appropriately triaged pulmonary interventional procedures including rigid bronchoscopy that were previously assigned to a traditional operating room setting improves provider flexibility, presents more cost-effective options while maintaining patient safety and satisfaction and reducing the time to recovery. Anesthesia practice has, therefore, shifted to caring for these sick patients outside the operating room and increasingly cooperation between anesthesiologist and proceduralist is required. PMID- 24785116 TI - The junctional epithelium originates from the odontogenic epithelium of an erupted tooth. AB - The junctional epithelium (JE) is an epithelial component that is directly attached to the tooth surface and has a protective function against periodontal diseases. In this study, we determined the origin of the JE using a bioengineered tooth technique. We transplanted the bioengineered tooth germ into the alveolar bone with an epithelial component that expressed green fluorescence protein. The reduced enamel epithelium from the bioengineered tooth fused with the oral epithelium, and the JE was apparently formed around the bioengineered tooth 50 days after transplantation. Importantly, the JE exhibited green fluorescence for at least 140 days after transplantation, suggesting that the JE was not replaced by oral epithelium. Therefore, our results demonstrated that the origin of the JE was the odontogenic epithelium, and odontogenic epithelium-derived JE was maintained for a relatively long period. PMID- 24785120 TI - Measuring mental health literacy--a review of scale-based measures. AB - BACKGROUND: Mental Health Literacy (MHL) has become an important concept in the literature; however, quantitative research on MHL methodology has been limited. AIMS: This review identified peer-reviewed papers investigating MHL, assessed psychometric attributes of scale-based measures of MHL, and the extent that studies assessed the attributes that define MHL. METHOD: A comprehensive review of the literature was conducted to identify measures which generate a total MHL or subscale score was also conducted. A total of 13 studies were identified and their psychometric attributes determined using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN). The extent to which each measure assessed the attributes of MHL was also determined. RESULTS: Results showed that included studies failed to report detailed information about the sample, measure development and testing to demonstrate the psychometric properties of their tool. CONCLUSION: There are substantial limitations in current ability to measure MHL and there is significant scope for the development and evaluation of psychometrically robust measures that assess the relevant attributes of MHL. Further research could also focus on the adequacy of the current definition of MHL. PMID- 24785121 TI - Mild Rh(III)-catalyzed direct C-H bond arylation of (hetero)arenes with arylsilanes in aqueous media. AB - An efficient rhodium(III)-catalyzed C-H bond activation and further direct arylation of (hetero)arenes with organosilanes in aqueous media was developed. This reaction shows good substrate scope and excellent functional group compatibility and gives the products in good yields with excellent regioselectivity. PMID- 24785122 TI - Grazing increases the concentration of CLA in dairy cow milka. AB - An experiment was conducted to examine whether increased CLA in milk of dairy cows fed fresh pasture compared with alfalfa and corn silages was because of ruminal or endogenous synthesis. Eight Holsteins were fed a total mixed ration using alfalfa and corn silages as the forage source in confinement or grazed in a replicated crossover design. The proportion of total fatty acids as CLA (primarily c9, t11-18:2) in g/100 g was 0.44 v. 0.28 in ruminal digesta, 0.89 v. 0.53 in omasal digesta and 0.71 v. 1.06 in milk during confinement feeding and grazing, respectively. Blood plasma CLA was 0.54 v. 1.05 mg/l for the two treatments, respectively. The increased concentration of CLA in milk with grazing likely resulted from increased synthesis through desaturation of t11-18:1 in the mammary gland. PMID- 24785123 TI - Climatic factors associated with peripartum pig deaths during hot and humid or cold seasons. AB - Our objective was to quantify the associations between climatic factors and a death occurrence of peripartum pigs from 16 to 19 weeks after successful service during hot and humid or cold seasons. The study used lifetime records of 93,837 females entered into 98 Japanese commercial herds from 2003 to 2007. The climate data were obtained from 21 weather stations close to the studied herds. Average daily maximum (HT) and minimum temperature (LT), and relative humidity for week 15 of gestation for each pregnant pig were coordinated with the respective pig's performance data. Multilevel logistic regression models were applied to two of the three separate datasets. One dataset included females due to farrow during the hot and humid season (June-September), and another comprised females due to farrow during the cold season (December-March). Of the 8381 females that died throughout the year, 11.5% of pregnant pigs died between 16 and 17 weeks after service, and 44.3% of farrowed females subsequently died from 16 to 19 weeks after service. Mean (ranges) HT in the hot and humid season and LT in the cold season were 28.7 (13.4-39.8) degrees C and 1.6 (-14.8 to 17.6) degrees C, respectively. Means of relative humidity in the hot and humid season and cold season were 73.6 (35-98)% and 64.9 (21-99)%, respectively. In the hot and humid season, a higher HT was associated with a higher occurrence of death for parity 0 1 females (P<0.05), but not for parity 2 or higher sows (P>=0.38). The odds ratio was 1.030 (95% confidence intervals: 1.005-1.056) for HT in parity 0-1 females. Also, higher relative humidity was associated with a higher occurrence of death for parity 0-3 females (P<0.05), but not parity 4 or higher sows (P>=0.21). In the cold season, a higher occurrence of death of parity 4 or higher sows was associated with lower LT (P<0.05). Also, the occurrence of death of parity 6 or higher sows was associated with higher relative humidity in the cold season (P<0.05). For parity 0-3 females, there were no associations between the occurrences of death and either LT or relative humidity during the cold season (P>=0.11). Therefore, it is recommended to install cooling systems and thick insulation to prevent increases in occurrences of pig deaths due to HT or LT. PMID- 24785124 TI - Melamine functionalized silver nanoparticles as the probe for electrochemical sensing of clenbuterol. AB - Clenbuterol, a member of beta-agonist family, has now been a serious threat to human health due to its illegal usage in the livestock feeding. Herein, we describe the application of melamine functionalized silver nanoparticles (M AgNPs) as the electrochemical probe for simple, fast, highly sensitive and selective detection of clenbuterol. Generally, AgNPs are prepared and functionalized by melamine. After interacting with melamine modified gold electrode in the presence of clenbuterol, M-AgNPs can be immobilized on the surface of the electrode via the hydrogen-bonding interactions between clenbuterol and melamine. This sandwich structure permits sensitive and selective detection of clenbuterol. Since M-AgNPs can provide a couple of well-defined sharp silver stripping peaks, which stands for a highly characteristic solid state Ag/AgCl reaction, a rather low detection limit of 10 pM can be achieved. The detection range is from 10 pM to 100 nM, which is quite wide. This developed biosensor can potentially be used for clenbuterol detection in biological fluids in the presence of various interferences. PMID- 24785125 TI - Computed tomography examination of the face of Macaca anderssoni (Early Pleistocene, Henan, northern China): Implications for the biogeographic history of Asian macaques. AB - Macaca anderssoni, a fossil macaque from the Early Pleistocene of northern China, has attracted much attention from researchers in terms of reconstructing the biogeographic history of Asian macaques, while its phylogenetic position remains debatable. In the present study, we evaluated patterns of variation in external and internal craniofacial morphologies among four phylogenetic groups of extant macaques (the fascicularis, sinica, silenus, and sylvanus groups), using computed tomography and multivariate analyses. We also reassessed the holotype of M. anderssoni, a partial cranium preserving the face and palate, to evaluate the phylogenetic group to which M. anderssoni is most closely related. Facial elongation was found to be significantly influenced by size. The particular combination of some allometric and non-allometric shape components was found to reflect phylogenetic relationships; however, these features of M. anderssoni fall intermediate among the four phylogenetic groups, with no typical similarities to any one group. The variations in nasal cavity shape were found to reflect phylogenetic relationships but those of the maxillary sinus did not. Macaca anderssoni has a nasal cavity that is laterally expanded anteriorly and constricted posteriorly, a unique morphology among macaques and shared only with larger members of the sinica group. This unique feature is considered to be a derived condition among macaques, suggesting that M. anderssoni is phylogenetically related to the sinica group (especially M. assamensis, M. thibetana, and M. arctoides) and that the populations of the sinica group were distributed in northern China during the Early Pleistocene. Currently, the populations of the sinica group are not distributed in northern East Asia, while those of the fascicularis group are. Thus, probably due to climatic deterioration in the Late Pleistocene, the former lineage has retreated southward or has become extinct in this region, being replaced by the latter lineage. PMID- 24785126 TI - Outcomes after through-the-PEG tube placement of jejunal extensions: a case series from a single center. PMID- 24785127 TI - Pediatric therapeutic endoscopy: endoscopic management of a congenital duodenal web. PMID- 24785128 TI - Vascular hamartomatous lesion of the ampulla Vateri: a very uncommon occurrence. PMID- 24785129 TI - Successful removal of intrahepatic bile duct stones by using a combination of extracorporeal shock wave lithotripsy and direct peroral cholangioscopy. PMID- 24785130 TI - Diagnostic and therapeutic utility of double-balloon enteroscopy for obscure GI bleeding in patients with surgically altered upper GI anatomy. PMID- 24785131 TI - Cold snare resection of a nonpolypoid lesion >45 mm. PMID- 24785132 TI - Hemospray for diffuse anastomotic bleeding. PMID- 24785133 TI - Genomic differentiation among two strains of the PS1 clade isolated from geographically separated marine habitats. AB - Using dilution-to-extinction cultivation, we isolated a strain affiliated with the PS1 clade from surface waters of the Red Sea. Strain RS24 represents the second isolate of this group of marine Alphaproteobacteria after IMCC14465 that was isolated from the East (Japan) Sea. The PS1 clade is a sister group to the OCS116 clade, together forming a putatively novel order closely related to Rhizobiales. While most genomic features and most of the genetic content are conserved between RS24 and IMCC14465, their average nucleotide identity (ANI) is < 81%, suggesting two distinct species of the PS1 clade. Next to encoding two different variants of proteorhodopsin genes, they also harbor several unique genomic islands that contain genes related to degradation of aromatic compounds in IMCC14465 and in polymer degradation in RS24, possibly reflecting the physicochemical differences in the environment they were isolated from. No clear differences in abundance of the genomic content of either strain could be found in fragment recruitment analyses using different metagenomic datasets, in which both genomes were detectable albeit as minor part of the communities. The comparative genomic analysis of both isolates of the PS1 clade and the fragment recruitment analysis provide first insights into the ecology of this group. PMID- 24785134 TI - Efficient biocatalysis in organic media with hemoglobin and poly(acrylic acid) nanogels. AB - We previously reported that the stability and aqueous catalytic activity of met hemoglobin (Hb) was improved when covalently conjugated with poly(acrylic acid) (PAA). In the current study, the Hb-PAA-water interface was modified to improve Hb catalytic efficiency in organic solvents (0-80% v/v organic solvent; remainder is the conjugate, the substrate, and water). The protein-polymer-solvent interface modification was achieved by esterifying the carboxylic acid groups of Hb-PAA with ethanol (EtOH) or 1-propanol (1-prop) after activation with carbodiimide. The resulting esters (Hb-PAA-Eth and Hb-PAA-1-prop, respectively) showed high peroxidase-like catalytic activities in acetonitrile (ACN), dimethylformamide (DMF), EtOH, and methanol (MeOH). Catalytic activities depended on the log(P) values of the solvents, which is a measure of solvent lipophilicity. The highest weighted-average activities were noted in MeOH for all three conjugates, and the lowest average activities were noted in DMF for two of the conjugates. Interestingly, the average activities of the conjugates were higher than that of Hb in all solvents except in ACN. The ratio of the catalytic rate constant (kcat) to the Michaelis constant (KM), the catalytic efficiency, for Hb-PAA-Eth in MeOH was the highest noted, and it is ~3-fold higher than that of Hb in buffer; conjugates offered higher efficiencies than Hb at most solvent compositions. This is the very first general, versatile, modular strategy of coupling the enhanced stability of Hb with improved activity in organic solvents via the chemical manipulation of the polymer shell around Hb and provides a robust approach to efficient biocatalysis in organic solvents. PMID- 24785135 TI - Tailoring dialysis and resuming low-protein diets may favor chronic dialysis discontinuation: report on three cases. AB - Renal function recovery (RFR), defined as the discontinuation of dialysis after 3 months of replacement therapy, is reported in about 1% of chronic dialysis patients. The role of personalized, intensive dialysis schedules and of resuming low-protein diets has not been studied to date. This report describes three patients with RFR who were recently treated at a new dialysis unit set up to offer intensive hemodialysis. All three patients were females, aged 73, 75, and 78 years. Kidney disease included vascular-cholesterol emboli, diabetic nephropathy and vascular and dysmetabolic disease. At time of RFR, the patients had been dialysis-dependent from 3 months to 1 year. Dialysis was started with different schedules and was progressively discontinued with a "decremental" policy, progressively decreasing number and duration of the sessions. A moderately restricted low-protein diet (proteins 0.6 g/kg/day) was started immediately after dialysis discontinuation. The most recent update showed that two patients are well off dialysis for 5 and 6 months; the diabetic patient died (sudden death) 3 months after dialysis discontinuation. Within the limits of small numbers, our case series may suggest a role for personalized dialysis treatments and for including low-protein diets in the therapy, in enhancing long term RFR in elderly dialysis patients. PMID- 24785136 TI - Improving adherence in African American women with uncontrolled hypertension. AB - BACKGROUND AND OBJECTIVES: African American women are disproportionately affected with hypertension (HTN). The aim of this randomized controlled trial was to evaluate the effectiveness of a 6-week culturally tailored educational intervention for 60 African American women with HTN. METHODS: Sixty African American women, 29 to 86 years old (mean +/- SD, 57.98 +/- 12.37 years), with primary HTN were recruited from 4 rural locations and randomized to intervention (n = 30) and control (n = 30) groups to determine the effectiveness of the intervention on knowledge, attitudes, beliefs, social support, adherence to an HTN regimen, and blood pressure control. Culturally tailored educational classes were provided for 90 minutes once a week for 6 weeks. The control group received usual care. RESULTS: A significant favorable overall main effect (time) was found for systolic blood pressure (F3,174 = 11.104, P = .000) and diastolic blood pressure (F3,174 = 4.781, P = .003) for both groups. Also for diastolic blood pressure, older age was a significant covariate (F1,56 = 6.798, P = .012). Older participants tended to have increased diastolic blood pressures. There were no significant differences between groups on knowledge, adherence, or attitudes. CONCLUSION: The culturally tailored program used the African American church as a basis for recruitment and implementation of the program that retained all participants over a 6-month period. African American women living in rural Texas who participated in a 6-week intervention program demonstrated a significant decrease in blood pressure over a 6-month period regardless of whether they were in the intervention or control group. In general, they had a relatively good knowledge of HTN and reported an average level of adherence. Future studies using a culturally tailored program with a larger sample size are warranted to decrease the high level of HTN-related complications in African American women. PMID- 24785137 TI - Transareola single-site laparoendoscopic bilateral thyroidectomy. AB - BACKGROUND: Transareola single-site endoscopic thyroidectomy has been successfully established as a surgical approach. This study investigated the feasibility and safety of transareola single-site endoscopic thyroidectomy for bilateral thyroid disease. PATIENTS AND METHODS: Twelve patients who underwent bilateral thyroidectomy were enrolled in this study. The surgical outcomes were analyzed, including operation time, intraoperative bleeding volume, postoperative pain score, and cosmetic satisfaction score. RESULTS: All patients underwent successful transareola single-site endoscopic bilateral thyroidectomy, and no patient was semiconverted to three-port endoscopic surgery or open surgery. Seven patients underwent bilateral partial thyroidectomy, and 5 patients underwent subtotal thyroidectomy plus contralateral partial thyroidectomy. The mean operation time was 165+/-23.8 minutes (range, 142-185 minutes). The mean intraoperative bleeding volume was 27.3+/-12.3 mL (range, 20-45 mL). The mean postoperative wound drainage was 121+/-45.8 mL (range, 85-137 mL). The drainage tube was removed 3-4 days after surgery. The mean visual analog scale score was 3.3+/-2.5 (range, 1-5) at 24 hours postoperatively. The patients were followed up for 2 month with no complaint of chest wall wound pain and numbness. The mean cosmetic satisfaction score was 9.55+/-0.8 (range, 8-10). CONCLUSIONS: Transareola single-site endoscopic bilateral thyroidectomy is feasible and safe and has the advantages of high cosmetic satisfaction. PMID- 24785138 TI - Errors (my very own) and the fearful uncertainty of numbers. PMID- 24785139 TI - [VKA anticoagulant bridging for an invasive procedure or planned surgery: A survey of practices in general practitioners]. AB - BACKGROUND: In 2011, 1.7 % of the French population was receiving a Vitamine K Antagonist (VKA) anticoagulant therapy. VKA related adverse events are the first cause for iatrogenic events in France. Anticoagulant bridging period is a period at both increased risk for thromboembolic and bleeding events. The Haute Autorite de sante (HAS) established in 2008 recommendations in order to help physicians to manage anticoagulant therapy in case of invasive procedure or surgery, according to the procedure and the indication of VKA. PRIMARY AIM: To assess anticoagulant treatment management by general physicians when an invasive procedure or a planned surgery in a patient receiving long-term VKA Data have been compared to HAS recommendations. METHODS: A descriptive transversal survey performed in general physicians a at the conference held in Nice in 2012. An anonymous questionnaire was built, including questions about clinical situations and knowledge questions. RESULTS: Eighty-eight out of 200 submitted questionnaires have been completed (44%). Overall, 4.5% of questioned physicians have managed fully in accordance with HAS recommendations the 6 clinical situations cliniques about patients receiving long-term VKA for atrial fibrillation, recurrent pulmonary embolism, and mechanical valvular prothesis. Bridgings using Low Molecular Weight Heparins have been excessively proposed by asked physicians and bridging prescription was most of the time wrong (9% correct). Otherwise, no physician has answered correctly all theoretical questions; patients at high and low thromboembolic risk are not well distinguished; 64% of physicians think they are influenced by specialists who have prescribed the procedure. DISCUSSION: Few physicians manage VKA therapy in accordance with HAS recommendations in case of invasive procedure. There are many hypotheses: bad knowledge of recommendations, overestimation of the thromboembolic risk related to VKA stopping during the period of the invasive procedure, underestimation of the risk of bleeding related to the bridging period of time; influence of specialists. We propose a decisional algorithm in order to improve the implementation of HAS recommendations in usual care. PMID- 24785140 TI - [What are the applications of biomarkers in ALS today?]. AB - Numerous biomarkers studies in ALS used targeted and non-targeted approaches, to help for the diagnosis, the prognosis or to identify new pathophysiological ways. The emerging approaches such as "omics" studies are very promising, but the practical and technical limits do not enable their optimization. Even if some biomarkers such as cystatin C or glutamate are highlighted in ALS, to date, no biomarker is currently used in routine practice. Diffusion-based neuroimaging has emerged as a tool to identify the involvement of the central neuron, but a recent meta-analysis shows a poor sensitivity and specificity. Spinal cord imaging has the advantage of simultaneoulsy investigating both the corticospinal tract and the peripheral motor neurons in the anterior horns of the spinal cord. Its interest to provide biomarkers in ALS is illustrated by recent studies that used a multiparametric approach. The limits of biomarkers studies are principally based on small cohorts, involving a control population who does not allow to assess specificity. The discrepancies between the biomarkers identified in the different studies are based on a strong heterogeneity of the disease and a lack of standardization of the research methodology, including the step of the validation of these molecules in independent cohorts. The perspectives in biomarker research in ALS imply the combination of analytical methods, human abilities and harmonization of the strategies. PMID- 24785141 TI - [Rubella: a current issue?]. AB - Sporadic cases of rubella infection are reported each year in France due to insufficient vaccination coverage. Rubella virus is a very unstable enveloped RNA virus. For this reason, transportation and storage of samples collected for its detection require particular conditions. The genetic stability of rubella virus has allowed the development of very effective vaccines. During the recent rubella outbreaks in Algeria and Tunisia, an unusual high rate of encephalitis was reported. The role of the laboratory is crucial in the management of rubella infection during pregnancy. Rubella serological results must be interpreted with caution. Congenital rubella is a severe disease that should already be eliminated thanks to a very effective vaccine that has been developed. All women of childbearing age should be vaccinated. Rubella vaccination of an unknowingly pregnant woman is not an indication for abortion. PMID- 24785142 TI - [Neurophysiological investigations in amyotrophic lateral sclerosis]. AB - Amyotrophic lateral sclerosis (ALS) is a degenerative disease which prognosis is poor. Early diagnosis permits to set up immediately adapted treatment and cares. Available diagnostic criteria are based on the detection of both the central and peripheral motor neuron injury in bulbar, cervical, thoracic and lumbar regions. Electromyographic study is the key tool to identify peripheral motor neuron involvement. Conduction velocities are systematically performed to rule out differential diagnosis. Needle examination records abnormal activities at rest and looks for neurogenic pattern during muscle contraction. Motor unit potentials morphology is modified primary to recruitment. Motor evoked potentials remain the test of choice to identify impairment of central motor neurons. For the monitoring of ALS patients, the MUNE technique (motor unit number estimation) seems the most interesting. PMID- 24785143 TI - [Mother-to-child transmission (MTCT) of HIV]. AB - Globally, an estimated 3.3 million children were living with HIV in 2012 (around 1500 in France) In developed countries, the risk of mother-to-child transmission (MTCT) of HIV-1 has been reduced to less than 1 %, thanks to the large diffusion of antiretroviral drugs given in pregnant women and in HIV-exposed children. The rare cases of HIV-1 MTCT are due to missed opportunities of HIV diagnosis in pregnant women or to late prescription of antiretroviral therapy during pregnancy. Neonatal screening for HIV in exposed newborns is based on repeated HIV RNA and/or DNA PCR, performed at 1-3days, 1, 3 and 6months of age. Even if the health of HIV-exposed children is not a concern in the vast majority of cases, future challenges will imply to study the potential long-term toxicity of ART because of the description of several biological, clinical and imaging alerts. PMID- 24785144 TI - [Hemochromatoses: a changing world]. PMID- 24785145 TI - [SBMA: a rare disease but a classic ALS mimic syndrome]. AB - Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder of lower motor neurons characterized by proximal limb muscular atrophy, bulbar involvement, marked fasciculation, hand tremor and gynaecomastia. SBMA is caused by a CAG-repeat expansion in the androgen receptor gene on the X-chromosome. Due to its mode of transmission, only male are symptomatic and clinical features appear progressively in adulthood. Motor signs and symptoms are restricted to lower motor neuron involvement, in contrast with amyotrophic lateral sclerosis (ALS) characterized by the association with upper motor neuron involvement. The diminution of sensory potential at electroneuromyogram is a major criteria discriminating between SBMA and ALS. Diagnostic confirmation is based on genetic testing. PMID- 24785146 TI - An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl Oxidase 2-like Protein. AB - Extracellular Hsp90 (eHsp90) activates a number of client proteins outside of cancer cells required for migration and invasion. Therefore, eHsp90 may serve as a novel target for anti-metastatic drugs as its inhibition using impermeant Hsp90 inhibitors would not affect the numerous vital intracellular Hsp90 functions in normal cells. While some eHsp90 clients are known, it is important to establish other proteins that act outside the cell to validate eHsp90 as a drug target to limit cancer spread. Using mass spectrometry we identified two precursor proteins Galectin 3 binding protein (G3BP) and Lysyl oxidase 2-like protein (LOXL2) that associate with eHsp90 in MDA-MB231 breast cancer cell conditioned media and confirmed that LOXL2 binds to eHsp90 in immunoprecipitates. We introduce a novel impermeant Hsp90 inhibitor STA-12-7191 derived from ganetespib and show that it is markedly less toxic to cells and can inhibit cancer cell migration in a dose dependent manner. We used STA-12-7191 to test if LOXL2 and G3BP are potential eHsp90 clients. We showed that while LOXL2 can increase wound healing and compensate for STA-12-7191-mediated inhibition of wound closure, addition of G3BP had no affect on this assay. These findings support of role for LOXL2 in eHsp90 stimulated cancer cell migration and provide preliminary evidence for the use of STA-12-7191 to inhibit eHsp90 to limit cancer invasion. PMID- 24785147 TI - Unsteady magnetohydrodynamic free convection flow of a second grade fluid in a porous medium with ramped wall temperature. AB - Magnetic field influence on unsteady free convection flow of a second grade fluid near an infinite vertical flat plate with ramped wall temperature embedded in a porous medium is studied. It has been observed that magnitude of velocity as well as skin friction in case of ramped temperature is quite less than the isothermal temperature. Some special cases namely: (i) second grade fluid in the absence of magnetic field and porous medium and (ii) Newtonian fluid in the presence of magnetic field and porous medium, performing the same motion are obtained. Finally, the influence of various parameters is graphically shown. PMID- 24785148 TI - Persistent Intramolecular C-H...X (X = O or S) Hydrogen-Bonding in Benzyl Meldrum's Acid Derivatives. AB - C-H...X (where X = O or S) intramolecular hydrogen bonding is investigated in three benzyl Meldrum's acid derivatives using a combination of solution phase NMR spectroscopy, gas phase infrared multiple photon dissociation spectroscopy, and density functional theory calculations. In one compound, an abnormally large C H...S hydrogen bond energy of 30.4 kJ mol-1 is calculated with a natural bond orbital analysis. Intramolecular C-H...O hydrogen bonding is found to persist in the gas phase. Gibbs energy decomposition pathways are calculated. PMID- 24785149 TI - Graphene- and aptamer-based electrochemical biosensor. AB - This study investigated the effectiveness of a graphene- and aptamer-based field effect-transistor-like (FET-like) sensor in detecting lead and potassium ions. The sensor consists of a graphene-covered Si/SiO2 wafer with thrombin binding aptamer (TBA) attached to the graphene layer and terminated by a methylene blue (MB) molecule. K(+) and Pb(2+) both bind to TBA and cause a conformational change, which results in MB moving closer to the graphene surface and donating an electron. Thus, the abundance of K(+) and Pb(2+) can be determined by monitoring the current across the source and drain channel. Device transfer curves were obtained with ambipolar field effect observed. Current readings were taken for K(+) concentrations of 100 MUM to 50 mM and Pb(2+) concentrations of 10 MUM to 10 mM. As expected, I d decreased as ion concentration increased. In addition, there was a negative shift in V Dirac in response to increased ion concentration. PMID- 24785151 TI - True katydids (Pseudophyllinae) from Guadeloupe: acoustic signals and functional considerations of song production. AB - Guadeloupe, the largest of the Leeward Islands, harbors three species of Pseudophyllinae (Orthoptera: Tettigoniidae) belonging to distinct tribes. This study examined the basic aspects of sound production and acousto-vibratory behavior of these species. As the songs of many Pseudophyllinae are complex and peak at high frequencies, they require high quality recordings. Wild specimens were therefore recorded ex situ. Collected specimens were used in structure function experiments. Karukerana aguilari Bonfils (Pterophyllini) is a large species with a mirror in each tegmen and conspicuous folds over the mirror. It sings 4-6 syllables, each comprising 10-20 pulses, with several peaks in the frequency spectrum between 4 and 20 kHz. The song is among the loudest in Orthoptera (> 125 dB SPL in 10 cm distance). The folds are protective and have no function in song production. Both mirrors may work independently in sound radiation. Nesonotus reticulatus (Fabricius) (Cocconotini) produces verses from two syllables at irregular intervals. The song peaks around 20 kHz. While singing, the males often produce a tremulation signal with the abdomen at about 8 10 Hz. To our knowledge, it is the first record of simultaneous calling song and tremulation in Orthoptera. Other males reply to the tremulation with their own tremulation. Xerophyllopteryx fumosa (Brunner von Wattenwyl) (Pleminiini) is a large, bark-like species, producing a syllable of around 20 pulses. The syllables are produced with irregular rhythms (often two with shorter intervals). The song peaks around 2-3 kHz and 10 kHz. The hind wings are relatively thick and are held between the half opened tegmina during singing. Removal of the hind wings reduces song intensity by about 5 dB, especially of the low frequency component, suggesting that the hind wings have a role in amplifying the song. PMID- 24785152 TI - A possible link between increased metabolic activity of fat tissue and aortic wall inflammation in subjects with COPD. A retrospective 18F-FDG-PET/CT pilot study. AB - BACKGROUND: Fat tissue, and particularly visceral fat, is known to play a role in low grade systemic inflammation in COPD, and is likely to contribute to the excess cardiovascular comorbidity in COPD. Therefore, we aimed to study (18)FDG PET-assessed inflammation of the aorta and the (visceral) fat, and evaluate its interrelations and differences in subjects with and without COPD. METHODS: We retrospectively identified 42 patients (71% male, 48% current smokers, mean age 66.6 +/- 8.3 years, mean BMI 25.1 +/- 4.3 kg/m(2)), who underwent (18)F-FDG PET/CT for suspected early stage bronchus carcinoma. COPD-diagnosis was based on spirometry and defined as FEV1/FVC < lower limit of normal. Inflammatory status of aortic and fat regions was defined as the average of obtained maximum target to-background ratios (meanTBRmax). The TBR is the standardized uptake value (SUV) normalized to (18)F-FDG blood pool activity. RESULTS: Compared to controls, patients with COPD (n = 19; 45%) had increased meanTBRmax of both the abdominal aorta (1.31 +/- 0.14 vs. 1.49 +/- 0.31; p = 0.02) and the abdominal visceral fat (0.28 +/- 0.09 vs. 0.38 +/- 0.18; p = 0.047), while inflammatory activity of the abdominal subcutaneous fat failed to show statistically significant differences (0.21 +/- 0.09 vs. 0.24 +/- 0.09; p = 0.345). In all patients, meanTBRmax of abdominal visceral fat was correlated with meanTBRmax of the abdominal aorta, independently of age and BMI (beta = 0.590, p = 0.002). CONCLUSION: Metabolic activity of the abdominal aorta and visceral fat is increased in COPD patients compared to peers. The degree of visceral fat metabolic activity is associated with aortic inflammation. More prospective research is warranted concerning the role of visceral fat in the development of vascular comorbidity in COPD. PMID- 24785153 TI - Recumbent deoxygenation in mild/moderate liver cirrhosis: the "clinodeoxia". The ortho-clino paradigm. AB - BACKGROUND: While the effects of postural change on arterial oxygenation have been well documented in normal subjects, and attributed to the relationship of closing volume (CV) to the tidal volume, in liver cirrhosis such postural changes have been evaluated mainly in a rare, peculiar clinical end-stage condition which is characterized by increased dyspnea shifting from supine to upright position ("platypnea"). The latter is associated with worsening of PaO2 ("orthodeoxia"). We evaluated the effects of postural changes on arterial oxygenation in patients affected by mild/moderate liver cirrhosis. METHODS: We performed pulmonary function tests and arterial blood gas evaluation in sitting and supine positions in 22 patients with mild/moderate liver cirrhosis, biopsy-proved, and 22 matched non-smokers control subjects. RESULTS: Recumbency elicited a decrease of PaO2 (Delta(sup-sit)PaO2) in 19 out of 22 controls and in all but one cirrhotics. The magnitude of this postural change was significantly (p = 0.04) greater in cirrhotics (9.6 +/- 5.3%) compared to controls (6.7 +/- 3.7%). In the subset of cirrhotics younger than 60 yrs and with PaO2 greater than 80 mmHg in sitting position, the Delta(sup-sit)PaO2 in recumbency further increased to 12 +/- 5.8%, significantly (p = 0.014) greater than in same subgroup of controls (7.1 +/- 3.8%). CONCLUSIONS: In mild/moderate liver cirrhosis the postural variations in PaO2 follow the normal trends, but are of greater magnitude probably as a consequence of hypoventilated units of lung for postural and disease-linked tidal airway closure, resulting in more pronounced recumbent hypoxemia ("clinodeoxia"). PMID- 24785154 TI - QDD version 3.1: a user-friendly computer program for microsatellite selection and primer design revisited: experimental validation of variables determining genotyping success rate. AB - Microsatellite marker development has been greatly simplified by the use of high throughput sequencing followed by in silico microsatellite detection and primer design. However, the selection of markers designed by the existing pipelines depends either on arbitrary criteria, or older studies on PCR success. Based on wet laboratory experiments, we have identified the following factors that are most likely to influence genotyping success rate: alignment score between the primers and the amplicon; the distance between primers and microsatellites; the length of the PCR product; target region complexity and the number of reads underlying the sequence. The QDD pipeline has been modified to include these most pertinent factors in the output to help the selection of markers. Furthermore, new features are also included in the present version: (i) not only raw sequencing reads are accepted as input, but also contigs, allowing the analysis of assembled high-coverage data; (ii) input data can be both in fasta and fastq format to facilitate the use of Illumina and IonTorrent reads; (iii) A comparison to known transposable elements allows their detection; (iv) A contamination check can be carried out by BLASTing potential markers against the nucleotide (nt) database of NCBI; (v) QDD3 is now also available imbedded into a virtual machine making installation easier and operating system independent. It can be used both on command-line version as well as integrated into a Galaxy server, providing a user-friendly interface, as well as the possibility to utilize a large variety of NGS tools. PMID- 24785156 TI - Intrinsic brain abnormalities in attention deficit hyperactivity disorder: a resting-state functional MR imaging study. AB - PURPOSE: To explore alterations of regional and network-level neural function using resting-state functional magnetic resonance (MR) imaging in children and adolescents with attention deficit hyperactivity disorder (ADHD) and to assess the association between these alterations of intrinsic neural activity and executive dysfunction in ADHD. MATERIALS AND METHODS: This prospective study was approved by the local ethical committee, and written informed consent was obtained from guardians of all participants. Thirty-three boys with ADHD who were not receiving medication and who were without comorbidity (aged 6-16 years) and 32 healthy control subjects (aged 8-16 years) underwent imaging by using resting state functional MR imaging. Amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were calculated to examine regional neural function and functional integration, respectively, and were compared between patients and control subjects by using the voxel-based two-sample t test, while Pearson correlation analyses were performed to identify neural correlates of executive function measured with the Wisconsin Card Sorting Test and the Stroop Color-Word Test. RESULTS: Relative to healthy control subjects, patients with ADHD showed impaired executive function (P < .05), along with the following: lower ALFF in the left orbitofrontal cortex (P = .004) and the left ventral superior frontal gyrus (P = .003); higher ALFF in the left globus pallidus (P = .004), the right globus pallidus (P = .002), and the right dorsal superior frontal gyrus (P = .025); lower long-range FC in the frontoparietal and frontocerebellar networks; and higher FC in the frontostriatal circuit that correlated across subjects with ADHD with the degree of executive dysfunction (P < .05). CONCLUSION: These findings of focal spontaneous hyper- and hypofunction, together with altered brain connectivity in the large-scale resting-state networks, which correlates with executive dysfunction, point to a connectivity based pathophysiologic process in ADHD. PMID- 24785157 TI - FXI concentrate use and risk of thrombosis. PMID- 24785155 TI - Differential pattern for regulating insulin secretion, insulin resistance, and lipid metabolism by osteocalcin in male and female T2DM patients. AB - BACKGROUND: Osteocalcin has been reported to be relevant to glucose and lipid metabolism, indicating it may stimulate insulin secretion and improve insulin resistance. Yet the difference between male and female patients is still not clear. We aimed to investigate the difference in serum osteocalcin, and its association with glucose, lipid metabolism, pancreatic function, insulin sensitivity, and resistance in male and female middle-aged and elderly type 2 diabetic (T2DM) patients. MATERIAL AND METHODS: 739 T2DM patients were included. After measurement of body mass index (BMI), the levels of fasting plasma glucose (FPG), insulin (FINS), C peptide (FC-P), 2-h post-OGTT plasma glucose (2h-PG), HbA1C, and osteocalcin were determined. Homeostasis model assessment of beta-cell function (HOMA-%B), homeostasis model assessment of insulin sensitivity (HOMA %S), and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. RESULTS: Females had higher osteocalcin concentration than males (P<0.05). In males, serum osteocalcin was negatively correlated with HbA1C, FPG, and 2-h PG (P<0.05), but positively with 2-h post-OGTT C peptide (2hC-P), 2-h post-OGTT serum insulin (2h-INS), and HOMA-%B (P<0.05). In females, serum osteocalcin was negatively correlated with HbA1C, FPG, triglyceride (TG), and HOMA-IR (P<0.05), but positively with 2-h C-P, 2-h INS, HOMA-%B, HOMA-%S, and high-density lipoprotein (HDL) (P<0.05). In all subjects, serum osteocalcin was inversely correlated with HbA1C, FPG, and 2-h PG (P<0.05), but positively with 2 h C-P, 2-h INS, HDL, and HOMA-%B (P<0.05). CONCLUSIONS: Osteocalcin might improve glucose metabolism through enhancing insulin secretion in males, and through increasing insulin secretion and improving insulin resistance in females with T2DM. Osteocalcin probably also plays an important role in lipid metabolism. PMID- 24785158 TI - Right ventricular systolic and diastolic function as assessed by speckle-tracking echocardiography improve with prolonged isolated left ventricular assist device support. AB - BACKGROUND: Right ventricular (RV) failure is a major cause of morbidity and mortality after left ventricular assist device (LVAD) implantation. Whether RV function deteriorates with prolonged LVAD support is unknown. Speckle-tracking echocardiography provides a sensitive, noninvasive, reproducible, and quantitative assessment of RV systolic and diastolic function. METHODS: Echocardiograms were retrospectively reviewed from before and after implantation of a Heartmate II LVAD. Speckle-tracking analysis was performed to measure RV longitudinal systolic strain, strain rate, and diastolic strain rate for each patient at baseline and over discrete time periods after LVAD implantation. RESULTS: Seventeen patients were included in the analysis, with an average follow up after LVAD implantation of 234 +/- 125 days. RV systolic strain improved in 15 patients, decreasing from -7.4 +/- 2.3% to -9.7 +/- 3.3% after LVAD (P = .026). Systolic strain rate improved in 11 patients, decreasing from -0.67 +/- 0.25%/s to -0.96 +/- 0.36%/s (P = .011). RV diastolic strain rate improved in 12 patients, increasing from 0.70 +/- 0.33%/s to 1.02 +/- 0.40%/s (P = .016). CONCLUSIONS: Chronic LVAD support improves RV systolic and diastolic function in LVAD patients who did not require an RV assist device. Speckle-tracking echocardiography may offer a noninvasive technique for identifying and monitoring improvements in RV function in LVAD patients. PMID- 24785159 TI - Assembly and function of the tRNA-modifying GTPase MnmE adsorbed to surface functionalized bioactive glass. AB - Protein adsorption onto solid surfaces is a common phenomenon in tissue engineering related applications, and considerable progress was achieved in this field. However, there are still unanswered questions or contradictory opinions concerning details of the protein's structure, conformational changes, or aggregation once adsorbed onto solid surfaces. Electron paramagnetic resonance (EPR) spectroscopy and site-directed spin labeling (SDSL) were employed in this work to investigate the conformational changes and dynamics of the tRNA-modifying dimeric protein MnmE from E. coli, an ortholog of the human GTPBP3, upon adsorption on bioactive glass mimicking the composition of the classical 45S5 Bioglass. In addition, prior to protein attachment, the bioactive glass surface was modified with the protein coupling agent glutaraldehyde. Continuous wave EPR spectra of different spin labeled MnmE mutants were recorded to assess the dynamics of the attached spin labels before and after protein adsorption. The area of the continuous wave (cw)-EPR absorption spectrum was further used to determine the amount of the attached protein. Double electron-electron resonance (DEER) experiments were conducted to measure distances between the spin labels before and after adsorption. The results revealed that the contact regions between MnmE and the bioactive glass surface are located at the G domains and at the N-terminal domains. The low modulation depths of all DEER time traces recorded for the adsorbed single MnmE mutants, corroborated with the DEER measurements performed on MnmE double mutants, show that the adsorption process leads to dissociation of the dimer and alters the tertiary structure of MnmE, thereby abolishing its functionality. However, glutaraldehyde reduces the aggressiveness of the adsorption process and improves the stability of the protein attachment. PMID- 24785160 TI - Who hid lesbian history? PMID- 24785161 TI - "Imagine my surprise". PMID- 24785162 TI - Zero degree deviancy. PMID- 24785163 TI - Lesbian ethics and female agency. PMID- 24785164 TI - Toward a Laboratory of One's Own. PMID- 24785165 TI - National lesbian health care survey. AB - Abstract This article presents demographic, lifestyle, and mental health information about 1,925 lesbians from all 50 states who participated as respondents in the National Lesbian Health Care Survey (1984-1985), the most comprehensive study on U.S. lesbians to date. Over half the sample had had thoughts about suicide at some time, and 18% had attempted suicide. Thirty-seven percent had been physically abused as a child or adult, 32% had been raped or sexually attacked, and 19% had been involved in incestuous relationships while growing up. Almost one third used tobacco on a daily basis, and about 30% drank alcohol more than once a week, 6% daily. About three fourths had received counseling at some time, and half had done so for reasons of sadness and depression. Lesbians in the survey also were socially connected and had a variety of social supports, mostly within the lesbian community. However, few had come out to all family members and coworkers. Level of openness about lesbianism was associated with less fear of exposure and with more choices about mental health counseling. PMID- 24785166 TI - Negative sexual experiences with men among heterosexual women and lesbians. AB - Abstract Survey responses on traumatic experiences with men were compared from 50 matched pairs of heterosexual women and lesbians. Prior research has implied that lesbians have had more traumatic experiences with men than heterosexual women. The purpose of this study was to test the hypothesis that lesbians would report more negative sexual experiences with men than heterosexual women. The findings of the present study did not support this hypothesis. The only significant difference found between the two groups was that heterosexual women were more likely to report multiple categories of traumatic experiences and lesbians were more likely to report experiences in only one category of trauma. Contrary to prior studies, these results indicate that previous traumatic experiences with men may not be a significant factor in the development of sexual orientation. PMID- 24785167 TI - Therapy for lesbians? AB - Abstract From a lesbian feminist perspective the problematic nature of developments in 'lesbian' and 'feminist' psychological therapies is considered. It is argued that such therapies are, despite their expressed aims, essentially anti-lesbian and anti-feminist. PMID- 24785168 TI - Putting the politics back into lesbianism. AB - Abstract This article contrasts lesbianism as a political movement to lesbianism as a lifestyle. It addresses the current emphasis in lesbian circles on "sex as salvation," and maintains that this emphasis re-sexualizes women and de politicizes lesbianism. The liberalism of lesbian lifestylism makes the male power modes of sexuality, such as s & m, butch-femme, and bondage and domination, sexy for women. In the name of tolerance, difference, and lesbian community, many lesbians are dissuaded from making judgments and opposing such acts. Finally, the article describes the values of a lesbian feminism that has principles, politics, and passion. It proposes a context for what lesbian sexuality might look like rooted in lesbian imagination-not lesbian fantasies. PMID- 24785170 TI - Combined effects of sivelestat and resveratrol on severe acute pancreatitis associated lung injury in rats. AB - Despite extensive research and clinical efforts made in the management of acute pancre-atitis during the past few decades, to date no effective cure is available and the mortality from severe acute pancre-atitis remains high. Given that lung is the primary cause of early death in acute pancreatitis patients, novel therapeutic approaches aiming to prevent lung injury have become a subject of intensive investigation. In a previous study, we demonstrated that sivelestat, a specific inhibitor of neutrophil elastase, is effective in protecting against lung failure in rats with taurocholate-induced acute pancreatitis. As part of the analyses extended from that study, the present study aimed to evaluate the role of sivelestat and/or resveratrol in the protection against acute pancreatitis associated lung injury. The extended analyses demonstrated the following: (1) sodium taurocholate induced apparent lung injury and dysfunction manifested by histological anomalies, including vacuolization and apoptosis of the cells in the lung, as well as biochemical aberrations in the blood (an increase in amylase concentration and a decrease in partial arterial oxygen pressure) and increases in activities of reactive oxygen species, interleukin 6, myeloperoxidase, neutrophil elastase, lung edema, bronchotracho alveolar lavage protein concentration, and bronchotracho alveolar lavage cell infiltration in the lung; and (2) in lung tissues, either sivelestat or resveratrol treatment effectively attenuated the taurocholate-induced abnormalities in all parameters analyzed except for serum amylase concentration. In addition, combined treatment with both sivelestat and resveratrol demonstrated additive protective effects on pancreatitis-associated lung injury compared with single treatment. PMID- 24785169 TI - Association of pulmonary function with adiposity and metabolic abnormalities in urban minority adolescents. AB - RATIONALE: Childhood obesity is a known risk factor for pulmonary diseases, likely due to obesity-mediated alteration of pulmonary function. Inflammation and mechanical fat load are two proposed causative mechanisms for altered pulmonary function among obese children; however, the association of metabolic abnormalities with pulmonary function among children is poorly understood. OBJECTIVES: We investigated the independent association of truncal and general adiposity and metabolic abnormalities with pulmonary function in a sample of urban minority adolescents. METHODS: Spirometry and lung volume indices were compared between adolescents with general (body mass index [BMI] > 95th percentile) or truncal adiposity (waist circumference > 90th percentile) and normal-weight (BMI < 85th percentile or waist circumference <= 90th percentile) and between those with metabolic abnormalities (homeostatic model assessment of insulin resistance [HOMA-IR] in the top quartile or high-density lipoprotein [HDL] < 40 mg/dl) and those with a normal metabolic profile. MEASUREMENTS AND MAIN RESULTS: Obese adolescents had lower lung volumes, including residual volume (RV), RV/TLC ratio, expiratory reserve volume (ERV), and FRC, and higher inspiratory capacity (IC) than normal-weight adolescents, but did not differ in measures of lower airway obstruction, FEV1/FVC ratio, and mid-expiratory flow rate. Adolescents with high HOMA-IR had lower FEV1/FVC ratio, RV, RV/TLC ratio, ERV, and FRC and higher IC, whereas those with low HDL had lower FEV1/FVC and RV/TLC ratios. After adjusting for adiposity, HOMA-IR remained a predictor of ERV (beta = -1.4; P = 0.02) and FEV1/FVC ratio (beta = -0.5; P = 0.03), and HDL remained a predictor of FEV1/FVC ratio (beta = 0.1; P = 0.01). General adiposity was a predictor of FRC (beta = -0.5; P < 0.001), IC (beta = 0.3; P < 0.001), RV (beta = -0.8; P < 0.0001), and RV/TLC ratio (beta = -0.2; P < 0.0001), and truncal adiposity was a predictor of RV (beta = -20.3; P = 0.03) and FRC (beta = 13.8; P = 0.004). Thus, adiposity and metabolic abnormalities were independent predictors of ERV, but only metabolic abnormalities independently predicted FEV1/FVC ratio. Although general adiposity predicted RV and RV/TLC ratio, truncal adiposity was predictive of RV and FRC, conferring additional risk above general adiposity. CONCLUSIONS: These results suggest that metabolic abnormalities and adiposity are independently associated with pulmonary function deficits among urban adolescents. Metabolic assessment of obese adolescents may identify those at risk of developing obesity-associated pulmonary morbidity. PMID- 24785171 TI - Survey of furan in foods and coffees from five European Union countries. AB - Canned and jarred baby foods (74), canned and jarred adult foods (63) and 70 coffees sold in Belgium, Italy, Portugal, Spain and The Netherlands were analysed for their furan content using a validated automated headspace GC-MS procedure. Seven balsamic vinegars from Italy and Spain were also analysed. All 74 baby food samples contained detectable furan, with an average level of 37 ng/g. A total of 54 of 63 canned and jarred foods contained detectable furan with an average level of 24 ng/g. Levels of furan in coffee as consumed were very variable and reflected different preparation methods and coffee strengths. Over 50% of Italian samples contained more than 200 ng/g, whereas over 20% of Belgian coffees contained less than 21 ng/g furan. Some brews made from fine grained coffee contained much more furan than did brews made from normal or coarse grained coffee. Although furan was low in most instant coffees, two Italian products "instant espresso" and "instant mocha" contained about 150 ng/g furan. Balsamic vinegars from Spain contained 159-662 ng/g of furan; however, other samples from Spain and Italy contained only 6-25 ng/g. PMID- 24785172 TI - Monitoring of pesticides and veterinary drugs in Australian cattle: verification of the residue control system. AB - The Australian National Residue Survey in partnership with the Australian Quarantine and Inspection Service and industry routinely monitors beef to ensure that regulatory requirements for residues are being met. In the 10-year period from 1997 to 2006 a total of 128,902 samples were subjected to residue testing covering veterinary drugs and veterinary and agricultural pesticides in a random monitoring program. Residues of agricultural and veterinary chemicals exceeded the Australian standard in 13 and 7 samples, respectively. Greater than 99% of samples did not contain detectable residues above the Australian standard while greater than 90% of samples did not contain any residues of compounds included in the survey. The results of the surveys provide verification that the Australian residue control system is appropriate and that the requirements of countries importing Australian meat products can be satisfied. The surveys have also demonstrated that industry based programs and state based regulatory controls over sites contaminated with organochlorine residues are effective in managing residues of these chemicals in cattle. PMID- 24785173 TI - Survey of total arsenic and arsenic speciation in US-produced rice as a reference point for evaluating change and future trends. AB - Rice generally contains higher levels of arsenic than most terrestrial-based foods. Studies related to dietary intake of arsenic from rice must take into account arsenic speciation due to toxicity differences in arsenic species. In this study, microwave-assisted extraction with trifluoroacetic acid was used to prepare rice samples for arsenic speciation analysis by high-performance liquid chromatography-inductively coupled plasma mass spectrometry. Fifty-three samples collected directly from the fields in four major rice-producing states in 1980 and 1981 were analysed for total and speciated arsenic and the results were compared with each other and with results for several more recently collected samples from local markets. The average content of total arsenic was 210 +/- 190 ng As g(-1). This study demonstrates that US rice samples with higher levels of total arsenic have higher levels of dimethylarsinic acid; however, inorganic arsenic levels, regardless of the total arsenic content, rarely exceed 150 ng As g(-1) dry weight. These data are consistent with more recent findings, thus establishing trends that arsenic content in US-grown rice has been relatively constant throughout the last 30 years. To the authors' knowledge, the presented data are unique in that they provide a historical reference point for arsenic distribution in US-produced rice. These data would be invaluable for several applications including long-term arsenic exposure studies, environmental clean-up assessments, and to establish models for future trends in arsenic contribution in total diet studies. PMID- 24785174 TI - Survey of trace elements (Al, As, Cd, Cr, Co, Hg, Mn, Ni, Pb, Se, and Si) in retail samples of flavoured and bottled waters. AB - Concentrations of eleven trace elements (Al, As, Cd, Cr, Co, Hg, Mn, Ni, Pb, Se, and Si) were measured in 39 (natural and flavoured) water samples. Determinations were performed using graphite furnace electrothermetry for almost all elements (Al, As, Cd, Cr, Co, Mn, Ni, Pb, and Si). For Se determination hydride generation was used, and cold vapour generation for Hg. These techniques were coupled to atomic absorption spectrophotometry. The trace element content of still or sparkling natural waters changed from brand to brand. Significant differences between natural still and natural sparkling waters (p < 0.001) were only apparent for Mn. The Mann-Whitney U-test was used to search for significant differences between flavoured and natural waters. The concentration of each element was compared with the presence of flavours, preservatives, acidifying agents, fruit juice and/or sweeteners, according to the labelled composition. It was shown that flavoured waters generally increase the trace element content. The addition of preservatives and acidifying regulators had a significant influence on Mn, Co, As and Si contents (p < 0.05). Fruit juice can also be correlated to the increase of Co and As. Sweeteners did not provide any significant difference in Mn, Co, Se and Si content. PMID- 24785175 TI - Survey of levels of cadmium in oysters, mussels, clams and scallops from the Pacific Northwest coast of Canada. AB - Field and retail collections of bivalves from the Pacific Northwest, Canada, were analysed for cadmium concentrations by atomic absorption spectrophotometry (AAS). Both collections of varnish (Nuttallia obscurata) and manila (Venerupis philippinarum) clams contained cadmium concentrations of less than 0.5 ug g(-1), well below international safety guidelines of 1 and 2 ug g(-1) wet weight cadmium for the European and Hong Kong markets, respectively, as well as the 2 ug g(-1) safety guideline set by the Codex Alimentarius Commission (CAC). Cadmium concentrations in retail collections of the Pacific oyster, Crassostrea gigas, were generally above 2 ug g(-1) wet weight (range = 1.5-3.56 ug g(-1)). Retail collections of the mussel, Mytilus spp., contained cadmium concentrations below the 2 ug g(-1) wet weight guideline, but not always the 1 ug g(-1) limit (range = 0.15-1.8 ug g(-1)). However, field collections of Mytilus spp. contained cadmium concentrations between 0.35 and 4.00 ug g(-1) wet weight, and depending on sampling location, concentrations exceeded the CAC guidelines by more than two fold. Locations where mussels had high cadmium concentrations correlated with regions that had previously reported high values for cadmium in Pacific oysters (r = 0.65; p < 0.05). Of the various shellfish analysed, the four species of scallops, Chlamys hastata, C. rubida, Crassadoma gigantea, and Patinopecten yessoensis, contained the greatest concentrations of cadmium, in excess of 5 ug g(-1) wet weight (range = 4.97-8.98 ug g(-1)) with the greatest concentrations determined for C. gigantea. Cadmium concentrations in shellfish from the Pacific Northwest are greater than values reported for shellfish from other regions of the world and consumers need be aware of Health Canada consumption guidelines for shellfish from this region. PMID- 24785176 TI - Pesticide residue monitoring of Brazilian fruit for export 2006-2007. AB - Brazil ranks 8th in the world for tropical fresh fruit production and exports almost 60% to Europe. A nationwide monitoring program "National Program Residues of Contaminants in Food (PNCRC)" checks compliance with the maximum residue levels, guaranteeing the quality of these commodities. Fruit samples (112) were analyzed between January 2006 and June 2007. Approximately 140 pesticides were evaluated by a multi-residue method using GC and HPLC methodologies. Dithiocarbamates were determined through conversion into carbon disulfide (CS2). A total of 76.8% of the samples were negative, with residues below the limit of detection. With reference to Brazilian legislation, 23.2% of the samples were positive (>MRL and not permitted for the crop (NPC), but only 4.4% were contaminated with multiple residues. A total of 14.3% of samples exceeded European Union MRLs. Samples of figs and persimmons had the highest violation rates. Action plans are being developed, with the cooperation of producers, to reduce pesticide residues. PMID- 24785177 TI - Survey of fumonisins B1, B2 and B3 in conventional and organic retail corn products in Spain and Italy and estimated dietary exposure. AB - A survey was conducted to determine the occurrence of fumonisin B1, B2 and B3 during 2007 in 186 samples of organic and conventional locally available corn products. Samples included baby food (n = 62), corn flour (11), cornflakes (23), pasta (14), cookies (17) and other corn products (59) were obtained from popular markets of Valencia (Spain) and Perugia (Italy). The analytical method used pressurized liquid extraction and liquid chromatography/electrospray ionization tandem mass spectrometry with a triple quadrupole (QqQ) analyser. Of the 104 Spanish samples, 22% contained levels in the range of 2-449 ug kg(-1), 2-229 ug kg(-1) and 6-105 ug kg(-1) for FB1, FB2 and FB3, respectively, while 19 (23%) of the 82 Italian samples were positive with quantifiable levels between 2-235 ug kg(-1), 3-187 ug kg(-1), and 4-40 ug kg(-1) for fumonisins B1, B2 and B3, respectively. Overall, none of the Italian samples and only one organic baby food sample from a Spanish market was above the maximum permitted levels established by European legislation. Fumonisins were found mostly in corn flour followed by cookies and cornflakes. Eleven samples from Spain and nine samples from Italy were organic products, being contaminated the 72% and 77% of the samples, respectively. Analysis of the results showed that levels of fumonisins in corn products were similar in Italy and Spain. The safety of fumonisin intake through corn products was demonstrated by the calculation of the estimated daily intake of both populations considering organic and conventional products separately, which ranged from 1.7 * 10(-3) to 0.72 ug kg(-1) bw day(-1) and comparing them with the provisional maximum total daily intake (PMTDI) of 2 ug kg(-1) bw day(-1) established by the European Union. PMID- 24785178 TI - Occurrence and intake of deoxynivalenol in cereal-based products marketed in Korea during 2007-2008. AB - The occurrence of deoxynivalenol (DON) was investigated in 514 cereal-based products (corn-based, n = 125; barley-based, n = 96; wheat-based, n = 94; rice based, n = 199) marketed in Korea during 2007-2008, and estimates of DON intake were determined. Samples were analysed by high-performance liquid chromatography (HPLC) with ultraviolet light (UV) detection after immunoaffinity clean-up. The limits of detection (LOD) and limits of quantification (LOQ) were 2.2 and 5.6 ug kg(-1), respectively. Recoveries and repeatability expressed as coefficients of variation (CV) were 82.3-100% and 2.4-15.3% in beer, bread and dried corn. The incidences and mean levels of DON were 56% and 68.9 ug kg(-1) for corn-based products, 49% and 24.1 ug kg(-1) for wheat-based products, 43% and 7.5 ug kg(-1) for barley-based products, and 16% and 3.4 ug kg(-1) for rice-based products, respectively. The estimated daily intake of DON from the consumption of rice based, wheat-based, barley-based and corn-based products were 0.0038 ug kg(-1) bw day(-1), 0.0032 ug kg(-1) bw day(-1), 0.0015 ug kg(-1) bw day(-1) and 0.0002 ug kg(-1) bw day(-1), respectively. These values represent 0.38%, 0.32%, 0.25% and 0.01% of the provisional maximum tolerable daily intake (PMTDI) of 1 ug kg(-1) bw day(-1). These results indicate that rice-based products are major contributors to DON exposure in Korea, even though the current exposure level is unlikely to cause adverse health effects. PMID- 24785179 TI - Correlation of rainfall and levels of deoxynivalenol in wheat from Uruguay, 1997 2003. AB - A total of 286 wheat samples for human consumption collected during 1997-2003 from four wheat-producing localities of south-western Uruguay were screened for deoxynivalenol (DON). Quantification was carried on by an immunochemical method using immunoaffinity columns and fluorimetric detection. The incidence of DON was high during the whole survey (58.5-100%), except in 1998 and 1999 in which no contamination occurred. During 2001 and 2002, 100% of samples contained detectable levels of DON, being the mean DON contents 6593 and 5880 ug kg(-1), respectively. The annual maximum levels ranged from 8800 to 11,400 ug kg(-1). A positive correlation between DON levels and precipitation was seen. The 70% of wheat samples destined for human consumption were contaminated with DON. To avoid the introduction of contaminated materials into the food chain process, the adoption of regular screening of the DON level in wheat is recommended, particularly in years with heavy rainfall during the flowering-to-early stages of grain maturity months. PMID- 24785180 TI - Survey of phthalate levels in Italian oily foods contained in glass jars with PVC gaskets. AB - A method based on gas chromatography/tandem mass spectrometry was used to assess levels of twelve phthalates in 50 samples of oily foods packed in glass jars with metal closure obtained from a retail market. The amounts of di-methyl phthalate, di-ethyl phthalate, di-propyl phthalate, di-butyl phthalate, di-pentyl phthalate, benzyl butyl phthalate, di-cyclohexyl phthalate, di-n-octyl phthalate, di isononyl phthalate and di-isodecyl phthalate in all samples analysed were less than the limit of quantification (LOQ). Di-(2-ethylhexyl) phthalate was detected in 20 samples in the range from 0.1 to 6 mg kg(-1) with an average of 1.0 mg kg( 1), and it exceeded the specific migration limit (SML) of 1.5 mg kg(-1) in five cases with an average of 3.0 mg kg(-1). Di-isobutyl phthalate was found in four samples at 0.1-0.4 mg kg(-1). The PVC gaskets used for the lids were negative for all tested phthalates, suggesting that the contamination of the foods originated from other sources, e.g. olive oil. PMID- 24785181 TI - Comparison of homogenization techniques and incidence of aflatoxin contamination in dried figs for export. AB - To determine differences in mean aflatoxin contamination and subsample variance from dry and slurry homogenizations, 10 kg of six different, naturally contaminated dried fig samples were collected from various exporting companies in accordance with the EU Commission Directive. The samples were first dry-mixed for 5 min using a blender and sub-sampled seven times; the remainder was slurry homogenized (1 : 1, v/v) and sub-sampled seven times. Aflatoxin B1 and total aflatoxin levels were recorded and coefficient of variations (CV) computed for all sub-samples. Only a small reduction in sub-sample variations, indicated by the lower CV values, and slight differences in mean aflatoxin B1 and total aflatoxin levels were observed when slurry homogenization was applied. Therefore, 7326 dried figs, destined for export from Turkey to the EU and collected during the 2008 crop year, were dry-homogenized and tested for aflatoxins (B1, B2, G1 and G2) by immunoaffinity column clean-up using RP-HPLC. While 34% of the samples contained detectable levels of total aflatoxins (0.20-208.75 ug kg(-1)), only 9% of them exceeded the EU limit of 4 ug kg(-1) in the range 2.0-208.75 ug kg(-1), respectively. A substantial increase in the incidence of aflatoxins was observed in 2008, most likely due to the drought stress experienced in Aydin province as occurred in 2007. PMID- 24785182 TI - Survey of aflatoxins in retail samples of whole and ground black and white peppercorns. AB - A total of 126 local and imported samples of commercial white and black pepper in Malaysia were analysed for aflatoxins B1, B2, G1 and G2 (AFB1, AFB2, AFG1, AFG2) content using high-performance liquid chromatography (HPLC) with a fluorescence detector (FD). An acetonitrile-methanol-water (17 : 29 : 54; v/v) mixture was used as a mobile phase and clean-up was using an immunoaffinity column (IAC). Seventy out of 126 (55.5%) samples were contaminated with total aflatoxins, although only low levels of aflatoxins were found ranging from 0.1 to 4.9 ng g( 1). Aflatoxin B1 showed the highest incidence of contamination and was found in all contaminated samples. There was a significant difference between type of samples and different brands (p < 0.05). The results showed black peppers were more contaminated than white peppers. PMID- 24785184 TI - In vitro inhibitory effect on digestive enzymes and antioxidant potential of commonly consumed fruits. AB - Dietary inhibitors of fats and carbohydrates degrading enzymes can reduce obesity and type 2 diabetes. In this study, we screened crude extracts from 30 commonly consumed fruits to test their in vitro inhibitory effect against key enzymes relevant for obesity (pancreatic lipase) and type 2 diabetes (alpha-glucosidase and alpha-amylase), total phenolic content (Folin-Ciocalteu method), and antioxidant capacity (ABTS and FRAP). The IC50 values of the fruits tested varied from 39.91 to >400 mg/mL, from 1.04 to >80 mg/mL, and from 0.72 to 135.07 mg/mL against alpha-glucosidase, alpha-amylase, and pancreatic lipase, respectively. Antioxidant capacity ranged from 0.66 to 124.66 MUmol of TE/g of fruit and strongly correlated with phenolic content, while the enzyme inhibition was poorly correlated with total phenolic and antioxidant capacity. Among fruits tested, blue honeysuckle and red gooseberry exhibited the highest inhibitory activity with respect to the carbohydrate degrading enzymes, while lingonberry had the strongest anti-lipase activity. PMID- 24785183 TI - The reliability of weight-for-length/height Z scores in children. AB - The World Health Organisation (WHO) recommends weight-for-length/height (WFL/H), represented as a Z score for diagnosing acute malnutrition among children aged 0 to 60 months. Under controlled conditions, weight, height and length measurements have high degree of reliability. However, the reliability when combined into a WFL/H Z score, in all settings is unclear. We conducted a systematic review of published studies assessing the reliability of WFL/Hz on PubMed and Google scholar. Studies were included if they presented reliability scores for the derived index of WFL/Hz, for children under 5 years. Meta-analysis was conducted for a pooled estimate of reliability overall, and for children above and below 24 months old. Twenty six studies on reliability of anthropometry were identified but only three, all community-based studies, reported reliability scores for WFL/Hz. The overall pooled intra-class correlation coefficient (ICC) estimate for WFL/Hz among children aged 0 to 60 months was 0.81 (95% CI 0.64 to 0.99). Among children aged less than 24 months the pooled ICC estimate from two studies was 0.72 (95% CI 0.67 to 0.77) while the estimate reported for children above 24 months from one study was 0.97 (95% CI 0.97 to 0.99). Although WFL/Hz is recommended for diagnosis of acute under nutrition among children below 5 years, information on its reliability in all settings is sparse. In community settings, reliability of WFL/Hz is considerably lower than for absolute measures of weight and length/height, especially in younger children. The reliability of WFL/Hz needs further evaluation. PMID- 24785185 TI - Physical and psychological implications in a multiple and preterm caesarean section. A case report. AB - Cesarean section (CS) in Italy has continuously increasing rates. Due to the primary CS, the repeated CS have shown a superimposable trend. Consequently, a number of pathologies are related to such surgery among which placenta previa, dehiscence of previous scar, placenta accreta and preterm delivery. The purpose of this case report is to discuss the physical and psychological implications correlated with a very unusual case of a consecutive seventh CS in the same pregnant woman associated with several diseases: preterm delivery, fetal distress, intrauterine growth retardation (IUGR) (-4 weeks), central placenta previa with metrorrhagia, dehiscence of hysterectomic scar. In spite of the therapy (antifibrinolytic, tocolytic drugs, iron, folates, betamethasone) a preterm CS could not be avoided. Surgery was challenging; hysterectomy was avoided and the mother followed a normal post-operative course, whereas fetal distress and IUGR did not allow the survival of the newborn. A review of the literature regarding the clinical management and psychological aspects of a pregnant woman undergoing multiple complicated CS with the aforementioned disorders will be undertaken. PMID- 24785186 TI - Characterization of microRNA transcriptome in lung cancer by next-generation deep sequencing. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Systematically characterizing miRNAs in NSCLC will help develop biomarkers for its diagnosis and subclassification, and identify therapeutic targets for the treatment. We used next-generation deep sequencing to comprehensively characterize miRNA profiles in eight lung tumor tissues consisting of two major types of NSCLC, squamous cell carcinoma (SCC) and adenocarcinoma (AC). We used quantitative PCR (qPCR) to verify the findings in 40 pairs of stage I NSCLC tissues and the paired normal tissues, and 60 NSCLC tissues of different types and stages. We also investigated the function of identified miRNAs in lung tumorigenesis. Deep sequencing identified 896 known miRNAs and 14 novel miRNAs, of which, 24 miRNAs displayed dysregulation with fold change >=4.5 in either stage I ACs or SCCs or both relative to normal tissues. qPCR validation showed that 14 of 24 miRNAs exhibited consistent changes with deep sequencing data. Seven miRNAs displayed distinctive expressions between SCC and AC, from which, a panel of four miRNAs (miRs-944, 205-3p, 135a-5p, and 577) was identified that cold differentiate SCC from AC with 93.3% sensitivity and 86.7% specificity. Manipulation of miR-944 expression in NSCLC cells affected cell growth, proliferation, and invasion by targeting a tumor suppressor, SOCS4. Evaluating miR-944 in 52 formalin-fixed paraffin-embedded SCC tissues revealed that miR-944 expression was associated with lymph node metastasis. This study presents the earliest use of deep sequencing for profiling miRNAs in lung tumor specimens. The identified miRNA signatures may provide biomarkers for early detection, subclassification, and predicting metastasis, and potential therapeutic targets of NSCLC. PMID- 24785187 TI - Magnetic resonance functional nano-hydroxyapatite incorporated poly(caprolactone) composite scaffolds for in situ monitoring of bone tissue regeneration by MRI. AB - In this study, we have reported the incorporation of a multi-modal contrast agent based on hydroxyapatite nanocrystals, within a poly(caprolactone)(PCL) nanofibrous scaffold by electrospinning. The multifunctional hydroxyapatite nanoparticles (MF-nHAp) showed simultaneous contrast enhancement for three major molecular imaging techniques. In this article, the magnetic resonance (MR) contrast enhancement ability of the MF-nHAp was exploited for the purpose of potentially monitoring as well as for influencing tissue regeneration. These MF nHAp containing PCL scaffolds were engineered in order to enhance the osteogenic potential as well as its MR functionality for their application in bone tissue engineering. The nano-composite scaffolds along with pristine PCL were evaluated physico-chemically and biologically in vitro, in the presence of human mesenchymal stem cells (hMSCs). The incorporation of 30-40 nm sized MF-nHAp within the nanofibers showed a substantial increase in scaffold strength, protein adsorption, proliferation, and osteogenic differentiation of hMSCs along with enhanced MR functionality. This preliminary study was performed to eventually exploit the MR contrast imaging capability of MF-nHAp in nanofibrous scaffolds for real-time imaging of the changes in the tissue engineered construct. PMID- 24785188 TI - Sodium and potassium regulate endothelial phospholipase C-gamma and Bmx. AB - The amount of Na(+) and K(+) in the diet promotes significant changes in endothelial cell function. In the present study, a series of in vitro and in vivo experiments determined the role of Na(+) and K(+) in the regulation of two pleckstrin homology domain-containing intracellular signaling molecules, phospholipase C (PLC)-gamma1 and epithelial and endothelial tyrosine kinase/bone marrow tyrosine kinase on chromosome X (Bmx), and agonist-generated Ca(2+) signaling in the endothelium. Extracellular K(+) concentration regulated the levels of activated PLC-gamma1, Bmx, and carbachol-stimulated intracellular Ca(2+) mobilization in human endothelial cells. Additional experiments confirmed that high-conductance Ca(2+)-activated K(+) channels and phosphatidylinositol 3 kinase mediated these effects. The content of Na(+) and K(+) in the diet also regulated Bmx levels in endothelial cells and activated PLC-gamma1 levels in rats in vivo. The effects of dietary K(+) on Bmx were more pronounced in rats fed a high-salt diet compared with rats fed a low-salt diet. These experiments elucidated an endothelial cell signaling mechanism regulated by electrolytes, further demonstrating an integral relationship between endothelial cell function and dietary Na(+) and K(+) content. PMID- 24785189 TI - Syncytial communication in descending vasa recta includes myoendothelial coupling. AB - Using dual cell patch-clamp recording, we examined pericyte, endothelial, and myoendothelial cell-to-cell communication in descending vasa recta. Graded current injections into pericytes or endothelia yielded input resistances of 220 +/- 21 and 128 +/- 20 MOmega, respectively (P < 0.05). Injection of positive or negative current into an endothelial cell depolarized and hyperpolarized adjacent endothelial cells, respectively. Similarly, current injection into a pericyte depolarized and hyperpolarized adjacent pericytes. During myoendothelial studies, current injection into a pericyte or an endothelial cell yielded small, variable, but significant change of membrane potential in heterologous cells. Membrane potentials of paired pericytes or paired endothelia were highly correlated and identical. Paired measurements of resting potentials in heterologous cells were also correlated, but with slight hyperpolarization of the endothelium relative to the pericyte, -55.2 +/- 1.8 vs. -52.9 +/- 2.2 mV (P < 0.05). During dual recordings, angiotensin II or bradykinin stimulated temporally identical variations of pericyte and endothelial membrane potential. Similarly, voltage clamp depolarization of pericytes or endothelial cells induced parallel changes of membrane potential in the heterologous cell type. We conclude that the descending vasa recta endothelial syncytium is of lower resistance than the pericyte syncytium and that high-resistance myoendothelial coupling also exists. The myoendothelial communication between pericytes and endothelium maintains near identity of membrane potentials at rest and during agonist stimulation. Finally, endothelia membrane potential lies slightly below pericyte membrane potential, suggesting a tonic role for the former to hyperpolarize the latter and provide a brake on vasoconstriction. PMID- 24785190 TI - LIM homeobox transcription factor 1B expression affects renal interstitial fibrosis and apoptosis in unilateral ureteral obstructed rats. AB - LIM homeobox transcription factor 1B (LMX1B) is a transcription factor of the LIM homeodomain type and has been implicated in the development of diverse structures such as limbs, kidneys, eyes, and the brain. Furthermore, LMX1B has been implicated in nail-patella syndrome, which is predominantly characterized by malformation of limbs and nails, and in 30% of patients, nephropathy, including renal fibrosis, is observed. Since no reports were available that studied the link between LMX1B expression and renal interstitial fibrosis, we explored if LMX1B affects typical markers of fibrosis, e.g., extracellular matrix components, profibrotic factors, and apoptosis as the final detrimental consequence. We recently showed that LMX1B acts as a negative regulator of transforming growth factor-betal, collagen type III, fibronectin, cleaved caspase-3, and the cell apoptosis rate in a renal tubular epithelial cell system under hypoxic conditions. Here, we confirmed these results in unilateral ureteral obstructed rats. Furthermore, LMX1B was distinctly expressed throughout the glomerulus and tubule lining, including epithelial cells. Knockdown of LMX1B aggravated the expression of fibrosis markers, oxidative stress, and apoptosis compared with the already increased levels due to unilateral ureteral obstruction, whereas overexpression attenuated these effects. In conclusion, reduced LMX1B levels clearly represent a risk factor for renal fibrosis, whereas overexpression affords some level of protection. In general, LMX1B may be considered to be a negative regulator of the fibrosis index, transforming growth factor-betal, collagen type III, fibronectin, cleaved caspase-3, cell apoptosis, ROS, and malondialdehyde (r = -0.756, -0.698, -0.921, -0.923, -0.843, -0.794, -0.883, and 0.825, all P < 0.01). PMID- 24785191 TI - Sophisticated digestive systems in early arthropods. AB - Understanding the way in which animals diversified and radiated during their early evolutionary history remains one of the most captivating of scientific challenges. Integral to this is the 'Cambrian explosion', which records the rapid emergence of most animal phyla, and for which the triggering and accelerating factors, whether environmental or biological, are still unclear. Here we describe exceptionally well-preserved complex digestive organs in early arthropods from the early Cambrian of China and Greenland with functional similarities to certain modern crustaceans and trace these structures through the early evolutionary lineage of fossil arthropods. These digestive structures are assumed to have allowed for more efficient digestion and metabolism, promoting carnivory and macrophagy in early arthropods via predation or scavenging. This key innovation may have been of critical importance in the radiation and ecological success of Arthropoda, which has been the most diverse and abundant invertebrate phylum since the Cambrian. PMID- 24785192 TI - Perovskite metal formate framework of [NH2-CH(+)-NH2]Mn(HCOO)3]: phase transition, magnetic, dielectric, and phonon properties. AB - We report the synthesis, crystal structure, and thermal, dielectric, phonon, and magnetic properties of [NH2-CH(+)-NH2][Mn(HCOO)3] (FMDMn). The anionic framework of [(Mn(HCOO)3(-)] is counterbalanced by formamidinium (FMD(+)) cations located in the cavities of the framework. These cations form extensive N-H...O hydrogen bonding with the framework. The divalent manganese ions have octahedral geometry and are bridged by the formate in an anti-anti mode of coordination. We have found that FMDMn undergoes a structural phase transition around 335 K. According to the X-ray diffraction, the compound shows R3c symmetry at 355 K and C2/c symmetry at 295 and 110 K. The FMD(+) cations are dynamically disordered in the high-temperature phase, and the disorder leads to very large bandwidths of Raman and IR bands corresponding to vibrations of the NH2 groups. Temperature-dependent studies show that the phase transition in FMDMn is associated with ordering of the FMD(+) cations. Detailed analysis shows, however, that these cations still exhibit some reorientational motions down to about 200 K. The ordering of the FMD(+) cations is associated with significant distortion of the anionic framework. On the basis of the magnetic data, FMDMn is a weak ferromagnet with the critical temperature Tc = 8.0 K. PMID- 24785193 TI - Characterization of pR18, a novel rolling-circle replication plasmid from Lactobacillus plantarum. AB - Lactobacillus plantarum PA18, a strain originally isolated from the leaves of Pandanus amaryllifolius, contains a pR18 plasmid. The pR18 plasmid is a 3211bp circular molecule with a G+C content of 35.8%. Nucleotide sequence analysis revealed two putative open reading frames, ORF1 and ORF2, in which ORF2 was predicted (317 amino acids) to be a replication protein and shared 99% similarity with the Rep proteins of pLR1, pLD1, pC30il, and pLP2000, which belong to the RCR pC194/pUB110 family. Sequence analysis also indicated that ORF1 was predicted to encode linA, an enzyme that enzymatically inactivates lincomycin. The result of Southern hybridization and mung bean nuclease treatment confirmed that pR18 replicated via the RCR mechanism. Phylogenetic tree analysis of pR18 plasmid proteins suggested that horizontal transfer of antibiotic resistance determinants without genes encoding mobilization has not only occurred between Bacillus and Lactobacillus but also between unrelated bacteria. Understanding this type of transfer could possibly play a key role in facilitating the study of the origin and evolution of lactobacillus plasmids. Quantitative PCR showed that the relative copy number of pR18 was approximately 39 copies per chromosome equivalent. PMID- 24785195 TI - Concentration mediated structural transition of triblock copolymer ultrathin films. AB - X-ray reflectivity, atomic force microscopy, X-ray photoelectron spectroscopy, and contact angle measurement techniques are used to study the structural changeover as a function of concentration of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymer diluted in toluene spin-coated as ultrathin films on hydrophilic Si substrate. A lamellar structure made of three alternating incomplete bilayers is observed until the concentration of copolymer solution attains a threshold value of about 3.6-4 g/L. Around this concentration and beyond, the entanglement of polymer chains takes place during drying and the growth of a homogeneous film made of complete bilayers on Si substrate is observed. The strong hydrophilic nature of the Si substrate dictates the growth of this amphiphilic copolymer. We evidence that the lower part of the films is made of hydrophilic PEO blocks attached to the substrate while the hydrophobic PPO blocks are directed toward air. PMID- 24785194 TI - Isolation and functional characterization of the promoter of a DEAD-box helicase Psp68 using Agrobacterium-mediated transient assay. AB - Helicases are molecular motor proteins that perform a variety of cellular functions including transcription, translation, DNA replication and repair, RNA maturation, ribosome synthesis, nuclear export and splicing processes. The p68 is an evolutionarily conserved protein which plays pivotal roles in all aspect RNA metabolism processes. It is well established that helicases provides abiotic stress adaptation in plants but analysis of cis-regulatory elements present in the upstream regions is still infancy. Here we report isolation and functional characterization of the promoter of a DEAD-box helicase Psp68 in response to abiotic stress and hormonal regulation. The promoter of Psp68 was isolated by gene walking PCR from pea genomic DNA library constructed in BD genome walker kit. In silico analysis revealed that promoter of Psp68 contained a TATA, a CAAT motif and also harbors some important stress and hormone associated cis regulatory elements, including E-box, AGAAA, GATA-box, ACGT, GAAAA and GTCTC. Functional analyses were performed by Agrobacterium-mediated transient assay in tobacco leaves. Very high level of GUS activity was observed in agroinfiltrated tobacco leaves by the construct carrying the Psp68 promoter::GUS, subjected to abiotic stress and exogenous hormonal treatments. Stress-inducible nature of Psp68 promoter opens possibility for the study of the gene regulation under stress condition. Therefore, may be useful in the field of agriculture and biotechnology. PMID- 24785196 TI - 2C-I-NBOMe, an "N-bomb" that kills with "Smiles". Toxicological and legislative aspects. AB - Substituted phenethylamines are a class of designer drugs that have recently emerged in the drug abuse market. Such substances remain legal to use, possess, and supply until these compounds become classified as scheduled. 2C-I-NBOMe or 25I-NBOMe is the N-benzyl-derivative of the iodo-substituted dimethoxy phenethylamine (2C-I) that appeared recently in the drug market under the street name "N-Bomb". Due to its high potency, intoxications and fatal cases related to 2C-I-NBOMe use are increased worldwide. The use and trafficking of this substituted phenethylamine is banned only in some countries. A comprehensive review was performed using PubMed and Medline databases, together with additional non-peer reviewed information sources, including books and publications of state authorities in different countries, regarding chemistry, availability, pharmacology, and toxicology of 2C-I-NBOMe. Intoxications or lethal cases, published or reported, as well as the current legislation on this newly introduced drug are also reviewed. PMID- 24785197 TI - Mesoscopic coarse-grained simulations of lysozyme adsorption. AB - Coarse-grained simulations are adopted to study the adsorption behavior of lysozyme on different (hydrophobic, neutral hydrophilic, zwitterionic, negatively charged, and positively charged) surfaces at the mesoscopic microsecond time scale (1.2 MUs). Simulation results indicate the following: (i) the conformation change of lysozyme on the hydrophobic surface is bigger than any other studied surfaces; (ii) the active sites of lysozyme are faced to the hydrophobic surface with a "top end-on" orientation, while they are exposed to the liquid phase on the hydrophilic surface with a "back-on" orientation; (iii) the neutral hydrophilic surface can induce the adsorption of lysozyme, while the nonspecific protein adsorption can be resisted by the zwitterionic surface; (iv) when the solution ionic strength is low, lysozyme can anchor on the negatively charged surface easily but cannot adsorb on the positively charged surface; (v) when the solution ionic strength is high, the positively charged lysozyme can also adsorb on the like-charged surface; (vi) the major positive potential center of lysozyme, especially the residue ARG128, plays a vital role in leading the adsorption of lysozyme on charged surfaces; (vii) when the ionic strength is high, a counterion layer is formed above the positively charged surface, which is the key factor why lysozyme can adsorb on a like-charged surface. The coarse grained method based on the MARTINI force field for proteins and the BMW water model could provide an efficient way to understand protein interfacial adsorption behavior at a greater length scale and time scale. PMID- 24785198 TI - Organocatalytic asymmetric epoxidation and aziridination of olefins and their synthetic applications. PMID- 24785199 TI - The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. AB - This guideline is the result of a systematic literature review using the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The life time prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). PMID- 24785200 TI - End-stage hindfoot arthrosis: outcomes of tibiocalcaneal fusion using internal and Ilizarov fixation. AB - End-stage post-traumatic pantalar arthrosis from ankle, pilon, and talus fractures has often been complicated by infection, bone loss, and a soft tissue deficit. Patients can present with neuropathy, diabetes, tobacco use, and previously failed arthrodesis. Fusion in this population has been challenging, with nonunion rates up to 30%, often leading to amputation. We reviewed the results of a standardized protocol that combined simultaneous internal fixation with the Ilizarov technique to achieve fusion in high-risk patients. With institutional review board approval, a retrospective review of the patients treated with simultaneous internal fixation and an Ilizarov frame was undertaken. The records and radiographs allowed identification of the comorbidities and the presence or absence of successful fusion. Complications were acknowledged and treated. Fifteen patients had undergone the procedure. The mean follow-up period was 27.9 (range 9 to 67) months. Thirteen patients (86.67%) had had previous fusion failure. Twelve patients (80%) had developed post-traumatic arthrosis, 5 (33.33%) of whom had open injuries. All patients had 1 comorbidity, and 10 (66.67%) had multiple, including rheumatoid arthritis, diabetes (types 1 and 2), and smoking. Four patients (26.67%) presented with deep infection and bone loss. Union was achieved in 11 (73.33%), with 12 (80%) patients experiencing profound pain relief. Seven patients (46.67%) required symptomatic hardware removal. Three patients (20%) eventually underwent below-the-knee amputation for recalcitrant nonunion. Statistically significant correlations were found between smoking and wound infection and revision and between nonunion and amputation. Our results have indicated that combined internal fixation with Ilizarov application can provide a strong surgical option for the management of end-stage, pantalar arthritis. More studies are needed to compare the cohort outcomes and gait analysis in these patients with those who have chosen below-the-knee amputation. PMID- 24785201 TI - A push-pull distraction method for arthroscopic subtalar joint arthrodesis. AB - Unlike ankle joint arthroscopy, distraction of the subtalar joint can be challenging. We introduce a powerful distraction method that can be used during an arthroscopic subtalar joint arthrodesis procedure using a "push-pull" technique. A fully threaded screw is used to push the talus while the calcaneus is pulled to distract the joint. The technique allows the surgeon to access the rather tight joint without disrupting a significant amount of the ligamentous and capsular structures. It also allows preservation of the vascular structures that supply the talus. The "push-pull" screw can also be converted to a second point of fixation at the end of the procedure. PMID- 24785202 TI - Epidemiology of foot and ankle fractures in the United States: an analysis of the National Trauma Data Bank (2007 to 2011). AB - Understanding the epidemiology of foot and ankle trauma could be useful in health services research and for policy makers. It can also define practice patterns. Using the National Trauma Data Bank data set from 2007 to 2011, we analyzed the frequency and proportion of each fracture in the foot and ankle in major trauma hospitals in the United States. A total of 280,933 foot and/or ankle fractures or dislocations were identified. Although oversampling of more severe trauma in younger patients might have occurred owing to the nature of the data set, we found that the most common fractures in the foot and ankle were ankle fractures. Midfoot fractures were the least common among all the foot and ankle fractures when categorized by anatomic location. Approximately 20% of all foot and ankle fractures were open. PMID- 24785203 TI - Three-dimensional lock and key colloids. AB - Colloids with well-defined multicavities are synthesized through the hydrolytic removal of silica cluster templates from organo-silica hybrid patchy particles. The geometry of the cavities stems from the originally assembled cluster templates, displaying well-defined three-dimensional symmetries, ranging from spherical, linear, triangular, tetrahedral, trigonal dipyramidal, octahedral, to pentagonal dipyramidal. The concave surface of the cavities is smooth, and the cavity shallowness and size can be varied. These particles with multicavities can act as "lock" particles with multiple "key holes". Up to n "key" particles can self-assemble into the lock particles via depletion interaction, resulting in multivalent, site-specific, reversible, and flexible bonding. PMID- 24785204 TI - University engagement in global health. PMID- 24785205 TI - Letting HIV transform academia--embracing implementation science. PMID- 24785208 TI - Global health and the law. PMID- 24785207 TI - Clinical practice. Lyme disease. PMID- 24785209 TI - Images in clinical medicine. Disseminated cryptococcosis. PMID- 24785210 TI - Clinical problem-solving. Out of the blue. PMID- 24785206 TI - Diagnosis of childhood tuberculosis and host RNA expression in Africa. AB - BACKGROUND: Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). METHODS: The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. RESULTS: We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. CONCLUSIONS: RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others). PMID- 24785211 TI - Convergence to common purpose in global health. PMID- 24785212 TI - Keshan disease, selenium deficiency, and the selenoproteome. PMID- 24785213 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24785214 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24785215 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24785216 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24785217 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24785218 TI - Genotype-guided dosing of vitamin K antagonists. PMID- 24785219 TI - Intussusception risk after rotavirus vaccination in U.S. infants. PMID- 24785220 TI - Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. PMID- 24785221 TI - Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. PMID- 24785222 TI - Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. PMID- 24785223 TI - Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. PMID- 24785224 TI - Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. PMID- 24785226 TI - Videos in clinical medicine. Gastrostomy-tube exchange. PMID- 24785227 TI - Images in clinical medicine. Superficial abdominal reflex. PMID- 24785228 TI - Screening of integrin-binding peptides in a laminin peptide library derived from the mouse laminin beta chain short arm regions. AB - Laminins, major components of basement membrane, consist of three different subunits, alpha, beta, and gamma chains, and so far, five alpha, three beta, and three gamma chains have been identified. We have constructed synthetic peptide libraries derived from the laminin sequences and identified various cell-adhesive peptides. Ten active peptides from the laminin alpha chain sequences (alpha1 alpha5) were found to promote integrin-mediated cell adhesion. Previously, we found fourteen cell-adhesive peptides from the beta1 chain sequence but their receptors have not been analyzed. Here, we expanded the synthetic peptide library to add peptides from the short arm regions of the laminin beta2 and beta3 chains and screened for integrin-binding peptides. Twenty-seven peptides promoted human dermal fibroblast (HDF) attachment in a peptide-coated plate assay. The morphological appearance of HDFs on the peptide-coated plates differed depending on the peptides. B34 (REKYYYAVYDMV, mouse laminin beta1 chain, 255-266), B67 (IPYSMEYEILIRY, mouse laminin beta1 chain, 604-616), B2-105 (APNFWNFTSGRG, mouse laminin beta2 chain, 1081-1092), and B3-19 (GHLTGGKVQLNL, mouse laminin beta3 chain, 182-193) promoted HDF spreading and HDF attachment was inhibited by EDTA, suggesting that the peptides interact with integrins. Immunostaining analyses revealed that B67 induced well-organized actin stress fibers and focal contacts containing vinculin, however, B34, B2-105, and B3-19 did not exhibit stress fiber formation or focal contacts. The inhibition assay using anti-integrin antibodies indicated that B67 interacts with alpha3, alpha6, and beta1 integrins, and B34 and B3-19 interact with beta1 integrin. Based on adhesion analysis of peptides modified with an alanine scan and on switching analysis with the homologous inactive sequence B2-64 (LPRAMDYDLLLRW, mouse laminin beta2 chain, 618-630), the Glu(8) residue in the B67 peptide was critical for HDF adhesion. These findings are useful for identifying an integrin binding motif. The B67 peptide has potential for use as a molecular probe for integrins. PMID- 24785229 TI - Dexmedetomidine renders a brain protection on hippocampal formation through inhibition of nNOS-NO signalling in endotoxin-induced shock rats. AB - BACKGROUND: Endotoxin shock (ES) and its severe complications, such as brain injury, remain a handicap clinically. Therefore, it is a clinical significance of developing a new drug to treat brain damage induced by ES. AIM: The present study aimed to observe the protective effect of dexmedetomidine (Dex) on hippocampal formation in endotoxin-induced shock rats and explore its possible mechanism. METHODS: High and low doses of Dex were tail intravenously administered slowly. After a 5-minute interval, lipopolysaccharide was tail intravenous injected slowly to establish the ES rats. Six hours after Dex administration, these rats were immediately sacrificed. Then, the brain water content was determined. NO amounts in homogenate, cerebrospinal fluid and serum were detected by Griess Reagent assay. nNOS mRNA in hippocampal formation was measured by RT-PCR and nNOS protein was determined by Western blotting and immunohistochemistry. RESULTS: ES rats showed that cerebral water contents were significantly increased, NO concentrations in brain tissues, serum and cerebrospinal fluid were each obviously raised and meanwhile expressions of nNOS mRNA and its protein in hippocampal formation were notably augmented. Treatment of these rats with Dex evidently decreased cerebral water contents, NO concentrations and nNOS mRNA and its protein expressions. CONCLUSION: These results demonstrated that Dex exerted a brain protection on hippocampal formation through inhibition of the nNOS-NO signalling in ES rats and Dex may have a favourably therapeutic value in treating brain damage in patients with endotoxin shock. PMID- 24785230 TI - Complications among adults hospitalized with influenza: a comparison of seasonal influenza and the 2009 H1N1 pandemic. AB - BACKGROUND: Persons with influenza can develop complications that result in hospitalization and death. These are most commonly respiratory related, but cardiovascular or neurologic complications or exacerbations of underlying chronic medical conditions may also occur. Patterns of complications observed during pandemics may differ from typical influenza seasons, and characterizing variations in influenza-related complications can provide a better understanding of the impact of pandemics and guide appropriate clinical management and planning for the future. METHODS: Using a population-based surveillance system, we compared clinical complications using International Classification of Diseases, Ninth Revision (ICD-9) discharge diagnosis codes in adults hospitalized with seasonal influenza (n = 5270) or 2009 pandemic influenza A(H1N1) (H1N1pdm09; n = 4962). RESULTS: Adults hospitalized with H1N1pdm09 were younger (median age, 47 years) than those with seasonal influenza (median age, 68 years; P < .01), and differed in the frequency of certain underlying medical conditions. Whereas there was similar risk for many influenza-associated complications, after controlling for age and type of underlying medical condition, adults hospitalized with H1N1pdm09 were more likely to have lower respiratory tract complications, shock/sepsis, and organ failure than those with seasonal influenza. They were also more likely to be admitted to the intensive care unit, require mechanical ventilation, or die. Young adults, in particular, had 2-4 times the risk of severe outcomes from H1N1pdm09 than persons of the same ages with seasonal influenza. CONCLUSIONS: Although H1N1pdm09 was thought of as a relatively mild pandemic, these data highlight the impact of the 2009 pandemic on the risk of severe influenza, especially among younger adults, and the impact this virus may continue to have. PMID- 24785231 TI - Reply to Zuluaga et al. PMID- 24785232 TI - Editorial commentary: Clostridium difficile in pediatric oncology patients: more questions than answers. PMID- 24785233 TI - Comparative evaluation of the tolerability of cefazolin and nafcillin for treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting. AB - BACKGROUND: Nafcillin and cefazolin are considered first-line therapy for most infections with methicillin-susceptible Staphylococcus aureus (MSSA), and recent studies have suggested similar clinical efficacy. Limited data are available on the comparative tolerability of these agents. METHODS: In this retrospective cohort analysis of patients treated with either nafcillin or cefazolin for MSSA infection in the outpatient parenteral antimicrobial therapy clinic at Massachusetts General Hospital from 2007 to 2011, the frequency of premature antimicrobial discontinuation (PAD) and drug-emergent events (DEEs) was calculated. RESULTS: Three hundred sixty-six and 119 patients were treated with nafcillin or cefazolin, respectively. The median anticipated duration of therapy was comparable at 28 (interquartile range [IQR], 16-37) and 29 (IQR, 24-39) days, respectively, for those treated with nafcillin and cefazolin. Fewer patients completed the prespecified treatment course with nafcillin than with cefazolin (PAD rate, 33.8% vs 6.7%; P < .0001). The hazard ratio for PAD in the nafcillin vs cefazolin groups was 2.81 (95% confidence interval [CI], 1.26-3.68). More patients in the nafcillin group developed rash (13.9% vs 4.2%; P = .002), renal dysfunction (11.4% vs 3.3%; P = .006), and liver function abnormalities (8.1% vs 1.6%; P = .01). Overall rates of DEEs per 1000 patient-days were 16.9 (95% CI, 10.4-27.3) and 4.8 (95% CI, 1.1-10.2), respectively. In 9 cases of nafcillin discontinuation, treatment was changed to cefazolin; all 9 completed treatment with no further observed DEEs. CONCLUSIONS: Nafcillin treatment was associated with higher rates of both PAD as well as DEEs compared with cefazolin treatment. This difference in tolerability, in addition to efficacy and cost, should be considered when decisions for outpatient parenteral MSSA treatment are made. PMID- 24785234 TI - About the validation of animal models to study the pharmacodynamics of generic antimicrobials. PMID- 24785235 TI - High colonization rate and prolonged shedding of Clostridium difficile in pediatric oncology patients. AB - Surveillance testing for Clostridium difficile among pediatric oncology patients identified stool colonization in 29% of patients without gastrointestinal symptoms and in 55% of patients with prior C. difficile infection (CDI). A high prevalence of C. difficile colonization and diarrhea complicates the diagnosis of CDI in this population. PMID- 24785237 TI - Comparing complications of pandemic and seasonal influenza is complicated. PMID- 24785236 TI - Differential impact of respiratory syncytial virus and parainfluenza virus on the frequency of acute otitis media is explained by lower adaptive and innate immune responses in otitis-prone children. AB - BACKGROUND: Acute otitis media (AOM) is a leading cause of bacterial pediatric infections associated with viral upper respiratory infections (URIs). We examined the differential impact of respiratory syncytial virus (RSV) and parainfluenza virus URIs on the frequency of AOM caused by Streptococcus pneumoniae (Spn) and nontypeable Haemophilus influenzae (NTHi) in stringently defined otitis-prone (sOP) and non-otitis-prone (NOP) children as a potential mechanism to explain increased susceptibility to AOM. METHODS: Peripheral blood and nasal washes were obtained from sOP and NOP children (n = 309). Colonization events and antiviral responses consisting of total specific immunoglobulin G (IgG) responses, neutralizing antibody responses, and T-cell responses were determined. Isolated neutrophils were infected with varying multiplicities of infection of both viruses, and opsonophagocytosis potential was measured. RESULTS: A significant increase was found in frequency of AOM events caused by Spn and NTHi, with a concurrent RSV infection in sOP children. These results correlated with diminished total RSV-specific IgG, higher viral nasal burdens, and lower IgG neutralizing capacity. The sOP children had diminished T-cell responses to RSV that correlated with lower Toll-like receptor 3/7 transcript and decreased expression of HLA-DR on antigen-presenting cells. RSV interfered with the Spn phagocytic capacity of neutrophils in a dose-dependent manner. Parainfluenza virus infections did not differentially affect AOM events in sOP and NOP children. CONCLUSIONS: Lower innate and adaptive immune responses to RSV in sOP children may slow the kinetics of viral clearance from the nasopharynx and allow for viral interference with antibacterial immune responses, thus contributing to increased frequency of AOMs. PMID- 24785238 TI - Editorial commentary: step on the GAS: are we almost there for clindamycin and intravenous immunoglobulin? PMID- 24785239 TI - Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group a streptococcal infections. AB - BACKGROUND: The use of clindamycin and intravenous immunoglobulin (IVIG) in treatment of invasive group A streptococcal (iGAS) infection, and the need for prophylactic antibiotics in close contacts, remains contentious. Controlled trials are unlikely to be conducted, so prospective, observational studies provide the best data to inform practice. METHODS: We conducted population-based, prospective, active surveillance of iGAS infections throughout the state of Victoria, Australia (population 4.9 million), from March 2002 through August 2004. RESULTS: Eighty-four cases of severe iGAS infection (streptococcal toxic shock syndrome, necrotizing fasciitis, septic shock, or GAS cellulitis with shock) were identified. Clindamycin-treated patients had more severe disease than clindamycin-untreated patients but lower mortality (15% vs 39%; odds ratio [OR], 0.28; 95% confidence interval [CI], .10-.80). Among those who received concurrent IVIG, the fatality rate was lower still (7%). The adjusted point estimate of the OR for mortality was lower in clindamycin-treated patients (0.31; 95% CI, .09 1.12) and clindamycin plus IVIG-treated patients (0.12; 95% CI, .01-1.29) compared with clindamycin-untreated patients. Three confirmed cases of iGAS infection occurred in household contacts of index cases. The incidence rate of iGAS disease in contacts was 2011 (95% CI, 413-5929) times higher than the population incidence in Victoria. CONCLUSIONS: Our data suggest that clindamycin treatment of patients with severe iGAS infections substantially reduces mortality and that this effect may be enhanced by concurrent treatment with IVIG. The dramatically increased risk of iGAS disease among household contacts within 1 month of the index case highlights a potential role for antibiotic prophylaxis. PMID- 24785240 TI - Detecting everyday action deficits in Alzheimer's disease using a nonimmersive virtual reality kitchen. AB - Alzheimer's disease (AD) causes impairments affecting instrumental activities of daily living (IADL). Transdisciplinary research in neuropsychology and virtual reality has fostered the development of ecologically valid virtual tools for the assessment of IADL, using simulations of real life activities. Few studies have examined the benefits of this approach in AD patients. Our aim was to examine the utility of a non-immersive virtual coffee task (NI-VCT) for assessment of IADL in these patients. We focus on the assessment results obtained from a group of 24 AD patients on a task designed to assess their ability to prepare a virtual cup of coffee, using a virtual coffee machine. We compared performance on the virtual task to an identical daily living task involving the actual preparation of a cup of coffee, as well as to global cognitive, executive, and caregiver-reported IADL functioning. Relative to 32 comparable, healthy elderly (HE) controls, AD patients performed worse than HE controls on all tasks. Correlation analyses revealed that NI-VCT measures were related to all other neuropsychological measures. Moreover, regression analyses demonstrated that performance on the NI VCT predicted actual task performance and caregiver-reported IADL functioning. Our results provide initial support for the utility of our virtual kitchen for assessment of IADL in AD patients. PMID- 24785241 TI - Characterization of the histone methyltransferase PRDM9 using biochemical, biophysical and chemical biology techniques. AB - PRDM proteins have emerged as important regulators of disease and developmental processes. To gain insight into the mechanistic actions of the PRDM family, we have performed comprehensive characterization of a prototype member protein, the histone methyltransferase PRDM9, using biochemical, biophysical and chemical biology techniques. In the present paper we report the first known molecular characterization of a PRDM9-methylated recombinant histone octamer and the identification of new histone substrates for the enzyme. A single C321P mutant of the PR/SET domain was demonstrated to significantly weaken PRDM9 activity. Additionally, we have optimized a robust biochemical assay amenable to high throughput screening to facilitate the generation of small-molecule chemical probes for this protein family. The present study has provided valuable insight into the enzymology of an intrinsically active PRDM protein. PMID- 24785242 TI - Mother lodes and mining tools: big data for nursing science. PMID- 24785243 TI - PhD preparation of nurse faculty and nurse scientists: do they have to be the same? PMID- 24785244 TI - Sleep quality and risk for sleep apnea in incarcerated women. AB - BACKGROUND: Little is known about characteristics of women's sleep during incarceration. OBJECTIVES: The study objectives were to describe incarcerated women's sleep quality, document incarcerated women's risk for sleep apnea, and identify other factors that contribute to poor sleep quality during incarceration. METHODS: This cross-sectional descriptive exploratory investigation was conducted in a maximum security women's prison in the United States. Incarcerated women's sleep quality and their risk for sleep apnea was assessed by using the Pittsburgh Sleep Quality Index and the Multivariable Apnea Prediction Score, respectively. RESULTS: Four hundred thirty-eight incarcerated women participated in this investigation. Results indicate that 72% of the sample met the Pittsburgh Sleep Quality Index criteria for "poor sleepers." Poor sleepers were significantly more likely to report sleep disturbances and scored significantly higher on the risk for sleep apnea scale compared to women who did not meet the poor sleep threshold. Approximately 10% of the sample had a probability for sleep apnea higher than .50. Factors that contributed to poor sleep included (a) "racing thoughts/worry/thinking about things," (b) environmental noise and other factors, (c) physical health conditions/pain, (d) nightmares and flashbacks, and (e) not taking sleep medication. DISCUSSION: Most participants reported poor sleep quality during incarceration. Poor sleep might exacerbate existing health conditions and contribute to the development of new health problems for incarcerated women. Furthermore, poor sleep quality may reduce a woman's ability to fully participate in beneficial prison programming. This investigation provides a first look at how women sleep in prison and offers recommendations for future research. PMID- 24785245 TI - Staff nurse commitment, work relationships, and turnover intentions: a latent profile analysis. AB - BACKGROUND: The three-component model of organization commitment has typically been studied using a variable-centered rather than a person-centered approach, preventing a more complete understanding of how these forms of commitment are felt and expressed as a whole. OBJECTIVES: Latent profile analysis was used to identify qualitatively distinct categories or profiles of staff nurses' commitment. Then, associations of the profiles with perceived work unit relations and turnover intentions were examined. METHODS: Three hundred thirty-six registered nurses provided data on affective, normative, and continuance commitment, perceived work unit relations, and turnover intentions. Latent profile analysis of the nurses' commitment scores revealed six distinct profile groups. Work unit relations and turnover intentions were compared in the six profile-defined groups. RESULTS: Staff nurses with profiles characterized by high affective commitment and/or high normative commitment in relation to other components experienced stronger work unit relations and reported lower turnover intentions. Profiles characterized by high continuance commitment relative to other components or by low overall commitment experienced poorer work unit relations, and the turnover risk was higher. High continuance commitment in combination with high affective and normative commitment was experienced differently than high continuance commitment in combination with low affective and normative commitment. DISCUSSION: Healthcare organizations often foster commitment by using continuance commitment-enhancing strategies (e.g., offer high salaries and attractive benefits) that may inadvertently introduce behavioral risk. This work suggests the importance of changing the context in which continuance commitment occurs by strengthening the other two components. PMID- 24785246 TI - Latina food patterns in the United States: a qualitative metasynthesis. AB - BACKGROUND: Obesity disproportionately affects Latinas living in the United States, and cultural food patterns contribute to this health concern. OBJECTIVE: The aim of this study was to synthesize the qualitative results of research regarding Latina food patterns in order to (a) identify common patterns across Latino culture and within Latino subcultures and (b) inform future research by determining gaps in the literature. METHODS: A systematic search of three databases produced 13 studies (15 manuscripts) that met the inclusion criteria for review. The Critical Appraisal Skills Program tool and the recommendations of Squires for evaluating translation methods in qualitative research were applied to appraise study quality. Authors coded through directed content analysis and an adaptation of the Joanna Briggs Institute Qualitative Assessment and Review Instrument coding template to extract themes. Coding focused on food patterns, obesity, population breakdown, immigration, acculturation, and barriers and facilitators to healthy eating. Other themes and categories emerged from this process to complement this approach. RESULTS: Major findings included the following: (a) Immigration driven changes in scheduling, food choice, socioeconomic status, and family dynamics shape the complex psychology behind healthy food choices for Latina women; (b) in Latina populations, barriers and facilitators to healthy lifestyle choices around food are complex; and (c) there is a clear need to differentiate Latino populations by country of origin in future qualitative studies on eating behavior. DISCUSSION: Healthcare providers need to recognize the complex influences behind eating behaviors among immigrant Latinas in order to design effective behavior change and goal-setting programs to support healthy lifestyles. PMID- 24785247 TI - Cerebral blood flow velocity and vasomotor reactivity during autonomic challenges in heart failure. AB - BACKGROUND: Significant alterations in autonomic nervous system (ANS) function, vasomotor reactivity, and cerebral blood flow may develop from damage to brain ANS regulatory areas in heart failure (HF). This preferentially right-sided injury occurs largely in autonomic structures perfused by the middle cerebral artery. Indications of altered, asymmetrical perfusion raise the potential for further neural damage. OBJECTIVE: To determine whether the extent of middle cerebral artery blood flow velocity and vasomotor reactivity is altered on one side of the brain over the other in HF versus control subjects, three ANS challenges were administered-each challenge recruited ANS regulatory areas potentially injured in HF. METHODS: Transcranial Doppler ultrasonography was used to measure cerebral blood flow velocity and vasomotor reactivity in 40 HF (mean age = 52.7 years, SD = 7.5; 27 men; left ventricular ejection fraction = 26.8, SD = 8.3) and 42 control subjects (mean age = 48.3 years, SD = 6.0; 22 men) during 5% CO2 and hyperventilation, Valsalva, and orthostatic (upper body tilt) challenges. RESULTS: Lower cerebral blood flow velocity and abnormal vasomotor reactivity (p < .01) were noted in HF middle cerebral arteries during all challenges. More right-sided flow velocity reductions appeared in HF, with laterality differences noted during CO2 and orthostatic (p < .05), but not Valsalva challenges. DISCUSSION: Diminished cerebral blood flow velocity and altered vasomotor reactivity were associated with HF, changes being preferentially on the right side; the asymmetry was more pronounced during CO2 and orthostatic challenges. The impaired blood flow regulation may contribute to the lateralized brain pathology in ANS areas, undermining autonomic control in HF. PMID- 24785248 TI - Surviving testicular cancer: the Lebanese lived experience. AB - BACKGROUND: Testicular cancer is thought to have a great impact on its survivors, yet there has been limited literature on the topic globally and no literature on the topic in Lebanon and the Arab region. OBJECTIVE: The purpose of this study was to explore the lived experience of Lebanese testicular cancer survivors and gain an in-depth understanding of the psychosexual aspect of their experience. METHODS: A hermeneutic phenomenological approach with semistructured digitally recorded interviews and observational field notes was utilized. A purposive sample of Lebanese testicular cancer survivors, aged between 18 and 50 years, in remission for at least 3 years, and willing to share personal information was recruited. Interviews were transcribed verbatim in Arabic. Data saturation was achieved at the seventh interview; a total of eight informants were recruited. The opening question was, "Tell me about your life since you got treated for testicular cancer," and was followed by probing questions. Two to three weeks after the initial interview, informants were called to validate the investigators' primary analysis. RESULTS: Six core themes emerged: cancer perception in the Lebanese culture; "do not show, do not tell"; cancer experience is a turning point; fertility, manhood, and relationships; coping with cancer; and preserved aspects of life. DISCUSSION: The findings provide an in-depth understanding of the experience of Lebanese testicular cancer survivors with a focus on the psychosexual aspect of this experience. The results suggest the need to educate patients about testicular cancer and its effect on their fertility. PMID- 24785249 TI - Cusp catastrophe model: a nonlinear model for health outcomes in nursing research. AB - BACKGROUND: Although health outcomes may have fundamentally nonlinear relationships with relevant behavioral, psychological, cognitively, or biological predictors, most analytical models assume a linear relationship. Furthermore, some health outcomes may have multimodal distributions, but most statistical models in common use assume a unimodal, normal distribution. Suitable nonlinear models should be developed to explain health outcomes. OBJECTIVE: The aim of this study is to provide an overview of a cusp catastrophe model for examining health outcomes and to present an example using grip strength as an indicator of a physical functioning outcome to illustrate how the technique may be used. Results using linear regression, nonlinear logistic model, and the cusp catastrophe model were compared. METHODS: Data from 935 participants from the Survey of Midlife Development in the United States (MIDUS) were analyzed. The outcome was grip strength; executive function and the inflammatory cytokine interleukin-6 were predictor variables. RESULTS: Grip strength was bimodally distributed. On the basis of fit and model selection criteria, the cusp model was superior to the linear model and the nonlinear logistic regression model. The cusp catastrophe model identified interleukin-6 as a significant asymmetry factor and executive function as a significant bifurcation factor. CONCLUSION: The cusp catastrophe model is a useful alternative for explaining the nonlinear relationships commonly seen between health outcome and its predictors. Considerations for the use of cusp catastrophe model in nursing research are discussed and recommended. PMID- 24785250 TI - Qualitative research publication rates in top-ranked nursing journals: 2002-2011. AB - BACKGROUND: Journal publication is the traditional means of disseminating research. Few top-ranked general medical and health services and policy research journals publish qualitative research. OBJECTIVES: This study examined qualitative research publication rates in top-ranked nursing journals with varying characteristics (general vs. specialty focus, number of issues per year) and compared publication rates with those previously reported for journals in related fields. METHODS: A bibliometric approach was used to identify and quantify qualitative articles published in 10 top-ranked nursing journals from 2002 to 2011. RESULTS: The percentage of qualitative empirical studies varied within and across nursing journals with no apparent association with journal characteristics. Although variable, qualitative research appears more common in high-ranking nursing journals than in general medical and health services and policy research journals. DISCUSSION: Examining factors that contribute to inconsistent rates may identify strategies to optimize qualitative research reporting and publication. PMID- 24785251 TI - Financial conflicts of interest in research: recognition and management. AB - Conflicts of interest (COIs) are of concern in research, and new regulations are in place to address financial COIs. Although not inherently wrong, a COI increases the risk of bias in research. The goal of the new regulation is to increase transparency to improve the public's trust in the research process. When a conflict is identified, it should be disclosed to the researcher's university, and if needed, a management plan is crafted to reduce the potential for bias.Management plans can include limiting a researcher's involvement in aspects of the research, disclosing this information to potential subjects, and reporting conflicts in presentations and publications. Addressing COI through education, disclosure, and management can protect investigators and all those involved in research and increase the integrity of the research process. PMID- 24785252 TI - Stimulation of central A1 adenosine receptors suppresses seizure and neuropathology in a soman nerve agent seizure rat model. AB - The current regimen for treating nerve agent poisoning does not sufficiently suppress the excitotoxic activity that causes severe brain damage, especially in cases where treatment is delayed and nerve agent-induced status epilepticus develops. New therapeutic targets are required to improve survivability and minimize neuropathology after irreversible acetylcholinesterase inactivation. Earlier studies have shown that systemic delivery of adenosine agonists decreases nerve agent lethality; however, the mechanism of protection remains to be understood. The primary aim of this study was to investigate the role of central adenosine receptor (AR) stimulation in neuroprotection by directly injecting (6) cyclopentyladenosine (CPA), an adenosine agonist specific to the A1 receptor subtype (A1R), into the brain intracerebroventricularly (ICV) in a soman seizure rat model. In addition to general A1R stimulation, we hypothesized that bilateral micro-injection of CPA into the cholinergic basal forebrain (BF) could also suppress excitotoxic activity. The results from these studies demonstrated that centrally administered adenosine agonists are anti-seizure and neuroprotective. CPA-delivered ICV prevented seizure and convulsion in 100% of the animals. Moreover, neuropathological evaluation indicated that adenosine treatments reduced brain damage from severe to minimal. Inhibition of the BF via CPA had varied results. Some animals were protected by treatment; however, others displayed similar pathology to the control. Overall, these data suggest that stimulating central ARs could be an effective target for the next generation countermeasures for nerve agent intoxication. PMID- 24785254 TI - Electron-doping-enhanced trion formation in monolayer molybdenum disulfide functionalized with cesium carbonate. AB - We report effective and stable electron doping of monolayer molybdenum disulfide (MoS2) by cesium carbonate (Cs2CO3) surface functionalization. The electron charge carrier concentration in exfoliated monolayer MoS2 can be increased by about 9 times after Cs2CO3 functionalization. The n-type doping effect was evaluated by in situ transport measurements of MoS2 field-effect transistors (FETs) and further corroborated by in situ ultraviolet photoelectron spectroscopy, X-ray photoelectron spectroscopy, and Raman scattering measurements. The electron doping enhances the formation of negative trions (i.e., a quasiparticle comprising two electrons and one hole) in monolayer MoS2 under light irradiation and significantly reduces the charge recombination of photoexcited electron-hole pairs. This results in large photoluminescence suppression and an obvious photocurrent enhancement in monolayer MoS2 FETs. PMID- 24785255 TI - Targeted BikDD expression kills androgen-dependent and castration-resistant prostate cancer cells. AB - Targeted gene therapy is a promising approach for treating prostate cancer after the discovery of prostate cancer-specific promoters such as prostate-specific antigen, rat probasin, and human glandular kallikrein. However, these promoters are androgen dependent, and after castration or androgen ablation therapy, they become much less active or sometimes inactive. Importantly, the disease will inevitably progress from androgen-dependent (ADPC) to castration-resistant prostate cancer (CRPC), at which treatments fail and high mortality ensues. Therefore, it is critical to develop a targeted gene therapy strategy that is effective in both ADPC and CRPC to eradicate recurrent prostate tumors. The human telomerase reverse transcriptase-VP16-Gal4-WPRE integrated systemic amplifier composite (T-VISA) vector we previously developed, which targets transgene expression in ovarian and breast cancer, is also active in prostate cancer. To further improve its effectiveness based on androgen response in ADPC progression, the ARR2 element (two copies of androgen response region from rat probasin promoter) was incorporated into T-VISA to produce AT-VISA. Under androgen analog (R1881) stimulation, the activity of AT-VISA was increased to a level greater than or comparable to the cytomegalovirus promoter in ADPC and CRPC cells, respectively. Importantly, AT-VISA demonstrated little or no expression in normal cells. Systemic administration of AT-VISA-BikDD encapsulated in liposomes repressed prostate tumor growth and prolonged mouse survival in orthotopic animal models as well as in the transgenic adenocarcinoma mouse prostate model, indicating that AT-VISA-BikDD has therapeutic potential to treat ADPC and CRPC safely and effectively in preclinical setting. PMID- 24785256 TI - Preferential estrogen receptor beta ligands reduce Bcl-2 expression in hormone resistant breast cancer cells to increase autophagy. AB - Acquired resistance to selective estrogen receptor (ER) modulators (SERM) and downregulators (SERD) is a significant clinical problem in the treatment of estrogen (E2) receptor-positive (ER(+)) breast cancers. There are two ER subtypes, ERalpha and ERbeta, which promote and inhibit breast cancer cell proliferation, respectively. Although ER(+) breast cancers typically express a high ratio of ERalpha to ERbeta, the acquisition of SERM resistance in vitro and in vivo is associated with increased relative expression of the ERbeta. On some gene enhancers, ERbeta has been shown to function in opposition to the ERalpha in the presence of E2. Here, we demonstrate that two different ERbeta agonists, WAY 20070 and a novel "A-CD" estrogen called L17, produce a marked reduction in G(2) M phase correlated with effects on cyclin D1 and cyclin E expression in a SERM/SERD-resistant breast cancer cell line. ERbeta agonists recruited both the ERalpha and ERbeta to the Bcl-2 E2-response element strongly reducing Bcl-2 mRNA and protein in an ERbeta-dependent manner. L17 recruited RIP140 to the Bcl-2 promoter in cells overexpressing ERbeta. Exposure to the ERbeta ligands also resulted in increased processing of LC3-I to LC3-II, indicative of enhanced autophagic flux. The coaddition of ERbeta agonist and the autophagy inhibitor chloroquine resulted in a significant accumulation of sub-G1 DNA which was completely prevented by the addition of the caspase inhibitor Z-VAD-FMK. We propose that combined therapies with an ERbeta agonist and an inhibitor of autophagy may provide the basis for a novel approach to the treatment of SERM/SERD-resistant breast cancers. PMID- 24785257 TI - MicroRNA-26b represses colon cancer cell proliferation by inhibiting lymphoid enhancer factor 1 expression. AB - microRNAs (miR) can act as oncogenes and tumor suppressors and several miRs are associated with cancer development and progression through the modulation of multiple cellular processes. miR26b is downregulated in several cancers and tumors and miR26b directly targets the lymphoid enhancer factor 1 (Lef1)3'UTR and inhibits endogenous Lef1 expression. We report that miR26b expression is associated with human colon cancer through the regulation of LEF1 expression in colon cancer cells. Analyses of multiple colon cancer cell lines revealed an inverse correlation between miR26b and LEF1 expression. Normal human colon cells express low levels of LEF1 and high levels of miR26b; however, human colon cancer cells have decreased miR26b expression and increased LEF1 expression. We demonstrate that miR26b expression is a potent inhibitor of colon cancer cell proliferation and significantly decreases LEF1 expression. The LEF1-regulated genes cyclin D1 and c-Myc were indirectly repressed by miR26b and this was consistent with decreased proliferation. miR26b overexpression in SW480 colon cancer cells also inhibited tumor growth in nude mice and this was due to decreased tumor growth and not apoptosis. Analyses of human colon cancer databases also demonstrated a link between miR26b and LEF1 expression. c-Myc expression is associated with multiple cancers and we propose that miR26b may act as a potential therapeutic agent in reducing cancer cell proliferation through repressing LEF1 activation of c-Myc and cyclin D1 expression. PMID- 24785258 TI - Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling. AB - Pancreatic ductal adenocarcinoma is one of the deadliest carcinomas and is characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. PMID- 24785259 TI - Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits. AB - In several genome-wide association studies, nonalcoholic fatty liver disease and alanine aminotransferase susceptibility variants have been identified in several genes, including LYPLAL1, ZP4, GCKR, HSD17B13, PALLD, PPP1R3B, FDFT1, TRIB1, COL13A1, CPN1, ERLIN1, CWF19L1, EFCAB4B, PZP, and NCAN. To investigate the relationship between these genes and nonalcoholic fatty liver disease in the Japanese population, we genotyped 540 patients and 1012 control subjects for 18 variations. We performed logistic regression analyses to characterize the association between the tested variations and nonalcoholic fatty liver disease. Metabolic syndrome and histological traits were also analyzed by linear regression. We also examined GCKR rs780094, TRIB1 rs2954021, and PNPLA3 rs738409 for epistatic effects. The A-allele of rs780094 in GCKR (P = 0.0024) and the A allele of rs2954021 TRIB1 (P = 4.5*10-5) were significantly associated with nonalcoholic fatty liver disease. GCKR rs780094 was also associated with decreased plasma glucose, and increased triglycerides in the patient and control groups. GCKR rs780094 was also associated with an increased ratio of visceral to subcutaneous fat area in the patients with nonalcoholic fatty liver disease. Variations in GCKR, TRIB1, and PNPLA3 independently influenced nonalcoholic fatty liver disease and had no epistatic effects. Our data suggest variations in GCKR and TRIB1 are involved in the development of nonalcoholic fatty liver disease. PMID- 24785260 TI - Heritable transmission of stress resistance by high dietary glucose in Caenorhabditis elegans. AB - Glucose is a major energy source and is a key regulator of metabolism but excessive dietary glucose is linked to several disorders including type 2 diabetes, obesity and cardiac dysfunction. Dietary intake greatly influences organismal survival but whether the effects of nutritional status are transmitted to the offspring is an unresolved question. Here we show that exposing Caenorhabditis elegans to high glucose concentrations in the parental generation leads to opposing negative effects on fecundity, while having protective effects against cellular stress in the descendent progeny. The transgenerational inheritance of glucose-mediated phenotypes is dependent on the insulin/IGF-like signalling pathway and components of the histone H3 lysine 4 trimethylase complex are essential for transmission of inherited phenotypes. Thus dietary over consumption phenotypes are heritable with profound effects on the health and survival of descendants. PMID- 24785262 TI - Nanoscale roughness affects the activity of enzymes adsorbed on cluster-assembled titania films. AB - In this study, we investigated how the adsorption properties governed by the nanometer-scale surface morphology of cluster-assembled titanium oxide films influence the catalytic activity of immobilized serine-protease trypsin. We developed an activity assay for the parallel detection of physisorbed enzyme activity and mass density of the adsorbed proteins in microarray format. The method combines a microarray-based technique and advanced quantitative confocal microscopy approaches based on fluorescent labeling of enzymes and covalent labeling of active sites of surface-bound enzymes. The observed diminishing trypsin binding affinity with increasing roughness, as opposed to the steep rise in its saturation uptake, was interpreted as heterogeneous nucleation-driven adsorption of trypsin at the rough nanoporous titania surface. The increase in relative activity of adsorbed trypsin is proportional to the fractional saturation of titania surfaces, expressed as percentage of saturation uptake. In turn, the specific activity, that is, the ratio of active proteins to the absolute number of adsorbed proteins, drops with growing saturation uptake and surface roughness, witnessing a reduction in the accessibility of enzyme active sites. Both geometrical constraints of titania nanopores and the clusterwise adsorption of trypsin were identified as the key factors underpinning the steric hindrance of the immobilized enzyme. These findings are relevant for the optimization of rough nanoporous surfaces as carriers of immobilized enzymes. The proposed activity assay is particularly advantageous in the screening of candidate materials for enzyme immobilization. PMID- 24785261 TI - Epigenetically regulated MIR941 and MIR1247 target gastric cancer cell growth and migration. AB - Altered expression of microRNA (miRNA) can significantly contribute to cancer development and recent studies have shown that a number of miRNAs may be regulated by DNA methylation. Through a candidate gene approach, we identified MIR941 and MIR1247 to be transcriptionally silenced by DNA hypermethylation in several gastric cancer cell lines. We confirmed that these miRNAs are also densely methylated in primary gastric cancers but not in normal gastric tissues. In addition, we demonstrated that ectopic expression of these two miRNAs in AGS gastric cancer cells resulted in suppression of growth and migration. Furthermore, we tested genes predicted to be the targets of MIR941 and MIR1247 and identified 7 and 6 genes, whose expressions were significantly downregulated by transfection of MIR941 and MIR1247 mimics, respectively, in gastric cancer cell lines. Some of these genes are known to promote proliferation and invasion, phenotypes we observed upon ectopic expression of the two miRNAs. Thus, we examined these candidates more closely and found that downregulation of mRNA corresponded to a decrease in protein levels (observed by western blot). Our study provides unequivocal evidence that MIR941 and MIR1247 are transcriptionally regulated by DNA methylation in gastric cancer and that they have tumor suppressor properties through their inhibition of key cancer promoting genes in this context. PMID- 24785263 TI - Organic semiconductors based on [1]benzothieno[3,2-b][1]benzothiophene substructure. AB - The design, synthesis, and characterization of organic semiconductors applicable to organic electronic devices, such as organic field-effect transistors (OFETs) and organic photovoltaics (OPVs), had been one of the most important topics in materials chemistry in the past decade. Among the vast number of materials developed, much expectation had been placed on thienoacenes, which are rigid and planar structures formed by fusing thiophenes and other aromatic rings, as a promising candidate for organic semiconductors for high-performance OFETs. However, the thienoacenes examined as an active material in OFETs in the 1990s afforded OFETs with only moderate hole mobilities (approximately 0.1 cm(2) V(-1) s(-1)). We speculated that this was due to the sulfur atoms in the thienoacenes, which hardly contributed to the intermolecular orbital overlap in the solid state. On the other hand, we have focused on other types of thienoacenes, such as [1]benzothieno[3,2-b][1]benzothiophene (BTBT), which seem to have appropriate HOMO spatial distribution for effective intermolecular orbital overlap. In fact, BTBT derivatives and their related materials, including dinaphtho[2,3-b:2',3' f]thieno[3,2-b]thiophene (DNTT), have turned out to be superior organic semiconductors, affording OFETs with very high mobilities. To illustrate some examples, we have developed 2,7-diphenyl BTBT (DPh-BTBT) that yields vapor deposited OFETs having mobilities of up to 2.0 cm(2) V(-1) s(-1) under ambient conditions, highly soluble dialkyl-BTBTs (Cn-BTBTs) that afford solution processed OFETs with mobilities higher than 1.0 cm(2) V(-1) s(-1), and DNTT and its derivatives that yield OFETs with even higher mobilities (>3.0 cm(2) V(-1) s( 1)) and stability under ambient conditions. Such high performances are rationalized by their solid-state electronic structures that are calculated based on their packing structures: the large intermolecular orbital overlap and the isotropic two-dimensional electronic structure are the key regardless of the molecular size and substituents on the BTBT and its related thienoacene cores. Along with the discovery of such attracting performances, versatile and practical methods for the synthesis of BTBT and its derivatives, and the pi-extended derivatives including DNTT, dianthra[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DATT), and the thienoacenes with two thieno[3,2-b]thiophene moieties, have been developed. In addition, the materials have been recently utilized in sophisticated devices and circuits, including all-printed transistor arrays, flexible circuits on ultrathin plastic substrates, and biomedical applications, underscoring their promise as practical semiconductors for electronic device applications. These exciting results of the present BTBT-based materials are expected to open doors to new horizons of organic semiconductors in terms of practical application and the design and synthesis of far more superior materials. PMID- 24785265 TI - Goal setting for health behavior change: evidence from an obesity intervention for rural low-income women. AB - INTRODUCTION: Rural, minority populations are disproportionately affected by overweight and obesity and may benefit from lifestyle modification programs that are tailored to meet their unique needs. Obesity interventions commonly use goal setting as a behavior change strategy; however, few have investigated the specific contribution of goal setting to behavior change and/or identified the mechanisms by which goal setting may have an impact on behavior change. Furthermore, studies have not examined goal setting processes among racial/ethnic minorities. Using data from an obesity intervention for predominately minority women in rural North Carolina, this study sought to examine whether intervention participation resulted in working on goals and using goal setting strategies which in turn affected health behavior outcomes. It also examined racial/ethnic group differences in working on goals and use of goal setting strategies. METHODS: Data came from a community-based participatory research project to address obesity among low-income, predominately minority women in rural North Carolina. A quasi-experimental intervention design was used. Participants included 485 women aged 18 years and over. Intervention participants (n=208) received health information and goal setting support through group meetings and tailored newsletters. Comparison participants (n = 277) received newsletters on topics unrelated to obesity. Surveys assessed physical activity, fruit and vegetable intake, goal-related stage of change, and use of goal setting strategies. Chi squared statistics were used to assess intervention group differences in changes in goal-related stage of change and use of goal setting strategies as well as racial/ethnic group differences in stage of change and use of goal setting strategies at baseline. The causal steps approach of Baron and Kenny was used to assess mediation. RESULTS: Intervention compared to comparison participants were more likely to move from contemplation to action/maintenance for the goals of improving diet (58% intervention, 44% comparison, p= 0.04) and physical activity (56% intervention, 31% comparison, p <= 0.0001). Intervention group differences were not found for moving from precontemplation to a higher category. At baseline, black compared to white participants were more likely to be working on the goals of getting a better education (p < 0.0001), owning a home (p < 0.01), starting a business (p < 0.0001), and improving job skills (p <0.05). For whites only, intervention participants were more likely than comparison participants to move from contemplation to action/maintenance for the goal of improving diet ( p< 0.05). For both blacks (p < 0.05) and whites (p < 0.0001), intervention participants were more likely than comparison participants to move from contemplation to action/maintenance for the goal of increasing physical activity. For all participants, progression in stages of change mediated the intervention effect on physical activity, but not fruit and vegetable intake. The intervention did not reveal an impact on use of goal setting strategies. CONCLUSIONS: In this sample of low-income, rural women, the intervention's goal setting component influenced behavior change for participants who were contemplating lifestyle changes at baseline. Racial/ethnic group differences in goal setting indicate the need to gain greater understanding of individual, social, and environmental factors that may uniquely have an impact on goal setting, and the importance of tailoring obesity intervention strategies for optimal, sustainable behavior change. PMID- 24785264 TI - Computational modeling of RNA 3D structures, with the aid of experimental restraints. AB - In addition to mRNAs whose primary function is transmission of genetic information from DNA to proteins, numerous other classes of RNA molecules exist, which are involved in a variety of functions, such as catalyzing biochemical reactions or performing regulatory roles. In analogy to proteins, the function of RNAs depends on their structure and dynamics, which are largely determined by the ribonucleotide sequence. Experimental determination of high-resolution RNA structures is both laborious and difficult, and therefore, the majority of known RNAs remain structurally uncharacterized. To address this problem, computational structure prediction methods were developed that simulate either the physical process of RNA structure formation ("Greek science" approach) or utilize information derived from known structures of other RNA molecules ("Babylonian science" approach). All computational methods suffer from various limitations that make them generally unreliable for structure prediction of long RNA sequences. However, in many cases, the limitations of computational and experimental methods can be overcome by combining these two complementary approaches with each other. In this work, we review computational approaches for RNA structure prediction, with emphasis on implementations (particular programs) that can utilize restraints derived from experimental analyses. We also list experimental approaches, whose results can be relatively easily used by computational methods. Finally, we describe case studies where computational and experimental analyses were successfully combined to determine RNA structures that would remain out of reach for each of these approaches applied separately. PMID- 24785266 TI - Copper-catalyzed asymmetric synthesis and comparative aldose reductase inhibition activity of (+)/(-)-1,2-benzothiazine-1,1-dioxide acetic acid derivatives. AB - A copper catalyst system for the asymmetric 1,4-hydrosilylation of the alpha,beta unsaturated carboxylate class was developed by which synthesis of (+)- and (-) enantiomers of 1,2-benzothiazine-1,1-dioxide acetates has been achieved with a good yield and an excellent level of enantioselectivity. A comparative structure activity relationship study yielded the following order of aldose reductase inhibition activity: (-)-enantiomers > racemic > (+)-enantiomers. Further, a molecular docking study suggested that the (-)-enantiomer had significant binding affinity and thus increased inhibition activity. PMID- 24785267 TI - Acid- and base-stable porous organic cages: shape persistence and pH stability via post-synthetic "tying" of a flexible amine cage. AB - Imine cage molecules can be reduced to amines to improve their chemical stability, but this introduces molecular flexibility. Hence, amine cages tend not to exhibit permanent solid-state porosity. We report a synthetic strategy to achieve shape persistence in amine cages by tying the cage vertices with carbonyls such as formaldehyde. Shape persistence is predicted by conformer stability calculations, providing a design basis for the strategy. The tied cages show enhanced porosity and unprecedented chemical stability toward acidic and basic conditions (pH 1.7-12.3), where many other porous crystalline solids would fail. PMID- 24785268 TI - Reporting risk, producing prejudice: how news reporting on obesity shapes attitudes about health risk, policy, and prejudice. AB - News reporting on research studies may influence attitudes about health risk, support for public health policies, or attitudes towards people labeled as unhealthy or at risk for disease. Across five experiments (N = 2123) we examined how different news framings of obesity research influence these attitudes. We exposed participants to either a control condition, a news report on a study portraying obesity as a public health crisis, a news report on a study suggesting that obesity may not be as much of a problem as previously thought, or an article discussing weight-based discrimination. Compared to controls, exposure to the public health crisis article did not increase perception of obesity-related health risks but did significantly increase the expression of antifat prejudice in four out of seven comparisons. Across studies, compared to controls, participants who read an article about weight-based discrimination were less likely to agree that overweight constitutes a public health crisis or to support various obesity policies. Effects of exposure to an article questioning the health risks associated with overweight and obesity were mixed. These findings suggest that news reports on the "obesity epidemic" - and, by extension, on public health crises commonly blamed on personal behavior - may unintentionally activate prejudice. PMID- 24785269 TI - Correlates of satisfaction with pain treatment in the acute postoperative period: results from the international PAIN OUT registry. AB - Patient ratings of satisfaction with their postoperative pain treatment tend to be high even in those with substantial pain. Determinants are poorly understood and have not previously been studied in large-scale, international datasets. PAIN OUT, a European Union-funded acute pain registry and research project, collects patient-reported outcome data on postoperative day 1 using the self-reported International Pain Outcome Questionnaire (IPO), and patient, clinical, and treatment characteristics. We investigated correlates of satisfaction and consistency of effects across centres and countries using multilevel regression modelling. Our sample comprised 16,868 patients (median age 55 years; 55% female) from 42 centres in 11 European countries plus Israel, USA, and Malaysia, who underwent a wide range of surgical procedures, for example, joint, limb, and digestive tract surgeries. Median satisfaction was 9 (interquartile range 7-10) on a 0-10 scale. Three IPO items showed strong associations and explained 35% of the variability present in the satisfaction variable: more pain relief received, higher allowed participation in pain treatment decisions, and no desire to have received more pain treatment. Patient factors and additional IPO items reflecting pain experience (eg, worst pain intensity), pain-related impairment, and information on pain treatment added little explanatory value, partially due to covariate correlations. Effects were highly consistent across centres and countries. We conclude that satisfaction with postoperative pain treatment is associated with the patients' actual pain experience, but more strongly with impressions of improvement and appropriateness of care. To the degree they desire, patients should be provided with information and involved in pain treatment decisions. PMID- 24785270 TI - Magnetic resonance imaging contribution for diagnosing symptomatic neurovascular contact in classical trigeminal neuralgia: a blinded case-control study and meta analysis. AB - Although classical trigeminal neuralgia (CTN) is frequently caused by neurovascular contact (NVC) at the trigeminal root entry zone (REZ), both anatomical and MRI studies have shown that NVC of the trigeminal nerve frequently occurs in individuals without CTN. To assess the accuracy of MRI in distinguishing symptomatic from asymptomatic trigeminal NVC, we submitted to high definition MRI the series of CTN patients referred to our outpatient service between June 2011 and January 2013 (n=24), and a similar number of age-matched healthy controls. Two neuroradiologists, blinded to the clinical data, evaluated whether the trigeminal nerve displayed NVC in the REZ or non-REZ, whether it was dislocated by the vessel or displayed atrophy at the contact site, and whether the offending vessel was an artery or a vein. Our data were meta-analyzed with those of all similar studies published from January 1970 to June 2013. In our sample, REZ contact, nerve dislocation and nerve atrophy were independently associated with CTN (P=.027; P=.005; P=.035 respectively). Compared to a rather low sensitivity of each of these items (alone or in combination), their specificity was high. When REZ contact and nerve atrophy coexisted, both specificity and positive predictive value rose to 100%. Meta-analysis showed that REZ NVC was detected in 76% of symptomatic and 17% of asymptomatic nerves (P<.0001), whereas anatomical changes were detected in 52% of symptomatic and 9% of asymptomatic nerves (P<.0001). In conclusion, trigeminal REZ NVC, as detected by MRI, is highly likely to be symptomatic when it is associated with anatomical nerve changes. PMID- 24785271 TI - Tear fluid hyperosmolality increases nerve impulse activity of cold thermoreceptor endings of the cornea. AB - Dry eye disease (DED) is a multifactorial disorder affecting the composition and volume of tears. DED causes ocular surface dryness, cooling, and hyperosmolality, leading ultimately to corneal epithelium damage and reduced visual performance. Ocular discomfort is the main clinical symptom in DED. However, the peripheral neural source of such unpleasant sensations is still unclear. We analyzed in excised, superfused mouse eyes, the effect of NaCl-induced hyperosmolality (325 1005 mOsm.kg(-1)) on corneal cold thermoreceptor and polymodal nociceptor nerve terminal impulse (NTI) activity. Osmolality elevations at basal corneal temperature (33.6 degrees C) linearly increased the ongoing NTI frequency of cold thermoreceptors, at a mean rate of 0.34 imp.s(-1)/10 mOsm. This frequency increase became significant with osmolality values greater than 340 mOsm. Comparison of cold thermoreceptor activity increase induced by a dynamic temperature reduction of 1.8 degrees C under iso- and hyperosmolal (360-mOsm) conditions provided evidence that more than 50% of the increased firing response was attributable to hyperosmolality. Comparatively, activation of corneal polymodal nociceptor endings by hyperosmolal solutions started with values of 600 mOsm and greater. Sensitization of polymodal nociceptors by continuous perfusion with an "inflammatory soup" (bradykinin, histamine, prostaglandin E2 [PGE2], serotonin, and adenosine triphosphate [ATP]) did not enhance their activation by hyperosmolal solutions. High osmolality also altered the firing pattern and shape of cold and polymodal NTIs, possibly reflecting disturbances in local membrane currents. Results strongly suggest that tear osmolality elevations in the range observed in DED predominantly excite cold thermoreceptors, supporting the hypothesis that dryness sensations experienced by these patients are due, at least in part, to an augmented activity of corneal cold thermoreceptors. PMID- 24785272 TI - Compositional variations in In(0.5)Ga(0.5)N nanorods grown by molecular beam epitaxy. AB - The composition of InxGa1 - xN nanorods grown by molecular beam epitaxy with nominal x = 0.5 has been mapped by electron microscopy using Z-contrast imaging and x-ray microanalysis. This shows a coherent and highly strained core-shell structure with a near-atomically sharp boundary between a Ga-rich shell (x ~ 0.3) and an In-rich core (x ~ 0.7), which itself has In- and Ga-rich platelets alternating along the growth axis. It is proposed that the shell and core regions are lateral and vertical growth sectors, with the core structure determined by spinodal decomposition. PMID- 24785273 TI - [Phenotypic genetic regulation and treatment of malignant lymphoma]. PMID- 24785274 TI - [Extraction and identification of exosomes from drug-resistant breast cancer cells and their potential role in cell-to-cell drug-resistance transfer]. AB - OBJECTIVE: To explore whether docetaxel-resistant cells (MCF-7/Doc) and doxorubicin-resistant cells (MCF-7/ADM) can secrete Exosomes and their potential role in cell-cell drug-resistance transfer. METHODS: Exosomes were extracted from the cell culture supernatants of MCF-7/Doc and MCF-7/ADM cells by fractionation ultracentrifugation, and were identified by transmission electron microscopy and Western blot analysis. GFP-MCF-7/S, a breast cancer parental sensitive cell line stably expressing green fluorescent protein (GFP), was constructed by recombinant lentiviral vector with GFP. Then the resistance experiment of cells and the experiment of resistance transfer by exosomes were designed to observe the phenomenon of cell-to-cell drug-resistance transfer. RESULTS: Similar to the breast cancer parental sensitive cells (MCF-7/S), the breast cancer resistant sublines could secrete exosomes, which exhibited round or elliptic shape ranging from 30 to 100 nm in diameter with intact membrane, and only expressed the protein marker of exosomes, Tsg101, did not express the endoplasmic reticulum marker calnexin. After MCF-7/S, MCF-7/DOC and MCF-7/ADM cells we cocultured with GFP-MCF-7/S cells for 72 h, there were no significant differences in the expression of fluorescence-labeled cells among the four groups. When treated by the drug ADM or DOC for 24 hours, the MCF-7/DOC+GFP-MCF-7/S group was in favor of a significant higher survival rate of fluorescence-labeled cells compared with the MCF-7/S+GFP-MCF-7/S group (65.5% vs. 25.5%, P < 0.001), and so did the MCF 7/ADM+GFP-MCF-7/S group (53.6% vs. 25.4%, P < 0.001). The exosomes extracted from MCF-7/S, MCF-7/DOC and MCF-7/ADM cells were cultured with the GFP-MCF-7/S cells for 48 h. Among these groups, no significant differences in the expression of fluorescence-labeled cells were found. After treated by the drug ADM or DOC for 24 hours, the exosomes extracted from MCF-7/DOC+GFP-MCF-7/S group was associated with a significant higher survival rate of fluorescence-labeled cells compared with the exosomes extracted from MCF-7/S+GFP-MCF-7/S group (59.9% vs. 32.4%, P < 0.001), and so did the exosomes extracted from the MCF-7/ADM)+GFP-MCF-7/S group (58.3% vs. 27.2%, P < 0.001). CONCLUSION: Our results suggest that drug resistance can be transferred between breast cancer cells, and exosomes are probably the transporter of the drug resistance. PMID- 24785276 TI - [Anti-tumor effect of Sendai virus Tianjin strain defective interfering particles on tumor-bearing mice]. AB - OBJECTIVE: To explore the anti-tumor effect and its mechanism of Sendai virus Tianjin strain defective interfering particles (DIP) on mouse models of colon carcinoma. METHODS: CT26 cells (5*10(6)/0.1 ml) were subcutaneously injected into the back of Bal B/c mice to establish murine colon carcinoma model. After the tumors reached 5 mm in diameter, the mice were randomly divided into Tianjin strain DIP group and saline control group. The former was intratumorally injected with Tianjin strain DIP (0.1 ml) once a day on day 4, 7, 10 and 13 after CT26 cell inoculation. The latter was intratumorally injected with the same volume of saline. Tumor volume and survival rate of the mice were calculated to confirm the anti-tumor effect of DIP. Flow cytometry and ELISA were used to examine the maturation and release of cytokines IL-6, IFN-alpha and TNF-alpha from murine myeloid dendritic cells (DCs) induced by Tianjin strain DIP. Moreover, real-time RT-PCR and immunohistochemistry were performed to identify whether the Tianjin strain DIP could induce infiltration of CD11c(+) DCs, CD4(+) and CD8(+) T cells in the tumors. RESULTS: On day 22 after CT26 cell inoculation, the average tumor volume of the Tianjin strain DIP group was (33.2 +/- 2.0) mm(3), significantly smaller than that of the control group [(2 376.0 +/- 130.8)mm(3), P < 0.01]. On day 50 after CT26 cell inoculation, the survival rate of mice was 90.0% in the Tianjin strain DIP group, much higher than that of the control group (30.0%, P < 0.01). Flow cytometry analysis showed that the expression of markers of DCs maturation, including CD40, CD80 and CD86, was dose-dependently increased by DIP or intact virus. No statistically significant difference was found betweent the DIP and intact virus groups. ELISA results showed that DIP could stimulate the secretion of IL-6, IFN-alpha and TNF-alpha from mouse DCs. The secretion of all of the cytokines was dose-dependently increased by DIP or intact virus. Real-time RT-PCR revealed that the expression of CD4, CD8 and CD11c mRNAs was increased in tumors treated with DIP compared with that of the saline group at all time points. Moreover, the expression level of all of them remained maximal at 120 h after the last treatment. Immunohistochemical staining revealed that the ratios of CD4(+), CD8(+) T cells or CD11c(+) DCs to total cells were (21.60 +/- 1.49)%, (22.12 +/- 2.84)% and (23.05 +/- 2.91)%, respectively, in the DIP-treated tumors. In the tumors treated by saline, the ratios were (2.62 +/- 0.60)%, (4.05 +/- 0.12)% and (3.10 +/- 0.09)%, respectively. The difference between experimental group and control group had statistical significance. CONCLUSIONS: Tianjin strain DIP may exert anti-tumor effect on tumor-bearing mice. The mechanism is related with the antitumor immunity induced by DCs and T cells. PMID- 24785275 TI - [Reversion of multidrug resistance of human gastric cancer SGC7901/DDP cells by E2F-1 gene silencing]. AB - OBJECTIVE: To investigate the effects of E2F-1 gene silencing on multidrug resistance of human gastric cancer SGC7901/DDP cells and its possible mechanisms. METHODS: Gastric cancer SGC7901/DDP cells were seeded in 6 well plates and divided into three groups: the experimental group, blank control and the negative control groups. For the experimental group, the SGC7901/DDP cells were transfected with recombinant lentivirus vector (Lv-shRNA-E2F-1), while the negative control with an control lentiviral vector (Lv-shRNA-NC) and the blank control with no treatment. The E2F-1 protein level was analyzed by Western blot. MTT assay was used to detect the half maximal inhibitory concentration (IC50) of three chemotherapy drugs including adriamycin, 5-fluorouracil (5-Fu) and cisplatine (DDP) of the three cell groups. Flow cytometry (FCM) was used to detect the pump-out rate of adriamycin and apoptosis rate of the three cell groups. Semi-quantitative RT-PCR and Western blot were also used to detect the protein and mRNA levels of multidrug resistance-associated genes (MDR1, MRP) and apoptosis-related genes (c-Myc, Skp2, cyclinD1). RESULTS: The expression of E2F-1 protein in the experimental group was significantly lower than that in the negative control and blank control groups (0.794 +/- 0.033 vs. 1.487 +/- 0.082 vs. 1.511 +/- 0.084, P < 0.01). The IC50 of the three chemotherapy drugs (adriamycin, 5-Fu and cisplatine) in the experimental group was significantly lower than that of the negative control and blank control groups, respectively (P < 0.01). Compared with the negative control and blank control groups, the pump out rate of adriamycin of the experimental group was significantly declined [(0.16 +/- 0.01)% vs. (0.37 +/- 0.01)% vs. (0.35 +/- 0.02)%, P < 0.01]. However, the apoptosis rate of the experimental group was significantly higher than that of the negative control and blank control groups [(33.82 +/- 1.26)% vs. (17.34 +/ 0.81)% vs. (13.16 +/- 1.06)%, P < 0.01]. The results of RT-PCR and Western blot assays showed that mRNA and protein expressions of five genes (MDR1, MRP, CyclinD1, c-Myc, Skp2) in the experimental group were significantly lower than that in the negative control and blank control groups, respectively (P < 0.01). CONCLUSIONS: E2F-1 gene silencing enhances the chemosensitivity of gastric cancer SGC7901/DDP cells to the chemotherapeutic drugs, directly or indirectly downregulated the expression of MDR1 and MRP, and finally reverses the multidrug resistance of the gastric cancer cells. The mechanism may be associated with the suppression of cyclinD1, c-Myc and Skp2. PMID- 24785277 TI - [HER-2 overexpression and gene amplification of advanced breast cancers determined by fluorescence in situ hybridization in fine needle aspiration specimens]. AB - OBJECTIVE: To explore the feasibility of testing HER-2 expression and gene amplification in fine needle aspiration specimens of advanced breast cancers, and to benefit the patients receiving targeted drug therapy. METHODS: Liquid-based cytology specimens by fine needle aspiration of 49 breast cancer cases were used in this study. The expression of HER-2 protein was detected by immunocytochemistry (ICC) and the gene amplification was assessed by fluorescence in situ hybridization (FISH). All the 49 cases had overexpression of HER-2 protein marked as ++ or +++ in immunohistochemistry (IHC), and had corresponding FISH results in formalin-fixed, paraffin-embedded (FFPE) tissue samples. RESULTS: FNA samples in all the 49 cases were tested by FISH, and showed a complete agreement with the FISH results in the histological specimens (kappa = 1.0). Of the 49 cases, 33 had HER-2 gene amplification in FFPE samples. So do that in FNA samples. Both had an amplification rate of 67.3%. Among the 33 cases with HER-2 gene amplification, 26 had an ICC score of +++ (78.8%). The conformity rate was 78.8%. Of the 33 cases, 29 had an IHC score of +++ (87.9%). Its conformity rate was 87.9%. The difference between the ICC and IHC results was statistically not significant (P = 0.322). Among the 16 cases with negative gene amplification by both ICC and IHC, 15 cases showed HER-2 protein expression as 0/+, and another one case was not counted because there was not enough cells. Of the 16 cases, 15 had an IHC score of ++ and one of +++ . To take the FISH results as gold standard, ICC results had a high sensitivity (87.9%) and specificity (100.0%). CONCLUSIONS: FISH in FNA samples can be used in the clinic to test HER-2 gene amplification and overexpression in breast cancers, with a high sensitivity and specificity in ICC. Our data support the use of FISH and ICC analysis to determine HER-2 status on FNA specimens in patients with advanced breast cancer and recurrence or metastatic tumors. When ICC score is +++ , it indicates that there is a HER-2 gene amplification by FISH. PMID- 24785278 TI - [CT diagnosis of different pathological types of ground-glass nodules]. AB - OBJECTIVE: To explore the CT features of ground-glass nodules (GGN) including preinvasive lesions [atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS)], minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC). METHODS: Ninety-seven GGN lesions confirmed by operation pathology were included in this study. The lesions were divided into three groups: preinvasive lesion group (24 cases), MIA group (39 cases), IAC group (34 cases). The lesion size, 3-dimensional ratio, 2-dimensional ratio in axial images, lesion density, shape, speculation, lobulation, air-containing space and pleural indentation on the preoperative CT images in the three groups were analyzed and compared with pathological results. The data were statistically analyzed using SPSS 17.0. RESULTS: All preinvasive lesions presented as pure GGN on CT image, most showed round-like shape, clear and smooth border. MIA presented as pure GGN or mixed GGN on CT image, most showed round-like shape, with a clear and smooth border. IAC most presented as mixed GGN on CT image, often showed irregular shape. Speculation, lobulation, air-containing space and pleural indentation displayed gradually increasing from preinvasive lesions to MIA and IAC. There were statistically significant differences in lesion size, CT density, shape, air containing space, speculation, pleural indentation and long diameter of solid component between the MIA and IAC groups (P < 0.05 for all). There were statistically significant differences in CT density values and long diameters of solid component of the lesions between the preinvasive lesion group and MIA group (P < 0.05). The AUC of solid component of the preinvasive lesion group and MIA group was 0.705, and that of the MIA and IAC groups was 0.814. CONCLUSION: Comprehensive analysis of the CT image features of GGNs, especially the solid component in the lesions, may help to the preoperative and differential diagnosis of preinvasive lesions, MIA and IAC. PMID- 24785279 TI - [CT and MRI Features and pathological characteristics of retroperitoneal localized Castleman's disease]. AB - OBJECTIVE: To analyze the CT and MRI findings and pathological characteristics of retroperitoneal localized Castleman's disease and discuss the diagnostic and differential value of CT and MRI. METHODS: CT, MRI and clinical data of retroperitoneal localized Castleman's disease, proved by surgery and pathology, of 13 patients were reviewed. Among them, all the 13 cases received CT, and 4 cases received MRI examination. RESULTS: Among the 13 cases, 12 cases were of hyaline vascular type, and one was of mixed type. All foci were single mass and most foci located in the periphery of the kidney. The maximum diameter was 4.2 cm to 8.6 cm and the mean diameter of all tumors was 5.9 cm. The outline of most tumors was clear and kidney-shaped. On unenhanced CT, 10 cases showed low density and 3 cases showed isodensity. On plain MRI, four cases showed iso-signal on T1WI, three cases showed slightly high signal on T2WI and one showed moderately high signal. The CT and MRI findings were similar on contrast enhanced scan. In arterial phase, 10 cases showed moderate enhancement, 2 cases showed significant enhancement and one case showed moderate enhancement. Five cases showed rather homogeneous enhancement and 8 cases showed heterogeneous enhancement.In venous phase, all the 13 tumors showed continuous enhancement. Eight cases showing heterogeneous enhancement in arterial phase showed expanded range, and among them two cases showed tending to be homogeneous enhancement. Six cases showed areas of low density without enhancement, and 9 cases were accompanied with single or multi-satellite punctuate or striped foci around the tumors. CONCLUSION: Dynamic contrast-enhanced CT and MRI combined with MR T2WI fat-suppression are of great importance in the diagnosis and identification of retroperitoneal localized Castleman's disease. PMID- 24785280 TI - [Analysis of predictive factors affecting sentinel lymph node status in early breast cancer patients]. AB - OBJECTIVE: To investigate the predictive factors affecting sentinel lymph node status in early breast cancer patients. METHODS: Clinicopathological data of 1 038 patients with early breast cancer, who underwent sentinel lymph node biopsy in Henan Tumor Hospital between July 2010 and August 2013, were reviewed. Logistic regression analysis was performed to identify the relevance of clinicopathological features with sentinel lymph node metastases. RESULTS: This group was consisted of 1 038 female patients with an average of 48.6 years. Positive sentinel lymph nodes were found in 22.9% (238/1 038) of the patients. The average number of sentinel lymph nodes removed by surgery was 3.8. Tumor size, tumor location, histopathology, ER/PR status and Ki-67 level were significantly correlated with SLN metastasis(P < 0.05 for all). All the above factors but Ki-67 level were significant independent predictors for SLN metastasis(P < 0.01 for all). CONCLUSION: Negative hormone receptor status, invasive cancer of non-specific histopathological type, tumor size >2 cm, and tumor location in the outer upper quadrat are independent predictive factors of sentinel lymph node metastasis in patients with early breast cancer. PMID- 24785281 TI - [Clinical and biological features of familial nonmedullary thyroid carcinoma]. AB - OBJECTIVE: To analyze the clinical and biological features of familial nonmedullary thyroid carcinoma (FNMTC). METHODS: Clinical data of 66 FNMTC cases of 32 pedigrees was retrospectively analyzed, compared with that of 182 control cases taken randomly from the patients with sporadic papillary thyroid carcinoma (SPTC), who were diagnosed and treated in Tianjin Cancer Hospital between January 2008 and November 2012. The features of FNMTC of the first and second generations were objectively analyzed. Some data quoted from the literature were also used for the analysis. RESULTS: The median age at diagnosis of all the 66 FNMTC patients was 44 years, and 57 (86.4%) were females. Moreover, 71.2% (47 patients, 23 pedigrees) of the FNMTC patients exhibited a sibling relationship, and 28.8% (19 patients, 9 pedigrees) of the FNMTC patients exhibited a parent-offspring relationship, and 9 cases in the first generation and 10 cases in the second generation. There were significant differences between the FNMTC group and SPTC group in terms of tumor multicentricity, tumor bilaterality, lymph node metastasis, central lymph node metastasis, concomitant chronic thyroiditis and recurrence (P < 0.05). Compared with SPTC, sibling FNMTC presented a higher rate of central lymph node metastasis, while parent-offspring FNMTC showed frequent tumor bilaterality and a higher rate of recurrence (P < 0.05). Besides, patients in the second generation were diagnosed at an earlier age and had a higher male rate, the tumors were more frequently multifocal and bilateral, and had a higher rate of lymph node metastasis. CONCLUSIONS: FNMTC may be more aggressive than SPTC and patients in the second generation may exhibit the "anticipation" phenomenon. It's necessary to make sufficient detailed interrogation and long term follow-up of the patients and their family for providing individual recommendations for clinical management. PMID- 24785282 TI - [Clinical characteristics and prognosis of three rare and poor-prognostic subtypes of primary liver carcinoma]. AB - OBJECTIVE: To explore the clinicopathological features and prognostic factors of three rare and poor-prognostic pathological subtypes of primary liver carcinoma, and improve the clinical diagnosis and surgical treatment. METHODS: A retrospective analysis of clinicopathological data of 69 patients with rare pathological subtypes of primary liver carcinoma, diagnosed by postoperative pathology in our hospital from October 1998 to June 2013 was carried out. The data of 80 cases of common poorly differentiated hepatocellular carcinoma treated in the same period were collected as control group. Kaplan-Meier method was used to analyze the survival rate, and Cox proportional hazards model was used for prognostic analysis in the patients. RESULTS: Thirty-four cases were combined hepatocellular carcinoma and cholangiocarcinoma (CCC, 28 males, 6 females), with a median age of 52 years (range, 33 to 73). Ninteen cases were giant cell carcinoma (GCC, 16 males and 3 females), with a median age of 59 years (range, 38 to 66). Sixteen cases were sarcomatoid carcinoma (SC, 14 males and 2 females), with a median age of 57 years (range, 46 to 70). The survival analysis revealed that median survival time and the 1-, 3-, 5-year survival rates for these 3 groups were 20 months, 61.8%, 29.4%, and 20.6% in the CCC patients, 13 months, 52.6%, 31.6%, and 0% in the GCC patients, and 8 months, 31.3%, 0%, 0% in the SC patients, respectively. The median survival time and survival rate of the SC group were significantly lower than those of the other three groups (P < 0.05). However, in the SC group, the incidences of hilar lymph nodes metastasis, vascular tumor emboli and invasion of adjacent organs were significantly higher than those in the other three groups (P < 0.05). There were no statistically significant differences among the other three groups (P > 0.05). The levels of carcino-embryonic antigen were higher in the three rare subtype groups than that of the control group. The incidences of multiple tumors of the three rare subtype groups were higher than that of the control group (P < 0.05). Positive surgical margin was an independent unfavorable prognostic factor. CONCLUSIONS: The combined hepatocellular carcinoma and cholangiocarcinoma, giant cell carcinoma and sarcomatoid carcinoma have a poor prognosis. Among them sarcomatoid carcinoma is the most malignant and poor prognostic one. Radical resection is recommended. PMID- 24785283 TI - [Treatment and prognosis of 117 patients with advanced urothelial carcinoma of the bladder]. AB - OBJECTIVE: The aim of this study was to analyze the clinical characteristics, treatment and prognosis of advanced urothelial carcinoma of the bladder (AUCB). METHODS: The clinicopathological data of 117 patients with AUCB admitted in our hospital from 1998 to 2009 were reviewed. All patients received first-line chemotherapy. The survival rate was calculated by Kaplan-Meier analysis and log rank test. RESULTS: The median age of all patients was 56 years and the male-to female ratio was 3.33:1. Their 6-, 12-, 24-, 36- and 60-month survival rates were 90.3%, 61.3%, 32.3%, 24.2% and 8.1%, respectively. In the first-line chemotherapy regimen, the effectiveness rate of gemcitabine + platinum drugs was 49.3% (37/75), the median progression-free survival(PFS) was 7.9 months and overall survival (OS) was 18.7 months. The effectiveness of cyclophosphamide + epirubicin + platinum drug regimen was 45.5% (10/22), Median PFS was 7.1 months and OS was 15.3 months. The effectiveness of paclitaxel + platinum drug regimen was 47.1% (8/17), median PFS was 6.5 months and OS was 13.7 months. Among them, the effectiveness rate of the gemcitabine + cisplatin regimen in 67 patients was 47.8%, the median PFS was 7.0 months and OS was 15.3 months. In the 13 patients who received paclitaxel + carboplatin regimen, the effectiveness rate was 53.8%, median PFS was 7.7 months and OS was 16.0 months. The major side effects were leucopenia and thrombocytopenia, mostly were tolerable, of grade I to II. CONCLUSIONS: In advanced unresectable and metastatic urothelial carcinoma of the bladder, GC regimen is recognized as a standard first-line chemotherapy, with a higher effectiveness and tolerable side effects. Taxane and molecular targeted drugs may further improve the therapeutic effect of the treatment of advanced urothelial carcinomas of the bladder in the future. PMID- 24785284 TI - [Outcome and prognostic factors of 125 loco-regionally advanced head and neck squamous cell carcinoma treated with multi-modality treatment]. AB - OBJECTIVE: To investigate the treatment outcome of loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) after been treated with multi-modality approach since 2005 in our hospital and to explore the prognostic factors for treatment outcomes. METHODS: Clinical data of 125 postoperative LA SCCHN patients treated in our department with radiotherapy/chemoradiotherapy from May 2005 to December 2011 were collected and reviewed in this study. The radiotherapy technique was intensity-modulated radiotherapy (IMRT) (93.6%) and a minority of patients received 3D-conformal radiotherapy (3D-CRT). RESULTS: Up to January 6th, 2013, 124 patients were followed up with a median follow-up duration of 25 months. The 3-year overall survival (OS), disease-free survival (DFS), loco regional control (LRC), distant metastasis-free survival (DMFS) were 69.7%, 56.1%, 80.8%, and 73.1%, respectively. A total of 37 patients died during the follow-up period. Among the 43 patients presented with treatment failure, 13 patients had loco-regional relapse, 20 patients had distant metastasis and 10 patients presented with both loco-regional and distant relapses. Distant metastasis accounted for the predominant cause of death. Lung and mediastinal lymph nodes are the most common sites involved by distant metastasis.Univariate analysis indicated that patients who underwent non-radical surgery, with larger size of invaded lymph nodes, higher N stage (N2b and above) and vascular tumor embolism had a lower OS (P = 0.001, 0.000, 0.032, 0.007, respectively). Patients who underwent neck dissection only, or those with higher N stage (N2b and above) or higher TNM stage or vascular tumor thrombi had higher distant metastasis rates (P = 0.017, 0.002, 0.008, 0.001, respectively). The multivariate analysis showed that non-radical surgery was an independent prognostic factor for OS (P = 0.001), larger size of invaded lymph nodes was an independent prognostic factor for poorer LRC (P = 0.001); higher N stage (N2b and above) or T4 stage and vascular tumor thrombi were independent prognostic factors for poorer distant metastasis free survival (P = 0.035, 0.008 and 0.050, respectively). CONCLUSIONS: Our results indicate that multi-modality treatment for LA-SCCHN has achieved better outcome than before. Distant metastasis has become the predominant pattern of failure as well as the primary cause of death instead of loco-regional relapse as a result of improved local control modality. More efforts should be made to decrease the rate of distant metastasis in the future. PMID- 24785285 TI - [Trastuzumab combined with chemotherapy in patients with HER2-positive chemo refractory advanced gastric or gastro-esophageal junction adenocarcinoma]. AB - OBJECTIVE: To evaluate the efficacy and safety of trastuzumab combined with chemotherapy in the treatment for HER-2-positive chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma. METHODS: Twenty consecutive cases of chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma treated in Peking University Cancer Hospital between 2009 June and 2013 August were included in this study. The patients with adenocarcinoma were previously confirmed and were eligible if their tumor showed overexpression of HER-2+++ by immunohistochemistry or HER-2 gene amplification-positive by FISH, and if they failed to at least one previous chemotherapy. Response and toxicities were evaluated with RECIST 1.0 and CTC AE 3.0 criteria. RESULTS: The twenty patients received trastuzumab plus second- or later-line chemotherapy, consisting of nine platinum with fluoropyrimidines, five paclitaxel with fluoropyrimidines, three fluoropyrimidines monotherapy, two irinotecan monotherapy, and one docetaxel monotherapy. In these 20 cases, 3 PR (15.0%) and 10 SD (50.0%) were achieved, with a disease control rate of 65.0%. The median PFS was 6.1 months (95%CI 3.0-9.2) and median OS was 11.1 months (95%CI 8.4-13.7). The median cycle number of Trastuzumab administration was 6.5. The patients treated with Trastuzumab >= 6 times had a median OS of 13.8 months, significantly longer than that of 9.5 months in the patients treated <6 times (P < 0.001). The patients treated with Trastuzumab >= 6 times had a median PFS of 7.8 months, significantly longer than that of 3.7 months in patients treated <6 times (P = 0.029). Among the 20 cases, loss of appetite (13 cases of grade 1-2), neutropenia (12 cases of grade 1-2 and 3 cases of grade 3-4) and fatigue (9 cases of grade 1-2 and 3 cases of grade 3-4) were the most frequent adverse events. No cardiac events including asymptomatic decreases in LVEF >= 10% and no treatment-related death were recorded. CONCLUSIONS: Combination of trastuzumab with chemotherapy is effective and safe in patients with HER2-positive advanced chemo-refractory gastric or gastro-esophageal junction adenocarninoma. However, prospective studies are warranted to further confirm its efficacy and safety. PMID- 24785286 TI - [Treatment of metastatic thoracolumbar tumors by percutaneous vertebroplasty combined with interstitial implantation of 125I seeds]. AB - OBJECTIVE: To explore the value of percutaneous vertebroplasty combined with interstitial implantation of 125I seeds in the treatment of metastatic thoracolumbar tumors. METHODS: Based on the CT images before 125I seed implantation, a computer-based treatment planning system (TPS) was used to determine the optimal seed distribution. Under CT guidance and local anaesthesia, 125I seeds were implanted into 22 osseous metastatic lesions in 18 patients. Based on the CT images after the implantation, quality check was carried out with TPS. DSA (digital subtraction angiography)-guided vertebroplasty was performed under local anaesthesia, and bone cement was injected into the vertebrae through pedicle of vertebral arch. RESULTS: All the 18 patients received percutaneous vertebroplasty combined with interstitial implantation of 125I seeds. Every vertebra was injected with 2-6 ml bone cement, average 3.5 ml, and was injected with 125I seeds 16-34 pills, average 26 pills. At 2-months follow-up, their numerical rating scale (NRS) pain scores were 7.12 +/- 1.48 before and 2.26 +/- 1.07 after treatment, with a significant difference (P < 0.05). CONCLUSIONS: Percutaneous vertebroplasty combined with interstitial implantation of 125I seeds is a minimally invasive procedure with small wound and minor complications, and no need of external radiation therapy. It is effective in the alleviation of pain in metastatic thoracolumbar tumor patients, restrains the tumor growth, and improves the quality of life. It is a promising minimally invasive method in the treatment of metastatic thoracolumbar tumors. PMID- 24785287 TI - [Clinical effects of pedicled omentum covering and wrapping the ureteral anastomosis to prevent ureteral anastomotic leakage after surgery of abdominal and pelvic tumors]. AB - OBJECTIVE: To explore the clinical effects of pedicled omentum covering and wrapping the ureteral anastomosis to prevent ureteral anastomotic leakage after surgery of abdominal and pelvic tumors. METHODS: Clinical data of 64 patients with ureteral anastomosis after surgery of abdominal and pelvic tumors treated in our department from May 2005 to May 2012 were retrospectively analyzed. They were assigned into 2 groups. There were 23 patients of ureteral anastomosis combined with pedicled omentum surrounding and wrapping the anastomotic site (optimization group), and 41 cases of ureteral anastomosis alone (control group). The clinical data of all the 64 patients were reviewed and the therapeutic effects of the two treatment approaches were compared. RESULTS: At one week after the operation, there were 8 cases (34.8%, 8/23) with ureteral anastomotic fistula in the optimization group and 31 cases (75.6%, 31/41) in the control group (P = 0.010). In the postoperative days 1-3, the average drainage everyday from abdominal tube around the anastomotic site was 260.4 ml and 320.8 ml, respectively (P = 0.446). The average drainage volume everyday was 80.5 ml and 160.5 ml from the postoperative day 4 to day 7 (P = 0.015). The average time of removal of the peritoneal cavity drainage tube was 18.5 d in the optimization group and 32.6 d postoperatively in the control group (P = 0.015). CONCLUSIONS: Covering and wrapping the ureteral anastomosis with pedicled omentum can promote the rapid adhesion of surrounding tissues to reduce urine leakage and postoperative complications, and shorten the surgical treatment cycle. PMID- 24785288 TI - [Accuracy and direct medical cost of different screening modalities for breast cancer among Chinese women]. AB - OBJECTIVE: To evaluate the accuracy and direct medical cost of different screening modalities of physical examination (PE), mammography (MAM), and high frequency ultrasonography (US) for breast cancer among Chinese women. METHODS: This study was designed as a blindly carried outcom parative parallel screening trial for breast cancer among Chinese women aged 35 years or older. Physical examination was conducted with the subjects in the first round of breast cancer screening. The negative cases were followed up approximately 1 year later and moved into the second round of screening. Using the results of biopsies and 1 year follow-up as the gold standards, the accuracy and cost indexes of different screening modalities were calculated. Data were analyzed by McNemar test. RESULTS: A total of 2 471 eligible women were included in this trial, and 14 breast cancers were identified among them. Mammography enabled to detect 11 cancers, high-frequency ultrasonography detected 9 cancers and physical examination detected 8 cancers. Considering the three modalities separately, MAM identified the fewest suspicious cases (52 cases) and detected the most cancers (11 cases). Using US alone at the first stage, followed by MAM when indicated, offered the highest specificity (99.7%)and correct positive predictive value (11.4%), meanwhile the sensitivity was 78.6%, and the mean costs of the screening modality in urban and rural areas were 291, 210 yuan and 886,050 yuan per cancer case detected. CONCLUSIONS: The strategy of screening with US alone at the first stage, followed by MAM when indicated, may be the most suitable modality of breast cancer detection in most regions of China, but the cost is still too high to develop the breast cancer screening in some low incidence regions with limited health resources. PMID- 24785289 TI - The more, the merrier: heterotroph richness stimulates methanotrophic activity. AB - Although microorganisms coexist in the same environment, it is still unclear how their interaction regulates ecosystem functioning. Using a methanotroph as a model microorganism, we determined how methane oxidation responds to heterotroph diversity. Artificial communities comprising of a methanotroph and increasing heterotroph richness, while holding equal starting cell numbers were assembled. We considered methane oxidation rate as a functional response variable. Our results showed a significant increase of methane oxidation with increasing heterotroph richness, suggesting a complex interaction in the cocultures leading to a stimulation of methanotrophic activity. Therefore, not only is the methanotroph diversity directly correlated to methanotrophic activity for some methanotroph groups as shown before, but also the richness of heterotroph interacting partners is relevant to enhance methane oxidation too. In this unprecedented study, we provide direct evidence showing how heterotroph richness exerts a response in methanotroph-heterotroph interaction, resulting in increased methanotrophic activity. Our study has broad implications in how methanotroph and heterotroph interact to regulate methane oxidation, and is particularly relevant in methane-driven ecosystems. PMID- 24785290 TI - Anterior Segment Ischemia in Viper Bite. AB - PURPOSE: To describe the clinical and histopathological features of post viper bite anterior segment ischemia. METHODS: Seven patients with ocular complications following viper bite referred to uveitis clinic had slit-lamp examination, intraocular pressure (IOP) measurement, and fundus evaluation. Iris and fundus fluorescein angiography was performed on 2 patients. Histopathological examination was performed on iris tissues collected during cataract surgery. RESULTS: Strikingly similar clinical findings were noted, including circumpupillary superficial iris atrophy, mid dilated fixed pupil, marked pigment dispersion, low IOP, and cataract. All clinical signs were noted only in the anterior segment; the posterior segment was normal. Histopathology of iris revealed atrophy of iris stroma, necrotic iris pigment epithelium, and infiltration of T lymphocytes and fibrous membrane. Poor visual outcome was noted in patients with low IOP. CONCLUSION: Viper bite victims presented with clinical and histopathological signs of anterior segment ischemia and secondary inflammatory signs mimicking uveitis. PMID- 24785291 TI - Increased prevalence of Dirofilaria immitis antigen in canine samples after heat treatment. AB - Canine serum samples may contain factors that prevent detection of antigen of Dirofilaria immitis on commercial assays, precluding accurate diagnosis. To determine the degree to which the presence of blocking antibodies or other inhibitors of antigen detection may interfere with our ability to detect circulating antigen in canine samples, archived plasma and serum samples (n=165) collected from dogs in animal shelters were tested for D. immitis antigen before and after heat treatment. Negative samples were also evaluated for their ability to block detection of D. immitis antigen in a sample from a positive dog. All 165 samples were negative prior to heating, but 11/154 (7.1%) became positive after heat treatment, a conversion that was documented and quantified on spectrophotometric plate assays, and 7/165 (4.2%) samples decreased detection of antigen when mixed with a known positive sample, suggesting some blocking ability was present. An additional 103 plasma and serum samples that tested positive prior to heating also were evaluated; the optical density of 14/101 (13.9%) increased by >=50%, and one sample by as much as 15-fold, after heat treatment. Our results suggest that canine serum and plasma samples from dogs in the southeastern United States can contain inhibitors of D. immitis antigen detection, and that prevalence estimates of heartworm infection based on these assays would benefit from heat treatment of samples prior to testing. PMID- 24785292 TI - Molecular epidemiology of Blastocystis in pigs and their in-contact humans in Southeast Queensland, Australia, and Cambodia. AB - Blastocystis, an intestinal protist commonly found in humans and animals worldwide, has been implicated by some as a causative agent in irritable bowel syndrome in humans. In pigs, infection with Blastocystis is commonly reported, with most pigs shown to harbour subtypes (ST) 1 or 5, suggesting that these animals are potentially natural hosts for Blastocystis. Although ST5 is considered rare in humans, it has been reported to be a potential zoonosis from pigs in rural China. To test these hypotheses, we conducted molecular analysis of faecal samples from pigs and in-contact humans from commercial intensive piggeries in Southeast Queensland (SEQ), Australia, and a village in rural Cambodia. The prevalence of Blastocystis in SEQ and Cambodian pigs was 76.7% and 45.2%, respectively, with all positive pigs harbouring ST5. It appears likely that pigs are natural hosts of Blastocystis with a high prevalence of ST5 that is presumably the pig-adapted ST in these regions. Amongst the SEQ piggery staff, 83.3% were Blastocystis carriers in contrast to only 55.2% of Cambodian villagers. The predominant STs found in humans were STs 1, 2 (Cambodia only) and 3. Interestingly, ST5 which is usually rare in humans was present in the SEQ piggery staff but not in the Cambodian villagers. We conclude that in intensive piggeries, close contact between pigs and their handlers may increase the risks of zoonotic transmission of Blastocystis. PMID- 24785293 TI - Ecological effects of the invasive giant madagascar day gecko on endemic mauritian geckos: applications of binomial-mixture and species distribution models. AB - The invasion of the giant Madagascar day gecko Phelsuma grandis has increased the threats to the four endemic Mauritian day geckos (Phelsuma spp.) that have survived on mainland Mauritius. We had two main aims: (i) to predict the spatial distribution and overlap of P. grandis and the endemic geckos at a landscape level; and (ii) to investigate the effects of P. grandis on the abundance and risks of extinction of the endemic geckos at a local scale. An ensemble forecasting approach was used to predict the spatial distribution and overlap of P. grandis and the endemic geckos. We used hierarchical binomial mixture models and repeated visual estimate surveys to calculate the abundance of the endemic geckos in sites with and without P. grandis. The predicted range of each species varied from 85 km2 to 376 km2. Sixty percent of the predicted range of P. grandis overlapped with the combined predicted ranges of the four endemic geckos; 15% of the combined predicted ranges of the four endemic geckos overlapped with P. grandis. Levin's niche breadth varied from 0.140 to 0.652 between P. grandis and the four endemic geckos. The abundance of endemic geckos was 89% lower in sites with P. grandis compared to sites without P. grandis, and the endemic geckos had been extirpated at four of ten sites we surveyed with P. grandis. Species Distribution Modelling, together with the breadth metrics, predicted that P. grandis can partly share the equivalent niche with endemic species and survive in a range of environmental conditions. We provide strong evidence that smaller endemic geckos are unlikely to survive in sympatry with P. grandis. This is a cause of concern in both Mauritius and other countries with endemic species of Phelsuma. PMID- 24785294 TI - Switchable S = 1/2 and J = 1/2 Rashba bands in ferroelectric halide perovskites. AB - The Rashba effect is spin degeneracy lift originated from spin-orbit coupling under inversion symmetry breaking and has been intensively studied for spintronics applications. However, easily implementable methods and corresponding materials for directional controls of Rashba splitting are still lacking. Here, we propose organic-inorganic hybrid metal halide perovskites as 3D Rashba systems driven by bulk ferroelectricity. In these materials, it is shown that the helical direction of the angular momentum texture in the Rashba band can be controlled by external electric fields via ferroelectric switching. Our tight-binding analysis and first-principles calculations indicate that S = 1/2 and J = 1/2 Rashba bands directly coupled to ferroelectric polarization emerge at the valence and conduction band edges, respectively. The coexistence of two contrasting Rashba bands having different compositions of the spin and orbital angular momentum is a distinctive feature of these materials. With recent experimental evidence for the ferroelectric response, the halide perovskites will be, to our knowledge, the first practical realization of the ferroelectric-coupled Rashba effect, suggesting novel applications to spintronic devices. PMID- 24785295 TI - Radiokrypton dating finally takes off. PMID- 24785296 TI - Metabolic role for yeast DJ-1 superfamily proteins. PMID- 24785297 TI - Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. AB - Folliculin-interacting protein 1 (Fnip1) is an adaptor protein that physically interacts with AMPK, an energy-sensing kinase that stimulates mitochondrial biogenesis and autophagy in response to low ATP, while turning off energy consumption mediated by mammalian target of rapamycin. Previous studies with Fnip1-null mice revealed that Fnip1 is essential for pre-B-cell development. Here we report a critical role of Fnip1 in invariant natural killer T (iNKT) cell development. Thymic iNKT development in Fnip1(-/-) mice was arrested at stage 2 (NK1.1(-)CD44(+)) but development of CD4, CD8, gammadelta T-cell, and NK cell lineages proceeded normally. Enforced expression of a Valpha14Jalpha18 iNKT TCR transgene or loss of the proapoptotic protein Bim did not rescue iNKT cell maturation in Fnip1(-/-) mice. Whereas most known essential transcription factors for iNKT cell development were represented normally, Fnip1(-/-) iNKT cells failed to down-regulate Promyelocytic leukemia zinc finger compared with their WT counterparts. Moreover, Fnip1(-/-) iNKT cells contained hyperactive mTOR and reduced mitochondrial number despite lower ATP levels, resulting in increased sensitivity to apoptosis. These results indicate that Fnip1 is vital for iNKT cell development by maintaining metabolic homeostasis in response to metabolic stress. PMID- 24785299 TI - Influence of place of residence on indications for genetic amniocentesis in the Pomeranian region of Poland before and after introduction of the Prenatal Screening Program in 2008. AB - BACKGROUND: The aim of the study was to analyze differences in the indications for amniocentesis in patients living in urban and rural areas before and after introduction of the Prenatal Screening Program by Polish National Health Insurance agency in the Pomeranian region in 2008. MATERIAL AND METHODS: Indications for 2578 amniocenteses performed in the Department of Obstetrics of the Medical University of Gdansk between 1996 and 2010 were recorded. RESULTS: Advanced maternal age accounted for 69% of women in urban areas and 61% of women in rural areas being referred for amniocentesis (p<0.001). There was also a significant difference between locations in chromosomal abnormality in previous pregnancy, accounting for 4% of referrals for amniocentesis in urban areas compared with 7% of referrals in rural areas. In urban areas, advanced maternal age accounted for 73% of referrals between 1996-2007 compared with 60% of referrals for amniocentesis between 2008 and 2010 (p=0.004), and in rural areas it was 66% and 54%, respectively (p<0.001). Abnormal result of biochemical screening surprisingly accounted for 13% of referrals for amniocenteses between 1996-2007 in urban areas compared with 28% after 2008 (p<0.001). In rural areas this indication accounted for 12% referrals before 2008 and for 28% from 2008 onward (p<0.001). CONCLUSIONS: The results of the study suggest that in both urban and rural areas there was a significant decrease in advanced maternal age as a reason for referral for amniocentesis, but a significant increase in abnormal results of biochemical screening as an indication for amniocentesis after 2008. PMID- 24785298 TI - Identification of Hipk2 as an essential regulator of white fat development. AB - Homeodomain-interacting protein kinase 2 (Hipk2) has previously been implicated in the control of several transcription factors involved in embryonic development, apoptosis, cell proliferation, and tumor development, but very little is understood about the exact mechanisms through which Hipk2 influences these processes. Analysis of gene expression in normal tissues from genetically heterogeneous mouse or human populations can reveal network motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function. Here we have applied this network strategy to uncover a role for the Hipk2 gene in the transcriptional system controlling adipogenesis. Both in vitro and in vivo models were used to show that knockdown or loss of Hipk2 specifically inhibits white adipose cell differentiation and tissue development. In addition, loss of Hipk2 leads to induction of pockets of multilocular brown fat-like cells in remaining white adipose depots, which express markers of brown and beige fat such as uncoupling protein 1 and transmembrane protein 26. These changes are accompanied by increased insulin sensitivity in Hipk2 knockout mice and reduced high-fat diet-induced weight gain, highlighting a potential role for this kinase in diseases such as diabetes and obesity. Our study underscores the versatility and power of a readily available tissue, such as skin, for network modeling of systemic transcriptional programs involved in multiple pathways, including lipid metabolism and adipogenesis. PMID- 24785300 TI - Clinical application of the second morning urine method for estimating salt intake in patients with hypertension. AB - Estimation of salt intake by cumbersome 24-h urine collection is not suitable for individual patients because of substantial daily variation in intake. We developed the second morning urine (SMU) method for monitoring daily salt intake in healthy subjects by calculating the daily creatinine excretion and measuring the ratio of sodium to creatinine in the SMU specimen. To determine whether the SMU method was applicable to hypertensive patients, we tested it in hospitalized patients under an equilibrated sodium balance as a model population. This review focuses on application of the SMU method in hypertensive patients with mild target organ damage. PMID- 24785301 TI - Efficacious inhaled PDE4 inhibitors with low emetic potential and long duration of action for the treatment of COPD. AB - Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential. PMID- 24785302 TI - Assessing knowledge and application of emergency risk communication principles among public health workers in China. AB - OBJECTIVE: Since 2003, the Chinese National Health and Family Planning Commission (formerly the Ministry of Health) has implemented changes to more effectively communicate risk during public health emergencies. In spite of ongoing improvements, provincial and sub-provincial leaders face barriers, such as established modes of operation, lack of training, shortage of trained risk communicators, and limited understanding and willingness of recipients to mitigate risks. METHODS: We assessed the current status of and barriers to risk communication knowledge and practice among public health practitioners in China. We designed the survey questionnaire to capture information related to the risk communication core capacities required by international health regulations and common risk communication principles. RESULTS: Our findings showed that risk communication training has successfully developed an awareness of risk communication principles and the ability to implement those principles in practice in China. CONCLUSIONS: Future efforts should focus on areas such as a dedicated risk communication workforce, requirements that public health agencies develop a risk communication plan, and additional training for public health practitioners and their partners. It is critical that the infectious diseases prevention and control law be amended to grant provincial and local public health agencies more autonomy to release information. PMID- 24785303 TI - Magnetic cross-linked laccase aggregates--bioremediation tool for decolorization of distinct classes of recalcitrant dyes. AB - The increasing use of laccase in waste water industries is useful to explore the high benefit/cost ratio of insolubilization technologies like cross linked enzyme aggregates (CLEAs) for the decolorization and detoxification of distinctive classes of recalcitrant dyes. Amino-functionalized magnetic nanoparticles bonded to CLEAs increased the potential of laccase-based CLEAs and are applicable for commercial implementation of this technology in environmental applications. The activity recovery obtained from the stable rigid structure of magnetic CLEAs was around 32%. High volumetric activity, increased in thermal and operational stability of laccase and its resistance to extreme conditions were the properties provided by these magnetic CLEAs. Kinetic studies show that the catalytic efficiency of the enzyme, based on the kcat/km value, changed significantly upon CLEAs and magnetic CLEA formations. When 0.2U/mL of magnetic CLEAs was used, the biocatalyst rapidly decolorized 61-96% of remazol brilliant blue R, malachite green and reactive black 5 initially at 50mgL(-1) at 20 degrees C and pH7.0. Investigation of dye degradation using both active and heat denatured CLEAs revealed a slight adsorption of dyes on inactivated biocatalysts. A laboratory scale perfusion basket reactor (BR) was used to study the continuous decolorization of dyes. The efficient decolorization (>90%) of remazol brilliant blue R and slight decrease in CLEA activity were measured over a 10h period of continuous operation, which illustrates the potential of CLEAs for the wastewater treatment. The present findings will advance the understanding of dye decolorization mechanism by CLEA laccase, which could provide useful references for developing industrial wastewater treatment. PMID- 24785305 TI - Vaccination for the expatriate and long-term traveler. AB - Duration of travel is an important factor in addressing travel health safety due to cumulative risk of exposure to illness and injury. The diverse group of expatriate and long-term business and leisure travelers present a different spectrum of issues for the travel medicine practitioner to address during consultation than does the short-term traveler, due to changes in travel patterns and activities, lifestyle alterations, and increased interaction with local populations. Immunization provides one safe and reliable method of preventing infectious illness in this group. We review travel patterns and available data on illnesses that they may be exposed to, including the increased risk of certain vaccine-preventable illnesses. We review the pre-travel management of these travelers, particularly the increased risk of certain vaccine-preventable illnesses as it applies to routine vaccines, recommended travel vaccines and required travel vaccines. PMID- 24785307 TI - In vivo neuronal action potential recordings via three-dimensional microscale needle-electrode arrays. AB - Very fine needle-electrode arrays potentially offer both low invasiveness and high spatial resolution of electrophysiological neuronal recordings in vivo. Herein we report the penetrating and recording capabilities of silicon-growth based three-dimensional microscale-diameter needle-electrodes arrays. The fabricated needles exhibit a circular-cone shape with a 3-MUm-diameter tip and a 210-MUm length. Due to the microscale diameter, our silicon needles are more flexible than other microfabricated silicon needles with larger diameters. Coating the microscale-needle-tip with platinum black results in an impedance of ~600 kOmega in saline with output/input signal amplitude ratios of more than 90% at 40 Hz-10 kHz. The needles can penetrate into the whisker barrel area of a rat's cerebral cortex, and the action potentials recorded from some neurons exhibit peak-to-peak amplitudes of ~300 MUVpp. These results demonstrate the feasibility of in vivo neuronal action potential recordings with a microscale needle-electrode array fabricated using silicon growth technology. PMID- 24785306 TI - How familiarization and repetition modulate the picture naming network. AB - A common strategy to reveal the components of the speech production network is to use psycholinguistic manipulations previously tested in behavioral protocols. This often disregards how implementation aspects that are nonessential for interpreting behavior may affect the neural response. We compared the electrophysiological (EEG) signature of two popular picture naming protocols involving either unfamiliar pictures without repetitions or repeated familiar pictures. We observed significant semantic interference effects in behavior but not in the EEG, contrary to some previous findings. Remarkably, the two protocols elicited clearly distinct EEG responses. These were not due to naming latency differences nor did they reflect a homogeneous modulation of amplitude over the trial time-window. The effect of protocol is attributed to the familiarization induced by the first encounter with the materials. Picture naming processes can be substantially modulated by specific protocol requirements controlled by familiarity and, to a much lesser degree, the repetition of materials. PMID- 24785308 TI - Sinonasal symptoms in adults with ear disease. AB - BACKGROUND: The association between eustachian tube dysfunction and middle-ear effusion is well established. Studies have also demonstrated pathological changes affecting the middle-ear mucosa associated with chronic sinonasal inflammation. No previous studies have evaluated symptoms related to sinonasal inflammatory disease in different ear diseases. OBJECTIVE: To assess the presence of sinonasal symptoms in ear diseases using the Dundee Rhinogram. METHODS: Data were collected prospectively in the period February-October 2011. Sinonasal symptoms were graded using the Dundee Rhinogram. Student's t-test analyses were performed to identify any statistically significant associations. RESULTS: In total, 164 patients were assessed. There was a statistically significant association between sinonasal symptoms and mucosal middle-ear diseases (p < 0.005). The mean sinonasal symptoms score for mucosal middle-ear disease patients was 5.94 (range, 0-32). CONCLUSION: Assessment of sinonasal symptoms is paramount in patients presenting with an ear symptom; inflammatory sinonasal disease treatment may become necessary in the management of middle-ear mucosal disease for better patient outcome. PMID- 24785309 TI - Profile and bioconcentration of minerals by King Bolete (Boletus edulis) from the Plocka Dale in Poland. AB - This study aimed to provide basic data on the composition of metallic elements, including toxicologically important Cd and Hg, in popular and prized wild King Bolete mushrooms. We investigated the importance of soil substratum as a source of these metals. ICP-OES and CV-AAS were applied to determine the profile of Al, Ba, Ca, Cd, Cu, Fe, Hg, K, Mg, Mn, Na, Sr and Zn in caps and stipes of King Bolete mushroom and in the surface layer of soil (0-10 cm) from the Plocka Dale area of Poland. Hg, Cu, Cd, Zn, Mg and K exhibited bioconcentration factors (BCF) > 1. Specifically, Hg, Cu and Cd (mean BCFs for caps were 110, 19 and 16, respectively) were efficiently bioconcentrated by King Bolete, while other elements were bioexcluded (BCF < 1). Cadmium was present in the caps at mean levels of 5.5 +/- 2.4 mg kg(-1) dry weight (dw) and mercury at levels of 4.9 +/- 1.4 mg kg(-1) dw, both occurring at elevated concentrations in those King Bolete mushrooms surveyed. PMID- 24785310 TI - Total arsenic, mercury, lead, and cadmium contents in edible dried seaweed in Korea. AB - Total arsenic, mercury, lead, and cadmium contents were determined in 426 samples of seaweed sold in Korea in 2007-08. The average concentrations, expressed in mg kg(-1), dry weight, were: total arsenic 17.4 (less than the limit of detection [LOD] to 88.8), Hg 0.01 (from 0.001 to 0.050), lead 0.7 (less than the LOD to 2.7), and cadmium 0.50 (less than the LOD to 2.9). There were differences in mercury, cadmium, and arsenic content in seaweed between different kinds of products and between coastal areas. The intakes of total mercury, lead, and cadmium for Korean people from seaweed were estimated to be 0.11, 0.65, and 0.45 ug kg(-1) body weight week(-1), respectively. With respect to food safety, consumption of 8.5 g day(-1) of the samples analysed could represent up to 0.2 6.7% of the respective provisional tolerable weekly intakes established by the World Health Organization (WHO). Therefore, even if Korean people have a high consumption of seaweed, this study confirms the low probability of health risks from these metals via seaweed consumption. PMID- 24785311 TI - Intake of essential and non-essential elements from consumption of octopus, cuttlefish and squid. AB - Total concentrations of essential (Cu, Zn, Se and Cr) and non-essential (Hg, Cd, Pb and As) trace elements were measured in the flesh and hepatopancreas of Octopodidae (Eledone moschata, Eledone cirrhosa, Octopus salutii), Sepiidae (Sepia elegans, Sepia orbignyana) and Loliginidae (Illex coindeti, Loligo vulgaris) from the Mediterranean Sea. As expected, the hepatopancreas showed higher metal concentrations than flesh; the only exceptions were Hg and As, which were equally distributed in the two tissues. Regarding the edible portion, the highest toxic metal concentrations were in Octopodidae (Hg: 0.44, Cd: 0.49, Pb: 0.10 ug g(-1) wet weight) and Sepiidae (Hg: 0.27, Cd: 0.50, Pb: 0.12 ug g(-1) wet weight), while Loliginidae tended to accumulate less metal, especially Hg (Hg: 0.11, Cd: 0.30, Pb: 0.05 ug g(-1) wet weight). The other elements showed a heterogeneous distribution among the different cephalopod families. Loliginidae showed the highest Se concentrations (1.18 ug g(-1) wet weight), Octopodidae of Cu (37.37 ug g(-1) wet weight) and Zn (42.00 ug g(-1) wet weight) and Sepiidae of As (61.43 ug g(-1) wet weight), while Cr was uniformly distributed among the various families (0.38-0.43 ug g(-1) wet weight). In these seafoods, the concentrations of essential and non-essential elements were within the prescribed limits set by various authorities, except for Cu and As. Health risks posed by toxic elements to humans via dietary intake of these mollusks were assessed on the basis on Provisional Tolerable Weekly Intake (PTWI), while the estimated intakes of essential elements were compared to Dietary Reference Intakes (RDIs). A 70-g serving of these mollusks was shown to provide a large contribution to Cd intake (0.89 ug kg(-1) body weight), corresponding to 35.6% of PTWI. Concerning the essential elements, the consumption of these mollusks made an important contribution to daily dietary intake of Se, Cu and Zn. PMID- 24785312 TI - Nitrate and nitrite content in organically cultivated vegetables. AB - The nitrate and nitrite content of leaf vegetables (Swiss chard, sea beet, spinach and cabbage), "inflorescence" vegetables (cauliflower) and fruit vegetables (eggplant and vegetable marrow) grown with organic fertilizers have been determined by a modified cadmium-Griess method. Samples were purchased from organic food stores as well as collected directly from an organic farm in Madrid (Spain). Nitrate levels were much higher in the leaf vegetables (especially Swiss chard species; average over the different samples and species of 2778.6 +/- 1474.7 mg kg(-1)) than in inflorescence or fruit products (mean values between 50.2 +/- 52.6 and 183.9 +/- 233.6 mg kg(-1)). Following Swiss chard species, spinach (1349.8 +/- 1045.5 mg kg(-1)) showed the highest nitrate content, and nitrite was found above the limit of detection in some samples only (spinach, 4.6 +/- 1.0 mg kg(-1); sea beet, 4.2 +/- 0.7 mg kg(-1) and Swiss chard, 1.2 +/- 0.4 mg kg(-1)). Some vegetables (spinach, cabbage and eggplant) had lower nitrate content in the samples harvested in summer, showing the influence of climatic conditions on the nitrate levels in a plant. The samples taken directly from the organic farm, with the exception of eggplant, had higher or slightly higher average nitrate values than samples purchased in the organic food stores, ranging from 117 to 1077%. PMID- 24785313 TI - Survey of lead, cadmium, mercury and arsenic in seafood purchased in Campania, Italy. AB - Lead, cadmium, mercury and arsenic were surveyed in fresh catch, farmed and frozen marine fish, cephalopods and mussels marketed in Campania (Italy), and the population's weekly intake from seafood was assessed. A total of 162 specimens of fish and cephalopods and 30 pools of mussels were analyzed. Pb levels in fresh catch species ranged between <20 and 689 ng/g; in farmed from <20 to 438 ng/g and in frozen from <20 to 541 ng/g. Cd values ranged in fresh catch seafood from <0.8 to 19.8 ng/g; in farmed from <0.8 to 42.3 ng/g; in frozen from <0.8 to 93.1. Hg levels ranged 8-339 ng/g in wild seafood; <5-226 ng/g in farmed and <5-313 ng/g in frozen. In fresh catch seafood, As values ranged <10-231 ng/g; in farmed from 12-310 ng/g and in frozen 12-272 ng/g. Cd and Hg concentrations were below the EU limits in all species; two samples of farmed European seabass and two frozen samples exceeded EU limits for Pb. The median weekly dietary intake could affect the provisional tolerable weekly intake (PTWI) of Pb by 2% (range 0.5-16.5%), Cd PTWI by 0.9% (range 0.1-8.0%), Hg PTWI by 9.6% (range 0.6-41.0%) and the As PTWI by 3.6% (range 0.4-12.5%). Considering the upper values in the ranges, seafood represents a non-negligible contribution to Pb weekly intake (16.5%), but mainly to the weekly intake of Hg (41.0%) for high seafood consumers and those consuming the most contaminated species. PMID- 24785314 TI - Survey of nitrite content in foods from north-east China. AB - This study reports a survey of nitrite in a variety of foods consumed in north east China and estimates the intake of nitrite for the north-east Chinese consumer. A total of 642 food categories including rice and rice products, flour and flour products, soybean and products, vegetables, fruit, preserved vegetables, cured meat products, dairy products, fish products, salt, and soy sauce were analysed for their content of nitrite. Nitrite content was quite different both between different food categories and within the same food category, ranging from not determined (n.d.) to 19.7 mg kg(-1). A great variation in the content of nitrite was found for all the food products. The average content of nitrite was highest in cured meat products (14.3 mg kg(-1)). Next to that, the nitrite content was high in the order of preserved vegetables (4.1 mg kg(-1)), soybean products (3.5 mg kg(-1)), and dairy products (1.9 mg kg(-1)). The lowest average values of nitrite were detected in soy sauce, rice and rice products, salt and fish products, the contents being 0.1, 0.3, 0.3, and 0.6 mg kg(-1). Calculations on the basis of these results and including dietary surveys show that the average intake of nitrite in north-east China from food was 0.03 mg kg(-1) body weight for an average Chinese person weighing 60 kg, and the data are lower than the established acceptable daily intake (ADI) for nitrite. Cured meat products are normally the major contributor to average nitrite intake of the north-east Chinese population. The second contributor is vegetables. PMID- 24785315 TI - Monitoring the levels of deoxynivalenol (DON) in cereals in Lebanon and validation of an HPLC/UV detection for the determination of DON in crushed wheat (bulgur). AB - This paper reports for the first time a method for determining deoxynivalenol (DON) in crushed wheat (bulgur) using an high-performance liquid chromatography (HPLC) method with ultraviolet light detection. Linearity (r (2) > 0.999), selectivity and recovery (70-110%) were acceptable. Results show that the limit of detection (LOD) was 50 ug kg(-1) and the limit of quantification (LOQ) was 80 ug kg(-1). The level of DON was determined in 165 samples of cereals - wheat, forkha (wheat flour special for cake) and bulgur (crushed wheat) - marketed in Lebanon. The results showed that the contamination with DON was 8.75%, 7.5% and 5.0% in bulgur, wheat and forkha, respectively. The LOD and LOQ for wheat (or forkha) were, respectively, 40 and 50 ug kg(-1). The level of DON in all samples was below 1250 ug kg(-1) as recommended by European Union Directives (Commission Regulation (EC) No. 1126/2007), except for one sample of wheat which contained 2307 ug kg(-1). These data suggest that the Lebanese population is exposed to DON through food ingestion at concentrations lower than the tolerable daily intake (TDI) and suggest that measures must be performed routinely to avoid high levels of DON contamination to be found on Lebanese market. PMID- 24785316 TI - Ochratoxin A levels in spices and dried nuts consumed in Tunisia. AB - A total of 112 samples of spices (24 caraway, 20 coriander, 25 curcuma, 20 black pepper and 23 red pepper) and 110 samples of dried nuts (44 almonds, 42 peanuts and 24 pistachio) purchased from popular markets in 24 regions of Tunisia were analyzed for ochratoxin A (OTA) by fluorescence HPLC. The average levels of contamination of OTA found in spice samples were 244, 206, 290, 274 and 203 ug/kg, respectively, for caraway, coriander, curcuma, black pepper and red pepper. Concerning dried nut samples, the average levels were 61, 60 and 89 ug/kg, respectively, for almonds, peanuts and pistachio. Contamination levels were higher than the usual norms (10.0 OTA ug/kg) established by the European Commission in 2005 . This survey is the first to be carried out on the natural occurrence of OTA in the main spices and dried nuts consumed by the Tunisian population. PMID- 24785317 TI - A survey of dioxins (PCDDs and PCDFs) and dioxin-like PCBs in sheep and goat milk from Campania, Italy. AB - In 2008, after the crisis of buffalo dairy fields in Campania, Italy, an assessment of the contamination of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) was also necessary for other animal species bred in the region. The contents of PCDDs, polychlorinated dibenzofurans (PCDFs), and dl-PCBs were determined by high-resolution gas chromatography/mass spectrometry (HR-GC/MS) (according to USEPA method 1613) in 69 sheep and goat milk samples from 63 farms. In eleven samples from six sheep farms, the PCDD/Fs levels exceeded the maximum limit of 3.0 pg g(-1) fat established by the European Commission, in particular the concentrations ranged between 3.89 and 12.90 pg g(-1) fat. Statistical treatment of the results for the congener profiles of the non-compliant and compliant samples has been used to identify the sources of contamination. PMID- 24785318 TI - Dioxins in beef samples from Mexico using a low resolution GC/MS screening method. AB - Dioxins in beef were quantified by high resolution gas chromatography coupled to low-resolution mass spectrometry (GC/LRMS). The analyses were performed according to the minimum requirements described in the USEPA 1613 method with some minor modifications. Levels found in the samples were in the range 1.02-8.04 pg WHO-TEQ PCDDs/PCDFs g(-1) fat. For comparison purposes, the maximum level allowed by the European Union is 3 pg WHO-TEQ PCDDs/PCDFs g(-1) fat, and some of these samples surpassed the above-mentioned limit and can be considered as contaminated food. The results confirm that a preliminary screening of dioxins in beef can be performed by GC/LRMS. As far as we know, this is the first report of dioxins in beef in Mexico. After the appropriated tests, the applied methodology could be considered as an alternative screening method for the analysis of PCDD/Fs in other food products. PMID- 24785319 TI - Twist-drill craniostomy with hollow screws for evacuation of chronic subdural hematoma. AB - OBJECT.: The incidence of chronic subdural hematoma (CSDH) is expected to increase substantially over the next 25 years. Continuing refinement of techniques for surgical evacuation is essential for optimizing patient outcomes. A novel technique involving a hollow screw, which is threaded through a twist drill hole in the cranium and then connected to a closed drainage system, has been increasing in popularity. The aim of this systematic review is to collate and analyze the published experience with this novel technique and to evaluate its efficacy in comparison with the other surgical treatment methods. METHODS: This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and has been registered with the PROSPERO International Prospective Register of Systematic Reviews (registration number CRD42013003544). MEDLINE, Web of Knowledge, EMBASE, and the Cochrane Database of Systematic Reviews were searched for published series involving more than 10 patients treated with these new techniques. RESULTS: Nine eligible studies were found (6 case series and 3 case-control studies) comprising 796 patients treated with these new techniques. Pooled analysis showed a "success rate" of 77.6% (95% CI 74.6%-80.4%), recurrence rate of 22.4%, and in-hospital mortality of 1.4%. CONCLUSIONS: This systematic review adds further evidence to the pool of data assessing the safety and efficacy of the use of this novel, minimally invasive technique for the treatment for CSDH. Overall, twist-drill craniostomy with hollow screws appears to be safe and effective. Class I evidence is necessary to optimize the surgical management of patients with CSDH. PMID- 24785320 TI - Arachnoid membranes in the posterior half of the incisural space: an inverted Liliequist membrane-like arachnoid complex. AB - OBJECT: The aim of this study was to describe the similarity of configuration between the arachnoid complex in the posterior half of the incisural space and the Liliequist membrane. METHODS: Microsurgical dissection and anatomical observation were performed in 20 formalin-fixed adult cadaver heads. The origin, distribution, and configuration of the arachnoid membranes and their relationships with the vascular structures in the posterior half of the incisural space were examined. RESULTS: The posterior perimesencephalic membrane and the cerebellar precentral membrane have a common origin at the tentorial edge and form an arachnoid complex strikingly resembling an inverted Liliequist membrane. Asymmetry between sides is not uncommon. If the cerebellar precentral membrane is hypoplastic on one side or both, the well-developed quadrigeminal membrane plays a prominent part in partitioning the subarachnoid space in the posterior half of the incisural space. CONCLUSIONS: The arachnoid complex in the posterior half of the incisural space can be regarded as an inverted Liliequist membrane. This concept can help neurosurgeons to gain better understanding of the surgical anatomy at the level of the tentorial incisura. PMID- 24785321 TI - Suprajugular extension of the retrosigmoid approach: microsurgical anatomy. AB - OBJECT: Jugular foramen tumors often extend intra- and extracranially. The gross total removal of tumors located both intracranially and intraforaminally is technically challenging and often requires a combined skull base approach. This study presents a suprajugular extension of the retrosigmoid approach directed through the osseous roof of the jugular foramen that allows the removal of tumors located in the cerebellopontine angle with extension into the upper part of the foramen, with demonstration of an illustrative case. METHODS: The cerebellopontine angles and jugular foramina were examined in dry skulls and cadaveric heads to clarify the microsurgical anatomy around the jugular foramen and to define the steps of the suprajugular exposure. RESULTS: The area drilled in the suprajugular approach is inferior to the acoustic meatus, medial to the endolymphatic depression and surrounding the superior half of the glossopharyngeal dural fold. Opening this area exposed the upper part of the jugular foramen and extended the exposure along the glossopharyngeal nerve below the roof of the jugular foramen. In the illustrative case, a schwannoma originating from the glossopharyngeal nerve in the cerebellopontine angle and extending below the roof of the jugular foramen and above the jugular bulb was totally removed without any postoperative complications. CONCLUSIONS: The suprajugular extension of the retrosigmoid approach will permit removal of tumors located predominantly in the cerebellopontine angle but also extending into the upper part of the jugular foramen without any additional skull base approaches. PMID- 24785323 TI - Endoscopic endonasal transsphenoidal approach to large and giant pituitary adenomas: institutional experience and predictors of extent of resection. AB - OBJECT.: While the use of endoscopic approaches has become increasingly accepted in the resection of pituitary adenomas, limited evidence exists regarding the success of this technique for patients with large and giant pituitary adenomas. This study reviews the outcomes of a large cohort of patients with large and giant pituitary adenomas who underwent endoscopic endonasal transsphenoidal surgery at the authors' institution and focuses on identifying factors that can predict extent of resection and hence aid in developing guidelines and indications for the use of endoscopic endonasal transsphenoidal surgery versus open craniotomy approaches to large and giant pituitary adenomas. METHODS: The authors reviewed 487 patients who underwent endoscopic endonasal transsphenoidal resection of sellar masses. From this group, 73 consecutive patients with large and giant pituitary adenomas (defined as maximum diameter >= 3 cm and tumor volume >= 10 cm(3)) who underwent endoscopic endonasal transsphenoidal surgery between January 1, 2006, and June 6, 2012, were included in the study. Clinical presentation, radiological studies, laboratory investigations, tumor pathology data, clinical outcomes, extent of resection measured by volumetric analysis, and complications were analyzed. RESULTS: The mean preoperative tumor diameter in this series was 4.1 cm and the volume was 18 cm(3). The average resection rate was 82.9%, corresponding with a mean residual volume of 3 cm(3). Gross-total resection was achieved in 16 patients (24%), near-total in 11 (17%), subtotal in 24 (36%), and partial in 15 (23%). Seventy-three percent of patients experienced improvement in visual acuity, while 24% were unchanged. Visual fields were improved in 61.8% and unchanged in 5.5%. Overall, 27 patients (37%) experienced a total of 32 complications. The most common complications were sinusitis (14%) and CSF leak (10%). Six patients underwent subsequent radiation therapy because of aggressive tumor histopathology. No deaths occurred in this cohort of patients. Statistically significant predictors of extent of resection included highest Knosp grade (p = 0.001), preoperative tumor volume (p = 0.025), preoperative maximum tumor diameter (p = 0.002), hemorrhagic component (p = 0.027), posterior extension (p = 0.001), and sphenoid sinus invasion (p = 0.005). CONCLUSIONS: Endoscopic endonasal transsphenoidal surgery is an effective treatment method for patients with large and giant pituitary adenomas, which results in high (> 80%) rates of resection and improvement in visual function. It is not associated with high rates of major complications and is safe when performed by experienced surgeons. The preoperative Knosp grade, tumor volume, tumor diameter, hemorrhagic components on MRI, posterior extension, and sphenoid sinus invasion may allow a prediction of extent of resection and in these patients a staged operation may be required to maximize extent of resection. PMID- 24785322 TI - Phase I/II study of resection and intraoperative cesium-131 radioisotope brachytherapy in patients with newly diagnosed brain metastases. AB - OBJECT: Resected brain metastases have a high rate of local recurrence without adjuvant therapy. Adjuvant whole-brain radiotherapy (WBRT) remains the standard of care with a local control rate > 90%. However, WBRT is delivered over 10-15 days, which can delay other therapy and is associated with acute and long-term toxicities. Permanent cesium-131 ((131)Cs) implants can be used at the time of metastatic resection, thereby avoiding the need for any additional therapy. The authors evaluated the safety, feasibility, and efficacy of a novel therapeutic approach with permanent (131)Cs brachytherapy at the resection for brain metastases. METHODS: After institutional review board approval was obtained, 24 patients with a newly diagnosed metastasis to the brain were accrued to a prospective protocol between 2010 and 2012. There were 10 frontal, 7 parietal, 4 cerebellar, 2 occipital, and 1 temporal metastases. Histology included lung cancer (16), breast cancer (2), kidney cancer (2), melanoma (2), colon cancer (1), and cervical cancer (1). Stranded (131)Cs seeds were placed as permanent volume implants. The prescription dose was 80 Gy at a 5-mm depth from the resection cavity surface. Distant metastases were treated with stereotactic radiosurgery (SRS) or WBRT, depending on the number of lesions. The primary end point was local (resection cavity) freedom from progression (FFP). Secondary end points included regional FFP, distant FFP, median survival, overall survival (OS), and toxicity. RESULTS: The median follow-up was 19.3 months (range 12.89 29.57 months). The median age was 65 years (range 45-84 years). The median size of resected tumor was 2.7 cm (range 1.5-5.5 cm), and the median volume of resected tumor was 10.31 cm(3) (range 1.77-87.11 cm(3)). The median number of seeds used was 12 (range 4-35), with a median activity of 3.82 mCi per seed (range 3.31-4.83 mCi) and total activity of 46.91 mCi (range 15.31-130.70 mCi). Local FFP was 100%. There was 1 adjacent leptomeningeal recurrence, resulting in a 1-year regional FFP of 93.8% (95% CI 63.2%-99.1%). One-year distant FFP was 48.4% (95% CI 26.3%-67.4%). Median OS was 9.9 months (95% CI 4.8 months, upper limit not estimated) and 1-year OS was 50.0% (95% CI 29.1%-67.8%). Complications included CSF leak (1), seizure (1), and infection (1). There was no radiation necrosis. CONCLUSIONS: The use of postresection permanent (131)Cs brachytherapy implants resulted in no local recurrences and no radiation necrosis. This treatment was safe, well tolerated, and convenient for patients, resulting in a short radiation treatment course, high response rate, and minimal toxicity. These findings merit further study with a multicenter trial. PMID- 24785324 TI - The endoscopic endonasal approach for the management of craniopharyngiomas: a series of 103 patients. AB - OBJECT: Despite their benign histological appearance, craniopharyngiomas can be considered a challenge for the neurosurgeon and a possible source of poor prognosis for the patient. With the widespread use of the endoscope in endonasal surgery, this route has been proposed over the past decade as an alternative technique for the removal of craniopharyngiomas. METHODS: The authors retrospectively analyzed data from a series of 103 patients who underwent the endoscopic endonasal approach at two institutions (Division of Neurosurgery of the Universita degli Studi di Napoli Federico II, Naples, Italy, and Division of Neurosurgery of the Bellaria Hospital, Bologna, Italy), between January 1997 and December 2012, for the removal of infra- and/or supradiaphragmatic craniopharyngiomas. Twenty-nine patients (28.2%) had previously been surgically treated. RESULTS: The authors achieved overall gross-total removal in 68.9% of the cases: 78.9% in purely infradiaphragmatic lesions and 66.3% in lesions involving the supradiaphragmatic space. Among lesions previously treated surgically, the gross-total removal rate was 62.1%. The overall improvement rate in visual disturbances was 74.7%, whereas worsening occurred in 2.5%. No new postoperative defect was noted. Worsening of the anterior pituitary function was reported in 46.2% of patients overall, and there were 38 new cases (48.1% of 79) of postoperative diabetes insipidus. The most common complication was postoperative CSF leakage; the overall rate was 14.6%, and it diminished to 4% in the last 25 procedures, thanks to improvement in reconstruction techniques. The mortality rate was 1.9%, with a mean follow-up duration of 48 months (range 3-246 months). CONCLUSIONS: The endoscopic endonasal approach has become a valid surgical technique for the management of craniopharyngiomas. It provides an excellent corridor to infra- and supradiaphragmatic midline craniopharyngiomas, including the management of lesions extending into the third ventricle chamber. Even though indications for this approach are rigorously lesion based, the data in this study confirm its effectiveness in a large patient series. PMID- 24785325 TI - Hemorrhage risks and functional outcomes of untreated brainstem cavernous malformations. AB - OBJECT.: Cerebral cavernous malformations have been studied widely, but the natural history of brainstem cavernous malformations (CMs) is not well defined, and hemorrhages caused by brainstem CMs are devastating. The goal of this study was to quantify the hemorrhage risks and functional outcomes of patients with brainstem CMs. METHODS: This prospective, longitudinal, cohort study included patients with brainstem CMs diagnosed between 1985 and 2012. The clinical courses of all patients were recorded. Predictors of hemorrhage and the overall untreated outcomes were evaluated. RESULTS: A total of 331 patients (46.5% female) were included, with a mean follow-up duration of 6.5 years. The annual hemorrhage rates in patients initially presenting with hemorrhage with (n = 215) or without (n = 34) focal neurological deficits were 15.9% and 12.4%, respectively. However, the annual hemorrhage rate was 8.7% in patients initially presenting without hemorrhage (n = 82). The risk factors for hemorrhage were female sex (hazard ratio [HR] 1.445, p = 0.041), prior hemorrhage (HR 1.277, p = 0.029), and perilesional edema (HR 1.830, p = 0.002). Overall, neurological function at the most recent assessment was improved compared with neurological function at diagnosis. Additionally, 307 patients (92.7%) improved or stabilized, 268 (81.0%) lived independently, and 95 (28.7%) completely recovered. Predictors favoring complete recovery were no prospective hemorrhage (HR 1.958, p = 0.001), younger age (HR 1.268, p = 0.001), and small lesion size (HR 1.578, p = 0.004). CONCLUSIONS: Patients' initial presentation predicts their prospective annual hemorrhage rate. This study suggests that several strong risk factors for hemorrhage and predictors of brainstem CM outcomes may enable clinicians to evaluate the potential hemorrhage risks of their patients and design personalized treatments. PMID- 24785326 TI - Brain shift during bur hole-based procedures using interventional MRI. AB - OBJECT.: Brain shift during minimally invasive, bur hole-based procedures such as deep brain stimulation (DBS) electrode implantation and stereotactic brain biopsy is not well characterized or understood. We examine shift in various regions of the brain during a novel paradigm of DBS electrode implantation using interventional imaging throughout the procedure with high-field interventional MRI. METHODS: Serial MR images were obtained and analyzed using a 1.5-T magnet prior to, during, and after the placement of DBS electrodes via frontal bur holes in 44 procedures. Three-dimensional coordinates in MR space of unique superficial and deep brain structures were recorded, and the magnitude, direction, and rate of shift were calculated. Measurements were recorded to the nearest 0.1 mm. RESULTS: Shift ranged from 0.0 to 10.1 mm throughout all structures in the brain. The greatest shift was seen in the frontal lobe, followed by the temporal and occipital lobes. Shift was also observed in deep structures such as the anterior and posterior commissures and basal ganglia; shift in the pallidum and subthalamic region ipsilateral to the bur hole averaged 0.6 mm, with 9% of patients having over 2 mm of shift in deep brain structures. Small amounts of shift were observed during all procedures; however, the initial degree of shift and its direction were unpredictable. CONCLUSIONS: Brain shift is continual and unpredictable and can render traditional stereotactic targeting based on preoperative imaging inaccurate even in deep brain structures such as those used for DBS. PMID- 24785327 TI - Ligustrazine corrects Th1/Th2 and Treg/Th17 imbalance in a mouse asthma model. AB - Asthma is an inflammatory disease closely associated with activated T cells in the lung. Imbalances in Th1/Th2 and Treg/Th17 have been found in asthmatic patients. Ligustrazine from the Chinese herb chuanxiong has been used in China in combination with glucocorticoids to treat asthma. Previous studies have proved that ligustrazine can modulate the expression of transcription factors for Th1 (T bet) and Th2 (Gata-3) in asthma. In the present study, ligustrazine alleviated allergic airway inflammation in a mouse asthmatic model by reducing the influx of eosinophils and neutrophils, which was mediated, at least in part, by the regulation of Th1/Th2 and Treg/Th17 via the re-balance of cytokine profiles and of ratios of transcription factors, T-bet/Gata-3 and Foxp3/RORgammat, thus providing new insights into the mechanisms of action for asthma treatment with ligustrazine. PMID- 24785329 TI - Electroencephalography/sonication-mediated human brain-brain interfacing technology. PMID- 24785328 TI - Amorfrutin A inhibits TNF-alpha-induced NF-kappaB activation and NF-kappaB regulated target gene products. AB - The nuclear factor-kappaB (NF-kappaB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and angiogenesis. In our search for NF-kappaB inhibitors from natural resources, we identified amorfrutin A as an inhibitor of NF-kappaB activation from the fruits of Amorpha fruticosa L. In present study, this compound significantly inhibited the TNF-alpha-induced expression of NF-kappaB reporter gene. Further analysis revealed that amorfrutin A was a potent inhibitor of NF-kappaB activation by the suppression of TNF-alpha-induced inhibitor of kappaBalpha (IkappaBalpha) degradation, p65 nuclear translocation, and DNA-binding activity of NF-kappaB. We also demonstrated that pretreatment of cells with this compound prevented the TNF alpha-induced expression of NF-kappaB target genes, such as antiapoptosis (cIAP-1 and FLIP), proliferation (COX-2 and cyclinD1), invasion (MMP-9), angiogenesis (VEGF), and major inflammatory cytokines (TNF-alpha, IL-8, and MCP1). Furthermore, our results suggest that amorfrutin A potentiates TNF-alpha-induced apoptosis. Taken together, amorfrutin A could be a valuable candidate for the intervention of NF-kappaB-dependent pathological conditions such as inflammation. PMID- 24785330 TI - Personalized therapy with probiotics from the host by TripleA. PMID- 24785331 TI - A multiplexer liquidchip technology for detecting single nucleotide polymorphisms from metabolism of anti-thrombotic drugs in dried blood spots on filter paper. PMID- 24785333 TI - Creating awareness and dialogue. PMID- 24785332 TI - A novel member of B-cell linker protein identified in lamprey, Lampetra japonica. PMID- 24785334 TI - Lesbians surviving childhood sexual abuse. AB - Abstract This qualitative, feminist study is focused on lesbians' experiences growing up in multiproblem families, surviving aftereffects of trauma, and struggling with alcohol problems. A multi-racial sample of 20 lesbians narrated life stories in a series of three in-depth interviews. The research report opens with one woman's narrative about surviving childhood sexual abuse and continues with explication of how differences and similarities within and between accounts pivot on the issues of sexual orientation, gender, and race. Results suggest that early in their lives, overwhelming violence and intrusive expectations were imposed, negating a clarity of experience about their authenticity. No participant expressed a belief that her sexual orientation was a result of childhood sexual abuse. The societal presumption of sexual abuse as an etiological factor in determining lesbian sexual orientation, nevertheless, was pivotal for these survivors because they had to constantly protect themselves from others' judgements about whether they were "real lesbians." They described a multi-faceted, ingenious strategy, gender-blurring, that helped them garner a place of some value in the family and stave off some of the violence, but this protective stance made them question whether they were "real women." Women also indicated that they grew up in families empty of cultural affiliation. Instead of knowledge and pride about connection with community, they experienced a gaping void about racial identification, ethnicity, parentage, and personal history. All in all, they survived a series of social identity exclusions. Conclusions call into question the usefulness and adequacy of theories about static psychological and social identities and suggest the importance of specific, localized analyses that explore narrative selves. PMID- 24785335 TI - Domestic violence in lesbian relationships. AB - Abstract This article reports on the findings of the Lesbian Relationships Research Project (LRRP), a 1993 study on the prevalence of emotional and physical abuse in lesbian relationships in the San Francisco Bay Area (Medina & Scherzer, 1993). This article reviews the literature on prevalence of domestic violence in lesbian relationships, describes the LRRP study, reports the findings from (1) the survey component of LRRP, which examined prevalence of specific abusive behaviors and respondents' help-seeking experiences, and (2) the qualitative component of the study, which asked respondents what behaviors they considered abusive, what happened when they sought help, and invited other comments. Lastly, the concepts and themes brought up from the qualitative data are discussed to suggest topics for further research. PMID- 24785336 TI - Lesbian Pass/ages. AB - Abstract Despite the greater inclusion of women in the recent literature on aging, lesbians continue to remain invisible. This article presents the inquiries of two mid-life lesbian social work academics into the lives of lesbian women growing older, and the gaps revealed between the images of lesbians constructed in the public domain, and the lives of women who do not fit the mainstream or dominant images. The inquiry begins with the voices of the "experts": women who are living their mid-life years as lesbians in a society which does not "see" or image them. Whether or not this invisibility in mid-life and old age can be overcome through access to a supportive community seems open to debate. PMID- 24785337 TI - Rural lesbians' strategies for coming out to health care professionals. AB - Abstract The authors conducted in-depth interviews with lesbians from rural communities in the midwest about their interactions with health care professionals and how they decided whether to disclose their sexual orientation to them. They described the protective strategies they used when seeking health care and the responses they received to the disclosure of their sexual orientation. The four primary protective strategies included screening, planned disclosure, unplanned disclosure and non-disclosure. Participants voiced concerns over rejection or retaliation by health care professionals and by other community residents if their sexual orientation became known, and that they would be unable to obtain safe, appropriate care given the limited availability of health care service providers in their region. PMID- 24785338 TI - The experiences of lesbians of color in health care encounters. AB - Abstract In this feminist narrative study, lesbians of color gave testimony to the effects of prejudice in face-to-face health care interactions. A major objective was to involve participants from a broad range of ethnic/racial backgrounds and socio-economic circumstances in open-ended interviews about their experiences receiving health care. Half of the 45 women in the sample were lesbians of color: 20% (9) African American, 18% (8) Latina, 11% (5) Asian/Pacific Islander, and 2% (1) Native American. Results suggest that if we wish to improve access to and quality of health services, those in the health care field must address race, class, gender, and sexual orientation prejudice in health care interactions, acknowledging the role discriminatory behavior plays in diminishing the availability of health care for lesbians of color. PMID- 24785339 TI - Room for improvement. AB - Abstract In small studies lesbians report avoiding health care because of difficulty communicating with providers. This study examines lesbians' perceptions of communication with medical and alternative primary care providers using a statewide self-administered survey of members of a lesbian community organization. Univariate and bivariate statistics were used to analyze lesbians' perceptions of communication with their primary care provider about sexual orientation, difficult issues, and health issues important to lesbians. Of 324 respondents, 31% received primary care from alternative providers and 90% are "out" to one or more providers. Respondents who were "out" to their primary care provider were more likely to seek health and preventive care (p <= .05), more likely to have ever had a Pap smear (p <= .02), and more likely to be comfortable discussing sensitive issues (p <= .0001). Respondents rated alternative providers easier to communicate with than M.D.s (4.53 vs. 3.99, p <= .001). They reported being more open about sexual orientation (4.58 vs. 4.05, p <= .001) and more comfortable discussing difficult issues (4.08 vs. 3.61, p <= .001) with alternative providers. Respondents believe alternative providers understand lesbian health needs better than medical doctors (4.21 vs. 3.45, p <= .001). Lesbians appear to be motivated to disclose sexual orientation to their primary care providers and disclosure is associated with positive health behaviors. Medical doctors appear to need improvement in their skills in communicating with lesbians so that important medical and psychosocial information can be shared. PMID- 24785340 TI - Fine needle aspiration cytology of inflammatory pseudotumour of the spleen. PMID- 24785341 TI - A label-free electrochemical aptasensor for the analysis of the potassium ion. AB - Herein, a simple and novel electrochemical method for the detection of potassium ions (K(+)) was developed. In the presence of potassium ions, the potassium ions aptamer will form a G-quadruplex complex. Thus, further addition of hemin in the presence of potassium ions will lead to the formation of a recombined G quadruplex. Then the electroactive label, hemin, will give an electrochemical response. The linear range of the method covered a large variation of K(+) concentration from 0.1 nM to 0.1 MU M and the detection limit of 0.1 nM was obtained. Moreover, this assay was able to detect K(+) with high selectivity and had great potential applications. PMID- 24785342 TI - Efficacy of a new class III drug niferidil in cardioversion of persistent atrial fibrillation and flutter. AB - AIMS: To study the efficacy and safety of the new class III antiarrhythmic agent niferidil for pharmacological cardioversion in patients with persistent atrial fibrillation (AF) and atrial flutter (AFl). METHODS AND RESULTS: One hundred thirty-four adults (aged 57.8 +/- 11 years, 90 males) were included with median AF duration of 3 (1.5-6) months. All patients received a total of 10-30 MUg/kg, niferidil, intravenously, in 1-3 (if needed) consecutive boluses at 15-minute intervals. Holter electrocardiogram monitoring was started before infusion and was continued for 24 hours. The criterion for an antiarrhythmic effect was sinus rhythm restoration within 24 hours of the initial bolus. Niferidil converted AF to sinus rhythm in 47.7% of cases after bolus 1, in 62% of cases after bolus 2, and in 84.6% of cases bolus 3. Niferidil induced a 100% recovery rate in patients with AFl and a 91.8% recovery rate in patients with AF of duration from 8 days to 3 months. Nonsustained torsade de pointes occurred in 1 patient (0.7%), and nonsustained monomorphic ventricular tachycardia was observed in 5 patients (3.7%). CONCLUSIONS: The new intravenous class III drug niferidil demonstrated high conversion rates of 84.6% in patients with persistent AF and 100% in patients with persistent AFl. Niferidil may be used as a possible alternative to electrical cardioversion for pharmacological cardioversion of persistent AF/AFl. PMID- 24785343 TI - Improved myocardial function with supplement of levosimendan to Celsior solution. AB - Levosimendan is a calcium-sensitizing agent shown to prevent myocardical contractile depression in various heart diseases. In this study, we investigated the effect of levosimendan on cardiac dysfunction and apoptosis in hypothermic preservation rat hearts. Isolated rat hearts were preserved in Celsior solution with or without levosimendan. The left ventricular developed pressure (LVDP) recovery rate of isolated rat heart significantly decreased, and the apoptosis index increased after 9 hours of hypothermic preservation. Supplement Celsior solution with levosimendan (10 and 10 mole/L) enhanced the LVDP recovery rate and reduced apoptosis. Levosimendan inhibited the hypothermic preservation-induced calpain activation and cleavage of Bid. Levosimendam induced increased myocardial inducible nitric oxide synthase but not endothelial nitric oxide synthase expression. A selective inducible nitric oxide synthase inhibitor 1400W, and a mitochondrial ATP-sensitive potassium (KATP) channel blocker 5-hydroxydecanoate but not a sarcolemmal KATP channel blocker HMR-1098 prevented improvement effect of levosimendam on LVDP recovery rate, abolished the inhibitory effect of levosimendan on hypothermic preservation-induced activation of calpain, cleavage of Bid, and apoptosis. These data suggested that Celsior solution supplement with levosimendan improved cardiac function recovery and reduced myocyte apoptosis in hypothermic preservation rat hearts. PMID- 24785344 TI - Toward safe inotropic therapy. AB - The use of currently available positive inotropic agents is associated with an unfavorable clinical outcome. The disappointment with positive inotropic therapy is to some extent foreseeable as currently available inotropic agents may precipitate ventricular arrhythmias due to a diastolic rise in intracellular [Ca], trigger/worsen myocardial ischemia due to an increased oxygen demand, and foster fuel deprivation from an energy starved heart. Safe use of presently available inotropic agents and development of novel inotropic agents must ensure that they are not associated with a diastolic rise in intracellular [Ca], an increase in myocardial oxygen consumption, and energy expenditure. Agents that improve left ventricular systolic performance through prolongation of left ventricular ejection time and not through increased myocardial contractility, that is, myosin activators, may be associated with a favorable outcome as they do not affect diastolic intracellular [Ca], myocardial oxygen demand, and presumably fuel expenditure. PMID- 24785345 TI - Small dedifferentiated cardiomyocytes bordering on microdomains of fibrosis: evidence for reverse remodeling with assisted recovery. AB - With the perspective of functional myocardial regeneration, we investigated small cardiomyocytes bordering on microdomains of fibrosis, where they are dedifferentiated re-expressing fetal genes, and determined: (1) whether they are atrophied segments of the myofiber syncytium, (2) their redox state, (3) their anatomic relationship to activated myofibroblasts (myoFb), given their putative regulatory role in myocyte dedifferentiation and redifferentiation, (4) the relevance of proteolytic ligases of the ubiquitin-proteasome system as a mechanistic link to their size, and (5) whether they could be rescued from their dedifferentiated phenotype. Chronic aldosterone/salt treatment (ALDOST) was invoked, where hypertensive heart disease with attendant myocardial fibrosis creates the fibrillar collagen substrate for myocyte sequestration, with propensity for disuse atrophy, activated myoFb, and oxidative stress. To address phenotype rescue, 4 weeks of ALDOST was terminated followed by 4 weeks of neurohormonal withdrawal combined with a regimen of exogenous antioxidants, ZnSO4, and nebivolol (assisted recovery). Compared with controls, at 4 weeks of ALDOST, we found small myocytes to be: (1) sequestered by collagen fibrils emanating from microdomains of fibrosis and representing atrophic segments of the myofiber syncytia, (2) dedifferentiated re-expressing fetal genes (beta-myosin heavy chain and atrial natriuretic peptide), (3) proximal to activated myoFb expressing alpha-smooth muscle actin microfilaments and angiotensin-converting enzyme, (4) expressing reactive oxygen species and nitric oxide with increased tissue 8-isoprostane, coupled to ventricular diastolic and systolic dysfunction, and (5) associated with upregulated redox-sensitive proteolytic ligases MuRF1 and atrogin-1. In a separate study, we did not find evidence of myocyte replication (BrdU labeling) or expression of stem cell antigen (c-Kit) at weeks 1-4 ALDOST. Assisted recovery caused complete disappearance of myoFb from sites of fibrosis with redifferentiation of these myocytes, loss of oxidative stress, and ubiquitin proteasome system activation, with restoration of nitric oxide and improved ventricular function. Thus, small dedifferentiated myocytes bordering on microdomains of fibrosis can re-differentiate and represent a potential source of autologous cells for functional myocardial regeneration. PMID- 24785346 TI - Inotropes and inodilators for acute heart failure: sarcomere active drugs in focus. AB - Acute heart failure (AHF) emerges as a major and growing epidemiological concern with high morbidity and mortality rates. Current therapies in patients with acute heart failure rely on different strategies. Patients with hypotension, hypoperfusion, or shock require inotropic support, whereas diuretics and vasodilators are recommended in patients with systemic or pulmonary congestion. Traditionally inotropic agents, referred to as Ca mobilizers load the cardiomyocyte with Ca and thereby increase oxygen consumption and risk for arrhythmias. These limitations of traditional inotropes may be avoided by sarcomere targeted agents. Direct activation of the cardiac sarcomere may be achieved by either sensitizing the cardiac myofilaments to Ca or activating directly the cardiac myosin. In this review, we focus on sarcomere targeted inotropic agents, emphasizing their mechanisms of action and overview the most relevant clinical considerations. PMID- 24785348 TI - Endosome-to-Plasma Membrane Recycling of VEGFR2 Receptor Tyrosine Kinase Regulates Endothelial Function and Blood Vessel Formation. AB - Rab GTPases are implicated in endosome-to-plasma membrane recycling, but how such membrane traffic regulators control vascular endothelial growth factor receptor 2 (VEGFR2/KDR) dynamics and function are not well understood. Here, we evaluated two different recycling Rab GTPases, Rab4a and Rab11a, in regulating endothelial VEGFR2 trafficking and signalling with implications for endothelial cell migration, proliferation and angiogenesis. In primary endothelial cells, VEGFR2 displays co-localisation with Rab4a, but not Rab11a GTPase, on early endosomes. Expression of a guanosine diphosphate (GDP)-bound Rab4a S22N mutant caused increased VEGFR2 accumulation in endosomes. TfR and VEGFR2 exhibited differences in endosome-to-plasma membrane recycling in the presence of chloroquine. Depletion of Rab4a, but not Rab11a, levels stimulated VEGF-A-dependent intracellular signalling. However, depletion of either Rab4a or Rab11a levels inhibited VEGF-A-stimulated endothelial cell migration. Interestingly, depletion of Rab4a levels stimulated VEGF-A-regulated endothelial cell proliferation. Rab4a and Rab11a were also both required for endothelial tubulogenesis. Evaluation of a transgenic zebrafish model showed that both Rab4 and Rab11a are functionally required for blood vessel formation and animal viability. Rab-dependent endosome to-plasma membrane recycling of VEGFR2 is important for intracellular signalling, cell migration and proliferation during angiogenesis. PMID- 24785349 TI - Potential of goat probiotic to bind mutagens. AB - The mutagen binding ability of the goat probiotics (Lactobacillus reuteri DDL 19, Lactobacillus alimentarius DDL 48, Enterococcus faecium DDE 39, and Bifidobacterium bifidum DDBA) was evaluated. The oral administration of these probiotics reduced fecal mutagens and intestinal cancer markers in goats. Secondly, the effects of probiotics against the mutagenesis induced by sodium azide (SA), and Benzopyrene (B[alpha]P) by performing the modified Ames test using Salmonella typhimurium TA 100 was investigated. The capacity to bind benzopyrene and the stability of the bacterial-mutagen complex was analyzed by HPLC. The dismutagenic potential against both mutagens was proportional to probiotic concentration. Results showed that probiotic antimutagenic capacity against SA was ranging from 13 to 78%. The mixture of four goat probiotics (MGP) displayed higher antimutagenic activity against SA than any individual strains at the same cell concentration. This study shows that the highest diminution of mutagenicity in presence of B[alpha]P (74%) was observed in presence of MGP. The antimutagenic activity of nearly all the individual probiotic and the MGP were in concordance with the B[alpha]P binding determined by HPLC. According to our results, the B[alpha]P binding to probiotic was irreversible still after being washed with DMSO solution. The stability of the toxic compounds-bacterial cell binding is a key consideration when probiotic antimutagenic property is evaluated. MGP exhibits the ability to bind and detoxify potent mutagens, and this property can be useful in supplemented foods for goats since it can lead to the removal of potent mutagens and protect and enhance ruminal health and hence food safety of consumers. PMID- 24785347 TI - TRP Channels Involved in Spontaneous L-Glutamate Release Enhancement in the Adult Rat Spinal Substantia Gelatinosa. AB - The spinal substantia gelatinosa (SG) plays a pivotal role in modulating nociceptive transmission through dorsal root ganglion (DRG) neurons from the periphery. TRP channels such as TRPV1 and TRPA1 channels expressed in the SG are involved in the regulation of the nociceptive transmission. On the other hand, the TRP channels located in the peripheral terminals of the DRG neurons are activated by nociceptive stimuli given to the periphery and also by plant-derived chemicals, which generates a membrane depolarization. The chemicals also activate the TRP channels in the SG. In this review, we introduce how synaptic transmissions in the SG neurons are affected by various plant-derived chemicals and suggest that the peripheral and central TRP channels may differ in property from each other. PMID- 24785350 TI - Anti-stress proteins produced by Bacteroides thetaiotaomicron after nutrient starvation. AB - Bacteroides thetaiotaomicron maybe one of the most adaptable intestinal bacteria due to its complex genome. Known to be an opportunistic pathogenic anaerobe, B. thetaiotaomicron has recently been described as a symbiont with anti-inflammatory properties. In this study, peptide mass finger printing technique was used to identify the stress proteins (maybe anti-stress proteins for the host) extracted from B. thetaiotaomicron grown under nutrient starvation (without heme, blood or bile) prior to be placed in an aerobic solution containing a mild non-ionic detergent derived from cholic acid. We focus here on proteins related to stress, knowing that superoxide dismutase was previously identified in the extract. In parallel, the morphology of the bacterial cells was observed using electronic microscopy before and after the extraction process. The effective antioxidant effect of the extract was evaluated in vitro against hydrogen peroxide. This work highlights the B. thetaiotaomicron ability to produce a large amount of stress proteins and to remain viable during the extraction. Budding vesicles were observed on its cell wall. The extraction process did not exceed 20 h in order to preserve the bacterial viability that decreased significantly after 24 h in preliminary studies. In our experimental conditions, an inhibitory effect of the extract was found against hydrogen peroxide. Animal models of inflammation will later check in vivo if this extract of anti-stress proteins is able to counter the respiratory burst beginning an inflammation process. PMID- 24785351 TI - Towards molecular biomarkers for biogas production from lignocellulose-rich substrates. AB - Biogas production from lignocellulose-rich agricultural residues is gaining increasingly importance in sustainable energy production. Hydrolysis/acidogenesis (H/A) of lignocellulose as the initial rate-limiting step deserves particular optimization. A mixture of straw/hay was methanized applying two-phase digester systems with an initial H/A reactor and a one-stage system at different, meso- and thermophilic temperatures. H/A was intensified with increasing pH values and increasing temperature. H/A fermenters, however, were prone to switch to methanogenic systems at these conditions. Substrate turnover was accelerated in the bi-phasic process but did not reach the methanation efficiency of the single stage digestion. There was no indication that two different cellulolytic inocula could establish in the given process. Bacterial communities were analyzed applying conventional amplicon clone sequencing targeting the hypervariable 16S rRNA gene region V6-V8 and by metagenome analyses applying direct DNA pyrosequencing without a PCR step. Corresponding results suggested that PCR did not introduce a bias but offered better phylogenetic resolution. Certain Clostridium IV and Prevotella members were most abundant in the H/A system operated at 38 degrees C, certain Clostridium III and Lachnospiraceae bacteria in the 45 degrees C, and certain Clostridium IV and Thermohydrogenium/Thermoanaerobacterium members in the 55 degrees C H/A system. Clostridium III representatives, Lachnospiraceae and Thermotogae dominated in the thermophilic single-stage system, in which also a higher portion of known syntrophic acetate oxidizers was found. Specific (RT-)qPCR systems were designed and applied for the most significant and abundant populations to assess their activity in the different digestion systems. The RT-qPCR results agreed with the DNA based community profiles obtained at the different temperatures. Up to 10(12) 16S rRNA copies mL(-1) were determined in H/A fermenters with prevalence of rRNA of a Ruminococcaceae subgroup. Besides, Thermohydrogenium/Thermoanaerobacterium rRNA prevailed at thermophilic and Prevotellaceae rRNA at mesophilic conditions. The developed (RT)-qPCR systems can be used as biomarkers to optimize biogas production from straw/hay and possibly other lignocellulosic substrates. PMID- 24785352 TI - No oxygen-still vigorous: 8th International Symposium on Anaerobic Microbiology (ISAM 8) Innsbruck, Austria. PMID- 24785353 TI - Synthesis of gem-difluoromethylene building blocks through regioselective allylation of gem-difluorocyclopropanes. AB - gem-Difluorocyclopropane derivatives react with allyltributylstannane in the presence of 2,2'-azobis(isobutyronitrile) to afford 1,6-dienes with a gem difluoromethylene moiety at the allylic position. The reaction proceeds regioselectively with high yields, and the 1,6-dinenes obtained are good precursors for cyclic systems containing a gem-difluoromethylene moiety. Although S-methyl carbonodithioate also works as a leaving group, rearrangement of the leaving group competes with the desired allylation, depending on the amount of allyltributylstannane. PMID- 24785354 TI - Energetic and structural study of bisphenols. AB - We have studied thermochemical, thermophysical and structural properties of bisphenols A, E, F, and AP. In particular, the standard enthalpies of sublimation and the standard enthalpies of formation in the gas phase at 298.15 K for all these species were experimentally determined. A computational study, through M05 2X density functional theory, of the various species shed light on structural effects and further confirmed, by means of the isodesmic reaction scheme, the excellent consistency of the experimental results. Our results reflect also the fact that energetic substituent effects are transferable from diphenylalkanes to bisphenols. PMID- 24785355 TI - Stochastic galactokinase expression underlies GAL gene induction in a GAL3 mutant of Saccharomyces cerevisiae. AB - GAL1 and GAL3 are paralogous signal transducers that functionally inactivate Gal80p to activate the Gal4p-dependent transcriptional activation of GAL genes in Saccharomyces cerevisiae in response to galactose. Unlike a wild-type strain, the gal3? strain shows delayed growth kinetics as a result of the signaling function of GAL1. The mechanism ensuring that GAL1 is eventually expressed to turn on the GAL switch in the gal3? strain remains a paradox. Using galactose and histidine growth complementation assays, we demonstrate that 0.3% of the gal3? cell population responds to galactose. This is corroborated by flow cytometry and microscopic analysis. The galactose responders and nonresponders isolated from the galactose-adapted population attain the original bimodal state and this phenotype is found to be as hard wired as a genetic trait. Computational analysis suggests that the log-normal distribution in GAL4 synthesis can lead to bimodal expression of GAL80, resulting in the bimodal expression of GAL genes. Heterozygosity at the GAL80 but not at the GAL1, GAL2 or GAL4 locus alters the extent of bimodality of the gal3? cell population. We suggest that the asymmetric expression pattern between GAL1 and GAL3 results in the ability of S. cerevisiae to activate the GAL pathway by conferring nongenetic heterogeneity. PMID- 24785356 TI - Myocardial infarction and gastro-intestinal bleeding risks associated with aspirin use among elderly individuals with type 2 diabetes. AB - INTRODUCTION: The benefit of aspirin in primary prevention of myocardial infarction and the associated gastro-intestinal bleeding risks have not been well established in the elderly population with diabetes. METHODS: Using Quebec administrative databases, we conducted two nested case-control analyses within a cohort of individuals aged >= 66 years newly treated with an oral antidiabetes drug between 1998 and 2003. The 28,067 individuals had no cardiovascular disease recorded in the database in the year prior cohort entry. They had not used prescribed aspirin, antiplatelet, or anticoagulant drugs, and were not hospitalized for gastro-intestinal bleeding in the year prior cohort entry. The odds of myocardial infarction and gastro-intestinal bleedings were compared between individuals who were current, past, or non-users of aspirin. RESULTS: There were 1101 (3.9%) cases of myocardial infarction. Compared to non-users, neither aspirin users (OR 0.89; 95% CI 0.71-1.13) nor aspirin past users (0.81; 0.62-1.06) showed a statistically significant lower risk of myocardial infarction. There were 373 (1.3%) cases of gastro-intestinal bleeding. Current users of aspirin had about a 2-fold greater risk of gastro-intestinal bleeding compared to non-users (2.19; 1.53-3.13). CONCLUSIONS: Our results suggest that individual assessment of bleeding risk and cardiovascular risk is mandatory among elderly people with diabetes before introducing aspirin therapy. PMID- 24785357 TI - Research opportunities for antimicrobial resistance control in China's factory farming. PMID- 24785358 TI - Growth of defect-free GaP nanowires. AB - The crystal structure of GaP nanowires grown by Au-assisted chemical beam epitaxy was investigated as a function of group V flux and growth temperature. By increasing the tertiarybutyl phosphine flux we obtained nanowires with a stacking defect-free wurtzite crystal structure. Variation of growth temperature also had a profound impact on the crystal structure. Lowering the growth temperature from 600 to 560 degrees C and keeping constant both triethylgallium and tertiarybutyl phosphine precursor fluxes, the crystal structure of GaP NWs was drastically improved from a highly defective intergrowth of zinc-blende and wurtzite to a wurtzite crystal structure free of stacking defects. These results are compared to current literature on GaP NW growth, and we suggest that the low V/III ratio is the key ingredient for the high crystal quality of our GaP nanowires. PMID- 24785359 TI - Animal models in chronic obstructive pulmonary disease-an overview. AB - ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction resultant from an augmented inflammatory response of the respiratory tract to noxious particles and gases. Previous reports present a number of different hypotheses about the etiology and pathophysiology of COPD. The generating mechanisms of the disease are subject of much speculation, and a series of questions and controversies among experts still remain. In this context, several experimental models have been proposed in order to broaden the knowledge on the pathophysiological characteristics of the disease, as well as the search for new therapeutic approaches for acute or chronically injured lung tissue. This review aims to present the main experimental models of COPD, more specifically emphysema, as well as to describe the main characteristics, advantages, disadvantages, possibilities of application, and potential contribution of each of these models for the knowledge on the pathophysiological aspects and to test new treatment options for obstructive lung diseases. PMID- 24785360 TI - Langmuir-Blodgett films of self-assembled (alkylether-derivatized Zn phthalocyanine)-(C60 imidazole adduct) dyad with controlled intermolecular distance for photoelectrochemical studies. AB - A multilayer Langmuir-Blodgett (LB) film of the self-assembled electron donor acceptor dyad of Zn phthalocyanine, appended with four long-chain aliphatic ether peripheral substituents, and an imidazole adduct of C60 was prepared and applied as a photoactive material in a photoelectrochemical cell. Changes in the simultaneously recorded surface pressure and surface potential vs area per molecule compression isotherms for Langmuir films of the dyad and, separately, of its components helped to identify phase transitions and mutual interactions of molecules in films. The Brewster angle microscopy (BAM) imaging of the Langmuir films showed circular condensed phase domains of the dyad molecules. The determined area per molecule was lower than that estimated for the dyad and its components, separately. The multilayer LB films of the dyad were transferred onto hydrophobized fluorine-doped tin oxide-coated (FTO) glass slides under different conditions. The presence of both components in the dyad LB films was confirmed with the UV-vis spectroscopy measurements. For the LB films transferred at different surface pressures, the PM-IRRAS measurements revealed that the phthalocyanine macrocycle planes and ether moieties in films were tilted with respect to the FTO surface. The AFM imaging of the LB films indicated formation of relatively uniform dyad LB films. Then, the femtosecond transient absorption spectral studies evidenced photoinduced electron transfer in the LB film. The obtained transient signals corresponding to both Zn(TPPE)(*+) and C60im(*-) confirmed the occurrence of intramolecular electron transfer. The determined rate constants of charge separation, kcs = 2.6 * 10(11) s(-1), and charge recombination, kcr = 9.7 * 10(9) s(-1), indicated quite efficient electron transfer within the film. In the photoelectrochemical studies, either photoanodic or photocathodic current was generated depending on the applied bias potential when the dyad LB film-coated FTO was used as the working electrode and ascorbic acid or methylviologen, respectively, as the charge mediator in an aqueous solution. PMID- 24785361 TI - Topically applied glycyrrhizic acid causes hair removal in rats. AB - CONTEXT: Anecdotic reports from Turkmenistan suggest an epilatory effect of sweet licorice extract after topical application. OBJECTIVE: This study examines hair removal after topical application of glycyrrhizic acid, the main compound of sweet licorice. MATERIALS AND METHODS: An aqueous solution containing 15% of the ammonium salt of glycyrrhizic acid, 10% urea, and 20% ethanol was topically applied two times per day on the neck areas of Wistar rats using a toothbrush. RESULTS: After 3 d, 20-30% of the treated areas were free of hair. After treatment for 6-12 d, 90-95% of the hair was gone. Clinical as well as immunohistological examinations showed no signs of inflammation even after long term treatment for more than 9 months. Interestingly, long-term treatment reduced the regrowth of hair of about 20%. Examination by scanning electron microscopy showed a smoothed hair cuticle that might facilitate detachment of the hair shaft from the follicular wall. DISCUSSION AND CONCLUSION: Our findings suggest glycyrrhizic acid as an interesting molecule for treating hypertrichosis in humans. PMID- 24785362 TI - The usability of the IR, RAC and MRI indices of heavy metal distribution to assess the environmental quality of sewage sludge composts. AB - To assess the environmental quality of compost, it is insufficient to use only total metal concentration. Therefore in this study, the stability of metals in compost and the environmental risk they pose were assessed by three indices that have been proposed for soils or sediments: the IR, the RAC and the MRI. In mature composts, the highest bonding intensity was for Ni (0.79=2 cm in diameter) by assembling FPSCs onto electrospun PLLA fiber membranes. Over 6 weeks in culture, it was possible to generate robust, flexible cartilage-like grafts of scale, opening up the possibility that tissues engineered using FPSCs derived from OA patients could potentially be used to resurface large areas of joint surfaces damaged by trauma or disease. PMID- 24785366 TI - Computed tomography virtual bronchoscopy: normal variants, pitfalls, and spectrum of common and rare pathology. AB - A broad spectrum of pathologies that involve the laryngotracheobronchial airway and imaging plays a crucial role in evaluating these abnormalities. Computed tomography with virtual bronchoscopy has been found to be very helpful in defining the location, extent, and nature of these lesions, and is increasingly being used even in patients with contraindications for fiberoptic bronchoscopy and laryngoscopy. Ionizing radiation, associated with virtual bronchoscopy, can be minimized by using low-dose multidetector computed tomography and hybrid iterative reconstruction techniques. Furthermore, retrospectively generated virtual bronchoscopy from a routinely acquired computed tomography data set eliminates additional cost and radiation. In the future, virtual bronchoscopy assisted with advanced navigational techniques will broaden the diagnostic and therapeutic landscape. This article presents the characteristic features of common and rare laryngotracheobronchial pathologies seen with virtual bronchoscopy. PMID- 24785367 TI - The impact of neuromuscular electrical stimulation on recovery after intensive, muscle damaging, maximal speed training in professional team sports players. AB - OBJECTIVES: During congested fixture periods in team sports, limited recovery time and increased travel hinder the implementation of many recovery strategies; thus alternative methods are required. We examined the impact of a neuromuscular electrical stimulation device on 24-h recovery from an intensive training session in professional players. DESIGN: Twenty-eight professional rugby and football academy players completed this randomised and counter-balanced study, on 2 occasions, separated by 7 days. METHODS: After baseline perceived soreness, blood (lactate and creatine kinase) and saliva (testosterone and cortisol) samples were collected, players completed a standardised warm-up and baseline countermovement jumps (jump height). Players then completed 60 m * 50 m maximal sprints, with 5 min recovery between efforts. After completing the sprint session, players wore a neuromuscular electrical stimulation device or remained in normal attire (CON) for 8 h. All measures were repeated immediately, 2 and 24-h post-sprint. RESULTS: Player jump height was reduced from baseline at all time points under both conditions; however, at 24-h neuromuscular electrical stimulation was significantly more recovered (mean+/-SD; neuromuscular electrical stimulation 3.2+/-3.2 vs. CON -7.2+/-3.7%; P<0.001). Creatine kinase concentrations increased at all time points under both conditions, but at 24-h was lower under neuromuscular electrical stimulation (P<0.001). At 24-h, perceived soreness was significantly lower under neuromuscular electrical stimulation, when compared to CON (P=0.02). There was no effect of condition on blood lactate, or saliva testosterone and cortisol responses (P>0.05). CONCLUSIONS: Neuromuscular electrical stimulation improves recovery from intensive training in professional team sports players. This strategy offers an easily applied recovery strategy which may have particular application during sleep and travel. PMID- 24785368 TI - Deoxycholic acid-grafted PEGylated chitosan micelles for the delivery of mitomycin C. AB - Mitomycin C (MTC) was incorporated to a micelle system preparing from a polymer named deoxycholic acid chitosan-grafted poly(ethylene glycol) methyl ether (mPEG CS-DA). mPEG-CS-DA was synthesized and characterized by (1)H nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. mPEG-CS-DA formed a core-shell micellar structure with a critical micelle concentration of 6.57 ug/mL. The mPEG-CS-DA micelles were spherical with a hydrodynamic diameter of about 231 nm. After poly(ethylene glycol)ylation of deoxycholic acid chitosan (CS-DA), the encapsulation efficiency and drug loading efficiency increased from 50.62% to 56.42% and from 20.51% to 24.13%, respectively. The mPEG-CS-DA micelles possessed a higher drug release rate than the CS-DA micelles. For pharmacokinetics, the area under the curve (AUC) of the mPEG-CS-DA micelles was 1.5 times higher than that of MTC injection, and these micelles can enhance the bioavailability of MTC. mPEG-CS-DA micelles reduced the distribution of MTC in almost all normal tissues and had the potential to improve the kidney toxicity caused by MTC injection. PMID- 24785369 TI - Characterization of growing bacterial populations in McMurdo Dry Valley soils through stable isotope probing with (18) O-water. AB - Soil microbial communities of the McMurdo Dry Valleys, Antarctica (MDV) contain representatives from at least fourteen bacterial phyla. However, given low rates of microbial activity, it is unclear whether this richness represents functioning rather than dormant members of the community. We used stable isotope probing (SIP) with (18) O-water to determine if microbial populations grow in MDV soils. Changes in the microbial community were characterized in soils amended with H2 (18) O and H2 (18) O-organic matter. Sequencing the 16S rRNA genes of the heavy and light fractions of the bacterial community DNA shows that DNA of microbial populations was labeled with (18) O-water, indicating these micro-organisms grew in the MDV soils. Significant differences existed in the community composition of the heavy and light fractions of the H2 (18) O and H2 (18) O-organic matter amended samples (Anosim P < 0.05 of weighted Unifrac distance). Control samples and the light DNA fraction of the H2 (18) O amended samples were dominated by representatives of the phyla Deinococcus-Thermus, Proteobacteria, Planctomyces, Gemmatimonadetes, Actinobacteria and Acidobacteria, whereas Proteobacteria were more prevalent in the heavy DNA fractions from the H2 (18) O-water and the H2 (18) O-water-organic matter treatments. Our results indicate that SIP with H2 (18) O can be used to distinguish active bacterial populations even in this low organic matter environment. PMID- 24785370 TI - Interactions between (+)-catechin and quercetin during their oxidation by nitrite under the conditions simulating the stomach. AB - When foods that contain catechins and quercetin glycosides are ingested, quercetin glycosides are hydrolyzed to quercetin during mastication by hydrolytic enzymes derived from oral bacteria and the generated quercetin aglycone is mixed with catechins in saliva. The present study deals with the interactions between (+)-catechin and quercetin during their reactions with nitrous acid under the conditions simulating the gastric lumen. Nitrous acid reacted with (+)-catechin producing 6,8-dinitrosocatechin, and quercetin partially suppressed the dinitrosocatechin formation. Nitric oxide, which was produced by not only (+) catechin/nitrous acid but also quercetin/nitrous acid systems, was used to produce 6,8-dinitrosocatechin. Furthermore, 6,8-dinitrosocatechin was oxidized by nitrous acid to the quinone form. The quinone formation was significantly suppressed by quercetin. Quercetin-dependent suppression of the above reactions accompanied the oxidation of quercetin, which was observed with the formation of 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone. Taking the above results into account, we proposed a possible mechanism of 6,8-dinitrosocatechin formation and discuss the importance of quercetin to prevent the quinone formation from 6,8-dinitrosocatechin in the gastric lumen, taking the interactions between quercetin and catechins into account. PMID- 24785371 TI - A data standard for sourcing fit-for-purpose biological samples in an integrated virtual network of biobanks. AB - Human tissue biobanks are at the epicenter of clinical research, responsible for providing both clinical samples and annotated data. There is a need for large numbers of samples to provide statistical power to research studies, especially since treatment and diagnosis are becoming ever more personalized. A single biobank cannot provide sufficient numbers of samples to capture the full spectrum of any disease. Currently there is no infrastructure in the United Kingdom (UK) to integrate biobanks. Therefore the National Cancer Research Institute (NCRI) Confederation of Cancer Biobanks (CCB) Working Group 3 looked to establish a data standard to enable biobanks to communicate about the samples they hold and so facilitate the formation of an integrated national network of biobanks. The Working Group examined the existing data standards available to biobanks, such as the MIABIS standard, and compared these to the aims of the working group. The CCB developed data standard has brought many improvements: (1) Where existing data standards have been developed, these have been incorporated, ensuring compatibility with other initiatives; (2) the standard was written with the expectation that it will be extended for specific disease areas, such as the Breast Cancer Campaign Tissue Bank (BCCTB) and the Strategic Tissue Repository Alliances Through Unified Methods (STRATUM) project; and (3) biobanks will be able to communicate about specific samples, as well as aggregated statistics. The development of this data standard will allow all biobanks to integrate and share information about the samples they hold, facilitating the possibility of a national portal for researchers to find suitable samples for research. In addition, the data standard will allow other clinical services, such as disease registries, to communicate with biobanks in a standardized format allowing for greater cross-discipline data sharing. PMID- 24785372 TI - Impact of low oxygen tension on stemness, proliferation and differentiation potential of human adipose-derived stem cells. AB - Adipose-derived stem cells (ASCs) have been found adapted to a specific niche with low oxygen tension (hypoxia) in the body. As an important component of this niche, oxygen tension has been known to play a critical role in the maintenance of stem cell characteristics. However, the effect of O2 tension on their functional properties has not been well determined. In this study, we investigated the effects of O2 tension on ASCs stemness, differentiation and proliferation ability. Human ASCs were cultured under normoxia (21% O2) and hypoxia (2% O2). We found that hypoxia increased ASC stemness marker expression and proliferation rate without altering their morphology and surface markers. Low oxygen tension further enhances the chondrogenic differentiation ability, but reduces both adipogenic and osteogenic differentiation potential. These results might be correlated with the increased expression of HIF-1alpha under hypoxia. Taken together, we suggest that growing ASCs under 2% O2 tension may be important in expanding ASCs effectively while maintaining their functional properties for clinical therapy, particularly for the treatment of cartilage defects. PMID- 24785373 TI - MiR-224 expression increases radiation sensitivity of glioblastoma cells. AB - Glioblastoma (GBM) is the most common and highly aggressive primary malignant brain tumor. The intrinsic resistance of this brain tumor limits the efficacy of administered treatment like radiation therapy. In the present study, effect of miR-224 expression on growth characteristics of established GBM cell lines was analyzed. MiR-224 expression in the cell lines as well as in primary GBM tumor tissues was found to be low. Exogenous transient expression of miR-224 using either synthetic mimics or stable inducible expression using doxycycline inducible lentiviral vector carrying miR-224 gene, was found to bring about 30 55% reduction in clonogenic potential of U87 MG cells. MiR-224 expression reduced clonogenic potential of U87 MG cells by 85-90% on irradiation at a dose of 6Gy, a dose that brought about 50% reduction in clonogenic potential in the absence of miR-224 expression. MiR-224 expression in glioblastoma cells resulted in 55-65% reduction in the expression levels of API5 gene, a known target of miR-224. Further, siRNA mediated down-regulation of API5 was also found to have radiation sensitizing effect on glioblastoma cell lines. Analysis of the Cancer Genome Atlas data showed lower miR-224 expression levels in male GBM patients to correlate with poorer survival. Higher expression levels of miR-224 target API5 also showed significant correlation with poorer survival of GBM patients. Up regulation of miR-224 or down-regulation of its target API5 in combination with radiation therapy, therefore appear as promising options for the treatment of glioblastoma, which is refractory to the existing treatment strategies. PMID- 24785374 TI - Downregulation of SCAI enhances glioma cell invasion and stem cell like phenotype by activating Wnt/beta-catenin signaling. AB - SCAI (suppressor of cancer cell invasion), has been recently characterized as a novel tumor suppressor that inhibits the invasive migration of several human tumor cells. However, the expression pattern, biological role and molecular mechanism of SCAI in human glioma remain unknown. In this study, we found that levels of SCAI protein and mRNA expression were significantly down-regulated in glioma tissues and cell lines. Overexpression of SCAI inhibited, but silencing of SCAI robustly promoted the invasive and cancer stem cell-like phenotypes of glioma cells. Furthermore, we demonstrated that SCAI downregualtion activated the Wnt/beta-catenin signaling, and blockade of the Wnt/beta-catenin pathway abrogated the effects of SCAI downregulation on glioma cell aggressiveness. Taken together, our results provide the first demonstration of SCAI downregulation in glioma, and its downregulation contributes to increased glioma cell invasion and self-renewal by activating the Wnt/beta-catenin pathway. PMID- 24785375 TI - Is the multicolored Asian ladybeetle, Harmonia axyridis, the most abundant natural enemy to aphids in agroecosystems? AB - The multicolored Asian ladybeetle, Harmonia axyridis Pallas (Coleoptera: Coccinellidae), was introduced into Western Europe in the late 1990s. Since the late 2000s, this species has been commonly considered one of the most abundant aphid predators in most Western European countries. In spite of the large amount of research on H. axyridis, information concerning its relative abundance in agroecosystems is lacking. This study aims to evaluate the abundance of H. axyridis within the aphidophage community in four crops situated in southern Belgium: wheat, Triticum aestivum L. (Poales: Poaceae), corn, Zea mays, potato, Solanum tuberosum (Solanales: Solanaceae), and broad bean Vicia faba (Fabales: Fabaceae). In order to assess the species diversity, the collected data were analyzed by considering (1) the species richness and (2) the evenness according to the Shannon diversity index. Eleven aphidophages were observed in every inventoried agroecosystem, including five abundant species: three coccinellids, the seven-spotted ladybug, Coccinella septempunctata L. (Coleoptera: Coccinellidae), the 14-spotted Ladybird, Propylea quatuordecimpunctata, and H. axyridis; one hoverfly, the marmalade hoverfly, Episyrphus balteatus De Geer (Diptera: Syrphidae); and one lacewing, the common green lacewing, Chrysoperla carnea Stephens sensu lato (= s.l.) (Neuroptera: Chrysopidae). Harmonia axyridis has been observed to thrive, breed, and reproduce on the four studied crops. Harmonia axyridis is the most abundant predator of aphids in corn followed by C. septempunctata, which is the main aphid predator observed in the three other inventoried crops. In wheat and potato fields, H. axyridis occurs in low numbers compared to other aphidophage. These observations suggest that H. axyridis could be considered an invasive species of agrosystems, and that potato and wheat may intermittently act as refuges for other aphidophages vulnerable to intraguild predation by this invader. Harmonia axyridis is not the most abundant aphid predator in the main Belgian crops. PMID- 24785376 TI - Foster children's attachment security and behavior problems in the first six months of placement: associations with foster parents' stress and sensitivity. AB - Both traumatic experiences in their birth families and multiple placement histories lead to increased mental health problems in foster children. The formation of secure attachments to new caregivers could be a protective factor for foster children. The current study focused on the associations between foster parents' sensitivity, parenting stress and foster children's attachment behavior as well as behavior problems. The sample consists of 48 children (aged from 1 to 6 years) and their foster caregivers. Attachment behavior and sensitivity were observed during home visits. Furthermore, caregiver reports were used to assess parenting stress and children's behavior problems. Compared to normative data, foster children showed lower levels of attachment security and more behavior problems. Foster children's attachment security and behavior problems were predicted significantly or marginally by foster parents' stress and supportive presence. PMID- 24785377 TI - High thermoelectric performance of p-type SnTe via a synergistic band engineering and nanostructuring approach. AB - SnTe is a potentially attractive thermoelectric because it is the lead-free rock salt analogue of PbTe. However, SnTe is a poor thermoelectric material because of its high hole concentration arising from inherent Sn vacancies in the lattice and its very high electrical and thermal conductivity. In this study, we demonstrate that SnTe-based materials can be controlled to become excellent thermoelectrics for power generation via the successful application of several key concepts that obviate the well-known disadvantages of SnTe. First, we show that Sn self compensation can effectively reduce the Sn vacancies and decrease the hole carrier density. For example, a 3 mol % self-compensation of Sn results in a 50% improvement in the figure of merit ZT. In addition, we reveal that Cd, nominally isoelectronic with Sn, favorably impacts the electronic band structure by (a) diminishing the energy separation between the light-hole and heavy-hole valence bands in the material, leading to an enhanced Seebeck coefficient, and (b) enlarging the energy band gap. Thus, alloying with Cd atoms enables a form of valence band engineering that improves the high-temperature thermoelectric performance, where p-type samples of SnCd(0.03)Te exhibit ZT values of ~0.96 at 823 K, a 60% improvement over the Cd-free sample. Finally, we introduce endotaxial CdS or ZnS nanoscale precipitates that reduce the lattice thermal conductivity of SnCd(0.03)Te with no effect on the power factor. We report that SnCd(0.03)Te that are endotaxially nanostructured with CdS and ZnS have a maximum ZTs of ~1.3 and ~1.1 at 873 K, respectively. Therefore, SnTe-based materials could be ideal alternatives for p-type lead chalcogenides for high temperature thermoelectric power generation. PMID- 24785378 TI - Tracing the long-term legacy of childhood lead exposure: a review of three decades of the port Pirie cohort study. AB - Several prospective cohort studies have demonstrated that childhood lead levels show small but statistically significant adjusted associations with subsequent development in later childhood and adolescence. The Port Pirie Cohort study is one of the few prospective cohort studies to follow participants into adulthood. This paper reviews all childhood and adulthood findings of the Port Pirie Cohort study to date. Cohort members (initially, 723 infants born in/around the lead smelting town of Port Pirie) showed a wide range of childhood blood lead levels, which peaked around 2 years old (M=21.3MUg/dL, SD=1.2). At all childhood assessments, postnatal lead levels - particularly those reflecting cumulative exposure - showed small significant associations with outcomes including cognitive development, IQ, and mental health problems. While associations were substantially attenuated after adjusting for several childhood covariates, many remained statistically significant. Furthermore, average childhood blood lead showed small significant associations with some adult mental health problems for females, including anxiety problems and phobia, though associations only approached significance following covariate adjustment. Overall, there did not appear to be any age of greatest vulnerability or threshold of effect, and at all ages, females appeared more susceptible to lead-associated deficits. Together, these findings suggest that the associations between early childhood lead exposure and subsequent developmental outcomes may persist. However, as the magnitude of these effects was small, they are not discernible at the individual level, posing more of a population health concern. It appears that the combination of multiple early childhood factors best predicts later development. As such, minimising lead exposure in combination with improving other important early childhood factors such as parent-child interactions may be the best way to improve developmental outcomes. PMID- 24785380 TI - Living with the nightmare of neuropathic pain. PMID- 24785379 TI - Development of status epilepticus, sustained calcium elevations and neuronal injury in a rat survival model of lethal paraoxon intoxication. AB - Paraoxon (POX) is an active metabolite of organophosphate (OP) pesticide parathion that has been weaponized and used against civilian populations. Exposure to POX produces high mortality. OP poisoning is often associated with chronic neurological disorders. In this study, we optimize a rat survival model of lethal POX exposures in order to mimic both acute and long-term effects of POX intoxication. Male Sprague-Dawley rats injected with POX (4mg/kg, ice-cold PBS, s.c.) produced a rapid cholinergic crisis that evolved into status epilepticus (SE) and death within 6-8min. The EEG profile for POX induced SE was characterized and showed clinical and electrographic seizures with 7-10Hz spike activity. Treatment of 100% lethal POX intoxication with an optimized three drug regimen (atropine, 2mg/kg, i.p., 2-PAM, 25mg/kg, i.m. and diazepam, 5mg/kg, i.p.) promptly stopped SE and reduced acute mortality to 12% and chronic mortality to 18%. This model is ideally suited to test effective countermeasures against lethal POX exposure. Animals that survived the POX SE manifested prolonged elevations in hippocampal [Ca(2+)]i (Ca(2+) plateau) and significant multifocal neuronal injury. POX SE induced Ca(2+) plateau had its origin in Ca(2+) release from intracellular Ca(2+) stores since inhibition of ryanodine/IP3 receptor lowered elevated Ca(2+) levels post SE. POX SE induced neuronal injury and alterations in Ca(2+) dynamics may underlie some of the long term morbidity associated with OP toxicity. PMID- 24785381 TI - Effects of N-acetyl-l-cysteine, in vivo, against pathological changes induced by malathion. AB - Malathion toxicity has been related to the inhibition of acetylcholinesterase, induction of oxidative stress, liver damage and impairment of kidney function as well as hematotoxicity. N-acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the protective effect of NAC against toxic consequences of malathion exposure in Wistar rats. Malathion was given daily to rats via oral gavage and NAC in drinking water during seven days. When malathion-treated rats were compared with control, a leukocytosis and reduced hemoglobin (HGB) content were detected. Furthermore, malathion produced a significant increase in liver enzymes such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and creatinine kinase. In addition, a decrease in acid phosphatase activity, protein and globulin levels were observed in malathion-treated rats compared with control. Moreover, analyses of the mineral status showed a disturbance in calcium, magnesium, phosphore and iron contents of the malathion-treated rats. Interestingly, NAC showed therapeutic effects against malathion toxicity. Indeed, HGB content and all liver enzymes were restored to normal values. Finally, the use of NAC as therapeutic agent for only seven days during malathion exposure showed interesting results on tissues damages. PMID- 24785382 TI - Vibrational sum frequency spectroscopy studies of the influence of solutes and phospholipids at vapor/water interfaces relevant to biological and environmental systems. PMID- 24785383 TI - Unfolding kinetics of periodic DNA hairpins. AB - DNA hairpin molecules with periodic base sequences can be expected to exhibit a regular coarse-grained free energy landscape (FEL) as a function of the number of open base pairs and applied mechanical force. Using a commonly employed model, we first analyze for which types of sequences a particularly simple landscape structure is predicted, where forward and backward energy barriers between partly unfolded states are decreasing linearly with force. Stochastic unfolding trajectories for such molecules with simple FEL are subsequently generated by kinetic Monte Carlo simulations. Introducing probabilities that can be sampled from these trajectories, it is shown how the parameters characterizing the FEL can be estimated. Already 300 trajectories, as typically generated in experiments, provide faithful results for the FEL parameters. PMID- 24785384 TI - Selective 4,6-O-benzylidene formation of methyl alpha-D-mannopyranoside using 2,6 dimethylbenzaldehyde. AB - While methyl alpha-d-glucopyranosides and alpha-d-galactopyranosides selectively form 4,6-O-benzylidenes when reacted with excess benzaldehyde in the presence of acid catalyst methyl alpha-d-mannopyranosides does not exhibit the same selectivity because of the cis-arrangement of the C2 and C3 hydroxyl groups. The selectivity for the 4,6-O-benzylidene is restored by using 2,6 dimethylbenzaldehyde instead of benzaldehyde. In addition the excess 2,6 dimethylbenzaldehyde is easily recovered from the reaction by extraction with petroleum ether and can be reused without further purification. The 2,6 dimethylbenzylidene exhibits properties similar to the unsubstituted benzylidene with regard to chemical synthesis. PMID- 24785385 TI - Supramolecular self-assembled aggregates formed by pentacosa-10,12-diynyl amidomethyl-beta-cyclodextrin. AB - Mono[6-deoxy-6-(pentacosa-10,12-diynyl amidomethyl)]-beta-cyclodextrin was successfully synthesized by reacting mono-6-amino-6-deoxy-beta-cyclodextrin with N-hydroxysuccinimide ester of 10,12-pentacosadiynoic acid in DMF. The modified beta-cyclodextrin self-assembled and aggregated to form a worm-like supramolecular structure, and the novel supramolecular aggregates were studied using 2D nuclear magnetic resonance spectroscopy, X-ray powder diffraction, thermogravimetry, and electron microscopy. Interestingly, the synthesized pentacosa-10,12-diynyl amidomethyl-beta-cyclodextrin formed columnar type self aggregates and it was clearly differentiated from cage-like structure of native beta-cyclodextrin. PMID- 24785386 TI - Synthesis of Calocybe indica var. APK2 polysaccharide repeating unit. AB - The first total synthesis of p-methoxyphenyl alpha-l-fucopyranosyl-(1->6)-alpha-d galactopyranosyl-(1->4)-beta-d-glucopyranosyl-(1->6)-beta-d-glucopyranosyl-(1->6) beta-d-glucopyranoside (2) was achieved starting from five monosaccharide building blocks. This structure represents the repeating unit of the polysaccharide isolated from edible mushroom Calocybe indica var. APK2, and was synthesized in high overall yield via a convergent '3+2' glycosylation strategy. PMID- 24785387 TI - Inhibitory effect and mode of action of chitosan solution against rice bacterial brown stripe pathogen Acidovorax avenae subsp. avenae RS-1. AB - Inhibitory effect and mode of action of chitosan solution against rice bacterial brown stripe pathogen Acidovorax avenae subsp. avenae (Aaa) strain RS-1 was examined in this study. Result from this study indicated that chitosan solutions at 0.10, 0.20, and 0.40mg/mL inhibited the in vitro growth of Aaa strain RS-1, and in general the inhibitory efficiency increased with the increase of both chitosan concentration and the incubation time. Antibacterial activity of chitosan in this study may be mainly due to the damage of cell membrane, which was evidenced by both the cell lysis observed by transmission electron microscopy, and the increased release of cell materials based on the measurement of cell membrane integrity. Furthermore, chitosan solutions at concentrations of 0.1, 0.2, and 0.4mg/mL markedly inhibited bacterial biofilm formation compared to the control, and the inhibitory effect increased with the increase of chitosan concentration. In addition, quantitative real-time PCR of the 10 secretion system related genes revealed the differential expression of genes in particular ompA/motB, emphasizing the importance of this gene in the response of Aaa strain RS-1 to chitosan stress. These results indicated that the antibacterial mode of action of chitosan may be mainly due to membrane disruption and lysis, reduction of biofilm formation, and gene expression change. Overall, the results clearly indicated that chitosan had the potential to control bacterial brown stripe of rice. PMID- 24785388 TI - Fast separation and determination of free myo-inositol by hydrophilic liquid chromatography. AB - A fast liquid chromatography method for separation and determination of myo inositol is reported. Determination of the biologically important isomer of inositols, myo-inositol, was optimized to avoid overlapping to possible interferents according to European Pharmacopoeia (glycerol, d-mannitol) and saccharose. The method in HILIC mode is extremely selective to other carbohydrates which allows to separate myo-inositol from allo- and d-chiro inositol with resolution 12.3 and 5.2, resp. and this way it enables to separate myo-inostiol from contingent carbohydrates present in a sample matrix. Retention time of myo-inositol was 12min at 10 degrees C, though higher temperatures (25 degrees C or 40 degrees C) or higher water content in the mobile phase could speed up the separation and determination to four minutes. LOD of the method was 9mg/L at 10 degrees C, and 5mg/L at 25 degrees C, resp. PMID- 24785389 TI - Selective detection of epimeric pentose saccharides at physiological pH using a fluorescent receptor. AB - Epimerisation between ribofuranose and arabinofuranose sugars is crucial in several biosynthetic pathways, but is typically challenging to monitor. Here, we have screened for fluorescent boronic acids that can be used as molecular probes for the specific detection of ribofuranose over arabinofuranose sugars in solution. We show excellent specificity of the fluorescent response of 3 biphenylboronic acid to ribofuranose at physiological pH. This provides a tool for in situ monitoring of carbohydrate modifying enzymes and provides a viable alternative to traditional radiolabelled assays. PMID- 24785390 TI - Synthesis of alpha-d-glucosyl substituted methyl glycosides of 3-deoxy-alpha-d manno- and d-glycero-alpha-d-talo-oct-2-ulosonic acid (Kdo/Ko) corresponding to inner core fragments of Acinetobacter lipopolysaccharide. AB - The alpha-d-glucopyranosyl-(1->5)-substituted methyl glycosides of 3-deoxy-alpha d-manno-oct-2-ulosonic acid (Kdo), 3-deoxy-alpha-d-lyxo-hept-2-ulosonic acid (Kdh), and d-glycero-alpha-d-talo-oct-2-ulosonic acid (Ko) were prepared using orthogonally protected glycosyl acceptor derivatives via glycosylation with a torsionally disarmed 4,6-O-benzylidene protected trifluoroacetimidate glucosyl donor followed by global deprotection. The related 6-O-phosphoryl-alpha-d glucopyranosyl-(1->5)-substituted Kdo and Kdh derivatives were derived from a benzylidene-protected glucosyl intermediate using phosphoramidite and phosphoryl chloride-based phosphorylation steps, respectively. The deprotected disaccharides serve as ligands to study lectin binding of Acinetobacter lipopolysaccharide core oligosaccharides. PMID- 24785391 TI - Synthesis and X-ray studies of novel 3-C-nitromethyl-hexofuranoses. AB - A practical method for the synthesis of three novel 3-C-nitromethyl-hexofuranoses is reported. The Henry reaction on a 1,2:5,6-di-O-isopropylidene-alpha-d gulofuranose-derived ketone provided a 3-C-branched gulo-isomer as the sole reaction product. The dehydration-rehydration of the latter yielded an isopropylidene-protected 3-C-nitromethyl-galactofuranose. The reaction sequence can be also used for the synthesis of a 3-deoxy-3-C-nitromethyl-hexofuranose derivative with a gulo-configuration. Two of the newly obtained carbohydrate derivatives were characterized by X-ray crystallography. PMID- 24785392 TI - Structure of the capsular polysaccharide of Acinetobacter baumannii ACICU containing di-N-acetylpseudaminic acid. AB - Capsular polysaccharide was isolated by the phenol-water extraction of Acinetobacter baumannii ACICU cells and studied by sugar analysis, partial acid hydrolysis, and 1D and 2D (1)H and (13)C NMR spectroscopy. The polysaccharide was found to contain 5,7-diacetamido-3,5,7,9-tetradeoxy-l-glycero-l-manno-non-2 ulosonic or di-N-acetylpseudaminic acid (Pse5Ac7Ac), and the following structure of the branched tetrasaccharide repeating unit was established: The genes present in the polysaccharide gene cluster of A. baumannii ACICU are appropriate to the structure established. PMID- 24785393 TI - Correlates of reduced exercise behaviour in depression: the role of motivational and volitional deficits. AB - OBJECTIVE: The study aimed at uncovering the correlates of reduced exercise in depressive patients. On the basis of the Health Action Process Approach (Schwarzer, 2011 ), we hypothesised that reduced exercise in depressive patients can be explained by motivational deficits and volitional deficits. DESIGN: A longitudinal sample of 56 clinically depressive outpatients was compared to a sample of 56 parallelised non-depressive controls. MAIN OUTCOME MEASURES: Self reported intention, exercise, and motivational and volitional HAPA variables were measured with self-report questionnaires at baseline and four-week follow-up. RESULTS: Depressive patients showed a motivational deficit: they had significantly reduced intentions to exercise compared to non-depressive participants, and they suffered from reduced self-efficacy and increased negative outcome expectations. No differences were found with regard to positive outcome expectations. Depressive patients also showed a volitional deficit: depressive high-intenders were less capable of transforming their intention into action than non-depressive high-intenders. They produced less action plans, had less maintenance self-efficacy and were more easily distracted by barriers. CONCLUSION: The lower level of exercise among depressive patients is partly due to motivational, partly to volitional deficits. Interventions should be stage matched and should focus on pessimistic beliefs (negative outcome expectations, self-efficacy) and planning deficits in depression. PMID- 24785394 TI - Development of mesoporosity in scandia-stabilized zirconia: particle size, solvent, and calcination effects. AB - We present the mechanisms of formation of mesoporous scandia-stabilized zirconia using a surfactant-assisted process and the effects of solvent and thermal treatments on the resulting particle size of the powders. We determined that cleaning the powders with water resulted in better formation of a mesoporous structure because higher amounts of surfactant were preserved on the powders after washing. Nonetheless, this resulted in agglomerate sizes that were larger. The water-washed powders had particle sizes of >5 MUm in the as-synthesized state. Calcination at 450 and 600 degrees C reduced the particle size to ~1-2 and 0.5 MUm, respectively. Cleaning with ethanol resulted in a mesoporous morphology that was less well-defined compared to the water-washed powders, but the agglomerate size was smaller and had an average size of ~250 nm that did not vary with calcination temperature. Our analysis showed that surfactant-assisted formation of mesoporous structures can be a compromise between achieving a stable mesoporous architecture and material purity. We contend that removal of the surfactant in many mesoporous materials presented in the literature is not completely achieved, and the presence of these organics has to be considered during subsequent processing of the powders and/or for their use in industrial applications. The issue of material purity in mesoporous materials is one that has not been fully explored. In addition, knowledge of the particle (agglomerate) size is essential for powder handling during a variety of manufacturing techniques. Thus, the use of dynamic light scattering or any other technique that can elucidate particle size is essential if a full characterization of the powders is needed for achieving postprocessing effectiveness. PMID- 24785396 TI - Intraepidermal nerve fiber density of healthy human. AB - OBJECTIVES: To analyze intraepidermal nerve fiber density (IEFND) by skin biopsy, evaluate the effect of age, anatomical sites, and ethnic origin on IEFND and develop a reference range of IENFD at the distal leg of healthy human. METHODS: Seventy skin biopsy specimens from surgical procedures involving 70 patients were analyzed. Specimens were fixed routinely in formalin and thereafter embedded in paraffin. Nerve fibers of 10-MUm-thick sections were observed using immunoperoxidase staining with panaxonal antibody protein gene product 9.5 (PGP 9.5). The morphology of intraepidermal nerve fibers (IENFs) and the IENFD was determined using light microscope. The statistical analysis was performed with SPSS 16.0 software. RESULTS: No significant correlation was observed between IENFD and age (Pwrist = 0.830, Pdistal leg = 0.478). The significant correlation was observed between IENFD and anatomic site (P = 0.001), the IENFD of upper arm and proximal thigh were significantly higher than that of wrist and distal leg. The reference range for IENFD of distal leg in normal Chinese humans was 40.55 fibers/mm(2). The IEFND of Chinese healthy human was significantly lower than that of Finnish (62.87 +/- 15.25 vs 114.617 +/- 32.322 fibers/mm(2), P < 0.05). DISCUSSION: Skin biopsy may be a useful tool in sensory neuropathies. IENFD is independent of age, but varies in different parts of the body. The proximal sites have a higher IENFD, but no significant difference is found between the wrist and distal leg. PMID- 24785395 TI - The atherogenic effects of serum amyloid A are potentially mediated via inflammation and apoptosis. AB - AIM: The mechanism through which SAA contributes to the pathogenesis of atherosclerosis remains unclear. The objective of this study was therefore to determine whether SAA plays a role in the onset of atherosclerosis via inflammatory and apoptotic pathways. METHODS: An array of experiments, including cell cultures, MTT assays, quantitative real-time PCR and Western blotting, were carried out in order to assess the effects of human recombinant SAA on NF-kappaB activation and the role of NF-kappaB in the onset of SAA-induced inflammation and apoptosis. RESULTS: We found that SAA (80MUg/mL) induced 3.5- to 37.8-fold increases in the expression of targets known to play important roles in the initiation and progression of atherosclerosis (i.e., ICAM-1, MCP-1, MMP-9 and TF) via NF-kappaB regulation within one hour after exposure. RAW264.7 cells treated with increasing doses of SAA showed regulation of apoptotic targets and a dose dependent reduction in cell viability, with 69% cell viability observed following exposure to 80MUg/mL of SAA for 24 hours. CONCLUSIONS: Our results suggest that SAA contributes to the pathogenesis of atherosclerosis via both inflammatory and apoptotic mechanisms. PMID- 24785397 TI - A new protocol to treat moderate to severe intraventricular hemorrhage with obstructive hydrocephalus. AB - OBJECTIVES: For patients with intraventricular hemorrhage (IVH) accompanied by obstructive hydrocephalus, external ventricular drainage (EVD) alone is proven to be often insufficient, and lumbar drainage (LD) is proven promising but considered contraindicative in the acute phase. The objective was to analyze the safety and feasibility of treatment for IVH with early continuous LD (CLD) in addition to open EVD regardless of the presence of acute obstructive hydrocephalus. METHODS: In this prospective study, 10 consecutive patients with moderate to severe IVH received emergency EVD and early CLD insertion regardless of the presence of obstructive hydrocephalus or blood clots in the third and fourth ventricles. During the whole course of treatment, the EVD was kept open at a safe height until replaced by CLD alone. When the drained CSF from CLD was nearly normal, gradual weaning of the CLD was attempted. Ventriculoperitoneal (VP) shunt would be performed if there was evidence of communicating hydrocephalus. RESULTS: In all the cases, EVD could be safely replaced by CLD alone. There was no evidence of axial herniation or infection, and no requirement of EVD revision. After CLD weaning, only two patients underwent VP shunt procedure. Follow-up study on 3 months and 6 months demonstrated that 7 (70%) patients had good (Glasgow Outcome Scale (GOS) 4 to 5) outcome and 1 (10%) patient died 1 month after discharge due to renal failure. CONCLUSIONS: RESULTS suggest that this new therapy which combines EVD with early CLD insertion is safe and easy to manage moderate to severe IVH with obstructive hydrocephalus. PMID- 24785398 TI - 'It's on your conscience all the time': a systematic review of qualitative studies examining views on obesity among young people aged 12-18 years in the UK. AB - OBJECTIVE: To explore the perspectives of young people in the UK on obesity, body size, shape and weight. DESIGN: Systematic review of qualitative studies using thematic synthesis. DATA SOURCES: Sensitive searches of 18 electronic databases from 1997 to February 2010 supplemented by grey literature searches. STUDY SELECTION: Studies produced since 1997 using qualitative methods to collect perspectives of people aged 12-18 years in the UK, reporting methods for data collection or analysis. Studies of people with eating disorders and those rated low in reliability and usefulness were excluded. RESULTS: Searches identified 30 studies involving over 1400 young people from a range of contexts. Young people of all sizes placed considerable emphasis on personal responsibility, and on the social, rather than health implications of being overweight. Young people with experience of obesity described severe, unrelenting, size-related abuse and isolation. Regardless of their own size, young people were judgemental of individuals who were overweight, but those with experience of obesity described an environment that contained multiple barriers to weight loss. Only one study asked young people directly what might support them to have a healthy body size. Study findings were configured under three main themes, labelled with quotes from included studies: general perceptions of size and society's responses ('It's on your conscience all the time'); the experiences of young people who were overweight ('If I had the choice I wouldn't be this size') and these larger young people's experiences of trying to loose weight and suggestions for action ('Make sure, even when it's hard, you've got people there'). CONCLUSIONS: The perspectives of young people in the UK, when synthesised across the spectrum of body sizes, paint a picture of a stigmatising and abusive social world. Research and policy need to engage young people actively so as to address the social implications of obesity. PMID- 24785399 TI - A Community Jury on PSA screening: what do well-informed men want the government to do about prostate cancer screening--a qualitative analysis. AB - OBJECTIVE: Cancer screening policies and programmes should take account of public values and concerns. This study sought to determine the priorities, values and concerns of men who were 'fully informed' about the benefits and harms of prostate-specific antigen (PSA) screening; and empirically examine the value of a community jury in eliciting public values on PSA screening. SETTING: Community jury was convened on the Gold Coast, Queensland (Australia) to consider PSA screening benefits and harms, and whether government campaigns on PSA screening should be conducted. PARTICIPANTS: 27 men (volunteers) aged 50-70 with no personal history of prostate cancer and willing to attend jury 6-7 April 2013: 12 were randomly allocated to jury (11 attended). OUTCOME MEASURES: A qualitative analysis was conducted of the jury deliberations (audio-recorded and transcribed) to elicit the jury's views and recommendations. A survey determined the impact of the jury process on participants' individual testing decisions compared with control group. RESULTS: The jury concluded governments should not invest in programmes focused on PSA screening directed at the public because the PSA test did not offer sufficient reassurance or benefit and could raise unnecessary alarm. It recommended an alternative programme to support general practitioners to provide patients with better quality and more consistent information about PSA screening. After the jury, participants were less likely to be tested in the future compared with the controls, but around half said they would still consider doing so. CONCLUSIONS: The jury's unanimous verdict about government programmes was notable in the light of their divergent views on whether or not they would be screened themselves in the future. Community juries provide valuable insights into the priorities and concerns of men weighing up the benefits and harms of PSA screening. It will be important to assess the degree to which the findings are generalisable to other settings. PMID- 24785400 TI - Immediate fluid management of children with severe febrile illness and signs of impaired circulation in low-income settings: a contextualised systematic review. AB - OBJECTIVE: To evaluate the effects of intravenous fluid bolus compared to maintenance intravenous fluids alone as part of immediate emergency care in children with severe febrile illness and signs of impaired circulation in low income settings. DESIGN: Systematic review of randomised controlled trials (RCTs), and observational studies, including retrospective analyses, that compare fluid bolus regimens with maintenance fluids alone. The primary outcome measure was predischarge mortality. DATA SOURCES AND SYNTHESIS: We searched PubMed, The Cochrane Library (to January 2014), with complementary earlier searches on, Google Scholar and Clinical Trial Registries (to March 2013). As studies used different clinical signs to define impaired circulation we classified patients into those with signs of severely impaired circulation, or those with any signs of impaired circulation. The quality of evidence for each outcome was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Findings are presented as risk ratios (RRs) with 95% CIs. RESULTS: Six studies were included. Two were RCTs, one large trial (n=3141 children) from a low-income country and a smaller trial from a middle-income country. The remaining studies were from middle-income or high-income settings, observational, and with few participants (34-187 children). SEVERELY IMPAIRED CIRCULATION: The large RCT included a small subgroup with severely impaired circulation. There were more deaths in those receiving bolus fluids (20-40 mL/kg/h, saline or albumin) compared to maintenance fluids (2.5-4 mL/kg/h; RR 2.40, 95% CI 0.84 to 6.88, p=0.054, 65 participants, low quality evidence). Three additional observational studies, all at high risk of confounding, found mixed effects on mortality (very low quality evidence). ANY SIGNS OF IMPAIRED CIRCULATION: The large RCT included children with signs of both severely and non severely impaired circulation. Overall, bolus fluids increased 48 h mortality compared to maintenance fluids with an additional 3 deaths per 100 children treated (RR 1.45, 95% CI 1.13 to 1.86, 3141 participants, high quality evidence). In a second small RCT from India, no difference in 72 h mortality was detected between children who received 20-40 mL/kg Ringers lactate over 15 min and those who received 20 mL over 20 min up to a maximum of 60 mL/kg over 1 h (147 participants, low quality evidence). In one additional observational study, resuscitation consistent with Advanced Paediatric Life Support (APLS) guidelines, including fluids, was not associated with reduced mortality in the small subgroup with septic shock (very low quality evidence). SIGNS OF IMPAIRED CIRCULATION, BUT NOT SEVERELY IMPAIRED: Only the large RCT allowed an analysis for children with some signs of impaired circulation who would not meet the criteria for severe impairment. Bolus fluids increased 48 h mortality compared to maintenance alone (RR 1.36, 95% CI 1.05 to 1.76, high quality evidence). CONCLUSIONS: Prior to the publication of the large RCT, the global evidence base for bolus fluid therapy in children with severe febrile illness and signs of impaired circulation was of very low quality. This large study provides robust evidence that in low-income settings fluid boluses increase mortality in children with severe febrile illness and impaired circulation, and this increased risk is consistent across children with severe and less severe circulatory impairment. PMID- 24785401 TI - Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT). AB - INTRODUCTION: Many patients with ulcerative colitis (UC) present with acute exacerbations needing hospital admission. Treatment includes intravenous steroids but up to 40% of patients do not respond and require emergency colectomy. Mortality following emergency colectomy has fallen, but 10% of patients still die within 3 months of surgery. Infliximab and ciclosporin, both immunosuppressive drugs, offer hope for treating steroid-resistant UC as there is evidence of their short-term effectiveness. As there is little long-term evidence, this pragmatic randomised trial, known as Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT), aims to compare the clinical and cost-effectiveness of infliximab and ciclosporin for steroid-resistant UC. METHODS AND ANALYSIS: Between May 2010 and February 2013, 52 UK centres recruited 270 patients admitted with acute severe UC who failed to respond to intravenous steroids but did not need surgery. We allocated them at random in equal proportions between infliximab and ciclosporin.The primary clinical outcome measure is quality-adjusted survival, that is survival weighted by Crohn's and Colitis Questionnaire (CCQ) participants' scores, analysed by Cox regression. Secondary outcome measures include: the CCQ-an extension of the validated but community-focused UK Inflammatory Bowel Disease Questionnaire (IBDQ) to include patients with acute severe colitis and stoma; two general quality of life measures-EQ-5D and SF-12; mortality; survival weighted by EQ-5D; emergency and planned colectomies; readmissions; incidence of adverse events including malignancies, serious infections and renal disorders; disease activity; National Health Service (NHS) costs and patient-borne costs. Interviews investigate participants' views on therapies for acute severe UC and healthcare professionals' views on the two drugs and their administration. ETHICS AND DISSEMINATION: The Research Ethics Committee for Wales has given ethical approval (Ref. 08/MRE09/42); each participating Trust or Health Board has given NHS Reseach & Development approval. We plan to present trial findings at international and national conferences and publish in high-impact peer-reviewed journals. TRIAL REGISTRATION NUMBER ISRCTN: 22663589; EudraCT number: 2008-001968 36. PMID- 24785402 TI - Breast-feeding and Helicobacter pylori infection: systematic review and meta analysis. AB - OBJECTIVE: To quantify the association between breast-feeding and Helicobacter pylori infection, among children and adolescents. DESIGN: We searched MEDLINETM and ScopusTM up to January 2013. Summary relative risk estimates (RR) and 95 % confidence intervals were computed through the DerSimonian and Laird method. Heterogeneity was quantified using the I2 statistic. SETTING: Twenty-seven countries/regions; four low-income, thirteen middle-income and ten high-income countries/regions. SUBJECTS: Studies involving samples of children and adolescents, aged 0 to 19 years. RESULTS: We identified thirty-eight eligible studies, which is nearly twice the number included in a previous meta-analysis on this topic. Fifteen studies compared ever v. never breast-fed subjects; the summary RR was 0.87 (95% CI 0.57, 1.32; I2=34.4%) in middle-income and 0.85 (95% CI 0.54, 1.34; I2=79.1%) in high-income settings. The effect of breast-feeding for >=4-6 months was assessed in ten studies from middle-income (summary RR=0.66; 95% CI 0.44, 0.98; I2=65.7%) and two from high-income countries (summary RR=1.56; 95% CI 0.57, 4.26; I2=68.3%). Two studies assessed the effect of exclusive breast feeding until 6 months (OR=0.91; 95% CI 0.61, 1.34 and OR=1.71; 95% CI 0.66, 4.47, respectively). CONCLUSIONS: Our results suggest a protective effect of breast-feeding in economically less developed settings. However, further research is needed, with a finer assessment of the exposure to breast-feeding and careful control for confounding, before definite conclusions can be reached. PMID- 24785403 TI - Digital process and materials 2014--where are you? PMID- 24785404 TI - Synthesis, structural characterization, and reactivity studies of 5-CF3SO3 B10H13. AB - In contrast to previous reactions carried out in cyclopentane solvent at room temperature that produced 6-TfO-B10H13 (TfO = CF3SO3), the reaction of closo B10H10(2-) with a large excess of trifluoromethanesulfonic acid in the ionic liquid 1-butyl-3-methylimidazolium trifluoromethanesulfonate (bmimOTf) gave exclusively the previously unknown 5-TfO-B10H13 isomer. Experimental and computational studies demonstrated that the difference in the products of the two reactions is a result of 6-TfO-B10H13 isomerizing to 5-TfO-B10H13 above room temperature in bmimOTf solutions. Reactivity studies showed that 5-TfO-B10H13: (1) is deprotonated by reaction with 1,8-bis(dimethylamino)naphthalene to form the 5-TfO-B10H12(1-) anion; (2) reacts with alcohols to produce 6-RO-B10H13 boryl ethers (R = Me and 4-CH3O-C6H4); (3) undergoes olefin-hydroboration reactions to form 5-TfO-6,9-R2-B10H11 derivatives; and (4) forms a 5-TfO-6,9-(Me2S)2-B10H11 adduct at its Lewis acidic 6,9-borons upon reaction with dimethylsulfide. The 5 TfO-6,9-(Me2S)2-B10H11 adduct was also found to undergo alkyne-insertion reactions to form a range of previously unreported triflate-substituted 4-TfO ortho-carboranes (1-R-4-TfO-1,2-C2B10H10) and reactions with triethylamine or ammonia to form the first TfO-substituted decaborate [R3NH(+)]2[2-TfO-B10H9(2-)], and [R3NH(+)]2[1-TfO-B10H9(2-)] (R = H, Et) salts. PMID- 24785405 TI - Public transit bus ramp slopes measured in situ. AB - Abstract Purpose: The slopes of fixed-route bus ramps deployed for wheeled mobility device (WhMD) users during boarding and alighting were assessed. Measured slopes were compared to the proposed Americans with Disabilities Act (ADA) maximum allowable ramp slope. Methods: A ramp-embedded inclinometer measured ramp slope during WhMD user boarding and alighting on a fixed-route transit bus. The extent of bus kneeling was determined for each ramp deployment. In-vehicle video surveillance cameras captured ramp deployment level (street versus sidewalk) and WhMD type. Results: Ramp slopes ranged from -4 degrees to 15.5 degrees with means of 4.3 degrees during boarding (n = 406) and 4.2 degrees during alighting (n = 405). Ramp slope was significantly greater when deployed to street level. During boarding, the proposed ADA maximum allowable ramp slope (9.5 degrees ) was exceeded in 66.7% of instances when the ramp was deployed to street level, and in 1.9% of instances when the ramp was deployed to sidewalk level. During alighting, the proposed ADA maximum allowable slope was exceeded in 56.8% of instances when the ramp was deployed to street level and in 1.4% of instances when the ramp was deployed to sidewalk level. Conclusions: Deployment level, built environment and extent of bus kneeling can affect slope of ramps ascended/descended by WhMD users when accessing transit buses. Implications for Rehabilitation Since public transportation services are critical for integration of wheeled mobility device (WhMD) users into the community and society, it is important that they, as well as their therapists, are aware of conditions that may be encountered when accessing transit buses. Knowledge of real world ramp slope conditions that may be encountered when accessing transit buses will allow therapists to better access capabilities of WhMD users in a controlled clinical setting. Real world ramp slope conditions can be recreated in a clinical setting to allow WhMD users to develop and practice necessary skills to safely navigate this environment. Knowing that extent of bus kneeling and ramp deployment level can influence ramp slope, therapists can educate WhMD users to request bus operators further kneel the bus floor and/or redeploy the ramp to a sidewalk level when appropriate, so that the least practicable slope will be presented for ingress/egress. PMID- 24785406 TI - Effects of ranolazine on torsades de pointes tachycardias in a healthy isolated rabbit heart model. AB - PURPOSE: Torsades de pointes (TdP) tachycardias are triggered, polymorphic ventricular arrhythmias arising from early afterdepolarizations (EADs) and increased dispersion of repolarization. Ranolazine is a new agent which reduces pathologically elevated late INa but also IKr . Aim of this study was to evaluate the effects of ranolazine in a validated isolated Langendorff-perfused rabbit heart model. METHODS: TdP was reproducibly induced with d-sotalol (10(-4) mol/L) and low potassium (K) (1.0 mmol/L for 5 min, pacing at CL 1000 ms). In 10 hearts, ECG and 8 epi- and endocardial monophasic action potentials were recorded. Action potential duration (APD) was measured at 90% repolarization and dispersion defined as APD max-min. RESULTS: D-sotalol prolonged APD90 and increased dispersion of APD90 , simultaneously causing EADs and induction of TdP. The combination of d-sotalol and two concentrations of ranolazine did not increase dispersion of ventricular APD90 as compared to vehicle. Ranolazine at 5 MUmol/L did not cause additional induction of EADs and/or TdP but also did not significantly suppress arrhythmogenic triggers. The higher concentration of ranolazine (10 MUmol/L) in combination with d-sotalol caused further prolongation of APD90 , at the same time reduction in APD90 dispersion. In parallel, the incidence of EADs was reduced and an antitorsadogenic effect was seen. CONCLUSIONS: In the healthy isolated rabbit heart (where late INa is not elevated), ranolazine does not cause proarrhythmia but exerts antiarrhythmic effects in a dose-dependent manner against d-sotalol/low K-induced TdP. This finding-despite additional APD prolongation-supports the safety of a combined use of both drugs and merits clinical investigation. PMID- 24785408 TI - Poly(3,4-ethylenedioxyselenophene) and its derivatives: novel organic electronic materials. AB - Since the discovery of high conductivity in iodine-doped polyacetylene, many interesting conducting polymers have been developed. Of these, polythiophenes have been most studied as electronic materials, with poly(3,4 ethylenedioxythiophene) (PEDOT) and the water-soluble PEDOT-PSS being the most successful commercially used conducting polymers. The polyselenophene family together with poly(3,4-ethylenedioxyselenophene) (PEDOS) and its derivatives have been shown to have slightly different properties compared to these of polythiophene and PEDOT because of their different electron donating characters, aromaticities (selenophene vs thiophene), oxidation potentials, electronegativities, and polarizabilities (Se vs S). As a result, the polyselenophenes, especially PEDOS and its derivatives, show a lower band gap and higher-lying highest occupied molecular orbital (HOMO) levels compared with those of thiophene and the PEDOT family. In an organic materials context, the PEDOS family offers some advantages over PEDOT derivatives. This Account draws on computational studies, synthetic methods, electrochemical polymerizations, chemical polymerizations, and the materials properties of PEDOS and its derivatives to demonstrate the importance of these novel materials, which lie at the frontier of conducting polymer research. In particular, we show that (i) PEDOS derivatives have a lower band gap (about 0.2 eV) than the corresponding PEDOT derivatives. Consequently, PEDOS derivatives can absorb the solar spectrum more efficiently compared to PEDOT derivatives and the properties of optoelectronic devices based on neutral and doped PEDOS should be somewhat different from these of PEDOT. (ii) EDOS derivatives have a greater tendency to undergo electrochemical polymerization compared to EDOT derivatives and offer stable and smooth polymer films. (iii) The PEDOS backbone is more rigid than the PEDOT backbone. (iv) PEDOS derivatives are excellent electrochromic materials with high transparency, and have higher contrast ratio and coloration efficiency. (v) The PEDOS/C electrode offers better control over the formation and size of nanoparticles through Se...Pt interactions compared with the PEDOT/C electrode. In addition to this, we summarize the synthesis, electrochemical polymerization, materials properties, and computational studies of fused polyselenophene analogues, namely, poly(cyclopenta[c]selenophene), and a series of low band gap thieno- or selenolo-fused polyselenophenes and selenolo-fused polythiophene. Additionally, we discuss oxidative and solid state polymerization to obtain conducting PEDOS, and its derivatives, and made throughout comparison with S analogue where applicable. We found that EDOS-based derivatives have a greater tendency toward solid state polymerization and working at a temperature about 20 degrees C lower than that required for EDOT-based compounds. Our results demonstrate the utility of EDOS unit for generating promising materials PEDOS and its derivatives for electronic devices. Consequently, EDOS structure is the basis for many functionalized polymers and copolymers with tunable optoelectronic and redox properties. These interesting properties, which include high conductivity, lower band gap, rigidity, multicolor electrochromism, and rapid redox switching, allow them to be used in a variety of electronic applications. PMID- 24785407 TI - Interplay between Polo kinase, LKB1-activated NUAK1 kinase, PP1betaMYPT1 phosphatase complex and the SCFbetaTrCP E3 ubiquitin ligase. AB - NUAK1 (NUAK family SnF1-like kinase-1) and NUAK2 protein kinases are activated by the LKB1 tumour suppressor and have been implicated in regulating multiple processes such as cell survival, senescence, adhesion and polarity. In the present paper we present evidence that expression of NUAK1 is controlled by CDK (cyclin-dependent kinase), PLK (Polo kinase) and the SCFbetaTrCP (Skp, Cullin and F-boxbetaTrCP) E3 ubiquitin ligase complex. Our data indicate that CDK phosphorylates NUAK1 at Ser445, triggering binding to PLK, which subsequently phosphorylates NUAK1 at two conserved non-catalytic serine residues (Ser476 and Ser480). This induces binding of NUAK1 to betaTrCP, the substrate-recognition subunit of the SCFbetaTrCP E3 ligase, resulting in NUAK1 becoming ubiquitylated and degraded. We also show that NUAK1 and PLK1 are reciprocally controlled in the cell cycle. In G2-M-phase, when PLK1 is most active, NUAK1 levels are low and vice versa in S-phase, when PLK1 expression is low, NUAK1 is more highly expressed. Moreover, NUAK1 inhibitors (WZ4003 or HTH-01-015) suppress proliferation by reducing the population of cells in S-phase and mitosis, an effect that can be rescued by overexpression of a NUAK1 mutant in which Ser476 and Ser480 are mutated to alanine. Finally, previous work has suggested that NUAK1 phosphorylates and inhibits PP1betaMYPT1 (where PP1 is protein phosphatase 1) and that a major role for the PP1betaMYPT1 complex is to inhibit PLK1 by dephosphorylating its T-loop (Thr210). We demonstrate that activation of NUAK1 leads to a striking increase in phosphorylation of PLK1 at Thr210, an effect that is suppressed by NUAK1 inhibitors. Our data link NUAK1 to important cell-cycle signalling components (CDK, PLK and SCFbetaTrCP) and suggest that NUAK1 plays a role in stimulating S-phase, as well as PLK1 activity via its ability to regulate the PP1betaMYPT1 phosphatase. PMID- 24785409 TI - Measurement of the visual attention patterns of people with aphasia: a preliminary investigation of two types of human engagement in photographic images. AB - The focus of this investigation was to examine the visual attention patterns of adults with aphasia on task-engaged contextualized images in which a human figure was engaged with the context of the image and camera-engaged contextualized images in which a human figure was looking forward toward the camera. Analysis revealed that adults with aphasia tend to fixate rapidly and frequently on human figures in contextualized images regardless of the type of engagement in the image. In addition, they responded to engagement cues when viewing task-engaged contextualized images by fixating more frequently and more rapidly on the object area of interest for these images than for camera-engaged contextualized images. PMID- 24785411 TI - Redox active iron nitrosyl units in proton reduction electrocatalysis. AB - Base metal, molecular catalysts for the fundamental process of conversion of protons and electrons to dihydrogen, remain a substantial synthetic goal related to a sustainable energy future. Here we report a diiron complex with bridging thiolates in the butterfly shape of the 2Fe2S core of the [FeFe]-hydrogenase active site but with nitrosyl rather than carbonyl or cyanide ligands. This binuclear [(NO)Fe(N2S2)Fe(NO)2](+) complex maintains structural integrity in two redox levels; it consists of a (N2S2)Fe(NO) complex (N2S2=N,N'-bis(2 mercaptoethyl)-1,4-diazacycloheptane) that serves as redox active metallodithiolato bidentate ligand to a redox active dinitrosyl iron unit, Fe(NO)2. Experimental and theoretical methods demonstrate the accommodation of redox levels in both components of the complex, each involving electronically versatile nitrosyl ligands. An interplay of orbital mixing between the Fe(NO) and Fe(NO)2 sites and within the iron nitrosyl bonds in each moiety is revealed, accounting for the interactions that facilitate electron uptake, storage and proton reduction. PMID- 24785410 TI - Catheter ablation of ventricular arrhythmia in nonischemic cardiomyopathy: anteroseptal versus inferolateral scar sub-types. AB - BACKGROUND: The aim was to relate distinct scar distributions found in nonischemic cardiomyopathy with ventricular tachycardia (VT) morphology, late potential distribution, ablation strategy, and outcome. METHODS AND RESULTS: Eighty-seven patients underwent catheter ablation for drug-refractory VT. Based on endocardial unipolar voltage, 44 were classified as predominantly anteroseptal and 43 as inferolateral. Anteroseptal patients more frequently fulfilled diagnostic criteria for dilated cardiomyopathy (64% versus 36%), associated with more extensive endocardial unipolar scar (41 [22-83] versus 9 [1-29] cm(2); P<0.001). Left inferior VT axis was predictive of anteroseptal scar (positive predictive value, 100%) and right superior axis for inferolateral (positive predictive value, 89%). Late potentials were infrequent in the anteroseptal group (11% versus 74%; P<0.001). Epicardial late potentials were common in the inferolateral group (81% versus 4%; P<0.001) and correlated with VT termination sites (kappa=0.667; P=0.014), whereas no anteroseptal patient had an epicardial VT termination (P<0.001). VT recurred in 44 patients (51%) during a median follow up of 1.5 years. Anteroseptal scar was associated with higher VT recurrence (74% versus 25%; log-rank P<0.001) and redo procedure rates (59% versus 7%; log-rank P<0.001). After multivariable analysis, clinical predictors of VT recurrence were electrical storm (hazard ratio, 3.211; P=0.001) and New York Heart Association class (hazard ratio, 1.608; P=0.018); the only procedural predictor of VT recurrence was anteroseptal scar pattern (hazard ratio, 5.547; P<0.001). CONCLUSIONS: Unipolar low-voltage distribution in nonischemic cardiomyopathy allows categorization of scar pattern as inferolateral, often requiring epicardial ablation mainly based on late potentials, and anteroseptal, which frequently involves an intramural septal substrate, leading to a higher VT recurrence. PMID- 24785412 TI - Computational repositioning and preclinical validation of pentamidine for renal cell cancer. AB - Although early stages of clear cell renal cell carcinoma (ccRCC) are curable, survival outcome for metastatic ccRCC remains poor. We previously established a highly accurate signature of differentially expressed genes that distinguish ccRCC from normal kidney. The purpose of this study was to apply a new individualized bioinformatics analysis (IBA) strategy to these transcriptome data in conjunction with Gene Set Enrichment Analysis of the Connectivity Map (C-MAP) database to identify and reposition FDA-approved drugs for anticancer therapy. Here, we demonstrate that one of the drugs predicted to revert the RCC gene signature toward normal kidney, pentamidine, is effective against RCC cells in culture and in a RCC xenograft model. ccRCC-specific gene expression signatures of individual patients were used to query the C-MAP software. Eight drugs with negative correlation and P-value <0.05 were analyzed for efficacy against RCC in vitro and in vivo. Our data demonstrate consistency across most patients with ccRCC for the set of high-scoring drugs. Most of the selected high-scoring drugs potently induce apoptosis in RCC cells. Several drugs also demonstrate selectivity for Von Hippel-Lindau negative RCC cells. Most importantly, at least one of these drugs, pentamidine, slows tumor growth in the 786-O human ccRCC xenograft mouse model. Our findings suggest that pentamidine might be a new therapeutic agent to be combined with current standard-of-care regimens for patients with metastatic ccRCC and support our notion that IBA combined with C MAP analysis enables repurposing of FDA-approved drugs for potential anti-RCC therapy. PMID- 24785413 TI - Enantioselective synthesis of 3,4-dihydro-1,2-oxazepin-5(2H)-ones and 2,3 dihydropyridin-4(1H)-ones from beta-substituted beta-hydroxyaminoaldehydes. AB - The synthesis of 3,4-dihydro-1,2-oxazepin-5(2H)-ones and 2,3-dihydropyridin-4(1H) ones from beta-substituted beta-hydroxyaminoaldehydes is reported. The beta hydroxyaminoaldehydes were prepared by enantioselective organocatalytic 1,4 addition of N-tert-butyl (tert-butyldimethylsilyl)oxycarbamate to alpha,beta unsaturated aldehydes (MacMillan protocol). Alkyne addition to the aldehydes followed by alcohol oxidation furnished N-Boc O-TBS-protected beta-aminoynones. Removal of the TBS protecting group initiated a 7-endo-dig cyclization to yield previously unknown 3,4-dihydro-1,2-oxazepin-5(2H)-ones. Reductive cleavage of the N-O bond of the oxazepinones and Boc-deprotection provided 2-substituted 2,3 dihydropyridin-4(1H)-ones via 6-endo-trig cyclization. 2,3-Dihydropyridin-4(1H) ones are versatile intermediates that have been used for the synthesis of many alkaloids. The new protocol allows the synthesis of 3-dihydropyridin-4(1H)-ones carrying an array of substituents at C2 that cannot be prepared from commercial beta-amino acids or by one-carbon homologation of proteinogenic amino acids. The use of readily available beta-hydroxylaminoaldehydes expands the utility of our previously reported method to prepare 2,3-dihydropyridin-4(1H)-ones from beta amino acids as the source of diversity and chirality. A broad substrate scope is possible because beta-aminoaldehydes can be prepared from alpha,beta-unsaturated aldehydes by an enantioselective organocatalytic process. PMID- 24785414 TI - Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis. AB - When two mutations, one dominant pathogenic and the other "confining" nonsense, coexist in the same allele, theoretically, reversion of the latter may elicit a disease, like the opening of Pandora's box. However, cases of this hypothetical pathogenic mechanism have never been reported. We describe a lethal form of keratitis-ichthyosis-deafness (KID) syndrome caused by the reversion of the GJB2 nonsense mutation p.Tyr136X that would otherwise have confined the effect of another dominant lethal mutation, p.Gly45Glu, in the same allele. The patient's mother had the identical misssense mutation which was confined by the nonsense mutation. The biological relationship between the parents and the child was confirmed by genotyping of 15 short tandem repeat loci. Haplotype analysis using 40 SNPs spanning the >39 kbp region surrounding the GJB2 gene and an extended SNP microarray analysis spanning 83,483 SNPs throughout chromosome 13 in the family showed that an allelic recombination event involving the maternal allele carrying the mutations generated the pathogenic allele unique to the patient, although the possibility of coincidental accumulation of spontaneous point mutations cannot be completely excluded. Previous reports and our mutation screening support that p.Gly45Glu is in complete linkage disequilibrium with p.Tyr136X in the Japanese population. Estimated from statisitics in the literature, there may be approximately 11,000 p.Gly45Glu carriers in the Japanese population who have this second-site confining mutation, which acts as natural genetic protection from the lethal disease. The reversion-triggered onset of the disesase shown in this study is a previously unreported genetic pathogenesis based on Mendelian inheritance. PMID- 24785415 TI - It is my pleasure and privilege to work as a guest editor for this symposium. Introduction. PMID- 24785416 TI - Secondary prevention of cervical cancer part 1: screening for cervical cancer and its precursors. AB - Discussion of screening for cervical cancer and it precursors, management of abnormal cervical cancer screening test, and evidence-based management of women with cervical intraepithelial neoplasia. PMID- 24785417 TI - Secondary prevention of cervical cancer part 2: initial management of abnormal cervical cancer screening test. AB - Cervical cancer screening has become more complex with the addition of HPV testing to pap testing. This chapter covers evidence based national recommendations for managing abnormal cervical cancer screening tests. PMID- 24785418 TI - Elective induction of labor, or induction of labor without a medical indication, is a commonly performed procedure. Introduction. PMID- 24785419 TI - Global perspectives on elective induction of labor. AB - Elective labor induction is an increasingly common practice not only in high income countries, but also in many low-income and middle-income countries. Many questions remain unanswered on the safety and cost-effectiveness of elective labor induction, particularly in resource-constrained settings where there may be a high unmet need for medically indicated inductions, as well as limited or no access to appropriate medications and equipment for induction and monitoring, comprehensive emergency obstetric care, safe and timely cesarean section, and appropriate supervision from health professionals. This article considers the global perspective on the epidemiology, practices, safety, and costs associated with elective labor induction. PMID- 24785420 TI - Methods of cervical ripening and labor induction: mechanical. PMID- 24785425 TI - The role of scar origin in shaping men's body image. AB - Men generally have a more positive body image than women. However, the extent to which scars negatively influence men's body image is uncertain. The aim of the current study was to assess body image in men with and without scars while taking scar origin into account (nonsuicidal self-harming injuries [NSSI] vs. accidents or surgery). One hundred and nine men (n = 19 with NSSI) and 185 women (n = 96 with NSSI) filled in multidimensional body image questionnaires. Results indicate that on most clinical subscales women had a significantly more negative body image compared with men. However, within a subsample whose scars resulted from NSSI, gender differences vanished. Among men, scar origin was significantly associated with negative body image after partialling out scar characteristics, age, and borderline symptomatology. The visibility of scars was not associated with more severe body image disturbances. The results of our study indicate that self-inflicted scars adversely affect body image. Although women generally reported having a more negative body image, disturbances in body image should not be neglected among men, especially in those who have self-inflicted scars. PMID- 24785424 TI - Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. AB - Reduced supply of the amino acid methionine increases longevity across species through an as yet elusive mechanism. Here, we report that methionine restriction (MetR) extends yeast chronological lifespan in an autophagy-dependent manner. Single deletion of several genes essential for autophagy (ATG5, ATG7 or ATG8) fully abolished the longevity-enhancing capacity of MetR. While pharmacological or genetic inhibition of TOR1 increased lifespan in methionine-prototroph yeast, TOR1 suppression failed to extend the longevity of methionine-restricted yeast cells. Notably, vacuole-acidity was specifically enhanced by MetR, a phenotype that essentially required autophagy. Overexpression of vacuolar ATPase components (Vma1p or Vph2p) suffices to increase chronological lifespan of methionine prototrophic yeast. In contrast, lifespan extension upon MetR was prevented by inhibition of vacuolar acidity upon disruption of the vacuolar ATPase. In conclusion, autophagy promotes lifespan extension upon MetR and requires the subsequent stimulation of vacuolar acidification, while it is epistatic to the equally autophagy-dependent anti-aging pathway triggered by TOR1 inhibition or deletion. PMID- 24785426 TI - How do African American men rate their health care? An analysis of the consumer assessment of health plans 2003-2006. AB - African American (AA) men remain one of the most disconnected groups from health care. This study examines the association between AA men's rating of health care and rating of their personal physician. The sample included 12,074 AA men aged 18 years or older from the 2003 to 2006 waves of the Consumer Assessment of Healthcare Providers and Systems Adult Commercial Health Plan Survey. Multilevel models were used to obtain adjusted means rating of health care systems and personal physician, and the relationship of ratings with the rating of personal physician. The adjusted means were 80 (on a 100-point scale) for most health ratings and composite health care scores: personal physician (83.9), specialist (83.66), health care (82.34), getting needed care (89.57), physician communication (83.17), medical staff courtesy (86.58), and customer service helpfulness (88.37). Physician communication was the strongest predictor for physician rating. AA men's health is understudied, and additional research is warranted to improve how they interface with the health care system. PMID- 24785427 TI - Risk factors for psychological distress in community-treated epilepsy. AB - The study aimed to determine risk factors for psychological distress in a community-treated sample of patients with epilepsy. This study investigated the Tasmanian Epilepsy Register participants. Participants included were as follows: aged 13 years and over, able to complete the individual computer-assisted participant interview, and diagnosed with epilepsy following an epilepsy specialist review of the diagnostic epilepsy interview, which was interpreted using standardized diagnostic guidelines. Psychological distress was assessed with the Kessler-10 questionnaire. Risk factors were grouped into four domains: sociodemographic factors, disease-related factors, psychological factors, and treatment-related factors. High or very high levels of psychological distress were reported by 22% of the participants, with 7.8% having very high distress. The regression model showed that psychological distress was significantly associated with female gender (F=18.1, p<0.001), diabetes mellitus (F=8.7, p=0.003), intellectual disability (F=7.1, p=0.06), and not receiving phenytoin (F=5.1, p=0.02). While the model was significant (F=5.78, p<0.001), only 11% of the variance of the K-10 score was explained by these factors (adjusted R squared=0.11). This study identifies female gender and comorbid medical conditions as risk factors for psychological distress and the use of phenytoin as a protective factor. The few factors identified and the limited variance explained suggest that a focus on epilepsy-related variables is unlikely to explain key influences underlying psychiatric comorbidity in patients with epilepsy. PMID- 24785428 TI - The practical impact of altered dosing on perampanel plasma concentrations: pharmacokinetic modeling from clinical studies. AB - RATIONALE: Perampanel is a selective AMPA receptor antagonist approved for adjunctive therapy in patients with refractory partial-onset seizures. Perampanel is metabolized primarily via CYP3A4, yet it has a relatively long half-life of 105h; it is, therefore, recommended that perampanel be given once daily (preferably at bedtime). Many patients occasionally have less-than-perfect adherence to their drug regimen, and given the known pharmacokinetic interactions of perampanel with commonly used enzyme-inducing antiepileptic drugs (EIAEDs), we explored the effects of a missed dose on steady-state perampanel plasma concentrations and the ramifications of "make up" doses in these patients. Although perampanel is approved for once-daily dosing, some clinicians may elect to give perampanel as a divided dose (i.e., twice daily), so we also sought to examine the pharmacokinetic impact of twice- versus once-daily dosing. METHODS: Pharmacokinetic simulations were performed using validated perampanel pharmacokinetic parameters, derived from 19 phase I studies in 606 subjects, to investigate the effect on perampanel plasma concentration of (1) missing a dose of perampanel followed by delayed replacement of the missed dose, (2) missing a dose followed by resumption of scheduled therapy, and (3) missing a dose in the presence/absence of carbamazepine. Simulations were done for a typical patient receiving an 8-mg once-daily or a 4-mg twice-daily dose using the nonlinear mixed effects program, NONMEM v7.2, in conjunction with PDx-pop v5. RESULTS: Our results corroborate that given the pharmacokinetic characteristics of perampanel, a missed dose is unlikely to cause as much fluctuation in plasma concentration as would be expected for a drug with a short half-life. Importantly, simulations suggest that supplementing a missed dose 6-12h later, followed by continuation of the regular schedule, may not result in any significant "spikes" in perampanel plasma concentrations. Simulations demonstrated that twice-daily dosing offered little advantage in further flattening the concentration-time profile of perampanel in the adherent patient. However, fluctuations in plasma concentrations are minimized by twice-daily dosing in patients receiving concomitant EIAEDs. CONCLUSIONS: These pharmacokinetic simulations suggest that the long half-life of perampanel may be advantageous in conferring a relatively smooth concentration-time profile with a once-daily or twice-daily dosing, even in the presence of concomitant EIAEDs. However, the results of the present study suggest that perampanel replacement is recommended for patients taking an EIAED to mitigate the potential risks associated with reduced exposure. Confirmation of the ultimate clinical impact of these findings will require further study. PMID- 24785429 TI - Sudden unexpected death in epilepsy: knowledge and experience among U.S. and Canadian neurologists. AB - IMPORTANCE: Sudden unexpected death in epilepsy (SUDEP) is a common cause of mortality in patients with the disease, but it is unknown how neurologists disclose this risk when counseling patients. OBJECTIVE: This study aimed at examining SUDEP discussion practices of neurologists in the U.S. and Canada. DESIGN: An electronic, web-based survey was sent to 17,558 neurologists in the U.S. and Canada. Survey questions included frequency of SUDEP discussion, reasons for discussing/not discussing SUDEP, timing of SUDEP discussions, and perceived patient reactions. We examined factors that influence the frequency of SUDEP discussion and perceived patient response using multivariate logistic regression. PARTICIPANTS: The participants of this study were neurologists who completed postgraduate training and devoted >5% of their time to patient care. RESULTS: There was a response rate of 9.3%; 1200 respondents met eligibility criteria and completed surveys. Only 6.8% of the respondents discussed SUDEP with nearly all (>90% of the time) of their patients with epilepsy/caregivers, while 11.6% never discussed it. Factors that independently predicted whether SUDEP was discussed nearly all of the time were the following: number of patients with epilepsy seen annually (OR=2.01, 95% CI=1.20-3.37, p<0.01) and if the respondent had a SUDEP case in the past 24 months (OR=2.27, 95% CI=1.37-3.66, p<0.01). A majority of respondents (59.5%) reported that negative reactions were the most common response to a discussion of SUDEP. Having additional epilepsy/neurophysiology training was associated with an increased risk of a perceived negative response (OR=1.36, 95% CI=1.02-1.82, p=0.038), while years in practice (OR=0.85, 95% CI=0.77-0.95, p<0.005) and seeing both adults and children were associated with a decreased likelihood of negative response (OR=0.15, 95% CI=0.032-0.74, p=0.02). CONCLUSIONS: U.S. and Canadian neurologists rarely discuss SUDEP with all patients with epilepsy/caregivers though discussions are more likely among neurologists who frequently see patients with epilepsy or had a recent SUDEP in their practice. Perceived negative reactions to SUDEP discussions are common but not universal; more experienced neurologists may be less likely to encounter negative reactions, suggesting that there may be ways to frame the discussion that minimizes patient/caregiver distress. PMID- 24785430 TI - Contributions of fMRI towards our understanding of the response to psychosocial stress in epilepsy and psychogenic nonepileptic seizures. AB - There are multiple definitions of stress. For this review, as a reference point, we will use the concept of acute emotional/psychosocial stress ("stress"). The presence of acute stress has been reported to have a significant effect on seizure control, with several studies showing patients with seizure disorders being able to predict with reasonable accuracy seizure occurrence within the following hours or days. However, neuroimaging investigations of the pathophysiological mechanisms underlying stress reactivity (e.g., hypothalamic pituitary-adrenal (HPA) axis activation) in humans, in general, and in patients with seizure disorders, in particular, are scarce. The reasons for this are multiple and likely include difficulty with designing appropriate probes that test various aspects of stress response, obtaining approval for studies that induce stress in patients who are prone to having stress-induced seizures, difficulties with assessing the physiological response to stress inside the scanner (e.g., heart rate, respiratory rate, oxygenation, cortisol levels, and galvanic skin responses), participant identification, and choice of epilepsy syndrome for investigation. With the recent explosion of neuroimaging literature focusing on correlating stress of various types and levels with cortical activations in healthy and diseased populations, it is incumbent upon us to examine the available neuroimaging data in patients with seizure disorders in order to identify the existing gaps and the needs/directions for future investigations. This approach is consistent with the goals of several of the 2014 Benchmarks for Epilepsy Research for the National Institute of Neurological Disorders and Stroke and the American Epilepsy Society. PMID- 24785432 TI - Mucins and tumor resistance to chemotherapeutic drugs. AB - Epithelial cancer patients not considered eligible for surgical resection frequently benefit from chemotherapy. Chemotherapy is the treatment of cancer with one or combination of cytotoxic or cytostatic drugs. Recent advances in chemotherapy allowed a great number of cancer patients to receive treatment with significant results. Unfortunately, resistance to chemotherapeutic drug treatment is a major challenge for clinicians in the majority of epithelial cancers because it is responsible for the inefficiency of therapies. Mucins belong to a heterogeneous group of large O-glycoproteins that can be either secreted or membrane-bound. Implications of mucins have been described in relation to cancer cell behavior and cell signaling pathways associated with epithelial tumorigenesis. Because of the frequent alteration of the pattern of mucin expression in cancers as well as their structural and functional characteristics, mucins are thought to also be involved in response to therapies. In this report, we review the roles of mucins in chemoresistance and the associated underlying molecular mechanisms (physical barrier, resistance to apoptosis, drug metabolism, cell stemness, epithelial-mesenchymal transition) and discuss the therapeutic tools/strategies and/or prognosis biomarkers for personalized chemotherapy that could be proposed from these studies. PMID- 24785433 TI - In vivo transcostal histotripsy therapy without aberration correction. AB - This study investigates the in vivo therapeutic capabilities of transcostal histotripsy without using aberration correction mechanisms and its thermal impact on overlying tissues. Non-invasive liver treatments were conducted in eight pigs, with four lesions generated through transcostal windows with full ribcage obstruction and four lesions created through transabdominal windows without rib coverage. Treatments were performed by a 750 kHz focused transducer using 5 cycle pulses at 200 Hz PRF, with estimated in situ peak negative pressures of 13-17 MPa. Temperatures on overlying tissues including the ribs were measured with needle thermocouples inserted superficially beneath the skin. Treatments of approximately 40 min were applied, allowing overlying tissue temperatures to reach saturation. Lesions yielded statistically comparable ablation volumes of 3.6 +/- 1.7 cm(3) and 4.5 +/- 2.0 cm(3) in transcostal and transabdominal treatments, respectively. The average temperature increase observed in transcostal treatments was 3.9 +/- 2.1 degrees C, while transabdominal treatments showed an increase of 1.7 +/- 1.3 degrees C. No damage was seen on the ribcage or other overlying tissues. These results indicate that histotripsy can achieve effective treatment through the ribcage in vivo without requiring correction mechanisms, while inducing no substantial thermal effects or damage to overlying tissues. Such capabilities could benefit several non-invasive therapy applications involving transcostal treatment windows. PMID- 24785434 TI - An ionizable active-site tryptophan imparts catalase activity to a peroxidase core. AB - Catalase peroxidases (KatG's) are bifunctional heme proteins that can disproportionate hydrogen peroxide (catalatic reaction) despite their structural dissimilarity with monofunctional catalases. Using X-ray crystallography and QM/MM calculations, we demonstrate that the catalatic reaction of KatG's involves deprotonation of the active-site Trp, which plays a role similar to that of the distal His in monofunctional catalases. The interaction of a nearby mobile arginine with the distal Met-Tyr-Trp essential adduct (in/out) acts as an electronic switch, triggering deprotonation of the adduct Trp. PMID- 24785435 TI - Real-time elastography in the diagnosis of patients suspected of having prostate cancer: a meta-analysis. AB - The goal of the study described here was to assess the performance of real-time elastography (RTE) in the detection of prostate cancers using a meta-analysis. A literature search of PubMed, Medline, Embase and the Cochrane Library was conducted. Published studies that evaluated the diagnostic performance of RTE in the diagnosis of prostate cancer and using the histopathology of the radical prostatectomy specimen as a reference standard were included. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and area under the curve were calculated to examine the accuracy of RTE. A total of seven studies that included 508 patients were analyzed. The pooled sensitivity and specificity for the diagnosis of prostate cancer by RTE were 0.72 (95% confidence interval: 0.70-0.74) and 0.76 (0.74-0.78), respectively. The summary diagnostic odds ratio was 12.59 (7.26-21.84), and the area under the curve was 0.841 (Q* = 0.773). In conclusion, RTE imaging has high accuracy in the detection of prostate cancers using the histopathology of the radical prostatectomy specimen as the reference standard and may reduce the number of core biopsies in the future. PMID- 24785436 TI - Combined vector velocity and spectral Doppler imaging for improved imaging of complex blood flow in the carotid arteries. AB - Color flow imaging and pulsed wave (PW) Doppler are important diagnostic tools in the examination of patients with carotid artery disease. However, measurement of the true peak systolic velocity is dependent on sample volume placement and the operator's ability to provide an educated guess of the flow direction. Using plane wave transmissions and a duplex imaging scheme, we present an all-in-one modality that provides both vector velocity and spectral Doppler imaging from one acquisition, in addition to separate B-mode images of sufficient quality. The vector Doppler information was used to provide automatically calibrated (angle corrected) PW Doppler spectra at every image point. It was demonstrated that the combined information can be used to generate spatial maps of the peak systolic velocity, highlighting regions of high velocity and the extent of the stenotic region, which could be used to automate work flow as well as improve the accuracy of measurement of true peak systolic velocity. The modality was tested in a small group (N = 12) of patients with carotid artery disease. PW Doppler, vector velocity and B-mode images could successfully be obtained from a single recording for all patients with a body mass index ranging from 21 to 31 and a carotid depth ranging from 16 to 28 mm. PMID- 24785437 TI - Elastic modulus of the prostate: a new non-invasive feature to diagnose bladder outlet obstruction in patients with benign prostatic hyperplasia. AB - The purpose of our study was to develop a reliable method for the non-invasive evaluation of bladder outlet obstruction (BOO) caused by benign prostate hyperplasia (BPH). In our study, the International Prostate Symptom Score was assessed in, and trans-rectal ultrasound (TRUS) and shear wave sonoelastography (SWE) were performed on, 55 patients with BPH who had undergone urodynamic evaluation (the gold standard diagnostic procedure for BOO). The results indicated that the elastic modulus of the transitional zone was the indicator most strongly correlated with BOO stage (r = 0.666, p < 0.001), and had the largest area under the receiver operating characteristic curve, 0.826 (95% confidence interval: 0.717-0.934, p = 0.001). An elastic modulus of the transitional zone >= 32.4 kPa or a total prostate volume >= 54.4 mL was diagnostic of BOO, with a sensitivity, specificity, positive predictive value, negative predictive value and accuracy for BOO of 97.2%, 62.5%, 85.4%, 90.9% and 86.5%, respectively. The elastic modulus of the transitional zone is a promising indicator in the assessment of the severity of BOO. In addition, the combination of elastic modulus and total prostate volume was the most accurate indicator in the non-invasive diagnosis of BOO in patients with BPH. PMID- 24785438 TI - Four-dimensional echocardiography with spatiotemporal image correlation and inversion mode for detection of congenital heart disease. AB - The aim of this study was to evaluate the use of 4-D echocardiography with inversion mode and spatiotemporal image correlation (IM-STIC) in the detection of normal and abnormal fetal hearts. We retrospectively studied 112 normal fetuses and 16 fetuses with a confirmed diagnosis of congenital heart disease. Two volumes were acquired from each of the fetuses using transverse and sagittal sweeps. Volumes were reconstructed with IM-STIC. In normal fetuses, IM-STIC facilitated visualization of the interior structures of the fetal heart and great vessels. The visualization rates of intended planes obtained from IM-STIC 4D data ranged from 55% to 100%. In 16 fetuses with congenital heart disease, IM-STIC was able to display the cardiac malformations using digital casting. Some of the malformations were suspected during pre-natal 2-D echocardiography, and their pre natal IM-STIC diagnoses were confirmed by post-natal echocardiography, surgery and/or autopsy. Hence, 4-D IM-STIC allows better visualization of complex congenital heart disease and should be considered a very useful addition to 2-D echocardiography. PMID- 24785439 TI - Effect of therapeutic ultrasound on folliculogenesis, angiogenesis and apoptosis after heterotopic mouse ovarian transplantation. AB - One of the challenges in ovarian transplantation is ischemia-reperfusion damage. When transitional tissue faces an acute and critical condition in terms of blood supply (immediately after organ transplantation), treatment with low-intensity pulsed ultrasound (LIPUS) seems to be very beneficial. The aim of this study was to evaluate the effects of ultrasound therapy on heterotopic transplanted mouse ovarian tissue. Adult female Naval Medical Research Institute mice were divided into three groups. In the experimental groups, the transplanted ovary was exposed 5 min daily to ultrasound with an intensity of 0.3 W/cm(2), frequency of 3 MHz and pulse mode of 1:4. The grafted ovaries were assessed with the usual histology and immunohistochemistry techniques. Results indicate that more CD31 angiogenic factor was expressed in irradiated animals than in control animals, and ultrasound therapy resulted in better follicular preservation, especially after 14 d. In conclusion, therapeutic ultrasound may accelerate and increase re angiogenesis and can help to promote ovarian follicular growth. PMID- 24785440 TI - In vivo observation of the hypo-echoic "black hole" phenomenon in rat arterial bloodstream: a preliminary Study. AB - The "black hole," a hypo-echoic hole at the center of the bloodstream surrounded by a hyper-echoic zone in cross-sectional views, has been observed in ultrasound backscattering measurements of blood with red blood cell aggregation in in vitro studies. We investigated whether the phenomenon occurs in the in vivo arterial bloodstream of rats using a high-frequency ultrasound imaging system. Longitudinal and cross-sectional ultrasound images of the rat common carotid artery (CCA) and abdominal aorta were obtained using a 40-MHz ultrasound system. A high-frame-rate retrospective imaging mode was employed to precisely examine the dynamic changes in blood echogenicity in the arteries. When the imaging was performed with non-invasive scanning, blood echogenicity was very low in the CCA as compared with the surrounding tissues, exhibiting no hypo-echoic zone at the center of the vessel. Invasive imaging of the CCA by incising the skin and subcutaneous tissues at the imaging area provided clearer and brighter blood echo images, showing the "black hole" phenomenon near the center of the vessel in longitudinal view. The "black hole" was also observed in the abdominal aorta under direct imaging after laparotomy. The aortic "black hole" was clearly observed in both longitudinal and cross-sectional views. Although the "black hole" was always observed near the center of the arteries during the diastolic phase, it dissipated or was off-center along with the asymmetric arterial wall dilation at systole. In conclusion, we report the first in vivo observation of the hypo-echoic "black hole" caused by the radial variation of red blood cell aggregation in arterial bloodstream. PMID- 24785441 TI - Acoustically active injection catheter guided by ultrasound: navigation tests in acutely ischemic porcine hearts. AB - Catheters are increasingly used therapeutically and investigatively. With complex usage comes a need for more accurate intracardiac localization than traditional guidance can provide. An injection catheter navigated by ultrasound was designed and then tested in an open-chest model of acute ischemia in eight pigs. The catheter is made "acoustically active" by a piezo-electric crystal near its tip, electronically controlled, vibrating in the audio frequency range and uniquely identifiable using pulsed-wave Doppler. Another "target" crystal was sutured to the epicardium within the ischemic region. Sonomicrometry was used to measure distances between the two crystals and then compared with measurements from 2-D echocardiographic images. Complete data were obtained from seven pigs, and the correlation between sonomicrometry and ultrasound measurements was excellent (p < 0.0001, rho = 0.9820), as was the intraclass correlation coefficient (0.96) between two observers. These initial experimental results suggest high accuracy of ultrasound navigation of the acoustically active catheter prototype located inside the beating left ventricle. PMID- 24785442 TI - Comparative study of ultrasound and computed tomography for incidentally detecting diffuse thyroid disease. AB - The aim of this study was to compare the diagnostic values of thyroid ultrasound (US) and neck computed tomography (CT) in incidentally detecting diffuse thyroid disease (DTD). A single radiologist made US and CT diagnoses of incidentally detected DTD in 130 consecutive patients before thyroidectomy for various malignancies. Histopathologic examinations confirmed normal thyroid (n = 80), Hashimoto thyroiditis (n = 20), non-Hashimoto lymphocytic thyroiditis (n = 28) and diffuse hyperplasia (n = 2). Receiver operating characteristic curves revealed that the best diagnostic indices of both imaging methods were achieved on the basis of two or more abnormal imaging findings. The sensitivity, specificity and accuracy of US and CT in incidentally detecting DTD by this classification were 72% and 72%, 87.5% and 91.3% and 81.5% and 83.8%, respectively. Thyroid US and neck CT have similar diagnostic values for differentiating incidental DTD from normal thyroid. PMID- 24785443 TI - Percutaneous radiofrequency ablation of benign thyroid nodules assisted by a virtual needle tracking system. AB - Our aim was to assess the feasibility and outcome of ultrasound (US)-guided percutaneous radiofrequency (RF) ablation of benign thyroid nodules assisted by a real-time virtual needle tracking (VT) system. Forty-five patients (34 females, mean age +/- standard deviation (SD): 44 +/- 16 y, range: 29-68 y) with 45 benign non-functioning thyroid nodules (mean volume +/- SD: 13.5 +/- 6.7 mL, range: 12 22 mL) underwent VT-assisted US-guided RF ablation. Nodule volume was evaluated before treatment and during 6-mo of follow-up. Complication rates and patient satisfaction after treatment were also evaluated. By use of the VT system, the tip of the RF electrode was identified during all ablation procedures. The overall mean volume reduction and complication rate were 72.6 +/- 11.3% and 2.5%, respectively. Overall satisfaction at the 6-mo follow-up was rated by patients as positive in 42 cases (93%). The VT system could be useful in thyroid nodule ablation procedures because it is able to track the RF electrode tip even when the tip is obscured by the bubbles produced by the ablative process. VT-assisted RF ablation can be a tolerable, non-surgical treatment for patients with benign non-functioning thyroid nodules. PMID- 24785444 TI - Predominant patterns of median nerve displacement and deformation during individual finger motion in early carpal tunnel syndrome. AB - Idiopathic carpal tunnel syndrome (CTS) is a common neuropathy, yet the pathologic changes do not explain the fleeting dynamic symptoms. Dynamic nerve tendon interaction may be a contributing factor. Based on dynamic ultrasonographic examination of the carpal tunnel, we quantified nerve-tendon movement in thumb, index finger and middle finger flexion in normal subjects and those with mild-idiopathic CTS. Predominant motion patterns were identified. The nerve consistently moves volar-ulnarly. In thumb and index finger flexion, the associated tendons move similarly, whereas the tendon moves dorsoradially in middle finger flexion. Nerve displacement and deformation increased from thumb to index finger to middle finger flexion. Predomination motion patterns may be applied in computational simulations to prescribe specific motions to the tendons and to observe resultant nerve pressures. By identification of the greatest pressure-inducing motions, CTS treatment may be better developed. Symptomatic subjects displayed reduced nerve movement and deformation relative to controls, elucidating the physiologic changes that occur during mild CTS. PMID- 24785445 TI - [Systemic cytomegalovirus infection: changes in serum calcium and magnesium levels with foscarnet treatment]. AB - Cytomegalovirus infection is common in cardiac transplant patients. Foscarnet is used, with limited evidence, as second-line treatment after ganciclovir failure in these patients. We describe the case of a paediatric cardiac transplant patient who developed electrolyte disturbances during foscarnet treatment for cytomegalovirus infection. The infection resolved after 6 weeks of treatment. Low ionized calcium and magnesium levels were observed during the drug infusion, which were treated with supplements. The serum levels reverted to normal after drug withdrawal. PMID- 24785446 TI - [Somatic complaints, emotional awareness and maladjustment in schoolchildren]. AB - INTRODUCTION: Somatic complaints are common in childhood. Research has shown their relationship with emotional awareness and maladjustment. The study had three objectives: 1) to analyze the prevalence of somatic complaints; 2) To explore the relationships between the variables evaluated: somatic complaints, differentiating emotions, verbal sharing of emotions, not hiding emotions, body awareness, attending to others' emotions, analysis of emotions, and personal, social, family, and school maladjustments; and 3) To identify predictors of somatic complaints. PATIENTS AND METHODS: The study included a total of 1,134 randomly selected schoolchildren of both sexes between 10-12 years old (M=10.99; SD=0.88). The Somatic Complaint List, Emotional Awareness Questionnaire, and Self reported Multifactor Test of Childhood Adaptation were used to gather information. RESULTS: The results showed that the prevalence of somatic complaints was 90.2%, with fatigue, headache and stomachache being the most frequently. Dizziness and headache were more common in girls, and the frequency of complaints decreases with age. Somatic complaints are negatively related to emotional awareness, and positively related to maladjustment. The variables that contribute the most to the prediction of somatic complaints are personal maladjustment (25.1%) and differentiating emotions (2.5%). CONCLUSIONS: The study shows that personal maladjustment is the best predictor of somatic complaints; the more emotional awareness and better adapted the child, the fewer somatic complaints they lodge. Childhood is a stage with significant physical discomfort. PMID- 24785447 TI - [An exceptional combination of pulmonary and systemic venous return in a case of heterotaxia syndrome]. PMID- 24785448 TI - [Birth rates evolution in Spain. Birth trends in Spain from 1941 to 2010]. AB - OBJECTIVES: The aim of this study was to analyse trends of births in Spain and its Autonomous Communities (CCAA) over a 70 year period (1941-2010). METHODS: The crude birth rates per 1,000 inhabitants/year were calculated by CCAA using Joinpoint regression models. Change points in trend and annual percentage of change (APC) were identified. RESULTS: The distribution of 38,160,305 births between 1941 and 2010 shows important changes in trends both nationally and among the CCAA. There is a general pattern for the whole country, with 5 turning points being identified with changes in trend and annual percentage change (APC). Differences are also found among regions. CONCLUSION: The analysis of trends in birth rates and the annual rates of change should enable public health authorities to properly plan pediatric care resources in our country. PMID- 24785450 TI - [Optimized anticoagulation therapy for deep vein thrombosis with traditional constraint breakthrough]. PMID- 24785449 TI - Pharmacomicrobiomics: the impact of human microbiome variations on systems pharmacology and personalized therapeutics. AB - The Human Microbiome Project (HMP) is a global initiative undertaken to identify and characterize the collection of human-associated microorganisms at multiple anatomic sites (skin, mouth, nose, colon, vagina), and to determine how intra individual and inter-individual alterations in the microbiome influence human health, immunity, and different disease states. In this review article, we summarize the key findings and applications of the HMP that may impact pharmacology and personalized therapeutics. We propose a microbiome cloud model, reflecting the temporal and spatial uncertainty of defining an individual's microbiome composition, with examples of how intra-individual variations (such as age and mode of delivery) shape the microbiome structure. Additionally, we discuss how this microbiome cloud concept explains the difficulty to define a core human microbiome and to classify individuals according to their biome types. Detailed examples are presented on microbiome changes related to colorectal cancer, antibiotic administration, and pharmacomicrobiomics, or drug-microbiome interactions, highlighting how an improved understanding of the human microbiome, and alterations thereof, may lead to the development of novel therapeutic agents, the modification of antibiotic policies and implementation, and improved health outcomes. Finally, the prospects of a collaborative computational microbiome research initiative in Africa are discussed. PMID- 24785451 TI - [Focus on pancreatic cancer lymph node dissection]. PMID- 24785452 TI - [Analysis of clinicopathological features of 1879 cases of gastric cancer in Southern China: a single center experience]. AB - OBJECTIVE: To investigate the clinicopathological features of gastric cancer in Southern China, and provide a base of research and therapy for gastric cancer. METHODS: A total of 1 879 cases of gastric cancer with radical gastrectomy from Southern China were collected from August 1994 to July 2012. Analyze and summarize the characters of gender, age, tumor location, WHO histopathologic type and grade, pTNM stage and family history, retrospectively. RESULTS: Among all cases, male to female ratio was 2.08: 1, while female was more than male before 40 years (chi(2) = 77.831, P = 0.000). Cases aged over 60 years had a highest incidence of gastric cancer (46.0%), with predilection of sinus (45.7%), body (26.3%) and cardia (20.1%). The common WHO histopathologic types were tubular or papillary adenocarcinoma (81.5%) and signet ring cell carcinoma (11.0%). Most patients were at III or IV stage on pTNM staging (40.5% and 26.5%). CONCLUSIONS: Gastric cancer in Southern China has a predilection on male, while female is more than male before 40 years. Gastric sinus and adenocarcinoma is most common. Most patients are diagnosed at advanced stages. PMID- 24785453 TI - [Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer-a multifactorial model of 191 patients]. AB - OBJECTIVE: To identify risk factors associated with overall survival (OS) for patients undergoing primary hepatic resection for metastatic colorectal cancer. METHODS: The clinical and pathological data were prospectively collected from 191 consecutive patients undergoing primary hepatic resection for colorectal liver metastases from January 2000 to August 2012. The survival curve was drawn by Kaplan-Meier method, and the survival rates were analyzed by Log-rank test. Parametric survival analysis was used to identify predictors of cancer-specific survival. RESULTS: The 5-year overall survival were 38.4% and median survival time was 33 months; 5-year disease-free survival were 23.6%, and the median disease-free survival time was 10.0 months. 5-years survival rate was significantly lower in patients with synchronal metastasis than in patients with heterochronia metastasis (27.4% vs. 51.8%, chi(2) = 6.527, P < 0.05). In overall survival, univariate analysis found 7 risk factors: gender (chi(2) = 5.219), N stage of the primary tumor (chi(2) = 5.591), bilobar metastases (chi(2) = 4.269), number of metastases >= 2 (chi(2) = 5.051), disease-free interval >= 6 months (chi(2) = 6.527), carcinoembyonic antigen level >= 30 ug/L (chi(2) = 4.454), and extrahepatic disease (chi(2) = 5.158). On multivariate analysis, 3 risk factors were found to be independent predictors of poor survival: N stage of the primary tumor (RR = 2.198, 95%CI: 1.146-4.216), disease-free interval >= 6 months (RR = 1.840, 95%CI: 1.139-2.973), carcinoembyonic antigen level >= 30 ug/L(RR = 1.854, 95%CI: 1.056-3.255). CONCLUSIONS: Resection of liver metastases provides good long-term cancer-specific survival benefit. N stage of the primary tumor, disease free interval, carcinoembyonic antigen level are important prognostic factors for colorectal liver metastasis. PMID- 24785454 TI - [Perioperative complications and recent results of Frey procedure in the treatment of chronic pancreatitis]. AB - OBJECTIVE: To analyze the perioperative complications and recent results of the Frey procedure in the treatment of chronic pancreatitis. METHODS: Between February 2009 and September 2012, 104 patients with chronic pancreatitis underwent the Frey procedures. This study included 91 male and 13 female patients, with a mean age of (49 +/- 11) years (range, 16 to 75 years). The most common symptoms were abdominal pain in 97 patients, diarrhea in 10 patients, obstructive jaundice in 5 patients, and 5 patients had no symptoms. Nine patients had history of pancreatic surgery. RESULTS: There was no mortality. Perioperative complications occurred in 25 patients (24.0%), included pancreatic fistula in 7 patients, delayed gastric emptying in 15 patients, bleeding in 2 patients, abdominal infection in 1 patient, pulmonary infection in 2 patients, delayed healing incision in 4 patients, and pancreatic pseudocyst in 1 patient with reoperation. Seventeen patients with preoperative hyperamylasemia had a higher risk of intranperative hemorrhea and perioperative complications rates. At a mean follow-up of (29 +/- 13) months, 8 patients had missed, 2 patients had died, and 3 patients was proved to be coexisted with pancreatic carcinoma. Among 87 patients with abdominal pain, 58 patients (66.7%) have complete pain relief and 23 patients (26.4%) have substantial pain relief. However, among 5 patients without abdominal pain, 2 had recurrent abdominal pain now. Seven of 17 patients with diabetes mellitus aggravated, and new onset of diabetes mellitus was observed in 10 patients. In addition, impaired glucose tolerance was developed in 13 patients. Among 10 patients with diarrhea, the symptom of 4 patients got worse. Thirty-one patients (33.7%) newly developed exocrine insufficiency, included 12 patients treated by patients oral administration of pancreatin and 19 patients only treated by diet control. Ten patients was readmitted and 5 patients underwent reoperation, included 1 patient of pancreatic pseudocyst, 3 patients of chronic pancratitis coexisted with pancreatic carcinoma, and 1 patient of chronic pancratitis with abdominal pain and obstructive jaundice. CONCLUSIONS: Frey procedure in the treatment of chronic pancreatitis is a safe technique with low mortality and morbidity rates, but indication should be strictly controlled and pancreatic tumorigenesis should be alerted. PMID- 24785455 TI - [The optimal insertion position of the lumbar interspinous dynamic stabilization device (Coflex): a biomechanical evaluation]. AB - OBJECTIVE: To evaluate the optimal insertion position of the Coflex lumbar interspinous dynamic stabilization device. METHODS: Six fresh adult human cadaveric lumbar spine specimens (L1-L5) were mounted in a materials testing machine by embedding to clamps with L1 and L5 vertebrae. L3-4 motion segment of each specimen was operated by selective decompression and Coflex interspinous device insertion. The L3 and L4 vertebrae was inserted one needle attached with four marker points respectively, which were used to record the range of motion (ROM). Each lumbar spine specimen was tested according to the loading sequence at 5 groups: intact (keeping lumbar ligamenta and facet joints intact) group, partial destabilized (resection of L3-4 interspinous ligamenta, ligamentum flavum, facet capsule, and bilateral resection 50% of L3 inferior facets) group, 10 mm insertion (distance between apex of U-shaped Coflex and dural sac was 10 mm)group, 5 mm insertion (distance was 5 mm)group, and 0 mm insertion (distance was 0 mm)group. Each lumbar spine specimen was tested repeatedly 3 times according to a loading sequence consisting of flexion, extension, left/right lateral bending, left/right axial rotation, loaded with pure moments of 8 N.m, and was recorded the ROM of operative segment at the third time. ROM of 5 groups in 6 directions respectively were analyzed with one-way ANOVA test and multiple comparisons were based on LSD method. RESULTS: The means ROM of 5 groups were not all equal in flexion, extension, left/right lateral bending, left/right axial rotation (F = 8.472, 18.301, 7.700, 12.473, 16.809, 6.624; all P < 0.01). The 10 mm insertion group had significant high ROM in 6 directions than the intact group (t = 3.80, 3.82, 4.49, 5.60, 4.96, 2.98, all P < 0.01), but it was no difference comparing with the partial destabilized group (P > 0.05). The ROM of the 5 mm and 0 mm insertion group were no significant differences comparing with the intact group in flexion, extension, left/right axial rotation (P > 0.05), but it were significant differences comparing with the partial destabilized group in the same directions (5 mm insertion group: t = 3.19, 6.34, 5.26, 3.43, all P < 0.01; 0 mm insertion group: t = 4.21, 6.68, 5.81, 3.72, all P < 0.01). There were significant differences in the ROM of left/right lateral bending between the 5mm/0mm insertion groups and the intact group (5 mm insertion group: t = 3.71 and 5.22, all P < 0.01; 0 mm insertion group: t = 3.44 and 4.95, all P < 0.01), but there were no differences comparing with the partial destabilized group in the same directions (P > 0.05). CONCLUSIONS: The insertion of Coflex interspinous dynamic stabilization device can maintain the stability of a partially destabilized specimen back to an intact one in flexion, extension and axial rotation when distance between apex of U-shaped Coflex and dural sac was <= 5 mm, but can't return the stability in lateral bending. The Coflex can't return the stability of a partially destabilized specimen back to an intact one in 6 directions when distance between apex of U-shaped Coflex and dural sac was >= 10 mm. PMID- 24785456 TI - [Clinical outcomes of two-part lesser tuberosity fracture with locked posterior shoulder dislocation treated with modified McLaughlin procedure]. AB - OBJECTIVE: To evaluate and compare the clinical and radiographic outcomes of both acute and chronic two-part lesser tuberosity fracture with locked posterior dislocation and analyze the risk factors for the clinical outcomes. METHODS: Between April 2003 and June 2010, 29 patients received surgical treatment for two part lesser tuberosity fractures with a locked posterior shoulder dislocation. Eighteen of these patients received modified McLaughlin procedures and were available for both clinical and radiographic evaluation for more than 2 years. All of the 18 patients were male. The average age was (40 +/- 11) years (range, 21-58 years). Nine patients had left arms involved while another 9 patients got right side involved, 9 of 18 patients had their dominant side involved. The average time from initial injury to surgery was (40 +/- 42)days (range, 4-123 days). The patients received follow-up 3 months, 6 months and 1 year after the operation, and the follow-up was performed once a year. The shoulder range of motion and visual analogue scale (VAS) were recorded at the final follow-up. The functional outcomes were evaluated using University of California-Los Angeles Shoulder Scale (UCLA), Constant Score, and American Shoulder and Elbow Surgeons Shoulder Score (ASES). The degree of humeral head necrosis was analysed according to plain radiographs taken at the final follow-up. The risk factors including patients' age, dominant side involvement and time from injury to surgery on the final clinical outcomes and the degree of humeral head necrosis were also analysed using Pearson correlation analysis and Wilcoxon analysis methods. RESULTS: The mean follow-up period was (38 +/- 16) months (range, 24-72 months). All of the patients regained shoulder stability postoperatively. At the final follow-up, the average VAS was 0.6 +/- 0.9 (0-3). The average UCLA was 28 +/- 4 (23-33). The average Constant was 85 +/- 8 (71-96). The average ASES was 83 +/- 7 (75-95). The time from injury to surgery was identified as the risk factor regarding UCLA (r = 0.648, P = 0.004), Constant score (r = 0.506, P = 0.032) and ASES score (r = 0.517, P = 0.028). CONCLUSIONS: Satisfactory results can be achieved with surgical treatment for lesser tuberosity fractures with locked posterior shoulder dislocations. The time from injury to surgery has a negative impact on the clinical function outcome. PMID- 24785457 TI - [Expression of Nodal in hepatocellular carcinoma and its relationship with angiogenesis and epithelial-mesenchymal transition]. AB - OBJECTIVE: To detect the expression of Nodal in hepatocellular carcinoma (HCC), and explore its relationship with angiogenesis and epithelial-mesenchymal transition (EMT). METHODS: From September 2006 to June 2010, the 16 self-paired frozen HCC specimens were collected and the expression of Nodal was detected by qPCR and Western blot. The 10 normal liver tissues and 96 cases of HCC tumor and paracarcinomatous tissues were collected. The expression of Nodal and relationship among Nodal, clinicopathological characteristics of HCC and patients' prognosis were detected and analyzed using immunohistochemistry. The expressions of Nodal, Vimentin and CD34 in 96 HCC tumor tissues were detected by immunohistochemistry, and then judgment relationship between the expression of Nodal, EMT and angiogenesis. RESULTS: Immunohistochemistry showed that Nodal mainly expressed in the cytoplasm. The high expression rate of Nodal in HCC tumor tissues was 72.9% (70/96), which was remarkably higher than that in paracarcinomatous tissues (8.3%) and normal liver tissues (0) (chi(2) = 83.001 and 24.470, both P < 0.001). qPCR and Western blot analysis showed that the expression level of Nodal in HCC was significantly higher than that in paracarcinomatous and normal tissues (P < 0.05). The high expression of Nodal in HCC was correlated with tumor size (chi(2) = 15.318, P = 0.000), alpha fetoprotein (chi(2) = 3.850, P = 0.049), indocyanine green retention rate at 15 minutes (chi(2) = 6.590, P = 0.010), and invasion and metastasis (chi(2) = 17.824, P = 0.000). High expression of Nodal was positively correlated with high microvascular density in HCC (t = 3.070, P = 0.006), but not with Vimentin (r = 0.198, P = 0.053). Survival analysis showed that accumulated survival rate of patients with high expression of Nodal was significantly less than that the low expression (chi(2) = 487.053, P < 0.001). The Cox multivariate analysis demonstrated that high expression of Nodal was independent risk factors for cumulative survival in patients with hepatocellular carcinoma after a curative resection (RR = 2.757, 95%CI: 1.450-5.240, P = 0.002). CONCLUSIONS: Nodal does not participate in EMT of HCC, but can promote angiogenesis, and it could be used as a predictor of poor prognosis. PMID- 24785458 TI - [Roles of heme oxygenase-1 promoting regeneration of peribiliary vascular plexus in bile duct ischemia/reperfusion injury]. AB - OBJECTIVE: To study the effect of heme oxygenase-1 (HO-1) on peribiliary vascular plexus (PVP) in rat bile duct ischemia/reperfusion injury. METHODS: Total 128 male SD rats were randomly divided into saline group (Saline), empty virus group (Adv), induced group (Adv-HO-1) and suppressed group (HO-1 siRNA), and there were 32 rats in each group. Rats were injected using 0.5 ml of saline, empty adenovirus, HO-1 adenovirus and siRNA adenovirus (2*10(9) TU/rat) via the dorsal penile vein 24 hours before surgery. Liver function was analyzed at 1 hour and 1, 7, 14 days after reperfusion. HO-1, hypoxiainducible factor-1alpha (HIF-1alpha), stromal cell derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF) protein content was analyzed by Western blot. The endothelial progenitor cells (EPCs) ratio in the liver and peripheral blood was detected by flow cytometry. Small vascular around the bile duct was observed by alpha-smooth muscle actin and von Willebrand factor double immunofluorescence staining. RESULTS: Reduced liver injury and higher expression of HIF-1alpha, SDF-1alpha and VEGF in the induced group after surgery (q = 5.68-7.52, P < 0.01). EPCs ratio in the liver and peripheral blood was significantly higher in the induced group than saline group (q = 12.14 and 15.26, P < 0.01), and the suppressed group at 7 days after surgery were less than saline group significantly (q = 4.83 and 5.07, P < 0.01). In comparison to the suppressed group, higher density of small vascular around the bile duct was seen in the liver tissue of induced group. CONCLUSIONS: HO-1 can induce the expression of HIF-1alpha, SDF-1alpha and VEGF, and mobilize the release of EPCs to the peripheral from the bone marrow. EPCs migrate to the liver and promote damaged PVP repair and regeneration. PMID- 24785459 TI - [Application of miRNAs in the occurrence and early diagnosis of pancreatic cancer]. AB - OBJECTIVE: To find the potential serum specific miRNAs with diagnostic value in early pancreatic cancer and study the alteration of miRNAs levels in the process of origin and development of pancreatic cancer and discuss the diagnostic value of miRNAs in early pancreatic cancer. METHODS: DMBA-induced rat model was established. The miRNAs expression profile of early stage was screened out by microarray. And confirmation study was performed. RESULTS: The 35 and 12 abnormally expressed miRNAs were acquired in pancreatic tissue and blood respectively. There were no significant differences between normal pancreas and pancreatic cancer in expressions of hsa-let-7c, hsa-miR-122-5p, hsa-miR-142-5p, hsa-miR-199a-3p and hsa-miR-451a (P > 0.05). CONCLUSIONS: miRNAs are the potential biomarkers of early pancreatic cancer. The establishment of the miRNAs expression profile has build the foundation of exploring the molecular mechanism of origin of pancreatic cancer. PMID- 24785460 TI - [Changes of folate receptor -alpha protein expression in human gliomas and its clinical relevance]. AB - OBJECTIVE: To study the expression level of folate receptor alpha (FR-alpha) in glioma tissue and its clinical significance. METHODS: Forty-eight human glioma specimens were collected from patients who underwent surgery from March 2012 to March 2013. These specimens were as follows:12 cases of glioblastoma (WHO IV), 6 cases of astrocytoma of each malignancy grade(WHO II, III), 6 cases of oligodendroastrocytoma of each malignancy grade (WHO II, III), 6 cases of oligodendroglioma of each malignancy grade (WHO II, III ). In addition, 6 cases of normal brain tissue resected from brain traumatic patients were taken as negative control, and one case of placental tissue (had got the consent of the parents and their families) was taken as positive control. The expression level of FR-alpha in tumor tissues was evaluated by Western blot analysis. The results of Western blot analysis were analyzed by t-test. The expression level of FR alpha and Ki-67 in tumor tissues was evaluated immunohistochemistry, the results were analyzed by Kruskal-Wallis test and Nemenyi test. The correlation between the expression level of FR-alpha and cell proliferation index Ki-67 was analyzed by Pearson correlation analysis. RESULTS: Western blot analysis showed that the FR-alpha was not expressed in normal brain tissue and oligodendroglioma tissue, but highly expressed in astrocytoma, oligodendroastrocytoma and gliomablastoma. The expression level in WHO III astrocytoma was significantly higher than in WHO II (t = 4.497, P < 0.05). FR-alpha was also highly expressed in oligodendroastrocytoma and its expression level in WHO III was also significantly higher than in the WHO II (t = 2.876, P < 0.05). Foremore, immunohistochemistry analysis also showed that FR-alpha was not expressed in oligodendroglioma, but expressed in astrocytoma, oligodendroastrocytoma and gliomablastoma. The positive rate of FR-alpha of WHO III was significantly higher than the WHO II astrocytoma(57.8% +/- 2.2% vs. 45.7% +/- 2.3%,chi(2) = 3.871, P = 0.034). In oligodendroastrocytoma, the positive rate of FR-alpha of WHO III was significantly higher than the WHO II(56.5% +/- 5.4% vs. 37.1% +/- 5.2%,chi(2) = 4.454, P = 0.021). Moreover, the expression level of FR-alpha in gliomablastoma was highest in all histological types of gliomas, the positive rate of FR-alpha was up to 65.0% +/- 4.5%. Pearson correlation analysis showed that the positive rate of FR-alpha was positively correlated with Ki-67 index (r = 0.903, P < 0.05). CONCLUSIONS: FR-alpha is expressed in astrocytoma, oligodendroastrocytoma and glioblastoma, and the expression level of FR-alpha is positively correlated with malignancy grade and Ki-67 index. Therefore, FR-alpha may be applied as a special target for diagnosis and treatment of glioma. PMID- 24785461 TI - Identifying a C-terminal ATP binding sites-based novel Hsp90-Inhibitor in silico: a plausible therapeutic approach in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive brain disorder, which gradually and irreversibly destroys the intellectual and cognitive abilities of the brain. Heat shock protein 90 (Hsp90alpha) is a molecular chaperone which was found to regulate the function of number of client proteins including tau that is involved in the cause of the AD. Inhibition of Hsp90alpha by C-Terminal domain (CTD) ATP binding-site blockage might be used as an effective treatment strategy against the disease via degradation of tau proteins that are involved in the progression of the disease. Till date, a variety of drugs have been identified as Hsp90alpha inhibitors, which include Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone. However, which drug among the four binds to the CTD ATP binding site strongly and what are the specific residue responsible for such binding, have not been reported so far. HYPOTHESIS: We hypothesize that binding site for ATP of Hsp90alpha CTD contains multiple ATP binding sites. We also hypothesize that a drug which can bind to the ATP binding site of CTD strongly can inhibit Hsp90alpha function which is in turn redirects towards the proteasomal degradation of diseased client protein like tau in AD. Such inhibition will find a novel therapeutic approach in the treatment of AD. EXPERIMENTAL DESIGN: The identification of ATP binding site of Hsp90alpha CTD was done using various software tools like Hex 6.3, CastP, protein Hydrophobicity plots, ATPint and LigPlot+ v.1.4.5. Docking experiments were conducted between Hsp90alphaCTD and its inhibitors at these ATP binding site using the Autodock 4.0. The docking energies were further compared to obtain the most effective Hsp90alpha inhibitor of CTD. RESULTS: From our experiments, Leucine (Leu) 665, Leu 666 and Leu 694 were predicted to be located in CTD ATP binding site. Furthermore, docking studies were performed of various Hsp90alpha inhibitors like Novobiocin, Clorobiocin, Epigallocatechingallate (EGCG) and Derrubone with the previously recognized ATP binding residues of CTD i.e. Leu 665, Leu 666 and Leu 694. The docking results of Derrubone showed the highest binding energy at all the three sites of ATP interaction. Additionally, Derrubone showed the best binding energy at Leu 666 (-7.53kcal/mol) compared to Leu 665 (-7.20kcal/mol) and Leu 694 (-6.67kcal/mol). CONCLUSION: Based on our findings, we propose that the recognized sites i.e. Leu665, Leu 666 and Leu694 could possibly be the binding sites of Hsp90alpha CTD for ATP and the Hsp90 inhibitors. It was predicted that Derrubone could bind with CTD of Hsp90alpha strongly and resulted tau protein degradation which might be considered to be a therapeutic approach in AD. PMID- 24785462 TI - Magnetic bead-based enzyme-chromogenic substrate system for ultrasensitive colorimetric immunoassay accompanying cascade reaction for enzymatic formation of squaric acid-iron(III) chelate. AB - This work reports on a simple and feasible colorimetric immunoassay with signal amplification for sensitive determination of prostate-specific antigen (PSA, used as a model) at an ultralow concentration by using a new enzyme-chromogenic substrate system. We discovered that glucose oxidase (GOx), the enzyme broadly used in enzyme-linked immunosorbent assay (ELISA), has the ability to stimulate in situ formation of squaric acid (SQA)-iron(III) chelate. GOx-catalyzed oxidization of glucose leads to the formation of gluconic acid and hydrogen peroxide (H2O2). The latter can catalytically oxidize iron(II) to iron(III), which can rapidly (<1 min) coordinate with the SQA. Formation of the iron squarate complex causes the color of the solution to change from bluish purple to bluish red accompanying the increasing absorbance with the increment of iron(III) concentration. On the basis of the SQA-iron(III) system, a new immunoassay protocol with GOx-labeled anti-PSA detection antibody can be designed for the detection of target PSA on capture antibody-functionalized magnetic immunosensing probe, monitored by recording the color or absorbance (lambda = 468 nm) of the generated SQA-iron(III) chelate. The absorbance intensity shows to be dependent on the concentration of target PSA. A linear dependence between the absorbance and target PSA concentration is obtained under optimal conditions in the range from 1.0 pg mL(-1) to 30 ng mL(-1) with a detection limit (LOD) of 0.5 pg mL(-1) (0.5 ppt) estimated at the 3Sblank level. The sensitivity displays to be 3-5 orders of magnitude better than those of most commercialized human PSA ELISA kits. In addition, the developed colorimetric immunoassay was validated by assaying 12 human serum samples, receiving in good accordance with those obtained by the commercialized PSA ELISA kit. Importantly, the SQA-based immunosensing system can be further extended for the detection of other low-abundance proteins or biomarkers by controlling the target antibody. PMID- 24785463 TI - Effect of manual therapy techniques on headache disability in patients with tension-type headache. Randomized controlled trial. AB - BACKGROUND: Tension-type headache (TTH) is the most common type of primary headache however there is no clear evidence as to which specific treatment is most effective or whether combined treatment is more effective than individual treatments. AIM: To assess the effectiveness of manual therapy techniques, applied to the suboccipital region, on aspects of disability in a sample of patients with tension-type headache. DESIGN: Randomized Controlled Trial. SETTING: Specialized centre for headache treatment. POPULATION: Seventy-six (62 women) patients (age: 39.9 +/- 10.9 years) with episodic chronic TTH. METHODS: Patients were randomly divided into four treatment groups: 1) suboccipital soft tissue inhibition; 2) occiput-atlas-axis manipulation; 3) combined treatment of both techniques; 4) control. Four sessions were applied over 4 weeks and disability was assessed before and after treatment using the Headache Disability Inventory (HDI). Headache frequency, severity and the functional and emotional subscales of the questionnaire were assessed. Photophobia, phonophobia and pericranial tenderness were also monitored. RESULTS: Headache frequency was significantly reduced with the manipulative and combined treatment (P<0.05), and the severity and functional subscale of the HDI changed in all three treatment groups (P<0.05). Manipulation treatment also reduced the score on the emotional subscale of the HDI (P<0.05). The combined intervention showed a greater effect at reducing the overall HDI score compared to the group that received suboccipital soft tissue inhibition and to the control group (both P<0.05). In addition, photophobia, phonophobia and pericranial tenderness only improved in the group receiving combined therapy (P<0.05). CONCLUSION: When given individually, suboccipital soft tissue inhibition and occiput-atlas-axis manipulation resulted in changes in different parameters related to the disability caused by TTH. However, when the two treatments were combined, effectiveness was noted for all aspects of disability and other symptoms including photophobia, phonophobia and pericranial tenderness. CLINICAL REHABILITATION IMPACT: Although individual manual therapy treatments showed a positive change in headache features, measures of photophobia, photophobia and pericranial tenderness only improved in the group that received the combined treatment suggesting that combined treatment is the most appropriate for symptomatic relief of TTH. PMID- 24785464 TI - Blood pressure lowering, vasodilator and cardiac-modulatory potential of Carum roxburghianum seed extract. AB - In current study, we describe blood pressure (BP)-lowering, endothelium dependent, and independent vasodilator and cardio-modulatory actions of Carum roxburghianum seed. The crude extract of C. roxburghianum seed (Cr.Cr) induced dose-dependent (10-100 mg/kg) fall in arterial BP of anaesthetized rats. In isolated rabbit aorta, Cr.Cr (0.3-10 mg/mL) inhibited high K+ (80 mM) and phenylephrine (PE, 1 uM)-induced contractions, like verapamil and papaverine. In endothelium-intact rat aortic preparations, Nomega-nitro-L-arginine methyl ester hydrochloride-sensitive vasodilator activity was observed with Cr.Cr, which also relaxed endothelium-denuded aorta tissues. In guinea-pig atria, Cr.Cr initially caused mild cardiac stimulation, followed by inhibition, as shown by papaverine. These results reveal that cardiovascular effects of C. roxburghianum seed extract are mediated possibly through combination of Ca++ antagonist, nitric oxide modulating and phosphodiesterase inhibitory mechanisms, though further in-depth studies are required for elucidating precise mode of action. PMID- 24785465 TI - Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases. AB - We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound 15 possessing IC50 values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model. PMID- 24785466 TI - Are immigrants responsible for the recent decline in Australian suicide rates? AB - AIMS: This study aims to examine Queensland suicide trends in the Australian-born population and in the overseas-born populations over the past 2 decades. METHODS: All suicide cases for the period 1991-2009 were identified in the Queensland Suicide Register. Age-standardised suicide rates were calculated. Joinpoint regression and Poisson regression were applied. RESULTS: A significant decline in suicide rates of young (15-44 years) overseas-born males was reported over the past 2 decades. Australian-born young males showed significant increase until 1996, followed by a significant decline; furthermore, their suicide rates were significantly higher when compared to overseas-born (RR = 1.36, 95%CI: 1.15; 1.62). Contrary older Australian-born males (45+ years) had significantly lower suicide rates than overseas-born males (RR = 0.90, 95%CI: 0.83; 0.98). Despite the convergence of the suicide trends for older males, changes were not significant. While Australian-born females had a significant increase in suicides, overseas-born females had a decline in 1991-2009. CONCLUSION: Significantly declining suicide rates of migrants have contributed to the declining in suicide trends in Queensland. Potential reasons for significantly lower suicide rates among young migrants might include the change in the nature of migration from involuntary to voluntary. PMID- 24785467 TI - Similar 5-year clinical outcomes in patients with stable coronary artery disease and myocardial ischaemia managed with an initial approach of medical therapy compared with medical therapy plus percutaneous coronary intervention. PMID- 24785468 TI - The difference in sensitivity between HPV testing and cytology for detecting current and future CIN2+ increases over time. PMID- 24785469 TI - Blood pressure reduction in elderly patients with hypertension decreases risk of adverse cardiovascular outcomes. PMID- 24785470 TI - Benzodiazepines and opioids need to be prescribed with caution in advanced COPD. PMID- 24785471 TI - Fifty years of age-based screening: time for a new risk-based screening approach. PMID- 24785472 TI - Sum frequency generation spectroscopy study of an ionic liquid at a graphene-BaF2 (111) interface. AB - Sum frequency generation (SFG) vibrational spectroscopy and contact angle measurements of an ionic liquid, 1-butyl-3-methylimidazolium dicyanamide [BMIM][DCA], at solid-liquid interfaces are reported. Bare solid single crystal BaF2 (111) surface, a single and few layer graphene-coated BaF2 (111) surface are used as the solid substrates. The SFG results indicate that both [BMIM](+) and [DCA](-) can be detected specifically on the graphene-coated BaF2 (111) surface, without coating only [DCA](-) are observed. [DCA](-) anions are attracted to the positively charged BaF2 (111) surface and occupy the first layer at the solid liquid interface. The graphene coating shields the charged crystal surface and allows both cations and anions to exist at the interface. Furthermore, increase in the contact angle of BaF2 surface after graphene layers deposition suggests that the graphene coating lowers the surface energy. PMID- 24785473 TI - Oestrogen induced downregulation of TFPI expression is mediated by ERalpha. AB - INTRODUCTION: Oestrogens influence the pathophysiology and development of hormone sensitive cancers, such as breast cancer. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor of the extrinsic coagulation pathway and has recently been associated with breast cancer cell development. Moreover, reduced TFPI levels have been reported in plasma of healthy post-menopausal women receiving hormone replacement therapy, indicating a possible link between oestrogen and TFPI. In our study, we aimed to examine the effects of oestrogen and oestrogen analogues on TFPI expression in breast cancer cells and to identify underlying mechanism(s). METHODS: Oestrogen receptor alpha (ERalpha) positive MCF7 and negative MDA-MB-231 cells were treated with 17-beta-oestradiol, 17-beta ethinyloestradiol, raloxifene and fulvestrant. TFPI mRNA and protein was measured using qRT-PCR and ELISA, respectively. Transient ERalpha knockdown was achieved using siRNA. RESULTS: In ERalpha expressing MCF7 cells, but not in MDA-MB-231 cells, the TFPI mRNA and protein levels were significantly downregulated by more than 50% after four or six hours of incubation with 17-beta-ethinyloestradiol and 17-beta-oestradiol, respectively. Moreover, a significant increase in FXa generation was detected in response to oestrogens. Breast tissue ER antagonists, raloxifene and fulvestrant, did not affect TFPI mRNA, however, fulvestrant blocked oestrogen mediated reduction of TFPI mRNA. Transient knockdown of ERalpha abolished the oestrogenic effect on TFPI and co-treatment of MCF7 cells with the protein synthesis inhibitor cycloheximide and 17-beta-oestradiol also led to reduction of TFPI mRNA. CONCLUSION: Our data establish a direct and time dependent regulation of TFPI expression by oestrogens through the ERalpha at the transcriptional level. PMID- 24785474 TI - Etiology of lumbar lordosis and its pathophysiology: a review of the evolution of lumbar lordosis, and the mechanics and biology of lumbar degeneration. AB - The goal of this review is to discuss the mechanisms of postural degeneration, particularly the loss of lumbar lordosis commonly observed in the elderly in the context of evolution, mechanical, and biological studies of the human spine and to synthesize recent research findings to clinical management of postural malalignment. Lumbar lordosis is unique to the human spine and is necessary to facilitate our upright posture. However, decreased lumbar lordosis and increased thoracic kyphosis are hallmarks of an aging human spinal column. The unique upright posture and lordotic lumbar curvature of the human spine suggest that an understanding of the evolution of the human spinal column, and the unique anatomical features that support lumbar lordosis may provide insight into spine health and degeneration. Considering evolution of the skeleton in isolation from other scientific studies provides a limited picture for clinicians. The evolution and development of human lumbar lordosis highlight the interdependence of pelvic structure and lumbar lordosis. Studies of fossils of human lineage demonstrate a convergence on the degree of lumbar lordosis and the number of lumbar vertebrae in modern Homo sapiens. Evolution and spine mechanics research show that lumbar lordosis is dictated by pelvic incidence, spinal musculature, vertebral wedging, and disc health. The evolution, mechanics, and biology research all point to the importance of spinal posture and flexibility in supporting optimal health. However, surgical management of postural deformity has focused on restoring posture at the expense of flexibility. It is possible that the need for complex and costly spinal fixation can be eliminated by developing tools for early identification of patients at risk for postural deformities through patient history (genetics, mechanics, and environmental exposure) and tracking postural changes over time. PMID- 24785475 TI - Unilateral versus bilateral iliac screws for spinopelvic fixation: are two screws better than one? AB - OBJECT: Long-segment spinal instrumentation ending at the sacrum places substantial biomechanical stress on sacral screws. Iliac (pelvic) screws relieve some of this stress by supplementing the caudal fixation. It remains an open question whether there is any clinically significant difference in sacropelvic fixation with bilateral versus unilateral iliac screws. The primary purpose of this study was to compare clinical and radiographic complications in the use of bilateral versus unilateral iliac screw fixation. METHODS: The authors retrospectively reviewed 102 consecutive spinal fixation cases that extended to the pelvis at a single institution (University of California, San Francisco) in the period from 2005 to 2012 performed by the senior authors. Charts were reviewed for the following complications: reoperation, L5-S1 pseudarthrosis, sacral insufficiency fracture, hardware prominence, iliac screw loosening, and infection. The t-test, Pearson chi-square test, and Fisher exact test were used to determine statistical significance. RESULTS: The mean follow-up was 31 months. Thirty cases were excluded: 12 for inadequate follow-up, 15 for lack of L5-S1 interbody fusion, and 3 for preoperative osteomyelitis. The mean age among the 72 remaining cases was 62 years (range 39-79 years). Forty-six patients underwent unilateral and 26 bilateral iliac screw fixation. Forty-one percent (n = 19) of the unilateral cases and 50% (n = 13) of the bilateral cases were treated with reoperation (p = 0.48). In addition, 13% (n = 6) of the unilateral and 19% (n = 5) of the bilateral cases developed L5-S1 pseudarthrosis (p = 0.51). There were no sacral insufficiency fractures. Thirteen percent (n = 6) of the unilateral and 7.7% (n = 2) of the bilateral cases developed postoperative infection (p = 0.70). CONCLUSIONS: In a retrospective single-institution study, single versus dual pelvic screws led to comparable rates of reoperation, iliac screw removal, postoperative infection, pseudarthrosis, and sacral insufficiency fractures. For spinopelvic fixation, placing bilateral (vs unilateral) pelvic screws produced no added clinical benefit in most cases. PMID- 24785476 TI - Radiographic and clinical outcomes following combined lateral lumbar interbody fusion and posterior segmental stabilization in patients with adult degenerative scoliosis. AB - OBJECT: A hybrid approach of minimally invasive lateral lumbar interbody fusion (LLIF) followed by supplementary open posterior segmental instrumented fusion (PSIF) has shown promising early results in the treatment of adult degenerative scoliosis. Studies assessing the impact of this combined approach on correction of segmental and regional coronal angulation, sagittal realignment, maximum Cobb angle, restoration of lumbar lordosis, and clinical outcomes are needed. The authors report their results of this approach for correction of adult degenerative scoliosis. METHODS: Twenty-six patients underwent combined LLIF and PSIF in a staged fashion. The patient population consisted of 21 women and 5 men. Ages ranged from 40 to 77 years old. Radiographic measurements including coronal angulation, pelvic incidence, lumbar lordosis, and sagittal vertical axis were taken preoperatively and 1 year postoperatively in all patients. Concurrently, the visual analog score (VAS) for back and leg pain, the Oswestry Disability Index (ODI), and Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were used to assess clinical outcomes in 19 patients. RESULTS: At 1-year follow-up, all patients who underwent combined LLIF and PSIF achieved statistically significant mean improvement in regional coronal angles (from 14.9 degrees to 5.8 degrees , p < 0.01) and segmental coronal angulation at all operative levels (p < 0.01). The maximum Cobb angle was significantly reduced postoperatively (from 41.1 degrees to 15.1 degrees , p < 0.05) and was maintained at follow-up (12.0 degrees , p < 0.05). The mean lumbar lordosis-pelvic incidence mismatch was significantly improved postoperatively (from 15.0 degrees to 6.92 degrees , p < 0.05). Although regional lumbar lordosis improved (from 43.0 degrees to 48.8 degrees ), it failed to reach statistical significance (p = 0.06). The mean sagittal vertical axis was significantly improved postoperatively (from 59.5 mm to 34.2 mm, p < 0.01). The following scores improved significantly after surgery: VAS for back pain (from 7.5 to 4.3, p < 0.01) and leg pain (from 5.8 to 3.1, p < 0.01), ODI (from 48 to 38, p < 0.01), and PCS (from 27.5 to 35.0, p = 0.01); the MCS score did not improve significantly (from 43.2 to 45.5, p = 0.37). There were 3 major and 10 minor complications. CONCLUSIONS: A hybrid approach of minimally invasive LLIF and open PSIF is an effective means of achieving correction of both coronal and sagittal deformity, resulting in improvement of quality of life in patients with adult degenerative scoliosis. PMID- 24785477 TI - Less invasive surgery for treating adult spinal deformities: ceiling effects for deformity correction with 3 different techniques. AB - OBJECT: Minimally invasive surgery (MIS) options for the treatment of adult spinal deformity (ASD) have advanced significantly over the past decade. However, a wide array of options have been described as being MIS or less invasive. In this study the authors investigated a multiinstitutional cohort of patients with ASD who were treated with less invasive methods to determine the extent of deformity correction achieved. METHODS: This study was a retrospective review of multicenter prospectively collected data in 85 consecutive patients with ASD undergoing MIS surgery. Inclusion criteria were as follows: age older than 45 years; minimum 20 degrees coronal lumbar Cobb angle; and 1 year of follow-up. Procedures were classified as follows: 1) stand-alone (n = 7); 2) circumferential MIS (n = 43); or 3) hybrid (n = 35). RESULTS: An average of 4.2 discs (range 3-7) were fused, with a mean follow-up duration of 26.1 months in this study. For the stand-alone group the preoperative Cobb range was 22 degrees -51 degrees , with 57% greater than 30 degrees and 28.6% greater than 50 degrees . The mean Cobb angle improved from 35.7 degrees to 30 degrees . A ceiling effect of 23 degrees for curve correction was observed, regardless of preoperative curve severity. For the circumferential MIS group the preoperative Cobb range was 19 degrees -62 degrees , with 44% greater than 30 degrees and 5% greater than 50 degrees . The mean Cobb angle improved from 32 degrees to 12 degrees . A ceiling effect of 34 degrees for curve correction was observed. For the hybrid group the preoperative Cobb range was 23 degrees -82 degrees , with 74% greater than 30 degrees and 23% greater than 50 degrees . The mean Cobb angle improved from 43 degrees to 15 degrees . A ceiling effect of 55 degrees for curve correction was observed. CONCLUSIONS: Specific procedures for treating ASD have particular limitations for scoliotic curve correction. Less invasive techniques were associated with a reduced ability to straighten the spine, particularly with advanced curves. These data can guide preoperative technique selection when treating patients with ASD. PMID- 24785478 TI - Comparison of radiographic results after minimally invasive, hybrid, and open surgery for adult spinal deformity: a multicenter study of 184 patients. AB - OBJECT: Various surgical approaches, including open, minimally invasive, and hybrid techniques, have gained momentum in the management of adult spinal deformity. However, few data exist on the radiographic outcomes of different surgical techniques. The objective of this study was to compare the radiographic and clinical outcomes of the surgical techniques used in the treatment of adult spinal deformity. METHODS: The authors conducted a retrospective review of two adult spinal deformity patient databases, a prospective open surgery database and a retrospective minimally invasive surgery (MIS) and hybrid surgery database. The time frame of enrollment in this study was from 2007 to 2012. Spinal deformity patients were stratified into 3 surgery groups: MIS, hybrid surgery, and open surgery. The following pre- and postoperative radiographic parameters were assessed: lumbar major Cobb angle, lumbar lordosis, pelvic incidence minus lumbar lordosis (PI-LL), sagittal vertical axis, and pelvic tilt. Scores on the Oswestry Disability Index (ODI) and a visual analog scale (VAS) for both back and leg pain were also obtained from each patient. RESULTS: Of the 234 patients with adult spinal deformity, 184 patients had pre- and postoperative radiographs and were thus included in the study (MIS, n = 42; hybrid, n = 33; open, n = 109). Patients were a mean of 61.7 years old and had a mean body mass index of 26.9 kg/m(2). Regarding radiographic outcomes, the MIS group maintained a significantly smaller mean lumbar Cobb angle (13.1 degrees ) after surgery compared with the open group (20.4 degrees , p = 0.002), while the hybrid group had a significantly larger lumbar curve correction (26.6 degrees ) compared with the MIS group (18.8 degrees , p = 0.045). The mean change in the PI-LL was larger for the hybrid group (20.6 degrees ) compared with the open (10.2 degrees , p = 0.023) and MIS groups (5.5 degrees , p = 0.003). The mean sagittal vertical axis correction was greater for the open group (25 mm) compared with the MIS group (<= 1 mm, p = 0.008). Patients in the open group had a significantly larger postoperative thoracic kyphosis (41.45 degrees ) compared with the MIS patients (33.5 degrees , p = 0.005). There were no significant differences between groups in terms of pre- and postoperative mean ODI and VAS scores at the 1-year follow-up. However, patients in the MIS group had much lower estimated blood loss and transfusion rates compared with patients in the hybrid or open groups (p < 0.001). Operating room time was significantly longer with the hybrid group compared with the MIS and open groups (p < 0.001). Major complications occurred in 14% of patients in the MIS group, 14% in the hybrid group, and 45% in the open group (p = 0.032). CONCLUSIONS: This study provides valuable baseline characteristics of radiographic parameters among 3 different surgical techniques used in the treatment of adult spinal deformity. Each technique has advantages, but much like any surgical technique, the positive and negative elements must be considered when tailoring a treatment to a patient. Minimally invasive surgical techniques can result in clinical outcomes at 1 year comparable to those obtained from hybrid and open surgical techniques. PMID- 24785479 TI - Limitations and ceiling effects with circumferential minimally invasive correction techniques for adult scoliosis: analysis of radiological outcomes over a 7-year experience. AB - OBJECT: Minimally invasive correction of adult scoliosis is a surgical method increasing in popularity. Limited data exist, however, as to how effective these methodologies are in achieving coronal plane and sagittal plane correction in addition to improving spinopelvic parameters. This study serves to quantify how much correction is possible with present circumferential minimally invasive surgical (cMIS) methods. METHODS: Ninety patients were selected from a database of 187 patients who underwent cMIS scoliosis correction. All patients had a Cobb angle greater than 15 degrees , 3 or more levels fused, and availability of preoperative and postoperative 36-inch standing radiographs. The mean duration of follow-up was 37 months. Preoperative and postoperative Cobb angle, sagittal vertical axis (SVA), coronal balance, lumbar lordosis (LL), and pelvic incidence (PI) were measured. Scatter plots were performed comparing the pre- and postoperative radiological parameters to calculate ceiling effects for SVA correction, Cobb angle correction, and PI-LL mismatch correction. RESULTS: The mean preoperative SVA value was 60 mm (range 11.5-151 mm); the mean postoperative value was 31 mm (range 0-84 mm). The maximum SVA correction achieved with cMIS techniques in any of the cases was 89 mm. In terms of coronal Cobb angle, a mean correction of 61% was noted, with a mean preoperative value of 35.8 degrees (range 15 degrees -74.7 degrees ) and a mean postoperative value of 13.9 degrees (range 0 degrees -32.5 degrees ). A ceiling effect for Cobb angle correction was noted at 42 degrees . The ability to correct the PI-LL mismatch to 10 degrees was limited to cases in which the preoperative PI-LL mismatch was 38 degrees or less. CONCLUSIONS: Circumferential MIS techniques as currently used for the treatment of adult scoliosis have limitations in terms of their ability to achieve SVA correction and lumbar lordosis. When the preoperative SVA is greater than 100 mm and a substantial amount of lumbar lordosis is needed, as determined by spinopelvic parameter calculations, surgeons should consider osteotomies or other techniques that may achieve more lordosis. PMID- 24785480 TI - Complications in adult spinal deformity surgery: an analysis of minimally invasive, hybrid, and open surgical techniques. AB - OBJECT: It is hypothesized that minimally invasive surgical techniques lead to fewer complications than open surgery for adult spinal deformity (ASD). The goal of this study was to analyze matched patient cohorts in an attempt to isolate the impact of approach on adverse events. METHODS: Two multicenter databases queried for patients with ASD treated via surgery and at least 1 year of follow-up revealed 280 patients who had undergone minimally invasive surgery (MIS) or a hybrid procedure (HYB; n = 85) or open surgery (OPEN; n = 195). These patients were divided into 3 separate groups based on the approach performed and were propensity matched for age, preoperative sagittal vertebral axis (SVA), number of levels fused posteriorly, and lumbar coronal Cobb angle (CCA) in an attempt to neutralize these patient variables and to make conclusions based on approach only. Inclusion criteria for both databases were similar, and inclusion criteria specific to this study consisted of an age > 45 years, CCA > 20 degrees , 3 or more levels of fusion, and minimum of 1 year of follow-up. Patients in the OPEN group with a thoracic CCA > 75 degrees were excluded to further ensure a more homogeneous patient population. RESULTS: In all, 60 matched patients were available for analysis (MIS = 20, HYB = 20, OPEN = 20). Blood loss was less in the MIS group than in the HYB and OPEN groups, but a significant difference was only found between the MIS and the OPEN group (669 vs 2322 ml, p = 0.001). The MIS and HYB groups had more fused interbody levels (4.5 and 4.1, respectively) than the OPEN group (1.6, p < 0.001). The OPEN group had less operative time than either the MIS or HYB group, but it was only statistically different from the HYB group (367 vs 665 minutes, p < 0.001). There was no significant difference in the duration of hospital stay among the groups. In patients with complete data, the overall complication rate was 45.5% (25 of 55). There was no significant difference in the total complication rate among the MIS, HYB, and OPEN groups (30%, 47%, and 63%, respectively; p = 0.147). No intraoperative complications were reported for the MIS group, 5.3% for the HYB group, and 25% for the OPEN group (p < 0.03). At least one postoperative complication occurred in 30%, 47%, and 50% (p = 0.40) of the MIS, HYB, and OPEN groups, respectively. One major complication occurred in 30%, 47%, and 63% (p = 0.147) of the MIS, HYB, and OPEN groups, respectively. All patients had significant improvement in both the Oswestry Disability Index (ODI) and visual analog scale scores after surgery (p < 0.001), although the MIS group did not have significant improvement in leg pain. The occurrence of complications had no impact on the ODI. CONCLUSIONS: Results in this study suggest that the surgical approach may impact complications. The MIS group had significantly fewer intraoperative complications than did either the HYB or OPEN groups. If the goals of ASD surgery can be achieved, consideration should be given to less invasive techniques. PMID- 24785481 TI - Editorial: Comparing minimally invasive, hybrid, and open surgical techniques for adult spinal deformity. PMID- 24785482 TI - Evaluation of complications and neurological deficits with three-column spine reconstructions for complex spinal deformity: a retrospective Scoli-RISK-1 study. AB - OBJECT: The goal in this study was to evaluate the risk factors for complications, including new neurological deficits, in the largest cohort of patients with adult spinal deformity to date. METHODS: The Scoli-RISK-1 inclusion criteria were used to identify eligible patients from 5 centers who were treated between June 1, 2009, and June 1, 2011. Records were reviewed for patient demographic information, surgical data, and reports of perioperative complications. Neurological deficits were recorded as preexisting or as new deficits. Patients who underwent 3-column osteotomies (3COs) were compared with those who did not (posterior spinal fusion [PSF]). Between-group comparisons were performed using independent samples t-tests and chi-square analyses. RESULTS: Two hundred seven patients were identified-75 who underwent PSF and 132 treated with 3CO. In the latter group, patients were older (58.9 vs 49.4 years, p < 0.001), had a higher body mass index (29.0 vs 25.8, p = 0.029), smaller preoperative coronal Cobb measurements (33.8 degrees vs 56.4 degrees , p < 0.001), more preoperative sagittal malalignment (11.7 cm vs 5.4 cm, p < 0.001), and similar sagittal Cobb measurements (45.8 degrees vs 57.7 degrees , p = 0.113). Operating times were similar (393 vs 423 minutes, p = 0.130), although patients in the 3CO group sustained higher estimated blood loss (2120 vs 1700 ml, p = 0.066). Rates of new neurological deficits were similar (PSF: 6.7% vs 3CO: 9.9%, p = 0.389), and rates of any perioperative medical complication were similar (PSF: 46.7% vs 3CO: 50.8%, p = 0.571). Patients who underwent vertebral column resection (VCR) were more likely to sustain medical complications than those treated with pedicle subtraction osteotomy (73.7% vs 46.9%, p = 0.031), although new neurological deficits were similar (15.8% vs 8.8%, p = 0.348). Regression analysis did not reveal significant predictors of neurological injury or complication from collected data. CONCLUSIONS: Despite higher estimated blood loss, rates of all complications (49.3%) and new neurological deficits (8.7%) did not vary for patients who underwent complex reconstruction, whether or not a 3CO was performed. Patients who underwent VCR sustained more medical complications without an increase in new neurological deficits. Prospective studies of patient factors, provider factors, and refined surgical data are needed to define and optimize risk factors for complication and neurological deficits. PMID- 24785483 TI - Complications and intercenter variability of three-column osteotomies for spinal deformity surgery: a retrospective review of 423 patients. AB - OBJECT: Three-column resection osteotomies (3COs) are commonly performed for sagittal deformity but have high rates of reported complications. Authors of this study aimed to examine the incidence of and intercenter variability in major intraoperative complications (IOCs), major postoperative complications (POCs) up to 6 weeks postsurgery, and overall complications (that is, both IOCs and POCs). They also aimed to investigate the incidence of and intercenter variability in blood loss during 3CO procedures. METHODS: The incidence of IOCs, POCs, and overall complications associated with 3COs were retrospectively determined for the study population and for each of 8 participating surgical centers. The incidence of major blood loss (MBL) over 4 L and the percentage of total blood volume lost were also determined for the study population and each surgical center. Complication rates and blood loss were compared between patients with one and those with two osteotomies, as well as between patients with one thoracic osteotomy (ThO) and those with one lumbar or sacral osteotomy (LSO). Risk factors for developing complications were determined. RESULTS: Retrospective review of prospectively acquired data for 423 consecutive patients who had undergone 3CO at 8 surgical centers was performed. The incidence of major IOCs, POCs, and overall complications was 7%, 39%, and 42%, respectively, for the study population overall. The most common IOC was spinal cord deficit (2.6%) and the most common POC was unplanned return to the operating room (19.4%). Patients with two osteotomies had more POCs (56% vs 38%, p = 0.04) than the patients with one osteotomy. Those with ThO had more IOCs (16% vs 6%, p = 0.03), POCs (58% vs 34%, p < 0.01), and overall complications (67% vs 37%, p < 0.01) than the patients with LSO. There was significant variation in the incidence of IOCs, POCs, and overall complications among the 8 sites (p < 0.01). The incidence of MBL was 24% for the study population, which varied significantly between sites (p < 0.01). Patients with MBL had a higher risk of IOCs, POCs, and overall complications (OR 2.15, 1.76, and 2.01, respectively). The average percentage of total blood volume lost was 55% for the study population, which also varied among sites (p < 0.01). CONCLUSIONS: Given the complexity of 3COs for spinal deformity, it is important for spine surgeons to understand the risk factors and complication rates associated with these procedures. In this study, the overall incidence of major complications following 3CO procedures was 42%. Risks for developing complications included an older age (> 60 years), two osteotomies, ThO, and MBL. PMID- 24785484 TI - Clinical improvement through nonoperative treatment of adult spinal deformity: who is likely to benefit? AB - OBJECT: The goal of this study was to determine the outcome and risk factors in patients with adult spinal deformity (ASD) who elected to receive nonoperative care. METHODS: In this retrospective study the authors reviewed a nonoperative branch of the International Spine Study Group database, derived from 10 sites across the US. Specific inclusion criteria included nonoperative treatment for ASD and the availability of Scoliosis Research Society (SRS)-22 scores and radiographic data at baseline (BL) and at 1-year (1Y) follow-up. Health-related quality of life measures were assessed using the SRS-22 and radiographic data. Changes in SRS-22 scores were evaluated by domain and expressed in number of minimum clinically important differences (MCIDs) gained or lost; BL and 1Y scores were also compared with age- and sex-matched normative references. RESULTS: One hundred eighty-nine patients (mean age 53 years, 86% female) met inclusion criteria. Pain was the domain with the largest offset for 43% of patients, followed by the Appearance (23%), Activity (18%), and Mental (15%) domains. On average, patients improved 0.3 MCID in Pain over 1Y, without changes in Activity or Appearance. Baseline scores significantly impacted 1Y outcomes, with up to 85% of patients in the mildest category of deformity being classified as < 1 MCID of normative reference at 1Y, versus 0% of patients with the most severe initial deformity. Baseline radiographic parameters did not correlate with outcome. CONCLUSIONS: Patients who received nonoperative care are significantly more disabled than age- and sex-matched normative references. The likelihood for a patient to reach SRS scores similar to the normative reference at 1Y decreases with increased BL disability. Nonoperative treatment is a viable option for certain patients with ASD, and up to 24% of patients demonstrated significant improvement over 1Y with nonoperative care. PMID- 24785485 TI - Incremental cost-effectiveness of adult spinal deformity surgery: observed quality-adjusted life years with surgery compared with predicted quality-adjusted life years without surgery. AB - OBJECT: Incremental cost-effectiveness analysis is critical to the efficient allocation of health care resources; however, the incremental cost-effectiveness ratio (ICER) of surgical versus nonsurgical treatment for adult spinal deformity (ASD) has eluded the literature, due in part to inherent empirical difficulties when comparing surgical and nonsurgical patients. Using observed preoperative health-related quality of life (HRQOL) for patients who later underwent surgery, this study builds a statistical model to predict hypothetical quality-adjusted life years (QALYs) without surgical treatment. The analysis compares predicted QALYs to observed postoperative QALYs and forms the resulting ICER. METHODS: This was a single-center (Baylor Scoliosis Center) retrospective analysis of consecutive patients undergoing primary surgery for ASD. Total costs (expressed in 2010 dollars) incurred by the hospital for each episode of surgical care were collected from administrative data and QALYs were calculated from the 6 dimensional Short-Form Health Survey, each discounted at 3.5% per year. Regression analysis was used to predict hypothetical QALYs without surgery based on preoperative longitudinal data for 124 crossover surgical patients with similar diagnoses, baseline HRQOL, age, and sex compared with the surgical cohort. Results were projected through 10-year follow-up, and the cost effectiveness acceptability curve (CEAC) was estimated using nonparametric bootstrap methods. RESULTS: Three-year follow-up was available for 120 (66%) of 181 eligible patients, who were predominantly female (89%) with average age of 50. With discounting, total costs averaged $125,407, including readmissions, with average QALYs of 1.93 at 3-year follow-up. Average QALYs without surgery were predicted to be 1.6 after 3 years. At 3- and 5-year follow-up, the ICER was $375,000 and $198,000, respectively. Projecting through 10-year follow-up, the ICER was $80,000. The 10-year CEAC revealed a 40% probability that the ICER was $80,000 or less, a 90% probability that the ICER was $90,000 or less, and a 100% probability that the ICER was less than $100,000. CONCLUSIONS: Based on the WHO's suggested upper threshold for cost-effectiveness (3 times per capita GDP, or $140,000 in 2010 dollars), the analysis reveals that surgical treatment for ASD is cost-effective after a 10-year period based on predicted deterioration in HRQOL without surgery. The ICER well exceeds the WHO threshold at earlier follow up intervals, highlighting the importance of the durability of surgical treatment in assessing the value of surgical intervention. Due to the study's methodology, the results are dependent on the predicted deterioration in HRQOL without surgery. As such, the results may not extend to patients whose HRQOL would remain steady without surgery. Future research should therefore pursue a direct comparison of QALYs for surgical and nonsurgical patients to better understand the cost-effectiveness of surgery for the average ASD patient. PMID- 24785486 TI - Editorial: Incremental cost-effectiveness of adult spinal deformity surgery. PMID- 24785487 TI - An algorithmic strategy for selecting a surgical approach in cervical deformity correction. AB - Adult degenerative cervical kyphosis is a debilitating disease that often requires complex surgical management. Young spine surgeons, residents, and fellows are often confused as to which surgical approach to choose due to lack of experience, absence of a systematic method of surgical management, and today's plethora of information regarding surgical techniques. Although surgeons may be able to perform anterior, posterior, or combined (360 degrees ) approaches to the cervical spine, many struggle to rationally choose an appropriate approach for deformity correction. The authors introduce an algorithm based on morphology and pathology of adult cervical kyphosis to help the surgeon select the appropriate approach when performing cervical deformity surgery. Cervical deformities are categorized into 5 different prevalent morphological types encountered in clinical settings. A surgical approach tailored to each category/type of deformity is then discussed, with a concrete case illustration provided for each. Preoperative assessment of kyphosis, determination of the goal for surgery, and the complications associated with cervical deformity correction are also summarized. This article's goal is to assist with understanding the big picture for surgical management in cervical spinal deformity. PMID- 24785488 TI - The minimally invasive spinal deformity surgery algorithm: a reproducible rational framework for decision making in minimally invasive spinal deformity surgery. AB - OBJECT: Minimally invasive surgery (MIS) is an alternative to open deformity surgery for the treatment of patients with adult spinal deformity. However, at this time MIS techniques are not as versatile as open deformity techniques, and MIS techniques have been reported to result in suboptimal sagittal plane correction or pseudarthrosis when used for severe deformities. The minimally invasive spinal deformity surgery (MISDEF) algorithm was created to provide a framework for rational decision making for surgeons who are considering MIS versus open spine surgery. METHODS: A team of experienced spinal deformity surgeons developed the MISDEF algorithm that incorporates a patient's preoperative radiographic parameters and leads to one of 3 general plans ranging from MIS direct or indirect decompression to open deformity surgery with osteotomies. The authors surveyed fellowship-trained spine surgeons experienced with spinal deformity surgery to validate the algorithm using a set of 20 cases to establish interobserver reliability. They then resurveyed the same surgeons 2 months later with the same cases presented in a different sequence to establish intraobserver reliability. Responses were collected and tabulated. Fleiss' analysis was performed using MATLAB software. RESULTS: Over a 3-month period, 11 surgeons completed the surveys. Responses for MISDEF algorithm case review demonstrated an interobserver kappa of 0.58 for the first round of surveys and an interobserver kappa of 0.69 for the second round of surveys, consistent with substantial agreement. In at least 10 cases there was perfect agreement between the reviewing surgeons. The mean intraobserver kappa for the 2 surveys was 0.86 +/- 0.15 (+/- SD) and ranged from 0.62 to 1. CONCLUSIONS: The use of the MISDEF algorithm provides consistent and straightforward guidance for surgeons who are considering either an MIS or an open approach for the treatment of patients with adult spinal deformity. The MISDEF algorithm was found to have substantial inter- and intraobserver agreement. Although further studies are needed, the application of this algorithm could provide a platform for surgeons to achieve the desired goals of surgery. PMID- 24785489 TI - Minimally invasive spine surgery for adult degenerative lumbar scoliosis. AB - OBJECT: Historically, adult degenerative lumbar scoliosis (DLS) has been treated with multilevel decompression and instrumented fusion to reduce neural compression and stabilize the spinal column. However, due to the profound morbidity associated with complex multilevel surgery, particularly in elderly patients and those with multiple medical comorbidities, minimally invasive surgical approaches have been proposed. The goal of this meta-analysis was to review the differences in patient selection for minimally invasive surgical versus open surgical procedures for adult DLS, and to compare the postoperative outcomes following minimally invasive surgery (MIS) and open surgery. METHODS: In this meta-analysis the authors analyzed the complication rates and the clinical outcomes for patients with adult DLS undergoing complex decompressive procedures with fusion versus minimally invasive surgical approaches. Minimally invasive surgical approaches included decompressive laminectomy, microscopic decompression, lateral and extreme lateral interbody fusion (XLIF), and percutaneous pedicle screw placement for fusion. Mean patient age, complication rates, reoperation rates, Cobb angle, and measures of sagittal balance were investigated and compared between groups. RESULTS: Twelve studies were identified for comparison in the MIS group, with 8 studies describing the lateral interbody fusion or XLIF and 4 studies describing decompression without fusion. In the decompression MIS group, the mean preoperative Cobb angle was 16.7 degrees and mean postoperative Cobb angle was 18 degrees . In the XLIF group, mean pre- and postoperative Cobb angles were 22.3 degrees and 9.2 degrees , respectively. The difference in postoperative Cobb angle was statistically significant between groups on 1-way ANOVA (p = 0.014). Mean preoperative Cobb angle, mean patient age, and complication rate did not differ between the XLIF and decompression groups. Thirty-five studies were identified for inclusion in the open surgery group, with 18 studies describing patients with open fusion without osteotomy and 17 papers detailing outcomes after open fusion with osteotomy. Mean preoperative curve in the open fusion without osteotomy and with osteotomy groups was 41.3 degrees and 32 degrees , respectively. Mean reoperation rate was significantly higher in the osteotomy group (p = 0.008). On 1-way ANOVA comparing all groups, there was a statistically significant difference in mean age (p = 0.004) and mean preoperative curve (p = 0.002). There was no statistically significant difference in complication rates between groups (p = 0.28). CONCLUSIONS: The results of this study suggest that surgeons are offering patients open surgery or MIS depending on their age and the severity of their deformity. Greater sagittal and coronal correction was noted in the XLIF versus decompression only MIS groups. Larger Cobb angles, greater sagittal imbalance, and higher reoperation rates were found in studies reporting the use of open fusion with osteotomy. Although complication rates did not significantly differ between groups, these data are difficult to interpret given the heterogeneity in reporting complications between studies. PMID- 24785490 TI - The axial transsacral approach to interbody fusion at L5-S1. AB - Lumbosacral interbody fusion may be indicated to treat degenerative disc disease at L5-S1, instability or spondylolisthesis at that level, and severe neural foraminal stenosis resulting from loss of disc space height. In addition, L5-S1 interbody fusion may provide anterior support to a long posterior fusion construct and help offset the stresses experienced by the distal-most screws. There are 3 well-established techniques for L5-S1 interbody fusion: anterior lumbar interbody fusion, posterior lumbar interbody fusion, and transforaminal lumbar interbody fusion. Each of these has advantages and pitfalls. A more recently described axial transsacral technique, utilizing the presacral corridor, may represent a minimally invasive approach to obtaining lumbosacral interbody arthrodesis. Biomechanical studies demonstrate that the stiffness of the axial rod is comparable to existing fixation devices, suggesting that, biomechanically, it may be a good implant for obtaining lumbosacral interbody fusion. Clinical studies have demonstrated good early results with the use of the axial transsacral approach in obtaining lumbosacral interbody fusion for degenerative disc disease, spondylolisthesis, and below long posterior fusion constructs. The technique is exacting and complications can be major, including rectal perforation and fistula, loss of correction, and pseudarthrosis. PMID- 24785491 TI - Long fusion from sacrum to thoracic spine for adult spinal deformity with sagittal imbalance: upper versus lower thoracic spine as site of upper instrumented vertebra. AB - OBJECT: Despite increasing numbers of patients with adult spinal deformity, it is unclear how to select the optimal upper instrumented vertebra (UIV) in long fusion surgery for these patients. The purpose of this study was to compare the use of vertebrae in the upper thoracic (UT) versus lower thoracic (LT) spine as the upper instrumented vertebra in long fusion surgery for adult spinal deformity. METHODS: Patients who underwent fusion from the sacrum to the thoracic spine for adult spinal deformity with sagittal imbalance at a single medical center were studied. The patients with a sagittal vertical axis (SVA) >= 40 mm who had radiographs and completed the 12-item Short-Form Health Survey (SF-12) preoperatively and at final follow-up (>= 2 years postoperatively) were included. RESULTS: Eighty patients (mean age of 61.1 +/- 10.9 years; 69 women and 11 men) met the inclusion criteria. There were 31 patients in the UT group and 49 patients in the LT group. The mean follow-up period was 3.6 +/- 1.6 years. The physical component summary (PCS) score of the SF-12 significantly improved from the preoperative assessment to final follow-up in each group (UT, 34 to 41; LT, 29 to 37; p = 0.001). This improvement reached the minimum clinically important difference in both groups. There was no significant difference in PCS score improvement between the 2 groups (p = 0.8). The UT group had significantly greater preoperative lumbar lordosis (28 degrees vs 18 degrees , p = 0.03) and greater thoracic kyphosis (36 degrees vs 18 degrees , p = 0.001). After surgery, there was no significant difference in lumbar lordosis or thoracic kyphosis. The UT group had significantly greater postoperative cervicothoracic kyphosis (20 degrees vs 11 degrees , p = 0.009). The UT group tended to maintain a smaller positive SVA (51 vs 73 mm, p = 0.08) and smaller T-1 spinopelvic inclination ( 2.6 degrees vs 0.6 degrees , p = 0.06). The LT group tended to have more proximal junctional kyphosis (PJK), although the difference did not reach statistical significance. Radiographic PJK was 32% in the UT group and 41% in the LT group (p = 0.4). Surgical PJK was 6.4% in the UT group and 10% in the LT group (p = 0.6). CONCLUSIONS: Both the UT and LT groups demonstrated significant improvement in clinical and radiographic outcomes. A significant difference was not observed in improvement of clinical outcomes between the 2 groups. PMID- 24785492 TI - Introduction: Adult spinal deformity: pathophysiology and corrective measures. PMID- 24785493 TI - Deletion of the nuclear localization sequences and C-terminus of PTHrP impairs embryonic mammary development but also inhibits PTHrP production. AB - Parathyroid hormone-related protein (PTHrP) can be secreted from cells and interact with its receptor, the Type 1 PTH/PTHrP Receptor (PTHR1) in an autocrine, paracrine or endocrine fashion. PTHrP can also remain inside cells and be transported into the nucleus, where its functions are unclear, although recent experiments suggest that it may broadly regulate cell survival and senescence. Disruption of either the PTHrP or PTHR1 gene results in many abnormalities including a failure of embryonic mammary gland development in mice and in humans. In order to examine the potential functions of nuclear PTHrP in the breast, we examined mammary gland development in PTHrP (1-84) knock-in mice, which express a mutant form of PTHrP that lacks the C-terminus and nuclear localization signals and which can be secreted but cannot enter the nucleus. Interestingly, we found that PTHrP (1-84) knock-in mice had defects in mammary mesenchyme differentiation and mammary duct outgrowth that were nearly identical to those previously described in PTHrP-/- and PTHR1-/- mice. However, the mammary buds in PTHrP (1 84) knock-in mice had severe reductions in mutant PTHrP mRNA levels, suggesting that the developmental defects were due to insufficient production of PTHrP by mammary epithelial cells and not loss of PTHrP nuclear function. Examination of the effects of nuclear PTHrP in the mammary gland in vivo will require the development of alternative animal models. PMID- 24785494 TI - Failure to learn a new spatial format in children with developmental dyslexia. AB - A general problem in studying children with developmental dyslexia is how to separate inefficiency in learning on the one hand from exposure to written texts on the other. To evaluate dyslexic children's learning abilities with graphemic materials, we tested their improvement in a condition that minimized previous experience with words (i.e., "novel words") and with the standard, horizontal spatial letter array (i.e., a non-canonical "zigzag" format). We selected five pairs of children with dyslexia and (younger) typically developing readers matched for reading speed and accuracy in these specific conditions. Reading performance on novel words in the zigzag format was measured in 23 sessions; learning curves were fitted by power functions. Similar to typically developing readers, children with dyslexia improved their reading of novel words presented in the new format; however, their rate of learning was slower than that of typically developing readers. Furthermore, their learning to read in the new format did not generalize to novel untrained items, whereas significant generalization was present in typically developing readers. As the failure to generalize learning of the spatial format could not be attributed to reduced experience, it indicates a genuine disability and points to impaired perceptual learning as a factor in developmental dyslexia. PMID- 24785495 TI - Assessing quality of raw milk in southern Greece in the aspect of certain benzimidazole residues. AB - Benzimidazoles are veterinary drugs widely used against endoparasites in food producing animals. Albendazole (ABZ), a benzimidazole, is believed to cause embryotoxicity, teratogenicity and other adverse health effects. This study assessed the residue levels of ABZ and its two major metabolites, the sulfoxide (ABZ-SO) and sulfone (ABZ-SO2), in raw milk samples collected from farms in southern Greece during the spring and autumn of 2008. Analysis was performed by HPLC using a diode array detector. A total of 16% of the 89 samples examined were positive for ABZ metabolites in the range 11-70 ng ml(-1), but the parent compound was not detected in any sample. A geographical variation in positive samples was observed, but season or milk type (ovine, bovine, goat) was unrelated to the presence of residues. Considering the lipophilic character of these substances and the possibility of higher concentrations in dairy foods, we suggest greater controlled usage of these drugs. PMID- 24785496 TI - Survey of iron, zinc, calcium, copper, lead, and cadmium in rice samples grown in Iran. AB - In the present study ninety nine polished white rice samples were collected in three areas, all over Lorestan Province located in the west of Iran, and analysed for six elements by Flame Atomic Absorption Spectrometry (FAAS). For individual elements, Zinc (Zn) showed the highest concentration among the analysed essential elements with a mean of 28.6 mg kg(-1) and next to copper (Cu) of 22.8 mg kg(-1). Analysis of the essential and toxic elements for possible inter-area variation by ANOVA showed that there are significant differences between the areas. There was no significant difference between areas for Zn concentrations. Most of the samples nearly contained world wide average concentration of iron (Fe) and Zn in rice grains that were reported by various researches. But, the content of calcium (Ca) in the rice samples produced in Lorestan Province were much lower than other countries, meanwhile Cu concentrations were much higher than other studies. Cadmium (Cd) and Lead (Pb) concentrations in the sampled rice were lower in comparison with their upper limits (0.1 and 0.2 mg kg(-1) for Cd and Pb, respectively) approved by Iranian Ministry of Health. Therefore, it can be concluded that there is no health problems result from Lorestan rice consumption, for these two elements. PMID- 24785497 TI - Survey of total mercury in foods from Taiwan containing red mould rice (Monascus) using a direct mercury analyser (DMA). AB - Total mercury concentrations in 69 red mould rice (Monascus) food samples purchased in Taipei, Taiwan, were determined using the direct mercury analyser (DMA) method. The highest mean levels of total mercury in these samples were observed in samples of canned roast eel (20 ug kg(-1)), soy fibrous product (14 ug kg(-1)), red mould rice (8.5 ug kg(-1)), cereal (7.6 ug kg(-1)), dried pork fibre (7.5 ug kg(-1)), and dietary supplement (7.2 ug kg(-1)). All samples analysed had mercury levels below the limit of 50 ug kg(-1) for food standards in rice, edible oil, and fat of Taiwan. The mercury concentration in the Monascus foods differed widely between different food varieties, suggesting that external contamination and raw materials are the main sources of mercury. This study shows that DMA is a simple method proposed for the determination of total mercury in foods containing Monascus. The method requires no sample pre-treatment, and it minimizes potential sources of contamination. The data (42+/-2 ug kg(-1)) obtained from five analyses of a standard reference material (apple leaves, NIST 1515) showed good agreement with the certified reference value (44+/-4 ug kg(-1)) provided by the US National Institute of Standards and Technology (NIST). The precision based on the analysis of standard reference material was 4.1%; the average recovery was 95%. PMID- 24785498 TI - Heavy metal levels in Spanish cheeses: influence of manufacturing conditions. AB - Heavy metal (Pb, Cd, Hg) and Ni contents were determined in a wide variety of cheeses consumed in Spain from all geographical regions and with the official "Protected Designation of Origin". Pb content ranged from 110 to 5 ug kg(-1), which can be considered safe as, in all cases, the Pb contribution did not exceed 50% of the toxic density. Cd levels ranged between 11.4 to 1.3 ug kg(-1); however, the toxic density values for Cd in different types of cheeses exceeded the reference value in some cases. The highest Hg content was found to Gata Hurdes (208.3 ug kg(-1)), corresponding to a very high toxic density value (325%). Ni levels in cheese indicated that they are not good sources of this element. The type of milk, rennet and coagulation process had a significant influence on heavy metal levels in cheeses. PMID- 24785499 TI - Survey of organophosphorus pesticide residues in virgin olive oils produced in Chile. AB - Dimethoate, diazinon, parathion methyl, pirimiphos methyl, malathion, fenthion, chlorpyriphos, methidathion and azinphos methyl were determined in 71 olive oil samples produced in Chile from different varieties of olives (arbequina, frantoio, picual, lechino and blend) at three different harvest periods (2007, 2008 and 2009). The target pesticides were determined using a validated analytical method based on microwave-assisted liquid-liquid and solid-phase extraction with subsequent GC-FPD detection and GC-MS/MS for confirmation purposes. In 79% of the samples, five of the nine pesticides tested were detected with a frequency of one pesticide per sample. The highest detection rates were observed for the residues of chlorpyriphos and diazinon. The average concentration of chlorpyriphos, diazinon, azinphos methyl and methidathion were 0.084, 0.057, 0.024 and 0.010 ug g(-1), respectively. Higher contents of organophosphorus pesticides (OPPs) were found in regions where intensive agriculture is practiced. However, the levels of OPPs were reassuringly low and indicate that olive oil produced and exported from Chile does not currently represent any risk for consumers. PMID- 24785500 TI - Nitrate in leafy vegetables, culinary herbs, and cucumber grown under cover in Estonia: content and intake. AB - The content of nitrate in leafy vegetables, culinary herbs, and cucumber was determined during the years 2006-2008. All samples of Estonian origin, except white cabbage, were grown under cover. Seasonal differences in nitrate concentrations were observed in lettuce and spinach. Nitrate concentrations in lettuce were 22% and those in spinach were 24% higher in winter crops compared with samples collected in summer. The mean nitrate level was 3023 mg kg(-1) for fresh lettuce and 2337 mg kg(-1) for spinach. On average, 11.6% of fresh lettuce and spinach samples nitrate concentration exceeded the maximum level specified in European Commission Regulation No. 1881/2006. The mean levels were 999 mg kg(-1) for imported iceberg lettuce and 1287 mg kg(-1) for frozen spinach, which are below the maximum European Commission limits. Parsley, dill, basil, thyme, and rucola contained high concentrations of nitrate from mean levels of 2134 mg kg( 1) for parsley up to 8150 mg kg(-1) for rucola. Mean nitrate concentrations ranged from 382 to 1115 mg kg(-1) for white cabbage and Chinese cabbage, respectively. The per capita mean daily intake of nitrates related to the consumption of leafy vegetables, culinary herbs, and cucumber for the whole Estonian population was 31.3 mg day(-1), which comprised 14.2% of the acceptable daily intake (ADI). PMID- 24785501 TI - Survey of the presence of patulin in fruit juices. AB - Patulin is a mycotoxin produced by fungi belonging to the Penicillium and Aspergillus genera. The occurrence of patulin in fruit juices marketed in Italy in 2008 and purchased from supermarkets and retail shops has been measured. The aim of this study was to assess the presence of patulin in order to evaluate the potential risk for the consumer and, at the end of this food chain, to determine the quality of the raw material used. One hundred and five fruit juices (35 apple juice, 35 mixed-taste juices, 35 pear juices), produced by various Italian and European companies, were analysed using a previously published method. The analytical investigation showed that apple juices had a concentration of patulin ranging between 6 and 30 ug l(-1), with a mean of 18 ug l(-1); mixed fruit juices had a concentration ranging between 1 and 45 ug l(-1), with a mean of 23 ug l( 1). Instead, pear juices had a concentration ranging between 5 and 92 ug l(-1), with a mean of 43 ug l(-1), and 14 samples of the 35 analysed juices showed a patulin level above the highest regulated limit of 50 ug l(-1), imposed by European Commission Regulation 1881/06. PMID- 24785502 TI - Surveys of aflatoxin B1 contamination of retail Turkish foods and of products intended for export between 2007 and 2009. AB - Surveys were carried out between 2007 and 2009 to determine the aflatoxin B1 content of 3345 commercial Turkish foodstuffs supplied by producers for testing for their own purposes or for export certification. To simplify the reporting of data, foods were categorized as: 1, high sugar products with nuts; 2, nuts and seeds; 3, spices; 4, grain; 5, cocoa products; 6, dried fruit and vegetables; 7, processed cereal products; 8, tea; and 9, baby food and infant formula. Aflatoxin analysis was carried out by high-performance liquid chromatography with fluorescence detection after immunoaffinity column clean-up, with a recoveries ranging from 91% to 99%, depending on the matrix. Of the 3345 samples analysed, 94% contained aflatoxin B1 below the European Union limit of 2 ug kg(-1), which applies to nuts, dried fruit, and cereals products. The 6% of the 206 contaminated samples were mainly nuts and spices. For pistachios, 24%, 38%, and 42% of the totals of 207, 182, and 24 samples tested for 2007, 2008 and 2009, respectively, were above 2 ug kg(-1), with 50 samples containing aflatoxin B1 at levels ranging from 10 to 477 ug kg(-1). PMID- 24785503 TI - Non-dioxin-like and dioxin-like polychlorinated biphenyls in butter sampled from the Polish retail market. AB - The aim was to investigate levels of polychlorinated biphenyls (PCBs) in butter available on the Polish retail market. A gas chromatography-based method was developed for the purpose of this study. An ion-trap mass spectrometer was used as a detection system with high-resolution chromatography. Recoveries of individual PCBs from spiked samples varied from 58% to 105% with a recovery relative standard deviation in the range 3-16%. Levels of eight non-dioxin-like and twelve dioxin-like congeners were determined. Toxic equivalent factors (TEQs) were calculated using World Health Organization (WHO) TEQs. The average concentration of the sum of six PCBs (28, 52, 101, 138, 153, and 180) was found to be 1561+/-728 pg g(-1) (fat) and the upper-bound concentrations of dioxin-like congeners were (1 standard deviation uncertainty) 0.441+/-0.384 pg PCB-TEQ g(-1) (fat). PMID- 24785504 TI - Social interactions dominate speed control in poising natural flocks near criticality. AB - Flocks of birds exhibit a remarkable degree of coordination and collective response. It is not just that thousands of individuals fly, on average, in the same direction and at the same speed, but that even the fluctuations around the mean velocity are correlated over long distances. Quantitative measurements on flocks of starlings, in particular, show that these fluctuations are scale-free, with effective correlation lengths proportional to the linear size of the flock. Here we construct models for the joint distribution of velocities in the flock that reproduce the observed local correlations between individuals and their neighbors, as well as the variance of flight speeds across individuals, but otherwise have as little structure as possible. These minimally structured or maximum entropy models provide quantitative, parameter-free predictions for the spread of correlations throughout the flock, and these are in excellent agreement with the data. These models are mathematically equivalent to statistical physics models for ordering in magnets, and the correct prediction of scale-free correlations arises because the parameters--completely determined by the data- are in the critical regime. In biological terms, criticality allows the flock to achieve maximal correlation across long distances with limited speed fluctuations. PMID- 24785506 TI - Bendamustine-induced immune hemolytic anemia in a chronic lymphocytic leukemia patient: A case report and review of the literature. AB - Bendamustine is an alkylating agent approved for the treatment of chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin lymphoma. There are scant reports on bendamustine-induced immune hemolytic anemia occurring mainly in CLL patients. We report a case of immune hemolytic anemia that developed after exposure to bendamustine in a 70-year-old female with CLL who was previously exposed to fludarabine. Previous exposure to fludarabine is a common finding in the majority of reported cases of bendamustine drug-induced immune hemolytic anemia (DIIHA), including our case. Bendamustine should be suspected as the cause of any hemolytic anemia that develops while on this drug, especially in CLL patients treated previously with fludarabine. PMID- 24785505 TI - Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer. AB - Generally, solid tumors (>400 mm(3)) are inherently acidic, with more aggressive growth producing greater acidity. If the acidity could be targeted as a biomarker, it would provide a means to gauge the pace of tumor growth and degree of invasiveness, as well as providing a basis for predicting responses to pH dependent chemotherapies. We have developed a (64)Cu pH (low) insertion peptide (pHLIP) for targeting, imaging, and quantifying acidic tumors by PET, and our findings reveal utility in assessing prostate tumors. The new pHLIP version limits indiscriminate healthy tissue binding, and we demonstrate its targeting of extracellular acidification in three different prostate cancer models, each with different vascularization and acid-extruding protein carbonic anhydrase IX (CAIX) expression. We then describe the tumor distribution of this radiotracer ex vivo, in association with blood perfusion and known biomarkers of acidity, such as hypoxia, lactate dehydrogenase A, and CAIX. We find that the probe reveals metabolic variations between and within tumors, and discriminates between necrotic and living tumor areas. PMID- 24785507 TI - Sporadic pancreatic vasoactive intestinal peptide-producing tumor (VIPoma) in a 47-year-old male. AB - VIPoma is an exceedingly unusual neuroendocrine neoplasm that autonomously secretes vasoactive intestinal polypeptide (VIP). Its reported incidence is approximately 1 per 10 million individuals per year. Herein, we report the case of sporadic pancreatic VIPoma in a 47-year-old male who presented with a six month history of chronic, plentiful, watery diarrhea. On physical examination, the patient looked sick, lethargic and had signs of dehydration. Laboratory investigations revealed high VIP hormone level (989pg/mL), hypokalemia, hypercalcemia, hyperglycemia, high blood urea nitrogen, high creatinine, and metabolic acidosis on arterial blood gas. Contrast-enhanced computed tomography (CT) scan showed a 3.1*3.3*4.7cm, well-defined, enhancing lesion involving the pancreatic tail with a cystic component. Moreover, a 5.7*6.1*6.8cm metastatic hepatic lesion was identified. The patient underwent distal pancreatectomy with splenectomy, hepatic lesion resection, and lymph node dissection. Histopathological and immunohistochemical examination of the pancreatic and hepatic lesions revealed neuroendocrine tumor (VIPoma). Postoperatively, the patient received radiofrequency ablation for the hepatic lesion. A post-operative six-month follow-up showed significant symptomatic relief, reduced VIP hormone level (71pg/mL) and normalized electrolyte and acid-base profiles. However, a magnetic resonance imaging (MRI) scan showed a small residual metastatic liver lesion which was considered for hepatic artery embolization (HAE). The patient is still alive with a residual hepatic disease at 18months. We also present a brief literature review on VIPoma. PMID- 24785508 TI - Blastic plasmacytoid dendritic cell neoplasm: a rare subtype of myeloid leukemia. PMID- 24785511 TI - Representing the 'real'. PMID- 24785510 TI - Conformity and robustness of gated rescanned carbon ion pencil beam scanning of liver tumors at NIRS. AB - PURPOSE: Pencil beam scanning offers excellent conformity, but is sensitive to organ motion. We conducted a simulation study to validate our rescanning approach in combination with gating in the irradiation of liver tumors. MATERIALS AND METHODS: 4DCT imaging was performed under free-breathing conditions in 30 patients with hepatocellular carcinoma. Dose distributions for a two-field approach were calculated for layered phase controlled rescannings (PCR) under organ motion conditions. A total dose of 45 Gy(RBE) was delivered to respective field-specific target volumes (FTVs) in two fractions, each composed of two orthogonal uniform fields of 11.25 Gy(RBE) at beam angles of either 0 degrees and 90 degrees or 0 degrees and 270 degrees . The number of rescannings was changed from 1 to 10. RESULTS: Good dose conformity was achieved with 4* PCR or more, and over 95% of the prescribed dose was delivered to the CTV independent of the use of gating. D95, Dmax/min and dose homogeneity were similar with or without gating, whereas V10 dose to the liver as well as maximal doses to healthy tissue (esophagus and cord) were about 40% lower with gating. However, total time increased by about 50% with gating. CONCLUSIONS: Gated rescanning provides good target coverage and homogeneity with maximal sparing of healthy tissue. Our results suggest that carbon-ion pencil beam scanning may soon be available for the safe treatment of liver tumors. PMID- 24785512 TI - Living performance. PMID- 24785513 TI - Another con-text. AB - Abstract Increasingly, performance by women questions existing binary definitions of gender and sexuality by destabilizing familiar notions of the 'real' and creating new production values and aesthetics in the process. This paper explores three theatre companies (Spin/Stir; Amy Roadstone Productions; ObScene Productions) and two performing artists (Helena Goldwater and Helen Paris), all U.K. based and at the cutting edge of contemporary lesbian performance, who personify these developments. PMID- 24785514 TI - Vanishing in your face. AB - Abstract Lesbian dance performance has to come to terms with the cultural invisibility of the lesbian body, and the dichotomy of traditional gender representation. This paper charts strategies for the play with the invisible, the grotesque and the liminal in the dance performance of three UK-based choreographers: Emilyn Claid, Yael Flexer and Kate Lawrence. Their performances create tension between the role and the body, between the public and the private, and it is this tension that points towards alternative representational strategies. PMID- 24785509 TI - A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity. AB - BACKGROUND AND PURPOSE: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2years after radiotherapy. MATERIALS AND METHODS: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. RESULTS: Quantile-quantile plots show more associations at the P<5*10(-7) level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. CONCLUSIONS: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable. PMID- 24785515 TI - Shall we dance? AB - Abstract This paper looks at the way in which linguistics has been used in the analysis of identity and suggests that we might now be able to go beyond linguistics and do a wider analysis of identity using performance. I look at race and sex/gender in the context of sexuality and, as a part of my argument, I suggest that processes of identification should not be analyzed as separable but rather as interlocking elements, making up the complete human being. At the end of this mainly theoretical piece, I begin to apply my theory, looking at the work of two of my doctoral research project participants, Patience Agbabi and Zahid Dar, performers of pieces which raise a number of questions about sexuality, performance and identification processes. PMID- 24785516 TI - Performing the lesbian body-the new wave. AB - Abstract In recent years a crop of fine, exhilarating new talent has burst onto the lesbian performance scene. It has thrown up a range of unique dyke representations-from big hair, high drag, post-modern stripping and reformed fan dancing through to irony and pigtails. In the past the famous dyke double negative-of being both female and 'homosexual'-has shadowed lesbian performance to such an extent that there have been few positive, out representations. The work of feminist/political performers which challenged this was often reactive and thus tended to narrow down, rather than open out, the range of 'acceptable' lesbian representation. But things are changing. In this chapter, six 'new wave' performers talk about creating work, getting seen, showing flesh, doing politics and making money. Although they affirm that presenting publicly as an out dyke is still hard, they have also discovered a richness and freedom that is essentially and uniquely lesbian. Given the grotesque stereotypes and stinking closets so many lesbian performers have endured in the past-this represents something of a genuine and much-needed break-through. PMID- 24785517 TI - Get your feminism off my floppy. AB - Abstract This paper is located at the collisions of femininities, technologies and performance, and in the CD-ROM format in particular. The paper begins by asking what it means to be located as Other to an insurgent technology, and develops this analysis in relation to the association of femininity with un-bound flow. It goes on to call for the marking of technology with the feminine. The latter part of the paper analyses specific examples of performative practice on CD-ROM. These are Gilson-Ellis/Povall's mouthplace, Adriene Jenik's Mauve Desert and Laurie Anderson's Puppet Motel. PMID- 24785518 TI - Fleshing it Out. AB - Abstract From the raw physicality of Aunt Bill to the radio mike performance of Push the Boat Out to the collaboration of Strange Relations, and finally to hypertext narrative work, live artist Leslie Hill traces the currents of her experimentation with form and content and explores the links between lived experience and issues of sexuality and gender in her performance work. PMID- 24785519 TI - Drama queens. AB - Abstract Why is it that many 'lesbian playwrights' are unwilling to define themselves as such? "Drama Queens: Ruling with a Rod of Irony" attempts to answer this question and to discover what the term 'lesbian playwright' means within contemporary culture. It dissects the dominant homophobic and misogynist mythologies that have outlawed 'queer' girl writers to the underskirts of British theatre, and ultimately denied them either artistic or commercial currency. It examines the history of the label in the context of feminism, gay liberation and positive representation, and queries its aesthetic and economic viability in a climate where the 'lesbian playwright' is not even supported by her own community. Finally, it is an exploration into radical forms, working methodologies and new genres stimulated by being neither semantic Man nor Woman. It is a piece about cultural terrorism-and how to avoid capture. PMID- 24785520 TI - From stage to screen and back tash fairbanks' nocturne shedding some light on lesbian representation, and the performance of lesbian desire. AB - Abstract This paper explores the differences in lesbian representation between theatre and film by focusing on Tash Fairbanks's television play Nocturne, which exemplifies the crossover from stage to television screen. The paper identifies the changes that have come about in lesbian theatre and the implications these changes have had for both the writer and the audience. A significant part of this change is the impact of Queer Politics and the political and social implications this has had on lesbian representation. The most radical area of Queer Politics is the 'mainstreaming' of lesbian performance and this paper explores the issues arising from Queering the performance space; the arguments for and against 'mainstreaming' lesbian performance and its implications for the future. PMID- 24785521 TI - The laugh that dare not speak its name. AB - Abstract This piece is an exploration into the world of lesbian humor, lesbian comedy and the lesbian comedian. A brief look at the history of lesbian comedy shows us that it is definitely not a contemporary movement but has been around for well over a decade. How do we define lesbian humor and what is a lesbian comic? The answers to these questions are discussed with reference tO my Own performing career as a lesbian comedian in Britain. The difference between the lesbian comedian and the gay comedian is explained and examined along with the attitudes of acceptability in Britain toward gay male humor and the gay performer. But what does the future hold for the lesbian stand-up comedian and what of the introduction of lesbian characters into mainstream sitcoms? Lesbian humor will certainly not be going away, but it is finally finding its own niche in the big wide world of comedy. PMID- 24785522 TI - Fo(u)r Women. AB - Abstract This piece is about Fo(u)r Women, a collaborative poly-vocal performance piece featuring music, poetry, prose and movement. It traces the journey from feeling through idea to actualization of a collaborative creative project: how to make a piece of Live Art from the experience of listening to a Nina Simone song and three lives. Dream, breath, hope, wish, act a prayer to you to reach out to touch Four women made flesh in a place of revelation.. In the essay, I explore aspects of process, collaboration, critical context and issues informing the art. Issues of race, gender, sexual identities, relationships, love and place. Dear reader, for those of you at home, it's like you were there, all the time it was being made. But to feel the show, you really have to see it. PMID- 24785523 TI - It's Queer Up North. AB - Abstract It's Queer Up North is a British national arts organization which promotes international queer work during a high profile, biennial festival of the same name. It has been running since 1992 and has been increasing in prestige and scope with every festival. Here, Sarah-Jane interviews Tanja Farman, its co director, raising important questions regarding the mainstreaming of lesbian and gay work, censorship, programming of lesbian work, targeting of a lesbian audience, and the power and influence of funding/sponsorship on the selection process, content and aesthetics. PMID- 24785524 TI - Performing butch/femme theory. AB - Abstract This paper is a description of a performance workshop that is designed to give the language of the butch/femme theory a ride. Using theatre exercises and performance techniques that put the terms butch and femme onto the actions of the body, the writer hopes to encourage both an irreverence and a respect for the arbitrary nature of a language that attempts to define identity. PMID- 24785525 TI - Coming out at night-performing as the lesbian vampire rosie lugosi. AB - Abstract Rosie Lugosi is the lesbian vampire queen of Manchester, an electrifying performance poet, a fang-in-cheek compere and a sultry chanteuse. This article examines what has led to her creation and development: her past incarnations as a Wicked Queen and screaming Goth; the impact of coming out; the discovery of feminism and the importance of the image of the lesbian vampire as defiant rebel. PMID- 24785526 TI - Presentation of self as performance. AB - Abstract Valerie Mason-John is an artist who draws on performance, orature and text. In an interview she traces the roots of her development as a performer to her early childhood; examines the creation of personas on stage and television, including outspoken, fun-loving Queenie, who has hosted at Pride; and explores the responses of black lesbian and other audiences. She also considers possible future directions for her work, including the impact which greater integration of different aspects of her life might have on her growth as a performer. PMID- 24785527 TI - Angela de castro. AB - Abstract Angela de Castro, 41, is a theatre clown. In a male-dominated genre that incorporates elements from mime and elevates traditional circus slapstick to a high art, she is internationally recognized as a performer and teacher. Born in Brazil, de Castro came to England in 1986 in order to train. She has worked with British street-and circus-theatre companies including Mummerandada, Ra Ra Zoo, and The Right Size, and women's theatre company Skin and Blisters. Her own show, The Gift, has toured throughout Britain, and she has directed and appeared in spectacular circus-inspired performances at London's Heaven night-club. In 1995 she was invited to work with world-famous exponent of the art, Slava Polunin, in his phenomenally successful Snowshow, in which Angela toured internationally during 1996. She lives in London with her partner, Catherine. PMID- 24785528 TI - Feminine and masculine personnas in performance. AB - Abstract Sade Huron is a self-confessed Lesbian drag artist. In this article she discusses how her performance character, the highly glamorized Tutu L'Amour, came into existence. She considers the role of Cabaret within her work, its importance historically for gay performers as a vehicle for raising issues concerned with sexuality. Sade goes on to explain that her performance looks at the complexities that surround the notion of gender, in particular femininity, and how she paradoxically presents Tutu L'Amour as a ludicrous parody of her own sex and an affirmation of 'glamorous femininity.' She introduces Elvis as a butch dyke icon to challenge the idea of binary opposites within gender, i.e., the masculine and the feminine. Lastly she looks at how these issues are received by different audiences. PMID- 24785529 TI - Drag kings and subjects. PMID- 24785530 TI - Genotyping of high-risk human papillomaviruses in p16/Ki-67-positive urothelial carcinoma cells: even a worm will turn. AB - OBJECTIVE: Co-expression of p16INK4a protein and Ki-67 (p16/Ki-67) is noted in almost all high-grade urothelial lesions. However, the aetiological role or, conversely, the absence of causative effect of high-risk human papillomaviruses (hr-HPVs) has not been documented. The purpose of this study is to evaluate HPV DNA in p16/Ki-67-positive, high-grade urothelial tumour cells. METHODS: Fifty seven urine samples collected from 50 patients, including 55 histologically proven high-grade proliferations and two cases with clinical evidence of malignancy, were analysed for p16/Ki-67. Immunolabelling was performed in destained Papanicolaou-stained slides after ThinPrep((r)) processing. HPV genotyping was performed by polymerase chain reaction (PCR) using a DNA microarray for 35 HPV types. Confirmation of the presence (or absence) of HPV in tissue samples was verified using a reasoned approach combining PCR and in situ hybridization (ISH) for hr-HPVs. RESULTS: Co-expression of p16/Ki-67 was noted in 43 of 57 (75.4%) cases. In these, hr-HPVs 16, 31 and 70, and low risk HPV 84, were detected in the urine in four patients (8%). Upregulation of p16INK4a protein was confirmed on bladder biopsy or transurethral resection specimens, but PCR and ISH for hr-HPVs were both negative on the tissue sections. CONCLUSION: Our results show a low prevalence of HPV infection in the urinary tract of patients with p16/Ki-67-positive urothelial malignancy. The study confirms that the deregulated cell cycle, as demonstrated by p16/Ki-67 dual labelling, is independent of the oncogenic action of hr-HPVs in high-grade urothelial proliferations. PMID- 24785531 TI - The spatiotemporal expression and localization implicates a potential role for SerpinB11 in the process of mouse spermatogenesis and apoptosis. AB - In this study, the spatiotemporal expression of SerpinB11 in the mouse testis from postnatal 1-60 d was checked, the SerpinB11 protein strongly localized in the intermediate spermatogonia, B-type spermatogonium, preleptotene spermatocyte, leptonema spermatocyte, zygotene spermatocyte, but weakly localized in the pachytene spermatocyte, diplotene spermatocyte, sphere sperm, and the apoptotic sperm was positive stained of SerpinB11 protein, the localization of cell cycle marker CDK4 and meiosis marker SCP3 were investigated, and the SCP3 and SerpinB11 colocalized in the intermediate spermatogonia, B-type spermatogonium, preleptotene spermatocyte. Taken together, these results suggested that SerpinB11 might involved in spermatogenesis and apoptosis. PMID- 24785538 TI - The experience of acupuncture care from the perspective of people with chronic low back pain: a grounded theory study. AB - OBJECTIVES: To explore the experience of acupuncture care from the perspective of people with chronic low back pain. METHODS: A grounded theory, qualitative study using indepth interviews was undertaken with 11 people who had received acupuncture care for chronic low back pain. Interviews were audio-recorded and transcribed verbatim. Initial, focused and theoretical coding were used to identify a core category and several other categories. RESULTS: The core category, Reclaiming Control, was related to the sense of well-being experienced by most of the participants as a result of undergoing acupuncture care. The other categories were Gaining Sanctuary, Gaining Trust and Working Together. These categories reflected the processes of participants entering an aesthetically appealing, calm and relaxing space; developing confidence in the acupuncturists' ability to care for them; and negotiating strategies and sharing decision-making with acupuncturists about their care. CONCLUSIONS: Clinicians using acupuncture as a management strategy for low back pain may elicit an immediate sense of calmness in patients with subsequent well-being benefits. A sense of calmness may also be enhanced through providing a relaxing physical environment. The transactional and interpersonal processes of establishing trust and rapport, and shared decision-making are important for clients. Shared decision-making can be improved by clinicians carefully considering the explanation of issues and plans to a particular patient, especially by developing an understanding of each patient's worldview and using language that the suits each individual's healthcare orientation. Our findings should be interpreted cautiously as the results may be generalisable only to private practice in affluent countries, and whether the findings are representative beyond this setting remains unclear. PMID- 24785539 TI - mRNA biogenesis, from the gene to polysomes. PMID- 24785540 TI - Promoting positive psychology using social networking sites: a study of new college entrants on Facebook. AB - This study explores the potential of promoting college students' positive psychological development using popular online social networks. Online social networks have dramatically changed the ways college students manage their social relationships. Social network activities, such as checking Facebook posts dominates students' Internet time and has the potential to assist students' positive development. Positive psychology is a scientific study of how ordinary individuals can apply their strength effectively when facing objective difficulties and how this capability can be cultivated with certain approaches. A positive message delivery approach was designed for a group of new college entrants. A series of positive messages was edited by university counselors and delivered by students to their Facebook social groups. Responses from each posted positive messages were collected and analyzed by researchers. The responses indicated that: (1) relationships of individual engagement and social influence in this study can partially explain the observed student behavior; (2) using class-based social groups can promote a positive atmosphere to enhance strong-tie relationships in both the physical and virtual environments, and (3) promoting student's positive attitudes can substantially impact adolescents' future developments, and many positive attitudes can be cultivated by emotional events and social influence. PMID- 24785541 TI - Effects of nutrition and exercise health behaviors on predicted risk of cardiovascular disease among workers with different body mass index levels. AB - Workplace health promotion programs should be tailored according to individual needs and efficient intervention. This study aimed to determine the effects of nutrition and exercise health behaviors on predicted risk for cardiovascular disease (CVD) when body mass index (BMI) is considered. In total, 3350 Taiwanese workers were included in this cross-sectional study. A self-reported questionnaire was used to measure their nutrition and exercise behaviors. Data on anthropometric values, biochemical blood determinations, and predicted CVD risk (using the Framingham risk score) were collected. In multiple regression analyses, the nutrition behavior score was independently and negatively associated with CVD risk. Exercise was not significantly associated with the risk. However, the interactive effect of exercise and BMI on CVD risk was evident. When stratified by BMI levels, associations between exercise and CVD risk were statistically significant for ideal weight and overweight subgroups. In conclusion, nutrition behavior plays an important role in predicting the CVD risk. Exercise behavior is also a significant predictor for ideal weight and overweight workers. Notably, for underweight or obese workers, maintaining health promoting exercise seems insufficient to prevent the CVD. In order to improve workers' cardiovascular health, more specific health-promoting strategies should be developed to suit the different BMI levels. PMID- 24785542 TI - A lightweight Web of Things Open Platform to facilitate context data management and personalized healthcare services creation. AB - In the last few years, many health monitoring systems have been designed to fullfil the needs of a large range of scenarios. Although many of those systems provide good ad hoc solutions, most of them lack of mechanisms that allow them to be easily reused. This paper is focused on describing an open platform, the micro Web of Things Open Platform (uWoTOP), which has been conceived to improve the connectivity and reusability of context data to deliver different kinds of health, wellness and ambient home care services. uWoTOP is based on a resource oriented architecture which may be embedded in mobile and resource constrained devices enabling access to biometric, ambient or activity sensors and actuator resources through uniform interfaces defined according to a RESTful fashion. Additionally, uWoTOP manages two communication modes which allow delivering user context information according to different methods, depending on the requirements of the consumer application. It also generates alert messages based on standards related to health care and risk management, such as the Common Alerting Protocol, in order to make its outputs compatible with existing systems. PMID- 24785543 TI - Synthesis and elimination of C-3-labeled thiosialosides. AB - The synthesis of C-3-labeled phenylthio sialic acid derivatives and an investigation of stereoselectivity in elimination reactions for the synthesis of 2,3-dehydro derivatives (glycals) is described. The experimental results are consistent with the existence of a conformational change and may be indicative of the intermediacy of an all-axial oxacarbenium ion. PMID- 24785544 TI - Symmetry Breaking in Platinum Acetylide Chromophores Studied by Femtosecond Two Photon Absorption Spectroscopy. AB - We study instantaneous two-photon absorption (2PA) in a series of nominally quasi centrosymmetric trans-bis(tributylphosphine)-bis-(4-((9,9-diethyl-7-ethynyl-9H fluoren-2-yl) ethynyl)-R)-platinum complexes, where 11 different substituents, R = N(phenyl)2(NPh2), NH2, OCH3, t-butyl, CH3, H, F, CF3, CN, benzothiazole, and NO2, represent a range of electron-donating (ED) and electron-withdrawing (EW) strengths, while the Pt core acts as a weak ED group. We measure the 2PA cross section in the 540-810 nm excitation wavelength range by complementary femtosecond two-photon excited fluorescence (2PEF) and nonlinear transmission (NLT) methods and compare the obtained values to those of the Pt-core chromophore and the corresponding noncentrosymmetric side group (ligand) chromophores. Peak 2PA cross sections of neutral and ED-substituted Pt complexes occur at S0 -> Sn transitions to higher energy states, above the lowest-energy S0 -> S1 transition, and the corresponding values increase systematically with increasing ED strength, reaching maximum value, sigma2 ~ 300 GM (1 GM = 10-50 cm4 s), for R = NPh2. At transition energies overlapping with the lowest-energy S0 -> S1 transition in the one-photon absorption (1PA) spectrum, the same neutral and ED-substituted Pt complexes show weak 2PA, sigma2 < 30-100 GM, which is in agreement with the nearly quadrupolar structure of these systems. Surprisingly, EW-substituted Pt complexes display a very different behavior, where the peak 2PA of the S0 -> S1 transition gradually increases with increasing EW strength, reaching values sigma2 = 700 GM for R = NO2, while in the S0 -> Sn transition region the peak 2PEF cross section decreases. We explained this effect by breaking of inversion symmetry due to conformational distortions associated with low energy barrier for ground-state rotation of the ligands. Our findings are corroborated by theoretical calculations that show large increase of the permanent electric dipole moment change in the S0 -> S1 transition when ligands with strong EW substituents are twisted by 90 degrees relative to the planar chromophore. Our NLT results in the S0 -> S1 transition region are quantitatively similar to those obtained from the 2PEF measurement. However, at higher transition energy corresponding to S0 -> Sn transition region, the NLT method yields effective multiphoton absorption stronger than the 2PEF measurement in the same systems. Such enhancement is observed in all Pt complexes as well as in all ligand chromophores studied, and we tentatively attribute this effect to nearly saturated excited-state absorption (ESA), which may occur if 2PA from the ground state is immediately followed by strongly allowed 1PA to higher excited states. PMID- 24785545 TI - Thermodynamic and structural analysis of HIV protease resistance to darunavir - analysis of heavily mutated patient-derived HIV-1 proteases. AB - We report enzymologic, thermodynamic and structural analyses of a series of six clinically derived mutant HIV proteases (PR) resistant to darunavir. As many as 20 mutations in the resistant PRs decreased the binding affinity of darunavir by up to 13 000-fold, mostly because of a less favorable enthalpy of binding that was only partially compensated by the entropic contribution. X-ray structure analysis suggested that the drop in enthalpy of darunavir binding to resistant PR species was mostly the result of a decrease in the number of hydrogen bonds and a loosening of the fit between the inhibitor and the mutated enzymes. The favorable entropic contribution to darunavir binding to mutated PR variants correlated with a larger burial of the nonpolar solvent-accessible surface area upon inhibitor binding. We show that even very dramatic changes in the PR sequence leading to the loss of hydrogen bonds with the inhibitor could be partially compensated by the entropy contribution as a result of the burial of the larger nonpolar surface area of the mutated HIV PRs. DATABASE: Atomic coordinates and structure factors for the crystal structures PRwt-DRV and PRDRV2-DRV complex have been deposited in the Protein Data Bank under accession codes 4LL3 and 3TTP, respectively. STRUCTURED DIGITAL ABSTRACT: * PR and PR bind by x-ray crystallography (View interaction). PMID- 24785546 TI - Predictors of pocket hematoma in patients on antithrombotic therapy undergoing cardiac rhythm device implantation: insights from the FinPAC trial. AB - BACKGROUND: The FinPAC trial showed that the strategy of uninterrupted oral anticoagulation (OAC) was non-inferior to interrupted OAC for the primary outcome of bleeding and thromboembolic complications in patients undergoing cardiac rhythm management device (CRMD) implantation. METHODS: We conducted a post hoc analysis of the FinPAC data to explore the incidence and predictors of significant (> 100 cm(2)) pocket hematoma after CRMD implantation among the study population (n = 447). A total of 213 patients were on OAC, 128 were on aspirin, and 106 on no antithrombotic therapy. RESULTS: The incidence of significant pocket hematoma during hospital stay was significantly higher among patients using OAC (5.6%) and aspirin (5.5%) than in those with no antithrombotic medications (0.9%), but only one patient (0.8%) in the aspirin group needed revision of hematoma. Two patients (0.9%) in the OAC group and one (0.8%) in the aspirin group needed blood products. In multivariable regression analysis, no pre procedural features predicted the significant hematoma in any of the groups. CONCLUSIONS: Clinically significant pocket hematoma is a rare complication after CRMD implantation in patients with ongoing therapeutic OAC. The incidence of significant pocket hematoma formation is similar in patients using OAC and those using aspirin. PMID- 24785547 TI - Growth modes of nanoparticle superlattice thin films. AB - We report on the fabrication and characterization of iron oxide nanoparticle thin film superlattices. The formation into different film morphologies is controlled by tuning the particle plus solvent-to-substrate interaction. It turns out that the wetting vs dewetting properties of the solvent before the self-assembly process during solvent evaporation plays a major role in determining the resulting film morphology. In addition to layerwise growth three-dimensional mesocrystalline growth is also evidenced. The understanding of the mechanisms ruling nanoparticle self-assembly represents an important step towards the fabrication of novel materials with tailored optical, magnetic or electrical transport properties. PMID- 24785548 TI - Laparoscopic rectopexy for solitary rectal ulcer syndrome without overt rectal prolapse: a case report and review of the literature. AB - Solitary rectal ulcer syndrome is a rare clinical entity. Several treatment options has been described. However, there is no consensus yet on treatment algorithm and standard surgical procedure. Rectopexy is one of the surgical options and it is generally performed in patients with solitary rectal ulcer accompanied with overt prolapse. Various outcomes have been reported for rectopexy in the patients with occult prolapse or rectal intussusception. In the literature; outcomes of laparoscopic non-resection rectopexy procedure have been reported in the limited number of case or case series. No study has emphasized the outcomes of laparoscopic non-resection rectopexy procedure in the patients with solitary rectal ulcer without overt prolapse. In this report we aimed to present clinical outcomes of laparoscopic non-resection posterior suture rectopexy procedure in a 21-year-old female patient with solitary rectal ulcer without overt prolapse. PMID- 24785549 TI - The role of family institutes in promoting the practice of family therapy. AB - Much of the development of family therapy as a discipline was an outcome of the clinical, training, and theory-building activities conducted at family institutes around the United States. Beginning in the 1960s, these institutes were the crucibles in which the concepts and practices of family therapy flourished. The author, a leader at one of the largest family institutes in the United States, discusses the role of family institutes in promoting the practice of family therapy, as well as the challenges of doing so. PMID- 24785550 TI - Pharmacokinetic and pharmacodynamic evaluation of donepezil for the treatment of Alzheimer's disease. AB - INTRODUCTION: Donepezil is a highly selective acetylcholinesterase inhibitor and one of the only four drugs currently approved for treatment of Alzheimer's dementia. Providing high bioavailability and a very long half-time, donepezil is regarded as effective and well tolerable in Alzheimer's disease patients, even in difficult clinical conditions such as hepatic or renal impairment. It moderately improves cognitive and global functioning scores in patients with mild to moderate Alzheimer's disease over the course of 6 - 12 months, with open-label extension studies suggesting effects of even longer duration. AREAS COVERED: We summarized relevant pharmacokinetic, pharmacodynamic, clinical trial and neuroimaging data of donepezil. A literature search was performed in the PubMed database; articles published until October 2013 have been considered for this review. Moreover, references from original work and reviews have been searched for further relevant literature. EXPERT OPINION: Donepezil is one of the most frequently prescribed anti-dementia drugs. The recent additional approval of the 23 mg formulation will expand its use in patients with moderate to severe Alzheimer's disease. After numerous Phase III study failures of novel disease modifying drugs for Alzheimer's disease, donepezil is likely going to stay a first-line therapeutic option in Alzheimer's disease in the upcoming years. PMID- 24785551 TI - Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic models for personalized medicine: application to temozolomide in brain tumors. AB - Optimizing anticancer therapeutics needs to account for variable drug responses in heterogeneous cell populations within the tumor as well as in organs of toxicity. To address cell heterogeneity, we propose a multiscale modeling approach-from in vitro to preclinical and clinical studies-to develop cell-type specific pharmacokinetic-pharmacodynamic (PK-PD) models. A physiologically based mechanistic modeling approach integrating data from aqueous solutions, U87 glioma cells, mice, and cancer patients was utilized to characterize the brain disposition of temozolomide (TMZ), the cornerstone of chemotherapy against glioblastoma multiforme. The final model represented intracellular normal brain and brain tumor compartments in which TMZ pH-dependent conversion to the DNA alkylating species leads to the formation of DNA adducts that serve as an entry point for a PD model. This multiscale protocol can be extended to account for TMZ PK-PD in different cell populations, thus providing a critical tool to personalize TMZ-based chemotherapy on a cell-type-specific basis. PMID- 24785552 TI - Aligned nanofibers as an interfacial layer for achieving high-detectivity and fast-response organic photodetectors. AB - We report that aligned nanofibers (ANs) prepared by electrostatic spinning technology as an interfacial layer can significantly enhance the performance of inverted organic photodetectors. With the insertion of ANs of titanium dioxide (TiO2), the optimized organic photodetectors had a highest detectivity of 2.93 * 10(13) Jones at zero bias, which is about 3 times higher than that of a similar organic photodetector without ANs and also markedly higher than that of traditional silicon photodetectors. The performance of the devices with different TiO2 ANs as the interfacial layer was investigated, and the results exhibited that photodetectors with one-way ANs had the highest detectivity and shortest response time. This work provides a new application of nanofibers fabricated by a simple and controllable process in high-performance organic photodetectors. PMID- 24785553 TI - Impact of boarding pediatric psychiatric patients on a medical ward. AB - BACKGROUND AND OBJECTIVES: Psychiatric disorders account for an increasing number of pediatric hospitalizations. Due to lack of psychiatric beds, patients on involuntary psychiatric holds may be admitted to medical units. Our objectives were to evaluate the rate of admission of psychiatric patients to a medical unit, psychiatric care provided, and estimated cost of care. METHODS: The study involved retrospective chart review of all patients on involuntary psychiatric holds presenting to 1 pediatric emergency department from July 2009 to December 2010. We determined the rate of admission to a medical unit, the rate of counseling or psychiatric medication administration, and the estimated cost of nonmedical admissions (boarding) of patients on the medical unit. RESULTS: A total of 555 (50.1%) of 1108 patients on involuntary psychiatric holds were admitted to the pediatric medical unit. The majority (523 [94.2%]) were admitted for boarding because no psychiatric bed was available. Thirty-two (6.1%) patients admitted for isolated psychiatric reasons had counseling documented, and 105 (20.1%) received psychiatric medications. Patients admitted to an affiliated psychiatric hospital were significantly more likely to receive counseling and medications. Psychiatric patients were boarded in medical beds for 1169 days at an estimated cost of $2 232 790 or $4269 per patient over the 18-month period. CONCLUSIONS: We found high admission rates of patients on involuntary psychiatric holds to a pediatric medical unit with little psychiatric treatment in 1 hospital. Further research in other centers is required to determine the extent of the issue. Future studies of longer term outcomes (including readmission rates and assessments of functioning) are needed. PMID- 24785554 TI - Boarding of pediatric psychiatric patients is a no-fly zone for value. PMID- 24785555 TI - Characteristics and outcomes of pediatric rapid response teams before and after mandatory triggering by an elevated Pediatric Early Warning System (PEWS) score. AB - BACKGROUND: The Pediatric Early Warning System (PEWS) was created to identify unstable patients before their deterioration. Rapid response teams (RRTs) were developed to assist with management of such patients. In 2009, our institution mandated the activation of RRTs if a PEWS score was elevated (ie, >=5). OBJECTIVES: The goal of this study was to examine changes in characteristics of RRT calls before and after the implementation of a mandatory hospital policy requiring RRT activation due to an elevated PEWS score. METHODS: This study was a retrospective database review, with RRT data from June 2007 to December 2010 examined. A total of 44 RRTs were recorded before mandatory triggering and 69 RRTs afterward in the study period (P = .32). RESULTS: Compared with the premandatory group, the mandatory triggering group found that tachycardia was a more frequent trigger for RRTs, with an increase of 26.1% (P = .004). RRTs triggered by a change in mental status/agitation decreased by 22.9% (P = .009). An increase of 15.1% of RRTs required no interventions with mandatory triggering. Nighttime RRTs increased by17.5% (P = .07). There was a trend toward decreased PICU transfers in the mandatory triggering group, with no significant change in code blue calls. CONCLUSIONS: A hospital policy of mandating RRT activation based on PEWS scores increased nighttime calls and altered the primary reasons for RRT activation in our center, with no evidence of improvements in patient care. These findings should be interpreted with caution given the relatively rare outcomes the policy is intended to prevent; however, our findings highlight the difficulties inherent in evaluating methods to improve pediatric patient safety. PMID- 24785556 TI - In search of the holy PEWS. PMID- 24785557 TI - Situation awareness: a new model for predicting and preventing patient deterioration. PMID- 24785558 TI - Demographic factors associated with bronchiolitis readmission. AB - OBJECTIVES: The goal of this study was to evaluate patient characteristics and medical management and their association with readmission in children with bronchiolitis. METHODS: This retrospective chart review included children admitted with bronchiolitis to 2 children's hospitals. Reviewers selected charts based on International Classification of Diseases, Ninth Revision, diagnosis and collected information on demographic characteristics, treatment, diagnostic testing, length of stay, and adverse outcomes. Univariate analyses were used to identify risk factors associated with any-cause readmission in 4 weeks. RESULTS: A total of 1229 patients met inclusion criteria. Younger children were more likely to be readmitted within 4 weeks of discharge compared with older children (mean age: 4.5 vs 5.7 months; P = .005). Readmissions did not differ based on length of stay, and no medical intervention was associated with risk for readmission. Of patients readmitted from the large service area hospital, 57% lived <=20 miles away, compared with 26.9% of those who were not readmitted (P = .03). Patients from the lowest income zip codes within the catchment area of the small service area hospital were more likely to be readmitted compared with patients from the highest income zip codes (7.8% vs 0%; P = .025). CONCLUSIONS: Overall, 6.4% of hospitalized patients with bronchiolitis were readmitted. Our data did not identify any inpatient medical management or modifiable risk factor associated with readmission. PMID- 24785559 TI - Hospital readmission in children with complex chronic conditions discharged from subacute care. AB - OBJECTIVES: Children with complex chronic conditions (CCC) are responsible for a disproportionate number of hospital readmissions. This study sought to determine 30-day hospital readmission rates in children with CCC discharged from a rehabilitation and transitional care hospital and to identify factors associated with increased risk of readmission. METHODS: We conducted a retrospective cohort study identifying children with CCC discharged over an 18-month period from a subacute care facility staffed by hospitalists from a freestanding children's hospital. The primary outcome measure was readmission to the referring acute care hospital within 30 days of the subacute discharge. RESULTS: Of the 272 discharged patients meeting inclusion criteria as children with at least 1 CCC, 19% had at least 1 readmission within 30 days of discharge. On univariate analysis, readmission was associated with the number of home medications (P = .001), underlying chronic respiratory illness (P < .001), home apnea or pulse oximetry monitor use (P = .02), tracheostomy and/or ventilator dependence (P = .003), length of stay (P = .04), and number of follow-up appointments (P = .02). On multivariate analysis, the number of discharge medications was associated with increased odds of readmission (odds ratio: 1.11 [95% confidence interval: 1.03 1.20]; P = .01). Receiver operating curve analysis identified a cutoff of 8 medications as most associated with readmission; in patients discharged with >=8 medications, the hospital readmission rate was 29%. CONCLUSIONS: This is the first known study that investigated hospital readmission rates in children with CCC discharged from a subacute facility and specifically identified the number of discharge medications as a significant risk factor for readmission. PMID- 24785560 TI - Administrative data misclassifies and fails to identify nephrotoxin-associated acute kidney injury in hospitalized children. AB - OBJECTIVES: Nephrotoxin exposure is a common cause of acute kidney injury (AKI) in hospitalized children. AKI detection relies on regular serum creatinine (SCr) screening among exposed patients. We sought to determine how well administrative data identify hospitalized noncritically ill children with nephrotoxic medication associated AKI in the contexts of incomplete and complete screening. METHODS: We conducted a single-center retrospective cohort study among noncritically ill hospitalized children. We compared administrative data sensitivity to that among a separate cohort for whom adequate screening was defined as daily SCr measurement. For the original cohort, nephrotoxin exposure was defined as exposure to >=3 nephrotoxins at once or >=3 days of aminoglycoside therapy. AKI was defined by the change in SCr (pediatric-modified Risk Injury Failure Loss End Stage Renal Disease [pRIFLE] criteria) or discharge code. Adequate SCr screening was defined as 2 measurements obtained <=96 hours apart. Administrative data and laboratory values were merged to compare AKI by discharge code and pRIFLE criteria. RESULTS: 747 of 1472 (50.7%) nephrotoxin-exposed patients were adequately screened; 82 (11.0%) had AKI by pRIFLE criteria, 52 (7.0%) by discharge code. Sensitivity of nephrotoxin-associated AKI diagnosis by discharge code compared with pRIFLE criteria was 23.2% (95% confidence interval = 14.0 32.3). In the comparison cohort, 70 (26.8%) patients had AKI by pRIFLE criteria and 26 (10.0%) by discharge code; sensitivity was 21.4% (95% confidence interval = 11.8%-31.0%). CONCLUSIONS: pRIFLE criteria identified more patients than were identified by discharge code. Identifying patients with nephrotoxin-associated AKI by discharge code, even in the presence of complete AKI detection, underrepresents the true incidence of nephrotoxin-associated AKI in hospitalized children. PMID- 24785561 TI - Clinical and laboratory characteristics of disseminated herpes simplex virus infection in neonates. AB - BACKGROUND AND OBJECTIVES: Disseminated herpes simplex virus (HSV) infection is the most fulminant type of neonatal HSV infection and has the highest mortality. Early diagnosis and treatment are essential for patient survival. We describe the clinical presentation, laboratory characteristics, and outcomes of neonates with disseminated HSV infection at our institution. METHODS: A retrospective review of electronic medical records from 2006 to 2013 was performed. Only neonates with disseminated HSV infection, confirmed by using polymerase chain reaction or viral culture results, were included. RESULTS: Twenty-two cases were identified; the age range was 1 to 14 days. The majority of patients did not have a maternal history of HSV or a history of maternal fever at delivery. Eleven of the patients were delivered by cesarean delivery, and 3 of these patients did not have prolonged rupture of membranes. Neonatal fever, the most common historical characteristic, was present in only one-half of the patients. Pneumonia and respiratory distress were present in one-half of the patients. Serum aspartate aminotransferase and alanine aminotransferase levels were elevated in most, but not all, patients. The blood HSV polymerase chain reaction was positive in all patients tested. Of the 22 study patients, 16 survived and 6 died. The majority of the patients who died had respiratory disease and a delay in the initiation of acyclovir therapy. CONCLUSIONS: Disseminated HSV infection in neonates can be challenging to diagnose and is associated with high mortality. Clinicians must strongly consider this diagnosis, test the blood for HSV polymerase chain reaction, and initiate early treatment in the appropriate clinical scenarios. PMID- 24785562 TI - Is dexamethasone an effective alternative to oral prednisone in the treatment of pediatric asthma exacerbations? AB - BACKGROUND: A short course of systemic corticosteroids is an important therapy in the treatment of pediatric asthma exacerbations. Although a 5-day course of oral prednisone or prednisolone has become the most commonly used regimen, dexamethasone has also been used for a shorter duration (1-2 days) with potential for improvement in compliance and palatability. We reviewed the literature to determine if there is sufficient evidence that dexamethasone can be used as an effective alternative in the treatment of pediatric asthma exacerbations in the inpatient setting. METHODS: A Medline search was conducted on the use of dexamethasone in the treatment of asthma exacerbations in children. The studies selected were clinical trials comparing the efficacy of dexamethasone with prednisone. Meta-analysis was performed examining physician revisitation rates and symptomatic return to baseline. RESULTS: Six completed pediatric clinical trials met the inclusion criteria. All of the pediatric trials found that prednisone is not superior to dexamethasone in treating mild to moderate asthma exacerbations. Meta-analysis demonstrated homogeneity between the dexamethasone and prednisone groups when examining symptomatic return to baseline and unplanned physician revisits after the initial emergency department encounter. Some studies found potential additional benefits of dexamethasone, including improved compliance and less vomiting. CONCLUSIONS: The current literature suggests that dexamethasone can be used as an effective alternative to prednisone in the treatment of mild to moderate acute asthma exacerbations in children, with the added benefits of improved compliance, palatability, and cost. However, more research is needed to examine the role of dexamethasone in hospitalized children. PMID- 24785563 TI - Nothing is simple about a complex febrile seizure: looking beyond fever as a cause for seizures in children. PMID- 24785564 TI - It doesn't have to be EviDense. PMID- 24785565 TI - Cognitive bias in inpatient pediatrics. PMID- 24785566 TI - Early infant growth is associated with the risk of islet autoimmunity in genetically susceptible children. AB - BACKGROUND: Islet autoimmunity commonly develops early in infancy. We assessed whether specific parameters of early growth (including weight gain) were associated with the development of islet autoimmunity in children of type 1 diabetes patients, taking individual developmental patterns into account. METHODS: Growth parameters were estimated in n = 1011 children followed from birth in the prospective BABYDIAB and BABYDIET studies using longitudinal models. Cox proportional hazard models, adjusted for study, sex, gestational age, birth weight percentile, and maternal type 1 diabetes status, were calculated to assess hazard ratios (HR) for islet autoimmunity with corresponding 95% confidence intervals (95% CI) by 2 SD increases in growth parameters. In a subset of n = 170 infants, we investigated whether the growth hormones insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) were in the causal pathway. RESULTS: We found an early age at infant body mass index (BMI) peak to be associated with the development of islet autoimmunity [HR 0.60 (95% CI 0.41-0.87), per 2 SD increase in age]. Islet autoimmunity was also associated with BMI difference between infant BMI peak and childhood BMI rebound [HR 1.52 (95% CI 1.04-2.22)], but not after adjustment for age at infant BMI peak, and not with other parameters such as peak height and weight velocity during infancy. Serum concentrations of IGF-1 and IGFBP-3 at birth, 9 months, and 2 yr, respectively, were not significantly different between children with and without later islet autoimmunity. CONCLUSIONS: Variations in early growth rate have subtle effects on the risk of islet autoimmunity with growth hormones unlikely to be in the causal pathway. PMID- 24785567 TI - Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6beta-naltrexol, using a novel LC Q-ToF MS assay. AB - Naltrexone (NTX) is a long-acting opiate antagonist. Low-dose naltrexone (LDN) therapy has shown promising results in the treatment of several autoimmune disorders. Our aim was to formulate NTX into a cream for the delivery of LDN and develop an analytical technique for the quantification of NTX and its active metabolite 6-beta-naltrexol (NTXol) during transdermal diffusion cell permeation studies. A 1% w/w NTX cream was formulated and drug permeation was examined over 24 h using static Franz diffusion cells mounted with pig skin. A Liquid Chromatography Quadrupole-Time of Flight Mass Spectrometry (LC-MS Q-ToF) method was developed for the detection of NTX and NTXol in the receptor solution, skin membrane and residual cream on the donor chamber after completion of the diffusion studies. The cream formulation exhibited steady state release of NTX over 24 h after an initial lag time of 2.74 h. The bioconversion of NTX to NTXol in the skin membrane was 1.1%. It was concluded that the cream may be an effective formulation for the sustained transdermal delivery of LDN. The novel LC Q-ToF MS method allowed the accurate measurement of NTX and NTXol levels across the diffusion cell assemblies and the quantification of NTX metabolism in the skin. PMID- 24785568 TI - Editorial overview: energy biotechnology. PMID- 24785569 TI - Lentiviral delivery of PPARgamma shRNA alters the balance of osteogenesis and adipogenesis, improving bone microarchitecture. AB - INTRODUCTION: Skeletal aging is associated not only with alterations in osteoblast (OB) and osteoclast (OC) number and activity within the basic metabolic unit, but also with increased marrow adiposity. Peroxisome proliferator activated receptor gamma (PPARgamma) is commonly considered the master transcriptional regulator of adipogenesis, however, it has known roles in osteoblast and osteoclast function as well. Here, we designed a lentiviral delivery system for PPARgamma shRNA, and examined its effects in vitro on bone marrow stromal cells (BMSC) and in a mouse intramedullary injection model. METHODS: PPARgamma shRNA was delivered by a replication-deficient lentiviral vector, after in vitro testing to confirm purity, concentration, and efficacy for Pparg transcript reduction. Next, control green fluorescent protein lentivirus or PPARgamma shRNA expressing lentivirus were delivered by intramedullary injection into the femoral bone marrow of male SCID mice. Analyses included daily monitoring of animal health, and postmortem analysis at 4 weeks. Postmortem analyses included high resolution microcomputed tomography (microCT) reconstructions and analysis, routine histology and histomorphometric analysis, quantitative real time polymerase chain reaction analysis of Pparg transcript levels, and immunohistochemical analysis for markers of adipocytes (PPARgamma, fatty acid binding protein 4 [FABP4]), osteoblasts (alkaline phosphatase [ALP], osteocalcin [OCN]), and osteoclasts (tartrate-resistant acid phosphatase [TRAP], Cathepsin K). RESULTS: In vitro, PPARgamma shRNA delivery significantly reduced Pparg expression in mouse BMSC, accompanied by a significant reduction in lipid droplet accumulation. In vivo, a near total reduction in mature marrow adipocytes was observed at 4 weeks postinjection. This was accompanied by significant reductions in adipocyte-specific markers. Parameters of trabecular bone were significantly increased by both microCT and histomorphometric analysis. By immunohistochemical staining and semi-quantification, a significant increase in OCN+osteoblasts and decrease in TRAP+multinucleated osteoclasts was observed with PPARgamma shRNA treatment. DISCUSSION: These findings suggest that acute loss of PPARgamma in the bone marrow compartment has a significant role beyond anti adipose effects. Specifically, we found pro-osteoblastogenic, anti-osteoclastic effects after PPARgamma shRNA treatment, resulting in improved trabecular bone architecture. Future studies will examine the isolated and direct effects of PPARgamma shRNA on OB and OC cell types, and it may help determine whether PPARgamma antagonists are potential therapeutic agents for osteoporotic bone loss. PMID- 24785570 TI - Place of death in patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a degenerative neurological disorder that affects motor neurons. Involvement of respiratory muscles causes the failure of the ventilator pump with more or less significant bulbar troubles. ALS course is highly variable but, in most cases, this disease entails a very significant burden for patients and caregivers, especially in the end-of-life period. In order to analyze the characteristics of ALS patients who die at home (DH) and in hospital (DHosp) and to study the variability of clinical practice, a retrospective medical records analysis was performed (n=77 from five hospitals). VARIABLES: time elapsed since the onset of symptoms and the beginning of ventilation, characteristics of ventilation (device, mask and hours/day), and support devices and procedures. RESULTS: In all, 14% of patients were ventilated by tracheotomy. From the analysis, 57% of patients were of DH. Mean time since the onset of symptoms was 35.93+/-25.89 months, significantly shorter in patients who DHosp (29.28+/-19.69 months) than DH (41.12+/-29.04) (p=0.044). The percentage of patients with facial ventilation is higher in DHosp (11.4% vs 39.4%, p<0.005). DH or not is related to a set of elements in which health resources, physician attitudes and support resources in the community play a role in the decision-making process. There is great variability between countries and between hospitals in the same country. Given the variability of circumstances in each territory, the place of death in ALS might not be the most important element; more important are the conditions under which the process unfolds. PMID- 24785571 TI - Risk factors for prolonged mechanical ventilation after total aortic arch replacement for acute DeBakey type I aortic dissection. AB - BACKGROUND: EuroSCORE II is an objective risk scoring model. The aim of this study was to assess the performance of EuroSCORE II in the prediction of prolonged mechanical ventilation following total aortic arch replacement for acute DeBakey type I aortic dissection and evaluate the risk factors for prolonged mechanical ventilation. METHODS: Between February 2009 to February 2012, data from 240 patients who underwent total aortic arch replacement for acute DeBakey type I aortic dissection were collected retrospectively. Mechanical ventilation after the surgery longer than 48 hours was defined as postoperative prolonged mechanical ventilation. EuroSCORE II was applied to predict prolonged mechanical ventilation. A C statistic (receiver operating characteristic curve) was used to test discrimination of the model. Calibration was assessed with a Hosmer-Lemeshow goodness-of-fit statistic. Multiple logistic regression analysis was used to identify the final risk factors of prolonged mechanical ventilation. RESULTS: The overall mortality was 10%. The mean length of mechanical ventilation after total aortic arch replacement was 42.72 +/- 51.45 hours. Total 74 patients needed prolonged mechanical ventilation. EuroSCORE II showed poor discriminatory ability (C statistic 0.52) and calibration (Hosmer-Lemeshow, p<0.05) in predicting prolonged mechanical ventilation. On multivariate analysis, independent risk factors for postoperative prolonged mechanical ventilation were age >= 48.5 years (p<0.001, OR=3.85), preoperative leukocyte count >= 13.5 * 109/L (p<0.001, OR=4.05) and symptom onset before the surgery less than one week (p=0.002, OR=3.75). CONCLUSIONS: EuroSCORE II could not predict prolonged mechanical ventilation following total aortic arch replacement for acute DeBakey type I aortic dissection. Preoperative high level of leukocyte, age and surgical period from symptom onset are risk factors for prolonged mechanical ventilation. PMID- 24785574 TI - Near-infrared spectroscopic analysis of the breaking force of extended-release matrix tablets prepared by roller-compaction: influence of plasticizer levels and sintering temperature. AB - The aim of this study was to investigate the feasibility of near-infrared (NIR) spectroscopy for the determination of the influence of sintering temperature and plasticizer levels on the breaking force of extended-release matrix tablets prepared via roller-compaction. Six formulations using theophylline as a model drug, Eudragit(r) RL PO or Eudragit(r) RS PO as a matrix former and three levels of TEC (triethyl citrate) as a plasticizer were prepared. The powder blend was roller compacted using a fixed roll-gap of 1.5 mm, feed screw speed to roller speed ratio of 5:1 and roll pressure of 4 MPa. The granules, after removing fines, were compacted into tablets on a Stokes B2 rotary tablet press at a compression force of 7 kN. The tablets were thermally treated at different temperatures (Room Temperature, 50, 75 and 100 degrees C) for 5 h. These tablets were scanned in reflectance mode in the wavelength range of 400-2500 nm and were evaluated for breaking force. Tablet breaking force significantly increased with increasing plasticizer levels and with increases in the sintering temperature. An increase in tablet hardness produced an upward shift (increase in absorbance) in the NIR spectra. The principle component analysis (PCA) of the spectra was able to distinguish samples with different plasticizer levels and sintering temperatures. In addition, a 9-factor partial least squares (PLS) regression model for tablets containing Eudragit(r) RL PO had an r(2) of 0.9797, a standard error of calibration of 0.6255 and a standard error of cross validation (SECV) of 0.7594. Similar analysis of tablets containing Eudragit(r) RS PO showed an r(2) of 0.9831, a standard error of calibration of 0.9711 and an SECV of 1.192. PMID- 24785575 TI - Spray drying of a poorly water-soluble drug nanosuspension for tablet preparation: formulation and process optimization with bioavailability evaluation. AB - Spray drying experiments of an itraconazole nanosuspension were conducted to generate a dry nanocrystal powder which was subsequently formulated into a tablet formulation for direct compression. The nanosuspension was prepared by high pressure homogenization and characterized for particle-size distribution and surface morphology. A central composite statistical design approach was applied to identify the optimal drug-to-excipient ratio and spray drying temperature. It was demonstrated that the spray drying of a nanosuspension with a mannitol-to drug mass ratio of 4.5 and at an inlet temperature of 120 degrees C resulted in a dry powder with the smallest increase in particle size as compared with that of the nanosuspension. X-ray diffraction results indicated that the crystalline structure of the drug was not altered during the spray-drying process. The tablet formulation was identified by determining the micromeritic properties such as flowability and compressibility of the powder mixtures composed of the spray dried nanocrystal powder and other commonly used direct compression excipients. The dissolution rate of the nanocrystal tablets was significantly enhanced and was found to be comparable to that of the marketed Sporanox(r). No statistically significant difference in oral absorption between the nanocrystal tablets and Sporanox(r) capsules was found. In conclusion, the nanosuspension approach is feasible to improve the oral absorption of a BCS Class II drug in a tablet formulation and capable of achieving oral bioavailability equivalent to other well established oral absorption enhancement method. PMID- 24785576 TI - Preparation and evaluation of orally disintegrating tablets of taste masked phencynonate HCl using ion-exchange resin. AB - This study was intended to design an orally disintegrating tablet (ODT) formulation that can mask the extremely bitter and metallic taste of phencynonate HCl by novel ion-exchange resins. The drug-resin complexes (DRCs) were prepared and characterized by scanning electron microscopy, X-ray powder diffraction and differential scanning calorimetry. In vitro properties (dissolution, wetting time and disintegration time) and in vivo behavior (disintegration time and taste masking effect) in healthy volunteers of the prepared ODTs were also investigated. The drug was changed from the crystal structure to the amorphous form in the DRC. Compared with commercial tablets, the in vitro and in vivo disintegration of optimized DRC-loaded ODTs with a drug-resin ratio of 1:1 was greatly improved and better palatability with a low bitterness index (0.33) was obtained. The current DRC-loaded ODT could promise a good way to mask the unpleasant taste of certain drugs and accordingly improve the patient compliance. PMID- 24785577 TI - Phenolic acids identified in sorghum distillery residue demonstrated antioxidative and anti-cold-stress properties in cultured tilapia, Oreochromis mossambicus. AB - This study aimed to identify the bioactive compounds and evaluate the anti-cold stress function of the sorghum distillery residue (SDR) using tilapia as an alternative animal model. The highest contents of water-soluble bioactive compounds in SDR were polyphenols, followed by tannins, anthocyanins, and flavonoids. SDR was extracted with double-distilled water, 95% ethanol, and ethyl acetate, separately. The ethanol extract (SDR-E) yielded the highest polyphenol content [15.03 mg/g of SDR dry weight (dw)], of which the EC50 value of R,R diphenyl-beta-picrylhydrazyl (DPPH) radical scavenging efficiency was 0.56 +/- 0.04 mg/mL. The SDR-E suppressed the oxidation of low-density lipoproteins (LDLs) more efficiently than that of other extracts. Tilapia fed a diet containing 3.6% SDR-E decreased accumulative mortality during cold stress, of 46.2%. The accumulative morality of the control was 92.9%. The phenolic acids identified in SDR included gallic acid (0.36 +/- 0.08 mg/g of SDR dw), 3,4-dihydroxybenzoic acid (0.16 +/- 0.12 mg/g of SDR dw), and 4-hydroxybenzoic acid (0.49 +/- 0.23 mg/g of SDR dw). Diets supplemented with 0.5% 4-hydroxybenzoic acid fed to tilapia showed a lower mortality rate than that fed 1.0% 4-hydroxybenzoic acid, comparable to that of the tilapia fed 20% SDR. The latter showed lower mortality than that of the control. These results suggested that 4-hydroxybenzoic acid is one of the major anti-cold-stress compounds in SDR. PMID- 24785578 TI - Silver nanoclusters for drug detection in biological samples: what is the future? PMID- 24785579 TI - Generalized modeling of spontaneous imbibition based on Hagen-Poiseuille flow in tortuous capillaries with variably shaped apertures. AB - Spontaneous imbibition of wetting liquids in porous media is a ubiquitous natural phenomenon which has received much attention in a wide variety of fields over several decades. Many traditional and recently presented capillary-driven flow models are derived based on Hagen-Poiseuille (H-P) flow in cylindrical capillaries. However, some limitations of these models have motivated modifications by taking into account different geometrical factors. In this work, a more generalized spontaneous imbibition model is developed by considering the different sizes and shapes of pores, the tortuosity of imbibition streamlines in random porous media, and the initial wetting-phase saturation. The interrelationships of accumulated imbibition weight, imbibition rate and gas recovery and the properties of the porous media, wetting liquids, and their interactions are derived analytically. A theoretical analysis and comparison denote that the presented equations can generalize several traditional and newly developed models from the literature. The proposed model was evaluated using previously published data for spontaneous imbibition measured in various natural and engineered materials including different rock types, fibrous materials, and silica glass. The test results show that the generalized model can be used to characterize the spontaneous imbibition behavior of many different porous media and that pore shape cannot always be assumed to be cylindrical. PMID- 24785580 TI - Variation in natural head position and establishing corrected head position. AB - Corrected head position (CHP) has been simulated by using the Frankfurt horizontal (FH) for over 100 years but FH varies between individuals. Because CHP is biologically relevant for orthodontic diagnosis and treatment planning, orthognathic surgical planning, and art, this study examined relationships between head position and selected cephalometric planes. Natural head position cephalograms of Aboriginal Australians and two contemporary samples from private orthodontic practices were analysed. Each sample comprised 40 individuals (20 males and 20 females). The Aboriginal Australian sample comprised longitudinal data (T1 early adolescent, T2 late adolescent, and T3 adult), enabling examination of natural head position (NHP) reproducibility over a period of approximately 8 years. Results of reproducibility differences revealed an absolute mean=2.9 degrees , range=-7.9 degrees to 8.2 degrees , and standard deviation=3.6 degrees . Stable basicranial line (SBL), neutral horizontal axis (NHA), FH, palatal plane (P plane), and Krogman-Walker plane (KW plane) demonstrated near parallelism and their mean angulations from the true horizontal (HOR) ranged between -4.6 degrees and 2.4 degrees . While NHP is not consistently reproducible at the individual level, the combined use of multiple planes such as SBL, P plane, and KW plane enables a more consistent CHP to be achieved. PMID- 24785581 TI - An efficient genomic DNA extraction from whole blood using Nextractor. AB - BACKGROUND: We evaluated the performance of the Nextractor NX-48 nucleic acid extractor system for the extraction of genomic DNA from whole blood samples. METHODS: We compared the performance of the Nextractor to that of the QIAamp DNA Blood Mini Kit and the Maxwell system, using five whole blood samples. Extraction efficiencies were compared based on the total amount of extracted DNA adjusted by input blood volume, and the purity was compared. Polymerase chain reaction analyses were performed using ACTB as a target. The real-time PCR assay was carried out for housekeeping gene GAPDH. Total elapsed time for DNA extraction was compared. RESULTS: Extraction efficiencies for the QIAamp, Maxwell, and Nextractor were 25.4+/-3.8ng/MUL, 9.2+/-0.6ng/MUL, and 31.0+/-5.6ng/MUL, respectively. No significant differences in purity were observed among three methods. DNA extracted using the ACTB was successfully amplified in all three methods. There were no obvious differences in Ct values for GAPDH real-time PCR. Total elapsed time for DNA extraction was about 50min for the QIAamp, 40min for the Maxwell, and 20min for the Nextractor. CONCLUSIONS: As the Nextractor is faster and requires less hands-on time than manual procedures, it may be useful for molecular diagnostic testing in clinical laboratories. PMID- 24785582 TI - Preparation of reference material for UGT1A1 (TA)n polymorphism genotyping. AB - BACKGROUND: Gilbert's syndrome is one of the most common metabolic syndromes in the human population characterised by mild unconjugated hyperbilirubinemia resulting from reduced activity of the bilirubin conjugating enzyme UDP glucuronosyltransferase (UGT1A1). Although Gilbert's syndrome is usually quite benign UGT1A1(TA)n genotyping is important in exclusion of more serious causes of hyperbilirubinemia and since it has significant implications for personalised medicine. The aim of our study was to develop plasmid based reference materials which could be used for UGT1A1(TA)n genotyping. METHODS: Plasmids were generated using recombinant DNA technology and their number of repeats as well as the entire sequence verified by Sanger sequencing. Their suitability as reference materials was tested using sizing by capillary electrophoresis and denaturing high performance liquid chromatography. RESULTS: Plasmids containing all four different alleles (TA)5, (TA)6, (TA)7 and (TA)8 that are present in the human population as well as a plasmid with (TA)4 repeats were successfully generated. CONCLUSIONS: Prepared plasmid reference materials allow the creation of all possible UGT1A1(TA)n polymorphism genotypes and can serve as an efficient substitute for the human genomic DNA reference material in routine genotyping and in the development of new genotyping tests. PMID- 24785583 TI - Estimated glomerular filtration rate by two equations and their relationship with metabolic syndrome. PMID- 24785584 TI - Prognostic relevance of plasma heart-type fatty acid binding protein after out-of hospital cardiac arrest. AB - OBJECTIVE: Heart-type fatty acid binding protein (H-FABP) is a tissue-specific protein which is rapidly released into the circulation when cardiomyocyte injury occurs. The aim of the study is to investigate the prognostic relevance of H-FABP for out-of-hospital cardiac arrest (OHCA) patients in the early post-cardiac arrest period. DESIGN AND METHODS: This is a prospective cohort study enrolling non-traumatic resuscitated OHCA patients. RESULTS: A total of 106 patients were enrolled. The H-FABP level at 24h was correlated to the duration from collapse to return of spontaneous circulation (p<0.001, R(2)=0.549). The outcomes of survival to discharge were worse in the patient group with the higher tertile of plasma H FABP level at 24h after the event (p=0.011). Multivariate analysis demonstrated that the significant predictors for in-hospital mortality were APACHE II score (p=0.010), gender (p=0.025) and the tertiles of H-FABP at 24h with hazard ratios for the lowest, middle, and highest tertiles being 1.0, 1.157 (95% confidence interval 0.435-3.075, p=0.770), and 2.840 (95% confidence interval 1.137-7.092, p=0.025), respectively. CONCLUSION: The plasma level of H-FABP at 24h after the event may be an early and independent factor associated with survival to discharge in OHCA patients. PMID- 24785585 TI - Possible incorrect genotyping of heterozygous factor V Leiden and Prothrombin 20210 gene mutations by the GeneXpert assay. AB - BACKGROUND: The GeneXpert analyzer is a hands-off system for the detection of Factor V Leiden and of Prothrombin G20210A (GPRO) gene thrombophilic mutations. Although the system is efficient and easy to use, we report the rare possibility of incorrect genotyping. METHODS: 1648 samples were evaluated using the GeneXpert HemosIL Factor II and Factor V assay: 1319 were freshly analyzed while 329 were frozen, thawed and diluted with saline prior to analysis to avoid clogging of the instrument syringe. RESULTS: Two samples, both heterozygous, one for the factor V Leiden and the other for the GPRO gene, were incorrectly genotyped as homozygous for the relative mutation. Inspection of the Ct values and amplification curves and genotyping with PCR revealed the correct genotype as heterozygous for factor V Leiden and GPRO mutation. DISCUSSION: The GeneXpert HemosIL Factor II and Factor V assay is an automated, fast genotyping assay requiring almost no sample manipulation, advantageous characteristics if compared with other PCR-based methods. However, an inattentive use of it can generate incorrect diagnosis. A careful handling of the sample, in particular correct dilution of frozen/thawed samples before analysis, and the inspection of the amplification curves and Ct values are required to avoid artifacts. PMID- 24785586 TI - Relationship between male age, accessory gland, sperm transferred, and fitness traits in Drosophila bipectinata. AB - The number of cells and the size of the cells in the male accessory gland, the quantity of accessory gland proteins, and their effects on fitness in males of different ages were studied in Drosophila bipectinata Duda (Diptera: Drosophilidae). Male age was significantly positively correlated with the size of accessory gland, the number of main cells of the accessory gland, the quantity of protein in unmated males, the duration of copulation, the transferred quantity of protein and sperm to the mated female, fecundity, and fertility, while male age was significantly negatively correlated with the size of main cell in the accessory gland and the quantity of protein in mated males. The size of the main cells was significantly positively correlated with the quantity of protein in unmated males but significantly negatively correlated with the size of the accessory gland and the number of main cells in the accessory gland. These results suggest that D. bipectinata young males, with their smaller size of their accessory glands and having fewer and larger main cells in their accessory glands, produced the least quantity of protein and transferred significantly less protein and sperm to the mated female than did middle and old age males. Thus, this study suggests that in D. bipectinata, male age affects the number of accessory gland cells and the quantity of protein in the accessory gland. The size and number of main cells in the accessory gland and the size of the accessory gland were related to the production of protein. Females who mated with old males obtained a fitness benefit. PMID- 24785587 TI - Regulation of ionizing radiation-induced adhesion of breast cancer cells to fibronectin by alpha5beta1 integrin. AB - Ionizing radiation (IR) is commonly used for cancer therapy, however, its potential influence on cancer metastatic potential remains controversial. In this study, we elucidated the role of integrins in regulation of IR-altered adhesion between breast cancer cells and extracellular matrix (ECM) proteins, which is a key step in the initial phase of metastasis. Our data suggest that the extent of effect that ionizing radiation had on cell adhesion depended on the genetic background of the breast cancer cells. Ionizing radiation was a better adhesion inducer for p53-mutated cells, such as MDA-MB-231 cells, than for p53 wild-type cells, such as MCF-7 cells. While IR-induced adhesions between MDA-MB-231 cells to fibronectin, laminin, collagen I and collagen IV, only blocking of the adhesion between alpha5beta1 integrin and fibronectin using anti-alpha5beta1 integrin antibody could completely inhibit the radiation-induced adhesion of the cells. A soluble Arg-Gly-Asp peptide, the binding motif for fibronectin binding integrins, could also reduce the adhesion of the cells to fibronectin with or without ionizing radiation exposure. The inhibition of the cell-fibronectin interaction also affected, but did not always correlate with, transwell migration of the cancer cells. In addition, our data showed that the total expression of alpha5 integrin and surface expression of alpha5beta1 integrin were increased in the cells treated with ionizing radiation. The increased surface expression of alpha5beta1 integrin, along with the adhesion between the cells and fibronectin, could be inhibited by both ataxia telangiectasia mutated (ATM) and Rad3-related (ATR) kinase inhibitors. These results suggested that ATM/ATR-mediated surface expression of alpha5beta1 integrin might play a central role in regulation of ionizing radiation-altered adhesion. PMID- 24785588 TI - Crosstalk with cancer-associated fibroblasts increases the growth and radiation survival of cervical cancer cells. AB - Crosstalk between cancer cells and the surrounding cancer associated fibroblasts (CAFs) plays an illusive role in cancer radiotherapy. This study investigated the effect of cancer cell-cancer associated fibroblasts crosstalk on the proliferation and survival of irradiated cervical cancer cells. A pretreatment with conditioned medium from a mixed culture of CAF and HeLa cells (mixCAF) had a stronger effect on enhancing the proliferation and survival of irradiated HeLa cells compared to pretreatment with CAF conditioned medium alone. In addition, pretreatment with a mixed culture of CAF and HeLa cells conditioned medium reduced the levels of two major radiation-induced genes, GADD45 and BTG2, and phosphorylation of p38. Profiling of the growth and survival factors in the conditioned medium revealed PDGF and VEGF, and IGF2, EGF, FGF-4, IGFBPs and GM CSF to be specifically secreted from HeLa cells and CAFs, respectively. This study demonstrated radiation protective effects of CAF-cancer cell crosstalk, and identified multiple growth factors and radiation response genes that might be involved in these effects. PMID- 24785590 TI - Towards an aging-specific cognitive phenotype: the freedom house study. AB - BACKGROUND/STUDY CONTEXT: The authors have previously reported latent growth curve (LGC) models of 3-year change in multiple cognitive measures among successfully aging volunteers. In this analysis, the authors apply growth mixture modeling (GMM) to demonstrate homogeneous subsets among them with discriminable trajectories. Only one trajectory class can be interpreted as the effect of Aging Proper. The goal of the study was to describe an aging-specific cognitive phenotype (ASCP). METHODS: Five hundred forty-seven noninstitutionalized septuagenarian and octogenarian volunteers, residing in a comprehensive care retirement community, were assessed longitudinally on a comprehensive battery of brief psychometric measures. RESULTS: All variables held more than one latent class. Members of an a priori defined "Aging Proper" class were highly concordant across measures, and allowed the aging-specific cognitive phenotype (ASCP) to be examined. The ASCP was characterized by simultaneous decline in visuospatial function, coupled with improving verbal fluency. The ASCP was not associated with decline in memory task performance. CONCLUSIONS: Previously reported age-related declines in memory are more likely to represent the effects of comorbid disease and not aging per se. The ASCP is more consistent with earlier "Right Hemisphere" models of aging and could provide clues to the mechanisms underlying true aging related cognitive changes. PMID- 24785589 TI - Exploration of scanning effects in multi-site structural MRI studies. AB - BACKGROUND: Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity. NEW METHOD: In the present study we use a source based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction. RESULTS: A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving coil. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach. COMPARISON WITH EXISTING METHOD(S): Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings. CONCLUSIONS: It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects. PMID- 24785591 TI - Confirmatory factor analysis of the quality of life in Alzheimer's disease scale in patients with Alzheimer's disease. AB - BACKGROUND/STUDY CONTEXT: Quality of life (QoL) has become an important outcome measure in clinical trials for Alzheimer's disease (AD). The Quality of Life in Alzheimer's Disease (QoL-AD) Scale is widely used for assessing QoL of patients with AD. This research aims to determine the factor structure of the QoL-AD Scale in AD patients. METHODS: One hundred thirty-nine patients with mild-to-moderate AD were administered the QoL-AD Scale. Based on the model proposed for healthy people, confirmatory factor models were built using modification indices and residual analysis to improve the model fit. RESULTS: Confirmatory factor analysis indicated poor fit for both the initial model and the single-factor model. Two models showed a good fit: a three-factor model (perceived health, perceived environment and perceived functional ability) and a two-factor model (perceived physical health and perceived psychological health). Because no differences in fit were found between both models, the authors proposed the more parsimonious solution as the best model. CONCLUSION: These results provide evidence supporting the construct validity of the QoL-AD Scale. This instrument seems to measure the perception of two related constructs (behavioral competence and environment) and could be used together with instruments measuring psychological well-being and the perception of health. PMID- 24785592 TI - Multitasking and aging: do older adults benefit from performing a highly practiced task? AB - BACKGROUND/STUDY CONTEXT: The present study examined the effect of training on age differences in performing a highly practiced task using the psychological refractory period (PRP) paradigm (Pashler, 1984, Journal of Experimental Psychology: Human Perception and Performance, 10, 358-377). Earlier training studies have concentrated on tasks that are not already overlearned. The present question of interest is whether task dual-task integration will be more efficient when single-task performance is approaching asymptotic levels. METHODS: Task 1 was red/green signal discrimination (green = "go" and red = "wait"; analogous to pedestrian signals) and Task 2 was tone discrimination (white noise vs. a horn "honk"; analogous to traffic sound). The stimulus onset asynchrony (SOA) between Task 1 and Task 2 was varied (50, 150, 600, and 1000 ms). All individuals participated in eight sessions spread over 8 weeks (one session per week). Participants completed a dual-task pretest (Week 1), followed by 6 weeks of single-task testing (Weeks 2-7), followed by a dual-task posttest (Week 8). RESULTS AND CONCLUSION: Although older adults showed larger overall dual-task costs (i.e., PRP effects), they were able to reduce the costs with practice as much as younger adults. However, even when training on Task 1 results in asymptotic performance, this still did not lead to an appreciable reduction in dual-task costs. Also, older adults, but not younger adults, responded more rapidly to green stimuli than to red stimuli in the Task 1 training latency data. The authors confirmed this green/go bias using diffusion modeling, which takes into account response time and error rates at the same time. This green/go bias is potentially dangerous at crosswalks, especially when combined with large dual task interference, and might contribute to the high rate of crosswalk accidents in the elderly. PMID- 24785593 TI - The effects of age on processing and storage in working memory span tasks and reading comprehension. AB - BACKGROUND/STUDY CONTEXT: Declines in verbal working memory span task performance have been associated with deficits in the language processing abilities of healthy older adults, but it is unclear how storage and processing contribute to this relationship. Moreover, recent studies of the psychometric properties of span measures in the general cognitive literature highlight the need for a critical reassessment of age-related differences in working memory task performance. METHODS: Forty-two young (Mage = 19.45 years) and 42 older participants (Mage = 73.00 years) completed a series of neuropsychological screening measures, four memory span tasks (one-syllable word span, three syllable word span, reading span, and sentence span), and a measure of reading comprehension. Each span measure was completed under self-paced and timed encoding conditions. A 2 (age) * 2 (task type) * 2 (encoding conditions) mixed model design was used. RESULTS: (1) Age effects were reliable for both simple and complex span task performance; (2) limiting the available encoding time yielded lower recall scores across tasks and exacerbated age differences in simple span performance; and (3) both encoding condition and age affected the relationship between each of the span measures and the relationship between span and reading comprehension. CONCLUSION: Declines in both storage and processing abilities contributed to age differences in span task performance and the relationship between span and reading comprehension. Although older people appear to benefit from task administration protocols that promote successful memory encoding, researchers should be aware of the potential risks to validity posed by such accommodations. PMID- 24785594 TI - Accuracy and speed feedback: global and local effects on strategy use. AB - BACKGROUND/STUDY CONTEXT: Skill acquisition often involves a shift from an effortful algorithm-based strategy to more fluent memory-based performance. Older adults' slower strategy transitions can be ascribed to both slowed learning and metacognitive factors. Experimenters often provide feedback on response accuracy; this emphasis may either inadvertently reinforce older adults' conservatism or might highlight that retrieval is generally quite accurate. Response time (RT) feedback can lead to more rapid shift to retrieval (Hertzog, Touron, & Hines, 2007, Psychology and Aging, 22, 607-624). METHODS: This study parametrically varied trial-by-trial feedback to examine whether strategy shifts in the noun pair task in younger (M = 19) and older (M = 67) adults were influenced by type of performance feedback: none, trial accuracy, trial RT, or both accuracy and RT. RESULTS: Older adults who received accuracy feedback retrieved more often, particularly on difficult rearranged trials, and participants who receive speed feedback performed the scanning strategy more quickly. Age differences were also obtained in local (trial-level) reactivity to task performance, but these were not affected by feedback. CONCLUSIONS: Accuracy and speed feedback had distinct global (general) influences on task strategies and performance. In particular, it appears that the standard practice of providing trial-by-trial accuracy feedback might facilitate older adults' use of retrieval strategies in skill acquisition tasks. PMID- 24785595 TI - Age differences in hindsight bias: the role of episodic memory and inhibition. AB - BACKGROUND/STUDY CONTEXT: After learning an event's outcome, people's recollection of their former prediction of that event shifts towards the actual outcome. This hindsight bias (HB) phenomenon tends to be stronger in older compared with younger adults; however, it is unclear whether age-related changes in other cognitive abilities mediate this relationship. METHODS: Sixty-four younger adults (Mage = 20.1; range = 18-25) and 60 community-dwelling older adults (Mage = 72.5; range = 65-87) completed a memory design HB task. Two aspects of HB, its occurrence and magnitude, were examined. Multiple regression and mediation analyses were conducted to determine whether episodic memory and inhibition mediate age differences in the occurrence and magnitude of HB. RESULTS: Older adults exhibited a greater occurrence and magnitude of HB as compared with younger adults. The present findings revealed that episodic memory and inhibition mediated age-related increases in HB occurrence. Conversely, neither cognitive ability mediated age-related increases in HB magnitude. CONCLUSION: Older adults' susceptibility to the occurrence of HB is partly due to age-related declines in episodic memory and inhibition. Conversely, age differences in the magnitude of HB appear to be independent of episodic memory and inhibition. These findings have important implications for understanding the mechanisms by which susceptibility to HB changes across the adult life span. PMID- 24785596 TI - The attractiveness halo effect and the babyface stereotype in older and younger adults: similarities, own-age accentuation, and older adult positivity effects. AB - BACKGROUND/STUDY CONTEXT: Two well-documented phenomena in person perception are the attractiveness halo effect (more positive impressions of more attractive people), and the babyface stereotype (more childlike impressions of more babyfaced people), shown by children, young adults (YA), and people from diverse cultures. This is the first study to systematically investigate these face stereotypes in older adults (OA) and to compare effects for younger and older adult faces. METHODS: YA and OA judges rated competence, health, hostility, untrustworthiness, attractiveness, and babyfaceness of older and younger neutral expression faces. Multilevel modeling assessed effects of rater age and face age on appearance stereotypes. RESULTS: Like YA, OA showed both the attractiveness halo effect and the babyface stereotype. However, OA showed weaker effects of attractiveness on impressions of untrustworthiness, and only OA associated higher babyfaceness with greater competence. There also was own-age accentuation, with both OA and YA showing stronger face stereotypes for faces closer to their own age. Age differences in the strength of the stereotypes reflected an OA positivity effect shown in more influence of positive facial qualities on impressions or less influence of negative ones, rather than vice versa. CONCLUSION: OA own-age biases, previously shown in emotion, age, and identity recognition, and OA positivity effects, previously revealed in attention, memory, and social judgments, also influence age differences in the strength and content of appearance stereotypes. Future research should assess implications of these results for age-related differences in susceptibility to appearance biases that YA have shown in socially significant domains, such as judicial and personnel decisions. PMID- 24785597 TI - Separating the baby from the bath water: breast self-awareness and breast self examination. PMID- 24785598 TI - Breast self-awareness: the evidence behind the euphemism. AB - Breast cancer is the most common malignancy among women. Breast self-examination originally was proposed and implemented under the assumption that it would increase early detection and, theoretically, improve survival. However, breast self-examination since has been proven to have no effect on mortality from breast cancer. Rather than being abandoned, breast self-examination has been repackaged into the new concept of breast self-awareness. Although the desire to empower women with self-detection of cancer is noble, teaching techniques that have been proven not to be effective likely causes more harm than good. PMID- 24785599 TI - Association of maternal body mass index, excessive weight gain, and gestational diabetes mellitus with large-for-gestational-age births. AB - OBJECTIVE: To estimate the percentage of large-for-gestational age (LGA) neonates associated with maternal overweight and obesity, excessive gestational weight gain, and gestational diabetes mellitus (GDM)-both individually and in combination-by race or ethnicity. METHODS: We analyzed 2004-2008 linked birth certificate and maternal hospital discharge data of live, singleton deliveries in Florida. We used multivariable logistic regression to assess the independent contributions of mother's prepregnancy body mass index (BMI), gestational weight gain, and GDM status on LGA (birth weight-for-gestational age 90 percentile or greater) risk by race and ethnicity while controlling for maternal age, nativity, and parity. We then calculated the adjusted population-attributable fraction of LGA neonates to each of these exposures. RESULTS: Large-for-gestational age prevalence was 5.7% among normal-weight women with adequate gestational weight gain and no GDM and 12.6%, 13.5% and 17.3% among women with BMIs of 25 or higher, excess gestational weight gain, and GDM, respectively. A reduction ranging between 46.8% in Asian and Pacific Islanders and 61.0% in non-Hispanic black women in LGA prevalence might result if women had none of the three exposures. For all race or ethnic groups, GDM contributed the least (2.0-8.0%), whereas excessive gestational weight gain contributed the most (33.3-37.7%) to LGA. CONCLUSION: Overweight and obesity, excessive gestational weight gain, and GDM all are associated with LGA; however, preventing excessive gestational weight gain has the greatest potential to reduce LGA risk. PMID- 24785600 TI - Hysteroscopic morcellation compared with electrical resection of endometrial polyps: a randomized controlled trial. AB - OBJECTIVE: To evaluate whether hysteroscopic morcellation or bipolar electrosurgical resection is more favorable for removing endometrial polyps in an office setting in terms of feasibility, speed, pain, and acceptability. METHODS: A multicenter, single-blind, randomized, controlled trial of office hysteroscopic morcellation compared with electrosurgical resection was conducted. A total of 121 women were randomly allocated to polyp removal by one of the two methods in an office setting. The outcomes assessed were time taken to complete the endometrial polypectomy, defined as the time from insertion to removal of vaginal instrumentation, completeness of polyp removal, acceptability, and pain measured on a 100-mm visual analog scale. RESULTS: The median time taken to complete the procedure was 5 minutes and 28 seconds for morcellation compared with 10 minutes and 12 seconds for electrosurgical resection (P<.001). The polyps were completely removed in 61 out of 62 (98%) women assigned to morcellation compared with 49 out of 59 (83%) women treated with electrosurgical resection (odds ratio 12.5; 95% confidence interval [CI] 1.5-100.6; P=.02). The mean pain scores during the procedure favored morcellation by 16.1 points on average (35.9 compared with 52.0; 95% CI for difference, -24.7 to -7.6; P<.001). Overall, 99% of women found office polypectomy to be acceptable, with only one woman in the electrosurgical resection group considering the procedure unacceptable. CONCLUSION: In comparison to electrosurgical resection during hysteroscopic polypectomy, morcellation was significantly quicker, less painful, more acceptable to women, and more likely to completely remove endometrial polyps compared with electrosurgical resection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01509313. PMID- 24785601 TI - Loop electrosurgical excision procedure and risk of preterm birth: a systematic review and meta-analysis. AB - OBJECTIVE: To assess whether loop electrosurgical excision procedure (LEEP) increases the risk for preterm birth before 37 weeks of gestation and clarify whether the increased risk for preterm birth is attributable to the procedure itself or to risk factors associated with cervical dysplasia. DATA SOURCES: Two authors performed a search of the relevant data through February 2013 using PubMed, Embase, Scopus, CENTRAL, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We included observational studies that compared rates of preterm birth in women with prior LEEP with women with no history of cervical excision. Nineteen of 559 identified studies met selection criteria. TABULATION, INTEGRATION, AND RESULTS: We compared women with a history of LEEP with two unexposed groups without a history of cervical excision: 1) women with an unknown or no history of cervical dysplasia; and 2) women with a history of cervical dysplasia but no cervical excision. The primary outcome was preterm birth before 37 weeks of gestation. Secondary outcomes were preterm birth before 34 weeks of gestation, spontaneous preterm birth, preterm premature rupture of membranes, and perinatal mortality. DerSimonian-Laird random effects models were used. We assessed heterogeneity between studies using the Q and I tests. Stratified analyses and metaregression were performed to assess confounding. Nineteen studies were included with a total of 6,589 patients with a history of LEEP and 1,415,015 without. Overall, LEEP was associated with an increased risk of preterm birth before 37 weeks of gestation (pooled relative risk 1.61, 95% confidence interval [CI] 1.35-1.92). However, no increased risk was found when women with a history of LEEP were compared with women with a history cervical dysplasia but no cervical excision (pooled relative risk 1.08, 95% CI 0.88-1.33). CONCLUSION: Women with a history of LEEP have similar risk of preterm birth when compared with women with prior dysplasia but no cervical excision. Common risk factors for both preterm birth and dysplasia likely explain findings of association between LEEP and preterm birth, but LEEP itself may not be an independent risk factor for preterm birth. PMID- 24785602 TI - Adjunctive social media for more effective contraceptive counseling: a randomized controlled trial. AB - OBJECTIVE: To determine whether social media, specifically Facebook, is an effective tool for improving contraceptive knowledge. METHODS: English-speaking women aged 18-45 years receiving care at an urban academic center obstetrics and gynecology clinic were included and randomized to a trial of standard contraceptive education and pamphlet (n=74) compared with standard contraceptive education and Facebook (n=69) information for contraception counseling. Contraceptive knowledge was evaluated preintervention and postintervention by the Contraceptive Knowledge Inventory. We evaluated the effect of the intervention by raw score and percent increase in Contraceptive Knowledge Inventory score, participant satisfaction with counseling method, and contraceptive preference postintervention. All analyses were stratified by age group. RESULTS: The median raw postintervention Contraceptive Knowledge Inventory score was significantly higher in the Facebook compared with the pamphlet group (15 compared with 12, P<.001) as was percentage increase in the Contraceptive Knowledge Inventory score (36% compared with 12%, P<.001). Participant satisfaction with counseling method was significantly higher in the Facebook group (median 10 compared with 6, P<.001). Participant contraceptive preference for long-acting reversible contraceptives (LARCs; intrauterine device or implant) postintervention was significantly greater in the Facebook compared with the pamphlet group (57% compared with 35%, P=.01). Among women currently using none or barrier contraception, contraceptive preference for implants was significantly greater in the Facebook compared with the pamphlet group (26% compared with 5%, P=.02), although, when analysis was extended to include implant or intrauterine device, LARCs were not significantly higher in the Facebook compared with the pamphlet group (48% compared with 33%, P=.19). CONCLUSION: Social media as an adjunct to traditional in-office counseling improves patient contraceptive knowledge and increases patient preference for LARCs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01994005. PMID- 24785603 TI - Change in sexual behavior with provision of no-cost contraception. AB - OBJECTIVE: To estimate whether providing no-cost contraception is associated with the number of sexual partners and frequency of intercourse over time. METHODS: This was an analysis of the Contraceptive CHOICE Project, a prospective cohort study of 9,256 adolescents and women at risk for unintended pregnancy. Participants were provided reversible contraception of their choice at no cost and were followed-up with telephone interviews at 6 and 12 months. We examined the number of male sexual partners and coital frequency reported during the previous 30 days at baseline compared with 6-month and 12-month time points. RESULTS: From our total cohort, 7,751 (84%) women and adolescents completed both 6-month and 12-month surveys and were included in this analysis. We observed a statistically significant decrease in the fraction of women and adolescents who reported more than one sexual partner during the past 30 days from baseline to 12 months (5.2% to 3.3%; P<.01). Most participants (70-71%) reported no change in their number of sexual partners at 6 and 12 months, whereas 13% reported a decrease and 16% reported an increase (P<.01). More than 80% of participants who reported an increase in the number of partners experienced an increase from zero to one partner. Frequency of intercourse increased during the past 30 days from baseline (median, 4) to 6 and 12 months (median, 6; P<.01). However, greater coital frequency did not result in greater sexually transmitted infection incidence at 12 months. CONCLUSION: We found little evidence to support concerns of increased sexual risk-taking behavior subsequent to greater access to no-cost contraception. PMID- 24785604 TI - Using a checklist to assess pregnancy in teenagers and young women. AB - OBJECTIVE: Health care providers should assess pregnancy in women seeking contraceptive services. Although urine pregnancy tests are available in most U.S. settings, their accuracy varies based on timing relative to missed menses, recent intercourse, or recent pregnancy. We examined the performance of a checklist based on criteria recommended in family planning guidance documents to assist health care providers in assessing pregnancy in a sample of U.S. teenagers and young women. METHODS: Study participants were a convenience sample of sexually active black females aged 14-19 years seeking care in an urban family planning clinic. Each participant provided a urine sample for pregnancy testing and was then administered the checklist in two formats, audio computer-assisted self interview and in-person interview. We estimated measures of the checklist performance compared with urine pregnancy test as the reference standard, including negative predictive value, sensitivity, specificity, and positive predictive value. RESULTS: Of 350 participants, 31 (8.9%) had a positive urine pregnancy test. The audio computer-assisted self-interview checklist indicated pregnancy was unlikely for 250 participants, of whom 241 had a negative urine pregnancy test (negative predictive value=96.4%). The sensitivity of the audio computer-assisted self-interview checklist was 71%, the specificity was 75.6%, and the positive predictive value was 22%. The in-person checklist yielded similar results. CONCLUSION: The checklist may be a valuable tool to assist in assessing pregnancy in teenagers and young women. Appropriate use of the checklist by family planning providers in combination with discussion and clinically indicated use of urine pregnancy tests may reduce unnecessary barriers to contraception in this population. PMID- 24785605 TI - Pregnancy outcomes in patients with prior uterine rupture or dehiscence. AB - OBJECTIVE: To report obstetric outcomes in a series of women with prior uterine rupture or prior uterine dehiscence managed with a standardized protocol. METHODS: Series of patients delivered by a single maternal-fetal medicine practice from 2005 to 2013 with a history of uterine rupture or uterine dehiscence. Uterine rupture was defined as a clinically apparent, complete scar separation in labor or before labor. Uterine dehiscence was defined as an incomplete and clinically occult uterine scar separation with intact serosa. Patients with prior uterine rupture were delivered at approximately 36-37 weeks of gestation or earlier in the setting of preterm labor. Patients with prior uterine dehiscence were delivered at 37-39 weeks of gestation based on obstetric history, clinical findings, and ultrasonographic findings. Patients with prior uterine rupture or uterine dehiscence were followed with serial ultrasound scans to assess fetal growth and lower uterine segment integrity. Outcomes measured were severe morbidities (uterine rupture, hysterectomy, transfusion, cystotomy, bowel injury, mechanical ventilation, intensive care unit admission, thrombosis, reoperation, maternal death, perinatal death). RESULTS: Fourteen women (20 pregnancies) had prior uterine rupture and 30 women (40 pregnancies) had prior uterine dehiscence. In these 60 pregnancies, there was 0% severe morbidity noted (95% confidence interval [CI] 0.0-6.0%). Overall, 6.7% of patients had a uterine dehiscence seen at the time of delivery (95% CI 2.6-15.9%). Among women with prior uterine rupture, the rate was 5.0% (95% CI 0.9-23.6%), whereas among women with prior uterine dehiscence, the rate was 7.5% (95% CI 2.6-19.9%). CONCLUSION: Patients with prior uterine rupture or uterine dehiscence can have excellent outcomes in subsequent pregnancies if managed in a standardized manner, including cesarean delivery before the onset of labor or immediately at the onset of spontaneous preterm labor. PMID- 24785606 TI - Regional distribution of cerebral white matter lesions years after preeclampsia and eclampsia. AB - OBJECTIVE: To assess the distribution of cerebral white matter lesions in women who had eclampsia, preeclampsia, or normotensive pregnancies. The pathophysiology of these lesions, more often seen in formerly eclamptic and preeclamptic women, is unclear but may be related to a predisposition for vascular disease, the occurrence of the posterior reversible encephalopathy syndrome, or both while pregnant. Assessing the distribution of such lesions may give insight into their pathophysiology and possible consequences. METHODS: This retrospective cohort study determined the presence, severity, and location of white matter lesions on cerebral magnetic resonance imaging scans of 64 formerly eclamptic, 74 formerly preeclamptic, and 75 parous control women. RESULTS: Formerly preeclamptic and eclamptic women have white matter lesions more often (34.4% [n=47] compared with 21.3% [n=16]; P<.05) and more severely (0.07 compared with 0.02 mL; P<.05) than parous women in a control group. In all women, the majority of lesions was located in the frontal lobes followed by the parietal, insular, and temporal lobes. CONCLUSION: White matter lesions are more common in women with prior pregnancies complicated by preeclampsia or eclampsia compared with parous women in a control group. In no group does regional white matter lesion distribution correspond to the occipitoparietal edema distribution seen in posterior reversible encephalopathy syndrome. PMID- 24785607 TI - Factors influencing the likelihood of instrumental delivery success. AB - OBJECTIVE: To evaluate risk factors for unsuccessful instrumental delivery when variability between individual obstetricians is taken into account. METHODS: We conducted a retrospective cohort study of attempted instrumental deliveries over a 5-year period (2008-2012 inclusive) in a tertiary United Kingdom center. To account for interobstetrician variability, we matched unsuccessful deliveries (case group) with successful deliveries (control group) by the same operators. Multivariate logistic regression was used to compare successful and unsuccessful instrumental deliveries. RESULTS: Three thousand seven hundred ninety-eight instrumental deliveries of vertex-presenting, single, term newborns were attempted, of which 246 were unsuccessful (6.5%). Increased birth weight (odds ratio [OR] 1.11; P<.001), second-stage labor duration (OR 1.01; P<.001), rotational delivery (OR 1.52; P<.05), and use of ventouse compared with forceps (OR 1.33; P<.05) were associated with unsuccessful outcome. When interobstetrician variability was controlled for, instrument selection and decision to rotate were no longer associated with instrumental delivery success. More senior obstetricians had higher rates of unsuccessful deliveries (12% compared with 5%; P<.05) but were used to undertake more complicated cases. Cesarean delivery during the second stage of labor without previous attempt at instrumental delivery was associated with higher birth weight (OR 1.07; P<.001), increased maternal age (OR 1.03; P<.01), and epidural analgesia (OR 1.46; P<.001). CONCLUSION: Results suggest that birth weight and head position are the most important factors in successful instrumental delivery, whereas the influence of instrument selection and rotational delivery appear to be operator-dependent. Risk factors for lack of instrumental delivery success are distinct from risk factors for requiring instrumental delivery, and these should not be conflated in clinical practice. PMID- 24785609 TI - Cancer risk in women with 10 or more deliveries. AB - OBJECTIVE: To determine cancer incidence among Finnish women with 10 or more deliveries. METHODS: Finnish women with at least 10 childbirths before December 31, 2010 (n=4,967) were identified from the Finnish Population Register and followed for cancer incidence through the Finnish Cancer Registry to the end of 2010. Cancer risks in this cohort were expressed as ratios between observed and expected numbers of cases (standardized incidence ratios), both drawn from the Finnish Cancer Registry, with 95% confidence intervals (CIs). RESULTS: Total cancer incidence was markedly lower than in the reference population (656 cases, standardized incidence ratio 0.76, 95% CI 0.73-0.79). There was clearly less breast (0.44, 0.35-0.53), ovarian (0.49, 0.28-0.80), endometrial (0.31, 0.17 0.44), and basal cell skin cancer (0.72, 0.60-0.85) than in the reference population. The incidence of thyroid cancer (2.33, 1.59-3.29), lip cancer (2.87, 1.05-6.24), and uterine sarcoma (3.41, 1.47-6.72) was markedly increased. CONCLUSION: Women with 10 or more deliveries show a decreased overall cancer incidence as a result of decreased risks of cancers of the ovary, endometrium, and breast and basal cell carcinoma of the skin. The increased risks were observed in thyroid cancer and some rare cancer types. PMID- 24785608 TI - Frequency of and factors associated with severe maternal morbidity. AB - OBJECTIVE: To estimate the frequency of severe maternal morbidity, assess its underlying etiologies, and develop a scoring system to predict its occurrence.Supplemental Digital Content is Available in the Text. METHODS: This was a secondary analysis of a Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network cohort of 115,502 women and their neonates born in 25 hospitals across the United States over a 3-year period. Women were classified as having severe maternal morbidity according to a scoring system that takes into account the occurrence of red blood cell transfusion (more than three units), intubation, unanticipated surgical intervention, organ failure, and intensive care unit admission. The frequency of severe maternal morbidity was calculated and the underlying etiologies determined. Multivariable analysis identified patient factors present on admission that were independently associated with severe maternal morbidity; these were used to develop a prediction model for severe maternal morbidity. RESULTS: Among 115,502 women who delivered during the study period, 332 (2.9/1,000 births, 95% confidence interval 2.6-3.2) experienced severe maternal morbidity. Postpartum hemorrhage was responsible for approximately half of severe maternal morbidity. Multiple patient factors were found to be independently associated with severe maternal morbidity and were used to develop a predictive model with an area under the receiver operating characteristic curve of 0.80. CONCLUSION: Severe maternal morbidity occurs in approximately 2.9 per 1,000 births, is most commonly the result of postpartum hemorrhage, and occurs more commonly in association with several identifiable patient characteristics. LEVEL OF EVIDENCE: : II. PMID- 24785610 TI - Human papillomavirus genotype prevalence in invasive vaginal cancer from a registry-based population. AB - OBJECTIVE: To describe the human papillomavirus (HPV) genotype distribution in invasive vaginal cancers diagnosed before the introduction of the HPV vaccine and evaluate if survival differed by HPV status. METHODS: Four population-based registries and three residual tissue repositories provided formalin-fixed, paraffin-embedded tissue from microscopically confirmed primary vaginal cancer cases diagnosed between 1994 and 2005 that were tested by L1 consensus polymerase chain reaction with type-specific hybridization in a central laboratory. Clinical, demographic, and all-cause survival data were assessed by HPV status. RESULTS: Sixty cases of invasive vaginal cancer were included. Human papillomavirus was detected in 75% (45) and 25% (15) were HPV-negative. HPV 16 was most frequently detected (55% [33/60]) followed by HPV 33 (18.3% [11/60]). Only one case was positive for HPV 18 (1.7%) Multiple types were detected in 15% of the cases. Vaginal cancers in women younger than 60 years were more likely to be HPV 16- or HPV 18-positive (HPV 16 and 18) than older women, 77.3% compared with 44.7% (P=.038). The median age at diagnosis was younger in the HPV 16 and 18 (59 years) group compared with other HPV-positive (68 years) and no HPV (77 years) (P=.003). The HPV distribution did not significantly vary by race or ethnicity or place of residence. The 5-year unadjusted all-cause survival was 57.4% for women with HPV-positive vaginal cancers compared with 35.7% among those with HPV-negative tumors (P=.243). CONCLUSION: Three fourths of all vaginal cancers in the United States had HPV detected, much higher than previously found, and 57% could be prevented by current HPV vaccines. PMID- 24785611 TI - Urinary incontinence, depression, and economic outcomes in a cohort of women between the ages of 54 and 65 years. AB - OBJECTIVE: To estimate the association between urinary incontinence (UI) and probable depression, work disability, and workforce exit. METHODS: The analytic sample consisted of 4,511 women enrolled in the population-based Health and Retirement Study cohort. The analysis baseline was 1996, the year that questions about UI were added to the survey instrument, and at which time study participants were 54-65 years of age. Women were followed-up with biennial interviews until 2010-2011. Outcomes of interest were onset of probable depression, work disability, and workforce exit. Urinary incontinence was specified in different ways based on questions about experience and frequency of urine loss. We fit Cox proportional hazards regression models to the data, adjusting the estimates for baseline sociodemographic and health status variables previously found to confound the association between UI and the outcomes of interest. RESULTS: At baseline, 727 participants (survey-weighted prevalence, 16.6%; 95% confidence interval [CI] 15.4-18.0) reported any UI, of which 212 (survey-weighted prevalence, 29.2%; 95% CI 25.4-33.3) reported urine loss on more than 15 days in the past month; and 1,052 participants were categorized as having probable depression (survey-weighted prevalence, 21.6%; 95% CI 19.8-23.6). Urinary incontinence was associated with increased risks for probable depression (adjusted hazard ratio, 1.43; 95% CI 1.27-1.62) and work disability (adjusted hazard ratio, 1.21; 95% CI 1.01-1.45), but not workforce exit (adjusted hazard ratio, 1.06; 95% CI 0.93-1.21). CONCLUSION: In a population-based cohort of women between ages 54 and 65 years, UI was associated with increased risks for probable depression and work disability. Improved diagnosis and management of UI may yield significant economic and psychosocial benefits. PMID- 24785612 TI - Early-onset group B streptococcal disease in the United States: potential for further reduction. AB - OBJECTIVE: To describe lapses in adherence to group B streptococcus (GBS) prevention guidelines among cases of early-onset GBS disease in term and preterm neonates and to estimate the potential for further reduction in disease burden under current prevention strategies. METHODS: We reviewed labor and delivery and prenatal records of mothers of neonates with early-onset GBS disease (aged younger than 7 days with GBS isolated from a normally sterile site) identified at population-based surveillance sites in 2008-2009. We interviewed prenatal care providers about GBS screening practices and obtained relevant laboratory records. We evaluated the data for errors in prenatal screening, laboratory methods, communication of results, and intrapartum antibiotic prophylaxis. Using published data on screening sensitivity and intrapartum prophylaxis effectiveness, we estimated the potential reduction in cases under optimal prevention implementation. RESULTS: Among 309 cases, 179 (57.9%) had one or more implementation errors. The most common error type in term and preterm case patients was prenatal screening (80 of 222 [36.0%]) and intrapartum prophylaxis (46 of 85 [54.1%]), respectively. We estimated that under optimal implementation, cases of early-onset GBS disease could be reduced by 26-59% with the largest benefit from a single intervention coming from improved use of intrapartum prophylaxis (16% decrease). CONCLUSION: Further reduction of early-onset GBS disease burden is possible under current prevention strategies, particularly with improved implementation of antibiotic prophylaxis. However, even with perfect adherence to recommended practices, the decline in cases may be modest. Therefore, novel prevention approaches such as improved intrapartum assays and vaccines are also needed. PMID- 24785613 TI - Effect of abuse during pregnancy on maternal and child safety and functioning for 24 months after delivery. AB - OBJECTIVE: To evaluate the long-term safety and functioning outcomes for abused women reporting abuse during pregnancy and their children's behavior compared with abused women who do not report abuse during pregnancy. METHODS: Forty-six abused women seeking assistance for partner abuse and reporting being pregnant during the preceding 4 months were evaluated every 4 months for 24 months to compare levels of abuse, danger for murder, anxiety, depression, somatization, and posttraumatic stress disorder (PTSD) for abused women who report abuse during pregnancy (n=24) compared with abused women reporting abuse only outside of pregnancy (n=22). Internalizing and externalizing behavior scores were evaluated for the children. RESULTS: At entry into the study, abused women reporting abuse during pregnancy reported significantly greater (P<.05) threats of abuse, sexual abuse, physical abuse, danger for murder, and PTSD compared with abused women not reporting abuse during pregnancy. Effect sizes were large. When evaluated over the course of 24 months after delivery, risk for murder remained higher for women reporting abuse during pregnancy for 8 months after delivery, depression was higher at 4, 8, 16, and 20 months after delivery, and PTSD was appreciably higher for 24 months. Children living with mothers abused during pregnancy displayed more behavioral problems for the entire 24-month period, especially problems of depression and anxiety. CONCLUSION: The study documents the negative safety and function effects of abuse in pregnant women that remain for at least 24 months after delivery. This warrants incorporating abuse screening during the antenatal and postdelivery periods and a protocol of care during the antenatal period and beyond. PMID- 24785614 TI - Postpartum internal carotid and vertebral arterial dissections. AB - OBJECTIVE: Headache and neck pain are common postpartum symptoms. However, these symptoms can rarely be associated with internal carotid artery and vertebral artery dissections. We aimed to review five cases of postpartum cervical artery dissection and to review the clinical course of previously reported cases. METHODS: Patients with postpartum dissections diagnosed at our institution since 2005 were identified through a database maintained by the senior author, and their clinical data were reviewed. Additionally, a literature search for previously reported cases was performed, and the clinical data in those reports were reviewed. RESULTS: Five patients presented with cervical artery dissections within 6 weeks postpartum. Four patients had delivered vaginally and one delivered by emergent cesarean. Headache and neck pain were the primary presenting symptoms of all five patients. Four patients demonstrated neurologic symptoms, and one had development of stroke. Two patients had single internal carotid artery dissections, one patient had bilateral dissections of the vertebral artery, and two patients had dissections in the internal carotid artery and vertebral artery. All patients were treated with either anticoagulation therapy or antiplatelet therapy. Two patients required endovascular stenting. Four of five patients returned to neurologic baseline after treatment. A literature search yielded 27 previously reported cases, with similar clinical characteristics of older reproductive age, presentation days to weeks from delivery, and recovery to neurologic baseline in the majority of patients. CONCLUSION: Postpartum cervical dissections are rare occurrences that require prompt diagnosis to prevent long-term neurologic deficits. Individualized management strategies include medical treatment (anticoagulation therapy, antiplatelet therapy, or anticoagulation and antiplatelet therapy) and endovascular recanalization. PMID- 24785616 TI - Health reform in action: updates on implementation of the Affordable Care Act. PMID- 24785615 TI - Obesity and mental disorders during pregnancy and postpartum: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the prevalence and risk of antenatal and postpartum mental disorders among obese and overweight women. DATA SOURCES: Seven databases (including MEDLINE and ClinicalTrials.gov) were searched from inception to January 7, 2013, in addition to citation tracking, hand searches, and expert recommendations. METHODS OF STUDY SELECTION: Studies were eligible if antenatal or postpartum mental disorders were assessed with diagnostic or screening tools among women who were obese or overweight at the start of pregnancy. Of the 4,687 screened articles, 62 met the inclusion criteria for the review. The selected studies included a total of 540,373 women. TABULATION, INTEGRATION, AND RESULTS: Unadjusted odds ratios were pooled using random-effects meta-analysis for antenatal depression (n=29), postpartum depression (n=16), and antenatal anxiety (n=10). Obese and overweight women had significantly higher odds of elevated depression symptoms than normal-weight women and higher median prevalence estimates. This was found both during pregnancy (obese odds ratio [OR] 1.43, 95% confidence interval [CI] 1.27-1.61, overweight OR 1.19, 95% CI 1.09-1.31, median prevalence: obese 33.0%, overweight 28.6%, normal-weight 22.6%) and postpartum (obese OR 1.30, 95% CI 1.20-1.42, overweight OR 1.09, 95% CI 1.05-1.13, median prevalence: obese 13.0%, overweight 11.8%, normal-weight 9.9%). Obese women also had higher odds of antenatal anxiety (OR 1.41, 95% CI 1.10-1.80). The few studies identified for postpartum anxiety (n=3), eating disorders (n=2), or serious mental illness (n=2) also suggested increased risk among obese women. CONCLUSION: Health care providers should be aware that women who are obese when they become pregnant are more likely to experience elevated antenatal and postpartum depression symptoms than normal-weight women, with intermediate risks for overweight women. PMID- 24785617 TI - Puerperal group A streptococcal infection: beyond Semmelweis. AB - Ignaz Semmelweiss made one of the most important contributions to modern medicine when he instituted handwashing in an obstetric clinic in Austria in 1847, decreasing mortality there from more than 10% to 2%. Unfortunately, puerperal sepsis remains a leading cause of maternal mortality throughout the world. Group A streptococcus (GAS), Streptococcus pyogenes, is an organism associated with high rates of morbidity and mortality from puerperal infections. When associated with sepsis, known as streptococcal toxic shock syndrome, mortality rates approach 30-50%. Group A streptococcus can cause invasive infections in the form of endometritis, necrotizing fasciitis, or streptococcal toxic shock syndrome. The clinical presentation of women with puerperal GAS infections is often atypical with extremes of temperature, unusual and vague pain, and pain in extremities. Toxin production by the organism may allow GAS to spread across tissue planes and cause necrosis while evading containment by the maternal immune system in the form of a discrete abscess. Endometrial aspiration in addition to blood cultures may be a useful rapid diagnostic tool. Imaging may appear normal and should not dissuade the clinician from aggressive management. When suspected, invasive GAS infections should be treated emergently with fluid resuscitation, antibiotic administration, and source control. The optimal antibiotic regimen contains penicillin and clindamycin. Source control may require extensive wound or vulvar debridement, hysterectomy, or a combination of these, which may be life saving. The benefit of immunoglobulins in management of puerperal GAS infections is unclear. PMID- 24785618 TI - What is new in obstetric antecedents of chronic disease? Best articles from the past year. AB - This month, we focus on current research in obstetric antecedents of chronic disease. Dr Malone discusses four recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page along with direct links to the abstracts. PMID- 24785619 TI - Comparison of robotic and laparoscopic hysterectomy for benign gynecologic disease. PMID- 24785620 TI - In reply. PMID- 24785621 TI - Interval from loop electrosurgical excision procedure to pregnancy and pregnancy outcomes. PMID- 24785622 TI - In reply. PMID- 24785623 TI - Terminal fetal heart rate decelerations and neonatal outcomes. PMID- 24785624 TI - In reply. PMID- 24785625 TI - Robotics in benign gynecologic surgery: where should we go? PMID- 24785626 TI - In reply. PMID- 24785627 TI - Surgical proctoring for gynecologic surgery. PMID- 24785628 TI - In reply. PMID- 24785633 TI - Executive summary: Neonatal encephalopathy and neurologic outcome, second edition. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Encephalopathy. PMID- 24785634 TI - Executive summary: Neonatal brachial plexus palsy. Report of the American College of Obstetricians and Gynecologists' Task Force on Neonatal Brachial Plexus Palsy. AB - The American College of Obstetricians and Gynecologists convened the Task Force on Neonatal Brachial Plexus Palsy to develop a comprehensive report summarizing a scientific literature on this subject. Clinically, neonatal brachial plexus palsy (NBPP) presents in a newborn as a weak or paralyzed upper extremity, with the passive range of motion greater than the active. The overall incidence of NBPP, both transient and persistent impairment, is 1.5 per 1,000 total births. Multiple reports in the peer-reviewed literature describe the occurrence of NBPP without concomitant clinically recognizable shoulder dystocia at the time of both vaginal and cesarean delivery. Chapter 1 of the report details the incidence of NBPP. PMID- 24785635 TI - ACOG Committee Opinion no. 592: Sexual assault. AB - Reproductive-aged victims of sexual assault are at risk of unintended pregnancy, sexually transmitted infections, and mental health conditions, including posttraumatic stress disorder. Health care providers should screen routinely for a history of sexual assault and offer victims both emergency contraception and sexually transmitted infection prophylaxis. The health care provider who examines victims of sexual assault has a responsibility to comply with state and local statutory or policy requirements for the use of evidence-gathering kits. PMID- 24785636 TI - ACOG Committee Opinion no. 593: Management of women with dense breasts diagnosed by mammography. AB - Women with dense breasts have a modestly increased risk of breast cancer and experience reduced sensitivity of mammography to detect breast cancer. However, evidence is lacking to advocate for additional testing until there are clinically validated data that indicate improved screening outcomes. Currently, screening mammography remains the most useful tool for breast cancer detection and has consistently demonstrated a reduction in breast cancer mortality. The American College of Obstetricians and Gynecologists does not recommend routine use of alternative or adjunctive tests to screening mammography in women with dense breasts who are asymptomatic and have no additional risk factors. The American College of Obstetricians and Gynecologists recommends that health care providers comply with state laws that may require disclosure to women of their breast density as recorded in a mammogram report. PMID- 24785637 TI - ACOG Committee Opinion no. 594: Immersion in water during labor and delivery. AB - Immersion in water has been suggested as a beneficial alternative for labor, or delivery, or both and over the past decades has gained popularity in many parts of world. Immersion in water during the first stage of labor may be associated with decreased pain or use of anesthesia and decreased duration of labor. However, there is no evidence that immersion in water during the first stage of labor otherwise improves perinatal outcomes, and it should not prevent or inhibit other elements of care. The safety and efficacy of immersion in water during the second stage of labor have not been established, and immersion in water during the second stage of labor has not been associated with maternal or fetal benefit. Given these facts and case reports of rare but serious adverse effects in the newborn, the practice of immersion in the second stage of labor (underwater delivery) should be considered an experimental procedure that only should be performed within the context of an appropriately designed clinical trial with informed consent. Facilities that plan to offer immersion in the first stage of labor need to establish rigorous protocols for candidate selection, maintenance and cleaning of tubs and immersion pools, infection control procedures, monitoring of mothers and fetuses at appropriate intervals while immersed, and immediately and safely moving women out of the tubs if maternal or fetal concerns develop. PMID- 24785638 TI - Biological macromolecules at interfaces probed by chiral vibrational sum frequency generation spectroscopy. PMID- 24785639 TI - The interplay between the Aharonov-Bohm interference and parity selective tunneling in graphene nanoribbon rings. AB - We report on a numerical study of the Aharonov-Bohm (AB) effect and parity selective tunneling in pn junctions based on rectangular graphene rings where the contacts and ring arms are all made of zigzag nanoribbons. We find that when applying a magnetic field to the ring, the AB interference can reverse the parity symmetry of incoming waves and hence can strongly modulate the parity selective transmission through the system. Therefore, the transmission between two states of different parity exhibits the AB oscillations with a pi-phase shift, compared to the case of states of the same parity. On this basis, it is shown that interesting effects, such as giant (both positive and negative) magnetoresistance and strong negative differential conductance, can be achieved in this structure. Our study thus presents a new property of the AB interference in graphene nanorings, which could be helpful for further understanding the transport properties of graphene mesoscopic systems. PMID- 24785641 TI - Adsorption of mixtures of poly(amidoamine) dendrimers and sodium dodecyl sulfate at the air-water interface. AB - We relate the adsorption from mixtures of well-defined poly(amidoamine) (PAMAM) dendrimers of generations 4 and 8 with sodium dodecyl sulfate (SDS) at the air water interface to the bulk solution properties. The anionic surfactant shows strong attractive interactions with the cationic dendrimers at pH 7, and electrophoretic mobility measurements indicate that the association is primarily driven by electrostatic interactions. Optical density measurements highlight the lack of colloidal stability of the formed bulk aggregates at compositions close to charge neutrality, the time scale of which is dependent on the dendrimer generation. Adsorption at the air-water interface was followed from samples immediately after mixing using a combination of surface tension, neutron reflectometry, and ellipsometry measurements. In the phase separation region for dendrimers of generation 4, we observed high surface tension corresponding to a depleted surfactant solution but only when the aggregates carried an excess of surfactant. Interestingly, these depleted adsorption layers contained spontaneously adsorbed macroscopic aggregates, and these embedded particles do not rearrange to spread monomeric material at the interface. These findings are discussed in relation to the interfacial properties of mixtures involving dendrimers of generation 8 as well as polydisperse linear and hyperbranched polyelectrolytes where there is polyelectrolyte bound to a surfactant monolayer. The results presented here demonstrate the capability of dendrimers to sequester anionic surfactants in a controllable manner, with potential applications as demulsification and antifoaming agents. PMID- 24785640 TI - Rational design of InhA inhibitors in the class of diphenyl ether derivatives as potential anti-tubercular agents using molecular dynamics simulations. AB - A series of diphenyl ether derivatives were developed and showed promising potency for inhibiting InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, leading to the lysis of Mycobacterium tuberculosis. To understand the structural basis of diphenyl ether derivatives for designing more potent inhibitors, molecular dynamics (MD) simulations were performed. Based on the obtained results, the dynamic behaviour in terms of flexibility, binding free energy, binding energy decomposition, conformation, and the inhibitor-enzyme interaction of diphenyl ether inhibitors were elucidated. Phe149, Tyr158, Met161, Met199, Val203 and NAD+ are the key residues for binding of diphenyl ether inhibitors in the InhA binding pocket. Our results could provide the structural concept to design new diphenyl ether inhibitors with better enzyme inhibitory activity against M. tuberculosis InhA. The present work facilitates the design of new and potentially more effective anti-tuberculosis agents. PMID- 24785642 TI - Selective culture method for hepatocyte-like cells differentiated from human induced pluripotent stem cells. AB - This study aimed to establish culture conditions which are able to give the differentiation of induced pluripotent (iPS) cells to hepatocytes. To this end, we examined the usefulness of a culture medium containing the components involved in the intermediary metabolism in the liver. More specifically, we examined the effect of the "modified L-15 medium" containing galactose, phenylalanine and ornitine, but deprived of glucose, tyrosine, arginine and pyruvic acid. The medium was altered according to changes in the expression of enzymes that participate in liver-specific pathways. After 25 days of differentiation, the differentiated cells expressed hepatocyte markers and drug-metabolizing enzymes. These expression levels were increased using modified L-15 medium. The survival of human fetal liver cells and the death of human fibroblasts were observed during culture in modified L-15 medium. Most of the cells that differentiated from human iPS cells using modified L-15 medium were stained by anti-human albumin antibody. These results suggest that iPS cells can be converted to high purity-differentiated hepatocytes by cultivating them in modified L-15 medium. PMID- 24785643 TI - Testosterone, cardiovascular disease, and mortality in men: living in the dark. PMID- 24785644 TI - EAACI Food Allergy and Anaphylaxis Guidelines. Food allergy health-related quality of life measures. AB - Instruments have been developed and validated for the measurement of health related quality of life in patients with food allergy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group. It draws on a systematic review of the literature on quality of life instruments for food allergy and the Appraisal of Guidelines for Research & Evaluation (AGREE II) guideline development process. Guidance is provided on the use of such instruments in research, and the current limitations of their use in clinical practice are described. Gaps in current knowledge as well as areas of future interest are also discussed. This document is relevant to healthcare workers dealing with food allergic patients, scientists engaging in food allergy research and policy makers involved in regulatory aspects concerning food allergy and safety. PMID- 24785645 TI - Association between home availability and vegetable consumption in youth: a review. AB - OBJECTIVE: To systematically review literature examining the association between vegetable home availability and vegetable intake in youth. DESIGN: Articles were identified through December 2012 using a search of PubMed, PsychINFO and OVID/Medline databases, using the following keywords in varying combinations: home, environment, availability, vegetable, intake, consumption, children. Quantitative studies examining home vegetable availability and vegetable intake in children and adolescents were included. Fifteen studies were included that met inclusion criteria. SETTING: Studies were conducted in the USA (n 8), Australia (n 1), Greece (n 1), Iceland (n 1), Denmark (n 1), the UK (n 1), the Netherlands (n 1) and a combination of nine European countries (n 1). SUBJECTS: Various populations of children and adolescents were examined. RESULTS: Seven of the studies (47 %) found a positive association between vegetable availability and intake, with the others reporting null findings. There were no clear patterns of association by study design, age of subjects included, comprehensiveness of measures, or inclusion of covariates in analyses. Child report of home availability was associated with child vegetable intake (n 6, all found a positive association), while parent report of home availability was only minimally associated (n 9, one found a positive association; P=0.001 from post hoc Fisher's exact test comparing parent v. child report). CONCLUSIONS: Parent perception of availability may be closer to truth, given the parental role in food shopping and preparation. Therefore, to impact child vegetable intake, absolute availability may not be as important as child perception of vegetables in the home. Child perception of availability may be altered by level of familiarity with vegetables. PMID- 24785646 TI - Progressive compression, plantar load and calf venous pump. PMID- 24785647 TI - Radial artery bypass graft is a feasible and durable conduit for challenging infrainguinal revascularization: 17 years of Melbourne experience. AB - OBJECTIVES: The superiority of autogenous venous conduits in infrainguinal bypass surgery is well established. In the absence of suitable leg or arm veins the radial artery can be utilized as an alternative autogenous conduit. In contrast to cardiac surgery, experience with the radial artery as a conduit for infrainguinal bypass surgery is limited. The purpose of this study was to review the outcomes of our radial artery bypasses over the last 17 years. METHODS: All radial artery bypasses performed between 1995 and 2012 were identified from a prospective database. Patency, limb salvage, and survival were calculated using the Kaplan-Meier survival estimate method. RESULTS: Twenty-nine radial artery bypasses were performed in 28 patients. Median follow-up was 55 months (range 1 170). Twelve-month primary, assisted primary, and secondary patency rates were 49%, 62%, and 73% respectively; Both 3-year and 5-year primary, assisted primary, and secondary patency rates were 49%, 56% and 67% respectively. Limb salvage rate was 75% at 1- and 5-year follow-up. Patient survival at 1, 3, and 5 years was 96%, 88%, and 76%. CONCLUSIONS: For patients with need of challenging infrainguinal revascularization without suitable autogenous venous conduit, a radial artery bypass can be performed safely with favorable long-term patency and limb salvage rates. PMID- 24785648 TI - Response to 'Re. Improvement of venous pumping function by double progressive compression stockings: higher pressure over the calf is more important than a graduated pressure profile'. PMID- 24785649 TI - Re. 'Carotid endarterectomy with stent removal in management of in-stent restenosis: a safe, feasible, and effective technique'. PMID- 24785650 TI - Treatment decisions for descending thoracic aneurysm: preferences for thoracic endovascular aneurysm repair or surveillance in a discrete choice experiment. AB - OBJECTIVE: To investigate and rank factors that influence endovascular treatment decisions by specialists for patients with descending thoracic aortic aneurysm (dTAA). METHODS: Specialists completed a diagrammatic survey describing uncertainty about the benefit of thoracic endovascular aneurysm repair (TEVAR) for dTAA with respect to age, sex, and aneurysm diameter. Subsequently, a detailed discrete choice experiment was designed. Specialists were recruited and asked to indicate treatment their preference (TEVAR or surveillance) in 25 hypothetical cases of dTAA, with variable patient attributes: age, sex, American Society of Anesthesiologists (ASA) grade, aneurysm diameter, adequate landing zone distal to left subclavian artery (LSA), and length of aortic coverage. Data were analysed using multiple logistic regression. RESULTS: The diagrammatic survey, based on 50 respondents, showed that uncertainty about the benefits of TEVAR was greatest for patients aged 80-85 years (up to 47% of respondents were "unsure") and that uncertainty increased with increasing aneurysm diameter (for an 80-year-old man, 7% were unsure at 5.5 cm and 33% were unsure at 7.0 cm). Seventy-one specialists (mainly from Europe and North America, 86% vascular surgeons and 98% working in units offering TEVAR) completed the discrete choice experiment. Preference for TEVAR increased greatly with enlarging diameter: adjusted odds ratios (OR) >5.5-6.0 cm = 15.8 (95% confidence interval [CI] 9.83 25.40); >6.0-6.5 cm = 393.0 (95% CI 202.00-766.00); >6.5-7.0 cm = 1829.0 (95% CI 400.00-4,181.00). TEVAR was less likely to be preferred in patients older than 75 years (>75-80 years OR 0.32, 95% CI 0.21-0.49; >80-85 years = 0.18, 95% CI 0.11 0.28); in women (OR 0.52, 95% CI 0.37-0.74); in patients classified as ASA grade 4 (OR 0.44, 95% CI 0.36-0.57); and in patients with aorta coverage >25 cm (OR 0.48, 95% CI 0.32-0.74). The proximal landing zone did not influence preference. CONCLUSION: Specialists' preferences for endovascular repair of degenerative dTAA vary widely, and demonstrate clinical uncertainty, especially in octogenarians, and a reluctance to offer TEVAR to women. Aneurysm diameter dominates treatment preferences, but patient fitness and length of aortic coverage (>25 cm) also were influential, although the landing zone distal to LSA was not. PMID- 24785651 TI - Quality of life, support and smoking in advanced lung cancer patients: a qualitative study. AB - BACKGROUND: Lung cancer is the most common cancer and smoking is the principal cause. Due to poor survival rates, symptom palliation and promotion of health related quality of life (HRQoL) are primary outcomes for lung cancer patients. Given the established relationship between smoking and lung cancer, patients who have smoked may feel stigmatised or guilty after diagnosis, and more pessimistic about their illness and likely outcomes. This may have adverse implications for HRQoL. OBJECTIVES: We explored HRQoL and support experiences among newly diagnosed patients with advanced lung cancer. DESIGN: Semistructured interviews were conducted with nine patients and analysed using interpretative phenomenological analysis. RESULTS: Patients described the physical, emotional and social impact of disease on HRQoL. Fear of compromising their immune system and adjusting to new relationship roles had a wide-ranging effect on patients' HRQoL. Patients acknowledged links between lung cancer and smoking but some continued to smoke. They were sensitive to the opinions of medical staff about smoking especially those who continued to smoke or recently quit. CONCLUSIONS: We conclude that staff should give clearer advice about the adverse implications of continued smoking. We discuss the potential value of diagnosis as a teachable moment for promoting smoking cessation among patients and family members. PMID- 24785652 TI - A rights-based approach to sexuality education: conceptualization, clarification and challenges. AB - CONTEXT: Although a rights-based approach to sexuality education has been increasingly discussed in the past decade, documented consensus regarding the goals, concepts and underlying assumptions of this approach is lacking. Differences in the assumed meaning of a rights-based approach can limit discussions of its implementation and evaluation, and impede opportunities to explore and critique a new model for sexuality education. METHODS: In-depth interviews were conducted in 2012 with 21 U.S. and international sexuality education experts. Data were thematically coded and analyzed using an iterative approach. Responses were compared according to respondents' professional discipline and geographic focus. RESULTS: A rights-based approach can be defined as the intersection of four elements: an underlying principle that youth have sexual rights; an expansion of programmatic goals beyond reducing unintended pregnancy and STDs; a broadening of curricula content to include such issues as gender norms, sexual orientation, sexual expression and pleasure, violence, and individual rights and responsibilities in relationships; and a participatory teaching strategy that engages youth in critical thinking about their sexuality and sexual choices. These elements were consistently identified by respondents across professional disciplines and geographic foci. In addition, all respondents raised questions about the feasibility of implementing a rights-based approach, particularly in the United States. CONCLUSIONS: While questions remain to be answered regarding the implementation and impact of rights-based sexuality education, the proposed conceptual definition suggests multiple avenues for advocates, researchers, program developers and funders to enhance adolescent sexual health. PMID- 24785654 TI - Chemically reversible reactions of hydrogen sulfide with metal phthalocyanines. AB - Hydrogen sulfide (H2S) is an important signaling molecule that exerts action on various bioinorganic targets. Despite this importance, few studies have investigated the differential reactivity of the physiologically relevant H2S and HS(-) protonation states with metal complexes. Here we report the distinct reactivity of H2S and HS(-) with zinc(II) and cobalt(II) phthalocyanine (Pc) complexes and highlight the chemical reversibility and cyclability of each metal. ZnPc reacts with HS(-), but not H2S, to generate [ZnPc-SH](-), which can be converted back to ZnPc by protonation. CoPc reacts with HS(-), but not H2S, to form [Co(I)Pc](-), which can be reoxidized to CoPc by air. Taken together, these results demonstrate the chemically reversible reaction of HS(-) with metal phthalocyanine complexes and highlight the importance of H2S protonation state in understanding the reactivity profile of H2S with biologically relevant metal scaffolds. PMID- 24785653 TI - Predicting tenderness of fresh ovine semimembranosus using Raman spectroscopy. AB - A hand held Raman probe was used to predict shear force (SF) of fresh lamb m. semimembranosus (topside). Eighty muscles were measured at 1 day PM and after a further 4 days ageing (5 days PM). At 1 day PM sarcomere length (SL) and particle size (PS) were measured and at 5 days PM, SF, PS, cooking loss (CL) and pH were also measured. SF values were regressed against Raman spectra using partial least squares regression and against traditional predictors (e.g. SL) using linear regression. The best prediction of SF used spectra at 1 day PM which gave a root mean square error of prediction (RMSEP) of 11.5 N (Null = 13.2) and the squared correlation between observed and cross validated predicted values (R(2)cv) was 0.27. Prediction of SF based on the traditional predictors had smaller R(2) values than using Raman spectra justifying further study on Raman spectroscopy. PMID- 24785655 TI - Rapid detection of infectious flacherie virus of the silkworm, Bombyx mori, using RT-PCR and nested PCR. AB - In this study, a method for detection of an ssRNA viral pathogen that causes viral flacherie in the silkworm, Bombyx mori (L.) (Lepidoptera: Bombycidae), was used for the detection of B. mori infectious flacherie virus (BmIFV). A combination of nested and reverse transcriptase polymerase chain reaction was used for detection. Although BmIFV has been reported in almost all the sericultural regions of the world, there had been no reports of BmIFV incidence in India. Therefore, the confirmation of the presence of BmIFV in Karnataka, India, is of great significance. The present method is advantageous because it can be used to detect the virus by using samples from infected midgut tissues, thus simplifying and avoiding laborious genome isolation procedures. This method could help in early detection of BmIFV disease pathogens and help reduce crop losses. PMID- 24785656 TI - Disease flare after 7 year-remission of systemic type juvenile idiopathic arthritis: is growth hormone therapy a culprit or innocent bystander? PMID- 24785658 TI - Dynamic plasticity of NMDA receptor-mediated calcium entry in neurons exposed to HIV-tat. PMID- 24785657 TI - NRBF2 regulates macroautophagy as a component of Vps34 Complex I. AB - Macroautophagy is a physiological cellular response to nutrient stress, which leads to the engulfment of cytosolic contents by a double-walled membrane structure, the phagophore. Phagophores seal to become autophagosomes, which then fuse with lysosomes to deliver their contents for degradation. Macroautophagy is regulated by numerous cellular factors, including the Class III PI3K (phosphoinositide 3-kinase) Vps34 (vacuolar protein sorting 34). The autophagic functions of Vps34 require its recruitment to a complex that includes Vps15, Beclin-1 and Atg14L (autophagy-related 14-like protein) and is known as Vps34 Complex I. We have now identified NRBF2 (nuclear receptor-binding factor 2) as a new member of Vps34 Complex I. NRBF2 binds to complexes that include Vps34, Vps15, Beclin-1 and ATG-14L, but not the Vps34 Complex II component UVRAG (UV radiation resistance-associated gene). NRBF2 directly interacts with Vps15 via the Vps15 WD40 domain as well as other regions of Vps15. The formation of GFP-LC3 (light chain 3) punctae and PE (phosphatidylethanolamine)-conjugated LC3 (LC3-II) in serum-starved cells was inhibited by NRBF2 knockdown in the absence and presence of lysosomal inhibitors, and p62 levels were increased. Thus NRBF2 plays a critical role in the induction of starvation-induced autophagy as a specific member of Vps34 Complex I. PMID- 24785659 TI - Dynamically analyte-responsive macrocyclic host-fluorophore systems. AB - CONSPECTUS: Host-guest chemistry commenced to a large degree with the work of Pedersen, who in 1967 first reported the synthesis of crown ethers. The past 45 years have witnessed a substantial progress in the field, from the design of highly selective host molecules as receptors to their application in drug delivery and, particularly, analyte sensing. Much effort has been expended on designing receptors and signaling mechanism for detecting compounds of biological and environmental relevance. Traditionally, the design of a chemosensor comprises one component for molecular recognition, frequently macrocycles of the cyclodextrin, cucurbituril, cyclophane, or calixarene type. The second component, used for signaling, is typically an indicator dye which changes its photophysical properties, preferably its fluorescence, upon analyte binding. A variety of signal transduction mechanisms are available, of which displacement of the dye from the macrocyclic binding site is one of the simplest and most popular ones. This constitutes the working principle of indicator displacement assays. However, indicator displacement assays have been predominantly exploited in a static fashion, namely, to determine absolute analyte concentrations, or, by using combinations of several reporter pairs, to achieve a differential sensing and, thus, identification of specific food products or brands. In contrast, their use in biological systems, for example, with membranes, cells, or with enzymes has been comparably less explored, which led us to the design of the so-called tandem assays, that is, dynamically analyte-responsive host-dye systems, in which the change in analyte concentrations is induced by a biological reaction or process. This methodological variation has practical application potential, because the ability to monitor these biochemical pathways or to follow specific molecules in real time is of paramount interest for both biochemical laboratories and the pharmaceutical industry. We will begin by describing the underlying principles that govern the use of macrocycle-fluorescent dye complexes to monitor time dependent changes in analyte concentrations. Suitable chemosensing ensembles are introduced, along with their fluorescence responses (switch-on or switch-off). This includes supramolecular tandem assays in their product- and substrate selective variants, and in their domino and enzyme-coupled modifications, with assays for amino acid decarboxylases, diamine, and choline oxidase, proteases, methyl transferases, acetylcholineesterase (including an unpublished direct tandem assay), choline oxidase, and potato apyrase as examples. It also includes the very recently introduced tandem membrane assays in their published influx and unpublished efflux variants, with the outer membrane protein F as channel protein and protamine as bidirectionally translocated analyte. As proof-of-principle for environmental monitoring applications, we describe sensing ensembles for volatile hydrocarbons. PMID- 24785660 TI - Designing AAC systems for children with autism: evidence from eye tracking research. AB - Autism is associated with a range of language difficulties that impact communication, behaviour management, and education. Consequently, a variety of augmentative and alternative communication (AAC) strategies may be employed to support people with autism to communicate. There is a growing body of evidence concerning the visual attention of individuals with autism, which may be relevant to AAC interventions. This review draws on evidence from eye tracking research specifically to inform the design of AAC systems for people with autism. In addition, we discuss the future of AAC for individuals with autism in light of relevant technological developments, and raise questions for future research. PMID- 24785661 TI - Dynamics of a producer-freeloader ecosystem on the brink of collapse. AB - Ecosystems can undergo sudden shifts to undesirable states, but recent studies with simple single-species ecosystems have demonstrated that advance warning can be provided by the slowing down of population dynamics near a tipping point. However, it is unclear how this 'critical slowing down' will manifest in ecosystems with strong interactions between their components. Here we probe the dynamics of an experimental producer-freeloader ecosystem as it approaches a catastrophic collapse. Surprisingly, the producer population grows in size as the environment deteriorates, highlighting that population size can be a misleading measure of ecosystem stability. By analysing the oscillatory producer-freeloader dynamics for over 100 generations in multiple environmental conditions, we find that the collective ecosystem dynamics slow down as the tipping point is approached. Analysis of the coupled dynamics of interacting populations may therefore be necessary to provide advance warning of collapse in complex communities. PMID- 24785662 TI - Calling all APRN researchers. PMID- 24785663 TI - Rehydration of children with gastroenteritis. AB - Review of recent evidence with translation to practice for the advanced practice nurse role is presented using a case study module for "Intravenous Dextrose for Children With Gastroenteritis and Dehydration: A Double-Blind Randomized Controlled Trial." The study results showed that 35% of the children who received dextrose in normal saline (D5NS) were hospitalized as compared with 44% who received normal saline. The implications and clinical relevance of these findings for advanced practice nurses are discussed highlighting best evidence. PMID- 24785664 TI - Kienbock's disease: A rare wrist disorder in a young male. AB - Kienbock's disease is a rare disorder involving the lunate, one of the carpal bones, and is, therefore, not commonly included in the differential diagnosis of patients presenting to the emergency department with wrist pain. Delay in diagnosis inevitably leads to disease progression, thereby reducing surgical options. This article presents a patient's case including patient history, differential diagnosis, radiographic findings, and management. The challenges in the diagnosis of this disease are discussed in relation to significance to clinical practice for nurse practitioners and emergency department physicians. PMID- 24785665 TI - Tranexamic acid for trauma-related hemorrhage. AB - Trauma-related deaths represent a leading cause of mortality among persons younger than 45 years. A significant percentage of these are secondary to hemorrhage. In trauma, massive and rapid loss of blood creates an imbalance in hemostasis. Mainstays of resuscitation include surgical interventions, restoring intravascular volume, and pharmacologic interventions. Providers continue to search for improved pharmacologic options for achieving hemostasis. Tranexamic acid is an antifibrinolytic and inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. Tranexamic acid works to stabilize and inhibit the degradation of existing clots. Tranexamic acid has been prospectively proven to reduce mortality in trauma-related hemorrhage. Its use will likely expand into such areas as resuscitation and massive transfusion protocols and the prehospital setting. Therefore, it is critical for emergency medicine providers to be familiar with appropriate use of tranexamic acid in order to maximize efficacy and decrease the potential adverse events. PMID- 24785667 TI - Caring for the postoperative patient with complications presenting to the emergency department. AB - The purpose of the article was to understand that the variations in common surgical procedures, physical, laboratory, and radiographic examinations that are typical in the postoperative patient can help direct treatment options. Nurse practitioners in outpatient settings need to quickly identify and treat postoperative complications. This article discusses three postoperative patients who presented to the emergency department. Data sources included personal health records and review of literature. Various factors that decrease hospital readmission rates include proper discharge education regarding signs and symptoms of infection, importance of medication compliance, and appropriate follow-up care. In addition, the outpatient nurse practitioners' knowledge of the surgical patient and common postoperative ailments will aid in more effective treatment and communication between the nurse practitioner and the surgeon if necessary. Nurse practitioners who have a better understanding of potential postoperative complications will be better equipped to care for this patient population when encountered in a nonsurgical, outpatient setting. PMID- 24785668 TI - Sensory stimuli as obstacles to emergency care for children with autism spectrum disorder. AB - Visits to the emergency department (ED) are stressful for any patient and pose special challenges and potential barriers to care for those with autism spectrum disorder (ASD). In addition, people (both children and adults) with ASD differ in their perception of, or responses to, environmental stimuli. Some people with ASD present with sensory defensiveness that is environmentally moderated, but there is a gap in our knowledge about patterns or thresholds of stimulation that kindle behavioral responses. We systematically recorded visual and auditory stimuli in an ED. Data were collected in four areas, hallway, doorway of waiting room, chair in waiting room, and treatment room, over several weeks and times of day. The mean light intensity ranged from 127 to 184 lux. There were significant differences (F = 16.77, df = 3, p > 0.001) between the five ED locations. Mean sound levels ranged from a high of 63.291 dB in the waiting room chair to a low of 51.289 dB in the treatment room. The highest consistent level of noise was recorded while sitting in the waiting room chair (60.657-63.291 dB). The findings suggest significant differences in light and sound intensity in common ED locations, with the highest mean readings of light and noise in the waiting areas. The differences and descriptions of light and sound patterns support the need for additional studies in both the measurement of the ED environment and its role in stimulating sensory defensiveness in people with ASD. PMID- 24785669 TI - The emergency department: experiences of patients, families, and their nurses. AB - Research regarding the triad of nurses, patients, and family members looking at the lived emergency department experiences and their perspective of each from the other is notably absent. In this study, M. van Manen's (1990) hermeneutic phenomenological approach was used to explore, understand, and describe the lived experiences of nurses, patients, and family members during critical illness in the emergency department. Data were collected over a 6-month period by means of in-depth interviews. While nurses perceived that addressing the patient's physiological deficit promptly is paramount in the emergency department, they also indicated that including family members as coparticipants in the care is equally important. Patients and family members perceived that communication, critical thinking, sensitivity, and caring are necessary for emergency department nurses. The study supports recognizing the patient and family as active participants in the patient's medical care, encouraging family member presence, and creating institutional policies for patient- and family-centered care. PMID- 24785670 TI - Nonviolent crisis intervention training and the incidence of violent events in a large hospital emergency department: an observational quality improvement study. AB - Violence in hospitals complicates patient care. Emergency department settings (ED) pose significant risk for caregivers. Nonviolent crisis intervention (NCI) training was initiated to reduce the incidence of violence in an acute care hospital ED with more than 75,000 annual visitors. Training intended to build skills to defuse potentially violent situations and significantly decrease incidents in the ED requiring emergency security team involvement (manifested as code purples). A quantitative quality improvement study evaluated the training investment. The study collected ED code purple and staff training data from November 2012 to October 2013. Correlations were derived using Pearson's r. A regression model determined incremental training impact. There was a negative correlation between violence and NCI training in the previous 90-150 days; regression determined a 23% decrease in code purples, pursuant to training. Risk mitigation justified the facility's investment to continue NCI training. Training reinforcement at 6-month intervals shall be implemented for continued benefit. PMID- 24785671 TI - The implementation and evaluation of an evidence-based protocol to treat diabetic ketoacidosis: a quality improvement study. AB - This retrospective observational quality improvement study was conducted to determine whether an evidence-based protocol for the treatment of diabetic ketoacidosis improved patient outcomes in our academic medical center. This study evaluated fidelity of providers to the protocol, as well as time to resolution of diabetic ketoacidosis as measured by closure of the anion gap (AG). Other secondary outcomes included time to intravenous fluids, time to potassium replacement, and rates of hypoglycemia and hypokalemia.Two cohorts including historical (N = 41) and current (N = 37) were compared to evaluate the effectiveness of the protocol. There were no differences between group demographics at baseline. After implementation of the protocol, 43.2% of patients were treated using full protocol fidelity, 21.6% were treated with partial fidelity, and 35.1% were not treated using the protocol. Although none of the outcomes reached statistical significance, patients in the current group who were treated with full protocol fidelity had an average time to AG closure that was 3 hr less than those who were not treated according to the protocol, and an average time to potassium replacement that was 2 hr less. When comparing the historical cohort with the patients treated with full protocol fidelity, there was improvement in protocol-treated patients in time to AG closure (2 hr), time to dextrose replacement (1.7 hr), and time to potassium replacement (2 hr). The rates of hypokalemia were improved with protocol treatment; 37.5% of protocol treated patients had hypokalemia as opposed to 63.4% of those not treated according to protocol.Overall, despite the low fidelity in our institution, the protocol promoted evidence-based practice and patients treated according to the protocol had decreased time to treatment outcomes including quicker AG closure, improved intravenous fluids resuscitation, and more accurate and timely electrolyte correction. PMID- 24785672 TI - Essential documentation elements: quality tool for the emergency department nurse. AB - The use of real-time feedback about documentation may improve compliance with best practice standards, provide immediate rewards for high-quality documentation, and present an opportunity to make instantaneous improvements to the documentation. This project was conducted in a large, urban emergency department (ED) to enhance patient safety, improve documentation quality, and increase timeliness of documentation. The PDSA (Plan, Do, Study, Act) model was used to develop a valid and reliable process to enhance the clinical care process. Passive electronic visual cues with real-time feedback to the clinician were developed. Between March 2011 and 2012, a total of 89,521 ED records were reviewed for compliance with 16 documentation elements. Documentation improvements were achieved with seven elements. There was a slight decrease in compliance for four elements, and equivalent levels of compliance in five elements were noted. Staff reported that the program was helpful in providing reminders and that passive cues were more helpful than hard stops. Areas for software refinement were also identified. This process demonstrated that the data collection burden was reduced and sampling error was eliminated. Although additional study is needed, the electronic health record can provide passive visual cues to enhance nursing care, improve regulatory compliance and data collection, and provide immediate feedback to the clinician. PMID- 24785673 TI - Mechanisms of right ventricular electromechanical dyssynchrony and mechanical inefficiency in children after repair of tetralogy of fallot. AB - BACKGROUND: Right bundle branch block and right ventricular (RV) dysfunction are common after tetralogy of Fallot repair (rTOF). We hypothesized that right bundle branch block is associated with specific RV mechanical dyssynchrony and inefficient contraction. METHODS AND RESULTS: We studied rTOF children and age matched controls. QRS duration and morphology were assessed. RV mechanical dyssynchrony, indicated by early septal activation (right-sided septal flash), RV lateral wall prestretch/late contraction, postsystolic shortening, and intraventricular delay were analyzed using 2-dimensional strain echocardiography. Peak oxygen consumption reflected exercise capacity. Pulmonary regurgitation and RV volumes were assessed by MRI. Forty-six rTOF patients and 46 controls were studied. Ninety-three percent of rTOF patients demonstrated a right-sided septal flash with simultaneous RV basal lateral wall prestretch/late activation. The RV basal segment was the most delayed in onset (115 [0-194] versus 35 [0-96] ms) and termination (462 [369-706] versus 412 [325-529] ms) of longitudinal shortening, with postsystolic shortening. QRS duration correlated with RV basal time to onset and peak shortening (P<0.05). Intra-RV delay was higher in rTOF (P<0.05) in association with RV dilatation (r=0.33; P=0.04). In rTOF, RV mechanics were inefficient, with prestretch and postsystolic shortening comprising 15+/-11% and 16+/-9% of total shortening, respectively. A composite parameter of electric and mechanical dyssynchrony correlated with RV end-diastolic volume (r=0.39; P=0.03). CONCLUSIONS: Typical electromechanical dyssynchrony associated with mechanical inefficiency, regional dysfunction, and RV dilatation is common in rTOF children, possibly contributing to progressive RV dysfunction. The potential of cardiac resynchronization in appropriate patients requires further study. PMID- 24785674 TI - Extracorporeal cardiopulmonary resuscitation. AB - PURPOSE OF REVIEW: To discuss the role of extracorporeal membrane oxygenation (ECMO) in patients with cardiac arrest. RECENT FINDINGS: Return to spontaneous circulation dramatically decreases with the duration of cardiopulmonary resuscitation (CPR). In this context, it has been proposed to implement venoarterial ECMO in order to assist CPR (ECPR) both in inhospital cardiac arrest (IHCA) and in out-of-hospital cardiac arrest (OHCA). SUMMARY: This review highlights that ECPR is feasible for both IHCA and OHCA. In the recent series, the outcome of ECPR in IHCA is satisfactory, with survival rates good with neurologic outcome reaching the 40-50% range. All series converge in highlighting that time from cardiac arrest to ECMO flow is a critical determinant of outcome, with survival rates of 50% when initiated within 30 min of IHCA, 30% between 30 and 60 min, and 18% after 60 min. Results of ECPR in OHCA are more challenging. Recent series suggest that good outcome can be obtained in 15-20% of the patients, provided that time from arrest to ECMO is shorter than 60 min. Duration of cardiac arrest seems to be more important than location of cardiac arrest. ECPR thus seems to be a valuable option in selected cases. PMID- 24785675 TI - Should we perform a coronary angiography in all cardiac arrest survivors? AB - PURPOSE OF REVIEW: Percutaneous coronary revascularization is the cornerstone treatment of acute coronary syndromes. Out-of-hospital cardiac arrest (OHCA) is in most cases related to a culprit coronary occlusion and should be treated as soon as possible. RECENT FINDINGS: To date, no biomarker has been evidenced to correctly predict culprit coronary occlusion in OHCA patients in order to select the best candidates for coronary angiography after OHCA. Moreover, successful percutaneous coronary intervention has been associated with better ICU and long term survival in such patients. Although all these data are provided by retrospective studies, results can be considered strong enough to support systematic coronary angiography after OHCA. Taken together, these findings strongly suggest the necessity to systematically perform coronary angiography after no obvious noncardiac cause of OHCA. SUMMARY: Systematic percutaneous coronary intervention after no obvious noncardiac cause of OHCA appears to be the most secure and the best adapted in these patients. PMID- 24785676 TI - Volumetric capnography: the time has come. AB - PURPOSE OF REVIEW: Volumetric capnography (VCap) measures the kinetics of carbon dioxide (CO2) elimination on a breath-by-breath basis. A volumetric capnogram contains extensive physiological information about metabolic production, circulatory transport and CO2 elimination within the lungs. VCap is also the best clinical tool to measure dead spaces allowing a detailed analysis of the functional components of each tidal volume, thereby providing clinically useful hints about the lung's efficiency of gas exchange. Difficulties in its bedside measurement, oversimplifications of its interpretation along with prevailing misconceptions regarding dead space analysis have, however, limited its adoption as a routine tool for monitoring mechanically ventilated patients. RECENT FINDINGS: Improvements in CO2 measuring technologies and more advanced algorithms for faster and more accurate analysis of volumetric capnograms have increased our physiological understanding and thus the clinical usefulness of VCap. The recently validated VCap-based method for estimating alveolar partial pressure of CO2 provided a breakthrough for a fully noninvasive breath-by-breath measurement of physiological dead space. SUMMARY: Recent advances in VCap and our improved understanding of its clinical implications may help in overcoming the known limitations and reluctances to include expired CO2 kinetics and dead space analysis in routine bedside monitoring. It is about time to start using this powerful monitoring tool to support decision making in the intensive care environment. PMID- 24785678 TI - Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS. AB - Mutation of TAR DNA-binding protein-43 (TDP-43) is detected in familial and sporadic amyotrophic lateral sclerosis (FALS and SALS). TDP-43-positive cytoplasmic inclusions are present in both neuron and glia of ALS, although not in mutant Cu/Zn-superoxide dismutase (mSOD1)-related or RNA binding protein Fused in sarcoma (FUS)-related ALS. Previous studies have established that cortical hyper-excitability is common to both FALS and SALS patients. Much of our current understanding of neuron excitability has come from studying the subtype of mSOD1 related ALS. Thus, we evaluated the excitable capability through analyzing properties of action potentials (APs) and voltage-gated sodium (Nav) channels on the cellular model, motoneuron-like cell lines that were steadily transfected with mutant Q331K and wild-type TDP-43. We found that wild-type TDP-43 increased firing frequency of APs, but the presence of mutant Q331K TDP-43 enhanced firing frequency and decreased the threshold of APs to a higher level. Further, we observed that mutant Q331K and wild-type TDP-43 induced more rapid speed of recovery from fast and slow inactivation of Nav channels and resulted in a reduction of voltage dependency of slow inactivation. These results provide evidence for high excitability that resulted from the presence of mutant and wild type TDP-43, and more toxicity of mutant TDP-43 than wild-type. Other studies suggest that Nav channel activity can be increased directly by different oxidative species and, we have shown previously that oxidative stress and mitochondrial dysfunction occurs simultaneously in the cellular model of mutant TDP-43 and can be ameliorated by dimethoxy curcumin (DMC), a safe and effective antioxidant. In the present study we found that the abnormities of APs and Nav channels were significantly ameliorated when treated with DMC (15MUM) for 24h, suggesting a dropping-excitability state. Taken together, mutant Q331K TDP-43 induces high excitability in a motoneuron-like cellular model, and this abnormal state is rescued by DMC which may act through alleviation of oxidative stress and mitochondrial dysfunction. PMID- 24785677 TI - The role of the immune system in central nervous system plasticity after acute injury. AB - Acute brain injuries cause rapid cell death that activates bidirectional crosstalk between the injured brain and the immune system. In the acute phase, the damaged CNS activates resident and circulating immune cells via the local and systemic release of soluble mediators. This early immune activation is necessary to confine the injured tissue and foster the clearance of cellular debris, thus bringing the inflammatory reaction to a close. In the chronic phase, a sustained immune activation has been described in many CNS disorders, and the degree of this prolonged response has variable effects on spontaneous brain regenerative processes. The challenge for treating acute CNS damage is to understand how to optimally engage and modify these immune responses, thus providing new strategies that will compensate for tissue lost to injury. Herein we have reviewed the available information regarding the role and function of the innate and adaptive immune responses in influencing CNS plasticity during the acute and chronic phases of after injury. We have examined how CNS damage evolves along the activation of main cellular and molecular pathways that are associated with intrinsic repair, neuronal functional plasticity and facilitation of tissue reorganization. PMID- 24785680 TI - Proton-counting radiography for proton therapy: a proof of principle using CMOS APS technology. AB - Despite the early recognition of the potential of proton imaging to assist proton therapy (Cormack 1963 J. Appl. Phys. 34 2722), the modality is still removed from clinical practice, with various approaches in development. For proton-counting radiography applications such as computed tomography (CT), the water-equivalent path-length that each proton has travelled through an imaged object must be inferred. Typically, scintillator-based technology has been used in various energy/range telescope designs. Here we propose a very different alternative of using radiation-hard CMOS active pixel sensor technology. The ability of such a sensor to resolve the passage of individual protons in a therapy beam has not been previously shown. Here, such capability is demonstrated using a 36 MeV cyclotron beam (University of Birmingham Cyclotron, Birmingham, UK) and a 200 MeV clinical radiotherapy beam (iThemba LABS, Cape Town, SA). The feasibility of tracking individual protons through multiple CMOS layers is also demonstrated using a two-layer stack of sensors. The chief advantages of this solution are the spatial discrimination of events intrinsic to pixelated sensors, combined with the potential provision of information on both the range and residual energy of a proton. The challenges in developing a practical system are discussed. PMID- 24785679 TI - The expression and roles of Nde1 and Ndel1 in the adult mammalian central nervous system. AB - Mental and neurological illnesses affect one in four people. While genetic linkage analyses have shown an association of nuclear distribution factor E (NDE1, or NudE) and its ohnolog NDE-like 1 (NDEL1, or Nudel) with mental disorders, the cellular mechanisms remain unclear. In the present study, we have demonstrated that Nde1 and Ndel1 are differentially localised in the subventricular zone (SVZ) of the forebrain and the subgranular zone (SGZ) of the hippocampus, two regions where neurogenesis actively occurs in the adult brain. Nde1, but not Ndel1, is localized to putative SVZ stem cells, and to actively dividing progenitors of the SGZ. The influence of these proteins on neural stem cell differentiation was investigated by overexpression in a hippocampal neural stem cell line, HCN-A94. Increasing Nde1 expression in this neural stem cell line led to increased neuronal differentiation while decreasing levels of astroglial differentiation. In primary cultured neurons and astrocytes, Nde1 and Ndel1 were found to have different but comparable subcellular localizations. In addition, we have shown for the first time that Nde1 is heterogeneously distributed in cortical astrocytes of human brains. Our data indicate that Nde1 and Ndel1 have distinct but overlapping distribution patterns in mouse brain and cultured nerve cells. They may function differently and therefore their dosage changes may contribute to some aspects of mental disorders. PMID- 24785681 TI - High spatiotemporal control of spontaneous reactions using ultrasound-triggered composite droplets. AB - Achieving high spatial and temporal control over a spontaneous reaction is a particularly challenging task with potential breakthroughs in various fields of research including surface patterning and drug delivery. We report here an exceptionally effective method that allows attaining such control. This method relies on a remotely triggered ultrasound-induced release of a reactant encapsulated in a composite microdroplet of liquid perfluorohexane. More specifically, the demonstration was achieved by locally applying a focused 2.25 MHz transducer onto a microfluidic channel in which were injected composite microdroplets containing a solution of an azidocoumarin and an external flow containing a reactive alkyne. PMID- 24785682 TI - Comparison of fenestrated endografts and the snorkel/chimney technique. AB - OBJECTIVE: Recent approval by the Food and Drug Administration of custom fenestrated endografts has increased endovascular options for patients with short neck or juxtarenal abdominal aortic aneurysms (AAAs). We sought to compare the early learning curve at a single institution of fenestrated repair vs the snorkel technique. METHODS: From 2009 to 2013, we performed 57 consecutive snorkel procedures for juxtarenal AAAs in an Institutional Review Board-approved prospective cohort, and since the summer of 2012, we gained access to the Food and Drug Administration-approved custom fenestrated device. Patient demographics, imaging, and operative techniques were compared between the first 15 cases for each of the snorkel (sn-EVAR) and fenestrated (f-EVAR) endovascular aneurysm repair (EVAR) techniques. RESULTS: Patient demographics and AAA morphology on preoperative imaging were similar between the groups. Operative time tended to be similar in the 3- to 4-hour range, with more fluoroscopy time and less contrast material used in f-EVAR than in sn-EVAR (P < .05) because of differing strategies of renal premarking. Larger delivery systems for f-EVAR required a higher rate of iliac conduits (40% vs 0%). Perioperative complications, short-term renal patency rates, and evidence of acute kidney injury were similar. CONCLUSIONS: The early experience of f-EVAR was similar to that of sn-EVAR in terms of patient demographics, case selection, and procedural characteristics. A significant portion of the learning curve for both procedures, particularly for f-EVAR, lies in the preoperative planning of fenestrations and the cannulation of branch vessels. Similar short-term postoperative outcomes between these two particular techniques indicate that both will have utility in the treatment of high-risk patients with complex anatomy. PMID- 24785683 TI - Renal function changes after snorkel/chimney repair of juxtarenal aneurysms. AB - OBJECTIVE: The snorkel approach for endovascular aneurysm repair (EVAR) has been found to be a safe and viable alternative to open repair for juxtarenal abdominal aortic aneurysms with good short-term outcomes. Concerns about long-term durability and renal branch patency with this technique have been raised with the increasing availability of fenestrated devices. We sought to evaluate renal function changes in patients undergoing "snorkel" EVAR (sn-EVAR). METHODS: Patients who underwent sn-EVAR from 2009 to 2012 were included in this analysis. Creatinine values were obtained throughout the patient's preoperative, perioperative, and postoperative course. Glomerular filtration rate (GFR) was estimated by the simplified Modification of Diet in Renal Disease formula. Acute renal dysfunction was analyzed according to the RIFLE (Risk, Injury, Failure, Loss, End stage) criteria, whereas chronic renal dysfunction was stratified by the chronic kidney disease staging system. RESULTS: Forty-three consecutive patients underwent sn-EVAR (31 double renal, 12 single renal) for juxtarenal aortic aneurysms. Mean follow-up time was 21 months. Mean aneurysm size was 6.6 cm (range, 5.1-10.5 cm) with anatomy not suitable for treatment with standard EVAR (mean neck length, 1.6 mm); 74 renal snorkel stents were placed in these patients with a 2-year primary patency of 95%. On average, the cohort at baseline was stratified as having moderate renal dysfunction. Mean baseline, maximum postoperative, and latest follow-up creatinine concentrations were 1.20, 1.49, and 1.43, respectively (P = .004). Mean baseline, maximum postoperative, and latest follow-up GFRs were 57.4, 47.8, and 49.2, respectively (P = .014). With use of RIFLE criteria, 14 patients (32.6%) experienced some form of acute kidney injury, although 10 of these patients (23.3%) were classified as mild (25%-50% decline in GFR). On analysis without the RIFLE criteria, 21.4% of patients had postoperative creatinine concentration >1.5 mg/dL, 28.6% had postoperative creatinine concentration increase >30%, and 28.6% had postoperative GFR decline >30%. For the entire study cohort at latest follow-up, 51% experienced no decline of chronic renal dysfunction and 8.1% had improvement in renal function. Renal function declined by one stage in 35.2% of the cohort and by two stages in 5.4%. On analysis without chronic kidney disease staging, 24.3% of patients had latest follow-up creatinine concentration >1.5 mg/dL, 29.7% had latest follow-up creatinine concentration increase >30%, and 24.3% had latest follow-up GFR decline >30%. Mean survival time from significant renal decline was 23.4 months. CONCLUSIONS: sn-EVAR continues to demonstrate a high rate of technical success and results in only mild rates of acute and midterm renal function decline according to a number of established definitions for renal dysfunction. Continued monitoring of renal function, renal stent behavior, and abdominal aortic aneurysm sac changes remains critically important in the long-term management of patients undergoing sn-EVAR, particularly given the high comorbidities associated with juxtarenal aortic aneurysms. PMID- 24785684 TI - Recall management of patients with Rofil Medical breast implants. AB - BACKGROUND: Some Rofil Medical breast implants are relabelled Poly Implant Prothese (PIP) implants, and it is recommended that Rofil implants be managed in the same way as PIP implants. We report the results of a systematic recall of patients who had received Rofil implants. METHOD: All patients who received Rofil implants at our centre were identified and invited for specialist consultation. In patients who opted for explantation, preoperative and intraoperative work-up was performed in accordance with national guidelines and analysed. In cases suspicious for rupture, an MRI scan was performed. RESULTS: Two-hundred and twenty-five patients (average age 56; range 28-80) received a total of 321 Rofil implants an average of 5.8 (range 1-11) years previously, 225/321 (70%) implants were used for reconstruction after breast cancer. A total of 43 implants were removed prior to 2011, mainly due to capsular contracture (CC). A total of 188 patients were still affected at the time of recall. Of the 188 patients, 115 (61%) attended for specialist consultation, of which 50 (44%) requested immediate implant removal. To date, 72 of 115 (63%) women attending consultation (38% of all affected) have chosen explantation, 66 of 72 (92%) opting for new implants. Of the 108 explanted implants, 25 (23%) had capsular rupture and 57 (53%) had implant bleeding. Preoperative clinical assessment was unreliable for predicting CC or rupture. CONCLUSION: The majority of patients attended for consultation and requested explantation. The quality of the explanted Rofil implants was comparable to PIP implants, with a higher rupture prevalence compared with other, non-affected implants. Nevertheless, the acceptance of breast implants for reimplantation remained high. PMID- 24785685 TI - Plasma Homocysteine is Associated with Retinopathy in Type 1 Diabetic Patients in the Absence of Nephropathy. AB - INTRODUCTION: Previous cross-sectional studies suggested that plasma total homocysteine (tHcy) is associated with retinopathy in patients with type 1 diabetes (T1DM) only in cases of impaired renal function. The objective of this study was to examine whether there is an independent relationship between tHcy and retinopathy in normoalbuminuric T1DM patients with normal estimated glomerular filtration rate (eGFR). METHODS: The study included 163 normoalbuminuric patients with T1DM and normal renal function (eGFR >60 <= 125 ml min(-1) 1.73 m(-2)). Urinary albumin excretion rate (UAE) was measured from at least two 24 h urine samples. Photodocumented retinopathy status was made according to the EURODIAB protocol. tHcy level was measured with the chemiluminescent immunoassay. RESULTS: Retinopathy was present in 48% of normoalbuminuric patients. Patients with retinopathy were older (49 vs 42 years, p = 0.001), had higher systolic blood pressure (130 vs 120 mmHg, p = 0.001), triglycerides (0.89 vs 0.77 mmol/L, p = 0.01), tHcy (9.8 vs 9.1 umol/L, p = 0.04), and lower eGFR (100 vs 106 ml min(-1) 1.73 m(-2), p = 0.03). In multivariate logistic regression analysis, after adjustment for variables that reached statistical significance in the univariate analysis, only tHcy was significantly associated with a risk of retinopathy in our subjects (p = 0.02), with odds ratios of 1.02 to 1.43. CONCLUSION: These data suggest that tHcy is independently associated with retinopathy in normoalbuminuric T1DM with normal eGFR. The mechanisms relating tHcy and retinopathy in T1DM are not clear. Prospectives studies are needed to confirm whether higher tHcy in normoalbuminuric T1DM patients has predictive value for development of retinopathy. PMID- 24785686 TI - The spatiotemporal program of DNA replication is associated with specific combinations of chromatin marks in human cells. AB - The duplication of mammalian genomes is under the control of a spatiotemporal program that orchestrates the positioning and the timing of firing of replication origins. The molecular mechanisms coordinating the activation of about [Formula: see text] predicted origins remain poorly understood, partly due to the intrinsic rarity of replication bubbles, making it difficult to purify short nascent strands (SNS). The precise identification of origins based on the high-throughput sequencing of SNS constitutes a new methodological challenge. We propose a new statistical method with a controlled resolution, adapted to the detection of replication origins from SNS data. We detected an average of 80,000 replication origins in different cell lines. To evaluate the consistency between different protocols, we compared SNS detections with bubble trapping detections. This comparison demonstrated a good agreement between genome-wide methods, with 65% of SNS-detected origins validated by bubble trapping, and 44% of bubble trapping origins validated by SNS origins, when compared at the same resolution. We investigated the interplay between the spatial and the temporal programs of replication at fine scales. We show that most of the origins detected in regions replicated in early S phase are shared by all the cell lines investigated whereas cell-type-specific origins tend to be replicated in late S phase. We shed a new light on the key role of CpG islands, by showing that 80% of the origins associated with CGIs are constitutive. Our results further show that at least 76% of CGIs are origins of replication. The analysis of associations with chromatin marks at different timing of cell division revealed new potential epigenetic regulators driving the spatiotemporal activity of replication origins. We highlight the potential role of H4K20me1 and H3K27me3, the coupling of which is correlated with increased efficiency of replication origins, clearly identifying those marks as potential key regulators of replication origins. PMID- 24785687 TI - Compilation of copy number variants identified in phenotypically normal and parous Japanese women. AB - With increasing public concern about infertility and the frequent involvement of chromosomal anomalies in miscarriage, analyses of copy number variations (CNVs) have been used to identify the genomic regions responsible for each process of childbearing. Although associations between CNVs and diseases have been reported, many CNVs have also been identified in healthy individuals. Like other types of mutations, phenotypically indefinite CNVs may have been retained and accumulated during anthropogenesis. Therefore to distinguish causative variants from other variants is a formidable task. Furthermore, because previous studies have predominantly focused on European and African populations, comprehensive detection of common Asian CNVs is eagerly awaited. Here, using a high-resolution genotyping array and samples from 411 Japanese women with normal parity without significant complications, we have compiled 1043 copy number variable regions. In total, the collected regions cover 164 Mb, or up to 0.5% of the genome. The copy number differences in these regions may be irrelevant not only to infertility but also to a wide range of diseases. The utility of this resource in reducing the candidate pathogenetic variants, especially in Japanese subjects, is also demonstrated. PMID- 24785688 TI - The imprinted gene LRRTM1 mediates schizotypy and handedness in a nonclinical population. AB - Imprinted genes have been posited to have important roles in human brain development and cognition, but their effects in nonclinical populations have yet to be investigated. Single-nucleotide polymorphisms (SNPs) of the imprinted gene LRRTM1 have previously been associated with schizophrenia risk and with handedness in individuals with dyslexia. We tested the hypothesis that genetic variation (SNPs) and epigenetic variation (methylation) in this gene are associated with schizotypy and handedness in a nonclinical population. Risk alleles of the three schizophrenia-linked SNPs were associated with significantly and substantially higher levels of total schizotypy. Variation in SNP genotypes was not associated with handedness, but levels of methylation in a block of CpG sites in the putative LRRTM1 promoter region were associated with more-mixed handedness. These findings provide evidence of continuity between schizophrenia and schizotypy with regard to the psychological effects of allelic variation in this imprinted gene, and show that epigenetic variation in an imprinted gene mediates the development and expression of human handedness. PMID- 24785689 TI - Limited evidence for adaptive evolution and functional effect of allelic variation at rs702424 in the promoter of the TAS2R16 bitter taste receptor gene in Africa. AB - Bitter taste perception, mediated by receptors encoded by the TAS2R loci, has important roles in human health and nutrition. Prior studies have demonstrated that nonsynonymous variation at site 516 in the coding exon of TAS2R16, a bitter taste receptor gene on chromosome 7, has been subject to positive selection and is strongly correlated with differences in sensitivity to salicin, a bitter anti inflammatory compound, in human populations. However, a recent study suggested that the derived G-allele at rs702424 in the TAS2R16 promoter has also been the target of recent selection and may have an additional effect on the levels of salicin bitter taste perception. Here, we examined alleles at rs702424 for signatures of selection using Extended Haplotype Homozygosity (EHH) and FST statistics in diverse populations from West Central, Central and East Africa. We also performed a genotype-phenotype analysis of salicin sensitivity in a subset of 135 individuals from East Africa. Based on our data, we did not find evidence for positive selection at rs702424 in African populations, suggesting that nucleotide position 516 is likely the site under selection at TAS2R16. Moreover, we did not detect a significant association between rs702424 alleles and salicin bitter taste recognition, implying that this site does not contribute to salicin phenotypic variance. Overall, this study of African diversity provides further information regarding the genetic architecture and evolutionary history of a biologically-relevant trait in humans. PMID- 24785690 TI - BCOR mutations and unstoppable root growth: a commentary on oculofaciocardiodental syndrome: novel BCOR mutations and expression in dental cells. PMID- 24785691 TI - Very early-onset inflammatory bowel disease (IBD) in infancy is a different disease entity from adult-onset IBD; one form of interleukin-10 receptor mutations. AB - Infantile periods may have stronger genetic influences. Recently, studies on genetic defects in the interleukin-10 (IL-10) signaling pathway have provided new insights into inflammatory bowel disease (IBD). This study is to reveal whether mutations of IL-10 signaling pathway genes contribute to the phenotypes of IBD. Forty children who were diagnosed with IBD below the age of 10 years were enrolled. We sequenced the genes interleukin-10 receptor A (IL-10RA), IL-10RB and IL-10, and analyzed the clinical characteristics of very early-onset IBD (VEO IBD). In total, 14 out of the 40 children developed their symptoms within 1 year of age. We found mutations in IL-10RA in 7 out of the 40 children (17.5%). All seven children had developed symptoms within the first year of life. Particularly, half of the children with infantile-onset IBD had IL-10RA mutations. None of the remaining 26 children diagnosed above 1 year of age had IL 10RA mutations. No mutations were found in IL-10RB and IL-10. Identified IL-10RA mutations were p.(R101W), p.(Y91C), p.(R262C), p.(R117H) and p.(W69R). IL-10RA mutations were associated with onset of infancy (P<0.001), perianal fistulae (P<0.001), poor response to medical management (P=0.017) and early surgical interventions (P<0.001). VEO-IBD in infancy is phenotypically and genetically different disease entity from adult-onset or older child-onset IBD. It has a strong association with IL-10 receptor gene. We should consider the genotyping of genes of the IL-10 signaling pathway including IL-10RA in patients with VEO-IBD, especially in whom with onset of perianal fistulae and severe colitis. PMID- 24785693 TI - An approach to building research capacity for health practitioners in a public health environment: an organisational perspective. AB - A unique opportunity to engage in research capacity-building strategies for health practitioners arose within public sector health services during the negotiations for an industrial agreement. A research capacity-building initiative for health practitioners that is allied health, oral health and scientist practitioners was funded and the components of this initiative are described. The initiative was implemented using a research capacity-building framework developed from a review of the literature and stakeholder consultations. The framework included leadership and governance, support to researchers and translation of evidence into practice and was contextualised to public health environments. There were several phases of implementation. An evaluation of the preliminary phase of establishing research positions and research activity was conducted and several successes of the capacity-building strategies were identified. These successes (e.g. solid partnerships with universities) are discussed, as are future concerns, such as sustainability of the initiative in a tighter fiscal context. PMID- 24785692 TI - Mutations in four glycosyl hydrolases reveal a highly coordinated pathway for rhodopsin biosynthesis and N-glycan trimming in Drosophila melanogaster. AB - As newly synthesized glycoproteins move through the secretory pathway, the asparagine-linked glycan (N-glycan) undergoes extensive modifications involving the sequential removal and addition of sugar residues. These modifications are critical for the proper assembly, quality control and transport of glycoproteins during biosynthesis. The importance of N-glycosylation is illustrated by a growing list of diseases that result from defects in the biosynthesis and processing of N-linked glycans. The major rhodopsin in Drosophila melanogaster photoreceptors, Rh1, is highly unique among glycoproteins, as the N-glycan appears to be completely removed during Rh1 biosynthesis and maturation. However, much of the deglycosylation pathway for Rh1 remains unknown. To elucidate the key steps in Rh1 deglycosylation in vivo, we characterized mutant alleles of four Drosophila glycosyl hydrolases, namely alpha-mannosidase-II (alpha-Man-II), alpha mannosidase-IIb (alpha-Man-IIb), a beta-N-acetylglucosaminidase called fused lobes (Fdl), and hexosaminidase 1 (Hexo1). We have demonstrated that these four enzymes play essential and unique roles in a highly coordinated pathway for oligosaccharide trimming during Rh1 biosynthesis. Our results reveal that alpha Man-II and alpha-Man-IIb are not isozymes like their mammalian counterparts, but rather function at distinct stages in Rh1 maturation. Also of significance, our results indicate that Hexo1 has a biosynthetic role in N-glycan processing during Rh1 maturation. This is unexpected given that in humans, the hexosaminidases are typically lysosomal enzymes involved in N-glycan catabolism with no known roles in protein biosynthesis. Here, we present a genetic dissection of glycoprotein processing in Drosophila and unveil key steps in N-glycan trimming during Rh1 biosynthesis. Taken together, our results provide fundamental advances towards understanding the complex and highly regulated pathway of N-glycosylation in vivo and reveal novel insights into the functions of glycosyl hydrolases in the secretory pathway. PMID- 24785695 TI - In search of genetic markers for nonsyndromic deafness in Africa: a study in Cameroonians and Black South Africans with the GJB6 and GJA1 candidate genes. AB - Deafness is the most common sensory disability in the world and has a variety of causes. Globally, mutations in GJB2 have been shown to play a major role in nonsyndromic deafness, but this has not been seen in Africans. Two other connexin genes, GJB6 and GJA1, have been implicated in hearing loss but have seldom been investigated in African populations. We set out to investigate the role of genetic variation in GJB6 and GJA1 in a group of Cameroonian and South African Blacks with nonsyndromic recessive hearing loss. A subset of 100 patients, affected with nonsyndromic hearing loss, from a cohort that was previously shown not to have GJB2 mutation, was analyzed by Sanger sequencing of the entire coding regions of GJB6 and GJA1. In addition, the large-scale GJB6-D3S1830 deletion was also investigated. No pathogenic mutation was detected in either GJB6 or GJA1, nor was the GJB6-D3S1830 deletion detected. There were no statistically significant differences in sequence variants between patients and controls. Mutations in GJB6 and GJA1 are not a major cause of nonsyndromic deafness in this group of Africans from Cameroon and South Africa. Currently, there is no sufficient evidence to support their testing in a clinical setting for individuals of African ancestry. PMID- 24785696 TI - Volarly displaced transscaphoid, translunate, transtriquetrum fracture of the carpus: case report. AB - A 16-year-old girl sustained a transscaphoid, translunate, transtriquetrum volarly displaced fracture due to shear stress in the coronal plane. Treatment involved open reduction and internal fixation of the fractures followed by immobilization. At 15 months' follow-up, grip strength and motion were diminished compared with the uninjured wrist. Radiographs demonstrated fully healed fractures with narrowing of the cartilage space between the capitate and the lunate. PMID- 24785697 TI - Collateral ligament laxity of the finger metacarpophalangeal joints: an in vivo study. AB - PURPOSE: To assess the normal degree of laxity of the collateral ligaments (CLs) of the finger metacarpophalangeal (MCP) joints and to compare side-to-side differences in CL laxity. METHODS: One hundred subjects had measurements of the degree of laxity in the radial (RCL) and ulnar (UCL) collateral ligaments of the MCP joints of each digit on both hands with the joints at neutral and at 30 degrees and 90 degrees of flexion using a custom-made measuring device. Statistical analysis was performed to assess both the difference in laxity for each ligament at each position of flexion and between sides for analogous ligaments (eg, the right index RCL at neutral compared to the left index RCL at neutral). RESULTS: There was a significant decrease in laxity for all ligaments between neutral (mean, 24 degrees laxity) and 90 degrees of flexion (mean, 15 degrees laxity). There was a side-to-side difference between the RCL of all digits in extension (mean, 3 degrees ) and the index RCL in flexion (2 degrees ). These differences were statistically significant but clinically minimal. There were no side-to-side differences between any of the other ligaments at any position. CONCLUSIONS: Finger MCP joint CL stability increases with increasing flexion of the joint. There is little to no difference between analogous ligaments on either hand of the subject when tested in the same position of MCP joint flexion. Knowledge of the average degree of MCP joint CL laxity can be helpful in assessing a potentially injured joint. A patient's contralateral, uninjured side can be used to determine that individual's normal laxity and a substantial increase from this on an injured digit can indicate CL rupture. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 24785698 TI - Long-nerve grafts and nerve transfers demonstrate comparable outcomes for axillary nerve injuries. AB - PURPOSE: To compare the functional and EMG outcomes of long-nerve grafts to nerve transfers for complete axillary nerve palsy. METHODS: Over a 10-year period at a single institution, 14 patients with axillary nerve palsy were treated with long nerve grafts and 24 patients were treated with triceps-to-axillary nerve transfers by the same surgeon (S.W.W.). Data were collected prospectively at regular intervals, beginning before surgery and continuing up to 11 years after surgery. Prior to intervention, all patients demonstrated EMG evidence of complete denervation of the deltoid. Deltoid recovery (Medical Research Council [MRC] grade), shoulder abduction ( degrees ), improvement in shoulder abduction ( degrees ), and EMG evidence of deltoid reinnervation were compared between cohorts. RESULTS: There were no significant differences between the long-nerve graft cohort and the nerve transfer cohort with respect to postoperative range of motion, deltoid recovery, improvement in shoulder abduction, or EMG evidence of deltoid reinnervation. CONCLUSIONS: These data demonstrate that outcomes of long nerve grafts for axillary nerve palsy are comparable with those of modern nerve transfers and question a widely held belief that long-nerve grafts do poorly. When healthy donor roots or trunks are available, long-nerve grafts should not be overlooked as an effective intervention for the treatment of axillary nerve injuries in adults with brachial plexus injuries. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 24785699 TI - Surgical accuracy in identifying the elbow rotation axis on fluoroscopic images. AB - PURPOSE: To assess the accuracy of surgeons in identifying elbow rotation axis (RA) on fluoroscopic images and to measure the interobserver variability. METHODS: Five healthy subjects underwent 3-dimensional computed tomography (CT) analysis of their nondominant elbow. Real-time rotation software enabled surgeons to approximate the elbow RA on CT-reconstructed fluoroscopy, which was repeated twice with different starting positions to increase the number of observations. The surgeons used anatomical landmarks of choice. Analysis of variance (ANOVA) was used to determine structural error differences between surgeons, and intraclass correlation coefficients (ICCs) were used to determine the corresponding interobserver variability. RESULTS: Eight subspecialty-trained trauma surgeons (P.K., N.W.L.S., V.M.d.J., P.J., G.M.K., R.W.P., T.S., B.A.v.D.) participated and attempted to identify the RA on reconstructed fluoroscopy. A total of 15 RA definitions on 5 elbows were recorded per surgeon. The surgeons had a mean rotational error of 5 degrees (range, < 1 degrees -13 degrees ) and mean translational error of 1 mm (range, < 1-8 mm), compared with the true elbow RA as measured by the 3-dimensional CT analysis. The ANOVA showed structural differences between surgeons in rotational and translational errors, indicating that some surgeons consistently had more accurately identified the elbow RA than others. The ICC was 0.12 for rotational error and 0.10 for translational error, indicating a large interobserver variability. CONCLUSIONS: We show in this in vivo study that identification of the elbow RA on fluoroscopy is associated with substantial rotational errors and large inconsistencies among surgeons. Implementation of standardized anatomical landmarks is required to improve surgeons' accuracy. These landmarks should preferably take into account both the coronal and the sagittal planes, using the orientation of the capitellum and trochlea as well as the posterior distal humeral cortex. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 24785700 TI - Ultrasound-assisted closed reduction of distal radius fractures. AB - PURPOSE: To assess the accuracy and ability of ultrasound for monitoring closed reduction for distal radius fractures. METHODS: Consecutive patients undergoing ultrasound-guided closed reduction of acute, displaced distal radius fractures between January 2003 and December 2006 at our department were enrolled. The control group was extracted from patients who underwent a closed reduction for similar fractures under fluoroscopy or without any imaging assistance. To confirm the accuracy of the ultrasonography measurements, displacement distance values were compared with those on radiographic imaging before and after reduction. X ray parameters for pre- and postreduction, reduction time, total cost, and success rate were compared between the ultrasound-guided and the control groups. RESULTS: The ultrasound-guided group consisted of 43 patients (mean age, 68 y) and the control group consisted of 57 patients, which included 35 patients (mean age, 74 y) with fluoroscopic reduction and of 22 patients (mean age, 72 y) with reduction unaided by imaging. There were no significant displacement differences between radiographic and ultrasound measurements. In x-ray parameters for pre- and postreduction, there were no significant differences between the 2 groups. Ultrasound-guided reduction took longer than the other 2 methods. The success rate of the ultrasound and the fluoroscopic groups were similar (95% and 94%, respectively). CONCLUSIONS: Our data suggest that ultrasound assistance can aid reduction of distal radius fractures as well as fluoroscopy. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 24785701 TI - Total dorsal capsulectomy for the treatment of mucous cysts. AB - PURPOSE: To describe the technique of total dorsal capsulectomy alone for mucous cysts of the distal interphalangeal (DIP) joint and evaluate its outcomes and complications. METHODS: Nineteen patients (18 women and 1 man) with 19 mucous cysts were treated by a total dorsal capsulectomy without cyst excision or osteophyte removal. The average age at surgery was 63 years. The thumb was involved in 4 patients, index finger in 1, middle finger in 7, ring finger in 4, and little finger in 3. Twelve patients had nail deformities associated with the mucous cyst. The average period of postoperative follow-up was 26 months. The dorsal half of the DIP joint capsule was resected with a punch and curette. The cyst and osteophytes were left intact. RESULTS: The average preoperative range of motion for the DIP joint was from 10 degrees of extension to 45 degrees of flexion. Radiographs showed osteophytes at the DIP joint in all affected digits. After surgery, all cysts disappeared at an average of 3 weeks. There was no recurrence at the time of final follow-up. All nail deformities had resolved at an average of 5 months after surgery. The average motion for the DIP joint at the time of final follow-up was from 8 degrees of extension to 56 degrees of flexion. There were no acquired nail deformities or other complications. CONCLUSIONS: A total dorsal capsulectomy alone was a simple treatment for mucous cysts and did not lead to any recurrence. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24785702 TI - Malpractice in distal radius fracture management: an analysis of closed claims. AB - PURPOSE: Distal radius fractures comprise the majority of hand- and wrist-related malpractice claims. We hypothesized that a majority of lawsuits would be for malunions resulting from nonsurgical treatment. Additional goals of this study were to quantify costs associated with claims, determine independent risk factors for making an indemnity payment, and illustrate trends over time. METHODS: Seventy closed malpractice claims filed for alleged negligent treatment of distal radius fractures by orthopedic surgeons insured by the largest medical professional liability insurer in New York State (NYS) from 1981 to 2005 were reviewed. We separately reviewed defendants' personal closed malpractice claim histories from 1975 to 2011. Overall incidence of malpractice claims among distal radius fractures treated in NYS was calculated using the NYS Statewide Planning and Research Cooperative System database and the 2008 American Academy of Orthopedic Surgeons census data. RESULTS: The overall incidence of malpractice claims for distal radius fracture management was low. Malunion was the most common complaint across claims regardless of treatment type. Claims for surgically treated fractures increased over time. A majority of claims documented poor doctor-patient relationships. Male plaintiffs in this group were significantly older than males treated for distal radius fractures in NYS. Most defendants had a history of multiple malpractice suits, all were male, and only a small percentage were fellowship-trained in hand surgery. Defendants lacking American Board of Orthopedic Surgery certification were significantly more likely to make indemnity payments. Thirty-eight of 70 cases resulted in an indemnity payment. CONCLUSIONS: Malunion and poor doctor-patient relationships are the major features of malpractice litigation involving distal radius fracture management. Older defendant age and lack of American Board of Orthopedic Surgery certification increase the likelihood of making an indemnity payment. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and decision analyses II. PMID- 24785703 TI - Sensory innervation of the triangular fibrocartilage complex: a cadaveric study. AB - PURPOSE: To describe the sensory innervation of the triangular fibrocartilage complex (TFCC) to understand the potential for selective denervation as an alternative treatment for recalcitrant pain from stable TFCC IA lesions after failed nonsurgical treatment. METHODS: Eleven fresh cadaveric limbs were dissected with * 3.2 loupe magnification in a proximal to distal manner. The candidate nerves were the dorsal cutaneous branch of the ulnar nerve, volar sensory branch of the ulnar nerve, anterior interosseous nerve, posterior interosseous nerve, medial antebrachial cutaneous nerve, and palmar cutaneous branch of the median nerve. We identified neural continuity to the TFCC histologically with S-100 protein antibody staining. RESULTS: In the 11 specimens, the TFCC was innervated by the dorsal cutaneous branch of the ulnar nerve (100%), medial antebrachial cutaneous nerve (91%), volar branch of the ulnar nerve (73%), anterior interosseous nerve (27%), posterior interosseous nerve (18%), and palmar branch of the median nerve (9%). CONCLUSIONS: These results provide an initial step in planning an operative partial TFCC denervation for recalcitrant TFCC IA injuries that fail nonsurgical treatment and possibly also arthroscopic debridement. CLINICAL RELEVANCE: Based on the results of this anatomic study, it is possible to create an algorithm for performing nerve blocks of the TFCC that would aid in planning a surgical denervation procedure. PMID- 24785704 TI - Marinobufagenin in essential hypertension and primary aldosteronism: a cardiotonic steroid with clinical and diagnostic implications. AB - BACKGROUND: The cardiotonic steroid marinobufagenin (MBG) is increasingly suggested to be responsible for some of the cardiovascular injury that has been previously attributed to aldosterone. We examined the clinical correlates of circulating MBG concentrations in hypertensive patients and tested the hypothesis that MBG serves as a reliable diagnostic tool for detecting primary aldosteronism (PA). METHODS: Plasma MBG concentrations (mean: 0.51+/-0.25 nmol/l) were measured in the morning fasting samples in 20 patients with PA and 20 essential hypertensive (EH) controls matched for age, sex, body mass index, renal function, urinary sodium and intake of antihypertensive medication (mean age: 51.6 years; 52.2% women). RESULTS: Overall, plasma MBG was directly correlated with plasma aldosterone, aldosterone to active renin ratio (AARR), diastolic blood pressure, mean carotid intima-media thickness, serum sodium, urinary protein to creatinine ratio and inversely with serum potassium levels. Plasma MBG levels were significantly higher in patients with PA compared to EH (mean: 0.68+/-0.12 versus 0.35+/-0.24 nmol/l; p<0.001). ROC analysis yielded a greater AUC for plasma MBG compared to the AARR, PAC and serum potassium levels for detecting PA. Youden's Index analyses yielded the optimal plasma MBG cut-off score for diagnosing PA at >0.49 nmol/l with specificity and sensitivity values of 0.85 and 0.95, respectively, which were higher than those at the optimum AARR cut-off at >3.32 ng/dl/uU/ml. CONCLUSIONS: In a well-characterized cohort, values of plasma MBG were significantly related to clinical correlates of cardiovascular and renal disease. Plasma MBG emerged as a valuable alternative to the AARR for screening of PA. PMID- 24785705 TI - Discovery of novel and selective SIRT6 inhibitors. AB - SIRT6 is an NAD(+)-dependent deacetylase with a role in the transcriptional control of metabolism and aging but also in genome stability and inflammation. Broad therapeutic applications are foreseen for SIRT6 inhibitors, including uses in diabetes, immune-mediated disorders, and cancer. Here we report on the identification of the first selective SIRT6 inhibitors by in silico screening. The most promising leads show micromolar IC50s, have significant selectivity for SIRT6 versus SIRT1 and SIRT2, and are active in cells, as shown by increased acetylation at SIRT6 target lysines on histone 3, reduced TNF-alpha secretion, GLUT-1 upregulation, and increased glucose uptake. Taken together, these results show the value of these compounds as starting leads for the development of new SIRT6-targeting therapeutic agents. PMID- 24785706 TI - Does the Strengths and Difficulties Questionnaire - self report yield invariant measurements across different nations? Data from the International Child Mental Health Study Group. AB - AIMS: This study evaluated the measurement invariance of the strengths and difficulties questionnaire (SDQ) self-report among adolescents from seven different nations. METHODS: Data for 2367 adolescents, aged 13-18 years, from India, Indonesia, Nigeria, Serbia, Turkey, Bulgaria and Croatia were available for a series of factor analyses. RESULTS: The five-factor model including original SDQ scales emotional symptoms, conduct problems, hyperactivity inattention problems, peer problems and prosocial behaviour generated inadequate fit degree in all countries. A bifactor model with three factors (i.e., externalising, internalising and prosocial) and one general problem factor yielded adequate degree of fit in India, Nigeria, Turkey and Croatia. The prosocial behaviour, emotional symptoms and conduct problems factor were found to be common for all nations. However, originally proposed items loaded saliently on other factors besides the proposed ones or only some of them corresponded to proposed factors in all seven countries. CONCLUSIONS: Due to the lack of a common acceptable model across all countries, namely the same numbers of factors (i.e., dimensional invariance), it was not possible to perform the metric and scalar invariance test, what indicates that the SDQ self-report models tested lack appropriate measurement invariance across adolescents from these seven nations and it needs to be revised for cross-country comparisons. PMID- 24785707 TI - "Light-on" sensing of antioxidants using gold nanoclusters. AB - Depletion of intracellular antioxidants is linked to major cytotoxic events and cellular disorders, such as oxidative stress and multiple sclerosis. In addition to medical diagnosis, determining the concentration of antioxidants in foodstuffs, food preservatives, and cosmetics has proved to be very vital. Gold nanoclusters (Au-NCs) have a core size below 2 nm and contain several metal atoms. They have interesting photophysical properties, are readily functionalized, and are safe to use in various biomedical applications. Herein, a simple and quantitative spectroscopic method based on Au-NCs is developed to detect and image antioxidants such as ascorbic acid. The sensing mechanism is based on the fact that antioxidants can protect the fluorescence of Au-NCs against quenching by highly reactive oxygen species. Our method shows great accuracy when employed to detect the total antioxidant capacity in commercial fruit juice. Moreover, confocal fluorescence microscopy images of HeLa cells show that this approach can be successfully used to image antioxidant levels in living cells. Finally, the potential application of this "light-on" detection method in multiple logic gate fabrication was discussed using the fluorescence intensity of Au-NCs as output. PMID- 24785708 TI - Health promotion in Local Health Unit 4 Chiavarese--Liguria Region, Italy. "Unplugged" project: needs, methodology and implementation. AB - AIM: The aim of this paper was to use and evaluate the unplugged project, a school-based program of proven effectiveness aimed at the prevention of substance abuse based on social influence. METHODS: This project was conducted during the school-year 2011/2012; it involved the Local Health Unit (LHU)'s personnel specifically and adequately formed and was addressed to teachers working in the three districts of the LHU4 Chiavarese. The courses involved teachers in three consecutive days and provided both theoretical inputs and practical exercises designed to enpower skills and to make the same effective. As a whole, 25 teachers of the secondary schools (public and private) of first and second level were trained. Following the training, 14 curricular courses have been launched and 286 students have been involved. RESULTS: The teachers have mainly worked on personal and social components of their students, stimulating their critical assessment of standards and skills potentially transferable in everyday life. The benefits for students have been: establishment of the classroom, positive relationship with the teacher, empathy, decrease of conflicts, increased self awareness and self-esteem, better school results. Besides, teachers benefit from increased respect, self-reliance and confidence, as well as acquisition of new skills. CONCLUSION: Both the interest shown by teachers and the results achieved in classrooms have stimulated school leadership and personnel belonging to LHU4 Chiavarese to plan a new edition of the program the next autumn. PMID- 24785709 TI - The expression pattern of PARP-1 and PARP-2 in the developing and adult mouse testis. AB - Although the importance of the PARP family members in the adult testis has already been acknowledged, their expression in the developing testis has not been addressed. We performed immunohistochemistry by using PARP-1 and PARP-2 antibodies on the developing mouse testis at embryonic day (E) 15.5, E17.5, postnatal day (PN) 0, PN3, PN9, PN20 and adult. Our results showed that at embryonic and early postnatal days, the expression of PARP-1 was in the nuclei of gonocytes and spermatogonia. PARP-1 was positive in interstitial cells with nuclear localization at all studied ages. At embryonic and early postnatal days, the expression of PARP-2 was in the cytoplasm of gonocytes and spermatogonia. During the progress of spermatogenesis, PARP-2 was localized in the cytoplasm of pre-leptotene spermatocytes on PN9, in the cytoplasm of pachytene spermatocytes on PN15 and in the cytoplasm of round spermatids on PN20. In the adult, PARP-2 staining can still be observed in the cytoplasm of spermatogonia, but to a much lesser degree than in the round and elongating spermatids. For all the studied ages, PARP-2 was positive in Sertoli cells and interstitial cells with cytoplasmic localization. Our results indicate that PARP proteins are present in germ and somatic cells during testis development in mice. PMID- 24785710 TI - Genotoxic effects and serum abnormalities in residents of regions proximal to e waste disposal facilities in Jinghai, China. AB - Electronic waste (e-waste) disposal is a growing problem in China, and its effects on human health are a concern. To determine the concentrations of pollutants in peripheral blood and genetic aberrations near an e-waste disposal area in Jinghai, China, blood samples were collected from 30 (age: 41+/-11.01 years) and 28 (age: 33+/-2.14 years) individuals residing within 5 and 40km of e waste disposal facilities in Jinghai (China), respectively, during the week of October 21-28, 2011. Levels of inorganic pollutants (calcium, copper, iron, lead, magnesium, selenium, and zinc) and malondialdehyde (MDA), identities of persistent organic pollutants (POPs), micronucleus rates, and lymphocyte subsets were analyzed in individuals. Total RNA expression profiles were analyzed by group and gender. The population group living in proximity to the e-waste site displayed significantly higher mean levels of copper, zinc, lead, MDAs, POPs (B4 6DE, B7-9DE, total polychlorinated biphenyls, and BB-153). In addition, micronucleus rates of close-proximity group were higher compared with the remote group (18.27% vs. 7.32%). RNA expression of genes involved in metal ion binding and transport, oxidation/reduction, immune defense, and tumorigenesis varied between groups, with men most detrimentally affected (p<0.05). CD4(+)/CD8(+)T cell ratios, CD4(+)CD25(nt/hi)CD127(lo)regulatory T cell percentages, and CD95 expression were greater in the e-waste group (p<0.05). Residing in close proximity to e-waste disposal facilities (<=5km) may be associated with the accumulation of potentially harmful inorganic/organic compounds and gender preferential genetic aberrations. PMID- 24785711 TI - Sodium chloride salinity reduces Cd uptake by edible amaranth (Amaranthus mangostanus L.) via competition for Ca channels. AB - Soil salinity is known to enhance cadmium (Cd) accumulation in crops. However, the mechanism by which this occurs independent of the surrounding soil remains unclear. In this study, root adsorption and uptake of salt cations and Cd by edible amaranth under NaCl salinity stress were investigated in hydroponic cultures with 0, 40, 80, 120, and 160mM of NaCl and 27nM Cd. The dominant Cd species in the nutrient solution changed from free Cd(2+) to Cd chlorocomplexes as NaCl salinity increased. High salinity significantly reduced K, Ca, and Cd root adsorption and K, Ca, Mg, and Cd uptake. High salinity decreased root adsorption of Cd by 43 and 58 percent and Cd uptake by 32 and 36 percent in salt tolerant and salt-sensitive cultivars, respectively. Transformation of Cd from free ion to chlorocomplexes is unlikely to have significantly affected Cd uptake by the plant because of the very low Cd concentrations involved. Application of Ca ion channel blocker significantly reduced Na, K, Ca, Mg, and Cd uptake by the roots, while blocking K ion channels significantly reduced Na and K uptake but not Ca, Mg, and Cd uptake. These results suggest that Na was absorbed by the roots through both Ca and K ion channels, while Cd was absorbed by the roots mainly through Ca ion channels and not K ion channels. Salinity caused a greater degree of reduction in Cd adsorption and uptake in the salt-sensitive cultivar than in the salt-tolerant cultivar. Thus, competition between Na and Cd for Ca ion channels can reduce Cd uptake at very low Cd concentrations in the nutrient solution. PMID- 24785712 TI - Seed dressing pesticides on springtails in two ecotoxicological laboratory tests. AB - Terrestrial ecotoxicological tests are powerful tools for assessing the ecological risks that pesticides pose to soil invertebrates, but they are rarely used to evaluate seed dressing pesticides. This study investigated the effects of seed dressing pesticides on survival and reproduction of Folsomia candida (Collembola), using standardized ecotoxicological tests (after ISO guidelines with few adaptations for tropical conditions). Commercial formulations of five seed dressing pesticides were tested individually in Tropical Artificial Soil (TAS): the insecticides imidacloprid, fipronil, thiametoxam, and the fungicides captan and carboxin+thiram. Thiametoxam, captan, and carboxin+thiram were only lethal to F. candida at the highest concentration tested (1000mg of active ingredient kg(-1) of dry soil). Imidacloprid and fipronil were lethal at lower concentrations (100 and 10mg a.i. kg(-1) soil d.w, respectively), however, these concentrations were much higher than those predicted (PEC) for soil. Imidacloprid and fipronil were the most toxic pesticides in both tests, reducing significantly collembolan reproduction (EC20=0.02 and 0.12mga.i.kg(-1) soil d.w, respectively). Further studies under more realistic conditions are needed, since imidacloprid and fipronil reduced collembolan reproduction at concentrations below or close to their respective PECs. PMID- 24785713 TI - Synergistic effects of NaOCl and ultrasound combination on the reduction of Escherichia coli and Bacillus cereus in raw laver. AB - The current study investigated the synergistic effects of NaOCl (50-200 ppm)/ultrasound (37 kHz, 380 W for 5-100 min) combination on the reduction of Escherichia coli and Bacillus cereus in raw laver. The synergistic reductions were not dependent on concentrations of NaOCl and times of ultrasound. Synergistic reduction ranged from 0.1 to 0.5 log10 colony-forming units (CFU)/g and 0.1-1.1 log10 CFU/g, respectively, for E. coli and B. cereus, with the largest synergistic reduction in the combination of 200 ppm NaOCl and 60-min ultrasound. Moreover, significant differences of "L" (lightness), "a" (redness), and "b" (yellowness) were not observed in combined with 50-200 ppm NaOCl and 100 min ultrasound compared to those in raw laver treated by only 100-min ultrasound. The results in the current study indicate that the combined treatment of 200 ppm NaOCl and 60-min ultrasound could be regarded a potential optimum hurdle approach in the seaweed production, processing, and distribution process to enhance seaweed safety. PMID- 24785714 TI - Nestin is an independent predictor of cancer-specific survival after radical cystectomy in patients with urothelial carcinoma of the bladder. AB - OBJECTIVES: To investigate the association between the expression of nestin, a class VI intermediate filament protein, and pathologic features or survival in patients with urothelial carcinoma of the bladder (UCB). METHODS: Nestin expression in tumor cells was immunohistochemically studied in 93 patients with UCB who underwent radical cystectomy with pelvic lymphadenectomy. The associations with clinicopathologic parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of nestin expression on survival. RESULTS: Nestin expression in cystectomy specimens was observed in 13 of 93 patients (14.0%). Nestin expression was associated with pathologic tumor stage (p = 0.006). Nestin-negative patients had better overall survival compared with nestin-positive patients (log-rank p = 0.0148). Univariable analysis indicated that nestin expression, lymphovascular invasion, and lymph node status were significantly associated with cancer specific survival (hazard ratios, 2.78, 2.15, and 2.80, respectively). On multivariable analysis, nestin expression and lymph node status were independent prognostic factors in cancer-specific survival (hazard ratios, 2.45 and 2.65, respectively). CONCLUSIONS: The results suggest that nestin expression is a novel independent prognostic indicator for patients with UCB and a potentially useful marker to select patients who may be candidates for adjuvant chemotherapy. PMID- 24785715 TI - Ultrametric distribution of culture vectors in an extended Axelrod model of cultural dissemination. AB - The Axelrod model of cultural diffusion is an apparently simple model that is capable of complex behaviour. A recent work used a real-world dataset of opinions as initial conditions, demonstrating the effects of the ultrametric distribution of empirical opinion vectors in promoting cultural diversity in the model. Here we quantify the degree of ultrametricity of the initial culture vectors and investigate the effect of varying degrees of ultrametricity on the absorbing state of both a simple and extended model. Unlike the simple model, ultrametricity alone is not sufficient to sustain long-term diversity in the extended Axelrod model; rather, the initial conditions must also have sufficiently large variance in intervector distances. Further, we find that a scheme for evolving synthetic opinion vectors from cultural "prototypes" shows the same behaviour as real opinion data in maintaining cultural diversity in the extended model; whereas neutral evolution of cultural vectors does not. PMID- 24785716 TI - A review of parasite studies of commercially important marine fishes in sub Saharan Africa. AB - Scattered records of parasitic species infecting commercially important marine fishes in sub-Saharan Africa are known from just a few countries where concerted efforts have been made by local parasitologists (e.g. Senegal, Nigeria, South Africa). Most of these consist of taxonomic records or general surveys of parasite faunas associated with marine hosts, which may or may not have been of commercial value. Little to no multi-disciplinary research is conducted in most parts of sub-Saharan Africa and hence parasitological data are not commonly used to advise fisheries management procedures. This review summarizes current knowledge on all parasitological research associated with commercially important marine fish species in sub-Saharan Africa. PMID- 24785717 TI - Survey of 11 nitroimidazole residues in hen and duck eggs from the Irish market. AB - A liquid chromatography-tandem mass spectrometry method, recently developed, validated and accredited, was used to screen for metronidazole, ronidazole dimetridazole ipronidazole, ternidazole, tinidazole, ornidazole carnidazole and three hydroxy metabolites (hydroxy-metronidazole, HMMNI and hydroxy-ipronidazole) in Irish retail egg samples. The method used had decision limits (CCalpha) in the range 0.33-1.26 ug kg(-1) and detection capabilities (CCbeta) ranging 0.56-2.15 ug kg(-1) for all analytes. Internal standard-corrected recovery, calculated for the various analytes, ranged 87.2-106.2%, while the coefficient of variance, expressed as % CV, ranged 3.7-11.3%. The method was applied to 160 samples of caged, free range and organic hen and duck eggs available on the Irish retail market as well as two incurred proficiency test egg samples. No nitroimidazole residues were detected in the survey samples above the CCalpha and the results achieved for the two proficiency test samples were acceptable when compared with the assigned values. PMID- 24785718 TI - Incidence of tetracycline residues in chicken meat and liver retailed to consumers. AB - The incidence of tetracyclines' (TCs) residue (oxytetracycline, tetracycline, chlorotetracycline and doxycycline) in fresh chicken samples (meat and liver) collected during one year was recorded. TC residues were analysed using an HPLC DAD method. The limit of detection for meat was 4.4, 5, 10 and 7 ng g(-1) for OTC, TTC, CTC and DOC, respectively, compared with 5.5, 6, 12 and 9 ng g(-1) stated for liver. The recovery of the method ranged from 91% to 70% depending upon both matrix type and tetracycline kind. The results revealed that 66 (44%) samples contained TC residues including 21 (42%) breast, 19 (38%) thigh and 26 (52%) liver samples. The corresponding contaminated ranges were 124-5812, 107 6010 and 103-8148 ug kg(-1). A total of 12 (8%), 13 (7.33%) and 20 (13.33%) samples of breast, thigh and liver, respectively, had TC residues above the Codex maximum residue limit (MRL). Liver samples had a higher incidence and level than those found in breast or thigh samples. PMID- 24785719 TI - Dietary exposure of Hong Kong adults to nitrate and nitrite from vegetable intake. AB - The aim of this study was to assess the dietary exposure of adults in Hong Kong to nitrate and nitrite from vegetables. If all vegetables consumed were raw, the dietary exposure to nitrate for average consumers was estimated to be 4.4 mg kg( 1) body weight (bw) day(-1) and, for high consumers, was estimated to be 13 mg kg(-1) bw day(-1), which is about 120 and 350% of acceptable daily intake (ADI), respectively. If all vegetables consumed were cooked, the dietary exposure to nitrate from vegetables for the average adult consumer was estimated to be 3.5 mg kg(-1) bw day(-1) and, for high consumer, was estimated to be 10 mg kg(-1) bw day(-1), which is about 95 and 270% of ADI, respectively. On the other hand, the dietary exposure to nitrite from vegetables for average and high consumers were well below the ADI. PMID- 24785721 TI - Survey of aflatoxins in watermelon seeds from Iran using immunoaffinity column cleanup and HPLC with fluorescence detection. AB - This survey was undertaken to determine the levels of aflatoxins in melon seeds. Among 65 samples analyzed by liquid chromatography (LC), the results showed that aflatoxin B1 (AFB1) was the major toxins in melon seeds, detected in 58 samples (89.2% of the total) at an average concentration of 8.5 ng g(-1). The level of AFB1 in 12 samples exceeded the maximum tolerated level for AFB1 in Iranian (5 ng g(-1)) regulations; in other words, 18.5% of samples were unfit for human consumption. PMID- 24785720 TI - Intake of aflatoxins through the consumption of peanut products in Brazil. AB - To estimate daily intake of aflatoxins from peanut products consumed by the population of Parana State (Brazil), 100 samples of peanut products were collected between July 2006 and April 2007. Aflatoxins were determined by an HPLC method with fluorescence detection. There was a 50% occurrence of aflatoxins (B1, B2, G1 and G2) in concentrations ranging from 0.5 to 113 ng g(-1), with 13 samples with levels above 20 ng g(-1). Intake was calculated for average and high adult consumers of peanut products and it was compared with provisional maximum tolerable daily intake (PMTDI). The estimated probable daily intake (PDI) for aflatoxin B1 (AFB1) varied from 0.6 to 10.4 ng kg(-1) bw day(-1), exceeding the PMTDI of 0.4 ng kg(-1) bw day(-1) for carriers of hepatitis B virus. PMID- 24785723 TI - Levels of total fumonisins in maize samples from Italy during 2006-2008. AB - We analysed a total of 2258 grain samples over a 3-year period (2006-2008) from 93 storage centers in the principal maize cultivation area of Italy to establish the levels of fumonisin contamination. Fumonisin concentrations were measured using ELISA (RIDASCREEN) fumonisin test kits. Mean levels of contamination were remarkably high in each year, with the highest value in 2006 (10.9 mg/kg) and the lowest in 2008 (4.8 mg/kg). Similarly, for each year, variations were quite large: from 5 ug kg(-1)) in oats, oat flakes, oat meal and oat by-products was 93, 77, 34 and 99%, respectively. The mean values of T-2 + HT-2 were 94, 17, 11 and 293 ug kg(-1) for oats, oat flakes, oat meal and oat by-products, respectively. T-2 and HT-2 occurred together and the T 2 level was 52% of HT-2 in oats. Maximal T-2 and HT-2 concentration in oat flakes and oat meal were 197 and 118 ug kg(-1). The toxins were reduced by 82-88% during processing, but increased 3.1 times in oat by-products. PMID- 24785724 TI - Concentrations and exposure estimates of deoxynivalenol in wheat products from Argentina. AB - The aim of this work was to determine deoxynivalenol (DON) contamination in wheat based food products in Argentina and to estimate DON exposure. The numbers of samples were determined according to a developed sampling plan. A total of 156 samples of different wheat products were randomly collected from food markets in Lujan, Argentina, and analyzed for DON by gas chromatography. DON contamination ranged 7-271 ng g(-1) for French bread, 5-149 ng g(-1) for Vienna bread, 11-85 ng g(-1) for crackers, 8-85 ng g(-1) for pizza, and was 79 ng g(-1) for noodles. The maximum contribution to DON intake was 7% of the PMTDI for French bread; the minimum was less than 1% for noodles. Assuming all groups had eaten all sampled foods and summing all groups' intake contribution, the highest estimate DON exposure would only be <14% (for the 18-24-year old men group) of the DON daily dietary intake. PMID- 24785725 TI - Natural occurrence of type-B trichothecene mycotoxins in Korean cereal-based products. AB - Type-B trichothecenes (deoxynivalenol (DON), nivalenol (NIV), fusarenone-X (FUS X), 15-acetyldeoxynivalenol (15ADON), and 3-acetyldeoxynivalenol (3ADON)) were determined in 338 cereal-based products. Detection limit, quantification limit and mean recovery for five toxins were in the ranges 0.7-2.6 ug kg(-1), 2.1-7.8 ug kg(-1) and 73-110%, respectively. The range of occurrence and average level in samples were, respectively, 21-88% and 5.2-121.8 ug kg(-1) for NIV, 10-96% and 1.7-109.5 ug kg(-1) for DON, 2-39% and 0.4-3.6 ug kg(-1) for FUS-X, 0-80% and 0 17.3 ug kg(-1) for 15ADON, and 0-29% and 0-1.5 ug kg(-1) for 3ADON. Regarding co occurrence, 64% of samples had more than two type-B trichothecenes. The estimated daily intakes of NIV, DON, FUS-X, 15ADON, and 3ADON were 0.077, 0.048, 0.004, 0.006 and 0.002 ug kg(-1) bw day(-1), respectively. These results suggest that current exposure levels do not indicate the possibility of adverse effects, but consideration of the combined exposure of type-B trichothecenes may be required due to the high frequency of co-occurrence. PMID- 24785726 TI - Polycyclic aromatic hydrocarbons in Brazilian commercial soybean oils and dietary exposure. AB - In this study the 13 polycyclic aromatic hydrocarbons (PAHs) identified as being genotoxic and carcinogenic by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) were determined in different brands of soybean oils available on the Brazilian market, totalling 42 samples. A solid-phase extraction (SPE) method for sample clean-up with a C18 cartridge, followed by reversed-phase HPLC with fluorescence detection, was used for determination. The method showed good recoveries for most PAHs studied with values between 74% and 111%. Good intra- and inter-day precisions (0.5 < RSD < 11.9) and high correlation coefficients (r(2)> 0.999) were obtained. The presence of PAHs was detected in all 42 samples with mean summed PAH levels ranging from 10.4 to 112.0 ug kg(-1). The mean and maximum dietary exposures for total PAHs were estimated as 12.4 and 19.1 ng kg bw(-1) day(-1), respectively. PMID- 24785727 TI - Introduction. PMID- 24785728 TI - Making a mockery of family life? AB - Summary In Britain, the legal treatment of lesbian mothers and co-parents has improved considerably over the past 15 years (Harne et al., 1997). Despite this, they are still vilified in occasional outbursts in the popular press. This article identifies arguments against lesbian parenting employed in a recent front page 'fury' article in a British daily tabloid newspaper, The Sun. Encouragingly, of the five arguments about the 'dangers' of lesbian parenting that can be identified in earlier legal battles (such as the 'risk' that children grow up gay, or become 'gender confused'), the only one which this article manages to present very convincingly is that of social stigma. Concern that the children of lesbians may experience name-calling or exclusion is, of course, a problem of discrimination and not a problem that is intrinsic to lesbian parenting (in contrast, say, to an argument about 'the psychology of lesbianism'). The rhetorical force of the piece comes from easily deconstructed journalistic techniques rather than coherent arguments. The sharpest condemnation of these women is actually for having a child whilst on welfare benefits. It is, therefore, economic concerns about 'state dependency,' rather than sexuality per se, which fuel the attack. The imagined financial self-sufficiency of heterosexual families which underpins this argument is outdated in its presumption of a bread-winning, male head of household. The fact that two days before the UK's 1997 General Election, the birth of a baby to a lesbian couple was granted front-page coverage is a sobering reminder of the hostility that lesbians still face through the scrutiny of their 'fitness to parent' and the intrusive condemnation of non-heterosexual domestic arrangements and relationships. PMID- 24785729 TI - Getting kids and keeping them: lesbian motherhood in europe. AB - Summary This article looks at two major issues faced by lesbian mothers in Europe: getting kids and keeping them. The first part focuses on the ways lesbians have children, and in particular the different levels of access to formal insemination services for lesbians in European countries. The second part examines custody issues faced by lesbians with children from previous heterosexual relationships, and those faced by lesbians who have children within a lesbian relationship; and legal recognition of the bond between non-biological parents and their children. The article is based on original research and interviews carried out by the author for the book Lesbian Motherhood in Europe. PMID- 24785730 TI - Raising children in an age of diversity-advantages of having a lesbian mother. AB - Summary Research into the influence of parental lesbianism on child development has not revealed any meaningful nor significant differences between the children of lesbian and heterosexual parents. While such research helps to disprove negative assumptions about lesbian mothers, the focus has been on the potential problems and disadvantages of this difference from the norm. In interviews with 17 British teenagers and adults who have lesbian mothers, respondents suggested distinct advantages for themselves which they attributed to their mother's sexuality. They spoke of the influence their mothers had on their moral development, particularly on their awareness of prejudice and their acceptance of diversity and of homosexuality. They felt they had benefited from the insights they gained into gender relations and from the broader, more inclusive definition of family they acquired through growing up in a different kind of family. PMID- 24785731 TI - The role of co-mothers in planned lesbian-led families. AB - Summary The present study examined the role of co-parents in children's lives by comparing the role of co-mothers in 15 British lesbian mother families with the role of resident fathers in two different groups of heterosexual families (43 families where the study-child was conceived through donor insemination, and 41 families where the child had been naturally conceived). Birth mothers in all three types of family were administered a semi-structured interview to assess the quality of family relationships. Questionnaire data on stress associated with parenting were obtained from co-mothers and fathers, and the children were administered the Family Relations Test. The results indicated that co-mothers played a more active role in daily caretaking than did most fathers. However, father-child and co-mother-child relationships were found to be equally warm and affectionate in all three groups and no group differences were found for children's scores on the Family Relations Test or co-mothers/fathers' scores on the Parenting Stress Index. PMID- 24785732 TI - Reclaiming the 'housewife'? AB - Summary This article addresses the contention that some research on household work in non-heterosexual households has been characterized by a tendency to 'empty' such households of any processes and practices associated with gendering. As a result, lesbians, particularly in co-residing, couple households, have been seen as having more egalitarian, democratic divisions of household labour. This article takes issue with such analyses and argues for the central importance of gender in constituting the organization of work in and between lesbians' households and kin networks. In particular, it addresses the contention that although gender difference may be less obvious in lesbian household arrangements, the issue of who gender is done for assumes key importance. The ways in which lesbians may or may not be constituted as 'housewives' are then unpacked and evaluated in terms of women's relationships to 'family' and in terms of 'housewife' as task-doer. Finally, a plea for the reclamation of the 'housewife,' and the associated need to place gender center-stage, is made evident. PMID- 24785733 TI - Working out. AB - Summary This paper explores the significance of space(s) for the construction and contestation of lesbian teachers' sexual identities. In so doing it reveals how spaces are not neutral, but are shot through with power, such that some locations, be they public or private, become hostile places for lesbians. Nevertheless, queer activists have begun to reclaim the largely heterosexual landscape and to extend the boundaries of sexual citizenship. Schools in England however remain largely sites of compulsory heterosexuality, where few have dared to cross the (sexual) boundaries. Finally, attention is also directed to the city and to the home as sites of resistance and places for possible border crossings. PMID- 24785735 TI - Autism traits may be more prevalent in ADHD than previously reported. PMID- 24785736 TI - Neonatal factors associated with autism spectrum disorders in infants. PMID- 24785737 TI - Therapeutic alpha-interferons protein: structure, production, and biosimilar. AB - In 2007, the world solemnized the golden jubilee of the discovery of interferon (IFN). Interferon is a small protein messenger called a pluripotent cytokine, produced by several cells of the host in response to various biological as well as synthetic stimuli. There are three major classes of interferons in humans: IFN alpha, IFN-beta, and IFN-gamma. As a treatment option, interferon-alpha (IFN alpha) is the most effective one. IFN-alpha has proved to be effective as an antiviral therapy and tumor-fighting drug in the past two decades. Meanwhile, great progress has been achieved in establishing IFN-alpha as the first choice of antiviral therapy for chronic hepatitis C virus (HCV) patients. Recently, novel pegylated IFN-alpha2 products with extended in vivo half-lives and consensus interferon, an artificially engineered type I interferon, have been developed to substantially improve treatment regimes for HCV patients. Undesirable acute and chronic side effects in addition to immunogenicity of therapeutic IFN products remain constraints to conquer for further improvements in clinical applications of IFN. It is certainly expected that more research will be conducted in the future, not only to face these challenges but also to extend the range of IFN products and their clinical targets. The objective herein is to review the current therapeutic alpha-interferons production, formulation technologies, and prospective future for the original entity and its biogeneric version. PMID- 24785738 TI - External validation of two diabetes risk scores in a young UK South Asian population. AB - AIMS: To externally validate the Leicester Practice Risk Score (LPRS) and the Leicester Risk Assessment score (LRAS) in a young South Asian population. METHODS: South Asian participants aged 25-39 years inclusive from a population based screening study were included. The risk scores were calculated and compared to the diagnosis of type 2 diabetes mellitus (T2DM) or T2DM and Impaired Glucose Regulation (IGR, including IFG and IGT) using either an oral glucose tolerance test (OGTT) or a HbA1c (<=48mmol/mol/6.5% and <=42mmol/mol/6.0% respectively). Measures of discrimination and calibration were calculated. RESULTS: Of the 331 participants 8 (2.4%) had undiagnosed T2DM and 30 (9.1%) had IGR using an OGTT, 11 (3.4%) and 39 (12.1%) were found using HbA1c. Using the LPRS to detect T2DM on an OGTT gives an area under the ROC curve of 0.91 (95% CI 0.86, 0.97), including those with IGR gives an ROC of 0.72 (0.62-0.81), these values are 0.93 (0.88, 0.98) and 0.68 (0.60, 0.77) when using an HbA1c to define outcome. Acceptable levels of calibration were seen. Similar results are found for the LRAS. CONCLUSIONS: These scores can be used to identify those with undiagnosed T2DM and/or IGR in a young South Asian population. This is the first study to externally validate scores developed for prevalent undiagnosed disease in this age group using both OGTT and HbA1c. PMID- 24785739 TI - Glycaemic and haemoglobin A1c thresholds for detecting diabetic retinopathy: the fifth Korea National Health and Nutrition Examination Survey (2011). AB - AIMS: Few representative population-based data are available regarding glycaemic and HbA1c thresholds for detecting diabetic retinopathy (DR) in Asia. We investigated the association between DR and fasting plasma glucose (FPG) and HbA1c levels among Korean adults. METHODS: Using data from the Korea National Health and Nutrition Examination Survey (2011), a total of 5212 adults (>=19 years old) were analysed. When participants had diabetes mellitus and/or a suspicion of DR in two-field nonmydriatic fundus photography, seven standard photographs were obtained after pupil dilatation (75.9% of men, 75.0% of women among the subjects). DR was defined as the presence of >=1 retinal microaneurysms or blot haemorrhages with or without more severe lesions. Receiver operating characteristic (ROC) curves were used to determine the optimal cut-off value for HbA1c or FPG. RESULTS: The overall glycaemic thresholds for DR were 6.3mmol/l for FPG and 6.2% (44mmol/mol) for HbA1c. The optimal thresholds did not differ by age group. The sensitivities and specificities were 82.6% and 91.2% for FPG and 93.9% and 89.7% for HbA1c, respectively. The diagnostic discrimination was better for HbA1c than FPG for DR-area under curve: 0.908 for FPG and 0.953 for HbA1c (p=0.007). After being controlled for other covariates, the odds ratio for the risk of DR increased significantly in a consistent way from 6.2% (44mmol/mol) for HbA1c and 6.3mmol/l for FPG. CONCLUSIONS: According to these nationally representative data, the current diabetes diagnostic values for FPG and HbA1c based on DR may be lower for the Korean population. PMID- 24785740 TI - Juvenile granulosa cell tumour: a pitfall in cytological diagnosis. PMID- 24785741 TI - The Arabidopsis Myb transcription factor MTF1 is a unidirectional regulator of susceptibility to Agrobacterium. AB - We recently described the Arabidopsis Myb transcription factor MTF1 that negatively regulates plant susceptibility to Agrobacterium-mediated transformation. Roots of mtf1 mutant plants show increased susceptibility to several Agrobacterium strains, and complementing the mutants with a MTF1 cDNA decreases transformation susceptibility to wild-type levels. Here, we show that overexpression of MTF1 in a wild-type Arabidopsis background does not result in altered transformation susceptibility. However, MTF1 overexpressing plants show increased root length and larger and darker leaves, indicating that MTF1 plays a role in plant growth and development. MTF1 decreases Arabidopsis root susceptibility specifically to Agrobacterium but plant responses to the pathogens Alternaria brassicicola or Pseudomonas syringae pv Tomato were not altered. However, the homozygous MTF1 mutant mtf1-4 is resistant to Botrytis cinerea strain BO5-10 and is regulated through the ethylene signaling pathway mediated by upregulation of the AP2/ERF transcription factor ORA59. PMID- 24785743 TI - Psychological health and life experiences of pregnant adolescent mothers in Jamaica. AB - A recent Jamaican school-based survey revealed that 23.1% of 13-15 year-olds, had attempted suicide one or more times during the last 12 months. Research that links adolescent pregnancy and suicidal behaviour is lacking in Jamaica. Psychological distress and suicidal behaviours amongst pregnant adolescents elsewhere in the Americas has been documented at prevalence of between 13.3%-20%. The purpose of the study was to explore the experiences and the impact of pregnancy on pregnant adolescent psychological health. Individual interviews and focus groups were conducted with adolescents in two Jamaican antenatal clinics. One clinic was designed as a 'Teen Pregnancy Clinic' and the other used the standard antenatal clinic design. The following themes were identified: decision making, resilience, social support, community support system, distress, and perceptions of service. Participants reported positively on the specific interventions tailored to their needs at the Teen Clinic. Although motherhood is valued, none of the pregnancies in this study were planned by the mother. Of the 30 adolescents interviewed, seven cases were referred for counseling due to their need for emotional and psychological support. One of the adolescents reported recent sexual violence and another reported having experienced childhood sexual abuse. Historically, Jamaican adolescent mothers faced barriers to education, self determination, and family planning. Empowering, adolescent-centred healthcare and comprehensive reproductive health education may mitigate psychosocial distress. PMID- 24785742 TI - Lessons from community mental health to drive implementation in health care systems for people with long-term conditions. AB - This paper aims to identify which lessons learned from the evidence and the experiences accruing from the transformation in mental health services in recent decades may have relevance for the future development of healthcare for people with long-term physical conditions. First, nine principles are discussed which we first identified to guide mental health service organisation, and all of which can be potentially applied to long term care as well (autonomy, continuity, effectiveness, accessibility, comprehensiveness, equity, accountability, co ordination, and efficiency). Second, we have outlined innovative operational aspects of service user participation, many of which were first initiated and consolidated in the mental health field, and some of which are now also being implemented in long term care (including case management, and crisis plans). We conclude that long term conditions, whether mental or physical, deserve a long term commitment from the relevant health services, and indeed where continuity and co-ordination are properly funded implemented, this can ensure that the symptomatic course is more stable, quality of life is enhanced, and the clinical outcomes are more favourable. Innovations such as self-management for long-term conditions (intended to promote autonomy and empowerment) need to be subjected to the same level of rigorous scientific scrutiny as any other treatment or service interventions. PMID- 24785744 TI - Unerupted lower third molar extractions and their risks for mandibular fracture. AB - As every surgical procedure extraction of third molars can result in several complications, among them the mandibular angle fracture. Predisposing factors for fracture should be analyzed during and after the surgery. This paper aims to discuss the predisposing factors to the occurrence of mandibular angle fractures during and after the procedure for third molars extraction, as well as surgical principles to avoid this complication. PMID- 24785745 TI - Odontogenic lesions in pediatric patients. AB - The purpose was to evaluate our 20-year experience of pediatric odontogenic lesions. Pediatric patients with a diagnosis of odontogenic lesion were identified. Three hundred ten patients were odontogenic; dentigerous cyst was seen in 62.0% of the cases. Most (70.2%) of them occurred in mixed dentition period, and it had a male preponderance. Odontogenic keratocystic tumor occurred in the permanent dentition period. It had an equal site distribution. Odontoma was seen in 20.0% of the cases. Its site of predilection was the mandible. Ameloblastoma was the most common odontogenic tumor. Most of the cases occurred in the permanent dentition period. It affected the male and female equally. Calcifying epithelioma odontogenic tumor was seen in 11.8% of the cases. All the lesions occurred in the primary dentition period. It had no sex or site preponderance. Myxoma was seen in 3.6% of the cases. It was most common in the permanent dentition period, and it was more frequent in the male. Iliac crest bone graft was successfully performed in 28 patients, postoperative infection occurred in 2 patients, and no donor-site dysfunctions were reported. The observed differences in lesion type and distribution in this study compared with previous researches may be attributable to genetic and geographic variation in the populations studied. Iliac crest bone graft was suggested for pediatric mandible reconstruction. PMID- 24785746 TI - Posttraumatic use of dental implants immediately after tooth extraction: clinical study. AB - PURPOSE: Root fracture is a combined injury of cementum, dentin, and pulp. Many of these traumas remain untreated, mistreated, or overtreated. It leads to a more complicated treatment in case of tooth loss. Many different treatment procedures, with a very changeable success rate, have been proposed for years to treat teeth with root fractures. The objective of the following clinical studies was to evaluate the clinical effectiveness of implants placed in fresh extraction sites to treat teeth with horizontal root fracture. METHODS: The study group included 25 patients (15 men and 10 women) between the ages of 20 and 65 years. After an initial examination and a treatment planning, all of the patients underwent periodontal treatment, which was deemed necessary to favor wound healing. All the 25 teeth were extracted because of horizontal root fracture located at the level of the middle third. The second-stage surgery was performed 6 months after the initial procedure. The following clinical parameters, presence or absence of mobility, presence or absence of pain, and presence or absence of suppuration, were evaluated in each patient at 6 and 12 months after implant placement. Radiographs were taken using the standard method to evaluate the marginal bone loss. RESULTS: The healing period was uneventful for all patients. All implants had osseointegrated. After 12 months, patients were asymptomatic and showed no signs of infection or bleeding when probed. CONCLUSIONS: On the basis of this study, implants placed right after tooth extraction are a valid treatment procedure, which induces predictable results as treatment of fractured teeth. PMID- 24785747 TI - Massive thrombosis of bilateral superior and inferior ophthalmic veins secondary to ethmoidal rhinosunisitis: imaging findings. AB - Ophthalmic vein thrombosis (OVT) is a rare condition occurring secondary to varied etiologies that commonly presents with proptosis, globe dystopia, ophthalmoplegia, periorbital edema, and occasionally diminished visual acuity. It may be related to inflammation of the orbit or paranasal sinuses. We herein report imaging findings of thrombosed superior and inferior ophthalmic veins in bilateral involvement in a 20-year-old male patient without cavernous sinus thrombosis. He presented with pain, swelling, and blurred vision in both eyes. Magnetic resonance (MR) imaging, cerebral MR angiography, and susceptibility weighted imaging were performed. Bilateral superior and inferior OVT due to a complication of ethmoidal sinusitis was diagnosed in the patient. Anticoagulant and systemic broad-spectrum antibiotic therapy was started. His symptoms were recorded at the end of 14 days of the treatment. PMID- 24785748 TI - Is use of laser really essential for release of tongue-tie? AB - Ankyloglossia, or tongue-tie, is a congenital condition characterized by a short, thickened, or abnormally tight lingual frenulum. This anomaly can cause a varying degree of reduced tongue mobility and has been associated with functional limitations including breastfeeding difficulties, atypical swallowing habits, speech articulation problems, mechanical problems such as inability to clean the oral cavity, and psychosocial stress. In this article, we report a 50-year-old female patient with tongue-tie having difficulty in speech and maintenance of oral hygiene due to high attachment of lingual frenum. The patient was managed by frenectomy by conventional method (scalpel and blade) under local anesthesia as an outpatient procedure without any complications. She later required speech therapy lessons for improvement of speech. PMID- 24785749 TI - Langerhans cell histiocytosis: treatment strategies. PMID- 24785750 TI - Can plasma rich in growth factors improve healing in patients who underwent radiotherapy for head and neck cancer? A split-mouth study. AB - OBJECTIVES: The objective of this study was to identify surgical protocols that can improve mucosal healing and postextraction socket closure in patients who underwent radiation therapy for head and neck cancer. METHODS: The study was designed as a prospective split-mouth trial on 20 patients who needed bilateral paired dental extractions. On the side directly impacted by radiation, chosen to be the study side, the sockets were filled with plasma rich in growth factors (PRGF), whereas, on the other side (control), they were allowed to undergo natural healing. Outcome variables were residual socket volume (RSV), healing index (HI), pain, and postsurgical complications as measured at the 2 sides at the 4 follow-up sessions (up to 30 days after the extraction). Continuous variables were analyzed with Wilcoxon (when matched) or Mann-Whitney (when independent) test; categorical variables, with Chi-squared or Fisher test. Statistical significance was set at P < 0.05. Correlation was estimated with Pearson linear correlation coefficient. RESULTS: The PRGF side showed statistically significant better values for RSV and HI at all checkups and no postoperative complications. The control side had a slower healing and 2 cases of bone exposure, which were successfully cured with PRGF application. The RSV on the 21st day after the extraction was correlated with the dose received but not with the time since radiotherapy. CONCLUSIONS: Plasma rich in growth factors proved to be effective in the management of patients with a history of head and neck radiotherapy, accelerating and fostering mucosal healing and avoiding postextraction bone exposures. PMID- 24785751 TI - Calcifying cystic odontogenic tumor associated with ameloblastic fibro-odontoma of the anterior mandible. AB - Calcifying cystic odontogenic tumor, which was formerly named calcifying odontogenic cyst, is a benign odontogenic tumor containing clusters of ghost cells within ameloblastic epithelium. Calcifying cystic odontogenic tumors have been associated with other odontogenic tumors, a finding that is a rare event in other types of odontogenic cysts or tumors. This report describes a case of hybrid odontogenic tumor composed of calcifying cystic odontogenic tumor and ameloblastic fibroma-odontoma of the anterior mandible that occurred in a 4-year old Korean girl. PMID- 24785752 TI - Increased neutrophil-lymphocyte ratio in patients with idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: The aim of this study was to determine whether neutrophil-lymphocyte ratio (NLR) levels are elevated in patients with idiopathic sudden sensorineural hearing loss (ISSHL) compared with healthy controls. Moreover, we aimed to find out whether there is a correlation between NLR levels and the severity of hearing loss. MATERIALS AND METHODS: The study group consisted of 40 subjects with ISSHL and 40 control subjects with no evidence of ear pathology. Severity of hearing loss in the ISSHL patients was classified as mild (<40 dB loss for any frequency), moderate (up to 80 dB), and severe (profound, >80 dB). RESULTS: The mean +/- SD NLR values were 5.53 +/- 1.72 in the ISHHL patients and 2.73 +/- 0.81 in the control group. The mean NLR values in the patients with ISHHL were significantly higher than in the control group (P = 0.0001). The mean +/- SD NLR values in the patients with mild (group A), moderate (group B), and severe (group C) sensorineural hearing loss were 5.53 +/- 1.72, 5.29 +/- 1.81, and 5.82 +/- 1.72, respectively. The mean NLR values in the patients with severe sensorineural hearing loss were significantly higher than in the other groups (P = 0.0001). Nevertheless, there was no correlation between NLR values and severity of hearing loss. CONCLUSIONS: There is no previous study that investigated the association between NLR and ISSHL in the literature. High NLR values in ISSHL patients may be a predictor of other ishemic conditions such as coronary or cerebral ischemia. Thus, the otorhinolaryngologist would then refer the patient to cardiology and then neurology specialists for the appropriate examinations. PMID- 24785753 TI - Effect of digital template in the assistant of a giant condylar osteochondroma resection. AB - PURPOSE: Exostosis osteochondroma is usually resected with the whole condyle even part of it is not involved. This study was to report the effect of using digital template in the assistant of resection while protecting the uninvolved condyle. METHODS: We used computer-aided design technique in the assistant of making preoperative plan of a patient with giant condylar osteochondroma of exogenous type, including determining the boundary between the tumor and the articular surface of condyle, and designing the virtual tumor resection plane, surgical approach, and remove-out path of the tumor. The digital osteotomy template was made by rapid prototyping technique based on the preoperative plan. Postoperative CT scan was performed and merged with the preoperative CT by the Proplan 1.3 system to evaluate the accuracy of surgical resection with the guide of digital template. RESULTS: The osteotomy template was attached to the lateral surface of condyle accurately, and the tumor was removed totally by the guide of the template without injuries to adjacent nerves and vessels. Postoperative CT showed that the osteochondroma was removed completely and the unaffected articular surface of condyle was preserved well. The merging of postoperative and preoperative CT by Proplan 1.3 system showed the outcome of the operation matched with the preoperative planning quite well with an error of 0.92 mm. There was no sign of recurrence after 6 months of follow-up. CONCLUSIONS: The application of digital template could improve the accuracy of the giant condylar tumor resection and help to preserve the uninvolved condyle. The use of digital template could reduce injuries to the nerves and vessels as well as save time for the operation. PMID- 24785754 TI - The impact of pharyngeal repair time and suture frequency on the development of pharyngocutaneous fistula after total laryngectomy. AB - OBJECTIVE: Pharyngocutaneous fistula (PCF) is the most common postoperative complication after total laryngectomy. The aim of this study was to determine the relationship between PCF with pharyngeal repair time and the number of mucosal sutures. METHODS: The medical records of 47 patients who underwent total laryngectomy were assessed prospectively. The pharyngeal repair time and the number of horizontal, vertical, and cricopharyngeal muscle sutures were recorded. We observed the occurrence of PCF in 14 patients (29.8%). The mean time for pharyngeal repair in the PCF group was 22 minutes 59 seconds +/- 5 minutes, and the mean number of vertical, horizontal, and cricopharyngeal muscle sutures was 8.57 +/- 2.6, 11.14 +/- 2.1, and 8.45 +/- 1.9, respectively. The mean time for pharyngeal repair in the non-PCF group was 22 minutes 21 seconds +/- 5 minutes, and the mean number of vertical, horizontal, and cricopharyngeal muscle sutures was 9.54 +/- 2.6, 10.84 +/- 2.3, and 7.36 +/- 2.7, respectively. The differences in the pharyngeal repair time and the number of vertical, horizontal, and cricopharyngeal sutures between the 2 groups were not statistically significant (P > 0.05). Besides, there was no statistically significant difference between the mean suture counts per centimeter in horizontal plane (1.46 +/- 0.35) and vertical plane (0.98 +/- 0.25) in the PCF group and the mean suture counts per centimeter in horizontal plane (1.42 +/- 0.37) and vertical plane (1.13 +/- 0.3) in the non-PCF group (P > 0.05). CONCLUSIONS: There was no relation between PCF development with pharyngeal repair time, mucosal suture count, and suture frequency after total laryngectomy. PMID- 24785755 TI - Does body mass index matter while selecting the flap type for pharyngeal reconstructions? AB - The aim of our study was to investigate the effect of patient-related factors, such as the body mass index (BMI) and tumor size, in selecting the flap type for the reconstruction of pharyngeal defects. This retrospective review included 182 patients with pharyngeal defect reconstructions with free and pedicled flaps at the Ohio State University from January 2005 to December 2008. We conducted a retrospective comparison of variety of different flap reconstruction techniques. We compared different flap reconstruction with BMI and tumor size without functional outcome such as swallowing and speech data. Although there was no statistically significant correlation (P > 0.05) when comparing the free flaps with pedicled flaps according to the BMI and tumor size, there was an obvious tendency to prefer radial forearm free flap over anterolateral thigh free flap in patients who are overweight and those with obesity with a ratio of 32:3. In the same group of patients, a similar tendency was observed to prefer fibular free flap over iliac crest free flap with a ratio of 14:5, whereas the ratio was becoming 3:5 in favor of iliac crest free flap over fibular free flap in patients with BMI of 24 or lower. Despite the fact that surgeons' experience with a certain flap type is one of the most important factors while determining which flap to reconstruct, BMI might have a significant impact while selecting the free flap types for the reconstruction of pharyngeal defects. PMID- 24785756 TI - Evaluation of the mandibular canal visibility on cone-beam computed tomography images of the mandible. AB - BACKGROUND: The mandibular canal (MC) is an important and necessary landmark that should be considered before any surgery in the posterior region of the mandible. This study is aimed to evaluate the visibility and position of the MC in an Iranian population using cone-beam computed tomography. METHODS: In this cross sectional study, cone-beam computed tomography images of 69 patients, which were available as soft copies in the archives of the databases in the Department of Oral Radiology at Hamadan University of Medical Sciences (Hamadan, Iran), were analyzed. The visibility, corticalization, and position of the MC were assessed by 2 expert oral radiologists independently. The chi2 test, unpaired t test, and 1-way analysis of variance were used for analysis. RESULTS: The right and left MCs were clearly visible in 89.6% and 84.7% of the cases, respectively. Among 87.5% of cases, the MC was observed simultaneously in 2 sides. Position of the MC in relation to surrounding structures showed lowest asymmetry at the second premolar area. There were no statistically significant difference between sex and the evaluated parameters. CONCLUSIONS: Cone-beam computed tomography was successful in most cases in displaying the MC. The areas with most MC visibility in the right and left sides were the second and third molar regions, respectively. This visibility declined forwardly in both sides. PMID- 24785757 TI - Eagle syndrome surgical treatment with piezosurgery. AB - INTRODUCTION: Eagle syndrome (ES) is an uncommon complication of styloid process elongation with stylohyoideal complex symptomatic calcification. It is an uncommon condition (4% of the population) that is symptomatic in only 4% of the cases. Eagle syndrome is usually an acquired condition that can be related to tonsillectomy or to a neck trauma. A type of ES is the styloid-carotid syndrome, a consequence of the irritation of pericarotid sympathetic fibers and compression on the carotid artery. Clinical manifestations are found most frequently after head turning and neck compression. Although conservative treatment (analgesics, anticonvulsants, antidepressants, local infiltration with steroids, or anesthetic agents) have been used, surgical treatment is often the only effective treatment in symptomatic cases. MATERIALS AND METHODS: We present the case of a 55-year-old patient, successfully treated under endotracheal anesthesia. The cranial portion of the calcified styloid process was shortened through an external approach, using a piezoelectric cutting device (Piezosurgery Medical II; Mectron Medical Technology, Carasco, Italy) with MT1-10 insert, pump level 4, vibration level 7. RESULTS: No major postoperative complications such as nerve damage, hematoma, or wound dehiscence occurred. After 6 months, the patient was completely recovered. Two years after the surgery, the patient did not refer any symptoms related to ES. CONCLUSIONS: The transcervical surgical approach in patients with ES seems to be safe and effective, despite the remarkable risk for transient marginal mandibular nerve palsy. This risk can be decreased by the use of the piezoelectric device for its distinctive characteristics--such as precision, selective cut action, and bloodless cut. PMID- 24785758 TI - Health professionals' knowledge of driving restrictions following stroke and TIA: experience from a hyperacute stroke centre. AB - BACKGROUND AND PURPOSE: Assessment of fitness to drive (FTD) is important after stroke or transient ischaemic attack (TIA) to ensure that neither patients nor public are at risk. This is particularly important in patients with TIAs or minor stroke as many are discharged directly from emergency departments by a range of health professionals. We assessed stroke-related FTD knowledge among physicians' and allied health professionals' (AHPs) treating patients with stroke at a hyperacute stroke centre. METHODS: Knowledge of FTD restrictions following a stroke or TIA for domestic and commercial use was assessed in 195 physicians and 45 AHPs using a multiple-choice questionnaire between January and December 2009. The effect of discipline, seniority, previous instruction in FTD restrictions and experience in stroke medicine on FTD was assessed. RESULTS: The correct driving restriction following stroke with domestic and commercial license was known to 29% and 73% of physicians, respectively. For AHPs, these figures were 36% and 20%. For TIA with domestic and commercial license, this was 37% and 43% for physicians, and 44% and 11% for AHPs. 25% of physicians and 11% of AHPs believed that no driving restrictions applied after a TIA. The correct office for reporting FTD was known to 180 (92%) doctors and 31 (69%) AHPs (p=0.0001); 160 (82%) physicians and 27 (60%) AHPs correctly identified that reporting was the patients' responsibility (p=0.001). FTD knowledge correlated with post in stroke (OR 3.2 (95% CI 1.6 to 6.2, p=0.001)) but not with seniority or previous FTD education. CONCLUSIONS: Health professionals providing stroke care showed limited knowledge of FTD regulations after minor stroke or TIA. Imparting accurate information on driving restrictions is an important but neglected part of stroke management. PMID- 24785759 TI - Functional characterization of FgERG3 and FgERG5 associated with ergosterol biosynthesis, vegetative differentiation and virulence of Fusarium graminearum. AB - The ergosterol biosynthesis pathway is well characterized in Saccharomyces cerevisiae, while little is known about the pathway in filamentous fungi. In this study, we isolated and genetically documented biological functions of FgErg3 and FgErg5, which are located upstream of FgErg4, the enzyme catalyzing the final step of ergosterol synthesis in Fusarium graminearum. Our results demonstrated that F. graminearum contains two paralogous FgERG3 and two FgERG5 genes. FgErg3, but not FgErg5, is involved in ergosterol biosynthesis. Double deletion mutants of FgERG3 alleles or the double deletion mutants of FgERG5 alleles showed decreased conidiation and produced abnormal conidia. Fungicide susceptibility tests revealed that FgERG3 and FgERG5 mutants have increased resistance towards triadimefon. However, FgERG3 mutants exhibited increased susceptibility to tebuconazole as well as increased susceptibility to oxidative stress, paraquat and to Mg(2+). Pathogenicity tests showed that the FgERG3 and FgERG5 double deletion mutant displayed dramatically attenuated virulence although they were able to successfully colonize flowering wheat head. In addition, complementation of FgERG3 and FgERG5 genes into S. cerevisiae partially rescued the susceptibility of S. cerevisiae ERG3 and ERG5 deletion mutants towards hydroxyurea and caffeine. Taken together, our results indicate that FgERG3 and FgERG5 play a crucial role in vegetative differentiation, resistance to fungicides and virulence in F. graminearum. FgErg3 alleles, but not FgErg5 alleles, are required for ergosterol biosynthesis in the filamentous fungus F. graminearum. PMID- 24785760 TI - Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling. AB - A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling. PMID- 24785762 TI - Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities: Abridged republication of a Cochrane systematic review. AB - We aimed to determine clinical effectiveness of pharmacological interventions for self-injurious behaviour in adults with intellectual disability. We searched the following databases: CENTRAL; MEDLINE; EMBASE; PsycINFO; CINAHL; SCI; SSCI; Conference Proceedings Citation Index - Science; Conference Proceedings Citation Index - Social Science and Humanities; ZETOC; World Cat .We also searched ClinicalTrials.gov,ICTRP and the reference lists of included trials. We included randomised controlled trials that examined drug interventions versus placebo for self-injurious behaviour. We found five double-blind, placebo-controlled trials, which included a total of 50 people. Four trials compared the effects of naltrexone versus placebo and one trial clomipramine versus placebo. We did not identify any relevant placebo-controlled trials for other drugs. We presented a narrative summary, as meta-analysis was not appropriate due to differences in study designs, differences between interventions and heterogeneous outcome measures. There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating self-injurious behaviour. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo. PMID- 24785761 TI - Dopamine D2/3 receptor availability and amphetamine-induced dopamine release in obesity. AB - INTRODUCTION: The neurotransmitter dopamine is important in the regulation of food intake. It is hypothesised that obese people experience less reward from food due to lower striatal dopamine release, which consequently leads to overeating. This study is the first to assess whether obese subjects have blunted striatal dopamine release. METHOD: We measured striatal dopamine D2/3 receptor (DRD2/3) availability and amphetamine-induced striatal dopamine release in 15 obese and 15 age-matched, normal-weight women using [(123)I]iodobenzamide single photon emission computed tomography (SPECT) imaging. In addition, correlations with food craving were examined. RESULTS: Baseline striatal DRD2/3 availability was lower in obese subjects (0.91 +/- 0.16) compared to controls (1.09 +/- 0.16; p = 0.006). Amphetamine-induced dopamine release was significant in controls (7.5% +/- 9.2; p = 0.007) and not in obese subjects (1.2% +/- 17.7; p = 0.802), although the difference in release between groups (d=0.45) was not significant. Dopamine release positively correlated with the trait food craving in obese subjects. CONCLUSION: This study replicates previous findings of lower striatal DRD2/3 availability in obesity and provides preliminary data that obesity is associated with blunted dopamine release. The positive correlation between dopamine release and food craving in obesity may seem contradictory with the latter finding but is presumably related to heterogeneity within the obese subjects. PMID- 24785763 TI - Evidence that the attentional set shifting test in rats can be applied in repeated testing paradigms. AB - The attentional set shifting task (ASST) can be used to assess aspects of executive function, including reversal learning and set shifting. It has frequently been employed in between-subjects experimental designs: however, the clear advantages of within-subjects designs (reduction in variance, animal numbers, and cost) mean that investigation of the suitability of the ASST for within subjects designs is warranted. Rats were tested three times: test 1 (24 h after training), test 2 (24 h later), and test 3 (seven days later). On all three test days, animals showed the expected pattern of performance across the seven task stages with evidence of normal reversal learning (significant increase in trials to criterion when the rule was reversed) and intact set formation (significantly more trials to criterion for an extradimensional shift than for an intradimensional shift). There was a small decrease in total trials required to complete the task between test 1 and test 3 but this was not specific to any stage of the task. Latency to dig decreased on repeated testing suggesting some facilitation of associative learning. In conclusion, the rodent ASST is suitable for within-subject design longitudinal studies, increasing the utility and the translational value of this test and reducing numbers of animals needed in studies. PMID- 24785764 TI - Early responding to traumatic events. AB - How to respond optimally following traumatic events remains a Holy Grail. A number of early interventions lack evidence of effect. Practical, pragmatic support provided in an empathic manner is likely to be an appropriate initial response and complement the high levels of resilience shown by individuals exposed to traumatic events. PMID- 24785765 TI - The 25th anniversary of the launch of Prozac gives pause for thought: where did we go wrong? AB - The creation, in DSM-III, of the category 'major depression' can be linked to the launch, and success, of Prozac. The consequences of creating this broad diagnostic category are of concern in relation to the treatment of individuals with a diverse variety of depressive disorders. PMID- 24785766 TI - Mindfulness for psychosis. AB - Mindfulness treatments and research have burgeoned over the past decade. With psychosis, progress has been slow and likely held back by clinicians' belief that mindfulness may be harmful for this client group. There is emerging evidence that mindfulness for psychosis - when used in an adapted form - is safe and therapeutic. PMID- 24785767 TI - Rates of post-traumatic stress disorder in trauma-exposed children and adolescents: meta-analysis. AB - BACKGROUND: It is unclear how many children and adolescents develop post traumatic stress disorder (PTSD) after trauma. AIMS: To determine the incidence of PTSD in trauma-exposed children and adolescents as assessed with well established diagnostic interviews and to examine potential moderators of the estimate. METHOD: A systematic literature search identified 72 peer-reviewed articles on 43 independent samples (n = 3563). Samples consisting only of participants seeking or receiving mental health treatment were excluded. Main analyses involved pooled incidence estimates and meta-analyses of variance. RESULTS: The overall rate of PTSD was 15.9% (95% CI 11.5-21.5), which varied according to the type of trauma and gender. Least at risk were boys exposed to non-interpersonal trauma (8.4%, 95% CI 4.7-14.5), whereas girls exposed to interpersonal trauma showed the highest rate (32.9%, 95% CI 19.8-49.3). No significant difference was found for the choice of assessment interview or the informant of the assessment. CONCLUSIONS: Research conducted with the best available assessment instruments shows that a significant minority of children and adolescents develop PTSD after trauma exposure, with those exposed to interpersonal trauma and girls at particular risk. The estimates provide a benchmark for DSM-5 and ICD-11. PMID- 24785768 TI - Confounders in studies of suicide by occupation. PMID- 24785769 TI - Confounders in studies of suicide by occupation. PMID- 24785770 TI - Author's reply: To PMID 24297788. PMID- 24785771 TI - The rural employment advantage for people with psychosis: is it real? PMID- 24785772 TI - Authors' reply. PMID- 24785773 TI - Religious service attendance as a protective factor against suicide. PMID- 24785774 TI - Authors' reply. PMID- 24785775 TI - Ten books. PMID- 24785776 TI - Functionalized carbon nanohoops: synthesis and structure of a [9]cycloparaphenylene bearing three 5,8-dimethoxynaphth-1,4-diyl units. AB - A functionalized [9]cycloparaphenylene ([9]CPP) bearing three evenly spaced 5,8 dimethoxynaphth-1,4-diyl units and two macrocyclic [6]CPP precursors have been synthesized. The Diels-Alder reaction between (E,E)-1,4-bis(4-bromophenyl)-1,3 butadiene and 1,4-benzoquinone followed by methylation produces cis-5,8-bis(4 bromophenyl)-5,8-dihydro-1,4-dimethoxynaphthalene as the key intermediate for the construction of the hooplike structures. The nickel-mediated homocoupling reactions followed by aromatization led to the functionalized [9]CPP. PMID- 24785777 TI - Homooligomerization is needed for stability: a molecular modelling and solution study of Escherichia coli purine nucleoside phosphorylase. AB - Although many enzymes are homooligomers composed of tightly bound subunits, it is often the case that smaller assemblies of such subunits, or even individual monomers, seem to have all the structural features necessary to independently conduct catalysis. In this study, we investigated the reasons justifying the necessity for the hexameric form of Escherichia coli purine nucleoside phosphorylase - a homohexamer composed of three linked dimers - since it appears that the dimer is the smallest unit capable of catalyzing the reaction, according to the currently accepted mechanism. Molecular modelling was employed to probe mutations at the dimer-dimer interface that would result in a dimeric enzyme form. In this way, both in silico and in vitro, the hexamer was successfully transformed into dimers. However, modelling and solution studies show that, when isolated, dimers cannot maintain the appropriate three-dimensional structure, including the geometry of the active site and the position of the catalytically important amino acids. Analytical ultracentrifugation proves that E. coli purine nucleoside phosphorylase dimeric mutants tend to dissociate into monomers with dissociation constants of 20-80 MUm. Consistently, the catalytic activity of these mutants is negligible, at least 6 orders of magnitude smaller than for the wild-type enzyme. We conclude that the hexameric architecture of E. coli purine nucleoside phosphorylase is necessary to provide stabilization of the proper three-dimensional structure of the dimeric assembly, and therefore this enzyme is the obligate (obligatory) hexamer. STRUCTURED DIGITAL ABSTRACT: ?PNP and PNP bind by molecular sieving (1, 2, 3, 4). PMID- 24785778 TI - Iron sulfide ink for the growth of pyrite crystals. AB - Iron pyrite (FeS2, Fool's Gold) is a non-toxic, earth abundant semiconductor that exhibits promise for use in energy conversion and storage devices, such as the cathode material for batteries, thermoelectrics and optoelectronics. However, pyrite's potential as an energy-critical material is being curbed due to problems with controlling composition, stoichiometry and bulk and surface defects. To overcome these problems, simple and scalable methods to grow high quality crystalline pyrite for in-depth studies are necessary. In this study, we report a facile approach to create high quality, micron sized pyrite crystals from the FeS wire molecular ink. Growth of high quality pyrite crystals is examined and a model for growth and surface facet dependent activation energy is proposed. Unique thermal measurements are preformed that allow for insight into the pyrite's crystallinity and thermoconductive properties. It is shown that as made pyrite crystals exhibit high crystallinity which will be vital for future in depth studies and device fabrication. PMID- 24785779 TI - Cross-sectional study of unexplained white matter lesions in HIV positive individuals undergoing brain magnetic resonance imaging. AB - White matter (WM) abnormalities are frequently seen on brain MRI of HIV positive (HIV+) patients. We aimed to determine the prevalence of unexplained WM abnormalities and their associations with HIV disease and cardiovascular risk factors. We conducted a retrospective, cross-sectional study of brain MRI of HIV+ patients conducted between 2004 and 2009 at our center. Clinical and laboratory data were compiled, and images were independently reviewed for WM lesions. Images were obtained from 254 patients: 70% male, 53% white, 40% black, mean age 42 years, median current CD4 count 240 cells/mm(3), and 41% not taking antiretroviral therapy (ART). Hyperintense WM lesions were present in 161 patients (63.4%): 89 scans (35.0%) showed diffuse WM signal abnormality (DWMSA), 61 (24.0%) were consistent with small vessel disease (SVD, graded by Fazekas' scale), and 37 (14.6%) showed large asymmetrical focal WM lesions. SVD changes were associated with age and cardiovascular risk factors, and while cerebral SVD may be related to HIV infection, the MRI findings were not associated with HIV related factors. The only risk factor for DWMSA was black race, and no correlation with cardiovascular risk factors, CD4 count, or clinical presentation was identified. DWMSA are therefore of uncertain neurological significance in HIV+ patients and could represent more than one clinicopathological entity. PMID- 24785780 TI - Impact of dispatcher-assisted bystander cardiopulmonary resuscitation on neurological outcomes in children with out-of-hospital cardiac arrests: a prospective, nationwide, population-based cohort study. AB - BACKGROUND: The impact of dispatcher-assisted bystander cardiopulmonary resuscitation (CPR) on neurological outcomes in children is unclear. We investigated whether dispatcher-assisted bystander CPR shows favorable neurological outcomes (Cerebral Performance Category scale 1 or 2) in children with out-of-hospital cardiac arrest (OHCA). METHODS AND RESULTS: Children (n=5009, age<18 years) with OHCA were selected from a nationwide Utstein-style Japanese database (2008-2010) and divided into 3 groups: no bystander CPR (n=2287); bystander CPR with dispatcher instruction (n=2019); and bystander CPR without dispatcher instruction (n=703) groups. The primary endpoint was favorable neurological outcome at 1 month post-OHCA. Dispatcher CPR instruction was offered to 53.9% of patients, significantly increasing bystander CPR provision rate (adjusted odds ratio [aOR], 7.51; 95% confidence interval [CI], 6.60 to 8.57). Bystander CPR with and without dispatcher instruction were significantly associated with improved 1-month favorable neurological outcomes (aOR, 1.81 and 1.68; 95% CI, 1.24 to 2.67 and 1.07 to 2.62, respectively), compared to no bystander CPR. Conventional CPR was associated with increased odds of 1-month favorable neurological outcomes irrespective of etiology of cardiac arrest (aOR, 2.30; 95% CI, 1.56 to 3.41). However, chest-compression-only CPR was not associated with 1-month meaningful outcomes (aOR, 1.05; 95% CI, 0.67 to 1.64). CONCLUSIONS: In children with OHCA, dispatcher-assisted bystander CPR increased bystander CPR provision rate and was associated with improved 1-month favorable neurological outcomes, compared to no bystander CPR. Conventional bystander CPR was associated with greater likelihood of neurologically intact survival, compared to chest-compression-only CPR, irrespective of cardiac arrest etiology. PMID- 24785781 TI - Dispatcher-directed CPR: an all-ages strategy to improve cardiac arrest survival. PMID- 24785782 TI - Highly stable, solution-processable phenothiazine derivative as hole collection material for organic solar cells. AB - In this study, we have synthesized a solution-processable phenothiazine, 4 phenothiazin-10-yl-anisole (APS), as hole collection material in organic solar cells (OSCs). The APS reveals unique optical and electronic properties which can efficiently modify the work function (PhiW) of indium tin oxide (ITO) electrode to enhance the electron blocking capability. Moreover, the results indicate that the APS is highly air-stable which can significantly enhance the long-term stability of OCSs. The inverted device based on APS reached a power conversion efficiency (PCE) of 3.56% and exhibited much better stability under ambient conditions relative to that of the corresponding PEDOT:PSS based device. PMID- 24785784 TI - Box-Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: stability assessment. AB - Bicalutamide (BCM) is an anti-androgen drug used to treat prostate cancer. In this study, nanostructured lipid carriers (NLCs) were chosen as a carrier for delivery of BCM using Box-Behnken (BB) design for optimizing various quality attributes such as particle size and entrapment efficiency which is very critical for efficient drug delivery and high therapeutic efficacy. Stability of formulated NLCs was assessed with respect to storage stability, pH stability, hemolysis, protein stability, serum protein stability and accelerated stability. Hot high-pressure homogenizer was utilized for formulation of BCM-loaded NLCs. In BB response surface methodology, total lipid, % liquid lipid and % soya lecithin was selected as independent variable and particle size and %EE as dependent variables. Scanning electron microscopy (SEM) was done for morphological study of NLCs. Differential scanning calorimeter and X-ray diffraction study were used to study crystalline and amorphous behavior. Analysis of design space showed that process was robust with the particle size less than 200 nm and EE up to 78%. Results of stability studies showed stability of carrier in various storage conditions and in different pH condition. From all the above study, it can be concluded that NLCs may be suitable carrier for the delivery of BCM with respect to stability and quality attributes. PMID- 24785783 TI - Mossbauer, EPR, and modeling study of iron trafficking and regulation in Deltaccc1 and CCC1-up Saccharomyces cerevisiae. AB - Strains lacking and overexpressing the vacuolar iron (Fe) importer CCC1 were characterized using Mossbauer and EPR spectroscopies. Vacuolar Fe import is impeded in Deltaccc1 cells and enhanced in CCC1-up cells, causing vacuolar Fe in these strains to decline and accumulate, respectively, relative to WT cells. Cytosolic Fe levels should behave oppositely. The Fe content of Deltaccc1 cells grown under low-Fe conditions was similar to that in WT cells. Most Fe was mitochondrial with some nonheme high spin (NHHS) Fe(II) present. Deltaccc1 cells grown with increasing Fe concentration in the medium contained less total Fe, less vacuolar HS Fe(III), and more NHHS Fe(II) than in comparable WT cells. As the Fe concentration in the growth medium increased, the concentration of HS Fe(III) in Deltaccc1 cells increased to just 60% of WT levels, while NHHS Fe(II) increased to twice WT levels, suggesting that the NHHS Fe(II) was cytosolic. Deltaccc1 cells suffered more oxidative damage than WT cells, suggesting that the accumulated NHHS Fe(II) promoted Fenton chemistry. The Fe concentration in CCC1 up cells was higher than in WT cells; the extra Fe was present as NHHS Fe(II) and Fe(III) and as Fe(III) oxyhydroxide nanoparticles. These cells contained less mitochondrial Fe and exhibited less ROS damage than Deltaccc1 cells. CCC1-up cells were adenine-deficient on minimal medium; supplementing with adenine caused a decline of NHHS Fe(II) suggesting that some of the NHHS Fe(II) that accumulated in these cells was associated with adenine deficiency rather than the overexpression of CCC1. A mathematical model was developed that simulated changes in Fe distributions. Simulations suggested that only a modest proportion of the observed NHHS Fe(II) in both strains was the cytosolic form of Fe that is sensed by the Fe import regulatory system. The remainder is probably generated by the reduction of the vacuolar NHHS Fe(III) species. PMID- 24785785 TI - Evaluation of ranirestat for the treatment of diabetic neuropathy. AB - INTRODUCTION: Pharmacologic maintenance of normoglycemia in diabetes cannot prevent the eventual complications mainly due to protein glycation-induced cell death, dysregulated antioxidant defense and signal transduction in affected tissues. The rate-limiting enzyme of this process, aldose reductase, is therefore a pharmacologic target. To date, nine inhibitors of this enzyme have been developed. Ranirestat has completed two Phase III clinical trials. The objective of this evaluation is to summarize and provide expert opinion on the status of ranirestat with an emphasis on its pharmacokinetics in the context of its potential effects to prevent/treat diabetic complications. AREAS COVERED: A qualitative systematic literature search of PubMed through November 2013 using MeSH terms - aldose reductase inhibitors, diabetic neuropathy, AS-3201, ranirestat, diabetic complications and pharmacokinetics/pharmacodynamics - identified relevant publications limited to human and rodent (mouse and rat) and English-language studies. EXPERT OPINION: Ranirestat is a well-tolerated front line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy. It is the furthest advanced in clinical trials with some depth of supporting preclinical data. Trials in subjects with newly diagnosed neuropathy along with the identification of objective biomarkers/measurements of efficacy will be critical in identifying the real value and effect of ranirestat. PMID- 24785786 TI - Application of rumen microbes to enhance food waste hydrolysis in acidogenic leach-bed reactors. AB - Effect of rumen microorganisms on hydrolysis of food waste in leach bed reactor (LBR) was investigated. LBRs were inoculated (20%, w/w) with cow manure and anaerobically digested sludge at different ratios, 0:1 (LBR-A), 1:3 (LBR-B), 1:1 (LBR-C), 3:1 (LBR-D) and 1:0 (LBR-E). High volatile solids (VS) conversion efficiency of 68% was achieved in LBR-E. Compared with LBR-A, chemical oxygen demand, total soluble products and total Kjeldahl nitrogen leaching of LBR-E were increased by 16%, 14.3% and 27%, respectively. Recovery of the highest amounts of ethanol and butyrate in LBR-E indicated that the metabolic pathway mediated by rumen microorganisms was favorable for subsequent methanogenesis. Phylogenetic analysis confirmed that the enhanced hydrolysis in LBR-E was mainly due to strong degraders, e.g. Enterobacter, Bifidobacterium thermacidophilum and Caloramator sourced from cow manure. Results demonstrate that rumen microorganisms rapidly degrade the VS and produce useful VFAs with high methane yields in subsequent methanogenesis. PMID- 24785787 TI - Accelerated glycerol fermentation in Escherichia coli using methanogenic formate consumption. AB - Escherichia coli can ferment glycerol anaerobically only under very defined restrictive conditions. Hence, it was the aim of this study to overcome this limitation via a co-cultivation approach. Anaerobic glycerol fermentation by a pure E. coli culture was compared to a co-culture that also contained the formate oxidizing methanogen Methanobacterium formicicum. Co-cultivation of the two strains led to a more than 11-fold increased glycerol consumption. Furthermore, it supported a constantly neutral pH and a shift from ethanol to succinate production. Moreover, M. formicicum was analyzed for its ability to grow on different standard media and a surprising versatility could be demonstrated. PMID- 24785788 TI - Development of a hybrid fermentation-enzymatic bioprocess for the production of ethyl lactate from dairy waste. AB - This work explores the potential for the development of a hybrid fermentation enzymatic process for the production of ethyl lactate from dairy waste. Cheese whey was used in Kluyveromyces marxianus and Lactobacillus bulgaricus batch cultures to produce ethanol and lactic acid respectively. Subsequently, the fermentation products were transferred into an organic phase through liquid liquid extraction and ethyl lactate was formed in an esterification reaction catalyzed by lipases. The production of ethanol and lactic acid achieved under different conditions was 23gL(-1) and 29gL(-1), respectively. Furthermore, the efficiency of various organic solvents for the esterification reaction was evaluated and toluene was chosen for application in the process. The effect of water content was determined aiming to maximize the product yield and 40mgml(-1) was the optimal enzyme concentration. The bioprocess achieved maximum conversion of 33% constituting a valuable alternative to the application of energy demanding chemically derived methods. PMID- 24785789 TI - Changes in fatty acid composition of Chlorella vulgaris by hypochlorous acid. AB - Hypochlorous acid treatment of a microalga, Chlorella vulgaris, was investigated to improve the quality of microalgal lipid and to obtain high biodiesel conversion yield. Because chlorophyll deactivates the catalyst for biodiesel conversion, its removal in the lipid-extraction step enhances biodiesel productivity. When microalgae contacted the hypochlorous acid, chlorophyll was removed, and resultant changes in fatty acid composition of microalgal lipid were observed. The lipid-extraction yield after activated clay treatment was 32.7 mg lipid/g cell; after NaClO treatment at 0.8% available chlorine concentration, it was 95.2 mg lipid/g cell; and after NaCl electrolysis treatment at the 1 g/L cell concentration, it was 102.4 mg lipid/g cell. While the contents of all of the unsaturated fatty acids except oleic acid, in the microalgal lipid, decreased as the result of NaClO treatment, the contents of all of the unsaturated fatty acids including oleic acid decreased as the result of NaCl electrolysis treatment. PMID- 24785790 TI - Anaerobic treatment of tequila vinasses under seasonal operating conditions: start-up, normal operation and restart-up after a long stop and starvation period. AB - This study examines the performance of an anaerobic fixed-film bioreactor under seasonal operating conditions prevailing in medium and small size Tequila factories: start-up, normal operation and particularly, during the restart-up after a long stop and starvation period. The proposed start-up procedure attained a stable biofilm in a rather short period (28 days) despite unbalanced COD/N/P ratio and the use of non-acclimated inoculum. The bioreactor was restarted-up after being shut down for 6 months during which the inoculum starved. Even when biofilm detachment and bioreactor clogging were detected at the very beginning of restart-up, results show that the bioreactor performed better as higher COD removal and methane yield were attained. CE-SSCP and Q-PCR analyses, conducted on the biofilm prokaryotic communities for each operating condition, confirmed that the high COD removal results after the bioreactor clogging and the severe starvation period were mainly due to the stable archaeal and resilient bacterial populations. PMID- 24785791 TI - Improving methane production and phosphorus release in anaerobic digestion of particulate saline sludge from a brackish aquaculture recirculation system. AB - In this study, batch tests were conducted to examine the effects of trehalose and glycine betaine as well as potassium on the specific methanogenic activity (SMA), acid and alkaline phosphatase activity of anaerobic biomass and phosphorus release in anaerobic digestion of saline sludge from a brackish recirculation aquaculture system. The results of ANOVA and Tukey's HSD (honestly significant difference) tests showed that glycine betaine and trehalose enhanced SMA of anaerobic biomass and reactive phosphorus release from the particulate waste. Moreover, SMA tests revealed that methanogenic sludge, which was long-term acclimatized to a salinity level of 17 g/L was severely affected by the increase in salinity to values exceeding 35 g/L. Addition of compatible solutes, such as glycine betaine and trehalose, could be used to enhance the specific methane production rate and phosphorus release in anaerobic digestion from particulate organic waste produced in marine or brackish aquaculture recirculation systems. PMID- 24785792 TI - Searching for the new normal: exploring the role of language and metaphors in becoming a cancer survivor. AB - PURPOSE: This qualitative exploratory study was grounded in local patient and service user experiences and was designed to investigate how the language and metaphors of cancer influence personal and social adjustment after completion of a course of treatment. METHODS: The study employed a focus group design, in which eighteen people, recruited through regional networks and support groups, participated. Meetings elicited participants' stories and focused discussion on key words and common phrases in the cancer lexicon. Data from transcribed focus group recordings were analysed thematically and organised into descriptive categories concerned with the interpretations of common terms and how these influenced the management of identity and emotions. RESULTS: The thematic categories emphasised the importance of language in the way participants managed their illness and sought to control their feelings and their interactions with others. Interpretation of findings revealed a strong central idea linking participants' accounts, which was that language, metaphor and euphemism are central to adjustment and the forging of an altered identity as a survivor of cancer diagnosis and treatment. CONCLUSIONS: The findings are consistent with what is already known about the language and metaphors of cancer, with language being an important mechanism for managing uncertainty. From participants' accounts it also appears that there may be subtle but important differences in professional and lay understandings of cancer language and metaphor. This suggests a need for oncology nurses to elaborate their broad understanding of communication skills and move toward a more detailed understanding of the language used during interactions with patients. PMID- 24785793 TI - You never know when your last day will come and your trip will be over- existential expressions from a melanoma diagnosis. AB - AIM: The aim of this study was to further explore expressions of existential experiences by patients diagnosed with malignant melanoma (MM). METHOD: Semi structured interviews were performed consecutively after diagnosis among 30 patients with MM. The methodological approach was inspired by Gadamer's hermeneutic philosophy. RESULTS: The analysis of expressions of existential experiences after having been diagnosed with malignant melanoma revealed that it is an existential process that people go through, beginning with feelings of suddenly becoming groundless at the time of the diagnosis, including being empty and in a vacuum, being in chaos and uncertainty and being confronted with one's own death. Next theme searching for solid ground included striving to understand what lies ahead, striving to find a balance in life - fighting, hoping, going on living and striving to prioritize family. The last theme creating islands of solid ground when living with cancer included understanding what is meaningful in life, living in the moment - seizing the day and keeping watch on the body. CONCLUSION: On being diagnosed with malignant melanoma, people go through a process where many questions emerge, including an existential turmoil, which health professionals should be aware of to provide these patients with sufficient support. PMID- 24785794 TI - ISCoS and World Health Organisation: a new frontier for cooperation and development. PMID- 24785796 TI - New roles for family therapists in the courts: an overview with a focus on custody dispute resolution. AB - Many legal issues involve conflicts that are at least as much psychological and relational as they are legal in nature. Juvenile and family courts have always embraced a helping philosophy under the parens patriae legal doctrine. These courts address problems where family relationships are central, for example, custody and coparenting disputes, divorce, child abuse and neglect, foster care, intimate partner violence, and juvenile delinquency. Family therapists are playing a growing role in all of these matters. In this article, we use child custody disputes as a more in-depth example for exploring new, potential roles for family therapists, particularly as mediators and parenting coordinators. To show the breadth of the role for family therapists, we also more briefly consider the topics of child abuse and neglect, foster care, juvenile delinquency, and drug and alcohol issues. PMID- 24785799 TI - 2. Clinical models applicable to disasters. AB - Processes used for research of disasters are similar to those used for the assessment, determination of needs, planning, selection of interventions and their implementation, and evaluation of patient outcomes in the clinical setting. A patient suffering a stroke and another patient with an acute inflammation of the gallbladder serve as examples. Patients travel along the same longitudinal progression as do disasters and clinical assessments are conducted using the body's organ systems. PMID- 24785800 TI - 3. Framework for the longitudinal phases of disasters. AB - The longitudinal framework facilitates the analysis of disasters by providing a series of phases based on properties rather than on absolute times. This framework allows the comparison of similar phases of a disaster regardless of the hazard involved and the society impacted. The phases, which may overlap include the: (1) pre-event state; (2) event; (3) damage; (4) changes in societal functions; (5) relief interventions; and (6) recovery interventions. Development is not a phase of a disaster and is addressed separately. For research and evaluation purposes, assessments, plans, and interventions must be described in relation to only one of the longitudinal phases of a disaster. PMID- 24785801 TI - 4. The transectional structure of society: the basic societal functions. AB - For the purposes of research and/or evaluation, a society is organised into 13 basic societal functions (BSFs) within an overall Coordination and Control system. This organisation facilitates transectional descriptions of society or a component of a society for assessment at any given time across the longitudinal phases of a disaster. An assessment results in a picture or description of function(s) limited to the point in time of the assessment. Together with simultaneous assessments of the functional status of all, some, or one of the other BSFs, such assessments deliver a transectional picture of the situation of a society. Since no function operates in isolation from the other functions, information of the concomitant status of several BSFs is crucial to gain a better understanding of functional losses and of the effects and side effects of an intervention. The 13 BSFs include: (1) Public Health (dominantly preventive); (2) Medical Care (dominantly curative); (3) Water and Sanitation; (4) Shelter and Clothing; (5) Food and Nutrition; (6) Energy Supplies; (7) Public Works and Engineering; (8) Social Structure; (9) Logistics And Transportation; (10) Security; (11) Communications; (12); Economy; and (13) Education. These BSFs relate with each other through the Coordination and Control function. Many functions of the BSFs and their respective subfunctions and elements overlap (they share some common subfunctions and elements). However, for the purposes of research/evaluation, it is necessary to assign subfunctions and elements to only one of the BSFs. Just as in the practice of clinical medicine, the sum of assessments provides the transectional description of the status of each of these BSFs at a given time. From this information, compared to the pre-event description of the society, interventions are selected that are likely to meet the defined objectives and their overarching goal(s), and respective plans are developed and implemented. The effects of each intervention are evaluated in reference to these goals and objectives and to their eventual effects on other BSFs or subfunctions of a BSF. PMID- 24785802 TI - 5. Interrelationships, functional packages and priorities. AB - The basic societal functions (BSFs) do not exist in isolation. Many of the functions are dependent and/or interdependent on one another and/or on the components that comprise the BSFs. Dependency occurs when goods and/or services are required for a function, subfunction, or a component of a function. Interdependency occurs when the same component (commodity, service, or process) is required by more than one BSF or component(s) of a BSF. Insufficiencies of functions that are interdependent are more likely to render a society dysfunctional than are those that are not interdependent. Combinations of functions from different BSF form functional packages. In times of disaster and limited resources, subfunctions, elements, and subelements, etc. must be prioritised in terms of their relative importance for the continuation of the most essential services. Priorities must be established so that when resources are scarce, nonessential services may be temporarily discontinued and similarly, priorities must be determined for re-establishment of services as needed resources become available. PMID- 24785803 TI - 6. Coordination and control. AB - Any complex operation requires a system for management. In most societies, disaster management is the responsibility of the government. Coordination and control is a system that provides the oversight for all of the disaster management functions. The roles and responsibilities of a coordination and control centre include: (1) planning; (2) maintenance of inventories; (3) activation of the disaster response plan; (4) application of indicators of function; (5) surveillance; (6) information management; (7) coordination of activities of the BSFs; (8) decision-making; (9) priority setting; (10) defining overarching goal and objectives for interventions; (11) applying indicators of effectiveness; (12) applying indicators of benefit and impact; (13) exercising authority; (14) managing resources; (15) initiating actions; (16) preventing influx of unneeded resources; (17) defining progress; (18) providing information; (19) liasing with responding organisations; and (20) providing quality assurance. Coordination and control is impossible without communications. To accomplish coordination and control, three factors must be present: (1) mandate; (2) power and authority; and (3) available resources. Coordination and control is responsible for the evaluation of the effectiveness and benefits/impacts of all interventions. Coordination and control centres (CCCs) are organised hierarchically from the on-scene CCCs (incident command) to local provincial to national CCCs. Currently, no comprehensive regional and international CCCs have been universally endorsed. Systems such as the incident command system, the unified command system, and the hospital incident command system are described as are the humanitarian reform movement and the importance of coordination and control in disaster planning and preparedness. PMID- 24785804 TI - 7. Administrative structures. AB - The basic systems of any society rarely can operate independently. Instead, they are dependent and often interdependent upon other entities. Such entities control the resources within their respective systems. Thus, coordination and control agencies require contracts or memoranda of understanding with these entities in order to assure access to the resources required during a crisis. These administrative structures include: (1) governmental institutions and agencies, including the military; (2) intergovernmental organisations; (3) nongovernmental organisations; (4) commercial private sector organisations; and (5) academic institutions. These dependencies create potential barriers to the provision of coordination and control including: (1) the complexity of the administrative structures with which coordination and control must interact; (2) the location of resources; (3) finding responsible person(s); (4) the competence and compatibility; (5) methods of access; (6) payment; (7) contracts and memoranda of understanding; (8) inventories of accessible resources; (9) competition for the mandate, power, and resources; and (10) jealousy. The need for potential interactions between administrative structures requires that agreements for the sharing of resources during crises be reached as part of planning and preparedness. Gaining an understanding of these relationships is an important area for research. PMID- 24785805 TI - 8. The operational processes. AB - There are two principal directions that disaster studies pursue: (1) interventional; and (2) noninterventional. Interventional studies are used to evaluate specific responses as to their effectiveness in meeting their respective objectives, their contribution to the overarching goal, the efficiency with which they are able to achieve their objectives, other effects created, and their respective costs. On the other hand, noninterventional studies examine the epidemiology of disasters and for the most part are observational. Both interventional and noninterventional studies require data/information obtained from assessments. This section of these Guidelines examines the operational framework used to study interventions/responses and includes the following processes: (1) assessments, (2) identification of needs; (3) strategic planning; (4) selection of intervention(s); (5) operational planning; (6) execution of interventions; and (7) monitoring and evaluation of effects and changes in levels of functions resulting from the intervention(s) being studied. PMID- 24785806 TI - 9. Assessments: structure, concepts, and methods. AB - Assessments are an essential element of proper disaster management. Assessments help to define the damage and changes in functions at the time of the assessment. Assessments are transectional across the longitudinal phases of the disaster. Any intervention should be preceded by an assessment(s). The assessment process is deconstructed into a series of 10 steps: (1) need to know; (2) define the goal(s) and objectives(s) of an assessment; (3) select the appropriate indicators; (4) define the methods to be used for the assessment; (5) develop and test a plan for data collection; (6) train and brief data collectors; (7) gather (collect) the data; (8) synthesise the data and information collected; (9) output information for decision-making; and (10) compare findings with overarching goal and objectives. Steps 7-9 constitute a production process. Understanding this process is essential for identification of points of success and failure in achieving the desired assessment. Assessments require careful selection of indicators. The selected indicators are used throughout the process. Currently, no standardised set of indicators has been validated. Criteria for the composition of assessment teams are provided and common sources of error are discussed. Prior to, during, and following disasters, assessments are directed by the appropriate coordination and control entity. PMID- 24785807 TI - 10. Identification of needs. AB - Needs are not directly assessed, but rather, the identification of needs is the result of a complex process that requires integration and synthesis of many factors, including the results from numerous assessments. The assessments synthesised into needs include: (1) the pre-event levels of function; (2) the amount and types of damage sustained initially and existing at the current time; current (3) levels of function and the levels of function detected by the last assessment; (4) the presence of a surge; (5) the demands of the population affected; (6) the culture in which the event occurred; (7) the climate in the affected area; (8) the geography and access to the affected area; and (9) politics. The process consumes resources (costs). The transformation process (synthesis) of these many factors requires that those charged with synthesis have knowledge, field experience, insight, and experience using the process. PMID- 24785808 TI - 11. Strategic planning. AB - There are several types of planning processes and plans, including strategic, operational, tactical, and contingency. For this document, operational planning includes tactical planning. This chapter examines the strategic planning process and includes an introduction into disaster response plans. "A strategic plan is an outline of steps designed with the goals of the entire organisation as a whole in mind, rather than with the goals of specific divisions or departments". Strategic planning includes all measures taken to provide a broad picture of what must be achieved and in which order, including how to organise a system capable of achieving the overall goals. Strategic planning often is done pre-event, based on previous experience and expertise. The strategic planning for disasters converts needs into a strategic plan of action. Strategic plans detail the goals that must be achieved. The process of converting needs into plans has been deconstructed into its components and includes consideration of: (1) disaster response plans; (2) interventions underway or planned; (3) available resources; (4) current status vs. pre-event status; (5) history and experience of the planners; and (6) access to the affected population. These factors are tempered by the local: (a) geography; (b) climate; (c) culture; (d) safety; and (e) practicality. The planning process consumes resources (costs). All plans must be adapted to the actual conditions--things never happen exactly as planned. PMID- 24785809 TI - 12. Selection of responses and interventions. AB - Generally, there are a host of potential interventions available during a disaster. The selection of the most appropriate interventions/responses is dependent upon the goals elaborated in the strategic plan. All interventions selected must be aimed at meeting the defined needs of the affected population. In this Chapter, the process used for the selection of interventions is deconstructed into its component steps. The steps in selecting interventions include (but are not limited to): (1) identify objectives that have a likelihood of contributing to achievement of the strategic goal outlined in the strategic plan; (2) identify potential interventions likely to achieve these objectives; (3) assure compatibility with other interventions; (4) develop new options (if necessary); (5) identify available and other required resources; (6) match objectives with resources; (7) weight interventions for their ability to meet the objectives; (8) coordinate with ongoing/planned activities; (9) select most appropriate options; (10) codify the operational objectives for the intervention(s) selected; (11) provide timelines and reporting structure; (12) establish evaluation methods; and (13) complete contracts and/or memoranda of understanding. Understanding this process is essential for the identification of critical points of success and failure. Correction of critical points of failure should facilitate the process next time interventions must be selected. PMID- 24785810 TI - 13. Operational planning for a specific intervention. AB - Every intervention must follow an operational plan. Operational plans delineate actions required to meet an objective that is part of the strategic plan (overarching goal). Operational plans dictate the critical pathways for the interventions that will be followed during and following the implementation of the intervention. Operational plans include: (1) an introduction and brief situation report; (2) an overview of the task(s), objectives, and the overarching goal to be addressed; (3) the methods that will be employed; (4) planning factors; (5) the resources that will be required including personnel, equipment, and supplies; (6) timelines, benchmarks, and milestones including their respective indicators, startup time, end point, and estimates of the time required for completion; (7) the administrative structure to be employed; (8) an operating budget; (9) the strategy for acquiring the funding required; (10) roles and responsibilities of the personnel including position descriptions and the competencies required of the personnel (skill sets); (11) mechanisms for monitoring the progress including the indicators that will be employed, (12) safety, including health of the personnel, required immunisations, accommodations, and reporting structure; (13) self-sufficiency; and (14) reporting and accounting. There are many generic items in an operational plan that can be used in successive plans. Without a detailed operational plan, interventions are doomed to probable failure and can profoundly negatively impact other projects operational in the area. PMID- 24785811 TI - 14. Implementation, execution, and completion of projects. AB - Once an intervention has been selected for implementation, it becomes a project. Implementation of a project is a complex process and requires completion of a host of tasks. The implementation process has been deconstructed into its components so that it can be analysed and evaluated. A prerequisite for implementation is an operational plan. The tasks that require completion include: (1) reassessing current status and verifying the needs; (2) activating the operational plan; (3) setting-up and operating an administrative structure; (4) identifying, acquiring, and organising resources (including human resources); (5) assigning roles and responsibilities; (6) educating and training personnel (including mission-specific); (7) briefing staff; (8) preparing/readying resources for transport; (9) assuring project self-sufficiency; (10) arranging for personal necessities; (11) ensuring the safety of personnel and the security of equipment and supplies; (12) insuring personnel; (13) coordinating with other projects/actors; (14) coordinating with other BSF systems (role of the coordination and control centre); (15) communicating with community leaders; (16) initiating the use of standardised progress reports; (17) deploying personnel, equipment, and supplies; (18) initiating the intervention(s); (19) executing the intervention(s); (20) reporting start of interventions; (21) completing the project; and (22) completing and submitting a formal report. This deconstruction is essential in order to study the process and identify critical points of success and failure. It also is recognised that many interventions consist of many components (subfunctions), each of which may be considered a production process. PMID- 24785812 TI - 15. Evaluation. AB - Evaluations are an essential part of disaster management and preparedness. Evaluations provide the evidence necessary to build the science. The deconstructed processes from assessments through implementation and conclusion of the interventions have been outlined and can now be evaluated so as to define critical points of success and/or failure within the respective processes. Interventions should be examined for their effectiveness in achieving the objectives for which they were selected and for their contributions to attaining the goal outlined in the strategic plan. Effects of an intervention other than those for which the intervention was selected may have an additive benefit or they may have a negative impact on the affected society. Resource consumption (costs) is an important element of evaluations. Health disaster management evaluations aim at quality improvement for future interventions (preparedness). However, evaluation based on participating and/or concomitant observation also may open for improvement of ongoing interventions. PMID- 24785813 TI - 16. Information. AB - Effective disaster management requires systems for data acquisition and information management that enable responders to rapidly collect, process, interpret, distribute, and access the data and information required for disaster management. Effective information sharing depends on the types of users, the type of damage, alterations of the functional status of the affected society, and how the information is structured. Those in need of information should be provided with the information necessary for their tasks and not be overloaded with unnecessary information that could serve as a distraction. Such information systems must be designed and exercised. To disseminate and share data with the relevant users, all disaster responses must include effective and reliable information systems. This information includes that acquired from repeated assessments in terms of available and needed human and material resources, which resources no longer are needed, and the status of the relief and recovery workers. It is through this information system that vital decisions are made that are congruent with the overall picture as perceived by the most relevant coordination and control centre. It is essential that information systems be designed and tested regularly as part of preparedness. Such systems must have the capacity to acquire, classify, and present information in an organised and useful manner. PMID- 24785814 TI - 17. Introduction to preparedness. AB - Preparedness is the aggregate of all measures and policies adopted before an event occurs that promotes mitigation of the damage caused by an event and minimises the dysfunction that could result from the damage. More specifically, it includes all planning and resources that are devoted to preventing deaths and morbidity and, thus, to the alleviation of human (individual and collective) suffering during and after the event has taken place. It consists of measures that individuals, a family, a community, locale, country, region, institution, and states maintain, at a particular time, to combat the potential deleterious effects of hazards. Preparedness includes the absorbing, buffering, and response capacities; it also has been called the resilience of the society at risk, to a hazard(s). As the level of preparedness increases, the vulnerability of the community at risk decreases. Preparedness is difficult to measure. The impact of preparedness measures cannot be realised until the next event occurs or it has been shown to be of benefit during disaster drills and exercises. Hence, investments in preparedness have been relatively meager worldwide. PMID- 24785815 TI - 18. Preparedness process. AB - This Chapter provides a layout for the development, implementation, and evaluation of interventions designed to enhance/augment the levels of preparedness of the public health and medical care aspects of disasters. The preparedness framework is provided for the analysis of the preparedness process and consists of 17 steps: (1) hazard and risk identification; (2) vulnerabilities, historical perspectives and predictions; (3) selection of hazard(s) to address; (4) selection of indicators; (5) standards and benchmarks for preparedness; (6) current status; (7) identification of preparedness needs; (8) strategic planning; (9) selection of intervention; (10) operational planning; (11) implementation; (12) conclusion/finalise: end points; (13) documentation of effects; (14) transition, maintenance, sustainability; (15) evaluation; and (16) feedback. At any time in this algorithm the process may be terminated by or after consultation with the coordination and control centre. Each of these processes is described in detail. In addition, attention is directed to the coordination and control centre during planning, preparedness, and evaluations of preparedness. PMID- 24785816 TI - 19. Putting it together. AB - The goal of these Guidelines is to benefit populations at risk through improving the quality of responses to the health aspects of disasters. This will be achieved through the development of methods that open disasters to structured, reproducible research, and thereby contributing to the science of health disaster management. Five major barriers were identified that impaired our ability to attain these goals: (1) lack of a endorsed terminology (2) lack of a standard descriptive system for society and its functions; (3) lack of structured description of disaster phases based on their properties; (4) widely distributed grey literature; and (5) no common structure to reports. In response to these findings, many commonly held processes have been deconstructed into a total of four frameworks, the use of which should help in meeting the goal. The use of the frameworks should provide further insight into the epidemiology of disasters in addition to the insight of the value of interventions provided for relief, recovery, and/or preparedness, once a disaster occurs or a hazard has been identified. The way forward should include the development of consensus on definitions used in the health aspects of disasters and for a repository of interventions applied in specific settings that include their respective effectiveness in attaining the goal for which they were selected. In addition, existing literature and future reports should be forced into the frameworks to facilitate our understanding and to develop the science of health disaster, evolution of standards, best practices, and competencies, but also to test and further improve these Guidelines. The frameworks should be augmented by standardised data collection instruments including templates for the gathering, organisation, and synthesis of data. PMID- 24785819 TI - A cone beam CT investigation of ponticulus posticus and lateralis in children and adolescents. AB - OBJECTIVES: To determine the prevalence and pathogenesis of ponticulus posticus (PP) and ponticulus lateralis (PL) in children and adolescents. METHODS: Cone beam CT scans of 576 patients were examined for PP and PL. The patients were divided into three age groups: 10 years and younger, 11-13 years and 14 years and older. Ponticulus formation was categorized as absent, partial or complete. Gender, race and location (right, left or bilateral) were recorded. Data were analysed with the chi(2) test, with significance at p < 0.050. Institutional review board approval was granted. RESULTS: Overall prevalence of PP was 26.2%, with complete lesions in 10.4%. The frequency of PP was greater in patients aged 14 years and older (p <= 0.038). The occurrence of complete PP was greater in patients aged 11 years and older (p = 0.028). Lesions were more common in males (p = 0.014) and in blacks compared with other non-white races (p = 0.035). Bilateral PP was more common than right-sided lesions (p = 0.008) and more frequent in the oldest cohort (p = 0.006). Overall prevalence of PL was 6.1% (3.0% complete), with no differences between age groups, genders, races or by location. CONCLUSIONS: PP is not uncommon even in the first decade and increases in frequency, completeness of calcification and numbers in mid-adolescence. It appears to be more common in males and in blacks. PP may be a congenital osseous anomaly of the atlas that mineralizes at various times. PL is less frequent with no demographic predilections. PMID- 24785821 TI - Finite-time boundedness filtering for discrete-time Markovian jump system subject to partly unknown transition probabilities. AB - This paper investigates the problem of finite-time boundedness filtering for discrete-time Markovian jump system subject partly unknown transition probabilities. By using the multiple Lyapunov function approach, a novel sufficient condition for finite-time bounded of Hinfinity filtering is derived and the system trajectory stays within a prescribed bound during a specified time interval. Finally, an example is provided to illustrate the usefulness and effectiveness of the proposed method. PMID- 24785820 TI - Descriptive study of the bifid mandibular canals and retromolar foramina: cone beam CT vs panoramic radiography. AB - OBJECTIVES: To examine the presence and morphologic characteristics of bifid mandibular canals (BMCs) and retromolar foramens (RFs) using cone beam CT (CBCT) and to determine their visualization on panoramic radiographs (PANs). METHODS: A sample of 225 CBCT examinations was analysed for the presence of BMCs, as well as length, height, diameter and angle. The diameter of the RF was also determined. Subsequently, corresponding PANs were analysed to determine whether the BMCs and RFs were visible or not. RESULTS: The BMCs were observed on CBCT in 83 out of the 225 patients (36.8%). With respect to gender, statistically significant differences were found in the number of BMCs. There were also significant differences in anatomical characteristics of the types of BMCs. Only 37.8% of the BMCs and 32.5% of the RFs identified on CBCT were also visible on PANs. The diameter had a significant effect on the capability of PANs to visualize BMCs and RFs (B = 0.791, p = 0.035; B = 1.900, p = 0.017, respectively). CONCLUSIONS: PANs are unable to sufficiently identify BMCs and RFs. The diameter of these anatomical landmarks represents a relevant factor for visualization on PANs. Pre operative images using only PANs may lead to underestimation of the presence of BMCs and to surgical complications and anaesthetic failures, which could have been avoided. For true determination of BMCs, a CBCT device should be considered better than a PAN. PMID- 24785822 TI - Finite-time master-slave synchronization and parameter identification for uncertain Lurie systems. AB - This paper investigates the finite-time master-slave synchronization and parameter identification problem for uncertain Lurie systems based on the finite time stability theory and the adaptive control method. The finite-time master slave synchronization means that the state of a slave system follows with that of a master system in finite time, which is more reasonable than the asymptotical synchronization in applications. The uncertainties include the unknown parameters and noise disturbances. An adaptive controller and update laws which ensures the synchronization and parameter identification to be realized in finite time are constructed. Finally, two numerical examples are given to show the effectiveness of the proposed method. PMID- 24785823 TI - Interior search algorithm (ISA): a novel approach for global optimization. AB - This paper presents the interior search algorithm (ISA) as a novel method for solving optimization tasks. The proposed ISA is inspired by interior design and decoration. The algorithm is different from other metaheuristic algorithms and provides new insight for global optimization. The proposed method is verified using some benchmark mathematical and engineering problems commonly used in the area of optimization. ISA results are further compared with well-known optimization algorithms. The results show that the ISA is efficiently capable of solving optimization problems. The proposed algorithm can outperform the other well-known algorithms. Further, the proposed algorithm is very simple and it only has one parameter to tune. PMID- 24785824 TI - Perceptions of the need for improvements in healthcare after implementation of the Chronic Care Model. AB - Older people with depression constitute a vulnerable group, and evidence from different parts of the world has demonstrated the need for healthcare improvements at the community level. In this study, we described team members' perceptions of improvements in the care of older people with depression living in the community after the implementation of the Chronic Care Model, with a focus on delivery-system design, self-management support, and teamwork. This follow-up study was based on focus-group interviews with healthcare team members. The data were analyzed by qualitative content analysis. Four themes emerged: (i) ensuring a pathway to the top level of the organization; (ii) the need for leadership from senior managers; (iii) the need to formalize collaboration; and (iv) increasing self-management. Senior managers should cooperate with specialist care givers and administrators in the community. They must also redesign the delivery system to facilitate teamwork and the self-management ability of older people with depression. PMID- 24785825 TI - Stimulation of osteogenic activity in human osteoblast cells by edible Uraria crinita. AB - Uraria crinita is an edible herb used as a natural food for childhood skeletal dysplasia. Ethyl acetate, n-butanol, and aqueous fractions of a 95% ethanol crude extract of U. crinita were obtained and the active ingredients isolated and purified using a bioguided method. In this manner, we isolated and identified a new active flavone glycoside, apigenin 6-C-beta-d-apiofuranosyl(1->2)-alpha-d xylopyranoside (3) and 10 known components with stimulatory activity on human osteoblast cells. The new compound 3 at 100 MUM significantly increased alkaline phosphatase activity (114.10 +/- 4.41%), mineralization (150.10 +/- 0.80%), as well as osteopontin (1.39 +/- 0.01-fold), bone morphogenetic protein-2 (BMP-2, 1.30 +/- 0.04-fold), and runt-related transcription factor 2 (Runx2, 1.43 +/- 0.10-fold) mRNA expression through the activation of the BMP-2/Runx2 pathway. Two other components, dalbergioidin (1) and byzantionoside B (9), displayed similar effects. These results show that U. crinita and its active compounds may have the potential to stimulate bone formation and regeneration. PMID- 24785826 TI - Adaptive immune response inhibits ectopic mature bone formation induced by BMSCs/BCP/plasma composite in immune-competent mice. AB - A combination of autologous bone marrow stromal cells (BMSCs) and biomaterials is a strategy largely developed in bone tissue engineering, and subcutaneous implantation in rodents or large animals is often a first step to evaluate the potential of new biomaterials. This study aimed at investigating the influence of the immune status of the recipient animal on BMSCs-induced bone formation. BMSCs prepared from C57BL/6 mice, composed of a mixture of mesenchymal stromal and monocytic cells, were combined with a biomaterial that consisted of biphasic calcium phosphate (BCP) particles and plasma clot. This composite was implanted subcutaneously either in syngenic C57BL/6 immune-competent mice or in T lymphocyte-deficient Nude (Nude) mice. Using histology, immunohistochemistry, and histomorphometry, we show here that this BMSC/BCP/plasma clot composite implanted in Nude mice induces the formation of mature lamellar bone associated to hematopoietic areas and numerous vessels. Comparatively, implantation in C57BL/6 results in the formation of woven bone without hematopoietic tissue, a lower number of new vessels, and numerous multinucleated giant cells (MNGCs). In situ hybridization, which enabled to follow the fate of the BMSCs, revealed that BMSCs implanted in Nude mice survived longer than BMSCs implanted in C57BL/6 mice. Quantitative expression analysis of 280 genes in the implants indicated that the differences between C57BL/6 and Nude implants corresponded almost exclusively to genes related to the immune response. Gene expression profile in C57BL/6 implants was consistent with a mild chronic inflammation reaction characterized by Th1, Th2, and cytotoxic T-lymphocyte activation. In the implants retrieved from T deficient Nude mice, Mmp14, Il6st, and Tgfbr3 genes were over-expressed, suggesting their putative role in bone regeneration and hematopoiesis. In conclusion, we show here that the T-mediated inflammatory microenvironment is detrimental to BMSCs-induced bone formation and shortens the survival of implanted cells. Conversely, the lack of T-lymphocyte reaction in T-deficient animals is beneficial to BMSCs-induced mature bone formation. This should be taken into account when evaluating cell/biomaterial composites in these models. PMID- 24785827 TI - Towards light-mediated sensing of bacterial comfort. AB - Bacterial comfort is central to biotechnological applications. Here, we report the characterization of different sensoring systems, the first step within a broader synthetic biology-inspired light-mediated strategy to determine Escherichia coli perception of environmental factors critical to bacterial performance. We did so by directly 'asking' bacterial cultures with light-encoded questions corresponding to the excitation wavelength of fluorescent proteins placed under the control of environment-sensitive promoters. We built four genetic constructions with fluorescent proteins responding to glucose, temperature, oxygen and nitrogen; and a fifth construction allowing UV-induced expression of heterologous genes. Our engineered strains proved able to give feedback in response to key environmental factors and to express heterologous proteins upon light induction. This light-based dialoguing strategy reported here is the first effort towards developing a human-bacteria interphase with both fundamental and applied implications. SIGNIFICANCE AND IMPACT OF THE STUDY: The results we present here are at the core of a larger synthetic biology research effort aiming at establishing a dialogue with bacteria. The framework is to convert the human voice into electric pulses, these into light pulses exciting bacterial fluorescent proteins, and convert light-emission back into electric pulses, which will be finally transformed into synthetic voice messages. We report here the first results of the project, in the form of light-based determination of key parameters for bacterial comfort. The ultimate goal of this strategy is to combine different engineered populations to have a combined feedback from the pool. PMID- 24785828 TI - Patterns of DNA methylation in animals: an ecotoxicological perspective. AB - DNA methylation refers to the addition of a methyl group to nucleotides within DNA. As with other epigenetic endpoints, patterns of DNA methylation are susceptible to alterations due to exposure to environmental stressors, including contaminants. These alterations can persist in the absence of the initial stressor as cells divide, and can even be inherited between generations if they occur in the germ line. Although our knowledge concerning patterns of DNA methylation in animals is increasing, there remains a gap in the literature when it comes to species outside of those typically used for biomedical research. Here, I review the literature relating to DNA methylation in an array of taxa (mammals, fish, birds, amphibians, reptiles, and invertebrates) and discuss these data from an ecotoxicological perspective. The pattern and extent of DNA methylation is well conserved across species of vertebrates; methylation appears mainly on cytosine residues within a CpG context, and much of the genome is methylated, with the notable exception of cytosines within CpG islands in the promoters of genes. Highly methylated genes in vertebrates tend to be transcriptionally repressed. However, large differences occur between classes of vertebrates in terms of the timing and nature of reprogramming and genomic imprinting: epigenetic processes that establish patterns of DNA methylation in the early embryo and which are sensitive to environmental stress. In invertebrates, patterns of DNA methylation are extremely variable and differ significantly from the condition observed in vertebrates. Some invertebrate genomes exhibit no DNA methylation while others are methylated to a level that is comparable to vertebrates. Additionally, DNA methylation may have different functions in invertebrates, e.g., alternative splicing. This variability in basic patterns of DNA methylation among species during sensitive periods of development suggests that responses to epigenetically active environmental contaminants may be similarly variable. For example, the timing of exposure to a contaminant may be a critical factor when considered in the light of variable reprogramming schedules among species. With this in mind, I review data relating to the effects of contaminants on DNA methylation in animals, focusing on non-model organisms and on exposures in natural environments, when possible. An ecotoxicological perspective on patterns of DNA methylation in animals may improve our understanding of the range and diversity of epigenetic phenomena in the natural world. PMID- 24785829 TI - Quantification of XRCC and DNA-PK proteins in cancer cell lines and human tumors by LC-MS/MS. AB - BACKGROUND: The x-ray repair cross-complementing (XRCC) proteins and a catalytic subunit of nuclear DNA-dependent serine/threonine protein kinase (DNA-PK) play important roles in cancer biology. Understanding the protein expression levels allows us to reconstruct in vivo functionality and to qualify protein biomarkers. METHODS & RESULTS: XRCC and DNA-PK proteins in human cancer cells and tumor tissues have been identified and quantified by selected peptides using NanoLC and high-resolution mass spectrometry. The stable isotope-labeled full-length protein XRCC4 ([(13)C6, (15)N4]-arginine and [(13)C6, (15)N2]-lysine) uses as the internal standard. CONCLUSION: The assay range is 0.140-450 fmol (coefficient of variation: 25%) for XRCC4 in bovine serum albumen. The quantitative protein expression levels for XRCC and DNA-PK in HeLa, Ramos and HEK-293 cells and tumor tissues (lung and lymphoma) are reported. PMID- 24785831 TI - Does long intestinal tube splinting aggravate intestinal adhesions? AB - OBJECTIVE: Long intestinal tube splinting (LITS) is useful for clinically reducing the recurrence of adhesive small bowel obstruction (ASBO). However, a controversy exists whether LITS aggravates intestinal adhesions. This study evaluated the postoperative effects of LITS relative to simple enterolysis on intestinal adhesions in an experimental porcine model. METHODS: A porcine model (n = 24) of dense intestinal adhesion was established by abrading the ileal wall with sterile P240 sandpaper. Enterolysis was performed on postoperative day 14. Animals were randomly divided into a group that underwent enterolysis only (control; n = 12) and those who underwent LITS as well as enterolysis (LITS; n = 12). The long intestinal tube was removed on post-LITS day 14, after abdominal radiography. All animals were euthanized on postenterolysis day 28 for assessment of intestinal adhesions using a semiquantitative macroscopic grading scale, hematoxylin-eosin histology, and hydroxyproline assay. RESULTS: Prior to enterolysis, the experimentally induced intestinal adhesions of the two groups were similar in extent and severity. On postenterolysis day 28 the LITS and control groups were comparable with regard to adhesion loop length (p = .440), macroscopic adhesion severity (p = .820), serosal fibrosis grading (p = .450), and hydroxyproline content of the adhesion ileal segment (p = .630). CONCLUSION: Placement of the long intestinal tube did not aggravate intestinal adhesions over that of simple enterolysis in this intestinal adhesion porcine model. PMID- 24785830 TI - Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect. AB - Congenital bony syngnathia, a rare but severe human birth defect, is characterized by bony fusion of the mandible to the maxilla. However, the genetic mechanisms underlying this birth defect are poorly understood, largely due to limitation of available animal models. Here we present evidence that transgenic expression of Bmp4 in neural crest cells causes a series of craniofacial malformations in mice, including a bony fusion between the maxilla and hypoplastic mandible, resembling the bony syngnathia syndrome in humans. In addition, the anterior portion of the palatal shelves emerged from the mandibular arch instead of the maxilla in the mutants. Gene expression assays showed an altered expression of several facial patterning genes, including Hand2, Dlx2, Msx1, Barx1, Foxc2 and Fgf8, in the maxillary and mandibular processes of the mutants, indicating mis-patterned cranial neural crest (CNC) derived cells in the facial region. However, despite of formation of cleft palate and ectopic cartilage, forced expression of a constitutively active form of BMP receptor-Ia (caBmprIa) in CNC lineage did not produce the syngnathia phenotype, suggesting a non-cell autonomous effect of the augmented BMP4 signaling. Our studies demonstrate that aberrant BMP4-mediated signaling in CNC cells leads to mis patterned facial skeleton and congenital bony syngnathia, and suggest an implication of mutations in BMP signaling pathway in human bony syngnathia. PMID- 24785832 TI - Repair of DNA double-strand breaks is not modulated by low-dose gamma radiation in C57BL/6J mice. AB - In this study, we sought to determine whether low-dose ionizing radiation, previously shown to induce a systemic adaptive response in C57BL/6J mice, is capable of enhancing the rate of DNA double-strand break repair. Repair capacity was determined by measuring gamma-H2AX levels in splenic and thymic lymphocytes, using flow cytometry, at different times after a challenge irradiation (2 Gy, (60)Co). Irradiation with low doses (20 and 100 mGy) was conducted in vivo, whereas the challenge dose was applied to primary cultures of splenocytes and thymocytes in vitro 24 h later. Obtained kinetics curves of formation and loss of gamma-H2AX indicated that cells from low-dose irradiated mice did not express more efficient DNA double-strand break repair compared to controls. Immunoblot analysis of gamma-H2AX and Phospho-Ser-1981 ATM confirmed that DNA damage signaling was not modulated by preliminary low-dose radiation. Mouse embryonic fibroblasts of C57BL genetic background failed to show clonogenic survival radioadaptive response or enhanced repair of DNA double-strand breaks as evaluated by immunofluorescence microscopy of gamma-H2AX foci. Our results indicate that radiation adaptive responses at systemic levels, such as increases in the tumor latency times in aging mice, may not be mediated by modulated DNA repair, and that the genetic background may affect expression of a radioadaptive response. PMID- 24785833 TI - Infrared Absorption Spectra of Jahn-Teller Systems: Application to the Transition Metal Trifluorides MnF3 and NiF3. AB - The theory for the calculation of vibronic absorption spectra within a Jahn Teller (JT) active electronic state from first principles has been developed. The infrared absorption spectra of the 5E' ground state, the low-lying 5E" excited state of MnF3, and the 4E' state of NiF3 have been computed and analyzed. Dipole moment derivatives have been determined by a linear-plus-quadratic expansion of nuclear dipole moment functions in the JT-active coordinates. Electronic transition dipole moments have been taken into account in the Condon approximation in the diabatic representation. The initial and final vibronic states have been expanded in a product of diabatic electronic states and vibrational basis functions. The effect of spin-orbit coupling on the vibronic infrared spectra of these molecules in their JT-active electronic states has been investigated, by employing the Breit-Pauli spin-orbit operator. The effect of temperature on the vibronic infrared spectra has also been explored. These results represent the first theoretical study of vibronic infrared spectra of JT active states in transition metal compounds. PMID- 24785835 TI - "Abortion--it is my own body": women's narratives about influences on their abortion decisions in Ghana. AB - Globally, abortion has emerged as a critical determinant of maternal morbidity and mortality. The Ghana government amended the country's abortion law in 1985 to promote safe abortion. This article discusses the findings of a qualitative study that explored the decision-making experiences of 28 female abortion seekers aged between 15 and 30 years in Ghana. Key findings from the study are that individuals claimed autonomy in their abortion decisions; underlying the abortion decisions were pragmatic concerns such as economic difficulties, child spacing, and fear of parental reaction. In conclusion, we examine the health implications of Ghanaian women's abortion decisions. PMID- 24785834 TI - CD4 T-cell activation and reduced regulatory T-cell populations are associated with early development of cataracts among HIV-infected adults in Uganda. AB - BACKGROUND: Cataracts contribute 12% of visual loss among HIV-infected adults in Uganda. Immuno-pathogenesis of cataracts may differ among HIV-infected individuals; thus the need for innovative therapeutic interventions among HIV infected adults. METHODS: In a laboratory based case-control study, nested in a clinical/surgical community outreach camp, 50 adults with cataracts eligible for surgery were selected consecutively. HIV testing was done for individuals with unknown HIV sero-status. Peripheral Blood Mononuclear Cells (PBMC) were collected from all HIV-positive-adults-with-cataracts (cases) and HIV-negative-adults-with cataracts (comparative group) and age-matched HIV-negative and HIV-positive adults-without-cataracts (comparative group). Treg were measured as CD3+CD4+FoxP3+CD25+(Bright) and immune activation as CD3+CD4+CD38+HALDR+ using a Facs Canto II flowcytometer. Mann Whitney test was used to compare expression among the four groups. RESULTS: Of 50 adults operated for cataracts, 24 (48%) were female, 25 (50%) were HIV-positive. HIV-positive-individuals had cataracts earlier [median; Inter-quartile Range (IQR); 49 (44-53) years] than HIV-negative [70 (IQR 59-75) years]; p=0.0005. Treg were lower among individuals with cataracts irrespective of HIV status; p=0.001; but comparable among younger HIV positive and elderly HIV-negative with cataracts; p=0.301. Immune activation levels were comparable among HIV-positive and HIV-negative individuals with cataracts. However, HIV-positive-individuals with cataracts expressed higher levels of immune activation than HIV-positive-individuals without cataracts; p=0.012 and HIV-negative-individuals-with-cataracts expressed higher levels of immune activation that HIV-negative-without-cataracts; p<0.0001. CONCLUSION: CD4 T-cell activation and reduced regulatory T-cell populations were associated with cataracts among adults aging with HIV. We recommend studies on clinical relevance of immune modulation in the prevention of early development of cataracts among adults aging with HIV in Africa. PMID- 24785836 TI - Light-fuelled transport of large dendrimers and proteins. AB - This work presents a facile water-based supramolecular approach for light-induced surface patterning. The method is based upon azobenzene-functionalized high molecular weight triazine dendrimers up to generation 9, demonstrating that even very large globular supramolecular complexes can be made to move in response to light. We also demonstrate light-fuelled macroscopic movements in native biomolecules, showing that complexes of apoferritin protein and azobenzene can effectively form light-induced surface patterns. Fundamentally, the results establish that thin films comprising both flexible and rigid globular particles of large diameter can be moved with light, whereas the presented material concepts offer new possibilities for the yet marginally explored biological applications of azobenzene surface patterning. PMID- 24785837 TI - Probability curves focusing on symptom severity during an oral food challenge. PMID- 24785838 TI - Human albumin causes anaphylaxis during bee venom immunotherapy. PMID- 24785839 TI - Cost matters. PMID- 24785840 TI - Promising surgical innovations involving buccal mucosa for vaginal creation and reconstruction. PMID- 24785841 TI - Carboxymethylcellulose adhesion barrier placement at primary cesarean delivery and outcomes at repeat cesarean delivery. AB - OBJECTIVE: To assess associations of a commercially available carboxymethylcellulose adhesion barrier placed during primary cesarean delivery with clinical outcomes of repeat cesarean deliveries. METHODS: We performed a retrospective cohort study of women undergoing primary cesarean delivery on or after January 1, 2008, and first repeat cesarean delivery in one of four hospitals in the same system by June 30, 2011. Women were included if both deliveries were live singletons at 34-42 weeks of gestation delivered through transverse abdominal incisions and the first hysterotomy was low transverse. Exclusion criteria included intervening delivery; puerperal infection, bowel injury, or bladder injury at primary cesarean delivery; uterine incision or laparotomy (except primary cesarean delivery) before repeat cesarean delivery; and use of another adhesion barrier at primary cesarean delivery. As a surrogate for adhesion grading, the primary outcome was time from skin incision to neonate delivery at repeat cesarean delivery. We also assessed total operative time and rates of selected surgical complications. RESULTS: There were 517 women who met criteria; 248 received the adhesion barrier during primary cesarean delivery and 269 did not. There were no demographic differences between groups except delivery hospital. In the adhesion barrier and no adhesion barrier groups, respectively, mean+/-standard deviation times to delivery at repeat cesarean delivery were 6.1+/-3.0 compared with 5.8+/-2.5 minutes (P=.25), and total operative times were 31.2+/-10.6 compared with 31.8+/-11.6 minutes (P=.56). Surgical complications were not different between groups. CONCLUSION: Placing a commercially available carboxymethylcellulose adhesion barrier at primary cesarean delivery is not associated with decreased time to delivery, total operative time, or complications during repeat cesarean deliveries. LEVEL OF EVIDENCE: II. PMID- 24785842 TI - Cost-effectiveness of testing hepatitis B-positive pregnant women for hepatitis B e antigen or viral load. AB - OBJECTIVE: To estimate the cost-effectiveness of testing pregnant women with hepatitis B (hepatitis B surface antigen [HBsAg]-positive) for hepatitis B e antigen (HBeAg) or hepatitis B virus (HBV) DNA, and administering maternal antiviral prophylaxis if indicated, to decrease breakthrough perinatal HBV transmission from the U.S. health care perspective. METHODS: A Markov decision model was constructed for a 2010 birth cohort of 4 million neonates to estimate the cost-effectiveness of two strategies: testing HBsAg-positive pregnant women for 1) HBeAg or 2) HBV load. Maternal antiviral prophylaxis is given from 28 weeks of gestation through 4 weeks postpartum when HBeAg is positive or HBV load is high (10 copies/mL or greater). These strategies were compared with the current recommendation. All neonates born to HBsAg-positive women received recommended active-passive immunoprophylaxis. Effects were measured in quality adjusted life-years (QALYs) and all costs were in 2010 U.S. dollars. RESULTS: The HBeAg testing strategy saved $3.3 million and 3,080 QALYs and prevented 486 chronic HBV infections compared with the current recommendation. The HBV load testing strategy cost $3 million more than current recommendation, saved 2,080 QALYs, and prevented 324 chronic infections with an incremental cost effectiveness ratio of $1,583 per QALY saved compared with the current recommendations. The results remained robust over a wide range of assumptions. CONCLUSION: Testing HBsAg-positive pregnant women for HBeAg or HBV load followed by maternal antiviral prophylaxis if HBeAg-positive or high viral load to reduce perinatal hepatitis B transmission in the United States is cost-effective. PMID- 24785843 TI - Cost-benefit analysis of indirect antiglobulin screening in Rh(D)-negative women at 28 weeks of gestation. AB - OBJECTIVE: To estimate the potential economic benefit of reduced indirect antiglobulin screening for Rh(D)-negative pregnant women. METHODS: A chart review of all Rh(D)-negative mothers delivering at the University of Washington from 2002 to 2012 was conducted to determine the rate of gestational seroconversion to anti-D antibodies before 28 weeks of gestation. A decision tree was constructed to estimate the economic effects of eliminating the indirect antiglobulin screen at 28 weeks of gestation and instead immunizing all Rh(D)-negative, anti-D antibody-negative women with anti-D immune globulin at that time. A theoretical cohort of 100,000 women was modeled. Probabilities and costs were derived from published literature, chart review, and expert opinion. Univariate sensitivity analyses followed by a Monte Carlo analysis examined assumptions and uncertainties in our model across entire distributions. RESULTS: The seroconversion rate of development of anti-D antibodies before 28 weeks of gestation in the cohort analyzed was 0.099% (2/2,029 women). From a societal perspective, the expected cost savings from implementing the reduced indirect antiglobulin screening strategy, per 100,000 women, ranged from $6 to $7.7 million. The overall cost savings for implementing this strategy in the United States for 1 year ranged from $34.7 to $35.6 million. This strategy remained cost beneficial when varying our parameters (eg, anti-D immune globulin, antibody test cost) to their logical extremes. The Monte Carlo analysis verified the cost savings of our strategy. CONCLUSION: The updated seroconversion rate and our model suggest that eliminating the 28-week antibody screen would be cost beneficial from a societal perspective while posing minimal potential harm to the recipients. PMID- 24785844 TI - Autologous buccal mucosa graft augmentation for foreshortened vagina. AB - BACKGROUND: Vaginal foreshortening after pelvic surgery or radiotherapy may lead to dyspareunia and decreased quality of life. Unfortunately, little literature exists regarding treatment options for this debilitating problem. Autologous buccal mucosal grafting has been previously reported for creation of a total neovagina and the repair of postvaginoplasty vaginal stenosis. TECHNIQUE: Autologous buccal mucosa offers several advantages as a replacement material for vaginal reconstruction. Vaginal and oral buccal mucosa are both hairless, moist, nonkeratinized stratified squamous epithelia. Buccal mucosa has a dense layer of elastic fibers, imparting both elasticity and strength, and acquires a robust neovascularity with excellent graft take. The graft material is readily available and donor site scars are hidden in the mouth. EXPERIENCE: A 60-year-old woman had vaginal foreshortening to 4.5 cm 15 years after radical hysterectomy and brachytherapy for endometrial cancer. She was unable to have intercourse despite attempted vaginal dilation. Her foreshortened vagina was successfully augmented with autologous buccal mucosa grafting at the apex, increasing her vaginal length to 8 cm and permitting pain-free intercourse. CONCLUSION: Even in the face of an altered surgical field after radical hysterectomy and radiation, autologous buccal mucosa is an option for vaginal reconstruction for vaginal foreshortening. PMID- 24785845 TI - Long-term outcomes of vaginoplasty with autologous buccal micromucosa. AB - OBJECTIVE: To evaluate the technical feasibility and anatomical and functional outcomes of one-stage vaginoplasty with autologous buccal micromucosa. METHODS: We retrospectively reviewed our experiences with 38 patients with vaginal agenesis treated with primary surgery from June 2006 to April 2012. All patients underwent transvestibular vaginoplasty with autologous buccal micromucosa. We describe the details of this technique and evaluate the long-term anatomical, functional, and sexual outcomes. RESULTS: A total of 38 patients (33 with Mayer Rokitansky-Kuster-Hauser syndrome and five with complete androgen insensitivity syndrome) were included in the present study. The mean operative time was 86.4 minutes (range 75-120 minutes). The mean blood loss was 68.5 mL (range 40-80 mL). At a mean follow-up of 33.5 months (range 15-76 months), the mean depth of the neovagina was 8.5+/-0.66 cm (range 7-10 cm), the mean circumference was 12.3+/ 1.24 cm (range 10-15 cm), and the mean volume was 100+/-8 mL (range 85-120 mL). By histologic examination, we found the neovaginal mucosa was stratified nonkeratinized squamous mucosa and had secretory function. The mean female sexual function index score of the 32 sexually active patients was 28.8+/-2.1. No spouse reported discomfort during intercourse. The mean postoperative dependence on the vaginal stent was 15+/-2.1 months (range 9-20 months). CONCLUSION: Transvestibular vaginoplasty with autologous buccal micromucosa is an effective and feasible approach for patients with Mayer-Rokitansky-Kuster-Hauser syndrome and complete androgen insensitivity syndrome. The procedure has satisfactory long term anatomical and functional results. LEVEL OF EVIDENCE: III. PMID- 24785846 TI - Effect of lymphovascular space invasion on survival of stage I epithelial ovarian cancer. AB - OBJECTIVE: To evaluate the effect of lymphovascular space invasion on survival of patients with early-stage epithelial ovarian cancer. METHODS: A multicenter retrospective study was conducted for patients with stage IA-C epithelial ovarian cancer who underwent primary comprehensive surgery including lymphadenectomy. Histopathology slides for ovarian tumors were examined by gynecologic pathologists for the presence or absence of lymphovascular space invasion. Survival analysis was performed examining tumoral factors. RESULTS: A total of 434 patients were included in the analysis. Lymphovascular space invasion was detected in 76 (17.5%) patients associated with histology (P=.042) and stage (P=.044). Lymphovascular space invasion was significantly associated with decreased survival outcomes (disease-free survival, 5-year rate 78.4% compared with 90.7%, P=.024 and overall survival, 84.9% compared with 93.2%, P=.031) in univariate analysis. In multivariate analysis, lymphovascular space invasion did not remain a significant variable for disease-free survival (hazard ratio [HR] 1.98, 95% confidence interval [CI] 0.97-3.97, P=.059) or overall survival (HR 2.41, 95% CI 0.99-5.85, P=.052). Lymphovascular space invasion was associated with increased risk of hematogenous and lymphatic metastasis (HR 4.79, 95% CI 1.75-13.2, P=.002) but not peritoneal metastasis (P=.33) in multivariate analysis. Among lymphovascular space invasion-expressing tumors, patients who received fewer than six cycles of postoperative chemotherapy had significantly poorer disease-free survival than those who received six or more cycles (HR 4.59, 95% CI 1.20-17.5, P=.015). CONCLUSION: Lymphovascular space invasion is an important histologic feature to identify a subgroup of patients with increased risk of recurrence in stage I epithelial ovarian cancer. LEVEL OF EVIDENCE: III. PMID- 24785847 TI - Risk of adverse pregnancy outcomes in women with mild chronic hypertension before 20 weeks of gestation. AB - OBJECTIVE: To evaluate whether blood pressure (BP) less than 140/90 mm Hg is associated with lower risk of adverse pregnancy outcomes in women with mild chronic hypertension. METHODS: This was a secondary analysis of women with chronic hypertension diagnosed before 20 weeks of gestation (either BP 140/90 mm Hg or greater on two occasions at least four hours apart or previously diagnosed and on antihypertensive therapy) enrolled in the Maternal-Fetal Medicine Units Network's High-risk Aspirin preeclampsia prevention trial. Outcomes including a primary composite (perinatal death, severe preeclampsia, placental abruption, and indicated preterm birth less than 35 weeks of gestation) and small for gestational age (SGA) were compared by study preenrollment BP analyzed as a categorical (less than 140/90, 140-150/90-99, or 151-159/100-109 mm Hg) and as a continuous variable. RESULTS: Among 759 women with singleton pregnancy and preenrollment BP less than 160/110 mm Hg, the incidence of the primary composite outcome (10.7%, 19.0%, 30%) and SGA (8.8%, 12.3%, 23.7%) increased with increasing BP category (P values<=.001). The adjusted odds ratio (95% confidence interval) for the primary composite was 2.0 (1.3-3.2) for 140-150/90-99 mm Hg and 3.2 (1.6-6.3) for 151-159/100-109 mm Hg compared with BP less than 140/90 mm Hg. The results for SGA were 1.6 (0.9-2.8) and 3.8 (1.8-7.9), respectively. Models including continuous systolic and diastolic BP revealed increasing adverse outcomes per 5-mm Hg rise in diastolic but not systolic BP: primary composite (19% per 5 mm Hg) and SGA (22% per 5 mm Hg). CONCLUSION: The risks of adverse pregnancy outcomes in women with chronic hypertension are lower with preenrollment BP less than 140/90 mm Hg as compared with higher BP categories and increase with increasing BP. LEVEL OF EVIDENCE: II. PMID- 24785848 TI - The National Partnership for Maternal Safety. AB - Recognition of the need to reduce maternal mortality and morbidity in the United States has led to the creation of the National Partnership for Maternal Safety. This collaborative, broad-based initiative will begin with three priority bundles for the most common preventable causes of maternal death and severe morbidity: obstetric hemorrhage, severe hypertension in pregnancy, and peripartum venous thromboembolism. In addition, three unit-improvement bundles for obstetric services were identified: a structured approach for the recognition of early warning signs and symptoms, structured internal case reviews to identify systems improvement opportunities, and support tools for patients, families, and staff that experience an adverse outcome. This article details the formation of the National Partnership for Maternal Safety and introduces the initial priorities. PMID- 24785849 TI - Facility-based identification of women with severe maternal morbidity: it is time to start. AB - Although maternal deaths have been the traditional indicator of maternal health, these events are the "tip of the iceberg" in that there are many women who have significant complications of pregnancy, labor, and delivery. Identifying women who experience severe maternal morbidity and reviewing their care can provide critical information to inform quality improvement in obstetrics. In this commentary, we review methods to identify women who experienced severe complications of pregnancy. We propose a simple validated approach based on transfusion of four or more units of blood products, admission to an intensive care unit, or both as a starting point for identification and review of severe maternal morbidity in health care settings for the purpose of understanding successes and failures in systems of care. PMID- 24785850 TI - Use of a novel visual aid to improve estimation of obstetric blood loss. AB - OBJECTIVE: Visual estimation of blood loss is often inaccurate and imprecise. Obstetric bleeding requires expedient identification and intervention to prevent maternal morbidity and mortality. We aimed to create a visual aid to improve accuracy of estimated obstetric blood loss. METHODS: We designed a pocket card containing images of blood on common obstetric materials to serve as a visual aid. We created six stations with known volumes of artificial blood using materials from standard delivery kits. Obstetric providers recorded visually estimated blood loss across a variety of volumes and materials before and after receiving our visual aid. We assessed the effects of blood volume, clinical role, and years of experience on accuracy of estimation. RESULTS: One hundred fifty-one participants assessed six stations. We categorized participants by percent error of estimated blood loss before and after receiving our visual aid. We found a significant improvement in accurate assessments for all provider types after intervention across four of the six volumes (P<.001). In a posttest survey, 90% of participants (n=136) reported subjective improvement in estimation ability. Provider type affected accuracy before intervention in two of six stations (P=.01 and P=.03). This difference persisted in one station after intervention (P<.01). Years of experience did not correlate with accuracy of blood volume estimation in five of six stations (P>.05). CONCLUSION: A visual aid depicting known volumes of blood on obstetric materials can improve accuracy of blood volume estimation among obstetric providers of varying types and with varying years of experience. LEVEL OF EVIDENCE: II. PMID- 24785851 TI - Postpartum venous thromboembolism: incidence and risk factors. AB - OBJECTIVE: To calculate incidence of postpartum venous thromboembolism by week after delivery and to examine potential risk factors for venous thromboembolism overall and at different times during the postpartum period. METHODS: A deidentified health care claims information database from employers, health plans, hospitals, and Medicaid programs across the United States was used to identify delivery hospitalizations among women aged 15-44 years during the years 2005-2011. International Classification of Diseases, 9th Revision, Clinical Modification diagnosis and procedure codes were used to identify instances of venous thromboembolism and associated characteristics and conditions among women with recent delivery. Incidence proportions of venous thromboembolism by week postpartum through week 12 were calculated per 10,000 deliveries. Logistic regression was used to calculate odds ratios for selected risk factors among women with postpartum venous thromboembolism and among women with venous thromboembolism during the early or later postpartum periods. RESULTS: The incidence proportion of postpartum venous thromboembolism was highest during the first 3 weeks after delivery, dropping from nine per 10,000 during the first week to one per 10,000 at 4 weeks after delivery and decreasing steadily through the 12th week. Certain obstetric procedures and complications such as cesarean delivery, preeclampsia, hemorrhage, and postpartum infection conferred an increased risk for venous thromboembolism (odds ratios ranging from 1.3 to 6.4), which persisted over the 12-week period compared with women without these risk factors. CONCLUSION: Risk for postpartum venous thromboembolism is highest during the first 3 weeks after delivery. Women with obstetric complications are at highest risk for postpartum venous thromboembolism, and this risk remains elevated throughout the first 12 weeks after delivery. LEVEL OF EVIDENCE: II. PMID- 24785852 TI - Increase in prescription opioid use during pregnancy among Medicaid-enrolled women. AB - OBJECTIVE: To report the prevalence of prescription opioid use and evaluate the trends in a large cohort of Medicaid-enrolled pregnant women. METHODS: A cohort of pregnancies was identified using data from the Medicaid Analytical eXtract for the period of 2000-2007. Dispensing of opioids, as a class and separately for individual agents, was evaluated using claims from filled prescriptions. Variations in patterns of prescription opioid fills were examined by demographic characteristics, by geographic region, and over time. Median number of opioid prescriptions dispensed and cumulative days of availability for prescription opioids during pregnancy were reported. RESULTS: The study population consisted of more than 1.1 million women with completed pregnancies from 46 U.S. states and Washington, DC. One of five women from our cohort (21.6%) filled a prescription for an opioid during pregnancy; this proportion increased from 18.5% in 2000 to 22.8% in 2007. Substantial regional variation was seen with the proportion of women who filled a prescription during pregnancy, ranging between 9.5% and 41.6% across the states. Codeine and hydrocodone were the most commonly prescribed opioids. Among women filling at least one opioid prescription, the median (interquartile range) number of prescriptions filled was 1 (1-2) and the median (interquartile range) cumulative days of opioid availability during pregnancy were 5 (3-13) days. CONCLUSION: We observed high and increasing number of filled prescriptions for opioids during pregnancy among Medicaid-enrolled women. These findings call for further safety evaluations of these drugs and their effects on the developing fetus to inform clinical practice. LEVEL OF EVIDENCE: II. PMID- 24785853 TI - Screening frequency and atypical cells and the prediction of cervical cancer risk. AB - OBJECTIVE: To evaluate the screening efficacy and importance of atypical squamous cells and atypical glandular cells in predicting subsequent cervical cancer risk. METHODS: This national cohort study in Taiwan analyzed associations between Pap test screening frequency and findings in 1995-2000 and subsequent risk of squamous cell carcinoma and adenocarcinoma after 2002. Women aged 30 years or older in 1995 without a cervical cancer history were included. Multivariate adjusted hazard ratios and their 95% confidence intervals (CIs) were assessed using Cox regression analysis. RESULTS: During a total follow-up of 31,693,980 person-years in 2002-2008, 9,471 squamous cell carcinoma and 1,455 adenocarcinoma cases were newly diagnosed, resulting in 2,067 deaths. The risk of developing and dying from squamous cell carcinoma decreased significantly with increasing attendance frequency between 1995 and 2000 (all P values for trend<.001). Women who attended more than three screenings in 1995-2000 had 0.69-fold and 0.35-fold decrease in incidence and mortality of adenocarcinoma, respectively, compared with women who never attended any screenings. Abnormal cytologic findings were significant predictors of the incidence and mortality of cervical cancers. The adjusted hazard ratio (95% CI) of developing squamous cell carcinoma was 29.94 (22.83-39.25) for atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions, and the adjusted hazard ratio (95% CI) of developing adenocarcinoma was 49.43 (36.49-66.97) for atypical glandular cells. CONCLUSION: Significant reductions in cervical adenocarcinoma occurred in women who attend three or more annual screenings in 6 years. High-grade atypical squamous cells and atypical glandular cells are important predictors of subsequent adenocarcinoma and squamous cell carcinoma. LEVEL OF EVIDENCE: II. PMID- 24785854 TI - Continuous compared with cyclic use of oral contraceptive pills in the Dominican Republic: a randomized controlled trial. AB - OBJECTIVE: To estimate whether continuous combined oral contraceptive pill (OCP) use leads to higher continuation and lower pregnancy rates over 12 months than cyclic use in a developing country setting. METHODS: We enrolled healthy women aged 18 to 30 years, in Santo Domingo, Dominican Republic. We randomly assigned women to cyclic or continuous use of OCPs. Participants made quarterly clinic visits for 12 months. During follow-up, we reviewed OCP adherence and continuation, side effects, and bleeding, and we tested for pregnancy. RESULTS: We enrolled 358 women (mean age, 22.7 years) and 335 (93.6%) completed the study. In intent-to-treat analyses, 77.6% of the continuous use group and 71.7% of the cyclic group continued OCPs at 12 months (P=.21). The main reason for OCP discontinuation in both groups was running out of OCPs or forgetting. Across all visits, 26.1% of women in the continuous use group and 22.3% of women in the cyclic group ever reported missing three or more OCPs in the past month (P=.43). In multivariable analyses, regimen was not associated with discontinuation, but both previous birth and perceived ease of use of OCPs decreased risk of discontinuation, whereas desire for reduced menstruation increased risk of discontinuation. Although more women reported amenorrhea or infrequent bleeding in the continuous use group, more women in the cyclic group found their bleeding patterns acceptable. Bleeding was not associated with discontinuation in multivariable analyses. Pregnancy rates at 12 months were similar (16.2% continuous and 17.4% cyclic). CONCLUSIONS: Continuous and cyclic OCP regimens were associated with similar 12-month continuation and pregnancy rates. Few factors predicted OCP discontinuation or pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00570440. LEVEL OF EVIDENCE: I. PMID- 24785855 TI - Symptom outcomes important to women with anal incontinence: a conceptual framework. AB - OBJECTIVE: To develop a framework that describes the most important symptom outcomes for anal incontinence treatment from the patient perspective. METHODS: A conceptual framework was developed by the Pelvic Floor Disorders Network based on four semistructured focus groups and confirmed in two sets of 10 cognitive interviews including women with anal incontinence. We explored: 1) patient preferred terminology for describing anal incontinence symptoms; 2) patient definitions of treatment "success"; 3) importance of symptoms and outcomes in the framework; and 4) conceptual gaps (defined as outcomes not previously identified as important). Sessions were conducted according to grounded theory transcribed, coded, and qualitatively and quantitatively analyzed to identify relevant themes. Content and face validity of the framework were further assessed using cognitive interviews. RESULTS: Thirty-four women participated in focus groups and 20 in cognitive interviews. Overall, 29 (54%) were aged 60 years or older, 42 (78%) were white, and 10 (19%) had a high school degree or less. Two overarching outcome themes were identified: "primary bowel leakage symptoms" and "ancillary bowel symptoms." Subdomains important in primary bowel leakage symptoms included leakage characteristics (symptom frequency, amount of leakage, symptom bother) and conditions when bowel leakage occurs (predictability, awareness, urgency). Subdomains important under ancillary bowel symptoms included emptying disorders (constipation, obstructed defecation, and wiping issues) and discomfort (pain, burning). New outcomes identified included predictability, awareness, wiping issues, and discomfort. CONCLUSION: Women with anal incontinence desire a wide range of symptom outcomes after treatment. These are captured in our conceptual framework, which can aid clinicians and researchers in assessing anal incontinence. LEVEL OF EVIEDENCE: II. PMID- 24785856 TI - Cost-effectiveness analysis of robotically assisted laparoscopy for newly diagnosed uterine cancers. AB - OBJECTIVE: To assess the direct costs of three surgical approaches in uterine cancer and the cost-effectiveness of incorporating robot-assisted surgery. METHODS: A cost system that allocates the actual cost of resources used to treat each patient, as opposed to borrowing cost data from a billing system, was used to determine direct costs for patients who underwent surgery for uterine cancer from 2009 to 2010. These costs included all aspects of surgical care up to 6 months after discharge. Total amortized direct costs included the capital cost of three dual-console robotic platforms with 5 years of service contracts. Nonamortized costs were also calculated (excluded capital costs). Modeling was performed to estimate the mean cost of surgical care for patients presenting with endometrial cancer from 2007 to 2010. RESULTS: Of 436 cases (132 laparoscopic, 262 robotic, 42 laparotomy), total mean amortized direct costs per case were $20,489 (laparoscopy), $23,646 (robot), and $24,642 (laparotomy) (P<.05 [robot compared with laparoscopy]; P=.6 [robot compared with laparotomy]). Total nonamortized costs per case were $20,289, $20,467, and $24,433, respectively (P=.9 [robot compared with laparoscopy]; P=.03 [robot compared with laparotomy]). The planned surgical approach in 2007 was laparoscopy, 68%; robot, 8%; and laparotomy, 24% compared with 26%, 64%, and 9%, respectively, in 2010 (P<.001). The modeled mean amortized direct costs per case were $21,738 in 2007 and $22,678 in 2010 (+$940). Nonamortized costs were $21,298 in 2007 and $20,573 in 2010 ( $725). CONCLUSION: Laparoscopy is least expensive when including capital acquisition costs. Laparoscopy and robotic surgery are comparable if upfront costs are excluded. There is cost neutralization with the robot when it helps decrease laparotomy rates. PMID- 24785857 TI - An economic analysis of robotically assisted hysterectomy. AB - OBJECTIVE: To perform an econometric analysis to examine the influence of procedure volume, variation in hospital accounting methodology, and use of various analytic methodologies on cost of robotically assisted hysterectomy for benign gynecologic disease and endometrial cancer. METHODS: A national sample was used to identify women who underwent laparoscopic or robotically assisted hysterectomy for benign indications or endometrial cancer from 2006 to 2012. Surgeon and hospital volume were classified as the number of procedures performed before the index surgery. Total costs as well as fixed and variable costs were modeled using multivariable quantile regression methodology. RESULTS: A total of 180,230 women, including 169,324 women who underwent minimally invasive hysterectomy for benign indications and 10,906 patients whose hysterectomy was performed for endometrial cancer, were identified. The unadjusted median cost of robotically assisted hysterectomy for benign indications was $8,152 (interquartile range [IQR] $6,011-10,932) compared with $6,535 (IQR $5,127-8,357) for laparoscopic hysterectomy (P<.001). The cost differential decreased with increasing surgeon and hospital volume. The unadjusted median cost of robotically assisted hysterectomy for endometrial cancer was $9,691 (IQR $7,591-12,428) compared with $8,237 (IQR $6,400-10,807) for laparoscopic hysterectomy (P<.001). The cost differential decreased with increasing hospital volume from $2,471 for the first 5 to 15 cases to $924 for more than 50 cases. Based on surgeon volume, robotically assisted hysterectomy for endometrial cancer was $1,761 more expensive than laparoscopy for those who had performed fewer than five cases; the differential declined to $688 for more than 50 procedures compared with laparoscopic hysterectomy. CONCLUSION: The cost of robotic gynecologic surgery decreases with increased procedure volume. However, in all of the scenarios modeled, robotically assisted hysterectomy remained substantially more costly than laparoscopic hysterectomy. PMID- 24785858 TI - Office visceral slide test compared with two perioperative tests for predicting periumbilical adhesions. AB - OBJECTIVE: To determine whether the office visceral slide test is an effective screening test for predicting obliterating periumbilical adhesions compared with two ultrasound tests performed in the operating room. METHODS: Women undergoing benign laparoscopic gynecologic surgery between July 2012 and August 2013 were invited to participate. All participants had an office-based ultrasound test at their preoperative visit (the office visceral slide test), two operating room ultrasound tests (the preoperative examination with visceral slide and the periumbilical ultrasound-guided saline infusion test), and then their scheduled laparoscopic procedure. We measured the ability of the three screening tests to detect obliterating periumbilical adhesions. RESULTS: Eighty-two women completed the study; 12 women were excluded because they had no history of surgery and 70 women with a history of abdominal and pelvic surgery were analyzed in the study group. The study group (n=70) had a median of two (range, 1-6) previous abdominal surgeries. The median number of previous laparotomies was 0 (range, 0-5). The median number of previous laparoscopies was 1 (range, 0-6). At laparoscopy, 6 of 70 women (8.6%) had periumbilical adhesions diagnosed; 18 of 70 women (25.7%) had any adhesions located in the abdomen or pelvis. The office visceral slide test had a sensitivity of 83.3%, specificity of 100%, positive predictive value of 100%, negative predictive value of 98.5% and diagnostic accuracy of 98.6%. CONCLUSION: The office visceral slide test is a simple and reliable test for detecting obliterating periumbilical adhesions in the outpatient setting. LEVEL OF EVIDENCE: II. PMID- 24785859 TI - A practical approach to fetal growth restriction. AB - Fetal growth restriction is one of the most complex problems encountered by obstetricians. Ultrasound-estimated fetal weight less than the 10th percentile for the gestational age is the most widely accepted diagnostic criterion. Management protocols vary from institution to institution. Doppler velocimetry provides valuable information about fetal status. We offer a practical approach to management and timing of delivery based on available data in the literature. PMID- 24785860 TI - Fetal imaging: executive summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Institute of Ultrasound in Medicine, American College of Obstetricians and Gynecologists, American College of Radiology, Society for Pediatric Radiology, and Society of Radiologists in Ultrasound Fetal Imaging workshop. AB - Given that practice variation exists in the frequency and performance of ultrasound and magnetic resonance imaging (MRI) in pregnancy, the Eunice Kennedy Shriver National Institute of Child Health and Human Development hosted a workshop to address indications for ultrasound and MRI in pregnancy, to discuss when and how often these studies should be performed, to consider recommendations for optimizing yield and cost effectiveness, and to identify research opportunities. This article is the executive summary of the workshop. PMID- 24785861 TI - Periviable birth: executive summary of a joint workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists. AB - This is an executive summary of a workshop on the management and counseling issues of women anticipated to deliver at a periviable gestation (broadly defined as 20 0/7 through 25 6/7 weeks of gestation), and the treatment options for the newborn. Upon review of the available literature, the workshop panel noted that the rates of neonatal survival and neurodevelopmental disabilities among the survivors vary greatly across the periviable gestations and are significantly influenced by the obstetric and neonatal management practices (eg, antenatal steroid, tocolytic agents, and antibiotic administration; cesarean birth; and local protocols for perinatal care, neonatal resuscitation, and intensive care support). These are, in turn, influenced by the variations in local and regional definitions of limits of viability. Because of the complexities in making difficult management decisions, obstetric and neonatal teams should confer prior to meeting with the family, when feasible. Family counseling should be coordinated with the goal of creating mutual trust, respect, and understanding and should incorporate evidence-based counseling methods. Since clinical circumstances can change rapidly with increasing gestational age, counseling should include discussion of the benefits and risks of various maternal and neonatal interventions at the time of counseling. There should be a plan for follow-up counseling as clinical circumstances evolve. The panel proposed a research agenda and recommended developing educational curricula on the care and counseling of families facing the birth of a periviable infant. PMID- 24785862 TI - Noninvasive prenatal testing for microdeletion syndromes and expanded trisomies: proceed with caution. AB - The identification of circulating cell-free fetal DNA in maternal plasma has led to the introduction of noninvasive prenatal tests with high sensitivity and high specificity for common aneuploidies (trisomy 13, trisomy 18, trisomy 21). A new expanded noninvasive prenatal testing panel that includes five microdeletion syndromes (22q11 deletion syndrome, cri-du-chat [5p minus], Prader Willi or Angelman syndrome, 1p36 deletion syndrome) and two aneuploidies usually associated with nonviable pregnancies (trisomy 16 and trisomy 22) is now available. This expanded panel will be performed unless an opt-out box is checked. Because these disorders are so rare, the positive predictive value is expected to be low. As with all new screening tests and technologies, the expanded panel should be appropriately studied before it is widely adopted. PMID- 24785863 TI - The fetus, the "potential child," and the ethical obligations of obstetricians. AB - The right of pregnant women to refuse obstetric interventions is an established tenet of obstetric ethics. However, that does not mean that fetal considerations are inconsequential. Although respect for negative autonomy is largely a settled issue, what is less clear is the degree to which a pregnant woman's affirmative autonomy (the right to demand) should be controlling. We discuss the ethical basis for deciding when a pregnant woman's affirmative autonomy should be decisive. We focus on the ethical consequences when a fetus is considered a "potential child" because of a woman's decision to continue a pregnancy. Her intention determines the relevance and nature of the interests of the future child. Although fetal interests may temporally approach those of a born child, they are, in all cases, still circumscribed by the de facto circumstance of the potential child, ie, the child cannot be treated without treating the mother. That treatment would implicate the pregnant woman's right to bodily integrity. This right is so fundamental to our conception of autonomy that its trespass should give serious pause to all who respect basic human dignity. Accordingly, the future interests of a child should not constrain a pregnant woman's right of negative autonomy (the right to refuse any intervention intended for the putative benefit of the fetus or herself). However, the interests of the potential child may factor into considerations of affirmative autonomy and, in parallel, on a physician's right to refuse a particular intervention or plan of care. PMID- 24785864 TI - What is new in chronic pelvic pain?: best articles from the past year. AB - This month, we focus on current research in chronic pelvic pain, a condition defined by location (pelvis, anterior abdominal wall at or below the umbilicus, lumbosacral back, or buttocks), duration (6 or more months), and severity (sufficient to cause functional disability or to seek medical care). Dr. Learman discusses four recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 24785865 TI - Diabetic ketoacidosis in pregnancy. PMID- 24785866 TI - In reply. PMID- 24785867 TI - Amniotic fluid embolism. PMID- 24785868 TI - In reply. PMID- 24785869 TI - Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial. PMID- 24785870 TI - In reply. PMID- 24785876 TI - ACOG Practice Bulletin No. 144: Multifetal gestations: twin, triplet, and higher order multifetal pregnancies. AB - The incidence of multifetal gestations in the United States has increased dramatically over the past several decades. The rate of twin births increased 76% between 1980 and 2009, from 18.9 to 33.3 per 1,000 births (). The rate of triplet and higher-order multifetal gestations increased more than 400% during the 1980s and 1990s, peaking at 193.5 per 100,000 births in 1998, followed by a modest decrease to 153.4 per 100,000 births by 2009 (). The increased incidence in multifetal gestations has been attributed to two main factors: 1) a shift toward an older maternal age at conception, when multifetal gestations are more likely to occur naturally, and 2) an increased use of assisted reproductive technology (ART), which is more likely to result in a multifetal gestation (). PMID- 24785877 TI - ACOG Committee Opinion no 595: Committee on Gynecologic Practice: Preexposure prophylaxis for the prevention of human immunodeficiency virus. AB - Preexposure prophylaxis is defined as the administration of antiretroviral medications to individuals who are not infected with human immunodeficiency virus (HIV) and are at the highest risk of acquiring HIV infection. In combination with other proven HIV-prevention methods, preexposure prophylaxis may be a useful tool for women at the highest risk of HIV acquisition. Obstetrician-gynecologists involved in the care of women using preexposure prophylaxis must reinforce adherence to daily medication. The Centers for Disease Control and Prevention's guidance for preexposure prophylaxis is likely to evolve in the coming years, and obstetrician-gynecologists should remain aware of new developments in this area. Risk reduction for all women at risk of HIV infection should include counseling about testing, safe-sex practices (including condom use), and other behavioral interventions. PMID- 24785878 TI - ACOG Committee Opinion no 596: Committee on Gynecologic Practice: Routine human immunodeficiency virus screening. AB - Early diagnosis and treatment of human immunodeficiency virus (HIV) can improve survival and reduce morbidity. The Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists recommend that females aged 13-64 years be tested at least once in their lifetime and annually thereafter based on factors related to risk. In addition, obstetrician gynecologists should annually review patients' risk factors for HIV and assess the need for retesting. The opportunity for repeat testing should be made available to all women even in the absence of identified risk factors. Women who are infected with HIV should receive or be referred for appropriate clinical and supportive care. Obstetrician-gynecologists who use rapid tests must be prepared to provide counseling to women who receive positive test results the same day that the specimen is collected. Obstetrician-gynecologists should be aware of and comply with legal requirements regarding HIV testing in their jurisdictions and institutions. PMID- 24785879 TI - ACOG Committee Opinion no. 597: Committee on Obstetric Practice: Labor induction or augmentation and autism. AB - Functional oxytocin deficiency and a faulty oxytocin signaling pathway have been observed in conjunction with autism spectrum disorder (ASD). Because exogenous synthetic oxytocin commonly is administered for labor induction and augmentation, some have hypothesized that synthetic oxytocin used for these purposes may alter fetal oxytocin receptors and predispose exposed offspring to ASD. However, current evidence does not identify a causal relationship between labor induction or augmentation in general, or oxytocin labor induction specifically, and autism or ASD. Recognizing the limitations of available study design, conflicting data, and the potential consequences of limiting labor induction and augmentation, the Committee on Obstetric Practice recommends against a change in current guidance regarding counseling and indications for and methods of labor induction and augmentation. PMID- 24785880 TI - ACOG Committee Opinion no. 598: Committee on Adolescent Health Care: The initial reproductive health visit. AB - : The initial visit for screening and the provision of reproductive preventive health care services and guidance should take place between the ages of 13 years and 15 years. The initial reproductive health visit provides an excellent opportunity for the obstetrician-gynecologist to start a patient-physician relationship, build trust, and counsel patients and parents regarding healthy behavior while dispelling myths and fears. The scope of the initial reproductive health visit will depend on the individual's need, medical history, physical and emotional development, and the level of care she is receiving from other health care providers. A general exam, a visual breast exam, and external pelvic examination may be indicated. However, an internal pelvic examination generally is unnecessary during the initial reproductive health visit, but may be appropriate if issues or problems are discovered in the medical history. Health care providers and office staff should be familiar with state and local statutes regarding the rights of minors to consent to health care services and the federal and state laws that affect confidentiality. PMID- 24785881 TI - ACOG Committee Opinion no. 599: Committee on Adoscent Health Care: Adolescent confidentiality and electronic health records. AB - Confidentiality concerns are heightened during adolescence, and these concerns can be a critical barrier to adolescents in receiving appropriate health care. Health care providers caring for minors should be aware of federal and state laws that affect confidentiality. State statutes on the rights of minors to consent to health care services vary by state, and health care providers should be familiar with the regulations that apply to their practice. Parents and adolescents should be informed, both separately and together, that the information each of them shares with the health care provider will be treated as confidential, and of any restrictions to the confidential nature of the relationship. Health care providers and institutions establishing an electronic health record (EHR) system should consider systems with adolescent-specific modules that can be customized to accommodate the confidentiality needs related to minor adolescents and comply with the requirements of state and federal laws. If the EHR system does not allow for procedures to maintain adolescent confidentiality, the health care provider or staff should inform the patient that parents will have access to the records, and the patient should be given the option for referral to a health care provider who is required to provide confidential care, such as one who participates in the Title X family planning program. PMID- 24785882 TI - Long-term evaluation of partial splenic embolization followed by interferon therapy in patients with hepatitis C virus (HCV) cirrhosis and thrombocytopenia. AB - OBJECTIVE: Patients with hepatitis C virus (HCV) cirrhosis and thrombocytopenia are often excluded from receiving interferon therapy because the treatment results in severe platelet depletion. Surgical splenectomy or partial splenic embolization (PSE) is a promising procedure for increasing the platelet count before interferon therapy. We performed PSE and evaluated the long-term clinical course in HCV cirrhotic patients. METHODS: Patients with HCV cirrhosis and thrombocytopenia were included (n=108) in this study. The straight-coiled PSE procedure (Takatsuka method) was performed. The platelet count, hemodynamic changes, rate of a sustained virological response (SVR) and prevalence of hepatocellular carcinoma (HCC) were evaluated. RESULTS: PSE resulted in a significant increase in the platelet count (before PSE: 7.9+/-2.3*10(4)/MUL, two weeks after PSE: 16.7+/-6.6*10(4)/MUL (p<0.001). Therefore, all participants were started on regular-dose interferon therapy. The SVR rate was 24% for serotype 1 and 62% for serotype 2. In the biochemical responders (BR) with SVR, the overall survival rate was 94.6% over five years and 89.3% over 10 years. In the non responders (NR), the overall survival rate was 78.7% over five years and 62.2% over 10 years. The overall survival rate of the patients with SVR+BR was significantly higher than that observed in the patients with NR (p=0.0082). There were no differences in the prevalence of HCC between the patients with SVR+BR and NR. CONCLUSION: PSE enabled the induction of regular-dose interferon therapy in patients with HCV cirrhosis and thrombocytopenia. Although the prevalence of HCC did not differ between the SVR+BR and NR patients, there was a significant survival benefit in the patients with SVR+BR. PMID- 24785884 TI - Effects of age on insulin resistance and secretion in subjects without diabetes. AB - OBJECTIVE: To examine whether aging itself affects insulin resistance (IR) and insulin secretion in the general Japanese population. METHODS: This study included data for 2,324 men and 1,472 women 30-79 years of age without diabetes who participated in a general health checkup program. The effects of age on homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-B) were examined using a linear regression model. Logistic regression models were used to identify clinical characteristics related to age. Multiple regression analyses using a stepwise form were performed to examine factors, including age, possibly affecting HOMA-IR and HOMA-B. RESULTS: The fasting plasma glucose (FPG) levels increased with age in both sexes, whereas the body mass index (BMI) and HOMA-B decreased with increasing age in men and the BMI increased with age in women. The HOMA-IR increased with increasing age in postmenopausal women. The proportion of physically active subjects increased in both sexes, and the proportion of current smokers decreased with age in men and postmenopausal women. The proportion of regular drinkers increased, and the proportion of subjects with a family history of diabetes decreased with age in men. The stepwise multiple regression analysis showed that age was inversely associated with the HOMA-B in both sexes and positively associated with the HOMA-IR in men and postmenopausal women. However, the BMI had the largest impact on the HOMA-IR and HOMA-B in both sexes. CONCLUSION: Age-related increases in the glucose levels in Japanese men and women may be associated with impaired insulin secretion. As a result, a sex difference was observed regarding the impact of aging on IR. PMID- 24785883 TI - Predictors of in-hospital outcomes after primary percutaneous coronary intervention for acute myocardial infarction in patients with a high Killip class. AB - OBJECTIVE: The predictors of in-hospital outcomes after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) complicated with heart failure or cardiogenic shock at presentation remain unclear. METHODS: Using the AMI-Kyoto Multi-Center Risk Study database, the clinical background characteristics, angiographic findings, primary PCI results, and in-hospital prognoses were retrospectively compared between primary PCI-treated AMI patients with a Killip class status of >=2 (Killip 2-4 patients, n=390) and those with a Killip class 1 status (Killip 1 patients, n=1,057). RESULTS: The Killip 2-4 patients were more likely to have a higher age and proportion of women and exhibited a higher prevalence of previous myocardial infarction, diabetes mellitus and chronic kidney disease or anemia on admission, lower systolic blood pressure (SBP) values on admission, a higher rate of multivessels or left main trunk as the culprit artery, a larger number of diseased vessels, a lower Thrombolysis In Myocardial Infarction (TIMI) grade in the infarct-related artery (IRA) before/after primary PCI and a significantly higher in-hospital mortality rate than the Killip 1 patients. According to a multivariate analysis, age was found to be an independent positive predictor of in-hospital mortality, while admission SBP was an independent positive predictor of in-hospital survival in both groups. In contrast, anemia on admission was found to be an independent predictor of in-hospital death, while the TIMI 3 flow in the IRA after PCI was found to be an independent factor for survival in the Killip 2-4 patients, but not the Killip 1 patients. CONCLUSION: Anemia on admission and the final TIMI 3 flow in the IRA are critical determinants of in-hospital death in AMI patients with a Killip class status of >=2 undergoing primary PCI. PMID- 24785885 TI - Non-superiority of Kakkonto, a Japanese herbal medicine, to a representative multiple cold medicine with respect to anti-aggravation effects on the common cold: a randomized controlled trial. AB - OBJECTIVE: Kakkonto, a Japanese herbal medicine, is frequently used to treat the common cold not only with a physician's prescription, but also in self-medication situations. This study aimed to examine whether Kakkonto prevents the aggravation of cold symptoms if taken at an early stage of illness compared with a well selected Western-style multiple cold medicine. METHODS: This study was a multicenter, active drug-controlled, randomized trial. Adults 18 to 65 years of age who felt a touch of cold symptoms and visited 15 outpatient healthcare facilities within 48 hours of symptoms onset were enrolled. The participants were randomly assigned to two groups: one treated with Kakkonto (Kakkonto Extract-A, 6 g/day) (n=209) and one treated with a Western-style multiple cold medicine (Pabron Gold-A, 3.6 g/day) (n=198) for at most four days. The primary outcome of this study was the aggravation of cold, nasal, throat or bronchial symptoms, scored as moderate or severe and lasting for at least two days within five days after entry into the study. RESULTS: Among the 410 enrollees, 340 (168 in the Kakkonto group and 172 in the Pabron group) were included in the analyses. The proportion of participants whose colds were aggravated was 22.6% in the Kakkonto group and 25.0% in the Pabron group (p=0.66). The overall severity of the cold symptoms was not significantly different between the groups. No harmful adverse events occurred in either group. CONCLUSION: Kakkonto did not significantly prevent the progression of cold symptoms, even when prescribed at an early stage of the disease. PMID- 24785886 TI - Analysis of recent cases of intestinal tuberculosis in Japan. AB - In Japan, which ranks first among developed countries in the incidence of tuberculosis, intestinal tuberculosis should be regarded as an important disease. However, few studies of this condition have recently been reported. We analyzed nine patients treated at our hospital during and after 2000. Our results differ from those of previous studies in that many of the patients were healthy, not elderly, had primary intestinal tuberculosis and presented with non gastrointestinal symptoms. All seven patients tested were found to be whole blood interferon gamma release assay (IGRA)-positive. These results suggest that IGRA is useful as an adjunct method for diagnosing intestinal tuberculosis. PMID- 24785887 TI - Refractory vasospasms of the coronary arteries due to multiple factors: an autopsy case. AB - A 41-year-old man was admitted with decompensated heart failure. Mechanical ventilation was maintained with a large dose of propofol. On day 4, significant ST elevation with complete atrioventricular block was noted, which subsequently induced cardiopulmonary arrest. Treatment with percutaneous cardiopulmonary support and therapeutic hypothermia was initiated. Emergent cardiac angiography showed simultaneous multivessel coronary spasms. Although nitroglycerin and nicorandil were ineffective, the intracoronary administration of fasudil, a Rho kinase inhibitor, successfully resolved the vasospasms. However, during rewarming, the coronary vasospasms recurred, and the patient died of cardiogenic shock. In addition to hypertrophy, the autopsied heart demonstrated the accumulation of inflammatory cells in the pericardium and adventitia of the coronary arteries. PMID- 24785888 TI - Infective endocarditis associated with mitral valve prolapse in a patient with Klinefelter syndrome. AB - We herein report a case of infective endocarditis associated with mitral valve prolapse (MVP) in a 34-year-old man with Klinefelter syndrome. The patient was admitted with a fever and headache that had persisted for three weeks. Repeated blood cultures showed growth of Streptococcus oralis. Echocardiography demonstrated severe mitral regurgitation with a large vegetation attached to the prolapsed anterior leaflet. Surgical plasty of the mitral valve was performed because the vegetation measured over 10 mm in diameter and there was a risk of recurrence of embolic complications. This case demonstrates the link between MVP and Klinefelter syndrome and highlights the importance of performing cardiovascular screening and preventing endocarditis. PMID- 24785889 TI - Arrhythmogenic right ventricular cardiomyopathy in a 20-year-old woman with systemic sclerosis. AB - A 20-year-old Japanese woman with systemic sclerosis was evaluated for the progressive aggravation of chest pain, palpitations and dyspnea. Cardiac magnetic resonance imaging revealed diffuse wall thinning, segmental dyskinesis and late gadolinium enhancement of the right ventricular (RV) myocardium. Cardiac catheterization demonstrated no pulmonary hypertension. 24-hour electrocardiography monitoring showed non-sustained ventricular tachycardia (VT). Pulseless VT was induced via programmed ventricular stimulation. An endomyocardial biopsy of the right side of the interventricular septum was performed, the histological specimen of which demonstrated massive myocardial atrophy and fibro-fatty replacement with predominant fibrotic changes. The patient was ultimately diagnosed with arrhythmogenic RV cardiomyopathy. PMID- 24785890 TI - A 22-year-old woman with hypocalcemia and clinical features of albright hereditary osteodystrophy diagnosed with sporadic pseudohypoparathyroidism type Ib using a methylation-specific multiplex ligation-dependent probe amplification assay. AB - A 22-year-old woman presented to us with seizures of a few minutes duration. She had clinical features of Albright hereditary osteodystrophy (AHO), including hypocalcemia, hyperphosphatemia and resistance to parathyroid hormone. Genetic testing revealed a sporadic form of pseudohypoparathyroidism type Ib (PHP-Ib). This is the first Japanese case involving overlap between pseudohypoparathyroidism type Ia (PHP Ia) associated with AHO and PHP Ib. It is important to perform both DNA sequencing and methylation status analyses in cases of suspected PHP in patients with signs of AHO. PMID- 24785891 TI - Two rare cases of familial (mother and daughter) adrenocorticotropic hormone independent Cushing's syndrome due to adrenal adenoma, as well as the asynchronous development of another contralateral adrenal adenoma in the mother. AB - We herein report two cases involving a mother and daughter who presented with clinical features of Cushing's syndrome (CS) at 50 and 29 years of age, respectively, and were both found to have adrenocorticotropic hormone-independent adrenal adenoma. Furthermore, a new adenoma was detected in the contralateral adrenal gland in the mother 10 years after surgical treatment, when she presented with subclinical CS. The pathogenesis of this disorder, including the presence of unknown genetic abnormalities causing hereditary CS, is currently poorly understood. In this report, we describe our experience with and consider the pathophysiological implications of two rare and very interesting cases of familial CS. PMID- 24785892 TI - Hyperthyroidism associated with obesity-related glomerulopathy-like pathologic features. AB - Thyroid dysfunction is related to many kidney diseases. We herein present the case of a 39-year-old woman who exhibited obesity-related glomerulopathy-like pathologic features in combination with hyperthyroidism. She displayed hyperthyroidism in spite of receiving anti-thyroid drug treatment, with massive proteinuria (4.5 g/gCr). A renal biopsy demonstrated glomerular hypertrophy (average diameter, 280 MUm) and an increased number of capillary vessels, both of which are compatible with a diagnosis of obesity-related glomerulopathy. Following thyroidectomy, the proteinuria gradually decreased in association with an improvement in hyperphagia and normalization of the thyroid function. Obesity related nephropathy associated with hyperthyroidism is very rare. In this report, we discuss the relationship between hyperthyroidism and obesity-related glomerulopathy-like pathologic features. PMID- 24785893 TI - Cystic, nodular and cavitary metastases to the lungs in a patient with endometrial stromal sarcoma of the uterus. AB - A 57-year-old woman, who had undergone hysterectomy for uterine myoma 11 years earlier presented with cystic, nodular and cavitary lesions simultaneously visible on computed tomography images of the chest. Histological examinations of both the resected lung and past "myoma" specimens demonstrated that the original uterine tumor was a low-grade endometrial stromal sarcoma (ESS) that had metastasized to the lungs. No previous reports have described the coexistence of cystic, nodular and cavitary lesions with pulmonary metastasis of ESS; however, we successfully correlated the radiologic appearance with the corresponding pathologic findings. Medroxyprogesterone acetate therapy has effectively kept the patient asymptomatic for approximately five years. PMID- 24785894 TI - Donepezil-induced cervical dystonia in Alzheimer's disease: a case report and literature review of dystonia due to cholinesterase inhibitors. AB - We herein report an 81-year-old woman with Alzheimer's disease (AD) in who donepezil, a cholinesterase inhibitor (ChEI), caused cervical dystonia. The patient had a two-year history of progressive memory disturbance fulfilling the NINCDS-ADRDA criteria for probable AD. Mini-Mental State Examination score was 19/30. The remaining examination was normal. After a single administration of donepezil (5 mg/day) for 10 months, she complained of dropped head. Neurological examination and electrophysiological studies supported a diagnosis of cervical dystonia. Antecollis disappeared completely at 6 weeks after cessation of donepezil. Dystonic posture can occur at various timings of ChEI use. Physicians should pay more attention to rapidly progressive cervical dystonia in ChEI treated AD patients. PMID- 24785895 TI - An adult case of multiphasic disseminated encephalomyelitis manifesting with optic neuritis. AB - A 25-year-old woman presented with a fever, headache, vomiting and somnolence. Cranial magnetic resonance imaging (MRI) showed multiple lesions in the cerebellum, brainstem, cerebral cortex and subcortex. Oligoclonal bands were positive in the cerebral spinal fluid (CSF). She experienced a good recovery after steroid treatment. Four months later, she developed right vision loss. Repeated MRI showed multiple cranial lesions different from those involved in the first attack in both size and distribution. An abnormal high signal was also observed in the front and intraorbital regions of the right optic nerve. The patient's vision progressively improved, and she obtained a full recovery following the administration of steroids. A diagnosis of multiphasic disseminated encephalomyelitis manifesting with optic neuritis was made. PMID- 24785896 TI - Transbrachial carotid artery stenting can prevent renal cholesterol embolism. AB - A 78-year-old man was admitted for the treatment of internal carotid artery stenosis. The left internal carotid artery was occluded and stenosis of the right internal carotid artery was progressive. The patient had a history of renal cholesterol embolism associated with percutaneous peripheral intervention. Stenting of the right internal carotid artery was successfully performed via the right brachial artery, and cholesterol embolism was not noted after the procedure. This case suggests that carotid artery stenting (CAS) performed via a brachial approach is less likely to elicit cholesterol embolism than CAS performed via a femoral approach. PMID- 24785897 TI - Methicillin-resistant Staphylococcus aureus-related septic pulmonary embolism and sacroiliitis treated with long-term linezolid in a patient with adult-onset Still's disease. AB - We herein report the case of a 21-year-old woman with refractory adult-onset Still's disease who developed central venous catheter-related methicillin resistant Staphylococcus aureus sepsis during aggressive immunosuppressive therapy. She subsequently experienced septic pulmonary embolism (SPE) and sacroiliitis during treatment with intravenous vancomycin and was successfully treated with long-term oral linezolid therapy. This case suggests that the occurrence of methicillin-resistant Staphylococcus aureus infection in immunosuppressive patients can trigger severe clinical manifestations such as SPE and septic sacroiliitis and that linezolid is suitable for treating such conditions. PMID- 24785898 TI - Infective endocarditis caused by Listeria monocytogenes forming a pseudotumor. AB - A 73-year-old woman with breast cancer and metastasis under chemotherapy suffered from fever, pleural effusion and pericardial effusion. Despite the administration of treatment with cefozopran and prednisolone, the patient's fever relapsed. An electrocardiogram identified a new complete atrioventricular block and an echocardiogram revealed vegetation with an unusual pseudotumoral mass in the right atrium. Blood cultures grew Listeria monocytogenes. The patient was eventually diagnosed with right-sided infective endocarditis, which improved following the six-week administration of ampicillin and gentamicin. Homemade yoghurt was suspected to be the cause of infection in this case. Listeria endocarditis is rare; however, physicians should pay more attention to preventing this fatal disease in immunocompromised patients. PMID- 24785899 TI - Embolization of a symptomatic intrahepatic portosystemic venous shunt. PMID- 24785900 TI - Triangle sign on neck MRI. PMID- 24785901 TI - Dual-mode triboelectric nanogenerator for harvesting water energy and as a self powered ethanol nanosensor. AB - When water is passing through the air or an insulating tube, it will contain not only the mechanical energy but also the electrostatic energy due to the existence of triboelectric charges on its surface as a result of contact with the air/solid surface. In this paper, a hybrid triboelectric nanogenerator (TENG) is designed to simultaneously harvest the electrostatic and mechanical energies of flowing water. Water-TENG, mainly constructed by a superhydrophobic TiO2 layer with hierarchical micro/nanostructures, is used to collect the electrostatic energy of water (Output 1). Contact-TENG, composed by a polytetrafluoroethylene film and a layer of assembled SiO2 nanoparticles, is used to collect the mechanical energy of water (Output 1 and Output 2). Using TiO2 nanomaterials in water-TENG provides the advantages of photocatalytic activity and antibacterial property for water purification. Under the impact of a water stream from a household faucet at a flowing rate of 40 mL s(-1), the generated short-circuit current from Output 1 and Output 2 of dual-mode TENG can reach 43 and 18 MUA, respectively. The instantaneous output power densities from Output 1 and Output 2 of dual-mode TENG are 1.31 and 0.38 W m(-2), respectively, when connecting to a load resistor of 44 MOmega. The rectified outputs have been applied to drive light-emitting diodes and charge commercial capacitors. Besides, the water-TENG has also been demonstrated as a self-powered nanosensor for ethanol detection. PMID- 24785902 TI - Characterization of the morphology of fast-tumbling bicelles with varying composition. AB - Small, fast-tumbling bicelles are frequently used in solution NMR studies of protein-lipid interactions. For this purpose it is critical to have information about the organization of the lipids within the bicelle structure. We have studied the morphology of small, fast-tumbling bicelles containing DMPC and DHPC as a function of temperature, lipid concentration, and the relative ratio (q value) of lipid (DMPC) to detergent (DHPC) amounts. Dynamic light scattering and cryo-transmission electron microscopy techniques were used to measure the size of the bicelles and to monitor the shape and dispersity of the particles in the samples. The stability and size of DMPC-containing bicelle mixtures were found to be highly dependent on temperature and the total lipid concentration for mixtures with q = 1 and q = 1.5. Stable DMPC/DHPC bicelles are only formed at low q values (0.5). Bicelle mixtures with q > 0.5 appear to be multidisperse containing more than one component, one with r(H) around 2.5 nm and one with r(H) of 6-8 nm. This is interpreted as a coexistence of small (possibly mixed micelles) bicelles and much larger bicelles. Incubating the sample at 37 degrees C increases the phase separation. Moreover, low total amphiphile concentrations and low q values lead to the formation of a temperature-independent morphology, interpreted as the formation of small particles in which the DHPC and DMPC are more mixed. On the basis of these results, we propose the existence of a critical bicelle concentration, a parameter that determines the existence of bilayered bicelles, which varies with q value. This polymorphism was not observed at any concentrations for q = 0.5 bicelles, for which a small but detectable temperature dependence was observed at high concentrations. The results demonstrate that q = 0.5 mixtures predominantly form "classical" bicelles, but that caution is needed when using fast-tumbling mixtures with q values higher than 0.5. PMID- 24785903 TI - New artificial diet for continuous rearing of the bean pod borer, Maruca vitrata. AB - The bean pod borer, Maruca vitrata Fabricius (Lepidoptera: Crambidae), is a serious pantropical pest of grain legumes. A suitable artificial diet is desirable for producing uniform insects for commercial purposes or research. Three previously described artificial diets, 1 newly-developed artificial diet, and cowpea (Vigna unguiculata (L.) Walp. (Fabales: Fabaceae)), the natural hostplant of M. vitrata, were used for rearing M. vitrata, and the life parameters were examined. The results indicated that insects completed a full life cycle only when the larvae were fed cowpea or the diet reported by Onyango and Ochieng'-Odero ( 1993 ), called the "D-OO diet." However, the rearing efficiency (i.e., larval and pupal survival, longevity of adults, and fecundity) on the D-OO diet was inferior to the rearing efficiency on cowpea. Subsequently, a new artificial diet was formulated based on soybean powder, Glycine max (L.) Merr. (Fabales: Fabaceae), and wheat germ, Triticum aestivum L. (Poales: Poaceae). The egg production, egg hatching, larval developmental duration, and pupal survival of the M. vitrata reared on the new artificial diet were found to be significantly improved relative to the D-OO diet, but were not significantly better than on the host-plant cowpea. The optimum rearing density was 15-25 larvae per box. There were no significant changes in reproductive potential after 8 successive generations of rearing on the new diet. These results indicated that the newly developed diet could serve as a viable alternative to cowpea plant for continuous rearing of M. vitrata. PMID- 24785904 TI - Access to and experience of later abortion: accounts from women in Scotland. AB - CONTEXT: Except in the presence of significant medical indications, the legal limit for abortion in Great Britain is 24 weeks' gestation. Nevertheless, abortion for nonmedical reasons is not usually provided in Scotland after 18-20 weeks, meaning women have to travel to England for the procedure. METHODS: In depth interviews were conducted with 23 women presenting for "later" abortions (i.e., at 16 or more weeks' gestation) in Scotland. Participants were women who sought an abortion at a participating National Health Service clinic between January and July 2013. Interviews addressed reasons for and consequences of later presentation, as well as women's experiences of abortion. Thematic analysis attended to emerging issues and employed the conceptual tool of candidacy. RESULTS: Delayed recognition of pregnancy, changed life circumstances and conflicting candidacies for motherhood and having an abortion were common reasons for women's presentation for later abortion. Women perceived that the resources required to travel to England for a later abortion were potential barriers to access, and felt that such travel was distressing and stigmatizing. Participants who continued their pregnancy did so after learning they were at a later gestational age than expected or after receiving assurances of support from partners, friends or family. CONCLUSIONS: Reasons for seeking later abortion are complex and varied among women in Scotland, and suggest that reducing barriers to access and improving local provision of such abortions are a necessity. The candidacy framework allows for a fuller understanding of the difficulties involved in obtaining abortions. PMID- 24785905 TI - TIMES-SS--recent refinements resulting from an industrial skin sensitisation consortium. AB - The TImes MEtabolism Simulator platform for predicting Skin Sensitisation (TIMES SS) is a hybrid expert system, first developed at Bourgas University using funding and data from a consortium of industry and regulators. TIMES-SS encodes structure-toxicity and structure-skin metabolism relationships through a number of transformations, some of which are underpinned by mechanistic 3D QSARs. The model estimates semi-quantitative skin sensitisation potency classes and has been developed with the aim of minimising animal testing, and also to be scientifically valid in accordance with the OECD principles for (Q)SAR validation. In 2007 an external validation exercise was undertaken to fully address these principles. In 2010, a new industry consortium was established to coordinate research efforts in three specific areas: refinement of abiotic reactions in the skin (namely autoxidation) in the skin, refinement of the manner in which chemical reactivity was captured in terms of structure-toxicity rules (inclusion of alert reliability parameters) and defining the domain based on the underlying experimental data (study of discrepancies between local lymph node assay Local Lymph Node Assay (LLNA) and Guinea Pig Maximisation Test (GPMT)). The present paper summarises the progress of these activities and explains how the insights derived have been translated into refinements, resulting in increased confidence and transparency in the robustness of the TIMES-SS predictions. PMID- 24785906 TI - Appetite testing in HIV-infected African adults recovering from malnutrition and given antiretroviral therapy. AB - OBJECTIVE: The Nutritional Support for Africans Starting Antiretroviral Therapy (NUSTART) trial was designed to determine whether nutritional support for malnourished HIV-infected adults starting antiretroviral therapy (ART) can improve early survival. Appetite is related to health outcomes in this population, but the optimal appetite metric for field use is uncertain. We evaluated two measures of appetite with the goal of improving understanding and treatment of malnutrition in HIV-infected adults. DESIGN: Longitudinal cohort study embedded in a clinical trial of vitamin and mineral-fortified, v. unfortified, lipid-based nutritional supplements. SETTING: HIV clinics in Mwanza, Tanzania and Lusaka, Zambia. SUBJECTS: Malnourished (BMI<18.5 kg/m2) HIV-infected adults starting ART. RESULTS: Appetite measurements, by short questionnaire and by weight of maize porridge consumed in a standardized test, were compared across time and correlated with changes in weight. Appetite questionnaire scores, from polychoric correlation, and porridge test results were normally distributed for Tanzanians (n 187) but clustered and unreliable for Zambians (n 297). Among Tanzanian patients, the appetite score increased rapidly from referral for ART, plateaued at the start of ART and then increased slowly during the 12-week follow up. Change in appetite questionnaire score, but not porridge test, correlated with weight change in the corresponding two-week intervals (P=0.002) or over the whole study (P=0.05) but a point estimate of hunger did not predict weight change (P=0.4). CONCLUSIONS: In Tanzania change in appetite score correlated with weight change, but single point measurements did not. Appetite increases several weeks after the start of ART, which may be an appropriate time for nutritional interventions for malnourished HIV-infected adults. PMID- 24785907 TI - Electronic structure and formation of simple ferryloxo complexes: mechanism of the Fenton reaction. AB - The Fenton reaction is a famous reaction in inorganic chemistry, with relevance to topics such as bioinorganic oxidation and fundamental redox chemistry of water and oxygen. It is also a reaction concerning which there has been very extensive mechanistic debate, with experimental and computational work leading to extensive evidence concerning its mechanism-not all of which is consistent. Here, we use this reaction as a challenge to modern electronic structure theory methods and show that density functional theory, when validated by accurate ab initio methods, can yield a picture of this reaction that is consistent with experiment. The article also highlights some of the challenges in accurate studies of reaction mechanisms of ionic species in water solution. PMID- 24785908 TI - Competing electronic states in high temperature phase of NaTiO(2). AB - First principle density functional theory calculations on the high temperature phase of layered triangular lattice system NaTiO2 have revealed that a collective electronic state exists energetically close to the ground state but with competing transport properties: the latter is metallic with partially occupied doubly degenerate e'g orbitals, whereas the former is insulating with a1g orbital fully occupied. Significant occupation of this excited state is possible at non zero temperature either thermally or thanks to very soft (large amplitude) oxygen vibrations. Possible explanations of the experimental low conductivity based on competing orbital transport and of the specific heat jump at a structural transition based on orbital entropy are discussed. PMID- 24785909 TI - Connect with the world...join the World Federation of Orthodontists. PMID- 24785910 TI - Why perform a literature review? PMID- 24785911 TI - Accuracy and reproducibility of dental measurements using different technologies, methodologic mistake. PMID- 24785912 TI - Authors' response. PMID- 24785913 TI - Authors' response. PMID- 24785914 TI - Tooth mineralization stages as a diagnostic tool for assessment of skeletal maturity. PMID- 24785915 TI - Oral epithelial cell reaction and Invisalign treatment. PMID- 24785916 TI - Author's response. PMID- 24785917 TI - Is ignorance bliss? PMID- 24785918 TI - Temporary skeletal anchorage devices: the case for miniscrews. PMID- 24785919 TI - Temporary skeletal anchorage devices: the case for miniplates. PMID- 24785921 TI - Comparative assessment of alignment efficiency and space closure of active and passive self-ligating vs conventional appliances in adolescents: a single-center randomized controlled trial. AB - INTRODUCTION: The aim of this study was to compare the time to initial alignment and extraction space closure using conventional brackets and active and passive self-ligating brackets. METHODS: One hundred adolescent patients 11 to 18 years of age undergoing maxillary and mandibular fixed appliance therapy after the extraction of 4 premolars were randomized with stratification of 2 age ranges (11 14 and 15-18 years) and 3 maxillomandibular plane angles (high, medium, and low) with an allocation ratio of 1:2:2. Restrictions were applied using a block size of 10. Allocation was to 1 of 3 treatment groups: conventional brackets, active self-ligating, or passive self-ligating brackets. All subjects were treated with the same archwire sequence and space-closing mechanics in a district general hospital setting. The trial was a 3-arm parallel design. Labial-segment alignment and space closure were measured on study models taken every 12 weeks throughout treatment. All measurements were made by 1 operator who was blinded to bracket type. The patients and other operators were not blinded to bracket type during treatment. RESULTS: Ninety-eight patients were followed to completion of treatment (conventional, n = 20; active self-ligating brackets, n = 37; passive self-ligating brackets, n = 41). The data were analyzed using linear mixed models and demonstrated a significant effect of bracket type on the time to initial alignment (P = 0.001), which was shorter with the conventional brackets than either of the self-ligating brackets. Sidak's adjustment showed no significant difference in effect size (the difference in average response in millimeters) between the active and passive self-ligating brackets (the results are presented as effect size, 95% confidence intervals, probabilities, and intraclass correlation coefficients) (-0.42 [-1.32, 0.48], 0.600, 0.15), but the conventional bracket was significantly different from both of these (-1.98 [ 3.19, -0.76], 0.001, 0.15; and -1.56 [-2.79, -0.32], 0.001, 0.15). There was no statistically significant difference between any of the 3 bracket types with respect to space closure. Space-closure times were shorter in the mandible, except for the Damon 3MX bracket (Ormco, Orange, Calif), where active and total space-closure times were shorter in the maxilla. No adverse events were recorded in the trial. CONCLUSIONS: Time to initial alignment was significantly shorter for the conventional bracket than for either the active or passive self-ligating brackets. There was no statistically significant difference in passive, active, or total space-closure times among the 3 brackets under investigation. PMID- 24785922 TI - Three-dimensional longitudinal changes in craniofacial growth in untreated hemifacial microsomia patients with cone-beam computed tomography. AB - INTRODUCTION: The purpose of this study was to evaluate the concept that the affected and contralateral sides do not grow at the same rate in patients with hemifacial microsomia. Changes in the cranial base, maxilla, mandible, and occlusal plane were evaluated on 3-dimensional images from cone-beam computed tomography data in untreated patients. METHODS: Six patients were classified as having mandibular Pruzansky/Kaban type I, IIA, or IIB hemifacial microsomia. Cone beam computed tomography (MercuRay; Hitachi, Tokyo, Japan) scans were taken before orthodontic treatment during both growth and postpuberty periods. RESULTS: The cranial base as defined by the position of the mastoid process was in a different position between the affected and contralateral control sides. The nasomaxillary length or height was shorter on the affected side for all 6 patients with hemifacial microsomia regardless of its severity, and it grew less than on the contralateral control side in 5 of the 6 patients. The occlusal plane angle became more inclined in 4 of the 6 patients. The mandibular ramus was shorter on the affected side in all patients and grew less on the affected side in 5 of the 6 patients. The mandibular body grew slower, the same, or faster than on the control side. CONCLUSIONS: The cranial base, position of the condyle, lengths of the condyle and ramus, and positions of the gonial angle and condyle can vary between the affected and contralateral control sides of patients with hemifacial microsomia, with the ramus and nasomaxillary length usually growing slower than they grow on the control side. These results suggest that many factors affect the growth rate of the craniofacial region and, specifically, the mandible in patients with hemifacial microsomia. PMID- 24785923 TI - Comparison of orthodontic treatment outcomes in nonextraction, 2 maxillary premolar extraction, and 4 premolar extraction protocols with the American Board of Orthodontics objective grading system. AB - INTRODUCTION: The aim of this study was to compare the orthodontic clinical outcomes of 2 maxillary premolar extraction, 4 premolar extraction, and nonextraction treatment protocols. METHODS: The sample for this retrospective study was selected randomly from the archives of postgraduate orthodontic clinics in various cities in Turkey. Posttreatment records including dental casts and panoramic radiographs of 1098 patients were divided into 3 groups: group 1 comprised 269 patients treated with 2 maxillary first premolar extraction, group 2 comprised 267 patients treated with 4 premolar extraction, and group 3 comprised 562 patients treated with a nonextraction protocol. Only 1 researcher evaluated all subjects using the American Board of Orthodontics objective grading system. RESULTS: There were no statistically significant differences among the 2 maxillary premolar extraction, 4 premolar extraction, and nonextraction treatment groups for alignment, marginal ridge height, buccolingual inclination, overjet, and interproximal contact measurements. Statistically significant differences were found in occlusal contacts, occlusal relationships, and root angulation measurements between the 4 premolar extraction and the nonextraction groups. CONCLUSIONS: The nonextraction patients had more teeth in occlusion than did the 4 premolar extraction patients. The nonextraction patients finished with more satisfactory sagittal dental relationships. The 4 premolar extraction group had the least satisfactory sagittal dental relationships. The nonextraction patients finished with better root angulations. PMID- 24785924 TI - Quantitative analysis of changes in salivary mutans streptococci after orthodontic treatment. AB - INTRODUCTION: The purpose of this study was to analyze the initial changes in salivary mutans streptococci levels after orthodontic treatment with fixed appliances. METHODS: Our subjects consisted of 58 adults. Whole saliva and simplified oral hygiene index values were obtained at 4 time points: at debonding (T1), 1 week after debonding (T2), 5 weeks after debonding (T3), and 13 weeks after debonding (T4). Repeated measures analysis of variance was used to determine the time-related differences in salivary bacterial levels and the simplified oral hygiene index values among the 4 time points after quantifying the salivary levels of Streptococcus mutans, Streptococcus sobrinus, and total bacteria with real-time polymerase chain reaction. RESULTS: Simplified oral hygiene index values and total bacteria significantly decreased, but salivary mutans streptococci levels significantly increased after orthodontic treatment. The amounts of total bacteria in saliva significantly decreased at T3 (T1, T2 > T3, T4), and the simplified oral hygiene index values decreased at T2 (T1 > T2, T3, T4). However, salivary S mutans and S sobrinus significantly increased at T3 and T4, respectively (T1, T2 < T3 < T4). Furthermore, the proportion of mutans streptococci to total bacteria significantly increased at T4 (T1, T2, T3 < T4). CONCLUSIONS: This study suggests that careful hygienic procedures are needed to reduce the risk for dental caries after orthodontic treatment, despite overall improved oral hygiene status. PMID- 24785925 TI - Stability of surgically assisted rapid palatal expansion with and without retention analyzed by 3-dimensional imaging. AB - INTRODUCTION: Surgically assisted rapid palatal expansion (SARPE) is the procedure of choice for treatment of adults with transverse maxillary deficiency greater than 7 mm. There is no consensus about the dentoskeletal effect of an orthodontic retainer on the outcome of SARPE. Our objective was to assess the effectiveness of an orthodontic retainer on dentoskeletal stability. METHODS: Ninety digitized dental casts of 30 adults undergoing SARPE were divided into 2 groups-no retention (n = 15) and retention (n = 15)-and assessed. The dental casts were obtained at 3 checkpoints: (1) 7 days on average before SARPE (preoperatively), (2) 4 months after expansion, and (3) 10 months after expansion was completed. The retention patients received a transpalatal arch just after expander removal, at checkpoint 2. The transpalatal arch was kept for 10 months after completion of the expansion (checkpoint 3 and end of the study). The dental casts were scanned with a Vivid 9i 3D laser scanner (Konica Minolta, Wayne, NJ). The distances measured were premolar and molar intercusp distances, premolar and molar intercervical distances, premolar and molar inter-WALA (Will Andrews and Lawrence Andrews) ridge distances, and palate height at the maxillary first molar. RESULTS: The planned maxillary expansion was within the expected amount (P <0.05). Palatal height at the 4-month checkpoint decreased by 0.79 mm (4.38%) (P <0.001) and again at the 10-month checkpoint by 0.38 mm (0.98%) (P >0.05) but not significantly in both groups. The premolar intercusp distance had a relapse at checkpoint 3 of 1.84 mm (7.18%) (P <0.001) in the no-retention group. Both groups had average relapses of 0.95 mm in the premolar intercervical distances, of 0.88 mm in the premolar inter-WALA ridge distances, of 1.04 mm in the molar intercusp distances, of 0.74 mm in the molar intercervical distances, and of 0.84 mm in the molar inter-WALA ridge distances (P <0.05) at checkpoint 3. CONCLUSIONS: The analysis of relapse in both groups suggests that the use of a transpalatal arch as a retaining device does not improve dento-osseous stability. PMID- 24785926 TI - Physical properties of root cementum: part 24. Root resorption of the first premolars after 4 weeks of occlusal trauma. AB - INTRODUCTION: In orthodontics, adding restorative materials on occlusal or lingual surfaces is a common method to create a mini-biteplane to increase patients' vertical dimension temporarily to facilitate several treatment procedures. However, this method transmits excessive occlusal forces through the periodontal ligament and causes trauma. In this prospective randomized clinical trial, we measured and compared quantitatively the volumes of root resorption after 4 weeks of occlusal trauma. METHODS: Forty-eight maxillary and mandibular first premolars of 12 patients (6 girls, 6 boys) comprised the sample for this study. One side of each patient was randomly selected as the control. On the contralateral side, a light-cured glass ionomer cement (Transbond Plus Light Cure Band Adhesive; 3M Unitek, Monrovia, Calif) was bonded onto the occlusal surface of the mandibular first premolar so that the cement was in contact with the maxillary first premolar. After 4 weeks, both first premolars were extracted. Each sample was imaged using a microcomputed tomography system (1172; SkyScan, Aartselaar, Belgium) and analyzed with specially designed software for volumetric measurements of resorption craters. Furthermore, pain was evaluated with a visual analog scale for 7 days. RESULTS: There were significant differences in the amounts of root resorption between the control and the experimentally traumatized teeth. No significant difference among the buccal, lingual, mesial, and distal surfaces was found in either jaw. Furthermore, no significant difference existed in the amount of root resorption among the cervical, middle, and apical thirds of both jaws. There was no correlation between age, sex, volume of the root resorption craters, and pain. CONCLUSIONS: Restorative buildups, used to increase the vertical dimension by 2 mm for 4 weeks, caused root resorption along the sides of the teeth during the active bite-increase period. PMID- 24785927 TI - Biologic evaluation of a hollow-type miniscrew implant: an experimental study in beagles. AB - INTRODUCTION: The aims of this study were to assess the biologic stability of a newly designed hollow (H-type) miniscrew compared with conventional (C-type) miniscrews through histomorphometric and histologic analysis. METHODS: Both types of miniscrews were placed into the maxillae and the mandibles of 12 beagles. Maximum insertion torque, Periotest (Siemens AG, Bensheim, Germany) value, bone implant contact, and bone volume were measured. RESULTS: The overall success rates of the H-type were 78.3% in the maxilla and 60.0% in the mandible. Mean maximum insertion torque values of the H-type were 14.2 N-cm in the maxilla and 20.9 N-cm in the mandible. The Periotest values of the H-type were -1.5 in the maxilla and -6.4 in the mandible. Mean maximum insertion torque and Periotest values of the H-type were higher than those of the C-type. In the maxilla, the bone-implant contact values of the H-type were 37.3% and 32.3% at 3 and 12 weeks, respectively. In the mandible, the bone-implant contact values were 31.4% and 18.5% at 3 and 12 weeks, respectively. CONCLUSIONS: Considering the lower success rate and the insufficient bone-implant contact and bone volume of the H-type in the mandible, the clinician should choose a suitable combination of miniscrews depending on local bone quality and implantation site, such as an H-type in the maxilla and a C-type in the mandible. PMID- 24785928 TI - Effect of bone-borne rapid maxillary expanders with and without surgical assistance on the craniofacial structures using finite element analysis. AB - INTRODUCTION: The aim of this study was to analyze stress distribution and displacement of the craniofacial structures resulting from bone-borne rapid maxillary expanders with and without surgical assistance using finite element analysis. METHODS: Five designs of rapid maxillary expanders were made: a tooth borne hyrax expander (type A); a bone-borne expander (type B); and 3 bone-borne surgically assisted modalities: separation of the midpalatal suture (type C), added separation of the pterygomaxillary sutures (type D), and added LeFort I corticotomy (type E). The geometric nonlinear theory was applied to evaluate the Von Mises stress distribution and displacement. RESULTS: The surgical types C, D, and E demonstrated more transverse movement than did the nonsurgical types A and B. The amounts of expansion were greater in the posterior teeth in types A and B, but in types C, D, and E, the amounts of expansion were greater in the anterior teeth. At the midpalatal suture, the nonsurgical types showed more anterior expansion than did the posterior region, and higher stresses than with the surgical types. Type B showed the highest stresses at the infraorbital margin, anterior and posterior nasal spines, maxillary tuberosity, and pterygoid plate and hamulus. CONCLUSIONS: The 3 surgical models showed similar amounts of stress and displacement along the teeth, midpalatal sutures, and craniofacial sutures. Therefore, when using a bone-borne rapid maxillary expander in an adult, it is recommended to assist it with midpalatal suture separation, which requires minimal surgical intervention. PMID- 24785929 TI - Accidental debondings: Buccal vs fully individualized lingual multibracket appliances. AB - INTRODUCTION: The aim of this study was to retrospectively assess the frequency and localizations of bond failures (BFs) in patients treated with either lingual (TOP-Service fur Lingualtechnik GmbH, a 3M Company, Bad Essen, Germany) or buccal (Mini Diamond brackets/Accent molar tubes; Ormco, Orange, Calif) full multibracket appliances in both dental arches. METHODS: Data were acquired by an independent investigator from the patient records of 3 practitioners. To establish a standardized observation period, the first year of treatment was analyzed for each patient. Statistical analysis comprised the Kruskal-Wallis, Wilcoxon, Mann-Whitney U, and Fisher exact tests. The significance level was set at P <0.05. RESULTS: The mean number of BFs per patient in the first year of treatment did not differ significantly between the lingual group (n = 59; mean age, 31.1 years; mean BFs per patient, 2.63; SD, 2.77; minimum, 0; maximum, 13) and the buccal group (n = 44; mean age, 15.14 years; mean BFs per patient, 2.61; SD, 3.41; minimum, 0; maximum, 14) (P = 0.428) or with respect to sex (lingual group, P = 0.251; buccal group, P = 0.414) or practitioner (lingual group, P = 0.755; buccal group, P = 0.060), but molar attachments were more prone to BFs than were premolar brackets (lingual group, P = 0.015; buccal group, P = 0.049), and premolar brackets were more prone to BF than anterior brackets (lingual group, P = 0.005; buccal group, P = 0.004). CONCLUSIONS: With both appliances, a mean of 2.62 BFs per patient in the first year of treatment can be expected; this benchmark provides a reference for patient briefing, which is very important considering the large interindividual variances and budgeting considerations. PMID- 24785930 TI - Bony adaptation after expansion with light-to-moderate continuous forces. AB - INTRODUCTION: The purpose of this study was to evaluate the biologic response of dentoalveolar bone to archwire expansion with light-to-moderate continuous forces. METHODS: With a split-mouth experimental design, the maxillary right second premolars of 7 adult male dogs were expanded for 9 weeks using passive self-ligating brackets (Damon Q; Ormco, Orange, Calif) and 2 sequential archwires (0.016 * 0.022-in copper-nickel-titanium alloy, followed by 0.019 * 0.025-in copper-nickel-titanium alloy). Intraoral and radiographic measurements were made to evaluate tooth movements and tipping associated with expansion; archwire forces were measured using a force gauge. Microcomputed tomography was used to compare buccal bone height, total tooth height, total root height, and buccal bone thickness. Bone formation was evaluated histologically using tetracycline and calcein fluorescent labels and hematoxylin and eosin stains. RESULTS: Buccal expansion was produced by forces between 73 and 178 g. Compared with the control side, which showed no tooth movement, the experimental second premolars were expanded by 3.5 +/- 0.9 mm and tipped by 15.8 degrees . Buccal bone thickness was significantly thinner (about 0.2 mm) in the coronal aspects and significantly thicker (about 0.9 mm) in the apical aspects over the mesial roots. The tipping and expansion significantly (P <0.05) reduced buccal bone height (ie, caused dehiscences) at the mesial (about 2.9 mm) and distal (about 1.2 mm) roots. Bony apposition occurred on the trailing edges of tooth movement and on the leading edges of the second premolar apices. The axial microcomputed tomography slices indicated, and the bone histomorphometry and histology demonstrated, newly laid down bone on the periosteal side of the buccal cortical surfaces. Ordered osteoblast aggregation was also evident on the periosteal surfaces of buccal bone, just cervical to the apparent center of rotation of the tooth. Tooth and root heights showed no significant differences between the experimental and control second premolars. CONCLUSIONS: Buccal expansion with light-to-moderate continuous forces produced 3.5 mm of tooth movement, uncontrolled tipping, and bone dehiscence, but no root resorption. Bone formation on the periosteal surfaces of cortical bone indicates that apposition is possible on the leading edge of tooth movements. PMID- 24785931 TI - Effect of 2 elastomeric ligatures on microbial flora and periodontal status in orthodontic patients. AB - INTRODUCTION: The aim of this study was to compare the effects of a nonconventional elastomeric ligature (Slide; Leone, Florence, Italy) with those of a conventional elastomeric ligature (Ormco, Orange, Calif) on microbial flora and periodontal status in orthodontic patients. METHODS: A total of 13 orthodontic patients scheduled for fixed orthodontic treatment were selected for this study. The use of Slide and conventional elastomeric ligatures in fixed orthodontic appliances was tested. Microbial and periodontal records were obtained before bonding and 1 and 5 weeks after bonding. For the statistical analysis and calculations, SPSS software (version 15.0; SPSS, Chicago, Ill) was used. In the statistical decisions, P <0.05 values were accepted as significantly different. RESULTS: No significant differences between Slide and conventional elastomeric ligatures were evident at 1 week or 5 weeks after bonding, with regard to gingival index, plaque index, gingival bleeding index, or pocket depth scores (P >0.05). Similarly, aerobic and anaerobic bacteria counts did not differ significantly on the surface or on the elastics (P >0.05). CONCLUSIONS: Although the Slide ligatures cover the total surface of the bracket, they do not cause significantly more plaque accumulation or periodontal problems than do the conventional elastomeric ligatures. PMID- 24785932 TI - Long-term orthodontic and surgical treatment and stability of a patient with Beckwith-Wiedemann syndrome. AB - Beckwith-Wiedemann syndrome (BWS) is a congenital growth disorder. Children born with BWS develop enlarged organs, including the tongue, a large body, and other signs. A woman with BWS was treated and followed for 30 years. Treatment consisted of tongue reduction, orthopedic and orthodontic treatment, orthognathic surgery, and retention. The patient was first treated when she was 5 years old. Her original orthodontic problems included macroglossia, anterior open bite, anterior crossbite, and a skeletal Class III jaw relationship caused by significant mandibular protrusion. The jaw-base relationships did not improve in the early preadolescent period after phase 1 of orthodontic treatment with a vertical chincap. With the growth spurt accompanying puberty, she developed a severe skeletal Class III jaw relationship and a constricted maxillary arch. Surgically assisted rapid maxillary expansion was performed at 23 years of age to correct the severe discrepancy between the maxillary and mandibular dental arch widths. Then, at 26 years, a LeFort I osteotomy, a horseshoe osteotomy, a bilateral sagittal split ramus osteotomy, and genioplasty were performed after presurgical orthodontic treatment with extraction of the mandibular first molars. Both the facial profile and the occlusion were stable after 6 years of retention. This case report discusses the result of long-term observation of a patient with BWS who underwent tongue reduction, early orthodontic treatment, and surgical orthodontic treatment. PMID- 24785933 TI - Orthodontic treatment in a periodontal patient with pathologic migration of anterior teeth. AB - A 22-year-old man with severe periodontitis and pathologic tooth migration sought orthodontic treatment. He was treated successfully with effective control of the strength and the direction of the orthodontic forces, and a combination of periodontic and orthodontic treatment. After 22 months of orthodontic treatment, his occlusal trauma resulting from pathologic tooth migration was relieved, a stable occlusion was achieved, and mutual aggravation of occlusal trauma and periodontitis was prevented. Furthermore, the patient's facial esthetics and self confidence were improved. Newly formed trabecular bone could be seen in the periapical x-rays in some regions where resorption had been severe. This case report shows that resorption of alveolar bone can be prevented and that multidisciplinary orthodontic treatment of a periodontal patient with pathologic tooth migration is effective and helpful. PMID- 24785934 TI - Virtually fabricated guide for placement of the C-tube miniplate. AB - INTRODUCTION: This paper introduces a virtually planned and stereolithographically fabricated guiding system that will allow the clinician to plan carefully for the best location of the device and to achieve an accurate position without complications. METHODS: The scanned data from preoperative dental casts were edited to obtain preoperative 3-dimensional (3D) virtual models of the dentition. After the 3D virtual models were repositioned, the 3D virtual surgical guide was fabricated. A surgical guide was created onscreen, and then these virtual guides were materialized into real ones using the stereolithographic technique. RESULTS: Whereas the previously described guide required laboratory work to be performed by the orthodontist, our technique is more convenient because the laboratory work is done remotely by computer-aided design/computer-aided manufacturing technology. Because the miniplate is firmly held in place as the patient holds his or her mandibular teeth against the occlusal pad of the surgical guide, there is no risk that the miniscrews can slide on the bone surface during placement. The software program (2.5-dimensional software) in this study combines 2-dimensional cephalograms with 3D virtual dental models. This software is an effective and efficient alternative to 3D software when 3D computed tomography data are not available. CONCLUSIONS: To confidently and safely place a miniplate with screw fixation, a simple customized guide for an orthodontic miniplate was introduced. The use of a custom-made, rigid guide when placing miniplates will minimize complications such as vertical mislocation or slippage of the miniplate during placement. PMID- 24785935 TI - Practicing what you preach-or not. PMID- 24785936 TI - Confounding. PMID- 24785937 TI - Association between intercellular adhesion molecule-1 gene K469E polymorphism and the risk of stroke in a Chinese population: a meta-analysis. AB - Several epidemiologic studies have evaluated the association between intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism and stroke, but the results were inconsistent. The present meta-analysis was performed to investigate the relationship between K469E polymorphism and stroke in the Chinese population. A comprehensive search for related studies from the electronic databases of PubMed, Embase, Web of Science, CBMdisc and CNKI as well as a manual search of the references of identified articles was performed. Data were extracted to calculate for allelic, additive, dominant and recessive models using pooled odds ratios (ORs) along with 95% confidence intervals (CIs) by Review Manager 5.0 and Stata 11.0. Different effect models, subgroup analysis, sensitivity analysis, publication bias and power calculations were used to improve the comprehensive analysis. Finally, a total of 12 studies containing 1593 cases and 1555 controls were included in the final meta-analysis. No evidence of significant association between ICAM-1 gene K469E polymorphism and stroke was found in all four models (allelic model: OR = 1.07, 95%CI = 0.78-1.47; additive model: OR = 1.21, 95% CI = 0.67-2.16 (EE vs. KK); OR = 1.04, 95%CI = 0.75-1.45 (EK vs. KK); dominant model: OR = 1.07, 95% CI = 0.73-1.56; and recessive model: OR = 1.18, 95% CI = 0.77-1.83, respectively) based on the overall population, as well as subgroup analysis and sensitivity analysis. In conclusion, the present meta-analysis showed no evidence of significant association between ICAM-1 gene K469E polymorphism and stroke in the Chinese population. Nonetheless, this conclusion should be interpreted cautiously due to the low statistical power and considerable heterogeneity. Therefore, larger sample-size studies with homogeneous cases and well-matched controls are needed to further address this correlation. PMID- 24785938 TI - An Empirical Investigation of Variance Design Parameters for Planning Cluster Randomized Trials of Science Achievement. AB - BACKGROUND: Prior research has focused primarily on empirically estimating design parameters for cluster-randomized trials (CRTs) of mathematics and reading achievement. Little is known about how design parameters compare across other educational outcomes. OBJECTIVES: This article presents empirical estimates of design parameters that can be used to appropriately power CRTs in science education and compares them to estimates using mathematics and reading. RESEARCH DESIGN: Estimates of intraclass correlations (ICCs) are computed for unconditional two-level (students in schools) and three-level (students in schools in districts) hierarchical linear models of science achievement. Relevant student- and school-level pretest and demographic covariates are then considered, and estimates of variance explained are computed. Subjects: Five consecutive years of Texas student-level data for Grades 5, 8, 10, and 11. MEASURES: Science, mathematics, and reading achievement raw scores as measured by the Texas Assessment of Knowledge and Skills. Results: Findings show that ICCs in science range from .172 to .196 across grades and are generally higher than comparable statistics in mathematics, .163-.172, and reading, .099-.156. When available, a 1 year lagged student-level science pretest explains the most variability in the outcome. The 1-year lagged school-level science pretest is the best alternative in the absence of a 1-year lagged student-level science pretest. CONCLUSION: Science educational researchers should utilize design parameters derived from science achievement outcomes. PMID- 24785939 TI - Evaluation of a competitive enzyme-linked immunosorbent assay for measurements of soluble HLA-G protein. AB - The human leukocyte antigen (HLA) class Ib molecule, HLA-G, has gained increased attention because of its assumed important role in immune regulation. The HLA-G protein exists in several soluble isoforms. Most important are the actively secreted HLA-G5 full-length isoform generated by alternative splicing retaining intron 4 with a premature stop codon, and the cleavage of full-length membrane bound HLA-G1 from the cell surface, so-called soluble HLA-G1 (sHLA-G1). A specific and sensitive immunoassay for measurements of soluble HLA-G is mandatory for conceivable routine testing and research projects. We report a novel method, a competitive immunoassay, for measuring HLA-G5/sHLA-G1 in biological fluids. The sHLA-G immunoassay is based upon a competitive enzyme-linked immunosorbent assay (ELISA) principle. It includes a recombinant sHLA-G1 protein in complex with beta2-microglobulin and a peptide as a standard, biotinylated recombinant sHLA-G1 as an indicator, and the MEM-G/9 anti-HLA-G monoclonal antibody (mAb) as the capture antibody. The specificity and sensitivity of the assay were evaluated. Testing with different recombinant HLA class I proteins and different anti-HLA class I mAbs showed that the sHLA-G immunoassay was highly specific. Optimal combinations of competitor sHLA-G1 and capture mAb concentrations were determined. Two versions of the assay were tested. One with a relatively wide dynamic range from 3.1 to 100.0 ng/ml, and another more sensitive version ranging from 1.6 to 12.5 ng/ml. An intra-assay coefficient of variation (CV) of 15.5% at 88 ng/ml and an inter-assay CV of 23.1% at 39 ng/ml were determined. An assay based on the competitive sHLA-G ELISA may be important for measurements of sHLA-G proteins in several conditions: assisted reproduction, organ transplantation, cancer, and certain pregnancy complications, both in research studies and possibly in the future also for clinical routine use. PMID- 24785940 TI - Comparison of urine and bladder or urethral mucosal biopsy culture obtained by transurethral cystoscopy in dogs with chronic lower urinary tract disease: 41 cases (2002 to 2011). AB - OBJECTIVES: To compare aerobic bacterial culture of urine to cystoscopically obtained mucosal biopsies of the lower urinary tract in dogs. METHODS: Retrospective review of case records from dogs that had transurethral cystoscopy at a veterinary teaching hospital between 2002 and 2011. Dogs that had culture results from cystocentesis obtained urine and transurethral cystoscopically obtained mucosal samples were included in the study. Pathogens identified were compared between sampling methods. RESULTS: Forty dogs underwent transurethral cystoscopy for lower urinary tract disease on 41 occasions. There was significant (P = 0 . 0003) agreement between urine and mucosal biopsy cultures. Both cultures were negative in 66% and positive in 17% of dogs. There was a 17% disagreement between the sampling methods. Although not statistically significant, more mucosal samples than urine cultures were positive for Escherichia coli. CLINICAL SIGNIFICANCE: There was a good agreement between pathogen identification from urine and lower urinary tract mucosal cultures. These results do not support the utilisation of transurethral cystoscopy to obtain biopsy samples for culture in dogs with urinary tract infection and positive urine culture. Individual cases with possible chronic urinary tract infection and negative urine culture may benefit from transurethral cystoscopy to obtain biopsies for culture. PMID- 24785941 TI - Stimuli responsive systems constructed using cucurbit[n]uril-type molecular containers. AB - Conspectus This Account focuses on stimuli responsive systems that function in aqueous solution using examples drawn from the work of the Isaacs group using cucurbit[n]uril (CB[n]) molecular containers as key recognition elements. Our entry into the area of stimuli responsive systems began with the preparation of glycoluril derived molecular clips that efficiently distinguish between self and nonself by H-bonds and pi-pi interactions even within complex mixtures and therefore undergo self-sorting. We concluded that the selectivity of a wide variety of H-bonded supramolecular assemblies was higher than previously appreciated and that self-sorting is not exceptional behavior. This lead us to examine self-sorting within the context of CB[n] host-guest chemistry in water. We discovered that CB[n] homologues (CB[7] and CB[8]) display remarkably high binding affinity (Ka up to 10(17) M(-1)) and selectivity (DeltaDeltaG) toward their guests, which renders CB[n]s prime components for the construction of stimuli responsive host-guest systems. The CB[7].adamantaneammonium ion complex, which is particularly privileged (Ka = 4.2 * 10(12) M(-1)), was introduced by us as a stimulus to trigger constitutional changes in multicomponent self-sorting systems. For example, we describe how the free energy associated with the formation of host-guest complexes of CB[n]-type receptors can drive conformational changes of included guests like triazene-arylene foldamers and cationic calix[4]arenes, as well as induced conformational changes (e.g., ammonium guest size dependent homotropic allostery, metal ion triggered folding, and heterochiral dimerization) of the hosts themselves. Many guests display large pKa shifts within their CB[n]-guest complexes, which we used to promote pH controlled guest swapping and thermal trans-to-cis isomerization of azobenzene derivatives. We also used the high affinity and selectivity of CB[7] toward its guests to outcompete an enzyme (bovine carbonic anhydrase) for a two-faced inhibitor, which allowed stimuli responsive regulation of enzymatic activity. These results prompted us to examine the use of CB[n]-type receptors in both in vitro and in vivo biological systems. We demonstrated that adamantaneammonium ion can be used to intracellularly sequester CB[7] from gold nanoparticles passivated with hexanediammonium ion.CB[7] complexes and thereby trigger cytotoxicity. CB[7] derivatives bearing a biotin targeting group enhance the cytotoxicity of encapsulated oxaliplatin toward L1210FR cells. Finally, acyclic CB[n]-type receptors function as solubilizing excipients for insoluble drugs for drug delivery purposes and as a broad spectrum reversal agent for the neuromuscular blocking agents rocuronium, vecuronium, and cis-atracurium in rats. The work highlights the great potential for integration of CB[n]-type receptors with biological systems. PMID- 24785943 TI - Feeling unreal: a functional imaging study in patients with Kleine-Levin syndrome. AB - Kleine-Levin syndrome is characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealization and behavioural disturbances. Between episodes, patients have normal sleep, mood and behaviour. Functional imaging studies performed in small series of patients with Kleine Levin syndrome with visual or semi-quantitative, uncontrolled analysis yielded equivocal brain changes. Using whole brain voxel-based group analysis, we compared brain perfusion scintigraphy during and between episodes in consecutive patients with Kleine-Levin syndrome versus healthy control subjects and correlated perfusion changes with disease severity and symptoms, focusing on less studied but disabling symptoms, such as apathy and derealization. During asymptomatic periods, 41 patients (mean age of 22.3 +/- 8.1 years, 56.1% male) and 15 age- and sex-matched healthy control subjects underwent single-photon emission computed tomography scanning with technetium-99m ethyl cysteinate dimer. Eleven patients repeated the test during a symptomatic period. Compared with controls, patients during asymptomatic periods had persistent hypoperfusion in the hypothalamus, the thalamus (mainly the right posterior part), the caudate nucleus, and cortical associative areas, including the anterior cingulate, (Brodmann area 25), the orbito-frontal (Brodmann area 11) and the right superior temporal cortices (Brodmann area 22), extending to the insula (P < 0.001 in all area). Two additional hypoperfused areas emerged during symptomatic periods (P < 0.001), located in the right dorsomedial prefrontal cortex (Brodmann area 8) and the right parieto-temporal junction (Brodmann areas 22 and 39). These two areas were more affected between episodes, when the mean episode duration was longer (r = -0.53; P < 0.001). The score for the Depersonalization/Derealization Inventory during symptomatic periods strongly correlated with the hypoperfusion of the right (r = -0.74, P < 0.001) and left (r = -0.59, P < 0.005) parieto-temporal junctions. No hyperperfusion was found. Because the parieto-temporal junction (including the angular gyrus) is involved in cross-modal association between somatosensory (body knowledge), auditory and visual information, the robust hypoperfusions and correlations observed in this area may underlie the striking derealization reported by patients during episodes. Defects in the dorsomedial prefrontal cortex may cause apathy. Persistent hypoperfusion in the diencephalic and associative cortical area during asymptomatic periods is a marker of the disease, suggestive of a scenario wherein patients compensate for these deficient circuitries. PMID- 24785944 TI - Effect of chocolate and Propolfenol on rabbit spermatogenesis and sperm quality following bacterial lipopolysaccharide treatment. AB - The aims of the study were to evaluate the effects of chocolate and propolis enriched diets on rabbit spermatogenesis, sperm motility, and ultrastructure following bacterial lipopolysaccharide (LPS) treatment. Thirty-two New Zealand White rabbits were divided into four groups. The LPS-Propolfenol((r)) group received propolis (500 mg/kg/day) in their diet for 15 days, while the LPS chocolate group was fed 70% cacao chocolate (1 g/1 kg/day) for the same period. Following the diet treatments, rabbits in the LPS-Propolfenol((r)) and LPS chocolate groups, and an LPS group received a single intraperitoneal dose of 50 MUg/kg LPS, and the control group received only saline. Kinematic sperm traits were evaluated with a computer assisted sperm analyzer (CASA) system, and ultrastructural characteristics were examined by transmission electron microscopy (TEM). Testicular and epididymal tissues were observed by light microscopy and TEM and multiplex real time reverse transcriptase-polymerase chain reaction (RT PCR) assay was used to detect and quantify toll-like receptor-4 (TLR-4) gene expression. The values of the analyzed semen parameters of rabbits treated with LPS-Propolfenol((r)) and LPS-chocolate did not show any variations compared with the control group, but they were lower in rabbits treated only with LPS. Alterations observed in the testicular tissue of LPS treated-rabbits were not detected in specimens from the LPS-chocolate and LPS-Propolfenol((r)) groups, which showed normal spermatogenesis. The TLR-4 mRNA expression was similar in controls, in LPS treated, and in LPS-chocolate groups, but it was significantly (p < 0.01) decreased in LPS-Propolfenol((r)) rabbits. In conclusion, a chocolate and propolis-enriched diet showed a protective effect on the spermatogenetic process of buck rabbits following LPS treatment. PMID- 24785942 TI - Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation. AB - Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation in TUBB4A, which encodes tubulin beta-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin beta-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients' magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype-phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated with TUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable. PMID- 24785945 TI - The role of mitochondrial aconitate (ACO2) in human sperm motility. AB - Deficiencies in tricarboxylic acid (TCA) cycle enzymes have been shown to cause a wide spectrum of human diseases, including malignancies and neurological and cardiac diseases. In mammalian spermatozoa mitochondria, the TCA cycle is known to be a crucial metabolic pathway that contributes to produce ATP. There is little known about the role and mechanism of mitochondrial aconitase (ACO2), which is an important regulatory enzyme of the TCA cycle, in asthenozoospermia. In the current study, immunofluorescence staining localized ACO2 to the human sperm mid-piece. By immunoblotting, we demonstrated that the level of ACO2 protein in asthenozoospermic samples was significantly decreased compared with that in normal fertile men. Importantly, we first observed that co-incubation of isocitrate with low motile sperm suspensions significantly improved sperm motility, which might be due to elevated intracellular ATP. The improvement of the sperm motility by isocitrate may have important clinical implications in the treatment of asthenozoospermia and certainly warrants further investigation. PMID- 24785946 TI - Fusion and self-assembly of biodegradable polymer particles into scaffoldlike and membranelike structures at room temperature for regenerative medicine. AB - We report here a novel surfactant mediated fusion of polylactide particles into scaffoldlike structures at room temperature. In the presence of ethanol, evenly spread surfactant coated polylactide particles fused immediately into membranelike structures. Polymer scaffolds of the desired shape and size could be fabricated from polylactide particles using this fusion process. Desorption of surfactant molecules from the surface of the particles during ethanol treatment and the degree of solubility of the polymer in alcohol were found to be the main reasons for the fusion of particles into a scaffold at room temperature. TGA and DSC studies of the polylactide particles showed that the particles were stable at room temperature, and FTIR studies showed that there was no change in characteristics of the polymer after the fusion of particles into a scaffold-type structure. These scaffolds supported three-dimensional growth of animal cells in vitro and release model protein in a sustained manner for a long period of time. In an experimental animal wound model, the polylactide membranes showed faster wound closure, indicating its use as a passive dressing material. This polymer particle fusion process thus provides a novel method of scaffold fabrication for various biomedical applications. PMID- 24785947 TI - The malaria parasite egress protease SUB1 is a calcium-dependent redox switch subtilisin. AB - Malaria is caused by a protozoan parasite that replicates within an intraerythrocytic parasitophorous vacuole. Release (egress) of malaria merozoites from the host erythrocyte is a highly regulated and calcium-dependent event that is critical for disease progression. Minutes before egress, an essential parasite serine protease called SUB1 is discharged into the parasitophorous vacuole, where it proteolytically processes a subset of parasite proteins that play indispensable roles in egress and invasion. Here we report the first crystallographic structure of Plasmodium falciparum SUB1 at 2.25 A, in complex with its cognate prodomain. The structure highlights the basis of the calcium dependence of SUB1, as well as its unusual requirement for interactions with substrate residues on both prime and non-prime sides of the scissile bond. Importantly, the structure also reveals the presence of a solvent-exposed redox sensitive disulphide bridge, unique among the subtilisin family, that likely acts as a regulator of protease activity in the parasite. PMID- 24785948 TI - Sequence variations in HIV-1 p24 Gag-derived epitopes can alter binding of KIR2DL2 to HLA-C*03:04 and modulate primary natural killer cell function. AB - OBJECTIVE: The aim of this study was to assess the consequence of sequence variations in HLA-C03:04-presented HIV-1 p24 Gag epitopes on binding of the inhibitory natural killer (NK) cell receptor KIR2DL2 to HLA-C03:04. DESIGN: HIV-1 may possibly evade recognition by KIR+ NK cells through selection of sequence variants that interfere with the interactions of inhibitory killer cell immunoglobulin-like receptors (KIRs) and their target ligands on HIV-1 infected cells. KIR2DL2 is an inhibitory NK cell receptor that binds to a family of HLA-C ligands. Here, we investigated whether HIV-1 encodes for HLA-C03:04-restricted epitopes that alter KIR2DL2 binding. METHODS: Tapasin-deficient 721.220 cells expressing HLA-C03:04 were pulsed with overlapping peptides (10mers overlapped by nine amino acids, spanning the entire HIV-1 p24 Gag sequence) to identify peptides that stabilized HLA-C expression. The impact that sequence variation in HLA-C03:04-binding HIV-1 epitopes has on KIR2DL2 binding and KIR2DL2+ NK cell function was determined using KIR2DL2-Fc constructs and NK cell degranulation assays. RESULTS: Several novel HLA-C03:04 binding epitopes were identified within the HIV-1 p24 Gag consensus sequence. Three of these consensus sequence peptides (Gag144-152, Gag163-171 and Gag295-304) enabled binding of KIR2DL2 to HLA-C03:04 and resulted in inhibition of KIR2DL2+ primary NK cells. Furthermore, naturally occurring minor variants of epitope Gag295-304 enhanced KIR2DL2 binding to HLA C03:04. CONCLUSION: Our data show that naturally occurring sequence variations within HLA-C03:04-restricted HIV-1 p24 Gag epitopes can have a significant impact on the binding of inhibitory KIR receptors and primary NK cell function. PMID- 24785949 TI - Drug resistance among newly diagnosed HIV-infected children in the era of more efficacious antiretroviral prophylaxis. AB - BACKGROUND: In the era of more efficacious prevention of mother-to-child transmission (PMTCT) regimens, documenting the profile of drug resistance in HIV infected infants and young children is critical to our efforts to improve care and treatment for children. METHODS: HIV drug resistance mutations in plasma virus were ascertained using population sequencing among 230 newly diagnosed HIV infected children under 2 years of age recruited in Johannesburg, South Africa, during 2011. By this time, more effective PMTCT regimens, including combination antiretroviral therapy for pregnant women, were being implemented. RESULTS: Two thirds (67.4%) of HIV-infected children had been exposed to some form of maternal (89%) and/or infant (97%) PMTCT. Among PMTCT-exposed, 56.8% had nonnucleoside reverse transcriptase inhibitor (NNRTI), 14.8% nucleoside reverse transcriptase inhibitor (NRTI), and 1.3% protease inhibitor mutations. NNRTI mutations were strongly related to younger age. The remaining third (32.6%) had no reported or recorded PMTCT exposures, but resistance to NNRTI was detected in 24.0%, NRTI in 10.7%, and protease inhibitor in 1.3%. CONCLUSION: The new PMTCT strategies dramatically reduce the number of children who acquire infection, but among those who do become infected, NNRTI resistance prevalence is high. In this South African setting with high PMTCT coverage, almost a quarter of children with no reported or recorded PMTCT also have drug resistance mutations. PMTCT history is an inadequate means of ruling out pretreatment drug resistance. Our results support the use of protease inhibitor-based first-line regimens in HIV-infected infants and young children regardless of PMTCT history. PMID- 24785950 TI - In-utero exposure to maternal HIV infection alters T-cell immune responses to vaccination in HIV-uninfected infants. AB - OBJECTIVE: In sub-Saharan Africa, HIV-exposed uninfected (HEU) infants have higher morbidity and mortality than HIV-unexposed infants. To evaluate whether immune dysfunction contributes to this vulnerability of HEU infants, we conducted a longitudinal, observational cohort study to assess T-cell immune responses to infant vaccines (Mycobacterium bovis BCG and acellular pertussis) and staphylococcal enterotoxin B (SEB). In total, 46 HEU and 46 HIV-unexposed infants were recruited from Khayelitsha, Cape Town. METHODS: Vaccine-specific T-cell proliferation (Ki67 expression) and intracellular expression of four cytokines [interferon-gamma, interleukin (IL)-2, IL-13 and IL-17] were measured after whole blood stimulation with antigens at 6 and 14 weeks of age. RESULTS: HEU infants demonstrated elevated BCG-specific CD4 and CD8 T-cell proliferative responses at 14 weeks (P = 0.041 and 0.002, respectively). These responses were significantly increased even after adjusting for birth weight, feeding mode and gestational age. Similar to BCG, increased CD4 and CD8 T-cell proliferation was evident in response to SEB stimulation (P = 0.004 and 0.002, respectively), although pertussis-specific T cells proliferated comparably between the two groups. Within HEU infants, maternal CD4 cell count and length of antenatal antiretroviral exposure had no effect on T-cell proliferation to BCG or SEB. HIV exposure significantly diminished measurable cytokine polyfunctionality in response to BCG, Bordetella pertussis and SEB stimulation. CONCLUSION: These data show for the first time, when adjusting for confounders, that exposure to HIV in utero is associated with significant alterations to CD4 and CD8T-cell immune responses in infants to vaccines and nonspecific antigens. PMID- 24785951 TI - Pre-exposure prophylaxis for HIV-1 prevention does not diminish the pregnancy prevention effectiveness of hormonal contraception. AB - BACKGROUND: For women at risk of HIV-1, effective contraception and effective HIV 1 prevention are global priorities. METHODOLOGY: In a clinical trial of pre exposure prophylaxis (PrEP) for HIV-1 prevention in HIV-1-serodiscordant couples, we estimated the effectiveness of hormonal contraceptives (oral contraceptive pills, injectable depot medroxyprogesterone acetate, and hormonal implants) for pregnancy prevention relative to no contraception among 1785 HIV-1-uninfected women followed up to 36 months. We compared the effectiveness of each method among women assigned PrEP versus placebo. Contraception was not required for participation, but was offered on-site and was recorded monthly; incident pregnancy was determined by monthly urine testing. RESULTS: For women using no contraception, overall pregnancy incidence was 15.4% per year. Women reporting oral contraceptive use had comparable pregnancy incidence to women using no contraception, and this lack of contraceptive effectiveness was similar for those assigned PrEP and placebo (17.7 and 10.0% incidence per year, respectively; P value for difference in effect by PrEP use = 0.24). Women reporting injectable contraception had reduced pregnancy incidence compared to those reporting no contraception, which did not differ by arm (PrEP 5.1%, placebo 5.3% per year; P value for difference = 0.47). Contraceptive effectiveness was highest among women using implants (pregnancy incidence <1% per year in both arms). CONCLUSION: PrEP had no adverse impact on hormonal contraceptive effectiveness for pregnancy prevention. As seen previously in similar populations, women reporting contraceptive pill use had little protection from pregnancy, possibly due to poor adherence. Injectable or implantable hormonal contraception and PrEP provide effective prevention for pregnancy and HIV-1. PMID- 24785952 TI - Risk of cancer among HIV-infected individuals compared to the background population: impact of smoking and HIV. AB - BACKGROUND: The relative impact of immune deficiency and lifestyle-related factors on risk of cancer in the HIV-infected population is controversial. We aimed to estimate the population-attributable fractions (PAFs) associated with smoking, being HIV-infected and with immune deficiency. METHODS: In a Danish, nationwide, population-based cohort study (1995-2011), incidences of cancer were compared between an HIV-infected cohort and a population-based matched cohort in analyses stratified on cancer category, smoking status and for HIV patients: low CD4 cell count. RESULTS: We included 3503 HIV patients [baseline CD4+ 450 cells/MUl (inter-quartile range 310-630)] and 12,979 population controls. Smoking related and virological cancers accounted for 23 and 43% of cancers in the HIV infected population. The risk of these cancers were higher among HIV patients compared to controls [incidence rate ratio (IRR) 2.8, 95% confidence interval (CI) 1.6-4.9; and IRR 11.5, 95% CI 6.5-20.5], whereas the risk of other cancers did not differ (IRR 1.0, 95% CI 0.7-1.3). Non-smoking HIV patients did not have increased risk of non-virological cancers compared to non-smoking controls (IRR 1.2, 95% CI 0.7-2.1). The PAFs of cancer associated with smoking and with being HIV-infected were 27 and 49%, respectively. For cancers not strongly related to smoking or viral infections, the PAFs associated with being HIV-infected and with immune deficiency were 0%. CONCLUSION: The risk of cancer is increased in HIV patients compared to the background population. In absence of smoking, the increase in risk is confined to cancers related to viral infections, whereas the risk of other cancers is not elevated and does not seem to be associated with immune deficiency. PMID- 24785953 TI - Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies? AB - Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment. PMID- 24785955 TI - The utility of different bioinformatics algorithms for genotypic HIV-1 tropism testing in a large clinical cohort with multiple subtypes. AB - OBJECTIVES: HIV-1 tropism needs to be determined before the use of CCR5 antagonist drugs such as maraviroc (MVC), which are ineffective against CXCR4 using HIV-1. This study assessed how different computational methods for predicting tropism from HIV sequence data performed in a large clinical cohort. The value of adding clinical data to these algorithms was also investigated. DESIGN AND METHODS: PCR amplification and sequence analysis of the HIV-1 gp120 V3 loop region was performed on triple replicates of plasma viral RNA or proviral DNA extracted from peripheral blood monocytes (PBMCs) in 242 patients. Coreceptor usage was predicted from V3 sequences using seven bioinformatics interpretation algorithms, combined with clinical data where appropriate. An intention-to-treat approach was employed for exploring outcomes and performance for different viral subtypes was examined. RESULTS: The frequency of R5 predictions varied by 22.6%, with all seven algorithms agreeing for only 75.3% of tests. The identification of individuals likely to fail was poor for all algorithms. The addition of clinical data improved this, but at the expense of their ability to predict success. The clinical algorithms varied across subtypes, whereas other algorithms were more consistent. Furthermore, individuals with discordant clonal and clinical predictions were more likely to fail MVC treatment. CONCLUSION: Eligibility for MVC varied depending on the algorithm method used. The addition of clinical parameters alongside sequence data may help predict X4 emergence during treatment. It could be that V3 loop analysis in isolation may not be the best method for selecting individuals for MVC. PMID- 24785954 TI - Epidermal nerve fiber density, oxidative stress, and mitochondrial haplogroups in HIV-infected Thais initiating therapy. AB - OBJECTIVE: We explored associations between mitochondrial DNA (mtDNA) haplogroups, epidermal nerve fiber density (ENFD), and HIV-associated sensory neuropathy (HIV-SN) in a randomized trial of Thai patients initiating antiretroviral therapy (ART). DESIGN: The South East Asia Research Collaboration with Hawaii 003 study evaluated toxicity of nucleoside reverse transcriptase inhibitors (stavudine vs. zidovudine vs. tenofovir). We present secondary analyses of mtDNA haplogroups and ENFD changes. METHODS: ENFD, peripheral blood mononuclear cell mitochondrial complex I and IV, and 8-oxo-deoxyguanine (8-oxo dG) were quantified. Peripheral blood mononuclear cell mtDNA sequences were obtained for haplogroup determination. Multivariate regression of ENFD change was performed. RESULTS: Paired ENFD was available from 118 patients. Median age, CD4 cell count, and height at entry were 34 years, 172 cells/MUl, and 162 cm, respectively. Major haplogroups included M (42%), F (21%), and B (16%). Baseline ENFD, CD4 cell count, randomized ART, and biomarkers did not differ by haplogroup. Haplogroup B patients were older (P=0.02) at baseline, and had an increase in median ENFD (+1.5 vs. -2.9 fibers/mm; P=0.03) and 8-oxo-dG break frequency (+0.05 vs. 0.00; P=0.05) compared to other haplogroups. In a multivariate model, haplogroup B was associated with increased ENFD (beta=3.5, P=0.009) at week 24, whereas older age (P=0.02), higher baseline CD4 cell count, (P=0.03), higher complex I level (P=0.03), and higher ENFD (P<0.001) at baseline were all associated with decreased ENFD. Three of the six HIV-SN cases were haplogroup B (P=0.05). CONCLUSIONS: Thai persons belonging to mtDNA haplogroup B had increased ENFD and 8-oxo-dG on ART, and were more likely to develop HIV-SN. These results suggest that mtDNA variation influences early oxidative damage and ENFD changes. PMID- 24785956 TI - Practical guidance for nonoccupational postexposure prophylaxis to prevent HIV infection: an editorial review. AB - Postexposure prophylaxis (PEP) with antiretroviral medication has been used as an HIV-prevention strategy for nearly 20 years. The fact that approximately 50 000 new HIV infections occur in the United States each year reflects marked underutilization of nonoccupational PEP (NPEP). There have been several advances in NPEP in the past 10 years. Clinical trials from different countries have demonstrated better tolerability, completion rates, and fewer drug-drug interactions with newer antiretroviral agents. Notably, there has been a shift from zidovudine-based to tenofovir-based regimens. Three-drug therapy is now favored for all potential HIV exposures. More recently, the US Public Health Service and the New York State Department of Health recommended tenofovir/emtricitabine and raltegravir as the first-line regimen universally for PEP. Advances in HIV testing technology may also allow shorter duration of follow up HIV testing after a high-risk exposure. This review will discuss challenges with previously recommended regimens, newer potential candidate agents and the rationale for using them, intervals for laboratory monitoring, and cost considerations for NPEP. NPEP can be viewed as an educable moment and a potential bridge to preexposure prophylaxis, as part of a combination prevention package, for those who are likely to have recurrent higher-risk exposures. Thus, risk reduction counseling should be an integral aspect of NPEP. PMID- 24785957 TI - Letter to the editor: "Quantifying albumin permeability with multiphoton microscopy: why the difference?". PMID- 24785958 TI - Reply to "Letter to the editor: 'Quantifying albumin permeability with multiphoton microscopy: why the difference?'". PMID- 24785959 TI - Reply to "Letter to the editor: 'Quantifying albumin permeability with multiphoton microscopy: why the difference?'". PMID- 24785960 TI - Evolution of "the guideline advantage": lessons learned from the front lines of outpatient performance measurement. PMID- 24785961 TI - High-density lipoprotein metabolism, composition, function, and deficiency. AB - PURPOSE OF REVIEW: To examine the recent advances in our knowledge of HDL metabolism, composition, function, and coronary heart disease (CHD), as well as marked HDL deficiency states because of mutations in the apolipoprotein (apo) A I, ATP-binding cassette transfer protein A1 and lecithin cholesterol acyltransferase (LCAT) gene loci. RECENT FINDINGS: It has been documented that apoA-I, myeloperoxidase and paraoxonase 1 (PON1) form a complex in HDL that is critical for HDL binding and function. Myeloperoxidase has a negative impact on HDL function, whereas PON1 has a beneficial effect. Patients who lack apoA-I develop markedly premature CHD. Patients who lack ATP-binding cassette transfer protein A1 transporter function have only very small discoidal prebeta-1 HDL, and develop hepatosplenomegaly, intermittent neuropathy and premature CHD, although significant heterogeneity for these disorders has been reported. Patients with LCAT deficiency have abnormal small discoidal LDLs and HDL particles, and develop kidney failure. Enzyme replacement therapy is being developed for the latter disorder. SUMMARY: Recent data indicates that proteins other than apoA-I and apoA II such as MPO and PON1 have important effects on HDL function. There has been considerable recent progress made in our understanding of HDL protein content and function. PMID- 24785962 TI - Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans. AB - PURPOSE OF REVIEW: Different sources of fatty acids (FA) used for VLDL triglyceride synthesis include dietary FA that clear to the liver via chylomicron uptake, FA synthesized de novo in the liver from carbohydrates, nonesterified fatty acids derived from adipose tissue, nonesterified fatty acids derived from the spillover of chylomicron-triglyceride in the fasted and fed states, and FA stored in liver lipid droplets. RECENT FINDINGS: Data have amassed on the contributions of each of these sources to liver-triglyceride accrual, VLDL triglyceride synthesis, and hypertriglyceridemia. Discussed here is the timing of use of FA from each of these sources for synthesis of VLDL-triglyceride. Secondly, as all of these FA sources have been shown to contribute significantly to nonalcoholic fatty liver disease (NAFLD), data are presented demonstrating how poor handling of FA and glucose in the periphery can contribute to NAFLD. Lastly, we highlight how the stress of excess FA availability on the liver can be corrected by reduction of dietary intake of sugars and fats, weight loss, and increased physical activity. SUMMARY: A better understanding of how lifestyle factors improve FA flux will aid in the development of improved treatments for the devastating condition of NAFLD. PMID- 24785963 TI - Editorial introduction. PMID- 24785964 TI - Multiple scattering of polarized light: influence of absorption. AB - This work continues previous research about multiple scattering of polarized light propagation in turbid media, putting emphasis on the imaginary part of the scatterers' complex refractive index. The whole angle-dependent Muller matrix is evaluated by comparing results of a polarization sensitive radiative transfer solution to Maxwell theory. Turbid media of defined scatterer concentrations are modelled in three dimensions by sphere ensembles kept inside a cubic or spherical simulation volume. This study addresses the impact of absorption on polarization characteristics for selected media from low to high absorption. Besides that, effects caused by multiple and dependent scattering are shown for increasing volume concentration. In this context some unique properties associated with multiple scattering and absorption are pointed out. Further, scattering results in two dimensions are compared for examples of infinite parallel cylinders of high absorption and perpendicularly incident plane waves. PMID- 24785965 TI - Thymol attenuates allergic airway inflammation in ovalbumin (OVA)-induced mouse asthma. AB - Thymol, a naturally occurring monocyclic phenolic compound derived from Thymus vulgaris (Lamiaceae), has been reported to exhibit anti-inflammatory property in vivo and vitro. However, the mechanism of thymol is not clear. The aim of the present study was to investigate the effects of thymol on allergic inflammation in OVA-induced mice asthma and explore its mechanism. The model of mouse asthma was established by the induction of OVA. Thymol was orally administered at a dose of 4, 8, and 16 mg/kg body weight 1h before OVA challenge. At 24h after the last challenge, mice were sacrificed, and the data were collected by various experimental methods. The results revealed that pretreatment with thymol reduced the level of OVA-specific IgE, inhibited recruitment of inflammatory cells into airway, and decreased the levels of IL-4, IL-5, and IL-13 in BALF. Moreover, the pathologic changes of lung tissues were obviously ameliorated and goblet cell hyperplasia was effectively inhibited by the pretreatment of thymol. In addition, thymol reduced the development of airway hyperresponsiveness and blocked the activation of NF-kappaB pathway. All data suggested that thymol ameliorated airway inflammation in OVA-induced mouse asthma, possibly through inhibiting NF kappaB activation. These findings indicated that thymol may be used as an alternative agent for treating allergic asthma. PMID- 24785966 TI - Gomisin N isolated from Schisandra chinensis augments pentobarbital-induced sleep behaviors through the modification of the serotonergic and GABAergic system. AB - The fruits of Schisandra chinensis have been used for the treatment of insomnia in oriental countries for more than thousands of years. However, the pharmacological properties and the mechanism of sedative and hypnotic effects have not yet been studied. Gomisin N is one of the major bioactive constituents from the fruits of Schisandra chinensis, and in this paper we reported a detailed study on the effects and mechanisms of Gomisin N on its sedative and hypnotic activity for the first time. These results implied that Gomisin N possessed weak sedative effects on locomotion activity in normal mice, and produced a dose dependent(5-45 mg/kg, i.p.) increase in sleep duration in pentobarbital-treated mice, thus, itself did not induce sleep at higher dose which was used in this experiment (45 mg/kg, i.p.). It also can reverse the rodent models of insomnia induced by p-chlorophenylalanine (PCPA) and caffeine, which could exhibit a synergistic effect with 5-hydroxytryptophan (5-HTP) as well; furthermore, the hypnotic effects of Gomisin N were inhibited by flumazenil (a specific GABAA-BZD receptor antagonist). Altogether, these results indicated that Gomisin N produced beneficial sedative and hypnotic bioactivity, which might be mediated by the modification of the serotonergic and GABAergic system. PMID- 24785967 TI - Complementary and alternative medicine for Duchenne and Becker muscular dystrophies: characteristics of users and caregivers. AB - BACKGROUND: Complementary and alternative medicine is frequently used in the management of chronic pediatric diseases, but little is known about its use by those with Duchenne or Becker muscular dystrophy. METHODS: Complementary and alternative medicine use by male patients with Duchenne or Becker muscular dystrophy and associations with characteristics of male patients and their caregivers were examined through interviews with 362 primary caregivers identified from the Muscular Dystrophy Surveillance, Tracking, and Research Network. RESULTS: Overall, 272 of the 362 (75.1%) primary caregivers reported that they had used any complementary and alternative medicine for the oldest Muscular Dystrophy Surveillance, Tracking, and Research Network male in their family. The most commonly reported therapies were from the mind-body medicine domain (61.0%) followed by those from the biologically based practice (39.2%), manipulative and body-based practice (29.3%), and whole medical system (6.9%) domains. Aquatherapy, prayer and/or blessing, special diet, and massage were the most frequently used therapies. Compared with nonusers, male patients who used any therapy were more likely to have an early onset of symptoms and use a wheel chair; their caregivers were more likely to be non-Hispanic white. Among domains, associations were observed with caregiver education and family income (mind-body medicines [excluding prayer and/or blessing only] and whole medical systems) and Muscular Dystrophy Surveillance, Tracking, and Research Network site (biologically based practices and mind-body medicines [excluding prayer and/or blessing only]). CONCLUSIONS: Complementary and alternative medicine use was common in the management of Duchenne and Becker muscular dystrophies among Muscular Dystrophy Surveillance, Tracking, and Research Network males. This widespread use suggests further study to evaluate the efficacy of integrating complementary and alternative medicine into treatment regimens for Duchenne and Becker muscular dystrophies. PMID- 24785968 TI - Treatment of craniocervical instability using a posterior-only approach: report of 3 cases. AB - The object of this study was to demonstrate that a posterior-only approach for craniocervical junction pathology is feasible with intraoperative reduction. The authors reviewed 3 cases of craniocervical instability. All patients had craniocervical instability according to radiological imaging and various methods of measurement, with results outside the normal range. Posterior instrumentation aided the intraoperative reduction techniques while maintaining structural integrity and the desired fusion construct. No anterior approach was necessary in any of the patients. Neurological symptoms resolved in two patients and significantly improved in another. Follow-up imaging demonstrated stable constructs. There are many approaches to anterior cervical pathology at the craniocervical junction. Posterior instrumented reduction and stabilization of the occipitocervical spine can be safely achieved, obviating the need for a transoral approach in the setting of craniocervical junction settling. PMID- 24785969 TI - Cervical facet fractures. PMID- 24785970 TI - Medical management. PMID- 24785971 TI - Axis fractures. PMID- 24785972 TI - Spindle cell hemangioendothelioma of the sacrum: case report. AB - Spindle cell hemangioendothelioma is a rare benign vascular tumor that is not known to involve the sacrum. The authors describe the case of a 31-year-old woman presenting with low-back and radicular pain without weakness or bowel or bladder dysfunction. Admission CT and MRI studies revealed a large S1-3 lytic sacral lesion. The patient initially underwent a nondiagnostic percutaneous biopsy. She subsequently underwent an open biopsy, during which the lesion was found to be highly vascular. Histological investigation revealed a vasoformative lesion consistent with spindle cell hemangioendothelioma. Preoperative embolization followed by resection via intralesional currettage resulted in resolution of symptoms up to 9 months postintervention. Despite the authors' recommendation, the patient became pregnant at that time and requested no additional follow-up imaging. The authors present the first reported case of a spindle cell hemangioendothelioma of the sacrum and review the current literature. PMID- 24785973 TI - Two-year comprehensive medical management of degenerative lumbar spine disease (lumbar spondylolisthesis, stenosis, or disc herniation): a value analysis of cost, pain, disability, and quality of life: clinical article. AB - OBJECT: Current health care reform calls for a reduction of procedures and treatments that are less effective, more costly, and of little value (high cost/low quality). The authors assessed the 2-year cost and effectiveness of comprehensive medical management for lumbar spondylolisthesis, stenosis, and herniation by utilizing a prospective single-center multidisciplinary spine center registry in a real-world practice setting. METHODS: Analysis was performed on a prospective longitudinal quality of life spine registry. Patients with lumbar spondylolisthesis (n = 50), stenosis (n = 50), and disc herniation (n = 50) who had symptoms persisting after 6 weeks of medical management and who were eligible for surgical treatment were entered into a prospective registry after deciding on nonsurgical treatment. In all cases, comprehensive medical management included spinal steroid injections, physical therapy, muscle relaxants, antiinflammatory medication, and narcotic oral agents. Two-year patient-reported outcomes, back-related medical resource utilization, and occupational work-day losses were prospectively collected and used to calculate Medicare fee-based direct and indirect costs from the payer and societal perspectives. The maximum health gain associated with medical management was defined as the improvement in pain, disability, and quality of life experienced after 2 years of medical treatment or at the time a patient decided to cross over to surgery. RESULTS: The maximum health gain in back pain, leg pain, disability, quality of life, depression, and general health state did not achieve statistical significance by 2 years of medical management, except for pain and disability in patients with disc herniation and back pain in patients with lumbar stenosis. Eighteen patients (36%) with spondylolisthesis, 11 (22%) with stenosis, and 17 (34%) with disc herniation eventually required surgical management due to lack of improvement. The 2-year improvement did not achieve a minimum clinically important difference in any outcome measure. The mean 2-year total cost (direct plus indirect) of medical management was $6606 for spondylolisthesis, $7747 for stenosis, and $7097 for herniation. CONCLUSIONS: In an institution-wide, prospective, longitudinal quality of life registry that measures cost and effectiveness of all spine care provided, comprehensive medical management did not result in sustained improvement in pain, disability, or quality of life for patients with surgically eligible degenerative lumbar spondylolisthesis, stenosis, or disc herniation. From both the societal and payer perspective, continued medical management of patients with these lumbar pathologies in whom 6 weeks of conservative therapy failed was of minimal value given its lack of health utility and effectiveness and its health care costs. The findings from this real-world practice setting may more accurately reflect the true value and effectiveness of nonoperative care in surgically eligible patient populations. PMID- 24785974 TI - A novel screw guiding method with a screw guide template system for posterior C-2 fixation: clinical article. AB - OBJECT: Accurate insertion of C-2 cervical screws is imperative; however, the procedures for C-2 screw insertion are technically demanding and challenging, especially in cases of C-2 vertebral abnormality. The purpose of this study is to report the effectiveness of the tailor-made screw guide template (SGT) system for placement of C-2 screws, including in cases with abnormalities. METHODS: Twenty three patients who underwent posterior spinal fusion surgery with C-2 cervical screw insertion using the SGT system were included. The preoperative bone image on CT was analyzed using multiplanar imaging software. The trajectory and depth of the screws were designed based on these images, and transparent templates with screw guiding cylinders were created for each lamina. During the operation, after templates were engaged directly to the laminae, drilling, tapping, and screwing were performed through the templates. The authors placed 26 pedicle screws, 12 pars screws, 6 laminar screws, and 4 C1-2 transarticular screws using the SGT system. To assess the accuracy of the screw track under this system, the deviation of the screw axis from the preplanned trajectory was evaluated on postoperative CT and was classified as follows: Class 1 (accurate), a screw axis deviation less than 2 mm from the planned trajectory; Class 2 (inaccurate), 2 mm or more but less than 4 mm; and Class 3 (deviated), 4 mm or more. In addition, to assess the safety of the screw insertion, malpositioning of the screws was also evaluated using the following grading system: Grade 0 (containing), a screw is completely within the wall of the bone structure; Grade 1 (exposure), a screw perforates the wall of the bone structure but more than 50% of the screw diameter remains within the bone; Grade 2 (perforation), a screw perforates the bone structures and more than 50% of the screw diameter is outside the pedicle; and Grade 3 (penetration), a screw perforates completely outside the bone structure. RESULTS: In total, 47 (97.9%) of 48 screws were classified into Class 1 and Grade 0, whereas 1 laminar screw was classified as Class 3 and Grade 2. Mean screw deviations were 0.36 mm in the axial plane (range 0.0-3.8 mm) and 0.30 mm in the sagittal plane (range 0.0-0.8 mm). CONCLUSIONS: This study demonstrates that the SGT system provided extremely accurate C-2 cervical screw insertion without configuration of reference points, high-dose radiation from intraoperative 3D navigation, or any registration or probing error evoked by changes in spinal alignment during surgery. A multistep screw placement technique and reliable screw guide cylinders were the key to accurate screw placement using the SGT system. PMID- 24785975 TI - Combined effect of hyperuricemia and overweight/obesity on the prevalence of hypertension among US adults: result from the National Health and Nutrition Examination Survey. AB - Hypertension is a large and growing public health problem worldwide. Hyperuricemia and overweight/obesity are two of the most important risk factors for hypertension. However, their combined effect on the risk of hypertension is not known. Participants aged 20 years and older from the National Health and Nutrition Examination Survey from 1999-2012 were used to evaluate the separate and combined effects of hyperuricemia and overweight/obesity on the risk of prevalent hypertension among different race, gender and age groups. Participants (31,473) were used to estimate separate and combined effects on the prevalence of hypertension. The overall prevalence of hypertension among adults with a combination of hyperuricemia and overweight/obesity (50.2%, 95% confidence interval (CI) 48.3-52.1%) was significantly higher than separate hyperuricemia (41.7%, 95% CI 37.2-46.2%) and overweight/obesity (30.6%, 95% CI 29.5-31.8%). The magnitude of odds ratio (OR) from the combination of hyperuricemia and overweight/obesity (OR=4.53, 95% CI 4.05-5.07) was significantly higher than both hyperuricemia (OR=2.62, 95% CI 2.07-3.32) and overweight/obesity (OR=2.08, 95% CI 1.89-2.30). Combined effect of hyperuricemia and overweight/obesity on the risk of hypertension is much stronger than any separate one. These data can provide important information for identification of target populations for future intervention and patient management. PMID- 24785977 TI - Subconjunctival epidermoid cysts in Gorlin-Goltz syndrome. AB - Epidermoid cysts are common benign cysts which occur particularly on the skin of the face, neck and upper trunk. Subconjunctival location of these cysts is very rare and, until today, only seen in patients with Gorlin-Goltz syndrome. Histopathological examination of these cysts show similarities with odontogenic keratocysts, a typical clinical manifestation of Gorlin-Goltz syndrome. PMID- 24785976 TI - Reduction of plasma aldosterone and arterial stiffness in obese pre- and stage1 hypertensive subjects after aerobic exercise. AB - Obesity-related hypertension is associated with increased activity of the renin angiotensin-aldosterone system (RAAS), increasing arterial stiffness. Aerobic exercise decreases pulse wave velocity (PWV), therefore a treatment option for hypertension and obesity. Assess RAAS activity and PWV before and after 4 weeks of aerobic training in unmedicated, pre-to-stage-1 hypertensives. Ten obese subjects (52+/-3.2 years, body mass index=33.5+/-1.4) performed 30 min of aerobic exercise on a treadmill 3 days per week at 65% of peak oxygen consumption (VO2peak). Descriptive characteristics, systolic and diastolic blood pressure (SBP and DBP), PWV, and a blood draw was performed at baseline, following the 4 week control and training interventions. No differences in descriptive characteristics during the control period were observed, however, a significant decrease in plasma aldosterone (ALDO) (255.4+/-75 to 215.8+/-66 pg ml(-1), P=0.001), SBP (140+/-12 to 136+/-10.4 mm Hg; P=0.02), DBP (89+/-4.2 to 85+/-6.3 mm Hg; P=0.03) and central PWV (11.2+/-0.6 to 9.8+/-0.8 m s(-1); P=0.04) was shown pre-to-post exercise training. Four weeks of moderate-intensity aerobic training in obese, hypertensives decreases plasma ALDO independently of body weight and is significantly correlated to decreases in PWV reductions. PMID- 24785978 TI - Persistent lipid abnormalities in patients with hypertension and dyslipidemia treated with statins: results of the Portuguese hypertensive subpopulation of the Dyslipidemia International Study (DYSIS). AB - This study aimed to assess the treatment patterns and prevalence of persistent lipid abnormalities in Portuguese hypertensive patients concomitantly treated with statins. Only 25% of the 656 hypertensive patients achieved the blood pressure goals in use during the study period. Similarly, only 33% and 37% attained the recommended levels of total cholesterol<4.5 mmol/L and LDL cholesterol<2.5 mmol/L, respectively. Relatively low doses of medium potency statins were the mainstay of therapy. There seems to be considerable room for improvement through the use of more potent statins, dose up-titration, and/or addition of other lipid-modifying therapies. PMID- 24785979 TI - Optimization of small-molecule inhibitors of influenza virus polymerase: from thiophene-3-carboxamide to polyamido scaffolds. AB - Influenza virus infections represent a serious concern to public health, being characterized by high morbidity and significant mortality. To date, compounds targeting the viral ion-channel M2 or the viral neuraminidase are the drugs available for treatment of influenza, but the emergence of drug-resistant viral mutants renders the search for novel targets and their possible inhibitors a major priority. Recently, we demonstrated that the viral RNA-dependent RNA polymerase (RdRP) complex can be an optimal target of protein-protein disruption by small molecules, with thiophene-3-carboxamide derivatives emerging as promising candidates for the development of new anti-influenza drugs with broad spectrum activity. Here, we report a further dissection of the thiophene-3 carboxamide structure. By using a GRID molecular interaction field (MIF)-based scaffold-hopping approach, more potent and nontoxic polyamido derivatives were identified, highlighting a new space in the chemical variability of RdRP inhibitors. Finally, a possible pharmacophoric model highlighting the key features required for RdRP inhibition is proposed. PMID- 24785980 TI - Disparities in mental health care provision to immigrants with severe mental illness in Italy. AB - AIM: To determine whether disparities exist in mental health care provision to immigrants and Italian citizens with severe mental illness in Bologna, Italy. METHODS: Records of prevalent cases on 31/12/2010 with severe mental illness and >=1 contact with Community Mental Health Centers in 2011 were extracted from the mental health information system. Logistic and Poisson regressions were carried out to estimate the probability of receiving rehabilitation, residential or inpatient care, the intensity of outpatient treatments and the duration of hospitalisations and residential care for immigrant patients compared to Italians, adjusting for demographic and clinical covariates. RESULTS: The study population included 8602 Italian and 388 immigrant patients. Immigrants were significantly younger, more likely to be married and living with people other than their original family and had a shorter duration of contact with mental health services. The percentages of patients receiving psychosocial rehabilitation, admitted to hospital wards or to residential facilities were similar between Italians and immigrants. The number of interventions was higher for Italians. Admissions to acute wards or residential facilities were significantly longer for Italians. Moreover, immigrants received significantly more group rehabilitation interventions, while more social support individual interventions were provided to Italians. CONCLUSIONS: The probability of receiving any mental health intervention is similar between immigrants and Italians, but the number of interventions and the duration of admissions are lower for immigrants. Data from mental health information system should be integrated with qualitative data on unmet needs from the immigrants' perspective to inform mental health care programmes and policies. PMID- 24785981 TI - Visual discrimination of phenolic group beta2-agonists and the ultrasensitive identification of their oxidation products by use of a tyrosinase-based catalytic reaction. AB - The fast, visual discrimination of beta2-agonist drugs is needed for the on-site screening of various types of beta2-agonists in blood and urine samples. We developed a simple, rapid, one-step colorimetric method to detect phenolic beta2 agonists by use of a tyrosinase catalytic reaction, which involved the oxidation of the phenol group on the benzene rings of beta2-agonists. The enzymatic oxidation products of beta2-agonists with phenolic groups exhibited different color transitions based on the different substituent groups on the aromatic ring, whereas beta2-agonists with the aniline group or the resorcinol group remained colorless. This visual color discrepancy has been used to intuitively and conveniently differentiate the phenolic group beta2-agonists, such as ractopamine, isoxsuprine, ritodrine, and fenoterol. The oxidation products of these compounds have been identified using mass spectrometry, and the possible reaction mechanisms between beta2-agonists and tyrosinase have been deduced. The parameters that govern the analytical performance of the reaction product, including the pH of the buffer solution, the concentration of tyrosinase, and the incubation time, have been studied and optimized using ultraviolet-visible (UV vis) spectroscopy and electrochemical methods. Under the optimal experimental conditions, the absorbance intensity and electrochemical signal were found to increase proportionally to the concentrations of the phenolic group beta2 agonists, which gave a quantitative description of the beta2-agonists in solution. PMID- 24785982 TI - Potentially preventable deaths from the five leading causes of death--United States, 2008-2010. AB - In 2010, the top five causes of death in the United States were 1) diseases of the heart, 2) cancer, 3) chronic lower respiratory diseases, 4) cerebrovascular diseases (stroke), and 5) unintentional injuries. The rates of death from each cause vary greatly across the 50 states and the District of Columbia (2). An understanding of state differences in death rates for the leading causes might help state health officials establish disease prevention goals, priorities, and strategies. States with lower death rates can be used as benchmarks for setting achievable goals and calculating the number of deaths that might be prevented in states with higher rates. To determine the number of premature annual deaths for the five leading causes of death that potentially could be prevented ("potentially preventable deaths"), CDC analyzed National Vital Statistics System mortality data from 2008-2010. The number of annual potentially preventable deaths per state before age 80 years was determined by comparing the number of expected deaths (based on average death rates for the three states with the lowest rates for each cause) with the number of observed deaths. The results of this analysis indicate that, when considered separately, 91,757 deaths from diseases of the heart, 84,443 from cancer, 28,831 from chronic lower respiratory diseases, 16,973 from cerebrovascular diseases (stroke), and 36,836 from unintentional injuries potentially could be prevented each year. In addition, states in the Southeast had the highest number of potentially preventable deaths for each of the five leading causes. The findings provide disease-specific targets that states can use to measure their progress in preventing the leading causes of deaths in their populations. PMID- 24785983 TI - Outbreak of campylobacteriosis associated with a long-distance obstacle adventure race--Nevada, October 2012. AB - On October 12, 2012, the Nellis Air Force Base Public Health Flight (Nellis Public Health), near Las Vegas, Nevada, was notified by the Mike O'Callaghan Federal Medical Center (MOFMC) emergency department (ED) of three active-duty military patients who went to the ED during October 10-12 with fever, vomiting, and hemorrhagic diarrhea. Initial interviews by clinical staff members indicated that all three patients had participated October 6-7 in a long-distance obstacle adventure race on a cattle ranch in Beatty, Nevada, in which competitors frequently fell face first into mud or had their heads submerged in surface water. An investigation by Nellis Public Health, coordinated with local and state health officials, identified 22 cases (18 probable and four confirmed) of Campylobacter coli infection among active-duty service members and civilians. A case-control study using data provided by patients and healthy persons who also had participated in the race showed a statistically significant association between inadvertent swallowing of muddy surface water during the race and Campylobacter infection (odds ratio = 19.4; p<0.001). Public health agencies and adventure race organizers should consider informing race attendees of the hazards of inadvertent ingestion of surface water. PMID- 24785984 TI - Falls and fall injuries among adults with arthritis--United States, 2012. AB - Falls are the leading cause of injury-related morbidity and mortality among older adults, with more than one in three older adults falling each year, resulting in direct medical costs of nearly $30 billion. Some of the major consequences of falls among older adults are hip fractures, brain injuries, decline in functional abilities, and reductions in social and physical activities. Although the burden of falls among older adults is well-documented, research suggests that falls and fall injuries are also common among middle-aged adults. One risk factor for falling is poor neuromuscular function (i.e., gait speed and balance), which is common among persons with arthritis. In the United States, the prevalence of arthritis is highest among middle-aged adults (aged 45-64 years) (30.2%) and older adults (aged >=65 years) (49.7%), and these populations account for 52% of U.S. adults. Moreover, arthritis is the most common cause of disability. To examine the prevalence of falls among middle-aged and older adults with arthritis in different states/territories, CDC analyzed data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS) to assess the state-specific prevalence of having fallen and having experienced a fall injury in the past 12 months among adults aged >=45 years with and without doctor-diagnosed arthritis. This report summarizes the results of that analysis, which found that for all 50 states and the District of Columbia (DC), the prevalence of any fall (one or more), two or more falls, and fall injuries in the past 12 months was significantly higher among adults with arthritis compared with those without arthritis. The prevalence of falls and fall injuries is high among adults with arthritis but can be addressed through greater dissemination of arthritis management and fall prevention programs in clinical and community practice. PMID- 24785985 TI - Notes from the field: Investigation of infectious disease risks associated with a nontransplant anatomical donation center--Arizona, 2014. AB - CDC is investigating reports of potential occupational exposure to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Mycobacterium tuberculosis among workers performing preparation and dissection procedures on human nontransplant anatomical materials at a nontransplant anatomical donation center in Arizona. CDC is working with Arizona public health officials to inform persons exposed to these potentially infected materials. Nontransplant anatomical centers around the United States process thousands of donated cadavers annually. These materials (which might be fresh, frozen, or chemically preserved) are used by universities and surgical instrument and pharmaceutical companies for medical education and research. The American Association of Tissue Banks has developed accreditation policies for nontransplant anatomical donation organizations. It also has written standards that specify exclusion criteria for donor material, as well as use of proper environmental controls and safe work practices to prevent transmission of infectious agents during receipt and handling of nontransplant anatomical materials. At the center under investigation, which is now closed, these standards might not have been consistently implemented. PMID- 24785986 TI - A population-based analysis of contemporary rates of reoperation for penile prosthesis procedures. AB - OBJECTIVE: To perform a population-based comparison of inflatable vs semirigid penile prostheses and to determine contemporary rates of reoperation and identify factors impacting the type of prosthetic implanted. METHODS: Patient-level discharge data and revisit files from the Agency for Healthcare Research and Quality for semirigid and inflatable prosthesis procedures performed for erectile dysfunction from 2006 to 2009 in the state of California were examined. Regression analysis was performed to determine differences between the procedures in terms of infectious and noninfectious failure. Regression analysis was performed to identify factors associated with revision and to identify associations between potential risk factors and the type of implant performed. RESULTS: A total of 2263 cases were included in the study (1824 inflatable and 439 semirigid). The overall reoperation rate was 7.42%. There was no difference in the overall revision rate between the 2 groups (7.52% semirigid and 7.40% inflatable; P=.94). The reoperation rate secondary to infectious complications was 3.6% (4.5% semirigid vs 3.23% inflatable; P=.18). The revision rate secondary to noninfectious failure was 2.96% in the semirigid vs 4.17% in the inflatable group (P=.25). Medicaid insurance (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.41-3.61), African American race (OR, 1.7; 95% CI, 1.20-2.49), age>80 (P=.046), and diabetes (OR, 1.67; 95% CI, 1.07-2.59) were associated with receiving a semirigid implant. CONCLUSION: Reoperation rates for infectious and noninfectious failure are equivalent between the semirigid and inflatable penile prostheses. Sociodemographic factors appear to significantly influence the type of prosthesis a patient receives. PMID- 24785987 TI - The impact of multiparametric pelvic magnetic resonance imaging on risk stratification in patients with localized prostate cancer. AB - OBJECTIVE: To determine the impact of multiparametric magnetic resonance imaging (MP-MRI) of the prostate on established risk stratification criteria in patients with clinically localized adenocarcinoma of the prostate (ACP). METHODS: The cohort included 71 patients who underwent MP-MRI of the prostate at a tertiary care referral center as part of their initial workup for ACP. Tumor characteristics comprising traditional risk stratification criteria (prostate specific antigen, clinical T stage, and biopsy Gleason score) were recorded, and the initial National Comprehensive Cancer Network risk group was calculated. The National Comprehensive Cancer Network risk group was then recalculated incorporating MRI findings. The impact of MRI findings on changes in risk group classification was evaluated using the Stuart-Maxwell test. For patients undergoing radical prostatectomy, MRI findings were correlated with pathologic findings. RESULTS: The cohort included 11 (15.5%), 39 (54.9%), and 21 patients (29.6%) with low-, intermediate-, and high-risk disease, respectively. MRI findings led to risk group upstaging in 12 cases (16.9%). The highest yield was demonstrated in patients with intermediate-risk disease, in whom MRI led to upstaging in 25.6% of patients. There was a significant difference between pre MRI and post-MRI risk group classifications (P<.01) for the entire cohort. Compared with radical prostatectomy specimens, the specificity of MRI for T3 disease was 92.9%. CONCLUSION: In our cohort of patients undergoing MP-MRI for previously untreated, clinically localized ACP, MRI findings led to changes in risk stratification in a substantial proportion of patients. Our findings support the use of MP-MRI in the workup of patients with localized ACP. PMID- 24785988 TI - Urethral sphincter fatigue after robot-assisted radical prostatectomy: descriptive questionnaire-based study and anatomic basis. AB - OBJECTIVE: To investigate the hypothesis that preservation of the neurovascular bundle (NVB) contributes to the recovery from sphincter fatigue symptoms after robot-assisted radical prostatectomy (RARP) and to examine the sarcolemmal localization of neuronal nitric oxide synthase (nNOS) and nNOS-positive nerves supplying striated muscles in the pelvic floor. METHODS: Whether preservation of the NVB influences early continence or sphincter fatigue symptoms was examined in 211 consecutive patients undergoing RARP. Continence and sphincter fatigue symptoms were assessed at 1, 3, and 6 months after surgery. An anatomic study was performed using semiserial sections obtained from 14 male cadavers. The association of continence rate and sphincter fatigue symptoms with preservation of the NVB was assessed by the chi-square test. RESULTS: There was a significant difference across the bilateral, unilateral, and non-nerve-sparing groups with regard to sphincter fatigue symptoms at 1 month (P=.0004) and 3 months (P=.0326) postoperatively. Sarcolemmal nNOS was detected in the rhabdosphincter (mean, 0.57 per 10 muscle fibers) and levator ani (mean, 1.13 per 10 fibers), with fibers originating from periprostatic nNOS-positive nerves. CONCLUSION: Postoperative sphincter fatigue was reduced by NVB preservation, suggesting that decreased sphincter fatigue may contribute to improvement of continence after RARP. As a background, existence of sarcolemmal nNOS and nNOS-positive nerve terminals arising from the NVB was confirmed in male pelvic floor striated muscles. PMID- 24785989 TI - Solifenacin is able to improve the irritative symptoms after transurethral resection of bladder tumors. AB - OBJECTIVE: To evaluate the efficacy and safety of solifenacin in the management of irritative symptoms after transurethral resection of bladder tumors (TURBTs) with subsequent intravesical chemotherapy. METHODS: A total of 116 patients undergoing TURBT were randomly allocated into 2 groups, 58 patients in each group. Group 1 patients received solifenacin 5 mg, 6 hours before surgery and 5 mg per day, after surgery for 2 weeks, whereas group 2 patients received a placebo. Patients with low-risk non-muscle-invasive bladder cancer received immediate postoperative instillation of epirubicin. Patients with medium- or high risk non-muscle-invasive bladder cancer received postoperative instillation twice within 2 weeks, once immediately following the operation and once on the eighth postoperative day. All patients completed bladder diaries before surgery, on the 1st, 7th, and 14th days after removal of the catheter with overactive bladder symptom scores completed preoperatively, and on the 7th and 14th days. Additionally, the incidence and severity of catheter-related bladder discomfort were recorded at 6, 12, 24, 48, and 72 hours after the surgery. RESULTS: The incidence and the severity of catheter-related bladder discomfort in group 1, compared with group 2, were significantly reduced (P<.05). There was a significant difference in overactive bladder symptom scores between the 2 groups (5.67 vs 7.86; P<.001). Episodes of daytime, frequency, nocturia, urgency, and urge urinary incontinence in group 1 were also significantly lower than in group 2 (P<.05). CONCLUSION: This study demonstrates that solifenacin can be beneficial for the management of irritative symptoms after TURBT with subsequent intravesical chemotherapy. PMID- 24785990 TI - The impact of flood and post-flood cleaning on airborne microbiological and particle contamination in residential houses. AB - In January 2011, Brisbane, Australia, experienced a major river flooding event. We aimed to investigate its effects on air quality and assess the role of prompt cleaning activities in reducing the airborne exposure risk. A comprehensive, multi-parameter indoor and outdoor measurement campaign was conducted in 41 residential houses, 2 and 6 months after the flood. The median indoor air concentrations of supermicrometer particle number (PN), PM10, fungi and bacteria 2 months after the flood were comparable to those previously measured in Brisbane. These were 2.88 p cm(-3), 15 MUg m(-3), 804 cf um(-3) and 177 cf um(-3) for flood-affected houses (AFH), and 2.74 p cm(-3), 15 MUg m(-3), 547 cf um(-3) and 167 cf um(-3) for non-affected houses (NFH), respectively. The I/O (indoor/outdoor) ratios of these pollutants were 1.08, 1.38, 0.74 and 1.76 for AFH and 1.03, 1.32, 0.83 and 2.17 for NFH, respectively. The average of total elements (together with transition metals) in indoor dust was 2296 +/- 1328 MUg m(-2) for AFH and 1454 +/- 678 MUg m(-2) for NFH, respectively. In general, the differences between AFH and NFH were not statistically significant, implying the absence of a measureable effect on air quality from the flood. We postulate that this was due to the very swift and effective cleaning of the flooded houses by 60,000 volunteers. Among the various cleaning methods, the use of both detergent and bleach was the most efficient at controlling indoor bacteria. All cleaning methods were equally effective for indoor fungi. This study provides quantitative evidence of the significant impact of immediate post-flood cleaning on mitigating the effects of flooding on indoor bioaerosol contamination and other pollutants. PMID- 24785991 TI - Copy number variation is a fundamental aspect of the placental genome. AB - Discovery of lineage-specific somatic copy number variation (CNV) in mammals has led to debate over whether CNVs are mutations that propagate disease or whether they are a normal, and even essential, aspect of cell biology. We show that 1,000 N polyploid trophoblast giant cells (TGCs) of the mouse placenta contain 47 regions, totaling 138 Megabases, where genomic copies are underrepresented (UR). UR domains originate from a subset of late-replicating heterochromatic regions containing gene deserts and genes involved in cell adhesion and neurogenesis. While lineage-specific CNVs have been identified in mammalian cells, classically in the immune system where V(D)J recombination occurs, we demonstrate that CNVs form during gestation in the placenta by an underreplication mechanism, not by recombination nor deletion. Our results reveal that large scale CNVs are a normal feature of the mammalian placental genome, which are regulated systematically during embryogenesis and are propagated by a mechanism of underreplication. PMID- 24785993 TI - Control of neglected tropical diseases in Burundi: partnerships, achievements, challenges, and lessons learned after four years of programme implementation. PMID- 24785994 TI - Disclosure, consent, and the exercise of patient autonomy in surgical innovation: a systematic content analysis of the conceptual literature. AB - The classification of surgical innovation as clinical care, research, or as third distinct type of activity creates ambiguity which impacts standards for disclosure and informed consent. We conducted a systematic review of the conceptual literature to identify positions expressed about consent and disclosure, as well as major tension points associated with this issue. Literature overwhelmingly favors special consent and disclosure. Four major tension points were identified: the use of biasing/biased terminology to characterize innovation; patient vulnerability; the relationship between surgeon innovator and patient; and practices and associated gaps related to consent and disclosure. Recommendations often focused on the informed consent process. PMID- 24785995 TI - The challenges for scientists in avoiding plagiarism. AB - Although it might seem to be a simple task for scientists to avoid plagiarism and thereby an allegation of research misconduct, assessment of trainees in the Responsible Conduct of Research and recent findings from the National Science Foundation Office of Inspector General regarding plagiarism suggests otherwise. Our experiences at a land-grant academic institution in assisting researchers in avoiding plagiarism are described. We provide evidence from a university-wide multi-disciplinary course that understanding how to avoid plagiarism in scientific writing is more difficult than it might appear, and that a failure to learn the rules of appropriate citation may cause dire consequences. We suggest that new strategies to provide training in avoiding plagiarism are required. PMID- 24785996 TI - Medical dominance within research ethics committees. AB - Qualitative research is reported which explores the perceptions of members of the U.K.'s independent Phase I ethics committees (IECs) about key issues identified following a literature review. Audio-recorded interviews were conducted with ten expert and ten lay members from all IECs except the one to which the lead author was attached. Transcripts were thematically analyzed following a broadly hermeneutical approach. The findings-dealing with such matters as recruitment strategies and length of service; attitudes towards member categories, published ethics guidelines, and the adequacy of insurance; levels of training and views on achieving a recognised level of competence-have an intrinsic interest, but it is when the findings are considered collectively using Freidson's theory of professional dominance that they reveal the influence the medical profession can have in shaping ethics review. PMID- 24785997 TI - Blood money: Bayer's inventory of HIV-contaminated blood products and third world hemophiliacs. AB - This article presents an overlooked case of research misconduct and violations of basic principles of medical and business ethics. When Bayer's Cutter Laboratories realized that their blood products, Factor VIII and IX or antihemophiliac factor (AHF), were contaminated with human immunodeficiency virus (HIV), the financial investment in the product was considered too high to destroy the inventory. Cutter misrepresented the results of its own research and sold the contaminated AHF to overseas markets in Asia and Latin America without the precaution of heat treating the product recommended for eliminating the risk. As a consequence, hemophiliacs who infused the HIV-contaminated Factor VIII and IX tested positive for HIV and developed AIDS. PMID- 24785998 TI - Letter to the editor: medical school, research misconduct policies, and procedures. PMID- 24786001 TI - In 2008, in recognition of the steady increase in surveillance papers being submitted to Food Additives and Contaminants, a decision was taken to split the journal into Parts A and B. PMID- 24786002 TI - Synthetic colourings of some snack foods consumed by primary school children aged 8-9 years in Hong Kong. AB - An HPLC method with photodiode array detection was used for the quantification of 11 synthetic dyes in 87 snack food products commonly consumed by children in Hong Kong, China. Dietary exposure to synthetic colours was estimated using food frequency questionnaire data obtained from 142 primary school children aged 8-9 years in three districts of Hong Kong. Dietary exposure to synthetic colours for an average primary school student was considerably lower than the threshold for acceptable daily intake (ADI) for their ages, except for sunset yellow FCF. Data obtained showed that the average daily intake of sunset yellow FCF (E110) was 51% over the ADI threshold in 9-year-old boys. The higher intakes of sunset yellow FCF were mainly due to the high consumption of soft drinks and desserts such as jellies, which have high concentrations of this synthetic colour additive. PMID- 24786000 TI - Margination of micro- and nano-particles in blood flow and its effect on drug delivery. AB - Drug delivery by micro- and nano-carriers enables controlled transport of pharmaceuticals to targeted sites. Even though carrier fabrication has made much progress recently, the delivery including controlled particle distribution and adhesion within the body remains a great challenge. The adhesion of carriers is strongly affected by their margination properties (migration toward walls) in the microvasculature. To investigate margination characteristics of carriers of different shapes and sizes and to elucidate the relevant physical mechanisms, we employ mesoscopic hydrodynamic simulations of blood flow. Particle margination is studied for a wide range of hematocrit values, vessel sizes, and flow rates, using two- and three-dimensional models. The simulations show that the margination properties of particles improve with increasing carrier size. Spherical particles yield slightly better margination than ellipsoidal carriers; however, ellipsoidal particles exhibit a slower rotational dynamics near a wall favoring their adhesion. In conclusion, micron-sized ellipsoidal particles are favorable for drug delivery in comparison with sub-micron spherical particles. PMID- 24786003 TI - Mycotoxin occurrence in commodities, feeds and feed ingredients sourced in the Middle East and Africa. AB - Between February and October 2009, 324 grain, feed and feed commodity samples were sourced directly at animal farms or feed production sites in Middle East and Africa and tested for the presence of A- and B-trichothecenes, zearalenone, fumonisins, aflatoxins and ochratoxin A, or for selected groups of mycotoxins only. Samples were analyzed after clean-up by immunoaffinity or solid-phase extraction followed by HPLC with derivatization where appropriate and fluorescence, UV or mass spectrometric detection. The percentage of positive samples of B-trichothecenes ranged from 0 to 87% of tested samples. The prevalence of fumonisins in the different countries was >50% in most cases. Zearalenone was present in tested commodities from all countries except three. The presence of aflatoxin in analyzed samples varied from 0 to 94%. Ochratoxin A was present in 67% of samples in Sudan and in 100% of Nigerian samples. No A trichothecenes were found in this survey. PMID- 24786004 TI - Cadmium concentrations in the liver of 10 different pig genetic lines from Vojvodina, Serbia. AB - Cadmium concentrations were determined in 480 liver samples from 10 different pig genetic lines produced in Vojvodina (Serbia). Cadmium levels were determined by flame atomic absorption spectrometry after mineralization by dry ashing. The difference in cadmium levels in analysed liver tissues was not significant (p > 0.05) between the various genetic lines. However, large variations in cadmium levels (from 0.03 to 0.27 mg/kg) in liver tissues indicated its availability in the local agricultural environment in Vojvodina. The average level of cadmium (0.13 mg/kg) was higher than the levels reported in pork liver from some developed countries. PMID- 24786005 TI - Survey on the occurrence of aflatoxins in rice from different provinces of Iran. AB - Aflatoxins were surveyed in 256 rice samples taken from retail markets in different provinces of Iran during October 2007 and July 2008. A methanol/water (80 : 20, v/v) mixture and an aflatoxin immunoaffinity column (IAC) were used for extraction and clean-up. Mycotoxins were determined using HPLC with fluorescence detection and post-column derivatization using a photo-ionization cell. Levels of contamination ranged 0.0-5.8 ng g(-1) (mean, 1.4 ng g(-1)) and 0.1-6.3 ng g(-1) (mean, 1.6 ng g(-1)) for AFB1 and total aflatoxins, respectively. AFB1 was detected in almost all samples. Results showed that 55 samples (21.5%) were contaminated with more than 2 ug kg(-1) of AFB1, while seven samples (2.7 %) contained more than 4 ug kg(-1) total aflatoxins. The calculated probable daily intake of AFB1 from rice for Iranians ranged 1.4-5.8 ng AFB1 per kg body weight per day for average consumers and, hence. exceeding the estimated provisional maximum tolerable daily intake. PMID- 24786006 TI - Survey of aflatoxin M1 in cow's milk for human consumption in Kerman Province of Iran. AB - The aim of this study was to assess levels of aflatoxin M1 (AFM1) in milk samples from Kerman, Iran. AFM1 was detected in 72 samples, ranging in concentration from <0.01 to 0.41 ug l(-1). The samples were analyzed using immunoaffinity column for clean-up and HPLC for determining AFM1. Milk samples were collected from six dairy farms. AFM1 was found in ~ 50% of the milk samples. The average level of AFM1 was below the tolerance limit (0.05 ug l(-1)), but 50% of the samples had greater levels than the maximum tolerance limit accepted by EU and the Iranian national standard. The method detection limit and limit of quantification were 0.01 and 0.03 ug l(-1), respectively, and recovery of the method was 87%. The results showed that AFM1 contamination is a serious problem for public health. To achieve a low level of AFM1 in milk, cattle feed must be monitored regularly for aflatoxin contamination and protected from fungal contamination as much as possible. PMID- 24786007 TI - Ethyl carbamate in fermented foods and beverages: dietary exposure of the Hong Kong population in 2007-2008. AB - To evaluate the potential public health risk of ethyl carbamate (EC), EC exposure from fermented foods and beverages for Hong Kong population was estimated. In 276 samples analysed, EC was detected (limit of detection (LOD) at 0.4 ug kg(-1)) in 202 samples (73%), with higher levels in fermented red bean curd (150-650 ug kg( 1)) and yellow wine (140-390 ug kg(-1)), while low or non-detected (ND) in preserved vegetables (ND-10 ug kg(-1)) and fermented tea (ND-15 ug kg(-1)). The estimated dietary exposure from all fermented foods and beverages was 8.27 ng kg( 1) bw day(-1), while exposure excluding alcoholic beverages was 5.42 ng kg(-1) bw day(-1), with calculated margins of exposure (MOEs) at 3.6 * 10(4) and 5.5 * 10(4) respectively. The risk of adverse health effects was low for the average population but higher (MOE of 10(3)) for high consumers of alcoholic beverages especially habitual drinkers of alcoholic types with high EC contents. PMID- 24786008 TI - Deoxynivalenol contamination in Tunisian barley in the 2009 harvest. AB - In Tunisia, barley is commonly used in human consumption in a variety of food forms. In this regard, a high quality of this agricultural product is always demanded by consumers. A survey of the natural occurrence of deoxynivalenol (DON), the most common Fusarium mycotoxin in small grain cereals, in barley harvested in the main cropping regions in Northern Tunisia in the 2009 harvest was conducted. A total of 72 samples were analysed for DON using high-performance liquid chromatography (HPLC) with a UV visible detector set at 220 nm. Between 36% and 100% of the samples were positive for DON with averages ranging from 1.2 to 2.4 mg kg(-1). A positive correlation between DON levels and temperature was seen; on the other side no correlation between DON contents and rainfall was observed. In this study we notably showed the effect of regions on DON contamination. PMID- 24786009 TI - Mercury and selenium content of Taiwanese seafood. AB - Fish consumption is avid in Taiwan (and other Asian nations), but little is known about the mercury and selenium content in local seafood. This paper reports on total mercury, methylmercury and selenium levels from 14 commonly consumed seafood items obtained from Taichung, Taiwan. Mean total mercury concentrations varied nearly 100-fold across species. Fifty per cent of the marlins sampled and 35% of the sharks exceeded the 0.3 ug g(-1) US Environmental Protection Agency (USEPA) guideline. Methylmercury comprised a majority of the total mercury in all species. In all species studied there was a molar excess of selenium over mercury. The rank order of mean selenium-mercury molar ratios was red tilapia (166.8) > abura (87.9) > river prawn (82.4) > whiteleg shrimp (64.2) > butterfish (44.6) > milkfish (37.0) > tuna (15.6) > grouper (13.9) > ayu (13.4) > coral hind (13.0) > weever (11.8) > saury (9.0) > shark (7.8) > marlin (4.2). PMID- 24786010 TI - Occurrence and infant exposure assessment of nitrates in baby foods marketed in the region of Lisbon, Portugal. AB - Commercial baby food labelled as from organic or conventional origin, including vegetable-based baby foods, fruit purees and fruit juices (n = 80), were analysed for nitrate content by an in-house validated HPLC method. Nitrate contents ranged from 5 to 230 mg kg(-1) with a mean concentration of 102 mg kg(-1) for vegetable based baby foods, and a median of 5 mg kg(-1) for both fruit purees and juices. One sample of vegetable-based baby food was higher than the legislated value (200 mg kg(-1)). There were no significant differences between average nitrate levels in analysed samples regarding both farming systems. The estimated nitrate intake through baby foods for a mean nitrate concentration of 47 mg kg(-1) ranged between 0.5 (15% of ADI) and 1.3 mg kg(-1) bw day(-1) (35% of ADI). The ADI level was exceeded (107-146% of ADI) only for the 95th and 99th percentiles of nitrate concentration. PMID- 24786011 TI - Survey of sulfites in wine and various Turkish food and food products intended for export, 2007-2010. AB - Surveys were carried out between 2007 and 2010 to determine the total levels of sulfites in 1245 samples of wines, dried apricots, dried vegetables, nuts, juices and purees, frozen foods and cereals containing dried fruit supplied by food inspectors and by food producers for testing or for export certification. Sulfite analysis of wine was carried out using the Ripper method with an LOQ of 5 mg l( 1) and for dried and other foods the Monier-Williams distillation procedure was employed with an LOQ of 10 mg kg(-1). In the survey all wines contained measurable sulfites, but with the exception of one sample of white wine they were otherwise below Turkish Food Codex limits of 160 mg kg(-1) for red wine, 210 mg kg(-1) to white wine and 235 mg kg(-1) for sparkling wine. None of the cereal products, frozen foods, juices or purees contained sulfites above 10 mg kg(-1). However, all dried apricot samples contained significant levels of sulfite with around 40% having levels exceeding the Turkish limit of 2000 mg kg(-1). Significant levels of sulfite were found in other samples of dried fruit with even a fruit and nut bar containing 1395 mg kg(-1) of sulfite, suggesting the dried fruit ingredients contained levels above regulatory limits. PMID- 24786012 TI - The expression of virulence for a mixed-mode transmitted parasite in a diapausing host. AB - Many parasites survive harsh periods together with their hosts. Without the possibility of horizontal transmission during host diapause, parasite persistence depends entirely on host survival. We therefore hypothesize that a parasite should be avirulent during its host's diapausing stage. In contrast, the parasite may express higher virulence, i.e. parasite-induced fitness reduction of the host, during host life stages with good opportunities for horizontal transmission. Here we study the effects of a vertically and horizontally transmitted microsporidium parasite, Hamiltosporidium tvaerminnensis, on the quantity and survival of resting eggs of its host Daphnia magna. We find that the parasite did not affect egg volume, hatching success and time to hatching of the Daphnia's resting eggs, although it did strongly reduce the number of resting eggs produced by infected females, revealing high virulence during the non diapause phase of the host's life cycle. These results also explain another aspect of this system - namely the strong decline in natural population prevalence across diapause. This decline is not caused by mortality in infected resting stages, as was previously hypothesized, but because infected female hosts produce lower rates of resting eggs. Together, these results help explain the epidemiological dynamics of a microsporidian disease and highlight the adaptive nature of life stage-dependent parasite virulence. PMID- 24786013 TI - Pharmacokinetics of a new orally soluble film formulation of sildenafil administered without water. AB - OBJECTIVE: To compare the pharmacokinetic profiles and to assess bioequivalence of a newly developed orally soluble film formulation of sildenafil, taken without water, with those of a conventional formulation of sildenafil. METHODS: This study was conducted in a population of healthy subjects as an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to 1 of 2 sequences of the two formulations: an orally soluble film (OSF) of 50 mg sildenafil as the test drug and a film coated tablet (FCT) of 50 mg sildenafil as the reference drug. Blood samples were collected at intervals from 0 to 24 hours after administration. Plasma concentrations of sildenafil and its active metabolite N-desmethyl sildenafil were analyzed using a liquid chromatography/tandem mass spectrometry method. RESULTS: 48 healthy male subjects completed the study. The geometric mean (CV%) for Cmax in the OSF and FCT formulations were 267.21 (4.68%) ng/mL and 285.97 (5.32%) ng/mL, respectively. The geometric mean for AUClast in the OSF and FCT formulations were 664.48 (4.40%) ng x h/mL and 647.96 (4.63%) ng x h/mL, respectively. The geometric mean for AUCinf in the OSF and FCT formulations were 685.65 (4.37%) ng x h/mL and 666.28 (4.60%) ng x h/ mL, respectively. The 90% confidence intervals of the ratios of the geometric means of the Cmax, AUClast, and AUCinf were 0.844 - 1.030, 0.961 - 1.091, and 0.965 - 1.093, respectively. CONCLUSIONS: The OSF sildenafil formulation exhibited no significant differences in its pharmacokinetics compared with those of the FCT formulation. Therefore this convenient OSF sildenafil formulation, which can be taken without the need for water or chewing, offers physicians a novel and attractive treatment option for men with erectile dysfunction. *These authors contributed equally to this work. PMID- 24786014 TI - In-depth investigation for prescribing trends of benzodiazepines in South Korea. AB - This study aimed to investigate national prescription trends of benzodiazepines (BZD) for adults between 2007 and 2011 using Health Insurance Review and Assessment Service (HIRA) database in South Korea. Data analysis was performed by claim unit or patient unit. For the analysis of patient unit, each claim was merged by the same patient. Defined daily dose (DDD) was used to analyze the data in terms of dose and periods of BZD prescription. We identified a total of 22,361,449 adult patients who had BZD prescription at least once in 1,989,263 claims during 5 years. The average national BZD prescription prevalence for 1 year was 23.7%, 7.9%, 4.7%, and 3.2% of >= 1 day supply, >= 30 days supply, >= 90 days supply, and >= 180 days supply, respectively. The trends for 5 years were very similar. Among study population, 87.7% visited only non-psychiatric departments and the most frequent indication was gastrointestinal related diseases. BZD consumption expressed as DDDs per 1,000 inhabitants per day was 109.2. BZD consumption tended to be ~ 4 x higher in elderly than that of non elderly (268.6 vs. 60.0 in male and 367.7 vs. 90.9 in female). Our study indicated the possibilities for inappropriate prescription of BZD, and the limitation policy on continuous prescription over 30 days supply did not seem to be effective. The effective interventions including an educational program for appropriate prescription of BZD should be considered. PMID- 24786015 TI - Assessing patient satisfaction with medication related services in hospital settings: a cross-sectional questionnaire survey in China. AB - OBJECTIVE: There are few prior studies on patient satisfaction with medication related services and the potential value of measurements of patient satisfaction to the development of pharmaceutical care service (PCS) strategies in China. The objectives of the current study were to assess patient satisfaction with medication-related services in Chinese tertiary hospitals, examine the possible impact of PCS on patient satisfaction, and form a development strategy to establish PCS strategy prioritization. METHODS: Self administered questionnaires were distributed to 540 patients before discharge from units in 18 tertiary general hospitals in six cities. The participants assessed their satisfaction with the hospital's medication-related services based on a 7-point Likert-type scale. A comparative analysis between PCS and non-PCS pilot hospitals was conducted to evaluate the impact of PCS on patient satisfaction. RESULTS: 501 valid questionnaires were collected: 247 samples from PCS pilot hospitals (PCS group) and 254 from non-PCS pilot hospitals (non-PCS group). Factor analysis resulted in three factors (dimensions): "consideration and explanation", "discharge instruction", and "efficacy and finance". The "efficacy and finance" scores indicated relative satisfaction with this dimension (mean = 5.63 +/- 1.36). However, the items "medication costs" and "other medical costs" were the lowest scored attributes (means = 4.98 +/- 1.62 and 4.95 +/- 1.63), indicating that most of the participants were dissatisfied with these financial attributes. The median score in the "consideration and explanation" dimension in the PCS group was 6.27, in comparison with 5.81 in the non-PCS group. This statistically significant difference (p < 0.01) demonstrates that the major impact of PCS on patient satisfaction is observed in the "consideration and explanation" dimension. CONCLUSIONS: This study revealed low patient satisfaction with the financial aspects of medication-related services, which must be improved to provide better inpatient hospital service. The clinical effectiveness of medication therapy at these 18 tertiary hospitals could meet patients' expectations, but PCS did not increase the level of patient satisfaction in the "efficacy and finance" dimension. Future PCS strategy in China should focus on improving the clinical and economic outcomes of medication-related services. PMID- 24786016 TI - Population pharmacokinetics of rhTNFR-Fc in Chinese patients with rheumatic arthritis. AB - OBJECTIVE: We aimed to investigate the population pharmacokinetics (PK) of soluble recombinant human tumor necrosis factor receptor fusion protein (rhTNFR- Fc) in Chinese patients with rheumatic arthritis (RA). The PK differences between Chinese patients with RA and healthy Chinese subjects were also compared. METHODS: 40 patients were randomized to a single subcutaneous (SC) injections of 12.5 mg (n = 10), 25 mg (n = 10), and 50 mg (n = 10) of rhTNFR-Fc, and six SC injection of rhTNFR- Fc at 25 mg once in 3 days (n = 10) respectively. A total of 550 serum concentration data points were collected in the RA patients. The population PK analysis was performed by NONMEM. Based on the population PK parameters obtained herein and those reported in healthy Chinese subjects, simulation was conducted to compare the difference of rhTNFR-Fc exposure between these populations. RESULTS: The PK data of Chinese patients with RA were best described by a one compartment model with lag time. A higher CL/F was noted in RA patients compared with that of the healthy Chinese subjects (1.64 L/h vs. 1.10 L/h), and a lower Ka was noticed in the RA patients compared with that of the healthy subjects (0.0317 h-1 vs. 0.0605 h-1). The simulate results showed that rhTNFR-Fc exposure in Chinese patients with RA was significantly lower than that in healthy subjects. The mean patients/healthy subjects C(max) and AUC(ss) ratios were 0.870 and 0.890, respectively. CONCLUSIONS: A population PK model of rhTNFR- Fc was developed in Chinese patients with RA. Statistical difference was noted in the PK of rhTNFR-Fc between Chinese patients with RA and healthy Chinese subjects. PMID- 24786017 TI - Pharmacokinetics and bioequivalence of sildenafil granules and sildenafil tablets in Korean healthy volunteers. AB - BACKGROUND: A sildenafil tablet formulation as a PDE-5 inhibitor is widely used for the treatment of erectile dysfunction. Recently, a fine granular formulation of sildenafil was developed by a domestic Korean pharmaceutical company. OBJECTIVES: This study was performed to compare the bioavailability of sildenafil fine granules with that of sildenafil tablets for assessing bioequivalence in 40 healthy male volunteers. METHODS: This was an open-label, randomized sequence, single-dose, two-period, and two-treatment crossover study. Half of the volunteers received a single dose of sildenafil fine granule 50 mg and then sildenafil tablet 50 mg after a 7-day washout period. The remaining half of volunteers received the tablet first and the the granule with the same washout period. 10- mL blood samples were serially sampled to measure the concentrations of sildenafil and the N-desmethyl metabolite. Tolerability was assessed during the study. RESULTS: The pharmacokinetic parameters of sildenafil were similar between granular and tablet formulations. The 90% CI of geometric mean ratios (sildenafil granule/tablet) for the pharmacokinetic parameters of sildenafil were within 0.8 a?? 1.25, as a bioequivalent acceptable range; 1.111 (90% CI, 1.002 - 1.231) for maximum plasma concentration (Cmax) and 1.092 (1.019 - 1.117) for area under the concentration- time curve from time zero to time of last measurable concentration (AUClast). Also, the 90% CI of geometric mean ratios for Cmax and AUClast of the metabolite were within 0.8 - 1.25. Both formulations were well tolerated by volunteers. CONCLUSION: This study confirmed that sildenafil granules and sildenafil tablet are bioequivalent with regards to pharmacokinetics of sildenafil and N-desmethyl sildenafil. PMID- 24786018 TI - Population genetics of the black scar oyster, Crassostrea iredalei: repercussion of anthropogenic interference. AB - Mitochondrial cytochrome oxidase subunit I (COI) gene was utilized to assess the population genetics of the commercially important black scar oyster, Crassostrea iredalei among 11 populations throughout the west and east coasts Peninsular Malaysia and Sabah (Malaysian Borneo). Overall, populations of C. iredalei demonstrated low nucleotide diversity pi (0.000-0.004) and low-to-high haplotype diversity h (0.000-0.795) levels. Genetic structuring was detected between the Peninsular Malaysia and Sabah populations as revealed by the FST analysis. However, the COI gene analyses showed minimal and non-significant (p > 0.05) population differentiation within the east and west coasts Peninsular Malaysia and Sabah regions. This was attributed to both high larval dispersal along the east and west coasts and human-driven spat translocation between the two coastlines due to C. iredalei cultivation practices. Phylogeographic relationships inferences were also conducted to further support these hypotheses. The neutrality and mismatch distribution analyses suggested that C. iredalei had experienced a/several bottleneck event(s), followed by population expansion. The molecular information obtained from this study could be incorporated in a pragmatic aquaculture management strategy of wild broodstock and the hatchery lines of C. iredalei in Malaysia. PMID- 24786019 TI - Introduction. PMID- 24786020 TI - The polyamory quilt. AB - SUMMARY A patchwork quilt of panels made by friends is the metaphor for the lessons of life, love and polyamory of the author. She discusses intimacy, jealousy, friendship, and honesty in the context of monogamy and polyamory. She also offers hope for lesbians to have continuing connections based on deep, lasting unconditional love. PMID- 24786021 TI - If this is tuesday, it must be dee ... confessions of a closet polyamorist. AB - SUMMARY The author discusses the evolution of non-monogamy in a 24-year lesbian relationship. The couple's initial agreement stipulated that outside liasions be concealed as much as possible. More recently, the couple has established a complex system for incorporating other paramours into their lives. PMID- 24786022 TI - Lesbians as luvbeins. AB - SUMMARY Lesbians who do not follow the imperative of monogamous, live-in lovers with one other woman are seen as traitors, heretics, and generally fallen women. In a community that often demands conformity, we must find language that includes other ways of being. Thus the idea that luvbeins (a new word that means any or all or more of the following: those that love being, love lesbians, a play on the language for lesbian, a sexual loving woman loving) can become a permutation of the word so that sexually innovative lesbians have another way of communication about themselves. The real fear is always am I loved, am I lovable, can I love? PMID- 24786023 TI - Patriarchal monogamy. AB - SUMMARY The equating of sex, sin and death in Patriarchal Judeo-Christian religions continues to affect the social and moral consciousness of Western societies. The concepts of the impure body, the inferiority of women, importance of monogamy and marriage, and the negative ideas of sexuality have been so absorbed into all cultures that their origins as mainstays of patriarchal religions have been obscured, and these ideas have become accepted as the natural phenomenon of human relationships. Lesbians, already out of the mainstream of heterosexual life, still structure their own lives around these archaic and restrictive codes. PMID- 24786024 TI - Turning down the jezebel decibels. AB - SUMMARY According to conventional wisdom, many breakups are due to "the other woman" -the home wrecker who comes between perfectly contented lesbian partners. In this excerpt from The Lesbian Love Companion: How to Survive Everything from Heartthrob to Heartbreak, author Hall explores the fresh ways we might retell the traditional "other woman" tale. Also included in this excerpt are the benefits that accrue to monogamous and polyamorous lesbians who learn to tell such alternative stories. PMID- 24786025 TI - Poly wants a lover. AB - SUMMARY Taking a humorous approach to the question of polyamo-ry, this article recalls the author's first and only brush with the concept. After exploring several real-life complications that might arise when polyamory is put into practice, the essay then acknowledges some practical benefits of the multi partnered lifestyle. PMID- 24786026 TI - Poly-friendships. AB - SUMMARY In contrast to the monogamous model for sexual relationships (including those of lesbians) in western society, friendships are permitted to be polyamorous. However, friendships do not receive the level of salience and priority that sexual relationships do. This article focuses on three issues that keep lesbians from prioritizing friendships: (1) the culture of sex in the U.S. and western nations; (2) the way we define "sex"; and (3) the way we define friendships. PMID- 24786027 TI - Seven poems for three. AB - SUMMARY These poems describe the evolution of a polyamorous relationship among three women over a period of a year and a half. The original couple had been together five years and was ready to explore a more complex family structure as a powerful alternative to the heterosexual nuclear family model. PMID- 24786028 TI - Addressee unknown. AB - SUMMARY In addition to furthering our knowledge and filling out resumes, academic conferences play an important role in the social lives of gay men and lesbians, providing many with unique opportunity to meet fellow queers in our fields. In a satirical spoof of the presumed bed-swapping that transpires at such meetings, "Addressee Unknown" is the correspondence-letters both mailed and those, more wisely, never posted-of Estelle, a collector of lesbian academics. PMID- 24786029 TI - Bad friend book. AB - SUMMARY This piece was written for a one-woman performance in San Francisco. The theme of the show was "mean and nasty," and this piece focuses, with humor and without mercy, on the less enticing aspects of lesbian polyamorous relationships. PMID- 24786030 TI - The spontaneous imaginative life. AB - SUMMARY From an interweaving of the journal entries of four dykes involved in a polyamorous network, a picture of the day-to-day complexities of polyamory emerges. Relationship to family and community, jealousy, shame and acceptance of self are some of the issues dealt with in this narrative. The story unfolds in a rural community in British Columbia, Canada, where they all live. This piece is an excerpt from a longer, ongoing work. PMID- 24786031 TI - Matriarchal village. AB - SUMMARY This story of a gypsy-dyke first experiencing polyamory is set in the 1970s in an Oregon college town, where radical feminists considered non-monogamy an important way to strengthen lesbian tribal bonds. Personal struggles with jealousy and community support for rejecting coupleism are captured in this piece. PMID- 24786032 TI - A Boomer's View of Non-Monogamy. AB - SUMMARY Recent generations of lesbians have been freer than ever to invent our own culture, including relationship models. My own experiments with relationships have prompted a new definition of poly-amory which has more associations with community than with sex. PMID- 24786033 TI - Impossible body. AB - SUMMARY This play tells the story of one woman coming to terms with her "poly" identity through a journey into the multiple layers of love, race, sex, appearance and Otherness. The one-woman show Impossible Body was first performed for a reading series sponsored by "Onstage" at the University of Colorado, Boulder, in February 1997. A revised version was developed and staged at the University of Puget Sound in Tacoma, Washington in April 1997. The current script, from which these excerpts are taken, was first presented at the Queer Studies Conference in Boulder, Colorado. PMID- 24786034 TI - Paradigms of polyamory. AB - SUMMARY The paradigm theory of Thomas Kuhn is used as a framework to discuss alternative ways of intimacy. The author discusses the implications of structuring actual lesbian relationships by a paradigm of monogamy among Latin American women. The author proposes that creating alternative paradigms of multiple relationships would be useful for many lesbians as models for alternative life patterns. PMID- 24786035 TI - If Love Is So Wonderful, What's So Scary About MORE? AB - SUMMARY Attaching oneself to a single lifelong partner in a sexually and emotionally exclusive, all-fulfilling relationship is the romantic goal for many women in our culture. However, monogamous relationships of this sort provide no guarantee for either permanence or bliss. As many women are beginning to explore polyamorous relating, fears arise about loss of love if a primary partner wishes to love others. When lesbians and bisexual women open their relationships, fears that a bisexual women will abandon her lesbian lover for a man may evoke old fears of a competition that cannot be won. PMID- 24786036 TI - A long journey towards polyamorous bliss. AB - SUMMARY The author describes how her life has evolved over two decades from lesbian coupling which mirrored a traditional heterosexual marriage, to increasingly unconventional styles of relating. An open primary relationship was the first step away from monogamy, followed by stages of casual sex with multiple partners, a long-distance bi-coast-al romance, being the "other woman" to someone with a primary partner, and finally, seeking multiple committed relationships. The question of how to maintain privacy while sharing honest communication is a theme throughout these different involvements. PMID- 24786037 TI - Kitaka's Experiment or Why I Started the Ecstasy Lounge. AB - SUMMARY The owner of Ecstasy Lounge describes her lesbian sex club that operated in San Francisco in 1991 through 1996. She tells how her philosophy and desires led her to start the business, and how the sexual habits of lesbians and bisexual women were influenced by the existence of this club. PMID- 24786038 TI - ("Denny's Tune") I'm Not Monogamous Anymore, But .... AB - SUMMARY Just months after declaring herself non-monogamous, the author falls in love and finds herself wanting only one woman. Her song "Denny's Tune" playfully contrasts philosophical convictions with heartfelt desire. PMID- 24786039 TI - Dinah, sam, beth, and jolyn say. AB - SUMMARY As lesbians interact with one another, we relate in a variety of ways through different degrees of intimacy and involvement. Finding and living the way that's right for each of us can be difficult. Lesbians can be judgmental, and the sexual aspects of relating seem to eclipse all other forms in importance, intensity, and the degrees of social ramifications and judgmental responses. This article discusses the experiences of several lesbians in the diverse ways they do their intimate relationships. PMID- 24786040 TI - Gays to Marry? Let's Not! AB - SUMMARY In the midst of the current publicity about gay marriages, a contrarian viewpoint is presented. Marriage is seen as a legal construct of the state to further its aims of sexism and capitalism. Marriage has lost any connection it may have had to spiritual or emotional bonding. The notion of pair-bonding for life as natural is also disputed. From these perspectives, gays and lesbians and polyamorous types are encouraged to fight for the abolition of marriage, rather than for inclusion in the privileged group allowed by the state to marry. PMID- 24786041 TI - Canary in the coal mine. AB - SUMMARY The author explains that lesbians' failure to "succeed" at coupling should be seen as a warning to all of humanity that the institution of marriage is not a viable relationship model. PMID- 24786042 TI - Safer sex and the polyamorous lesbian. AB - SUMMARY In recent years, concern about transmission of AIDS and other STDs has prompted people of all sexual orientations to use various safer sex techniques. This article explains why monogamy is not necessarily any safer than polyamory. Research on the low risk of woman-to-woman transmission of HIV and other STDs is described. PMID- 24786043 TI - Models of open relationships. AB - SUMMARY This article describes three categories of open relationships: the primary/secondary model, the multiple primary partners model, and the multiple non-primary relationships model. Examples of each type are given, and the advantages and drawbacks of each model are discussed. PMID- 24786044 TI - The flexible house. AB - SUMMARY "The Flexible House: A Fairy Tale" is a fictionalized account of a long term lesbian relationship, which uses the metaphor of building a house for the development of the relationship. The narrator invites a mysterious third woman into their home, and then must live with the aftershocks the house goes through. PMID- 24786046 TI - Foreword. PMID- 24786048 TI - The power of curiosity. PMID- 24786047 TI - The pro-inflammatory potential of microparticles in red blood cell units. AB - BACKGROUND: Microparticles (MPs) are submicron size cell fragments that are released from cells. OBJECTIVES: We hypothesise that MPs increase during red blood cell (RBC) storage and are part of the pro-inflammatory activity, which accumulates in the RBC supernatant. METHODS/MATERIALS: RBC units were separated from whole blood of eight healthy donors: 5 U were split, with 50% undergoing leucoreduction (LR) and the remaining left as unmodified controls. The remaining 3 U were leucoreduced. Samples were obtained at days (D) 1 and 42 and cell-free supernatants separated and stored. The supernatants were centrifuged at 17 000 * g (60 min) or 100 000 * g (120 min) into microparticle-rich (MPR) and microparticle-poor (MPP) portions, resuspended in albumin, incubated with antibodies to CD235 (RBCs), CD45 [white blood cells (WBCs)] and CD41a [platelets (Plts)], and analysed by flow cytometry. Isolated neutrophils were incubated with these samples, and priming activity measured. RESULTS: Total MPs increased during storage; however, MPs that marked for precursor cell types did not. Significant priming accumulated in the MPP fraction during storage with some activity present in the MPR fraction from D1 and D42 LR-RBCs. CONCLUSION: Most of the pro inflammatory priming activity from stored RBCs resides in the MPP supernatant, although the MPR fraction from D42 LR-RBCs does contain some priming activity. PMID- 24786052 TI - Emerging diseases. Soaring MERS cases in Saudi Arabia raise alarms. PMID- 24786053 TI - Energy technology. Perovskite solar cells keep on surging. PMID- 24786054 TI - Wildlife conservation. Drones flying high as new tool for field biologists. PMID- 24786055 TI - Defense science. As Pentagon downsizes, budgets shrink for academic research. PMID- 24786056 TI - Animal research. Male scent may compromise biomedical studies. PMID- 24786057 TI - Stem cells. Therapeutic cloning reaches milestone. PMID- 24786058 TI - Economic geology. Seafloor mining plan advances, worrying critics. PMID- 24786059 TI - Death of the stars. PMID- 24786060 TI - Shining a light on solar water splitting. PMID- 24786061 TI - Shining a light on solar water splitting--response. PMID- 24786062 TI - Advanced photon source upgrade benefits all. PMID- 24786064 TI - Climate adaptation. Evaluating flood resilience strategies for coastal megacities. PMID- 24786065 TI - Ecology. Tolerance for predatory wildlife. PMID- 24786066 TI - Cell biology. Dysfunctional mechanosensing in aneurysms. PMID- 24786067 TI - Planetary science. Forming terrestrial planets. PMID- 24786068 TI - Neuroscience. A new wrap for neuronal activity? PMID- 24786069 TI - Chemistry. Assembly and disassembly of ferrocene-based nanotubes. PMID- 24786070 TI - Physics. Nonlinear optics pushed to the edge. PMID- 24786071 TI - Botany. Limits on yields in the Corn Belt. PMID- 24786072 TI - Edge nonlinear optics on a MoS2 atomic monolayer. AB - The translational symmetry breaking of a crystal at its surface may form two dimensional (2D) electronic states. We observed one-dimensional nonlinear optical edge states of a single atomic membrane of molybdenum disulfide (MoS2), a transition metal dichalcogenide. The electronic structure changes at the edges of the 2D crystal result in strong resonant nonlinear optical susceptibilities, allowing direct optical imaging of the atomic edges and boundaries of a 2D material. Using the symmetry of the nonlinear optical responses, we developed a nonlinear optical imaging technique that allows rapid and all-optical determination of the crystal orientations of the 2D material at a large scale. Our technique provides a route toward understanding and making use of the emerging 2D materials and devices. PMID- 24786073 TI - Probing exchange pathways in one-dimensional aggregates with super-resolution microscopy. AB - Supramolecular fibers are prominent structures in biology and chemistry. A quantitative understanding of molecular exchange pathways in these one dimensional aggregates was obtained by a combination of super-resolution stochastic optical reconstruction microscopy and stochastic simulation. The potential of this methodology is demonstrated with a set of well-defined synthetic building blocks that self-assemble into supramolecular fibrils. Previous ensemble measurements hid all molecular phenomena underpinning monomer exchange, but the molecular pathway determined from single-aggregate studies revealed unexpected homogeneous exchange along the polymer backbone. These results pave the way for experimental investigation of the structure and exchange pathways of synthetic and natural supramolecular fibers. PMID- 24786074 TI - Interfacial effects in iron-nickel hydroxide-platinum nanoparticles enhance catalytic oxidation. AB - Hybrid metal nanoparticles can allow separate reaction steps to occur in close proximity at different metal sites and accelerate catalysis. We synthesized iron nickel hydroxide-platinum (transition metal-OH-Pt) nanoparticles with diameters below 5 nanometers and showed that they are highly efficient for carbon monoxide (CO) oxidation catalysis at room temperature. We characterized the composition and structure of the transition metal-OH-Pt interface and showed that Ni(2+) plays a key role in stabilizing the interface against dehydration. Density functional theory and isotope-labeling experiments revealed that the OH groups at the Fe(3+)-OH-Pt interfaces readily react with CO adsorbed nearby to directly yield carbon dioxide (CO2) and simultaneously produce coordinatively unsaturated Fe sites for O2 activation. The oxide-supported PtFeNi nanocatalyst rapidly and fully removed CO from humid air without decay in activity for 1 month. PMID- 24786075 TI - Manipulation of discrete nanostructures by selective modulation of noncovalent forces. AB - Covalent organic synthesis commonly uses the strategy of selective bond cleavage and formation. If a similar approach can be applied stepwisely to noncovalent synthesis, more exotic or challenging nanostructures might become achievable. Here, we report that ferrocene-based tetratopic pyridyl ligands, which can dynamically change their geometry by means of thermal rotation of their cyclopentadienyl rings in solution, assemble with AgBF4 into discrete metal organic nanotubes with large and uniform diameters. The nanotubes can be cut into metal-organic nanorings through selective attenuation of the inter-nanoring interaction via ferrocene oxidation. The resultant nanorings can be transferred onto inorganic substrates electrostatically or allowed to reassemble to form the original nanotube by the reductive neutralization of their oxidized ferrocene units. PMID- 24786076 TI - Vibrationally promoted dissociation of water on Ni(111). AB - Water dissociation on transition-metal catalysts is an important step in steam reforming and the water-gas shift reaction. To probe the effect of translational and vibrational activation on this important heterogeneous reaction, we performed state-resolved gas/surface reactivity measurements for the dissociative chemisorption of D2O on Ni(111), using molecular beam techniques. The reaction occurs via a direct pathway, because both the translational and vibrational energies promote the dissociation. The experimentally measured initial sticking probabilities were used to calibrate a first-principles potential energy surface based on density functional theory. Quantum dynamical calculations on the scaled potential energy surface reproduced the experimental results semiquantitatively. The larger increase of the dissociation probability by vibrational excitation than by translation per unit of energy is consistent with a late barrier along the O-D stretch reaction coordinate. PMID- 24786077 TI - Genomic signatures of specialized metabolism in plants. AB - All plants synthesize basic metabolites needed for survival (primary metabolism), but different taxa produce distinct metabolites that are specialized for specific environmental interactions (specialized metabolism). Because evolutionary pressures on primary and specialized metabolism differ, we investigated differences in the emergence and maintenance of these processes across 16 species encompassing major plant lineages from algae to angiosperms. We found that, relative to their primary metabolic counterparts, genes coding for specialized metabolic functions have proliferated to a much greater degree and by different mechanisms and display lineage-specific patterns of physical clustering within the genome and coexpression. These properties illustrate the differential evolution of specialized metabolism in plants, and collectively they provide unique signatures for the potential discovery of novel specialized metabolic processes. PMID- 24786078 TI - Deception by flexible alarm mimicry in an African bird. AB - Deception is common in nature, but victims of deception discriminate against and ultimately ignore deceptive signals when they are produced too frequently. Flexible variation of signals could allow evasion of such constraints. Fork tailed drongos (Dicrurus adsimilis) use false alarm calls to scare other species away from food that they then steal. We show that drongos mimic the alarms of targeted species. Further, target species reduce their response to false alarm calls when they are repeated. However, the fear response is maintained when the call is varied. Drongos exploit this propensity by changing their alarm-call type when making repeated theft attempts on a particular species. Our results show that drongos can evade the frequency-dependent constraints that typically limit deception payoffs through flexible variation of their alarm calls. PMID- 24786079 TI - Greater sensitivity to drought accompanies maize yield increase in the U.S. Midwest. AB - A key question for climate change adaptation is whether existing cropping systems can become less sensitive to climate variations. We use a field-level data set on maize and soybean yields in the central United States for 1995 through 2012 to examine changes in drought sensitivity. Although yields have increased in absolute value under all levels of stress for both crops, the sensitivity of maize yields to drought stress associated with high vapor pressure deficits has increased. The greater sensitivity has occurred despite cultivar improvements and increased carbon dioxide and reflects the agronomic trend toward higher sowing densities. The results suggest that agronomic changes tend to translate improved drought tolerance of plants to higher average yields but not to decreasing drought sensitivity of yields at the field scale. PMID- 24786080 TI - Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. AB - To extend our understanding of the genetic basis of human immune function and dysfunction, we performed an expression quantitative trait locus (eQTL) study of purified CD4(+) T cells and monocytes, representing adaptive and innate immunity, in a multi-ethnic cohort of 461 healthy individuals. Context-specific cis- and trans-eQTLs were identified, and cross-population mapping allowed, in some cases, putative functional assignment of candidate causal regulatory variants for disease-associated loci. We note an over-representation of T cell-specific eQTLs among susceptibility alleles for autoimmune diseases and of monocyte-specific eQTLs among Alzheimer's and Parkinson's disease variants. This polarization implicates specific immune cell types in these diseases and points to the need to identify the cell-autonomous effects of disease susceptibility variants. PMID- 24786081 TI - Reconstructing the DNA methylation maps of the Neandertal and the Denisovan. AB - Ancient DNA sequencing has recently provided high-coverage archaic human genomes. However, the evolution of epigenetic regulation along the human lineage remains largely unexplored. We reconstructed the full DNA methylation maps of the Neandertal and the Denisovan by harnessing the natural degradation processes of methylated and unmethylated cytosines. Comparing these ancient methylation maps to those of present-day humans, we identified ~2000 differentially methylated regions (DMRs). Particularly, we found substantial methylation changes in the HOXD cluster that may explain anatomical differences between archaic and present day humans. Additionally, we found that DMRs are significantly more likely to be associated with diseases. This study provides insight into the epigenetic landscape of our closest evolutionary relatives and opens a window to explore the epigenomes of extinct species. PMID- 24786082 TI - Chemical inhibition of NAT10 corrects defects of laminopathic cells. AB - Down-regulation and mutations of the nuclear-architecture proteins lamin A and C cause misshapen nuclei and altered chromatin organization associated with cancer and laminopathies, including the premature-aging disease Hutchinson-Gilford progeria syndrome (HGPS). Here, we identified the small molecule "Remodelin" that improved nuclear architecture, chromatin organization, and fitness of both human lamin A/C-depleted cells and HGPS-derived patient cells and decreased markers of DNA damage in these cells. Using a combination of chemical, cellular, and genetic approaches, we identified the acetyl-transferase protein NAT10 as the target of Remodelin that mediated nuclear shape rescue in laminopathic cells via microtubule reorganization. These findings provide insights into how NAT10 affects nuclear architecture and suggest alternative strategies for treating laminopathies and aging. PMID- 24786083 TI - Molecular-level functional magnetic resonance imaging of dopaminergic signaling. AB - We demonstrate a technique for mapping brain activity that combines molecular specificity and spatial coverage using a neurotransmitter sensor detectable by magnetic resonance imaging (MRI). This molecular functional MRI (fMRI) method yielded time-resolved volumetric measurements of dopamine release evoked by reward-related lateral hypothalamic brain stimulation of rats injected with the neurotransmitter sensor. Peak dopamine concentrations and release rates were observed in the anterior nucleus accumbens core. Substantial dopamine transients were also present in more caudal areas. Dopamine-release amplitudes correlated with the rostrocaudal stimulation coordinate, suggesting participation of hypothalamic circuitry in modulating dopamine responses. This work provides a foundation for development and application of quantitative molecular fMRI techniques targeted toward numerous components of neural physiology. PMID- 24786084 TI - Multiple dimensions of climate change and their implications for biodiversity. AB - The 21st century is projected to witness unprecedented climatic changes, with greater warming often reported for high latitudes. Yet, climate change can be measured in a variety of ways, reflecting distinct dimensions of change with unequal spatial patterns across the world. Polar climates are projected to not only warm, but also to shrink in area. By contrast, today's hot and arid climates are expected to expand worldwide and to reach climate states with no current analog. Although rarely appreciated in combination, these multiple dimensions of change convey complementary information. We review existing climate change metrics and discuss how they relate to threats and opportunities for biodiversity. Interpreting climate change metrics is particularly useful for unknown or poorly described species, which represent most of Earth's biodiversity. PMID- 24786087 TI - People with coexisting diabetes, chronic kidney disease and hypertension report the psychosocial effects of being prescribed multiple medications. PMID- 24786086 TI - Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure. AB - Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non workplace ambient exposure levels. Here, we further characterize these dose dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response representative genes (identified by clustering) exhibited similar apparent supra linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings. PMID- 24786088 TI - Indian hedgehog in synovial fluid is a novel marker for early cartilage lesions in human knee joint. AB - To determine whether there is a correlation between the concentration of Indian hedgehog (Ihh) in synovial fluid (SF) and the severity of cartilage damage in the human knee joints, the knee cartilages from patients were classified using the Outer-bridge scoring system and graded using the Modified Mankin score. Expression of Ihh in cartilage and SF samples were analyzed with immunohistochemistry (IHC), western blot, and enzyme-linked immunosorbent assay (ELISA). Furthermore, we detected and compared Ihh protein levels in rat and mice cartilages between normal control and surgery-induced osteoarthritis (OA) group by IHC and fluorescence molecular tomography in vivo respectively. Ihh expression was increased 5.2-fold in OA cartilage, 3.1-fold in relative normal OA cartilage, and 1.71-fold in OA SF compared to normal control samples. The concentrations of Ihh in cartilage and SF samples was significantly increased in early-stage OA samples when compared to normal samples (r = 0.556; p < 0.001); however, there were no significant differences between normal samples and late-stage OA samples. Up-regulation of Ihh protein was also an early event in the surgery-induced OA models. Increased Ihh is associated with the severity of OA cartilage damage. Elevated Ihh content in human knee joint synovial fluid correlates with early cartilage lesions. PMID- 24786089 TI - Recent advances in bacteria identification by matrix-assisted laser desorption/ionization mass spectrometry using nanomaterials as affinity probes. AB - Identifying trace amounts of bacteria rapidly, accurately, selectively, and with high sensitivity is important to ensuring the safety of food and diagnosing infectious bacterial diseases. Microbial diseases constitute the major cause of death in many developing and developed countries of the world. The early detection of pathogenic bacteria is crucial in preventing, treating, and containing the spread of infections, and there is an urgent requirement for sensitive, specific, and accurate diagnostic tests. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is an extremely selective and sensitive analytical tool that can be used to characterize different species of pathogenic bacteria. Various functionalized or unmodified nanomaterials can be used as affinity probes to capture and concentrate microorganisms. Recent developments in bacterial detection using nanomaterials-assisted MALDI-MS approaches are highlighted in this article. A comprehensive table listing MALDI MS approaches for identifying pathogenic bacteria, categorized by the nanomaterials used, is provided. PMID- 24786090 TI - Proteomic study of differential protein expression in mouse lung tissues after aerosolized ricin poisoning. AB - Ricin is one of the most poisonous natural toxins from plants and is classified as a Class B biological threat pathogen by the Centers for Disease Control and Prevention (CDC) of U.S.A. Ricin exposure can occur through oral or aerosol routes. Ricin poisoning has a rapid onset and a short incubation period. There is no effective treatment for ricin poisoning. In this study, an aerosolized ricin exposed mouse model was developed and the pathology was investigated. The protein expression profile in the ricin-poisoned mouse lung tissue was analyzed using proteomic techniques to determine the proteins that were closely related to the toxicity of ricin. 2D gel electrophoresis, mass spectrometry and subsequent biological functional analysis revealed that six proteins including Apoa1 apolipoprotein, Ywhaz 14-3-3 protein, Prdx6 Uncharacterized Protein, Selenium binding protein 1, HMGB1, and DPYL-2, were highly related to ricin poisoning. PMID- 24786091 TI - Efficient delivery of plasmid DNA using cholesterol-based cationic lipids containing polyamines and ether linkages. AB - Cationic liposomes are broadly used as non-viral vectors to deliver genetic materials that can be used to treat various diseases including cancer. To circumvent problems associated with cationic liposome-mediated delivery systems such as low transfection efficiency and serum-induced inhibition, cholesterol based cationic lipids have been synthesized that resist the effects of serum. The introduction of an ether-type linkage and extension of the aminopropyl head group on the cholesterol backbone increased the transfection efficiency and DNA binding affinity compared to a carbamoyl-type linkage and a mono aminopropyl head group, respectively. Under optimal conditions, each liposome formulation showed higher transfection efficiency in AGS and Huh-7 cells than commercially available cationic liposomes, particularly in the presence of serum. The following molecular structures were found to have a positive effect on transfection properties: (i) extended aminopropyl head groups for a strong binding affinity to plasmid DNA; (ii) an ether linkage that favors electrostatic binding to plasmid DNA; and (iii) a cholesterol backbone for serum resistance. PMID- 24786092 TI - Genome-wide identification, 3D modeling, expression and enzymatic activity analysis of cell wall invertase gene family from cassava (Manihot esculenta Crantz). AB - The cell wall invertases play a crucial role on the sucrose metabolism in plant source and sink organs. In this research, six cell wall invertase genes (MeCWINV1 6) were cloned from cassava. All the MeCWINVs contain a putative signal peptide with a predicted extracellular location. The overall predicted structures of the MeCWINV1-6 are similar to AtcwINV1. Their N-terminus domain forms a beta propeller module and three conserved sequence domains (NDPNG, RDP and WECP(V)D), in which the catalytic residues are situated in these domains; while the C terminus domain consists of a beta-sandwich module. The predicted structure of Pro residue from the WECPD (MeCWINV1, 2, 5, and 6), and Val residue from the WECVD (MeCWINV3 and 4) are different. The activity of MeCWINV1 and 3 were higher than other MeCWINVs in leaves and tubers, which suggested that sucrose was mainly catalyzed by the MeCWINV1 and 3 in the apoplastic space of cassava source and sink organs. The transcriptional levels of all the MeCWINVs and their enzymatic activity were lower in tubers than in leaves at all the stages during the cassava tuber development. It suggested that the major role of the MeCWINVs was on the regulation of carbon exportation from source leaves, and the ratio of sucrose to hexose in the apoplasts; the role of these enzymes on the sucrose unloading to tuber was weaker. PMID- 24786093 TI - Characterisation of Indica Special Protein (ISP), a marker protein for the differentiation of Oryza sativa subspecies indica and japonica. AB - Based on both morphological and physiological traits, Asian cultivated rice (Oryza sativa L.) can be classified into two distinct subspecies, indica and japonica. To better understand the differences between the two subspecies, a proteomic approach was used to profile proteins present in the yellow seedling stage of 10 indica and 10 japonica rice varieties. We report the discovery of a new protein, Indica Special Protein (ISP), which was only detected in yellow seedlings of indica varieties, and was absent from japonica varieties. Hence, ISP may represent a key gene for the differentiation of indica and japonica subspecies. PMID- 24786094 TI - Symbiotic activity of pea (Pisum sativum) after application of Nod factors under field conditions. AB - Growth and symbiotic activity of legumes are mediated by Nod factors (LCO, lipo chitooligosaccharides). To assess the effects of application of Nod factors on symbiotic activity and yield of pea, a two-year field experiment was conducted on a Haplic Luvisol developed from loess. Nod factors were isolated from Rhizobium leguminosarum bv. viciae strain GR09. Pea seeds were treated with the Nod factors (10-11 M) or water (control) before planting. Symbiotic activity was evaluated by measurements of nitrogenase activity (acetylene reduction assay), nodule number and mass, and top growth by shoot mass, leaf area, and seed and protein yield. Nod factors generally improved pea yield and nitrogenase activity in the relatively dry growing season 2012, but not in the wet growing season in 2013 due to different weather conditions. PMID- 24786096 TI - The role of symbiotic nitrogen fixation in sustainable production of biofuels. AB - With the ever-increasing population of the world (expected to reach 9.6 billion by 2050), and altered life style, comes an increased demand for food, fuel and fiber. However, scarcity of land, water and energy accompanied by climate change means that to produce enough to meet the demands is getting increasingly challenging. Today we must use every avenue from science and technology available to address these challenges. The natural process of symbiotic nitrogen fixation, whereby plants such as legumes fix atmospheric nitrogen gas to ammonia, usable by plants can have a substantial impact as it is found in nature, has low environmental and economic costs and is broadly established. Here we look at the importance of symbiotic nitrogen fixation in the production of biofuel feedstocks; how this process can address major challenges, how improving nitrogen fixation is essential, and what we can do about it. PMID- 24786097 TI - A novel protein is lower expressed in renal cell carcinoma. AB - Engrailed-2 (EN2) has been identified as a candidate oncogene in breast cancer and prostate cancer. It is usually recognized as a mainly nuclear staining in the cells. However, recent studies showed a cytoplasmic staining occurred in prostate cancer, bladder cancer and clear cell renal cell carcinoma. The inconsistency makes us confused. To clarify the localization and expression of EN2 in renal cell carcinoma, anti-EN2 antibody (ab28731) and anti-EN2 antibody (MAB2600) were used for immunohistochemistry (IHC) respectively. Interestingly, we found that EN2 detected by ab28731 was mainly presented in cytoplasm while EN2 detected by MAB2600 was mainly presented in nucleus. To further investigate the different patterns observed above, lysates from full-length EN2 over expression in HEK293T cells were used to identify which antibody the EN2 molecule bound by western blot. Results showed ab28731 did not react with the lysates. For this reason, the novel specific protein detected by ab28731 was not the EN2 molecule and was named nonEN2. Then using the renal carcinoma tissue microarray and renal tissues, we found that the protein expression levels of nonEN2 in kidney tumor tissues was significantly lower than that in kidney normal tissues (p < 0.05), so was in renal cell lines. Taken together, nonEN2 is lower expressed and may play an important role in renal cell carcinoma. PMID- 24786095 TI - Molecular mechanisms and new treatment strategies for non-alcoholic steatohepatitis (NASH). AB - Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), in which most patients exhibit non-progressive, non alcoholic fatty liver (NAFL) attributable to simple steatosis. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the progression of NASH. NAFLD is strongly associated with obesity, which induces adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level, which in turn induces hepatic steatosis, inflammation and fibrosis. Among these factors, gut microbiota are acknowledged as having an important role in initiating this multifactorial disease. Oxidative stress is considered to be a key contributor in the progression from NAFL to NASH. Macrophage infiltration is apparent in NAFL and NASH, while T-cell infiltration is apparent in NASH. Although several clinical trials have shown that antioxidative therapy with vitamin E can effectively control hepatitis pathology in the short term, the long-term effects remain obscure and have often proved to be ineffective in many other diseases. Several long-term antioxidant protocols have failed to reduce mortality. New treatment modalities that incorporate current understanding of NAFLD molecular pathogenesis must be considered. PMID- 24786098 TI - Potential for layered double hydroxides-based, innovative drug delivery systems. AB - Layered Double Hydroxides (LDHs)-based drug delivery systems have, for many years, shown great promises for the delivery of chemical therapeutics and bioactive molecules to mammalian cells in vitro and in vivo. This system offers high efficiency and drug loading density, as well as excellent protection of loaded molecules from undesired degradation. Toxicological studies have also found LDHs to be biocompatible compared with other widely used nanoparticles, such as iron oxide, silica, and single-walled carbon nanotubes. A plethora of bio molecules have been reported to either attach to the surface of or intercalate into LDH materials through co-precipitation or anion-exchange reaction, including amino acid and peptides, ATPs, vitamins, and even polysaccharides. Recently, LDHs have been used for gene delivery of small molecular nucleic acids, such as antisense, oligonucleotides, PCR fragments, siRNA molecules or sheared genomic DNA. These nano-medicines have been applied to target cells or organs in gene therapeutic approaches. This review summarizes current progress of the development of LDHs nanoparticle drug carriers for nucleotides, anti inflammatory, anti-cancer drugs and recent LDH application in medical research. Ground breaking studies will be highlighted and an outlook of the possible future progress proposed. It is hoped that the layered inorganic material will open up new frontier of research, leading to new nano-drugs in clinical applications. PMID- 24786099 TI - Antenna-specific glutathione S-transferase in male silkmoth Bombyx mori. AB - Glutathione S-transferases (GSTs) are multifunctional enzymes that are widely distributed in different species. GSTs detoxify exogenous and endogenous substances by conjugation to reduced glutathione. We characterized BmGSTD4, an antenna-specific GST, in male silkmoths. The full-length mRNA of Bmgstd4 was cloned by RACE-PCR and contained an open reading frame of 738 bp encoding a 245 amino acid protein. The antenna specificity of BmGSTD4 was validated at the mRNA and protein levels and BmGSTD4 was shown to localize in the sensillum of male silkmoth antennae. Homology modeling and multi-sequence alignment suggested that BmGSTD4 was a typical GST belonging to the delta class and had a canonical GST fold with a conserved N-terminus, including a glutathione-binding site and a C terminal domain harboring a hydrophobic substrate-binding site. Restricted expression of BmGSTD4 in silkmoth antennae combined with GST activity suggested that BmGSTD4 was involved in the detoxification of harmful chemicals. PMID- 24786102 TI - Initial Treatment for Primary Angle-Closure Glaucoma in China. AB - China has a large burden of primary angle-closure glaucoma (PACG) and the approach to treatment is different from that in most parts of the world. In China, trabeculectomy is a mainstay of initial treatment for PACG and laser peripheral iridotomy is reserved for PAC and PACG with peripheral angle synechiae <=180 degrees. The greater reduction of and more stable IOP, lower frequency of acute angle closure, decreased progression of peripheral anterior synechia and glaucoma, and the reduction of ocular complications associated with long-term use of glaucoma medications support the use of initial trabeculectomy in PACG without significant lens opacities. Further study is required to determine the indications and effectiveness of initial trabeculectomy for PACG in a developing country setting. PMID- 24786100 TI - Effect of fiber length on carbon nanotube-induced fibrogenesis. AB - Given their extremely small size and light weight, carbon nanotubes (CNTs) can be readily inhaled by human lungs resulting in increased rates of pulmonary disorders, particularly fibrosis. Although the fibrogenic potential of CNTs is well established, there is a lack of consensus regarding the contribution of physicochemical attributes of CNTs on the underlying fibrotic outcome. We designed an experimentally validated in vitro fibroblast culture model aimed at investigating the effect of fiber length on single-walled CNT (SWCNT)-induced pulmonary fibrosis. The fibrogenic response to short and long SWCNTs was assessed via oxidative stress generation, collagen expression and transforming growth factor-beta (TGF-beta) production as potential fibrosis biomarkers. Long SWCNTs were significantly more potent than short SWCNTs in terms of reactive oxygen species (ROS) response, collagen production and TGF-beta release. Furthermore, our finding on the length-dependent in vitro fibrogenic response was validated by the in vivo lung fibrosis outcome, thus supporting the predictive value of the in vitro model. Our results also demonstrated the key role of ROS in SWCNT-induced collagen expression and TGF-beta activation, indicating the potential mechanisms of length-dependent SWCNT-induced fibrosis. Together, our study provides new evidence for the role of fiber length in SWCNT-induced lung fibrosis and offers a rapid cell-based assay for fibrogenicity testing of nanomaterials with the ability to predict pulmonary fibrogenic response in vivo. PMID- 24786101 TI - Autophagy-related direct membrane import from ER/cytoplasm into the vacuole or apoplast: a hidden gateway also for secondary metabolites and phytohormones? AB - Transportation of low molecular weight cargoes into the plant vacuole represents an essential plant cell function. Several lines of evidence indicate that autophagy-related direct endoplasmic reticulum (ER) to vacuole (and also, apoplast) transport plays here a more general role than expected. This route is regulated by autophagy proteins, including recently discovered involvement of the exocyst subcomplex. Traffic from ER into the vacuole bypassing Golgi apparatus (GA) acts not only in stress-related cytoplasm recycling or detoxification, but also in developmentally-regulated biopolymer and secondary metabolite import into the vacuole (or apoplast), exemplified by storage proteins and anthocyanins. We propose that this pathway is relevant also for some phytohormones' (e.g., auxin, abscisic acid (ABA) and salicylic acid (SA)) degradation. We hypothesize that SA is not only an autophagy inducer, but also a cargo for autophagy-related ER to vacuole membrane container delivery and catabolism. ER membrane localized enzymes will potentially enhance the area of biosynthetic reactive surfaces, and also, abundant ER localized membrane importers (e.g., ABC transporters) will internalize specific molecular species into the autophagosome biogenesis domain of ER. Such active ER domains may create tubular invaginations of tonoplast into the vacuoles as import intermediates. Packaging of cargos into the ER-derived autophagosome-like containers might be an important mechanism of vacuole and exosome biogenesis and cytoplasm protection against toxic metabolites. A new perspective on metabolic transformations intimately linked to membrane trafficking in plants is emerging. PMID- 24786103 TI - Long-term 24-hour intraocular pressure control with travoprost monotherapy in patients with primary open-angle glaucoma. AB - PURPOSE: The aim of the study was to evaluate the long-term 24-hour intraocular pressure (IOP) efficacy of travoprost monotherapy in primary open-angle glaucoma patients. PATIENTS AND METHODS: A total of 36 previously untreated primary open angle glaucoma patients were enrolled in this 5-year study. Patients underwent an untreated 24-hour IOP evaluation. Subsequently all patients were assigned to topical therapy with travoprost 0.004% eye-drops preserved with benzalkonium chloride (Travatan, Alcon Laboratories Inc., Fort Worth, TX) administered once in the evening (8:00 PM) in both eyes. All patients were then scheduled for a 24 hour IOP assessment approximately 12 months after the baseline visit. This schedule of follow-up was maintained for the whole duration of the trial. The predetermined range of target IOP reduction selected in this cohort of patients ranged between 20% and 30%. RESULTS: A total of 34 patients completed all phases of the investigation. The mean survival time was 57.3+/-2.0 months and the cumulative survival rate was 0.82+/-0.6 at 60 months. Travoprost reduced the mean 24-hour IOP from 23.4+/-1.7 mm Hg at baseline to 16.8+/-2.4 mm Hg (28.4%), 16.8+/ 2.5 mm Hg (28.1%), 16.8+/-2.4 mm Hg (28.5%), 16.7+/-2.5 mm Hg (28.6%), and 16.9+/ 2.4 mm Hg (27.8%), respectively at the end of the first, second, third, fourth, and fifth year follow-up. No drug-related serious adverse events were registered during the study. CONCLUSIONS: The present study demonstrated the long-term 24 hour efficacy of travoprost for the treatment of primary open-angle glaucoma. PMID- 24786104 TI - Expression of small heat shock protein (sHSP) genes in the garden pea (Pisum sativum) under slow horizontal clinorotation. AB - Plant cells respond to stress conditions, such as high temperatures, by synthesizing small heat shock proteins (sHSPs). sHSPs are molecular chaperones that assist in protein folding and prevent irreversible protein aggregation. Although many sHSP genes are temperature-inducible, other variables, such as altered gravity, can induce significant changes in plant cell gene expression. Furthermore, not all subfamilies of sHSP genes share the same expression pattern. The objective of our research was to determine the effect of simulated microgravity (clinorotation) on the expression of sHSP gene subfamilies with different subcellular locations in etiolated pea (Pisum sativum) seedlings. sHSP gene expression levels were examined using quantitative real-time RT-PCR (qPCR). qPCR results demonstrated that sHSP genes were constitutively expressed in seedlings. High temperatures increased the expression of sHSP genes by several thousand-fold. However, simulated microgravity did not have any significant effects on sHSP gene expression. PMID- 24786105 TI - Euechinoidea and Cidaroidea respond differently to ocean acidification. AB - The impact of the chemical changes in the ocean waters due to the increasing atmospheric CO2 depends on the ability of an organism to control extracellular pH. Among sea urchins, this seems specific to the Euechinoidea, sea urchins except Cidaroidea. However, Cidaroidea survived two ocean acidification periods: the Permian-Trias and the Cretaceous-Tertiary crises. We investigated the response of these two sea urchin groups to reduced seawater pH with the tropical cidaroid Eucidaris tribuloides, the sympatric euechinoid Tripneustes ventricosus and the temperate euechinoid Paracentrotus lividus. Both euechinoid showed a compensation of the coelomic fluid pH due to increased buffer capacity. This was linked to an increased concentration of DIC in the coelomic fluid and thus of bicarbonate ions (most probably originating from the surrounding seawater as isotopic signature of the carbon - delta13C - was similar). On the other hand, the cidaroid showed no changes within the coelomic fluid. Moreover, the delta13C of the coelomic fluid did not match that of the seawater and was not significantly different between the urchins from the different treatments. Feeding rate was not affected in any species. While euechinoids are able to regulate their extracellular acid-base balance, many questions are still unanswered on the costs of this capacity. On the contrary, cidaroids do not seem affected by a reduced seawater pH. Further investigations need to be undertaken to cover more species and physiological and metabolic parameters in order to determine if energy trade-offs occur and how this mechanism of compensation is distributed among sea urchins. PMID- 24786106 TI - N-Arylations of sulfoximines with 2-arylpyridines by copper-mediated dual N-H/C-H activation. AB - A high-yielding method providing rapid access to new N-arylated sulfoximines has been developed. A stoichiometric amount of copper facilitates the C-H activation of 2-arylpyridines which then undergo oxidative C-N cross-couplings with various sulfoximine derivatives. PMID- 24786107 TI - Selection of high-affinity Centyrin FN3 domains from a simple library diversified at a combination of strand and loop positions. AB - Alternative scaffold molecules represent a class of proteins important to the study of protein design and mechanisms of protein-protein interactions, as well as for the development of therapeutic proteins. Here, we describe the generation of a library built upon the framework of a consensus FN3 domain sequence resulting in binding proteins we call Centyrins. This new library employs diversified positions within the C-strand, CD-loop, F-strand and FG-loop of the FN3 domain. CIS display was used to select high-affinity Centyrin variants against three targets; c-MET, murine IL-17A and rat TNFalpha and scanning mutagenesis studies were used to define the positions of the library most important for target binding. Contributions from both the strand and loop positions were noted, although the pattern was different for each molecule. In addition, an affinity maturation scheme is described that resulted in a significant improvement in the affinity of one selected Centyrin variant. Together, this work provides important data contributing to our understanding of potential FN3 binding interfaces and a new tool for generating high-affinity scaffold molecules. PMID- 24786109 TI - Nitrogen-doped carbon dots derived from polyvinyl pyrrolidone and their multicolor cell imaging. AB - Nitrogen-doped carbon dots (N-CDs) with a high quantum yield of 19.6% were prepared by calcining polyvinyl pyrrolidone (PVP, K-30), and then modified with 4,7,10-trioxa-1,13-tridecanediamine. The as-prepared N-CDs exhibited excitation dependent and pH-sensitive photoluminescence. Transmission electron microscopy and Raman spectra demonstrated the graphitic structure of the N-CDs. Fourier transform infrared spectroscopy and x-ray diffraction studies revealed successful passivation and the presence of hydrophilic groups on the surface. Importantly, such modified quantum dots acted as good multicolor cell imaging probes due to their excellent fluorescent properties, low cytotoxicity and fine dispersity. PMID- 24786111 TI - In reply. PMID- 24786112 TI - Site of origin of dysplastic epithelium in colonic mucosa. PMID- 24786113 TI - p40 (DeltaNp63), a lung squamous cell marker, can also be used to label breast myoepithelial cells. PMID- 24786114 TI - Phasing-in RHD genotyping. PMID- 24786115 TI - Intradepartmental consultation: what is the pathologist's legal liability? PMID- 24786116 TI - Whole slide images add value to journal article figures. PMID- 24786117 TI - The incredible shrinking billing codes. PMID- 24786118 TI - Surgical pathology report defects: a College of American Pathologists Q-Probes study of 73 institutions. AB - CONTEXT: The rate of surgical pathology report defects is an indicator of quality and it affects clinician satisfaction. OBJECTIVE: To establish benchmarks for defect rates and defect fractions through a large, multi-institutional prospective application of standard taxonomy. DESIGN: Participants in a 2011 Q Probes study of the College of American Pathologists prospectively reviewed all surgical pathology reports that underwent changes to correct defects and reported details regarding the defects. RESULTS: Seventy-three institutions reported 1688 report defects discovered in 360,218 accessioned cases, for an aggregate defect rate of 4.7 per 1000 cases. Median institutional defect rate was 5.7 per 1000 (10th to 90th percentile range, 13.5-0.9). Defect rates were higher in institutions with a pathology training program (8.5 versus 5.0 per 1000, P = .01) and when a set percentage of cases were reviewed after sign-out (median, 6.7 versus 3.8 per 1000, P = .10). Defect types were as follows: 14.6% misinterpretations, 13.3% misidentifications, 13.7% specimen defects, and 58.4% other report defects. Overall, defects were most often detected by pathologists (47.4%), followed by clinicians (22.0%). Misinterpretations and specimen defects were most often detected by pathologists (73.5% and 82.7% respectively, P < .001), while misidentifications were most often discovered by clinicians (44.6%, P < .001). Misidentification rates were lower when all malignancies were reviewed by a second pathologist before sign-out (0.0 versus 0.6 per 1000, P < .001), and specimen defect rates were lower when intradepartmental review of difficult cases was conducted after sign-out (0.0 versus 0.4 per 1000, P = .02). CONCLUSION: This study provides benchmarking data on report defects and defect fractions using standardized taxonomy. PMID- 24786119 TI - False-positive Papanicolaou (PAP) test rates in the College of American Pathologists PAP education and PAP proficiency test programs: evaluation of false positive responses of high-grade squamous intraepithelial lesion or cancer to a negative reference diagnosis. AB - CONTEXT: In cytology proficiency testing (PT), participants fail for incorrectly interpreting a high-grade squamous intraepithelial lesion or cancer (HSIL+) Papanicolaou test result as negative. This penalty may lead to a false-positive interpretation of negative slides as HSIL+ to avoid failure. OBJECTIVE: To investigate factors related to false-positive responses in a PT versus an educational environment. DESIGN: We analyzed 420,079 responses from 9414 validated negative reference slides in the College of American Pathologists Interlaboratory Comparison Program in Gynecologic Cytopathology (PAP Education) and compared them with responses from the Gynecologic Cytology Proficiency Testing Program for the percentage of false-positive (HSIL+) interpretations in each of 7 negative subcategories. We evaluated the influence of preparation type (ThinPrep, SurePath, and conventional Papanicolaou test), participant type (pathologist or cytotechnologist), and program time interval (preproficiency test or PT) on a false-positive response. RESULTS: Reference diagnosis and participant type, but not preparation type, were statistically correlated to false-positive responses. The interaction between program time interval and participant type was also significant. Pathologists had higher rates of false-positive results on preproficiency test (1.2% [800 of 68,690]) than they did on PT (0.8% [993 of 129,857]). Cytotechnologists had no differences between program time intervals (preproficiency, 0.9% [515 of 63,281] versus PT, 1.0 [1231 of 121,621]; P = .91). Negative subcategories frequently mistaken for HSIL+ were reparative changes (4.7% [427 of 9069]), atrophic vaginitis (1.8% [18 of 987]), and negative for intraepithelial lesion or malignancy (1.2% [2143 of 178,651]), but during PT, false-positive rates were significantly increased only for the negative for intraepithelial lesion or malignancy and herpes simplex virus (P < .001). CONCLUSIONS: Pathologists had lower false-positive rates in the Gynecologic Cytology Proficiency Testing Program than they did in PAP Education, but participants were more likely to report a false-positive response (HSIL+) for negative for intraepithelial lesion or malignancy and herpes simplex virus in the Gynecologic Cytology Proficiency Test Program. PMID- 24786120 TI - Policies and procedures related to testing for weak D phenotypes and administration of Rh immune globulin: results and recommendations related to supplemental questions in the Comprehensive Transfusion Medicine survey of the College of American Pathologists. AB - CONTEXT: Advances in RHD genotyping offer an opportunity to update policies and practices for testing weak D phenotypes and administration of Rh immune globulin to postpartum women. OBJECTIVES: To repeat questions from a 1999 College of American Pathologists proficiency test survey, to evaluate current practices for testing for weak D and administration of Rh immune globulin, and to determine whether there is an opportunity to begin integrating RHD genotyping in laboratory practice. DESIGN: The College of American Pathologists Transfusion Medicine Resource Committee sent questions from the 1999 survey to laboratories that participated in the 2012 proficiency test survey. The results of the 2012 survey were compared with those from 1999. Results from published RHD genotyping studies were analyzed to determine if RHD genotyping could improve current policies and practices for serological Rh typing. RESULTS: More than 3100 survey participants responded to the 2012 questions. The most significant finding was a decrease in the number of transfusion services performing a serological weak D test on patients as a strategy to manage those with a weak D as Rh negative (from 58.2% to 19.8%, P < .001). Data from RHD genotyping studies indicate that approximately 95% of women with a serological weak D could be managed safely and more logically as Rh positive. CONCLUSIONS: Selective integration of RHD genotyping policies and practices could improve the accuracy of Rh typing results, reduce unnecessary administration of Rh immune globulin in women with a weak D, and decrease transfusion of Rh-negative red blood cells in most recipients with a serological weak D phenotype. PMID- 24786121 TI - Differential expression patterns of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) -1, -4, -5, and -14 in human placenta and gestational trophoblastic diseases. AB - CONTEXT: The ability of intermediate trophoblasts to invade maternal tissue during placentation depends on how well they can degrade the extracellular matrix. Invasion into the extracellular matrix requires many complex proteases. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) is a novel family of secreted metalloproteinases. The ADAMTS-1, -4, -5, and -14 subtypes are known to be expressed in human placenta, but little is understood about their expression patterns. OBJECTIVE: To examine the expression patterns of ADAMTS-1, 4, -5, and -14 in specific human placenta cell types during gestation and in gestational trophoblastic diseases. DESIGN: Placental tissues were obtained from 25 pregnant women and 21 cases of gestational trophoblastic diseases (10 early complete moles, 3 placental site trophoblastic tumors, 4 invasive moles, and 4 choriocarcinomas). The expression of the 4 ADAMTS was analyzed by immunohistochemistry. RESULTS: ADAMTS-1, -4, -5, and -14 were differentially expressed by the human placenta throughout gestation in a time-specific and cell type-specific manner, as well as in gestational trophoblastic diseases. ADAMTS-1 showed gradually strong staining intensity in gestational trophoblastic diseases according to the invasive potential but showed consistent strong intensity throughout normal placenta. ADAMTS-4 and ADAMTS-5 exhibited higher and restricted expression in first-trimester intermediate trophoblasts. They also exhibited comparably strong expression in gestational trophoblastic diseases. However, ADAMTS-14 expression remained unchanged throughout gestation. CONCLUSIONS: The restricted expression pattern of ADAMTS-4 and ADAMTS-5 and their increased expression in gestational trophoblastic diseases suggest that these 2 ADAMTS subtypes are associated with a biological phenotype of trophoblasts involved in human placentation and the development of gestational trophoblastic diseases. PMID- 24786122 TI - Detection of malignancy in body fluids: a comparison of the hematology and cytology laboratories. AB - CONTEXT: Body fluids submitted to the hematology laboratory for cell counts may also be examined for the presence of malignancy. Previous studies evaluating the hematology laboratory's performance at detecting malignancy in body fluids have reached conflicting conclusions. OBJECTIVE: To investigate the hematology laboratory's ability to detect malignancy in body fluids by comparison with cytology. DESIGN: Retrospective analysis of 414 body fluid samples during an 18 month period, with introduction of new quality assurance measures after the first 210 cases. If no concurrent cytology was ordered, results were compared with recent previous and/or subsequent cytologic, histologic, or flow cytometric diagnoses. RESULTS: Of the initial 210 cases, the hematology laboratory detected 3 of 13 malignancies diagnosed by concurrent cytology (23% sensitivity), with no false-positives (100% specificity). Malignancy was not identified on retrospective review of the hematology slides in the 10 discrepant cases. After the initial study, educational sessions on morphology for the medical technologists and a more thorough hematology-cytology correlation policy were implemented. The subsequent 204 hematology laboratory cases had increased sensitivity for the detection of malignancy (60%; 6 of 10). Definitive features of malignancy were seen in only one discrepant hematology laboratory slide on retrospective review. This case had not been flagged for hematopathologist review. None of the discrepancies before or after implementation of the additional quality assurance measures impacted patient care. CONCLUSIONS: Body fluid processing by the hematology laboratory is not optimized for the detection of malignancy. Concurrent cytologic examination is critical for the detection of malignancy, and needs to be considered as cost-saving measures are increasingly implemented. PMID- 24786124 TI - Evaluation of chromogenic in situ hybridization for the determination of monosomy 3 in uveal melanoma. AB - CONTEXT: Loss of 1 copy of chromosome 3 is considered a significant indicator of metastatic dissemination in uveal melanoma. Fresh or paraffin-embedded tumor tissue is most commonly used for current cytogenetic techniques for determining chromosome 3 status in uveal melanoma and often requires referral to an external specialist laboratory for analysis. OBJECTIVES: To assess the chromogenic in situ hybridization assay for detecting chromosome 3 alterations using frozen tumor imprints and to compare the results obtained with those obtained by standard fluorescence in situ hybridization or single-nucleotide polymorphism array techniques. DESIGN: Chromogenic in situ hybridization was performed on 52 frozen uveal melanoma tumor imprints. The genetic status of 26 of the 52 cases had been determined previously by fluorescence in situ hybridization (group 1); the status of 26 cases had been determined using single-nucleotide polymorphism array (group 2). RESULTS: Chromogenic in situ hybridization was successfully performed on 48 of 52 tumor imprints. Chromogenic in situ hybridization showed excellent agreement in all 24 cases determined by fluorescence in situ hybridization (100% concordance; kappa = 1; P < .001; 95% confidence interval, 100%-100%), and disagreed in 4 of the 24 cases previously studied by single-nucleotide polymorphism array (83% concordance; kappa = 0.67; P < .001; 95% confidence interval, 95%-39%). All 4 discordant cases were classified as disomic for chromosome 3 by chromogenic in situ hybridization and monosomic by SNP array. On histologic examination, the 4 discordant cases corresponded to 2 mixed cell tumors and 2 spindle cell tumors. CONCLUSIONS: Chromogenic in situ hybridization using tumor imprints is a reliable technique for determining chromosome 3 status in uveal melanoma. Furthermore, it can also be easily integrated into a routine histopathology laboratory. PMID- 24786123 TI - Classification of thymic epithelial neoplasms is still a challenge to thoracic pathologists: a reproducibility study using digital microscopy. AB - CONTEXT: Thymic epithelial tumors are rare, constituting interpretive challenges for pathologists. Digital imaging can be useful as an educational tool for these rare tumors. OBJECTIVES: To evaluate the diagnostic reproducibility of thymic tumors among thoracic pathologists. DESIGN: Twenty cases of thymoma or thymic carcinoma were scanned into the Aperio system. The images were sent to pathologists with expertise in thoracic pathology at 6 different centers, who were asked to classify the tumors according to the 2004 World Heath Organization classification and to diagnose invasion. Interobserver agreement was evaluated. After discussion of the first 20 cases, a second set of 10 cases was evaluated. RESULTS: There was agreement for the diagnosis of thymoma and thymic carcinoma in 70% of cases (n = 14); in the remaining 6 cases, there was disagreement for cases of B3 thymoma (n = 5) and type A thymoma (n = 1) and thymic carcinoma. The overall kappa was 0.39. When invasion was evaluated, the overall kappa was 0.45. In the second round of the study, after discussion of diagnostic criteria, the interobserver agreement for the diagnosis of thymoma versus thymic carcinoma was 0.67 and that for the determination of invasion was 0.57-suggesting interpretative improvement. CONCLUSION: The reproducibility of diagnosis of thymic epithelial tumors, using digital imaging, is comparable to that in previous studies using glass slides. Digital imaging is a good tool for remote consultation and for educational purposes. This technology could be used to train pathologists with low-level experience in thymic epithelial tumors and to foster collaborative work in the field. PMID- 24786125 TI - An analysis of clinical consultation activities in clinical chemistry: implications for transformation and resident training in chemical pathology. AB - CONTEXT: Clinical consultation is a key role of pathologists. Many have advocated that pathologists expand their consulting activities to improve laboratory utilization. Although many have suggested that residency programs need to provide experience in clinical consultation, little has been written on the nature of consultation or on the methods of training. OBJECTIVE: To characterize the content of consultations and to describe training in consultation in chemical pathology within the residency program at the University of Utah, Salt Lake City. DESIGN: Retrospective review of the consultation database for the period between July 2011 and July 2012. RESULTS: Residents performed an average of 159 consultations a month covering 276 topics during the course of a year. Each topic involved 1 or more specific tests. Eighty percent of the topics received fewer than 12 calls. The most common topics involved virus testing (eg, hepatitis B virus, hepatitis C virus, human immunodeficiency virus). Consultations most often involved test interpretation (53%), selection (38%), and performance characteristics (21%). Twenty-seven percent of consultations involved 2 or more consultation categories (eg, interpretation and performance). CONCLUSIONS: Consultation calls in chemical pathology are widely distributed across topics. Consultations most often involve test interpretation and selection. Methods to assess the effectiveness of consultations and resident teaching should be devised. PMID- 24786126 TI - Circulating cell-free DNA in sickle cell disease: is it a potentially useful biomarker? AB - CONTEXT: Vascular occlusion in sickle cell disease causes increased levels of plasma cell-free DNA as a result of cell death and tissue damage. OBJECTIVES: This study investigates plasma cell-free DNA concentrations in sickle cell disease patients, and aims at exploring the significance of plasma cell-free DNA as a potential biomarker in predicting its complications. DESIGN: Plasma cell free DNA levels were measured using real-time quantitative polymerase chain reaction to quantitatively measure beta-globin gene in blood samples from 57 sickle cell disease patients with acute vaso-occlusive crisis, 42 patients in steady state, 16 individuals with sickle cell trait, and 40 healthy controls. RESULTS: Plasma cell-free DNA level was significantly elevated in samples from patients with acute vaso-occlusive crisis when compared with those in steady state (P = .002), and was significantly higher both in crisis and in steady state when compared with individuals with sickle cell trait and healthy controls (P < .001). There was no difference in cell-free DNA levels between individuals with sickle cell trait and healthy controls. There was no association between plasma cell-free DNA levels and various clinical complications of sickle cell disease and comorbidity. CONCLUSIONS: Plasma cell-free DNA, as quantified by polymerase chain reaction amplification of the beta-globin and human telomerase reverse transcriptase genes, is increased in sickle cell disease patients in vaso occlusive crisis and in steady state compared with individuals with sickle cell trait and healthy controls, and may be used as a tool to diagnose and monitor the sickle cell crisis and differentiate post-packed red cell transfusion sickle cell disease patients from individuals with sickle cell trait. PMID- 24786127 TI - Predictors of red cell alloimmunization in multitransfused Egyptian patients with beta-thalassemia. AB - CONTEXT: Thalassemia is a major health problem in Egypt. Red blood cell alloimmunization is an important complication in transfusion-dependent patients. OBJECTIVES: To determine alloimmunization prevalence in Egyptian patients with beta-thalassemia and to evaluate risk factors that could influence alloimmunization, with the hope of minimizing transfusion-associated risks in those patients. DESIGN: Records of 272 patients with beta-thalassemia who are receiving regular blood transfusions, matched for ABO-Rh(D), were analyzed. Alloantibody identification was performed by DiaMed-ID microtyping system. Autoantibodies were detected by direct Coombs test. RESULTS: Alloimmunization incidence was 22.8% with 123 alloantibodies detected in 62 patients. The most common alloantibody was Rh-related (37.4%; 46 of 123), comprising anti-E (14.6%; 18 of 123), anti-D (8.9%; 11 of 123), anti-C (8.9%; 11 of 123), and anti-c (4.9%; 6 of 123), followed by anti-Kell (26%; 32 of 123), -> anti-MNS (9.8%; 12 of 123), -> anti-Kidd (8.9%; 11 of 123) -> anti-Duffy (8.1%; 10 of 123), -> anti-Le (5.7%; 7 of 123), -> anti-Lu (2.4%; 3 of 123), and -> anti-P1 (1.6%; 2 of 123). Anti-D antibodies developed in 34.5% of all Rh-negative patients. Eighty percent of all anti-D antibodies developed in patients older than 18 years. Males had the highest alloimmunization incidence. Alloimmunization incidence increased with the number of units transfused (P = .01). Patients who received unfiltered blood had a higher alloimmunization rate than did those who always received leukoreduced blood (P < .001). Splenectomized patients had a higher alloimmunization rate (32%; 40 of 125) than did those who did not have a splenectomy (16.3%; 24 of 147; P = .003). Autoantibodies occurred in 1.5% (4 of 272) of all patients. CONCLUSION: Transfusion of leukoreduced and phenotypically matched cells for selective antigens may help reduce expenses and risks of alloimmunization in patients with thalassemia. PMID- 24786128 TI - Renal lipidosis in patients enrolled in a methadone substitution program. AB - Kidney biopsies often show accumulation of lipids or lipidlike material. Evidence has been provided that lipids can directly initiate and contribute to the progression of glomerular and tubulointerstitial lesions. In this study we describe a renal lipidosis occurring in patients with a positive history of narcotic abuse who were enrolled in a methadone substitution program. All 3 patients presented with proteinuria (2.5-20 g/d) and impaired renal function. Renal biopsy revealed a pronounced extracellular and intracellular deposition of lipidlike material in the glomerular, interstitial, and tubular compartments. Known causes of lipid storage could be excluded clinically and morphologically. We consider this to be a distinct renal lipidosis associated with narcotic abuse, methadone intake, or intravenous abuse thereof. PMID- 24786129 TI - Parosteal osteosarcoma. AB - Parosteal osteosarcoma is a rare malignant bone tumor arising from the bone cortical surface. It most commonly occurs in young women over the metaphyseal region, especially the long bones near the knee joint. Patients usually report a slow-growing mass for years. The tumor is characterized by its bland microscopic morphology, prone to be misdiagnosed as other benign tumors. In the absence of dedifferentiation, the prognosis is generally better than that of conventional osteosarcoma. Recent studies demonstrated distinctive cytogenetic abnormality resulting in amplification of the CDK4 and MDM2 genes, which may serve as markers for molecular diagnosis. In this article, we review the clinical, radiologic, and pathologic features of parosteal osteosarcoma and identify some diagnostic pitfalls, discuss the prognostic variables, and update recent molecular advances and their application in the diagnosis. PMID- 24786131 TI - Dual-layer-structured nickel hexacyanoferrate/MnO2 composite as a high-energy supercapacitive material based on the complementarity and interlayer concentration enhancement effect. AB - A dual-layer composite structure composed of a metal-organic framework structure (NiHCF) with tunable open channels and typical pseudocapacitive manganese dioxide is constructed here as an electrode material for supercapacitors. This type of structure shows enhanced specific capacitance, high energy density, and excellent rate capability and stability. The specific capacitance of the composite electrode is much larger than the sum of each part, and a synergy effect of the dual-layer structure named "interlayer concentration enhancement effect" (ICE effect for short) was proposed to account for this excellent electrochemical performance. PMID- 24786132 TI - Tooth movement in orthodontic treatment systematic review omitted significant articles. PMID- 24786133 TI - (11)C-labeling and preliminary evaluation of vortioxetine as a PET radioligand. AB - Vortioxetine is a new multi-modal drug against major depressive disorder with high affinity for a range of different serotonergic targets in the CNS. We report the (11)C-labeling of vortioxetine with [(11)C]MeI using a Suzuki-protocol that allows for the presence of an unprotected amine. Preliminary evaluation of [(11)C]vortioxetine in a Danish Landrace pig showed rapid brain uptake and brain distribution in accordance with the pharmacological profile, all though an unexpected high binding in cerebellum was also observed. [(11)C]vortioxetine displayed slow tracer kinetics with peak uptake after 60 min and with limited wash-out from the brain. Further studies are needed but this radioligand may prove to be a valuable tool in unraveling the clinical effects of vortioxetine. PMID- 24786135 TI - Determination of original infection source of H7N9 avian influenza by dynamical model. AB - H7N9, a newly emerging virus in China, travels among poultry and human. Although H7N9 has not aroused massive outbreaks, recurrence in the second half of 2013 makes it essential to control the spread. It is believed that the most effective control measure is to locate the original infection source and cut off the source of infection from human. However, the original infection source and the internal transmission mechanism of the new virus are not totally clear. In order to determine the original infection source of H7N9, we establish a dynamical model with migratory bird, resident bird, domestic poultry and human population, and view migratory bird, resident bird, domestic poultry as original infection source respectively to fit the true dynamics during the 2013 pandemic. By comparing the date fitting results and corresponding Akaike Information Criterion (AIC) values, we conclude that migrant birds are most likely the original infection source. In addition, we obtain the basic reproduction number in poultry and carry out sensitivity analysis of some parameters. PMID- 24786134 TI - GATA3: a master of many trades in immune regulation. AB - GATA3 has conventionally been regarded as a transcription factor that drives the differentiation of T helper (Th) 2 cells. Increasing evidence points to a function for GATA3 beyond controlling Th2 differentiation. GATA3 regulates T cell development, proliferation, and maintenance. Furthermore, recent studies have demonstrated important roles for GATA3 in innate lymphoid cells. Thus, GATA3 emerges as a factor with diverse functions in immune regulation, which are in some cases cell-type specific and in others shared by multiple cell types. Here, I discuss recent discoveries and the current understanding of the functions of GATA3 in immune regulation. PMID- 24786136 TI - Accuracy of peri-implant bone evaluation using cone beam CT, digital intra-oral radiographs and histology. AB - OBJECTIVES: The present study assesses the accuracy of three-dimensional (3D) cone beam CT (CBCT) and intra-oral radiography (CR) in visualizing peri-implant bone compared with histology. METHODS: 26 titanium dental implants were placed in dog jaws with chronic type vestibular defects. After a healing period of 2 and 8 weeks (n = 12 dogs) the animals were sacrificed. CBCT scans and CR of the specimen were recorded. Dissected blocks were prepared, and histomorphometric analysis was performed. Both modalities were measured twice by two observers and compared with histomorphometry regarding bone levels and thickness around implants as well as length and diameter of implants. RESULTS: Measurements of CBCT correlated well with histomorphometry of the vestibular bone level, oral bone thickness and implant length (all p-values <0.05). Compared with histomorphometry, the mean differences between CBCT and histomorphometry were between 0.06 and 2.61 mm. Mesial bone level (MBL) and distal bone level (DBL) were underestimated by both CR and CBCT. CR and histology measurements were only significantly correlated for implant length measurements. All intraclass correlations were highly significant. CONCLUSIONS: 3D CBCT provides usable information about bone in all dimensions around implants with varying accuracy. CR and CBCT perform similar in assessing MBL and DBL, but, within its limits, the CBCT can assess oral and buccal bone. Metallic artefacts limit the visualization quality of bone around implants and further research could elucidate the value of post-processing algorithms. When information about osseous perforation of implants is needed, CBCT may still provide clinically valuable information. PMID- 24786137 TI - Tooth shape reconstruction from dental CT images with the region-growing method. AB - OBJECTIVES: The three-dimensional shape information of teeth provides useful information. However, obtaining accurate three-dimensional shapes of teeth is difficult without extracting them physically. In this study, we aimed to develop a method for automatically extracting accurate three-dimensional shapes of teeth from dental CT images. METHODS: The proposed method includes pre-processing and region extraction. Pre-processing is a combination of image-processing techniques that enhances tooth regions. In the region-extraction process, the region-growing method is introduced for extracting a region of each tooth. Constraint conditions determined by considering the characteristics of the structure of teeth are introduced for accurate extraction. Finally, morphological image processing is applied for eliminating discontinuous points. RESULTS: We carried out an experiment in which the three-dimensional shapes of teeth were reconstructed from dental CT images. Quantitative evaluation was performed by measuring the three dimensional spatial accordance rates between the region obtained by the proposed method and the manually extracted region. The proposed method was significantly more accurate than an existing method at the 5% level. CONCLUSIONS: The experimental results showed that the proposed method reconstructs the shapes of teeth with high precision. However, an unextracted region remained at the surface of the enamel. Solving this problem and improving the extraction accuracy are important topics for future work. PMID- 24786138 TI - Initial experience of robotic anterior pelvic exenteration at a single institute. AB - OBJECTIVE: To present the initial experience with robotic anterior pelvic exenteration in patients with advanced pelvic cancer at Galaxy Care Laparoscopy Institute, Pune, India. METHODS: A retrospective chart review of data from 10 patients with advanced cervical carcinoma and bladder involvement or with vault recurrence following hysterectomy who were treated at the study hospital between November 2009 and May 2011. Clinicopathologic data and postoperative data including operative time, blood loss, blood transfusions, hospital stay, lymph node yield, and complications were recorded. RESULTS: The mean operative time was 180 minutes, the mean blood loss was 110mL, and the mean duration of hospital stay was 5 days. There were no treatment-related morbidities or mortalities. A mean parametrial clearance of 3cm with a distal vaginal margin of 3.5cm was achieved. All patients had tumor-free margins. The mean number of harvested lymph nodes was 24. Six patients had positive lymph nodes on pathologic examination and were treated with chemoradiotherapy. At a median follow-up of 11 months, 8 patients were disease-free. CONCLUSION: Robot-assisted anterior pelvic exenteration had favorable operative, pathologic, and short-term clinical outcomes. A large multicenter study is required to confirm the results. PMID- 24786140 TI - Expanding the use of manual vacuum aspiration for incomplete abortion in selected health institutions in Yaounde, Cameroon. AB - Preference for manual vacuum aspiration (MVA) and its use for the treatment of incomplete abortion were evaluated among 52 healthcare professionals in 7 Yaounde hospitals in Cameroon. All but one healthcare professional preferred MVA; however, this technique was available at all times in only two hospitals. In some hospitals, MVA use was only available during the day, while in others it was not available at all. Based on these findings, MVA kits were obtained from the International Federation of Gynecology and Obstetrics (FIGO) for training and to supply selected hospitals. The result was a dramatic increase in the use of MVA in all of the hospitals that received the kits. In one hospital, no kits were received; however, the staff had been sensitized to the problem and the equipment belonging to one of the physicians was put into service. The successful experience of this pilot project provides a rationale for expanding MVA use for incomplete abortion to the entire country. PMID- 24786139 TI - Community-based prenatal screening for postpartum depression in a South African township. AB - OBJECTIVE: To assess the feasibility of using community health workers to administer short or ultra-short screening instruments during routine community based prenatal outreach for detecting probable depression at 12 weeks postpartum. METHODS: During pregnancy and at 12 weeks postpartum, the 10-item Edinburgh Postnatal Depression Scale (EPDS-10) was administered to 249 Xhosa-speaking black African women living in Khayelitsha, South Africa. We compared the operating characteristics of the prenatal EPDS-10, as well as 4 short and ultra-short subscales, with the criterion standard of probable postpartum depression. RESULTS: Seventy-nine (31.7%) women were assessed as having probable postpartum depression. A prenatal EPDS-10 score of 13 or higher had 0.67 sensitivity and 0.67 specificity for detecting probable postpartum depression. Briefer subscales performed similarly. CONCLUSION: Community health workers successfully conducted community-based screening for depression in a resource-limited setting using short or ultra-short screening instruments. However, overall feasibility was limited because prenatal screening failed to accurately predict probable depression during the postpartum period. PMID- 24786141 TI - Aerobic cervical bacteriology and antibiotic sensitivity patterns in patients with advanced cervical cancer before and after radiotherapy at a national referral hospital in Uganda. AB - OBJECTIVE: To determine prevalent aerobic cervical bacteria and sensitivity to commonly used antibiotics in patients with advanced cervical cancer before and after 4 weeks of external beam radiotherapy (EBRT). METHODS: Cervical swabs were collected prior to the initial radiation dose and after 4 weeks of radiotherapy at Mulago Hospital. Aerobic culture was performed on blood agar, chocolate agar, and MacConkey agar, and incubated at 35-37 degrees for 24-48 hours. Isolates were identified using colonial morphology, Gram staining, and biochemical analysis. Sensitivity testing was performed via Kirby-Bauer disk diffusion and dilution. Differences in the proportions of bacteria isolated before and after radiotherapy were compared. Paired t test was used to obtain differences in sensitivity before and after radiotherapy. RESULTS: Normal flora increased significantly after EBRT (P=0.02). There was no significant change in overall proportion of positive cultures. Sensitivity to commonly used antibiotics improved (P=0.05) and resistance significantly decreased (P=0.005). Significant differences were seen mainly with ciprofloxacin, ceftriaxone, and gentamicin. CONCLUSION: Four weeks of EBRT did not sterilize the cervix but resulted in an increase in normal flora. Radiotherapy appeared to reduce resistance to commonly used antibiotics. Sensitivity to chloramphenicol was higher than for the more commonly used antibiotics. PMID- 24786142 TI - Increasing access to legal termination of pregnancy and postabortion contraception at the University Teaching Hospital, Lusaka, Zambia. AB - The Zambian Association of Gynecology and Obstetrics is one of the International Federation of Gynecology and Obstetrics (FIGO) member societies participating in the FIGO Initiative for the Prevention of Unsafe Abortion and its Consequences from the East, Central, and Southern Africa region. The activities included in this country's plan of action were to provide access to safe abortion within the full extent of the law to women receiving care at the University Teaching Hospital in Lusaka, and to increase the proportion of women leaving the hospital with a contraceptive method. Zambian law regarding abortion is liberal, but in general it was not applied until very recently. The proportion of legal terminations of pregnancy among patients receiving abortion care at the hospital increased from 3.2% in 2009 to 7.7% in 2011, while the percentage of women leaving the hospital with a contraceptive method increased from 25.3% to 69.4% over the same period. PMID- 24786143 TI - The incidence of kidney injury for patients treated with a high-potency versus moderate-potency statin regimen after an acute coronary syndrome. AB - BACKGROUND: Observational studies have raised concerns that high-potency statins increase the risk of acute kidney injury. We therefore examined the incidence of kidney injury across 2 randomized trials of statin therapy. METHODS AND RESULTS: PROVE IT-TIMI 22 enrolled 4162 subjects after an acute coronary syndrome (ACS) and randomized them to atorvastatin 80 mg/day versus pravastatin 40 mg/day. A-to Z enrolled 4497 subjects after ACS and randomized them to a high-potency (simvastatin 40 mg/day * 1 months, then simvastatin 80 mg/day) versus a delayed moderate-potency statin strategy (placebo * 4 months, then simvastatin 20 mg/day). Serum creatinine was assessed centrally at serial time points. Adverse events (AEs) relating to kidney injury were identified through database review. Across both trials, mean serum creatinine was similar between treatment arms at baseline and throughout follow-up. In A-to-Z, the incidence of a 1.5-fold or >= 0.3 mg/dL rise in serum creatinine was 11.4% for subjects randomized to a high potency statin regimen versus 12.4% for those on a delayed moderate-potency regimen (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.76 to 1.10; P=0.33). In PROVE IT-TIMI 22, the incidence was 9.4% for subjects randomized to atorvastatin 80 mg/day and 10.6% for subjects randomized to pravastatin 40 mg/day (OR, 0.88; 95% CI, 0.71 to 1.09; P=0.25). Consistent results were observed for different kidney injury thresholds and in individuals with diabetes mellitus or with moderate renal dysfunction. The incidence of kidney injury-related adverse events (AEs) was not statistically different for patients on a high-potency versus moderate-potency statin regimen (OR, 1.06; 95% CI, 0.68 to 1.67; P=0.78). CONCLUSIONS: For patients enrolled in 2 large randomized trials of statin therapy after ACS, the use of a high-potency statin regimen did not increase the risk of kidney injury. PMID- 24786144 TI - Predisposing factors associated with development of persistent compared with paroxysmal atrial fibrillation. AB - BACKGROUND: Once atrial fibrillation (AF) progresses to sustained forms, adverse outcomes increase and treatment success rates decrease. Therefore, identification of risk factors predisposing to persistence of AF may have a significant impact on AF morbidity. METHODS AND RESULTS: We prospectively examined the differential associations between traditional, lifestyle, and biomarker AF risk factors and development of paroxysmal versus nonparoxysmal AF (persistent/permanent) among 34 720 women enrolled in the Women's Health Study who were free of cardiovascular disease and AF at baseline. AF patterns were defined based on current guidelines and classified according to the most sustained form of AF within 2 years of diagnosis. During a median follow-up of 16.4 years, 690 women developed paroxysmal AF and 349 women developed nonparoxysmal AF. In multivariable time varying competing risk models, increasing age (hazard ratio [HR] 1.11, 95% CI 1.10 to 1.13, versus HR 1.08, 1.07 to 1.09, per year), body mass index (HR 1.07, 1.05 to 1.09, versus HR 1.03, 1.02 to 1.05, per kg/m(2)), and weight (HR 1.30, 1.22 to 1.39, versus HR 1.14, 1.08 to 1.20, per 10 kg) were more strongly associated with the development of nonparoxysmal AF compared with paroxysmal AF. Hemoglobin A1c levels at baseline were directly related to the development of nonparoxysmal AF but inversely associated with paroxysmal AF in multivariable competing risk models (P for nonequal association=0.01). CONCLUSIONS: In women without AF or CVD at baseline, increasing age, adiposity, and higher hemoglobin A1c levels were preferentially associated with the early development of nonparoxysmal AF. These data raise the hypothesis that efforts aimed at weight reduction or glycemic control may affect the proportion of the population with sustained AF. PMID- 24786145 TI - Link N and mesenchymal stem cells can induce regeneration of the early degenerate intervertebral disc. AB - Link N is a naturally occurring peptide that can stimulate proteoglycan synthesis in intervertebral disc (IVD) cells. IVD repair can also potentially be enhanced by mesenchymal stem cell (MSC) supplementation to maximize extracellular matrix (ECM) production. In a previous study, we have shown that Link N can inhibit osteogenesis and increase the chondrogenesis of MSCs in vitro. The aim of the present study was to determine the potential of MSCs and Link N alone or in combination with regard to tissue repair in the degenerate disc. Bovine IVDs with trypsin-induced degeneration were treated with MSCs, Link N, or a combination of MSCs and Link N. Trypsin-treated discs were also injected with phosphate-buffered saline to serve as a degeneration control. The ECM proteins and proteoglycans were extracted from the inner nucleus pulposus (NP) of the discs, and sulfated glycosaminoglycans (GAGs) were analyzed by the dimethyl methylene blue dye binding assay. The expression of type II collagen was analyzed by western blot. To track the MSCs after injection, MSCs were labeled with PKH67 and observed under confocal microscopy after the 2 week culture period. The GAG content significantly increased compared with the degeneration control when degenerate discs were treated with MSCs, Link N, or a combination of both Link N and MSCs. Histological analysis revealed that the newly synthesized proteoglycan was able to diffuse throughout the ECM and restore tissue content even in areas remote from the cells. The quantity of extractable type II collagen was also increased when the degenerate discs were treated with MSCs and Link N, either alone or together. MSCs survived, integrated in the tissue, and were found distributed throughout the NP after the 2 week culture period. MSCs and Link N can restore GAG content in degenerate discs, when administered separately or together. Treatment with MSCs and Link N can also increase the expression of type II collagen. The results support the concept that biological repair of disc degeneration is feasible, and that the administration of either MSCs or Link N has therapeutic potential in early stages of the disease. PMID- 24786146 TI - Cysteine-conjugated metabolites of ginger components, shogaols, induce apoptosis through oxidative stress-mediated p53 pathway in human colon cancer cells. AB - Shogaols, the major constituents of thermally processed ginger, have been proven to be highly effective anticancer agents. Our group has identified cysteine conjugated shogaols (M2, M2', and M2") as the major metabolites of [6]-, [8]-, and [10]-shogaol in human and found that M2 is a carrier of its parent molecule [6]-shogaol in cancer cells and in mice, while being less toxic to normal colon fibroblast cells. The objectives of this study are to determine whether M2' and M2" behave in a similar manner to M2, in both metabolism and efficacy as anticancer agents, and to further explore the biological pro-apoptotic mechanisms of the cysteine-conjugated shogaols against human colon cancer cells HCT-116 and HT-29. Our results show that [8]- and [10]-shogaol have similar metabolic profiles to [6]-shogaol and exhibit similar toxicity toward human colon cancer cells. M2' and M2" both show low toxicity against normal colon cells but retain potency against colon cancer cells, suggesting that they have similar activity to M2. We further demonstrate that the cysteine-conjugated shogaols can cause cancer cell death through the activation of the mitochondrial apoptotic pathway. Our results show that oxidative stress activates a p53 pathway that ultimately leads to p53 up-regulated modulator of apoptosis (PUMA) induction and down-regulation of B-cell lymphoma 2 (Bcl-2), followed by cytochrome c release, perturbation of inhibitory interactions of X-linked inhibitor of apoptosis protein (XIAP) with caspases, and finally caspase 9 and 3 activation and cleavage. A brief screen of the markers attenuated by the proapoptotic activity of M2 revealed similar results for [8]- and [10]-shogaol and their respective cysteine-conjugated metabolites M2' and M2". This study highlights the cysteine-conjugated metabolites of shogaols as novel dietary colon cancer preventive agents. PMID- 24786147 TI - Diffusion-weighted imaging vs STIR turbo SE imaging: capability for quantitative differentiation of small-cell lung cancer from non-small-cell lung cancer. AB - OBJECTIVE: To compare the capability of differentiation of small-cell lung cancer (SCLC) from non-SCLC (NSCLC) between diffusion-weighted imaging (DWI) and short tau inversion recovery (STIR) turbo spin-echo imaging. METHODS: The institutional review board of Kobe University Hospital, Kobe, Japan, approved this study, and written informed consent was obtained from each patient. 49 patients with NSCLC (30 males and 19 females; mean age, 66.8 years) and 7 patients with SCLC (5 males and 2 females; mean age, 68.6 years) enrolled and underwent DWI and STIR. To quantitatively differentiate SCLC from NSCLC, apparent diffusion coefficient (ADC) values on DWI and contrast ratios (CRs) between cancer and muscle on STIR were evaluated. ADC values and CRs were then compared between the two cell types by Mann-Whitney's U-tests, and the diagnostic performances were compared by McNemar's test. RESULTS: There were significant differences of mean ADC values (p < 0.001) and mean CRs (p = 0.003). With adopted threshold values, the specificity (85.7%) and accuracy (85.7%) of DWI were higher than those of STIR (specificity, 63.3%; p = 0.001 and accuracy, 66.1%; p = 0.001). In addition, the accuracy of combination of both indexes (94.6%; p = 0.04) could significantly improve as compared with DWI alone. CONCLUSION: DWI is more useful for the differentiation of SCLC from NSCLC than STIR, and their combination can significantly improve the accuracy in this setting. ADVANCES IN KNOWLEDGE: Pulmonary MRI, including DWI and STIR, had a potential of the suggestion of the possibility as SCLC. PMID- 24786148 TI - The G551D CFTR chloride channel spurs the development of personalized medicine. PMID- 24786149 TI - High dose EPO--friend or foe in the newborn? PMID- 24786150 TI - Complexity, confusion and controversy continue complicating the contribution of RyR2 channel phosphorylation to heart function. PMID- 24786151 TI - Influencing mitochondrial membrane composition and bioenergetics through omega-3 supplementation. PMID- 24786152 TI - Pushing the limits: exercise stress in the healthy human heart. PMID- 24786153 TI - Serotonergic modulation in neuropathy induced by oxaliplatin: effect on the 5HT2C receptor. AB - Fluoxetine has been shown to be effective in clinical and experimental studies of neuropathic pain. Besides to increase serotonin levels in the synaptic cleft, fluoxetine is able to block the serotonergic 5-HT2C receptor subtype, which in turn has been involved in the modulation of neuropathic pain. This study investigated the effect of repeated treatments with fluoxetine on the neuropathic nociceptive response induced by oxaliplatin and the effects of both treatments on 5-HT2C receptor mRNA expression and protein levels in the rat spinal cord (SC), rostral ventral medulla (RVM), midbrain periaqueductal gray (PAG) and amygdala (Amy). Nociception was assessed by paw-pressure, cold plate and Von Frey tests. Fluoxetine prevented mechanical hypersensitivity and pain threshold alterations induced by oxaliplatin but did not prevent the impairment in weight gain induced by this anticancer drug. Ex vivo analysis revealed that oxaliplatin increased the 5-HT2C receptor mRNA expression and protein levels in the SC and PAG. Similar effects were observed in fluoxetine-treated animals but only within the PAG. While oxaliplatin decreased the 5-HT2C mRNA expression levels in the Amy, fluoxetine increased their protein levels in this area. Fluoxetine impaired the oxaliplatin effects on the 5-HT2C receptor mRNA expression in the SC and Amy and protein levels in the SC. All treatments increased of 5-HT2C receptor mRNA expression and protein levels in the PAG. These results suggest that the effects of fluoxetine on neuropathic pain induced by oxaliplatin are associated with quantitative changes in the 5-HT2C receptors located within important areas of the nociceptive system. PMID- 24786157 TI - The veterinary profession and precarious values. PMID- 24786158 TI - What is your diagnosis? Heart base tumors. PMID- 24786159 TI - Theriogenology question of the month. Peritonitis secondary to a vaginal laceration during natural breeding in a mare. PMID- 24786160 TI - Animal behavior case of the month. Spinning. PMID- 24786161 TI - Pathology in practice. Parvoviral myocarditis. PMID- 24786162 TI - Pathology in practice. Granulosa cell tumor (GCT) of an ovary in a 2-year-old Savannah goat. PMID- 24786163 TI - Efficacy of orally administered maropitant citrate in preventing vomiting associated with hydromorphone administration in dogs. AB - OBJECTIVE: To evaluate the effectiveness of orally administered maropitant citrate in preventing vomiting after hydromorphone hydrochloride administration in dogs. DESIGN: Randomized, blinded, prospective clinical study. ANIMALS: 40 dogs with American Society of Anesthesiologists status of I or II, > 6 months of age, and weighing between 24 and 58.2 kg (52.8 and 128.04 lb). PROCEDURES: Dogs were randomly selected to receive maropitant (2.0 to 4.0 mg/kg [0.9 to 1.8 mg/lb]) or placebo (lactose monohydrate) orally 2 hours prior to receiving hydromorphone (0.1 mg/kg [0.045 mg/lb], IM). A blinded observer recorded the occurrence of vomiting or signs of nausea (eg, salivation or lip-licking) during a 30-minute period after hydromorphone administration. Two-tailed Fisher exact tests were used to compare the incidences of vomiting and signs of nausea with or without vomiting between treatment groups. Results-Of the 20 dogs receiving maropitant, none vomited but 12 (60%) developed signs of nausea. Of the 20 dogs receiving placebo, 5 (25%) vomited and 11 (55%) developed signs of nausea; overall, 16 of 20 (80%) dogs in the placebo treatment group vomited or developed signs of nausea. Compared with the effects of placebo, maropitant significantly decreased the incidence of vomiting but not signs of nausea in dogs administered hydromorphone. CONCLUSIONS AND CLINICAL RELEVANCE: Among the 40 study dogs, the incidence of vomiting associated with hydromorphone administration was 25%. Oral administration of maropitant prevented vomiting but not signs of nausea associated with hydromorphone administration in dogs. PMID- 24786164 TI - Comparison of rectal and axillary temperatures in dogs and cats. AB - OBJECTIVE: To compare rectal versus axillary temperatures in dogs and cats. DESIGN: Prospective observational study. ANIMALS: 94 dogs and 31 cats. PROCEDURES: Paired axillary and rectal temperatures were measured in random order with a standardized method. Animal signalment, initial complaint, blood pressure, blood lactate concentration, and variables associated with vascular perfusion and coat were evaluated for associations with axillary and rectal temperatures. RESULTS: Axillary temperature was positively correlated with rectal temperature (rho = 0.75 in both species). Median axillary temperature (38.4 degrees C [101.1 degrees F] in dogs, and 38.4 degrees C [101.2 degrees F] in cats) was significantly different from median rectal temperature in dogs (38.9 degrees C [102.0 degrees F]) but not in cats (38.6 degrees C [101.5 degrees F]). Median rectal-axillary gradient (difference) was 0.4 degrees C (0.7 degrees F; range, 1.3 degrees to 2.3 degrees C [-2.4 degrees to 4.1 degrees F]) in dogs and 0.17 degrees C (0.3 degrees F; range -1.1 degrees to 1.6 degrees C [-1.9 degrees to 3 degrees F]) in cats. Sensitivity and specificity for detection of hyperthermia with axillary temperature were 57% and 100%, respectively, in dogs and 33% and 100%, respectively, in cats; sensitivity and specificity for detection of hypothermia were 86% and 87%, respectively, in dogs and 80% and 96%, respectively, in cats. Body weight (rho = 0.514) and body condition score (rho = 0.431) were correlated with rectal-axillary gradient in cats. CONCLUSIONS AND CLINICAL RELEVANCE: Although axillary and rectal temperatures were correlated in dogs and cats, a large gradient was present between rectal temperature and axillary temperature, suggesting that axillary temperature should not be used as a substitute for rectal temperature. PMID- 24786165 TI - Yersinia pestis infection in dogs: 62 cases (2003-2011). AB - OBJECTIVE: To describe the epidemiology, clinical signs, and treatment practices in dogs with Yersinia pestis infection in New Mexico. DESIGN: Retrospective case series. ANIMALS: 62 dogs with plague in New Mexico. PROCEDURES: Confirmed case animals had isolation of Yersinia pestis from a clinical specimen, a positive direct fluorescent antibody test result, or a minimum 4-fold change between acute and convalescent serum antibody titers with clinically compatible illness. Retrospective review of cases of laboratory-confirmed plague from 2003 to 2011 was performed with a standardized chart abstraction form. Epidemiologic, clinical, and treatment data were evaluated. RESULTS: 62 confirmed cases of canine plague were identified from 2003 to 2011. Most cases (85%) were confirmed by serologic titers alone or in conjunction with other testing methods. Clinical signs included fever (100%), lethargy (97%), anorexia (77%), lymphadenopathy (23%), vomiting (13%), diarrhea (8%), and abscesses (2%). Most case animals (73%) were treated with multiple antimicrobials. Sixty (97%) case animals survived; of the 2 nonsurvivors, one was euthanized and another died. Potential sources of exposure to Y pestis included hunting, rodent or rabbit exposure, and residence in rural areas. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that dogs with exposure to Y pestis can develop moderate to severe illness or die as a result of infection. Veterinarians practicing in and examining animals from the western United States need to be familiar with the epidemiology of plague and query owners about potential plague exposures when consistent clinical signs are present. Veterinarians are often the first to recognize signs of plague among sentinel populations and have the opportunity to intervene and prevent zoonotic disease transmission. PMID- 24786166 TI - Clinical findings in dogs with incidental adrenal gland lesions determined by ultrasonography: 151 cases (2007-2010). AB - OBJECTIVE: To determine the prevalence of and clinical features associated with incidental adrenal gland lesions (IAGLs) discovered during abdominal ultrasonography in dogs. DESIGN: Retrospective case series. ANIMALS: 151 dogs with an IAGL and 400 control dogs. PROCEDURES: Reports of ultrasonographic examinations of the abdomen of dogs performed during a 3.5-year period were reviewed. Adrenal glands were classified as having an IAGL if a nodule or mass was described or the width of either gland was >= 10 mm. For dogs with an IAGL, information regarding signalment, concurrent disorders, and outcome was obtained from the medical record. Findings were compared with those in a control population of 400 dogs examined during the same period. RESULTS: An IAGL was detected in 151 of 3,748 (4%) dogs. Dogs with an IAGL were significantly older (median age, 11.25 years) and heavier (median body weight, 21 kg [46.2 lb]) than the control population (median age, 9.5 years; median body weight, 14 kg [30.8 lb]). Malignant tumors were reported in 6 of 20 (30%) dogs that underwent adrenal glandectomy or necropsy and had a maximum IAGL dimension that ranged from 20 to 46 mm; benign lesions all had a maximum dimension < 20 mm. Various coincidental conditions were reported in dogs with an IAGL, including nonadrenal gland malignant neoplasia in 43 (28.5%) dogs. CONCLUSIONS AND CLINICAL RELEVANCE: IAGLs were more likely in dogs >= 9 years of age. On the basis of this small data set, malignancy should be suspected for IAGLs >= 20 mm in maximum dimension. PMID- 24786167 TI - Effect of limb positioning on the radiographic appearance of the distal and proximal interphalangeal joint spaces of the forelimbs of horses during evaluation of dorsopalmar radiographs. AB - OBJECTIVE: To determine the effect of limb positioning on the radiographic appearance of the distal and proximal interphalangeal joint spaces of the forelimbs of horses during evaluation of dorsopalmar radiographs. DESIGN: Evaluation study. ANIMALS: 14 forelimbs from 9 adult horses. PROCEDURES: Each horse was in standing position with its forelimbs positioned on blocks. Dorsopalmar radiographs of each foot were obtained with the forelimbs positioned squarely (the metacarpus of both forelimbs was perpendicular to the ground as determined by visual examination [abducted 0 degrees ]; baseline) and abducted 5 degrees and 10 degrees . The width of the space at the medial and lateral aspects of the distal and proximal interphalangeal joints (medial and lateral joint space width, respectively) was measured. Mediolateral joint balance was calculated as the difference between the widths of the lateral and medial joint spaces, and joint space width and mediolateral joint balance were compared among all 3 positions. RESULTS: As the extent of limb abduction increased, the medial aspect of the proximal and distal interphalangeal joints became narrower, compared with the corresponding lateral aspect of those joints. For both the distal and proximal interphalangeal joints, the mediolateral joint balance differed significantly among all limb positions. CONCLUSIONS AND CLINICAL RELEVANCE: Forelimb position significantly affected the mediolateral joint balance of the interphalangeal joints of horses. Thus, it is crucial that the forelimbs of horses be squarely positioned when dorsopalmar radiographs are obtained for accurate evaluation of interphalangeal joint space and balance. PMID- 24786168 TI - Use of a motorized morcellator for elective bilateral laparoscopic ovariectomy in standing equids: 30 cases (2007-2013). AB - OBJECTIVE: To describe the use of a motorized morcellator for elective bilateral laparoscopic ovariectomy in standing equids and to evaluate long-term outcome. DESIGN: Retrospective case series. ANIMALS: 30 equids (20 horses, 9 mules, and 1 pony). PROCEDURES: Medical records of equids undergoing elective bilateral laparoscopic ovariectomy from 2007 to 2013 were evaluated. Cases were selected on the basis of use of a motorized morcellator for ovary extraction. Data collected included age, breed, reason for surgery, surgery date, surgical approach, intraoperative complications, surgery and morcellation times, postoperative complications, and duration of hospitalization. Long-term follow-up was obtained by telephone interview with owners, and included effectiveness at resolving original reason for surgery, time to return to usual activity, incision site appearance, signs of estrus after surgery, and overall owner satisfaction. RESULTS: 30 equids underwent laparoscopic bilateral ovariectomy with the morcellator technique. Median surgery time was 102 minutes (range, 47 to 150 minutes). Median single ovary morcellation time was 3.5 minutes (range, 2 to 8 minutes). Intraoperative complications occurred in 2 of 30 cases and included iatrogenic organ damage (uterus; 1) and persistent hemorrhage (1). Nineteen of 20 mares for which long-term follow-up was available returned to their previous use at a median of 60 days after surgery (range, 21 to 180 days). CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study indicated that use of a mechanical morcellator with a 2-portal technique for bilateral laparoscopic ovariectomy in clinically normal equids eliminated the need for a larger laparotomy incision as well as a third portal. Few complications occurred, and clients were satisfied with the procedure. The morcellator technique may offer advantages over other techniques but should only be used by experienced laparoscopic surgeons following adequate training. PMID- 24786169 TI - Development of a new minipig model to study radiation-induced gastrointestinal syndrome and its application in clinical research. AB - Because of insufficient clinical data regarding acute radiation damage after single high-dose radiation exposure, acute radiation-induced gastrointestinal (GI) syndrome remains difficult to treat. The goal of this study was to establish an appropriate and efficient minipig model to study high-dose radiation-induced GI syndrome after radiation exposure. For endoscopic access to the ileum, ileocutaneous anastomosis was performed 3 weeks before irradiation in six male Gottingen minipigs. Minipigs were locally irradiated at the abdominal area using a gamma source as follows: 1,000 cGy (n = 3) and 1,500 cGy (n = 3). Endoscopic evaluation for the terminal ileum was periodically performed via the ileocutaneous anastomosis tract. Pieces of tissue were serially taken for histological examination. The irradiated intestine presented characteristic morphological changes over time. The most obvious changes in the ileum were mucosal atrophy and telangiectasia from day 1 to day 17 after abdominal irradiation. Microscopic findings were characterized as architectural disorganization, loss of villi and chronic active inflammation. Increase in cyclooxygenase-2 (COX-2) expression was closely correlated with severity of tissue damage and inflammation. Particularly, the plasma citrulline level (PCL), a potential marker for radiation-induced intestinal damage, was significantly decreased the day after irradiation and recovered when irradiated mucosa was normalized. Our results also showed that PCL changes were positively correlated with microscopic changes and the endoscopic score in radiation-induced mucosal damage. In conclusion, the ileocutaneous anastomosis model using the minipig mimics human GI syndrome and allows the study of sequential changes in the ileum, the main target tissue of abdominal irradiation. In addition, PCL could be a simple biomarker for radiation-induced intestinal damage. PMID- 24786171 TI - How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study. AB - Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition-elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman's phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman. PMID- 24786173 TI - Incidence of Recreational Alpine Skiing and Snowboarding Injuries: Six Years Experience in the Largest Ski Resort in Finland. AB - BACKGROUND AND AIMS: The aim of this study was to provide information on incidences and severity of recreational alpine skiing and snowboarding injuries in Northern Finland and to discuss possible preventive measures to reduce the number and severity of injuries in the future. MATERIALS AND METHODS: This retrospective study consists of all injured skiers and snowboarders in the Levi Ski Resort during the 2006-2012 winter seasons. The Levi Ski Resort has a SKIDATA(r) system which records automatically every ski-lift run taking place. The emergency system of the resort registers the data (conditions during the injury, patient characteristics, and observed and/or suspected injuries) of all injured persons they meet. The severity of injury is defined by the needed level of care: Grade 1 (treated by the emergency system with no need for further referral), Grade 2 (referral to the local primacy care clinic), Grade 3 (transfer to hospital by ambulance), and Grade 4 (transfer to tertiary care by helicopter). RESULTS: During the 6-year study period, there were 29,576.132 lift runs and 2911 injuries were met by the emergency system, resulting in the average injury incidence of 0.98 injuries per 10,000 lift runs. Vice versa, the average number of the ski-lift rides needed to generate one injury was 10,160. The knee injuries of the skiers constituted almost one-third of all cases, whereas snowboarders sustained more injuries to the upper limb and axial areas. CONCLUSION: Skiing and snowboarding are related to a relatively high risk of injury. The most common injuries affect the knee in skiers and the upper extremity, especially the wrist, in snowboarders. A continuous and systematic review of injuries is needed to monitor the effects of changes made in terms of the safety. PMID- 24786172 TI - Trauma-Induced Coagulopathy: An Institution's 35 Year Perspective on Practice and Research. AB - INTRODUCTION: Injury is the second leading cause of death worldwide, and as much as 40% of injury-related mortality is attributed to uncontrollable hemorrhage. This persists despite establishment of regionalized trauma systems and advances in the management of severely injured patients. Trauma-induced coagulopathy has been identified as the most common preventable cause of postinjury mortality. METHODS: A review of the current literature was performed by collecting PUBMED references related to trauma-induced coagulopathy. Data were then critically analyzed and summarized based on the authors' clinical and research perspective, as well as that reported by other institutions and researchers interested in trauma-induced coagulopathy. A particular focus was placed on those aspects of coagulopathy in which agreement among clinical and basic scientists is currently lacking; these include, pathophysiology, the role of blood components and factor therapy, and goal-directed assessment and management. RESULTS: Trauma-induced coagulopathy has been recognized in approximately one-third of trauma patients. There is a vast range of severity, and the emergence of viscoelastic assays, such as thrombelastography and rotational thromboelastogram, has refined its diagnosis and management, particularly through the establishment of goal-directed massive transfusion protocols. Despite advancements in the diagnosis and management of trauma-induced coagulopathy, much remains to be understood regarding its pathophysiology. The cell-based model of hemostasis has allowed for characterization of endothelial dysfunction, impaired thrombin generation, platelet dysfunction, fibrinolysis, endogenous anticoagulants such as protein-C, and antifibrinolytic proteins. These concepts collectively compose the contemporary, but still partial, understanding of trauma-induced coagulopathy. CONCLUSION: Trauma-induced coagulopathy is a complex pathophysiological condition, of which some mechanisms have been characterized, but much remains to be understood in order to translate this knowledge into improved outcomes for the injured patient. PMID- 24786174 TI - Potent adjuvant effects of novel NKT stimulatory glycolipids on hemagglutinin based DNA vaccine for H5N1 influenza virus. AB - H5N1 influenza virus is a highly pathogenic virus, posing a pandemic threat. Previously, we showed that phenyl analogs of alpha-galactosylceramide (alpha GalCer) displayed greater NKT stimulation than alpha-GalCer. Here, we examined the adjuvant effects of one of the most potent analogs, C34, on consensus hemagglutinin based DNA vaccine (pCHA5) for H5N1 virus. Upon intramuscular electroporation of mice with pCHA5 with/without various alpha-GalCer analogs, C34 adjuvanted group developed the highest titer against consensus H5 and more HA specific IFN-gamma secreting CD8 cells (203+/-13.5) than pCHA5 alone (152.6+/ 13.7, p<0.05). Upon lethal challenge of NIBRG-14 virus, C34-adjuvanted group (84.6%) displayed higher survival rate than pCHA5 only group (46.1%). In the presence of C34 as adjuvant, the antisera displayed broader and greater neutralizing activities against virions pseudotyped with HA of clade 1, and 2.2 than pCHA5 only group. Moreover, to simulate an emergency response to a sudden H5N1 outbreak, we injected mice intramuscularly with single dose of a new consensus H5 (pCHA5-II) based on 1192 full-length H5 sequences, with C34 as adjuvant. The latter not only enhanced the humoral immune response and protection against virus challenge, but also broadened the spectrum of neutralization against pseudotyped HA viruses. Our vaccine strategy can be easily implemented for any H5N1 virus outbreak by single IM injection of a consensus H5 DNA vaccine based on updated HA sequences using C34 as an adjuvant. PMID- 24786175 TI - Women's health in women's hands: a pilot study assessing the feasibility of providing women with medications to reduce postpartum hemorrhage and sepsis in rural Tanzania. AB - In rural Africa, deaths from childbirth are common and access to health care facilities with skilled providers is very limited. Leading causes of death for women are bleeding and infection. In this pilot study, we establish the feasibility of distributing oral medications to women in rural Tanzania to self administer after delivery to reduce bleeding and infection. Of the 642 women provided with medications, 90% of the women took them appropriately, while the remaining 10% did not require them. We conclude that is it feasible to distribute oral medications to rural women to self-administer after delivery. PMID- 24786176 TI - Self-immolative polymersomes for high-efficiency triggered release and programmed enzymatic reactions. AB - Stimuli-triggered disassembly of block copolymer vesicles or polymersomes has been conventionally achieved via solubility switching of the bilayer-forming block, requiring cooperative changes of most of the repeating units. Herein we report an alternative approach by incorporating hydrophobic blocks exhibiting stimuli-triggered head-to-tail cascade depolymerization features. Amphiphilic block copolymers bearing this motif self-assemble into self-immolative polymersomes (SIPsomes). By modular design of terminal capping moieties, visible light, UV light, and reductive milieu can be utilized to actuate SIPsomes disintegration into water-soluble small molecules and hydrophilic blocks. The design of SIPsomes allows for triggered drug co-release and controllable access toward protons, oxygen, and enzymatic substrates. We also demonstrate programmed (OR-, AND-, and XOR-type logic) enzymatic reactions by integrating SIPsome encapsulation and trigger/capping moiety-selective cascade depolymerization events. PMID- 24786177 TI - Transapical aortic valve and mitral valve in ring prosthesis implantation - a new advance in transcatheter procedures. AB - Transcatheter valve implantation offers a new treatment modality to those patients whose general condition makes conventional surgery very risky. However, the transcatheter option has only been available for the aortic valve. We describe a case of a successful implantation of two Edwards SAPIEN((r)) 26 and 29 mm transapical valves, respectively, in aortic and mitral positions, on a 74-year old patient with severe aortic and mitral stenosis. The procedure progressed uneventfully. Predischarge echocardiogram showed a peak aortic gradient of 20 mmHg, mild periprosthetic regurgitation, peak and mean mitral gradients of 12 and 4, respectively, and moderate (II/IV) periprosthetic regurgitation. Indications for transapical valve implantation will rapidly increase in the near future. It is essential to individualize the treatment be applied for each patient, in order to optimize the success of the procedure. PMID- 24786178 TI - Severe stenosis of left coronary artery originating from right sinus of Valsalva treated with off-pump coronary artery bypass surgery. AB - Anomalous origin of the left coronary artery originating from the opposite sinus of Valsalva is a coronary anomaly with a consistently low prevalence rate. Different patterns have been described for this type of anomaly with respect to the position and course of the coronary arteries. The interarterial type can be considered a malignant variant, as it is characterized by a left main coronary artery that is positioned between the aortic root and the pulmonary artery root, and it frequently presents with syncope or aborted sudden cardiac death. Other symptoms or clinical presentations include the presence or development of angina, acute myocardial infarction and ventricular tachycardia. We present the case of a 49-year old man who presented with a new onset of chest pain; a coronary angiogram showed an anomalous left main coronary artery arising from the right Valsalva sinus, accompanied by a long and severe stenosis. It was found that multi-scan cardiac tomography is very useful in identifying the position of the coronary arteries when coronary anomalies occur. PMID- 24786179 TI - IgG3 is the dominant subtype of anti-isoniazid antibodies in patients with isoniazid-induced liver failure. AB - Isoniazid (INH) therapy is associated with a significant incidence of idiosyncratic liver failure. We recently reported eight cases of INH-induced liver failure in which patients had antidrug and anticytochrome P450 antibodies. However, it was unclear what role these antibodies play in the mechanism of INH induced liver injury. Here, we report that the dominant isotype of anti-INH antibodies was IgG, with IgG3 being the dominant subtype. IgG3 antibodies are associated with a Th1-type immune response and fix complement. IgG3 antibodies have been associated with other forms of liver injury and may play a pathogenic role in INH-induced liver injury. PMID- 24786180 TI - Age, gender, and interracial variability of normal lacrimal gland volume using MRI. AB - PURPOSE: Aimed to evaluate normal volume of the lacrimal gland in patients of different age groups and race. METHODS: All MRI studies of the brain that were done between June 2012 and April 2013 were examined. Lacrimal glands were identified using fat-saturated fluid-attenuated inversion recovery (FLAIR) images, and the volumes were calculated using TeraRecon iNtuition viewer. Volumes for the right and left lacrimal glands were recorded for persons of different age groups and race, and the results were compared with those of a randomly selected group of patients who had undergone the same calculation method using CT of the brain, orbit, or paranasal sinuses. RESULTS: The authors included 998 lacrimal glands of 499 patients. The mean volumes for the right and left lacrimal glands were 0.770 and 0.684 cm, respectively. Lacrimal glands were larger in women; the largest volumes were observed during the second decade of life. Mean volumes also varied with race: 0.840 cm in Asians, 0.790 cm in Africans, 0.760 cm in Indians, and 0.710 cm in Middle Easterners. The consultant neuroradiologist and the intern showed excellent agreement for measurements of lacrimal gland volume. No significant difference was observed between lacrimal gland measurements method on MRI and CT. CONCLUSION: Lacrimal gland volume varies according to age, gender, race, and laterality. Measurements with MRI using fat-saturated FLAIR images and TeraRecon iNtuition viewer software are reliable, accurate, and can be used by junior staff with less radiation exposure to patients. PMID- 24786181 TI - A special issue on plant stress biology: from model species to crops. PMID- 24786183 TI - Mycosis inhibits cannibalism by Melanoplus sanguinipes, M. differentialis, Schistocerca americana, and Anabrus simplex. AB - Cannibalism is common among the Acrididae and the Mormon cricket, Anabrus simplex Haldeman (Orthoptera: Tettigoniidae). This behavior has been proposed as a mechanism for the horizontal transmission of Microsporida and entomopathogenic fungi. Aanecdotal observations suggested that the migratory grasshopper, Melanoplus sanguinipes Fabricius (Acrididae), and A. simplex did not eat cadavers that had been killed by insect pathogenic fungi. The hypothesis tested was that A. simplex or M. sanguinipes would not cannibalize individuals freshly killed by the entomopathogenic fungi, Beauveria bassiana Bals.-Criv. (Vuill.) (Hypocreales: Clavicipitaceae), or Metarhizium acridum (Driver and Milner) Bischoff, Rehner, and Humber. Cannibalism was examined in a series of no-choice tests with individual insects. Test insects included healthy adults of M. sanguinipes; the differential grasshopper, M. differentialis (Thomas); the American grasshopper, Schistocerca americana (Drury) (Acrididae); and A. simplex. Individual, starved Acrididae or A. simplex were confined in small cages with either a fungus-killed (but unsporulated) or uninfected cadaver. The insects were then observed periodically for the first 4 hr. After 24 hr, the cadavers were scored for the degree to which they had been consumed. Very few mycotic cadavers were fed upon by the healthy insects, and, at most only the tarsi were eaten. All four species generally refused to eat fungus-infected cadavers. In contrast, freeze-killed cadavers were partly or entirely consumed by most of the test insects, often within a few hours. Transmission of infection through contact in these tests was between 0-18.9%, depending upon the fungus and insect species, and was lower than the prevalence of cannibalism in all cases. PMID- 24786184 TI - Distinctive interactions of oleic acid covered magnetic nanoparticles with saturated and unsaturated phospholipids in Langmuir monolayers. AB - The growing number of innovations in nanomedicine and nanobiotechnology are posing new challenges in understanding the full spectrum of interactions between nanomateriales and biomolecules at nano-biointerfaces. Although considerable achievements have been accomplished by in vivo applications, many issues regarding the molecular nature of these interactions are far from being well understood. In this work, we evaluate the interaction of hydrophobic magnetic nanoparticles (MNP) covered with a single layer of oleic acid with saturated and unsaturated phospholipids found in biomembranes through the use of Langmuir monolayers. We find distinctive interactions among the MNP with saturated and unsaturated phospholipids that are reflected by both, the compression isotherms and the surface topography of the films. The interaction between MNP and saturated lipids causes a noticeable reduction of the mean molecular area in the interfacial plane, while the interaction with unsaturated lipids promotes area expansion compared to the ideally mixed films. Moreover, when liquid expanded and liquid condensed phases of the phospholipid(s) coexist, the MNP preferably partition to the liquid-expanded phase, thus hindering the coalescence of the condensed domains with increasing surface pressure. In consequence organizational information on long-range order is attained. These results evidence the existence of a sensitive composition-dependent surface regulation given by phospholipid nanoparticle interactions which enhance the biophysical relevance of understanding nanoparticle surface functionalization in relation to its interactions in biointerfaces constituted by defined types of biomolecules. PMID- 24786185 TI - Immunotoxicity risk assessment for chemicals and regulatory science. PMID- 24786186 TI - Provider counseling to young women seeking family planning services. AB - CONTEXT: Contraceptive nonuse and misuse contribute to rates of unintended pregnancy and STDs among young women in the United States. Clinical providers assume an important role in guiding youths' contraceptive method choices. METHODS: Sixty-seven women aged 16-21 were recruited as part of a cohort study, conducted in 2009-2012, that examined provider-patient interactions during family planning visits at six San Francisco clinics. Interactions between patients and providers were audio-recorded. Participants completed questionnaires about method preference immediately before seeing the provider; they reported on method choice immediately after the visit and by telephone three and six months later. Transcripts were analyzed to examine providers' strategies for guiding decision making and addressing youths' contraceptive concerns. Missed opportunities for promoting young women's reproductive health were identified. RESULTS: Twenty-one percent of young women who did not report desiring a hormonal or long-acting reversible method (IUD or implant) before seeing their provider chose one after counseling. Use of a hormonal or long-acting reversible contraceptive method at follow-up was more common among women who had received interactive counseling by providers who guided them to consider contextual influences than among those who had not received such counseling. Attention to relationship characteristics, sexual behavior patterns and STD risk was largely absent from contraceptive counseling. CONCLUSION: High-quality strategies used by providers to guide contraceptive decision making were tailored to adolescents' developmental and environmental needs. Several areas of counseling require increased attention and seem vital to providing comprehensive reproductive health care to adolescents. PMID- 24786187 TI - Management of refractory telaprevir-induced dermatitis using oral corticosteroids. AB - We present a series of 12 patients with telaprevir-induced skin toxicity. Some patients presented eczematous lesion, while others presented nonscaling macular lesions that became more purpuric in the lower limbs. Seven of the 12 patients had skin lesions affecting more than 50% of the body surface area, but none had systemic manifestations. Oral corticosteroids, prescribed in 7 patients, produced symptomatic improvement, and the response to the antiviral treatment in these patients was good. The 3 biopsies performed showed a superficial perivascular dermatitis with foci of red cell extravasation. Monitoring is central to the management of skin reactions secondary to the protease inhibitors, as severe drug eruptions have been reported. Treatment is usually symptomatic. We describe 7 cases in which oral corticosteroids-whose use continues to be controversial -were administered as a last resort for the control of pruritus. PMID- 24786188 TI - Sodium content of bread from bakeries and traditional markets in Maputo, Mozambique. AB - OBJECTIVE: The Na content of bread is one of the most common targets of initiatives to reduce Na intake worldwide. Assessing the Na content of staple foods is of major relevance in Mozambique, given the high burden of hypertension in this setting. We aimed to estimate the Na content of white bread available in different bakeries and markets in Maputo. DESIGN: A cross-sectional study of the Na content of white bread available for sale at twenty-five bakeries and markets in Mozambique. Flame photometry was used to quantify the Na content of the bread. The percentage of samples meeting manufacturer Na targets from South Africa and six countries from other regions, selected as benchmarks, was computed. SETTING: Maputo, Mozambique. SUBJECTS: Three loaves of white bread from each selected bakery/market. RESULTS: The mean Na content of bread was 450.3 mg/100 g (range: 254.9-638.3 mg/100 g), with no significant differences between bakeries and traditional markets. Most samples (88 %) did not meet the regulation in South Africa (<= 380 mg/100 g). When considering the targets from other countries (range: <= 360-550 mg/100 g), the prevalence of non-compliance varied between 8 % and 92 %. There were no significant differences in the price of bread with Na content below and above the targets. CONCLUSIONS: The content of Na in bread varies widely in Mozambique, reaching high values in a high proportion of the bakeries and markets in Maputo. Measures to regulate the Na content in bread may contribute to a reduction in Na intake and improved health at the population level. PMID- 24786189 TI - Identification and quantitative determination of the polar constituents in Helichrysum italicum flowers and derived food supplements. AB - Helichrysum italicum is widely used in traditional medicine, in cosmetic, in food and pharmaceutical field. In spite of this, very little is known about the chemical composition of its polar extracts. Therefore this study was addressed to the determination of the metabolite profile of the methanol extract of H. italicum flowers, by using LC-ESI(IT)MSMS. This approach oriented the isolation of 14 compounds, whose structures were unambiguously elucidated by NMR as belonging to flavonoid, phenylpropanoid and acylbenzofuran classes. In addition, one novel drimane sesquiterpene was identified. The quantitative determination of the main compounds occurring in the methanol extract of H. italicum flowers was carried out and their content was compared with that of three selected commercial food supplements based on H. italicum, by using LC-ESI(QqQ)MS. In conclusion the wide occurrence, in high amounts, of quinic acid derivatives in all the analyzed samples was highlighted, showing these compounds as chemical markers of the species for standardization procedures. PMID- 24786190 TI - Liquid chromatography-tandem mass spectrometry for simultaneous measurement of thromboxane B2 and 12(S)-hydroxyeicosatetraenoic acid in serum. AB - Arachidonic acid (AA) is metabolized in human platelets by two main pathways: via cyclooxygenase (COX-1) to prostaglandins and thromboxane (TX)A2 and via 12 lipoxygenase (12-LOX) to 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). While COX products are known to regulate platelet reactivity, the role of 12-LOX metabolites is still controversial. To better understand the platelet enzymatic pathways, we developed a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous measurement of both platelet metabolites in human serum. After the addition of deuterated d4-TXB2 and d8-12(S) HETE as internal standards and the solid-phase extraction of serum samples, analytes were resolved using reversed-phase C18 column and quantified using negative ion electrospray ionization-tandem mass spectrometry. Intra and interassay imprecisions were less than 10% for both analytes. The lower limits of quantification were 0.244ng/ml and 0.976ng/ml for TXB2 and 12(S)-HETE, respectively. This method was applied to measure platelet metabolites in healthy subjects (n=35). LC-MS/MS allows rapid, simultaneous, sensitive and accurate quantification of both platelet AA products in human serum with a small sample volume required and a minimal sample preparation. PMID- 24786191 TI - Putting a terbium-monometallic cyanide cluster into the C82 fullerene cage: TbCN@C2(5)-C82. AB - The first terbium (Tb)-monometallic cyanide clusterfullerene (CYCF), TbCN@C82, has been successfully synthesized and isolated, whose molecular structure was determined unambiguously as TbCN@C2(5)-C82 by single crystal X-ray diffraction. The C2(5)-C82 isomeric cage represents a new cage capable of encapsulating a monometallic cyanide cluster. The C-N bond length within the encaged TbCN cluster is determined to be 0.94(5) A, which is smaller by at least 0.17 A than those of the reported C-N triplet bonds in traditional cyanide/nitrile compounds and cyano coordination complexes. An electronic configuration of [Tb(3+)(CN)( )](2+)@[C82](2-) was proposed for TbCN@C82. PMID- 24786192 TI - Effects of water activity and low molecular weight humectants on skin permeability and hydration dynamics - a double-blind, randomized and controlled study. AB - OBJECTIVES: The mammalian skin is a barrier that effectively separates the water rich interior of the body from the normally dryer exterior. Changes in the external conditions, for example ambient humidity, have been shown to affect the skin barrier properties. The prime objective of this study was to evaluate the effect of water activity of a topical formulation on skin hydration and permeability. A second objective was to gain more understanding on how two commonly used humectants, urea and glycerol, affect skin barrier function in vivo. METHODS: Simple aqueous formulations were applied under occlusion to the volar forearm of healthy volunteers. Following 4-h exposure, skin water loss (by transepidermal water loss measurements), skin hydration (by Corneometry) and skin permeability (by time to vasodilation due to benzyl nicotinate exposure) were monitored. RESULTS: The results demonstrate that a relatively small change in the water activity of a topical formulation is sufficient to induce considerable effects on stratum corneum hydration and permeability to exogenous substances. Exposing the skin to high water activity leads to increased skin hydration and also increased permeability. Furthermore, urea and glycerol promote skin hydration and permeability even at reduced water activity of the applied formulation. CONCLUSION: These results highlight the importance of considering the water activity in topically applied formulations and the potential benefit of using humectants. The results may impact formulation optimization in how to facilitate skin hydration and to modify skin permeability by temporarily open and close the skin barrier. PMID- 24786193 TI - X-ray photoemission study of CeTIn(5) (T = Co, Rh, Ir). AB - We investigated CeTIn5 (T = Co, Rh, Ir) using temperature- and angle-dependent x ray photoemission spectroscopy. The Ce 3d core level has a very similar shape for all three materials and is indicative of weak f-hybridization. The spectra were analyzed using a simplified version of the Anderson impurity model, which yields a Ce 4f occupancy that is larger than 0.9. The temperature dependence shows a continuous, irreversible and exclusive broadening of the Ce 3d peaks, due to oxidation of Ce at the surface. PMID- 24786194 TI - Carotid endarterectomy in octogenarian: short- and midterm results. AB - BACKGROUND: Randomized controlled trials that have established recommendations for carotid surgery have excluded patients >79 years of age, and in our day to day practice, patients in this age group are becoming more common. We sought to analyze the outcomes of carotid endarterectomy (CEA) in octogenarians, determine the risk factors of morbidity and mortality, and evaluate the midterm survey of these patients. METHODS: Age was the only selection criteria for inclusion in this study. We compared symptomatic and asymptomatic populations and retrospectively analyzed the CEA results performed in patients >=80 years of age in each group. We calculated the combined ipsilateral stroke/death for each group. RESULTS: In the 6-year study period (2002-2007), 132 CEAs were performed in 118 octogenarians. The mean age was 83.2 years (range: 80-93), and there were 70 men (59.3%) and 48 women (40.6%). In this study group, 37.9% of patients were symptomatic and 62.1% were asymptomatic; the rate of internal carotid stenosis was 81.6% (standard deviation: +/-8.5%). The combined ipsilateral stroke/death rate was 3.79% (4 deaths and 1 stroke): 2% in the symptomatic patients and 4.88% in the asymptomatic patients. No differences were found between the groups' combined ipsilateral stroke/death rate (P > 0.05), but there were significant more patients with coronary artery disease and peripheral artery disease in the asymptomatic patients. A contralateral significant internal carotid stenosis was a risk factor of combined ipsilateral stroke and death (P = 0.024). The mean duration of follow-up was 3.8 +/- 2.0 years, and 73% +/- 5% of the patients were alive at 3 years. CONCLUSION: The good immediate results and good probability of survival at 3 years after surgery conveys a real benefit of this surgery in this age group, but patients should be selected on a case by case basis. In our experience, the presence of bilateral lesions should be a significant influence criterion in the preoperative risk assessment. Other evaluation criteria, such as cardiac status, are needed to optimize the selection of asymptomatic patients in particular. PMID- 24786195 TI - The effect of season and track condition on injury rate in racing greyhounds. AB - OBJECTIVES: To identify environmental and management factors affecting injury rate in racing greyhounds. METHODS: Surveys of racing injuries at two greyhound tracks in the UK were conducted using injury data collected by track veterinary surgeons. At Track A the relative frequency of common injuries was determined and compared with previously published studies conducted in the UK. At Track B the effects of month of the year, ambient temperature and track condition ("going") on injury rate were determined. RESULTS: Comparison of common injuries at Track A with previous studies suggested a change in the relative frequency of some injury types following a change in track surface from grass to sand. Estimated injury rates suggest improved track safety with the change in track surface. At Track B, injury rate increased significantly with faster track conditions. Time of year and ambient temperature had no significant effect on injury rate. CLINICAL SIGNIFICANCE: Changes in track maintenance resulting in a slower track may reduce injury rate in racing greyhounds, with associated welfare benefits. PMID- 24786196 TI - Effects of Jitai tablet, a traditional Chinese medicine, on plasma adrenocorticotropic hormone and cortisol levels in heroin addicts during abstinence. AB - OBJECTIVES: To investigate the changes in adrenocorticotropic hormone (ACTH) and cortisol in heroin addicts given Jitai tablet treatment during abstinence. DESIGN: Double-blind, randomized, placebo-controlled clinical trial. SETTINGS/LOCATION: Drug Rehabilitation Bureau of Shanghai Police, China. PARTICIPANTS: 99 volunteers, including 69 heroin addicts and 30 healthy volunteers. INTERVENTIONS: 69 heroin addicts randomly divided into two groups: the Jitai tablet group, which comprised 34 heroin addicts given Jitai tablet treatment during abstinence, and the placebo group, which comprised 35 heroin addicts given placebo. A control group consisted of 30 sex- and age-matched healthy volunteers. OUTCOME MEASURES: ACTH and cortisol in plasma were measured in all groups at baseline and in the Jitai tablet and placebo groups on the third, seventh, and 14th days of abstinence. RESULTS: Levels of both ACTH (p<.01) and cortisol (p<.001) were significantly higher in heroin addicts at baseline than in the healthy volunteers. Jitai tablet treatment restored plasma cortisol levels to normal more rapidly than did placebo treatment (p<.05), but not ACTH levels. A positive correlation between ACTH and cortisol values at baseline (p<.01) was also found with withdrawal symptom scores and daily dosages of heroin. CONCLUSIONS: Heroin addicts could respond to Jitai tablets through changes in the hypothalamus-pituitary-adrenal axis. PMID- 24786197 TI - Potential energy surfaces and reaction pathways for light-mediated self organization of metal nanoparticle clusters. AB - Potential energy surfaces are the central concept in understanding the assembly of molecules; atoms form molecules via covalent bonds with structures defined by the stationary points of the surfaces. Similarly, dispersion interactions give Lennard-Jones potentials that describe atomic clusters and liquids. The formation of molecules and clusters can follow various pathways depending on the initial conditions and the potentials. Here we show that analogous mechanistic effects occur in light-mediated self-organization of metal nanoparticles; atoms are replaced by silver nanoparticles that are arranged by electrodynamic (that is, optical trapping and optical binding) interactions. We demonstrate this concept using simple Gaussian optical fields and the formation of stable clusters with various two-dimensional (2D) and three-dimensional (3D) geometries. The formation of specific clusters is 'path-dependent'; the particle motions follow an electrodynamic potential energy surface. This work paves the way for rational design of photonic clusters with combinations of imposed beam shapes, gradients and optical binding interactions. PMID- 24786198 TI - Relationships and health. PMID- 24786199 TI - Beyond relational oblivion. PMID- 24786200 TI - The other mother: a narrative analysis of the postpartum experiences of nonbirth lesbian mothers. AB - The purpose of this study was to develop a metastory of nonbiological lesbian mothers' postpartum experiences utilizing Riessman's structural approach to thematic analysis. Ten nonbirth lesbian mothers were interviewed. Each shared a unique story of her first year of motherhood. Themes were individually analyzed within each story. The metastory of the postpartum experiences of nonbirth lesbian mothers revealed 6 themes including the following: At the mercy of health care providers, Nursing is the major difference between us, Defined by who I am not, Fighting for every piece of motherhood: The world can take them away, What's in a name?, and Epilogue: The new normal. PMID- 24786201 TI - Professionalizing familial care: examining nurses' unpaid family care work. AB - An emergent grounded theory was used to examine Professionalizing Familial Care, the processes by which registered nurses enact professional care work within the familial care domain. A sample of registered nurses (n = 32) were interviewed by telephone at multiple time points over a 6- to 12-month period. The findings revealed that the professionalization of care work was often reinforced by societal, familial, and self-expectations. Setting Limits and Making Connections were the dialectical overarching processes shaping the professionalizing of care while 6 interdependent substrategies emerged: assessing, advising, advocating, collaborating, coordinating, and consulting. These findings will help inform refinement of policies and practices for nurses who provide care for an older relative. PMID- 24786202 TI - Caring as emancipatory nursing praxis: the theory of relational caring complexity. AB - In the culture of health care, nurses are challenged to understand their values and beliefs as humanistic within complex technical and economically driven bureaucratic systems. This article outlines the language of social justice and human rights and the advance of a Theory of Relational Caring Complexity, which offers insights into caring as emancipatory nursing praxis. Recommendations provide knowledge of the struggle to balance economics, technology, and caring. As nurses practice from a value-driven, philosophical, and ethical social justice framework, they will find "their voice" and realize the full potential that the power of caring has on patient and organizational outcomes. PMID- 24786203 TI - Critical perspectives on nursing as bodywork. AB - Nursing is grounded in care of the body. This article examines nursing as bodywork, as experienced intersubjectively by nurses together with patients and collectively as a body within the health care labor force. The relation of nurses to the body generates conflicting and contradictory social meanings from intimate and sacred work to dirty work. Such meanings have contributed to stigmatizing the work and the worker within the labor force as well contributing to an ongoing stratification in the labor force as nurses have shifted bodywork "to lower level" or ancillary workers. PMID- 24786204 TI - Informed advocacy: rural, remote, and northern nursing praxis. AB - To explore what we have learned about informed advocacy from and with nurses working in rural, remote, and northern communities. Focuses on registered nurses who work in geographically isolated communities in Canada. A synthesis of the work of 2 nurse researchers drawing on critical feminist, postcolonial, and social justice theories. The following 4 types of advocacy are discussed: (1) ensuring that people's concerns are heard, (2) contextualizing practices, (3) safeguarding, and (4) addressing systemic health inequities. An informed advocacy perspective helps registered nurses make an important contribution toward improving the health of people living in rural, remote, and northern communities. PMID- 24786205 TI - Family adjustment across cultural groups in autistic spectrum disorders. AB - This pilot ethnomethodological study examined perceptions of parents/caregivers of children diagnosed with autistic spectrum disorders concerning actions, norms, understandings, and assumptions related to adjustment to this chronic illness. The sample included 14 caregivers (75% Hispanic of various ethnic groups). Maximum variation sampling was used to compare participants on variables that were inductively derived via constant comparative methods of analysis. The following action categories emerged: "Seeking Diagnosis," "Engaging in Routines to Control behavior," "Finding Therapies (Types of Therapies)," "Finding School Accommodations," "Educating Others," "Rising to Challenges," and "Finding the Role of Spiritual and Religious Belief." PMID- 24786206 TI - SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. AB - Breast cancer mortality is principally due to tumor recurrence; however, the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the suppressor of cytokine signaling protein SPSB1 is spontaneously upregulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that preexisting SPSB1-overexpressing tumor cells are selected for following HER2/neu downregulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in patients with breast cancer in a manner that is dependent upon c-MET activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer. SIGNIFICANCE: The principal cause of death from breast cancer is recurrence. This study identifies SPSB1 as a critical mediator of breast cancer recurrence, suggests activation of the SPSB1-c-MET pathway as an important mechanism of therapeutic resistance in breast cancers, and emphasizes that pharmacologic targets for recurrence may be unique to this stage of tumor progression. PMID- 24786208 TI - Study of electrode pattern design for a CZT-based PET detector. AB - We are developing a 1 mm resolution small animal positron emission tomography (PET) system using 3D positioning cadmium zinc telluride photon detectors comprising 40 mm * 40 mm * 5 mm crystals metalized with a cross-strip electrode pattern with a 1 mm anode strip pitch. We optimized the electrode pattern design for intrinsic sensitivity and spatial, energy and time resolution performance using a test detector comprising cathode and steering electrode strips of varying dimensions. The study found 3 and 5 mm width cathode strips locate charge-shared photon interactions near cathode strip boundaries with equal precision. 3 mm width cathode strips exhibited large time resolution variability as a function of photon interaction location between the anode and cathode planes (~26 to ~127.5 ns full width at half maximum (FWHM) for 0.5 mm and 4.2 mm depths, respectively). 5 mm width cathode strips by contrast exhibited more stable time resolution for the same interaction locations (~34 to ~83 ns FWHM), provided more linear spatial positioning in the direction orthogonal to the electrode planes, and as much as 68.4% improvement in photon sensitivity over the 3 mm wide cathode strips. The results were understood by analyzing the cathode strips' weighting functions, which indicated a stronger 'small pixel' effect in the 3 mm wide cathode strips. Photon sensitivity and anode energy resolution were seen to improve with decreasing steering electrode bias from 0 to -80 V w.r.t. the anode potential. A slight improvement in energy resolution was seen for wider steering electrode strips (400 versus 100 um) for charge-shared photon interactions. Although this study successfully focused on electrode pattern features for PET performance, the results are generally applicable to semiconductor photon detectors employing cross-trip electrode patterns. PMID- 24786209 TI - N-gram support vector machines for scalable procedure and diagnosis classification, with applications to clinical free text data from the intensive care unit. AB - BACKGROUND: Existing risk adjustment models for intensive care unit (ICU) outcomes rely on manual abstraction of patient-level predictors from medical charts. Developing an automated method for abstracting these data from free text might reduce cost and data collection times. OBJECTIVE: To develop a support vector machine (SVM) classifier capable of identifying a range of procedures and diagnoses in ICU clinical notes for use in risk adjustment. MATERIALS AND METHODS: We selected notes from 2001-2008 for 4191 neonatal ICU (NICU) and 2198 adult ICU patients from the MIMIC-II database from the Beth Israel Deaconess Medical Center. Using these notes, we developed an implementation of the SVM classifier to identify procedures (mechanical ventilation and phototherapy in NICU notes) and diagnoses (jaundice in NICU and intracranial hemorrhage (ICH) in adult ICU). On the jaundice classification task, we also compared classifier performance using n-gram features to unigrams with application of a negation algorithm (NegEx). RESULTS: Our classifier accurately identified mechanical ventilation (accuracy=0.982, F1=0.954) and phototherapy use (accuracy=0.940, F1=0.912), as well as jaundice (accuracy=0.898, F1=0.884) and ICH diagnoses (accuracy=0.938, F1=0.943). Including bigram features improved performance on the jaundice (accuracy=0.898 vs 0.865) and ICH (0.938 vs 0.927) tasks, and outperformed NegEx-derived unigram features (accuracy=0.898 vs 0.863) on the jaundice task. DISCUSSION: Overall, a classifier using n-gram support vectors displayed excellent performance characteristics. The classifier generalizes to diverse patient populations, diagnoses, and procedures. CONCLUSIONS: SVM-based classifiers can accurately identify procedure status and diagnoses among ICU patients, and including n-gram features improves performance, compared to existing methods. PMID- 24786210 TI - Expression and clinical significance of galectin-3 in osteosarcoma. AB - Galectin-3 is a multifunctional beta-galactoside-binding protein which has been shown to play a role in carcinogenesis. However, the involvement of galectin-3 in osteosarcoma remains unclear. In this study, we aimed to examine the serum level of galectin-3 in osteosarcoma patients and healthy controls, and the protein expression of galectin-3 in osteosarcoma tissues and their adjacent non-malignant tissues. We further aimed to investigate the clinical significance of galectin-3 serum and protein expression levels. Galectin-3 serum level was evaluated using ELISA in 132 osteosarcoma patients and 184 healthy controls, while the protein expression of galectin-3 was determined using immunohistochemistry in the malignant and the surrounding non-malignant tissues of the same 132 osteosarcoma patients. Our results showed that the mean galectin-3 serum level was significantly higher in patients than in controls (2.35 +/- 0.91 ng/ml vs. 0.86 +/- 0.20 ng/ml) (p<0.0001). Among patients, a higher galectin-3 serum level was significantly associated with the Enneking stage of cancer (p<0.0001). In addition, we found a significant overrepresentation of high galectin-3 expression in osteosarcoma tissues than in non-malignant tissues (p<0.0001). Galectin-3 expression in osteosarcoma tissues was also found to be correlated with the Enneking stage of cancer (p<0.0001) and the occurrence of metastasis (p<0.0001). In conclusion, galectin-3 could serve as a useful prognostic marker in osteosarcoma. PMID- 24786211 TI - A study of the role of GATA2 gene polymorphism in coronary artery disease risk traits. AB - The GATA2 is a multi-catalytic transcription factor believed to play an important role in regulating inflammatory processes, largely contributory to cardiovascular related events. However, its role in coronary artery disease (CAD) risk traits remains poorly understood. In a preliminary study using Affymetrix 250K, we established a link on chromosome (chr) 3, which harbors the GATA2 gene, to early onset of CAD in two families with heterozygous familial hyperlipidemia (HFH), suggesting a role for the gene in metabolic-related CAD in the general population. We then sequenced the gene in the families and an additional 200 individuals in the general population, followed by an association study for 8 SNPs on CAD metabolic risk traits in a total of 4557 individuals (2386 CAD cases versus 2171 angiographed controls) by the Applied Biosystems real-time PCR system. The rs1573949_C [1.15(1.00-1.32); p=0.049] was associated with MI, rs7431368_AA [5.2(1.05-26.60); p=0.43] conferred risk for harboring low high density lipoprotein, and obesity was linked to rs10934857_AA [5.69(1.04-30.98); p=0.045] following Bonferroni corrections and multivariate adjustments for confounders. Furthermore, a haplotype CCCGGGTC (chi(2)=4.23; p=0.04) constructed from the eight studied SNPs and its 6-mer derivative CGGGTC (chi(2)=5.05; p=0.025) were associated with CAD. Obesity was associated with the 6-mer CATAAA (chi(2)=3.66; p=0.049), and hypercholesterolemia was linked to the 8-mer CCTGGACC (chi(2)=6.02; p=0.014), but most significantly so with its 5-mer derivative, CTGGA (chi(2)=6.75; p=0.009). On the other hand, high low density lipoprotein was linked to TGG (chi(2)=4.48; p=0.034). Our study points to an association of GATA2 at both SNP and haplotype levels with important metabolic risk traits for atherosclerosis. PMID- 24786212 TI - Synergistic effect of anti and pro-inflammatory cytokine genes and their promoter polymorphism with ST-elevation of myocardial infarction. AB - BACKGROUND: The single-gene approach in association studies of polygenic diseases such as acute myocardial infarction (AMI) is likely to provide limited value. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) plasma levels may be genetically influenced. AIM: We evaluate the impact of single nucleotide polymorphism of the promoter region of these genes, as well as reciprocal interaction of these genes with ST-elevation of myocardial infarction (STEMI). METHODS: In a case-control study 500 STEMI patients and 500 age- and sex-matched controls were studied. Three single-nucleotide polymorphism genotypes were evaluated by polymerase chain reaction and restriction enzyme analysis and assessed their association with STEMI. The synergistic effects of IL 6, TNF-alpha and IL-10 gene polymorphisms were evaluated by using logistic regression analysis. RESULTS: We found that IL-6 and TNF-alpha concentrations of studied population were significantly different (p<0.0001) in each genotype of IL 6 -174G>C and TNF-alpha -308G>A gene polymorphisms respectively. A significant association was found in multivariate analysis for the IL-6 -174G>C [odds ratio (OR): 0.390; 95% confidence interval (CI): 0.176-0.865, p=0.020] and TNF-alpha 308G>A [OR: 0.372; 95% CI: 0.171-808, p=0.012] gene polymorphisms with STEMI. In contrast, IL-10 -592C>A gene polymorphism was no longer significant in the multivariate model (OR: 0.678; 95% CI: 0.288 to 1.594, p=0.373) whereas significant in univariate analysis (OR: 0.697; 95% CI: 0.523-0.929, p=0.014). CONCLUSIONS: Our findings suggest that IL-6, TNF-alpha and IL-10 gene polymorphisms all contribute in the association with STEMI whereas the association persisted only for IL-6 and TNF-alpha but not for IL-10 gene polymorphism with this disease in the multivariate analysis. PMID- 24786213 TI - Identification and expression analysis of twenty ARF genes in Populus. AB - The auxin response factor (ARF) family of transcription factors is a crucial component of auxin signaling and plays important roles regulating numerous growth and developmental processes in plants. We isolated and characterized 20 ARF genes involved in adventitious root development of Populus. Multiple protein sequence alignments revealed that the PeARF proteins contained a highly conserved region in their N-terminal portion corresponding to the DNA-binding domain of the Arabidopsis ARF family. Except for PeARF3.1, PeARF3.2, PeARF17.1 and PeARF17.2, the PeARF proteins contained a carboxyl-terminal domain related to the Arabidopsis domains III and IV, which are involved in homo- and heterodimerization. The exon-intron structures of the PeARF genes were determined by aligning cDNA and genomic sequences. As expected, most PeARF genes had a similar distribution of exon-intron structures. Temporal expression patterns of these genes were profiled during adventitious root development. All 20 PeARF genes were expressed in root, stem and leaf in a dynamic manner. Transient expression assays with Populus protoplasts demonstrated that these PeARFs were localized to the nucleus. These results suggest that PeARFs may play diverse regulatory roles in adventitious root development of Populus and contribute to improving our understanding of conserved and divergent aspects of auxin signaling in various species. PMID- 24786214 TI - Tracing the origin and evolution of plant TIR-encoding genes. AB - Toll-interleukin-1 receptor (TIR)-encoding proteins represent one of the most important families of disease resistance genes in plants. Studies that have explored the functional details of these genes tended to focus on only a few limited groups; the origin and evolutionary history of these genes were therefore unclear. In this study, focusing on the four principal groups of TIR-encoding genes, we conducted an extensive genome-wide survey of 32 fully sequenced plant genomes and Expressed Sequence Tags (ESTs) from the gymnosperm Pinus taeda and explored the origins and evolution of these genes. Through the identification of the TIR-encoding genes, the analysis of chromosome positions, the identification and analysis of conserved motifs, and sequence alignment and phylogenetic reconstruction, our results showed that the genes of the TIR-X family (TXs) had an earlier origin and a wider distribution than the genes from the other three groups. TIR-encoding genes experienced large-scale gene duplications during evolution. A skeleton motif pattern of the TIR domain was present in all spermatophytes, and the genes with this skeleton pattern exhibited a conserved and independent evolutionary history in all spermatophytes, including monocots, that followed their gymnosperm origin. This study used comparative genomics to explore the origin and evolutionary history of the four main groups of TIR encoding genes. Additionally, we unraveled the mechanism behind the uneven distribution of TIR-encoding genes in dicots and monocots. PMID- 24786215 TI - Differential distributions of mononucleotide repeat sequences in 256 viral genomes and its potential implications. AB - Mononucleotide repeats (MNRs) have been systematically investigated in the genomes of eukaryotic and prokaryotic organisms. However, detailed information on the distribution of MNRs in viral genomes is limited. In this study, we examined the distributions of MNRs in 256 fully sequenced virus genomes which showed extensive variations across viral genomes, and is significantly influenced by both genome size and CG content. Furthermore, the ratio of the observed to the expected number of MNRs (O/E ratio) appears to be influenced by both the host range and genome type of a particular virus. Additionally, the densities and frequencies of MNRs in genic regions are lower than in non-coding regions, suggesting that selective pressure acts on viral genomes. We also discuss the potential functional roles that these MNR loci could play in virus genomes. To our knowledge, this is the first analysis focusing on MNRs in viruses, and our study could have potential implications for a deeper understanding of virus genome stability and the co-evolution that occurs between a virus and its host. PMID- 24786216 TI - Identification and characterization of a Sox2 homolog in the Japanese flounder Paralichthys olivaceus. AB - Sox2 plays an essential role in maintaining the pluripotency of embryonic and neural stem cells as well as in the neurogenesis. While it has been well studied in mammals, information from lower invertebrate especially marine fish is still limited. In this study, we cloned and sequenced the full-length cDNA and partial 5'-flanking region of the Japanese flounder Sox2. Phylogenetic, gene structure, and protein comparison analyses revealed that Paralichthys olivaceus Sox2 (Po Sox2) was homologous to mammalian Sox2. Quantitative real-time RT-PCR results showed that Po-Sox2 was not maternal inherited, and the transcripts were present from high blastula-stage onwards, with the highest level at the mid-gastrula stage. Tissue distribution analysis revealed that Po-Sox2 was present not only in neural tissues, but also in gonadal and gill tissues. In addition, we analyzed the Po-Sox2 promoter region for several species-conserved motifs as well as various transcription factor binding sites. The overall hypomethylation status of the identified CpG sites in the 5'-regulatory region revealed that it was not involved in the transcriptional modulation of Po-Sox2. All these results suggest that Po-Sox2 may have a conserved function in neurogenesis and early embryonic development. PMID- 24786217 TI - Predictors of spontaneous reverse remodeling in mild heart failure patients with left ventricular dysfunction. AB - BACKGROUND: There are limited data regarding factors associated with spontaneous left ventricular reverse remodeling (S-LVRR) among mildly symptomatic heart failure (HF) patients and its prognostic implications on clinical outcomes. METHODS AND RESULTS: Best subsets logistic regression analysis was used to identify factors associated with S-LVRR (defined as >=15% reduction in left ventricular end-systolic volume at 1-year of follow-up) among 612 patients treated with internal cardioverter defibrillator-only therapy in Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT) and to create a score for the prediction of S-LVRR. Cox proportional hazards regression modeling was used to assess the clinical outcome of all internal cardioverter defibrillator-only patients (n=714) with a high S-LVRR score. S-LVRR occurred in 25% of internal cardioverter defibrillator-only patients. Predictors of S-LVRR included systolic blood pressure>=140 mm Hg, serum creatinine<1.0 mg/dL, QRS 130 to 160 ms, and nonischemic cardiomyopathy. Multivariate analysis showed that each 1-point increment in S-LVRR score (range, 0-7) was associated with an 11% (P=0.019) reduction in the risk of HF or death. Treatment with cardiac resynchronization therapy was associated with a significant reduction in the risk of HF or death only among internal cardioverter defibrillator-treated patients with a low (Q1-3) S-LVRR score (hazard ratio=0.55; P<0.001), but not among those with a higher (Q4) score (hazard ratio=1.06; P=0.72). CONCLUSIONS: Our data suggest that approximately one quarter of mild HF patients eligible for biventricular pacing experience S-LVRR. Combined assessment of clinical factors associated with S-LVRR can be used to identify mild HF patients with a low risk for clinical events without cardiac resynchronization therapy intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271. PMID- 24786218 TI - Development and validation of LC-MS/MS method for quantitative determination of ( )-securinine in mouse plasma. AB - (-)-Securinine (SE) is a major alkaloid found in plant Securinega suffruticosa, which has a wide range of pharmacological activities including anticancer, anti parasitic and central nervous system stimulating effects, etc. To aid the pharmacological study of SE, we developed an LC-MS/MS method for quantitative determination of SE in mouse plasma. In this method, plasma samples were first prepared with salting-out assisted liquid-liquid extraction using cold acetonitrile (-20 degrees C) and 2.00 M ammonium acetate. Separation of SE and the internal standard (IS) from sample matrix was achieved on a Gemini Nx C18 column using 40% acetonitrile and 60% 10.0mM ammonium acetate at a flow rate of 0.200 mL min(-1). Quantification of SE was accomplished with positive electrospray ionization tandem mass spectrometry using mass transitions m/z 218.1 >84.1 for SE, and m/z 204.1->70.2 for the IS. This method has a lower limit of quantitation (LLOQ) of 0.600 ng mL(-1) and a linear calibration range up to 600 ng mL(-1) in mouse plasma. The intra- and inter-run accuracy (%RE) and precision (%CV) were <= +/- 6% and 6%, respectively. The IS normalized matrix factors from six lots of plasma matrices ranged 0.92-1.07, and the recoveries of plasma SE were 99-109%. The validated method has been applied to the measurement of SE in plasma samples of a mouse study. PMID- 24786219 TI - A downstream process allowing the efficient isolation of a recombinant amphiphilic protein from tobacco leaves. AB - The 65-kDa isoform of human glutamic acid decarboxylase (hGAD65) is a major autoantigen in autoimmune diabetes. The heterologous production of hGAD65 for diagnostic and therapeutic applications is hampered by low upstream productivity and the absence of a robust and efficient downstream process for product isolation. A tobacco-based platform has been developed for the production of an enzymatically-inactive form of the protein (hGAD65mut), but standard downstream processing strategies for plant-derived recombinant proteins cannot be used in this case because the product is amphiphilic. We therefore evaluated different extraction buffers and an aqueous micellar two-phase system (AMTPS) to optimize the isolation and purification of hGAD65mut from plants. We identified the extraction conditions offering the greatest selectivity for hGAD65mut over native tobacco proteins using a complex experimental design approach. Under our optimized conditions, the most efficient initial extraction and partial purification strategy achieved an overall hGAD65mut yield of 92.5% with a purification factor of 12.3 and a concentration factor of 23.8. The process also removed a significant quantity of phenols, which are major contaminants present in tobacco tissue. This is the first report describing the use of AMTPS for the partial purification of an amphiphilic recombinant protein from plant tissues and our findings could also provide a working model for the initial recovery and partial purification of hydrophobic recombinant proteins from transgenic tobacco plants. PMID- 24786220 TI - Comparison of a novel TiO2/diatomite composite and pure TiO2 for the purification of phosvitin phosphopeptides. AB - A novel TiO2/diatomite composite (TD) was prepared and then characterized by scanning electron microscope (SEM) and Fourier Transform Infrared (FTIR). The results of SEM showed that after modification, the porous surface of diatomite was covered with TiO2. Both diatomite and TD had clear disc-shaped structures with average grain diameters of around 25 MUm. Then TD and pure TiO2 were applied in the purification of phosvitin phosphopeptides (PPPs) from the digest of egg yolk protein, and a comparative study of adsorption properties of PPPs on TD and TiO2 was performed. In the study of adsorption kinetics, the adsorption equilibrium of PPPs on TD and TiO2 fitted well with the Langmuir model, and the time needed to reach adsorption equilibrium were both around 10 min. The maximum dynamic adsorption capacity of TD (8.15 mg/g) was higher than that of TiO2 (4.96 mg/g). The results of repeated use showed that TD and TiO2 were very stable after being subjected to ten repeated adsorption-elution cycles, and TD could easily be separated from aqueous solution by filtration. On the other hand, the present synthetic technology of TD was very simple, cost-effective, organic solvent-free and available for large-scale preparation. Thus, this separation method not only brings great advantages in the purification of PPPs from egg yolk protein but also provides a promising purification material for the enrichment of phosphopeptides in proteomic researches. PMID- 24786221 TI - UHPLC-ESI-MS/MS determination and pharmacokinetic study of two alkaloid components in rat plasma after oral administration of the extract of Corydalis bungeana Turcz. AB - Corynoline and acetycorynoline are active compounds of Corydalis bungeana Turcz. with various pharmacological effects such as sedation, anti-leptospira and liver injury protection effects. A specific, simple and sensitive UHPLC-ESI-MS/MS method was developed and validated for the pharmacokinetic study of corynoline and acetycorynoline in rat plasma. Corynoline and acetycorynoline were extracted from plasma samples by liquid-liquid extraction. The analysis was carried out on an Agilent SB-C18 column (1.8 MUm, 50 mm*2.1mm) with the mobile phase of acetonitrile-0.1% formic acid (80:20, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source in positive mode. The current UHPLC ESI-MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability. The lower limits of quantification were 0.10 ng/mL for corynoline and 0.353 ng/mL for acetycorynoline. Intra-day and inter-day precision were less than 12.3% and accuracy ranged from 0.18% to 14.9%. The mean extraction recoveries of analytes and internal standard (IS) from rat plasma were all more than 76.2%. This validated method was successfully applied to pharmacokinetic study in rats after oral administration of corynoline, acetycorynoline and the extract of Corydalis bungeana Turcz. PMID- 24786222 TI - Quantitation of phlorizin and phloretin using an ultra high performance liquid chromatography-electrospray ionization tandem mass spectrometric method. AB - A sensitive and selective ultra high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for the determination of phlorizin and phloretin in human plasma has been firstly developed. Samples were prepared after protein precipitation and analyzed on a C18 column interfaced with a triple quadrupole tandem mass spectrometer. Negative electrospray ionization was employed as the ionization source. The mobile phase consisted of acetonitrile water (0.02% formic acid), using a gradient procedure. The analytes and internal standard dihydroquercetin were both detected by use of multiple reaction monitoring mode. The method was linear in the concentration range of 2.5-1000.0 ng/mL. The lower limit of quantification (LLOQ) was 2.5 ng/mL. The intra- and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 9.2%. The accuracy determined at three concentrations was within +/- 7.3% in terms of relative error. The total run time was 12.0 min. This assay offers advantages in terms of expediency, and suitability for the analysis of phlorizin and phloretin in various biological fluids. PMID- 24786223 TI - UVB radiation illuminates the role of TLR3 in the epidermis. AB - UV radiation poses a significant risk to human health. The mechanisms that help repair UV-damaged cells have recently been more clearly defined with the observation that Toll-like receptor 3 can sense self RNA released from necrotic keratinocytes following UV damage. TLR3 activation in the skin induces inflammation and increases the expression of genes involved in skin barrier repair. Activation of TLR2 in the skin by commensal microbial products prevents excessive inflammation by blocking downstream TLR3 signaling. This review highlights how UV damage-induced inflammation in the skin is propagated by host products and regulated by host inhabitants. PMID- 24786224 TI - Simultaneous diagnosis of ipsilateral adenoid cystic carcinoma of the lacrimal gland and orbital cavernous hemangioma: case report. AB - To describe a patient with coexistence of ipsilateral adenoid cystic carcinoma of the lacrimal gland and orbital cavernous hemangioma. The patient presented a 2 month history of painful swelling of left upper eyelid, which did not resolve on a course of oral steroid. On clinical examination, she had moderate medial and inferior dislocation of the eye globe, edema of the temporal superior eyelid and moderate restriction upgaze. Magnetic resonance imaging identified two left orbital tumors: one was a lesion that arose from the lacrimal gland, and the second was a well-defined, ovoid, intraconal mass. The patient underwent lateral orbitotomy and excision of both lesions. Postoperative histological features demonstrated two different lesions: an adenoid cystic carcinoma of the lacrimal gland and a cavernous hemangioma. The clinical presentation of the present case was strongly suggestive of a lacrimal gland malignancy, although the imaging features did not show typical invasive aspects. This is the first report of coexistence of lacrimal gland adenoid cystic carcinoma and cavernous hemangioma in the ipsilateral orbit. PMID- 24786225 TI - Sequential exposure of Malassezia pachydermatis to azoles: enhanced or decreased activity? PMID- 24786226 TI - Identification of an Atg8-Atg3 protein-protein interaction inhibitor from the medicines for Malaria Venture Malaria Box active in blood and liver stage Plasmodium falciparum parasites. AB - Atg8 is a ubiquitin-like autophagy protein in eukaryotes that is covalently attached (lipidated) to the elongating autophagosomal membrane. Autophagy is increasingly appreciated as a target in diverse diseases from cancer to eukaryotic parasitic infections. Some of the autophagy machinery is conserved in the malaria parasite, Plasmodium. Although Atg8's function in the parasite is not well understood, it is essential for Plasmodium growth and survival and partially localizes to the apicoplast, an indispensable organelle in apicomplexans. Here, we describe the identification of inhibitors from the Malaria Medicine Venture Malaria Box against the interaction of PfAtg8 with its E2-conjugating enzyme, PfAtg3, by surface plasmon resonance. Inhibition of this protein-protein interaction prevents PfAtg8 lipidation with phosphatidylethanolamine. These small molecule inhibitors share a common scaffold and have activity against both blood and liver stages of infection by Plasmodium falciparum. We have derivatized this scaffold into a functional platform for further optimization. PMID- 24786227 TI - The relationship between biogenetic attributions and desire for social distance from persons with schizophrenia and major depression revisited. AB - AIMS: Previous population-based studies did not support the view that biological and genetic causal models help increase social acceptance of people with mental illness. However, practically all these studies used un-labelled vignettes depicting symptoms of the disorders of interest. Thus, in these studies the public's reactions to pathological behaviour had been assessed rather than reactions to psychiatric disorders that had explicitly been labelled as such. The question arises as to whether results would have been similar if respondents had been confronted with vignettes with explicit mention of the respective diagnosis. METHODS: Analyses are based on data of a telephone survey in two German metropolises conducted in 2011. Case-vignettes with typical symptoms suggestive of depression or schizophrenia were presented to the respondents. After presentation of the vignette respondents were informed about the diagnosis. RESULTS: We found a statistically significant association of the endorsement of brain disease as a cause with greater desire for social distance from persons with schizophrenia. In major depression, this relation was absent. With both disorders, there was no statistically significant association between the endorsement of hereditary factors as a cause and social distance. CONCLUSIONS: Irrespective of whether unlabelled or labelled vignettes are employed, the ascription to biological or genetic causes seems not to be associated with a reduction of the public's desire for social distance from people with schizophrenia or depression. Our results corroborate the notion that promulgating biological and genetic causal models may not help decrease the stigma surrounding these illnesses. PMID- 24786228 TI - Usefulness of morning home blood pressure measurements in patients with type 2 diabetes mellitus: results of a 10-year, prospective, longitudinal study. AB - Previous cross-sectional studies and 6-year longitudinal study have demonstrated that home blood pressure (HBP) measurements upon awakening have a stronger predictive power for death, micro- and macrovascular complications than clinic blood pressure (CBP) measurements in patients with type 2 diabetes (T2DM). This study investigated which of these measurements offers stronger predictive power for outcomes over 10 years. At baseline, 400 Japanese patients with T2DM were classified as having hypertension (HT) or normotension (NT) based on HBP and CBP. The mean survey duration was 95 months. Primary and secondary end-points were death and new or worsened micro- and macrovascular complications, respectively. Differences in outcomes for each end-point between HT and NT patients were analyzed using Kaplan-Meier survival curves and log-rank testing. Associated risk factors were assessed using Cox proportional hazards analysis. Based on HBP, death and micro- and macrovascular complications were significantly higher in patients with HT than with NT at baseline and end-point. Based on CBP, there were no significant differences in incidence of death, micro- or macrovascular complications between patients with HT and NT at baseline and end-point, although a significant difference in incidence of death was observed between the HT and NT groups at end-point. However, the significance was significantly lower in CBP than in HBP. One risk factor associated with micro- and macrovascular complications in patients with HBP was therapy for HT. This 10-year longitudinal study of patients with T2DM demonstrated that elevated HBP upon awakening is predictive of death, and micro- and macrovascular complications. PMID- 24786229 TI - Microchip zone electrophoresis for high-throughput analysis of monoclonal antibody charge variants. AB - A high-throughput screening assay on a microfluidic chip was developed for the determination of charge variants of monocolonal antibodies (mAbs) in pI range of 7-10. This method utilizes microchip zone electrophoresis for rapid separation (<90 s) of mAb charge variants that are labeled fluorescently without altering the overall charge. The microfluidic assay achieves between 8- and 90-fold times faster separation time over conventional methods while maintaining comparable resolution and profiles of charge variant distributions. We further characterized the assay with respect to (i) the effect of pH on resolution, (ii) the effect of excipients and buffering agents, (iii) the performance of the assay compared to conventional methods, and (vi) the reproducibility of charge variant profiles. Finally, we explored the utility of the assay with four case studies: (i) monitoring C-terminal lysine modification of a mAb, (ii) quantifying the extent of deamidation of a mAb, (iii) providing charge variant information on which to base clone selection, and (iv) making process parameter-related decisions from a "design of experiment" (DoE) study. The results of these case studies demonstrate the applicability of the microfluidic assay for high-throughput monitoring of mAb quality in process development of biopharmaceuticals. PMID- 24786230 TI - Immunomodulatory effects of lactoferrin. AB - Lactoferrin (Lf) is an iron-binding glycoprotein of the transferrin family, which is expressed in most biological fluids with particularly high levels in mammalian milk. Its multiple activities lie in its capacity to bind iron and to interact with the molecular and cellular components of hosts and pathogens. Lf can bind and sequester lipopolysaccharides, thus preventing pro-inflammatory pathway activation, sepsis and tissue damages. Lf is also considered a cell-secreted mediator that bridges the innate and adaptive immune responses. In the recent years much has been learned about the mechanisms by which Lf exerts its activities. This review summarizes the recent advances in understanding the mechanisms underlying the multifunctional roles of Lf, and provides a future perspective on its potential prophylactic and therapeutic applications. PMID- 24786231 TI - Abscisic acid perception and signaling: structural mechanisms and applications. AB - Adverse environmental conditions are a threat to agricultural yield and therefore exert a global effect on livelihood, health and the economy. Abscisic acid (ABA) is a vital plant hormone that regulates abiotic stress tolerance, thereby allowing plants to cope with environmental stresses. Previously, attempts to develop a complete understanding of the mechanisms underlying ABA signaling have been hindered by difficulties in the identification of bona fide ABA receptors. The discovery of the PYR/PYL/RCAR family of ABA receptors therefore represented a major milestone in the effort to overcome these roadblocks; since then, many structural and functional studies have provided detailed insights into processes ranging from ABA perception to the activation of ABA-responsive gene transcription. This understanding of the mechanisms of ABA perception and signaling has served as the basis for recent, preliminary developments in the genetic engineering of stress-resistant crops as well as in the design of new synthetic ABA agonists, which hold great promise for the agricultural enhancement of stress tolerance. PMID- 24786232 TI - SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models. AB - AIM: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic beta-cell function were also investigated. METHODS: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control. RESULTS: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg.kg(-1).d(-1)) dose dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice. CONCLUSION: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes. PMID- 24786233 TI - Isoindolone derivative QSN-10c induces leukemic cell apoptosis and suppresses angiogenesis via PI3K/AKT signaling pathway inhibition. AB - AIM: 2-(4,6-Dimethoxy-1,3-dioxoisoindolin-2-yl) ethyl 2-chloroacetate (QSN-10c) is one of isoindolone derivatives with antiproliferative activity against human umbilical vein endothelial cells (HUVECs). The aim of this study was to investigate its antitumor activity in vitro and anti-angiogenic effects in vitro and in vivo. METHODS: K562 leukemic cells and HUVECs were used for in vitro studies. Cell viability was examined using MTT assay. Cell apoptosis and mitochondrial transmembrane potential (Deltapsim) were detected with flow cytometry. Tube formation and migration of HUVECs were studied using two dimensional Matrigel assay and wound-healing migration assay, respectively. VEGF levels were analyzed with RT-PCR and Western blotting. A zebrafish embryo model was used for in vivo anti-angiogenic studies. The molecular mechanisms for apoptosis in K562 cells and antiangiogenesis were measured with Western blotting. RESULTS: In antitumor activity studies, QSN-10c suppressed the viability of K562 cells and induced apoptosis in dose- and time-dependent manners. Furthermore, QSN 10c dose-dependently decreased the Deltapsim in K562 cells, increased the release of cytochrome c and the level of Bax, and decreased the level of Bcl-2, suggesting that QSN-10c-induced apoptosis of K562 cells was mediated via the mitochondrial apoptotic pathway. In anti-angiogenic activity studies, QSN-10c suppressed the viability of HUVECs and induced apoptosis in dose dependent manners. QSN-10c treatment did not alter the Deltapsim in HUVECs, but dose dependently inhibited the expression of VEGF, inhibited the tube formation and cell migration in vitro, and significantly suppressed the number of ISVs in zebrafish embryos in vivo. Furthermore, QSN-10c dose-dependently suppressed the phosphorylation of AKT and GSK3beta in both HUVECs and K562 cells. CONCLUSION: QSN-10c is a novel antitumor compound that exerts both antitumor and anti angiogenic effects via inhibiting the PI3K/AKT/GSK3beta signaling pathway. PMID- 24786235 TI - Development of beta-amino-carbonyl compounds as androgen receptor antagonists. AB - AIM: Androgen receptor (AR) antagonists have proven to be useful in the early control of prostate cancer. The aim of this study was to identify and characterize a novel beta-amino-carbonyl-based androgen receptor antagonist. METHODS: Different isomers of the beta-amino-carbonyl compounds were obtained by chiral separation. The bioactivities of the isomers were evaluated by AR nuclear translocation, mammalian two-hybrid, competitive receptor binding and cell proliferation assays. The expression of genes downstream of AR was analyzed with real-time PCR. The therapeutic effects on tumor growth in vivo were observed in male SCID mice bearing LNCaP xenografts. RESULTS: Compound 21 was previously identified as an AR modulator by the high-throughput screening of a diverse compound library. In the present study, the two isomers of compound 21, termed compounds 21-1 and 21-2, were characterized as partial AR agonists in terms of androgen-induced AR nuclear translocation, prostate-specific antigen expression and cell proliferation. Further structural modifications led to the discovery of a androgen receptor antagonist (compound 6012), which blocked androgen receptor nuclear translocation, androgen-responsive gene expression and androgen-dependent LNCaP cell proliferation. Four stereoisomers of compound 6012 were isolated, and their bioactivities were assessed. The pharmacological effects of 6012, including AR binding, androgen-induced AR translocation, NH2- and COOH-terminal interaction, growth inhibition of LNCaP cells in vitro and LNCaP xenograft growth in nude mice, were mainly restricted to isomer 6012-4 (1R, 3S). CONCLUSION: Compound 6012-4 was determined to be a novel androgen receptor antagonist with prostate cancer inhibitory activities comparable to bicalutamide both in vitro and in vivo. PMID- 24786234 TI - HapMap-based study on the association between MPO and GSTP1 gene polymorphisms and lung cancer susceptibility in Chinese Han population. AB - AIM: Myeloperoxidase (MPO) and glutathione S-transferase pi 1 (GSTP1) are important carcinogen-metabolizing enzymes. The aim of this study was to investigate the association between the common polymorphisms of MPO and GSTP1 genes and lung cancer risk in Chinese Han population. METHODS: A total of 266 subjects with lung cancer and 307 controls without personal history of the disease were recruited in this case control study. The tagSNPs approach was used to assess the common polymorphisms of MOP and GSTP1 genes and lung cancer risk according to the disequilibrium information from the HapMap project. The tagSNP rs7208693 was selected as the polymorphism site for MPO, while the haplotype tagging SNPs rs1695, rs4891, rs762803 and rs749174 were selected as the polymorphism sites for GSTP1. The gene polymorphisms were confirmed using real time PCR, cloning and sequencing. RESULTS: The four GSTP1 haplotype-tagging SNPs rs1695, rs4891, rs762803 and rs749174, but not the MPO tagSNP rs7208693, exhibited an association with lung cancer susceptibility in smokers in the overall population and in the studied subgroups. When Phase 2 software was used to reconstruct the haplotype for GSTP1, the haplotype CACA (rs749174+rs1695 + rs762803+rs4891) exhibited an increased risk of lung cancer among smokers (adjust odds ratio 1.53; 95%CI 1.04-2.25, P=0.033). Furthermore, diplotype analyses demonstrated that the significant association between the risk haplotype and lung cancer. The risk haplotypes co-segregated with one or more biologically functional polymorphisms and corresponded to a recessive inheritance model. CONCLUSION: The common polymorphisms of the GSTP1 gene may be the candidates for SNP markers for lung cancer susceptibility in Chinese Han population. PMID- 24786236 TI - Inhibitory effects of phytochemicals on metabolic capabilities of CYP2D6(*)1 and CYP2D6(*)10 using cell-based models in vitro. AB - AIM: Herbal products have been widely used, and the safety of herb-drug interactions has aroused intensive concerns. This study aimed to investigate the effects of phytochemicals on the catalytic activities of human CYP2D6(*)1 and CYP2D6(*)10 in vitro. METHODS: HepG2 cells were stably transfected with CYP2D6(*)1 and CYP2D6(*)10 expression vectors. The metabolic kinetics of the enzymes was studied using HPLC and fluorimetry. RESULTS: HepG2-CYP2D6(*)1 and HepG2-CYP2D6(*)10 cell lines were successfully constructed. Among the 63 phytochemicals screened, 6 compounds, including coptisine sulfate, bilobalide, schizandrin B, luteolin, schizandrin A and puerarin, at 100 MUmol/L inhibited CYP2D6(*)1- and CYP2D6(*)10-mediated O-demethylation of a coumarin compound AMMC by more than 50%. Furthermore, the inhibition by these compounds was dose dependent. Eadie-Hofstee plots demonstrated that these compounds competitively inhibited CYP2D6(*)1 and CYP2D6(*)10. However, their Ki values for CYP2D6(*)1 and CYP2D6(*)10 were very close, suggesting that genotype-dependent herb-drug inhibition was similar between the two variants. CONCLUSION: Six phytochemicals inhibit CYP2D6(*)1 and CYP2D6(*)10-mediated catalytic activities in a dose dependent manner in vitro. Thus herbal products containing these phytochemicals may inhibit the in vivo metabolism of co-administered drugs whose primary route of elimination is CYP2D6. PMID- 24786237 TI - The effects of calcitriol treatment in glucocorticoid-resistant asthma. PMID- 24786239 TI - Reply: To PMID 24290281. PMID- 24786238 TI - Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. AB - BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory disease. Evolving disease models link changes in epidermal growth and differentiation to T(H)2/T(H)22 cytokine activation. However, these models have not been tested by in vivo suppression of T-cell cytokines. Cyclosporine (CsA) is an immunosuppressant that is highly effective for severe disease, but its mechanism in AD skin lesions has not been studied. OBJECTIVE: We sought to establish the ability of a systemic immunosuppressant to modulate immune and epidermal alterations that form the pathogenic disease phenotype and to correlate changes with clinical improvement. METHODS: CsA's effects on AD skin pathology were evaluated by using gene expression and immunohistochemistry studies in baseline, week 2, and week 12 lesional and nonlesional biopsy specimens from 19 patients treated with 5 mg/kg/d CsA for 12 weeks. RESULTS: After 2 and 12 weeks of treatment, we observed significant reductions of 51% and 72%, respectively, in SCORAD scores. Clinical improvements were associated with significant gene expression changes in lesional but also nonlesional skin, particularly reductions in levels of T(H)2-, T(H)22-, and some T(H)17-related molecules (ie, IL-13, IL 22, CCL17, S100As, and elafin/peptidase inhibitor 3), and modulation of epidermal hyperplasia and differentiation measures. CONCLUSIONS: This is the first study that establishes a relationship between cytokine activation and molecular epidermal alterations, as well as correlations between disease biomarkers in the skin and clinical improvement. The reversal of the molecular phenotype with CsA and the associated biomarkers can serve as a reference for the successful modulation of tissue inflammation with specific immune antagonists in future studies, contributing to the understanding of the specific cytokines involved in epidermal pathology. PMID- 24786240 TI - Test for respiratory and asthma control in kids (TRACK): a validated control tool for preschool-aged children. PMID- 24786241 TI - beta3-Adrenergic receptor gene modifies the association between childhood obesity and asthma. PMID- 24786242 TI - Trans-generational effects of early life stress: the role of maternal behavior. AB - Using a rodent paradigm of early life stress, infant maternal separation (IMS), we examined whether IMS-triggered behavioral and epigenetic phenotypes of the stress-susceptible mouse strain Balb/c are propagated across generations. These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex. These behavioral and epigenetic phenotypes are transmitted to the first progeny of IMS Balb/c mothers, but not fathers, and cross-fostering experiments revealed that this transmission is triggered by maternal behavior and modulated by the genetic background of the pups. In the continued absence of the original stressor, this transmission fades in later progenies. An adolescent treatment that lowers the levels of acH4K12 in IMS Balb/c mice augments their emotional abnormality but abolishes their cognitive deficits. Conversely, a treatment that further elevates the levels of acH4K12 improved the emotional phenotype but had no effects on the cognitive deficits. Moreover, treatments that prevent the emergence of either emotional or cognitive deficits in the mother also prevent the establishment of such deficits in her offspring, indicating that trans-generational effects of early life stress can be prevented. PMID- 24786243 TI - Immunological characterization of a chimeric form of Schistosoma mansoni aquaporin in the murine model. AB - Aquaporin (SmAQP) is the most abundant transmembrane protein in the tegument of Schistosoma mansoni. This protein is expressed in all developmental stages and seems to be essential in parasite survival since it plays a crucial role in osmoregulation, nutrient transport and drug uptake. In this study, we utilized the murine model to evaluate whether this protein was able to induce protection against challenge infection with S. mansoni cercariae. A chimeric (c) SmAQP was formulated with Freund's adjuvant for vaccination trial and evaluation of the host's immune response was performed. Our results demonstrated that immunization with cSmAQP induced the production of high levels of specific anti-cSmAQP IgG antibodies and a Th1/Th17 type of immune response characterized by IFN-gamma, TNF alpha and IL-17 cytokines. However, vaccination of mice with cSmAQP failed to reduce S. mansoni worm burden and liver pathology. Finally, we were unable to detect humoral immune response anti-cSmAQP in the sera of S. mansoni-infected human patients. Our results lead us to believe that SmAQP, as formulated in this study, may not be a good target in the search for an anti-schistosomiasis vaccine. PMID- 24786244 TI - Survey of benzoic acid in cheeses: contribution to the estimation of an admissible maximum limit. AB - Benzoic acid and its salts are commonly used additives in the food industry. Their use is not allowed in dairy products even though they can be found naturally. In this work, 100 cheese samples were tested to establish the maximum concentration that can be considered as "natural" and, therefore, permitted in cheeses. Analyses were carried out by a validated ion chromatography method and "positive" samples were confirmed by two other HPLC methods. Benzoic acid concentrations higher than the method LOQ (8.8 mg kg(-1)) were found in 18 samples, ranging from 11.3 to 28.7 mg kg(-1), with a mean value of 20.5 mg kg( 1). Taking into account the distribution of benzoic acid concentrations observed in "positive" samples, it is plausible to estimate a maximum admissible limit of 40.0 mg kg(-1) for benzoic acid in cheese. Below this value, samples can be considered "compliant". PMID- 24786245 TI - Levels of copper in Nile tilapia from Brazil. AB - The purpose of this work was to determine the concentration of copper in samples of farmed Nile tilapia (Oreochromis niloticus L.) fillets purchased in the city of Botucatu (Sao Paulo, Brazil) and in fillet and liver samples of Tilapia fed diets supplemented with different concentrations of Cu from the Laboratory of Aquatic Organism Nutrition/FMVZ-UNESP (Botucatu, Brazil). The fillet samples were prepared by lyophilisation and cryogenic grinding into particles smaller than 60 um, and copper was extracted ultrasonically using 0.10 mol l(-1) HCl as extraction solution. Copper determination was performed by graphite furnace atomic absorption spectrometry (GFAAS) with optimised temperatures of drying, pyrolysis, atomisation and cleaning. Palladium nitrate was injected into the samples as a chemical modifier and tungsten as a permanent modifier. Copper concentrations of 0.70-1.60 mg kg(-1) were found, which are in line with Brazilian regulations. The accuracy and precision of the copper concentrations determined in this study were evaluated using certified standard Lake Michigan fish tissue (NIST SRM 1947). PMID- 24786246 TI - Determination of aflatoxins in edible oil from markets in Hebei Province of China by liquid chromatography-tandem mass spectrometry. AB - Analysis of aflatoxin B1 (AFB1), B2 (AFB2), G1 (AFG1) and G2 (AFG2) in 76 edible oil samples (peanut oil, soybean oil, corn embryo oil and blended oil) was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The oils were sampled from three areas (Shijiazhuang, Baoding and Tangshan) of Hebei Province of China. AFB1 was detected in 22 samples representing 28.9%, followed by AFB2 (7.89%) and AFG1 (3.95%), while no AFG2 contamination was detected in any samples. AFB1 levels in oil samples ranged 0.14-2.72 ug kg(-1) and AFB2 ranged 0.15-0.36 ug kg(-1), while lower levels of 0.01-0.02 ug kg(-1) for AFG1 were recorded. The paper is part of an on-going investigation of aflatoxin contamination in Chinese edible oils. PMID- 24786247 TI - Aluminium content of some processed foods, raw materials and food additives in China by inductively coupled plasma-mass spectrometry. AB - The level of aluminium in 178 processed food samples from Shenzhen city in China was evaluated using inductively coupled plasma-mass spectrometry. Some processed foods contained a concentration of up to 1226 mg/kg, which is about 12 times the Chinese food standard. To establish the main source in these foods, Al levels in the raw materials were determined. However, aluminium concentrations in raw materials were low (0.10-451.5 mg/kg). Therefore, aluminium levels in food additives used in these foods was determined and it was found that some food additives contained a high concentration of aluminium (0.005-57.4 g/kg). The results suggested that, in the interest of public health, food additives containing high concentrations of aluminium should be replaced by those containing less. This study has provided new information on aluminium levels in Chinese processed foods, raw materials and a selection of food additives. PMID- 24786248 TI - Determination of lead and cadmium content in sausages from Iran. AB - The contents of lead and cadmium in five major brands of six types of cooked beef sausages consumed in Iran were determined by a graphite furnace atomic absorption spectrometer (GFAAS) after hydrogen peroxide/nitric acid digestion. The metal content in the samples, expressed in ug kg(-1) wet weight, varied from 24.0 to 158.7 with an average of 53.5 for lead and from 2.2 to 13.5 with an average of 5.7 for cadmium. The highest lead and cadmium concentrations were obtained from a German sausage (158.7 ug kg(-1); brand B) and hot dog (13.5 ug kg(-1); brand D), respectively. The results indicate that the sausages from Iran have concentrations below the permitted levels for these heavy metals. The daily dietary intakes and the percentage contribution of the two considered metals to the provisional tolerable weekly intake (PTWI) were calculated for sausages. PMID- 24786249 TI - Residue control of coccidiostats in food of animal origin in Poland during 2007 2010. AB - Coccidiostats are widely used as feed additives to prevent coccidiosis. The off label use of anticoccidials or feeding non-target animals with cross-contaminated feedingstuffs may result in the occurrence of coccidiostat residues in animal tissues and eggs. In EU countries, food of animal origin is subjected to official control of residues according to Council Directive 96/23/EC. In Poland, within the framework of the National Residue Control Plan, 3718 samples (3533 targeted and 185 suspect) of animal liver, eggs, drinking water and feed were tested for coccidiostats between 2007 and 2010. Violative residues of nicarbazin, lasalocid, maduramicin, salinomycin, semduramicin and robenidine were detected in 77 food samples (53 samples of chicken liver, 23 samples of eggs and 1 sample of turkey liver). A high percentage (31%) of non-compliant feed samples collected during follow-up investigations was observed, which confirms that feed cross contamination may be the reason of the occurrence of coccidiostat residues in food. PMID- 24786250 TI - Total mercury, methylmercury and ethylmercury in marine fish and marine fishery products sold in Seoul, Korea. AB - In 2009, a survey of 177 samples of fish and fishery products from the markets in Seoul was carried out to investigate total mercury and organic mercury (methylmercury) concentrations and to establish a correlation, if any, between total and organic mercury levels. Concentrations of total and organic mercury in canned tuna ranged 0.001-2.581 and 0.003-1.307 mg/kg, respectively; those for fish, such as cod or salmon, ranged 0.012-2.529 and 0.021-0.507 mg/kg, respectively. Ethylmercury was not detected. More than 50% of total mercury in the samples existed as organic mercury. The correlation coefficients (r(2)) between total mercury and methylmercury concentrations of fish and fishery products found to have methylmercury were 0.844 and 0.976, respectively, which was statistically significant. There was a higher correlation in fishery products than in fish. Although there was no product in which mercury exceeded the standard set by the Food Code in 2008, with the exception of marlin steak, a processed food, which contained 1.307 mg/kg methylmercury. None exceeded the provisional tolerable weekly intake (PTWI) for mercury. Collectively, the results indicate that fish or fishery products marketed in Seoul, with the exception of marlin, have low levels of total or organic mercury and, thus, intake of these products is not a risk to public health. PMID- 24786251 TI - Profiles of non-essential trace elements in ewe and goat milk and their yoghurt, Torba yoghurt and whey. AB - The objectives of this study were to determine the profiles of non-essential trace elements in ewes' and goats' milk and manufactured products, such as yoghurt, torba yoghurt and whey, as well as changes in trace element content during Torba yoghurt-making processes. Concentrations of non-essential trace elements in ewe (Awassi) and goat (Damascus) milk and their yoghurt, torba yoghurt and whey were quantitatively determined by simultaneous inductively coupled plasma optical emission spectrometer (ICP-OES), after microwave digestion. Aluminium, antimony, arsenic, boron, beryllium, cadmium, nickel, lead, silver, titanium, thallium and vanadium were determined for both types of milk and their products. Barium was not detected in goats' milk or their products. Among all trace elements, boron was the most abundant and beryllium was least present in milk and the manufactured products. The results showed that goats' and ewes' milk and their manufactured products may be a source of 13 non-essential trace elements. PMID- 24786252 TI - Aflatoxin M1 contamination in cow and buffalo milk samples from the North West Frontier Province (NWFP) and Punjab provinces of Pakistan. AB - A total of 178 milk samples (94 of buffalo and 84 of cow) were randomly taken from Punjab and the North West Frontier Province (NWFP) of Pakistan (n = 89 in each province) and analysed for the presence of aflatoxin M1 (AFM1) by HPLC-FLD. From Punjab about 46% of buffalo's and 49% of cow's milks were contaminated with AFM1 as compared with 52% and 51% for milk samples from NWFP, respectively. Overall, the mean AFM1 concentration was 0.046 ug kg(-1) with a maximum of 0.350 ug kg(-1). All samples complied with the Codex Alimentarius limit of 0.50 ug kg( 1) for AFM1 in milk, but 16.3% of samples exceeded the European Union maximum level of 0.05 ug kg(-1). Another set of 415 buffalo's and cow's milk samples (213 morning milks and 202 evening milks) were analysed. Statistical analysis revealed significant differences (p < 0.05) between mean AFM1 concentrations in milk during the morning (0.043 ug kg(-1)) and the evening (0.028 ug kg(-1)) lactation times. PMID- 24786253 TI - Determination of ochratoxin A in wine from the southern region of Brazil by thin layer chromatography with a charge-coupled detector. AB - The presence of ochratoxin A (OTA) is evaluated using thin layer chromatography (TLC) with a charge-coupled detector (CCD) in 88 red wine samples (2009 vintage) from Brazil. Samples included 75 wines from Rio Grande do Sul, nine from Santa Catarina and four from Parana state; 56 wines were Cabernet Sauvignon and 32 were Merlot varieties. The method included the analysis of fluorescent images, acquired under UV light, using ImageJ software. Mean recovery of OTA was 82.3% using immunoaffinity columns (IAC). The limits of quantification (LOQ) and detection (LOD) were 0.8 and 0.2 ug l(-1), respectively. Results showed a 5.7% contamination of OTA, with five positive samples--three Cabernet Sauvignon and two Merlot. Santa Catarina and Parana showed one positive sample each, although the concentrations were below the limit of quantification. The highest concentration found was 0.84 ug l(-1) in one sample from Rio Grande do Sul. PMID- 24786254 TI - A survey of selected essential and heavy metals in milk from different regions of Egypt using ICP-AES. AB - The aim of this paper was to assess the content of selected essential metals (Fe, Zn, Cu and Cr) and some heavy metals (Pb and Cd) in raw cow's milk collected from different Egyptian areas during different periods of one year (January-February, May-June and September-October 2009). Twenty-one samples of raw milk were analysed using inductively coupled plasma-atomic emission spectrometry for quantitative determination. The highest metal accumulation levels for Cd, Cr, Fe and Cu are found in milk samples collected from Shubra, while samples from Menofia and Tanash are high in Pb and Zn, respectively. On the other hand, the highest metal accumulation levels were during January-February for Cd, Cr and Zn. In the period of May-June, the content of Pb, Cu and Fe were the highest, while the samples during the September-October period are characterised by the lowest metal content. PMID- 24786256 TI - The gull (Chroicocephalus brunnicephalus) as an environmental bioindicator and reservoir for antibiotic resistance on the coastlines of the Bay of Bengal. AB - The presence and frequency of multiresistant bacteria in wild birds act as indicators of the environmental contamination of antibiotic resistance. To explore the rate of contamination mediated by Escherichia coli, 150 fecal samples from the brown-headed gull (Chroicocephalus brunnicephalus) and 8 water samples from the Bay of Bengal area were collected, cultured, and tested for antibiotic susceptibility. Special attention was paid to extended-spectrum beta-lactamase (ESBL)-producing isolates, which were further characterized genetically. Antibiotic resistance was found in 42.3% (36/85) of the E. coli isolates and multidrug resistance in 11.8%. Isolates from the area with a higher human activity were more resistant than those from an area with a lower level of activity. Most frequent was resistance to ampicillin (29.4%), followed by trimethoprim-sulfamethoxazole (24.7%) and quinolones (22.4%). Carriage of ESBL producing E. coli was relatively high (17.3%) in the gulls, whereas no ESBL producers were found in the water. All ESBL-producing E. coli isolates, but one, carried bla(CTX-M-15) or bla(CTX-M-15)-like genes. A bla(CTX-M-14)-like enzyme was found as an exception. Gulls from two different colonies shared E. coli clones and harbored the clinically relevant sequence types ST10, ST48, and ST131. The high frequency of antibiotic resistance and ESBL production among E. coli isolates from gulls indicates that the environmental contamination of antibiotic resistance has already gone far on the coastlines of the Bay of Bengal. Considering the limited control over the antibiotic consumption and waste from human activities in Bangladesh, there is no easy solution in sight. PMID- 24786257 TI - Middle East Respiratory Syndrome coronavirus - two years into the epidemic. PMID- 24786258 TI - A case of imported Middle East Respiratory Syndrome coronavirus infection and public health response, Greece, April 2014. AB - On 18 April 2014, a case of Middle East Respiratory Syndrome coronavirus (MERS CoV) infection was laboratory confirmed in Athens, Greece in a patient returning from Jeddah, Saudi Arabia. Main symptoms upon initial presentation were protracted fever and diarrhoea, during hospitalisation he developed bilateral pneumonia and his condition worsened. During 14 days prior to onset of illness, he had extensive contact with the healthcare environment in Jeddah. Contact tracing revealed 73 contacts, no secondary cases had occurred by 22 April. PMID- 24786259 TI - Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels, Oman, 2013. AB - A countrywide survey in Oman revealed Middle Eastrespiratory syndrome coronavirus (MERS-CoV) nucleicacid in five of 76 dromedary camels. Camel-derivedMERS-CoV sequences (3,754 nucleotides assembled from partial sequences of the open reading frame (ORF)1a, spike, and ORF4b genes) from Oman and Qatar were slightly different from each other, but closely related to human MERS-CoV sequences from the same geographical areas, suggesting local zoonotic transmission. High viral loads in nasal and conjunctival swabs suggest possible transmission by the respiratory route. PMID- 24786260 TI - West Nile virus surveillance in mosquitoes, April to October 2013, Vojvodina province, Serbia: implications for the 2014 season. AB - After the West Nile virus (WNV) outbreak in 2012, we collected mosquito samples from Vojvodina province, Serbia, in 2013. We found high WNV infection rate in two species, Culex pipiens and Anopheles maculipennis. Phylogenetic analysis showed that Serbian WNV strains from 2013 were most closely related to Italian and Greek strains isolated in 2012 and 2010, respectively. Public health authorities should be aware of a potentially increased risk of WNV activity during the 2014 season. PMID- 24786261 TI - Smoking and older age associated with mumps in an outbreak in a group of highly vaccinated individuals attending a youth club party, the Netherlands, 2012. AB - We describe a mumps outbreak in a highly-vaccinated population attending a party at a youth club. In a retrospective cohort study with 60 of approximately 100 participants responding, vaccination status was verified for 58/59 respondents, of whom 54 were vaccinated twice and four once. The attack rate was 22% (13 cases, all vaccinated), with smoking at the party (risk ratio (RR) 3.1; 95% confidence interval (CI): 1.6-6.0, p=0.001) and age >=21 years (RR 4.7; 95% CI: 2.1-10.2, p<0.0001) as risk factors for disease in the binominal regression analysis. Mild upper respiratory illness was also highly prevalent in those who did not meet the mumps case definition (n=46) after the party, suggesting that mumps virus infection may cause mild disease in vaccinated individuals. Our investigation adds toevidence that crowded social events and smoking may facilitate spread of mumps virus among vaccinated populations, with waning immunity playing a role. The suggestion that mumps virus infection in vaccinated individuals may manifest as mild upper respiratory illness could have implications for transmission and warrants further investigation. PMID- 24786262 TI - Seasonal influenza immunisation in Europe. Overview of recommendations and vaccination coverage for three seasons: pre-pandemic (2008/09), pandemic (2009/10) and post-pandemic (2010/11). AB - Since 2008, annual surveys of influenza vaccination policies, practices and coverage have been undertaken in 29 European Union (EU)/ European Economic Area (EEA) countries. After 2009, this monitored the impact of European Council recommendation to increase vaccination coverage to 75% among risk groups. This paper summarises the results of three seasonal influenza seasons: 2008/09, 2009/10 and 2010/11. In 2008/09, 27/29 countries completed the survey; in 2009/10 and 2010/11, 28/29 completed it. All or almost all countries recommended vaccination of older people (defined as those aged >=50, >=55, >=59, >=60 or >=65 years), and people aged >=6 months with clinical risk and healthcare workers. A total of 23 countries provided vaccination coverage data for older people, but only 7 and 10 had data for the clinical risk groups and healthcare workers, respectively. The number of countries recommending vaccination for some or all pregnant women increased from 10 in 2008/09 to 22 in 2010/11. Only three countries could report coverage among pregnant women. Seasonal influenza vaccination coverage during and after the pandemic season in older people and clinical groups remained unchanged in countries with higher coverage. However, small decreases were seen in most countries during this period. The results of the surveys indicate that most EU/EEA countries recommend influenza vaccination for the main target groups; however, only a few countries have achieved the target of 75% coverage among risk groups. Coverage among healthcare workers remained low. PMID- 24786265 TI - Introduction. PMID- 24786266 TI - To(o) Queer or Not? AB - SUMMARY While much has been written on the implications of queer theory for lesbian sexuality, little attention has been paid to its impact on lesbian community and subsequent formulations of lesbian identity. The essay argues that theories of identity emerge in part from their interactions with lesbian sexual practice situated within the context of lesbian community. Because lesbian community serves as an important base for socio-political activism, queer theory's destabilization of identity and sexuality has a direct impact on our ability to effect social change. The essay concludes with suggestions for more positive relationships between queer and lesbian communities than have been explored in the past. PMID- 24786267 TI - What Do You Call a Lesbian Who's Only Slept with Men? Answer. AB - SUMMARY Lesbian, gay, lesbian-identified bisexual-what do we call women who have sex with other women? What about the character "Ellen," played by actor/comedian Ellen DeGeneres, who identifies as gay but has not (yet?) slept with a woman? Can she legitimately call herself gay? More significantly, what exactly is a "legitimate" lesbian? Further, what does the Ellen show tell the millions who viewed the "coming out episodes" about lesbianism? Ellen provides an interesting, and highly public, test-case for these questions. This essay will examine three texts: (1) the three "coming-out" episodes, (2) the coverage in the popular press, and (3) the coverage in the queer press. We critique the ways in which the straight and gay communities interpret lesbian identity via their representation of the character "Ellen." PMID- 24786268 TI - To love women, or to not love men. AB - SUMMARY A discussion of the ways three women of the San Francisco Bay Area navigate their attractions and identifications, and the reasoning behind and consequences of their choices. Donna is attracted to women and men and identifies as lesbian; Dahlia identifies as a bisexual lesbian; Aviva used to identify as lesbian and now calls herself as a lesbian-identified bisexual woman. Their ideologies are compared, and the interaction of their race, ethnicity, and sexual identification is also discussed. PMID- 24786269 TI - 'Without contraries is no progression'. AB - SUMMARY Some lesbians subject other queer women to a type of purity test, stereotyping bisexuals, transsexuals, and leatherwomen as threats to the lesbian and feminist movements. Such attitudes frequently reveal rigid, binary, either-or thinking and an intolerance of difference. This essay, by contrast, argues in favor of an embrace of diversity within the queer women's community and examines the way bisexuals, transsexuals, and leatherwomen exhibit a resistance to binary thinking and a "tolerance for ambiguity." PMID- 24786270 TI - Gender role reversal and the violated lesbian body. AB - SUMMARY The lesbian sadomasochist exists in the feminist community as doubly other. If she is addressed at all in feminist discourses, she is often accused of wielding the weapons of patriarchy (violence, danger, fear) against all that feminism is. In what follows I will construct a theoretical framework which suggests that lesbian sadomasochism is not antithetical to feminism. In fact, lesbian sadomasochism is, on numerous levels, a response to those things deemed damaging to women. PMID- 24786271 TI - The materiality of gender. AB - SUMMARY Lesbian and transgender histories often recuperate the same historical figures; however, many lesbian spaces (like the Michigan Womyn's Music Festival) have excluded lesbian-identified male-to-female transsexuals. Through an analysis of historical inclusion and socio-political exclusion, this essay examines the relationship between "birth bodies," gender and sexuality. It argues that the lesbian body appears in history through the naturalization of "birth-bodies" and the recuperation of cross-gender behavior. In this way, the body becomes a template for lesbian historical recuperation and an organizing principle for contemporary lesbian communities. PMID- 24786273 TI - Eroticizing safe sex. AB - SUMMARY This paper considers several lesbian-produced safe sex tapes which engage pornographic vernacular with a dual purpose, offering both a very pointed counter to the dearth of erotic imagery depicting lesbian sex/sexuality specifically by and for women, but also functioning as pedagogical (self-help) tools for rethinking safe sex. PMID- 24786272 TI - Toward a dyke discourse. AB - SUMMARY This essay argues the need for a dyke discourse that is a parallel project to queer theory but considers female subjectivity first and foremost and pays specific attention to desire and sexual practice as a mode of identity formation. The primary subject is the stonebutch -a queer masculine female, not a woman/not a man -and her partnered identity, the straight-appearing femme. Together, they fall out of the "woman-loving-woman" definition of lesbian, and problematize feminism's evacuation of female gender difference and assimiliationist strategies. PMID- 24786274 TI - Women on the Edge of a Dyke-otomy. AB - SUMMARY This paper considers some of the contradictions of authenticity as a defining feature of lesbian community in Aotearoa/ New Zealand. We sketch the genealogy of marginalization within the lesbian community through the development of subjectivity, community and political struggle for equality. To this end, we deconstruct three major, interrelated "problems" in speaking of lesbian politics: subjectivity, community and universality. At its broadest, the lesbian subject refers to any woman who desires women. But in practice such a "continuum" does not satisfactorily identify a bounded community. In articulating its voice, any community necessarily creates a governing discourse, thereby creating outsiders and insiders to that community. This paper explores the conditions under which the lesbian community has marginalized an "other" lesbian subject with particular reference to sexual practices and associations with heterosexuality in order to establish an authenticity of identity. PMID- 24786275 TI - Sticks and stones. AB - SUMMARY "Sticks and Stones" is an exploration of life-in-the-ghetto; twenty five years of sex and politics, and wrestling with sexual correctness. It is concerned with the changing paradigms of lesbian 'vice and virtue': the butch-femme bar girl; the feminist woman-identified-woman; the sex radical warrior; the chic babe who's Queer and Here. How's a lesbian supposed to find an identity in all that? And remain true to her erotic preferences and sexual practices, frequently in the face of severe opposition? Joan Nestle, Gayle Rubin, Emma Healey and Sue O'Sullivan act as critical guides through this retrospective view of my collisions with erotic orthodoxy; they add discursive weight to the recollected experiences of negotiating historical shifts and re-alignments in ideology and practice of (Western) lesbian sexuality. Is the only way to spot a 'real' lesbian to watch what she does in bed? PMID- 24786276 TI - Lesbian sexual renegades? AB - SUMMARY Whereas gay men have idealized the gay man as a sexual renegade, lesbians often are eager to distance themselves from practitioners of "deviant" lesbian sexuality. This paper explores how "acceptable" lesbian desire has been articulated in terms of a vision of "normal" sex that reflects feminine norms, making much of lesbian sex literally and figuratively unspeakable-yet also creating a potentially radical fringe of lesbian sexual outlaws. PMID- 24786277 TI - Sex radical communities and the future of sexual ethics. AB - SUMMARY Many urban-based gay male, lesbian, and mixed-gender sexually radical communities (such as leather and/or S/M groups) portray their interests in sexuality in terms of arousal and pleasure. The writings of many gays, lesbians, bisexuals, and queers involved in such communities suggest that sexual pleasure is based on individual preference, and that all sexual activities need only the consent of participating individuals to render those activities moral and good. Thus, as long as people consent, a wide variety of practices can be authorized in this system, such as non-monogamy, group sex, anonymous sex, domination, etc. In this paper, I will suggest that something much more radical is happening in these communities, that "individual preference" and "consent"-although present -are perhaps not the most interesting way to describe what is happening here. Rather, I will explore the possibility that these sex groups are in the process of providing for us a new kind of ethic based not on individuality, but rather based on community. PMID- 24786278 TI - New tools in the box: an evolutionary synopsis of chromatin insulators. AB - Despite progress in understanding genome organization and gene expression during the last decade, the evolutionary pathways that led to the intricate patterns of gene expression in different cells of an organism are still poorly understood. Important steps in this regulation take place at the level of chromatin, where the (epi)genomic environment of a gene determines its expression in time and space. Although the basic mechanisms of gene expression apply to all eukaryotes, multicellular organisms face the additional challenge of coordinating gene expression during development. In this review we summarize and put into evolutionary context current knowledge about chromatin insulators, an important class of regulatory factors mediating these tasks. Our interpretation of historical and recent findings points to a dynamic and ongoing evolution of insulator proteins characterized by multiple instances of convergent evolution, gene loss, and binding site changes in different organisms. The idea of two autonomously evolving insulator functions (as a barrier element and an enhancer blocker) further suggests that the evolution of metazoans and their enhancer-rich gene regulatory repertoire might be connected to the radiation of enhancer blocking insulators. Although speculative at the moment, such coevolution might create tools for complex gene regulation and therefore influence the evolutionary roadmaps of metazoans. PMID- 24786279 TI - Commentary on Twycross A, Finley GA (2013) Children's and parents' perceptions of postoperative pain management: a mixed methods study. Journal of Clinical Nursing 22, 3095-3108. PMID- 24786280 TI - Kala-azar in pregnancy in Mymensingh, Bangladesh: a social autopsy. PMID- 24786283 TI - Influence of dopant distribution on the plasmonic properties of indium tin oxide nanocrystals. AB - Doped metal oxide nanocrystals represent an exciting frontier for colloidal synthesis of plasmonic materials, displaying unique optoelectronic properties and showing promise for a variety of applications. However, fundamental questions about the nature of doping in these materials remain. In this article, the strong influence of radial dopant distribution on the optoelectronic properties of colloidal indium tin oxide nanocrystals is reported. Comparing elemental depth profiling by X-ray photoelectron spectroscopy (XPS) with detailed modeling and simulation of the optical extinction of these nanocrystals using the Drude model for free electrons, a correlation between surface segregation of tin ions and the average activation of dopants is observed. A strong influence of surface segregation of tin on the line shape of the localized surface plasmon resonance (LSPR) is also reported. Samples with tin segregated near the surface show a symmetric line shape that suggests weak or no damping of the plasmon by ionized impurities. It is suggested that segregation of tin near the surface facilitates compensation of the dopant ions by electronic defects and oxygen interstitials, thus reducing activation. A core-shell model is proposed to explain the observed differences in line shape. These results demonstrate the nuanced role of dopant distribution in determining the optoelectronic properties of semiconductor nanocrystals and suggest that more detailed study of the distribution and structure of defects in plasmonic colloidal nanocrystals is warranted. PMID- 24786281 TI - Heterogeneity in the frequency and characteristics of homologous recombination in pneumococcal evolution. AB - The bacterium Streptococcus pneumoniae (pneumococcus) is one of the most important human bacterial pathogens, and a leading cause of morbidity and mortality worldwide. The pneumococcus is also known for undergoing extensive homologous recombination via transformation with exogenous DNA. It has been shown that recombination has a major impact on the evolution of the pathogen, including acquisition of antibiotic resistance and serotype-switching. Nevertheless, the mechanism and the rates of recombination in an epidemiological context remain poorly understood. Here, we proposed several mathematical models to describe the rate and size of recombination in the evolutionary history of two very distinct pneumococcal lineages, PMEN1 and CC180. We found that, in both lineages, the process of homologous recombination was best described by a heterogeneous model of recombination with single, short, frequent replacements, which we call micro recombinations, and rarer, multi-fragment, saltational replacements, which we call macro-recombinations. Macro-recombination was associated with major phenotypic changes, including serotype-switching events, and thus was a major driver of the diversification of the pathogen. We critically evaluate biological and epidemiological processes that could give rise to the micro-recombination and macro-recombination processes. PMID- 24786284 TI - A new lignan glycoside from Trigonostemon heterophyllus. AB - Phytochemical investigation on the stems of Trigonostemonheterophyllus led to the isolation of a new lariciresinol-based lignan glycoside, trigonoheteran (1), together with a known lignan glycoside, aviculin (2). Their structures were elucidated by spectroscopic methods including 1D and 2D NMR (HMQC, (1)H-(1)H COSY, HMBC, and NOESY). PMID- 24786285 TI - Successful laparoscopic management of a giant ovarian cyst. PMID- 24786287 TI - No association between CCL2 gene polymorphisms and risk of inflammatory demyelinating diseases in a Korean population. AB - Inflammatory demyelinating disease (IDD), which includes multiple sclerosis (MS) and neuromyelitis optica (NMO), affects the central nervous system. Chemokine ligand 2 (CCL2/MCP-1) is considered an important contributor to the development or progression of IDD. However, genetic association studies of Asian populations are lacking. In this study, we investigated a possible association between CCL2 polymorphisms (rs1024611, rs28730833, and rs2857657) and a Korean population (178 IDD patients and 237 healthy controls) using multiple logistic regression models. However, we did not find any association, which was consistent with other studies in Caucasian populations. In conclusion, our results suggest that CCL2 variants may not contribute to the pathogenesis of IDD. PMID- 24786286 TI - Ion channels under the sun. PMID- 24786288 TI - The minor structural difference between the antioxidants quercetin and 4'O methylquercetin has a major impact on their selective thiol toxicity. AB - Antioxidants act as intermediates by picking up the high unselective reactivity of radicals and transferring it to other molecules. In this process the reactivity is reduced and becomes selective. This channeling of the reactivity can cause selective toxicity. The antioxidant quercetin is known to channel the reactivity towards thiol groups. The present study compares the thiol reactivity of quercetin with that of 4'O-methylquercetin (tamarixetin) towards creatine kinase (CK), a vital protein that contains a critical thiol moiety. Our results showed that oxidized quercetin and oxidized tamarixetin both adduct CK, which then loses its enzymatic function. Ascorbate, an important representative of the antioxidant network, is able to prevent adduction to and thus the inhibition of the enzyme by tamarixetin but not by quercetin. Apparently, tamarixetin is less thiol toxic than quercetin, because--rather than adduction to CK--tamarixetin quinone prefers to pass reactivity to the antioxidant network, i.e., to ascorbate. The findings exemplify that radical scavenging flavonoids pick up the reactivity of radicals and act as a pivot in directing the way the reactivity is channeled. A mere minor structural difference of only one methyl moiety between quercetin and tamarixetin appears to have a high impact on the selective, thiol toxicity. PMID- 24786289 TI - The relationship between dioxin congeners in the breast milk of Vietnamese women and sister chromatid exchange. AB - The aim of this study was to clarify the relationship between dioxin concentrations in breast milk and the sister chromatid exchange (SCE) frequency in women from herbicide-sprayed and non sprayed areas. Blood samples were taken from 21 women with high TCDD (tetrachlorodibenzo-p-dioxin) levels from sprayed areas, 23 women with moderate TCDD levels from sprayed areas, and 19 women from non sprayed areas to determine their SCE frequency. The SCE frequencies for the high and moderate TCDD groups from the sprayed area and for the non sprayed area group were 2.40, 2.19, and 1.48 per cell, respectively. Multiple regression analysis showed that the standardized beta values for 1,2,3,6,7,8-hexaCDD (beta = 0.60), 1,2,3,4,6,7,8-heptaCDD (beta = 0.64), and octaCDD (beta = 0.65) were higher than those for TCDD (beta = 0.34) and 1,2,3,7,8-pentaCDD (beta = 0.42). The adjusted R2 value for polyCDDs (R2 = 0.38) was higher than that for polyCDD toxic equivalents (TEQ (toxic equivalents); R2 = 0.23). This study therefore shows that levels of hexa-, hepta-, and octaCDD, which were previously regarded as being less toxic than TCDD, are closely related to SCE frequency and that the level of dioxin (pg/g lipid) is potentially more useful as an indicator than TEQ value for explaining SCE frequency. PMID- 24786290 TI - Current status in the therapy of liver diseases. AB - Hepatic diseases, like viral hepatitis, autoimmune hepatitis, hereditary hemochromatosis, non-alcoholic fatty liver disease (NAFLD) and Wilson's disease, play an important role in the development of liver cirrhosis and, hence, hepatocellular carcinoma. In this review, the current treatment options and the molecular mechanisms of action of the drugs are summarized. Unfortunately, the treatment options for most of these hepatic diseases are limited. Since hepatitis B (HBV) and C (HCV) infections are the most common causes of liver cirrhosis and hepatocellular carcinoma, they are the focus of the development of new drugs. The current treatment of choice for HBV/HCV infection is an interferon-based combination therapy with oral antiviral drugs, like nucleos(t)ide analogues, which is associated with improving the therapeutic success and also preventing the development of resistances. Currently, two new protease inhibitors for HCV treatment are expected (deleobuvir, faldaprevir) and together with the promising drug, daclatasvir (NS5A-inhibitor, currently in clinical trials), adequate therapy is to be expected in due course (circumventing the requirement of interferon with its side-effects), while in contrast, efficient HBV therapeutics are still lacking. In this respect, entry inhibitors, like Myrcludex B, the lead substance of the first entry inhibitor for HBV/HDV (hepatitis D) infection, provide immense potential. The pharmacokinetics and the mechanism of action of Myrcludex B are described in detail. PMID- 24786293 TI - Taking the tension out of hypertension: a prospective study of psychological well being and hypertension. AB - BACKGROUND: Previous studies have shown that psychological well being is associated with reduced risk of cardiovascular disease. However, whether well being might be specifically associated with reduced risk of hypertension has not been rigorously investigated in prospective studies. OBJECTIVE: This study examined the prospective association between two measures of psychological well being and incident hypertension. METHODS: Participants were 6384 healthy British civil servants aged 39-63 from the Whitehall II cohort. Psychological well being (emotional vitality and optimism) and cardiovascular risk factors (demographic characteristics, health status, health behaviors, psychological ill being) were assessed during the 1991-1994 baseline. Incident hypertension was defined by clinical measures of SBP or DBP at least 140/90 mmHg, self-reported physician diagnosed hypertension, or treatment for hypertension. Follow-up assessments of hypertension took place approximately every 3 years through 2002-2004. Cox proportional hazards regression models estimated hazard ratios. RESULTS: There were 2304 cases of incident hypertension during the follow-up period. High versus low emotional vitality was associated with a significantly reduced risk of hypertension in an age-adjusted model (hazard ratio = 0.89; 95% confidence interval 0.80-0.98). This association was maintained after controlling for demographic characteristics and health status, but was slightly attenuated after adjusting for health behaviors and ill being. Optimism was not significantly associated with hypertension. CONCLUSION: High emotional vitality was associated with reduced hypertension risk; favorable health behaviors explained only part of the relationship. Associations did not differ by age, were similar for men and women, and were maintained after accounting for ill being. PMID- 24786294 TI - Old spontaneously hypertensive rats gather together typical features of human chronic left-ventricular dysfunction with preserved ejection fraction. AB - OBJECTIVE: Heart failure with preserved left-ventricular ejection fraction (HF PEF) is an entity leading to pulmonary congestion because of impaired diastolic filling. This syndrome usually strikes those who have experienced a long history of hypertension or metabolic risk factors. Pathophysiological mechanisms are not fully understood, and standard therapy is not established. Relevant preclinical models are still lacking. The aim of this work was to evaluate aging spontaneously hypertensive rats (SHRs) as a model of HF-PEF. METHODS: Serial echocardiographic and blood pressure (BP) measurements were performed in 28, 36, 43, 47 and 51-week-old SHRs and their normotensive controls (Wistar-Kyoto rats). In 52-53-week-old animals, final investigations included ECG, invasive left ventricular (LV) and aortic catheterization, brain natriuretic peptide (BNP) plasma concentrations, ventricular reverse transcription-qPCR evaluations (beta myosin heavy chain, atrial natriuretic peptide, BNP, sarco/endoplasmic reticulum calcium ATPase 2a and collagens 1a, 3a and 2a) and cardiac histology. RESULTS: SHRs develop a progressive alteration of the early diastole, some of the echocardiographic parameters being not sensitive to BP reduction by the calcium blocker, nicardipine. The systolic function evaluated by echocardiography and invasive catheterization was preserved. When the observation period was over, an increase in collagen synthesis and deposits were identified in subendocardial layers. This attested a probable myocardial ischemia that was confirmed by ECG changes of the ST segment. BNP increased in the blood and at the mRNA level in the myocardium. CONCLUSION: When aging, SHRs progressively develop HF-PEF showed by impaired LV relaxation and hypertrophy, BNP increase but preserved contractility and fibrosis. This model seems pertinent for further pharmacological preclinical studies in the field. PMID- 24786291 TI - The oligomycin-sensitivity conferring protein of mitochondrial ATP synthase: emerging new roles in mitochondrial pathophysiology. AB - The oligomycin-sensitivity conferring protein (OSCP) of the mitochondrial F(O)F1 ATP synthase has long been recognized to be essential for the coupling of proton transport to ATP synthesis. Located on top of the catalytic F1 sector, it makes stable contacts with both F1 and the peripheral stalk, ensuring the structural and functional coupling between F(O) and F1, which is disrupted by the antibiotic, oligomycin. Recent data have established that OSCP is the binding target of cyclophilin (CyP) D, a well-characterized inducer of the mitochondrial permeability transition pore (PTP), whose opening can precipitate cell death. CyPD binding affects ATP synthase activity, and most importantly, it decreases the threshold matrix Ca2+ required for PTP opening, in striking analogy with benzodiazepine 423, an apoptosis-inducing agent that also binds OSCP. These findings are consistent with the demonstration that dimers of ATP synthase generate Ca2+-dependent currents with features indistinguishable from those of the PTP and suggest that ATP synthase is directly involved in PTP formation, although the underlying mechanism remains to be established. In this scenario, OSCP appears to play a fundamental role, sensing the signal(s) that switches the enzyme of life in a channel able to precipitate cell death. PMID- 24786296 TI - ERalpha directly activated the MDR1 transcription to increase paclitaxel resistance of ERalpha-positive breast cancer cells in vitro and in vivo. AB - Chemotherapy is commonly used to treat early-stage invasive and advanced-stage breast cancer either before or after surgery. Increasing evidence from clinical analysis and in vitro studies has shown that ER-positive breast cancer cells are insensitive to chemotherapy. Complete understanding of how ERalpha mediates drug resistance is prerequisite to improvement of the chemotherapeutic efficacy. Over expression of P-glycoprotein (P-gp) encoded by MDR1 gene is one of the major causes of drug resistance. The association between ERalpha and MDR1 in breast cancer is still unclear and the limited reports are conflict. This study systematically explored intrinsic link between ERalpha and the P-gp over expression in paclitaxel-resistant ERalpha(+) breast cancer cell lines and mouse model in molecular details. Our data showed that ERalpha activated the MDR1 transcription in MCF-7/PTX breast cancer cells by binding to ERE1/2 and interacting with Sp1 that bridged to the downstream CG-rich element within the MDR1 promoter. Knockdown of MDR1 restrained the effect of ERalpha in MCF-7 cells and sensitized the cells to paclitaxel. Treatment of ICI 182,780 that selectively suppressed ERalpha significantly decreased the MDR1 expression and increased the sensitivity of drug resistant breast cancer cells and xenograft tumors to paclitaxel. Our data strongly demonstrated that ERalpha was able to increase drug resistance of breast cancer cells through activating MDR1 transcription. This novel mechanism provides new insight to how the ERalpha signaling regulates response of ERalpha(+) breast tumors to chemotherapy, which may be exploited for developing novel therapeutic strategies for breast cancer in the future. PMID- 24786297 TI - The epigenetic landscape of T-cell acute lymphoblastic leukemia. AB - The genetic landscape of T-ALL has been very actively explored during the past decades. This leads to an overwhelming body of exciting novel findings providing insight into (1) the genetic heterogeneity of the disease with marked genetic subsets, (2) the mechanisms by which aberrant T-cell development drive leukemogenesis and (3) emerging opportunities for novel therapeutic interventions. Of further interest, recent genome wide sequencing studies identified proteins that actively participate in the regulation of the T-cell epigenome as novel oncogenes and tumor suppressor genes in T-ALL. The identification of these perturbed molecular epigenetic events in the pathogenesis of T-ALL will contribute to the further exploration of novel therapies in this cancer type. As some epigenetic therapies have recently been approved for a number of hematological neoplasms, one could speculate that targeted therapies against epigenetic regulators might offer good prospects for T-ALL treatment in the near future. In this review, we summarize the epigenetic discoveries made in T-ALL hitherto and discuss possible new venues for epigenetic therapeutic intervention in this aggressive subtype of human leukemia. This article is part of a Directed Issue entitled: Rare Cancers. PMID- 24786295 TI - Naturally occurring deletions of hunchback binding sites in the even-skipped stripe 3+7 enhancer. AB - Changes in regulatory DNA contribute to phenotypic differences within and between taxa. Comparative studies show that many transcription factor binding sites (TFBS) are conserved between species whereas functional studies reveal that some mutations segregating within species alter TFBS function. Consistently, in this analysis of 13 regulatory elements in Drosophila melanogaster populations, single base and insertion/deletion polymorphism are rare in characterized regulatory elements. Experimentally defined TFBS are nearly devoid of segregating mutations and, as has been shown before, are quite conserved. For instance 8 of 11 Hunchback binding sites in the stripe 3+7 enhancer of even-skipped are conserved between D. melanogaster and Drosophila virilis. Oddly, we found a 72 bp deletion that removes one of these binding sites (Hb8), segregating within D. melanogaster. Furthermore, a 45 bp deletion polymorphism in the spacer between the stripe 3+7 and stripe 2 enhancers, removes another predicted Hunchback site. These two deletions are separated by ~250 bp, sit on distinct haplotypes, and segregate at appreciable frequency. The Hb8Delta is at 5 to 35% frequency in the new world, but also shows cosmopolitan distribution. There is depletion of sequence variation on the Hb8Delta-carrying haplotype. Quantitative genetic tests indicate that Hb8Delta affects developmental time, but not viability of offspring. The Eve expression pattern differs between inbred lines, but the stripe 3 and 7 boundaries seem unaffected by Hb8Delta. The data reveal segregating variation in regulatory elements, which may reflect evolutionary turnover of characterized TFBS due to drift or co-evolution. PMID- 24786298 TI - Epigenetic mechanisms of hyperglycemic memory. AB - Recently the concept emerged that prolonged exposure to altered metabolic conditions, including hyperglycemia, may epigenetically imprint human cells permitting vertical or horizontal transfer to "descendants". Although mechanistically ill understood, the hyperglycemic/epigenetic memory may represent one of the major limitations for the application of cell therapy to treatment of chronic heart disease where a relatively prolonged period of ex vivo cellular expansion is required. Hyperglycemic memory, in fact, seems to contribute to the establishment of an epigenetic "reminiscence" of the altered metabolic state, to which, cells from diseased bodies have been exposed. This review summarizes the most relevant concepts and observations about the mechanisms underlying the onset of stable information inside the epigenome leading to the development of a diseased phenotype. Special attention is given to epigenetic drugs and how they have been used in experimental, preclinical and clinical settings to treat dysmetabolism, diabetes and their complications. PMID- 24786299 TI - Ultrafast oleophobic-hydrophilic switching surfaces for antifogging, self cleaning, and oil-water separation. AB - Smooth copolymer-fluorosurfactant complex film surfaces are found to exhibit fast oleophobic-hydrophilic switching behavior. Equilibration of the high oil contact angle (hexadecane = 80 degrees ) and low water contact angle (<10 degrees ) values occurs within 10 s of droplet impact. These optically transparent surfaces display excellent antifogging and self-cleaning properties. The magnitude of oleophobic-hydrophilic switching can be further enhanced by the incorporation of surface roughness to an extent that it reaches a sufficiently high level (water contact angle <10 degrees and hexadecane contact angle >110 degrees ), which, when combined with the inherent ultrafast switching speed, yields oil-water mixture separation efficiencies exceeding 98%. PMID- 24786300 TI - Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs. AB - AIM: Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis. METHODS AND RESULTS: We annotated the mouse transcriptome after myocardial infarction via RNA sequencing and ab initio transcript reconstruction, and integrated genome-wide approaches to associate specific lncRNAs with developmental processes and physiological parameters. Expression of specific lncRNAs strongly correlated with defined parameters of cardiac dimensions and function. Using chromatin maps to infer lncRNA function, we identified many with potential roles in cardiogenesis and pathological remodelling. The vast majority was associated with active cardiac-specific enhancers. Importantly, oligonucleotide-mediated knockdown implicated novel lncRNAs in controlling expression of key regulatory proteins involved in cardiogenesis. Finally, we identified hundreds of human orthologues and demonstrate that particular candidates were differentially modulated in human heart disease. CONCLUSION: These findings reveal hundreds of novel heart-specific lncRNAs with unique regulatory and functional characteristics relevant to maladaptive remodelling, cardiac function and possibly cardiac regeneration. This new class of molecules represents potential therapeutic targets for cardiac disease. Furthermore, their exquisite correlation with cardiac physiology renders them attractive candidate biomarkers to be used in the clinic. PMID- 24786301 TI - Early discharge using single cardiac troponin and copeptin testing in patients with suspected acute coronary syndrome (ACS): a randomized, controlled clinical process study. AB - AIMS: This randomized controlled trial (RCT) evaluated whether a process with single combined testing of copeptin and troponin at admission in patients with low-to-intermediate risk and suspected acute coronary syndrome (ACS) does not lead to a higher proportion of major adverse cardiac events (MACE) than the current standard process (non-inferiority design). METHODS AND RESULTS: A total of 902 patients were randomly assigned to either standard care or the copeptin group where patients with negative troponin and copeptin values at admission were eligible for discharge after final clinical assessment. The proportion of MACE (death, survived sudden cardiac death, acute myocardial infarction (AMI), re hospitalization for ACS, acute unplanned percutaneous coronary intervention, coronary artery bypass grafting, or documented life threatening arrhythmias) was assessed after 30 days. Intention to treat analysis showed a MACE proportion of 5.17% [95% confidence intervals (CI) 3.30-7.65%; 23/445] in the standard group and 5.19% (95% CI 3.32-7.69%; 23/443) in the copeptin group. In the per protocol analysis, the MACE proportion was 5.34% (95% CI 3.38-7.97%) in the standard group, and 3.01% (95% CI 1.51-5.33%) in the copeptin group. These results were also corroborated by sensitivity analyses. In the copeptin group, discharged copeptin negative patients had an event rate of 0.6% (2/362). CONCLUSION: After clinical work-up and single combined testing of troponin and copeptin to rule-out AMI, early discharge of low- to intermediate risk patients with suspected ACS seems to be safe and has the potential to shorten length of stay in the ED. However, our results need to be confirmed in larger clinical trials or registries, before a clinical directive can be propagated. PMID- 24786302 TI - Dual C-H functionalization of N-aryl amines: synthesis of polycyclic amines via an oxidative Povarov approach. AB - Iminium ions generated in situ via copper(I) bromide catalyzed oxidation of N aryl amines readily undergo [4 + 2] cycloadditions with a range of dienophiles. This method involves the functionalization of both a C(sp(3))-H and a C(sp(2))-H bond and enables the rapid construction of polycyclic amines under relatively mild conditions.